Total Synthesis of (-)-Apicularen A

Article abstract of DOI:10.1021/ja037957x

Complete details of an asymmetric synthesis of apicularen (1) are described. The synthesis has been accomplished using a highly diastereo- and enantioselective [4 + 2] annulation for the assembly of the functionalized pyran core. An underdeveloped lactoni

Full text of DOI:10.1021/ja037957x

Published on Web 02/04/2004
Total Synthesis of (-)-Apicularen A
Qibin Su and James S. Panek*
Contribution from the Department of Chemistry and Center for Chemical Methodology and
Library Design, Metcalf Center for Science and Engineering, 590 Commonwealth AVenue,
Boston UniVersity, Boston, Massachusetts 02215
Received August 15, 2003; E-mail: panek@chem.bu.edu
Abstract: Complete details of an asymmetric synthesis of apicularen (1) are described. The synthesis has
been accomplished using a highly diastereo- and enantioselective [4 + 2] annulation for the assembly of
the functionalized pyran core. An underdeveloped lactonization method involving an NaH promoted
transesterification of an advanced intermediate bearing an aryl cyanomethyl ester was used for the
macrolactonization step.
Introduction
Apicularen A, 1, was identified by Jansen and co-workers
during a screening of the myxobacterial genus for biologically
active metabolites.1 During this process, it was determined that
nearly all strains from the genus Chondromyces produced this
common highly cytotoxic metabolite. This compound is a
powerful inhibitor of human cancer cells, including the multi-
drug-resistant line KB-VI.2 In addition, the effects of apicularen
A on in vivo angiogenesis of bovine aortic endothelial cells
(BAECs) were investigated by Kwon and co-workers. It was
found that apicularen A exhibited potent and inhibitory effect
on the growth of BAECs without any evidence of cytotoxicity
even when concentrations were increased to 10 ng/mL. This
agent also showed inhibition of basic fibroblast growth factor
(bFGF)-induced invasion and capillary tube formation of BAECs
at low concentration. Accordingly, apicularen A represents a
novel antiangiogenic compound with potent antitumor activity.3
Structurally, this compound features a trans-hydroxypyran with
a salicylic acid residue within a 10-membered lactone, which
bears a highly unsaturated enamide side chain. This natural
product is usually found with varying amounts of its glycocon-
jugate with N-acetyl glucose, known as apicularen B. Biosyn-
thetic studies showed that they are acetate-derived polyketides
containing a glycine residue as a precursor of an enamide side
chain. Herein we report a total synthesis of apicularen A using
an enantioselective [4 + 2] dihydropyran annulation to assemble
the core of the natural product.4
Figure 1.
nection of the macrolide revealed the hydroxy-ester 4. We
reasoned this intermediate could be obtained from an asymmetric
allylation of aldehyde 5.6 This material was derived from
dihydropyran 6a, which was envisioned to result from a [4 +
2] annulation of the illustrated chiral allylsilane 7a and
salicylate-aldehyde 8a.7
Synthesis of Dihydropyran through [4 + 2] Annulation.
When we initiated a study concerning [4 + 2] annulation
between chiral allylsilanes 7 and aldehydes, we chose pheny-
lacetaldehyde as one of the reaction partners because of its loose
structural resemblance to the salicylate moiety of apicularen A.
We soon learned that the organosilanes used in this study
exhibited a turnover in the stereochemical course of the annu-
lation from our earlier studies with related crotylsilanes; for
instance, where a cis-pyran was assembled from a syn-crotyl-
silane 7d,7a a cis-pyran resulted from an anti diastereomer of
(4) For previous total syntheses of apicularen A, see: (a) Bhattacharjee, A.;
Seguil, O. R.; De Brabander, J. K. Tetrahedron Lett. 2001, 42, 1217. (b)
Nicolaou, K. C.; Kim, D. W.; Baati, R. Angew. Chem., Int. Ed. 2002, 41,
3701. For studies toward syntheses of apicularen A, see: (c) Bhattacharjee,
A.; De Brabander, J. K. Tetrahedron Lett. 2000, 41, 8069. (d) Lewis, A.;
Stefanuti, I.; Swain, S. A.; Smith, S. A.; Taylor, R. J. K. Tetrahedron Lett.
