Concise asymmetric synthesis of α-amino acid derivatives from N- sulfinylimino esters

Full text of DOI:10.1021/jo990303f

3396
J . Org. Chem. 1999, 64, 3396-3397
Sch em e 1
Con cise Asym m etr ic Syn th esis of r-Am in o
Acid Der iva tives fr om N-Su lfin ylim in o Ester s
Franklin A. Davis* and William McCoull
Department of Chemistry, Temple University,
Philadelphia, Pennsylvania 19122
Received February 18, 1999
Glyoxylate imines provide access to nonproteinogenic
R-amino acid derivatives through ene reactions,1 cycloaddi-
tion reactions,2,3 radical addition,4 or nucleophilic addition.5-8
However, a major drawback with glyoxylate imines is the
absence of regioselectivity. Only allylating reagents have
been found synthetically useful for such transformations.5i,6,7
We have shown that the N-sulfinyl group in sulfinimines is
an excellent imine auxiliary that activates the CdN bond
for nucleophilic addition, exerts a powerful stereodirecting
effect, and is easily deprotected in the product.9-11
In this communication we describe our initial results in
the use of chiral N-sulfinyl auxiliaries for the activation of
glyoxylate sulfinimines toward regioselective attack by
organometallic reagents.9,12 Sulfinimines 2a /b, solid and oil,
respectively, were prepared by 4 Å MS mediated condensa-
tion13 of (S)-(+)-p-toluenesulfinamide13 (1a ) or (R)-(+)-tert-
butanesulfinamide14 (1b) with ethyl glyoxylate (Scheme 1).
Initial studies with (S)-2a found that BnMgCl added regio-
selectively at the imino carbon to give (SS,2R)-3 and (SS,2S)-4
in 56% combined yield (82:18 diastereomer ratio). These
diastereomers were not separable by chromatography, and
using other solvents (toluene, THF, Et2O) failed to give
improved yields or diastereoselectivity. Oligomerization was
identified as the major competing reaction pathway.15 Pre-
complexation of (S)-2a with BF3‚OEt2 (2 equiv) significantly
reduced this oligomerization, but at the expense of yield
(31%), diastereoselectivity (63:37), and activation of addition
to sulfur to produce p-toluene benzyl sulfoxide16 (p-tolyl-
SOBn) in 36% yield. The more sterically demanding tert-
butanesulfinyl auxiliary was envisaged to reduce the like-
lihood of reaction at sulfur.
Initial results (Table 1, entries 1 and 2) for the reaction
of BnMgCl (typically 0.25 mmol) with (R)-(-)-2b indicated
some improvement in the crude diastereoselectivity. The
diastereomers were separable by chromatography, but the
major diastereomer was isolated in poor yield (24%). Sur-
prisingly, oligomerization did still occur, and significant
amounts of tert-butane benzyl sulfoxide (t-BuSOBn)17 were
isolated corresponding to reaction at sulfur despite being
adjacent to the bulky tert-butyl group. Lewis acids were
precomplexed with sulfinimine (R)-2b in an effort to increase
the desired reaction at the imine group. Ellman has used
trimethylaluminum to increase the reaction yield of orga-
nolithiums with N-tert-butanesulfinyl ketimines,18 but in our
glyoxylate sulfinimine case, yields were not improved and
oligomerization and t-BuSOBn formation were not sup-
pressed greatly although the diastereoselectivity was en-
hanced (Table 1, entries 3 and 4). It was found that BF3‚
OEt2 (1 equiv) improved the desired reaction yield and
diastereoselectivity (92:8). Use of a second equivalent of BF3‚
OEt2 further improved diastereoselectivity (94:6), and (RS,2R)-
(-)-5 was isolated in 70% yield. Oligomerization and t-BuSO-
Bn formation were virtually eliminated. In addition, 2 equiv
of BnMgCl were also found necessary for optimal yield and
diastereoselectivity (Table 1, entries 5-7). Other Lewis acids
(ZnCl2, SnCl4) gave inferior results, and BnZnCl gave no
desired product (Table 1, entries 8-10).
(1) (a) Tschaen, D. M.; Weinreb, S. M. Tetrahedron Lett. 1982, 23, 3015-
3018. (b)Tschaen, D. M.; Turos, E.; Weinreb, S. M. J . Org. Chem. 1984, 49,
5058-5064. (c) Mikami, K.; Kaneko, M.; Yajima, T. Tetrahedron Lett. 1993,
34, 4841-4842. (d) Tietze, L. F.; Bratz, M. Synthesis 1989, 439-443. (e)
Tidwell, J . H.; Buchwald, S. L. J . Am. Chem. Soc. 1994, 116, 11797-11810.
