Diels - Alder reaction - Aromatization approach toward functionalized ring C allocolchicinoids. Enantioselective total synthesis of (-)-7S-allocolchicine

Article abstract of DOI:10.1021/jo034420t

Allocolchicinoids are analogues of the important antimitotic compound (-)-colchicine 1. A strategy is reported for the synthesis of ring C functionalized allocolchicinoids, which is based on a Diels - Alder reaction - aromatization sequence. This route is complementary to the previously disclosed benzannulation approach involving Fischer carbene complexes and alkynes. Dienes 12 and 14 incorporate the natural substitution pattern on ring A and undergo Diels - Alder reactions with various dienophiles. Subsequent aromatization affords the set of differently functionalized ring C allocolchicinoids 15-19, 23, and 25, with high regioselectively and in moderate to good yields. An intramolecular Diels - Alder reaction - aromatization sequence allows for access to allocolchicinoids with reversed regiochemical introduction of ring C substituents. The equilibria of the atropisomers of 15 and 19 are studied in three NMR solvents. Reactions of the dienes 12 and 14 with DMAD lead to the corresponding cycloadducts, but the subsequent aromatization is complicated. A regioselective Diels - Alder reaction - aromatization sequence is utilized as the key step in the first stereoselective total synthesis of (-)-allocolchicine 2. Asymmetric introduction of hydroxy group at C7 is achieved by the enantioselective reduction of ketone 29. The correct stereochemistry is then established by Mitsunobu inversion reaction using Zn(N₃)₂-2Py.

Full text of DOI:10.1021/jo034420t

Diels-Ald er Rea ction -Ar om a tiza tion Ap p r oa ch tow a r d
F u n ction a lized Rin g C Allocolch icin oid s. En a n tioselective Tota l
Syn th esis of (-)-7S-Allocolch icin e
Andrei V. Vorogushin,†,‡ Alexander V. Predeus,† William D. Wulff,*,† and
Hans-J u¨rgen Hansen‡
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, and Institute of
Organic Chemistry, University of Zu¨rich, Winterthurerstrasse 190, CH-8057, Zu¨rich, Switzerland
wulff@cem.msu.edu
Received April 1, 2003
Allocolchicinoids are analogues of the important antimitotic compound (-)-colchicine 1. A strategy
is reported for the synthesis of ring C functionalized allocolchicinoids, which is based on a Diels-
Alder reaction-aromatization sequence. This route is complementary to the previously disclosed
benzannulation approach involving Fischer carbene complexes and alkynes. Dienes 12 and 14
incorporate the natural substitution pattern on ring A and undergo Diels-Alder reactions with
various dienophiles. Subsequent aromatization affords the set of differently functionalized ring C
allocolchicinoids 15-19, 23, and 25, with high regioselectively and in moderate to good yields. An
intramolecular Diels-Alder reaction-aromatization sequence allows for access to allocolchicinoids
with reversed regiochemical introduction of ring C substituents. The equilibria of the atropisomers
of 15 and 19 are studied in three NMR solvents. Reactions of the dienes 12 and 14 with DMAD
lead to the corresponding cycloadducts, but the subsequent aromatization is complicated. A
regioselective Diels-Alder reaction-aromatization sequence is utilized as the key step in the first
stereoselective total synthesis of (-)-allocolchicine 2. Asymmetric introduction of hydroxy group at
C7 is achieved by the enantioselective reduction of ketone 29. The correct stereochemistry is then
established by Mitsunobu inversion reaction using Zn(N3)2-2Py.
In tr od u ction
(-)-Colchicine 1 (Figure 1), the major alkaloid from
Colchicum autumnale, is one of the oldest known natural
products.1 It binds to the cytoskeletal protein tubulin,
disrupting the microtubule-dependent functions in the
cell and thereby suppressing the cell division process.2
Similarly, active compounds with an aryl ring C, such
as natural allocolchicine 2, N-acetylcolchinyl-O-methyl
ether 3, and their derivatives,3,4 are functional analogues
of colchicine. Some other colchicine analogues with five-
membered5 and eight-membered6 B rings, as well as
allocolchicinoids with the functionality at C7 moved to
C5,7 have been recently prepared but found not to affect
F IGURE 1. (-)-Colchicine and active allocolchicinoids.
the tubulin polymerization process, despite their close
structural similarity with the active allocolchicinoids. It
was also shown that any alteration to the trioxygenated
moiety of ring A leads to compounds with decreased
tubulin-binding ability.8 In contrast, the biological activ-
ity of ring C substituted allocolchicinoids varies with size,
position, and nature of the substituents.9,10 It was found
that only natural (-)-7S-colchicine 1, which adopts an
aR biaryl configuration, but not its 7R enantiomer, binds
effectively to tubulin. In solution, 7S-allocolchicinoids
exist in equilibrium between aR (major) and aS (minor)
† Michigan State University.
