Enantioselective double Michael addition/cyclization with an oxygen- centered nucleophile as the first step in a concise synthesis of natural (+)- asteriscanolide

Article abstract of DOI:10.1021/ja994053w

The total synthesis of (+)-asteriscanolide (1) starting from 2-bromo- 4,4-dimethylcyclopentenone has been accomplished. The synthetic route features two key steps. The first step is an unprecedented Michael-Michael reaction sequence that involves a hetero

Full text of DOI:10.1021/ja994053w

2742
J. Am. Chem. Soc. 2000, 122, 2742-2748
Enantioselective Double Michael Addition/Cyclization with an
Oxygen-Centered Nucleophile as the First Step in a Concise Synthesis
of Natural (+)-Asteriscanolide
Leo A. Paquette,* Jinsung Tae, Mark P. Arrington, and Aladin H. Sadoun
Contribution from the EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
ReceiVed NoVember 18, 1999
Abstract: The total synthesis of (+)-asteriscanolide (1) starting from 2-bromo-4,4-dimethylcyclopentenone
has been accomplished. The synthetic route features two key steps. The first step is an unprecedented Michael-
Michael reaction sequence that involves a heteronucleophile and proceeds with complete asymmetric induction.
The two five-membered rings of the target molecule are thereby generated enantioselectively in a single
laboratory step. The second step is based on utilization of ring-closing metathesis to provide an eight-membered
ring in which a conjugated 1,3-diene unit resides. Other features of the synthetic stratagem involve the utilization
of singlet oxygen in a regiocontrolled ene reaction, the fully stereocontrolled hydrogenation of a dienone, and
a chemoselective ruthenium tetraoxide oxidation.
(+)-Asteriscanolide (1) has captured the attention of the
such as ethers,13 amides,14 urethanes,15 sulfonamides,16 and
esters17 greatly facilitate the assembly of cyclooctyl derivatives.
This phenomenon has been interpreted by Fu¨rstner and co-
workers to be a function of the relay properties of these
heteroatoms “which help to assemble the reacting sites within
the coordination sphere of the metal and thus confer bias to
cyclization over competing intermolecular metathesis events”.18
In the absence of these internal ligands, the formation of eight-
membered rings via metathesis has been documented much less
frequently.19
organic chemical community since San Feliciano et al. first
reported its isolation from Asteriscus aquaticus L and structure
determination in 1985.1 The attraction offered by 1 is chiefly
structural. Its sesquiterpenoid framework consists of a rather
Nonetheless, we looked forward to the successful involvement
of RCM as a key element of our synthetic protocol because of
the pronounced restriction in the degrees of conformational
freedom available to the projected triene precursor (Scheme 1).
Beyond this, the issue of involving a conjugated diene in an
RCM reaction was unprecedented when this work was originated
and held specific interest.20 We hoped that in this way we could
also evaluate the possibility of deriving the three stereogenic
centers resident therein in their proper absolute configuration
uncommon bicyclo[6.3.0]undecane ring system bridged by a
butyrolactone fragment. The challenge offered by the construc-
tion of its cyclooctanoid core2 has been approached from several
directions. The only prior enantioselective synthesis of 1 has
been described by the Wender group, their stratagem featuring
the deployment of a Ni(0)-promoted [4 + 4] cycloaddition in
the pivotal step.3 The route utilized by Booker-Milburn and co-
workers to produce the 7-desmethyl derivative involved the
sequential application of intramolecular [2 + 2] photocycload-
dition, Curtius rearrangement, and oxidative fragmentation steps
on arrival at the cyclooctane lactone stage.4 Several other
innovative strategies have been less rewarding.5-10
Despite the entropic and enthalpic factors that impede the
preparation of eight-membered rings,11 the issue of the feasible
application of ring-closing metathesis (RCM)12 in the construc-
tion of asteriscanolide attracted our attention. In recent years,
it has become increasingly apparent that polar functional groups
(6) (a) Booker-Milburn, K. I.; Cowell, J. K.; Harris, L. J. Tetrahedron
Lett. 1994, 35, 3883. (b) Booker-Milburn, K. I.; Cowell, J. K. Tetrahedron
Lett. 1996, 37, 2177.
(7) Lange, G. L.; Organ, M. G. J. Org. Chem. 1996, 61, 5358.
(8) Sarkar, T. K.; Gangopadhyay, P.; Ghorai, B. K.; Nandy, S. K.; Fang,
J.-M. Tetrahedron Lett. 1998, 39, 8365.
(9) Cheung, Y. Y.; Krafft, M. E.; Juliano-Capucao, C. A. Book of
Abstracts, 216th ACS National Meeting, Boston, August 23-27, 1998;
American Chemical Soceity: Washington, DC, 1998; ORGN-238.
(10) Liu, S.; Crowe, W. E. Book of Abstracts, 216th ACS National
Meeting, Boston, August 23-27, 1998; American Chemical Soceity:
Washington, DC, ORGN-235.
(11) Table 2 in the 1998 review by S. K. Armstrong [J. Chem. Soc.,
Perkin Trans. 1 1998, 371] dramatically points to the dearth of eight-
membered ring examples as of that date.
(12) For recent reviews, consult: (a) Grubbs, R. H.; Miller, S. J.; Fu, G.
C. Acc. Chem. Res. 1995, 28, 446. (b) Schmalz, H.-G. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1833. (c) Fu¨rstner, A. Topics Catal. 1997, 4, 285. (d)
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2037.
(e) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792. (f) Philips, A. J.;
Abell, A. D. Aldrichim. Acta 1999, 32, 75. (g) Pariya, C.; Jayaprakash, K.
N.; Sarkar, A. Coord. Chem. ReV. 1998, 168, 1. (h) Randall, M. L.; Snapper,
M. L. J. Mol. Catal. A: Chem. 1998, 133, 29. (i) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (j) Ivin, K. J. J. Mol. Catal. A: Chem. 1998,
133, 1. (k) Wright, D. L. Curr. Org. Chem. 1999, 3, 211.
(1) San Feliciano, A.; Barrero, A. F.; Medarde, M.; Miguel del Corral,
J. M.; Aramburu, A.; Perales, A.; Fayos, J. Tetrahedron Lett. 1985, 26,
2369.
(2) (a) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757. (b)
Rousseau, G. Tetrahedron 1995, 51, 2777. (c) Mehta, G.; Singh, V. Chem.
ReV. 1999, 99, 81.
(3) Wender, P. A.; Ihle, N. C.; Correia, C. R. D. J. Am. Chem. Soc.
1988, 110, 5904.
(4) Booker-Milburn, K. I.; Cowell, J. K.; Harris, L. J. Tetrahedron 1997,
53, 12319.
(5) Mehta, G.; Murty, A. N. J. Org. Chem. 1990, 55, 3568.
