Stereoselective synthesis of microcarpalide.

Article abstract of DOI:10.1021/ol0265463

The first total synthesis of the naturally occurring nonenolide, microcarpalide, is described. The key step in the synthesis was the ring-closing metathesis of a dienic ester prepared in turn by coupling an acid and an alcohol stereoselectively synthesize

Full text of DOI:10.1021/ol0265463

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3447-3449
Stereoselective Synthesis of
Microcarpalide
,†
Juan Murga,† Eva Falomir,† Jorge Garc´ıa-Fortanet,† Miguel Carda,* and
,‡
J. Alberto Marco*
U.P. de Qu´ımica Inorga´nica y Orga´nica, UniVersidad Jaume I, Castello´n,
E-12080 Castello´n, Spain, and Departamento de Qu´ımica Orga´nica,
UniVersidad de Valencia, E-46100 Burjassot, Valencia, Spain
alberto.marco@uV.es
Received July 17, 2002
ABSTRACT
The first total synthesis of the naturally occurring nonenolide, microcarpalide, is described. The key step in the synthesis was the ring-closing
metathesis of a dienic ester prepared in turn by coupling an acid and an alcohol stereoselectively synthesized from (S,S)-tartaric acid and
(R)-glycidol, respectively.
From fermentation broths of an unidentified endophytic
fungus growing on the bark of Ficus microcarpa L., T.
Scheme 1
Hemscheidt and co-workers were able to isolate a cytotoxic
lactone, which they named microcarpalide. The compound
showed strong antimicrofilament activity and was shown to
have structure 1 by means of spectroscopic methods. Its
absolute configuration was determined with the aid of the
exciton chirality method.1
Within our recently initiated program on the synthesis of
natural lactones using ring-closing metathesis (RCM) as one
of the key steps,2 we have devised a stereoselective syntheses
for nonenolide 1. The retrosynthetic analysis is depicted in
Scheme 1. The macrocyclization step relies on a RCM of
diolefinic ester 2. Disconnection of the ester bond in 2 leads
to chiral nonracemic fragments 3 and 4 (MOM ) meth-
oxymethyl),3 derived in turn from (S,S)-tartaric acid and (R)-
glycidol 5, respectively.
† Universidad Jaume I, Castello´n.
‡ Universidad de Valencia.
(1) Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T.
Org. Lett. 2001, 3, 3479-3481.
(2) (a) Carda, M.; Castillo, E.; Rodr´ıguez, S.; Marco, J. A. Tetrahedron
Lett. 2000, 5511-5513. (b) Carda, M.; Rodr´ıguez, S.; Segovia, B.; Marco,
The known acid 3 was readily prepared from (S,S)-tartaric
acid by means of a literature procedure.4 Homoallylic alcohol
4 was prepared from 5 as described in Scheme 2. Silylation
J. A. J. Org. Chem. 2002, 67, 6560-6563.
(3) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; 3rd ed.; Wiley and Sons: New York, 1999; pp 27-33.
10.1021/ol0265463 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/30/2002

