Sequential intramolecular cyclobutadiene cycloaddition, ring-opening metathesis, and cope rearrangement: Total syntheses of (+)- and (-)-asteriscanolide [1]

Full text of DOI:10.1021/ja001946b

J. Am. Chem. Soc. 2000, 122, 8071-8072
8071
Communications to the Editor
Sequential Intramolecular Cyclobutadiene
Cycloaddition, Ring-Opening Metathesis, and Cope
Scheme 1. Retrosynthetic Analysis of Asteriscanolide
Rearrangement: Total Syntheses of (+)- and
(-)-Asteriscanolide
John Limanto and Marc L. Snapper*
Department of Chemistry, Merkert Chemistry Center
Boston College, Chestnut Hill, Massachusetts 02467
ReceiVed June 2, 2000
The value of new transformations can become apparent when
brought to bear in complex molecule synthesis. To demonstrate
1
the utility of intramolecular cyclobutadiene cycloadditions and
As illustrated in Scheme 1, our strategy was to also prepare
the natural product through the intermediacy of cyclooctadiene
2
ring-opening metatheses, we report herein the first application
of these complementary transformations in the total syntheses of
+)- and (-)-asteriscanolide (1). The incorporation of these
reactions into the synthesis of asteriscanolide provides a nine-
step route (longest linear sequence) to the natural product. The
key synthetic disconnections are illustrated in Scheme 1.
Since its discovery more than 15 years ago, the novel
sesquiterpene lactone ring system of 1 has drawn considerable
attention from the synthetic community. In particular, successful
syntheses of asteriscanolide have been reported by the Krafft and
Paquette laboratories. Predating these more recent contributions,
however, is the first and, to date, shortest synthesis of 1, by
2; instead of using a [4 + 4] cycloaddition, however, we planned
(
to generate 2 through a Cope rearrangement on the dialkenyl-
cyclobutane 3. Precursor 3, in turn, would be prepared through a
ring-opening metathesis of the highly functionalized cyclobutene
4
and ethylene. An intramolecular Diels-Alder reaction between
3
cyclobutadiene (6) and dimethylcyclopentenol (7) would be
employed to generate compound 4.
4
Achieving the absolute stereochemistry of the natural product
was dependent upon the stereochemical identity of allylic alcohol
5
7. As illustrated in eq 1, compound 7 can be prepared in
6
Wender, Ihle, and Correia. The Wender strategy centered on a
Ni(0)-catalyzed intramolecular [4 + 4] cycloaddition of a highly
functionalized bis-1,3-diene to provide the cyclooctadiene-
containing intermediate 2. This advanced cycloadduct was then
converted to 1 in two steps. The intramolecular [4 + 4]
cycloaddition-based approach provided an asymmetric synthesis
of (+)-asteriscanolide in 13 steps from commercially available
starting materials.
nonracemic form from commercially available ketone 8. A Pd-
catalyzed Saegusa oxidation of the silyl enol ether derived from
7
ketone 8 (60% yield), followed by a (S)-B-Me-CBS-catalyzed
(
1) (a) Tallarico, J. A.; Randall, M. L.; Snapper, M. L. J. Am. Chem. Soc.
enantioselective reduction8 of the enone produces the (S)-
1
996, 118, 9196-9197. (b) Limanto, J.; Snapper, M. L. J. Org. Chem. 1998,
9
6
3, 6440-6441.
dimethylcyclopentenol 7 in 94% ee and 56% yield. While this
(
2) (a) Randall, M. L.; Tallarico, J. A.; Snapper, M. L. J. Am. Chem. Soc.
configuration of 7 lead to the natural product, employing the (R)-
CBS catalyst in the reduction delivered the antipode of 7, which
was used to prepare (-)-asteriscanolide.
Initial attempts to carry out the intramolecular Diels-Alder
between the ester-linked cyclobutadiene and dimethylcyclopen-
tenol (5 f 4) proved unsuccessful; the failure is presumably due
to the unfavorable conformational constraints of the ester
functionality. The cycloaddition became possible, however, if the
two functional groups were connected instead through an ether
linkage.
1
995, 117, 9610-9611. (b) Snapper, M. L.; Tallarico, J. A.; Randall, M. L.
J. Am. Chem. Soc. 1997, 119, 1478-1479. (c) Tallarico, J. A.; Bonitatebus,
P. J., Jr.; Snapper, M. L. J. Am. Chem. Soc. 1997, 119, 7157-7158. (d)
Tallarico, J. A.; Randall, M. L.; Snapper, M. L. Tetrahedron 1997, 53, 16511-
1
3
3
3
6520. (e) Schneider, M. F.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996,
5, 411-412. (f) Cuny, G. D.; Cao, J.; Hauske, J. R. Tetrahedron Lett. 1997,
8, 5237-5240. (g) Cuny, G. D.; Hauske, J. R. CHEMTECH 1998, 28, 25-
1. (h) Randall, M. L.; Snapper, M. L. J. Mol. Catal. 1998, 133, 29-40.
