Asymmetric Strecker synthesis using enantiopure sulfinimines and diethylaluminum cyanide: The alcohol effect

Full text of DOI:10.1021/jo9519928

440
J . Org. Chem. 1996, 61, 440-441
Sch em e 1
Asym m etr ic Str eck er Syn th esis Usin g
En a n tiop u r e Su lfin im in es a n d
Dieth yla lu m in u m Cya n id e: Th e Alcoh ol
Effect
Franklin A. Davis,*,† Padma S. Portonovo,†
Rajarathnam E. Reddy,‡ and Yu-hung Chiu‡
Department of Chemistry, Temple University, Philadelphia,
Pennsylvania 19122, and Department of Chemistry, Drexel
University, Philadelphia, Pennsylvania 19104
Received November 9, 1995
The development of new and improved methods for the
asymmetric synthesis of protein and nonprotein R-amino
acids is of considerable current interest because of their
importance in biological systems and their exceptional
utility as chiral building blocks.1 Of the many methods
used to prepare R-amino acids, the asymmetric Strecker
synthesis should hold particular prominence because of
its simplicity.2 Unfortunately, the auxiliary-controlled
nucleophilic addition of cyanide or its equivalent to
enantiopure imines is problematic for several reasons.
First, the diastereoselectivity, with rare exception, is
mostly modest (22-60% de), although fractionation can
often be used to give a diastereomerically pure product.2
Second, removal of the chiral auxiliary without destroy-
ing or epimerizing the R-amino acid is a frequent
problem.
Recently, we reported that diethylaluminum cyanide
(Et2AlCN) adds to enantiopure sulfinimines (thiooxime
S-oxides) 1 to give R-amino nitriles 2 (Scheme 1).3
Treatment of 2 with acid removes the chiral auxiliary
and hydrolyzes the nitrile, affording the R-amino acid 3
in good to excellent yield and without epimerization, thus
eliminating one of the problems with the Strecker
synthesis protocol. However, as observed in the other
procedures, the diastereoselectivities never exceeded
54%.3,4 We now report that addition of 2-propanol
(i-PrOH) to the Et2AlCN-sulfinimine 1 mixture results
in a dramatic improvement in the diastereoselectivity
and a practical asymmetric Strecker synthesis.
used it was first added to Et2AlCN at rt, and this mixture
was combined with a -78 °C solution of 1.0 mmol of 1 in
THF. After 10 min, the solution was warmed to rt,
monitored by TLC, cooled to -78 °C, and quenched by
addition of 0.05 N HCl. The reaction mixture was diluted
with EtOAc and water and filtered through Celite
powder. Drying and removal of the organic solvent
afforded the crude amino nitriles 2 (Table 1). A simple
crystallization from ether afforded the diastereomerically
pure products 2a ,b in 80-90% yield.7 Sulfinimines 1a 5
and 1b6 were prepared in enantiopure form as previously
described.
The results summarized in Table 1 indicate that the
de’s and yields are highly dependent on the ratio of the
sulfinimine 1 to Et2AlCN and i-PrOH. At low ratios of
Et2AlCN the reaction is slow, and optimum results are
obtained with an excess (1.5 equiv) of this reagent
(compare entries 1 and 8 with 2 and 9). The addition of
1.0 equiv of i-PrOH improves the de’s from 14-27% to
82-84% (compare entries 2 and 9 with 4, 7, 10, and 14).8
Addition of 1 to a -78 °C solution of Et2AlCN/i-PrOH
had no effect on the selectivity of 2 (entries 5 and 11).
The hydrocyanation of 1 appears to be kinetically con-
trolled because increasing the time of reaction has little
effect on the diastereoselectivity or yield of 2. Finally, it
is important to note that the rate of hydrocyanation is
much faster for the pivalaldehyde sulfinimine 1b than
for 1a ; e.g., hydrocyanation of 1b was complete within
20 min (entry 10). In a competitive experiment where
equal amounts of 1a /1b were treated with 1.5/1.0 equiv
of Et2AlCN/i-PrOH, amino nitrile 2a was not detected;
e.g., 2b:2a >95:5.
