Effect of 9,10-cyclic acetal stereochemistry on feasible operation of the α-ketol rearrangement in highly functionalized paclitaxel (Taxol) precursors

Article abstract of DOI:10.1021/jo020627v

The convergent, stereocontrolled synthesis of enantiopure stereoisomeric 9,10-cyclic acetals, whose designed role was to serve as potential precursors to Taxol, is reported. These advanced intermediates are multiply functionalized and carry a bridgehead α

Full text of DOI:10.1021/jo020627v

Effect of 9,10-Cyclic Aceta l Ster eoch em istr y on F ea sible Op er a tion
of th e r-Ketol Rea r r a n gem en t in High ly F u n ction a lized P a clita xel
(Ta xol) P r ecu r sor s†
Leo A. Paquette* and J ohn E. Hofferberth
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received September 30, 2002
The convergent, stereocontrolled synthesis of enantiopure stereoisomeric 9,10-cyclic acetals, whose
designed role was to serve as potential precursors to Taxol, is reported. These advanced
intermediates are multiply functionalized and carry a bridgehead R-ketol array which was key to
isomerization into the proper framework. In agreement with relative strain energy values obtained
by MM3 calculations, a dichotomy was observed between these two families. While the trans-fused
acetals failed to undergo bridge migration, their cis counterparts did so efficiently. In fact,
isomerization was sufficiently rapid that oxygenation at C2 was now precluded. The operation of
several unusual transannular hydride shifts is also detailed.
The synthetic planning and strategy associated with
our exploration of concise routes to taxusin,1 paclitaxel
(Taxol),2 and their analogues have been based on the
substantial scaffolding power of the anionic oxy-Cope
rearrangement and the feasibility of regiocontrolled 1,2-
carbon shifts in advanced bridged intermediates. While
the first of these tactics has been widely exploited and is
well understood mechanistically,3 the adaptability of the
R-ketol rearrangement to complex target synthesis is far
less advanced.4 Certainly, bridgehead R-keto carbinols
are recognized for their ability to isomerize under a
variety of conditions.4,5 However, since this isomerization
is equilibrium-controlled, thermodynamics plays an obvi-
ous key role in determining the direction in which bond
reorganization will proceed preferentially. As a conse-
quence of our early investigations of this process, alu-
minum alkoxides were determined to be notably effica-
cious promoters.6,7 After noting the ready, near-quan-
titative conversion of 1 to 2 in refluxing benzene contain-
ing 3 equiv of Al(O-i-Pr)3,6 we turned our attention to 3
where the B/C ring fusion was now trans as in all taxanes
(Scheme 1). Heating this R-ketol with either Al(O-i-Pr)3
or Al(O-t-Bu)3 in benzene for 3 h resulted in its total
consumption. At this point, the reaction mixture was
constituted of 15% of 4 and 85% of 5. Extension of the
reaction time to 12 h afforded pure 5 in 93% isolated
yield.7
Although the thermodynamic bias in this system was
not in line with our objectives, two subsequent observa-
tions proved highly encouraging (Scheme 2). The sub-
stantially more functionalized diketo alcohol 6 was found
to isomerize smoothly in the desired manner and furnish
exclusively 7 (94%).8 Of added importance was the 8 f
9 isomerization.9 Although the C-ring is lacking in this
example, the benzoate functionality residing adjacent to
the ketone carbonyl was found not to impede bridge
migration. Taxol (10) carries an R-oriented benzoate
group at C-2.10
One of the synthetic routes projected by us for the
enantioselective synthesis of 10 involves the construction
from D-camphor of stereoisomeric 9,10-p-methoxyben-
zylidene (PMP) acetals11 otherwise functionalized to a
level exemplified by 11 and 14 (Table 1). MM3 calcula-
tions suggested that an interesting dichotomy may dis-
tinguish these compound families. In the trans series,
isotaxane 11 is estimated to be 4.6 kcal/mol less sterically
strained than 12 and approximately 3 kcal/mol less ther-
modynamically favored than the undesirable bond shift
† After common usage of the term taxol for nearly two decades, it
was selected as a registered trademark by Bristol-Myers Squibb. This
fact is recognized when Taxol is cited in this paper.
(1) (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.
(2) For a summary of the early progress, consult: 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.
(3) (a) Paquette, L. A.; Tetrahedron 1997, 53, 13971. (b) Paquette,
L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609.
(4) Paquette, L. A.; Hofferberth, J . E. Org. React., in press.
(5) (a) Selman, S.; Eastham, J . F. Quart. Rev. Chem. Soc. 1960, 14,
221. (b) Wendler, N. L. In Molecular Rearrangements; de Mayo, P.,
Ed.; Interscience: New York, 1963; Chapter 16. (c) Redmore, G.;
Gutsche, C. D. In Advances in Alicyclic Chemistry; Hart, H., Karabat-
sos, G. J ., Eds.; Academic Press: New York, 1971; Chapter 1. (d)
Gutsche, C. D.; Redmore, D. Carbocyclic Ring Expansion Reactions;
Academic Press: New York, 1968.
(8) Paquette, L. A.; Montgomery, F. J .; Wang, T.-Z. J . Org. Chem.
1995, 60, 7857.
(9) Zeng, Q.; Bailey, S.; Wang, T.-Z.; Paquette, L. A. J . Org. Chem.
1998, 63, 137.
(10) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail,
A. T. J . Am. Chem. Soc. 1971, 93, 2325.
(11) Taxane numbering is used throughout for simplicity. Where
isotaxanes are involved, the operation of 1,2-bridge migration must
be anticipated.
(6) Paquette, L. A.; Elmore, S. W.; Combrink, K. D.; Hickey, E. R.;
Rogers, R. D. Helv. Chim. Acta 1992, 75, 1755.
(7) Paquette, L. A.; Combrink, K. D.; Elmore, S. W.; Zhao, M. Helv.
Chim. Acta 1992, 75, 1772.
10.1021/jo020627v CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/19/2003
2266
J . Org. Chem. 2003, 68, 2266-2275

R-Ketol Rearrangement in Functionalized Paclitaxel Precursors
TABLE 1. Rela tive Ster ic Str a in En er gies Estim a ted by
MM3 Ca lcu la tion s
SCHEME 1
SCHEME 2
the vinyllithium intermediate generated by halogen-
metal exchange in 18 to dimethylformamide13 followed
by Wittig condensation of aldehyde 19 with (iodometh-
ylene)triphenylphosphorane.14,15 Attention then shifted
to the lithiation of 20 and subsequent coupling to readily
available, enantiopure norbornanone 21.9 As expected,16
addition to the carbonyl group proceeded only from the
endo direction under steric control without loss of geo-
metrical configuration about the double bond.8,17 Alcohol
22 underwent ready [3.3] sigmatropic rearrangement
when treated with potassium hexamethyldisilazide and
18-crown-6 in THF at low temperature. The necessary
adoption of an endo-chair transition state18 resulted in
the highly stereoselective generation of an enolate anion
whose in situ methylation gave rise to 23 in 81% yield.
Entry of the alkyl group proceeded from the less sterically
congested π-surface.8,17 With 23 in hand, we were able
to take advantage of the more elevated tendency of this
bridgehead double bond to become engaged in reaction.
A three-step sequence involving regioselective dihydroxy-
lation with osmium tetraoxide, reaction with phosgene
in the presence of pyridine to generate a cyclic carbonate,
and desilylation in the presence of a Dowex resin
produced 26 in good overall yield. These tactics made
possible subsequent Swern oxidation19 to deliver keto
isomer 13. The steric energy gaps arrived at when a cis-
locked PMP acetal is involved are smaller in magnitude.
Although 16 is predicted to be the least stable isomer by
more than 2 kcal/mol, it is difficult to conjecture which
candidates will be favored under equilibrating conditions.
In this paper, we describe a convergent approach to these
potential Taxol precursors and document their differing
response to R-ketol rearrangement.
(12) Harris, G. D., J r.; Herr, R. J .; Weinreb, S. M. J . Org. Chem.
1993, 58, 5452.
(13) Traas, P. C.; Boelens, H.; Takken, H. J . Tetrahedron Lett. 1976,
2287.
(14) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
(15) Paquette, L. A.; Shih, T.-L.; Zeng, Q.; Hofferberth, J . E.
Tetrahedron Lett. 1999, 40, 3519.
(16) Elmore, S. W.; Paquette, L. A. J . Org. Chem. 1995, 60, 889.
(17) (a) Paquette, L. A.; Bailey, S. J . Org. Chem. 1995, 60, 7849. (b)
J ohnston, J . N.; Tsui, H.-C.; Paquette, L. A. J . Org Chem. 1998, 63,
129.
Resu lts a n d Discu ssion
Assem bly of th e Com m on Tr icyclic P r ecu r sor .
The critical role planned for a common precursor de-
manded that a concise route be developed. This objective
was met by initial hydride reduction of the known ester
1712 and protection of the primary hydroxyl so generated
as the TBS ether (Scheme 3). A two-step procedure for
the conversion of 18 into 20 was accomplished by coupling
(18) Paquette, L. A.; Pegg, N. A.; Toops, D.; Maynard, G. D.; Rogers,
R. D. J . Am. Chem. Soc. 1990, 112, 277.
(19) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480.
J . Org. Chem, Vol. 68, No. 6, 2003 2267

Paquette and Hofferberth
SCHEME 3
SCHEME 4
aldehyde 27. The candidate reaction for elaborating the
fully functionalized C ring was the intramolecular aldol.
It was expected that this ring closure would be properly
stereocontrolled by virtue of the steric destabilization of
the pseudoaxial aldehyde conformer A relative to its
pseudoequatorial counterpart B.20 The possible operation
of metal counterion chelation also favors involvement of
the latter transition state. In early experiments, treat-
ment of 27 with lithium hexamethyldisilazide was indeed
found to give rise to 28, albeit in modest yield. Note that
the newly established stereocenters at C7 and C8 conform
precisely in absolute configuration to the structural
features resident in Taxol (10).