‡ University of Zu¨rich.
(1) (a) Capraro, H.-G.; Brossi. A. In The Alkaloids; Brossi, A. Ed.;
Academic Press: New York, 1984; Vol. 23, p 1 and references therein.
(b) Boye, O.; Brossi, A. In The Alkaloids; Brossi, A., Cordell, G. A.,
Eds.; Academic Press: New York, 1992; Vol. 41, p 125 and references
therein.
(2) Brossi, A. J . Med. Chem. 1990, 33, 2311 and references therein.
(3) Shi, Q.; Chen, K.; Brossi, A.; Verdier-Pinard, P.; Hamel, E.;
McPhail, A. T.; Lee, K.-H. Helv. Chim. Acta 1998, 81, 1023.
(4) Shi, Q.; Chen, K.; Chen, X.; Brossi, A.; Verdier-Pinard, P.; Hamel,
E.; McPhail, A. T.; Tropsha, A.; Lee, K.-H. J . Org. Chem. 1998, 63,
4018.
(5) Berg, U.; Bladh, H. Acta Chem. Scand. 1998, 52, 1380.
(6) Brecht, R.; Seitz, G.; Guenard, D.; Thoret, S. Bioorg. Med. Chem.
2000, 8, 557.
(7) Boye, O.; Brossi, A.; Yeh, H. J . C.; Hamel, E.; Wegrzynski, B.;
Toome, V. Can. J . Chem. 1992, 70, 1237.
(8) Banwell, M. G.; Cameron, J . M.; Collins, M. P.; Crisp, G. T.;
Gable, R. W.; Hamel, E. Aust. J . Chem. 1991, 44, 705.
(9) Banwell, M. G.; Fam, M.-A.; Gable, R. W.; Hamel, E. J . Chem.
Soc., Chem. Commun. 1994, 2647.
(10) Banwell, M. G.; Cameron, J .; Corbett, M.; Dupuche, J . R.;
Hamel, E.; Lambert, J . N.; Lin, C. M.; Mackay, M. F. Aust. J . Chem.
1992, 45, 1967.
10.1021/jo034420t CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/28/2003
5826
J . Org. Chem. 2003, 68, 5826-5831

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

Vorogushin et al.
SCHEME 3. Diels-Ald er Rea ction s of Dien e 12a
SCHEME 4. Attem p ted Rever sa l of
Regioch em istr y by Lew is Acid P a r ticip a tion
giving a mixture of Diels-Alder adducts. Upon treatment
with DBU in CH2Cl2, elimination of both phenylsufonyl
groups from these diastereomeric adducts can be achieved,
leading to the single aromatized product 17 in high
overall yield. Compounds 16 and 17 represent two new
classes of allocolchicinoids, arylsulfonyl-substituted and
unsubstituted on ring C, respectively. To the best of our
knowledge, such compounds have never been prepared
before. It is expected that their biological evaluation could
help establish the role of ring C substituents in binding
to tubulin.
It would also be important to explore the possibility of
a regio-reversed Diels-Alder reaction-aromatization
sequence, which would lead to the regioisomer of 15 and
thus allow access to a new class of allocolchicinoids with
substituents at C8 on ring C. We have envisioned that
the use of ethyl â-nitroacrylate21 would demonstrate the
reversed regiochemistry22 relative to methyl propiolate.
As it was anticipated, this strong dienophile readily
reacted with 12 at 80 °C, giving a mixture of Diels-Alder
adducts. After the elimination of nitrous acid by DBU
and the subsequent aromatization by DDQ one compound
mobile on TLC was observed. It was isolated in moderate
yield and identified as 18. To our surprise, the carboxy-
ethyl group in 18 was found to be in the C9 position, the
same as the carboxymethyl group in 15. Therefore, the
regiochemistry of the cycloaddition was controlled by
COOR group on the dienophile for reasons which are not
completely understood at the moment.
