Stereoselectivity of methyl aryldiazoacetate cyclopropanations of 1,1-diarylethylene. Asymmetric synthesis of a cyclopropyl analogue of tamoxifen.

Article abstract of DOI:10.1021/ol005563u

[formula: see text] Dirhodium tetrakis(S-(N-dodecylbenzenesulfonyl)prolinate) (Rh2(S-DOSP)4)-catalyzed decomposition of methyl phenyldiazoacetate in the presence of 1,1-diarylethylenes results in intermolecular cyclopropanation with high enantioselectivity (up to 99% ee) and moderate diastereoselectivity (up to 80% de). The reaction was applied to the asymmetric synthesis of a cyclopropyl analogue of tamoxifen.

Full text of DOI:10.1021/ol005563u

ORGANIC
LETTERS
2000
Vol. 2, No. 6
823-826
Stereoselectivity of Methyl
Aryldiazoacetate Cyclopropanations of
1,1-Diarylethylene. Asymmetric
Synthesis of a Cyclopropyl Analogue of
Tamoxifen
Huw M. L. Davies,* Tadamichi Nagashima, and James L. Klino III
Department of Chemistry, State UniVersity of New York at Buffalo,
Buffalo, New York 14260
hdaVies@acsu.buffalo.edu
Received January 18, 2000
ABSTRACT
Dirhodium tetrakis(S-(N-dodecylbenzenesulfonyl)prolinate) (Rh2(S-DOSP)4)-catalyzed decomposition of methyl phenyldiazoacetate in the presence
of 1,1-diarylethylenes results in intermolecular cyclopropanation with high enantioselectivity (up to 99% ee) and moderate diastereoselectivity
(up to 80% de). The reaction was applied to the asymmetric synthesis of a cyclopropyl analogue of tamoxifen.
Tamoxifen 1 is a very effective medication for the treatment
and possible prevention of breast cancer (Figure 1).1 Due to
has not been reported. In this paper, we describe the synthesis
of enantiomerically pure 2 by means of an asymmetric
cyclopropanation of 1,1-diarylethylenes.
The background behind this current study was the dis-
covery that the decomposition of methyl phenyldiazoacetate
(3) by dirhodium tetraprolinates such as Rh2(S-DOSP)4 (4)4
in the presence of alkenes results in highly enantioselective
and diastereoselective intermolecular cyclopropanations to
form 5 (Scheme 1).5 Furthermore, it has been shown that
Figure 1. Tamoxifen (1) and tamoxifen analogue 2.
Scheme 1
its useful therapeutic properties, the synthesis and biological
evaluation of numerous analogues of tamoxifen have been
described.2 These have included various triarylcyclopro-
panes;3 however, the cyclopropyl analogue 2 of tamoxifen
(1) (a) Crommentuyn, K. M. L.; Schellens, J. H. M.; Vandenberg, J. D.;
Beijnen, J. H. Cancer Treat. ReV. 1998, 24, 345. (b) White, I. N.
Carcinogenesis 1999, 20, 1153. (c) Jordan, V. C.; Morrow, M. Endocrine
ReV. 1999, 20, 253. (d) Furr, B. J. A.; Jordan, V. C. Pharmacol. Ther.
1984, 25, 127.
(2) Gao, H.; Katzenellenbogen, J. A.; Garg, R.; Hansch, C. Chem. ReV.
1999, 99, 723.
10.1021/ol005563u CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/24/2000

