MXPA99002576A

MXPA99002576A - Process for producing ecteinascidin compounds

Info

Publication number: MXPA99002576A
Application number: MXPA/A/1999/002576A
Authority: MX
Inventors: J Corey Elias; Gin David
Original assignee: President And Fellows Of Harvard College
Priority date: 1996-09-18
Filing date: 1999-03-17
Publication date: 2000-04-24

Abstract

The present invention is directed to a synthetic process for the formation of ecteinascidin compounds and related structures, such as the saframycins. In one particularly preferred embodiment, the present invention provides a synthetic route for the formation of ecteinascidin 743 (1), an exceedingly potent and rare marine-derived antitumor agent which is slated for clinical trials. The process of this invention is enantio- and stereocontrolled, convergent and short. Also disclosed are novel process intermediates, useful not only in the total synthesis of ecteinascidin 743, but also other known ecteinascidin compounds, including derivatives and analogs thereof.

Description

PROCESS TO PRODUCE ECTEINASCIDNA COMPOUNDS DECLARATION OF GOVERNMENT SUPPORT This invention was supported in part by the support of the National Institutes of Health and the National Science Foundation. Accordingly, the Government of the United States may have certain rights in this invention.

COMPENDIUM OF THE INVENTION The present invention is directed to a synthetic process for the formation of ecteinascidin compounds and related structures, such as saframycins. In a particularly preferred embodiment, the present invention provides a synthetic route for the formation of ecteinascidin 743 (1) 1, an extremely potent antitumor agent and derived from rare marine products, which is placed on a smooth surface for clinical analysis when adequate amounts are made available. 2,3 This process is controlled enantiomérica and stereoisoméricamente, is convergent and is short. The preferred embodiment of the synthetic process of the present invention is best presented in the following Scheme I: SCHEME I 13, FMluoranOo 14 As shown above in Scheme I, the preferred process for the synthetic formation of ecteinascidin 743 comprises the sequential steps of: (a) forming a α, β-unsaturated malonic ester of Formula 2, as a mixture of E and Z isomers from 2-benzyloxy-3-methyl-4,5-methylenedioxybenzaldehyde and allyl 2,2-dimethoxyethyl malonate; (b) stereospecifically converting the compound of Formula 2 to the compound of Formula 3, through selective ester cleavage, rearrangement of Curtius, and reaction of the intermediate isocyanate with benzyl alcohol; (c) converting the compound of Formula 3 to the compound of Formula 4 through catalytic hydrogenation over: Rh [(COD) tf, R-DIPAMP] + BF4 '; (d) converting the compound of Formula 4 to the compound of Formula 5 through cleavage of acetal, wherein the isolation and exposure of the resulting aldehyde to BF3 »Et2O and sieves of 4 A moles produces the bridged lactone compound of Formula 5; (e) converting the lactone bridge compound of Formula 5 to the free amino phenol compound of Formula 6 through hydrogenolysis over 10% Pd-C; (f) forming the protected a-amino ester compound of Formula 7 by reacting 3,5-bis-tert-butyl-dimethyl-s-loxethane-4-methox-benzaldehyde and malonate methyl acid, (g) converting the protected a-amino ester compound from the Formula 7 to chiral aldehyde 8 through reduction, (h) combining the compounds of Formulas 6 and 8 to provide the key mono-bridge pentacyclic intermediate of Formula 10, as follows to react the compounds of Formulas 6 and 8 to give a coupled phenolic a-amino nitrole, followed by O-allylation to give the allylic ether compound of Formula 9, selectively converting the lactone function in the compound of Formula 9 to a lactol by reacting the compound of Formula 9 with dnsobutylaluminum hydride, desilylating the lactol compound, and lifting the desilylated compound to provide the pentacycle compound of Formula 10 through an internal Mannich bisanulation, (i) converting the pentacycle compound from the Formula 10 to the compound of Formula 11 through selective pfluoromethanesulfonation of less hindered phenolic hydroxyl, followed by (1) s 111 selective selection of the primary hydroxyl, (2) protection of the remaining phenolic group such as methoxymethyl ether (3) double dealkylation (4) N-reductive methylation, and (5) replacement of CF3SO3 by CH3, (j) oxidize the phenol compound of Formula 11 by performing angular hydroxylation of selective position for after desilylation, the dihydroxy dienone compound of Formula 12, (k) forms the compound of Formula 13 by means of the primary hydroxyl function of the compound of Formula 12 with (S) -N-al? lox? carbon? - (9-fluoren? Lmet? L) cysteine, (I) transforming the compound of Formula 13 to the bridged lactone compound of Formula 14 by, (1) the reaction of the compound of Formula 13 with a generated Swern reagent in situ, (2) followed by the formation of the quinone methide exend, (3) the destruction of excess reagent Swern, (4) the addition of N-tert-butyl-N ', N "-tetramethylguanidine in excess to generate the 10-member lactone bridge, and (5) the addition of an excess of Ac2O to acylate the group resulting phenoxide, (m) unfold the N-haloxycarbonyl group of the compound of the Formula 14 and oxidize the resulting a-amino lactone to the corresponding lactone aketo by transformation thereby forming the compound of Formula 15, (n) to stereospecifically form a spiro tetrahydro-isoquinoline compound by reacting the compound of Formula 15 with 2- [3-hydroxy-4-methoxy-phenyl] ethylamine; (o) followed by cleavage of methoxymethyl (yielding Et 770) followed by replacement of CN with HO to form the compound of Formula 1, ecteinascidin 743. In addition to the preferred process of Scheme I, the present invention also provides novel intermediate compounds useful for the synthesis of known ecteinascidin compounds, as well as analogs and derivatives of said compounds. These novel intermediates include the following compounds: X - COjCHjCHßCH, [E * Z) 2 27 X-NHCO: CHlC, Hf 37 38 39 40 ei Z? s * TI SdOBi.0 tt £ fr Zfr Ifr sjaaio COpUlyt 14 47 48 DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The preferred process of the present invention is illustrated in Scheme I. As shown therein, and as discussed in more detail in the Examples that follow, this process was conducted as follows. The α, β-unsaturated malonic ester 2 was prepared as a mixture of E and Z isomers from 2-benzyloxy-3-met? l-4,5-met? leod? ox? -benzaldehyde43 and 2,2-d? methox? -ethyl malonate of allyl4 ( 2 equivalents of pipepdine and 4 equivalents of acetic acid in C6H6 or C7H8 at 23 ° C for 18 hours, 99%), was subjected to selective splitting of allyhc ester (Et3N-HCOOH, cat Pd (PPh3) 4, at 23 ° C , 4 hours, yield 94%), rearrangement of Curtius (1 2 equivalents of (PhO) 2P (O) N3, 4 equivalents of Et3N, in C7H8 containing sieves of 4 A moles at 70 ° C for 2 hours) and the reaction of the intermediate isocyanate with benzyl alcohol at 23 ° C for 1 hour to form 3 stereospecifically (yield 93%) 5 The hydrogenation of 3 to 3 atmospheres with Rh ^ COD ^. ? -DIPAMP] * BF4 as a catalyst at 23 ° C for 16 hours provided 4 in a yield of 97% and 96% ee6 The splitting of acetal of 4 (10 equivalents of BF3 »Et2O and 10 equivalents of H2O in CH2CI2 at 0 ° C for 10 minutes), isolation and exposure of the resulting aldehyde to BF3"Et2O (17 equivalents) and sieves of 4 A moles in CH2Cl2 at 23 ° C for 18 hours gave the lactone bridge 5 in a yield of 73% 7 Hydrogenolysis of 5 (1 atm of H2, 10% Pd-C, EtOAc, 23 ° C, 6 hours) produced the free 6-amino phenol in 100% yield The protected a-amino ester 7 was synthesized by an analogous route, starting with 3 5-b? s-ter-but? ld? met? l? l? lox? -4-methox? benzaldehyde and malonate methyl acid, and then reduced (2 equivalents of dnsobutylaluminum hydride in CH2CI2 to - 78 ° C for 1 hour) to give the chiral aldehyde 8 (yield> 90%) The next stage of the synthesis, which involves the combination of the building blocks 6 and 8 and the s ubsequent elaboration to construct the mono-bridge pentacyclic intermediate 10 starts with the reaction of 6 and 8 in HOAc containing 25 equivalents of KNC at 23 ° C for 18 hours to give a coupled phenolic amino-N-atom (61%) and the Subsequent Oation to give allyl ether 9 in a yield of 87% (2 equivalents of Cs 2 CO 3 and 5 equivalents of bromide of aillo in DMF at 23 ° C for 1 hour) Beginning with intermediate 10, it is believed that all compounds of known ecteinascidin can be synthetically prepared, as well as analogues and derivatives thereof The treatment of 9 with 1 2 equivalents of dnsobutylaluminium hydride in toluene at -78 ° C for 5 hours effected selective conversion of the lactone function to a lactol, which was desilylated through exposure to an excess of KF * 2h2O in CH3OH at 23 ° C for 20 minutes and cyclized to pentacycle 10 through internal Mannich bisanulation with 20 equivalents of CH3SO3H in CH2Cl2 in the presence of 3 A moles at 23 ° C for 5 hours (55% total from 9) The selective sulfonation with tpfluoromethane of the least hindered phenolic hydroxyl (5 equivalents of Tf2NPh, Et3N, 4,4-dimethylaminopipdine (DMAP) in CH2Cl2 at 23 ° C for 6 hours, yield 72%) was followed by (1) the selective sililation of the primary hydroxyl (excess of tert-butyldiphenyl-DMPA chloride in CH2Cl2 at 23 ° C for 13 hours, 89%), (2) the protection of the remaining phenolic group such as methoxymethyl ether (MeOCH2Br and / -Pr2Net in CH2CI2 at 23 ° C for 20 minutes, 92%), (3) double dealkylation (Bu3SnH cat CI2Pd (PPh3) 2, excess HOAc in CH2CI2 at 23 ° C for 15 minutes 100%), (4) reductive N-methylation (formaldehyde excess, NaBH3CN, HOAc in CH3CN at 23 ° C for 30 minutes, 95%), and (5) replacement of CF3SO3 with CH3 (excess of Me4Sn, CI2Pd (Ph3P) 2, LiCI, DMF, 80 ° C, 2 hours) to give 11 in a yield of 83% 5 Oxidation of phenol 11 with 1 1 equivalents of (PhSeO) 2 in CH2CI2 at 23 ° C for 15 minutes carried out angular hydroxylation of selective position to give after deflation (2 equivalents of Bu4NF in THF at 23 ° C for 10 minutes), dihydroxy dienone 12 (75% from 11 ) l? The last three rings of ecteinascidin 743, the 10-member lactone bridge and the spiro subunit tetrahydro-isoquinoline, were then added in the final stage of the synthesis of 1 through the following sequence of reactions. The primary hydroxyl function of 12 was esterified with (S) -N-15 al-l-oxocarbon? LS- (9-fluoren? Lmet? L) cysteine, using 5 equivalents of 1- (3-d? Meth? L-am? Noprop) ?) -3-et? l-carbod? m? da * HCI and 5 equivalents of DMAP in CH2CI2 at 23 ° C for 30 minutes to form 13 (91%), which was then transformed into a flask at room temperature. bridge lactone in a total yield of 79% through these operations (1) the reaction of 13 with the Swern reagent generated in situ of an excess of tpflico anhydride and DMSO at -40 ° C for 30 minutes, 83 (2) the addition of / -Pr2Net and heating at 0 ° C for 30 minutes to form quinone methoda8b exend, (3) extinction with tert-butyl alcohol (to destroy excess Swern reagent), (4) 2 ^ addition of an excess of N-ter-but? L-N ', N' -tetramethylguanidine9 to convert the 9-fluorenylmethyl thiol ether to the thiolate ion and to promote the nucleophilic addition of sulfur to the quinone metide to generate the bridge of 10-member lactone, and (5) the addition of an excess of Ac2O to acylate the resulting phenoxide group. The N-allyloxycarbonyl group of 14 was cleaved (excess of Bu3SnH, HOAc and cat. CI2Pd (PPh3) 2 in CH2CI2 at 23 ° C for 5 minutes, 84%) and the resulting a-amino lactone was oxidized to the α-keto corresponding lactone through transamination with the pyridine-4-carboxaldehyde metiodide, DBU, and DMF in CH2CI2 at 23 ° C for 40 minutes to give 15 (70%). Reaction of 15 with 2- [3-hydroxy-4-methoxy-phenyl] ethylamine (16) in EtOH in the presence of silica gel at 23 ° C generated the spiro tetrahydroisoquiniline stereospecifically (82%), which was then subjected to splitting with methoxymethyl (4: 1: 1 CF3CO2H-H2O-THF at 23 ° C for 9 hours) and replacement of CN with HO (AgNO3 in CH3CN-H2O at 23 ° C for 11 hours) to form in a high yield ecteinascidin 743 (1), identical in all respects with an authentic sample.10 The synthetic process of the present invention provides access not only to 1 but also to a host of other members of the ecteinascidin family and the like, as well as to structures simpler related ones such as saframycins.11 The preparation and characterization of the novel intermediates described above are described in more detail in the Examples. The present invention will be further illustrated with reference to the following examples, which will aid in the understanding of the present invention, but which are not constructed as limiting thereof.

