A rapid entry into major groups of taxoids

Article abstract of DOI:10.1016/S0040-4039(99)02176-0

We report here the construction of 3 to 12, equipped with functionalization suitable for further elaboration to various taxoids, that demonstrates the validity of our four-step synthesis of the taxoid ABC framework by the transmetallation (C10-C11)-aldol (C1-C2) route. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02176-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 863–866
A rapid entry into major groups of taxoids
José Ignacio Martín Hernando, Maria del Rosario Rico Ferreira, José Ignacio Candela Lena,
Nicolas Birlirakis and Siméon Arseniyadis ∗
Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette, France
Received 5 October 1999; accepted 20 November 1999
Abstract
We report here the construction of 3 to 12, equipped with functionalization suitable for further elaboration to
various taxoids, that demonstrates the validity of our four-step synthesis of the taxoid ABC framework by the
transmetallation (C10–C11)-aldol (C1–C2) route. © 2000 Elsevier Science Ltd. All rights reserved.
The ABC core of the taxoid diterpene skeleton still posses challenging synthetic problems despite
the impressive number of strategies which have culminated in six complete total syntheses.1 We had
developed an attractive approach2 that relies on an α-alkoxy stabilized carbanion for the A+C coupling,
using the stannylation/destannylation methodology developed by Still3 and on one of the oldest reactions
known in synthesis, the aldol condensation4 for the central B-ring formation. We now report further
elaboration of the tricyclic system 1 which is used as a starting point towards various members of
the taxoid family offering practical access into the, hitherto never approached, C12–C13 double bond
containing Taxezopidine K I, Taxuspine D II5 as well as to the major groups of taxanes, those containing
an exocyclic olefin at C4–C20 such as Taxuyunnanine C III,6 a β-epoxide at C4–C20 such as Baccatin
I IV,7 and those with an oxetane ring such as Taxol V (Scheme 1). With the crucial ABC intermediate,
the 12,4(20)-taxadiene 1 in hand, we turned our attention to the more elaborated intermediate 3, which
bears the C-5 α-OH necessary for the corresponding esters and for the C4–C20 epoxide, precursor for
the oxetane synthesis and functionality for the C-1 hydroxyl group. The double bonds in 2 can easily be
chemodifferentiated; when dienone 2 was subjected to nucleophilic epoxidation, it was clearly evident
that the C1–C2 double bond of the dienone system had a much higher reactivity to epoxidation than the
C12–C13 double bond. Indeed, when 2 was treated with H2O2 and 6N NaOH in methanol at 0°C to room
temperature, the epoxy ketone 3 ([α]D –62, c 1.1), that incorporates all carbon atoms of the final taxoid
skeleton, was obtained in 91% isolated yield as a single diastereoisomer (Scheme 2).
Next, oxygenation of the C4–C20 olefin, in the presence of the C-5α hydroxyl group, was attempted
using standard literature conditions for osmium tetroxide catalyzed dihydroxylation, with a hope for
obtaining synthetically useful levels of stereoselection.8 But, in contrast to the nucleophilic epoxidation,
∗
Corresponding author. Fax: 33-1-69-07-72-47; e-mail: simeonarseniyadis@icsn.cnrs-gif.fr (S. Arseniyadis)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02176-0
tetl 16104

864
Scheme 1.
which proceeded exclusively from the β-face of dienone 2 forming the β-epoxide 3, osmylation (various
conditions) of the latter led to a 1.4:1 mixture of triols 4 ([α]D –63, c 2.3) and 5 ([α]D –55, c 1.2)
respectively, in 75% combined yield. Protection of triol 5 as its mono-tert-butyldimethylsilyl (TBDMS)
ether was carried out using standard protocols (TBSCl, Im., DMF, under argon, room temperature, 2.5
h) affording 6 ([α]D –45, c 0.9), in 92% isolated yield. The target C-5 mesylate 7 was then obtained in
88% yield by reacting 6 with MsCl, in dry pyridine, in the presence of cat. DMAP (0°C, 55 min). The
synthesis of 7, a possible direct precursor of oxetane containing taxoids,9 was therefore achieved in six
steps from 1.
Scheme 2. (a) Ac2O, Py, DMAP, 0°C then DBU, rt. (b) cat. SeO2, tBuOOH 70% in H2O, CH2Cl2, rt. (c) 30% H2O2, 6N NaOH,
MeOH, 0°C to rt. (d) OsO4, NMO, tBuOH:H2O (3:1), Py, rt. (e) TBSCl, Im., DMF, rt. (f) MsCl, Py, DMAP, 0°C
The observed lack of stereoselectivity in the osmium mediated dihydroxylation on tricyclic interme-
diate 3 allowed a modulable stereoselectivity for the introduction of the C-4 stereocenter. The flexibility
of the current method to efficiently introduce and further modify various substituents around the core
tricyclic intermediate is demonstrated by the transformations shown in Scheme 3.
The synthetic route that led to the β-C4(20)-epoxy group containing 9, to the rearranged epoxy
alcohol 10 and the C-14 β-OH containing 12 started with the elaboration of triol 4. Tosylation (TsCl,
pyridine, DMAP, 0°C to room temperature) of 4 occurred in high yield, and furnished the required C-
20 tosylate 8 ([α]D −58, c 1.4). Subsequent displacement of the tosylate under mild basic conditions
proved beneficial; prolonged reaction times resulted in Payne rearrangement leading to 10 ([α]D −81, c
0.5), which reinforces the synthetic utility of the osmylation step. Thus, displacement of the tosylate in 8
under mild conditions (K2CO3 in anhydrous methanol at −40°C, 1 h) gave epoxide 9 ([α]D –66, c 1.0), in
98% isolated yield. At longer reaction times, as expected from stereoelectronic considerations,10 a larger