Table 1. Stereoselectivity of Methyl Aryldiazoacetate Cyclopropanations of 1,1-Diarylethylenes
entry
R1
R2
R3
product
yield, %
ratio 6:7
6, % ee
7, % ee
1a
2
3
4b
5b
6
H
NO2
H
H
NO2
H
H
H
H
H
H
H
H
Cl
OMe
a
b
c
d
e
f
87
90
84
75
80
94
84
97
95
99
92
93
99
98
55:45
87:13
76:24
88:12
89:11
90:10
91
96
88
74
95
94
OMe
NHAc
OMe
OMe
OMe
7
H
g
a For a similar reaction using Rh2(S-TBSP)4 as catalyst, see ref 6. b Solvent was pentane/CH2Cl2.
exceptionally high levels of enantioselectivity (97% ee) are
obtained when 1,1-diphenylethylene is the substrate for these
cyclopropanations.6 To extend this reaction to the synthesis
of the tamoxifen analogue 2, unsymmetrical 1,1-diaryleth-
ylenes would need to be used, and therefore, issues of
diastereoselectivity in addition to enantioselectivity would
need to be addressed.
To evaluate the stereochemical issues of this chemistry,
the Rh2(S-DOSP)4-catalyzed reaction of methyl aryldiazoac-
etates with a series of 1,1-diarylethylenes was examined and
the results are summarized in Table 1. For most of the
reactions, pentane was used as the solvent, because it has
been found to give the highest enantioselectivity in Rh2(S-
DOSP)4-catalyzed cyclopropanations between 3 and styrene.5
For 1-(4-acetamidophenyl)-1-phenylethylene and 1-(4-meth-
oxyphenyl)-1-(4-nitrophenyl)ethylene, pentane/CH2Cl2 was
used as solvent due to their poor solubility in pentane.
The first group of reactions was carried out using methyl
phenyldiazoacetate (3) as the carbenoid precursor (entries
1-5), so that the effect of modifications to the 1,1-
diarylethylene could be determined.7 A very interesting effect
of electron-donating substituents on the diastereoselectivity
of these reactions was observed. Even though the reaction
of 1-(4-nitrophenyl)-1-phenylethylene gave essentially a 1:1
mixture of diastereomers (dr ) 55:45, entry 2), the reaction
with 1-(4-methoxyphenyl)-1-phenylethylene was consider-
ably more diastereoselective, resulting in a 87:13 mixture
of 6c and 7c (entry 3). Similar effects were seen with 1-(4-
acetamidophenyl)-1-phenylethylene (dr ) 76:24, entry 4) and
also with 1-(4-methoxyphenyl)-1-(4-nitrophenyl)ethylene (dr
) 88:12, entry 5).
To study the electronic effects of the aryl group in the
carbenoid intermediate on the diastereoselectivity, (4-chlo-
rophenyl)diazoacetate and (4-methoxyphenyl)diazoacetate
were tried next (entries 6 and 7). The diastereoselectivity
and enantioselectivity obtained with these substrates were
virtually the same as was obtained with methyl phenyldi-
azoacetate (entry 3).
The enantioselectivity of the cyclopropanation was found
to be good to excellent. Especially, high ee’s (98-99% ee)
were observed for the major diastereomer derived from 1-(4-
methoxyphenyl)-1-phenylethylene (entries 3, 6, and 7). The
ee’s were found to be slightly lower with 1-(4-acetami-
dophenyl)-1-phenylethylene (92% ee, entry 4) and 1-(4-
methoxyphenyl)-1-(4-nitrophenyl)ethylene (93% ee, entry 5).
This is probably because CH2Cl2/pentane was used as solvent
with these substrates, as polar solvents lower the enantio-
selectivity in Rh2(S-DOSP)4-catalyzed cyclopropanation of
styrene with aryldiazoacetates.8
To probe further the cause of the diastereoselectivity of
these reactions, the reactions between methyl phenyldi-
azoacetate and 1-[4-(2-chloroethoxy)phenyl]-1-phenylethyl-
ene 8 were conducted using several rhodium(II) catalysts in
CH2Cl2 (Table 2). In the case of Rh2(OAc)4, a fairly moderate
diastereoselectivity (64:36) was obtained, favoring 9-E (entry
1). The diastereoselectivity was slightly improved with the
more electron deficient catalyst Rh2(TFA)4 (70:30, entry 2)
(3) (a) Abidi, S. M. A.; Howard, E. W.; Dmytryk, J. J.; Pent, J. T. Clin.
Exp. Metathesis 1998, 16, 235. (b) Rajah, T. T.; Dunn, S. T.; Pento, J. T.
Anticancer Res. 1996, 16, 837. (c) Jain, P. T.; Pento, J. T.; Magarian, R.
A. Cancer Chemother. Pharmacol. 1996, 38, 238. (d) Day, B. W.; Magarian,
R. A.; Jain, P. T.; Pento, J. T.; Mousissian, G. K.; Meyer, K. L. J. Med.
Chem. 1991, 34, 842. (e) Bedford, G. R.; Walpole, A. L.; Wright, B. J.
Med. Chem. 1974, 17, 147.
(4) (a) Davies, H. M. L. Aldrichimica Acta 1997, 30, 107. (b) Davies,
H. M. L. Eur. J. Org. Chem. 1999, 2459.
(5) Davies, H. M. L.; Bruzinski, P. R.; Fall, M. J. Tetrahedron Lett. 1996,
37, 4133.
(6) Doyle, M. P.; Zhou, Q.-L.; Charnsangavej, C.; Longoria, M. A.;
McKervey, M. A.; Garcia, C. F.. Tetrahedron Lett. 1996, 37, 4129
(7) The relative configuration of 6 and 7 was determined by NOE. The
absolute configuration is tentatively assigned by analogy to related reactions,
see ref 4 and Moye-Sherman, D.; Welch, M. B.; Reibenspies, J.; Burgess,
K. J. Chem. Soc., Chem. Commun. 1998, 2377.
(8) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M.
J. J. Am. Chem. Soc. 1996, 118, 6897.
824
Org. Lett., Vol. 2, No. 6, 2000

