Diastereoselective Henry reaction catalyzed by guanidine-thiourea bifunctional organocatalyst

Article abstract of DOI:10.1055/s-2005-922770

A highly diastereoselective Henry reaction (diastereomer ratio of 84:16 to 99:1) of α-substituted aldehydes with nitromethane was developed using guanidine-thiourea bifunctional catalyst 1. N,N-Dibenzyl-protected α-amino aldehydes (2a, 2d-h) and α-hydroxy

Full text of DOI:10.1055/s-2005-922770

144
CLUSTER
Diastereoselective Henry Reaction Catalyzed by Guanidine–Thiourea
Bifunctional Organocatalyst
?
????
?
oshihiro Sohtome,a Nobuko Takemura,b Toshitsugu Iguchi,b Yuichi Hashimoto,a Kazuo Nagasawa*b
a
Institute of Molecular and Cellular Biosciences, The University of Tokyo Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
b
Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology,
2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan
Fax +81(42)3887295; E-mail: knaga@cc.tuat.ac.jp
Received 3 October 2005
substituted aldehydes with nitromethane. First, the reac-
tion of the N,N-dibenzyl-a-amino aldehyde 2a7 derived
from (S)-phenylalanine with nitromethane was carried out
in toluene–H2O (1:1) at 0 °C using KOH (8 mol%) and KI
Abstract: A highly diastereoselective Henry reaction (diastereo-
mer ratio of 84:16 to 99:1) of a-substituted aldehydes with ni-
tromethane was developed using guanidine–thiourea bifunctional
catalyst 1. N,N-Dibenzyl-protected a-amino aldehydes (2a, 2d–h)
and a-hydroxy aldehydes protected as silyl ethers (2i–j) were suit- (50 mol%) in the presence of (R,R)-1 (10 mol%) to give
able substrates. The matched combination of this catalytic system,
i.e., S-aldehydes and (R,R)-1 catalyst, can be understood in terms of
the nitro alcohols anti-3a and syn-4a in a ratio of 95:5 with
75% yield (Table 1, entry 1).8 In this case, the enantiomer-
the transition state of the asymmetric version of the Henry reaction
ic excess of 3a was found to be 99%. On the other hand,
catalyzed by 1.
the diastereoselectivity of 3a and 4a was only 64:36 with
Key words: bifunctional organocatalyst, guanidine, thiourea,
8% yield, when the reaction was performed using (S,S)-1
Henry reaction, diastereoselective reaction
(entry 2).
C18H37
Cl
The Henry (nitroaldol) reaction is an important carbon–
NH
H
H
H
H
carbon bond forming reaction that affords valuable syn-
thetic intermediates,1 and controlling the newly generat-
ing stereochemistry of the Henry adducts continues to be
a challenging issue.2 However, the selectivity of the dia-
stereoselective version of this reaction utilizing chiral
aldehydes is usually moderate to low when an achiral
catalyst or no catalyst is used.3 The first diastereoselective
catalytic Henry reaction of optically active amino alde-
hydes with nitromethane was reported by Shibasaki’s
group, utilizing chiral LLB (lanthanide–Li–BINOL) cata-
lyst.4 Corey and Zhang subsequently employed cinchona
alkaloid derivatives (quaternary ammonium salts) as
chiral catalysts for this reaction, which was utilized in the
synthesis of the HIV protease inhibitor amprenavir.5
Besides these catalysts, a guanidine-type chiral organo-
catalyst6 has also been reported for enantioselective6a,b
and/or diastereoselective Henry reaction.6i Ma et al. re-
ported diastereoselective Henry reactions with moderate
to high selectivity utilizing chiral guanidine catalysts.6i
We recently have developed the guanidine-containing
bifunctional organocatalyst 1, which efficiently catalyzes
the enantioselective Henry reaction (Figure 1).6f Herein,
we describe a highly diastereoselective Henry reaction
utilizing the guanidine–thiourea bifunctional organo-
catalyst 1.
F3C
N
N
N
N
CF3
N
N
H
H
S
Bn
Bn
S
CF3
CF3
(R,R)-1
Figure 1 Structure of guanidine–thiourea bifunctional organo-
catalyst 1
Table 1 Diastereoselective Henry Reaction of 2 and Nitromethane
1 (10 mol%)
CH3NO2 (10 equiv)
KI (50 mol%)
X
Y
CHO
S
NO2
Ph
Ph
KOH (8 mol%)
toluene–H2O (1:1)
24 h
NRR'
NRR'
2
3: X = H, Y = OH (anti)
4: X = OH, Y = H (syn)
Entry Aldehyde
Catalyst Yield
Ratio
ee of 3, 4
1
(%)
3:4a
(%)b
1
2
3
R = R¢ = Bn (2a) R,R
75
8
95:5
99, 85
80, 62
20, 22
2a
S,S
64:36
50:50
R = H, R¢ = Boc
(2b)
R,R
70
4
5
2b
S,S
67
70
50:50
50:50
20, 19
25, 18
R = H, R¢ = Cbz
(2c)
R,R
Based upon our recent success with asymmetric Henry
reaction catalyzed by 1,6f we applied this catalyst to the
diastereoselective Henry reaction of optically active a-
