Conformational restriction by repulsion between adjacent substituents on a cyclopropane ring: Design and enantioselective synthesis of 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides as potent NMDA receptor antagonists

Article abstract of DOI:10.1021/jo9518056

Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly, because they are fixed in eclipsed conformation to each other. Based on this structural feature of the cyclopropane ring, conformationally restricted analogs of milnacipran (1), namely 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides (2, 3, ent-2, and ent-3) were designed as potent NMDA receptor antagonists and were synthesized highly enantioselectively. Reaction of (R)-epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH₂ in benzene gave a chiral cyclopropane derivative that was isolated as lactone 4 with 96% ee in 67% yield, after alkaline hydrolysis of the cyano group. The nucleophilic addition reaction of Grignard reagents to aldehyde 10, which was readily prepared from 4, proceeded highly selectively from the si-face to afford addition products 11 in high yields. Although hydride reduction of the corresponding ketone 15b, prepared from 11b, with L-Selectride also proceeded highly diastereoselectively, the facial selectivity was reversed to give the re-face addition product lib. On the other hand, reduction of 15 with DIBAL-H afforded the si-face addition product 12 in high yields. These results suggested that these nucleophilic addition reactions proceeded via either the bisected s-trans or s-cis conformation of the cyclopropylcarbonyl derivatives. From 11 and 12, the target conformationally resticted analogs, 2 and 3, were synthesized, respectively. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, ent-2 and ent-3, were also synthesized. The structures of the conformationally restricted analogs detected by the X-ray crystallographic analysis suggested that their conformations can be restricted as we hypothesized. Thus, a new method for restricting the conformation of cyclopropane derivatives has been developed.

Full text of DOI:10.1021/jo9518056

J . Org. Chem. 1996, 61, 915-923
915
Con for m a tion a l Restr iction by Rep u lsion betw een Ad ja cen t
Su bstitu en ts on a Cyclop r op a n e Rin g: Design a n d
En a n tioselective Syn th esis of
1-P h en yl-2-(1-a m in oa lk yl)-N,N-d ieth ylcyclop r op a n eca r boxa m id es
a s P oten t NMDA Recep tor An ta gon ists
Satoshi Shuto,*,† Shizuka Ono,† Yukako Hase,† Noriko Kamiyama,† Hironao Takada,‡
Kanako Yamasihita,‡ and Akira Matsuda†
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060, J apan
and Institute for Life Science Research, Asahi Chemical Industry Co., Ltd.,
Mifuku, Ohito-cho, Shizuoka 410-23, J apan
Received October 4, 1995X
Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly,
because they are fixed in eclipsed conformation to each other. Based on this structural feature of
the cyclopropane ring, conformationally restricted analogs of milnacipran (1), namely 1-phenyl-2-
(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides (2, 3, ent-2, and ent-3) were designed as potent
NMDA receptor antagonists and were synthesized highly enantioselectively. Reaction of (R)-
epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH2 in benzene gave a chiral
cyclopropane derivative that was isolated as lactone 4 with 96% ee in 67% yield, after alkaline
hydrolysis of the cyano group. The nucleophilic addition reaction of Grignard reagents to aldehyde
10, which was readily prepared from 4, proceeded highly selectively from the si-face to afford addition
products 11 in high yields. Although hydride reduction of the corresponding ketone 15b, prepared
from 11b, with L-Selectride also proceeded highly diastereoselectively, the facial selectivity was
reversed to give the re-face addition product 11b. On the other hand, reduction of 15 with DIBAL-H
afforded the si-face addition product 12 in high yields. These results suggested that these
nucleophilic addition reactions proceeded via either the bisected s-trans or s-cis conformation of
the cyclopropylcarbonyl derivatives. From 11 and 12, the target conformationally resticted analogs,
2 and 3, were synthesized, respectively. Starting from (S)-epichlorohydrin [(S)-5], their corre-
sponding enantiomers, ent-2 and ent-3, were also synthesized. The structures of the conforma-
tionally restricted analogs detected by the X-ray crystallographic analysis suggested that their
conformations can be restricted as we hypothesized. Thus, a new method for restricting the
conformation of cyclopropane derivatives has been developed.
In tr od u ction
effects4ab probably due to neuronal vacuolization,4c while
the competitive ones were often inactive in vivo because
of poor transport to the brain.5 Therefore, development
of other types of efficient NMDA receptor antagonists has
been awaited.
Activation of N-methyl-D-aspartate (NMDA) receptor,
a subclass of glutamate receptors, has been implicated
in the initiation of neuronal cell death due to hypoxia
and in the pathophysiology of epilepsy.1 Because of the
potential involvement of the NMDA receptor in both
chronic and acute neurodegenerative disorders, an ex-
tensive effort to identify novel agents that block activa-
tion of NMDA receptor by glutamate, or related excita-
tory neurotransmitters, has been undertaken.1-3 MK-
801 [10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-
5,10-imine]2 and CGS 19755 [(()cis-4-(phosphonomethyl)-
2-piperidinecarboxylic acid],3 which are typical non-
competitive and competitive NMDA receptor antagonists,
respectively, are effective in experimental models of
epilepsy and stroke. Disadvantages of these compounds
are that noncompetitive inhibitors had serious behavioral
Recently we reported that (()-(Z)-2-(aminomethyl)-1-
phenyl-N,N-diethylcyclopropanecarboxamide (milnacip-
ran, (()-1), known as an efficient antidepressant due to
inhibiting the reuptake of serotonin by the nerve terminal
in CNS,6,7 was a new class of NMDA receptor antago-
nists.8 Although the binding affinity of 1 for the NMDA
receptor is not strong enough, it has vital importance as
a prototype for novel potent NMDA receptor antagonists
because of the characteristic structure, which is clearly
different from those of known competitive and noncom-
petitive antagonists of the receptor.8 In recent years, we
(4) (a) Willetts, J .; Balster, R. L.; Leander, J . D. Trends Pharmacol.
Sci. 1990, 11, 423-428. (b) Tricklebank, M. D.; Singh, L.; Oles, R. J .;
Preston, C.; Iversoen, S. D. Eur. J . Pharmacol. 1989, 167, 127-135.
(c) Olney, J . W.; Labruyere, J .; Price, M. T. Science 1989, 244, 1360-
1362.
(5) (a) Meldrum, B. S.; Croucher, M. J .; Czuczwar, S. J .; Collins, J .
F.; Curry, K.; J oseph, M.; Stone, T. W. Neuroscience 1983, 9, 925-
930. (b) Hogan, M. J .; Gjedde, A.; Hakem, A. M. J . Neurochem. 1992,
58, 186-191.
(6) (a) Briley, M. Drugs Future 1986, 11, 21-23. (b) Moret, C.;
Charveron, M.; Finberg, J . P. M.; Cozinier, J .; M. Briley, M. Neurop-
harmacology 1985, 24, 1211-1219.
* Author to whom correspondence should be addressed.
† Hokkaido University.
‡ Asahi Chemical Industry Co.
X Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
(1) Collingridge, G. L. Watkins, J . C. The NMDA Receptor; IRL Press
at Oxford Univ. Press: Oxford, UK, 1994.
(2) (a) Wong, E. H. F.; Kemp, J . A.; Priestley, T.; Knight, A. R.;
Woodruff, G. N.; Iversen, L. L. Proc Natl. Acad. Sci. U.S.A. 1986, 83,
7104-7108. (b) Gill, R.; Foster, A. C.; Woodruff, G. N. J . Neurosci. 1987,
7, 3343-3349.
(3) Hutchison, A. J .; Williams, M.; Angst, C.; de J esus, R.; Blanchard,
L.; J ackson, R. H.; Wilusz, E. J .; Murphy, D. E.; Bernard, P. S.;
Schneider, J .; Campbell, T.; Guida, W.; Sills, M. A. J . Med. Chem. 1989,
32, 2171-2178.
(7) Bonnaud, B.; Cousse, H.; Mouzin, G.; Briley, M.; Stenger, A.;
Fauran, F.; Couzinier, J .-P. J . Med. Chem. 1987, 30, 318-325.
(8) Shuto, S.; Takada, H.; Mochizuki, D.; Tsujita, R.; Hase, Y.; Ono,
S.; Shibuya, N.; Matsuda, A. J . Med. Chem. 1995, 38, 2964-2968.
0022-3263/96/1961-0915$12.00/0 © 1996 American Chemical Society

916 J . Org. Chem., Vol. 61, No. 3, 1996
Shuto et al.
F igu r e 1. Milnacipran and its conformationally restricted analogs.
F igu r e 2. Conformational restriction by the repulsion be-
tween adjacent substituents on a cyclopropane ring.
have been engaged in a modification study of milnacip-
ran, increasing the specific affinity for the NMDA recep-
tor, to develop a clinically useful agent. Because our
previous study showed that modification of functional
groups of milnacipran did not improve the activity,8 we
planned to investigate the effects of conformational
changes of the molecule on the activity. Therefore, we
designed conformationally restricted analogs of 1, in
which a new method for restricting the conformation of
cyclopropane derivatives has been developed.
