Toward the total synthesis of variecolin

Article abstract of DOI:10.1021/ol015763l

(matrix presented) An annulative approach toward the total synthesis of the sesterterpenoid variecolin (1) is presented. Synthesis of the key hemiketal, containing the core ABC ring skeleton, has been achieved on a model system by an expeditious route uti

Full text of DOI:10.1021/ol015763l

ORGANIC
LETTERS
2001
Vol. 3, No. 15
2257-2260
Toward the Total Synthesis of Variecolin
Gary A. Molander,* Michael S. Quirmbach, Luiz F. Silva, Jr.,
Keith C. Spencer, and Jaume Balsells
Roy and Diana Vagelos Laboratories, Department of Chemistry,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
Received February 26, 2001 (Revised Manuscript Received June 19, 2001)
ABSTRACT
An annulative approach toward the total synthesis of the sesterterpenoid variecolin (1) is presented. Synthesis of the key hemiketal, containing
the core ABC ring skeleton, has been achieved on a model system by an expeditious route utilizing samarium(II) iodide. Furthermore,
enantioselective syntheses of component fragments for the total synthesis have been developed.
Herein we report progress toward the total synthesis of
variecolin (1) using a modified samarium(II) iodide mediated
annulation approach. We have demonstrated the feasibility
of the formation of the core ABC carbocyclic skeleton on a
model system and also report first-generation syntheses of
the two components to be utilized in the total synthesis.
The sesterterpenoid variecolin (1) was first isolated by
Hensens in 1991 and found to possess a number of interesting
biological properties.1 It is an antagonist of the angiotensin-
II AT1 receptor and more recently has been shown to be a
potent immunosuppressant.1,2 This immunosuppressant activ-
ity is of notable interest because of the simplicity of 1 in
comparison to other immunosuppressants such as FK-506
and cyclosporin. Despite such interesting properties, variecolin
has received little synthetic attention,3 and so was an
attractive target for total synthesis. Furthermore, at the outset
of our studies the absolute configuration of variecolin had
not been unambiguously determined and so an enantio-
selective synthesis would also provide a definitive structural
determination.
3, and chloro ketone, 4, mediated by SmI2 (Scheme 1). We
previously reported this approach to medium sized carbo-
Scheme 1
cycles on simplified systems, and it was hoped that a similar
strategy could be used to construct 2.4 Nevertheless, the use
of an annulation to construct an elaborate carbon skeleton
was not without risk.
Formation of the eight-membered ring hemiketal 2 was
to be accomplished by a sequenced reaction of an iodo ester,
(1) Hensens, O. D.; Zink, D.; Williamson, J.; Lotti, V. J.; Chang, R. S.
L.; Goetz, M. A. J. Org. Chem. 1991, 56, 3399-3403.
(2) Fujimoto, H.; Nakamura, E.; Okuyama, E.; Ishibashi, M. Chem.
Pharm. Bull. 2000, 48, 1436-1441.
(4) (a) Molander, G. A.; Alonso-Alija, C. J. J. Org. Chem. 1998, 63,
4366-4373. (b) Molander, G. A.; Machrouhi, F. J. Org. Chem. 1999, 64,
4119-4123 and references therein.
(3) Piers, E.; Boulet, S. L. Tetrahedron Lett. 1997, 38, 8815-8818.
10.1021/ol015763l CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/28/2001

