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Enantioselective Synthesis of “Quaternary” 1,4-Benzodiazepin-2-one Scaffolds via Memory of Chirality
Paul R. Carlier, Hongwu Zhao, Joe DeGuzman, and Polo C.-H. Lam
J. Am. Chem. Soc., 2003, 125 (38), 11482-11483• DOI: 10.1021/ja0365781 • Publication Date (Web): 28 August 2003 Downloaded from http://pubs.acs.org on March 6, 2009

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4-Benzodiazepin-2-one Scaffolds via Memory of Chirality Paul R. Carlier. and treatment with n-BuLi before addition of the electrophile (Table 1). stabilizing the pseudoequatorial conformer. we reason that an N-Me group is not large enough to impart sufficient conformational stability to the enolate ring at -78 °C on the deprotonation/alkylation time scale. MeI. c Racemic 4 is also obtained if BnBr is added only 10 s after deprotonation by LDA.12 Conversion to the N-Me (2b 94%) and the N-i-Pr derivatives (2c 82%.* Hongwu Zhao. d The extent of deuteration is 96%. thus. Virginia Tech. CHEM. the resulting enolate would remain chiral by virtue of the nonplanar diazepine ring.3-dialkyl-1. b % ee measured by chiral stationary phase HPLC (Chiralcel OD. Me. We envisioned that the effective stereochemical cooperativity demonstrated by 3-alkyl-1. Although deprotonation of (3S)-2b would destroy the stereogenic center at C3. AM. 3c. allyl 6 4 2 6 4 2 bromide. Even with short deprotonation times (LDA only. 2003. representing the prototypical “privileged structure”..4benzodiazepin-2-ones have been previously reported11 as a means to prepare novel benzodiazepines and the corresponding amino acids.11b However.4-benzodiazepin-2-ones (3S)-2a and (3S)-3a (R1 ) H) were prepared in 91% and 67% yield from (S)Boc-Ala and (S)-Boc-Phe.4-Benzodiazepin-2-ones entry R1 R2 Ea product % yield % eeb 1 2 3 4 5 6 7 8 Me i-Pr i-Pr i-Pr i-Pr i-Pr i-Pr i-Pr Me Me Me Me Me Me Bn Bn Bn Bn 4-MeC6H4CH2 2-PhC6H4CH2 allyl D Me allyl (()-4 (+)-5 (+)-6 (+)-7 (+)-8 (+)-9 (-)-5 (+)-10 72 74 68 70 76 85d 64 57 0c 97 (3R) 95 (3R) 99 94 99 (3S) 95 (3S) 86 a Electrophiles used: BnBr. substituent (Scheme 1). Knowing that the inversion barrier of benzodiazepines is a function of the size of the N1 11482 9 Scheme 1. When the N1 substituent is relatively small (H.g.1021/ja0365781 CCC: $25.13 After considerable optimization. the only reported R-alkyation route to 3.1 Tens of thousands of these compounds have been prepared on solid phase and in solution. 2). (3S)-stereochemistry will induce the diazepine ring to adopt the (M)-conformation (Scheme 1). 2b).e.and (P)-enantiomers. entries 1. reaction of the enolate derived from (3S)-2c with other active electrophiles proceeds 10. cf. E-mail: pcarlier@vt. SOC. including an auxiliary-based asymmetric method.and (P)-conformational enantiomers6 (Scheme 1). Lam Department of Chemistry.. 11482-11483 . Despite the absence of a stereogenic center.4-benzodiazepin-2-ones that relies upon the intrinsic chirality of the benzodiazepine ring.4-benzodiazepine drug candidates shows no sign of abating. preventing resolution of these compounds.g.4. 