Organoselenium-based entry into versatile, α-(2-tributylstannyl)vinyl amino acids in scalemic form: A new route to vinyl stannanes [14]

Full text of DOI:10.1021/ja0055110

J. Am. Chem. Soc. 2000, 122, 11031-11032
11031
or L-enantiomer at will, and adds a dimension of synthetic
flexibility inherent in the stannylvinyl R-branch.
Organoselenium-Based Entry into Versatile,
r-(2-Tributylstannyl)vinyl Amino Acids in Scalemic
Form: A New Route to Vinyl Stannanes
Scheme 1
David B. Berkowitz,* Jill M. McFadden, Esmort Chisowa, and
Craig L. Semerad
Department of Chemistry, UniVersity of Nebraska
Lincoln, Nebraska 68588-0304
ReceiVed August 4, 2000
Described herein is a synthetically malleable class of quater-
nary, R-(2-trialkylstannyl)vinyl amino acid (AA) building blocks
with potential applications in de noVo peptide design and
engineering. The stereocontrolled route to these AAs highlights
the versatility of the phenylseleno group, acting to (i) mask a
double bond, (ii) direct a low-temperature alkylation reaction, (iii)
facilitate an alkene unmasking step, and (iv) mediate the introduc-
tion of a stannylvinyl group through a new substitution reaction
that is expected to prove useful in other synthetic contexts.
In recent years, there has been heightened interest in R-branched
AAs, in general. As the free monomers, quaternary AAs bearing
â,γ-unsaturation are potential suicide inactivators for AA-
processing enzymes.1 When incorporated into peptides, quaternary
AAs can be used to promote R-helical,2 310-helical,3 or â-turn4
secondary structures. They may also be site-specifically engi-
neered into proteins.5 They are useful building blocks for natural
products6 or combinatorial libraries,7 and generally enhance the
proteolytic stability of their derivative peptides.8 For all such
applications, scalemic R-branched AAs are desirable.9-11 The
stereodivergent route detailed below allows one to access the D-
Our approach emanates from N-benzoyl-protected L-vinylgly-
cine12 and involves the installation of a directing â-stereocenter
in an episelenonium ion-mediated 5-exo-trig cyclization (Scheme
1). Readily separable by SiO2 chromatography, diastereomeric
oxazolines 2 and 3,13 serve as precursors to enantiomeric enolates,
each of which undergoes R-alkylation with essentially absolute
1,2-stereoinduction (Table 1). Thus, 2 and 3 may be regarded as
synthons for L- and D-higher vinyl AAs, respectively.
Interestingly, intermolecular R-alkylation effectively competes
with intramolecular expulsion of the â-amidate leaving group,
presumably for stereoelectronic reasons. That the alkyl halide
approaches the enolate exclusively anti to the â-(phenylseleno)-
methyl directing group was verified by independent synthesis of
both the anti (4a) and (hypothetical) syn (7a) BnBr-alkylation
products (Scheme 2). The alkylation reactions of 2 and 3 with
BnBr produce cleanly the anti alkylation products, L-4a and D-4a,
respectively. The syn alkylation product (7a) is absent (chiral
HPLC).
(1) Berkowitz, D. B.; Jahng, W.-J.; Pedersen, M. L. Bioorg. Med. Chem.
Lett. 1996, 6, 2151-2156; Elegant mechanistic work: Nanavati, S. M.;
Silverman, R. B. J. Am. Chem. Soc. 1991, 113, 9341-9349.
(2) (a) Schafmeister, C. E.; Po, J.; Verdine, G. L. J. Am. Chem. Soc. 2000,
122, 5891-5892. (b) Yokum, T. S.; Gauthier, T. J.; Hammer, R. P.;
McLaughlin, M. L. J. Am. Chem. Soc. 1997, 119, 1167-1168. (c) Altmann,
K.-H.; Altmann, E.; Mutter, M. HelV. Chim. Acta 1992, 75, 1198-1210. (d)
Karle, I.; Balaram, P. Biochemistry 1990, 29, 6747-6756.
(3) (a) Jaun, B.; Tanaka, M.; Seiler, P.; Ku¨hnle, F. N. M.; Braun, C.;
Seebach, D. Liebigs Ann./Recueil 1997, 1697-1710. (b) Aubry, A.; Bayeul,
D.; Pre´cigoux, G.; Pantano, M.; Formaggio, F.; Crisma, M.; Toniolo, C.;
Boesten, W. H. J.; Schoemaker, H. E.; Kamphuis, J. J. Chem. Soc., Perkin
Trans. 2 1994, 525-529.
