Catalytic asymmetric synthesis of diarylacetates and 4,4-diarylbutanoates. A formal asymmetric synthesis of (+)-sertraline

Article abstract of DOI:10.1021/ol9905699

(equation presented) The intermolecular C-H insertion chemistry of phenyldiazoacetates catalyzed by dirhodium tetrakis((S)-N-(dodecylbenzenesulfonyl)prolinate) (Rh₂(S-DOSP)₄) can be effectively carried out on cyclohexadienes, leading to the asymmetric synthesis of diarylacetates. The reaction of vinyldiazoacetates with cyclohexadienes results in an unprecedented carbenoid reaction that is formally a combined C-H insertion/Cope rearrangement. The synthetic utility of this novel transformation was demonstrated by its utilization in a formal asymmetric synthesis of (+)-sertraline.

Full text of DOI:10.1021/ol9905699

ORGANIC
LETTERS
1999
Vol. 1, No. 2
233-236
Catalytic Asymmetric Synthesis of
Diarylacetates and 4,4-Diarylbutanoates.
A Formal Asymmetric Synthesis of
(+)-Sertraline
Huw M. L. Davies,* Douglas G. Stafford, and Tore Hansen
Department of Chemistry, State UniVersity of New York at Buffalo,
Buffalo, New York 14260
hdaVies@acsu.buffalo.edu
Received April 9, 1999
ABSTRACT
The intermolecular C−H insertion chemistry of phenyldiazoacetates catalyzed by dirhodium tetrakis((S)-N-(dodecylbenzenesulfonyl)prolinate)
(Rh2(S-DOSP)4) can be effectively carried out on cyclohexadienes, leading to the asymmetric synthesis of diarylacetates. The reaction of
vinyldiazoacetates with cyclohexadienes results in an unprecedented carbenoid reaction that is formally a combined C−H insertion/Cope
rearrangement. The synthetic utility of this novel transformation was demonstrated by its utilization in a formal asymmetric synthesis of
(+)-sertraline.
The gem-diarylalkyl group is present in a number of
important pharmaceuticals,1 such as tolterodine (1),1a,b CDP-
840 (2),1c and nomifensine (3).1d Consequently, a number
of reports have recently appeared describing methods for the
asymmetric synthesis of gem-diarylalkyl derivatives.2 Par-
ticularly effective have been the asymmetric conjugate
(1) (a) Nilvebrant, L.; Andersson, K.-E.; Gillberg, P.-G.; Stahl, M.; Sparf,
B. Eur. J. Pharmacol. 1997, 327, 195. (b) Nilvebrant, L.; Hallen, B.;
Larsson, G. Life Sci. 1997, 60, 1129. (c) Hughes, B.; Howat, D.; Lisle, H.
M.; James, T.; Gozzard, N.; Blease, K.; Hughes, P.; Kingaby, R.; Warrellow,
addition of organometallic reagents to cinnamates2a-e and
G.; Alexander, R.; Head, J.; Boyd, E.; Eaton, M.; Perry, M.; Wales, M.;
Smith, B.; Owens, R.; Catterall, C.; Lumb, S.; Russell, A.; Allen, R.;
Merriman, M.; Bloxham, D.; Higgs, G. Br. J. Pharmacol. 1996, 118, 1183.
2-phenylcyclopropane-1,1-dicarboxylate.2f In this paper we
(d) Hoffmann, I.; Ehrhart, G.; Schmitt, K. Arzneim.-Forsch. 1971, 21, 1045.
the aryl cuprate addition to enantiomerically pure dimethyl
(e) Lowe, J. A., III; Hageman, D. L.; Drozda, S. E.; McLean, S.; Bryce, D.
K.; Crawford, R. T.; Zorn, S.; Morrone, J.; Bordner, J. J. Med. Chem. 1994,
37, 3789. (f) McCague, R.; Leclercq, G. J. Med. Chem. 1987, 30, 1761.
(g) Bogeso, K. P.; Christensen, A. V.; Hyttel, J.; Liljefors, T. J. Med. Chem.
1985, 28, 1817.
(2) (a) Frey, L. F.; Tillyer, R. D.; Caille, A.-S.; Tschaen, D. M.; Dolling,
U.-H.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1998, 63, 3120. (b)
Andersson, P. G.; Schink, H. E.; Osterlund, K. J. Org. Chem. 1998, 63,
8067. (c) Houpis, I. N.; Molina, A.; Dorziotis, I.; Reamer, R. A.; Volante,
R. P.; Reider, P. J. Tetrahedron Lett. 1997, 38, 7131. (d) Christenson, B.;
Hallnemo, G.; Ullenius, C. Tetrahedron 1991, 47, 4739. (e) Alexakis, A.;
Sedrani, P.; Mangeney, P.; Normant, J. F. Tetrahedron Lett. 1988, 29, 4411.
(f) Corey, E. J.; Gant, T. G. Tetrahedron Lett. 1994, 35, 5373.
(3) (a) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911. (b) Calter,
M. A. Curr. Org. Chem. 1997, 1, 37. (c) Doyle, M. P.; McKervey, M. A.;
Ye, T. In Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley-Interscience: New York, 1998.
10.1021/ol9905699 CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/05/1999

