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Synthesis of Enantiopure N-and C-Protected home-P-Amino Acids by Direct Homologation of a-Amino AcidW

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Synthesis of Enantiopure N-and C-Protected home-P-Amino Acids by Direct Homologation of a-Amino AcidW
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  Pergamon 0040.4020(05)00778-4 7wahedron Vol. 51, No. 45, 12337-12350. p. 1995 Copynght B 1995 Elsewer Science Ltd Printed in Great Britam. All rights reserved 0040.4020195 $9.50+0.00 Synthesis of Enantiopure N- and C-Protected home-P-Amino Acids by Direct Homologation of a-Amino AcidW Romualdo Cap&o, Ersilia Cassano, Luigi Longobardo*, Giovanni Palumbo Dipartimento di Chimica Organica e B~~loy~a. Universiti di Napol Federico II Via Mezzocarmone, 16 l-X0134 Nspol (Italy) Abstract: Enantiopure N- and/or C-protected hor~~o-p-amino acids are prepared readily and in good yields from N-protected a-amino acids with the same side chain, via reduction of the carboxyl function and conversion of the resulting N-protected b-amino alcohol into the corresponding p-amino iodide and then @mine cyanide. The key step of this strategy is represented by the synthesis of the enantiopure N-protected p-amino iodides 2 and 3 that are smoothly obtained from the parent amino alcohols I by polymer bound triarylphosphine-12 complex in anhydrous dichloromethane. Design and synthesis of nev+, moditied peptides depend largciy upon the availability of uncommon amino acids, and in recent years p-amino acids (homu-P-amino acids’) have increased enormously their importance for the preparation of peptides with enhanced in viva stability’ ’ JS uell as for the synthesis of p-lactam antibiotics’. Beside some early syntheses of racenuc materials’.45 a nunlber ot methods for the preparation of enantiopure p-amino acids and their drr-ivatives already exist, and iuo rxceilent reviews on the topic have recently appeared’ b. Excepting the multi-step syntheses unwed .II ttx preparation of individual p-amino acid? or particular Llasses of substituted $-amino acids’, two ~IILIII btrdteglcs are nowadays available to obtain home-P-amino acids from their c-amino auld countt:rp,irt5. i1a11~1y ;L “true” homologation process of the carboxyt end II~ the latter, under the classical’ (11 1~10~11ft’d” Arntlt-Eistert conditions, and a “formal” homologation process exploiting the preexistent /j-amjno carboxy mulet? of aspartic acid and its derivatives to build up the p-amino acid mc,tecule’““. Unfortunately, the Arlldt-Eistert conditions of direct homologation are not suitable for large scale preparations and, besldea. are ‘1, I i\frui for preserving the N-Fmoc protection of the starting a-amino acids. The tormal homologation based ~LII /le use of ~spartic acid derivatives, on the other hand. consists of the convzrslon of the u-carboxyl groull 111[1) n amino acid side chain that sometimes may require several steps and IS generally accomphshed with rdtnel- 1~~. ove1~11 yield. We have now de~lscd a new process tar the dlrr<r coll\ers1on 01 A-protected a-amino acids into their P-homologues under smooth, cican, quick. and iarge-scale applicable conditions. The key step of the whole conversion (Scheme 1) Ix represented by the \\nth<~\l\ k>f the enantiomerically pure N-protected p-amino iodides 2 and 3. Based on our former experience III the use of polymer bound triarylphosphine-halogen comptexes’4, the latter were n f’act prepared by treatrnt-nl .lt tllrlr <.orre\ponding N-protected p-amino alcohols  (obtained by N-protection”*” of commercially available p-amino alcohols, or by reduction of parent a-amino acid derivatives’7-‘B) with polystyryl diphenylphosphine-iodine (PDPI) complex, in high yield and without any detectable epimerization of the chiral center. The subsequent replacement of the iodine atom in 2 and 3 by a cyan0 group, and hydrolysis (or alcoholysis) of the latter, then completed the synthetic sequence leading to N- and/or C-protected home-@mine acids. The extent of racemization at the chiraJ center of the starting a-amino acids and/or ~-amino alcohols was checked at the various stages of the whole process by chiral column HPLC comparative analysis with specially prepared racemic intermediates. Under our conditions no traces of