Design of Con for m a tion a lly Restr icted An a logs
of Miln a cip r a n
It is known that as a result of free rotation about single
bonds in compounds, a drug molecule can assume a
variety of conformations. Only one of these conformers
would bind to a receptor. If the lead compound has low
binding affinity for the receptor, it may only be because
the population of the active conformer in solution is low.
So, the synthesis of conformationally restricted analogs
of a lead compound can bring an improvement of the
specific binding affinity for the receptor.9
F igu r e 3. Conformational restriction of milnacipran by
introducing an alkyl group.
Sch em e 1
Sch em e 2
We designed the conformationally restricted analogs
based on the structural feature of 1, as shown in Figure
1. Adjacent substituents on a cyclopropane ring mutually
exert steric repulsion quite significantly, because they
are fixed in eclipsed conformation to each other. Con-
sequently, conformations of the substituents on a cyclo-
propane can be restricted by the steric effect of adjacent
substituents, especially when they are bulky as indicated
in Figure 2. Because the primary amino function of 1 is
essential for the binding affinity for the NMDA receptor,8
we presumed the conformation of the aminomethyl
moiety would significantly affect the activity of the
compound. While the aminomethyl moiety is not so
bulky and may freely rotate at least to some extent, the
conformers A and B may be preferable to conformer C,
because of the serious steric repulsion for the bulky
diethylcarbamoyl group in conformer C as shown in
Figure 3. Introducing an alkyl group into the R-position
of the amino function of 1 would prevent the rotation, to
restrict the location of the amino function in space due
to its steric repulsion for the diethycarbamoyl group.
Therefore, depending on the configuration of the alkyl
group introduced, the conformation of the compounds can
be restricted; conformer B would be predominant in 2
and ent-2, conversely, conformer A would be predominant
in 3 and ent-3 (Figure 3).
Resu lts a n d Discu ssion
We have reported an easy synthetic method for (()-
milnacipran [(()-1] and its derivatives via racemic lac-
tone (()-4 as the key intermediate as shown in Scheme
1.8 The racemic lactone (()-4 is readily prepared from
epichlorohydrin [(RS)-5] and phenylacetonitrile (6).10 The
corresponding optically active lactones 4 and ent-4 were
thought to be efficient intermediates for the target
compounds as shown in Scheme 2. In the cyclopropane
(9) (a) Silverman, R. B. The organic chemistry of drug design and
drug action; Academic Press: San Diego, 1992. (b) Kozikowski, A., Eds.
Drug design for neuroscience; Raven Press: New York, 1993.
(10) Mouzin, G.; Cousse, H.; Bonnaud, B. Synthesis 1978, 304-305.

New Method for Conformational Restriction
J . Org. Chem., Vol. 61, No. 3, 1996 917
Sch em e 3
Sch em e 4
We investigated the reaction of (R)-5 and an anion of
phenylacetonitrile under various conditions. The result-
ing cyclopropane product was isolated as lactone 4, after
alkaline hydrolysis of the nitrile group followed by
treatment with HCl (Scheme 3). When the reaction was
done with NaNH2, as a base, in benzene at room
temperature, the result was the most desirable; (1S,2R)-
lactone 4 with 96% e.e was isolated in 67% yield. This
reaction can be readily done on a large scale; more than
30 g of chiral product 4 was prepared in one experiment.
Use of other bases such as LDA, NaH, or LiNH2 and
solvents such as THF or toluene decreased the yield and/
or optical purity of 4. The absolute stereochemistry of 4
was assigned as 1S,2R, from X-ray crystallographic
analysis of the final product (ent-2) as described below.
This result indicates that the nucleophile attacks highly
selectively at the epoxide through path-b. Therefore, it
is suggested that chiral epichlorohydrins can be efficient
synthons for preparing chiral cyclopropanes.
Treatment of 4 with LiNEt2 in THF at -78 °C afforded
a ring-opened product 9, which was subjected to Swern
oxidation to give aldehyde 10 in high yield (Scheme 5).
Reaction of aldehyde 10 and MeMgBr at -20 °C in THF
gave addition product 11a highly stereoselectively, which
was isolated in 92% yield, with a trace of diastereomer
12a . The corresponding ethyl derivative 11b was also
obtained with EtMgBr in high yield. While the reaction
with MeLi, instead of MeMgBr, also afforded 11a as a
major product, the stereoselectivity was reduced (11a :
12a ) 70:23).
ring-closure reaction of 5 and 6 in the presence of a base,
two pathways, namely path-a and -b, could be considered
(Scheme 3). If a nucleophilic attack occurs highly
selectively either through path-a or -b, this would provide
an efficient method to access both lactone 4 and ent-4 in
optically active forms, because both (R)- and (S)-epichlo-
rohydrins are available. Chiral epoxypropanes including
epichlorohydrins have been widely used as chiral syn-
thons for synthesizing various optically active com-
pounds.11 MaClure and co-workers studied the mode of
nucleophilic substitution on various chiral 2,3-epoxypro-
panes with a leaving group at the 1-position; they
concluded that the mode of nucleophilic attacks depends
on the leaving group as well as the conditions used, in
which a few highly selective reactions were observed.12
When carbanions are used as a nucleophile in the
reaction, the corresponding cyclopropane derivatives can
be produced in the reaction.13,14 Burgess and Ho reported
that when an optically active triflate 7 was treated with
a carbanion of di-tert-butyl malonate, nearly all of the
optical activity of 7 was transferred to the cyclopropane
product 8 (yield 50%, 91% ee; Scheme 4). However, a
significant instability of 7, which would decrease the
optical purity, has also been recognized.11a On the other
hand, when a chiral epichlorohydrin is used instead of
the corresponding triflate in similar reactions, decreases
of optical activity of the products have been observed.14
This is a consequence of direct displacement of the
chloride with a nucleophile (path-a) competing with an
attack at the epoxide (path-b), the latter being the major
pathway, as suggested by McClure and co-workers.12 In
recent years, both (R)-5 and (S)-5 of high optical purity
(>98% ee) have been commercially available15 and are
significantly more stable than the corresponding triflate.
However, cyclopropane-ring-closure reactions with opti-
cally active epichlorohydrins have not been studied in
detail. Therefore, we decided to try synthesizing chiral
lactones 4 and ent-4 of high optical purity starting from
chiral epichlorohydrins, (R)-5 and (S)-5.
The 2′-configuration of 11 and 12 was confirmed as
follows. Compound 11a was heated with HCl in MeOH
to give lactone 13 in 63% yield (Scheme 6).16 Similarly,
the corresponding diastereomer 14 was obtained from
12a . The relative configuration between 2-H and 2′-H
1
was assigned from the H NMR spectra of conformation-
ally rigid lactones 13 and 14 based on the Karplus
equation; the coupling constant between H-2 and H-2′ of
14 was 4.5 Hz, while the coupling was not observed in
13. Thus, the stereochemistry of 11 was assigned as
1S,2R,2′S, and 12 as 1S,2R,2′R.17
It has been recognized that cyclopropyl carbaldehydes
and cyclopropyl ketones preferentially exist in bisected
conformations, namely s-trans and s-cis conformers, due
to the characteristic stereoelectronic effects of the cyclo-
propane ring; the s-trans conformer is predominant in
cyclopropyl carbaldehydes, conversely, the s-cis conformer
is predominant in cyclopropyl ketones,18 as shown in
Figure 4. In fact the X-ray crystallographic analysis of
aldehyde 10 (Figure 5) indicates the bisected s-trans
conformation is preferable, as expected. The nucleophilic
(11) (a) Hanson, R. M. Chem. Rev. 1991, 91, 437-475. (b) Cimetire,
B.; J acob, L.; J ulia, M. Tetrahedron Lett. 1986, 27, 6329-6332. (c)
Takano, S.; Yanase, M.; Sekiguchi, Y.; Ogasawara, K. Tetrahedron Lett.
1987, 28, 1783-1784. (d) Kuehne, M. E.; Podhore, D. E. J . Org. Chem.
1985, 50, 924-929. (e) Mouzin, G.; Cousse, H.; Rieu, J . P.; Duflos, A.
Synthesis 1983, 117-118. (f) Tsuda, Y.; Yoshimoto, K.; Nishikawa, T.
Chem. Pharm. Bull. 1981, 29, 3593-3600.
(12) McClure, D. E.; Arison, B. H.; Baldwin, J . J . J . Am. Chem. Soc.
1979, 101, 3666-3668.
(13) Burgess, K.; Ho, K.-K. J . Org. Chem. 1992, 57, 5931-5936.
(14) (a) Russell, S. W.; Pabon, H. J . J . J . Chem Soc., Perkin Trans.
1 1982, 545-552. (b) Pirrung, M. C.; Dunlap. S. E.; Trinks, U. P. Helv.
Chim. Acta 1989, 72, 1301-1310.
(16) Successive treatment of 11a with KOH/ethylene glycol and
DCC/MeOH also gave 13.
