Enantiospecific total synthesis of natural (+)-taxusin. 2. Functionalization of the A-ring and arrival at the target

Article abstract of DOI:10.1021/ja980538t

A total synthesis of (+)-taxusin (1) has been realized by virtue of the development of a practical route for complete functionalization of the A ring. To achieve this goal, it proved necessary to devise a strategy that would enable chemical transformation

Full text of DOI:10.1021/ja980538t

J. Am. Chem. Soc. 1998, 120, 5213-5225
5213
Enantiospecific Total Synthesis of Natural (+)-Taxusin. 2.
Functionalization of the A-Ring and Arrival at the Target
Leo A. Paquette,* Hui-Ling Wang, Zhuang Su, and Mangzhu Zhao
Contribution from the EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
ReceiVed February 17, 1998
Abstract: A total synthesis of (+)-taxusin (1) has been realized by virtue of the development of a practical
route for complete functionalization of the A ring. To achieve this goal, it proved necessary to devise a
strategy that would enable chemical transformations to proceed in a very congested environment. The successful
pathway from 2 required 19 steps consisting principally of chemoselective oxidation and reduction maneuvers
of various types. The requisite methyl substituent was introduced by 1,2-addition of the methylcerate reagent
to a C(12) ketone intermediate. Several tactics that ultimately proved unsatisfactory are also discussed in an
effort to set important boundary limits on chemical reactivity. The pivotal roles played by samarium diiodide
and tetrapropylammonium perruthenate in permitting the deployment of appropriate chemical changes are
noteworthy.
The preceding paper details a convergent strategy for the
concise construction of taxane systems.1 The specific focus of
these initial chemical studies was taxusin (1), whose carbocyclic
framework and fully functionalized B and C rings were
assembled in only 17 steps. The building block approach
developed in the early phases of this investigation was expected
to have important consequences in an anticipated parallel
synthesis of taxol. Indeed, good progress has been made on
the elaboration of more highly oxygenated intermediates as
required of that target.2 The development of this useful
methodology has given impetus to the need for practical
double bond. Since a possible agenda dealing with synthetic
efforts in this domain could include the migration of an
exocyclic π-bond to the proper internal site, we were led to
gain some perspective of the energetic imbalances separating
these isomers. Molecular mechanics calculations3 were there-
fore performed on compounds A-C as depicted in Table 1.
Although these three compounds are clearly not related as
conformers or diastereomers, and the comparison of their strain
energies is therefore subject to pitfalls,4 the greater stability of
A relative to B proved adequately attractive to us to warrant
experimental evaluation. In view of the thermodynamic rela-
tionship of A to C, one might speculate that taxanes as a class
represent hyperstable olefins.5
Refining the matter still further, we directed our attention to
enolate oxidation studies involving 2.1 In line with earlier
observations,2c it was possible to effect the R-oxygenation of
this ketone with the sulfonyl oxaziridine popularized by Davis.6
By maintenance of the reaction temperature at -78 °C, 3 was
reproducibly obtained in 50% yield (Scheme 1). The occasion
also presented itself to examine the direct oxygenation of the
enolate of 2 at 0 °C in THF solution. At this higher temperature,
more advanced oxidation became operative and the useful
R-diketone 4 was obtained directly (80%). Although 3 proved
to be unresponsive to possible R-ketol rearrangement, access
to 5a could be gained alternatively by the reduction of 4 with
lithium aluminum hydride. No hydride attack was anticipated
at C(13) because the enol positioned there will have been rapidly
transformed into its enolate anion and transiently protected from
nucleophilic attack. Indeed, the regioselective conversion of 4
into 5a was accomplished in 65% yield alongside 28% of
unreacted R-diketone.
methodology designed to introduce the characteristic substitution
pattern resident in ring A. The schemes detailed below
constitute the most elaborate investigation devoted to this topic
yet reported. The knowledge gained in this final drive to taxusin
is of general chemical interest in that it addresses simultaneously
the twin issues of severe steric screening and bridgehead
unsaturation on chemical reactivity. These factors are recog-
nized to impact heavily on this structural sector.
Consideration of Metal-Promoted Exocyclic to Endocyclic
Olefin Isomerization
The first of the intrinsically challenging issues to be addressed
is the most noteworthy feature of the taxusin A-ring, its strained
To this point, the hydroxyl oxygen in 5a has played a highly
instrumental role in furthering the synthetic strategy to this
(1) Paquette, L. A.; Zhao, M. J. Am. Chem. Soc. 1998, 120, 5203.
(2) Elmore, S. W.; Combrink, K. D.; Paquette, L. A. Tetrahedron Lett.
1991, 32, 6679. (b) Paquette, L. A.; Combrink, K. D.; Elmore, S. W.; Zhao,
M. HelV. Chim. Acta 1992, 75, 1772. (c) Elmore, S. W.; Paquette, L. A. J.
Org. Chem. 1993, 58, 4963; 1995, 60, 889. (d) Paquette, L. A.; Huber, S.
K.; Thompson, R. C. J. Org. Chem. 1993, 58, 6874. (e) Paquette, L. A.;
Bailey, S. J. Org. Chem. 1995, 60, 7849. (f) Paquette, L. A.; Montgomery,
F. J.; Wang, T.-Z. J. Org. Chem. 1995, 60, 7857. (g) Zeng, Q.; Bailey, S.;
Wang, T.-Z.; Paquette, L. A. J. Org. Chem. 1998, 63, 3, in press.
(3) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton,
M.; Canfield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem.
1990, 11, 440. The illustrations were generated with Chem 3-D (Cambridge
Scientific Co., Inc., Cambridge, MA).
(4) Taber, D. F. Tetrahedron Lett. 1993, 34, 1883.
(5) Maier, W. F.; Schleyer, P. v. R. J. Am. Chem. Soc. 1981, 103, 1891.
(6) Davis, F. A.; Chen, B.-C. Chem. ReV. 1992, 92, 919.
S0002-7863(98)00538-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/12/1998

5214 J. Am. Chem. Soc., Vol. 120, No. 21, 1998
Paquette et al.
Table 1. Global Minimum Energy Conformations of an
Endocyclic Unsaturated (A), Exocyclic Unsaturated (B), and Fully
Saturated Taxane Systems as Obtained Using the Model KS 2.96
Software Package and Chem 3-D output
Scheme 1
advanced stage. Initially responsible for driving the pinacol-
like bridge migration, this oxygen center subsequently made
possible useful adjustment of the oxidation level in ring A.
However, its role had not yet been played out in that benzoyl-
ation as in 5b was necessary in order to guide regioselective
deprotonation exclusively to the C(12)-position. Indeed, the
sequential exposure of 5b to lithium diisopropylamide and
freshly prepared monomeric formaldehyde solution7 led ef-
ficiently to 6 alone (86%). At this stage, the benzoate group
had accomplished its worthwhile function and was reductively
cleaved by reaction with samarium iodide in a mixture of THF
and methanol at -78 °C.8 It is noteworthy that enone 7a is
not further reduced by this reagent under the conditions
employed.
protecting group, a likely consequence of acid buildup as the
catalyst experiences slow degradation. No conditions were
found to bring about the desired isomerization. Other reagents
such as [(Ph3P)3RhCl] and Pd(OAc)2/Ph2PCH2CH2PPh2 pro-
moted no observable chemical change. One of the deterrents
to migration of the double bond into the interior of ring A may
be a less than ideal stereoelectronic alignment of an allylic C-H
bond.
Of the limited number of known methods for olefin isomer-
ization, that involving rhodium trichloride9 appeared best suited
to our needs. However, heating 7 with RhCl3 in various solvents
with or without added triethylamine failed to give 8. Prolonged
heating in the absence of base resulted in loss of the MOM
Introduction of the C(12)-Methyl Substituent
(7) Schlosser, M.; Jenny, T.; Guggisberg, Y. Synlett 1990, 704.
(8) (a) Molander, G. A. Org. React. 1994, 46, 211. (b) Molander, G. A.
Chem. ReV. 1992, 92, 29. (c) Molander, G. A.; Hahn, G. J. Org. Chem.
1986, 51, 1135, 5259. (d) Kagan, H. B.; Namy, J. L. Tetrahedron 1986,
42, 6573.
(9) (a) Andrieux, J.; Barton, D. H. R.; Patin, H. J. Chem. Soc., Perkin
Trans. 1 1977, 359. (b) Grieco, P. A.; Nishizawa, M.; Marinovic, N.;
Ehmann, W. J. J. Am. Chem. Soc. 1976, 98, 7102. (c) Genet, J. P.; Ficini,
J. Tetrahedron Lett. 1979, 1499.
In view of this development, it seemed appropriate to explore
C-methylation prior to generation of the enone segment. The
potential for undesired competing elimination in the exocyclic
direction did not escape our attention. The pursuit of this
strategy began by conventional alkylation of the enolate anion
of 5b. This reactive intermediate proved to be very prone to

Synthesis of Natural (+)-Taxusin
J. Am. Chem. Soc., Vol. 120, No. 21, 1998 5215
Scheme 2
Scheme 3
and chlorotris(triphenylphosphine)rhodium(II) in refluxing ben-
zene gave in 93% yield the desired silyl enol ether 12. Rather
unexpectedly, all attempts to bring about the selenenylation of
12 with PhSeCl, PhSeBr, and CH3SeBr were not at all
promising. However, a bromine atom could be suitably
introduced by exposure of 12 to N-bromosuccinimide in the
presence of propylene oxide, whose role it was to serve as an
acid scavenger. The resulting R-bromo ketone 13 proved
responsive to the action of DBU in THF at room temperature.
However, dehydrobromination in this fashion returned only 7a.
Recourse to other reagent combinations such as LiBr and Li2CO3
in DMF or LiF and Li2CO3 in HMPA resulted in the generation
of very complex product mixtures. These findings should not
be construed to be evidence for an inability to introduce the
bridgehead double bond by an elimination process (see below).
Nor do they necessarily shed light on the thermodynamic issues
surrounding Table 1. What is clear is that the availability of
three methyl protons fosters facile kinetically controlled anti-
periplanar E2 elimination in the exocyclic direction.
Consideration of Dual Activation as a Tool for Possible
Introduction of the Bridgehead Olefinic Bond
O-alkylation, giving rise to 9 in 92% yield (Scheme 2). This
eventuality conforms to the driving force underlying rehybrid-
ization of the carbon atoms in ring A from sp3 to sp2 status
whenever possible. The previously discussed conversion of 2
to 4 constitutes a related example.
Some advancement toward our goal was alternatively realized
by exploiting the susceptibility of 6 to stoichiometric conjugate
reduction with triphenylphosphine copper hydride hexamer.10
Exposure of benzene solutions of this enone to this hydride
source in the presence of chlorotrimethylsilane or phenylsele-
nenyl chloride led cleanly to 10 without evidence for significant
incorporation of either electrophile. The configuration at C(12)
was ascertained by NOE methods. Attempts to force selenen-
ylation by deprotonation of 10 with excess lithium diisopropyl-
amide followed by PhSeCl returned only the oxidation product
11.
A different agenda for realizing the direct introduction of
C(11)-C(12) unsaturation emerged from the concept of dual
activation. The guiding paradigm was the discovery of a
completely stereoselective epoxidation of 7a with alkaline
hydrogen peroxide12 and the remarkable conversion of 14 to
15 under conditions of attempted lithium triethylborohydride
reduction13 (Scheme 3). Although this reagent has displayed
an ability to attack labile epoxides prone to electrophilic
rearrangement in advance of structural isomerization,14 the only
characterizable product in the present instance was the enolic
â-keto aldehyde 15. By comparison, exposure of 14 to LDA
or to diethylaluminum tetramethylpiperidide gave rise to
complex reaction mixtures. Also, whereas zinc iodide alone
(11) (a) Ojima, I.; Kogure, T.; Nihonyanagi, M.; Nagai, Y. Bull. Chem.
Soc. Jpn. 1972, 45, 3506. (b) Ojima, I.; Kogure, T. Organometallics 1982,
1, 1390.
(12) Solladie´, G.; Hutt, J. J. Org. Chem. 1987, 52, 3560.
(13) Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J. Org. Chem. 1980,
45, 1.
(14) (a) Krishnamurthy, S.; Schubert, R. M.; Brown, H. C. J. Am. Chem.
Soc. 1973, 95, 8486. (b) Kitamura, M.; Isobe, M.; Ichikawa, Y.; Goto, T.
J. Am. Chem. Soc. 1984, 106, 3252.
This complication was skirted by exploiting the Ojima 1,4-
hydrosilylation protocol.11 Treatment of 7a with triethylsilane
(10) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291. (b) Koenig, T. M.; Daeuble, J. F.; Brestensky, D. M.;
Stryker, J. M. Tetrahedron Lett. 1990, 31, 3237. (c) Brestensky, D. M.;
Stryker, J. M. Tetrahedron Lett. 1989, 30, 5677.

