structure of the left part plays a key role in the selectivity
and therapeutic efficacy of these drugs.3
Scheme 1a
This work reports a new synthesis of alkylating left-part
derivatives, involving a key photochemical cyclization of
stilbenoids developed by our group.5 It is exemplified by
the preparation of the furan-containing derivative 2.
Condensation of the LDA-generated anion of sulfone 36
with furaldehyde 4,7 leads to alcohol 5,8 which is obtained
as a single diastereomer of unknown but irrelevant stereo-
chemistry (Scheme 1). Oxidation with DDQ in hot chloro-
benzene yields ketone 6. Treatment with acetyl chloride and
triethylamine produces stilbenoid 7. Only one isomer on the
central double bond is obtained. As the ensuing photochemi-
cal irradiation produces a photostationary equilibrium of the
(E) and (Z) isomers, no effort was made to assign the
stereochemistry to stilbenoid 7. Irradiation with a medium-
pressure mercury lamp of this stilbenoid in a benzene
solution, with 1 equiv of iodine and excess propylene oxide
leads to 91% furoindol 8.9 Propylene oxide is used to destroy
the generated HI. The tosyl substituent on stilbenoid 7
imparts an electron deficiency that protects stilbenoid 7
against unwanted oxidations during this photochemical
reaction. We wish to note the high yield obtained in this
key photochemical reaction of a molecule with a dense
functionality.
Deprotection of the MOM group with formic acid,
followed by treatment with magnesium in methanol, produces
the removal of the tosyl group and deacetylation of the
phenol. The resulting furoindol 10 was reduced to the
corresponding furoindoline 11 by ionic hydrogenation with
Et3SiH in trifluoroacetic acid. The unstable furoindoline 11
was immediately protected on the nitrogen with Boc
anhydride. Silylation of the phenol with TBDMSCl, followed
by regioselective reduction of the aliphatic ester with LiAlH4
at -78 °C, led to the alcohol 14. This alcohol was treated
with triphenylphosphine in CCl4, yielding the key substrate
15, which contains a silicon-protected phenol and a chloride.
Treatment of compound 15 with TBAF in chloroform led
to the desilylation and simultaneous formation of the
cyclopropane ring.10 We believe that the nascent phenoxide,
(4) (a) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A.
Chem. ReV. 1997, 97, 787-828. (b) Patel, V. F.; Andis, S. L.; Enkema, J.
K.; Johnson, D. A.; Kennedy, J. H.; Mohamadi, F.; Schultz, R. M.; Soose,
D. J.; Spees, M. M. J. Org. Chem. 1997, 62, 8868-8874. (c) Muratake,
H.; Okabe, K.; Takahashi, M.; Tonegawa, M.; Natsume, M. Chem. Pharm.
Bull. 1997, 45, 799-806. (d) Muratake, H.; Hayakawa, A.; Natsume, M.
Tetrahedron Lett. 1997, 43, 7577-7580. (e) Atwell, G. J.; Tercel, M.; Boyd,
M.; Wilson, W. R.; Denny, W. A. J. Org. Chem. 1998, 63, 9414-9420. (f)
Boger, D. L.; Boyce, C. W. J. Org. Chem. 2000, 65, 4088-4100. (g) Boger,
D. L.; Santilla´n, A.; Searcey, M.; Brunette, S. R.; Wolkenberg, S. E.;
Hedrick, M. P.; Jin, Q. J. Org. Chem. 2000, 65, 4101-4111. (h) Castedo,
L.; Delamano, J.; Enjo, J.; Ferna´ndez, J.; Gra´valos, D. G.; Leis, R.; Lo´pez,
C.; Marcos, C. F.; R´ıos, A.; Tojo, G. J. Am. Chem. Soc. In press.
(5) Antelo, B.; Castedo, L.; Delamano, J.; Go´mez, A.; Lo´pez, C.; Tojo,
G. J. Org. Chem. 1996, 61, 1188-1189.
a (i) LDA, THF, -78 to -50 °C, 90%; (ii) DDQ, chlorobenzene,
reflux, 82%; (iii) ClAc, Et3N, CH2Cl2, -40 °C; 97%; (iv) hν, I2,
PO, benzene, 91%; (v) HCOOH, 96%; (vi) Mg, MeOH, 70%; (vii)
Et3SiH, F3CCO2H, 82%; (viii) Boc2O, DMAP, CH2Cl2, 81%; (ix)
TBDMSCl, imidazole, DMF, 98%; (x) LiAlH4, THF, -78 °C, 79%;
(xi) Ph3P, CCl4, CH2Cl2, 98%; (xii) n-Bu4NF, CHCl3, 100%.
produced after the fluoride attack on the silicon, cyclizes to
compound 2, before it completely detaches from the silicon,
as the treatment of the corresponding phenol with TBAF or
with other bases does not produce compound 2.
(6) Castedo, L.; Delamano, J.; Lo´pez, C.; Lo´pez, M. B.; Tojo, G.
Heterocycles 1994, 38, 495-502.
(7) (a) Garc´ıa Gonza´lez, F. AdV. Carbohydr. Chem. 1956, 11, 97. (b)
Rosenkranz, R. E.; Allner, K.; Good, R.; Philipsborn, W. v.; Eugster, C.
H. HelV. Chim. Acta 1963, 46, 1259.
1
(8) New compounds are characterized at least by H and 13C NMR, EI
or FAB mass spectra, and combustion analysis or HRMS.
(9) Longin, L.; Bingwei, Y.; Katz, T. J.; Poindexter, M. K. J. Org. Chem.
1991, 56, 3769-3775.
(10) (a) Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H.; Kitos, P. A.;
Suntornwat, O. J. Org. Chem. 1990, 55, 4499-4502. (b) Wang, Y.; Gupta,
R.; Huang, L.; Lown, J. W. J. Med. Chem. 1993, 36, 4172-4182.
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Org. Lett., Vol. 3, No. 9, 2001