During the preparation of this Letter, Fujimoto and co-
workers demonstrated that the absolute configuration of
variecolin was, in fact, 1. This is the enantiomer of the
originally reported structure.2 Unfortunately, the synthetic
work carried out in our laboratory to that point was based
on the original assignment which was founded upon bio-
synthetic considerations. However, the approach described
herein retains its validity because both enantiomers of 3 and
4 are readily available by making simple adaptations in the
synthetic schemes.
Scheme 3
Model Studies. A racemic model system was first utilized
to investigate the feasibility of the coupling step. We hoped
lactone 5 would be a suitable precursor to the iodo ester
model for 3 and that 9 would serve as a surrogate for the
chloro ketone 4.4,5 After significant experimentation it was
found, much to our frustration, that the cis geometry of all
iodo carboxylic acid derivatives 8 prevented the expected
SmI2-promoted sequenced reaction from occurring under all
conditions attempted (Scheme 2). Presumably, formation of
ide generated in situ from sodium periodate and ruthenium
chloride.7 Use of this protocol would avoid tedious depro-
tection and oxidation of the alcohol. To our delight, oxidation
of 13 indeed furnished the lactone 10 directly in 65% yield.
Finally, cyclization of 10 with SmI2 under photochemical
conditions yielded the desired hemiketal 14 in 63% yield
(Scheme 3). With the successful synthesis of racemic
hemiketal 14 achieved, enantioselective syntheses of lactone
29 (precursor to the iodo ether) and chloro ketone ent-4 were
investigated.
Scheme 2
Synthesis of Enantiopure Lactone 29. The commercially
available and inexpensive tetrahydrophthalic anhydride 15
was converted into the diester 16 (Scheme 4). Subsequent
oxidation of the double bond furnished 17.8 Cyclization and
decarboxylation of 17 to 18 followed by protection under
standard conditions yielded the 1,3-dioxane 19 in 95% yield.
a cis-fused cyclobutanone occurs, leading to a complex
mixture of degradation products.
Scheme 4
Therefore, a stepwise approach was investigated wherein
the carbonyl group of the iodo ester was replaced by a
protected alcohol. Hence, reduction of the racemic lactone
5 with LiAlH4 gave the diol 11 in 92% yield. In attempted
transformations to the desired halide, the sterically demand-
ing cis geometry prevented the use of large ether protecting
groups such as TBDMS because iodination of the remaining
free alcohol failed. Synthesis of the seemingly unattractive
methyl ether and subsequent iodination of this material gave
12 in 66% yield over two steps (Scheme 3). Coupling of 12
with the chloro ketone 9 proceeded in 72% yield to give
racemic 13 as a 1:1 mixture of diastereomers owing to the
use of racemic components.6
Sharpless had reported oxidation of methyl ethers to the
corresponding methyl esters using catalytic ruthenium tetrox-
(5) Padwa, A.; Hornbuckle, S. F.; Fryxell, G. E.; Stull, P. D. J. Org.
Chem. 1989, 54, 817-824.
(6) Previous studies demonstrated that addition to the ketone is always
trans to the adjacent alkyl chloride chain. See ref 4.
2258
Org. Lett., Vol. 3, No. 15, 2001

It was found that reduction of 19 to the diol 20 was best
achieved using LiAlH4.9
of 24 afforded 25 in 65-75% yield. Cleavage of the acetyl
group of 25 with K2CO3 in methanol and conversion of the
resultant hydroxyl group to the carbonate 27 proceeded
without difficulty. Finally, carbonate 27 was treated with
KOt-Bu and afforded, after heating at reflux in the presence
of p-TsOH, enantiomerically enriched keto lactone 29
(Scheme 5).
Synthesis of Chloro Ketone ent-4. We selected as starting
material for the synthesis of chloro ketone ent-4 the enan-
tiomerically pure Hajos-Parrish ketone 31. The preparation
of this compound has been carefully described in the
literature.12 The enantiomer of 31 is easily available using
the less expensive (S)-proline. Reduction of dione 31 to the
alcohol under modified literature conditions and protection
of the crude alcohol as the pivaloyl ester furnished 32 in
81% yield (Scheme 6).13
The enantiospecific introduction of the acyl unit (which
serves as a temporary protecting group) to give ultimately
23 can be envisaged to occur in a number of ways. Either
asymmetric hydrolysis and deprotection of the diacetate 21
or asymmetric acylation of 22 would afford the correct
enantiomer 23. Gais, in fact, had shown that porcine pancreas
lipase (PPL) could be used for either asymmetric hydrolysis
or asymmetric acylation on substrates similar to 21 and 22
by choice of suitable conditions.10
Reaction of crude PPL enzyme (immobilized on Kieselgur)
with 22 utilizing vinyl acetate as the acylating agent and
solvent gave 23 in 47% yield and 96% ee (Scheme 5).11 The
Scheme 5
Scheme 6
Alkylation of indanone 32 using published procedures was
not straightforward. The desired product 33 was obtained in
only 31% yield.14 To our delight, however, use of a mixture
of THF and DMSO as solvent in the initial step gave 33 in
61% yield.
enantioselectivity was verified by chiral GC. Clearly, the free
hydroxyl group of 23 can be orthogonally protected and the
acetyl group removed to furnish the enantiomer required for
the synthesis of 3.
Conversion of 23 to the xanthate ester 24 under standard
conditions occurred with no observable racemization as
verified by chiral HPLC. Reduction of the xanthate group
Reduction of the alkylated indanone 33 (NaBH4/NiCl2)
gave the unstable trans-fused ketone in a modest 49% yield.15
(10) (a) Gais, H.-J.; Hemmerle, H. Tetrahedron Lett. 1987, 28, 3471-
3474. (b) Gais, H.-J.; Hemmerle, H.; Kossek, S. Synthesis 1992, 169-173.
(c) Hemmerle, H. Ph.D. Dissertation, Universita¨t Freiburg, 1990.
(11) Unreacted starting material and diacylated material were recycled
easily to improve the overall conversion to 23.
(12) Hajos, Z. G.; Parrish, D. R. Org. Synth. 1984, 63, 26-36.
(13) Micheli, R. A.; Hajos, Z. G.; Cohen, N.; Parrish, D. R.; Portland,
L. A.; Scimanna, W.; Scott, M. A.; Wehrli, P. A. J. Org. Chem. 1975, 40,
675-681.
(14) (a) Ihara, M.; Tokunaga, Y.; Fukumoto, K. J. Org. Chem. 1990,
55, 4497-4498. (b) Sugimura, T.; Paquette, L. A. J. Am. Chem. Soc. 1987,
109, 3017-3024.
(7) Gais, H. J.; Bu¨low, G.; Zatorski, A.; Jentsch, M.; Maidonis, P.;
Hemmerle, H. J. Org. Chem. 1989, 54, 5115-5122.
(8) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936-3938.
(9) Cope, A. C.; Herrick, E. C. J. Am. Chem. Soc. 1950, 72, 983-987.
Org. Lett., Vol. 3, No. 15, 2001
2259