10.1021/ja994053w CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/11/2000

Concise Synthesis of Natural (+)-Asteriscanolide
J. Am. Chem. Soc., Vol. 122, No. 12, 2000 2743
Scheme 1
Scheme 2
by chirality transfer from the enantiodefined sulfoxide substitu-
ent in cyclopentenone 3. The success of this tactic was
dependent on the operation of a highly enantioselective Michael
addition to 3 by an oxygen-centered heteronucleophile. Although
the Posner vinyl sulfoxide system has been scrutinized in detail
for its ability to capture carbanions and organometallic reagents
enantioselectively,21 the literature describes no comparable
evaluation of the magnitude and direction of possible stereoin-
(13) (a) Ko¨nig, B.; Horn, C. Synlett 1996, 1013. (b) Clark, J. S.; Kettle,
J. G. Tetrahedron Lett. 1997, 38, 127. (c) Chang, S.; Grubbs, R. H.
Tetrahedron Lett. 1997, 38, 4757. (d) Delgado, M.; Martin, J. D.
Tetrahedron Lett. 1997, 38, 6299. (e) Linderman, R. J.; Siedliecki, J.;
O’Neill, S. A.; Sun, H. J. Am. Chem. Soc. 1997, 119, 6919. (f) Crimmins,
M. T.; Choy, A. L. J. Org. Chem. 1997, 62, 7548. (g) Joe, D.; Overman,
L. E. Tetrahedron Lett. 1997, 38, 8635. (h) Rutjes, F. P. J. T.; Kooistra, T.
M.; Hiemstra, H.; Schoemaker, H. E. Synlett 1998, 192. (i) Stefinovic, M.;
Snieckus, V. J. Org. Chem. 1998, 63, 2808. (j) Oishi, T.; Nagumo, Y.;
Hirama, M. Chem. Commun. 1998, 1041. (k) Clark, J. S.; Hamelin, O.;
Hufton, R. Tetrahedron Lett. 1998, 39, 8321. (l) Edwards, S. D.; Lewis,
T.; Taylor, R. J. K. Tetrahedron Lett. 1999, 40, 4267. (m) Delgado, M.;
Martin, J. D. J. Org. Chem. 1999, 64, 4798. (n) Crimmins, M. T.; Choy,
A. L. J. Am. Chem. Soc. 1999, 121, 5653. (o) Clark, J. S.; Kettle, J. G.
Tetrahedron 1999, 55, 8248. (p) Crimmins, M. T.; Emmitte, K. A. Org.
Lett. 1999, 1, 2029.
(14) (a) Pandit, U. K.; Borer, B. C.; Biera¨ugel, H. Pure Appl. Chem.
1996, 68, 659. (b) Barrett, A. G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles,
M. R.; Marshall, E. L.; Procopiou, P. A. Chem. Commun. 1996, 2231. (c)
Winkler, J. D.; Stelmach, J. E.; Axten, J. Tetrahedron Lett. 1996, 37, 4317.
(d) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996,
118, 9606. (e) Barrett, A. G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles, M.
R.; Marshall, E. L.; Procopiou, P. A. Chem. Commun. 1997, 155. (f)
Veerman, J. J. N.; van Maarseveen, J. H.; Visser, G. M.; Kruse, C. G.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Eur. J. Org. Chem.
1998, 2583. (g) Grigg, R.; Sridharan, V.; York, M. Tetrahedron Lett. 1998,
39, 4139. (h) Barrett, A. G. M.; Baugh, S. P. D.; Braddock, D. C.; Flack,
K.; Gibson, V. C.; Giles, M. R.; Marshall, E. L.; Procopiou, P. A.; White,
A. J. P.; Williams, D. J. J. Org. Chem. 1998, 63, 7893. (i) Martin, S. F.;
Humphrey, J. M.; Ali, A.; Hillier, M. C. J. Am. Chem. Soc. 1999, 121,
866. (j) Diedrichs, N.; Westermann, B. Synlett 1999, 1127. (k) Grossmith,
C. E.; Senia, F.; Wagner, J. Synlett 1999, 1660. (l) Tarling, C. A.; Holmes,
A. B.; Markwell, R. E.; Pearson, N. D. J. Chem. Soc., Perkin Trans. 1
1999, 1695.
(15) (a) References 14a and 14c. (b) Martin, S. F.; Chen, H.-J.; Courtney,
A. K.; Liao, Y.; Pa¨tzel, M.; Ramser, M. N.; Wagman, A. S. Tetrahedron
1996, 52, 7251. (c) White, J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am.
Chem. Soc. 1998, 120, 7359.
(16) (a) Visser, M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.; Hoveyda,
A. H. J. Am. Chem. Soc. 1996, 118, 4291. (b) Fu¨rstner, A.; Picquet, M.;
Bruneau, C.; Dixneuf, P. H. Chem. Commun. 1998, 1315. (c) Fu¨rstner, A.;
Hill, A. F.; Liebl, M.; Wilton-Ely, J. D. E. T. Chem Commun. 1999, 601.
(d) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda, A.
H. J. Am. Chem. Soc. 1999, 121, 791. (e) Ackermann, L.; Fu¨rstner, A.;
Weskamp, T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron Lett. 1999, 40,
4787. (f) Paquette, L. A.; Leit, S. M. J. Am. Chem. Soc. 1999, 121, 8126.
(17) Evans, P.; Grigg, R.; Ramzan, M. I.; Sridharan, V.; York, M.
Tetrahedron Lett. 1999, 40, 3021.
duction attainable during the conjugate addition of alcohols to
such acceptors.22 This facet of the problem added significantly
to the general interest in the total synthesis goal that otherwise
held promise to deliver 1 in concise fashion. In this paper, we
document the successful realization of a short route that gives
rise to the natural dextrorotatory enantiomer of asteriscanolide.
Results and Discussion
Our synthesis was initiated as projected with ketalization of
the known 2-bromo-4,4-dimethylcyclopentenone.23 Although all
attempts to accomplish the preparation of 2 by stirring in
ethylene glycol and a catalytic quantity of p-toluenesulfonic acid
in dichloromethane at room temperature as recommended by
Ladlow and Pattenden24 were uniformly unsuccessful, recourse
to more forcing conditions25 provided 2 in 77% yield. Arrival
at 3 was modeled after the earlier work of Posner et al. involving
the parent cyclopentenone26 and involved halogen-metal
exchange with subsequent condensation of the vinyllithium
reagent with (S)-(-)-menthyl p-toluenesulfinate27,28 (Scheme 2).
(18) (a) Fu¨rstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130.
(b) Fu¨rstner, A.; Gastner, T.; Weintritt, H. J. Org. Chem. 1999, 64, 2361.
(c) Fu¨rstner, A.; Siedel, G.; Kindler, N. Tetrahedron 1999, 55, 8215.
(19) (a) Miller, S. J.; Kim, S.-H.; Chen Z.-R.; Grubbs, R. H. J. Am. Chem.
Soc. 1995, 117, 2108. (b) Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996,
61, 8746. (c) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310.
(d) Stragies, R.; Blechert, S. Synlett 1998, 169. (e) Holt, D. J.; Barker, W.
