Total synthesis of spinosyn A. 1. Enantioselective construction of a key tricyclic intermediate by a multiple configurational inversion scheme

Article abstract of DOI:10.1021/ja974009l

The condensation of (+)-7,7-dimethoxynorbomen-2-one with the cerium reagent derived from enantiopure bromide (+)-11 gives rise to an exo carbinol, which readily undergoes highly stereocontrolled anionic oxy-Cope rearrangement. Conversion of the resulting

Full text of DOI:10.1021/ja974009l

J. Am. Chem. Soc. 1998, 120, 2543-2552
2543
Total Synthesis of Spinosyn A. 1. Enantioselective Construction of a
Key Tricyclic Intermediate by a Multiple Configurational Inversion
Scheme
Leo A. Paquette,* Zhongli Gao,1a Zhijie Ni,1b and Graham F. Smith1c
Contribution from the EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
ReceiVed NoVember 24, 1997
Abstract: The condensation of (+)-7,7-dimethoxynorbornen-2-one with the cerium reagent derived from
enantiopure bromide (+)-11 gives rise to an exo carbinol, which readily undergoes highly stereocontrolled
anionic oxy-Cope rearrangement. Conversion of the resulting ketone into 20 proceeds with clean epimerization
at C-11 (spinosyn numbering) to properly set the absolute configuration at that site. Reduction of 20 with
lithium in liquid ammonia serves to introduce two additional stereogenic centers of the perhydro-as-indacene
core. In addition, the protocol makes possible the convenient incorporation of a functionalized two-carbon
appendage at C-3 and ultimate generation of a cyclohexene double bond after stereochemical inversion at C-7.
This scheme leads to 34, a tricyclic compound subsequently shown to be an advanced precursor to the powerful
insecticide spinosyn A.
The macrocyclic lactone class of natural products, encom-
passing hundreds of compounds possessing varied biological
activity, is often regarded as one of the more challenging areas
of total synthesis as a consequence of the substantive structural
variation among its members.2,3 In 1991, impressive insecticidal
inhibitory properties, most notably against Lepidoptera larvae,
were reported for a multifactored complex produced by the
newly discovered species Saccharopolyspora spinosa.4 This
soil microbe is responsible for producing a polar, nine-
component mixture whose constituents differ in the level of N,
O, and C methylation of the sugar and aglycone components.
The most prevalent member was initially shown by spectro-
scopic means, including X-ray crystallography, to be 1.5 The
absolute stereochemical assignment to spinosyn A (1)6 as well
as its eventual common name7 materialized later.
The revolutionary discovery of the insecticidal potency of
this macrolide has been met with intense degradative8 and
(1) (a) Current address: Hoechst Marion Roussel, Inc., Route 202-206,
P.O. Box 6800, Bridgewater, NJ 08807-0800. (b) Current address: Versicor,
Inc., 34790 Ardentech Court, Fremont, CA 94555. (c) Current address:
Pfizer Central Research, Sandwich, Kent CT13 9NJ, United Kingdom.
(2) Omura, S.; Ed. Macrolide Antibiotics: Chemistry, Biology, and
Practice; Academic Press: Orlando, FL, 1984.
(3) Campbell, W. C., Ed. IVermectin and Abamectin; Springer-Verlag:
New York, 1989.
(4) Boeck, L. D.; Chio, E. H.; Eaton, T. E.; Godfrey, O. W.; Michel, K.
H.; Nakatsukasa, W. M.; Yao, R. C. Eur. Pat. Appl. 375316, 1990; Chem.
Abstr. 1991, 114, 80066.
(5) Kirst, H. A.; Michel, K. H.; Martin, J. W.; Creemer, L. C.; Chio, E.
H.; Yao, R. C.; Nakatsukasa, W. M.; Boeck, L. D.; Occolowitz, J. L.;
Paschal, J. W.; Deeter, J. B.; Jones, N. D.; Thompson, G. D. Tetrahedron
Lett. 1991, 32, 4839.
(6) Kirst, H. A.; Michel, K. H.; Mynderase, J. C.; Chio, E. H.; Yao, R.
C.; Natsukasa, W. M.; Boeck, L. D.; Occolowitz, J. L.; Paschal, J. W.;
Deeter, J. B.; Thompson, G. D. In Synthesis and Chemistry of Agrochemicals
III; Baker, D. R., Fenyes, J. G., Steffens, J. J., Eds.; ACS Symposium Series
No. 504; American Chemical Society: Washington, DC, 1992; pp 214-
215 and references therein.
synthetic scrutiny.9 Although 1 does contain D-(+)-forosamine10
and tri-O-methyl-D-rhamnose as unique appendages, its perhy-
dro-as-indacene core is recognized to be present in a relatively
small number of antibiotics such as ikarugamycin (2)11,12 and
capsimycin (3).13 Despite this similarity, noteworthy differences
exist. Thus, the absolute configuration of the perhydro-as-
(7) The names initially adopted for 1 (LY232105, A83543A, and lepicidin
A) have been recently abandoned in favor of spinosyn A (Kirst, H. A.;
communication dated June 7, 1994).
(9) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1992, 114, 2260;
1993, 115, 4497.
(10) Stevens, C. L.; Gutowski, G. E.; Taylor, K. G.; Bryant, C. P.
Tetrahedron Lett. 1966, 5717.
(8) Martynow, J. G.; Kirst, H. A. J. Org. Chem. 1994, 59, 1548.
S0002-7863(97)04009-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/10/1998

2544 J. Am. Chem. Soc., Vol. 120, No. 11, 1998
Paquette et al.
indacene subunit in 1 is opposite to that of 2 and 3. Further-
more, the tricyclic ring system of the latter two are fused to a
16-membered lactam into which a tetramic acid moiety is
embedded, rather than to a 12-membered lactone. Finally, the
pattern and type of substituents positioned around the structural
core of 1 are entirely different from those of 2 and 3, neither of
which carry saccharide substituents. An inference which can
be drawn from this combination of facts is that significant
differences in biogenetic origin are at play.
Scheme 1
Retrosynthetic Analysis. A distinctive feature of virtually
all of the preparations of 5,6,5-cis-anti-trans-decahydro-as-
indacenes except for those developed in this laboratory12b-d and
by Whitesell14 is the utilization of an intramolecular Diels-
Alder cycloaddition as the key step for structural assembly. The
success realized by us in synthesizing ikarugamycin (2) through
application of an anionic oxy-Cope pathway prompted examina-
tion of the feasibility of elaborating 1 by this means also. Under
these circumstances, the substantial thermodynamic preferences
resident in these tricyclic networks require proper consid-
eration.12c,15,16
A particularly attractive feature of the oxy-Cope approach is
the ability to elaborate the entire tricyclic core of 1 carrying an
appropriate array of functionality in a single step. The first
retrosynthetic plan to have been considered is outlined in
Scheme 1. Following coupling of the proper antipodes of two
building blocks to generate A-5, the only geometrically feasible
boatlike [3.3] sigmatropic transition state was expected to
generate enolate anion A-4. In earlier ground-breaking work,12b-d
it was learned that protonation of enolates configured in this
way under equilibrating conditions would result in the introduc-
tion of a trans-fused ring arrangement for thermodynamic
reasons. The direct acquisition of A-3 in this manner properly
sets the absolute configuration at C-7 and C-11 (spinosyn A
numbering). Complete inversion of stereochemistry at C-4 and
C-12 as in A-1 was expected to materialize cleanly following
upon migration of the double bond to an intraring site as in
A-2 and subsequent dissolving metal reduction.12b-d This
maneuver would serve to complete the plan for setting the
absolute configuration of the core.
The promise offered by Scheme 1 was briefly thwarted when
the unexpected discovery was made that the conditions required
for the A-3 to A-2 conversion were sufficiently basic to effect
a â f R configurational change at C-11. When ancillary studies
confirmed that A-2 was less thermodynamically stable than its
cis isomer, it became clear that purposeful adjustments of
absolute configuration were necessary in order to accommodate
these thermodynamic facets of the problem. Herein, we describe
how advantage can effectively be taken of these inherent
thermodynamic biases to arrive at an advanced precursor of
spinosyn A (1). The ensuing paper describes a body of new
chemistry, including the degradation of 1 to 34 and completion
of the total synthesis.17
Results and Discussion
Resolution of 7,7-Dimethoxynorborn-5-en-2-one. The im-
mediate goal was to obtain both antipodes of ketone 5. Since
the racemate is produced by oxidation of 4a,18,19 attempts were
initially directed to enzyme-catalyzed kinetic resolution20 of the
chloroacetate derivative 4b. However, the enantioselectivity
uncovered for hydrolysis of 4b by several lipases proved to be
very low. With lipase derived from P. fluorescens, for example,
the percent ee after 40% reaction was only 3%. Consequently,
Johnson’s sulfoximine protocol21 was used instead (Scheme 2).
The sterically enforced endo directionality of nucleophilic attack
on (()-5 results in the production of only the two diastereomers
6 and 7, which are readily amenable to chromatographic
separation and individual thermolysis to regenerate (+)-5 and
(-)-5, respectively. The absolute configurational assignments
to these enantiomers are based reliably on an X-crystallographic
analysis of (+)-6 (Figure 1), which allowed for direct correlation
of the known stereochemistry at sulfur with that resident in the
norbornenyl substructure.
(11) Isolation: (a) Jomon, K.; Kuroda, Y.; Ajisaka, M.; Sakai, H. J.
Antibiot. 1972, 25, 271. (b) Ito, S.; Hirata, Y. Tetrahedron Lett. 1972, 1181,
1185, 2257. (c) Ito, S.; Hirata, Y. Bull. Chem. Soc. Jpn. 1977, 50, 227,
1813.
(12) Total synthesis: (a) Boeckman, R. K., Jr.; Weidner, C. H.; Perni,
R. B.; Napier, J. J. J. Am. Chem. Soc. 1989, 111, 8036. (b) Paquette, L. A.;
Macdonald, D.; Anderson, L. G.; Wright, J. J. Am. Chem. Soc. 1989, 111,
8037. (c) Paquette, L. A.; Romine, J. L.; Lin, H. S.; Wright, J. J. Am. Chem.
Soc. 1990, 112, 9284. (d) Paquette, L. A.; Macdonald, D.; Anderson, L. G.
J. Am. Chem. Soc. 1990, 112, 9292. (e) Roush, W. R.; Wada, C. K. J. Am.
Chem. Soc. 1994, 116, 2151.
The Consequences of Coupling to (-)-5. As a prelude to
the requisite coupling reaction, the readily available 4(R)-(tert-
butyldimethylsiloxy)-2-cyclopenten-1-one (8)22 was reduced
with L-Selectride, and the enolate anion resulting from 1,4-
addition was captured with N-phenyltriflimide to afford the enol
triflate 9 (Scheme 3).23 Treatment of 9 with hexamethylditin
(13) (a) Aizawa, S.; Akutsu, H.; Satomi, T.; Nagatsu, T.; Taguchi, R.;
Seino, A. J. Antibiot. 1979, 32, 193. (b) Seto, H.; Yonehara, H.; Aizawa,
S.; Akutsu, H.; Clardy, J.; Arnold, E.; Tanabe, M.; Urano, S. Tennen Yuki
Kagobutsu Toronkai Koen Yoshishu 1979, 394; Chem. Abstr. 1980, 92,
211459u.
(14) Whitesell, J. K.; Minton, M. A. J. Am. Chem. Soc. 1987, 109, 6403.
