Asymmetric Mannich-type reactions of aldimines with a chiral acetate

Article abstract of DOI:10.1021/ol000099e

(Formula presented) We introduce here a strategy that enables effective addition of lithium enolates of acetates to aldimines. The new method depends strongly on the use of o-alkoxy (or o-fluoro) aniline-derived aldimines which have been found to have a potential effect on the enolate addition. This scope was expanded to the asymmetric process using the chiral acetate. A Lewis acid additive has a complementary role in the pronounced activation of imine functionalities.

Full text of DOI:10.1021/ol000099e

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1891-1894
Asymmetric Mannich-Type Reactions of
Aldimines with a Chiral Acetate
Susumu Saito, Keiko Hatanaka, and Hisashi Yamamoto*
Graduate School of Engineering, Nagoya UniVersity, CREST, Japan Science and
Technology Corporation (JST), Furo-cho, Chikusa, Nagoya 464-8603, Japan
j45988a@nucc.cc.nagoya-u.ac.jp
Received April 20, 2000
ABSTRACT
We introduce here a strategy that enables effective addition of lithium enolates of acetates to aldimines. The new method depends strongly
on the use of o-alkoxy (or o-fluoro) aniline-derived aldimines which have been found to have a potential effect on the enolate addition. This
scope was expanded to the asymmetric process using the chiral acetate. A Lewis acid additive has a complementary role in the pronounced
activation of imine functionalities.
Chiral auxiliaries are powerful molecular elements for
creating optically active compounds. When covalently at-
tached to the auxiliaries, carboxylic acid derivatives expanded
the scope of the asymmetric aldol reaction with aldehydes
and have constituted a molecular library of â-hydroxycar-
bonyl compounds.1 In contrast, due to the inherent instability
of imines (e.g., imine-enamine equilibration) and the poor
electrophilicity of stable N-substituted imines2 especially
toward acetate enolates, there are few reports in the
literature3,4 on the asymmetric Mannich-type reaction using
this approach. We address these limitations using 2,6-bis-
(2-isopropylphenyl)-3,5-dimethylphenol (1)5 as an effective
chiral auxiliary in the diastereoselective Mannich-type reac-
tion of acetate 26 with specialized aldimines (Scheme 1).
Although studies have investigated many aspects of high
reactivity of the enolates of propionates and isobutylates,3a
Chem. 1999, 64, 12. (d) Mu¨ller, R.; Goesmann, H.; Waldmann, H. Angew.
Chem., Int. Ed. 1999, 38, 184. (e) Davis, F. A.; Szewczyk, J. M.; Reddy,
R. E. J. Org. Chem. 1996, 61, 2222. For reactions using chiral metal
catalysts, see: (f) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc.
1998, 120, 2472. (g) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J.
Am. Chem. Soc. 1998, 120, 4548. (h) Ferraris, D.; Young, B.; Cox, C.;
Drury, W. J., III; Dudding, T.; Lectka, T. J. Org. Chem. 1998, 63, 6090.
(i) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120,
431. (j) Ishihara, K.; Miyata, M.; Hattori, K.; Yamamoto, H. J. Am. Chem.
Soc. 1994, 116, 10520.
(4) For asymmetric Mannich-type reactions using a chiral acetate
equivalent (chiral iron acyl complex), see: (a) Liebeskind, L. S.; Welker,
M. E.; Fengel, R. W. J. Am. Chem. Soc. 1986, 108, 6328. (b) Liebeskind,
L. S.; Welker, M. E.; Goedken, V. J. Am. Chem. Soc. 1984, 106, 441. Very
recent example, see: (c) Palomo, C.; Oiarbide, M.; Concepcio´n, M.;
Gonza´lez-Rego, C.; Sharma, A. K.; Garc´ıa, M.; Gonza´lez, A.; Landa, C.;
Linden, A. Angew. Chem., Int. Ed. 2000, 39, 1063.
(1) (a) Evans, D. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: San diego, CA, 1984; Vol. 3, Chapter 1. (b) Asymmetric Synthesis;
Procter, G., Ed.; Oxford University Press: Oxford, 1996; Chapter 5. (c)
Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835.
(2) (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed.
1998, 37, 1044. (b) Denmark, S. E.; Nicaise, O. J.-C. Chem. Commun. 1996,
999. (c) Risch, N.; Arend, M. In StereoselectiVe Synthesis (Houben-Weyl),
Vol. E21/b; Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E.,
Eds.; Thieme: Stuttgart, 1996; p 1833.
(3) (a) Most examples concerning the asymmetric Mannich-type reaction
employ chiral sources appended to the N atom of aldimines. For leading
reviews, see: (a) Hart, D. J.; Ha, D.-C. Chem. ReV. 1989, 89, 1447. (b)
EnantioselectiVe Synthesis of â-Amino Acids; Juraisti, E., Ed.; Wiley-
VCH: New York, 1997. For recent outstanding examples using chiral
aldimines and related reactions, see: (c) Tang, T. P.; Ellman, J. A. J. Org.
(5) For preliminary synthesis of 1, see: (a) Saito, S.; Kano, T.; Hatanaka,
K.; Yamamoto, H. J. Org. Chem. 1997, 62, 5651. For the more efficient
synthesis of 1 we developed recently, see: (b) Saito, S.; Kano, T.; Muto,
H.; Nakadai, M.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 8943.
(6) Saito, S.; Hatanaka, K.; Kano, T.; Yamamoto, H. Angew. Chem.,
Int. Ed. 1998, 37, 3378.
10.1021/ol000099e CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/06/2000