Ad va n cem en t in to th e Tr a n s Ser ies. With technol-
ogy available for the preparation of 30 in quantity, this
advanced intermediate was oxidized with DDQ in dry
ether containing 4 Å molecular sieves.22 As a consequence
of the presence of a neighboring free hydroxyl, the ben-
zylic carbocation so generated was trapped intramolecu-
larly to provide the PMP acetal 3123 (Scheme 5). The
endo projection of the PMP group in 31 was confirmed
by NOE analysis (see structure). Selective protection of
the secondary hydroxyl resident in 31 with benzyloxy-
methyl (BOM) chloride24 led to the isolation of 32 (43%)
and 33 (18%). Following chromatographic purification,
the bridgehead R-ketol 32 was deprotonated with 10
equiv of potassium hexamethyldisilazide in THF at -78
°C. Activation of the anionic species by means of 30 equiv
of 18-crown-6 preceded oxygenation of the cold solution.25
To improve the efficiency of the aldol cyclization,
possible catalysis by several other bases was screened.
The use of 0.5 N NaOH in 2.3:1 methanol/THF was met
not only with a doubling of efficiency but was also
accompanied by formation of a 6:1 mixture of 29 and the
transannular hydride shift product 30 (Scheme 4).21 In
an important development, the discovery was made that
potassium tert-butoxide in benzene is capable of bringing
about the wholesale conversion of 29 to 30. In final
optimized form, the conversion of 27 to 30 can be
performed in a single operation in nearly quantitative
yield, providing material of sufficient purity for use in
subsequent steps without recourse to chromatography.
Crystallographic data are available for both 29 and 30.21
(22) Stu¨rmer, R.; Ritter, K.; Hoffmann, R. W. Angew. Chem., Int.
Ed. Engl. 1993, 32, 105.
(23) (a) Oikawa, Y.; Yoshioka, T.; Yonemitzu, O. Tetrahedron Lett.
1982, 23, 889. (b) Sviridov, A. F.; Ermolenko, M. S.; Yashunsky, D. V.;
Borodkin, V. S.; Kochetkov, N. K. Tetrahedron Lett. 1987, 28, 3835.
(c) Yadav, J . S.; Chander, M. C.; J oshi, B. V. Tetrahedron Lett. 1988,
29, 2737. (d) Marshall, J . A.; Xie, S. J . Org. Chem. 1995, 60, 7230. (e)
Martin, S. F.; Hida, T.; Kym, P. R.; Loft, M.; Hodgson, A. J . Am. Chem.
Soc. 1997, 119, 3193.
(20) Paquette, L. A.; Zeng, Q.; Tsui, H.-C.; J ohnston, J . N. J . Org.
Chem. 1998, 63, 8491.
(21) Hofferberth, J . E.; Lo, H. Y.; Paquette, L. A. Org. Lett. 2001, 3,
1777.
(24) Stork, G.; Isobe, M. J . Am. Chem. Soc. 1975, 97, 4745.
(25) Paquette, L. A.; DeRussy, D. T.; Pegg, N. A.; Taylor, R T.;
Zydowsky, T. M. J . Org. Chem. 1989, 54, 4576.
2268 J . Org. Chem., Vol. 68, No. 6, 2003

R-Ketol Rearrangement in Functionalized Paclitaxel Precursors
SCHEME 5
SCHEME 6
energy of 77.1 kcal/mol to be substantially favored
relative to the Z-enol (Es ) 94.0 kcal/mol). Additionally,
the intracyclic double bond in C is projected upward in
the direction of C15 such that only the R-surface can be
approached without encountering severe nonbonded ster-
ic compression.
TABLE 2. Ch em ica l Sh ift Da ta for C2-Oxygen a ted
tr a n s-9,10-Isota xa n e P MP Aceta ls (300 MHz, CDCl3, δ)
It will be recognized that the strongly basic condi-
tions applied to 32 will result in initial generation of
the R-keto alkoxide. Notably, bridge migration operated
neither at this stage nor when the dianion was subse-
quently generated. This lack of a sufficient driving force
for rearrangement foreshadowed the properties inherent
to 34.
Heating 34 with Al(O-t-Bu)3 in benzene under condi-
tions known to isomerize structurally related systems
resulted in its rapid consumption. Detailed NMR analysis
of the product did not support the formation of 35 but
was entirely consistent with the generation of the ring-
cleaved product 36 (Scheme 6). Thus, it appeared that a
Lewis acid-promoted 1,2-hydride shift as in E was
kinetically favored, thereby giving rise to F , an interme-
diate amenable to retroaldol fragmentation. The precise
status of the several functional groups in 36 were
deduced by the application of nOe and HNDC techniques
(see the Supporting Information).
Several attempts were made to render this ring-
fragmentation process nonoperational.26 Of these, the
specific fate of dibenzoate 11 proved to be particularly
informative (Scheme 7). Introduction of the C2 R-hy-
droxyl into 31 followed the now-established protocol to
successfully deliver 37. The steric congestion present in
this triol conveniently allowed for efficient dibenzoylation
to operate at C2 and C7. With 11 available in this man-
ner, reaction with aluminum trialkoxide in the manner
defined in E is no longer possible. However, opportunities
for R-ketol rearrangement were not similarly precluded.
Notwithstanding, in no instance was conversion to taxane
R
R′
OH
R′′
Ha
Hb
Hc
H
OH
OH
OH
OBn
OH
OH
OH
2.25
3.15
3.08
3.42
3.17
3.00
3.15
5.02
5.29
5.26
5.22
5.16
5.12
5.07
4.70
4.86
4.85
4.86
4.65
4.57
4.66
OH
OH
OH
OTES
OAc
OBz
OH
OBn
OBn
OTES
OAc
OBz
After short-term exposure of the reaction mixture to
triphenylphosphine, the resultant colorless oil was shown
to be 34. This chemical transformation was accompanied
by two significant changes in the 1H NMR spectrum
(recorded in CDCl3). In the first instance, the absorptions
attributable to the exomethylene protons were displaced
from their original location (δ 5.02 and 4.71 ppm) to more
downfield positions (δ 5.26 and 4.85 ppm), presumably
as a direct consequence of the proximity of the newly
introduced C2 hydroxyl. Also, COSY analysis revealed
the new carbinyl proton having a chemical shift of 4.55
ppm to be coupled to the newly introduced hydroxyl
proton as well as to H3. Still more convincing was the
striking downfield shift of H13R that is observed when C2
is oxygenated from the R direction (Table 2).
This structural assignment was also in line with MM3
calculations involving the minimum energy conforma-
tions for enols C and D corresponding to the enolates
presumably involved in the oxidation. Following adapta-
tion of the Monte Carlo conformational searching proto-
col, additional minimization was accomplished through
use of the full-matrix Newton Raphson method. This
direct comparison revealed the E-enol with a steric
(26) Hofferberth, J . E. Ph.D. Dissertation, The Ohio State Univer-
sity, 2002.
J . Org. Chem, Vol. 68, No. 6, 2003 2269

Paquette and Hofferberth
SCHEME 7
The conversion of 42 to 43 implies that the alkoxide of
42 is particularly prone to R-ketol rearrangement. The
rapidity with which 1,2-bridge migration operates pre-
cludes oxygenation of the enolate of 42. Instead, R-oxy-
genation occurs only after the taxane framework has been
adopted.1b
Over view . Considerable process has been achieved in
our appreciation of the energetics that can conspire to
facilitate or disallow operation of the R-ketol rearrange-
ment in bridgehead R-hydroxy ketones. A trans-locked
PMP-acetal introduces steric strain too elevated for ready
isomerization to the taxane ring system. On the other
hand, the corresponding cis acetal is so prone to struc-
tural change that proper C2 oxygenation cannot be
accomplished. Neither scenario is conducive to a concise
synthesis of Taxol. In the following paper,27 additional
subtleties associated with this chemistry are presented
and a workable advance involving a favorable rearrange-
ment arising from a derivative of 39 (where it appears
as 3) is therein documented.
Exp er im en ta l Section
Vin yl Br om id e 18. To a slurry of lithium aluminum
hydride (2.75 g, 66 mmol) in ether (60 mL) was added dropwise
a solution of 17 in ether (40 mL) at a rate such that a gentle
reflux was maintained. The reaction mixture was stirred for
3 h and carefully quenched with water (8 mL) and 1 N NaOH
(2.5 mL). The resulting suspension was stirred for 3 h to obtain
a flocculent white precipitate. The slurry was filtered, the
filtrate was dried and evaporated, and the residue was
dissolved in dry CH2Cl2 (200 mL). To the resulting solution
were added freshly distilled Et3N (9.2 mL, 66 mmol), DBU (2.0
mL, 13.2 mmol), and tert-butyldimethylsilyl chloride (10.93 g,
72.5 mmol). The cloudy reaction mixture was stirred overnight,
diluted with CH2Cl2 (200 mL), and washed with 5% HCl (200
mL), saturated NaHCO3 solution (200 mL), and brine (200
mL). The organic layer was dried, filtered, and freed of solvent
to leave a residue that was chromatographed over silica gel
(elution with 2% EtOAc in hexane) to give 18 (15.74 g, 95%
for two steps) as a clear oil: IR (neat, cm-1) 1256, 1206, 1104;
1H NMR (300 MHz, CDCl3) δ 5.57 (s, 1 H), 5.40 (s, 1 H), 3.64
(t, J ) 6.1 Hz, 2 H), 2.52 (t, J ) 7.2 Hz, 2 H), 1.75 (tt,J ) 7.2,
6.1 Hz, 1 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR (75 MHz,
CDCl3) δ 140.5, 128.2, 62.6, 31.0, 26.1 (3C), 24.5, 18.7, -5.1
(2C); EI HRMS m/z (M+) calcd 278.0701, obsd 278.0672.
Ald eh yd e 19. A solution of 18 (10.0 g, 35.8 mmol) in THF
(300 mL) was cooled to -78 °C, and tert-butyllithium (1.42 M
in pentane, 53.6 mL, 76.1 mmol) was added in one portion.
The resulting mixture was stirred for 30 min, and neat DMF
(27.7 mL, 358 mmol) was introduced at a rate of 0.5 mL/min.
Following the addition, stirring was maintained for 3 h at -78
°C prior to quenching with saturated NH4Cl solution (200 mL)
and extraction of the aqueous phase with ether (3 × 200 mL).