865
Scheme 3. (a) TsCl, Py, DMAP, 0°C to rt. (b) K2CO3, MeOH. (c) Ac2O, Py, DMAP, 0°C. (d) NaBH4–CeCl3, EtOH–CH2Cl2
predominance of the Payne rearrangement11 product 10 was observed, until total conversion of 9 to 10.
Finally, conversion of 9 to 12 was achieved via careful acetylation (to avoid the Payne rearrangement
product formation) of the bis-epoxy-enone 9, successfully carried out at 0°C in dry pyridine using
Ac2O and DMAP as catalyst. Subsequent reduction of 11 thus obtained with sodium borohydride in
the presence of CeCl3 in ethanol–methylene chloride (1:1, at −25°C, 40 min) gave the alcohol 12 as a
single stereomer in 98% isolated yield.12 The β-OH stereochemistry at C-14 and the β-disposition of the
epoxy functionality at C4(20) were supported by the observation of diagnostic NOEs involving Me-17,
Me-19 and H-14, H-2, H-20 protons.
The route followed is operationally simple and serves to further validate the synthetic utility of our
A+C strategy. The synthetic scheme described herein represents one of the most straightforward routes
to these compounds. The oxetane D-ring construction is deferred to the end of the synthetic scheme,
1
and so is the C-3 stereochemistry. Complete IR, mass, H and 13C NMR data were obtained for each
compound synthesized; optical rotations were measured in chloroform.
Acknowledgements
The authors thank Ministerio de Educacion y Cultura (Spain) for a fellowship to Dr J. I. Martin
Hernando, the European Commission for a Research Training Grant to Dr J. I. Candela Lena and
Professor P. Potier for his kind interest and constant encouragements.
References
1. For review articles, see: Nicolaou, K. C.; Dai, W. M.; Guy, R. K. Angew. Chem., Int. Ed. Engl. 1994, 33, 15–44; Boa, A.
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866
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8. For empirical rules for substrate controlled delivery of OsO4 to allylic systems, see: Cha, J. K.; Christ, W. J.; Kishi, Y.
Tetrahedron Lett. 1983, 39, 3951–3954.
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12. Compound 12: [α]D –3 (c 1.21). IR (film): 3493, 2974, 1739, 1462, 1372, 1234, 1190, 1078, 1031, 949, 916, 866, 738, 702,
675 cm−1. 1H NMR (800 MHz): 1.02 (3H, s, Me-16), 1.16 (9H, s, tBu), 1.22 (3H, s, Me-19), 1.41 (3H, s, Me-17), 1.61 (1H,
d, J=12.4, H-3), 1.74 (1H, dd, J=7.2, 16.0, H-9α), 1.88 (3H, d, J=1.3, Me-18), 1.95 (1H, d, J=16.0, H-9β), 1.99 (1H, td,
J=3.4, 14.9, H-6α), 2.08 (3H, s, MeCO), 2.16 (1H, ddd, J=3.3, 11.7, 14.9, H-6β), 2.71 (1H, d, J=4.8, H-20), 2,81 (1H, d,
J=4.8, H-20), 3.19 (1H, d, J=12.4, H-2), 3.43 (3H, s, OMe), 3.68 (1H, dd, J=3.4, 11.7, H-7), 3.72–3.73 (1H, m, H-14), 3.84
(1H, s, OH), 3.94 (1H, d, J=7.2, H-10), 4.63 (1H, br.s, H-5), 4.65 (1H, d, J=6.9), 4.75 (1H, d, J=6.9), 5.84–5.86 (1H, m,
H-13). 13C NMR (200 MHz): 17.4 (Me-19), 19.6 (Me-18), 19.7 (Me-16), 21.3 (MeCO), 27.1 (Me-17), 28.8 (3C, tBu), 33.0
(C-6), 40.0 (Cq-15), 40.5 (C-9), 40.8 (Cq-8), 47.2 (C-3), 49.4 (C-20), 55.2 (Cq-4), 55.9 (MeO), 64.8 (Cq-1), 67.0 (C-2), 68.3
(C-7), 73.8 (Cq–tBu), 74.7 (C-14), 75.6 (C-5), 76.7 (C-10), 80.8 (Cq-11), 94.3 (-OCH2O-), 124.2 (C-13), 141.4 (Cq-12),
169.2 (MeCO). CIMS: 525 ([MH]+, 5), 449 (3), 435 (16), 405 (19), 389 (79), 271 (38), 253 (48), 153 (100), 135 (69), 121
(37), 95 (50). HRCIMS: calcd for C28H45O9 m/z 525.3063, found 525.3069.