Enantiodivergent total syntheses of (+)- and (-)-scopadulcic acid A

Article abstract of DOI:10.1021/ja990404v

The first enantioselective total synthesis of scopadulcic acid A is described. The key step is a cascade intramolecular Heck reaction of a methylenecycloheptene iodide, which generates the B, C, and D rings of the scopadulan ring system in 90% yield as a

Full text of DOI:10.1021/ja990404v

J. Am. Chem. Soc. 1999, 121, 5467-5480
5467
Enantiodivergent Total Syntheses of (+)- and (-)-Scopadulcic
Acid A
Martin E. Fox,1a Chi Li,1b Joseph P. Marino, Jr.,1c and Larry E. Overman*
Contribution from the Department of Chemistry, UniVersity of California, 516 Rowland Hall,
IrVine, California 92697-2025
ReceiVed February 8, 1999
Abstract: The first enantioselective total synthesis of scopadulcic acid A is described. The key step is a cascade
intramolecular Heck reaction of a methylenecycloheptene iodide, which generates the B, C, and D rings of the
scopadulan ring system in 90% yield as a single stereoisomer. A distinctive feature of these syntheses is the
use of stereoselective enolization to dictate which enantiomer of the natural product is produced.
Introduction
Scoparia dulcis L. (Scrophuraliaceae) is an erect perennial
herb growing to a half-meter in size and is found in many
tropical countries of the world. There are numerous reports of
its use as an herbal remedy of a variety of disorders.2,3 For
example, the Paraguayan crude drug Typcha´-Kuratuˆ prepared
from whole plants of S. dulcis L. is claimed by indigenous
peoples to improve digestion and protect the gastrointestinal
system.3c,4 During their investigations of this folk medicine,
Hayashi and co-workers identified from its pharmacologically
active extracts two structurally unique tetracyclic diterpene acids,
scopadulcic acids A (1, SDA) and B (2, SDB).5,6 Scopadulciol
(3) was later isolated by these workers from S. dulcis indigenous
to Taiwan and gives the same triol as 2 when reduced with
LiAlH4.7 A diterpene alcohol originally called dulcinol had been
described earlier from a Bangladeshi collection of S. dulcis8
and is believed to be identical with scopadulciol from 1H NMR
comparisons.9 Several years later, three additional diterpene
acids, exemplified by thyrsiflorin A (4), having the scopadulan
ring system (5) were isolated from Calceolaria thyrsiflora L.,
a plant also of the Scrophuraliaceae family.10
The scopadulcic acids and some of their semisynthetic
analogues exhibit a broad pharmacological profile, including
in vitro antiviral activity against herpes simplex virus type 1,11,12
in vitro and in vivo antitumor activity in various human cell
lines,13,14 and inhibition of tumor promotion by phorbol esters.15
SDB also shows powerful inhibitory activity against H+,K+-
adenosine triphosphatase (ATPase), the proton pump for gastric
acid secretion.16-18 Interestingly, SDB inhibits H+,K+-ATPase
quite differently from Omeprazole, a highly successful clinical
proton pump inhibitor.16 More recently, SDB has been shown
to inhibit bone resorption by osteoclast cells, suggesting that
the scopadulan diterpenes might be leads for developing
therapeutic agents to treat osteoporosis.19
(1) Current address: (a) Chiroscience Limited, C. S. P.-M. R., Cambridge,
CB4 4WE, U.K. (b) Bristol-Myers Squibb Pharmaceutical Research Institute,
P.O. Box 4000, Princeton, NJ 08543-4000. (c) SmithKline Beecham
Pharmaceuticals, P.O. Box 1539, King of Prussia, PA 19406-0939.
(2) Hostettmann, K. Phytochemistry of Plants Used in Traditional
Medicine; Oxford University Press: New York, 1995.
(3) See, inter alia: (a) Satyanarayana, K. J. Indian Chem. Soc. 1969,
46, 765-766. (b) Chow, S. Y.; Chen, S. M.; Yang, C. M.; Hsu, H. J.
Formosan Med. Assoc. 1974, 73, 739. (c) Gonzales Torres, D. M. Catalogo
de Plantas Medicinales (y Alimenticias y Utiles) Usada en Paraguay,
Asuncio´n, Paraguay, 1986; p 394.
(4) Shimizu, M.; Horie, S.; Terashima, S.; Ueno, H.; Hayashi, T.;
Arisawa, M.; Suzuki, S.; Yoshizaki, M.; Morita, N. Chem. Pharm. Bull.
1989, 37, 2531-2532.
(5) Hayashi, T.; Kishi, M.; Kawasaki, M.; Arisawa, M.; Shimizu, M.;
Suzuki, S.; Yoshizaki, M.; Morita, N.; Tezuka, Y.; Kikuchi, T.; Berganza,
L. H.; Ferro, E.; Basualdo, I. Tetrahedron Lett. 1987, 28, 3693-3696.
(6) Hayashi, T.; Kishi, M.; Kawasaki, M.; Arisawa, M.; Morita, N. J.
Nat. Prod. 1988, 51, 360-363.
(7) Hayashi, T.; Asano, S.; Mizutani, M.; Takeguchi, N.; Kojima, T.;
Okamura, K.; Morita, N. J. Nat. Prod. 1991, 54, 802-809.
(8) Ahmed, M.; Jakupovic, J. Phytochemistry 1990, 29, 3035-3037.
(9) Hayashi, T.; Okamura, K.; Tamada, Y.; Iida, A.; Fujita, T.; Morita,
N. Phytochemistry 1993, 32, 349-352
(10) Chamy, M. C.; Piovano, M.; Garbarino, J. A.; Miranda, C.;
Gambaro, V.; Rodriguez, M. L.; Ruiz-Perez, C.; Brito, I. Phytochemistry
1991, 30, 589-592.
(11) Hayashi, K.; Niwayama, S.; Hayashi, T.; Nago, R.; Ochiai, H.;
Morita, N. AntiViral Res. 1988, 9, 345-354.
(12) Hayashi, T.; Hayashi, K.; Uchida, K.; Niwayama, S.; Morita, N.
Chem. Pharm. Bull. 1990, 38, 239-242.
(13) Hayashi, T.; Kawasaki, M.; Miwa, Y.; Taga, T.; Morita, N. Chem.
Pharm. Bull. 1990, 38, 945-947.
(14) Hayashi, K.; Hayashi, T.; Morita, N. Phytother. Res. 1992, 6, 6-9.
(15) Nishino, H.; Hayashi, T.; Arisawa, M.; Satomi, Y.; Iwashima, A.
Oncology 1993, 50, 100-103.
(16) Asano, S.; Mizutani, M.; Hayashi, T.; Morita, N.; Takeguchi, N. J.
Biol. Chem. 1990, 265, 22167-22173.
(17) Hayashi, T.; Okamura, K.; Kakemi, M.; Asano, S.; Mizutani, M.;
Takeguchi, N.; Kawasaki, M.; Tezuka, Y.; Kikuchi, T.; Morita, N. Chem.
Pharm. Bull. 1990, 38, 2740-2745.
(18) Hayashi, T.; Kawasaki, M.; Okamura, K.; Tamada, Y.; Morita, N.;
Tezuka, Y.; Kikuchi, T.; Miwa, Y.; Taga, T. J. Nat. Prod. 1992, 55, 1748-
1755.
10.1021/ja990404v CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/20/1999

5468 J. Am. Chem. Soc., Vol. 121, No. 23, 1999
Fox et al.
Figure 1. X-ray model of scopadulcic acid A.
Figure 3. Plan for preparing (R,R)-7.
The unique and synthetically challenging atom connectivity
of the scopadulan diterpenes prompted us to extend our studies
in this area to develop an enantioselective route to this class of
pharmacologically significant natural products. In this paper,
we describe enantioselective total syntheses of (+)- and (-)-
scopadulcic acid A. Besides constituting the inaugural enanti-
oselective entry to the scopadulcic acids, these syntheses for
the first time rigorously establish the absolute configuration of
natural (-)-SDA (1).
Figure 2. Sequential Heck cyclizations to form the B, C, and D rings
of SDA.
Based initially on spectroscopic investigations, 1 and 2 were
advanced in 1987 as the structures of SDA and SDB, respec-
tively.5 Soon thereafter, the relative stereochemistry of SDA
was confirmed by single-crystal X-ray analysis of its methanol
solvate (Figure 1).6 The absolute stereochemistry of SDA and
SDB depicted in structures 1 and 2 has been proposed on the
basis of the positive Cotton effect observed in the CD spectra
of each diterpene acid.5
In 1993, our group reported the first total syntheses of (()-
SDA20 and (()-SDB,21,22 using in each case a bis-Heck
cyclization to create the B, C, and D rings of the scopadulan
ring system (Figure 2). The formation of the C9 and C12
quaternary stereocenters efficiently in a single step in these total
syntheses showcased the exceptional ability of intramolecular
Heck reactions to forge quaternary carbon centers, even in highly
congested environments.23 Ziegler and Wallace subsequently
reported total syntheses of (()-SDA, (()-SDB, and (()-
scopadulciol using a different strategy.24 More recently, Zara-
goza´ and co-workers reported the elaboration of (+)-podocarp-
8(14)-en-13-one to the methyl ester of the simplest scopadulan
diterpene, (-)-thyrsiflorin A (4).25 Approaches to the scopadulan
ring system have also been described by several research
groups.26,27
Results and Discussion
A. Synthesis Plan. In our earlier synthesis of (()-SDA, we
first formed the B, C, D rings as depicted in Figure 2, and at a
late stage generated the A ring through an aldol cyclization.20
During an early phase of these studies in the racemic series,
we learned that only one of the two C6 siloxy epimers of 6
underwent the pivotal Heck insertion of the exomethylene group
from the desired R-face to generate the trans-B/C ring fusion
of the scopadulan diterpenes.28,29 Heck cyclization of the other
epimer led to a mixture of products, two of which contain
bridged bicyclooctane units having the B/C cis-ring fusion found
in tetracyclic diterpenes of the aphidicolin and stemarin
families.30
Prior to the studies disclosed herein, the methylenecyclohep-
tene diastereomer that cyclized to generate the scopadulan ring
system was believed to possess the relative stereochemistry
depicted in intermediate 7 (Figure 3).20,31 As a result, our
inaugural studies directed toward (-)-SDA targeted cyclization
precursor 7, having the 6R,8R absolute configuration. As in our
(26) (a) Robichaud, A. J.; Meyers, A. I. J. Org. Chem. 1991, 56, 2607-
2609. (b) Tagat, J. R.; McCombie, S. W.; Puar, M. S. Tetrahedron Lett.
1996, 37, 8459-8462. (c) Tagat, J. R.; Puar, M. S.; McCombie, S. W.
Tetrahedron Lett. 1996, 37, 8463-8466. (d) Hall, D. G.; Caille, A. S.;
Drouin, M.; Lamothe, S.; Muller, R.; Deslongchamps, P. Synthesis 1995,
1081-1088. (e) Reddy, S. H. K.; Moeller, K. D. Tetrahedron Lett. 1998,
39, 8027-8030.
(27) The scopadulan skeleton has also been generated by rearrangement
of an aphidicolin derivative: Hanson, J. R.; Hitchcock, P. B.; Jarvis, A.
G.; Ratcliffe, A. H. J. Chem. Soc., Perkin Trans. 1 1992, 1773-1778.
(28) Kucera, D. J. Ph.D. Dissertation, University of California, Irvine,
1991.
(29) The scopadulan numbering system will be employed in the
discussion of all synthetic intermediates. Correct IUPAC designations of
intermediates are found in the Experimental Section.
(30) Rucker, P. V.; Overman, L. E. Unpublished studies, UCI.
(31) This erroneous assignment resulted in an incorrect specification of
the relative stereochemistry at C6 of structures 10-13 in ref 20.
(19) Miyahara, T.; Hayashi, T.; Matsuda, S.; Yamada, R.; Ikeda, K.;
Tonoyama, H.; Komiyama, H.; Matsumoto, M.; Nemoto, N.; Sankawa, U.
Bioorg. Med. Chem. Lett. 1996, 6, 1037-1042.
(20) Kucera, D. J.; O’Connor, S. J.; Overman, L. E. J. Org. Chem. 1993,
58, 5304-5306.
(21) Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem. Soc. 1993,
115, 2042-2044.
(22) Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem. Soc. 1997,
119, 12031-12040.
(23) For recent reviews of the use of intramolecular Heck reactions in
natural products total synthesis, see: (a) Link, J. T.; Overman, L. E. In
Metal-Catalyzed Cross Coupling Reactions; Stang, P. J., Diederich, F., Eds.;
Wiley-VCH: Weinheim, 1998; Chapter 6. (b) Link, J. T.; Overman, L. E.
CHEMTECH 1998, 28 (8, August), 19-26.
(24) Ziegler, F. E.; Wallace, O. B. J. Org. Chem. 1995, 60, 3626-3636.
(25) Abad, A.; Agullo´, C.; Arno´, M.; Marin, M. L.; Zaragoza´, R. J. Synlett
1997, 574-576.

