A delicate balance of energetics. Subtleties associated with α-ketol-based bridge migration to afford 9-keto-10β-p-methoxybenzyloxytaxanes

Article abstract of DOI:10.1021/jo020628n

The feasibility of the title reaction has been pursued for the purpose of advancing a concise total synthesis of Taxol. Of the two closely related series examined, the first featured an exo-methylene group at C4. The second consisted of an α-epoxide at th

Full text of DOI:10.1021/jo020628n

A Delica te Ba la n ce of En er getics. Su btleties Associa ted w ith
r-Ketol-Ba sed Br id ge Migr a tion To Affor d
9-Keto-10â-p-m eth oxyben zyloxyta xa n es
Leo A. Paquette,* Ho Yin Lo, J ohn E. Hofferberth, and J udith C. Gallucci
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received October 1, 2002
The feasibility of the title reaction has been pursued for the purpose of advancing a concise total
synthesis of Taxol. Of the two closely related series examined, the first featured an exo-methylene
group at C4. The second consisted of an R-epoxide at that site. Strikingly, the olefinic construct
proved inert to attempted R-ketol rearrangement. In contrast, the oxiranyl derivative isomerized
smoothly. The reaction sequence associated with arrival at taxane 18 is short (15 steps from a
D-camphor derivative) and notably efficient. The thermodynamic issues that are raised by this
investigation have been clarified by an assessment of molecular mechanics-derived (MM3) steric
energy calculations.
As noted in the preceding paper,1 a central challenge
in a total synthesis of Taxol based on D-camphor as the
starting material is that of gaining proper control in the
operation of a necessary R-ketol rearrangement.2 The
potential complications can be concisely summarized in
the response of 9,10-acetal derivatives to the action of
aluminum alkoxides. When this functionality is trans-
fused, steric strain considerations preclude operation of
the key 1,2-carbon shift, in line with molecular mechanics
(MM3) calculations. Comparable scrutiny of a represen-
tative cis acetal revealed that the R-ketol rearrangement
is now so facile that prior oxygenation at C2 is not
feasible. Three potential modifications have more recently
been entertained by us to confront the issue of framework
equilibration in the proper direction, viz. 1 f 2. First,
the acetal protecting group across C9 and C10 should be
supplanted with a noncyclic equivalent such as that
illustrated. The avoidance of a heterocyclic ring in this
locale was expected to make available added conforma-
tional mobility that could be used to advantage. As well,
the R-ketol rearrangement should be attempted only after
the C2 hydroxyl had been transformed into a benzoate
group (as is already present in taxol). On the basis of
precedent,1,3 it seemed unlikely that bridge migration
would be deterred under these circumstances. Beyond
that, retroaldol fragmentation of ring B would be pre-
cluded if the targeted pathway was slowed kinetically.1
Finally, the opportunity to modify the chemical nature
of X was viewed to be a useful adjunct in view of the
striking electronic transmission effects we have observed
in compounds having generic formulas reflected by 1 and
2.4 As matters have turned out, it is precisely the subtle
characteristic associated with chemical manipulations at
C4 that exert the greatest control on unilateral progres-
sion in the direction of the taxanes.
Resu lts a n d Discu ssion
Th e Con sequ en ces of C4 exo-Meth ylen e Su bstitu -
tion . One available option was to arrive at our objectives
by placement of an exo-methylene group at C4 in an
otherwise suitably functionalized isotaxane, with the
ultimate goal of utilizing this unsaturated center to craft
the oxetane ring. This retrosynthetic consideration led
us back to the conveniently available dihydroxy ketone
3.1,5 A primary concern was that 3 would be notably prone
to transannular hemiketal formation. Such proved not
to be the case, thereby permitting Swern oxidation to be
entirely workable (Scheme 1). We expected that the base-
promoted enolization of 4 would proceed regioselectively
along the leading edge6 and provide a suitable means for
activating C2. Indeed, the deprotonation of this diketone
with potassium hexamethyldisilazide and ensuing oxida-
tion with the Davis sulfonyloxaziridine7 afforded 5 in 98%
(4) Paquette, L. A.; Zhao, M.; Montgomery, F.; Zeng, Q.; Wang, T.
Z.; Elmore, S.; Combrink, K.; Wang, H.-L.; Bailey, S.; Su, Z. Pure Appl.
Chem. 1998, 70, 1449.
(5) Hofferberth, J . E.; Lo, H. Y.; Paquette, L. A. Org. Lett. 2001, 3,
1777.
(1) Paquette, L. A.; Hofferberth, J . E. J . Org. Chem. 2003, 68, 2266.
(2) Paquette, L. A.; Hofferberth, J . E. Org. React., in press.
(3) Zeng, Q.; Bailey, S.; Wang, T. Z.; Paquette, L. A. J . Org. Chem.
1998, 63, 137.
(6) Paquette, L. A.; O’Neil, S. V.; Guillo, N.; Zeng, Q.; Young, D. G.
Synlett 1999, 1857.
(7) (a) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703.
(b) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919.
10.1021/jo020628n CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/19/2003
2276
J . Org. Chem. 2003, 68, 2276-2281

9-Keto-10â-p-methoxybenzyloxytaxanes
SCHEME 1
to be not only a robust compound but spectacularly
crystalline as well. Single-crystal X-ray diffraction mea-
surements conducted on 10 unequivocally corroborated
the fact that both oxiranes had formed on the R-surface
in line with steric approach control involving the lowest
energy conformer.
Considerable effort was expended for the purpose of
uncovering ways to effect bridge migration within 10.