Scheme 1
the lithium enolates of acetates are almost inert to the
the rather low Lewis acidic Li+ requires chelation to enable
the effective activation of aldimines. Indeed, aldimine 12
with which the chelation control further operates had a
similar effect on the addition efficacy (entry 6); dimethoxy
derivatives 14 and 15 showed similar productivity (entries
8 and 9). However, o,o-disubstituted derivatives 16-18 were
absolutely inert under the present conditions even at higher
temperature (0 °C) (entries 10-12).
N-phenyl-7a and N-trimethylsilylaldimines7b of benzalde-
hyde.7 Thus, our first attempt was to find a potential aldimine
partner that reacts smoothly with the acetate enolates. The
results are summarized in Table 1, which shows that the
Table 1. Reaction of the Lithium Enolate of Methyl Acetate
with Various Aldiminesa
Table 2
a Unless otherwise specified, reaction was performed using the acetate
(1.0 equiv), a THF solution of LDA (1.0 equiv) and aldimine (1.0 equiv)
at -78 °C for 3 h. b Of isolated â-aminoesters. NR ) no reaction. c The
isolated yield of the corresponding â-lactam. d See ref 7a. e See ref 7b.
aldimines of o-anisidine and o-fluoroaniline (9 and 13)
facilitate the reaction most efficiently (entries 3 and 7).8 The
alkoxy and fluoro groups are essential and must be attached
to the ortho-position of the aniline nitrogen. For example,
m- and p-anisidine derivatives 10 and 11 did not lead to the
desired adducts (entries 4 and 5). These results imply that
a Unless otherwise specified, reaction was performed using enolate (1.0
equiv), aldimine (1.0 equiv), and R2Zn (0.5 equiv) at -78 °C for 18-48 h.
b Of isolated purified product. c Determined by HPLC analysis. d Absolute
configuration of samples. e Et2Zn (1.0 equiv) was used. f Salt free reagent.
g Ethylated product was obtained (10%).
(7) (a) Gluchowski, C.; Cooper, L.; Bergbreiter, D. E.; Newcomb, M. J.
Org. Chem. 1980, 45, 3413. (b) Ha, D.-C.; Hart, D. J.; Yang, T.-K. J. Am.
Chem. Soc. 1984, 106, 4819. The trimethylsilyl ketene acetal of methyl
acetate also shows poor reactivity, see: (c) Colvin, E. W.; Macgarry, D. J.
Chem. Soc., Chem. Commun. 1985, 539. (d) Colvin, E. W.; Macgarry, D.;
Nugent, M. J. Tetrahedron 1988, 44, 4157.
(8) In the meantime, restraining effects of the o-methoxyphenyl sub-
stituent of aldimines on the formation of â-amino esters, not the â-lactams,
was reported in the Refomatsky reaction using R-bromoacetate and Zn,
see: Adrian, J. C. Jr.; Barkin, J. L.; Hassib, L. Tetrahedron Lett. 1999, 40,
2457. Moreover, Kobayashi et al. reported a marked influence of aldimines
9 and 17 on the enantioselectivity and reactivity in the Mannich-type reaction
using chiral zirconium reagents (ref 3i). Although both aldimines are
employable, the reaction mechanism remains totally unclear.
1892
Org. Lett., Vol. 2, No. 13, 2000