(f) Drury, W. J ., III; Ferraris, D.; Cox, C.; Young, B.; Lectka, T. J . Am. Chem.
Soc. 1998, 120, 11006-11007.
(2) For lead references on Diels-Alder reactions, see (a) Hamada, T.;
Zenkoh, T.; Sato, H.; Yonemitsu, O. Tetrahedron Lett. 1991, 32, 1649-1652.
(b) Hamley, P.; Holmes, A. B.; Kee, A.; Ladduwahetty, T.; Smith, D. F.
Synlett 1991, 29-30. (c) Bailey, P. D.; Londesbrough, D. J .; Hancox, T. C.;
Heffernan, J . D.; Holmes, A. B. J . Chem. Soc., Chem. Commun. 1994, 2543-
2544. (d) Abraham, H.; Stella, L. Tetrahedron 1992, 48, 9707-9718. (e)
Maggini, M.; Prato, M.; Scorrano, G. Tetrahedron Lett. 1990, 43, 6243-
6246. (f) Heintzelman, G. R.; Weinreb, S. M. J . Org. Chem. 1996, 61, 4594-
4599. (g) Yao, S.; J ohannsen, M.; Hazell, R. G.; J ørgensen, K. A. Angew.
Chem., Int. Ed. 1998, 37 (7), 3121-3124.
(3) For an example of a [2 + 2] cycloaddition, see Barreau, M.; Commer-
c¸on, A.; Mignani. S.; Mouysset, D.; Perfetti, P.; Stella, L. Tetrahedron 1998,
54, 11501-11516.
(4) Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett 1998, 780-
782.
(5) Organometallic additions: (a) Fiaud, J .-C.; Kagan, H. B. Tetrahedron
Lett. 1970, 1813- 1816. (b) Fiaud, J .-C.; Kagan, H. B. Tetrahedron Lett. 1971,
1019-1022. (c) Mu¨nster, P.; Steglich, W. Synthesis 1987, 223-225. (d)
Harwood, L. M.; Vines, K. J .; Drew, M. G. B. Synlett 1996, 1051-1053. (e)
Courtois, G.; Miginiac, L. J . Organomet. Chem. 1989, 376, 235-243. (f)
Courtois, G.; Miginiac, L. J . Organomet. Chem. 1993, 450, 33-40. (g)
Courtois, G.; Miginiac, L. J . Organomet. Chem. 1993, 452, 5-12. (h) Uno,
H.; Okada, S.; Ono, T.; Shiraishi, Y.; Suzuki, H. J . Org. Chem. 1992, 57,
1504-1513. (i) Yamamoto, Y.; Ito, W. Tetrahedron 1988, 44, 5415-5423.
(j) Bravo, P.; Crucianelli, M.; Vergani, B.; Zanda, M. Tetrahedron Lett. 1998,
39, 7771-7774.
(6) Boron reagents: (a) Yamamoto, Y.; Ito, W.; Maruyama, K. J . Chem.
Soc., Chem. Commun. 1985, 1131-1132. (b) Yamamoto, Y.; Nishii, S.;
Maruyama, K.; Komatsu, T.; Ito, W. J . Am. Chem. Soc. 1986, 108, 7778-
7786.
(7) Allyl stannanes: (a) Bellucci, C.; Cozzi, P. G.; Umani-Ronchi, A.
Tetrahedron Lett. 1995, 36, 7289-7292. (b) Bradley, G. W.; Hallet, D. J .;
Thomas, E. J . Tetrahedron: Asymmetry 1995, 6, 2579-2582 and references
therein.
(8) Carbon nucleophiles: (a) Yamamoto, Y.; Kubota, Y.; Honda, Y.; Fukui,
H.; Asao, N.; Nemoto, H. J . Am. Chem. Soc. 1994, 116, 3161-3162. (b)
Hagiwara, E.; Fujii, A.; Sodeoka, M. J . Am. Chem. Soc. 1998, 120, 2474-
2475. (c) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J . Am. Chem. Soc.
1998, 120, 4548-4549. (d) Ferraris, D.; Young, B.; Cox, C.; Drury, W. J .,
III; Dudding, T.; Lectka, T. J . Org. Chem. 1998, 63, 6090-6091.
(9) For a review on chiral sulfinimines see: Davis, F. A.; Zhou, P.; Chen,
B.-C. Chem. Soc. Rev. 1998, 27, 13-18.