We then attempted to reverse the regiochemistry of the
cycloaddition of 12 and methyl propiolate by using
different Lewis acidic additives (1 equiv), which were
expected to coordinate to the C7 oxygen functionality of
diene 12 and also to the oxygen of the dienophile. This
should favor the regio-reversed products and therefore
the formation of 19 upon aromatization (Scheme 4).
Among the additives screened, the Lewis acids FeCl3,
TiCl4, SnCl4, Zn(OTf)2. Cu(OTf)2, Sc(OTf)3, Yb(OTf)3, and
La(OTf)3 led to the destruction of diene. Low conversion
to cycloadducts with concomitant dienophile polymeri-
zation was observed with Zr(O-i-Pr)4 and Ti(O-i-Pr)4 as
additives at 80 °C, but the regiochemistry of the product
was found to be the same as that without the Lewis acid.
a
Conditions: (i) (1) methyl propiolate, toluene, 110 °C, 24 h,
(2) DDQ, CH2Cl2, rt, 1 h; (ii) (1) TsCCH, toluene, 110 °C, 13 h, (2)
DDQ, toluene, 110 °C, 9 h; (iii) (1) trans-PhO2SCHdCHSO2Ph,
toluene, 140 °C, 15 h, (2) DBU, CH2Cl2, rt, 20 h; (iv) (1) trans-
O2NCHdCHCO2Et, THF, 80 °C, 24 h, (2) DBU, THF, rt, 4 h, (3)
DDQ, CH2Cl2, reflux, 2 h.
bromide 10 directly to diene 12 was taken by using the
Stille coupling reaction,18 which gives the diene in almost
quantitative yield. Despite the known problems associ-
ated with the separation of the Stille coupling products
from organotin byproducts, purification of 12 was achieved
by a single column chromatography.
A similar approach was taken toward the synthesis of
homologous diene 14. Reaction of the vinyllithium,
derived from 10 prepared according to the above proce-
dure, with acetone afforded, after workup, the tertiary
alcohol 13. Dehydration of 13 proceeded smoothly, giving
14 in good overall yield. As was the case for 5, alcohol
13 can also be used as an in situ source of diene 14 in
the subsequent Diels-Alder reactions.
Rea ction s of Dien e 12 w ith Va r iou s Dien op h iles.
Diels-Alder reaction of diene 12 with methyl propiolate
was performed at 110 °C, giving the adducts, which were
not isolated, but directly treated with DDQ. We were glad
to discover that the reaction proceeded with complete
regiocontrol, giving allocolchicinoid 15 as the only regio-
isomer (Scheme 3). It is likely that the steric interaction
of the approaching dienophile with the C7 functionality
in 12 was responsible for the regioselectivity, since
similar reaction with the C7-unsubstituted diene 6
proceeded without any regiocontrol (Scheme 1). The
substitution pattern of ring C in 15 matches that of
allocolchicine and other active allocolchicinoids, thus
opening the way toward their total synthesis.
Since a regio-reversed Diels-Alder reaction could not
be effected in an intermolecular fashion, we decided to
pursue this goal via an intramolecular Diels-Alder
reaction followed by aromatization and ring opening
(Scheme 5). For this purpose, diene 21 was prepared from
the corresponding bromide 2014 by Stille coupling in a
manner analogous to that of the synthesis of 12 from 10.
Coupling of 21 and propiolic acid was performed in the
The analogous reaction of diene 12 with tosyl-
acetylene19 proceeded at 110 °C to give, after DDQ
aromatization, the tosyl-substituted product 16, again
with complete regiocontrol. Cycloaddition of 12 and trans-
1,2-bis(phenylsulfonyl)ethylene20 took place at 140 °C,
(18) Farina, V.; Krishnamurthy, V.; Scott, W. J . Organic Reactions;
Wiley: New York, 1997; Vol. 50, p 1.
(19) Chen, Z.; Trudell, M. L. Synth. Commun. 1994, 24, 3149.
(20) De Lucchi, O.; Modena, G. Tetrahedron Lett. 1983, 24, 1653.
(21) McMurry, J . E. Musser, J . H. Organic Syntheses; Wiley: New
York, 1977; Vol. 56, p 65.
(22) Tanis, S. P.; Abdallah, Y. M. Synth. Commun. 1986, 16, 251.
