Total synthesis of antheliolide A

Article abstract of DOI:10.1021/ja066336b

The first synthesis of the structurally unique marine natural product antheliolide A (1) has been accomplished by the pathway outlined in Scheme 1. The sequence is stereocontrolled and has led to the synthesis of (±)-1, and ent-1 as well as 1. The route c

Full text of DOI:10.1021/ja066336b

Published on Web 10/06/2006
Total Synthesis of Antheliolide A
Chandra Sekhar Mushti, Jae-Hun Kim, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received August 31, 2006; E-mail: corey@chemistry.harvard.edu
The structurally unusual and compact marine natural product
antheliolide A (1) has remained a formidable challenge to syn-
thetic chemists since the isolation from Anthelia glauca and the
determination of structure almost 20 years ago.1-3 The frame-
work of four-, five-, six-, and nine-membered rings and the
particular arrangement of functionality and multiple embedded
stereocenters sharply limit the range of chemical reactions that
are applicable to the synthesis. Further, there is little in the
existing synthetic literature to define an effective strategy of syn-
thesis. This paper describes the development of a logical syn-
thetic pathway to 1 that efficiently assembles this acetoacetate-
diterpenoid composite with excellent stereocontrol. The present
synthesis has allowed the assignment of absolute configuration to
antheliolide A (as in 1) as well as laboratory access to this scarce
natural product.
to a â-keto sulfone, R2CHCOCH2SO2Ph. Treatment of 9 with
benzenesulfinyl chloride, Et3N and 4-(dimethylamino)pyridine
(DMAP) in CH2Cl2 at 0 °C for 2 h provided the benzenesulfinate
ester 10 which underwent Pd-catalyzed [2,3]-sigmatropic rearrang-
ment12 upon exposure to Pd2(dba)3 in toluene at 60 °C for 2 h to
form the isomeric allenic sulfone, R2CdCdCHSO2Ph. Reaction
of this intermediate with Et2NH at 23 °C to effect conjugate addition
followed by hydrolysis with aqueous 1 N HCl and desilylation
produced the â-keto sulfone 11 (76% yield from 10). The primary
hydroxyl of 11 was esterified with methyl chloroformate-DMAP
to afford the corresponding allylic methoxycarbonyl derivative
which served as the substrate for ring closure to 12 by a method
that we had applied earlier to the closure of the 11-membered rings
in â-arenosene and humulene.13 Treatment of the methoxycarbonate
of 11 with a catalytic amount of Pd2(dba)3‚CHCl3 and 1,4-
bisdiphenylphosphinobutane using the base diazabicycloundecene
(DBU) in THF at 55 °C for 2 h resulted in smooth cyclization to
form 12 in 75% yield. Reductive C-SO2 cleavage of 12 was
effected with Al(Hg)-THF-H2O at 23 °C for 16 h to form the ketone
13 in 88% yield.14
The pathway for the synthesis of 1 is outlined in Scheme 1.
Conversion of the vinylic bromide 24 to the corresponding vinyl-
lithium reagent using 2 equiv of t-BuLi5 and subsequent reaction
with the tert-butyldiphenylsilyl-protected ꢀ-hydroxy aldehyde 3 (R1
) t-BuPh2Si)6 afforded the trienol 4. Double bond transposition-
homologation of 4 to form stereoselectively the Z-homoallylic
alcohol 5 was effected by application of Still’s methodology7 using
the following sequence: (1) deprotonation of the allylic hydroxyl
of 4 with KH and etherification with Bu3SnCH2I and (2) Sn-Li
exchange and [2,3]-sigmatropic rearrangement with n-BuLi in THF.
