Enantio- and diastereoselective, stereospecific Mannich-type reactions in water

Article abstract of DOI:10.1021/ja048607t

Catalytic asymmetric Mannich-type reactions in water proceeded in high yields and selectivities using a combination of ZnF₂ and a chiral diamine that has the methoxy groups on the aromatic rings. In these reactions, either syn- or anti-Mannich

Full text of DOI:10.1021/ja048607t

Published on Web 06/04/2004
Enantio- and Diastereoselective, Stereospecific Mannich-Type Reactions in
Water
Tomoaki Hamada, Kei Manabe, and Shuj Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received March 10, 2004; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Table 2. Asymmetric Mannich-Type Reactions in Water
In recent years, use of water as a reaction solvent has received
much attention in synthetic organic chemistry,1 because water is
safe, cheap, and environmentally friendly. In addition, dehydrative
drying of substrates and solvents is not required, and unique
reactivity and selectivity are often observed when water is used as
a solvent. Whereas catalytic asymmetric carbon-carbon bond-
forming reactions in organic solvents have reached a fairly high
level of sophistication, comparable progress has not yet been
achieved for the reactions in aqueous solvents. In particular, these
reactions in water without using organic cosolvents are difficult to
achieve. Recently, some catalytic asymmetric reactions in water
have been developed.2 However, to the best of our knowledge,
catalytic asymmetric Mannich-type reactions in water have not been
reported despite the synthetic utility of the Mannich adducts (â-
amino ketones or esters), which are versatile chiral building blocks
for the preparation of many nitrogen-containing, biologically
important compounds.3 Previously, we reported catalytic asymmetric
Mannich-type reactions in aqueous THF.4,5 However, direct ap-
plication of this catalytic system to reactions in water without THF
gave unsatisfactory results. In this paper, we report that further
exploration has led to a new system that enables enantio- and
diastereoselective, stereospecific Mannich-type reactions in water
without any organic cosolvents.
additive
(mol %)
yield
(%)
1
2
3
entry
R
R
R
syn/anti
ee (%)
1a
H
H
H
H
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
91
93
94
6
5
9
95
2a
H
H
H
H
H
H
H
H
H
H
91 (98)b
95
3a,c
4d Me
5d Me
6d Me
7d Me
8d Me
9d Me
10d,f Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
91/9
91/9
91/9
94e
TfOH (1)
SDS (5)
90e
78e
Triton X-405(5) 10 91/9
93e
CTAB (5)
CTAB (2)
CTAB (2)
CTAB (2)
94 94/6
93 94/6
84 93/7
76 96/4
97e
96e
97e
11
12g,h Me
13h,j
Et
96e
(98.5/1.5)b (>99.5e)b
H
Et
CTAB (2)
57 86/14
97i
(98.5/1.5)b (>99.5i)b
H
Me Et
CTAB (2)
CTAB (2)
CTAB (2)
CPB (2)
94 12/88
94i
94i
67i
62i
14k Me
H
StBu
39 8/92
51 93/7
69 92/8
15l
H
H
Me StBu
Me StBu
16l,m
a 1c was used instead of 1b. b After one recrystallization. c Time ) 36
h. d E/Z ) <1/>99. e Ee of syn adduct. f Performed with 5 mol % 1b. g E/Z
) 2/98. h Time ) 72 h. i Ee of major diastereomer. j E/Z ) 76/24. k E/Z )
98/2. l E/Z ) 3/97. m Time ) 48 h.
Initial examination focused on the reaction of acylhydrazono ester
2 with the silyl enol ether derived from acetophenone (Table 1).
THF (entry 1 vs 2). To our delight, however, the enantioselectivity
obtained was higher in water. We then decided to examine several
conditions to speed up the reaction in water. After many trials, we
finally found that use of 1b7d led to remarkable acceleration of the
reaction in water (entry 3). Furthermore, when 1c was used, a 95%
yield was obtained after 20 h, and a high level of selectivity was
also attained (entry 4). Finally, it was surprising to find that the
reaction proceeded smoothly with excellent enantioselectivity in
the absence of TfOH (entry 5).9
Table 1. Improvement of Asymmetric Mannich-Type Reaction
Since the new catalyst system using 1c has been established,
we then employed this system in reactions with other silyl enol
ethers in water. In the cases of 4′-substituted acetophenone-derived
silyl enol ethers, the corresponding adducts were obtained in high
yields with excellent ees (Table 2, entries 1-3).
entry
diamine
time (h)
yield (%)
ee (%)
1a
2
3
1a
1a
1b
1c
1c
72
72
20
20
20
93
55
86
95
91
92
95
93
96
95
4
5b
We next turned our attention to the enantio- and diastereoselec-
tive reactions using the silyl enol ethers derived from R-monosub-
stituted carbonyl compounds such as propiophenone. Unexpectedly,
this type of reaction was found to proceed sluggishly regardless of
the existence of TfOH (entries 4, 5).10 To accelerate the reaction,
addition of surfactants was then investigated.11 While sodium
dodecyl sulfate (SDS) or Triton X-405 was not effective (entries
6, 7), it was remarkable that cetyltrimethylammonium bromide
(CTAB) gave an excellent yield and that it also improved the ee
slightly (entry 8). It is noteworthy that a cationic surfactant is
effective in this reaction,12 while an anionic surfactant has been
a H2O/THF ) 1/9 was used as a solvent instead of H2O. b Without TfOH.