(15) Jurecek, F.; Hanus, V.; Sedmera, P.; Antropiusova, H.; Mach, K.
Tetrahedron 1979, 35, 1463.
(17) Paquette, L. A.; Collado, I.; Purdie, M. J. Am. Chem. Soc. 1998,
120, 2553-2562.
(18) Jung, M. E.; Hudspeth, J. P. J. Am. Chem. Soc. 1977, 99, 5508.
(19) Paquette, L. A.; Learn, K. S.; Romine, J. L.; Lin, H.-S. J. Am. Chem.
Soc. 1988, 110, 879.
(20) Schwartz, A.; Madan, P.; Whitesell, J. K.; Lawrence, R. M. Org.
Synth. 1990, 69, 1.
(21) Johnson, C. R.; Zeller, J. R. J. Am. Chem. Soc. 1982, 104, 4021.
(22) Paquette, L. A.; Earle, M. J.; Smith, G. F. Org. Synth. 1996, 73,
36.
(16) For a preliminary account of a portion of this investigation, consult
Paquette, L. A.; Gao, Z.; Ni, Z.; Smith, G. F. Tetrahedron Lett. 1997, 38,
1271.
(23) Review: Ritter, K. Synthesis 1993, 735.

Total Synthesis of Spinosyn A
J. Am. Chem. Soc., Vol. 120, No. 11, 1998 2545
Scheme 3
Figure 1. Computer-generated perspective drawing of 6 as determined
by X-ray crystallography.
Scheme 2
occurred from the endo direction to deliver (-)-12 in 76% yield.
When this carbinol was treated with potassium hydride in THF,
the oxy-Cope rearrangement was complete within 3 h at room
temperature. Although a reaction efficiency of 90% was
realized, the isomerization was found to vary appreciably in
both rate and yield with the source of KH. On some occasions,
decomposition to unidentified compounds was unaccountably
observed. No parallel complications unfolded during the use
of sodium hydride in THF at reflux (4 h), a fact which led to
wholesale adoption of this procedure as this study progressed.
It is noteworthy that the addition of 18-crown-6 was unnecessary
in either instance as a consequence of the substantial strain
release that accompanies dismantling of the norbornene ring.
To allow for complete equilibration to (+)-13, the highly
alkaline aqueous quench solution was allowed to stir for at least
30 min prior to isolation. The stereochemical assignment to
this ketone was supported by the determination of NOE effects.
Reduction of the carbonyl functionality in (+)-13 with
diisobutylaluminum hydride proceeded stereoselectively from
the â-direction as revealed after acetal hydrolysis by the NOE
effects exhibited by (-)-14 (Scheme 4). Arrival at this
intermediate set the stage for base-promoted migration of the
cyclopentenone double bond to the intracyclic site. It was soon
recognized that this necessary chemical change, best effected
with potassium carbonate in hot methanol, also brought about
complete configurational inversion at the tertiary allylic site.
Equilibration studies performed on 15 and its congeners 16a
and 16b gave no indication of any return to the respective trans-
fused isomer, a feature which we attribute to the thermodynamic
bias intrinsic to this particular decahydro-as-indacene network.
Establishment of Proper Absolute Configuration. The
contrasting thermodynamic preferences that distinguish 13 from
15 are noteworthy in that they demand inversion of the absolute
configuration of both stereogenic centers at the conjoined B/C
rings in order to accommodate ultimate access to spinosyn A.
This challenge was easily met and required only that (+)-5 be
involved initially. The advance to diastereomer 20 was ac-
complished in a fashion entirely parallel to that developed earlier
(Scheme 5). Note that the change in configuration of the MOM
substituent at C-6 does not alter the overwhelming preference
for adoption of a cis B/C ring junction.
in the presence of a catalytic amount of tetrakis(triphenylphos-
phine)palladium24 gave rise to vinylstannane 10a, brominative
substitution25,26 of which delivered 11 in 80% overall yield.
Somewhat greater efficiency (94%) was realized when 9 was
reacted with a stannyl cyanocuprate to generate 10b in advance
of conversion to 11.
As a consequence of the ease of deprotonation of (-)-5,
recoruse was made to cerium trichloride-mediated coupling27
with lithiated (+)-11. Under these circumstances, 1,2-addition
(24) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron,
K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J.
Org. Chem. 1986, 51, 277.
(25) Crisp, G. T.; Scott, W. J. Synthesis 1985, 335.
(26) Barth, W.; Paquette, L. A. J. Org. Chem. 1985, 50, 2438.
(27) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392.

2546 J. Am. Chem. Soc., Vol. 120, No. 11, 1998
Paquette et al.
recorded for 14, and (d) ultimate arrival at spinosyn A.17
Scheme 4
The critical side chain extension was now undertaken.
Exposure of 21 to conventional Wadsworth-Emmons condi-
tions involving the sodium salt of trimethyl phosphonoacetate28
gave rise to an inseparable 2.5:1 E/Z mixture of R,â-unsaturated
ester (85%). As foreshadowed by precedent, the deprotonation
of these isomers with LDA followed by quenching with aqueous
NH4Cl solution at -78 °C furnished the desired â,γ-isomer
cleanly in 93% yield. Exposure of 22 to lithium aluminum
hydride29 then made available the primary carbinol 23, which
was transformed under basic conditions30 into the p-methoxy-
benzyl derivative. Although we were now positioned to effect
the hydroboration-oxidation of 24, initial probe experiments
involving use of the borane‚THF complex31a proved disappoint-
ing in terms of regiochemistry, stereochemistry, and efficiency.31b
Dramatically, the presence of lithium borohydride32a caused 25
to predominate heavily (72%) over the unwanted tertiary C-3
isomer (11%). This observation,32b in combination with a
substantial difference in polarity between these isomers, was
responsible for the ultimate adoption of this protocol.
The protection of the hydroxyl group in 25 as the tert-
butyldiphenylsilyl derivative proceeded smoothly, thereby mak-
ing possible selective removal of the MOM functionality with
B-bromocatecholborane.33,34 This course of action was followed
in order to permit subsequent oxidation of 27 and epimerization
of this ketone to deliver the targeted intermediate 29. That
configuration had been inverted from â to R in order to generate
the more stable trans B/C arrangement was evident from relevant
spectral changes. With arrival at 29, the absolute configuration
at all four stereogenic centers of the tricyclic core had been
properly secured.
Scheme 5
Functionalization of the ABC Subtarget. Reduction of 29
with DIBAL-H provided a conveniently separable 3:2 mixture
of R- and â-alcohols. Dehydration of the R-isomer with the
Martin sulfurane35 followed immediately by selective removal
of the TBS group under aqueous acetic acid conditions led to
the isolation of 30 (Scheme 7). While the R-alcohol leads
predominantly to the indicated product (TLC, NMR analysis,
etc.) in relatively rapid fashion (<1 h at 25 °C), the â-alcohol
reacts much more slowly (>15 h at 25 °C) and inefficiently
and gives rise to a different product in low (15-20%) yield.
This dichotomy may be steric in origin. Thus, the E2 elimination
pathway normally adopted by adducts of the sulfurane to
secondary alcohols35 can be readily accommodated in the
R-series (see A). For the â-isomer, steric crowding precludes
extensive population of that conformation (B) which projects
the leaving group axially. When it does so, elimination to give
the more highly substituted cyclohexene isomer would be
kinetically favored as is observed. The latter product was not
fully characterized due to our inability to separate it from
contaminants derived from decomposition of the sulfurane.
The dissolving metal reduction of 20 exhibits considerable
sensitivity to preexisting stereochemistry and results in the
exclusive formation of 21 (Scheme 6). As a consequence of
the clustering of many of the proton signals from this ketone
into a rather narrow chemical shift range, the stereochemical
assignment was based on several alternative considerations,
including (a) the customary adherence to thermodynamic control
at the â-enone carbon, which would set C-11 and C-12 in a
trans relationship; (b) the recognized greater stability of cis,-
anti,cis isomers relative to their cis,anti,trans counterparts,12c,15
which would position H-4 and H-12 cis to each other; (c) the
distinctive appearance of the NMR spectra of 21 relative to those
Protection of the C-9 hydroxyl in 30 as the pivalate provided
a sufficiently stable setting for the steps required to unmask
the TBDPS ether and to transform 32 into ketone 33. The
(32) (a) Arase, A.; Nunokawa, Y.; Masuda, Y.; Hoshi, M. J. Chem. Soc.,
Chem. Commun. 1991, 205 and references therein. (b) This effect can be
attributed to the in situ generation of a different borane species. For a
summary of past observations, consult Banfi, L.; Narisano, E.; Riva, R.
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; J.
Wiley and Sons, Inc.; Chichester, England; 1995; Volume 5, pp 3046-
3049.
(33) Boeckman, R. K., Jr.; Potenza, J. C. Tetrahedron Lett. 1985, 26,
1411.
(34) King, P. F.; Stroud, S G. Tetrahedron Lett. 1985, 26, 1415.
(35) (a) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327.
(b) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 4997, 5003.
(28) Wadsworth, W. D., Jr.; Emmons, W. D. Org. Synth. 1965, 45, 44.
(29) For example: Hori, K.; Hikaga, N.; Inagaki, A.; Mori, S.; Nomura,
K.; Yoshii, E. J. Org. Chem. 1992, 57, 2888.
(30) Evans, D. A.; Rieger, D. L.; Jones, T. K.; Kaldor, S. W. J. Org.
Chem. 1990, 55, 6260.
(31) (a) Brown, H. C.; Vander Jagt, D. L.; Rothberg, I.; Hammer, W. J.;
Kawakami, J. H. J. Org. Chem. 1985, 50, 2179. (b) Under these
circumstances, four isomers were produced in a 40:12:9:39 ratio and isolated
in a combined 60% yield. The first of these products was subsequently
identified as 25. All four gave the same molecular ion peak in high resoluton
MS.

Total Synthesis of Spinosyn A
J. Am. Chem. Soc., Vol. 120, No. 11, 1998 2547
Scheme 6
Scheme 7
CH2OPMB chain from the sterically congested â interior to the
uncluttered R surface could readily be implemented.
Summary. A unified, highly convergent synthesis of (-)-
34 has been realized. The linear sequence from the point where
(+)-11 is conjoined to (+)-5 is constituted of 21 steps. The
route defined herein requires that the absolute configuration at
C-11 be properly introduced first. This key issue, which was
addressed during the conversion of 19 to 20, allows for the
correct establishment of C-4 and C-12 by reduction under
dissolving metal conditions. Finally, reliance is placed on
thermodynamically driven epimerization to realize suitable
configurational control at C-7. Thus, the protocol is based
entirely on the greater stability of the trans fusion of the
cyclopentane rings across the “rear” section of the central
cyclohexane ring, as well as the energetic preference enjoyed
by the overall cis,anti,trans tricyclic arrangement relative to the
cis,anti,cis option. Finally, the degradation of spinosyn A to
34 reported in the sequel17 confirms the assigned structural
features. The adaptability of 34 to the total synthesis of 1 to
be described subsequently completes the objectives of this
investigation.
Experimental Section
General Methods. Melting points are uncorrected. The column
chromatographic separations were performed with Woelm silica gel
(230-400 mesh). Solvents were reagent grade and in most cases dried
prior to use. The purity of all compounds was shown to be >95% by
1
TLC and high field H and 13C NMR. The high-resolution and fast-
atom-bombardment spectra were recorded at The Ohio State University
Campus Chemical Instrumentation Center. Elemental analyses were
performed at the Scandinavian Microanalytical Laboratory, Herlev,
Denmark or at Atlantic Microlab, Inc., Norcross, GA.
