Synthesis of the C12-C19 fragment of (+)-peloruside a through A diastereomer-discriminating RCM reaction

Article abstract of DOI:10.1021/ol050588k

(Chemical Equation Presented) A short and efficient asymmetric synthesis of the C12-C19 fragment of the cytotoxic macrolide (+)-peloruside A has been achieved via a highly diastereomer-discriminating RCM of α-branched but-3-enoate ester of a methallylic a

Full text of DOI:10.1021/ol050588k

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2225-2228
Synthesis of the C12
−C19 Fragment of
(+
)-Peloruside A through a
Diastereomer-Discriminating RCM
Reaction
Emmanuel Roulland and Mikhail S. Ermolenko*
Institut de Chimie des Substances Naturelles, CNRS, aVenue de la Terrasse, 91198
Gif-sur-YVette, France
mikhail.ermolenko@icsn.cnrs-gif.fr
Received March 17, 2005
ABSTRACT
A short and efficient asymmetric synthesis of the C12
highly diastereomer-discriminating RCM of
)-propylene oxide.
−
C19 fragment of the cytotoxic macrolide (
+
)-peloruside A has been achieved via a
r
-branched but-3-enoate ester of a methallylic alcohol derived from hydrolytically resolved (S)-
(
−
(+)-Peloruside A 1 is a secondary metabolite isolated from
a New Zealand marine sponge, Mycale hentscheli.1 This 16-
membered macrolide possesses potent taxol-like cytotoxic
properties acting on the cell mitotic process at the G2 stage
through a mechanism blocking microtubule depolymeriza-
tion.2 Peloruside A is less lipophilic than paclitaxel and binds
to a different site on tubulin. These properties make this
compound a promising candidate for the development of new
anticancer agents, especially for multidrug-resistant solid
tumors. The structure and relative stereochemistry of peloru-
side A have been determined by spectroscopic methods,
while its absolute stereochemistry was presumed to be related
to another cytotoxic natural product, bryostatin. A number
of synthetic approaches toward peloruside A were built upon
this assumption,3 culminating in the total synthesis of the
nonnatural (-)-peloruside A,3a the subsequent efforts being
directed toward the naturally occurring enantiomer 1.4
We envisioned completion of the synthesis of (+)-
peloruside A 1 (Scheme 1) occurring through an aldol
Scheme 1. Retrosynthetic Scheme
(1) West, L. M.; Northcote, P. T.; Battershill, C. N. J. Org. Chem. 2000,
65, 445-449.
(2) (a) Hood, K. A.; Ba¨ckstro¨m, B. T.; West, L. M.; Northcote, P. T.;
Berridge, M. V.; Miller, J. H. Anti-Cancer Drug Des. 2001, 16, 155-166.
(b) Hood, K. A.; West, L. M.; Rouwe´, B.; Northcote, P. T.; Berridge, M.
V.; Wakefield, S. J.; Miller, J. H. Cancer Res. 2002, 62, 3356-3360.
reaction between ketone 2 and aldehyde 3 to create the C11-
C12 bond followed by stereoselective reduction of the C11
ketone function and macrolactonization. The synthesis of the
10.1021/ol050588k CCC: $30.25
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C12-C19 fragment 2 relies on the ring-closing metathesis
(RCM) of the diene ester 5 derived from the secondary
methallylic alcohol 6 and R-branched but-3-enoic acid 7, as
a method for stereospecific creation of the Z double bond.
In the course of our work, we discovered an unprecedented
example of diastereomer-discriminating RCM that dramati-
cally shortens the synthesis.
Scheme 3. Synthesis of (R)-2-Ethylbut-3-enoic Acid 7
The allylic alcohol 6 (Scheme 2) was obtained from (S)-
Scheme 2. Synthesis of Allylic Alcohol 6
The coupling of alcohol 6 and acid 7 using classical DCC/
DMAP esterification conditions proceeded in a disappoint-
ingly low yield (40-57%) and was accompanied by a severe
racemization of the acid to give an inseparable mixture of
esters 5R and 5S. A concurrent ketene pathway10 is suspected
for this loss of stereointegrity. Prior to tackling the ester
preparation issue, we subjected a small sample of diene (5R/
5S ) 6/4) to a RCM test with second-generation Grubbs’
catalyst, (PCy3)(H2IMes)Cl2RudCHPh, in refluxing CH2Cl2.
The reaction was sluggish and appeared incomplete after 3
days. However, when the main components of the reaction
were isolated, we were delighted to find that an unexpected
resolution of the diastereomers had taken place. Thus,
unreacted diene ester was recovered as an almost pure 5S
isomer, while diene 5R underwent the RCM giving the
required syn-lactone 4. The relative stereochemistry of the
substituents of lactone 4 was proved by the NOE observed
between H15 and H18 (Scheme 4).
propylene oxide 8 (98% ee) conveniently prepared in bulk
by hydrolytic kinetic resolution of the cheap racemate using
the (S,S)-salen-Co(III) complex.5
The reaction of epoxide 8 with 2-methyl-propenylmag-
nesium bromide in the presence of a catalytic amount of CuI
led to homoallylic alcohol 9.6 VO(acac)2-catalyzed epox-
idation of 9 afforded the volatile, water-soluble epoxy alcohol
10, which could not be isolated in high yield using the
standard aqueous workup procedure.7 Therefore, crude epoxy
alcohol 10, obtained by a careful concentration of the reaction
mixture, was directly protected as 4-methoxybenzyl (MPM)
ether 11. Without further purification, the epoxide was
rearranged by treatment with i-Pr2NMgBr8 furnishing meth-
allylic alcohol 6 (dr 95:5, by GC and NMR) in 71% overall
yield from 8. The preparation of 6 only required one short
column chromatography, the final purification being per-
formed by distillation.
In a scale-up preparation, two additional minor lactones
were also isolated in comparable yields (ca. 5% of each).
The first of them, 4a, possessed anti relative stereochemistry,
as evidenced by the observed H14/H18 NOE. To confirm
the structure of 4a as a RCM product from (S)-2-ethylbut-
3-enoate 5S, a sample of recovered pure ester 5S was treated
with Grubbs’ catalyst (10 mol %) for an extended reaction
time (5 days). Indeed, lactone 4a was isolated but was found
to be a minor product, the major one being syn-lactone 4
(4/4a ) 2/1), along with a mixture of linear dimers. Thus,
(R)-2-ethylbut-3-enoate 5R undergoes a RCM, while the
slow-reacting ester 5S mainly isomerizes into 5R, thus
rendering a dynamic kinetic resolution possible. However,
this isomerization is slow, and more investigations are
necessary to understand the mechanism involved in this step
and to make the overall process truly efficient. Studies on
the mechanism of this isomerization are currently in progress
in our laboratory.
The required (R)-2-ethylbut-3-enoic acid 7 was prepared
in ca. 30% overall yield from the commercially available
(E)-pent-2-en-1-ol by adapting the known method9 using a
regioselective oxirane ring opening of the protected epoxy
alcohol 12, as shown in Scheme 3.
(3) (-)-Peloruside A: (a) Liao, X.; Wu, Y.; De Brabander J. K. Angew.
Chem., Int. Ed. 2003, 42, 1648-1652. (b) Paterson, I.; Di Francesco, M.
E.; Ku¨hn, T. Org. Lett. 2003, 5, 599-602. (c) Ghosh, A. K.; Kim, J.-H.
Tetrahedron Lett. 2003, 44, 3967-3969. (d) Ghosh, A. K.; Kim, J.-H.
Tetrahedron Lett. 2003, 44, 7659-7661. (e) Gurjar, M. K.; Pedduri, Y.;
Ramana, C. V.; Puranik, V. G.; Gonnade, R. Tetrahedron Lett. 2004, 45,
387-390.
(4) (+)-Peloruside A: (a) Taylor, R. E.; Jin, M. Org. Lett. 2003, 5, 4959-
4961. (b) Lui, B.; Zhou, W.-S. Org. Lett. 2004, 6, 71-74. (c) Engers, D.
W.; Bassindale, M. J.; Pagenkopf, B. L. Org. Lett. 2004, 6, 663-666. (d)
Jin, M.; Taylor, R. E. Org. Lett. 2005, 7, 1303-1305 (total synthesis).
(5) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 936-938. (S)-Propylene oxide (99% ee) is also commercially
available from Aldrich.
The second minor lactone 4b (syn isomer, as determined
by NOE) was identified as the RCM product derived from
the allylic alcohol 6a present in 6 (vide supra). This was
proved by its directed synthesis, as shown in the Scheme 4.
(6) Wolfe, S.; Zhang, C.; Johnston, B. D.; Kim, C.-K. Can J. Chem.
1994, 72, 1066-1075.
(7) Minhelich, E. D.; Daniels, K.; Eickhoff, D. E. J. Am. Chem. Soc.
1981, 103, 7690-7692.
(8) Corey, E. J.; Marfat, A.; Falck, J. R.; Albright, J. O. J. Am. Chem.
Soc. 1980, 102, 1433-1435.
(9) Kitano, Y.; Kobayashi, Y.; Sato, F. J. Chem. Soc., Chem. Commun.
1985, 498-499.
(10) (a) Lombardo, L. Tetrahedron Lett. 1985, 26, 381-384. (b) Hudicky,
T.; Radesca, L.; Rigby, H. L. J. Org. Chem. 1987, 52, 4397-4399.
2226
Org. Lett., Vol. 7, No. 11, 2005

