Total synthesis of (±)-garsubellin A

Article abstract of DOI:10.1021/ja055301t

The first total synthesis of garsubellin A, a neurotrophic compound with potent choline acetyltransferase-inducing activity, is described. Keys for success were (1) stereoselective intermolecular aldol reaction at the C-4 position with acetaldehyde, (2) stereoelective Claisen rearrangement to introduce an allyl group to the most sterically crowded position at C-6, (3) ring-closing metathesis to construct the B-ring, and (4) Wacker-type oxidative C-ring formation. This synthetic route can be extended to an asymmetric synthesis of garsubellin A using the Koga catalytic enantioselective alkylation, which produced enantioenriched α-prenyl cyclohexenone with excellent enantioselectivity (95% ee). Copyright

Full text of DOI:10.1021/ja055301t

Published on Web 09/21/2005
Total Synthesis of (()-Garsubellin A
Akiyoshi Kuramochi, Hiroyuki Usuda, Kenzo Yamatsugu, Motomu Kanai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Tokyo 113-0033, Japan
Received August 12, 2005; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Scheme 1. Synthetic Plan for Garsubellin A
Garsubellin A (1) was isolated from Garcinia subelliptica by
Fukuyama et al., and its structure was determined through intensive
NMR studies.1 Structurally, garsubellin A is a polyprenylated
phloroglucin derivative that contains a characteristic highly con-
gested bicyclo[3.3.1]nonane-1,3,5-trione core fused to a tetrahy-
drofuran ring. Garsubellin A has potent neurotrophic activity by
inducing choline acetyltransferase, a key enzyme for physiologic
acetylcholine synthesis in the nervous system. Due to its significant
biological activity and challenging structure, garsubellin A is an
attractive synthetic target.2 In this communication, we report the
first total synthesis of garsubellin A.
The most difficult step in the synthesis of 1 was anticipated to
be the construction of the extremely congested quaternary carbon,
C-6. Our previous studies targeting 8-deprenyl garsubellin A2e
demonstrated that the B-ring could be constructed via an intramo-
lecular aldol-type reaction between C-1 and C-6 (Scheme 2;
R ) H). When this strategy was applied to the real system (R )
prenyl, Scheme 2), however, the desired cyclization did not proceed,
possibly due to the destabilization of the reactive conformation for
this cyclization by the prenyl group.
On the basis of these preliminary results, we developed a new
synthetic plan, as shown in Scheme 1. The prenyl group at C-2
would be introduced at the last stage through Stille coupling
between a prenyl tin reagent and vinyl iodide 2. The C-ring in 2
would be constructed via a Wacker-type oxidative cyclization of
hydroxyenone 3. For the key B-ring formation, we planned to apply
ring-closing metathesis (RCM) to diene 4, which would be produced
via Claisen rearrangement of allyl ether 5. The precursor ketone
for 5 would be produced through a stereoselective aldol condensa-
tion at C-4 followed by dihydroxylation from 6, which can be
rapidly assembled from enone 7. The advantages of this new
strategy for B-ring formation, compared to the previous intramo-
lecular aldol strategy, include the following: (1) irreversibility and
robustness of RCM in six-membered ring formation; (2) the
connection at the C-2-C-3 bond is entropically more favorable
than the previous C-1-C-6 connection. We expected that the two
alkenes at C-4 and C-6 should be introduced in a cis fashion, which
is an essential requirement for RCM, based on the following
considerations: (1) Claisen rearrangement of 5 will produce the
desired R-allylated product 4 stereoselectively via a six-membered
chair transition state; (2) intermolecular aldol reaction at C-4 will
proceed from the R-face through an axial attack.
We began our synthesis with enone 7 prepared from com-
mercially available 8 via prenylation followed by methylation and
acid hydrolysis of the vinyl ether. Cu-catalyzed conjugate addition
of the methyl group and an in situ trapping of the resulting
magnesium enolate by isobutyraldehyde gave the anti-aldol product
as a major isomer (anti:syn ) >50:1, 4:1 of two possible anti-
isomers), which was protected by a TIPS group to give 9. After
protecting the prenyl group using Mukaiyama hydration,3 a second
prenyl group was introduced to C-4 predominantly (>30:1) at the
axial position to give 6. Because C-6 is significantly more crowded
Scheme 2. Intramolecular Aldol Strategy (from ref 2e)
than C-4, selective deprotonation occurred at C-4 to produce
∆(4,5)-enolate when 6 was treated with base.4 Thus, aldol reaction
with acetaldehyde proceeded selectively (>50:1) at C-4 from the
R-side (axial attack). Dehydration of this aldol to 10 was con-
ducted using Martin sulfurane. Chemoselective dihydroxylation of
the prenyl group was possible at this stage using AD-mix-R
(diastereoselectivity ) 1:1), giving diol 11.5 Protection of the diol
as its carbonate, followed by desilylation and oxidation, produced
diketone 12.
The crucial B-ring formation was accomplished in three straight-
forward steps from 12: O-allylation,6 stereoselective Claisen
rearrangement through a hypothetical transition state 13 (>50:1),
and ring-closing metathesis using the Hoveyda-Grubbs catalyst
