Bifunctional-thiourea-catalyzed diastereo- And enantioselective Aza-Henry reaction

Article abstract of DOI:10.1002/chem.200500735

Bifunctional thiourea 1a catalyzes aza-Henry reaction of nitroalkanes with N-Boc-imines to give syn-β-nitroamines with good to high diastereo- and enantioselectivity. Apart from the catalyst, the reaction requires no additional reagents such as a Lewis acid or a Lewis base. The N-protecting groups of the imines have a determining effect on the chirality of the prod ucts, that is, the reaction of N-Bocimines gives R adducts as major products, whereas the same reaction of N-phosphonoylimines furnishes the corresponding S adducts. Various types of nitroalkanes bearing aryl, alcohol, ether, and ester groups can be used as nucleophiles, providing access to a wide range of useful chiral building blocks in good yield and high enantiomeric excess. Synthetic versatility of the addition products is demonstrated by the transformation to chiral piperidine derivatives such as CP-99,994.

Full text of DOI:10.1002/chem.200500735

DOI: 10.1002/chem.200500735
Bifunctional-Thiourea-CatalyzedDiastereo- andEnantioselective
Aza-Henry Reaction
Xuenong Xu, Tomihiro Furukawa, Tomotaka Okino, Hideto Miyabe, and
Yoshiji Takemoto*[a]
In memoriam Professor Kiyoshi Tanaka
Abstract: Bifunctional thiourea 1a cat-
alyzes aza-Henry reaction of nitroal-
kanes with N-Boc-imines to give syn-b-
nitroamines with good to high diaster-
eo- and enantioselectivity. Apart from
the catalyst, the reaction requires no
additional reagents such as a Lewis
acid or a Lewis base. The N-protecting
groups of the imines have a determin-
ing effect on the chirality of the prod-
ucts, that is, the reaction of N-Boc-
imines gives R adducts as major prod-
ucts, whereas the same reaction of N-
phosphonoylimines furnishes the corre-
sponding S adducts. Various types of
nitroalkanes bearing aryl, alcohol,
ether, and ester groups can be used as
nucleophiles, providing access to
a
wide range of useful chiral building
blocks in good yield and high enantio-
meric excess. Synthetic versatility of
the addition products is demonstrated
by the transformation to chiral piperi-
dine derivatives such as CP-99,994.
Keywords: asymmetric catalysis
·
ꢀ
C C Coupling · enantioselectivty ·
nitroamines · nucleophilic addition
Introduction
development of catalytic asymmetric aza-Henry reaction
over the past several years.[6–10] As a result, two groups ach-
ieved initial breakthroughs in this field. Shibasaki et al. re-
ported that heterobimetallic complexes with lanthanide
BINOL (2,2’-dihydroxy-1,1’-binaphthyl) systems promoted
the aza-Henry reaction of N-phosphinoylimines with nitro-
methane to give b-nitroamines with high enantioselectivity.[6]
Jørgensen et al. also developed a catalytic asymmetric ver-
sion of this reaction with (N-p-methoxybenzyl)-a-imino
esters and bis-oxazoline copper(ii) complexes.[7] Recently,
we[8] and Johnston et al.[9] independently reported enantiose-
lective aza-Henry reactions with different organocatalysts.
However, each reaction is limited to a few substrates or
moderate enantioselectivity. To improve the enantioselectiv-
ity of the aza-Henry adducts, we continued studies focusing
on the effects of N-substituents of imines. During that time,
Jacobsen et al. discovered that aza-Henry reaction catalyzed
by a combination of chiral thiourea (10 mol%) and tertiary
amine (100 mol%) proceeded with high enantio- and dia-
stereoselectivity to provide syn-b-nitroamines as major
products with up to 97% ee.[10] Here we present the reaction
of N-Boc imines with various nitroalkanes in the presence
of bifunctional thiourea catalyst 1a,[11] which proceeded effi-
ciently without any external amine to give the desired ad-
ducts with high diastereo- and enantioselectivity (Scheme 1).
In addition, successful transformation of the obtained prod-
The development of stereoselective carbon–carbon bond-
forming reactions that create contiguous stereogenic centers
bearing heteroatom functionality can provide valuable
building blocks for organic synthesis. The aza-Henry (nitro-
Mannich) reaction, that is, nucleophilic addition of nitroal-
kanes to imines,[1] is a useful carbon–carbon bond-forming
process. The thus-obtained b-nitroamines can be trans-
formed into valuable compounds such as vicinal diamines
and a-amino acids by reduction[2] and Nef reaction[3] of the
nitro moiety (Scheme 1). The class of diamines is of particu-
lar interest owing to their broad utility as biologically active
natural products, drug candidates, and, more recently, chiral
ligands for asymmetric reactions.[4] Although a variety of
synthetic procedures have been devised to carry out the
Mannich reaction enantioselectively,[5] until quite recently
the enantioselective aza-Henry reaction was unknown.
Therefore, considerable effort has been directed toward the
[a] Dr. X. Xu, T. Furukawa, Dr. T. Okino, Prof. Dr. H. Miyabe,
Prof. Dr. Y. Takemoto
Graduate School of Pharmaceutical Sciences, Kyoto University
Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
Fax : (+81)75-753-4569
E-mail: takemoto@pharm.kyoto-u.ac.jp
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Chem. Eur. J. 2006, 12, 466 – 476

FULL PAPER
onstrate its utility, the obtained b-nitroamine 4 f (90% ee)
was treated with NiCl2 and NaBH4 in MeOH[2a] to give the
desired N-Boc-vic-diamine 5[12] in 95% yield with 89% ee
(Scheme 2). Furthermore, Nef reaction (NaNO2 and AcOH
Scheme 1. Top: Aza-Henry reaction and subsequent conversion of the re-
suling b-nitroamines into valuable compounds such as vicinal diamines.
Bottom: Chiral urea and amide catalysts 1a–d used in the reaction.
Scheme 2. Transformation of b-nitroamine 4 f into 5 and 6.
in DMSO)[3b] and subsequent methylation of 4 f gave a-phe-
nylglycine derivative 6[13] in 70% yield with 87% ee. The ab-
solute configuration of 4 f was unambiguously determined to
be R by comparison of its [a]D value with authentic data [5:
[a]2D5 =39.6 (c=1.10, CHCl3), lit.:[12] [a]2D5 =44 (c=1.1,
CHCl3); 6: [a]D22 =111 (87% ee, c=1.00, CHCl3), lit.:[13]
[a]D =132.3 (c=1.1, CHCl3)]. It is noteworthy that aza-
Henry reaction with N-phosphinoylimine 2b[6a] afforded the
corresponding antipode adduct (S)-4b[8] under the same re-
action conditions as with 2 f. These results indicate that the
substituents X on the nitrogen atom of imines 2a–f have a
determinant effect on the absolute configuration of the addi-
tion products and the enantiomeric excess. Furthermore, the
selectivity (ee) was improved by simply decreasing the reac-
tion temperature to ꢀ208C, whereby b-nitroamine 4 f was
obtained in 90% yield with 94% ee (Table 1, entry 7).
ucts into chiral piperidine derivatives such as CP-99,994 is
also described.
Results andDiscussion
Enantioselective aza-Henry reaction of nitromethane 3a
with aldimines 2a–f: We initially screened several imines
2a–f that had electron-withdrawing groups in the presence
of thiourea 1a (10 mol%) and nitromethane 3a (10 equiv)
in dichloromethane at room temperature (Table 1). Among
Table 1. Enantioselective aza-Henry reaction of imines 2a-f with nitro-
methane 3a.[a]
Having established the optimal reaction conditions of 4 f
with nitromethane 3a, we next examined the aza-Henry re-
action of other N-Boc imines 2A–H under the same reac-
tion conditions; representative results are shown in Table 2.
The reaction proceeded smoothly with imine 2A bearing an
electron-withdrawing group to give product 7A in 80%
yield with 98% ee (Table 2, entry 1). In the case of imines
Entry
2 (X)
Time [h]
Product
Yield [%][b]
ee [%][c]
1
2
3
4
2a (Ts)
2b (P(O)Ph2)
2c (Ac)
2d (CO2Me)
2e (CO2Bn)
2 f (Boc)
4.5
24
24
24
24
4a
4b
4c
4d
4e
4 f
4 f
99
87
95
64
68
76
90
4
67 (S)
63
83
85
90 (R)
94 (R)
5
6
24
24
7[d]
2 f (Boc)
Table 2. Thiourea-catalyzed enantioselective aza-Henry reaction of N-
Boc imines 2A–H with 3a.[a]
[a] The reaction was carried out with imines 2a–f and nitromethane (3a,
10 equiv) in CH2Cl2 at room temperature in the presence of
1
(10 mol%). [b] Yield of isolated product after chromatography. [c] Enan-
tiomeric excess was determined by HPLC analysis of 4a–f on a chiral
column. [d] The reaction was carried out at ꢀ208C.
Entry 2 (Ar)
Time [h] Product Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
2A (p-CF3C6H4)
2B (p-MeC6H4)
2C (p-MeOC6H4) 60
2D (1-naphthyl)
2E (2-naphthyl)
2F (2-furyl)
2G (3-pyridyl)
2H (2-thyenyl)
24
24
7A
7B
7C
7D
7E
7F
80
82
71
85
85
81
89
83
98
93
95
95
85
91
98
83
the imines examined, N-Boc imines 2 f gave the best results
in terms of chemical yield and enantiomeric excess (4 f:
76%, 90% ee), while the reactions with N-alkoxycarbonyl
imines 2d–f tended to provide the desired products with
good enantioselectivity compared with the other imines 2a–
c (Table 1, entries 1–6). From the standpoint of synthetic ad-
vantages of N-protecting groups in the following transforma-
tion, N-Boc imines would be the best choice as starting ma-
terial. To determine the absolute configuration and to dem-
24
48
60
24
24
7G
7H
[a] The reaction was carried out with imines 2A–H and nitromethane 3a
(10 equiv) in CH2Cl2 at ꢀ208C in the presence of 1 (10 mol%). [b] Yield
of isolated product after chromatography. [c] Enantiomeric excess was
determined by HPLC analysis of 7A–H on a chiral column.
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467

Y. Takemoto et al.
2B and 2C bearing an electron-donating group, the reaction
required a prolonged reaction time, but the corresponding
products 7B and 7C were obtained with 93 and 95% ee, re-
spectively (Table 2, entries 2 and 3). On the other hand, N-
Boc imines 2D–H bearing a naphthyl or heteroaromatic
ring provided the corresponding a-nitroamines 7D–H in
good yield, but the enantioselectivities of 7D–H were some-
what affected by the linked position of the naphthyl group
(85–95% ee, Table 2, entries 4 and 5) and the heteroatom of
the heteroaromatic rings (83–98% ee, Table 2, entries 6–8).
Although we have no reasonable explanation for these re-
sults at this stage, the various b-nitroamines 7 could be syn-
thesized in good yields with up to 98% ee by just using
10 mol% of bifunctional thiourea catalyst 1a without any
additional reagents such as a Lewis acid or a Lewis base.
moting the reaction; 2) Although thiourea catalysts without
a tertiary amino group have no catalytic activity, the urea
and thiourea moieties have crucial effects on the diastereo-
and enantioselectivity.
Once the optimal conditions were established, the scope
and limitations of the reaction with various nitroalkanes 3c–
k were examined. Table 3 shows representative results. In all
Table 3. Enantio- and diastereoselective aza-Henry reaction of N-Boc
imines 2 f, 2A, 2B, and 2G with prochiral nitroalkanes 3c–k.[a]
Entry
2
3 (R)
Product Yield [%][b] d.r. (8/
9)[c]
ee [%][d]
Enantioselective aza-Henry reaction of nitroalkanes 3b–k
withaldimines 2: Having succeeded in the development of
enantioselective aza-Henry reaction of nitromethane (3a)
with several N-Boc imines 2A–H, we next investigated
whether the same reaction of nitroalkanes 3b–k proceeded
in a diastereo- and enantioselective manner to provide syn-
or anti-b-nitroamine 8 or 9 as a major product. In the begin-
ning, the reaction of nitropropane 3b with N-Boc imine 2 f
was carried out under the same reaction conditions as that
of 3a (Scheme 3). Thiourea 1a efficiently prompted the re-
1
2
3
4
5
6
2 f 3c (CH3)
3d (C5H11)
3e(CH2Ph)
3 f (CH2OH)
3g (CH2OBn)
3h
8B
8C
8D
8E
8F
92
82
84
75
80
86
90/10
93/7
83/17
75/25
86/14
93/7
93
99
97
90
95
94
8G
[(CH2)2OBn]
3i
[(CH2)3OBn]
3j [(CH2)3OH] 8I
3k
7
8H
8 J
80
91/9
92
8
9
80
78
92/8
93/7
89
90
[(CH2)3OTf]
10
11
12
2A 3e (CH2Ph)
2B 3e (CH2Ph)
2G 3e (CH2Ph)
8K
8L
8M
94
90
93
97/3
93/7
83/17
95
92
93
[a] The reaction was carried out with N-Boc imines 2 and nitroalkanes
3c–k (2–10 equiv) in CH2Cl2 at ꢀ208C in the presence of 1 (10 mol%).
[b] Yield of isolated product after chromatography. [c] Diastereomeric
ratio was determined by 1H NMR and HPLC analysis. [d] Enantiomeric
excess of 8 was determined by HPLC analysis of 8B–M on a chiral
column.
