Studies toward the total synthesis of garsubellin A: A concise synthesis of the 18-epi-tricyclic core

Article abstract of DOI:10.1021/ol0255965

(equation presented) During studies directed toward the total synthesis of garsubellin A, a concise stereocontrolled synthesis of the 18-epi-tricyclic compound 3 was achieved. Key steps were a one-pot stereoselective construction of the bicyclic lactone 2

Full text of DOI:10.1021/ol0255965

ORGANIC
LETTERS
2002
Vol. 4, No. 5
859-862
Studies toward the Total Synthesis of
Garsubellin A: A Concise Synthesis of
the 18-epi-Tricyclic Core
Hiroyuki Usuda, Motomu Kanai, and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
mshibasa@mol.f.u-tokyo.ac.jp
Received January 21, 2002
ABSTRACT
During studies directed toward the total synthesis of garsubellin A, a concise stereocontrolled synthesis of the 18-epi-tricyclic compound 3
was achieved. Key steps were a one-pot stereoselective construction of the bicyclic lactone 23 followed by a formal migration to the bicyclo-
[3.3.1]nonane-1,3,5-trione and an intramolecular Wacker-type tetrahydrofuran ring formation.
There is an increasing demand for agents to treat neuro-
degenerative diseases, such as Alzheimer disease. Degenera-
tion of cholinergic neurons is implicated in Alzheimer
disease; thus compounds that can protect neurons or promote
their survival (neurotrophic mimics) could provide promising
pharmaceutical leads.1 Garsubellin A (1, Figure 1), which
garsubellin A is a polyprenylated phloroglucin derivative,
characterized by a highly oxygenated and densely substituted
bicyclo[3.3.1]nonane-1,3,5-trione core fused to a tetra-
hydrofuran ring and appended by a prenyl side chain.
Nicolaou et al. recently reported the synthesis of the bicyclic
core, using a selenium-mediated cyclization.3 We are inter-
ested in the structure and activity of garsubellin A, snd started
a total synthesis project. Here, we describe our efforts, in
model systems 2 and 3, to construct the most advanced
tricyclic core of garsubellin A.
Our initial retrosynthetic analysis is shown in Scheme 1.
The prenyl group at the C-2 position should be introduced
at the last stage via Stille coupling between tributylprenyltin
(5) and vinyl iodide 4. The tetrahydrofuran ring of 4 should
be constructed via an intramolecular Wacker-type reaction
of enone 6. For key construction of the bicyclo[3.3.1]nonane-
(1) Cacabelos, R.; Lombardi, A.; Fernandez-Novoa, L.; Corzo, L.; Perez,
P. Laredo, M.; Pichel, V.; Hernandez, A.; Varela, M.; Figueroa, J.; Prous,
J.; Windisch, M. Vigo, C. Drugs Today 2000, 36, 415-499.
(2) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull. 1997,
45, 947-949.
(3) (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Kim, S.; Wei, H. X. J. Am.
Chem. Soc. 1999, 121, 4724-4725. (b) Nicolaou, K. C.; Pfefferkorn, J.
A.; Cao, G.-Q.; Kim, S.; Kessabi, J. Org. Lett. 1999, 1, 807-810.
Figure 1. Garsubellin A (1) and our model (2 and 3)
was isolated by Fukuyama et al.,2 potently induces choline
acetyltransferase (ChAT), which is a key enzyme in the
synthesis of the neurotransmitter acetylcholine. Structurally,
10.1021/ol0255965 CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/08/2002

Scheme 1. Retrosynthetic Strategy
Scheme 2a
a Conditions: (a) 1. CuI (0.07 equiv), MeMgBr, Me2S-THF; 2.
isobutyraldehyde, 55%; (b) TBSOTf, 2,6-lutidine, CH2Cl2, 59%;
(c) 1. KHMDS, THF; 2. BrCH2CO2Et, HMPA, 85%; (d) DIBAL-
H, CH2Cl2, 88%; (e) TMSCN, Et3N (cat.), CH2Cl2; (f) CuCN/MeLi
) 1/3, Et2O; H+, 55% (2 steps); (g) MeMgBr, Et2O, 83%; (h)
dimethoxyacetone, PPTS, DMF, 80%; (i) BF3‚OEt2, CHCl3; (j)
Dess-Martin periodinane, CH2Cl2, 80% (2 steps).