(4) (a) Obrecht, D.; Altorfer, M.; Lehmann, C.; Schonholzer, Muller, K. J.
Org. Chem. 1996, 61, 4080-4086. (b) Wipf, P.; Hemgartner, H. HelV. Chim.
Acta 1988, 71, 258-267.
(5) (a) Mendel, D.; Ellman, J.; Schultz, P. G. J. Am. Chem. Soc. 1993,
115, 4359-4360. (b) See also: van Hest, J. C. M.; Kiick, K. L.; Tirrell, D.
A. J. Am. Chem. Soc. 2000, 122, 1282-1288.
(6) (a) Murray, W. V.; Sun, S.; Turchi, I. J.; Brown, F. K.; Gauthier, A. D.
J. Org. Chem. 1999, 64, 5930-5940. (b) Campbell, A. D.; Raynam, T. M.;
Taylor, R. J. K. Tetrahedron Lett. 1999, 40, 5263-5266. (c) Trost, B. M.;
Lemoine, R. C. ibid. 1996, 37, 9161-9164. (d) Huwe, C. M.; Blechert, S.
Ibid. 1995, 36, 1621-1624. (e) Krol, W. J.; Mao, S.; Steele, D. L.; Townsend,
C. A. J. Org. Chem. 1991, 56, 728-731. (f) Shaw, K. J.; Luly, J. R.; Rapoport,
H. J. Org. Chem. 1985, 50, 4515-4523.
Table 1. Stereocontrolled Side Chain Introduction/Alkene
Unmasking
(7) (a) Fornicola, R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem. 1998,
63, 3528-3529. (b) Scott, W. L.; Zhou, C.; Fang, Z.; O’Donnell, M. J.
Tetrahedron Lett. 1997, 38, 3695-3698. (c) O’Donnell, M. J.; Zhou, C.; Scott,
W. L. J. Am. Chem. Soc. 1996, 118, 6070-6071. (d) Wenschuh, H.;
Beyermann, M.; Krause, E.; Brudel, M.; Winter, R.; Schu¨mann, M., Carpino,
L. A.; Bienert, M. J. Org. Chem. 1994, 59, 3275-3280.
(8) (a) Sall, D. J.; Shuman, R. T.; Smith, G. F.; Wiley: M. R. U.S. Patent
No. 5,484,772, July 16, 1996; (b) Frauer, A.; Mehlfu¨hrer, M.; Thirring, K.;
Berner, H.; J. Org. Chem. 1994, 59, 4215-4222. (c) Veber, D. F.; Freidinger,
R. M. Trends Neurosci. 1985, 8, 392-396. (d) Khosla, A.; Stachowiak, K.;
Smeby, R. R.; Bumpus, F. M.; Piriou, F.; Lintner, K.; Fermandjian, S. Proc.
Natl. Acad. Sci. U.S.A. 1981, 78, 757-760.
(9) Reviews: (a) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517-3599. (b) Davis. F. A.; Zhou, P.; Chen, B.-C. Chem.
Soc. ReV. 1998, 27, 13-18. (c) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 225-227. (d) Goodman, M.; Zhang, J. Chemtracts: Org. Chem. 1997,
10, 629-645. (e) Seebach, D.; Sting, A. R.; Hoffman, M. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2708-2748. (f) Ojima, I. Acc. Chem. Res. 1995, 28, 383-
389. (g) Williams, R. M. Synthesis of Optically ActiVe Amino Acids; Pergamon
Press: Oxford, 1989.
alkyl unmask
starting
%
yieldb yieldb
oxazoline
alkyl halide
BnBr
BnBr
CH3I
CH3I
BnOCH2Br
EtO2CCH2Br
AA analogue
eea
(%)
(%)
2
3
2
3
2
2
2
2
Phe(L-4/5a)
Phe(D-4a)
Ala(L-4/5b)
Ala(D-4/5b)
Ser(L-4/5c)
Asp(L-4/5d)
99
>99
99
>99
99
99
90
80
82
79
80
86
90
78
76
---
77
71
80
74
75
---
ICH2C6H4-m-OTBS m-Tyr(L-4/5e)
98
E-PhCHdCHCH2Br Cinn-Gly(L-4f) >99
a ee’s are determined by chiral HPLC (Chiracel OD) vs racemic
standard for 4a-f. b Yields are of isolated, purified compounds.
