The sulfinimine-mediated asymmetric Strecker synthesis
involves addition of ethylaluminum cyanoisopropoxide [EtAl-
(O-i-Pr)CN], generated in situ by addition of i-PrOH to
diethylaluminum cyanide (Et2AlCN) to the sulfinimine.16
Thus treatment of 7 (1.0 mmol) at -78 °C in THF with 1.5/
1.0 equiv of Et2AlCN/i-PrOH give amino nitriles 8 in good
yield (54-68%) and de (74-95%). Interestingly the des for
8c and 8d were 82 and 84%, respectively (Table 1; entries
3 and 5), but improved to >90 when different ratios of
Et2AlCN/i-PrOH were used (Table 1; entries 4, 6, and 9).
When these conditions were used with 7e, there was no effect
(entry 9) on the diastereoselectivity. Since the sulfinyl group
controls the stereochemistry of cyanide addition to the C-N
double bond of the sulfinimine, (S)-7 is predicted to give
amino nitrile 8 where the major diastereoisomer has the
(SS,S)-configuration. Likewise (R)-7a gives (RSR)-8 (Table
1; entry 1). The stereochemistry of the proline and pipecolic
acid derivatives confirm these assignments. These results are
summarized in Table 1.
to give the iminium ion 10. The aqueous mixture containing
10 was extracted with ethyl ether to remove p-toluenesulfinic
acid and glycol byproducts, and the solvent was removed to
give the crude imine salt 10. The salt, dissolved in MeOH,
was hydrogenated (H2/10% Pd/C) for 8 h at atmospheric
pressure, and the cyclic amino acids 11 were isolated using
a Dowex-50 ion-exchange column. However, attempts to
isolate 6-methyl-2-pipecolic acid (11c) and 6-phenyl-2-
pipecolic acid (11d) in this manner resulted in poorer yields
and/or decomposition. We found that these products could
be obtained by first washing the HCl salt with acetone several
times to remove the ethylene glycol byproducts which
afforded (-)-11c in 85% yield. Further crystallization gave
11d in 48% yield.
Hydrogenation is expected to occur from the least hindered
direction, and the cis amino acids 11 were formed exclusively
(Scheme 4).17 The cis stereochemistry of 11b-d was
unambiguously assigned by comparison with authentic
materials and with literature values. The enantiomeric purity
of the products were determined to be >93% ee by
comparison with literature values and making the Mosher
amides (Table 2).18 Because cyclization to an azetidine
Hydrolysis of the diastereomerically pure amino nitriles
8a-d in refluxing 6 N HCl for 3-5 h accomplishes five
operations in a single pot (Scheme 4). Hydrolysis removes
Scheme 4
Table 2. Hydrolysis of Masked Oxo Sulfinimines 8 and 12
entry
8
amino acids 11 and 12 % yield (% ee)
1
2
3
4
5
(RS,R)-(-)-8a
(SS,S)-(+)-8b
(SS,S)-(+)-8c
(SS,S)-(+)-8d
(SS,S)-(+)-8e
(R)-(+)-11a
77 (98)
80 (95)
85 (97)
48 (95)
95 (93)
(2S,5S)-(-)-11b
(2S,6S)-(-)-11ca
(2S,6S)-(-)-11d a
(S)-(+)-12
a Isolated as the hydrochloride salt.
carboxylic acid is energetically unfavorable, hydrolysis of
8e affords (S)-(+)-â-benzoylalanine (12)19 in 95% yield
(Table 2; entry 5).
In summary, masked oxo sulfinimines, in combination with
the sulfinimine-mediated asymmetric Strecker synthesis,
provide easy access to oxo R-amino acids, which are
precursors of cis proline and pipecolic acid derivatives. Our
procedure avoids many of the limitations associated with their
preparation from proteinogenic amino acids, i.e., limited
access to both enantiomers and extensive protection/depro-
tection chemistry. Masked oxo sulfinimines are examples
of polyfunctionalized chiral building blocks in that they have
at least one stereogenic center and more than one chemically
the N-sulfinyl auxiliary with concomitant conversion of the
nitrile to the acid. The protected oxo group is unmasked to
give the intermediate oxo R-amino acid 9, which cyclizes
(15) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J. Org. Chem. 1999, 64, 1403. (b) Fanelli, D. L.; Szewczyk,
J. M.; Zhang, Y.; Reddy, G. V.; Burns, D. M.; Davis, F. A. Org. Synth.
1999, 77, 50.
(16) For examples of the sulfinimine-mediated asymmetric Strecker
synthesis, see (a) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y.-H.
J. Org. Chem. 1996, 61, 440. (b) Davis, F. A.; Fanelli, D. L. J. Org. Chem.
1998, 63, 1981. (c) Davis, F. A.; Srirajan, V.; Titus, D. D. J. Org. Chem.
1999, 64, 6931. (d) Portonovo, P.; Liang, B.; Joullie, M. M. Tetrahedron:
Asymmetry 1999, 10, 1451. (e) Davis, F. A.; Srirajan, V. J. Org. Chem.
2000, 64, 3248. (f) Davis, F. A.; Srirajan, V.; Fanelli, D. L.; Portonovo, P.
J. Org. Chem. 2000, 65, 7663. (g) Boisnard, S.; Neuville, L.; Bois-Choussy,
M.; Zhu, J. Org. Lett. 2000, 2, 2459. (h) Davis, F. A.; Lee, S.; Zhang, H.;
Fanelli, D. L. J. Org. Chem. 2000, 65, 8704.
(17) van der Werf, A.; Kellogg, R. M. Tetrahedron Lett. 1991, 32, 3727.
(18) References to cyclic amino acids (a) (R)-(+)-11a: Shiraiwa, T.;
Shinjo, K.; Kurokawa, H. Chem. Lett. 1989, 1413. (b) (5S,2S)-(-)-11b:
Overberger, C. G.; David, K. H.; Morre, J. A. Macromolecules 1972, 5,
368. (c) (2S,6S)-(-)-11c: Berrien, J.-F.; Royer, J.; Husson, H.-P. J. Org.
Chem. 1994, 59, 3769. (d) (2S,6R)-(-)-11d: ref 8b. (e) (S)-(+)-11e: ref
19.
(19) Golubev, A. S.; Sewald, N.; Burger, K. Tetrahedron 1996, 52,
14757.
(20) For leading references to sulfinimine-derived polyfunctionalized
chiral building blocks, see (a) Davis, F. A.; Chao, B.; Fang, T.; Szewczyk,
J. M. Org. Lett. 2000, 2, 1041. (b) Davis, F. A.; Chao, B. Org. Lett. 2000,
2, 2623. (c) ref 4.ed.
Org. Lett., Vol. 3, No. 5, 2001
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