Scheme 2a
Scheme 3a
a Reagents and conditions: (a) (i) TPSCl, Et3N, DMAP, CH2Cl2,
rt, 18 h, 93%; (ii) CH3(CH2)4MgBr, CuI, THF, -30 °C, 87%. (b)
MOMCl, Et3N, DMAP, CH2Cl2, rt, 18 h, 87%. (c) TBAF, THF, 5
h, rt, 93%. (d) (COCl)2, DMSO, CH2Cl2, -78 °C, 30 min, then
N,N-diisopropyl ethylamine, 2 min at -78 °C, then rt. (e)
Bu3SnCH2CHdCH2, MgBr2‚Et2O, 3 Å MS, CH2Cl2, 3 h at -78
°C, then 1.5 h at -40 °C, 60% combined yield of the two last
steps.
of the hydroxyl group of 55 followed by epoxide opening
with a n-pentyl cuprate reagent6 afforded alcohol 6, which
was then protected as its MOM derivative 7. Desilylation of
the latter to 8 followed by Swern oxidation under mild
conditions7 afforded R-alkoxy aldehyde 98 which, without
purification, was immediately allowed to react with allyl tri-
n-butylstannane in the presence of MgBr2‚Et2O (chelation
control conditions).9 This provided 4 in good yield and with
high stereoselectivity (dr was judged to be g98%, as the
minor stereoisomer was not detected by means of high-field
1H and 13C NMR).
Carboxylic acid 3 was then coupled with alcohol 4 to yield
diene ester 10 (Scheme 3). This reaction set the stage for
the crucial RCM, which was successful with ruthenium
catalyst A.10 Thus, a 0.001 M solution of 10 and 20 mol %
of A was heated at reflux for 24 h in dry, degassed CH2Cl2.
This provided a 2:1 E/Z mixture of macrocyclic lactones from
which the (E)-isomer 11 was isolated by means of column
chromatography on silica gel. It is worth mentioning here
that the use of the second-generation ruthenium catalyst B11
gave rise to the almost exclusive formation of (Z)-11. Similar
a Reagents and conditions: (a) DCC, DMAP, CH2Cl2, rt, 18 h,
86%. (b) 20 mol % of catalyst A, CH2Cl2, reflux, 24 h (see text),
67%. (c) SMe2, BF3‚Et2O, -10 °C, 30 min, 71%. (d) (CH2SH)2,
BF3, CH2Cl2, 0 °C, 1 h, 66%.
differences in behavior between these catalyst types have
previously been observed by Fu¨rstner and co-workers in their
approach to other natural nonenolides.12 One of the catalysts
these authors used was structurally similar to A but had an
indenylidene group instead of the benzylidene moiety. The
other catalyst was close to B but with an additional CdC
bond in the imidazole ring. They attributed the different
stereochemical outcome to the higher activity of the imida-
zolylidene-substituted catalyst, which was able to isomerize
the CdC bond of the RCM product. In consequence, the
E/Z ratio was no longer kinetically controlled but rather the
result of a chemical equilibrium. This caused a marked
enhancement in the percentage of the (Z)-isomer, which in
(11) For recent examples of uses of this catalyst type, see: (a) Scholl,
M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999,
2247-2250. (b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953-956. (c) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1,
1751-1753. (d) Briot, A.; Bujard, M.; Gouverneur, V.; Nolan, S. P.;
Mioskowski, C. Org. Lett. 2000, 2, 1517-1519. (e) Wright, D. L.; Schulte,
J. P., II; Page, M. A. Org. Lett. 2000, 2, 1847-1850. (f) Lee, C. W.; Grubbs,
R. H. Org. Lett. 2000, 2, 2145-2147. (g) Morgan, J. P.; Grubbs, R. H.
Org. Lett. 2000, 2, 3153-3155. (h) Ackermann, L.; El Tom, D.; Fu¨rstner,
A. Tetrahedron 2000, 56, 2195-2202. (i) Fu¨rstner, A.; Thiel, O. R.;
Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204-
2207. (j) Heck, M. P.; Baylon, C.; Nolan, S. P.; Mioskowski, C. Org. Lett.
2001, 3, 1989-1991. (k) Kinderman, S. S.; van Maarseveen, J. H.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Org. Lett. 2001, 3,
2045-2048.
(12) Fu¨rstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C.
W.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061-7069. For creation of
medium-sized rings via RCM and previous examples of reversibility during
these processes, see pertinent citations in this paper. Catalyst A is also able
to induce E-Z isomerizations: Kalesse, M.; Quitschalle, M.; Claus, M.;
Gerlach, K.; Pahl, A.; Meyer, H. H. Eur. J. Org. Chem. 1999, 2817-2823.
(4) Batty, D.; Crich, D. J. Chem. Soc., Perkin Trans. 1 1992, 3193-
3204.
(5) Hanson, R. M. Chem. ReV. 1991, 91, 437-475.
(6) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-631.
(7) Dondoni, A.; Perrone D. Synthesis 1997, 527-529. Racemization
of aldehyde 8 was minimized when N,N-diisopropyl ethylamine was used
as the base (ee of 8 was judged to be g98% in an indirect way, because no
minor stereoisomers were detected by high-field NMR analysis of crude
ester 10).
(8) Both racemic and enantiomerically pure (R)-9 have been previously
synthesized using a different methodology. See: (a) Banfi, L.; Bernardi,
A.; Colombo, L.; Gennari, C.; Scolastico, C. J. Org. Chem. 1984, 49, 3784-
3790. (b) Banfi, L.; Cabri, W.; Poli, G.; Potenza, D.; Scolastico, C. J. Org.
Chem. 1987, 52, 5452-5457.
(9) For recent reviews on reactions with allyl tin reagents: (a) Nishigaichi,
Y.; Takuwa, A.; Naruta, Y.; Maruyama, K. Tetrahedron 1993, 49, 7395-
7426. (b) Yamamoto, Y.; Shida, N. AdVances in Detailed Reaction
Mechanisms 1994, 3, 1-44.
(10) (a) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (b)
Trnka, T.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
3448
Org. Lett., Vol. 4, No. 20, 2002