5216 J. Am. Chem. Soc., Vol. 120, No. 21, 1998
Paquette et al.
Scheme 4
and CCl4.18 More forceful conditions typified by bromine in
pyridine or treatment with ICl and NaN319 led to decomposition.
The pursuit of this objective was motivated by an expectation
that the halogen, once installed, could be substituted by a methyl
group.
The possibility of utilizing epoxy ketone 20 surfaced when
19 was found to be amenable to epoxidation with 30% hydrogen
peroxide and K2CO3 in methanol at 0 °C. The projected use
of 20 that most attracted our attention was the reaction of lithium
dimethylcuprate with epoxy oximes such as 22 reported by
Corey and co-workers.20 This route to 23, when applied in the
present context, would skirt the need for heavily encumbered
backside attack by (CH3)2CuLi on the epoxide ring. In practice,
however, we were singularly unsuccessful in attempts to
generate an oxime from 20.
This setback prompted consideration of the direct opening
of the oxirane ring in 20 with cuprate reagents.21 The general
consequence of these studies, which also included the higher-
order (CH3)2Cu(CN)Li2,22 was reductive cleavage to the â-hy-
droxy ketone.23 Since it seemed that a modest change in the
nature of the reaction substrate might render the desired reaction
more amenable, 20 was deprotonated with LDA prior to the
addition of methyllithium.24 When no observable change
occurred up to 0 °C, CH3MgBr was additionally introduced
followed by warming to room temperature. Under these
circumstances, a methyl group was indeed incorporated. How-
ever, it was immediately evident following spectroscopic
analysis of this product that the C(14)-methylated compound
(21) had formed by SN2′ addition to the enolate anion followed
by the â-elimination of water.
elicited no chemical change in 14, the co-addition of lithium
iodide did indeed lead to 15, but with decreased efficiency.
The strong implication provided by these results is that the
heightened steric congestion localized on both surfaces of ring
A precludes operation of normal attack trajectories. Without
doubt, this steric crowding also impacts heavily on the reactivity
of 15. The inherent problem is reflected, for example, in our
inability to effect its oxidation to 16 with a variety of reagents
including phenylselenenyl chloride15 and DDQ,16 despite wide-
spread reports of their utility in related contexts. The pertinence
of an inability to access 16 led us to consider introduction of
the bridgehead olefinic bond in advance of any C(12) substitu-
ent.
Response of a Hindered Bridgehead Epoxide to Lithium
Dimethylcuprate
Extended Oxygenation of the A-Ring: Net C(11)
Methylation
Phenylselenenylation of the lithium enolate of 5b with freshly
prepared phenylselenyl bromide17 afforded 17 in 92% yield
(Scheme 4). Subsequent elimination of the derived selenoxide
proceeded with equal efficiency to deliver 18. In contrast to
the fate of 17, which experiences exclusive cleavage of the PhSe
group under conditions of samarium iodide reduction, 18
undergoes chemoselective loss of the benzoate functionality to
give 19 (82%). Despite the successful acquisition of enone 19
in a very direct way, one cannot lose sight of the fact that steric
inhibition of an array of potential synthetic transformations
continues to be observed. An example is the inertness of 19 to
R-iodination upon treatment with I2 in a mixture of pyridine
The successful union of a methyl substituent to 20, although
incorrectly positioned, suggested the viability of a route in which
coupling to an enol triflate was to figure prominently. Con-
struction of the appropriate intermediate began with oxidation
(18) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.;
Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917.
(19) McIntosh, J. M. Can. J. Chem. 1971, 49, 3045.
(20) Corey, E. J.; Melvin, L. S., Jr.; Haslanger, M. F. Tetrahedron Lett.
1975, 3117.
(21) See, for example: (a) Acker, R.-D. Tetrahedron Lett. 1977, 3407.
(b) Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G. Tetrahedron Lett.
1979, 1503. (c) Fuchs, P. L. J. Org. Chem. 1976, 41, 2935. (d) Szajewski,
R. P. J. Org. Chem. 1978, 43, 1819. (e) Lipshutz, B. H.; Kozlowski, J.;
Wilhelm, R. S. J. Am. Chem. Soc. 1982, 104, 2305. (f) Lipshutz, B. H.;
Sengupta, S. Org. React. 1992, 41, 135.
(22) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. Tetrahedron Lett.
1982, 23, 3755.
(23) Zhao, M. Unpublished work performed in this laboratory.
(24) Wender, P. A.; Erhardt, J. M.; Letendre, L. J. J. Am. Chem. Soc.
1981, 103, 2114.
(15) For example: Liotta, D.; Barnum, C.; Puleo, R.; Zima, G.; Bayer,
C.; Kezar, H. S., III J. Org. Chem. 1981, 46, 2920.
(16) For example: Kende, A. S.; Blacklock, T. J. Tetrahedron Lett. 1980,
21, 3119.
(17) Reich, H. J.; Reich, I. L.; Renga, J. M. J. Am. Chem. Soc. 1973,
95, 5813.

Synthesis of Natural (+)-Taxusin
J. Am. Chem. Soc., Vol. 120, No. 21, 1998 5217
Scheme 5
Scheme 6
via the illustrated six-membered transition state would deliver
the observed triflate. The ultimate conversion to 27 rests finally
on an alkylative substitution at that bridgehead carbon adjacent
to the ketone carbonyl.
of 5b to the R-hydroxy ketone 24. The Davis oxaziridine
approach provided 24 as the major product (70%, Scheme 5).
Selective removal of the R-benzoyloxy group with samarium
iodide followed by careful oxidation with the Dess-Martin
periodinane25 furnished the R-diketone 26a. The 1H NMR
spectrum of this advanced intermediate revealed its wholesale
adoption of the enol structure shown. In CDCl3, the hydrogen-
bonded OH proton appears as a sharp singlet at δ 5.94, and the
vinylic C(14) proton is displayed as a doublet with J ) 6.9 Hz.
As a consequence of these structural features, it proved an easy
matter to accomplish O-silylation to give 26b.
The Successful Dihydroxylation Pathway
At this stage, our thinking was much influenced by the
sensitivity of ketone 26b to strong base. Notwithstanding, it
seemed appropriate to entertain the notion that introduction of
the C(12)-methyl could be accomplished by 1,2-addition to a
ketone structurally related to 26. Toward this goal, 19 was
reduced with Dibal-H to the R-alcohol 32, which was amenable
to protection as either the TBS or SEM derivative (Scheme 7).
Dihydroxylation with osmium tetraoxide then provided diols
34a and 34b, perruthenate oxidation of which afforded 35a and
35b, respectively, thereby setting the stage for the projected
nucleophilic methyl addition to C(12). An unanticipated
limitation to this strategy surfaced when 35a was treated with
methylmagnesium bromide in ether at 0 °C. Although a rapid
reaction ensued, the product proved to be isomeric with 35a,
indicating, of course, that the intended 1,2-addition had not
materialized. Rather, the Grignard reagent had functioned as a
base and promoted an R-ketol rearrangement to deliver 36, the
carbonyl group in which is sufficiently congested to ward off
attack by the excess organometallic.
Although the facility with which this framework reorganiza-
tion operates appeared to represent an insurmountable obstacle
to arrival at 1, increased attention to the conformational features
of these taxane intermediates spawned a resolution to the
synthetic goal. Specifically, the presence of an R-oxygenated
substituent at C(13) was recognized to favor a boatlike A-ring
arrangement as in D in order to skirt steric compression on the
molecular interior. However, adoption of this conformation has
Initial attempts to produce the targeted enol triflate by reaction
of 26b with LDA followed by N-phenyltriflimide26 resulted in
no reaction. When recourse was made instead to potassium
hexmethyldisilazide as the base, a clean spot-to-spot transforma-
tion occurred (TLC analysis). When attempts to purify this
product resulted in decomposition, the assumed triflate was not
isolated, but treated directly with lithium dimethylcuprate in a
one-pot procedure. To our delight, a methyl-substituted com-
1
pound could be isolated in 89% yield. However, H NMR
analysis clearly showed this material to be the C(11)-methyl
derivative 27.
This outcome prompted closer investigation of the triflate
generation step. The instability of the enolate of 26b was
initially ascertained on the basis of the complete fading within
minutes of the yellow color that develops immediately after
introduction of the KN(SiMe3)2. Also, TLC analysis at this early
stage showed 26b to be totally consumed before the triflimide
1
was ever introduced. Indeed, the H NMR spectrum of the
unpurified triflate bore little resemblance to that of 26b. Most
striking was the Scheme 6 appearance of two mutually coupled
doublets at δ 6.28 and 5.85. The large coupling constant of
17.8 Hz suggested that â-elimination had occurred with loss of
acetone and introduction of an R,â double bond in ring B (see
29 in Scheme 6). This occurrence sets the stage for O-triflation
of the alkoxide anion to generate 30, rearrangement of which
(25) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(26) Ritter, K. Synthesis 1993, 735.

5218 J. Am. Chem. Soc., Vol. 120, No. 21, 1998
Paquette et al.
Scheme 7
Scheme 8
the effect of disrupting a reasonable stereoalignment between
the carbonyl π-cloud and the C(11)-C(15) σ bond. Accord-
ingly, it is very likely that bridge migration operates only when
the chair topology is attained and is necessarily accompanied
by a substantial release of nonbonded strain. Conversely, a
â-substituent at C(13) is best accommodated in a chairlike
A-ring setting (see E). However, no unusual steric driving force
to isomerization of the R-hydroxy ketone rearrangement is now
apparent. Were this the actual scenario, then the 13â-substituted
intermediate could be sufficiently long-lived to experience
capture of the Grignard reagent.
The reversal in stereochemistry required to test this hypothesis
was easily realized in the manner summarized in Scheme 8.
Dihydroxylation of the bridgehead enone 19 afforded 37, which
was transformed into acetal 38. The fusion of a dioxolane ring
in this manner renders hydride attack from the R-surface more
kinetically favored and delivers 39a. The ensuing SEM
protection and PMP removal steps proceeded quite smoothly
to make diol 40 easily available. At this point, we were again
able to take advantage of the selective oxidizing power of the
TPAP reagent to provide 41 (92%) without detectable overoxi-
dation. This compound was in turn successfully condensed with
the cerate derived from methyllithium, thereby producing 42
in 83% yield. Although these conditions led most efficiently
to 42, neither methyllithium alone nor methylmagnesium
bromide gave any evidence for inducing R-ketol rearrangement.
Thus, the impact exerted by the stereochemistry of substitution
at C(13) is notably influential on A-ring reactivity.
of the R-OH with samarium iodide in THF.8 This accomplished,
â-elimination was induced with thionyl chloride in pyridine.
At this juncture, it was timely to reduce 8 so as to introduce
the R-hydroxyl at C(13) in advance of the deprotection steps.27
Concomitant hydrolytic removal of the MOM and acetonide
protecting groups was accomplished by treatment with lithium
tetrafluoroborate in wet acetonitrile.28 However, the sensitivity
of the resulting tetraol to acidic environments, likely due to the
allylic functionality resident in both rings A and C, required
that very careful attention be paid to reaction conditions. In
(27) For stereochemical precedence, consult inter alia: (a) Hara, R.;
Furukawa, T.; Horiguchi, Y.; Kuwajima, I. J. Am. Chem. Soc. 1996, 118,
9186. (b) Mukaiyama, T.; Shiima, I.; Iwadare, H.; Sakoh, H.; Tani, Y.;
Hasegawa, M.; Saitoh, K. Proc. Japan Acad., Ser. B 1997, 73, 95.
(28) Ireland, R. E.; Varney, M. D. J. Org. Chem. 1986, 51, 635.
Spurred on by these developments, we proceeded to convert
42 by conventional means into ketone 43 and to implement
removal of the neighboring hydroxyl groups therein. The best
sequence uncovered involved preliminary reductive cleavage

