Total synthesis and structural confirmation of (+)-longicin

Article abstract of DOI:10.1021/ol051483k

(Chemical Equation Presented) A stereocontrolled total synthesis of (+)-longicin, a representative of the class of mono-THF-acetogenins, is described. The strategy involves the utilization of D- and L-glutamic acids as chirons that correspond to two five-carbon segments harboring stereogenic centers at C4 and at C17 of the C₃₂ polyketide-derived natural product. The use of Grubbs' RCM reaction as a novel "chain elongation" strategy for the synthesis of acetogenin-type structures and a new protocol for butenolide incorporation are also described.

Full text of DOI:10.1021/ol051483k

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3989-3992
Total Synthesis and Structural
Confirmation of ( )-Longicin
+
Stephen Hanessian,* Simon Giroux, and Maxime Buffat
Department of Chemistry, UniVersite´ de Montre´al, C.P. 6128, Succursale Centre-Ville,
Montre´al, Que´bec H3C 3J7, Canada
stephen.hanessian@umontreal.ca
Received June 24, 2005
ABSTRACT
A stereocontrolled total synthesis of (+)-longicin, a representative of the class of mono-THF-acetogenins, is described. The strategy involves
the utilization of - and -glutamic acids as chirons that correspond to two five-carbon segments harboring stereogenic centers at C4 and at
D
L
C17 of the C32 polyketide-derived natural product. The use of Grubbs’ RCM reaction as a novel “chain elongation” strategy for the synthesis
of acetogenin-type structures and a new protocol for butenolide incorporation are also described.
The acetogenin family of natural products is a class of
polyketide-derived metabolites originally isolated from tropi-
cal and subtropical plants commonly known as Annonacea.1
They are usually characterized by the presence of one or
more tetrahydrofuran units embedded within a long fatty acid
chain also bearing noncontiguous secondary hydroxyl groups.
This unique class of annonaceous acetogenins, represented
by several hundred well-defined structures, has attracted
particular attention due to their broad range of physiological
effects.1,2 Tumor cell death by apoptosis due to interference
with ATP supply via inhibition of mitochondrial complex I
is among the diverse biological modes of action of the
acetogenins.3 Their antitumor activity in particular4 has
instigated intense efforts toward the stereocontrolled total
synthesis of several members of this class.5,6 Indeed, there
are a number of reported total syntheses of acetogenins that
contain a central tetrahydrofuran ring,7 as well as those with
more than one ring.8
(4) (a) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.
Nat. Prod. Rep. 1996, 13, 276. (b) Oberlies, N. H.; Croy, V. L.; Harrison,
M. L.; McLaughlin, J. L. Cancer Lett. 1997, 115, 73. See also ref 1a,b.
(5) For relevant reviews, see: Hoppe, R.; Scharf, H. D. Synthesis 1995,
1447. Figade`re, B. Acc. Chem. Res. 1995, 28, 359. See also ref 1b. Marshall,
J. A.; Hinkle, K. W.; Hagedorn, C. E. Israel J. Chem. 1997, 37, 97.
(6) For a summary of synthetic approaches, see: Prestat, G.; Baylon,
C.; Heck, M.-P.; Grasa, G. A.; Nolan, S. P.; Mioskowski, C. J. Org. Chem.
2004, 69, 5770.
(7) For selected syntheses, see Solamin: (a) Trost, B. M.; Shi, Z. J. Am.
Chem. Soc. 1994, 116, 7459. (b) Sinha, S. C.; Keinan, E. J. Am. Chem.
Soc. 1993, 115, 4891. (c) Makabe, H.; Tanaka, A. J.; Oritani, T. J. Chem.
Soc. Perkin Trans. 1 1994, 1975. Kuriyama, W.; Ishigami, K.; Kitahara, T.
Heterocycles 1999, 50, 981. Corossolone: Yao, Z.-J.; W, Y.-L. J. Org.
Chem. 1995, 60, 1170. Reticulacin: ref 6b,c. Longifolicin: Marshall, J.
A.; Jiang, H. Tetrahedron Lett. 1998, 39, 1497. Murisolin: Zhang, Q.; Lu,
H.; Richard, C.; Curran, D. J. Am. Chem. Soc. 2004, 126, 36.
(8) See for example selected total syntheses: (a) Avedissian, H.; Sinha,
S. C.; Yazbak, A.; Sinha, A.; Neogi, P.; Sinha.S. C.; Keinan, E. J. Org.
Chem. 2000, 65, 6035. (b) Trost, B. A.; Calkins, T. L.; Bochet, C. G. Angew.
Chem. Int. Ed. 1997, 36, 2632. (c) Marshall, J. A.; Hinkle, K. W. J. Org.
Chem. 1997, 62, 5989. (d) Marshall, J. A.; Chem, M. J. Org. Chem. 1997,
62, 5996. (e) Wo¨krle, I.; Claben, A.; Peterek, M.; Scharf, H.-D. Tetrahedron
Lett. 1996, 37, 7001. (f) Makabe, H.; Tanimoto, H.; Tanaka, A.; Oritami,
T. Heterocycles 1997, 38, 4247. (g) Sinha, S. C.; Sinha, A.; Yazbak, A.;
Keinan. E. J. Org. Chem. 1996, 61, 7640. (h) Sinha, S. C.; Sinha, A.; Keinan,
E. J. Am. Chem Soc. 1998, 120, 4017. (i) Hoye, T. R.; Ye, Z. J. Am. Chem.
Soc. 1996, 118, 1801. (j) Naito, H.; Kawahara, E.; Maruta, M.; Sasaki, S.
J. Org. Chem. 1995, 60, 4419 and references therein.
(1) (a) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999,
62, 504. (b) Zafra-Polo, M.-C.; Figade`re, B.; Gallardo, T.; Tormo, J. R.;
Cortes, D. Phytochemistry 1998, 48, 1087. (c) Cave´, A.; Figade`re, B.;
Laurens, A.; Cortes, D. Progress in The Chemistry of Organic Natural
Products; Herz, W., Kirby, G.-W., Moore, R. E., Steglich, W., Tamm, Ch.,
Eds.; Springer-Verlag: New York, 1997, Vol. 70, pp 81-288. (d) Zeng.
L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J. L.
Nat. Prod. Rep. 1996, 13, 275.
(2) McLaughlin, J. L.; Chang, C.; Smith, D. L. Human Medicinal Agents
from Plants; Kinghorm, A. D., Balardin, M. F., Eds.; American Chemical
Society: Washington, DC, 1993; Chapter 9, p 117.
(3) See for example: (a) Gallardo, T.; Saez, J.; Granados, H.; Tormo, J.
R.; Velez, I. D.; Brun, N.; Torres, B.; Cortes, D. J. Nat. Prod. 1998, 61,
1001. (b) Oberlies, N. H.; Chang, C.-J.; McLaughlin, J. L. J. Med. Chem.
1997, 40, 2102. (c) Holligworth, R. M.; Ahmmadsahib, K. I.; Gadelhac,
G.; McLaughlin, J. L. Biochem. Soc. Trans. 1994, 22, 230.
10.1021/ol051483k CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/05/2005