describe a novel method for the synthesis of diarylacetates
and 4,4-diarylbutanoates that is based on asymmetric car-
benoid transformations.3 The practical utility of this meth-
odology is demonstrated by a short formal synthesis of the
antidepressant (+)-sertraline (4).4
The two general methods used to prepare gem-diarylalkyl
compounds were discovered during exploratory studies into
the synthetic potential of intermolecular asymmetric C-H
insertions of Rh2(S-DOSP)4 (5) catalyzed5 decomposition of
diene, as this resulted in the formation of the C-H insertion
product 10 with very little occurrence of the cyclopropanation
reaction. The absolute stereochemistry of 10 was determined
to be R by reduction of 10 to the cyclohexane 9 (80% overall
yield from 6 with a 91% ee).
The reaction with 1,4-cyclohexadiene could be carried out
with a range of aryldiazoacetates 11, as illustrated in Scheme
2. In each case the C-H insertion product 12 was produced
Scheme 2
aryldiazoacetates.6 Previously, we had shown that the
decomposition of aryldiazoacetates in the presence of cy-
cloalkanes or tetrahydrofuran resulted in C-H insertion with
high asymmetric induction.5 On evaluation of the possibility
that this reaction may be favored at allylic C-H bonds, it
was discovered that the reaction of 6 with 1,3-cyclohexadiene
resulted in the preferential formation of the C-H insertion
product 7 rather than the cyclopropanated product 8 (Scheme
1). The C-H insertion product 7 was formed as an
in >90% ee. Furthermore, 12 could be readily oxidized by
DDQ to the diarylacetate 13 without racemization. The
absolute stereochemistry for 12 and 13 is tentatively assigned
on the assumption that the asymmetric induction would
parallel that observed in the formation of 10.
The new strategy to 4,4-diarylbutanoates was discovered
on attempting the C-H insertion reaction with the phenyl-
vinyldiazoacetate 14. Reaction of 14 with 1,3-cyclohexadiene
did not result in the formation of the expected C-H insertion
product. Instead, the 1,4-cyclohexadiene 15 was formed in
63% yield and 98% ee (Scheme 3). A side product in this
reaction is the cyclopropanation/Cope rearrangement product
16. The catalyst has a major effect on the product distribution
in this reaction.8 When rhodium(II) octanoate is used as
Scheme 1
Scheme 3
inseparable 4:1 mixture of diastereomers, and so in order to
determine the extent of the asymmetric induction, 7 was
reduced to the known cyclohexane 9, which was formed in
92% ee (R configuration).7 An even more effective C-H
insertion was achieved on reaction of 6 with 1,4-cyclohexa-
(4) (a) Coe, B. K.; Weissman, A.; Welch, W. M.; Broune, R. G. J.
Pharmacol. Exp. Ther. 1983, 226, 686. (b) Welch, W. M.; Kraska, A. R.;
Sarges, R.; Coe, K. B. J. Med. Chem. 1984, 27, 1508. (c) Quallich, G. J.;
Woodall, T. M. Tetrahedron 1992, 48, 10239.
(5) (a) Davies, H. M. L. Curr. Org. Chem. 1998, 2, 463. (b) Davies, H.
M. L. Aldrichim. Acta 1997, 30, 107.
(6) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
(7) Camps, P.; Gimenez, S. Tetrahedron: Asymmetry 1996, 7, 1227.
234
Org. Lett., Vol. 1, No. 2, 1999

