General entry to asymmetric one-pot [ N + 2 + n ] cyclization for the synthesis of three- to seven-membered azacycloalkanes

Article abstract of DOI:10.1021/jo301495a

Enantio- and diastereoselective one-pot synthesis of three- to seven-membered cis-azaheterocycles was achieved using a triggered asymmetric conjugate addition reaction of lithium amide with an enoate, followed by alkylation of the resulting lithium enolat

Full text of DOI:10.1021/jo301495a

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pubs.acs.org/joc
General Entry to Asymmetric One-Pot [N + 2 + n] Cyclization for the
Synthesis of Three- to Seven-Membered Azacycloalkanes
Shingo Harada,† Takeo Sakai,† Kiyosei Takasu,† Ken-ichi Yamada,† Yasutomo Yamamoto,‡
and Kiyoshi Tomioka*,‡
†Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
‡Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe 610-0395, Japan
S
* Supporting Information
ABSTRACT: Enantio- and diastereoselective one-pot synthesis of three- to
seven-membered cis-azaheterocycles was achieved using a triggered asymmetric
conjugate addition reaction of lithium amide with an enoate, followed by
alkylation of the resulting lithium enolate with α,ω-dihaloalkane and N-
alkylation. Isomerization of cis-azaheterocycles with a base yielded the trans-
product, constituting a one-pot synthesis of cis-azacycles and a two-step
synthesis of trans-azacycles. The four-step asymmetric synthesis of nemonapride
highlights the general utility of the method.
Enantioselective construction of three- to six-membered
cyclic α-amino acid derivatives was recently reported by
Maruoka,26 who utilized a three-step sequence, including chiral
ammonium-catalyzed asymmetric α-alkylation of α-amino acid
derivatives. To the best of our knowledge, this is the only
method that is generally applicable for the construction of
chiral azacycloalkanes with different ring sizes starting from
easily available reagents. The formation of a four-membered
ring, which involves challenging alkylation with 1,2-dihalo-
ethane as an ethylene dication equivalent, however, has been
reported, albeit in low yield.27,28
Azacyclic β-amino acid derivatives are not only potential
intermediates for azacyclic bioactive compounds, such as
azirinomycin (1),29 piperazine surrogate 2,18 β-proline
(3),30,31 antipsychotic nemonapride (4),32 substance P
antagonist CP-99,994 (5),33 and croomine (6),34 but also
interesting building blocks for artificial peptides35,36 (Figure 1).
We recently reported the asymmetric total synthesis of
INTRODUCTION
■
Azacycloalkane is a fundamental component of structures often
occurring in biologically active natural products, pharmaceut-
icals, organocatalysts, and ligands. Preparation methodologies
of chiral azacycloalkanes are therefore studied extensively,
especially the five-membered pyrrolidines1 and the six-
membered piperidines,2,3 by intramolecular hydroamination
of olefins,4 cycloaddition,5,6 and N-alkylation of chiral amines.7
Chiral piperidines are also available by asymmetric hydro-
genation of N-iminopyridinium8 and desymmetrization of N-
Boc-piperidine by asymmetric deprotonation.9 In contrast,
synthesis of chiral azacycloalkanes of other ring sizes has been
less explored. For example, a three-membered chiral aziridine, a
useful building block and substructure of some biologically
significant compounds,10 was constructed from chiral 1,2-
aminoalcohol11 or by a transition-metal-catalyzed reaction of
nitrenoid with alkene12 or carbenoid with imine.13 A chiral
Lewis14 or Brønsted15 acid-catalyzed reaction of diazoacetic
acid derivatives with imines has been also reported. Although
cis-aziridines are obtained with high enantioselectivity by the
above-mentioned methods,14b the trans-selective asymmetric
aziridination reported so far suffered from moderate diaster-
eoselectivity and/or yield.12−16 Chiral azacyclobutane, an
important azetidine class of azacyclic compounds endowed
with remarkable bioactivity,17,18 is prepared from chiral
amines19 or chiral diols20 through a multistep synthesis and
by enzymatic kinetic resolution of racemic azetidines.21 A chiral
seven-membered azepane, often found in natural products22
and extensively developed as pharmacophores,23 is usually
synthesized by cyclization of chiral amines through a multistep
sequence,24 although asymmetric synthesis of 4,5,6- and 3,4,5,6-
substituted azepanes by a diastereo- and enantioselective
lithiation−conjugate addition sequence has been reported.25
Thus, different methods are needed for the synthesis of
azacycloalkanes with different ring sizes.
Figure 1. Pharmaceuticals and bioactive compounds with three- to
seven-membered azacycloalkane moieties.
Received: July 16, 2012
Published: August 15, 2012
© 2012 American Chemical Society
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(−)-kopsinine based on one-pot [N + 2 + 3] cyclization
strategy (Scheme 1, n = 3),37 that is, chiral diether-controlled
confirmed by epimerization to the thermodynamically more
stable trans-10a in a >98:2 ratio through sodium methoxide
treatment for 3.5 h in refluxing xylene (Scheme 2).43 Thus,
one-pot cyclization allowed for the preparation of both cis- and
trans-azacycloalkanes with high enantio- and diastereoselectiv-
ity.
Scheme 1. Asymmetric One-Pot [N + 2 + n] Cyclization
Strategy for Three- to Seven-Membered Azacycloalkanes
Chiral ligand 11 was not responsible for the alkylation
diastereoselectivity because no enantioselectivity was observed
in the reaction of tert-butyl acrylate, in place of cinnamate, to
give the corresponding racemic piperidinecarboxylate in 42%
yield. The observed diastereoselectivity was predictable based
on the preferred axial alkylation44 in conformer A, giving cis-10a
(Scheme 3).45 The conformer B should be less stable because
of steric repulsion caused by the phenyl and the trimethylsilyl
group on the nitrogen.
Piperidine functionalized with an exomethylene was available
using dibromoisobutene 9b instead of 9a to give isomer-free cis-
10b with 97% ee in 86% yield (entry 3). The asymmetric one-
pot piperidine formation was generally applicable to enoates
other than cinnamate 8a (Table 1, entries 4−8). The reaction
of naphthalene-2-propenoate 8b with 9a afforded the
corresponding piperidine 10c with 94% ee and 99:1 dr in
73% yield (entry 4). Indolepropenoate 8c gave cyclization
product 10d with 98% ee and >99:1 dr in 85% yield (entry
5).37 Crotonate 8d was also converted to column chromato-
graphically separable cis-10e with 97% ee and 72:28 dr in 93%
yield (entry 6). Heptenoate 8e quantitatively gave cis-10f with
95% ee in 86:14 dr (entry 7). In the reaction of 8f, isomer-free
trans-fused bicyclic 10g having a quaternary asymmetric center
with 87% ee was obtained in 90% yield (entry 8).
Isopropyldimethylsilyl Group to Improve Diastereo-
selectivity. Although sufficiently high >99:1 diastereoselectiv-
ity was observed in most of the cyclization, an unsatisfactory
poor 72:28 diastereoselectivity was observed in the reaction of
crotonate 8d (Table 1, entry 6). On the basis of the assumption
of lesser steric repulsion between the methyl group, in place of
the phenyl, and the trimethylsilyl group (or benzyl group) on
the nitrogen of the chelate B (Scheme 3), a more bulky
trialkylsilyl group of 7 was screened in the reaction of crotonate
8d (Table 2, entries 1−4). As expected, the reaction with TBS-
amide 7b gave the product with the highest dr (95:5), whereas
the yield of 10e decreased unexpectedly to 32% due to the γ-
deprotonation of 8d (entry 2). TES-amide 7c did not improve
the selectivity, giving 10e with 63:37 dr (entry 3). The most
reliable diastereomeric ratio, 86:14, was obtained with
isopropyldimethylsilylamide 7d, giving chromatographically
separable cis-10e with 98% ee in 92% yield (entry 4). The
trialkylsilyl group on the nitrogen did not affect the sense of
enantioselectivity, giving cis-10e with the same absolute
configuration.
asymmetric conjugate addition of lithium N-benzyltrimethylsi-
lylamide (7a: R′ = Me) to indolepropenoate (8c: R = N-Boc-
indol-3-yl)38,39 followed by C,N-dual alkylation with 1-chloro-
3-iodopropane (9a: n = 3, X1 = Cl, X2 = I).40,41 Herein, we
describe an extension of this methodology to realize general
entry to enantio- and diastereoselective one-pot [N + 2 + n]
cyclization for azacyclic β-amino acid derivatives (Scheme 1, n
= 0−4). The present study also addresses the above-mentioned
ethylene dication equivalent problem in the synthesis of
pyrrolidines. This methodology provides the first general
entry to a one-pot synthesis of three- to seven-membered
chiral azacycloalkanes from readily available starting materials.
RESULTS AND DISCUSSION
■
One-Pot Asymmetric Construction of Piperidine-3-
carboxylate. Asymmetric one-pot [N + 2 + 3] cyclization
giving piperidine 10a was started with the chiral diether 11-
controlled conjugate addition of 3 equiv of lithium amide 7a
with tert-butyl cinnamate (8a) in toluene at −78 °C for 1.5
h,38a followed by successive treatment with 1-chloro-3-
iodopropane (9a)42 in DMPU at −40 °C for 2 h and then
tetrabutylammonium fluoride (TBAF) at 75 °C for 4 h,
affording cis-10a with 97% ee as a single diastereomer in 93%
yield (Scheme 2 and Table 1, entry 1). Chiral ligand 11 was
Scheme 2. [N + 2 + 3] Cyclization Giving Piperidine cis-10a
and Epimerization to trans-10a
Competitive Alkylation, Halogenation, and Protona-
tion in the Construction of Five-Membered Pyrrolidine.
To construct the five-membered pyrrolidines using the [N + 2
+ 2] cyclization strategy, we first addressed the ethylene
dication problem. Competitive halogenation27a and proto-
nation27b are both observed when 1,2-dihaloethane 9 is used as
a C2 source (Scheme 4).27 Indeed, the reaction of 7a and 8a
followed by an alkylative cyclization process with 1-chloro-2-
iodoethane (9c) afforded column chromatographically separa-
ble three-membered trans-aziridine 10i46 with 97% ee and
87:13 dr in 92% yield, without the formation of pyrrolidine 10h
(Table 3, entry 1). The relative configuration of trans-10i was
determined based on the 2.2 Hz coupling constant of the
quantitatively recovered and reused. Since both enantiomers of
11 are available, each enantiomer of the azacycloalkane can be
synthesized. Notably, the amount of lithium amide could be
reduced to 1.5 equiv, giving cis-10a with the same level of
selectivity in 83% yield (entry 2).