Scheme 2a
a (a) Bu4NOH, THF, 0 °C, 99%; (b) TMSCHN2, MeOH, rt, 99%; for 3 and 19: (c) AgNO3, (NH4)2S2O8. THF-H2O-MeCN, 60 °C,
53%; for 20: (d) CAN, H2O-MeCN, 0 °C, 91%, for 21.
Unfortunately, the lithium enolate of 2, generated by
treatment with n-BuLi in THF at -78 °C for 0.5 h, was
almost inert to aldimines 9 and 13 under the above optimized
conditions (for aldimine 9, 15% yield, 93:7 dr). We thus
focused on the use of a Lewis acid additive, anticipating the
pronounced activation of imine functionalities (Scheme 1).
The addition of 2 to aldimine 9 occurred effectively in the
presence of 0.5 equiv of R2Zn (R ) Me, Et) at -78 °C to
give â-aminoester 3 in 70% and 69% yields with diastere-
omeric ratios (dr) of 95.5:4.5. Using 1.0 equiv of Et2Zn was
generally ineffective in terms of chemical yield due to side
reactions, which in some cases generated a considerable
amount of ethylated products (entry 16).9 With the exception
of inertness with the 2-hexenal-derived aldimine (entry 11),
Table 2 shows that this method proved to be effective in
substrate scope, giving high dr up to 99:1. Comparable yields
and dr values were obtained whether a Lewis acid was added
after or before treatment of aldimine with the enolate. While
varying aldimines (entries 4-6) or Lewis acids for 9 (Me3-
Al, 90.5:9.5 dr; i-Bu3Al, 94.5:5.5 dr; Me3Ga, 97:3 dr) had
appreciable effect, absolute S configuration at the emerging
chiral center was induced throughout. o,o-Disubstituted
aniline-derived aldimines 16-18 underwent no addition to
give complete recovery of the acetate.
of (R,R)-2, adduct 3 was obtained (3S:3R ) 85:15 () dr)),
with the absolute configuration being consistent with the
other examples we tested (entries 1-3 and 12-16). It should
be pointed out that the reactions showed a general preference
for si face attack of aldimines, which is opposite to that for
the addition of aldehydes.6
The chiral auxiliary can readily be recovered (>99%) from
Mannich adduct 3 (95.5:4.5 dr) by treatment with NH4OH
in THF,13 followed by subsequent methylation of the
resulting acid with TMSCHN2. Oxidative cleavage of the
methoxyphenyl group was effected by catalytic AgNO3 (0.29
equiv) in the presence of excess (NH4)2S2O8 (7.0 equiv)14 to
afford aminoester 22 in 53% yield (90% ee) (Scheme 2).
When we used CAN as an alternative oxidant, aminoester
20 underwent considerable dimerization, resulting in negli-
gible formation of 22.15 This can be circumvented by use of
14 as an aldimine to give Mannich adduct 19 in 63% yield
(96:4 dr). Sequential hydrolysis and methylation were
followed by oxidation of 21 with CAN (4 equiv) to give
22 in 91% yield (92% ee), where no dimerization was
observed.
In conclusion, this work features a strategy that enables
effective addition of acetate enolates to aldimines and
expands this scope to the asymmetric process using a chiral
auxiliary. We propose that the successful asymmetric reaction
originated in part from control of the two possible enolate
conformations W-form and U-form,16 which have been
The equilibrium between (E)- and (Z)-aldimines is known
to be involved in the presence of Lewis acid and to affect
the stereochemistry of the asymmetric Mannich-type reac-
tion.10 Thus, there is a possibility that the isomerization to
(Z)-aldimines could have a potential effect on the rate
