Taxane synthesis through intramolecular pinacol coupling at C-1 - C-2. Highly oxygenated C-aromatic taxanes

Article abstract of DOI:10.1021/jo9519367

Chiral, nonracemic intramolecular pinacol coupling substrates 3/20 and 30 have been prepared from ethyl isopropyl ketone and acryloyl chloride, which provide the A-ring and either o-iodobenzyl alcohol or 2,4-dimethoxybenzyl alcohol, which provide the respective aromatic C-rings, in 14-16 linear steps in overall yields of approximately 20%. Potential pinacol coupling substrate 23 could not be made available for investigation due to intervening pinacol rearrangement in the acetonide formation step. 3/20 undergo stereoselective cyclizations mediated by TiCl₄-Zn in which the C-9 oxygen substituent plays the dominant role in determining the stereochemical outcome at C-1 and C-2 in the respective tricyclic products 4 and 21. The formation of 21 is the more stereoselective process. The reagent of choice for the transformation of 30 into 31 is SmI₂, which, although less stereoselective than TiCl₄-Zn, leads to higher yielding carbon-carbon bond formation relative to carbonyl reduction. These pinacol cyclizations are interpreted to occur through endo boat-chair transition structures that prefer to orient the developing C-2 substituent and the preexisting C-9 substituent equatorially. Pinacol product 31 was converted through three additional steps into 40 having a B-ring closely related to that of taxol. We believe that these studies indicate pinacol cyclizations at C-1-C-2 to have considerable potential for producing advanced intermediates for syntheses of taxol and related complex taxanes.

Full text of DOI:10.1021/jo9519367

J . Org. Chem. 1996, 61, 1109-1118
1109
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. High ly Oxygen a ted C-Ar om a tic Ta xa n es
Charles S. Swindell* and Weiming Fan
Department of Chemistry, Bryn Mawr College, 101 North Merion Avenue,
Bryn Mawr, Pennsylvania 19010-2899
Received October 31, 1995X
Chiral, nonracemic intramolecular pinacol coupling substrates 3/20 and 30 have been prepared
from ethyl isopropyl ketone and acryloyl chloride, which provide the A-ring and either o-iodobenzyl
alcohol or 2,4-dimethoxybenzyl alcohol, which provide the respective aromatic C-rings, in 14-16
linear steps in overall yields of approximately 20%. Potential pinacol coupling substrate 23 could
not be made available for investigation due to intervening pinacol rearrangement in the acetonide
formation step. 3/20 undergo stereoselective cyclizations mediated by TiCl4-Zn in which the C-9
oxygen substituent plays the dominant role in determining the stereochemical outcome at C-1 and
C-2 in the respective tricyclic products 4 and 21. The formation of 21 is the more stereoselective
process. The reagent of choice for the transformation of 30 into 31 is SmI2, which, although less
stereoselective than TiCl4-Zn, leads to higher yielding carbon-carbon bond formation relative to
carbonyl reduction. These pinacol cyclizations are interpreted to occur through endo boat-chair
transition structures that prefer to orient the developing C-2 substituent and the preexisting C-9
substituent equatorially. Pinacol product 31 was converted through three additional steps into 40
having a B-ring closely related to that of taxol. We believe that these studies indicate pinacol
cyclizations at C-1-C-2 to have considerable potential for producing advanced intermediates for
syntheses of taxol and related complex taxanes.
Sch em e 1
In tr od u ction
In the preceding article,1 we showed that a taxane (cf.
taxol2) synthesis strategy having an intramolecular pi-
nacol coupling at C-1-C-2 as the key step could ef-
ficiently deliver potential advanced tricyclic intermedi-
ates. The appropriate relative stereochemistry at the
conjoined carbons in the example demonstrated (1 f 2;
Scheme 1) is a presumed reflection of an endo transition
structure closely related in conformation to the product.
Herein we examine more complex intramolecular pinacol
couplings (e.g., 3 f 4)3 in which the issue is whether
preexisting stereogenic centers at C-9 and C-10 can exert
productive stereochemical control over the closure of the
C-1-C-2 bond.4
equivalent 1,1-dimethylpropargyl alcohol followed by
silylation, base-catalyzed ejection of acetone, and partial
hydrogenation of the terminal acetylene group thus
revealed led to styrenes 8 and 9, respectively. These
materials were subjected to Sharpless hydroxylation,5
and the vicinal diols so produced were converted to the
Resu lts a n d Discu ssion
(2) 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.
(3) For a preliminary report of part of this work, see: Swindell, C.
S.; Fan, W.; Klimko, P. G. Tetrahedron Lett. 1994, 35, 4959-4962.
(4) 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.
(5) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;
Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768-2771.
The concept behind the construction of the necessary
pinacol coupling substrates (e.g., 3) required the three
aromatic C-ring progenitors 12-14 (Scheme 2). They
were prepared, in the first case, from commercially
available o-iodobenzyl alcohol (5), with 13 and 14 arising
from commercially available 2,4-dimethoxybenzyl alcohol
(6). The latter starting material was converted to iodide
7, and 5 and 7 were then processed further in similar
fashion. Palladium-induced coupling with the acetylene
X Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
(1) Swindell, C. S.; Chander, M. C.; Heerding, J . M.; Klimko, P. G.;
Rahman, L. T.; Raman, J . V.; Venkataraman, H. J . Org. Chem. 1996,
61, 1101-1108.
0022-3263/96/1961-1109$12.00/0 © 1996 American Chemical Society

1110 J . Org. Chem., Vol. 61, No. 3, 1996
Swindell and Fan
Sch em e 2
Following the protocol that had succeeded in the
transformation of 1 into 2,1 keto aldehyde 3 was exposed
to the TiCl4-Zn reagent8 whereupon expected tricycle 4
was formed as the major component of a three-isomer
product mixture. The structure of pinacol 4 was con-
firmed upon its conversion to benzoate 19, a substance
previously prepared and characterized through X-ray
crystallography by Nicolaou9 whose published spectral
parameters matched those we observed. However, it was
keto aldehyde 20 that proved to be the more effective
pinacol coupling substrate, delivering 21 in high yield
and without contamination by alternative diastereomers.
Benzoate 22, epimerically related to 19, could be pre-
pared from 21. The cleavage of the cis-fused acetonide
in the sequence that produced 22 was considerably more
difficult under hydrolytic conditions, which made neces-
sary the use of BCl3. That 21 and 22 differ from 4 and
19 only in configuration at C-10 was indicated by a
number of NOE experiments carried out on these sub-
stances.10 The endo conformation of 21 (and thus 22)
follows from the NOE’s observed for protons at C-13/C-
14 and protons on the aromatic C-ring; equivalent data
were obtained for 4. Furthermore, 22 reveals its Me-18
signal to possess the shielded chemical shift (δ ) 0.81)
characteristic of the endo conformation of C-aromatic
taxanes.11 This conformational assignment is also im-
plied by the stereochemical relationships in 22 defined
by NOE’s involving Me-16 and H-2, H-9, and H-10, as
well as ones involving H-2 and H-9. Pinacol 21 yields
analogous data, as does pinacol 4, except the latter
substance replaces the NOE involving Me-16 and H-10
with one involving Me-18 and H-10. The signals for Me-
16, Me-17, and Me-18 could be assigned from the mutual
NOE relationship of the first two.
We interpret the successful formation of 4 and 21 to
be the result of pinacol coupling transition structures that
have conformational properties similar to those of the
products.1 It is noteworthy that the configuration of C-9
plays the dominant role in determining the stereochem-
ical outcome at the linked C-1 and C-2 sites. Still12 has
estimated the energetic penalty for moving substituents
from equatorial to axial positions at the five unique sites
on the boat-chair conformation of the eight-membered
ring. This penalty is greatest at the position character-
istic of C-9 and essentially nil at that characteristic of
C-10 (cf. conformational structures 19 and 22, Scheme
3) in 4 and 21. Thus, the stereochemical induction
exemplified in these intramolecular pinacol couplings
largely reflects the preference for the developing oxygen
group at C-2 and the pre-existing one at C-9 to be
equatorial in the endo boat-chair transition structures
we believe to be involved;13 the configuration of C-10
appears to be of secondary importance. Nevertheless, the
highly efficient formation of 21 indicates it to represent
the stereochemical manifold of choice given a protocol for
respective protected hydroxy aldehydes 12 and 13 through
a series of unremarkable functional group manipulations.
Hydroxy aldehyde 14 was derived from 13 through acid-
catalyzed hydrolysis. The enantiomeric purity of 12 was
assumed to reflect closely that of its vicinal diol precursor
10, which was established by Mosher ester analysis.6 The
ee of 14, however, was determined by reduction to 11 and
remeasurement, which revealed a modest level of epimer-
ization either at the stage of 13 or 14. Through these
routes, C-ring intermediates 12-14 were available in
9-11 steps in overall yields of approximately 45%.
The desmethoxy series was pursued as outlined in
Scheme 3. Thioacetal iodide 16 was derived from known7
dioxolane iodide 15, and the former was lithiated and
subsequently involved in an addition to protected hydroxy
aldehyde 12. The formation of 17 and 18 was planned
to occur without emphasis on achieving stereochemical
control since the investigation of the pinacol closures of
both 3 and 20 were, in fact, of interest, and since it
seemed likely that the formation of either stereochemical
type could be optimized as desired. By pairing the
lithium reagent derived from 16 with 12, Cram-Felkin-
Ahn adduct 18 predominated over chelation-controlled
adduct 17. The further processing of 17 and 18 into
pinacol coupling substrates 3 and 20 was uneventful.
(8) (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.
(9) Nicolaou, K. C.; Claiborne, C. F.; Nantermet, P. G.; Couladouros,
E. A.; Sorensen, E. J . J . Am. Chem. Soc. 1994, 116, 1591-1592.
(10) Woods, M. C.; Chiang, H.-C.; Nakadaira, Y.; Nakanishi, K. J .
Am. Chem. Soc. 1968, 90, 522-523.
(11) Shea, K. J .; Gilman, J . W.; Haffner, C. D.; Dougherty, T. K. J .
Am. Chem. Soc. 1986, 108, 4953-4956.
(6) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
(7) DiGrandi, M. J .; J ung, D. K.; Krol, W. J .; Danishefsky, S. J . J .
Org. Chem. 1993, 58, 4989-4992.
(12) For an excellent discussion of some aspects of medium ring
conformational analysis, see: Still, W. C.; Galynker, I. Tetrahedron
1981, 37, 3981-3996.
(13) For a counterexample, see ref 2c.

Taxane Synthesis through Pinacol Coupling at C-1-C-2
Sch em e 3
J . Org. Chem., Vol. 61, No. 3, 1996 1111
addressing the C-9-C-10 substructure in the final stages
of sequences to the natural product targets of interest.