The S-absolute configuration at the chiral center-attached
nitrogen of 10a was constructed at the stage of the conjugate
addition of lithium amide, as reported previously.38 The cis-
configuration of 10a was apparent from the 4.9 Hz coupling
constant of the two adjacent methine protons and was further
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a
Table 1. One-Pot Asymmetric [N + 2 + 3] Construction of Piperidines
a
b
Conditions: N-trimethylsilylbenzylamine (1.5 mmol), BuLi (1.5 mmol), 11 (1.8 mmol), 8 (0.5 mmol), and 9 (5 mmol). The % ee of the major
c
d
diastereomer. Conditions: N-trimethylsilylbenzylamine (0.75 mmol), BuLi (0.75 mmol), 11 (0.9 mmol), 8 (0.5 mmol), and 9 (2.5 mmol). Quoted
from ref 37.
Scheme 3. Diastereoselective Alkylation via Conformation A
Scheme 4. Competitive Alkylation, Halogenation, and
Protonation of 12 with Dihaloethane 9 Giving Pyrrolidine
10h, Aziridine 10i, and β-Amino Ester 16
Table 2. Diastereoselectivity Dependency on
a
Trialkylsilylamide 7
a
entry
7
R
yield %
ee %
cis:trans
b
epimerization with sodium methoxide in refluxing xylene for 5
h to a separable 8:92 mixture of cis-10h and thermodynamically
more stable trans-10h.
1
7a
7b
7c
7d
Me3Si
93
32
85
92
97
97
95
98
72:28
95:5
2
3
4
t-BuMe2Si
Et3Si
63:37
86:14
Protonation of 12 with 9d was confirmed by successive
workup with tetradeuteriomethanol to give 16 in 69% yield
without any incorporation of deuterium, whereas direct
treatment of 12 with tetradeuteriomethanol gave a 4:1
diastereomeric mixture of 16 with 94% deuterium incorpo-
ration at the α-position in 97% yield (entry 4). When 2-
chloroethyl tosylate (9f) was used, no alkylation proceeded at
all and 16 was produced in 70% yield (entry 6). The use of
dibromoethane (9e) or 2-bromoethyl triflate (9g) also gave 16
as a major product along with a small amount of 10h (entries 5
and 7). Vinyl sulfonium salt 9h47 was a nonprotonating C2
source that unfortunately afforded 16 in 81% yield at −40 °C
(entry 8). Finally, ethylene sulfate (9i)48 was found to be a
satisfactory C2 source, giving separable cis-10h with 97% ee and
9:1 dr quantitatively with no production of 10i and 16 (entry
9).
i-PrMe2Si
b
a
The % ee of cis-10e. Quoted from Table 1, entry 6.
adjacent methine protons.46 The 2S,3R-absolute configuration
was apparent from the conjugate amination chemistry and
further confirmed by conversion to (S)-phenylalanine tert-butyl
ester (vide infra).
The intermediacy of α-iodide 15 (X = I) by diastereose-
lective iodination with 9c was further confirmed by treatment
of the resulting lithium enolate 12 with iodine to afford trans-
10i with 76:24 dr in 38% yield (entry 2). With 1-bromo-2-
chloroethane (9d)27b in place of iodide 9c, the expected
pyrrolidine cis-10h with 96% ee was obtained in 27% yield,
along with protonated 1638a with 97% ee in 62% yield (entry
3). The relative configuration of cis-10h was confirmed by
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Table 3. [N + 2 + n] Cyclization to Pyrrolidine 10h, Aziridine 10i, and β-Amino Ester 16 by the Reaction of 7a, 8a, and Ethylene
Dication Source 9c−i
a
b
The % ee of the major diastereomer. No deuterium incorporation at the α-position upon workup with CD3OD, whereas 94% deuterium
c
incorporation upon direct CD3OD quench of lithium enolate 12. Not determined.
Successful block of the protonation with 9i is rationalized
based on the unfavorable and not local minimum conformation
B, where H−C and the adjacent C−O bonds are anti-periplanar
to proceed to elimination (Scheme 5, HF/6-31G* level of
separable cis-10m with 99% ee and 93:7 dr in 73% yield along
with 16 in 24% yield, indicating that a steric environment
affects the competitive alkylation−protonation step (Table 4
entry 6 vs Table 3 entry 3). Interestingly, pyrrolidine trans-10m
was obtained as a 90:10 major isomer with 96% ee when 9i was
used as the C2 source (Table 4, entry 7). Epimerization of a 1:1
diastereomixture of 10m to 83:17 trans-major 10m quantita-
tively by sodium methoxide in refluxing xylene for 5 h clearly
confirmed the relative configuration of both isomers. The
relative and absolute configuration of cis-10m was further
confirmed by a short-step conversion to the dopamine D2 and
D3 receptor antagonist nemonapride 4 (Scheme 6). Production
of trans-major 10m by alkylation with 9i likely occurs through
syn-alkylation of the enolate 12 and not through epimerization.
Although the reason for this reversal of diastereoselectivity is
not clear, coordination of the sulfonate moiety to the lithium of
a chelate A could be responsible (Scheme 3).
Scheme 5. Conformations A−D in Ethylene Sulfate (9i) and
1-Bromo-2-chloroethane (9d) for E2 Elimination (HF/6-
31G*)
An [N + 2 + 0] cyclization of 7d and 8a/8d with 9c as a
halogen source proceeded smoothly to afford trans-aziridine 10i
with 98% ee and >99:1 dr in 86% yield and 10j with 98% ee
and 81:19 dr in 93% yield (Table 4, entries 1 and 2). The
relative and absolute configuration of trans-10j was confirmed
by its conversion to the azirinomycin intermediate 18.29e An [N
+ 2 + 1] cyclization was possible using bromoiodomethane (9j)
as the C1 source to give cis-azetidine 10k and 10l with high
enantio- and diastereoselectivity (entries 3 and 4). The [N + 2
+ 4] cyclization used C4 sources, 1,4-diiodobutane (9k) and
1,2-bis(bromomethyl)benzene (9l), to afford diastereomer-free
cis-azepane 10n and benzazepane 10o enantioselectively
(entries 8 and 9). The relative configuration of cis-10k, cis-
10l, cis-10n, and cis-10o was assigned by analogy. The absolute
configuration assignment of 10k−o was based on the
stereochemistry of the conjugate addition.38a
calculations). In the stable conformation A, the dihedral angle
of these two bonds is around 150° and does not proceed easily
to elimination. In contrast, conformation D of 9d is a local
minimum that proceeds to E2 elimination; that is, protonation
occurs on enolate 12 (Table 3, entry 3).
One-Pot Asymmetric [N + 2 + n] Construction of
Three-, Four-, Five-, and Seven-Membered Azacycles.
Having established the conditions for asymmetric and
diastereoselective one-pot [N + 2 + n] construction of
azacycloalkanes using 7d as an initiating lithium amide and 9i
as a C2 source, cinnamate 8a and crotonate 8d were
incorporated into the corresponding azacycloalkanes, as
summarized in Table 4. The reaction of 7d, 8a, and 9i
provided cis-pyrrolidine 10h with 97% ee and 97:3 dr in 97%
yield (Table 4, entry 5). The reaction of 7d, crotonate 8d, and
9d proceeded relatively smoothly to give chromatographically
Short-Step Asymmetric Synthesis of Phenylalanine,
Azirinomycin Ester, and Nemonapride. Aziridine trans-10i
was hydrogenated under hydrogen atmosphere (1 atm) in
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Table 4. One-Pot Asymmetric [N + 2 + n] Cyclization to Aziridine, Azetidine, Pyrrolidine, and Azepane
a
b
c
The ee % of the major diastereomer. The ee % of the minor diastereomer is in the parentheses. With aqueous HCl at 0 °C for 0.5 h and then
d
aqueous NaHCO3 at 100 °C for 1 h instead of TBAF treatment for cyclization. With aqueous HCl at 0 °C for 0.5 h and then aqueous NaHCO3 at
100 °C for 24 h instead of TBAF treatment for cyclization.
temperature for 5 h cleaved off the N-benzyl group to give
18, a known intermediate of azirinomycin tert-butyl ester (19),
in 71% yield.29e
Scheme 6. Asymmetric Synthesis of (S)-Phenylalanine,
Azirinomycin Ester, and Nemonapride
Conversion of cis-10m with TFA to carboxylic acid, Curtius
rearrangement with DPPA,51 and hydrolysis in the presence of
p-toluenesulfonic acid afforded the known intermediate 20 in
52% overall yield (Scheme 6). Amidation gave antipsychotic
nemonapride (4) in 83% yield. Similarly, piperidine cis-10a is
likely convertible into an NK1 antagonist, CP-99,994 (5)33
(Figure 1), in an analogous reaction sequence.
CONCLUSIONS
■
A highly enantio- and diastereoselective one-pot [N + 2 + n]
synthesis of azacycles was developed using a chiral diether-
controlled asymmetric aza-Michael addition−alkylation−cycli-
zation sequence. Two stereogenic centers in cis and three
covalent bonds were constructed in one pot, and three- to
seven-membered chiral azacyclic esters were generally acces-
sible. The high applicability of the developed methodology was
clearly demonstrated by the shortest synthesis of nemonapride
and azirinomycin ester.
EXPERIMENTAL SECTION
General. All melting points are uncorrected. Silica gel was used for
column chromatography. NMR (500 MHz for H and 125 MHz for
methanol at 50 °C for 24 h into (S)-phenylalanine tert-butyl
ester (17)49 in 75% yield (Scheme 6).50 Hydrogenolysis of
trans-10j under hydrogen atmosphere (1 atm) at room
■
1
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13C) was measured in CDCl3 unless otherwise mentioned. Chemical
shifts and coupling constants (J) are presented in parts per million
relative to tetramethylsilane and hertz, respectively. Abbreviations are
as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad. 13C peak multiplicity assignments were made based on DEPT
data. The wave numbers of maximum absorption peaks of IR
spectroscopy are presented in cm−1. A double-focusing magnetic
sector mass spectrometer was used for low- and high-resolution
FABMS and high-resolution EIMS, while low-resolution EIMS was
measured with a quadrupole mass spectrometer.
BnNH2 and DMPU were distillated from CaH2 prior to use.
Dehydrated solvents and anhydrous Et3N were purchased for the
reactions and used without further desiccation. N-Benzyl-N-
trimethylsilylamine,52 N-benzyl-N-tert-butyldimethylsilylamine,53 N-
benzyl-N-triethylsilylamine,53 enoates 8b38a and 8e,54 vinyl sulfonium
salt 9h,47 (1S,2S)-1,2-dimethoxy-1,2-diphenylethane (11),55 and 4-
carboxy-2-chloro-5-methoxy-N-methylammonium hydrogen sulfate56
were prepared according to reported procedures. Other reagents were
purchased and used as received.
