Taxane synthesis through intramolecular pinacol coupling at C-1-C-2. Construction and oxidative transformations of a C-aromatic taxane diene

Article abstract of DOI:10.1021/jo951935e

A ten-linear-step construction of C-aromatic taxane diene 14 from ethylisopropyl ketone, acryloyl chloride, and commercially available 8 is reported. This sequence concludes with an intramolecular pinacol coupling carried out on 13. 14 is oxidized by m-ch

Full text of DOI:10.1021/jo951935e

J . Org. Chem. 1996, 61, 1101-1108
1101
Ta xa n e Syn th esis th r ou gh In tr a m olecu la r P in a col Cou p lin g a t
C-1-C-2. Con str u ction a n d Oxid a tive Tr a n sfor m a tion s of a
C-Ar om a tic Ta xa n e Dien e
Charles S. Swindell,* Madhavi C. Chander, J ulia M. Heerding, Peter G. Klimko,
Leera T. Rahman, J . Venkat Raman, and Hemalatha Venkataraman
Department of Chemistry, Bryn Mawr College, 101 North Merion Avenue,
Bryn Mawr, Pennsylvania 19010-2899
Received October 31, 1995X
A ten-linear-step construction of C-aromatic taxane diene 14 from ethyl isopropyl ketone, acryloyl
chloride, and commercially available 8 is reported. This sequence concludes with an intramolecular
pinacol coupling carried out on 13. 14 is oxidized by m-chloroperbenzoic acid and dimethyldioxirane
to give 17 through intermediate epoxide 20 and by VO(acac)2-t-BuOOH and Mo(CO)6-t-BuOOH
to give 13. 17 is converted efficiently into 22 upon treatment with Mo(CO)6-t-BuOOH, apparently
through an unusual equilibration with isomeric 20, which is converted irreversibly to 22. While
these oxidative transformations highlight some of the peculiar reactivity patterns characteristic of
taxane-related structures, the formation of 14 through an intramolecular pinacol coupling that
joins C-1 and C-2 demonstrates the potential of this strategy for stereoselectively delivering advanced
taxane synthesis intermediates.
In tr od u ction
The clinically effective antitumor agent taxol1 pos-
sesses an eight-membered B-ring that adheres closely to
the conformational ideal.2 An examination of the X-ray
crystallographic structure3 of the related semisynthetic
analog Taxotere4 reveals the B-ring to adopt the typically
favored boat-chair conformation, with the C-2 benzoyloxy
substituent disposed equatorially and thereby avoiding
contact with the axial C-16 methyl group. Planar trigo-
nal carbons are located at sites associated either with
large substituent A-values (C-9) or with severe transan-
nular interactions (C-11). The transannular contact with
C-11 that remains is minimized to involve hydrogen by
the configuration of C-3. Furthermore, C-8 occurs at a
boat-chair site characterized by negligible substituent
A-values, a situation advantageous for geminal disub-
) OH, R2 ) H, X ) OMe6 and for the simple structure
(not shown) lacking the A-ring methyl groups and having
R1,R2 ) carbonyl, X ) H.5
stitution.
The endo conformation of the structurally complex
natural taxanes possesses the face-to-face relationship
of the A- and C-rings typified by structurally simple endo-
1. In his investigations of C-aromatic taxane conforma-
tions, Shea demonstrated, for example, that endo-1 was
favored for R1,R2 ) carbonyl, X ) H5 and for R1 ) H, R2
) OH, X ) OMe6 but that exo-1 was more stable for R1
X Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
(1) Isolation: (a) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon,
P.; McPhail, A. T. J . Am. Chem. Soc. 1971, 93, 2325-2327. Synthesis:
(b) Holton, R. A.; et al. J . Am. Chem. Soc. 1994, 116, 1597-1598, 1599-
1600. (c) Nicolaou, K. C.; et al. J . Am. Chem. Soc. 1995, 117, 624-
633, 634-644, 645-652, 653-659. Recent reviews: (d) Kingston, D.
G. I.; Molinero, A. A.; Rimoldi, J . M. In Progress in the Chemistry of
Organic Natural Products; Herz, W., Kirby, G. W., Moore, R. E.,
Steglich, W., Tamm, Ch., Eds.; Springer-Verlag: Vienna, 1993; Vol.
61, pp 1-206. (e) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 15-44. (f) Boa, A. N.; J enkins, P. R.; Lawrence,
N. J . Contemp. Org. Synth. 1994, 1, 47-75.
One of the chemical challenges posed by the taxanes
is to define how these structural features can produc-
tively influence synthetic processes expected to form the
eight-membered B-ring, especially those that lead to
advanced tricyclic intermediates and create one or more
of the B-ring stereogenic centers under kinetic control.
The most fundamental issue is whether endo or exo7
transition structures obtain. To the extent that starting
material and/or product ground state structure can
suggest mediating transition structure, endo transition
structures are often encountered (Figure 1). Thus, in-
(2) For an excellent discussion of some aspects of medium ring
conformational analysis, see: Still, W. C.; Galynker, I. Tetrahedron
1981, 37, 3981-3996.
(3) Gue´ritte-Voegelein, F.; Gue´nard, D.; Mangatal, L.; Potier, P.;
Guilhem, J .; Cesario, M.; Pascard, C. Acta Crystallogr. 1990, C46, 781-
784.
(4) Mangatal, L.; Adeline, M.-T.; Gue´nard, D.; Gue´ritte-Voegelein,
F.; Potier, P. Tetrahedron 1989, 45, 4177-4190.
(5) Shea, K. J .; Gilman, J . W. Tetrahedron Lett. 1984, 25, 2451-
2454.
(6) J ackson, R. W.; Higby, R. G.; Gilman, J . W.; Shea, K. J .
Tetrahedron 1992, 48, 7013-7032.
(7) In this context, the terms endo and exo are used in the sense
defined by endo-1 and exo-1.
0022-3263/96/1961-1101$12.00/0 © 1996 American Chemical Society

1102 J . Org. Chem., Vol. 61, No. 3, 1996
Swindell et al.
F igu r e 1. Examples of endo and exo modes of taxane B-ring formation.
Sch em e 1
tramolecular Diels-Alder cycloadditions that form the
taxane A-ring8 and the C-ring,9 cationic cyclizations at
C-9-C-10,10 and an Ireland-Claisen rearrangement that
joins C-1-C-211 apparently can proceed through the endo
manifold. On the other hand, counterexamples of exo-
mode intramolecular A-ring Diels-Alder cycloadditions12
and C-9-C-10 cationic cyclizations10a have been reported,
as well. Indeed, conflicts between the transition struc-
ture requirements of the reaction types chosen to imple-
ment B-ring-forming strategies and the conformational
and stereochemical features of the intended taxane
products have complicated much work in this area.
