Diastereoselective asymmetric nitro-aldol reaction of α-amino aldehydes under high pressure without catalyst

Article abstract of DOI:10.1002/1521-3773(20020315)41:6<1031::AID-ANIE1031>3.0.CO;2-K

Under pressure, the nitro-aldol reaction of (S)-N,N-dibenzylphenylalaninal and related compounds with nitroalkanes was highly stereoselective (see scheme; R¹, R² = Me, H; R = Ph, Me, iPr, iBu). This reaction is very convenient, as it

Full text of DOI:10.1002/1521-3773(20020315)41:6<1031::AID-ANIE1031>3.0.CO;2-K

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599.53, a ˆ 10.465(8), b ˆ 15.279(8), c ˆ 15.425(12) ä, b ˆ 104.60(5)8, Vˆ
2387(3) ä3, Z ˆ 4, 1calcd ˆ 1.668 gcmÀ3, m ˆ 1.827 mmÀ1, F(000) ˆ 1208, R ˆ
0.0609, Rw ˆ 0.1736, GOF ˆ 1.006 for 344 parameters, 2606 reflections with
jFo jˆ 4s(Fo).
Diastereoselective Asymmetric Nitro-Aldol
Reaction of a-Amino Aldehydes under High
Pressure without Catalyst**
Yukihiro Misumi and Kiyoshi Matsumoto*
Received: September 6, 2001
Revised: December 14, 2001 [Z17862]
Dedicated to Professor Rolf Huisgen
on the occasion of his 81st birthday
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2101 2102.
The Henry (nitro-aldol) reaction is one of the most valuable
À
methods for carbon carbon bond formation and its stereo-
chemical control continues to be a challenge for organic
chemists.[1 6] Specifically, an efficient synthesis of medicinally
important intermediates such as phenylnorstatine through a
diastereoselective catalytic (rare earth-Li-(R)-BINOL) asym-
metric nitro-aldol reaction of optically active a-amino alde-
hydes with nitromethane has been reported.[4] Tetrabutylam-
monium fluoride has been also used, albeit with less success.[5]
More recently, Corey and Zhang employed a rigid chiral
quaternary ammonium salt for this reaction, which leads to a
highly stereoselective synthesis of the HIV protease inhibitor
amprenavir.[6] More generally, nitro-aldol adducts provide
ready access to non-natural 3-amino-2-hydroxy acids and 1,3-
diamino-2-hydroxy units, which are substructures of medici-
nally important compounds.[7, 8] One of us previously demon-
strated that the Henry reaction is highly accelerated by
pressure.[9] However, to our knowledge, no attempts have ever
been made to perform a diastereoselective nitro-aldol reac-
tion without a catalyst.[10] We envisaged that the amino group
of optically active a-amino aldehydes might act as a base, and
that such aldehydes would react with nitromethane under
high pressure without a catalyst, thus offering a clean reaction
system. Herein, we report the first example of the diaster-
eoselective nitro-aldol reaction without any added catalyst.
N,N-Dibenzyl a-amino aldehydes 1 (Scheme 1) were chos-
en as a model substrate since they bear a free amino group
and are relatively stable. The adducts may serve as versatile
synthetic intermediates for the synthesis of non-natural
[13] F. Neese, W. G. Zumft, W. E. Antholine, P. M. H. Kroneck, J. Am.
Chem. Soc. 1996, 118, 8692 8699.
[14] D. D. LeCloux, R. Davydov, S. J. Lippard, J. Am. Chem. Soc. 1998,
120, 6810 6811.
[15] A mixture of phen (0.117 g) or bpy (0.102g), H 2tp (0.041 g), NaOH
(0.02g), and water (10 mL) in the molar ratio 1.3:0.25:0.5:1100 was
sealed in 23-mL Teflon reactor, which was heated in an oven at 1608C
for 144 h. No solid hydroxylated organic product was observed.
[16] Crystal data for 3: monoclinic, space group P21/n, Mr ˆ 517.47,
a ˆ 10.651(8), b ˆ 6.180(4), c ˆ 15.079(13) ä, b ˆ 94.160(10)8, Vˆ
989.9(13) ä3, Z ˆ 2.
[17] S. Ferguson-Miller, G. T. Babcock, Chem. Rev. 1996, 96, 2889 2907;
G. A. Baranovic, J. Coyle, C. G. Coates, J. J. McGarvey, V. McKee, J.
Nelson, Inorg. Chem. 1998, 37, 3567 3574; S. Iwata, C. Ostermeier, B.