Synthesis of Natural (+)-Taxusin
J. Am. Chem. Soc., Vol. 120, No. 21, 1998 5219
product was extracted into ether prior to drying. Following solvent
evaporation, the residue was subjected to chromatography on silica gel
(elution with 1:4 ether/ hexanes) to provide 209 mg (80%) of 4 as a
white solid, mp 165-166 °C; IR (CHCl3, cm-1) 3460, 1677, 1660; 1H
NMR (300 MHz, CDCl3) δ 6.03 (d, J ) 6.6 Hz, 1 H), 5.89 (s, 1 H),
5.05 (s, 1 H), 4.86 (s, 1 H), 4.37 (d, J ) 6.7 Hz, 1 H), 4.33 (d, J ) 6.7
Hz, 1 H), 4.27 (d, J ) 9.7 Hz, 1 H), 4.12 (br s, 1 H), 4.02 (d, J ) 9.7
Hz, 1 H), 3.31 (s, 3 H), 2.96 (d, J ) 6.6 Hz, 1 H), 2.67 (br d, J ) 3.7
Hz, 1 H), 2.38 (dd, J ) 2.0, 6.4 Hz, 1 H), 2.12 (ddd, J ) 2.0, 6.4, 16.0
Hz, 1 H), 1.81-1.56 (m, 5 H), 1.41 (s, 6 H), 1.34 (s, 3 H), 1.20 (s, 3
H), 0.88 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 198.7, 148.9, 147.2,
118.4, 112.6, 104.8, 92.2, 83.6, 78.0, 75.5, 55.1, 54.0, 45.3, 38.2, 36.9,
36.5, 35.5, 28.8, 27.5, 25.1, 24.5, 23.5, 17.2; MS m/z (M+) calcd
the final analysis, a 5% level of water, a reaction temperature
of 45 °C, and a total exposure time not exceeding 2 h were
found to be near optimal. Finally, acetylation of this highly
polar penultimate intermediate under standard conditions gave
(+)-taxusin (1), [R]25D +105.5 (c 0.09, CHCl3), which exhibited
1H NMR, 13C NMR, and IR spectra indistinguishable from those
of natural taxusin, [R]25 +103.8 (c 0.16, CHCl3).
D
Summary
A total synthesis of naturally occurring (+)-taxusin that is
intrinsically different from the routes to (-)-taxusin29 and (()-
taxusin27a reported earlier has been completed. The present
approach proceeds from 21 in 19 steps and 1.3% overall yield.
The successful protocol features chemoselective oxidation/
reduction processes of varied type within the confines of the A
ring, and proper introduction of the C(12) methyl substituent
via an organocerate reagent. A number of ancillary studies have
demonstrated certain tactics to be unsatisfactory for use in the
extremely congested and rather strained environment present
in the A-ring sector of taxane intermediates. These include
possible isomerization of an exocyclic double bond to the
internal bridgehead position, dehydrogenation of a â-dicarbonyl
system, and cuprate attack on an epoxy ketone. Several
rearrangement reactions are now recognized to be capable of
implementation. The transformations of 26b into 27 and of 35b
into 36 are exemplary.
420.2512, obsd 420.2507; [R]23 +28.5 (c 1.04, CHCl3).
D
Anal. Calcd for C24H36O6: C, 68.55; H, 8.63. Found: C, 68.35;
H, 8.65.
(3S,4aR,6S,7S,10S,11R,12R,12aR)-Dodecahydro-7-hydroxy-11,12-
(isopropylidenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-4-
methylene-6,10-methanobenzocyclodecen-8(2H)-one (5a). A slurry
of lithium aluminum hydride (53 mg, 1.39 mmol) in anhydrous ether
(20 mL) was treated with 4 (195 mg, 0.464 mmol) in ether (16 mL),
stirred for 30 min, and cooled to -78 °C prior to a methanol quench
(2 mL). Saturated NH4Cl solution (4 mL) was next introduced and
the temperature was allowed to rise to 25 °C. The aqueous phase was
extracted with 1:1 ethyl acetate/hexanes (3 × 20 mL), and the combined
organic layers were dried and concentrated. Chromatographic purifica-
tion on silica gel (gradient elution with 33-50% ethyl acetate in
hexanes) returned 54 mg (28%) of unreacted 4 and provided 128 mg
(65%) of 5a, a colorless solid of mp 192-194 °C: IR (CHCl3, cm-1
)
1
3500, 1704; H NMR (300 MHz, CDCl3) δ 5.08 (br s, 1 H), 5.00 (br
s, 1 H), 4.67 (d, J ) 6.9 Hz, 1 H), 4.63 (d, J ) 6.9 Hz, 1 H), 4.35 (br
d, J ) 7.6 Hz, 1 H), 4.31 (d, J ) 9.8 Hz, 1 H), 4.13 (t, J ) 2.8 Hz, 1
H), 3.90 (d, J ) 9.8 Hz, 1 H), 3.37 (s, 3 H), 3.15 (d, J ) 2.6 Hz, 1 H),
3.03 (ddd, J ) 1.3, 9.7, 18.1 Hz, 1 H), 2.62 (d, J ) 18.1 Hz, 1 H),
2.54 (d, J ) 9.7 Hz, 1 H), 2.35 (t, J ) 6.7 Hz, 1 H), 2.23 (ddd, J )
1.5, 6.1, 15.5 Hz, 1 H), 1.83-1.51 (m, 6 H), 1.46 (s, 3 H), 1.37 (s, 3
H), 1.36 (s, 3 H), 1.29 (s, 3 H), 0.87 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 209.9, 146.5, 113.0, 105.1, 92.8, 83.4, 82.7, 75.6, 74.0,
55.0, 49.6, 45.9, 44.1, 39.1, 38.9, 37.4, 35.0, 28.3, 27.6, 26.8, 26.7,
In the final analysis, our route to 1 (36 steps) is somewhat
longer than those developed by Holton (31 steps)29 and
Kuwajima (25 steps).27a Work continues on the development
of a workable strategy that would transform ketones such as 2
more directly into products having the C(11)-C(14) functional-
ity characteristic of the taxane family of diterpenoids.
Experimental Section
For general methods, consult ref 1.
25.3, 19.6, 17.7; MS m/z (M+) calcd 422.2668, obsd 422.2665; [R]23
D
(3S,4aR,6S,8S,10S,11R,12R,12aR)-Dodecahydro-8-hydroxy-11,12-
(isopropylidenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-4-
methylene-6,10-methanobenzocyclodecen-7(1H)-one (3). To a so-
lution of 2 (41 mg, 0.10 mmol) in dry THF (3 mL) cooled to -78 °C
was added potassium hexamethyldisilazide (0.22 mL of 0.5 M in
toluene, 0.11 mmol). After 30 min, the reaction mixture was treated
with the Davis oxaziridine6 (29 mg in 2 mL of THF), and stirring was
continued for 30 min prior to quenching with cold saturated NH4Cl
solution. TLC analysis at this point indicated that conversion had
proceeded only to approximately the 60% level. The product was
extracted into ethyl acetate/hexanes (1:1), dried, concentrated, and
chromatographed on silica gel to give 21 mg (50%) of 3: 1H NMR
(300 MHz, CDCl3) δ 5.09 (br s, 1 H), 4.82 (br s, 1 H), 4.50 (d, J ) 9.1
Hz, 1 H), 4.43 (d, J ) 6.4 Hz, 1 H), 4.40 (d, J ) 6.4 Hz, 1 H), 4.29
(d, J ) 9.8 Hz, 1 H), 4.22 (dd, J ) 3.2, 9.8 Hz, 1 H), 4.13 (t, J ) 2.8
Hz, 1 H), 3.63 (s, 1 H), 3.30 (s, 3 H), 2.56-2.47 (m, 2 H), 2.34-2.15
(m, 3 H), 2.01 (dd, J ) 6.8, 15.9 Hz, 1 H), 1.90-1.56 (m, 4 H), 1.40
(s, 6 H), 1.37 (s, 3 H), 0.98 (s, 3 H), 0.93 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 215.0, 148.0, 112.3, 106.6, 92.8, 83.0, 81.8, 76.7, 72.8,
58.4, 55.2, 46.5, 40.3, 39.2, 37.9, 37.8, 35.7, 28.3, 27.4, 26.8, 26.5,
25.2, 22.6, 17.4; FAB MS m/z (M+ + 1) calcd 423.28, obsd 423.38.
(3S,4aR,6S,10S,11R,12R,12aR)-2,3,4,4a,5,6,10,11,12,12a-Decahy-
dro-8-hydroxy-11,12-(isopropylidenedioxy)-3-(methoxymethoxy)-
12a,13,13-trimethyl-4-methylene-6,10-methanobenzocyclodecen-
7(1H)-one (4). A solution of 2 (252 mg, 0.62 mmol) and 18-crown-6
(246 mg, 0.93 mmol) in dry THF (31 mL) was oxygenated with O2 for
30 min and treated with potassium hexamethyldisilazide (1.86 mL of
0.5 M in toluene, 0.93 mmol) at 0 °C. After 10 min of stirring, the
reaction mixture was quenched with saturated NH4Cl solution, and the
-99.2 (c 1.02, CHCl3).
Anal. Calcd for C24H38O6: C, 68.22; H, 9.06. Found: C, 68.28;
H, 9.13.
(3S,4aR,7S,10S,11R,12R,12aR)-Dodecahydro-7-hydroxy-11,12-
(isopropylidenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-4-
methylene-6,10-methanobenzocyclodecen-8(2H)-one Benzoate (5b).
A solution of 5a (78 mg, 0.185 mmol), 4-(dimethylamino)pyridine (2
mg), and benzoyl chloride (60 mg, 0.43 mmol) in pyridine (2 mL)
was stirred overnight, quenched with water, and extracted with 1:1 ethyl
acetate/hexanes. The combined organic layers were dried and con-
centrated, and the residue was chromatographed on silica gel (elution
with 1:3 ethyl acetate/hexanes) to give 5b (83 mg, 85%) as a white
foam: IR (neat, cm-1) 1720; 1H NMR (300 MHz, CDCl3) δ 8.09 (dd,
J ) 1.3, 8.0 Hz, 2 H), 7.55 (tt, J ) 1.3, 7.4 Hz, 1 H), 7.41 (d, J ) 7.5
Hz, 1 H), 5.90 (d, J ) 6.9 Hz, 1 H), 5.26 (br s, 1 H), 5.02 (br s, 1 H),
4.52 (d, J ) 7.3 Hz, 1 H), 4.47 (d, J ) 7.5 Hz, 1 H), 4.34 (d, J ) 9.8
Hz, 1 H), 4.23 (br s, 1 H), 3.98 (d, J ) 9.8 Hz, 1 H), 3.23 (s, 3 H),
3.13 (dd, J ) 10.2, 18.5 Hz, 1 H), 2.66 (d, J ) 18.5 Hz, 1 H), 2.60 (d,
J ) 9.6 Hz, 1 H), 2.37 (t, J ) 6.4 Hz, 1 H), 2.24 (ddd, J ) 1.7, 6.0,
16.3 Hz, 1 H), 2.08 (d, J ) 4.5 Hz, 1 H), 1.83-1.57 (m, 5 H), 1.51 (s,
6 H), 1.40 (s, 3 H), 1.31 (s, 3 H), 0.92 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 202.0, 165.8, 148.5, 133.3, 130.1, 129.3, 128.2, 112.3,
105.0, 93.2, 83.2, 82.8, 75.3, 75.0, 54.8, 48.4, 45.4, 45.0, 39.4, 38.7,
38.0, 35.1, 28.7, 27.6, 26.7, 26.4, 25.3, 20.7, 17.6; MS m/z (M+) calcd
526.2930, obsd 526.2911; [R]23 -51.4 (c 1.10, CHCl3).
D
Anal. Calcd for C31H42O7: C, 70.70; H, 8.04. Found: C, 70.83;
H, 8.19.
(3S,4aR,6S,7S,10R,11R,12R,12aR)-Dodecahydro-7-hydroxy-11,12-
(isopropylidenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-4-
methylene-6,10-methanobenzocyclodecen-8(2H)-one Benzoate (6).
A solution of 5b (82 mg, 0.156 mmol) in dry THF (5 mL) was cooled
(29) Holton, R. A.; Juo, R. R.; Kim, H. B.; Williams, A. D.; Harusawa,
S.; Lowenthal, R. E.; Yogai, S. J. Am. Chem. Soc. 1988, 110, 6558.