Acylhydrazones are imine surrogates that are more stable than
imines even in aqueous media.6,7 Moreover, hydrazines such as the
products in the Mannich-type reactions are interesting compounds,
not only because hydrazines themselves can be used as unique
building blocks8 but also because the N-N bond can be easily
cleaved to afford amines. When a combination of ZnF2 (100 mol
%), 1a (10 mol %), and TfOH (1 mol %) was used,4 the reaction
in pure water proved to give a much lower yield than that in H2O/
9
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J. AM. CHEM. SOC. 2004, 126, 7768-7769
10.1021/ja048607t CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
was not necessary in the system, and a cationic surfactant was
effective in some cases. (3) In contrast with most asymmetric
Mannich-type reactions, either syn or anti adducts were stereospe-
cifically obtained from (E)- or (Z)-silicon enolate. (4) Some
pertinent information on the chiral catalysts, the Zn-chiral diamine
complexes, was obtained. We anticipate that this work will provide
a useful guide for the development of asymmetric carbon-carbon
bond-forming reactions in water.
Acknowledgment. This work was partially supported by
CREST, SORST, and ERATO, Japan Science and Technology
Agency (JST), and a Grant-in-Aid for Scientific Research from
Japan Society of the Promotion of Science. T.H. thanks the JSPS
fellowship for Japanese Junior Scientists.
Figure 1. Ortep drawing of [ZnCl2-1b] moiety in the X-ray crystal
structure of [ZnCl2-1b‚CH2Cl2]. Hydrogen atoms except NH are omitted
for clarify.
reported to work well in Lewis acid-catalyzed aldol reactions.13
The reaction under neat conditions gave a much lower yield (4%
yield, syn/anti ) 91/9, 94% ee (syn) for 5 h) than that in water
(68% yield, syn/anti ) 94/6, 97% ee (syn) for 5 h), suggesting the
importance of water. Moreover, it was found that 2 mol % CTAB
was sufficient for giving high yield and ee (entry 9). Under these
optimized conditions, it was possible to reduce the amount of 1b
to 5 mol % (entry 10). Butyrophenone-derived silyl enol ether also
afforded the adduct in good yield with high stereoselectivity (entry
11).
Supporting Information Available: Experimental section including
determination of stereochemistry (PDF, CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Li, C.-J.; Chan, T.-H. Organic Reactions on Aqueous Media; John
Wiley & Sons: New York, 1997. (b) Organic Synthesis in Water; Grieco,
P. A., Ed.; Blackie Academic and Professional: London, 1998.
(2) (a) Sinou, D. AdV. Synth. Catal. 2002, 344, 221. (b) Lindstro¨m, U. M.
Chem. ReV. 2002, 102, 2751. (c) Manabe, K.; Kobayashi, S. Chem. Eur.
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(3) (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (b) Taggi, A.
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The reaction of 2 with the (Z)-silyl enol ether derived from
3-pentanone (3Z) using 1b and CTAB afforded the adduct with
good syn selectivity and high ee (entry 12). To our surprise, the
anti adduct was obtained with good diastereoselectivity by the
reaction with the (E)-silyl enol ether (3E) under the same conditions
(entry 13). We next took an interest in the stereospecificity in the
reactions using the (E)- and (Z)-ketene silyl acetal derived from
S-tert-butyl thiopropionate (4E and 4Z), which gave synthetically
useful â-hydrazino thioesters. When 4E was employed, the anti
adduct was obtained selectively with high diastereo- and enantio-
selectivity (entry 14). In contrast, 4Z proved to afford high syn
selectivity (entry 15). It was found that use of cetylpyridinium
bromide (CPB) instead of CTAB suppressed the hydrolysis of 4Z
to some degree to improve the yield (entry 16).14 In effect, good to
high stereospecificities were observed in the reactions with both 3
and 4.15 It is noted that these stereospecificities are rare examples
in the catalytic asymmetric Mannich-type reactions16 and that both
syn and anti adducts can be prepared by simply changing the
geometry of the silicon enolates. Furthermore, in many cases, the
adducts were highly crystalline, and one recrystallization from
ethanol/hexane afforded the diastereomerically and enantiomerically
almost pure materials (entries 2, 8,4 11, and 12).
To clarify the origin of the unique stereoselectivities, we finally
investigated the structure of the chiral catalyst. Although the single
crystal of ZnF2-1b complex was difficult to prepare due to the
low solubility of ZnF2, a complex suitable for X-ray analysis was
obtained from ZnCl2 and 1b (Figure 1). In this X-ray structure, the
asymmetric environment of the two Ph groups on the asymmetric
carbons was transferred to the two benzyl moieties on the nitrogen
atoms, as expected, which would play a key role for the high
stereoselectivity. In addition, interactions between the MeO groups
of 1b and Zn2+ were not observed. On the basis of this observation
and the the similar ees given by 1a and 1b (Table 1), it is implied
that the MeO groups of 1b do not coordinate to Zn2+ even in the
transition states in the asymmetric reactions.
