CZ306596A3 - Process for preparing prototypes of renin inhibitors - Google Patents

Abstract

Prototype renin inhibitors having general structure (I), where n is 0-3 inclusive, A are either both hydrogen atoms or together are a single carbon-nitrogen bond, R1 is hydrogen, or hydrocarbylcarboxy wherein the hydrocarbyl entity is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, R2 and R3 or independently alkyl of 1 to 4 carbon atoms, R4 is alkyl of 1 to 6 carbon atoms or a substituent of aliphatic character such as, for example, butyl, 2-morpholinoethyl or 2-carbamoyl-2-methyl-propyl, R5 is selected from aromatics, substitued aromatics and heteroaromatics, substituted or unsubstituted cycloalkyls, cycloalkenes having 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy of 3 to 10 carbon atoms and alkoxy derivatives such as 3-methoxy-propyloxy, primary and secondary amides, alkyl derivatives, are prepared by novel multistep synthesis. Such compounds are valuable intermediates for the manufacture of pharmaceutical such as Renin inhibitors and HIV-protease inhibitors.

Description

Technical field

The invention falls within the field of biological activity related to enzymatic and similar specific chemical cleavage of angiotensinogen by cleavage to angiotensin-I, then to angiotensin-II, which, as is well known, binds receptors initiating biological activity.

BACKGROUND OF THE INVENTION

It has long been known that compounds of similar chemical properties and general stereochemical conformations can be used either as a substitute for activators to produce positive effects or to block specific receptors to prevent negative effects. In practice, despite the considerable advances in the knowledge of the conformational structure of chemical compounds, neither the exact conformation of a particular compound, nor its chemical synthesis nor its biological properties are convincingly predictable. The compounds of the present invention are important intermediates for the preparation of prototype renin inhibitors. Renin inhibitors prevent the formation of angiotensin-II, a potent vasoconstrictor, and are therefore potent antihypertensive agents. The basic action of renin, as described below, is that angiotensinogen is first cleaved to form a specific fragment (angiotensin-I), then further cleaved to a second specific fragment (angiotensin-II) that binds the respective receptor, thereby initiating biological activity:

-2renin

AND

Asp-Arg-Val-Ileu-His-Pro-Phe-His-Leu-Val-Ileu-Val-Ileu-His ▼ angiotensin converting enzyme

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu

AND

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe

A-II receptor -► biological activity

SUMMARY OF THE INVENTION

The present invention provides a new stereoselective chemical synthesis of compounds of formula (I)

Although the present invention describes specific compounds and their preparation processes, the principles of the present invention are as well

It is understood that the present invention is not limited to these compounds and processes for their preparation.

The present invention presupposes a deep knowledge of stereospecific synthetic organic chemistry. This field is developing rapidly and much time is needed to keep up with general trends, especially in the field of human medicine applications.

The Applicant is not aware of any prior art relating to this specific nature of the invention described herein.

An essential feature of the present invention is the development of novel compounds useful as prototypes for renin inhibitors. Another essential feature is the process for preparing these new compounds by new chemical processes. An additional feature is to find practical synthesis schemes for the preparation of these novel compounds. Another additional feature is. preparing these novel compounds as stereoisomerically pure as possible. Another feature is the characterization of all the compounds thus prepared as much as possible. Other features will be apparent to those skilled in the art from the following description, claims, and disclosed schemes and formulas.

The present invention provides a chemical compound of formula (I)

-4where n means zero to 3 inclusive,

And they are either hydrogen or together they form a single carbon-nitrogen bond,

R 1 represents a hydrogen atom or a carboxy group substituted by a hydrocarbon radical, wherein the hydrocarbon radical is selected from the group consisting of C 1 -C 6 alkyl or C 7 -C 10 aralkyl;

R2 and R3 are independently C1-C4alkyl,

R 4 represents an alkyl group having 1 to 6 carbon atoms or a substituent of an aliphatic nature,

R 5 is selected from the group consisting of aromatic radicals, substituted aromatic radicals and heteroaromatic radicals, substituted or unsubstituted cycloalkyl groups, cycloalkenyl groups having 3 to 8 carbon atoms, with substituents selected from the group consisting of alkyl, alkoxy of 3 to 10 carbon atoms, and alkoxy derivatives , primary and secondary amides and alkyl derivatives. Alkyl derivatives of primary and secondary amides are, for example, primary and secondary carbamoylalkyl groups. Preferably n is zero.

Aliphatic substituents are, for example, butyl, 2-morpholinoethyl or 2-carbamoyl-2-methylpropyl. Alkoxy derivatives are, for example, alkoxyalkoxy groups such as 3-methoxypropyloxy.

The two substituents A together may form a single carbon-nitrogen bond together. In one variation, R 1 is preferably a carboxy group substituted with an alkyl group and the alkyl group has 1 to 6 carbon atoms. A preferred compound is (1'S, 2S, 3R, 3'R, 5S) -5 - [(3'-Butylcarbamoyl) -1 'hydroxybutyl-3-methyl'-2-phenylpyrrolidine-1-carboxylic acid tert-butyl ester

-5acids. Another preferred compound is (1'S, 2S, 3R, 3'R, 5S) 5 - [(3'-butylcarbamoyl) -1'-hydroxybutyl] -3-methyl-2-phenylpyrrolidine.

In a second variant, R 1 is preferably a carboxy group substituted with an aralkyl group and the aralkyl group has 7 to 10 carbon atoms. A preferred compound is (1'S, 2S, 3R, 3'R, 5S) -5 - [(3'-Butylcarbamoyl) -1'-hydroxybutyl] -3-methyl-2-phenylpyrrolidine-1-carboxylic acid benzyl ester.

Both A substituents can be hydrogen atoms when R 1 is preferably a carboxy group substituted with an alkyl group and the alkyl group has 1 to 6 carbon atoms. A preferred compound is (2R, 4S, 5S, 7R) -5 - [[1,1-dimethylethoxy) carbonyl] amino] -4-hydroxy-2,7-dimethyl-8-phenyloctanoic acid butylamide. Another preferred compound is (2R, 4S, 5S, 7R) -5-amino-4-hydroxy-2,7-dimethyl-8-phenyloctanoic acid butylamide.

The invention further provides processes for the preparation of a first chemical compound of formula (I)

where n is zero to 3 inclusive,

And they are either hydrogen or they form a single carbon-nitrogen bond,

R 1 represents a hydrogen atom or a carboxy group substituted with a hydrocarbon radical, wherein the hydrocarbon radical is selected from

-6-C 1 -C 6 alkyl or C 7 -C 10 aralkyl;

R1 and R3 are independently C1-C4alkyl,

R a represents a C 1 -C 6 alkyl group or an aliphatic substituent such as butyl, 2-morpholinoethyl or 2-carbamoyl-2-methylpropyl,

R 5 is selected from the group consisting of aromatic radicals, substituted aromatic radicals and heteroaromatic radicals, substituted or unsubstituted cycloalkyl groups, cycloalkenyl groups having 3 to 8 carbon atoms, with substituents selected from the group consisting of alkyl, alkoxy of 3 to 10 carbon atoms, and alkoxy derivatives such as 3-methoxypropyloxy, primary and secondary amides, and alkyl derivatives. These methods include a step selected from the group consisting of (a) hydrogenolysis of a second compound of the above formula wherein both A together form a single carbon-nitrogen bond and R 1 is a carboxy group substituted by an alkyl group wherein the alkyl group has 1 to 6 carbon atoms in the presence Pd (OH) 2 / C, (b) hydrogenolysing a third compound of the above formula wherein both A forms a single carbon-nitrogen bond and R 1 is a carboxy group substituted with an aralkyl group wherein the aralkyl group has 7 to 10 carbon atoms in the presence of Pd ( OH) 2 / C and a dialkyl dicarbonate wherein both alkyl groups are the same and have 1 to 6 carbon atoms, and (c) reacting a fourth compound of formula II

R, (II)

-Ίwhere η means zero to 3 inclusive,

R1 is a carboxy group substituted by a hydrocarbon radical, wherein the hydrocarbon radical is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms,

R @ ₂ and R @ 3 are each independently C1 -C4 alkyl, R @ 1 N, NH2 Me @, wherein R @ 1 is C1 -C6 alkyl. In both formulas, n is preferably zero. A preferred method of claim 14 comprises the hydrogenolysis step of said second compound. Another preferred method comprises the hydrogenolysis step of said third compound. Another preferred method comprises the step of reacting said fourth compound, wherein in a preferred step R 1 is a carboxy group substituted with an alkyl group wherein the alkyl group has 1 to 6 carbon atoms. Alternatively, R 1 may be a carboxy group substituted with an aralkyl group wherein the aralkyl group has 7 to 10 carbon atoms.

