Total synthesis and absolute configuration of (-)-anthoplalone

Article abstract of DOI:10.1021/jo990302n

We report the total synthesis of the cytotoxic agent (-)-anthoplalone and the determination of its absolute stereochemistry. The cyclopropane moiety was prepared using a nonracemic bicyclic chloroallyl phosphonamide anion addition to tert-butyl 3,3-dimethyl acrylate. Several pathways were studied to secure the E-trisubstituted olefin of the left part of the molecule.

Full text of DOI:10.1021/jo990302n

J . Org. Chem. 1999, 64, 4893-4900
4893
Tota l Syn th esis a n d Absolu te Con figu r a tion of (-)-An th op la lon e
Stephen Hanessian,* Louis-David Cantin, and Daniele Andreotti
Department of Chemistry, Universite´ de Montre´al, C.P. 6128, Succursale Centre-ville,
Montre´al, Que´bec H3C 3J 7 Canada
Received February 17, 1999
We report the total synthesis of the cytotoxic agent (-)-anthoplalone and the determination of its
absolute stereochemistry. The cyclopropane moiety was prepared using a nonracemic bicyclic
chloroallyl phosphonamide anion addition to tert-butyl 3,3-dimethyl acrylate. Several pathways
were studied to secure the E-trisubstituted olefin of the left part of the molecule.
In tr od u ction
The secosesquiterpene anthoplalone 1, isolated from
the Okinawan actinian Anthopleura pacifica,1 exhibits
antitumor activity against murine melanoma cells at a
concentration of 22 µg/mL, and it is thought to be
biosynthetically related to lepidozenal 2, which inhibits
the growth of rice seedlings.2 The absolute stereochem-
istry of anthoplalone has only been inferred from the
stereochemistry of lepidozenes such as 3,1 while its
F igu r e 1.
relative stereochemistry has been implied from the
coupling constant (J ) 6.0 Hz) of the cyclopropane ring
protons.3 This determination was confirmed by McMurry
and Bosch4 and by Fukumoto,5 who independently re-
ported the synthesis of racemic anthoplalone. The first
synthesis4 started with geranyl acetone which was con-
verted in some steps to a mixture of cis and trans
substituted cyclopropane precursors to 1, even though the
natural product had not been reported yet at the time.
Preparative HPLC allowed the separation of 1 and its
cis isomer, which was transformed into isomeric bicy-
clogermacranes related to lepidozene. The Fukumoto
synthesis5 of racemic 1 started with a bicyclic cyclobutane
intermediate obtained by a multistep procedure. A rear-
rangement reaction led to a cyclopropane analogue, which
was in turn subjected to a sequence of functional adjust-
ments to provide a ketone precursor. A J ulia type
coupling led to a predominantly Z-trisubstituted olefin,
which was partially isomerized to the desired E-config-
uration as in 1. In this article, we report the first
enantioselective synthesis of (-)-anthoplalone 1 and the
assignment of its absolute configuration.
are concerned with the stereochemistry of the cyclopro-
pane and with the control of the geometry of the isolated
double bond.6 Interestingly, these issues were the stum-
bling blocks in the McMurry and Fukumoto syntheses,
respectively. Among several approaches, we chose first
to disconnect at the allylic position, in order to couple
an allylic anion with a cyclopropyl methyl electrophile
as shown in Figure 2. The strong preference for the
regioselective R-addition of allyl sulfone anions to various
electrophiles encouraged us to explore this approach
first.7
(6) For leading references see: (a) Smith, A. B., III; Condon, S. M.;
McCauley, J . A. Acc. Chem. Res. 1998, 31, 35-46. (b) Westwell, A. D.;
Williams, J . M. J . In Preparation of Alkenes: A Practical Approach;
Williams, J . M. J ., Ed.; Oxford University Press: New York, 1996;
Chapter 9. (c) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-
927. (d) Faulkner, D. J . Synthesis 1971, 175-189. For recent applica-
tions of vinyl triflates: (e) Smith, A. B., III; Condon, S. M.; McCauley,
J . A.; Leazer, J . L., J r.; Leahy, J . W.; Maleczka, R. E., J r. J . Am. Chem.
Soc. 1997, 119, 947-961, and references cited. (f) Ritter, K. Synthesis
1993, 735-762. (g) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1980,
21, 4313-4316. For examples of rearrangements: (h) Smith, A. B.,
III; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J . M.; Salvatore, B. A. J .
Am. Chem. Soc. 1995, 117, 12013-12014. (i) Overman, L. E.; Lin, N.-
H. J . Org. Chem. 1985, 50, 3669-3670. (j) Wilson, S. R.; Price, M. F.
J . Org. Chem. 1984, 49, 722-725. (k) Wakabayashi, N.; Waters, R.
M.; Church, J . P. Tetrahedron Lett. 1969, 3253-3256. For the examples
of phosphorus reagents: (l) Yue, X.; Li, Y. Synthesis 1996, 736-740.
(m) Vedejs, E.; Cabaj, J .; Peterson, M. J . J . Org. Chem. 1993, 58, 6509-
6512. (n) J ones, T. K.; Mills, S. G.; Reamer, R. A.; Askin, D.; Desmond,
R.; Volante, R. P.; Shinkai, I. J . Am. Chem. Soc. 1989, 111, 1157-
1159. (o) Schreiber, S. L.; Sammakia, T.; Uehling, D. E. J . Org. Chem.
1989, 54, 15-16. For the use of alkyne metalation strategies: (p) Wipf,
P.; Smitrovich, J . H.; Moon, C.-W. J . Org. Chem. 1992, 57, 3178-3186.
(q) Carr, D. B.; Schwartz, J . J . Am. Chem. Soc. 1979, 101, 3521-3531.
(r) Ireland, R. E.; Wipf, P. J . Org. Chem. 1990, 55, 1425-1426. (s)
Marfat, A.; McGuirk, P. R.; Helquist, P. J . Org. Chem. 1979, 44, 3888-
3901.
Resu lts a n d Discu ssion
Despite its relatively simple structure, the synthesis
of anthoplalone presents two potential difficulties that
* Corresponding author. Phone: (514) 343-6738. Fax: (514) 343-
5728. E-mail: hanessia@ere.umontreal.ca.
(1) (a) Zheng, G.-C.; Hatano, M.; Ishitsuka, M. O.; Kusumi, T.;
Kakisawa, H. Tetrahedron Lett. 1990, 31, 2617-2618, 4522. See also:
(b) Zheng, G.-C.; Ichikawa, A.; Ishitsuka, M. O.; Kusumi, T.; Yama-
moto, H.; Kakisawa, H. J . Org. Chem. 1990, 55, 3677-3679.
(2) (a) Matsuo, A.; Kubota, N.; Nakayama, M.; Hayashi, S. Chem.
Lett. 1981, 1097-1100. (b) Whittacker, R. H.; Feeny, P. P. Science 1971,
171, 757-770.
(3) Bramwell, A. F.; Crombie, L.; Hemesley, P.; Pattenden, G.
Tetrahedron 1969, 25, 1727-1741.
(4) McMurry, J . E.; Bosch, G. K. J . Org. Chem. 1987, 52, 4885-
4893
(7) (a) Ito, H.; Imai, N.; Tanikawa, S.; Kobayashi, S. Tetrahedron
Lett. 1996, 37, 1795-1798. (b) Ito, H.; Imai, N.; Takao, K.-I.; Kobayashi,
S. Tetrhedron Lett. 1996, 37, 1798-1780. (c) Hanessian, S.; Cooke, N.
G.; DeHoff, B.; Sakito, Y. J . Am. Chem. Soc. 1990, 112, 5276-5290.
(d) Marshall, J . A.; Andrews, R. C. J . Org. Chem. 1985, 50, 1602-
1606. (e) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147-
155.
(5) Ihara, M.; Taniguchi, T.; Tokunaga, Y.; Fukumoto, K. J . Org.
Chem. 1994, 59, 8092-8100.
10.1021/jo990302n CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/02/1999

4894 J . Org. Chem., Vol. 64, No. 13, 1999
Hanessian et al.