(17) The configuration of 2′-position of 11a was also assigned as S
by modified Mosher’s method: Ohtani, I.; Kusumi, T.; Kashman, Y.;
Kakisawa, H. J . Am. Chem. Soc. 1991, 113, 4092-4096.
(15) Available from Daiso Co., Ltd.

918 J . Org. Chem., Vol. 61, No. 3, 1996
Shuto et al.
Sch em e 5
Sch em e 6
F igu r e 4. Bisected conformations of cyclopropyl carbaldehyde
and cyclopropyl ketone.
addition reactions would proceed from the least hindered
si-face of 10 in the s-trans conformation to give 11 highly
diastereoselectively.
Since we required both diastereomers 11 and 12 to
access the target compounds, 2 and 3, inversion of the
configuration at the 2′-position of 11 was investigated.
First, mesylation or tosylation of the 2′-hydroxyl group
of 11a was attempted; however, these reactions did not
proceed due probably to steric hindrance around the
hydroxyl group. Although the Mitsunobu reaction of 11a
with DEAD (diethyl azodicarboxylate), Ph3P, and chlo-
roacetic acid gave the corresponding 2′-chloroacetate, the
configuration was retained.19 Next, stereoselective re-
duction of the ketone 15, which was readily prepared by
PDC oxidation of 11, was attempted. Reduction of 15b
with NaBH4 in MeOH afforded the undesired 2′S-alcohol
11b as the major product in 70% yield (11b:12b ) 4:1).
When L-Selectride was used, 11b was obtained highly
selectively (91%, 11b:12b ) 50:120 ). If the conformation
F igu r e 5. X-ray crystallographic structures of 10 (left) and
15b (right).
of 15b in the reaction course is similar to that in crystals
observed by its X-ray crystallographic analysis as shown
in Figure 5, the stereoselectivity of the reaction with
these nucleophilic hydride reagents can be explained as
the hydride attack occurring from the least hindered face
(re-face) to the carbonyl of 15b. The result is also
consistent with the previous reports that cyclopropyl
ketones preferentially exist in the bisected s-cis confor-
mation.18 Surprisingly, when 15b was treated with
DIBAL-H in THF at -78 °C, the reaction gave the desired
2′R-alcohol 12b highly selectively in 95% yield (11b:12b
) 1:50).20 A similar desirable result was also obtained
in the DIBAL-H reduction of methyl ketone 15a (yield
90%, 11a :12a ) 1:3320). When DIBAL-H, which is
considered to be a relatively electrophilic reducing re-
agent for carbonyl groups, coordinates to the carbonyl of
(18) (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-Y.; Yip, Y.-C. Chem.
Rev. 1989, 89, 165-198. (b) Gerasimos, J . K.; Nelsom, J . J . Am. Chem.
Soc. 1965, 87, 2864-2870. (c) Pierre, J . L.; Arnaud, P. Bull. Soc. Chim.
Fr. 1966, 1690-1693. (d) Bartell, L. S.; Guillory, J . P.; Parks, A. T. J .
Phys. Chem. 1965, 69, 3043-3048. (e) Bartell, L. S.; Guillory, J . P. J .
Phys. Chem. 1965, 43, 647-654. (f) Bordner, J .; J ones, L. A.; J ohnson,
R. L. Cryst. Struct. Commun. 1972, 1, 389-391. (g) Lute, C. N. A.;
Stam, C. H. Rec. Trav. Chim. Pays-Bas (Rec. J . R. Neth. Chem. Soc.)
1976, 95, 130-132. (h) Roques, R.; Crasnier, F.; Declercq, J . P.
Germain, G.; Cousse, H.; Mouzin, G. Acta Crystallogr. 1982, B38,
1375-1377. (i) Crasnier, F.; Labarre, J . F.; Cousse, H.; D’Hinterland,
L. D.; Mouzin, G. Tetrahedron 1975, 31, 825-829.
(19) Removal of the chloroacetyl group by treating with NaOMe/
MeOH gave 2′S-alcohol 11a .
(20) The ratio of diastereomers produced was measured by the 1H
NMR spectrum (500 MHz) of the crude product.

New Method for Conformational Restriction
J . Org. Chem., Vol. 61, No. 3, 1996 919
SN2 reaction pathway,22 in our study, the reaction gave
configuration-retained azide derivatives 16 and 17. On
the other hand, when 2′-trifluoroacetyl derivative 18,
which was readily prepared from 11a , was treated with
NaN3 in DMF, the configuration of the azide product 16a
was also retained. These results suggest a reaction
pathway via the neighboring group participated inter-
mediates I and II (Scheme 5) in the nucleophilic substi-
tution reaction at the 2′-position of the compounds. This
assumption would also be consistent with the result of a
reaction under the Mitsunobu reaction conditions de-
scribed above.
F igu r e 6. Conceivable reaction pathway of the nucleophilic
addition reaction in aldehyde 10.
Catalytic hydrogenations of azide derivatives, 16a ,
16b, 17a , and 17b, with Pd-C in MeOH gave the target
conformationally restricted analogs, 2a , 2b, 3a , and 3b,
in high yields, respectively.
Starting from (+)-epichlorohydrine [(S)-5], the corre-
sponding enantiomers, ent-2a , ent-2b, ent-3a , and ent-
3b, were also synthesized.
Studies on synthesizing optically active cyclopropane
derivatives have been done in recent years due to their
biological importance.23 This procedure with (R)- or (S)-
epichlorohydrin as a synthon for chiral cyclopropanes
would be one of the most useful methods; both chiral
epichlorohydrins are available readily in high optical
purity and are stable, and cyclopropane products of high
optical purity can be obtained on a large scale as
demonstrated in this study.
F igu r e 7. Conceivable reaction pathway of the nucleophilic
addition reaction of ketone 15.
Cyclopropyl carbaldehydes and cyclopropyl ketones
have been shown to exist preferentially in the bisected
s-trans and s-cis conformations, respectively,18 from their
NMR analyses,18b,c electron diffraction studies,18d,e X-ray
crystallographic analyses,18f-h and theoretical calcula-
tions.18i This study may be the first experimental result
that demonstrates the stereochemical pathways of the
nucleophilic attack on the cyclopropyl carbonyl can
depend upon the predominant bisected conformation of
cyclopropane derivatives which is predictable from the
stereoelectronic effects. In this study, the predominant
conformations of the cyclopropyl carbaldehyde and the
corresponding ketone were also suggested from their
X-ray crystallographic analyses. Especially, X-ray crys-
tallographic analysis of cyclopropyl carbaldehyde 10 is
important, because it is the first one that detects the
bisected s-trans conformation of cyclopropyl carbaldehyde
in crystal structure, though X-ray structures of cyclo-
propyl ketones of bisected conformations have been
reported.18f-h In the reaction course of the nucleophilic
addition reaction, electrons of the cyclopropane ring,
which can be characterized as a strong π-donor, interact
with the antibonding orbital of the incipient bond be-
tween the nucleophile and the carbonyl carbon.24 The
nucleophilic addition reaction can be facilitated by this
interaction, which is maximal when the cyclopropyl
carbonyl derivatives exist either in the bisected s-trans
or s-cis conformations. In nucleophilic substitution reac-
tions at the cyclopropylmethyl position, similar signifi-
cant facilitation of the reaction when the substrates can
exist in the bisected conformation has been already
recognized.25
F igu r e 8. X-ray crystallographic structures of ent-2b (left)
and ent-3b (right).
15, a conformation like s-trans (shown in Figure 7) would
be preferred due to steric repulsion between the two
bulky isobutyl and diethylcarbamoyl groups. The hy-
dride attack from the least hindered face (si-face) to the
intermediate would give the desired product highly
selectively. These results showed the stereoselectivity
of the hydride reduction almost completely reversed when
the reaction was done by nucleophilic or electrophilic
reducing reagents. To our knowledge, only one example
on steroid derivatives that showed almost complete
reversion of stereoselectivity in hydride reductions21
similar to our results, has appeared.
Treatments of 11a and 11b with the NaN3/CBr4/Ph3P
system in DMF22 gave azide derivatives, 16a and 16b,
with retention of the configuration at the 2′-position in
excellent yields, respectively. Similar treatments of the
corresponding 2′-diastereomers, 12a and 12b, also af-
forded azide derivatives, 17a and 17b, respectively, of
which the 2′-configurations were also retained. The
configurations at the 2′-position were confirmed from
X-ray crystallographic analysis of an enantiomer of the
final product (ent-2b) as shown in Figure 8. Although
the reaction conditions, namely treatment of an alcohol
with the NaN3/CBr4/Ph3P system in DMF, has been
known to give the corresponding azide derivative via the
(23) Salaun, J . Chem. Rev. 1989, 89, 1247-1270.
(24) Importance of the antibonding orbital in the reaction course of
nucleophilic addition reactions on carbonyls has been recognized: (a)
Cieplak, A. S. J . Am. Chem. Soc. 1981, 103, 4540-4552. (b) Cieplak,
A. S.; Tait, B. D. J . Am. Chem. Soc. 1989, 111, 5875-5876. (c) Satoh,
M.; Murakami, M.; Sunami, S.; Kaneko, C.; Furuya, T.; Kurihara, H.