In the face of the above experience with the conversion
of 20 to 21, and with the expectation that Birch reduction
would offer the best opportunity for downstream process-
ing of the aromatic C-ring, the preparation of dimethoxy
pinacol coupling substrate 23 was of interest. Addition
of the lithium reagent derived from 16 to 13 (Scheme 4)
led to Cram-Felkin-Ahn adduct 24 in high yield as the
sole detectable isomer. However, closure of the acetonide
ring proved unavoidably problematic. Mild treatment of
24 with acid, even in the presence of excess 2-methoxy-
propene, gave only 25. When harsher conditions were
employed, as when 24 was exposed to acid at higher
temperatures (again, even in the presence of excess
2-methoxypropene), pinacol rearrangement intervened to
give 28.14 Given the high migratory aptitude of the
electron-rich aromatic ring, this complication is perhaps
not surprising. Neither were we successful in carrying
out modifications of the vicinal diol substructure under
basic conditions. For example, conversion to a cyclic
carbonate could not be brought about. The only scheme
we could reduce to practice was the conversion of 25 to
diacetate 26. However, 26 was not a competent intramo-
lecular pinacol coupling substrate, either because it lacks
the rotational restriction afforded by the acetonide, which
favors eight-membered ring formation, or because the
acetyl groups are incompatible with the reductive condi-
tions required. We were unable to characterize tricyclic
products from the exposure of 26 to the TiCl4-Zn reagent
15
or to SmI2 (vide infra).
Fortunately, the alternative diastereomeric series proved
amenable to providing a viable intramolecular pinacol
coupling substrate in 30 (Scheme 5). The addition of the
A-ring lithium reagent to 14 now provided chelation-
controlled product 29, again without detectable contami-
nation by its diastereomer. Unlike previously encoun-
tered 24, 29 was readily convertible to acetonide 30. Keto
aldehyde 30 could then by cyclized through the use of
the TiCl4-Zn reagent or by treatment with SmI2.
(14) Likewise with the corresponding oxygen acetal, we observed
the following:
(15) (a) Namy, J . L.; Souppe, J .; Kagan, H. B. Tetrahedron Lett.
1983, 24, 765-766. (b) Molander, G. A.; Kenny, C. J . Org. Chem. 1988,
53, 2132-2134. (c) Chiara, J . L.; Cabri, W.; Hanessian, S. Tetrahedron
Lett. 1991, 32, 1125-1128.

1112 J . Org. Chem., Vol. 61, No. 3, 1996
Swindell and Fan
Sch em e 4
Sch em e 6
Sch em e 5
4), whereas the cyclizations carried out with SmI2
consistently produced an approximately 10% yield of an
additional uncharacterized stereoisomer. NOE experi-
ments again proved decisive in defining the endo con-
formation and stereochemistry of 31 (cf. conformational
structure 19, Scheme 3) by classifying important proton
signals into three interacting sets: one involving Me-16,
H-2, and H-9; another involving Me-18 and H-10; and a
third including protons at C-13/C-14 and H-4.
It proved possible to manipulate the B-ring of 31 to
provide materials clearly relevant to the construction of
taxol and to demonstrate the structures of the latter by
taking advantage of the NOE relationships exploited
above. Monoacetate 32 was readily available and exhib-
ited selective reactivity toward acetylation at C-9 to give
33 (Scheme 6). Oxidation of 33 then furnished keto
diacetate 37 having its B-ring C-9-C-10 substructure in
the correct oxidation state relative to taxol but with an
incorrect arrangement of functional groups. Cleavage of
the acetonide group from 31 led to tetrol 34. The
silylation of 34 was somewhat capricious but generally
supported the notion that of the secondary hydroxyls
those at C-2 and C-9 were the more reactive. Thus 35
was easily accessible and amenable to oxidation to give
bis(silyloxy) ketone 38. Precedent established by
Nicolaou2c and Holton2b suggested that the R-hydroxy
ketone subunit at C-9-C-10 might be made subject to a
keto-enol equilibrium that would lead predominantly to
the natural arrangement having the carbonyl at C-9 and
a â-oriented oxygen at C-10.16 However, attempted
saponification (KOH, MeOH-water) of 37 simply led to
its destruction, fluoride-induced desilylation of 38 pro-
Several features of the pinacol cyclizations of 30 are
particularly noteworthy. Both reagent systems proved
to be sensitive to temperature, with lower temperatures
favoring simple carbonyl reduction and higher temper-
atures favoring carbon-carbon bond formation. With the
TiCl4-Zn reagent, only reduction occurred at -78 °C,
whereas the optimal yield indicated in Scheme 5 was
obtained in an experiment conducted at 65 °C that also
produced an equivalent amount of keto alcohol reduction
byproduct. SmI2 behaved similarly. At -78 °C, only
reduction took place, but when 30 was exposed to a 10-
fold excess of SmI2 at room temperature, a 63% yield of
31 was obtained along with an approximately 10% yield
of reduction byproduct. Its relative inefficiency notwith-
standing, the TiCl4-Zn reagent mediated inherently
more stereoselective pinacol cyclizations. In none of the
experiments with TiCl4-Zn was another diastereomer of
31 detected (in contrast to previous experience with 3 f
(16) For another solution, see: Young, W. B.; Link, J . T.; Masters,
J . J .; Snyder, L. B.; Danishefsky, S. J .; De Gala, S. Tetrahedron Lett.
1995, 36, 4963-4966.

Taxane Synthesis through Pinacol Coupling at C-1-C-2
J . Org. Chem., Vol. 61, No. 3, 1996 1113
role in the delivery of advanced intermediates for syn-
theses of taxol and related complex taxanes. Indeed,
potential intermediate 40 has been produced from pinacol
31 in three additional steps. Recent reports from the
Wender19 group have highlighted the use of Birch reduc-
tion chemistry to process the aromatic C-rings of inter-
mediates related to 40.
Exp er im en ta l Section 20
2-Meth yl-4-[2-(h yd r oxym eth yl)p h en yl]-3-bu tyn -2-ol. A
solution of 2-iodobenzyl alcohol (5; 46.8 g, 0.2 mol), 2-methyl-
3-butyn-2-ol (29 mL, 0.3 mol), and Ph3P (3.67 g, 0.014 mol) in
diethylamine (200 mL) at 25 °C was sparged with N2 for 30
min, PdCl2 (1.42 g, 0.008 mol) and CuI (1.52 g, 0.008 mol) were
added, and cooling with an ice-water bath was applied. After
being stirred for 2 h, the reaction mixture was concentrated
to afford a residue which was taken up in ether (250 mL) and
water (50 mL), the organic layer was washed with saturated
brine (2 × 50 mL), the aqueous layer was extracted with ether
(2 × 50 mL), and the combined organic layers were dried
(MgSO4). Concentration gave a brown solid (37.6 g, quantita-
tive) which could be purified by dissolution in ethyl acetate
followed by precipitation with hexane to give a yellow solid:
mp 69-71 °C; 1H NMR δ 7.36-7.13 (m, 4H), 4.70 (s, 2H), 4.48
(s, 1H), 4.00 (s, 1H), 1.57 (s, 6H); 13C NMR δ 142.2, 131.9,
128.3, 127.7, 127.3, 121.4, 98.7, 79.4, 65.2, 63.2, 31.2; IR
(CH2Cl2) 3600, 2200 (w) cm-1. Anal. Calcd for C12H14O2: C,
75.77; H, 7.41. Found: C, 75.67; H, 7.23.
F igu r e 1. Proposed endo transition structures for the pinacol
cyclizations reported in this and the preceding1 paper.
duced 39, and base treatment of 39 either left it un-
changed (Et3N, CH2Cl2) or decomposed it to uncharac-
terizeable material (MeONa, MeOH). 2,9-Disilyl
derivative 36, which was available in modest yield from
34, furnished 40 on oxidation. Tricycle 40 possesses the
B-ring functionality and stereochemistry characteristic
of taxol except for the placement of the acyl groups on
the C-2 and C-10 oxygens.
Ar yl Iod id e 7. A mixture of 3,5-dimethoxybenzyl alcohol
(33.6 g, 0.20 mol) and I2 (50.8 g, 0.20 mol) in acetic acid (300
mL) was cooled to 0 °C, and 30% aqueous H2O2 (24.9 g, 0.22
mol) added slowly. After the reaction mixture was stirred at
0 °C for 0.5 h, intermittent cooling was employed to keep the
reaction mixture at 25 °C for 2 h. At this time, the reaction
mixture was poured into cold 1:1 ethyl acetate-saturated
aqueous sodium metabisulfite. The aqueous layer was ex-
tracted with ethyl acetate (2 × 200 mL), and the combined
organic layers were washed with saturated aqueous NaCl (3
× 200 mL) and saturated aqueous NaHCO3, dried (MgSO4),
and concentrated. The white solid product (50.7 g, 87%) could
be further purified through dissolution in ethyl acetate and
Con clu sion
In this and the preceding article,1 we have demon-
strated four intramolecular pinacol cyclizations (1 f 2;
3 f 4; 20 f 21; and 30 f 31) that serve to join C-1 and
C-2 of the taxane skeleton with the appropriate stereo-
chemical disposition of the substituents at these sites.
All of these processes can be interpreted to proceed
through endo transition structures that prefer to orient
the developing oxygen group at C-2 equatorially on the
boat-chair-like eight-membered being formed. In similar
fashion, the cyclizations that allow for stereoinduction
by pre-existing substituents at C-9 and C-10 show a
preference for equatorial orientation of the C-9 acetonide
oxygen, as well. The configuration of C-10 plays a
subordinate role in determining the stereochemical out-
come at conjoined C-1 and C-2. Nevertheless, the stereo-
chemical manifold represented by the transformation 20
f 21 is characterized by greater selectivity. Given the
variable endo-exo selectivity of intramolecular (A-ring)
Diels-Alder17 and (C-9-C-10-linking) vinylogous aldol18
routes to tricyclic taxane synthesis intermediates with
heavily functionalized B-rings, the consistently favorable
transition structure features that typify the pinacol
cyclizations leading to 2, 4, 21, and 31 are noteworthy.
The three endo transition structures that we believe
apply to these processes are illustrated in Figure 1. On
the basis of these studies, pinacol cyclizations that
connect C-1 and C-2 appear capable of playing the key
1
precipitation with hexane: mp 90-92 °C; H NMR δ 6.68 (d,
J ) 2.5, 1H), 6.33 (d, J ) 2.5, 1H), 4.63 (s, 2H), 3.82 (s, 3H),
3.78 (s, 3H).
2-Meth yl-4-[2,4-d im eth oxy-6-(h yd r oxym eth yl)p h en yl]-
3-b u t yn -2-ol was prepared as for 2-methyl-4-[2-(hydroxy-
methyl)phenyl]-3-butyn-2-ol (97%) from 7 with a reaction time
of 50 h: mp 115-117 °C; 1H NMR δ 6.61 (d, J ) 2.3, 1H), 6.34
(d, J ) 2.3, 1H), 4.74 (d, J ) 5.6, 2H), 3.83 (s, 3H), 3.82 (s,
3H), 2.76 (s, 1H), 2.53 (t, J ) 5.6, OH), 1.63 (s, 6H); 13C NMR
δ 161.9, 161.0, 145.7, 103.4, 102.2, 101.9, 97.4, 75.8, 65.9, 63.8,
56.2, 55.5, 31.4; IR (CH2Cl2) 3580, 2200 cm-1
. Anal. Calcd
for C14H18O4: C, 67.19; H, 7.25. Found: C, 67.34; H, 7.42.