Such reagents as aluminum tri-tert-butoxide, zinc chlo-
ride, and potassium tert-butoxide had no effect. In
contrast, boron trifluoride etherate, camphorsulfonic acid,
diethylaluminum chloride, pyridinium p-toluenesulfonate,
and triethylsilyl triflate uniformly transformed 10 into
13 in quantitative yield. The structure of 13 was con-
firmed crystallographically. As shown in A, this trans-
formation can be economically rationalized in terms of
an acetal oxygen-assisted transannular hydride shift
from C9 to C1 with configurational inversion during the
ring opening.
yield. No attempt was made to promote the base-cata-
lyzed rearrangement of 4 as this process does not advance
the synthesis.
Attempts to bring about the R-ketol rearrangement of
5 led as anticipated to a complex mixture of products.
The need for suitable protection of the C2 hydroxyl was
thereby again implicated.1 Conversion to monobenzoate
6 occurred smoothly with benzoyl chloride and pyridine
in the presence of DMAP. The spectral characterization
of 6 was initially hampered by the fact that this com-
pound exists as a mixture of atropisomers at room
temperature. Variable-temperature 1H NMR studies
removed all ambiguities and confirmed that esterification
had occurred uniquely at C2. Quite unexpectedly, expo-
sure of 6 to a significant number of potential promoters
did not result in isomerization to the taxane system 7.
After the expenditure of considerable effort at this point,
it was made clear that an alternative thrust had to be
implemented.
Exp lor a tion of a n Alter n a tive C2-Hyd r oxyla tion
P r otocol. Undertaken concurrently with the preceding
investigation was a plan to bring about the oxidation of
C2 by prior generation of an enol ether. This tactic, which
envisioned isomerization of the derived oxirane, was
considered likely to involve concurrent epoxidation of the
exo-methylene group that resides on the periphery of ring
C. The introduction of an additional oxygen in this
manner could serve to expedite ultimate generation of
the oxetane ring.
The early aspects of this phase of investigation involved
the known ketone 8.1 The synthesis of 10 began with the
highly regioselective O-methylation of 8. Thus, treatment
with 2 equiv of potassium tert-butoxide in DMF at 0 °C
followed by dimethyl sulfate8 afforded enantiomerically
pure 9 in 58% yield (Scheme 2).
Exposure of 9 in turn to dimethyl dioxirane at 0 °C9
gave rise to 12, thereby demonstrating that initial
reaction with this oxidant proceeds via attack at the
exocyclic π-bond. When attempts were made to force this
reaction by allowing it to proceed at room temperature,
oxidative cleavage of the PMP acetal occurred with
formation of benzoate ester 11.
Rea liza tion of a n r-Ketol Rea r r a n gem en t. In the
spirit of our routing paradigm, 4 was transformed into
the benzyl enol ether 14 in order to probe its utility. In
the ensuing treatment of 14 with an excess of MCPBA,
we discovered that the single diepoxide 15 could be
generated with essentially the same stereocontrol and
efficiency as in the O-methyl series (Scheme 3). The
important distinction between 10 and 15 is the inherent
stability of the latter toward transannular migrations.
The absence of a hydrogen at C9 is, of course, responsible
for the inoperability of this otherwise troublesome pro-
cess.
To pave the way for construction of a taxane derivative,
15 was admixed with a catalytic quantity of camphor-
sulfonic acid in CH2Cl2 at room temperature. Opening
of the oxirane ring with loss of the benzyl group mate-
rialize readily and the R,R′-dihydroxy ketone array
contained in 16 was established in 95% yield. With this
chemistry worked out, the time had arrived to bring
about benzoylation at C2 and the all-important bridge
migration. The implementation of both steps took place
uneventfully and a path to taxane 18 was made clear. It
may well be possible to transform 6 into 18. This pathway
was not examined because of the limiting scale of the
R-hydroxylation step (4 f 5), an undesirable feature not
associated with the epoxidation of enol ether 14.
Ster ic Str a in Con sid er a tion s. While 6 was recalci-
trant to equilibration with its isomeric taxane counter-
part 7, the structurally related epoxide 17 proved notably
amenable to conversion to 18. To the extent that MM3
calculations dealing with these polycyclic systems can be
relied upon to provide guidance regarding relative ther-
modynamic stabilities, the contrasting energetic prefer-
ence profiles must necessarily be viewed with special
interest. For the exo-methylene triads 6, 7, and 19
(Scheme 4), the data infer that placement of an exocyclic
double bond at C4 causes the undesired isomer 19 to be
Under buffered m-CPBA conditions, the surprisingly
recalcitrant methyl enol ether functionality was seen to
experience epoxidation. The resulting product 10 proved
(8) Paquette, L. A. Broadhurst, M. J . J . Org. Chem. 1973, 38, 1886.
(9) Troisi, L.; Cassidei, L.; Lopez, L.; Curci, R. Tetrahedron Lett.
1989, 30, 257.
J . Org. Chem, Vol. 68, No. 6, 2003 2277

Paquette et al.
SCHEME 2
SCHEME 3
SCHEME 5
SCHEME 4
Simple modulation of the hybridization of C4 from
trigonal to that offered by an oxiranyl carbon switches
the relative ordering of 18 and 20 (Scheme 5). Thus, the
minimally strained conformer in this subgroup is com-
puted to be the taxane derivative. The thermodynamic
favoring of 18 is reflected in the fact that it is indeed the
heavily dominant R-ketol under equilibrating conditions.
A logical outgrowth of these findings is the promise that
MM3-derived steric strain values offer a reasonable level
of suggestive insight to warrant their acquisition prior
to embarking on a synthetic undertaking based on
preparative-scale equilibration.