(CH), 127.8 (CH), 128.0 (CH), 128.4 (CH), 129.4 (CH), 139.4 (C),
139.9 (C), 172.2 (C); IR 2932, 1728, 1149; EIMS m/z 351 (M+), 294
(M − t-Bu), 260 (M − Bn). Anal. Calcd for C23H29NO2: C, 78.59; H,
8.32; N, 3.99. Found: C, 78.31; H, 8.38; N, 3.99. The enantiomeric
excess was determined by HPLC analysis (Daicel Chiralcel OD-3, 254
nm, hexane/i-PrOH = 200/1, 1 mL/min, major 7.0 min and minor 7.5
min). The chiral diether ligand 11 (436 mg, quant) was recovered as
colorless plates.
(+)-tert-Butyl (2S,3R)-1-Benzyl-5-methylene-2-phenylpiperidine-
3-carboxylate (cis-10b). The typical procedure A with 9b in place
of 9a and column chromatography (hexane/AcOEt = 50/1) gave the
title compound (86%, >99:1 dr, 97% ee) as a colorless oil: Rf = 0.5
(hexane/AcOEt = 4/1); [α]2D5 +25.5 (c 0.90, CHCl3); 1H NMR δ 1.20
(9H, s), 2.55 (1H, dd, J = 5.2, 14.6), 2.82 (1H, m), 2.85 (1H, d, J =
13.8), 3.10 (1H, ddd, J = 5.2, 5.7, 10.9), 3.33 (1H, d, J = 13.8), 3.50
(1H, d, J = 13.8), 3.63 (1H, d, J = 13.8), 4.12 (1H, d, J = 5.7), 4.75
(1H, s), 4.86 (1H, s), 7.22−7.43 (10H, m); 13C NMR δ 27.7 (CH3),
31.8 (CH2), 45.0 (CH), 53.2 (CH2), 58.5 (CH2), 63.9 (CH), 80.3
(C), 110.2 (CH2), 126.9 (CH), 127.1 (CH), 128.0 (CH), 128.2 (CH),
128.8 (CH), 129.3 (CH), 139.0 (C), 139.5 (C), 142.3 (C), 172.1 (C);
IR 2977, 1728, 1149; EIMS m/z 363 (M+), 306 (M − t-Bu), 272 (M −
Bn); HRMS−FAB (m/z) [M + H]+ calcd for C24H30NO2 364.2277,
found 364.2278. The enantiomeric excess was determined by HPLC
analysis (Daicel Chiralcel OD-3, 254 nm, hexane/i-PrOH = 1000/1, 1
mL/min, minor 14.1 min and major 17.1 min). The chiral diether
ligand 11 was quantitatively recovered as colorless plates.
N-Benzyl-N-(isopropyldimethylsilyl)amine. To a solution of
BnNH2 (15.4 mL, 141 mmol), Et3N (25.3 mL, 183 mmol), and
DMAP (172 mg, 1.41 mmol) in Et2O (140 mL) was added
dimethylisopropylchlorosilane (25.0 mL, 162 mmol) over 20 min at
0 °C, and the mixture was stirred for 16 h at rt, and generated
precipitate was removed by filtration. Concentration of the filtrate and
distillation (70 °C/0.1 mmHg) gave title compound (24.2 g, 83%) as a
1
(−)-tert-Butyl (2S,3R)-1-Benzyl-2-(naphthalen-2-yl)piperidine-3-
carboxylate (cis-10c). The typical procedure A with 8b in place of
8a and column chromatography (hexane/AcOEt = 50/1) gave the title
compound (73%, >99:1 dr, 94% ee) as a colorless oil: Rf = 0.5
(hexane/AcOEt = 4/1); [α]2D5 −10.0 (c 0.99, CHCl3); 1H NMR δ 1.09
(9H, s), 1.63 (1H, m), 1.85 (1H, m), 2.06−2.16 (2H, m), 2.28 (1H,
m), 2.94−3.01 (2H, m), 3.30 (1H, d, J = 14.0), 3.66 (1H, d, J = 14.0),
4.02 (1H, d, J = 5.2), 7.20−7.33 (5H, m), 7.42−7.46 (2H, m), 7.59
(1H, m), 7.76−7.81 (3H, m), 7.85 (1H, s); 13C NMR δ 22.6 (CH2),
24.7 (CH2), 27.7 (CH3), 46.8 (CH), 49.2 (CH2), 59.5 (CH2), 66.2
(CH), 79.8 (C), 125.5 (CH), 125.8 (CH), 126.7 (CH), 127.4 (CH),
127.5 (CH), 127.8 (CH), 127.9 (CH), 128.0 (CH), 128.1 (CH),
128.6 (CH), 132.7 (C), 133.1 (C), 138.0 (C), 139.3 (C), 174.2 (C);
IR 2970, 1728, 1149; EIMS m/z 401 (M+), 344 (M − t-Bu), 310 (M −
Bn). Anal. Calcd for C27H31NO2: C, 80.76; H, 7.78; N, 3.49. Found:
C, 80.67; H, 7.84; N, 3.51. The enantiomeric excess was determined
by HPLC analysis (Daicel Chiralpak AD-3, 254 nm, hexane/i-PrOH =
100/1, 1 mL/min, major 5.7 min and minor 6.3 min). The chiral
diether ligand 11 was quantitatively recovered as colorless plates.
(−)-tert-Butyl (2R,3R)- and (2S,3R)-1-Benzyl-2-methylpiperidine-
3-carboxylate (cis- and trans-10e). The typical procedure A with 8d
in place of 8a and column chromatography (hexane/AcOEt = 100/1
to 19/1) gave cis-10e (67%, 97% ee) as a colorless powder of mp 57−
58 °C, trans-10e (26%, 97% ee) as a colorless oil, and chiral diether
ligand 11 (quantitative recovery) as colorless plates. The enantiomeric
excess of cis- and trans-10e was determined by HPLC analysis (cis-10e:
Daicel Chiralcel OJ-H × 2, 254 nm, hexane/i-PrOH = 1000/1, 2 mL/
min, major 13.4 min and minor 16.5 min; trans-10e: Daicel Chiralcel
OD-3, 254 nm, hexane/i-PrOH = 1500/1, 2 mL/min, major 9.0 min
and minor 10.2 min).
colorless oil: H NMR δ 0.02 (6H, s), 0.71 (1H, br s), 0.79 (1H, m),
0.97 (6H, d, J = 7.5), 3.94 (2H, d, J = 8.0), 7.21 (1H, m), 7.29−7.31
(4H, m); 13C NMR δ −4.0 (CH3), 14.9 (CH), 17.4 (CH3), 46.1
(CH2), 126.3 (CH), 126.9 (CH), 128.2 (CH), 144.4 (C); IR 3402,
2947, 1250; EIMS m/z 207 (M+), 164 (M − i-Pr), 106 (M − Me2i-
PrSi); HRMS−EI (m/z) [M]+ calcd for C12H21NSi 207.1443, found
207.1449.
tert-Butyl Cyclopentene-1-carboxylate (8f). To a stirred
solution of cyclopentene-1-carboxylic acid (10 g, 89 mmol) in THF
(18 mL) was added SOCl2 (8.4 mL, 116 mmol) at rt, and the mixture
was heated under reflux for 1 h. After being cooled to rt, the mixture
was concentrated in vacuo, and the residue was dissolved in THF (21
mL). To the solution was added a solution of t-BuOLi (11 g, 133
mmol) in THF (24 mL) at 0 °C, and the mixture was stirred at rt.
After 2 h, saturated NH4Cl (50 mL) was added to the mixture, and the
whole was extracted with AcOEt. The organic layer was washed with
saturated NaHCO3 and brine and then dried over Na2SO4.
Concentration followed by distillation (80−81 °C/13 mmHg) gave
1
the title compound as a colorless oil (13 g, 61%). The H and 13C
NMR, IR, and MS were identical to those reported.57
One-Pot Asymmetric [N + 2 + n] Construction of Three- to
Seven-Membered Azacycloalkanes. Typical Procedure A:
(−)-tert-Butyl (2S,3R)-1-Benzyl-2-phenylpiperidine-3-carboxylate
(cis-10a): To a solution of N-benzyl-N-trimethylsilylamine (0.29 mL,
1.5 mmol) in toluene (4 mL) was added a 1.61 M hexane solution of
BuLi (0.93 mL, 1.5 mmol) at −78 °C over 4 min, and the mixture was
stirred for 30 min at −78 °C. A solution of chiral diether 11 (436 mg,
1.8 mmol) in toluene (2 mL) was added over 5 min, and after 30 min,
a solution of enoate 8a (102 mg, 0.5 mmol) in toluene (2 mL) was
added over 8 min. The mixture was stirred for 1.5 h at −78 °C, and a
solution of 1-chloro-3-iodopropane 9a (0.54 mL, 5 mmol) in DMPU
(8 mL) was added over 30 min at −78 °C. The mixture was stirred for
2 h at −40 °C, and a 1.0 M THF solution of TBAF (7.5 mL, 7.5
mmol) was added. The whole was stirred for 4 h at 75 °C, then cooled
to rt, and diluted with water and toluene. The organic layer was
washed with water three times and brine and dried over Na2SO4.