EXAMPLES General Procedures All reactions were carried out in Schlenk flasks (Kjeldahl shape) with a round bottom or flame-dried modified flasks, equipped with rubber septa under positive argon pressure, unless otherwise indicated. Liquids and air-sensitive solutions were transferred and moisture through a syringe or stainless steel cannula When necessary (as observed), the solutions were deoxygenated through alternate cycles of evacuation / washing with argon (more than three iterations) The organic solutions were concentrated by rotary evaporation below 30 ° C to about 25 Torr Flash column chromatography was performed, as described by Still and others, using 230-400 mesh silica gel 12 thin layer chromatography (analytical and preparation) using glass plates pre-coated to a depth of 0 25 mm with silica gel 230-400 meshes impregnated with a fluorescent indicator (254 nm) Materials. Commercial reagents and solvents were used as received, with the following exceptions. Tetrahydrofuran and ethyl ether were distilled from benzophenone cetyl Dichloromethane, hexanes, N, Nd? Soprop? L-et? Lam? Na, dnsopropylamine, t-tetylamine were distilled , pipdin, toluene, benzene, TMEDA, pipepdma and acetonitplo from calcium hydride at 760 Torr The molability of n-butyl lithium solutions was determined by titration using diphenylacetic acid as an indicator (average of three determinations) 13 Instrumentation. Infrared (IR) spectra were obtained using a Nicolet 5ZDX FT-IR spectrophotometer considered as a standard of styrene. The data were presented as follows absorption frequency (cm 1), and absorption intensity (s = strong, m = mean, w = weak) Carbon-13 and proton nuclear magnetic resonance spectra (1H NMR or 13C NMR) were recorded with an NMR Bruker AM500 spectrometer (500 MHz), Bruker AM400 (400 MHz), or Bruker AM300 (300 MHz) , the chemical shifts were expressed in parts per million (scale d) of downfield from tetramethylsilane and were considered as residual protium in the NMR solvent (CHCl3 d 7 26, C6HD5 d 7 20, CDHCI2 d 5 38, CD3COCD2H d 2 04 CD2HOD d 3 30) The data were presented as follows chemical shift, multiplicity (s = single band d = doublet t = quartet m = multiple bands and / or multiple resonances) integration constant coupling in Hertz (Hz) and assignment He drove the c chiral high-performance liquid chromatography (HPLC) with an Isco 2350, equipped with the specific column (see below). The melting points were recorded with a Fisher-Johns melting point apparatus and were not corrected. The following Schemes 2-7 illustrate the following Examples: SCHEME 2 - LEFT FRAGMENT I U3? (1.0"qutv), eitO. , CM, -40 'C, 1 h; CO | (M), os- Y «< ^ '-40' C- »23 * C.1; 71% o or 24 »O ^ OCH, SCHEME 3 - LEFT FRAGMENT II H, (4S p «i), Rh [(COD) S.? - OiPAMPr BF4- (c« t), CH, OM. CH, a ,, 23 * C 1ß; 97%; 9Í% •• BF, < ? et, (1ß4quiv), 4 A. CH, to "23" C.19 h; 73% SCHEME 4 - RIGHT FRAGMENT 29 31 POC (2.S aquiv). 4 A so much ** motocukVM, alavaa, Ot-Ct ,; 23 * C, 2; 99% H, (4S p «?). Rh ((COO)? _ * OIPA PrBF4 - («t) CH, OH.23« C, 24 p; 100%; 9%% • * Olbal-H (2 «quiv), CH, CI ,. -T «* C, 1 h SCHEME 5 - PENTACICLO I (2 aqutv). Bromide of adío (S aqulv). OMF, 23 • (., 1 fi; 17% KF-2H, 0 (xs), CH, OH. 23 * C.20 mln Tf, NPh (2.S «quiv), Et, .N (S« quiv), OMAP. CH, C! T, 23 «C .. (h.72% 41 SCHEME 6 - PENTACICLO II SnM «. (20 «qutv). (Ph, P), PdCtt LICt (20 aquiv). OMF, 10 * C. 1; 93% 12 SCHEME 7 - FINAL STEPS 1 (ET743) LEFT FRAGMENT EXAMPLE 1 Methoxymethyl Ether 18 17 18 To a solution of 17 (10 2 g, 74 3 mmol, 1 equiv) in a mixture of ethyl ether and DMF (4 1 (v / v), 100 ml) at 0 ° C was added a solution of sodium hydride in mineral oil (57% (w / w), 4 97 g, 96 6 mmol, 1 3 equiv) The resulting suspension was stirred at 0 ° C for 35 minutes, and then, bromomethylmethyl ether (7%) was added dropwise. 89 mL, 96 6 mmol, 1 3 equiv) The suspension was stirred at 0 ° C for 5 minutes and then at 23 ° C for 1 hour before neutralizing the excess sodium hydride with the slow addition of methyl alcohol (5 mL). ) at 0 ° C The solution was partitioned between ethyl acetate (500 ml) and water (300 ml), and the organic phase was then washed with a saturated aqueous solution of sodium chloride (200 ml), dried (sodium sulfate), sodium) and concentrated The residue was purified by flash column chromatography (7% ethyl acetate in hexanes) to provide 18 (13 1 g 90%) as a colorless oil Rf 0 32 (10% strength). ethyl acetate in hexanes) 1 H NMR (500 MHz CDCl 3) d 670 (d, 1H, J = 84 Hz ArH), 6 62 (d, 1H, J = 2 4 Hz, ArH), 649 (dd, 1H, J = 84, 24 Hz, ArH), 5 91 (s, 2H, ArOCH2OAr), 5 10 (s, 2H, MOM CH2), 3 50 (s, 3H, OCH3), 3C NMR (100 MHz, CDCI3) d 152 5, 148 1, 142 5, 108 5, 1080, 101 1, 99 7, 95 5, 60 3, 55 8, 14 1, IR (net film) 2990 (m), 2847 (m), 2827 (m) , 1632 (m), 1611 (m), 1502 (s), 1486 (s), 1451 (m), 1245 (s), 1213 (s), 1152 (s), 1069 (s), 1004 (s) , 922 (s) cm HRMS (EP) m / z Cale for C9H10O4 (M +) 1820578, 182 0582 was found EXAMPLE 2 Methoxymethyl Ether 19 OCH, 18 19 To a solution of 18 (6 76 g, 37 1 mmol, 1 equiv) and tetramethylethylenediamine (16 mL, 111 mmol, 30 equiv) in hexanes (70 mL) at 0 ° C was added dropwise a lithium solution. n-butyl co (1 55 M in hexanes 72 ml, 74 2 mmol, 2.0 equiv) and the resulting yellow suspension was stirred at 0 ° C for 2.5 hours. A solution of iodomethane (11.5 ml, 186 mmol, 50 equiv) in diethyl ether (12 ml) was added dropwise at 0 ° C, and the resulting slurry was stirred at 23 ° C for 1 hour before it was quenched with the slow addition of water (10 ml). The reaction was diluted with diethyl ether (500 mL), the product solution was washed sequentially with water (50 mL) and a saturated aqueous solution of sodium chloride (50 mL), and then dried (sodium sulfate) and concentrated The residue was purified by flash column chromatography (gradient elution 2%? 3% ethyl acetate in hexanes) to provide 19 (6 32 g, 87% ) as a pale yellow oil Rf 0 31 (10% ethyl acetate in hexanes), 1 H NMR (500 MHz, CDCl 3) d 657 (d, 1H, J = 8 5 Hz, ArH), 6 51 (d, 1H , J = 8 5 Hz, ArH), 5 91 (s, 2H, ArOCH2OAr), 5 11 (s, 2H, MOM CH2), 349 (s, 3H, OCH3), 2 14 (s, 3H, ArCH3), 13 C NMR (126 MHz, CDCl 3) d 151 0.1466, 141 9, 110 7, 106 7, 104 8, 100 9, 95 7, 560, 8 9, IR (net film) 2928 (w), 1479 (s) ), 1468 (s), 1242 (s), 1155 (m), 1103 (s) 1068 (s), 1020 (m), 988 (m), 793 (w) cm \ HRMS (The +) m / z Cale for C? 0H12O4 (M +) 196 0735, it was found 196 0729 EXAMPLE 3 Aldehyde 20 19 20 To a solution of 19 (7 50 g 38 3 mmol, 1 equiv) in a mixture of 1 1 (v / v) of ether di et 11 ico and hexanes (70 ml) at 0 ° C was added dropwise a n-butyl lithium solution (1 50 M in hexanes, 77.0 ml, 115 mmol, 3.0 equiv.). The reaction mixture was allowed to warm to 23 ° C and was stirred at this temperature for 5 hours. The yellow suspension was cooled to -10 ° C, and then N, N-dimethylformamide (14.7 ml, 191 mmol, 5.0 equiv.) Was added. The resulting solution was stirred at -10 ° C for 1 hour. The excess base was neutralized through the slow addition of glacial acetic acid (10 ml) at -10 ° C, and the resulting suspension was stirred at 23 ° C for 5 minutes. The reaction mixture was diluted with ethyl acetate (500 ml), and the product solution was washed sequentially with a saturated aqueous solution of sodium bicarbonate (400 ml), water (400 ml) and a saturated sodium chloride solution. (300 mi) The organic phase was dried (sodium sulfate) and concentrated, and the product was crystallized from 10% ethyl acetate in hexanes (4.05 g). The mother liquor was purified by flash column chromatography (15% ethyl acetate in hexanes) to provide additional 20 (1.35 g) (64% total) as a pale yellow solid (mp 91.5 ° C). Rf 0.22 (ethyl acetate in hexanes); 1 H NMR (400 MHz, CDCl 3) d 10.15 (s 1 H, CHO), 7.13 (s, 1 H, Ar H), 6.03 (s, 2 H, ArOCH 2 O), 5.03 (s, 2 H, MOM CH 2), 3.59 (s, 314 , OCH3), 2.19 (s, 3H, ArCH3); 13C NMR (100 MHz, CDCI3) d 189.0, 157.0, 152.4, 144.2, 123.8, 113.7, 103.3, 102.1, 101.3, 58.0, 9.4: IR (net film) 2925 (w), 1670 (s), 1614 (w) , 1473 (m), 1452 (m). 1399 (m), 1280 (m), 1155 (m), 1059 (m), 935 (s), 927 (s), 860 (m) cm "1; HRMS (The +) m / z: Cale, for d, H1205, (M +) 224.0684, 224.0684 was found.

EXAMPLE 4 Aldehyde 22 To a solution of 20 (3.70 g, 16.5 mmol, 1 equiv) in dichloromethane (50 ml) and water (10 ml) at 0 ° C methanesulfonic acid (1.50 ml, 22.5 mmol, 1.4 equiv.) Was added. The reaction mixture was then neutralized with a saturated aqueous solution of sodium bicarbonate (50 ml) at 0 ° C, and the resulting mixture was partitioned between a saturated aqueous solution of sodium bicarbonate (400 ml) and dichloromethane (3 x 200 ml). mi) The combined organic layers were dried (sodium sulfate) and concentrated to provide 21 as a crude intermediate. To the solution of 21 in N, N-dimethylformamide (16.0 ml) at 0 ° C was added a suspension of sodium hydride in mineral oil (57% (w / w), 903 mg, 21.5 mmol, 1.3 equiv.), And the resulting suspension was stirred at 0 ° C for 40 minutes. Benzyl bromide (2 94 ml, 248 mmol, 1.5 equiv) was added to the reaction mixture at 0 °. C and the resulting suspension was stirred at 23 ° C for 30 minutes. The excess base was neutralized through the slow addition of methanol (2.0 mL) at 0 ° C, and the reaction mixture was diluted with ethyl acetate ( 250 ml) The product solution was washed sequentially with water (200 ml) and a saturated aqueous solution of sodium chloride (200 ml), then dried (sodium sulfate) and concentrated. The residue was purified by column chromatography. flash (10% ethyl acetate in hexanes) to provide 22 (3 85 g, 86%) as a viscous syrup Rf 0 18 (10% ethyl acetate in hexanes), 1 H NMR (400 MHz, CDCl 3) d 1008 (s, 1H, CHO), 7 40 (m, 5H, Bn ArH), 712 (s, 1H, ArH), 604 (s, 2H, ArOCH2OAr), 4 93 (s, 2H, Bn CH2), 1 60 (s, 3H, ArCH3), 13C NMR (100 MHz, CDCI3) d 188 5, 1583, 152 6, 144 1, 135 7, 128 7, 128 3, 123 6, 113 8, 103 2, 102 1, 78 5, 11 8, 9 1, IR (net film) 2923 (w), 1674 (s), 1612 (w), 1470 (m), 1420 (m), 1375 (m), 1352 (m), 1278 (s), 1170 (m), 1096 (s), 1069 (m) cm 1, HRMS (El +) m / z Cale for C 16 H 14 O 4 (M +) 270 0892, 270 0892 was found EXAMPLE 5 Monoalloy Malonate 24 - ^, 0 CH, U3A (1.0 * qUiV, .et, O. T ^ '^ ^' • ^ TT -M «to I re COI or»). ot, - "¡f Jj o •» - o o 23 -M 'C -. 23 * C.1 IB 7S% 2 A solution of n-butyl lithium (1 56 M in hexanes, 19.2 mL, 300 mmol, 1.0 equiv) was added to a solution of dnsopropylamine (5 47 mL, 39.0 mmol, 1 3 equiv) in ethyl ether (30 mL). 0 ml) at -78 ° C. The reaction flask was briefly transferred to an ice bath (10 minutes), and then cooled again to -78 ° C. 23-allyl acetate (233 ml, 30.0 mmol) was added. , 1.0 equiv) to the cold solution of lithium diisopropylamide, and the resulting solution was stirred at 40 ° C for 1 hour. The reaction mixture was cooled to -78 ° C and the excess solid carbon dioxide was added to the reaction mixture before it was allowed to warm to 23 ° C over a period of 1 hour. The cloudy solution was diluted with water (100 ml) and washed with ethyl ether (3 x 50 ml). The aqueous layer was acidified at 0 ° C to a pH of 2 with the slow addition of concentrated hydrochloric acid and then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried (sodium sulfate) and concentrated to provide crude acid 24 (3.35 g, 76%) as a pale yellow oil, which was used without further purification. 1 H NMR (400 MHz, CDCl 3) d 5.92 (m, 1 H, CH 2 = CH-), 5.36 (m, 1 H, CH 2 = CH-), 5.27 (m, 1 H, CH 2 = CH-), 4.68 (dt, 2H , J = 5.7, ~ 1 Hz, CH2 = CHCH2-), 3.48 (s, 2H, CH2); IR (net film) 3300-2400 (m), 1744 (s), 1322 (m), 1156 (m) crrf1.

EXAMPLE 6 Allyl-2,2-dimethoxyethyl Malonate 26 -i? \ .0- ^ - ^? N 0CN, BOPC1 < 1.S.qU, v). OCH, o or * ^ - ^^ OCH, > . c?, ^ v p n ^^ 0 = ". 24 2 CH-Ct ?, 23« C, h; O or 73% a To a solution of acid 24 (7.50 g, 52 0 mmol, 1 equiv.) 2 2-d? Methoxy? Ethanol (25) (5 50 g, 52 0 mmol, 10 equiv.) And tpetylamine (36 g. mmoles, 5.0 equiv) in dichloromethane (100 ml) was added BOPCI (20.0 mg, 78.7 mmol, 1.5 equiv.), and the resulting slurry was stirred at 23 ° C for 1 hour. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate (400 ml), and the product solution was washed sequentially with water (2 x 300 ml) and a saturated aqueous solution of sodium chloride (300 ml). The organic layer was dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (gradient elution: 20-33% ethyl acetate in hexanes) to provide 26 (8.81 g. , 73%) as a colorless liquid. Rf 0.26 (25% ethyl acetate in hexanes); 1 H NMR (300 MHz, CDCl 3) d 5.91 (m, 1 H, CH 2 = CH-), 5.34 (m, 1 H, CH 2 = CH-), 5.26 (m, 1 H, CH 2 = CH), 4.64 (dt, 2H, J = 5.6, ~ 1 Hz, CH2 = CHCH2), 4.58 (t, 1H, J = 5.3 Hz, CH (OCH3) 2), 4.17 (d, 2H, J = 5.3 Hz, CH2CH (OCH3) 2), 3.46 (s, 2H, CH2), 3.39 (s, 6H, OCH3); 13 C NMR (100 MHz, CDCl 3) d 166.0, 165.9, 131.5, 118.7, 101.0, 66.0, 63.8, 53.9, 41.2; FTIR (net film) 2955 (m), 1757 (s), 1738 (s), 1447 (m), 1412 (m), 1367 (s), 1340 (s), 1323 (s), 1276 (s), 1193 (s), 1134 (s), 1102 (s), 1078 (s), 1046 (s) cm-1; HRMS (Cl +) m / z: Cale, for C10H20NO6 (M + NH4) + 250.1291, 250.1296 was found.

EXAMPLE 7 Diester a.ß-unsaturated 2 To a mixture of aldehyde 20 (384 g, 14 2 mmol, 1 equiv), 26 (300 g, 12 9 mmol, 1 equiv), pipepdine (2 80 ml, 284 mmol, 2 0 equiv) and molecular sieves of 4 A triturated activated (~6 g) in benzene (40 ml) was added dropwise glacial acetic acid (3 25 ml, 56 8 mmol, 40 equiv), and the resulting suspension was stirred at 23 ° C for 18 hours. The reaction was filtered and the filtrate was concentrated. The residue was purified through flash column chromatography (gradient elution 20:33% ethyl acetate in hexanes) to provide 2 (620 g, 99%) as an inseparable mixture. of E / Z isomers (1 3 1) Rf 062 (10% ethyl ether in dichloromethane), 1 H NMR (500 MHz, CDCl 3) d major isomer 807 (s, 1H, ArCH), 7 38 (m, 5H, Ph -H), 6 83 (s, 1H, ArH), 5 98 (s, 2H, ArOCH2OAr), 5 75 (m, 1H, CH2 = CH), 5 34 (m, 1H, CH2 = CH), 5 24 (m, 1H, CH2 = CH), 4 77 (s, 2H, Bn CH2), 4 72 (m, 2H, CH2 = CHCH2) 4 64 (t, 1H, J = 5 6 Hz, CH (OCH3) 2), 432 (d, 2H, J = 5 6 Hz, CH2CH (OCH3) 2), 341 (s, 614, OCH3), 2 16 (s, 3H, ArCH,), isomer lower 8 06 (s, 1H, ArCH), 7 38 (m, 5H, Ph-H), 6 76 (s, 1H, ArH), 5 98 (s 2H, ArOCH2OAr), 5 73 (m, 1H, CH2 = CH), 5 38 (m, 1H, CH2 = CH), 5 28 (m, 1H, CH2 = CH), 4 77 (s, 2H, Bn CH2), 4 78 (m, 2H, CH2 = CHCH2) 4 59 (t, 1 H J = 56 Hz, CH (OCH 3) 2), 4 23 (d, 2 H, J = 5 6 Hz, CH 2 CH (OCH 3) 2) 340 (s, 6 H, OCH 3), 2 16 (s , 3 H, ArCH 3), 13 C NMR (100 MHz CDCl 3) d 166 3, 166 2, 163 9, 163 8, 153 5, 149 5, 143 6 139 1 139 0 136 3 131 8, 131 4, 128 6, 1284 , 1236, 1194, 119 1 118 2 114 1 104 7, 1046, 101 7, 101 2, 101 0, 77 5, 77 4, 66 2 65 8, 63 9 63 8, 53 9 538, 14 1, 9 3 IR (net film) 2928 (w), 1732 (s), 1609 (m), 1476 (m), 1423 (m), 1243 (s), 1217 (s), 1186 (s), 1096 (s), 1079 (s) cm \ HRMS (FAB +) m / z Cale for C26H28O9Na (MNa +) 507 1631, 507 1640 was found EXAMPLE 8 α-β-saturated acid 27 To a solution of 2 (6 20 g, 12 8 mmol, 1 equiv) in tetrahydrofuran (30 ml) was added sequentially a solution of tetthylammonium formate (1 M in tetrahydrofuran, 384 ml, 38 4 mmol, 30 equiv) and solid palladium tetra (tr? phenolphosphine) (120 mg), and the resulting solution was stirred at 23 ° C for 4 hours. All volatiles were removed in vacuo, and the residue was purified through of flash column chromatography (10% methyl alcohol in dichloromethane) to yield yellow oil 27 (5 33 g, 94%) as a mixture of E / Z isomers (4 1) Rf 0 21 (methyl alcohol 10 % in dichloromethane), 1 H NMR (500 MHz, CDCl 3) d isomer greater 8 19 (s 1 H, ArCH), 740 (m, 5 H, Ph-H), 6 82 (s 1 H Ar H), 6 00 (s 2 H, ArOCH2OAr) 4 78 (s, 2H, Bn CH2) 4 61 (t, 1H J = 5 8 Hz CH (OCH3) 2), 4 29 (d, 214, J = 5 8 Hz C02CH2) 340 (s 6H, OCH3 ), 2 15 (s, 3H ArCH3), minor isomer 821 (s, 1H, ArCH), 740 (m, 5H, Ph-H), 713 (s, 1H, ArH), 596 (s, 2H, ArOCH2OAr) , 478 (s, 2H, Bn CH2), 459 (t, 1H, J = 58 Hz, CH (OCH3) 2), 424 (d, 2H, J = 58 Hz, CO2CH2), 338 (s, 6H, OCH3 ), 215 (s, 3H, ArCH3), 13C NMR (100 MHz, CDCl3) d 1693, 1689, 1663, 1648, 1538, 1499, 1436, 1435, 141 6, 141 4, 1361, 1359, 1287, 1285, 1284, 1283, 1220, 121 5, 1192, 1191, 1140, 1138, 1052, 1047, 101 7, 101 0, 1009, 776, 775, 639, 637, 539, 538, 533, 503, 92, IR (film net) 3500-2500 (m), 2958 (m), 1735 (s), 1701 (s), 1608 (m), 1476 (s), 1423 (s), 1258 (s), 1218 (m), 1188 (s), 1135 (m), 1096 (s) cm 1, MS (El +) m / z 444 (M +) EXAMPLE 9 Benzyl Carbamate 3 To a solution of 27 (5 32 g, 11 2 mmoles, 1 equiv), tetylamine (6 24 mi 44 8 moles, 4 0 equiv), and crushed activated 4A molecular sieves (-20 g) in toluene (53 ml) azide of d if was added in i or osf or (3 10 ml, 144 mmol, 1 2 equiv), and the resulting suspension was heated at 70 ° C for 2 hours. The reaction mixture was cooled to 23 ° C and then benzyl alcohol (1 73 ml 16 8 mmol 1 5 equiv) was added, the suspension was stirred at 23 ° C for 1 hour, filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (gradient elution: 20-50 ethyl acetate in hexanes) to provide 3 (5.90 g, 93%) as a pale yellow solid (mp 102-103 °). C) .Rf 0.25 (33% ethyl acetate in hexanes); 1 H NMR (400 MHz, CDCl 3) d 7.40 (m, 1H, Ph-H &ArCH), 6.92 (s, 1H, ArH), 6.70 ( s (br), 1H, NH), 5.99 (s, 2H, ArOCH2OAr), 5.10 (s, 2H, Cbz CH2), 4.70 (m (br), 2H, Bn CH2), 4.58 (t (br), 1H , J = unres, CH (OCH3) 2), 4.23 (d (br), 2H, J = unres, CO2CH2CH), 3.39 (s, 6H, OCH3), 2.18 (s, 3H, ArCH3), Z configuration verified by 5.8% NOE of Ar-H on NH irradiation; 13C NMR (100 MHz, CDCI3) d, 165. 0, 151.7, 148.1, 143.4, 136.3, 135.9, 128.6, 128.5, 128.4, 128.3, 128. 1, 126.3, 123.6, 120.1, 113.9, 105.0, 101.5, 101.1, 67.3, 64.0, 53.9, 9.4; IR (net film) 3350 (w, br), 2940 (w), 1718 (s), 1498 (m), 1473 (m), 1423 (m), 1247 (s), 1193 (s), 1130 (m) ), 1094 (s), 1069 (m) cm-1; HRMS (FAB +) m / z: Cale, for C30H31NO9Na (MNa +) 572.1896, 572.1909 was found.

