In search of high stereocontrol for the construction of cis-disubstituted cyclopropane compounds. Total synthesis of a cyclopropane-configured urea-PETT analogue that is a HIV-1 reverse transcriptase inhibitor.

Article abstract of DOI:10.1021/ol017276b

[reaction: see text] A new azetidine-ligated dirhodium(II) catalyst that possesses a l-menthyl ester attachment provides significant diastereocontrol and high enantiocontrol for the formation of cis-cyclopropane products from reactions of substituted styr

Full text of DOI:10.1021/ol017276b

ORGANIC
LETTERS
2002
Vol. 4, No. 6
901-904
In Search of High Stereocontrol for the
Construction of cis-Disubstituted
Cyclopropane Compounds. Total
Synthesis of a Cyclopropane-Configured
Urea-PETT Analogue That Is a HIV-1
Reverse Transcriptase Inhibitor
Wenhao Hu, Daren J. Timmons, and Michael P. Doyle*
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721
mdoyle@u.arizona.edu
Received December 19, 2001
ABSTRACT
A new azetidine-ligated dirhodium(II) catalyst that possesses a l-menthyl ester attachment provides significant diastereocontrol and high
enantiocontrol for the formation of cis-cyclopropane products from reactions of substituted styrenes with diazo esters.
Recently considerable attention has been directed to a new
class of potent non-nucleoside HIV-1 reverse transcriptase
inhibitors structurally defined as phenylethylthiazolylthiourea
(PETT) derivatives.1-4 Subsequent research revealed that the
urea-PETT analogues had toxicological and pharmacokinetic
advantages over the thiourea derivatives and that their
antiviral activity in cell culture in the presence of human
serum was superior to that of the thiourea compounds.5,6 The
most advantageous of the compounds examined were cis-
cyclopropyl derivatives, designated by 1, but stereoselective
synthesis of the cis-disubstituted ring from a multisubstituted
styrene was the greatest obstacle.
(1) Ahgren, C.; Ba¨ckbro, K.; Bell, F. W.; Cantrell, A. S.; Clemens, M.;
Colacino, J. M.; Deeter, J. B.; Engelhardt, J. A.; Ho¨gberg, M.; Jaskunas, S.
R.; Johansson, N. G.; Jordan, C. L.; Kasher, J. S.; Kinnick, M. D.; Lind,
P.; Lopez, D.; Morin, Jr., J. M.; Muesing, M. A.; Nore´en, R.; O¨ berg, B.;
Paget, C. J.; Palkowitz, J. A.; Parrish, C. A.; Pranc, P.; Rippy, M. K.;
Rydergard, C.; Sahlberg, C.; Swanson, S.; Ternansky, R. J.; Unge, T.;
Vasileff, R. T.; Vrang, L.; West, S. J.; Zhang, H.; Zhou, X.-X. Antimicrob.
Agents Chemother. 1995, 39, 1329.
(2) Bell, F. W.; Cantrell, A. S.; Ho¨gberg, M.; Jaskunas, S. R.; Johansson,
N. G.; Nore´en, R.; O¨ berg, B.; Palkowitz, J. A.; Parrish, C. A.; Prane, P.;
Sahlberg, C.; Ternansky, R. J.; Vasileff, R. J.; Vrang, L.; West, S. J.; Zhang,
H.; Zhou, X.-X. J. Med. Chem. 1995, 38, 4929.
(3) Zhang, H.; Vrang, L.; Ba¨ckbro, K.; Lind, P.; Sahlberg, C.; Unge, T.;
O¨ berg, B. AntiViral Res. 1995, 28, 331.
(4) Cantrell, A. S.; Engelhardt, P.; Ho¨gberg, M.; Jaskunas, S. R.;
Johansson, N. G.; Jordan, C. L.; Kangasmetsa¨, J.; Kinnick, M. D.; Lind,
P.; Morin, J. M., Jr.; Muesing, M. A.; Nore´en, R.; O¨ berg, B.; Pranc, P.;
Sahlberg, C.; Ternansky, R. J.; Vasileff, R. T.; Vrang, L.; West, S. J.; Zhang,
H. J. Med. Chem. 1996, 39, 4261.
The preparation of cis-disubstituted cyclopropane com-
pounds has been particularly challenging, but several catalytic
(5) Sahlberg, C.; Nore´en, R.; Engelhardt, P.; Ho¨gberg, M.; Kangasmetsa¨,
J.; Vrang, L.; Zhang, H. Bioorg. Med. Chem. Lett. 1998, 8, 1511.
10.1021/ol017276b CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/26/2002