Sch em e 1a
a
Reagents: (a) BuLi, Et2O, -78 °C, 46% (b) Ozone, CH2Cl2, MeOH; NaBH4, 83%. (c) CBr4, PPh3, MeCN, 73%. (d) t-Butyl
trichloroacetimidate, BF3‚Et2O, CH2Cl2, cyclohexane (e) Ozone, CH2Cl2, MeOH; NaBH4, 63% over 2 steps.
protocol, which led to the alcohol derivative 8. An
independent synthesis from the commercially available
trans-chrysanthemic acid 9 confirmed the stereochemis-
try assigned to 8 based on the anticipated mode of attack9
of the anion derived from 5, followed by intramolecular
enolate alkylation, as illustrated in Scheme 1. The
alternative pathway to 4 via a carbene insertion mech-
anism, which is not expected to proceed with such high
diastereoselectivity, cannot be excluded. Alcohol 8 was
converted to the required bromide 10 using standard
methods, providing us with the right-hand segment of
the molecule.
The sulfone segment (Figure 2) was prepared from
6-methyl-5-hepten-2-ol 11 (Scheme 2). Protection under
standard conditions,10 followed by ozonolysis, afforded the
corresponding aldehyde, which was subjected to a modi-
fied11 Horner-Emmons olefination to give 13 as the pure
E-isomer. Reduction with DIBAL-H afforded the allylic
alcohol 14, which was converted to the corresponding
bromide 15,12 and the latter was transformed to the
desired sulfone derivative 16 by treatment with sodium
phenyl sulfinate. The potassium anion of 16, generated
with t-BuOK, was reacted with 10 in the presence of
n-Bu4NI to afford the coupling product 17 in 61% yield
after deprotection.
There remained the seemingly simple task of desulfon-
ylating the allylic sulfone en route to the intended target
1. It is at this step that we encountered difficulties in
securing the desired trisubstituted E double bond. Using
methods of desulfonylation that rely on electron transfer
or radicals (Na/Hg, Li/EtNH2, SmI2-HMPA),13 the reac-
tion proceeded in good yield to generate a 1:1 mixture of
two regioisomers (18a and 18b). The isomer ratio was
enriched to a mixture favoring the desired regioisomer
F igu r e 2.
The right-hand segment of the molecule, consisting of
a trans tetrasubstituted cyclopropane, presented a cer-
tain challenge in view of the need to secure an enantio-
selective synthesis of an appropriately functionalized
intermediate. Previous studies in our laboratories have
demonstrated the utility of chloroallyl phosphonamides
in the highly diastereoselective synthesis of polysubsti-
tuted cyclopropanes such as 4.8 The (S,S)-reagent 5,
shown in Figure 2, would be needed to generate the
desired substitution pattern in the cyclopropane precur-
sor intended for anthoplalone.
In the event, treatment of the readily available 5 with
n-BuLi generated the corresponding chloroallyl anion, to
which was added tert-butyl 3,3-dimethyl acrylate 6 as
shown in Scheme 1. A diastereomerically pure cyclopro-
pane adduct 4 was obtained in 46% yield. Unfortunately,
attempts to optimize this yield were not successful. To
ascertain the absolute stereochemistry of the adduct, we
opted for an ozonolytic oxidative cleavage and reduction
(9) (a) Hanessian, S.; Gomtsyan, A. Tetrahedron Lett. 1994, 35,
7509-7512. (b) Hanessian, S.; Gomtsyan, A.; Payne, A.; Herve´, Y.;
Beaudoin, S. J . Org. Chem. 1993, 58, 5032-5034.
(10) Hanessian, S.; Lavalle´e, P. Can. J . Chem. 1975, 53, 2975-2977.
(11) (a) Tse, B. J . Am. Chem. Soc. 1996, 118, 7094-7100. (b)
Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-2186.
(12) Corey, E. J .; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972,
4339-4342.
(8) Hanessian, S.; Andreotti, D.; Gomtsyan, A. J . Am. Chem. Soc.
1995, 117, 10393-10394.

Total Synthesis of (-)-Anthoplalone
J . Org. Chem., Vol. 64, No. 13, 1999 4895
Sch em e 2a
a
Reagents: (a) TBDPSCl, imidazole, DMF, quant. (b) Ozone, CH2Cl2, DMS (c) (EtO)2P(O)CH(Me)CO2Et, LiCl, MeCN, 89% over 2
steps. (d) DIBAL-H, toluene, 98%. (e) DMS, NBS, CH2Cl2, 67%. (f) PhSO2Na, DMF, 89%. (g) t-BuOK, TBAI, THF; 10, THF. (h) TBAF,
THF, 61% over 2 steps. (i) Pd(dppp), LiBHEt3, THF, 76% (3:1, 18a /18b).
18a using Pd(dppp)/LiEt3BH as the desulfonylation
reagent.14 Variation of the protective group on the alcohol
(MOM, MEM, TBDPS), or the nature of the hydride
source, did not improve this ratio. The mixture of isomers
was carried through to the final product as a 3:1 mixture
(NMR) of double-bond regioisomers, but could not be
separated at any stage.
In exploring other approaches to sulfone anion cou-
pling, we prepared the â-hydroxysulfone intermediate 19
from the sulfone 16 and the aldehyde prepared from 8.
However, the sequential removal of the sulfone and
hydroxyl groups was not successful, resulting in ring
opening and elimination products.15 When we attempted
to “protect” the olefin by oxidizing it to the diol 20, the
desulfonylation led to the J ulia elimination product even
F igu r e 3.
when the hydroxyls were protected.
Having access to the diene 21 by the elimination of the
â-hydroxysulfone 19, we attempted many conditions for
After exploring several unproductive approaches, we
concluded that the J ulia coupling, through a different
disconnection, might prove successful (Figure 4). Thus a
sulfone anion coupling was envisaged with ketone 22
the selective reduction of the olefin adjacent to the
cyclopropane.16 Treatment with diimide led to the slow
and unselective reduction of both olefins. The use of other
reducing systems (Rh/C, PtO2, Wilkinson’s catalyst)
under a hydrogen atmosphere also failed to provide the
derived from an extension of the original intermediate
8. This type of disconnection was also the basis of the
Fukumoto synthesis.5 However, previous work in this
desired precursor to 1. In the hope of providing an anchor
area did not augur well for the creation of the E-
for the catalyst to favor the selective reduction of the
trisubstituted olefin using a phenyl sulfone union.17 This
undesired disubstituted double bond, we attempted the
prompted us to look at heteroaromatic sulfone anions to
reaction with a variety of catalysts on the primary alcohol
effect the coupling and subsequent elimination.
rather than the ester. Again, no selectivity was observed.
Recent work by Kende,18 S. J ulia,19 and Kocienski20
showed that heterocyclic sulfone anions offered an ad-
vantageous alternative to the classical phenyl sulfone,
(13) For Li/EtNH2: (a) Trost, B. M.; Weber, L.; Strege, P.; Fullerton,
T. J .; Dietsche, T. J . J . Am. Chem. Soc. 1978, 100, 3426-3435. (b)
Grieco, P. A.; Masaki, Y. J . Org. Chem. 1974, 39, 2135-2136. For Li/
EtNH2 vs Na(Hg): (c) Sato, K.; Inoue, S.; Onishi, A.; Uchida, N.;
Minowa, N. J . Chem. Soc., Perkin Trans. 1 1981, 761-769. (d) J ulia,
M.; Uguen, D.; Callipolitis, A. Bull. Soc. Chim. Fr. 1976, 519-524.
For SmI2: (e) Ku¨nzer, H.; Stahnke, M.; Sauer, G.; Wiechert, R.
Tetrahedron Lett. 1991, 32, 1949-1952.
(14) (a) Kende, A. S.; Liu, K.; Kaldor, I.; Dorey, G.; Koch, K. J . Am.
Chem. Soc. 1995, 117, 8258-8270. (b) Inomata, K.; Igarashi, S.; Mohri,
M.; Yamamoto, T.; Kinoshita, H.; Kotake, H. Chem. Lett. 1987, 707-
710. (c) Mohri, M.; Kinoshita, H.; Inomata, K.; Kotake, H. Chem. Lett.