Concentration and column chromatography (hexane/AcOEt = 100/1
to 10/1) gave the title compound (164 mg, 93%, >99:1 dr) as a
colorless oil: Rf = 0.7 (hexane/AcOEt = 4/1); [α]2D5 −13.2 (c 1.13,
CHCl3); 1H NMR δ 1.16 (9H, s), 1.59 (1H, m), 1.79 (1H, m), 1.99−
2.09 (2H, m), 2.25 (1H, m), 2.84−2.94 (2H, m), 3.26 (1H, d, J =
14.0), 3.56 (1H, d, J = 14.0), 3.89 (1H, d, J = 4.9), 7.19−7.41 (10H,
m); 13C NMR δ 22.8 (CH2), 24.3 (CH2), 27.7 (CH3), 46.8 (CH),
48.7 (CH2), 59.3 (CH2), 66.0 (CH), 79.7 (C), 126.6 (CH), 127.0
cis-10e: Rf = 0.5 (hexane/AcOEt = 4/1); [α]2D5 −6.55 (c 1.47,
1
CHCl3); H NMR δ 0.94 (3H, d, J = 6.6), 1.43 (9H, s), 1.46−1.73
(4H, m), 2.34−2.42 (2H, m), 2.74 (1H, ddd, J = 12.3, 4.3, 4.0), 3.40
(1H, dq, J = 4.3, 6.6), 3.52 (1H, d, J = 17.2), 3.67 (1H, d, J = 17.2),
7.21−7.35 (5H, m); 13C NMR δ 6.0 (CH3), 20.5 (CH2), 24.4 (CH2),
28.0 (CH3), 44.2 (CH2), 46.8 (CH), 54.6 (CH), 59.2 (CH2), 79.9
(C), 126.7 (CH), 128.1 (CH), 128.5 (CH), 139.8 (C), 173.4 (C); IR
2939, 1720, 1134; EIMS m/z 289 (M+), 274 (M − Me), 232 (M − t-
Bu); HRMS−FAB (m/z) [M + H]+ calcd for C18H28NO2 290.2120,
found 290.2127.
trans-10e: Rf = 0.5 (hexane/AcOEt = 4/1); [α]2D5 −24.5 (c 0.89,
1
CHCl3); H NMR δ 1.20 (3H, d, J = 5.7), 1.45 (9H, s), 1.48−1.52
(3H, m), 1.84 (1H, m), 2.05 (1H, m), 2.23 (1H, m), 2.64−2.74 (2H,
m), 3.25 (1H, d, J = 13.2), 3.97 (1H, d, J = 13.2), 7.21−7.31 (5H, m);
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Featured Article
13C NMR δ 17.4 (CH3), 23.9 (CH2), 27.5 (CH2), 28.1 (CH3), 50.4
100/1, 1 mL/min, major 4.6 min and minor 5.3 min). The chiral
diether ligand 11 was quantitatively recovered as colorless plates.
(−)-tert-Butyl (2S,3R)-1-Benzyl-3-phenylaziridine-2-carboxylate
(CH), 51.3 (CH2), 57.4 (CH2), 57.6 (CH), 80.1 (C), 127.0 (CH),
128.1 (CH), 128.9 (CH), 139.5 (C), 174.5 (C); IR 2978, 1728, 1157;
EIMS m/z 289 (M+), 274 (M − Me), 232 (M − t-Bu). Anal. Calcd for
C18H27NO2: C, 74.70; H, 9.40; N, 4.84. Found: C, 74.81; H, 9.25; N,
4.82.
(trans-10i). The typical procedure
A with N-benzyl-N-
(isopropyldimethylsilyl)amine and 9c in place of N-benzyl-N-
trimethylsilylamine and 9a, respectively, and column chromatography
(hexane/AcOEt = 150/1) gave the title compound (94%, >99:1 dr,
98% ee) as a colorless powder of mp 51−52 °C: Rf = 0.5 (hexane/
(−)-tert-Butyl (2S,3R)-1-Benzyl-2-butylpiperidine-3-carboxylate
(cis-10f). The typical procedure A with 8e in place of 8a and column
chromatography (hexane/AcOEt = 100/1 to 50/1) gave a 79:21
mixture of cis- and trans-10f (66%) as a colorless oil, cis-10f (33%, 95%
ee) as a colorless oil, and chiral diether ligand 11 (quantitative
recovery) as colorless plates. The enantiomeric excess of cis-10f was
determined by HPLC analysis (Daicel Chiralcel OD-3, 254 nm,
hexane/i-PrOH = 600/1, 1 mL/min, minor 7.3 min and major 8.3
min).
1
AcOEt = 4/1); [α]2D5 −8.55 (c 1.07, CHCl3). H and 13C NMR, and
MS were identical to those reported.58 The enantiomeric excess was
determined by HPLC analysis (Daicel Chiralpak AD-3, 254 nm,
hexane/i-PrOH = 100/1, 1 mL/min, major 6.5 min and minor 7.3
min). The chiral diether ligand 11 was quantitatively recovered as
colorless plates.
(−)-tert-Butyl (2S,3R)- and (2R,3R)-1-Benzyl-3-methylaziridine-2-
carboxylate (trans- and cis-10j). The typical procedure A with N-
benzyl-N-(isopropyldimethylsilyl)amine, 8d, and 9c in place of N-
benzyl-N-trimethylsilylamine, 8a, and 9a, respectively, and column
chromatography (hexane/AcOEt = 98/2 to 85/15) gave trans-10j
(75%, 98% ee) as a colorless oil, cis-10j (18%, 97% ee) as colorless
needles of mp 62−63 °C, and chiral diether ligand 11 (quantitative
recovery) as colorless plates. The enantiomeric excess of trans- and cis-
10j was determined by HPLC analysis (trans-10j: Daicel Chiralpak
AD-3, 254 nm, hexane/i-PrOH = 100/1, 1 mL/min, major 18.2 min
and minor 34.3 min; cis-10j: Daicel Chiralpak AD-3, 254 nm, hexane/
i-PrOH = 100/1, 1 mL/min, major 22.1 min and minor 23.2 min).
trans-10j: Rf = 0.4 (hexane/AcOEt = 4/1); [α]2D5 −70.8 (c 0.97,
CHCl3). Two isomers, probably invertomers of the nitrogen atom,59
cis-10f: Rf = 0.2 (hexane/AcOEt = 9/1); [α]2D5 −6.58 (c 1.11,
1
CHCl3); H NMR δ 0.87 (3H, d, J = 7.2), 1.09 (1H, m), 1.23−1.76
(9H, m), 1.42 (9H, s), 2.48 (1H, m), 2.67 (1H, m), 2.80 (1H, m), 3.06
(1H, m), 3.70 (1H, d, J = 13.5), 3.85 (1H, d, J = 13.5), 7.21−7.35 (5H,
m); 13C NMR δ 14.1 (CH3), 21.0 (CH2), 21.6 (CH2), 22.7 (CH2),
25.1 (CH2), 28.1 (CH3), 30.1 (CH2), 42.8 (CH), 43.7 (CH2), 58.2
(CH2), 59.8 (CH), 79.9 (C), 127.6 (CH), 128.1 (CH), 128.6 (CH),
140.3 (C), 174.0 (C); IR 2932, 1728, 1142; EIMS m/z 331 (M+), 274
(M − Bu); HRMS−FAB (m/z) [M + H]+ calcd for C21H34NO2
332.2590, found 332.2585.
(−)-tert-Butyl (4R,7R)-1-Benzyloctahydro-1H-cyclopentapyridine-
4-carboxylate (trans-10g). The typical procedure A with 8f in place
of 8a and column chromatography (hexane/AcOEt = 100/1 to 50/1)
gave the title compound (90%, >99:1 dr, 87% ee) as a colorless oil: Rf
= 0.4 (hexane/AcOEt = 8/2); [α]2D5 −36.3 (c 1.20, CHCl3); 1H NMR
δ 1.02 (1H, m), 1.42−1.49 (2H, m), 1.49 (9H, s), 1.67−1.93 (6H, m),
2.11−2.19 (2H, m), 2.37 (1H, m), 2.82 (1H, m), 3.70 (1H, d, J =
13.5), 3.97 (1H, d, J = 13.5), 7.19−7.36 (5H, m); 13C NMR δ 20.3
(CH2), 23.8 (CH2), 27.5 (CH2), 28.2 (CH3), 35.0 (CH2), 35.6 (CH2),
53.7 (C), 54.9 (CH2), 60.2 (CH2), 73.7 (CH), 79.6 (C), 126.5 (CH),
127.9 (CH), 128.6 (CH), 140.1 (C), 174.6 (C); IR 2955, 1713, 1150;
EIMS m/z 315 (M+), 258 (M − t-Bu); HRMS−FAB (m/z) [M + H]+
calcd for C20H30NO2, 316.2277; found, 316.2281. The enantiomeric
excess was determined by HPLC analysis (Daicel Chiralcel OD-3, 254
nm, hexane/i-PrOH = 600/1, 1 mL/min, major 7.2 min and minor 7.8
min). The chiral diether ligand 11 was quantitatively recovered as
colorless plates.
Typical Procedure B: (−)-tert-Butyl (2S,3R)-1-Benzyl-2-phenyl-
pyrrolidine-3-carboxylate (cis-10h). To a solution of N-benzyl-N-
(isopropyldimethylsilyl)amine (311 mg, 1.5 mmol) in toluene (4 mL)
was added a 1.61 M hexane solution of BuLi (0.93 mL, 1.5 mmol) at
−78 °C over 4 min, and the mixture was stirred for 30 min at −78 °C.
A solution of chiral diether 11 (436 mg, 1.8 mmol) in toluene (2 mL)
was added over 5 min, and after 30 min, a solution of enoate 8a (102
mg, 0.5 mmol) in toluene (2 mL) was added over 8 min. The mixture
was stirred for 1.5 h at −78 °C, and a solution of ethylene sulfate 9i
(620 mg, 5 mmol) in DMPU (8 mL) was added over 30 min at −78
°C. The mixture was stirred for 2 h at −40 °C, and 10% HCl (3 mL)
was added. The whole was stirred for 0.5 h at 0 °C, and then saturated
NaHCO3 (12 mL) was added. The whole was stirred for another 1 h
at 100 °C, then cooled to rt, and diluted with water and toluene. The
organic layer was washed with water three times and brine and dried
over Na2SO4. Concentration and column chromatography (hexane/
AcOEt = 97/3 to 9/1) gave the title compound (164 mg, 97%, 97%
ee) as a colorless oil: Rf = 0.7 (hexane/AcOEt = 4/1); [α]2D5 −13.2 (c
1.13, CHCl3); 1H NMR δ 0.98 (9H, s), 1.92 (1H, m), 2.22−2.37 (2H,
m), 3.11 (1H, d, J = 13.5), 3.14−3.26 (2H, m), 3.80 (1H, d, J = 12.0),
3.83 (1H, d, J = 13.5), 7.19−7.31 (8H, m), 7.45−7.46 (2H, m); 13C
NMR δ 26.8 (CH2), 27.4 (CH3), 49.8 (CH), 52.3 (CH2), 57.5 (CH2),
70.4 (CH), 79.8 (C), 126.7 (CH), 127.3 (CH), 127.9 (CH), 128.1
(CH), 128.6 (CH), 129.1 (CH), 139.2 (C), 140.0 (C), 172.0 (C); IR
2970, 1720, 1149; EIMS m/z 337 (M+), 264 (M − t-BuO), 246 (M −
Bn). Anal. Calcd for C22H27NO2: C, 78.30; H, 8.06; N, 4.15. Found:
C, 78.23; H, 8.11; N, 4.10. The enantiomeric excess was determined
by HPLC analysis (Daicel Chiralpak AD-3, 254 nm, hexane/i-PrOH =
1
were observed in 7:3 ratio by NMR: H NMR δ 1.24 (2.1H, d, J =
5.4), 1.35 (0.9H, d, J = 6.0), 1.38 (6.3H, s), 1.45 (2.7H, s), 1.89 (0.3H,
d, J = 2.6), 2.27 (0.7H, dq, J = 2.8, 5.4), 2.38 (0.7H, d, J = 2.8), 2.55
(0.3H, dq, J = 2.6, 6.0), 3.70 (0.3H, d, J = 14.5), 3.82 (0.3H, d, J =
14.5), 3.88 (0.7H, d, J = 14.0), 4.05 (0.7H, d, J = 14.0), 7.21−7.39
(5H, m). Major isomer of trans-10j: 13C NMR δ 17.8 (CH3), 27.9
(CH3), 42.1 (CH), 42.5 (CH), 54.7 (CH2), 81.3 (C), 126.7 (CH),
127.9 (CH), 128.2 (CH), 139.6 (C), 168.7 (C). Minor isomer of
trans-10j: 13C NMR δ 10.7 (CH3), 28.0 (CH3), 39.4 (CH), 45.2
(CH), 54.5 (CH2), 81.0 (C), 126.7 (CH), 127.4 (CH), 128.4 (CH),
139.2 (C), 170.3 (C); IR 2978, 1720, 1157; EIMS m/z 247 (M+), 232
(M − Me), 190 (M − t-Bu), 146 (M − CO2t-Bu); HRMS−FAB (m/
z) [M + H]+ calcd for C15H22NO2 248.1651, found 248.1661.
