GB2395480A - Pyrrolo[1,2-a]pyridine & pyrrolo[1,2-a]azepine scaffolds useful for the synthesis of compounds with biological activity - Google Patents

Abstract

Cyclic compounds of formula (I) having an azabicycloalkane structure are useful as intermediates for the synthesis of compounds with biological activity. <EMI ID=1.1 HE=44 WI=37 LX=1118 LY=308 TI=CF> <PC>[wherein: the symbol <EMI ID=1.2 HE=8 WI=3 LX=887 LY=809 TI=UI> <PC>represents a bond above or below the plane of the page, n is the number 1 or 2, m is an integer from 1 to 5, X is OH, N3, NH2, or COOH; and R<1> is H, C1-C4 alkyl or a suitable protecting group and R<2> is H or a suitable protecting group; or a salt thereof; or racemates, single enantiomers, single diastereoisomers or mixtures of such compounds and/or of such salts] Cyclic peptides of formula (I) are claimed wherein R<1> and R<2> together are a peptide sequence, with the RGD sequence -Asp-Gly-Arg- being particularly preferred. The latter are selective antagonists for a v b 3 and/or a v b 5 integrins, and are useful for the treatment of an altered angiogenesis, or for the treatment of tumor metastasis, retinopathy, acute kidney failure or osteoporosis. The above compounds may be used as carriers for the selective delivery of drugs, the carried drug being linked by a chemical bond, eg one formed by reaction of the drug with group X. They may also be used as reverse-turn inducers.

Description

J 1 2395480

Scaffolds useful to the synthesis of compounds with biological activity The present invention relates to cyclic compounds having the azabicycloalkane structure. Said compounds are useful as intermediates for the synthesis of compounds with biological activity. Background of the invention

Design and synthesis of novel bicyclic lactams as peptidomimetics is currently an area of intensive research in the field of peptide and

medicinal chemistry (L. Halab et al. Biopolymers, Peptide Science, 2000, 55, 101; S. Hanessian et al., Tetrahedron 1997, 53, 12789; J. Mulzer, et al., Tetrahedron 2000, 56, 4289; C. E. Grossmith, et al., Syalett 1999, 1660; J. A. J. Becker, et al., J. Biol. Chem. 1999, 274, 27513; D. J. Witter, et al., Bioorg. Med. Chem. Lett. 1998, 8, 3137; M. A. Estiarte, et al., J. Org. Chem. 2000, 65, 6992; F. Polyak, et al., J. Org. Chem. 2001, 66, 1171; Z. Feng, et al., J. Org. Chem. 2001, 66, 1181).

Because of the intrinsic interest of these substrates as ligands for a wide variety of biological receptors, incorporation of these scaffolds into peptide chains can be used to generate novel structures of relevance to biological application. In the course of previous studies on peptide Secondary structure mimics, the present inventors have synthesized several 6,5- and 7,5-fused azabicycloalkane amino acids (L. Colombo, et al., Tetrahedron Lett.

1995, 36, 625; L. Colombo, et al., Tetrahedron Lett. 1995, 36, 625; L. Colombo, et al., Gazz. Chim. It. 1996, 126, 543; L. Colombo, et al., Gazz. Chim. It. 1996, 126, 543; L. Colombo, et al., Tetrahed ron 1998, 54, 5325; M. Angiolini, et al., Eur. J. Org. Chem. 2000, 2571; L. Manzoni et al., Tetrahedron, 2001, 57, 249; L. Selfish et al., Tetrahed ron, 2001, 57, 6463; EP 1 077 218). These structures can be regarded as conformationally restricted substitutes for Ala-Pro

and Phe-Pro dipeptide units (L. Belvisi et al., Eur. J. Org. Chem. 2000, 2563; L. Belvisi et al., Eur. J. Org. Chem. 1999, 389; C. Gennan, et al.' Eur. J. Org. Chem. 1999, 379).

Functionalizing these molecules with different appendages is a very attractive target, because the side chains could improve peptide-receptor affinity by interacting with hydrophobic or hydrophilic pockets. On the other hand, diversification of bicyclic lactams by tethering of different pharmacophoric groups may provide library members exhibiting different biological activity.

Finally, in analogy to the unsubstituted conformational constrained dipeptide mimics (L. Belvisi et al., Org. Lett., 2001, 3, 1001), these lactams can be incorporated into cyclic pseudopeptides containing the ROD epitope. As such, these molecules can be homed selectively to tissues that over-express these receptors (e.g. epithelial cells involved in vascular growth), and thus can serve to control selective delivery of drugs which may be appended to the lactam substituent (W. Arap, et al., Science, 1998, 279, 377).

Notwithstanding the number of scaffolds available in the art, there is still the need of expanding these libraries with different conformationally constrained dipeptide mimetic units, particularly in the light of the importance of amino acid side chains as sites for interaction in various recognition events.

Abstract of the invention It has now been found that conformationally constrained azabicyclo[X.Y.0]alkane that posses heteroatom-substituted side chains at the 7 (or 8)-position satisfy the needs perceived in this field of technology.

Accordingly, it is an object of the present invention a compound of formula (I)

Flex ( >R2 Nl R. (I) wherein: the symbol can represent a bond above or below the plane of the page, n is the number 1 or 2, m is an integer from 1 to 5, X is OH, N3, NH2, and COOH; Rot is H. Cl-C4 alkyl or a suitable protecting group; R2 is H or a suitable protecting group, their salts, racemates, single enantiomers, single diastereoisomers as well as their mixtures.

These compounds are useful as intermediates for the synthesis of cyclic peptides, in particular those containing the Arg-Gly-Asp (ROD) sequence.

Accordingly, it is an object of the present invention a compound of formula (I) as defined above, a process for its preparation, its use as intermediated for the preparation of cyclic peptides with biological activity and the cyclic peptides thereby obtained, as well as their use as medicaments.

In a particularly preferred embodiment of the present invention, the compounds of formula (I), wherein the groups Rat and R2 form the tripeptide Arg-Gly-Asp are a further object of the present invention. In another preferred embodiment of the present invention, the compound of formula (I) is used as carrier for the selective delivery

of drugs. In carrying out this embodiment of the present invention, the person skilled in the art will be able to select a suitable drug depending on the target which the compound of formula (I) is directed to. For example, compounds of formula (I) containing the ROD sequence are integrin inhibitors, and in particular cubs selective inhibitors provided with antiangiogenic activity. The drug to be carried will be a drug of choice in the disease to be treated wherein an antiangiogenic activity is beneficial. For a guidance of the antiangiogenic treatment, a reference for the skilled person is, for instance EP 1 077 218. The carried drug can be linked to the compound of formula (I) in any well-known conventional manner through the groups available for a chemical bond, which will be cleaved at the target site in physiological conditions. For example, in the compound of formula (I), the group X is available for the bond with the drug.

The compounds of the present invention can be seen as conformationally constrained scaffolds with the potentiality to replicate the backbone geometry and side-chain function of dipeptide residues like serine, lysine, glutamate, and related amino acids. These amino acid motifs may be used as conformationally constrained entities that mimic segments of natural peptide substrates. Alternatively, the functionalised side chain could be used as a site to append pharmacologically relevant groups to enhance protein-protein or receptor-substrate interaction. The bans relation between the steneocenter in 6 and 9 and 7 and 10 respectively, in the bicyclic lactams, was achieved by a stereoselective allylation of the hemiaminal 11. After hydrogenation, the lactams were obtained as easily separable stereoisomeric mixture at the N-bearing carbon atom.

