Construction of a cis-Cyclopropane via Reductive Radical Decarboxylation. Enantioselective Synthesis of cis- and trans-1-Arylpiperazyl-2-phenylcyclopropanes Designed as Antidopaminergic Agents

Article abstract of DOI:10.1021/jo0302206

(1S,2S)-, (1S,2R)-, and (1R,2S)-1-(2,4-Dimethylphenyl)piperazyl-2-phenylcyclopropane (2a, 3, and ent-3, respectively), which were designed as conformationally restricted analogues of haloperidol (1), a clinically effective antipsychotic agent, were synthe

Full text of DOI:10.1021/jo0302206

Con str u ction of a cis-Cyclop r op a n e via Red u ctive Ra d ica l
Deca r boxyla tion . En a n tioselective Syn th esis of cis- a n d
tr a n s-1-Ar ylp ip er a zyl-2-p h en ylcyclop r op a n es Design ed a s
An tid op a m in er gic Agen ts
Kazuya Yamaguchi, Yuji Kazuta, Hiroshi Abe, Akira Matsuda, and Satoshi Shuto*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku,
Sapporo 060-0812, J apan
shu@pharm.hokudai.ac.jp
Received J uly 8, 2003
(1S,2S)-, (1S,2R)-, and (1R,2S)-1-(2,4-Dimethylphenyl)piperazyl-2-phenylcyclopropane (2a , 3, and
en t-3, respectively), which were designed as conformationally restricted analogues of haloperidol
(1), a clinically effective antipsychotic agent, were synthesized from chiral epichlorohydrins using
the Barton reductive radical decarboxylation as the key step. (1S,2R)-1-(tert-Butyldiphenylsilyloxy)-
methyl-2-carboxy-2-phenylcyclopropane (5), which was prepared from (S)-epichlorohydrin ((S)-7),
was converted into its N-hydroxypyridine-2-thione ester 12, the substrate for the reductive radical
decarboxylation. When 12 was treated with TMS3SiH in the presence of Et3B or AIBN, the
decarboxylation and subsequent hydride attack on the cyclopropyl radical intermediate from the
side opposite to the bulky silyloxymethyl moiety occurred, resulting in selective formation of the
corresponding reductive decarboxylation product 4-cis with the cis-cyclopropane structure. From
4-cis, the cis-cyclopropane-type target compound 3 was readily synthesized. Starting from (R)-
epichlorohydrin ((R)-7), en t-3 was similarly synthesized. Epimerization of the cyclopropanecar-
boxamide en t-16-cis, a synthetic intermediate for en t-3, on treatment with a base prepared from
Bu2Mg and i-Pr2NH in THF occurred effectively to give the corresponding trans isomer 16-tr a n s,
which was converted into 2a with the trans-cyclopropane structure.
In tr od u ction
restrict the bioactive conformations of a variety of
compounds having pharmacological activity.2,3,4
The binding affinity of biologically active compounds
for the target molecule can be improved by the confor-
mational restriction as a result of reducing the entropic
loss upon binding. In the design of conformationally
restricted analogues, it is essential that the analogues
are as similar as possible to the parent compound in size,
shape, and molecular weight.1 Because of its character-
istic small rigid carbocyclic structural feature, a cyclo-
propane ring is effective in restricting the conformation
of a molecule without significantly changing the chemical
and physical properties of the lead compounds.2,3 Thus,
cyclopropanes have already been successfully used to
Haloperidol (1, Figure 1) is a clinically effective anti-
psychotic agent, and the pharmacological effect is con-
sidered to be due to the antagonism of dopaminergic
receptors.5 One drawback is the side effects from its
affinity for other receptors, particularly adrenergic recep-
tors,5,6 which may be attributed to its conformationally
flexible structure. Recently, Thurkauf and co-workers
designed and synthesized the arylpiperazine derivatives
2a and 2b, which have a trans-cyclopropane structure,
and identified them as potent dopamine receptor antago-
nists with reduced adrenergic R1 receptor affinity.6 These
compounds can be considered as conformationally re-
* Author to whom correspondence may be addressed. Phone: +81-
11-706-3229. Fax: +81-11-706-4980.
(1) (a) Silverman, R. B. The Organic Chemistry of Drug Design and
Drug Action; Academic Press: San Diego, 1992. (b) Drug Design for
Neuroscience; Kozikowski, A., Ed.; Raven Press: New York, 1993. (c)
The Practice of Medicinal Chemistry; Wermuth, C. G., Ed.; Academic
Press: San Diego, 1996.
(2) For examples, see: (a) Shimamoto, K.; Ofune, Y. J . Med. Chem.
1996, 39, 407-423. (b) Armstrong, D. P.; Cannon J . G. J . Med. Chem.
1970, 13, 1037-1039. (c) Martin, S. F.; Dwyer, M. P.; Hartmann, B.;
Knight, K. S. J . Org. Chem. 2000, 65, 1305-1318. (d) Sekiyama, T.;
Hatsuya, S.; Tanaka, Y.; Uchiyama, M.; Ono, N.; Iwayama, S.; Oikawa,
M.; Suzuki, K.; Okunishi, M.; Tsuji, T. J . Med. Chem. 1998, 41, 1284-
1298.
(4) A new method for restricting the conformation of cyclopropane
derivatives based on the fact that adjacent substituents on the ring
exert significant mutual steric repulsion because of their eclipsed
conformation to each other was devised by us: (a) Shuto, S.; Ono, S.;
Hase, Y.; Kamiyama, N.; Takada, H.; Yamashita, K.; Matsuda, A. J .
Org. Chem. 1996, 61, 915-923. (b) Shuto, S.; Ono, S.; Hase, Y.; Ueno,
Y.; Noguchi, T.; Yoshii, K.; Matsuda, A. J . Med. Chem. 1996, 39, 4844-
4852. (c) Shuto, S.; Ono, S.; Imoto, H.; Yoshii, K.; Matsuda, A. J . Med.
Chem. 1998, 41, 3507-3514. (d) Shuto, S.; Yoshii, K.; Matsuda, A. J pn.
J . Pharmacol. 2001, 85, 207-213.
(5) (a) The Dopamine Receptors; Neve, K. A., Neve, R. L., Eds.;
Humana Press: Totowa, NJ , 1997. (b) Sibley, D. R.; Monsma, F. J .,
J r. Trends Pharmacol. Sci. 1992, 13, 61-69.
(3) (a) Kazuta, Y.; Matsuda, A.; Shuto, S. J . Org. Chem. 2002, 67,
1669-1677. (b) Kazuta, Y.; Hirano, K.; Natsume, K.; Yamada, S.;
Kimura, R.; Matsumoto, S.; Furuichi, K.; Matsuda, A.; Shuto, S. J .
Med. Chem., 2003, 46, 1980-1988, and references therein.
(6) Zhang, X.; Hodgetts, K.; Rachwal, S.; Zhao, H.; Wasley, J . W.
F.; Craven, K.; Brodbeck, R.; Kieltyka, A.; Hoffman, D.; Bacolod, M.