1985, 451-454. (d) Kotake, H.; Yamamoto, T.; Kinoshita, H. Chem.
Lett. 1982, 1331-1334. (e) Hutchins, R. O.; Learn, K. J . Org. Chem.
1982, 47, 4380-4382.
(15) For similar problems in reducing homoallylic alcohols see:
Brown, M. J .; Harrison, T.; Overman, L. E. J . Am. Chem. Soc. 1991,
113, 5378-5384.
(16) For leading references on the difficulty of the selective reduction
of conjugated dienes: (a) J ames, B. R. Compr. Organomet. Chem.
Wilkinson, G., Stone, F. G. A., Abell, E. W., Eds.; 1982, Vol 8.; Chapter
51, pp 285-369. For reductions with diimide: (b) Pasto, D. J .; Taylor,
R. T. Org. React. 1991, 40, 91-155. (c) Siegel, S.; Foreman, M.; Fisher,
R. P.; J ohnson, S. E. J . Org. Chem. 1975, 40, 3599-3601. For
homogeneous catalysts: (d) Reger, D. L.; Habib, M. M.; Fauth, D. J .
J . Org. Chem. 1980, 45, 3860-3865. (e) Kawakami, K.; Mizoroki, T.;
Ozaki, A. Chem. Lett. 1976, 847-848. (f) Birch, A. J .; Williamson, D.
N. Org. React. 1976, 24, 1-186. For heterogeneous catalysts: (g) Card,
R. J .; Neckers, D. C. Isr. J . Chem. 1978, 17, 269-273. (h) Cortese, N.
A.; Heck, R. F. J . Org. Chem. 1978, 43 (3), 3985-3986. For some
successful selective reductions: (i) Wender, P. A.; Holt, D. A. J . Am.
Chem. Soc. 1985, 107, 7771-7772. (j) Choudary, B. M.; Sharma, G. V.
M.; Bharathi, P. Angew. Chem., Int. Ed. Engl. 1989, 28, 465-466.

4896 J . Org. Chem., Vol. 64, No. 13, 1999
Hanessian et al.
Sch em e 3a
a
Reagents: (a) DMSO, (COCl)2, Et3N, CH2Cl2; Ph3PdCHC(O)Me. (b) H2, Pd(OH)2/C, EtOAc, 82% over 2 steps. (c) BuLi, THF, -78 °C,
1 h., 98%. (d) SmI2, THF, 84%. (e) LiAlH4, THF, 55 °C, 87%. Separation of E/Z isomers. (f) Amberlite (IR-120, H+), MeOH, 79%. (g) TPAP,
NMO, 4 Å sieves, CH2Cl2, 75%.
Furthermore, it has been shown that the presence of
HMPA lowers the E/Z ratio in the cleavage vinyl sul-
fones.22
Thus, the required ketone 22 was prepared from
alcohol 8 using a one-pot Swern oxidation/Wittig olefi-
nation protocol, to give the corresponding volatile enone,
which was hydrogenated in the presence of Pd(OH)2/C
to give ketone 22 (Scheme 3). The lithium anion of sulfone
23 was added to 22, to give the corresponding â-hydroxy-
sulfone 24 as a mixture of isomers. Monitoring of the
temperature (-78 °C) was crucial, because this addition
is reversible at higher temperatures.23 Treatment of 24
with SmI2 led to 25 as a 2:1 mixture of E/Z-isomers.6n,s
Although this ratio constitutes an improvement of the
originally reported ratio of 1:2.6 (E/Z),5 it is still disap-
pointing, even if one can ultimately resort to recycling
F igu r e 4.
the minor isomer.24 Attempts to improve this ratio by
since elimination to the olefin is highly facilitated. Work
(19) (a) Baudin, J . B.; Hareau, G.; J ulia, S. A.; Ruel, O. Bull. Soc.
Chim. Fr. 1993, 130, 336-357. (b) Baudin, J . B.; Hareau, G.; J ulia, S.
A.; Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856-878. (c)
Baudin, J . B.; Hareau, G.; J ulia, S. A.; Ruel, O. Tetrahedron Lett. 1991,
32, 1175-1178. For applications in synthesis see: (d) Pattenden, G.;
Plowright, A. T.; Tornos, J . A.; Ye, T. Tetrahedron Lett. 1998, 39, 6099-
6102. (e) Charette, A. B.; Lebel, H. J . Am. Chem. Soc. 1996, 118,
10327-10328. (f) Bellingham, B.; J arowicki, K.; Kocienski, P.; Martin,
V. Synthesis 1996, 285-296. (g) Smith, N. D.; Kocienski, P. J .; Street,
S. D. A. Synthesis 1996, 652-666.
in this area has focused primarily on additions of sulfone
anions to aldehydes. In fact, using benzothiazole sulfone
anions on model ketones failed to provide the desired
olefin in our hands in significant amount.
We then turned to an imidazole sulfone anion for the
coupling to ketone 22, since in such cases, reduction with
SmI2 need not be done in the presence of HMPA.18,21
(20) Blakemore, P. R.; Cole, W. J .; Kocienski, P. J .; Morley, A. Synlett
1998, 26-28.
(17) (a) Simpkins, N. S. Sulfones in Organic Synthesis: Tetrahedron
Organic Chemistry Series, vol. 10; Pergamon: New York, 1993. (b)
Kocienski, P. Phosphorus Sulfur 1985, 24, 97-127. For examples of
uses for the synthesis of trisubstituted olefins: (c) Khandekar, G.;
Robinson, G. C.; Stacey, N. A.; Thomas, E. J .; Vather, S. J . Chem. Soc.,
Perkin Trans. 1 1993, 1507-1512. (d) J ones, A. B.; Villalobos, A.; Linde,
R. G., II; Danishefsky, S. J . J . Org. Chem. 1990, 55, 2786-2797. (e)
Villalobos, A.; Danishefsky, S. J . J . Org. Chem. 1989, 54, 12-15. (f)
Baker, R.; Borges, M.; Cooke, N. G.; Herbert, R. H. J . Chem. Soc.,
Chem. Commun. 1987, 414-416. (g) Hanessian, S.; Ugolini, A.; Hodges,
P. J .; Beaulieu, P.; Dube´, D.; Andre´, C. Pure Appl. Chem. 1987, 59,
299-316. (h) Barrett, A. G. M.; Carr, R. A. E.; Attwood, S. V.;
Richardson, G.; Walshe, N. D. A. J . Org. Chem. 1986, 51, 4840-4856.
(18) Kende, A. S.; Mendoza, J . S. Tetrahedron Lett. 1990, 31, 7105-
7108.
(21) (a) Shabangi, M.; Flowers, R. A., II. Tetrahedron Lett. 1997,
38, 1137-1140. (b) Hasegawa, E.; Curran, D. P. J . Org. Chem. 1993,
58, 5008-5010.
(22) Keck, G. E.; Savin, K. A.; Weglarz, M. A. J . Org. Chem. 1995,
60, 3194-3204.
(23) (a) Hart, D. J .; Wu, W.-L. Tetrahedron Lett. 1996, 37, 5283-
5286. (b) Marko´, I. E.; Murphy, F.; Dolan, S. Tetrahedron Lett. 1996,
37, 2089-2092. (c) J ulia, M.; Paris, J .-M. Tetrahedron Lett. 1973,
4833-4836.
(24) (a) Annunziata, R.; Cinquini, M.; Cozzi, F.; Gennari, C.;
Raimondi, L. J . Org. Chem. 1987, 52, 4674-4681. (b) Dervan, P. B.;
Shippey, M. A. J . Am. Chem. Soc. 1976, 98, 1265-1267. (c) Vedejs,
E.; Fuchs, P. L. J . Am. Chem. Soc. 1973, 95, 822-825. (d) See also ref
5.