Scheme 3. Aza-Henry reaction of nitropropane (3b) with catalysts 1a–d.
cases, the corresponding syn-b-nitroamines 8B–M were ob-
tained as major products in good yields with good diastereo-
and enantioselectivity (89–99% ee). The reactions of 2 f with
nitroalkanes 3c–e bearing different alkyl chains under the
same conditions gave the desired products 8B–D with high
enantioselectivities, while the diastereoselectivity somewhat
decreased for 3e (Table 3, entries 1–3). Functionalized nitro-
alkanes such as 3 f–k would be more promising nucleophiles
from the viewpoint of utility of these products as synthetic
intermediates. To synthesize 1,3-amino alcohols, 2-nitroethan-
ol 3 f was treated with imine 2 f in the presence of 1a, and
this provided the desired product 8E with good enantio-
selectivity, but with moderate diastereoselectivity (Table 3,
entry 4). However, using benzyl ether derivative 3g over-
came the problem and provided 8F with improved diaster-
eoselectivity (Table 3, entry 5). Similarly, high stereoselectiv-
ities (d.r. and ee) were consistently obtained in the reaction
of 2 f with several nitroalkanol derivatives 3h–k bearing a
longer carbon chain (Table 3, entries 6–9). It is also notewor-
thy that unlike 2-nitroethanol (3 f), 4-nitrobutanol 3j could
be employed in the aza-Henry reaction to yield the corre-
action to furnish a mixture of b-nitroamines 8A and 9A in
90% yield with good diastereoselectivity (syn-8A/anti-9A
88/12). In addition, the ee of the major product 8A was high
(95%). To clarify the effects of bifunctional thiourea 1a on
the diastereo- and enantioselectivity, we carried out the
same reaction with other catalysts 1b–d (Scheme 1). The
use of urea 1b[11] for the aza-Henry reaction gave syn-b-ni-
troamine 8A as a major product in a similar diastereomeric
ratio (d.r.=89/11) but with a somewhat lower enantioselec-
tivity (92% ee). In contrast, the same reaction with 1c,[11]
which has an amide group in the place of the urea moiety,
did not proceed smoothly and led to a 52/48 mixture of 8A
and 9A in only 12% yield. Furthermore, the enantioselec-
tivity for 8A was only 7% ee. Thiourea catalyst 1d without
a tertiary amino group has no catalytic activity. These results
indicate the following characteristics of the thiourea-cata-
lyzed aza-Henry reaction: 1) Since the reaction hardly
occurs at ꢀ208C with only a tertiary amine as catalyst, thio-
urea and urea moieties should play a important role in pro-
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Bifunctional-Thiourea-Catalyzed Aza-Henry Reaction
FULL PAPER
sponding adduct 8I with high stereoselectivities (Table 3,
entry 8: d.r. 92/8, 89% ee). Next, we examined other N-Boc
imines 2A, 2B, and 2G as reaction partners (Table 3, en-
tries 10–12). This revealed that phenyl groups with electron-
withdrawing or electron-donating substituents and pyridyl
groups on the imines had marginal effects on both stereose-
lectivities, and the corresponding adducts 8K–M were ob-
tained as major products with up to 95% ee and 97/3 d.r.
These results demonstrate that the scope of the reaction is
quite broad with respect to the nitroalkanes and N-Boc
imines. To the best of our knowledge, this is the first report
of highly diastereo- and enantioselective aza-Henry reaction
of various functionalized nitroalkanes to give N-protected
imines.
The absolute configuration of 8B was determined by
1H NMR spectroscopy and HPLC analysis,[9] and those of
the other adducts 8A and 8C–M were deduced on the basis
of this result. To account for the current highly stereoselec-
tive reaction, we propose a ternary complex C of catalyst
1a, imine 2 f, and nitronate of 3 as a plausible transition
state, in which 2 f and the nitronate anion may coordinate to
a thiourea moiety and a tertiary amino group of 1a by hy-
drogen bonding[14] (Scheme 4). Ternary complex C can be
be obtained enantioselectively. Furthermore, to determine
whether syn-b-nitroamines 8 are the kinetically or thermo-
dynamically controlled products, a 90/10 mixture of 8B and
9B was subjected to the reaction conditions (10 mol% of
1a, CH2Cl2, ca. 208C, 48 h). However, neither enantioselec-
tivity nor diastereoselectivity of the products 8B and 9B
changed, and the ee and dr values remained constant. In
contrast, treatment of the same mixture with thiourea 1a
(10 mol%) at room temperature for 48 h resulted in a signif-
icant decrease in dr (8B/9B) from 90/10 to 64/36, but the ee
values of 8B and 9B did not change at all. These results
reveal that the retro aza-Henry reaction seems not to occur
even at room temperature, but epimerization of the C2 posi-
tion of the products, undoubtedly induced by the thiourea
catalyst at elevated temperature, lowers the diastereoselec-
tivity.
Asymmetric synthesis of biologically important piperidines
from b-nitroamines: Asymmetric synthesis of 2,3-disubstitut-
ed and 2,3,6-trisubstituted piperidines is becoming increas-
ingly important, since their unique biological activities, such
as neurokinin-1 (NK-1) receptor antagonist behavior, have
been demonstrated in medicinal research.[15] Although the
physiological role of the NK-1
receptor remains to be more
clearly defined, selective NK-1
receptor antagonists such as
CP-99,994 may be of potential
therapeutic value (Scheme 5).[16]
Although various types of
asymmetric syntheses of CP-
99,994 have been reported,[17]
there are still problems to be
solved in terms of overall yield,
enantioselectivity, and opera-
tional simplicity. By using the
aza-Henry reaction established
above, we planned a five-step
synthesis of chiral CP-99,994
without any separation of dia-
stereomers (Scheme 6).
Scheme 4. Proposed reaction process of the thiourea-catalyzed aza-Henry reaction.
considered to be generated through route a or route b. In
the former, thiourea catalyst 1a first activates nitroalkane 3
by hydrogen-bonding interaction (A), which is followed by
intra- or intermolecular deprotonation by the amino group
of 1a to generate nitronate complex B. Subsequent coordi-
nation of imine 2 f to the thiourea moiety in place of the
generated nitronate produces complex C. On the other
hand, complex C might be formed by the successive interac-
tion of imine 2 f and nitroalkane 3 with thiourea catalyst 1a
via coordination and deprotonation (D!C). In any event,
the thiourea moiety of 1a would play a crucial role in acti-
vation of N-Boc imine 2 in the nucleophilic addition step
and/or nitroalkane 3 in the deprotonation step. If complex C
were predominantly produced, syn-b-nitroamines 8 should
Scheme 5. Asymmetric synthesis of (ꢀ)-CP-99,994.
To this end, mesylate 10, prepared from a known nitroal-
cohol,[18] was treated with imine 2 f at ꢀ208C in the presence
of thiourea 1a (10 mol%) to give aza-Henry adducts 11 as a
mixture of diastereomers (11a/11b=86/14) in 80% yield.
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469

Y. Takemoto et al.
then Wittig olefination). The aza-Henry reaction of imine
2 f with (E)-14, which was carried out at room temperature
due to the prolonged reaction time at ꢀ208C, gave adducts
15a and 15b as a mixture of diastereomers (15a/15b=79/
21) in 81% yield. Although the ee of the major adduct 15a
was still high (92%), that of the minor adduct 15b became
somewhat low (72% ee). It is noteworthy that the major
product could be obtained with high enantioselectivity even
at room temperature. Successive treatment of 15 with TFA
and Et3N induced intramolecular Michael addition of pri-
mary amine to a,b-unsaturated ester to furnish cyclized ad-
ducts 16. Although the obtained crude products consisted of
several diastereoisomers of the C3 and C6 positions, purifi-
cation by column chromatography on SiO2 provided the
thermodynamically stable (2S,3R,6S)-piperidine 16 as a
single product in 70% yield with 87% ee.
Scheme 6. Potent neurokinin-1 (NK-1) receptor antagonists.
The enantiomeric excesses of 11a and 11b were 96% ee and
83% ee, respectively. Removal of the N-Boc group from 11
with TFA and subsequent treatment of the crude product
with aqueous K2CO3 gave the cyclized products 12 as a 9/1
mixture of trans and cis isomers in 80% yield. Epimeriza-
tion of the C3 position of 12 was successfully performed by
the kinetically controlled protonation protocol. Thus, succes-
sive treatment of 12 with tBuOK (2.0 equiv) in THF at 08C
and AcOH at ꢀ788C provided the desired cis-12 as a major
product (cis/trans=95/5). It is noteworthy that our success-
ful result is in sharp contrast with the previous report[19] in
which the 2-piperidinone derivative of trans-12 failed to epi-
merize into the corresponding cis isomer by a similar proce-
dure. Since cis-12 thus obtained was liable to isomerize into
trans-12, crude cis-12 was directly reduced with zinc in
AcOH without any purification to afford diamine 13. Final-
ly, the 3-aminopiperidine 13 was treated with o-anisaldehyde
in the presence of NaBH3CN and AcOH to give (ꢀ)-CP-
99,994: [a]2D0 ꢁ63 (c=0.27, CHCl3) [lit.:[17f] (+)-CP-99,994:
[a]2D0 =+67.2 (c=1.0, CHCl3)] as a single product in 75%
Conclusion
We have demonstrated that bifunctional thiourea catalyst
1a catalyzes the aza-Henry reaction of nitroalkanes with N-
Boc imines to give syn-b-nitroamines with good diastereose-
lectivity and high enantioselectivity. Similar to the previous-
ly reported Michael reaction of malonates to give nitroal-
kenes,[11] the urea and thiourea groups were revealed to play
a crucial role both for activating substrates and inducing
chirality. Various types of nitroalkanes bearing aryl, alcohol,
ether, and ester groups were shown to participate in the re-
action with high stereoselectivity. In addition, the reaction
required no additional reagents other than the catalyst. It
was also revealed that syn-b-nitroamines thus obtained
could be prepared with good to high enantioselectivity even
at room temperature. The synthetic utility of this methodol-
ogy was demonstrated by further application to the enantio-
selective synthesis of (ꢀ)-CP-99,994 and 2,3,6-trisubstituted
piperidines.
1
yield from 12. The H NMR data of the synthetic compound
were identical with those reported in the literature.[17]
The same method was applied to the preparation of 2,3,6-
trisubstituted piperidine 16 (Scheme 7). The requisite nitro-
ester (E)-14 was synthesized from a known nitroalcohol[18]
in two steps (oxidation with 2-iodoxybenzoic acid (IBX) and
Experimental Section
General: Nominal (LRMS) and high-resolution mass spectra (HRMS)
were recorded on a JEOL JMS-01SG-2 or JMS-HX/HX 110A mass spec-
trometer. 1H and 13C NMR spectra were registered on a JEOL JNM-
LA500 spectrometer in CDCl3 or some other suitable solvent with TMS
as internal standard. IR spectra were obtained in CHCl3 solution on a
JASCO FT-IR-410 spectrometer. Melting points were recorded on a YA-
NAGIMOTO micro melting point apparatus and are uncorrected. Opti-
cal rotations were measured in CHCl3, unless otherwise noted, with a
JASCO DIP-360 digital polarimeter. For column chromatography, Kanto
Silica Gel 60 (spherical, 63–210 mm) was employed and preparative TLC
(PTLC) was carried out on Silica Gel 60 (Merck). Diastereomer ratios
were determined by 1H NMR analysis. Enantiomer ratios were deter-
mined by chiral HPLC on a Shimadzu SPD-10A with Daicel Chemical
Industries, Ltd., Chiralpak AD, AD-H, AS-H and Chiralcel OD, OD-H,
OJ, and OJ-H (0.46”25 cm). Unless otherwise noted, materials were pur-
chased from Tokyo Kasei Co., Aldrich Inc., and other commercial suppli-
ers and were used without purification.
Scheme 7. Asymmetric synthesis of 2,6-cis-piperidine derivative 16.
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Bifunctional-Thiourea-Catalyzed Aza-Henry Reaction
FULL PAPER
Materials: Imines 2a–f and 2A–G were prepared according to literature
procedures.[6,8–10,20] Nitroalkanes 3e, 3g–i, 3j–k and 10 were prepared ac-
cording to literature procedure.[18, 21]
and 1a (0.1 equiv, 8.3 mg) in CH2Cl2 (0.40 mL), and the mixture was stir-
red for 24 h. Then the reaction mixture was condensed in vacuo, and the
obtained residue was purified by column chromatography on silica gel
(hexane/AcOEt 5/1 as eluant) to afford desired product 4e (40.6 mg,
68%). HPLC analysis (Chiralpak AD-H, hexane/EtOH 70/30, flow
Typical procedure for enantioselective aza-Henry reaction of nitrome-
thane with imines 2a–f at room temperature: MeNO2 (10 equiv, 0.11 mL)
was added to a stirred solution of imine 2 (0.2 mmol) and thiourea
(0.1 equiv, 8.3 mg) in CH2Cl2 (0.4 mL), and the mixture was stirred for
24 h (4.5 h for 4a). Then the reaction mixture was condensed in vacuo,
and the obtained residue was purified by column chromatography on
silica gel to afford desired product 4.
rate=1 mLminꢀ1
, l=210 nm): tr (major)=23.1, tr (minor)=30.3 min;
m.p. 93–948C (CHCl3/hexane); [a]2D3 =11.0 (85% ee, c=0.98, CHCl3);
1H NMR (500 MHz, [D6]DMSO) d=8.24 (d, J=9.2 Hz, 1H), 7.52–7.11
(m, 10H), 5.33 (dt, J=4.7, 9.5 Hz, 1H), 5.01 (d, J=12.5 Hz, 1H), 4.97 (d,
J=12.8 Hz, 1H), 4.91 (dd, J=4.6, 13.1 Hz, 1H), 4.75 ppm (dd, J=10.2,
13.3 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=155.5, 136.5, 135.8, 129.3,
128.9, 128.6, 128.4, 128.2, 126.3, 78.6, 67.4, 53.1 ppm; IR (CHCl3): n˜ =
3437, 3031, 1723, 1558, 1500 cmꢀ1; MS (FAB+): m/z (%): 301 [M+H]+
(27), 91 (100); elemental analysis (%) calcd for C16H16N2O4: C 63.99, H
5.37, N 9.33; found: C 63.93, H 5.43, N 9.37.