Con clu sion s. Presented herein is a unified synthetic
approach to a highly functionalized taxane system that
is well poised for A-ring functionalization and introduc-
tion of the oxetane D-ring. The successful strategy
exploited and extended our early investigations of the
R-ketol rearrangement in bridgehead contexts. The dra-
matic interrelationship between the presence of a double
bond or an oxirane ring at C4 and the inherent capacity
for 1,2-shifting was not expected to be so sharply demar-
cated. Notably, the isomerization that leads to 18 pro-
the global energy minimum. The positioning of an sp2-
hybridized carbon at C4 is seen to cause both 7 and 19
to be less strained than 6, the more so for 19. Since we
saw no hint indicating that the 6 f 7 isomerization was
operative, the prevailing thermodynamic imbalance could
reflect a somewhat greater relative Es value for 7, though
not in excess of that realized for 19.
2278 J . Org. Chem., Vol. 68, No. 6, 2003

9-Keto-10â-p-methoxybenzyloxytaxanes
For 6: 1H NMR (500 MHz, C6D6, 40 °C) δ 8.11 (d, J ) 7.2
Hz, 2 H), 7.43 (d, J ) 8.5 Hz, 2 H), 7.07 (t, J ) 7.4 Hz, 1 H),
7.00 (t, J ) 8.1 Hz, 2 H), 6.83 (d, J ) 8.7 Hz, 2 H), 6.17 (d, J
) 5.3 Hz, 1 H), 5.21 (s, 1 H), 4.95 (s, 1 H), 4.73 (d, J ) 8.7 Hz,
2 H), 4.45 (dd, J ) 11.4, 4.4 Hz, 1 H), 4.37 (s, 1 H), 4.28 (d, J
) 10.6 Hz, 1 H), 4.09-4.04 (m, 1 H), 4.61 (d, J ) 4.4 Hz, 1 H),
3.33 (s, 3 H), 3.03-2.98 (m, 1 H), 2.55-2.50 (m, 1 H), 2.29-
2.24 (m, 1 H), 2.05-1.88 (m, 3 H), 1.86-1.78 (m, 1 H), 1.70 (s,
3 H), 1.65-1.56 (m, 1 H), 1.49-1.41 (m, 1 H), 1.39 (s, 3 H),
1.23 (s, 3 H), 0.85 (s, 9 H), 0.01 (s, 3 H), -0.02 (s, 3 H); 13C
NMR (125 MHz, CDCl3) δ 207.0, 159.4, 133.9, 131.2, 130.4
(2C), 129.6, 128.92 (2C), 128.91 (2C), 114.1 (2C), 89.5, 72.9,
55.7, 34.9, 31.8, 30.1, 26.5, 26.0, 23.1, 18.8, 11.3, -2.8 (due to
atropisomerism not all carbons are apparent); ES HRMS m/z
(M + Na)+ calcd 713.3480, obsd 713.3504.
vides important insight into our capacity to carry many
chiral centers and oxygenated appendages directly cor-
relatable to the taxol substitution pattern and stereo-
chemistry through a key framework isomerization step.
The further development of our targeted objectives will
be the subject of future reports.
Exp er im en ta l Section
Sw er n Oxid a tion of 3. To a solution of oxalyl chloride (69
µL, 0.79 mmol) in CH2Cl2 (2.5 mL) cooled to -78 °C was added
a solution of DMSO (112 µL, 1.6 mmol) in CH2Cl2 (2.5 mL).
The resulting solution was stirred for 20 min, treated with a
solution of 3 (45 mg, 0.079 mmol) in CH2Cl2 (2.5 mL) via
cannula, stirred for 1 h at -78 °C, and slowly warmed to -50
°C over 30 min. After 3 h at this temperature, the solution
was returned to -78 °C, and freshly distilled Et3N (330 µL,
2.4 mmol) was added prior to warming to rt over 1 h,
quenching with water, and extraction with dichloromethane
(3 × 40 mL). The combined organic layers were dried, filtered,
and freed of solvent. The yellow residue was chromatographed
over silica gel (elution with 9% EtOAc in hexanes) to give 4
as a white solid (45 mg, quant): mp 150-151 °C; IR (neat,
Selective O-Meth yla tion of 8. Potassium tert-butoxide (27
mg, 0.24 mmol) was placed under high vacuum in a 50 mL
round-bottomed flask for 1 h. After the solid was blanketed
with dry N2, anhydrous DMF (10 mL) was added to achieve
dissolution at rt. After being cooled to 0 °C, a solution of 8 (56
mg, 0.121 mmol) in dry DMF (3 mL) was added, stirring was
maintained at this temperature for 30 min, dimethyl sulfate
(23 µL, 0.24 mmol) was introduced, and the solution was
stirred for another 30 min at 0 °C. Sodium hydroxide (2 N, 3
mL) was added, the product was extracted into Et2O (2 × 10
mL), the combined organic extracts were dried, filtered, and
concentrated, and the residue was subjected to flash chroma-
tography on silica gel (elution with 7:1 hexane/EtOAc) to afford
9 (40.9 mg, 71%) as a colorless oil: IR (neat, cm-1) 3271, 1754,
1
cm-1) 3488, 1705, 1680, 1609; H NMR (300 MHz, CDCl3) δ
7.26 (d, J ) 8.1 Hz, 2 H), 6.83 (d, J ) 8.1 Hz, 2 H), 4.99 (s, 1
H), 4.68 (s, 1 H), 4.62 (dd, J ) 11.4, 4.1 Hz, 1 H), 4.58 (d, J )
2.5 Hz, 1 H), 4.33 (d, J ) 10.8 Hz, 1 H), 4.15 (d, J ) 10.8 Hz,
1 H), 3.78 (s, 3 H), 3.30 (d, J ) 10.2 Hz, 1 H), 3.09 (s, 1 H),
2.88 (dd, J ) 15, 2.5 Hz, 1 H), 2.78 (d, J ) 12 Hz, 1 H), 2.63-
2.60 (m, 2 H), 2.49 (d, J ) 13 Hz, 1 H), 2.24-2.09 (m, 5 H),
1.66-1.65 (m, 1 H), 1.13 (s, 3 H), 1.06 (s, 3 H), 1.01 (s, 3 H),
0.85 (s, 9 H), 0.07 (s, 3 H), 0.01 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 214.9, 210.9, 158.7, 144.2, 130.8, 128.4, 113.4, 100.1,
87.4, 85.2, 76.9, 71.4, 59.6, 55.1, 54.2, 49.6, 43.9, 37.0, 34.0,
31.9, 31.5, 30.1, 26.3, 25.6, 18.6, 18.5, 9.14, -2.32, -2.50; ES
HRMS m/z (M + Na)+ calcd 593.3274, obsd 593.3269; [R] -25.8
(c 0.08, CHCl3).