1,3,5-trione core of 6, we planned a one-pot Michael
addition-elimination (bond-formation at C-4) followed by
a Dieckmann ester condensation (bond-formation at C-6)
between nucleophile 7 and electrophile 8. The face-selectivity
of the electrophile entry to 7 might be controlled by the
stereochemistry of C-18; however, it could not be predicted
at this stage. We planned to construct the secondary alcohol
at C-18 via a cyanosilylation of aldehyde 10 to extend this
synthetic approach to a catalytic enantioselective synthesis
of garsubellin A.4,5 Eventually, the relative stereochemistry
between C-18 and C-4, -6, and -27 was not a major concern
because the stereochemistry of the latter three carbons
disappeared at the later stage. Aldehyde 10 should be rapidly
synthesized via a Michael-aldol reaction and a regioselective
alkylation of 3-methylcyclohexen-2-one (11).
The initial stage of the synthesis is shown in Scheme 2.
Catalytic conjugate addition of methylcuprate to enone 11
followed by a kinetic trap of the resulting magnesium enolate
with isobutyraldehyde gave threo-isomer 12 as the sole
stereoisomer.6 After protection of the alcohol with a TBS
group, the kinetically formed potassium enolate of 13 was
alkylated with ethyl bromoacetate through an axial attack to
give the trans-isomer 14 with complete selectivity. The ester
group was selectively reduced using DIBAL-H, and aldehyde
10 was obtained in four steps from 11. Cyanosilylation of
10 in the presence of a catalytic amount of Et3N7 gave
cyanohydrin 9 as a mixture of diastereomers (1.3:1), which
was converted to methyl ketone 158 using a higher order
cuprate prepared from CuCN and MeLi in a 1:3 ratio.9
Selective methylation of the methyl ketone gave diol 16,
which was protected as an acetonide to give 17. Deprotection
10
of the TBS group with BF3‚OEt2 and oxidation of the
resulting alcohol gave diketone 19 as a diastereo-mixture
(1.3:1).11
Having established a facile synthetic route to 19, the key
bicyclic core construction was studied intensively.12 To
determine the feasibility of this idea, we first attempted a
step-by-step reaction (Scheme 3). After deprotonation of 19
(4R*,6R*,18R*) with KOtBu, the corresponding enolate was
treated with electrophile 20.13 The resulting major product
was 21 (ca. 50%), which was formed through a Michael
addition-elimination reaction at C-4 (garsubellin number-
ing), together with Claisen condensation product 22 (10%).
These results indicated that the steric factor, not the pKa value
(4) We developed general enantioselective catalysts for cyanosilylation
of aldehydes: (a) Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 1999, 121, 2641-2642. (b) Kanai, M.; Hamashima, Y.;
Shibasaki, M. Tetrahedron Lett. 2000, 41, 2405-2409.
(5) Preliminary results indicated the feasibility of this idea (see the
following scheme). Absolute configurations of the cyanohydrins are
temporarily assigned from the preceding examples (ref 4b).
(7) Cyanosilylation promoted by a Lewis acid catalyst (Et2AlCl) failed.
For Lewis base-catalyzed cyanosilylation of aldehydes, see: (a) Evans, D.
A.; Truesdale, L. K. Tetrahedron Lett. 1973, 49, 4929-4932. (b) Kobayashi,
S.; Tsuchiya, Y.; Mukaiyama, T. Chem. Lett. 1991, 537-540.
(8) The diastereomers of 15 or 19 could be separated by column
chromatography. We continued the synthesis as a diatereo-mixture, because
the stereochemistry of C-4, -6, and -27 disappeared at the later stage.
