Synthesis of Functionalized Ring C Allocolchicinoids
SCHEME 1. Mod el Stu d iesa
forms. Although the 7R enantiomer of allocolchicine 2
does not interfere with tubulin polymerization, several
active 7R allocolchicinoids are known.3 It is still not clear
whether the aR,7S form or a small amount of the aS,7S
form, present in equilibrium, is active in the tubulin-
binding process.
Therefore, the preparation and biological evaluation
of configurationally stable allocolchicinoids would be
highly desirable. Very recently, three-dimensional quan-
titative structure-activity studies on colchicine ana-
logues have been initiated,11 demanding more such
compounds with predictable variability of functionaliza-
tion. To date, only a limited number of reports describe
synthetic pathways toward the preparation of allocolchi-
cinoids,9,12 and the vast majority of these compounds are
still being prepared from natural (-)-colchicine.
We have recently reported a strategy for the conver-
gent13 and stereoselective14 construction of ring C func-
tionalized allocolchicinoids based on the benzannulation
reaction of correctly substituted Fischer carbene com-
plexes with alkynes. However, since electron-deficient
acetylenes are known to be sluggish partners in the
benzannulation reaction,15 a complementary approach
was necessary to achieve the introduction of electron-
withdrawing substituents on ring C of allocolchicinoids.
a
Conditions: (i) (1) vinylMgBr, THF, 0 °C, 1 h, (2) H2O/H+; (ii)
MgSO4, benzene, reflux 2.5 h; (iii) (1) MgSO4, DMAD, benzene,
reflux 4 h, (2) DDQ, benzene, reflux 1 h; (iv) (1) silica gel, methyl
propiolate, toluene, 150 °C, 14 h, (2) DDQ, benzene, reflux 1.5 h.
SCHEME 2. Syn th esis of C7 F u n ction a lized
Dien esa
Resu lts a n d Discu ssion
We present herein our results on the way to allocolchi-
cinoids based on an approach that constructs the aro-
matic C-ring by a Diels-Alder reaction-aromatization
sequence. The viability of this strategy is demonstrated
by the preparation of differently substituted ring C
allocolchicine analogues and by the first total synthesis
of natural (-)-(7S)-allocolchicine.
Mod el Stu d ies. Initial studies were carried out with
diene 6, which lacked the substituent at C7. This diene
was prepared from the known benzosuberone 4 by the
addition of vinylmagnesium bromide, followed by dehy-
dration of the intermediate alcohol 5 (Scheme 1). The
alcohol 5 was used as a convenient in situ source of diene
6 for the subsequent reactions. Thus, treatment of 5 with
MgSO4 and dimethyl acetylenedicarboxylate (DMAD) in
refluxing benzene, followed by DDQ aromatization gave
C7 unfunctionalized allocolchicinoid 7.16 Similar reaction
of 5 with methyl propiolate was conducted at higher
temperature (150 °C), using silica gel to induce dehydra-
tion. As expected, subsequent DDQ aromatization of the
intermediate Diels-Alder adducts furnished almost
equimolar mixture of regioisomers 8a and 8b.
a
Conditions: (i) (1) 2-bromo-1,3,2-benzodioxaphosphole, Br2,
CH2Cl2, rt, 30 min, (2) 4 in CH2Cl2, 0 °C, 30 min, rt, 15 min, (3)
aq Na2CO3, 0 °C; (ii) (1) NBS, CCl4, reflux, 20 min, (2) NaHCO3,
MeOH, rt, 12 h; (iii) (1) t-BuLi, ether -78 °C, 15 min, (2) CH3CHO,
-78 °C to rt, 1.5 h, (3) H2O; (iv) Et3N+SO2N-CO2Me, benzene, rt,
30 min, 50 °C, 30 min; (v) vinylSnBu3, 2% PdCl2, 4% PPh3, toluene,
80 °C, 3.5 h; (vi) (1) t-BuLi, ether -78 °C, 15 min, (2) (CH3)2CO,
-78 °C to rt, 1 h, (3) H2O; (vii) MgSO4, benzene, reflux, 1.5 h.
can be prepared14 from benzosuberone 4 via vinyl bro-
mide 9 (Scheme 2). Metal-halogen exchange was per-
formed using t-BuLi, and the resulting organolithium
compound was immediately reacted with acetaldehyde,
giving intermediate alcohols 11. Dehydration of 11 using
acidic reagents or MgSO4 appeared problematic, since
competing elimination of C7 functionality was possible
under these conditions. Therefore, Burgess reagent
(Et3N+SO2N-CO2Me)17 was chosen for the generation of
diene 12. Although 12 was thus obtained, the low yield
of the overall transformation had prompted us to explore
other options for its preparation. The shortcut from
Syn t h esis of Dien es 12 a n d 14 Bea r in g t h e C7
Su bstitu en t. Preparation of the C7-functionalized diene
12 was envisioned starting from the bromide 10, which
(11) Zhang, S.-X.; Feng, J .; Kuo, S.-C.; Brossi, A.; Hamel, E.;
Tropsha, A.; Lee, K.-H. J . Med. Chem. 2000, 43, 167.
(12) Sawyer, J . S.; Macdonald, T. L. Tetrahedron Lett. 1988, 29,
4839.
(13) Vorogushin, A. V.; Wulff, W. D.; Hansen, H.-J . Org. Lett. 2001,
3, 2641.
(14) Vorogushin, A. V.; Wulff, W. D.; Hansen, H.-J . J . Am. Chem.
Soc. 2002, 124, 6512.
(15) Wulff, W. D.; Chan, K.-S.; Tang, P.-C. J . Org. Chem. 1984, 49,
2293.
(16) Compounds 7 and 8a ,b have been previously prepared using a
different route: Schreiber, J .; Leimgruber, W.; Pesaro, M.; Schudel,
P.; Threlfall, T.; Eschenmoser, A. Helv. Chim. Acta 1961, 65, 540.
(17) Burgess, E. M.; Penton, H. R.; Taylor, E. A.; Williams, W. M.
Organic Syntheses; Wiley: New York, 1977; Vol. 56, p 40.
J . Org. Chem, Vol. 68, No. 15, 2003 5827