Concise total synthesis of (-)-muricatacin by tandem ring-closing/cross metathesis

Article abstract of DOI:10.1021/ol040047f

(Chemical Equation Presented) A strategy for the synthesis of chiral 5-(1-hydroxyalk-2-enyl)-5H-furan-2-ones and its application to the total synthesis of (-)-muricatacin, in four steps and 37% overall yield from (R,R)-hexa-1,5-diene-3,4-diol, are describ

Full text of DOI:10.1021/ol040047f

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4143-4145
Concise Total Synthesis of
)-Muricatacin by Tandem Ring-Closing/
(−
Cross Metathesis
Kevin J. Quinn,* Andre´ K. Isaacs, and Rebecca A. Arvary
Department of Chemistry, College of the Holy Cross,
Worcester, Massachusetts 01610-2395
kquinn@holycross.edu
Received July 9, 2004
ABSTRACT
A strategy for the synthesis of chiral 5-(1-hydroxyalk-2-enyl)-5H-furan-2-ones and its application to the total synthesis of (−)-muricatacin, in
four steps and 37% overall yield from (R,R)-hexa-1,5-diene-3,4-diol, are described. The key synthetic step in this approach is a highly regioselective
and stereoselective tandem ring-closing/cross metathesis reaction in which both lactone formation and alkyl chain extension are accomplished
in an efficient one-pot process.
The chiral 5-hydroxyalkylbutan-4-olide nucleus is an integral
structural component of an ever increasing number of
biologically and chemically significant natural products,
including many members of the Annonaceous acetogenin
family.1 (-)-Muricatacin (1, Scheme 1) is a simple example.
1 is isolated as the major component of a scalemic mixture
(ca. 25% ee based on optical rotation) from the seeds of
Annona muricata and has received a great deal of attention
due to its diverse biological profile.2 Notably, both 1 and its
enantiomer exhibit potent cytotoxicity toward several human
tumor cell lines with SAR studies showing that activity is
influenced significantly by the nature of the side chain.3 In
addition to their interesting biological properties, muricatacin
and related hydroxylactones have served as precursors in
syntheses of more complex acetogenins and other natural
products.4 The biological and chemical potential of muri-
catacin has prompted many syntheses;5 however, develop-
ment of general and flexible strategies for the preparation
of more highly functionalized side chain analogues6 and other
hydroxyalkylbutanolide natural products remains a goal.
Herein, we report an approach to the synthesis of (R,R)-
5-hydroxyalkylbutan-4-olides and demonstrate its utility by
application to the total synthesis of (-)-muricatacin. Our
retrosynthetic analysis is outlined in Scheme 1. Key to our
approach is the recognition that protected 5-(1-hydroxyalk-
Scheme 1. Retrosynthetic Analysis
(1) For reviews, see: (a) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J.
Nat. Prod. 1999, 62, 504. (b) Zafra-Polo, M. C.; Figadere, B.; Gallardo,
T.; Tormo, J. R.; Cortes, D. Phytochemistry 1998, 48, 1087.
(2) Rieser, M. J.; Kozlowski, J. F.; Wood, K. V.; McLaughlin, J. L.
Tetrahedron Lett. 1991, 32, 1137.
(3) Cave, A.; Chaboche, C.; Figadere, B.; Harmange, J. C.; Laurens, A.
Peyrat, J. F.; Pichon, M.; Szlosek, M.; Cotte-Lafitte, J.; Quero, A. M. Eur.
J. Med. Chem. 1997, 32, 617.
10.1021/ol040047f CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/12/2004