Total Syntheses of (+)- and (-)-Scopadulcic Acid A
J. Am. Chem. Soc., Vol. 121, No. 23, 1999 5469
Scheme 1a
the reaction of water with 2 equiv of the ketocarbenoid. When
these precautions were taken, 14 could be prepared on multigram
scales in 80% yield and 88% ee.38,39 Even though butyrolactone
14 is a low-melting solid (mp 58-59 °C), the corresponding
racemate is a liquid at room temperature, allowing the enan-
tiomeric purity of this intermediate to be enhanced to greater
than 99% ee by a single recrystallization. The absolute config-
uration of 14 was confirmed by single-crystal X-ray analysis
of amide 15, which was formed from the reaction of 14 with
(S)-(-)-1-(1-naphthyl)ethylamine and acylation of this product
with 3,5-dinitrobenzoyl chloride.40,41 Treatment of lactone 14
with N,O-dimethylhydroxylamine hydrochloride in the presence
of trimethylaluminum provided amide 16 in high yield.42
Oxidation of this intermediate with tetrapropylammonium
perruthenate (TPAP) and N-methylmorpholine N-oxide (NMO)43
yielded aldehyde 17, which underwent subsequent Wittig
methylenation to give rise to cyclopropyl amide 11 in 43%
overall yield from 12.
The (R)-alkyl iodide 23, which contains 9 of the 10 skeletal
carbons of the A and B rings, was next prepared as summarized
in Scheme 2. Reaction of 3-(tert-butyldimethylsiloxy)propanal
(18)44 with the lithium salt of 2-(4′-pentynyl)-1,3-dioxolane45
provided rac-19, which was oxidized by the Swern procedure46
to yield ynone 20. A variety of asymmetric reducing conditions,
including Darvon-alcohol-LiAlH4,47-50 (R)-BINAL-H,51 and
oxazaborolidine-catalyzed borane reduction,52,53 were screened
for enantioselective reduction of 20; however, either the
efficiency of the reaction was poor or the enantiomeric excess
a Reaction conditions: (a) (S)-(-)-1-(1-naphthyl)ethylamine, Me3Al,
92%; (b) 3,5-dinitrobenzoyl chloride, DMAP, Et3N, CH2Cl2, 74%; (c)
MeNH(OMe)‚HCl, Me3Al; (d) TPAP, NMO; (e) Ph3PdCH2, THF, 0
°C.
earlier investigations in the racemic series, vinyl iodide 7 would
derive through standard synthetic transformations from cyclo-
heptenone 8. This ketone, which contains the critical C6 and
C8 stereocenters, was envisaged to arise from divinylcyclopro-
pane rearrangement of (Z)-enoxysilane 9.32-35 Since divinyl-
cyclopropane sigmatropic rearrangements strictly adhere to a
boat topography,35 the Z geometry of the enoxysilane unit would
translate to the R absolute configuration at C8 of cycloheptenone
8. Generation of the Z enoxysilane stereoisomer from a
cyclopropyl ketone precursor seemed plausible on the basis of
ample literature guidance on stereoselective enolization of
acyclic ketones.36 Last, the cyclopropyl ketone precursor of 9
would come from coupling the lithium reagent derived from
(R)-iodide 10 with cyclopropyl amide 11.
B. Unanticipated Synthesis of the 8S Stereoisomer of the
Cycloheptenone Intermediate. Our investigations began with
the enantioselective synthesis of 3-oxabicyclo[3.1.0]hexan-1-
one (14) by catalytic asymmetric intramolecular cyclopropana-
tion of diazoester 12 (Scheme 1). After screening several
possible catalysts, we found that the (R,R)-bis(oxazoline)copper
catalyst 13 reported by Evans and Woerpel was optimal.37 This
reaction was best performed by adding diazoacetate 12 slowly
using a syringe pump to a dilute chloroform solution of 13 (0.6
mol %). These conditions obviated the formation of the maleate
and fumarate byproducts arising from formal dimerization of
the ketocarbenoid intermediate. In addition, moisture had to be
rigorously excluded to prevent competitive formation of di(2-
methyl-2-propenyloxycarbonylmethyl) ether, which arises from
(38) Enantioenriched 5-methyl-2-oxo-3-oxabicyclo[3.1.0]hexane has also
been prepared from 12 by Doyle and co-workers.39 These workers studied
the enantioselectivity of this intramolecular cyclopropanation using several
asymmetric catalysts [chiral Rh(I) and Rh(II) catalysts and ent-13]; the
copper bis-oxazoline catalyst provides highest enantioselection.39c The
absolute configuration for the levorotatory (1S,5R) enantiomer of 14 is
incorrectly specified in refs 39a and 39c.
(39) (a) Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.; Dyatkin,
A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C. J.; Pieters,
R. J.; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L.; Martin,
S. F. J. Am. Chem. Soc. 1995, 117, 5763-5775. (b) Doyle, M. P.; Zhou,
Q. L.; Dyatkin, A. B.; Ruppar, D. A. Tetrahedron Lett. 1995, 36, 7579-
7582. (c) Doyle, M. P.; Peterson, C. S.; Zhou, Q.-L.; Nishiyama, H. Chem.
Commun. 1997, 36, 211-212.
(40) The authors have deposited coordinates for this derivative with the
Cambridge Crystallographic Data Centre. The coordinates can be obtained,
on request, from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, U.K.
(41) At the time 14 was first prepared, the sense of asymmetric induction
with copper(I) complexes of 13 in intramolecular cyclopropanations had
not been established. The model advanced by Evans and Woerpel37 to
rationalize bimolecular cyclopropanations brought about with this catalyst
correctly predicts the formation of (1S,2R)-14.
(42) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818. (b) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12,
989-993.
(43) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13-19.
(44) Prepared from 3-buten-1-ol: Pirrung, M. C.; Webster, N. J. G. J.
Org. Chem. 1987, 52, 3603-3613.
(45) Prepared from 5-hexyn-1-ol by Swern oxidation46 followed by
acetalization.
(32) (a) Piers, E.; Nagakura, I. Tetrahedron Lett. 1976, 3237-3240. (b)
Piers, E.; Burmeister, M. S.; Ressig, H.-U. Can. J. Chem. 1986, 64, 180-
187.
(33) Marino, J. P.; Browne, L. J. Tetrahedron Lett. 1976, 37, 3245-
3248.
(34) (a) Wender, P. A.; Filosa, M. P. J. Org. Chem. 1976, 41, 3490-
3491. (b) Wender, P. A.; Eissenstat, M. A.; Filosa, M. P. J. Am. Chem.
Soc. 1979, 101, 2196-2198.
(35) For a brief review, see: Piers, E. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
5, pp 971-998.
(36) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1984; Vol. 3, Part B, pp 1-110.
(37) (a) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J.
Am. Chem. Soc. 1991, 113, 726-728. (b) Evans, D. A.; Woerpel, K. A.;
Scott, M. J. Angew. Chem., Int. Ed. Engl. 1992, 31, 430-432.
(46) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(47) Yamaguchi, S.; Mosher, H. S. J. Org. Chem. 1973, 38, 1870-1877.
(48) Brinkmeyer, R. S.; Kapoor, V. M. J. Am. Chem. Soc. 1977, 99,
8339-8341.
(49) Cohen, N.; Lopresti, R. J.; Neukom, C.; Saucy, G. J. Org. Chem.
1980, 45, 582-588.
(50) Deeter, J.; Frazier, J.; Staten, G.; Staszak, M.; Weigel, L. Tetrahe-
dron Lett. 1990, 31, 7101-7104.
(51) Noyori, R.; Tomino, I.; Tanamoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6709-6716.
(52) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chung-Pin, C.; Singh, V.
K. J. Am. Chem. Soc. 1987, 109, 7925-7926.
(53) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.;
Carroll, J. D.; Corley, E. G.; Grabowski, E. J. J. Org. Chem. 1993, 58,
2880-2888.

5470 J. Am. Chem. Soc., Vol. 121, No. 23, 1999
Fox et al.
Scheme 2a
Scheme 3a
a Reaction conditions: (a) TMSOTf, Et3N, -25 °C; (b) HCl-H2O.
R1 ) CH2CH2CH(OCH2CH2O).
hydrogens in other stereoisomerically pure enoxysilanes failed
to offer conclusive evidence for the enoxysilane geometry, an
issue we will return to shortly.61 Heating 25 at 110 °C for 24 h
induced smooth Cope rearrangement to generate 26, and this
intermediate upon exposure to dilute aqueous HCl at room
temperature furnished a single cycloheptenone in 76% overall
yield from 24. The stereochemistry of this product was
misassigned at the time and resulted in us initially preparing
the unnatural enantiomer of scopadulcic acid A (vide infra).
This unexpected result prompted a careful reinvestigation of
our scopadulan A synthetic sequence, which, we will see,
demonstrated that the product of the sequence summarized in
Scheme 3 was ent-27.62
Unable to confirm the relative stereochemistry at C8 of
cycloheptenone intermediate produced from 24 by NMR
techniques, we attempted to obtain a crystalline derivative.
Numerous derivatives of ent-27 were prepared; however, all
failed to crystallize. After much experimentation, we succeeded
in converting ent-27 to the crystalline hexacyclic polyether 31,
which contains two units of the starting cycloheptenone (Scheme
4). Reduction of ent-27 with lithium tri-sec-butylborohydride
(L-Selectride) provided a single alcohol,63 which was semi-
hydrogenated to provide 29. Discharge of the silyl protecting
group and hydroxyl-directed epoxidation with VO(acac)2 and
t-BuO2H64 provided epoxy diol 30. Finally, when this interme-
diate was exposed to a catalytic amount of p-toluenesulfonic
acid, hexacyclic polyether 31 was formed in 64% yield. Single-
crystal X-ray analysis of this product revealed, to our surprise
at the time, that the cycloheptenone product of the Cope
rearrangement sequence had the S configuration at C8.40 It was
now clear, as is depicted in Scheme 3, that enolsilylation under
the Simchen conditions60 had generated the E enoxysilane
stereoisomer.
a Reaction conditions: (a) (OCH2CH2O)CH(CH2)3CtCLi, THF, -78
f 23 °C; (b) TPAP, NMO, 94%; (c) (R)-R-pinene, 9-BBN; (d) TIPS-
Cl, imidazole; (e) AcOH/H2O, THF; (f) I2, Ph3P, imidazole; (g) t-BuLi,
-78 °C, 11.
of 19 thus obtained was low. Asymmetric reduction of 20 was
best realized with (R)-B-isopinocampheyl-9-borabicyclo[3.3.1]-
nonane [(R)-Alpine-Borane] following procedures developed by
Brown and Midland54,55 to generate (R)-19 in 94% yield and
88% ee.56,57 The assignment of the R absolute configuration to
this product rested initially upon analogy with the known
absolute stereochemical bias for the reduction of ynones by (R)-
Alpine-Borane.54,55 Unambiguous confirmation of the absolute
configuration of (R)-19 was obtained through 1H NMR analysis
of the R and S Mosher esters of alcohol (R)-19.58 Protection of
alcohol (R)-19 as its triisopropylsilyl (TIPS) ether, followed by
selective cleavage of the TBDMS group with aqueous acetic
acid and reaction of the resulting primary alcohol with Ph3P,
I2, and imidazole, proceeded smoothly to form alkyl iodide (R)-
23. Generation of the organolithium derivative at -78 °C in
ether by reaction of (R)-23 with 2 equiv of t-BuLi,59 followed
by addition of amide 11, provided cyclopropyl ketone 24 in
84% yield.
Enolsilylation of cyclopropyl ketone 24 with TMSOTf and
Et3N60 led to the isolation of a single enoxysilane 25 (Scheme
1
3). This intermediate showed a H NMR signal at δ 5.16 for
the vinylic hydrogen of the enoxysilane grouping. However,
comparison of this signal with signals of comparable vinylic
(54) Brown, H. C.; Pai, G. G. J. Org. Chem. 1985, 50, 1384-1394.
(55) Midland, M. M.; Graham, R. S. Organic Syntheses; Wiley: New
York, 1990; Collect. Vol. 7, pp 402-406.
With the relative stereochemistry of the C6 and C8 centers
in ent-27 established through X-ray analysis of 31, we were in
a position to establish which C6 epimer of the trienyl iodide
intermediate efficiently undergoes bis-Heck cyclization to
generate rings B, C, and D of the scopadulan skeleton. To this
(56) Enantiomeric purity of this intermediate was determined by 1H NMR
analysis of the methyl mandelate derivative.
(57) Asymmetric reducing conditions recently described by Noyori and
co-workers, which were published after this phase of our synthesis was
completed, would appear to be particularly attractive for the synthesis of
(R)-21: Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738-8739.
(58) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543-2549.
(59) Neumann, H.; Seebach, D. Chem. Ber. 1978, 111, 2785-2812.
(60) (a) Simchen, G.; Kober, W. Synthesis 1976, 259-261. (b) Koba-
yashi, M.; Masumoto, K.; Nakai, E.; Nakai, T. Tetrahedron Lett. 1996, 37,
3005-3008. (c) For a review of enolsilylation with trialkyllsilyl perfluo-
roalkanesulfonates, see: Emde, H.; Domsch, D.; Feger, H.; Frick, U.; Go¨tz,
A.; Hergott, H. H.; Hofmann, K.; Kober, W.; Kra¨geloh, K.; Oesterle, T.;
Steppan, W.; West, W.; Simchen, G. Synthesis 1982, 1-26.
(61) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.;
Sohn, J. E.; Lampe, J. J. Org. Chem. 1980, 45, 1066-1080.
(62) When both enantiomers of an intermediate have been prepared, those
in the series leading to unnatural (+)-SDA are specified with the ent
designation. The preparation of 27, which is a precursor of natural (-)-
SDA, is described in Scheme 8.
(63) Ando, K.; Condroski, K. R.; Houk, K. N.; Wu, Y.-D.; Ly, S. K.;
Overman, L. E. J. Org. Chem. 1998, 63, 3196-3203.
(64) Sharpless, B.; K. B.; Michaelson, R. C. J. Org. Chem. 1970, 35,
6136.