10.1021/ja0055110 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

11032 J. Am. Chem. Soc., Vol. 122, No. 44, 2000
Communications to the Editor
Scheme 2
vinyl-m-Tyr, a potent suicide substrate for DOPA DC)1 with
stereospecific deuterium incorporation also available, if desired.
Investigations into the range/efficiency of synthetic elaboration
possible with these quaternary, R-stannylvinyl AAs, and into the
scope and mechanism of this new deselenative route to vinyl
stannanes are underway and will be described in due course.
Acknowledgment. Financial support from the National Institutes of
Health (CA 62034) is gratefully acknowledged. D.B.B. is an Alfred P.
Sloan Fellow (1997-2001). C.L.S. was a participant in the UNL Summer
Undergraduate Research Program. We thank R. K. Shoemaker and R. L.
Cerny for 2D NMR and MS support, respectively. This research was
facilitated by grants for NMR and GC/MS instrumentation from the NIH
(SIG 1-S10-RR06301) and the NSF (CHE-93000831), respectively.
Following installation of the AA side chain in a D- or L-fashion,
the original â,γ-unsaturation is unmasked via base-mediated
oxazoline ring-opening (Table 1). The â-phenylseleno group
presumably promotes this reaction by increasing the acidity of
the â-protons. The reaction is stereoselective, producing only the
E-vinyl selenides here.
Supporting Information Available: Complete experimental proce-
dures, spectral product characterization, and chiral HPLC traces (enan-
tiomeric purity) (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Table 2. A New Transformation: Deselenative Stannylation
JA0055110
(10) Recent advances: (a) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka,
K. J. Am. Chem. Soc. 2000, 122, 5228-5229. (b) Davis, F. A.; Zhou, P.;
Fang, T.; Reddy, G. V.; Zhang, Y. J. Org. Chem. 1999, 64, 7559-7567. (c)
Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121, 10727-10737. (d)
Wenglowsky, S.; Hegedus, L. S. J. Am. Chem. Soc. 1998, 120, 12468-12473.
(e) Seebach, D.; Hoffmann, M. Eur. J. Org. Chem. 1998, 1337, 7-1351. (f)
Meyer, L.; Poirier, J. M.; Duhamel, P. Duhamel, L. J. Org. Chem. 1998, 63,
8094-8095. (g) Charette, A. B.; Mellon, C. Tetrahedron, 1998, 54, 10525-
10535. (h) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445-
446.
(11) For enantiocontrolled syntheses of higher (R * H) R-vinyl AAs, see:
(a) Berkowitz, D. B.; McFadden, J. M.; Sloss, M. K. J. Org. Chem. 2000, 65,
2907-2918. (b) Frutos, R. P.; Spero, D. M. Tetrahedron Lett. 1998, 39, 2475-
2478. (c) Colson, P.-J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918-5924.
(d) Seebach, D.; Bu¨rger, H. M.; Schickli, C. P. Liebigs Ann. Chim. 1991,
669-684. (e) Weber, T.; Aeschimann, R.; Maetzke, T.; Seebach, D. HelV.
Chim. Acta 1986, 69, 1365-1377.
(12) Berkowitz, D. B.; Smith, M. K. Synthesis 1996, 39-41 and references
therein.
(13) Oxazolines 2 and 3 (1:1-1.3:1) are obtained with an ee that reflects
the enantiomeric purity of the starting vinylglycine derivative, provided that
this cyclization is performed at low temperature. We note that even in cases
where this is 96% ee, say, either 2 or 3 may be obtained in >99%ee with a
single recrystallization from hexane.
(14) (a) Hollingsworth, G. J.; Perkins, G.; Sweeney, J. J. Chem. Soc., Perkin
Trans. I 1996, 1913-1919. (b) Williams, J. P. Ph.D. Thesis, University of
Michigan, 1991. (c) White, J. D.; Pallenberg, A. J. Tetrahedron Lett. 1986,
27, 5591-5594. (d) Tanaka, H.; Hayakawa, H.; Obi, Kikoh; Miyasaka, T.
Tetrahedron 1986, 42, 4187-4195. (e) Schmidt, R. R.; Betz, R. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 430-431.