(+)-(S)-S-[[(1R,2S,4R)-2-Hydroxy-7,7-dimethoxybicyclo[2.2.1]-
hept-5-en-2-yl]methyl]-N-methyl-S-phenylsulfoximine (6) and (-)-
(S)-S-[[(1S,2R,4S)-2-Hydroxy-7,7-dimethoxybicyclo[2.2.1]hept-5-en-
2-yl]methyl]-N-methyl-S-phenylsulfoximine (7). A cold (-78 °C)
solution of (+)-(S)-N,S-dimethyl-S-phenylsulfoximine (1.51 g, 9.19
mmol) in dry THF (40 mL) was treated with n-butyllithium (6.2 mL
of 1.5 M in hexanes, 9.3 mmol) and stirred for 30 min. A solution of
(()-5 (1.52 g, 9.05 mmol) in dry THF (10 mL) was added dropwise,
stereochemical assignment to 33 was corroborated by multiple
NOE experiments. The latter was next exposed to potassium
carbonate in methanol at the reflux temperature. Although
insufficient quantities of 33 precluded an exhaustive study of
this epimerization, it was made clear that migration of the CH2-

2548 J. Am. Chem. Soc., Vol. 120, No. 11, 1998
Paquette et al.
and stirring was maintained at low temperature for 2 h prior to warming
to 20 °C. After an additional 3 h of agitation, water (10 mL) was
added, the aqueous layer was extracted with ether (2 × 50 mL), and
the combined organic phases were washed with water and brine, dried,
and concentrated. The residue was chromatographed on silica gel
(elution with ethyl acetate) to give 1.33 g (44%) of 6, 0.85 g (29%) of
7, and 0.31 g (20%) of recovered 5.
combined organic layers were washed with brine, dried, and concen-
trated. The residue was passed through a short column of silica gel
(elution with 1% triethylamine in petroleum ether), and the eluent was
concentrated and dissolved in CH2Cl2 (200 mL). Bromine (0.1 M in
CH2Cl2, 130 mL, 13.0 mmol) was introduced at -78 °C, and the
solution was washed sequentially after 20 min with aqueous ammonia
solution (20 mL of 30% ammonium hydroxide was diluted to 200 mL),
water, and brine and then dried and concentrated. Purification was
effected by chromatography on silica gel (elution with 1% triethylamine
and 1% ethyl acetate in petroleum ether) afforded an oil that was
distilled in vacuo in a Kugelrohr apparatus to give 11 (2.76 g, 80%);
IR (neat, cm-1) 1462, 1365, 1260, 1197; 1H NMR (300 MHz, CDCl3)
δ 5.79-5.76 (m, 1 H), 4.59-4.52 (m, 1 H), 2.91-2.77 (m, 1 H), 2.65-
2.49 (m, 2 H), 2.39-2.23 (m, 1 H), 0.89 (s, 9 H), 0.06 (s 6 H); 13C
NMR (75 MHz, CDCl3) ppm 128.6, 118.0, 71.7, 49.3, 43.0, 25.8, 18.1,
-4.78, -4.81; MS m/z (M+ - Br) calcd 197.1362, obsd 197.1340;
[R]2D2 +18.5 (c 0.96, C6H6). Anal. Calcd for C12H21BrOSi: C, 47.64;
H, 7.64. Found: C, 47.54; H, 7.62.
For 6: colorless crystals, mp 109-110 °C (from ether); IR (CHCl3,
cm-1) 3490; 1H NMR (300 MHz, CDCl3) δ 7.88-7.84 (m, 2 H), 7.61-
7.50 (m, 3 H), 6.18 (dd, J ) 6.2, 3.3 Hz, 1 H), 6.09 (ddd, J ) 6.2, 3.3,
0.9 Hz, 1 H), 5.92 (s, 1 H), 3.34 (d, J ) 13.9 Hz, 1 H), 3.31-3.21 (br
s, 1 H), 3.30 (s, 3 H), 3.22 (d, J ) 13.9 Hz, 1 H), 3.17 (s, 3 H), 2.86
(br s, 1 H), 2.60 (s, 3 H), 2.01 (dd, J ) 12.9, 3.7 Hz, 1 H), 1.41 (d, J
) 12.9 Hz, 1 H); 13C NMR (75 MHz, CDCl3) ppm 139.1, 134.9, 133.7,
132.8, 129.3, 129.1, 120.1, 78.6, 64.7, 54.5, 51.9, 49.8, 44.7, 39.5, 29.0;
MS m/z (M+ - CH3) calcd 322.1113, obsd 322.1114; [R]22 +105 (c
D
0.56, CHCl3). Anal. Calcd for C17H23NO4S: C, 60.52; H, 6.87.
Found: C, 60.94; H, 7.24.
For 7: colorless crystals, mp 113-4 °C (from ether); IR (CHCl3,
cm-1) 3485; 1H NMR (300 MHz, CDCl3) δ 7.86-7.83 (m, 2 H), 7.55-
7.47 (m, 3 H), 6.14 (m, 2 H), 4.80 (br s, 1 H), 3.40 (d, J ) 13.8 Hz,
1 H), 3.35 (d, J ) 13.8 Hz, 1 H), 3.22 (s, 3 H), 3.22 (d, J ) 13.9 Hz,
1 H), 3.16 (s, 3 H), 2.84 (br s, 1 H), 2.59 (s, 3 H), 1.83 (dd, J ) 12.9,
3.7 Hz, 1 H), 1.39 (d, J ) 12.9 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
ppm 139.3, 135.9, 132.38, 132.36, 129.3, 128.9, 120.1, 78.4, 64.6, 53.6,
52.2, 49.5, 44.7, 40.2, 29.1; MS m/z (M+ - CH3) calcd 322.1113, obsd
322.1120; [R]2D2 -29.7 (c 0.62, CHCl3). Anal. Calcd for C17H23-
NO4S: C, 60.52; H, 6.87. Found: C, 60.58; H, 6.92.
(+)-(1R,4R)-7,7-Dimethoxybicyclo[2.2.1]hept-5-en-2-one ((+)-5).
A 1.50 g (4.6 mmol) sample of 6 was placed in a preheated (120 °C)
flask containing 1.53 g of finely powdered glass equipped with a short-
path distillation column. After evacuation to 0.1-0.3 Torr, the distillate
was collected in a cold (-78 °C) receiver and subjected to flash
chromatography on silica gel (elution with hexanes/ethyl acetate 4:1)
to give pure (+)-5 (0.59 g, 80%) as a colorless oil; [R]2D2 +596 (c
0.28, CHCl3).
B. By Way of Stannane 10b. Diisopropylamine (1.11 g, 11.0
mmol) was cooled to -78 °C and treated sequentially with n-
butyllithium (6.87 mL of 1.6 M, 11.0 mmol), dry THF (20 mL), and
tri-n-butyltin hydride (2.76 g, 9.5 mmol). After 30 min in the cold,
copper(I) cyanide (0.40 g, 4.5 mmol) was introduced, the suspension
was warmed slightly until the solid dissolved to give a yellow-green
solution, and the mixture was returned to -78 °C prior to the dropwise
addition of 9 (1.04 g, 3.0 mmol) dissolved in dry THF (5 mL). After
1 h, a saturated solution of NaHCO3 (50 mL) was added, and the
product was extracted into petroleum ether, dried, and concentrated.
Flash chromatography on the residue on silica gel (elution with 0.5%
triethylamine in petroleum ether) removed some but not all of the tin
impurities. This material (0.88 g, 1.81 mmol) in CH2Cl2 (10 mL) at
-78 °C was added to a solution of bromine in CH2Cl2 (7.24 mL of
0.25 M, 1.81 mmol) until the color of bromine just persisted. After
the workup described above, there was isolated 0.44 g (94%) of 11.
(1S,2R,4S)-2-[(S)-4-(tert-Butyldimethylsiloxy)-1-cyclopenten-1-yl]-
7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-ol (12). Cerium chloride
heptahydrate (0.89 g, 2.4 mmol) was dried at 140 °C under vacuum
for 2 h. After being cooled to room temperature, dry THF (10 mL)
was added. The slurry was stirred overnight and cooled to -78 °C
prior to introduction of the lithium reagent. A solution of (+)-11 (0.56
g, 2.0 mmol) in dry THF (10 mL) at -78 °C was treated dropwise
with tert-butyllithium (1.7 M in hexanes, 2.5 mL, 4.2 mmol), stirred
for 30 min, transferred via cannula to the cerium chloride slurry, and
stirred at -78 °C for another 30 min. To this solution was added (-)-5
(0.32 M in THF, 4.67 mL, 1.5 mmol), and the mixture was stirred at
-78 °C for 2 h, warmed to room temperature over 2 h, and agitated
overnight. After being returned to -78 °C, the reaction mixture was
treated with 10% acetic acid (20 mL) and diluted with petroleum ether
(50 mL). The aqueous layer was extracted with petroleum ether (50
mL), and the combined organic layers were washed with brine, dried,
and evaporated. The residue was purified by flash chromatography
on silica gel (elution with 20% ethyl acetate in petroleum ether) to
afford 12 (0.42 g, 76%), mp 34.5-36 °C; IR (CHCl3, cm-1) 3480; 1H
NMR (300 MHz, C6D6) δ 5.97 (ddd, J ) 6.1, 3.4, 1.0 Hz, 1 H), 5.91
(ddd, J ) 6.1, 3.4, 0.8 Hz, 1 H), 5.26 (t, J ) 1.9 Hz, 1 H), 4.57-4.51
(m, 1 H), 4.43 (s, 1 H), 3.23 (ddd, J ) 13.0, 5.8, 1.4 Hz, 1 H), 2.98 (s,
3 H), 2.96 (s, 3 H), 2.83 (br s, 1 H), 2.72 (br s, 1 H), 2.62-2.38 (m,
3 H), 1.90-1.79 (m, 2 H), 1.02 (s, 9 H), 0.12 (s, 3 H), 0.10 (s, 3 H);
13C NMR (75 MHz, C6D6) ppm 145.6, 135.8, 131.1. 123.0, 121.1,
79.4, 73.3, 54.3, 52.1, 49.0, 46.0, 43.2, 42.6, 39.1, 26.1, 18.3, -4.6,
(+)-(1S,4S)-7,7-Dimethoxybicyclo[2.2.1]hept-5-en-2-one ((-)-5).
A solution of 7 (2.40 g, 7.11 mmol) in deoxygenated toluene (150 mL)
was heated at reflux for 13 h, cooled, and carefully concentrated at 30
°C and 0.8 Torr. The residue was purified by chromatography on silica
gel (elution with hexane) to give (-)-5 (0.73 g, 61%) of (-)-6 as a
colorless oil; [R]2D2 -586 (c 0.27, CHCl3).