As an example, the compound 5a can be converted to other heterosubstituted side chains via displacement of its respective methansulfonate with sodium aside.

Applications of these compounds as reverse-turn inducers and as scaffolds for the synthesis of biologically active compounds are one possible embodiment of the present invention.

The present invention shall now be described in detail, also by means of examples.

Detailed description of the invention

According to the present invention, preferred compounds are those of formula (I) wherein: a) n is 1, m is 2, X is OH; b)nis2,mis2,XisOH; A process for the preparation of the compounds of the present invention shall be described in details, by making reference to the synthetic schemes appended as Figures, wherein: Figure 1 is a general scheme for the synthesis of the compounds of formula (I), where, by way of example to show the stereospecificty of the process, only a single diastereoisomer is shown, being intended that the skilled reader will be able to carry out this process over the whole width of the present invention; Figure 2 is an example of synthesis of the intermediate 5- allyl praline 12; Figure 3 is an example of synthesis of the preferred compounds of formula (I); Figure 4 is an example of transformation of the group X in the compounds of formula (I).

Figure 5 is a graphical explanation of the stereochemistry of the compounds of the present invention.

Figure 6 is an exemplary list of suitable protecting groups. Any other suitable protecting group is within the general knowledge of a person of ordinary experience in this art.

All the figures show, for sake of clarity, the preparation of the preferred compounds of formula (I), but the skilled reader will understand and be able to carry out the whole invention as foreseen in formula (I).

According to the present invention and with reference to Figure 1, the compounds of formula (I) can be prepared with a process comprising: a) Horner-Emmons olefination of a compound of formula 1 or 2, to give a compound of formula 3 or 4; b) hydrogenation of the compound obtained in step a) and cyclisation to give the final compound of formula (I), wherein X is OH; and c) optionally converting the group X into another one comprised in the definition; and d) optionally converting the compound of formula (I) into a salt thereof or isolating a single enantiomer or a single diastereoisomer.

The synthetic process for the preparation of the compounds of formula (I) above relies on the (,)-selective Horner-

Emmons/double bond reduction that has been described for the unsubstituted compounds (see Eur. J. Org. Chem. 2000, 2571, and EP 1 077 218 above mentioned), but uses as starting material the aldehydes 1 and 2, which carry an appendage on the Pro ring. The resulting lactams 5a,b and 6a,b (Figure 3) feature a hydroxy terminal side-chain. Elaboration of the side chain to modify the heteroatom is also demonstrated starting from 5b (Figure 4).

Other transformations of the X group from OH into the other meanings provided in formula (I) are within the general knowledge

of the person skilled in the art.

For example, when X is OH, it can be transformed into the amino group, through aside and then by catalytic hydrogenation with He on 10% Pd/C in MeOH. (Chem.Commun. 2001 (2), 203-4).

Alternatively, when X is OH, it can be transformed into the carboxy group by means of well-known oxidising methods, for example by using the reactant TEMPO (2,2,6,6-tetramethylpiperidine- 1 -oxyl) (JACS 1984, 106, 3374).

Referring to Figure 2, the length of the side chain depends on the value of (m), which can be varied according to the processing of the double bond through the synthetic process. The double bond can be submitted to ozonolysis, and in this case, the number of carbon atoms on the chain will be 2. A side chain with 3 carbon atoms (m=3) will be obtained by submitting the double bond to hydroboration. Higher values of m can be achieved by means of olefin metathesis. All these transformations are well-known in the art and disclosed in the literature.

As shown in Figure 1, the process according to the present invention employs conventional protecting groups, which are well known in the general knowledge of this field. For example, suitable

protecting groups are 9-fluorenyl-methoxy-carbonyl (Fmoc), butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), for the amino group; whereas the carboxy group is usually protected in the form of ester, for example lower alkyl or benzyl ester. The N-Cbz group is then deprotected by catalytic hydrogenation, for example on 10% Pd/C in MeOH for 24 hours. The N-Boc group is then deprotected by treatment with 70% HC104 in AcOtBu at 0 C for 4 hours and the COO-tBu group is then deprotected by treatment with CFaCOOH in CHICO, 1 hour at room temperature.

The synthesis of lactams Sa-b and 6a-b was accomplished

following the steps outlined in Figure 1. The starting aldehydes 1 and 2 were stereoselectively synthesized from the 3-allyl-

pyroglutamic ester 7 (Figure 2), readily obtainable from glutamic acid via a known procedure (S. Hanessian, R. Margarita, Tetrahedron Lett. 1998, 39, 5887). After protecting group exchange, ozonolysis of 8 followed by treatment with NaBH gave the corresponding alcohol which was protected as silyl ether (texyldimethylsilyl chloride and imidazole in DMF) giving 9 in 78% yield over two steps. The lactam 9 was N-protected as an N-Cbz derivative using LiHMDS and CbzC1 in a THE solution affording 10 in 80% yield.

Selective reduction of the imide 10 to the hemiaminal 11 was performed using lithium triethylborohydride at -78 C. The hemiaminal was then treated with allyltrimethylstannane in the presence of tertbutyldimethylsilyltriflate in anhydrous CHICK to afford 12 in 62% yield after the two steps as the only isomer. The stereochemistry of the newly formed stereocentre was determined by NOE experiments. The nucleophilic addition of the allyl unit selectively occurs bans to the adjacent sidechain, as we have already observed in a previous work (see the above mentioned Tetrahedron, 2001, 57, 6463).

The 5-allyl praline 12 was further elaborated to obtain either aldehyde 1 or 2 (Figure 3).

The aldehyde 1 was obtained via reductive ozonolysis, and was treated with the commercially available phosphonate to give 3 in 65% yield over two steps [9:1 (Z)/(E) ratio]. Treatment of 3 with Bock followed by hydrogenation and by refluxing in MeOH/DIPEA gave a mixture of easily separable 5a and 5b in 66% yield and 2:8 diastereoisomeric ratio, over the three steps.

The aldehyde 2 was prepared starting from the 5-allyl proline 12 by hydroboration and Swern oxidation (67% over 2 steps). The

aldehyde was treated with the phosphonate to give 47 mainly as a Z-isomer, in 92% yield. Boc-nitrogen protection followed by methyl ester hydrolysis with NaOH in THE gave the corresponding acid, which was reduced (H2/Pd-C) and subsequently cyclized with condensing agents to give the easily separated lactams 6a and 6b in 46% overall yield. The stereochemistry of the final products was unequivocally determined by NOE experiments.

Finally, modification of the lactam side-chain was demonstrated in the case of 5b, as shown in Figure 4. Thus, deprotection of 5b (TBAF, THE 98%) and activation of 13 with MsCl followed by nucleophilic displacement with sodium aside in DMF at 80 C gave aside 14. The azide was isolated in 94% overall yield from 5b.

If desired, the compounds of formula (I) can be further transformed into biologically active compounds, for example cyclic peptides, such as those comprising the ROD sequence. The preparation of cyclic peptides is described in the above mentioned EP 1 077 218 and the referenced literature.

In this aspect, another object of the present invention is a compound of formula (II) MARX (L:R2 NIR, (II) wherein: the symbol) can represent a bond above or below the plane of the page, n is the number 1 or 2, m is an integer from 1 to 5,

X is OH, N3, NH2, and COOH; Rot and R2 together are the group Asp-Gly-Arg, their pharmaceutically acceptable salts, their racemates, single enantiomers, single diastereoisomers as well as their mixtures.