racemized products could be detected, even in the racemization prone” phenylglycine series. It is noteworthy that, otherwise some reported procedures’“~‘*, the N-protected p-amino cyanides 4 and 5 (not 6) may be obtained from their parent p-amino iodides 2 and 3 under experimental conditions that are compatible with the presence of the usual alkoxycarbonyl N-protecting groups currently utilized in peptide chemistry, namely N-Boc (f-butoxycarbonyl) and N-Cbz (benzyloxycarbonyl). N-Fmoc (9-fluorenylmetboxy carbonyl) derivatives 6, due to their sensitivity to the basic treatments (vi& i&r), are however prepared via N-protection exchange from their N(Boc) analogs 5. The aspects that are peculiar of the various steps of the homologation process will be discussed in the following sections A-D. A. SYNTHESIS OF N-PROTECTED P-AMINO ALCOHOLS N-Protected p-amino alcohols 1 were prepared either t’rorn commercial p-amino alcohols and N-urethane bond forming reagents, by modified literature procedures’5,‘0, or from N-protected a-amino acid mixed anhydrides by sodium borohydride reduction”-‘” The free p-amino alcohols were treated with commercial reagents for selective N-protection, as di-r-butyl-dicarbonate [(r-Boc)~O] and N-(benzyloxycarbonyloxy)~succinimide [Cbz-OSu], in tetrahydrofuran at room temperature III the presence of triethylamine, the latter being conveniently replaced by diluted aq sodium carbonate when 9-fluotenylrnethyl-succinimidyl carbonate [Fmoc-OSu] was used as the N-protection reagent. The N-protected p-amino alcohols thus obtained (Table 1)” were then crystallized from hexane-ethyl acetate (N-Boc) or hexane-dichloromethae (N-Cbz and N-Fmoc) mixtures. The reducuon of N-protected a-amino acid mixed anhydrides was found very convenient for preparing N-protected p-amino alcohols from trifunctional a-amino acids carrying a further protective group on their side chain and was thus utilized successfully to synthestze the compounds lg,h,n (Table 1)23. B. CONVERSION OF N-PROTECTED &AMINO ALCOHOLS INTO N-PROTECTED f&AMINO IODIDES N(Cbz)-Protected ~-ammo iodides 2i and 2j (Table 2)’ were already reported to be intermediates in the synthesis of chiral trcl~-2,5-dimethylp~ol~dines” and of HIV-1 protease inhibitors2’ respectively. N(Cbz)-Protected p-r-butyl aspartate p’amino iodide (paralleling 2g in Table 2)23 was also reported”. The preparation of such compounds is accomplished invariably in two steps by conversion of the parent ~-amino alcohols into their tosyl or mesyl esters which in their turn le:td to the iodides under the Fiielstein conditions (NaI in acetone). The conditions we have devised for the prepanlruon ot :L’-pt-otected p-amino iodides 2, in only one step  N and C-Protected Ilomo-B-amino acids 12339 Scheme 1. Synthetic Pathways for N- and/or C-Protected home-B-Amino Acid Preparation 1 (P = Boc, Cbz, Fmoc) + 6% CbzklN -, R 2 I r -- f (Cbz)HN - CN R 4 1 v + (B%K1N , I+ 5 i. PDPI, imidazole, CH2C12, reflux 1 h: ii. E~N’CN. CH2C12, rcllux 4 h: m. 30% TFA in CH2C12, 0” C, 0.5 h, then FmocOSl 10% aq Na2C0,,THF, mom temp. 1 h: iv. excess cont. HCl/MeOH. Et,O, 4’ C 12 h; v. as iv without Et20r room temp. 12 h vi. excess cow. aq HCI, dioxane. rrflux 8 h. /-- ‘I i Iii CN t (FmdHN- CN i 6 iv 4 Cl-H N+ 3 -CO,Me I i WNHN-cO ,, 2 R fi 8 9 from their corresponding N-protected p-amino alcohols 1, utilizes a triarylphosphine-iodine complex in the presence of imidazole14 to accomplish the OH+1 replacement in high yield and under very mild conditions (1 h reflux, in dichloromethane), suitable for the preservation of the commonly used N- and side chain-protecting groups and, at the same time, unaffecting the chiral center configuration. Imidazole should act as a proton trap for the hydrogen ions released during the reaction. Imidazole has been also suggested (although without experimental evidence26) to play an active role at least in some other reactions involving the triphenylphosphine-iodine reagent The choice of a polymer bound triarylphosphine, like polystyryl diphenylphosphine, to prepare the iodide ensures that the phosphine oxide, which is formed under our conditions as the only byproduct of the reaction, is linked to a polymeric matrix and, thus, can be separated by simple filtration. This avoids time consuming and circumstantial purification procedures to obtain the pure product that in fact can be directly  K (‘.4PUTO Cf f/l. Table 1. N-Protected B-Amino Akohok N-Protection m.p. (“C) [al: cc) b Yield W c Ref. la Bw Ala 59-61 -8.9 (1.01) 92 28 lb BK Abu 43-44 -13.0 (0.73) 93 __ 1C Hoc Vat ml -17.0 (1.68) 94 29d Id Btx- Leu 011 -72.0 (1.66) 90 29d le Exx Phe 95~97 -27.7 (1.11) 90 17 If Bcx Phg Il:-I3x + 9.4 (1.67) 96 30 lk? Bnc Asp(OBn) WI -6.2 (1.08)e 87 18 lh Btx Tyr(Bn) IO?