Total Syntheses of (+)- and (-)-Scopadulcic Acid A
J. Am. Chem. Soc., Vol. 121, No. 23, 1999 5471
Scheme 4a
hydride (Red-Al)65 and reaction of the resulting vinylalane
intermediate with N-iodosuccinimide (NIS) gave ent-34 in 84%
overall yield from ent-27. To achieve high yields in the reductive
iodination step, it was essential to use freshly recrystallized NIS.
If any adventitious iodine was present, cyclization of the C6
hydroxyl group and the exomethylene group became a serious
side reaction. Protection of the C6 alcohol of ent-34 with a
TBDMS group generated the Z trienyl iodide cyclization
substrate ent-35. Much to our delight, the critical palladium-
catalyzed cyclization of ent-35 proceeded cleanly to afford, after
desilylation, a single tricyclic product, ent-36, [R]24 -42 (c
D
1.2, CHCl3), in 90% yield. The presence of Ag2CO3 in this bis-
Heck cyclization was paramount in suppressing migration of
the initially formed 1,2-disubstituted double bond of ent-36. As
first revealed in earlier studies in the racemic series,20 protection
of the C6 alcohol is required in order to achieve high yields in
the bis-Heck cyclization.
Consistent with the assignment of the C6-C8 relative
stereochemistry of ent-27, the alcohol substituent of ent-36 was
1
pseudoequatorial, as signaled by a 5% H-1H NOE observed
between the axial C6 and C8 methine hydrogens. As a final
check on the constitution of the tricyclic Heck product, ent-36
was oxidized43 to the enone, and the corresponding crystalline
thiosemicarbazone 37 was subjected to single-crystal X-ray
analysis.40 This examination confirmed both the relative and
absolute configuration of the tricyclic Heck product ent-36.
The high-yielding conversion of the (6R,8S)-trienyl iodide
ent-35 to ent-36 established that our earlier surmise in the
racemic series as to which diastereomer undergoes bis-Heck
cyclization was incorrect.20,66 A rationale for the success of this
and related Heck cyclizations will be presented later in this
paper.
a Reaction conditions: (a) L-Selectride, -25 °C; (b) Pd‚BaSO4, H2,
benzene; (c) Bu4NF; (d) VO(acac)2, t-BuO2H; (e) p-TsOH, CHCl3.
Scheme 5a
C. An Enantiodivergent Strategy for Preparing Both
Enantiomers of the Heck Cyclization Substrate. At this point,
we had established that the 6R,8R enantiomer of the Heck
cyclization precursor would be required to access natural (-)-
scopadulcic acid A (1). We entertained two possibilities for
obtaining this intermediate. One approach would be to synthesize
the enantiomer of cyclopropyl ketone 24 from the S enantiomer
of alkyl iodide 23 and the 1R,2S enantiomer of cyclopropyl
amide 11. However, a more intriguing strategy would be to
utilize the Z enoxysilane intermediate 40 in the [3,3]-rearrange-
ment step in order to establish the R configuration at the pivotal
C8 stereocenter (Figure 4). This latter approach had the attraction
that we could employ (1S,2R)-cyclopropyl amide 11, which was
already in hand and would only require that we prepare (S)-23.
To establish conditions for generating the Z enoxysilane
stereoisomer from a cyclopropyl ketone intermediate, we
examined enolization of the model ketone 44 having a â ethyl,
rather than a â vinyl, substituent (Scheme 6). This intermediate
was readily accessed from iodide 42 and amide 11, using
Wilkinson’s catalyst to selectively hydrogenate the vinyl group
of 43.67 The Simchen conditions (TMSOTf and Et3N)60 gener-
ated a 4:1 mixture of enoxysilanes 45 (δ 4.93, dCH) and 46 (δ
4.58, dCH). Fortunately, Ireland’s conditions, enolization with
LDA in 20% HMPA-THF followed by quenching with
a Reaction conditions: (a) Ph3PdCH2, THF, 0 °C; (b) TBAF, THF,
23 °C; (c) Red-Al, Et2O, 23 °C, NIS, -78 f 23 °C; (d) TBDMSCl,
imidazole, DMF; (e) 10% Pd(OAc)2, 20% Ph3P, Ag2CO3, THF, reflux,
TBAF, THF, 23 °C; (f) TPAP, NMO, 95%; (g) H2NCSNHNH2, AcOH,
82%. R1 ) CH2CH2CH(OCH2CH2O).
1
TMSCl,68 to the limits of detection by 500-MHz H NMR
(65) Denmark, S. E.; Jones, T. K. J. Org. Chem. 1982, 47, 4595-4597.
(66) The relative stereochemistry at C6 of rac-36 could easily been
established by careful H NMR analysis during our earlier investigations.
end, ent-27 was converted to trienyl iodide ent-35 by the four-
step sequence summarized in Scheme 5. Wittig methylenation
of ent-27 initially provided ent-32, [R]24D -58 (c 1.0, CHCl3),
which was treated with tetrabutylammonium fluoride (TBAF)
to remove the TIPS group. Reduction of the resulting propargylic
alcohol ent-33 with sodium bis(2-methoxyethoxy)aluminum
1
That the next step in the synthetic sequence was oxidation to the C6 ketone
undoubtedly contributed to this oversight.20
(67) Zutterman, F.; Krief, A. J. Org. Chem. 1983, 48, 1135-1137.
(68) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc.
1976, 98, 2868-2876.

5472 J. Am. Chem. Soc., Vol. 121, No. 23, 1999
Fox et al.
Scheme 7a
a Reaction conditions: (a) LDA, 20% HMPA-THF, -78 °C,
TMSCl, -78 f 0 °C; (b) HCl-H2O; (c) Ph3PdCH2, THF, 0 °C; (d)
TBAF, THF, 23 °C; (e) DEAD, PPh3, p-NO2-C6H4CO2H, 0 °C, 67%;
(f) NaOH (aq), 23 °C, 94%. R1 ) CH2CH2CH(OCH2CHO).
To examine the divinylcyclopropane rearrangement with
a Z enoxysilane unit, we treated cyclopropyl ketone 24 at
-78 °C sequentially with LDA in 20% HMPA-THF and
TMSCl. In this case, the presumed Z enoxysilane 47 underwent
rearrangement prior to warming to room temperature to furnish
siloxy cycloheptadiene 48 (Scheme 7). Hydrolysis of this
intermediate then gave rise to (6R,8R)-cycloheptenone 49, as a
single detectable stereoisomer, in 59% overall yield from 24. It
is reasonable that Cope rearrangement of the Z enoxysilane
intermediate took place at a temperature at least 80 °C lower
than that required for rearrangement of the corresponding E
enoxysilane intermediate, since boat conformer 47 has a
hydrogen (rather than the side chain) thrust over the cyclopro-
pane ring.
Figure 4. Enantiodivergent strategy for preparing (+)- and (-)-
scopadulcic acid A.
Scheme 6
Since 49 and diastereomer ent-27 showed nearly identical
NMR spectra, we decided to unambiguously confirm that we
had finally accessed an intermediate having the R configuration
at C8. This objective was accomplished in straightforward
fashion by conversion of 49 to 33 (Scheme 7). The optical
rotation of 33, [R]24D +65 (c 1.0, CHCl3), was opposite in sign
to that of ent-33, [R]24 -58 (c 1.0, CHCl3), which had been
D
synthesized earlier (Scheme 5). The somewhat higher optical
rotation of 33 likely arises from the lower temperature of the
Cope rearrangement of the Z enoxysilane intermediate. Since
the iodide employed to prepare 24 was not enantiopure (88%
ee), 24 was contaminated with ∼6% of its C6 epimer. Boat
topography rearrangement of the Z enoxysilane derivative of
this minor C6 epimer would lead to 27 and consequently slightly
decrease the enantiopurity of ent-27. In contrast, any E enoxy-
silane derivative of the minor C6 epimer would not rearrange
at room temperature; thus, the presence of this minor epimer in
24 would not erode the enantiopurity of 49 produced by the
sequence summarized in Scheme 7.
analysis, led to the formation of only the Z stereoisomer 46.
Since Heathcock had previously demonstrated that the chemical
shift of the â vinylic hydrogen was not a reliable method to
assign enoxysilane stereochemistry,61 the 13C NMR method
introduced by these workers was employed; diagnostic carbon
shifts are shown in Scheme 6.

Total Syntheses of (+)- and (-)-Scopadulcic Acid A
J. Am. Chem. Soc., Vol. 121, No. 23, 1999 5473
Scheme 8a
Scheme 9a
a Reaction conditions: (a) TPAP, NMO; (b) Me2Zn, Ni(acac)2, 0 f
23 °C; (c) (CH2OH)2, (OCH2CH2O)CHOMe, Amberlyst 15; (d)
m-CPBA, NaHCO3, 0 °C; (e) LiAlH4, 23 °C; (f) 20% aqueous HCl,
THF, 50 °C; (g) MOM-Cl, (i-Pr)2NEt.
a Reaction conditions: (a) steps c-f of Scheme 2 with (S)-R-pinene
used in step c; (b) t-BuLi, Et2O, -78 °C, 11, -78 f 0 °C; (c) LDA,
20% HMPA-THF, -78 °C, TMSCl, -78 f 0 °C; (d) HCl-H2O; (e)
Ph3PdCH2, THF, 0 °C; (f) TBAF, THF, 23 °C; (g) Red-Al, Et2O, 23
°C, NIS, -78 f 23 °C; (h) TBDMSCl, imidazole, DMF; (i) 30%
Pd(OAc)2, 60% Ph3P, Ag2CO3, THF, reflux, TBAF, THF, 23 °C. R1
) CH2CH2CH(OCH2CH2O).
From this stage on, the synthesis of (-)-SDA (1) was
accomplished by an optimized version of the sequence employed
in our earlier synthesis of (()-SDA.20 Since the synthesis of
(()-SDA has been described in communication format only,
key problems that were overcome in developing the ultimately
successful sequence for preparing scopadulcic acid A from a
tricyclic Heck product will be briefly noted. A challenging
aspect of this sequence was introducing the angular methyl
group at C10, since C10 is contiguous to the C9 quaternary
center. Oxidation of allylic alcohol 36 with TPAP and NMO
provided enone 53 (Scheme 9), which was a much better
Michael acceptor than a related tetrasubstituted enone that
was an intermediate in our synthesis of (()-SDB.21,22 Thus,
53 did react with Me2CuLi to provide 54; however, in
some runs the product of 1,2-addition was a significant
byproduct. More reliable was Ni(acac)2-catalyzed addition of
Me2Zn,71 which provided 54 in 88% yield. As expected,
conjugate addition of the methyl group was highly stereoselec-
tive and occurred from the face opposite the axial ethano bridge.
The oxygen functionality at C13 was next introduced by
protecting the C6 ketone as a 1,3-dioxolane and oxidation of
the resulting bis-ketal 55 with m-chloroperbenzoic acid, which
also occurred selectively from the â-face, to deliver 56 in
excellent overall yield. Reduction of 56 with LiAlH4 led to a
single secondary alcohol 57. That this product arose from axial
hydride delivery was readily confirmed by the absence of
D. Total Synthesis of (-)- and (+)-Scopadulcic Acid A.
With our ability to establish the C8 R stereochemistry of a Heck
cyclization precursor through divinylcyclopropane rearrange-
ment of a Z enoxysilane intermediate established, and the
knowledge that the 6S,8R stereochemistry is required for
efficient bis-Heck cyclization, we turned to the total synthesis
of (-)-SDA. The synthesis began with the preparation of iodide
(S)-23 from ketone 20 (Scheme 8). This iodide was available
in 85-89% ee69 by the sequence described in Scheme 2, with
an important exception that reduction of 20 was accomplished
with (S)-B-isopinocampheyl-9-borabicyclo[3.3.1]nonane.54,55 Lithi-
ation of (S)-23 with t-BuLi, followed by condensation of the
resulting organolithium intermediate with amide 11, provided
cyclopropyl ketone 52 in good yield. Careful purification of 52
by flash chromatography employing a solvent gradient allowed
the minor C6 epimer to be removed to provide 52 on multigram
scale as a single stereoisomer.
Ketone 52 was then added dropwise at -78 °C to 1.25 equiv
of LDA in 20% HMPA-THF and quenched with 3.0 equiv of
TMSCl, and after the solution warmed to room temperature,
the resulting siloxy cycloheptadiene was hydrolyzed with dilute
aqueous HCl to provide (6S,8R)-cycloheptenone 27 in 75%
overall yield (Scheme 8). Following exactly the sequence
optimized in the enantiomeric series, this intermediate was
(70) The enantiopurity of 33 should be at least 99.8%, since it derives
from combination of fragments of 88 and >99% ee. Two factors, each of
which alone would have been sufficient, dictate that there would have been
no loss in enantiopurity in the conversion of 52 f 27: (a) the sample of
52 employed in the Cope rearrangement step contained no detectable C6
epimer, and (b) any (E)-enoxysilane produced upon enolization of 52 would
not undergo Cope rearrangement at room temperature.
converted to 33, [R]24 +64 (c 1.0, CHCl3).70 Transformation
D
of 33 to 35, Heck cyclization of 35, and discharge of the alcohol
protecting group provided the key tricyclic intermediate 36,
[R]24 +49 (c 1.2, CHCl3), in 90% yield.
D
(71) Luche, J.-L.; Petrier, C.; Lansard, J.-P.; Greene, A. E. J. Org. Chem.
1983, 48, 3837-3839.
(69) Determined for alcohol precursor (S)-19.56

5474 J. Am. Chem. Soc., Vol. 121, No. 23, 1999
Fox et al.
Scheme 10a
provide the C6 axial alcohol, which was silylated to furnish
61. The remaining substituent at C4 was introduced with
complete stereocontrol by deprotonation of 61 with LDA
followed by quenching with (benzyloxy)methyl bromide (BOM-
Br) to give 62 in 82% yield. To ensure the success of this
reaction, BOM-Br must be freshly prepared and purified by
distillation prior to use.73 Again, the angular methyl group at
C10 regulated facial selectivity and the alkoxymethyl group
was introduced exclusively from the R face.
Hydrolysis of the axial, tertiary carbinyl nitrile was ac-
complished under forcing conditions by heating 62 at 140 °C
with KOH. Acidification of this product and esterification of
the resulting carboxylic acid with diazomethane provided 63
in high yield. At this point, the axial C6 benzoate was introduced
by reaction of 63 with benzoyl chloride and 4-(dimethylamino)-
pyridine (DMAP) in pyridine at 100 °C to provide benzoate 64
in an optimized overall yield of 76% from 62. The MOM ether
was then cleaved in excellent yield with hot methanolic HCl,
and the resulting alcohol 65 was oxidized with pyridinium
chlorochromate (PCC)74 to furnish 66. Finally, the methyl ester
was cleaved with lithium n-propylmercaptide75 and the benzyl
ether cleaved by conventional catalytic hydrogenolysis to furnish
(-)-scopadulcic acid A (1), [R]24D -5.8 (c 0.4, CHCl3), in 65%
yield. Since the reported rotation of natural SDA at the sodium
D line is small, [R]24D -5.7 (c 0.1, CHCl3), confirmation of the
identity of synthetic (-)-SDA with a sample of the natural
product was unambiguously secured by circular dichroism
spectra: synthetic (-)-SDA, [Θ]24
+8230 (c 0.71 mM,
292
MeOH); natural (-)-SDA, [Θ]24292 +6140 (c 0.7 mM, MeOH).
Following exactly the sequence described for the natural
series, ent-36 was converted to (+)-scopadulcic acid. Synthetic
(+)-SDA (1) showed [R]24D +5.4° (c 0.4, CHCl3) and [Θ]24
a Reaction conditions: (a) Et2AlCN, TMSCl, THF, 0 °C; (b) LiAlH4,
-78 °C, TMSCl, DMAP, pyridine-CH2CH2; (c) LDA, THF, 0 °C,
BnOCH2Br, -78 f 0 °C; (d) KOH, K2CO3, 140 °C; CH2N2, Et2O, 0
f 23 °C; (e) BzCl, DMAP, pyridine, 100 °C; (f) HCl, MeOH, 70 °C;
(g) PCC, 4-Å molecular sieves, 23 °C; (h) n-PrSLi, HMPA, 23 °C,
72%; H2, 10% Pd-C, MeOH, 90%.
291
-6620 (c 0.7 mM, MeOH).
E. Stereoselection in the Bis-Heck Cyclization. The ster-
eochemical requirements for the central bis-Heck cyclization
of our scopadulan diterpene synthesis approach are now clearly
defined; the analysis that follows corrects the erroneous31 brief
discussion of this issue in our preliminary communication.20
As illustrated for the 6S,8R-enantiomer in Figure 5, the B, C,
and D rings of the scopadulan skeleton are generated when the
C6 and C8 stereocenters of the cyclization precursor have
opposite absolute configurations. In this series, the C6 siloxy
substituent of intermediates 68 and 69, and tricyclic product
70, would be quasi-equatorial. Examination of molecular models
suggests that insertion topography 67, which involves reaction
of the Si face of the exomethylene group and has a favored
(nearly coplanar) orientation of the Pd-C σ bond and the C-C
π bonds,76 would have the nascent B ring coiled in a twist
conformation in which the siloxy substituent would be quasi-
equatorial.77
1
coupling in the H NMR spectrum between the C8 and C13
methine hydrogens.
Exposure of 57 to 10% aqueous HCl-THF at room temper-
ature selectively cleaved the C6 dioxolane, while the use of
20% aqueous HCl-THF led to cleavage of both dioxolane
groups. The keto aldehyde produced under these second
conditions could be isolated and subsequently treated with acid
at higher temperature to close the A ring. However, we found
that the conversion of 57 to the crystalline tetracyclic enone 58
was most efficiently accomplished in one step by heating a 4:1
solution of THF and 20% aqueous HCl at 50 °C, which provided
58 in 74% yield. At this point, the C13 alcohol was protected
as a methoxymethyl (MOM) ether to furnish 59.
Under identical Heck reaction conditions, the diastereomeric
cyclization precursor (illustrated in Figure 5 for the 6R,8R
enantiomer 71) cyclizes to form a complex mixture of polycyclic
products.20 Although this mixture has not been resolved for
After examining several strategies for elaborating the remain-
ing functionality at carbons 4 and 6, a quite direct strategy
emerged (Scheme 10). Conjugate addition of Et2AlCN72 to
enone 59 took place solely from the â-face; however, quenching
of the resulting aluminum enolate with acid provided some of
the A/B cis product in addition to 60. Fortunately, if the addition
of Et2AlCN was conducted in the presence of freshly purified
TMS-Cl and the resulting ∆5,6 enoxysilane was hydrolyzed
with dilute aqueous HCl, the trans-fused ketone 60 was
generated cleanly in 88% yield. Reaction of this intermediate
with LiAlH4 at -78 °C selectively reduced the C6 ketone,
exclusively from the face opposite to the C10 methyl group, to
(73) Connor, D. S.; Klein, G. W.; Taylor, G. N.; Boeckmann, R. K., Jr.;
Medwid, J. B. Orgaic Syntheses; Wiley: New York, 1988; Collective
Volume 6, pp 101-103.
(74) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647.
(75) Bartlett, P. A.; Johnson, W. S. Tetrahedron Lett. 1970, 4459.
(76) (a) Abelman, M. M.; Overman, L. E.; Tran, V. D. J. Am. Chem.
Soc. 1990, 112, 6959. (b) Overman, L. E.; Abelman, M. M.; Kucera, D. J.;
Tran, V. D.; Ricca, D. J. Pure Appl. Chem. 1992, 64, 1813.
(77) That the nascent B ring would adopt a twist conformation was
missed in our earlier analysis of insertion topographies and contributed to
our initial misassignment20 of which diastereomer would lead to the
scopadulan ring system.
(72) Nagata, W. In Organic Reactions; Wiley: New York, 1977; Vol.
25, pp 255-476.