A brief description of the formulas and schemes is given below. Scheme 1 shows a first synthetic process of the invention.

Description of preferred embodiments ...

The chemical formulas of some of the compounds of the invention are shown below.

hydrophobic portion

The chemical formulas of the first and second compounds are given below:

Detailed steps of the synthetic procedure from (S) -methylmandelate 4 to the starting precursors, (2S, 3R) -3-methyl-5-oxo-2-phenylpyrrolidine-1-carboxylic acid tert-butyl ester 12 and (2S, 3R) 3 -methyl-2-phenyl-3,4-dihydro-2H-pyrrole 14 are as follows:

[α] D ⁺ 85 ° (c = 1.55) * -5, R = Bom, [α] D + 119 ° (c = 1.24)

13, R = H, [α] D -27 ° (c = 1.055), mp = 105-106 ° C

-10a) PhCH ₂ OCH ₂ Cl (Bom-Cl), iPr ₂ EtN, CH ₂ Cl ₂ , 100 hours, 83%,

b) 1) DIBAL-H, toluene, -78 ° C, 3.5 hours, 2) MeOH, -78 ° C, 30 minutes, 3) methyltriphenylphosphoranylideneacetate, room temperature, 20 minutes, 75% trans, 6% cis,

c) Me ₂ CuLi ₂ .3TMSCl, THE, -78 ° C, 2 hours,

d) TMSBr, CH ₂ Cl ₂ , -23 ° C to room temperature, 72% for steps

c) and d),

e) 1) 0.5 N NaOH, MeOH, 0 ° C to room temperature, 2 hours, 2)

N HCl, 3) CH ₂ N ₂ -Et ₂ O, EtOAc, 0 ° C, 98%,

f) (PhO) ₂ P (O) N 3, DEAD, PPh 3, THF, 0 ° C to room temperature, 16 hours, 89%,

g) 1,3-propanediol, R ₂ EtN, MeOH, room temperature, 18 hours,%,

h) (BOC) ₂ O, iPr ₂ EtN, DMPA, CH ₂ Cl ₂ , room temperature, 24 hours,%,

i) 1) DIBAL-H, toluene, -78 ° C, 1 hour, 2) MeOH, -78 ° C, 20 minutes, 77%,

j) PPh 2, toluene, 16 hours.

This step starts from methylmandelate 4, in which the hydroxyl group is protected by the formation of bromo (benzyloxymethyl) acetal 5 in 83% yield. The carbon chain is then extended by effectively inserting the trans double bond to form a phenyl-trans-2-butenoic acid homolog 6, in a yield of 75% with 6% of the cis isomer. Compound 6 is then methylated to give unpurified compound 7 as a 94: 6 mixture of diastereoisomers, including 5% crude deconjugated product in about 96% yield. Crude compound 7 was cyclized to lactone 8, phenylmethyldihydrofuranone, in 72% yield (from compound 6). Compound 8 was converted to the equivalent hydroxymethyl ester 9 by hydrolysis and methylation in 98% yield. Compound 9 was converted to the equivalent azidoester 10 in 89% yield as a 96: 4 diastereoisomeric mixture. Compound 10 is in one

The method was cyclized to lactam 11, methylphenylpyrrolidinone in 86% yield, followed by protection of the hydrogen at the amino group with a carboxybutyl ester to give 12 in 99% yield. In an alternative method, compound 10 is converted to equivalent azidoaldehyde 13 in 77% yield and then cyclized to imine 14, methylphenyldihydro-H-pyrrole.

The detailed steps of the further synthetic process starting from compound 12 for the preparation of (2R, 45,5S, 7R) -butyl amide -5 [[1,1-dimethylethoxy) carbonyl] amino] -4-hydroxy-2,7-dimethynyl-8-phenyloctanoic acid 3a are Shown below:

17a, [α] _D -188 ° (c = 1.55) mp 150-151 ° C

-18a, R = H, [α] D -49.6 ° (c = 1.015)

mp 123-125 ° C e * 19a, R = Me, [α] D -31.7 ° (c = 0.85)

mp 143-144 ° C

[Α] D -79.9 ° (c = 1.015)

3a, [α] D -17.1 ° (c = 1.47) mp 83-84 ° C

a) 1) DIBAL-H, toluene, -78 ° C, 4 hours, 2) MeOH, -78 ° C, 30 minutes, 72%,

b) CSA, MeOH, room temperature, 1 hour, 100%,

c) 2- (trimethylsilyloxy) furan, BF 3 .Et 2 O, CH 2 Cl 2, -78 ° C, 1 hour, threo: erythro = 6: 1, 98%;

(d) 10% Pd-C, H; (0,1 MPa), EtOAc :, temperature rooms, 1 hour, 93%, E) 1) (TMS) ₂ NLi THF, -78 ° C, 40 ° C minutes, 2) MeJ, -78 ° C 90 minutes, -50 ° C hour, 3) AcOH-THF, 67%,

f) BuNHA1Me2, CH2Cl2, room temperature, 7 hours, 76%,

g) 20% Pd (OH) ₂ , H ₂ , (386 kPa), EtOH / EtOAc (2: 3), room temperature, 48 hours, 73%.

This process starts from the protected lactam 12, whose amidocarbonyl group is effectively reduced to the hydroxyl

113%, yielding hemiamiri rotamers in 72% yield.

Compound 16a in the form of a mixture This compound is then nonmethoxy with a substrate of unsaturated lactone ring and 98% and in the isomer ratio of compound 17a is overlaid with 17 and hydrogenated with saturation: compound 18a in the form of two rotamers in 93% yield. The saturated lactone ring 18 is methylated to give 67% of the desired monomethyl derivative 19a and 15% dimethyl lactone. The crystalline compound 19a is subjected to X-ray analysis. The lactone ring is opened with t-butylamide to give compound 2a in 7 (hydrogenolysis) to give

Detailed degrees next

15a in the form of a mixture of anomers and Sn is then methylated to give of the four isomers in 100% yield.

reacted with effective displacement with Rz furan to give compound 17a in a yield: eo: erythro = 6: 1. Pure erythroit as a mixture of rotamers. The furan / lactone divalent bond compound yields |%. Then, the pyrrolidine ring of compound 3a was obtained in 73% yield. of the pathetic process starting from compound 14 to form compound 3, the following are shown:

15b, R = H * 16b, R = Me

17b, (α) _D -168 ° (c = 1.02) mp 157-158 ° C

-18b, R = H, [α] 0-52 ° (c = 0.86) * -19b, R = Me, [α] _D -32 ° (c = 0.71)

3a, [α] _D -17.1 ° (c = 1.47) mp 83-84 ° C

a) 1) PhCH ₂ C (O) Cl, toluene, -78 ° C, 1 hour, 2) 2 N HCl, -78 ° C to room temperature, 67%,

b) CSA, MeOH, room temperature, 1 hour, 89%,

c) 2- (trimethylsilyloxy) furan, BF ₃ .Et ₂ O, CH ₂ Cl ₂ , -78 ° C, 2 hours, threo: erythro = 5: 1, 78%;

d) 5% Pd-C, H ₂ (0.1 MPa), benzene, room temperature, 30 minutes,

-1590%,

e) 1) (TMS) ₂ NLi, MeJ, THF, -78 ° C, 40 min, 2) saturated solution

NaHCOa, 57%,

f) BuNHAlMe ₂ , CH 2 Cl 2, room temperature, 2 hours, 52%,

g) (Boc) ₂ O, 20% Pd (OH) ₂ , H ₂ (414 kPa), EtOH / EtOAc (2: 3), room temperature, 72 hours, 46%.

This procedure is generally analogous to the scheme

2, starting from cyclized imine 14 and protecting the nitrogen in the imino group with a carboxybenzyl group rather than a carboxybutyl group to give compound 15b as a mixture of anomers and rotamers in 67% yield (from compound 13). Then the steps are very similar, yielding compound 16b in 89% yield and compound 17b in 78% yield in a threo: erythro = 5: 1 isomer ratio. The pure compound 17b crystallizes as a mixture of rotamers. Crystalline compound 17b is subjected to X-ray analysis. Further purification afforded 90% of compound 18b, 56% of compound 19b, 52% of compound 2b, which was directly converted to compound 3a in a yield of 46%.