2-Met h yl-4-[2-[((ter t-b u t yld im et h ylsilyl)oxy]m et h yl]-
p h en yl]-3-b u t yn -2-ol. A solution of 4-[2-(hydroxymethyl)-
phenyl]-2-methyl-3-butyn-2-ol (37.6 g, 0.20 mol), imidazole
(20.00 g, 0.30 mol), and tert-butyldimethylsilyl chloride (30.15
g, 0.20 mol) in CH2Cl2 (500 mL) at room temperature was
stirred for 2 h, washed with saturated brine (3 × 150 mL),
dried (MgSO4), and concentrated to give a yellow solid (56.8
g, 93%) sufficiently pure for the next step. Further purification
could be carried out by chromatography: mp 26-28 °C; 1H
NMR δ 7.54 (d, J ) 7.7, 1H), 7.38-7.18 (m, 3H), 4.87 (s, 2H),
1.63 (s, 6H), 0.96 (s, 9H), 0.12 (s, 6H); 13C NMR δ 143.2, 131.5,
128.5, 126.4, 125.7, 119.3, 98.8, 79.5, 65.7, 63.1, 31.5, 25.9, 18.4,
(19) (a) Wender, P. A.; et al. In Taxane Anticancer Agents: Basic
Science and Current Status; Georg, G. I., Chen, T. T., Ojima, I., Vyas,
D. M., Eds.; ACS Symp. Series 583; American Chemical Society:
Washington, DC, 1995; Chapter 24. (b) Wender, P. A.; Glass, T. E.;
Krauss, N. E.; Mu¨hlebach, M.; Peschke, B.; Rawlins, D. B. Abstracts
of Papers, 209th National Meeting of the American Chemical Society,
Anaheim, CA; American Chemical Society: Washington, DC, 1995;
ORGN 210.
(17) (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.
(18) Seto, M.; Morihira, K.; Horiguchi, Y.; Kuwajima, I. J . Org.
Chem. 1994, 59, 3165-3174.
(20) For general features, see the preceding article (ref 1).

1114 J . Org. Chem., Vol. 61, No. 3, 1996
Swindell and Fan
-5.3. Anal. Calcd for C18H28O2Si: C, 71.00; H, 9.26. Found:
C, 71.00; H, 9.29.
25.8, 18.3, -5.3. Anal. Calcd for C15H26O3Si: C, 63.79; H,
9.27. Found: C, 64.00; H, 9.18.
R Diol 11 was prepared similarly (quantitative) from 9 with
2-Me t h yl-4-[2,4-d im e t h oxy-6-[[(t er t -b u t yld im e t h yl-
silyl)oxy]m eth yl]p h en yl]-3-bu tyn -2-ol was prepared simi-
larly (98%) from 2-methyl-4-[2,4-dimethoxy-6-(hydroxy-
a reaction time of 9 h: 87% ee; [R]20 -4.6° (c 0.020, CH2Cl2);
D
1H NMR (C6D6) δ 6.81 (d, J ) 2.2, 1H), 6.26 (d, J ) 2.2, 1H),
5.28-5.26 (m, 1H), 4.86 (d, J ) 13.1, 1H), 4.72 (d, J ) 13.1,
1H), 4.03 (t, J ) 9.9, 1H), 3.92-3.82 (m, 2H), 3.41 (s, 3H), 3.06
(s, 3H), 2.98 (d, J ) 5.4, 1H), 0.97 (s, 9H), 0.08 (s, 3H), 0.05 (s,
3H); 13C NMR δ 160.3, 159.1, 141.7, 119.0, 105.1, 98.5, 71.4,
66.4, 64.0, 54.9, 54.8, 26.1, 18.5, -5.3. Anal. Calcd for
C17H30O5Si: C, 59.62; H, 8.82. Found: C, 59.57; H, 8.98.
(R )-1-[1-H y d r o x y -2-(p i v a lo y lo x y )e t h y l]-2-[[(t er t -
bu tyld im eth ylsilyl)oxy]m eth yl]ben zen e. To a solution of
10 (15.1 g, 53.5 mmol) and DMAP (0.065 g, 0.54 mmol) in
pyridine (100 mL) at 0 °C was added slowly pivaloyl chloride
(5.58 mL, 45.6 mmol). After 1 h, the mixture was diluted with
CH2Cl2 (150 mL) and washed with saturated brine (100 mL),
the aqueous layer was extracted with ether (2 × 50 mL), and
the combined organic layers were dried (MgSO4) and concen-
trated. Chromatography of the residue gave a colorless oil
1
methyl)phenyl]-3-butyn-2-ol: mp 78-80 °C; H NMR δ 6.76
(d, J ) 2.3, 1H), 6.31 (d, J ) 2.3, 1H), 4.81 (s, 2H), 3.83 (s,
3H), 3.82 (s, 3H), 2.29 (s, 1H), 1.63 (s, 6H), 0.96 (s, 9H), 0.11
(s, 6H); 13C NMR δ 160.9, 160.9, 146.7, 102.2, 102.1, 100.7,
96.6, 75.6, 65.8, 63.2, 55.9, 55.3, 31.7, 25.9, 18.4, -5.4. Anal.
Calcd for C20H32O4Si: C, 65.90; H, 8.84. Found: C, 66.08; H,
9.00.
1-[[(ter t-Bu tyld im eth ylsilyl)oxy]m eth yl]-2-eth yn ylben -
zen e. A mixture of 2-methyl-4-[2-[[(tert-butyldimethylsilyl)-
oxy]methyl]phenyl]-3-butyn-2-ol (56.8 g, 0.187 mol) and crushed
NaOH (7.48 g, 0.187 mol) in benzene (300 mL) was heated to
reflux for 3.5 h. After being cooled to ambient temperature,
the reaction mixture was washed with saturated brine (3 ×
100 mL), the combined aqueous layers were extracted with
ether (3 × 150 mL), and the combined organic layers were
dried (MgSO4) and concentrated to give a brown oil (44.3 g,
96%). Further purification could be carried out by kugelrohr
distillation (115-120 °C; 0.55 mmHg) to give a colorless oil:
1H NMR δ 7.61-7.20 (m, 4H), 4.93 (s, 2H), 3.32 (s, 1H), 0.99
(s, 9H), 0.15 (s, 6H); 13C NMR δ 143.8, 132.3, 129.0, 126.4,
125.8, 118.8, 82.0, 81.1, 63.1, 26.0, 18.4, -5.3; IR (CCl4) 3300,
2100 (w) cm-1. Anal. Calcd for C15H22OSi: C, 73.12; H, 8.99.
Found: C, 73.30; H, 9.09.
(15.8 g, 81%): [R]20 -20.9° (c 0.0109, CH2Cl2); 1H NMR δ
D
7.52-7.25 (m, 4H), 5.22 (dd, J ) 3.6, 7.2, 1H), 4.81 (d, J )
12.3, 1H), 4.77 (d, J ) 12.3, 1H), 4.36-4.25 (m, 2H), 3.10 (d,
J ) 3 Hz, OH), 1.21 (s, 9H), 0.92 (s, 9H), 0.12 (s, 3H), 0.11 (s,
3H); 13C NMR δ 178.7, 138.5, 137.7, 128.5, 128.0, 128.0, 126.7,
69.1, 68.4, 64.0, 38.8, 27.1, 25.9, 18.3, -5.3; IR (CCl4) 3600,
1760 cm-1
. Anal. Calcd for C20H34O4Si: C, 65.53; H, 9.34.
Found: C, 65.64; H, 9.36.
(R)-1-[1-Hyd r oxy-2-(p iva loyloxy)eth yl]-2,4-d im eth oxy-
6-[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]ben zen e was pre-
2,4-Dim eth oxy-6-[[(ter t-bu tyld im eth ylsilyl)oxy]m eth -
yl]eth yn ylben zen e was prepared similarly (91%) from 2-meth-
yl-4-[2,4-dimethoxy-6-[[(tert-butyldimethylsilyl)oxy]methyl]-
phenyl]-3-butyn-2-ol with a reaction time of 30 h: 1H NMR
(C6D6) δ 6.97 (s, 1H), 6.19 (s, 1H), 5.04 (s, 2H), 3.42 (s, 3H),
3.30 (s, 3H), 3.27 (s, 1H), 0.97 (s, 9H), 0.05 (s, 6H); 13C NMR
δ 161.8, 161.2, 147.4, 102.2, 100.0, 96.5, 85.0, 77.3, 63.1, 55.9,
pared similarly (80%) from 11: [R]20 -16° (c 0.028, CH2Cl2);
D
1H NMR (C6D6) δ 6.74 (d, J ) 2.3, 1H), 6.22 (d, J ) 2.3, 1H),
5.36-5.29 (m, 1H), 4.86 (d, J ) 13, 1H), 4.79 (dd, J ) 9.1,
11.2, 1H), 4.72 (d, J ) 13, 1H), 4.36 (dd, J ) 4.6, 11.2, 1H),
3.73 (d, J ) 10.3, 1H), 3.41 (s, 3H), 3.08 (s, 3H), 1.19 (s, 9H),
0.95 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (C6D6) δ 178.1,
160.4, 159.4, 141.5, 118.6, 105.0, 98.3, 68.5, 67.6, 64.0, 54.9,
54.8, 38.9, 27.4, 26.1, 18.4, -5.3, -5.3; IR (CH2Cl2) 3540, 1715
55.3, 25.9, 18.3, -5.4; IR (CH2Cl2) 3300 cm-1
. Anal. Calcd
for C17H26O3Si: C, 66.63; H, 8.55. Found: C, 66.81; H, 8.71.
Styr en e 8. A mixture of 1-[[(tert-butyldimethylsilyl)oxy]-
methyl]-2-ethynylbenzene (44.3 g, 0.182 mol), commercial
Lindlar’s catalyst (Aldrich; 3.1 g), and quinoline (0.93 mL) in
hexane (300 mL) was stirred at room temperature under an
atmoshphere of H2 for 3.5 h, then diluted with ether (200 mL),
filtered through Celite, and concentrated to give a yellow oil
contaminated by quinoline (quantitative). Further purification
could be carried out by Kugelrohr distillation (125-130 °C;
0.55 mmHg) to give a colorless oil: 1H NMR δ 7.50-7.22 (m,
4H), 7.00 (dd, J ) 11, 17.4, 1H), 5.66 (dd, J ) 1.4, 17.4, 1H),
5.32 (dd, J ) 1.4, 11, 1H), 4.80 (s, 2H), 0.95 (s, 9H), 0.11 (s,
6H); 13C NMR δ 138.1, 135.7, 133.9, 127.6, 127.2, 126.9, 125.4,
115.8, 63.1, 25.9, 18.4, -5.3. Anal. Calcd for C15H24OSi: C,
72.52; H, 9.73. Found: C, 72.40; H, 9.86.
cm-1
.
Anal. Calcd for C22H38O6Si: C, 61.94. H, 8.97.
Found: C, 61.99; H, 8.81.