J . Am. Chem. Soc. 1995, 117, 4279-4287.
(21) Midland. M. M.; Kwon, Y. C. J . Am. Chem. Soc. 1983, 105,
3725-3727.
(22) Yamamoto, I.; Sekine, M.; Hata, T. J . Chem. Soc., Perkin Trans.
1 1983, 306-310.

920 J . Org. Chem., Vol. 61, No. 3, 1996
Shuto et al.
16 mmol) in THF (20 mL), BuLi (1.64 M in hexane, 11 mL, 16
mmol) was added slowly at 0 °C under argon, and then the
mixture was cooled to -78 °C. To the resulting cooled mixture,
a solution of 4 (1.7 g, 10 mmol) in THF (20 mL) was added
slowly, and the whole was stirred at the same temperature.
After 2 h, the reaction was quenched with saturated NH4Cl
(10 mL), and the resulting mixture was concentrated in vacuo
(for removing THF) and then AcOEt was added. The sepa-
rated organic phase was dried (Na2SO4), evaporated, and
purified by flash column chromatography (silica gel; AcOEt/
hexane, 1:1) to give 9 as an oil (2.1 g, 87%). 1H-NMR (400
MHz, CDCl3) 0.91 (3 H, t, J ) 7.0 Hz), 1.08 (1 H, dd, J ) 5.0,
6.5 Hz), 1.14 (3 H, t, J ) 7.0 Hz), 1.55 (1 H, dddd, J ) 5.0, 6.5,
9.0, 10.5 Hz), 1.65 (1 H, dd, J ) 5.0, 9.0 Hz), 3.17 (1 H, ddd, J
) 2.5, 10.5, 12.0 Hz), 3.32-3.56 (4 H, m), 4.40 (1 H, ddd, J )
5.0, 11.0, 12.0 Hz), 4.74 (1 H, dd, J ) 2.5, 11.0 Hz), 7.19-7.32
(5 H, m). 13C-NMR (125 MHz, CDCl3) 12.60, 13.33, 17.07,
32.09, 34.64, 39.77, 42.24, 65.06, 125.97, 126.85, 128.92,
140.55, 171.46. HR-MS (EI) calcd for C15H21NO2 247.1572,
found 247.1564. Anal. Calcd for C15H21NO2‚0.1H2O: C, 72.31;
H, 8.50; N, 5.57. Found: C, 72.29; H, 8.77; N, 5.57.
The structures of X-ray crystallographic analysis of ent-
2b and ent-3b, indicated in Figure 8, clearly demonstrate
that 2 (ent-2) and 3 (ent-3) exist in conformer B and A,
respectively, as we hypothesized. Although the confor-
mations detected in this study were in the solid state,
this result suggests that the conformation of substituents
on a cyclopropane ring would be restricted by the steric
effect of adjacent substituents even in the solution. In
design of conformationally restricted analogs, it should
be imperative that the conformationally restricted ana-
logs and the lead drug molecule should be as similar as
possible in size, shape, and molecular weight.9 Confor-
mationally restricted analogs have usually been designed
and synthesized by introducing cyclic moieties into lead
compounds that were often rather bulky. Consequently,
the chemical and physical properties can be changed.
From these points of view, our methodology for restricting
the conformation of a key functional group, due to the
repulsion of the adjacent substituents by introducing only
a small alkyl group such as a methyl or ethyl group,
would be useful. This method can be applicable for
conformational restriction of various cyclopropane de-
rivatives.
(1S,2R)-1-P h en yl-2-for m yl-N,N-d iet h ylcyclop r op a n e-
ca r boxa m id e (10). To a solution of oxalyl chloride (0.55 mL,
6.4 mmol) in CH2Cl2 (4 mL) was added a mixture of DMSO
(0.91 mL, 13 mmol) and CH2Cl2 (4 mL) slowly at -78 °C for
30 min under argon. To the resulting mixture was added a
solution of 9 (805 mg, 3.26 mmol) in CH2Cl2 (4 mL) slowly,
the whole was stirred at the same temperature for 2 h, and
then Et3N (1.9 mL, 26 mmol) was added. After being stirred
at -78 °C for further 1 h, the reaction mixture was quenched
with saturated NH4Cl (5 mL), and then CHCl3 (10 mL) was
added. The organic layer separated was washed with brine,
dried (Na2SO4), evaporated, and purified by column chroma-
tography (silica gel; AcOEt/hexane, 1:2) to give 10 as a white
crystal (766 mg, 96%). Mp 56-57 °C. 1H-NMR (400 MHz,
CDCl3) 0.69 (3 H, t, J ) 7.0 Hz), 1.11 (3 H, t, J ) 7.0 Hz), 1.71
(1 H, dd, J ) 5.5, 8.5 Hz), 2.28 (1 H, dd, J ) 5.5, 6.0 Hz), 2.50
(1 H, ddd, J ) 6.0, 6.0, 8.5 Hz), 3.18 (1H, dq, J ) 14.0, 7.0
Hz), 3.26 (1H, dq, J ) 14.0, 7.0 Hz), 3.42 (1H, dq, J ) 14.0,
7.0 Hz), 3.46 (1H, dq, J ) 14.0, 7.0 Hz), 7.23-7.38 (5 H, m),
In a preliminary binding study of the compound on
NMDA receptor, 2a and 2b showed about 30 times
stronger binding affinity for the receptor, compared with
milnacipran.8 The details of the biological activity of the
compounds will be reported elsewhere.
Exp er im en ta l Section
Melting points are uncorrected. NMR spectra were recorded
at 270, 400, or 500 MHz (1H) and at 100 or 125 MHz (13C) and
are reported in ppm downfield from TMS. Mass spectra were
obtained by electron ionization. Thin-layer chromatography
was done on Merck coated plate 60F254. Silica gel chromatog-
raphy and flash silica gel chromatography were done with
Merck silica gel 5715 and 9385, respectively.
9.05 (1 H, d, J ) 6.0 Hz).
13C-NMR (125 MHz, CDCl3) 12.50,
13.00, 20.23, 36.63, 39.88, 40.35, 41.79, 126.13, 127.74, 129.21,
138.18, 167.54, 198.30. HR-MS (EI) calcd for C15H19NO2
245.1416, found 245.1431. Anal. Calcd for C15H19NO2: C,
73.44; H, 7.81; N, 5.71. Found: C, 73.48; H, 7.92; N, 5.66.
(1S,2R)-1-P h en yl-2-[(S)-1-h yd r oxyet h yl]-N,N-d iet h yl-
cyclop r op a n eca r boxa m id e (11a ). To a solution of 10 (1.59
g, 6.5 mmol) in THF (40 mL) was added MeMgBr (0.99 M in
THF, 16.5 mL, 16.3 mmol) slowly at -20 °C under argon. The
mixture was stirred at the same temperature for 2 h and was
quenched with saturated NH4Cl (20 mL). The resulting
mixture was concentrated in vacuo (for removing THF), and
then AcOEt was added. The separated organic phase was
dried (Na2SO4), evaporated, and purified by column chroma-
tography (silica gel; AcOEt/hexane, 1:2) to give 11a as white
(1S,2R)-2-Oxo-1-p h en yl-3-oxa bicyclo[3.1.0]h exa n e (4).
A solution of phenylacetonitrile (34.5 mL, 300 mmol) in
benzene (60 mL) was added slowly to a suspension of NaNH2
(25.8 g, 660 mmol) in benzene (120 mL) at 0 °C under argon,
and the mixture was stirred at room temperature for 3 h. To
the resulting mixture, a solution of (R)-epichlorohydrin [(R)-
5, 20.4 mL, 261 mmol] in benzene (60 mL) was added at 0 °C,
and the whole was stirred at room temperature for 2 h. After
the solvent was evaporated, EtOH (60 mL) and 1 N KOH (30
mL) were added to the residue, and the mixture was heated
under reflux for 15 h and then acidified with 12 N HCl at 0
°C (pH of the mixture was about 1). The resulting mixture
was evaporated, and AcOEt (900 mL) was added to the residue.