Other objects of the present invention are the uses of the compounds of formula (II) as medicaments, in particular for the preparation of a medicament having a selective antagonist action for aV'B3 integrins. More in detail, the medicament is intended for the treatment of an altered angiogenesis, such as in diseases selected from tumor metastasis, retinopathy, acute kidney failure and osteoporosis.

Assaying the compounds of formula (II) for their capacity as selective antagonists for avp3 / Avis integrins can be done with conventional tests, for example as disclosed in the above mentioned EP 1 077 218.

Conventional pharmaceutical compositions comprising a compound of formula (II) in admixture with at least a pharmaceutically acceptable excipient and/or vehicle are still another object of the present invention.

The present invention shall now be further illustrated by means of Examples.

General Remarks: 1H- and iC-NMR spectra were recorded in CDC13 solution as indicated, at 200 (or 300, 400) and 50.3 MHz, respectively. The chemical shift values are given in ppm and the coupling constants in Hz. - Optical rotation data were obtained with a Perkin-Elmer model 241 polarimeter. Thin-layer chromatography (TLC) was carried out using Merck precoated silica gel F-254 plates. Flash chromatography was carried out using Macherey-Nagel silica gel 60, 230-400 mesh. - Solvents were dried according to standard procedures, and reactions requiring anhydrous conditions were performed under nitrogen. Solutions

containing the final products were dried with Na2SO4, filtered, and concentrated under reduced pressure using a rotary evaporator.

Example 1

General Procedure A: Preparation of Acrvlic Ester 3 and 4 bv HornerEmmons Reaction (Figure 1) To a stirred solution of tBuOK (0.115 mmol) in dry CHC12 (1 mL) under nitrogen, a solution of (Z)-oc-phosphonoglycine trimethyl ester (0.115 mmol) in dry CH2C12 (0.5 mL) was added at-78 C.

The resulting mixture was stirred for 30 min at this temperature and then a solution of the appropriate aldehyde (0.076 mmol) in dry CHCl (1 mL) was added. After 5 h, the solution was allowed to warm to room temperature and neutralized with phosphate buffer. The aqueous phase was extracted with CHCl2, the combined extracts were dried with Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate) to afford the acrylic ester as a (Z)/(E) diastereoisomeric mixture.

General Procedure B: Preparation of the N-Boc-Protected Acrylic Ester A solution of the acrylic ester (0.058 mmol), (Boc)oO (0.117 mmol), and a catalytic amount of DMAiP in dry THE (1 mL) was stirred for 30 min under nitrogen. The solution was then quenched with water ( 1 mL) and extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4 and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate) to yield the Boc-

protected acrylic ester.

Synthesis of the intermediate 12 (Figure 2)

Ester 8: To a solution of 7 (1.7 g, 9.34 mmol) in THE (93.4 mL) was added 2 N NaOH (9.34 mL, 18.68 mmol). After stirring for 30 min. at room temperature IRA 120 H+ was added and then the reaction mixture was filtered and the solvent was evaporated under reduced pressure to yield 1. 56 g of acid (99%) as white solid; m.p. 123-124 C. - [a]D20 = + 57.1 (c = 0.94, CHC13). - AH NMR (200 MHz, CDCl3): 6= 1.95 (m, 1 H. -HCH-), 2.2 (m, 1 H. -HCH-), 2.61 (m, 2 H. -CH2-), 3.71 (m, 1 H. -CHC=O), 4.3 (m, 1 H. -CHCO2H), 5.1 (m, 2 H. -

CH=CH2), 5.72 (m, 1 H. -CH=CH2), 7.52 (bs, 1 H. NI:1). - i3C NMR (50.3 MHz, CDCl3): = 180.6, 174.9, 134.6, 117.5, 54.5, 41.2, 34.7, 30.2. - FAB+ MS: calcd. For CgHNO3 169.07; found 170. -

CsHNO3 (169.07): calcd. C 56.80, H 6.55, N 8.28; found C 56.74, H 6.55, N 8.27. - To a solution of acid (1.58 g, 9.34 mmol) in dry CH2C12 (93.4 mL) was added O-tert-butyl-N,N-diisopropyl-isourea (6.7 mL, 28.01 mmol) and the mixture was refluxed for 48 h. The solvent was then evaporated and the residue was washed with Et20 to remove the major urea formed as byproduct. The collected organic solvents were evaporated and the crude was purified by flash chromatography (hexane/ethyl acetate, 3:7) affording 2. 08 g of 8 (99%) as colorless oil. - [a]D20 = + 31.9 (c = 1, CHCl3). - H NMR (400 MHz, CDCl3): = 1.48 [s, 9 H. C(CH3)3], 1.81 (m, 1 H. -

HCH-), 2.17 (m, 1 H. -HCH-), 2.55 (m, 3 H. -CH2-), 4.1 (m, 1 H. -

CHCO2tBu), 5.1 (m, 2 H. -CH=CH2), 5.71 (m, 1 H. -CH=CH2), 5.81 (bs, 1 H. NH). - 13C NMR (50.3 MHz, CDCl3): = 178.5, 170.9, 135.2, 117.0, 82.2, 54. 3, 40.6, 35.0, 30.4, 27.9. - FAB+MS: calcd.

For C2HsNO3 225.14; found 226. - C2HsNO3 (225.14): calcd. C 63.98, H 8.50, N 6.22; found C 64.04, H 8.52, N 6.23.

Silyl derivative 9: A stirred solution of 8 (1.16 g, 5.16 mmol) in MeOH (51.6 mL) was cooled to-60 C, whereupon O3 was bubbled through it (flow rate = 30 L/h). After 1.5 h, N2 was bubbled through it in order to eliminate the excess of O3. To the solution was then added NaBH in portions until the intermediate was completely disappeared, the solvent was evaporated under reduced pressure and the residue was redissolved in EtOAc and washed

) with brine. The organic phases were dried with Na2SO and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate) to yield 0.946 g of alcohol (80%) as white solid. m.p. 82-83 C. - [a]D20 = 14.25 (c = 1, CHC13). - 1H NMR (400 MHz, CDC13): = 1.48 [s,9 H. -C(CH3)3], 1.75 (m, 1 H. -HCHCH20H), 1.81 (m, 1 H. -HCHCHCOOtBu), 2.0 (m, 1 H. -HCHCH20H), 2.69 (m, 1 H. -CHC=O), 2.7 (m, 1 H. -

HCHCHCOOtBu), 3.8 (m, 2 H. -CH20H), 4.15 (m, 1 H. CHCOOtBu), 5.9 (bs, 1 H. NH). - i3C NMR (50.3 MHz, CDC13): = 179.4,170.0,81.8,60.7,54.4,40.0,33.4, 31.7,27.3. - FAB+MS:

calcd. For CHgNO4 229.13; found 230. - CHgNO. (229.13): calcd. C 57.62, H 8.35, N 6.11; found C 57.56, H 8.34, N 6.11.