5828 J . Org. Chem., Vol. 68, No. 15, 2003

Synthesis of Functionalized Ring C Allocolchicinoids
TABLE 1. Equ ilibr iu m of Rota m er s of Allocolch icin oid s
15 a n d 19 a t Room Tem p er a tu r e
SCHEME 5. P r ep a r a tion of Tetr a cyclic La cton e
23a
solvent
15
19
CDCl3
C6D6
CD3OD
10.5:1
12.0:1
12.7:1
2.5:1
2.0:1
2.9:1
SCHEME 7. Syn th esis of Con figu r a tion a lly Sta ble
Allocolch icin oid s 25a ,ba
a
Conditions: (i) (1) NBS, CCl4, reflux, 20 min, (2) NaHCO3,
DME/H2O, rt, 15 h; (ii) vinylSnBu3, 2% PdCl2, 4% PPh3, toluene,
80 °C, 4 h; (iii) propiolic acid, DCC, 10% DMAP, CH2Cl2, 0 °C, 10
min; (iv) (1) benzene, reflux, 60 h, (2) DDQ, benzene, rt, 1 h; (v)
(1) propiolic acid, toluene, 85 °C, 20 h, (2) DDQ, toluene, rt, 2 h.
SCHEME 6. Rin g Op en in g in La cton e 23a
a
Conditions: (i) silica gel, toluene, 165 °C; (ii) methyl propiolate,
toluene, 165 °C, 24 h; (iii) DDQ, benzene, reflux, 2 h.
SCHEME 8. Diels-Ald er Rea ction of Dien es 12, 14
w ith DMADa
a
Conditions: (i) 50% aq NaOH, EtOH, reflux, 1.5 h; (ii) 10%
aq HCl; (iii) (1) NaH (60% in oil), THF, reflux, 3 h, (2) Me2SO4,
THF, reflux 15 h.
presence of DCC and DMAP,23 giving the tethered
substrate 22 in moderate yield. Intramolecular Diels-
Alder reaction of 22 proceeded in refluxing benzene,
giving after DDQ aromatization the expected tetracyclic
lactone 23 in good yield. The only difficulty associated
with the described procedure was the separation of 22
from dicyclohexylurea, which required repeated column
chromatography. In an attempt to avoid the use of DCC,
alcohol 21 was heated at 85 °C with propiolic acid in a
“one-pot” approach to 23. We have reasoned that the
initial reaction between 21 and propiolic acid would
afford 22 under these conditions, followed by the intra-
molecular Diels-Alder reaction of 22. Indeed, the start-
ing alcohol was consumed in 44 h, giving the mixture of
adducts, which was cooled to room temperature and
treated with DDQ. Lactone 23 was the only product
isolated from the reaction mixture, albeit in the low yield,
which is probably due to the partial polymerization of
diene and dienophile during the reaction.
a
Conditions: (i) silica gel, toluene, 110 °C; (ii) DMAD, toluene;
R ) H: 100 °C, 15 h; R ) Me: 110 °C, 36 h.
As was mentioned in the Introduction, all known
allocolchicinoids exist in a solvent-dependent equilibrium
of rotameric forms. We have also observed such behavior
for the analogue 15 and its regioisomer 19. The ratio of
the two atropisomeric forms was measured in three NMR
solvents at room temperature (Table 1).
Contrary to previous observations with allocolchicine
derivatives,4 compounds 15 and 19 did not reveal a corre-
lation between the solvent polarity and the atropisomeric
ratio. Instead, the ratio strongly depended on the position
of the CO2Me group: the (aR,7S; aS,7R) isomer was
clearly the favored one for 15, whereas for 19 both
isomers appeared in comparable amounts.
P r ep a r a tion of Con figu r a tion a lly Sta ble Allo-
colch icin oid s. For those allocolchicinoids that are sub-
stituted at C11, an equilibrium between the atropisomers
would not be expected at room temperature. Synthetic
access to this class of compounds proved possible via
Diels-Alder reaction of diene 14. The Diels-Alder reac-
Opening of lactone ring in 23 was performed by
ethanolic NaOH solution (Scheme 6). The intermediate
sodium salt 24 did not give the corresponding carboxylic
acid upon neutralization, but reverted to the starting
lactone 23. However, when 24 was thoroughly dried and
methylated by NaH/Me2SO4, the expected allocolchicinoid
19 with the COOMe functionality at the C8 position was
obtained.
(23) Yamada, S.; Nagashima, S.; Takaoka, Y.; Torihara, S.; Tanaka,
M.; Suemune, H.; Aso, M. J . Chem. Soc., Perkin Trans. 1 1998, 1269.