(-)-(S)-4-(tert-Butyldimethylsiloxy)-1-cyclopenten-1-yl Trifluo-
romethanesulfonate (9). To a solution of L-Selectride (1.0 M in THF,
14.1 mL, 14.1 mmol) in dry THF (110 mL) at -78 °C was added
dropwise a solution of (+)-8 (3.0 g, 14.1 mmol) and triethylamine (0.2
mL) in THF (50 mL) over 15 min. After 10 additional min,
N-phenyltriflimide (4.5 g, 12.6 mmol) was added in two portions. The
mixture was gradually warmed to room temperature, stirred for 3 h,
freed of THF in vacuo, and partitioned between petroleum ether (200
mL) and saturated NaHCO3 solution (100 mL) overnight. The aqueous
layer was extracted with petroleum ether (2 × 150 mL), the combined
organic layers were washed with brine, dried, and concentrated, and
the residue was purified by flash chromatography on silica gel (elution
with 1% triethylamine and 1% ethyl acetate in petroleum ether) to give
1
9 (4.1 g, 94%); IR (neat, cm-1) 1430, 1215, 1148, 1085; H NMR
(300 MHz, CDCl3) δ 5.54 (br t, J ) 2.2 Hz, 1 H), 4.57 (hept, J ) 3.8
Hz, 1 H), 2.82 (br dd, J ) 15.3, 7.3 Hz, 1 H), 2.69 (br dd, J ) 15.3,
7.3 Hz, 1 H), 2.55 (br d, J ) 16.3 Hz, 1 H), 2.34 (br d, J ) 16.3 Hz,
1 H), 0.89 (s, 9 H), 0.07 (s, 6 H); 13C NMR (75 MHz, CDCl3) ppm
146.5, 118.6 (q, JC-F ) 320.9, Hz), 115.3, 69.6, 41.2, 39.1, 25.7, 18.0,
-4.9; MS m/z (M+ - OSO2CF3) calcd 197.1362, obsd 197.1359;
[R]2D2 -1.69 (c 0.77, CHCl3). Anal. Calcd for C12H21F3O4SSi: C,
41.60; H, 6.11. Found: C, 41.83; H, 6.20.
(+)-[[(S)-3-Bromo-3-cyclopenten-1-yl]oxy]-tert-butyldimethylsi-
lane (11). A. Via 10a. A mixture of 9 (4.30 g, 12.4 mmol),
hexamethylditin (4.30 g, 13.0 mmol), Pd(PPh3)4 (0.25 g, 0.02 mmol),
and lithium chloride (4.02 g, 94 mmol) in dry THF (100 mL) was
refluxed under N2 for 3.5 h. Petroleum ether (300 mL) was added, the
mixture was washed with NaHCO3 solution (100 mL), the aqueous
layer was extracted with petroleum ether (2 × 200 mL), and the
-4.7; MS m/z (M+ - OCH3) calcd 335.2042, obsd 335.2067; [R]22
D
-138 (c 0.49, CHCl3). Anal. Calcd for C20H34O4Si: C, 65.53; H,
9.35. Found: C, 65.26; H, 9.26.
(2S,3aR,5aS,8aR,8bS)-2-(tert-Butyldimethylsiloxy)-2,3,3a,5,5a,6,-
8a,8b-octahydro-6,6-dimethoxy-as-indacen-4(1H)-one (13). A. Use
of Potassium Hydride. To a suspension of potassium hydride
(prewashed with hexane and dried under vacuum, 14 mg, 0.35 mmol)
in dry THF (30 mL) at -40 °C was added 12 (0.10 g, 0.27 mmol) in
one portion. The mixture was warmed to room temperature and stirred
for 3 h, cooled again in an ice-bath, and treated with water (1 mL) and
methanol (1 mL). The reaction mixture was stirred at room-temperature

Total Synthesis of Spinosyn A
J. Am. Chem. Soc., Vol. 120, No. 11, 1998 2549
overnight, diluted with hexane (100 mL), washed with brine, and dried.
Purification of the residue by flash chromatography on silica gel (elution
with 10% ethyl acetate in petroleum ether) afforded 13 (91 mg, 91%);
temperature for 5 h, diluted with CH2Cl2 (20 mL) and saturated NaHCO3
solution (10 mL), and stirred for another 30 min. The aqueous layer
was extracted with CH2Cl2 (2 × 10 mL), the combined organic layers
were washed with brine, dried, and concentrated, and the residue was
purified by chromatography on silica gel (elution with 50% ethyl acetate
in petroleum ether) to give 16a (48 mg, 84%); IR (neat, cm-1) 1700,
1647; 1H NMR (300 MHz, C6D6) δ 4.56 (d, J ) 6.8 Hz, 1 H), 4.42 (d,
J ) 6.8 Hz, 1 H), 4.14-4.10 (m, 1 H), 3.35-3.21 (m, 1 H), 3.15 (s,
3 H), 2.83 (q, J ) 8.8 Hz, 1 H), 2.61 (br d, J ) 16.5 Hz, 1 H), 2.45
(quint, J ) 8.0 Hz, 1 H), 2.19-2.10 (m, 1 H), 2.06 (t, J ) 4.6 Hz, 2
H), 1.92-1.67 (series of m, 4 H), 1.61-1.53 (m, 1 H), 1.17-1.08 (m,
1 H), 0.95 (s, 9 H), 0.05 (s, 6 H); 13C NMR (75 MHz, C6D6) ppm
206.0, 173.0, 135.6, 95.2, 75.5, 73.1, 55.2, 41.6, 40.3, 40.2, 39.9, 35.0,
28.0, 25.5, 18.2, -4.60, -4.64; MS m/z (M+) calcd 366.2226, obsd
366.2282; [R]2D2 -29.4 (c 0.47, CHCl3).
(5R,5aR,7S,8aS)-1,4,5,5a,6,7,8,8a-Octahydro-7-hydroxy-5-(meth-
oxymethoxy)-as-indacen-3(2H)-one (16b). To a solution of 16a (83
mg, 0.23 mmol) in acetonitrile (30 mL) was added a solution of 48%
aqueous hydrofluoric acid in acetonitrile (1.38 M, 1.64 mL, 2.26 mmol).
The mixture was stirred at room temperature for 0.5 h, quenched with
triethylamine (0.5 mL), and concentrated. Purification of the residue
by flash chromatography on silica gel (elution on ethyl acetate) afforded
16b (53 mg, 93%); IR (CHCl3, cm-1) 3550, 1692, 1644; 1H NMR (300
MHz, C6D6) δ 4.53 (d, J ) 6.8 Hz, 1 H), 4.40 (d, J ) 6.8 Hz, 1 H),
4.13-4.08 (m, 1 H), 3.33-3.21 (m, 1 H), 3.14 (s, 3 H), 2.83 (q, J )
8.6 Hz, 1 H), 2.60 (br d, J ) 16.4 Hz, 1 H), 2.45 (quint, J ) 8.1 Hz,
1 H), 2.18-2.08 (m, 1 H), 2.05 (t, J ) 4.6 Hz, 2 H), 1.92-1.67 (m, 5
H), 1.60-1.51 (m, 1 H), 1.16-1.07 (m, 1 H); 13C NMR (75 MHz,
C6D6) ppm 206.1, 173.0, 135.5, 95.2, 75.3, 72.0, 55.2, 41.6, 40.1, 39.8,
39.4, 35.0, 30.1, 25.4; MS m/z (M+) calcd 252.1361, obsd 252.1303;
[R]2D2 -44.7 (c 0.3, CHCl3).
1
IR (neat, cm-1) 1719; H NMR (300 MHz, C6D6) δ 5.86 (m, 1 H),
5.68 (m, 1 H), 4.06 (m, 1 H), 2.95 (s, 3 H), 2.92 (s, 3 H), 2.63-2.43
(m, 2 H), 2.17-1.92 (m, 2 H), 1.88-1.67 (m, 2 H), 1.51-1.21 (m, 4
H), 0.94 (s, 9 H), 0.03 (s, 3 H), 0.01 (s, 3 H); 13C NMR (75 MHz,
C6D6) ppm 209.4, 134.5, 133.1, 112.4, 73.0, 49.2, 48.5, 48.0, 44.4,
43.5, 41.4, 39.1, 38.0, 34.4, 26.0, 18.2, -4.6, -4.7; MS m/z (M+) calcd
336.2226, obsd 336.2253; [R]2D2 +46 (c 0.60, CHCl3). Anal. Calcd
for C20H34O4Si: C, 65.53; H, 9.35. Found: C, 65.79; H, 9.47.
B. With Sodium Hydride as Base. To a solution of 12 (0.21 g,
0.57 mmol) in THF (60 mL) at 0 °C was added sodium hydride (60%,
53 mg, 1.3 mmol). The mixture was refluxed for 4 h, cooled to -20
°C, and quenched with water (2 mL) and methanol (3 mL). The
identical workup delivered 0.16 g (77%) of 13 very reproducibly.
(3aS,5R,5aR,7S,8aS,8bR)-2-(tert-Butyldimethylsiloxy)-4,5,5a,6,7,8,-
8a,8b-octahydro-5-hydroxy-as-indacen-3(3aH)-one (14). Ketone 13
(0.11 g, 0.31 mmol) and 4 Å molecular sieves were mixed in CH2Cl2
(15 mL), stirred at room temperature for 30 min, and cooled to -78
°C. To this mixture was added dropwise a solution of DIBAL-H (0.62
mL, 0.62 mmol) in CH2Cl2 (5 mL). After 10 min, saturated NaHCO3
solution (0.5 mL) was added, and the mixture was stirred and filtered
through a pad of Celite and sodium sulfate, which was rinsed with
CH2Cl2. The filtrate was treated with p-toluenesulfonic acid (20 mg)
and water (1 mL), stirred for 10 min, washed with water and brine,
and then dried. Purification of the residue by flash chromatography
on silica gel (elution with 50% ethyl acetate in petroleum ether) gave
14 (51 mg, 51%), mp 103-4 °C (from ether); IR (CHCl3, cm-1) 3660,
1700; 1H NMR (300 MHz, CDCl3) δ 7.62 (dd, J ) 5.9, 2.5 Hz, 1 H),
6.30 (dd, J ) 5.9, 2.0 Hz, 1 H), 4.36-4.29 (m, 1 H), 3.61-3.54 (m,
1 H), 3.27-3.21 (m, 1 H), 2.56 (q, J ) 6.1 Hz, 1 H), 2.21-2.08 (m,
2 H), 1.94-1.68 (m, 3 H), 1.56-1.36 (m, 4 H), 0.86 (s, 9 H), 0.03 (s,
3 H), 0.02 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 212.1, 162.1,
134.4, 74.0, 72.4, 46.2, 43.9, 42.7, 41.3, 40.0, 38.4, 32.8, 25.8, 18.1,
-4.77, -4.80; MS m/z (M+) calcd 322.1964, obsd 322.1965; [R]2D2
-129 (c 0.4, CHCl3). Anal. Calcd for C18H30O3Si: C, 67.03; H, 9.38.
Found: C, 66.81; H, 9.37.