Total Synthesis of (-)-Anthoplalone
J . Org. Chem., Vol. 64, No. 13, 1999 4897
1.00 (1H, m); 13C (100.4 MHz, CDCl3) δ (ppm) 170.31, 150.87,
150.82, 120.90, 119.37, 80.62, 64.65, 64.57, 63.62, 63.56, 36.22,
36.17, 35.93, 29.35, 28.72, 28.67, 28.63, 28.56, 28.54, 28.11,
28.08, 28.00, 24.17, 24.08, 22.04, 20.08; 31P (161.3 MHz, CDCl3)
δ (ppm) 32.80; LRMS 405 (M + Na), 383 (M + 1), 327 (M -
55); HRMS (C20H36N2O3P) calcd 383.24637, found 383.24500,
σ ) 3.6 ppm.
varying the temperature and the use of additives (MgBr2,
ZnCl2, ethylene glycol) were not met with success.
After reduction of ester 25 to primary alcohol 26 with
LAH, the isomers could be separated by chromatography.
The E-isomer was converted into the natural product by
acidic deprotection of the ketal and oxidation of the
primary alcohol with tetrapropylammonium perruthen-
ate (TPAP).25 Although the NMR spectral characteristics
were identical to those reported,1 the value of the optical
rotation of our synthetic sample was found to be signifi-
cantly greater than the one reported for the natural
product.1 This may be due to the low concentration and
the small amount of sample available from natural
sources.
3(R)-Hyd r oxym eth yl-2,2-d im eth yl-cyclop r op a n e-1(R)-
ca r boxylic Acid ter t-Bu tyl Ester (8). The preceding com-
pound 4 (547 mg, 1.43 mmol) was dissolved in CH2Cl2 (23 mL)
and MeOH (26 mL). The solution was cooled to -78 °C, and
ozone was bubbled until the solution turned blue. The solution
was then flushed with nitrogen to remove excess ozone, and
NaBH4 (110 mg, 2.89 mmol) was added. The solution was then
warmed to 0 °C and stirred until the aldehyde had disappeared
by TLC analysis. Acetone (10 mL) was added, and the solvents
were evaporated. The residue was dissolved in EtOAc, washed
with aqueous NH4Cl and brine. The organic phase was dried
with Na2SO4 and evaporated. The residue was purified by flash
chromatography (1:1 EtOAc/hexanes) to give the title com-
pound as a colorless oil (239 mg, 83%): [R]D -38.7 (c 0.86,
Con clu sion
The total synthesis of enantiopure anthoplalone was
accomplished in only nine steps and overall yield of 9%
from readily available precursors. A number of connec-
tivities were investigated utilizing various sulfone anion
couplings to appropriately functionalized cyclopropanes,
which are available in enantiopure form utilizing allylic
phosphonamides as chiral reagents.26 Securing the cor-
rect regioisomer or the E-geometry of the trisubstituted
double bond proved to be a major challenge. Our total
synthesis of (-)-anthoplalone also confirmed the absolute
configuration as 2R, 3R.
1
CHCl3); H (400 MHz, CDCl3) δ (ppm) 3.65 (1H, dd, J 1 ) 6.6
Hz, J 2 ) 12.6 Hz), 3.48 (1H, dd, J 1 ) 8.2 Hz, J 2 ) 12.6 Hz),
2.60 (1H, broad), 1.58-1.53 (1H, m), 1.38 (9H, s), 1.25 (1H, d,
J ) 5.5 Hz), 1.16 (3H, s), 1.12 (3H, s); 13C (100.4 MHz, CDCl3)
δ (ppm) 171.44, 80.15, 61.51, 33.54, 32.49, 28.07, 27.87, 26.36,
20.53; LRMS 201 (M + 1), 154, 107; HRMS calcd (C11H21O3)
201.14906, found 201.14950, σ ) 3.6 ppm.
Syn th esis of 8 fr om Ch r ysa n th em ic Acid (9). To a
solution of chrysanthemic acid (180 mg, 1.07 mmol) in CH2-
Cl2 (5 mL) at 0 °C was added tert-butyl 2,2,2-trichloroacetimi-
date (0.47 mL, 2.1 mmol) in pentane (5 mL), followed by BF3‚
Et2O (10 µL). After stirring for 12 h, NaHCO3 (1 g) was added,
the solids were filtered, and the solvents were evaporated. The
product was purified by column chromatography (9:1 hexanes/
EtOAc), and the product was carried directly into the next step.
A solution of the ester in a mixture of CH2Cl2 (4 mL) and
EtOH (4 mL) was cooled to -78 °C, and ozone was bubbled
until the solution turned blue. The solution was then flushed
with nitrogen to remove excess ozone, and NaBH4 (41 mg, 1.08
mmol) was added. The solution was warmed to 0 °C and stirred
until the aldehyde had disappeared by TLC analysis. Acetone
(5 mL) was added, and the solvents were evaporated. The
residue was dissolved in EtOAc and washed with aqueous NH4-
Cl and brine. The organic phase was dried with Na2SO4 and
evaporated. The residue was purified by flash chromatography
(1:1 EtOAc/hexanes) to give the title compound as a colorless
oil (134 mg, 63%): [R]D -35.5 (c 1.02, CHCl3); the NMR and
MS data are identical to 8 prepared from phosphonamide 4.
3(R)-Br om om eth yl-2,2-dim eth ylcyclopr opan e-1(R)-car -
boxylic Acid ter t-Bu tyl Ester (10). To a solution of 8 (60
mg, 0.30 mmol) and CBr4 (124 mg, 0.38 mmol) in acetonitrile
(7 mL) at 0 °C was added PPh3 (118 mg, 0.45 mmol) in small
portions under a nitrogen atmosphere, and the solution was
warmed to room temperature and stirred for 3 h. The solvent
was then evaporated and the residue purified by column
chromatography (9:1 hexanes/EtOAc) to give the title com-
pound as a volatile liquid (58 mg, 73%): [R]D - 4.4 (c 0.77,
Exp er im en ta l Section
Gen er a l P r oced u r es. All commercially available reagents
were used without further purification. Solvents were distilled
under positive pressure of dry nitrogen before use; THF and
ether, from K/benzophenone; and CH2Cl2 and toluene, from
CaCl2. NMR (1H, 13C, 31P) spectra were recorded on 300, 400,
or 600 MHz spectrometers in CDCl3, and DEPT experiments
were performed routinely. Low- and high-resolution mass
spectra were measured using fast atom bombardment (FAB)
or electrospray techniques. Optical rotations were measured
at the sodium line at ambient temperature. Flash column
chromatography27 was performed in the usual way using (40-
60 µm) silica gel. Melting points are uncorrected.
5
3(R)-[2-(1,3-Dim eth yl-2-oxo-octa h yd r o-2λ -ben zo[1,3,2]-
d ia za p h osp h ol-2-yl)-vin yl]-2,2-d im et h ylcyclop r op a n e-
1(R)ca r boxylic Acid ter t-Bu tyl Ester (4). To a solution of
n-BuLi (0.334 mL, 0.836 mmol, 2.5 M solution in hexanes) in
Et2O (4 mL) was added phosphonamide 5 (200 mg, 0.760
mmol) in Et2O at -78 °C under a nitrogen atmosphere. After
5 min, tert-butyl 3,3-dimethyl acrylate 6 (143 mg, 0.916 mmol)
in Et2O was added. The solution was stirred for 16 h at -78
°C and then poured in a 1:1 mixture of aqueous NH4Cl and
EtOAc (100 mL). The product was extracted with EtOAc (3 ×
100 mL) and dried with MgSO4, and the solvent was evapo-
rated under reduced pressure. The residue was purified by
flash chromatography (95:5 EtOAc/MeOH) to give the title
compound as a pale yellow oil (150 mg, 46%): [R]D + 28.7 (c
1
CHCl3); H (400 MHz, CDCl3) δ (ppm) 3.64 (1H, dd, J 1 ) 6.5
Hz, J 2 ) 10.5 Hz), 3.24 (1H, t, J ) 10.2 Hz), 1.84 (1H, ddd, J 1
) 5.4 Hz, J 2 ) 6.5 Hz, J 3 ) 9.9 Hz), 1.45 (9H, s), 1.36 (1H, d,
J ) 5.3 Hz), 1.24 (3H, s), 1.23 (3H, s); 13C (100.4 MHz, CDCl3)
δ (ppm) 170.24, 80.46, 36.08, 33.55, 32.55, 28.84, 28.10, 20.32,
20.24; MS, the compound does not ionize with FAB and
electrospray.