(9) Reactions using a normal higher order cuprate (CuCN/MeLi ) 1/2)
gave unpredictable results. On the other hand, reactions performed under
the conditions described in the text were completely reproducible.
(10) Kelly, D. R.; Roberts, S. M.; Newton, R. F. Synth. Commun. 1979,
9, 295-299.
(11) The relative configuration was determined by X-ray analysis.
(12) These preliminary studies were conducted with the diastereomeri-
cally pure compound.
(13) 20 was prepared from the corresponding carboxylic acid: Grandjean,
D.; Pale, P.; Chuche, J. Tetrahedron 1993, 49, 5225-5236.
(6) Other isomers emerged through a retro aldol-aldol sequence, if the
reaction temperature was raised to slightly over -70 °C or if there was a
long reaction time (>1 h). For an organocuprate conjugate addition-threo-
selective aldol reaction, see: Heng, K. K.; Smith R. A. J. Tetrahedron 1979,
35, 425-435.
860
Org. Lett., Vol. 4, No. 5, 2002

Scheme 3. Preliminary Results of the Cyclization Reaction
Table 1. Optimization of Cyclization Reaction
23 +
entry
1
19
conditions
24/%a
4R*,6R*,18R* 1. KOtBu (2 equiv), -78 °C, 1 h
2. 20 (3 equiv), -78 °C, 1 h
15
3. KOtBu (2.1 equiv), -78 °C to rt, 16 h
4R*,6R*,18R* 1. KOtBu (2.1 equiv), -78 °C, 1 h
2. LiBr (2.5 equiv), -78 °C, 1 h
2
3
16
3. 20 (1.5 equiv), -78 °C to rt
4. DMAP (3 equiv), -78 °C to rt, 16 h
4R*,6R*,18R* 1. KOtBu (2.1 equiv) -78 °C, 1 h
2. LiBr (3 equiv), -78 °C, 1 h
40
3. 20 (3 equiv), -78 °C, 3 h
4. DMAP (6 equiv), 12-crown-4,
(6 equiv) -78 °C to rt, 36 h
4
4R*,6R*,18R* 1. KOtBu (3 equiv), -78 °C, 100 min
2. LiClO4 (4.5 equiv), -78 °C, 50 min
3. 20 (2 equiv), -78 °C, 5.5 h
76
(25:1)b
of R-protons, determined the position of the deprotonation,
and sterically less hindered C-4 was selectively deproto-
nated.14 Isolated 21 was then treated with a second base
(KOtBu or KHMDS); however, no cyclization occurred,
probably due to the trans geometry of the carbon-carbon
double bond (Scheme 3, (1)). On the other hand, when the
crude mixture was treated with KOtBu, cyclized compounds
23 + 2415 were obtained, albeit in low yield (20%) (Scheme
3, (3)). Although 23 + 24 (O-acylated compounds) were not
the compounds we initially expected (i.e., C-6-acylated
compound), there was a great possibility of accessing the
desired bicyclic system from these compounds. We rational-
ized the partial success of the cyclization as follows: because
of the side reaction of the Claisen condensation, the crude
mixture should contain a p-nitrophenol, which could perform
a conjugate addition to the R,â-unsaturated ester part of 21
(+ diastereomer) in the presence of a base in the cyclization
step. This should make the activated ester accessible to the
nucleophilic oxygen atom, and O-acylation followed by
elimination of the p-nitrophenoxide should give unsaturated
lactones 23 + 24. Consistent with this rationale, 23 was
obtained in ca. 20% yield from isolated 21, when p-
nitrophenol was added to the reaction mixture of the
cyclization step (Scheme 3, (2)).
These promising results prompted us to investigate the
possibility of one-pot cyclization from 19 (Table 1). Detect-
ing the formation of 21 on TLC after the first step, KOtBu
was then added and the reaction temperature was allowed
to rise to room temperature (entry 1). This one-pot procedure
gave the target bicyclic compounds in 15% yield, which was
only slightly worse than the two-step procedure. Tracing the
reaction by TLC indicated that the low yield of 23 + 24
should be attributed to the first Michael addition-elimination
step, possibly due to the high nucleophilicity of the potassium
enolate. Therefore, we planned to convert the initially formed
potassium enolate to a milder nucleophile by transmetalation.