(2-seleno)-
vinyl AA
AA
analogue
yield 8a yield 9a
(%) (%)
R
L-5a
L-5b
D-5b
L-5c
L-5d
L-5e
Bn
Me
Me
Phe
84
87
85
85
85
83
85
83
90
98
82
91b
L-Ala
D-Ala
Ser
Asp
m-Tyr
CH2OBn
CH2CO2Me
CH2C6H4-m-OTBS
a Yields are of isolated, purified compounds. b Isolated as the HCl
salt.
Upon heating with HSnBu3 and AIBN in toluene, the R-(2-
phenylseleno)vinyl branch is smoothly converted to an R-(2-
tributylstannyl)vinyl branch (Table 2). While substitution reactions
of vinyl sulfides14 and sulfones15 with trialkyltin hydrides have
been described; for vinyl selenides, to our knowledge, only
instances of reduction16 or reductive cyclization17 reactions have
been reported heretofore. Seeing as 8a-e are obtained exclusively
as the E-isomers, this new substitution reaction appears to be
highly stereoselective.18,19
(15) (a) McCarthy, J. R.; Huber, E. W.; Le, T.-H.; Laskovics; F. M.;
Matthews, D. P. Tetrahedron 1996, 52, 45-58. (b)Wnuk, S. F.; Robins, M.
J. Can. J. Chem. 1993, 71, 192-198. (c) McCarthy, J. R.; Matthews, D. P.;
Stemerick, D. M.; Huber, E. W.; Bey, P.; Lippert, B. J.; Snyder, R. D.; Sunkara,
P. S. J. Am. Chem. Soc. 1991, 113, 7439-7440. (d) Dubois, E.; Beau, J.-M.
Tetrahedron Lett. 1990; 31, 5165-5168. (e) Watanabe, Y.; Ueno. Y.; Araki,
T.; Endo, T.; Okawara, M. Tetrahedron Lett. 1986, 27, 215-218.
(16) (a) Saluzzo, C.; Alvernhe, G.; Anker, D.; Haufe, G. Tetrahedron Lett.
1990, 31, 2127-2130. (b) Denis, J. N.; Krief, A. Tetrahedron Lett. 1982, 23,
3411-3414.
Scheme 3a
(17) Batty, D.; Crich, D. J. Chem. Soc., Perkin Trans. I 1991, 2894-2895.
(18) We note that one must always be concerned about the possible
isomerization of vinyl stannanes in the presence of HSnBu3 and ∆: (a)
Leusink, A. J.; Budding, H. A. J. Organomet. Chem. 1968, 11, 541-547.
However, in no cases were the Z-isomers of vinyl stannanes 8a-e observed
here, even where reactions of vinyl selenides 5 were stopped prior to complete
1
conversion and analyzed by H NMR.
a Key: (i) Pd2dba3, p-I-C6H4-NO2, THF (85%); (ii) DCl, D2O, ∆,
then Dowex-50 (75%); (iii) I2, CCl4 (92%); (iv) H2CdCHSnBu3, Pd2dba3,
Pfur3, NMP (65%) (v) DMAD, ∆ then Br2, CCl4/KOtBu, DMF.
(19) It is possible that this new transformation (5 f 8) is stereospecific,
proceeding with retention of alkene configuration. However, in the absence
of data for the corresponding Z-vinyl selenides (not available here), one cannot
yet evaluate this. Indeed, the situation in an apparently related reaction is
complex. Namely, McCarthy15a reports that, whereas the conversion of â,â-
disubstituted-R-fluorovinyl sulfones to the corresponding R-fluorinated vinyl
stannanes is stereospecific (retention), for â-monosubstituted-R-fluorovinyl
sulfones the transformation is not stereospecific. Hence, a definitive conclusion
must await the results of a thorough investigation of this new transformation
across a spectrum of alkene substitution patterns and geometric isomers.
(20) For Stille couplings with R-unbranched AAs, see: (a) Reginato, G.;
Mordini, A.; Caracciolo, M. J. Org. Chem. 1997, 62, 6187-6192. (b) Crisp,
G. T.; Gebauer, M. G. Tetrahedron Lett. 1995, 36, 3389-3392.
Scheme 3 illustrates the results of an initial survey of the
versatility of this R-stannylvinyl branch. These quaternary AAs
effectively serve as either vinyl stannane or vinyl halide Stille
coupling partners,20 allowing for diene installation and Diels-
Alder chemistry along the R-branch. Alternatively, protodestan-
nylation provides the free, L- or D-vinyl AAs (Table 2; includes