(R)-1-[1-[(2-Meth oxypr op-2-yl)oxy]-2-(pivaloyloxy)eth yl]-
2-[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]ben zen e. A mix-
ture of (R)-1-[1-hydroxy-2-(pivaloyloxy)ethyl]-2-[[(tert-butyldi-
methylsilyl)oxy]methyl]benzene (14.6 g, 39.8 mmol), 2-meth-
oxypropene (7.65 mL, 80 mmol), and PPTS (1.0 g, 4.0 mmol)
in CH2Cl2 (150 mL) was stirred at 0 °C for 3.5 h and then
washed with saturated aqueous NaHCO3 (100 mL), the
aqueous layer was extracted with CH2Cl2 (2 × 50 mL), and
the combined organic layers were dried (MgSO4) and concen-
trated to give a colorless oil (17.1 g, 98%). Further purification
could be carried out by chromatography: [R]20 -41.4° (c
D
1
0.0105, CH2Cl2); H NMR δ 7.53-7.21 (m, 4H), 5.23 (dd, J )
Styr en e 9 was prepared similarly (94%) from 2,4-dimethoxy-
6-[[(tert-butyldimethylsilyl)oxy]methyl]ethynylbenzene with a
reaction time of 20 h: 1H NMR δ 6.79 (d, J ) 2.3, 1H), 6.68
(dd, J ) 11.8, 17.9, 1H), 6.38 (d, J ) 2.3, 1H), 5.50 (dd, J )
2.2, 17.9, 1H), 5.41 (dd, J ) 2.2, 11.8, 1H), 4.77 (s, 2H), 3.81
(s, 3H), 3.80 (s, 3H), 0.95 (s, 9H), 0.10 (s, 6H); 13C NMR δ 159.5,
158.4, 141.4, 129.8, 118.1, 117.4, 103.0, 97.1, 63.1, 55.5, 55.1,
25.9, 18.3, -5.3. Anal. Calcd for C17H28O3Si: C, 66.19; H,
9.14. Found: C, 65.97; H, 9.12.
5, 6.7, 1H), 4.88 (d, J ) 12.5, 1H), 4.76 (d, J ) 12.5, 1H), 4.13
(app d, J ) 6.7, 1H), 4.12 (app d, J ) 5, 1H), 3.07 (s, 3H), 1.42
(s, 3H), 1.17 (s, 9H), 1.11 (s, 3H), 0.93 (s, 9H), 0.13 (s, 3H),
0.10 (s, 3H); 13C NMR δ 178.3, 139.2, 137.2, 127.5, 127.4, 127.4
(double signal), 101.1, 68.2, 67.2, 63.4, 49.1, 38.7, 27.2, 26.0,
25.9, 25.1, 18.4, -5.3, -5.4; IR (CCl4) 1735 cm-1. Anal. Calcd
for C24H42O5Si: C, 65.72; H, 9.65. Found: C, 65.56; H, 9.71.
(R)-1-[1-[(2-Meth oxypr op-2-yloxy)-2-(pivaloyloxy)eth yl]-
2,4-d im eth oxy-6-[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-
b en zen e was prepared similarly (quantitative) from
(R)-1-[1-hydroxy-2-(pivaloyloxy)ethyl]-2,4-dimethoxy-6-[[(tert-
R Diol 10. A mixture of tert-butyl alcohol (20 mL), water
(20 mL), and AD-mix-â (5.60 g) was stirred at ambient
temperature until two clear phases were produced and then
cooled to 0 °C, and a solution of 8 (0.99 g, 4.0 mmol) in tert-
butyl alcohol (5 mL) and water (5 mL) was added. After being
stirred at 0 °C for 20 h, the mixture was treated with Na2SO3
(6 g) with stirring at ambient temperature for 30 min. The
aqueous layer was extracted with CH2Cl2 (2 × 25 mL), and
the combined organic layers were dried (MgSO4) and concen-
trated. Chromatography of the residue gave a colorless oil
butyldimethylsilyl)oxy]methyl]benzene: [R]20 -29° (c 0.026,
D
CH2Cl2); 1H NMR (CD3CN) δ 6.80 (br s, 1H), 6.46 (d, J ) 2.2,
1H), 5.05 (v br s, 1H), 5.00 (s, 2H), 4.40 (br s, 1H), 4.09 (dd, J
) 5.8, 11.1, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.05 (s, 3H), 1.39
(s, 3H), 1.13 (s, 9H), 1.12 (s, 3H), 0.99 (s, 9H), 0.17 (s, 3H),
0.16 (s, 3H); 13C NMR (C6D6) δ 178.3, 159.7, 157.5 (w, br), 142.6
(w, br), 117.7, 102.9, 100.9, 96.3 (w, br), 66.4, 64.7 (w, br), 62.6
(w, br), 55.6, 55.0, 48.9, 38.6, 27.1, 25.9, 25.1, 24.8, 18.3, -5.3,
-5.3; IR (CCl4) 1735 cm-1
. Anal. Calcd for C26H46O7Si: C,
62.62; H, 9.29. Found: C, 62.39; H, 9.15.
(0.92 g, 82%): 82% ee; [R]20 -18.7° (c 0.0113, CH2Cl2); 1H
D
NMR δ 7.48-7.24 (m, 4H), 5.01 (dd, J ) 5.3, 6.6, 1H), 4.79 (d,
J ) 12.4, 1H), 4.72 (d, J ) 12.4, 1H), 3.76 (app d, J ) 6.6, 1
H), 3.75 (app d, J ) 5.3, 1H), 0.92 (s, 9H), 0.11 (s, 6H); 13C
NMR δ 139.0, 137.7, 128.4, 128.0, 127.8, 126.3, 70.9, 66.8, 63.8,
(R)-1-[1-[(2-Meth oxyp r op -2-yl)oxy]-2-h yd r oxyeth yl]-2-
[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]ben zen e. To a mix-
ture of LiAlH4 (1.67 g, 44 mmol) in ether (200 mL) at 0 °C

Taxane Synthesis through Pinacol Coupling at C-1-C-2
J . Org. Chem., Vol. 61, No. 3, 1996 1115
was added dropwise a solution of (R)-1-[1-[(2-methoxyprop-2-
yl)oxy]-2-(pivaloyloxy)ethyl]-2-[[(tert-butyldimethylsilyl)oxy]-
methyl]benzene (17.0 g, 39 mmol) in ether (50 mL). The
reaction mixture was stirred at 0 °C for an additional 1 h, then
water (100 mL) was added dropwise, and the mixture was
extracted with ether (2 × 100 mL). The combined organic
layers were dried (MgSO4) and concentrated to give a colorless
oil (12.8 g, 92%) sufficiently pure for the next step. Further
temperature for 3.5 h. After being washed with saturated
aqueous NaHCO3 (150 mL), the aqueous layer was extracted
with CH2Cl2 (3 × 100 mL), and the combined organic layers
were dried (MgSO4) and concentrated to give a yellow oil (10.6
g; quantitative): 80% ee; [R]20D -21° (c 0.013, CH2Cl2); 1H NMR
δ 9.67 (s, 1H), 6.62 (d, J ) 2.3, 1H), 6.41 (d, J ) 2.3, 1H), 5.33
(s, 1H), 4.84 (d, J ) 12.8, 1H), 4.68 (d, J ) 12.8, 1 H), 3.83 (s,
3H), 3.77 (s, 3H), 0.92 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H); 13C
NMR δ 199.7, 160.9, 158.6, 142.7, 114.8, 105.2, 97.6, 73.4, 63.5,
purification could be carried out by chromatography: [R]20
D
-38° (c 0.0091, CH2Cl2); 1H NMR δ 7.52-7.49 (m, 1H), 7.34-
7.21 (m, 3H), 5.09 (dd, J ) 5.2, 7.3, 1H), 4.82 (d, J ) 12.4,
1H), 4.73 (d, J ) 12.4, 1H), 3.74-3.56 (m, 2H), 3.13 (s, 3H),
2.60-2.52 (m, OH), 1.42 (s, 3H), 1.13 (s, 3H), 0.95 (s, 9H), 0.16
(s, 3H), 0.13 (s, 3H); 13C NMR δ 139.7, 137.0, 127.7, 127.7,
127.3, 127.1, 101.2, 69.8, 67.2, 63.5, 49.2, 25.9, 25.8, 25.1, 18.4,
-5.3, -5.4; IR (CCl4) 3600 cm-1. Anal. Calcd for C19H39O4Si:
C, 64.37; H, 9.66. Found: C, 64.30; H, 9.80.
55.5, 55.1, 25.6, 18.0, -5.5, -5.6; IR (CH2Cl2) 3525, 1760 cm-1
.
Anal. Calcd for C17H28O5Si: C, 59.98; H, 8.28. Found: C,
59.78; H, 8.12.
Vin yl Iod id e 16. To a solution of 15 (15.5 g, 50 mmol) and
ethanedithiol (8.4 mL) in CH2Cl2 (100 mL) at ambient tem-
perature was added BF3‚OEt2 (5.2 mL). After being stirred 3
h, the reaction mixture was diluted with CH2Cl2 (100 mL) and
washed with 10% aqueous NaOH (100 mL), the aqueous layer
was extracted with CH2Cl2 (2 × 50 mL), and the combined
organic layers were dried (MgSO4) and concentrated to give a
yellow solid (17.7 g; quantitative) sufficiently pure for the next
step. Further purification could be carried out by chrom-
(R)-1-[1-[(2-Met h oxyp r op -2-yl)oxy]-2-h yd r oxyet h yl]-
2,4-d im eth oxy-6-[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-
ben zen e was prepared similarly (96%) from (R)-1-[1-[(2-meth-
oxyprop-2-yl)oxy]-2-(pivaloyloxy)ethyl]-2,4-dimethoxy-6-[[(tert-
butyldimethylsilyl)oxy]methyl]benzene: [R]20D -39° (c 0.0091,
CH2Cl2); 1H NMR δ 6.81 (d, J ) 2.2, 1H), 6.35 (d, J ) 2.2,
1H), 5.42 (dd, J ) 5.4, 7.8, 1H), 4.96 (d, J ) 14.4, 1H), 4.90 (d,
J ) 14.4, 1H), 3.79 (s, 3H), 3.79 (s, 3H), 3.75-3.52 (m, 2H),
3.17 (s, 3H), 2.43 (dd, J ) 3.7, 8.3, 1H), 1.38 (s, 3H), 1.16 (s,
3H), 0.96 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3 H); 13C NMR δ 159.7,
157.5, 142.7, 117.6, 103.3, 101.1, 97.0, 68.8, 64.9, 62.9, 55.7,
55.1, 49.2, 25.9, 24.9, 24.8, 18.4, -5.3, -5.3; IR (CH2Cl2) 3590
cm-1. Anal. Calcd for C21H38O6Si: C, 60.84; H, 9.23. Found:
C, 60.79; H, 9.34.
1
atography: mp 46-48 °C; H NMR δ 3.22 (s, 4H), 2.38-2.25
(m, 4H), 1.85 (s, 3H), 1.37 (s, 6H); 13C NMR δ 137.4, 114.5,
76.0, 47.6, 39.1 (double signal), 36.6, 32.9, 31.0, 29.1, 28.6.
Anal. Calcd for C11H17IS2: C, 38.83; H, 5.03. Found: C, 38.92;
H, 5.18.