Formation of the amino nitrile 2 typically involved
addition of 1.0-1.5 equiv of Et2AlCN to 1.0 mmol of the
sulfinimine 15,6 in THF at -78 °C. When 2-propanol was
† Temple University.
‡ Drexel University.
(1) (a) Barrett, G. C., Ed. Chemistry and Biochemistry of the Amino
Acids; Chapman and Hall: London, 1985. (b) Greenstein, J . P.; Wintz,
M. Chemistry of the Amino Acids; Robert E. Krieger: FL, 1984; Vols.
1-3. (c) Coppala, G. M.; Schuster, H. F. Asymmetric Synthesis:
Construction of Chiral Molecules using Amino Acids; Wiley: New York,
1987. (d) Hanessian, S. Total Synthesis of Natural Products: The
Chiron Approach; Pergamon Press: Oxford, 1983. (e) O’Donnell, M.
J ., Ed. Tetrahedron Symposia-in-Print 1988, 44, 5253. (f) Williams,
R. M. In Organic Chemistry Series Volume 7: Synthesis of Optically
Active R-Amino Acids; Baldwin, J . E., Magnus, P. D., Eds.; Pergamon
Press: Oxford, 1989. (g) Duthaler, O. R. Tetrahedron 1994, 50, 1539.
(h) Kunz, H. In Stereoselective Synthesis; Helmechen, G., Hoffmann,
R. W., Mulzer, J ., Schaumann, E., Eds.; Georg Theime Verlag:
Stuttgart 1995; Vol. E21b, 1931.
Consistent with these results is the mechanistic hy-
pothesis outlined in Scheme 2, based in part on the
pioneering studies of Nagata et al. on the hydrocyanation
of R,â-unsaturated ketones with Et2AlCN.9,10 In THF Et2-
AlCN exists in equilibrium with the solvated monomer
(2) For excellent reviews on the asymmetric Strecker synthesis see
ref 1f-h. See also: Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V.
Tetrahedron 1995, 51, 9179.
(3) Davis, F. A., Reddy, R. E.; Portonovo, P. S. Tetrahedron Lett.
1994, 35, 9351.
(4) A low de of 30% has recently been reported for the addition of
Et2AlCN to an N-[1-(triethoxymethyl)ethylidene]sulfinamide. Hua, D.
H.; Lagneau, Wang, H.; Chen, C. Tetrahedron: Asymmetry 1995, 6,
349.
(5) (a) Davis, F. A., Reddy, R. E. Szewczyk, J . M.; Portonovo, P. S.
Tetrahedron Lett. 1993, 34, 6229. (b) Davis, F. A.; Reddy, R. E.
Szewczyk, J . M. J . Org. Chem. 1995, 60, 7037.
(6) Sulfinimine (+)-1b has the following properties: mp 73-75 °C:
[R]20 +371.5 (c 1.94, CHCl3).
D
(7) The amino nitriles had the following properties. (SS,S)-2a : mp
123-24 °C; [R]20 +177.4 (c 2.2, CHCl3); (SS,S)-2b: mp 129-30 °C;
D
[R]20 +59.2 (c 2.2, CHCl3).
D
(8) Other primary and secondary alcohols behave similarly to
2-propanol. tert-Butyl alcohol apparently does not react with Et2AlCN
as evidenced by the lack of ethane formation and the similar de’s to
those observed in the absence of added alcohol.
(9) Nagata, W.; Yoshioka, M.; Hirai, S. J . Am. Chem. Soc. 1972, 94,
4635.