To a stirred solution of alcohol (0.708 g, 3.09 mmol), in DMF (4.41 mL), texyldimethylsilyl chloride (1.82 mL, 9.27 mmol) and imidazole (1.26 g, 18.55 mmol) were added sequentially. After 16 h the solvent was evaporated and the crude was purified by flash chromatography (hexane/ethyl acetate 1:1) to yield 1.12 g of 9 (98%) as a colorless oil. - [a]D20= + 10.02 (c = 1.025, CHC13). - H NMR (400 MHz, CDC13): = 0.12 [s, 6 H. -Si(CH3)2], 0.90 [m, 12 H. -CH3), 1.50 [s,9 H. -C(CH3)3], 1.51 (m, 1 H. -HCHCH20Si), 1.6 [m, 1 H. -CH(CH3)2], 1.82 (m, 1 H. -HCHCHCOOtBu), 2. 15 (m, 1 H. -

HCHCH20Si), 2.6 (m 1 H. -CHC=O), 2.61 (m, 1 H. -

HCHCHCOOtBu), 3.75 (m, 2 H. -CH20Si), 4.21 (m, 1 H. CHCOOtBu), 6.2 (bs, 1 H. NIT). - i3C NMR (50.3 MHz, CDC13): = 179.1, 170.8,60.8,54.4,38.7, 33.8, 32.1,27.8,20.2, 18.4, -3.5, -

3.6. - FAB+MS: calcd. For CisH37NO4Si 371.25; found 372. -

CsH37NOSi (371.25): calcd. C 61.41, H 10.04, N 3.77; found C 61.47, H 10. 05, N 3.77.

N-Cbz-Protected Silyl derivative 10: To a solution of 9 (0.552 g, 1.48 mmol) in THF (5 ml) was added LiHMDS 1 M in THF (1.63 mL, 1.63 mmol) at 50 C. After 20 min benzyl chloroformate (0.230 ml, 1.63 mmol) was added and the solution was stirred for 20 min then a NHC1 satured solution was added, the aqueous phase extracted with EtOAc and the organic phase dried over

Na2SO, filtered and evaporated. The crude material was purified by flash chromatography (hexane/ethyl acetate 8:2) yielding 0.603 g (80%) of 10 as colorless oil. - [a]D20 = - 10.6 (c = 0.996, CHCl3). -

lH NMR (400 MHz, CDCl3): = 0.12 [s, 6 H. -Si(CH3)2], 0.61 (m, 12 H. -CH3), 1.48 [s, 9 H. -C(CH3)3], 1.55 [m, 2 H. -HCHCH20Si, -

CH(CH3)2], 1.75 (m, 1 H. -HCHCHCOOtBu), 2.11 (m, 1 H. HCHCH2OSi), 2.55 (m, 1 H. -HCHCHCOOtBu), 2.7 (m, 1 H. -

CHC=O), 3.7 (m, 2 H. -CH20Si), 4.48 (m, 1 H. -CHCOOtBu), 5.25 (s, 2 H. CH2Ph), 7.3 (m, 5 H. aromatics). - i3C NMR (50.3 MHz, CDC13): = 175.2, 170.2, 128.4, 128.3, 128.1, 82.2, 68.2, 60.3,

58.0, 39.9, 34.0, 28.1, 27.7, 20.2, 18.4, -3.6. - FAB+MS: calcd. For C27H3NOSi 505.29; found 506. - C2H3NOSi (505.29): calcd. C 64.12, H 8.57, N 2.77; found C 64.18, H 8.59, N 2.77.

Hemiaminal 11: To a solution of 10 (0.754 g, 1.49 mmol) in dry THE (14.8 ml), LiEt3BH 1M (1.79 ml, 1.79 mmol) was added at -78 C and the solution was stirred for 3 h, then a saturated NHC1 solution (10 ml) was added. The aqueous phase was extracted with EtOAc, the combined organic layers were dried over Na2SO, filtered and evaporated. The crude, as a yellowish oil, was submitted to the next reaction without further purification. - tH NMR (200 MHz, CDC13): = 0.12 [s, 6 H. -Si(CH3)2], 0.81 (m, 12 H. -CH3), 1.42 [s, 9 H. -C(CH3)3], 1.55-2.20 [m, 6 H], 3.60 (m, 2 H. -

CH20TDS), 4.20 (m, 1 H. -CHCOOtBu), 5.05 (s, 2 H. -CH2Ph), 5.41, 5.43 (2 m, 2 H. -CHOH) 7.3 (m, 5 H. aromatics).

Allyl pyrrolidine 12: To a solution of 11 (0.678 g, 1.34 mmol) and allyltributyltin (0.48 mL, 1.61 mmol) in dry CH2C12 (13 mL), under argon atmosphere and at - 78 C, tert-butyldimethylsilyltriflate (0.37 mL, 1.61 mmol) was added dropwise. The reaction mixture was stirred for 1 h, then a NaHCO3 satured solution (10 mL) was added and the aqueous phase was extracted with CH2C12. The collected organic phases were dried with Na2SO, filtered and evaporated. The crude was purified by flash chromatography (hexane/ethyl acetate 9:1) affording 0.44 g (62% over two steps) of

12 (only trans-isomer) as a colorless oil. - [a]D20 = 43.1 (c = 1.001, CHCl3). - 1H NMR (200 MHz, CDCl3): = 0.02 [s, 6 H. -Si(CH3)2], 0.85 (s, 12 H. -CH3), 1.47 [s, 9 H. -C(CH3)3], 1.53 (m, 1 H. -

HCHCH20Si), 1.6 [m, 1 H. -CH(CH3)2], 1.73 (m, 1 H. -HCHCH20Si), 1.78 (m, 1 H. -HCHCHCOOtBu), 2.30 (m, 2 H. -CH2CH=CH2), 2.40 (m, 1 H. -HCCH2CH20Si) , 2.52 (m, 1 H. -HCHCHCOOtBu), 3.55 (m, 2 H. -CH20Si), 3.85 (m, 1 H. CHCH2CH=CH2), 4.21 (m, 1 H. -

CHCOOtBu), 5.1 (s, 2 H. -CH2Ph), 5.1 (m, 1 H. CH2=), 7.35 (m, 5 H. aromatics). - i3C NMR (50.3 MHz, CDCl3): = 129.0, 118.0, 67.0, 64.0, 61.0, 60.0, 38.2, 38.0, 37.5, 34.0, 28.0, 20.0.

FAB+MS: calcd. For C30H4gNOsSi 531.34; found 532.

C30HsNOsSi (531.34): calcd. C 67.76, H 9.29, N 2.63; found C 67.69, H 9. 28, N 2.63.

Example 2

Synthesis of functionalized 6,5-fused bicyclic lactams (Figure 3).

Aldehyde 1: A stirred solution of 12 (0.335 g, 0.63 mmol) in MeOH (6.3 mL) was cooled to-78 C, whereupon O3 was bubbled through it (flow rate = 30 L/h). After 1.5 h, N2 was bubbled through it in order to eliminate the excess of O3. The solution was then warmed to 0 C by means of an ice bath and Me2S (39.7 mmol, 0.29 mL) was added. After stirring for 24 h at room temperature, the solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography (hexane/ethyl acetate 9:1) to yield 0.268 g of aldehyde 1 (80 ) as colorless oil. - [a] D20 = 26.1 (c = 1.001, CHCl3). - tH NMR (400 MHz, CDCl3) (signals are split due to amidic isomerism): = 0.12 [s, 6 H. -Si(CH3)2], 0.81 (m, 12 H. -

CH3), 1.40 [s, 9 H. -C(CH3)3], 1.55 (m, 1 H. -HCHCH20Si), 1.65 [m, 1 H. CH(CH3)2], 1.75 (m, 1 H. -HCHCHCOOtBu), 1.81 (m, 1 H. -

HCHCH20Si), 2.12 (m, 1 H. -CHCH2CH20Si -), 2.48 (m, 1 H. HCHCHCOOtBu), 2. 65 (m, 1 H. -HCHCHO), 2.85 (m, 1 H. -

HCHCHO), 3.61 (m, 2 H. -CH20Si), 4.2 (m, 1 H. -CHCH2CHO), 4.25 (m, 1 H. CHCOOtBu), 5.12 (m, 2 H. -CH2Ph), 7.28 (m, 5 H. aromatics), 9.8 (s, 1 H. CHO). - 3C NMR (50.3 MHz, CDCl3)

(signals are split due to amidic isomerism): = 128.4, 128.2, 128.1, 127.8, 81.4, 67.0, 60.6, 59.8, 59.7, 48.7, 47.5, 40.0, 36.3,

36.2, 34.0, 33.9, 32.7, 27.8, 27.7, 24.9, 20.2, 18.4, -3.7, -3.6.-

FAB+MS: calcd. For C2sH47NO6Si 533.32; found 534.