6
2c
S,S
68
50:50
28, 25
a The stereochemistry and diastereoselectivity of the products were
determined by 1H NMR.5,
b The ee values of the products were determined by HPLC using a
chiral column.
SYNLETT 2006, No. 1, pp 0144–0146
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5.
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1.
2
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Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-922770; Art ID: Y07305ST
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Diastereoselective Henry Reaction
145
These results indicate that the combination of catalyst
(R,R)-1 and (S)-a-amino aldehyde is required to obtain a
nitro alcohol with high diastereoselectivity. This is well
explained by our previously proposed transition state for
the asymmetric Henry reaction catalyzed by 1 (Figure 2).
In our proposed transition state, the guanidine group of 1
coordinates nitromethane through ionic interactions,9 and
the thiourea group interacts with aldehyde, lowering the
LUMO energy of the carbonyl group, which acts as a
Brønsted acid.10 In this case, the aldehyde R group favors
the anti conformer rather than a gauche position (Figure 2,
transition state I), and affords a nitro alcohol with high
enantioselectivity.6f This transition state can be applied to
the diastereoselective version of the Henry reaction, and
the possible transition states of the combinations of S-al-
dehyde catalyst (S,S)-1 and (R,R)-1 are depicted in
Figure 2, II and III, respectively. In the former combina-
tion (corresponding to the transition state II), there is ster-
ic interference between the phenyl group and the
guanidine–nitromethane complex moiety. In contrast, no
serious steric hindrance arises in the latter combination,
i.e., S-aldehyde and catalyst (R,R)-1, which corresponds
to the transition state III. Thus, the nitro alcohol 3a is ob-
tained with high selectivity and good yield. Moreover, no
epimerization of the aldehyde 2a occurred under these re-
action conditions, and the enantiomeric excess of 3a was
99% (Table 1, entry 1). Interestingly, no diastereoselec-
tivity was observed when the protective group of the
amine in a-amino aldehyde was changed to Boc or Cbz
(Table 1, entries 3 and 5). The carbonyl group of the car-
bamate is thought to disrupt the coordination of the carbo-
nyl group of the aldehyde to the catalyst 1. Furthermore,
aldehydes 2b and 2c are not stable under the reaction
conditions, and epimerizations were observed in all cases
(Table 1, entries 3–6).
Table 2 Diastereoselective Henry Reaction with Various
Aldehydes
(R,R)-1 (10 mol%)
OH
CH3NO2 (20 equiv)
KI (50 mol%)
R
CHO
S
R
NO2
KOH
toluene–H2O (1:1)
24 h
X
X
2
3 (anti)
Entry Aldehyde
KOH
Product, Ratio an- ee of 3
(mol%) yield (%) ti:syna
(%)b
1
20
6
3d (70) 99:1
99
Me CHO
NBn2
2d
2c
3d
3e (70)
3f (33)
99:1
99:1
95
99
Me
CHO
Me NBn2
2e
10
Me
CHO
Me
NBn2
2f
4
10
10
3g (70)
99:1
95
99
CHO
2NBn2
TBSO
2g
5c
3h (62) 99:1
CHO
NBn2
Bn2N
4
2h
6
7
5
2
3i (82)
3j (80)
86:14
84:16
99
99
Ph CHO
OTBS
2i
Me CHO
OTBS
C18H37
2j
NH
(S,S)-1
a The ratios (anti:syn) were determined by HPLC.
H
N
H
N
H
Ph
b The ee values were determined by HPLC using a chiral column.
c 10 equiv of nitromethane were used.
S
S
N
N
H
OH
d 30 equiv of nitromethane were used.
O
O
Ar
NO2
N
R
H
I
H
O
The diastereoselective Henry reaction of various alde-
hydes 2d–j catalyzed by (R,R)-1 was explored, and the
results are summarized in Table 2. In the case of N,N-
dibenzyl a-amino aldehydes derived from the correspond-
ing amino acids, anti-nitro alcohols 3d–h were obtained
with high diastereoselectivity (entries 1–5).6i However,
the bulky b-branched aldehyde 2f gave the alcohol 3f in
only 33% yield, although the selectivity was still high
(entry 3). Reaction with a-substituted aldehydes 2i and 2j
derived from (S)-mandelic acid and (S)-lactic acid also
proceeded and gave the nitro alcohols 3i and 3j with good
selectivity (84:16 to 86:14) and high yield (entries 6, 7).11
In all cases, no epimerization of the aldehydes occurred
under the reaction conditions.
R
C18H37
NH
C18H37
NH
(R,R)-1
(S,S)-1
N
Ph
R
N
H
H
N
H
Ph
O
H
S
N
N
S
O
H
N
H
S
H
N
H
O
N
H2C
Ar
O
H
N
O
N
Ar
H
H
II
H2C
O
Bn
Bn2N
H
H
S
Bn
Bn2N
S
H
III
3a
Figure 2 Proposed transition state of the Henry reaction catalyzed
by 1
Synlett 2006, No. 1, 144–146 © Thieme Stuttgart · New York