5220 J. Am. Chem. Soc., Vol. 120, No. 21, 1998
Paquette et al.
to -78 °C, treated with lithium diisopropylamide (0.67 mL in THF,
0.17 mmol), and stirred for 30 min at which point freshly prepared
monomeric formaldehyde solution (1.5 mL, ca. 1 mmol) was introduced.
The reaction mixture was allowed to warm to 0 °C for 1 h, quenched
with saturated NH4Cl solution, and extracted with 1:1 ethyl acetate/
hexanes. The combined organic layers were dried and concentrated,
and the residue was chromatographed on silica gel (elution with 1:4
ethyl acetate/hexanes) to afford 6 (72 mg, 86%) as a white foam, mp
mixture was allowed to warm to 0 °C during 1 h, quenched with
saturated NH4Cl solution, and extracted with hexanes. The combined
organic phases were dried and evaporated, whereupon the residue was
chromatographed on silica gel (elution with 1:4 ethyl acetate/hexanes)
to furnish 14.1 mg (92%) of 9 as a white solid, mp 145-146 °C: IR
1
(CHCl3, cm-1) 1710; H NMR (300 MHz, C6D6) δ 8.38-8.33 (m, 2
H), 7.15-7.13 (m, 3 H), 6.24 (td, J ) 1.9, 6.9 Hz, 1 H), 5.10 (br s, 1
H), 4.94 (d, J ) 6.8 Hz, 1 H), 4.72 (s, 1 H), 4.44 (d, J ) 6.8 Hz, 1 H),
4.41 (dd, J ) 1.4, 5.8 Hz, 1 H), 4.31 (d, J ) 9.8 Hz, 1 H), 4.29 (s, 1
H), 4.07 (d, J ) 9.8 Hz, 1 H), 3.51 (br d, J ) 4.5 Hz, 1 H), 3.21 (s,
3 H), 3.12 (s, 3 H), 2.74 (d, J ) 4.5 Hz, 1 H), 1.98-1.60 (m, 6 H),
1.45 (s, 3 H), 1.42 (s, 3 H), 1.39-1.23 (m, 1 H), 1.33 (s, 3 H), 1.16 (s,
3 H), 0.97 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 166.6, 152.9, 150.0,
132.8, 131.0, 130.7, 111.7, 104.6, 100.4, 93.6, 83.9, 80.5, 77.2, 70.1,
54.9, 54.3, 44.1, 43.9, 38.7, 37.4, 36.5, 35.0, 31.9, 29.1, 27.8, 27.1,
25.73, 25.67, 23.0, 20.9, 17.6, 14.3; MS m/z (M+) calcd 540.3087, obsd
145-147 °C (from hexanes containing ethyl acetate): IR (CHCl3, cm-1
)
1723, 1703; 1H NMR (300 MHz, CDCl3) δ 8.10 (dd, J ) 1.5, 7.4 Hz,
2 H), 7.56 (tt, J ) 1.4, 7.4 Hz 1 H), 7.42 (t, J ) 7.4 Hz, 2 H), 6.41 (br
s, 1 H), 5.96 (d, J ) 7.0 Hz, 1 H), 5.60 (t, J ) 1.3 Hz, 1 H), 5.24 (br
s, 1 H), 4.99 (br s, 1 H), 4.49 (d, J ) 7.3 Hz, 1 H), 4.47 (d, J ) 7.3
Hz, 1 H), 4.29 (d, J ) 9.9 Hz, 1 H), 4.22 (t, J ) 2.9 Hz, 1 H), 4.02 (d,
J ) 9.9 Hz, 1 H), 3.25 (s, 3 H), 3.24 (s, 1 H), 2.37 (t, J ) 6.8 Hz, 1
H), 2.22 (ddd, J ) 1.7, 5.7, 16.3 Hz, 1 H) 2.07 (br d, J ) 3.6 Hz, 1 H),
1.82-1.53 (m, 5 H), 1.51 (s, 3 H), 1.43 (s, 3 H), 1.36 (s, 3 H), 1.33 (s,
3 H), 0.91 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 192.7, 166.0,
148.1, 147.0, 133.2, 130.2, 129.4, 128.3, 128.2, 112.3, 104.9, 93.3,
84.0, 83.3, 75.2, 74.3, 54.9, 50.9, 47.2, 39.5, 39.3, 36.3, 35.4, 28.7,
27.5, 26.8, 25.8, 25.2, 20.3, 17.3; MS m/z (M+) calcd 538.2930, obsd
540.3071; [R]23 -113.8 (c 0.90, CH2Cl2).
D
(3S,4aR,6S,10R,11R,12R,12aR)-2,3,4,4a,5,6,10,11,12,12a-Decahy-
dro-8-hydroxy-11,12-(isopropylidenedioxy)-3-(methoxymethoxy)-
9,12a,13,13-tetramethyl-4-methylene-6,10-methanobenzocyclodecen-
7(1H)-one (11). To a solution of 6 (8.5 mg, 16 µmol) in dry benzene
(2 mL) were added chlorotrimethylsilane (0.01 mL) and a solution of
[Ph3PCuH]6 (22 mg, 0.011 mmol) in dry benzene (2 mL). After 1.5 h
of stirring, the color had completely faded, the reaction mixture was
quenched with saturated NaHCO3 solution, stirred overnight, and
extracted with hexanes. After drying and evaporation, 10 was isolated
as a white foam (7.0 mg, 82%): 1H NMR (300 MHz, CDCl3) δ 8.08
(dd, J ) 1.4, 7.4 Hz, 2 H), 7.55 (tt, J ) 1.4, 7.4 Hz, 1 H), 7.41 (br t,
J ) 7.4 Hz, 2 H), 5.90 (d, J ) 7.1 Hz, 1 H), 5.24 (br s, 1 H), 5.02 (br
s, 1 H), 4.54 (d, J ) 7.2 Hz, 1 H), 4.48 (d, J ) 9.7 Hz, 1 H), 4.41 (d,
J ) 7.2 Hz, 1 H), 4.19 (br s, 1 H), 4.08 (dd, J ) 1.4, 9.7 Hz, 1 H),
3.25-3.16 (m, 1 H), 3.19 (s, 3 H), 2.51 (br d, J ) 7.7 Hz, 1 H), 2.45
(br t, J ) 6.6 Hz, 1 H), 2.31-2.23 (m, 1 H), 1.98 (br d, J ) 5.8 Hz,
1 H), 1.82-1.56 (m, 4 H), 1.62 (s, 3 H), 1.57 (s, 3 H), 1.40 (s, 3 H),
1.32 (s, 3 H), 1.29 (d, J ) 6.7 Hz, 3 H), 0.92 (s, 3 H).
A solution of the above material (5.4 mg, 10.0 µmol) in dry THF
(1.5 mL) at -78 °C was treated with lithium diisopropylamide (0.19
mL in THF, 30 µmol), stirred for 1 h at this temperature prior to the
addition of phenylselenenyl chloride (10 mg, 50 µmol), allowed to warm
to 0 °C, quenched with saturated NaHCO3 solution, and extracted with
hexanes. The combined organic phases were dried and concentrated
to leave a residue which was chromatographed on silica gel (elution
with 1:5 ethyl acetate/hexanes) to give 2.4 mg (56%) of 11 as a white
solid: 1H NMR (300 MHz, C6D6) δ 6.16 (s, 1 H), 4.99 (br s, 1 H),
4.78 (br s, 1 H), 4.58 (d, J ) 6.8 Hz, 1 H), 4.50 (d, J ) 6.8 Hz, 1 H),
4.30 (d, J ) 9.7 Hz, 1 H), 4.19 (t, J ) 2.7 Hz, 1 H), 4.12 (d, J ) 9.7
Hz, 1 H), 3.20 (s, 3 H), 2.72-2.69 (m, 2 H), 2.16 (dd, J ) 1.5, 6.6 Hz,
1 H), 2.05 (ddd, J ) 2.2, 6.6, 15.6 Hz, 1 H), 1.91 (s, 3 H), 1.88-1.75
(m, 2 H), 1.69-1.50 (m, 2 H), 1.46 (ddd, J ) 1.8, 5.7, 15.6 Hz, 1 H),
1.39 (s, 3 H), 1.30 (m, 3 H), 1.18 (s, 3 H), 0.91 (s, 6 H); MS m/z (M+)
calcd 434.2669, obsd 434.2681.
(3S,4aR,6R,10S,11R,12R,12aR)-9-Bromododecahydro-11,12-(iso-
propylidenedioxy)-3-(methoxymethoxy)-9,12a,13,13-tetramethyl-4-
methylene-6,10-methanobenzocyclodecen-8(2H)-one (13). To a mix-
ture of 7a (10 mg, 23.9 µmol) and tris(triphenylphosphine)rhodium
chloride (1 mg) under N2 were added benzene (1 mL) and triethylsilane
(0.1 mL). The mixture was refluxed for 2 h, cooled, and freed of
benzene and excess silane in vacuo. The residue was purified by
chromatography on silica gel (elution with 1:10 ether/hexanes) to give
12 as a colorless oil (12 mg, 93%): 1H NMR (300 MHz, C6D6) δ 5.06
(br s, 1 H), 4.86 (d, J ) 7.1 Hz, 1 H), 4.84 (br s, 1 H), 4.78 (d, J ) 7.1
Hz, 1 H), 4.40 (d, J ) 9.8 Hz, 1 H), 4.33 (br s, 1 H), 4.29 (d, J ) 9.8
Hz, 1 H), 3.33 (s, 3 H), 3.10 (br s, 1 H), 2.56 (br s, 1 H), 2.30-2.20
(m, 1 H), 2.08-1.58 (series of m, 8 H), 1.84 (br s, 3 H), 1.48 (s, 3 H),
1.41 (s, 3 H), 1.39 (s, 3 H), 1.10 (s, 3 H), 1.03 (s, 3 H), 0.97 (t, J )
7.9 Hz, 9 H), 0.58 (q, J ) 7.9 Hz, 6 H).
538.2935; [R]23 -91.1 (c 1.03, hexanes).
D
Anal. Calcd for C32H42O7: C, 71.35; H, 7.86. Found: C, 71.31;
H, 7.87.
(3S,4aR,6R,10R,11R,12R,12aR)-Dodecahydro-11,12-(isopropyl-
idenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-4,9-dimethyl-
ene-6,10-methanobenzocyclodecen-8(2H)-one (7a). To a solution of
6 (70 mg, 0.13 mmol) in a mixture of THF (5 mL) and methanol (2.5
mL) cooled to -78 °C was added dropwise a 0.10 M solution of
samarium iodide in THF until a blue color persisted (ca. 3 mL); the
mixture was quenched with saturated NH4Cl solution and extracted
with 1:1 ethyl acetate/hexanes. The combined extracts were dried and
evaporated, and the residue was purified by chromatography on silica
gel (elution with 1:4 ethyl acetate/hexanes) to deliver 44 mg (91%) of
7a as an off-white solid, mp 130 °C (dec): IR (CHCl3, cm-1) 1684;
1H NMR (300 MHz, CDCl3) δ 6.43 (t, J ) 1.4 Hz, 1 H), 5.52 (t, J )
1.4 Hz, 1 H), 5.11 (d, J ) 1.2 Hz, 1 H), 4.95 (d, J ) 1.2 Hz, 1 H),
4.41 (d, J ) 7.1 Hz, 1 H), 4.34 (d, J ) 7.1 Hz, 1 H), 4.22 (d, J ) 9.8
Hz, 1 H), 4.13 (t, J ) 3.0 Hz, 1 H), 4.01 (d, J ) 9.8 Hz, 1 H), 3.30 (s,
3 H), 3.11 (br s, 1 H), 2.67 (dd, J ) 8.1, 19.8 Hz, 1 H), 2.01 (d, J )
19.8 Hz, 1 H), 1.95-1.82 (m, 2 H), 1.81-1.57 (m, 5 H), 1.53-1.43
(m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.33 (s, 3 H), 1.05 (s, 3 H), 0.87
(s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 197.6, 147.5, 146.6, 127.2,
112.7, 104.7, 92.6, 84.9, 83.6, 75.1, 55.0, 49.7, 41.2, 39.9, 39.2, 38.7,
35.5, 34.5, 28.3, 27.4, 26.8, 25.3, 25.1, 25.0, 17.4; MS m/z (M+) calcd
418.2719, obsd 418.2723; [R]23 -96.9 (c 0.87, CHCl3).
D
Anal. Calcd for C25H38O5: C, 71.74; H, 9.15. Found: C, 72.00;
H, 9.16.
(3S,4aR,6R,10R,11R,12R,12aR)-Dodecahydro-3-hydroxy-11,12-
(isopropylidenedioxy)-12a,13,13-trimethyl-4,9-dimethylene-6,10-
methanobenzocyclodecen-8(2H)-one (7b). A mixture of 7a (4 mg)
and rhodium trichloride trihydrate (2 mg) was placed under high vacuum
for 1.5 h, blanketed with N2, and taken up in acetonitrile (4 mL). The
mixture was refluxed for 2 h, cooled to room temperature, and freed
of solvent. The residue was purified by chromatography on silica gel
(elution with 1:2 ethyl acetate/hexanes) to furnish 3 mg (75%) of 7b:
1H NMR (300 MHz, C6D6) δ 6.44 (t, J ) 1.5 Hz, 1 H), 5.23 (t, J )
1.5 Hz, 1 H), 4.88 (br s, 1 H), 4.61 (br s, 1 H), 4.24 (d, J ) 9.7 Hz, 1
H), 4.13 (d, J ) 9.7 Hz, 1 H), 4.09 (br s, 1 H), 3.18 (br s, 1 H), 2.37
(dd, J ) 7.4, 18.8 Hz, 1 H), 2.06 (d, J ) 18.8 Hz, 1 H), 2.09-1.98 (m,
2 H), 1.84-1.77 (m, 1 H), 1.64-1.45 (m, 6 H), 1.41 (s, 3 H), 1.33 (s,
3 H), 1.24 (s, 3 H), 0.92 (s, 3 H), 0.80 (s, 3 H); MS m/z (M+) calcd
374.2458, obsd 374.2442.
(3S,4aR,6S,7S,10S,11R,12R,12aR)-1,2,3,4,4a,5,6,7,10,11,12,12a-
Dodecahydro-11,12-(isopropylidenedioxy)-8-methoxy-3-(meth-
oxymethoxy)-12a,13,13-trimethyl-4-methylene-6,10-methanobenzo-
cyclodecen-7-ol Benzoate (9). A cold (-78 °C) solution of 5b (15
mg, 0.028 mmol) in dry THF (2 mL) was treated with lithium
diisopropylamide (0.20 mL in THF, 0.034 mmol) and stirred for 1 h,
at which point dry HMPA (0.12 mL) and freshly distilled methyl iodide
(0.01 mL, 0.16 mmol) were introduced sequentially. The reaction
A solution of 12 (5.0 mg, 9.3 µmol) and propylene oxide (3 drops)
in THF (2 mL) at 0 °C was treated with N-bromosuccinimide (2 mg,
11 µmol) and allowed to warm to 25 °C during 2 h. An additional 2
mg of NBS was introduced; after another 3 h, the reaction mixture
was quenched with saturated NaHCO3 solution and brine, and the