(1R,2S,4R)-2-[(S)-4-(tert-Butyldimethylsiloxy)-1-cyclopenten-1-yl]-
7,7-dimethoxybicyclo[2.2.2]hept-5-en-2-ol (17). To a solution of (+)-
11 (1.51 g, 5.4 mmol) in dry THF (50 mL) at -78 °C was added tert-
butyllithium (1.7 M in pentane, 7.6 mL, 13 mmol) during 10 min. This
solution was transferred via cannula to a slurry of dry cerium(III)
chloride (7.0 mmol) in THF (30 mL). The resulting deep orange
solution was stirred at -78 °C for 30 min, at which point a solution of
(+)-5 (0.60 g, 3.6 mmol) in dry THF (6 mL) was added dropwise at
-78 °C. The mixture was warmed to 20 °C overnight and cooled in
ice before being quenched with 20% acetic acid (50 mL). The separated
aqueous phase was extracted with petroleum ether (2 × 50 mL), and
the combined organic fractions were dried and evaporated. The residue
was purified by MPLC on silica gel (elution with 20% ethyl acetate in
petroleum ether) to give 17 (1.10 g, 86%) as a colorless oil which
solidified on standing, mp 68-69 °C; IR (CHCl3, cm-1) 3560, 1155,
(5R,5aR,7S,8aS)-7-(tert-Butyldimethylsiloxy)-1,4,5,5a,6,7,8,8a-oc-
tahydro-5-hydroxy-as-indacen-3(2H)-one (15). A slurry of 13 (20
mg, 0.05 mmol) and 4 Å molecular sieves (200 mg) in CH2Cl2 (10
mL) was stirred for 10 min and cooled to -78 °C. To the mixture
was added DIBAL-H (1 M in hexane, 0.11 mL, 0.11 mmol) dropwise.
The mixture was stirred at -78 °C for 1 h, quenched with saturated
NaHCO3 solution (2 mL), stirred at room temperature for 30 min, and
filtered through a Celite pad (CH2Cl2 rinse). The aqueous layer was
extracted with CH2Cl2 (2 × 20 mL), and the combined organic layers
were treated with p-toluenesulfonic acid monohydrate (100 mg, 0.520
mmol), shaken occasionally for 5-10 min, and neutralized with
saturated NaHCO3 solution (10 mL). The aqueous layer was extracted
with CH2Cl2 (2 × 10 mL), and the combined organic phases were
washed with brine, dried, and concentrated. The residue was dissolved
in methanol (3 mL), treated with potassium carbonate (50 mg), refluxed
for 2 h, and freed of methanol in vacuo. The residue was purified by
flash chromatography on silica gel (elution with 50% ethyl acetate in
petroleum ether) to afford 15 (11 mg, 60%) as white crystals, mp 104-5
1
1100; H NMR (300 MHz, CDCl3) δ 6.10 (m, 1 H), 5.86 (m, 1 H),
5.28 (m, 1 H), 4.48 (m, 1 H), 4.36 (s, 1 H), 3.33 (s, 3 H), 3.19 (s, 3 H),
2.95-2.92 (m, 1 H), 2.80-2.78 (m, 1 H), 2.57-2.40 (m, 3 H), 2.30-
2.21 (m, 1 H), 1.84 (dd, J ) 12.9, 0.8 Hz, 1 H), 1.77 (dd, J ) 12.9,
3.4 Hz, 1 H), 0.87 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H); 13C NMR (75
MHz, CDCl3) ppm 144.4, 135.4, 131.5, 123.5, 120.6, 78.8, 72.9, 54.0,
52.3, 49.5, 45.4, 42.6, 42.0, 38.4, 25.9, 18.1, -4.7, -4.8; MS m/z (M+)
calcd 366.2227, obsd 366.2218.
(2S,3aS,5aR,8aS,8bR)-2-(tert-Butyldimethylsiloxy)-2,3,3a,5,5a,6,-
8a,8b-Octahydro-6,6-dimethoxy-as-indacen-4(1H)-one (18). Sodium
hydride (60% in mineral oil, 0.33 g, 8.4 mmol) was added in one portion
to a solution of 17 (1.80 g, 4.9 mmol), in dry THF (150 mL) at 0 °C.
The solution was refluxed for 2 h, cooled to 20 °C, diluted with
petroleum ether (200 mL), and extracted with NaHCO3 solution (2 ×
100 mL) and brine (2 × 100 mL) prior to drying and concentration.
The resulting brown oil was purified by MPLC on Florisil (10% ethyl
acetate in petroleum ether as eluent) to yield 18 (1.39 g, 77%) as a
1
°C (from petroleum ether); IR (CHCl3, cm-1) 3600, 1688, 1640; H
NMR (300 MHz, C6D6) δ 4.16-4.11 (m, 1 H), 3.32-3.27 (m, 1 H),
2.88-2.85 (m, 1 H), 2.54 (br d, J ) 14.0 Hz, 1 H), 2.30-2.24 (m, 1
H), 2.11-1.62 (series of m, 9 H), 1.18-1.10 (m, 1 H), 0.96 (s, 9 H),
0.05 (s, 6 H); 13C NMR (75 MHz, C6D6) ppm 206.8, 173.9, 135.9,
73.2, 69.9, 43.5, 40.5, 39.8, 35.1, 28.8, 28.2, 26.1, 26.0, 18.2, -4.58,
-4.64; MS m/z (M+) calcd 322.1964, obsd 322.1955; [R]2D2 -11.2 (c
0.25, CHCl3). Anal. Calcd for C20H30O3Si: C, 67.03; H, 9.38.
Found: C, 66.75; H, 9.30.
1
colorless oil; IR (film, cm-1) 1720; H NMR (300 MHz, CDCl3) δ
5.98 (dd, J ) 6.1, 1.8 Hz, 1 H), 5.68 (dd, J ) 6.1, 2.6 Hz, 1 H), 4.13
(m, 1 H), 3.02 (s, 3 H), 2.98 (s, 3 H), 2.89 (m, 1 H), 2.62 (dd, J )
17.4, 2.6 Hz, 1 H), 2.49 (m, 1 H), 2.33-1.96 (m, 5 H), 1.63 (m, 1 H),
1.21 (m, 1 H), 1.00 (s, 9 H), 0.011 (s, 3 H), 0.013 (s, 3 H); 13C NMR
(75 MHz, CDCl3) ppm 212.1, 135,3, 132.4, 112.0, 72.3, 49.5, 48.8,
48.6, 44.0, 43.1, 40.2, 38.9, 38.2, 34.7, 25.8, 18.0, -4.7, -4.8; MS
m/z (M+ - OMe) calcd 335.2042, obsd 335.2049.
(5R,5aR,7S,8aS)-7-(tert-Butyldimethylsiloxy)-1,4,5,5a,6,7,8,8a-oc-
tahydro-5-(methoxymethoxy)-as-indacen-3(2H)-one (16a). Hydroxy
ketone 15 (50 mg, 0.15 mmol) was dissolved in Hunig’s base (2 mL)
and cooled to 0 °C. Chloromethyl methyl ether (0.2 mL, 1.5 mmol)
was introduced dropwise, and the mixture was stirred at room

2550 J. Am. Chem. Soc., Vol. 120, No. 11, 1998
Paquette et al.
(3aR,5S,5aS,7S,8aR,8bS)-7-(tert-Butyldimethylsiloxy)-4,5,5a,6,7,8,-
8a,8b-octahydro-5-(methoxymethoxy)-as-indacen-3(3aH)-one (19).
Diisobutyl aluminum hydride (1 M in hexanes, 5 mL, 5 mmol) was
added over 5 min to a solution of 18 (0.33 g, 0.91 mmol) in dry hexanes
(50 mL) at -78 °C. After 10 min, saturated potassium sodium tartrate
solution (20 mL) was added, and the reaction mixture was allowed to
warm to 20 °C, stirred for 6 h, washed with water (50 mL), 10%
aqueous acetic acid (3 × 50 mL), and brine (100 mL), and finally dried
and evaporated. The residue was purified by MPLC on silica gel
(elution with 50% petroleum ether in ethyl acetate) to give the hydroxy
Methyl (3aR,5S,5aS,7S,8aS,8bS)-7-(tert-Butyldimethylsiloxy)-1,-
3a,4,5,5a,6,7,8,8a,8b-decahydro-5-(methoxymethoxy)-as-indacene-
3-acetate (22). A solution of trimethyl phosphonoacetate (0.68 g, 3.73
mmol) in dry THF (20 mL) was added via cannula to a flame-dried
flask containing 0.14 g (3.3 mmol) of sodium hydride. After 20 min
of stirring, this solution was added to a solution of 21 (0.46 g, 1.24
mmol) in THF (15 mL) at 30-40 °C, kept at this temperature for 1 h,
and then refluxed for 3 h. The reaction mixture was quenched by the
careful addition of 5 mL of water. The separated aqueous layer was
extracted with ether (50 mL x 4), and the combined extracts were
washed with aqueous NaHCO3 solution (10 mL) and brine (10 mL)
prior to drying and concentration. The residue was purified by
chromatography on silica gel (elution with hexanes-ethyl acetate, 8:1)
to provide 0.45 g (85%) of R,â-unsaturated esters as an oily liquid.
A solution of diisopropylamine (1.5 mL, 10.6 mmol) in dry THF
(20 mL) was cooled to -15 °C, treated with a solution of n-butyllithium
in hexanes (6.3 mL, 1.6 M, 10.1 mmol), stirred for 15 min at -15 °C,
and cooled to -78 C. To this solution was added a solution of the
above esters (430 mg, 1.0 mmol) in THF (20 mL). Stirring was
maintained for 30 min before quenching with saturated NH4Cl solution
(5 mL). The mixture was extracted with ether (4 × 15 mL), and the
combined ether extracts were washed with aqueous NaHCO3 solution
(5 mL) and brine (5 mL). The ethereal solution was dried and
evaporated to leave a crude product which was purified by chroma-
tography on silica gel (hexanes-ethyl acetate 8:1 as eluent) to yield
1
ketone (0.27 g, 92%) as a colorless oil; IR (CHCl3, cm-1) 1695; H
NMR (300 MHz, CDCl3) δ 7.55 (dd, J ) 5.8, 2.5 Hz, 1 H), 6.26 (dd,
J ) 5.8, 2.0 Hz, 1 H), 4.25 (m, 1 H), 3.68 (m, 1 H), 3.28 (m, 1 H),
2.56 (m, 1 H), 2.34 (m, 1H), 2.23-2.10 (m, 2 H), 1.84-1.72 (m, 2 H),
1.72 (br s, 1 H), 1.55 (m, 1 H), 1.28 (m, 1 H), 1.06 (m, 1 H), 0.87 (s,
9 H), 0.03 (s, 6 H); 13C NMR (75 MHz, CDCl3) ppm 210.6, 160.9,
134.2, 73.4, 72.3, 46.0, 45.4, 42.5, 41.3, 40.3, 38.3, 33.5, 26.1, 18.3,
-4.5, -4.7; MS m/z (M+) calcd 322.1964, obsd 322.1969.
Methoxymethyl chloride (350 µL, 5 mmol) was added dropwise to
a solution of the hydroxy ketone (0.28 g, 0.86 mmol) dissolved in
diisopropylethylamine (3 mL) and CH2Cl2 (2 mL). After 18 h of
stirring, saturated NaHCO3 solution was introduced. After 30 min, the
separated organic layer was washed with water and brine prior to drying
and solvent evaporation. The residue was purified by MPLC on silica
gel (30% ethyl acetate in petroleum ether as eluent) to give 19 (0.23 g,
71%) as a colorless oil; IR (CHCl3, cm-1) 1695; 1H NMR (300 MHz,
CDCl3) δ 7.52 (dd, J ) 5.8, 2.4 Hz, 1 H), 6.22 (dd, J ) 5.8, 2.1 Hz,
1 H), 4.65 (d, J ) 7.0 Hz, 1 H), 4.51 (d, J ) 7.0 Hz, 1 H), 4.24 (m,
1 H), 3.61 (m, 1 H), 3.31 (s, 3 H), 3.26 (m, 1 H), 2.51 (m, 1 H), 2.32
(m, 1 H), 2.19-2.03 (m, 2H), 1.83 (m, 1 H), 1.73 (m, 1 H), 1.58 (m,
1 H), 1.31-1.13 (m, 2 H), 0.85 (s, 9 H), 0.02 (s, 3 H), 0.01 (s, 3 H);
13C NMR (75 MHz, CDCl3) ppm 211.0, 161.8, 134.4, 94.5, 78.0, 71.8,
55.1, 45.2, 43.1, 42.6, 41.1, 40.0, 38.1, 29.5, 25.8, 18.0, -4.8, -4.8;
MS m/z (M+) calcd 366.2226, obsd 366.2173. Anal. Calcd for
C20H34O4Si: C, 65.53; H, 9.36. Found: C, 65.55; H, 9.29.