Primary alcohol 5 was oxidized by periodinane into the corre-
sponding aldehyde which was then transformed into the dimethyl
acetal 6 with methyl orthoformate and a catalytic amount of
pyridinium tosylate.8 Partial acetal exchange using HOCH2COOCH3
and pyridinium tosylate converted 6 to the mixed acetal methyl
ester 7. Saponification of the ester 7 gave the corresponding carbox-
ylic acid which was converted to the triethylammonium salt by
treatment with triethylamine. Slow addition of this salt to a solution
of tosyl chloride and triethylamine in toluene at reflux resulted in
ketene formation and diastereoselective internal [2 + 2]-cyclo-
addition to produce the bicyclic ketone 8.9 Ethynylation of the
carbonyl group of 8 by the reagent from lithium trimethylsilyl-
Starting with the enantiomer of 9 with the shorter retention time
(4.75 min) we obtained the dextrorotatory form of 13 ([R]23D +34
in CHCl3) to which we assign the absolute stereochemistry shown
in Scheme 1. From the enantiomer of 9 with the longer reten-
tion time (6.14 min) we obtained the levorotatory product, ketone
ent-13 ([R]23 -34 in CHCl3). These assignments were made by
D
comparison with a close model, the known levorotatory bicyclic
ketone 19 ([R]D -72 in CHCl3) that had been correlated with
naturally occurring â-caryophyllene (20).15,16
10
acetylide and CeCl3 in THF at -78 °C afforded the expected
Using the (+)-enantiomer 13, we were able to synthesize the
naturally occurring form of 1 as outlined in Scheme 1. Methyl-
enation of the dextrorotatory ketone 13 using the Tebbe reagent,17
Cp2TiCH2‚Me2AlCl in toluene at 20 °C for 2 h furnished the
required triene 14. The next task in the synthesis, the conversion
of the lactal 14 to the corresponding lactol and lactone 15, turned
out to be a challenge because of the great sensitivity of the
caryophyllene-like subunit to acids, electrophiles, and oxidants. The
only satisfactory solution that we were able to find involved
propargylic alcohol which was desilylated by exposure to LiOH in
MeOH at 23 °C to give the ethynyl carbinol (()-9 as a single
diastereomer.
We were pleased to find that the two enantiomers of (()-9 were
separated with remarkable facility on a Chiral Technologies OD-H
HPLC column with 97:3 hexane-i-PrOH as eluent because of
greatly different retention times (baseline separation with the two
enantiomers typically eluting at 4.75 and 6.14 min). This separation
was performed on a 4.2 g sample to afford each of the oily
enantiomers of 9 in pure form and >99.9% ee.11 Each of the
enantiomers of 9 was then carried forward through the steps k-q
of Scheme 1 to afford the enantiomers of tricyclic ketone 13 in the
following way. This sequence includes a new and potentially
broadly useful method for effecting the change of a ketone, R2CO,
18
sequential treatment of 14 with (1) PhSeAlMe2 in CH2Cl2 at 23
°C for 2 h to replace methoxy by phenylseleno, (2) AgNO3 in
Me2CO-H2O to replace phenylseleno by hydroxyl, and (3) oxidation
-
with catalytic Pr4N+ RuO4 (TPAP) and N-methylmorpholine
N-oxide in CH2Cl2 which gave the desired lactone 15.19 Conversion
of 15 to the potassium enolate with potassium hexamethyldisilazide
9
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J. AM. CHEM. SOC. 2006, 128, 14050-14052
10.1021/ja066336b CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1 a
a Reagents and conditions: (a) 2-equiv t-BuLi, 2, Et2O, -78 °C; -20 °C, 6 h; then 3, -78 °C, 2 h; (90%); (b) KH, THF, -40 °C, 30 min; then
Bu3SnCH2I at -40 °C; 0 °C, 16 h; (c) n-BuLi, THF, -78 °C, 3 h (61% from 4); (d) Dess-Martin periodinane, CH2Cl2, 23 °C, 30 min; (e) HC(OMe)3, pyH+