catalyst, cyclopropanation becomes the preferred reaction,
and from the range of catalysts that were studied, it is
apparent that the catalyst exhibits a subtle combination of
steric and electronic effects. So far, Rh2(S-DOSP)4 is the best
catalyst for limiting the cyclopropanation reaction, resulting
in a 84:16 ratio of 15 to 16.
Scheme 5
The most obvious mechanism for the formation of cyclo-
hexadiene 15 would be an allylic C-H insertion between
14 and 1,3-cyclohexadiene to form 17, followed by a Cope
rearrangement to 15 (Scheme 4). There is no obvious driving
Scheme 4
the reactions with o-substituted benzene 18d or 1-naphthyl
(18e) result in the formation of 19d or 19e with lower
enantioselectivity (84-86% ee). Also the yields of 19d and
19e were greatly decreased compared to those of 19a-c,
because the major product in these last two reactions was
the cyclopropanation/Cope rearrangement product, analogous
to 16.
The cyclohexadiene 19b is an excellent precursor for the
formal synthesis of (+)-sertraline, as illustrated in Scheme
6. Oxidation of 19b with DDQ followed by catalytic
force, however, for the Cope rearrangement of 17 to 15.
Indeed, it was confirmed that the driving force for the Cope
rearrangement is in the reverse direction by heating 15 in
refluxing hexane, because under these conditions, 15 slowly
rearranged to 17. Consequently, alternative mechanistic
possibilities need to be considered. It is conceivable that 15
is derived by an intercepted C-H insertion process or by
means of an ene reaction where the vinylcarbenoid reacts
as a 2π system. Further studies will be needed to determine
the actual mechanism of this most unusual carbenoid
transformation.
Scheme 6
The reaction can be extended to a range of arylvinyldi-
azoacetates 18, as illustrated in Scheme 5.9 The reactions
with m- or p-substituted benzenes 18a and 18b or 2-naphthyl
(18c) result in the formation of 19a-c with exceptionally
high levels of asymmetric induction (99% ee). In contrast,
(8) For other examples of ligand effects on carbenoid reactivity, see:
(a) Padwa, A.; Ustin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.;
Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem. Soc. 1993,
115, 8669. (b) Padwa, A.; Austin, D. J.; Hornbuckle, S. F.; Semones, M.
A.; Doyle, M. P.; Protopopova, M. N. J. Am. Chem. Soc. 1992, 114, 1874.
(c) Davies, H. M. L.; Saikali, E.; Clark, T. J.; Chee, E. H. Tetrahedron
Lett. 1990, 31, 6299.
hydrogenation formed the 4,4-diarylbutanoate 20 (52% yield
for 3 steps from 18b) with minimal racemization (96% ee).
Ester hydrolysis of 20 followed by an intramolecular
Friedel-Crafts acylation generated the tetralone 21 (79%
yield for two steps), which has been previously converted
to (+)-sertraline.2f,10
The general chemistry is applicable to other vinylcarbenoid
systems, as illustrated in Scheme 7. Rh2(S-DOSP)4-catalyzed
decomposition of the cyclic vinyldiazoacetate 22 in the
(9) General Procedure for Rh2(S-DOSP)4 Catalyzed Decomposition