2001, 42, 5549. (e) Kuhnert, S. M.; Maier, M. E. Org. Lett. 2002, 4, 643.
(f) Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith, S. A.; Taylor, R. J. K.
Org. Biomol. Chem. 2003, 1, 104. (g) Graetz, B. R.; Rychnovsky, S. D.
Org. Lett. 2003, 5, 3357.
(5) For preparation of amide side chain, 3, see: (a) Labrecque, D.; Charron,
S.; Rej, R.; Blais, C.; Lamothe, S. Tetrahedron Lett. 2001, 42, 2645. (b)
Fu¨rstner, A.; Dierske, T.; Thiel, O.; Blanda, G. Chem.sEur. J. 2001, 7,
5286. (c) Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407.
(6) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem.
1986, 51, 432.
Results and Discussion
Retrosynthesis of Apicularen A. Scheme 1 outlines our
retrosynthetic strategy for apicularen A where the first bond
disconnection relied on a vinylic substitution between vinyl
iodide 2 and unsaturated amide side chain 3.5 Further discon-
(1) Kunze, B.; Jansen, R.; Sasse, F.; Ho¨fle, G.; Reichenbach, H. J. Antibiot.
1998, 51, 1075.
(2) Jansen, R.; Kunze, B.; Reichenbach, H.; Ho¨fle, G. Eur. J. Org. Chem. 2000,
913.
(7) For related annulations, see: (a) Huang, H.; Panek, J. S. J. Am. Chem.
Soc. 2000, 122, 9836. (b) Huang, H.; Panek, J. S. Org. Lett. 2003, 5, 1991.
(c) Roush, W. R.; Dilley, G. J. Synlett 2001, SI, 955.
(3) Kwon, J. H.; Kim, D. H.; Shim, J. S.; Ahn, J. W. J. Microbiol. Biotechnol.
2002, 12, 702.
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J. AM. CHEM. SOC. 2004, 126, 2425-2430
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A R T I C L E S
Su and Panek
Scheme 1. Retrosynthesis of Apicularen A
Table 1. Synthesis of Dihydropyran via the [4 + 2] Annulation
a Stereochemistry of the pyrans was assigned by NOE experiments. b Yields were based on pure materials isolated by chromatography on SiO2. c The
1
product ratios were determined by H NMR (400 MHz).
allylsilane 7b. In the course of the development of our annu-
lation, Roush and co-workers reported the synthesis of cis-2,6-
disubstituded dihydropyrans using allylsilanes derived from an
asymmetric γ-silyl allylboration of aldehydes. In that report, a
similar turnover in the diastereoselectivity was observed for the
annulation between aldehydes and allylsilanes that possessed
an anti stereochemical relationship.7c We learned that the
stereochemical course of the annulation was determined by
relative stereochemical arrangement (syn or anti) of the silicon
and adjacent silyl ether (OTMS) of the crotylsilane.7a Thus, in
our initial studies we investigated the reaction between phenyl-
acetaldehyde and syn-allylsilane 7, the results of which are
summarized in Table 1. To our surprise, the diastereoselectivity
of annulation was dependent on the type of the functional group
X associated with the organosilanes (Table 1). We have
observed that the functional group X directly affected the sense
and magnitude of diastereoselectivity. For instance, silane 7a
(X ) CH2OMe, entry 1, Table 1) produced a pyran with an
excellent level of diastereoslectivity, and only a trans diastere-
omer was detected in the reaction crude mixture; whereas silane
7c (X ) CO2Me, entry 3, Table 1) was unselective. The
stereochemical outcome of the annulation between aldehyde 8b
and silane 7b (X ) CH2OAc, entry 2, Table 1) resulted in the
formation of a cis-pyran as the major isomer. Our mechanistic
interpretation for the reversal of the stereochemical course of
the annulation is illustrated in Scheme 2. To achieve an effective
σ-p orbital overlap for stabilization of the developing â-car-
bocation in the ring formation process, we have positioned the
silicon group in a pseudoaxial orientation in a twist boatlike
transition state and an axial orientation in a chairlike transition
state.8 Formation of the trans-dihydropyran from the reaction
between silane 7a and aldehyde 8b may proceed through a twist
boatlike transition state. It is possible that electrostatic attraction
between the nonbonding lone pair of electrons of methyl ether
and the positively charged oxocarbenium, which resides on the
carbon atom, stabilizes the twist boat conformer and accelerates
the annulation as illustrated in eq 1 (Scheme 2).9 The compli-
mentary cis-dihydropyran derived from the reaction of silane
7b and aldehyde 8b may proceed through a chairlike transition
(8) Lambert, J. B. Tetrahedron 1990, 46, 2677.