Our plan for constructing the taxanes focuses on
formation of the B-ring to yield tricyclic intermediates
by closure of the C-1-C-2 bond. Were this bond to be
formed through an intramolecular pinacol coupling car-
ried out on C-aromatic intermediate 2 (Scheme 1), the
foregoing conformational considerations and the involve-
ment of an endo transition structure would suggest the
formation of 3 with an equatorial 2-OH group.13 Like-
wise, stereochemically complicated acetonide 4 would be
(8) (a) Park, T. K.; Kim, I. J .; Danishefsky, S. J .; de Gala, S.
Tetrahedron Lett. 1995, 36, 1019-1022. See also: (b) Shea, K. J .;
Gilman, J . W. J . Am. Chem. Soc. 1985, 107, 4791-4792. (c) Bonnert,
R. V.; J enkins, P. R. J . Chem. Soc., Perkin Trans. 1 1989, 413-418.
(d) For a related Diels-Alder cycloaddition, see: Winkler, J . D.; Kim,
H. S.; Kim, S. H. Tetrahedron Lett. 1995, 36, 687-690.
(9) (a) Sakan, K.; Craven, B. M. J . Am. Chem. Soc. 1983, 105, 3732-
3734. (b) For a related Diels-Alder cycloaddition, see: Lu, Y. F.; Fallis,
A. G. Tetrahedron Lett. 1993, 34, 3367-3370.
(10) (a) Seto, M.; Morihira, K.; Horiguchi, Y.; Kuwajima, I. J . Org.
Chem. 1994, 59, 3165-3174. (b) For a related pinacol coupling, see
ref 1c.
(11) Funk, R. L.; Dailey, W. J .; Parvez, M. J . Org. Chem. 1988, 53,
4141-4143.
expected to provide analogous tricycle 5 in which the
newly created C-1 and C-2 stereogenic centers would be
correctly induced by those preexisting at C-9 and C-10,
all such sites bearing equatorial oxygen substituents in
5. Herein14 and in the following article we describe our
construction of substances related to 3 and 5, as well as
(12) (a) J ackson, R. W.; Shea, K. J . Tetrahedron Lett. 1994, 35,
1317-1320. See also: (b) Alaimo, C. A.; Coburn, C. A.; Danishefsky,
S. J . Tetrahedron Lett. 1994, 35, 6603-6606. (c) Kim, I. J .; Park, T.
K.; Danishefsky, S. J . Tetrahedron Lett. 1995, 36, 1015-1018.
(13) For an analysis of stereoselective medium and large ring
formation through the pinacol coupling, see: McMurry, J . E.; Siemers,
N. O. Tetrahedron Lett. 1993, 34, 7891-7894.

Taxane Synthesis through Pinacol Coupling at C-1-C-2
J . Org. Chem., Vol. 61, No. 3, 1996 1103
Sch em e 2
companied the 12 so produced, but it proved convenient
to convert unpurified 12 to 14 through intermediate keto
aldehyde 13, probably because alternative keto aldehyde
byproducts fail to undergo efficient pinacol cyclization.
When the pinacol coupling step16 was carried out with
pure 13, 14 was formed in 86% yield.14a The sequence
illustrated in Scheme 2 provides 14 in ten linear steps
from commercially available materials.
The endo conformation and relative stereochemistry
at C-1 and C-2 of 14 (see model 3, Scheme 1) rest on
several NOE experiments involving protons at key sites.
The NOE relationship between H-4 (δ 6.88) and H-13 and
H-14 (δ 2.17-2.31) defines the endo conformation of 14.
This conformational assignment is further supported by
the anomalously high field signal for Me-18 (δ 0.80) due
to shielding by the aromatic C-ring.17 This signal fails
to exhibit an NOE of either of the remaining carbon-
bound methyl singlets. Me-17 (δ 1.14) was identified by
its NOE relationship with H-13 and H-14, leaving the
singlet at δ 1.20 to be assigned to Me-16. The NOE
relationship between H-2 (δ 4.74) and Me-16 then defines
the relative stereochemistry of 14. The existence of
atropisomers was not indicated for 14. While we cannot
rule out unequivocally a rapid equilibration with an
1
undetectable exo component, the H NMR spectral data
and NOE experiments could be interpreted in a straight-
forward fashion in terms of 14 having a single nonflux-
ional endo conformation.
Before examining the pinacol cyclization of 13, we
converted 12 into iodide 15 to investigate the closure of
18
the C-1-C-2 bond through Barbier chemistry. SmI2
and Zn-Cu19 couple transformed 15 into complex mix-
tures. However, exposure of 15 to either tert-butyl-
lithium or lithium-sodium dispersion indeed caused
cyclization to occur but to give 6-7-6 ring system 1620
through the attachment of the iodomethyl carbon to the
conjugated diene substructure.
transformations relevant to their utility as synthesis
intermediates for the preparation of the complex natural
taxanes.
Resu lts a n d Discu ssion
Our initial goal was the preparation of C-aromatic
taxane diene 14 (Scheme 2). Birch reduction and sub-
sequent elaboration of its C-ring, perhaps preceded by
the introduction of oxygen functionality at C-9 and C-10,
would enable 14 to function as an intermediate for the
synthesis of the complex taxanes of interest. Monoacetal
6,15 available in three simple operations from ethyl
isopropyl ketone and acryloyl chloride, is an ideal struc-
turally uncomplicated progenitor for the taxane A-ring.
The conversion of 6 into propargylic alcohol 7 could be
carried out with commercial lithium acetylide-ethylene-
diamine complex; 10 was then available through the
indicated Pd-induced coupling of 7 and 9. The Z-selective
partial reduction of the triple bond of 11 and related
substances proved difficult to implement and was by-
passed initially14a through a cumbersome sequence that
involved photoisomerization of an E relative of 12. We
eventually discovered conditions for the partial reduction
of 11 in which both the Pd-BaSO4 catalyst and the free
hydroxyl are crucial. An unidentified contaminant ac-
Our expectation that 14 could serve as an intermediate
for complex taxane synthesis was predicated on the
hypothesis that the double bond at C-9-C-10, positions
that are sterically hindered and unreactive in the natural
taxanes, would be susceptible to oxidation intended to
introduce appropriate functionality. The encumbered
bridgehead double bond was anticipated to focus attack
at C-9 and C-10, and the sterically undemanding aro-
matic C-ring, particularly the absence of the angular
(16) (a) Mukaiyama, T.; Sato, T.; Hanna, J . Chem. Lett. 1973, 1041-
1044. (b) Kato, N.; Takeshita, H.; Kataoka, H.; Ohbuchi, S.; Tanaka,
S. J . Chem. Soc., Perkin Trans. 1 1989, 165-174.
(17) Shea, K. J .; Gilman, J . W.; Haffner, C. D.; Dougherty, T. K. J .
Am. Chem. Soc. 1986, 108, 4953-4956.