cis-10j: Rf = 0.3 (hexane/AcOEt = 4/1); [α]2D5 +76.1 (c 1.04,
CHCl3); 1H NMR δ 1.28 (3H, d, J = 5.7), 1.47 (9H, s), 1.92 (1H, dq, J
= 6.8, 5.7), 2.11 (1H, d, J = 6.8), 3.54 (1H, d, J = 14.0), 3.63 (1H, d, J
= 14.0), 7.23−7.37 (5H, m); 13C NMR δ 13.0 (CH3), 28.1 (CH3),
41.3 (CH), 43.6 (CH), 63.4 (CH2), 81.6 (C), 126.9 (CH), 127.6
(CH), 128.2 (CH), 138.4 (C), 168.9 (C); IR 2970, 1728, 1157; EIMS
m/z 247 (M+), 232 (M − Me), 190 (M − t-Bu), 146 (M − CO2t-Bu).
Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C,
72.59; H, 8.34; N, 5.66.
(−)-tert-Butyl (2S,3R)-1-Benzyl-2-phenylazetidine-3-carboxylate
(cis-10k). The typical procedure B with N-benzyl-N-trimethylsilyl-
amine and 9j in place of N-benzyl-N-(isopropyldimethylsilyl)amine
and 9i, respectively, and column chromatography (hexane/AcOEt =
100/1 to 50/1) gave the title compound (82%, >99:1 dr, 97% ee) as a
colorless powder of mp 83−84 °C: Rf = 0.3 (hexane/AcOEt = 4/1);
[α]2D5 −118.4 (c 1.16, CHCl3); 1H NMR δ 1.00 (9H, s), 2.93 (1H, dd,
J = 7.2, 7.2), 3.34 (1H, ddd, J = 9.2, 7.2, 2.6), 3.45 (1H, d, J = 13.5),
3.69 (1H, dd, J = 7.2, 2.6), 3.86 (1H, d, J = 13.5), 4.55 (1H, d, J = 9.2),
7.21−7.49 (10H, m); 13C NMR δ 27.5 (CH3), 42.0 (CH), 51.1
(CH2), 60.8 (CH2), 69.1 (CH), 80.1 (C), 126.8 (CH), 127.3 (CH),
127.4 (CH), 127.9 (CH), 128.2 (CH), 128.5 (CH), 137.9 (C), 139.0
(C), 170.4 (C); IR 2978, 1728, 1157; EIMS m/z 323 (M+), 266 (M −
t-Bu), 232 (M − Bn); HRMS−FAB (m/z) [M + H]+ calcd for
C21H25NO2 324.1964, found 324.1951. The enantiomeric excess was
determined by HPLC analysis (Daicel Chiralpak AD-3, 254 nm,
hexane/i-PrOH = 100/1, 1 mL/min, major 6.5 min and minor 7.6
min). The chiral diether ligand 11 was quantitatively recovered as
colorless plates.
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(−)-tert-Butyl (2R,3R)-1-Benzyl-2-methylazetidine-3-carboxylate
(cis-10l). The typical procedure B with 8d and 9j in place of 8a and
9i, respectively, and column chromatography (hexane/AcOEt = 24/1
to 10/1) gave a 7:3 mixture of trans- and cis-10l (16%) as a colorless
oil, cis-10l (41%, 98% ee) as a colorless oil, and chiral diether ligand 11
(quantitative recovery) as colorless plates. The enantiomeric excess of
cis-10l was determined by HPLC analysis (Daicel Chiralpak AD-3, 254
nm, hexane/i-PrOH = 100/1, 1 mL/min, minor 6.3 min and major
19.9 min).
140.5 (C), 141.7 (C), 172.9 (C); IR 2924, 1728, 1149; EIMS m/z 365
(M+), 308 (M − t-Bu), 274 (M − Bn); HRMS−FAB (m/z) [M + H]+
calcd for C24H32NO2 366.2433, found 366.2431. The enantiomeric
excess was determined by HPLC analysis (Daicel Chiralcel OD-3, 254
nm, hexane/i-PrOH = 400/1, 1 mL/min, major 8.4 min and minor 8.9
min). The chiral diether ligand 11 was quantitatively recovered as
colorless plates.
(+)-tert-Butyl (2S,3R)-1-Benzyl-3-phenyl-2,3,4,5-tetrahydro-1H-
benzoazepine-4-carboxylate (cis-10o). The typical procedure B
with N-benzyl-N-trimethylsilylamine and 9l in place of N-benzyl-N-
(isopropyldimethylsilyl)amine and 9i, respectively, and column
chromatography (hexane/AcOEt = 50/1) gave the title compound
(57%, >99:1 dr, 98% ee) as a colorless oil: Rf = 0.6 (hexane/AcOEt =
4/1); [α]2D5 +59.3 (c 1.14, CHCl3); 1H NMR δ 1.30 (9H, s), 3.22 (1H,
m), 3.29 (1H, d, J = 15.5), 3.50−3.65 (4H, m), 4.02 (1H, d, J = 15.5),
4.57 (1H, d, J = 3.7), 6.87 (1H, d, J = 7.5), 7.08 (1H, dd, J = 7.3, 0.7),
7.16 (1H, dd, J = 7.5, 1.2), 7.22−7.37 (9H, m), 7.60−7.62 (2H, m);
13C NMR δ 27.8 (CH3), 31.2 (CH2), 42.8 (CH), 53.0 (CH2), 56.9
cis-10l: Rf = 0.3 (hexane/AcOEt = 4/1); [α]2D5 −1.54 (c 1.10,
CHCl3); 1H NMR δ 1.05 (3H, d, J = 6.3), 1.47 (9H, s), 2.91 (1H, dd, J
= 7.8, 7.5), 3.09 (1H, m), 3.56 (1H, d, J = 13.0), 3.57 (1H, m), 3.65
(1H, m), 3.66 (1H, d, J = 13.0), 7.21−7.32 (5H, m); 13C NMR δ 17.2
(CH3), 28.2 (CH3), 39.6 (CH), 52.3 (CH2), 61.6 (CH2), 62.8 (CH),
80.6 (C), 126.9 (CH), 128.1 (CH), 128.8 (CH), 138.0 (C), 171.7
(C); IR 2970, 1728, 1150; EIMS m/z 261 (M+), 204 (M − t-Bu), 170
(M − Bn); HRMS−FAB (m/z) [M + H]+ calcd for C16H24NO2
262.1807, found 262.1792.
(−)-tert-Butyl (2R,3S)-1-Benzyl-2-methylpyrrolidine-3-carboxy-
late (trans-10m). The typical procedure B with N-benzyl-N-
(trimethylsilyl)amine and 8d in place of N-benzyl-N-
(isopropyldimethylsilyl)amine and 8a, respectively, and column
chromatography (hexane/AcOEt = 50/1 to 9/1) gave a 9:1 mixture
of trans- and cis-10m (97%, 96% ee for trans-isomer) as a colorless oil
and chiral diether ligand 11 (quantitative recovery) as colorless plates.
The enantiomeric excess of trans-10m was determined by HPLC
analysis (Daicel Chiralcel OD-3, 254 nm, hexane/i-PrOH = 1000/1, 1
mL/min, major 13.7 min and minor 18.0 min).
(CH2), 66.0 (CH), 80.8 (C), 125.9 (CH), 126.8 (CH), 126.9 (CH),
127.1 (CH), 128.1 (CH), 128.2 (CH), 128.6 (CH), 128.9 (CH),
129.1 (CH), 129.7 (CH), 138.6 (C), 139.3 (C), 140.3 (C), 140.7 (C),
173.7 (C); IR 2977, 1720, 1149; EIMS m/z 413 (M+), 356 (M − t-
Bu), 322 (M − Bn); HRMS−FAB (m/z) [M + H]+ calcd for
C28H32NO2 414.2433, found 414.2448. The enantiomeric excess was
determined by HPLC analysis (Daicel Chiralcel OZ-H, 254 nm,
hexane/i-PrOH = 600/1, 1 mL/min, major 8.9 min and minor 16.8
min). The chiral diether ligand 11 was quantitatively recovered as
colorless plates.
trans-10m: Rf = 0.4 (hexane/AcOEt = 4/1); [α]2D5 −60.1 (c 1.15,
( )-tert-Butyl 1-Benzylpiperidine-3-carboxylate. The typical pro-
cedure A with N-benzyl-N-(isopropyldimethylsilyl)amine and tert-
butyl acrylate in place of N-benzyl-N-trimethylsilylamine and 8a,
respectively, and column chromatography (hexane/AcOEt = 19/1)
gave the title compound (42%, 0% ee) as a colorless oil: Rf = 0.4
1
CHCl3); H NMR δ 1.29 (3H, d, J = 5.2), 1.46 (9H, s), 1.91−1.97
(2H, m), 2.21 (1H, m), 2.49−2.55 (2H, m), 2.88 (1H, m), 3.12 (1H,
d, J = 13.3), 4.01 (1H, d, J = 13.3), 7.22−7.30 (5H, m); 13C NMR δ
18.7 (CH3), 25.9 (CH2), 28.1 (CH3), 51.5 (CH), 53.2 (CH2), 58.0
(CH2), 63.6 (CH), 80.3 (C), 126.9 (CH), 128.2 (CH), 129.0 (CH),
139.2 (C), 174.3 (C); IR 2970, 1728, 1157; EIMS m/z 275 (M+), 260
(M − Me), 218 (M − t-Bu), 204 (M − Me − t-Bu), 184 (M − Bn).
Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15; N, 5.09. Found: C,
74.17; H, 9.27; N, 5.10.
1
(hexane/AcOEt = 4/1); H NMR δ 1.41 (9H, s), 1.42 (1H, m), 1.54
(1H, m), 1.69 (1H, m), 1.86−2.17 (3H, m), 2.47 (1H, m), 2.70 (1H,
m), 2.92 (1H, m), 3.46 (1H, d, J = 13.2), 3.53 (1H, d, J = 13.2), 7.22−
7.39 (5H, m); 13C NMR δ 24.5 (CH2), 27.0 (CH2), 28.0 (CH3), 42.7
(CH), 53.6 (CH2), 55.7 (CH2), 63.3 (CH2), 80.0 (C), 126.9 (CH),
128.1 (CH), 129.0 (CH), 138.5 (C), 173.7 (C); IR 2939, 1728, 1150;
FABMS m/z 276 (M + H)+, 218 (M − t-Bu); HRMS−FAB (m/z) [M
+ H]+ calcd for C17H26NO2 276.1964, found 276.1965. The
enantiomeric excess of the title compound was determined by
HPLC analysis (Daicel Chiralcel OD-3, 254 nm, hexane/i-PrOH =
400/1, 1 mL/min, 13.0 and 15.9 min). The chiral diether ligand 11
was quantitatively recovered as colorless plates.
(−)-tert-Butyl (2R,3R)-1-benzyl-2-methylpyrrolidine-3-carboxy-
late (cis-10m). The typical procedure B with 8d and 9d in place of
8a and 9i, respectively, and column chromatography (hexane/AcOEt
= 19/1) gave a 93:7 mixture of cis- and trans-10m (73%, 99% ee for
cis-isomer) as a colorless oil and chiral diether ligand 11 (quantitative
recovery) as colorless plates. The enantiomeric excess of cis-10m was
determined by HPLC analysis (Daicel Chiralcel OD-3, 254 nm,
hexane/i-PrOH = 400/1, 1 mL/min, minor 10.2 min and major 10.9
min).
Epimerization of cis-10a (Scheme 2). (+)-tert-Butyl (2S,3S)-1-
Benzyl-2-phenylpiperidine-3-carboxylate (trans-10a). A suspension
of cis-10a (50 mg, 0.14 mmol) and NaOMe (31 m, 0.57 mmol) in
xylene (1 mL) was stirred under reflux. After 3.5 h, saturated NaHCO3
(2 mL) was added, and the organic layer was separated. The aqueous
layer was extracted with AcOEt, and the combined organic layers were
washed with brine and then dried over Na2SO4. The diastereomer
cis-10m: Rf = 0.4 (hexane/AcOEt = 4/1); [α]2D5 −41.7 (c 1.53,
CHCl3); 1H NMR δ 1.07 (3H, d, J = 6.2), 1.46 (9H, s), 1.83 (1H, m),
2.13 (1H, m), 2.28 (1H, m), 2.89−2.97 (3H, m), 3.38 (1H, d, J =
13.3), 3.89 (1H, d, J = 13.3), 7.21−7.34 (5H, m); 13C NMR δ 14.6
(CH3), 25.7 (CH2), 28.1 (CH3), 48.1 (CH), 52.1 (CH2), 57.4 (CH2),
59.9 (CH), 80.2 (C), 126.7 (CH), 128.1 (CH), 128.7 (CH), 139.3
(C), 172.9 (C); IR 2970, 1728, 1150; EIMS m/z 275 (M+), 260 (M −
Me), 218 (M − t-Bu), 204 (M − Me − t-Bu), 184 (M − Bn);
HRMS−FAB (m/z) [M + H]+ calcd for C17H26NO2 276.1964, found
276.1971.
1
ratio was determined to be >98:2 by H NMR of the crude material.
Concentration and column chromatography (hexane/AcOEt = 50/1)
gave the title compound (93%, >99:1 dr, 97% ee) as a colorless oil: Rf
= 0.7 (hexane/AcOEt = 4/1); [α]2D5 +37.1 (c 1.28, CHCl3); 1H NMR
δ 1.13 (9H, s), 1.60−1.71 (3H, m), 1.96−2.03 (2H, m), 2.61 (1H, m),
2.79 (1H, d, J = 13.5), 2.95 (1H, m), 3.30 (1H, d, J = 10.0), 3.70 (1H,
d, J = 13.5), 7.16−7.45 (10H, m); 13C NMR δ 24.7 (CH2), 27.7
(CH3), 28.7 (CH2), 52.6 (CH2), 52.7 (CH), 59.1 (CH2), 70.3 (CH),
79.8 (C), 126.6 (CH), 127.4 (CH), 128.0 (CH), 128.2 (CH), 128.6
(CH), 128.7 (CH), 140.0 (C), 141.7 (C), 173.4 (C); IR 2939, 1728,
1149; EIMS m/z 351 (M+), 294 (M − t-Bu), 260 (M − Bn); HRMS−
FAB (m/z) [M + H]+ calcd for C23H30NO2 352.2277, found 352.2272.
The enantiomeric excess was determined by HPLC analysis (Daicel
Chiralpak AD-3, 254 nm, hexane/i-PrOH = 200/1, 1 mL/min, major
5.8 min and minor 6.4 min).
(+)-tert-Butyl (2S,3R)-1-Benzyl-2-phenylazepane-3-carboxylate
(cis-10n). The typical procedure B with N-benzyl-N-trimethylsilyl-
amine and 9k in place of N-benzyl-N-(isopropyldimethylsilyl)amine
and 9i, respectively, and column chromatography (hexane/AcOEt =
100/1 to 9/1) gave the title compound (71%, >99:1 dr, 97% ee) as a
colorless powder of mp 116−118 °C: Rf = 0.5 (hexane/AcOEt = 4/1);
[α]2D5 +79.7 (c 1.01, CHCl3); H NMR δ 1.25 (9H, s), 1.31 (1H, m),
1
1.55 (1H, m), 1.63 (1H, m), 1.85−1.93 (2H, m), 2.10 (1H, m), 2.64
(1H, m), 2.75 (1H, m), 2.99 (1H, m), 3.25 (1H, d, J = 14.0), 3.67
(1H, d, J = 14.0), 4.11 (1H, d, J = 6.3), 7.17−7.30 (10H, m); 13C
NMR δ 24.1 (CH2), 27.9 (CH3), 28.1 (CH2), 30.7 (CH2), 49.5
(CH2), 51.6 (CH), 59.9 (CH2), 69.2 (CH), 80.2 (C), 126.6 (CH),
127.3 (CH), 127.8 (CH), 128.0 (CH), 128.4 (CH), 129.1 (CH),
A Control Experiment for Table 3, entry 4. (R)-tert-Butyl 3-
(Benzylamino)-2-deuterio-3-phenylpropanoate (16d). To a solution
of N-benzyl-N-trimethylsilylamine (0.29 mL, 1.5 mmol) in toluene (4
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The Journal of Organic Chemistry
Featured Article
mL) was added a 1.61 M hexane solution of BuLi (0.93 mL, 1.5
mmol) at −78 °C over 4 min, and the mixture was stirred for 30 min
at −78 °C. A solution of chiral diether 11 (436 mg, 1.8 mmol) in
toluene (2 mL) was added over 5 min, and after 30 min, a solution of
enoate 8a (102 mg, 0.5 mmol) in toluene (2 mL) was added over 8
min. The mixture was stirred for 15 h at −78 °C, and CD3OD (0.75
mL) was added at −78 °C. The mixture was warmed up to rt and
stirred for 20 min, and aqueous NH4Cl (2 mL) and saturated
NaHCO3 (12 mL) were added. The aqueous layer was extracted with
AcOEt, and the combined organic layers were washed with brine and
dried over Na2SO4. Concentration and column chromatography
(hexane/AcOEt = 97/3 to 92/8) gave the title compound (151 mg,
97%, 80:20 dr, 94%-deuteration) as a colorless oil: Rf = 0.5 (hexane/
AcOEt = 4/1); 1H NMR δ 1.37 (9H, s), 2.05 (1H, br s), 2.51 (0.2H, d,
J = 5.2), 2.62 (0.8H, d, J = 8.9), 3.54 (1H, d, J = 13.0), 3.62 (1H, d, J =
13.0), 4.06 (1H, d, J = 6.4), 7.22−7.37 (10H, m); 13C NMR δ 28.0
(CH3), 43.9 (CH), 51.4 (CH2), 59.1 (CH), 80.6 (C), 126.8 (CH),
127.2 (CH), 127.3 (CH), 128.1 (CH), 128.3 (CH), 128.4 (CH),
140.3 (C), 142.6 (C), 171.1 (C); IR 2978, 1721, 1153; EIMS m/z 312
(M+), 255 (M − t-BuO), 221 (M − Bn); HRMS−FAB (m/z) [M +
H]+ calcd for C20H24DNO2 313.2026, found 313.2030. The
mL) was added. The aqueous layer was extracted with AcOEt, and the
combined organic layers were dried over Na2SO4. Concentration and
column chromatography (hexane/AcOEt = 1/4) gave the title
compound (34 mg, 83%) as a colorless powder: Rf = 0.5 (AcOEt);
1
[α]1D9 −1.42 (c 0.60, CHCl3). H and 13C NMR, IR, and MS were
identical to those reported.62
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tomioka@pharm.kyoto-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
1
diastereomer ratio was determined by the integration area of the H
■
NMR signals at 2.51 and 2.62 ppm. The percent deuterium
incorporation was determined by the integration area of the 1H
NMR signals at 2.54 and 2.63 ppm (the two diastereomeric α-protons
of 16). The chiral diether ligand 11 was quantitatively recovered as
colorless plates.
We are grateful to JSPS and JST for financial support.
REFERENCES
■
(1) (a) Tomioka, K.; Nakajima, M.; Koga, K. J. Am. Chem. Soc. 1987,
109, 6213. (b) Pichon, M.; Figader
7, 927.
̀
e, B. Tetrahedron: Asymmetry 1996,
Short Step Asymmetric Synthesis of Phenylalanine, Azir-
inomycin Ester, and Nemonapride. (+)-L-Phenylalanine tert-
Butyl Ester (17). A suspension of trans-10i (15 mg, 0.046 mmol) and
10% Pd/C (4.9 mg, 4.6 μmol) in MeOH (1 mL) was stirred under H2
(1 atm) for 24 h at 50 °C and filtrated through Celite pad, which was
then washed with CHCl3. The filtrate was washed with saturated
NaHCO3 (5 mL), and the aqueous layer was extracted with CHCl3.