In 1995, McLaughlin and co-workers9 reported the isola-
tion of longicin 1 and the C-18 epimer goniothalamicin from
Asimina longiolia (annonacea), commonly known as long
leaf paw paw (Figure 1). Longicin is reported to exhibit over
the latter reacted with C14H29MgBr in THF solution to afford
the corresponding ketone in 80% yield (Scheme 1).
Scheme 1. Synthesis of Intermediate 7
After several attempts to achieve anti selectivity in the
reduction of the ketone, it was found that n-Bu3SnH in the
presence of silica gel in a dichloromethane suspension12
provided the desired alcohol in an 81:19 diastereomeric ratio
that could be easily separated by chromatography.13 Protec-
tion of this alcohol as a MOM ether afforded 3 in excellent
overall yield.
Figure 1. Retrosynthetic analysis.
1 million-fold selective antitumor activity against pancreatic
cancer cells compared to adriamycin.9 This unique potency,
as well as an uncommon threo-trans-erythro stereochemical
pattern and the presence of the hydroxyl substituent specif-
ically at C10, prompted us to investigate its total synthesis.
In this Letter, we wish to report the first total synthesis,
stereochemical assignment, and structural confirmation of
longicin, 1. The disconnective analysis (Figure 1) relies on
a novel strategy that uses the venerable RCM reaction as a
“chain elongating” method to access advanced macrolactone
intermediates A and B independently. Thus, a disconnection
at C7-C8 in both A and B generates olefinic subunits that
can be accessed from the common lactone precursor C,
harboring the threo-trans-threo pattern. Lactone C can be
generated by the well-precedented vinylogous aldol-type
reaction10 on an oxocarbenium ion readily available from
D-glutamic acid (red). An eight-carbon carboxylic acid chain
elongator D that contains the C4 hydroxyl group and a
terminal olefin originates from L-glutamic acid (blue).
The readily available lactone 2, prepared in one step from
D-glutamic acid,11 was converted to the acyl chloride, and
The next crucial step involved a four-carbon extension
based on previous experience with annoanacin A.14 Thus,
lactone 3 was reduced with Dibal-H in toluene to the
corresponding hemiacetal and acetylated to give 4 in 78%
yield for the two steps. Addition of 2-trimethylsiloxyfuran
in the presence of BF3‚Et2O gave the desired trans junction
at C13 in a ratio >20:1 and a ratio of 1:1 at C12 in 93%
yield.10,15 The desired threo isomer 5 could be easily
separated from its erythro isomer 6 by flash column
chromatography. Catalytic hydrogenation of 5 and 6 afforded
the corresponding reduced lactones, which were treated with
HCl‚HN(OMe)Me in the presence of dimethylaluminum
chloride16 to afford amides 7 and 8 in excellent yields. The
undesired isomer 8 could be recycled through a Mitsunobu
inversion17 to give 7 in 56% yield for the two-step process.
Thus, the desired threo-trans-erythro isomer 7 could be
obtained in a combined overall yield of 55% from 4.
(11) Rouessac, F. P.; Gringore, O. H. Org. Synth. 1984, 63, 121.
(12) (a) Figade`re, B.; Chaboche, C.; Franck, X.; Peyrat, J.-F.; Cave´, A.
J. Org. Chem. 1994, 59, 7138. (b) Peyrat, J.-F.; Chaboche, C.; Figade`re,
B.; Cave´, A. Tetrahedron Lett. 1995, 36, 2757. See also: Fung, N. Y.; De
Mayo, P.; Schauble, J. H.; Weedon, A. C. J. Org. Chem. 1978, 43, 3977.
(13) Stereochemistry at C18 (longicin numbering) was confirmed by
X-ray crystallography; see Supporting Information.
(14) Hanessian, S.; Grillo, T. A. J. Org. Chem. 1998, 63, 1049.
(15) Stereochemistry at C13 and C14 (longicin numbering) was con-
firmed by X-ray crystallography; see Supporting Information.
(16) Levin. J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12,
989.
(9) Ye, Q.; Zeng, Lu.; Zhang, Y.; Zhao, G.-X.; McLaughlin, J. L. J.
Nat. Prod. 1995, 58, 1398.
(10) For examples of related reactions, see: (a) Zanardi, F.; Battistini,
L.; Rassu, G.; Pinna, L.; Mor, M.; Culeddu, N.; Casiraghi, G. J. Org. Chem.
1998, 63, 1368. (b) Casiraghi, G., Zanardi, F.; Battistini, L.; Rassu, G.;
Appendino, G. Chemtracts 1998, 11, 803 (c) Figade`re, B.; Peyrat, J.-F.;
Cave´, A. J. Org. Chem. 1997, 62, 3428. (d) Koert, U.; Stein, M.; Harms,
K. Tetrahedron Lett. 1993, 34, 2299. (e) Rassu G.; Spanu, G.; Casiraghi,
G.; Pinn, L. Tetrahedron 1991, 47, 8025. (f) Jefford, C. W.; Jaggi, D.;
Boukouvalas, J. Tetrahedron Lett. 1987, 28, 4037.
(17) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org. React.
1992, 42, 335.
3990
Org. Lett., Vol. 7, No. 18, 2005