DETAILED DESCRIPTION OF THE INVENTION

(S) - (Benzyloxymethoxy) -phenylacetic acid methyl ester 5:

To a solution of 6.5 g (39.9 mmol) of (S) -methyl derivative in 90 mL of anhydrous THF was added sequentially 12.0 mL (69 mmol) of i-Pr ₂ EtN, 8.2 mL (59.5 mmol) of benzyl chloromethyl ether and 1.46 g (3.95 mmol) of BU4N-I-. Then the reaction mixture was stirred at room temperature overnight. 4.0 ml (23.0 mmol) of i-Pr ₂ EtN and 2.7 ml (19.65 mmol) of benzyl chloromethyl ether are then added. The reaction mixture was stirred at room temperature for 40 hours, then 2.0 mL (11.5 mmol) of i-Pr ₂ EtN and 1.35 mL (9.8 mmol) of the alkylating agent were added and

The mixture was stirred for an additional 44 hours at room temperature. Methanol (1.5 mL) was added to consume excess alkylating agent. After 30 minutes, the reaction mixture was partitioned between 150 mL of water and 250 mL of EtOAc. The organic layer was washed with 0.5 N HCl, pH 7 phosphate buffer, then brine, dried over magnesium sulfate, and concentrated. Purification of the residue by column chromatography (silica gel, 15% EtOAc / hexanes) afforded 9.25 g (83%) of ester 5 as a colorless syrup. [ ^α ] D + 119 ^O (c 1.24, CHCl 3), IR (thin film) 1730, 1445, 1260, 1200, 1160, 1040 cm -1 40 NMR (CDCl ₃ , 300 MHz) ^δ 7.50-7, 27 (m, 10H, ArH), 5.25 (s, 1H, PhCHO), 4.92 and 4.84 (AB quartet, 1 H, J = 7 Hz, OCH 2 O), 4.69 and 4.59 (AB quartet, 2H, J = 12 Hz, OCH 2 Ph), 3.7 (s, 3H, OCH 3), ¹³ C (CDCl 3, 75 MHz) ^δ 171, 1, 137.3, 135, 9, 128.7, 128.6, 128.3, 127.8, 127.7, 127.3, 93.2, 70.0, 52.2, exact mass calculated for C1-H19O4 287, 128334, found

287.130.

(2Ξ, 4R) -4-Benzyloxymethoxy) -4-phenyl-2-butenoic acid methyl ester 6:

To a cooled (-78 ° C) solution of 8.5 g (29.7 mmol) of ester 5 in 100 mL of anhydrous toluene was added dropwise a cooled (-78 ° C) solution of DIBAL-H (33 mL, 1 M in syringe). toluene, 33 mmol) in anhydrous toluene (20 mL) over 30 minutes. The reaction mixture was stirred at -78 ° C for an additional 3 hours. Methanol (3.5 mL, 89 mmol) was then added dropwise and the resulting solution was stirred at -78 ° C for 30 minutes. Remove the cooling bath and allow the reaction mixture to warm to room temperature. To the reaction mixture was added methyltriphenylphosphoranylidene acetate (15.0 g, 44.8 mmol) and the mixture was stirred for 20 minutes. The aluminum complex was filtered off and the solvent was removed

-17 evaporate. Ether and insoluble PPI 13 O were added and excess reagent was filtered off. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 12% EtOAc / hexanes) to give 0.7 g (6% for two steps) of the cis ester and 8.5 g (75% for two steps) of the trans ester 6 in the form of a colorless syrup. [ ^α ] _D + 85 ° (c 1.55, CHCl 3), IR (thin film) 1710, 1645, 1440, 1290,

1260, 1010 cm ^{-1 X} H NMR (CDCl3, 300 MHz) ⁵ 7.39-7.27 (m, 10H,

ArH), 7.0 (dd, 1H, J = 5Hz, 16Hz, CHCH =), 6.13 (dd, 1H, J = 2)

Hz, = CHCO ₂ Me), 4.81 and 4.74 (AB quartet, 2H, J = 7 Hz, OCH ₂ O), 4.64 and 4.56 (AB quartet, 2H, J = 12 Hz, OCH ₂ Ph), 3.74 (s, 3H, OCl 2), ¹³ C (CDCl ₃ , 75 MHz) ^δ 166, 6, 147.1, 138.4, 138.3, 128.6, 128.3, 128 , 2, 127.9, 127.7, 127.3, 120.4, 91.9, 76.3, 69, 7, 51, 5, exact mass calculated for C19H21O4 313.143984, found

313.1433.

(3R, 4R) -4- (Benzyloxymethoxy) -3-methyl-4-phenylbutanoic acid methyl ester 7:

To a suspension of 15.54 g (81.6 mmol) of CuI in 400 mL of anhydrous THF at -78 ° C was added methyllithium (116.6 mL, 1.4 M in ether, 163.2 mmol). The mixture is warmed to 0 ° C, maintained at this temperature for 10 minutes, and then recooled to -78 ° C. TMS-C1 (31 mL, 244.8 mmol) was added followed by a solution of unsaturated ester 6 (8.49 g, 27.2 mmol) in anhydrous THF (40 mL). The reaction mixture was stirred at -78 ° C for 2 hours and then washed with 15 mL of 1:15% aqueous NH 4 OH and saturated aqueous NH 4 Cl. Cooling bath ... se. The reaction mixture was allowed to warm to room temperature. Then, 10% aqueous NH 4 OH (50 mL) and ether (300 mL) were added and the resulting mixture was stirred until a homogeneous organic phase and a deep blue aqueous phase were obtained. The two layers are separated, the organic phase is washed with water,

· -18roztokem chloride solution, dried over magnesium sulfate and concentrated, to afford an inseparable mixture of 7 as a 94: 6 diastereomeric mixture and the deconjugated product (5% ^X by H NMR). ¹ H NMR (CDCl ₃ , 300 MHz) ^δ 7.39-7.23 (m, 10H, ArH), 4.68 and 4.46 (AB quartet, 2H, J = 12 Hz, OCTLO), 4.67 and 4.58 (AB quartet, 2H, J = 7 Hz, OCl 2 Ph), 4.42 (d, 1H, J = 8 Hz, PhCHO),

3.67 (s, 3H, OCft), 2.73 (dd, 1H, J = 5Hz, 15Hz, one of

CH ₂ CO ₂ CH ₃ ), 2.42 (m, 1H, CHCH ₃ ), 2.24 (dd, 1H, J = 9Hz, 15Hz, $)

one of ΟΗ ₂ ΟΟ ₂ ΟΗ ₃ ), 0.83 (d, 3H, J = 7 Hz, CHCH 3), mass spectrum m / e 329 (Μ + H).

(4R, 5R) -4-Methyl-5-phenyldihydrofuran-2-one 8:

To a cooled solution (-23 ° C) of unpurified ester 7 according to the above example (8.55 g, theoretical yield, 26.1 mmol) in 260 mL of anhydrous CH 2 Cl 2 was added 10.3 mL (78.3 mmol) of TMS-Br. and the solution was gradually allowed to warm to room temperature overnight. The reaction mixture was diluted with additional CH 2 Cl 2 (100 mL), washed with saturated aqueous NaHCO ₃ (2 x 50 mL), water, brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography .- (silica gel, 24% EtOAc / Nexan) to yield 3.45 g (72% for two steps) of compound 8 as a crystalline solid, mp 53-54 ° ^C, [ ] ₃₆₅

-4 ⁰ (c 0.88, CHCl 3) IR (CHCl 3) 1780, 1280, 1150, 1005 cm ^-1 , (CDCI3, 300 MHz) δ 7 _Z 44-7.27 (m, 5H, ArH), 4.95 (d, 1H, J = 8) Hz, PhCHO), 2.81 (dd, 1H, 7Hz, 17) Hz, one of CH 2 CO), 2.49 (m, 1H, CHCH3), 2.3 (dd, 1H, J = 10Hz) 17 Hz one of CH 2 CO 1, 1.21 (d, 3H, J = 6 Hz, CHCH 3), "C (CDCl 3, 75 MHz) δ 176.0, 137.8, 128 , 6,

-19125, 8, 88.0, 39, 7, 37.1, 16, 3, overweight calculated for

C11H13O2 177.091555, found 177, 0909.