1
1725; H NMR (300 MHz, CDCl3) δ 7.32 (d, J ) 8.7 Hz, 2 H),
6.88 (d, J ) 8.7 Hz, 2 h), 5.75 (s, 1 H), 4.94 (s, 1 H), 4.76 (s, 1
H), 4.62 (d, J ) 11.7 Hz, 1 H), 4.58 (s, 1 H), 4.22 (m, 4 H), 3.80
(s, 3 H), 3.68 (s, 1 H), 3.63 (s, 3 H), 2.93 (m, 2 H), 2.63 (m, 1
H), 2.40 (m, 1 H), 2.12 (t, J ) 8.5 Hz, 2 H), 2.04 (m, 1 H), 1.90
(m, 1 H), 1.57 (m, 1 H), 1.13 (s, 3 H), 1.10 (s, 3 H), 1.08 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 160.4, 157.3, 145.5, 130.2,
128.0, 113.8, 110.7, 99.7, 96.2, 87.0, 85.2, 84.2, 72.6, 55.3, 54.6,
51.5, 50.0, 42.7, 41.4, 35.4, 32.8, 30.2, 29.9, 26.0, 20.0, 13.0;
ES HRMS (M + Na)+ calcd 493.2566, obsd 493.2562; [R] -9.2
(c 4.2, CHCl3).
r-Oxygen a tion of 4. To a solution of 4 (43 mg, 0.075 mmol)
in THF (30 mL) at -78 °C were added a solution of KHMDS
(0.45 M in toluene, 840 µL, 0.38 mmol) and Davis’ oxaziridine
(98 mg, 0.38 mmol). The reaction mixture was slowly warmed
to 10 °C over 2 h, quenched with saturated NH4Cl solution,
and extracted with EtOAc (3 × 100 mL). The combined organic
layers were washed with 1 N HCl, and dried, filtered, and
evaporated. The residue was chromatographed over silica gel
(elution with 8% EtOAc in hexanes) to give 5 as a clear oil (43
Diep oxid a tion of 9. To a solution of 9 (4.8 mg, 0.01 mmol)
in CH2Cl2 (10 mL) at 0 °C were added NaHCO3 (8.4 mg, 0.1
mmol) and m-CPBA (8.7 mg, 0.05 mmol). The mixture was
stirred vigorously at 0 °C for 28 h, quenched with saturated
NaHCO3 solution (10 mL), and extracted with EtOAc (2 × 10
mL). The combined organic extracts were dried, filtered, and
concentrated. Purification of the residue by flash chromatog-
raphy on silica gel (elution with 1:2 hexane/EtOAc) gave 10
(3.9 mg, 76%) as a white crystalline solid: mp 138-140 °C;
1
mg, 98%): IR (neat, cm-1) 3400, 1704, 1614, 1514; H NMR
(500 MHz, CDCl3) δ 7.33 (d, J ) 8.0 Hz, 2 H), 6.91 (d, J ) 8.6
Hz, 2 H), 5.14 (s, 1 H), 5.09 (s, 1 H), 4.60 (dd, J ) 11.3, 4.3 Hz,
1 H), 4.51 (s, 1 H), 4.50 (d, J ) 10.2 Hz, 1 H), 4.42 (d, J ) 2.9
Hz, 1 H), 4.20 (d, J ) 10.8 Hz, 1 H), 3.85 (s, 3 H), 3.81 (d, J )
9.0 Hz, 1 H), 3.29 (s, 1 H), 3.12-3.10 (m, 1 H), 3.02 (s, 1 H),
2.82-2.79 (m, 1 H), 2.54-2.50 (m, 1 H), 2.49-2.45 (m, 1 H),
2.23-2.11 (m, 3 H), 2.04-2.00 (m, 1 H), 1.78-1.70 (m, 1 H),
1.28 (s, 3 H), 1.21 (s, 3 H), 1.13 (s, 3 H), 0.91 (s, 9 H), 0.13 (s,
3 H), 0.11 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 212.5, 211.4,
158.9, 139.3, 130.9, 128.5 (2C), 113.8, 113.6 (2C), 88.7, 86.3,
76.9, 72.1, 60.3, 56.1, 55.2, 50.3, 43.5, 34.7, 33.3, 31.8, 31.7,
26.3, 25.2 (3C), 25.8, 19.0, 18.5, 11.1-2.4, -2.9; ES HRMS m/z
(M + Na)+ calcd 609.3218, obsd 609.3204; [R] +0.8 (c 0.89,
CHCl3).
