Utilization of the versatility of sulfur in C-C bond formation and cleavage: Synthesis of ABC taxoid skeletons

Article abstract of DOI:10.1002/ejoc.200700301

A practical and convenient five-step protocol is described to access the ABC ring system of Taxol by utilizing the versatility of the sulfur atom in its various oxidation states viz., condensation/Pummerer cyclization/coupling/ annulation/fragmentation. W

Full text of DOI:10.1002/ejoc.200700301

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700301
Utilization of the Versatility of Sulfur in C–C Bond Formation and Cleavage:
Synthesis of ABC Taxoid Skeletons
Subhash P. Chavan,*[a] Sambhaji P. Chavan,[a] Harikisan R. Sonawane,[a]
Uttam R. Kalkote,[a] Surendra G. Sudrik,[a] Rajesh G. Gonnade,[a] and
Mohan M. Bhadbhade[a]
Keywords: Rearrangement / C–C coupling / Metalation / Ring expansion / Isomerization
A practical and convenient five-step protocol is described to
access the ABC ring system of Taxol by utilizing the versatil-
ity of the sulfur atom in its various oxidation states viz., con-
densation/Pummerer cyclization/coupling/annulation/frag-
mentation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
rings, and to test our idea we chose Taxol®. Thus, the 6-8-
6 ABC ring system 2 of Taxol® was envisioned to arise from
the tetracyclic intermediate 3 (Scheme 1). The key precursor
could be constructed by intramolecular ring annulation of
compound 4, which in turn could be derived by alkylation
of the bicyclic system 5. We report herein our successful
preliminary results for the preparation of the ABC ring tax-
ane skeleton by a lead tetraacetate mediated oxidative frag-
mentation reaction of 3 as the key step.[4] This indirect
method of construction of the central eight-membered B-
ring circumvents the well-known problem of the high de-
gree of ring strain and the transannular interactions associ-
ated with cyclooctane annulations.[5]
Introduction
Taxol®, the best-selling anti-cancer drug, has attracted
the attention of organic chemists, biologists, medicinal
chemists and pharmacologists for the past two decades
owing to its unique structural framework, unique mecha-
nism of action towards cancer tumor cells, limited supplies,
and difficulties in the formulation of the drug (Figure 1).[1]
Taxol®, a tetracyclic diterpenoid was isolated from the bark
of a slow-growing Pacific yew tree (Taxus brevifolia), and its
structure was elucidated by Wall and Wani.[2] Tremendous
efforts towards its synthesis have been made during the last
two decades by organic chemists, which have so far resulted
in six elegant and successful total syntheses of this mole-
cule.[3]
Figure 1. Taxol® (1).
The main challenge in the Taxol® synthesis lies in the
construction of the sterically congested central eight-mem-
bered B-ring, bridgehead double bond and dense pattern
of oxygenated functionality present at the periphery of the
molecule. In this context, we have devised a novel sulfur-
assisted synthetic protocol to access fused medium-sized
Scheme 1. Retrosynthesis.
Results and Discussion
[a] Division of Organic Chemistry: Technology, National Chemical
Laboratory
The bicyclic system
5 was prepared as follows
Pune 411008, India
Fax: +91-020-25902629
E-mail: sp.chavan@ncl.res.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
(Scheme 2). A-ring ester 7 was prepared in 75% yield by
classical Diels–Alder strategy[6] using 2,4-dimethyl-1,3-pen-
tadiene and methyl acrylate. The A-ring ester 7 was acylated
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S. P. Chavan et al.
SHORT COMMUNICATION
with dimsylsodium[7] to form β-oxo sulfoxide 8 in 70% cleavage as reported by Trost[12] in a norbornane system. To
yield. Pummerer reaction[8] on β-oxo sulfoxide 8 furnished the best of our knowledge this elegant methodology re-
the bicyclic ring system 5 as inseparable diastereomeric and mained largely unexplored and was never used for the syn-
regioisomeric mixture in 60% yield. The formation of 5 as thesis of any medium- to large-sized ring. Therefore, we de-
a mixture of four isomers during the Pummerer cyclization cided to exploit this methodology for the synthesis of the
of 8 was surprising in view of the fact that in a similar cyclooctane ring by fragmentation of the tetracyclic com-
substrate lacking the two geminal methyl groups, the forma- pound 11. Accordingly, compound 11 was subjected to
tion of a single bicyclic isomer with an exocyclic double treatment with LTA. The IR, 1H NMR and 13C NMR spec-
bond and endo-oriented –SCH3 group was reported.[8] tra of 12 support the formation of a fragmented product
Thus, formation of four isomers in our case may be attrib- and the GC-MS data reveal two peaks in an almost 1:1
uted to steric hindrance by the two geminal methyl groups. ratio, each having the same [M+] peak in its mass spectrum
Although a mixture of isomers was obtained, it was decided with similar fragmentation patterns.