D.; Girard, B.; Tran, J .; Thurkauf, A. J . Med. Chem. 2000, 43, 3923-
3932.
10.1021/jo0302206 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/06/2003
J . Org. Chem. 2003, 68, 9255-9262
9255

Yamaguchi et al.
SCHEME 1
tives.3,4,11 Throughout these studies, we have shown that
(R)- and (S)-epichlorohydrins, which are commercially
available in high optical purity, are efficient synthons for
preparing the asymmetric cyclopropane structures.3,4 On
the basis of these findings, we planned to synthesize the
target compounds starting from chiral epichlorohydrins.
Our synthetic plan for the cis-cyclopropane compound
3 with the (1S,2R) configuration and its trans congener
2a with the (1S,2S) configuration is summarized in
Scheme 1. The compounds 4-cis and 4-tr a n s were
considered effective precursors for the target compounds
3 and 2a , respectively. The key point in the synthesis is
the stereoselective construction of the chiral cis- and
trans-cyclopropane structures. Cyclic radicals can only
exist in a reduced number of conformations relative to
acyclic ones, and stereochemistry of the radical reactions
of cyclic systems, including cyclopropropnes, has been
extensively investigated. These studies make prediction
of the stereochemical results possible and were nicely
documented by Curran et al.12 Thus, construction of the
cis- and trans-cyclopropanes by radical reaction was
planned. We anticipated that both 4-cis and 4-tr a n s
might be stereoselectively prepared by the Barton reduc-
tive decarboxylation13,14 of the chiral phenylcyclopropane
carboxylic acid 5 under radical conditions by employing
F IGURE 1. Haloperidol (1) and its cyclopropane-based con-
formationally restricted analogues.
stricted analogues of haloperidol, in which the three-
dimensional positioning of the two aromatic and basic
piperazine rings is restricted by the trans-cyclopropane
structure.
We are interested in the pharmacological effect of the
corresponding cis-cyclopropane congener 3 and its enan-
tiomer en t-3 (Figure 1), in which the three rings are
conformationally restricted differently from those in 2a
and 2b. In this paper, we describe the synthesis of these
conformationally restricted analogues 3 and en t-3 having
the cis-cyclopropane structure from chiral epichlorohy-
drins, using the Barton reductive decarboxylation as the
key step to construct the cis-cyclopropane structure. An
alternative synthesis of the potent antipsychotic agent
2a having the trans-cyclopropane ring from an interme-
diate for the synthesis of en t-3 has also been ac-
complished.
Resu lts a n d Discu ssion
(9) For examples of synthesis of chiral cyclopropanes via chemical
or enzymatic optical resolutions, see: (a) Laumen, K.; Schneider, M.
Tetrahedron Lett. 1985, 26, 2073-2076. (b) Ader, U.; Breitgoff, D.;
Klein, P.; Laumen, K. E. J . Org. Chem. 1989, 30, 1793-1796. (c)
Grandjean, D.; Chuche, P. P. J . Tetrahedron 1991, 47, 1215-1230. (d)
Silva, C. B.-D.; Benkouider, A.; Pale, P. Tetrahedron Lett. 2000, 41,
3077-3081.
Syn th etic P la n . Considerable effort has been devoted
to developing efficient methods for preparing cyclopro-
pane derivatives because of their chemical and medicinal
chemical importance.2-4,7-11 Optical resolution of racemic
cyclopropane derivatives is one such method for providing
chiral cyclopropanes.9 In fact, Thurkauf and co-workers
synthesized 2a and 2b via optical resolution of a racemic
cyclopropane intermediate with a chiral amine.6
(10) For examples of synthesis of chiral cyclopropanes from chiral
synthons, see: (a) Yamanoi, K.; Ohfune, Y. Tetrahedron Lett. 1988,
29, 1181-1184. (b) Shimamoto, K.; Ohfune, Y. Tetrahedron Lett. 1989,
30, 3803-3804. (c) Pirrung, M. C.; Dunlap, S. E.; Trinks, V. P. Helv.
Chim. Acta 1989, 72, 1301-1310. (d) Morikawa, T.; Sasaki, H.; Hanai,
R.; Shibuya, A.; Taguchi, T. J . Org. Chem. 1994, 59, 97-103. (e)
Critcher, D. J .; Connolly, S.; Wills, M. J . Org. Chem. 1997, 62, 6638-
6657. (f) Takemoto, Y.; Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.;
Tanaka, T.; Ibuka, T. Tetrahedron Lett. 2000, 41, 3653-3656.
(11) Kazuta, Y.; Abe, H.; Yamamoto, T.; Matsuda, A.; Shuto, S. J .
Org. Chem. 2003, 68, 3511-3521.
In recent years, we have been working to develop a
stereoselective synthesis of chiral cyclopropane deriva-
(7) (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-Y.; Yip, Y.-C.; Tanko, J .;
Hudlicky, T. Chem. Rev. 1989, 89, 165-198. (b) Stammer, S. H.
Tetrahedron 1990, 46, 2231-2254. (c) Small Ring Compounds in
Organic Synthesis VI; De Meijero, A, Ed.; Topic in Current Chemistry
207; Springer: Berlin, 1999.
(8) Reviews on the synthesis of chiral cyclopropanes: (a) Singh, V.
K.; DattaGupta, A.; Sekar, G. Synthesis 1997, 137-149. (b) Doyle, M.
P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919-7946. (c) Lebel,
H.; Marcoux, J .-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103,
977-1050.
(12) Curran, D. P.; Porter, N. D.; Giese, B. Stereochemistry of
Radical Reactions; VCH: Weinheim, 1996.
(13) (a) Barton, D. H. R.; Chen, C.; Wall, G. M. Tetrahedron 1991,
47, 6127-6138. (b) Barton, D. H. R.; Samadi, M.; Tetrahedron 1992,
48, 7083-7090.
(14) For the formation of a cyclopropyl radical by the Barton
decarboxylation, see: Gawronska, K.; Gawronski, J .; Walborsky, H.
M. J . Org. Chem. 1991, 56, 2193-2197.
9256 J . Org. Chem., Vol. 68, No. 24, 2003

cis-Cyclopropane via Radical Decarboxylation
F IGURE 2. Possible reaction pathway for the hydrogen
abstraction by the cyclopropyl σ radical generated via the
radical decarboxylation of 12.
F IGURE 3. Possible cyclopropyl π radical generated by the
radical decarboxylation of 12 (a), the model cyclopropyl radical
for the calculations (b), and the calculated structure of the
model radical (c).
the bulky tert-butyldiphenylsilyl (TBDPS) protecting
group (see below). Compound 5 would be prepared from
lactone 6 by functional group transformations. The chiral
lactone 6 is readily prepared via condensation of (S)-
epichlorohydrin (7) and phenylacetonitrile (8) under basic
conditions.4a Starting from (R)-epichlorohydrin ((R)-7),
en t-3 would also be synthesized.