of Vinyldiazomethanes in the Presence of Cyclohexadienes. A solution
of vinyldiazoacetate 18b (207 mg, 0.764 mmol) in dry hexanes (20 mL)
was added dropwise over 15 min to a flame-dried flask containing a stirred
solution of Rh2(S-DOSP)4 (12 mg, 6.4 × 10-3 mmol) and the diene (0.4
mL, 4 mmol) in dry hexane (30 mL) at room temperature. After 16 h the
solvent was removed under reduced pressure. Purification by flash silica
gel column chromatography (9:1 petroleum ether/Et2O, Rf ) 0.24) gave
19b in 59% yield as a clear oil: 99% ee (determined by HPLC: Daicel-
OD, 0.8% i-Pr-OH in hexanes, 0.8 mL/min; Tr ) 12.06 min (minor), 23.73
min (major)); [R]25 ) +4° (c 2.08, CHCl3); IR (neat) 3029, 2954, 2863,
D
2817, 1726, 1651 cm-1; 1H NMR (300 MHz) δ 7.36 (d, 1 H, J ) 8.0 Hz),
7.27 (d, 1 H, J ) 2.5 Hz), 7.10 (dd, 1 H, J ) 15.5, 8.5 Hz), 7.02 (dd, 1 H,
J ) 8.0, 2.5 Hz), 5.81 (d, 1 H, J ) 15.5 Hz), 5.75 (br d, 2 H, J ) 12.0 Hz),
5.57 (br d, 1 H, J ) 10.0 Hz), 5.43 (br d, 1 H, J ) 10.0 Hz), 3.71 (s, 3 H),
3.38 (dd, 1 H, J ) 8.5, 8.0 Hz), 3.17-3.15 (m, 1 H), 2.62-2.48 (m, 2 H);
13C NMR (125 MHz) δ 166.5, 148.1, 140.7, 132.4, 130.8, 130.4, 130.2,
127.6, 126.83, 126.79, 125.7, 125.3, 122.9, 53.6, 51.6, 40.1, 26.3; HRMS
calcd for C17H16O2Cl2 322.0527, found 322.0504.
(10) The absolute configuration of compound 21 is S: found [R]26
)
D
+66° (c ) 2.04, PhH); lit.2f value [R]23D ) +71.3° (c ) 1.1, PhH), S-isomer.
(11) The absolute configuration of compound 23 was determined by DDQ
oxidation and ozonolysis to afford partially racemized 2-phenylcyclohex-
anone in 56% yield: found [R]26D ) -17 (c ) 1.66, PhH); lit. value [R]24
) -113.5 (c ) 0.60, PhH), S-isomer (Berti, G.; Macchia, B.; Macchia, F.;
Monti, L. J. Chem. Soc. 1971, 3371).
D
Org. Lett., Vol. 1, No. 2, 1999
235

25 (60% yield and 99% ee), in which both diene components
have moved out of conjugation.
Scheme 7
In summary, the intermolecular C-H insertion chemistry
of phenyldiazoacetates can be effectively carried out on
cyclohexadienes, leading to the asymmetric synthesis of
diarylacetates. The reactions of vinyldiazoacetates with
cyclohexadienes result in an unprecedented carbenoid reac-
tion that is formally a combined C-H insertion/Cope
rearrangement. The synthetic utility of this novel transforma-
tion was demonstrated by its utilization in a formal asym-
metric synthesis of (+)-sertraline.
Acknowledgment. Financial support of this work by the
National Science Foundation (Grant No. CHE 9726124) is
gratefully acknowledged.
Supporting Information Available: Full experimental
data for compounds 13, 15-21, 23, and 25. This material is
available free of charge via the Internet at http://pubs.acs.org.
presence of 1,3-cyclohexadiene resulted in the formation of
the 1,4-cyclohexadiene 23 in 73% yield and 97% ee.11
Similarly, decomposition of the dienyldiazoacetate 24 in the
presence of 1,3-cyclohexadiene resulted in the formation of
OL9905699
236
Org. Lett., Vol. 1, No. 2, 1999