their molecules was shown to be the thermodynamically
more stable one. In the case of lactone 11, theoretical
calculations have shown that the (Z)-isomer is more stable
than the (E)-isomer by about 2 kcal/mol.13 Consequently,
the same explanation proposed by Fu¨rstner et al. might be
valid here.
Selective removal of the MOM group in 11 was feasible
under mild conditions14 and furnished acetonide 12, the
properties of which (NMR, MS) were identical to those
reported.1 Preparation of the target molecule 1 was finally
achieved by one-pot removal of all protecting groups in
compound 11.15 The physical and spectral properties of
synthetic 1 turned out to be identical to those reported for
the natural compound. As reported by Hemscheidt and co-
workers for the natural product,1 the NMR spectra of
synthetic 1 at room temperature revealed the presence of two
slowly interconverting conformers in an approximate 3-3.5:1
ratio.
In summary, a convergent, stereoselective synthesis of the
pharmacologically active lactone 1 has been achieved with
two commercially available, chiral reagents (R)-glycidol and
(S,S)-tartaric acid as the starting materials. Minor modifica-
tions of the synthetic route described above will lead to
nonnatural diastereoisomers of the natural lactone, to be used
for studies on relationships between structure and pharma-
cological activity. Such studies are underway and will be
published soon.
Acknowledgment. Financial support has been granted by
the Spanish Ministry of Education (DGICYT project
BQU2002-00468) and by BANCAJA (Project P1B99-18).
J.M. thanks the Spanish Ministry of Science and Technology
for a Ramo´n y Cajal fellowship.
Supporting Information Available: 1H and 13C NMR
spectra of compounds 10-12 and 1, optical rotation values
and tabulated IR data of 10-12 and 1, and MS data of 10-
12. This material is available free of charge via the Internet
at http://pubs.acs.org.
(13) Theoretical calculations were first performed at the semiempirical
level (AM1) and gave a difference in energy contents of 2 kcal/mol between
both stereoisomers. When the calculations were made with ab initio methods
(HF/3-21G), the difference turned out to be 1.9 kcal/mol.
(14) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J. Org.
Chem. 1995, 60, 4419-4427. See also: Fuji, K.; Kawabata, T.; Fujita, E.
Chem. Pharm. Bull. 1980, 28, 3662-3664.
(15) Sinha, S. C.; Keinan, E. J. Org. Chem. 1997, 62, 377-386.
OL0265463
Org. Lett., Vol. 4, No. 20, 2002
3449