(3R, 4R) -4-Hydroxy-3-methyl-4-phenylbutanoic acid methyl ester 9:

To a cooled (0 ° C) solution of 2.43 g (13.8 mmol) of lactone 8 in methanol (40 mL) was added 41 mL of 0.5 N aqueous NaOH. The reaction mixture was warmed to room temperature and stirred for 2 hours. The methanol was removed under reduced pressure and the residue was diluted to 140 mL with water. The reaction mixture was cooled and the pH was adjusted to 4 using 1 N aqueous HCl. Solid NaCl was added and the mixture was allowed to warm to room temperature. It was then extracted with EtOAc (200 mL x 3). The combined organic layer was washed with brine, dried (MgSO 4) and concentrated. The residue was dissolved in EtOAc and methylated with diazomethane in ether. Evaporation of the solvent gave 2.82 g (98%) of hydroxyester 9, which was used in the next step without further purification. IR (thin film) 3600-3260, 1740, 1725, 1460, 1170, 1020 cm ^-1 , NMR (CDCl 3). (300 MHz), ^δ 7.37-7.27 (m, 5H, ArH),

4.43 (d, 1H, J = 7Hz, PhCHOH), 3.66 (s, 3H, OCH3), 2.63 (dd, 1H, J = 5Hz, 15Hz, one of CH2CO2CH3), 2, 38 (broad s, 1H, OH),

2.36 (m, 1H, CHCH 3), 2.26 (dd, 1H, J = 8 Hz, 15 Hz, one of

CH 2 CO 2 CH 3), 0.85 (d, 3H, J = 7 Hz, CHCH 3), mass spectrum m / e

209 (M @ ⁺ + H).

(3R, 4R) -4-Azido-3-methyl-4-phenyl-butanoic acid methyl ester 10:

To a solution of 2.82 g (13.56 mmol) of hydroxyester 9 in 70 mL of anhydrous THF was added triphenylphosphine (5.33 g, 20.3 mmol) and cooled to 0 ° C. DEAD is added dropwise and again dropwise

- (PhO) 2P (O) Nj is added. The reaction mixture was gradually allowed to warm to room temperature overnight. The THF was removed and the residue was purified by column chromatography (silica gel, 12% EtOAc / hexanes) to give 2.8 g (89%) of azidoester 10 as a 96: 4 diastereomeric mixture, [ ^α ] D -164 ° (c) 1.27, CHCl 3); IR (thin film) 2100, 1740, 1450, 1250, 1165 cm ^{-1 X} H NMR (CDCl3, 300 MHz) δ 7.42-7.26 (m, 5H, Ar) 4.48 (d, 1H, J = 6 Hz, PhCHN ₃ ), 3.65 (s, 3H, CHCl 3), 2.37 (m, 2H, CHCH ₃ , one of CH 2 CO 2 CH 3), 2.09 (dd, 1H, J = 10 Hz, 17 Hz, one of CH 2 CO 2 CH 3), 0.99 (d, 3H, J = 6 Hz, CHCH 3), C (CDCl 3, 75 MHz) ^δ 172.6, 137, 9, 128, 5, 128.1, 127.1, 102.0, 51.4, 37.9, 36.0, 15.6, exact mass calculated for C 12 H 16 N 3 O 2 234.124252, found 234.125.

(4R, 5S) -4-Methyl-5-phenyl-pyrrolidin-2-one 11:

To a solution of 2.5 g (10.73 mmol) of azidoester 10 in methanol (55 mL) at room temperature was sequentially added 14 mL (80.48 mmol) of i-Pr 2 EtN and 5.39 mL (53.65 mmol). 1,3-propanedithiol and the mixture was stirred for 43 hours. The methanol was removed under reduced pressure and the residue was diluted with EtOAc. The mixture was washed with 0.5 N aqueous NaOH (80 mL x 2), water, brine, dried (MgSO 4) and concentrated. The residue was purified by column chromatography (silica gel, 25% EtOAc / hexanes first and then 20% acetone / CHCL ·) to give 1.62 g (86%) of lactam 11 as a colorless solid, mp 105-106 ° C ^[a] _D -27 ⁰ (c 1, 055, CHCl3) IR (CHCl3) 3460, 1710, 1450, 1340 cm ^{-1 X} H

NMR (CDCl ₃ , 300 MHz) ^δ 7.4-7.17 (m, 5H, Artf), 6.12 (broad s,

1H, Ntf), 4.79 (d, 1H, J = 8Hz, PhCHN), 2.86 (m, 1H, CHCH3), 2.53 (dd, 1H, J = 8Hz, 17Hz, one of CH 2 CO), 2.13 (dd, 1H, J = 8 Hz, 17 Hz one of CH 2 CO), 0.66 (d, 3H, J = 7 Hz, CHCl 3), ¹³ C NMR (CDCl 3, 75 MHz) ^δ 178 , 1, 138.6, 128.4, 127.7, 126, 5, 61, 5,

-2137, 6, 34.2, 16.2, exact mass calculated for C 11 H 13 NO

175.09972, found 175.10029.

(2S, 3R) -3-Methyl-5-oxo-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 12:

To a solution of 1.37 g (7.83 mmol) of lactam 11 in anhydrous CH ₂ Cl ₂ (32 mL) was gradually added a solution of 3.76 g (17.2 mmol) of di-tert-butyl dicarbonate in CH 2 Cl 2 (5 mL), 3.4 mL (19.58 mmol) i-PrzEtN and 96 mg (0.78 mmol) DMAP and the mixture was stirred at room temperature for 24 hours. The initially colorless reaction mixture turned dark brown towards the end of the reaction. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 30% EtOAc / hexanes) to give 2.12 g (99%) of 12 as a colorless solid, mp 74-75 ° C, -4.6 ^° (c 0.88, CHCl 3), IR (CHCl 3) 1780, 1740,

1720, 1460, 1340, 1150 cm ^-1 . ¹ H NMR (CDCl 3, 300 MHz) ^δ 7.38-7.10 (m, 5H, ArH), 5.10 (d, 1H, J = 8 Hz PhCHN) 2.75 (m, 1H, CH CH 3),

2, 58 (dd, 1 H, J = 8) Hz, 17 Hz, one of CH ₂ CO), 2.37 (dd, 1H, J = 12 Hz, 17 Hz, one from CH ₂ CO), 1.27 (s, 9H, C (CH ₃ ) 3, 0.69 (d, 3H, J = 7 Hz, CHCH 3), ¹³ C (CDCl 3, 75 MHz) ^δ 174.3, 149.3, 137.0, 128, 3, 127.6, 126 , 2, 82.5, 65.5, 38.8, 30.8, 27.5, 15.7, accurate

mass calculated for C 16 H 21 NO 3 275.15213, found 275, 15394.

(2S, 3R, 5R, 5S) -5-Hydroxy-3-methyl-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 15a:

To a cooled (-78 ° C) solution of 1.1 g (4 mmol) of compound 12 in 10 mL of anhydrous toluene was added DIBAL-H (4.4 mL, 1 M in toluene, 4.4 mmol) dropwise. Stir for 4 hours.

and

Methanol (1.5 mL) was added and the reaction mixture was stirred at temperature

-22-78 ° C for 30 minutes. The reaction mixture was warmed to room temperature and 50 mL of ether and a drop of water were added. The aluminum complex was filtered off and the solvent was evaporated. The residue was purified by column chromatography (silica gel, 20% EtOAc / hexanes) to give 800 mg (72%) of 15a as a mixture of nanomers and rotamers and 240 mg of the starting compound. ¹ H NMR (CDCl 3, 300 MHz) δ 7, 33-7.2 (m, 16H, 4 × ArH), 7.02 (m, 4H, 4 × ArH), δ, 94, 5.82 and 5, 83-5.56 (m, 4H, 4 * CHOH), 4.89, 4.74 (3 * d, 4H, J = 8 Hz, PhCHN), 4.47, 3.74, 3.52 and 3, 21 (4 x wide, 4H, 4 x OH), 2.98-2.86 and 2.56-2, 40 (2 x m, 4H, 4 x CHCH3), 2.33-1.64 (m, 8

H, 4 x CH2CHOH), 1.2 and 1.18 (2 xs, 36H, 4 x C, O) 3), 0.64 and 0.63 (2 xd, 12H, J = 7 Hz, 4 x CH 2 CH 3), mass spectrum m / e 260 (M + - OH).