EXAMPLE 10 Amino Acid Protected 4 A solution of 3 (800 mg, 1 46 mmol, 1 equiv.) And Rh [(COD) R, f? -D? PAMP] + BF4_ (20 mg) in a mixture of methyl alcohol and dichloromethane (10: 1 ( v / v), 11.0 ml) was placed in a high pressure Parr reactor and purged with hydrogen gas (5 x 3.515 kg / cm2). The reaction mixture was sealed under hydrogen (3.515 kg / cm2) and stirred at 23 ° C for 16 hours. The solution was concentrated and the residue was purified by flash column chromatography (gradient elution '33-50% ethyl acetate in hexanes) to yield 4 (774 mg, 97%) as a white solid (mp. 93.5-940 ° C). Rf 0.25 (33% ethyl acetate in hexanes), 96% ee (Chiracel OD HPLC, 10% isopropyl alcohol in hexanes); [a] D23 -1.9 * (c = 0.67, CH2Cl2), 1H NMR (500 MHz, CDCl3) d 7.36 (m, 1014, Ph-H), 6.50 (s, 1H, ArH), 5.92 (s, 2H, ArOCH2OAr), 5.75 (d, 1 H, J = 7 8 Hz, NH), 5 03 (s, 2H, Cbz CH2), 4.76 (s, 2H, Bn CH2), 4 53 (m, 1H, CHCO2), 446 (t, 1H, J = 56 Hz, CH (OCH3) 2), 4.09 (m, 2H, CO2CH2CH), 3 35 (s, 6H, OCH3), 3 06 (dd, 1H, J = 4 7, 134 Hz, ArCH2), 2.94 (dd, 1H, J = 7.6, 13 4 Hz, ArCH2), 2 20 (s, 3H, ArCH3); 13C NMR (126 MHz, CDCI3) d 171 3, 155 8, 150 5, 146 2, 143 3, 136 8, 136.5, 128.5, 1284, 128.1, 127.9, 127 8, 121 2, 113 6 107.1, 101 2, 101 1, 754, 66 6, 636, 55 2 , 53.9, 53 8, 32 7, 9 7 IR (net film) 3390 (w), 2949 (w), 1724 (s), 1500 (m), 1476 (s) 1213 (m), 1034 (m), 1091 (s), 1027 (m) cm 1, HRMS (El +) m / z Cale for C3oH33NO9 (M +) 551 2153, 551 2159 was found EXAMPLE 11 Aldehyde 28 To a solution of 4 (175 mg, 0.318 mmol, 1 equiv.) And water (57 ml, 3 18 mmol, 10.0 equiv.) In dichloromethane (100 ml) at 0 ° C was added boron trifluoride etherate (392). mi, 3 18 mmol, 10 0 equiv), and the resulting solution was stirred at this temperature for 10 minutes. The Lewis acid was neutralized with the slow addition of a saturated aqueous solution of sodium bicarbonate (10.0 ml), and the resulting mixture was then partitioned between a saturated aqueous solution of sodium bicarbonate (80 ml) and dichloromethane (40 ml). aqueous phase was further extracted with ethyl acetate (2 x 50 mL), and the combined organic layers were dried (sodium sulfate) and concentrated to provide crude aldehyde 28 of sufficient purity Rf 0 24 (50% ethyl acetate in hexanes), 1 H NMR (500 MHz, CDCl 3) d 944 (s, 1 H, CHO), 7 32 (m, 10 H, Ph-H), 6 50 (s, 1 H, Ar H), 5 95 (s, 2 H , ArOCH2OAr), 5 72 (d, 1H, J = 74 Hz, NH), 5 07 (d, 1H, J = 10 7 Hz, Cbz CH2), 5 02 (d, 1H, J = 10 7 Hz, Cbz CH2), 4 78 (d, 1H, J = 10 2 Bn CH2), 4 74 (d, 1H, J = 10 2 Bn CH2), 4 58 (m, 1H, CHC02), 453 (d 1H, J = 16 8 Hz, CH 2 CHO), 448 (d, 1 H, J = 16 8 Hz, CH 2 CHO), 3 04 (m 2 H ArCH 2), 2 20 (s, 3 H, ArCH 3), IR (net film) 3353 (w, br), 2913 (w), 1724 (s), 1476 (m), 1254 (m), 1215 (m), 1184 (m) ), 1090 (s), 1063 (m), 1027 (m) cm 1 EXAMPLE 12 Lactone 5 Boron trifluoride etherate (640 ml, 520 mmol, 164 equiv) was added to a mixture of crude aldehyde 30 (0 318 mmol, 1 equiv) and ground, activated 4A molecular sieves (2.8 g) in dichloromethane (32 ml). ) at 0 ° C, and the resulting suspension was stirred at 23 ° C for 18 hours The reaction mixture was quenched through the addition of a saturated aqueous solution of sodium bicarbonate (100 ml), and the mixture was partitioned. The aqueous layer was further extracted with ethyl acetate (3 x 50 mi), and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified through flash column chromatography (gradient elution 0-5% ethyl acetate in dichloromethane) to provide 5 ( 113 mg, 73%) as a white solid (mp 53-55 ° C) Rf 0 19 (dichloromethane), [a] D23 -9 8 * (c = 040 CH 2 Cl 2) 1 H NMR (500 MHz, CDCl 3, 55 ° C) d 7 38 (m, 1014, Ph-H) 6 00 (s 1H, ArOCH2OAr), 5 97 (s, 1H, ArOCH2OAr) 549 (m (br), 1H ArCH), 5.19 (m, 3H, Cbz CH, &CHCO2), 4.72 (m, 314, Bn CH2 &CO2CH2), 4.43 (d, 1H, J = 10.4 Hz, CO2CH2), 3.18 (m, 1H, ArCH2), 2.98 (m, 1H, ArCH2), 2.18 (s, 314, ArCH3); 13C NMR (100 MHz, CDCI3) d 167.8, 153.1, 149.9, 145.3, 139.3, 136.8, 135.4, 128.5, 128.4, 128.3, 128.1, 127.6, 118.5, 118.1, 114.0, 113.8, 111.5, 101.6, 74.6, 73.4, 67.9 , 52.8, 52.1, 45.4, 44.5, 28.1, 27.6, 9.3; IR (net film) 2920 (w), 1747 (s), 1710 (s), 1455 (s), 1432 (s), 1321 (m), 1299 (s), 1230 (m), 1163 (m), 1096 (s), 1058 (m), 1042 (m) crn "1; HRMS (El *) m / z: Cale, for C28H25NO7 (M +) 487.1629, 487.1628 was found.

EXAMPLE 13 Aminophenol 6 A mixture of lactone 5 (240 mg, 0.493 mmol, 1 equiv.) And 10% palladium on carbon (20 mg) in ethyl acetate (10.0 ml) was stirred under 1 atm of hydrogen at 23 ° C for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated to provide 6 (131 mg, cant) as a colorless film. Rf 0.20 (ethyl acetate); 1 H NMR (400 MHz, CDCl 3) d 5 94 (d, 1 H, J ~ 1 Hz, OCH 2 O), 5 91 (d, 1 H, J-1 Hz OCH 2 O) 4 76 (dd, 1 H, J = 3 7, 10.6 Hz, CH2O2C), 4.43 (d, 1H, J 10 6 Hz, CH2O2C), 4 38 (d, 1H, J = 3 7 Hz, ArCH), 4 29 (d (br), 1H, J = 6 2 Hz , CHCO2), 3.00 (dd, 1H, J = 1 1, 169 Hz, ArCH2), 2 91 (dd, 1H, J = 62, 169 Hz, ArCH2), FTIR (net film) 3360 (w, br), 2951 (w), 1731 (s), 1461 (s), 1432 (s), 1241 (m), 1117 (m), 1096 (s), 1076 (m), 1048 (s), 1025 (m) cm \ HRMS (The +) m / z Cale for C? 3H13NO5 (M +) 263 0794, 263 0802 was found Right Fragment EXAMPLE 14 Acid 33 Pipepdine (10 ml, 10 2 mmol, 2.0 equiv) was added to a suspension of 32 (2 02 g, 5 10 mmol, 1 equiv), monoethyl malonate (3 01 g, 25 5 mmol, 50 equiv) , acetic acid (2 92 ml, 51 0 mmol, 100 equiv) and activated 3 A molecular sieves, triturated (-12 g) in toluene (25.0 ml), and the resulting suspension was stirred at 23 ° C for 18 hours. hours The reaction mixture was filtered, washing well with ethyl acetate (100 ml) The filtrate was concentrated, and the residue was purified by flash column chromatography (4% methyl alcohol in dichloromethane) to give the acid 33 (2 32 g 92%) as an inseparable mixture of E / Z isomers Rf 042 (10% methyl alcohol in dichloromethane), 1 H NMR (500 MHz, CDCl 3) d (major isomer) 7 71 (s, 1H, ArCH ), 683 (s, 2H, ArH), 3.90 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 1.00 (s, 18H, t-butyl), 018 (s, 12H, S? CH3) ), d (minor isomer) 7.71 (s, 1H, ArCH), 6.65 (s, 2H, ArH), 3 81 (s, 3H, OCH3), 3.77 (s, 3H, OC H3), 1 00 (s, 18H, t-butyl), 018 (s, 12H, SiCH3); 13C NMR (126 MHz, CDCI3) d 169 9, 165.3, 1500, 145.8, 144.5, 127.4, 122.5, 116 8, 60 0, 52.8, 25.6, 18 2, -47, IR (net film) 3600-2600 (m , br), 2955 (s), 1741 (s), 1713 (s), 1569 (s), 1493 (s), 1253 (s), 1219 (m), 1096 (s), 864 (s) crn " , HRMS (FAB *) m / z: Cale, for C24H39O7Si2 (MH) 495.2234, it was found 4952253 EXAMPLE 15 Benzyl Carbamate 34 to a suspension of 33 (3 35 g, 6.75 mmol, 1 equiv), tetylamine (4 71 ml 33 8 mmol, 5 0 equiv) and activated 3 A molecular sieves, crushed (-15 g) in toluene (50 ml) azide of d ifen ilfosf oplo (2 90 ml, 13.5 mmol, 2.0 equiv) was added and the resulting suspension was heated at 70 ° C for 2 hours. Then benzyl alcohol (1.40 ml, 13.5 mmol, 2.0 equiv) was added. .) to the reaction mixture, and the suspension was stirred at 70 ° C for 1 hour. The reaction was filtered, washing well with ethyl acetate (100 mL), and the filtrate was concentrated. The residue was purified by flash column chromatography (10% ethyl acetate in hexane) to provide 34 as a pale yellow oil (3.62 g, 89%). Rf 0.53 (25% ethyl acetate in hexane); 1 H NMR (500 MHz, CDCl 3) d 7.34 (m, 5 H, Cbz Ar H), 7.18 (s, 1 H, ArCH), 6.77 (s, 2 H, Ar H), 6.14 (s (br), 1.14, NH), 5.13 (s, 2H, Cbz CH2), 3.81 (s (br), 3H, OCH3), 3.75 (s, 3H, OCH3), 1.00 (s, 18H, t-butyl), 0.16 (s, 12H, SiCH3), Z configuration verified by 11.6% NOE of ArH's on NH irradiation; 3C NMR (100 MHz, CDCI3) d 165.8, 149.8, 144.4, 135.8, 1.32.5, 130.0, 128.5, 128.4, 128.2, 126.1, 123.4, 1.20.2, 116.4, 67.6, 60.0, 52.5, 25.7, 18.3, - 4.7; IR (net film) 3500 (w, br), 2951 (m), 1723 (s), 1567 (m), 1493 (s), 1424 (m), 1289 (s), 1259 (s), 1122 (s) ), 1006 (w), 829 (s) cm "1; HRMS (FAB *) m / z: Cale, for C31H48NO7Si2 (MH +) 602.2969, 602.2993 was found.

EXAMPLE 16 Protected Amino Acid 35 A solution of 34 (6.00 g, 9.98 mmol, 1 equiv.) And Rh [(COD) ft, f? -DiPAMP] * BF4"(75 mg) in a mixture of methyl alcohol and dichloromethane (10: 1 (v / v), 110 ml) was placed in a high pressure Parr reactor and purged with hydrogen gas (5 x 3.515 kg / cm2) .The reaction mixture was sealed under hydrogen (3.515 kg / cm2) and stirred at 23 ° C. C for 24 hours The solution was concentrated, and the residue was purified by flash column chromatography (2.5% ethyl acetate in dichloromethane) to yield 35 (6.01 g, qty) as a colorless viscous oil. Rf 0.41 (20% ethyl acetate in hexane): ee: 96% (HPLC ChirIPAK AD, 1% isopropyl alcohol in hexanes); [a] D23 + 30.5 * (c = 0.40, CH2Cl2); 1H NMR ( 400 MHz, CDCl 3) d 7.32 (m, 5H, Cbz ArH), 6.23 (s, 2H, ArH), 5.18 (d, 1H, J = 8.0 Hz, NH), 5.12 (d, 1H, J = 12.3 Hz, Cbz CH2), 5.07 (d, 1H, J = 12.3 Hz, Cbz CH2), 4.59 (m, 1H, ArCH2CH), 3.72 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 2.95 (d, 2H, J = 5.3 H z, ArCH2), 0.98 (s, 18H, t-butyl), 0.15 (s, 12H, SiCH3); 13 C NMR (100 MHz, CDCl 3) d 171.9, 155.6, 149.8, 142.1, 1.36.2, 130.5, 1.28.5, 128.1, 115.6, 67.0, 59.9, 54.5, 52.2, 37.6, 25.7, 18.3, -4.7; IR (net film) 3350 (w, br), 2931 (m), 2858 (w), 1728 (s), 1577 (m), 1496 (s), 1434 (s), 1360 (m), 1253 (s) ), 1230 (s), 1209 (m), 1091 (s), 831 (s) cm "1; HRMS (FAB *) m / z: Cale, for C3? H50NO7Si2 (MH +) 604.3126, 604.3103 was found.

EXAMPLE 17 Amino Ester 36 A solution of 35 (1.00 g, 1.66 mmol, 1 equiv.) And palladium on 10% activated carbon (50 mg) in ethyl acetate (40 ml) was stirred under 1 atm of hydrogen gas at 23 ° C for 2 hours. . The reaction mixture was filtered by gravity, and the filtrate was concentrated to provide 36 (780 mg, quant.) As a viscous oil. Rf 0.38 (50% ethyl acetate in hexane), [α] D23 + 5.7 * (c = 0.70, CH2Cl2); 1 H NMR (500 MHz, CDCl 3) d 6.35 (s, 2 H, Ar H), 3.71 (s, 3 H, OCH 3), 3.69 (s, 3 H, OCH 3), 3.67 (dd, 1 H, J = 5.4, 7.9 Hz, CHCO2CH3), 2.92 (dd, 1H, J = 5.4, 13.5 Hz, ArCH2), 2.71 (dd, 1H, J = 7.9, 13.5 Hz, ArCH2), 1.00 (s, 9H, t-butyl), 0.19 (s, 6H, Si (CH3) 2); 13 C NMR (100 MHz, CDCl 3) d 175.2, 149.6, 141.7, 132.1, 115.5, 59.8, 55.6, 51.9, 40.5, 25.6, -4.7; FTIR (net film) 2955 (m), 2930 (m), 2858 (m), 1743 (s), 1577 (m), 1495 (m), 1433 (m), 1356 (m), 1252 (m), 1229 (m), 1087 (s), 858 (s) cm "1; HRMS (FAB *) m / z: Cale, for C23H43NO5Si2Na (MNa *) 492.2578, 492.2580 was found.