to carry forward with them since the steoreogenic center
Though success was achieved in obtaining the ABC skel-
would be destroyed subsequently as delineated in the retro- eton of the taxane system 12, it was obtained as an insepa-
synthesis (Scheme 1), whereas the olefinic isomers could be rable mixture of exo and endo double bond isomers. The
easily equilibrated to a single isomer (vide infra).
next task was to isomerize the double bond. Amongst the
array of known methods for olefin isomerization, the one
involving rhodium trichloride[13] appeared best suited to
our needs. Therefore, compound 12 was isomerized with a
catalytic amount of rhodium trichloride to deliver the ther-
modynamically more stable endo olefin 13 in 80% yield.
1
The H NMR, 13C NMR and GCMS spectroscopic data
clearly reveal the formation of the C-aromatic ABC ring
system 13 of Taxol®. Further, single-crystal X-ray crystal-
lography of compound 13 provided the unambiguous evi-
dence and vindicated the assigned structure (Figure 2).[14]
Scheme 2. Synthesis of the C-aromatic ABC taxane system:
a) dimsylsodium, THF, 0 °C to room temp., 70%; b) (CF3CO)2O,
dichloromethane, 50 °C, 3 h, 60%; c) i. NaH, THF, 0 °C, 1 h, ii. o-
iodobenzyl bromide (9), THF, 0 °C to room temp., 70%; d) nBuLi,
THF, –78 °C, 3 h, 80%; e) Pb(OAc)4, PhCH3/AcOH (4:1), 0 °C,
6 h, 75%; f) RhCl3·3H2O, EtOH, 80 °C, 24 h, 80%.
The bicyclic system 5 was alkylated with o-iodobenzyl
bromide (9) to afford 10 in 70% yield (Scheme 2).
The key tetracyclic intermediate 11 was prepared by in-
tramolecular metal/halogen exchange methodology.[9] Thus,
addition of nBuLi to 10 afforded the tetracyclic compound
11 in 80% yield.[10] Having secured the requisite 6-5-5-6
skeleton, the next task was to unmask the eight-membered
ring to access the 6-8-6 skeleton. This could be readily Figure 2. ORTEP view of 13.
achieved by cleaving the bond shared by the two five-mem-
bered rings bearing heteroatoms as the handle. The obvious
After successful synthesis of the C-aromatic ABC skel-
choice of accomplishing the cleavage of the vicinal thioether eton, we focused our attention towards the synthesis of
alcohol was a photo-induced electron transfer.[11] However, more advanced taxoids. To this end, a C-alicyclic ABC skel-
in our hands the photochemical cleavage of 11 was unsuc- eton of the taxane system was the immediate target.
cessful and the starting material remained unchanged. Hav-
Therefore, we needed the appropriate alicyclic C-ring
ing failed to cleave the bond photochemically, the next op- unit 14 which was readily prepared from cyclohexanone ac-
tion available was the lead tetraacetate (LTA) mediated cording to a reported procedure.[15] Having secured the 1-
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Synthesis of ABC Taxoid Skeletons
SHORT COMMUNICATION
bromo-2-(bromomethyl)cyclohex-1-ene (14), it was coupled NMR and 13C NMR spectroscopic data support the as-
with the bicyclic ring system 5 to obtain 15 in 70% yield signed structure. Here too, GC-MS data reveal that the C-
(Scheme 3). The next step, a five-membered ring annulation alicyclic ABC taxane system 17 exists as a mixture (1:1) of
was carried out by using the metal/halogen exchange meth- exo/endo double-bond isomers. Therefore, 17 was iso-
odology. Thus, addition of sBuLi to 15 delightfully afforded merized with catalytic amounts of rhodium trichloride and
the tetracyclic compound 16 in 60% yield. The IR, 1H para-toluenesulfonic acid to furnish 18 in 80% yield.[16] The
NMR, 13C NMR spectra support the assigned structure. 1H NMR, 13C NMR spectroscopic data support the as-
The GC-MS data of 16 reveal two major and two minor signed structure 18. Further, the structure was unambigu-
peaks (5.0:1.0:1.8:10.0) whose corresponding mass spectral ously assigned by X-ray crystallography (Figure 3).[17]
analysis exhibits similar fragmentation patterns with the