1
1.82, CHCl3); H (400 MHz, CDCl3) δ (ppm) 6.41 (1H, ddd, J 1
) 9.4 Hz, J 2 ) 16.5 Hz, J 3 ) 19.9 Hz), 5.53 (1H, dd, J 1 ) 6.5
Hz, J 2 ) 21.3 Hz), 2.76-2.70 (1H, m), 2.49-2.43 (6H, m), 2.44-
2.38 (1H, m), 2.08 (1H, dd, J 1 ) 5.3 Hz, J 2 ) 9.3 Hz), 2.01-
1.95 (2H, m), 1.83-1.78 (2H, m), 1.69 (1H, d, J ) 5.3 Hz), 1.43
(9H, s), 1.39-1.17 (3H, m), 1.22 (3H, s), 1.18 (3H, s), 1.13-
t er t -B u t y l-(1,5-d im e t h y lh e x -4-e n y lo x y )d ip h e n y l-
sila n e (12). To a solution of 6-methyl-5-hepten-2-ol 11 (4.0 g,
31 mmol) and imidazole (4.6 g, 68 mmol) in DMF (150 mL)
was added TBDPSCl (8.9 mL, 34.1 mmol) under a nitrogen
atmosphere, and the solution was stirred overnight for 18 h.
Water was added to the solution, and the product was
extracted with ether. The organic layer was washed with brine,
dried with Na2SO4, and evaporated. The residue was purified
by flash chromatography (hexanes) to give the title compound
as a colorless oil (11.3 g, quantitative): 1H (400 MHz, CDCl3)
(25) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 1625-1627.
(26) (a) Bennani, Y.; Hanessian, S. Chem. Rev. 1997, 97, 3161-3195.
(b) Boyle, C. D.; Kishi, Y. Tetrahedron Lett. 1995, 36, 4579-4582. (c)
Paquette, L. A.; Wang, T.-Z.; Pinard, E. J . Am. Chem. Soc. 1995, 117,
1455-1456.
(27) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

4898 J . Org. Chem., Vol. 64, No. 13, 1999
Hanessian et al.
δ (ppm) 7.76-7.68 (4H, m), 7.48-7.36 (6H, m), 5.03-4.98 (1H,
m), 3.92-3.85 (1H, m), 2.04-1.93 (2H, m), 1.67 (3H, d, J )
0.8 Hz), 1.57 (3H, d, J ) 0.8 Hz), 1.55-1.42 (2H, m), 1.10 (3H,
d, J ) 5.9 Hz), 1.09 (9H, s); 13C (100.4 MHz, CDCl3) δ (ppm)
135.83, 135.82, 134.87, 134.49, 131.17, 129.34, 129.28, 127.37,
127.29, 124.35, 69.27, 39.49, 26.96, 25.59, 23.89, 23.08, 19.20,
17.50; LRMS 365 (M - H), 309 (M - t-Bu), 289 (M - Ph);
HRMS calcd (C24H33OSi) (M - H) 365.23007, found 365.23100,
σ ) -2.5 ppm.
6-(ter t-Bu t yld ip h en ylsila n yloxy)-2-m et h ylh ep t -2(E)-
en oic Acid Eth yl Ester (13). Compound 12 (3 g, 8.19 mmol)
was dissolved in 150 mL of CH2Cl2 and cooled to -78 °C. Ozone
was bubbled in the solution until the blue color persisted, at
which time nitrogen was passed through the solution to
remove the excess ozone. Dimethyl sulfide (4 mL) was added,
the solution was warmed to room temperature, and the
solvents were evaporated to give the crude aldehyde as a
yellowish oil, which was used in the next step without further
purification.
To a suspension of dry LiCl (1.39 g, 32.8 mmol) and triethyl
2-phosphonopropionate (6.98 mL, 32.8 mmol) in MeCN (80 mL)
was added DBU (3.65 mL, 24.1 mmol). The mixture was stirred
at room temperature until it became homogeneous. Then the
aldehyde in MeCN (25 mL) was added to the solution at 0 °C.
The solution was stirred until the reaction was complete (∼3
h), the solvent was removed under reduced pressure, the
residue was dissolved in CH2Cl2, washed with water and brine,
and dried (MgSO4), and the solvent was evaporated. The
residue was purified by flash chromatography (15:1 hexanes/
EtOAc) to give the title compound as a colorless oil (3.09 g,
89%): 1H (400 MHz, CDCl3) δ (ppm) 7.71-7.67 (4H, m), 7.46-
7.36 (6H, m), 6.71-6.65 (1H, m), 4.19 (2H, q, J ) 7.1 Hz), 3.94-
3.86 (1H, m), 2.26-2.13 (2H, m), 1.78 (3H, d, J ) 1.3 Hz),
1.64-1.49 (2H, m), 1.30 (3H, t, J ) 7.2 Hz), 1.10 (3H, d, J )
6.1 Hz), 1.07 (9H, s); 13C (100.4 MHz, CDCl3) δ (ppm) 168.11,
141.94, 135.78, 135.73, 134.56, 134.19, 129.47, 129.39, 127.64,
127.45, 127.35, 68.98, 60.26, 37.92, 26.92, 24.45, 23.04, 19.17,
14.22, 12.17; LRMS 423 (M - H), 367 (M - t-Bu); HRMS calcd
(C26H35O3Si) 423.23553, found 423.23330, σ ) 5.3 ppm.
6-(ter t-Bu t yld ip h en ylsila n yloxy)-2-m et h ylh ep t -2(E)-
en -1-ol (14). To a solution of ester 13 (2.4 g, 5.7 mmol) in
toluene (60 mL) at -78 °C was added DIBAL-H (12.4 mmol,
1.5 M solution in toluene) under a nitrogen atmosphere. The
solution was stirred at that temperature for 30 min, then at
room temperature for 1 h, and cooled to 0 °C, and MeOH (20
mL) was added slowly. The solution was stirred for 1 h, and
the translucent solid was filtered off and washed with boiling
THF (200 mL). The solvents were then evaporated and the
residue was purified by flash chromatography (95:5 hexanes/
EtOAc) to give the title compound as a colorless oil (2.15 g,
98%): 1H (400 MHz, CDCl3) δ (ppm) 7.73-7.70 (4H, m), 7.46-
7.28 (6H, m), 5.29-5.25 (1H, m), 3.95 (2H, s), 3.92-3.85 (1H,
m), 2.18-1.97 (2H, m), 1.62 (3H, s), 1.59-1.42 (2H, m), 1.41
(1H, s), 1.12 (3H, d, J ) 6.1 Hz), 1.08 (9H, s); 13C (100.4 MHz,
CDCl3) δ (ppm) 135.83, 135.81, 134.74, 134.60, 134.43, 129.40,
129.34, 127.39, 127.32, 126.01, 69.11, 68.84, 39.06, 26.96,
23.42, 23.06, 19.18, 13.47; LRMS 381 (M - 1), 239 (TBDPS);
HRMS calcd (C24H33O2Si) 381.22498, found 381.22370, σ ) 3.3
ppm.
131.24, 129.34, 127.41, 127.32, 68.95, 41.75, 38.49, 26.93,
24.09, 23.05, 19.16, 14.43; LRMS 445 (M + 1), 389 (M - t-Bu),
365 (M - Br); HMRS calcd (C24H32OSi79Br) 443.14059, found
443.14150, σ ) -2.0 ppm.