The combined organic layers were washed with water (200 mL)
and brine (200 mL), dried, and filtered. The solvent was
removed under reduced pressure, and the residue was chro-
matographed over silica gel (elution with 10% EtOAc in
hexane) to give 19 as a yellow oil (8.05 g, 99%): 1H NMR (300
MHz, CDCl3) δ 9.51 (s, 1 H), 5.57 (s, 1 H), 5.40 (s, 1 H), 3.64
(t, J ) 6.1 Hz, 2 H), 2.52 (t, J ) 7.2 Hz, 2 H), 1.75 (tt, J ) 7.2,
6.1 Hz, 2 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR (75 MHz,
CDCl3) δ 194.8, 140.5, 128.2, 62.6, 31.0, 26.1 (3C), 24.5, 18.7,
-5.1 (2C).
12 achieved. In one of the survey experiments, 11 was
heated with aluminum tri-tert-butoxide in benzene.
Under these conditions, isomerization to 13 (95%) was
prevalent. Alternative treatment of 11 with the more
potent Lewis acid ethylaluminum dichloride in CH2Cl2
at low temperature afforded 38. This eventuality is the
result of a transannular hydride shift process that is
accorded mechanistic rationalization in the sequel.27 The
structural assignments to 11, 13, and 38 are fully con-
sistent with the HMBC studies compiled in the Support-
ing Information.
The preferential isomerization of 11 to 13 is consistent
with the MM3-derived steric energy values found in
Table 1. Once the equilibration of 11 is initiated, the
system advances in the direction of the global energy
minimum, which in this instance happens not to be a
taxane.
P r obe of Rea ctivity in th e Cis Ser ies. To address
the matter of preparing a cis PMP-acetal related to 32,
we began by subjecting 30 to regioselective silylation and
base-promoted transannular hydride migration.21 In turn,
39 was reduced with LiAlH4 in order to achieve stereo-
selective introduction of the C9 hydroxyl on the â face1a
(Scheme 8). DDQ oxidation of triol 40 in dry ether led
quantitatively to the desired benzylidine acetal 41. The
conformational rigidity of this intermediate was particu-
larly conducive to NOE analysis, this technique serving
to confirm the overall stereochemical relationships of its
functional groups, most relevantly at C-9 and the PMP-
substituted carbon. Swern oxidation of 41 proved to be a
reasonably sluggish process, but extended reaction times
had to be skirted because of side-product formation. At
this stage, we had need to introduce an R-hydroxyl at
C2 to correspond to the Taxol substitution profile. Oxida-
tion of 42 under the predescribed basic conditions af-
forded 43 in 76% yield.
Iod obu ta d ien e 20. To a suspension of iodomethyltriphen-
ylphosphonium iodide (9.10 g, 17.1 mmol) in THF (150 mL)
cooled to 0 °C was added a solution of sodium hexamethyld-
isilazide (0.79 M in THF, 21.6 mL, 17.1 mmol). The ylide
solution was stirred for 20 min and cooled to -78 °C. The
reaction flask was covered with aluminum foil to avoid
(27) Paquette, L. A.; Lo, H. Y.; Hofferberth, J . E.; Gallucci, J . C. J .
Org. Chem. 2003, 68, 2276.
2270 J . Org. Chem., Vol. 68, No. 6, 2003

R-Ketol Rearrangement in Functionalized Paclitaxel Precursors
SCHEME 8
exposure to light, and a solution of 19 (3.0 g, 13.1 mmol) in
THF (50 mL) was introduced via cannula. The reaction
mixture was stirred for 3 h and warmed to -30 °C. At this
temperature, saturated NH4Cl solution (200 mL) was intro-
duced, and the aqueous layer was extracted with ether (3 ×
100 mL). The combined organic layers were washed with brine
(200 mL), dried, and freed of solvent under reduced pressure.
The residue was chromatographed over silica gel in an
aluminum foil-wrapped column (elution with 10% EtOAc in
hexane) to give 20 as a clear yellow oil (4.08 g, 88%) which
decomposed rapidly in light or in the dark at rt. However, the
iodide can be preserved for up to 72 h by immediately freezing
it in benzene. For 20: 1H NMR (300 MHz, C6D6) δ 6.58 (d,
J ) 8.5 Hz, 1 H), 6.26 (d, J ) 8.5 Hz, 1 H), 5.19 (s, 1 H), 5.05
(s, 1 H), 3.53 (t, J ) 7.8 Hz, 2 H), 2.19 (t, J ) 7.8 Hz, 2 H),
1.55-1.71 (m, 2 H), 0.80 (s, 9 H), 0.00 (s, 6 H).
Con ver gen t Syn th esis of Nor bor n a n ol 22. A stirred
solution of 20 (4.6 g, 13 mmol) in dry ether (100 mL) at -78
°C was treated with tert-butyllithium (1.1 M in pentane, 23.6
mL, 26 mmol), stirred for 2 min, and admixed with a solution
of 21 (4.6 g, 16 mmol) in dry ether (150 mL) via cannula. The
reaction mixture was stirred for 3 h at -78 °C, warmed to 0
°C over 30 min, quenched with saturated NH4Cl solution (250
mL), and extracted with ether (3 × 150 mL). The combined
organic layers were dried, filtered, and freed of solvent under
reduced pressure. The residue was chromatographed over
silica gel (elution with 1-3.5% EtOAc in hexane) to afford
22 as a yellowish oil (6.57 g, 96%) alongside recovered 21
(0.51 g).
For 22: IR (neat, cm-1) 3511, 1608, 1507; 1H NMR (300
MHz, C6D6) δ 7.23 (d, J ) 8.6 Hz, 2 H), 6.79 (d, J ) 8.6 Hz, 2
H), 6.55 (dd, J ) 17.8, 11.0 Hz, 1 H), 5.80 (d, J ) 12.6 Hz, 1
H), 5.68 (d, J ) 12.6 Hz, 1 H), 5.35 (dd, J ) 11.0, 2.2 Hz, 1 H),
5.18 (s, 1 H), 5.09 (dd, J ) 17.8, 2.2 Hz, 1 H), 4.96 (s, 1 H),
4.38 (dd, J ) 18.6, 10.8 Hz, 2 H), 3.67 (s, 1 H), 3.58 (t, J )
6.3 Hz, 2 H), 3.52 (s, 1 H), 3.33 (s, 3 H), 2.26 (t, J ) 9.6 Hz,
2 H), 1.92 (d, J ) 4.6 Hz, 1 H), 1.78-1.60 (m, 3 H), 1.58 (s,
3 H), 1.48-1.44 (m, 1 H), 0.99 (s, 9 H), 0.96-0.91 (m, 2 H),
0.84 (s, 3 H), 0.07 (s, 6 H); 13C NMR (75 MHz, C6D6) δ 160.1,
146.9, 137.1, 136.1, 131.3, 130.3, 129.8 (2C), 117.3, 114.6
(2C), 114.0, 88.4, 83.2, 71.7, 63.3, 60.5, 55.2, 50.6, 49.1, 34.5,
32.1, 26.5, 26.0, 24.7, 23.2, 22.9, 18.9 (3C), -4.8 (2C); EI HRMS
m/z (M+) calcd 526.3478, obsd 526.3455; [R] -105.4 (c 1.06,
CHCl3).
(6.8 mL, 110 mmol) in THF (70 mL) was added. The reaction
mixture was stirred for 3 h at -78 °C, quenched by the
addition of brine, and extracted with ether (3 × 250 mL). The
combined organic layers were dried, filtered, and evaporated.
The residue was chromatographed over silica gel (elution with
1.5% EtOAc in hexane) to give 23 as a yellowish oil (4.8 g,
1
81%): IR (neat, cm-1) 1710, 1613, 1514; H NMR (300 MHz,
CDCl3) δ 7.22 (d, J ) 8.5 Hz, 2 H), 6.84 (d, J ) 8.6 Hz, 2 H),
5.32 (dd, J ) 11.7, 4.6 Hz, 1 H), 4.92 (s, 1 H), 4.87 (s, 1 H),
4.52 (d, J ) 12.0 Hz, 1 H), 4.01 (d, J ) 12.0 Hz, 1 H), 3.79 (s,
3 H), 3.68 (dd, J ) 6.5, 3.8 Hz, 2 H), 3.61 (d, J ) 1.6 Hz, 1 H),
2.72 (dd, J ) 8.2, 3.6 Hz, 1 H), 2.70-2.10 (m, 8 H), 1.85-1.65
(m, 2 H), 1.61-1.45 (m, 2 H), 1.22 (s, 3 H), 1.06 (s, 3 H), 1.03
(d, J ) 7.2 Hz, 3 H), 0.91 (s, 9 H), 0.07 (s, 6 H); 13C NMR (75
MHz, CDCl3) δ 212.0, 159.2, 150.8, 148.4, 130.9, 129.2 (2C),
122.9, 113.9 (2C), 111.9, 89.8, 71.2, 63.6, 55.5, 54.9, 53.3, 45.9,
45.7, 32.2, 30.5, 30.4, 26.8, 26.3, 26.2 (3C), 26.1, 23.8, 20.5,
18.6, -5.0 (2C); FAB LRMS m/z (M + H)+ calcd 541.37, obsd
541.38; [R] -21.2 (c 1.68, CHCl3).
Dih yd r oxyla tion of 23. To a solution of 23 (1.6 g, 2.9
mmol) in acetone (800 mL) at 0 °C were added NMO‚H2O (805
mg, 5.9 mmol), OsO4 (254 mg, 0.89 mmol), and water (1 mL).