C2sH4NOSi (533.32): calcd. C 65.25, H 8.88, N 2.62; found C 65.34, H 8.89, N 2.62.

Acrylic ester 3: According to the General Procedure A, 1 was subjected to the Horner-Emmons reaction. The crude product was purified by flash chromatography (hexane/ethyl acetate, 7:3) to afford the acrylic ester 3 in 81% yield [diastereomeric ratio (Z)/(E) = 9:1]. - (E)-isomer: - OH NMR (400 MHz, CDC13) (signals are split due to amidic isomerism): = - 0.10 [s, 6 H. -Si(CH3)2], 0.85 (s, 12 H. -CH3), 1.35 [s, 9 H. -C(CH3)3], 1.55 [m, 1 H. -CH(CH3)2], 1.7, 2.1, 2.5, 2.9 3.0 (5 m, 6 H), 3.55 (m, 2 H. -CH20Si) , 3.7 (s, 3 H. -

CO2CH3), 3.9 (m, 1 H. -CHCH2CH=), 4.30 (m, 1 H. -CHCOOtBu), 5.10 (m, 2 H. -CH2Ph), 6.9 (m, 1 H. -CH=), 7.40 (m, 10 H. aromatics). - FAB+MS: calcd. For C40HsgN2OsSi 738.39; found 739.

- C40HssN2OgSi (738.39): calcd. C 65.01, H 7.91, N 3.79; found C 65.00, H 8.87, N 3.79. - (Z)-isomer: - tH NMR (400 MHz, CDC13) (signals are split due to amidic isomerism): = 0.10 [s, 6 H. -

Si(CH3)2], 0.80 (s, 12 H. -CH3), 1.39 [s, 9 H. -C(CH3)3], 1.55 [m, 1 H. CH(CH3)2], 1.7, 2.1, 2.4, 2.5 2.65 (5 m, 6 H), 3.52 (m, 2 H. -

CH20Si), 3.7 (s, 3 H. -CO2CH3), 3.8 (m, 1 H. -CHCH2CH=), 4.20 (m, 1 H. CHCOOtBu), 5.15 (m, 2 H. -CH2Ph), 6.5 (m, 1 H. -CH=), 7.40 (m, 10 H. aromatics). - i3ú: NMR (50.3 MHz, CDC13) (signals are split due to amidic isomerism): = 171.7, 154.5, 154.0, 130.7, 128.4, 128.3, 128.2, 128.1, 128. 0, 127.9, 81.2, 67.4, 67.1, 66.9,

63.5, 62.6, 60.7, 59.8, 52.2, 39.7, 39.6, 36.6, 33.3, 33.1, 31.5,

27.9, 27.6, 24.9, 20.2, 18.4, -3.61, -3.69. - FAB+MS: calcd. For C40HssN2OsSi 738.39; found 739. - C40HssN2OsSi (738.39): calcd. C 65.01, H7.91, N 3.79; found C 65.02, H 8.88, N 3.80.

trans-6,5-Fused Bicyclic Lactams 5a and 5b: According to the General Procedure B. 3 was N-Boc-protected. The crude product was purified by flash chromatography (hexane/ethyl acetate, 6:4)

to yield the acrylic ester (91%). - Mixture of two diastereoisomers: -

tH NMR (400 MHz, CDCl3) (signals are split due to amidic isomerism): = 0. 10 [s, 6 H. -Si(CH3)2], 0.85 (s, 12 H. -CH3), 1.31 [s, 9 H. -C(CH3)3], 1. 40 [m, 1 H. -CH(CH3)2], 1.45 [s, 9 H. -C(CH3)3], 1.7, 1.9, 2.3, 2.6 (4 m, 6 H), 3.48 (m, 2 H. -CH20Si), 3.7 (s, 3 H. -

CO2CH3), 3.9 (s, 3 H. -CO2CH3), 3.9 (m, 1 H. -CHCH2CH=), 4.20 (m, 1 H. CHCOOtBu), 5.10 (m, 2 H. -CH2Ph), 6.8 (m, 1 H. -CH=), 7.30 (m, 10 H. aromatics). - l3C NMR (50.3 MHz, CDCl3) (signals are split due to amidic isomerism): = 171.7, 163.7, 151.7, 138.7, 137.7, 136.4, 136.2, 135.2, 130. 0, 128.3, 128.2, 128.0, 127.9,

127.8, 83.4, 81.3, 81.2, 68.3, 67.1, 66.9, 62.8, 62.2, 61.2, 61.1,

60.2, 59.6, 52.2, 40.3, 38.8, 36.8, 34.0, 33.9, 32.8, 31.4, 27.8,

27.7, 24.9, 20.2, 18.4, -3.6. - FAB+MS: calcd. For CsH66N2OllSi 838.44; found 839. - CsH66N2OllSi (838.44): calcd. C 64.41, H 7.93, N 3.34; found C 64.40, H 7.92, N 3.34.

A solution of N-Boc-protected compound (0.0647 g, 0.077 mmol) in MeOH (2 mL) containing a catalytic amount of 10% Pd/ C was stirred for about 16 h under H2. The catalyst was then removed by filtration through Celite and the collected solid was washed with MeOH. The combined filtrate and washings were then concentrated under reduced pressure, the residue was redissolved in MeOH (20 mL) and DIPEA (0.066 mL, 0.38 mmol) was added.

The mixture was refluxed for 48 h. The solvent was removed and the two diastereoisomers thus obtained were separated by flash chromatography (hexane/ethyl cetate, 8:2) to yield 5.7 mg of 5a and 24.8 mg of 5b (73% over two steps) in a 1:4.3 diastereoisomeric ratio as a colorless oil. 5a: - [a]D20 = 62.5 (c = 0.08, CHC13). - lH NMR (400 MHz, CDC13): = 0.10 [s, 6 H. Si(CH3)2], 0.80 (s, 12 H. -CH3), 1.48 (m, 1 H. H10), 1.5 (m, 1 H. H5), 1.51 (m, 1 H. H8), 1.51 [s, 9 H. -C(CH3)3], 1.53 [s, 9 H. C(CH3)3], 1.60 [m, 1 H. -CH(CH3)2], 1.65 (m, 1 H. H4), 1.78 (m, 1 H. H10], 1.90 (m, 1 H. H7), 2.11 (m, 1 H. H5], 2.40 (m, 1 H. H4l, 2.52 (m, 1 H. H8l, 3.38 (m, 1 H. H6), 3.67 (m, 2 H. Hll), 4.30 (m, 1 H. H3), 4.37 (m, 1 H. H9), 5. 55 (s, 1 H. NIT). - 13C NMR (50.3

l MHz, CDC13): = 171.1, 81.7, 79.6, 61.8, 60.9, 59.0, 50.8, 43.8, 34.8, 34.3, 29.8, 28.1, 27.1, 25.2, 25.0, 20.5, 20.2, 18.6, -3.2.-