Total Syntheses of (+)- and (-)-Scopadulcic Acid A
J. Am. Chem. Soc., Vol. 121, No. 23, 1999 5475
Figure 5. Bis-Heck cyclizations of the 6S,8R- and 6R,8R-diastereomers; ligands on palladium are not shown.
cyclization substrates having R ) (OCH2CH2O)CH2CH2CH2,
in a model series (R ) Me) that will be described elsewhere,78
the major product 76 has a trans relationship of the 1 carbon
bridge and the C8 hydrogen. Since 76 would derive from initial
insertion into the Re face of the exomethylene group (74 f
75, R ) Me), and since the initial insertion step is not likely to
be reversible,79,80 we conclude that the disparate outcome of
Heck cyclizations in the two diastereomeric series arises in the
initial insertion step. As suggested in Figure 5, a destabilizing
interaction between the palladium substituent and the siloxy
group in 71 could direct the 6R,8R diastereomer toward the 74
f 75 pathway and, thus, away from forming the scopadulan
skeleton.
Regioselection in the second insertion step is undoubtedly
influenced by the dramatically decreasing stability of metal-C
σ bonds as the degree of substitution at carbon increases.81,82
Product 70, which is formed exclusively, would arise from
insertion of 68 to generate cyclohexylpalladium intermediate
69, having palladium attached to the secondary carbon center
C13.
∼1% from (1S,5R)-γ-butyrolactone 14, which is available in
two steps and 60% yield from methallyl alcohol. These inaugural
enantioselective total syntheses of the scopadulan diterpenes,
moreover, rigorously establish the absolute configuration of
scopadulcic acid A. The central transformation is a palladium-
catalyzed bis-Heck cyclization of a 5-methylenecycloheptenyl
iodide, which occurs with complete stereo- and regioselectivity,
to construct the B, C, and D rings of the scopadulan skeleton
(Figure 2). An additional notable feature of these syntheses is
the use of enolization stereoselection to dictate which enantiomer
of the natural product is produced (Figure 4). We anticipate
that the enantioselective synthesis strategy detailed here could
be used to prepare other scopadulan diterpenes and analogues,
as well as to access different polycyclic structures containing a
bicyclo[3.2.1]octane substructure.
Experimental Section83
(1S,5R)-5-Methyl-2-oxo-3-oxabicyclo[3.1.0]hexane (14). The (R,R)-
bis(oxazoline) catalyst 1337 (130 mg, 0.26 mmol) was weighed in a
glovebox and added to a reaction flask; the flask was purged with argon,
and freshly distilled CHCl3 (415 mL) was added under an argon
atmosphere. A solution of diazoester 12 (5.52 g, 39.4 mmol)84 and
CHCl3 (100 mL) then was added by syringe pump (2.3 mL/min) at
room temperature. After the addition was complete, the reaction solution
was washed with aqueous EDTA (0.1 M, 100 mL), and the aqueous
layer was extracted with CH2Cl2 (2 × 50 mL). The combined organic
Conclusion
Total syntheses of (-)- and (+)-scopadulcic acid A (1 and
ent-1) were completed in 27 steps and with an overall yield of
(78) Overman, L. E.; Rucker, P. V.; O’Connor, S. J. Manuscript to be
submitted for publication.
(79) We are not aware of documented examples of â-alkyl elimination
of alkylpalladium complexes. Heck insertions to generate cyclopropylcarbi-
nylpalladium complexes are reversible.80
(80) Owczarczyk, Z.; Lamaty, F.; Vawter, E. J.; Negishi, E. J. Am. Chem.
Soc. 1992, 114, 10091.
(81) Jones, W. D., Feher, F. J. Acc. Chem. Res. 1989, 22, 91.
(82) More than this factor is obviously involved, since stereoisomer 75
(R ) Me) preferentially inserts to form 76.78
(83) General experimental details have been described: Minor, K. P.;
Overman, L. E. J. Org. Chem. 1997, 62, 6379. Optical rotations were
measured with a Jasco DIP-360 polarimeter. N-Iodosuccinimide was purified
by recrystallization from CCl4-1,4-dioxane, and LiBr was dried by placing
it in an evacuated flask and heating with a heat gun until the solid just
began to melt.
(84) Doyle, M. P.; Bagheri, V.; Wandless, T. J.; Harn, N. K.; Brinker,
D. A.; Eagle, C. T.; Loh, K.-L. J. Am. Chem. Soc., 1990, 112, 1906-1912.

5476 J. Am. Chem. Soc., Vol. 121, No. 23, 1999
Fox et al.
layers were dried (Na2SO4), filtered, and concentrated. The residue was
purified by flash chromatography (1:1 hexanes-Et2O) to give 3.55 g
(80%) of lactone 14 as a colorless solid, which was recrystallized from
hexanes to give 2.20 g (62%) of enantiomerically pure (>99% ee, GLC
analysis of 16 using a cyclodextrin column) 14 as long colorless needles:
1.31 (s, 3H), 1.04 (dd, J ) 7.8, 4.6, 1H); 13C NMR (125 MHz, CDCl3)
δ 171.2, 139.7, 113.0, 61.5, 32.5, 27.2, 27.1, 21.7, 20.2; IR (film) 1655,
993 cm-1; HRMS (CI, isobutane) m/z 170.1176 (170.1181 calcd for
C9H16NO2, MH). Anal. Calcd for C9H15NO2: C, 63.88; H, 8.93; N,
8.28. Found: C, 63.69; H, 9.00; N, 8.25.
38 mp 58-59 °C; Rf ) 0.25 (1:1 hexanes-Et2O); [R]26D -53.3, [R]26
(1S,2R,2′S-1-[1′-Oxo-4′-(triisopropylsiloxy)-10′-(1,3-dioxolanyl)-
5′-decynyl]-2-ethenyl-2-methylcyclopropane (52). A solution of iodide
(S)-23 (12.3 g, 25.7 mmol) and Et2O (25 mL) was added dropwise by
cannula to a solution of tert-butyllithium (1.58 M in pentane, 34.2 mL)
and Et2O (25 mL) at -78 °C. The resulting solution was maintained
at -78 °C for 30 min, and then a solution of amide 11 (4.79 g, 28.2
mmol) and Et2O (25 mL) was added dropwise. After being stirred for
10 min, the reaction was warmed to 0 °C, maintained at 0 °C for 1.5
h, and quenched with saturated aqueous NH4Cl (25 mL) and H2O (300
mL). The resulting mixture was extracted with CH2Cl2 (4 × 250 mL),
and the combined organic layers were dried (Na2SO4), filtered, and
concentrated. The crude product was purified by flash chromatography
(12:1 hexanes-EtOAc) to yield 8.2 g (70%) of cyclopropyl ketone 52
as a clear oil: Rf ) 0.30 (12:1 f 10:1 hexanes-EtOAc); [R]24D +75.7,
[R]24 +81.2, [R]24 +94.8, [R]24 +196, [R]24 +259 (c 1.0,
577
-59.6, [R]26546 -71.2, [R]26435 -162, [R]26405 -226 (c 1.0, EtOH); 1H
NMR (300 MHz, CDCl3) δ 4.23 (d, J ) 9.1 Hz, 1H), 4.09 (d, J ) 9.1
Hz, 1H), 1.85 (dd, J ) 9.0, 3.3 Hz, 1H), 1.39 (s, 3H), 1.19 (dd, J )
9.0, 4.7 Hz, 1H), 1.03 (dd, J ) 4.6, 3.3 Hz, 1H); 13C NMR (300 MHz,
CDCl3) δ 176.7, 73.5, 25.3, 23.7, 19.0, 17.0; IR (KBr) 1751 cm-1
.
Anal. Calcd for C6H8O2: C, 64.27; H, 7.19. Found: C, 64.28; H, 7.18.
(1S,2R)-1-(N,O-Dimethylhydroxamido)-2-hydroxymethyl-2-me-
thylcyclopropane (16). Trimethylaluminum (2.0 M in toluene, 21.4
mL) was added dropwise to a stirring suspension of N,O-dimethylhy-
droxylamine hydrochloride (4.18 g, 42.8 mmol)42 in toluene (72 mL)
at 0 °C. The mixture was allowed to warm to room temperature for 30
min. It then was recooled to 0 °C, and a solution of lactone 14 (2.40
g, 21.4 mmol) and toluene (24 mL) was added dropwise. The reaction
was warmed to room temperature and maintained at room temperature
for 30 min before being transferred into a solution of saturated aqueous
potassium sodium tartrate-H2O (1:1, 240 mL). The resulting mixture
was extracted with CH2Cl2 (240 mL), the organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (2 × 150 mL). The
combined organic layers were dried (Na2SO4), filtered, and concentrated
to give 3.62 g (98%) of amide 16 as a colorless oil: Rf ) 0.20 (Et2O);
[R]24 +49.8, [R]24 +45.0, [R]24 +61.4, [R]24 +101, [R]24
577
546
435
405
1
CHCl3); H NMR (400 MHz, CDCl3) δ 5.75 (dd, J ) 17.4, 10.8 Hz,
1H), 5.02 (dd, J ) 17.4, 1.4 Hz, 1H), 4.98 (dd, J ) 10.8, 1.4 Hz, 1H),
4.84 (t, J ) 4.6 Hz, 1H), 4.50 (m, 1H), 3.95-3.89 (m, 2H), 3.86-3.80
(m, 2H), 2.72-2.62 (m, 2H), 2.22 (td, J ) 7.0, 1.8 Hz, 2H), 2.12 (dd,
J ) 7.4, 6.1 Hz, 1H), 1.91-1.85 (m, 2H), 1.75-1.70 (m, 2H), 1.62-
1.56 (m, 3H), 1.30 (s, 3H), 1.10-1.04 (m, 22H); 13C NMR (125 MHz,
CDCl3) δ 207.0, 138.5, 113.3, 104.1, 84.3, 81.6, 64.8, 62.1, 40.0, 37.0,
D
577
546
435
405
32.9, 32.8, 30.7, 23.0, 22.7, 22.1, 18.6, 18.0, 12.2; IR (film) 1698 cm-1
;
1
+121 (c 1.2, CHCl3); H NMR (300 MHz, C6D6) δ 3.77-3.74 (m,
2H), 3.19 (s, 3H), 2.93 (t, J ) 6.1 Hz, 1H), 2.89 (s, 3H), 1.89 (br s,
1H), 1.50 (t, J ) 5.0 Hz, 1H), 1.05 (s, 3H), 0.58 (dd, J ) 8.2, 4.3,
1H); 13C NMR (125 MHz, C6D6) δ 173.2, 64.9, 61.5, 33.0, 29.2, 24.5,
23.1, 18.6; IR (film) 1635 cm-1; HRMS (CI, isobutane) m/z 174.1123
(174.1130 calcd for C8H16NO3, MH). Anal. Calcd for C8H15NO3: C,
55.47; H, 8.73; N, 8.09. Found: C, 55.21; H, 8.80; N, 8.01.
HRMS (CI, isobutane) m/z 462.3155 (462.3165 calcd for C27H46O4Si,
M).
(2R,2′S-2-[2′-(Triisopropylsiloxy)-8′-(1,3-dioxolanyl)-3′-octynyl]-
5-methyl-cyclohept-4-en-1-one (27). n-Butyllithium (2.47 M in hex-
anes, 1.6 mL) was added dropwise to stirring diisopropylamine (0.51
mL, 3.9 mmol) at 0 °C, and the concentrated hexane solution of LDA
was maintained for 10 min at 0 °C. Tetrahydrofuran (52 mL) was added,
the resulting solution was cooled to -78 °C, and freshly distilled HMPA
(17.5 mL) was then added.68 After the mixture was stirred for 15 min,
a solution of ketone 52 (1.4 g, 3.0 mmol) and THF (18 mL) was added
dropwise. After 5 min, TMSCl (1.2 mL, 9.0 mmol) was added, and
the reaction was stirred for 15 min at -78 °C. The reaction was then
warmed to 0 °C and, after 45 min, was poured into saturated aqueous
NaHCO3 (100 mL), and the aqueous solution was extracted with pentane
(4 × 75 mL). The pentane extracts were then washed with saturated
aqueous NaHCO3 (3 × 50 mL), dried (Na2SO4), filtered, and
concentrated to provide the crude siloxy cycloheptadiene intermediate
as a yellow oil.
(1S,2R)-1-(N,O-Dimethylhydroxamido)-2-formyl-2-methylcyclo-
propane (17). A suspension of alcohol 16 (6.14 g, 35.5 mmol),
N-methylmorpholine N-oxide (NMO, 6.24 g, 53.2 mmol), 4-Å molec-
ular sieves (6.2 g, powdered, activated), and CH2Cl2-MeCN (9:1, 220
mL) was stirred for 30 min at room temperature, and then tetra-n-
propylammonium perruthenate (TPAP, 310 mg, 0.89 mmol) was added
portionwise.43 The resulting mixture was stirred at room temperature
for 30 min and filtered through a short silica gel column (Et2O). The
filtrate was carefully concentrated at room temperature, and the residue
was purified by flash chromatography (2:1 Et2O-pentane) to give 5.56
g (92%) of aldehyde 17 as a colorless oil: Rf ) 0.45 (Et2O); [R]24
D
+102, [R]24 +105, [R]24 +119, [R]24 +232, [R]24 +296 (c
577
1
546
435
405
1.2, CHCl3); H NMR (300 MHz, C6D6) δ 9.44 (s, 1H), 2.97 (s, 3H),
2.76 (s, 3H), 2.19 (br s, 1H), 1.96 (dd, J ) 6.6, 4.9 Hz, 1H), 1.05 (s,
3H), 0.74 (dd, J ) 7.8, 4.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
201.3, 169.3, 61.8, 35.2, 32.5, 28.1, 19.5, 17.2; IR (film) 1707, 1654
cm-1; HRMS (CI, isobutane) m/z 172.0975 (172.0973 calcd for C8H14-
NO3, MH). Anal. Calcd for C8H13NO3: C, 56.13; H, 7.65; N, 8.18.
Found: C, 55.91; H, 7.61; N, 8.12.
A solution of this material (1.6 g, 2.9 mmol), 5% aqueous HCl (1
mL), and a 10:1 solution of THF/H2O (22 mL) was maintained at room
temperature for 1 h and then diluted with H2O (10 mL). The reaction
mixture was extracted with CHCl3 (4 × 25 mL), the CHCl3 extracts
were dried (Na2SO4), filtered, and concentrated, and the residue was
purified by flash chromatography (7:1 f 5:1 f 4:1 petroleum ether-
Et2O) to provide 1.04 g (74%) of cycloheptenone 27 as a clear oil: Rf
) 0.30 (5:1 petroleum ether-Et2O); [R]24D -1.9, [R]24577 -1.0, [R]24
(1S,2R)-1-(N,O-Dimethylhydroxamido)-2-ethenyl-2-methylcyclo-
propane (11). Potassium hexamethyldisilazide (0.5 M in toluene, 78
mL) was added dropwise to a rapidly stirring suspension of methyl-
triphenylphosphonium bromide (15.1 g, 42.3 mmol) in THF (75 mL)
at 0 °C. The resulting yellow suspension was warmed to room
temperature for 30 min and then cooled to -78 °C. A solution of
aldehyde 17 (5.56 g, 32.5 mmol) and THF (75 mL) was added by
cannula. The reaction was warmed to 0 °C for 1 h and quenched with
saturated aqueous NH4Cl (0.75 mL). The mixture was diluted with
pentane (300 mL) and filtered, and the filtrate was cooled to -30 °C.
The resulting suspension was filtered, and the filtrate was concentrated
(trituration with pentane was repeated 3 times). The remaining liquid
was purified by bulb-to-bulb distillation (100 °C, 0.5 mm) to give 4.34
546
1
+0.5, [R]24 +13.6, [R]24 +27.4 (c 1.3, CHCl3); H NMR (300
435
405
MHz, CDCl3) δ 5.48-5.45 (m, 1H), 4.85 (t, J ) 4.6 Hz, 1H), 4.49 (t,
J ) 6.5 Hz, 1H), 3.98-3.81 (m, 4H), 3.17-3.09 (m, 1H), 2.70-2.65
(m, 1H), 2.64-2.45 (m, 2H), 2.36-2.03 (m, 7H), 1.78-1.69 (m, 2H),
1.74 (br s, 3H), 1.65-1.56 (m, 2H) and 1.09-1.03 (m, 21H); 13C NMR
(75 MHz, CDCl3) δ 213.8, 137.4, 122.5, 104.2, 84.4, 82.1, 64.9, 61.4,
47.0, 41.8, 40.0, 33.0, 31.2, 29.2, 26.2, 23.0, 18.6, 18.1, 12.3; IR (film)
1706 cm-1; HRMS (EI) m/z 462.3149 (462.3165 calcd for C27H46O4-
Si, M). Anal. Calcd for C27H46O4Si: C, 70.08; H, 10.02. Found: C,
70.16; H, 9.97.
(2R,2′S)-2-[2′-Triisopropylsilyloxy-8′-(1,3-dioxolanyl)-3′-octynyl]-
5-methyl-1-methylenecyclohept-4-ene (32). sec-Butyllithium (1.3 M
in cyclohexane, 16.4 mL) was added dropwise to a stirred suspension
of methyltriphenylphosphonium bromide (10.1 g, 28.3 mmol) in THF
(40 mL) at 0 °C. The resulting solution was maintained at 0 °C for 30
min and then cooled to -78 °C, and a solution of ketone 27 (3.28 g,
7.09 mmol) and THF (28 mL) was added dropwise by cannula. The
g (79%) of 11 as a colorless liquid: Rf ) 0.57 (Et2O); [R]24 +77.0,
D
[R]24 +81.0, [R]24 +92.2, [R]24 +163, [R]24 +201 (c 1.2,
577
546
435
405
1
CHCl3); H NMR (300 MHz, CDCl3) δ 5.76 (dd, J ) 17.4, 10.8 Hz,
1H), 5.08 (dd, J ) 17.4, 1.2 Hz, 1H), 5.02 (dd, J ) 10.8, 1.2 Hz, 1H),
3.65 (s, 3H), 3.19 (s, 3H), 2.25 (br s, 1H), 1.53 (dd, J ) 5.8, 4.6, 1H),

