Synthesis of the fully functionalized bicyclic core of garsubellin A

Full text of DOI:10.1021/ja9905445

4724
J. Am. Chem. Soc. 1999, 121, 4724-4725
Synthesis of the Fully Functionalized Bicyclic Core of
Garsubellin A
K. C. Nicolaou,* J. A. Pfefferkorn, S. Kim, and H. X. Wei
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road La Jolla, California 92037
Department of Chemistry and Biochemistry
UniVersity of California, San Diego
9500 Gilman DriVe, La Jolla, California 92093
ReceiVed February 22, 1999
In 1997, Fukuyama et al. disclosed the structure of garsubellin
A (1, Figure 1), a polyisoprenylated phloroglucinol isolated from
Garcinia subelliptica found on the Okinawa Islands of Japan.1a
Structurally, 1 is characterized by a highly oxygenated and densely
substituted bicyclo[3.3.1]nonane-1,3,5-trione core fused to a
tetrahydrofuran ring and appended with lipophilic side chains.
Preliminary biological investigations revealed 1 to be a potent
inducer of choline acetyltransferase (ChAT), the enzyme respon-
sible for the biosynthesis of the neurotransmitter acetylcholine
(ACh) and a biomarker for cholinergic neuron function. It was
reported that 1 could increase in vitro ChAT activity by 154% at
10 µM in cultures of P10 rat septal neurons.1a Since the dementia
associated with neurodegenerative diseases such as Alzheimer’s
has been partially attributed to an atrophy of cholinergic neurons
and corresponding deficiencies in ACh levels, the use of protein
neurotrophic factors or neurotrophic mimics (such as garsubellin
A) which are capable of increasing neurotransmitter biosynthesis
and possibly supporting the survival of cholinergic neurons holds
therapeutic potential.2 Herein, we report the construction of a fully
functionalized [3.3.1] bicyclic system 2 which contains the key
structural features of garsubellin’s framework.
Figure 1. Structure and retrosynthetic analysis of garsubellin A (1).
Scheme 1. Assembly of Bicyclic Skeleton of Garsubellin Aa
As shown in Figure 1, initial retrosynthetic inspection of the
targeted system 2 reveals the lactone fused at C-1 and C-2 as a
retron for a selective Baeyer-Villiger oxidation3 between C-1
and C-23, giving rise to fused cyclobutanone 3, which can be
further disconnected via the intermediacy of an enone to
intermediate 4. The realization that the C-8 appendage might be
installed via an intramolecular radical cyclization reveals selenide
5 as the retron for a selenium-induced electrophilic cyclization4
of prenylated â-ketoester 6 to rapidly establish the bicyclic
skeleton through construction of the sterically demanding C-6 to
C-9 bond with concomitant installation of the requisite radical
precursor functionality at C-8.
Initial synthetic efforts, as illustrated in Scheme 1, focused on
effecting the anticipated electrophilic cyclization. Readily avail-
able cyclohexadione 75 was C-alkylated using the Fuji6 conditions
to give diketone 8 in 80% yield, which was stereoselectively
reduced with LiAlH(O-t-Bu)3 to dihydroxy-ester 9. After hy-
drolysis of the ethyl ester of diol 9 to give carboxylic acid 10,
lactonization was accomplished by treatment with DCC and
a (a) 2.0 equiv of BrCH2CO2Et, 1.2 equiv of DBU, 1.2 equiv of Lil,
THF, 65 °C, 24 h, 80%; (b) 2.5 equiv of LiAlH(O-t-Bu)3, THF, 0 °C,
2.5 h; (c) 1.3 equiv of LiOH, THF:H2O (4:1), 25 °C, 30 min; (d) 1.2
equiv of DCC, 0.2 equiv of 4-DMAP, CH2Cl2, 25 °C, 30 min, 73% over
three steps; (e) 1.3 equiv of PDC, Celite, CH2Cl2, 25 °C, 6 h, 77%; (f)
1.2 equiv of LHMDS, 1.2 equiv of HMPA, 1.5 equiv of CNCO2Me, THF,
-78 °C, 30 min; (g) 0.5 equiv of DMAP, Ac2O, 70 °C, 1 h, 75% over
two steps; (h) 1.1 equiv of N-PSP, 1.0 equiv of SnCl4, CH2Cl2, -23 °C,
15 min, 95%; (i) 2.0 equiv of n-Bu3SnH, 0.1 equiv of AlBN, CH3C6H6,
80 °C, 2 h, 89%; (j) 1.3 equiv of LiAlH(O-t-Bu)3, THF, 0 °C f
25 °C, 2.5 h, 95%; (k) 1.1 equiv of LHMDS, 1.1 equiv of trans-
PhSO2CHdCHSO2Ph, THF, 0 °C f 25 °C, 2.5 h, 82%; (l) 1.5 equiv
of n-Bu3SnH, 0.3 equiv of AlBN, C6H6, 80 °C, 12 h, 93%; (m) 6.0 equiv
of DIBAL, CH2Cl2, -78 °C f 25 °C, 12 h, 80%. AlBN ) 2,2′-
azobisisobutyronitrile, DBU ) 1,8-diazabicyclo[5.4.0]undec-7-ene, DCC
) 1,3-dicyclohexylcarbodiimide, DIBAL ) diisobutylaluminum hydride,
HMPA ) hexamethylphosphoramide, LHMDS ) lithium bis(trimethyl-
silyl)amide, N-PSP ) N-(phenylseleno)phthalimide, PDC ) pyridinium
dichromate.
