General strategy toward the tetrahydronaphthalene skeleton. An expedient total synthesis of sertraline

Full text of DOI:10.1021/jo971115x

5246
J . Org. Chem. 1997, 62, 5246-5247
Ta ble 1. En a n tioselective Rin g Op en in g of
Gen er a l Str a tegy tow a r d th e
Tetr a h yd r on a p h th a len e Sk eleton . An
Exp ed ien t Tota l Syn th esis of Ser tr a lin e
Oxa ben zon or bor n en es
Mark Lautens* and Tomislav Rovis
Department of Chemistry, University of Toronto,
Toronto, Ontario M5S 3H6, Canada
Received J une 19, 1997
The enantioselective synthesis of therapeutically im-
portant molecules remains a major focus of attention
among organic chemists. Particularly appealing is the
notion of using asymmetric catalysis to control the
absolute stereochemistry of newly generated stereo-
centers. A large number of bioactive molecules possess
a tetrahydronaphthalene core (e.g., the antidepressant
sertraline,1 1, and the anticancer agent podophyllotoxin,2
2), and we now report a general method for the enanti-
oselective synthesis of this important skeleton.
a
All reactions were run in the presence of 14 mol % Ni(COD)2
and 21 mol % (R)-BINAP at room temperature unless otherwise
b
noted. Addition of DIBAL-H to a solution of Ni(COD)2, (R)-
d
BINAP, and the alkene via syringe pump. c Isolated yield. Mea-
sured by capillary GC (Chiraldex G-TA or B-TA column) or chiral
HPLC (Chiracel OD or OJ column). e Hydroalumination at -40
°C.
Sch em e 1a
Recently, we reported that nickel-phosphine com-
plexes catalyze the regioselective and enantioselective
reductive ring opening of oxabicyclic alkenes.4 For
example, the reaction of 3 with a DIBAL-H and Ni(COD)2/
BINAP system gave the substituted cyclohexenol 4 in
95% yield and 97% ee (eq 1).
a
Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2,
DMAP, 88%; (b) Br2, CH2Cl2, Et3N, 0 °C then DBU, PhH, 83%.
in THF, entry 3. Alcohol 6, a formal hydrate of naph-
thalene, is surprisingly stable to dehydration6 and can
be purified by column chromatography on silica gel.
In light of the limited methods available for the
synthesis of compounds of general structure 6, the scope
of this reaction was investigated. Substituents at the
allylic bridgehead position lead to a decrease in enantio-
selectivity, entry 4, Table 1. However, better enantiose-
lectivity is observed with substrates bearing methyl
substituents distal to the olefin as was seen with sub-
strate 9 (88% ee). We also studied the electronic effects
of substituents on the aromatic ring. Subjecting the 1,3-
dioxolane-substituted oxabicyclic 11 to the reaction con-
ditions leads to 12 in 94% ee. We noticed a drop in
chemical yield to 58% for 12, likely owing to increasing
ease of dehydration. Significantly, the presence of two
electron-withdrawing fluorine substituents in compound
13 leads to no discernible change in enantioselectivity
(96% ee), indicating the reaction is insensitive to elec-
tronic effects on the aromatic ring.
Subjecting 53 to our enantioselective hydrometalation/
fragmentation sequence would afford 6, which has the
requisite functionality in place to use as a central
template for the synthesis of a variety of substituted
tetrahydronaphthalenes.
Reacting 5 under the previously described conditions
in toluene gave a complex mixture of products including
6 in modest ee, entry 1, Table 1. However, changing the
solvent from toluene to THF gave much better results,
perhaps because of the reduced Lewis acidity of DIBAL-H
(1) (a) Welch, W. M.; Kraska, A. R.; Sarges, R.; Koe, B. K. J . Med.
Chem. 1984, 27, 1508. (b) Williams, M.; Quallich, G. Chem. Ind.
(London) 1990, 10, 315. (c) Quallich, G. J .; Woodall, T. M. Tetrahedron
1992, 48, 10239. (d) Corey, E. J .; Gant, T. G. Tetrahedron Lett. 1994,
35, 5373. (e) J ohnson, B. M.; Chang, P.-T. L. Anal. Profiles Drug Subst.
1996, 24, 443.
(2) Kamal, A.; Gayatri, N. L. Tetrahedron Lett. 1996, 37, 3359 and
references therein.