11 with Rh/Al2O3 gave ethylcyclopropane 12 in 69% yield.
The primary chloride in 12 was readily displaced by Me2-
NH in the presence of NaI in DMF-H2O at 55 °C to give
2 in 98% yield, which was further purified as its hydrochlo-
ride salt by recrystallization from EtOAc. The other enan-
tiomer of 2 was prepared in the same way from the
enantiomer of 9-E that was obtained using Rh2(R-DOSP)4
as catalyst.
Table 2. Effect of Catalyst on Diastereoselectivity
The high enantioselectivity observed in these cyclopro-
panations further demonstrates the synthetic utility of Rh2-
(S-DOSP)4 as a chiral catalyst. The reasonable diastereose-
lectivity of these cyclopropanations is intriguing because the
diastereocontrol is caused by the distant para substituents
on the aryl rings. Previously, we reported highly diastereo-
selective cyclopropanation reactions between phenyldi-
azoacetate and styrenes (>30:1 E/Z ratios) catalyzed by Rh2-
(S-DOSP)4.5 On the basis of the configuration of the major
diastereomer, a hypothetical model to explain the formation
of the major diastereomer was suggested as 13 in Figure
2.4,5 In this model, the CdC bond in styrene approaches side-
and with the more sterically demanding catalyst Rh2-
(triphenylacetate)4 (80:20, entry 3). The highest diastereo-
selectivity (87:13, 89% combined yield) was obtained using
Rh2(S-DOSP)4, which is more electron deficient and sterically
demanding than Rh2(OAc)4. Furthermore, with Rh2(S-
DOSP)4 in pentane, 9-E was obtained in 98% ee and 75%
isolated yield after preparative thin-layer chromatography.
Cyclopropane 9-E was readily converted to tamoxifen
analogue 2 as illustrated in Scheme 2. The methyl ester in
9-E was reduced by LiAlH4 to give alcohol 10 in 93% yield.
The alcohol was oxidized under Swern conditions to give
the corresponding aldehyde; however, since the aldehyde was
unstable to purification by chromatography on SiO2, the
crude product was immediately treated with Ph3PdCH2 to
give alkene 11 in 88% yield (two steps). Hydrogenation of
Scheme 2
Figure 2. Models for stereocontrol.
on from the ester side, forming a partial positive charge R
to the phenyl group. Our recent Hammet study on cyclo-
propanation reactions between methyl aryldiazoacetate and
various 4-substituted styrenes also suggests that considerable
positive charge is built up at the R carbon of styrene during
these cyclopropanations.9
Our current hypothetical model to explain the formation
of the major diastereomer in cyclopropanation with 1,1-
diarylethylenes is analogous to model 13 and is shown as
14 in Figure 2. In this model, the CdC bond in the 1,1-
diarylethylene approaches in a similar way to styrene. Both
aryl groups in 1,1-diaryethylenes cannot be coplanar due to
steric reasons. To minimize the steric interaction from the
ligand on rhodium, the aryl group closer to the ligand prefers
(9) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, in press.
Org. Lett., Vol. 2, No. 6, 2000
825