(14) For preliminary reports of this work, see: (a) Swindell, C. S.;
Chander, M. C.; Heerding, J . M.; Klimko, P. G.: Rahman, L. T.; Raman,
J . V.; Venkataraman, H. Tetrahedron Lett. 1993, 34, 7005-7008. (b)
Swindell, C. S.; Chander, M. C. Tetrahedron Lett. 1994, 35, 6001-
6004.
(15) (a) Hargreaves, J . R.; Hickmott, P. W.; Hopkins, B. J . J . Chem.
Soc. C 1968, 2599-2603. (b) Detering, J .; Martin, H. D. Angew. Chem.,
Intl. Ed. Engl. 1988, 27, 695-698.
(18) (a) Molander, G. A.; Etter, J . B.; Zinke, P. W. J . Am. Chem.
Soc. 1987, 109, 453-463. (b) Molander, G. A.; McKie, J . A. J . Org.
Chem. 1991, 56, 4112-4120.
(19) Wang, Z. Y.; Warder, S. E.; Perrier, H.; Grimm, E. L.; Bernstein,
M. A.; Ball, R. G. J . Org. Chem. 1993, 58, 2931-2932.
(20) It is noteworthy that 16 is structurally related to the rearranged
abietane diterpenes exemplified by barbatusol: Kelecom, A. Tetrahe-
dron 1983, 39, 3603-3608.

1104 J . Org. Chem., Vol. 61, No. 3, 1996
Swindell et al.
Sch em e 3
Sch em e 4
methyl group, was expected to permit sufficient reactiv-
ity.21 However, exposure of 14 to m-chloroperbenzoic acid
delivered in 81% yield 17 with its B-ring olefinic bond
intact (Scheme 3). Presumably, it is the methoxy group
at C-7 that is responsible for shielding the R face of the
C-9-C-10 olefin, whereas the â face of this substructure
is inherently inaccessible owing to the conformation of
the eight-membered ring. A repetition of this experiment
with acetate 18 afforded analogous 19 in 79-86% yield
after column chromatography, but when this reaction
mixture was purified by radial chromatography, or when
the oxidation was carried out by dimethyldioxirane,22
epoxide 21 could be isolated in 70% or quantitative yields,
respectively.23 The appearance of the acetyl group on the
C-2 oxygen evidently confers on 21 a degree of stability
toward isomerization.24 Nevertheless, 21 could be readily
isomerized into 19, for example, upon more prolonged
exposure to silica gel. Thus, 20 must mediate the
transformation of 14 into 17. It seems likely that the
crowded conformation that results from the C-11 sp3
bridgehead in 20 and 21 is alleviated by the introduction
of the A-ring-flattening double bond in 17 and 19, an
effect that might provide the driving force for the forma-
tion of the latter isomerization products. An attempt to
force diepoxidation of the A- and B-ring double bonds of
14 through exposure to dimethyldioxirane resulted in the
low-yield (29%) formation of 22 (Scheme 3).
festations of the strain of the ring system and the
favorable stereoelectronic alignment of the C-1-C-2 bond
broken and the aromatic π-system; the C-1-C-2-C-3-
C-4 dihedral angle for 14 is calculated (MM2) to be
approximately 90°.
Given the reactivity of 14 toward oxidative vicinal diol
cleavage, the C-2 hydroxyl was masked in 23 and the
latter material subjected to reaction with Mo(CO)6-t-
BuOOH (Scheme 4). Nonetheless, 13 predominated
again owing to in situ desilylation and subsequent
oxidative vicinal diol cleavage. Accompanying 13 was its
apparent epoxidation product 22.26 However, control
experiments indicated 13 to be reactive neither to Mo-
(CO)6-t-BuOOH nor to dimethyldioxirane. To remove
all doubt regarding the structure of 22 produced through
the chemistry of Scheme 3 (vide supra) and Scheme 4
(and Scheme 5; vide infra), it was independently derived
from 13 as indicated in Scheme 4. Thus, 22 must be
formed in the Mo(CO)6-t-BuOOH reaction through the
initial epoxidation of 23 followed by desilylation and
vicinal diol cleavage. Under the conditions of the Mo-
(CO)6-t-BuOOH reaction, strained intermediate 20 mani-
fests its anomalous reactivity in a more rapid vicinal diol
The facile cleavage of the C-1-C-2 bond reappeared
when 14 was subjected to attempted epoxidations involv-
ing VO(acac)2 or Mo(CO)6 and t-BuOOH. In both cases,
quantitative formation of keto aldehyde 13 resulted
instead. The action of these reagents on 14 as well as
the cleavage of 20 by dimethyldioxirane, which are
uncharacteristic of these oxidants,22,25 are probably mani-
(21) For an early preparation of a taxane diene related to 14, see:
Kende, A. S.; J ohnson, S.; Sanfilippo, P.; Hodges, J . C.; J ungheim, L.
N. J . Am. Chem. Soc. 1986, 111, 8277-8279.
(22) For reviews, see: (a) Adam, W.; Curci, R.; Edwards, J . O. Acc.
Chem. Res. 1989, 22, 205-211. (b) Murray, R. W. Chem. Rev. 1989,
89, 1187-1201.
(23) For related observations, see: Holton, R. A. In Strategies and
Tactics in Organic Synthesis; Lindberg, T., Ed.; Academic Press: San
Diego, 1991; Vol. 3, Chapter 5.
(24) Silyl ether 23 behaves similarly. Chander, M. C., unpublished
results.
(25) For reviews, see: (a) Sharpless, K. B.; Verhoeven, T. R.
Aldrichimica Acta 1979, 12, 63-74. (b) J orgensen, K. A. Chem. Rev.
1989, 89, 431-458.
(26) Treatment of 23 with VO(acac)2-t-BuOOH produces in 60%
yield the secondary tert-butyldimethylsilyl derivative of 17. Chander,
M. C., unpublished results.

Taxane Synthesis through Pinacol Coupling at C-1-C-2
J . Org. Chem., Vol. 61, No. 3, 1996 1105
Sch em e 5
investigation of its oxidative chemistry and that of
several of its relatives. Such procedures focus reactivity
on the A-ring and/or lead to the facile oxidative cleavage
of the C-1-C-2 vicinal diol, the latter transformation
occurring under unconventional conditions. An unusual
Mo(CO)6-mediated isomerization of an allylic alcohol into
an epoxide was detected in the conversion of 17 into 22.
These observations highlight some of the peculiar reac-
tivity patterns characteristic of taxane-related structures.
Most importantly, however, the formation of 14 through
an intramolecular pinacol coupling that joins C-1 and C-2
demonstrates the potential of this strategy for stereose-
lectively delivering advanced taxane synthesis intermedi-
ates. The development of this approach in the context
of routes that install C-9 and C-10 oxygenation at an
early stage is the subject of the following article.