D.; Jenkins, P. R.; Davies, D. L.; Garrat, S.; Fawcett, J.; Russell, D. R.;
Ghosh, S. Angew. Chem., Int. Ed. 1998, 37, 3298. (f) Paquette, L. A.;
Mendez-Andino, J. Tetrahedron Lett. 1999, 40, 4301.
(20) More recently, the right-hand sector of sanglifehrin, which contains
a 22-membered ring, was elaborated by RCM of a precursor that featured
a diene moiety: Cabrejas, L. M. M.; Rohrbach, S.; Wagner, D.; Kallen, J.;
Zenke, G.; Wagner, J. Angew. Chem., Int. Ed. 1999, 38, 2443.
(21) Posner, G. H. In Asymmetric Synthesis, Volume 2; Morrison, J. D.,
Ed.; Academic Press: New York, 1983; Chapter 8.
(22) In addition, a single report on the involvement of amines as
heteronucleophiles in these processes has appeared: Matsuyama, H.; Itoh,
N.; Yoshida, M.; Kamigata, N.; Sasaki, S.; Iyoda, M. Chem Lett. 1997,
375. In this study, 2-(p-tolylsulfinyl)cinnamates served as the Michael
acceptors.
(23) Wakui, T.; Otsuji, Y.; Imoto, E. Bull. Chem. Soc. Jpn. 1974, 47,
2267.
(24) Ladlow, M.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1988,
1107.
(25) Smith, A. B., III; Branca, S. J.; Guaciaro, M. A.; Wovkulich, P.
M.; Korn, A. Organic Syntheses; Wiley: New York, 1990; Collect Vol.
VII, p 271.

2744 J. Am. Chem. Soc., Vol. 122, No. 12, 2000
Paquette et al.
pentenone.26,32 These events can be concisely rationalized in
terms of a chelate model such as B, although other rotamers
may play an equally influential role in the stereodirective
outcome. The significant issues here are twofold: (a) the
Michael addition of a heteroatom-centered nucleophile is
seemingly subject to forces not dissimilar to those involving
carbon, and (b) the initial product of 1,4-conjugate addition is
capable of intramolecular addition to the triple bond. The overall
consequence is the one-step fully controlled conversion of 3 to
4, the tandem process offsetting to a reasonable degree the
modest yield realized for this pivotal transformation.
Now that the chiral sulfoxide auxiliary had served its intended
purpose, we sought to address the issue of the reductive
desulfurization of 4. Our expectation that hydrogenation of 4
in the presence of Raney nickel would result in carbon-sulfur
bond cleavage concomitant with saturation of the olefinic
linkage was readily reduced to practice. Evidence that the newly
generated stereogenic centers in 5 were properly installed was
gained simply by encouraging overreduction to occur. An
increase in hydrogen pressure to 1000 psi was sufficient to
reduce the ketone carbonyl as well. This step was followed by
in situ intramolecular cyclization to give lactone 9 (65% yield),
an event that could not materialize had a different diastereomer
been initially produced.
Figure 1. Computer-generated perspective model of the final X-ray
model of 4.
Considerable experimentation was devoted to investigating
the way in which the Michael reaction of methyl 4-hydroxy-
2-butynoate29 with 3 could be exploited such that a second-
stage conjugate addition would follow and give rise directly to
the bicyclic ester 4.30 Initially, attention was directed to the use
of DBN and DBU over a wide range of temperatures, with and
without the co-addition of potential Lewis acid promoters such
as La(OTf)3, Ti(Oi-Pr)4, CeCl3, and LiBF4. Several general
conclusions emerged. Temperatures above -40 °C resulted in
the onset of rapid and uncontrolled reactions, as shown also in
the presence of larger amounts of base. In general, Lewis acid
catalysts did not help matters to any measurable extent, with
one exception. In an experiment involving the use of 3 equiv
of lithium tetrafluoroborate in acetonitrile containing 0.03 equiv
of DBU (-40 °C, 7 h), monoadduct A was formed efficiently
as a mixture of diastereomers. Proper conditions for bringing
about the further cyclization of A were not uncovered.
In the event, the desired conversion to 4 was found to occur
when the reaction was promoted with potassium carbonate in
THF at room temperature.31 The major product, isolated in 38%
yield, was shown to be the required 4 on the basis of an X-ray
crystallographic analysis (Figure 1). Our prior knowledge of
the S configuration at sulfur in 3 makes possible the assignment
of absolute configuration to 4 as shown in the illustrated formula.
With the configurational assignments secure, it is evident that
the butynoate adds to 3 from the a-surface with asymmetric
induction, paralleling closely the outcome of organometallic
conjugate additions to (S)-(+)-2-(p-toluenesulfinyl)-2-cyclo-
Before embarking on the metathesis phase of the synthesis,
it seemed appropriate to investigate the regioselectivity of
nucleophilic additions to 5. Quite unexpectedly, exposure of 5
to the organometallic reagents exemplified by C-F gave no
evidence of adduct formation. The keto ester was invariably
recovered unscathed. When the inspection of molecular models
gave no suggestion of overwhelming steric hindrance to attack
at the ketone carbonyl, suspicion arose that 5 was especially
prone to enolization. Considerable credence was lent to this
hypothesis when it was discovered that recourse to an excess
of the “slimmer” lithium trimethylsilylacetylide reagent gave
6a, the result of twofold addition to the ester carbonyl. This
ester functionality, which is sterically shielded, was nevertheless
attacked to the exclusion of the ketone when the size of the
nucleophile was reduced to a suitable level.
(26) Earl, R. A.; Townsend, L. B. Organic Syntheses; Wiley: New York,
1990; Collect. Vol. VII, p 334.
(27) Posner, G. H.; Mallamo, J. P.; Hulce, M.; Frye, L. L. J. Am. Chem.
Soc. 1982, 104, 4180.
(28) Hulce, M.; Mallamo, J. P.; Frye, L. L.; Kogan, T. P.; Posner, G. H.
Organic Syntheses; Wiley: New York, 1990; Collect. Vol. VII, p 495.
(29) Solladie´, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173.
(30) Nitro olefins and particularly 1-nitrocyclohexene have been shown
to be particularly conducive to this type of double Michael addition/
cyclization: Yakura, T.; Yamada, S.; Shima, M.; Iwamoto, M.; Ikeda, M.
Chem. Pharm. Bull. 1998, 46, 744.
(31) The use of potassium carbonate in refluxing THF has been shown
to be effective in bringing about the condensation of acyloins with dimethyl
acetylenedicarboxylate to give 4-hydroxy-4,5-dihydrofurans: Jauch, J.;
Schurig, V. Tetrahedron Lett. 1991, 32, 4687.
(32) Posner, G. G.; Mellamo, J. P.; Miura, K. J. Am. Chem. Soc. 1981,
103, 2886.