(1) (a) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull.
1997, 45, 947-949. See also: (b) Fukuyama, Y.; Minami, H.; Kuwayama,
A. Phytochemistry 1998, 49, 853-857. (c) Fukuyama, Y.; Shida, N.; Kodama,
M.; Chaki, H.; Yugami, T. Chem. Pharm. Bull. 1995, 43, 2270-2272.
(2) (a) Hefti, F. J. Neurobiol. 1994, 1418-1435. (b) Hefti, F. Annu. ReV.
Pharmacol. Toxicol. 1997, 37, 239-267.
4-DMAP to provide lactone 11 (73% yield over three steps),
which was subsequently oxidized with PDC to keto-lactone 12
in 77% yield. Construction of the requisite â-ketoester moiety
was accomplished by acylation of the enolate, generated from
ketone 12, with methyl cyanoformate7 to give 13 as a tautomeric
(3) Grieco, P. A.; Oguri, T.; Gilman, S.; DeTitta, G. T. J. Am. Chem. Soc.
1978, 100, 1616-1618.
(4) For early precedent, see: (a) Jackson, W. P.; Ley, S. V.; Whittle, A. J.
J. Chem. Soc., Chem. Commun. 1980, 1173-1174. (b) Jackson, W. P.; Ley,
S. V.; Morton, J. A. Tetrahedron Lett. 1981, 22, 2601-2604.
(5) Verhe´, R.; Schamp, N.; De Buyck, L. Synthesis 1975, 392-393.
(6) Bedekar A. V.; Watanabe, T.; Tanaka, K.; Fuji, K. Synthesis 1995,
1069-1070.
(7) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425-5428.
10.1021/ja9905445 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/04/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 19, 1999 4725
keto-enol mixture. The latter compound (13) was acetylated to
enol acetate 6 in 75% yield over two steps. With the requisite
precursor in hand, the selenium-mediated cyclization4 was at-
tempted by treating a solution of 6 and N-(phenylseleno)phthal-
imide8 with SnCl4 at -23 °C. Gratifyingly, substrate 6 underwent
facile and remarkably clean conversion to the desired carbocycle
14 in 95% yield. The structure of 14 was confirmed by conversion
(n-Bu3SnH, AIBN, 89% yield) to crystalline 14a which was
subjected to X-ray analysis (see Supporting Information).
Scheme 2. Completion of Bicyclic Core of Garsubellin Aa
According to the retrosynthetic planning, the next stage of the
synthesis was to convert the phenylselenide at C-8 of 14, via a
radical, to a two-carbon sulfone-terminated side chain. Tethering
of the intramolecular radical acceptor was accomplished by initial
reduction of the C-5 ketone of 14 to afford a single compound
15 in 95% yield, with reduction occurring exclusively from the
opposite side of the gem-dimethyl group at C-9. The required
vinylogous sulfonate 16 was then constructed in 82% yield by
treatment of alcohol 15 with LHMDS at 0 °C, followed by
addition of trans-1,2-bis(phenylsulfonyl)ethylene.9 Syringe-pump
addition of n-Bu3SnH and AIBN to a refluxing solution of 16
provided tetracycle 4 as the sole product in 93% yield, with the
stereochemistry at C-12 shown as suggested by NOE experiments.
Experimentation revealed that the new tetrahydropyran ring would
undergo facile opening via â-elimination upon treatment with
base, thereby releasing the C-8 substituent; it was decided,
however, to postpone such release and use the embedded ring as
a temporary protecting group for the C-5 alcohol. Continuing
toward the desired bicyclic core 2, tetracycle 4 was exhaustively
reduced with DIBAL to give triol 17 in 80% yield.
Selective protection (Scheme 2) of the least hindered primary
alcohol with TBDPS-Cl afforded diol 18 (89% yield), which was
selectively oxidized with TEMPO to the corresponding aldehyde
19.10 Initial attempts to effect the addition of isopropylmagnesium
bromide to aldehyde 19 met with failure, as the severe steric
hindrance around the C-27 aldehyde resulted in reduction,
presumably through â-hydride elimination of the Grignard reagent
as previously reported.11 Fortunately, the use of isopropenylmag-
nesium bromide effected the desired addition to C-27 with
concomitant â-elimination of the sulfone side chain to give 20 in
57% yield (two steps) as a single stereoisomeric compound with
the illustrated stereochemistry as determined by NOE studies of
a subsequent intermediate (23). Since hydrogenation conditions
to simultaneously reduce both the C-12 and C-28 olefins could
not be defined, the one at C-28 was reduced first by treatment of
20 with H2/PtO2 to give 21 in 73%. Subsequently, the free
hydroxyls at C-5 and C-27 were selectively protected as a cyclic
carbonate by exposure of 21 to triphosgene and pyridine12 to
afford 22 in 86% yield, which then was treated with H2/Pd-C to
give 23 in 88% yield. The free hydroxyl at C-3 was then oxidized
with TPAP-NMO13 to the corresponding ketone 24 in 87% yield.