Ben zoyla tion of 5. To a solution of 5 (12 mg, 0.020 mmol)
and DMAP (1 crystal, cat) in dry pyridine (0.2 mL) was added
benzoyl chloride (24 µL, 0.2 mmol). The solution was stirred
for 6 h, and the reaction mixture was diluted with water and
EtOAc. The aqueous layer was extracted with EtOAc (3 × 30
mL), and the combined organic layers were dried over MgSO4,
filtered, and freed of solvent under reduced pressure. The
residue was chromatographed on silica gel (3-5% EtOAc in
hexanes) to give 10.8 mg (85%) of 6 as a colorless solid, mp
143-145 °C, and return 2 mg (15%) of unreacted 5.
1
IR (neat, cm-1) 1678, 1590; H NMR (500 MHz, C6D6) δ 7.45
(d, J ) 8.5 Hz, 2 H), 6.81 (d, J ) 8.5 Hz, 2 H), 5.84 (s, 1 H),
4.53 (d, J ) 9.7 Hz, 1 H), 4.18 (s, 1 H), 4.04 (dd, J ) 2.1, 9.7
Hz, 1 H), 3.98 (m, 1 H), 3.32 (s, 3 H), 3.04 (d, J ) 10.8 Hz, 1
H), 2.91 (s, 1 H), 2.90 (s, 3 H), 2.88 (br s, 2 H), 2.43 (t, J )
11.1 Hz, 1 H), 2.30 (d, J ) 4.5 Hz, 1 H), 2.10 (t, J ) 6 Hz, 2
H), 1.99 (d, J ) 10.7 Hz, 1 H), 1.96 (m, 1 H), 1.79 (m, 2 H),
1.55 (s, 3 H), 1.34 (s, 3 H), 1.30 (s, 3 H), 1.16 (m, 2 H); 13C
NMR (75 MHz, C6D6) δ 160.6, 129.2, 128.2, 113.8, 99.8, 86.0,
85.3, 84.2, 83.3, 72.0, 58.4, 55.3, 54.8, 50.5, 50.0, 48.9, 47.9,
42.3, 38.3, 32.2, 31.6, 31.2, 28.8, 23.7, 21.4, 14.0; ES HRMS
m/z (M + Na)+ calcd 525.2464, obsd 525.2462; [R] -3.2 (c 0.23,
CHCl3). Crystallographic details for 10 are provided as Sup-
porting Information.
Oxid a tion of 9 w ith Oxon e a t Room Tem p er a tu r e. To
a solution of 9 (8.1 mg, 0.017 mmol) in CH3CN (5 mL) and
H2O (1 mL) at rt were added NaHCO3 (14.3 mg, 0.17 mmol),
acetone (6.3 µL, 0.086 mmol) and oxone (52 mg, 0.086 mmol).
The reaction mixture was stirred vigorously for 24 h and
diluted with EtOAc (2 × 10 mL). The combined organic
extracts were dried, filtered, and concentrated. The residue
was subjected to flash chromatography on silica gel (elution
with 1:3 hexane/EtOAc) to deliver 11 (3.4 mg, 40%) as a
J . Org. Chem, Vol. 68, No. 6, 2003 2279

Paquette et al.
1
colorless oil: IR (neat, cm-1) 3428, 1703, 1603; H NMR (300
H), 4.69 (d, J ) 11 Hz, 1 H), 4.68-4.66 (m, 2 H), 4.50 (d, J )
3.2 Hz, 1 H), 4.42 (d, J ) 11 Hz, 1 H), 4.17 (d, J ) 11 Hz, 1 H),
3.84 (s, 3 H), 3.72 (d, J ) 12 Hz, 1 H), 3.57 (s, 1 H), 2.96 (d, J
) 12 Hz, 1 H), 2.75-2.70 (m, 1 H), 2.50 (d, J ) 10 Hz, 1 H),
2.30-2.23 (m, 3 H), 2.16-2.11 (m, 1 H), 2.11-2.03 (m, 1 H),
1.73-1.69 (m, 1 H), 1.11 (s, 3 H), 1.09 (s, 3 H), 1.07 (s, 3 H),
0.89 (s, 9 H), 0.13 (s, 3 H), 0.10 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 210.2, 158.7, 157.1, 144.2, 136.3, 131.2, 128.5, 128.3,
128.0, 113.5, 110.7, 97.8, 86.3, 85.1, 76.9, 71.8, 69.9, 59.9, 57.0,
55.2, 51.7, 39.0, 35.6, 32.9, 31.6, 26.4, 26.3, 19.3, 18.5, 9.5, -2.2,
-2.8; ES HRMS m/z (M + Na)+ calcd 683.3744, obsd 683.3736;
[R] -74 (c 0.3, CHCl3).
MHz, CDCl3) δ 7.97 (d, J ) 8.8 Hz, 2 H), 6.91 (d, J ) 8.8 Hz,
2 H), 5.56 (dd, J ) 2,8, 7.7 Hz, 1 H),4.29 (dd, J ) 0.9, 5 Hz, 1
H), 4.19 (d, J ) 11 Hz, 1 H), 4.11 (d, J ) 4 Hz, 1 H), 4.09 (d,
J ) 7.2 Hz, 1 H), 3.86 (s, 3 H), 3.55 (s, 3 H), 3.09 (d, J ) 12
Hz, 1 H), 2.89 (d, J ) 3 Hz, 1 H), 2.74 (d, J ) 16 Hz, 1 H), 2.62
(d, J ) 4.4 Hz, 1 H), 2.58 (m, 1 H), 2.41 (m, 1 H), 2.20 (m, 1
H), 1.95 (m, 1 H), 1.91 (m, 3 H), 1.80 (m, 1 H), 1.40 (m, 1 H),
1.22 (s, 3 H), 1.17 (s, 3 H), 1.05 (s, 3 H); ES HRMS m/z (M +
Na)+ calcd 525.2464, obsd 525.2452; [R] -18.3 (c 0.3, CHCl3).