Insoluble salts were filtered off, and the filtrate was washed
with brine, dried (Na2SO4), and evaporated. The residue was
purified by column chromatography (silica gel; AcOEt/hexane,
1:3) to give 4 as orange crystals (30.3 g, 67%). The optical
purity was determined by a chiral HPLC (CHIRALCEL-OJ ,
0.46 × 25 cm, Daicel Chemical Industries Co., Ltd.; hexane/
2-propanol, 4:1; 0.4 mL/min; 200 nm): 96% ee, mp 56-57 °C.
crystals (1.55 g, 93%). Mp 72-73 °C. [R]28 ) -27.5 (c 1.12,
D
MeOH). 1H-NMR (400 MHz, CDCl3) 0.93 (3 H, t, J ) 7.0 Hz),
1.03 (1 H, dd, J ) 5.5, 6.5 Hz), 1.14 (3 H, t, J ) 7.0 Hz), 1.28
(1 H, ddd, J ) 6.5, 9.0, 9.0 Hz), 1.31 (3 H, d, J ) 6.5 Hz), 1.67
(1 H, dd, J ) 5.5, 9.0 Hz), 3.26-3.34 (1 H, m), 3.35-3.46 (3 H,
m), 3.52 (1 H, dq, 14.0, 7.0 Hz), 5.41 (1H, s), 7.19-7.31 (5 H,
m). 13C-NMR (100 MHz, CDCl3) 12.38, 13.19, 16.79, 21.45,
34.35, 38.15, 39.52, 42.01, 70.74, 125.68, 126.59, 128.68,
140.27, 171.45. HR-MS (EI) calcd for C16H23NO2 261.1729,
found 261.1722. Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87;
N, 5.36. Found: C, 73.52; H, 9.04; N, 5.30.
[R]20 ) -78.5 (c 1.42, MeOH). 1H-NMR (500 MHz, CDCl3)
D
1.36 (1 H, dd, J ) 4.5, 5.0 Hz), 1.65 (1 H, dd, J ) 5.0, 8.0 Hz),
2.55 (1 H, ddd, J ) 4.5, 4.5, 8.0 Hz), 4.29 (1 H, d, J ) 9.0 Hz),
4.46 (1 H, dd, J ) 4.5, 9.0 Hz), 7.28-7.44 (5 H, m). 13C-NMR
(125 MHz, CDCl3) 20.41, 25.36, 31.95, 68.34, 127.92, 128.57,
128.85, 134.40, 176.29. HR-MS (EI) calcd for C11H10O2 174.0681,
found 174.0684. Anal. Calcd for C11H10O2: C, 75.84; H, 5.79.
Found: C, 75.96; H, 5.87.
(1S,2R)-1-P h en yl-2-[(S)-1-h yd r oxyp r op yl]-N,N-d ieth yl-
cyclop r op a n eca r boxa m id e (11b). Compound 11b was
prepared as described above for 11a , with EtMgBr instead of
MeMgBr. After purification by column chromatography (silica
gel; AcOEt/hexane, 1:3), 11b was obtained as an oil (3.22 g,
(1S,2R)-1-P h en yl-2-(h yd r oxym eth yl)-N,N-d ieth ylcyclo-
p r op a n eca r boxa m id e (9). To a solution of Et2NH (1.7 mL,
90% yield). [R]26 ) -17.6 (c 1.11, MeOH). 1H-NMR (500
D
MHz, CDCl3) 0.93 (3 H, t, J ) 7.0 Hz), 1.00 (3 H, t, J ) 7.5
Hz), 1.06 (1 H, dd, J ) 5.5, 6.5 Hz), 1.14 (3 H, t, J ) 7.0 Hz),
1.26 (1 H, ddd, J ) 6.5, 9.0, 9.5 Hz), 1.61-1.73 (2 H, m), 1.70
(1 H, dd, J ) 5.5, 9.0 Hz), 3.08 (1 H, ddd, J ) 6.5, 9.5, 9.5 Hz),
(25) (a) Haywood-Farmer, J . Chem. Rev. 1974, 74, 315-350. (b)
Wilcox, C. F.; Loew, M. M.; Hoffmann, R. J . Am. Chem. Soc. 1973, 95,
8192-8193.

New Method for Conformational Restriction
J . Org. Chem., Vol. 61, No. 3, 1996 921
3.33-3.46 (3 H, m), 3.48-3.55 (1 H, dq, J ) 14.0, 7.0 Hz), 5.44
(1 H, br s), 7.18-7.30 (5 H, m). 13C-NMR (100 MHz, CDCl3)
10.24, 12.29, 13.08, 17.05, 29.08, 33.25, 36.61, 39.39, 41.90,
75.66, 125.62, 126.48, 128.58, 140.29, 171.41. HR-MS (EI)
calcd for C17H25NO2 275.1885, found 275.1909. Anal. Calcd
for C17H25NO2: C, 74.14; H, 9.15; N, 5.09. Found: C, 73.88;
H, 9.20; N, 5.09.
14.45, 29.72, 32.79, 34.95, 39.52, 42.21, 69.29, 125.62, 126.30,
128.64, 141.11, 171.87. HR-MS (EI) calcd for C17H25NO2
275.1885, found 275.1858. Anal. Calcd for C17H25NO2: C,
74.14; H, 9.15; N, 5.09. Found: C, 73.75; H, 9.26; N, 4.96.
Red u cton of 15b w ith L-Selectr id e. Reaction was done
as described above for the reduction of 15b, with L-Selectride
(1.0 M in THF) instead of DIBAL-H. After purification by
column chromatography (silica gel; AcOEt/hexane, 1:1), a
mixture of 11b and 12b was obtained as an oil (114 mg, 91%,
11b:12b ) 50:1).
Red u cton of 15b w ith Na BH4. To a solution of 15b (82
mg, 0.30 mmol) in MeOH (0.5 mL) was added NaBH4 (9.8 mg,
0.26 mmol). The mixture was stirred at room temperature
for 2 h and then quenched with saturated NH4Cl. The
resulting mixture was concentrated in vacuo, then AcOEt was
added. The separated organic phase was dried (Na2SO4),
evaporated, and purified by column chromatography (silica gel;
AcOEt/hexane, 1:1) to give 11a (46 mg, 56%) and 12b (12 mg,
15%).
(1S,4S,5R)-4-Meth yl-2-oxo-1-ph en yl-3-oxabicyclo[3.1.0]-
h exa n e (13). To a solution of 11a (750 mg, 2.87 mmol) in
MeOH (5 mL) was added 6 N HCl (5 mL), and the whole was
heated under reflux for 45 min. The solvent was evaporated,
and then the residue was partitioned between saturated
NaHCO3 and AcOEt. The organic phase washed with brine
was dried (Na2SO4) and evaporated. The residue was purified
by column chromatography (silica gel; AcOEt/hexane, 1:3) to
give 13 as white powder (340 mg, 63%). 1H-NMR (400 MHz,
CDCl3) 1.38 (1 H, dd, J ) 4.5, 5.0 Hz), 1.52 (3 H, d, J ) 6.5
Hz), 1.63 (1 H, dd, J ) 5.0, 8.0 Hz), 2.32 (1 H, dd, J ) 4.5, 8.0
Hz), 4.54 (1 H, q, J ) 6.5 Hz), 7.28-7.42 (5 H, m). 13C-NMR
(100 MHz, CDCl3) 20.12, 22.62, 31.26, 32.48, 75.99, 127.76,
128.51, 128.66, 134.25, 175.46. MS (EI) m/ z 188 (M+). Anal.
Calcd for C12H12O2: C, 76.57; H, 6.43. Found: C, 76.59; H,
6.42.
(1S,4R,5R)-4-Meth yl-2-oxo-1-ph en yl-3-oxabicyclo[3.1.0]-
h exa n e (14). Compound 14 was prepared as described above
for 13. After purification by column chromatography (silica
gel; AcOEt/hexane, 1:3), 14 was obtained as white powder (44
mg, 68%). 1H-NMR (400 MHz, CDCl3) 1.42 (3 H, d, J ) 6.0
Hz), 1.41-1.43 (1 H, m), 1.48 (1 H, dd, J ) 5.0, 8.0 Hz), 2.51
(1 H, ddd, J ) 4.5, 5.0, 8.0 Hz), 4.90 (1 H, dq, J ) 4.5, 6.0 Hz),
7.27-7.43 (5 H, m). 13C-NMR (100 MHz, CDCl3) 16.75, 17.59,
29.78, 33.12, 74.27, 127.56, 128.16, 128.55, 134.25, 175.79. HR-
MS (EI) calcd C12H12O2 188.0837, found 188.0824. Anal.
Calcd for C12H12O2: C, 76.57; H, 6.43. Found: C, 76.37; H,
6.59.
(1S,2R)-1-P h en yl-2-a cet yl-N,N-d iet h ylcyclop r op a n e-
ca r boxa m id e (15a ). A mixture of 11a (1.33 g, 5.10 mmol),
PDC (7.67 g, 20.4 mmol), and molecular sieves 4A (6.65 g) in
CH2Cl2 (20 mL) was stirred at room temperature for 2 h, and
the resulting mixture was filtered through Celite. The filtrate
was evaporated, and the residue was purified by column
chromatography (silica gel; AcOEt/hexane, 1:1) to give 15a as
white crystals (1.24 g, 94%). Mp 73-74 °C. [R]28 ) -220.3
D
(c 0.91, MeOH). 1H-NMR (400 MHz, CDCl3) 0.86 (3 H, t, J )
7.0 Hz), 1.09 (3 H, t, J ) 7.0 Hz), 1.66 (1 H, dd, J ) 5.0, 8.0
Hz), 2.22 (1 H, dd, 5.0, 6.5 Hz), 2.38 (3 H, s), 2.44 (1 H, dd, J
) 6.5, 8.0 Hz), 3.24 (1 H, dq, J ) 14.0, 7.0 Hz), 3.25 (1 H, dq,
J ) 14.0, 7.0 Hz), 3.39 (1 H, dq, J ) 7.0, 14.0 Hz), 3.45 (1 H,
dq, J ) 7.0, 14.0 Hz), 7.24-7.35 (5 H, m). 13C-NMR (100 MHz,
CDCl3) 12.40, 13.19, 19.78, 31.46, 37.02, 39.32, 41.64, 41.95,
126.06, 127.25, 128.80, 139.10, 167.76, 204.33. HR-MS (EI)
calcd for C16H21NO2 259.1572, found 259.1601. Anal. Calcd
for C16H21NO2: C, 74.10; H, 8.16; N, 5.40. Found: C, 74.23;
H, 8.21; N, 5.35.