Application of our optimized conditions to other Grignard
reagents gave good diastereoselectivity and isolated yields
(Scheme 2, Table 2). Sulfinimine (R)-2b was precomplexed
with 2 equiv BF3‚OEt2 in CH2Cl2 at -78 °C for 5 min and
(13) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J . Org. Chem., 1999, 64, 1403-1406. Attempted condensation
using Ti(OEt)4 did not lead to the formation of (R)-2b.
(14) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J .; Ellman, J . A. J . Am.
Chem. Soc. 1998, 120, 8011-8019.
(15) Dimers and trimers of 3/4 were identified by MS where the amine
functionality had reacted with the ester group of another molecule of 3/4.
(16) Stirling, C. J . M. J . Chem. Soc. 1963, 5741-5745.
(17) Mislow, K.; Green, M. M.; Raban, M. J . Am. Chem. Soc. 1965, 87,
2761-2762.
(10) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-
1946.
(11) Bloch, R. Chem. Rev. 1998, 98, 1407-1438.
(12) For a review on N-sulfonyl imines of glyoxylates see: Weinreb, S.
M. in Top. Curr. Chem. 1997, 190, 131-184.
(18) Cogan, D. A.; Ellman, J . A. J . Am. Chem. Soc. 1999, 121, 268-269.
10.1021/jo990303f CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/27/1999

Communications
J . Org. Chem., Vol. 64, No. 10, 1999 3397
Ta ble 1. Ad d ition of Ben zyl Or ga n om eta llic Rea gen ts to Glyoxyla te Su lfin im in e (R)-2b
time
(min)
entry
lewis acid (min)a
reagent
(RS,2R)-5,b %
(RS,2R)-5/(RS,2S)-6c
t-BuSOBn, %
1
2
none
20
10
1 equiv of BnMgCl
2 equiv of BnMgCl
2 equiv of BnMgCl
2 equiv of BnMgCl
2 equiv of BnMgCl
2 equiv of BnMgCl
1.2 equiv of BnMgCl
2 equiv of BnMgCl
2.1 equiv of BnMgCl
2 equiv of BnZnCld
24
90:10
89:11
93:7
93:7
92:8
94:6
92:8
77:23
e
23
10
12
8
none
28
3
1.1 equiv of AlMe3 (5)
2.1 equiv of AlMe3 (10)
1 equiv of BF3‚OEt2 (5)
2 equiv of BF3‚OEt2 (5)
2 equiv of BF3‚OEt2 (10)
2 equiv of ZnCl2 (10)
2.1 equiv of SnCl4 (10)
none
40
23
4
20
28
5
20
50
3
6
10
70
trace
8
20
e
28
7
40
48
8
40
30
9
210
210
17
10
none
e
a
b
Glyoxylate sulfinimine was precomplexed with Lewis acid at -78 °C for time indicated in parentheses. Isolated yield after
chromatography. c Measured by 500 MHz 1H NMR of crude reaction mixture. Prepared in situ from BnMgCl and ZnCl2 at -78 °C. e Not
determined.
d
Sch em e 2
Ta ble 2. P r ep a r a tion of r-a m in o Acid Der iva tives
(RS,2R)-(-)-7 Usin g Gr ign a r d /Dia lk ylzin c Rea gen ts
R
methoda
(RS,2R)-7
crude dr
Bn
Ph
Et
A
A
A
B
A
B
70%
70%
27%b
88%c
59%
43%d
94:6
84:16
>99:1
>99:1
83:17
92:8
F igu r e 1.
Grignard reagent, but the reaction was slow (3 h) and the
yield was 43%.
Et
Me
Me
Removal of the N-tert-butanesulfinyl group was readily
accomplished using methanolic HCl18 to give the known
R-amino esters (R ) Bn, 74%; R ) Ph, 88%) and allowed
assignment of the absolute stereochemistry.20 As anticipated
no epimerization occurred during the cleavage procedure as
evidenced by preparation of Mosher amide derivatives (R )
Me, Ph, Bn).
a
Method A: precomplexation with 2 equiv BF3‚OEt2 (5 min,
-78 °C) and then RMgX (10-20 min, -78 °C). Method B: 2-3
equiv R2Zn, -78 °C. 16% t-BuSONHCH2CO2Et also isolated.c 25
b
d
min at -78 °C. 3 h at -78 °C.
the Grignard reagent added in one portion at this temper-
ature. The reaction was generally complete within 20 min
and quenched using NH4Cl (satd aq) allowing, after aqueous
workup, chromatographic separation of diastereomers. Most
notable is the isolation of (RS,2R)-(-)-7 (R ) Me) in 59% yield
since MeMgBr has been reported to give desulfinylation in
the presence of p-toluenesulfinimine.19 Ethylmagnesium
A rationale for the observed stereoselectivity is that (R)-
2b adopts the conformation shown in Figure 1a21 where the
sulfinyl oxygen coordinates to BF3 and sterically shields the
Si face of the imine to give the Cram product. A second
equivalent of BF3 may act to further activate the imine bond.