The reaction mixture was stirred for 5 days at 0 °C, quenched
with 10% sodium dithionite solution (50 mL), and stirred for
2 h at 0 °C prior to dilution with water and extraction with
CH2Cl2 (3 × 300 mL). The combined organic layers were dried,
filtered, and evaporated to leave a residue that was chromato-
graphed over silica gel (elution with 14% EtOAc in hexane) to
give 24 as a pale tan oil (900 mg, 54%, 75% at 70% conversion)
and unreacted 23 (470 mg, 30%); IR (neat, cm-1) 3416, 1700,
1612, 1514; 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J ) 8.6 Hz,
2 H), 6.85 (d, J ) 8.6 Hz, 2 H), 4.98 (s, 1 H), 4.91 (s, 1 H), 4.45
(d, J ) 11.5 Hz, 1 H), 4.09 (d, J ) 11.5 Hz, 1 H), 3.88 (s, 1 H),
3.79 (s, 3 H), 3.65-3.57 (m, 3 H), 3.35 (s, 1 H), 2.89 (s, 1 H),
2.76-2.70 (m, 1 H), 2.68-2.35 (m, 3 H), 2.14-2.01 (m, 3 H),
1.95-1.80 (m, 3 H), 1.70-1.56 (m, 3 H), 1.09 (s, 3 H), 1.04 (s,
3 H), 1.00 (d, J ) 6.7 Hz, 3 H), 0.89 (s, 9 H), 0.05 (s, 6 H); 13
C
NMR (75 MHz, CDCl3) δ 213.1, 159.4, 149.4, 130.2, 129.4 (2C),
113.9 (2C), 111.9, 90.6, 83.1, 71.2, 69.3, 62.6, 56.4, 55.4, 50.2,
48.4, 37.0, 34.9, 32.8, 32.0, 31.7, 30.1, 28.6, 26.2 (3C), 18.5,
17.0, 9.7, -5.1 (2C); FAB LRMS m/z (M + H)+ calcd 575.38,
obsd 575.35; [R] +175.7 (c 0.94, CHCl3).
Cyclic Ca r bon a tes 25 a n d 26. To a solution of 24 (1.1 g,
1.9 mmol) in CH2Cl2 (120 mL) at -78 °C were added pyridine
(1.5 mL, 19 mmol) and a solution of phosgene (1.9 M in toluene,
5.0 mL, 9.6 mmol). The reaction mixture was stirred for 15
min at -78 °C and quenched by the addition of water (100
mL). After reaching rt, the reaction mixture was extracted with
CH2Cl2 (3 × 100 mL). The combined organic layers were dried,
filtered, and evaporated to give 25 as a tan oil. This material
was directly dissolved in methanol (100 mL), and Dowex 50X4-
400 (350 mg) was added. The suspension was stirred for 2.5
h, filtered, and freed of solvent to leave a residue that was
chromatographed on silica gel (elution with 35-45% EtOAc
An ion ic Rea r r a n gem en t a n d Meth yla tion of 22. A dry
1 L round-bottomed flask was charged with 18-cr-6 (10.1 g,
38 mmol) pumped down under high vacuum for 24 h and filled
with an argon atmosphere. A solution of 22 (5.78 g, 11 mmol)
in THF (380 mL) was added, and the reaction mixture was
cooled to -78 °C, treated with
a solution of potassium
hexamethyldisilazide (0.48 M in toluene, 68 mL, 33 mmol) via
cannula over 4 min, allowed to warm to -40 °C over 1 h, and
stirred at that temperature for 25 min. The reaction vessel
was returned to -78 °C, and a solution of freshly distilled MeI
J . Org. Chem, Vol. 68, No. 6, 2003 2271

Paquette and Hofferberth
in hexane) to give 26 as a colorless oil (890 mg, 96% for two
9.4; EI HRMS m/z (M+) calcd 484.2461, obsd 484.2461; [R]
-12.7 (c 0.34, CHCl3).
steps).
1
For 25: IR (neat, cm-1) 1805, 1704, 1611, 1510; H NMR
Ald ol Cycliza tion of 27 P r om oted by Sod iu m Hyd r ox-
id e. Tr a n sa n n u la r Hyd r id e Sh ift. A solution of 27 (119 mg,
0.25 mmol) in methanol (4 mL) was treated with THF (800
µL) and 0.5 N NaOH (2.5 mL, 1.2 mmol), stirred overnight,
quenched with saturated NH4Cl solution, and extracted with
EtOAc (3 × 20 mL). The combined organic layers were dried,
filtered, and freed of solvent under reduced pressure. The
residue was chromatographed over silica gel (elution with 15%
EtOAc in hexane) to give 29 (77 mg, 68%) and 30 (14 mg, 12%),
both as white solids.
(300 MHz, CDCl3) δ 7.21 (d, J ) 8.7 Hz, 2 H), 6.86 (d, J ) 8.7
Hz, 2 H), 5.04 (s, 1 H), 4.88 (s, 1 H), 4.46 (dd, J ) 12.5, 3.5 Hz,
1 H), 4.38 (d, J ) 11.3 Hz, 1 H), 4.06 (d, J ) 11.3 Hz, 1 H),
3.93 (s, 1 H), 3.79 (s, 3 H), 3.66-3.57 (m, 2 H), 2.69-2.57 (m,
3 H), 2.34 (dd, J ) 6.7, 1.9 Hz, 1 H), 2.26-2.00 (m, 5 H),
1.85-1.56 (m, 4 H), 1.17 (s, 6 H), 1.01 (d, J ) 6.7 Hz, 3 H),
0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 212.4,
159.4, 152.9, 148.1, 129.4 (3C), 113.8 (2C), 112.1, 93.8, 89.5,
76.8, 70.9, 62.1, 55.2, 54.5, 49.2, 48.8, 34.9, 31.7, 31.6, 31.4,
29.3, 28.5, 27.9, 25.9 (3C), 18.3, 15.9, 8.3, -5.3 (2C); FAB
LRMS m/z (M+) calcd 600.35, obsd 600.28; [R] +28.2 (c 3.2,
CHCl3).
For 29: mp 155-156 °C; IR (neat, cm-1) 3431, 1691, 1642,
1
1612; H NMR (300 MHz, CDCl3) δ 7.29 (d, J ) 8.7 Hz, 2 H),
6.86 (d, J ) 8.7 Hz, 2 H), 4.99 (s, 1 H), 4.86 (s, 1 H), 4.51 (d,
J ) 12.1 Hz, 1 H), 4.41 (d, J ) 2.9 Hz, 1 H), 4.18-4.11 (m, 2
H), 3.85-3.83 (m, 1 H), 3.80 (s, 3 H), 3.14 (s, 1 H), 2.77-2.65
(m, 3 H), 2.54-2.40 (m, 2 H), 2.20-1.37 (m, 9 H), 1.08 (s, 6
H), 1.00 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 213.4, 159.1,
145.9, 131.5, 129.0 (2C), 113.9 (2C), 111.1, 86.1, 83.6, 75.8, 71.1,
69.4, 59.6, 56.4, 55.5, 49.4, 38.6, 34.5, 33.8, 32.4, 32.2, 29.9,
26.2, 17.3, 9.8; ES HRMS m/z (M + Na)+ calcd 481.2566, obsd
481.2572; [R] -153.7 (c 0.35, CHCl3).
1
For 26: IR (neat, cm-1) 3520, 1797, 1700, 1611, 1509; H
NMR (300 MHz, C6D6) δ 7.19 (d, J ) 8.6 Hz, 2 H), 6.86 (d, J
) 8.6 Hz, 2 H), 5.04 (s, 1 H), 4.87 (s, 1 H), 4.43 (dd, J ) 9.0,
3.9 Hz, 1 H), 4.42 (d, J ) 11.5 Hz, 1 H), 4.09 (d, J ) 11.5 Hz,
1 H), 3.91 (s, 1 H), 3.79 (s, 3 H), 3.63 (dt, J ) 6.1, 1.7 Hz, 2 H),
2.67-2.55 (m, 3 H), 2.33-1.92 (m, 5 H), 1.84-1.55 (m, 5 H),
1.16 (s, 6 H), 0.99 (d, J ) 6.7 Hz, 3 H), OH not apparent; 13C
NMR (75 MHz, CDCl3) δ 212.6, 159.6, 153.2, 148.3, 129.9 (2C),
129.5, 114.1 (2C), 112.3, 94.1, 89.0, 77.0, 71.0, 62.2, 55.5, 54.6,
49.4, 48.9, 35.2, 31.9, 31.6, 31.4, 29.6, 28.6, 28.2, 16.1, 8.5; EI
HRMS m/z (M+) calcd 486.2617, obsd 486.2617; [R] +40.8 (c
2.7, CHCl3).
Ald eh yd e 27. To a solution of oxalyl chloride (0.57 mL, 6.6
mmol) in CH2Cl2 (25 mL) at -78 °C was added a solution of
DMSO (0.93 mL, 13 mmol) in CH2Cl2 (25 mL). The resulting
solution was stirred for 10 min, and a solution of 26 (800 mg,
1.6 mmol) in CH2Cl2 (25 mL) was added via cannula. After 1
h at -78 °C, freshly distilled Et3N (2.2 mL, 16 mmol) was
introduced, stirring was maintained for 20 min at -78 °C, and
warming to rt ensued over 1 h, prior to quenching with water
and extraction with CH2Cl2 (3 × 100 mL). The combined
organic layers were dried, filtered, and evaporated to leave a
yellow residue that was chromatographed over silica gel
(elution with 25-30% EtOAc in hexane) to give 27 (780 mg,
98%) as a colorless oil: IR (neat, cm-1) 1801, 1721, 1705, 1612,
1509; 1H NMR (300 MHz, CDCl3) δ 9.80 (s, 1 H), 7.21 (d, J )
8.6 Hz, 2 H), 6.87 (d, J ) 8.6 Hz, 2 H), 5.01 (s, 1 H), 4.94 (s, 1
H), 4.45 (dd, J ) 12.3, 3.4 Hz, 1 H), 4.42 (d, J ) 11.5 Hz, 1 H),
4.11 (d, J ) 11.6 Hz, 1 H), 3.95 (s, 1 H), 3.81 (s, 3 H), 2.69-
2.62 (m, 4 H), 2.36-2.14 (m, 6 H), 1.82-1.77 (m, 2 H), 1.65-
1.55 (m, 1 H), 1.19 (s, 6 H), 1.01 (d, J ) 6.7 Hz, 3 H); 13C NMR
(75 MHz, CDCl3) δ 211.4, 200.8, 159.7, 153.1, 147.2, 129.8 (2C),
129.5, 114.1 (2C), 112.3, 94.0, 89.2, 76.9, 71.1, 55.5, 54.6, 49.5,
48.8, 42.5, 36.3, 31.6, 29.6, 28.7, 28.3, 27.2, 16.1, 8.7; EI HRMS
m/z (M+) calcd 484.2461, obsd 484.2452; [R] +40.0 (c 0.6,
CHCl3).