Total Syntheses of (+)- and (-)-Scopadulcic Acid A
J. Am. Chem. Soc., Vol. 121, No. 23, 1999 5477
reaction was allowed to warm to 0 °C over 1 h and was quenched with
saturated aqueous NH4Cl (100 mL). The resulting mixture was extracted
with CH2Cl2 (100 mL and 2 × 50 mL), and the combined organic
layers were dried (Na2SO4), filtered, and concentrated. The residue was
purified by flash chromatography (32:1 f 19:1 hexanes-EtOAc) to
give 2.79 g (85%) of diene 32 as a colorless oil: Rf ) 0.25 (19:1
colorless oil: Rf ) 0.35 (95:5 hexanes-EtOAc); [R]24D +45.8, [R]24
577
+48.7, [R]24546 +56.8, [R]24435 +108, [R]24405 +136 (c 1.1, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 5.52 (d, J ) 7.6 Hz, 1H), 5.44 (t, J ) 7.6
Hz, 1H), 4.88-4.84 (m, 1H), 4.75-4.67 (m, 2H), 4.22-4.15 (m, 1H),
3.99-3.82 (m, 4H), 2.57-2.49 (m, 3H), 2.28-2.01 (m, 6H), 1.74 (s,
3H), 1.64-1.63 (m, 4H), 1.61-1.37 (m, 2H), 0.87 (s, 9H), 0.06 (s,
3H) and 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.5, 139.9,
139.2, 122.6, 110.0, 105.7, 104.2, 76.0, 64.8, 45.0, 40.8, 40.2, 34.7,
hexanes-EtOAc); [R]24D +16.7, [R]24577 +15.9, [R]24546 +18.5, [R]24
435
1
+33.4, [R]24 +41.7 (c 0.6, CHCl3); H NMR (500 MHz, C6D6) δ
405
5.45 (t, J ) 6.6 Hz, 1H), 4.92 (d, J ) 2.2 Hz, 1H), 4.79 (d, J ) 2.6
Hz, 1H), 4.74 (t, J ) 4.6 Hz, 1H), 4.67 (t, J ) 7.0, Hz, 1H), 3.51-
3.49 (m, 2H), 3.34-3.31 (m, 2H), 2.24-1.90 (m, 11H), 1.81-1.77
(m, 2H), 1.67-1.61 (m, 2H), 1.63 (s, 3H), 1.11-1.06 (m, 21H); 13C
NMR (125 MHz, C6D6) δ 155.0, 140.0, 122.7, 110.4, 104.4, 84.7, 83.0,
64.8, 62.0, 43.1, 42.1, 35.0, 33.4, 32.4, 32.4, 25.9, 23.6, 18.9, 18.5,
12.9; IR (film) 884 cm-1; HRMS (CI, NH3) m/z 461.3440 (461.3451
calcd for C28H49O3Si, MH). Anal. Calcd for C28H48O3Si: C, 72.99; H,
10.50. Found: C, 72.77; H, 10.53.
33.8, 32.4, 26.0, 23.6, 18.0, -3.7, -4.5; IR (film) 888, 835, 811 cm-1
;
HRMS (CI, isobutane) m/z 547.2086 (547.2106 calcd for C25H44IO3Si,
MH).
(2S,4aS,7S,9aS)-4-[4-(1,3-Dioxolanyl)butyl]-7-methyl-1,2,5,6,7,9a-
hexahydro-4a,7-methano-4aH-benzocyclohepten-2-ol (36). A solution
of vinyl iodide 35 (740 mg, 1.35 mmol) and THF (75 mL) was degassed
(Ar, evacuate-refill), and Ph3P (107 mg, 0.41 mmol), Ag2CO3 (410
mg, 1.5 mmol), and Pd(OAc)2 (46 mg, 0.20 mmol) were added. The
resulting suspension was stirred at room temperature for 15 min and
then heated at 65 °C in a sealed tube for 12 h. A black suspension
resulted after 10-20 min at 65 °C. After GC analysis of a filtered
aliquot showed that the reaction had not proceeded to completion,
additional Ph3P (107 mg, 0.41 mmol), Ag2CO3 (411 mg, 1.49 mmol),
and Pd(OAc)2 (46 mg, 0.20 mmol) were added, and the black
suspension was stirred in a sealed tube at 65 °C for an additional 6 h.
The suspension was then cooled to room temperature and filtered
through a plug of silica gel (1.5 cm × 12 cm, EtOAc), and the filtrate
was concentrated to give the crude Heck product as a yellow oil.
This sample was dissolved in THF (4 mL), and TBAF (1.0 M
solution in THF, 2.0 mL) was added. The resulting solution was
maintained at room temperature for 20 h and quenched with saturated
aqueous NH4Cl (20 mL). The resulting mixture was extracted with CH2-
Cl2 (3 × 20 mL), the combined organic layers were dried (Na2SO4),
filtered, and concentrated, and the residue was purified by flash
chromatography (4:1 hexanes-EtOAc) to provide 370 mg (90%) of
tricyclic allylic alcohol 36 as a pale yellow oil: Rf ) 0.25 (5:1 hexanes-
EtOAc); [R]24 +49.5, [R]24 +53.9, [R]24 +61.6, [R]24 +109,
(2R,2′S)-2-[2′-Hydroxy-8′-(1,3-dioxolanyl)-3′-octynyl]-5-methyl-
1-methylenecyclohept-4-ene (33). A solution of 32 (2.79 g, 6.07
mmol), tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 6.7 mL)
and THF (30 mL) was maintained at room temperature for 1 h and
then quenched with saturated aqueous NH4Cl (100 mL). The mixture
was extracted with CH2Cl2 (100 mL and 2 × 50 mL), and the combined
organic layers were dried (Na2SO4), filtered, and concentrated. The
residue was purified by flash chromatography (3:1 hexanes-EtOAc)
to afford 1.84 g (100%) of propargyl alcohol 33 as a pale yellow oil:
Rf ) 0.25 (3:1 hexanes-EtOAc); [R]24D +64.3, [R]24577 +66.6, [R]24
546
+76.9, [R]24 +134, [R]24 +164 (c 1.0, CHCl3); H NMR (500
1
435
405
MHz, CDCl3) δ 5.61 (d, J ) 12.5 Hz, 1H), 5.42 (t, J ) 6.4 Hz, 1H),
4.86 (t, J ) 4.6 Hz, 1H), 4.75-4.73 (m, 2H), 4.28 (t, J ) 6.6 Hz, 1H),
3.97-3.92 (m, 2H), 3.87-3.82 (m, 2H), 2.73-2.69 (m, 1H), 2.27-
2.26 (m, 2H), 2.25-2.04 (m, 6H), 1.80-1.60 (m, 6H), 1.72 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 154.6, 140.3, 121.9, 110.8, 104.1, 84.7,
81.9, 64.8, 60.9, 41.6, 40.8, 34.5, 32.8, 32.2, 31.5, 25.8, 23.1, 18.6; IR
(film) 3448, 894 cm-1; HRMS (CI, isobutane) m/z 305.2118 (305.2116
calcd for C19H29O3, MH). Anal. Calcd for C19H28O3: C, 74.96; H, 9.27.
Found: C, 75.01; H, 9.32.
D
577
1
546
435
[R]24 +133 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 5.53 (d,
405
J ) 9.5 Hz, 1H), 5.32 (br s, 1H), 5.19 (dd, J ) 9.5, 1.6 Hz, 1H), 4.87
(t, J ) 4.5 Hz, 1H), 4.33 (t, J ) 7.5 Hz, 1H), 4.00-3.83 (m, 4H), 2.50
(d, J ) 13.3 Hz, 1H), 2.52-1.25 (m, 15H), 1.11 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 145.3, 137.2, 127.7, 125.0, 104.4, 68.4, 64.8, 47.3,
46.4, 45.2, 42.4, 41.3, 34.0, 33.6, 32.4, 30.6, 23.9, 22.8; IR (film) 3390,
1652 cm-1; HRMS (EI) m/z 304.2042 (304.2038 calcd for C19H28O3,
M).
(2R,2′S)-(Z)-2-[2′-Hydroxy-8′-(1,3-dioxolanyl)-4′-iodo-3′-octenyl]-
5-methyl-1-methylenecyclohept-4-ene (34). A solution of the prop-
argyl alcohol 33 (0.44 g, 1.46 mmol) and Et2O (5 mL) was added
dropwise by cannula to a solution of sodium bis(2-methoxyethoxy)-
aluminum hydride (3.5 M in THF, 0.66 mL)65 and Et2O (30 mL) at 0
°C. The resulting solution was allowed to warm to room temperature
and, after 15 h, was cooled to -78 °C. A solution of freshly purified
N-iodosuccinimide (0.82 g, 3.6 mmol) and THF-Et2O (10:7, 17 mL)
was then added dropwise by cannula. The solution was maintained at
0 °C for 5 min, allowed to warm to room temperature, and then
quenched by sequential addition of saturated aqueous Na2SO3-H2O
(1:1, 20 mL) and H2O (50 mL). The organic layer was separated, the
aqueous layer was extracted with CH2Cl2 (3 × 75 mL), and the
combined organic layers were dried (Na2SO4), filtered, and concentrated.
Purification of the residue by flash chromatography (3:1 hexanes-
EtOAc) furnished 0.61 g (97%) of 34 as a colorless oil: Rf ) 0.20
(3:1 hexanes-EtOAc); [R]24 +38.7, [R]24 +42.2, [R]24 +49.1,
(4aS,7S,9aS)-4-[4-(1,3-Dioxolanyl)butyl]-7-methyl-1,2,5,6,7,9a-
hexahydro-4a,7-methano-4aH-benzocyclohepten-2(1H)-one (53). Al-
cohol 36 (170 mg, 0.56 mmol) was oxidized with TPAP (10 mg, 0.03
mmol) and NMO (130 mg, 1.1 mmol) as described for the preparation
of 17 to provide the crude enone, which was then purified by flash
chromatography (5.7:1 hexanes-EtOAc) to give 160 mg (95%) of
enone 53 as a colorless oil: Rf ) 0.40 (3:2 hexanes-EtOAc); [R]24
D
+56.2, [R]24577 +60.8, [R]24546 +73.2, [R]24435 +188, [R]24405 +308 (c
1.2, CHCl3); 1H NMR (300 MHz, CDCl3) δ 5.80 (s, 1H), 5.61 (d, J )
9.5 Hz, 1H), 5.20 (dd, J ) 9.4, 1.7 Hz, 1H), 4.88 (t, J ) 4.3 Hz, 1H),
4.00-3.82 (m, 4H), 2.98 (br d, J ) 13.0 Hz, 1H), 2.49-2.08 (m, 5H),
1.92 (d, J ) 10.6 Hz, 1H), 1.78-1.40 (m, 8H), 1.17 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 199.3, 170.5, 137.8, 125.9, 124.9, 104.0, 64.9,
48.1, 46.1, 45.3, 42.4, 40.5, 38.6, 33.3, 31.7, 28.8, 23.8, 21.5; IR (film)
1674, 1602 cm-1; HRMS (CI, isobutane) m/z 303.1960 (303.1946 calcd
for C19H27O3, MH). Anal. Calcd for C19H26O3: C, 75.46; H, 8.66.
Found: C, 75.35; H, 8.93.
D
577
546
[R]24 +89.8, [R]24 +111 (c 1.1, CHCl3); 1H NMR (300 MHz,
435
405
CDCl3) δ 5.61 (d, J ) 7.5 Hz, 1H), 5.44 (t, J ) 6.3 Hz, 1H), 4.86 (t,
J ) 3.7 Hz, 1H), 4.76-4.72 (m, 2H), 4.24 (m, 1H), 3.99-3.82 (m,
4H), 2.62-2.49 (m, 3H), 2.26-2.04 (m, 6H), 1.83-1.45 (m, 7H), 1.65
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.5, 140.4, 134.9, 122.1, 110.5,
108.4, 104.1, 74.8, 64.9, 45.0, 41.3, 38.4, 34.5, 32.9, 32.3, 31.7, 25.8,
23.6; IR (film) 3417, 843 cm-1; HRMS (CI, isobutane) m/z 433.1239
(433.1239 calcd for C19H30IO3, MH).
(2R,2′S)-(Z)-2-[2′-(tert-Butyldimethylsilyloxy)-8′-(1,3-dioxolanyl)-
4′-iodo-3′-octenyl]-5-methyl-1-methylenecyclohept-4-ene (35). A so-
lution of alcohol 34 (1.74 g, 4.0 mmol), imidazole (0.77 g, 11.4 mmol),
tert-butyldimethylsilyl chloride (0.86 g, 5.7 mmol), and DMF (25 mL)
was maintained at room temperature for 8.5 h and then quenched with
H2O (50 mL). The resulting mixture was extracted with hexanes (3 ×
75 mL), and the combined organic layers were dried (Na2SO4), filtered,
and concentrated. The residue was purified by flash chromatography
(19:1 hexanes-EtOAc) to afford 2.15 g (97%) of vinyl iodide 35 as a
(4S,4aS,7S,9aS)-4-[4-(1,3-Dioxolanyl)butyl]-4,7-dimethyl-
1,2,3,4,5,6,7,9a-octahydro-4a,7-methano-4aH-benzocyclohepten-
2(1H)-one (54). Using a glovebox, a flask was charged with dry LiBr
(650 mg, 7.5 mmol) and Ni(acac)2 (7 mg, 0.03 mmol) and then flushed
with Ar, and dry Et2O was added. Dimethylzinc (0.26 mL, 3.8 mmol)
was added dropwise to this stirred suspension at 0 °C under Ar.71 The
brown heterogeneous mixture was stirred at 0 °C for 10 min, and then
a solution of enone 53 (280 mg, 0.93 mmol) and Et2O (6 mL) was
added by cannula. The reaction was allowed to warm to room
temperature and stirred at room temperature for 17 h. This mixture
was cooled to 0 °C and quenched with saturated aqueous NH4Cl (14