methodologies have been advanced to address this need.
Katsuki has reported remarkably high cis-selectivity (up to
98:2) and very high enantioselectivity (up to 98% ee) for
reactions of styrene with tert-butyl diazoacetate.7,8 Use of
the cobalt-salen complex 2a showed distinct advantages in
reactivity and product yield over the ruthenium complex 2b.
Other reports have documented enhanced cis-selectivity over
two oxygen atoms and that each set had their atoms cis rather
than trans. The menthyl esters were selected from a series
of 2-oxaazetidine-4(S)-carboxylates having chiral ester sub-
stituents, including those from methyl lactate and methyl
mandelate, on the basis of the selectivities that their derivative
catalysts exhibited in cyclopropanation reactions, but only
those with the menthyl esters, Rh2(S,S-MenthAZ)4 and Rh2-
(S,R-MenthAZ)4, will be reported here.
In preliminary determinations with styrene and a series
of diazoacetates (Table 1), both diastereoselectivities and
Table 1. Cyclopropanation of Styrene with Various
Diazoacetates Catalyzed by Rh2(S,S-MenthAZ)4 (3b) and
Rh2(S,R-MenthAZ)4 (3c)a
N2CHCOOR,
product
yield, %b
% ee
c-4c
% ee
t-4c
R )
catalyst
c-4:t-4c
standard copper catalysts, but none with high enantiocon-
trol.9-11 We have previously reported that dirhodium(II)
tetrakis[alkyl 2-oxaazetidine-4(S)-carboxylates] (3) offer
Et
3b
3c
3b
3c
3b
3c
3b
3c
68
67
53
47
85
65
78
70
63:37
73:27
58:42
74:26
50:50
54:46
58:42
66:34
67
83
77
94
83
83
83
90
23
48
25
71
38
54
47
70
t-Bu
d-menthyl
l-menthyl
a Reactions were performed with 1.0 mol % of catalyst in refluxing
CH2Cl2 with a 1-h addition of the diazo compound to 10 equiv of styrene.
b Isolated yield of cyclopropane products following column chromatography.
c Determined by GC.
enantioselectivities were seen to reflect structural match/
mismatch with the diastereomeric dirhodium(II) catalysts (eq
modest cis-selectivity in reactions of diazoacetates with
styrene (up to 69:31 with 3a),12 but their advantages in ligand
simplicity did not outweigh the much lower selectivities that
characterized their applications. We now report a new
azetidine-ligated dirhodium(II) catalyst that, possessing a
chiral ester attachment, offers dynamic match/mismatch for
cyclopropanation of substituted styrenes that favors formation
of cis-cyclopropane isomers with high enantiocontrol. Ap-
plication to the synthesis of one representative structure for
1 has allowed the resolution of significant reactivity/
selectivity problems associated with the cyclopropanation of
ortho-substituted styrenes.
Menthyl esters of 2-oxaazetidine-4(S)-carboxylate were
prepared in good yield and affixed to the dirhodium(II) core
by standard methods (Scheme 1). Spectral characterization
1). Catalyst 3c gives higher preference for the cis-diastereo-
mer and higher enantiocontrol than does catalyst 3b. The
(6) Ho¨gberg, M.; Sahlberg, C.; Engelhardt, P.; Nore´en, R.; Kangasmetsa¨,
J.; Johansson, N. G.; O¨ berg, B.; Vrang, L.; Zhang, H.; Sahlberg, B.-L.;
Unge, Lo¨vgren, S.; Fridborg, K.; Ba¨ckbro, K. J. Med. Chem. 1999, 42,
4150.
Scheme 1
(7) Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron Lett. 2000,
41, 3647.
(8) Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron 2000, 56, 3501.
(9) Alexander, K.; Cook, S.; Gibson, C. L. Tetrahedron Lett. 2000, 41,
7135.
(10) Diaz-Requejo, M. M.; Belderrain, T. R.; Trofimenko, S.; Pe´rez, P.
J. J. Am. Chem. Soc. 2001, 123, 3167.
(11) Bachmann, S.; Furler, M.; Mezzetti, A. Organometallics 2001, 20,
2102.
(12) Doyle, M. P.; Davies, S. B.; Hu, W. J. Chem. Soc., Chem. Commun.
2000, 867.
established them as the (cis-2,2)-dirhodium(II) isomers,
meaning that each rhodium was linked to two nitrogen and
902
Org. Lett., Vol. 4, No. 6, 2002