Scheme 2. Total Synthesis of (+)-Longicin 1
Having secured the requisite threo-trans-erythro pattern
reaction with (-)-B-allyl(diisopinocampheyl)borane,20 and
the resulting alcohol (dr > 95:5) was protected as a MOM
ether to give diolefin 11 in 50% overall yield for three steps.
In the second approach, common precursor 7 was homolo-
gated to the allylic alcohol 12 in excellent overall yield.
Esterification with the chain-elongating acid 9 gave the
diolefin 13 in 83% yield.
With diolefins 11 and 13 in hand, we were ready to apply
the ester-tethered RCM macrocyclization21 to 14- (14) and
11-membered (15) ring lactones, respectively. Much to our
delight, in the presence of 5 mol % Grubbs’ second-
generation catalyst in refluxing CH2Cl2, 11 was smoothly
for the core THF subunit, the stage was set for the installation
of the olefinic partners as esters on strategically located
hydroxyl groups to carry out the respective “chain-elongat-
ing” RCM reactions, eventually leading to a common
advanced intermediate. In the first of two approaches,
acylation of 7 with acid 918 in the presence of DCC and
DMAP gave amide 10 in 98% yield. Direct Mitsunobu
inversion of 8 with 9 to give 10 (40% yield) could also be
achieved in lieu of the three-step process shown in Schemes
1 and 2 (8f7f10).19 Amide 10 was selectively reduced to
the corresponding aldehyde (Dibal-H, THF, -78 °C) without
any detectable reduction of the ester. The aldehyde was then
subjected to an asymmetric Racherla-Brown allylation
(20) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
(21) For relevant reviews, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413. (b) Armstrong, S. K. J. Chem Soc., Perkin Trans. 1 1998,
371. (c) Schuster M., Blechert, S. Angew. Chem. Int. Ed. 1997, 36, 2037.
(d) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem.
Int. Ed. 1995, 34, 2039. For recent reference to the synthesis of 11-
membered rings by RCM, see: Nicolaou, K. C.; Montagnon, T.; Vassil-
ikogiannakis, G.; Mathison, C. J. N. J. Am. Chem. Soc. 2005, 127, 8872.
(18) See Supporting Information for synthesis.
(19) For an excellent discussion on the importance of pKa in Mitsunobu
esterification, see: Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski,
E. J. J. J. Am. Chem. Soc. 1988, 110, 6487. See also: Camp, D.; Jenkins,
I. D. J. Org. Chem. 1989, 54, 3045, 3049.
Org. Lett., Vol. 7, No. 18, 2005
3991

