Dearomatizing cyclization of arylsulfonylalkoxymethyl lithiums: A route to the podophyllotoxin skeleton

Article abstract of DOI:10.1021/ol0340585

(Matrix presented) The phenylsulfonyl group promotes the dearomatizing cyclization of tethered organolithiums onto aromatic rings. With an ether tether, the cyclizations create a new tetrahydrofuran ring, and both cyclization and subsequent electrophilic

Full text of DOI:10.1021/ol0340585

ORGANIC
LETTERS
2003
Vol. 5, No. 6
831-834
Dearomatizing Cyclization of
Arylsulfonylalkoxymethyl Lithiums:
A Route to the Podophyllotoxin
Skeleton
Jonathan Clayden,* Martin N. Kenworthy, and Madeleine Helliwell
Department of Chemistry, UniVersity of Manchester, Oxford Road,
Manchester M13 9PL, U.K.
j.p.clayden@man.ac.uk
Received January 13, 2003
ABSTRACT
The phenylsulfonyl group promotes the dearomatizing cyclization of tethered organolithiums onto aromatic rings. With an ether tether, the
cyclizations create a new tetrahydrofuran ring, and both cyclization and subsequent electrophilic quenches proceed with high levels of
diastereoselectivity. The sulfonyl group can be removed from the cyclized products oxidatively or reductively. The dearomatizing cyclization
of a naphthyl sulfone was used in the synthesis of a close structural analogue of podophyllotoxin.
Dearomatizing additions to aromatic systems1 allow the
stereocontrolled formation of cyclohexene and cyclohex-
anone derivatives with regiocontrol offered by aromatic
substitution chemistry and with stereochemistry controlled
in the addition step. While Birch reduction generates
nucleophilic partially saturated arene derivatives that react
with electrophiles,2 polarity-reversed synthetic equivalents
to the Birch reduction in which nucleophiles are added to
electrophilic3 aromatic (particularly naphthyl) rings are also
known. When the nucleophile is intramolecular, a dearoma-
tizing cyclization reaction ensues,4,5 allowing the stereo-
selective synthesis of ring-fused molecules. We used dearo-
D.; Barner, B. A.; Laucher, D. J. Am. Chem. Soc. 1988, 110, 4611. Meyers,
A. I.; Lutomski, K. A.; Laucher, D. Tetrahedron 1988, 44, 3107. Shimano,
M.; Meyers, A. I. J. Am. Chem. Soc. 1994, 116, 6437. Gant, T. G.; Meyers,
A. I. Tetrahedron 1994, 50, 2297. Esters: Shindo, M.; Koga, K.; Asano,
Y.; Tomioka, K. Tetrahedron 1999, 55, 4955. Carboxylates: Plunian, B.;
Mortier, J.; Vaultier, M.; Toupet, L. J. Org. Chem. 1996, 61, 5206.
Amides: Clayden, J.; Frampton, C. S.; McCarthy, C.; Westlund, N.
Tetrahedron 1999, 55, 14161. Clayden, J.; Foricher, Y. J. Y.; Lam, H. K.
Chem. Commun. 2002, 2138. Clayden, J.; Foricher, Y. J. Y.; Lam, H. K.
Eur. J. Org. Chem. 2002, 3558. Nitriles: Sanchez, C. M. A.; Iglesias, M.
J.; Ortiz, F. L. Tetrahedron Lett. 2002, 43, 2565. Imines: Meyers, A. I.;
Brown, J. D.; Laucher, D. Tetrahedron Lett. 1987, 28, 5279 and 5283.
Metals: Maruoka, K.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1995,
117, 9091. Pape, A. R.; Kaliappan, K. P.; Ku¨ndig, E. P. Chem. ReV. 2000,
100, 2917. Bao, M.; Nakamura, H.; Yamamoto, Y. J. Am. Chem. Soc. 2001,
123, 759.
(1) Bach, T. Angew. Chem., Int. Ed. 1996, 35, 729. Mander, L. N. Synlett
1991, 134.
(2) Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1. Donohoe,
T. J.; Garg, R.; Stevenson, C. A. Tetrahedron: Asymmetry 1996, 7, 317.
Schultz, A. G. Chem. Commun. 1999, 1263.
(3) For additions to unactivated naphthalene, see: Dixon, J. A.; Fishman,
D. H.; Dudinyak, R. S. Tetrahedron Lett. 1964, 5, 613. See the following
for dearomatizing addition to rings activated by the substituents indicated.
Sulfones: Stoyanovich, F. M.; Karpenko, R. G.; Gol’dfarb, Y. L.
Tetrahedron 1971, 27, 433. Oxazolines: Meyers, A. I.; Roth, G. P.; Hoyer,
(4) For a review of organolithium cyclization, see: Clayden, J. Orga-
nolithiums: SelectiVity for Synthesis; Pergamon: Oxford, 2002; pp 282-
335. Mealy, M. J.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59.
10.1021/ol0340585 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/26/2003