(6-Ben zen esu lfon yl-1.5-dim eth ylh ex-4(E)-en yloxy)-ter t-
bu tyld ip h en ylsila n e (16). To a solution of 15 (1.54 g, 3.46
mmol) in DMF (85 mL) was added sodium benzene sulfinate
(1.13 g, 6.89 mmol) under a nitrogen atmosphere. The solution
was stirred for 15 h at room temperature, ether was added,
followed by successive washes with water and brine, and the
organic layer was dried with Na2SO4. After evaporation of the
solvent, the residue was purified by flash chromatography (5:1
hexanes/EtOAc) to give the title compound as a colorless oil
(1.56 g, 89%): 1H (400 MHz, CDCl3) δ (ppm) 7.82-7.81 (2H,
m), 7.71-7.66 (3H, m), 7.60-7.56 (1H, m), 7.50-7.36 (9H, m),
4.89-4.85 (1H, m), 3.78-3.70 (1H, m), 3.67 (2H, s), 2.00-1.83
(2H, m), 1.71 (3H, d, J ) 1.2 Hz), 1.36-1.17 (2H, m), 1.07 (9H,
s), 1.04 (3H, d, J ) 8.5 Hz); 13C (100.4 MHz, CDCl3) δ (ppm)
138.18, 136.07, 135.79, 135.75, 134.56, 134.28, 133.37, 129.50,
129.43, 128.74, 128.43, 127.46, 127.37, 123.15, 68.85, 66.12,
38.33, 26.95, 24.05, 23.00, 19.18, 16.14; LRMS 507 (M + 1),
429 (M - Ph); HRMS (C30H39O3SiS) calcd 507.23892, found
507.23731, σ ) 3.2 ppm.
3(R)-(2-Ben zen esu lfon yl-7-h yd r oxy-3-m eth yloct-3(E)-
en yl)-2,2-dim eth ylcyclopr opan e-1(R)-car boxylic Acid ter t-
Bu tyl Ester (17). To a solution of 16 (192 mg, 0.380 mmol)
and tetrabutylammonium iodide (84 mg, 0.228 mmol) in THF
(3 mL) was added t-BuOK (0.418 mmol, 1 M solution in THF)
under a nitrogen atmosphere at -78 °C. After 10 min, bromide
10 (50 mg, 0.190 mmol) in THF (3 mL) was added dropwise to
the yellow solution, which was left to slowly warm to room
temperature overnight, and brine was added. The solution was
then extracted with EtOAc, and the organic phase was dried
with Na2SO4 and evaporated. The residue was purified by flash
chromatography (9:1 hexanes/EtOAc) to give a mixture of
starting sulfone and addition product.
The mixture was dissolved in 15 mL of THF and cooled to
0 °C, and TBAF (0.760 mmol, 1 M solution in THF) was added
under a nitrogen atmosphere. The solution was stirred for 10
h at room temperature, after which aqueous NH4Cl was added.
The solution was then extracted with EtOAc, the organic phase
was dried with Na2SO4 and evaporated, and the residue was
purified by flash chromatography (2:1 hexanes/EtOAc) to give
the title compound as a colorless oil as a mixture of isomers
(104 mg, 61%): 1H (400 MHz, CDCl3) δ (ppm) 7.80-7.78 (2H,
m), 7.61-7.58 (1H, m), 7.52-7.47 (2H, m), 5.21-5.16 (0.5H,
m), 5.15-5.10 (0.5H, m), 3.62-3.52 (1H, m), 3.51-3.44 (1H,
m), 2.25-2.17 (0.5H, m), 2.07-1.92 (2H, m), 1.89-1.76 (0.5H,
m), 1.68-1.65 (4H, m), 1.39 (5H, s), 1.38 (4H, s), 1.31-1.22
(4H, m), 1.15-1.03 (10H, m); 13C (100.4 MHz, CDCl3) δ (ppm)
171.32, 171.28, 137.95, 137.92, 135.79, 135.69, 133.27, 128.67,
128.64, 126.64, 126.61, 126.48, 80.08, 80.05, 80.00, 67.08,
67.05, 67.01, 51.93, 37.96, 37.94, 37.91, 37.89, 34.29, 34.27,
33.29, 33.24, 29.70, 29.59, 29.54, 29.07, 28.99, 28.12, 28.11,
27.68, 27.56, 25.90, 25.88, 25.40, 24.66, 24.53, 24.43, 24.36,
24.33, 24.31, 23.88, 23.42, 23.39, 23.36, 23.34, 21.58, 20.96,
20.37, 20.32, 20.30, 20.13, 13.96, 13.81, 13.68, 13.55, 13.49;
HRMS calcd (C25H39O5S) 451.25183, found 451.25410, σ ) -5.0
ppm.
(6-Br om o-1,5-d im et h ylh ex-4(E)-en yloxy)-ter t-b u t yl-
d ip h en ylsila n e (15). To a solution of NBS (1.52 g, 8.57 mmol)
in CH2Cl2 (25 mL) was added DMS (0.75 mL, 10.3 mmol) very
slowly at 0 °C under a nitrogen atmosphere. The mixture was
cooled to -20 °C, 14 (2.18 g, 5.71 mmol) in CH2Cl2 (8 mL) was
added dropwise, the temperature was raised to 0 °C, and the
solution was stirred for 3 h. The solution was then diluted with
pentane and washed with cold water and cold brine. The
organic phase was dried with Na2SO4 and evaporated, and the
residue was rapidly purified by flash chromatography (9:1
hexanes/EtOAc) to give the title compound as a colorless oil
(1.70 g, 67%): 1H (400 MHz, CDCl3) δ (ppm) 7.70-7.67 (4H,
m), 7.46-7.27 (6H, m), 5.45-5.42 (1H, m), 3.92 (2H, s), 3.90-
3.81 (1H, m), 2.10-1.93 (2H, m), 1.69 (3H, t, J ) 0.7 Hz), 1.57-
1.40 (2H, m), 1.08 (3H, d, J ) 6.1 Hz), 1.06 (9H, s); 13C (100.4
MHz, CDCl3) δ (ppm) 135.80, 135.77, 134.63, 134.29, 131.73,
3(R)-(7-Hyd r oxy-3-m eth yloct-3(E)-en yl)-2,2-d im eth yl-
cyclop r op a n e-1(R)-ca r boxylic Acid ter t-Bu tyl Ester (18a
a n d 18b). To a solution of sulfone 17 (50 mg, 0.111 mmol) in
THF (6 mL) was added PdCl2(dppp) (2 mg, 0.003 mmol), and
the solution was cooled to 0 °C under a nitrogen atmosphere.
The solution was stirred for a few minutes, and LiBHEt3 (0.333
mmol, 1 M solution in THF) was added dropwise, upon which
the solution turned red. The reaction was stirred for 3 h at
that temperature, and 5% NaOH (2 mL) followed by KCN (10
mg) were added. The solution was then diluted with brine and
extracted with ether. The organic phase was dried with Na2-
SO4 and evaporated, and the residue was purified by flash
chromatography (9:1 hexanes/EtOAc) to give the title com-
pounds as a colorless oil (26 mg, mixture of 2 regioisomers,
76%): 1H (400 MHz, CDCl3) δ (ppm) 5.15-5.12 (1H, m), 3.80-
3.77 (1H, m), 2.11-1.99 (4H, m), 1.68 (1H, s), 1.61 (2.25H, s),

Total Synthesis of (-)-Anthoplalone
J . Org. Chem., Vol. 64, No. 13, 1999 4899
1.57 (0.75H, s) 1.52-1.40 (5H, m), 1.43 (9H, s), 1.19 (3H, d, J
) 6.2 Hz), 1.18 (3H, s), 1.12 (3H, s), 1.07 (1H, d, J ) 5.5 Hz);
13C (100.4 MHz, CDCl3) δ (ppm) 172.18, 135.09, 135.05, 124.33,
124.26, 123.77, 123.22, 79.63, 67.89, 67.72, 39.10, 39.08, 38.67,
33.96, 32.63, 32.59, 32.40, 32.37, 31.57, 29.56, 28.19, 26.92,
26.84, 26.69, 24.27, 24.23, 23.90, 23.79, 23.40, 23.35, 23.16,
21.29, 21.20, 20.70, 15.85, 15.81; LRMS 311 (M + 1), 237 (M
- Ot-Bu); HRMS calcd (C19H35O3) 311.25861, found 311.26023,
σ ) 0.3 ppm.
