Studies on the synthesis of (-)-spinosyn A: Application of the steric directing group strategy to transannular Diels-Alder reactions

Article abstract of DOI:10.1021/jo025580s

A highly diastereoselective and enantioselective synthesis of the decahydro-as-indacene nucleus 12 of (-)-spinosyn A (1) is reported. By implementing the steric directing group strategy, tricyclic lactone 37 was produced from a remarkably diastereoselective transannular Diels-Alder reaction of lactone 9. The tricyclic core of the natural product was then obtained by using an Ireland-Claisen ring contraction of 37. Reversal of the order of these two steps resulted in an almost complete loss of diastereoselectivity.

Full text of DOI:10.1021/jo025580s

4316
J . Org. Chem. 2002, 67, 4316-4324
Stu d ies on th e Syn th esis of (-)-Sp in osyn A: Ap p lica tion of th e
Ster ic Dir ectin g Gr ou p Str a tegy to Tr a n sa n n u la r Diels-Ald er
Rea ction s
Scott A. Frank and William R. Roush*
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055
roush@umich.edu
Received February 2, 2002
A highly diastereoselective and enantioselective synthesis of the decahydro-as-indacene nucleus
12 of (-)-spinosyn A (1) is reported. By implementing the steric directing group strategy, tricyclic
lactone 37 was produced from a remarkably diastereoselective transannular Diels-Alder reaction
of lactone 9. The tricyclic core of the natural product was then obtained by using an Ireland-
Claisen ring contraction of 37. Reversal of the order of these two steps resulted in an almost complete
loss of diastereoselectivity.
In tr od u ction
Alder reaction of an appropriately substituted (E,E,E)-
cyclododeca-1,6,8-triene such as 2.2,13 Hirata has sug-
gested that an analogous transannular Diels-Alder
reaction may be involved in the biosynthesis of ikarug-
amycin.4b
Spinosyn A (1)1-3 is a member of a group of natural
products that possess perhydro-as-indacene ring sys-
tems.4-7 The spinosyn family displays very potent insec-
ticidal activity,8,9 and the biosynthetic mixture (consisting
of ca. 85% of 1) is marketed for use against a wide variety
of insects.9,10 Although total syntheses of the (+)- and (-)-
enantiomers of spinosyn A have been reported by Evans
and Paquette,11,12 these molecules remain as challenging
targets for total synthesis. Our interest in the spinosyns
was inspired by the hypothesis that these molecules are
assembled biosynthetically by the transannular Diels-
(1) Kirst, H. A.; Michel, K. H.; Martin, J . W.; Creemer, L. C.; Chio,
E. H.; Yao, R. C.; Nakatsukasa, W. M.; Boeck, L. B.; Occolowitz, J . L.;
Paschal, J . W.; Deeter, J . B.; J ones, N. D.; Thompson, G. D. Tetrahe-
dron Lett. 1991, 32, 4839.
(2) Kirst, H. A.; Michel, K. H.; Mynderase, J . S.; Chio, E. H.; Yao,
R. C.; Nakatsukasa, W. M.; Boeck, L. D.; Occolowitz, J . L.; Paschal, J .
W.; Deeter, J . B.; Thompson, G. D. In Fermentation-Derived Tetracyclic
Macrolides; 1992; pp 214-225.
(3) Martynow, J . G.; Kirst, H. A. J . Org. Chem. 1994, 59, 1548 and
references therein.
(4) Ikarugamycin: (a) J omon, K.; Kuroda, Y.; Ajisaka, M.; Sakai,
H. J . Antibiot. 1972, 25, 271. (b) Ito, S.; Hirata, Y. Tetrahedron Lett.
1972, 2557. (c) Ito, S.; Hirata, Y. Bull. Chem. Soc. J pn. 1977, 50, 1813.
(5) Capsimycin: Aizawa, S.; Akutsu, H.; Satomi, T.; Nagatsu, T.;
Taguchi, R.; Seino, A. J . Antibiot. 1979, 32, 193.
(6) Mangicol A: Renner, M. K.; J ensen, P. R.; Fenical, W. J . Org.
Chem. 2000, 65, 4843.
(7) Sato, B.; Muramatsu, H.; Miyauchi, M.; Hori, Y.; Takase, S.;
Hino, M.; Hashimoto, S.; Terano, H. J . Antibiot. 2000, 53, 123. (b) Sato,
B.; Nakajima, H.; Hori, Y.; Hino, M.; Hashimoto, S.; Terano, H. J .
Antibiot. 2000, 53, 204. (c) Yoshimura, S.; Sato, B.; Kinoshita, T.;
Takase, S.; Terano, H. J . Antibiot. 2000, 53, 615.
Transannular Diels-Alder (TDA) reactions display
significant advantages over conventional intramolecular
Diels-Alder variants due to a lowered ∆Gq resulting from
a decreased ∆Sq.14,15 As a result, cycloaddition reactions
of (noncyclic) trienes that do not proceed efficiently in
the intramolecular mode work smoothly in the transan-
nular version,16 sometimes with substantially improved
diastereoselectivity.17,18
We established in earlier studies that the transannular
Diels-Alder reactions of 4a and 4b, which were in situ
generated by Ireland enolate Claisen ring contractions19-21
of 16-membered lactones 3a and 3b, proceed readily at
(8) Creemer, L. C.; Kirst, H. A.; Paschal, J . W. J . Antibiot. 1998,
51, 795.
