Diastereoselective Henry reactions of N,N-dibenzyl α-amino aldehydes with nitromethane catalyzed by enantiopure guanidines

Article abstract of DOI:10.1016/S0040-4039(02)02332-8

Several enantiopure guanidines are studied as the catalysts of Henry reactions of N,N-dibenzyl α-amino aldehydes with nitromethane. Good diastereoselectivity is observed in the reactions of L-valine or L-isoleucine derived aldehydes catalyzed by a (R)-1-(

Full text of DOI:10.1016/S0040-4039(02)02332-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9401–9403
Diastereoselective Henry reactions of N,N-dibenzyl a-amino
aldehydes with nitromethane catalyzed by enantiopure guanidines
Dawei Ma,a,* Qiangbiao Panb and Fushe Hana
aState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
bDepartment of Chemistry, Fudan University, Shanghai 200433, China
Received 3 September 2002; revised 30 September 2002; accepted 11 October 2002
Abstract—Several enantiopure guanidines are studied as the catalysts of Henry reactions of N,N-dibenzyl a-amino aldehydes with
nitromethane. Good diastereoselectivity is observed in the reactions of L-valine or L-isoleucine derived aldehydes catalyzed by a
(R)-1-(1-naphthyl)ethylamine derived guanidine. © 2002 Elsevier Science Ltd. All rights reserved.
The Henry reaction1 of enantiopure N-protected a-
amino aldehydes with nitromethane provides 3-amino-
2-hydroxy-1-nitro derivatives. They are readily
converted into pharmacologically important molecules
such as the anti-HIV drug amprenavir2 as well as
a-hydroxyl b-aminoacids, a valuable backbone of pep-
tide mimetics.3 It was reported that the diastereoselec-
tivity of this reaction was poor when achiral catalysts
were used.2a,4 In order to overcome this drawback, two
chiral catalysts including a rare earth–Li-(R)–BINOL
complex2b and a rigid chiral quaternary ammonium
salt2a were explored and improved diastereoselectivity
was observed. However, the former catalyst system
suffered from inconvenient operation whilst the latter
still gave unsatisfactory diastereoselectivity. Thus, other
catalyst systems are still needed.
known procedure.2b After screening these guanidines
for Henry reactions of enantiopure N,N-dibenzyl a-
amino aldehydes8 with nitromethane, we found that
some of them induced these reactions in a highly
diastereoselective manner. Herein we wish to report our
results.
As shown in Table 1, the reaction of the a-amino
aldehyde 2a derived from (S)-phenylalanine with
nitromethane was carried out in toluene at −20°C using
10 mol% of the guanidine 1a as catalyst to provide 3a
and its 2-epimer 4a in 96% yield. The ratio of 3a:4a was
about 4.8:1 (entry 1). The stereochemistry of 3a and 4a
was assigned by comparison of their 1H NMR data
with those reported.2a Using the guanidine 1b gave a
slightly improved result (entry 2). The absolute configu-
rations of the guanidines obviously influenced the
diastereoselectivity because the (R,R)-guanidine 1i
showed a higher preference towards 3a than (S,S)-
guanidine 1j (compare entries 9 and 10). This result also
implied that the chiralities of both catalyst and sub-
strate influenced the asymmetric induction. Further
attempts to increase the diastereoselectivity by utilizing
guanidines 1c–f derived from different primary
monoamines were found to give similar results (entries
3–6). The best selectivity was obtained when the
bicyclic guanidine 1h was used. However, a different
diastereoselectivity pattern was observed when the sub-
strate was switched to the amino aldehyde 2b. In this
case the best result (92% de) was obtained when the
(R)-1-(1-naphthyl)ethylamine derived guanidine 1d was
employed as the catalyst (entry 14). The other similar
catalysts (1c, 1e and 1f) gave considerably lower
As a class of asymmetric catalysts, enantiopure guanidi-
nes have advantages in convenient reaction operation
and efficient catalyst recycling. The potential of this
type of catalyst has received considerable attention
recently.5 In connection with our efforts on the devel-
opment of chiral guanidine catalyzed reactions,5c we
have synthesized a group of enantiopure guanidines
with diversity as shown in Fig. 1. The compounds,
except for 1g and 1h, were assembled from the corre-
sponding enantiopure monoamines or diamines via
direct reaction with BrCN.6 The guanidine 1g was
obtained from the reaction of the corresponding pri-
mary amine with N,N-di-Boc-triflylguanidine7 followed
by deprotection, whilst 1h was prepared according to a
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02332-8