For 30: mp 158-160 °C; IR (neat, cm-1) 3406, 1681, 1644,
1
1613; H NMR (300 MHz, CDCl3) δ 7.23 (d, J ) 8.7 Hz, 2 H),
6.88 (d, J ) 8.7 Hz, 2 H), 4.97 (s, 1 H), 4.89 (s, 1 H), 4.67 (d,
J ) 10.7 Hz, 1 H), 4.63 (s, 1 H), 4.43 (d, J ) 10.9 Hz, 1 H),
4.39 (s, 1 H), 4.03 (dd, J ) 11.1, 4.5 Hz, 1 H), 3.80 (s, 3 H),
3.75 (dd, J ) 9.5, 1.8 Hz, 1 H), 3.54 (d, J ) 9.1 Hz, 1 H), 3.08
(s, 1 H), 2.93-2.86 (m, 1 H), 2.77-2.60 (m, 3 H), 2.58-2.45
(m, 1 H), 2.41-2.34 (m, 1 H), 2.24-1.99 (m, 3 H), 1.88-1.82
(m, 1 H), 1.80-1.65 (m, 1 H), 1.60-1.46 (m, 1 H), 1.14 (s, 3
H), 1.05 (s, 3 H), 1.04 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
217.2, 159.8, 146.8, 129.8 (2C), 129.1, 114.3 (2C), 110.1, 87.7,
83.0, 77.6, 73.7, 73.6, 55.5, 50.3, 48.9, 44.7, 44.2, 39.7, 34.4,
31.4, 31.0, 30.4, 25.8, 19.3, 12.5; EI HRMS m/z (M - H)+ calcd
457.2590, obsd 457.2545; [R] -37.6 (c 1.54, CHCl3).
Con ver sion of 29 to 30. To a solution of 29 (36 mg, 0.079
mmol) in dry benzene (20 mL) was added potassium tert-
butoxide (5.0 mg, 0.044 mmol). The suspension was stirred
for 30 min and quenched with pH 8 buffer (NH4Cl/NH4OH,
saturated). The resulting biphasic suspension was stirred for
10 min, and the aqueous layer was removed. To the organic
phase was added MgSO4, and the suspension was stirred for
10 min, filtered, and freed of solvent under reduced pressure
to give 30 (32 mg, 89%). 1H NMR analysis of this material
indicated it to be >98% pure).
Dir ect Con ver sion of 27 to 30. To a solution of 27 (786
mg, 1.6 mmol) in methanol (16.3 mL) were added THF (5.5
µL) and 0.5 N NaOH (16.3 mL, 8.1 mmol). The resulting
solution was stirred overnight, quenched with saturated
NH4Cl solution, and extracted with benzene (3 × 330 mL). The
combined organic layers were dried and filtered. To this
benzene solution was added potassium tert-butoxide (330 mg,
2.9 mmol), and the suspension was stirred for 30 min,
quenched with pH 8 buffer (NH4Cl/NH4OH, saturated), and
stirred 20 min longer. The separated organic layer was dried
and freed of solvent under reduced pressure to give 30 (728
mg, 99%).
The structural assignments to both 29 and 30 were con-
firmed by three-dimensional crystallographic analysis.21
DDQ Oxid a tion of 30. To a solution of 30 (2.4 g, 5.2 mmol)
in dry ether (450 mL) were added 4 Å molecular sieves (2 g).
In a separate flask, a solution of DDQ (1.3 g, 5.8 mmol) in dry
ether (400 mL) was prepared, and to it were added 4 Å
molecular sieves (1 g). Both suspensions were stirred sepa-
rately for 1 h. While both were being vigorously stirred, the
DDQ suspension was cannulated into the solution of 30. The
resulting suspension turned rapidly from yellow to green. After
6 h, saturated NH4Cl solution was introduced, and the product
was extracted into ether (3 × 300 mL). The combined organic
layers were dried, filtered, and evaporated to leave a waxy
Ald ol Cycliza tion of 27 P r om oted by P ota ssiu m Hex-
a m eth yld isila zid e. A dry 25 mL round-bottomed flask was
charged with 27 (24 mg, 0.050 mmol), 18-cr-6 (70 mg, 0.25
mmol), and dry THF (2 mL). The resulting solution was cooled
to -78 °C, and potassium hexamethyldisilizide (0.5 M in
toluene, 109 µL, 0.055 mmol) was added. The reaction mixture
was warmed to rt over 3 h, stirred overnight, quenched with
saturated NH4Cl solution, and extracted with EtOAc (3 × 20
mL). The combined organic layers were dried, filtered, and
evaporated to leave a residue that was chromatographed over
silica gel (elution with 10-30% EtOAc in hexane) to give 28
(9.7 mg, 40%) as a colorless oil: IR (neat, cm-1) 3482, 1801,
1
1779, 1696, 1612; H NMR (300 MHz, CDCl3) δ 7.26 (d, J )
8.6 Hz, 2 H), 6.86 (d, J ) 8.6 Hz, 2 H), 5.04 (s, 1 H), 4.81 (s, 1
H), 4.71 (dd, J ) 12.4, 3.7 Hz, 1 H), 4.47 (d, J ) 11.8 Hz, 1 H),
4.46 (d, J ) 2.7 Hz, 1 H), 4.16-4.09 (m, 2 H), 3.81 (s, 3 H),
2.71-2.43 (m, 4 H), 2.18-1.80 (m, 7 H), 1.59-1.54 (m, 1 H),
1.34-1.27 (m, 1 H), 1.24 (s, 3 H), 1.16 (s, 3 H), 1.05 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 213.6, 158.9, 153.1, 144.8, 130.9,
128.8 (2C), 113.7 (2C), 111.6, 93.6, 84.6, 76.2, 75.5, 70.7, 58.9,
55.3, 53.9, 48.7, 37.4, 34.3, 32.2, 31.8, 28.7, 28.3, 25.6, 16.3,
2272 J . Org. Chem., Vol. 68, No. 6, 2003

R-Ketol Rearrangement in Functionalized Paclitaxel Precursors
yellow solid that was recrystallized from methanol to give 31
point the reaction was complete by TLC analysis. The hydro-
peroxide was reduced by the addition of triphenylphosphine
(40 mg) and vigorous stirring for 10 min prior to quenching
with half-saturated brine and extraction with EtOAc (3 × 30
mL). The combined organic layers were dried, filtered, and
freed of solvent under reduced pressure. The residue was
chromatographed on silica gel (elution with 15-25% EtOAc
in hexane) to give 34 (22 mg, 74%) as a colorless oil: IR (neat,
(1.8 g, 78%) as white rods: mp 171-174 °C; IR (neat, cm-1
)
3486, 1682, 1644, 1614; 1H NMR (500 MHz, CDCl3) δ 7.30 (d,
J ) 8.6 Hz, 2 H), 6.90 (d, J ) 8.6 Hz, 2 H), 5.75 (s, 1 H),
5.02 (s, 1 H), 4.70 (s, 1 H), 4.39 (dd, J ) 9.6, 1.9 Hz, 1 H),
4.20-4.16 (m, 2 H), 3.85 (d, J ) 9.6 Hz, 1 H), 3.80 (s, 3 H),
3.05-2.95 (m, 2 H), 2.90-2.50 (m, 4 H), 2.45-2.35 (m, 1 H),
2.30-2.22 (m, 1 H), 2.20-2.05 (m, 2 H), 2.00-1.90 (m, 1 H),
1.80-1.70 (m, 1 H), 1.65-1.50 (m, 1 H), 1.17 (s, 3 H), 1.15 (s,
3 H), 1.00 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 217.5, 160.9,
146.3, 128.8, 128.6 (2C), 114.1 (2C), 110.2, 100.3, 87.3, 84.9,
83.1, 72.2, 55.5, 48.7, 47.8, 44.9, 43.5, 40.2, 34.4, 31.6, 30.9,
29.3, 25.5, 19.9, 12.8; EI HRMS m/z (M+) calcd 456.2512, obsd
456.2515; [R] -8.2 (c 2.4, CHCl3).
1
cm-1) 3426, 1673, 1615, 1589; H NMR (500 MHz, CDCl3) δ
7.40-7.30 (m, 7 H), 6.86 (d, J ) 8.7 Hz, 2 H), 5.69 (s, 1 H),
5.26 (s, 1 H), 4.96 (d, J ) 6.8 Hz, 1 H), 4.88 (d, J ) 6.8 Hz, 1
H), 4.85 (s, 1 H), 4.70 (d, J ) 11.9 Hz, 1 H), 4.59 (d, J ) 11.9
Hz, 1 H), 4.55 (dd, J ) 11.5, 2.2 Hz, 1 H), 4.25 (dd, J ) 8.8,
2.0 Hz, 1 H), 3.97 (dd, J ) 10.7, 4.4 Hz, 1 H), 3.80 (s, 3 H),
3.62 (d, J ) 8.8 Hz, 1 H), 3.08 (ddd, J ) 14.6, 10.3, 3.6 Hz, 1
H), 3.03 (s, 1 H), 2.69 (d, J ) 11.8 Hz, 1 H), 2.66 (d, J ) 11.5
Hz, 1 H), 2.61 (d, J ) 2.2 Hz, 1 H), 2.54-2.46 (m, 1 H), 2.45-
2.42 (m, 1 H), 2.33-2.30 (m, 1 H), 2.17-1.99 (m, 2 H), 1.72-
1.66 (m, 1 H), 1.65-1.48 (m, 1 H), 1.20 (s, 3 H), 1.19 (s, 3 H),
1.16 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 211.1, 171.3, 160.7,
143.8, 137.8, 128.9 (2C), 128.8 (2C), 128.6, 128.1 (2C), 128.0,
114.0 (2C), 111.9, 101.0, 93.8, 87.4, 82.1, 81.8, 78.8, 70.3, 55.6,
49.4, 49.3, 47.5, 45.3, 35.1, 29.5, 29.1, 28.8, 24.8, 19.9, 14.5;
ES HRMS m/z (M + Na)+ calcd 615.2935, obsd 615.2912; [R]
-30.2 (c 0.33, CHCl3).