Synthesis of Natural (+)-Taxusin
J. Am. Chem. Soc., Vol. 120, No. 21, 1998 5221
product was extracted into ether. The combined organic layers were
dried and concentrated to leave a residue which was chromatographed
on silica gel (elution with 1:10 ether/hexanes). There was isolated 3.4
mg (74%) of 13 as a white solid: 1H NMR (300 MHz, C6D6) δ 4.93
(br s, 1 H), 4.71 (d, J ) 7.4 Hz, 1 H), 4.70 (d, J ) 7.4 Hz, 1 H), 4.66
(br s, 1 H), 4.49 (d, J ) 9.7 Hz, 1 H), 4.28 (d, J ) 9.7 Hz, 1 H), 4.19
(t, J ) 2.6 Hz, 1 H), 3.41 (br s, 1 H), 3.22 (s, 3 H), 2.77 (dd, J ) 7.8,
18.5 Hz, 1 H), 2.42 (s, 3 H), 1.90 (d, J ) 18.9 Hz, 1 H), 1.79-1.43
(series of m, 8 H), 1.57 (s, 3 H), 1.38 (s, 3 H), 1.31 (s, 3 H), 1.30 (s,
3 H), 0.86 (s, 3 H); FAB MS m/z calcd 498.20, obsd 498.41.
Conversion of 13 to 7a. A solution of 13 (10 mg, 0.02 mmol) in
dry THF (4 mL) was treated with 4 drops of DBU and stirred overnight
at 25 °C. After the addition of saturated NH4Cl solution, the product
was extracted into ethyl acetate/hexanes (1:1), and the combined organic
phases were dried and evaporated. Chromatography of the residue on
silica gel afforded 6.3 mg (75%) of 7a as a white solid, mp 135 °C
(dec), identical with the compound of the same structure described
earlier.
NMR (300 MHz, C6D6) δ 8.33-8.29 (m, 2 H), 7.66-7.61 (m, 2 H),
7.13-7.07 (m, 3 H), 6.95-6.90 (m, 3 H), 6.50 (d, J ) 6.2 Hz, 1 H),
5.20 (br s, 1 H), 4.87 (br s, 1 H), 4.77 (d, J ) 7.4 Hz, 1 H), 4.61 (d,
J ) 7.4 Hz, 1 H), 4.31 (br s, 2 H), 4.28 (d, J ) 9.8 Hz, 1 H), 4.03 (d,
J ) 4.0 Hz, 1 H), 4.12 (s, 1 H), 3.07 (s, 3 H), 2.35 (br d, J ) 4.9 Hz,
1 H), 2.04-1.96 (m, 2 H), 1.84-1.76 (m, 2 H), 1.67-1.55 (m, 2 H),
1.49 (s, 3 H), 1.46-1.37 (m, 1 H), 1.34 (s, 3 H), 1.27 (s, 3 H), 1.20 (s,
3 H), 0.92 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 200.0, 165.7, 149.0,
135.8, 133.2, 131.2, 130.6, 130.2, 129.3, 128.9, 128.7, 128.4, 111.9,
105.0, 93.8, 84.4, 83.5, 75.5, 73.1, 54.8, 52.6, 52.1, 48.6, 39.5, 39.3,
37.7, 36.0, 29.1, 27.6, 26.8, 26.5, 25.8, 20.6, 17.7.
A solution of the above material (119 mg, 0.17 mmol) in THF (4.0
mL) was cooled to 0 °C, treated with acetic acid (3 drops) and 30%
hydrogen peroxide (0.1 mL), and stirred at 0 °C for 1 h. The THF
was removed on a rotary evaporator, and the residue was neutralized
with saturated NaHCO3 solution and processed in the usual way to
give 18 (85 mg, 92%) as a white solid, mp 156-157 °C: IR (CHCl3,
cm-1) 1720, 1680; 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J ) 8.0 Hz,
2 H), 7.54 (t, J ) 7.4 Hz, 1H), 7.40 (dd, J ) 7.4, 8.0 Hz, 2 H), 6.25
(d, J ) 5.7 Hz, 1 H), 6.24 (s, 1 H), 5.13 (s, 1 H), 4.80 (s, 1 H), 4.54
(d, J ) 9.3 Hz, 1 H), 4.46 (d, J ) 7.0 Hz, 1 H), 4.33 (d, J ) 9.3 Hz,
1 H), 4.27 (d, J ) 20 Hz, 1 H), 4.16 (br s, 1 H), 3.26-3.24 (m, 1 H),
3.24 (s, 3 H), 2.71-2.61 (m, 1 H), 2.15-2.08 (m, 1 H), 1.89-1.64
(m, 5 H), 1.69 (s, 3 H), 1.60 (s, 3 H), 1.50 (s, 3 H), 1.43 (s, 3 H), 0.90
(s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 194.1, 166.1, 164.1, 149.7,
133.3, 132.4, 130.1, 129.2, 128.2, 111.7, 108.6, 92.8, 82.0, 79.4, 76.0,
73.9, 55.0, 51.0, 41.2, 40.5, 37.0, 35.8, 28.5, 27.0, 26.7, 24.9, 24.3,
20.9, 17.4; MS m/z (M+) calcd 524.2774, obsd 524.2769; [R]23D +25.5
(c 1.00, CHCl3).
(3S,4aR,6,9R,10S,11R,12R,12aR)-Dodecahydro-11,12-(isopro-
pylidenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-4-methyl-
enespiro[6,10-methanobenzocyclodecene-9(8H),2′-oxiran]-8-one (14).
To a cold (0 °C) solution of 7a (100 mg, 0.239 mmol) in methanol (10
mL) were added water (5 mL) and 30% hydrogen peroxide (0.5 mL).
Potassium carbonate (150 mg) was introduced and the mixture was
stirred for 4 h, quenched with saturated NH4Cl solution, and freed of
methanol in vacuo. The product was extracted into ethyl acetate (3 ×
20 mL), washed with water (10 mL) and brine (10 mL), dried,
evaporated, and chromatographed on silica gel. There was obtained
103 mg (99%) of 14 as a white solid, mp 146-148 °C: IR (CHCl3,
cm-1) 1710; 1H NMR (300 MHz, C6D6) δ 4.97 (br s, 1 H), 4.70 (br s,
3 H), 4.29 (d, J ) 9.7 Hz, 1 H), 4.22 (br t, J ) 3 Hz, 1 H), 4.15 (d, J
) 9.7 Hz, 1 H), 3.69 (d, J ) 6.2 Hz, 1 H), 3.23 (s, 3 H), 2.71 (d, J )
6.2 Hz, 1 H), 2.50 (dd, J ) 7.7, 19.2 Hz, 1 H), 2.35 (br s, 1 H), 1.94-
1.77 (m, 4 H), 1.69-1.41 (m, 5 H), 1.36 (s, 3 H), 1.27 (s, 3 H), 1.21
(s, 3 H), 1.14 (s, 3 H), 0.92 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm
203.4, 148.0, 112.5, 105.3, 93.2, 82.9, 80.8, 75.1, 60.2, 55.0, 52.5, 50.6,
42.5, 40.7, 39.7, 39.4, 37.0, 33.3, 28.7, 27.7, 26.9, 25.8, 25.6, 25.1,
Anal. Calcd for C31H40O7: C, 70.97; H, 7.68. Found: C, 71.06;
H, 7.76.
(3S,4aR,6R,9Z,11R,12R,12aR)-1,3,4,4a,5,6,7,11,12,12a-Decahydro-
11,12-(isopropylidenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-
4-methylene-6,10-methanobenzocyclodecen-8(2H)-one (19). To a
solution of 18 (399 mg, 0.76 mmol) in 1:1 tetrahydrofuran-methanol
(40 mL) cooled to -78 °C was added 0.12 M samarium diiodide
solution in THF via a syringe pump (0.25 mL/min). The progress of
reaction was monitored by TLC, and the mixture was quenched with
saturated NaHCO3 solution (5 mL) and extracted with ethyl acetate
when no 18 remained. The combined organic phases were washed
with brine, dried, and concentrated to leave a residue, purification of
which by chromatography on silica gel (elution with 3:1 hexanes/ethyl
acetate) gave 19 (108 mg, 82%) as a colorless crystalline solid, mp
194-195 °C (from 2:1 hexanes/ethyl acetate): IR (neat, cm-1) 1671;
1H NMR (300 MHz, CDCl3) δ 6.08 (s, 1 H), 5.07 (s, 1 H), 4.81 (s, 1
H), 4.48 (d, J ) 9.3 Hz, 1 H), 4.37 (d, J ) 6.7 Hz, 1 H), 4.27 (d, J )
6.7 Hz, 1 H), 4.22 (d, J ) 9.3 Hz, 1 H), 4.10 (t, J ) 2.6 Hz, 1 H), 3.29
(s, 3 H), 3.05 (br d, J ) 3.1 Hz, 1 H), 2.88 (dd, J ) 9.5, 6.7 Hz, 1 H),
2.25 (m, 1 H), 1.92-1.55 (series of m, 7 H), 1.59 (s, 3 H), 1.48 (s, 3
H), 1.41 (s, 3 H), 1.27 (s, 3 H), 0.87 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 199.7, 162.0, 149.6, 131.5, 112.2, 108.2, 92.0, 82.1, 79.9,
75.9, 55.1, 43.4, 40.6, 40.3, 40.0, 36.8, 35.3, 28.4, 27.0, 26.7, 26.5,
17.9; MS m/z (M+) calcd 434.2668, obsd 434.2633; [R]23 -158.5 (c
D
1.00, CHCl3).
Anal. Calcd for C25H38O6: C, 69.10; H, 8.81. Found: C, 69.46;
H, 8.88.
(3S,4aR,6R,10S,11R,12R,12aR)-1,2,3,4,4a,5,6,7,10,11,12,12a-
Dodecahydro-8-hydroxy-11,12-(isopropylidenedioxy)-3-(meth-
oxymethoxy)-12a,13,13-trimethyl-4-methylene-6,10-methanobenzo-
cyclodecene-9-carboxaldehyde (15). A solution of 14 (5.5 mg, 12.7
µmol) in dry THF (1 mL) was cooled to -78 °C, treated with lithium
triethylborohydride (0.20 mL of 0.1 M in THF), stirred at -10 °C for
3 h, and quenched with saturated NH4Cl solution. Extraction with 1:1
ethyl acetate/hexanes was followed by drying and evaporation of the
combined extracts, and chromatography of the residue on silica gel
(elution with 1:4 ether/hexanes) to give 3 mg (55%) of 15: 1H NMR
(300 MHz, C6D6) δ 15.4 (d, J ) 2 Hz, 1 H), 8.82 (d, J ) 2 Hz, 1 H),
4.97 (br s, 1 H), 4.72 (d, J ) 6.9 Hz, 1 H), 4.68 (br s, 1 H), 4.60 (d,
J ) 6.9 Hz, 1 H), 4.21 (br s, 1 H), 4.19 (d, J ) 9.6 Hz, 1 H), 3.95 (d,
J ) 9.6 Hz, 1 H), 3.20 (s, 3 H), 2.86 (br s, 1 H), 2.51 (br s, 1 H), 2.30
(dd, J ) 8.2, 19.9 Hz, 1 H), 1.80-1.73 (m, 2 H), 1.76 (d, J ) 19.9 Hz,
1 H), 1.60-1.54 (m, 2 H), 1.45 (t, J ) 3.9 Hz, 2 H), 1.39 (s, 3 H),
1.35 (br s, 1 H), 1.27 (s, 3 H), 1.24 (s, 3 H), 0.91 (s, 3 H), 0.73 (s, 3
H); MS m/z (M+) calcd 434.2668, obsd 434.2676.
(3S,4aR,6S,7S,9Z,11R,12R,12aR)-1,3,4,4a,5,6,7,11,12,12a-Decahy-
dro-7-hydroxy-11,12-(isopropylidenedioxy)-3-(methoxymethoxy)-
12a,13,13-trimethyl-4-methylene-6,10-methanobenzocyclodecen-
8(2H)-one Benzoate (18). To a solution of 5b (100 mg, 0.19 mmol)
in dry THF (5.0 mL) at -78 °C was added lithium diisopropylamide
(1.7 mL of 0.16 M in THF, 0.27 mmol). After 3 min, phenylselenenyl
bromide (0.2 M in THF) was introduced until the color persisted. The
reaction mixture was allowed to warm to room temperature during 1
h, at which point saturated NaHCO3 solution was added and the product
was extracted into 1:3 ethyl acetate/ hexanes. The combined extracts
were dried and evaporated. Purification of the residue by chromatog-
raphy on silica gel afforded 119 mg (92%) of 17 as a white foam: 1H
24.9, 23.4, 17.5; MS m/z (M+) calcd 404.2563, obsd 404.2567; [R]24
+90.9 (c 0.74, CHCl3).
D
(3S,4aR,6R,9S,10R,11S,12R,12aR)-9,10-Epoxydodecahydro-11,12-
(isopropylidenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-4-
methylene-6,10-methanobenzocyclodecen-8(2H)-one (20). To a so-
lution of 19 (8.5 mg, 0.021 mmol) in methanol (2 mL) at 0-5 °C were
added 30% hydrogen peroxide (5 drops) and potassium carbonate (5
mg). The reaction mixture was stirred overnight at 0 °C, quenched
with 1% citric acid, and extracted with 1:3 ethyl acetate/hexanes. The
combined extracts were dried, evaporated, and chromatographed on
silica gel to give 7.0 mg (79%) of 20 as white crystals, mp 184-186
1
°C: IR (CHCl3, cm-1) 1721; H NMR (300 MHz, C6D6) δ 4.89 (s, 1
H), 4.58 (s, 1 H), 4.48 (d, J ) 6.6 Hz, 1 H), 4.37 (d, J ) 6.6 Hz, 1 H),
4.23 (d, J ) 9.8 Hz, 1 H), 4.09 (t, J ) 2.7 Hz, 1 H), 3.40 (d, J ) 9.8
Hz, 1 H), 3.13 (s, 3 H), 2.96 (s, 1 H), 2.88-2.86 (m, 1 H), 2.41 (dd,
J ) 7.6, 20.1 Hz, 1 H), 1.70 (d, J ) 20.1 Hz, 1 H), 1.70-1.37 (m, 7
H), 1.44 (s, 3 H), 1.41 (s, 3 H), 1.29 (s, 3 H), 0.89 (s, 3 H), 0.75 (s, 3
H); 13C NMR (75 MHz, C6D6) ppm 205.9, 149.4, 111.4, 107.6, 92.9,
83.5, 81.6, 76.5, 58.8, 55.0, 54.5, 44.5, 41.9, 39.1, 38.5, 38.0, 28.6,