Concise Synthesis of Natural (+)-Asteriscanolide
J. Am. Chem. Soc., Vol. 122, No. 12, 2000 2745
Scheme 3
These workers demonstrated the ene reaction of G to be strongly
dependent on solvent. In aqueous methanol, the conversion to
dioxetane I is very much favored (I:H ) 5.5). A change in
solvent to dichloromethane (I:H ) 0.1) or to acetonitrile (I:H
) 0.01) alters the ratio toward hydroperoxide H by a factor
larger than 500. On this basis, we elected to explore the
photooxygenation of 13 in CH2Cl2 solution containing 5,10,-
15,20-tetraphenyl-21H,23H-porphine (TPP) as sensitizer. In this
way, we were able to reach a hydroperoxide, direct hydride
reduction of which gave rise to sensitive diallylic carbinol 14
in 61% overall yield. Detailed spectroscopic analysis established
that the major product of this reaction occurred with conversion
of the original methyl substituent into an exocyclic methylene
group. The hydroxyl functionality in 14 was assigned the b
configuration in order to conform to the substantial spatial
demands of the singlet oxygen ene transition state36 and assumed
preferred approach of the reagent to the less congested convex
surface of the diene segment. Since oxidation to the ketone level
is next to be implemented, only minor importance is associated
with this deduction.
As the projected route continued, we made recourse to the
Dess-Martin periodinane38 for generation of the dienone in
preparation for exhaustive hydrogenation. Here it is critical that
saturation of the pair of double bonds proceed from the exterior
surface of the semispherical compound, for proper introduction
of the final two stereogenic centers is dependent on this
differentiation. The decision to proceed in this direction was
rewarded by the isolation of a single tetrahdyro ketone. That
this penultimate intermediate was, indeed, 15 was confirmed
by its regioselective oxidation to crystalline (+)-1 with ruthe-
nium tetraoxide.39 The spectral data of the fully synthetic keto
lactone were identical to those reported by San Feliciano et al.
This property of 5 played nicely into our hands. Thus, the
generation of enol triflate 7 was straightforwardly accomplished
in near-quantitative yield.33 The use of 7 as the coupling partner
for tributylvinylstannane in a Stille coupling34 proceeded
smoothly to deliver diene 8 very efficiently. This important
compound was reduced to the primary carbinol 10 and
subsequently transformed into iodide 11 by deployment of
conventional methods (Scheme 3). Copper-catalyzed substitu-
tion35 of iodide by methallylmagnesium chloride proceeded with
the anticipated level of regioselectivity and without any visible
degradation to provide 12 (98%).
As previously indicated, the time had now come to involve
12 in a ring-closing metathesis reaction. Our reservations with
regard to the efficiency of this cyclization were quickly
dismissed when the generation of 13 was seen to proceed in
93% yield. Evidently, the limited conformational flexing avail-
able to the side chains in 12 serves to facilitate their conjoining
via a ruthenium carbenoid.
With this critical step accomplished, the next consideration
was to achieve suitable oxygenation of the double bond internal
and not external to the eight-membered ring. When preliminary
studies involving epoxidation and hydroboration options were
found not to conform to our goals, we turned to singlet oxygen
as the potential reagent of choice.36 The decision was made to
take a lead from Hasty and Kearns’s careful investigation of
the photooxygenation of 2,5-dimethyl-2,4-hexadiene (G).37
for authentic 1. In addition, the [R]22 of our material is +8.5
D
(c 0.019, CHCl3), a value closely comparable to the +12.1
originally registered.1
Summary
The chemistry detailed herein defines a concise 13-step
strategy for the synthesis of (+)-asteriscanolide (1). In the
recapitulation of this venture, it is important to emphasize that
the convergent merging of the readily available enantiopure
cyclopentenone sulfoxide 3 and methyl 4-hydroxy-2-butynoate
proved to be especially profitable in that it resulted in a series
of highly enantioselective bonding events. The capture by a
cyclic Michael acceptor such as 3 of a heteronucleophile has
not been previously described. In the present setting, the first-
stage Michael addition proceeds with a strong kinetic bias for
R-attack as a direct consequence of precoordination. The
stereochemical course of the second conjugate addition is
inextricably linked to that manifested during prior C-O bond
formation, thereby ultimately providing a substrate properly
configured and functionalized for eventual arrival at the target.
Use of the Stille coupling protocol constituted a productive step
in paving the way for critical adaptation of ring-closing
metathesis. A key finding was that a conjugated diene typified
by 13 can be produced in this manner with exceptional
efficiency.
(35) Review: Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
(36) (a) Denny, R. W.; Nickon, A. Org. React. 1973, 20, 133. (b)
Wasserman, H. H.; Murray, R. W. Singlet Oxygen; Academic Press: New
York, 1979.
(37) Hasty, N. M.; Kearns, D. R. J. Am. Chem. Soc. 1973, 95, 3380.
(38) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c) Ireland,
R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(39) Johnson, B. D.; Slessor, K. N.; Oehlschlager, A. C. J. Org. Chem.
1985, 50, 114.
(33) Review: Ritter, K. Synthesis 1993, 735.
(34) Review: Farina, V.; Krishnamurthy, V.; Scott, W. T. Org. React.
1997, 50, 1.

2746 J. Am. Chem. Soc., Vol. 122, No. 12, 2000
Paquette et al.
A solution of acetal (3.87 g, 13.2 mmol) and camphorsulfonic acid
(0.37 g, 1.3 mmol) in acetone (50 mL) and water (10 mL) was stirred
at room temperature for 15 h, treated with K2CO3 (0.37 g, 2.7 mmol),
and stirred 30 min longer. The mixture was concentrated under reduced
pressure, the brown oily biphasic residue was taken up in ether (40
mL), and the ethereal solution was washed with water, saturated
NaHCO3 solution, and brine prior to drying and solvent evaporation.
Flash chromatography of the residue on silica gel (elution with 60%
ethyl acetate in hexanes) furnished 3 as white crystals: mp 93.5-94
°C (from 10:1 ethyl acetate/ether); IR (CHCl3, cm-1) 1706, 1592, 1295,
The tricyclic conjugated diene 13 served in turn as a reliable
platform for directing the regioselectivity of the singlet oxygen
ene process and the stereoselectivity of the subsequent catalytic
hydrogenation. The remarkable success of this sequence of
reactions was matched in the final RuO4 oxidation that
established the butyrolactone ring.
A particularly rewarding aspect of this undertaking was the
ability to start with 3 and to install all of the requisite
stereochemistry inherent to asteriscanolide without recourse to
resolution. In this study, the feasibility of generating dienes by
RCM has been demonstrated, and an original means was
developed for assembly of the unusual framework of the target
structure. We anticipate that the present route will prove
adaptable to diversely functionalized intermediates and lend
itself to the rational synthesis of other structurally complex
medium-ring natural products.
1
1042; H NMR (300 MHz, CDCl3) δ 7.89 (s, 1 H), 7.64 (d, J ) 8.1
Hz, 2 H), 7.28 (d, J ) 8.1 Hz, 2 H), 2.46 (d, J ) 18.8 Hz, 1 H), 2.39
(s, 3 H), 2.33 (d, J ) 18.8 Hz, 1 H), 1.32 (s, 3 H), 1.22 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 201.5, 171.3, 148.7, 142.2, 139.2, 130.0 (2
C), 125.1 (2 C), 51.9, 40.5, 27.9, 27.6, 21.5; HRMS (EI) m/z (M+)
calcd 248.0871, obsd 248.0876; [R]22 +212 (c 0.025, CHCl3).