146
Y. Sohtome et al.
CLUSTER
(7) Reetz, M. T. Chem. Rev. 1999, 99, 1121.
(8) Diastereoselective Henry Reaction of 2a with
Nitromethane in the Presence of (R,R)-1.
In conclusion, a highly diastereoselective Henry reaction
of a-substituted aldehydes and nitromethane was demon-
strated utilizing the guanidine–thiourea bifunctional orga-
nocatalyst 1. The differences of diastereoselectivity of a-
substituted aldehydes 2 with (R,R)- and (S,S)-1 can be
consistently explained in terms of the previously proposed
transition state for the asymmetric Henry reaction. Further
applications of the guanidine–thiourea bifunctional cata-
lyst 1 to a variety of reactions are in progress.
To a mixture of (R,R)-1 (8.4 mg, 0.0073 mmol), KI (6.0 mg,
0.037 mmol), 2a (24.0 mg, 0.073 mmol) and nitromethane
(392 mL, 0.73 mmol) in toluene (0.7 mL) was added 8 mM
aq KOH (0.7 mL) at 0 °C. The resulting mixture was stirred
vigorously at 0 °C for 24 h. Then, sat. aq NH4Cl was added,
and the organic layer was extracted with EtOAc. The
extracts were dried over MgSO4, filtered and concentrated in
vacuo, and the residue was purified by column
chromatography on silica gel (hexane–EtOAc = 20:1, 10:1,
5:1, 1:0) to give 3a (21.1 mg, 75%) and (R,R)-1 (8.3 mg,
99% recovery). The relative stereochemistry and
Acknowledgment
We thank Dr. Yukihiro Misumi for helpful discussions. This re-
search was supported by Nagase Science and Technology Founda-
tion. Y.S. is grateful for a JSPS Research Fellowship for Young
Scientists.
diastereoselectivity of 3a (95:5) were determined based on
the 1H NMR spectra reported by Corey et al.5 The
enantiomeric excess of 3a (99% ee) was determined by
means of chiral HPLC analysis. [CHIRALCEL OJ-H, 0.46
cm (∅) × 25 cm (L), n-hexane–ethanol = 90:10, 1.0 mL/min,
minor: 28.8 min, major: 31.3 min].
References and Notes
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NOE
NO2
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OH
H
O
1) HF, MeCN, r.t.
H
Ph
NO2
Ph
O
2) acetone dimethyl acetal
PTS, CH2Cl2, r.t.
3i
OTBS
Me
5i
Me
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Scheme 1
Synlett 2006, No. 1, 144–146 © Thieme Stuttgart · New York