Ad d u cts 17 a n d 18. To a solution of 16 (15.30 g, 43 mmol)
in THF (150 mL) at -78 °C was added dropwise tert-
butyllithium (52.94 mL, 1.7 M in pentane, 90 mmol), and the
mixture was stirred for 30 min. At this time, a solution of 12
(7.92 g, 22.5 mmol) in THF (25 mL) was added rapidly, the
mixture was stirred for 30 min, diluted with ether (100 mL),
and warmed to 0 °C, and water (50 mL) was added. The
aqueous layer was extracted with ether (2 × 50 mL), and the
combined organic layers were dried (MgSO4) and concentrated.
Chromatography of the residue gave 17 (1.78 g, 14%) and 18
R Ald eh yd e 12. To a solution of oxalyl chloride (6.77 g, 56
mmol) in CH2Cl2 (150 mL) at -78 °C was added dropwise a
solution of DMSO (10.50 g, 134 mmol) in CH2Cl2 (35 mL). The
mixture was stirred at -78 °C for an addtional 20 min; then
a
solution of (R)-1-[1-[(2-methoxyprop-2-yl)oxy]-2-hydroxy-
(8.85 g, 70%), both as colorles oils. 17: [R]20 -6.4° (c 0.017,
ethyl]-2-[[(tert-butyldimethylsilyl)oxy]methyl]benzene (9.94 g,
28 mmol) in CH2Cl2 (35 mL) was added dropwise. After an
additional 20 min, triethylamine (37 mL) was added slowly
dropwise. After this addition was complete, the mixture was
warmed slowly to 0 °C; then water (50 mL) added. The
aqueous layer was extracted with CH2Cl2 (2 × 30 mL), and
the combined organic layers were dried (MgSO4) and concen-
D
1
CH2Cl2); H NMR δ 7.53-7.20 (m, 4H), 5.27 (d, J ) 9.7, 1H),
4.88 (d, J ) 13.4, 1H), 4.52 (d, J ) 13.4, 1H), 4.29 (d, J ) 9.7,
1H), 3.25-3.04 (m, 7H), 2.33-2.15 (m, 4H), 2.08 (s, 3H), 1.41
(s, 3H), 1.23 (s, 3H), 1.09 (s, 3H), 0.95 (s, 9H), 0.13 (s, 6H),
0.10 (s, 3H); 13C NMR δ 138.9, 138.7, 136.4, 134.6, 127.8, 127.4,
126.5, 125.9, 101.8, 79.0, 74.5, 69.3, 62.1, 49.5, 43.7, 38.9, 38.8,
36.7, 33.0, 26.3, 26.0, 25.4, 25.2, 23.5 (w), 21.5, 18.4, -5.2, -5.2.
trated. Chromatography of the residue gave a yellow oil (8.16
1
g, 83%): [R]20 -20.2° (c 0.0062, CH2Cl2); H NMR δ 9.57 (d,
Anal. Calcd for C30H50O4S2Si: C, 63.56; H, 8.88. Found: C,
D
1
63.38; H, 8.65. 18: [R]20 -1.7° (c 0.0092, CH2Cl2); H NMR
J ) 1.7, 1H), 7.52-7.28 (m, 4H), 5.43 (d, J ) 1.7, 1H), 4.82 (s,
2H), 3.12 (s, 3H), 1.45 (s, 3H), 1.27 (s, 3H), 0.94 (s, 9H), 0.13
(s, 3H), 0.12 (s, 3H); 13C NMR δ 198.6, 138.7, 133.7, 128.3,
127.8, 127.7, 127.7, 101.8, 75.0, 63.3, 49.1, 25.9, 25.4, 25.0, 18.4,
-5.3, -5.4; IR (CCl4) 1740 cm-1. Anal. Calcd for C19H32O4Si:
C, 64.73; H, 9.14. Found: C, 64.66; H, 8.96.
D
δ 7.63-7.24 (m, 4H), 5.23 (d, J ) 9.5, 1H), 5.03 (d, J ) 13.1,
1H), 4.92 (d, J ) 13.1, 1H), 4.37 (dd, J ) 3.4, 9.5, 1H), 3.26 (s,
4H), 2.80 (s, 3H), 2.50-2.05 (m, 4H), 1.96 (s, 3H), 1.53 (s, 3H),
1.36 (s, 3H), 1.35 (s, 3H), 1.03 (s, 3H), 0.95 (s, 9H), 0.13 (s,
3H), 0.11 (s, 3H); 13C NMR δ 141.7, 138.7, 138.6, 131.3, 127.4,
127.1, 126.5, 126.1, 101.3, 79.0, 74.9, 69.0, 63.1, 48.8, 44.0, 38.8,
38.6, 36.8, 32.6, 25.9, 25.9, 25.8, 24.8, 23.5 (w), 20.9, 18.4, -5.3,
-5.4. Anal. Calcd for C30H50O4S2Si: C, 63.56; H, 8.88.
Found: C, 63.73; H, 8.93.
R Ald eh yd e 13 was prepared similarly (65%) from (R)-1-
[1-[(2-methoxyprop-2-yl)oxy]-2-hydroxyethyl]-2,4-dimethoxy-6-
[[(tert-butyldimethylsilyl)oxy]methyl]benzene: [R]20 -62° (c
D
1
0.011, CH2Cl2); H NMR δ 9.64 (s, 1H), 6.81 (d, J ) 2.2, 1H),
6.38 (d, J ) 2.2, 1H), 5.72 (s, 1H), 4.90 (d, J ) 14.5, 1H), 4.57
(d, J ) 14.5, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.08 (s, 3H), 1.39
Keto Ald eh yd e 3. A mixture of 17 (2.04 g, 3.60 mmol),
2-methoxypropene (3.16 mL, 33.0 mmol), and PPTS (50 mg,
0.20 mmol) in CH2Cl2 (300 mL) at 0 °C was stirred at ambient
temperature for 3.5 h and then washed with saturated aqueous
NaHCO3 (50 mL), the aqueous layer was extracted with
CH2Cl2 (2 × 50 mL), and the combined organic layers were
dried (MgSO4) and concentrated to give the acetonide as a
yellow oil (1.89 g, 98%) sufficiently pure for the next step.
Further purification could be carried out by chromatography:
(s, 3H), 1.23 (s, 3H), 0.93 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H); 13
C
NMR δ 199.8, 160.7, 157.9, 143.9, 113.8, 103.4, 101.4, 97.1,
71.7, 62.6, 55.9, 55.1, 49.0, 25.9, 24.9, 24.7, 18.3, -5.3, -5.4;
IR (CCl4) 1750 cm-1. Anal. Calcd for C21H36O6Si: C, 61.14;
H, 8.79. Found: C, 61.24; H, 9.00.
Alternatively, a mixture of (R)-1-[1-[(2-methoxyprop-2-yl)-
oxy]-2-hydroxyethyl]-2,4-dimethoxy-6-[[(tert-butyldimethyl-
silyl)oxy]methyl]benzene (20.5 g, 50 mmol), N-methylmorpho-
line N-oxide (8.74 g, 75 mmol), powdered activated 4 Å
molecular sieves (24.9 g), and tetrapropylammonium per-
ruthenate (0.44 g, 1.3 mmol) in CH2Cl2 (100 mL) was stirred
at ambient temperature for 1.5 h at which time additional
tetrapropylammonium perruthenate (0.43 g, 0.12 mmol) was
added. After 7 h, the mixture was filtered through silica gel,
eluting with CH2Cl2, and concentrated. Chromatography of
the residue gave 13 (15.8 g, 76%).
[R]20 +14.3° (c 0.017, CH2Cl2); 1H NMR δ 7.59-7.24 (m, 4H),
D
5.50 (d, J ) 9.1, 1H), 4.92 (d, J ) 13.4, 1H), 4.66 (d, J ) 13.4,
1H), 4.42 (d, J ) 9.1, 1H), 3.51-3.08 (m, 4H), 2.34-2.16 (m,
4H), 1.97 (br s, 3H), 1.63 (s, 3H), 1.62 (s, 3H), 1.28 (br s, 3H),
0.93 (s, 9H), 0.50 (br s, 3H), 0.11 (s, 3H), 0.06 (s, 3H); 13C NMR
δ 139.5, 135.4, 134.6, 131.2, 127.8, 127.1, 126.3, 126.1, 107.6,
82.2, 78.5, 76.0, 62.4, 43.5, 38.9, 38.9, 36.6, 33.2, 27.5, 26.9,
26.0, 25.9, 23.5 (br and w), 20.4, 18.3, -5.1, -5.3. Anal. Calcd
for C29H46O3S2Si: C, 65.12; H, 8.66. Found: C, 64.80; H, 8.60.
A mixture of the above acetonide (1.89 g, 3.54 mmol) and
tetrabutylammonium fluoride (7.08 mL, 1 M in THF, 7.08
mmol) in THF (150 mL) at ambient temperature was stirred
R Ald eh yd e 14. A mixture of 13 (12.7 g, 31 mmol), PPTS
(231 mg, 0.92 mmol), and four drops of water in CH2Cl2 (500
mL) was stirred initially at 0 °C and subsequently at ambient

1116 J . Org. Chem., Vol. 61, No. 3, 1996
Swindell and Fan
for 30 min and then washed with saturated aqueous NaCl (50
mL), the aqueous layer was extracted with ether (3 × 50 mL),
and the combined organic layers were dried (MgSO4) and
concentrated to give a yellow oil. To this oil in benzene (100
mL) was added MnO2 (6.16 g, 71 mmol), and the mixture was
stirred at ambient temperature for 19 h, filtered through
Celite, and concentrated. Chromatography of the residue gave
H-10), 3.17 (br s, OH), 3.04 (br s, OH), 2.39-2.25 (m, 2H, H-13),
1.60 (s, 3H), 1.59 (s, 3H), 1.56 (s, 3H, H-16), 1.50-1.20 (m,
2H, H-14), 1.15 (s, 3H, H-17), 0.66 (s, 3H, H-18); 13C NMR δ
141.4, 140.5, 134.3, 127.3, 127.1, 126.6, 125.4, 122.1, 110.3,
86.3, 80.6, 77.9, 71.4, 41.1, 30.5, 27.4, 27.3, 26.8, 24.9, 20.6,
19.2. Anal. Calcd for C21H28O4: C, 73.23; H, 8.19. Found:
C, 73.47; H, 8.20.
Ben zoa te 19. To a mixture of 4 (86 mg, 0.25 mmol) and
pyridine (0.85 mL, 10 mmol) in CH2Cl2 (35 mL) was added
dropwise benzoyl chloride (0.58 mL, 5.0 mmol). The mixture
was stirred at ambient temperature for 36 h and washed with
saturated aqueous NaHCO3 (15 mL), the aqueous layer was
extracted with CH2Cl2 (2 × 25 mL), and the combined organic
layers were dried (MgSO4) and concentrated. Chromatography
a yellow viscous oil (1.21 g, 82%): [R]20 -5.2° (c 0.011,
D
CH2Cl2); 1H NMR δ 10.23 (s, 1H), 7.83-7.38 (m, 4H), 6.14 (d,
J ) 8.9, 1H), 4.45 (d, J ) 8.9, 1H), 3.16-3.05 (m, 4H), 2.28-
2.14 (m, 4H), 1.88 (br s, 3H), 1.63 (s, 6H), 1.29 (br s, 3H), 0.51
(br s, 3H); 13C NMR δ 190.9, 140.5, 136.7, 134.5, 134.0, 129.7,
129.6, 128.2, 127.2, 108.2, 82.8, 78.5, 75.0, 43.5, 38.9, 38.9, 36.5,
33.0, 27.5, 26.7, 25.6 (w, br), 23.5 (w, br), 20.5; IR (CH2Cl2)
1700 cm-1
. Anal. Calcd for C23H30O3S2: C, 65.99; H, 7.22.
of the residue gave the acetonide benzoate as a colorless oil
1
(105 mg, 94%): [R]20 -20.2° (c 0.0047, CH2Cl2); H NMR δ
Found: C, 65.79; H, 7.49.
