Stereocontrolled synthesis of kelsoene by the homo-Favorskii rearrangement

Article abstract of DOI:10.1021/ol026739q

(graph presented) (±)-Kelsoene (4) has been synthesized from 2,5-dihydroanisole in 16 steps in 12.5% overall yield. The key step involves a base-catalyzed reaction of γ-keto tosylate (5), which effects a homo-Favorskii rearrangement to 16 as well as the c

Full text of DOI:10.1021/ol026739q

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3755-3758
Stereocontrolled Synthesis of Kelsoene
by the Homo-Favorskii Rearrangement
,†,‡
Liming Zhang† and Masato Koreeda*
Departments of Chemistry and Medicinal Chemistry, UniVersity of Michigan,
Ann Arbor, Michigan 48109-1055
koreeda@umich.edu
Received August 15, 2002
ABSTRACT
(±)-Kelsoene (4) has been synthesized from 2,5-dihydroanisole in 16 steps in 12.5% overall yield. The key step involves a base-catalyzed
reaction of γ-keto tosylate (5), which effects a homo-Favorskii rearrangement to 16 as well as the corresponding intramolecular SN2 product
15 from the enolate of 5. Ketone 15 can efficiently be isomerized to cyclobutanone 17 having the kelsoene carbon skeleton upon acid treatment.
Upon treatment with base, certain γ-keto p-toluenesulfonates
undergo a stereospecific homoallyl rearrangement, commonly
referred to as a homo-Favorskii rearrangement.1 For example,
2-methyl-2-tosyloxymethyl-cyclohexanone (1) provides
bicyclo[3.2.0]heptanone 2 in 48% yield together with
bicyclo[3.1.1]heptanone 3 (34%) (Scheme 1).2 While the
infra),3 presumably a manifestation of their relative strain
energies.4 Despite detailed mechanistic understanding and
the potential access to synthetically versatile ring structures,5
this reaction has been scarecely exploited by practicing
synthetic chemists. In connection with our interest in the
synthesis of cyclobutane-containing natural products, it was
envisaged that the use of a homo-Favorskii rearrangement
reaction could be ideally suited for the construction of the
bicyclo[3.2.0]heptane carbon framework present in the
sesquiterpene kelsoene, i.e., C-1∼C-7 (see 4).
Scheme 1
(1) (a) Tsuda, Y.; Tanno, T.; Ukai, A.; Isobe, K. Tetrahedron Lett. 1971,
2009-2012. (b) Bisceglia, R. H.; Cheer, C. J. J. Chem. Soc., Chem. Comm.
1973, 165-166. (c) Wolff, S.; Agosta, W. C. J. Chem. Soc., Chem. Comm.
1973, 771. (d) Review: Methods of Organic Chemistry (Houben-Weyl);
de Meijere, A., Ed.: Georg Thieme Verlag: Stuttgart, Germany, 1997; Vol
E 17e, pp 234-237.
(2) Wenkert, E.; Bakuzis, P.; Baumgarten, R. J.; Leight, C. L.; Schenk,
H. P. J. Am. Chem. Soc. 1971, 93, 3208-3216.
(3) (a) Erman, W. F. J. Am. Chem. Soc. 1969, 91, 779-780. (b) Erman,
W. F.; Treptow, R. S.; Bakuzis, P.; Wenkert, E. J. Am. Chem. Soc. 1971,
93, 657-665. (c) Kirmse, W.; Alberti, J. Chem. Ber. 1973, 106, 236-245.
(d) Klinkmu¨ller, K.-D.; Marschall, H.; Wyerstahl, P. Chem. Ber. 1975, 108,
191-202.
(4) Strain energies for bicyclo[3.1.1]heptane and bicyclo[3.2.0]-heptane
have been calculated to be, respectively, 35.85 and 30.48 kcal/mol. See:
Engler, E. M.; Andose, J. D.; von R. Schleyer, P. J. Am. Chem. Soc. 1973,
95, 8005-8025. Review: (b) Liebman, J. F.; Greenberg, A. Chem. ReV.
1976, 76, 311-365.
(5) For a review, see, for example: Wong, H. N. C.; Lau, K.-L.; Tam,
K.-F. Top. Cur. Chem. 1986, 133, 83-157.
former ketone represents the product of the homo-Favorskii
rearrangement, the latter corresponds to that of the direct
displacement of the tosylate group by the ketone enolate.
However, it is of considerable interest to note that, in general,
the bicyclo[3.1.1]heptanone products readily rearrange to
bicyclo[3.2.0]heptanones upon treatment with mild acid (vide
† Department of Medicinal Chemistry.
‡ Department of Chemistry.
10.1021/ol026739q CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/18/2002