Subjection of the trans-fused ketone to traditional hydro-
genolysis conditions yielded the ketal 34. Direct hydrogena-
tion, avoiding isolation of the sensitive intermediate ketone,
led to an increased yield of 52% over the two steps.
Removal of the pivaloate ester of 34 with LiAlH4 furnished
the desired unprotected alcohol. Oxidation of the secondary
alcohol was most successfully achieved by employing Dess-
Martin conditions to furnish 35 in 57% yield from 34.16
Confirmation of the structure of 35 was achieved by X-ray
analysis.
Scheme 8
R,â-Unsaturation was introduced following a two-step
procedure that gave 36 in 77% yield (Scheme 7).17 We
Scheme 7
planned to introduce the desired isopropenyl group of the
natural product by means of an organocuprate Michael
addition. On the basis of a previous report on a similar
system, we expected the axial methyl of the fused bicyclic
system to effectively block the pro-S face of the R,â-
unsaturated ketone.3 Ketone 37 was obtained in 82% yield
as a single diastereomer. However, X-ray analysis showed
the isopropenyl group to be cis to the methyl substituent on
the cyclopentanone ring.
To correct the configuration of the isopropenyl group, we
decided to oxidize the double bond to a methyl ketone and
epimerize it. A quick computational study (MacSpartan Pro,
AM1) showed the desired isomer (8R)-40 to be 1.6 kcal/
mol more stable than its epimer (8S)-39.
Reduction of ketone 37 proved troublesome. The proce-
dure described by Schmuff and Trost afforded 38 in a
moderate 52% yield (Scheme 8).18 Ozonolysis of 38 provided
ketone 39 in 87% yield. To our delight, epimerization of
(8S)-39 with a catalytic amount of sodium methoxide in
methanol afforded ketone (8R)-40 in quantitative yield.
Wittig reaction to reinstall the double bond afforded ketal
41 in 99% yield.
42 having the correct stereochemistry on all stereogenic
centers was confirmed by X-ray. Finally, treatment of 42
with Ph3P and CCl4, in CH3CN afforded chloro ketone ent-4
in 72% yield, along with 22% of unreacted starting material.20
To conclude, we have developed an approach to the
synthesis of variecolin via a modified annulation procedure.
Efforts are underway to synthesize the correct enantiomers
of each component fragment, and more efficient second-
generation syntheses of these fragments along with improved
methods to couple them are being investigated.
Acknowledgment. We thank the National Institutes of
Health (GM35249) and Merck & Co., Inc., for funding this
work. A FAPESP Postdoctoral Fellowship to L.F.S.,
Deutsche Forschungsgemeinschaft (DFG) Postdoctoral Fel-
lowship to M.S.Q., and NATO Postdoctoral Fellowship to
J.B. are gratefully acknowledged. We also thank Prof. H. J.
Gais for useful information and Dr. Patrick Carroll for X-ray
analyses.
Supporting Information Available: Experimental pro-
cedures and characterization of all novel compounds and
X-ray data. This material is available free of charge via the
Internet at http://pubs.acs.org.
Deprotection of the ketal 41 to the corresponding hemiketal
42 with catalytic amounts of PdCl2(MeCN)2 in a mixture of
CH3CN and H2O occurred in 85% yield.19 The structure of
OL015763L
(15) Khurana, J. M.; Gogia, A. Org. Prep. Proced. Int. 1997, 29, 1-32.
(16) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 49, 4155-4156.
(b) Corey, E. J.; Huang, A. X. J. Am. Chem. Soc. 1999, 121, 710-714.
(17) Krafft, M. E.; Dasse, O. A.; Fu, Z. J. Org. Chem. 1999, 64, 2475-
2485.
(19) (a) Kharasch, M. S.; Seyler, R. C.; Mayo, F. R. J. Am. Chem. Soc.
1938, 60, 882-884. (b) Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki,
H. Tetrahedron Lett. 1985, 26, 705-708. (c) Molander, G. A.; Ro¨nn, M.
J. Org. Chem. 1999, 64, 5183-5187
(18) Schmuff, N. R.; Trost, B. M. J. Org. Chem. 1983, 48, 1404-1412
(20) Appeal, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801-811.
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