5478 J. Am. Chem. Soc., Vol. 121, No. 23, 1999
Fox et al.
mL). Saturated aqueous EDTA (5 mL) was then added, and the organic
layer was separated. The aqueous layer was extracted with CH2Cl2 (2
× 20 mL), and the combined organic layers were dried (Na2SO4),
filtered, and concentrated. Purification of the residue by flash chro-
matography (5.7:1 hexanes-EtOAc) afforded 258 mg (88%) of ketone
[R]24D +8.6, [R]24577 +9.3, [R]24546 +10.4, [R]24435 +18.1, [R]24405 +22.3
1
(c 0.7, CHCl3); H NMR (300 MHz, CDCl3) δ 4.81 (t, J ) 4.7 Hz,
1H), 3.96-3.77 (m, 8H), 3.38 (br s, 1H), 2.18 (m, 1H), 1.73-1.12 (m,
19H), 0.99 (s, 3H), 0.95 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 108.7,
104.5, 74.7, 64.7, 64.4, 63.2, 50.6, 43.7, 42.5, 38.5, 38.4, 37.6, 36.4,
36.3, 34.9, 32.5, 23.9, 21.8, 21.6, 18.6; IR (film) 3480 cm-1; HRMS
(CI, isobutane) m/z 381.2627 (381.2641 calcd for C22H37O5, MH).
(6aS,8S,9S,11aS,11bS)-8-Hydroxy-9,11b-dimethyl-1,2,3,6a,7,8,9,-
10,11,11b-decahydro-9,11a-methano-11aH-cyclohepta[a]naphtha-
len-5(6H)-one (58). A solution of alcohol 57 (150 mg, 0.39 mmol),
20% aqueous HCl (2.6 mL), and THF (7.8 mL) was maintained at
room temperature for 12 h and then heated at 50 °C for an additional
12 h. The resulting yellow solution was cooled to room temperature,
poured into ice-cold saturated aqueous NaHCO3 (15 mL), and extracted
with Et2O (3 × 25 mL). The combined organic extracts were washed
with saturated aqueous NaHCO3 (25 mL), dried (MgSO4), filtered, and
concentrated. The residue was purified by flash chromatography (4:1
hexanes-EtOAc) to provide 80 mg (74%) of 58 as a colorless solid.
Recrystallization from hexanes-Et2O provided analytically pure 58 as
54 as a colorless oil: Rf ) 0.45 (3:2 hexanes-EtOAc); [R]24 +47.2,
D
[R]24 +49.7, [R]24 +57.2, [R]24 +108, [R]24 +136 (c 1.2,
577
546
435
405
CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.57 (d, J ) 9.3 Hz, 1H), 5.14
(dd, J ) 9.4, 1.1 Hz, 1H), 4.85 (t, J ) 4.5 Hz, 1H), 3.97-3.83 (m,
4H), 3.00 (br d, J ) 13.5 Hz, 1H), 2.35 (t, J ) 14.2 Hz, 1H), 2.24 (dd,
J ) 14.8, 4.4 Hz, 1H), 2.18 (d, J ) 13.9 Hz, 1H), 2.12 (d, J ) 13.9
Hz, 1H), 1.86-1.22 (m, 12H), 1.11 (s, 3H), 0.88 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 212.2, 138.1, 127.6, 104.9, 65.5, 51.0, 50.8, 44.6,
44.5, 43.3, 42.7, 42.6, 41.9, 35.9, 35.3, 26.2, 24.4, 21.2, 18.9; IR (film)
1706, 1668, 1656 cm-1. Anal. Calcd for C20H30O3: C, 75.43; H, 9.49.
Found: C, 75.26; H, 9.50.
(4S,4aS,7S,9aS)-2-(1,3-Dioxolanyl)-4-[4-(1,3-dioxolanyl)butyl]-4,7-
dimethyl-1,2,3,4,5,6,7,9a-octahydro-4a,7-methano-4aH-benzocyclo-
heptene (55). A mixture of ketone 54 (150 mg, 0.47 mmol), ethylene
glycol (0.25 mL, 5 mmol), 2-methoxy-1,3-dioxolane (0.16 mL, 1.7
mmol), Amberlyst-15 acidic resin (44 mg), and MeCN (4 mL) was
stirred at room temperature for 12 h and then filtered. The Amberlyst
resin was thoroughly washed with CH2Cl2 (20 mL), the combined
filtrates were concentrated, and the residue was purified by flash
chromatography (9:1 hexanes-EtOAc) to provide 157 mg (92%) of
colorless needles: mp 146 °C; Rf ) 0.50 (3:2 hexanes-EtOAc); [R]25
D
+72.3, [R]25577 +76.6, [R]25546 +87.6, [R]24435 +125, [R]24405 +102 (c
0.6, CHCl3); 1H NMR (500 MHz, CDCl3) δ 6.60 (dd, J ) 5.7, 2.1 Hz,
1H), 3.48 (br s, 1H), 2.57 (dd, J ) 19.0, 7.5 Hz, 1H), 2.46 (m, 1H),
2.19-2.12 (m, 1H), 2.07-1.99 (m, 1H), 1.97 (dd, J ) 19.1, 9.0 Hz,
1H), 1.75-1.39 (m, 10H), 1.25-1.22 (m, 2H), 1.19 (d, J ) 11.2 Hz,
1H), 1.09 (s, 3H), 1.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 201.9,
142.6, 134.6, 74.5, 50.6, 44.5, 42.5, 38.5, 37.7, 37.5, 36.3, 31.9, 29.3,
55 as a colorless oil: Rf ) 0.45 (4:1 hexanes-EtOAc); [R]23 +63.2,
D
[R]23 +67.3, [R]23 +77.5, [R]23 +140, [R]23 +174 (c 1.1,
577
546
435
405
25.5, 24.5, 24.2, 23.9, 18.2; IR (film) 3460, 1686, 1672, 1617 cm-1
;
CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.48 (d, J ) 9.6 Hz, 1H), 5.11
(d, J ) 9.5 Hz, 1H), 4.83 (t, J ) 4.8 Hz, 1H), 3.96-3.80 (m, 8H),
2.86 (br d, J ) 12.8 Hz, 1H), 1.70-1.47 (m, 9H), 1.42-1.24 (m, 7H),
1.05 (s, 3H), 0.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 136.8, 128.4,
109.2, 104.5, 64.8, 64.4, 63.4, 50.1, 44.3, 42.5, 42.1, 41.4, 37.6, 36.9,
36.0, 34.9, 24.1, 23.8, 20.5, 18.6; IR (film) 1086, 1063 cm-1; HRMS
(CI, isobutane) m/z 363.2533 (363.2536 calcd for C22H35O4, MH).
(4S,4aS,7S,8R,9S,9aS)-8,9-Epoxy-2-(1,3-dioxolanyl)-4-[4-(1,3-di-
oxolanyl)butyl]-4,7-dimethyl-1,2,3,4,5,6,7,8,9,9a-decahydro-4a,7-
methano-4aH-benzocycloheptene (56). A mixture of 55 (200 mg, 0.55
mmol), NaHCO3 (56 mg, 0.67 mmol), and CH2Cl2 (6.9 mL) was cooled
to 0 °C, and m-chloroperbenzoic acid (95%, 143 mg, 0.79 mmol) was
added. The reaction was allowed to warm to room temperature over 3
h. This mixture was diluted with CH2Cl2 (20 mL) and washed
sequentially with 5% aqueous NaOH (10 mL), saturated aqueous Na2-
SO3 (10 mL), and 5% aqueous NaOH (10 mL). The organic phase
was dried (MgSO4), filtered, and concentrated, and the residue was
purified by flash chromatography (17:3 hexanes-EtOAc) to give 206
mg (99%) of epoxide 56 as a colorless oil: Rf ) 0.40 (2:1 hexanes-
EtOAc); [R]24 +18.0, [R]24 +19.7, [R]24 +22.9, [R]24 +40.4,
HRMS (CI, isobutane) m/z 275.1994 (275.2011 calcd for C18H27O2,
MH). Anal. Calcd for C18H26O2: C, 78.79; H, 9.55. Found: C, 78.52;
H, 9.59.
(6aS,8S,9S,11aS,11bS)-8-(Methoxymethyl)oxy-9,11b-dimethyl-
1,2,3,6a,7,8,9,10,11,11b-decahydro-9,11a-methano-11aH-cyclohepta-
[a]naphthalen-5(6H)-one (59). N,N-Diisopropylethylamine (0.4 mL,
2.3 mmol) and chloromethyl methyl ether (0.12 mL, 1.6 mmol) were
added to a solution of enone 58 (149 mg, 0.54 mmol) and CH2Cl2 (2.5
mL) at 0 °C. The reaction was maintained at room temperature for 7
h and then diluted with CH2Cl2 (5 mL). The resulting mixture was
washed sequentially with 1 M HCl (2 × 2 mL) and saturated aqueous
NaHCO3 (2 mL). The organic extracts were dried (NaSO4), filtered,
and concentrated. The residue was purified by flash chromatography
(9:1 hexanes-EtOAc) to give 159 mg (92%) of 59 as a colorless solid.
Recrystallization from hexanes produced analytically pure 59 as
colorless needles: mp 87-87.5 °C; Rf ) 0.77 (3:2 hexanes-EtOAc);
[R]24D +106, [R]24577 +109, [R]24546 +123, [R]24435 +190, [R]24405 +191
1
(c 1.2, CHCl3); H NMR (500 MHz, CDCl3) δ 6.60 (dd, J ) 5.5, 2.0
Hz, 1H), 4.71 (d, J ) 6.9 Hz, 1H), 4.57 (d, J ) 6.9 Hz, 1H), 3.38 (s,
3H), 3.31 (s, 1H), 2.57 (dd, J ) 19.1, 7.5 Hz, 1H), 2.39 (m, 1H), 2.20-
1.96 (m, 2H), 1.99 (dd, J ) 19.1, 9.2 Hz, 1H), 1.83 (ddd, J ) 14.6,
5.1, 1.2 Hz, 1H), 1.78-1.41 (m, 8H), 1.21-1.17 (m, 3H), 1.08 (s, 3H),
1.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 201.8, 142.7, 134.4, 95.5,
79.9, 55.5, 50.2, 44.2, 42.6, 38.5, 38.3, 36.4, 34.3, 32.4, 29.4, 25.4,
24.5, 24.3, 24.1, 18.3; IR (film) 1684, 1619 cm-1; HRMS (CI,
isobutane) m/z 319.2273 (319.2273 calcd for C20H31O3, MH).
(4S,4aS,6aS,8S,9S,11aS,11bS)-4-Cyano-8-(methoxymethyl)oxy-9,-
11b-dimethyl-1,2,3,4,6,6a,7,8,9,10,11,11b-dodecahydro-9,11a-methano-
11aH-cyclohepta[a]naphthalen-5(4aH)-one (60). Diethyl aluminum
cyanide (1.0 M in toluene, 1.1 mL) was added dropwise to a solution
of enone 59 (170 mg, 0.53 mmol) and THF (11 mL) at 0 °C.72 After
10 h at 0 °C, a viscous solution of Et3N (0.75 mL, 5.4 mmol), TMSCl
(0.34 mL, 2.7 mmol), and THF (0.5 mL) was added using a 16-18-
gauge cannula. The resulting mixture was allowed to warm to room
temperature, and Et2O (30 mL) and saturated aqueous NaHCO3 (10
mL) were added. The phases were separated, and the aqueous layer
was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were washed with saturated aqueous NaHCO3 (25 mL), dried (K2CO3),
and filtered through a short column of silica gel (Et2O) to provide the
crude ∆5,6-enoxysilane.
D
577
546
435
1
[R]24 +48.6 (c 0.7, CHCl3); H NMR (500 MHz, CDCl3) δ 4.81 (t,
405
J ) 4.5 Hz, 1H), 3.97-3.78 (m, 8H), 2.80 (d, J ) 3.3 Hz, 1H), 2.60
(d, J ) 3.8 Hz, 1H), 2.36 (dd, J ) 13.3, 4.3 Hz, 1H), 1.78-1.54 (m,
7H), 1.44-1.08 (m, 9H), 1.14 (s, 3H), 0.88 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 109.0, 104.4, 64.8, 64.5, 63.5, 60.8, 55.1, 48.8, 42.2,
40.8, 38.7, 38.3, 37.6, 36.9, 36.4, 35.6, 34.9, 24.6, 22.2, 20.6, 18.5; IR
(film) 1247 cm-1; HRMS (CI, isobutane) m/z 379.2473 (379.2484 calcd
for C22H35O5, MH). Anal. Calcd for C22H34O5: C, 69.81; H, 9.13.
Found: C, 69.94; H, 9.13.
(4S,4aS,7S,8S,9aS)-2-(1,3-Dioxolanyl)-4-[4-(1,3-dioxolanyl)butyl]-
4,7-dimethyl-1,2,3,4,5,6,7,8,9,9a-decahydro-4a,7-methano-4aH-ben-
zocyclohepten-8-ol (57). A solution of epoxide 56 (235 mg, 0.62 mmol)
and Et2O (4.2 mL) was added dropwise to a solution of LiAlH4 (1.0 M
in THF, 1.2 mL) and Et2O (0.4 mL). The reaction was stirred vigorously
at room temperature for 14 h. After the mixture was cooled to 0 °C, a
solution of EtOAc (1.3 mL) and Et2O (6.6 mL) was added dropwise.
The resulting suspension was warmed to room temperature, and 15%
aqueous NaOH (0.2 mL) and H2O (0.4 mL) were added. The mixture
was stirred vigorously for 15 min, and Na2SO4 (2.6 g) was added. After
being stirred for 15 min, the mixture was filtered through a plug of
Celite (1 cm × 5 cm). The plug was washed with Et2O (50 mL), and
the filtrate was concentrated. Purification of the residue by flash
chromatography (4:1 hexanes-EtOAc) afforded 212 mg (90%) of
alcohol 57 as a viscous colorless oil: Rf ) 0.38 (1:1 hexanes-EtOAc);
A solution of this material, 10:1 THF-H2O (5 mL), and 1 M HCl
(0.05 mL) was maintained at room temperature for 15 min and then
diluted with Et2O (15 mL), and K2CO3 (150 mg) was added. The

