Diastereoselective and enantioselective Henry (nitroaldol) reaction utilizing a guanidine-thiourea bifunctional organocatalyst

Article abstract of DOI:10.1002/ejoc.200600307

A highly enantio- and diastereoselective Henry reaction of various aldehydes with nitroethane was developed using the guanidine-thiourea bifunctional catalyst 1 (syn selectivity of 86:14 to 99:1 with 84-99% ee). A variety of nitroalkanes was treated with

Full text of DOI:10.1002/ejoc.200600307

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600307
Diastereoselective and Enantioselective Henry (Nitroaldol) Reaction Utilizing a
Guanidine-Thiourea Bifunctional Organocatalyst
Yoshihiro Sohtome,[a] Yuichi Hashimoto,[a] and Kazuo Nagasawa*[b]
Keywords: Organocatalysis / Bifunctional catalyst / Guanidine / Thiourea / Henry reaction
A highly enantio- and diastereoselective Henry reaction of
various aldehydes with nitroethane was developed using the
guanidine-thiourea bifunctional catalyst 1 (syn selectivity of
86:14 to 99:1 with 84–99% ee). A variety of nitroalkanes was
treated with unbranched and branched aldehydes and gave
nitro alcohols with high syn diastereoselectivities (90:10 to
99:1) and high enantioselectivities (85–95% ee). This reac-
tion was successfully utilized in a straightforward synthesis
of (4S,5R)-epi-cytoxazone.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
The Henry (nitroaldol) reaction is an important carbon– aldehyde coordinate to the guanidine and thiourea groups[7]
carbon bond-forming reaction which affords valuable syn- in 1, respectively, and the Henry reaction proceeds via the
thetic intermediates.[1] Much effort has been made to de- anti-conformational transition state I rather than the gauche
velop an asymmetric version of this reaction,[2] using pro- conformation II (Figure 2). Therefore, nitro alcohol ad-
chiral aldehydes and nitromethane in the presence of a chi- ducts with (R) configuration were obtained as the major
ral metal catalyst[3] or organocatalyst.[4] Nevertheless, only isomer when (S,S)-1 was used. In the case of the Henry
one report has appeared on highly diastereo- and enantiose- reaction with prochiral nitroalkanes (R2 = alkyl groups etc.,
lective catalytic Henry reactions of nitroalkanes and prochi- Figure 2), the anti conformation of the R2 group with re-
ral aldehydes by Shibasaki et al., utilizing LLB (La-lithium- spect to the carbonyl group of the aldehyde is also consid-
BINOL) catalyst.[5] As part of our program to develop gua- ered to be more favorable (conformation I) than the gauche
nidine-containing organocatalysts,[6] we recently reported conformation III, and the diastereo- and enantioselectivit-
on the guanidine-thiourea bifunctional organocatalyst 1 ies of the nitro alcohol adducts are expected to be well con-
that efficiently catalyzes the Henry reaction with high trolled, if the reaction proceeds via a transition state similar
enantioselectivity.[6d] Here, we describe the first example of to that in the reaction with nitromethane (3a). On the basis
the organocatalyst 1 catalyzing the Henry reaction with of these speculations, the diastereo- and enantioselective
high diastereo- and enantioselectivity. (Figure 1).
Henry reaction with the bifunctional organocatalyst 1 was
further explored.
First, the Henry reaction was examined with 3-phenyl-
propionaldehyde (2a) and nitroethane (3b) in the presence
of (S,S)-1. After optimization of the reaction conditions,[8]
the syn-nitro alcohol product (R,R)-4a[9] was obtained with
high diastereo- and enantioselectivity (syn/anti = 90:10,
83% ee) in 76% yield, by using toluene/aqueous potassium
hydroxide (10 mol-%)[10] in the presence of 10 mol-% of cat-
alyst (S,S)-1 at 0 °C for 48 h (Scheme 1).
The newly generated stereochemistry of the nitro alcohol
4a, i.e. (R,R) configuration, is consistent with the proposed
reaction transition state (Figure 2, conformation I). Since
the ee value of 4a is much higher than in the case of the
Henry reaction with nitromethane (3a) and 2a (55% ee),[6d]
the transition state of the reaction with nitroethane (3b) is
considered to be strictly controlled by the methyl group
(corresponding to the R2 group in Figure 2).