EXAMPLE 18 Allyl Carbamate 7 3S 7 To a solution of 36 (780 mg, 1.66 mmol, 1 equiv.) In pyridine (8 ml) at 0 ° C was added allyl chloroformate (352 ml, 3.32 mmol, 2.0 equiv.), And the reaction was stirred at 23 ° C for 2 minutes. The mixture was concentrated at 23 ° C and the residue was partitioned between water (50 ml) and dichloromethane (3 x 25 ml). The combined organic layers were dried (sodium sulfate) and concentrated and the residue was purified by flash column chromatography (15% ethyl acetate in hexane) to give 7 (856 mg, 93%) as a colorless oil. Rf 0.37 (20% ethyl acetate in hexane); [a] D23 + 26.2 * (c = 0.40, CH2Cl2); 1 H NMR (400 MHz, CDCl 3) d 6.28 (s, 2 H, Ar H), 5.89 (m, 1 H, vinyl H), 5.28 (d, 1 H, J = 17.3 Hz, vinyl H), 5.20 (d, 1 H, J = 10.5 Hz, vinyl H), 5.14 (d.1H, J = 7.9 Hz, NH), 4.35 (m, 3H, allylic CH, and CHCOCH3), 3.73 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 2.94 (d, 2H, J = 9.4 Hz, ArCH2), 1.00 (s.9H, t-butyl), 0.19 (s, 6H, Si (CH3) 2); 13 C NMR (100 MHz, CDCl 3) d 171.9. 149.8, 132.6, 130.6, 117.8, 115.6, 65.8, 59.9, 54.5, 52.3. 37.5. 25.7, 18.3, -4.7; FTIR (net film) 3280 (w, br), 2955 (s). 2931 (s), 2858 (s), 1737 (s), 1716 (s), 1578 (s), 1519 (s), 1472 (s), 1361 (m), 1253 (s), 1229 (s), 1207 (m), 1092 (s), 1011 (m), 832 (s) cm "1; HRMS (FAB *) m / z: Cale, for C27H47NO7Si2Na (MNa *) 576. 2789, 576.2777 was found.

EXAMPLE 19 Aldehyde 8 To a solution of 7 (850 mg, 1.54 mmol, 1 equiv.) In dichloromethane (85 m) at -78 ° C was added diisobutylaluminum hydride (1 5 M in toluene, 2.05 ml, 3.08 mmol, 2.0 equiv.) and the reaction mixture was stirred at -78 ° C for 1 hour. The excess of the reducing agent was quenched through the sequential addition of methyl alcohol (700 ml), sodium decahydrate sulfate (-5 g) and Celite (-2 g). The mixture was stirred at 23 ° C for 1 hour, and then filtered through a pad of Celite. The filtrate was concentrated and the residue was dissolved in diethyl ether (150 ml). The solution was again filtered through a pad of Celite, and the filtrate was concentrated to give the crude aldehyde 8, which was used immediately without further purification in the coupling reaction with 6 R (033 (ethyl acetate). % in hexanes), 1H NMR crude product (400 MHz, CDCl 3) d 961 (s, 1H, CHO), 628 (s, 2H, ArH), 5 90 (m, 1H, vmilo H), 5.30 (dd , 1H, J = 1 2, 17 2 Hz, vinyl H), 5 21 (m, 2H, vinyl H, NH), 4 58 (m, 2H, aillo H), 441 (m, 1H, CHCHO), 3 70 (s, 3 H, OCH 3), 301 (dd, 1 H, J = 6 0, 144 Hz, ArCH 2), 2 94 (dd, 1 H, J = 6 8, 144 Hz, ArCH 2), 0 99 (s , 18H, Si-t-butyl), 0 15 (s, 12H, S? CH3) s synthesis of the Pentacicl EXAMPLE 21 Aminoni tril or 37 To a solution of amine 6 (123 mg, 0 467 mmol, 1 equiv) and crude aldehyde 8 (489 mg, 0 935 mmol, 2 0 equiv) in glacial acetic acid (5 ml) was added solid potassium cyanide (608). mg, 9 35 mmol, 20 equiv) and the resulting mixture was stirred at 23 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate (80 ml) and washed sequentially with a saturated aqueous solution of sodium bicarbonate ( 3 x 60 mL) and a saturated aqueous solution of sodium chloride (60 mL) The organic layer was dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (gradient elution 15% ethyl acetate? 20% in hexane) to provide 37 (159 mg) and its amino-caprylic epimer (67 mg) in separate fractions ( 61% total) 37 R, 0 19 (25% ethyl acetate in hexane), [α] D23 -368 * (c = 1 30, CH 2 Cl 2), 1 H NMR (400 MHz, CDCl 3) d (multiple resonances and widened due to carbamate rotamers at 23 ° C) 6 34 (s, ArH), 6 32 (s, ArH), 6 30 (s, ArH), 5 98-580 (m, vmilo H and OCH2O), 5 33 ( m), 5 28 (m), 5 23 (m), 52-48 (m (br)), 4 63 (m), 4 57 (m), 445 (m (br)), 4 40-4 25 (m) 4 10 (m (br)), 393 (m (br)), 3 70 (s, OCH3), 361 (s, OCH3), 2 13 (s, ArCH3), 2 08 (s, ArCH3) , 1 00 (s, t-butyl), 099 (s, t-butyl), 0 19 (s, S? (CH3) 2), 0 11 (s, S? (CH3) 2), 13C NMR (100 MHz, CDCl 3) d 171 3, 169 7, 169 2, 156 1, 155 5, 150 1, 150 0, 146 3, 145 1, 142 2, 142 0, 137 9, 132 3, 132 1, 131 3, 130 7, 118 1, 117 9, 117 8, 115 9, 115 5, 1154, 115 2, 115 0, 110 1, 109 1, 108 9, 107 3, 101 4 101 3, 73 7, 734, 66 0, 604, 59 9, 59 8, 57 1, 57 0, 55 2, 55 0, 52 0, 50 7, 47 9, 46 7, 38 2 , 35 1, 31 6, 25 7, 22 9, 22 6, 22 0, 21 0, 18 3, 14 1, 8 7, 8 6, -4 7, -4 8, FTIR (net film) 3300 (m br), 2955 (s), 2932 (s), 2858 (s), 1727 (s), 1712 (s), 1578 (m), 1495 (m), 1434 (s), 1360 (m), 1255 (s) s), 1233 (s), 1095 (s) 1043 (m), 1009 (s), 86.0 (s) 832 (s) cm 1, HRMS (FAB *) m / z Cale for C40H58 3O10S? 2 ( MH +) 796 3661 796 3636 was found EXAMPLE 22 Allyl Ether 9 To a solution of aminonitrile 37 (986 mg, 1.24 mmol, 1 equiv.) In DMF (10 ml) was added sequentially dried cesium carbonate with flames (809 mg, 2.78 mmol, 2.0 equiv.) And allyl bromide (537 mg). mi, 6.20 mmoles, 5.0 equiv.), and the mixture was stirred at 23 ° C for 1 hour. The excess base was neutralized with the addition of acetic acid (4 mL), and the mixture was then partitioned between a saturated aqueous solution of sodium bicarbonate (100 mL) and dichloromethane (2 x 50 mL). The aqueous layer was further extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (20% ethyl acetate in hexane) to provide 9 (901 mg, 87%) as a colorless film. Rf 0 41 (25% ethyl acetate in hexane); [α] D23 -40.0 '(c = 0.53, CH2Cl2); 1 H NMR (500 MHz, CDCl 3) d (multiple and widened resonances due to carbamate rotamers at 23 ° C) 6 32 (s, Ar H), 6.29 (s, Ar H), 6.1-5.7 (m, vinyl H and OCH 2 O) , 5.41 (m, vinyl H), 5.29 (m, vinyl H), 5 31 (m, vinyl H), 5.30-5.10 (m), 4.93 (m (br)), 4.79 (m (br)), 4.70 -4.05 (m), 3.91 (m (br)), 3.70 (s, OCH3), 3.60 (s, OCH3), 3.42 (m), 3.19 (m), 3.04-2.89 (m), 2.64 (m), 2.17 (s, ArCH3), 2.10 (s, ArCH3), 1.01 (s, t-butyl), 0.98 (s, t-butyl), 0.18 (s, Si (CH3) 2), 0.11 (s, Si (CH3) 2); 13C NMR (100 MHz, CDCI3) d 169.3, 168.8, 156.1, 155.4, 150.1, 150.0, 149.9, 149.7, 145.4, 145.3, 142.2, 142.0, 140.4, 140.2, 133.4, 133.3, 132.4, 1.32.1, 131.3, 130.8 , 118.1, 117.9, 117.6, 117.5, 117.1, 116.0, 115.4, 115.2, 115.0, 114.1, 113.8, 109.8, 109.2, 109.2, 101.7, 101.6, 73.6, 73.5, 73.2, 66.0, 66.0, 59.9, 59.8, 57.2, 56.9, 55.3, 54.9 , 53.4, 52.1, 50.6, 48.2, 46.8, 38.1, 35.13, 25.7, 25.6, 23.5, 22.5, 18.3, 9.4, 9.3, -4.7, -4.8; FTIR (net film) 3300 (w, br), 2955 (m), 2932 (s), 2858 (m), 1727 (s), 1577 (m), 1494 (m), 1461 (s), 1434 (m) ), 1253 (s), 1232 (s), 1095 (s), 1043 (m), 1009 (m), 860 (m), 832 (s) cm'1; HRMS (FAB *) m / z: Cale. for C43H61 N3O10Si2Na (MNa *) 858.3793, 858.3820 was found.

EXAMPLE 23 Triol 10 To a solution of 9 (390 mg, 0.467 mmol, 1 equiv.) In a solution of toluene (50 ml) at -78 ° C was added a solution of diisobutylaluminum hydride (1.5 M in toluene, 374 ml, 0.560 mmol). , 1.2 equiv.), And the resulting solution was stirred at -78 ° C for 5 hours. The excess reducing agent was quenched through the slow sequential addition of methyl alcohol (500 ml), sodium sulfate decahydrate (~ 5 g), and Celite at -78 ° C. The suspension was stirred at 23 ° C for 1 hour before it was filtered through Celite. The filtrate was concentrated, and the residue (38) was dissolved in methyl alcohol (4 mL).

To this solution was added potassium fluoride dihydrate (250 mg, 2.66 mmol, 5.7 equiv.), And the reaction was stirred at 23 ° C for 20 minutes. The mixture was partitioned between dichloromethane (50 ml) and a saturated aqueous solution of 80% sodium chloride (80 ml), and the aqueous phase was further extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried (sodium sulfate) and concentrated, and the residue (39) was dissolved in dichloromethane (100 ml).

To this solution were added crushed, flamed 3A molecular sieves (620 g) followed by methanesulfonic acid (531 ml, 8 21 mmol, 20 equiv), and the suspension was stirred at 23 ° C for 5 hours. Extinguished through the addition of pipdin (1 32 ml, 164 mmol, 40 equiv), and the mixture was filtered by suction, washing well with 10% isopropyl alcohol in dichloromethane (4 x 20 ml) The product solution was washed with a saturated aqueous solution of sodium chloride (150 ml), and the aqueous layer was further extracted with ethyl acetate (2 x 100 ml). The combined organic layers were dried (sodium sulfate) and concentrated and the residue was purified. by flash column chromatography (gradient elution 60% ethyl acetate? 100% in hexane) to provide 10 (152 mg, 55%, 3 steps) as a colorless oil Rf 023 (66% ethyl acetate in hexane), [a] D23-44 '(c = 048, CH2Cl2), 1H NMR (500 MHz, CDCl3) d (resonances multiple and widened due to carbamate rotamers at 23 ° C) 6 32 (s, 1H ArH), 6 31 (s 1H, ArH), 6 29 (m, 1H, vinyl H) 5 90 (m vinyl H OCH 2 O) 5 60 (s (br) ArOH), 5 50 (s (br), ArOH) 5 42 (m, 1H) 5 39 (m, 1H) 5 32-5 17 (m), 4 91 (m, 1H), 4 83 (m 1 H) 4 62 (m) 4 20 (m), 4 31 (m, 1 H) 3 97 (m 2 H) 3 83 (s 3 H OCH 3), 3 82 (s, 3 H, OCH 3), 3 66 -320 (m), 2 74 (m, 1H, ArCH2), 2 12 (s, 3H, ArCH3), 087 (m, 1H, ArCH2), 13C NMR (100 MHz, CDCl3) d 171 3, 1544, 1539, 1487, 148 6, 1484, 1462, 145 9, 145 5, 144 6, 144 5, 139 0, 133 7, 1336, 132 6, 132 3, 1320, 130 8, 1304, 121 3, 120 6, 1204, 118 8, 118 0, 117 9, 117 8, 117 5, 117 2, 116 3, 116 1, 1159, 113 7, 112 5, 113 3, 112 1, 107 7, 107 2, 106 6, 101 2, 744, 74 1, 66 8, 66 5, 64 3, 60 9, 604, 59 0, 58 9, 582, 56 6, 52 9, 51 4, 49 8, 494, 489, 46 6, 31 0 , 306, 304, 25 9, 21 0, 14 1, 9 3, FTI R (net film) 3300 (m, br), 2902 (m), 1686 (s), 1460 (s), 1432 (s), 1372 (m), 1328 (m) 1291 (m), 1264 (w) , 1106 (s), 1064 (m), 1027 (m), 954 (m) cm 1, HRMS (FAB *) m / z Cale for C31H33N3O9Na (MNa *) 614 2114, 614 2133 was found EXAMPLE 24 Aryl Triflate 40 To a solution of 10 (150 mg, 0.253 mmol, 1 equiv) and 11 min ina (177 ml, 27 mmol, 5.0 equiv) in dichloromethane (15 mL) was sequentially added N-phenyl-propaphenol (227 mg, 0.degree. 634 mmol 2 5 equiv) and DMAP (1 mg), and the reaction was stirred at 23 ° C for 6 5 hours Each excess was neutralized through the addition of acetic acid (145 ml, 2 53 mmol, 10 equiv) followed by pipdin (306 ml, 3 79 mmol, 15 equiv) The mixture was partitioned between dichloromethane (50 ml) and a saturated aqueous solution of sodium chloride (80 ml) and the aqueous layer was further extracted with ethyl acetate (2 × 50 mL) The combined organic layers were dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (60% ethyl acetate in hexane) to provide 40 (132 mg, 72%). %) as a colorless film Rf 044 (50% ethyl acetate in hexane), [a] D23 + 323 * (c = 060, CH2Cl2), 1H NMR (500 MHz, CDCI3) d (signal s widened due to carbamate rotamers at 23 ° C) 6 65 (s, 1H, ArH), 6 10 (m, 1H, vinyl H), 5 92 (m, vmilo H and OCH2O), 568 (s, ArOH) , 5 57 (s (br)), 540 (m), 5 26 (, vmilo H), 4 93 (m), 487 (), 4 63 (m), 421 (m), 3 98 (m), 3 92 (s, 3 H, OCH 3), 17-34 (m), 3 30 (m), 2 86 (m) 2 13 (s, 3 H, ArCH 3), 1 81 (m, 1 H, ArCH), 13 C NMR (126 MHz, CDCl 3) d 154 1, 1539, 148 7, 148 5, 147 2, 1466, 144 8, 144 7, 141 1, 1409, 139 1, 138 9, 136 9, 136 7, 134 2, 133 7, 132 2, 132 1, 131 7, 1294, 127 1, 123 2, 122 3, 121 3, 121 2, 120 1, 1199, 119 8, 118 2 176, 117 5, 117 2, 116 2, 116 1, 112 8, 112 7, 112 3, 112 2, 112 1 101 2 744, 66 9, 66 7, 656, 654, 61 9, 59 5, 594, 58 5 56 5 497, 49 2, 48 9, 48 3, 309, 30 3, 259, 14 1, 93, FTIR (net film) 3350 (w br), 2928 (w), 1694 (s) 1685 (s), 1451 (s), 1422 (s) 1319 (m), 1257 (s), 1214 (s), 1138 (s) 1102 (s) 1026 (s), 989 () cm 1 HRMS (FAB *) m / z Cale for Ca ^ a ^ NaO, - SNa (MNa *) 746 1607, it was found 746 1616 EXAMPLE 25 Silyl Ether 41 To a solution of 41 (90 mg, 0.124 mmol, 1 equiv) and DMAP (152 mg, 1 24 mmol, 10 equiv) in dichloromethane (10 mL) was added t-butyldiphenylsiyl chloride (162 mL, 0622 mmol, 50 equiv), and the solution was stirred at 23 ° C for 13 hours The base excess was quenched by the addition of acetic acid (150 ml), and the mixture was divided between water (50 ml), and dichloromethane (3 × 30 mL) The combined organic layers were dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (gradient elution 25% ethyl acetate-50% in hexane) to provide 41 (106 mg, 89%) as a colorless glassy solid Rf (50% ethyl acetate in hexane) [a] D23 +45 2 * (c = 1 00, CH2Cl2) 1HNMR (500 MHz, CDCl3) d (resonances multiple and widened due to carbamate rotamers at 23 ° C) 5 70 (m, 1H ArH), 7 56 (m, ArH) 745-7 15 (m, ArH) 6 58 (m 1H ArH) 6 06 (m 1H , vinyl H), 5 90 (m 1H vmilo H), 5.80 (s, 1H, OCH2O), 5.13 (m, 2H, ArOH and OCH2O), 5.4-5.1 (m), 4.92 (m), 4.83 (m), 4.61 (m), 4.20 (m), 4.09 (m), 3.92 ( s, 3H, OCH3), 3.7-3.2 (m), 2.98 (m, 1H, ArCH), 2.11 (s, 3H, ArCH3), 1.90 (m, 1H, ArCH), 1.01 (s, t-butyl), 1.00 (s, t-butyl); 13C NMR (126 MHz, CDCI3) d 171.2, 154.2, 148.6, 148.5, 147.4, 146.7, 144.6, 144.4, 141. 3, 141.2, 139.3, 139.1, 136.6, 136.4, 135.7, 135.3, 134.8, 133.8, 133.0, 132.5, 132.4, 129.8, 129.7, 127.7, 122.2, 122.1, 120.5, 120.4, 119.9, 118.2, 1.17.6, 117.5, 1.17.3, 117.2, 116.9, 116.7, 112.7, 112. 4, 112.1, 111.8, 101.0, 74.4, 69.3, 68.8, 66.8, 66.5, 65.3, 61.9, 60.5, 60.4, 60.3, 59.3, 56.6, 49.8, 49.2, 48.9, 48.3, 31.6, 30.7, 30.0, 26. 8, 26.5, 26.2, 26.1, 22.6, 21.0, 19.0, 14.2, 14.1, 9.3, 9.2; FTIR (net film) 3350 (w, br), 2951 (m), 1694 (s), 1458 (m), 1451 (s), 1425 (s), 1317 (m), 1257 (m), 1214 (s) ), 1139 (s), 1110 (s), 1038 (m), 989 (m), 824 () cm "1; HRMS (FAB *) m / z: Cale for C4ßH5oF3N3O? 1SSiNa (MNa *) 984.2785, 984.2771 was found.