0022-3263/96/1961-0440$12.00/0 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 2, 1996 441
Ta ble 1: Ster eoselective Ad d ition of Dieth yla lu m in u m Cya n id e to Su lfin im im in es 1 in THF
conditions
Et2AlCN/1/R′OH
R-amino nitrile 2
[SS,S)/(SS,R)]a
T (°C)/time
entry
sulfinimine 1
(equiv)
(h)
% de
% yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(()-1a (R ) Ph)
1.0:1.0:0
1.5:1.0:0
-78 to rt/3
-78 to rt/3
-78 to rt/1
-78 to rt/3
-78 to rt/3
-78 to rt/24
-78 to rt/3
-78 to rt/0.5
-78 to rt/0.3
-78 to rt/0.3
-78 to rt/0.3
-78 to rt/1
-78 to rt/24
-78 to rt/0.3
71/29
64/36
90/10
92/8
92/8
90/10
92/8
97/33
57/43
89/11
89/11
87/13
86/14
90/10
42
27
80
84
84
80
84
33
14
78
78
73
72
80
76 (18)c
94
1.5:1.0:1.0 [i-PrOH]
1.5:1.0:1.0
64 (33)c
86
1.5:1.0:1.0d
83
79
86
1.5:1.0:1.0
1.5:1.0:1.0 [i-PrOH]
1.0:1.0:0
(+)-1a (R ) Ph)
(()-1b (R ) t-Bu)
78 (5)c
94
1.5:1.0:0
1.5:1.0:1.0 [i-PrOH]
91
91
86
80
1.5:1.0:1.0d
1.5:1.0:1.0
1.5:1.0:1.0
1.5:1.0:1.0 (i-PrOH)
(+)-1b (R ) t-Bu)
91
a
b
d
Determined by 1H NMR on crude material. Isolated material. c Recovered starting material 1. Addition of 1 to Et2AlCN/i-PrOH.
Sch em e 2
addition to highly stereoselective 1,4-hydrocyanation via
TS-1, 1,2-addition from TS-2 to the opposite face of the
C-N bond by the more reactive Et2AlCN is also possible.
This would result in a deterioration in the selectivity.
Additional studies will be necessary to confirm this
mechanistic scenario.
Finally, refluxing diastereomeric pure R-amino nitriles
2a ,b with 6 N HCl followed by purification on Dowex 50
× 8-100 ion exchange resin afforded enantiomerically
pure (>95%) (S)-(+)-phenylglycine (3a )15 and (S)-(+)-tert-
leucine (3b)16 in 78% yield. Earlier asymmetric synthesis
of tert-leucine (3b), an important chiral auxiliary,17
involved more lengthy routes.18
In summary, the diastereoselective addition of Et2-
AlCN/i-PrOH to enantiopure sulfinimines, ammonia
imine building blocks,19 results in a practical asymmetric
Strecker synthesis. Studies are currently underway
extending this protocol to the asymmetric synthesis of
other R-amino acids.
“S-Et2AlCN”.10 Addition of 2-propanol to Et2AlCN re-
sults in the irreversible formation of ethyl aluminum
cyanide alkoxide 4 as evidenced by the evolution of
ethane. We suggest that this species sheds its aluminum-
coordinated solvent and forms cyclic TS-1 which ulti-
mately delivers cyanide to the Si-face of the C-N double
bond of 1.11 However, activation of the imine double bond
by a second Lewis acid aluminum species is first required;
e.g., TS-2. Formation of the iminum ion species TS-2
explains the higher reactivity of 1 in the presence of
excess Et2AlCN and the fact that 1b is much more
reactive than 1a .12,13 The reason for the improved
diastereoselectivity of aluminum alkoxide 4 compared to
Et2AlCN is uncertain but may be related to it lower Lewis
acidity14 which enhances selectivity. Furthermore, in
Ack n ow led gm en t. We thank Professors David R.
Dalton and Grant R. Krow, Temple University, for
helpful discussions. This work was supported by grants
from the National Institutes of Health and the National
Science Foundation.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the preparation of 1a ,b, 2a ,b, and 3a ,b and their 1H
and 13C NMR spectra are provided (3 pages).