(9) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel, K.
A. J. Am. Chem. Soc. 2003, 125, 15521 and references therein.
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2426 J. AM. CHEM. SOC. VOL. 126, NO. 8, 2004

Total Synthesis of (−)-Apicularen A
A R T I C L E S
Scheme 2. Possible Transition States for [4 + 2] Annulation
Scheme 3. Synthesis of Allyl Silanes
(Table 2). Importantly, the functionalized aldehyde 8a intended
for the apicularen synthesis also gave the desired pyran in high
yield and diastereoselectivity (entry 1, Table 2).
Synthesis of Allylsilane. To access useful quantities of
enantiomerically enriched allylsilane 7a, an efficient synthesis
was developed using a modification of Chong’s protocol
(Scheme 3).10 The allylic alcohol 9 was obtained via a platinum
catalyzed regioselective hydrosilation.11 This material was
subjected to a Sharpless epoxidation to produce highly enan-
tiomerically enriched epoxy alcohol 10 (ee ) 97%).12 After
protection of free alcohol as its methyl ether, the epoxide 11
underwent a regioselective ring opening with vinylmagnesium
bromide and a catalytic amount of CuI providing a chiral
allylsilane in an excellent yield and as a single regioisomer.
Not surprisingly, the protection of primary alcohol was crucial
to the success of this reaction as it shut down the undesired
Peterson elimination pathway (Peterson olefination).13 The
desired chiral allylsilane 7a was obtained in quantitative yield
after silylation of the secondary alcohol. This silane was made
available in useful quantities (>15 g) using an efficient five-
step sequence with an overall yield of 74%.
Synthesis of the Macrolide of Apicularen A. With a reliable
route to useful quantities of the required allylsilane in hand,
we began the synthesis of apicularen A with the annulation
between aldehyde 8a and chiral organosilane 7a. Gratifyingly,
the first step of our route proceeded smoothly in the presence
of TMSOTf to afford desired dihydropyran 6a in excellent yield
and as a single diastereoisomer (Scheme 4). Methanolysis of
the phenolic acetate followed by protection of the free phenol
as a silyl ether with TBDPSCl gave dihydropyran 12. The
state shown in eq 2. The electron density at the oxygen atom
may be decreased by the electron withdrawing acetate group
(Ac) in 7b that leads to a decrease of the electrostatic effect.
The chair conformer is favored under this circumstance con-
sidering the steric destabilizing interaction between X (X ) CH2-
OAc) and bulky silyl group (SiMe2Ph) in twist boat conformer.
The turnover of the sense of diastereoselectivity resulting from
the subtle structural changes of silane reagents (7a, X ) CH2-
OCH3 f 7b, X ) CH2OAc) underscored the unique reactivity
and selectivity profile of these chiral organosilanes and is
currently under further investigation. In addition, when conju-
gated aldehydes were employed, only allylsilane 7c (X ) CO2-
Me) gave high levels of diastereoselectivity to produce a cis-
pyrans (entries 4 and 5, Table 1). Once assured that allylsilane
7a consistently provided a trans-pyran, we evaluated the scope
of the reaction using a range of aldehydes. We have showed
that the annulation between allylsilane 7a and aliphatic alde-
hydes proceeded smoothly to produce a trans-dihydropyran
(10) Chauret, D. C.; Chong, J. M.; Ye, Q. Tetrahedron: Asymmetry 1999, 10,
3601.