(
3) San Feliciano, A.; Barrero, A. F.; Medarde, M.; Miguel del Corral, J.
M.; Aramburu, A.; Perales, A.; Fayos, J. Tetrahedron Lett. 1985, 26, 2369-
372.
4) (a) Sarkar, T. K.; Gangopadhyay, P.; Binay, K.; Nandy, S. K.; Fang,
2
(
J.-M. Tetrahedron Lett. 1998, 39, 8365-8366. (b) Liu, S.; Crowe, W. E.;
ACS 216th National Meeting Abstracts, American Chemical Society, Wash-
ington, DC, 1998; ORGN-235. (c) Booker-Milburn, K. I.; Cowell, J. K.; Harris,
L. J. Tetrahedron 1997, 53, 12319-12338. (d) Lange, G. L.; Organ, M. G. J.
Org. Chem. 1996, 61, 5358-5361. (e) Booker-Milburn, K. I.; Cowell, J. K.
Tetrahedron Lett. 1996, 37, 2177-2180. (f) Juliano, C. A. Thesis Dissertation,
Florida State University, 1994. (g) Booker-Milburn, K. I.; Cowell, J. K.; Harris,
L. J. Tetrahedron Lett. 1994, 35, 3883-3886. (h) Meister, P. G. Thesis
Dissertation, Ohio State University 1991. For recent reviews on the synthesis
of cyclooctanoids, see: (i) Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 881-
The successful route to 1 is summarized in Scheme 2. The
iron-complexed cyclobutadiene portion (10) of the molecule can
be prepared through the photolysis of the commercially available
R-pyrone 9 in the presence of Fe(CO)
5
or by mild heating of the
Compound 11 was then
10
photolysis product with Fe
2
(CO)
9
.
(7) (a) Yoshihiko, I.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011-
1013. (b) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zeng, D.
Tetrahedron Lett. 1995, 36, 2423-2426.
(8) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551-5553. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. Engl.
1988, 37, 1986-2012. (c) Deloux, L.; Srebnik, M. Chem. ReV. 1993, 93, 763-
784.
(9) Enantiomeric excess of 7 was determined by gas chromatography
analysis on Supelco’s Alpha Dex 120 fused silica capillary column.
(10) Agar, J.; Kaplan, F.; Roberts, B. W. J. Org. Chem. 1974, 39, 3451-
3452.
9
30. (j) Molander, G. A. Acc. Chem. Res. 1998, 31, 603-609.
5) (a) Cheung, Y. Y.; Krafft, M. E.; Juliano-Capucao, C. A. ACS 216th
National Meeting Abstracts, American Chemical Society, Washington, DC,
(
1
998; ORGN-238. (b) Paquette, L. A.; Tae, J.; Arrington, M. P.; Sadoun, A.
H. J. Am. Chem. Soc. 2000, 122, 2742-2748. (c) Krafft, M. E.; Juliano-
Capucao, C. A. Synthesis 2000, 0000.
(6) (a) Wender, P. A.; Ihle, N. C.; Correia, C. R. D. J. Am. Chem. Soc.
1
988, 110, 5904-5906. (b) Ihle, N. C. Thesis Dissertation, Stanford University,
1
989.
1
0.1021/ja001946b CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/04/2000

8072 J. Am. Chem. Soc., Vol. 122, No. 33, 2000
Communications to the Editor
Scheme 2. Total Synthesis of (+)-Asteriscanolidea
ethylene atmosphere, followed by reflux (10 h) produced cy-
clooctadiene 15 in 74% yield. Evidently, the dialkenyl cyclobutane
17 formed initially in the ring-opening metathesis proceeds with
the Cope rearrangement under the relatively mild reaction
conditions. One reason we had not observed previously this facile
2
b
rearrangement may be that, in contrast to our earlier examples,
cyclobutane 17 lacks a â-alkyl substituent on C-8 (i.e., 17 R )
H).
a
Key: (a) hν, C
NCH
THF; NaH, 7, THF/DMF (50%), (e) Me
CdCH , 16, benzene, 50-80 °C (74%), (g) PCC, pyr, 4 Å MS, CH
79%), (h) Red-Al, CuBr; AcOH, THF (89%), (i) BH ‚OEt , THF; PCC,
Å MS, CH Cl (60%).