58%) in 100% ee was achieved upon treatment of the sodium salts with the corresponding alkyl triflates. Virginia 24061 Received June 9.3 In this Communication. glycine-derived 1. identical treatment of the N-i-Pr analogue (3S)-2c gave the desired product 5 in 97% ee (Table 1. R1 ) t-Bu) is the racemization barrier high enough to allow preparative resolution of the (M). In contrast. 3c) Deprotonation/Trapping Reactions of 1. Blacksburg.11a Enantiomerically pure 1. 4-MeC H CH Br. Racemizing (2b) and Enantioselective (2c. 1a-c). using a modification of Shea’s protocol. N-Me benzodiazepine (3S)-2b produces racemic 4. Deprotonation/alkylation sequences of glycine-derived 1. and the development of new 1. 1d.-H.4-benzodiazepin-2-ones such as 2b might allow the development of an enantioselective R-alkylation protocol.00 © 2003 American Chemical Society J.4-benzodiazepin-2-ones (e.4benzodiazepin-2-ones 1 such as diazepam (1b) are chiral. Dynamic Chirality of 1a-c and Stereochemical Cooperativity in 2b (∆Gq Values Were Determined by 1H NMR Spectroscopy (Coalescense)) Table 1. In addition to benzylation.7 Only when the N1 substituent is very large (e. we determined that acceptable yields of desired R-alkylation products could be attained by deprotonating 2b-c and 3c with LDA in the presence of HMPA. AD).4. and Polo C. 2-PhC H CH Br.5 existing as (M).14 However. Joe DeGuzman. Fortunately. deprotonation/ trapping reactions of the N-i-Pr analogues examined thus far are highly enantioselective. 125. D-OTFA.2 Yet amidst this impressive diversity.4-Benzodiazepines are among the most important scaffolds in medicinal chemistry. i.8 It is well known5.4. i-Pr. 2003. 10 s). racemization is facile at room temperature.Published on Web 08/28/2003 Enantioselective Synthesis of “Quaternary” 1. application of this protocol to the enolate of N-Me benzodiazepine (3S)-2b and BnBr gave 4 in a disappointing 0% ee.8-10 that placement of a single substituent at C3 perturbs the conformational equilibrium of N-Me 1.edu 1. we report an enantioselective R-alkylation route to “quaternary” 1. the reliance of most of these syntheses upon proteinogenic amino acid starting materials has systematically excluded one class of targets: enantiopure benzodiazepines possessing a quaternary stereogenic center.4-benzodiazepin-2-ones affords low (0-20%) yields..

Inc. Head-Gordon. 460465. Rittle. A. Anderson. J. Retentive alkylation of the enolate of (3S)-2c was established by hydrolysis of (+)-5 and (+)-6 to the corresponding quaternary amino acids 11 and 12 (Scheme 2).. (c) Wanyoike. 4. J. C. D. R. Chem.. J. (13) Less reactive alkylating agents (MeI. Chim. Kling.11. B..3-bis(hydroxymethyl)-1. S. 112.. J.8 min. Tetrahedron Lett. F. B. W. V. 1998. Adamo. 1998. Org.. 1996. K. FitzGerald. conformational chirality (rather than static. K.. M.3disubstituted benzodiazepines 4-8. Chem. K. AM... H. Gaussian 98.. M. Toso.. F..org. Soc. D. Fox. (c) Kim. J. 96949696.. we find that. Ercole.. R. Biochem.. P. Nanayakkara. S.4-benzodiazepin-2ones: Avdagic.. J.. entries 1. Andres.. Acta 1998. entries 7. G. Mennucci. Pharm. 3741-3744. S. respectively. 166-171. the divergent stereochemical outcomes for deprotonation/benzylation of 2b and 2c JA0365781 J. 2003. Daniels.. 