D
A mixture of the above thioketal aldehyde (0.84 g, 2.0 mmol),
CaCO3 (4.80 g, 48 mmol), HgCl2 (6.02 g, 24 mmol), and water
(33 mL) in acetonitrile (130 mL) at ambient temperature was
stirred for 13 h and then filtered through Celite. After being
washed with saturated brine (50 mL), the aqueous layer was
extracted with ether (3 × 30 mL), and the combined organic
layers were dried (MgSO4) and concentrated. Chromatography
of the residue gave 3 as a yellow oil (0.49 g, 71%): [R]20D -49.2°
(c 0.012, CH2Cl2); 1H NMR δ 10.14 (s, 1H), 7.87-7.42 (m, 4H),
6.15 (d, J ) 9, 1H), 4.27 (d, J ) 9, 1H), 2.53-2.33 (m, 4H),
1.97 (s, 3H), 1.66 (s, 3H), 1.64 (s, 3H), 1.17 (s, 3H), 0.34 (s,
3H); 13C NMR δ 213.9, 190.9, 140.3, 137.6, 134.5, 134.4, 130.5,
128.6, 128.4, 127.0, 108.7, 82.6, 74.9, 47.5, 35.6, 32.6, 27.5, 26.6,
8.11-8.07 (m, 2H), 7.61-7.45 (m, 5H), 7.24-7.15 (m, 2H), 6.36
(s, 1H), 5.35 (d, J ) 8.9, 1H), 4.22 (d, J ) 8.9, 1H), 2.52-2.35
(m, 3H), 1.91-1.80 (m, 1H), 1.73 (s, 3H), 1.69 (s, 3H), 1.64 (s,
3H), 1.20 (s, 3H), 0.70 (s, 3H); 13C NMR δ 165.9, 141.4, 137.7,
134.9, 133.3, 130.0, 129.7, 128.5, 127.4, 127.1 (double signal),
124.7, 122.7, 110.6, 86.5, 80.2, 78.3, 74.4, 41.5, 30.4, 27.5, 27.4,
26.9, 25.8, 20.6, 19.2; IR (CH2Cl2) 3600, 1730 cm-1. Anal. Calcd
for C28H32O5: C, 74.98; H, 7.19. Found: C, 75.16, H, 7.38.
A mixture of the above acetonide benzoate (33 mg, 0.074
mmol) and 1 N aqueous HCl (0.30 mL) in methanol (15 mL)
at ambient temperature was stirred for 20 min, diluted with
CHCl3 (30 mL), and washed with saturated aqueous NaHCO3
(30 mL). The aqueous layer was extracted with CHCl3 (3 ×
25 mL), and the combined organic layers were dried (MgSO4)
and concentrated. Chromatography of the residue gave a
24.9, 23.1, 20.4; IR (CH2Cl2) 1710, 1690 cm-1
. Anal. Calcd
for C21H26O4: C, 73.66; H, 7.65. Found: C, 73.49; H, 7.80.
Keto Ald eh yd e 20. A similar sequence was applied to the
stereoisomeric series to deliver first an analogous acetonide
white solid (25.4 mg, 83%): mp 85-88 °C; [R]20 -6.3° (c
D
0.0071, CH2Cl2); 1H NMR δ 8.09-8.06 (m, 2H), 7.75-7.72 (m,
1H), 7.61-7.44 (m, 4H), 7.17 (m, 2H), 6.32 (s, 1H), 5.40 (d, J
) 8.9, 1H), 4.51 (d, J ) 8.9, 1H), 2.97 (br s, OH), 2.65 (br s,
OH), 2.45-2.22 (m, 3H), 1.84 (m, 1H), 1.74 (s, 3H), 1.16 (s,
(94%): [R]20 -13.3° (c 0.0092, CH2Cl2); 1H NMR δ 7.56-7.22
D
(m, 4H), 5.65 (d, J ) 7.9, 1H), 5.14 (br s, 1H), 4.92 (d, J )
13.1, 1H), 4.75 (d, J ) 13.1, 1H), 3.24-2.99 (m, 4 H), 2.29-
1.92 (m, 4H), 1.77 (s, 3 H), 1.72 (s, 3H), 1.51 (s, 3H), 1.28 (br
s, 3H), 1.16 (br s, 3H), 0.94 (s, 9H), 0.10 (s, 3H), 0.06 (s, 3H);
13C NMR δ 138.8, 135.4, 134.0, 132.1, 128.8, 127.4, 126.9,
126.2, 106.5, 78.4 (br, double signal), 76.2, 63.3, 43.6, 38.9, 38.7,
36.5, 32.9, 26.0, 25.9, 25.8, 23.1, 22.6, 22.5, 18.2, -5.2, -5.3.
Anal. Calcd for C29H46O3S2Si: C, 65.12; H, 8.66. Found: C,
64.94; H, 8.66.
3H), 0.64 (s, 3H); IR (CH2Cl2) 3560-3430, 1700 cm-1
.
Tr icycle 21 was prepared (91%) from 20 as in the case of
4: mp 130-132 °C; [R]20 +211° (c 0.016, CH2Cl2); 1H NMR δ
D
7.67 (d, J ) 7.8, 2H, H-4 and H-7), 7.29-7.12 (m, 2H), 5.25 (d,
J ) 6.1, 1H, H-10), 5.10 (d, J ) 6.1, 1H, H-9), 4.56 (s, 1H,
H-2), 3.18 (br s, 1H, OH), 2.89 (br s, OH), 2.37-2.25 (m, 2H,
H-13), 1.76 (s, 3H, H-20), 1.65-1.57 (m, 2H), 1.53 (s, 3H, H-19),
1.33 (s, 3H, H-16), 1.14 (s, 3H, H-17), 0.76 (s, 3H, H-18); 13C
NMR δ 141.6, 139.0, 137.5, 126.7, 125.8, 125.8, 125.3, 124.4,
109.7, 80.9, 80.1, 79.6, 69.8, 41.2, 31.1, 27.2, 26.1, 25.3, 25.1,
20.3, 19.6. Anal. Calcd for C21H28O4: C, 73.23; H, 8.19.
Found: C, 73.00; H, 7.91.
This acetonide was converted to the analogous thioketal
1
aldehyde (73%): [R]20 -31.2° (c 0.0095, CH2Cl2); H NMR δ
D
10.22 (s, 1H), 7.80-7.39 (m, 4H), 6.40 (d, J ) 6.1, 1H), 5.22
(br s, 1H), 3.11-3.01 (m, 4H), 2.33-1.93 (m, 4H), 1.72 (s, 3H),
1.57 (s, 3H), 1.53 (s, 3H), 1.30 (s, 3H), 1.19 (s, 3H); 13C NMR
δ 192.8, 140.3, 135.3, 134.2, 132.6, 132.3, 131.6, 129.2, 127.6,
107.1, 78.4, 78.2, 75.5, 43.8, 38.9 (double signal), 36.4, 32.6,
28.4, 25.9, 25.6, 23.1, 22.6; IR (CCl4) 1700 cm-1. Anal. Calcd
for C23H30O3S2: C, 65.99; H, 7.22. Found: C, 65.80; H, 7.24.
Ben zoa te 22. The acetonide benzoate derived from 21 was
prepared (96%) as in the case of the corresponding acetonide
benzoate derived from 4 except for the inclusion of an
equivalent amount of DMAP: mp 61-63 °C; [R]20 +48.8° (c
D
The thioketal aldehyde was converted to 20 (74%): [R]20
0.010, CH2Cl2); 1H NMR δ 8.07-7.13 (m, 9H), 6.07 (s, 1H),
5.51 (d, J ) 6.2, 1H), 5.40 (d, J ) 6.2, 1H), 2.54-2.34 (m, 3H),
1.88-1.84 (m, 1H), 1.79 (s, 3H), 1.59 (s, 3H), 1.49 (s, 3H), 1.20
(s, 3H), 0.81 (s, 3H); 13C NMR δ 165.7, 139.4, 138.8, 137.9,
133.3, 129.9, 129.6, 128.5, 126.7, 126.3, 126.2, 125.4, 124.0,
109.8, 81.0, 80.2, 79.0, 73.0, 41.7, 31.0, 27.2, 26.8, 25.3, 25.2,
D
-44.6° (c 0.0033, CH2Cl2); 1H NMR δ 10.05 (s, 1H), 7.90-7.42
(m, 4H), 6.28 (d, J ) 7.9, 1H), 5.20 (br s, 1H), 2.20-2.11 (m,
4H), 1.77 (s, 3H), 1.56 (s, 3H), 1.60-1.11 (br s, 6H), 1.11 (s,
3H); 13C NMR δ 214.5, 191.2, 140.9, 138.5 (br), 133.7, 133.2,
131.8 (br), 130.4 (br), 128.6, 127.9, 107.7, 78.3 (br), 76.2, 48.2,
35.7, 31.6, 26.4, 24.9 (br, double signal), 23.7, 22.2; IR (CCl4)
1715, 1695 cm-1. Anal. Calcd for C21H26O4: C, 73.66; H, 7.65.
Found: C, 73.64; H, 7.41.
20.3, 19.7; IR (CH2Cl2) 3600, 1730 cm-1
.
To a solution of the above acetonide benzoate (88 mg, 0.196
mmol) in CH2Cl2 (30 mL) at -78 °C was added BCl3 (0.80 mL,
1 M in CH2Cl2, 0.80 mmol). The mixture was stiirred for 1 h
and then diluted with CH2Cl2 (30 mL), and saturated aqueous
NaHCO3 (30 mL) was added. The aqueous layer was extrated
with CH2Cl2 (3 × 20 mL), and the combined organic layers
were dried (MgSO4) and concentrated. Chromatography of the
residue gave a colorless viscous oil (63 mg, 79%): [R]20D +20.8°
Tr icycle 4. To THF (200 mL) at 0 °C was added dropwise
TiCl4 (1.17 mL, 10.7 mmol), the mixture was warmed to
ambient temperature, and Zn dust (1.40 g, 21.4 mmol) was
added, followed after 10 min by pyridine (0.91 mL, 10.7 mmol).