(9) Sparks, T. C.; Crouse, G. D.; Durst, G. Pest. Management Sci.
2001, 57, 896.
(10) Dagani, R. Chem. Eng. News 1999, 77 (J uly 5), 30.
(11) Evans, D. A.; Black, W. C. J . Am. Chem. Soc. 1993, 115, 4497.
(12) (a) Paquette, L. A.; Gao, Z.; Ni, Z.; Smith, G. F. Total Synthesis
of Spinosyn A. 1. Enantioseletive Construction of a Key Tricyclic
Intermediateby a Multiple Configurational Inversion Scheme. J . Am.
Chem. Soc. 1998, 120, 2543. (b) Paquette, L. A.; Collado, I.; Purdie,
M. Total Synthesis of Spinosyn A. 2. Degradation Studies Involving
the Pure Factor and Its Complete Reconstitution. J . Am. Chem. Soc.
1998, 120, 2553.
(13) Kirst, H. A.; Michel, K. H.; Chio, E. H.; Yao, R. C.; Nakatsukasa,
W. M.; Boeck, L. D.; Occolowitz, J . L.; Paschal, J . W.; Deeter, J . B.;
Thompson, G. D. In Microbial Metabolites; Nash, C., Ed.; Wm. C.
Brown: Dubuque, 1991; Vol. 32, p 109.
(14) Deslongchamps, P. Aldrichim. Acta 1991, 24, 43.
(15) Marsault, E.; Toro´, A.; Nowak, P.; Deslongchamps, P. Tetra-
hedron 2001, 57, 4243.
(16) Be´rube´, G.; Deslongchamps, P. Tetrahedron Lett. 1987, 28,
5255.
10.1021/jo025580s CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/16/2002

Synthesis of (-)-Spinosyn A
J . Org. Chem., Vol. 67, No. 12, 2002 4317
ambient temperature.22,23 Other strategies for synthesis
of the strained (E,E,E)-cyclododeca-1,6,8-triene systems
have met with considerably greater difficulty.24 The TDA
reactions of 4 illustrate the great rate accelerations that
can be achieved by working in the transannular Diels-
Alder manifold, as analogous intramolecular Diels-Alder
reactions of trienes with unactivated dienophiles require
temperatures in excess of 150 °C for reaction to occur.25-27
However, the diastereoselectivity of the cyclization reac-
tions of 4a and 4b is incorrect for ultimate application
to the synthesis of 1, since the C(7)-C(11) and C(4)-
C(12) ring fusions in the natural product are trans and
cis, respectively, whereas these two relationships are
reversed in tricycles 5a and 5b. Consequently, we decided
to introduce additional stereochemical control elements
into the macrocyclic triene substrate in order to induce
the transannular Diels-Alder reaction to produce the
stereoisomer required for use in a spinosyn A total
synthesis.
introduction of a removable steric directing group at C(6)
of the triene substrate led to a substantial increase in
selectivity for formation of the trans-ring fusion at the
adjacent position (e.g., at C(7)-C(11) in 8), even in cases
where the cis-ring fusion is favored in the absence of the
steric directing group substituent.28,30,31 Accordingly, we
anticipated that the diastereoselectivity of the cycliza-
tions of 4 could be reversed by use of a C(6)-substituted
triene such as 7 as the transannular Diels-Alder sub-
strate. However, MM2 analysis33 of transition states of
the TDA cyclization of 7 led us to suspect that control of
the stereochemical relationship between the C(7)-C(11)
trans-fusion and the preexisting C(9)-alkoxy substituent
would be poor. Therefore, we also decided to introduce a
C(8)-OTBS unit in the Diels-Alder substrate (cf., 10)
in order to better control the transmission of stereochem-
ical information from C(9) to the developing trans-ring
fusion in the Diels-Alder reaction. Minimization of
potential allylic strain interactions leads to the conclusion
that the preferred product of the Diels-Alder reaction
of 10 should have the stereostructure depicted in 11.31,34
We also anticipated, based on MM2 analysis of possible
transition states, that the C(9)-alkoxy group might help
to control the stereochemistry of the Ireland enolate
Claisen ring contraction of macrocyclic precursor 9 (cf.
for control of the C(3)-C(9) stereochemical relationship
in 10).33
In 1985, Boeckman and our group introduced the steric
directing group strategy for controlling the diastereose-
lectivity of intramolecular Diels-Alder reactions.28,29 We
have used this technology to considerable advantage in
our total synthesis of chlorothricolide28,30,31 and in the
synthesis of the bottom half fragments of kijanolide and
tetronolide.32 In all of the examples studied to date,
(17) Porco, J . A., J r.; Schoenen, F. J .; Stout, T. J .; Clardy, J .;
Schreiber, S. L. J . Am. Chem. Soc. 1990, 112, 7410. This paper
describes a facile macrolactonization and transannular Diels-Alder
reaction that proceeds with reversed regiochemistry compared to a
related type II intramolecular Diels-Alder reaction.