B-Rin g F r a gm en ta tion of 34. A solution of 34 (3.0 mg,
5.0 µmol) in dry benzene (1 mL) was treated with aluminum
tri-tert-butoxide (5.8 mg, 0.024 mmol), stirred at reflux for 50
min, and quenched with saturated Rochelle’s salt solution. The
product was extracted into EtOAc (3 × 10 mL), and the
combined organic layers were dried, filtered, and freed of
solvent under reduced pressure. The residue was chromato-
graphed on silica gel (elution with 6-12% EtOAc in hexane)
to give 36 as a cloudy oil (2.4 mg, 80%): IR (neat, cm-1) 3446,
1732, 1615, 1517; 1H NMR (300 MHz, CDCl3) δ 7.60-7.27 (m,
7 H), 6.85 (d, J ) 8.8 Hz, 2 H), 5.50 (s, 1 H), 4.98 (s, 1 H), 4.82
(d, J ) 6.7 Hz, 1 H), 4.77 (d, J ) 6.7 Hz, 1 H), 4.63 (d, J )
11.6 Hz, 1 H), 4.53 (s, 1 H), 4.52 (d, J ) 11.6 Hz, 1 H), 4.46 (d,
J ) 7.0 Hz, 1 H), 4.25 (dd, J ) 12.7, 3.1 Hz, 1 H), 4.21 (dd, J
) 12.7, 3.1 Hz, 1 H), 4.08 (d, J ) 6.7 Hz, 1 H), 3.80 (s, 3 H),
3.60 (dd, J ) 7.3, 3.3 Hz, 1 H), 3.34 (s, 1 H), 3.06 (t, J ) 3.1
Hz, 1 H), 2.50-1.85 (m, 8 H), 1.67-1.55 (m, 1 H), 1.34 (s, 3
H), 1.08 (s, 3 H), 1.03 (s, 3 H); ES HRMS m/z (M + Na)+ calcd
615.2928, obsd 615.2975.
BOM P r otection of 31. To a solution of 31 (65 mg, 0.14
mmol) in DMPU (2.5 mL) were added 4 Å molecular sieves
(100 mg), Hunig’s base (490 µL, 2.8 mmol), and BOMCl (221
µL, 1.4 mmol). The flask was shielded from light with
aluminum foil, and tetra-n-butylammonium iodide (5.0 mg,
0.014 mmol) was added. The reaction mixture was warmed to
70 °C, stirred for 16 h, treated with additional BOMCl (100
µL, 0.64 mmol), and stirred at 70 °C for an additional 24 h.
The flask was cooled to rt, and methanol was added. The
resulting suspension was stirred for 1 h, water and saturated
NH4Cl solution were added, the product was extracted into
EtOAc (3 × 30 mL), and the combined organic layers were
dried, filtered, and evaporated. The remaining DMPU was
removed under high vacuum and the yellow residue was
chromatographed on silica gel (elution with 6-10% EtOAc in
hexane) to give 32 as a pale yellow oil (30 mg, 43%) and 33 as
a pale yellow glass (15 mg, 18%) alongside unreacted 31 (10
mg, 15%).
1
For 32: IR (neat, cm-1) 3500, 1674, 1644, 1614; H NMR
(500 MHz, CDCl3) δ 7.41-7.30 (m, 7 H), 6.91 (d, J ) 8.4 Hz,
2 H), 5.73 (s, 1 H) 5.03 (d, J ) 6.8 Hz, 1 H), 5.02 (s, 1 H),
4.95 (d, J ) 6.8 Hz, 1 H), 4.76 (d, J ) 11.8 Hz, 1 H), 4.71 (s,
1 H), 4.63 (d, J ) 11.9 Hz, 1 H), 4.32 (d, J ) 8.8 Hz, 1 H),
4.04 (dd, J ) 11.3, 4.2 Hz, 1 H), 3.84 (s, 3 H), 3.71 (d, J )
8.8 Hz, 1 H), 3.13 (s, 1 H), 2.97 (dd, J ) 15.3, 1.9 Hz, 1 H),
2.86 (dd, J ) 15.4, 12.6 Hz, 1 H), 2.77 (d, J ) 11.4 Hz, 1 H),
2.71 (d, J ) 12.1 Hz, 1 H), 2.65-2.59 (m, 1 H), 2.49-2.46
(m, 1 H), 2.35-2.26 (m, 2 H), 2.17-2.10 (m, 2 H), 1.74-1.63
(m, 2 H), 1.24 (s, 3 H), 1.20 (s, 3 H), 1.14 (s, 3 H); 13C NMR
(125 MHz, CDCl3) δ 216.5, 160.5, 146.4, 137.6, 129.2, 128.6
(2C), 128.5, 128.3 (2C), 127.9 (2C), 113.7 (2C), 109.7, 100.9,
93.7, 87.6, 82.8, 81.7, 79.1, 70.0, 55.3, 48.8, 48.1, 44.8, 44.3,
41.3, 34.4, 30.8, 29.3, 28.0, 25.4, 19.4, 12.9; ES HRMS m/z (M
+ Na)+ calcd 599.2985, obsd 599.2991; [R] -27.6 (c 1.21,
CHCl3).
r-Oxygen a tion of 31. Through a solution of 31 (250 mg,
0.55 mmol) and 18-crown-6 (1.2 g, 4.5 mmol) in dry THF (60
mL) at -78 °C was bubbled dry molecular oxygen for 3 min.
With continued bubbling, a solution of potassium hexameth-
yldisilazide (0.50 M in toluene, 6.6 mL, 3.3 mmol) was added.
The reaction mixture was stirred with continuous bubbling
for 10 min at -78 °C. The bubbling was arrested and under
an atmosphere of O2 the solution was warmed to 0 °C and
stirred for 1 h. Dimethyl sulfide (1 mL) was introduced, and
the solution was stirred at rt for 1 h, quenched with water,
and extracted with EtOAc (3 × 100 mL). The combined organic
layers were dried, filtered, and evaporated under reduced
pressure. The residue was chromatographed on silica gel
(elution with 15-35% EtOAc in hexane) to give 37 (230 mg,
89%) as clear needles: mp 91-93 °C; IR (neat, cm-1) 3422,
1
For 33: IR (neat, cm-1) 1688, 1644, 1614, 1518; H NMR
(300 MHz, CDCl3) δ 7.37-7.27 (m, 12 H), 6.86 (d, J ) 8.7 Hz,
2 H), 5.63 (s, 1 H), 4.97 (d, J ) 6.8 Hz, 1 H), 5.90 (d, J ) 6.8
Hz, 1 H), 4.87 (s, 1 H), 4.83 (d, J ) 7.6 Hz, 1 H), 4.71 (d, J )
11.8 Hz, 1 H), 4.64 (d, J ) 7.6 Hz, 1 H), 4.55 (d, J ) 11.9 Hz,
1 H), 4.49 (d, J ) 3.1 Hz, 2 H), 4.42 (s, 1 H), 4.22 (dd, J ) 9.0,
1.1 Hz, 1 H), 3.96 (dd, J ) 11.1, 4.1 Hz, 1 H), 3.89 (d, J ) 9.0
Hz, 1 H), 3.80 (s, 3 H), 2.90 (d, J ) 13.1 Hz, 1 H), 2.70-2.43
(m, 4 H), 2.42-2.23 (m, 4 H), 2.06-1.98 (m, 1 H), 1.74-1.57
(m, 2 H), 1.29 (s, 3 H), 1.17 (s, 3 H), 1.08 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 211.8, 160.5, 146.5, 137.7, 129.6, 128.7 (2C),
128.4 (2C), 128.3 (2C), 127.9 (2C), 127.8 (2C), 127.7, 127.6,
113.7 (2C), 109.5, 100.8, 93.8, 92.1, 90.4, 82.6, 81.9, 79.2, 70.6,
70.0, 55.3, 50.1, 48.1, 46.5, 44.5, 41.5, 34.3, 29.5, 29.3, 29.0,
28.1, 26.3, 20.0, 13.0; ES HRMS m/z (M + Na)+ calcd 719.3560,
obsd 719.3497; [R] -11.6 (c 1.35, CHCl3).
r-Oxygen a tion of 32. To a solution of 32 (29 mg, 0.050
mmol) and 18-cr-6 (135 mg, 0.50 mmol) in dry THF (20 mL)
at -78 °C was added a solution of potassium hexamethyl-
disilazide (0.42 M in toluene, 600 µL, 0.25 mmol). Dry
molecular oxygen was bubbled through the solution for 10 min,
and the flask was allowed to warm to 0 °C over 5 min.
Molecular oxygen was again introduced for 5 min, at which
1
1682, 1652, 1615; 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), 5.29 (s, 1
H), 4.86 (s, 1 H), 4.55 (d, J ) 11.2, 2.5 Hz, 1 H), 4.37 (dd, J )
9.7, 2.3 Hz, 1 H), 4.17-4.12 (m, 1 H), 3.99 (s, 1 H), 3.82 (d, J
) 9.7 Hz, 1 H), 3.80 (s, 3 H), 3.15 (ddd, J ) 11.6, 10.8, 4.2 Hz,
1 H), 2.98 (s, 1 H), 2.84-2.80 (m, 2 H), 2.69 (d, J ) 11.2 Hz,
1 H), 2.62-2.48 (m, 1 H), 2.43-2.37 (m, 1 H), 2.11-1.97 (m, 3
H), 1.69-1.52 (m, 2 H), 1.18 (s, 3 H), 1.16 (s, 6 H); 13C NMR
(75 MHz, CDCl3) δ 212.3, 160.9, 143.5, 128.9, 128.5 (2C), 114.1
(2C), 112.4, 101.1, 86.9, 83.9, 82.8, 78.7, 72.4, 55.5, 49.1, 48.1,
47.0, 43.8, 35.6, 32.9, 29.4, 29.0, 24.6, 20.3, 13.9; ES HRMS
m/z (M + Na)+ calcd 495.2359, obsd 495.2352; [R] -10.6 (c 0.75,
CHCl3).