(1S,2R)-1-P h en yl-2-pr opan oyl-N,N-dieth ylcyclopr opan -
eca r boxa m id e (15b). Compound 15b was prepared as
described above for 15a . After purification by column chro-
matography (silica gel; AcOEt/hexane, 1:3), 15b was obtained
as white crystals (600 mg, 87% yield). Mp 84-85 °C. [R]27
D
) -220.3 (c 0.73, MeOH). 1H-NMR (400 MHz, CDCl3) 0.88 (3
H, t, J ) 7.0 Hz), 1.08 (3 H, t, J ) 7.0 Hz), 1.14 (3 H, t, J ) 7.5
Hz), 1.65 (1 H, dd, J ) 5.0, 8.0 Hz), 2.23 (1 H, dd, J ) 5.0, 6.5
Hz), 2.42 (1 H, dd, J ) 6.5, 8.0 Hz), 2.61 (1 H, dq, J ) 17.5,
7.5 Hz), 2.78 (1 H, dq, J ) 17.5, 7.5 Hz), 3.21 (1 H, dq, 14.0,
7.0 Hz), 3.22 (1 H, dq, 14.0, 7.0 Hz), 3.41 (1 H, dq, 14.0, 7.0
Hz), 3.47 (1 H, dq, 14.0, 7.0 Hz), 7.24-7.35 (5 H, m). 13C-NMR
(100 MHz, CDCl3) 7.99, 12.36, 13.22, 19.53, 36.05, 37.60, 39.28,
41.57, 126.10, 127.19, 128.79, 139.26, 167.72, 206.91. HR-MS
(EI) calcd C17H23NO2 273.1729, found 273.1701. Anal. Calcd
for C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.58;
H, 8.60; N, 5.01.
(1S,2R)-1-P h en yl-2-[(R)-1-h yd r oxyeth yl]-N,N-d ieth yl-
cyclop r op a n eca r boxa m id e (12a ). To a solution of 15a (100
mg, 0.386 mmol) in THF (5 mL) was added DIBAL-H (0.93 M
in hexane, 0.83 mL, 0.97 mmol) slowly at -78 °C under argon.
The mixture was stirred at the same temperature for 1 h and
quenched with 1 N HCl. The resulting mixture was concen-
trated in vacuo (for removing THF), and then AcOEt and H2O
was added. The separated organic phase was dried (Na2SO4),
evaporated, and purified by flash column chromatography
Gen er a l P r oced u r e for P r ep a r in g Azid e Der iva tives
16a , 16b, 17a , a n d 17b. To a solution of 2′-alcohol (11 or 12,
3.30 mmol) in DMF (25 mL) were added NaN3 (3.20 g, 65.0
mmol), Ph3P (2.60 g, 19.9 mmol), and CBr4 (3.30 g, 10.0 mmol)
at 0 °C, and the whole was stirred at room temperature for 3
h. Water was added and the resulting mixture was evapo-
rated, and then the residue was partitioned between brine and
AcOEt. The organic phase was dried (Na2SO4) and evaporated.
The residue was purified by column chromatography (silica
gel; AcOEt/hexane, 1:5) to give azide 16 or 17 as an oil.
(1S,2R)-1-P h en yl-2-[(S)-1-a zid oet h yl]-N,N-d iet h ylcyclo-
(silica gel; AcOEt/hexane, 1:1) to give 12a (91 mg, 90%). [R]28
D
) -127.0 (c 0.98, MeOH). 1H-NMR (500 MHz, CDCl3) 0.76 (3
H, t, J ) 7.0 Hz), 1.12 (3 H, t, J ) 7.0 Hz), 1.27 (3 H, d, J )
6.5 Hz), 1.39-1.46 (2 H, m), 1.50 (1 H, dd, 4.0, 6.5 Hz), 3.00 (1
H, brs), 3.26 (1 H, dq, J ) 14.0, 7.0 Hz), 3.31 (1 H, dq, J )
14.0, 7.0 Hz), 3.41 (1 H, dq, J ) 14.0, 7.0 Hz), 3.49 (1 H, dq, J
) 14.0, 7.0 Hz), 4.17 (1 H, dt, J ) 10.0, 6.5 Hz), 7.20-7.30 (5
H, m). 13C-NMR (100 MHz, CDCl3) 12.29, 12.71, 14.91, 22.51,
33.40, 36.19, 39.59, 42.28, 64.89, 125.69, 126.39, 128.68,
140.98, 171.62. HR-MS (EI) calcd for C16H23NO2 261.1729,
found 261.1724. Anal. Calcd for C16H23NO2‚0.1H2O: C, 73.02;
H, 8.89; N, 5.32. Found: C, 73.07; H, 9.01; N, 5.15.
p r op a n eca r boxa m id e (16a ). Yield 62% (585 mg). [R]28
)
D
-137.3 (c 0.99, MeOH).1H-NMR (400 MHz, CDCl3) 0.37 (3 H,
t, J ) 7.0 Hz), 0.91 (1 H, dd, J ) 5.0, 9.5 Hz), 1.11 (3 H, t, J
) 7.0 Hz), 1.45 (3 H, d, J ) 7.0 Hz), 1.61 (1 H, dd, J ) 5.0, 6.5
Hz), 1.95 (1 H, ddd, J ) 6.5 Hz, 9.5 Hz, 10.0 Hz), 2.98-3.08 (2
H, m), 3.12 (1 H, dq, J ) 14.0, 7.0 Hz), 3.57 (1 H, dq, J ) 14.0,
7.0 Hz), 3.68 (1 H, dq, J ) 14.0, 7.0 Hz), 7.19-7.32 (5 H, m).
13C-NMR (125 MHz, CDCl3) 12.11, 12.47, 19.71, 19.99, 28.99,
36.82, 40.06, 42.48, 58.47, 126.90, 127.18, 128.98, 141.02,
169.65. MS (EI) m/ z 286 (M+). Anal. Calcd for C16H22N4O:
C, 67.11; H, 7.74; N, 19.56. Found: C, 67.30; H, 7.84; N, 19.67.
(1S,2R)-1-P h en yl-2-[(S)-1-a zid op r op yl]-N,N-d ieth ylcyclo-
(1S,2R)1-P h en yl-2-[(R)-1-h yd r oxyp r op yl]-N,N-d ieth yl-
cyclop r op a n eca r boxa m id e (12b). Compound 12b was
prepared as described above for 12a . After purification by
column chromatography (silica gel; AcOEt/hexane, 1:2), 12b
was obtained as an oil (130 mg, 95% yield). [R]27 ) -125.0
D
(c 0.99, MeOH). 1H-NMR (500 MHz, CDCl3) 0.75 (3 H, t, J )
7.0 Hz), 1.00 (3 H, t, J ) 7.5 Hz), 1.12 (3 H, t, J ) 7.0 Hz),
1.37-1.44 (2 H, m), 1.52-1.64 (3 H, m), 2.88 (1 H, brs), 3.26
(1 H, dq, J ) 14.0, 7.0 Hz), 3.31 (1 H, dq, J ) 14.0, 7.0 Hz),
3.41 (1 H, dq, J ) 14.0, 7.0 Hz), 3.47 (1 H, dq, J ) 14.0, 7.0
Hz), 4.00 (1 H, ddd, 4.0, 4.0, 8.0 Hz), 7.17-7.22 (3 H, m), 7.27-
7.31 (2 H, m). 13C-NMR (100 MHz, CDCl3) 10.22, 12.29, 12.66,
p r op a n eca r boxa m id e (16b). Yield 72% (713 mg). [R]26
)
D
-160.0 (c 0.91, MeOH).1H-NMR (400 MHz, CDCl3) 0.37 (3 H,
t, J ) 7.0 Hz), 0.95 (1 H, dd, J ) 5.0, 9.5 Hz), 1.07 (3 H, t, J
) 7.5 Hz), 1.13 (3 H, t, J ) 7.0 Hz), 1.66 (1 H, dd, J ) 5.0, 6.5
Hz), 1.74-1.87 (2 H, m), 1.96 (1 H, ddd, J ) 6.5, 9.5, 10.0 Hz),
2.86 (1 H, ddd, J ) 5.0, 8.0, 10.0 Hz), 3.04 (1 H, dq, J ) 14.0,

922 J . Org. Chem., Vol. 61, No. 3, 1996
Shuto et al.