Conversion of 24 to the requisite enone 25 proved more difficult
than anticipated, as all attempts to effect olefination by generation,
oxidation, and elimination of an R-phenylselenide at C-2 failed,
such that 25 could only be obtained by treatment of ketone 24
with SeO2 in AcOH at 110 °C (60% yield).
a (a) 1.5 equiv of TBDPS-Cl, 0.5 equiv of 4-DMAP, pyridine, 25 °C,
12 h, 89%; (b) 0.2 equiv of TEMPO, 1.2 equiv of Phl(OAc)2, CH2Cl2,
25 °C, 5 h; (c) 10 equiv of isopropenyl MgBr, THF, -78 °C f 25 °C,
12 h, 57% over two steps; (d) 0.1 equiv of PtO2, H2, EtOH, 25 °C, 72 h,
73%; (e) 2.0 equiv of triphosgene, 25 equiv of pyridine, CH2Cl2, -78
°C f 25 °C, 30 min, 86%; (f) 0.1 equiv of Pd-C, H2, EtOH, 25 °C, 24
h, 88%; (g) 0.05 equiv of TPAP, 2.0 equiv of NMO, 4 Å MS, CH2Cl2,
25 °C, 12 h, 87%; (h) 4.0 equiv of SeO2, AcOH, 110 °C, 1 h, 60%; (i)
20 equiv of (MeO)2dCH2, hν, C6H6, 25 °C, 8 h, 44%; (j) 3.0 equiv of
H2SO4, Et2O, 25 °C, 12 h, 82%; (k) 2.0 equiv of TsOH, MeOH, 25 °C,
86%; (l) 10 equiv of m-CPBA, 20 equiv of NaHCO3, CH2Cl2 25 °C,
85%. 4-DMAP ) 4-(dimethylamino)pyridine, m-CBPA ) 3-chloroper-
oxybenzoic acid, NMO ) 4-methylmorpholine N-oxide, TBDPS-Cl )
tert-butylchlorodiphenylsilane, TPAP ) tetrapropylammonium perruth-
enate, TsOH ) p-toluenesulfonic acid.
albeit in only modest yield (44%) to give the protected cyclo-
butanone adduct 26. In preparation for the anticipated Baeyer-
Villiger oxidation, the dimethoxyketal at C-23 was hydrolyzed
with H2SO4 in Et2O to give cyclobutanone 27. Before the
Baeyer-Villiger oxidation could be performed, however, the
carbonyl at C-3 had to be protected by conversion to the mixed
ketal 28 via exposure of 27 to TsOH in MeOH (86% yield).
Earlier attempts to effect the Baeyer-Villiger oxidation without
this carbonyl protection resulted in the formation of a highly
unstable lactone that underwent facile â-elimination to give the
free acid at C-23. After protection, however, treatment of
cyclobutanone 28 with excess m-CPBA6 resulted in clean conver-
sion to the now robust lactone 2, in 85% yield, completing the
construction of the fully functionalized bicyclic core 2 of
garsubellin A (1).
With enone 25 at hand, the stage was set for completion of
the bicyclic core. The anticipated [2 + 2] cycloaddition occurred
regio- and stereoselectively from the exo-face of the molecule
upon irradiation of a solution of 25 and dimethoxyethylene,14
The chemistry described is expected to facilitate the total syn-
thesis of garsubellin A as well as other natural1b and designed
members of this class of compounds for biological studies.
(8) (a) Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P. J.
Am. Chem. Soc. 1979, 101, 3704-3706. (b) Nicolaou, K. C.; Petasis, N. A.;
Claremon, D. A. Tetrahedron 1985, 41, 4835-4841.
Acknowledgment. This work was financially supported by The
Skaggs Institute for Chemical Biology, the NIH, a fellowship from the
Department of Defense (to J.P.).
(9) Evans, P. A.; Manangan, T. Tetrahedron Lett. 1997, 38, 8165-8168.
(10) Mico, A. D.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G.
J. Org. Chem. 1997, 62, 6974-6977.
(11) Kharasch, M. S.; Reinmuth, O. Grignard Reactions of Nonmetallic
Substances; Prentice Hall: New York, 1954; p 65.
Supporting Information Available: Data and procedures for all
compounds as well as selected spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Burk, R. M.; Roof, M. B. Tetrahedron Lett. 1993, 34, 395-398.
(13) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13-19.
(14) Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem.
Soc. 1964, 86, 5570-5583.
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