(2S, 3R, 5R, 5S) -5-Methoxy-3-methyl-2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 16a:

To a solution of hemiaminal 15a (745 mg, 2.69 mmol) in methanol (20 mL) was added OSA (31 mg, 0.133 mmol) and the reaction mixture was stirred at room temperature for 1 h. Et 3 N (10 drops) was added and methanol was removed under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc / hexanes) to give 780 mg (100%) of 16a as an anomeric and rotamer mixture of four isomers, ¹ H NMR (CDCl 3, 300 MHz), δ 7,337,21 (m, 12H, 4 * ArH), 7.02 and 7.0 (2 * d, J = 8 Hz, 4 * ArH), 5.42 and 5.20 (2 * d, 2H, J = 5 Hz, 2) x CHCOCH 3), 5.26 (broad s, 2H, 2 x CHOCH), 4.92 (broad s, 2H, 2 x PhCHN), 4.88 and 4.78 (2 xd, 2H, J = 8 Hz, 2 x PhCHN), 3, 54, 3, 48 and 3.43 (3 xs, 12H, -4 x OCHa), 2.93-1.63 (m, 12H, 4 x CHCH ₃ and 4 x CH 2 CHOHCH 3), 1,44 a

I, 08 (2 xs, 36H, 4 x C (CHa) 3), 0, 67, 0.59 and 0.57 (3 xd, 12H, J = 7 Hz, 4 x CHCH 3), mass spectrum m / e 290 (M ^& lt ^{; +} & gt ^; - H).

(2S, 2'S, 3R, 5S) -3-Methyl-5-oxo- (5'-oxo-2 ', 5'-dihydrofuran-2-yl) -2-phenyl-pyrrolidine-1-carboxylic acid-23-tert-butyl ester 17a :

To a cooled solution (-78 ° C) of 740 mg (2.54 mmol) of compound 16a in 26 mL of anhydrous CH ₂ Cl ₂ was added sequentially 0.64 mL (3.81 mmol) of 2- (trimethylsilyloxy) furan and 0.30 mL (3.71 mmol) of aq. 19 mL (1.52 mmol) of BF ₃ Et ₂ O was added and the solution was stirred for 1 hour. The reaction mixture was washed with 10 mL of 2 N aqueous HCl and warmed to room temperature. The mixture was then diluted with EtOAc, washed with water, brine, dried (MgSO 4) and concentrated. There were obtained 860 mg (98%) of 6: 1 (by ^X H NMR) of threo: erythro isomers. Threoisomer Pure 17a was obtained as a mixture of rotamers by fractional recrystallization from 30% EtOAc / hexanes, mp 150-151 ° C, ^[a] D -188 ⁰ (c 1.115, CHC13) IR (CHC) 1755

1685, 1450, 1370, 1165, 1085 cm ^{-1 X} H NMR (CDCl3, 300 MHz) ⁵ 7.68 and 7.58 (2x dd, 2H, J = 2Hz, 2 x OCHCH =), 7.31 -7.17 (m, 6H, 2 × ArH), 7.0 and 6.97 (2 × d, 4H, J = 7 Hz, 2 × Ar #), 6.24 and 6.08 (2 × dd, 2K, J = 2Hz, 6Hz, 2 x CH-CHCO), 5.55 (dt, 1H, J = 2Hz, 4Hz, CHO), 5.40 (dt, IH, J = 2Hz, 3) Hz, CHO), 4.88 and 4.71 (2 xd, 2H, J = 8 Kz, 2 x PhCHN), 4.66 (dt, 1H, J = 3 Hz, 4 Hz, CHN),

4.62 (m, 1H, CHN), 2.77 and 2.35 (2 * m, 2H, CHCH3), 2.05-1.83 (m, 2H, CH2CHN), 1.76 (dd, IH, J = 8 Hz, 13 Hz, one of CEphenCHN), 1.60 (dd, IH, J = 7 Hz, 13 Hz, one of CfizCHN), 1.44 and 1.02 (2 xs, 18H, 2 x C) (CH ₃ ) ₃ ), 0.55 and 0.53 (2 xd, 6H, J = 7 Hz, 2 x CHCl 3), ¹³ C (CDCl 3, 75 MHz) ^δ 173.1, 154, 8, 154, 7 , 141.2, 127.8, 126.7, 126, 3, 120.3, 84, 7, 79, 7, 66.7, 58.0, .36, 1, 32, 5, 27, 5,

15.3, exact mass calculated for C 20 H 26 NO 4 344, 18619, found 344.1867.

(2S, 2'S, 3R, 5S) -3-Methyl-5- (5'-oxo-tetrahydro-24-furan-2'-yl) -2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 18a:

To a solution of Compound 17a (250 mg, 0.73 mmol) in EtOAc (3 mL) was added 10% Pd / C (30 mg) and the mixture was stirred under H 2 for 1 h. The catalyst was filtered off through a pad of celite and the solvent evaporated to give 230 mg (93%) of 18a as a mixture of two rotamers, mp 123-125 ° C, ^[a] D -49 6 ⁰ (c 1.015, CHCl?) IR (CHCl3) 1760, 1675, 1400, 1350, 1150 cm ^-1 , ¹ H NMR (CDCl ₃ , 300 MHz) ^δ 7.31 and 7.21 (m, 6H, 2 x

Artf), 7.0 (d, 4H, J = 8 Hz, 2 x Ar #), 4.80 (dt, 2H, J = 3 Hz, 7 Hz, 2 x ZHO), 4.91 and 4.76 (2 xd, 2H, J = 8Hz, 2 x PhCHN), 4.53 (dd, 1H, J = 3Hz, 7Hz, CHN), 4.41 (t, 1H, J = 7Hz, CHN) 2.86 (m, 1H, CHCH 3), 2.68-2.22 (m, 4H, CH ₂ CH ₂ CO), 1.96-1.90 (m, 2H, CH ₂ CHN),

2, 86-1,79 (m, 7H, CHCH _3, ZH2ZH2ZZ), CH ₂ CHN), 1.42 and 1.05 (2 x s,

18H, 2 x C (CH ₃ ) ₃ ), 0.58 and 0.56 (2 x d, 6H, J = 7 Hz, 2 x CHCH 3), ¹³ C (CDCl 3, 75 MHz) ^δ 177, 0, 155, 3, 141.5, 127.7, 126.5, 126, 2,

82.4, 79.4, 67, 0, 58.7, 35, 9, 33, 4, 28.3, 27.5, 24.6, 15, 4, exact mass calculated for C ₂₀ H _2a NO ₄ 346, 20184, found 346.20230.

(2S, 2'S, 3R, 4'R, 5S) -3-Methyl-5- (4'-methyl-5'-oxotetrahydrofuran-2-yl) -2-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester 19a:

To the cooled (-78 ° C) solution (TMS) ₂ NLi (0.27 mL, 1 M in THF, 0.27 mmol) was added a solution of compound 18a (85 mg, 0.25 mmol) at rt. ml of anhydrous THF by syringe over 3 minutes and the solution is then stirred for 40 minutes. Mel (0.16 mL, 2.5 mmol) was added and the solution was stirred at -78 ° C for 90 minutes, then the reaction mixture was warmed to -50 ° C and stirred for an additional 1 hour. The reaction mixture was washed with AcOH solution

-25 (0.15 mL) in 0.4 mL of anhydrous THF and allowed to warm to room temperature, then diluted with EtOAc, washed with water, brine, dried (MgSO 4) and concentrated. Purification of the residue by column chromatography (silica gel, 25%

EtOAc / hexanes) afforded 14 mg (15%) of dimethylated lactone and 59 mg (67%) of product monomethylovaného 19a as a mixture of rotamers, mp 143-144 ° ^C, [J _D -31.7 ⁰ (c 0, 85,

CHCl ₃ ), IR (CHCl ₃ ) 1750, 1680, 1440, 1355, 1150, 1000 cm ^-1 , ^::

NMR (CDCl 3, 300 MHz) ^δ 7.31-7.18 (m, 6H, 2 × ArH), 7.0 and 6.98 (2 × ^d , 4H, J = 7 Hz, 2 × ArH), 4, 91 and 4.73 (2 × d, 2H, J = 8 Hz, 1 × PhCHN), 4.65 (dt, 1 H, J = 4 Hz, 7 Hz, CHO), 4.59 (dt, 1 H, J = 4

Hz, 8 Hz, CHO), 4.5 (dd, 1 H, J = 4 Hz, 8 Hz, CHN), 4.32 (t, 1 H,

J = 8 Hz, CHN), 2.94-2.62 (m, 5H, 2 x CHCH 3 CO, one of

OCHCH 2 CHCH 3), 2.62-2.29 (m, 1H, one of OCHCH 2), 2.03-1.81 (m,

5H, 3 x one of CH2CHN, 2 x one of OCHCH2), 1.70 (dd, 1H, J = 6

Hz, 13 Hz, one of CH 2 N), 1.31 and 1.27 (2 x d, 6H, J = 7 Hz,

CHCH 3 CO), 1.39 and 1.03 (2 x s, 18H, 2 x C (CH ₃ ) ₃ ), 0.54 and 0.57 (2 x d, 6H, J = 7 Hz, 2 x CHCH 3), ¹³ C (CDCl 3, 75 MHz) ^δ igo _z 2, 155.6, 141.7, 128.0, 127.8, 126, 6, 126, 4, 80, 8, 79, 6, 67.2, 59, 3,

35, 9, 35, 1, 34.2, 33.7, 33.3, 32.7, 28.0, 27, 6, 16, 0, 15.5, exact mass calculated for C21H30NO4 360, 2175, found

360.2159.