(18) Roush, W. R.; Koyama, K.; Curtin, M. L.; Moriarty, K. J . J .
Am. Chem. Soc. 1996, 118, 7502.
(19) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J . Am. Chem. Soc.
1976, 98, 2868.
(20) Abelman, M. M.; Funk, R. L.; Munger, J . D., J r. J . Am. Chem.
Soc. 1982, 104, 4030.
(21) Funk, R. L.; Abelman, M. M.; Munger, J . D., J r. Tetrahedron
1986, 42, 2831.
(22) Roush, W. R.; Works, A. B. Tetrahedron Lett. 1996, 37, 8065.
(23) Frank, S. A.; Works, A. B.; Roush, W. R. Can. J . Chem. 2000,
78, 757.
(24) Roush, W. R.; Warmus, J . S.; Works, A. B. Tetrahedron Lett.
1993, 34, 4427.
(25) Ciganek, E. Org. React. 1984, 32, 1.
(26) Craig, D. Chem. Soc. Rev. 1987, 16, 187.
(27) Roush, W. R. In Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, pp 513-550.
(28) Roush, W. R.; Kageyama, M. Tetrahedron Lett. 1985, 26, 4327.
(29) Boeckman, R. K., J r.; Barta, T. E. J . Org. Chem. 1985, 50, 3421.
(30) Roush, W. R.; Kageyama, M.; Riva, R.; Brown, B. B.; Warmus,
J . S.; Moriarty, K. J . J . Org. Chem. 1991, 56, 1192.
(31) Roush, W. R.; Sciotti, R. J . J . Am. Chem. Soc. 1998, 120,
7411.
We describe herein a synthesis of the spinosyn A
tricycle 12 by a route involving the tandem ring contrac-
tion-transannular Diels-Alder reaction of macrocycle 9.
A second-generation synthesis of intermediate 12 by the
transannular Diels-Alder reaction of 9 followed by the
Ireland enolate Claisen ring contraction of the initial
TDA product is also described.
(33) MM2 analysis of the transition states of this reaction was
performed as described in ref 21.
(34) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(32) Roush, W. R.; Brown, B. B. J . Am. Chem. Soc. 1993, 115,
2268.

4318 J . Org. Chem., Vol. 67, No. 12, 2002
Frank and Roush
Resu lts a n d Discu ssion
OTf as the promoter42 gave results similar results to
those for the TrBF4-catalyzed procedure (56% isolated
yield of 15). We also prepared a cyclohexylidene ketal
protected analogue of 13, and this presumably more
stable acceptor gave identical results in the glycosidation
reaction. Attempts to use the much more reactive trichlo-
roacetimidate 18 as the donor, using catalytic TBS-OTf
(15%) as the promoter, also provided a 1:3 mixture of 15
and 16, even though this reaction was complete within
30 min at -78 °C.43 Because ketal equilibration (13 to
17) should not occur rapidly at -78 °C, we suspect that
16 arises by attack of the relatively unhindered primary
ether oxygen atom of 13 on the activated glycosyl donor,
followed by ketal migration.
Syn th esis of La cton e 9. We elected to use the readily
available alcohol 1335 as the starting material for the
synthesis of 12. The free hydroxyl group of 13 was
destined to become the C(9)-substituent of 9-12, while
the second stereocenter of 13 would serve as a precursor
to the C(8)-OTBS substituent of 9-11. Another key
strategic decision on our part was to install the rham-
nosyl unit at the very beginning of the synthesis, so as
to avoid protection/deprotection sequences for C(9)
throughout the synthesis.
Alcohol 13 is easily prepared in excellent yield and with
high diastereoselectivity by the asymmetric allylboration
of D-glyceraldehyde pentylidene ketal36 by using the
diisopropyl (R,R)-tartrate modified allylboronate re-
agent.37,38 Treatment of 13 with 1.2 equiv of tri-O-methyl-
R-L-rhamnopyranosyl acetate 1439 in Et2O in the presence
of catalytic amounts (6%) of trityl tetrafluoroborate
(TrBF4)40 afforded the desired R-glycoside 15 in 61% yield
after chromatographic purification. Also isolated was the
regioisomeric glycoside 16 (15% yield). Glycoside 16
results from isomerization of the pentylidene group to
the internal diol unit and glycosidation of the primary
alcohol.41 Control experiments showed that treatment of
an Et2O solution of 13 with TrBF4 (0.1 equiv) and AcOH
(1 equiv) rapidly produced a 4:1 equilibrium mixture of
13 and the migrated ketal isomer 17. Apparently, as the
glycosidation reaction progresses, an equilibrium is set
up between 13 and 17, and both isomers undergo
glycosidation with donor 14.
