Diphenylprolinol silyl ether as a catalyst in an enantioselective, catalytic, tandem Michael/Henry reaction for the control of four stereocenters

Article abstract of DOI:10.1002/anie.200700909

(Chemical Equation Presented) A choice of three: The tandem Michael/ Henry reaction of a nitroalkene and pentane-1,5-dial (generated in situ) proceeded efficiently when diphenylprolinol silyl ether was used as an organocatalyst to afford substituted nitrocyclohexanecarbaldehydes with high diastereo- and enantioselectivity (see scheme; TMS: trimethylsilyl). Isomerization under basic or acidic conditions diastereoselectively converts the product into two stereoisomers, without compromising the enantioselectivity.

Full text of DOI:10.1002/anie.200700909

Communications
DOI: 10.1002/anie.200700909
Tandem Reactions
Diphenylprolinol Silyl Ether as a Catalyst in an Enantioselective,
Catalytic, Tandem Michael/Henry Reaction for the Control of Four
Stereocenters**
Yujiro Hayashi,* Tsubasa Okano, Seiji Aratake, and Damien Hazelard
The formation of carbon–carbon bonds with the control of
multiple stereocenters in a single operation is not only a
synthetic challenge but also a useful method for the con-
struction of complex molecules. Tandem reactions are a very
powerful example of a methodology used to achieve these
aims.[1] Substituted chiral cyclohexanes are important building
blocks in organic synthesis,and the control of the relative and
absolute configurations is a key issue in the preparation of
these versatile frameworks. The Diels–Alder cycloaddition is
one widely employed method for the catalytic enantioselec-
tive synthesis of cyclohexane derivatives,most often catalyzed
by either a chiral Lewis acid[2] or one of the recently
developed chiral organocatalysts.[3]
dehydes with excellent diastereo- and enantioselectivities and
control of four stereogenic centers.
We anticipated that pentane-1,5-dial and a nitroalkene
would act as a four-carbon unit and a two-carbon unit,
respectively. That is,as shown in Scheme 1,we hypothesized
that enamine 2 would be generated from pentane-1,5-dial and
catalyst 1 and that it would react with a nitroalkene in a
Michael reaction to generate 3,in accordance with our
previous findings.[7a] Zwitterion 3 would then react with the
aldehyde moiety in an intramolecular Henry reaction to
provide 4,which would be hydrolyzed to provide substituted
nitrocyclohexanecarbaldehyde 5. The order of these last two
reactions might be reversed (that is,hydrolysis of iminium ion
3 followed by the Henry reaction might provide 5).
Many effective organocatalysts have been developed in
recent years,[4] and chiral cyclohexanes and cyclohexenes have
been synthesized by organocatalysts with high enantioselec-
tivity.[5] Diarylprolinol silyl ether,which was originally
developed by Jørgensenꢀs[5c,d,f,6] and our groups[7] independ-
ently,has recently been utilized in several enantioselective
reactions.[8] We have found that diphenylprolinol silyl ether is
an effective organocatalyst for the direct enantioselective
Michael reaction of aldehydes and nitroalkenes to afford the
Michael adduct with high syn selectivity and excellent
enantioselectivity.[7a] After our discovery,diphenylprolinol
methyl ether was found to promote the enantioselective
Michael reaction of aldehydes and methyl vinyl ketone,[8a] and
Enders and co-workers expanded our reaction to a triple
cascade reaction for the synthesis of chiral cyclohexenecar-
baldehydes with control of four stereocenters in one oper-
ation.[5e] Just recently,Jørgensen and co-workers also
reported a triple cascade reaction involving diarylprolinol
silyl ether.[5f] As a further application of this organocatalyst in
asymmetric reactions,we have developed a highly enantiose-
lective tandem Michael[9]/Henry[10] reaction,which affords,in
a single operation,substituted chiral nitrocyclohexanecarbal-
It would be convenient if commercially available aqueous
2,5-dihydroxy-3,4-dihydrofuran solution[11] could be used as a
surrogate for pentane-1,5-dial. Pentane-1,5-dial would be
generated from 2,5-dihydroxy-3,4-dihydrofuran in aqueous
solution under equilibrium conditions,and it is known that
organocatalyst-mediated aldol[12,13] and Michael reactions[14]
can proceed in aqueous conditions or in the presence of
water.[15] This reaction would generate,in one operation,four
stereogenic centers with the formation of two carbon–carbon
bonds,and control of the relative and absolute configurations
would therefore be an important issue.