EXAMPLE 26 Methoxymethyl Ether 42 42 To a solution of 41 (94 mg, 0.0978 mmol, 1 equiv.) And diisopropylethylamine (340 mL, 1 96 mmol, 20 equiv) in dichloromethane (6 mL) at 0 ° C was added bromo-methylmethoxyl ether (80 mL, 0 978 mmol, 10 equiv), and the solution was stirred at 23 ° C for 20 minutes. After the reaction was quenched with methyl alcohol (100 ml), the mixture was partitioned between a saturated aqueous solution of sodium bicarbonate (30 ml). , and dichloromethane (2 x 30 ml) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography (25% ethyl acetate in hexane) to provide the residue. (90 mg, 92%) as a colorless film Rf 066 (50% ethyl acetate in hexane), [a] D23 +570 (c = 10, CH2Cl2), 1H NMR (400 MHz, CDCl3) d (resonances multiple and widened due to carbamate rotamers at 23 ° C) 7 6-7 1 (m, 10H, ArH), 674 (s, 1H, ArH), 6 10 (m, 1H, vinyl H), 5 93 (m , 1H, vinyl H), 5 81 ( s, 1 H, OCH 2 O), 5 65 (s, 1 H, OCH 2 O), 545-5 13 (m, vinyl H and OCH 2 O), 4 91 (m, 1 H), 4 69 (m, 1 H), 4 59 (m , 2H), 4 16 (m, 2H) 4 07 (m, 1H), 3 87 (m, 3H, OCH3), 3 73-360 (m, 4H, OCH3 and CHOSi) 3 4-32 (, 3H, CHOSi and ArCH), 2 97 (m, 1H, ArCH2), 2 12 (s, 3H ArCH3), 1 83 (m, 1H, ArCH2), 0 97 (m, 9H, 1 -butyl), 13C NMR (100 MHz, CDCI3) d 154 1, 153 9, 148 5, 147 9, 1446, 142 6, 142 4 142 1 139 3, 139 2 135 7, 135 3, 134 8, 133 7, 132 9, 132 5, 1324 132 3 129 8, 128 8 1287, 127 7, 120 3, 120 1, 118 5, 118 1, 117 5 117 1 116 7, 116 6 116 5, 112 5, 112 -4, 112 0 111 8, 101 1 , 99 7 74 2 69 2, 68 8, 67 0, 66 7 61 1, 604, 60 2, 59 2, 584, 58 1, 56 5 50 2 49 3, 49 2 48 3, 30 7 30 1 29 7 , 26 8, 26 1 26 0, 190, 9 2 FTIR (net film) 2959 (m), 1709 (s), 1426 (s), 1315 (m), 1253 (m), 1213 (s), 1140 ( s), 1110 (s), 1066 (s), 1015 (s), 987 (s), 921 (s), 825 (m) cm 1, MS (FAB) m / z: Cale for C5oH54F3N3O12Ss? Na (MNa *) 1028, 1028 was found.

EXAMPLE 27 Aminophenol 43 • «2 43 To a solution of 42 (90 mg, 0.895 mmol, 1 equiv.), Acetic acid (102 ml, 1 79 mmol, 20 equiv.) And dichloro-palladium of b? S (tphenyl phosphine) (5 mg) in dichloromethane ( 4 ml) was added tpbutyltin hydride (120 ml, 0.448 mmol, 5.0 equiv.), And the yellow / brown solution was stirred at 23 ° C for 15 minutes. The mixture was loaded on a column of silica gel, and the product was purified by flash column chromatography (gradient elution 50% ethyl acetate in hexane? 100% ethyl acetate) to provide 43 ( 79 mg, quant.) As a colorless film Rf 0 30 (50% ethyl acetate in hexane), [α] D 23 +34 0 (c = 10, CH 2 Cl 2), 1 H NMR (500 MHz, CDCl 3) d 7 59 (d, 2H, J = 94 Hz, ArH), 73-7 2 (m, 8H, ArH) 6 76 (s, 1H, ArH), 5 75 (s, 1H, OCH2O), 561 (s, 1H , OCH2O), 5.39 (d, 1H, J = 5.3 Hz, OCH2O), 5.22 (d, 1H, J = 5.3 Hz, OCH2O), 5.14 (s, 1H, ArOH), 4.60 (d, 1 H, J = 1. 1Hz, ArCH), 4.49 (d, 1H, J = 2.3 Hz, CHCN), 4.07 (m, 1H, ArCH), 3.85 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.75- 3.40 (m (br)), 3.35 (dd, 1H, J = 7.6, 10.2 Hz, CHOSi), 3.28 (dd, 1H, J = ~1.10.2 Hz, CHOSi), 3.13 (m, 2H, ArCH2), 2.94 (d, 1H, J = 15.9 Hz, ArCH2), 2.07 (s, 3H, ArCH3), 1.77 (dd, 1H, J = 11.0, 13.6 Hz, ArCH2), 0.95 (s, 9H, t-butyl); 13C NMR (100 MHz, CDCI3) d 171.2, 148.4, 145.2, 144.5, 142.0, 141.2, 136.6, 135.6, 135.3, 133.0, 132.9, 132.6, 130.8, 129.7, 127.6, 120.2, 117.9, 117.1, 116.5, 112.4, 111.7 , 106.0, 100.6, 99.9, 77.2, 69.2, 61.3, 61.2, 60.4, 59.5, 58.1, 56.8, 49.8, 49.2, 31.0, 26.7, 26.2, 21.0, 19.0, 14.1, 8.7; FTIR (net film) 3400 (w, br), 2929 (m), 1488 (), 1460 (m), 1426 (s), 1250 (m), 1213 (s), 1158 (m), 1140 (s) , 1105 (s), 1034 (m), 1011 (m), 982 (m), 915 (m), 824 (m) cm "1; HRMS (FAB *) m / z: Cale, for C43H47F3N3? 10SSiNa ( MNa *) 882.2704, 882.2694 was found.

EXAMPLE 28 Phenol 44 43 To a solution of 43 (79 mg, 0.896 mmol, 1 equiv) and a solution of formalin (600 ml) in acetonitoplo (6 ml) was added solid sodium cyanoborohydride (17 mg, 0.269 mmol, 5.0 equiv) and the solution was stirred at 23 ° C for 30 minutes. Acetic acid (102 ml.1.79 mmol, 20 equiv) and the reaction was stirred at 23 ° C for a further 1.5 hours. The mixture was partitioned between a saturated aqueous solution of sodium bicarbonate (40 ml) and dichloromethane (30 ml), and the aqueous layer it was further extracted with ethyl acetate (2 x 30 mL) The combined organic layers were dried (sodium sulfate) and concentrated and the residue was purified by flash column chromatography (gradient elution of ethyl acetate at 37 ° C). %? 50% in hexane) to provide 44 (76 mg, 95%) as a colorless film R (0 60 (50% ethyl acetate in hexane), [a] D23 +335 (c = 10, CH2Cl2) , 1 H NMR (500 MHz, CDCl 3) d 7 59 (m, 2 H, Ar H), 7 46-7 22 (m, 8 H, Ar H), 6 74 (s, 1 H, Ar H), 574 (d, 1 H, J = 1 5 Hz, OCH2O), 560 (d, 1H, J = 1 5 Hz, OCH2O), 5 35 (d, 1H, J = 57 Hz, OCH2O), 521 (d, 1H, J = 57 Hz, OCH2O ), 5 01 (s, 1H, ArOH), 4 89 (m, 1H), 460 (d, 1H, J = 30 Hz), 4 25 (m 1H), 4 11 (m, 1H), 3 86 ( s, 3H, OCH3), 367 (s, 3H, OCH3), 3 39-3 30 (m, 3H) , 309 (dd, 1H, J 26, 152 Hz, ArCH2), 301 (dd, 1 H, J = 7 3, 18 2 Hz, ArCH2), 2 74 (d, 1H, J = 18 2 Hz, ArCH2) , 2 30 (s, 3 H, NCH 3), 2 05 (s, 3 H, ArCH 3), 1 79 (dd, 1 H, J = 11 3, 15 2 Hz, ArCH 2) 0 97 (s, 9 H t -butyl), 13 C NMR (100 MHz, CDCl 3) d 150 1, 145 1 144 4, 141 8 141 7, 136 7, 135 7, 135 3, 133 0, 132 6, 132 2 129 7 1 276, 1268 1203, 118 3, 1180 117 1 1160, 112 5, 111 9, 1061, 100.7, 999, 772, 693, 61 6, 61 3, 589, 582, 569, 568, 550, 487, 41 6, 267, 258, 256, 190, 141, 87, FTIR (net film) 3400 (w, br), 2932 (m), 1466 (m), 1426 (s), 1249 (m), 1213 (s), 1156 (s), 1140 (s) , 1107 (s), 1063 (m), 1035 (m), 1013 (s), 992 (s), 976 (s), 958 (m), 934 (m) cm "1 HRMS (FAB +) m / z - Cale, for C44H49F3N3O? OSS? (MH *) 8962860, 8962872 was found EXAMPLE 29 Phenol 11 eleven To a solution of 44 (17 mg, 0.0190 mmol, 1 equiv), lithium chloride (16 mg, 0 380 mmol, 20 equiv) and dichloro-palladium of b? S (phosphine tpheni ca) (1 mg) in DMF (0 5 ml) was added tetramethyltin (53 ml, 0 380 mmol, 20 equiv), and the brown solution was stirred at 80 ° C for 2 hours. The reaction mixture was partitioned between water (30 ml) and dichloromethane ( 2 x 20 mL) The aqueous layer was further extracted with ethyl acetate (2 x 20 mL), and the combined organic layers were dried (sodium sulfate) and concentrated. The product was purified by flash column chromatography. (gradient elution 33% ethyl acetate? 50% in hexane) to provide 11 (14 mg, 96%) as a colorless film. Rf 0.27 (20% ethyl acetate in benzene) [a] D23 +11.2 (c = 0.55, CH2Cl2); 1 H NMR (400 MHz, CDCl 3) d 7.56 (m, 2 H, Ar H), 7.41-7.25 (m, 8 H, Ar H), 6.67 (s, 1 H, Ar H), 5.72 (d, 1 H, J = 1.0 Hz, OCH 2 O ), 5.58 (d, 1H, J = 1.0 Hz, OCH2O), 5.51 (s, 1H, ArOH), 5.38 (d, 1H, J = 5.7 Hz, OCH2O), 5.16 (d, 1H, J = 5.7 Hz, OCH2O), 4.57 (d, 1H, J = 2.9 Hz), 4.21 (m, 1H), 4.09 (m, 1H), 3.72 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.68 (dd) , 1H, J = 2.1, 10.4 Hz), 3.38-3.26 (m, 3H), 3.11 (dd, 1H, J = 2.5, 15.7 Hz, ArCH2), 3.01 (dd, 1H, J = 8.9, 17.9 Hz, ArCH2 ), 2.70 (d, 1H, J = 17.9 Hz, ArCH2), 2.31 (s, 3H, NCH3), 2.25 (s, 3H, ArCH3), 2.06 (s, 3H, ArCH3), 1.89 (dd, 1 H " J = 12.1, 15.7 Hz, ArCH2), 0.90 (s, 9H, t-butyl), +3.1% nOe of ArH on irradiation of ArCH3; 13 C NMR (100 MHz, CDCl 3) d 149.0, 147.4, 145.3, 144.3, 136.3, 136.3, 135.7, 135.4, 133.2, 130.9, 130.5, 129.6, 129.5, 127.5, 125.0. 118.6, 112.5, 112.1, 105.7, 100.5, 99.8, 68.5, 61.5, 59.7, 58.8, 57.7, 56.9, 56.5, 55.4, 41.7, 26.6, 26.2, 25.5, 18.9, 15.8, 14.2, 8.7; FTIR (net film) 3400 (w, br), 2928 (s), 2855 (s), 1459 (s), 1432 (s), 1156 (m), 1106 (s), 1061 (m), 1046 (m) ), 1023 (m), 967 (m), 926 (m) cm-1; HRMS (FAB *) m / z: Cale, for C44H51 N3O7SiNa (MNa *) 784.3394, 784.3367 was found.

EXAMPLE 30 Hydroxy Dienone 45 To a solution of 11 (40 mg, 0.0525 mmol, 1 equiv.) In dichloromethane (6 ml) was added benzenesinic anhydride (21 mg, 0.0578 mmol, 1 equiv.), And the purple solution was stirred at 23 ° C. during 15 minutes. The mixture was quenched with a saturated aqueous solution of sodium bicarbonate (6 ml) before being partitioned between a saturated aqueous solution of sodium bicarbonate (30 ml) and dichloromethane (2 x 20 ml). The aqueous layer was further extracted with ethyl acetate (2 x 20 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography (gradient elution: 33% ethyl acetate? 50% in hexane) to give 45 (33 mg, 82%) as a colorless film. Rf 0.27 '(50% ethyl acetate in hexane); [a] D23 +148.2 (c = 0.50, CH2Cl2); 1 H NMR (400 MHz, CDCl 3) d 7.7-7.3 (m, 10 H, Ar H), 6.54 (s, 1 H, Ar H), 5 28 (s, 1 H, OCH 20), 5.23 (s, 1 H, OCH 2 O), 5.02 ( d, 1H, J = 5.7 Hz OCH20), 4.99 (d, 1H, J = 5.7 Hz, OCH2O), 4.46 (d, 1H, J = 2.8 Hz), 4.35 (dd, 1H, J = 2.8, 14.5 Hz) , 4.05-3.95 (m, 2H), 3.88 (m, 1H), 3.79 (m, 1H), 3.63 (s, 3H, OCH3), 3.31 (5, 3H, OCH3), 2.90 (dd, 1H, J = 8.7, 17.8 Hz, ArCH2), 2.39 (d, 1H, J = 17.8 Hz, ArCH2), 2.23 (s, 3H, NCH3), 2.21 (m, 1H, CH2COH), 2.19 (s, 3H, ArCH3), 2.03 (m, 1 H, CH 2 OH), 1.73 (s, 3 H, CH 3), 1. 10 (s, 9 H, t-butyl); 13C NMR (100 MHz, CDCI3) d 200.9, 160.2, 148.6, 148.0, 137.7, 135.8, 135.6, 133.6, 132.6, 132.9, 130.5, 130.2, 129.8, 129.7, 129.7, 129.6, 129.5, 127.7, 127.6, 127.5, 125.1, 124.4, 117.2 , 113.5, 100.2, 99.1, 77.2, 72.9, 64.3, 60.3, 60.3, 59.2, 59.6, 58.9, 57.7, 56.5, 56.5, 56.2, 55.3, 55.2, 52.2, 42.6, 41.6, 41.6, 41.6, 35.6, 26.9, 25.5, 25.8, 25.6, 21.0, 19.4 , 19.0, 15.8, 14.2, 7.0; FTIR (net film) 3500 (w, br), 2929 (s), 1634 (s), 1428 (m), 1377 (m) v 1346 (s), 1330 (s), 1232 (m), 1145 (s) ), 112 (s), 1065 (s), 1054 (s), 1034 (s), 1014 (s), 998 (m), 925 (s), 823 (m) cm "1; HRMS (FAB +) m / z: Cale, for C44H51N3O8SiNa (MNa *) 800.3340, 800.3313 was found.

