The enantioselective synthesis of α-amino acid derivatives via organoboranes

Article abstract of DOI:10.1021/ja017522e

Optically active (S)-α-amino acids are prepared in 54-95% ee (12 cases) by reaction of the Schiff base acetate of glycine tert-butyl ester with B-alkyl-9-BBN derivatives in the presence of the Cinchona alkaloid, cinchonidine, and base. The enantiomeric (R)-α-amino acids are available in 59-92% ee (3 cases) by using cinchonine as the chiral control element. Copyright

Full text of DOI:10.1021/ja017522e

Published on Web 07/19/2002
The Enantioselective Synthesis of r-Amino Acid Derivatives via
Organoboranes
Martin J. O’Donnell,* Mark D. Drew, Jeremy T. Cooper, Francisca Delgado, and Changyou Zhou
Department of Chemistry, Indiana UniVersity Purdue UniVersity Indianapolis, Indianapolis, Indiana 46202
Received November 12, 2001
New methods for preparing optically active R-amino acids, the
building blocks of life”, continue to attract considerable attention.
The benzophenone imines of glycine esters (1 and 2) have been
lithium chloride (5 equiv) at 0 °C. The B-alkyl-9-BBN (7, 1.2 equiv)
in THF was then added, followed by a solution of 2b (1.0 equiv)
in THF. The reaction mixture was stirred for 4 h at 0 °C and then
subjected to an aqueous workup followed by flash chromatography.
1,2
“
used as glycine anion and cation equivalents in solution and on-
2
resin for the synthesis of optically active R-amino acids. The
methods involve chiral catalysts, reagents, or auxiliaries, as well
as racemic synthesis followed by resolution. In 1985, we reported
the synthesis of racemic R-amino acids from organoboranes by the
Using conditions developed for the enantioselective boron
alkylation to form the cyclohexylglycine (S)-8a, we prepared a
number of homologous cycloalkylglycine derivatives (Table 1,
3
reaction of 2a (R ) Et) with B-alkyl-9-BBN derivatives, which
provides a method for “appending” the R-amino acid subunit onto
functional groups such as alkenes or alkyl halides that can be readily
converted into organoboranes.4 We now report that this reaction
can be used to prepare optically active R-amino acids by employing
the inexpensive and readily available Cinchona alkaloids, cinchoni-
(S)-8a-(S)-8f). Such amino acids, which contain a secondary
-6
â-carbon, can be difficult to obtain from a glycine anion equiv-
alent because of competing elimination. The B-alkyl-9-BBN
reagents 7a and 7d-7f were readily prepared by hydroboration of
the corresponding cycloalkene with 9-BBN, while the cyclopropyl
and cyclobutyl reagents, 7b and 7c, were obtained by reaction of
the organolithium derivative with B-methoxy-9-BBN. While the
enantioselectivity for the three- and four-membered ring analogues
was only moderate, products containing a five-, six-, seven-, or
eight-membered ring were obtained with excellent enantioselectivity
7
dine (3) or cinchonine (4), to control the stereochemistry at the
R-carbon center.
(89-95% ee). Three homologous cycloalkylmethylglycine deriva-
tives (Table 1, (S)-8g-(S)-8i) were prepared by hydroboration of
Table 1. Enantioselective Alkylation of Acetate 2 with
Organoboranes 7a
Preliminary studies focused on the enantioselective synthesis of
the benzophenone imine of cyclohexylglycine tert-butyl ester (8a)
by reaction of 2b with B-cyclohexyl-9-BBN (7a) in the presence
of the lithium alkoxide of cinchonidine (5) (eq 1). When the reaction
was carried out in THF at 0 °C for 4 h, (S)-8a was isolated in 77%
yield and 61% ee. The enantiomeric product ((R)-8a) was prepared
(73%, 61% ee) using the alkoxide from cinchonine (6). Next, several
reaction variables were studied: (a) esters that were either less or
more sterically demanding than the tert-butyl ester 2b gave poorer
8
9
results, (b) THF was the optimal solvent, (c) best results were
obtained at 0 °C,10 and (d) the product was not racemized under
the reaction conditions.11
A dramatic increase in the enantioselectiVity (61% ee to 92%
ee) was achieved by the addition of lithium chloride to the reaction
mixture.1
2,13
On the basis of these early results, the optimal procedure (eq 1)
used in subsequent studies involved addition of n-BuLi (1.3 equiv)
to a solution of the alkaloid 3 or 4 (1.3 equiv) containing anhydrous
a
See eq 1 and text for reaction procedure.
the methylenecycloalkanes, followed by the standard organoborane
alkylation (eq 1), while the straight-chain derivatives (S)-8j-(S)-
*
To whom correspondence should be addressed. E-mail: odonnell@
chem.iupui.edu.