D
Anal. Calcd for C14H16O2S: C, 67.71; H, 6.49. Found: C, 67.53;
H, 6.40.
Methyl (3aS,6aR)-4,5,6,6a-Tetrahydro-6,6-dimethyl-4-oxo-3a-
[(S)-p-tolylsulfinyl]-2H-cyclopenta[b]furan-D3(3aH),r-acetate (4). A
THF solution (50 mL) of 3 (5.00 g, 20.1 mmol) and methyl 4-hydroxy-
2-butynoate (5.00 g, 43.8 mmol) was treated with K2CO3 (5.50 g, 39.8
mmol) at room temperature for 5 h, filtered, and concentrated. The
residue was purified by flash chromatography on silica gel (elution
with 10% ethyl acetate in hexanes) to furnish 4 (2.77 g, 38%) as a
colorless solid: mp 109-110 °C (from 3:2:2 methanol/THF/ethanol);
IR (film, cm-1) 1747, 1714, 1651; 1H NMR (300 MHz, CDCl3) δ 7.49
(d, J ) 8.1 Hz, 2 H), 7.31 (d, J ) 8.1 Hz, 2 H), 6.34 (m, 1 H), 4.77
(dd, J ) 17.7, 2.4 Hz, 1 H), 4.70 (s, 1 H), 3.76 (s, 3 H), 3.65 (dd, J )
17.7, 2.8 Hz, 1 H), 2.40 (d, J ) 16.9 Hz, 1 H), 2.41 (s, 3H), 2.26 (d,
J ) 16.9 Hz, 1 H), 1.24 (s, 3 H), 0.95 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 205.4, 165.6, 152.6, 143.4, 135.7, 129.9 (2 C), 125.5 (2 C),
115.0, 85.7 83.8, 74.1, 53.2, 51.8, 38.6, 26.5, 23.1, 21.5; HRMS (EI)
Experimental Section
General Information. Tetrahyrofuran and ether were distilled from
sodium benzophenone ketyl under nitrogen just prior to use. For
dichloromethane and dimethyl sulfoxide, the drying agent was calcium
hydride. All reactions were performed under a nitrogen atmosphere.
Analytical thin-layer chromatography was carried out on E. Merck silica
gel 60 F245 aluminum-backed plates. The 230-400 mesh size of the
same absorbent was utilized for all chromatographic purifications. The
organic extracts were dried over anhydrous MgSO4. 1H and 13C NMR
spectra were recorded on Bruker instruments at 300 and 75 MHz,
respectively. Infrared spectra were recorded with a Perkin-Elmer 1320
spectrometer. The high-resolution mass spectra were recorded at The
Ohio State University Campus Chemical Instrumentation Center.
4,4-Dimethyl-2-[(S)-p-tolylsulfinyl]-2-cyclopenten-1-one (3). A
solution of 2-bromo-4,4-dimethylcyclopentenone23 (3.00 g, 15.9 mmol),
ethylene glycol (3.64 mL, 65.2 mmol), and camphorsulfonic acid (42
mg, 0.18 mmol) in benzene (50 mL) was heated to reflux under a
Dean-Stark trap and maintained at this temperature overnight with
azeotropic removal of water. The solvent was removed under reduced
pressure, the residue was taken up in ethyl acetate (200 mL), and this
solution was washed with water, saturated NaHCO3 solution, and brine
prior to drying and concentration. Chromatography on silica gel (elution
with 15:1 hexanes/ethyl acetate) followed by Kugelrohr distillation
afforded 2.79 g (75%) of 2 as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 5.99 (s, 1 H) 4.18 (m, 2 H), 3.96 (m, 2 H), 1.99 (s, 2 H),
1.14 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 145.7, 122.0, 117.1, 65.4,
49.7, 41.7, 28.3.13
m/z (M+) calcd 362.1188, obsd 362.1198; [R]22 -14.5 (c 0.020,
D
CHCl3).
Anal. Calcd for C19H22O5S: C, 62.96; H, 6.12. Found: C, 62.97;
H, 6.11.
Methyl (3aS,3aR,6aS)-Hexahydro-6,6-dimethyl-4-oxo-2H-cyclo-
penta[b]furan-3-acetate (5). Into a stainless steel autoclave were placed
4.20 g (11.6 mmol) of 4, 10 mL of THF, 40 mL of methanol, and 42
g of Raney nickel (as a 50% water slurry), which had previously been
washed several times with water and methanol. Stirring was initiated,
and the apparatus was pressurized to 150 psi with hydrogen. After 4 h,
the reaction mixture was filtered through Celite. The pad was washed
with copious amounts of CH2Cl2, and the combined filtrates were
concentrated to leave a residue that was chromatographed on silica gel.
Elution with 9:1 hexanes/ethyl acetate afforded 2.30 g (88%) of 5 as
a colorless oil: IR (neat, cm-1) 1736, 1466, 1172; 1H NMR (300 MHz,
CDCl3) δ 4.09 (d, J ) 3.3 Hz, 1 H), 4.03 (m, 1 H), 3.67 (s, 3 H), 3.42
(m, 1 H), 2.94 (m, 2 H), 2.68 (dd, J ) 17.1, 6.4 Hz, 1 H), 2.26 (dd, J
) 17.1, 7.8 Hz, 1 H), 2.23 (d, J ) 17.5 Hz, 1 H), 2.00 (d, J ) 17.5
Hz, 1 H), 1.20 (s, 3 H), 0.93 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
217.6, 172.6, 90.2, 73.2, 53.8, 51.6 (2 C), 39.0, 38.2, 32.7, 26.9, 22.9;
HRMS (EI) m/z (M+) calcd 226.1205, obsd 226.1213; [R]23D -77.0 (c
0.087, CHCl3).
A 250-mL flask containing a magnetic stirring bar was charged with
anhydrous THF (25 mL) and cooled to -78 °C prior to the introduction
of n-butyllithium (14.1 mL of 1.6 M in hexanes, 23 mmol) and freshly
distilled 2 (4.765 g, 20.44 mmol) dissolved in THF (10.8 mmol) via
cannula under positive N2 pressure. The clear yellow solution was stirred
for 3.5 h and transferred via cannula to a cold (-78 °C) vigorously
stirred mixture of (-)-menthyl (5S)-p-toluenesulfinate (8.65 g, 30.4
mmol) in THF (180 mL). The cooling bath was removed, 50 mL of
saturated KH2PO4 solution was added, and the reaction mixture was
warmed to room temperature. The THF was removed under reduced
pressure, and the product was extracted into CHCl3. The combined
organic layers were dried and concentrated to leave a residue,
purification of which by chromatography on silica gel (elution with
40% ethyl acetate in hexane) returned 2.97 g of the sulfinate and
provided 4.63 g (77%) of the sulfoxide acetal as a white crystalline
Anal. Calcd for C12H18O4: C, 63.70; H, 8.02. Found: C, 63.58; H,
8.08.