14.7 Allylic oxidation of 15 under Barton’s conditions8 produced
the corresponding enone in excellent yield. The order of the
following conversions was crucial for the success of the total
synthesis. First, the MOM ether was cleaved using CSA to give
the tertiary alcohol 16. Next, hydrolysis of the carbonate (giving
3) followed by Wacker oxidative cyclization produced 17. Then,
iodination and dehydration under acidic conditions to regenerate
the prenyl group at C-8 produced vinyl iodide 2. Finally, Stille
coupling of 2 with tributyl prenyl tin completed the total synthesis
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10.1021/ja055301t CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Total Synthesis of (()-Garsubellin Aa
i
a Conditions: (a) LDA; prenyl bromide, Bu4NI. (b) MeLi‚LiBr; HCl, 100% (two steps). (c) MeMgBr, CuI (22 mol %); PrCHO, 61%. (d) TIPSOTf,
i
2,6-lutidine, 92%. (e) PhSiH3, Co(acac)2 (20 mol %), O2, 73%. (f) MOMCl, Pr2NEt, Bu4NI, 96%. (g) KHMDS, prenyl bromide, Bu4NI, 98%. (h) LDA,
TMEDA; CH3CHO, 94%. (i) Martin sulfurane, 98%. (j) AD-mix-R (0.4 mol % of Os), CH3SO2NH2. (k) Triphosgene, pyridine; separation, 30% (two steps).
(l) HF‚pyridine. (m) PDC, Celite, 70% (two steps). (n) NaHMDS, MS4A, ethylene carbonate; allyl iodide, 82%. (o) NaOAc, 200 °C, 96%. (p) 14 (20 mol
%), 92%. (q) (PhSe)2, PhIO2, pyridine. (r) CSA, 70% (two steps). (s) LiOH. (t) Na2PdCl4, TBHP, 71% (two steps). (u) I2, CAN. (v) p-TsOH‚H2O, 80% (two
steps). (w) PdCl2‚dppf, tributyl prenyl tin, 20%.
1H and 13C NMR charts of garsubellin A. We also thank the late
Professor Kenji Koga and Dr. Kei Manabe (RIKEN Institute) for
Scheme 4. Application of Koga Alkylation to Asymmetric
Synthesis of Garsubellin Aa
providing and allowing us to use unpublished chiral amine 18 for
the Koga alkylation.
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Conditions: (a) MeLi‚LiBr, 18 (5 mol %), Me2N(CH2)3NMe2, prenyl
bromide. (b) MeLi; (c) PCC, 93% (two steps).
References
of (()-garsubellin A. Spectroscopic data (1H NMR, IR, MS,
HRMS) of synthetic 1 were completely identical to the isolated
garsubellin A.
(1) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull. 1997,
45, 947.
(2) For synthetic studies of garsubellin A, see: (a) Nicolaou, K. C.;
Pfefferkorn, J. A.; Kim, S.; Wei, H. X. J. Am. Chem. Soc. 1999, 121,
This synthesis can be extended to an asymmetric synthesis of
garsubellin A using the catalytic enantioselective alkylation method
developed by Koga9 (Scheme 4). Koga alkylation of the lithium
enolate derived from 2-cyclohexenone produced the prenylated
product 19 with 95% ee in the presence of chiral amine 18 (5 mol
%). 19 was converted to enone 7 (enantioenriched form), an early-
stage intermediate in our synthesis, via the addition of MeLi to the
ketone followed by allylic rearrangement using PCC.
In conclusion, we have achieved the first total synthesis of
garsubellin A. The keys for success are (1) the stereo- and regio-
selective introduction of the vinyl group at C-4 via aldol condensa-
tion, (2) the stereoselective allylation at C-6 via Claisen rearrange-
ment, and (3) ring-closing metathesis for construction of the
sterically congested B-ring. On the basis of these results, catalytic
asymmetric synthesis of garsubellin A and studies of its biological
activity are currently ongoing.
4724. (b) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q.; Kim, S.; Kessabi,
J. Org. Lett. 1999, 1, 807. (c) Nicolaou, K. C.; Carenzi, G. E. A.; Jeso,
V. Angew. Chem., Int. Ed. 2005, 44, 3895. (d) Usuda, H.; Kanai, M.;
Shibasaki, M. Org. Lett. 2002, 4, 859. (e) Usuda, H.; Kanai, M.; Shibasaki,
M. Tetrahedron Lett. 2002, 43, 3621. (f) Spessard, S. J.; Stoltz, B. M.
Org. Lett. 2002, 4, 1943. (g) Kraus, G. A.; Nguyen, T. H.; Jeon, I.
Tetrahedron Lett. 2003, 44, 659. (h) Kraus, G. A.; Dneprovskaia, E.;
Nguyen, T. H.; Jeon, I. Tetrahedron Lett. 2003, 44, 8975. (i) Ciochina,
R.; Grossman, R. B. Org. Lett. 2003, 5, 4619. (j) Mehta, G.; Bera, M. K.
Tetrahedron Lett. 2004, 45, 1113. (k) Young, D. G.; Zeng, D. J. Org.
Chem. 2002, 67, 3134.
(3) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 1071.
(4) Attempted alkylation of the enolate failed on substrates in which the prenyl
group had been dihydroxylated.
(5) Using AD-mix-â retarded the reaction without changing the selectivity.
Prenyl group-selective dihydroxylation was not possible after cleavage
of the TIPS group.
(6) (a) Ethylene carbonate was added to prevent undesired carbonate
hydrolysis. (b) Although the regioselectivity of this enolization/O-allylation
was not rigorously determined, either of the two possible products (5 or
C-27 allyl ether) can stereoselectively give 4 via Claisen rearrangement.
(7) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 8168.
Acknowledgment. Dedicated to the memory of Professor Kenji
Koga. Financial support was provided by a Grant-in-Aid for
Specially Promoted Research of MEXT. We thank Professor
Yoshiyasu Fukuyama in Tokushima Bunri University for providing
(8) Barton, D. H. R.; Crich, D. Tetrahedron 1985, 41, 4359.
(9) Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K. J. Am. Chem.
Soc. 1994, 116, 8829.
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