7.0 Hz), 3.17 (1 H, dq, J ) 14.0, 7.0 Hz), 3.53 (1 H, dq, J )
14.0, 7.0 Hz), 3.72 (1 H, dq, J ) 14.0, 7.0 Hz), 7.19-7.32 (5 H,
m). 13C-NMR (100 MHz, CDCl3) 10.22, 11.80, 12.29, 19.62,
27.27, 28.24, 35.88, 39.96, 42.08, 64.17, 126.63, 126.99, 128.71,
140.82, 169.48. HR-MS (EI) calcd for C17H24N4O 300.1950,
found 300.1978. Anal. Calcd for C17H24N4O: C, 67.97; H, 8.05;
N, 18.65. Found: C, 68.15; H, 8.08; N, 18.43. (1S,2R)-1-
P h en yl-2-[(R)-1-a zid oet h yl]-N,N-d iet h ylcyclop r op a n e-
ca r boxa m id e (17a ). Yield 86% (812 mg). [R]28D ) -118.4 (c
1.25, MeOH). 1H-NMR (500 MHz, CDCl3) 0.69 (3 H, t, J )
7.0 Hz), 1.11 (3 H, t, J ) 7.0 Hz), 1.48-1.52 (3 H, m), 1.51 (3
H, d, J ) 6.5), 3.18 (1 H, dq, J ) 14.0, 7.0 Hz), 3.23 (1 H, dq,
J ) 14.0, 7.0 Hz), 3.33-3.38 (1 H, m), 3.45 (1 H, dq, J ) 14.0,
7.0 Hz), 3.49 (1 H, dq, J ) 14.0, 7.0 Hz), 7.20-7.32 (5 H, m).
13C-NMR (100 MHz, CDCl3) 12.31, 12.66, 18.20, 20.37, 32.90,
34.15, 39.43, 41.95, 59.20, 126.04, 126.70, 128.75, 140.47,
169.22. HR-MS (EI) calcd for C16H22N4O 286.1793, found
286.1765. Anal. Calcd for C16H22N4O: C, 67.11; H, 7.74; N,
19.56. Found: C, 67.10; H, 7.82; N, 19.37. (1S,2R)-1-P h en yl-
2-[(R)-1-a zid op r op yl]-N,N-d ieth ylcyclop r op a n eca r boxa -
10.0, 10.0 Hz), 3.29 (1 H, dq, J ) 14.0, 7.0 Hz), 3.34-3.48 (3
H, m), 7.20-7.23 (3 H, m), 7.27-7.31 (2 H, m), 9.00 (3 H, br
s). 13C-NMR (125 MHz, CDCl3) 11.01, 12.45, 13.29, 18.59,
26.78, 30.66, 33.28, 39.92, 42.21, 57.77, 126.26, 127.53, 129.21,
138.36, 171.12. HR-MS (EI) calcd for C17H26N2O 274.2045,
found 274.2046. Anal. Calcd for C17H26N2O‚HCl‚0.1H2O: C,
64.93; H, 8.78; N, 8.91. Found: C, 65.04; H, 9.11; N, 8.98.
(1S,2R)-1-P h en yl-2-[(R)-1-a m in oeth yl]-N,N-d ieth ylcyclo-
p r op a n eca r boxa m id e Hyd r och lor id e (3a ). Yield 68% (604
mg). Mp 179-182 °C. [R]21 ) +41.8 (c 0.968, CHCl3). 1H-
D
NMR (500 MHz, CDCl3) 0.75 (3 H, t, J ) 7.0 Hz), 1.09 (3 H, t,
J ) 7.0 Hz), 1.55 (1 H, dd, J ) 5.5, 5.5 Hz), 1.60-1.70 (2 H,
m), 1.65 (3 H, d, J ) 6.5 Hz), 3.21-3.30 (2 H, m), 3.35-3.50 (3
H, m), 7.19-7.29 (5 H, m), 8.58 (3 H, br s). 13C-NMR (100
MHz, CDCl3) 12.35, 12.82, 17.68, 18.87, 31.46, 35.15, 39.56,
42.03, 50.24, 126.15, 126.92, 128.79, 139.54, 169.38. HR-MS
(EI) calcd for C16H24N2O 260.1889, found 260.1870. Anal.
Calcd for C16H24N2O‚HCl‚0.6H2O: C, 62.47; H, 8.58; N, 9.11.
Found: C, 62.45; H, 8.58; N, 9.14. (1S,2R)-1-P h en yl-2-[(R)-
1-a m in op r op yl]-N,N-d iet h ylcyclop r op a n eca r b oxa m id e
Hyd r och lor id e (3b). Yield 81% (753 mg). Mp 165-167 °C.
m id e (17b). Yield 93% (921 mg). [R]28 ) -101.4 (c 0.73,
D
MeOH). 1H-NMR (500 MHz, CDCl3) 0.69 (3 H, t, J ) 7.0 Hz),
1.04 (3 H, t, J ) 7.5 Hz), 1.11 (3 H, t, J ) 7.0 Hz), 1.47-1.60
(3 H, m), 1.61-1.72 (1 H, m), 2.01 (1 H, ddq, J ) 14.5, 3.5, 7.5
Hz), 3.12-3.26 (3 H, m), 3.48 (1 H, dq, J ) 14.0, 7.0 Hz), 3.49
(1 H, dq, J ) 14.0, 7.0 Hz), 719-7.32 (5 H, m). 13C-NMR (100
MHz, CDCl3) 10.65, 12.35, 12.68, 17.98, 28.37, 31.35, 33.82,
39.43, 41.92, 64.98, 126.12, 126.70, 128.79, 140.62, 169.28. HR-
MS (EI) calcd for C17H24N4O 300.1950, found 300.1926. Anal.
Calcd for C17H24N4O: C, 67.97; H, 8.05; N, 18.65. Found: C,
68.26; H, 8.28; N, 18.27.
[R]21 ) +52.9 (c 0.648, CHCl3). 1H-NMR (500 MHz, CDCl3)
D
0.75 (3 H, t, J ) 7.0 Hz), 1.09 (3 H, t, J ) 7.0 Hz), 1.20 (3 H,
t, J ) 7.5 Hz), 1.51-1.59 (2 H, m), 1.73 (1 H, dd, J ) 5.5, 8.0
Hz), 1.94-2.03 (1 H, m), 2.26-2.31 (1 H, m), 3.16-3.28 (3 H,
m), 3.39 (1 H, dq, J ) 14.0, 7.0 Hz), 3.43 (1 H, dq, J ) 14.0,
7.0 Hz), 7.18-7.30 (5 H, m), 8.55 (3 H, br s). 13C-NMR (100
MHz, CDCl3) 10.55, 12.38, 12.84, 17.83, 26.94, 31.04, 35.43,
39.43, 41.86, 56.26, 125.97, 126.94, 128.84, 139.79, 169.11. HR-
MS (EI) calcd for C17H26N2O 274.2045, found 274.2025. Anal.
Calcd for C17H26N2O‚HCl‚0.4H2O: C, 64.19; H, 8.81; N, 8.81.
Found: C, 64.11; H, 9.09; N, 8.76.
Syn th esis of 16a via 18. To a solution of 11a (141 mg,
0.54 mmol) and DMAP (132 mg, 1.08 mmol) in CH2Cl2 (2 mL)
was added trifluoroacetic anhydride (150 µL, 1.08 mmol), and
the mixture was stirred at room temperature for 15 h. To the
resulting mixture were added DMF (2 mL) and NaN3 (53 mg,
0.81 mmol), and the whole was sttired at room temperature
for 45 min and further stirred at 45 °C for 15 min. Water
was added, the resulting mixture was evaporated, and then
the residue was partitioned between brine and AcOEt. The
organic phase was dried (Na2SO4) and evaporated. The
residue was purified by column chromatography (silica gel;
AcOEt/hexane, 1:5) to give 16a as an oil (128 mg, 83%).
Gen er a l P r oced u r e for th e Red u ction of Azid e De-
r iva tives. A mixture of 16 or 17 (3.00 mmol) and 10% Pd-
charcoal (200 mg) in MeOH (35 mL) was stirred under
atmospheric pressure of hydrogen at room temperature for 1.5
h, and then the catalyst was filtered off. The filtrate was
evaporated, and the residue was purified by column chroma-
tography (silica gel; CHCl3/MeOH/28% NH4OH, 90:20:0.5) to
give free amine 2 or 3 as an oil. The oil was partitioned
between CHCl3 and 1 N NaOH, and then CHCl3 phase was
washed twice with brine, dried (Na2SO4), and evaporated. The
residue was dissolved in MeOH (3 mL), the solution was put
on a column of Diaion WA-30 resin (3 × 10 cm, Cl- form), and
the column was developed with MeOH. The solvent was
evaporated, and the residue was treated with ether to give
white crystals of 2 or 3 as hydrochloride. (1S,2R)-1-P h en yl-
2-[(S)-1-a m in oet h yl]-N,N-d iet h ylcyclop r op a n eca r b oxa -
m id e Hyd r och lor id e (2a ). Yield 60% (529 mg). Mp 210-
X-r a y Cr ysta llogr a p h ic Da ta of 10. C15H19NO2, M )
245.32, monoclinic, P21 (no. 4), a ) 8.056(2) Å, b ) 14.108(4)
Å, c ) 6.627(1) Å, â ) 112.76(1) Å, V ) 694.6(2) Å, Z ) 2,
Dcalcd ) 1.17 g cm-3
.