Oxid a tion w ith Oxon e a t 0 °C. To a solution of 9 (10 mg,
0.021 mmol) in CH3CN (5 mL) and H2O (1 mL) at 0 °C were
added NaHCO3 (17.6 mg, 0.21 mmol), acetone (3 µL, 0.042
mmol), and Oxone (26 mg, 0.042 mmol), respectively. The
solution mixture was stirred vigorously at 0 °C for 7 h.
Saturated NaHCO3 solution (10 mL) was added to the mixture.
The resulting aqueous solution was extracted with EtOAc (2
× 10 mL). The combined organic extracts were dried over
MgSO4 and filtered. Concentration of the filtrate followed by
flash chromatography on silica gel (elution with 2:1 hexane/
EtOAc) afforded epoxy ether 12 (5.9 mg, 58%) as a colorless
oil: IR (neat, cm-1) 1607, 1513; 1H NMR (500 MHz, CDCl3) δ
7.32 (d, J ) 8.7 Hz, 2 H), 6.88 (d, J ) 8.7 Hz, 2 H), 5.75 (s, 1
H), 4.50 (br s, 1 H), 4.22 (dd, J ) 2.1, 9.7 Hz, 1 H), 4.14 (m, 3
H), 3.80 (s, 3 H), 3.61 (s, 1 H), 3.55 (s, 3 H), 2.94 (d, J ) 12 Hz,
1 H), 2.90 (s, 1 H), 2.87 (d, J ) 18 Hz, 1 H), 2.61 (d, J ) 4.3
Hz, 1 H), 2.60 (m, 1 H), 2.40 (m, 1 H), 2.20 (m, 1 H), 1.93 (m,
2 H), 1.78 (m, 1 H), 1.71 (m, 1 H), 1.40 (m, 1 H), 1.22 (s, 3 H),
1.13 (s, 3 H), 1.07 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 160.9,
160.6, 130.6, 128.4, 114.2, 100.1, 92.5, 86.9, 85.6, 84.7, 72.6,
57.9, 55.7, 54.9, 52.0, 50.4, 50.2, 43.4, 39.2, 36.0, 32.4, 29.0,
26.3, 20.4, 13.6; ES HRMS m/z (M + Na)+ calcd 509.2515, obsd
509.2513; [R] -3.5 (c 1.13, CHCl3).
Diep oxid a tion of 14. A solution of 14 (103 mg, 0.16 mmol)
in CH2Cl2 (30 mL) at 0 °C was treated with NaHCO3 (250 mg,
1.5 mmol) and m-CPBA (138 mg, 0.8 mmol). The reaction
mixture was stirred vigorously at 0 °C for 36 h prior to
quenching with saturated NaHCO3 solution (10 mL). The
product was extracted into EtOAc (2 × 30 mL), the combined
organic extracts were dried and filtered, and the concentrate
was flash chromatographed on silica gel (elution with 4:1
hexane/EtOAc) to afford 15 (88 mg, 80%) as a white solid: mp
1
133-134 °C; IR (neat, cm-1) 1703, 1509; H NMR (500 MHz,
C6D6) δ 7.46 (d, J ) 8.6 Hz, 2 H), 7.23 (d, J ) 7.4 Hz, 2 H),
7.14-7.11 (m, 2 H), 7.09-7.02 (m, 1 H), 6.79 (d, J ) 8.6 Hz, 2
H), 4.54 (d, J ) 10.6 Hz, 1 H), 4.51 (d, J ) 3.6 Hz, 1 H), 4.45
(dd, J ) 4.3, 11.3 Hz, 1 H), 4.35 (s, 2 H), 4.32 (d, J ) 10.8 Hz,
1 H), 3.28 (s, 3 H), 3.04 (d, J ) 10.8 Hz, 1 H), 2.86-2.84 (m,
1 H), 2.78 (d, J ) 3.6 Hz, 1 H), 2.53 (d, J ) 10.8 Hz, 1 H),
2.45-2.40 (m, 1 H), 2.23-2.22 (d, J ) 4.4 Hz, 1 H), 2.19-2.10
(m, 2 H), 1.76-1.72 (m, 2 H), 1.63 (s, 1 H), 1.62 (s, 3 H), 1.60-
1.49 (m, 2 H), 1.22 (s, 3 H), 1.14 (s, 3 H), 1.11-1.05 (m, 1 H),
0.83 (s, 9 H), -0.01 (s, 3 H), -0.05 (s, 3 H); 13C NMR (500
MHz, C6D6) δ 209.2, 159.6, 138.1, 133.5, 131.5, 128.9, 128.8,
128.5, 114.1, 86.6, 86.5, 85.9, 76.6, 72.0, 65.2, 58.5, 57.9, 56.4,
55.4, 54.8, 50.0, 49.3, 37.0, 32.6, 32.5, 32.1, 30.7, 26.6, 23.9,
21.0, 18.9, 10.7, -2.16, -2.23; ES HRMS m/z (M + Na)+ calcd
715.3642, obsd 715.3632; [R] -34.5 (c 0.87, CHCl3).