Ludwig, H. Michel, Nature 1995, 376, 660 669; T. Tsukihara, H.
Aoyama, E. Yamashita, T. Tomizaki, H. Yamaguchi, K. Shinzawa-
Itoh, R. Nakahima, R. Yaono, S. Yoshikawa, Science 1996, 272, 1136
1144.
[18] General crystallographic information: MoKa radiation (l ˆ
0.71073 ä). Tˆ 293 K. Siemens R3m diffractometer, w scan mode
(4 ꢀ 2q ꢀ 528 for 1 and 4 ꢀ 2q ꢀ 528 for 2), solved with direct methods
(SHELXS-97)[19] and refined with full-matrix least-squares
(SHELXL-97).[20] CCDC-170016 and CCDC-170017 contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrie-
ving.html (or from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB21EZ, UK; fax: (‡44)1223-336-033; or
deposit@ccdc.cam.ac.uk).
Scheme 1. Reaction of a-amino aldehydes 1 with nitroalkanes 2.
[*] Prof. Dr. K. Matsumoto, Y. Misumi
Graduate School of Human and Environmental Studies
Kyoto University
[19] G. M. Sheldrick, SHELXS-97, Program for Crystal Structure Solution,
Gˆttingen University, Germany, 1997.
[20] G. M. Sheldrick, SHELXL-97, Program for Crystal Structure Refine-
ment, Gˆttingen University, Germany, 1997.
Kyoto 606-8501 (Japan)
Fax : (‡81)75-753-2969
E-mail: kimatsu@ip.media.kyoto-u.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan. The authors are also grateful to the Ministry of
Education, Culture, Sports, Science, and Technology, Japan for the
high-field NMR instruments (JEOL JNM-A500 and JNM-EX270)
from the special fund to K.M. (1992).
Angew. Chem. Int. Ed. 2002, 41, No. 6
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3-amino-2-hydroxy acids. First, we examined the nitro-aldol
reaction of (S)-N,N-dibenzylphenylalaninal (1a) with nitro-
methane (2a) under high pressure without a catalyst. The
starting optically active a-amino aldehyde (1a) was prepared
from the corresponding (S)-phenylalanine in two steps
according to the procedure of Corey and Zhang.[6] Under
atmospheric pressure, 1a did not react with 2a (10 equiv) in
acetonitrile. However, to our delight, the reaction did occur at
8 kbar (room temperature, 12h) to give a mixture of
diastereomers (2R,3S)-3a and (2S,3S)-epi-3a (83:17, 81%)
(Scheme 1). The mixture was purified by means of chroma-
tography on silica gel to give a pure sample of (2R,3S)-3a and
(2S,3S)-epi-3a. The major product (2R,3S)-3a was identified
by comparison with literature data (1H and 13C NMR
spectroscopy).[6] The correct choice of solvent is crucial for
an efficient diastereoselective nitro-aldol reaction (Table 1,
entries 1 6). Among the solvents examined thus far, CH3CN
gave the best result; the yield of 3a decreased in the order
CH3CN > CH3NO2 > MeOH > CHCl3 > CH2Cl2 > toluene,
whereas the diastereoselectivity of 3a decreased in the order
CH3CN > MeOH > CH3NO2 > CHCl3. The optical purity was
>99% ee in CH3CN which indicates that no racemization
occurred during the reaction.[11] (S)-N-(tert-Butoxycarbonyl)-
phenylalaninal did not react with 2a at 8 kbar, presumably
because of the lower basicity of the amino group. The reaction
is quite general (e.g. Table 1, entries 7 11). The pressure and
the amount of 2a did not significantly affect the diastereose-
lectivity, although the yields did increase under pressure.
Notably, very high diastereoselectivity was observed in the
reaction of 1a with 2-nitropropane (2c) (Table 1, entry 11).
The diastereoselective reaction of (R)-N,N-dibenzylphenyl-
alaninal (4) with 2a produced the corresponding anti nitro-
alcohol 5 as a single enantiomer. Thus there was also no
racemization in this case (Scheme 2).