5222 J. Am. Chem. Soc., Vol. 120, No. 21, 1998
Paquette et al.
28.1, 27.2, 26.7, 25.6, 25.5, 24.5, 17.4; MS m/z (M+) calcd 420.2513,
obsd 420.2514.
9(1H)-one (26a). A solution of 25 (30 mg, 0.071 mol) in CH2Cl2 (3
mL) was treated with the Dess-Martin periodinane (1.5 equiv), stirred
for 1 h, and quenched with saturated NaHCO3 solution. The product
was extracted into 1:2 ethyl acetate/hexanes, dried, concentrated, and
chromatographed on silica gel (elution with 1:4 ethyl acetate/hexanes)
to give 24 mg (80%) of 26a: 1H NMR (300 MHz, CDCl3) δ 5.94 (s,
1 H), 5.74 (d, J ) 6.9 Hz, 1 H), 5.10 (br s, 1 H), 4.88 (br s, 1 H), 4.43
(d, J ) 6.9 Hz, 1 H), 4.24 (d, J ) 6.9 Hz, 1 H), 4.24 (d, J ) 9.7 Hz,
1 H), 4.13 (br s, 1 H), 4.08 (dd, J ) 1.0, 9.7 Hz, 1H), 3.30 (s, 3 H),
2.86 (s, 1 H), 2.46 (dt, J ) 1.6, 6.9 Hz, 1 H), 2.10 (br s, 1 H), 1.94-
1.86 (m, 1 H), 1.80-1.44 (m, 5 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.35
(s, 3 H), 1.16 (s, 3 H), 0.93 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
197.2, 148.3, 147.5, 117.5, 112.7, 105.4, 92.2, 82.8, 77.7, 75.5, 56.4,
55.1, 44.1, 38.5, 37.71, 37.67, 35.7, 28.3, 27.4, 26.7, 25.2, 24.9, 22.4,
18.0; MS m/z (M+) calcd 420.2512, obsd 420.2523.
(3S,4aR,6R,7R,9Z,11R,12R,12aR)-1,3,4,4a,5,6,7,11,12,12a-Decahy-
dro-11,12-(isopropylidenedioxy)-3-(methoxymethoxy)-7,12a,13,13-
tetramethyl-4-methylene-6,10-methanobenzocyclodecen-8(2H)-
one (21). A solution of 20 (2 mg, 4.7 µmol) in dry THF (1 mL) was
cooled to -78 °C and treated with lithium diisopropylamide (0.10 mL,
30 µmol). After 30 min, methyllithium (0.04 mL of 1.4 M in ether,
56 µmol) was introduced, and the reaction mixture was allowed to warm
to 0 °C during 3 h and stirred overnight at this temperature. At this
point, no reaction was evident by TLC analysis. Methylmagnesium
bromide (0.05 mL of 3 M in ether, 150 µmol) was added and the
reaction mixture was stirred at room temperature for 3 h prior to being
quenched with saturated NH4Cl solution. The product was extracted
into 1:3 ethyl acetate/hexanes, dried, and concentrated. Purification
of the residue by chromatography on silica gel afforded 1 mg of 21:
IR (neat, cm-1) 1691; 1H NMR (500 MHz, C6D6) δ 6.11 (s, 1 H), 4.91
(s, 1 H), 4.62 (s, 1 H), 4.52 (d, J ) 6.5 Hz, 1 H), 4.44 (d, J ) 9.4 Hz,
1 H), 4.36 (d, J ) 6.5 Hz, 1 H), 4.19 (d, J ) 9.4 Hz, 1 H), 4.07 (t, J
) 3 Hz, 1 H), 3.20 (br s, 1 H), 3.13 (s, 3 H), 1.90 (q, J ) 7.3 Hz, 1
H), 1.90-1.43 (series of m, 7 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.35 (s,
3 H), 1.35 (d, J ) 7.3 Hz, 3 H), 1.07 (s, 3 H), 0.92 (s, 3 H); 13C NMR
(125 MHz, C6D6) ppm 201.6, 160.1, 150.8, 131.3, 111.8, 108.0, 92.8,
82.5, 80.1, 76.8, 55.0, 50.2, 46.7, 40.6, 40.1, 37.3, 36.4, 28.8, 27.3,
26.9 (2 C), 25.4, 23.6, 19.4, 17.8; MS m/z (M+) calcd 418.2720, obsd
418.2726.
(3S,4aR,6R,10S,11R,12R,12aR)-8-(tert-Butyldimethylsiloxy)-
2,3,4,4a,5,6,10,11,12,12a-decahydro-11,12-(isopropylidenedioxy)-3-
(methoxymethoxy)-12a,13,13-trimethyl-4-methylene-6,10-metha-
nobenzocyclodecen-9(1H)-one (26b). A mixture of 26a (24 mg, 0.057
mmol), imidazole (100 mg, 1.47 mmol), and tert-butyldimethylsilyl
chloride (70 mg, 0.46 mmol) in DMF (1 mL) was stirred overnight at
room temperature, quenched with water (5 mL), and extracted with
hexanes (10 mL). The organic solution was dried over sodium sulfate
and sodium bicarbonate, then concentrated. Purification of the residue
by chromatography on silica gel delivered 30 mg (98%) of 26b as a
1
white solid: IR (CHCl3, cm-1) 1675; H NMR (300 MHz, C6D6) δ
5.52 (d, J ) 6.9 Hz, 1 H), 5.03 (s, 1 H), 4.73 (d, J ) 7.1 Hz, 1 H),
4.71 (s, 1 H), 4.66 (d, J ) 7.1 Hz, 1 H), 4.45 (dd, J ) 0.7, 9.8 Hz, 1
H), 4.26 (br s, 1 H), 4.24 (d, J ) 9.8 Hz, 1 H), 3.31 (s, 3 H), 3.00 (s,
1 H), 2.30 (br s, 1 H), 1.93-1.80 (m, 3 H), 1.66-1.41 (m, 4 H), 1.39
(s, 3 H), 1.29 (s, 3 H), 1.23 (s, 3 H), 0.99 (s, 9 H), 0.98 (s, 6 H), 0.42
(s, 3 H), 0.10 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 196.2, 150.1,
148.7, 125.8, 112.2, 105.3, 92.7, 83.2, 78.5, 75.7, 58.2, 55.1, 45.1, 39.0,
38.0, 37.3, 35.9, 28.9, 27.7, 26.8, 25.8, 25.7, 24.7, 22.7, 18.7, 18.4,
-3.6, -4.5; MS m/z (M+) calcd 534.3377, obsd 534.3356.
(3S,4aR,6S,7S,9S,10R,11R,12R,12aR)-Dodecahydro-7,9-dihydroxy-
11,12-(isopropylidenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-
4-methylene-6,10-methanobenzocyclodecen-8(2H)-one 7-Benzoate
(24). A cold (-78 °C), magnetically stirred solution of 5b (70 mg,
0.133 mmol) in dry THF (5 mL) was treated with potassium
hexamethyldisilazide (0.32 mL of 0.5 M in toluene, 1.2 equiv) and, 30
min later, with the Davis oxaziridine (52 mg, 0.20 mmol) dissolved in
1 mL of dry THF. The reaction mixture was stirred at -78 °C for 1
h, quenched with saturated NH4Cl solution, and extracted with 1:3 ethyl
acetate/hexanes. The combined extracts were dried and concentrated
to leave a residue which was subjected to chromatography on silica
gel (elution with 1:3 ethyl acetate/hexanes). There was obtained 50
mg (70%) of 24: 1H NMR (300 MHz, CDCl3) δ 8.07-8.03 (m, 2H),
7.58-7.53 (m, 1 H), 7.44-7.39 (m, 2 H), 6.10 (d, J ) 7.1 Hz, 1 H),
5.16 (br s, 1 H), 4.88 (br s, 1 H), 4.49 (d, J ) 7.1 Hz, 1 H), 4.41 (d,
J ) 7.1 Hz, 1 H), 4.28-4.25 (m, 2 H), 4.22 (br s, 1 H), 4.06 (d, J )
9.8 Hz, 1 H), 3.27 (s, 3 H), 2.58 (s, 1 H), 2.43 (br t, J ) 5.3 Hz, 1 H),
2.13-2.06 (m, 1 H), 1.83-1.59 (m, 6 H), 1.49 (s, 3 H), 1.46 (s, 3 H),
1.41 (s, 3 H), 1.35 (s, 3 H), 0.90 (s, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 206.3, 165.9, 147.6, 133.3, 130.2, 129.1, 128.2, 112.0, 104.9, 93.3,
82.9, 81.6, 78.9, 75.8, 72.5, 55.0, 50.4, 47.8, 39.2, 39.1, 36.7, 34.2,
28.6, 27.3, 26.7, 26.4, 25.3, 19.9, 17.3; MS m/z (M+) calcd 540.2723,
obsd 540.2712.
(3S,4aR,6R,9S,10R,11R,12R,12aR)-Dodecahydro-9-hydroxy-11,12-
(isopropylidenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-4-
methylene-6,10-methanobenzocyclodecen-8(2H)-one (25). A vig-
orously stirred solution of 24 (50 mg, 0.092 mmol) in a cold (-78 °C)
mixture of THF (4 mL) and methanol (2 mL) was treated dropwise
with a solution of samarium iodide (0.1 M in THF) until the reaction
mixture was no longer UV-active, quenched with saturated NH4Cl
solution, and extracted with 1:3 ethyl acetate/hexanes. The combined
extracts were dried and evaporated prior to chromatographic purification
of the residue on silica gel. There was isolated 34 mg (87%) of 25:
1H NMR (300 MHz, CDCl3) δ 5.14 (d, J ) 1.3 Hz, 1 H), 4.90 (d, J )
1.3 Hz, 1 H), 4.46 (d, J ) 6.5 Hz, 1 H), 4.28 (d, J ) 6.5 Hz, 1 H),
4.23-4.16 (m, 4 H), 3.27 (s, 3 H), 2.81 (dd, J ) 9.7, 19.8 Hz, 1 H),
2.42 (dd, J ) 1.1, 3.5 Hz, 1 H), 2.31 (br s, 1 H), 2.07-2.03 (m, 1 H),
1.91-1.59 (m, 8 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.34 (s, 3 H), 0.92 (s,
6 H); 13C NMR (75 MHz, CDCl3) ppm 214.8, 148.6, 112.0, 104.8,
92.7, 83.5, 81.4, 77.6, 76.8, 55.2, 53.7, 42.5, 39.0, 38.6, 38.4, 37.0,
33.7, 28.3, 27.2, 26.7, 25.4, 24.9, 24.8, 17.6; MS m/z (M+) calcd
422.2669, obsd 422.2654.
(3S,4aS,6R,10R,11E,12aS)-8-(tert-Butyldimethylsiloxy)-2,3,4,
4a,5,6,10,11,12,12a-octahydro-3-(methoxymethoxy)-10,12a,13,13-tet-
ramethyl-4-methylene-6,10-methanobenzocyclodecen-9(1H)-one (27).
To a solution of 26b (8.8 mg, 0.016 mmol) in cold (-78 °C), dry THF
(2 mL) was added potassium hexamethyldisilazide (0.15 mL of 0.5 M
in toluene, 0.075 mmol). After 30 min, a solution of N-phenyltriflimide
(30 mg, 0.084 mmol) in dry THF (1 mL) was introduced, and the
reaction mixture was allowed to warm to -20 °C over 2 h. A solution
of lithium dimethylcuprate was prepared by adding methyllithium-
lithium bromide complex (0.25 mL of 1.5 M in ether) to a slurry of
copper(I) bromide-dimethyl sulfide complex (45 mg, 0.22 mmol) in
dry THF (2 mL) at 0 °C, followed by stirring for 10 min. The original
reaction mixture was returned to -78 °C, treated with the cuprate
solution, allowed to warm to 0 °C during 1.5 h, diluted with hexanes
(20 mL), and filtered through a pad of Florisil. The filtrate was
concentrated and the residue was purified by chromatography on silica
gel to furnish 27 (7 mg, 89%) as a white solid: IR (neat, cm-1) 1703;
1H NMR (300 MHz, C6D6) δ 6.28 (d, J ) 17.8 Hz, 1 H), 5.85 (d, J )
17.8 Hz, 1 H), 5.63 (d, J ) 5.7 Hz, 1 H), 4.94 (s, 1 H) 4.67 (d, J ) 6.5
Hz, 1 H), 4.60 (t, J ) 1.4 Hz, 1 H), 4.54 (d, J ) 6.5 Hz, 1 H), 4.10 (t,
J ) 2.8 Hz, 1 H), 3.26 (s, 3 H), 2.91 (br d, J ) 9.0 Hz, 1 H), 2.15 (dt,
J ) 4.4, 13.5 Hz, 1 H), 1.95-1.90 (m, 1 H), 1.88-1.80 (m, 1 H),
1.68-1.60 (m, 1 H), 1.51-1.47 (m, 2 H), 1.40-1.33 (m, 1 H), 1.24
(s, 3 H), 1.06 (s, 9 H), 0.89 (s, 3 H), 0.82 (s, 3 H), 0.78 (s, 3 H), 0.35
(s, 3 H), 0.29 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 199.7, 151.6,
148.1, 140.0, 135.6, 124.7, 110.6, 93.4, 77.2, 55.2, 53.1, 50.7, 49.4,
45.8, 42.2, 33.1, 29.3, 28.4, 26.8, 26.0, 22.7, 19.5, 18.6, 11.1, -4.1;
MS m/z (M+) calcd 474.3169, obsd 474.3814.
(3S,4aR,6R,9S,10S,11S,12R,12aR)-Dodecahydro-9,10-dihydroxy-
11,12-(isopropylidenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-
4-methylene-6,10-methanobenzocyclodecen-8(2H)-one (37). A so-
lution of 19 (110.5 mg, 0.273 mmol) in THF (3.0 mL) at -18 °C was
treated with pyridine (92.8 µL, 1.148 mmol) and osmium tetraoxide
(73.0 mg, 0.287 mmol), stirred for 2 h, quenched with 20% NaHSO3
solution (10 mL), stirred overnight, and extracted with ethyl acetate.
Following the predescribed workup, purification by chromatography
(3S,4aR,6R,10S,11R,12R,12aR)-2,3,4,4a,5,6,10,11,12,12a-Decahy-
dro-8-hydroxy-11,12-(isopropylidenedioxy)-3-(methoxymethoxy)-
12a,13,13-trimethyl-4-methylene-6,10-methanobenzocyclodecen-