SCHEME 2a
Cyclopropyl radicals are considered to be σ radicals in
which the electron occupies a hybridized orbital.15 There-
fore, in the key Barton radical decarboxylation of 5, the
intermediate radical might be in equilibrium between the
σ radicals A (cis) and B (trans), as shown in Figure 2,
which could be isomerized faster than their hydrogen
abstraction from a donor X-H, i.e., k1, k-1 . k2, k′2.15-17
Accordingly, the cis/trans ratio of the products would
depend on the A/B equilibrium, when the rates of the
hydrogen transfer from X-H (hydrogen donor) to both
radicals A and B are similar, i.e., k2 ≈ k′2. Because of
the steric repulsion between the phenyl and bulky
a
Reagents: (a) NaBH4, THF/MeOH, quant.; (b) (1) TBDSCl,
imidazole, DMF, 54%, (2) Swern ox., 86%; and (c) Me(MeO)NH,
AlCl3, CH2Cl2, (2) TBDPSCl, imidazole, DMF, 94%; (d) DIBALH,
CH2Cl2, 80%; (3) NaClO2, NaH2PO4, 2-methyl-2-butene, 86%.
from 5, having the delocalizing phenyl group, might not
be in equilibrium between the σ radicals A and B (Figure
2) but also might be a π radical, in which the electron
occupies a p orbital, as shown in Figure 3a. In such a
case, 4-cis could be selectively obtained via the hydrogen
abstraction from the sterically unhindered face, which
can be explained by the antirule.20
Syn th esis of th e cis-Cyclop r op a n e Ta r gets 3 a n d
en t-3. The synthesis of the key intermediate 5 is sum-
marized in Scheme 2. The chiral lactone 6 with 96% ee,
prepared from (S)-epichlorohydrin ((S)-7) by our previous
method,4a was reduced with NaBH4 in THF/MeOH to give
the diol 9. Although treatment of 9 with TBDPSCl/
imidazole in DMF at -20 °C and subsequent Swern
oxidation gave the desired aldehyde 11, the yield was low.
When the lactone 6 was treated with Me(MeO)NH21a in
the presence of AlCl3 in CH2Cl2 followed by TBDPSCl/
imidazole in DMF, the corresponding Weinreb amide 10
was obtained in 94% yield. The DIBALH reduction of the
amide 10 by the method reported by Hollenberg21b
provided the aldehyde 11 in excellent yield. Oxidation of
11 with a NaClO2/NaH2PO4/2-methyl-2-butene system22
gave the desired cyclopropanecarboxylic acid 5.
silyloxymethyl moiety, the cis radical A might be more
16,17
unstable than the trans radical B, i.e., k1 > k-1
.
Therefore, we expected that 4-tr a n s could be selectively
obtained when an effective hydrogen donor, such as
PhSH or Bu3SnH,17 was used. On the other hand, the
hydrogen abstraction could proceed mainly via the cis
radical A to give 4-cis by using the sterically demanding
TMS3SiH as a donor19 because the attack of TMS3SiH
on the trans radical B would be hampered due to the
steric repulsion of the bulky silyloxymethyl group at the
position cis to the radical. Thus, we expected that both
4-cis and 4-tr a n s could be selectively obtained by chang-
ing the hydrogen donor in the radical reaction.
On the other hand, Boche and Walborsky previously
described that delocalizing substituents, such as a car-
bomethoxy and a cyano group, attached to the radical
site could convert the cyclopropyl σ radical to a π
radical.16a Therefore, the intermediate radical produced
(15) Cyclopropyl radicals have been shown to be a rapidly inverting
bent σ radical: J ohnson, L. J .; Ingold, K. U. J . Am. Chem. Soc. 1986,
108, 2343-2348. (b) Zerbetto, F.; Zgiarski, M.; Siebrand, W. J . Am.
Chem. Soc. 1989, 111, 2799-2802.
(16) (a) Boche, G.; Walborsky, H. M. In Cyclopropane Derived
Reactive Intermediates; Patai, S., Rappoport, Z., Eds.; J ohn Wiley &
Sons: Chichester, 1990; pp 1-108. (b) Walborsky, H. M. Tetrahedron
1981, 37, 1625-1651.
(17) Apeloig, Y.; Nakash, M. J . Am. Chem. Soc. 1994, 116, 10781-
10782.
(18) Chatgilialoglu, C. T. In Radicals in Organic Synthesis; Renaud,
P., Sibo, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 28-49.
(19) Kanabus-Kaminska, J . M.; Hawari, J . A.; Griller, D.; Chatgil-
ialoglu, C. J . Am. Chem. Soc. 1987, 109, 5267-5268.
The stereoselective radical decarboxylation was next
examined. The carboxylic acid 5 was converted into the
(20) Renaud, P. In Radicals in Organic Synthesis; Renaud, P., Sibo,
M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, p 400.
(21) (a) Nahn, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818. (b) Toy, P. H.; Dhanabalasingam, B.; Newcomb, M.; Hanna, I.
H.; Hollenberg, P. F. J . Org. Chem. 1997, 62, 9114-9122.
(22) Isobe, M.; Ichikawa, Y.; Bai, D.-L.; Goto, T. Tetrahedoron 1987,
43, 4767-4776.
J . Org. Chem, Vol. 68, No. 24, 2003 9257

Yamaguchi et al.
SCHEME 3
SCHEME 4a
a
Reagents: (a) TPAP, NMO, CH2Cl2, 88%; (b) NaClO2, NaH2PO4,
2-methyl-2-butene, aq acetone, 97%; (c) 2,4-dimethylphenylpip-
erazine, EDC, CH2Cl2, 60%; (d) AlH3, THF, quant.
TABLE 1. Ra d ica l Deca r boxyla tion of th e Ba r ton
Ester 12a
SCHEME 5
entry reductant initiator solvent temp yield (%)b cis/transc
1
2
3
4
5
6
7
8
9
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
t-BuSH
PhSH
Et3B
Me2Zn
hν
AIBN
AIBN
Et3B
Et3B
AIBN
THF rt
THF rt
THF rt
PhH 80 °C
PhCl 130 °C
THF rt
THF rt
PhH 80 °C
THF rt
70
48
36
80
69
80
70
27
74
47
22
75
2.8:1
2.8:1
2.6:1
2.7:1
2.6:1
3.0:1
3.1:1
2.5:1
10:1
14:1
14:1
11:1
propylammonium perruthenate (TPAP)/N-methylmor-
pholine N-oxide (NMO) in CH2Cl2 and NaClO2/NaH2PO4/
2-methyl-2-butene in aqueous acetone to give the carbox-
ylic acid 15 (Scheme 4). When 15 was condensed with
N-(2,4-dimethylphenyl)piperazine using 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide (EDC), the cis isomer
16 was successfully obtained in pure form after silica gel
column chromatography. Reduction of 16 with AlH3 in
THF furnished the conformationally restricted target
analogue 3 with the cis-cyclopropane structure.