The pentylidene ketal protecting group of 15
was hydrolyzed by using an excess of p-toluenesulfonic
acid in a 1:1 mixture of THF and water at 65 °C, there-
by giving the corresponding diol in 96% yield. The diol
was then treated with excess TBS-OTf in the pre-
sence of 2,6-lutidine to provide the bis-TBS ether 19 in
88% yield after chromatographic purification. Selec-
tive removal of the primary TBS ether was achieved
by treatment of 19 with PTSA (10%) in MeOH for 3 h.44
This provided the mono-TBS ether 20 in 71% yield
along with 25% of recovered 19. It was necessary to
stop this deprotection reaction short of completion in
order to prevent competitive hydrolysis of the second-
ary TBS ether. Accordingly, resubjection of recovered 19
to the deprotection conditions provided additional quanti-
ties of 20; the yield of 20 was 88% after one such recycle
step.
Oxidation of alcohol 20 to the corresponding aldehyde
was effected by using the Dess-Martin periodinane
reagent.45 Treatment of the crude aldehyde with a
premixed solution of Ph3P and CBr4 gave dibromoolefin
21 in 97% yield after chromatographic purification.46
Selective ozonolysis of the vinyl group was achieved in a
4:1 CH2Cl2-MeOH solvent system containing KHCO3 at
-78 °C, without special precaution for ozone stoichiom-
etry, since deactivated, halogen-substituted olefins un-
dergo ozonolysis at considerably slower rates.47 The
resulting aldehyde, obtained in 96% yield after the
intermediate R-methoxy hydroperoxide was reduced with
triphenylphosphine, was treated with 1.4 equiv of vinyl-
magnesium bromide to give a 2:1 mixture of allylic
alcohols 22. These alcohols, without separation of the
diastereomers, were then subjected to the J ohnson
orthoester Claisen protocol, thereby providing 23 in 94%
yield as a single olefin isomer.48 The importance of
stereocontrol for this step is paramount, as this olefin
Several attempts to suppress the formation of the
unwanted glycoside 17 were unsuccessful. Performing the
glycosidation reaction in toluene or CH2Cl2 gave dimin-
ished ratios of 15 with respect to 16 (2:1). Subsequent
control experiments established that the equilibrium
mixture of 13 and 17 was reached in 1.5 h in toluene
under the conditions of the glycosidation reaction (23 °C).
Attempts to perform the glycosidation by using TBS-
(35) Roush, W. R.; Grover, P. T. J . Org. Chem. 1995, 60, 3806.
(36) Schmid, C. R.; Bradley, D. A. Synthesis 1992, 587.
(37) Roush, W. R.; Walts, A. E.; Hoong, L. K. J . Am. Chem. Soc.
1985, 107, 8186.
(38) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J .; Straub, J . A.;
Palkowitz, A. D. J . Org. Chem. 1990, 55, 4117.
(39) Bols, M.; Binderup, L.; Hansen, J .; Rasmussen, P. J . Med.
Chem. 1992, 35, 2768.
(40) Mukaiyama, T.; Kobayashi, S.; Shoda, S. Chem. Lett. 1984, 907.
(41) Coe, J . W.; Roush, W. R. J . Org. Chem. 1989, 54, 915.
(42) Roush, W. R.; Bennett, C. E. J . Am. Chem. Soc. 2000, 122,
6124.
(43) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem.
1994, 50, 21.
(44) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031.
(45) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.
(46) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(47) Pryor, W. A.; Giamalva, D.; Church, D. F. J . Am. Chem. Soc.
1983, 105, 6858.

Synthesis of (-)-Spinosyn A
Sch em e 1a
J . Org. Chem., Vol. 67, No. 12, 2002 4319
Ta ble 1. Syn th esis of Ma cr ola cton e 9 by Cycliza tion of
Seco Acid 27
T
(°C)
yieldb
(%)
conditionsa
2-chloro-1-methylpyridinium iodide, Et3N, CH2Cl2 45
33
38
54
48
37
70
2,4,6-trichlorobenzoyl chloride, DMAP, toluene
Ph3P, DEAD, THF
65
45
45
23
23
Ph3P, DIAD, THF
PyBrOP, DMAP, CH2Cl2
PyBOP, DMAP, CH2Cl2
a
All reactions were performed by addition of 27 to the reaction
mixtures over 8-12 h. The final concentration of 27 in all cases
b
was 0.003 M. Yields are of chromatographically purified 9.
provided the desired conjugated triene 26 in 75-87%
yield.
Saponification of 26 afforded seco-acid 27 in 87% yield,
thereby setting the stage for the key macrolactonization
experiment (see Table 1).58 Initial attempts to effect the
macrocyclization of 27 by using Mukaiyama conditions
(2-chloro-1-methylpyridinium iodide, Et3N, CH2Cl2, 45
°C)59 provided the desired lactone 9 in only 33% yield.