FAB+MS: calcd. For C2gHs2N2O6Si 540.36; found 541. -

C2sHs2N2O6Si (540.36): calcd. C 62.18, H 9.69, N 5.18; found C 62.20, H 9. 68, N 5.18. - 5b: - [a]D20 = 21.8 (c = 0.22, CHCl3). - AH NMR (400 MHz, CDCl3): = 0.00 [s, 6 H. -Si(CH3)2], 0.87 (s, 12 H. -

CH3), 1.40 (m, 1 H. H10), 1.45 (m, 1 H. H5), 1.45 (m, 1 H. H8), 1.45 [s, 9 H. -C(CH3)3], 1.50 [s, 9 H. -C(CH3)3], 1.60 [m, 1 H. -

CH(CH3)2], 1.70 (m, 1 H. H4), 1.75 (m, 1 H. H10'), 1.85 (m, 1 H. H7), 2. 15 (m, 1 H. H5], 2.58 (m, 1 H. H43, 2.60 (m, 1 H. H8l, 3.30 (m, 1 H. H6), 3.65 (m, 2 H. H11), 4.10 (m, 1 H. H3), 4.30 (m, 1 H. H9), 5.55 (s, 1 H. NIT). - 13C NMR (50.3 MHz, CDCl3): = 171.4, 167.5, 156.2, 81.4, 79.5, 64. 6, 60.7, 58.1, 52.3, 43.1, 34.7, 34.1,

28.6, 28.3, 28.0, 26.3, 20.3, 18.4, -3.5. - FAB+MS: calcd. For C2sHs2N2O6Si 540.36; found 541. - C2gHs2N206Si (540.36): calcd. C 62.18, H 9.69, N 5.18; found C 62.21, H 9.69, N 5.19.

Example 3

Synthesis of functionalized 7 5-fused bicyclic lactams (Fiure 3).

Aldehyde 2: To a stirred solution of 12 (0.181 g, 0.341 mmol) in dry THF (3.4 mL) was added a 0.5 M solution of 9-BBN in THF (2.1 mL, 1.06 mmol). The reaction mixture was stirred for 3 h, then cooled to 0 C, whereupon water (3 mL), a 3 M solution of NaOH (1.03 mL) and 30% H202 (0.317 mL) were added. The resulting mixture was stirred for 1 h at room temperature and then refluxed for a further 16 h. After cooling, the aqueous phase was extracted with EtOAc and the combined organic phases were dried with Na2SO, fltered, and concentred under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate 7:3) to yield 0. 156 g of alcohol (83%) as a yellow oil. - [a]D20 = - 32.9 (c = 1.0, CHCl3) . - H NMR (200 MHz, CDCl3) (signals are split due to amidic isomerism): = 0.1 [s, 6 H. -Si(CH3)2], 0.81 (m, 12 H. -CH3), 1.30 [s, 9 H. -C(CH3)3], 1. 40-2.6 (m, 10 H), 3.40-3.90

(m, 6 H. -CH20Si, -CH20H, -OH, -CHN-), 4.20 (m, 1 H. -

CHCOOtBu), 5.1 (s, 2 H. -CH2Ph), 7.3 (m, 5 H. aromatics). - 13C.

NMR (50.3 MHz, CDCl3) (signals are split due to amidic isomerism): 6= 171. 9, 171.5, 154.6, 136.3, 134.8, 128.4, 128.2, 128.1, 127.9,

127.8, 127.6, 117.2, 81.2, 67.0, 66.9, 66.8, 63.8, 63.5, 63.0, 62.4,

62.2, 61.3, 60.6, 60.3, 60.0, 59.7, 40.8, 39.1, 39.0, 38.1, 37.0,

34.7, 34.3, 34.1, 33.7, 32.7, 32.1, 30.5, 30.4, 29.7, 28.8, 28.5,

27.8, 27.7, 26.7, 24.9, 20.2, 18.4, -3.6. - FAB+MS: calcd. For C30HsNOSi 549.35; found 550. - C30HsNOSi (549.35): calcd. C 65.54, H 9.35, N 2.55; found C 65.53, H 9.34, N 2.53.

To a stirred solution of oxalyl chloride (0.093 mL, 1.071 mmol) in CH2C12 (2 mL), DMSO (0.104 mL, 1.46 mmol), a solution of the alcohol (0.196 g, 0. 357 mmol) in CH2C12 (3 mL), and TEA (0.41 mL, 2.93 mmol) were added at 60 C. The reaction mixture was allowed to warm to room temperature and after 1 h it was washed with water (2 mL) and the aqueous phase was extracted with CH2C12. The combined organic layers were dried with Na2SO. The solvent was evaporated under reduced pressure and the crude was purified by flash chromatography (hexane/ethyl acetate 8:2) to yield 0. 158 g of 2 (81%) as colorless oil. - [a]D20 = 41.2 (c = 0.95, CHC13). - tH NMR (200 MHz, CDC13) (signals are split due to amidic isomerism): = 0. 1 [s, 6 H. -Si(CH3)2], 0.9 (m, 12 H. -CH3), 1.38 [s, 9 H. -C(CH3)3], 1.402.6 (m, 10 H), 3.45 (m, 3 H. -CH20Si), 3.6 (m, 1 H. -CHN-), 4.20 (m, 1 H. -CHCOOtBu), 5.05 (m, 2 H. -CH2Ph), 7.2 (m, 5 H. aromatics), 9.45,-9.6 (2 s, 1 H. -CHO). - i3C NMR (50.3 MHz, CDC13) (signals are split due to amidic isomerism): = 201.6, 201.1, 171.9, 154.6, 128.5, 128.3, 128.1, 128. 0, 81.3, 67.2,

67.0, 66.9, 63.6, 62.8, 61.5, 60.8, 60.6, 60.5, 60.2, 59.8, 40.5,

40.2, 39.2, 38.1, 36.9, 34.2, 33.9, 32.8, 29.7, 27.9, 27.8, 26.6,

26.0, 25.9, 25.1, 20.3, 18.5, -3.5, -5.4. - FAB+MS: calcd. For C30HsNOcSi 547.33; found 548. - C30HsNOSi (547.33): calcd. C 65.78, H 9.02, N 2.56; found C 65.77, H 9.00, N 2.55.

Acrylic ester 4: According to the General Procedure A, 2 was

subjected to the Horner-Emmons reaction. The crude product was purified by flash chromatography (hexane/ethyl acetate, 8:2) to afford the acrylic ester 4 in 92% yield [diastereomeric ratio (Z)/(E) = 9:1] as a yellow oil. - Mixture of two diastereoisomers: - AH NMR (200 MHz, CDCl3) (signals are split due to amidic isomerism): = 0.0 [s, 6 H. -Si(CH3)2], 0.82-0.88 (4 s, 12 H. -CH3), 1.33 [s, 9 H. -

C(CH3)3], 1.55 [m, 1 H. -CH(CH3)2], 1.7, 2.1, 2.5, (5 m, 6 H), 3.57 (m, 2 H. -CH20Si), 3.72 (s, 3 H. -CO2CH3), 3.78 (m, 1 H. -CHN-), 4.30 (m, 1 H. CHCOOtBu), 5.05 (m, 2 H. -CH2Ph), 6.5 (m, 1 H. -

CH=), 7.40 (m, 10 H. aromatics). - i3C NMR (50.3 MHz, CDCl3) (signals are split due to amidic isomerism): = 171.9, 154.6, 136.6, 136.3, 128.4, 128. 0, 127.8, 126.0, 81.2, 67.2, 66.9, 64.2,

63.5, 60.8, 60.2, 59.8, 52.2, 39.3, 38.2, 37.9, 37.1, 36.9, 34.1,

33.9, 33.3, 32.8, 31.7, 29.6, 27.8, 25.9, 25.0, 24.8, 24.4, 20.3,

18.5, -3.4. - FAB+MS: calcd. For C4H6ON2OgSi 752.41; found 753.