N-(2-Nitro-1-phenylethyl)] p-toluenesulfonamide (4a): MeNO2 (10 equiv,
0.11 mL) was added to a stirred solution of N-tosylimine 2a (0.2 mmol,
51.8 mg) and 1a (0.1 equiv, 8.3 mg) in CH2Cl2 (0.40 mL), and the mixture
was stirred for 4.5 h. Then the reaction mixture was condensed in vacuo,
and the obtained residue was purified by column chromatography on
silica gel (CHCl3/acetone 4/1 as eluant) to afford desired product 4a
(63.3 mg, 99%).
tert-Butyl (1R)-2-nitro-1-phenylethylcarbamate (4 f): MeNO2 (10 equiv,
0.11 mL) was added to a stirred solution of N-Boc-imine 2 f (0.2 mmol,
41.1 mg) and 1a (0.1 equiv, 8.3 mg) in CH2Cl2 (0.40 mL), and the mixture
was stirred for 24 h. Then the reaction mixture was condensed in vacuo,
and the obtained residue was purified by column chromatography on
silica gel (hexane/AcOEt 5/1 as eluant) to afford desired product 4 f
(40.4 mg, 76%). HPLC analysis (Chiralpak AD-H, hexane/EtOH 85/15,
(S)-N-(2-Nitro-1-phenylethyl)] diphenylphosphinamide (4b): MeNO2
(10 equiv, 0.11 mL) was added to a stirred solution of N-phosphinoyli-
mine 2b (0.2 mmol, 61.1 mg) and 1a (0.1 equiv, 8.3 mg) in CH2Cl2
(0.40 mL), and the mixture was stirred for 24 h. Then the reaction mix-
ture was condensed in vacuo, and the obtained residue was purified by
column chromatography on silica gel (CHCl3/acetone, 10/1 as eluant) to
afford desired product 4b (63.7 mg, 87%). HPLC analysis (Chiralcel
OD-H, hexane/2-propanol 90/10, flow rate=1.0 mLminꢀ1, l=210 nm):
retention time tr (major)=13.9 min, tr (minor)=21.9 min; m.p. 197–
1988C (CHCl3/hexane); [a]2D8 =+33.2 (76% ee, c=0.90, CHCl3);
1H NMR (500 MHz, CDCl3): d=7.93–7.67 (m, 4H), 7.59–7.10 (m, 11H),
4.97–4.77 (m, 3H), 4.36 ppm (dd, J=8.2, 7.3 Hz, 1H); 13C NMR
(126 MHz, CDCl3): d=138.04, 137.99, 132.44, 132.36, 132.3, 131.8, 131.7,
131.3, 130.8, 129.1, 128.7, 128.6, 128.5, 126.4, 80.8, 80.7, 53.3, 53.2 ppm;
IR (CHCl3): n˜ =3371, 3063, 3034, 2991, 1555 cmꢀ1; MS (FAB+): m/z (%):
367 [M+H]+ (76), 154 (100); HRMS (FAB+) calcd for [C20H20N2O3P]+:
367.1211; found: 367.1210.
flow rate=1.0 mLminꢀ1
, l=210 nm): tr (major)=11.8, tr (minor)=
14.3 min; m.p. 108–1098C (CHCl3/hexane); [a]2D3 =23.7 (90% ee, c=0.98,
CHCl3); 1H NMR (500 MHz, [D6]DMSO): d=7.76 (d, J=9.16 Hz, 1H),
7.51–7.11 (m, 5H), 5.27 (dt, J=5.0, 9.4 Hz, 1H), 4.86 (dd, J=4.9, 13.2 Hz,
1H), 4.72 (dd, J=10.4, 12.8 Hz, 1H), 1.33 ppm (s, 9H); 13C NMR
(126 MHz, [D6]DMSO): d=155.1 138.8, 128.9, 128.2, 127.0, 78.82, 78.76,
52.6, 28.2 ppm; IR (CHCl3): n˜ =3442, 3029, 2981, 2932, 1713, 1557,
1492 cmꢀ1; MS (FAB+): m/z (%): 267 [M+H]+ (10), 150 (100); elemental
analysis (%) calcd for C13H18N2O4: C 58.63, H 6.81, N 10.2; found: C
58.53, H 6.85, N 10.41.
tert-Butyl (R)-2-amino-1-phenylethylcarbamate (5): NaBH4 (12 equiv,
90.8 mg) was added to a stirred suspension of 4 f (53.3 mg, 0.20 mmol,
90% ee) and NiCl2·6H2O (1.0 equiv, 47.5 mg) in MeOH (1.1 mL) at 08C.
After 60 min, the reaction mixture was quenched with a saturated NH4Cl
solution, and the aqueous phase was extracted with CHCl3. The com-
bined organic layers were dried over K2CO3, filtered, and concentrated
in vacuo. The residue was purified by column chromatography on silica
gel (CHCl3/MeOH 5/1 as eluant) to afford desired product 7 (44.7 mg,
95%, 89% ee). HPLC analysis (Chiralcel OJ-H, hexane/2-propanol 70/30
with 0.1 vol% diethylamine, flow rate=0.8 mLminꢀ1): tr (major)=14.0, tr
(minor)=12.7 min; m.p. 70–728C (EtOH/hexane); [a]2D5 =39.6 (89% ee,
c=1.10, CHCl3); 1H NMR (500 MHz, CDCl3): d=7.46–7.12 (m, 5H),
5.46 (brs, 1H), 4.68 (brs, 1H), 3.01 (brs, 2H), 1.73 (brs, 2H), 1.43 ppm
(s, 9H); 13C NMR (126 MHz, CDCl3): d=155.7, 140.8, 128.7, 127.4, 126.4,
79.5, 56.4, 47.1, 28.3 ppm; IR (CHCl3): n˜ =3439, 30009, 2979, 2875, 1707,
1495 cmꢀ1; MS (FAB+): m/z (%): 237 [M+H]+ (66), 181 (100); HRMS
(FAB+) calcd for [C13H21N2O2]+: 237.1603; found: 237.1600; elemental
analysis (%) calcd for C13H20N2O2: C 66.07, H 8.53, N 11.85; found: C
65.95, H 8.42, N 11.57.
N-(2-Nitro-1-phenylethyl)acetamide (4c): MeNO2 (10 equiv, 0.11 mL)
was added to a stirred solution of N-Ac-imine 2c (0.2 mmol, 29.4 mg)
and 1a (0.1 equiv, 8.3 mg) in CH2Cl2 (0.40 mL), and the mixture was stir-
red for 24 h. Then the reaction mixture was condensed in vacuo, and the
obtained residue was purified by column chromatography on silica gel
(CHCl3/MeOH 20/1 as eluant) to afford desired product 4c (39.6 mg,
95%). HPLC analysis (Chiralpak AD-H, hexane/EtOH 80/20, flow
rate=0.8 mLminꢀ1, l=210 nm): tr (major)=10.2, tr (minor)=11.3 min;
m.p. 166–1698C (AcOEt); [a]2D5 =30.8 (63% ee, c=1.00, CHCl3);
1H NMR (500 MHz, CDCl3): d=7.47–7.28 (m, 5H), 6.23 (d, J=7.3 Hz,
1H), 5.80–5.58 (m, 1H), 4.93 (dd, J=6.3, 13.0 Hz, 1H), 4.75 (dd, J=5.7,
13.0 Hz, 1H), 2.07 ppm (s, 3H); 13C NMR (126 MHz, CDCl3): d=170.0,
136.4, 129.2, 128.8, 126.4, 78.1, 51.2, 23.0 ppm; IR (CHCl3): n˜ =3437,
3013, 2925, 2848, 1681, 1557, 1496 cmꢀ1; MS (FAB+): m/z (%): 209
[M+H]+ (68), 154 (100); elemental analysis (%) calcd for C10H12N2O3: C
57.69, H 5.81, N 13.45; Found: C 57.96, H 5.71, N 13.15.
Methyl 2-nitro-1-phenylethylcarbamate (4d): MeNO2 (10 equiv, 0.11 mL)
was added to
a stirred solution of N-methoxycarbonylimine 2d
(R)-N-(tert-Butoxycarbonyl)phenylglycine methyl ester (6): A solution of
4 f (53.3 mg, 0.20 mmol, 90% ee), sodium nitrite (3 equiv, 41.4 mg), and
acetic acid (10 equiv, 0.11 mL) in DMSO (1.4 mL) was heated at 608C
for 14 h. After the mixture had been cooled to room temperature, 1n
HCl solution (1.5 mL) was added to the solution, and the aqueous phase
was extracted with CHCl3. The combined organic phases were washed
with brine and dried over MgSO4. After filtration and evaporation of
CHCl3 in vacuo, K2CO3 (20 equiv, 552 mg) and MeI (16 equiv, 0.20 mL)
were added to the obtained residue, and the mixture stirred for 3.5 h.
Then water was added to the reaction mixture, and the aqueous phase
extracted with Et2O. The combined organic phases were washed with
brine and dried over MgSO4. After filtration and concentration in vacuo,
the residual oil was purified by column chromatography on silica gel
(hexane/AcOEt 5/1 as eluant) to afford desired product 8 (36.9 mg, 70%,
87% ee). HPLC analysis (Chiralcel OD-H, hexane/2-propanol 99.5/0.5,
flow rate=1.0 mLminꢀ1): tr (major)=18.5, tr (minor)=21.0 min; m.p.
105–1068C (CHCl3/hexane); [a]2D2 =111 (87% ee, c=1.00, CHCl3);
(0.2 mmol, 32.6 mg) and 1a (0.1 equiv, 8.3 mg) in CH2Cl2 (0.40 mL), and
the mixture was stirred for 24 h. Then the reaction mixture was con-
densed in vacuo, and the obtained residue was purified by column chro-
matography on silica gel (hexane/AcOEt 3/1 as eluant) to afford desired
product 4d (28.5 mg, 64%). HPLC analysis (Chiralpak AD-H, hexane/
EtOH 70/30, flow rate=0.8 mLminꢀ1, l=210 nm): tr (major)=12.2, tr
(minor)=11.2 min; m.p. 102–1108C (CHCl3/hexane); [a]2D1 =31.8
1
(83% ee, c=1.05, CHCl3); H NMR (500 MHz, CDCl3): d=7.43–7.27 (m,
5H), 5.66 (d, J=6.7 Hz, 1H), 5.45 (d, J=5.5 Hz, 1H), 4.92–4.80 (m 1H),
4.77–4.64 (m, 1H), 3.69 ppm (s, 3H); 13C NMR (126 MHz, CDCl3): d=
156.2, 136.6, 129.2, 128.8, 126.3, 78.6, 53.1, 52.6 ppm; IR (CHCl3): n˜ =
34.38, 3030, 2958, 1725, 1558, 1504 cmꢀ1; MS (FAB+): m/z (%): 225
[M+H]+ (100); elemental analysis (%) calcd for C10H12N2O4: C 53.57, H
5.39, N 12.42; found: C 53.49, H 5.33, N 12.50.
Benzyl 2-nitro-1-phenylethylcarbamate (4e): MeNO2 (10 equiv, 0.11 mL)
was added to a stirred solution of N-Cbz-imine 2e (0.2 mmol, 47.9 mg)
Chem. Eur. J. 2006, 12, 466 – 476
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
471

Y. Takemoto et al.
1H NMR (500 MHz, CDCl3): d=7.55–7.17 (m, 5H), 5.57 (d, J=6.1 Hz,
1H), 5.33 (d, J=7.3 Hz, 1H), 3.72 (s, 3H), 1.43 ppm (s, 9H); 13C NMR
(126 MHz, CDCl3): d=171.7, 154.8, 136.9, 128.9, 128.5, 127.1, 80.1, 57.5,
52.6, 28.2 ppm; IR (CHCl3): n˜ =3438, 3030, 3010, 2981, 2958, 2934, 1742,
1711 cmꢀ1; MS (FAB+): m/z (%): 266 [M+H]+ (26), 210 (100); elemental
analysis (%) calcd for C14H19NO4: C 63.38, H 7.22, N 5.28; found: C
63.09, H 7.00, N 5.34.