stannylene acetal of 5.11 Subsequent acylation of the remain-
ing hydroxyl with acryloyl chloride provided easy access to
triene 4 in 70% yield over two steps and set the stage for
examination of the proposed metathesis reaction.
Scheme 2. Preparation and RCM of 4
To establish the feasibility of our approach, we first needed
to determine the regiochemical outcome of ring-closing
metathesis of 4. Two modes of closure, metathesis between
the acrylate group and either the proximal olefin to give 3
or the distal olefin to give 6, are possible (Scheme 2). At
the outset, it was unclear which pathway would be favored;
however, both 3 and 6 are potentially valuable synthetic
intermediates, so we felt that either outcome would be
productive. In the event, we found that treatment of 4 with
10 mol % of the second generation Grubbs’ catalyst 712 in
either refluxing PhH or CH2Cl2 resulted in the formation of
3 as the only isolable product in 52 and 58% yield,
respectively. The assignment of 3 as the RCM product was
based on the relatively large downfield shifts of the â proton
(7.47 ppm) in the 1H NMR spectrum and the carbonyl carbon
(172.6 ppm) in 13C NMR spectrum and later confirmed by
comparison (vide infra). In a preliminary examination of the
effect of the protecting group on regioselectivity, we found
that RCM of the TBS-protected analogue of 4 also gave only
the five-membered lactone product (55%). Efforts to ma-
nipulate the observed RCM regiochemistry to provide for
complementary preparation of dihydropyranones such as 6
are in progress.
2-enyl)-5H-furan-2-ones, such as muricatacin precursor 2,
could be constructed directly from acyclic trienes (4) by a
tandem process in which lactone ring formation and chain
extension are achieved by olefin metathesis. Initial ring-
closing metathesis7 (RCM) of 4 would provide an intermedi-
ate butenolide 3, in which the two olefins are clearly
differentiated by their electronic environments. Intermolecu-
lar cross metathesis8 (CM) between the terminal olefin of 3
and an alkene coupling partner (RCHdCH2) would complete
the tandem to provide an extended hydroxyalkenylbutenolide
(2).9 Specific to our proposed muricatacin synthesis, benzyl-
protected acrylate ester 4, available from C2-symmetric
dienediol 5, and 1-dodecene would serve as substrates for
the RCM/CM tandem.
Encouraged by the yield and selectivity observed for RCM
of 4, we turned our attention to its incorporation into the
proposed RCM/CM process for the preparation of the chain-
extended butenolide 2. Two procedures were examined: a
sequential method in which the cross coupling partner (1-
dodecene) was added after RCM of 4 was complete and a
tandem method in which both 1-dodecene and triene 4 were
present at the time of addition of metathesis catalyst 7.13 Our
results are summarized in Table 1. For the sequential
procedure, a 0.005 M solution of triene 414 and catalyst 7
(10 mol %) in either PhH or CH2Cl2 was refluxed until TLC
analysis indicated complete conversion of 4 to RCM product
3 at which time 5 equiv of 1-dodecene was added (entries 1
and 2). At either temperature, conversion of 4 to 3 required
approximately 24 h. We were pleased to find that addition
of the alkene coupling partner resulted in completion of the
metathesis sequence to provide 2 in respectable overall yields.
CM generated 2 with complete (E)-selectivity for the acyclic
Preparation of metathesis substrate 4 began with (R,R)-
hexa-1,5-diene-3,4-diol 5, which is conveniently prepared
in multigram quantities from D-mannitol (Scheme 2).10
Desymmetrization was achieved by monobenzylation of the
(4) For examples, see: (a) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J.
Org. Chem. 2004, 69, 1993. (b) Sinha, S. C; Sinha, S. C; Keinan, E. J.
Org. Chem. 1999, 64, 7067. (c) Ha, J. D.; Cha, J. K. J. Am. Chem. Soc.
1999, 121, 10012. (d) Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996,
61, 7217.
(5) For recent syntheses of muricatacin, see: (a) Yoshimitsu, T.; Makino,
T.; Nagaoka, H. J. Org. Chem. 2003, 68, 7548. (b) Bernard, A. M.; Frongia,
A.; Piras, P. P.; Secci, F. Org. Lett. 2003, 5, 2923. (c) Popsavin, V.; Krstic,
I.; Popsavin, M. Tetrahedron Lett. 2003, 44, 8897. (d) Raghavan, S.; Joseph,
S. C. Tetrahedron: Asymmetry 2003, 14, 101. (e) Carda, M.; Rodriguez,
S.; Gonzalez, F.; Castillo, E.; Villanueva, A.; Marco, J. A. Eur. J. Org.
Chem. 2002, 15, 2649. (f) Chandrasekhar, M.; Chandra, K. L.; Singh, V.
K. Tetrahedron Lett. 2002, 43, 2773. (g) Konno, H.; Hiura, N.; Yanura,
M. Heterocycles 2002, 57, 1793. (h) Baylon, C.; Prestat, G.; Heck, M. P.;
Mioskowski, C. Tetrahedron Lett. 2000, 41, 3833. (i) Trost, B. M.; Rhee,
Y. H. J. Am. Chem. Soc. 1999, 121, 11680. (j) Solladie, G.; Hanquet, G.;
Izzo, I.; Crumbie, R. Tetrahedron Lett. 1999, 40, 3071. (k) Couladouros,
E. A.; Mihou, A. P. Tetrahedron Lett. 1999, 40, 4861.
1
olefin as determined by H NMR (J ) 15.4 Hz). None of
the (Z)-isomer was detected.
For the tandem procedure, catalyst 7 (10 mol %) was
added to a 0.005 M solution of triene 414 and 5 equiv of
1-dodecene in either PhH or CH2Cl2, and the reaction
mixtures were heated to reflux. Considering the expected
rate difference for intra- vs intermolecular metatheses, we
(6) For two recently isolated examples, see: (a) Liaw, C. C.; Chang, F.
R.; Wu, M. J.; Wu, Y. C. J. Nat. Prod. 2003, 66, 279. (b) Xie, H. H.; Wei,
X. Y.; Wang, J. D.; Liu, M. F.; Yang, R. Z. Chin. Chem. Lett. 2003, 14,
588.
(7) For recent reviews on the use of ring-closing metathesis for the
synthesis of heterocycles, see: (a) Dieters, A.; Martin, S. F. Chem. ReV.
2004, 104, 2199. (b) Walters, M. A. Prog. Heterocycl. Chem. 2003, 15, 1.
(c) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
(8) For a recent review of olefin cross metathesis, see: Connon, S. J.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 2003, 42, 1900.
(9) For synthesis of δ-alkenyl â,γ-unsaturated δ-lactones by RCM/CM,
see: Virolleaud, M. A.; Bressy, C.; Piva, O. Tetrahedron Lett. 2003, 44,
8081.
(10) (a) Burke, S. D.; Sametz, G. M. Org. Lett. 1999, 1, 72. (b) Crombez-
Robert, C.; Benazza, M.; Frechou, C.; Demailly, G. Carbohydr. Res. 1997,
303, 359.
(11) Rama Rao, A. V.; Mysorekar, S. V.; Gurjar, M. K.; Yadav, J. S.
Tetrahedron Lett. 1987, 28, 2183.
(12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(13) For definitions of sequential and tandem reactions, see: Denmark,
S. E.; Thorasen, A. Chem. ReV. 1996, 96, 137.
(14) Yields were greatly diminished if reactions were performed at higher
concentration.
4144
Org. Lett., Vol. 6, No. 23, 2004