Indeed a similar Lewis activation has been proposed in the
sulfinimine-mediated asymmetric Strecker synthesis.22 This
open transition state model is similar to that proposed by
Yamamoto6b,23 and contrasts with the analogous sulfinimine
case where the opposite induction can be explained by a
chelated transition state as shown in Figure 1b.18,22,24 This
difference is obviously due to the presence of the ester
functionality, and we speculate that chelation of the incom-
ing organometallic reagent by the ester carbonyl disrupts
and prevents the chelated transition state forming.
In summary, N-sulfinylimino esters 2 represent a new
chiral glycine cation equivalent for the asymmetric synthesis
of R-amino acids. Problems of regiochemistry that plague
nucleophilic additions to most glyoxylate imines are avoided
because the N-sulfinyl group selectively activates the CdN
bond for addition as well as being an effective stereodirecting
group.
1
bromide gave only one detectable diastereomer by H NMR
(500 MHz) analysis, but reduction of the imine bond lowered
the yield. Use of Et2Zn circumvented this problem, affording
88% yield of (RS,2R)-(-)-7 (R ) Et) as a single diastereomer
even in the absence of Lewis acid activation. The less
reactive Me2Zn gave increased diastereoselectivity over the
(19) Moreau, P.; Essiz, M.; Me´rour, J .-Y.; Bouzard, D. Tetrahedron:
Asymmetry 1997, 8, 591-598.
(20) (a) (R)-Phenylalanine ethyl ester: Bergel, F.; Lewis, G. E.; Orr, S.
F. D.; Butler, J . J . Chem. Soc. 1959, 1431-1437. (b) (R)-Phenylglycine ethyl
ester: Harada, K.; Tamura, M. Bull. Chem. Soc. J pn. 1979, 52, 1227-1228.
(21) The X-ray structure of N-benzylidene-p-toluenesulfinamide indicates
that it adopts a syn-periplanar arrangement of the C-N-S-O unit. Davis,
F. A.; Reddy, R. E.; Szewczyk, J . M.; Reddy. G. V.; Portonovo, P. S.; Zhang,
H.; Fanelli, D.; Thimma Reddy, R.; Zhou, P.; Carroll, P. J . J . Org. Chem.
1997, 62, 2555-2563. However, we cannot rule out the possibility of a
chelated intermediate containing a Z-imino bond as a result of E to Z
isomerization during the BF3‚OEt2 precomplexation.
(22) (a) Davis, F. A.; Fanelli, D. L. J . Org. Chem. 1998, 63, 1981-1985.
(b) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y.-H. J . Org. Chem.
1996, 61, 440-441.
Ack n ow led gm en t. We thank Dr. Yemane Andemicha-
el and Mark E. McDonnell for preliminary studies and Dr.
Bang-Chi Chen (Bristol-Myers Squibb) for helpful discus-
sion. This work was supported by grants from the National
Institutes of Health (GM 51982) and the National Science
Foundation.
(23) Yamamoto, Y.; Komatsu, T.; Maruyama, K. J . Am. Chem. Soc. 1984,
106, 5031-5033.
(24) (a) Davis, F. A.; Szewczyk, J . M.; Reddy, R. E. J . Org. Chem. 1996,
61, 2222-2225. (b) Davis, F. A.; Zhou, P.; Reddy, G. V. J . Org. Chem. 1994,
59, 3243-3245.
(25) Selected properties: (S)-(+)-2a : mp 37 °C, [R]20 +307 (c 0.945,
D
Su p p or tin g In for m a tion Ava ila ble: Full characterization
data and experimental procedures. This material is available free
of charge via the Internet at http://pubs.acs.org.
CHCl3); (R)-(-)-2b: oil, [R]20D -313 (c 1.01, CHCl3); (RS,2R)-(-)-5: oil, [R]20
D
-60.9 (c 1.06, CHCl3); (RS,2R)-(-)-7 (R ) Ph): oil, [R]20 -183 (c 0.59,
D
CHCl3); (RS,2S)-(+)-7 (R ) Ph); oil, [R]20 +55 (c 0.55, CHCl3); (RS,2R)-(-
D
)-7 (R ) Et): oil, [R]20 -100 (c 1.23, CHCl3); (RS,2R)-(-)-7 (R ) Me): oil,
D
[R]20 -98.2 (c 0.815, CHCl3).
J O990303F
D