TsO-, 23 °C, 12 h (85% from 5); (f) HOCH2COOMe, pyH+ TsO-, 60-65 °C, 1.5 h (73%); (g) LiOH, MeOH, 22 °C, 2 h; adjust to pH 3.3 and extract with
Et2O; (h) p-TsCl, Et3N, C7H8, at reflux for 7 h (66%); (i) TMSCtCCeCl2, THF, -78 °C, 3 h; (j) 3N-LiOH, MeOH-H2O, 23 °C, 2 h; (k) PhS(O)Cl, Et3N,
DMAP, CH2Cl2, 0 °C, 2 h (87% from 8); (l) Pd2(dba)3, C7H8, 60 °C, 2 h; (m) Et2NH, CH2Cl2, 23 °C, 1 h then 1N-HCl (aq) (76% of â-keto sulfone from
10); (n) desilylation, py (HF)x, py, 0-23 °C over 3 h (89% of hydroxy â-keto sulfone 11); (o) MeOCOCl, DMAP, CH2Cl2, 0-23 °C over 6 h (88% of the
methoxy carbonate ester of 11); (p) Pd2(dba)3‚CHCl3, 1,4-bis-diphenylphosphinobutane, DBU, THF, 55 °C, 2 h (75% of 12); (q) Al(Hg), THF-H2O 23 °C,
16 h (88% of 13); (r) Tebbe reagent (Cp2TiCH2‚Me2AlCl), C7H8, (85% of 14); (s) PhSeAlMe2, CH2Cl2, 23 °C, 2 h; then AgNO3 in 1:1 Me2CO-H2O at 23
°C for 2 h; (t) TPAP, NMO, 4A mol sieves, CH2Cl2, 23 °C, 2 h (55% of 15 from 14); (u) (Me3Si)2NK, THF -78 C, 45 min; then PhCH(O)NSO2Ph, THF,
-78 °C, 2 h followed by Me2S and then H2O (90% of R-hydroxy 15); (v) CH3CtCLi, THF, -78 °C, 12 h (90% of 16 from 15); (w) NaIO4 on silica gel,
CH2Cl2, 25 °C, 3 h (93% of 17); (x) piperidine, THF, 23 °C, 4 h (98% of 18); (y) silica gel, C6H6, 23 °C, 6 h (74% of 1 from 18).
in THF and subsequent treatment with the Davis oxaziridine
afforded a 5:1 mixture of diastereomeric R-hydroxy lactones20 which
upon reaction with 1-propynyllithium were transformed into 16.21
Oxidative cleavage of 16 with sodium periodate supported on silica
gel22 provided aldehyde ester 17 in excellent yield. Exposure of
17 to piperidine at 23 °C gave the vinylogous enamide aldehyde
18 cleanly. Antheliolide A was produced in a single step from 18
simply by stirring in C6H6 solution with silica gel at 23 °C for 6 h.
Since the absolute configuration of antheliolide A had not been
determined previously, we also employed the sequence shown in
Scheme 1 to synthesize ent-antheliolide A (from ent-13) and racemic
antheliolide A (from (()-9 via (()-13). We found that the
enantiomers of antheliolide A are cleanly separated by HPLC using
a Chiral Technologies Chiralpak-AD column with 97:3 hexane-
i-PrOH for elution (23 °C, 1 mL/min flow rate): ent-antheliolide
A eluted at 14.01 min; synthetic or naturally occurring antheliolide
A (1) eluted identically at 20.28 min.23 The 1H and 13C NMR data
for synthetic 1 agreed completely with that reported for antheliolide
A, including the observation in the 1H NMR spectrum of two
conformational forms of the nine-membered ring that intercon-
vert slowly on the NMR time scale.24 Although we measured the
optical rotation of synthetic antheliolide A, [R]23D -111 (c ) 0.2,
CH2Cl2), it was not possible to make a comparison with the natural
product since that rotation had not been reported and since there
was insufficient reference sample available to us. The assignment
of the absolute configuration 1 to antheliolide A brings it in line
with the absolute stereochemistry of the majority of the related
xenicane family of marine natural products.25,26 It is noteworthy
9
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C O M M U N I C A T I O N S
(6) Prepared by sequential epoxidation and acidic periodate cleavage of
t-BuPh2Si-protected geraniol.
(7) (a) Still, W. C.; Mitra, A. J. Am. Chem. Soc. 1978, 100, 1927-1928. (b)
Still, W. C.; McDonald, J. H., III; Collum, D. B.; Mitra, A. Tetrahedron
Lett. 1979, 593-594.
that the absolute stereoarrangement of 1 is opposite to that of the
plant-derived natural product â-caryophyllene (20).