Scheme 4. Preparation of Diene Esters and RCM
Both minor isomers 4a and 4b were easily separable from
our target lactone 4 that ensured a high enantiomeric purity
of the C12-C19 fragment 2.
C5, and the exo-Cl of the catalyst maintains the lactone ring
puckering, which reinforces the essential steric strains on
the endo side of the transition state. Consistently, the
calculations predict a significant loss of selectivity for diene
esters lacking the branching methyl at this position. This is
in accordance with available experimental observations.13
The lactone product distribution, determined at 15%
conversion, revealed the unprecedented level of diastereomer
discrimination in RCM for this archetype of diene substrates
(4/4a g 44/1, starting from 5R/5S ) 44/56). Several selective
RCM reactions have recently been reported;11 however, to
the best of our knowledge, no prominent selectivity for the
metathesis cyclization leading to â,γ-unsaturated δ-lactones12
or lactams13 has been described so far.
The theoretical investigation of credible reaction pathways
by semiempirical (MP3) calculations allowed us to locate
the transition states of RCM for ester dienes 5 and to identify
synergetic steric interactions responsible for the observed
selectivity. The bulky ruthenium catalyst occupies an equato-
rial position (Figure 1).
The lowest energy transition state for RCM of diene 5S
was calculated to be ca. 4 kcal/mol less favorable, as
compared to its 5R isomer, in good qualitative agreement
with the data calculated from the selectivity observed
(∆∆Ecalcd g 2.52 kcal/mol). Assuming the entirely reversible
mechanism of olefin metathesis reaction,14 the slow-reacting
diene ester 5S should mainly be regenerated from the
corresponding ruthenium carbene complex by the available
terminal alkenes or should undergo a cross-metathesis
reaction to give a linear dimer.
It became obvious that the serious problems of esteri-
fication of alcohol 6 could be circumvented, and the synthesis
advantageously simplified, by exploiting the discovered
diastereomer-discriminating RCM reaction. Indeed, the es-
terification of alcohol 6 with crotonoyl chloride in triethyl-
amine gave the â,γ-unsaturated ester 16, which was alkylated
by ethyl iodide to furnish a mixture of dienes 5R and 5S
(ca. 4/6 by 1H NMR). Under the RCM conditions described,
this mixture afforded lactone 4 in a 36% yield (95% based
on 5R present) along with the unreacted diene ester that was
recovered as an almost pure diastereomer 5S (>95% by 1H
NMR). The recovered ester was then treated with LDA in
(11) (a) Evans, P. A.; Cui, J.; Buffone, G. P. Angew. Chem., Int. Ed.
2003, 42, 1734-1737 and references therein. (b) Van de Weghe, P.; Aoun,
D.; Boiteau, J.-G.; Eustache, J. Org. Lett. 2002, 4, 4105-4108. (c) Deiters,
A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-2238. (d) Hoye, T. R.;
Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc.
2004, 126, 10210-10211.
Figure 1. Transition state of RCM for 5S (truncated).
The difference in the transition state energies for the
diastereomeric substrates is mainly due to the steric interac-
tion between the endo-Cl atom, a substituent at C2 (H for
5R, Et for 5S), and H5 of the lactone cycle. The steric
interaction between methyl group at C4, the substituent at
(12) Andeana, P. R.; McLellan, J. S.; Chen, Y.; Wang, P. G. Org. Lett.
2002, 4, 3875-3878.
(13) Boucard, V.; Sauriat-Dorizon, H.; Guibe´, F. Tetrahedron 2002, 58,
7275-7290.
(14) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Chem. Soc., Chem.
Commun. 1997, 3887-3897.
Org. Lett., Vol. 7, No. 11, 2005
2227