1
0.40 g (93%) of 22 as a colorless oil; IR (film, cm-1) 1743; H NMR
(300 MHz, CDCl3) δ 5.47 (br s, 1 H), 4.74 (d, J ) 6.8 Hz, 1 H), 4.64
(d, J ) 6.8 Hz, 1 H), 4.29 (m, 1 H), 3.68 (s, 3 H), 3.56 (m, 1 H), 3.38
(s, 3 H), 3.10 (m, 2 H), 2.76 (m, 1 H), 2.40 (m, 1 H), 2.25 (m, 1 H),
2.08-2.01 (m, 5 H), 1.81 (m, 1 H), 1.65 (m, 1 H), 1.34 (m, 1 H), 1.01
(m, 1 H), 0.87 (s, 9 H), 0.03 (s, 6 H); 13C NMR (75 MHz, CDCl3)
ppm 171.9, 139.6, 126.6, 95.2, 77.7, 72.9, 55.3, 51.7, 44.3, 42.5, 41.7,
40.5, 40.0, 39.8, 36.7, 35.2, 31.7, 25.9, 18.1, -4.8; MS m/z (M+ - H)
calcd 423.2536, obsd 423.2533. Anal. Calcd for C23H40O5Si: C, 65.05;
H, 9.49. Found: C, 65.17; H, 9.47.
(3aR,5S,5aS,7S,8aS,8bS)-7-(tert-Butyldimethylsiloxy)-1,3a,4,5,-
5a,6,7,8,8a,8b-decahydro-5-(methoxymethoxy)-as-indacene-3-etha-
nol (23). To a suspension of lithium aluminum hydride (0.11 g, 2.8
mmol) in dry ether (20 mL) was added a solution of 22 (0.40 g, 0.95
mmol) in 20 mL of ether at 0 °C. The mixture was stirred for 10 min,
quenched with wet ether (20 mL), treated with saturated Rochelle salt
solution (10 mL), agitated vigorously, and extracted with ether. The
combined ethereal phases were washed with NaHCO3 solution and
brine, dried, and concentrated. The crude product was purified by
chromatography on silica gel (elution with hexanes-ethyl acetate 1:1)
to give 360 mg (97%) of 23 as a colorless oil; IR (film, cm-1) 3439;
1H NMR (300 MHz, CDCl3) δ 5.42 (m, 1 H), 4.73 (d, J ) 6.8 Hz, 1
H), 4.64 (d, J ) 6.8 Hz, 1 H), 4.65 (m, 2 H), 4.60 (m, 2 H), 3.95 (m,
1H), 3.66 (m, 2 H), 2.70 (m, 2 H), 2.5-1.8 (series of m, 7 H), 1.7-1.0
(series of m, 6 H), 0.88 (s, 9 H), 0.04 (s, 6 H); MS m/z (M+) calcd
396.2699, obsd 396.2708.
tert-Butyl[[(2S,3aS,4S,5aR,8aS,8bS)-1,2,3,3a,4,5,5a,8,8a,8b-decahy-
dro-6-[2-[(p-methoxybenzyl)oxy]ethyl]-4-(methoxymethoxy)-as-in-
dacen-2-yl]oxy]dimethylsilane (24). A solution of 23 (0.29 g, 0.73
mmol) in DMF/THF (1.1 v/v, 8 mL) was added to a flask containing
sodium hydride (37 mg of 60% mineral oil dispersion, 0.92 mmol) at
-20 °C. After 15 min at 0 °C, p-methoxybenzyl chloride (0.27 g, 1.7
mmol) was introduced in one portion, and the reaction mixture was
allowed to stir overnight at room temperature, warmed to 40 °C, stirred
for 2 h, cooled in an ice-water bath, and quenched with water (2 mL).
Diethylamine (2.0 mL) was added to destroy the excess p-methoxy-
benzyl chloride. The mixture was stirred at 0 °C for an additional 1 h
and diluted with ether (50 mL). The ethereal solution was washed
with water and brine. After drying and concentration, the crude product
was chromatographed on silica gel (hexanes-ethyl acetate 8:1 as eluent)
to provide 0.37 g (99%) of 24 as a colorless oil; IR (film, cm-1) 1248,
1172, 1100, 1040; 1H NMR (300 MHz, CDCl3) δ 7.27 (m, 2 H), 6.89
(m, 2 H), 5.30 (br s, 1 H), 4.73 (d, J ) 6.8 Hz, 1 H), 4.64 (d, J ) 6.8
Hz, 1 H), 4.45 (m, 2 H), 4.21 (m, 1 H), 3.81 (s, 2 H), 3.80 (s, 3 H),
3.55 (m, 1 H), 3.38 (s, 3 H), 2.51-2.17 (series of m, 2 H), 2.11-1.99
(m, 8 H), 1.81 (m, 1 H), 1.65 (m, 1 H), 1.28 (m, 1 H), 1.01 (m, 1 H),
(5S,5aS,7S,8aR)-7-(tert-Butyldimethylsiloxy)-1,4,5,5a,6,7,8,8a-oc-
tahydro-5-(methoxymethoxy)-as-indacen-3(2H)-one (20). A mixture
of 19 (0.23 g, 0.61 mmol) and potassium carbonate (20 mg) in methanol
(25 mL) was refluxed for 2 h, cooled, and freed of solvent. The residue
was dissolved in CH2Cl2 (25 mL), rinsed with water (5 mL) and brine
(2 × 10 mL), dried, evaporated, and purified by MPLC on silica gel
(50% ethyl acetate in petroleum ether as eluent) to give 20 (0.18 g,
78%) as a colorless oil; IR (CHCl3, cm-1) 1690, 1650; 1H NMR (300
MHz, CDCl3) δ 4.70 (d, J ) 6.9 Hz, 1 H), 4.64 (d, J ) 6.9 Hz, 1 H),
4.30 (m, 1 H), 3.85 (m, 1 H), 3.36 (s, 3 H), 2.86 (m, 1 H), 2.61-2.07
(series of m, 9 H), 1.59 (m, 1 H), 1.43 (m, 1 H), 0.83 (s, 9 H), 0.02 (s,
6 H); 13C NMR (75 MHz, CDCl3) ppm 207.7, 175.1, 134.6, 95.2, 74.1,
73.0, 55.5, 41.7, 39.7, 39.5, 38.5, 34.9, 28.2, 25.7, 23.9, 18.0, -4.8,
-4.9; MS m/z (M+) calcd 366.2226, obsd 366.2294. Anal. Calcd for
C20H34O4Si: C, 65.53; H, 9.36. Found: C, 65.26; H, 9.32.
(3aR,5S,5aS,7S,8aS,8bS)-7-(tert-Butyldimethylsiloxy)decahydro-
5-(methoxymethoxy)-as-indacen-3(2H)-one (21). A solution of 20
(0.20 g, 0.53 mmol) in dry THF (5 mL) containing tert-butyl alcohol
(40 µL, 0.41 mmol) was added dropwise over 3 min to a solution of
liquid ammonia (20 mL) containing lithium wire (40 mg, excess) at
-33 °C. After 3 min, isoprene (0.5 mL) was introduced followed by
solid ammonium chloride (2 g) and saturated NH4Cl solution (5 mL).
The reaction mixture was allowed to warm to 20 °C over 4 h and the
aqueous residue was extracted with ether (3 × 10 mL). The combined
organic phases were washed with water (10 mL) and brine (2 × 10
mL) prior to drying. The solvent was evaporated, and the residue was
purified by MPLC on silica gel (20% ethyl acetate in petroleum ether
as eluent) to give 21 (0.12 g, 62%) as a colorless oil; IR (CHCl3, cm-1
)
1
1740; H NMR (300 MHz, CDCl3) δ 4.71 (d, J ) 6.8 Hz, 1 H), 4.60
(d, J ) 6.8 Hz, 1 H), 4.26 (m, 1 H), 3.65 (m, 1 H), 3.35 (s, 3 H),
2.43-1.81 (series of m, 11 H), 1.71-1.64 (m, 1 H), 1.49-1.37 (m, 2
H), 0.88 (s, 9 H), 0.04 (s, 6 H); 13C NMR (75 MHz, CDCl3) ppm 220.4,
95.4, 75.7, 72.6, 55.4, 46.5, 42.1, 41.9, 39.4, 37.8, 35.9, 26.9, 25.9,
25.5, 18.0, -4.8; MS m/z (M+) calcd 368.2383, obsd 368.2335. Anal.
Calcd for C20H36O4Si: C, 65.18; H, 9.85. Found: C, 65.24; H, 9.84.

Total Synthesis of Spinosyn A
J. Am. Chem. Soc., Vol. 120, No. 11, 1998 2551
0.88 (s, 9 H), 0.04 (s, 6 H); 13C NMR (75 MHz, CDCl3) ppm 159.2,
144.4, 130.6, 129.4, 129.2, 122.9, 113.8, 95.3, 78.0, 72.9, 72.5, 68.6,
55.2, 44.7, 43.0, 41.9, 40.4, 40.1, 39.9, 36.8, 32.2, 29.6, 25.9, 18.1,
-4.8; MS m/z (M+) calcd 516.3271, obsd 516.3254.
2 H), 2.16-2.08 (m, 2 H), 1.99-1.68 (series of m, 6 H), 1.64-1.54
(m, 4 H), 1.51-1.36 (m, 3 H), 1.04 (s, 9 H), 0.87 (s, 9 H), 0.74 (m, 1
H), 0.021 (s, 3 H), 0.016 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
159.1, 135.9, 134.8, 134.4, 130.8, 129.51, 129.46, 129.1, 127.51, 127.46,
113.8, 78.8, 72.6, 72.3, 71.7, 69.3, 55.3, 50.6, 43.2, 42.0, 41.6, 39.06,
39.05, 38.8, 37.6, 31.9, 28.6, 27.1, 25.9, 19.2, 18.0, -4.8; MS m/z (M+)
calcd 728.9429, obsd 728.9464.