Kelsoene (4), isolated in 1997 from the topical marine
sponge Cymbastela hooperi collected from Kelso reef in
Australia,6 possesses a unique 5-5-4 ring-fused tricarbo-
cyclic structure, which has now been found in several other
natural products.7 This compound has recently been synthe-
sized by Mehta,8 Schultz,9 and Piers’10 groups, all of which
employed a photochemical [2 + 2] cycloaddition reaction
to introduce the four-membered carbocyclic unit. Interest-
ingly, the absolute configuration postulated by the use of an
empirical NMR method11 has been revised as the result of
the synthesis of optically active kelsoene commencing with
compounds of known absolute stereochemistry.8b,9 In the
following, we present a highly efficient synthesis of (()-
kelsoene (4) by the use of a homo-Favorskii reaction as a
salient feature toward the elaboration of the 4-5 ring-fused
portion of the molecule.
Scheme 3. Synthesis of Enone 6a
As summarized in the retrosynthetic analysis of kelsoene
(Scheme 2), the last few steps, i.e., 5 f 4, feature the ring-
a Reagents and conditions: (a) (HOCH2)2, CH2Cl2, p-TsOH (cat.)
(99%); (b) MCPBA (1.5 mol equiv)/CH2Cl2, rt, 10 h (quantitative);
(c) di(p-chlorophenyl) diselenide (2.0 mol equiv), NaH (1.0 mol
equiv)/THF, rt, 10h; (d) 30% aq H2O2 (5.0 mol equiv)/EtOH, rt,
0.5 h, then dilution with EtOH and NaHCO3, and reflux, 12 h; (e)
pivaloyl chloride (2.0 mol equiv), DMAP (4.2 mol equiv)/CH2Cl2,
rt, 4 h (quantitative); (f) TMS-CtCCH2CH2MgBr (3.0 mol equiv),
CuCN (0.5 mol equiv)/THF, rt, 12 h then MeOH, K2CO3, rt, 4 h
(94%); (g) Pd(OAc)2 (5 mol %), AsPh3 (15 mol %), AcOH (3 mol
equiv)/benzene, 60 °C, 18 min; (h) CoCl2‚2H2O (2.0 mol equiv),
LiBH4 (2.4 mol equiv)/2:1 THF/MeOH, -78 °C, 2 h, workup with
TFA (10 mol equiv)/hexanes, rt, 14 h.
Scheme 2. Retrosynthetic Analysis of Kelsoene (4)
ketal oxygen atom. In contrast, the use of ArSe-, generated
from (ArSe)2/NaH13 (Ar ) p-chlorophenyl), resulted in its
exclusive attack at the oxirane carbon further away from the
ketal. Oxidation of the resulting selenide to the selenoxide
at room temperature followed by refluxing in ethanol
afforded the desired allylic alcohol 9. This regioselectivity
in the epoxide ring opening of 11 may be explainable in
terms of the axial attack by the ArSe- going through
transition state A (see Figure 1). The epoxide-ring opening
through transition state B is likely to encounter severe steric
as well as repulsive electrostatic interactions between the
ArSe anion and the ketal oxygen, which is 1,3-diaxially
juxtaposed against the incoming selenide anion.
contracting homo-Favorskii rearrangement. We considered
that the stereocontrolled synthesis of the requisite γ-keto
tosylate 5 in turn should be achievable from enone 6 by
taking advantage of its conformationally well-definable
bicyclic cis 5-6-fused ring system.
On the basis of the approach outlined in Scheme 2, enone
6 was synthesized from commercially available 2,5-dihydro-
anisole (10) (Scheme 3). The treatment of epoxide 1112 with
LDA provided, upon aqueous workup, exclusively the allylic
alcohol 13 (see Figure 1) (80% yield), presumably a
consequence of the initial complexation of the Li+ with the
(6) Ko¨nig, G. M.; Wright, A. D. J. Org. Chem. 1997, 62, 3837.
(7) (a) Arnone, A.; Nasini, G.; Vajna de Pava, O. J. Chem. Soc., Perkin
Trans. 1 1993, 2723-2725. (b) Schulz, S.; Messer, C.; Dettner, K.
Tetrahedron Lett. 1997, 38, 2077-2080.
(8) (a) Mehta, G.; Srinivas, K. Tetrahedron Lett. 1999, 40, 4877-4880.
(b) Mehta, G.; Srinivas, K. Tetrahedron Lett. 2001, 42, 2855-2857.
(9) Fietz-Razavian, S.; Schultz, S.; Dix, I.; Jones, P. G. Chem. Commun.
2001, 2154-2155.
(10) Piers, E.; Orellana, A. Synthesis 2001, 2138-2142; Synthesis 2002,
300.
(11) Nabeta, K.; Yamamoto, M.; Koshino, H.; Fukui, H.; Fukushi, Y.;
Tahara, S. Biosci. Biotechnol. Biochem. 1999, 63, 1772-1776.
(12) Cheng, C.-Y.; Wu, S.-C.; Hsin, L.-W.; Tam, S. W. J. Med. Chem.
1992, 35, 2243-2247.
Figure 1. Epoxide-ring opening of 11 by ArSe-.
Org. Lett., Vol. 4, No. 21, 2002
(13) Krief, A.; Trabelsi, M.; Dumont, W. Synthesis 1992, 933-935.
3756