Figure 1. Structure of guanidine-thiourea bifunctional catalyst 1.
In the Henry reaction of nitromethane (3a) (R2 = H, Fig-
ure 2) and prochiral aldehydes in the presence of the guani-
dine-thiourea bifunctional catalyst 1, nitromethane and the
[a] Institute of Molecular and Cellular Biosciences, The University
of Tokyo,
Bunkyo-ku, Tokyo 113-0032, Japan
[b] Department of Biotechnology and Life Science, Faculty of
Technology, Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan
Fax: +81-042-388-7295
E-mail: knaga@cc.tuat.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Using the optimized conditions in Scheme 1, the reac-
tions with various aldehydes and nitroethane (3b) were ex-
amined (Table 1). Unbranched aliphatic butyraldehyde (2b)
2894
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2894–2897

Diastereoselective and Enantioselective Henry (Nitroaldol) Reaction
SHORT COMMUNICATION
Table 1. Enantio- and syn-selective Henry reaction of aldehydes 2b–
h with nitroethane (3b) in the presence of 1.
[a] Diastereoselectivities were determined by 1H NMR spec-
troscopy. The relative stereochemistry was determined from the 1H
NMR chemical shifts. [b] The enantiomeric excess was determined
by HPLC using a chiral column. [c] In all cases, the enantiomeric
excess of anti adducts was low (10–30% ee).
Figure 2. Transition state of the Henry reaction catalyzed by (S,S)-
1. Conformation I: anti conformation (nitro group and R1 are in
an anti relationship, carbonyl group and R2 are anti); conformation
II: gauche conformation; conformation III: gauche conformation
(R2 and carbonyl group, and R2 and R1 are in gauche relation-
ships).
Table 2. Enantio- and syn-selective Henry reaction of 2b or 2e with
nitroalkanes 3c–3f in the presence of 1.
Scheme 1. Henry reaction of 2a with nitroethane (3b) catalyzed by
(S,S)-1.
[a] Diastereoselectivities were determined by 1H NMR spec-
troscopy. The relative stereochemistry was determined from the 1H
NMR chemical shifts. [b] The enantiomeric excess was determined
by HPLC using a chiral column. [c] In all cases, the enantiomeric
excess of anti adducts was low. [d] 10 equiv. of 3c was used.
gave 4b with similar enantio- and syn selectivity to 2a (En-
try 1). In the case of the aliphatic α-branched-chain and
cyclic aldehydes, the corresponding Henry adducts (R,R)-
4c–e were obtained with high syn selectivity and high enan-
tiomeric excess (Entries 2–4, 97:3 to 99:1, 90–93% ee). β-
Substituted aliphatic aldehydes 2f and α- and β-heteroatom-
substituted aldehydes 2g and 2h also served as substrates
and gave the nitro alcohols 4f–h with high selectivity (En-
tries 5–7, 86:14 to 93:7, 92–99% ee).[11]
Other nitroalkanes 3c–3f were treated with unbranched
and cyclic-aliphatic aldehydes 2b and 2e (Table 2). In most
instances, high syn selectivity and enantioselectivity were
observed, with ratios of 90:10 to 99:1 (syn/anti) and 85–
95% ee.
Reduction of 4q with NiCl2/NaBH4,[14] followed by cycliza-
tion with N,NЈ-carbonyldiimidazole (CDI), and subsequent
deprotection of the TBS group with HF gave 5 in 43% yield
(3 steps).
The success of the syn-selective enantioselective nitroal-
dol reaction led to a practical synthesis of (4S,5R)-epi-
cytoxazone (5), a type-2 cytokine selective inhibitor[12]
(Scheme 2). Nitroaldol reaction of 2g with 3g[13] (3 equiv.)
in the presence of (R,R)-1 gave the nitro alcohol (4S,5R)-4q
Scheme 2. Synthesis of (4S,5R)-epi-cytoxazone (5): a) 2g, (R,R)-1,
KOH, KI, toluene/H2O, 0 °C, 76%; b) (1) NiCl2, NaBH4, MeOH,
with high syn selectivity (90:10) and 95% ee in 76% yield. 0 °C, (2) CDI, CH3CN, 80 °C, (3) HF, CH3CN, 0 °C, 43% (3 steps).