(%) calcd for C14H20N2O5: C 56.75, H 6.80, N 9.45; found: C 56.50,
H6.60, N 9.33.
tert-Butyl (R)-2-nitro-1-(1-naphthyl)ethylcarbamate (7D): According to
the typical procedure, imine 2D (0.2 mmol, 51.1 mg) and MeNO2 were
stirred for 24 h and converted to the product 7D (53.4 mg, 85%) as a
white solid. HPLC analysis (Chiralpak AD-H, hexane/EtOH 85/15, flow
rate=1.0 mLminꢀ1, l=210 nm): tr (major)=10.2, tr (minor)=7.5 min;
m.p. 177–1788C (hexane/EtOAc); [a]2D8 =6.13 (95% ee, c=1.00, CHCl3);
1H NMR (500 MHz, CDCl3): d=8.12 (d, J=8.2 Hz, 1H), 7.90 (d, J=
8.2 Hz, 1H), 7.84 (dd, J=5.7, 3.5 Hz, 1H), 7.61 (t, J=7.3 Hz, 1H), 7.54
(t, J=7.5 Hz, 1H), 7.45 (m, 2H), 6.27 (s, 1H), 5.37 (d, J=4.9 Hz, 1H),
4.88 (brs, 2H), 1.43 ppm (s, 9H); 13C NMR (126 MHz, CDCl3): d=154.7,
134.1, 132.6, 130.3, 129.5, 129.3, 127.3, 126.3, 125.2, 123.3, 122.2, 80.7,
78.2, 49.2, 28.2 ppm; IR (CHCl3): n˜ =3440, 3030, 2982, 1713, 1558,
1164 cmꢀ1; MS (FABꢀ): m/z (%): 315 [MꢀH]ꢀ (90), 153 (100); HRMS
(FABꢀ) calcd for [C17H19N2O4]ꢀ: 315.1345; found: 315.1344; elemental
analysis (%) calcd for C17H20N2O4: C 64.54, H 6.37, N 8.86; found: C
64.38, H 6.34, N 8.76.
Typical procedure for enantioselective aza-Henry reaction of MeNO2
with N-Boc-imines at ꢀ208C: MeNO2 (10 equiv, 0.11 mL) was added to a
stirred solution of benzaldehyde N-(tert-butoxycarbonyl) imine 2 f, 2A–H
(0.2 mmol) and 1a (0.1 equiv, 8.3 mg) in CH2Cl2 (0.4 mL) at ꢀ208C, and
the mixture was stirred for 24 h to 60 h. Then the reaction mixture was
condensed in vacuo, and the obtained residue was purified by column
chromatography on silica gel (hexane/EtOAc 5/1 as eluant) to afford de-
sired product 4 f, 7A–H.
tert-Butyl (R)-2-nitro-1-phenylethylcarbamate (4 f): According to the typ-
ical procedure, imine 2 f (0.2 mmol, 41.1 mg) and MeNO2 were stirred for
24 h and converted to the product 4 f (47.9 mg, 90%) as a white solid.
HPLC analysis (Chiralpak AD-H, hexane/EtOH 85/15, flow rate=
tert-Butyl (R)-2-nitro-1-(2-naphthyl)ethylcarbamate (7E): According to
the typical procedure, imine 2E (0.2 mmol, 51.1 mg) and MeNO2 were
stirred for 48 h and converted to the product 7E (53.7 mg, 85%) as a
white solid. HPLC analysis (Chiralpak AD-H, hexane/EtOH 85/15, flow
rate=1.0 mLminꢀ1, l=210 nm): tr (major)=14.6, tr (minor)=11.7 min;
m.p. 168–1698C (hexane/EtOAc); [a]2D8 =28.6 (88% ee, c=1.0, CHCl3);
1H NMR (500 MHz, CDCl3): d=7.88 (s, 1H), 7.86 (s, 1H), 7.83 (m, 2H),
7.77 (s, 1H), 7.52 (m, 2H), 7.40 (dd, J=8.6, 1.5 Hz, 1H), 5.47 (m, 2H),
4.95 (brs, 1H), 4.80 (m, 1H), 1.45 ppm (s, 9H); 13C NMR (126 MHz,
CDCl3): d=154.7, 134.1, 132.6, 130.3, 129.6, 129.3, 127.3, 126.3, 125.3,
123.2, 122.2, 80.8, 78.2, 49.2, 28.2 ppm; IR (CHCl3): n˜ =3440, 3027, 2982,
1714, 1557, 1163 cmꢀ1; MS (FABꢀ): m/z (%): 315 [MꢀH]ꢀ (75), 153
(100); HRMS (FABꢀ) calcd for [C17H19N2O4]ꢀ: 315.1345; found:
315.1354.
1.0 mLminꢀ1
, l=210 nm): tr (major)=9.0, tr (minor)=11.2 min; m.p.
107–1088C (hexane/EtOAc); [a]3D0 =25.3 (94% ee, c=1.20, CHCl3);
1H NMR (500 MHz, CDCl3): d=7.35 (m, 5H), 5.38 (brs, 1H), 5.28 (brs,
1H), 4.69–4.87 (m, 2H), 1.44 ppm (s, 9H); 13C NMR (126 MHz, CDCl3):
d=154.9, 137.0, 129.3, 128.9, 126.4, 80.8, 79.0, 52.9, 28.3 ppm; IR
(CHCl3): n˜ =3442, 3027, 2981, 1713, 1557, 1164 cmꢀ1; MS (FAB+): m/z
(%): 267 [M+H]+ (100); HRMS (FAB+) calcd for [C13H19N2O4]+:
267.1345; found: 267.1352; elemental analysis (%) calcd for C13H18N2O4:
C 58.63, H 6.81, N 10.52; found: C 58.84, H 6.82, N 10.77.
tert-Butyl (R)-2-nitro-1-(p-trifluoromethylphenyl)ethylcarbamate (7A):
According to the typical procedure, imine 2A (0.2 mmol, 55.2 mg) and
MeNO2 were stirred for 24 h and converted to the product 7A (53.5 mg,
80%) as a white solid. HPLC analysis (Chiralpak AD-H, hexane/EtOH
85/15, flow rate=1.0 mLminꢀ1, l=210 nm): tr (major)=8.3, tr (minor)=
6.6 min; m.p. 143–1448C (hexane/EtOAc); [a]2D7 =11.0 (98% ee, c=0.99,
tert-Butyl (R)-2-nitro-1-(2-furyl)ethylcarbamate (7F): According to the
typical procedure, imine 2F (0.20 mmol, 39.1 mg) and MeNO2 were stir-
red for 60 h and converted to the product 7F (41.1 mg, 81%) as a white
solid. HPLC analysis (Chiralpak AD-H, hexane/EtOH 85/15, flow rate=
1.0 mLminꢀ1, l=210 nm): tr (major)=9.1, tr (minor)=13.9 min; m.p. 98–
1008C (hexane/EtOAc); [a]D28 =6.13 (79% ee, c=1.00, CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.38 (d, J=1.5 Hz, 1H), 6.53 (m, 1H), 6.31 (d, J=
3.1 Hz, 1H), 5.47 (d, J=6.1 Hz, 1H), 5.32 (s, 1H), 4.85 (s, 1H), 4.73 (dd,
J=13.0, 5.7 Hz, 1H), 1.46 ppm (s, 9H); 13C NMR (126 MHz, CDCl3): d=
154.7, 149.5, 142.9, 110.7, 107.8, 80.8, 76.5, 47.1, 28.2 ppm; IR (CHCl3):
n˜ =3443, 3029, 2982, 1714, 1559, 1162 cmꢀ1; MS (FABꢀ): m/z (%): 255
[MꢀH]ꢀ (85), 153 (100); HRMS (FABꢀ) calcd for [C11H15N2O5]ꢀ:
255.0981; found: 255.0974; elemental analysis (%) calcd for C11H16N2O5:
C 51.56, H 6.29, N 10.93; found: C 51.62, H 6.10, N 10.66.
1
CHCl3); H NMR (500 MHz, CDCl3): d=7.18 (s, 4H), 5.33 (d, J=5.8 Hz,
1H), 5.22 (brs, 1H), 4.83 (s, 1H), 4.68 (dd, J=12.4, 5.7 Hz, 1H), 2.34 (s,
3H), 1.44 ppm (s, 9H); 13C NMR (126 MHz, CDCl3): d=154.8, 138.7,
133.9, 129.9, 126.3, 80.6, 78.9, 52.6, 28.2 21.0 ppm; IR (CHCl3): n˜ =3442,
3027, 2981, 1713, 1557, 1164 cmꢀ1; MS (FABꢀ): m/z (%): 333 [MꢀH]ꢀ
(76), 216 (100); HRMS (FABꢀ) calcd for [C14H16F3N2O4]ꢀ: 333.1062;
found: 333.1054; elemental analysis (%) calcd for C14H17F3N2O4: C 50.30,
H 5.13, N 8.38; found: C 50.03, H 5.13, N 8.34.
tert-Butyl (R)-2-nitro-1-(4-methylphenyl)ethylcarbamate (7B): Accord-
ing to the typical procedure, imine 2B (0.2 mmol, 43.8 mg) and MeNO2
were stirred for 24 h and converted to the product 7B (46.2 mg, 82%) as
a white solid. HPLC analysis (Chiralpak AD-H, hexane/EtOH 85/15,
flow rate=1.0 mLminꢀ1
,
l=210 nm): tr (major)=9.1, tr (minor)=
tert-Butyl (R)-2-nitro-1-(3-pyridyl)ethylcarbamate (7G): According to
the typical procedure, imine 2G (0.20 mmol, 41.2 mg) and MeNO2 were
stirred for 24 h and converted to the product 7G (47.2 mg, 89%) as a
white solid. HPLC analysis (Chiralpak AD-H, hexane/EtOH 85/15, flow
rate=1.0 mLminꢀ1, l=210 nm): tr (major)=24.1, tr (minor)=19.4 min;
m.p. 151–1528C (hexane/EtOAc); [a]2D8 =21.0 (98% ee, c=1.00, CHCl3);
1H NMR (500 MHz, CDCl3): d=8.63 (d, J=21.4 Hz, 2H), 7.70 (d, J=
7.9 Hz, 1H), 7.34 (dd, J=7.5, 4.7 Hz, 1H), 5.73 (s, 1H), 5.43 (s, 1H), 4.91
(s, 1H), 4.76 (d, J=8.9 Hz, 1H), 1.44 ppm (s, 9H); 13C NMR (126 MHz,
CDCl3): d=154.7, 149.7, 148.0, 134.4, 133.1, 123.9, 81.0, 78.2, 50.7,
28.1 ppm; IR (CHCl3): n˜ =3440, 3029, 2982, 1714, 1560, 1163 cmꢀ1; MS
(FABꢀ): m/z (%): 266 [MꢀH]ꢀ (50), 153 (100); HRMS (FABꢀ) calcd for
[C12H16N3O4]ꢀ: 266.1141; found: 266.1143; elemental analysis (%) calcd
for C12H17N3O4: C 53.92, H 6.41, N 15.72; found: C 53.72, H 6.43, N
15.68.
10.9 min; m.p. 135–1368C (hexane/EtOAc); [a]2D7 =28.0 (93% ee, c=1.01,
CHCl3); 1H NMR (500 MHz, CDCl3): d=7.18 (s, 4H), 5.33 (d, J=5.8 Hz
1H), 5.22 (brs, 1H), 4.83 (s, 1H), 4.68 (dd, J=12.4, 5.7 Hz, 1H), 2.34 (s,
3H), 1.44 ppm (s, 9H); 13C NMR (126 MHz, CDCl3): d=154.8, 138.7,
133.9, 129.9, 126.3, 80.6, 78.9, 52.6, 28.2, 21.0 ppm; IR (CHCl3): n˜ =3442,
3027, 2981, 1713, 1557, 1164 cmꢀ1; MS (FAB+): m/z (%): 281 [M+H]+
(35), 164 (100); HRMS (FAB+) calcd for [C14H21N2O4]+: 281.1501;
found: 281.1499; elemental analysis (%) calcd for C14H20N2O4: C 59.99,
H 7.19, N 9.99; found: C60.25, H 7.31, N 9.84.
tert-Butyl (R)-2-nitro-1-(p-methoxyphenyl)ethylcarbamate (7C): Accord-
ing to the typical procedure, imine 2C (0.2 mmol, 59.2 mg) and MeNO2
were stirred for 60 h and converted to the product 7C (42.3 mg, 71%) as
a white solid. HPLC analysis (Chiralpak AD-H, hexane/EtOH 85/15,
flow rate=1.0 mLminꢀ1
, l=210 nm): tr (major)=14.0, tr (minor)=
13.2 min; m.p. 145–1468C (hexane/EtOAc); [a]2D7 =36.0 (95% ee, c=1.00,
CHCl3); 1H NMR (500 MHz, CDCl3): d=7.22 (d, J=8.6 Hz, 2H), 6.89
(d, J=8.6 Hz, 2H), 5.31 (s, 1H), 5.23 (d, J=7.0 Hz, 1H), 4.83 (s, 1H),
4.66 (dd, J=12.0, 5.3 Hz, 1H), 3.80 (s, 3H), 1.44 ppm (s, 9H); 13C NMR
(126 MHz, CDCl3): d=159.8, 154.8, 128.9, 127.6, 114.6, 80.6, 78.9, 55.3,
tert-Butyl (R)-2-nitro-1-(2-thienyl)ethylcarbamate (7H): According to
the typical procedure, imine 2H (0.20 mmol, 42.2 mg) and MeNO2 were
stirred for 24 h and converted to the product 7H (49.0 mg, 90%) as a
white solid. HPLC analysis (Chiralpak AD-H, hexane/EtOH 85/15, flow
rate=1.0 mLminꢀ1, l=210 nm): tr (major)=11.2, tr (minor)=14.7 min;
m.p. 113–1148C (hexane/EtOAc); [a]3D0 =5.4 (83% ee, c=1.0, CHCl3);
1H NMR (500 MHz, CDCl3): d=7.28 (dd, J=4.9, 1.2 Hz, 1H), 7.00 (m,
52.4, 28.2 ppm; IR (CHCl3): n˜ =3443, 3027, 2980, 1712, 1557, 1164 cmꢀ1
MS (FAB+): m/z (%): 297 [M+H]+ (45), 180 (100); elemental analysis
;
472
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 466 – 476

Bifunctional-Thiourea-Catalyzed Aza-Henry Reaction
FULL PAPER
2H), 5.62 (m, 1H), 5.32 (brs, 1H), 4.83 (m, 2H), 1.46 ppm (s, 9H);
13C NMR (126 MHz, CDCl3): d=154.8, 140.3, 127.6, 126.0, 125.6, 81.1,
78.8, 49.1, 28.4 ppm; IR (CHCl3): n˜ =2959, 2928, 2360, 1716, 1559,
1161 cmꢀ1; MS (FABꢀ): m/z (%): 271 [MꢀH]ꢀ (50), 153 (100); HRMS
(FABꢀ) calcd for [C11H15N2O4S]ꢀ: 271.0753; found: 271.0747.