2,2-Dim eth yl-3(R)-(3-oxobu tyl)cyclop r op a n e-1(R)-ca r -
boxylic a cid ter t-Bu tyl Ester (22). To a solution of oxalyl
chloride (0.151 mL, 1.73 mmol) in CH2Cl2 (5 mL) at -78 °C
was added dropwise DMSO (0.237 mL, 3.35 mmol) under a
nitrogen atmosphere. A solution of 8 (239 mg, 1.20 mmol) in
CH2Cl2 (5 mL) was added dropwise via cannula. The solution
was stirred 30 min, and Et3N (0.635 mL, 4.54 mmol) was added
dropwise. Then the mixture was warmed to room temperature
and stirred for 90 min. A solution of 1-triphenylphosphoran-
ylidene-2-propanone (1.53 g, 4.78 mmol) in CH2Cl2 (10 mL)
was added. After stirring for 24 h, a further 1.53 g of Wittig
reagent was added, and the solution was stirred for another
24 h. The solvent was removed under reduced pressure, and
the residue purified by flash chromatography (9:1 hexanes/
EtOAc). The compound was carried into the next step directly
because of its volatility.
Anal. Calcd (C11H18N2O4S): C 48.16, H 6.61, N 10.21, S 11.69.
Found: C 48.07, H 6.72, N 10.14, 11.62.
3(R)-[3-Hyd r oxy-3-m eth yl-6-(2-m eth yl[1,3]d ioxola n -2-
yl)-4-(1-m e t h yl-1H -im id a zole -2-su lfon yl)h e xyl]-2,2-d i-
m eth ylcyclop r op a n e-1(R)-ca r boxylic Acid ter t-Bu tyl Es-
ter (24). To a solution of sulfone 23 (356 mg, 1.30 mmol) in
THF (4 mL) was slowly added BuLi (1.43 mmol, 2.5 M solution
in hexane) at -78 °C under a nitrogen atmosphere. Ketone
22 (104 mg, 0.430 mmol) in THF (4 mL) was added slowly,
and the solution was stirred at -78 °C for 1 h. Then the
reaction was stopped by adding saturated NH4Cl (5 mL) at
-78 °C, and the mixture was allowed to warm to room
temperature. The product was extracted with EtOAc, and the
organic phase was washed with brine, dried with MgSO4, and
evaporated. The residue was purified by flash chromatography
(3:1 hexanes/EtOAc) to give the title compound as an insepa-
rable mixture of isomers (217 mg, 98%): 1H (400 MHz, CDCl3)
δ (ppm) 7.11 (0.4H, s) 7.10 (0.6H, s), 6.98 (0.4H, s), 6.97 (0.6H,
s), 4.18 (1H, broad), 3.96 (1.5H, s), 3.95 (1.5H, s) 3.89-3.80
(4H, m), 3.67-3.65 (0.6H, m), 3.53-3.50 (0.4H, m), 2.03-1.79
(3H, m), 1.74-1.44 (5H, m), 1.41 (4H, s) 1.40 (5H, s), 1.38-
1.32 (3H, m), 1.20-1.05 (11H, m); 13C (100.4 MHz, CDCl3) δ
(ppm) 171.96, 142.70, 142.18, 128.87, 128.82, 128.71, 125.53,
109.10, 109.02, 79.72, 74.57, 74.53, 74.37, 74.31, 73.45, 73.41,
72.23, 72.15, 64.45, 64.41, 60.26, 41.26, 41.19, 39.17, 39.10,
38.22, 37.83, 35.19, 35.13, 33.96, 33.88, 33.83, 33.80, 32.44,
32.40, 32.28, 28.16, 28.04, 26.85, 26.81, 26.77, 25.81, 25.76,
23.94, 23.88, 23.45, 22.51, 22.47, 22.01, 21.96, 21.14, 21.02,
20.76, 20.68; LRMS 515 (M + 1); HRMS calcd (C25H43N2O7S)
515.27911, found 515.27760, σ ) 1.8 ppm.
To a solution of the enone in EtOAc (15 mL) was added Pd-
(OH)2 (85 mg, 10% w/w), and the flask was evacuated prior to
placing it under H2 atmosphere. The suspension was stirred
for 4 h, the catalyst was filtered off, and the solvent was
evaporated to give the desired ketone (237 mg) as a colorless
2,2-Dim eth yl-3(R)-[3-m eth yl-6-(2-m eth yl-[1,3]d ioxola n -
2-yl)h ex-3-en yl]cyclop r op a n e-1(R)-ca r boxylic Acid ter t-
Bu tyl Ester (25). Under a nitrogen atmosphere were placed
metallic Sm (246 mg, 1.64 mmol) and EtI2 (369 mg, 1.31 mmol).
Nitrogen was passed for 5 min, THF (10 mL) was added, and
the solution was stirred until a deep blue color persisted (45-
60 min), after which the hydroxy sulfone 24 (217 mg, 0.422
mmol) in THF (10 mL) was added dropwise. The reaction was
complete within 20 min, and the solution was poured in 10%
aqueous Na2S2O3. The product was extracted with EtOAc, and
the organic phase was washed with brine, dried with MgSO4,
and evaporated. The residue was purified by flash chroma-
tography (5:1 hexanes/EtOAc) to give the title compound as
an inseparable mixture of isomers (125 mg, 84%, 2:1 E/Z): 1H
(400 MHz, CDCl3) δ (ppm) 5.12-5.08 (1H, m), 3.94-3.88 (4H,
m), 2.10-1.99 (4H, m), 1.65-1.60 (3H, m), 1.57 (2H, s), 1.48-
1.33 (2H, m), 1.44 (3H, s), 1.43 (6H, s), 1.30 (3H, s), 1.22-1.18
(1H, m), 1.17 (1H, s), 1.16 (2H, s), 1.13 (1H, s), 1.10 (2H, s),
1.07 (0.33H, d, J ) 5.4 Hz), 1.05 (0.66H, d, J ) 5.6 Hz); 13C
(100.4 MHz, CDCl3) δ (ppm) 172.12, 172.06, 134.85, 134.67,
124.75, 124.14, 109.75, 109.69, 79.61, 79.55, 64.48, 39.31,
39.19, 38.91, 33.86, 32.41, 31.47, 28.14, 26.99, 26.91, 26.78,
23.66, 23.35, 22.52, 22.37, 21.17, 21.04, 20.71, 20.67, 15.78;
LRMS 353 (M + 1), 297 (M - t-Bu), 279 (M - Ot-Bu); HRMS
calcd (C21H37O4) 353.26920, found 353.27010, σ ) -2.6 ppm.
{2,2-Dim eth yl-3(R)-[3-m eth yl-6-(2-m eth yl-[1,3]dioxolan -
2-yl)-h ex-3(E)-en yl]-cyclop r op yl}-1(R)-m eth a n ol (26). To
a suspension of LAH (32 mg, 0.842 mmol) in THF (2 mL) was
added ester 25 (68 mg, 0.193 mmol) in THF (3 mL) at 0 °C
under a nitrogen atmosphere. The reaction mixture was heated
to 55 °C for 5 h and then quenched at 0 °C by carefully adding
water (1 mL), 2 M NaOH (2 mL), and water (2 mL). The solid
was filtered off, brine was added, and the product was
extracted with EtOAc. The organic phase was dried with
MgSO4 and evaporated, and the residue was purified by flash
chromatography (7:1 petroleum ether/EtOAc) to give the title
compound as a colorless oil (48 mg, 87%). The E/Z-isomers can
be separated with the above conditions to give the pure
E-isomer (30 mg): [R]D +0.7 (c 0.93, CHCl3); 1H (400 MHz,
CDCl3) δ (ppm) 5.13 (1H, dt, J 1 ) 1.1 Hz, J 2 ) 7.0 Hz), 3.99-
3.89 (4H, m), 3.65 (1H, dd, J 1 ) 6.9 Hz, J 2 ) 11.4 Hz), 3.51
(1H, dd, J 1 ) 8.3 Hz, J 2 ) 11.4 Hz), 2.12-2.02 (2H, m), 2.03
(2H, t, J ) 7.3 Hz), 1.69-1.63 (2H, m), 1.60 (3H, s), 1.56-1.44
(2H, m), 1.32 (3H, s), 1.29 (1H, broad), 1.08 (3H, s), 1.06 (3H,
s), 0.59-0.52 (1H, m), 0.34-0.28 (1H, m); 13C (100.4 MHz,
1
and volatile liquid: [R]D -25.3 (c 0.63, CHCl3); H (400 MHz,
CDCl3) δ (ppm) 2.44 (2H, t, J ) 7.6 Hz), 2.08 (3H, s), 1.62-
1.49 (2H, m), 1.39-1.34 (1H, m), 1.36 (9H, s), 1.10 (3H, s), 1.07
(3H, s), 1.03 (1H, d, J ) 5.5 Hz); 13C (100.4 MHz, CDCl3) δ
(ppm) 208.29, 171.74, 79.75, 43.22, 33.80, 31.64, 29.93, 28.08,
26.74, 22.51, 21.03, 20.51; LRMS (M + 1) 241; HMRS calcd
(C14H25O3) 241.18037, found 241.17960, σ ) 3.2 ppm.