-10’) -Ii.? (0.5.5) 94 31 li Ch7 Ala 62~fl-I -6.4 (1.00) 92 30 lj C-t)2 Phe Y)o-01 -32.5 c1.05y 95 30 lk Fmtx Ala 13 I“ -11.6 (1.02) 92 11 Fmcc Lru I if?- i -24.6 (0.53) 94 __ lm Fmrx Phc lf,f? I fl- -21.0 (1.03) 96 16f III Fmw u-Asp(OfBu) Y5-90 +20.0 (0.54) 88 lgd ’ Considered as the side chain of the a-ammo acid indxarcd. ” CHCh solutions (1.0 dm cell). ’ Yield of pure crystal- liled product. d Enantmmer rcportcd. e Measured m hlcOH.~Rot;i~~u~ WI reported. Table 2. S-Protected P-Amino lodides from N-Protected P-Amino Alcohols K ‘I Yield% c Ref. Za Zb zc Zd 2e 2f 44 Zh All AhU Val LCU Phc Phg Asp(OBn) Tyr( Bn) -I X.6 (0.99) 90 -36.7 (0.49) 94 -18.7 (2.10) 78 -70.‘) (I 30) 90 +I l(1.20) 92 +il o (0.88) 91 +(I (I i I .08) 82 tll 2 (0.80) 86 __ __ __ __ __ __ Zi (h/ Ala ,:_ -1 I.? (2.86)d 89 24 2j (‘h,, Pht, 1,. ‘1.~ +K.?. (0.88) 90 25 3k I “lil Al.1 I.” I?\ -I1 { (1.02) 92 __ 31 t.ni<ll Lcu #II iii -21.3 (1.20) 94 __ 3m kmoL Phc I4h IJY +7.7 ( 1.36) 94 __ 3, PIlIcK o-Asp(OlBu) 14s I46 -9.4 (0.98) 90 __ ’ Consldcred as the side cham of the a-ammn acid mdlcawd. ” . lued product d Measured in CH:C12. < ti(‘I: wtutions (1.0 dm cell). ’ Yield of pure crystal-  N- and C-Protected home-p-ammo acids 12341 crystallized from a suitable solvent (hexane-dichloromethane). The N-protected p-amino iodides 2 and 3, prepared under such conditions, are reportedz3 in Table 2. Attempts to prepare some of them by using the dichloromethane soluble -and much less expensive- triphenylphosphine-iodine complex were also successful but the product yields were somewhat lower, in the range 70-75%. It is also noteworthy that we did not observe any formation of aziridines that instead occurs in the reactions of either N-alky127 or N-tosyl*’ lkrmino alcohols with triphenylphosphine in carbon tetrachloride or carbon tetrabromide. c. N-PROTECTEDP-AMINOCYANIDES Preparations of chiral N-protected lkmino cyanides (as 4, 5. and 6) have been very seldom reported. N-Tosyl p-amino cyanides were prepared” from N-tosyl aziridines by uimethylsilyl cyanide in the presence of lanthanoid cyanides as catalysts: N,N-dibenzyl p-amino cyanides have been also obtained by Barton deoxygenation3* of N,N-dibenzyl-a-amino aldehyde cyanohydrins” or by an intriguing monosubstitution operated by LiCN in DMF onto the mesyl diester of the N,N-diprotected amino diol coming from aspartic acid reductior?. To the best of our knowledge, the conversion of N(Boc)-(R)-phenylglycinol tosyl ester into the corresponding lkirnino cyanide by NaCN in DMSO (90” C, 1 h) represents (although questionable33) the only example of synthesis of N(alkoxycarbonylamino)-protected p-amino cyanides34. In our hands N(Boc)- and N(Cbz)-protected p-amino iodides 2 were smoothly converted into their corresponding cyanides 4 and 5 by 4 h reflux with tetraethylammonium cyanide3’ in dichloromethane. Unfortunately N(Fmoc)-protected p-amino iodides 3 under these conditions undergo partial nitrogen Table 3. N-Protected B-Amino Cyanides from N-Protected B-Amino lodides N-Protection RU m.p. (“C’l [al;>5 (c)b Yield% c Ref. -. 4i chz Ala 46-47 -76.0 (0.50) 84 __ 4j chz Phe 110-111 -40.5 (0.24) 78 __ 5a BK Ala 69-7 1 -87.0 (1.00) 84 __ Sb BK Abu 75-76 - X.X (0.23) 83 _- 5c Be2 Val 82-84 -4 I 5 (0.65) 82 __ Sd BK Leu 75-77 -< 3 2 (0.82) 82 __ 5e BIX Phe 119-120 -1X.7 (0.48) 83 __ 5f BLX fig 112.113 + 41.2 (0.45)d.= 80 33,34 5h BOC Tyr(Bn) 113-114 -1 I.5 (0.34) 77 _- 6k Fmoc Ala 115.118 4h.O (0.42) 95f -- 61 Fma: Leu 101-103 -55. I (0.63) 94f __ 6m FmlX Phe 148-150 -20. I (0.81) 91f __ 60 Fmoc Abu 130-132 -5u.2 (0.55) 9sf -- 6~ Fmoc Val 127.128 -55.4 (0.33) 92f -- ’ Considered as the side chain of the a-amino acid indicated. b CHCll solutions (1.0 dm cell). c Yield of pure crystal- lized product. d Measured in EtOH. eEnantiomer reported./ From their N(Boc)-analogues.
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