Ph2SiH2
TMS3SiH Et3B
10 TMS3SiH Et3B
11 TMS3SiH Et3B
12 TMS3SiH AIBN
THF 0 °C
THF -20 °C
PhH 80 °C
a
The radical reaction was carried out using 5 equiv of reductant
in the presence of an initiator (Et3B, 0.3 equiv; Me2Zn, 0.3 equiv;
hν, high-pressure mercury lamp, 300 W; AIBN, 0.2 equiv). b Isolate
yield after deprotection. c Determined by 1H NMR.
N-hydroxypyridine-2-thione ester 12,13 which, without
purification, was immediately subjected to the radical
reaction (Scheme 3). The yield and cis/trans ratio of the
products were determined after removal of the silyl
protecting group, and the results are summarized in
Table 1. The reaction was first examined with Bu3SnH,
which is an effective hydrogen donor,18 as the reductant
at room temperature by employing different radical
initiation methods (entries 1-3). Thus, the desired
reductive radical decarboxylation proceeded smoothly,
and all three reactions gave the 4-cis as the major
product while the selectivity was low (cis/trans ) 2.6-
2.8:1). The reactions at higher temperature using a Bu3-
SnH/AIBN system gave the reduction products in similar
cis/trans ratios (entries 4 and 5). Other reductants were
subsequently examined. However, use of t-BuSH, PhSH,
or Ph2SiH2 as the reductant did not improve the cis/trans
selectivity (entries 6-8).
On the other hand, when the Barton ester 12 was
treated with TMS3SiH/Et3B at room temperature in THF,
4-cis was obtained highly selectively as expected (entry
9, yield 74%, cis/trans ) 10:1). In similar reactions with
the TMS3SiH/Et3B system at lower temperatures, the cis
selectivity was further improved, while the yield de-
creased (entries 10 and 11). An excellent cis selectivity
was also observed by treating 12 with TMS3SiH and
AIBN in refluxing benzene (entry 12, yield 75%, cis/trans
) 11:1).
Starting from (R)-epichlorohydrin ((R)-7), en t-3 was
similarly synthesized.
Syn th esis of th e tr a n s-Cyclop r op a n e Ta r get 2a .
We next tried to synthesize another target compound 2a
with the trans-cyclopropane structure via the cis-trans
epimerization of en t-14-cis. Sasaki and co-workers re-
ported that when racemic 14-cis was treated with MeI
in the presence of silica gel in DMSO at 80 °C, epimer-
ization at the 1-position occurred to form the correspond-
ing cis isomer.23 Therefore, we heated en t-14-cis, which
was obtained in pure form by careful silica gel column
chromatography, under the same MeI/silica gel/DMSO
conditions to give the isomerized trans product 14-tr a n s
in 71% yield. However, the optical purity proved to be
only 13% (Scheme 5).
In the isomerization reaction, two pathways could be
considered, i.e., via the enol intermediate pathway (path
a) and the ring-cleaved pathway (path b), as shown in
Scheme 6. The experimental results suggest that the
epimerization proceeds via the ring-cleaved pathway at
least to some extent to result in racemization. Isomer-
ization of en t-14-cis under basic conditions was also
examined; however, it was unsuccessful.
Most recently, Eaton and Zhang reported that a novel
base, prepared from Bu2Mg and i-Pr2NH, effectively
removes a proton on the cyclopropane ring at the position
adjacent to the amide carbonyl in cyclopropanecarboxa-
mides.24 They successfully introduced carbon substituents
As described, although 4-tr a n s could not be selectively
obtained, the cis cyclopropane key intermediate 4-cis was
successfully prepared by radical decarboxylation.
The reduction product, including predominantly 4-cis
(cis/trans ) 11:1), was successively treated with tetra-
(23) Sasaki, T.; Eguchi, S.; Ohno, M. Bull. Chem. Soc. J pn. 1980,
53, 1469-1470.
(24) Zhang, M.-X.; Eaton, P. E. Angew. Chem., Int. Ed. 2002, 41,
2169-2171.
9258 J . Org. Chem., Vol. 68, No. 24, 2003

cis-Cyclopropane via Radical Decarboxylation
SCHEME 6
TMS3SiH than for Bu3SnH to transfer a hydrogen atom
to the bicyclic cyclopropyl σ radical from the less hindered
side. In the reduction of the Barton ester 12, the
significantly bulky TBDPS-O-CH2 moiety might ef-
fectively block the access of the sterically demanding
TMS3SiH to the σ radical orbital of the radical intermedi-
ate to form the cis product with high selectivity, similar
to the case of Apeloig and Nakash.
Although most of cyclopropyl radicals have been con-
sidered to be σ radicals,15-17 the experimental results in
this study also suggest another possibility, namely, that
the cyclopropyl radical intermediate derived from 12 is
not in equilibrium between the σ radicals A and B
(Figure 2) but is also the π radical due to the delocalizing
phenyl group,16a as shown in Figure 3a. Thus, we in-
vestigated the radical intermediate by theoretical calcu-
lations. The structure of the radical was studied using a
model radical, 1-phenyl-2-methylcyclopropyl radical (Fig-
ure 3b), by DFT calculation using the Gaussian98
program.25 As shown in Figure 3c, the calculations per-
formed at the UB3LYP/6-31G(d)//UB3LYP/6-31G(d) level
clarified that it is a π radical, which is stabilized by the
orbital interaction with the p orbitals of the adjacent
benzene ring. Accordingly, the stereoselectivity would be
explained by the access of the hydrogen donor from the
less-hindered side of the π radical intermediate to result
in forming mainly the cis product, in which the stereo-
selectivity can be increased by using a sterically demand-
ing donor such as TMS3SiH.
SCHEME 7
Although the selective formation of the trans product
by the reductive radical decarboxylation was unsuccessful
because of the constrained structure, epimerization of cis-
cyclopropanes bearing an electron-withdrawing group,
such as a carbonyl, often occurs to produce the more
stable trans isomer. The target 2a was actually synthe-
sized via the cis-trans epimerization by using Eaton’s
base.24
Enantioselective olefin cyclopropanation reactions have
been extensively studied.8 Although the methods have
been advanced in enantioselectivity, the cis/trans diaste-
reocontrol has remained somewhat elusive.8,26 In par-
ticular, selective preparation of both the chiral cis- and
trans-cyclopropane stereoisomers with high optical purity
from the same precursor is often difficult.27 The procedure
developed in this study, i.e., construction of the chiral
cyclopropane structures with high optical purity28 from
on the cyclopropane ring by treating cyclopropanecar-
boxamides with this base and then electrophiles. During
these studies, they observed a cis-trans epimerization
of the cyclopropanecarboxamides by the base as a side
reaction. We expected that epimerization might occur by
treating the cis-cyclopropanecarboxamide (en t-16-cis)
with the Eaton base. Thus, when en t-16-cis was treated
with the base prepared from Bu2Mg (2 equiv) and i-Pr2-
NH (1 equiv) in THF at room temperature, the desired
epimerization actually occurred. After purification by
silica gel column chromatography, 16-tr a n s was isolated
in 78% yield. Reduction of 16-tr a n s by AlH3 was ulti-
mately carried out to provide the target 2a .