We observed a dienyl acetylene, resulting from dehydro-
aKey: (a) p-TsOH, 1:1 THF, H2O, 65 °C, 1 h, 96%; (b) TBS-OTf,
CH2Cl2 2,6-lutidine, 0-23 °C, 88%; (c) p-TsOH, MeOH, 0 23 °C,
3 h, 88% after one recycle of recovered 19; (d) Dess-Martin
periodinane, wet CH2Cl2, pyridine; (e) Ph3P, CBr4, CH2Cl2, 0-23
°C, 0.5 h, 95% from 20; (f) O3, 4:1 CH2Cl2-MeOH, KHCO3, -78
°C, then Ph3P, -78 to +23 °C, 96%; (g) H2CdCHMgBr, THF, -78
to +23 °C, 91%; (h) CH3C(OMe)3, EtCO2H, toluene, 110 °C, 72 h,
94%.
1
bromination of 26, in the H NMR spectrum of the crude
reaction product; however, we were unable to isolate the
dienyne product owing to its apparent decomposition on
silica gel. Use of less basic reaction conditions, such as
the Yonemitsu variant60 of the Yamaguchi macrolacton-
ization procedure,61 gave only a slight improvement in
the isolated yield of 9 (38%). A significant improvement
(54% isolated yield of 9) was achieved when Mitsunobu
conditions were employed.62 However, substantial amounts
of the hydrazide coupling product 28 were also obtained,
a side product that is known to occur when the concen-
tration of the acid coupling partner is low with respect
to the alcohol.63 All attempts to minimize the formation
of 28 by modification of reaction conditions were unsuc-
cessful. Replacement of diethyl azodicarboxylate in the
Mitsunobu protocol with the more sterically hindered
diisopropyl azodicarboxylate, which has been used previ-
ously to suppress formation of hydrazide substitution
products,64 led to the formation of 9 in only 48% yield.
Ultimately, the best results were obtained when the
macrolactonization of 27 was performed by using the
peptide coupling agent benzotriazol-1-yloxytripyrrolidi-
nophosphonium hexafluorophosphate (PyBOP).65 Indeed,
we were delighted to discover that slow addition of 27 to
a CH2Cl2 solution of PyBOP and DMAP provided 9 in
70% yield. However, use of the related peptide coupling
agent PyBrOP provided 9 in only 37% yield.66
serves as the dienophilic segment of the transannular
Diels-Alder substrate 10 (Scheme 1).
Vinylboronic acid 25, needed for the subsequent Suzuki
cross-coupling reaction49,50 with 23, was prepared in 81%
yield by hydroboration of the readily available acetylene
2451 with 2.2 equiv of catecholborane.52,53 Because vinyl-
boronic acid 25 is quite unstable (substantial amounts
of intractable material were produced when 25 was
stored neat), this material generally was used in the cross
coupling reaction with 23 immediately following its
preparation. The Pd(0)-catalyzed cross coupling reactions
of 1,1-dibromoolefins and vinylboronic acids are known
to produce 2-bromo (Z)-1,3-dienes with excellent selectiv-
ity.54,55 The efficiency of these reactions is greatly en-
hanced when performed using thallium hydroxide as the
base, which enhances the rate of cross-coupling at the
expense of competitive dehydrohalogenation reactions.55,56
We recently introduced the use of thallium ethoxide in
these reactions, owing to problems with the availability
and shelf life of TlOH.57 Accordingly, treatment of dibro-
moolefin 23 with 3 equiv of 25, 1.8 equiv of TlOEt, and
catalytic amounts of (Ph3P)4Pd in aqueous THF (3:1)
Rin g Con tr a ction a n d Cycloa d d ition of 9. Treat-
ment of lactone 9 with KHMDS and TBS-OTf in 4:1
THF-HMPA at -78 °C followed by heating the inter-
mediate silyl ketene acetal at 140 °C overnight afforded
a mixture of tricyclic adducts. The mixture was subjected
to an aqueous workup to hydrolyze the TBS esters,
followed by esterification of the mixture of carboxylic
acids with TMSCHN2, thereby giving a mixture of four
(48) J ohnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J .; Li, T.-t.; Faulkner, D. J .; Petersen, M. R. J . Am. Chem. Soc. 1970,
92, 741.
(49) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(50) Suzuki, A. J . Organomet. Chem. 1999, 576, 147.
(51) Feldman, K. S. Tetrahedron Lett. 1982, 23, 3031.
(52) Brown, H. C.; Gupta, S. K. J . Am. Chem. Soc. 1975, 97,
5249.
(53) Kabalka, G. W.; Baker, J . D., J r.; Neal, G. W. J . Org. Chem.
1977, 42, 512.
(54) Roush, W. R.; Riva, R. J . Org. Chem. 1988, 53, 710.
(55) Roush, W. R.; Moriarty, K. J .; Brown, B. B. Tetrahedron Lett.
1990, 31, 6509.
1
diastereomeric methyl esters as determined by H NMR
analysis. Partial separation of two of the diaster-
eomers, 30 and 31, was achieved by column chromatog-
raphy; 30 was isolated in 23% yield while 31 was
obtained in 10% yield. The two remaining cycload-
(56) Uenishi, J .-i.; Beau, J .-M.; Armstrong, R. W.; Kishi, Y. J . Am.
Chem. Soc. 1987, 109, 4756.