analysis (%) calcd for C18H28N2O4: C 64.26, H 8.39, N 8.33; found: C
63.78, H 8.30, N 8.27.
tert-Butyl (1R,2S)-2-nitro-1,3-diphenylpropylcarbamate (8D): According
to the typical procedure, imine 2 f (0.20 mmol, 41.1 mg) and nitro com-
pound 3e were converted to the product 8D as a white solid (60.0 mg,
84%) and a 83/17 mixture of diastereomers by 1H NMR ([D6]DMSO)
analysis. The major diastereomer was determined to have 97% ee by
chiral HPLC analysis (Chiralpak AD-H, hexane/EtOH 85/15,
0.5 mLminꢀ1, l=210 nm): tr (major)=14.3 min, tr (minor)=15.2 min; and
the minor diastereomer was determined to have 78% ee under the same
HPLC analysis conditions: tr (major)=17.7 min, tr (minor)=16.2 min;
Typical procedure for enantioselective aza-Henry reaction of nitro sub-
strates with N-Boc-imines: Nitro substrate (3b–k, 2.0–5.0 equiv) was
added to
a stirred solution of benzaldehyde N-(tert-butoxycarbonyl)
imines 2 f, 2A–B, 2G (0.2 mmol) and thiourea (0.1 equiv, 8.3 mg) in
CH2Cl2 (0.4 mL), and the mixture was stirred for 24 h to 72 h at the
ꢀ208C. Then the reaction mixture was condensed in vacuo and the ob-
tained residue was purified by column chromatography on silica gel
(hexane/EtOAc 5/1 as eluant) to afford desired products 8A–M, 9A.
1
m.p. 189–1908C (hexane/EtOAc); [a]3D0 =51.6 (c=1.00, CHCl3); H NMR
(500 MHz, CDCl3):d=7.33–7.41 (m, 3H), 7.26–7.31 (m, 4H), 7.12–7.25
(m, 3H), 5.19–5.30 (m, 2H), 4.99–5.10 (brs, 1H), 3.25–3.35 (m, 1H),
3.13–3.20 (dd, J=3.5, 14.8 Hz, 1H), 1.46 ppm (s, 9H); 13C NMR
(126 MHz, CDCl3): d=155.0, 136.4, 135.5, 129.2, 129.0, 128.9, 128.8,
127.5, 127.0, 92.7, 80.8, 57.3, 36.2, 28.2 ppm; IR (CHCl3): n˜ =3436, 3019,
1715, 1556, 1369, 1162 cmꢀ1; MS (FABꢀ): m/z (%): 355 [MꢀH]ꢀ (100);
HRMS (FABꢀ) calcd for [C20H23N2O4]ꢀ: 355.1658; found: 355.1651; ele-
mental analysis (%) calcd for C20H24N2O4: C 67.40, H 6.79, N 7.86;
found: C 67.26, H 6.67, N 7.82.
tert-Butyl (1R,2S)-2-nitro-1-phenylbutylcarbamate (8A) and tert-Butyl
(1R,2R)-2-nitro-1-phenylbutyl carbamate (9A): According to the typical
procedure, imine 2 f (0.20 mmol, 41.1 mg) and nitro compound 3b were
converted to products 8A and 9A as white solids (53.0 mg, 90%) and a
8A/9A (88/12) mixture of diastereomers by 1H NMR ([D6]DMSO) anal-
ysis. The ee of major diastereomer 8A was determined to be 95% by
chiral HPLC analysis (Chiralpak AD-H, hexane/EtOH 85/15,
1 mLminꢀ1, l=210 nm): tr (major)=5.3 min, tr (minor)=5.8 min; and
that of the the minor diastereomer 9A was determined to be 79% (Chir-
alpak AD, hexane/iPrOH 85/15, 1 mLminꢀ1, l=210 nm): tr (major)=
tert-Butyl (1R,2S)-3-hydroxy-2-nitro-1-phenylpropylcarbamate (8E): Ac-
cording to the typical procedure, imine 2 f (0.20 mmol, 41.1 mg) and nitro
15.1 min, tr (minor)=13.0 min; m.p. 156–1578C (hexane/EtOAc); [a]D30
=
compound 3 f were converted to the product 8E as
a white solid
29.6 (c=1.01, CHCl3); 1H NMR (500 MHz, CDCl3): d=730–7.40 (m,
3H), 7.22–7.26 (m, 2H), 5.14–5.20 (brs, 1H), 5.10–5.14 (m, 1H), 4.74
(brs, 1H), 1.84–1.92 (m, 2H), 1.43 (s, 9H), 0.96–1.03 ppm (t, J=3.5 Hz,
3H); 13C NMR (126 MHz, CDCl3): d=154.9, 136.7, 129.0, 128.7, 126.9,
93.0, 74.8, 56.8, 28.2, 24.8, 10.4 ppm; IR (CHCl3): n˜ =3441, 2961, 2928,
1713, 1491, 1423 cmꢀ1; MS (FABꢀ): m/z (%): 293 [MꢀH]ꢀ (100); HRMS
(FABꢀ) calcd for [C15H21N2O4]ꢀ: 293.1501; found: 293.1509; elemental
analysis (%) calcd for C15H22N2O4: C 61.21, H 7.53, N 9.52; found: C
60.43, H 6.87, N 9.53.
(44.5 mg, 75%) and
a
75/25 mixture of diastereomers by 1H NMR
([D6]DMSO) analysis. The major diastereomer was determined to have
90% ee by chiral HPLC analysis (Chiralpak AD-H, 85/15 hexane/EtOH,
1.0 mLminꢀ1, l=210 nm): tr (major)=14.9 min, tr (minor)=10.4 min; and
the minor diastereomer was determined to have 82% ee under the same
HPLC analysis conditions: tr (major)=12.1 min, tr (minor)=21.5 min;
1
m.p. 103–1098C (hexane/EtOAc); [a]3D0 =24.5 (c=0.85, CHCl3); H NMR
(500 MHz, CDCl3):d= 7.27–7.41 (m, 5H), 5.41–5.66 (m, 1H), 5.19–5.35
(m, 1H), 4.77–5.03 (m, 1H), 4.06–4.19 (m, 2H), 3.48–3.97 (m, 1H),
1.44 ppm (s, 9H); 13C NMR (126 MHz, CDCl3): d=156.3, 136.4, 129.3,
128.7, 126.3, 91.6, 81.4, 61.5, 58.7, 28.2 ppm; IR (CHCl3): n˜ =3437, 3019,
1714, 1555, 1360, 1060 cmꢀ1; MS (FABꢀ): m/z (%): 295 [MꢀH]ꢀ (45), 153
(100); HRMS (FABꢀ) calcd for [C14H19N2O5]ꢀ: 295.1294; found:
295.1297; elemental analysis (%) calcd for C14H20N2O5: C 56.75, H 6.80,
N 9.45; found: C 55.48, H 6.58, N 9.57.
tert-Butyl (1R,2S)-2-nitro-1-phenylpropylcarbamate (8B): According to
the typical procedure, imine 2 f (0.20 mmol, 41.1 mg) and nitro compound
3c were converted to the product 8B (51.5 mg, 92%) as a white solid
and a 90/10 mixture of diastereomers by 1H NMR ([D6]DMSO) analysis.
The major diastereomer was determined to have 93% ee by chiral HPLC
analysis (Chiralpak AD-H, hexane/iPrOH 90/10, 1 mLminꢀ1, l=210 nm):
tr (major)=10.7 min, tr (minor)=9.9 min; and the minor diastereomer
was determined to have 83% ee under the same HPLC analysis condi-
tions: tr (major)=13.0 min, tr (minor)=15.8 min; m.p. 143–1448C
(hexane/EtOAc); [a]3D0 =22.0 (c=1.10, CHCl3); 1H NMR (500 MHz,
CDCl3): d=7.28–7.34 (m, 3H), 7.18–7.21 (m, 2H), 5.32 (brs, 1H), 5.16
(dd, J=8.8, 5.8 Hz, 1H), 4.88 (brs, 1H), 1.49 (d, J=6.7 Hz, 3H),
1.39 ppm (s, 9H); 13C NMR (126 MHz, CDCl3): d=155.2, 136.7, 129.3,
129.0, 127.2, 86.0, 80.0, 57.7, 28.4, 15.5 ppm; IR (CHCl3): n˜ =3439, 2982,
2937, 1713, 1554 cmꢀ1; MS (FABꢀ): m/z (%): 279 [MꢀH]ꢀ (90), 153
(100); HRMS (FABꢀ) calcd for [C14H19N2O4]ꢀ: 279.1345; found:
279.1350; elemental analysis (%) calcd for C14H20N2O4: C 59.99, H 7.19,
N 9.99; found: C 59.84, H 6.92, N 9.92.
tert-Butyl (1R,2S)-3-benzyloxy-2-nitro-1-phenylpropylcarbamate (8F):
According to the typical procedure, imine 2 f (0.20 mmol, 41.1 mg) and
nitro compound 3g were converted to the product 8F as a white solid
(61.5 mg, 80%) and
a
86/14 mixture of diastereomers by 1H NMR
([D6]DMSO) analysis. The major diastereomer was determined to have
95% ee by chiral HPLC analysis (Chiralpak AD-H, hexane/iPrOH 85/15,
flow rate=0.5 mLminꢀ1, l=210 nm): tr (major)=26.8 min, tr (minor)=
30.2 min; and the minor diastereomer was determined to have 89% ee
under the same HPLC analysis conditions: tr (major)=24.7 min, tr
(minor)=28.4 min; m.p. 101–1028C (hexane/EtOAc); [a]3D0 =12.4 (c=
1.03, CHCl3); 1H NMR (500 MHz, CDCl3): d=7.30–7.37 (m, 6H), 7.21–
7.25 (m, 4H), 5.58 (brs, 1H), 5.10–5.25 (m, 1H), 5.06 (brs, 1H), 4.46–
4.53 (s, 2H), 3.67–4.03 (m, 2H), 1.41 ppm (s, 9H); 13C NMR (126 MHz,
CDCl3): d=154.9, 136.9, 136.6, 129.2, 128.6, 127.9, 127.8, 126.7, 126.2,
90.7, 80.5, 73.6, 68.6, 56.8, 28.2 ppm; IR (CHCl3): n˜ =3436, 3010, 1715,
1561, 1369, 1097 cmꢀ1; MS (FABꢀ): m/z (%): 385 [MꢀH]ꢀ (100); HRMS
(FABꢀ) calcd for [C21H25N2O5]ꢀ: 385.1763; found: 385.1786; elemental
analysis (%) calcd for C21H26N2O5: C 65.27, H 6.78, N 7.25; found: C
66.41, H 6.70, N 6.69.
tert-Butyl (1R,2S)-2-nitro-1-phenylhexylcarbamate (8C): According to
the typical procedure, imine 2 f (0.20 mmol, 41.1 mg) and nitro compound
3d were converted to product 8C as a white solid (55.0 mg, 82%) and a
93/7 mixture of diastereomers by 1H NMR ([D6]DMSO) analysis. The
major diastereomer was determined to have 99% ee by chiral HPLC
analysis (Chiralpak AD-H, hexane/iPrOH 80/20, 0.5 mLminꢀ1
, l=
210 nm): tr (major)=13.8 min, tr (minor)=10.2 min; and the minor dia-
stereomer was determined to have 97% ee under the same HPLC analy-
sis conditions: tr (major)=12.7 min, tr (minor)=15.6 min; m.p. 113–
1148C (hexane/EtOAc); [a]3D0 =14.7 (c=1.14, CHCl3); 1H NMR
(500 MHz, CDCl3):d=7.28–7.38 (m, 3H), 7.19–7.26 (m, 2H), 5.02–5.29
(m, 2H), 4.72–4.78 (brs, 1H), 1.76–2.04 (m, 2H), 1.43 (s, 9H), 1.24–1.35
(m, 6H), 0.84–0.87 ppm (t, J=6.71, 10.7 Hz, 3H); 13C NMR (126 MHz,
CDCl3): d=154.9, 136.7, 129.0, 128.7, 126.9, 126.3, 91.5, 80.5, 56.9, 31.0,
29.7, 28.2, 25.5, 22.2, 13.8 ppm; IR (CHCl3): n˜ =3440, 3026, 1714, 1554,
1211, 1023 cmꢀ1; MS (FABꢀ): m/z (%): 335 [MꢀH]ꢀ (100); HRMS
(FABꢀ) calcd for [C18H27N2O4]ꢀ: 335.1971; found: 335.1978; elemental
tert-Butyl (1R,2S)-4-benzyloxy-2-nitro-1-phenylbutylcarbamate (8G): Ac-
cording to the typical procedure, imine 2 f (0.20 mmol, 41.1 mg) and nitro
compound 3h were converted to the product 8G as a white solid
(68.5 mg, 86%) and
a
93/7 mixture of diastereomers by 1H NMR
(CDCl3) analysis. The major diastereomer was determined to have
94% ee by chiral HPLC analysis (Chiralpak AD-H, 85/15 hexane/EtOH,
1.0 mLminꢀ1, l=210 nm): tr (major)=9.6 min, tr (minor)=12.3 min; and
the minor diastereomer was determined to have 98% ee under the same
HPLC analysis condition: tr (major)=15.5 min, tr (minor)=11.3 min;
m.p. 69–708C (hexane/EtOAc); [a]3D0 =35.0 (c=1.22, CHCl3); 1H NMR
Chem. Eur. J. 2006, 12, 466 – 476
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
473

Y. Takemoto et al.
(500 MHz, CDCl3): d=7.26–7.37 (m, 8H), 7.20–7.25 (m, 2H), 5.15–5.28
(m, 2H), 5.08 (brs, 1H), 4.42–4.49 (m, 2H), 3.36–3.61 (m, 2H), 2.13–2.36
(m, 2H), 1.43 ppm (s, 9H); 13C NMR (126 MHz, CDCl3): d=154.9, 137.8,
136.7, 129.0, 128.6, 128.5, 127.9, 126.9, 88.3, 80.4, 73.3, 65.8, 56.9, 30.3,
28.2 ppm; IR (CHCl3): n˜ =3437, 3028, 1714, 1555, 1369, 1163 cmꢀ1; MS
(FABꢀ): m/z (%): 399 [MꢀH]ꢀ (100); HRMS (FABꢀ) calcd for
[C22H27N2O5]ꢀ: 399.1920; found: 399.1925; elemental analysis (%) calcd
for C14H20N2O4: C 59.99, H 7.19, N 9.99; found: C 59.84, H 6.92, N 9.92.