Total Syntheses of (+)- and (-)-Scopadulcic Acid A
J. Am. Chem. Soc., Vol. 121, No. 23, 1999 5479
resulting mixture was stirred for 10 min, dried (Na2SO4), filtered, and
concentrated. Purification of the residue by flash chromatography (4:1
hexanes-EtOAc) afforded 162 mg (88%) of 60 as a colorless solid.
Recrystallization from hexanes-Et2O provided analytically pure 60 as
-78 °C, and freshly distilled benzyl bromomethyl ether73 (65 µL, 0.5
mmol) was added rapidly. The reaction was maintained at 0 °C for 2
h, quenched with saturated aqueous NaHCO3 (1.5 mL), and warmed
to room temperature, and then additional saturated aqueous NaHCO3
(10 mL) was added. This mixture was extracted with CH2Cl2 (3 × 10
mL), and the combined organic phases were dried (MgSO4), filtered,
and concentrated. Purification of the residue by flash chromatography
(99:1 f 98:2 hexanes-EtOAc) afforded 59 mg (82%) of ether 62 as
colorless needles: mp 168 °C; Rf ) 0.37 (3:2 hexanes-EtOAc); [R]24
D
+72.2, [R]24577 +74.3, [R]24546 +84.8, [R]24435 +149, [R]24405 +183 (c
1.6, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.67 (d, J ) 6.9 Hz, 1H),
4.54 (d, J ) 6.9 Hz, 1H), 3.34 (s, 3H), 3.29 (br s, 1H), 2.96 (br s, 1H),
2.38-2.30 (m, 2H), 2.22 (d, J ) 4.6 Hz, 1H), 2.08-1.95 (m, 2H),
1.87-1.44 (m, 10H), 1.38 (tt, J ) 13.8, 4.1 Hz, 1H), 1.28 (ddd, J )
18.2, 11.8, 3.6 Hz, 1H), 1.20 (d, J ) 11.4 Hz, 1H), 1.13 (s, 3H), 1.04
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 207.5, 122.0, 95.5, 79.7, 55.5,
53.4, 51.8, 43.9, 43.9, 41.8, 37.7, 35.9, 35.0, 33.5, 30.3, 28.6, 24.0,
23.9, 23.3, 18.1, 18.0; IR (film) 2233, 1701 cm-1; HRMS (CI,
isobutane) m/z 346.2372 (346.2383 calcd for C21H32NO3, MH). Anal.
Calcd for C21H31NO3: C, 73.01; H, 9.04. Found: C, 72.74; H, 9.06.
(4S,4aS,5R,6aS,8S,9S,11aS,11bS)-4-Cyano-8-(methoxymethyl)-
oxy-9,11b-dimethyl-5-trimethylsiloxy-1,2,3,4,4a,5,6,6a,7,8,9,10,11,-
11b-tetradecahydro-9,11a-methano-11aH-cyclohepta[a]naphtha-
lene (61). Lithium aluminum hydride (1.0 M in THF, 0.48 mL) was
added dropwise to a solution of ketone 60 (158 mg, 0.46 mmol) and
THF (5.5 mL) at -78 °C. The reaction was maintained at -78 °C for
30 min and was quenched by sequential additions of H2O (0.02 mL),
15% aqueous NaOH (0.02 mL), and H2O (0.06 mL). The mixture was
warmed to room temperature and diluted with Et2O (15 mL), and
MgSO4 (750 mg) was then added. After being stirred vigorously for
10 min, the mixture was filtered through a plug of silica gel (1 cm ×
4 cm, Et2O), and the filtrate was concentrated. The residue was purified
by flash chromatography (4:1 hexanes-EtOAc) to give 143 mg (90%)
of (4S,4aS,5R,6aS,8S,9S,11aS,11bS)-4-cyano-8-(methoxymethyl)oxy-
9,11b-dimethyl-1,2,3,4,4a,5,6,6a,7,8,9,10,11,11b-tetradecahydro-9,11a-
methano-11aH-cyclohepta[a]naphthalen-5-ol as a colorless solid: mp
a colorless oil: Rf ) 0.29 (15:1 hexanes-EtOAc); [R]24D +13.8, [R]24
577
+14.0, [R]24 +15.9, [R]24 +26.5, [R]24 +31.0 (c 1.7, CHCl3);
546
435
405
1H NMR (500 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 4.72 (d, J ) 6.9
Hz, 1H), 4.60 (d, J ) 7.0 Hz, 1H), 4.60 (d, J ) 12.1 Hz, 1H), 4.43 (d,
J ) 12.3 Hz, 1H), 3.90 (m, 1H), 3.53 (d, J ) 9.0 Hz, 1H), 3.39 (m,
1H), 3.39 (s, 3H), 3.25 (br s, 1H), 2.26 (m, 1H), 2.00-1.87 (m, 2H),
1.72-1.58 (m, 6H), 1.48-1.40 (m, 3H), 1.43 (s, 3H), 1.36 (t, J ) 7.7
Hz, 2H), 1.30 (d, J ) 2.0 Hz, 1H), 1.31-1.10 (m, 3H), 1.02 (s, 3H),
0.05 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 137.5, 128.4, 127.9, 127.8,
124.0, 95.8, 80.8, 73.3, 72.8, 66.3, 55.4, 52.3, 45.3, 43.1, 38.7, 38.6,
38.4, 37.6, 36.2, 36.0, 33.3, 33.2, 28.6, 24.2, 21.9, 20.0, 19.0, 0.32; IR
(film) 2231 cm-1; HRMS (CI, isobutane) m/z 540.3490 (540.3509 calcd
for C32H50NO4Si, MH).
(4S,4aS,5R,6aS,8S,9S,11aS,11bS)-4-(Benzyloxymethyl)oxy-5-hy-
droxy-4-methoxycarbonyl-8-(methoxymethyl)oxy-9,11b-dimethyl-
1,2,3,4,4a,5,6,6a,7,8,9,10,11,11b-tetradecahydro-9,11a-methano-11aH-
cyclohepta[a]naphthalene (63). A mixture of K2CO3 (33 mg, 0.24
mmol), KOH (78 mg, 1.4 mmol), nitrile 62 (17 mg, 0.031 mmol), and
MeOH (1 mL) was concentrated to dryness under a stream of N2, and
the residue was heated at 140 °C for 24 h. After being cooled to room
temperature, the resulting solid mass was dissolved in H2O (3.5 mL)
and cooled to 0 °C. Ether (3.5 mL) was added, and the mixture was
carefully acidified to pH 2 with 1 M aqueous HCl. The layers were
separated, and the aqueous layer was extracted with Et2O (5 × 7 mL).
The combined organic layers were washed with saturated aqueous 1:1
NaCl-H2O (7 mL), dried (MgSO4), filtered, and concentrated to afford
the corresponding carboxylic acid.
129-130 °C; Rf ) 0.53 (1:1 hexanes-EtOAc); [R]24D +58.6, [R]24
577
+59.5, [R]24546 +67.5, [R]24435 +110, [R]24405 +130 (c 0.6, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 4.70 (d, J ) 6.9 Hz, 1H), 4.54 (d, J ) 6.9
Hz, 1H), 3.91 (br s, 1H), 3.36 (s, 3H), 3.26 (br s, 1H), 2.76 (br s, 1H),
2.33 (m, 1H), 2.15-2.02 (m, 2H), 1.95-1.78 (m, 1H), 1.72-1.09 (m,
15H), 1.43 (s, 3H), 1.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 124.3,
95.1, 79.6, 71.4, 55.5, 52.0, 44.7, 43.1, 38.3, 38.2, 37.8, 36.2, 33.0,
The crude acid was dissolved in Et2O (2 mL), and excess diaz-
omethane (generated from 70 mg of 1-methyl-5-nitro-1-nitrosoguani-
dine) was added at 0 °C. The resulting solution was allowed to stand
at 0 °C for 30 min until a pale yellow color persisted. Excess
diazomethane was removed with a stream of N2, the solution was
concentrated, and the residue was purified by flash chromatography
(4:1 hexanes-EtOAc) to provide 13.5 mg (86%) of ester 63 as a
32.6, 31.0, 29.3, 29.0, 24.1, 21.7, 19.8, 18.8; IR (film) 3483, 2232 cm-1
;
HRMS (CI, isobutane) m/z 348.2536 (348.2538 calcd for C21H34NO3,
MH). Anal. Calcd for C21H33NO3: C, 72.58; H, 9.57. Found: C, 72.68;
H, 9.63.
colorless oil: Rf ) 0.60 (3:2 hexanes-EtOAc); [R]24D +34.9, [R]24
577
Pyridine (0.5 mL), DMAP (4.5 mg, 0.037 mmol), and freshly distilled
TMSCl (0.07 mL, 0.55 mmol) were added sequentially to a solution
of this alcohol (51 mg, 0.147 mmol) and CH2Cl2 (0.5 mL) at 0 °C.
The resulting solution was stirred at 0 °C for 2 h and then partitioned
between saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (3 × 10 mL).
The combined organic phases were dried (Na2SO4), filtered, and
concentrated. Purification of the residue by flash chromatography (19:1
hexanes-Et2O) yielded 60 mg (97%) of 61 as a colorless solid.
Recrystallization from hexanes afforded analytically pure 61 as colorless
+36.4, [R]24 +41.8, [R]24 +69.6, [R]24 +82.3 (c 0.9, CHCl3);
546
435
405
1H NMR (500 MHz, CDCl3) δ 7.35-7.29 (m, 2H), 7.28-7.24 (m,
3H), 5.21 (s, 1H), 4.72 (d, J ) 7.0 Hz, 1H), 4.53 (d, J ) 7.0 Hz, 1H),
4.50 (d, J ) 12.4 Hz, 1H), 4.42 (d, J ) 12.4 Hz, 1H), 4.23 (br s, 1H),
3.76 (s, 3H), 3.74 (d, J ) 8.4 Hz, 1H), 3.37 (s, 3H), 3.36 (d, J ) 8.4
Hz, 1H), 3.28 (br s, 1H), 2.41 (dd, J ) 13.3, 1.1 Hz, 1H), 2.35 (m,
1H), 1.82-1.72 (m, 2H), 1.69-1.48 (m, 5H), 1.44-1.24 (m, 6H), 1.17-
1.08 (m, 3H), 1.09 (s, 3H), 1.02 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 180.1, 138.0, 128.3, 127.6, 127.2, 94.8, 79.4, 78.0, 73.3, 65.4, 55.5,
52.8, 52.7, 50.9, 49.7, 43.0, 39.0, 38.6, 37.7, 36.6, 34.0, 33.8, 32.2,
28.5, 24.3, 22.3, 20.9, 19.3; IR (film) 1728, 1696 cm-1; HRMS (CI,
isobutane) m/z 501.3199 (501.3216 calcd for C30H45O6, MH).
needles: mp 141 °C; Rf ) 0.55 (8:1 hexanes-EtOAc); [R]24 +42.1,
D
[R]24 +45.2, [R]24 +50.7, [R]24 +84.0, [R]24 +99.2 (c 1.0,
577
546
435
405
CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.72 (d, J ) 7.0 Hz, 1H), 4.60
(d, J ) 7.0 Hz, 1H), 3.82 (br s, 1H), 3.39 (s, 3H), 3.25 (br s, 1H), 2.60
(br s, 1H), 2.31 (m, 1H), 2.05 (br d, J ) 12.9 Hz, 1H), 1.95-1.87 (m,
(4S,4aS,5R,6aS,8S,9S,11aS,11bS)-5-Benzoyloxy-4-(benzyloxy-
methyl)oxy-4-methoxycarbonyl-8-(methoxymethyl)oxy-9,11b-dim-
ethyl-1,2,3,4,4a,5,6,6a,7,8,9,10,11,11b-tetradecahydro-9,11a-methano-
11aH-cyclohepta[a]naphthalene (64). A solution of alcohol 63 (54
mg, 0.11 mmol), freshly distilled benzoyl chloride (54 mg, 0.11 mmol),
DMAP (130 mg, 1.1 mmol), and pyridine (1.2 mL) was heated at 100
°C for 5 h and then cooled to room temperature. The reaction was
diluted with CH2Cl2 (4 mL) and then cooled to 0 °C, and ethylenedi-
amine (0.2 mL, 3 mmol) was added. The resulting suspension was
stirred at 0 °C for 30 min, diluted with CH2Cl2 (24 mL), and poured
into H2O (24 mL). The layers were separated, and the aqueous phase
was extracted with CH2Cl2 (2 × 24 mL). The combined organic layers
were washed sequentially with 5% aqueous HCl (24 mL) and saturated
aqueous NaHCO3 (24 mL), dried (MgSO4), filtered, and concentrated.
The solid residue was washed thoroughly with Et2O (5 × 10 mL), and
the combined ether extracts were concentrated (BzNHCH2CH2NH2
1H), 1.70-1.10 (m, 15H), 1.41 (s, 3H), 1.02 (s, 3H), 0.15 (s, 9H); 13
C
NMR (125 MHz, CDCl3) δ 123.8, 95.7, 80.5, 71.5, 55.5, 52.0, 45.3,
43.1, 38.5, 38.4, 37.9, 36.3, 33.2, 33.1, 31.8, 29.9, 29.1, 24.2, 21.8,
19.6, 19.0, 0.09; IR (film) 2360 cm-1; HRMS (CI, isobutane) m/z
420.2929 (420.2935 calcd for C24H42NO3Si, MH).
(4S,4aS,5R,6aS,8S,9S,11aS,11bS)-4-(Benzyloxymethyl)oxy-4-cy-
ano-8-(methoxymethyl)oxy-9,11b-dimethyl-5-trimethylsiloxy-1,2,3,4,-
4a,5,6,6a,7,8,9,10,11,11b-tetradecahydro-9,11a-methano-11aH-cy-
clohepta[a]naphthalene (62). n-Butyllithium (2.0 M in hexanes, 0.14
mL) was added dropwise to a solution of diisopropylamine (0.04 mL,
0.31 mmol) and THF (0.6 mL) at -78 °C, and the solution of LDA
was warmed to 0 °C for 30 min. A solution of nitrile 61 (56 mg, 0.133
mmol) and THF (0.50 mL) was then added dropwise by cannula. After
being stirred for 15 min at 0 °C, the yellow solution was cooled to