EXAMPLE 31 Diol 12 To a solution of 45 (30 mg, 0.0386 mmol, 1 equiv.) In THF (4 ml) s was added tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 77 ml, 00772 mmol, 2.0 equiv), and the solution was added to the solution. stirred at 23 ° C for 10 minutes. The mixture was partitioned between a saturated aqueous solution of sodium chloride (30 ml) and ethyl acetate (3 x 20 ml). The aqueous layer was further extracted with dichloromethane (2 x 20 ml), and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography (gradient elution 75% ethyl acetate? 100% in hexane) to provide 12 (19 mg , 91%) as a colorless film Rf 025 (75% ethyl acetate in hexane), [a] D23 +156 2 (c = 011, CH2Cl2), 1H NMR (500MHz, CDCl3) d672 (s, 1 H, Ar H), 5 86 (s, 2 H, OCH 2 O), 5 12 (s, 2 H, OCH 2 O), 4 10 (m, 2 H), 3 92 (s, 3 H, OCH 3), 3 88 (m, 1 H) , 3 80 (m 1 H), 362 (, 1 H), 3 52 (s, 3 H, OCH 3), 334 (m, 1 H), 304 (dd) , 1H, J = 7 7, 18 0 Hz, ArCH2), 268 (m, 1H), 2 62 (d, 1H, J = 180 Hz, ArCH2), 2 32 (s, 3H, NCH3), 2 24 ( s, 3 H, ArCH 3), 2 21 (m, 1 H, CH 2 COH), 2 00 (dd, 1 H, J = 8 5, 15 1 Hz, CH 2 COH), 1 80 (s, 3 H, CH 3), 13 C NMR (100 MHz, CDCl 3) d 1987, 1589, 1488, 1484, 1404, 131 3 130 3, 1254, 1230, 116 9, 11 1 1, 104 3, 101 6, 994, 77 2 70 3, 61 7, 60 5, 58 5, 58 0, 57 6, 57 2, 55 2, 41 6, 36 3, 256, 15 7, 7 2 FTIR (net film) 3450 (w, br), 2926 (s), 1645 (s), 1417 (m) 1378 (m), 1345 (s) 1234 (m), 1157 (m), 1133 (m), 1089 (m), 1059 (), 1038 (m), 995 (m), 970 (m) ), 954 (m), 924 (m) cm 1, HRMS (FABT) m / z Cale for CsaHssNaOgNa (MNa *) 562 2165, 562 2173 were found. Basic Steps EXAMPLE 32 Ester 13 To a solution of alcohol 12 (9.0 mg, 00167 mmol, 1 equiv) and acid 46 (19 mg, 0501 mmol, 3.0 equiv) in dichloromethane (1.5 mL) was added DMAP (10 mg, 0 0835 mmol) , 5 0 equiv) and 1 - (3-d? Met? Lam? Noprop?) -3-et? Lcarbodomide (1 mg, 0 0835 mmol, 5 equiv), and the solution The resulting mixture was stirred at 23 ° C for 1.5 hours. The reaction mixture was partitioned between a saturated aqueous solution of sodium bicarbonate (30 ml) and dichloromethane (2 x 20 ml), and the aqueous layer was further extracted with ethyl acetate. (2 x 20 mL) The combined organic layers were dried (sodium sulfate) and concentrated, and the residue was purified by flash column chromatography (gradient elution 50-60% ethyl acetate in hexanes) to provide 13 (137 mg, 91%) Rf 0 15 (50% ethyl acetate in hexanes) [a] D23 +200 (c = 0 2, CH 2 Cl 2) 1 H NMR (400 MHz, CDCl 3) d 7.75 (m, 2H, ArH), 7.62 (m, 2H, ArH), 7.40 (m, 2H, ArH), 7.30 (m, 2H, ArH), 6 .63 (s, 1H, ArH), 5.90 (m, 1H, vinyl H), 5.74 (s, 1H, OCH2O), 5.71 (s, 1H, OCH2O), 5.52 (d, 1H, J = 8.3 Hz, NH ), 5.32 (d, 1H, J = 16.7 Hz, vinyl H), 5.22 (d, 1H, J = 10.0 Hz, vinyl H), 5.10 (m, 2H, OCH2O), 4.57 (m, 2H), 4.50 ( m, 1H), 4.23 (dd, 1H, J = 6.2, 11.2 Hz), 4.04 (m, 1H), 4.00 (dd, 1H, J = 2.5, 13.3 Hz), 3.93 (m, 1H), 3.84 (m , 3H, OCH3), 3.49 (m, 3H, OCH3), 3.24 (m, 1H), 3.08 (m, 3 H), 2.95 (m, 3H), 2.44 (d, 1H, J = 18.1 Hz), 2.36 (dd, 1H, J = 5.8, 15.0 Hz), 2.25 (s, 3H, NCH3), 2.20 (s, 3H, ArCH3), 1.83 (dd, 1H, J = 9.4, 15.0 Hz, C (OH) -CH ), 1.78 (s, 3H, CH3), 3C NMR (100 MHz, CD2Cl2) d 198.7, 170.6, 158.4, 155.8, 149.0, 148.9, 146.1, 142.8, 141.4, 133.0, 131.5, 130.5, 128.0, 127.4, 125.5, 125.1, 123.4, 120.2, 118.0, 117.6, 108.5, 104.6, 102.1, 99.7, 70.9, 66.7, 66.3, 61.2, 60.4, 57.9, 57.2, 56.5, 56.0, 55.7, 54.2, 47.3, 41.5, 37.3, 35.6, 25.9, 15.9, 7.5; FTIR (net film) 3400 (w, br), 2921 (m), 1722 (s), 1650 (s), 1448 (m), 1378 (m), 1346 (s), 1251 (m, 1234 (m) , 1208 (m), 1205 (m), 1157 (m), 1133 (m), 1054 (m), 1040 (m), 1033 (m), 995 (m) cm HRMS (FAB *) m / z: Cale, for C49H62N4O1 TSNa (MNa *) 927. 3251, 927.3255 was found.

EXAMPLE 33 Lactone 14 To a solution of triflic anhydride (8 mL, 0.0476 mmol, 16.5 equiv.) In dichloromethane (2.6 mL) at -78 ° C was added DMSO (18 mL)., 0.254 mmole, 88 equiv.), And the solution was stirred at -78 ° C for 15 minutes. A solution of 13 (2.6 mg, 0.00287 mmol, 1 equiv.) In dichloromethane (2.6 ml) was added dropwise to the reaction mixture, which was then stirred at -40 ° C for 45 minutes. To the yellow / brown reaction mixture was added diisopropylethylamine (51 ml, 0.288 mmol, 100 equiv.), And the yellow solution was stirred at 0 ° C for 45 minutes before the excess of Swern's reagent was quenched through. of the addition of t-butyl alcohol (13 mg, 0.176 mmol, 61 equiv.) at 0 ° C. T-butyl-tetramethyl guanidine (49 ml, 0.288 mmol, 100 equiv.) Was added to the solution, which was stirred at 23 ° C for 1.5 hours, during which time the solution became almost colorless. Acetic anhydride was added ( 50 mL, 0.530 mmol, 184 equiv), and after 1 hour at 23 ° C the reaction mixture was filtered through a short column of silica gel, eluting with 50% ethyl acetate in hexanes. The filtrate was concentrated, and the residue was purified by flash column chromatography (gradient elution: 25-33% ethyl acetate in hexanes) to give 14 (1.7 mg, 79%). Rf 0.40 (50% ethyl acetate in hexanes); [a] D23 -6.0, (c = 0.083, CH2Cl2); 1 H NMR (500 MHz, CDCl 3) d 6.80 (s, 1 H, Ar H), 6.09 (d, 1 H, J = 1.4 Hz, OCH 2 O), 6.00 (d, 1 H, J = 1.4 Hz, OCH 2 O), 5.93 (m, 1H, vinyl H), 5.32 (dd, 1H, J = 1.4, 17.0 Hz, vinyl H), 5.23 (d, 1H, J = 9.9 Hz, vinyl H), 5.22 (d, 1H, J = 5.2 Hz, OCH2O ), 5.14 (d, 1H, J = 5.2 Hz, OCH2O), 5.03 (d, 1H, J = 13.2 Hz), 4.83 (d, 1H, J = 9.3 Hz), 4.52 (m, 3H), 4.31 (m, 2H), 4.24 (s, 1H), 4.16 (m, 2H), 3.74 (s, 3H, OCH3), 3.56 (s, 3H, OCH3) 3.45 (m, 1H, ArCH), 3.40 (m, 1H, ArCH), 2.92 (m, 1H, ArCH). 2.29 (s 3 H, NCH 3), 2.28 (s, 3 H, ArCH 3), 2.22 (s, 3 H, ArCH 3), 2.13 (m, 1 H, ArCH), 2.03 (s, 3 H, AcO); 13C NMR (126 MHz, CD2CI2) d 170.7 / 168.9, 166.9, 155.6, 150.2, 148.8, 146.1, 141.5, 140.8, 133.5, 132.2, 130.7, 125.3, 120.8, 118.3, 117.9, 113.9, 102.6, 99.5, 66.1, 61.7, 61.0, 60.6, 60.0, 59.6, 59.4, 57.8, 55.4, 55.0, 54.2, 42.1, 41.4, 33.2, 30.1, 24.1, 20.6, 16.0, 14.4, 9.7; FTIR (net film) 3450 (w, br), 2930 (m), 1760 (s), 1724 (s), 1515 (m), 1507 (m), 1488 (m), 1456 (m). 1436 (m), 1194 (s), 1089 (m), 1062 (m), 1053 (m), 997 (m), 915 (m) cm "1; HRMS (FAB *) m / z: Cale, for C37H42N4O11SNa (MNa *) 773.2469, 773.2466 was found.

"S EXAMPLE 34 Amine 47 To a solution of 14 (5.0 mg, 0.00666 mmol, 1 equiv.), PdCI2 (PPh3) 2 (0.5 mg), and acetic acid (4 mL, 0.0666 mmol, 10 equiv.) In dichloromethane (1 mL) was added. tributyltin hydride (9 ml, 0.0333 mmol, 5.0 equiv.), and the brown solution was stirred at 23 ° C for 5 minutes. The reaction mixture was loaded directly onto a column of silica gel, and the product was purified by flash column chromatography (gradient elution: ethyl acetate, 4% isopropyl alcohol in ethyl acetate) to give amine 47 (3.6 mg, 84%). Rf 0.25 (ethyl acetate); [α] D23 +10 (c = 0.10, CH2Cl2); 1 H NMR (500 MHz, CDCl 3) d 6.73 (s 1 H, Ar H), 6.08 (d, 1 H, J = 1.0 Hz, OCH 2 O), 5.99 (d, 1 H, J = 1.0 Hz, OCH 2 O), 5.21 (d, 1 H , J = 3.4 Hz, OCH2O), 5.14 (d, 1H, J = 3.4 Hz, OCH2O), 5.02 (d.1H, = 12.0 Hz), 4.51 (m, 1H), 4.34 (d, 1H, J = 4 7 Hz), 4.27 (s, 1H), 4 20 (d, 1H, J = 3.0 Hz), 4.13 (d, 1H, J = 12 0 Hz), 3.79 (s, 3H, OCH3), 357 (s , 3H, OCH3), 3.45 (d, 1H, J = 4.7 Hz), 3 41 (m, 1H), 3 31 (m, 1H), 2 92 (m, 2H), 2.29 (s, 3H, NCH3) , 2.25 (s, 3 H ArCH 3), 2 19 (s, 3 H ArCH 3), 2 16 (m, 1 H), 2 04 (s, 3 H, AcO 1 NMR (100 MHz, CD 2 Cl 2) d 174.7, 149.8, 148.7, 141 4, 140.7, 132.7 , 132.4, 132.2, 131.6, 130.8, 128.9, 128.8, 125.4, 125.2, 121.2, 118.4, 114.3, 102.5, 99.5, 61.9, 60.2, 60.1, 59.4, 59.2, 57.7, 55.4, 55.0, 54.6, 42.1, 41.5, 35.1 , 30.1, 24.1, 20.6, 19.8, 15.8, 9.7, FTIR (net film) 3100 (w), 2920 (w), 1760 (m), 1749 (m), 1462 (m), 1454 (m), 1446 ( m), 1436 (m), 1423 (m), 1266 (s), 1238 (m), 1197 (m), 1160 (m), 1089 (m) cm "1; HRMS (FAB *) m / z: Cale for C33H38N4O9SNa (MNa *) 689.2257, 689.2243 was found.

EXAMPLE 35 Ketone 15 To a solution of the amine 47 (2.9 mg, 0.00435 mmol, 1 equiv) in a mixture of DMF in dichloromethane (1: 3 (v / v), 640 ml) was added the solid 48 (22 mg, 0.0871 mmol, 20 equiv.), And the red solution was stirred at 23 ° C for 40 minutes, DBU (15 ml, 0 0871 mmol, 20 equiv.) Was added, and the black suspension was stirred at 23 ° C during 15 minutes before adding a saturated aqueous solution of oxalic acid (0.5 ml) The yellow mixture was stirred at 23 ° C for 30 minutes before it was partitioned between a saturated aqueous solution of sodium bicarbonate (10 ml) and ethyl ether ( 30 mi). The organic layer was dried (magnesium sulfate) and concentrated and filtered through a short plug of silica gel with 50% ethyl acetate in hexanes to give the ketone 15 (2.0 mg, 70%). Rf 0.30 (50% ethyl acetate in hexanes); [a] D23 +102 (c = 0.10, CH2Cl2); 1 H NMR (400 MHz, CDCl 3) d 6.70 (s, 1 H, Ar H), 6.12 (d, 1 H, J = 1.7 Hz, OCH 2 O), 6.03 (d, 1 H, J = 1.7 Hz, OCH 2 O), 5.20 (d, 1H, J = 5.5 Hz, OCH2O), 5.13 (d, 1H, J = 5.5 Hz, OCH2O), 5.10 (d, 1H, J = 12.0 Hz), 4.68 (m, 1H), 4.40 (s, 1H), 4.38 (dd, 1H, J = 2.1, 5.1 Hz), 4.22 (dd, 1H, J = 2.1, 10.9 Hz), 4.18 (d, 1H, J = 2.8 Hz), 3.75 (s, 3H, OCH3), 3.58 (m, 1H), 3.57 (s, 3H, OCH3) 3.44 (m, 2H), 2.90 (m, 1H), 2.82 (d, 1H, J = 13.3 Hz), 2.71 (d, 1H, J = 17.3 Hz ), 2.32 (s, 3H, NCH3), 2.22 (s, 3H, ArCH3), 2.17 (m, 1H), 2.16 (s, 3H, ArCH3), 2.05 (s, 3H, AcO); 13C NMR (100 MHz, CD2CI2) d 149.7, 149.5, 148.8, 146.8, 132.3, 130.8, 125.7, 124.6, 122.4, 120.6, 118.2, 114.0, 102.8, 99.7, 78.2, 62.1, 61.9, 60.4, 59.5, 59.1, 57.8 , 55.3, 55.0, 43.8, 41.6, 37.5, 30.5, 30.1, 24.5, 20.4, 16.0, 9.8; FTIR (net film) 2923 (s), 1764 (s), 1730 (s), 1463 (m), 1456 (s), 1447 (m), 1436 (m), 1195 (s), 1160 (m), 1089 (s) cm "1; HRMS (FAB *) m / z: Cale, for C33H36N3? 10S (MH *) 666.2121, 666.2124 was found.

EXAMPLE 36 Tristetrahydroisoquinoline 49 Ketone 15 (1.7 mg, 0.00256 mmol, 1 equiv.), Together with phenethylamine 16 (10 mg, 0.0599 mmol, 23 equiv.) Were dissolved in absolute ethanol (500 ml), and to this solution was added silica gel ( 10 mg) The suspension was stirred at 23 ° C for 10 hours before the mixture was diluted with ethyl acetate (5 mL) and filtered. The filtrate was concentrated, and the residue was purified by flash column chromatography. Instantaneous (5% methanol in dichloromethane) to provide 49 ((1.7 mg, 82%) Rf 0 32 (5% methanol in dichloromethane), [α] D23 -10 (c = 0 10CH2Cl2), 1 H NMR (400 MHz, CD 2 Cl 2) d 6 86 (s, 1 H, Ar H), 6 52 (s, 1 H, Ar H), 6.51 (s, 1 H Ar H), 6 12 (d, 1 H, J = 0 9 Hz, OCH 2 O), 6 06 (d, 1H, J = 0 9 Hz, OCH 2 O), 5 26 (d 1 H, J = 5 6 Hz, OCH 2 O), 5 22 (d, 1 H, J = 56 Hz, OCH 2 O), 5 06 (d, 1H, J = 11 6 Hz), 4.62 (m, 1H), 4.42 (d, 1H, J = 5 4 Hz) 4 36 (s, 1H) 4 25 (d, 1H, J = 27 Hz), 4 19 (dd, 1H, J = 2 3, 11 4 Hz), 3 84 (s 3 H, OCH 3), 369 (s, 3 H, OCH 3), 3 63 (s, 3 H, OCH 3) 3 55 (m 1 H) 348 (m 1 H), 3 42 (m, 1 H), 3 12 (m, 1 H), 3 00 (m 2 H), 2 85 (m, 1 H), 2 76 (dd, 1 H, J = 6 9, 13 7 Hz), 2 62 (m, 2H), 2 45 (m, 2H), 234 (s, 3H, NCH3), 231 (s, 3H, ArCH3), 225 (s, 3H, ArCH3 ), 2 09 (s, 3 H, AcO), 13 C NMR (100 MHz, CD 2 Cl 2) d 144 8, 141 8, 131 1, 125 3, 125 1, 1184, 114 5, 114 3, 110 3, 102 5, 99 5, 61 6, 60 3, 59 7, 59 5, 57 7, 556, 554, 55 1, 547, 43 0, 42 2, 41 6, 40 2, 30 1, 294, 24 5, 204, 159 , 98, FTIR (net film) 3400 (s, br), 2950 (s), 1741 (s), 1512 (s), 1462 (s), 1455 (s), 1442 (s), 1226 (s), 1194 (s), 1088 (s), 1052 (s), 1028 (s) cm "1, HRMS (FAB *) m / z Cale for C42H46N4OnSNa (MNa *) 837 2782, 837 2797 was found EXAMPLE 37 Ecteinascidin 770 (50) 49 Methoxymethyl ether 49 (2 8 mg, 0,0034 mmol, 1 equiv) was dissolved in a mixture of THF-fluoroacetic acid THF water (4 1 1 (v / v), 2.8 ml), and the solution was stirred at 23 ° C for 9 hours The reaction mixture was diluted with toluene (8 mL), and the solution was concentrated at 23 ° C. All volatiles were removed in vacuo through azeotropic stirring with toluene (2 X 2 mL). The residue was purified through of flash column chromatography (5% methanol in dichloromethane) to provide 50 (2.2 mg, 78%). Rf 0.28 (5% methanol in dichloromethane); [α] D23 -35 (c = 0.10, CH2Cl2); 1 H NMR (400 MHz, CD 2 Cl 2) d 6.59 (s, 1 H, Ar H), 6.46 (s, 1 H, Ar H), 6.46 (s, 1 H, Ar H), 6.06 (s, 1 H, OCH 2 O), 6.01 (s, IH , OCH2O), 5.84 (s, 1H), 5.47 (s, 1H), 5.02 (d, 1H, J = 11.6 Hz), 4.62 (m, 1H), 4.28 (m, 2H), 4.18 (d, 1H, J = 2.6 Hz), 4.14 (m, 1H), 3.79 (s, 3H, OCH3), 3.63 (s, 3H, OCH3), 3.46 (m, 1H), 3.41 (m, 1H), 3.08 (m, 1H ), 2.92 (m, 2H), 2.79 (m, 1H), 2.56 (, 1H), 2.3 (m, 2H), 2.28 (m, 2H), 2.32 (s, 3H, NCH3), 2.26 (s, 3H) , ArCH3), 2.19 (s, 3H, ArCH3), 2.03 (s, 3H, AcO); 13C NMR (100 MHz, CD2CI2) d 168.6, 148.9, 146.7, 146.1, 131.1, 126.0, 120.7, 120.0, 118.0, 117.9, 114.5, 113.5, 109.5, 102.8, 66.2, 62.2, 61.4, 60.5, 59.8, 55.9, 54.9, 54.7, 43.4, 41.5, 40.1, 38.5, 30.0, 24.8, 24.4, 20.5, 16.0, 9.9; FTIR (net film) 3400 (s, br), 2950 (s), 1741 (s), 1512 (s), 1462 (s), 1455 (s), 1442 (s), 1226 (s), 1194 (s) ), 1088 (s), 1052 (s), 1028 (s) cm "1; EXAMPLE 38 Ecteinascidin 743 (1) KET713) Ectemascidin 770 (50) (2.2 mg, 0.00285 mmol, 1 equiv) was dissolved in a mixture of acetonitrile and water (3 2 (v / v), 10 mL), and solid silver nitrate (15 mg) was added to this solution. mg, 0088 mmol, 30 equiv) The suspension was stirred at 23 ° C for 11 hours, at which time a mixture of a saturated aqueous solution of sodium chloride and a saturated aqueous solution of sodium bicarbonate (11) was added (v. / v), 2 0 ml) The mixture was vigorously stirred at 23 ° C for 15 minutes, before it was partitioned between a mixture of a saturated aqueous solution of sodium chloride and a saturated aqueous solution of sodium bicarbonate (11). (v / v), 15 mL) and dichloromethane (3 x 10 mL) The combined organic layers were dried (sodium sulfate) and filtered through a pad of Celite. The filtrate was concentrated to give clean 1 (20 mg., 95%), identical in all respects to that of an authentic HPLC sample (Zorbax ODS, C18, 46 mm x 25 cm, flow rate 10 mL / minute) Rt 11 28 minutes 8 cm-nyecc, 25 % CH3CN in H2O with 0 2% TFA), [a] D23 -34 (c = 0 10, CH2Cl2), 1 H NMR (500 MHz, CD2Cl2) d 6 59 (s, 1H, ArH), 647 (s, 1H , Ar H), 646 (s, 1 H, Ar H), 6 03 (d 1 H, J = 1 1 Hz, OCH 2 O), 5 98 (d, 1 H, J = 1 1 Hz, OCH 2 O), 5 80 (s 1 H ), 5 09 (d 1H, J = 10 9 Hz), 4 77 (s (br), 1H), 443 (d, 1H, J = 2 8 Hz), 4 36 (m 1H), 405 (dd, 1 H, J = 24, 11 2 Hz), 3 79 (s, 3 H, OCH 3), 3 61 (s 3 H OCH 3) 3 54 (d, 1 H, J = 4 5 Hz), 3 20 (m, 1 H), 3 10 (m 1 H) 2 84 (m, 2 H), 2 78 (m 1 H), 2 57 (m, 1 H), 240 (dt 1 H J = 15 9 3 3 Hz), 2 32 (s, 3 H, NCH 3 ), 2 26 (s, 3H, ArCH3), 2 17 (s 3H ArCH3) 2 02 (s, 3H AcO), 13C NMR (100 MHz CD2CI2) d 162 2 141 0 121 1 1144, 109 7 102 7 82 1 , 65 3, 62 5 61 2 60.6, 59.7, 56.4, 55.7, 55 5, 42.9, 40.6, 40.3, 30.1, 24.7, 20.5, 16.1, 9.9; FTIR (net film) 3400 (m, br), 2933 (s), 1760 (m), 1741 (s), 1456 (s), 1448 (s), 1430 (s), 1235 (s), 1195 (s) ), 1088 (s) cm "1; Exact Mass (ES *) m / z: Cale, for C39H 4N3OHS (MH *) 762.2697, 762.2683 was found.