Discu ssion
In this study we showed that the chiral cis-cyclopro-
pane structure could be constructed stereoselectively by
the radical reduction. Walborsky pointed out that the
stereoselectivity of the radical reduction could be deter-
mined by the cis/trans equilibrium in the cyclopropyl σ
radical intermediate when an effective hydrogen donor
was used.16 The reductions of the Barton ester 12 with
Bu3SnH, t-BuSH, PhSH, and Ph2SiH2 gave the products
in an almost constant cis/trans ratio (2.5-3.1:1). In these
cases, the rate of hydrogen transfer from X-H to both
the cis radical A and the trans radical B (Figure 2) might
be similar, i.e., k2 ≈ k′2, which is in accord with Walbor-
sky’s findings.16
(25) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.6; Gaussian, Inc.: Pittsburgh, PA,
1998.
(26) D´ıaz-Requejo, M. M.; Caballero, A.; Belderra´ın, T. R.; Nicasio,
M. C.; Trofimenko, S.; Pe´tez, P. J . J . Am. Chem. Soc. 2002, 124, 978-
983.
(27) A few examples of the cis-selective asymmetric cyclopropanation
of olefins have been recently reported: (a) Niimi, T.; Uchida, T.; Irie,
R.; Katsuki, T. Tetrahedron Lett. 2000, 41, 3647-3651. (b) Bachmann,
S.; Furler, M.; Mezzetti, A. Organometallics 2001, 20, 2102-2108.
(28) Optical purity was determined by chiral HPLC.
On the other hand, the previous studies of the radical
reduction of bicyclic cyclopropanes by Apeloig and Na-
kash suggested that the stereoselectivity could be changed
by the hydrogen donor used, i.e., Bu3SnH or TMS3SiH.17
They reported that there is a stronger preference for
J . Org. Chem, Vol. 68, No. 24, 2003 9259

Yamaguchi et al.
Calcd for C29H35NO3Si: C, 73.53; H, 7.45; N 2.96. Found: C,
73.42; H, 7.36; N 2.85.
(R)- and (S)-epichlorohydrins and a carbanion, Barton
reductive decarboxylation forming the cis-cyclopropanes,
and the cis-trans epimerization, is an effective method
for preparing all four types of chiral cyclopropane com-
pounds, i.e., the (1S,2S), (1S,2R), (1R,2S), and (1R,2R)
stereoisomers. This method can be applied to the syn-
thesis of various chiral cyclopropane compounds.
(1S,2R)-1-(ter t-Bu tyld ip h en ylsilyloxy)m eth yl-2-for m yl-
2-p h en ylcyclop r op a n e (11) fr om 9. To a mixture of 9 (1.48
g, 8.3 mmol) and imidazole (0.57 g, 8.3 mmol) in DMF (20 mL)
was slowly added TBDPSCl (2.16 mL, 8.3 mmol) at -20 °C,
and the mixture was stirred at the same temperature for 10
min. After addition of MeOH, the resulting mixture was
evaporated and the residue was partitioned between AcOEt
and H2O. The organic layer was washed with brine, dried (Na2-
SO4), and evaporated. The residue was purified by column
chromatography (silica gel, hexane/AcOEt, 30:1) to give the
corresponding monosilylated product (1.87 g, 54%) as an oil.
A mixture of DMSO (1.28 mL, 18.0 mmol) and CH2Cl2 (10 mL)
was added slowly to a solution of (COCl)2 (0.79 mL, 9.0 mmol)
in CH2Cl2 (20 mL) at -78 °C over 30 min, and then a solution
of the monosilylated product (1.87 g, 4.5 mmol) in CH2Cl2 (10
mL) was added. The resulting mixture was stirred at the same
temperature for 2 h, and then Et3N (5.02 mL, 36.0 mmol) was
added. After the mixture was stirred at the same temperature
for further 30 min, aqueous saturated NH4Cl and then CHCl3
and aqueous 10% NaClO were added to the mixture and the
whole was partitioned. The organic layer was washed with
brine, dried (Na2SO4), and evaporated. The residue was
purified by column chromatography (silica gel, hexane/AcOEt,
Con clu sion
The chiral cis- and trans-1-arylpiperazyl-2-phenylcy-
clopropanes 2a , 3, and en t-3, designed as conformation-
ally restricted analogues of haloperidol, were synthesized
from (R)- and (S)-epichlorohydrins. Construction of the
key cis-cyclopropane structure was effectively accom-
plished by the Barton reductive radical decarboxylation,
in which a combination of the bulky O-TBDPS protecting
group and TMS3SiH as the reductant was employed.
Pharmacological evaluation of the synthesized target
compounds as dopaminergic receptor ligands is now in
progress.29
30:1) to give 11 (3.13 g, 86%) as an oil: [R]25 +50.66 (c 0.930,
Exp er im en ta l Section
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.07 (9 H, s), 1.53 (1 H,
dd, J ) 5.0, 8.6 Hz), 1.74 (1 H, dd, 5.0, 10.8 Hz), 2.03 (1 H, m),
3.69 (1 H, dd, J ) 9.6, 11.5 Hz), 4.07 (1 H, dd, J ) 5.3, 11.5
Hz), 7.30-7.47 (11 H, m), 7.64-7.71 (4 H, m), 9.66 (1 H, s);
13C NMR (100 MHz, CDCl3) δ 18.9, 19.3, 26.9, 35.3, 41.7, 61.4,
127.5, 127.6, 129.6, 129.6, 130.0 133.1, 133.4, 135.4, 135.4,
199.8; LR-MS (EI) m/z 414 (M+). Anal. Calcd for C27H30O2Si:
C, 78.20; H, 7.45. Found: C, 78.22; H, 7.29.
(1S,2R)-1-(ter t-Bu tyld ip h en ylsililoxy)m eth yl-2-for m yl-
2-p h en ylcyclop r op a n e (11) fr om 10. To a solution of 10 (23
mg, 0.48 mmol) in CH2Cl2 (3 mL) was added DIBALH (0.95
M in hexane, 0.68 mL, 0.65 mmol) at -78 °C, and the mixture
was stirred at the same temperature for 2 h. After addition of
MeOH, the resulting mixture was partitioned between CHCl3
and 1 N HCl and the organic layer was washed with brine,
dried (Na2SO4), and evaporated. The residue was purified by
column chromatography (silica gel, hexane/AcOEt, 30:1-8:1)
to give 11 (16 mg, 80%) as an oil.