transformed to the desired 14-membered lactone (E/Z > 10:
1). Reduction with H2 and 10% Pd/C in EtOAc gave 14 in
83% yield for the two steps. The 11-membered lactone 15
could also be prepared in the same sequence in an astounding
92% overall yield.21 It should be noted that both cyclizations
were also possible using Grubbs’ first-generation catalyst
(20-30 mol %) but with slightly lower yields (75-80%).
Saponification of macrolactones 14 and 15 with NaOMe in
refluxing methanol, followed by protection of the two
respective hydroxyesters as the MOM ethers, gave the
common intermediate 16 with identical physical data inde-
pendent of the route used. Previous syntheses of acetoge-
nins7,8 have utilized an intermolecular aldol reaction followed
by elimination to install the butenolide moiety. Thus, the
lithium enolate formed from 16 with LDA at -78C was
treated with 17,18 and the resulting aldol product was
subjected to de-O-silylation and in situ lactonization with
Bu4NF. Mesylation of the intermediate â-hydroxylactone and
elimination with DBU gave 18. Removal of the MOM groups
with TMSBr22 afforded crude longicin 1, which was purified
by flash chromatography, giving material identical to the
natural product on the basis of the reported physical
constants.9
Scheme 3. Internal Translactonization Strategy
RCM reaction for “chain-elongation”, thus assembling the
entire aliphatic chain of longicin. A new strategy was used
to construct the butenolide subunit via an aldol reaction with
a macrocyclic lactone precursor. The RCM macrocyclization
via “chain elongation” with diolefinic ester precursors should
find extensive application in the synthesis of biogenetically
related acetogenins.23,24
Having secured the stereochemical identity of longicin by
a stereocontrolled route, we opted for an alternative strategy
that exploits the inherent features of macrolactone intermedi-
ates. Thus, formation of the Li-enolate of 15 and treatment
with 17 led to the corresponding mixture of aldol products
19 (Scheme 3). Desilylation with TBAF led, via internal
translactonization, to the corresponding γ-lactone. Esterifi-
cation with TFAA/NEt3 in the presence of catalytic amount
of DBU gave the butenolide 20. Finally, treatment of 20 with
4 M HCl in dioxane/MeOH (2:1) gave (+)-longicin in 7.5%
overall yield from 2 (18 steps for the longest linear sequence).
Acknowledgment. We thank NSERC for financial as-
sistance and Michel Simard for X-ray analysis.
Supporting Information Available: Typical exprimental
procedures for key reactions, NMR spectra, and X-ray
ORTEP structures (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
OL051483K
We have described the first total synthesis of longicin, a
new member of annonaceous mono-THF-containing me-
tabolite, relying on a strategy that capitalizes on the efficient
utilization of D- and L-glutamic acids as chirons. Subunit
coupling was achieved by a novel application of the Grubbs’
(23) For the use of the RCM reaction to construct THF rings of
acetogenins, see: (a) Schauss, S. E.; Brånalt, J.; Jacobsen, E. N. J. Org.
Chem. 1998, 63, 4876. For other RCM/CM approaches, see: (b) Lei, Z.;
Mootoo, D. R. Org. Lett. 2003, 5, 3475. (c) Evans, P. A.; Cui, J.; Gharpure,
S. J.; Polosukhin, A.; Zhang, R.-H. J. Am. Chem. Soc. 2003, 125, 14702.
(d) Nattrass, G. L.; D´ıez, E.; McLachlan, M. M.; Dixon, D. J.; Ley, S. V.
Angew. Chem., Int. Ed. 2005, 44, 580. See also ref 6.
(22) Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett. 1984,
25, 2515.
(24) Bermejo, A.; Figade`re, B.; Zafra-Polo, M.-C.; Barrachina, I.;
Estornell. E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269.
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