Synthesis of Natural (+)-Taxusin
J. Am. Chem. Soc., Vol. 120, No. 21, 1998 5223
on silica gel (elution with 2:1 hexanes/ethyl acetate) furnished 79.1
H), 4.21-4.18 (m, 2 H), 3.79 (s, 3 H), 3.63 (td, J ) 10.0, 6.5 Hz, 1
H), 3.45 (td, J ) 10.0, 6.5 Hz, 1 H), 3.36 (s, 3 H), 2.21-2.14 (m, 1
H), 2.08 (br s, 1 H), 1.99-1.93 (m, 1 H), 1.89-1.60 (m, 7 H), 1.43 (s,
3 H), 1.42 (s, 3 H), 1.38 (s, 3 H), 1.35 (s, 3 H), 0.89 (s, 3 H) 0.92-
0.78 (m, 2 H), -0.04 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm 160.6,
148.4, 129.5 (2 C), 129.4, 113.4 (2 C), 111.9, 104.8, 101.8, 95.3, 92.7,
84.4, 83.0, 81.5, 79.9, 76.0, 68.9, 64.9, 55.2, 55.1, 44.0, 40.3, 39.3,
38.3, 32.2, 30.7, 28.2, 27.1, 26.6, 25.7, 25.5, 24.4, 18.0, 17.6, -1.5 (3
C); MS m/z (M+) calcd 688.4006, obsd 688.4032; [R]25D +28.1 (c 2.7,
CHCl3).
mg (66%) of 37 as a white solid, mp 139-141 °C: IR (neat, cm-1
)
1
3349, 1713; H NMR (300 MHz, CDCl3) δ 5.13 (s, 1 H), 4.87 (s, 1
H), 4.49 (d, J ) 6.5 Hz, 1 H), 4.40 (d, J ) 9.4 Hz, 1 H), 4.36 (d, J )
6.5 Hz, 1 H), 4.23 (d, J ) 4.8 Hz, 1 H), 4.15 (t, J ) 2.3 Hz, 1 H), 4.03
(d, J ) 9.4 Hz, 1 H), 4.02 (s, 1 H), 4.00 (s, 1 H), 3.27 (s, 3 H), 2.88
(dd, J ) 19.0, 10.1 Hz, 1 H), 2.48 (br d, J ) 2.7 Hz, 1 H), 2.15 (m,
1 H), 1.93-1.60 (m, 7 H), 1.42 (s, 3 H), 1.37 (s, 3 H), 1.34 (s, 3 H),
0.95 (s, 3 H), 0.92 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 210.6,
148.6, 112.0, 105.8, 92.7, 82.7, 81.9, 79.1, 77.9, 76.5, 55.2, 43.1, 42.7,
39.1, 39.0, 38.7, 30.7, 28.2, 27.0, 26.7, 25.4, 25.2, 22.5, 17.7; MS m/z
Anal. Calcd for C38H60O9Si: C, 66.24; H, 8.78. Found: C, 66.19;
H, 8.86.
(M+) calcd 438.2617, obsd 438.2613; [R]24 -52.8 (c 1.0, CHCl3).
D
Anal. Calcd for C24H38O7: C, 65.71; H, 8.74. Found: C, 65.61;
H, 8.68.
(3S,4aR,6R,8R,9R,10S,11S,12R,12aR)-Dodecahydro-11,12-(iso-
propylidenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-4-
methylene-8-[[2-(trimethylsilyl)ethoxy]methoxy]-6,10-methanoben-
zocyclodecene-9,10(2H)-diol (40). A solution of 39b (13.1 mg, 0.019
mmol), pyridinium p-toluenesulfonate (44 mg, 0.175 mmol), and DDQ
(39.3 mg, 0.173 mmol) in methanol (2.0 mL) was stirred for 12 h,
quenched with saturated NaHCO3 solution (3 mL), evaporated to
remove methanol, and extracted with brine, dried, and concentrated.
The residue was chromatographed on silica gel (elution with 5:1
hexanes/ethyl acetate) to afford 40 as a colorless oil (9.9 mg, 91%):
(3S,4aR,6R,9S,10R,11S,12R,12aR)-Dodecahydro-11,12-(iso-
propylidenedioxy)-9,10-[(R)-(p-methoxybenzylidene)dioxy]-3-(meth-
oxymethoxy)-12a,13,13-trimethyl-4-methylene-6,10-methanobenzo-
cyclodecen-8(2H)-one (38). A solution of 37 (24.3 mg, 0.055 mmol)
in DMF (1.0 mL) containing camphorsulfonic acid (3.0 mg) and
p-methoxybenzylidene dimethyl acetal (50.0 mg, 0.275 mmol) was
heated at 50-55 °C for 6 h, cooled to room temperature, quenched
with saturated NaHCO3 solution (5 mL), and stirred overnight. The
product was extracted into ethyl acetate, the combined organic phases
were washed with brine, dried, and concentrated, and the residue was
purified by chromatography on silica gel (elution with 5:1 hexanes/
ethyl acetate) to afford 38 as a colorless crystalline solid (30.5 mg,
1
IR (neat, cm-1) 3467 (br); H NMR (300 MHz, CDCl3) δ 5.13 (s, 1
H), 4.85 (s, 1 H), 4.79 (d, J ) 8.0 Hz, 1 H), 4.77 (s, 2 H), 4.60 (s, 2
H), 4.20 (m, 2 H), 3.83 (d, J ) 5.0 Hz, 1 H), 3.81 (d, J ) 8.0 Hz, 1
H), 3.70 (s, 1 H), 3.73-3.59 (m, 2 H), 3.35 (s, 3 H), 2.91 (br s, 1 H),
2.50 (d, J ) 8.2 Hz, 1 H), 2.19 (m, 1 H), 1.99 (t, J ) 8.2 Hz, 1 H),
1.90-1.51 (m, 7 H), 1.46 (s, 3 H), 1.43 (s, 3 H), 1.41 (s, 3 H), 1.32 (s,
3 H), 0.91 (s, 3 H), 0.96-0.88 (m, 2 H), 0.01 (s, 9 H); 13C NMR (75
MHz, CDCl3) ppm 150.3, 112.3, 109.6, 94.6, 92.7, 81.9, 80.5, 77.4,
76.2, 74.6, 74.5, 65.5, 55.1, 43.1, 41.3, 40.0, 39.1, 32.5, 29.2, 28.2,
27.8, 26.9, 26.6, 25.0, 24.4, 18.1, 17.4, -1.4 (3 C); MS m/z (M+) calcd
1
100%), mp 111-112 °C: IR (neat, cm-1) 1709, 1613; H NMR (300
MHz, CDCl3) δ 7.41-7.37 (m, 2 H), 6.87-6.82 (m, 2 H), 5.93 (s, 1
H), 5.15 (s, 1H), 4.90 (s, 1 H), 4.66 (s, 1 H), 4.47 (d, J ) 6.6 Hz, 1 H),
4.42 (d, J ) 9.3 Hz, 1 H), 4.36 (d, J ) 9.3 Hz, 1 H), 4.32 (d, J ) 6.6
Hz, 1 H), 4.19 (s, 1 H), 3.79 (s, 3 H), 3.27 (s, 3 H), 2.87 (dd, J ) 20.0,
9.5 Hz, 1 H), 2.23 (m, 2 H), 1.96-1.68 (m, 7 H), 1.48 (s, 3 H), 1.46
(s, 3 H), 1.40 (s, 3 H), 1.07 (s, 3 H), 0.94 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 207.7, 160.8, 147.9, 129.2 (2 C), 127.7, 113.6 (2 C), 112.0,
105.3, 102.5, 92.6, 87.0, 84.6, 83.2, 79.3, 76.1, 55.3, 55.2, 44.3, 42.0,
39.7, 39.5, 38.4, 30.5, 28.3, 27.1, 26.6, 25.5, 24.8, 22.9, 17.5; MS m/z
570.3588, obsd 570.3571; [R]25 -71.4 (c 1.75, CHCl3).
D
(3S,4aR,6R,8R,10R,11S,12R,12aR)-Dodecahydro-10-hydroxy-
11,12-(isopropylidenedioxy)-3-(methoxymethoxy)-12a,13,13-trimethyl-
4-methylene-8-[[2-(trimethylsilyl)ethoxy]methoxy]-6,10-methanoben-
zocyclodecen-9(1H)-one (41). Tetrapropylammonium perruthenate
(1.8 mg, 0.005 mmol), N-methylmorpholine N-oxide (7.4 mg, 0.063
mmol), and 4 Å molecular sieves (7.4 mg) were added to a solution of
40 (12.0 mg, 0.021 mmol) in CH2Cl2 (1.0 mL); the reaction mixture
was stirred for 5 h before being diluted with hexanes (1.0 mL), filtered
through a pad of silica gel, and eluted with 5:1 hexanes/ethyl acetate.
The combined organic filtrates were evaporated to give 41 as a colorless
oil (11.0 mg, 92%): IR (neat, cm-1) 3535, 1732; 1H NMR (300 MHz,
CDCl3) δ 5.18 (s, 1 H), 4.89 (s, 1 H), 4.83 (d, J ) 7.2 Hz, 1 H), 4.79
(d, J ) 7.2 Hz, 1 H), 4.65 (m, 4 H), 4.24 (t, J ) 2.8 Hz, 1 H), 4.05 (d,
J ) 7.1 Hz, 1 H), 3.72 (s, 1 H), 3.72-3.59 (m, 2 H), 3.35 (s, 3 H),
2.53 (d, J ) 6.8 Hz, 1 H), 2.30-2.19 (m, 1 H), 2.10-1.42 (m, 8 H),
1.39 (s, 3 H), 1.36 (s, 3 H), 1.25 (s, 3 H), 1.03 (s, 3 H), 0.96 (s, 3 H),
0.97-0.82 (m, 2 H), 0.01 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm
209.6, 149.8, 112.2, 111.3, 94.9, 92.5, 82.4, 79.9, 77.6, 76.1, 75.4, 65.6,
55.1, 43.2, 42.0, 41.1, 39.1, 33.7, 30.7, 28.3, 27.0, 26.5, 26.4, 24.8,
22.6, 18.0, 17.4, -1.5 (3 C); MS m/z (M+-CH3) calcd 553.3256, obsd
(M+) calcd 556.3036, obsd 556.3006; [R]24 -45.7 (c 1.0, CHCl3).
D
(3S,4aR,6R,8R,9R,10S,11S,12R,12aR)-Tetradecahydro-11,12-(iso-
propylidenedioxy)-9,10-[(R)-(p-methoxybenzylidene)dioxy]-3-(meth-
oxymethoxy)-12a,13,13-trimethyl-4-methylene-6,10-methanobenzo-
cyclodecen-8-ol (39a). Lithium aluminum hydride (83 µL of 1.0 M
in THF, 0.083 mmol) was added to a solution of 38 (30.5 mg, 0.055
mmol) in dry ether (5.0 mL) at 0 °C. The reaction mixture was
quenched with saturated Na2SO4 solution, stirred for an additional hour,
filtered through a cake of Celite, and eluted with ether. The combined
organic filtrates were evaporated to afford pure 39a as a colorless oil
1
(28.5 mg, 93%): IR (neat, cm-1) 3516; H NMR (300 MHz, CDCl3)
δ 7.48-7.43 (m, 2 H), 6.90-6.86 (m, 2 H), 5.95 (s, 1 H), 5.12 (s, 1
H), 4.89 (s, 1 H), 4.50 (d, J ) 6.5 Hz, 1 H), 4.47 (d, J ) 6.5 Hz, 1 H),
4.41 (d, J ) 7.3 Hz, 1 H), 4.34 (d, J ) 9.3 Hz, 1 H), 4.29-4.20 (m,
3 H), 3.80 (s, 3 H), 3.33 (s, 3 H), 3.16 (s, 1 H), 2.26-2.17 (m, 1 H),
2.06-1.99 (m, 2 H), 1.87-1.58 (m, 7 H), 1.45 (s, 6 H), 1.43 (s, 3 H),
1.37 (s, 3 H), 0.90 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 160.9,
148.3, 129.1 (2 C), 128.5, 113.8 (2 C), 111.9, 104.9, 101.8, 92.6, 84.3,
82.9, 80.9, 79.4, 76.0, 63.0, 55.2, 55.1, 44.0, 40.6, 39.0, 38.3, 31.9,
30.8, 28.1, 27.0, 26.6, 25.8, 25.4, 24.6, 17.7; MS m/z (M+) calcd
553.3226; [R]25 -39.7 (c 0.78, CHCl3).
D
(3S,4aR,6R,8R,9R,10R,11S,12R,12aR)-Dodecahydro-11,12-(iso-
propylidenedioxy)-3-(methoxymethoxy)-9,12a,13,13-tetramethyl-4-
methylene-8-[[2-(trimethylsilyl)ethoxy]methoxy]-6,10-methanoben-
zocyclodecene-9,10(2H)-diol (42). A slurry of dried cerium(III)
chloride (1.18 mmol) in anhydrous THF (3.0 mL) at -78 °C was treated
with methyllithium (759 µL of 1.4 M in ether, 1.06 mmol) and stirred
for 2 h. A solution of 41 (51.3 mg, 0.09 mmol) in THF (1.0 mL) was
introduced, followed 30 min later with water (5 mL). The product
was extracted into ethyl acetate and the combined organic phases were
dried and concentrated to leave a residue, purification of which by
chromatography on silica gel (elution with 4:1 hexanes/ethyl acetate)
afforded recovered 41 (8.1 mg, 16%) and 42 (44.0 mg, 83%), the latter
558.3193, obsd 558.3183; [R]24 -48.4 (c 6.9, CHCl3).
D
Trimethyl-[2-[[[(3S,4aR,6R,8R,9R,10S,11S,12R,12aR)-tetradecahy-
dro-11,12-(isopropylidenedioxy)-9,10-[(R)-(p-methoxybenzylidene)-
dioxy]-3-(methoxymethoxy)-12a,13,13-trimethyl-4-methylene-6,10-
methanobenzocyclodecen-8-yl]oxy]methoxy]ethyl]silane (39b). A
solution of 39a (28.5 mg, 0.051 mmol) in CH2Cl2 (1.0 mL) was treated
with diisopropylethylamine (177 µL, 1.017 mmol) and SEM chloride
(135 µL, 0.765 mmol), stirred for 16 h, quenched with saturated
NaHCO3 solution, and extracted with ethyl acetate. The combined
organic phases were washed with brine, dried, and concentrated. The
residue was chromatographed on silica gel (elution with 10:1 hexanes/
ethyl acetate) to give 39b as a colorless oil (29.6 mg, 87%): IR (neat,
1
as a white solid, mp 116-117 °C: IR (neat, cm-1) 3474; H NMR
(300 MHz, C6D6) δ 5.03 (s, 1 H), 4.95 (d, J ) 8.0 Hz, 1 H), 4.90 (d,
J ) 6.8 Hz, 1 H), 4.84 (d, J ) 6.8 Hz, 1 H), 4.74 (d, J ) 7.2 Hz, 1 H),
4.70 (s, 1 H), 4.66 (d, J ) 7.2 Hz, 1 H), 4.27 (t, J ) 2.9 Hz, 1 H), 4.17
(d, J ) 8.0 Hz, 1 H), 4.11 (dd, J ) 11.9, 6.5 Hz, 1 H), 3.86 (s, 1 H),
1
cm-1) 1248, 1093, 1033; H NMR (300 MHz, CDCl3) δ 7.52-7.47
(m, 2 H), 6.87-6.82 (m, 2 H), 5.89 (s, 1 H), 5.13 (s, 1 H), 4.91 (s, 1
H), 4.76-4.58 (m, 4 H), 4.42 (d, J ) 7.8 Hz, 1 H), 4.37-4.30 (m, 2