(57) Frank, S. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J .; Roush,
W. R. Org. Lett. 2000, 2, 2691.

4320 J . Org. Chem., Vol. 67, No. 12, 2002
Frank and Roush
same side of the molecule, and that H(4) and H(12) are
trans.
ducts, 11 and 32, were inseparable by HPLC and
therefore were obtained as a mixture (20% yield, com-
bined). Tricycle 11 was subsequently prepared by an
alternative route (vide infra), and the stereochemistry
of this compound was assigned at that time. The stereo-
structural assignment of 32 is tentative and is based
1
upon correlation of the H NMR resonances for C(7)-H,
1
C(11)-H, and C(14)-H with the same protons in the H
NMR spectrum of 11.
The stereostructures of 30 and 31 were assigned on
the basis of the 1H NMR data summarized below. 1H
NOESY experiments established NOE contacts between
H(11) and H(8) and between H(11) and H(2) in diaste-
reomer 30. These data, together with the coupling
constant data that indicate trans relationships between
H(7)-H(8), H(7)-H(11), and H(11)-H(12), are uniquely
consistent with the stereochemistry depicted for 30. Key
NOE and coupling constant data similarly highlighted
for structure 31 establish that H(7), H(11) and H(4) are
cis; that H(12) and the vinyl group are on the
The fact that the two major products (30 and 31) of
the tandem ring contraction-transannular Diels-Alder
reaction of 9 have incorrect stereochemistry at C(3)
indicates that the Claisen ring contraction step provided
a ca. 1.5:1 mixture of isomeric cyclododecatrienes 29 and
10, presumably by way of transition states A and B. On
the basis of our earlier studies,23 we anticipated that the
Claisen ring contraction would proceed by way of the
Z(O)-silyl ketene acetal, but we were unable to isolate or
characterize this intermediate in the present instance.
(58) Meng, Q.; Hesse, M. Topics Curr. Chem. 1991, 161, 107.
(59) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49.
(60) Tone, H.; Nishi, T.; Oikawa, Y.; Hikota, M.; Yonemitsu, O.
Tetrahedron Lett. 1987, 28, 4569.
(61) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989.
(62) Hughes, D. L. Org. React. 1992, 42, 335.
(63) Hughes, D. L.; Reamer, R. A.; Bergan, J . J .; Grabowski, E. J .
J . J . Am. Chem. Soc. 1988, 110, 6487.

Synthesis of (-)-Spinosyn A
J . Org. Chem., Vol. 67, No. 12, 2002 4321
MM2 calculations of possible transition states had led
us to expect that the Claisen ring contraction would occur
preferentially via by way of transition state B, with an
extended conformation of the conjugated triene. Our
modeling studies also predicted that the alternative,
isomeric E(O)-silyl ketene acetal (not shown) also should
cyclize to provide 10 preferentially, although the transi-
tion states in this case were predicted to be much higher
in energy than either A or B. Nevertheless, the results
clearly indicate that the two predominant Diels-Alder
adducts derive from 29, which implicates transition state
A as being the lowest energy pathway for the Claisen
ring-contraction step.
The two major tricycloadducts 30 and 31 arise from
29 through the transannular Diels-Alder transition
states C and D, respectively. It is interesting that the
H(7)-H(8) stereochemistry is trans in all four of the
tricyclic products, indicating that the C(6)-Br steric
directing group was effective in controlling this relation-
ship in all four of the transannular Diels-Alder transi-
tion states. The C(6)-Br steric directing group also
played the anticipated role28,30 in inducing a C(7)-C(11)
trans-ring fusion in 30, although the ratio of C(7)-C(11)
trans/cis ring fusion isomers (30/31) was only 2:1 in this
series. In the absence of the steric directing group, the
transannular Diels-Alder reactions of 4a and 4b pro-
ceeded with ca. 4:1 selectivity toward tricycles 5a and
5b with C(7)-C(11) cis ring fusions.22,23
The two remaining tricycles, 11 and 32, derive from
the originally targeted cyclododecatriene 10 via transition
states E and F. Although A(1,3) interactions between the
C(3)-vinyl group and the C(4)-C(5) olefin that are
present in transition states C and D are absent in E and
F, the ratio of C(7)-C(11) trans/cis ring fusion isomers
(11 and 32, respectively) in this series is approximately
1.5:1, roughly comparable (within the experimental
error of our measurements) of the ratio of the cycload-
ducts 30 and 31 deriving from the isomeric cyclododec-
atriene 29.
While we were disappointed that the Claisen ring
contraction of 9 did not proceed with better stereoselec-
tivity, we were modestly encouraged that the C(6)-Br
steric directing group had reversed the stereochemi-
calpreference of the transannular Diels-Alder reaction
compared to the results of our earlier investigations of
4a and 4b.22,23 Because earlier studies had established
that a C(6)-SiMe3 steric directing group is capable of
exerting a larger influence on the stereochemical course
of intramolecular Diels-Alder reactions than the C(6)-
Br directing group,28-30 we also synthesized and exam-
ined the ring contraction-transannular Diels-Alder re-
action of 33. Lactone 33 was converted to the correspond-
ing ketene silyl acetal by using the procedure developed
for 9, and the silyl ketene acetal was then heated at 140
°C to effect the Ireland-Claisen ring contraction. Acidic
hydrolysis of the reaction mixture followed by esterifi-
cation of the crude carboxylic acids afforded a mixture
of three tricyclic products 34-36. These isomers were
purified by HPLC and characterized by 1H NMR analysis.