(3S,3aR,6aS)-3-(2-Ethynyl-2-hydroxy-3-butynyl)hexahydro-6,6-
dimethyl-4H-cyclopenta[b]furan-4-one (6b). Freshly distilled trim-
ethylsilylacetylene (0.39 mL, 2.7 mmol) was taken up in dry THF (5
mL) under N2, cooled to 0 °C, treated with n-butyllithium (1.40 mL of
2.04 M in hexanes, 2.85 mmol), stirred for 15 min, and cooled to -78
°C. A solution of 5 (200 mg, 2.21 mmol) in dry THF (3 mL) was
slowly introduced, and the reaction mixture was stirred for 3 h at this
temperature before being quenched with saturated NH4Cl solution. The
separated aqueous phase was extracted with ether (2 × 10 mL), and
the combined organic layers were washed with water and brine, dried,
and concentrated. Purification of the residue by chromatography on
silica gel (elution with 25:1 hexanes/ethyl acetate) afforded 112 mg
(43%) of 6a, which was directly desilylated.
solid: mp 116.5-117.5 °C (from CH2Cl2/hexanes); IR (CHCl3, cm-1
)
1317, 1234, 1025; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J ) 8.1 Hz,
2 H), 7.29 (d, J ) 8.1 Hz, 2 H), 6.52 (s, 1 H), 3.87-3.59 (m, 4 H),
2.40 (s, 3 H), 2.07 (d, J ) 13.5 Hz, 1 H), 2.01 (d, J ) 13.5 Hz, 1 H),
1.20 (s, 3 H), 1.18 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 151.3, 145.0,
141.6, 140.4, 129.6 (2 C), 125.8 (2 C), 117.7, 65.3, 65.0, 52.6, 41.4,
28.2 (2 C), 21.4; HRMS (EI) m/z (M+) calcd 292.1133, obsd 292.1125;
[R]22 +98.8 (c 0.026, CHCl3).
D
Anal. Calcd for C16H20O3S: C, 65.72; H, 6.89. Found: C, 65.59;
H, 6.89.

Concise Synthesis of Natural (+)-Asteriscanolide
J. Am. Chem. Soc., Vol. 122, No. 12, 2000 2747
A solution of 6a (143 mg, 0.49 mmol) in DMF (5 mL) was treated
with potassium fluoride (45 mg, 0.74 mmol), stirred for 20 min, and
quenched with saturated NaHCO3 solution. After 10 min, the product
was extracted into ether (4 × 10 mL), and the combined organic phases
were washed with water (4 × 10 mL) and brine prior to drying and
solvent evaporation. Chromatography of the residue on silica gel (elution
with 20:1 hexanes/ethyl acetate) gave 6b (60 mg, 56%) as a colorless
rinsed with CH2Cl2 (2 × 20 mL), the combined filtrates were
concentrated to leave alcohol 10 as a colorless liquid (525 mg, 94%).
A solution of 10 (585 mg, 2.81 mmol) in CH2Cl2 (20 mL) was treated
with triethylamine (0.78 mL, 5.62 mmol) and methanesulfonyl chloride
(0.33 mL, 4.21 mmol) at 0 °C for 1.5 h, diluted with saturated NaHCO3
solution (20 mL), and extracted with CH2Cl2 (3 × 20 mL). The
combined organic phases were dried and evaporated to leave the
mesylate that was dissolved in acetone, added to acetone (50 mL)
containing sodium iodide (4.21 g, 28.1 mmol) and NaHCO3 (500 mg),
stirred for 15 h at 20 °C, diluted with saturated Na2S2O3 solution (100
mL), and extracted with CH2Cl2 (3 × 50 mL). The combined organic
solutions were dried and concentrated to leave a residue, purification
of which by flash chromatography on silica gel (elution with 5% ethyl
acetate in hexanes) gave 702 mg (79% for two steps) of iodide 11 as
a colorless oil that was used directly.
1
oil: IR (neat, cm-1) 3287, 1732; H NMR (300 MHz, CDCl3) δ 4.16
(m, 2 H), 3.37 (t, J ) 9.9 Hz, 1 H), 3.15 (m, 1 H), 3.03 (m, 1 H), 2.55
(s, 2 H), 2.28 (dd, J ) 5.6, 4.1 Hz, 1 H), 2.25 (d, J ) 14.5 Hz, 1 H),
2.10 (d, J ) 14.5 Hz, 1 H), 2.06 (dd, J ) 5.6, 5.2 Hz, 1 H), 1.20 (s,
3 H), 0.93 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 221.3, 90.3, 84.5,
82.8, 73.6, 72.0, 71.1, 62.4, 54.8, 52.2, 40.8, 39.4, 38.9, 26.9, 23.0;
HRMS (EI) m/z (M+) calcd 246.1256, obsd 246.1247.
Methyl (3S,3aS,6aS)-3,3a,6,6a-Tetrahydro-6,6-dimethyl-4-vinyl-
2H-cyclopenta[b]furan-3-acetate (8). To a THF solution (25 mL) of
5 (802 mg, 3.54 mmol) at -78 °C was added potassium hexamethyl-
disilazide (7.09 mL of 0.5 N in toluene, 3.54 mmol), followed by
N-phenyl triflimide (1.40 g, 3.92 mmol) in THF (5 mL) 20 min later.
The reaction mixture was stirred for 3 h at -78 °C, quenched with
saturated NH4Cl solution, and extracted with ether (3 × 50 mL). The
combined organic phases were dried and concentrated to leave a residue
that was purified by flash chromatography on silica gel (elution with
5% ethyl acetate in hexanes). In addition to the recovery of unreacted
5 (83 mg, 10%), 1.12 g (98% based on consumed 5) of 7 was isolated,
which was used directly.
To magnesium turnings (3.25 g, 0.134 mmol) that had been dried
under a flow of N2 for 15 h40 was added dry THF (25 mL), followed
by the introduction of methallyl chloride (2.50 mL, 25.2 mmol) slowly
over 1.5 h at 0 °C. This Grignard solution was added to a THF (10
mL) solution of copper(I) iodide (421 mg, 2.21 mmol) at 0 °C and
stirred for 10 min before being treated with a solution of 11 (702 mg,
2.21 mmol) in THF (5 mL). The reaction mixture was stirred for 4 h
at 0 °C and quenched with saturated NH4Cl solution at this temperature.