J . Org. Chem, Vol. 68, No. 15, 2003 5829

Vorogushin et al.
SCHEME 9. Tota l Syn th esis of (-)-(7S)-Allocolch icin e 2a
a
Conditions: (i) TBDMSCl, imidazole, DMF, rt, 15 h; (ii) methyl propiolate, toluene, 110 °C, 20 h; (iii) DDQ, CH2Cl2, rt, 3 h; (iv)
TBAF-3H2O, THF, rt, 1.25 h; (v) NMO-H2O, 5% TPAP, MS 4 Å CH2Cl2, rt, 1 h; (vi) (1) TarB-NO2 (0.4 M in THF), LiBH4 (2 M in THF),
(2) H2O, H+; (vii) Ph3P, DIAD, Zn(N3)2-2Py, toluene, rt, 2 h; (viii) H2, 5% Pd/CaCO3/3.5% Pb, EtOH, rt., 30 h; (ix) Ac2O, Py, CH2Cl2, rt,
0.5 h.
tion of diene 14, generated in situ from 13, proceeded
with methyl propiolate at 165 °C, giving the intermediate
cycloadducts. After DDQ aromatization two atropisomeric
allocolchicinoids 25a ,b were isolated (Scheme 7). Analo-
gous to the reaction of 12 described above, complete
regiocontrol was also observed in this case, giving only
C9-carboxymethyl derivatives. Unfortunately, the reac-
tion showed no stereocontrol: 25a ,b were obtained as a
1:1 mixture. They could, however, be separated by
column chromatography. The relative stereochemistry of
25a ,b was assigned by comparison of their 1H NMR
spectra with those of the known allocolchicinoids, whose
structure had been previously secured by our group14 and
others4 using X-ray crystallographic analysis. The isola-
tion of the configurationally stable atropisomers 25a and
25b is an important step toward the understanding of
the role of axial configuration in binding to tubulin.
Allocolchicinoids 25a ,b will not undergo atropisomeriza-
tion at room temperature and thus, it will be possible to
separately evaluate their biological activity, revealing the
effect of the axial configuration on binding. These evalu-
ations are planned soon.
Diels-Ald er Rea ction s of Dien es 12 a n d 14 w ith
DMAD. The cycloaddition reaction between the isolated
diene 12 and diene 14, generated in-situ from 13, with
DMAD proceeded at 100-110 °C, giving the correspond-
ing Diels-Alder adducts 26a ,b and 27a ,b, respectively
(Scheme 8). Diastereomeric structures were tentatively
assigned to 26a ,b and 27a ,b (shown) based on COSY
and NOESY NMR experiments. To our surprise, aroma-
tization with DDQ failed to give the expected allocolchi-
cinoids, but rather generated mixtures of products with
low mass balance.
that the plan would include the generation of chiral
nonracemic alcohol (7R)-30 from ketone 29 by asym-
metric reduction. The synthesis begins with the protec-
tion of the OH group in diene 21 with TBDMS. This
group is supposed to function not only for protection
purposes, but also as an important element of regio-
control during the cycloaddition reaction. Indeed, the
Diels-Alder reaction of the protected diene with methyl
propiolate was complete in 20 h at 110 °C. Subsequent
DDQ aromatization afforded the protected allocolchici-
noid 28 as the only regioisomer in 79% yield. Deprotec-
tion by TBAF, followed by oxidation with N-methyl-
morpholine N-oxide (NMO) catalyzed by 5% tetrapropyl-
ammonium perruthenate (TPAP)24 gave ketone 29 in 76%
yield. Racemic (()-2 can be prepared from 29 by reductive
amination followed by acetylation (50% yield, unopti-
mized). We expected that CBS reduction25 of 29 would
furnish (7R)-30 in high yield and enantiomeric purity.
However, a maximum of 70% ee could be obtained in the
reduction of 29 with (S)-2-methyl-CBS-oxazaborolidine
and even then only when employed in equimolar amounts.
Kinetic resolution of racemic alcohol (()-30 by palladium-
catalyzed air oxidation26 proceeded with low selectivity
(s ) 2.9) and, therefore, is not synthetically useful.
Fortunately, a recently developed asymmetric method for
27
the reduction of ketones using TarB-NO2 was found
to afford alcohol (7R)-30 in better enantiomeric purity.