Once again, the major product 34 (obtained in 18% yield)
possessed the incorrect stereochemistry at C(3), indicat-
ing that the Claisen ring contraction step had occurred
with poor diastereoselectivity. Tricycles 35 and 36,
obtained in 12% and 10% yield respectively, have the
desired C(3)-C(8) stereochemical relationship. However,
the fact that a ca. 1:1 mixture of the two was obtained
indicated that the C(6)-TMS steric directing group un-
derperformed our expectations,29,30 and did not ad-
equately control the stereochemical course of the tran-
sannular Diels-Alder reaction.
(64) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J . Am.
Chem. Soc. 1995, 117, 3448.
(65) Coste, J .; Fre´rot, E.; J ouin, P. Tetrahedron Lett. 1991, 32, 1967.
(66) Fre´rot, E.; Coste, J .; Pantaloni, A.; Dufour, M.-N.; J ouin, P.
Tetrahedron 1991, 47, 259.

4322 J . Org. Chem., Vol. 67, No. 12, 2002
Frank and Roush
the only products that were observed were the C(2)-(E)-
isomer of 26 and trienal 38 resulting from a 1,5-hydrogen
shift pathway. Consequently, the successful TDA reaction
of 9 adds to the list of examples of Diels-Alder reactions
that are successful in the transannular mode, but which
fail altogether in the IMDA manifold.14-16
Ster eoselective Syn th esis of th e Deca h yd r o-a s-
in d a cen e Cor e Str u ctu r e of 1. At this stage, we elected
to reorder the pericyclic steps leading from lactone 9 to
tricycle 11. We anticipated that if the Diels-Alder
reaction of 9 was performed before the Ireland-Claisen
ring contraction step, then it might be possible to control
the stereochemistry of the C(3) vinyl substituent in the
targeted tricycle 11 owing to the geometrical constraints
of the nine-membered lactone unit of 37.20,21,67 The key
would be to achieve high selectivity in the transannular
Diels-Alder reaction of 9.15
We were very pleased to find that heating a degassed
solution of 9 in toluene at 180 °C for 36 h provided a
single tricyclic product 37 in 46% yield; 41% of 9 was
recovered and could be recycled to produce additional
We next turned our attention to the Ireland enolate
Claisen ring contraction of 37. As we had anticipated,
the cis C(4)-C(12) ring fusion of 37 indeed proved
effective in controlling the diastereoselectivity of the
Claisen rearrangement leading to the targeted tricycle
11. Best results, at least initially, were obtained when
37 was treated with LiHDMS and TIPS-OTf in THF at
-78 °C with warming to ambient temperature to promote
the Ireland Claisen rearrangement step.68 This reaction
provided the targeted tricycle 11 in 48% yield after
hydrolysis of the TIPS ester and esterification of the
crude carboxylic acid with TMSCHN2. However, signifi-
cant quantities of the cycloheptene product 39 (15% yield)
resulting from a competitive [1,3]-Claisen ring contrac-
tion process were also obtained. Products of [1,3]-Claisen
rearrangements have been observed previously in ring
contraction experiments.69
1
quantities of 37. H NMR analysis of the reaction mix-
tures failed to detect any other diastereomers of 37 in
these experiments. No reaction was observed when the
transannular Diels-Alder reaction was attempted at 140
°C. The stereochemistry indicated for 37 was assigned
on the basis of NOE interactions observed between H(11)
and H(3), and between H(11) and H(8), which indicates
that these three units are positioned on the same face of
the molecule. The large coupling constants observed be-
tween H(7)-H(8), H(7)-H(11), and H(11)-H(12) indicate
that H(7), H(8), H(11), and H(12) are trans-diaxial. These
data are uniquely consistent with the stereochemistry
depicted for 37. It is tempting to attribute the exquisite
diastereoselectivity of the transannular Diels-Alder reac-
tion of 9 to the C(6)-bromine steric directing group,28-30
but until the TDA reaction of the analogous C(6)-H sub-
stituted triene is performed this conclusion is speculative.
We were unsuccessful in our attempts to drive the
Diels-Alder reaction of 9 to completion, as starting
material was consistently recovered after the reaction
mixture was heated at 180 °C for several days in a sealed
tube, or for several days in higher boiling solvents
(e.g., decalin or triisopropylbenzene). Control ex-
periments established that the formation of 37 is
kinetically controlled, as 37 does not revert to 9 at 180
°C.
The stereochemistry of 11 was easily assigned based
on the coupling constant data provided with the three-
dimensional structure. This assignment was confirmed
by an NOE experiment, which established that H(3) and
H(11) are on the same face of the molecule.
(67) Funk, R. L.; Olmstead, T. A.; Parvez, M.; Stallman, J . B. J .
Org. Chem. 1993, 58, 5873 and references cited therein.