J O9519928
(14) Lehmkuhl, H. Angew. Chem., Int. Ed. Engl. l964, 3, 107.
(15) Cark, J . C.; Phillips, A. H.; Steer, M. R.; Stephenson, L.;
Cooksey, A. R. J . Chem. Soc., Perkin Trans. 1 1976, 471.
(16) Miyazawa, T.; Takashaima, K.; Mitsuda, Y.; Yamada, T.;
Kuwata, S.; Watanabe, H. Bull. Chem. Soc. J pn. 1979, 52, 1539.
(17) Kogen, H.; Tomioka, K.; Hashimoto, S.-I.; Koga, K. Tetrahedron
1981, 37, 3951. Schollkopf, U.; Neubauer, H.-J . Synthesis 1982, 861.
Hayashi, T.; Konishi, M.; Fukushima, M; Kanehira, K.; Hioki, T.;
Kumada, M. J . Org. Chem. 1983, 48, 2195. Whittaker, M.; McArthur,
C. R.; Leznoff, C. C. Can J . Chem. 1985, 63, 2844. Tomioka, K.;
Masumi, F.; Yamashita, T.; Koga, K. Tetrahedron 1989, 45, 643. Zhou,
Q.-L.; Pfaltz, A. Tetrahedron Lett. 1993, 34, 7725. Meyers, A. I.;
Elworthy, T. R. J . Org. Chem. 1992, 57, 4732. Evans, D. A.; Faul, M.
M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. J . Am. Chem. Soc.
1993, 115, 5328.
(10) Nagata, W.; Yoshioka, M.; Murakami, M. J . Am. Chem. Soc.
1972, 94, 4644.
(11) Shift reagents studies with tris[3-heptafluoropropylhydroxym-
ethylene-(+)-camphorato]europium(III) indicates that the sulfinyl
oxygen is the site of greatest Lewis basicity in 1.
(12) Under similar conditions, the N-(p-nitrobenzylidene)sulfinamide
1 (R ) p-nitrophenyl) fails to react within 3 h. Davis, F. A.; Portonovo,
P. S; Fanelli, D. Unpublished results.
(13) For substituted aromatic aldehydes and imines, electron-
attracting substituents increase the rate of addition. Aliphatic alde-
hydes are somewhat more reactive than aromatic aldehydes because
of resonance stabilization in the latter. In aliphatic aldehydes R-methyl
groups reduce the reactivity toward addition of nucleophiles. For
discussions of these points see: Reeves, R. L. In The Chemistry of the
Carbonyl Group; Patai, S., Ed.; J ohn Wiley: New York, 1966; Vol. 1,
Chapter 12. Ogata, Y.; Kawasaki, A. In The Chemistry of the Carbonyl
Group; Zabicky, J ., Ed.; J ohn Wiley: New York, 1970; Vol. 2, Chapter
1.
(18) Speelman, J . C.; Talma, A. G.; Kellogg, R. M.; Meetsma, A.; de
Boer, J . L.; Beurskens, P. T.; Bosman, W. P. J . Org. Chem. 1989, 54,
1055. Yamada, S.; Hashimoto, S.; Chem. Lett. 1976, 921.
(19) (a) â-Amino acids: Davis, F. A.; Reddy, R. T.; Reddy, R. E. J .
Org. Chem. 1992, 57, 6387. Davis, F. A.; Reddy, R. E. Tetrahedron:
Asymmetry 1994, 5, 955. J iang, J .; Schumacher, K. K.; J oullie, M. M.;
Davis, F. A.; Reddy, R. E. Tetrahedron Lett, 1994, 35, 2121. Reference
5a. (b) Aziridines: Davis, F. A.; Zhou, P.; Reddy, G. V. J . Org. Chem.
1994, 59, 3243. Davis, F. A.; Zhou, P. Tetrahedron Lett. 1994, 35, 7525.
Davis, F. A.; Reddy, G. V.; Liu, H. J . Am. Chem. Soc. 1995, 117, 3651.