The precipitated white solid was filtered off and rinsed with CH2Cl2
(2 × 20 mL). The combined filtrates were concentrated and subjected
to flash chromatography on silica gel (elution with 5% ethyl acetate in
hexanes) to yield 531 mg (98%) of 12 as a colorless oil: IR (neat,
cm-1) 1435, 1355, 1080; 1H NMR (300 MHz, CDCl3) δ 6.42 (dd, J )
17.5, 10.7 Hz, 1 H), 5.48 (s, 1 H), 5.13 (dd, J ) 17.5, 1.3 Hz, 1 H),
5.03 (dd, J ) 10.7, 1.4 Hz, 1 H), 4.65 (d, J ) 10.6 Hz, 2 H), 4.18 (d,
J ) 7.9 Hz, 1 H), 3.70 (d, J ) 4.4 Hz, 2 H), 3.57 (t, J ) 8.1 Hz, 1 H),
2.25-2.15 (m, 1 H), 2.10-1.85 (m, 2 H), 1.68 (s, 3 H), 1.55-0.95
(series of m, 4 H), 1.062 (s, 3 H), 1.057 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 146.0, 142.3, 137.3, 134.2, 114.1, 109.6, 90.6, 73.1, 52.7,
46.6, 41.8, 37.8, 30.0, 28.2, 27.1, 22.4, 21.3; HRMS (EI) m/z (M+)
Enol triflate 7 (994 mg, 2.77 mmol) was dissolved in THF (20 mL),
treated with tributylvinylstannane (1.62 mL, 5.54 mmol), lithium
chloride (706 mg, 16.7 mmol), and Pd2(dba)3‚CHCl3 (64 mg, 0.57
mmol), stirred at 20 °C for 15 h, diluted with saturated NaHCO3 solution
(20 mL), and extracted with ether (3 × 50 mL). The combined organic
phases were dried and concentrated to leave a residue that was subjected
to flash chromatography on silica gel (elution with 5% ethyl acetate in
hexanes). Diene ester 8 was isolated as a colorless liquid (622 mg,
95%): IR (neat, cm-1) 1725, 1425, 1155; 1H NMR (300 MHz, CDCl3)
δ 6.43 (dd, J ) 17.6, 10.7 Hz, 1 H), 5.50 (s, 1 H), 5.13 (d, J ) 17.6
Hz, 1 H), 5.06 (d, J ) 10.7 Hz, 1 H), 4.16 (d, J ) 8.0 Hz, 1 H), 3.74
(d, J ) 3.2 Hz, 2 H), 3.67-3.60 (m, 1 H), 3.64 (s, 3 H), 2.85-2.70
(m, 1 H), 2.35 (dd, J ) 16.6, 3.3 Hz, 1 H), 2.16 (dd, J ) 16.6, 11.4
Hz, 1 H), 1.07 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 174.1, 143.3,
136.9, 134.0, 114.9, 90.8, 74.2, 52.0, 51.6, 46.7, 37.7, 33.7, 30.2, 21.4;
calcd 246.1984, obsd 246.1978; [R]22 -3.0 (c 0.070, CHCl3).
D
(2aS,9aS,9bS)-1,2a,3,7,8,9,9a,9b-Octahydro-3,3,6-trimethyl-2-ox-
acycloocta[cd]pentalene (13). To a refluxing CH2Cl2 (750 mL) solution
of Grubbs’s catalyst (152 mg, 10 mol %) was added 12 (424 mg, 1.72
mmol) dissolved in CH2Cl2 (10 mL). The reaction mixture was refluxed
for 7 h, an additional 10% of catalyst was introduced, and this procedure
was repeated again after 24 h. Following a total reflux period of 48 h,
the solvent was evaporated, and the residue was purified by flash
chromatography on silica gel (elution with 5% ethyl acetate in hexanes).
In addition to 46 mg (11%) of recovered 12, 313 mg (93% based on
HRMS (EI) m/z (M+) calcd 236.1412, obsd 236.1390; [R]22 -7.2 (c
D
0.028, CHCl3).
Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 71.07; H,
8.52.
unreacted 12) of 13 was isolated as a colorless oil: IR (neat, cm-1
)
(2aS,4aS,7aS,7bS)-Hexahydro-3,3-dimethyl-1H-2,5-dioxacyclopent-
[cd] inden-6-(2aH)-one (9). A 50% slurry of Raney nickel in water
(1.01 g) was washed with methanol (3 × 5 mL) and transferred in
methanol (5.8 mL) to 4 (69 mg, 0.30 mmol). This mixture was stirred
under 1000 psi of hydrogen for 12 h at room temperature and filtered
through Celite. After rinsing of the filter cake with THF (250 mL), the
combined filtrates were concentrated, and the residue was subjected to
flash chromatography on silica gel. Elution with 50% ethyl acetate in
hexanes gave 9 (38 mg, 65%) as a colorless crystalline solid: mp 72-
74 °C (from THF-hexanes); IR (neat, cm-1) 1744, 1468, 1402, 1368;
1H NMR (300 MHz, CDCl3) δ 5.00 (m, 1 H), 3.85 (d, J ) 6.4 Hz, 1
H), 3.72 (dd, J ) 9.1, 5.1 Hz, 1 H), 3.65 (dd, J ) 9.1, 2.1 Hz, 1 H),
3.00 (m, 1 H), 2.76 (m, 1 H), 2.61 (dd, J ) 16.0, 5.8 Hz, 1 H), 2.43
(dd, J ) 16.1, 10.2 Hz, 1 H), 1.97 (dd, J ) 12.8, 7.1 Hz, 1 H), 1.77
(dd, J ) 12.8, 9.9 Hz, 1 H), 1.15 (s, 3 H), 0.97 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 171.2, 92.7, 80.6, 73.2, 45.4, 42.4, 39.2, 36.9, 32.2,
1
1435, 1350, 1195, 1075; H NMR (300 MHz, C6D6) δ 6.11 (s, 1 H),
5.34 (s, 1 H), 4.32 (d, J ) 6.4 Hz, 1 H), 3.83 (dd, J ) 8.1, 7.1 Hz, 1
H), 3.68 (t, J ) 7.4 Hz, 1 H), 3.20 (dd, J ) 10.6, 8.2 Hz, 1 H), 2.85-
2.70 (m, 1 H), 2.07-1.90 (m, 1 H), 1.70-1.15 (series of m, 5 H), 1.65
(d, J ) 1.0 Hz, 3 H), 1.20 (s, 3 H), 0.96 (s, 3 H); 13C NMR (75 MHz,
C6D6) δ 141.4, 137.4, 134.3, 126.2, 93.0, 74.0, 54.2, 47.1, 44.1, 31.5,
30.1, 26.5, 26.4, 24.6, 22.4; HRMS (EI) m/z (M+) calcd 218.1671, obsd
218.1679; [R]22 +21.1 (c 0.070, CHCl3).