J . Org. Chem, Vol. 68, No. 6, 2003 2273

Paquette and Hofferberth
Diben zoyla t ion of 37. To a solution of 37 (90 mg, 0.19
mmol) and DMAP (2.0 mg, 0.018 mmol) in dry pyridine (4 mL)
was added benzoyl chloride (200 µL, 1.7 mmol). The reaction
mixture was stirred for 12 h, diluted with water and CH2Cl2,
and extracted with EtOAc (3 × 30 mL). The combined organic
layers were dried, filtered, and evaporated under reduced
pressure. The residue was chromatographed on silica gel
(elution with 8% EtOAc in hexane) to give 11 (106 mg, 82%)
as clear needles: mp 135-137 °C; IR (neat, cm-1) 3486, 1713,
1614, 1518; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J ) 7.2 Hz,
2 H), 7.98 (d, J ) 7.2 Hz, 2 H), 7.62-7.47 (m, 2 H), 7.46-7.42
(m, 4 H), 6.77 (d, J ) 8.7 Hz, 2 H), 6.69 (d, J ) 8.7 Hz, 2 H),
5.99 (d, J ) 11.9 Hz, 1 H), 5.52 (dd, J ) 10.8, 4.4 Hz, 1 H),
5.07 (s, 1 H), 5.05 (s, 1 H), 4.66 (s, 1 H), 4.26 (dd, J ) 9.3, 2.0
Hz, 1 H), 3.91 (d, J ) 9.3 Hz, 1 H), 3.74 (s, 3 H), 3.19-3.12
(m, 1 H), 3.11 (d, J ) 11.9 Hz, 1 H), 2.80 (s, 1 H), 2.77 (d, J )
11.7 Hz, 1 H), 2.67-2.59 (m, 1 H), 2.45-2.43 (m, 1 H), 2.28-
2.12 (m, 3 H), 1.81-1.61 (m, 2 H), 1.50 (s, 3 H), 1.22 (s, 3 H),
1.14 (s, 3 H); 13C NMR (75 MHz, C6D6) δ 206.9, 165.4, 164.9,
160.7, 141.5, 133.1, 133.0 (2C), 130.7 (2C), 130.0 (2C), 129.9,
129.8 (2C), 129.4, 128.9, 128.5 (2C), 128.4 (2C), 113.5, 111.5,
101.1, 86.9, 82.3, 82.1, 78.7, 73.7, 54.5, 49.0, 47.4, 47.0, 45.0,
35.0, 29.4, 29.2, 28.8, 24.4, 20.1, 14.8; ES HRMS m/z (M +
Na)+ calcd 703.2883, obsd 703.2878; [R] +57.7 (c 0.98, CHCl3).
(s, 3 H), 0.94 (s, 3 H); 13C NMR (125 MHz, C6D6) δ 215.3, 169.8,
165.7, 141.8, 134.3, 133.9, 130.6 (2C), 130.1 (2C), 129.6, 129.2,
129.0 (2C), 128.9 (2C), 113.5, 81.8, 80.2, 78.1, 71.9, 60.8, 54.9,
50.1, 47.1, 35.2, 32.0, 31.7, 28.9, 27.8, 24.2, 17.5, 14.6; ES
HRMS m/z (M+Na)+ calcd 585.2464, obsd 585.2472; [R] -122.0
(c 0.75, CHCl3).
Hyd r id e Red u ction of 39. To a solution of 39 (52 mg,
0.087 mmol) in ether (5 mL) was added a solution of lithium
aluminum hydride (1 M in ether, 437 µL, 0.44 mmol) in three
equal portions at 5 min intervals. The reaction mixture was
stirred for 5 min, carefully treated with methanol (1 mL),
diluted with saturated Rochelle’s salt solution, and extracted
with ether (3 × 15 mL). The combined organic layers were
dried, filtered, and evaporated under reduced pressure. The
residue was chromatographed on silica gel (elution with
8-12% EtOAc in hexane) to give 40 (47 mg, 90%) as white
needles: mp 148-149 °C; IR (neat, cm-1) 3519, 1700, 1653,
1
1612; H NMR (500 MHz, C6D6) δ 7.32 (d, J ) 8.1 Hz, 2 H),
6.90 (d, J ) 8.5 Hz, 2 H), 5.13 (s, 1 H), 4.97 (s, 1 H), 4.85 (s, 1
H), 4.60 (d, J ) 10.1 Hz, 1 H), 4.50 (d, J ) 10.2 Hz, 1 H), 4.07
(s, 1 H), 3.89 (dd, J ) 10.9, 5.0 Hz, 1 H), 3.74 (d, J ) 16.9 Hz,
1 H), 3.69 (s, 1 H), 3.41 (s, 3 H), 3.27 (s, 1 H), 3.11 (d, J ) 12.2
Hz, 1 H), 2.76 (s, 1 H), 2.50-2.10 (m, 5 H), 2.00-1.62 (m, 6
H), 1.58 (s, 3 H), 1.47 (s, 3 H), 1.28 (s, 3 H), 1.06 (s, 9 H), 0.16
(s, 3 H), 0.15 (s, 3 H); 13C NMR (75 MHz, C6D6) δ 159.6, 149.2,
145.6, 130.5 (2C), 114.0 (2C), 108.4, 87.2, 85.9, 78.0, 77.5, 73.6,
72.0, 54.8, 54.5, 47.5, 46.4, 40.2, 34.6, 33.6, 32.6, 32.1, 25.9,
25.8 (3C), 25.4, 19.4, 11.1, 1.1, -3.1, -4.8; ES HRMS m/z (M
+ Na)+ calcd 597.3587, obsd 597.3592; [R] -68.6 (c 1.45,
CHCl3).
r-Ketol Rea r r a n gem en t of 11. To a solution of 11 (2.0
mg, 0.0029 mmol) in dry benzene (5 mL) was added aluminum
tri-tert-butoxide (10 mg, 0.040 mmol). The resulting solution
was stirred at reflux for 2 h, treated with a saturated solution
of Rochelle’s salt, stirred for an additional 20 min, and
extracted with EtOAc (3 × 10 mL). The combined organic
layers were dried, filtered, and evaporated under reduced
pressure. The residue was chromatographed on silica gel
(elution with 8% EtOAc in hexane) to give 13 as a cloudy oil
(2.0 mg, quant). Proton NMR analysis indicated the product
to be contaminated with a copolar impurity (∼5% by integra-
tion) making the [R]D value for the mixture meaningless and
it was not measured. For 13: IR (film, cm-1) 3480, 1714, 1651,
DDQ Oxid a tion of 40. To a solution of 40 (60 mg, 0.10
mmol) in dry ether (55 mL) were added 4 Å molecular sieves
(∼100 mg). In a separate flask, a solution of DDQ (119 mg,
0.52 mmol) in dry ether (55 mL) was prepared, and to it were
added 4 Å molecular sieves (100 mg). Both suspensions were
stirred separately for 1 h. While both were stirring vigorously,
the DDQ suspension was cannulated into the solution of 40.
The resulting suspension, which turned rapidly from yellow
to green, was stirred for 8 h, quenched with saturated NH4Cl
solution, and extracted with ether (3 × 100 mL). The combined
organic layers were dried, filtered, and evaporated. The waxy
yellow solid residue was recrystallized from methanol to give
41 as a glass (59 mg, 99%): IR (neat, cm-1) 3562, 1722, 1613,
1
1616; H NMR (500 MHz, CDCl3) δ 8.00-7.96 (m, 4 H), 7.55
(t, J ) 7.4 Hz, 1 H), 7.50 (t, J ) 7.5 Hz, 1 H), 7.49 (t, J ) 7.4
Hz, 2 H), 7.34 (t, J ) 8.1 Hz, 1 H), 6.93 (d, J ) 8.7 Hz, 2 H),
6.65 (d, J ) 8.7 Hz, 2 H), 5.76 (d, J ) 9.4 Hz, 1 H), 5.51 (dd,
J ) 8.5, 4.6 Hz, 1 H), 5.34 (s, 1 H), 5.08 (s, 1 H), 4.71 (s, 1 H),
4.43 (d, J ) 8.3 Hz, 1 H), 3.75 (d, J ) 5.5 Hz, 1 H), 3.74 (d, J
) 5.4 Hz, 1 H), 3.16 (s, 1 H), 2.84 (d, J ) 9.4 Hz, 1 H), 2.76 (d,
J ) 11.1 Hz, 1 H), 2.73-2.65 (m, 2 H), 2.48-2.35 (m, 2 H),
2.29-2.20 (m, 1 H), 2.04-1.98 (m, 1 H), 1.95-1.88 (m, 1 H),
1.85-1.75 (m, 1 H), 1.46 (s, 3 H), 1.44 (s, 3 H), 1.39 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 219.8, 167.4, 165.0, 160.4, 143.0,
133.4, 133.2, 130.4, 130.1 (2C), 129.9 (2C), 128.9 (2C), 128.6
(2C), 128.3 (2C), 128.1 (2C), 127.7, 113.6, 113.1, 102.2, 84.6,
82.7, 77.9, 73.4, 72.9, 55.4, 47.4, 47.3, 46.1, 42.7, 34.2, 30.2,
28.4, 25.5, 24.7, 23.2, 16.9; ES HRMS m/z (M + Na)+ calcd
703.2883, obsd 703.2882.
1
1511; H NMR (500 MHz, C6D6) δ 7.48 (d, J ) 8.4 Hz, 2 H),
6.78 (d, J ) 8.7 Hz, 2 H), 6.12 (s, 1 H), 5.04 (s, 1 H), 4.87 (s, 1
H), 4.34 (d, J ) 5.8 Hz, 1 H), 4.29 (t, J ) 5.7 Hz, 1 H), 3.95 (s,
1 H), 3.57 (dd, J ) 10.9, 5.0 Hz, 1 H), 3.34 (s, 3 H), 3.10 (dd,
J ) 16.5, 3.0 Hz, 1 H), 2.93 (ddd, J ) 12.5, 5.7, 3.6 Hz, 1 H),
2.62 (s, 1 H), 2.26 (d, J ) 9.9 Hz, 1 H), 2.22-2.01 (m, 4 H),
1.80-1.70 (m, 2 H), 1.59-1.55 (m, 1 H), 1.48-1.38 (m, 3 H),
1.37 (s, 3 H), 1.35 (s, 3 H), 1.07 (s, 3 H), 0.66 (s, 9 H), -0.10 (s,
3 H), -0.22 (s, 3 H); 13C NMR (75 MHz, C6D6) δ 159.8, 148.8,
133.7, 127.0 (2C), 113.7 (2C), 108.7, 98.9, 86.6, 81.4, 80.6, 77.4,
74.0, 56.1, 54.5, 46.4, 45.7, 39.8, 34.5, 33.2, 32.9, 32.3, 25.9,
25.5 (3C), 23.0, 18.5, 17.5, 11.4, -3.9, -5.4; ES HRMS m/z (M
+ H)+ calcd 573.3606, obsd 573.3587; [R] +117.8 (c 0.37,
CHCl3).