A solution of 3 (187 mg, 0.54 mmol) in THF (20 mL) was added
dropwise via syringe pump over 2 h, and the mixture was
stirred for an additional 30 min and then treated with 10%
aqueous K2CO3 (100 mL). The aqueous layer was extracted
with ethyl acetate (3 × 100 mL), and the combined organic
layers were dried (MgSO4) and concentrated. Chromatography
of the residue gave a white solid (129 mg, 69%) comprised of
4 (75%) and two minor diastereomers (25%). 4: mp 179-181
°C; [R]20D +42.2° (c 0.013, CH2Cl2); 1H NMR δ 7.65 (d, J ) 7.8,
1H, H-4), 7.48 (d, J )2.8, 1H, H-7), 7.46-7.14 (m, 2H), 5.00
(d, J ) 8.8, 1H, H-9), 4.77 (s, 1 H, H-2), 4.16 (d, J ) 8.8, 1H,
1
(c 0.0037, CH2Cl2); H NMR δ 8.10-8.07 (m, 2H), 7.62-7.45
(m, 5H), 7.23-7.11 (m, 2H), 6.09 (s, 1H, H-2), 5.36 (d, J ) 4.7,
1H, H-9), 4.99 (m, 1H, H-10), 3.43 (br s, OH), 2.83 (br s, OH),
2.50-2.27 (m, 3H), 1.80 (m, 1H), 1.39 (s, 3H, H-16), 1.14 (s,
3H, H-17), 0.81 (s, 3H, H-18); 13C NMR δ 166.1, 138.8, 137.9,
137.1, 133.3, 129.8, 129.7, 129.6, 128.5, 126.8, 126.3, 125.3,
123.0, 79.4, 75.5, 74.3, 71.6, 41.1, 31.7, 26.4, 26.1, 19.9, 19.3;
IR (CH2Cl2) 3600, 1720 cm-1. Anal. Calcd for C25H28O5: C,
73.51; H, 6.91. Found: C, 73.75; H, 7.19.

Taxane Synthesis through Pinacol Coupling at C-1-C-2
J . Org. Chem., Vol. 61, No. 3, 1996 1117
Diol 29 was prepared (70%) from 14 and 16 similarly to
the preparation of 17/18 except that excess 16-tert-butyl-
) 2.4, 1H), 6.06 (s, 1H), 5.16 (d, J ) 9.6, 1H), 4.67 (d, J ) 9.6,
1H), 3.79 (s, 3H), 3.78 (s, 3H), 2.24-2.16 (m, 2H), 2.13 (s, 3H),
1.76-1.70 (m, 1H), 1.62 (s, 3H), 1.61 (s, 3H), 1.60 (s, 3H), 1.47-
1.32 (m, 1H), 1.13 (s, 3H), 0.86 (s, 3H); 13C NMR δ 170.4, 159.6,
159.5, 141.4, 140.2, 128.5, 114.7, 110.5, 103.6, 97.9, 82.2, 80.0,
78.2, 73.9, 56.3, 55.3, 41.5, 30.5, 27.6, 27.5, 26.8, 25.6, 21.3,
lithium was employed: mp 40-42 °C; [R]20 +35° (c 0.029,
D
CH2Cl2); 1H NMR δ 6.76 (d, J ) 2.4, 1H), 6.36 (d, J ) 2.4,
1H), 5.03 (app t, J ) 10.2, 1H), 4.78 (d, J ) 14.2, 1H), 4.61 (d,
J ) 10.2, 1H), 4.57 (d, J ) 14.2, 1H), 3.87 (s, 3H), 3.80 (s, 3H),
3.44 (s, 1H), 3.16-3.01 (m, 4H), 2.36-2.04 (m, 4H), 2.00 (s,
20.7, 19.2; IR (CH2Cl2) 3590, 1735 cm-1
.
3H), 1.26 (s, 3H), 0.95 (s, 9H), 0.43 (br s, 3H), 0.12 (s, 6H); 13
C
A mixture of the above acetonide monoacetate (19 mg, 0.043
mmol), PPTS (10 mg, 0.043 mmol), and water (2 drops) in
CH2Cl2 (10 mL) at ambient temperature was stirred for 18 h,
diluted with CH2Cl2 (30 mL), washed with saturated aqueous
NaHCO3 (15 mL), dried (MgSO4), and concentrated. Chro-
matography of the residue gave 32 as a white solid (16 mg,
92%): mp 79-81 °C; [R]20D +109° (c 0.0014, CH2Cl2); 1H NMR
δ 6.68 (d, J ) 2.3, 1H), 6.29 (d, J ) 2.3, 1H), 6.00 (s, 1H, H-2),
5.04 (app t, J ) 10, 1H, H-9), 4.91 (d, J ) 10, OH), 4.66 (d, J
) 10, 1H, H-10), 3.84 (s, 3H), 3.77 (s, 3H), 3.06 (br s, 1H, OH),
2.35 (s, OH), 2.24-2.16 (m, 2H), 2.12 (s, 3H), 1.73-1.65 (m,
1H), 1.63 (s, 3H, H-16); 1.29-1.17 (m, 1H), 1.09 (s, 3H, H-17),
0.84 (s, 3H, H-18); 13C NMR δ 170.2, 159.0, 158.7, 141.8, 137.6,
132.5, 118.4, 103.8, 96.9, 79.2, 77.4, 75.3, 73.8, 55.9, 55.3, 41.7,
30.0, 27.6, 25.9, 21.2, 20.5, 19.5; IR (CH2Cl2) 3590-3500, 1735
NMR δ 160.1, 158.7, 142.5, 137.1, 133.6, 116.9, 103.4, 97.2,
78.7, 71.5, 70.6, 62.5, 55.4, 55.2, 43.7, 38.8 (double signal), 36.7,
32.9, 27.3 (br), 25.8, 23.1 (br), 21.4, 18.2, -5.1, -5.3.
Keto Ald eh yd e 30. A sequence similar to that applied in
the preparation of 3 delivered first an intermediate acetonide
1
(96%): mp 47-49 °C; [R]20 +36° (c 0.023, CH2Cl2); H NMR
D
δ 6.77 (d, J ) 2.2, 1H), 6.32 (d, J ) 2.2, 1H), 5.46 (br s, 1H),
5.06 (br s, 1H), 4.93 (d, J ) 13.9, 1H), 4.80 (br s, 1H), 3.79 (s,
6H), 3.17-3.03 (m, 4H), 2.34-2.12 (m, 4H), 1.97 (s, 3H), 1.58
(s, 6H), 1.32 (s, 3H), 0.95 (s, 9H), 0.66 (s, 3H), 0.12 (s, 3H),
0.09 (s, 3H); 13C NMR δ 160.4, 159.6, 143.5, 134.4, 131.7, 112.1,
107.5, 102.7, 97.4, 78.9, 76.1, 75.0, 62.7, 55.2, 55.1, 43.5, 38.9,
38.9, 36.7, 33.4, 27.8, 27.2, 26.5 (br), 25.9, 23.7 (br), 20.3, 18.3,
-5.1, -5.2. Anal. Calcd for C31H50O5S2Si: C, 62.59; H, 8.47.
Found: C, 62.70; H, 8.39.
(br) cm-1
.
This acetonide was then converted (quantitative) to an
Dia ceta te 33. A solution of 32 (73 mg, 0.18 mmol), pyridine
(0.25 mL, 2.90 mmol), DMAP (22 mg, 0.18 mmol), and acetic
anhydride (36 µL, 0.38 mmol) in CH2Cl2 (6 mL) was stirred at
ambient temperature for 1.5 h, diluted with CH2Cl2 (40 mL),
and washed with saturated aqueous NaHCO3 (20 mL), the
aqueous layer was extracted with CH2Cl2 (3 × 20 mL), and
the combined organic layers were dried (MgSO4) and concen-
trated. Chromatography of the residue gave 33 (59 mg, 73%)
intermediate thioketal aldehyde: mp 56-59 °C; [R]20 +34°
D
1
(c 0.024, CH2Cl2); H NMR δ 10.76 (s, 1H), 6.93 (d, J ) 2.5,
1H), 6.56 (d, J ) 2.5, 1H), 5.96 (d, J ) 9.4, 1H), 4.78 (d, J )
9.4, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.12-3.01 (m, 4H), 2.28-
2.02 (m, 4H), 1.92 (s, 3H), 1.57 (s, 3H), 1.55 (s, 3H), 1.27 (s,
3H), 0.60 (s, 3H); 13C NMR δ 192.2, 160.2, 159.5, 138.2, 135.3,
130.0, 118.8, 107.7, 103.8, 102.4, 79.8, 78.7, 73.7, 55.6, 55.3,
43.3, 38.8, 38.7, 36.5, 33.3, 27.5, 27.2, 26.2, 24.3, 20.3; IR
and the 2,9,10-triacetate (6 mg, 7%), both as a colorless oils.
(CH2Cl2) 1695 cm-1
. Anal. Calcd for C25H34O5S2: C, 62.73;
1
33: [R]20 +112° (c 0.0037, CH2Cl2); H NMR δ 6.68 (d, J )
D
H, 7.16. Found: C, 62.65; H, 7.01.
2.4, 1H), 6.27 (d, J ) 2.4, 1H), 6.20 (s, 1H), 6.14 (d, J ) 10.5,
1H), 5.08 (d, J ) 10.5, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 2.40-
2.20 (m, 2H), 2.17 (s, 3H), 2.15 (s, 3H), 1.76-1.66 (m, 1H), 1.69
(s, 3H), 1.32-1.20 (m, 1H), 1.13 (s, 3H), 0.90 (s, 3H); 13C NMR
δ 170.7, 170.2, 159.3, 158.9, 142.1, 138.8, 131.9, 116.8, 103.5,
97.5, 79.1, 74.8, 73.8, 73.8, 55.9, 55.3, 41.8, 30.1, 27.7, 26.0,
The thioketal aldehyde was then converted (71%) to 30: mp
1
109-111 °C; [R]20 +64° (c 0.0063, CH2Cl2); H NMR δ 10.80
D
(s, 1H), 6.94 (d, J ) 2.5, 1H), 6.60 (d, J ) 2.5, 1H), 5.94 (d, J
) 9.3, 1H), 4.72 (d, J ) 9.3, 1H), 3.82 (s, 3H), 3.77 (s, 3H),
2.43-2.31 (m, 4H), 1.90 (s, 3H), 1.62 (s, 3H), 1.60 (s, 3H), 1.25
(s, 3H), 0.58 (s, 3H); 13C NMR δ 214.1, 192.5, 160.5, 159.4,
138.6, 135.7, 129.3, 118.3, 108.4, 103.9, 103.3, 80.0, 74.2, 55.7,
55.5, 47.6, 35.7, 32.9, 27.5, 27.2, 25.2, 23.4, 20.3; IR (CH2Cl2)
1710, 1685 cm-1. Anal. Calcd for C23H30O6: C, 68.64; H, 7.51.
Found: C, 68.47; H, 7.65.
21.2, 20.9, 20.7, 19.5; IR (CH2Cl2) 3590, 1740 cm-1
.