APOSTILLAS AND DESCRIPTION OF INFORMATION The following apostilles and / or reference notes have been presented previously. The inventors therefore wish to cite the publications that follow as the potential prior art to the invention claimed herein. In addition, the publications cited below are incorporated herein by reference. (1) The initial investigation in this area is due to Prof. Kenneth L. Rinehart and his group. See, (a) Rinehart, K. L .; Shield, L. S. In Topics in Pharmaceutical Sciences, eds., Breimer, D. D .; Crommehn, D. J. A .; Midha, K. K. (Amsterdam Medical Press, Noordwijk, The Netherlands), 1989, p. 613. (b) Rinehart, K. L .; Holt, T G .; Fregeau, N. L .; Keifer, P. A .; Wilson, G. R .; Perun, T. J, Jr, Sakai, R; Thompson, A. G .; Stroh, J. G .; Shield, L S, Seigler, D S, Li, L. H .; Martin, D. G .; Grimmelikhuijzen, C. J P Gide G J Nat Prod. 1990, 53, 771. (c) Rinehart, K. L. Sakai, R Holt T G., Fregeau, N. L .; Perun, T. J., Jr; Seigler DS, Wilson, GR, Shield, LS Pure Appl Chem 1990, 62, 1277 (d) Rinehart, KL, Holt, TG, Fregeau, NL, Stroh, JG, Keifer, PA, Sun, F, Li, LH, Martin, DGJ Org Chem 1990, 55, 4512 (e) Wright, AE, Forleo, DA, Gunawardana, GP, Gunasekera, SP, Koehn, FE, McConnell, OJJ Org Chem 1990, 55, 4508 (f) Sakai, R, Rinehart, KL, Guan, Y, Wang, H-J Proc Nati Acad Sci USA 1992, 89, 11456 See also, U.S. Patent Nos. 5,089,273, 5,149,804, 5,256,663, and 5,478,932, each incorporated herein by reference (2) Science 1994, 266, 1324 (3) The current clinical plan requested for the administration of three doses of 0 5 mg of 1 per patient, personal communication from Dr Glynn Faircloth PharmaMar USA, Cambridge, MA (4) (a) Ether preparation 3,4 -met? oxod? ox? methoxymethyl by sequencing (1) hcylation in C-2 (3 equiv of BuLi, 3 equiv of tetramethylenediamine in hexane at 0 ° C for 4 hours) and reaction with CH3I (6 equiv. -78? 23 ° C for 15 minutes cough) to exclusively provide the 2-methyl derivative (87%), (2) ortho-operation (2 equiv of BuLi in THF at -30 ° C for 13 hours) and subsequent formulation with 4 equiv of DMF (yield 64 %) (3) cleavage of the protective group MeOCH2 (0 55 equ? V CH3SO3H in CH2Cl2 at 0 ° C) and (4) treatment of 3-met? L-4 5-met? Leod? Ox? resulting salicylaldehyde with 1 5 equiv of NaH in DMF at 0 ° C for 5 minutes and 2 equiv of benzyl bromide at 23 ° C for 40 minutes (total 86%) (b) Prepared from monoalkyl ester of malonic acid through of the conversion to mixed anhydride with BOP chloride (Aldrich) and reaction with 2,2-d? methoxyethanol (5) This step, which involves complete isomepzation to the thermodynamically more stable Z-α-acylaminoacrylic ester, represents a process generally useful for the stereospecific synthesis of said compounds (6) Koenig, KE In Asymmetric Synthesis, JD, Ed, Academic Press, Inc., Orlando, FL, Vol 5, 1985, p 71 (7) The conversion of 4-5 demonstrates a useful method for the control of stereochemistry in the series of tetrahydroisoquinine na (8) (a) This step converts the tertiary hydroxyl group of 13 to the derivative Od? met? lsulfon? or the use of oxa chloride lo-DMSO as reagent is not satisfactory due to the interference by the chloride in the Subsequent steps of the formation and addition of quinone meth (b) This step generates the quinone methylation probably through cycloelimination of the oxysulfonium wall intermediate of the Swern type (9) Barton DHR Elliot JD, Géro, SDJ Chem Soc Perkin Trans 1, 1982 2085 (10) Obtained from Prof. KL Rinehart and PharmaMar USA (11) For previous work on the synthesis of saframycins see (a) Fukuyama, T .; Sachleben, R.A.J. Am. Chem. Soc. 1982, 104, 4957. (b) Fukuyama, T .; Yang, L .; Ajeck, K. L .; Sachleben, R.A.J. Am. Chem. Soc. 1990, 112, 3712, (c) Saito, N .; Yamauchi, R .; Nishioka, H .; Ida, S .; Kubo, A. J. Org. Chem. 1989, 54, 5391. (12) Still, W. C; Kahn, M .; Mitra, A. J. Org. Chem., 1978, 43, 2923. (13) Kofron, W. G .; Baclawski, L. M. J. Org. Chem., 1976, 41, 1979.

The present invention has been described in detail, including its preferred embodiments. However, it will be appreciated by those skilled in the art, after consideration of the present disclosure, that modifications and / or improvements may be made in this invention and remain within the scope and spirit of this invention as set forth in the following claims.