(1S ,2R )-1,2-Di(h y d r o x ym e t h y l)-2-p h e n ylc y c lo p r o-
p a n e (9). A mixture of 6 (9.69 g, 55.6 mmol) and NaBH4
(4.18 g, 110 mmol) in THF/MeOH (4:1, 100 mL) was stirred
at room temperature for 12 h. After addition of H2O at 0 °C,
the solvent was evaporated and the residue was partitioned
between AcOEt and 1 N HCl. The organic layer was washed
with brine, dried (Na2SO4), and evaporated. The residue was
purified by column chromatography (silica gel, hexane/AcOEt,
1:1 then AcOEt) to give 9 (9.94 g, 100%) as an oil: [R]20D -56.52
1
(c 1.06, CHCl3); H NMR (400 MHz, CDCl3) δ 0.79 (1 H, dd,
J ) 4.6, 5.3 Hz), 1.09 (1 H, dd, J ) 5.3, 8.6 Hz), 1.70 (1 H, m),
2.43 (1 H, br s), 2.94 (1 H, br s), 3.44 (1 H, dd, J ) 11.5, 11.8
Hz), 3.58 (1 H, d, J ) 11.8 Hz), 4.18 (2 H, m), 7.21-7.43 (5 H,
m); 13C NMR (100 MHz, CDCl3) δ 16.8, 25.7, 32.3, 63.4, 67.4,
126.4, 128.1, 129.0, 143.4; LR-MS (EI) m/z 178 (M+). Anal.
Calcd for C11H14O2: C, 74.13; H, 7.98. Found: C, 73.73; H,
7.92.
(1S,2R)-1-(ter t-Bu tyldiph en ylsilyloxy)m eth yl-2-(N-m eth -
oxy-N-m eth ylca r ba m oyl)-2-p h en ylcyclop r op a n e (10). A
mixture of Me(MeO)NH‚HCl (4.52 g, 46.3 mmol) and Et3N
(6.40 mL, 46.3 mmol) in CH2Cl2 (20 mL) was stirred at room
temperature for 30 min, and the resulting precipitates were
filtered off. The filtrate was added slowly to a mixture of 6
(2.02 g, 11.6 mmol) and AlCl3 (3.09 g, 23.2 mmol) in CH2Cl2
(20 mL) at 0 °C, and the resulting mixture was stirred at room
temperature. After disappearance of 6 on TLC, TBDPSCl (7.60
mL, 25.5 mmol), imidazole (1.75 g, 25.5 mmol), and DMF (50
mL) were added and the mixture was stirred at room temper-
ature for 15 h and then evaporated. The residue was parti-
tioned between AcOEt and 1 N HCl, and the organic layer was
washed with brine, dried (Na2SO4), and evaporated. The
residue was purified by column chromatography (silica gel,
hexane/AcOEt, 30:1-8:1) to give 10 (5.09 g, 94%) as an oil:
(1S,2R)-1-(ter t-Bu t yld ip h en ylsilyloxy)m et h yl)-2-ca r -
boxy-2-p h en ylcyclop r op a n e (5). A mixture of 11 (1.30 g,
3.20 mmol), NaClO2 (1.0 g, 11 mmol), NaH2PO4‚2H2O (0.50 g,
3.2 mmol), and 2-methyl-2-butene (1.2 mL, 14 mmol) in
acetone/H2O (3:1, 40 mL) was stirred at room temperature for
12 h and then evaporated. The residue was partitioned
between AcOEt and H2O, and the organic layer was washed
with brine, dried (Na2SO4), and evaporated. The residue was
purified by column chromatography (silica gel, hexane/AcOEt,
30:1) to give 5 (1.18 g, 86%) as a foam: [R]24 +22.19 (c 1.020,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.04 (9 H, s), 1.38 (1 H,
dd, J ) 4.6, 8.9 Hz), 1.63 (1 H, dd, J ) 4.6, 7.3 Hz), 1.95 (1 H,
m), 3.96 (1 H, dd, J ) 9.0, 11.1 Hz), 4.04 (1 H, dd, J ) 5.8,
11.1 Hz), 7.25-7.43(11 H, m), 7.64-7.72 (4 H, m); 13C NMR
(100 MHz, CDCl3) δ 19.2, 20.0, 26.7, 32.7, 33.0, 61.2, 127.0,
127.3. 127.9, 129.3, 130.2, 133.2, 133.4, 135.2, 135.2, 139.7,
177.6. HRMS (FAB) (MH+) calcd for C27H31O3Si, 431.2041;
found, 431.2069 (MH+).
[R]24 +102.76 (c 1.040, CHCl3); 1H NMR (500 MHz, CDCl3) δ
D
0.87 (1 H, dd, J ) 4.8, 8.9 Hz), 1.11 (9 H, s), 1.54 (1 H, dd,
J ) 4.8, 5.7 Hz), 2.08 (1 H, m), 3.06 (3 H, s), 3.14 (3 H, br s),
3.72 (1 H, m), 3.77 (1 H, m), 7.20 (1 H, dd, J ) 7.0, 7.0 Hz),
7.28 (4 H, dd, J ) 8.0, 15.2 Hz), 7.38-7.45 (6 H, m), 7.68 (2 H,
d, J ) 7.4 Hz), 7.72 (2 H, d, J ) 6.4 Hz); 13C NMR (100 MHz,
CDCl3) δ 19.4, 26.7, 27.0, 35.0, 126.4, 127.5, 128.3, 129.5, 129.5,
133.6, 133.7, 135.4, 135.5; LR-MS (ESI) m/z 496 (MNa+). Anal.
Gen er a l P r oced u r e for th e Ra d ica l Deca r boxyla tion
(Ta ble 1, Syn th esis of 13 fr om 5). A mixture of 5 (86 mg,
0.20 mmol), 2,2′-dithiopyridine-1,1′-dioxide (61 mg, 0.24 mmol),
Bu3P (125 µL, 0.50 mmol), and a hydrogen donor (5 equiv) in
a solvent (THF, benzene, or chlorobenzene; 5 mL) was stirred
at room temperature under shading. After disappearance of 5
on TLC, the radical reaction was carried out by addition of an
initiator (Et3B and Me2Zn, 0.3 equiv or AIBN, 0.2 equiv) or
irradiation with high-pressure mercury lamp (300 W) under
the conditions indicated in Table 1. The resulting reaction
(29) Preliminary results of the binding affinities for human dopa-
mine D4 and adrenaline R1 receptors using [3H]YM-09151-2 and [3H]-
prazosin, respectively: 2a , 0.20 µM (D4), 1.79 µM (R1); 3, 1.39 µM (D4),
2.16 µM (R1); en t-3, 3.16 µM (D4), 2.22 µM (R1).
9260 J . Org. Chem., Vol. 68, No. 24, 2003

cis-Cyclopropane via Radical Decarboxylation
mixture was evaporated, and the residue was partitioned
between AcOEt and H2O. The organic layer was washed with
brine, dried (Na2SO4), and evaporated. The residue was
purified by column chromatography (silica gel, hexane/i-Pr2O,
100:1) to give the reductive decarboxylation products as an
oil. A mixture of the oil and TBAF (1.0 M in THF, 400 µL,
0.40 mmol) in THF (5 mL) was stirred at room temperature
for 12 h and then evaporated. The residue was partitioned
between AcOEt and H2O, and the organic layer was washed
with brine, dried (Na2SO4), and evaporated. The residue was
purified by column chromatography (silica gel, hexane/AcOEt,
9:1) to give 13 as an oil: 1H NMR (270 MHz, CDCl3) for 13-
cis δ 0.88 (1 H, dd, J ) 5.5, 11.4 Hz), 1.05 (1 H, ddd, J ) 5.5,
8.5, 8.5 Hz), 1.50 (1 H, m), 2.30 (1 H, ddd, J ) 6.2, 8.5, 8.5
Hz), 3.27 (1 H, dd, J ) 8.6, 11.2 Hz), 3.48 (1 H, dd, J ) 6.4,
µL, 280 µmol) at 0 °C, and the mixture was stirred at room
temperature for 30 min. The resulting mixture was added
slowly to a solution of 16 (32 mg, 94 µmol) in THF at 0 °C,
and the mixture was stirred at room temperature for 90 min.