9
348 J. AM. CHEM. SOC. 2002, 124, 9348-9349
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10.1021/ja017522e CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
8
l were prepared by using the corresponding B-(n-alkyl)-9-BBN
(6) 9-BBN: Soderquist, J. A. 9-Borabicyclo[3.3.1]nonane Dimer. In Ency-
clopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; John
Wiley: Chichester, U.K., 1995; Vol. 1, pp 622-630.
(7). The enantiomeric products ((R)-8d, (R)-8i, and (R)-8k) were
14
prepared using cinchonine (4).
(7) (a) Recent review concerning Cinchona alkaloids in asymmetric synthe-
sis: Kacprzak, K.; Gawro n´ ski, J. Synthesis 2001, 961-998. (b) The
pseudoenantiomers cinchonidine (3) and cinchonine (4) are available from
the chiral pool ($165 and $169 per mole, respectively, Aldrich Catalog,
While the full mechanistic and stereochemical details of the
enantioselective organoborane alkylation are complex and remain
to be elucidated, a number of points are noted. The use of lithium
halide additives to improve selectivity in enolate reactions is well
known.15 The Cinchona alkaloid plays two crucial roles in this
reaction: as the lithium alkoxide (5 or 6), it deprotonates the
starting acetate 2b, which then reacts with the B-alkyl-9-BBN
reagent 7 to give the ate complex 9. Migration of the alkyl group
with loss of acetate yields the R-boryl ester 10, which tautomerizes17
2
000-2001). (c) Blaser, H.-U. Chem. ReV. 1992, 92, 935-952.
8) Ester R group, % yield, % ee: Me, 76%, 26% ee; Et, 72%, 42% ee; tert-
Bu, 77%, 61% ee; Et
C-, 52%, 14% ee.
(9) Solvent, % yield, % ee: THF, 77%, 61% ee; CH
CH Cl (1:1), 76%, 58% ee; PhMe, 76%, 58% ee; DME, 83%, 49% ee;
tert-BuOMe, 31%, 24% ee; Et O, 64%, 23% ee.
(
3
2 2
Cl , 29%, 75% ee; THF/
1
6
2
2
2
(
10) Temp, % yield, % ee: 25 °C, 79%, 43% ee; 0 °C, 77%, 61% ee; -20 °C,
60%, 27% ee; -40 °C, 88%, 34% ee; -78 to 0 °C, 76%, 46% ee.
(11) Rx time, % ee: 1 h, 62% ee; 2 h, 63% ee; 4 h, 62% ee; 6 h, 62% ee; 16
h, 63% ee.
to the boron enolate 11. The final step in the sequence is the crucial
(12) LiCl (eq), % yield, % ee: 0, 77%, 61% ee; 0.5, 83%, 89% ee; 1, 78%,
enantioselective protonation (12),1
8-23
89% ee; 2, 73%, 91% ee; 5, 84%, 92% ee.
which is mediated by the
(
(
(
13) Additive (eq), % yield, % ee: LiCl (5), 84%, 92% ee; LiBr (5), 85%,
parent alkaloid, to give the product 8.24
62% ee; LiCl (4) + LiBr (1), 81%, 67% ee.
14) Optical purities of 8 or derivatives can be increased by recrystallization:
O’Donnell, M. J.; Delgado, F. Tetrahedron 2001, 57, 6641-6650.
15) Lithium halide effects, reviews, and mechanistic studies: (a) Hall, P. L.;
Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum, D. B. J. Am. Chem.