1988. Martin. Cazaux. DiPardo.. Komaromi. G. 992-997. Supporting Information Available: Experimental procedures... M. E. D. Kajfez. (3) The only published route to such compounds involves lipase-catalyzed acylation of prochiral 3. Maki. entry 2)... Barone.c. R. and the Virginia Tech Department of Chemistry for financial support. Acknowledgment.9 s.. (b) Decorte. Mathieu. A. C.. and by the calculated (B3LYP/6-31G*) equilibrium geometries and ring inversion transition structures of the (des-chloro) enolate anions 13b. (10) Paizs. G. G. P.. Tomasi.. 3109-3113. High enantioselectivities are also observed in methylation and allylation of the enolate of Phederived (3S)-3c (Table 1.8°). (17) (a) Kawabata. (7) Application of the Eyring equation allows the racemization t1/2 values (298 K) of 1a-c to be estimated as 60 µs.. Clifford. Chirality 1999.. T.. J. J. B. 4. M. A. Foresman.. (2) (a) Ellman. Cammi. Gaussian. G. V.....4 and 17. The transformations of 2c and 3c described above can be viewed as examples of Seebach’s “self-regeneration of stereocenters (SRS)” principle. F. Shea. Y. Soc. Nardin. Mitchell.. E.. Braz. Sunjic. N.-Eur.17 Dynamic chirality of the enolates is suggested by the sensitivity of the R-alkylation % ee to the size of the N1 substituent. B. W. R. C. We thank the National Science Foundation (CHE-0213525). Sting. (18) Frisch.. A. J. Pomelli. T. M.. Chem. P. Cheeseman. Rush. Correlation of Benzodiazepines 5 and 6 by Conversion to the Corresponding Quaternary Amino Acids 11 and 12 in 94-99% ee (Table 1. 81.c (derived from 2b.. Lesac. Am.... 2003 11483 . Z. 1145-1149. R. Ruscic... (b) Fuji.. Hoffman. F. B. B. Sandanayake. D. E. J. Burant. 43. 11. Jayatissa.. Lundell. 10 exist as ∼1:1 mixtures of (M). A. J.. Hollosi. Chem. 1624-1654. 1967. 132-143. 2000.. Chem. CDCl3) of 5 indicates that the conformers exchange at a rate of 0. M. V. 0. L. N. E. A. Rabuck.. Am. S. 1979. B. A. Y. R.. K.. Onomura. J. Schlegel.5 kcal/mol. Freidinger. Rendic. and significant amounts of starting material are recovered. V.18 The equilibrium geometries of enolates 13b.. C. B. S. Palacios. J. (16) Seebach. alkylation and deuteration yields decrease. D. Peng. A. M. A. Cui..and (P)-conformers. F. Chen. J. Campbell.. 35. K. 2002. C. Yahiro. 2001. 12. Ede. Ellman. M. A. Sachdeva. A. based on the sign of the τ2345 torsional angle. Guerret. Chem.. Y... Piskorz. Angew. O. Soc. M. M. J. M.. O. N. R. C.. (d) Goumri-Magnet. Stefanov. J. Morokuma.. G.0°). (11) (a) Reitter. and 2. T.. B3LYP/6-31G* equilibrium geometry and ring inversion transition structure of N-i-Pr enolate anion 13c (relative free energies at B3LYP/6-31+G*//B3LYP/6-31G*).. Engl.. 7). (d) Brewster. M.. 9. M. Raghavachari. Z. P.. Volkman. Pham.. J. The ring inversion transition structures of 13b. NO. 651-658. K.. after a deprotonation time of 8 h at -78 °C. i-PrOTs) give partial racemization. A.. and computational details (PDF). Org. G. D.. Gomperts. Alebic-Kolbah. A. J.4°. J.. This material is available free of charge via the Internet at http:// pubs. T. consistent with the similar local steric demands of the C3 substituents. K. Chim. J. J. 1988. entries 2.5 kcal/mol). K.. 38.. Lett. 31. F. B. 13c depicted in Figure 1). Engl. O. 2002.. N. P. W. 3969-3978..... Kovac. Sunjic. G. PA. Fuji. 2) may be rationalized. 