(68) Magriotis, P. A.; Kim, K. D. J . Am. Chem. Soc. 1993, 115, 2972.
(69) (a) Khan, K. M.; Knight, D. W. J . Chem. Soc., Chem. Commun.
1991, 1699. (b) Vourloumis, D.; Kim, K. D.; Petersen, J . L.; Magriotis,
P. A. J . Org. Chem. 1996, 61, 4848.
Interestingly, attempts to effect a conventional in-
tramolecular Diels-Alder cyclization of seco ester 26
failed to give any Diels-Alder products when this
compound was heated to 195 °C. Under these conditions,
(70) Hartwig, W. Tetrahedron 1983, 39, 2609.
(71) Ge, Y.; Isoe, S. Chem. Lett. 1992, 139.
(72) Neumann, W. P. Synthesis 1987, 665.
(73) Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.;
Utimoto, K. Bull. Chem. Soc. J pn. 1989, 62, 143.

Synthesis of (-)-Spinosyn A
J . Org. Chem., Vol. 67, No. 12, 2002 4323
Completion of the synthesis of the spinosyn tricyclic
nucleus 12 involved reductive removal of the C(6)-
bromide and C(8)-hydroxyl substituents. This was ac-
complished by treatment of 41 with 1,1-thiocarbonyldi-
imidazole and DMAP in toluene at reflux for 24 h to give
the thiocarbonyl derivative 42 in 77% yield.70 The hy-
droxyl group of 41 is relatively hindered, and it was
necessary to use 3 equiv. of the thiocarbonyl diimidazole
reagent for the reaction to go to completion. Under these
conditions, 10% of the elimination product 43 was also
obtained. Diene 43 presumably derives from a thermal
syn elimination pathway.71
We anticipated at the outset that treatment of 42 with
Bu3SnH and AIBN would effect reduction of both the
vinylbromide and thiocarbonyl derivatives.70,72 However,
heating a mixture of 42, Bu3SnH and AIBN in benzene
at reflux led to substantial decomposition. Alternatively,
when a benzene solution of 42 was treated with Bu3SnH
and Et3B at ambient temperature in the presence of a
catalytic amount of air, C(8) deoxygenation occurred
smoothly and 44 was obtained in 80% yield.73 It was
necessary to exercise careful control over the stoichiom-
etry of this reaction in order to minimize formation of
alcohol 41 by reduction of the intermediate thioketal
radical by excess Bu3SnH.74 However, owing to the
relatively low temperature of this reaction, the C(6)-
bromine substituent was not reduced.
Attempts to perform the ring contraction of 37 by using
KHDMS and TBS-OTf in THF-HMPA, LDA and TBS-
Cl in THF-HMPA, or LiHMDS and TBS-OTf in THF
were unsuccessful. However, treatment of 37 with 2,2,6,6-
tetramethylpiperidine (TMP) and triisopropylsilyl triflate
(TIPS-OTf) in CH2Cl2 at ambient temperature for 48 h
provided the chromatographically stable TIPS ester 40
in up to 71% yield, with 10-19% of recovered 37. For-
tunately, products of the [1,3]-rearrangement were not
observed. Simultaneous removal of the TIPS and TBS
groups was accomplished by exposure of 40 to 3.5 equiv
of TBAF in THF at ambient temperature. After esteri-
fication of the carboxylic acid with TMSCHN2, tricyclic
alcohol 41 was obtained in 82% yield, together with 10%
of 11. Treatment of 11 with TBAF in THF provided 41
in 99% yield.
Surprisingly, treatment of 44 with Bu3SnH and AIBN
in refluxing benzene gave products of hydrostannylation

4324 J . Org. Chem., Vol. 67, No. 12, 2002
Frank and Roush
of the vinyl group. Accordingly, the C(6)-Br was removed
by reduction of 44 with a zinc amalgam generated from
Zn, Cu(OAc)2 and AgNO3,75 which provided the targeted
tricycle 12 in 61% yield. This final reduction could also
be accomplished by using 5% Na(Hg) in methanol, but
products of ester hydrolysis and epimerization of the
C(14) stereocenter were also observed.
of the steric directing group strategy to the transannular
Diels-Alder reaction. Another attractive feature of this
synthesis is that the rhamnosyl substituent is introduced
at the very beginning, thereby minimizing protecting
group manipulations as the synthesis progresses. Further
progress toward completion of a total synthesis of spi-
nosyn A will be reported in due course.
Con clu sion
Ack n ow led gm en t. Financial support provided by
the National Institute of General Medical Sciences (GM
26782) is gratefully acknowledged.
In summary, we have developed a highly diastereose-
lective, 19-step synthesis of the perhydro-as-indacene
nucleus 12 of spinosyn A. The transannular Diels-Alder
reaction of 9 represents the first successful application
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
1
mental details and selected H NMR spectra. This material is
(74) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1988,
29, 6125.
available free of charge via the Internet at http://pubs.acs.org.
(75) Boland, W.; Schroer, N.; Sieler, C.; Feigel, M. Helv. Chim. Acta
1987, 70, 1025.
J O025580S