Although transmetalation to the zinc enolate with ZnCl2 did
4. DMAP (5 equiv), 12-crown-4
(6 equiv), -78 °C to rt, 30 h
5
6
4S*,6S*,18R* same as entry 4
63
(5:1)b
71
4R*,6R*,18R* same as entry 4
+
(11:1)b
4S*,6S*,18R*
a Isolated yield after purification. b Ratio of 23:24.
not give the initial product 21, the lithium enolate formed
through the transmetalation with LiBr gave a clean conver-
sion to 21.16 This time, however, the second cyclization step
became problematic due to the lower nucleophilicity of the
lithium enolate at C-6 compared to the potassium enolate,
even in the presence of DMAP as an activating reagent of
the electrophile (entry 2). To improve the nucleophilicity of
the C-6 lithium enolate for the cyclization, we added 12-
crown-4 and the yield of 23 + 24 improved to 40% (entry
3). Transmetalation with LiClO4, instead of LiBr, gave 23
+ 24 in a much higher yield of 76% (entry 4). Although
predominant isomer 23 was the unnatural one (18-epi), this
one-pot cyclization is useful for the synthesis of the epi-
form.17 This reaction was also applicable to the other
diastereomer 19 (4S*,6S*,18R*), and 23 + 24 were obtained
in 63% yield with a ratio of 5:1, again with 23 as the major
isomer (entry 5).18 Finally, even using a mixture (1.3:1) of
19 (4R*,6R*,18R*) and 19 (4S*,6S*,18R*), 23 + 24 were
obtained in 71% yield (23:24 ) 11:1), which greatly
simplified the synthetic route.
With lactone 23 at hand, the next task was to convert the
lactone to the [3.3.1] bicyclic system (Scheme 4). The results
described above suggested that it was necessary to use a
softer electrophile, such as an aldehyde, instead of a hard
(16) Direct formation of the lithium enolate with LiOtBu failed due to
the lower basicity of the base.
(17) Preliminary studies to reverse the stereoselectivity of this one-pot
cyclization revealed that employing a cyclic carbonate for the protecting
group of the diol instead of the acetonide gave an ca. 1:1 mixture of
diastereomers. Although the origin of the high stereoselectivity in the case
of acetonide-protected 19 is not clear, coordination of the 18-oxygen atom
to the lithium atom of the enolate might fix the substrate conformation to
block the entry of the electrophile from the â-side.
(14) The possibility that the reaction proceeded through a dianion could
be excluded because the reaction using 1.2 equiv of KOtBu under the
optimized conditions (see below) gave 23 + 24 in 43% yield.
(15) The structure of 23 was unequivocally determined by X-ray
crystallography. See Supporting Information for details.
(18) These results indicated that the observed high stereoselectivity was
derived from the C-18 configuration.
Org. Lett., Vol. 4, No. 5, 2002
861

the pentamethyldisilyl group21 was best for our purpose.
Thus, pentamethyldisilyllithium reacted with 23 in a 1,4-
fashion to give 25 in 91% yield. Lactone 25 was next
converted to thiol ester 26 using an aluminum thiolate;22 then
26 was reduced under Fukuyama conditions23 to aldehyde
27. Successive treatment of 27 with a base (K2CO3/MeOH)
and Dess-Martin periodinane gave 29 containing a bicyclo-
[3.3.1]nonane-1,5-dione structure (98% from 26). â-Silyl
ketone 29 was then converted to enone 30 in one pot through
a modified Tamao-type oxidation24 followed by â-elimina-
tion.
Scheme 4a
Having established the synthesis of the bicyclic core, the
stage was set for the construction of the tetrahydrofuran ring
and introduction of the prenyl group at C-2 to complete the
synthesis. These manipulations were achieved in three steps
(Scheme 4). When 30 was subjected to Wacker oxidation
conditions,25 deprotection of the acetonide first occurred,
followed by an intramolecular Wacker-type reaction, giving
tricyclic compound 31 in 69% yield. Oxidative vinyl iodide
formation26,27 followed by Stille coupling with tributyl-
prenyltin28 completed the synthesis of 18-epi-8-deprenyl-
garsubellin A (3).