Bor on Tr iflu or id e-Ca ta lyzed Isom er iza tion of 10. A
solution of 10 (2.8 mg, 56 µmol) in dry CH2Cl2 (3 mL) at -78
°C under N2 was treated with boron trifluoride etherate (10
mL of 1.1 M in benzene, 0.011 mmol), stirred for 5 h at -78
°C, and quenched with saturated NaHCO3 solution (5 mL)
prior to extraction with EtOAc (2 × 10 mL). The combined
organic extracts were dried, filtered, and freed of solvent. The
residue was purified by flash chromatography on silica gel
(elution with 1:5 hexane/EtOAc) to furnish 13 (2.2 mg, 100%)
as a white solid: mp 214-215 °C; IR (neat, cm-1) 3506, 1660,
Acid Tr ea tm en t of 15. A solution of 15 (320 mg, 0.46
mmol) in CH2Cl2 (50 mL) was treated with CSA (214 mg, 0.92
mmol), stirred for 24 h under N2, and quenched with saturated
NaHCO3 solution (5 mL). The product was extracted into
EtOAc (2 × 50 mL), the combined organic extracts were dried
and filtered, and the concentrate was purified by flash chro-
matography on silica gel (elution with 2:1 hexane/EtOAc) to
give 16 (263 mg, 95%) as a white solid: mp 177-179 °C; IR
1
1437; H NMR (500 MHz, DMSO-d6) δ 5.04 (d, J ) 5.2 Hz, 1
H), 4.48 (s, 1 H), 4.30 (br s, 2 H), 4.09 (t, J ) 5.6 Hz, 1 H),
4.02 (dd, J ) 6.9, 14.3 Hz, 1 H), 3.66 (s, 1 H), 3.43 (s, 1 H),
3.19 (s, 3 H), 2.92 (m, 2 H), 2.82 (s, 1 H), 2.79 (s, 1 H), 2.42 (d,
J ) 11.7 Hz, 1 H), 2.21 (m, 2 H), 1.77 (m, 3 H), 1.63 (m, 1 H),
1.24 (d, J ) 15.4 Hz, 1 H), 1.13 (s, 3 H), 0.91 (s, 3 H), 0.84 (s,
3 H); 13C NMR (75 MHz, DMSO-d6) δ 216.3, 81.7, 78.8, 78.1,
74.3, 68.2, 62.9, 58.7, 55.3, 54.3, 51.5, 49.3, 41.1, 33.3, 31.3,
29.4, 28.4, 23.3, 17.6, 11.7; ES HRMS m/z (M + Na)+ calcd
407.2046, obsd 407.2048; [R] -29 (c 0.37, CHCl3). Crystal-
lographic details for 13 are provided in the Supporting
Information.
1
(neat, cm-1) 3424, 1701, 1507; H MMR (500 MHz, CDCl3) δ
7.27 (d, J ) 8.7 Hz, 2 H), 6.85 (d, J ) 8.7 Hz, 2 H), 4.58 (dd,
J ) 4.1, 11.1 Hz, 1 H), 4.45 (s, 1 H), 4.43 (d, J ) 7.5 Hz, 1 H),
4.18-4.14 (m, 1 H), 4.11 (d, J ) 7.1 Hz, 1 H), 4.07 (d, J ) 2.5
Hz, 1 H), 3.80 (s, 3 H), 3.79 (s, 1 H), 3.68 (dd, J ) 1.5, 4.6 Hz,
1 H), 3.18 (d, J ) 4.7 Hz, 1 H), 3.09-3.06 (m, 1 H), 2.80-2.71
(m, 2 H), 2.58 (d, J ) 4.7 Hz, 1 H), 2.22-2.11 (m, 2 H), 2.10-
2.04 (m, 2 H), 1.89-1.84 (m, 1 H), 1.36-1.34 (m, 1 H), 1.33 (s
3 H), 1.15 (s, 3 H), 1.02 (s, 3 H), 0.86 (s, 9 H), 0.09 (s, 3 H),
0.07 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 211.0, 209.9, 158.9,
130.7, 128.4, 113.6, 88.5, 85.9, 76.9, 76.1, 72.1, 60.6, 60.0, 55.9,
55.2, 53.2, 50.1, 38.4, 34.3, 34.0, 31.9, 30.1, 26.1, 25.8, 18.8,
18.4, 11.2, -2.4, -3.1; ES HRMS m/z (M + Na)+ calcd
625.3173, obsd 625.3167; [R] -16 (c 0.64, CHCl3).
O-Ben zyla tion of 4. Potassium tert-butoxide (154 mg, 1.4
mmol) was placed under high vacuum in a 100 mL round-
bottomed flask for 1 h. After the solid had been blanketed with
dry N2, anhydrous DMF (20 mL) was added to achieve
dissolution at rt. The reaction mixture was cooled to 0 °C,
treated with a solution of 4 (400 mg, 0.7 mmol) in dry DMF
(10 mL), and stirred at the same temperature for 30 min.