- C4H60N2OsSi (752.41): calcd. C 65.40, H 8.03, N 3.72; found C 65.39, H 8.01, N 3.71.

trans-7,5-Fused Bicyclic Lactams 6a and fib: According to the General Procedure B. 4 was N-Boc-protected. The crude product was purified by flash chromatography (hexane/ethyl acetate, 8:2) to yield the acrylic ester (87%). - Mixture of two diastereoisomers: 1 H NMR (200 MHz, CDC13) (signals are split due to amidic isomerism): = 0.10 [s, 6 H. -Si(CH3)2], 0.85 (s, 12 H. -CH3), 1.31 [s, 9 H. -C(CH3)3], 1.40 [m, 1 H. -CH(CH3)2], 1.45 [s, 9 H. -C(CH3)3], 1.3, 2.5 (m, 9 H), 3.5 (m, 2 H,-CH20Si), 3.68 (s, 3 H. -CO2CH3), 3.75 (m, 1 H. -CHN-), 4.15 (m, 1 H. -CHCOOtBu), 5.10 (m, 4 H. CH2Ph), 6.8 (m, 1 H. -CH=), 7.25 (m, 10 H. aromatics). - i3C NMR (50. 3 MHz, CDCl3) (signals are split due to amidic isomerism): = 171.9, 171.4, 170.8, 164.1, 154.6, 154.3, 153.7, 146.1, 145.8,

141.8, 141.3, 136.5, 135.4, 128.7, 128.4, 128.2, 127.8, 127.6

83.5, 81.2, 68.7, 68.2, 66.8, 64.6, 64.1, 63.9, 63.5, 61.2, 60.8,

60.1, 52.1, 39.5, 39.1, 38.9, 38.1, 37.8, 34.1, 33.7, 32.9, 32.1,

31.9, 31.0, 30.1, 29.9, 29.3, 27.8, 25.8, 25.0, 24.7, 24.0, 22.6,

20.3, 18.4, -3.4. - FAB+MS: calcd. For C46H6sN2OSi 852.46;

found 853. - C6H6sN2OSi (852.46): calcd. C 64.76, H 8.03, N 3.28; found C 64.77, H 8.01, N 3.28.

To a solution of the N-Boc protected compound (0.15 g, 0.17 mmol) in THE (2 mL) was added 2 N NaOH (1.36 mmol, 0.453 mL) and heated to 50 C. After 16 h the solution was acidified to pH = 3 with IRA 120 H+ and then filtered. The solvent was evaporated and the crude residue was used for the next reaction without further purification. - Mixture of two diastereoisomers: - tH NMR (200 MHz, CDCl3) (signals are split due to amidic isomerism): = 0.07 [s, 6 H. -Si(CH3)2], 0.84 (s, 12 H. -CH3), 1.31 [s, 9 H. -C(CH3)3], 1.46 [s, 9 H. -C(CH3)3], 1.45-2.0 (m, 7 H), 2.0-2.6 (m, 3 H), 3.58 (m, 2 H. -CH20Si), 3.8 (m, 1 H. -CHN-), 4.2 (m, 1 H. CHCOOtBu), 5.10 (m, 4 H. -CH2Ph), 6.05 (bs, -NH), 6.4 (bs, -NH), 6.6 (m, 1 H. -CH=), 7.30 (m, 10 H. aromatics). - i3C NMR (50.3 MHz, CDCl3) (signals are split due to amidic isomerism): = 172.2, 171.8, 168.9, 155.0, 154.8, 141.0, 137.6, 137.5, 136.7, 136.6, 128.6, 128.5, 128.3,

128.2, 128.1, 127.6, 127.1, 81.5, 67.3, 67.2, 65.2, 64.5, 63.8,

61.1, 60.9, 60.3, 59.9, 39.3, 38.1, 37.2, 34.3, 34.0, 32.9, 31.7,

30.5, 29.8, 28.2, 28.3, 27.9, 25.2, 25.0, 20.5, 18.7, -3.2.

A solution of the crude compound in MeOH (1 mL) containing a catalytic amount of 10% Pd/C was stirred for about 16 h under H2.

The catalyst was then removed by filtration through Celite and the collected solid was washed with MeOH. The combined filtrate and washings were then concentrated under reduced pressure and the crude was used for the next reaction without further purification.

To a mixture of crude, HOAt (0.0456 g, 0.335 mmol), HATU (0.127 g, 0.335 mmol) was added DMF (8 mL) and then sym-collidine (0.335 mmol, 47 pi). The solution was stirred for 48 h. Thereafter, the solvent was evaporated under reduced pressure, EtOAc was added and washed with a satured solution of NaHCO3 and 1 M HC1. The organic phase was dried over Na2SO, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography (hexane/ethyl acetate 8:2) to afford 42.1 mg

of 6a and 7.8 mg of 6b in a 5.4:1 diastereoisomeric ratio (53% over 3 steps). - 6a: - [a]D20 = 19.4 (c = 1.98, CHC13). - IH NMR (400 MHz, CDCl3) : = 0.1 [s, 6 H. -Si(CH3)2], 0.90 (s, 12 H. -CH3), 1.3 (m, 1 H. H6), 1.5 (m, 1 H. H4), 1.52 (m, 1 H. Hll), 1.45 [s, 18 H. -

C(CH3)3], 1.60 [m, 1 H. -CH(CH3)2], 1.7 (m, 1 H. H9), 1.80 (m, 1 H. Hit'), 1.81 (m, 1 H. H5), 1.89 (m, 1 H. H6'), 1.95 (m, 1 H. H5], 2.10 (m, 1 H. H4], 2.10 (m, 1 H. H8), 2.40 (m, 1 H. H9'), 3.59 (m, 1 H. H7), 3.62 (m, 2 H. H12), 4.24 (m, 1 H. H3), 4.32 (m, 1 H. H10), 5.55 (s, 1 H. NH). - 13C NMR (100.6 MHz, HETCOR, CDC13): = 65.0, 61.7, 61.0, 55.0, 44.0, 37.5, 35. 5, 34.9, 33.0, 32.5, 28.0,

20.0. - FAB+MS: calcd. For C2sHs4N2O6Si 554.38; found 555. -

C2sHs4N2O6Si (554.38): calcd. C 62.78, H 9.81, N 5.05; found C 62.77, H 9. 80, N 5.05. - 6b: - [a]D20 = 14.9 (c = 0.37, CHC13). - H NMR (400 MHz, CDC13): = 0.1 [s, 6 H. -Si(CH3)2], 0.85, 0.89 (2 s, 12 H. -CH3), 1.36 (m, 1 H. Hll), 1.41 (m, 1 H. H9), 1.46 [s, 18 H. -

C(CH3)3], 1.47 (m, 1 H. H5), 1.60 [m, 1 H. -CH(CH3)2], 1.62 (m, 1 H. H5], 1.66 (m, 1 H. H6), 1.80 (m, 1 H. H11l, 1.86 (m, 1 H. H8), 2.02 (m, 1 H. H6'), 2.04 (m, 2 H. H4), 2.48 (m, 1 H. H9'), 3.31 (m, 1 H. H7), 3.65 (m, 2 H. H12), 4.22 (m, 1 H. H3), 4.39 (m, 1 H. H10), 5.74 (s, 1 H. NH). - i3C NMR (100.6 MHz, CDC13): = 64.97, 61.51, 61. 15, 53.22, 43.47, 35.27, 35.09, 34.82, 33.63, 29.08, 28.53,

23.79, 20.87, 19.05, 3.29. - FAB+MS: calcd. For C2sHs4N2O6Si 554.38; found 555. - C2gHs4N2O6Si (554.38): calcd. C 62.78, H 9.81, N 5.05; found C 62.79, H 9.80, N 5.04.