Exp er im en ta l Section
In general, reactions were carried out under N2. ”Chroma-
tography” refers to flash chromatography conducted with
Merck silica gel (230-400 mesh; 60 Å) with elution carried
out with ethyl acetate-hexanes. Radial chromatography was
conducted with Analtech precast rotors (silica gel GF) with
elution again carried out with ethyl acetate-hexanes. Melting
points were determined on a capillary apparatus and are
uncorrected. 1H NMR spectroscopy at 300 MHz and 13C NMR
spectroscopy at 75 MHz were carried out on CDCl3 solutions
using TMS as internal standard (δ ) 0); coupling constants
are reported in hertz.
cleavage similar to that experienced by 14 above, rather
than rearrangement to 17, as occurs in the m-chloro-
perbenzoic acid-involving process of Scheme 3.
P r op a r gylic Alcoh ol 7. To 90% lithium acetylide-ethyl-
enediamine complex (25.80 g, 252.5 mmol) in 180 mL of THF
under a nitrogen atmosphere was added dropwise a solution
of ketal ketone 6 (20 g, 101 mmol) in 150 mL of THF. The
reaction mixture was stirred for 48 h at ambient temperature
and then cautiously poured into 600 mL of a 1:1 mixture of
ether-saturated aqueous NH4Cl. The aqueous layer was
extracted with ether (2 × 500 mL), and the combined organic
layers were washed with water and brine, dried (Na2SO4), and
concentrated. Chromatography of the residue gave 6 (19.68
Among our further attempts to functionalize the B-ring
of intermediates derived from 14 was the reaction of 17
with Mo(CO)6-t-BuOOH (Scheme 5). Surprisingly, this
experiment produced previously encountered 22 in sub-
stantial yield. Neither Mo(CO)6 nor t-BuOOH alone was
able to effect this transformation. From the experience
described above, this observation implies the interme-
diacy of epoxide 20, which must be produced through an
equilibrium between isomers 17 and 20 established by
Mo(CO)6. We are unaware of a similar transformation
induced by Mo(CO)6. Since the experiments portrayed
in Scheme 3 demonstrate that 17 is the dominant
equilibrium partner, it is only due to the fortuitous
irreversible Mo(CO)6-t-BuOOH-induced transformation
of 20 into 22 that the low equilibrium concentration of
1
g, 87%) as a white, crystalline solid: mp 92-93 °C; H NMR
δ 3.99-3.85 (m, 4H), 3.80 (s, OH), 2.40 (s, 1H), 2.02-1.95 (m,
1H), 1.79 (dt, J ) 5.65, 13.20, 1H), 1.61-1.43 (m, 3H), 1.24 (s,
3H), 1.13 (s, 3H), 1.10 (d, J ) 6.7, 3H); 13C NMR δ 122.71,
84.90, 78.43, 72.42, 65.78, 64.36, 45.72, 35.90, 30.01, 26.27,
22.30, 17.12, 16.55; IR (CHCl3) 3500, 2120 cm-1. Anal. Calcd
for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.51; H, 9.01.
3,5-Dim eth oxyben zyl Aceta te. To 39.0 g (232 mmol) of
8 in 100 mL of CH2Cl2 containing 26.4 g (334 mmol) of pyridine
was added dropwise a solution of 22.1 g (281 mmol) of acetyl
chloride in 100 mL of CH2Cl2. After the addition was complete,
a thick white precipitate formed. The reaction mixture was
then poured into 500 mL of 1:1 ether-5 M HCl. The layers
were separated, and the aqueous layer was extracted with
ether (2 × 100 mL). The combined organic layers were washed
successively with 5 M HCl (2 × 100 mL) and saturated
aqueous NaHCO3 (2 × 100 mL). The organic layer was dried
(MgSO4) and concentrated to afford 45 g (93%) of the title
compound as an oil: 1H NMR δ 6.48 (d, J ) 2.4, 2H), 6.41 (t,
J ) 2.4, 1H), 5.02 (s, 2H), 3.79 (s, 6H), 2.11 (s, 3H).
20 present in this reaction medium is reported.
A
mechanistic explanation for the equilibration of 17 and
20 induced by thermally generated Mo(CO)5 is presented
in Scheme 5.27
Con clu sion
We have synthesized C-aromatic taxane diene 14
through an efficient sequence that has allowed the
(27) Among the alternatives is the following. It is unappealing since
in the direction 20 f 17 it requires the insertion of Mo into an
unactivated carbon-hydrogen bond.
2-Iod o-3,5-d im eth oxyben zyl Aceta te (9). To 3,5-dimeth-
oxybenzyl acetate (49.99 g, 238.1 mmol) in a 1000 mL Erlen-
meyer flask open to the air containing 200 mL of acetic acid
and iodine (48.34 g, 190.4 mmol) was added a 30% w/w solution
of H2O2 in water (29.38 g, 259.3 mmol) in one portion. The
reaction mixture was stirred until GC analysis indicated that
all of the starting material had been consumed (5-8 h). The
mixture was then poured into 500 mL of 1:1 ethyl acetate-
saturated aqueous Na2S2O5 to discharge the dark brown color
of the remaining iodine. After separation of the two layers,
the aqueous layer was extracted with ethyl acetate (2 × 200
mL) and the combined organic layers were washed twice with
water, then saturated aqueous NaHCO3, water, and brine.
Drying (Na2SO4) and concentration provided 9 (74 g, 94%) as

1106 J . Org. Chem., Vol. 61, No. 3, 1996
Swindell et al.
an ivory solid: mp 74-75 °C; 1H NMR δ 6.62 (d, J ) 2.4, 1H),
6.40 (d, J ) 6.4, 1H), 5.14 (s, 2H), 3.88 (s, 3H), 3.82 (s, 3H),
2.16 (s, 3H). Anal. Calcd for C11H13IO4: C, 39.31; H 3.90.
Found: C 39.52; H 4.06.
aldehydes of which 13 was the major component. A sample
purified by radial chromatography yielded the following data:
mp 79-81 °C; 1H NMR δ 10.03 (s, 1H), 6.92 (d, J ) 2.53, 1H),
6.69 (d, J ) 2.53, 1H), 6.66 (d, J ) 12.39, 1H), 6.37 (dd, J )
12.39, 1.02, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 2.37 (br t, J ) 6.68,
2H), 2.35 (br t, J ) 6.68, 2H), 1.24 (s, 6H), 1.08 (s, 3H); 13C
NMR δ 215.13, 192.40, 159.74, 158.17, 134.58, 133.05, 132.86,
132.33, 125.14, 123.65, 104.47, 100.71, 55.76, 55.54, 47.29,
P r op a r gylic Alcoh ol 10. To 100 mL of triethylamine,
which had been sparged with N2 for 20 min, were added 7 (9.58
g, 42.8 mmol), 9 (10.1 g, 30 mmol), Pd(OAc)2 (560 mg, 2.5
mmol), and PPh3 (920 mg, 3.5 mmol). The solution was heated
to a gentle reflux and gradually turned black. After 3.5 h,
the solution was cooled to 25 °C and poured into 300 mL of
1:1 ether-saturated aqueous NH4Cl. The aqueous layer was
extracted with ether (2 × 100 mL), and the combined organic
layers were dried (MgSO4) and concentrated. Chromatography
of the amber residue afforded 10 (11.0 g, 85%) as a white
36.05, 30.32, 29.68, 25.08, 21.40; IR (CHCl3) 1715, 1690 cm-1
.