(1'S, 2S, 3R, 3R, 5S) -5- (3'-Butylcarbamoyl-1 'hydroxybutyl) -3-methyl-2-phenylpyrrolidine-1-carboxylic acid tert-butyl ester 2a:

To a solution of 56 mg (0.156 mmol) of 19a in 0.9 mL of anhydrous CH 2 Cl 2 was added BuNHAlMe ₂ (0.28 mL, 0.67 M in CH 2 Cl 2, 0.23 mmol) and the mixture was stirred at room temperature for 7 hours . The reaction mixture was cooled to 0 ° C and rinsed with 2 mL of 1 N

-26 aqueous HCl, then diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated. Purification of the residue by column chromatography (silica gel, 10% acetone / CHCl ₃ ) gave 51 mg (76%) of amide 2a as a syrup. ^[A] _D -79.9 ° (c 1.015, CHC1 ₃₎ IR (CHCl3) 3480, 3500-3300, 1665, 1465, 1415,

1155 cm ^{-1, Χ Η} NMR (CDCl3, 300 MHz) ^δ 7.30-7.19 (m, 3H, Ar)

6.98 (d, 2H, J = 7 Hz, ArH), 6.0 (broad t, 1H, J = 5 Hz, NH), 4.78 (d, 1H, J = 6 Hz, OH), 4, 71 (d, 1H, J = 8Hz, PhCHN), 4.12 (t, 1H, J = 8Hz, CHN), 3.50 (m, 1H, CHOH), 3.35-3.15 (m 2H, CH 2 NH), 2.74-2.49 (m, 2H, CHCH ₃ , CHCH ₃ CO), 1.94-1.70 (m, 3H), 1.54-1.21 (m, 5H) ), 1.17 (d, 3H, J = 7Hz, CH ₃ CO), 1.06 (s, 9H, C (CH3) ₃₎

0.93 (t, 3H, J = 7 Hz, CHzCHz), 0.55 (d, 3H, J = 7Hz, CH CH _3), ¹³ C

NMR (CDCl ₃ , 75 MHz) ^δ 176, 1, 158.0, 141.0, 127, 8, 126, 8, 80, 3,

74.5, 63, 4, 40, 9, 38.9, 37, 1, 35.7, 32.9, 31.7, 27.7, 20.0,

18.5, 15.0, 13.7; mass spectrum m / e 433 (M ⁺ H).

(2R, 4S, 5S, 7R) -5 - [[(1,1-Dimethylethoxy) carbonyl] amino] -4-hydroxy-2,7-dimethyl-8-phenyloctanoic acid butylamide 3a:

To a solution of 40 mg (0.93 mmol) of amide 2a in 1 mL of 40% EtOH / EtOAc was added 10 mg of Pearlmen catalyst (20% Pd (OH) 2 / C) and the suspension was stirred under 50 psi of hydrogen for 2 hours. days. The catalyst was filtered off and the solvent was evaporated. Purification of the residue by PTLC (10% acetone / _CHCl3) afforded 4 mg of the starting compound and 29 mg (73%) of compound 3, melting point 83-84 ° C, ^[a] D -17.1 ⁰ (c 1.47 , CHCl3), IR (CHCl3) 3460, 3400-3300,

1710, 1660, 1500, 1370, 1170 cm -1 ¹ H NMR (CDCl ₃ , 300 MHz) ^δ

7.29-7.15 (m, 5H, ArH), 5.82 (broad s, CH2 NH), 4.75 (d, 1H,

J = 8 Hz, NHBoc), 3.72-3.61 (m, 2H, CHOH, CHNHBoc), 3.33-3.17 (m, 2H _from CH 2 N), 2.86 (dd, 1H, J = 5 Hz, one of PhCH 2), 2.55 (m, 1H, CHCH ₃ CO), 2.26 (dd, 1H, J = 9 Hz, 13 Hz, one of PhCH 2), 1.80 (m,

-271H, CHCH 3), 1.68 (t, 2H, J = 6Hz), 1.55-1.23 (m, 6H), 1.47 (s, 9H, C (CH 3) ₃ ), 1, 20 (d, 3H, J = 7Hz, CHCH3CO), 0.93 (t, 3H, J = 7)

Hz, CH 2 CH 3), 0.87 (d, 3H, J = 7 Hz, CH CH 3), ¹³ C (CDCl 3, 75 MHz) δ 176, 8, 156.4, 141, 1, 129, 1, 127.9, 125, 6, 79, 1, 70, 1, 52, 1, 42, 6, 40.0, 39, 1, 38.4, 37.6, 31.9, 31.6, 28.3, 19, 9, 19, 8, 17.0, 13.6, mass spectrum m / e 435 (M ⁺ + H).

(3R, 4S) -4-Azido-3-methyl-4-phenylbutyraldehyde 13:

To a cooled (-78 ° C) solution of 820 mg (3.52 mmol) of 10 in 35 mL of anhydrous toluene was added dropwise DIBAL-H (3.9 mL, 1 M in toluene, 3.9 mmol) via syringe. The reaction mixture was stirred for an additional 45 minutes. Methanol (0.43 mL, 10.6 mmol) was added and the reaction mixture was stirred at -78 ° C for 20 minutes. The reaction mixture was then allowed to warm to room temperature and ether and a drop of water were added. The aluminum complex was filtered off and the solvent was evaporated. The residue was purified by column chromatography (silica gel, 1% Et3N, 14% EtCAc, 85% hexanes) to give SE- 550 mg (77%) of Compound 13 ^[?] _D -205 ⁰ (c 1.33, CHCl3) IR (thin film)

2100, 1730, 1450, 1245 cm ^{-1 X} H NMR (CDCl3, 300 MHz) δ 9.66 _(s, 1H, CHO), 7.4 to 7.26 (m, 5H, Ar-H). 4 46 (d, 1H, J = 7Hz, PhCHN _3), 2.48 (m, 2H, _CHCH3, one of CH2CHO), 2.22 (dd, 1H, J = 9Hz, 18Hz, one of CH2CHO 1.02 (d, 3H, J = 7 Hz, CHCH 3), ¹³ C (CDCl 3, 75 MHz) ^δ 200.9, 137.7, 128.7, 128.3, 128.2, 70.4 , 47.4, 33.9,

16.1, mass spectrum m / e 103 (M +).

(2S, 3R) -3-Methyl-2-phenyl-4-dihydro-2H-pyrrole 14:

To a solution of 527 mg (2.6 mmol) of azidoaldehyde 13 in 36 mL of anhydrous toluene was added triphenylphosphine (750 mg, 2.86 mmol) and

The mixture was stirred for 16 hours until the reaction was judged to be complete by testing. The compound was used in the next step.