menthyl diazoacetates offered no advantage, especially
because diastereoselection was diminished relative to reac-
tions in which smaller diazoacetates were used. Optimal
results were obtained with the use of tert-butyl diazoacetate
and Rh2(S,R-MenthAZ)4.
Application now to a representative cyclopropane com-
pound from which 1 could be constructed, we targeted 9,
which was prepared by the sequence of steps that is outlined
in Scheme 2. Previously the racemic cis-9 was produced in
The absolute configuration of c-4 was established by
comparing the observed optical rotation with that of the
known compound previously reported by Katsuki.8 Its
positive rotation corresponded to an absolute configuration
for c-4 of (1S,2R). That for t-4 was not determined but was
assumed by analogy to be (1R,2R).
Scheme 2
Application to a series of substituted styrenes and tert-
butyl diazoacetate provided the results that are reported in
Table 2. Here comparison is made to the diastereoselectivities
Table 2. Cyclopropanation of Substituted Styrenes with
tert-Butyl Diazoacetate Catalyzed by Rh2(S,R-MenthAZ)4 (3c)a
Z-styrene,
product
% ee % ee
Z )
catalyst
yield, %b c-4:t-4c c-4d t-4d
a : p-methyl
Rh2(OAc)4
3c
68
54
64
25
63
47
60
39
69
44
35:65
72:28
34:66
72:28
34:66
71:29
45:55
86:14
42:58
92:8
93
81
95
97
97
nd
81
nd
nd
76
b: p-trifluoromethyl Rh2(OAc)4
3c
c: o-chloro
Rh2(OAc)4
3c
Rh2(OAc)4
3c
Rh2(OAc)4
3c
only 20% yield with a CuI/Pd(OAc)2 catalyst,5 but Aggarwal
prepared directly the corresponding racemic cyclopropyl-
amine from N-vinyl phthalimide and a phenyldiazomethane
precursor in 76% yield (cis:trans ) 85:15).13 Our efforts to
prepare 9c are revealed in the data of Table 3. Note that the
d : 2,6-dichloro
e: 2,4,6-trimethyl
a Reactions were performed with 1.0 mol % of catalyst in refluxing
CH2Cl2 with a 5-h addition of tert-butyl diazoacetate to 10 equiv of the
substituted styrene. b Isolated yield of cyclopropane products following
column chromatography. c Determined by GC using a SPB-5 column.
d Determined by GC on Chiraldex columns. nd ) not determined.
Table 3. Cyclopropanation of Styrene 8; Catalyst and Diazo
Compound Influence on Stereoselectivitya
N2CHCOOR,
yield
9c, %b
% ee
9cd
obtained from Rh2(OAc)4. Enantioselectivities from the use
of Rh2(S,R-MenthAZ)4 are remarkably similar, except for
cyclopropanation of the styrene having the electron-
withdrawing p-trifluoromethyl substituent. When both ortho
positions of styrene are substituted, diastereoselectivity
favoring the cis-cyclopropane isomer increases without
diminishing enantioselectivity (with 3c). With 2,4,6-tri-
methylstyrene, for example, the cis:trans product ratio
reached 92:8 with Rh2(S,R-MenthAZ)4, and enantioselectivity
for the dominant isomer was 97% ee. However, the reac-
tivities of the ortho-disubstituted styrenes were slower than
that for styrene, presumably because of the inability of the
alkene to achieve orbital alignment with the benzene ring.
In a competing experiment in which 10 equiv each of
styrenes and 2,4,6-trimethylstyrene were used, the cyclo-
propane products, each set exhibiting the same selectivities
as are reported in Table 2, showed a relative reactivity of
styrene to 2,4,6-trimethylstyrene of 1.6:1. This structural
congestion is the probable cause for the significantly
enhanced diastereoselectivity achieved in these cyclopropa-
nation reactions. The absolute configurations of these
products were assumed to be the same as those formed by
cyclopropanation of styrene.
catalyst
R )
9c:9tc
Rh2(OAc)4
3a
Et
Et
30
32
0
29
42
52f
21f
42:58
75:25
80
d-menthyl
Et
Et
Et
Cu(box)OTfe
3c
51:49
72:28
79:21
82:18
89
86
86
97
t-Bu
a Unless specified otherwise, reactions were performed with 1.0 mol %
of catalyst in refluxing CH2Cl2 with a 5-h addition of diazoacetate to 10
equiv of 8 with initial [8] ) 0.2 M. b Isolated yield of 9c only. c Determined
by GC on a SPB-5 column. d Determined by GC on a Chiraldex B-DM
column. e 5 mol % of catalyst was used. f [8] ) 1.8 M.
yields given for 9c are those for the pure cis-isomer following
chromatography.
Diastereoselectivity for cyclopropanation of 8 was predict-
able from results obtained for 2,6-dichlorostyrene, but as can
be seen from results in Table 3 the use of Rh2(4S-IBAZ)4
(3a) afforded modestly higher preference for the cis-
(13) Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. Org. Lett. 2001, 3,
2785.
Org. Lett., Vol. 4, No. 6, 2002
903