acceleration of the Mannich addition. In fact, when the
SnCl4-(Z)-9 complex12 was exposed to the lithium enolate
(12) Rasmussen, K. G.; Hazaell, R. G.; Jorgensen, K. A. Chem. Commun.
1997, 1103. (b) Rasmussen, K. G.; Juhl, K.; Hazaell, R. G.; Jorgensen, K.
A. J. Chem. Soc., Perkin Trans. 2 1998, 1347.
(13) Hasegawa, T.; Yamamoto, H. Synlett 1998, 882. See also ref 6.
(14) Bhattarai, K.; Cainelli, G.; Panunzio, M. Synlett 1990, 229.
(15) Although it has been reported that aminoester 20 was readily
oxidized by CAN to give 22 (ref 8), we were unable to detect the formation
of 22 using CAN by varying numerous reaction conditions. No attempt
was made here to characterize the exact structure of the dimer. Competitive
dimerization is a significant problem in certain cases using CAN, see: Jacob,
P., III; Callery, P. S.; Shulgin, A. T.; Castagnoli, N., Jr. J. Org. Chem.
1976, 41, 3627. We also tried oxidative removal of the o-fluorophenyl group
from methyl 3-(2-fluorophenyl)amino-3-phenylpropionate (entry 7, Table
1) under conditions similar to those employed for 20 and 21 using CAN.
However, product 22 was formed in 14% yield.
(16) It was proposed that the boron enolates of R-unsubstituted ketones
favor the more stable U-form by 1-2 kcal/mol than the W-form. Similarly,
it is conceivable that the bulky phenoxy group of the enolate of 2 renders
the U-form most likely and gives a twist-boat transition structure: (a)
Gennari, C.; Todeschini, R.; Beretta, M. G.; Favini, G.; Scolastico, C. J.
Org. Chem. 1986, 51, 612. (b) Hoffmann, R. W.; Ditrich, K.; Froech, S.
Tetrahedron 1985, 41, 5517. (c) Braun, M. Angew. Chem., Int. Ed. Engl.
1987, 26, 24.
(9) To explain the difference in the reaction profiles using 0.5 and 1.0
equiv of Et2Zn, distinctive zincate species (enolate)R2ZnLi (Li-enolate:R2-
Zn ) 1:1) and (enolate)2R2ZnLi2 (Li-enolate:R2Zn ) 2:1) might be invoked.
At present, we have no evidence for the formation of these species and
further research is needed. Regarding the search on the reactivity difference
between R3ZnLi and R4ZnLi2, see: (a) Uchiyama, M.; Kameda, M.;
Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.; Sakamoto, T. J. Am.
Chem. Soc. 1998, 120, 4934.
(10) For example, the reaction of the aldimine derived from 3-trimeth-
ylsilyl-2-propynal with a ketene silyl acetal exhibits reversal in the absolute
configuration, compared with that of the aldimine derived from benzalde-
hyde using a chiral boron reagent. This implies that the (Z)-structure is the
reactive form for the former aldimine, whereas it is (E)-isomer for the latter,
see ref 3j. In good contrast, the present reaction using the o-anisidine-derived
aldimines derived from these two types of aldehydes showed an identical
S configuration.
(11) See Supporting Information for experimental details.
Org. Lett., Vol. 2, No. 13, 2000
1893

proposed to contribute to the chair and twist boat transition
structures, respectively, using the bulky auxiliary. However,
an understanding of further mechanistic aspects of the
reaction is required to give marked improvement in synthetic
efficiency. Efforts toward this end are currently underway
in our laboratory.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL000099E
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Org. Lett., Vol. 2, No. 13, 2000