(2S, 3R, 5R, 5S) -5-Hydroxy-3-methyl-2-phenyl-pyrrolidine-1-carboxylic acid benzyl ester 15b:

To the above solution of imine in toluene was added benzyl chloroformate (0.37 mL, 2.6 mmol) at -78 ° C and the reaction mixture was stirred for 1 hour. The reaction mixture was washed with 2 N aqueous HCl and allowed to warm to room temperature. Then, the reaction mixture was diluted with EtOAc, washed with an unsaturated sodium chloride solution, and brine, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, 1% Et ₃ N, 29% EtOAc, 70% hexanes) to give 541 mg (67% for two steps) of the hemiaminal 15a as an anomeric and rotameric mixture ^X H NMR (CDCl , 300 MHz) ^δ 7.4-7.16 (m, 18H, 2 × ArH), 7.37-7.02 (m, 13H, 2 × ArH), 6.9-6.87 (m, 2H) 2 x ArH), 6.80 (d, 2H, J = 7 Hz, 2 x ArH), 5.86 and 5.77 (2 xd, 2H, J = 6 Hz, 2 x CHOH), 5.68 (t, 2H, J = 7 Hz, 2 x CHOH), 5.21 and 5.12, 5.08 and 4.98 (2 x AB quartet, 4H, J = 13 Hz, 2 x CO2 / FePh), 5.22 and 5.11, 5.07 and 4.93 (2 x AB quartet, 4H, J = 13 Hz, 2 x artςΟΗςΡΙλ), 4.98 and 4.96 (2 xd, 2H, J = 9 Hz) , 2 x PhCHN), 4.95 and 4.88 (2 xd, 2H, J = 8 Hz,

PhCHN), 4, 38, 4, 0, 3.52 and 3.26 (4 x wide s, 4H, 4 x OH), 2.96 and 2.51 (2 x m, 4H, CHCH ₃ ), 2, 30, 1.73 and 1.99-1.75 (3 × m, 8H, 4 × CH 2 CHOH), 0, 65, 0, 64, and 0.63 (3 × d, 12H, J = 7 Hz, 4 × CHCH 3) Mass Spectrum (m / e) 310 (M ⁺ -H).

(2S, 3R, 5R, 5S) -5-Methoxy-3-methyl-2-phenyl-pyrrolidine-1-carboxylic acid benzyl ester 16b:

To a solution of 540 mg (1.74 mmol) of hemiaminal 15b in 9 mL of methanol was added 18 mg (0.078 mmol) of CSA and the reaction mixture was stirred at room temperature for 1 hour. Ethine (10 drops) was added and methanol was removed under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc / hexanes) to give 502 mg (89%) of Compound 16b as a mixture of anomers and rotamers, ^X H NMR (CDCl3, 300 MHz) δ 7,37-6, 98 (m, 36H, 4 * ArH), 6.82 and 6.6 (2 * d, 4H, J = 7 Hz, 4 * ArH), 5.46 and 5.30 (2 * d, 2H, J = 5) Hz, CHOCH3), 5.34 (broad s,

2H, 2 x CHOCH3), 5.18 and 5.08, 5.02 and 4.82 (2x AB quartet, 8H, J = 13 Hz 4 x (CH2 Cl2), 4.96 and 4.91 (2 x d, 4H, J = 7Hz, 4x PhCHN), 3.56 (broad s, 3H, OCH 3), 3.52, 3.50 and 3.53 (3x s, 9H, 3x OCH3), 2.99-1.66 (m, 12H, 4xCHCH3, 4 X CH2CHOCH3),

0.68 and 0.61 (2 × d, 12H, J = 7 Hz, 4 × CHCH 3), mass spectrum m / e 324 (M ⁺ - H).

(2S, 2'S, 3R, 5S) -3-Methyl-5-oxo-5'-oxo-2 ', 5'-dihydrofuran-2-yl) -2-phenyl-pyrrolidine-1-carboxylic acid benzyl ester 17b:

To a cooled (-78 ° C) solution of 500 mg (1.54 mmol) of 16b in 15 mL of anhydrous CH 2 Cl 2 was added sequentially 0.38 mL (2.31 mmol) of 2- (trimethylsilyloxy) furan and 0.11 mL ( 0.92 mmol) of BF 3 .Et 2 O and the solution was stirred for 2 hours. The reaction mixture was washed with 5 mL of 2 N aqueous HCl and warmed to room temperature. The mixture was diluted with EtOAc, washed with water, brine, dried (MgSO 4) and concentrated. There were obtained 452 mg (78%) of a 5: 1 (by ^X H NMR) of threo: erythro isomers. Threoisomer Pure 17b was obtained as a mixture of rotamers by fractional recrystallization from EtOAc / hexanes, mp 157-158 ° C, ^[a] _D -168 ⁰ (c 1.02, CHCl 3); IR (thin film) 1750, 1690 , 1390, 1330, 1010 cm ^{-1, Χ Η} NMR (CDCl3, 300 MHz) δ

-307.67 (dd, 2H, J = 2Hz, 6Hz, 2 * OCHCH =), 7.41-6.94 (m, 16H, 2 * ArH), 6.6 (d, 4H, J = 7 Hz, 2 x ArH), 6.08 (dd, 2H, J = 2 Hz, 2 x CH = CHCO), 5.48 (dt, 2H, J = 2 Hz, 5 Hz, 2 x CHO), 5 , 16 and 5.07,

4.89 and 4.75 (2 x AB quartet, 4H, J = 13 Hz, 2 x CO ₂ CH ₂ Ph), 4.93 and 4.84 (2 x d, 2H, J = 8 Hz, 2 x PhCHN 4.71 (dd, 2H, J = 2 Hz, 5

Hz, 2 x CHN), 2.74 and 2.45 (2 xm, 2H, 2 x CH _3), 1.92 to 1.61 (m, 4H, 2 x CHzCHN), 0.55 and 0.53 (2 xd, 6H, J = 7 Hz, 2 x CHCH 3), ¹³ C (CDCl 3, 75 MHz) ^δ 173.0, 154, 4, 140, 3, 135.7, 128, 6, 128.3, 128 , 2, 128.0, 127.5, 127.2, 127.1, 127.0, 126, 1, 120, 8, 66, 9,

66.4, 58.6, 36.3, 32.2, 15.2, exact mass calculated for C 23 H 23 NO 4 378.170534, found 378.1681.

(2S, 2'S, 3R, 4S) -3-Methyl-5- (5'-oxo-tetrahydro-furan-2'-yl) -2-phenyl-pyrrolidine-1-carboxylic acid benzyl ester 18b:

To a solution of compound 17b (210 mg, 0.56 mmol) in benzene (4 mL) was added 5% Pt / C (20 mg) and the mixture was stirred under hydrogen for 1 hour. The catalyst was filtered off through a pad of celite and the solvent was evaporated. 190 mg (90%) rotameric mixture of 18b as a syrup, ^[a] D -52 ⁰ (c 0.86, CHCl 3) IR (thin film) 1780, 1700, 1400, 1340, 1160 cm ^{-1, X} 1 H NMR (CDCl 3, 300 MHz) ^δ 7.33-6, 96 (m, 16H, 2 × ArH), 6.66 (d, 4H, J = 7Hz, 2 × ArH), 5.1 (AB quartet) , 2H, J = 12 Hz, CO2CH ₂ Ph), 4.97 (d, IH, J = 8Hz, PhCHN), 4, 90-4, 68 (m, 5H, 2 x OCH, PhCHN, CO ₂ CH ₂ Ph), 4.58 (m, 1H, CHN), 4.48 (t, 1H, J = 7Hz, CHN), 2-88-1, 83 (m, 14H), 0.58 and 0, 57 (2 × d, 6H, J = 7 Hz, CHCH 3), ¹³ C NMR (CDCl 3, 75 MHz) ^δ 176, 9, 156.0, 140, 6, 135, 8, 128.2, 128.0, 127 , 4, 127.3, 126, 9, 126.2, 81.8, 66, 9, 66.6, 59.3, 36, 3, 32.9,

28.5, 24, 7, 15, 5, exact mass calculated for C ₂ 3 H ₂ NO 4 λ

380.186184, found 380.1822.