D
(2aS,5S,9aS,9bS)-1,2a,3,5,6,7,8,9,9a,9b-Decahydro-3,3-dimethyl-
6-methylene-2-oxacycloocta[cd]pentalen-5-ol (14). Dry oxygen was
passed through a CH2Cl2 (5 mL) solution of 13 (69 mg, 0.32 mmol)
and TPP sensitizer (5 mg) with concurrent radiation from a tungsten
halogen lamp for 40 min. The reaction mixture was directly chromato-
graphed on silica gel, elution with 10% ethyl acetate in hexanes
affording the hydroperoxide. This material was immediately reduced
with lithium aluminum hydride (70 mg, 1.8 mmol) in THF (10 mL) at
20 °C for 30 min and quenched with 3 N NaOH solution at 0 °C. The
white solid was filtered off and rinsed with CH2Cl2 (2 × 20 mL). The
combined filtrates were concentrated to give 45 mg (61%) of 14 as an
unstable colorless oil (1.9:1 epimeric mixture) that was immediately
oxidized: IR (neat, cm-1) 3400, 1630, 1435, 1350; 1H NMR (300 MHz,
CDCl3) δ 6.29 (s, 0.34 H), 5.58 (s, 0.66 H), 5.53 (s, 0.34 H), 5.14 (s,
26.7, 22.9; HRMS (EI) m/z (M+) calcd 196.1099, obsd 196.1081; [R]23
+10.5 (c 0.087, CHCl3).
D
Anal. Calcd for C11H16O3: C, 67.32; H, 8.22. Found: C, 67.43; H,
8.27.
(3S,3aS,6aS)-3,3a,6,6a-Tetrahydro-6,6-dimethyl-3-(4-methyl-4-
pentenyl)-4-vinyl-2H-cyclopenta[b]furan (12). A THF (30 mL)
solution of 8 (622 mg, 2.63 mmol) was treated with lithium aluminum
hydride (100 mg, 2.63 mmol) at 20 °C for 30 min, quenched with 3 N
NaOH solution at 0 °C, and filtered. After the filter cake had been
(40) Baker, K. V.; Brown, J. M.; Hughes, N.; Skarnulis, A. J.; Sexton,
A. J. Org. Chem. 1991, 56, 698.

2748 J. Am. Chem. Soc., Vol. 122, No. 12, 2000
Paquette et al.
0.66 H), 4.90 (s, 0.66 H), 4.72 (s, 0.66 H), 4.25 (m, 1 H), 3.98 (s, 0.68
H), 3.95-3.75 (m, 1.34 H), 3.58 (t, J ) 8.3 Hz, 0.66 H), 3.40 (dd, J
) 8.4, 6.7 Hz, 0.66 H), 3.12 (dd, J ) 10.8, 8.3 Hz, 0.34 H), 2.84 (m,
0.34 H), 2.50-1.20 (series of m, 7.66 H), 1.04 (s, 2 H), 1.01 (s, 3 H),
0.96 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 150.6, 144.4, 142.9, 139.8,
136.9, 136.0, 125.1, 112.7, 92.5, 92.3, 76.6, 75.9, 73.4, 68.2, 53.5, 51.6,
46.8, 46.1, 43.4, 42.9, 30.6, 30.4, 29.6, 29.4, 27.1, 26.9, 26.7, 24.0,
21.5, 21.3; HRMS (EI) m/z (M+) calcd 234.1620, obsd 234.1617.
(2aS,4aS,6R,9aS,9bS)-Decahydro-3,3,6-trimethyl-2-oxacycloocta-
[cd] pentalen-5(1H)-one (15). A solution of 14 (43 mg,0.18 mmol) in
CH2Cl2 (5 mL) was oxidized with the Dess-Martin periodinane (156
mg, 0.37 mmol) at room temperature for 30 min and subjected directly
to flash chromatography on silica gel. Elution with 10% ethyl acetate
in hexanes gave the dienone, which was dissolved in ethanol (3 mL),
treated with 10% palladium on charcoal (20 mg), and hydrogenated at
300 psi for 1 h. The insolubles were separated by filtration and rinsed
with CH2Cl2 (2 × 20 mL). Concentration of the filtrate followed by
flash chromatography on silica gel (elution with 5% ethyl acetate in
hexanes) provided 29 mg (67%) of 15 as a white solid: mp 83-85
°C; IR (neat, cm-1) 1690, 1445, 1360, 1060; 1H NMR (300 MHz,
CDCl3) δ 3.96 (dd, J ) 6.9, 1.1 Hz, 1 H), 3.83 (t, J ) 7.8 Hz, 1 H),
3.35 (m, 1 H), 3.20-3.09 (m, 2 H), 2.56-2.43 (m, 2 H), 2.40-2.22
(m, 1 H), 2.00 (t, J ) 12.8 Hz, 1 H), 1.90-1.65 (m, 2 H), 1.65-1.43
(m, 2 H), 1.37-1.20 (m, 1 H), 1.12-1.00 (m, 1 H), 1.10 (d, J ) 6.8
Hz, 3 H), 1.09 (s, 3 H), 0.88 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
215.5, 94.4, 74.9, 50.7, 48.7, 45.8, 44.2, 41.7, 40.5, 28.7, 25.9, 23.2,
23.1, 22.3, 13.5; HRMS (EI) m/z (M+) calcd 236.1776, obsd 236.1777;
mg, 1.23 mmol) in 2:2:1 CH3CN-CCl4-H2O (2.5 mL) was stirred for
5 h, diluted with CH2Cl2 (5 mL), dried, and filtered. After solvent
evaporation, the residue was subjected to flash chromatography on silica
gel. Elution with 20% ethyl acetate in hexanes gave 19 mg (63%) of
1 as a white solid: mp 156-158 °C; IR (neat, cm-1) 1755, 1685, 1450,
1360; 1H NMR (300 MHz, CDCl3) δ 4.26 (dd, J ) 5.3, 1.1 Hz, 1 H),
3.73 (ddd, J ) 11.1, 9.7, 5.3 Hz, 1 H), 3.20 (ddd, J ) 13.0, 11.1, 6.8
Hz, 1 H), 2.71 (ddd, J ) 12.4, 9.7, 4.7 Hz, 1 H), 2.57-2.35 (m, 2 H),
2.18 (d, J ) 13.0, 13.0 Hz, 1 H), 2.05-1.20 (series of m, 6 H), 1.20
(s, 3 H), 1.12 (d, J ) 6.8 Hz, 3 H), 1.00 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 213.8, 178.1, 91.1, 50.4, 46.0, 45.9, 43.4, 41.0, 38.6, 28.3,
24.8, 23.2 (2 C), 22.7, 13.5; HRMS (EI) m/z (M+) calcd 250.1569,
obsd 250.1557; [R]22 +8.5 (c 0.019, CHCl3).
D
Acknowledgment. The authors are appreciative of the efforts
of Prof. Robin Rogers with regard to the X-ray analysis, Dr.
Craig Blankenship (Boulder Scientific) for a sample of the
Grubbs catalyst, and of Dr. Kurt Loening for assistance with
nomenclature.
1
Supporting Information Available: Copies of the H and
13C NMR spectra of 1 as well as tables giving the crystal data
and structure refinement information, bond lengths and bond
angles, atomic and hydrogen coordinates, and isotropic and
anisotropic displacement coordinates for 4 (PDF). This informa-
tionisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
[R]22 +4.9 (c 0.020, CHCl3).
D
(+)-Asteriscanolide (1). A mixture of 15 (29 mg, 0.12 mmol),
ruthenium trichloride (26 mg, 0.12 mmol), and sodium periodate (263
JA994053W