After addition of aqueous NaOH (10%) and CHCl3, the
resulting mixture was partitioned. The organic layer was
washed with brine, dried (Na2SO4), and evaporated. The
residue was purified by column chromatography (silica gel,
hexane/AcOEt, 3:1) to give 3 (31 mg, 100%) as an oil: [R]22
D
+48.88 (c 0.880, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.85 (1
H, dd, J ) 5.6, 11.3 Hz), 1.13 (1 H, ddd, J ) 5.6, 8.3, 8.3 Hz),
1.30 (1 H, m), 1.83 (1 H, dd, J ) 8.3, 12.8 Hz), 2.20 (1 H, dd,
J ) 8.7, 11.6 Hz), 2.22 (3 H, s), 2.257 (3 H, s), 2.46 (1 H, dd,
J ) 4.8, 12.8 Hz), 2.51 (4 H, br s), 2.87 (4 H, m), 6.91-6.97 (3
H, m), 7.18-7.30 (5 H, m). To a solution of 3 (31 mg, 97 µmol)
in i-PrOH (1 mL) was added aqueous HBr (48%) (33 µL) in
which the pH was ca. 3. To the solution was added i-Pr2O to
give white precipitates of 3 (47 mg, quant.) as a dihydrobro-
1
11.2 Hz), 7.20-7.32 (5 H, m); H NMR (270 MHz, CDCl3) for
13-tr a n s δ 0.93 (2 H, m), 1.45 (1 H, m), 1.83 (1 H, m), 3.62 (2
H, m), 7.06-7.32 (5 H, m). HRMS (EI) calcd for C10H12O,
148.0888 (M+); found, 148.0887 (M+).
mide: mp 200-204 °C; [R]25 -43.02 (c 0.520, CH3OH); 1H
D
NMR (500 MHz, CD3OD) δ 1.37 (1 H, dd, J ) 5.7, 11.8 Hz,
H-3), 1.50 (1 H, ddd, J ) 5.7, 8.4, 8.3 Hz, H-3), 1.73 (1 H, m,
H-1), 2.38 (3 H, s, CH3), 2.39 (3 H, s, CH3), 2.66 (1 H, dd, J )
8.6, 15.3 Hz, H-2), 2.74 (1 H, dd, J ) 9.4, 13.5 Hz, H-1′a) 3.19-
3.50 (7 H, m, H-1′b, piperazyl NCH2), 3.74 (2 H, m, piperazyl
NCH2), 7.10-7.15 (3 H, m, aromatic), 7.40-7.50 (5 H, m,
aromatic), the assignment is based on the COSY spectrum;
LR-MS (FAB) m/z 321 (MH+). Anal. Calcd for C22H30N2Br2:
C, 54.76; H, 6.27; N, 5.81; Br, 33.13. Found: C, 54.13; H, 6.16;
N, 5.70; Br, 33.39.
(1S)-1-F or m yl-2-p h en ylcyclop r op a n e (14). A mixture of
13 (cis/trans ) 11:1, 343 mg, 2.3 mmol), TPAP (41 mg, 0.12
mmol), and NMO (408 mg, 3.5 mmol) in CH2Cl2 (25 mL) was
stirred at room temperature for 30 min. The resulting mixture
was filtered with Celite, and the filtrate was evaporated. The
residue was purified by column chromatography (silica gel,
hexane/AcOEt, 9:1) to give 14 (cis/trans ) 12:1, 297 mg, 88%)
as an oil: 1H NMR (270 MHz, CDCl3) for 14-cis δ 1.59 (1 H,
m), 1.88 (1 H, m), 2.14 (1H, m), 2.83 (1 H, m), 7.21-7.32 (5 H,
1
m), 8.67 (1 H, d, J ) 6.6 Hz); H NMR (270 MHz, CDCl3) for
(1R,2S)-1-(2,4-Dim eth ylph en yl)piper azylm eth yl-2-ph en -
ylcyclop r op a n e (en t-3). en t-3 was prepared from en t-64a
by the same procedure for the synthesis of 3 from 6. en t-3‚
2HBr: mp 208-209 °C; [R]25D +49.48 (c 0.440, CH3OH). Anal.
Calcd for C22H30N2Br2: C, 54.76; H, 6.27; N, 5.81; Br, 33.13.
Found: C, 54.19; H, 6.16; N, 5.68; Br, 33.18.
14-tr a n s δ 1.53 (1 H, m), 1.73 (1 H, m), 2.28 (1 H, m), 2.63 (1
H, m), 7.11 (2 H, m), 7.19-7.33 (3 H, m), 9.33 (1 H, d, J ) 4.6
Hz). HRMS (EI) calcd for C10H10O, 146.0732 (M+); found,
146.0737 (M+).
(1S)-1-Ca r boxy-2-p h en ylcyclop r op a n e (15). A mixture
of 14 (cis/trans ) 12:1, 298 mg, 2.0 mmol), NaClO2 (643 mg,
7.1 mmol), NaH2PO4‚2H2O (317 mg, 2.0 mmol), and 2-methyl-
2-butene (767 µL, 9.1 mmol) in acetone/H2O (3:1, 24 mL) was
stirred at room temperature for 15 h and then evaporated. The
residue was partitioned between AcOEt and 1 N HCl, and the
organic layer was washed with brine, dried (Na2SO4), and
evaporated. The residue was purified by column chromatog-
raphy (silica gel, hexane/AcOEt, 9:1 then CHCl3/MeOH, 20:1)
to give 15 (cis/trans ) 12:1, 320 mg, 97%) as an oil: 1H NMR
(400 MHz, CDCl3) for 15-cis δ 1.37 (1 H, m), 1.66 (1 H, m),
2.04 (1 H, m), 2.63 (1 H, m), 7.18-7.29 (5 H, m); 1H NMR (400
MHz, CDCl3) for 15-tr a n s δ 1.41 (1 H, m), 1.66 (1 H, m), 1.91
(1 H, m), 2.61 (1 H, m), 7.11 (2 H, m), 7.16-7.32 (3 H, m).
HRMS (EI) calcd for C10H10O2, 162.0681 (M+); found, 162.0685
(M+).