To elucidate a plausible mechanism (e.g. inter- or intra-
molecular), a control experiment was performed: the cross
nitro-aldol reaction of 1a (1.0 equiv) and 3-phenylpropanal
(4) (1.0 equiv) with 2a (1.0 equiv) was carried out under
pressure (8 kbar) at room temperature, and provided a
mixture of 3a and 5 in yields of 12and 13%, respectively
(Scheme 3).
Scheme 3. Cross nitro-aldol reaction of (S)-N,N-dibenzylphenylalaninal
(1a) and 3-phenylpropanal (4) with 2a.
A plausible mechanism for this reaction involves the initial
reaction of the base 1a with 2a to give a carbanion.
Nucleophilic attack of the carbanion at the formyl carbon
atom from the Re face gave predominantly the 2R,3S
nitroalcohol, in agreement with the Felkin Anh model
(Scheme 4). This was further supported by the fact that the
reaction of sterically hindered 2-nitropropane (2c) with 1a
was highly diastereoselective (Table 1, entry 11).
Scheme 4. Plausible mechanism for nitro-aldol reaction without catalyst.
In conclusion, we have presented the first diastereoselective
nitro-aldol reaction without a catalyst. Although the diaster-
eoselectivities do not rival those of reactions that require
Scheme 2. Reaction of (R)-N,N-dibenzylphenylalaninal (4) with 2a.
Table 1. Diastereoselective nitro-aldol reaction of a-amino aldehydes 1 with nitroalkanes 2 without catalyst under high pressure.[a]
Entry
Aldehyde
Nitroalkane
Solvent
Product
Yield [%][b]
3/epi-3
ee (3) [%]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1c
2a
2a
2a
2a
2a
2a
2b
2a
2a
CH3CN
CH3NO2
CH3OH
CHCl3
CH2Cl2
toluene
CH3CN
CH3CN
CH3CN
3a
3a
3a
3a
3a
3a
3b
3d
3e
3e
3 f
3 f
3c
81
69
29
27
83:17[c]
74:26
78:22
> 99
98
96
71:29
89
[d]
3
[d]
trace
78
67
66 (11)
79[g]
70
83 (4)[h]
68 (17)
59:25:9:7[c]
71:29[c]
89:11[e]
86:14[e]
73:27[e]
85:15[e]
99: < 1
99
96[f]
96[f]
90[f]
91[f]
92
10
11
1d
1a
2a
2c
CH3CN
CH3CN
[a] Reaction conditions: 1 (0.2mmol), 2 (2.0 mmol), solvent (3 mL), 8 kbar, 12 h, room temperature. [b] Yield of isolated product, based on 1. Values in
parentheses are the amounts of 1 recovered (%). [c] Separable by chromatography. [d] Not determined. [e] The ratio was determined by means of 13C NMR
spectroscopy. [f] The ee value was not accurate because of partial overlap of peaks in chiral HPLC analysis. [g] Reaction time: 24 h. [h] Reaction conditions:
1d (0.4 mmol), 2a (4.0 mmol), acetonitrile (2.7 mL), 8 kbar, 12 h, room temperature.
1032
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highly sophisticated catalysts,[4, 6] the experimental procedure
is extremely simple, because there is no need to quench the
catalyst (see Experimental Section). Partial racemization that
would result from using a catalyst is avoided. Furthermore,
the use of toxic and expensive catalysts that are difficult to
prepare is not necessary. This strategy, that is, pressure-
mediated substrate-catalyzed reactions might also be amena-
ble to other reactions (Michael, Mannich, Baylis Hillman),
which are accelerated by pressure.[12] Further work along
these lines is in progress.
C. Najera, P. Sanchez-Agullo, Tetrahedron: Asymmetry 1994, 5, 1393;
H. Sasai, Y. M. A. Yamada, T. Suzuki, M. Shibasaki, Tetrahedron 1994,
50, 12313; H. Sasai, N. Itoh, T. Suzuki, M. Shibasaki, Tetrahedron Lett.
1993, 34, 855; H. Sasai, T. Suzuki, N. Itoh,; M. Shibasaki, Tetrahedron
Lett. 1993, 34, 851; H. Sasai, T. Suzuki, S. Arai, M. Shibasaki, J. Am.
Chem. Soc. 1992, 114, 4.
[4] H. Sasai, W.-S. Kim, T. Suzuki, M. Shibasaki, M. Mitsuda, J.
Hasegawa, T. Ohashi, Tetrahedron Lett. 1994, 35, 6123, see also
references in [3] from this group.