hexane/iPrOH 90/10, 1.0 mLminꢀ1, l=210 nm): tr (major)=12.9 min, tr
(minor)=9.9 min; and the minor diastereomer was determined to have
87% ee under the same HPLC analysis conditions: tr (major)=10.8 min,
tr (minor)=28.7 min; m.p. 205–2068C (hexane/EtOAc); [a]3D0 =50.0 (c=
0.10, CHCl3); 1H NMR (500 MHz, CDCl3): d=7.62–7.65 (dd, J=12.8,
7.9 Hz, 2H), 7.39–7.42 (d, J=7.9 Hz, 1H), 7.25–7.37 (m, 4H), 7.12–7.16
(m, 2H), 5.29 (brs, 1H), 5.21 (s, 1H), 5.04–5.13 (m, 1H), 3.15–3.38 (m,
2H), 1.44 ppm (s, 9H); 13C NMR (126 MHz, CDCl3): d=172.7, 154.8,
134.9, 129.2, 129.0, 128.8, 127.7, 126.7, 126.1, 92.2, 81.2, 56.8, 37.5,
28.2 ppm; IR (CHCl3): n˜ =3438, 2932, 1715, 1557 cmꢀ1; MS (FABꢀ): m/z
(%): 423 [MꢀH]ꢀ (60), 153 (100); HRMS (FABꢀ) calcd for
[C21H22F3N2O4]ꢀ: 423.1532; found: 423.1528; elemental analysis (%)
calcd for C21H23N2O4: C 59.43, H 5.46, N 6.60; found: C 59.21, H 5.44, N
6.47.
tert-Butyl (1R,2S)-5-benzyloxy-2-nitro-1-phenylpentylcarbamate (8H):
According to the typical procedure, imine 2 f (0.20 mmol, 41.1 mg) and
nitro compound 3i were converted to the product 8H as a white solid
(66.0 mg, 80%) and
a
91/9 mixture of diastereomers by 1H NMR
([D6]DMSO) analysis. The major diastereomer was determined to have
92% ee by chiral HPLC analysis (Chiralpak AD-H, 80:20 hexane/EtOH,
0.5 mLminꢀ1, l=210 nm): tr (major)=14.8 min, tr (minor)=13.7 min; and
the minor diastereomer was determined to have 73% ee under the same
HPLC analysis conditions: tr (major)=17.8 min, tr (minor)=16.5 min;
m.p. 75–768C (hexane/EtOAc); [a]3D0 =3.91 (c=0.72, CHCl3); 1H NMR
(500 MHz, CDCl3):d=7.27–7.35 (m, 7H),M 7.15–7.24 (m, 3H), 5.05–5.29
(m, 2H), 4.72–4.99 (brs, 1H), 4.42–4.50 (s, 2H), 3.33–3.46 (m, 2H), 1.99–
2.30 (m, 2H), 1.53–1.75 (m, 2H), 1.41 ppm (s, 9H); 13C NMR (126 MHz,
CDCl3): d=154.9, 138.2, 136.7, 129.0, 128.7, 128.6, 128.5, 127.7, 126.9,
91.2, 80.5, 72.9, 68.9, 65.8, 56.9, 28.2, 26.0 ppm; IR (CHCl3): n˜ =3436,
3026, 1715, 1554, 1368, 1164 cmꢀ1; MS (FABꢀ): m/z (%): 413 [MꢀH]ꢀ
(100); HRMS (FABꢀ) calcd for [C23H29N2O5]ꢀ: 413.2076; found:
413.2070; elemental analysis (%) calcd for C23H30N2O5: C 66.98, H 7.05,
N 7.00; found: C 66.18, H 6.96, N 6.76.
tert-Butyl (1R,2S)-1-(p-methylphenyl)-2-nitro-1,3-diphenylpropylcarba-
mate (8L): According to the typical procedure, imine 2B (0.20 mmol,
43.8 mg) and nitro compound 3e were converted to the product 8L
(66.5 mg, 90%) as a white solid and a 93/7 mixture of diastereomers by
1H NMR ([D6]DMSO) analysis. The major diastereomer was determined
to have 92% ee by chiral HPLC analysis (Chiralpak AD-H, hexane/
iPrOH 95/5, 1.0 mLminꢀ1, l=210 nm): tr (major)=24.7 min, tr (minor)=
22.4 min; and the minor diastereomer was determined to have 57% ee
under the same HPLC analysis conditions: tr (major)=34.1 min, tr
(minor)=21.6 min; m.p. 156–1578C (hexane/EtOAc); [a]3D0 =73.0 (c=
0.20, CHCl3); 1H NMR (500 MHz, CDCl3): d=7.26–7.29 (m, 3H), 7.14–
7.17 (m, 6H), 5.19 (brs, 2H), 5.05–5.09 (m, 1H), 3.14–3.30 (m, 2H), 2.34
(s, 3H), 1.44 ppm (s, 9H); 13C NMR (126 MHz, CDCl3): d=155.0, 138.8,
135.5, 133.3, 129.8, 128.8, 127.4, 126.8, 126.2, 92.8, 80.6, 57.1, 36.2,
28.2 ppm; IR (CHCl3): n˜ =3025, 2360, 1714, 1556, 1162 cmꢀ1; MS (FABꢀ):
m/z (%): 369 [MꢀH]ꢀ (80), 153 (100); HRMS (FABꢀ) calcd for
[C21H25N2O4]ꢀ: 369.1814; found: 369.1819; elemental analysis (%) calcd
for C21H26N2O4: C 68.09, H 7.07, N 7.56; found: C 68.01, H 7.00, N 7.50.
tert-Butyl (1R,2S)-5-hydroxy-2-nitro-1-phenylpentylcarbamate (8I): Ac-
cording to the typical procedure, imine 2 f (0.20 mmol, 41.1 mg) and nitro
compound 3j were converted to the product 8I as a white solid (51.5 mg,
80%) and a 92/8 mixture of diastereomers by 1H NMR ([D6]DMSO)
analysis. The major diastereomer was determined to have 89% ee by
chiral HPLC analysis (Chiralpak AD-H, 85/15 hexane/EtOH,
1.0 mLminꢀ1, l=210 nm): tr (major)=6.2 min, tr (minor)=8.0 min; and
the minor diastereomer was determined to have 87% ee under the same
HPLC analysis conditions: tr (major)=15.8 min, tr (minor)=17.0 min;
tert-Butyl
(1R,2S)-2-nitro-1-(3-pyridine)-1,3-diphenylpropylcarbamate
(8M): According to the typical procedure, imine 2G (0.20 mmol,
41.2 mg) and nitro compound 3e were converted to the product 8M
(66.5 mg, 93%) as a white solid and a 83/17 mixture of diastereomers by
1H NMR ([D6]DMSO) analysis. The major diastereomer was determined
to have 93% ee by chiral HPLC analysis (Chiralpak AD-H, hexane/
iPrOH 90/10, 1 mLminꢀ1, l=210 nm): tr (major)=23.9 min, tr (minor)=
20.4 min; and the minor diastereomer was determined to have 65% ee
under the same HPLC analysis conditions: tr (major)=44.0 min, tr
(minor)=30.4 min; m.p. 169–1708C (hexane/EtOAc); [a]3D0 =26.1 (c=
0.72, CHCl3); 1H NMR (500 MHz, CDCl3): d=8.55–8.58 (d, J=12.8 Hz,
2H), 7.57–7.62 (m, 1H), 7.27–7.34 (m, 4H), 7.14–7.17 (dd, J=11.1,
7.2 Hz, 2H), 5.92 (brs, 1H), 5.19–5.23 (m, 1H), 5.04–5.06 (m, 1H), 3.29–
3.40 (m, 1H), 3.16–3.19 (dd, J=14.7, 3.7 Hz, 1H), 1.44 ppm (s, 9H);
13C NMR (126 MHz, CDCl3): d=149.9, 134.3, 133.8, 129.2, 129.0, 128.8,
128.6, 128.0, 127.7, 123.8, 92.9, 81.8, 59.5, 38.6, 28.2 ppm; IR (CHCl3): n˜ =
3437, 2984, 2360, 1715, 1557 cmꢀ1; MS (FABꢀ): m/z (%): 356 [MꢀH]ꢀ
(75), 153 (100); HRMS (FABꢀ) calcd for [C19H22N3O4]ꢀ: 356.1610;
found: 356.1622; elemental analysis (%) calcd for C19H23N3O4: C 63.85,
H 6.49, N 10.97; found: C 63.65, H 6.70, N 10.97.
1
m.p. 155–1568C (hexane/EtOAc); [a]3D0 =3.72 (c=1.50, CHCl3); H NMR
(500 MHz, CDCl3):d=7.31–7.40 (m, 3H), 7.21–7.26 (m, 2H), 5.13–5.24
(m, 2H), 4.92 (brs, 1H), 3.63–3.72 (m, 2H), 3.1.96–2.17 (m, 2H), 1.64–
1.66 (m, 1H), 1.54–1.59 (m, 1H), 1.43 ppm (s, 9H); 13C NMR (126 MHz,
CDCl3): d=155.0, 136.7, 129.1, 128.9, 126.9, 91.1, 83.8, 61.7, 56.9, 28.6,
28.2 26.5 ppm; IR (CHCl3): n˜ =3033, 2959, 2927, 1731, 1554, 1376, 1161,
1046 cmꢀ1; MS (FABꢀ): m/z (%): 323 [MꢀH]ꢀ (100); HRMS (FABꢀ)
calcd for [C16H24N2O5]ꢀ: 323.1607; found: 323.1617.
tert-Butyl (1R,2S)-2-nitro-1-phenyl-5-(trifluoromethanesulfonyloxy)pent-
ylcarbamate (8J): According to the typical procedure, imine 2 f
(0.20 mmol, 41.1 mg) and nitro compound 3k were converted to the
product 8J as a white solid (71.0 mg, 78%) and a 93/7 mixture of diaster-
1
eomers by H NMR (CDCl3) analysis. The major diastereomer was deter-
mined to have 90% ee by chiral HPLC analysis (Chiralpak AD-H,
hexane/iPrOH 85/15, 1.0 mLminꢀ1, l=210 nm): tr (major)=13.7 min, tr
(minor)=9.1 min; and the minor diastereomer was determined to have
55% ee under the same HPLC analysis conditions: tr (major)=15.2 min,
tr (minor)=19.2 min; m.p. 94–958C (hexane/EtOAc); [a]3D0 =8.42 (c=
0.95, CHCl3); 1H NMR (500 MHz, CDCl3):d=7.32–7.40 (m, 3H), 7.22–
7.26 (d, J=7.0 Hz, 2H), 5.06–5.24 (m, 2H), 4.80–4.95 (brs, 1H), 4.29–4.36
(m, 2H), 1.94–2.27 (m, 2H), 1.76–1.92 (m, 2H), 1.43 ppm (s, 9H);
13C NMR (126 MHz, CDCl3): d=161.9, 154.9, 136.3, 129.2, 126.9, 126.4,
90.6, 80.7, 74.7, 67.8, 56.9, 28.2, 24.8 ppm; IR (CHCl3): n˜ =3443, 3024,
tert-Butyl (1R,2S)-5-(methanesulfonyloxy)-2-nitro-1-phenylpentylcarba-
mate (11): 4-O-methanesulfonyl-1-nitrobutane[7] (10, 0.60 mmol,
1.5 equiv, 118.2 mg) was added to
a stirred solution of imine 2 f
(0.40 mmol, 82.3 mg) and 1a (0.1 equiv, 16.5 mg) in CH2Cl2 (0.8 mL,
0.5m) at ꢀ208C and then stirred for 72 h. The reaction mixture was con-
centrated in vacuo, and the obtained residue was purified by flash
column chromatography on silica gel (hexane/EtOAc 2/1 as eluant) to
afford desired product 11 as a white solid (131.9 mg, 80%) as a 80/20
(11a/11b) mixture of diastereomers by 1H NMR (CDCl3) analysis. The
major diastereomer 11a was determined to have 96% ee by chiral HPLC
1714, 1556, 1393, 1164, 1052 cmꢀ1
;
MS (FABꢀ): m/z (%): 305
[MꢀHOTf]ꢀ (100); HRMS (FABꢀ) calcd for C16H21N2O4 [MꢀHOTf)]ꢀ:
305.1501; found: 305.1515.
