matizing cyclization of lithiated amides to make intermedi-
ates for the synthesis of kainoid amino acids,6 and recently
we reported cyclization of some lithiated oxazolines.7
gave the silyl ether 7. A second bromine-lithium exchange,
trapping with diphenyl disulfide, and oxidation gave the
sulfone 10, which was deprotected. Alkylation of 16 with
iodomethyltributylstannane11 gave the cyclization precursor
18. A parallel route gave the chiral stannane 19: enantio-
merically enriched material was obtained by CBS reduction12
(to 11) of the ketone 6 derived by Weinreb acylation13 of 3;
11 was obtained in racemic form by addition of MeLi to
aldehyde 4. Protection, introduction of the sulfone, and
deprotection gave alcohol 17 and hence the stannane 19, in
both racemic and enantiomerically enriched14 forms.
Treatment of a THF solution of 18 with methyllithium in
the presence of TMEDA promoted transmetalation to the
organolithium 20 (Scheme 2). Even at -78 °C, this orga-
nolithium cyclized to 21 by attack on the naphthyl ring:
quenching the orange anion 21 with a solution of NH4Cl
returned the unstable tricyclic enol ether exo-22a as a single
diastereoisomer in 60% yield. Hydrolysis of the enol ether
to ketone exo-23a (obtained in 69% yield) was accompanied
by a small amount (10%) of epimerization to endo-23. This
diastereoisomer was obtained as the only product when the
reaction mixture, instead of being quenched with ammonium
chloride quench at -78 °C, was warmed to 20 °C with
methanol. A different unstable enol ether, presumably endo-
22, was observed in the crude reaction mixture, and acid
hydrolysis gave solely the ketone endo-23 in 59% yield.
X-ray crystal structures (Figure 1a,b) proved the stereochem-
istry of the products. Epimerization of the sulfonyl group to
the endo face appears to be due to warming in the presence
of methoxide, though it is not clear why endo-22 should be
more stable than exo-22a.
A scattered handful of reports8 suggested to us that the
dearomatizing cyclization of lithiated sulfones and sulfon-
amides might also be generalized into a valuable synthetic
method and that we might be able to capitalize on the
versatility of sulfone chemistry9 in the transformation of the
products into useful targets. In this paper, we report that
organolithiums tethered to aryl sulfones cyclize with dearo-
matization and describe the transformation of the products
of this reaction into an analogue of the anticancer agent
podophyllotoxin.
The starting materials 18 and 19 (Scheme 1) for the
cyclization were made straightforwardly from 1-methoxy-
Scheme 1. Synthesis of the Cyclization Precursora
Alkylation of the sulfone anion 21 followed by hydrolysis
gave good yields of single diastereoisomers of alkylated
ketones 23b-d, all with the same relative stereochemistry:
the sulfonyl group in 23a-d occupies the exo face of the
cis-fused tricycle.15
Cyclization of the chiral stannane 19 was fully diastereo-
selective at both new stereogenic centers when the inter-
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a Reagents: (i) Br2, CH2Cl2 100%; (ii) n-BuLi (0.95 equiv), Et2O,
-78 °C; (iii) Me2NCHO; (iv) NaBH4, MeOH, 84% from 2; (v)
MeLi, THF, -78 °C, 88% (()-11; (vi) MeCON(OMe)Me, 57%;
(vii) CBS reagent, BH3:SMe2, THF, 99% (+)-11 (95% ee); (viii)
t-BuMe2SiCl, DMAP, Et3N, CH2Cl2, 90%; (ix) n-BuLi, THF, -78
°C; (x) Ph2S2, 92% 9 from 7; (xi) m-CPBA, EtOAc, NaHCO3, 93%
10, or Na2B2O6, AcOH, 80% 15 from 12; (xii) t-BuMe2SiOTf,
lutidine, CH2Cl2, 0 °C, 93%; (xiii) Bu4NF, THF, 94% 16 from 10,
62% 16 from 7, or 98% 17 from 15; (xiv) NaH, THF, then
Bu3SnCH2I, 75% 18 or 60% 19.
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(10) See: Green, K. J. Org. Chem. 1991, 56, 4325.
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naphthalene 1 by bromination and selective bromine-lithium
exchange10 of 2 to yield the more stable monolithio species
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(14) Ee of 95% determined by HPLC (Whelk-O1).
(15) Stereochemistry of alkylated compounds exo-23b-d was deduced
from the X-ray crystal structures of exo-23b and exo-23d.
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832
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