Eur. J. Org. Chem. 2006, 2894–2897
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2895

Y. Sohtome, Yu. Hashimoto, K. Nagasawa
SHORT COMMUNICATION
b) M. T. Allingham, A. Howard-Jones, P. J. Murphy, D. A.
Thomas, P. W. R. Caulkett, Tetrahedron Lett. 2003, 44, 8677;
c) T. Ooi, K. Doda, K. Maruoka, J. Am. Chem. Soc. 2003, 125,
2054; d) H. Li, B. Wang, L. Deng, J. Am. Chem. Soc. 2006,
128, 732; e) T. Marcelli, R. N. S. van der Haas, J. H. van Maar-
seveen, H. Hiemstra, Angew. Chem. Int. Ed. 2006, 45, 929; dia-
stereoselective Henry reaction with chiral aldehydes, see; f) D.
Ma, Q. Pan, F. Han, Tetrahedron Lett. 2002, 43, 9401; g) E. J.
Corey, F.-Y. Zhang, Angew. Chem. Int. Ed. 1999, 38, 1931; Aza-
Henry reaction, see: h) B. M. Nugent, R. A. Yoder, J. N. John-
ston, J. Am. Chem. Soc. 2004, 126, 3418; i) T. Okino, S. Naka-
mura, T. Furukawa, Y. Takemoto, Org. Lett. 2004, 6, 625; j) X.
Xu, T. Furukawa, T. Okino, H. Miyabe, Y. Takemoto, Chem.
Eur. J. 2006, 12, 466; k) T. P. Yoon, E. N. Jacobsen, Angew.
Chem. Int. Ed. 2005, 44, 466; l) F. Fini, V. Sgarzani, D. Pet-
tersen, R. P. Herrera, L. Bernardi, A. Ricci, Angew. Chem. Int.
Ed. 2005, 44, 7975; m) C. Palomo, M. Oiarbide, A. Laso, R.
Lopez, J. Am. Chem. Soc. 2005, 127, 17622; n) L. Bernardi, F.
Fini, R. P. Herrera, A. Ricci, V. Sgarzani, Tetrahedron 2006,
62, 375.
In conclusion, highly enantio- and syn-selective Henry
reactions have been achieved by using the guanidine-thio-
urea bifunctional organocatalyst 1 under mild biphasic re-
action conditions. This reaction is applicable to a variety of
aldehydes and nitroalkanes, and was successfully utilized in
a straightforward synthesis of (4S,5R)-epi-cytoxazone (5).
Experimental Section
Typical Procedure for Enantioselective and syn-Selective Henry Re-
action of 2e with 3b: To
a mixture of (S,S)-1e (12.9 mg,
0.0112 mmol), KI (9.3 mg, 0.0558 mmol) and nitroethane (3b)
(80.1 µL, 1.12 mmol) in toluene (1.12 mL)/8 m KOH(aq)
(1.12 mL) was added cyclohexanecarboxaldehyde (2e) (13.4 µL,
0.112 mmol) at 0 °C. The resulting mixture was stirred vigorously
at 0 °C for 24 h. Then saturated NH4Cl(aq) was added, and the
organic layer was extracted with ethyl acetate. The extracts were
dried with MgSO4, filtered, and concentrated in vacuo, and the
residue was purified by column chromatography on silica gel (n-
hexane/ethyl acetate, 20:1, 10:1, and chloroform/methanol, 9:1) to
give 4e (16.0 mg, 77%); 1e was recovered (12.8 mg, 99%). Relative
stereochemistry and diastereoselectivity (syn/anti = 99:1) of 4e were
determined based upon the reported 1H NMR data.[15] [α]2D6 = –6.7
[5]
[6]
H. Sasai, T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh, M.
Shibasaki, J. Org. Chem. 1995, 60, 7388.
a) K. Nagasawa, A. Georgieva, H. Takahashi, T. Nakata, Tet-
rahedron 2000, 56, 187; b) K. Nagasawa, A. Georgieva, H. Tak-
ahashi, T. Nakata, Tetrahedron 2001, 57, 8959; c) T. Kita, A.