analysis (Chiralpak AD, hexane/iPrOH 90/10, flow rate=1.0 mLminꢀ1
,
tert-Butyl (1R,2S)-2-nitro-1-(p-triflouromethylphenyl)-1,3-diphenylpro-
pylcarbamate (8K): According to the typical procedure, imine 2A
(0.20 mmol, 54.6 mg) and nitro compound 3e were converted to the
product 8K (79.5 mg, 94%) as a white solid and a 97/3 mixture of diaster-
eomers by 1H NMR ([D6]DMSO) analysis. The major diastereomer was
determined to have 95% ee by chiral HPLC analysis (Chiralpak AD-H,
l=210 nm): tr (major)=39.8 min, tr (minor)=36.4 min; and the minor di-
astereomer 11b was determined to have 83% ee under the same HPLC
analysis conditions: tr (major)=64.0 min, tr (minor)=81.0 min; m.p. 85–
868C (hexane/EtOAc); [a]2D5 =ꢀ24.4 (c=0.82, CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.29–7.40 (m, 3H), 7.21–7.27 (m, 2H), 5.20–5.27
474
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 466 – 476

Bifunctional-Thiourea-Catalyzed Aza-Henry Reaction
FULL PAPER
(m, 1H), 5.07–5.20 (m, 1H), 4.90 (brs, 1H), 4.18–4.31 (m, 2H), 3.01 (s,
3H), 2.04–2.18 (m, 2H), 1.76–1.84 (m, 2H), 1.43 ppm (s, 9H); 13C NMR
(126 MHz, CDCl3): d=155.0, 136.3, 129.1, 126.9, 126.3, 90.5, 80.6, 68.2,
56.8, 37.3, 28.1, 26.2, 25.4 ppm; IR (CHCl3): n˜ =3036, 2927, 1735,
1231 cmꢀ1; MS (FAB+): m/z (%): 403 [M+H]+ (7), 347 (100); HRMS
(FAB+) calcd for [C17H27N2O7S]+: 403.1539; found: 403.1534; elemental
analysis (%) calcd for C17H26N2O7S: C 50.73, H 6.51, N 6.96; found: C
50.57, H 6.24, N 7.00.
J=13.7, 1H), 3.27 (brd, J=12.5 Hz, 1H), 2.75- 2.85 (m, 2H), 2.14 (brd,
J=14.6 Hz, 1H), 1.92 (m, 1H), 1.64–1.74 (brs, 2H), 1.61 (tt, J=13.4,
3.7 Hz, 1H), 1.40 ppm (brd, J=13.1 Hz, 1H); 13C NMR (126 MHz,
CDCl3): d=157.7, 142.5, 129.6, 128.3, 128.2, 127.8, 126.6, 126.3, 120.0,
109.8, 63.9, 54.70, 54.65, 47.7, 46.7, 28.1, 20.3 ppm; IR (CDCl3): n˜ =3320,
3064, 2939, 1601, 1493, 1462 cmꢀ1; MS (FAB+): m/z (%): 297 [M+H]+
(92), 121 (100); HRMS (FAB+) calcd for [C19H25N2O]+: 297.1967; found:
297.1975.
(2R,3S)-3-Nitro-2-phenylpiperidine (12): Trifluoroacetic acid (TFA,
280.2 mg, 2.0 mmol, 10 equiv) was added to a stirred ice-cooled solution
of 11 (80.4 mg, 0.2 mmol, mixture of diastereomers 11a/11b=86/14) in
CH2Cl2 (1.0 mL), and stirring was continued for 3 h under a N2 atmos-
phere. After addition of saturated aqueous K2CO3 (5 mL), the aqueous
phase was extracted with AcOEt. The combined organic phases were
washed with brine, dried (Na2SO4), and concentrated in vacuo, and the
crude material was purified by column chromatography on silica gel
(hexane/EtOAc 1/1 as eluant) to give 12 as a colorless oil (33.0 mg, 80%)
as a 9/1 (trans/cis) mixture of diastereomers by 1H NMR (CDCl3) analy-
sis. The major diastereomer was determined to have 94% ee by chiral
HPLC analysis (Chiralpak AD-H, hexane/iPrOH 90/10, 1.0 mLminꢀ1, l=
210 nm): tr (major)=16.1 min, tr (minor)=14.7 min; and the minor dia-
stereomer was determined to have 98% ee under the same HPLC analy-
sis condition: tr (major)=18.5 min, tr (minor)=20.1 min; [a]2D5 =+48.9
Methyl trans-6-nitro-2-hexenoate ((E)-14): IBX (1.5 equiv, 5.83 g) was
added to
a stirred solution of 4-nitro-1-butanol (1.57 g, 13.2 mmol),
DMSO (7 mL), and THF (7 mL). After 2 h, saturated aqueous NaHCO3
was added to the reaction mixture, which was extracted with Et2O. The
combined organic extracts were washed with saturated aqueous NaHCO3
and brine, dried over MgSO4, filtered, and concentrated in vacuo to
afford the crude aldehyde (1.20 g). The crude aldehyde was dissolved in
benzene (20 mL) and the Wittig reagent (1.5 equiv, 5.12 g) was added to
the reaction mixture at room temperature. After 20 h, the reaction mix-
ture was concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane/AcOEt 3/1 as eluant) to afford
(Z)-14 (130 mg, 5%) and (E)-14 (893 mg, 36%). E isomer: 1H NMR
(500 MHz, CDCl3): d=6.91 (dt, J=15.6, 7.0 Hz, 1H), 5.90 (dt, J=15.6,
1.5 Hz, 1H), 4.42 (t, J=6.9 Hz, 2H), 3.74 (s, 3H), 2.41–2.29 (m, 2H),
2.27–2.13 ppm (m, 2H); 13C NMR (126 MHz, CDCl3): d=166.5, 145.7,
1
122.8, 74.4, 51.5, 28.4, 25.4 ppm; IR (CHCl3): n˜ =1719, 1660, 1555 cmꢀ1
;
(94% ee, c=1.21, CHCl3); trans isomer: H NMR (500 MHz, CDCl3): d=
MS (CI+): m/z (%): 174 [M+H]+ (100); HRMS (CI+) calcd for
[C7H12NO4]+: 174.0766; found: 174.0763. Z isomer: 1H NMR (500 MHz,
CDCl3): d=6.21 (ddd, J=11.4, 7.8, 7.6 Hz, 1H), 5.89 (dt, J=11.3, 1.5 Hz,
1H), 4.42 (t, J=7.0 Hz, 2H), 3.72 (s, 3H), 2.77 (ddt, J=1.5, 7.5, 7.5 Hz,
2H), 2.19 (ddt, J=7.0, 7.3, 7.4 Hz, 2H); 13C NMR (126 MHz, CDCl3):
d=166.4, 146.6, 121.4, 74.6, 51.1, 26.2, 25.3 ppm; IR (CHCl3): n˜ =1718,
148, 1554 cmꢀ1; MS (CI+): m/z (%): 174 [M+H]+ (32), 42 (100); HRMS
(CI+) calcd for [C7H12NO4]+: 174.0766; found: 174.0768.
7.28–7.38 (m, 5H), 4.58 (ddd, J=9.8, 9.5, 4.3 Hz, 1H), 4.02 (d, J=9.5 Hz,
1H), 3.16 (brd, J=11.9 Hz, 1H), 2.85 (ddd, J=11.9, 11.9, 2.7, 1H), 2.43
(m, 1H), 2.12 (ddd, J=12.5, 12.5, 4.3 Hz, 1H), 1.89 (m, 1H), 1.67–
1.83 ppm (m, 2H); 13C NMR (126 MHz, CDCl3): d=138.7, 128.8, 127.5,
122.2, 89.3, 64.9, 46.3, 30.9, 24.4 ppm; IR (CDCl3): n˜ =3694, 3027, 1603,
1556; MS (FAB+): m/z (%): 207 [M+H]+ (100), 160 (28); HRMS (FAB+)
calcd for [C11H25N2O2]+: 207.1134; found: 207.1137. cis isomer: [a]2D5
=
+17.5 (c=0.24, CHCl3); 1H NMR (500 MHz, CDCl3): d=7.27–7.37 (m,
5H), 4.95 (brs, 1H), 4.13 (brs, 1H), 3.43 (brd, J=13.1 Hz, 1H), 2.87
(ddd, J=12.8, 13.1, 3.1 Hz 1H), 2.50 (brs, 1H), 2.48 (brd, J=15.0, 1H),
2.14 (m, 1H), 2.03 (m, 1H), 1.60 ppm (m, 1H); 13C NMR (126 MHz,
CDCl3): d=138.5, 128.7, 127.9, 125.8, 84.0, 61.2, 46.0, 28.8, 20.1 ppm; IR
(CDCl3): n˜ =3693, 3028, 1601, 1552 cmꢀ1; MS (FAB+): m/z (%): 207
[M+H]+ (100), 91 (44); HRMS (FAB+) calcd for [C11H25N2O2]+:
207.1134; found: 207.1132.
Methyl
(6R,7S)-trans-7-[N-(tert-butoxycarbonyl)amino]-6-nitro-7-
phenyl-2-heptenoate (15): 1a (0.1 equiv, 5.5 mg) was added to a stirred
solution of N-Boc-imine 2 f (0.13 mmol, 27.1 mg) and nitroalkane (E)-14
(2 equiv, 49.5 mg) in CH2Cl2 (0.26 mL) at room temperature, and the
mixture was stirred for 24 h. Then the reaction mixture was purified by
column chromatography on silica gel (hexane/AcOEt 5/1 as eluant) to
afford a 79/21 mixture of diastereomers of 15 (40.7 mg, 81%). HPLC
analysis (Chiralpak AS-H, hexane/EtOH 90:10, flow rate=
1.0 mLminꢀ1): 15a (92% ee): tr (major)=9.1 min, tr (minor)=14.8 min;
15b (72% ee): (tr major)=12.4 min, tr (minor)=7.4 min. 1H NMR
(500 MHz, CDCl3): d=7.44–7.28 (m, 3H), 7.25–7.17 (m, 2H), 6.91–6.78
(m, 1H), 5.84 (d, J=15.9 Hz, 1H), 5.24–5.06 (m, 2H), 4.81 (brs, 1H),
3.74 (s, 3H), 2.42–2.10 (m, 3H), 2.03–1.89 (m, 1H), 1.43 ppm (s, 9H);
13C NMR (126 MHz, CDCl3): Major isomer (15a): d=166.6, 155.0, 145.8,
136.4, 128.9, 128.7, 126.8, 122.6, 90.4, 80.4, 56.8, 51.4, 28.3, 28.1, 28.0 ppm.
Minor isomer (15b): d=166.5, 155.0, 145.4, 137.1, 129.0, 128.5, 126.3,
122.7, 91.0, 80.3, 56.0, 51.4, 29.3, 28.0, 27.9 ppm; IR (CHCl3): n˜ =3443,
3028, 3006, 2979, 1716, 1554 cmꢀ1; MS (FAB+): m/z (%): 379 [M+H]+
(6), 212 (100); HRMS (FAB+) calcd for [C19H27N2O6]+: 379.1869; found:
379.1866.
(2R,3R)-3-[N-(2-methoxybenzyl)amino]-2-phenylpiperidine
((ꢀ)-CP-99,994): tBuOK (22.5 mg, 0.20 mmol) was added to a solution of
the 9/1 mixture of diastereomers of 12 (20.7 mg, 0.10 mmol) in THF
(0.5 mL) at 08C under N2 atmosphere. After the mixture was stirred at
this temperature for 1 h, the temperature was reduced to ꢀ788C, and
AcOH (0.1 mL) was added. After stirring for 1 h at this temperature, the
mixture was allowed to warm slowly to room temperature. The reaction
was quenched with saturated aqueous Na2CO3 (5 mL), and the mixture
was extracted with AcOEt. The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated in vacuo to give cis-12. Zn
(156 mg, 2.40 mmol) and AcOH (0.3 mL) were added to a stirred solu-
tion of the obtained cis-12 in THF (1.0 mL). After stirring the mixture at
room temperature under N2 atmosphere for 8 h, it was quenched with sa-
turated aqueous NaHCO3 (5 mL) and extracted with CHCl3. The com-
bined organic layers were washed with brine, dried (K2CO3), and concen-
trated in vacuo to give 13 as a pale yellow oil. o-Anisaldehyde (13.6 mg,
0.10 mmol) was added to a solution of the obtained 13 in 1,2-dichloro-
ethane (DCE, 1.0 mL). After stirring the mixture for 1 h at room temper-
ature, NaBH3CN (6.9 mg, 0.11 mmol), AcOH (6.8 mL, 0.11 mmol) and
MeOH (0.4 mL) were added. After stirring for 6 h at room temperature,
the mixture was basified with aqueous NaHCO3 and solid K2CO3 (ca.