(11) Beresis, R. T.; Solomon, J. S.; Yang, M.; Jain, N. F.; Panek, J. S. Org.
Synth. 1997, 75, 78.
(12) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(13) Peterson, D. J. J. Org. Chem. 1968, 33, 780.
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J. AM. CHEM. SOC. VOL. 126, NO. 8, 2004 2427

A R T I C L E S
Su and Panek
Scheme 4
Scheme 5
Scheme 6
the epoxidation reaction gave the wrong diastereomer as the
major product. Accordingly, a Mitsunobu reaction was used to
invert the resulting secondary alcohol and install the correct
stereochemistry.18 The primary methyl ether 15 was selectively
cleaved with BBr3/NaI/15-crown-5 at -35 °C (Scheme 5).19
Protection of primary alcohol as a TBS silyl ether was followed
by methanolysis of the chloroacetate. The resulting secondary
alcohol was reprotected as a base-stable benzyl ether 16.20
Acidic cleavage of primary TBS ether afforded alcohol 17,
which was subsequently oxidized to an aldehyde with PCC in
the presence of molecular sieves in CH2Cl2.21 The resulting
aldehyde was homologated using a phosphorus-based olefination
with methoxymethylene triphenylphosphine.22 Hydrolysis of the
enol ether mediated by Hg(OAc)2 provided the homologated
aldehyde 5 in high yield. This material was treated with
(+)-Ipc2Ballyl furnishing the desired advanced intermediate 18
in 71% yield (dr ) 12:1).23 Hydrolysis of this material using
LiOH in a solution of MeOH/THF/H2O (1:4:1) at reflux
delivered hydroxy acid 19. Unfortunately, attempts to directly
lactonize the resulting hydroxy acid 19 failed. We reasoned that
the acidity of the free phenol could be problematic for
lactonization protocols employing carboxylate activation meth-
attempts to install an 11-hydroxy group by oxymercuration14
or hydroboration15 gave a complex mixture of regio- and
diastereoisomers. Therefore, the dihydropyran 12 was subjected
to m-CPBA epoxidation (CCl4, 0 °C), and a useful diastereo-
selectivity was achieved (R:â ) 7.5:1).16 Regioselective epoxide
opening by DIBAL-H reduction was realized at -78 °C without
involvement of the aryl ester to give hydroxy pyran 14.17 The
configuration of the newly installed 11-hydroxy group turned
out to be opposite to the one of apicularen A indicating that
(18) (a) Saiah, M.; Bessodes, M.; Antonakis, K. Tetrahedron Lett. 1992, 33,
4317. (b) Mitsunobu, O. Synthesis 1981, 1.
(19) Niwa, H.; Hida, T.; Yamada, K. Tetrahedron Lett. 1981, 22, 4239.
(20) Iversen, T.; Bundle, K. R. J. Chem. Soc., Chem. Commun. 1981, 1240.
(21) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 31, 2647.
(22) Maercker, A. Org. React. 1965, 14, 270.
(23) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem.
1986, 51, 432.
(14) Brown, H. C.; Geoghegan, P., Jr. J. Am. Chem. Soc. 1967, 89, 1522.
(15) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1959, 81, 247.
(16) Huang, H.; Panek, J. S. Org. Lett. 2001, 3, 1693.
(17) Hayakawa, H.; Iida, K.; Miyazawa, M.; Miyashita, M. Chem. Lett. 1999,
601.
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Total Synthesis of (−)-Apicularen A
A R T I C L E S
Table 2. Construction of trans-Dihydropyran via [4 + 2] Annulation
a The stereochemistry of the pyran products was assigned by NOE measurements. b Yields were based on pure materials isolated by chromatography on
1
SiO2. c The product ratio was determined by H NMR (400 MHz). d See ref 7a.