the use of CoCl2/LiBH4 in 2/1 THF/MeOH at -78 °C,18
regio- and stereoselectively providing enone 6 in 75% yield.
The stereocontrolled elaboration of enone 6 into γ-keto
tosylate 5 was achieved in four steps (Scheme 4). Thus,
sequential methylation and hydroxymethylation followed by
tosylation afforded the enone-tosylate 14. The introduction
of the isopropenyl group to the enone â-carbon proved to
be sluggish by the use of standard cuprate reaction conditions.
It was found that the use of the CuX3Li2-catalyzed Kharasch
reaction19 was necessary in order to effect the conjugate
addition of the isopropenyl group to the enone 14.
Scheme 4. Completion of the Synthesis of Kelsoene (4)a
Treatment of γ-keto tosylate 5 with excess t-BuOK at
room temperature resulted in the rapid (<2 min) formation
of a 5:4 mixture of two cyclobutanones, 15 (IR 1773 cm-1;
13C NMR 213.8 ppm) and 16 (IR 1774 cm-1; 13C NMR 210.4
ppm), in a combined yield of 95%. The latter cyclobutanone
corresponds to the product of the homo-Favorskii reaction
(Figure 2). In a formal sense, the direct intramolecular SN2
a Reagents and conditions: (a) LDA (2.0 equiv)/THF, -78 °C,
then MeI (excess)/HMPA (1.0 equiv), -78 f -20 °C (73%); (b)
LDA (1.5 equiv)/THF, -78 °C, then CH2O (gas) (excess), -78 f
0 °C (85%); (c) TsCl (3 mol equiv), DMAP (6.3 equiv)/CH2Cl2, 0
°C (93%); (d) isopropenyl-magnesium bromide (5 mol equiv), CuI
(2 mol equiv), LiCl (4 mol equiv), TMS-Cl (10 mol equiv)/THF,
0 °C, 12 h; (e) t-BuOK (8 mol equiv)/t-BuOH, rt, 2 min; (f) p-TsOH
(1 mol equiv to 15)/CF3CH2OH, 0 °C, 4 h; (g) TsNHNH2 (4 mol
equiv)/benzene, 60 °C, 12 h (98%); (h) NaBH3CN (24.7 mol equiv),
p-TsOH (1.64 mol equiv)/1:1:2 sulfolane/DMF/hexanes, 110 °C,
6 h (78%).
The cyanocuprate reaction in THF14 of the pivaloate
derivative from 9 proceeded smoothly to give the butynyl
group-appended product 8, which underwent a smooth,
Pd(0)-mediated enyne cyclization15 to afford bicyclic diene
7. Somewhat surprisingly, the selective reduction of the exo-
methylene CdC bond of the diene 7 proved to be highly
problematic. Diimide reduction and catalytic hydrogenation
were not highly regioselective. The use of Wilkinson’s
catalyst16 or RuCl2(PPh3)317 in H2 led to extensive CdC bond
migration. This unexpected problem was circumvented by
Figure 2. Base-catalyzed reactions of γ-keto tosylate 5.
reaction of the keto enolate C from 5 leads to 15. However,
this transformation 5 f 15 may be more likely to go through
a nonclassical ion form such as D. Although both 15 and 16
can easily be isolated to purity, a mixture of the two ketones
was subjected to acidic conditions in an effort to isomerize
the more strained bicyclo[3.1.1]heptane 15 to its bicyclo-
[3.2.0]heptane isomer. Thus, exposure of the mixture to
p-TsOH (1 mol equiv to 15 in the mixture) in trifluoroethanol
at 0 °C for 4 h induced the clean isomerization into a roughly
1:1, separable mixture (90%) of two cyclobutanones, 17 (IR
1776 cm-1; 13C NMR 217.7 ppm) and 16, indicating that
virtually all of 16 remained unchanged during this mild acid
treatment. This rearrangement appears to go through a cation
species such as F or its nonclassical cation equivalent (Figure
3), and the overall stereochemistry of the quaternary methyl
group is maintained. The results of the AM1 calculations of
(14) This reaction has been shown to be highly solvent-dependent. See:
(a) Ba¨ckvall, J.-E.; Selle´n, M.; Grant, B. J. Am. Chem. Soc. 1990, 112,
6615-6621. For the reaction in diethyl ether, see: (b) Tseng, C. C.; Paisley,
S. D.; Goering, H. L. J. Org. Chem. 1986, 51, 2884-2891.
(15) Interestingly, the use of AsPh3 as the catalyst was found to be crucial
for this Pd(0)-mediated efficient enyne cyclization. Other ligands such as
PPh3 and tris(2-furyl)phosphine proved to be less efficient as the catalyst
for this reaction. Reviews: (a) Trost, B. M. Acc. Chem. Res. 1990, 23,
34-42. (b) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102,
813-834. (c) Link, J. T. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002;
Vol. 1, pp 1523-1559. (d) de Meijere, A.; Reiser, O. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002; Vol. 1, pp 1647-1650.
(18) Chung, S. K. J. Org. Chem. 1979, 44, 1014-1016. Review: (b)
Ganem, B.; Osby, J. O. Chem. ReV. 1986, 86, 763-780.
(19) Reetz, M. T.; Kindler, A. J. Organomet. Chem. 1995, 502, C5-
C7.
(16) Hall, P. S.; Evans, D.; Osborn, J. A.; Wilkinson, G. Chem. Commun.
1967, 305.
(17) Tsuji, J.; Suzuki, H. Chem. Lett. 1977, 1083-1084.
Org. Lett., Vol. 4, No. 21, 2002
3757