Claims

CLAIMS 1. - A controlled enantiomeric and stereoisomerically process for the preparation of ecteinascidin 743, comprising the steps of: (a) forming an α, β-unsaturated malonic ester of Formula 2, as a mixture of E and Z isomers from 2 - benzyloxy-3-methyl-4,5-methylenedioxybenzaldehyde and allyl 2,2-dimethoxyethyl malonate; (b) stereospecifically converting the compound of the Formula 2 to the compound of Formula 3, through cleavage of selective allyl ester, rearrangement of Curtius, and reaction of the intermediate isocyanate with benzyl alcohol; (c) converting the compound of Formula 3 to the compound of Formula 4 through catalytic hydrogenation on: Rh [(COD), R-DIPAMP] * BF4"; (d) converting the compound of Formula 4 to the compound of Formula 5 through cleavage of acetal, wherein the isolation and the exposure of the resulting aldehyde to BF3"Et2O and sieves of 4 A mol produces the bridged lactone compound of Formula 5; (e) converting the lactone bridge compound of Formula 5 to the free amino phenol compound of the Formula 6 through hydrogenolysis on 10% Pd-C; (f) forming the protected a-amino ester compound of Formula 7 by reacting 3,5-bis-tert-butyl-dimethyl-silyloxy-4-methoxybenzaldehyde and methyl acid malonate; (g) converting the protected a-amino ester compound of Formula 7 to chiral aldehyde 8 through reduction; (h) combining the compounds of Formulas 6 and 8 to provide the key mono-bridge pentacyclic intermediate of Formula 10, as follows: reacting the compounds of Formulas 6 and 8 to give a coupled a-amino phenolic nitrile, followed by O-allylation to give the allyl ether compound of Formula 9; selectively convert the lactone function in the compound of Formula 9 to a lactol making Reacting the compound of Formula 9 with diisobutylaluminum hydride; I i i the r lactol compound; and cyclizing the desill compound to provide the pentacycle compound of Formula 10 through 20 an internal Mannich bisanulation; (i) converting the compound pentacycle of Formula 10 to the compound of Formula 11 through selective trifluoromethanesulfonation of less hindered phenolic hydroxyl; followed by: - > (1) selective silylation of the primary hydroxyl; (2) protection of the remaining phenolic group such as methoxymethyl ether, (3) double desalting, (4) reductive N-methylation, and (5) replacement of CF3SO3 by CH3, (j) oxidizing the phenol compound of Formula 11 by carrying out angular hydroxylation of selective position to give after the deionization the dihydroxy dienone compound of Formula 12, (k) form the compound of Formula 13 by stepping the primary hydroxyl function of the compound of Formula 12 with (S) -N-al β-carbon β1- (9-fluorenylmethox) cysteine, (I) transforming the compound of Formula 13 to the bridged lactone compound of Formula 14 by, (1) the reaction of the compound of Formula 13 with a Swern reagent generated in situ, (2) followed by the formation of the quinone methide exend, (3) the destruction of excess reagent from Swern, (4) the addition of N-ter-but? L-N ', N "- tetramethylguanidine in excess to generate the 10-membered lactone bridge, and (5) the addition of an excess of Ac2O to acylate the group resulting phenoxide, (m) unfold the N-allyloxycarbonyl group of the compound of the Formula 14 and oxidizing the resulting a-amino lactone to the corresponding lactone aketo by transformation thereby forming the compound of Formula 15; (n) stereospecifically forming a spiro tetrahydro-isoquinoline compound by reacting the compound of Formula 15 with 2- [3-hydroxy-4-methoxy-phenyl] ethylamine; (o) followed by the cleavage of methoxymethyl and replacement of CN by HO to form the compound of the Formula 1, ecteinascidin 743.
2. A controlled enantiomeric and stereoisomerically process for the preparation of ecteinascidin 743, comprising the steps of: (a) forming an α, β-unsaturated malonic ester of Formula 2, as a mixture of isomers E and Z from 2-benzyloxy-3-methyl-4,5-methylenedioxybenzaldehyde and allyl 2,2-dimethoxyethyl malonate; (b) stereospecifically converting the compound of the Formula 2 to the compound of Formula 3, through cleavage of the ester to the ionic ion, rearrangement of Curtius, and the reaction of the intermediate isocyanate with benzyl alcohol; (c) converting the compound of Formula 3 to the compound of Formula 4 through catalytic hydrogenation over: Rh [(COD) R, ft-DIPAMP] * BF4"; (d) converting the compound of Formula 4 to the compound of Formula 5 through cleavage of acetal, wherein the isolation and exposure of the resulting aldehyde to BF3"Et2O and sieves of 4 A mol produces the bridged lactone compound of Formula 5, (e) converting the lactone compound to bridge of Formula 5 to the free amino phenol compound of Formula 6 through hydrogenolysis over 10% Pd-C; (f) forming the protected a-amino ester compound of Formula 7 by reacting 3,5-bis-tert-butyl-dimethyl-s-yloxy-4-methoxybenzaldehyde and methyl acid malonate; (g) converting the protected a-amino ester compound of Formula 7 to chiral aldehyde 8 through reduction, (h) combining the compounds of Formulas 6 and 8 to provide the key mono-bridge pentacyclic intermediate of Formula 10, as follows: reacting the compounds of Formulas 6 and 8 to give an a-amino n tt p lo phenolic coupled, followed by O-allylation to give the allylic ether compound of Formula 9; selectively converting the lactone function in the compound of Formula 9 to a lactol by reacting the compound of Formula 9 with diisobutylaluminum hydride, leaving the lactol compound, and removing the de-oiled compound to provide the pentacyclo compound of Formula 10 through an internal Mannich bisanulation, i) converting the pentacycle compound of Formula 10 to the compound of Formula 11 through selective trifluoromethanesulfonation of less hindered phenolic hydroxyl; followed by: (1) selective silylation of the primary hydroxyl; (2) protection of the remaining phenolic group such as methoxymethyl ether; (3) double dealkylation; (4) Reductive N-methylation; and (5) replacement of CF3SO3 with CH3; (j) oxidizing the phenol compound of Formula 11 by performing angular hydroxylation of selective position to give, after de-allylation, the dihydroxy dienone compound of Formula 12; (k) forming the compound of Formula 13 by esterifying the primary hydroxyl function of the compound of Formula 12 with (S) -N-allyloxycarbonyl-S- (9-fluorenylmethyl) cysteine; (I) transforming the compound of Formula 13 to the bridged lactone compound of Formula 14 by; (1) the reaction of the compound of Formula 13 with a Swern reagent generated in situ; (2) followed by the formation of the quinone quinidine exend; (3) the destruction of excess Swern reagent; (4) the addition of excess N-tert-butyl-N ', N "-tetramethylguanidine to generate the 10-membered lactone bridge, and (5) the addition of an excess of Ac 2 O to acylate the resulting phenoxide group, ( m) unfolding the N-allyloxycarbonyl group of the compound of the Formula 14 and oxidizing the resulting a-amino lactone to the corresponding lactone aketo by transformation thereby forming the compound of Formula 15, (n) forming stereospecifically a spiro tetrahydroisoquinone compound by reacting the compound of Formula 15 with 2- [3-h? Drox? -4-methox? -fen? L] et? Lam? Na, and (o) cleavage of methoxymethyl to form the compound of Formula 50, ecteinascidin 770 3 - A process controlled enantiomépca and estereoisomépcamente for the preparation of the synthetic intermediate compound of ecteinascidma, spiro tetrahydro-isoquinoline of Formula 49, comprising the steps of (a) forming an α, β-unsaturated malonic ester of Formula 2, as a mixture of E and Z isomers from 2-benzyl-3-methyl-4,5-methylene-oxo-benzaldehyde and allyl-2,2-dimethoxyethyl-malonate, (b) stereospecifically converting the compound of Formula 2 to the compound of Formula 3, through cleavage of selective allyl ester, rearrangement of Curtius, and reaction of the intermediate isocyanate with benzyl alcohol, (c) converting the compound of Formula 3 to the compound of Formula 4 through catalytic hydrogenation on Rh [(COD ) R, f? -DIPAMP] + BF4, (d) converting the compound of Formula 4 to the compound of Formula 5 through cleavage of acetal, wherein the isolation and exposure of the resulting aldehyde to BF3 »Et2O and sieves of 4 A moles produces the bridged lactone compound of Formula 5, (e) converting the lactone compound to the bridge of Formula 5 to the free amino phenol compound of Formula 6 through hydrogenolysis over 10 Pd-C. %, (f) forming the protected a-amino ester compound of Formula 7 by reacting 3,5-b? s-tert-but? ld? met? l-lox? -4-methox? benzaldehyde and acid malonate of methyl, (g) converting the protected a-amino ester compound of Formula 7 to chiral aldehyde 8 through reduction, (h) combining the compounds of Formulas 6 and 8 to provide the key mono-bridge pentacyclic intermediate of Formula 10, as follows to react the compounds of Formulas 6 and 8 to give a coupled phenolic a-amino nitploy, followed by O-allylation to give the allyl ether compound of Formula 9, selectively converting the lactone function in the compound of Formula 9 to a lactol by reacting the compound of Formula 9 with dnsobutylaluminium hydride, Sea the lactol compound, and cichzar the desilylated compound to provide the pentacyclo compound of Formula 10 through an internal Mannich bisanulation, i) convert the pentacycle compound of Formula 10 to the compound of Formula 11 through selective phthalimomethanesulfonation of less hindered phenolic hydroxyl, followed by (1) selective silylation of the primary hydroxyl, (2) protection of the remaining phenolic group such as methoxymethyl ether, (3) double sahlation, (4) reductive N-methylation, and (5) replacement of CF3SO3 by CH3, (j) oxidizing the phenol compound of Formula 11 by performing selective position angular hydroxylation to give after dihydroxy dihydroxy dienone compound of Formula 12, (k) forming the compound of Formula 13 by stepping the primary hydroxyl function of the compound of Formula 12 with (S) -N-al? lox? carbon? lS- (9-fluoren? lmet? l) cysteine, (I) transforming the compound of Formula 13 to the bridge lactone compound of Formula 14 by (1) the reaction of the compound of Formula 13 with a Swern reagent generated in situ, (2) followed by the formation of the quinone methide exend, (3) the destruction of excess Swern reagent, (4) the addition of N-ter-but? l-N ', N "- tetramethylguanidine in excess to generate the 10-member lactone bridge , and (5) the addition of an excess of Ac2O to acylate the resulting phenoxide group, (m) unfold the N- group ahloxycarbonyl of the compound of Formula 14 and oxidizing the resulting α-amino lactone to the corresponding lactone aketo by transformation thereby forming the compound of Formula 15, (n) forming stereospecifically a spiro tetrahydro-isoquinoline compound of Formula 49 by reacting the compound of Formula 15 with 2- [3- h? drox? -4-methox? -fen? l] et? lam? na 4 - A process controlled enantiomépca and estereoisomépcamente for the preparation of the synthetic intermediate of ecteinascidina Formula 15, which comprises the steps of (a) forming an α, β-unsaturated malonic ester of Formula 2, as a mixture of E and Z isomers from 2-benzyl-3-met-1-4 , 5-meth? Ood? Ox? Benzaldehyde and 2, 2-dimethoxyethyl malonate, (b) stereospecifically converting the compound of Formula 2 to the compound of Formula 3, by cleaving the ester to the ionic ion, rearrangement of Curtius, and the reaction of the intermediate isocyanate or with benzyl alcohol; (c) converting the compound of Formula 3 to the compound of Formula 4 through catalytic hydrogenation over: Rh [(COD) f ?, R-DIPAMP] * BF4"(d) converting the compound of Formula 4 to compound of Formula 5 through cleavage of acetal, wherein the isolation and exposure of the resulting aldehyde to BF3 »Et2O and sieves of 4 A mol produces the compound of lactone bridge of Formula 5; (e) convert the bridged lactone compound of Formula 5 to the free amino phenol compound of Formula 6 through hydrogenolysis over 10% Pd-C; (f) forming the protected a-amino ester compound of Formula 7 by reacting 3,5-bis-tert-butyl-dimethyl-silyloxy-4-methoxybenzaldehyde and methyl acid malonate; (g) converting the protected a-amino ester compound of Formula 7 to chiral aldehyde 8 through reduction; (h) combining the compounds of Formulas 6 and 8 to provide the key mono-bridge pentacyclic intermediate of Formula 10, as follows: reacting the compounds of Formulas 6 and 8 to give a coupled a-amino phenolic nitrile, followed by O-allylation to give the allyl ether compound of Formula 9; selectively converting the lactone function in the compound of Formula 9 to a lactol by reacting the compound of Formula 9 with diisobutylaluminum hydride; desilylate the lactol compound; and cyclizing the desilylated compound to provide the pentacyclo compound of Formula 10 through an internal Mannich bisanulation; (i) converting the compound pentacycle of Formula 10 to the compound of Formula 11 through selective trifluoromethanesulfonation of less hindered phenolic hydroxyl; followed by: (1) selective silylation of the primary hydroxyl; (2) protection of the remaining phenolic group such as methoxymethyl ether; (3) double dealkylation; (4) Reductive N-methylation; and (5) replacement of CF3SO3 with CH3; (j) oxidizing the phenol compound of Formula 11 by carrying out angular hydroxylation of selective position to give after diilelation the dihydroxy dienone compound of Formula 12; (k) forming the compound of Formula 13 by esterifying the primary hydroxyl function of the compound of Formula 12 with (S) -N-allyloxycarbonyl-S- (9-fluorenylmethyl) cysteine; (I) transforming the compound of Formula 13 to the bridged lactone compound of Formula 14 by; (1) the reaction of the compound of Formula 13 with a Swern reagent generated in situ; (2) followed by the formation of the quinone quinidine exend; (3) the destruction of excess Swern reagent; (4) the addition of excess N-tert-butyl-N ', N "-tetramethylguanidine to generate the 10-membered lactone bridge, and (5) the addition of an excess of Ac 2 O to acylate the resulting phenoxide group; m) unfolding the N-allyloxycarbonyl group of the compound of the Formula 14 and oxidizing the resulting a-amino lactone to the corresponding lactone a-keto by transformation thereby forming the compound of Formula 15. 5. A controlled enantiomeric and stereoisomerically process for the preparation of the synthetic ecteinascidin intermediate of Formula 14, comprising the steps of: (a) forming a α, β-unsaturated malonic ester of Formula 2, as a mixture of E and Z isomers from 2-benzyloxy-3-methyl-4,5-methylenedioxybenzaldehyde and 2, 2- allyl dimethoxyethyl malonate; (b) stereospecifically converting the compound of Formula 2 to the compound of Formula 3, through cleavage of selective allyl ester, rearrangement of Curtius, and reaction of the intermediate isocyanate with benzyl alcohol; (c) converting the compound of Formula 3 to the compound of Formula 4 through catalytic hydrogenation over: Rh [(COD) R, R-DIPAMP] * BF4"(d) converting the compound of Formula 4 to the compound of Formula 5 through cleavage of acetal, where the isolation and exposure of the resulting aldehyde to BF3"Et2O and sieves of 4 A mol produces the bridged lactone compound of Formula 5; Lactone bridging compound of Formula 5 to the free amino phenol compound of Formula 6 through hydrogenolysis on 10% Pd-C; (f) forming the protected a-amino ester compound of Formula 7 by reacting 3,5-bis-tert-butyl-dimethyl-silyloxy-4-methoxybenzaldehyde and methyl acid malonate; (g) converting the protected a-amino ester compound of Formula 7 to chiral aldehyde 8 through reduction; (h) combining the compounds of Formulas 6 and 8 to provide the key mono-bridge pentacyclic intermediate of Formula 10, as follows: reacting the compounds of Formulas 6 and 8 to give a coupled a-amino phenolic nitrile, followed by O-allylation to give the allylic ether compound of Formula 9, selectively converting the lactone function in the compound of Formula 9 to a lactol by reacting the compound of Formula 9 with dnsobutylaluminum hydride, desilylating the lactol compound , and cycling the desired compound to provide the pentacyclo compound of Formula 10 through an internal Mannich bisanulation, (i) converting the pentacycle compound of Formula 10 to the compound of Formula 11 through selective hydroxyl tpfluoromethanesulfonation less hindered phenolic, followed by (1) selective sililation of the primary hydroxyl, (2) protection of the remaining phenolic group such as methoxymethyl ether, ( 3) double dealkylation, (4) reductive N-methylation, and (5) replacement of CF3SO3 by CH3 (j) oxidize the phenol compound of Formula 11 by performing angular hydroxylation of selective position to give after dihydylation the dihydroxy compound dienone of Formula 12, (k) forming the compound of Formula 13 by stepping the primary hydroxyl function of the compound of Formula 12 with (S) -N-allyloxycarbonyl-S- (9-fluorenylmethyl) cysteine; (I) transforming the compound of Formula 13 to the bridged lactone compound of Formula 14 by; (1) the reaction of the compound of Formula 13 with a Swern reagent generated in situ; (2) followed by the formation of the quinone quinidine exend; (3) the destruction of excess Swern reagent; (4) the addition of excess N-tert-butyl-N ', N "-tetramethylguanidine to generate the 10-membered lactone bridge, and (5) the addition of an excess of Ac 2 O to acylate the resulting phenoxy group. - A controlled enantiomeric and stereoisomerically process for the preparation of the synthetic intermediate of ecteinascidin of Formula 13, comprising the steps of: (a) forming an α, β-unsaturated malonic ester of Formula 2, as a mixture of E isomers and Z from 2-benzyloxy-3-methyl-4,5-methylenedioxybenzaldehyde and allyl 2,2-dimethoxyethyl malonate: (b) stereospecifically converting the compound of the Formula 2 to the compound of Formula 3, through cleavage of ester to selective ion, rearrangement of Curtius, and reaction of the intermediate isocyanate with benzyl alcohol; (c) converting the compound of Formula 3 to the compound of Formula 4 through catalytic hydrogenation over: Rh [(COD) R, R-DIPAMP] * BF4"(d) converting the compound of Formula 4 to the compound of Formula 5 through cleavage of acetal, wherein the isolation and exposure of the resulting aldehyde to BF3"Et 2 O and sieves of 4 A mol produces the bridged lactone compound of Formula 5. (e) converting the compound of bridge lactone of Formula 5 to the free amino phenol compound of Formula 6 through hydrogenolysis over 10% Pd-C; (f) forming the protected a-amino ester compound of Formula 7 by reacting 3,5-bis-tert-butyl-dimethyl-silyloxy-4-methoxybenzaldehyde and methyl acid malonate; (g) converting the protected a-amino ester compound of Formula 7 to chiral aldehyde 8 through reduction; (h) combining the compounds of Formulas 6 and 8 to provide the key mono-bridge pentacyclic intermediate of Formula 10, as follows: reacting the compounds of Formulas 6 and 8 to give a coupled a-amino phenolic nitrile, followed by O-allylation to give the allylic ether compound of Formula 9; selectively converting the lactone function in the compound of Formula 9 to a lactol by reacting the compound of Formula 9 with dnsobutylaluminum hydride, de-lacting the lactol compound, and ciching the desilylated compound to provide the pentacycle compound of Formula 10 through an internal Mannich bisanulation, (i) converting the pentacyclo compound of Formula 10 to the compound of Formula 11 through selective phenol hydroxyl selective sulfonating with less impeded, followed by (1) selective hydroxyl primary (2) protection of the remaining phenolic group such as methoxymethyl ether, (3) double dealkylation, (4) reductive N-methylation, and (5) replacement of CF3SO3 with CH3, (j) oxidizing the phenol compound of Formula 11 by carrying out angular hydroxylation of selective position to give, after desilylation, the dihydroxy dienone compound of Formula 12, (k) to form the compound of Formula 1 3 isopficando the primary hydroxyl function of the compound of Formula 12 with (S) -N-al? Lox? Carbon? LS- (9-fluoren? Lmet? L) cysteine 7 - A process controlled enantiomépca and stereoisomepcamente for the preparation of the intermediary Synthetic of ecteinasctdin of Formula 12, comprising the steps of (a) forming an α, β-unsaturated malonic ester of Formula 2, as a mixture of E and Z isomers from 2-benzyl? -3 -met? l-4,5-met? leod? ox? benzaldehyde and 2,2-dimethoxyethyl malonate of aillo, (b) stereospecifically converting the compound of Formula 2 to the compound of Formula 3, through ester cleavage selective allylic, rearrangement of Curtius, and the reaction of the intermediate isocyanate with benzyl alcohol, (c) converting the compound of Formula 3 to the compound of Formula 4 through catalytic hydrogenation on Rh [(COD) R, R-DIPAMP] * BF4, (d) converting the compound of Formula 4 to the compound of Formula 5 through s of acetal cleavage, wherein the isolation and exposure of the resulting aldehyde to BF3 * Et2O and sieves of 4 A mol produces the bridged lactone compound of Formula 5, (e) converting the lactone compound to the bridge of the Formula 5 to the free amino phenol compound of Formula 6 through hydrogenolysis on 10% Pd-C, (f) forming the protected a-amino ester compound of Formula 7 by reacting 3,5-b? s-tert-but? ld? met? l-lox? -4-methox? benzaldehyde and acid malonate of methyl, (g) converting the protected a-amino ester compound of Formula 7 to chiral aldehyde 8 through reduction (h) combining the compounds of Formulas 6 and 8 to provide the key mono-bridge pentacyclic intermediate of Formula 10 , as follows. reacting the compounds of Formulas 6 and 8 to give a coupled a-amino phenolic nitrile, followed by O-allylation to give the allyl ether compound of Formula 9; selectively converting the lactone function in the compound of Formula 9 to a lactol by reacting the compound of Formula 9 with diisobutylaluminum hydride; desilylate the lactol compound, and cyclize the desilylated compound to provide the pentacyclo compound of Formula 10 through 15 an internal Mannich bisanulation; (i) converting the compound pentacycle of Formula 10 to the compound of Formula 11 through selective pfluoromethansulfonation of less hindered phenolic hydroxyl, followed by selective (20) selective hydroxyl hydroxide, (2) protection of the remaining phenolic group as methoxymethyl ether, (3) double dealkylation, (4) reductive N-methylation, and (5) replacement of CF3SO3 by CH3, "> (j) oxidize the phenol compound of Formula 11 by effecting selective position angular hydroxylation to give after desilylation the dihydroxy dienone compound of Formula 12. 8. An enantiomerically and stereoisomerically controlled process for the preparation of the synthetic ecteinascidin intermediate of Formula 11, comprising the steps of: (a) forming a malonic ester at , β-unsaturated of Formula 2, as a mixture of E and Z isomers from 2-benzyloxy-3-methyl-4,5-methylenedioxybenzaldehyde and 2,2-dimethoxyethyl malonate from ilo; (b) stereospecifically converting the compound of Formula 2 to the compound of Formula 3, through cleavage of selective allyl ester, rearrangement of Curtius, and reaction of the intermediate isocyanate with benzyl alcohol; (c) converting the compound of Formula 3 to the compound of Formula 4 through catalytic hydrogenation over: Rh [(COD) R, R-DIPAMP] * BF4"(d) converting the compound of Formula 4 to the compound of Formula 5 through cleavage of acetal, wherein the isolation and exposure of the resulting aldehyde to BF3"Et 2 O and sieves of 4 A mol produces the bridged lactone compound of Formula 5. (e) converting the compound of bridge lactone of the Formula 5 to the free amino phenol compound of Formula 6 through hydrogenolysis on 10% Pd-C; (f) forming the protected a-amino ester compound of Formula 7 by reacting 3.5 bis-tert-butyl-dimethyl-silyloxy-4-methoxybenzaldehyde and methyl acid malonate: (g) converting the protected a-amino ester compound of Formula 7 to chiral aldehyde 8 through reduction; compounds of Formulas 6 and 8 to provide the pentacyclic mono-bridge intermediate bird of Formula 10, as follows: react the compounds of Formulas J6 and 8 to give a coupled phenolic a-amino nitrile, followed by O-allylation to give the allylic ether compound of Formula 9; Selectively converting the lactone function in the compound of Formula 9 to a lactol by reacting the compound of Formula 9 with diisobutylaluminum hydride; desilylate the lactol compound; and 20 cyclizing the side compound to provide the pentacycle compound of Formula 10 through an internal Mannich bisanulation; (i) converting the compound pentacycle of Formula 10 to the compound of Formula 11 through "> Selective trifluoromethanesulfonation of less hindered phenolic hydroxyl followed by: (1) selective silylation of the primary hydroxyl, (2) protection of the remaining phenolic group such as methoxymethyl ether, (3) double dealkylation, (4) N-reductive methylation and (5) replacement of CF3SO3 by CH3 9.- A controlled enantiomeric and stereoisomerically process for the preparation of the synthetic ecteinascidin intermediate of Formula 14, comprising the steps of: (a) forming a malonic ester a, β- unsaturated of Formula 2, as a mixture of E and Z isomers from 2-benzyloxy-3-methyl-4,5-methylenedioxybenzaldehyde and 2,2-dimethoxyethyl malonate of allyl (b) stereospecifically converting the compound of the Formula 2 to the compound of Formula 3, through cleavage of selective allyl ester, rearrangement of Curtius, and reaction of the intermediate isocyanate with benzyl alcohol; (c) converting the compound of Formula 3 to the compound of Formula 4 through catalytic hydrogenation over: Rh [(COD) R, R-DIPAMP] * BF4"(d) converting the compound of Formula 4 to the compound of Formula 5 through cleavage of acetal, wherein the isolation and exposure of the resulting aldehyde to BF3 »Et2O and sieves of 4 A mol produces the bridged lactone compound of Formula 5; (e) converting the lactone bridge compound of Formula 5 to the free amino phenol compound of Formula 6 through hydrogenolysis on 10% Pd-C; (f) forming the protected a-amino ester compound of Formula 7 by reacting 3,5-bis-tert-butyl-dimethyl-silyloxy-4-methoxybenzaldehyde and methyl acid malonate; (g) converting the protected a-amino ester compound of Formula 7 to chiral aldehyde 8 through reduction; (h) combining the compounds of Formulas 6 and 8 to provide the key mono-bridge pentacyclic intermediate of Formula 10, as follows: reacting the compounds of Formulas 6 and 8 to give an a-amino phenolic nitrile coupled, followed by O-allylation to give the allylic ether compound of Formula 9; selectively converting the lactone function in the compound of Formula 9 to a lactol by reacting the compound of Formula 9 with diisobutylaluminum hydride; desilylate the lactol compound; and cyclizing the frayed compound to provide the pentacycle compound of Formula 10 through an internal Mannich bisanulation. The α, β-unsaturated diester compound of Formula 2: The benzyl carbamate compound of the Formula: The protected amino acid compound of Formula 4: The lactone compound of Formula 5: The aminophenol compound of Formula 6: 5. - The aminonitrile compound of Formula 37: 6. The allyl ether compound of Formula 9: 17. The compound of Formula 38: 18 - The compound of Formula 39: 19. - The triol compound of Formula 10: 20. The aryl triflate compound of Formula 40: ? or 21.- The silyl ether compound of Formula 14: 22. - The methoxymethyl ether compound of Formula 42: 23. - The aminophenol compound of Formula 43: 24 -. 24 - The phenol compound of Formula 44: 25. - The phenol compound of Formula 11 26 -. 26 - The hydroxy dienone compound of Formula 45: oraocs 27.- The diol compound of Formula 12: 28. - THE ester compound of Formula 13: 29. - The lactone compound of Formula 14: The amine compound of Formula 47: - The ketone compound of Formula 15: - The tristetrahydroisoquinoline compound of Formula 48: