Heteroatomic Modulation of Oxyanionic Cope Rearrangement Rates. Consequences on Competing Nucleophilic Cleavage of an Oxetane Ring in Precursors to Paclitaxel

Full text of DOI:10.1021/jo981059f

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J . Org. Chem. 1998, 63, 6432-6433
Both ketonic precursors are available by chemoselective
homologation of 54a with the appropriate Wittig reagent.7,8
In the coupling reactions of 6 and 7 with enantiopure (Z)-
vinyl iodide 8,9 halogen-metal exchange was accomplished
with n-butyllithium. The steric control associated with this
process distinctively relegates nucleophilic addition to the
endo surface and gives rise to 9 and 10 in good yield. When
samples of 10 were subjected to the action of potassium
hexamethyldisilazide and 18-crown-6 in THF at -78 °C,
Heter oa tom ic Mod u la tion of Oxya n ion ic
Cop e Rea r r a n gem en t Ra tes. Con sequ en ces
on Com p etin g Nu cleop h ilic Clea va ge of a n
Oxeta n e Rin g in P r ecu r sor s to P a clita xel
Leo A. Paquette,* Hui-Ling Wang, Qingbei Zeng, and
Tzenge-Lien Shih
Evans Chemical Laboratories, The Ohio State University,
Columbus, Ohio 43210
complete conversion to an isomeric ketone (ν ) 1692 cm-1
)
was seen to occur in less than 5 min. This compound is
1
formulated to be 12 (85% isolated) on the strength of its H
Received J une 3, 1998
and 13C NMR signals and selected NOE experiments (see
formula).
The condensation of alkenyl and cycloalkenyl organome-
tallic reagents with bridgehead vinyl camphor derivatives
and subsequent oxyanionic rearrangement of these divinyl
carbinols,1,2 hold considerable promise for the synthesis of
taxoids. Earlier work from our laboratory along these lines
When 9 was treated in comparable fashion, rearrange-
ment did not occur at a useful rate until the reaction
temperature reached ca. 0 °C.10 Very modest literature
precedent exists for widely divergent kinetic effects on
oxyanionic sigmatropy attributable to heteroatomic influ-
ences.11,13 The heightened reactivity of 10 can be attributed
to lessened steric interactions in the relevant transition state
brought on by the increased length of a C-S bond relative
to one of the C-O type. Electronic effects resulting from
the disparity in electronegativety between S and O as well
as the carbanion and radical stabilization capacity of S could
also be contributory. This new finding provided us with an
opportunity to probe its potential in synthesis.
has culminated in
a
total synthesis of taxusin.3 The
heightened oxygenation levels present in paclitaxel require
that a number of these additional substituents be incorpo-
rated early in the synthetic scheme.4 Instructive examples
Toward this end, 6 and 13 were brought into reaction with
the (Z)-alkenyllithium derived from 14.14 In both instances,
coupling occurred with an efficiency in excess of 80%
(Scheme 2). At this point, the vinyl sulfide 16 was carried
on to 18 without event. As before, the rearrangement was
complete within a few minutes following admixing of the
reagents at -78 °C. Without doubt, the change in the
structural features of the heavily substituted side chain to
one containing an oxetane ring had an effect neither on the
reactivity characteristics of the system nor on the product
outcome.
Notably, however, the scenario was radically different for
vinyl ether 15. Exposure of 15 to the same strongly basic
conditions resulted in its rapid consumption at a rate
comparable to that exhibited by 16! The spectral data for
this new compound revealed it to be isomeric with the
starting carbinol but indicated also that it was neither a
ketone nor structurally related to 11, 12, or 18. In view of
the widely recognized principle that alkoxides generated in
the presence of 18-crown-6 find themselves relatively dis-
sociated from their potassium counterions and consequently
in a highly reactive state, we reasoned that an alternative
pathway involving SN2 attack at the oxetane ring may well
have occurred. Molecular models revealed that proximity
are given by 1 and 2, where the absolute configuration at
C-2 is controlled directly by the geometry of the enol ether
double bond. Thus, 1 leads only to 3, while 2 affords
exclusively 4.5
During the course of an extension of this study, which
included possible use of a vinyl sulfide as an oxygen
surrogate,6 we had occasion to make direct comparison of
the response of 9 and 10 to charge-accelerated structural
rearrangement (Scheme 1).
(7) (a) Marino, J . P.; Kaneko, T. Tetrahedron Lett. 1973, 3975. (b) Vlattas,
I.; Lee, A. O. Tetrahedron Lett. 1974, 4451. (c) Muthukrishnan, R.; Schlosser,
M. Helv. Chim. Acta 1976, 59, 13.
(8) Prepared by reaction of the phosphonium salt (Scho¨nauer, K.; Zbiral,
E. Tetrahedron Lett. 1983, 24, 573) with KHMDS in ether at 0 °C.
(9) Vinyl iodide 8 was prepared from D-mannitol by a route closely allied
to one already detailed: Paquette, L. A.; Zeng, Q.; Tsui, H.-C.; J ohnston, J .
N. Submitted for publication.
(10) Since 11 and 12 have the same bridgehead olefin geometry and exo-
directed (â) oxygenated side chains, the rate differences are clearly not
related to the operation of both chair and boat pathways.
(11) Evans, D. A.; Baillargeon, D. J .; Nelson, J . V. J . Am. Chem. Soc.
1978, 100, 2242.
(12) (a) Paquette, L. A. Tetrahedron 1997, 53, 13971. (b) Paquette, L. A.
Angew. Chem., Int. Ed. Engl. 1990, 29, 609.
(13) It will be noted that 11 and 12 belong to different atropisomeric
series. In line with earlier discoveries realized in this laboratory, this
phenomenon is related to reaction temperature.
(1) (a) Zeng, Q.; Bailey, S.; Wang, T.-Z.; Paquette, L. A. J . Org. Chem.
1998, 63, 137 and references cited therein.
(2) Paquette, L. A.; Pegg, N. A.; Toops, D.; Maynard, G. D.; Rogers, R.
D. J . Am. Chem. Soc. 1990, 112, 277.
(3) (a) Paquette, L. A.; Zhao, M. J . Am. Chem. Soc. 1998, 120, 5203. (b)
Paquette, L. A.; Wang, H.-L.; Su, Z.; Zhao, M. J . Am. Chem. Soc. 1998,
120, 5213.
(4) (a) Elmore, S. W.; Paquette, L. A. J . Org. Chem. 1995, 60, 889. (b)
Paquette, L. A.; Su, Z.; Bailey, S.; Montgomery, F. J . J . Org. Chem. 1995,
60, 897. (c) Paquette, L. A.; Bailey, S. J . Org. Chem. 1995, 60, 7849. (d)
Paquette, L. A.; Montgomery, F. J .; Wang, T.-Z. J . Org. Chem. 1995, 60,
7857.
(5) Paquette, L. A.; Huber, S. K.; Thompson, R. C. J . Org. Chem. 1993,
58, 6874.
(6) J ohnston, J . N.; Tsui, H.-C.; Paquette, L. A. J . Org. Chem. 1998, 63,
129.
(14) Vinyl iodide 14 was prepared in several steps from D-glucose. The
details of this synthetic sequence will appear elsewhere.
S0022-3263(98)01059-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/25/1998

Communications
J . Org. Chem., Vol. 63, No. 19, 1998 6433
Sch em e 1
Sch em e 2
Sch em e 3
entirely by a simple OR f SR transposition. These results
are considered to provide the first unambiguous glimpse of
a subtle way in which [3.3] sigmatropic transpositions can
be modulated. The extremely selective nature of the pro-
cesses described here supports the contention that mecha-
nistic diversity is capable of being sharply delineated.
In the context of paclitaxel synthesis, the facts are
presently clear. Any intent to carry a fully functionalized
oxetane ring from the outset to arrival at the target along
this oxy-Cope pathway must be matched with the use of
sulfur-containing norbornanones such as 7 and 13. Failure
to do so will likely result in an early rerouting.
effects and orientational alignments for backside attack on
either C-O bond were quite suitable. Since the 300 MHz
1H NMR spectrum did not completely resolve matters, its
oxidation was effected with TPAP since one mechanistic
option would give rise to an aldehyde and the other to a
ketone. The distinctive spectral characteristics exhibited by
19 unequivocally define it to have arisen by intramolecular
cleavage of the oxetane at its less substituted C-O bond with
formation of 17 (Scheme 3).
Ack n ow led gm en t. This work was partially supported
by the National Cancer Institute and the Eli Lilly Com-
pany.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectral data for all new compounds (7 pages).
The highly divergent response to deprotonation exhibited
by 15 and 16 is remarkable in that it is brought about
J O981059F