Enantioselective taxanes approach using both enantiomers of the same building-block. Part 1: Taxol A-ring subunit

Article abstract of DOI:10.1055/s-2002-32968

An efficient enantioselective synthesis of fully-oxygenated Taxol A-ring subunit has been achieved using (-)-karahana lactone, (-)-2, as an enantiopure starting building-block and a diastereoselective allylic hydroxylation as the key step.

Full text of DOI:10.1055/s-2002-32968

LETTER
1261
Enantioselective Taxanes Approach Using Both Enantiomers of the Same
Building-Block. Part 1: Taxol® A-Ring Subunit
Enantioselective
T
é
axanes rard Audran, Jean-Pierre Uttaro, Honoré Monti*
Laboratoire de Réactivité Organique Sélective UMR 6516 Faculté des Sciences de St-Jérôme (case 551), Avenue Escadrille Normandie-
Niemen, 13397 Marseille Cedex 20, France
Fax +33(4)91288862; E-mail: honore.monti@univ.u-3mrs.fr
Received 14 May 2002
In spite of these successes, convenient accesses to the ful-
Abstract: An efficient enantioselective synthesis of fully-oxygen-
ly-functionalized A-ring, C-ring and the construction of
the sterically congested eight-membered ring remain a
challenge and excellent work is still in progress.5 Recent-
ly, we have published6 the efficient enantioselective syn-
thesis of (–)-karahana lactone, (–)-2, using a domino ring
closure sequence starting from enantiopure (R)-4-hy-
droxy-3-methyl-cyclohex-2-en-1-one (Scheme 1, path a).
ated Taxol® A-ring subunit has been achieved using (–)-karahana
lactone, (–)-2, as an enantiopure starting building-block and a dias-
tereoselective allylic hydroxylation as the key step.
Key words: stereoselectivity, enantioselective synthesis, Taxol®,
antitumor agents
Paclitaxel1 (Taxol®, Figure 1), a substance originally
isolated2 from Pacific yew tree Taxus brevifolia, and its
synthetic analogs,3 have attracted considerable interest
from synthetic organic chemists owing to their remark-
able anticancer activities and their low natural availabili-
ty. At this time, six total syntheses of Taxol® have been
reported4 and two of them, the Nicolaou4a,b and
Danishefsky4c,d convergent strategies, utilized an A + C
connection to form the central B-ring.
Based upon a related methodology, we investigated syn-
theses for the taxoid diterpene framework and we reported
recently a stereocontrolled construction of bicyclic sys-
tems with the appropriate stereochemical disposition of
the substituents belonging either to baccatin-I C-ring or
Taxol® CD-ring precursors.7 Formally, starting from
enantiopure (S)-4-hydroxy-3-methyl-cyclohex-2-en-1-
one, this strategy allowed the construction of these bicy-
clic systems with the required absolute configuration
(Scheme 1, path b). In the continuation of our endeavor
directed towards a stereocontrolled access to highly oxy-
genated taxane precursors, we were keen to incorporate
enantioselectively the required (S)-C-13 oxygenation
(taxane numbering) of the A-ring synthon directly rather
than introducing it later by oxidation of C-13. Herein we
report an enantioselective synthesis of fully-oxygenated
Taxol® A-ring 1 using (1S,5R)-karahana lactone, (–)-2,
as an enantiopure starting building block and a diastereo-
Figure 1 Paclitaxel (Taxol®)
Scheme 1
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1261,1264,ftx,en;G13102ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1262
G. Audran et al.
LETTER