Scheme 3. Completion of the Synthesis of (-)-Muricatacin
Table 1. RCM/CM of 4 and 1-Dodecene
entry
procedure
solvent
time (h)a
yield (%)
concentration (0.01 M in 4) leading to an optimal yield of
65% (entry 7).
1
2
3
4
5b
6c
7c,d
sequential
sequential
tandem
tandem
tandem
PhH
CH2Cl2
PhH
CH2Cl2
PhH
CH2Cl2
CH2Cl2
38
48
32
42
44
18
12
49
55
20
57
55
60
65
Completion of the synthesis of required only reduction of
the olefins and removal of the benzyl protecting group. This
was accomplished smoothly by catalytic hydrogenation/
hydrogenolysis of 2 to give 1 as a white solid in 82% yield
(Scheme 3). (-)-Muricatacin produced in this manner
displays spectral data, optical rotation, and melting point
consistent with those reported the literature.2,5 (+)-Muri-
catacin should also be readily available from (S,S)-hexa-1,5-
diene-3,4-diol16 by this route.
tandem
tandem
a Reactions were considered complete when TLC indicated that 4 and
3, generated in situ, were no longer present. b Reaction performed at 40
°C. c Slow addition of 7 as a solution via syringe pump. d Concentration of
0.01 M in 4.
In summary, an efficient strategy for the synthesis of
5-hydroxyalkylbutan-4-olides via tandem RCM/CM has been
demonstrated by application to the total synthesis of (-)-
muricatacin. The flexibility inherent in this approach and the
high degree of functionality present in tandem products such
as 2 make it broadly applicable. Extension to the synthesis
of more complex Annonaceous acetogenins and other
oxygenated alkylbutyrolactone natural products is currently
underway, and results will be reported in due course.
anticipated that RCM would occur much faster than CM and,
thus, a timing of events similar to those under sequential
conditions. As such, we were surprised to find that tandem
reactions run at 80 °C gave much lower yields of 2 than
sequential reactions at the same temperature (entry 3). We
believe this is due to deleterious CM processes prior to RCM
at elevated temperature.15 Fortunately, the yield of 2 was
increased dramatically to 57% when the reaction was
conducted at 40 °C (entries 4 and 5). In these cases, RCM
product 3 was observed as the sole intermediate by TLC
prior to the formation of 2.
Although we were gratified by the success of tandem
RCM/CM, we hoped to reduce the extended times required
for completion. We felt that decomposition of catalyst 7 and/
or propagating catalytic species during the course of the
reaction was a possible cause. To better maintain a concen-
tration of active catalyst, 7 was added as a 0.01 M solution
over 8 h via syringe pump (entries 6 and 7). Using this
modification, we observed substantial reductions in comple-
tion times and found that reactions could be run at higher
Acknowledgment. Financial support from the Charles
and Rosanna Batchelor (Ford) Foundation, the Simeon A.
Fortin Charitable Trust, and Pfizer is gratefully acknowl-
edged. Mass spectral data were obtained at the University
of Massachusetts Mass Spectrometry Facility, which is
supported, in part, by the National Science Foundation.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for the monobenzyl derivative of 5 and compounds 4, 3, 2,
and 1. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL040047F
(15) As evidenced by the observation of products of CM between 4 and
1-dodecene by H NMR.
1
(16) King, S. H.; Ryu, D. H. J. Chem. Soc., Chem. Commun. 1996, 355.
Org. Lett., Vol. 6, No. 23, 2004
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