Cell parameters were determined and
refined from 20 reflections in the range 56° < 2θ < 60°.
A
colorless crystal (0.35 × 0.20 × 0.20 mm) was mounted on a
Mac Science MXC18 diffractometer with graphite-monochro-
mated Cu KR radiation (λ ) 1.54178 Å). Data collection using
the ω/2θ scan technique to a maximum 2θ value of 120° gave
1174 reflections at room temperature, 1051 unique, of which
983 with I > 3.00σ(I) reflections were used in calculations. The
intensities were corrected for the Lorentz and polarization
factors but not for the absorption or the extinction effect. The
structure was solved by direct method and refined by full-
matrix least squares technique (Crystan-GM system26 as the
computer program and SIR9227 as the structure solution
method). The non-hydrogen atoms were refined anisotropi-
cally. The hydrogen atoms were included by calculation, but
these positions were not refined. The unweighted and weighted
values (with a weighting scheme W ) exp(15 sin2 θ/λ2)/σ2(Fo))
were 0.057 and 0.064, respectively. No peak above 0.18 e Å-3
in the last Fourier-difference map.
X-r a y Cr ysta llogr a p h ic Da ta of 15b.28 C17H23NO2, M )
273.38, orthorhombic, P212121 (no. 19), a ) 13.450(4) Å, b )
17.846(5) Å, c ) 6.672(4) Å, V ) 1602(1) Å3, Z ) 4, Dcalcd
)
1.13 g cm-3
. Cell parameters were determined and refined
from 15 reflections in the range 57° < 2θ < 60°. A colorless
prism (0.5 × 0.3 × 0.1 mm) was mounted on a Mac Science
MXC18 diffractometer with graphite-monochromated Cu KR
radiation (λ ) 1.54178 Å). Data collection using the ω/2θ scan
technique to a maximum 2θ value of 120° gave 1463 reflections
at room temperature, 1396 unique, of which 1280 with I >
3.00σ(I) reflections were used in calculations. The intensities
were corrected for the Lorentz and polarization factors but not
for the absorption or the extinction effect. The structure was
solved by direct method and refined by full-matrix least
squares technique (Crystan-GM system26 as the computer
program and SIR9227 as the structure solution method). The
non-hydrogen atoms were refined anisotropically. The hydro-
gen atoms were included by calculation, but these positions
were not refined. The unweighted and weighted values (with
a weighting scheme W ) exp(20 sin2 θ/λ2)/σ2(Fo)) were 0.059
and 0.063, respectively. No peak above 0.20 e Å-3 in the last
Fourier-difference map.
213 °C. [R]18 ) +90.1 (c 0.260, MeOH). 1H-NMR (400 MHz,
D
CDCl3) 0.92 (3 H, t, J ) 7.0 Hz), 1.05 (1 H, dd, J ) 6.0, 6.5
Hz), 1.10 (3 H, t, J ) 7.0 Hz), 1.60 (1 H, ddd, J ) 6.5, 9.5, 10.5
Hz), 1.73 (3 H, d, J ) 6.5 Hz), 1.85 (1 H, dd, J ) 6.0, 9.5 Hz),
2.79 (1 H, dq, J ) 10.5, 6.5 Hz), 3.25-3.50 (4 H, m), 7.17-
7.31 (5 H, m), 8.99 (3 H, br s). 13C-NMR (100 MHz, CDCl3)
12.27, 13.10, 17.63, 18.33, 32.17, 35.00, 39.65, 42.01, 52.43,
125.91, 127.34, 129.01, 138.13, 170.85. MS (EI) m/ z 260 (M+).
Anal. Calcd for C16H24N2O‚HCl: C, 64.74; H, 8.49; N, 9.44.
Found: C, 64.78; H, 8.62; N, 9.32. (1S,2R)-1-P h en yl-2-[(S)-
1-a m in op r op yl]-N,N-d iet h ylcyclop r op a n eca r b oxa m id e
Hyd r och lor id e (2b). Yield 76% (707 mg). Mp 200-203 °C.
[R]21 ) +100.8 (c 0.900, CHCl3). 1H-NMR (500 MHz, CDCl3)
D
0.90 (3 H, t, J ) 7.0 Hz), 1.08-1.12 (7 H, m), 1.50 (1 H, ddd,
J ) 6.5, 9.0, 10.0 Hz), 1.92 (1 H, dd, J ) 5.5, 9.0 Hz), 2.05-
2.14 (1 H, m), 2.30-2.38 (1 H, m), 2.63 (1 H, ddd, J ) 5.0,

New Method for Conformational Restriction
J . Org. Chem., Vol. 61, No. 3, 1996 923
X-r a y Cr ysta llogr a p h ic Da ta of En t-2b Hyd r och lo-
r id e.28 C17H27ClN2O, M ) 310.91, orthorhombic, P212121 (no.
19), a ) 8.571(2) Å, b ) 26.996(5) Å, c ) 7.981(2) Å, V ) 1846.7-
2θ value of 120 Å gave 1614 reflections at room temperature,
1509 unique, of which 1390 with I > 3.00σ(I) reflections were
used in calculations. The intensities were corrected for the
Lorentz and polarization factors, but not for the absorption or
the extinction effect. The structure was solved by direct
method and refined by full-matrix least squares technique
(Crystan-GM system26 as the computer program and SIR9227
as the structure solution method). The non-hydrogen atoms
were refined anisotropically. The hydrogen atoms were in-
cluded by calculation, but these positions were not refined.
Both enantiomorphous structures were refined with final
disagreement factors R1 ) 0.043, R1w ) 0.049 and R2 ) 0.046,
R2w ) 0.051 (with a weighting scheme W ) exp(10 sin2 θ/λ2)/
σ2(Fo)) for the two enantiomers, respectively. The correct
absolute configuration was assigned to the enantiomer dis-
playing the lower values of the disagreement factors. No peak
above 0.14 e Å-3 in the last Fourier-difference map.
(7) Å3, Z ) 4, Dcalcd ) 1.12 g cm-3
. Cell parameters were
determined and refined from 22 reflections in the range 53°
< 2θ < 60°. A colorless plate (0.4 × 0.4 × 0.1 mm) was
mounted on a Mac Science MXC18 diffractometer with graphite-
monochromated Cu KR radiation (λ ) 1.54178 Å). Data
collection using the ω/2θ scan technique to a maximum 2θ
value of 120° gave 1874 reflections at room temperature, 1791
unique, of which 1275 with I > 3.00σ(I) reflections were used
in calculations. The intensities were corrected for the Lorentz
and polarization factors but not for the absorption or the
extinction effect. The structure was solved by direct method
and refined by full-matrix least squares technique (Crystan-
GM system26 as the computer program and SIR9227 as the
structure solution method). The non-hydrogen atoms were
refined anisotropically. The hydrogen atoms were included
by calculation, but these positions were not refined. Both
enantiomorphous structures were refined with final disagree-
Ack n ow led gm en t. This study was supported in
part by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports, and Culture of
J apan. We are grateful to Daiso Co., Ltd. for their gift
of chiral epichlorohydrins.
ment factors R1 ) 0.079, R1w ) 0.082 and R2 ) 0.085, R2w
)
0.086 (with a weighting scheme W ) exp(10 sin2 θ/λ2)/σ2(Fo))
for the two enantiomers, respectively. The correct absolute
configuration was assigned to the enantiomer displaying the
lower values of the disagreement factors. No peak above 0.51
e Å-3 in the last Fourier-difference map.
J O9518056
X-r a y Cr ysta llogr a p h ic Da ta of En t-3b Hyd r och lo-
r id e.28 C17H27ClN2O, M ) 310.91, monoclinic, C2 (no. 5), a )
23.794(6) Å, b ) 6.024(2) Å, c ) 16.350(4) Å, â ) 128.66(2)°, V
(26) A computer program for the solution and refinement of crystal
structures from X-ray diffraction data; Mac Science Co., Ltd., version
6.1, 1994.
(27) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;
Burla, M. C.; Polidori, G.; Camalli, M. J . Appl. Crystallogr. 1994, 27,
435-436.
(28) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
) 1830(1) Å3, Z ) 4, Dcalcd ) 1.13 g cm-3
. Cell parameters
were determined and refined from 20 reflections in the range
53° < 2θ < 60°. A colorless crystal (0.50 × 0.15 × 0.05 mm)
was mounted on a Mac Science MXC18 diffractometer with
graphite-monochromated Cu KR radiation (λ ) 1.54178 Å).
Data collection using the ω/2θ scan technique to a maximum