5. 3919-3922... K. revision A.. J.. Simonyi. see: Seebach. 8). A. References (1) Evans. Hirschfield. S. Sega. If treatment of the enolate with n-BuLi is not carried out before trapping. Thus. T.. 64. D.-M. G. J. Chem.. K. Rosen.. P.. R. S. Res. (b) Wu.. Cook. Riley. J. Earley. N. benzylation of the enolate of (3S)-2c occurs in 92% ee (cf. Acta 1981. L. Bertrand..acs. Sunjic. A. HelV.. M. E. M. L. P. 27. Ruzic-Toros. Farkas. Chim. 1981. 3945-3949. Montgomery. L. Kunkel. SOC. M. E. A.. We suspect that enolate‚diisopropylamine complexes produce starting material via an internal return mechanism.and (P)-. Ochterski. Trucks. M. W. J. J. A. S. Ortiz. E. 1875-1877. 29. Ed. Randaccio. V. Int. 113. Kudin. C. spectroscopic data and HPLC chromatograms. Bray. Zakrzewski.. J. 28. 1999. Comb.. 1 (15) H-1H EXSY NMR spectroscopy (297 K. Chem. 375-379.2 s-1 (∆Gq ) 18. Bresciani-Pahor. Kajfez. Pople. central chirality) to control alkylation stereochemistry of the enolates. A.. 1996.c indicate near eclipsing of the N1 substituent (R1) and C8 (dihedral angles 13.. D. Robb. V.. V. Challacombe. D. V. Fr.. Majer. Chem.c are chiral and feature essentially flat C3 carbons (sum of angles 358. Johnson. B. from this perspective. Sega. F. Matsumura. 125. A. Jr.. B3LYP/6-31+G*//B3LYP/6-31G* activation free energies for ring inversion at 195 K of 13b (N-Me) and 13c (N-i-Pr) are 12... (12) Hart. Am. Soc. Strain. K. P.. Interestingly. The same sense of chirality is noted using the more easily perceived τ(R1)178 or τ2176 torsional angles. A. Int. Schofield. 757-761. A. CHEM. Y. 1979. Rea. the Jeffress Memorial Trust. 9 VOL. Figure 1. B.. 122.11 min and 970 h. Cerino.. Lisini. Kawabata. (5) Konowal. which correspond to racemization t1/2 (195 K) values of 0. Retentive conversion of Phe-derived (3S)-3c to (3S)-(-)-5 was confirmed by HPLC and optical rotation (Table 1. Dapprich. Cioslowski.5°...... R. Malick.. J. 2708-2748. Soc. G. Med. Heterocycl.15 The stereochemical course of these reactions appears to be uniformly retentive. P. W. S.COMMUNICATIONS (Table 1. W.. Springer. R. Angew. Wong. J.. Millam... Table 1. J. 359. Bull.. Org. 373-376.. Retentive deuteration of the enolate of (3S)(+)-2c was established by comparison of (+)-9 with the starting material. J.. Chang.. 2235-2246. T. (6) The sense of chirality of the ring has traditionally been described using the helical descriptors (M). 1990. (14) No alkylation products are obtained in the absence of HMPA.. L. J. Liashenko.. J. P. Todaro.. 3. HelV. B. Cossi. 64. J. Whitter. M. B. Lehn. Bock. T. Chem. 1991. Chem. G.. B. Ayala.. Stoodley. Gill.. A.. J. Y. (9) Sunjic.: Pittsburgh... N. Acc. Scheme 2. Kojic-Prodic. Q.. J.. J. 1H and 13C NMR spectroscopy demonstrate that. 46. Chen. J. Snatzke. Petersson. Liu. Ed.. entries 3-6). Finally. Scuseria. Stratmann. (4) Linscheid. P. V. Perera. B. G.. Wolfe. R.... M. unlike 2c and 3c. R.1. Bigg. Gonzalez.16 The novel feature here is the use of dynamic. Gornitzka. consistent with this high racemization t1/2 estimate for 13c. Chem. S. Chem.. Veber. M. Replogle. R. these transformations also rely upon “memory of chirality”. H. Keith. D. J. 1567-1582. I. 16. G. (8) Gilman.. J.. K. L.. Al-Laham.. Z.. Lotti.