9402
D. Ma et al. / Tetrahedron Letters 43 (2002) 9401–9403
Figure 1.
Table 1. Henry reactions of aldehydes 2 with nitromethane catalyzed by various enantiopure guanidinesa
Guanidine
2a
Yield (%)b
2b
Entry
Time (h)
3a:4ac
Entry
Time (h)
Yield (%)b
3b:4bc
1a
1b
1c
1d
1e
1
2
3
4
5
6
7
8
9
10
20
10
15
20
20
10
20
15
15
4
96
75
95
95
92
92
95
92
92
93
97
4.8:1
6:1
11
12
13
14
15
16
17
18
48
48
48
48
48
48
48
48
96
72
85
92
85
70
90
87
8.7:1
17:1
13.7:1
24.1:1
15:1
13.6:1
13.9:1
17.2:1
6.2:1
6.7:1
6.4:1
6.6:1
5.9:1
8.8:1
6.1:1
3.9:1
2.9:1
1f
1g
1h
1i
1j
TMG
10
19
a Reaction conditions: a-amino aldehyde (1 mmol), nitromethane (10 mmol), guanidine (0.1 mmol) in 2 mL of toluene, −20°C.
b Isolated yield.
c Determined by HPLC.
diastereoselectivity (compare entries 14 with 13, 15, and
16). Enantiopure guanidines were essential for improve-
ment of the diastereoselectivity of the present reaction
because tetramethylguanidine (TMG) provided a poor
result (entry 19).
diastereoselectivity was still highly dependent on the
substrates. When the -isoleucine derived aldehyde was
used as the substrate, good diastereoselectivity (91%)
was observed. Other substrates provided moderate or
L
poor (for the
selectivity.
L-proline derived aldehyde) diastereo-
Considering the fact that guanidine 1d showed better
asymmetric inducing ability in the above two reactions,
we chose it as a catalyst to investigate other reactions of
a-amino aldehydes. As summarized in Table 2, the
In conclusion, we have demonstrated that some enan-
tiopure guanidines are effective catalysts for the
diastereoselective Henry reaction of a-amino aldehydes

D. Ma et al. / Tetrahedron Letters 43 (2002) 9401–9403
Table 2. Guanidine 1d catalyzed Henry reactionsa
9403
a
b
c
Reaction conditions: a-amino aldehyde (1 mmol), nitromethane (10 mmol), guanidine (0.1 mmol) in 2 mL of toluene, −20°C.
Isolated yield.
Determined by HPLC.
and nitromethane. Although in many cases these cata-
lysts only gave moderate diastereoselectivity, the good
results observed in some cases indicated that the present
catalysts provide an efficient, alternative catalyst system
for this important reaction.9 Further improvement uti-
lizing other guanidine catalysts is in progress.
5. For the Strecker reaction, see (a) Lyer, M. S.; Gigstad, K.
M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996,
118, 4910–4911; (b) Corey, E. J.; Grogan, M. J. Org. Lett.
1999, 1, 157–160. For the Michael reaction, see: (c) Ma,
D.; Cheng, K. Tetrahedron: Asymmetry 1999, 10, 713–719;
(d) Howard-Jones, A.; Murphy, P. J.; Thomas, D. A.;
Caulkett, P. W. R. J. Org. Chem. 1999, 64, 1039–1041; (e)
Ishikawa, T.; Araki, Y.; Kumamoto, T.; Seki, H.; Fukuda,
K.; Isobe, T. Chem. Commun. 2001, 245–246. For the
Henry reaction, see: (f) Chinchilla, R.; Najera, C.;
Sanchez-Agullo, P. Tetrahedron: Asymmetry 1994, 5,
1393–1402. For silylation reactions, see: (g) Isobe, T.;
Fukuda, K.; Araki, Y.; Ishikawa, T. Chem. Commun.
2001, 243–244.
6. Maillard, M. C.; Perlman, M. E.; Amitay, O.; Baxter, D.;
Berlove, D.; Connaughton, S.; Fischer, J. B.; Guo, J. Q.;
Hu, L.-T.; McBurney, R. N.; Nagy, P. I.; Subbarao, K.;
Yost, E. A.; Zhang, L.; Durant, G. J. J. Med. Chem. 1998,
41, 3048–3061.
7. (a) Feichtinger, K.; Sings, H. L.; Baker, T. J.; Matthews,
K.; Goodman, M. J. Org. Chem. 1998, 63, 8432–8439; (b)
Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J.
Org. Chem. 1998, 63, 3804–3805.
Acknowledgements
The authors are grateful to the Chinese Academy of
Sciences, National Natural Science Foundation of
China (grant 20132030), and Qiu Shi Science & Tech-
nologies Foundation for their financial support.
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