Anal. Calcd for C20H24O4: C, 73.15; H, 7.37. Found: C, 72.96;
H, 7.53.
Tr icyclic Diol 14. To 500 mL of THF cooled to 0 °C was
added cautiously TiCl4 (23 mL, 205 mmol). The ice bath was
removed, and activated Zn (28 g, 430 mmol) and pyridine (17
mL, 208 mmol) were added sequentially. To this mixture at
ambient temperature was added over 4.5 h via syringe pump
a solution of crude 13 (7 g, 21.3 mmol) in 300 mL of THF. The
reaction mixture was stirred for an additional 30 min and then
treated for 10 min with 300 mL of 10% aqueous K2CO3. This
mixture was extracted three times with ether, and the
combined organic layers were washed twice with water and
brine, dried (Na2SO4), and concentrated to give crude 14
estimated by NMR and GC to be 70% pure. Purification by
chromatography gave 14 as white crystals (4.8 g, 62% from
1
crystalline solid: mp 97 °C; H NMR δ 6.51 (d, J ) 2.1, 1H),
6.38 (d, J ) 2.1, 1H), 5.23 (s, 2H), 4.05-3.88 (m, 4H), 2.11 (s,
3H), 1.92-1.75 (m, 1H), 1.63-1.47 (m, 3H), 1.32 (s, 3H), 1.22
(s, 3H), 1.20 (d, J ) 6.6, 3H); 13C NMR δ 170.6 (C), 162.0 (C),
160.3 (C), 139.8 (C), 112.8 (C), 104.7 (CH), 104.6 (C), 98.6 (C),
97.6 (CH), 79.1 (C), 77.5 (C), 65.6 (CH2), 64.9 (CH2), 64.2 (CH2),
55.7 (CH3), 55.3 (CH3), 46.1 (C), 36.3 (CH), 30.1 (CH2), 26.3
(CH2), 22.4 (CH3), 20.1 (CH3), 17.3 (CH3), 16.5 (CH3); IR (neat)
3470, 2220, 1720 cm-1. Anal. Calcd for C24H32O7: C, 66.65;
H 7.46. Found: C, 66.79; H 7.30.
1
12): mp 116-118 °C; H NMR δ 6.88 (d, J ) 2.40, 1H), 6.52
En yn e 11. To a solution of 10 (37 g, 85.7 mmol) in 300 mL
of benzene was added 40 mL of pyridine followed by the
dropwise addition of POCl3 (32.83 g, 214.1 mmol) in 200 mL
of benzene. After being stirred for 18 h at ambient temper-
ature, the reaction mixture was cautiously poured into 600
mL of 1:1 ether-saturated aqueous NaHCO3. The two layers
were separated, and the aqueous layer was extracted with
ether (2 × 200 mL). The combined organic layers were washed
with water and brine, dried (Na2SO4), and concentrated.
Chromatography of the residue gave transparent, cubic crys-
tals of the acetate ester of 11 (25.5 g, 80%): mp 93-94 °C; 1H
NMR δ 6.56 (d, J ) 2.12, 1H), 6.42 (d, J ) 2.12, 1H), 5.25 (s,
2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.62-2.48 (m, 4H), 2.11 (s, 3H),
2.09 (s, 3H), 1.37 (s, 3H); 13C NMR δ 213.39, 170.29, 161.14,
160.02, 138.96, 138.84, 123.59, 104.67, 104.58, 97.46, 94.46,
86.54, 64.58, 55.47, 55.05, 46.27, 35.19, 30.88, 24.90, 21.80,
(d, J ) 10.30, 1H), 6.41 (dd, J ) 10.30, 1.21, 1H), 6.33 (d, J )
2.40, 1H), 4.74 (s, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.28 (br s,
OH), 2.93 (br s, OH), 2.31-2.17 (m, 2H), 1.59 (dt, J ) 3.30,
13.10, 1H), 1.32-1.20 (m, 1H), 1.20 (s, 3H), 1.14 (s, 3H), 0.80
(s, 3H); 13C NMR δ 158.52, 157.73, 144.59, 134.59, 134.32,
133.21, 127.04, 119.89, 103.55, 96.50, 78.95, 71.62, 55.74,
55.25, 38.79, 28.68, 26.34, 23.46, 21.41, 20.54; HRMS calcd
for C20H26O4 330.1831, found 330.1845. Anal. Calcd for C20
H26O4: C, 72.70; H, 7.93. Found: C, 72.88; H, 7.83.
-
Iod id e 15. To a solution of 12 (1.09 g, 3.3 mmol) in 10 mL
of dry DMF were added sequentially LiI (490 mg, 3.6 mmol),
diisopropylethylamine (870 µL, 5 mmol), and methanesulfonyl
chloride (510 µL, 6.6 mmol), and the mixture was stirred for
6.5 h at ambient temperature. At this point, additional LiI (3
mmol), diisopropylethylamine (8.2 mmol), and methanesulfo-
nyl chloride (6.6 mmol) were added and the mixture was
stirred for an additional 1 h, poured into 40 mL of saturated
aqueous NaHSO3, and extracted with ethyl acetate (3 × 40
mL). The combined organic layers were dried (MgSO4) and
concentrated to give 15 (940 mg, 65%): 1H NMR δ 6.50 (d, J
) 2.4, 1H), 6.36 (d, J ) 12.4, 1H), 6.33 (d, J ) 2.4, 1H), 6.26
(d, J ) 12.4, 1H), 4.38 (s, 2 H), 3.80 (s, 3 H), 3.64 (s, 3 H), 2.43
(t, J ) 7.1, 2H), 2.24 (t, J ) 7.1, 2H), 1.28 (s, 6 H), 1.16 (s, 3
H); 13C NMR δ 215.0 (C), 159.4 (C), 157.6 (C), 137.7 (C), 135.2
(C), 130.3 (C), 129.7 (CH), 124.6 (CH), 119.6 (C), 105.6 (CH),
98.6 (CH), 55.2 (CH3), 55.0 (CH3), 47.0 (C), 35.9 (CH2), 30.2
(CH2), 24.8 (CH3), 21.5 (CH3), 5.8 (CH2).