In summary, we have achieved a highly efficient total
synthesis of (()-kelsoene (4) from commercially available
2,5-dihydroanisole (10) in 16 steps in overall 12.5% yield.
The salient feature of the synthesis lies in the use of a base-
catalyzed reaction of γ-keto tosylate 5, which afforded
products of an intramolecular SN2 reaction of the enolate
and a homo-Favorskii reaction, 15 and 16, respectively, in
excellent yield. A mixture of cyclobutanones 15 and 16 has
been treated with p-TsOH to effect a clean conversion of
the former to 17, whereas the latter remains unchanged. This
isomerized cyclobutanone 17 has the same carbon skeleton
as kelsoene. This combination of the acid-catalyzed isomer-
ization and a homo-Favorskii reaction of γ-keto tosylates
seems to hold excellent potential for the synthesis of a variety
of natural products having the bicyclo[3.2.0]heptane carbon
framework.
Figure 3. Acid-catalyzed rearrangement of 15 to 17.
heats of formation for the two ketones 15 and 17 are
consistent with observed results. Thus, heats of formation
of ketone 17 have been shown to be over 17 kcal/mol lower
than that of 15.20
The mixture of ketones 16 and 17 was next converted to
their tosylhydrazone derivatives. These tosylhydrazones were
subsequently reduced to the hydrocarbon kelsoene (4) by
the use of Hutchins’ two-phase procedure21 with NaB(CN)H3
in the presence of anhydrous p-TsOH in overall 76% yield.
Acknowledgment. L.Z. thanks the Eli Lilly Company
for a 2002-2003 Industrial Graduate Student Fellowship
administered through the Department of Chemistry, Univer-
sity of Michigan.
1
The kelsoene thus obtained exhibited IR and H and 13C
Supporting Information Available: Experimental details
as well as analytical and spectroscopic data for new
compounds described. This material is available free of
charge via the Internet at http://pubs.acs.org.
NMR spectroscopic properties identical to those reported.6
(20) Heats of formation calculated for cyclobutanones 15 and 17 by the
AM1 method are, respectively, -14.578 and -31.925 kcal/mol.
(21) Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. J. Am. Chem.
Soc. 1973, 95, 3662-3668.
OL026739Q
3758
Org. Lett., Vol. 4, No. 21, 2002