Exnple 4 Synthesis of alcohol 13: Compound 5b (27.9 ma, 0.051 mmol) in 1 mL of THF was treated with TBAF (62 '1L, 0.062 mmol) and stirred for 2 h at room temperature. The reaction mixture was washed with brine ( 1 mL), dried and evaporated. The residue was chromatographed using EtOAc to give the alcohol 14 (21.6 ma, 98 %) as white solid. - m.p. 144-145 C. - [a] D20 = 36.7 (c = 0.87, CHC13). - IH NMR (400 MHz, CDC13): = 1.3 [s, 9 H. C(CH3)3], 1.5 [s, 9 H. -C(CH3)3], 1.7 (m, 2 H), 1.85 (m, 2 H), 2.2 (m, 1 H), 2.6 (m,

2 H. -HCHCHCOOtBu, -HCHCHNHBoc), 3.38 (ddd, 1 H. J = 3.9 Hz, J = 10.8 Hz, J = 10.8 Hz, -CHN), 3.71 (m, 3 H. -CH20H, -01), 4.08 (m, 1 H. -CHNHBoc), 4.32 (dd, 1 H. J = 8.6 Hz, J = 8.6 Hz, -

CHCOOtBu), 5.3 (bs, 1 H. -NH). - 13C NMR (100.6 MHz, CDCl3): = 65.4, 61.5, 58.8, 52.8, 43.6, 35.0, 34.3, 30.1, 29.0, 28.7, 26.5,

14.4. - FAB+MS: calcd. For C20H3N206 398.24; found 399. -

C20H34N2O6 (398.24): calcd. C 60.28, H 8.60, N 7.03; found C 60.26, H 8. 62, N 7.03.

Synthesis of aside 14: Alcohol 13 (17.5 ma, 0.04 mmol) in 3 mL of CH2C12 was treated with methanesulfonil chloride (6.2 I1L, 0.08 mmol) and Et3N (13.91lL, 0.1 mmol) and stirred at O C for 1 h. The ice bath was removed, and the reaction mixture was stirred an additional 1 h at room temperature. The solution was diluted with CH2C12 (1 mL) and washed with a phosphate buffer solution (3 mL), dried, evaporated and used without further purification. - OH NMR (200 MHz, CDC13): = 1.45,1.48 [2 s,18 H. C(CH3)3], 1.55-

2.2 (m, 7 H), 2.55 (m, 2 H), 3.01 (s,3 H. -OCH3), 3.37 (m, 1 H. -

CHN-), 4.01 (m, 1 H. -CHNHBoc), 4.2-4.4 (m, 3 H. -CHCOOtBu, -

CH20Ms), 5.22 (bs, 1 H. -NH).

The crude residue was dissolved in DMF (3 mL), treated with NaN3 (7.8 ma, 0.12 mmol) stirred at 80 C for 3 h, and evaporated. The crude was dissolved in EtOAc (2 mL), washed with a phosphate buffer solution (2 mL), dried and evaporated to give 14 (16.2 ma, 96 %) as yellow oil. - [a]D20 = -019.3 (c = 1.62, CHC13). - H NMR (200 MHz, CDC13): = 1.43,1.48 [2 s,18 H. -C(CH3)3], 1.55-2.0 (m, 6 H), 2.12 (m, 1 H), 2.51 (m, 2 H), 3.38 (m, 3 H. -CH2N3, -CHN-), 4.01 (m, 1 H. -CHNHBoc), 4.32 (dd, 1 H. -CHCOOtBu), 5. 25 (bs, 1 H. -NH). - t3C NMR (50.3 MHz, CDC13): = 171.1, 167.3, 156.1, 81. 6, 79.5, 64.3, 57.9, 52.2, 49.5, 43.3, 34.3, 30.2, 29.6, 28.2,

27.9,26.3. - FAB+MS: calcd. For C20H33NsOs 423.25; found 424. -

C20H33NsOs (423.25): calcd. C 56.72, H 7.85, N 16.54; found C 56.71, H 7. 85, N 16.53.

Claims (13)

-24 CLAIMS

1. A compound of formula (I) (CH2)X

()n4_cOo-R2 NH-R (I) 5 wherein: the symbol represents a bond above or below the plane of the page, n is the number 1 or 2, m is an integer from 1 to 5, X is OH, N3, NH2, or COOH; and 10 (a) R' is H. C1-C4 alkyl or a suitable protecting group and R2 is H or a suitable protecting group, or (b) R' and R2 together are the group Asp Gly-Arg; or a salt thereof; or racemates, single enantiomers, single diastereoisomers or mixtures of such compound or andfor of such salt.

15.-

2. A compound according to claim 1, wherein: a) nis 1,mis2,XisOH; b) nis2,mis2,XisOH; 20

3. A process for the preparation of a compound of claim 1 or 2, comprising: a) Horner-Emmons olefination of a compound of formula II, to give a compound of formula III:

-25 (cH2)m-x (cH2)m-x () 'I ()n' N1CO2R2 CO2Me (II) (In) wherein X, n, m, R' and R2 are as defined above; b) hydrogenation of the compound obtained in step a) and cyclisation to give a compound of formula (I); and 5 c) optionally converting the group X into another as defined; and d) optionally converting the compound of formula (I) into a salt thereof or isolating a single enantiomer or a single diastereoisomer thereof.

4. The use of a compound of claim I or 2, wherein R' and R2 are as given at (a) 10 above, as intermediates for the preparation of cyclic peptides.

5. Use according to claim 4, wherein said peptides contain the sequence Arg-

Gly-Asp. 15

6. Use of a compound of claim 1 or 2 as reverse-turn inducers.

7. Use of a compound of claim 1 or 2 as a carriers for the selective delivery of a drug. 20

8. A cyclic peptide comprising a compound of claim 1.

9. A compound according to claim 1 or 2 in which R' and R2 are as given at (b)

-26 above, for use as a medicament.

10. Use of a compound of claim 1 or 2 in which Ret and R2 are as given at (b) above for the preparation of a medicament having a selective antagonist action for 5 av,B3 and/or av,B5 integrins, or for the preparation of a medicament useful for the treatment of an altered angiogenesis, or for the preparation of a medicament useful for the treatment of a disease selected from tumor metastasis, retinopathy, acute kidney failure and osteoporosis.

10

11. A pharmaceutical composition comprising a compound of claim l or 2, in admixture with at least a pharmaceutically acceptable excipient and/or vehicle.

12. A compound according to claim 1 substantially as herein described with reference to any of the accompanying drawings.

13. A process for preparing a compound of claim 1 substantially as herein described with reference to any of the accompanying drawings.