We chose nitrostyrene as our model nitroalkene. We first
used water as the solvent,but the reaction scarcely proceeded
because the solid nitrostyrene did not dissolve. Next,the use
of organic solvents such as CH2Cl2,toluene, N,N-dimethyl-
formamide (DMF),hexane,and tetrahydrofuran (THF) was
investigated,under which conditions compounds 5a–d could
be isolated (Table 1). Both the yield and the diastereomer
ratio were dependent on the solvent. After some experimen-
tation,it was found that 5a was obtained in good yield with
high diastereoselectivity and excellent enantioselectivity
when THF was used as the solvent. That is,after stirring of
the reaction mixture comprising nitrostyrene with 2,5-dihy-
droxy-3,4-dihydrofuran solution (50% in water) in THF in
the presence of catalyst 1 (10 mol%) for 17 h, 5a was
obtained in 66% yield and nearly optically pure (99% ee),
along with the other diastereomers (5b–d),also with excellent
enantioselectivities (Table 1,entry 6). As the generation of 5b
was not indicated in the 1H NMR spectrum of the crude
reaction mixture, 5b was thought to be formed by isomer-
ization during column chromatography (see below). It should
be noted that a large-scale experiment was possible and the
loading of catalyst 1 can be reduced to 2 mol%; in this
[*] Prof. Dr. Y. Hayashi, T. Okano, S. Aratake, Dr. D. Hazelard
Department of Industrial Chemistry
Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162–8601 (Japan)
Fax: (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Homepage: http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
[**] This work was partially supported by the Toray Science Foundation
and a Grand-in-Aid for Scientific Research from MEXT.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Scheme 1. The reaction mechanism. TMS: trimethylsilyl.
Table 1: The effect of solvent in the Michael/Henry reaction.[a]
ents on the aryl moiety (Table 2,entries 1–7). Not only
aromatic groups but also heteroaromatic groups,such as furan
and indole,could be successfully employed as the 2-substitu-
tent of the nitroethene to afford the respective cyclohexane
derivatives with excellent enantioselectivity (Table 2,
entries 8 and 9). Furthermore,4-phenyl-1-nitro-1,3-butadiene
or a nitroalkene substituted with an alkyl group such as a
cyclohexyl moiety can also act as effective two-carbon units in
this reaction (Table 2,entries 10 and 11).
The major product obtained, 5a (5a/5b 13:1, 5a: 99% ee),
was isomerized by thin-layer chromatography (TLC),[16] to
afford 5b in 93% yield with 96% ee; the formyl group in 5b
has been isomerized from the axial to equatorial position
under the weak acidic conditions of the silica gel. When 5a
was treated with a catalytic amount of 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) in MeOH, 5a was isomerized to 5c
in 80% yield with 95% ee. In 5c,not only the formyl group
but also the hydroxy group has been isomerized into the
equatorial position while the same excellent enantioselectiv-
ity is maintained. Deprotonation and protonation,as well as
retro-Henry and Henry reactions,proceed under these basic
conditions. DBU also isomerizes 5b into 5c in 83% yield with
96% ee. Thus,synthesis can be directed to give selectively any
one of three (5a–c) out of the eight (23 = 8) possible different
substituted nitrocyclohexanecarbaldehydes through the
tandem Michael/Henry reaction followed by the proper
isomerization conditions (Scheme 2).