(3) Fieser, L. F.; Haddadin, M. J . Can. J . Chem. 1965, 43, 1599.
(4) Lautens, M.; Chiu, P.; Ma, S.; Rovis, T. J . Am. Chem. Soc. 1995,
117, 532. For an early attempt at asymmetric hydroalumination see:
Giacomelli, G.; Bertero, L.; Lardicci, L. Tetrahedron Lett. 1981, 22,
883.
(5) For a racemic route to 6 from 5, see: Brown, H. C.; Vara Prasad,
J . V. N. J . Org. Chem. 1985, 50, 3002. Alcohol 6 has been isolated in
high ee from the microbial oxidation of dihydronaphthalene (62% yield).
(a) Boyd, D. R.; McMordie, R. A. S.; Sharma, N. D.; Dalton, H.;
Williams, P.; J enkins, R. O. J . Chem. Soc., Chem. Commun. 1989, 339.
(b) Boyd, D. R.; Sharma, N. D.; Kerley, N. A.; McMordie, R. A. S.;
Sheldrake, G. N.; Williams, P.; Dalton, H.; J . Chem. Soc., Perkin Trans.
1 1996, 67.
In order to illustrate the utility of alcohol 6 in the
synthesis of bioactive products, we undertook the total
synthesis of the clinically important antidepressant agent
sertraline.
To access 1, we required enant-6, readily available from
5 using (S)-BINAP as the ligand. On a 7.7 mmol scale,
the use of 1.9 mol % of Ni(COD)2 and 3.3 mol % of (S)-
(6) For a study of the relative tendencies of some aromatic hydrates
to aromatize, see: Rao, S. N.; More O’Ferrall, R. A.; Kelly, S. C.; Boyd,
D. R.; Agarwal, R. J . Am. Chem. Soc. 1993, 115, 5458.
S0022-3263(97)01115-8 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 16, 1997 5247
Sch em e 2a
Sch em e 4a
a
a
Reagents and conditions: (a) dppa, DBU, THF, 88%, 98:2; (b)
Reagents and conditions: (a) 5% (MeCN)2PdCl2, 20% AsPh3,
(3,4-diCl)C6H3SnMe3, NMP, 80 °C, 1.5 h, 55%; (b) TBAF, THF,
AcOH, 3 d, quant.
(i) H2, Pd-C, EtOH, (ii) ClCO2Et, MeCN, K2CO3, (iii) LiAl-
H(OMe)3, THF, reflux, 40 h, 86%.
complete consumption of the starting material at 1000
psi of hydrogen. A 10:1 mixture of 19 and its epimer was
obtained along with a second unidentified side product.
Purification by chromatography gave 19 in 74% yield
(Scheme 3). Crabtree’s catalyst (10 mol % [Ir(COD)py-
PCy3]PF6) gave 19 in better yield (88%) and with higher
selectivity (28:1).10
Sch em e 3a
Oxidation of 19 with MnO2 gave tetralone 20 which
represented a formal synthesis of sertraline.11 However,
the subsequent reductive amination gave sertraline and
its epimer in a 3:1 ratio. Our route, via 19, provided an
opportunity to introduce the amine via a stereoselective
displacement reaction using conditions developed by
Thompson and co-workers.12 Reaction of diphenylphos-
phoryl azide [dppa] in THF followed by the addition of
DBU gave the azide 21 in 88% yield and 98:2 selectivity
(Scheme 4). The azide was reduced to the free amine,
which was then treated with ethyl chloroformate and
subsequently reduced with LiAlH(OMe)3 in refluxing
THF. This protocol was done without isolation of inter-
mediates and afforded sertraline, 1, in 86% overall yield
from the azide.
In summary, we have illustrated that the oxaben-
zonorbornadienes are excellent substrates for the nickel-
catalyzed hydroalumination reaction, and the products
are promising precursors to a wide range of biologically
important compounds. We have shown that significantly
less catalyst (2 mol %) can be employed than reported in
our original disclosure (14 mol %). A total synthesis of
the important antidepressant sertraline has been achieved
in eight steps with an overall yield of 33% starting from
the oxabenzonorbornadiene 5.
a
Reagents and conditions: (a) 10 mol % [Ir(COD)pyPCy3]PF6,
H2 (1000 psi), CH2Cl2, 88%, 28:1; (b) activated MnO2, CHCl3,
quant; (c) NaBH4, EtOH, quant, 1.1:1.