(1S,2R)-1-[4-(2,4-Dim et h ylp h en y)p ip er a zyl]ca r bon yl-
2-p h en ylcyclop r op a n e (16). A mixture of 15 (14 mg, 88
µmol), 2,4-dimethylphenylpiperazine (17 mg, 88 µmol), and
EDC‚HCl (19 mg, 97 µmol) in CH2Cl2 (1 mL) was stirred at 0
°C for 30 min and then at room temperature for 90 min. The
reaction mixture was partitioned between H2O and CHCl3, and
the organic layer was washed with brine, dried (Na2SO4), and
evaporated. The residue was purified by column chromatog-
Tr ea tm en t of en t-14-cis w ith MeI/DMSO. A mixture of
en t-14-cis (41 mg, 0.28 mmol), MeI (18 µL, 0.28 mmol), and
silica gel (20 mg) in DMSO (1 mL) was stirred at 80 °C for 1
week. The silica gel was filtered off, and the filtrate was
partitioned between AcOEt and H2O. The organic layer was
washed with brine, dried (Na2SO4), and evaporated. The
residue was purified by column chromatography (silica gel,
hexane/AcOEt, 19:1) to give 14-tr a n s (29 mg, 71%) as an oil:
[R]25 +42.9 (c 0.680, CHCl3) (lit. en t-14-tr a n s, [R]26 -324
D
D
(c 0.333, CHCl3)).30
(1S,2S)-1-(2,4-Dim et h ylp h en yl)p ip er a zylca r b on yl-2-
p h en ylcyclop r op a n e (16-tr a n s). A mixture of Bu2Mg (1.0
M in heptane, 0.22 mL, 0.22 mmol) and i-Pr2NH (14 µL, 0.10
mmol) in THF (1 m) was stirred at room temperature for 20
min and then was added to a solution of en t-16-cis (33 mg,
0.10 mmol), which was synthesized from en t-6 as described
above for 16-cis, in THF (1 mL). The resulting mixture was
stirred at room temperature for 2 days and then partitioned
between AcOEt and saturated aqueous NH4Cl. The organic
layer was washed with brine, dried (Na2SO4), and evaporated.
The residue was purified by column chromatography (silica
gel, hexane/AcOEt, 15:1-9:1) to give 16-tr a n s (26 mg, 78%)
as an oil: [R]25D +109.46 (c 0.670, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 1.30 (1 H, m), 1.70 (1 H, m), 2.01 (1 H, m), 2.27 (3 H,
s), 2.28 (3 H, s), 2.51 (1 H, m), 2.86 (4 H, m), 3.77 (4 H, m),
6.88 (1 H, d, J ) 7.9 Hz), 6.99 (2 H, m), 7.12 (2 H, d, J ) 7.9
Hz), 7.19 (1 H, m), 7.28 (2 H, m). HRMS (EI) calcd for
raphy (silica gel, hexane/AcOEt, 4:1-1:1) to give 16 (21 mg,
1
60%) as an oil: [R]25 -123.16 (c 1.01, CHCl3); H NMR (400
D
MHz, CDCl3) δ 1.35 (1 H, ddd, J ) 5.6, 8.5, 8.5 Hz), 1.85 (1 H,
dd, J ) 5.6, 12.6 Hz), 2.01 (1 H, m), 2.18 (2 H, m), 2.21 (3 H,
s), 2.25 (3 H, s), 2.45 (1 H, ddd, J ) 6.2, 9.1, 9.1 Hz), 2.68 (2
H, m), 3.24 (1 H, m), 3.54 (1 H, m), 3.72 (1 H, m), 3.88 (1 H,
m), 6.60 (1 H, d, J ) 7.9 Hz), 6.94 (2 H, m), 7.15-7.19 (3 H,
m), 7.25-7.29 (2 H, m); 13C NMR (100 MHz, CDCl3) δ 10.8,
17.7, 20.8, 24.2, 24.6, 42.5, 45.8, 51.8, 52.1, 119.0, 126.2, 126.8,
127.3, 127.8, 128.0, 129.1, 131.6, 132.4, 132.9, 137.5, 148.3,
167.0. HRMS (EI) calcd for C22H26N2O, 334.2045 (M+); found,
334.2045 (M+).
C
22H26N2O, 334.2045 (M+); found, 334.2044.
(1S,2S)-1-(2,4-Dim eth ylph en yl)piper azylm eth yl-2-ph en -
ylcyclop r op a n e (2a ). Compound 2a (19 mg 91%) was syn-
thesized from 16-tr a n s (22 mg, 66 µmol) as described above
for the synthesis of 3: [R]25D +82.20 (c 0.660, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 0.87 (1 H, m, H-3), 0.98 (1 H, m, H-3),
1.29 (1 H, m, H-1), 1.71 (1 H, m, H-2), 2.26 (6 H, s, CH3), 2.44
(1S,2R)-1-(2,4-Dim eth ylph en yl)piper azylm eth yl-2-ph en -
ylcyclop r op a n e (3). To a suspension of AlCl3 (13 mg, 94
µmol) in THF (0.5 mL) was added LiAlH4 (1 M in THF, 280
(30) Kaye, P. T.; Molema, W. E. Chem. Commun. 1998, 22, 2479-
2480.
J . Org. Chem, Vol. 68, No. 24, 2003 9261

Yamaguchi et al.
(1 H, dd, J ) 6.6, 12.4 Hz, H-1′a), 2.58 (1 H, dd, J ) 6.3, 12.4
Hz, H-1′b), 2.69 (4 H, m, piperazyl NCH2), 2.92 (4 H, m,
piperazyl NCH2), 6.98-7.27 (8 H, m, aromatic); the H NMR
Research (S.S.), and Research Fellowships for Young
Scientists (H.A.) from the J apan Society for the Promo-
tion of Science. We are grateful to Dr. A. Thurkauf
1
chart was identified with that of authentic 2a and the
assignment was based on the COSY spectrum; LR-MS (FAB)
m/z 321 (MH+). Anal. Calcd for C22H30N2Br2 (dihydrobro-
mide): C, 54.76; H, 6.27; N, 5.81; Br 33.13. Found: C, 54.76;
H, 6.22; N, 5.86; Br, 32.80. The optical purity was 97% ee
(Chiralcel OD; EtOH, room temperature, 270 nm).
Ca lcu la tion s. All calculations were performed using the
Gaussian98 program on a SGI O2 workstation. UHF/6-31G*
were taken to be the input geometries for final optimization
by UB3LYP/6-31G*. The stationary points were characterized
by frequency analysis (minimum with 0).
1
(Achillion Pharmaceuticals) for providing the H NMR
chart of compound 2a , to Daiso Co., Ltd., for gift of chiral
epichlorohydrins, to Prof. S. Yamada (University of
Shizuoka) for pharmacological assay, and to Ms. H.
Matsumoto, A. Maeda, and S. Oka (Center for Instru-
mental Analysis, Hokkaido University) for technical
assistance with NMR, MS, and elemental analyses.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods, table of atomic coordination for the calculated
structure in Figure 3c, and 1H NMR charts of compounds 5,
13-16, 16-tr a n s, and 2a . This material is available free of
charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t . This investigation was sup-
ported by a Grant-in-Aid for Creative Scientific Re-
search (13NP0401) (A.M.), a Grant-in-Aid for Scientific
J O0302206
9262 J . Org. Chem., Vol. 68, No. 24, 2003