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-
Ortiz, F. L.; Tejerina, B.; Granda, S. G. Org. Lett. 2001, 3, 1339. Go´mez,
G. R.; Ortiz, F. L. Synlett 2002, 781. Ferna´ndez, I.; Ortiz, F. L.; Velazquez,
A. M.; Granda, S. G. J. Org. Chem. 2002, 67, 3852. Nishiwaki, K.; Ogawa,
T.; Matsuo, K. Angew. Chem., Int. Ed. 2002, 41, 484.
(6) Clayden, J.; Tchabanenko, K. Chem. Commun. 2000, 317. Clayden,
J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002, 58, 4727. Ahmed,
A.; Bragg, R. A.; Clayden, J.; Tchabanenko, K. Tetrahedron Lett. 2001,
42, 3407. Bragg, R. A.; Clayden, J.; Bladon, M.; Ichihara, O. Tetrahedron
Lett. 2001, 42, 3411.
(7) Clayden, J.; Kenworthy, M. N. Org. Lett. 2002, 4, 787.
(8) Breternitz, H.-J.; Schaumann, E.; Adiwidjaja, G. Tetrahedron Lett.
1991, 32, 1299; Crandall, J. K.; Ayers, T. A. J. Org. Chem. 1992, 57, 2993.
Padwa, A.; Filipkowski, M. A.; Kline, D. N.; Murphree, S. S.; Yeske, P.
E. J. Org. Chem. 1993, 58, 2061. Aggarwal, V. K.; Ferrara, M. Org. Lett.
2000, 2, 4107. Aggarwal, V. K.; Alonso, E.; Ferrara, M.; Spey, S. E. J.
Org. Chem. 2002, 67, 2335.
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.
(9) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon: Oxford,
1993.
(10) See: Green, K. J. Org. Chem. 1991, 56, 4325.
(11) Seitz, D. E.; Carroll, J. J.; Cartaya, C. P.; Lee, S.-H.; Zapata, A.
Synth. Commun. 1983, 13, 129.
naphthalene 1 by bromination and selective bromine-lithium
exchange10 of 2 to yield the more stable monolithio species
3. Formylation with DMF, reduction to 5, and protection
(12) Prasad, K. R. K.; Joshi, N. N. Tetrahedron: Asymmetry 1996, 7,
3147.
(13) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(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.
(5) Ahmed, A.; Clayden, J.; Rowley, M. Chem. Commun. 1998, 297.
Ahmed, A.; Clayden, J.; Yasin, S. A. Chem. Commun. 1999, 231. Clayden,
J.; Tchabanenko, K.; Yasin, S. A.; Turnbull, M. D. Synlett 2001, 302.
Clayden, J.; Menet, C. J.; Mansfield, D. J. Org. Lett. 2000, 2, 4229. Clayden,
J.; Menet, C. J.; Mansfield, D. J. Chem. Commun. 2002, 38. Ferna´ndez, I.;
832
Org. Lett., Vol. 5, No. 6, 2003

Scheme 2. DearomatizIng Cyclizationsa
Figure 1. X-ray crystal structures of cyclized sulfones.
exploited, it can be disposed of by oxidation, reduction, or
elimination.9 Scheme 3 shows some representative reductive
and oxidative transformations of cyclized sulfones 23 and
27. The sulfonyl group of both exo and endo sulfones appears
Scheme 3. Desulfonylations of the Productsa
a Reagents: (i) MeLi, TMEDA, THF, -78 °C; (ii) E+ ) NH4Cl
(-78 °C) or MeOH (from -78 to 20 °C), MeI, allyl bromide or
b
c
BnBr; (iii) 2 M HCl (aq). From NH4Cl quench. From MeOH
quench.
mediate 25 was alkylated. Good yields of single diastereo-
isomers of the stable enol ethers exo-26b-d were obtained,
in which the methyl group R to oxygen occupies the exo
face during the cyclization and the sulfone adopts the exo
face during the alkylation. As with 18, protonation with NH4-
Cl returned diastereoisomer exo-26a, which hydrolyzed to
give ketone exo-27 (97% ee), while protonation by warming
with MeOH gave predominantly a different (presumably
endo) diastereoisomer of the enol ether 26, which hydrolyzed
to give mainly the ketone endo-27 (94% ee) bearing the
sulfonyl group on the endo face.16 Figure 1c,d shows the
X-ray crystal structures of exo- and endo-27.
a Reagents: (i) LiBHEt3, THF; (ii) NaBH4, MeOH; (iii) Na/Hg,
MeOH, Na2HPO4; (iv) i-Pr3SiOTf, lutidine, CH2Cl2, 0 °C, 72%.
(v) (1) n-BuLi, THF, -78 °C; (2) MoO5‚py‚DMPU (“MoOPD”),
THF, 72% (99% based on recovered starting material, which is
enriched in 28a). b28b made by LiBHEt3 reduction of exo-23a and
not isolated before protection. Only 28b was silylated; 28a was
removed as an alcohol.
Sulfones are valuable synthetic intermediates because once
the anion-stabilizing ability of the sulfonyl group has been
(16) Ee of exo-27 was deduced from the ee of an enone byproduct formed
in 34% yield by 5-endo-trig retro-Michael elimination of alkoxide from
exo-27. An X-ray crystal structure of this byproduct confirmed the absolute
stereochemistry of 19 and 24-27. The ees of this byproduct and of endo-
27 were determined by HPLC (Whelk-O1).
Org. Lett., Vol. 5, No. 6, 2003
833