THF at -78 °C, and the enolate thus formed was quenched
by addition of acetic acid to provide a mixture of diene esters
5R and 5S (ca. 1/1 as estimated by NMR), which can be
directly recycled in a new RCM sequence.
Despite the inconvenience of a recycling procedure, this
method has a significant advantage since it avoids a lengthy
preparation of (R)-2-ethylbut-3-enoic acid 7. The unique
source of chirality of lactone 4 thus becomes the highly
efficient, recyclable (S,S)-salen-Co(III) catalyst.
primary alcohol function of diol 17 was selectively silylated
(18), and the secondary alcohol function was protected as a
3-methoxybenzyl (3-MPM) ether to give 19. The following
selective oxidative cleavage15 of the 4-methoxybenzyl ether
led to alcohol 20 from which the targeted C12-C19 fragment
of (+)-peloruside A, the ketone 2, was obtained using Ley’s
oxidation (TPAP/NMO).
The optical rotation of ketone 2 ([R]23 -21.3 (c 1.3,
D
CHCl3)) is in good agreement with the data reported for the
closely related MPM-protected enantiomer described by
The enantiomerically pure lactone 4 was then cleanly
reduced to diol 17 using LiAlH4 in THF (Scheme 5). The
Paterson ([R]20 +22.4 (c 1.3, CHCl3)).3b
D
In summary, the C12-C19 fragment 2 of (+)-peloruside
A has been synthesized in 11 steps from epoxide 8 in a 13%
overall yield (not taking into account the possibility of
recycling the unreacted diene 5S; average step efficiency )
83%) or in ca. 20% yield after one two-step recycling of
diene ester 5S (average step efficiency ) 88%). The key
step of this synthesis, an unprecedented diastereomer-
discriminating RCM reaction leading to lactones, seems to
have significant potential in the synthesis of polyketide
natural products. Further investigations along this line are
currently in progress and will be reported in due course.
Scheme 5. C12-C19 Fragment of (+)-Peloruside A
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL050588K
(15) Nakajima, N.; Abe, R.; Yonemitsu, O. Chem. Pharm. Bull. 1988,
36, 4244-4247.
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