Tr icycle 16. To a solution of 15 (650 mg, 1.5 mmol) in 50
mL of 2:3 ether-THF at -78 °C was added freshly distilled
boron trifluoride etherate (200 µL, 230 mg, 1.63 mmol). The
mixture was stirred for 20 min, at which time a solution of
tert -butyllithium in pentane (1.7 M, 1.9 mL, 2.23 mmol) was
added dropwise over 2 min. The mixture became red and was
stirred for 50 min and poured into 150 mL of 1:1 ether-
saturated aqueous NH4Cl, the aqueous layer was extracted
with ether (2 × 75 mL), and the combined organic layers were
dried (MgSO4) and concentrated. Chromatography of the
residue gave 16 (193 mg, 41%).
20.52; IR (CHCl3) 2240, 1730, 1715 cm-1. Anal. Calcd for C22
H26O5: C, 71.33; H, 7.07. Found: C, 71.23; H, 7.10.
-
Treatment of the acetate ester of 11 (21 g, 56.8 mmol) with
2 g of KOH (86% w/w) in 250 mL of 1:2:1 THF-MeOH-water
for 5 h at ambient temperature was followed by the addition
of the reaction mixture to 600 mL of 1:1 ether-saturated
aqueous NH4Cl, extraction of the aqueous layer with ether (2
× 150 mL), and drying (Na2SO4) of the combined organic
layers. Concentration afforded 11 as fluorescent crystals (17
1
g, 91%): mp 117-119 °C; H NMR δ 6.62 (d, J ) 2.04, 1H),
6.36 (d, J ) 2.04, 1H), 4.80 (d, J ) 6.20, 2H), 3.83 (s, 3H), 3.82
(s, 3H), 2.56-2.48 (m, 4H), 2.06 (s,3H), 1.94 (t, J ) 6.20, 1H),
1.35 (s, 6H); 13C NMR δ 213.69, 161.49, 160.67, 144.68, 139.13,
123.88, 103.28, 103.18, 97.33, 94.81, 87.08, 64.06, 55.77, 55.37,
46.59, 35.51, 31.17, 25.30, 22.19; IR (CHCl3) 3636, 2240, 1720
cm-1. Anal. Calcd for C20H24O4: C, 73.15; H, 7.37. Found:
C, 72.96; H, 7.54.
Z-Dien e 12. A mixture of 11 (7.00 g, 21.3 mmol) and Pd-
BaSO4 (1.5 g, 20% w/w) in 50 mL of pyridine was shaken for
6 h in an atmosphere of hydrogen (60 psi) in a Parr apparatus.
The reaction mixture was filtered through Celite and concen-
trated to give crude 12. A purified sample yielded the
1
following data: mp 86-87 °C; H NMR δ 6.66 (d, J ) 2.38,
1H), 6.38 (d, J ) 12.01, 1H), 6.35 (d, J ) 2.38, 1H), 6.12 (d, J
) 12.01, 1H), 4.58 (d, J ) 3.52, 2H), 3.82 (s, 3H), 3.68 (s, 3H),
2.44 (t, J ) 6.76, 2H), 2.24 (app t, J ) 6.74, 2H), 1.60 (br s,
OH), 1.27 (s, 6H), 1.13 (s, 3H); 13C NMR δ 215.59, 159.59,
157.17, 140.12, 134.99, 130.35, 129.19, 124.75, 118.36, 102.86,
97.44, 62.99, 60.12, 55.15, 54.95, 47.01, 35.89, 30.17, 24.73,
Alternatively the following procedure could be employed. To
a Li-Na dispersion (21 mg of a 30% dispersion in mineral oil;
5% Na) suspended in THF (2 mL) under Ar was added solid
15 (100 mg, 0.23 mmol). The mixture was stirred at ambient
temperature for 3 h, and then 1 mL of 10% aqueous NH4Cl
was added via syringe. The mixture was poured into 50 mL
of 1:1 10% aqueous NH4Cl-ethyl acetate, the aqueous layer
was extracted with ethyl acetate (40 mL), and the organic
layers were combined, dried (MgSO4), and concentrated.
Purification, as above, gave 16 (44 mg, 62%): 1H NMR δ 6.53
(d, J ) 2.3, 1H), 6.30 (d, J ) 2.3, 1H), 5.74 (dd, J ) 8.1, 4.1,
1H), 3.80 (s, 6H), 3.61 (dd, J ) 17.4, 8.1 Hz, 1H), 3.29 (dd, J
) 17.4, 4.1, 1H), 3.17 (d, J ) 13.3, 1H), 2.70-2.40 (m, 3H),
21.24; IR (CH2Cl2) 3610, 1715 cm-1. Anal. Calcd for C20
H26O4: C, 72.70; H, 7.93. Found: C, 72.58; H, 7.65.
-
Z-Keto Ald eh yd e 13 fr om 12. To a solution of crude 12
(7.00 g, 21.2 mmol) in 60 mL of dry benzene was added in one
portion activated MnO2 (18.43 g, 212 mmol), and the resulting
slurry was stirred at ambient temperature for 30 min. Filtra-
tion through Celite and concentration gave a mixture of

Taxane Synthesis through Pinacol Coupling at C-1-C-2
J . Org. Chem., Vol. 61, No. 3, 1996 1107
IR (CHCl3) 3500, 1730 cm-1
. Anal. Calcd for C22H28O6: C,
2.26-2.10 (m, 2H), 1.24 (s, 3H), 1.18 (s, 3H), 0.81 (s, 3H); 13
NMR δ 216.96 (CO), 158.22 (C), 156.18 (C), 150.65 (C), 140.71
(C), 121.65 (C), 120.65 (CH), 106.98 (CH), 96.08 (CH), 55.57
(CH3), 55.23 (CH3), 49.75 (C), 47.61 (CH2), 38.22 (C), 35.28
(CH2), 33.66 (CH2), 30.16 (CH3), 27.63 (CH3), 23.97 (CH3), 22.60
(CH2); IR (CHCl3) 1715 cm-1; HRMS cald for C20H26O3 314.1882,
found 314.1893.
C
68.02; H, 7.27. Found: C, 67.97; H, 7.40.
Ep oxy Keto Ald eh yd e 22 fr om 20. To a solution of 14
(66 mg, 0.2 mmol) in 1 mL of CH2Cl2 at 0 °C was added in
aliquots until 14 was consumed a solution of freshly prepared
dimethyldioxirane in acetone (approximate 0.1 M). Concen-
tration and radial chromatography gave 22 (20 mg, 29%): mp
1
107-109 °C; H NMR δ 10.08 (s, 1H), 7.02 (d, J ) 2.34, 1H),
Tr iol 17. To a solution of 14 (33 mg, 0.1 mmol) in 3 mL of
CH2Cl2 at -15 °C was added m-chloroperbenzoic acid (17.30
mg, 0.10 mmol). The reaction mixture was stirred at this
temperature for 30 min and then slowly brought to room
temperature over a period of 2 h, diluted with 20 mL of CH2-
Cl2, washed with 20% aqueous NaHSO3, 10% aqueous NaH-
CO3, water, and brine, dried (Na2SO4), and concentrated.