The combined organic layers were washed with brine and then dried
over Na2SO4. Concentration and column chromatography (hexane/
AcOEt = 4/1 to 1/1) gave the title compound (8.0 mg, 75%) as a
colorless oil: Rf = 0.1 (hexane/AcOEt = 3/2); [α]2D5 +14.5 (c 0.80,
CHCl3). 1H and 13C NMR, IR, and MS were identical to those
reported.60
(2) Buffat, M. G. P. Tetrahedron 2004, 60, 1701.
(3) Review: Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding,
D. R. Tetrahedron 2003, 59, 2953.
(4) (a) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M.
̈
Chem. Rev. 2008, 108, 3795. (b) Hong, S.; Marks, T. J. Acc. Chem. Res.
2004, 37, 673. (c) Ogata, T.; Ujihara, A.; Tsuchida, S.; Shimizu, T.;
Kaneshige, A.; Tomioka, K. Tetrahedron Lett. 2007, 48, 6648.
(d) Manna, K.; Xu, S.; Sadow, A. D. Angew. Chem., Int. Ed. 2011,
50, 1865. (e) Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.;
Toste, F. D. Nature 2011, 470, 245.
(5) Pyrrolidine: (a) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev.
2006, 106, 4484. (b) Pearson, W. H. Pure Appl. Chem. 2002, 74, 1339.
(6) Piperidine: Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,
12234.
(7) (a) Davis, F. A.; Prasad, K. R.; Nolt, M. B.; Wu, Y. Org. Lett.
2003, 5, 925. (b) Yamashita, M.; Yamada, K.; Tomioka, K. J. Am.
Chem. Soc. 2004, 126, 1954. (c) Reddy, L. R.; Das, S. G.; Liu, Y.;
Prashad, M. J. Org. Chem. 2010, 75, 2236. (d) Cui, Z.; Yu, H. J.; Yang,
R. F.; Gao, W. Y.; Feng, C. G.; Lin, G. Q. J. Am. Chem. Soc. 2011, 133,
12394.
(8) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966.
(9) (a) Carbone, G.; O’Brien, P.; Hilmersson, G. J. Am. Chem. Soc.
2010, 132, 15445. (b) Stead, D.; Carbone, G.; O’Brien, P.; Campos, K.
R.; Coldham, I.; Sanderson, A. J. Am. Chem. Soc. 2010, 132, 7260.
(c) Bilke, J. L.; Moore, S. P.; O’Brien, P.; Gilday, J. Org. Lett. 2009, 11,
1935.
(+)-tert-Butyl (2S,3R)-3-Methylaziridine-2-carboxylate (18). A
suspension of trans-10j (165 mg, 0.67 mmol) and 10% Pd/C (71
mg, 0.067 mmol) in MeOH (5 mL) was stirred under H2 (1 atm) for 5
h at rt and filtrated through Celite pad, which was then washed with
CHCl3. Concentration and column chromatography (pentane/Et2O =
85/15) gave the title compound (75 mg, 71%) as a colorless oil: Rf =
0.2 (pentane/Et2O = 85/15); [α]2D5 +63.0 (c 1.03, CHCl3). 1H and 13
C
NMR, IR, and MS were identical to those reported.61
(−)-(2R,3R)-1-Benzyl-2-methylpyrrolidin-3-amine (20). A solution
of cis-10m (70 mg, 0.254 mmol) in TFA (0.5 mL) and CH2Cl2 (2.5
mL) was stirred under reflux 12 h and then concentrated to give a
black oil.
To the black oil were added toluene (5 mL), Et3N (0.14 mL, 1.0
mmol), and then diphenylphosphoryl azide (0.071 mL, 0.33 mmol).
The mixture was stirred at rt for 30 min and then at 90 °C for 1 h. To
the solution were added TsOH·H2O (483 mg, 2.54 mmol) and H2O
(1 mL), and the mixture was stirred at 90 °C. After 15 h, 10% NaOH
(5 mL) was added, and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were dried over Na2SO4 and
concentrated. The resulting residue was purified by column
chromatography (CH2Cl2/MeOH = 4/1 to 1/1) to give the title
compound (25 mg, 52%) as a colorless oil: Rf = 0.1 (CH2Cl2/ MeOH
(10) Singh, G. S.; D’hooghe, M.; Kimpe, N. D. Chem. Rev. 2007, 107,
2080.
(11) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
(12) (a) Muller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905. (b) First
̈
catalytic, asymmetric aziridination of olefin: Evans, D. A.; Woerpel, K.
A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726.
(13) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.;
Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433.
(14) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121,
5099. (b) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129,
7185.
= 7/3); [α]2D5 −83.1 (c 1.25, CHCl3). H and 13C NMR, IR, and MS
1
were identical to those reported.62
Nemonapride (4). To a solution of 4-carboxy-2-chloro-5-methoxy-
N-methylammonium hydrogen sulfate (70 mg, 0.16 mmol) and Et3N
(0.12 mL, 0.84 mmol) in CH2Cl2 (1 mL) was added ClCO2Et (0.015
mL, 16 mmol) at 0 °C, and the whole was stirred for 0.5 h at 0 °C. To
the solution was added 20 (20 mg, 0.105 mmol) in CH2Cl2 (1 mL),
the mixture was stirred for 2 h at 0 °C, and then saturated NaHCO3 (3
(15) Hashimoto, T.; Uchiyama, N.; Maruoka, K. J. Am. Chem. Soc.
2008, 130, 14380.
(16) Deiana, L.; Dziedzic, P.; Zhao, G.-L.; Vesely, J.; Ibrahem, I.;
Rios, R.; Sun, J.; Cor
́
dova, A. Chem.Eur. J. 2011, 17, 7904.
7220
dx.doi.org/10.1021/jo301495a | J. Org. Chem. 2012, 77, 7212−7222

The Journal of Organic Chemistry
Featured Article
(17) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108,
3988.
(18) (a) Burkhard, J.; Carreira, E. M. Org. Lett. 2008, 10, 3525.
(i) Huang, W.; Ma, J.-Y.; Yuan, M.; Xu, L.-F.; Wei, B.-G. Tetrahedron
2011, 67, 7829.
(33) Fu, R.; Zhao, B.; Shi, Y. J. Org. Chem. 2009, 74, 7577.
(34) Isolation: (a) Noro, T.; Fukushima, S.; Ueno, A.; Iitaka, Y.;
Saiki, Y. Chem. Pharm. Bull. 1979, 27, 1495. Synthesis: (b) Williams,
D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc. 1989, 111, 1923.
(c) Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118, 3299.
(35) Enantioselective Synthesis of β-Amino Acids, 2nd ed.; Juaristi, E.,
Soloshonok, V. A., Eds.; Wiley-VCH: New York, 2005.
(36) Porter, E. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc.
2002, 124, 7324.
(b) Burkhard, J. A.; Wagner, B.; Fischer, H.; Schuler, F.; Muller, K.;
̈
Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 3524. (c) Burkhard, J.
́
A.; Guerot, C.; Knust, H.; Carreira, E. M. Org. Lett. 2012, 14, 66.
(19) Kozikowski, A. P.; Liao, Y.; Tueckmantel, W.; Wang, S.;
Pshenichkin, S.; Surin, A.; Thomsen, C.; Wroblewski, J. T. Bioorg. Med.
Chem. Lett. 1996, 6, 2559.
(20) Marinetti, A.; Hubert, P.; Genet, J.-P. Eur. J. Org. Chem. 2000,
1815.
(37) Harada, S.; Sakai, T.; Takasu, K.; Yamada, K.; Yamamoto, Y.;
Tomioka, K. Chem. Asian J., DOI: 10.1002/asia.201200575.
(38) (a) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K; Tomioka, K. J.
Am. Chem. Soc. 2003, 125, 2886. (b) Sakai, T.; Doi, H.; Kawamoto, Y.;
Yamada, K.; Tomioka, K. Tetrahedron Lett. 2004, 45, 9261. (c) Doi,
H.; Sakai, T.; Yamada, K.; Tomioka, K. Chem. Commun. 2004, 1850.
(d) Sakai, T.; Doi, H; Tomioka, K. Tetrahedron 2006, 62, 8351.
(39) (a) Hawkins, J. M.; Fu, G. C. J. Org. Chem. 1986, 51, 2820.
(b) Rico, J. G.; Lindmark, R. J.; Rogers, T. E.; Bovy, P. R. J. Org. Chem.
1993, 58, 7948. (c) Enders, D.; Wahl, H.; Bettray, W. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 455. (d) Sewald, N.; Hiller, K. D.; Helmreich,
B. Liebigs Ann. 1995, 925. (e) Bull, S. D.; Davies, S. G.; Robert, P. M.;
Savory, E. D.; Smith, A. D. Tetrahedron 2002, 58, 4629. Reviews:
(f) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 117. (g) Liu, M.;
Sibi, M. P. Tetrahedron 2002, 58, 7991. (h) Xu, L. W.; Xia, G. G. Eur. J.
Org. Chem. 2005, 633. (i) Davies, S. G.; Smith, A. D.; Price, P. D.
Tetrahedron: Asymmetry 2005, 16, 2833.
(21) (a) Starmans, W. A.; Doppen, R. G.; Thijs, L.; Zwanenburg, B.
Tetrahedron: Asymmetry 1998, 9, 429. (b) Leng, D.-H.; Wang, D.-X.;
Pan, J.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2009, 74, 6077.
(22) (a) Jacobi, P. A.; Lee, K. A. J. Am. Chem. Soc. 2000, 122, 4295.
(b) Boeckman, R. K.; Clark, T. J.; Shook, B. C. Org. Lett. 2002, 4,
2109. (c) Wipf, P.; Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225.
(23) (a) Smith, A. B., III; Cho, Y. S.; Pettit, G. R.; Hirschmann, R.
Tetrahedron 2003, 59, 6991. (b) Li, H.; Bleriot, Y.; Mallet, J. M.;
Rodriguez-Garcia, E.; Vogel, P.; Zhang, Y.; Sinay, P. Tetrahedron:
Asymmetry 2005, 16, 313.
́
(24) (a) Wishka, D. G.; Bedard, M.; Brighty, K. E.; Buzon, R. A.;
Farley, K. A.; Fichtner, M. W.; Kauffman, G. S.; Kooistra, J.; Lewis, J.
G.; O’Dowd, H.; Samardjiev, I. J.; Samas, B.; Yalamanchi, G.; Noe, M.