Many of the steps used in the synthesis of antheliolide A
described above have implications beyond the present work, as well
as being of crucial importance to the success of this project. These
include (1) formation of the mixed acetal 7, (2) the diastereose-
lective bicyclization to form 8 in which stereocenters are correctly
established at each carbon of the four-membered ring, (3) the chain
extension 8 f 11, (4) the efficient closure of the nine-membered
ring of 12, (5) the mild oxidative cleavage sequence 14 f 17, and
(6) the successful and quick formation of the last three rings of 1
from aldehyde 17 via 18. It seems logical that the one-step
conversion of 18 to 1 occurs via the intermediate 21 by [2 +
4]-cycloaddition which is made even more facile by steric accelera-
tion. The same pathway may be involved in the biosynthesis of 1.
The approach described above for the synthesis of 1 is completely
different from that employed in these laboratories earlier for the
construction of the structural relative â-caryophyllene.27
(8) Napolitano, E.; Fiaschi, R.; Mastrorilli, E. Synthesis 1986, 122-125.
(9) For background on methodology, see (a) Corey, E. J.; Rao, K. S.
Tetrahedron Lett. 1991, 36, 4623-4626. (b) Corey, E. J.; Kang, M.-C.;
Desai, M. C.; Ghosh, A. K.; Houpis, I. N. J. Am. Chem. Soc. 1988, 110,
649-650. (c) Corey, E. J.; Gavai, A. V. Tetrahedron Lett. 1988, 29, 3201-
3204. (d) Corey, E. J.; Desai, M. C.; Engler, T. A. J. Am. Chem. Soc.
1985, 107, 4339-4340. (e) Snider, B. B.; Hui, R. A. H. F.; Kulkarni, Y.
S. J. Am. Chem. Soc. 1985, 107, 2194-2196.
(10) Suzuki, M.; Kimura, Y.; Terashima, S. Chem. Lett. 1984, 1543-1546.
(11) This separation was accomplished in one pass using a 2 cm diameter OD-H
column available from Chiral Technologies, Inc.
(12) (a) Hiroi, K.; Kato, F. Tetrahedron 2001, 57, 1543-1550. (b) Hiroi, K.;
Kato, F.; Nakasato, H. Chem. Lett. 1998, 27, 553-554.
(13) Hu, T.; Corey, E. J. Org. Lett. 2002, 4, 2441-2443.
(14) See Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345-
1353 and also ref 13.
(15) (a) Maurer, B.; Hauser, A. HelV. Chim. Acta 1983, 66, 2223-2235. (b)
Kaiser, R.; Lamparsky, D. HelV. Chim. Acta 1976, 59, 1803-1808.
(16) This assignment is also consistent with a three-dimensional analysis of
the structures 13 and 19 for an n f π* transition as the basis for optical
rotation.
(17) (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978,
100, 3611-3613. (b) Pine, S. H.; Shen, G. S.; Hoang, H. Synthesis 1991,
165-167. (c) Pine, S. H.; Kim, G.; Lee, V. Org. Synth. 1993, Vol. VIII,
512-516.
(18) (a) Corey, E. J.; Shibasaki, M.; Knolle, J.; Sugahara, T. Tetrahedron Lett.
1977, 785-788. (b) Hong, B.-C.; Kim, S.; Kim, T.-S.; Corey, E. J.
Tetrahedron Lett. 2006, 47, 2711-2715.
(19) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639-666.
(20) (a) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. G.; Finn, J. J. Org.
Chem. 1984, 49, 3241-3243. (b) It is essential that any unreacted PhCH-
(O)NSO2Ph be reduced by quenching of the reaction mixture with Me2S
before product isolation in order to prevent further oxidation of the
R-hydroxy lactone.
(21) (a) Ogura, H.; Takahashi, H.; Itoh, T. J. Org. Chem. 1972, 37, 72-75.
(b) 1-Lithiopropyne was generated by reaction of 1-bromo-1-propene with
n-Buli in THF at -78 °C for 2 h.