Tetr ol 34. A mixture of 31 (0.51 g, 1.26 mmol), PPTS (0.17
g, 0.63 mmol), and H2O (0.20 mL) in CH2Cl2 (40 mL) at
ambient temperature was stirred for 20 h and washed with
saturated aqueous NaHCO3 (20 mL), the aqueous layer was
extracted with CH2Cl2 (3 × 20 mL), and the combined organic
layers were dried (MgSO4) and concentrated to give a white
solid (0.44 g, 95%) sufficiently pure for the next step. Further
Tr icycle 31. To Sm (2.61 g, 17.4 mmol) in THF (90 mL) at
ambient temperature was added slowly diiodomethane (0.70
mL, 8.7 mmol). The mixture was stirred for an additional 1.5
h; then a solution of 30 (0.35 g, 0.87 mmol) in THF (3 mL)
was added. The reaction mixture was stirred for 0.5 h, diluted
with ether (90 mL), and washed with saturated aqueous
NaHCO3 (50 mL), the aqueous layer was extracted with ether
(2 × 40 mL), and the combined organic layers were dried
(MgSO4) and concentrated to give a 5.5:1:1 mixture of 31, an
uncharacterized reduction product, and an uncharacterized
diasteromer, respectively (0.30 g, 86% total yield, 63% yield
of 31). Chromatography and trituration with ether gave 31
purification could be carried out by chromatography: mp 87-
1
89 °C; [R]25 +70° (c 0.0052, CH2Cl2); H NMR (CDCl3-D2O)
D
δ 6.97 (d, J ) 2.4, 1H), 6.27 (d, J ) 2.4, 1H), 4.88 (d, J ) 9.8,
1H), 4.73 (s, 1H), 4.66 (d, J ) 9.8, 1H), 3.82 (s, 3H), 3.78 (s,
3H), 2.45-2.05 (m, 2H), 1.65-1.45 (m, 1H), 1.55 (s, 3H), 1.22-
1.04 (m, 1H), 1.07 (s, 3H), 0.83 (s, 3H); 13C NMR δ 158.8, 158.2,
144.6, 137.4, 132.5, 118.0, 103.3, 97.3, 79.9, 77.2, 75.1, 71.1,
55.7, 55.3, 41.3, 30.1, 27.5, 25.3, 20.5, 19.7. Anal. Calcd for
C20H28O6: C, 65.92; H, 7.74. Found: C, 65.74; H, 7.62.
Disilyl Eth er s 35 a n d 36. A solution of 34 (73 mg, 0.20
mmol), triethylamine (0.56 mL, 4.0 mmol), and trimethylsilyl
chloride (152 µl, 1.20 mmol) in CH2Cl2 (10 mL) at ambient
temperature was stirred for 4 h, diluted with CH2Cl2 (30 mL),
and washed with saturated aqueous NaHCO3 (20 mL), the
aqueous layer was extracted with CH2Cl2 (3 × 15 mL), and
the combined organic layers were dried (MgSO4) and concen-
trated. Chromatography of the residue gave 35 (69 mg, 68%)
as a white solid and 36 (12 mg, 12%) as a colorless oil. 35:
mp 125-127 °C; [R]20D +43° (c 0.0022, CH2Cl2); 1H NMR δ 6.81
(d, J ) 2.5, 1H), 6.25 (d, J ) 2.5, 1H), 5.09 (d, J ) 9.6, 1H),
4.85 (d, J ) 9.6, 1H), 4.81 (s, 1H), 3.79 (s, 3H), 3.77 (s, 3H),
3.25 (s, OH), 2.70 (s, OH), 2.22-1.96 (m, 2H), 1.66-1.61 (m,
1H), 1.58 (s, 3H), 1.17-1.04 (m, 1H), 1.13 (s, 3H), 0.88 (s, 3H),
0.11 (s, 3H), 0.07 (s, 3H); 13C NMR δ 159.7, 158.7, 144.7, 138.3,
132.2, 118.9, 103.2, 97.5, 78.7, 76.1, 74.1, 73.4, 55.3, 55.2, 41.0,
30.4, 28.1, 26.2, 20.9, 20.0, 0.1, 0.0. Anal. Calcd for C26H44O6-
as a white solid: mp 175-177 °C; [R]20 +132° (c 0.0033,
D
CH2Cl2); 1H NMR δ 6.90 (d, J ) 2.4, 1H, H-4), 6.22 (d, J )
2.4, 1H, H-6), 4.88 (d, J ) 9.5, 1H, H-9), 4.73 (s, 1H, H-2),
4.61 (d, J ) 9.5, 1H, H-10), 3.78 (s, 3H), 3.77 (s, 3H), 2.32-
2.10 (m, 2H, H-13), 1.65-1.35 (m, 2H, H-14), 1.56 (s, 3H), 1.55
(s, 3H), 1.51 (s, 3H, H-16), 1.12 (s, 3H, H-17), 0.82 (s, 3H, H-18);
13C NMR δ 159.4, 159.0, 144.5, 140.3, 128.5, 113.8, 110.2,
103.4, 97.6, 82.2, 80.3, 77.8, 71.5, 55.8, 55.2, 41.2, 30.7, 27.6,
27.5, 26.7, 25.2, 20.7, 19.4. Anal. Calcd for C23H32O6: C, 68.30;
H, 7.97. Found: C, 68.23; H, 8.19.
Aceta te 32. A solution of 31 (0.40 g, 1.0 mmol), pyridine
(3.40 mL, 40 mmol), DMAP (0.12 g, 1 mmol), and acetic
anhydride (0.66 mL, 10.0 mmol) in CH2Cl2 (50 mL) was stirred
at ambient temperature for 2 h, diluted with CH2Cl2 (100 mL),
and washed with saturated aqueous NaHCO3 (70 mL), the
aqueous layer extracted with CH2Cl2 (3 × 40 mL), and the
combined organic layers were dried (MgSO4) and concentrated.
Chromatography of the residue gave the corresponding acetate
Si2: C, 61.38; H, 8.71. Found: C, 61.52; H, 8.58. 36: [R]20
D
as a white solid (0.41 g, 92%): mp 122-124 °C; [R]20 +137°
+103° (c 0.0053, CH2Cl2); 1H NMR δ 6.83 (d, J ) 2.5, 1H),
D
(c 0.0095, CH2Cl2); 1H NMR δ 6.68 (d, J ) 2.4, 1H), 6.31 (d, J
6.27 (d, J ) 2.5, 1H), 4.99 (app t, J ) 10.6, 1H), 4.80 (s, 1H),

1118 J . Org. Chem., Vol. 61, No. 3, 1996
Swindell and Fan
4.69 (d, J ) 9.5, 1H), 4.54 (d, J ) 10.6, 1H), 3.85 (s, 3H), 3.78
(s, 3H), 3.29 (s, 1H, OH), 2.14-1.96 (m, 2H), 1.66-1.63 (m,
1H), 1.59 (s, 3H), 1.17-1.04 (m, 1H), 1.08 (s, 3H), 0.87 (s, 3H),
0.18 (s, 3H), 0.03 (s, 3H); 13C NMR δ 158.4, 158.4, 145.1, 135.1,
134.8, 119.7, 103.9, 97.3, 78.4, 77.2, 75.0, 73.3, 55.7, 55.3, 41.1,
30.2, 28.0, 26.3, 20.5, 20.0, 0.2, 0.0. Anal. Calcd for C26H44O6-
Si2: C, 61.38; H, 8.71. Found: C, 61.58; H, 8.64.
Keto Dia ceta te 37. A mixture of 33 (41 mg, 0.092 mmol),
N-methylmorpholine N-oxide (100 mg, 0.85 mmol), powdered
activated 4 Å molecular sieves (125 mg), and tetrapropyl-
ammonium perruthenate (16 mg, 0.046 mmol) in CH2Cl2 (4
mL) was stirred at ambient temperature for 1.5 h and then
29.6, 27.1, 26.0, 20.7, 20.2, 0.1, -0.1; IR (CH2Cl2) 3535, 1715
cm-1
.
Anal. Calcd for C26H42O6Si2: C, 61.62; H, 8.35.
Found: C, 61.83; H, 8.16.
Keto Disilyl Eth er 40 was prepared (61%) as a colorless
oil as in the case of 37 with a reaction time of 24 h and
purification by chromatography: [R]20D -1.4 (c 0.0076, CH2Cl2);
1H NMR δ 6.73 (d, J ) 2.1, 1H), 6.24 (d, J ) 2.1, 1H), 5.24 (s,
1H, H-10), 4.67 (s, 1H, H-2), 3.80 (s, 3H), 3.74 (s, 3H), 3.24 (s,
OH), 2.35-1.55 (m, 3H), 1.34 (s, 3H, H-16), 1.33-1.25 (m, 1H),
1.09 (s, 3H, H-17), 1.05 (d, J ) 0.5, 3H, H-18), 0.20 (s, 3H),
0.00 (s, 3H); 13C NMR δ 206.8, 160.2, 155.6, 144.0, 137.5, 132.5,
120.8, 103.1, 96.3, 81.8, 78.1, 73.2, 55.8, 55.4, 41.6, 29.9, 26.8,
25.8, 20.9, 18.5, 0.1, -0.2; IR (CH2Cl2) 3530, 1715 cm-1. Anal.
Calcd for C26H42O6Si2: C, 61.62; H, 8.35. Found: C, 61.46; H,
8.39.
subjected to chromatography to afford a yellow oil (37 mg,
1
90%): [R]20 -66° (c 0.0075, CH2Cl2); H NMR δ 6.74 (d, J )
D
2.4, 1H), 6.69 (s, 1H, H-2), 6.29 (d, J ) 2.4, 1H), 6.26 (s, 1H,
H-9), 3.79 (s, 3H), 3.77 (s, 3H), 2.50-2.05 (m, 2H), 2.26 (s, 3H),
2.18 (s, 3H), 1.90-1.60 (m, 2H), 1.52 (s, 3H, H-16), 1.12 (s,
3H, H-17), 0.81 (s, 3H, H-18); 13C NMR δ 198.3, 170.3, 169.9,
160.1, 160.0, 141.9, 140.1, 134.4, 114.8, 104.2, 97.8, 78.1, 76.9,
74.2, 56.3, 55.3, 39.6, 29.5, 26.8, 26.2, 21.1, 20.8, 20.4, 20.2;
Ack n ow led gm en t. Support through USPHS Grant
No. 41349 awarded by the National Cancer Institute,
DHHS, is gratefully acknowledged. We are grateful to
Dr. Peter G. Klimko for his early work on the prepara-
tion of 15.
IR (CH2Cl2) 3580, 1740, 1720 cm-1
.
Anal. Calcd for
C24H30O8: C, 64.56; H, 6.77. Found: C, 64.36; H, 6.76.
Keto Disilyl Eth er 38 was prepared (72%) similarly from
35 with a reaction time of 16 h and purification by chrom-
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the preparation of 24-26 and 28 (2 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
1
atography: mp 84-86 °C; [R]20 -65° (c 0.0022, CH2Cl2); H
D
NMR δ 6.78 (d, J ) 2.5, 1H), 6.15 (d, J ) 2.5, 1H), 5.52 (s, 1H,
H-2), 4.86 (s, 1H, H-9), 3.70 (s, 3H), 3.62 (s, 3H), 3.25 (s, 1H,
OH), 2.17-1.96 (m, 2H), 1.65-1.49 (m, 1H), 1.25 (s, 3H, H-16),
1.18-1.05 (m, 1H), 1.02 (s, 3H, H-17), 0.68 (s, 3H, H-18), 0.03
(s, 3H), 0.00 (s, 3H); 13C NMR δ 202.8, 160.2, 159.2, 144.0,
139.1, 134.9, 118.3, 104.0, 97.8, 77.8, 77.1, 73.9, 55.6, 55.2, 38.7,
J O9519367