C. J. Org. Chem. 2011, 76, 1937. (b) Dhavale, D. D.; Markad, S. D.;
Karanjule, N. S.; PrakashaReddy, J. J. Org. Chem. 2004, 69, 4760.
(25) Lee, S. J.; Beak, P. J. Am. Chem. Soc. 2006, 128, 2178.
(26) Kano, T.; Sakamoto, R.; Mii, H.; Wang, Y. G.; Maruoka, K.
Tetrahedron 2010, 66, 4900.
(40) (a) Asao, N.; Uyehara, T.; Yamamoto, Y. Tetrahedron 1990, 46,
4563. (b) Enders, D.; Bettray, W.; Raabe, G.; Runsink, J. Synthesis
1994, 1322. (c) Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem.
Soc., Perkin Trans. 1 1994, 1141. (d) Hawkins, J. M.; Lewis, T. A. J.
Org. Chem. 1994, 59, 649.
(27) 1,2-Dihaloethane problem: (a) Alder, R. W.; Sessions, R. B.
Tetrahedron Lett. 1982, 23, 1121. (b) Kashima, C.; Harada, K. J. Chem.
Soc., Perkin Trans. 1 1988, 1521. (c) Ibarzo, J.; Ortuno, R. M.
̃
Tetrahedron 1994, 50, 9825. (d) Bhatt, U; Just, G Helv. Chim. Acta
2000, 83, 722. (e) Vartak, A. P.; Young, V. G., Jr.; Johnson, R. L. Org.
Lett. 2005, 7, 35. See also ref 26.
(41) (a) Ma, D.; Sun, H. J. Org. Chem. 2000, 65, 6009.
(b) Chippindale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin, R. M.;
Smethurst, C. A. P.; Smith, A. D.; Rodriguez, H. S. Tetrahedron 2003,
59, 3253. (c) Yao, W.; Zhuo, J.; Burns, D. M.; Xu, M.; Zhang, C.; Li,
Y.-L.; Qian, D.-Q.; He, C.; Weng, L.; Shi, E.; Lin, Q.; Agrios, C.; Burn,
T. C.; Caulder, E.; Covington, M. B.; Fridman, J. S.; Katiyar, S.; Hollis,
K. G.; Li, Y.; Liu, C.; Liu, X.; Marando, C. A.; Newton, R.; Pan, M.;
Scherle, P.; Taylor, N.; Vaddi, K.; Wasserman, Z. R.; Wynn, R.;
Yeleswaram, S.; Jalluri, R.; Bower, M.; Zhou, B.-B.; Metcalf, B. J. Med.
Chem. 2007, 50, 603. (d) Fustero, S.; Moscard, J.; Rosell, M. S.; Flores,
S.; Guerola, M.; Pozo, C. Tetrahedron 2011, 67, 7412.
(42) Colpaert, F.; Mangelinckx, S.; De Kimpe, N. J. Org. Chem. 2011,
76, 234.
(43) D’hooghe, M.; Dejaegher, Y.; De Kimpe, N. Tetrahedron 2008,
64, 4575.
(44) Tomioka, K.; Kawasaki, H.; Yasuda, K.; Koga, K. J. Am. Chem.
Soc. 1988, 110, 3597.
(45) Sakai, T.; Kawamoto, Y.; Tomioka, K. J. Org. Chem. 2006, 71,
4706.
(46) Haga, T.; Ishikawa, T. Tetrahedron 2005, 61, 2857.
(47) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem., Int.
Ed. 2008, 47, 3784.
(48) (a) Tomalia, D. A.; Falk, J. C. J. Heterocycl. Chem. 1972, 9, 891.
(b) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7539. X-ray
structure: (c) Boer, F. P.; Flynn, J. J.; Kaiser, E. T.; Zaborsky, O. R.;
Tomalia, D. A.; Young, A. E.; Tong, Y. C. J. Am. Chem. Soc. 1968, 90,
2970.
(49) Konda, Y.; Takahashi, Y.; Arima, S.; Sato, N.; Takeda, K.;
Dobashi, K.; Baba, M.; Harigaya, Y. Tetrahedron. 2001, 57, 4311.
(50) (a) Lee, K. D.; Suh, J. M.; Park, J. H.; Ha, H. J.; Choi, H. G.;
Sun, C.; Jae, P.; Chang, W.; Lee, W. K.; Dong, Y.; Yun, H. Tetrahedron
2001, 57, 8267. (b) Manaka, T.; Nagayama, S.; Desadee, W.; Yajima,
N.; Kumamoto, T.; Watanabe, T.; Ishikawa, T.; Kawahata, M.;
Yamaguchi, K. Helv. Chim. Acta 2007, 90, 128.
(28) Indirect C2 source: (a) Xue, C.-B.; He, X.; Roderick, J.; Corbett,
R. L.; Decicco, C. P. J. Org. Chem. 2002, 67, 865. (b) Xue, C.-B.; Chen,
X.-T.; He, X.; Roderick, J.; Corbett, R. L.; Ghavimi, B.; Liu, R.-Q.;
Covington, M. B.; Qian, M.; Ribadeneira, M. D.; Vaddi, K.; Trzaskos,
J.; Newton, R. C.; Duan, J. J.-W.; Decicco, C. P. Bioorg. Med. Chem.
Lett. 2004, 14, 4453.
(29) Bioactivity: (a) Stapley, E. O.; Hendlin, D.; Jackson, M.; Miller,
A. K. J. Antibiot. 1971, 24, 42. Isolation and structure: (b) Miller, T.
W.; Tristram, E. W.; Wolf, F. J. J. Antibiot. 1971, 24, 48. Synthesis:
(c) Luca, G.; Yvonne, G.; Lambertus, T.; Binne, Z. Tetrahedron Lett.
1995, 36, 4665. (d) Verstappen, M. M. H.; Ariaans, G. J. A.;
Zwanenburg, B. J. Am. Chem. Soc. 1996, 118, 8491. (e) Hodgson, D.
M.; Humphreys, P. G.; Xu, Z.; Ward, J. G. Angew. Chem., Int. Ed. 2007,
46, 2245.
(30) (a) Zhang, H.; Mifsud, M.; Tanaka, F.; Barbas, C. F., III. J. Am.
Chem. Soc. 2006, 128, 9630. Synthesis: (b) Mazzini, C.; Lebreton, J.;
Alphand, V.; Furstoss, R. J. Org. Chem. 1997, 62, 5215. (c) Thomas,
̌
C.; Orecher, F.; Gmeiner, P. Synthesis 1998, 1491. (d) Stoncius, R.;
Nahrwold, M.; Sewald, N. Synthesis 2005, 1829.
(31) Enders, D.; Gries, J. Synthesis 2005, 3508.
(32) (a) Murakami, K.; Takahashi, M.; Hirata, Y.; Takashima, M.;
Iwanami, S.; Hasegawa, O.; Nozaki, Y.; Tashikawa, S.; Takeda, M.;
Usuda, S. U.S. Patent 4,097,487, June 27, 1978. (b) Takashima, M.;
Iwanami, S.; Usuda S. Benzamide derivatives. U.S. Patent 4,210,660,
July 1, 1980. (c) Iwanami, S.; Takashima, M.; Hirata, Y.; Hasegawa, O.;
Usuda, S. J. Med. Chem. 1981, 24, 1224. (d) Huang, P. Q.; Wang, S. L.;
Zheng, H.; Fei, X. S. Tetrahedron Lett. 1997, 38, 271. (e) Huang, P. Q.;
Wang, S. L.; Ye, J. L.; Ruan, Y. P.; Huang, Y. Q.; Zheng, H.; Gao, J. X.
Tetrahedron 1998, 54, 12547. (f) Shibuguchi, T.; Mihara, H.;
Kuramochi, A.; Ohshima, T.; Shibasaki, M. Chem. Asian J. 2007, 2,
794. (g) Hoang, C. T.; Nguyen, V. H.; Alezra, V.; Kouklovsky, C. J.
Org. Chem. 2008, 73, 1162. (h) Handa, S.; Gnanadesikan, V.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 4925.
(51) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94,
6203.
7221
dx.doi.org/10.1021/jo301495a | J. Org. Chem. 2012, 77, 7212−7222

The Journal of Organic Chemistry
Featured Article
(52) Watanabe, Y.; Nishiyama, K.; Zhang, K.; Okuda, F.; Kondo, T.;
Tsuji, Y. Bull. Chem. Soc. Jpn. 1994, 67, 879−882.
(53) Colvin, E. W.; McGarry, D.; Nugent, M. J. Tetrahedron 1988,
44, 4157.
(54) Bennett, N. J.; Mcinally, T.; Mochel, T.; Thom, S.; Tiden, A.-K.
Preparation of Pyrimidine Derivatives for the Treatment of Various
Diseases. WO Patent 2009067081 A1, May 28, 2009; Chem Abstr.
2009, 151, 8526.
(55) Mizuno, M.; Kanai, M.; Iida, A.; Tomioka, K. Tetrahedron 1997,
53, 10699.
(56) Hoang, C. T.; Nguyen, V. H.; Alezra, V.; Kouklovsky, C. J. Org.
Chem. 2008, 73, 1162.
(57) Erickson, K. L.; Markstein, J.; Kim, K. J. Org. Chem. 1971, 36,
1024.
(58) Haga, T.; Ishikawa, T. Tetrahedron 2005, 61, 2857.
(59) (a) Rauk, A.; Allen, L. C.; Mislow, K. Angew. Chem., Int. Ed. Engl.
1970, 9, 400. (b) Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno,
H.; Miwa, Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N. J. Org.
Chem. 1997, 62, 999. (c) Ibuka, T.; Mimura, N.; Ohno, H.; Nakai, K.;
Akaji, M.; Habashita, H.; Tamamura, H.; Miwa, Y.; Taga, T.; Fujii, N. J.
Org. Chem. 1997, 62, 2982. (d) Hada, K.; Watanabe, T.; Isobe, T.;
Ishikawa, T. J. Am. Chem. Soc. 2001, 123, 7705.
(60) Konda, Y.; Takahashi, Y.; Arima, S.; Sato, N.; Takeda, K.;
Dobashi, K.; Baba, M.; Harigaya, Y. Tetrahedron 2001, 57, 4311.
(61) Hodgson, D. M.; Humphreys, P. G.; Xu, Z.; Ward, J. G. Angew.
Chem., Int. Ed. 2007, 46, 2245.
(62) Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.;
Shibasaki, M. Chem. Asian J. 2007, 2, 794.
7222
dx.doi.org/10.1021/jo301495a | J. Org. Chem. 2012, 77, 7212−7222