BINAP led to an 88% yield of enant-6 with an ee of 91%.
Recrystallization of the alcohol from hexanes gave enant-6
in 98% ee. Protection of the alcohol as its silyl ether
proceeded in 88% yield using TBDPSCl (TBDPSCl ) tert-
butyl diphenylsilyl chloride) in the presence of imidazole
and DMAP, Scheme 1. Treatment of the silyl ether 15
with bromine in CH2Cl2 at 0 °C7 gave the dibromide,
which was not isolated but instead immediately treated
with an excess of diazabicycloundecene (DBU) to give the
vinyl bromide 16 in 83% isolated yield. We found that
both 15 and 16 were prone to elimination, so on scale-
up, the silylation and bromination/dehydrobromination
steps were done without purification of intermediates,
giving rise to 16 in 88% isolated yield from the alcohol
enant-6.
The vinyl bromide 16 was subjected to a palladium-
catalyzed Stille cross coupling with a suitably substituted
arylstannane, Scheme 2. A number of typical Stille
coupling conditions were examined, but the best yields
were obtained using Farina’s conditions (triphenylarsine
as ligand and N-methylpyrrolidinone (NMP) as solvent).8
Under these conditions, the coupling proceeded to comple-
tion at 80 °C in 1.5 h. Longer reaction times or higher
temperatures led to formation of significant amounts of
the substituted naphthol arising from dehydrogenation
of the product by the palladium catalyst. The product
was isolated in only 55% yield due to the extreme
sensitivity of the silyl ether 17 to elimination, and in fact,
higher yields were realized by treatment of the crude
reaction mixture with tetrabutylammonium flouride/
acetic acid to give the alcohol 18 in a 64% overall yield
from 16. Acetic acid was an essential additive in order
to avoid aromatization via elimination of silanol.
Ack n ow led gm en t. The E. W. R. Steacie Memorial
Fund and the NSERC of Canada are thanked for
financial support. T.R. thanks NSERC for a postgradu-
ate scholarship. We thank Professor R. H. Morris and
C. Forde for technical help in the preparation of Crab-
tree’s catalyst and Professor S. V. Ley for first bringing
sertraline to our attention.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for all new compounds reported
herein (33 pages).
J O971115X
(9) For a review on the directed homogeneous hydrogenation, see:
Brown, J . M. Angew. Chem., Int. Ed. Engl. 1987, 26, 190. For a recent
review encompassing directed hydrogenations, see: Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307. Following
completion of our work, a report appeared in the literature describing
the use of the cationic rhodium complex in the directed hydrogenation
of a dihydronaphthalenol: Kuroda, T.; Takahashi, M.; Kondo, K.;
Iwasaki, T, J . Org. Chem. 1996, 61, 9560.
(10) For a seminal reference, see: Stork, G.; Kahne, D. E. J . Am.
Chem. Soc. 1983, 105, 1072. For a synthesis of Crabtree’s catalyst,
see: Crabtree, R. H.; Morehouse, S. M. Inorganic Syntheses; Shreeve,
J . M., Ed.; Wiley: New York, 1986; Vol. 24, p 173.
(11) Reduction yielded a 1.1:1 mixture of 19 and epi-19. Tetralone
20 exhibited spectral data identical to the reported values; see ref 1d
above.
(12) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre,
D. J .; Grabowski, E. J . J . J . Org. Chem. 1993, 58, 5886.
A directed hydrogenation reaction was used in order
to control the stereochemistry of the carbon bearing the
dichloroaryl group. While significant precedent exists for
the rhodium- and iridium-catalyzed directed hydrogena-
tions of substituted cyclohex-3-en-1-ols, the selectivity in
a nearly planar system such as 18 was less well docu-
mented.9 Treatment of 18 with Brown’s cationic rhodium
catalyst (1 mol % [Rh(NBD)dppb]BF4) in CH2Cl2 led to
(7) Willems, A. G. M.; Pandit, U. K.; Huisman, H. O. Recl. Trav.
Chim. Pays-Bas 1965, 84, 389.
(8) Farina, V. Pure Appl. Chem. 1996, 68, 73 and references therein.