Georgieva, Y. Hashimoto, T. Nakata, K. Nagasawa, Angew.
Chem. Int. Ed. 2002, 41, 2832; d) Y. Sohtome, Y. Hasimoto, K.
Nagasawa, Adv. Synth. Catal. 2005, 347, 1643; diastereoselec-
tive Henry reaction using 1, see: e) Y. Sohtome, N. Takemura,
T. Iguchi, Y. Hashimoto, K. Nagasawa, Synlett 2006, 144.
Reviews, see: a) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289;
b) P. M. Pihko, Angew. Chem. Int. Ed. 2004, 43, 2062; asym-
metric reaction using Jacobsen’s catalyst, see: c) Y. Takemoto,
Org. Biomol. Chem. 2005, 3, 4299; d) M. S. Taylor, E. N. Ja-
cobsen, Angew. Chem. Int. Ed. 2006, 45, 1520; e) D. E. Fuerst,
E. N. Jacobsen, J. Am. Chem. Soc. 2005, 127, 8964, and refer-
ences cited therein; Takemoto’s bifunctional catalyst, see: f) Y.
Hoashi, T. Okino, Y. Takemoto, Angew. Chem. Int. Ed. 2005,
44, 4032, and references cited therein; bis-thiourea-type cata-
lyst, see: g) Y. Sohtome, A. Tanatani, Y. Hashimoto, K. Nagas-
awa, Tetrahedron Lett. 2004, 45, 5589; other catalysts, see: h)
Y. Sohtome, A. Tanatani, Y. Hashimoto, K. Nagasawa, Chem.
Pharm. Bull. 2004, 52, 477; i) B. Vakulya, S. Varga, A. Csam-
pai, T. Soos, Org. Lett. 2005, 7, 1967; j) R. P. Herrera, V. Sgarz-
ani, L. Bernardi, A. Ricci, Angew. Chem. Int. Ed. 2005, 44,
6576.
(c = 0.52, CHCl ). IR (neat): ν = 2925, 2852, 1552, 1450, 1391 cm–1.
˜
3
1H NMR (400 MHz, CDCl3): δ = 4.72 (dq, J = 6.8, 6.8 Hz, 1 H),
3.65 (dd, J = 6.8, 4.9 Hz, 1 H), 2.13 (br. s, 1 H), 1.78–1.65 (m, 4
H), 1.53 (d, J = 6.7 Hz, 3 H), 1.48–0.94 (m, 7 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 85.5, 77.2, 39.9, 30.0, 26.3, 26.2, 26.1, 25.9,
16.6 ppm. The enantiomeric excess of 4e (93% ee) was determined
by means of chiral HPLC analysis [CHIRALPAC AD-H; 0.46 cm
(diameter)×25 cm (length); n-hexane/2-propanol, 97:3; 1.0 mL/
min; minor: 16.8 min, major: 25.3 min].
[7]
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data for 4a–d and 4f–4p, and synthesis of 5.
Acknowledgments
This research was supported by the Nagase Science and Technol-
ogy Foundation. Y. S. is grateful for a JSPS Research Fellowship
for Young Scientists. We thank Dr. Sakamoto (RIKEN) for kindly
providing the spectra of synthetic (4S,5R)-epi-cytoxazone (5).
As in the Henry reaction of nitromethane (3b);[6d] potassium
iodide was effective to improve the enantiomeric excess of the
nitro alcohol adduct 4a.
[8]
[9]
Relative stereochemistry and absolute stereochemistry of 4a
[1] L. Henry, C. R. Hebd. Seances Acad. Sci. 1895, 120, 1265.
[2] For recent reviews, see: a) C. Palomo, M. Oiarbide, A. Mielgo,
Angew. Chem. Int. Ed. 2004, 43, 5442; b) F. A. Luzio, Tetrahe-
dron 2001, 57, 915; c) N. Ono, The Nitro Group in Organic
Synthesis, Wiley-VCH, New York, 2001; d) M. Shibasaki, H.