Entry Solvent t [h] Yield [%][b] 5a/5b/5c/5d[c] ee value of 5a [%][d]
1
2
3
4
CH2Cl2
toluene
DMF
6
8
64
58
63:24:4:9
64:24:6:6
70:17:6:7
58:33:6:3
80:9:5:6
75:8:8:9
73:8:7:12
99
99
99
96
10 90
hexane 15 64
5
THF
THF
THF
13 81
17 88
22 92
99
6[e]
7[i]
99 (94,[f] 99,[g] 87[h])
99
[a] Unless otherwise noted, the reaction was performed by employing b-
nitrostyrene (0.27 mmol), 2,5-dihydroxy-3,4-dihydrofuran (50% in solu-
tion, 147 mL, 0.81 mmol), and organocatalyst 1 (0.054 mmol) in the
indicated solvent (0.54 mL) at room temperature. [b] Yield of an isolated
mixture of 5a–d. [c] Determined by 1H NMR spectroscopy. [d] Deter-
mined by HPLC analysis on a chiral phase. [e] Catalyst 1 was employed at
a concentration of 10 mol%. [f] ee value of 5b. [g] ee value of 5c. [h] ee
value of 5d. [i] Conditions: Nitrostyrene (36.7 mmol), 2,5-dihydroxy-3,4-
dihydrofuran (13.3 mL), catalyst
(36.7 mL).
1 (2 mol%, 238.7 mg) and THF
experiment, 5a was obtained in 67% yield with 99% ee
(Table 1,entry 7).
While the relative configuration was determined from
As excellent conditions had been discovered,the general-
ity of the reaction was investigated by using several nitro-
alkenes. The results,recorded in the presence of 10 mol% of
catalyst 1,are summarized in Table 2. The reaction is fast with
electron-deficient aryl-substituted nitroethenes,while it is
slow with electron-rich,aryl-substituted ones. Excellent
enantioselectivities were obtained regardless of the substitu-
1H NMR coupling constants,the absolute configuration of 7c,
with
a p-bromophenyl group,was determined by the
advanced Mosherꢀs a-methoxy-a-trifluoromethylphenylace-
tic acid (MTPA) method.[17]
In summary,we have developed a highly diastereo- and
enantioselective tandem Michael/Henry reaction that is
catalyzed by readily available diphenylprolinol silyl ether
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Communications
Table 2: Catalytic asymmetric tandem Michael/Henry reactions cata-
lyzed by diphenylprolinol silyl ether 1.[a]
Entry
1
Product
t [h]
Yield [%][b]
66
ee [%][c]
17
99
2
3
3.5
4
71
64
97
99
Scheme 2. Isomerization from 5a to 5b and 5c.
conditions can diastereoselectively convert the tandem prod-
uct into a different stereoisomer in each case,without
compromising the enantioselectivity. The cyclohexane deriv-
ative obtained is a useful chiral synthetic intermediate that
possesses several functional groups.
4
5
6
7
8
5
6
56
66
60
63
68
99
99
98
99
99
Experimental Section
Typical procedure for the synthesis of 5 (Table 2,Entry 1): 1 (8.8 mg,
0.027 mmol) was added to a mixture of 1-phenyl-2-nitroethylene
(40.3 mg, 0.27 mmol) and 2,5-dihydroxy-3,4-dihydrofuran solution
(50% in water,147 mL,0.81 mmol) in THF (0.54 mL) at room
temperature. After the reaction mixture had been stirred for 17 h at
this temperature,the reaction was quenched by addition of 1 n
hydrochloric acid and the organic materials were extracted twice
with ethyl acetate. The combined organic extracts were washed five
20
21
20
times with brine,dried over anhydrous Na SO4,and concentrated in
2
vacuo after filtration. Purification by neutral silica gel column
chromatography (hexane/AcOEt 2:1) gave 4-hydroxy-3-nitro-2-phe-
nylcyclohexanecarbaldehyde (50.6 mg,0.20 mmol) in 88% yield as a
diastereomeric mixture (5a/5b/5c/5d 75:8:8:9). The enantiomeric
excess was determined by HPLC with a Chiralpak IA column
(hexane/2-propanol 25:1; flow rate: 1.0 mLminÀ1; minor enantiomer
tr = 46.9 min,major enantiomer tr = 57.8 min).
9
15
58
98
Received: February 28,2007
Published online: May 22,2007
Keywords: domino reactions · Henry reactions ·
Michael reactions · organocatalysis · tandem reactions
.
10
10
24
55
45
98
99
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