Chromatography of the residue provided triol 17 (28 mg, 81%),
as white crystals: mp 149-153 °C; 1H NMR δ 6.71 (d, J )
2.25, 1H), 6.52 (d, J ) 12, 1H), 6.32 (d, J ) 2.25, 1H), 5.68 (d,
J ) 12, 1H), 4.96 (s, 1H), 4.74-4.72 (m, 1H), 3.83 (s, 3H), 3.78
(s,3H), 3.35 (br s, OH), 3.26 (br s, OH), 2.25 (dd, J ) 17.38,
6.02, 1H), 2.04 (d, J ) 17.38, 1H), 1.70 (br s, OH), 1.15 (s,3H),
1.14 (s, 3H), 1.08 (s, 3H); 13C NMR δ 157.96, 154.58, 142.88,
136.93, 133.55, 121.05, 120.50, 115.02, 100.99, 94.52, 77.95,
73.62, 67.04, 53.55, 53.19, 41.53, 31.88, 19.97, 16.74, 15.32;
IR (CHCl3) 3500 cm-1. Anal. Calcd for C20H26O5: C, 69.34;
H, 7.57. Found: C, 69.44; H, 7.55.
6.74 (d, J ) 12.59, 1H), 6.62 (d, J ) 2.34, 1H), 6.16 (d, J )
12.59, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 2.38-2.06 (m, 4H), 1.26
(s, 3H), 1.23 (s, 3H), 1.09 (s, 3H); 13C NMR δ 211.20, 191.17,
159.44, 157.59, 134.84, 128.25, 126.43, 123.02, 103.36, 99.87,
68.45, 61.46, 55.03, 54.99, 47.50, 32.90, 26.95, 22.61, 20.30,
18.22; IR (CHCl3) 1715, 1700 cm-1. Anal. Calcd for C20
H24O5: C, 69.75 ; H, 7.02. Found: C, 69.72 ; H, 7.19.
-
Z-Keto Ald eh yd e 13 fr om 14. To a solution of 14 (40 mg,
0.12 mmol) and VO(acac)2 (0.5 mg) in 3 mL of benzene at
ambient temperature was added dropwise a solution of tert-
butyl hydroperoxide in 2,2,4-trimethylpentane (3 M, 48 µL,
0.15 mmol). After being stirred for 2 h, the reaction mixture
was diluted with water and extracted three times with ether.
The combined organic layers were washed with water and
brine, dried (Na2SO4), and concentrated to furnish 13 in
quantitative yield.
To a solution of 14 (33 mg, 0.1 mmol) and Mo(CO)6 (2 mg)
in 2.5 mL of benzene was added dropwise a solution of tert-
butyl hydroperoxide in 2,2,4-trimethylpentane (3 M, 40 µL,
0.12 mmol). No reaction was observed at ambient tempera-
ture, but upon heating to reflux for 1.5 h, 14 was converted to
13, which was obtained in quantitative yield after workup as
above.
Silyl Eth er 23. To a solution of 14 (850 mg, 2.6 mmol),
imidazole (352 mg, 5.2 mmol), and DMAP (10 mg) in 16 mL of
DMF was added tert-butyldimethylsilyl chloride (467 mg, 3.09
mmol), and the mixture was heated to 60 °C and stirred for 2
h. The reaction mixture was cooled, diluted with 20 mL of
water, and extracted three times with ether. The organic
layers were combined, washed three times with water and
brine, dried (Na2SO4), and concentrated. Chromatography of
the residue gave 23 (900 mg, 82%): 1H NMR δ 6.74 (d, J )
2.29, 1H), 6.53 (d, J ) 10.22, 1H), 6.46 (app dd, J ) 10.22,
1.23, 1H), 6.30 (d, J ) 2.29, 1H), 4.76 (s, 1H), 3.79 (s, 3H),
3.77 (s, 3H), 2.28-2.07 (m, 2H), 1.67 (dt, J ) 13.16, 3.15, 1H),
1.29-1.17 (m, 1H), 1.22 (s, 3H), 1.15 (s, 3H), 0.87 (s, 9H), 0.79
(s, 3H), -0.10 (s, 3H), -0.34 (s, 3H); 13C NMR δ 158.34, 157.72,
145.17, 135.36, 135.19, 133.56, 126.77, 119.73, 104.32, 96.67,
77.72, 77.23, 73.78, 55.77, 55.25, 38.77, 28.99, 27.29, 25.81,
25.72, 23.80, 21.65, 20.76, 18.18, -4.96, -5.71.
Rea ction of 23 w ith Mo(CO)6-t-Bu OOH. To a mixture
of 23 (88 mg, 0.2 mmol), Mo(CO)6 (2 mg), and solid Na2HPO4
(100 mg) in 10 mL of benzene was added dropwise tert-butyl
hydroperoxide (70% in water, 23 µL, 0.24 mmol). The reaction
mixture was heated to reflux for 6 h and cooled, and solid Na2-
SO3 was added, followed by dilution with water. The aqueous
layer was extracted three times with ether, and the combined
organic layers were washed with 10% aqueous NaHCO3, water,
and brine, dried (Na2SO4), and concentrated. Chromatography
of the residue gave 13 (35 mg, 53%) and 22 (19 mg, 29%).
Ep oxy Keto Ald eh yd e 22 fr om 13. To a solution of 13
(300 mg, 0.92 mmol) in 10 mL of ethanol at 0 °C was added
solid NaBH4 (35 mg, 0.9 mmol). After being stirred for 30 min,
acetone and water were added sequentially. The reaction
mixture was extracted three times with ether, and the organic
layers were combined, washed with water and brine, dried
(Na2SO4), and evaporated. Chromatography of the residue
gave the related diol (220 mg, 73%): 1H NMR δ 6.65 (d, J )
2.31, 1H), 6.39 (d, J ) 2.31, 1H), 6.32 (d, J ) 11.89, 1H), 6.23
(d, J ) 11.89, 1H), 4.63 (1/2 ABq, J ) 12.56, 1H), 4.46 (1/2 ABq,
J ) 12.56, 1H), 3.62-3.53 (m, 1H), 2.51-2.30 (m, 1H), 2.15-
2.02 (m, 1H), 1.93-1.83 (m, 1H), 1.77-1.62 (m, 1H), 1.16 (s,
3H), 1.14 (s,3H), 1.06 (s, 3H).