selective allylic hydroxylation as the key step In summary, as part of a program aimed at the enantiose-
(Scheme 2).5h,j,8,9
lective synthesis of taxanes using both enantiomers of the
same building block, we have developed a new approach
to a fully-oxygenated paclitaxel A-ring subunit. Starting
from the opposite enantiomer, the synthetic studies on
baccatin-I C-ring and Taxol® CD-ring are currently un-
derway in our laboratory. The results of these studies will
be reported shortly.
Allylic hydroxylation of (–)-2 using selenium dioxide and
tert-BuOOH (70 wt% in water) in dichloromethane af-
forded, after stirring for 3 days at reflux, the alcohol (–)-
310 as a single stereomer in 85% isolated yield. 1H and 13C
NMR data for (–)-3 were fully determined by HMBC and
COSY experiments.11 The stereochemistry at the 3-posi-
tion was unambiguously assigned based on NOESY anal-
ysis (Figure 2). A NOE effect between Me -8, H -4, H-9
( = 5.18 ppm) and H-3 established a H-3 position and
thus the configuration of the hydroxy group.
Acknowledgement
We are thankful to Dr R. Faure for 2D NMR experiments.
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Synlett 2002, No. 8, 1261–1264 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
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(10) Preparation of (–)-3. To a stirred solution of karahana
lactone (–)-26 (400 mg, 2.41 mmol) in dry CH2Cl2 (40 mL)
was added selenium dioxide (107 mg, 0.96 mmol), tert-butyl
hydroperoxide (70 wt% in water, 868 mg, 9.64 mmol) and a
catalytic amount of salicylic acid under an argon
atmosphere. The reaction mixture was heated to reflux for 3
d, cooled to r.t. and Na2SO3 (2.5 g, 20 mmol) and 1 mL of
water were added. The mixture was stirred for a further 30
min, filtered through a pad of MgSO4 and concentrated.
After purification by crystallization from Et2O–hexane, 354
mg of pure alcohol (–)-3 were obtained as white crystals (rdt
85%).
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(11) Spectroscopic data of compounds (–)-3 and (–)-1: (–)-3: mp
155 °C, [ ]D25 –142.9 (c 1.0, CHCl3). IR (KBr): 3440, 3091,
1759, 1036, 905 cm–1. 1H NMR (500 MHz, CDCl3): = 5.18
(s, 1 H, H-9), 5.08 (s, 1 H, H-9), 4.42 (d, J = 6.1 Hz, 1 H, H-
3), 4.36 (br. d, J = 3.7 Hz, 1 H, H-5), 2.77 (s, 1 H, H-1), 2.22
(dd, J = 15.7, 3.8 Hz, 1 H, H -4), 2.08 (ddd, J = 15.7, 6.1, 1.5
Hz, 1 H, H -4), 1.21 (s, 3 H, CH3 ), 0.95 (s, 3 H, CH3 ).
13C NMR (125 MHz, CDCl3): = 176.6 (C-7), 143.9 (C-2),
117.0 (CH2-9), 84.3 (CH-5), 68.0 (CH-3), 56.6 (CH-1), 42.8
(C-8), 32.6 (CH2-4), 25.3 (CH3), 20.1 (CH3). Anal. Calcd for
C10H14O3: C, 65.92; H, 7.74. Found: C, 65.64; H 7.72.
(–)-1: Mp 59 °C, [ ]D25 –39.0 (c 1.0, CHCl3). IR (KBr):
1661, 1630, 1254, 1104 cm–1. 1H NMR (200 MHz, CDCl3):
= 5.37 (s, 1 H, H-7), 4.26 (t, J = 4.8 Hz, 1 H, H-5), 4.12–
4.05 (m, 2 H, Hdioxolane), 3.94–3.87 (m, 2 H, Hdioxolane), 2.76
and 2.60 (ABX, J = 13.7, 5.8, 4.4 Hz, 2 H, H-6), 1.92 (s,
3 H, H-8), 1.30 (s, 3 H, CH3) 1.22 (s, 3 H, CH3), 0.85 (s, 9 H,
(CH3)3C-), 0.06 (s, 3 H, CH3-Si), 0.05 (s, 3 H, CH3-Si).
13C NMR (50 MHz, CDCl3): = 212.2 (C-1), 139.1 (C=),
133.0 (C=), 102.0 (CH-7), 72.2 (CH-5), 64.7 (CH2dioxolane),
64.4 (CH2dioxolane), 47.1 (C-2), 45.6 (CH2-6), 25.6 (CH3)3C-),
24.6 (CH3), 23.8 (CH3), 17.9 (CH3)3C-), 17.2 (CH3-8), –4.6
(CH3-Si), –4.8 (CH3-Si). Anal. Calcd for C18H32O4Si: C,
63.49; H, 9.47. Found: C, 63.67; H 9.45.
Synlett 2002, No. 8, 1261–1264 ISSN 0936-5214 © Thieme Stuttgart · New York