Benzyl bromide (0.17 mL, 1.4 mmol) was added, and the
solution was stirred for another 30 min at 0 °C prior to
quenching with NaOH solution (10 mL). After 5 min, the
product was extracted into Et2O (2 × 10 mL), the combined
organic extracts were dried, filtered, and concentrated, and
the residue was flash chromatographed on silica gel (elution
with 6:1 hexane/Et2O) to provide 14 (412 mg, 89%) as a white
solid: mp 157-158 °C; IR (neat, cm-1) 1705, 1703, 1609, 1514;
1H NMR (500 MHz, CDCl3) δ 7.42-7.34 (m, 7 H), 6.90 (d, J )
8.6 Hz, 2 H), 4.95 (s, 1 H), 4.74 (d, J ) 11 Hz, 1 H), 4.72 (s, 1
Ben zoyla tion of 16. To a solution of 16 (265 mg, 0.44
mmol) in CH2Cl2 (30 mL) were added Et2N (0.30 mL, 2.2
mmol), DMAP (5.0 mg, 0.044 mmol), and benzoyl chloride (0.10
mL, 0.88 mmol) sequentially under N2. The reaction mixture
was stirred for 12 h, and saturated NaHCO3 solution (20 mL)
was introduced prior to extraction of the product into EtOAc
(2 × 50 mL). The combined organic extracts were dried and
filtered. The concentrate was flash chromatographed on silica
gel (elution with 5:1 hexane/EtOAc) to afford 17 (291 mg, 94%)
1
as a colorless oil: IR (neat, cm-1) 3448, 1730, 1706, 1513; H
NMR (500 MHz, CDCl3) δ 7.67-7.62 (m, 2 H), 7.54-7.52 (m,
2 H), 7.42 (s, 1 H), 7.36 (d, J ) 8.6 Hz, 2 H), 6.92 (d, J ) 8.6
Hz, 2 H), 5.66 (d, J ) 2.3 Hz, 1 H), 4.65 (dd, J ) 4.3, 11.4 Hz,
2280 J . Org. Chem., Vol. 68, No. 6, 2003

9-Keto-10â-p-methoxybenzyloxytaxanes
1 H), 4.57 (d, J ) 10.7 Hz, 1 H), 3.86 (s, 3 H), 3.79 (d, J ) 4.3
Hz, 1 H), 3.60 (s, 1 H), 3.31 (d, J ) 12.7 Hz, 1 H), 2.98-2.88
(m, 1 H), 2.75-2.70 (m, 1 H), 2.65 (d, J ) 4.9 Hz, 1 H), 2.34-
2.27 (m, 2 H), 2.17-2.12 (m, 2 H), 1.94-1.86 (m, 1 H), 1.50-
1.47 (m, 1 H), 1.26 (s, 3 H), 1.25 (s, 6 H), 0.89 (s, 9 H), 0.15 (s,
3 H), 0.14 (s, 3 H); ES HRMS m/z (M + Na)+ calcd 729.3435,
obsd 729.3435; [R] +2.4 (c 1.3, CHCl3).
r-Ketol Rea r r a n gem en t of 17. A solution of 17 (10 mg,
0.014 mmol) in dry benzene (10 mL) was treated with
aluminum isopropoxide (7.1 mg, 0.028 mmol) and the reaction
mixture was stirred at 50 °C under N2 for 24 h, cooled to rt,
and quenched with 3% HCl (5 mL). The product was extracted
into EtOAc (2 × 20 mL), the combined organic extracts were
dried and filtered, and the concentrate was flash chromato-
graphed on silica gel (elution with 6:1 hexane/EtOAc) to
furnish 18 (5.5 mg, 55%) as a colorless oil alongside an isomer
(4 mg), which was put to the same reaction procedure again
2.49-2.41 (m, 1 H), 2.29-2.21 (m, 2 H), 2.12-2.05 (m, 1 H),
1.97-1.93 (m, 1 H), 1.76 (s, 3 H), 1.77-1.71 (m, 1 H), 1.15 (s,
3 H), 1.07-1.04 (m, 1 H), 1.02 (s, 3 H), 0.94 (s, 9 H), 0.15 (s, 3
H), 0.04 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 211.8, 209.4,
165.1, 159.4, 133.5, 129.6, 129.5, 128.7, 128.4, 113.8, 84.3, 84.0,
73.3, 71.8, 70.5, 57.5, 56.5, 55.2, 54.3, 52.2, 43.1, 42.0, 38.1,
30.9, 27.7, 27.3, 26.7, 25.9, 23.0, 18.2, 12.1, -1.8, -4.2; ES
HRMS m/z (M + Na)+ calcd 729.3429, obsd 729.3492; [R] +60.7
(c 0.27, CHCl3).
Ack n ow led gm en t. This work was financially sup-
ported by a grant from the National Cancer Institute
(CA-83830). J .E.H. was a trainee in the NIH Chemistry/
Biology Interface Program.
Su p p or tin g In for m a tion Ava ila ble: Details surrounding
the X-ray crystallographic analysis of 10 and 13 including
experimental protocols, ORTEP diagrams, crystallographic
data, and tables of bond lengths and bond angles, atomic
coordinates, and thermal parameters. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
to yield and additional crop of 18 (2.2 mg, 22%): IR (neat, cm-1
)
1
3494, 1734, 1514; H NMR (500 MHz, CDCl3) δ 8.00 (d, J )
7.6 Hz, 2 H), 7.63 (t, J ) 7.3 Hz, 1 H), 7.50 (t, J ) 7.6 Hz, 2
H), 7.37 (t, J ) 8.5 Hz, 2 H), 6.93 (d, J ) 8.5 Hz, 2 H), 5.64 (d,
J ) 6.3 Hz, 1 H), 4.13 (d, J ) 4.3 Hz, 1 H), 4.06 (d, J ) 10.7
Hz, 1 H), 3.86 (s, 3 H), 3.42 (d, J ) 6.3 Hz, 1 H), 2.86-2.83
(m, 2 H), 2.80 (d, J ) 3.3 Hz, 1 H), 2.63 (d, J ) 3.3 Hz, 1 H),
J O020628N
J . Org. Chem, Vol. 68, No. 6, 2003 2281