Aceta te 18. To a solution of 14 (66 mg, 0.2 mmol) in 3 mL
of CH2Cl2 at ambient temperature were added DMAP (3 mg),
triethylamine (40 µL, 0.3 mmol), and acetic anhydride (23 µL,
0.24 mmol). After being stirred for 30 min, the reaction
mixture was poured into 40 mL of 1:1 ethyl acetate-10%
aqueous NH4Cl. The aqueous layer was extracted twice with
ethyl acetate, and the combined organic layers were washed
with water and brine, dried (Na2SO4), and concentrated.
Filtration of the residue through silica gel provided 18 (72 mg,
1
96%) as a white solid: mp 133-136 °C; H NMR δ 6.64 (d, J
) 2.33, 1H), 6.60 (d, J ) 10.33, 1H), 6.48 (d, J ) 10.33, 1H),
6.35 (d, J ) 2.33, 1H), 5.96 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H),
2.34-2.20 (m, 2H), 2.09 (s, 3H), 1.73 (dt, J ) 13.69, 4.01, 1H),
1.36-1.22 (m, 1H), 1.28 (s, 3H), 1.15 (s, 3H), 0.82 (s, 3H); 13
C
NMR δ 171.50, 158.35, 158.04, 142.11, 135.55, 134.58, 133.08,
127.16, 120.04, 103.55, 96.50, 78.99, 74.82, 55.74, 55.28, 38.80,
28.68, 26.38, 23.64, 21.41, 21.23, 20.58; IR (CHCl3) 3540, 1730
cm-1. Anal. Calcd for C22H28O5: C, 70.95; H, 7.58. Found:
C, 70.98; H, 7.64.
Aceta te 19. To a solution of 18 (100 mg, 0.27 mmol) in 5
mL of CH2Cl2 at 0 °C was added m-chloroperbenzoic acid (93
mg, 0.54 mmol). After being stirred at this temperature for
20 min, the reaction mixture was diluted with 50 mL of CH2-
Cl2, washed with 20% aqueous NaHSO3, 10% aqueous NaH-
CO3, water, and brine, dried (Na2SO4), and concentrated.
Chromatography of the residue gave 19 (82 mg, 79%). Alter-
natively, when the reaction was carried out in 6 mL of 1:1 CH2-
Cl2-saturated aqueous NaHCO3, 19 was obtained in 86%
yield: IR (CHCl3) 3510, 1730 cm-1 1H NMR δ 6.66 (d, J )
;
11.97, 1H), 6.46 (d, J ) 2.19, 1H), 6.32 (d, J ) 2.19, 1H), 6.12
(s, 1H), 5.76 (d, J ) 11.97, 1H), 4.76-4.74 (m, 1H), 3.81 (s,
3H), 3.77 (s, 3H), 2.52 (br s, OH), 2.30 (dd, J ) 17.39, 5.29,
1H), 2.13 (s, 3H), 2.09 (d, J ) 17.39, 1H), 1.80 (br s, OH), 1.22
(s, 3H), 1.20 (s, 3H), 1.14 (s, 3H).
Ep oxid e 21. To a solution of 18 (100 mg, 0.27 mmol) in 5
mL of CH2Cl2 at 0 °C was added a solution of freshly prepared
dimethyldioxirane in acetone (approximately 0.1 M, 4.4 mL,
0.44 mmol). After 10 min, concentration and purification of
the residue by radial chromatography provided 21 (103 mg,
quantitative) as white crystals. Alternatively, radial chroma-
tography of the reaction mixtures above that otherwise led to
19 allowed the isolation of 21: mp 118-120 °C; 1H NMR δ
6.86 (d, J ) 11.07, 1H), 6.72 (d, J ) 2.17, 1H), 6.34 (d, J )
2.17, 1H), 6.00 (d, J ) 11.07, 1H), 5.96 (s, 1H), 3.84 (s, 3H),
3.77 (s, 3H), 2.36 (br s, OH), 2.29 (ddd, J ) 11.40, 5.67, 2.65,
1H), 2.10 (s, 3H), 1.89 (app dt, J ) 12.06, 5.67, 1H), 1.57 (app
t, J ) 12.06, 1H), 1.36 (s, 3H), 1.34-1.23 (m, 1H), 1.02 (s, 3H),
0.14 (s, 3H); 13C NMR δ 206.85, 169.49, 160.16, 158.54, 139.75,
129.66, 125.97, 120.11, 103.98, 96.09, 75.18, 74.62, 66.27,
61.90, 55.37, 55.17, 39.57, 27.45, 25.92, 22.63, 21.28, 20.85;
To a solution of the above diol (200 mg, 0.6 mmol) in 3 mL
of 1:1 CH2Cl2-saturated aqueous NaHCO3 at 0 °C was added
m-chloroperbenzoic acid (155 mg, 0.9 mmol). The reaction
mixture was stirred for 40 min and then diluted with 30 mL
of CH2Cl2, and the organic layer was washed with 20% aqueous

1108 J . Org. Chem., Vol. 61, No. 3, 1996
Swindell et al.
NaHSO3, 10% aqueous NaHCO3, water, and brine, dried (Na2-
SO4), and concentrated. Chromatography of the residue gave
the related epoxy diol (120 mg, 57%): 1H NMR δ 6.69 (d, J )
2.40, 1H), 6.50 (d, J ) 12.05, 1H), 6.33 (d, J ) 2.40, 1H), 5.93
(d, J ) 12.05, 1H), 4.55-4.34 (m, 2H), 3.84 (s, 3H), 3.77 (s,
3H), 3.30-3.12 (m, 1H), 2.40-2.28 (m, 1H), 2.25-2.10 (m, 1H),
1.89-1.78 (m, 1H), 1.70-1.53 (m, 1H), 1.39 (s, 3H), 1.21 (s,
3H), 1.08 (s, 3H).
To a solution of the above epoxy diol (60 mg, 0.17 mmol) in
10 mL of CH2Cl2 at ambient temperature were added 4 Å
molecular sieves (1 g), tetrapropylammonium perruthenate (2
mg), and N-methylmorpholine N-oxide (35 mg, 0.262 mmol).
The reaction mixture was stirred for 30 min, filtered through
silica gel with the aid of ethyl acetate, and concentrated to
provide 22 in quantitative yield.
Rea ction of 17 w ith Mo(CO)6-t-Bu OOH. To a solution
of 17 (20 mg, 0.06 mmol) and Mo(CO)6 (3 mg) in 6 mL of 2:1
benzene-CH2Cl2 was added dropwise tert-butyl hydroperoxide
(70% in water, 16 µL, 0.14 mmol). The reaction mixture was
refluxed for 10 h and then cooled. Workup and purification
as above for the reaction of 23 with Mo(CO)6-t-BuOOH gave
22 (16 mg, 80%).
Ack n ow led gm en t. Support through USPHS Grant
No. 41349 awarded by the National Cancer Institute,
DHHS, is gratefully acknowledged. L.T.R. thanks the
United States Department of Education for a GAANN
fellowship.
J O951935E