5480 J. Am. Chem. Soc., Vol. 121, No. 23, 1999
Fox et al.
is insoluble in Et2O at room temperature). The residue was purified by
1.48 (m, 9H), 1.26 (s, 3H), 1.09 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 213.3, 176.0, 165.9, 138.3, 133.0, 130.3, 129.6, 128.5, 128.4, 127.5,
127.3, 74.9, 73.1, 69.2, 52.8, 52.2, 51.7, 47.4, 45.3, 44.0, 42.4, 38.8,
36.6, 35.7, 34.7, 33.9, 33.2, 23.3, 20.7, 19.7, 18.7; IR (film) 1726, 1711
cm-1; HRMS (CI, isobutane) m/z 559.3048 (559.3059 calcd for
C35H43O6, MH).
(-)-Scopadulcic acid A (1). Ester 66 (20 mg, 0.036 mmol) was
azeotropically dried with benzene (3 × 2 mL), and freshly prepared
lithium n-propylmercaptide (ca. 0.5 M in HMPA, 0.5 mL) was then
added dropwise under Ar at room temperature. The yellow solution
was maintained at room temperature for 8 h, cooled to 5 °C, and
quenched with 1 M aqueous HCl (1 mL) and H2O (10 mL). The
resulting mixture was extracted with EtOAc (5 × 15 mL), and the
combined organic layers were washed with saturated aqueous NaCl
(25 mL), dried (MgSO4), filtered, and concentrated. The residue was
purified by flash chromatography (17:3 f 4:1 hexanes-EtOAc) to
provide 14 mg (72%) of the derived carboxylic acid as a colorless solid.
It was critical for the success of this reaction to prepare75 n-PrSLi in a
Schlenk flask so that excess LiH could be removed by Schlenk filtration.
flash chromatography (9:1 hexanes-EtOAc) to give 57 mg (88%) of
64 as a colorless oil: Rf ) 0.41 (4:1 hexanes-EtOAc); [R]24 -20.9,
D
[R]24 -21.7, [R]24 -24.5, [R]24 -44.7, [R]24 -54.4 (c 1.5,
577
546
435
405
CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J ) 7.6 Hz, 2H), 7.54
(t, J ) 7.3 Hz, 1H), 7.44 (t, J ) 7.6 Hz, 2H), 7.36-7.33 (m, 2H),
7.29-7.26 (m, 3H), 5.47 (br s, 1H), 4.65 (d, J ) 6.9 Hz, 1H), 4.50
(ABq, J ) 12.4 Hz, 2H), 4.50 (d, J ) 7.1 Hz, 1H), 3.57 (s, 2H), 3.31
(s, 3H), 3.27 (br s, 1H), 3.07 (s, 3H), 2.31-2.14 (m, 2H), 2.04 (d, J )
12.1 Hz, 1H), 1.86-1.73 (m, 3H), 1.65-1.11 (m, 12H), 1.49 (s, 3H),
1.04 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 176.2, 166.0, 138.4, 132.8,
130.6, 129.6, 128.4, 128.3, 127.4, 127.2, 95.1, 79.5, 75.6, 73.1, 69.7,
55.5, 52.7, 51.6, 47.5, 44.4, 43.3, 38.6, 38.5, 36.4, 34.7, 33.8, 33.4,
32.5, 29.7, 24.3, 22.2, 21.3, 18.8; IR (film) 1727, 1717 cm-1; HRMS
(FAB, NBA) m/z 605.3473 (605.3478 calcd for C37H49O7, MH).
(4S,4aS,5R,6aS,8S,9S,11aS,11bS)-5-Benzoyloxy-4-(benzyloxy-
methyl)oxy-8-hydroxy-4-methoxycarbonyl-9,11b-dimethyl-1,2,3,4,-
4a,5,6,6a,7,8,9,10,11,11b-tetradecahydro-9,11a-methano-11aH-cy-
clohepta[a]naphthalene (65). A solution of 64 (56 mg, 0.093 mmol)
and acidic MeOH (4 mL, prepared by adding 2 drops of concentrated
aqueous HCl to 5 mL of MeOH) was heated at 70 °C for 45 min. The
reaction was cooled to room temperature and partitioned between
saturated aqueous NaHCO3 (15 mL) and CH2Cl2 (25 mL). The aqueous
layer was extracted with CH2Cl2 (2 × 15 mL), and the combined organic
layers were dried (Na2SO4), filtered, and concentrated. Purification of
the crude residue by flash chromatography (17:3 hexanes-EtOAc)
afforded 51 mg (98%) of alcohol 65 as a colorless solid, which was
recrystallized from hexanes-Et2O: mp 79-81 °C dec; Rf ) 0.36 (3:1
A flask containing the crude acid (14 mg) and 10% Pd on activated
carbon (10 mg) was evacuated and then flushed with H2 (3 ×). Freshly
distilled MeOH (1.4 mL) was added, H2 was bubbled into the stirring
mixture for 2 min, and the reaction was stirred at room temperature
under a H2 atmosphere for 9 h. The mixture was filtered through a
plug of silica gel (1 cm × 4 cm, EtOAc), and the filtrate was
concentrated to give 12 mg of crude 1 as a colorless solid. Recrystal-
lization from methanol provided 10.5 mg (90%) of analytically pure
(-)-scopadulcic acid A (1) as colorless prisms: mp 171-173 °C
(MeOH); Rf ) 0.67 (4:1 EtOAc-hexanes); [R]24D -5.8, [R]24577 -5.58,
[R]24 -7.5, [R]24 +10.8, [R]24 +32.4 (c 0.4, MeOH); [Θ]24
hexanes-EtOAc); [R]24D -64.5, [R]24577 -68.0, [R]24546 -78.0, [R]24
435
-136, [R]24 -164 (c 1.3, CHCl3); H NMR (500 MHz, CDCl3) δ
1
405
546
435
405
292
8.01 (d, J ) 7.6 Hz, 2H), 7.54 (t, J ) 7.3 Hz, 1H), 7.43 (t, J ) 7.7 Hz,
2H), 7.36-7.33 (m, 2H), 7.29-7.27 (m, 3H), 5.45 (br s, 1H), 4.50
(ABq, J ) 12.3 Hz, 2H), 3.57 (ABq, J ) 9.2 Hz, 2H), 3.42 (br s, 1H),
3.07 (s, 3H), 2.28-2.23 (m, 2H), 2.04 (d, J ) 12.1 Hz, 1H), 1.87-
1.74 (m, 3H), 1.63-1.22 (m, 13H), 1.49 (s, 3H), 1.02 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 176.3, 166.0, 138.5, 132.9, 130.6, 129.7,
128.4, 128.3, 127.5, 127.2, 75.6, 74.7, 73.1, 69.6, 53.1, 51.6, 47.5, 44.4,
43.6, 38.6, 37.7, 36.2, 36.0, 34.7, 33.8, 33.4, 29.3, 23.9, 22.0, 21.3,
18.8; IR (film) 3541, 1715 cm-1; HRMS (FAB, NBA) m/z 561.3204
(561.3216 calcd for C35H45O6, MH).
+8230 (c 0.73 mM, MeOH). This sample was identical to an authentic
1
specimen of natural (-)-SDA by H NMR, 13C NMR, IR, MS, and
TLC comparisons.
Acknowledgment. This research was supported by grants
from NIGMS (GM-30859) and through postdoctoral fellowships
to M.E.F. (SmithKline Beecham) and J.P.M. (NIH CA-71099).
Additional support was provided by Merck, Pfizer, Roche
Biosciences, SmithKline Beecham, and Zeneca. We particularly
thank Professor David A. Evans for detailed experimental
procedures for preparing the (R,R)-bis(oxazoline) catalyst 13,
Professor Toshimitsu Hayashi for providing a sample of natural
(+)-SDA, and Professor Larry Vickery for access to a CD
spectrometer. NMR and mass spectra were determined at UCI
using instruments acquired with the assistance of shared
instrumentation grants from NSF and NIH. We are grateful to
Dr. Joseph Ziller for single-crystal X-ray analyses and Dr. John
Greaves for mass spectrometric analyses.
(4S,4aS,5R,6aS,9S,11aS,11bS)-5-Benzoyloxy-4-(benzyloxy-
methyl)oxy-4-methoxycarbonyl-9,11b-dimethyl-8-oxo-1,2,3,4,4a,5,6,-
6a,7,8,9,10,11,11b-tetradecahydro-9,11a-methano-11aH-cyclohepta-
[a]naphthalene (66). A mixture of Celite (100 mg), 4-Å molecular
sieves (40 mg, powdered, activated), pyridinium chlorochromate (32
mg, 0.15 mmol), a portion of alcohol 65 (28 mg, 0.05 mmol), and
CH2Cl2 (4 mL) was stirred at room temperature for 2.5 h.74 The resulting
suspension was diluted with Et2O (15 mL) and filtered through a plug
of silica gel (1 cm × 5 cm, Et2O). The filtrate was concentrated, and
the residue was purified by flash chromatography (17:3 hexanes-
EtOAc) to afford 25 mg (90%) of ketone 66 as a colorless foam: Rf )
0.43 (3:1 hexanes-EtOAc); [R]24 -22.3, [R]24 -23.4, [R]24
Supporting Information Available: Experimental proce-
dures and characterization data for new compounds not de-
scribed in the Experimental Section and optical rotation data
for compounds in the ent series (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
D
577
546
1
-25.5, [R]24 -35.6, [R]24 -36.7 (c 1.2, CHCl3); H NMR (500
435
405
MHz, CDCl3) δ 7.99 (d, J ) 7.5 Hz, 2H), 7.55 (t, J ) 7.4 Hz, 1H),
7.44 (t, J ) 7.7 Hz, 2H), 7.38-7.34 (m, 2H), 7.31-7.26 (m, 3H), 5.50
(br s, 1H), 4.52 (ABq, J ) 12.2 Hz, 2H), 3.66 (d, J ) 9.2 Hz, 1H),
3.53 (d, J ) 9.2 Hz, 1H), 3.08 (s, 3H), 2.44 (m, 1H), 2.31 (m, 1H),
2.23-2.15 (m, 2H), 2.05-1.95 (m, 3H), 1.87-1.82 (m, 2H), 1.78-
JA990404V