(2R,3R,3aR,5S,5aS,7S,8aS,8bS)-7-(tert-Butyldimethylsiloxy)-
dodecahydro-3-[2-[(p-methoxybenzyl)oxy]ethyl]-5-(methoxymethoxy)-
as-indacen-2-ol (25). To a cooled (-30 °C) mixture of 24 (31 mg,
0.06 mmol) and lithium borohydride (26 mg, 1.2 mmol) in THF (1.0
mL) was added dropwise a solution of BH3‚THF (1 M solution in THF,
1.2 mL, 1.2 mmol, 20 equiv) in THF. The reaction mixture was stirred
at -20 to -30 °C for 4.5 h, quenched with careful addition of 0.2 mL
of water at -20 °C, and allowed to warm to 20 °C. To this white
slurry was added 0.2 mL of premixed 1:1 (v/v) of 3 N sodium hydroxide
and 30% hydrogen peroxide at room temperature. The mixture was
stirred for an additional 1 h, diluted with 5 mL of water, and extracted
with ethyl acetate (5 × 15 mL). The combined extracts were washed
with NaHCO3 solution and brine, dried, and freed of solvent. The crude
product was purified on a silica gel column (hexanes/ethyl acetate 1:1
as eluent) to obtain 22 mg (72%) of major component 25 as an oily
(2S,3aS,5aR,6R,7S,8aR,8bS)-2-(tert-Butyldimethylsiloxy)-7-(tert-
butyldiphenylsiloxy)decahydro-6-[2-[(p-methoxybenzyl)oxy]ethyl]-
as-indacen-4(1H)-one (28). To a solution of 27 (19 mg, 0.026 mmol)
in dry CH2Cl2 (2.0 mL) was added a 3-fold excess of pyridinium
chlorochromate on alumina in small portions with stirring. After 2 h,
the brown suspension was passed through a Florisil column (elution
with CH2Cl2), and the colorless eluate was concentrated to dryness.
The residue was purified on silica gel (elution with hexanes-ethyl
acetate 5:1) to furnish 16 mg (86%) of pure 28 as a colorless oil; IR
1
(film, cm-1) 1712; H NMR (300 MHz, CDCl3) δ 7.67-7.64 (m, 4
H), 7.43-7.33 (m, 6 H), 7.21 (m, 2 H), 6.87 (m, 2H), 4.33 (ABq, J )
11.6 Hz, ∆ν ) 12.1 Hz, 2 H), 4.13 (m, 2 H), 3.81 (s, 3 H), 3.26 (t, J
) 7.1 Hz, 2 H), 2.61 (m, 1 H), 2.48 (m, 1 H), 2.39 (m, 1 H), 2.23-
2.17 (m, 2 H), 2.12-2.06 (m, 2 H), 2.01-1.80 (m, 4 H), 1.68-1.53
(m, 2 H), 1.46 (m, 1 H), 1.31 (m, 1 H), 1.05 (s, 9 H), 0.86 (s, 9 H),
0.03 (s, 3 H), 0.02 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 213.2,
159.1, 135.8, 134.4, 134.2, 130.6, 129.61, 129.56, 129.2, 127.6, 127.5,
113.8, 78.2, 72.5, 72.4, 69.0, 55.3, 50.1, 48.1, 43.4, 41.7, 39.6, 39.0,
38.8, 38.5, 35.3, 28.6, 27.0, 25.8, 19.2, 18.0, -4.8, -4.9; MS m/z (M+)
calcd 711.3921, obsd 711.3925.
(2S,3aR,5aR,6R,7R,8aR,8bS)-2-(tert-Butyldimethylsiloxy)-7-(tert-
butyldiphenylsiloxy)decahydro-6-[2-[(p-methoxybenzyl)oxy]ethyl]-
as-indacen-4(1H)-one (29). A flame-dried flask was charged with 6.3
mg of NaH (55% dispersion in mineral oil, 0.144 mmol) and a solution
of 78 mg (10.7 mmol) of 28 in THF. The suspension was allowed to
stir overnight, cooled to -78 °C, and quenched with 0.5 mL of aqueous
NH4Cl solution. The mixture was extracted with ether, and the
combined extracts were dried and concentrated. The residue was
purified by silica gel chromatography (elution with 3.2% of ethyl acetate
in benzene) to afford 24 mg (94%, based on unreacted 28, 35%
conversion) of the epimerized ketone with 53 mg (65% recovery) of
the starting material. The recovered 28 can easily be recycled.
For 29: 1H NMR (300 MHz, CDCl3) δ 7.67-7.64 (m, 4 H), 7.52-
7.28 (m, 6 H), 7.23 (m, 2 H), 6.87 (m, 2 H), 4.32 (ABq, J ) 11.6 Hz,
∆ν ) 12.0 Hz, 2 H), 3.95 (m, 2 H), 3.81 (s, 3 H), 3.29 (t, J ) 7.1 Hz,
2 H), 2.61-1.70 (series of m, 11 H), 1.69-1.10 (series of m, 4 H),
1.06 (s, 9 H), 0.86 (s, 9 H), 0.02 (s, 6 H); MS m/z (M+ - CH3) calcd
711.3921, obsd 711.3940.
(2R,3aS,5aR,6R,7R,8aS,8bR)-6-(tert-Butyldiphenylsiloxy)-1,2,3,-
3a,5a,6,7,8,8a,8b-decahydro-6-[2-[(p-methoxybenzyl)oxy]ethyl]-as-
indacen-2-ol (30). To a cold (-78 °C) solution of 29 (65 mg, 0.09
mmol) in 15 mL of dry CH2Cl2 was added 0.91 mL (0.9 mmol) of 1.0
M DIBAL-H in hexanes. The resulting solution was stirred at -78
°C for 10 min, quenched with saturated NaHCO3 (2 mL) and saturated
sodium potassium tartrate solutions (5 mL), and warmed to 20 °C during
30 min. The separated aqueous layer was extracted with ethyl acetate
(4 × 20 mL). The combined organic layers were washed with 5 mL
of saturated sodium potassium tartrate solution and brine, passed through
a pad of magnesium sulfate, and concentrated in vacuo. The residue
was chromatographed on silica gel (elution with 25% ethyl acetate in
hexanes) to give 38 mg of the major R-alcohol and 15 mg of the minor
â-alcohol (83% total yield).
1
liquid; IR (film, cm-1) 3418; H NMR (300 MHz, CDCl3) δ 7.18 (m,
2 H), 6.81 (m, 2 H), 4.68 (d, J ) 6.7 Hz, 1 H), 4.61 (d, J ) 6.7 Hz,
1 H), 4.40 (m, 2 H), 4.22 (m, 1 H), 3.95 (m, 1 H), 3.74 (s, 3 H), 3.61
(m, 1 H), 3.47 (m, 2 H), 3.32 (s, 3 H), 2.19-1.61 (series of m, 14 H),
1.36 (td, J ) 12.6, 6.0 Hz, 1 H), 0.86 (m, 1 H), 0.81 (s, 9 H), 0.04 (s,
6 H); 13C NMR (75 MHz, CDCl3) ppm 159.4, 129.5, 114.0, 99.7, 96.1,
78.0, 77.3, 76.8, 73.0, 72.4, 70.5, 55.4, 55.2, 53.3, 42.0, 41.3, 40.9,
39.2, 38.7, 38.2, 30.1, 29.5, 25.9, 18.1, -4.75, -4.80; MS m/z (M+)
calcd 534.3377, obsd 534.3389. Anal. Calcd for C30H50O6Si: C, 67.38;
H, 9.42. Found: C, 67.42; H, 9.41.
tert-Butyl[[(2R,3R,3aR,5S,5aS,7S,8aSS,8bS)-7-(tert-butyldimeth-
ylsiloxy)dodecahydro-3-[2-[(p-methoxybenzyl)oxy]ethyl]-5-(meth-
oxymethoxy)-as-indacen-2-yl]oxy]diphenylsilane (26). A solution of
25 (0.50 g, 0.94 mmol), imidazole (0.32 g, 4.68 mmol), and DMAP
(55 mg, 0.45 mmol) in 15 mL of dry CH2Cl2 was stirred for 15 min at
0 °C, treated with tert-butyldiphenylsilyl chloride (0.69 g, 2.3 mmol),
stirred at 0 °C overnight, quenched with 0.8 mL of absolute ethanol,
and after 1 h poured into 10 mL of cold (0 °C) NaHCO3 solution. The
separated aqueous phase was extracted with CH2Cl2, and the combined
organic extracts were washed with water (5 mL) and brine (5 mL).
After drying and removal of solvent, the crude product was purified
by chromatography on silica gel (elution with hexanes-ethyl acetate
6:1) to yield 0.70 g (96%) of 26 as a colorless oil; IR (film, cm-1
)
1472, 1248, 1110; 1H NMR (300 MHz, CDCl3) δ 7.71-7.64 (m, 4 H),
7.45-7.36 (m, 6 H), 7.26-7.21 (m, 2 H), 6.90-6.85 (m, 2 H), 4.63
(ABq, J ) 6.7 Hz, ∆ν ) 20.4 Hz, 2 H), 4.37 (ABq, J ) 11.5 Hz, ∆ν
) 14.0 Hz, 2 H), 4.25 (m, 1 H), 4.06 (m, 1 H), 3.81 (s, 3 H), 3.49 (m,
1 H), 3.41 (t, J ) 6.8 Hz, 2 H), 3.35 (s, 3 H), 2.21-1.42 (series of m,
12 H), 1.29-1.26 (m, 2 H), 1.05 (s, 9 H), 0.87 (s, 9 H), 0.84 (m, 1 H),
0.02 (s, 6 H); 13C NMR (75 MHz, CDCl3) ppm 159.1, 135.9, 134.4,
130.8, 129.50, 129.46, 129.1, 127.51, 127.47, 113.8, 95.7, 78.8, 78.0,
72.5, 72.3, 69.5, 55.4, 55.3, 50.6, 41.9, 41.7, 41.4, 39.3, 39.0, 38.8,
37.5, 29.0, 28.7, 27.1, 25.9, 18.1, 14.1, -4.7, -4.8; MS m/z (M+) calcd
772.4554, obsd 772.4538. Anal. Calcd for C46H68O6Si2: C, 71.46;
H, 8.86. Found: C, 71.64; H, 8.99.
(2S,3aS,4S,5aR,6R,7R,8aS,8bS)-2-(tert-Butyldimethylsiloxy)-7-
(tert-butyldiphenylsiloxy)dodecahydro-6-[2-[(p-methoxybenzyl)oxy]-
ethyl]-as-indacen-4-ol (27). A solution of 26 (39 mg, 0.05 mmol) in
12 mL of dry CH2Cl2 was cooled to -78 °C and treated with a solution
of B-bromocatecholborane in CH2Cl2 (0.47 mL of 0.194 M, 0.09 mmol).
The reaction mixture was stirred at -78 °C for 15 min, quenched with
2 mL of saturated NaHCO3 solution at -78 °C, allowed to warm to 20
°C, and diluted with 2 mL of 0.2 N sodium hydroxide. The separated
aqueous layer was extracted with CH2Cl2, and the combined organic
extracts were washed with 0.1 N aqueous sodium hydroxide, water,
and brine prior to drying and concentration. The crude product was
purified by chromatography on silica gel (elution with hexanes-ethyl
acetate 2:1) to furnish 19 mg (51%) of 27 as a colorless oil; IR (film,
For the R-alcohol: IR (film, cm-1) 3449; 1H NMR (300 MHz,
CDCl3) δ 7.66-7.63 (m, 4 H), 7.39-7.34 (m, 6 H), 7.23-7.20 (m, 2
H), 6.88-6.85 (m, 2 H), 4.35 (ABq, J ) 11.5 Hz, ∆ν ) 11.5 Hz, 2
H), 4.20 (m, 1 H), 3.96 (m, 2 H), 3.80 (s, 3 H), 3.35 (t, J ) 6.7 Hz, 2
H), 2.09 (m, 2H), 1.95 (m, 3 H), 1.74 (m, 4 H), 1.49 (m, 3 H), 1.33-
1.16 (m, 3 H), 1.04 (s, 9 H), 0.88 (m, 1 H), 0.86 (s, 9 H), 0.01 (s, 6 H);
13C NMR (75 MHz, CDCl3) ppm 159.1, 135.9, 134.6, 134.4, 130.6,
129.6, 129.5, 129.2, 128.1, 127.8, 127.52, 127.50, 113.8, 79.0, 74.1,
72.6, 72.3, 69.7, 55.3, 48.8, 48.6, 47.8, 42.8, 42.0, 40.4, 39.6, 38.6,
34.3, 30.5, 27.0, 25.9, 19.1, 18.1, -4.8.