(2S, 2'S, 3R, 4'R, 5S) -3-Methyl-5- (4'-methyl-5'-oxo-tetrahydro-furan-2'-yl) -2-phenyl-pyrrolidine-1-carboxylic acid benzyl ester 19b:

To a cooled (-78 ° C) solution (TMSHLi (0.24 mL, 1 M in hexanes, 0.24 mmol) in 0.24 mL anhydrous THF was added Mel (0.14 mL, 2.19 mmol) then solution of 18b (79 mg, 0.21 mmol) in 1 mL of anhydrous THF and stirred for 40 minutes, rinsing the reaction mixture with saturated aqueous NaHCO ₃ and allowing to warm to room temperature, then diluting with EtOAc, washing Purification of the residue by column chromatography (silica gel, 35% EtOAc / hexanes) gave 46 mg (56%) of the monomethylated product 19b as a mixture of rotamers, [ ^a ] D -32 ⁰ (c 1.43, CHCl3) IR (thin film) 1775, 1675, 1440, 1390,

1225 cm ^-1 , ¹ H NMR (CDCl3, 300 MHz) ⁵ 7,39-6 , 95 m 16H, 2 x ArH), 6.65 (d, 4H, J = 7Hz, 2 x ArH), 5,07 and 4.82 (2 x AB quartet, 4H, J = 12 Hz, 2 x CO ₂ CH ₂ Ph), 4 , 97 a 4.87 (2 x d, , 2H, J = 8Hz, 2 x PhCHN) , 4.71 and 4.62 (2 x m, 2H, 2 x CHO), 4.53 (dd, 1H, J = 5Hz, CHN) 4.4 (t, 1H, J = 7Hz) CHN), 2.9-1.7 (m, 12H),

1.27 and 1.18 (2 x d, 6H, 2 x CHCH 3 CO), 0.57 and 0.55 (2 x d, 6H,

J = 7 Hz, 2 x CHCH 3), ¹³ C NMR (CDCl 3, 75 MHz) ^δ 179, 9, 156, 1, 140, 6, 135.8, 128.2, 128.0, 127.4, 126, 8, 126, 1, 80.0, 66, 9, 66, 6, 59, 8, 36, 1, 33, 6, 33, 5, 33, 1, 15, 9, 15, 4, exact mass calculated for C 24 H ₂ aNO4 394.201834, found 394, the 20,260th

(1'S, 2S, 3R, 3'R, 5S) -5- (3'-Butylcarbamoyl) -1'-hydroxybutyl) -3-methyl-2-phenylpyrrolidine-1-carboxylic acid benzyl ester 2b:

-32K solution of 45 mg (0.11 mmol) of 19b in 0.5 mL of anhydrous CH ₂ C1 ₂ was added BuNHAlMe ₂ (0.33 mL, 0.67 M in CH ₂ C1 _2, 0.22 mmol) and the reaction the mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0 ° C and rinsed with 2 mL of 1 N aqueous HCl, diluted with EtAOc, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by PTLC (10% acetone / CHCl 3). To give 22 mg (52%) of the amide 2b as a syrup, ^[a] _D -80, 0 ⁰ (c 0.99, CHCl 3); IR (thin film) 3500-3300, 1710, 1670, 1550, 1410, 1340 cm ^-1 , Έ NMR (CDCl 3, 300 MHz) ^δ 7.4-6.96 (m, 8H, ArH), 6.63 (d, 2H, J = 7 Hz, ArH), 5.9 (broad s , 1H, NH), 4.85 (d, 1H, J = 7Hz, PhCHN), 4.89 (AB quartet, 2H, J = 13 Hz, CO ₂ CH ₂ Ph), 4.63 (br s, 1H, OH)

4.17 (dt, 1H, J = 2Hz, 9Hz, CHN), 3.56 (dt, 1H, J = 2Hz, 9Hz, CHOH), 3.36-3.17 (m, 2H, CH 2 NH), 2.75-2.51 (m, 2H, CHCH ₃ , CHCH ₃ CO), 1.96-1.72 (m, 3H), 1.55-1.23 (m, 5H), 1.19 (d, 3H,

J = 7Hz, CH ₃ CO), 0.93 (t, 3H, J = 7Hz, CH ₂ CH _3), 0.57 (d, 3H, J = 7

Hz, CHCH α), ¹³ C (CDCl 3, 75 MHz) ^δ 176, ^δ , 158.3 140.2, 135.8,

128.1, 128.0, 127.4, 127.0, 126.9, 126.3, 74.3, 67.2, 66.2,

64.0, 40.6, 38.9, 37.1, 20.0, 18.4, 14.9, 13.6, exact mass calculated for C ₂ H ₃ N ₃ O ₂ 467.290983, found 467.2925.

(2R, 4S, 5S, 7R) -5 - [[1,1-Dimethylethoxy) carbonyl] amino] 4-hydroxy-2,7-dimethyl-8-phenyloctanoic acid butylamide 3a:

To a mixture of 15 mg (0.023 mmol) of amide 2b and 28 mg (0.129 mmol) of di-tert-butyl dicarbonate in 0.5 mL of 40% MeOH / EtOAc was added 15 mg of Pearlman catalyst (20% Pd (OH) ₂ /). C) and the suspension is stirred under 50 psi of hydrogen for 3 days. The catalyst was filtered off and the solvent was evaporated. The residue was purified using PTLC (10% acetone / CHCl ₃ ) to give 6.4 mg (46%) of the compound.

-333a, which is identical to the compound obtained by hydrogenolysis of amide 2a.

If those skilled in the art realize these preferred embodiments, it will be understood that they may be varied, modified, alternated, and replaced without affecting or modifying the function. Although the invention is described herein by these details and procedures, the invention is not limited to them and it will be apparent to those skilled in the art that numerous modifications and variations can be made without departing from the spirit, nature, and scope of the present invention.

Industrial applicability

The compounds prepared according to the invention are valuable intermediates for the preparation of pharmaceutical agents such as renin inhibitors and HIV protease inhibitors.

3 & 6 <Γ- 6 6

Claims (10)

PATENT CLAIMS A process for preparing a first compound of formula I wherein n is zero to 3 inclusive, And they are either hydrogen or they form a single carbon-nitrogen bond, R 1 represents a hydrogen atom or a carboxy group substituted by a hydrocarbon radical, wherein the hydrocarbon radical is selected from the group consisting of C 1 -C 6 alkyl or C 7 -C 10 aralkyl; R and R ₃ are independently alkyl having 1 to 4 carbon atoms, R ₄ represents an alkyl group having 1 to 6 carbon atoms or a substituent of an aliphatic nature, such as butyl, 2-morpholinoethyl or 2-carbamoyl-2-methylpropyl, R 5 is selected from the group consisting of aromatic radicals, substituted aromatic radicals and heteroaromatic radicals, substituted or unsubstituted cycloalkyl groups, cycloalkenyl groups having from 3 to 8 carbon atoms, with substituents selected from the group consisting of alkyl, alkoxy of 3 to 10 carbon atoms, and alkoxy derivatives , such as 3-methoxypropyloxy, primary and secondary amides, and alkyl derivatives, -35 comprising a step selected from the group consisting of (a) hydrogenolysis of a second compound of the above general formula; I of the formula wherein both A together form a single carbon-nitrogen bond and R 1 represents a carboxy group substituted by an alkyl group wherein the alkyl group has 1 to 6 carbon atoms, in the presence of Pd (OH) ₂ / C, of formula wherein both A forms a single carbon-nitrogen bond and R 1 is a carboxy group substituted with an aralkyl group wherein the aralkyl group has 7 to 10 carbon atoms, in the presence of Pd (OH) ₂ / C and a dialkyl dicarbonate and (c) reacting a fourth compound of formula (II) wherein n is zero to 3 inclusive, R 1 represents a carboxy group substituted with a hydrocarbon radical, wherein the hydrocarbon radical is selected from the group consisting of C 1 -C 6 alkyl or C 7 -C 10 aralkyl, R ₂ and R 3 are each independently C 1 -C 4 alkyl, with R ₄ NHHA Me ₂ , wherein R 1 is C 1 -C 6 alkyl. -362. The method of claim 1 wherein n is zero in both general formulas. 3. The process of claim 2, comprising the step of hydrogenolysis of the second compound. The method of claim 1, comprising the step of hydrogenolysis of the third compound. 5. The process of claim 1 comprising the step of reacting the fourth compound. The method of claim 5, wherein R 1. represents a carboxy group substituted by an alkyl group wherein the alkyl group has 1 to 6 carbon atoms. The process of claim 5 wherein R 1 is a carboxy group substituted with an aralkyl group wherein the aralkyl group has 7 to 10 carbon atoms. A compound of formula II wherein n is zero to 3 inclusive, -37R1 represents a carboxy group substituted by a hydrocarbon radical, wherein the hydrocarbon radical is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, _R2 and R3 are independently alkyl having 1 to 4 carbon atoms, and R ₅ is selected from the group consisting of aromatic radicals, substituted aromatic radicals and heteroaromatic radicals, substituted or unsubstituted cycloalkyl groups, cycloalkenyl groups having 3 to 8 carbon atoms, with substituents selected from the group consisting of alkyl, alkoxy of 3 to 10 carbon atoms, and C 3 -C 10 alkoxy derivatives such as 3-methoxypropyloxy, primary and secondary amides, and alkyl derivatives, or salts thereof. A compound according to claim 8 of the formula A compound according to claim 8 of the formula