Soc. 1991, 113, 9575-9585. (b) Loupy, A.; Tchoubar, B. Salt Effects in
Organic and Organometallic Chemistry; VCH: Weinheim, Germany,
1
992. (c) Seeback, D.; Beck, A. K.; Studer, A. In Modern Synthetic
Methods 1995; Ernst, B., Leumann, C., Eds.; VCH: Weinheim, Germany,
995; pp 1-178. (d) Henderson, K. W.; Dorigo, A. E.; Liu, Q.-Y.;
Williard, P. G.; Schleyer, P. v. R.; Bernstein, P. R. J. Am. Chem. Soc.
1
1
996, 118, 1339-1347. (e) Abu-Hasanayn, F.; Streitwieser, A. J. Am.
Chem. Soc. 1996, 118, 8136-8137. Recent asymmetric protonations: (f)
Yamashita, Y.; Emura, Y.; Odashima, K.; Koga, K. Tetrahedron Lett.
2
000, 41, 209-213. (g) Yanagisawa, A.; Watanabe, T.; Kikuchi, T.;
Yamamoto, H. J. Org. Chem. 2000, 65, 2979-2983. (h) Cuenca, A.;
Medio-Sim o´ n, M.; Aguilar, G. A.; Weibel, D.; Beck, A. K.; Seebach, D.
HelV. Chim. Acta 2000, 83, 3153-3162. (i) Asensio, G.; Gil, J.; Alem a´ n,
P.; Medio-Sim o´ n, M. Tetrahedron: Asymmetry 2001, 12, 1359-1362.
(
16) Use of Cinchona alkoxides: (a) Huffman, M. A.; Yasuda, N.; DeCamp,
A. E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590-1594. (b) Amadji,
M.; Vadecard, J.; Cahard, D.; Duhamel, L.; Duhamel, P.; Plaquevent, J.-
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Motoyama, Y.; Wakita, H.; Nagase, H. Synlett 1997, 1147-1148.
In summary, the enantioselective synthesis of R-amino acids from
organoboranes has been realized in up to 95% ee. The versatile
and well-established chemistry of the organoboranes, combined with
their structural variability, holds considerable promise for the
application of this new methodology to the synthesis of optically
active R-amino acids. Future work will expand the studies reported
here, as well as explore the use of chiral, nonracemic organoboranes
for the preparation of optically active R-amino acids containing
multiple stereogenic centers.
(
17) (a) Ibrahim, M. R.; B u¨ hl, M.; Knab, R.; Schleyer, P. v. R. J. Comput.
Chem. 1992, 13, 423-428. (b) Reference 5d.
(
18) Hypercoordination of boron: Ooi, T.; Uraguchi, D.; Kagoshima, N.;
Maruoka, K. J. Am. Chem. Soc. 1998, 120, 5327-5328.
(19) Asymmetric protonation of a chiral boron enolate: Haubenreich, T.; H u¨ nig,
S.; Schulz, H.-J. Angew. Chem., Int. Ed. Engl. 1993, 32, 398-399.
(
20) Reviews of asymmetric protonations: (a) Duhamel, L.; Duhamel, P.;
Launay, J.-C.; Plaquevent, J.-C. Bull. Soc. Chim. Fr. II 1984, 421-430.
(b) Koga, K. Pure Appl. Chem. 1994, 66, 1487-1492. (c) Waldmann, H.
In Organic Synthesis Highlights II; Waldmann, H., Ed.; VCH: Weinheim,
Germany, 1995; pp 19-27. (d) H u¨ nig, S. In Methods of Organic Synthesis
Acknowledgment. This work is dedicated to Professor H. C.
Brown on the occasion of his 90th birthday. We acknowledge the
National Institutes of Health (GM 28193) for support. We thank
Dr. Mary Mader for detailed discussions.
(
Houben-Weyl); Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann,
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3
851-3911. (e) Fehr, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2566-
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Supporting Information Available: Experimental procedures and
analytical data for products 8 (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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Y.; Curran, D. P. Tetrahedron 2000, 56, 351-356. (b) Vedejs, E.; Kruger,
A. W.; Lee, N.; Sakata, S. T.; Stec, M.; Suna, E. J. Am. Chem. Soc. 2000,
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(
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(
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835.
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