1-Meth yl-2-[3-(2-m eth yl-[1,3]d ioxola n -2-yl)p r op a n e-1-
su lfon yl]-1H-im id a zole (23). To a suspension of NaH (636
mg of a 60% dispersion in oil, 15.9 mmol) in DMF (20 mL)
was added slowly a solution of 2-mercapto-1-methylimidazole
(2.1 g, 18.3 mmol) in DMF (20 mL) at 0 °C. After the evolution
of gas had ceased, the commercially available 5-chloro-2-
pentanone ethylene ketal (2.0 g, 12.2 mmol) was added
dropwise. The solution was stirred at room temperature for
12 h and quenched with H2O (30 mL). The product was then
extracted with ether, and the organic phase was then succes-
sively washed with H2O, saturated NaHCO3, and brine. The
organic phase was dried with MgSO4 and evaporated, and the
residue was purified by flash chromatography (2:1 EtOAc/
hexanes) to give a yellowish oil (1.2 g, 41%): 1H (400 MHz,
CDCl3) δ (ppm) 6.98 (1H, d, J ) 1.3 Hz), 6.85 (1H, d, J ) 1.3
Hz), 3.87-3.81 (4H, m), 3.55 (3H, s), 3.06-3.00 (2H, m), 1.71-
1.68 (4H, m), 1.23 (3H, s); 13C (100.4 MHz, CDCl3) δ (ppm)
141.61, 129.07, 121.93, 109.55, 64.50, 37.70, 34.37, 33.06,
24.22, 23.75; LRMS 243 (M + 1), 154, 129 (M - imidazole);
HRMS calcd (C11H19N2O2S) 243.11673, found 243.11630, σ )
1.8 ppm.
To a suspension of this product (1.15 g, 4.8 mmol) and
NaHCO3 (2.4 g, 28.8 mmol) in CH2Cl2 (50 mL) was added
MCPBA (2.5 g, 14.4 mmol). The solution was stirred at room
temperature for 3 h and then poured into a 1:1 mixture of
saturated NaHCO3 and 10% aqueous Na2S2O3. The product
was extracted with CH2Cl2, and the organic phase was washed
with brine, dried (MgSO4), and evaporated. The crude product
was purified by flash chromatography (2:1 EtOAc/hexanes) to
give the title compound as a white solid (1.12 g, 85% yield):
1
mp 44-45 °C (Et2O, pentane); H (400 MHz, CDCl3) δ (ppm)
7.09 (1H, d, J ) 0.9 Hz), 6.98 (1H, d, J ) 0.7 Hz), 3.94 (3H, s),
3.93-3.85 (4H, m), 3.48-3.44 (2H, m), 1.91-1.87 (2H, m), 1.73
(2H, t, J ) 7.5 Hz), 1.25 (3H, s); 13C (100.4 MHz, CDCl3) δ
(ppm) 141.68, 128.97, 125.47, 109.19, 64.56, 55.89, 36.86, 34.40,
23.75, 16.86; LRMS 275 (M + 1), 231, 136, 87; HRMS calcd
(C11H19N2O4S) 275.10657, found 275.10700, σ ) -1.6 ppm.

4900 J . Org. Chem., Vol. 64, No. 13, 1999
Hanessian et al.
CDCl3) δ (ppm) 135.15, 124.05, 109.77, 64.50, 63.79, 39.91,
38.94, 32.83, 29.11, 27.08, 23.66, 22.49, 21.71, 21.61, 19.75,
15.68; LRMS 283 (M + 1), 265 (M - OH), 115; HRMS calcd
(C17H29O3) 281.21167, found 281.21090, σ ) -2.7 ppm.
8(R)-(3(R)-Hyd r oxym et h yl-2,2-d im et h ylcyclop r op yl)-
6-m eth yloct-5(E)-en -2-on e (27). To a solution of ketal 26 (28
mg, 0.099 mmol) in MeOH (3 mL) was added Amberlite (IR-
120, H+). The solution was stirred at room temperature for 4
h, and the resin was filtered off. The solvent was evaporated,
and the residue was purified by flash chromatography (5:1
petroleum ether/EtOAc) to give the title compound as a
atmosphere. After 15 min, the solution was loaded directly on
a silica gel column, and purification by flash chromatography
(100% CH2Cl2) gave the title compound (12.6 mg, 75%) as a
pale yellow oil: [R]D -14.8 (c 0.62, CHCl3); 1H (600 MHz,
CDCl3) 9.30 (1H, d, J ) 5.7 Hz), 5.08-5.02 (1H, m), 2.47 (2H,
t, J ) 7.3 Hz), 2.27 (2H, q, J ) 7.2 Hz), 2.15 (3H, s), 2.05-
2.02 (2H, m), 1.62 (3H, s), 1.61-1.55 (2H, m), 1.47-1.45 (1H,
m), 1.39 (1H, t, J ) 5.2 Hz), 1.30 (3H, s), 1.19 (3H, s); 13C (100.4
MHz, CDCl3) δ (ppm) 208.57, 201.56, 135.25, 123.32, 43.47,
43.28, 39.08, 35.35, 30.80, 29.79, 26.49, 22.22, 22.09, 21.23,
15.73; LRMS 345 (M + thioglycerol), 237 (M + 1); HRMS calcd
(C15H25O2) 237.18546, found 237.18470, σ ) + 3.2 ppm. Also
obtained: COSY, NOESY, HMQC.
1
colorless oil (19 mg, 79%): [R]D +0.2 (c 0.61, CHCl3); H (400
MHz, CDCl3) δ (ppm) 5.10-5.06 (1H, m), 3.65 (1H, dd, J 1
)
6.9 Hz, J 2 ) 11.4 Hz), 3.53 (1H, dd, J 1 ) 8.2 Hz, J 2 ) 11.4
Hz), 2.46 (2H, t, J ) 7.5 Hz), 2.31-2.23 (2H, m), 2.13 (3H, s),
2.02 (2H, t, J ) 8.4 Hz), 1.60 (3H, s), 1.53-1.47 (1H, m), 1.37-
1.27 (1H, m), 1.25-1.23 (1H, broad), 1.08 (3H, s), 1.06 (3H, s),
0.58-0.52 (1H, m), 0.32-0.27 (1H, m); 13C (100.4 MHz, CDCl3)
δ (ppm) 208.72, 136.34, 122.65, 63.78, 43.57, 39.89, 32.83,
29.78, 29.08, 27.03, 22.27, 21.71, 21.61, 19.78, 15.75; LRMS
239 (M + 1), 221 (M - OH); HRMS calcd (C15H27O2) 239.2011,
found 239.20000, σ ) +4.6 ppm.
(-)-An th op la lon e (1). To a solution of alcohol 27 (17 mg,
0.071 mmol) and 4 Å molecular sieves (16 mg) in CH2Cl2 was
added N-methylmorpholine oxide (16 mg, 0.137 mmol), fol-
lowed by a catalytic amount of TPAP under a nitrogen
Ack n ow led gm en t. We thank NSERC for financial
assistance through the Medicinal Chemistry Chair
Program. L.-D.C. thanks Servier Laboratories for a
fellowship.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 1, 4 (also 31P NMR), 8, 10, 12-18, and 22-27. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O990302N