[5] S. Hanessian, P. V. Devasthale, Tetrahedron Lett. 1996, 37, 987.
[6] E. J. Corey, F.-Y. Zhang, Angew. Chem. 1999, 111, 2057; Angew. Chem.
Int. Ed. 1999, 38, 1931.
[7] M. T. Reetz, Angew. Chem. 1991, 103, 1559; Angew. Chem. Int. Ed.
Engl. 1991, 30, 15.
[8] M. T. Reetz, M. W. Drews, A. Schmitz, Angew. Chem. 1987, 99, 1186;
Angew. Chem. Int. Ed. Engl. 1987, 26, 1141.
Experimental Section
[9] K. Matsumoto, Angew. Chem. 1984, 96, 599; Angew. Chem. Int. Ed.
Engl. 1984, 23, 617.
[10] For a review on stereoselective reactions under high pressure, see: G.
Jenner, Tetrahedron 1997, 53, 2669.
[11] The effect of pressure and solvent on the diastereoselectivity of
reactions under high pressure have been discussed extensively by
Tietze and co-workers; see: M. Buback, K. Gerke, C. Ott, L. F. Tietze,
Chem. Ber. 1994, 127, 2241; L. F. Tietze, M. Henrich, I. Rothert, G.
Kuchta, M. Buback, Pol. J. Chem. 1997, 71, 1749; M. Buback, G.
Kuchta, A. Niklaus, M. Henrich, I. Rothert, L. F. Tietze, Liebigs Ann.
1996, 1151; L. F. Tietze, M. Henrich, A. Niklaus, M. Buback, Chem.
Eur. J. 1999, 5, 297.
3a: A solution 1a (66 mg, 0.2mmol) and 2a (108 mL, 2.0 mmol) in
acetonitrile (3 mL) was placed in a sealed Teflon vessel. The reaction
mixture was stirred at room temperature under atmospheric pressure until
most of 1a had dissolved (5 min). The tube was placed in a high-pressure
reactor, and pressurized to 8 kbar at 258C. After 12h, the pressure was
released, and the reaction mixture was transferred from the Teflon vessel
into a flask. The solvent was removed under reduced pressure. The crude
products were purified by means of column chromatography (SiO2,
hexane/Et2O 10:1) to give the anti isomer 3a (52mg, 67%) and the syn
isomer (11 mg, 14%) (total yield 81%, anti/syn 83:17). The enantiomeric
excess was determined by means of HPLC analysis on DAICEL
CHIRALCEL OJ.
[12] For reviews of organic reactions under high pressure from our
laboratory, see: Organic Reactions at High Pressures (Eds.: K.
Matsumoto, R. M. Acheson), Wiley, New York, 1991; M. Ciobanu,
K. Matsumoto, Liebigs Ann. 1997, 623; K. Matsumoto, M. Kaneko, H.
Katsura, N. Hayashi, T. Uchida, R. M. Acheson, Heterocycles 1998, 47,
1135.
Received: October 4, 2001 [Z18018]
[1] For the most recent reviews on the Henry condensation, see: a) G.
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b) F. A. Luzzio, Tetrahedron 2001, 57, 915, and references therein.
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Sigmatropic Shiftamers: Fluxionality in Broken
Ladderane Polymers**
Dean J. Tantillo and Roald Hoffmann*
Construction principles: Consider the hypothetical ladder
polymer 1-™[1]-ladderane.∫[1, 2] A formal [2‡2] cyclorever-
sion would lead to 2 in which a local ™defect,∫ consisting of
two parallel p bonds, is formed. Cope rearrangement via a
boatlike transition structure would give 2', which is, of course,
equivalent to 2 (Scheme 1). Continued indefinitely, this
process would lead to a pair of double bonds running down
the polymer chain.
[*] Prof. R. Hoffmann, Dr. D. J. Tantillo
Department of Chemistry
Baker Laboratory
Cornell University, Ithaca NY 14853-1301 (USA)
Fax : (‡1)607-255-5707
E-mail: rh34@cornell.edu
[**] We gratefully acknowledge support from the National Science
Foundation (through research grant CHE 99-70089) and the National
Computational Science Alliance.
Supporting information for this article (Coordinates and energies for
computed structures from Scheme 2, as well as structures involved in
the Cope rearrangements of 6 and 7.) is available on the WWW under
http://www.angewandte.com or from the authors.
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¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
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