(4) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002, 124, 5640.
(5) For the other recent reports on the asymmetric reactions of imines with
silicon enolates in water-containing solvents, see: (a) Notz, W.; Tanaka,
F.; Watanabe, S.-I.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.;
Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624. (b) Josephsohn, N. S.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4018.
(6) (a) Kobayashi, S.; Hamada, T.; Manabe, K. Synlett 2001, 1140. (b)
Oyamada, H.; Kobayashi, S. Synlett 1998, 249. (c) Manabe, K.; Oyamada,
H.; Sugita, K.; Kobayashi, S. J. Org. Chem. 1999, 64, 8054.
(7) For reports on the catalytic asymmetric carbon-carbon bond-forming
reactions using acylhydrazones, see: (a) Kobayashi, S.; Hasegawa, Y.;
Ishitani, H. Chem. Lett. 1998, 1131. (b) Kobayashi, S.; Shimizu, H.;
Yamashita, Y.; Ishitani, H.; Kobayashi, J. J. Am. Chem. Soc. 2002, 124,
13678. (c) Kobayashi, S.; Ogawa, C.; Konishi, H.; Sugiura, M. J. Am.
Chem. Soc. 2003, 125, 6610. (d) Hamada, T.; Manabe, K.; Kobayashi, S.
Angew. Chem., Int. Ed. 2003, 42, 3927. (e) Friestad, G. K.; Shen, Y.;
Ruggles, E. L. Angew. Chem., Int. Ed. 2003, 42, 5061. (f) Keith, J. M.;
Jacobsen, E. N. Org. Lett. 2004, 6, 153. See also ref 4.
(8) Schiessl, H. W. In Kirk-Othmer Encyclopedia of Chemical Technology,
4th ed.; Kroschwitz, J. I., Howe-Grant, M., Eds.; Wiley: New York, 1995;
Vol. 13, pp 560-606.
(9) In a H2O/THF (1:9) solvent, the reaction using 1a proceeded sluggishly
without TfOH.4
(10) In the reactions using the silyl enol ethers derived from R-monosubstituted
carbonyl compounds, 1b was used instead of 1c, because 1b gave higher
selectivities (Table 2, entry 9) in the reactions using propiophenone-derived
silyl enol ether than 1c (86%, syn/anti ) 94/6, 92% ee).
(11) (a) Fendler, J. H.; Fendler, E. J. Catalysis in Micellar and Macromolecular
Systems; Academic Press: London, 1975. (b) Mixed Surfactant Systems;
Holland, P. M., Rubingh, D. N., Eds.; American Chemical Society:
Washington, DC, 1992. (c) Structure and ReactiVity in Aqueous Solution;
Cramer, C. J., Truhlar, D. G., Eds.; American Chemical Society:
Washington, DC, 1994. (d) Surfactant-Enhanced Subsurface Remediation;
Sabatini, D. A., Knox, R. C., Harwell, J. H., Eds.; American Chemical
Society: Washington, DC, 1994. (e) Reactions and Synthesis in Surfactant
Systems; Texter, J., Ed.; Marcel Dekker: New York, 2001.
(12) When CTAB (5 mol %) was used in the reaction in Table 1, entry 5,
remarkable acceleration of the reaction was not observed, and the ee was
decreased (56% yield, 92% ee for 5 h).
(13) (a) Manabe, K.; Mori, Y.; Wakabayashi, T.; Nagayama, S.; Kobayashi,
S. J. Am. Chem. Soc. 2002, 124, 5640. (b) Kobayashi, S.; Mori, Y.;
Nagayama, S.; Manabe, K. Green Chem. 1999, 175. (c) Kobayashi, S.;
Wakabayashi, T.; Nagayama, S.; Oyamada, H. Tetrahedron Lett. 1997,
26, 4559.
(14) Use of CPB in the reactions shown in Table 2, entries 12 and 14, gave
almost the same results (R1 ) Me, R2 ) H, R3 ) Et, CPB (2 mol %)
58% yield, syn/anti ) 87/13, 97% ee (syn); R1 ) Me, R2 ) H, R3
StBu, CPB (2 mol %) 38% yield, syn/anti ) 10/90, 94% ee (anti)).
)
(15) With regard to the relationship between the configurations of the enolates
and the relative configurations of the products, 3 and 4 afforded opposite
results, possibly due to the steric difference between the Ph and StBu
groups.
In conclusion, we have developed efficient enantio- and diaste-
reoselective Mannich-type reactions of a hydrazono ester with
silicon enolates. Characteristic points of these reactions are as
follows: (1) The new catalyst system remarkably accelerated the
reactions in water without using any organic cosolvents. (2) TfOH
(16) Although diastereoselectivities were not as high as the present reactions,
stereospecificities were also observed in the asymmetric Mannich-type
reactions. See: Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa,
H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507.
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