to give 29. Oxidative removal of the sulfone18 was also
possible, and the lithio derivative of a protected form of
sulfone 28b reacted cleanly with the DMPU equivalent of
MoOPH (“MoOPD”)19 to yield ketone 30.
Scheme 4. Synthesis of the Core Skeleton of Podophyllotoxina
The 6,6,5-tricyclic system present in these desulfonylated
products is also found in lignan and alkaloid natural products
such as podophyllotoxin 4220 and himbacine 43.21 We were
able to convert 30 into a known skeletal analogue 4022 of
podophyllotoxin, with full relative stereochemical control.
Conversion of ketone 30 to the enol triflate 3523 allowed
us to introduce the aryl substituent of 36 by a Suzuki
coupling.24 Oxidation of this allylic ether was attempted
under a number of conditions, and the most successful
method we found was to deprotonate 36 with t-BuLi,
oxidizing the anion with Davis’ oxaziridine25 to yield the
aldehyde 37. Careful hydrogenation (over-reduction was
always a problem) of 37 gave trans hemiacetal 38 with
introduction of hydrogen trans to the bulky i-Pr3SiO group
and perhaps also directed syn by the primary alcohol.
Oxidation to the lactone with pyridinium chlorochromate and
deprotection with HF-pyridine yielded 40,26 a structural
analogue of the core tetracycle of podophyllotoxin. Depro-
tection under more basic conditions (Bu4NF, THF) caused
a precedented27 epimerization R to the lactone carbonyl and
gave 41, an analogue of picropodophyllin.20
a Reagents: (i) (1) LiHMDS, THF, -78 °C; (2) 5-chloropy-
ridylNTf2, THF, from -78 to 20 °C, 91% (97% based on recovered
starting material). (ii) PhB(OH)2, Pd(PPh3)4, K3PO4, KBr, dioxane,
90 °C, 90%. (iii) (1) t-BuLi, THF, -78 °C; (2) Davis’ oxaziridine
(PhCH(O)NTs), THF, 56% (69% based on recovered starting
material); (iv) H2, Pd/C, EtOH, 57% + 27% diol from over-
reduction; (v) PCC, CH2Cl2, 72%; (vi) HF:py, MeCN, 62%; (vii)
Bu4NF, THF, 72%.
Acknowledgment. We are grateful to the EPSRC and to
Knoll-BASF Pharma for support.
Supporting Information Available: Experimental pro-
cedures and characterization for new compounds and X-ray
data for exo-23a, endo-23, exo-27, endo-27. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0340585
to shield very effectively one face of the ketone (see Figure
1), allowing stereoselective reduction of exo- and endo-23a
to 28a and 28b,17 respectively, and of exo-23d to 31. In the
reduction of endo-27 with lithium triethylborohydride,
epimerization of the endo sulfone to exo competed with the
reduction and gave a mixture of diastereoisomers 33.
Desulfonylation of 31 and 33 with sodium amalgam gave
good yields of the tricyclic alcohols 32 and 34; direct
reduction of the ketosulfone exo-23a promoted both de-
sulfonylation and nonstereoselective reduction of the ketone
(18) Chemla, F. J. Chem. Soc., Perkin Trans. 1 2002, 275.
(19) Little, R. D.; Myong, S. O. Tetrahedron Lett. 1980, 21, 3330.
Anderson, J. C.; Smith, S. C. Synlett 1990, 107.
(20) Ayres, D. C.; Loike, J. D. Lignans; Chemical, Biological and
Clinical Properties; Cambridge University Press: Cambridge, 1990. An-
drews, R. C.; Teague, S. J.; Meyers, A. I. J. Am. Chem. Soc. 1988, 110,
7854.
(21) Takadoi, M.; Katoh, T.; Ishiwata, A.; Terashima, S. Tetrahedron
Lett. 1999, 40, 3399
(22) Macdonald, D. I.; Durst, T. J. Org. Chem. 1988, 53, 3663. Charlton,
J. L.; Plourde, G. L.; Koh, K.; Secco, A. S. Can. J. Chem. 1990, 68, 2022
(23) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(24) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201.
(25) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703.
(26) Spectroscopic data for this compound agreed with the literature:
see ref 22.
(17) Alcohol 28a has the relative stereochemistry (proved by the X-ray
crystal structure) of epipodophyllin, the lignan component of the drug’s
etoposide and teniposide (see ref 20)
(27) Bertounesque, E.; Imbert, T.; Monneret, C. Tetrahedron 1996, 52,
14235.
834
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