Although the xenicane family of marine natural products is
sizable and growing steadily,28 only a few studies have appeared
on approaches to their synthesis.29 Structurally intricate and rigid
polycylic natural products such as 1 are likely to possess interesting
biological activity. The availability of synthetic 1 should facilitate
the study of this possibility.
(22) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622-2624.
(23) A sample of naturally occurring antheliolide A (ca. 200 µg) was obtained
from Prof. Yoel Kashman, Tel Aviv University, who generously provided
his remaining stock of natural 1 for this research.
(24) Details are provided in the Supporting Information.
(25) (a) Miyaoka, H.; Nakano, M.; Iguchi, K.; Yamada, Y. Heterocycles 2003,
61, 189-196. (b) Miyaoka, H.; Mitome, H.; Nakano, M.; Yamada, Y.
Tetrahedron 2000, 56, 7737-7740. (c) Miyaoka, H.; Nakano, M.; Iguchi,
K.; Yamada, Y. Tetrahedron 1999, 55, 12977-12982.
Acknowledgment. We thank Drs. Tao Hu and Wei-Dong Z.
Li for their contributions in the exploratory phase of this work and
also Prof. Y. Kashman and Dr. Thomas B. Lewis, of Chiral
Technologies, Inc., for their kind assistance.
(26) For two apparent exceptions, see Norte, M.; Gonza´lez, A. G.; Arroyo, P.;
Za´rraga, M.; Perez, C.; Rodriguez, M. L.; Ruiz-Perez, C.; Dorta, L.
Tetrahedron 1990, 46, 6125-6132.
(27) (a) Corey, E. J.; Mitra, R. B.; Uda, H. J. Am. Chem. Soc. 1963, 85, 362-
363. (b) Corey, E. J.; Mitra, R. B.; Uda, H. J. Am. Chem. Soc. 1964, 86,
485-492. (c) Corey, E. J.; Bass, J. D.; Le Mahieu, R. E.; Mitra, R. B. J.
Am. Chem. Soc. 1964, 86, 5570-5583. (d) Liu, D.; Hong, S.; Corey, E.
J. J. Am. Chem. Soc. 2006, 128, 8160-8161.
Supporting Information Available: Experimental procedures and
characterization data for all reactions and products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(28) (a) Shen, Y.-C.; Lin, Y.-C.; Ahmed, A. F.; Kuo, Y.-H. Tetrahedron Lett.
2005, 46, 4793-4796. (b) El-Gamal, A. A. H.; Chiang, C.-Y.; Huang,
S.-H.; Wang, S.-K.; Duh, C.-Y. J. Nat. Prod. 2005, 68, 1336-1340. (c)
El-Gamal, A. A. H.; Wang, S.-K.; Duh, C.-Y. Tetrahedron Lett. 2005,
46, 6095-6096. (d) El-Gamal, A. A. H.; Wang, S.-K.; Duh, C.-Y.
Tetrahedron Lett. 2005, 46, 4499-4500. (e) El-Gamal, A. A. H.; Wang,
S.-K.; Duh, C.-Y. Org. Lett. 2005, 7, 2023-2025. (f) Anta, C.; Gonza´lez,
N.; Santafe´, G.; Rodr´ıguez, J.; Jime´nez, C. J. Nat. Prod. 2002, 65, 766-
768.
(29) (a) Renneberg, D.; Pfander, H.; Leumann, C. J. J. Org. Chem. 2000, 65,
9069-9079. (b) Liu, G.; Smith, T. C.; Pfander, H. Tetrahedron Lett. 1995,
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References
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(2) The absolute configuration of antheliolide A has remained undetermined.
(3) Antheliolide A is related structurally to the xenicane family of marine
natural products: Hooper, G. J.; Davies-Coleman, M. T.; Schleyer, M. J.
Nat. Prod. 1997, 60, 889-893.
(4) The vinylic bromide 2 was prepared in 91% yield by reaction of
prenylmagnesium bromide with 2-bromoallyl bromide in the presence of
10 mol % of CuCN in THF at -78 °C for 2 h.
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