Scheme 7
ods. In that regard, we sought a viable solution that would
efficiently lead to the formation of the macrolide. Recently,
Porco, Shen, and Lin have used a salicylic cyanomethyl ester
moiety for an efficient intermolecular transesterification.24 In
the present case, this ester was selectively installed using the
chloroacetonitrile in the presence of Et3N at 50 °C (Scheme
6).25 Selective protection of the free phenol as a MOM ether
was achieved using MOMCl in aqueous NaOH solution.26 The
crucial lactonization of cyanomethyl ester 4 was accomplished
using a NaH promoted transesterification in a dilute solution
of refluxing THF affording macrolide 20 in good chemical yield.
Completion of the Synthesis of Apicularen A. With the
apicularen macrolide core 20 in hand, we were positioned for
introduction of the enamide side chain and completion of the
synthesis. Two-step oxidative cleavage of terminal olefin
provided an unstable aldehyde 21 (Scheme 7). The crude
material was used without purification in the Takai iodoolefi-
nation providing E-vinyl iodide 22 (E:Z ) 6:1) in mixed solvents
of THF and dioxane.27 Complete deprotection of this advanced
intermediate was achieved using BCl3 at -78 °C. In the final
stage, the CuTC catalyzed substitution of vinyl iodide 2 with
unsaturated amide 3 proceeds to yield apicularen A, 1 (E:Z )
8:1), in 40% yield at 58 °C under conditions described by Porco
and Shen.28 In our case, the diamine ligand and reaction
temperature were crucial to the success of the reaction and
completing the synthesis of the natural product. No diamine
ligand resulted in no product and decomposition of vinyl iodide.
(24) For base-induced intermolecular transesterification reaction of cyano-
methyl ester, see: (a) Scherlock, M. H. S. African Pat. ZA 6802187, CAN
70, 106224. (b) Shen, R.; Lin, C. T.; Porco, J. A., Jr. J. Am. Chem. Soc.
2002, 124, 5650.
(25) Hugel, H. M.; Bhaskar, K. V.; Longmore, R. W. Synth. Commun. 1992,
22, 693.
(26) For selectively protecting phenol, see: Kelly, T. R.; Jagoe, C. T.; Li, Q. J.
Am. Chem. Soc. 1989, 111, 4522.
(27) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408. For
an optimization of the solvent system for Takai olefination reaction, see:
Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
(28) (a) Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2, 1333. (b) Shen, R.; Lin,
C.; Bowman, E.; Bowman, B. J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003,
125, 7889.
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A R T I C L E S
Su and Panek
And, high temperature (80 °C) resulted in olefin at C17 position
as a 1:1 E/Z mixture. The chromatographic and spectroscopic
data of synthetic 1 are fully consistent with those of an authentic
sample.1
Acknowledgment. This paper is dedicated to Professor Dale
Boger on the occasion of his 50th birthday. We are grateful to
Prof. R. Jansen of the Gesellschaft fu¨r Bitechnologische
Forschung for kindly providing an authentic sample of apicu-
1
laren A and copies of H NMR and 13C NMR spectra. The
Conclusion
authors are grateful to Prof. J. A. Porco Jr. for stimulating
discussions. Financial support was obtained from the NIH
GM55740. J.S.P. is grateful to Johnson & Johnson, Merck Co.,
Novartis, Pfizer, and GSK for financial support.
We have completed the total synthesis of apicularen A. A
key feature of this synthesis included highly enantio- and
diastereoselective construction of trans-2,6-disubstituted dihy-
dropyran via a [4 + 2] annulation between a functionalized
phenylacetaldehyde and syn-allylsilane 7a. Also we detailed the
underdeveloped base-promoted transesterification reactions of
cyanomethyl ester for synthesis of a 10-member macrolactone.
In summary, the enantioselective annulation methodology of
chiral allylsilane reagents offers a promising and novel approach
to the synthesis of pyran containing natural products.
Supporting Information Available: Detailed experimental
procedure, including spectroscopic and analytical data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA037957X
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