Gröger, in Comprehensive Asymmetric Catalysis, vol. III (Eds.:
E. N. Jacobsen, A. Pfaltz, H, Yamamoto), Springer, Berlin,
1999, pp. 1075–1090; e) M. Shibasaki, H. Gröger, M. Kanai,
in Comprehensive Asymmetric Catalysis, suppl. 1 (Eds.: E. N.
Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg,
2004, pp. 131–133..
[3] a) H. Sasai, T. Suzuki, S. Arai, T. Arai, M. Shibasaki, J. Am.
Chem. Soc. 1992, 114, 4418; b) B. M. Trost, V. S. C. Yeh, An-
gew. Chem. Int. Ed. 2002, 41, 861; c) D. A. Evans, D. Seidel,
M. Rueping, H. W. Lam, J. T. Shaw, C. W. Downey, J. Am.
Chem. Soc. 2003, 125, 12692; d) C. Christensen, K. Juhl, R. G.
Hazell, K. A. Jorgensen, J. Org. Chem. 2002, 67, 4875; e) C.
Palomo, M. Oiarbide, A. Laso, Angew. Chem. Int. Ed. 2005,
44, 3811.
1
were determined based upon the reported H NMR chemical
shift and [α]D value.[5]
[10]
[11]
The concentration of potassium hydroxide strongly influences
the enantioselectivities of the nitro alcohols 4.
In the case of benzaldehyde, diastereo- and enantioselectivity
were low (dr = 63:37, 16% and 0% ee, respectively). Applica-
tion of alternative catalysts to aromatic aldehydes is under in-
vestigation.
Isolation and structure determination of (4R,5R)-cytoxazone,
see: a) H. Kakeya, M. Morishita, K. Kobinata, M. Osono, M.
Ishizuka, H. Osada, J. Antibiot. 1998, 51, 1126; b) H. Kakeya,
M. Morishita, H. Koshino, T. Morita, K. Kobayashi, H. Os-
ada, J. Org. Chem. 1999, 64, 1052; first synthesis and recent
synthesis of (4R,5R)-cytoxazone and/or 5, see: c) Y. Sakamoto,
A. Shiraishi, J. Seonhee, T. Nakata, Tetrahedron Lett. 1999, 40,
4203; d) Z. Tokic-Vujosevic, G. Petrovic, B. Rakic, R. Matovic,
R. N. Saicic, Synth. Commun. 2005, 35, 435; e) S. Tosaki, R.
Tsuji, T. Ohshima, M. Shibasaki, J. Am. Chem. Soc. 2005, 127,
2147; f) N. R. Swamy, P. Krishnaiah, N. S. Reddy, Y. Venkates-
warlu, J. Carbohydr. Chem. 2004, 23, 217; g) S. Milicevic, R.
[12]
[4] Enantioselective Henry reaction, see: a) R. Chinchilla, C. Na-
jera, P. Sanchez-Agullo, Tetrahedron: Asymmetry 1994, 5, 1393;
2896
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2894–2897

Diastereoselective and Enantioselective Henry (Nitroaldol) Reaction
SHORT COMMUNICATION
Matovic, R. N. Saicic, Tetrahedron Lett. 2004, 45, 955; h) P. H.
Carter, J. R. LaPorte, P. A. Scherle, C. P. Decicco, Bioorg. Med.
Chem. Lett. 2003, 13, 1237; other synthetic studies of (4R,5R)-
cytoxazone are cited in ref.[12g]
[14] A. Nose, T. Kudo, Chem. Pharm. Bull. 1981, 29, 1159.
[15] S. E. Denmark, B. S. Kesler, Y.-C. Moon, J. Org. Chem. 1992,
57, 4912.
Received: April 8, 2006
Published Online: May 8, 2006
[13] R. Ballini, L. Barboni, G. Giarlo, J. Org. Chem. 2004, 69, 6907.
Eur. J. Org. Chem. 2006, 2894–2897
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2897