1
cm-1) 3426, 1611, 1513, 1249, 1110; H NMR (300 MHz, CDCl3) δ
7.66-7.44 (m, 4 H), 7.42-7.32 (m, 6 H), 7.25-6.89 (m, 2 H), 6.88-
6.86 (m, 2 H), 4.36 (ABq, J ) 11.6 Hz, ∆ν ) 16.4 Hz, 2 H), 4.21 (m,
1 H), 4.05 (m, 1 H), 3.81 (s, 3 H), 3.57 (m, 1 H), 3.41 (t, J ) 7.0 Hz,
Martin’s sulfurane (70 mg) was suspended in 4 mL of dry CH2Cl2,
and the suspension was treated with 38 mg (0.05 mmol) of the R-alcohol

2552 J. Am. Chem. Soc., Vol. 120, No. 11, 1998
Paquette et al.
dissolved in 5 mL of dry CH2Cl2. The resulting mixture was stirred
for 1 h before being quenched with saturated NaHCO3 solution (1.5
mL), diluted with ether (25 mL), and washed with saturated NaHCO3
solution (2 × 5 mL). The organic phase was dried and concentrated
to provide a residue which was chromatographed on silica gel (elution
with 14% of ethyl acetate in hexanes) to give the dehydration product,
which was dissolved in 0.4 mL of THF and treated with 0.4 mL of
water, followed by 1.2 mL of acetic acid. The cloudy solution was
stirred overnight, cooled in an ice bath, basified with powdered sodium
bicarbonate, and extracted with ethyl acetate (6 × 15 mL). The
combined organic extracts were washed with brine, dried, and
evaporated. The residue was purified by flash chromatography (silica
gel, elution with 33% ethyl acetate in hexanes) to give 16 mg (54%
over two steps) of 30 as a colorless oil; IR (film, cm-1) 3380; 1H NMR
(300 MHz, CDCl3) δ 7.74-7.63 (m, 4 H), 7.55-7.28 (m, 6 H), 7.24-
6.80 (m, 4 H), 5.88 (m, 1 H), 5.63 (m, 1 H), 4.35 (m, 1 H), 4.22 (br
s, 2 H), 4.11 (m, 1 H), 3.79 (s, 3 H), 3.22 (m, 1 H), 2.99 (t, J ) 9.3
Hz, 2 H), 2.96-2.08 (m, 4 H), 2.05-1.89 (m, 3 H), 1.79 (m, 1 H),
1.71-1.37 (m, 4 H), 1.26 (br s, 1 H), 1.05 (s, 9 H); MS m/z (M+)
calcd 596.8822, obsd 596.8814.
(2R,3aS,5aR,6S,8aS,9bS)-1,2,3,3a,5a,6,7,8,8a,8b-Decahydro-6-[2-
[(p-methoxybenzyl)oxy]ethyl]-7-oxo-as-indacen-2-yl Pivalate (34).
To a solution of 11 mg (0.025 mmol) of 32 in 2.5 mL of dry CH2Cl2
was added 5 equiv of pyridinium chlorochromate on alumina. The
resulting suspension was stirred at 0 °C overnight, passed through a
short silica gel column (elution with ethyl acetate), and evaporated in
vacuo. The residue was purified by chromatography on silica gel
(elution with 25% ethyl acetate in hexanes) to give 9 mg of ketone 33
as a colorless oil; IR (film, cm-1) 1723; 1H NMR (300 MHz, C6D6) δ
7.28-7.21 (m, 2 H), 6.82-6.79 (m, 2 H), 5.73 (d, J ) 10.0 Hz, 1 H),
5.42 (dt, J ) 10.0, 3.3 Hz, 1 H), 5.07 (m, 1 H), 4.39 (ABq, J ) 11.6
Hz, ∆ν ) 8.4 Hz, 2 H), 3.61 (td, J ) 6.5, 1.3 Hz, 1 H), 3.57 (m, 1 H),
3.30 (s, 3 H), 2.65 (m, 1 H), 2.26 (m, 2 H), 2.01-1.92 (m, 4 H), 1.80-
1.70 (m, 3 H), 1.21 (m, 1 H), 1.15 (s, 9 H), 0.88 (td, J ) 12.4, 4.8 Hz,
1 H), 0.71 (m, 1 H); MS m/z (M+) calcd 440.2563, obsd 440.2552.
The above ketone was dissolved in 2.5 mL of dry methanol, treated
with a crystal of K2CO3, heated to reflux for 1 h, and cooled to 20 °C.
The solution was diluted with 5 mL of ethyl acetate, passed through a
silica gel plug to remove potassium carbonate, and evaporated. The
residue was purified by chromatography on silica gel (elution with 25%
ethyl acetate in hexanes) to return 6 mg of 33 and give 2 mg of 34
(70% combined recovery) as a colorless oil; IR (CH2Cl2, cm-1) 1732,
(2R,3aS,5aR,6R,7R,8aS,8aR)-7-(tert-Butyldiphenylsiloxy)-1,2,3,-
3a,5a,6,7,8,8a,8b-decahydro-6-[2-[(p-methoxybenzyl)oxy]ethyl]-as-
indacen-2-yl Pivalate (31). To a cold (0 °C) solution of 30 (16 mg,
0.03 mmol) and 2 mg of DMAP in 0.8 mL of pyridine was added neat
pivaloyl chloride (20 mg). The resulting mixture was stirred overnight
at 0 °C, quenched with absolute ethanol (0.05 mL), poured into saturated
NaHCO3 solution, and extracted with ether (4 × 15 mL). The combined
organic layers were dried and evaporated to leave a residue, which
was purified by flash chromatography on silica gel to furnish 18 mg
1
1716; H NMR (300 MHz, C6D6) δ 7.29-7.25 (m, 2 H), 6.87-6.82
(m, 2 H), 5.72 (s, 2 H), 5.19-5.12 (m, 1 H), 4.37 (s, 2 H), 3.67-3.54
(m, 2 H), 3.34 (s, 3 H), 2.34-2.28 (m, 1 H), 2.12-1.94 (m, 6 H),
1.91-1.76 (m, 3 H), 1.32 (td, J ) 7.6, 13.3 Hz, 1 H), 1.21 (s, 9 H),
0.96 (td, J ) 4.8, 12.3 Hz, 1 H), 0.74 (qd, J ) 11.8, 6.4 Hz, 1 H); 1H
NMR (300 MHz, CDCl3) δ 7.24 (d, J ) 8.7 Hz, 2 H), 6.87 (d, J ) 8.7
Hz, 2 H), 5.90 (d, J ) 9.8 Hz, 1 H), 5.80 (dt, J ) 9.8, 3.1 Hz, 1 H),
5.21-5.14 (m, 1 H), 4.41 (s, 2 H), 3.81 (s, 3 H), 3.60 (t, J ) 6.4 Hz,
2 H), 2.69-2.62 (m, 1 H), 2.47-2.31 (m, 3 H), 2.28-2.17 (m, 2 H),
2.09-1.99 (m, 1 H), 1.96-1.85 (m, 3 H), 1.63-1.52 (m, 1 H), 1.28-
1.15 (m, 2 H), 1.19 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm 219.3,
178.2, 159.1, 130.4, 129.6, 129.3, 129.2 (2 C), 113.7 (2 C), 74.2, 72.5,
67.3, 55.3, 50.4, 44.6, 43.1, 42.3, 41.7, 38.5, 38.3, 37.8, 36.8, 29.1,
27.1 (3 C); MS m/z (M+) calcd 440.2563, obsd 440.2557; [R]2D2 -30.8
(c 0.60, CH2Cl2). Anal. Calcd for C27H36O5‚0.5H2O: C, 72.12; H,
8.29. Found: C, 72.35; H, 8.12.
1
(97%) of 31 as a colorless oil; IR (film, cm-1) 1723; H NMR (300
MHz, CDCl3) δ 7.67-7.62 (m, 4 H), 7.43-7.28 (m, 6 H), 7.24-6.80
(m, 4 H), 5.98 (d, J ) 15 Hz, 1 H), 5.64 (dt, J ) 15, 4.2 Hz, 1 H),
5.09 (m, 1 H), 4.22 (s, 2 H), 4.07 (m, 1 H), 3.80 (s, 3 H), 3.28 (m, 1
H), 3.00 (t, J ) 11.0 Hz, 2 H), 2.33-2.23 (m, 2 H), 1.99-1.82 (m, 6
H), 1.58-1.34 (m, 4 H), 1.17 (s, 9 H), 1.05 (s, 9 H); MS m/z (M+)
calcd 681.0001, obsd 681.0026.
(2R,3aS,5aR,6R,7R,8aS,8bR)-1,2,3,3a,5a,6,7,8,8a,8b)-Decahydro-
7-hydroxy-6-[2-(p-methoxybenzyl)oxy]ethyl]-as-indacen-2-yl Piv-
alate (32). A solution of 31 (18 mg, 0.026 mmol) in 2.0 mL of dry
THF was treated with tetrabutylammonium fluoride (0.15 mL of 1 M
solution in THF, 0.15 mmol). The reaction mixture was stirred at 40
°C for 4 h, cooled in an ice bath, diluted with water (5 mL), and
extracted with ethyl acetate (5 × 15 mL). The combined organic layers
were dried and evaporated to leave a residue, which was purified by
flash chromatography (silica gel, elution with 50% of ethyl acetate in
Acknowledgment is made to the National Institutes of Health
and Eli Lilly and Company for financial support, Prof. Robin
Rogers for the X-ray analysis, Dr. Martyn Earle for early
experiments, and Dr. Kurt Loening for assistance with nomen-
clature.
hexanes) to give 11 mg (97%) of 32 as a colorless oil; IR (film, cm-1
)
3429, 1723; 1H NMR (200 MHz, CDCl3) δ 7.24-7.22 (m, 2 H), 6.90-
6.85 (m, 2 H), 5.87 (d, J ) 9.8 Hz, 1 H), 5.61 (dt, J ) 9.8, 2.9 Hz, 1
H), 5.13 (m, 1 H), 4.44 (s, 2 H), 3.97 (m, 1 H), 3.80 (s, 3 H), 3.57 (t,
J ) 5.6 Hz, 2 H), 3.53 (m, 1 H), 3.02 (m, 1 H), 2.40-2.34 (m, 2 H),
2.17 (m, 1 H), 2.04-1.73 (series of m, 6 H), 1.54 (m, 1 H), 1.41 (m,
1 H), 1.16 (s, 9 H), 0.99 (m, 1 H); MS m/z (M+) calcd 442.5957, obsd
442.5983.
Supporting Information Available: Crystal data collection
for 6 including tables of bond distances and angles, least-squares
planes, final fractional coordinates, and thermal parameters (8
pages, print/PDF). See any current masthead page for ordering
information and Web access instructions.
JA974009L