6
H
6
; Fe
2
2
(CO)
9
, 50 °C (64%), (b) LAH, BF
, CH CO H, 100 °C (67%); (d) MeI,
NO, acetone, 56 °C (63%), (f)
Cl
2
3
‚OEt
2
(
93%), (c) Me
2
2
NMe , H
3
PO
4
3
2
Completion of the formal synthesis of 1 was accomplished
through allylic oxidation of compound 15.14 Treatment of 15 with
PCC, 4 Å MS, and pyridine in CH Cl provided a 79% yield of
2 2
3
H
(
4
2
2
2
3
2
2
2
Wender’s lactone 2.15 Further elaboration of intermediate 2 to
the natural product followed the sequence described in the Wender
synthesis: Selective 1,4-reduction of the unsaturated lactone was
accomplished with Red-Al and CuBr. To complete the synthesis,
3
the C-7 ketone was then installed through a BH reduction of the
generated from 10 by exhaustive reduction of the ester functional-
1
1
16
ity to a methyl group using LAH and BF
3
‚OEt
2
.
Further
functionalization of the cyclobutadiene moiety was accomplished
through an electrophilic aminomethylation12 to provide the
p-substituted cyclobutadiene complex 12 and the corresponding
o-substituted product (67% yield, 3:1). After in situ methylation
of cyclobutadiene 12, etherification with the sodium salt of
cyclopentenol 7 generated the cycloaddition precursor 13.
The release of iron tricarbonyl from cyclobutadiene 13 under
mild conditions (CAN, 23 °C, acetone) formed products resulting
predominantly from intermolecular cycloadditions; however,
increasing the reaction temperature and reducing the rate of the
oxidation of the iron tricarbonyl group improved the efficiency
of the intramolecular process. After optimization, the highly
functionalized cycloadduct 14 could be obtained in 63% yield
by heating compound 13 with trimethylamine N-oxide in acetone.
With the key cycloadduct 14 in hand, efforts turned toward
generating the dialkenyl cyclobutane (i.e., 17). Precedent for a
selective ring-opening metathesis of a strained trisubstituted olefin,
however, was lacking. Given that the metathesis partner was
ethylene and the recent introduction of more reactive ruthenium
alkylidenes (16),13 there were grounds for optimism. Nonetheless,
had the cross metathesis failed, recourse to a protocol involving
oxidative cleavage of the trisubstituted olefin followed by bis-
olefination of the bis-aldehyde was still available.
remaining olefin, followed by PCC oxidation of the resulting alkyl
borane.17
This nine-step route to asteriscanolide serves, in part, to
demonstrate the utility of several transformations that have not
yet been tested in complex molecule synthesis. An intramolecular
cyclobutadiene cycloaddition was employed to prepare a highly
functionalized trisubstituted cyclobutene (13 f 14). This hindered
cyclobutene was then subjected to a selective ring-opening
metathesis with ethylene to generate directly the ring system of
the natural product (14 f [17] f 15). The convergent nature of
the synthesis (7 + 12 f 13), coupled with the effective
preparation of the cyclooctadiene functionality using several new
transformations allowed for a concise preparation of the natural
product. Efforts to explore and expand further the utility of these
transformations are underway.
Acknowledgment. We are grateful to the National Science Foundation
and ACS PRF for generous support of this research. Discussions with
John Tallarico and Suzanne Stokes are also appreciated. M.L.S. also
acknowledges the Alfred P. Sloan Foundation, the Camille and Henry
Dreyfus Foundation, Glaxo-Wellcome, and DuPont for additional support.
Supporting Information Available: Experimental procedures and
data on new compounds are provided (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Gratifyingly, treatment of cyclobutene 14 with ruthenium
benzylidene 16 (5 mol %, 50 °C, 10 h) in benzene under an
JA001946B
(
11) For an alternative preparation of complex 11, see: Bunz, U. Orga-
nometallics 1993, 12, 3594-3597.
12) For a similar reaction with ferrocene, see: Lednicer, D.; Hauser, C.
(14) (a) Bonadies, F.; Di Fabio, R. J. Org. Chem. 1984, 49, 1647-1649.
(b) Bonadies, F.; Bonini, C. Synth. Commun. 1988, 18, 1573-1580.
(15) Spectrographic and physical properties of the compound generated
were identical to previously reported data.
(
R. Organic Syntheses; Wiley & Sons, New York, 1973; Collect. Vol. 5, pp
4
34-436.
(16) Semmelhack, M. F.; Stauffer, R. D.; Yamashita, A. J. Org. Chem.
1977, 42, 3180.
(
13) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1
1
, 953-956. (b) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751-
(17) (a) Rao, V. V. R.; Devaprabhakara, D.; Chandrasekaran, S. J.
Organomet. Chem. 1978, 162, C9. (b) Lansbury, P. T.; Nickson, T. E.
Tetrahedron Lett. 1982, 23, 2627. (c) Piancatelli, G.; Scettri, A.; D’Auria, M.
Synthesis 1982, 245.
753 and references therein. For references to related ruthenium catalysts,
see: (c) F u¨ rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S.
P. J. Org. Chem. 2000, 65, 2204-2207 and references therein.