Con ver sion of 11 to 38. To a solution of 11 (42 mg, 0.061
mmol) in CH2Cl2 (3 mL) at -78 °C was added a solution of
ethylaluminum dichloride (1 M in hexane, 490 µL, 0.49 mmol).
The resulting solution was allowed to warm to 0 °C over 3 h,
treated with methanol (2 mL), diluted with saturated Roch-
elle’s salt solution, and extracted with CH2Cl2 (3 × 30 mL).
The combine organic layers were dried, filtered, and freed of
solvent. The residue was chromatographed on silica gel (elu-
tion with 8% EtOAc in hexane) to give 38 (30.3 mg, 88%) as a
white solid: mp 128-132 °C; IR (neat, cm-1) 3470, 1716, 1602,
Sw er n Oxid a tion of 41. To a solution of oxalyl chloride
(20 µL, 0.23 mmol) in CH2Cl2 (2.5 mL) at -78 °C was added a
solution of DMSO (32 µL, 0.45 mmol) in CH2Cl2 (2.5 mL). The
reaction mixture was stirred for 20 min, a solution of 41 (26
mg, 0.045 mmol) in CH2Cl2 (5 mL) was introduced by cannula,
and stirring was maintained for 1 h at -78 °C prior to slow
warming to -40 °C over 30 min and recooling to -78 °C.
Freshly distilled Et3N (94 µL, 0.68 mmol) was added, and
stirring was maintained at -78 °C for 30 min followed by
warming to rt over 1 h. Thirty minutes later, water was added
and the product was extracted with CH2Cl2 (3 × 40 mL). The
combined organic layers were dried, filtered, and evaporated
under reduced pressure. The yellow residue was chromato-
graphed on silica gel (elution with 2% EtOAc in hexane) to
1
1584; H NMR (500 MHz, CDCl3) δ 8.00 (d, J ) 8.3 Hz, 2 H),
7.91 (dd, J ) 8.2, 1.3 Hz, 2 H), 7.64 (t, J ) 7.4 Hz, 1 H), 7.60
(t, J ) 7.5 Hz, 1 H), 7.51-7.45 (m, 4 H), 5.61 (d, J ) 11.7 Hz,
1 H), 5.58 (dd, J ) 11.2, 4.3 Hz, 1 H), 5.18 (s, 1 H), 4.74 (d, J
) 5.8 Hz, 1 H), 4.64 (s, 1 H), 3.54 (t, J ) 4.3 Hz, 1 H), 3.95 (d,
J ) 4.7 Hz, 1 H), 3.74 (d, J ) 5.6 Hz, 1 H), 3.60 (d, J ) 11.7
Hz, 1 H), 3.52 (s, 1 H), 2.86-2.80 (m, 1 H), 2.76-2.70 (m, 1
H), 2.59-2.53 (m, 2 H), 2.42-2.32 (m, 2 H), 2.23-2.16 (m, 1
H), 1.91-1.87 (m, 1 H), 1.77-1.72 (m, 1 H), 1.56 (s, 3 H), 1.04
2274 J . Org. Chem., Vol. 68, No. 6, 2003

R-Ketol Rearrangement in Functionalized Paclitaxel Precursors
give 42 as a white solid (18 mg, 70%, 90% at 77% conversion)
and unreacted 41(6 mg, 23%).
continued bubbling, a solution of potassium hexamethyldisi-
lazide (0.45 M in toluene, 500 µL, 0.23 mmol) was added
followed by a solution 42 (13 mg, 0.023 mmol) in dry THF (2.5
mL). The reaction mixture was stirred with continuous bub-
bling for 30 min at 0 °C. Dimethyl sulfide (300 µL) was
introduced, and the solution was stirred at 0 °C for 5 min at
rt for an additional 5 min, quenched with water, and extracted
with EtOAc (3 × 30 mL). The combined organic layers were
dried, filtered, and evaporated. The residue was chromato-
graphed on silica gel (elution with 2-3% EtOAc in hexane) to
give 43 as an oily solid (10.2 mg, 76%); IR (neat, cm-1) 3460,
For 42: mp 86-88 °C; IR (neat, cm-1) 3436, 1684, 1508; 1H
NMR (500 MHz, C6D6) δ 7.45 (d, J ) 8.6 Hz, 2 H), 6.79 (d, J
) 8.6 Hz, 2 H), 6.06 (s, 1 H), 5.09 (s, 1 H), 5.05 (s, 1 H), 4.83
(s, 1 H), 4.37 (d, J ) 5.6 Hz, 1 H), 4.33 (t, J ) 5.7 Hz, 1 H),
4.04 (d, J ) 15.4 Hz, 1 H), 3.51 (dd, J ) 10.9, 4.9 Hz, 1 H),
3.35 (s, 3 H), 3.09 (dd, J ) 15.4, 11.0 Hz, 1 H), 3.05-3.00 (m,
1 H), 2.76 (d, J ) 11.7 Hz, 1 H), 2.17-2.11 (m, 2 H), 2.08-
1.99 (m, 1 H), 1.90-1.87 (m, 1 H), 1.63-1.58 (m, 1 H), 1.55-
1.40 (m, 3 H), 1.39 (s, 3 H), 1.23 (s, 3 H), 1.02 (s, 3 H), 0.66 (s,
9 H), -0.11 (s, 3 H), -0.23 (s, 3 H);13C NMR (75 MHz, C6D6)
δ 212.2, 159.9, 144.6, 133.2, 126.9 (2C), 113.8 (2C), 109.8, 99.2,
89.5, 81.8, 80.5, 74.1, 56.7, 54.6, 48.2, 45.9, 40.5, 39.4, 36.7,
31.4 (2C), 25.5, 25.4 (3C), 24.5, 19.2, 17.5, 10.5, -3.9, -5.5;
ES HRMS m/z (M + Na)+ calcd 593.3269, obsd 593.3234; [R]
+20.8 (c 0.43, CHCl3).
1
1679, 1659, 1612; H NMR (500 MHz, CDCl3) δ 7.38 (d, J )
8.7 Hz, 2 H), 6.88 (d, J ) 8.7 Hz, 2 H), 6.22 (s, 1 H), 6.10 (d,
J ) 6.3 Hz, 1 H), 5.85 (s, 1 H) 4.86 (s, 1 H), 4.70 (s, 1 H), 4.41
(dd, J ) 5.7, 3.0 Hz, 1 H), 4.36 (d, J ) 5.7 Hz, 1 H), 3.83 (s, 3
H), 3.23 (dd, J ) 10.9, 4.9 Hz, 1 H), 3.13-3.11 (m, 2 H), 3.03
(dd, J ) 15.2, 3.4 Hz, 1 H), 2.72 (s, 1 H), 2.24-2.20 (m, 1 H),
1.83-1.76 (m, 2 H), 1.72-1.69 (m, 1 H), 1.56 (s, 3 H), 1.53-
1.46 (m, 1 H), 1.21 (s, 3 H), 0.91 (s, 3 H), 0.57 (s 9 H), -0.05
(s, 3 H), -0.30 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 200.2,
159.7, 149.2, 147.1, 132.9, 127.0 (2C), 118.5, 114.0 (2C), 108.1,
99.0, 81.0, 79.6, 78.8, 74.8, 55.5, 52.6, 46.4, 42.8, 40.8, 34.9,
33.9, 31.9, 28.7, 25.6 (3C), 20.7, 17.7, 11.6, -3.6, -5.0; ES
HRMS m/z (M + Na)+ calcd 607.3062, obsd 607.3055; [R] +12.7
(c 0.77, CHCl3).
If the reaction mixture is allowed stand at rt for longer than
30 min before the water quench, 41 will be completely
consumed.
For i: colorless solid; mp 160-162 °C; IR (neat, cm-1) 3572,
1717, 1510; 1H NMR (500 MHz, C6H6) δ 9.56 (s, 1 H), 7.48 (d,
J ) 8.7 Hz, 2 H), 6.80 (d, J ) 8.7 Hz, 2 H), 6.10 (s, 1 H), 4.84
(s, 1 H), 4.82 (s, 1 H), 4.35 (d, J ) 5.6 Hz, 1 H), 4.13 (t, J ) 5.3
Hz, 1 H), 3.36 (dd, J ) 10.7, 5.0 Hz, 1 H), 3.34 (s, 3 H), 2.40
(dd, J ) 16.3, 3.1 Hz, 1 H), 2.36 (ddd, J ) 10.7, 6.4, 2.6 Hz, 1
H), 2.15-2.06 (m, 3 H), 1.97-1.92 (m, 2 H), 1.78-1.72 (m, 1
H), 1.60-1.57 (m, 1 H), 1.54-1.48 (m, 1 H), 1.43 (s, 3 H), 1.30-
1.26 (m, 1 H), 1.21-1.17 (m, 1 H), 1.13 (s, 3 H), 0.93 (s, 3 H),
0.69 (s, 9 H), -0.12 (s, 3 H), -0.31 (s, 3 H); 13C NMR (125
MHz, C6D6) δ 200.4, 160.2, 148.2, 134.1, 127.4 (2C), 114.1 (2C),
108.6, 99.0, 81.1, 80.9, 75.8, 59.6, 57.1, 54.9, 47.9, 46.3, 43.7,
34.7, 32.2, 30.0, 27.8, 27.6, 25.9 (3C), 22.3, 20.5, 17.9, 12.5,
-3.9, -5.0; ES HRMS m/z (M + Na)+ m/z calcd 571.3449, obsd
571.3466; [R] +22.0 (c 0.63, 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: Selected 1H NMR
data for 36 and HMBC correlations for 11, 13, and 38. This
material is available free of charge via the Internet at
http://pubs.acs.org.
r-Ketol Rea r r a n gem en t/Oxid a tion of 42. Through a
solution of 18-cr-6 (160 mg, 0.60 mmol) in dry THF (2.5 mL)
at 0 °C was bubbled dry molecular oxygen for 1 min. With
J O020627V
J . Org. Chem, Vol. 68, No. 6, 2003 2275