In summary, we developed a concise stereocontrolled
synthetic route for a model compound that contains the
tricyclic core of garsubellin A. The chemistry described in
this paper should be very useful, not only for the total
synthesis of garsubellin A but also for related natural
compounds.29 Efforts toward a total synthesis of garsubellin
A are currently ongoing.
a Conditions: (a) Me5Si2Li, THF-HMPA, 91%; (b) Me2AlSEt,
CH2Cl2, 96%; (c) Et3SiH, Pd/C, CH2Cl2; (d) K2CO3, MeOH; (e)
Dess-Martin periodinane, CH2Cl2, 98% (3 steps); (f) 1. mCPBA,
CH2Cl2; 2. TBAF, THF, 77%; (g) Na2PdCl4 (40 mol %), TBHP,
AcOH-H2O, 69%; (h) I2, CAN, CH3CN, 84%; (i) PdCl2(dppf),
tributylprenyltin, DMF, 39%.
Acknowledgment. Financial support was provided by
RFTF of the Japan Society for the Promotion of Science.
activated ester to achieve the desired carbon (C-6)-carbon
(C-1) bond formation. Considering the geometric instability
of an enal derived from 23, we first masked the carbon-
carbon double bond of the unsaturated lactone by introducing
a silicon atom. This transformation should facilitate the
desired cyclization because of the increased flexibility of the
electrophile to reach the C-6 nucleophilic center. Further-
more, the silicon-carbon bond should be stable enough to
tolerate several conversions, and it should be possible to
regenerate an olefin via Tamao oxidation19 and elimination,
when necessary. After intensive effort,20 we determined that
Supporting Information Available: Experimental pro-
cedures and characterization of new compounds, including
X-ray data (cif). This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0255965
(22) Hatch, R. P.; Weinreb, S. M. J. Org. Chem. 1977, 42, 3960-3961.
(23) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112,
7050-7051.
(24) Suginome, M.; Matsunaga, S.; Ito, Y. Synlett 1995, 941-942.
Reaction under normal Tamao-oxidation conditions failed, possibly due to
the instability of the intermediate alcohol under basic conditions.
(25) Tsuji, J.; Nagashima, H.; Hori, K. Chem. Lett. 1980, 257-260.
(26) Zhang, F. J.; Li, Y. L. Synthesis 1993, 565-567.
(27) The structure of 4 was unequivocally determined by X-ray crystal-
lography. See the Supporting Information for details.
(28) Naruta, Y.; Nishigaichi, Y.; Maruyama, K. Org. Synth. 1992, 71,
118-124.
(19) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599-7662.
(20) We tried dimethylphenylsilyl, (diethylamino)diphenylsilyl, and
dimethyl(o-methoxy)phenylsilyl groups, in addition to the pentamethyldisilyl
group. The former two silyl groups could be introduced to 23 by conjugate
addition in high yields (>90%); however, later conversions were unsuc-
cessful. The third one (Lee, T. W.; Corey, E. J. Org. Lett. 2001, 3, 3337-
3339) did not produce the conjugate adduct to 23.
(21) (a) Krohn, K.; Khanbabaee, K. Angew. Chem., Int. Ed. Engl. 1994,
33, 99-100. (b) Barret, A. G. M.; Head, J.; Smith, M. L.; Stock, N. S.;
White, A. J. P.; Williams, D. J. J. Org. Chem. 1999, 64, 6005-6018.
(29) For examples, see: (a) Fukuyama, Y.; Minami, H.; Kuwayama, A.
Phytochemistry 1998, 49, 853-857. (b) Shan, M. D.; Hu, L. H.; Chen, Z.
L. J. Nat. Prod. 2001, 64, 127-130.
862
Org. Lett., Vol. 4, No. 5, 2002