same molecular ion peak at m/z = 304. After having suc-
Conclusions
cessfully achieved the five-membered ring annulation to
form the 6-5-5-6 fused system, the next task was to unmask
the eight-membered ring which was achieved by LTA to
afford the fragmented product 17 in 75% yield. The IR, 1H
We have demonstrated a concise, simple, practical and
convenient route to access the C-aromatic as well as the
C-alicyclic ABC ring system of Taxol® with differentiated
carbonyl groups for further elaborations, using cheap and
readily available starting materials. No functional group
protection/deprotection steps were required in the synthetic
sequence. The salient feature of this protocol is the versatile
role played by sulfur, in C–C bond formation as well as
in cleavage, in its various oxidation state viz., (i) sulfoxide-
stabilized anion in the C–C bond formation to furnish the
β-oxo sulfoxide, (ii) sulfoxide-mediated intramolecular
Pummerer cyclization forming the bicyclic compound (C-
10–C-11 bond), (iii) as α-oxo sulfide, stabilizing the enolate,
in forming the coupled product during alkylation (C-9–C-
10 bond), and (iv) pivotal lead tetraacetate cleavage of the
β-methyl sulfide alcohol (C-2–C-10 bond) leading to the
formation of the vinyl sulfide group (masked ketone). Liter-
ally, sulfur acted as a vehicle for vital formations and frag-
mentations of C–C bonds to deliver the ABC ring skeleton
of Taxol®. We believe that this practical five-step protocol,
i.e. condensation/Pummerer cyclization/coupling/annulation/
fragmentation will deliver a large number of advanced
taxoids as well as fused ring systems whose further elabora-
tion may lead to complex fused natural products. The
success of the above protocol will provide impetus for the
synthesis of the more complicated CD ring system and its
conversion to more advanced taxoids. The work in this di-
rection is in progress in our laboratory and will be commu-
nicated in due course.
Scheme 3. Synthesis of the C-alicyclic ABC taxane system: a) i.
NaH, THF, 0 °C, 1 h; ii. 14, THF, 0 °C (1 h) to room temp. (8 h),
70%; b) sBuLi, THF, –100 °C, 3 h, 60%; c) Pb(OAc)4, PhCH3/
AcOH (4:1), 0 °C, 6 h, 75%; d) RhCl3·3H2O, p-toluenesulfonic
acid, EtOH, 80 °C, 24 h, 80%.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, full spectroscopic data of all new
compounds along with 1H NMR, 13C NMR, DEPT and GC-mass
spectra.
Acknowledgments
We thank Professor K. K. Balasubramanian for providing the ex-
perimental procedure and spectroscopic data of 14. S. P. C. thanks
the Council of Scientific and Industrial Research (CSIR), New
Delhi, India for the award of a fellowship.
[1] D. G. I. Kingston, Chem. Commun. 2001, 867–880.
[2] M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggon, A. T.
McPhail, J. Am. Chem. Soc. 1971, 93, 2325–2327.
[3] a) K. C. Nicolaou, Z. Yang, J. J. Liu, H. Ueno, P. G. Nanter-
met, R. K. Guy, C. F. Claiborne, J. Renaud, E. A. Coula-
Figure 3. ORTEP view of 18.
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www.eurjoc.org
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S. P. Chavan et al.
[8] L. N. Mander, P. H. C. Mundill, Synthesis 1981, 620–622.
[9] a) H. R. Sonawane, D. K. Maji, G. H. Jana, G. Pandey, Chem.
Commun. 1998, 1773–1774; b) E. Akgun, M. B. Glinski, K. L.
Dhawan, T. Durst, J. Org. Chem. 1981, 46, 2730–2734; c) C. A.
Hergrueter, P. D. Brewer, J. Tagat, P. Helquist, Tetrahedron
Lett. 1977, 18, 4145–4147.
[10] We have not observed any nucleophilic addition of nBuLi to
the carbonyl group.
[11] D. Gravel, L. Farmer, R. C. Denis, E. Schultz, Tetrahedron
Lett. 1994, 35, 8981–8984.
[12] a) B. M. Trost, K. Hiroi, J. Am. Chem. Soc. 1975, 97, 6911–
6914; b) B. M. Trost, Acc. Chem. Res. 1978, 11, 453–461; c)
B. M. Trost, K. Hiroi, L. N. Jungheim, J. Org. Chem. 1980, 45,
1839–1847; d) D. Caine, A. S. Frobese, Tetrahedron Lett. 1977,
18, 3107–3110.