cyclopropane isomer than did Rh2(S,R-MenthAZ)4 (3c).
However, enantioselectivity with Rh2(S,R-MenthAZ)4 was
greater than with Rh2(4S-IBAZ)4. Modest improvement in
diastereoselectivity and in product yield was achieved with
highly concentrated 8, and we attribute this to a solvent
effect; enantioselectivity was unaffected by the increase in
concentration for 8. Use of Cu(box)OTf (box ) 10)14 gave
a reasonable level of enantioselectivity for the cis-isomer
9c, but diastereoselectivity was low.
Scheme 3
The cis-cyclopropane isomer from reaction with ethyl
diazoacetate was converted to the urea-PETT derivative 12
by the sequence of steps outlined in Scheme 3. The overall
process from styrene 8 could be accomplished in four steps
in modest yield but high selectivity. Efforts are underway
to improve the overall conversion and to develop the
generality of this cis-selective cyclopropanation process. The
simplicity of the ligands and the tolerance of dirhodium(II)
catalysts for multisubstituted styrenes makes this methodol-
ogy especially attractive.15
Acknowledgment. We are grateful to the National
Science Foundation and to the National Institutes of Health
(GM 46503) for their support of this research.
Supporting Information Available: Experimental and
spectral data that include the synthesis and characterization
of catalysts 3b and 3c and relevant information for com-
pounds 4-9 and 11-12. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos,
K. R.; Woerpal, K. A. J. Org. Chem. 1998, 63, 4541.
(15) For relevant reviews of dirhodium(II) carboxamidate catalysts and
their influence on selectivity, see: (a) Doyle, M. P.; McKervey, M. A.;
Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds: From Cyclopropanes to Ylides; John Wiley and Sons: New
York, 1998. (b) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911. (c)
Timmons, D. J.; Doyle, M. P. J. Organomet. Chem. 2001, 617-618, 98.
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Org. Lett., Vol. 4, No. 6, 2002