Thus, the reaction of 29 with 2 equiv of TarB-NO2 and
2.1 equiv of LiBH4 gave (7R)-30 in 97% yield and 91%
ee. Inversion of stereochemistry at C7 with concomitant
introduction of the nitrogen functionality was achieved
by Mitsunobu reaction with Zn(N3)2-2Py as azide source,28
giving (7S)-31 in 92% yield. Several methods were tested
for the reduction of (7S)-31 to the corresponding amine,29
including PPh3/H2O;29a SmI2;29b FeSO4-7H2O/NH3;29c H2
over 10% Pd/C,29d Pd/CaCO3,29e PtO2,29f Pd/BaSO4, 5% Pd/
Attempts to aromatize 26a ,b using o- and p-chloranil,
Pd/C, C2Cl6/t-BuOK, and Br2/CCl4, then DBU also met
with no success. The reason for such difficulties is not
clear, since both 7 and 15 have been readily prepared by
DDQ aromatization. Attempts are currently being made
to overcome this limitation.
Tota l Syn th esis of (-)-(7S)-Allocolch icin e. Our
synthetic approach involved the regioselective Diels-
Alder reaction of methyl propiolate with a protected form
of diene 21 as the key step (Scheme 9). We envisioned
(24) For a review, see: Ley, S. V.; Norman, J .; Griffith, W. P.;
Marsden, S. P. Synthesis 1994, 639.
(25) For a review, see: Corey, E. J .; Helal, C. J . Angew. Chem., Int.
Ed. 1998, 37, 1987.
(26) Ferreira, E. M.; Stolz, B. M. J . Am. Chem. Soc. 2001, 123, 7725.
(27) Suri, J . T.; Vu, T.; Hernandez, A.; Congdon, J .; Singaram, B.
Tetrahedron Lett. 2002, 43, 3649.
(28) Viaud, M. C.; Rollin, P. Synthesis 1990, 130.
5830 J . Org. Chem., Vol. 68, No. 15, 2003

Synthesis of Functionalized Ring C Allocolchicinoids
CaCO3/3.5% Pb. Heterogeneous hydrogenation over 5%
Pd/CaCO3/3.5% Pb was found to give the best results,
affording after reduction and acetylation (-)-(7S)-allo-
colchicine 2 in 77% yield and 89% ee. The enantiomeric
purity of 2 was improved to 99% ee by single recrystal-
lization. Compound 2 showed identical physical proper-
ties with natural allocolchicine (mp, spectroscopic data).
and with controlled variability of functionalization on
ring C. This strategy is complementary to the previously
described benzannulation approach which works best
in those cases where electron-releasing substituents on
ring C are desired. The strategy developed in present
work is used in the first stereoselective total synthesis
of (-)-(7S)-allocolchicine, accomplished in 10 steps and
13% overall yield from benzosuberone 4, which is readily
available in large scale (4 steps, ∼53%) from 3,4,5-
trimethoxybenzoic acid.
Con clu sion s
Regioselective Diels-Alder reactions of the dienes
incorporating the A and B rings of allocolchicines can be
achieved with a variety of dienophiles leading, after
aromatization, to the efficient construction of allocolchi-
cinoids. This is used in the synthesis of allocolchicine
analogues with natural substitution pattern on ring A
Ack n ow led gm en t. This work was supported by a
grant from the National Institutes of Health (NIH GM
33589). A.V. is grateful to the Swiss National Science
Foundation for the financial support of the collaborative
project. This work was carried out at both Michigan
State University and the University of Zu¨rich.
(29) (a) Vaultier, M.; Knouzi, N.; Carrie, R. Tetrahedron Lett. 1983,
24, 763. (b) Yi, Y.-P.; Chen, S.-Y.; Wang, Y.-G.; Chen, Y.-Z. Tetrahedron
Lett. 1999, 40, 1967. (c) Kamal, A.; Laxman, E.; Arifuddin, M.
Tetrahedron Lett. 2000, 41, 7743. (d) Lautens, M.; Rovis, T. J . Org.
Chem. 1997, 62, 5246. (e) Lakshman, M.; Nadkarni, D. V.; Lehr, R. E.
J . Org. Chem. 1990, 55, 4892. (f) Lakshman, M. K.; Chaturvedi, S.;
Lehr, R. E. Synth. Commun. 1994, 24, 2983.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O034420T
J . Org. Chem, Vol. 68, No. 15, 2003 5831