SHORT COMMUNICATION
douros, K. Paulvannan, E. J. Sorensen, Nature 1994, 367, 630–
634; b) R. A. Holton, C. Somoza, H. B. Kim, F. Liang, R. J.
Biediger, P. D. Boatman, M. Shindo, C. C. Smith, S. Kim, H.
Nadizadeh, Y. Suzuki, C. Tao, P. Vu, S. Tang, P. Zhang, K. K.
Murthi, L. N. Gentile, J. H. Liu, J. Am. Chem. Soc. 1994, 116,
1597–1598; c) J. J. Masters, J. T. Link, L. B. Snyder, W. B.
Young, S. J. Danishefsky, Angew. Chem. Int. Ed. Engl. 1995,
34, 1723–1726; d) P. A. Wender, N. F. Badham, S. P. Conway,
P. E. Floreansig, T. E. Glass, J. B. Houze, N. E. Krauss, D. Lee,
D. J. Marquess, P. L. McGrane, W. Meng, M. G. Natchus, A. J.
Shuker, J. C. Sutton, R. E. Taylor, J. Am. Chem. Soc. 1997, 119,
2757–2758; e) T. Mukaiyama, I. Shiina, H. Iwadare, H. Sakoh,
Y. Tani, M. Hasegawa, K. Saitoh, Proc. Jpn. Acad. Ser. B 1997,
73, 95–100; f) K. Morihara, R. Hara, S. Kawahara, T. Nishi-
mori, N. Nakamura, H. Kusama, I. Kuwajima, J. Am. Chem.
Soc. 1998, 120, 12980–12981; g) T. Doi, S. Fuse, S. Miyamoto, [13] R. Bujok, M. Bieniek, M. Masnyk, A. Michrowska, A. Sa-
K. Nakai, D. Sasuga, T. Takahashi, Chem. Asian J. 2006, 1,
370–383.
[4] a) B. M. Trost, H. Hiemstra, J. Am. Chem. Soc. 1982, 104, 886–
887; b) B. M. Trost, M. J. Fray, Tetrahedron Lett. 1984, 25,
4605–4608; c) S. Blechert, A. Kleine-Klausing, Angew. Chem.
Int. Ed. Engl. 1991, 30, 412–414; d) W. F. Berkowitz, J. Perum-
rosiek, H. Stepowska, D. Arlt, K. Grela, J. Org. Chem. 2004,
69, 6894–6896 and references cited therein.
[14] CCDC-633193 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
attam, A. Amarasekara, Tetrahedron Lett. 1985, 26, 3665– [15] T. Rajamannar, K. K. Balasubramanian, Tetrahedron Lett.
3668; e) T. Kojima, Y. Inouye, H. Kakisawa, Chem. Lett. 1985,
323–326; f) G. Saha, A. Bhattacharya, S. S. Roy, S. Ghosh, Tet-
rahedron Lett. 1990, 31, 1483–1484; g) H. Nagaoka, K. Ohs-
awa, T. Takata, Y. Yamada, Tetrahedron Lett. 1984, 25, 5389–
5392; h) M. Toyota, M. Rudyanto, M. Ihara, Tetrahedron Lett.
1988, 29, 5789–5792.
[16] After refluxing 17 in ethanol in the presence of RhCl3 for 3 d,
it was observed that the isomerization was incomplete. Surpris-
ingly, the addition of a catalytic amount of p-toluenesulfonic
acid accelerated the isomerization. See ref.[13]
2000, 41, 8929–8932; i) Y. Shimada, M. Nakamura, T. Suzuka, [17] CCDC-633194 contains the supplementary crystallographic
J. Matsui, R. Tatsumi, K. Tsutsumi, T. Morimoto, H. Kuros-
awa, K. Kakiuchi, Tetrahedron Lett. 2003, 44, 1401–1403; j) S.
Hamon, N. Birlirakis, L. Toupet, S. Arseniyadis, Eur. J. Org.
Chem. 2005, 4082–4092.
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: April 4, 2007
Published Online: May 25, 2007
[5] G. Mehta, V. Singh, Chem. Rev. 1999, 99, 881–930.
[6] U. Steiner, H. Schinz, Helv. Chim. Acta 1951, 34, 1176–1183.
[7] E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1345–
1353.
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