240 mg) and extracted with CHCl3. The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated in vacuo. The resi-
due was purified by column chromatography on silica gel (AcOEt/
hexane/MeOH/TEA 100/50/5/1 as eluant) to give (ꢀ)-CP-99,994 as a col-
orless oil (22.3 mg, 75% from 12): [a]2D0 =63.0 (c=0.27, CHCl3) (lit.:[17f]
[a]2D0 =+67.2 (c=1.0, CHCl3) as (+)-CP-99,994); 1H NMR (500 MHz,
CDCl3): d=7.21–7.31 (m, 5H), 7.15 (td, J=7.9, 1.5 Hz, 1H), 6.97 (dd, J=
7.3, 1.5 Hz, 1H), 6.80 (brt, J=7.3 Hz, 1H), 6.68 (brd, J=8.2 Hz, 1H),
3.88 (d, J=2.4 Hz, 1H), 3.67 (d, J=13.7 Hz, 1H), 3.45 (s, 3H), 3.41 (d,
Methyl 2-[(2S,3R,6S)-5-nitro-6-phenylpiperidin-2-yl]acetate (16): TFA
(0.20 mL) was added to a stirred solution of 15 (37.8 mg, 0.10 mmol, 15a/
15b 79/21) in CH2Cl2 (0.20 mL) at 08C. After 2 h, the reaction mixture
was concentrated in vacuo. The residual solid was dissolved in THF
(1.0 mL), and then TEA (5 equiv, 0.070 mL) was added to the mixture.
After 2 h, saturated aqueous NaHCO3 was added to the reaction mixture,
and the aqueous phase was extracted with CHCl3. The combined organic
extract was dried over Na2SO4, filtered, and evaporated in vacuo. The
residue was purified by column chromatography on silica gel (hexane/
AcOEt 3/1 as eluant) to afford desired product 16 (19.6 mg, 70%).
HPLC analysis (Chiralpak AD, hexane/EtOH 90:10, flow rate=
1.0 mLminꢀ1): tr (major)=12.4, tr (minor)=15.1 min; m.p. 1148C (CHCl3/
hexane); [a]2D3 =+16.7 (87% ee, c=1.01, CHCl3); 1H NMR (500 MHz,
CDCl3): d=7.42–7.27 (m, 5H), 4.54 (ddd, J=4.0, 9.8, 11.9 Hz, 1H), 4.13
(d, J=9.8 Hz, 1H), 3.66 (s, 3H), 3.31–3.17 (m, 1H), 2.54–2.47 (m, 1H),
2.47–2.38 (m, 2H), 2.33 (s, 1H), 2.27–2.11 (m, 1H), 1.93–1.83 (m, 1H),
Chem. Eur. J. 2006, 12, 466 – 476
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
475

Y. Takemoto et al.
1.52–1.36 ppm (m, 1H); 13C NMR (126 MHz, CDCl3): d=172.3, 138.7,
128.80, 128.75, 127.6, 89.2, 64.5, 52.7, 51.7, 40.1, 30.5, 30.2 ppm; IR
(CHCl3): n˜ =3330, 3030, 2952, 2950, 1731, 1550 cmꢀ1; MS (FAB+): m/z
(%): 279 [M+H]+ (100); HRMS (FAB+) calcd for [C14H19N2O4]+:
279.1345; found: 279.1342; elemental analysis (%) calcd for C14H18N2O4:
C 60.40, H 6.52, N 10.07; found: C 60.12, H 6.55, N 9.99.
[10] T. P. Yoon, E. N. Jacobsen, Angew. Chem. 2005, 117, 470–472;
Angew. Chem. Int. Ed. 2005, 44, 466–468.
[11] a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125,
12672–12673; b) T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Take-
moto, J. Am. Chem. Soc. 2005, 127, 119–125; c) Y. Hoashi, T.
Okino, Y. Takemoto, Angew. Chem. 2005, 117, 4100–4103; Angew.
Chem. Int. Ed. 2005, 44, 4032–4035; Other urea-catalysts: d) M. S.
Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 10558–10559;
and references therein; e) Y. Sohtome, A. Tanatani, Y, Hashimoto,
K. Nagasawa, Tetrahedron Lett. 2004, 45, 5589–5592; f) A. Berkes-
sel, F. Cleemann, S. Mukherjee, T. N. Müller, J. Lex, Angew. Chem.
2005, 117, 817–821; Angew. Chem. Int. Ed. 2005, 44, 807–811; g) A.
Berkessel, S. Mukherjee, F. Cleemann, T. N. Müller, J. Lex, Chem.
Commun. 2005, 1898–1900; h) B.-J. Li, L. Jiang, M. Liu, Y.-C. Chen,
L.-S. Ding, Y. Wu, Synlett 2005, 603–606; i) B. Vakulya, S. Varga, A.
Csampai, T. Soos, Org. Lett. 2005, 7, 1967–1969.
Acknowledgements
This work was supported by grants from 21st Century COE Program
“Knowledge Information Infrastructure for Genome Science”, Grant-in-
Aid for Scientific Research on Priority Areas (17035043) from MEXT,
and JSPS. KAKENHI (16390006).
[12] P. M. OꢁBrien, D. R. Sliskovic, C. J. Blankley, B. D. Roth, M. W.
Wilson, K. L. Hamelehle, B. R. Krause, R. L. Stanfield, J. Med.
Chem. 1994, 37, 1810–1822.
[13] P. Merino, E. Castillo, S. Franco, F. L. Merchan, T. Tejero, J. Org.
Chem. 1998, 63, 2371–2374.
[14] a) M. C. Etter, Z. UrbaÇczyk-Lipkowska, M. Zia-Ebrahimi, T. W.
Panunto, J. Am. Chem. Soc. 1990, 112, 8415–8426; b) T. R. Kelly,
M. H. Kim, J. Am. Chem. Soc. 1994, 116, 7072–7080; c) D. P.
Curran, L. H. Kuo, J. Org. Chem. 1994, 59, 3259–3261; d) B. R.
Linton, M. S. Goodman, A. D. Hamilton, Chem. Eur. J. 2000, 6,
2449–2455; e) P. R. Schreiner, A. Wittkopp, Org. Lett. 2002, 4, 217–
220; f) A. Wittkopp, P. R. Schreiner, Chem. Eur. J. 2003, 9, 407–414;
g) D. J. Maher, S. J. Connon, Tetrahedron Lett. 2004, 45, 1301–1305;
h) P. M. Pihko, Angew. Chem. 2004, 116, 2110–2113; Angew. Chem.
Int. Ed. 2004, 43, 2062–2064.
[1] a) H. H. Baer, L. Urbas in The Chemistry of the Nitro and Nitroso
Groups (Ed.: S. Patai), Interscience, New York, 1970, Part 2,
p. 117; b) N. Ono, The Nitro Group in Organic Synthesis, 1st ed.,
Wiley, New York, 2001; c) B. Westermann, Angew. Chem. 2003,
115, 161–163; Angew. Chem. Int. Ed. 2003, 42, 151–153; d) C.
Palomo, M. Oiarbide, A. Mielgo, Angew. Chem. 2004, 116, 5558–
5560; Angew. Chem. Int. Ed. 2004, 43, 5442–5444; e) J. C. Anderson,
A. J. Blake, G. P. Howell, C. Wilson, J. Org. Chem. 2005, 70, 549–
555.
[2] a) D. N. Sarma, R. P. Sharma, Tetrahedron Lett. 1985, 26, 371–372;
b) D. H. Lloyd, D. E. Nichols, J. Org. Chem. 1986, 51, 4294–4295;
c) A. G. M. Barrett, C. D. Spilling, Tetrahedron Lett. 1988, 29, 5733–
5734; d) A. S. Kende, J. S. Mendoza, Tetrahedron Lett. 1991, 32,
1699–1702; e) M. A. Sturgess, D. J. Yarberry, Tetrahedron Lett.
1993, 34, 4743–4746; f) H. Adams, J. C. Anderson, S. Peace,
A. M. K. Pennell, J. Org. Chem. 1998, 63, 9932–9934.
[15] a) F.-X. Felpin, J. Lebreton, Eur. J. Org. Chem. 2003, 3693–3712;
b) P. M. Weintraub, J. S. Sabol, J. M. Kane, D. R. Borcherding, Tetra-
hedron 2003, 59, 2953–2989; c) M. G. P. Buffat, Tetrahedron 2004,
60, 1701–1729.
[3] a) H. W. Pinnick, Org. React. 1990, 38, 655–792; b) C. Matt, A.
Wagner, C. Moiskowski, J. Org. Chem. 1997, 62, 234; c) R. Ballini,
M. Petrini, Tetrahedron 2004, 60, 1017–1047.
[16] a) J. W. Watson, S. F. Gonsalves, A. A. Fossa, S. McLea, T. Seeger, S.
Obach, P. L. R. Andrews, Br. J. Pharmacol. 1995, 115, 84–94; b) S.
Zaman, A. J. Woods, J. W. Watson, D. J. M. Reynolds, P. L. R. An-
drews, Neuropharmacology 2000, 39, 316–323; c) P. Datar, S. Srivas-
tava, E. Coutinho, G. Govil, Curr. Top. Med. Chem. 2004, 4, 75–103.
[17] Asymmetric synthesis of CP-99,994: a) M. C. Desai, S. L. Lefkowitz,
P. F. Thadeio, K. P. Longo, R. M. Snider, J. Med. Chem. 1992, 35,
4911–4913; b) S. Chandrasekhar, P. K. Mohanty, Tetrahedron Lett.
1999, 40, 5071–5072; c) N. Tsuritani, K. Yamada, N. Yoshikawa, M.
Shibasaki, Chem. Lett. 2002, 276–277; d) P.-Q. Huang, L.-X. Liu, B.-
G. Wei, Y.-P. Ruan, Org. Lett. 2003, 5, 1927–1929; e) A. Lemire, M.
Grenon, M. Pourashraf, A. B. Charette, Org. Lett. 2004, 6, 3517–
3520; f) M. Atobe, N. Yamazaki, C. Kibayashi, J. Org. Chem. 2004,
69, 5595–5607.
[18] T. Nagano, H. Kinoshita, Bull. Chem. Soc. Jpn. 2000, 73, 1605–1613.
[19] M. C. Desai, P. F. Thadeio, S. L. Lefkowitz, Tetrahedron Lett. 1993,
34, 5831–5834.
[20] a) B. M. Trost, C. Jonasson, Angew. Chem. 2003, 115, 2109–2112;
Angew. Chem. Int. Ed. 2003, 42, 2063–2066; b) C. Qian, F. Gao, R.
Chen, Tetrahedron Lett. 2001, 42, 4673–4675; c) J. Vidal, S. Dames-
toy, L. Guy, J. Hannachi, A. Aubry, A. Collet, Chem. Eur. J. 1997, 3,
1691–1709; d) R. Kupfer, S. Meier, E. Würthwein, Synthesis 1984,
688–690.
[4] D. Lucet, T. Le Gall, C. Mioskowski, Angew. Chem. 1998, 110,
2724–2772; Angew. Chem. Int. Ed. 1998, 37, 2580–2627.
[5] a) A. Córdova, Acc. Chem. Res. 2004, 37, 102–112; b) W. Notz, F.
Tanaka, C. F. Barbas, III, Acc. Chem. Res. 2004, 37, 580–591; c) S.
Matsunaga, T. Yoshida, H. Morimoto, N. Kumagai, M. Shibasaki, J.
Am. Chem. Soc. 2004, 126, 8777–8785; d) N. S. Josephsohn, M.
Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 2004, 126, 3734–3735;
e) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356–5357;
f) T. Hamada, K. Manabe, S. Kobayashi, J. Am. Chem. Soc. 2004,
126, 7768–7769; g) T. Ooi, M. Kameda, J. Fujii, K. Maruoka, Org.
Lett. 2004, 6, 2397–2399; h) T. Akiyama, J. Itoh, K. Yokota, K. Fu-
chibe, Angew. Chem. 2004, 116, 1592–1594; Angew. Chem. Int. Ed.
2004, 43, 1566–1568; i) W. Zhuang, S. Saaby, K. A. Jørgnesen,
Angew. Chem. 2004, 116, 4576–4578; Angew. Chem. Int. Ed. 2004,
43, 4476–4478.
[6] a) K. Yamada, S. J. Harwood, H. Grçger, M. Shibasaki, Angew.
Chem. 1999, 111, 3713–3715; Angew. Chem. Int. Ed. 1999, 38, 3504–
3506; b) K. Yamada, G. Moll, M. Shibasaki, Synlett 2001, 980–982;
c) N. Tsuritani, K. Yamada, N. Yoshikawa, M. Shibasaki, Chem.
Lett. 2002, 276–277.
[7] a) K. R. Knudsen, T. Risgaard, N. Nishiwaki, K. V. Gothelf, K. A.
Jørgensen, J. Am. Chem. Soc. 2001, 123, 5843–5844; b) N. Nishiwa-
ki, K. R. Knudsen, K. V. Gothelf, K. A. Jørgensen, Angew. Chem.
2001, 113, 3080–3083; Angew. Chem. Int. Ed. 2001, 40, 2992–2995;
c) K. R. Knudsen, K. A. Jørgensen, Org. Biomol. Chem. 2005, 3,
1362–1364.
[21] 3e: a) M. Fujii, Bull. Chem. Soc. Jpn. 1988, 61, 4029–4035; 3g–i:
b) P. Eckenberg, U. Groth, T. Huhn, N. Richter, C. Schmeck, Tetra-
hedron 1993, 49, 1619–1624; c) H. P. Wessel, T. Iversen, D. R.
Bundle, J. Chem. Soc. Perkin Trans. 1 1985, 2247–2250; 3j–k: d) Y.
Yoshida, Y. Sakakura, N. Aso, S. Okada, Y. Tanabe, Tetrahedron
1999, 55, 2183–2192.
[8] T. Okino. S. Nakamura, T. Furukawa, Y. Takemoto, Org. Lett. 2004,
6, 625–627.
[9] B. M. Nugent, R. A. Yoder, J. N. Johnston, J. Am. Chem. Soc. 2004,
126, 3418–3419.
Received: June 27, 2005
Published online: September 27, 2005
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