5224 J. Am. Chem. Soc., Vol. 120, No. 21, 1998
Paquette et al.
3.75-3.60 (m, 2 H), 3.35 (s, 3 H), 2.68 (dd, J ) 7.5, 0.4 Hz, 1 H),
2.45-2.36 (m, 2 H), 1.93-1.79 (m, 3 H), 1.82 (s, 3 H), 1.72-1.53
(m, 5 H), 1.49 (s, 3 H), 1.40 (s, 3 H), 1.30 (s, 3 H), 1.26 (s, 3 H),
0.95-0.88 (m, 2 H), 0.93 (s, 3 H), -0.07 (s, 9 H); 13C NMR (75 MHz,
C6D6) ppm 150.9, 111.8, 109.2, 94.7, 93.2, 82.8, 79.5, 79.3, 79.2, 77.3,
76.2, 65.4, 55.0, 43.3, 42.1, 41.7, 39.4, 34.9, 30.5, 28.5, 21.8, 27.1,
26.7, 26.2, 25.4, 23.4, 18.2, 17.7, -1.5 (3 C); MS m/z (M+ - H) calcd
The above material (9.4 mg, 0.021 mmol) was dissolved in pyridine
(0.5 mL), cooled to 0 °C, and treated with 4-(dimethylamino)pyridine
(2.6 mg, 0.021 mmol) and thionyl chloride (45.7 µL, 0.65 mmol). The
reaction mixture was stirred at room temperature for 16 h, quenched
with cold water (2 mL), and extracted with ethyl acetate. The combined
organic phases were washed with brine, dried, and concentrated.
Purification of the residue was accomplished by chromatography on
silica gel (elution with 5:1 hexanes/ethyl acetate) to give 8 (5.8 mg,
583.3634, obsd 583.3650; [R]24 -78.3 (c 0.59, CHCl3).
D
1
64%) as a white solid, mp 157-158 °C: IR (neat, cm-1) 1670; H
(3S,4aR,6R,9S,10R,11S,12R,12aR)-Dodecahydro-9,10-dihydroxy-
11,12-(isopropylidenedioxy)-3-(methoxymethoxy)-9,12a,13,13-tet-
ramethyl-4-methylene-6,10-methanobenzocyclodecen-8(2H)-one (43).
A solution of 42 (60.5 mg, 0.104 mmol) in THF (3.0 mL) containing
tetra-n-butylammonium fluoride (2.0 mL of 1.0 M in THF, 2.0 mmol)
was refluxed for 3 days, cooled, quenched with water (5 mL), and
extracted with brine, dried, and concentrated. Purification of the residue
by chromatography on silica gel (elution with 2:1 hexanes/ethyl acetate)
furnished the alcohol (44.5 mg, 86%) as a white solid, mp 144-146
°C: IR (neat, cm-1) 3470; 1H NMR (300 MHz, C6D6) δ 4.99 (s, 1 H),
4.98 (d, J ) 8.1 Hz, 1 H), 4.75 (d, J ) 6.6 Hz, 1 H), 4.67 (s, 1 H),
4.63 (d, J ) 6.6 Hz, 1 H), 4.22 (m, 1 H), 4.19 (t, J ) 2.8 Hz, 1 H),
4.13 (d, J ) 8.1 Hz, 1 H), 3.94 (s, 1 H), 3.18 (s, 3 H), 2.65 (br d, J )
6.1 Hz, 1 H), 2.41-2.32 (m, 1 H), 2.11-1.99 (m, 1 H), 1.91-1.79
(m, 2 H), 1.72-1.19 (series of m, 5 H), 1.60 (s, 3 H), 1.42 (s, 3 H),
1.33 (s, 3 H), 1.26 (s, 3 H), 1.21 (s, 3 H), 0.91 (s, 3 H); 13C NMR (75
MHz, C6D6) ppm 150.6, 111.8, 109.2, 92.9, 83.1, 79.6, 79.0, 77.3, 76.5,
72.1, 55.1, 43.2, 41.9, 41.7, 38.7, 34.2, 34.0, 28.8, 27.2, 27.0, 26.7,
25.9, 25.1, 22.7, 17.5; MS m/z (M+) calcd 454.2930, obsd 454.2915;
NMR (300 MHz, C6D6) δ 5.01 (d, J ) 9.2 Hz, 1 H), 4.89 (s, 1 H),
4.58 (s, 1 H), 4.50 (d, J ) 6.6 Hz, 1 H), 4.35 (d, J ) 6.6 Hz, 1 H),
4.28 (d, J ) 9.2 Hz, 1 H), 4.09 (t, J ) 2.8 Hz, 1 H), 3.11 (s, 3 H), 2.97
(m, 1 H), 2.77 (dd, J ) 19.3, 7.3 Hz, 1 H), 2.16 (s, 3 H), 1.95-1.64
(m, 5 H), 1.58-1.24 (m, 3 H), 1.46 (s, 3 H), 1.45 (s, 3 H), 1.41 (s, 3
H), 1.06 (s, 3 H), 0.91 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 198.8,
152.9, 150.4, 138.8, 111.6, 107.7, 92.5, 83.1, 76.6, 76.3, 54.9, 41.7,
40.3, 40.20, 40.17, 37.3, 35.4, 28.8, 27.4, 27.0, 26.7, 26.4, 24.5, 17.6,
14.1; MS m/z (M+) calcd 418.2719, obsd 418.2721; [R]24 +122.4 (c
D
0.17, CHCl3).
(3S,4aR,6R,8S,9Z,11R,12R,12aR)-1,2,3,4,4a,5,6,7,8,11,12,12a-
Dodecahydro-11,12-(isopropylidenedioxy)-3-(methoxymethoxy)-
9,12a,13,13-tetramethyl-4-methylene-6,10-methanobenzocyclodecen-
8-ol (44). A solution of 8 (3.4 mg, 0.008 mmol) in CH2Cl2 (1.0 mL)
cooled to -78 °C was treated with Dibal-H (12 µL of 1.0 M in hexanes,
0.012 mmol), stirred for 10 min, quenched with saturated NH4Cl
solution, and extracted with ethyl acetate. The combined organic phases
were washed with brine, dried, and concentrated. The residue was
subjected to chromatography on silica gel (elution with 4:1 hexanes/
ethyl acetate) to furnish pure 44 (2.3 mg, 67%) as a white solid, mp
[R]24 -73.1 (c 0.80, CHCl3).
D
A solution of this alcohol (4.5 mg, 0.01 mmol) in CH2Cl2 (1.0 mL)
was treated with 4 Å molecular sieves (3.5 mg), N-methylmorpholine
N-oxide (3.5 mg, 0.03 mmol), and tetrapropylammonium perruthenate
(1.0 mg, 0.003 mmol) at 0 °C and allowed to warm slowly to 15 °C
during overnight stirring. The mixture was filtered through a pad of
silica gel, eluted with 2:1 hexanes/ethyl acetate, and evaporated.
Chromatography of the residue on silica gel (elution with 4:1 hexanes/
1
143-145 °C: IR (neat, cm-1) 3487; H NMR (300 MHz, CDCl3) δ
5.05 (s, 1 H), 4.87 (d, J ) 9.4 Hz, 1 H), 4.75 (s, 1 H), 4.60 (s, 2 H),
4.58-4.35 (m, 1 H), 4.16 (d, J ) 9.4 Hz, 1 H), 4.11 (t, J ) 2.6 Hz, 1
H), 3.33 (s, 3 H), 2.96 (m, 1 H), 2.85 (ddd, J ) 15.4, 10.3, 9.1 Hz, 1
H), 2.68 (d, J ) 11.2 Hz, 1 H), 2.05 (d, J ) 1.3 Hz, 3 H), 1.90-1.03
(series of m, 8 H), 1.50 (s, 3 H), 1.46 (s, 3 H), 1.42 (s, 3 H), 1.00 (s,
3 H), 0.86 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 150.6, 142.7,
135.2, 110.9, 106.7, 94.1, 82.9, 78.9, 75.4, 68.7, 55.4, 40.3, 39.5, 39.0,
36.6, 36.4, 32.7, 27.5, 27.4, 27.3, 27.0, 26.0, 25.2, 17.4, 16.7; MS m/z
(M+) calcd 420.2876, obsd 420.2886; [R]24D +136.7 (c 0.060, CHCl3).
ethyl acetate) gave 43 as a colorless oil (3.0 mg, 67%): IR (neat, cm-1
)
1715; 1H NMR (300 MHz, C6D6) δ 5.07 (d, J ) 7.2 Hz, 1 H), 5.04 (s,
1 H), 4.88 (d, J ) 7.2 Hz, 1 H), 4.75 (d, J ) 8.2 Hz, H), 4.66 (s, 1 H),
4.28 (t, J ) 2.7 Hz, 1 H), 3.97 (d, J ) 8.2 Hz, 1 H), 3.96 (s, 1 H), 3.28
(s, 3 H), 3.12 (dd, J ) 16.2, 9.0 Hz, 1 H), 2.71 (s, 1 H), 2.14 (br d, J
) 4.9 Hz, 1 H), 1.93-1.38 (series of m, 8 H), 1.65 (s, 3 H), 1.50 (s,
3 H), 1.31 (s, 3 H), 1.20 (s, 3 H), 1.16 (s, 3 H), 0.87 (s, 3 H); 13C
NMR (75 MHz, C6D6) ppm 208.2, 149.6, 112.5, 109.1, 93.2, 83.0, 82.9,
78.5 (2 C), 75.3, 55.0, 43.0, 42.5, 41.3, 40.2, 37.7, 33.9, 28.8, 26.9 (2
C), 26.7, 25.6, 24.8, 20.7, 17.8; MS m/z (M+) calcd 452.2774, obsd
(+)-Taxusin (1). A magnetically stirred solution of 44 (2.2 mg,
0.005 mmol) in acetonitrile (1.0 mL) was treated with water (50 mL)
and lithium tetrafluoroborate (3.1 mg, 0.033 mmol), heated at 45 °C
for 2 h, returned to room temperature, and diluted with brine (1 mL).
The product was extracted into ethyl acetate, and the combined organic
phases were dried and concentrated to leave a residue which was
chromatographed on silica gel (elution with 1:2 hexanes/ethyl acetate)
to afford the tetraol (0.9 mg, 51%) as a white solid, mp 209-211 °C:
452.2773; [R]24 -121.7 (c 0.23, CHCl3).
D
(3S,4aR,6R,9Z,11R,12R,12aR)-1,3,4,4a,5,6,7,11,12,12a-Decahydro-
11,12-(isopropylidenedioxy)-3-(methoxymethoxy)-9,12a,13,13-tet-
ramethyl-4-methylene-6,10-methanobenzocyclodecen-8(2H)-one (8).
To a solution of 43 (10.2 mg, 0.023 mmol) in 2.0 mL of THF/methanol
(1:1) at -78 °C was added samarium(II) iodide (2.4 mL of 0.085 M in
THF, 0.203 mmol) until the mixture became green in color. After being
warmed to room temperature and stirred for an additional 2 h, the
mixture was quenched with saturated NaHCO3 solution (2 mL) and
extracted with ethyl acetate. The combined organic phases were washed
with brine, dried, and concentrated to leave a residue, purification of
which by chromatography on silica (elution with 6:1 hexanes/ethyl
acetate) afforded the â-hydroxy ketone (7.1 mg, 72%) as a white solid,
1
IR (neat, cm-1) 3416 (br); H NMR (300 MHz, CD3OD) δ 5.03 (s 1
H), 4.74 (d, J ) 9.6 Hz, 1 H), 4.56 (s, 1 H), 4.35 (m, 1 H), 4.21 (t, J
) 2.5 Hz, 1 H), 3.95 (d, J ) 9.6 Hz, 1 H), 2.77 (m, 1 H), 2.05 (d, J
) 1.3 Hz, 3 H), 1.77-1.57 (m, 7 H), 1.47 (s, 3 H), 1.22 (m, 2 H), 1.00
(s, 3 H), 0.86 (s, 3 H); 13C NMR (75 MHz, CD3OD) ppm 155.9, 140.5,
139.0, 110.2, 80.1, 75.8, 73.7, 69.6, 45.0, 41.6, 40.2, 37.9, 37.0, 33.3,
31.6, 28.7, 26.9, 26.8, 18.2, 16.9; MS m/z (M++H) calcd 335.2222,
obsd 335.2224; [R]25 +133.3 (c 0.045, CH3OH).
D
A cold (0 °C) solution of the above tetraol (1.4 mg, 0.004 mmol) in
CH2Cl2 (1.0 mL) was treated with DMAP (1.0 mg, 0.008 mmol),
triethylamine (17 µL, 0.125 mmol), and acetic anhydride (7.8 µL, 0.083
mmol), and stirred at room temperature for 20 h. The reaction mixture
was quenched with saturated NaHCO3 solution, the product was
extracted into ethyl acetate, and the combined organic phases were
washed with brine, dried, and concentrated. Purification of the residue
by chromatography on silica gel (elution with 2:1 hexanes/ethyl acetate)
afforded 1 (1.8 mg, 85%): IR (neat, cm-1) 1738, 1240; 1H NMR (300
MHz, CDCl3) δ 6.08 (d, J ) 10.7 Hz, 1 H), 5.90-5.84 (br m, 1 H),
5.87 (d, J ) 10.7 Hz, 1 H), 5.36 (t, J ) 2.4 Hz, 1 H), 5.21 (s, 1 H),
4.85 (s, 1 H), 3.00 (br d, J ) 5.5 Hz, 1 H), 2.79 (dt, J ) 14.6, 9.9 Hz,
1 H), 2.16 (s, 3 H), 2.11 (d, J ) 11.4 Hz, 3 H), 2.07 (s, 3 H), 2.05 (s,
3 H), 2.01 (s, 3 H), 1.87-1.50 (m, 7 H), 1.62 (s, 3 H), 1.11 (s, 3 H),
1.06 (dd, J ) 14.8, 7.3 Hz, 1 H), 0.75 (s, 3 H); 13C NMR (75 MHz,
1
mp 112-113 °C: IR (neat, cm-1) 3494, 1700; H NMR (300 MHz,
C6D6) δ 5.10 (d, J ) 7.2 Hz, 1 H), 5.05 (s, 1 H), 4.89 (d, J ) 7.2 Hz,
1 H), 4.69 (d, J ) 8.1 Hz, 1H), 4.67 (s, 1 H), 4.29 (t, J ) 2.8 Hz, 1 H),
4.08 (s, 1 H), 3.90 (d, J ) 8.3 Hz, 1 H), 3.29 (s, 3 H), 2.81 (q, J ) 6.4
Hz, 1 H), 2.34 (dd, J ) 16.4, 9.3 Hz, 1 H), 2.18 (dd, J ) 6.6, 1.4 Hz,
1 H), 1.92-1.79 (m, 3 H), 1.66 (t, J ) 8.5 Hz, 1 H), 1.64-1.36 (m, 4
H), 1.35 (s, 3 H), 1.32 (s, 3 H), 1.30 (d, J ) 6.4 Hz, 3 H), 1.24 (s, 3
H), 1.20 (s, 3 H), 0.89 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 209.5,
150.1, 112.3, 109.7, 93.1, 83.2, 78.6, 76.9, 75.5, 55.6, 55.0, 43.1, 42.8,
42.6, 41.4, 37.3, 32.0, 28.9, 27.0, 26.6, 26.5, 24.7, 23.8, 18.0, 7.9; MS
m/z (M+) calcd 436.2825, obsd 436.2819; [R]24 -107.4 (c 0.47,
D
CHCl3).

Synthesis of Natural (+)-Taxusin
J. Am. Chem. Soc., Vol. 120, No. 21, 1998 5225
CDCl3) ppm 170.4, 169.94, 169.91, 148.8, 137.0, 134.8, 114.1, 77.2,
76.3, 72.5, 70.7, 42.9, 40.3, 39.3, 38.0, 31.9, 31.1, 28.3, 27.34, 27.31,
27.28, 21.8, 21.5, 21.0, 20.8, 17.7, 14.8; [R]25D +105.5 (c 0.09, CHCl3).
Kurt Loening for assistance with nomenclature. M.Z. served as
a Merck Postdoctoral Fellow during 1993.
Supporting Information Available: Experimental details
for the preparation of 32-36 as well as final calculated atomic
coordinates for A-C in Table 1 (9 pages, print/PDF). See any
current masthead page for ordering information and Web access
instructions.
Acknowledgment. We express our thanks to the National
Cancer Institute for financial support, to Professors Kwei-Ju
Chen, Ming-Kuo Yeh, and Fa-Ching Chen (Tamkang Univer-
sity, Taiwan, R.O.C.) for an authentic sample of the natural
taxusin, to Professor Robert Holton for comparison spectra, Dr.
James Lanter for the molecular mechanics calculations, and Dr.
JA980538T