a conformation in which the aryl group and the CdC bond
are orthogonal rather than coplanar. On the other hand, the
aryl group that is far from the ligand may rotate more freely,
so that the aryl group maintains conjugation with the CdC
bond. This model is consistent with the observation that 1,1-
diarylethylene with an electron-donating group at the para
position of the phenyl group (methoxy, 2-chloroethoxy, and
NHAc) gave moderate to good diastereoselectivity. Accord-
ing to model 14, an electron-donating group at the R2 position
would stabilize the partial positive charge more effectively
through conjugation rather than would one at R1, thus
accounting for the energy difference between the diastere-
omeric transition states. Curiously, an electron-withdrawing
group on the aromatic ring has much less of an effect on the
diastereoselectivity than an electron-donating group.10
A related electronic effect has been reported by Corey and
Helal during studies on highly enantioselective CBS reduc-
tion of 4-methoxy-4′-nitrobenzophenone.11 They suggested
a model in which the 4-methoxyphenyl group and the
carbonyl group are in the same plane to stabilize the Lewis
acid-base interaction, while the 4-nitrophenyl group and the
carbonyl group are orthogonal with the substituent on the
boron to minimize the steric repulsion.
In summary, Rh2(S-DOSP)4-catalyzed decomposition of
aryldiazoacetates in the presence of unsymmetrical 1,1-
diarylethylenes was found to give cyclopropanation products
with high enantiomeric excesses. The diastereoselectivity was
influenced by the electronic properties of the substituents
on the 1,1-diarylethylene. Electron-donating groups such as
alkoxy gave good diastereoselectivity. The synthetic utility
of this cyclopropanation was demonstrated by the synthesis
of both enantiomers of the cyclopropyl analogue of tamoxifen
2. Further studies are in progress to evaluate the biological
activity of these new tamoxifen analogues.
(10) A possible explanation for this difference in effect may come from
Hammet studies we have carried out for competition reactions of substituted
styrenes with various carbenoids (ref 9). In these studies, we found that
vinyldiazoacetates and phenyldiazoacetates (in contrast to simple diazoac-
etates) display considerable selectivity in competition studies with various
styrenes and the reactivity correlates well with a σ+ scale rather than a σ
scale. This would suggest that the benzylic carbon of the styrene has some
carbocation character in the transition state of the cyclopropanation and is
stabilized by resonance through to the aromatic substituent. Consequently,
it is reasonable that the methoxy group would have a more significant effect
on the diastereoselectivity of the 1,1-diarylethylene cyclopropanation than
a nitro group. The influence of the nitro group would be primarily through
a polar effect rather than a resonance effect and would be largely
independent of aromatic ring orientation. For a general discussion, see: Hine,
J. In Structural Effects on Equilibra in Organic Chemistry; John Wiley &
Sons: New York, 1975; pp 55-105.
Acknowledgment. Financial support of this work by the
National Science Foundation (CHE 9726124) and by NIH
(CA 85641) is gratefully acknowledged. We thank Professor
John P. Richard for helpful discussions.
Supporting Information Available: Full experimental
data for compounds 2, 6, 7, and 10-12. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL005563U
(11) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153.
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