Enantioselective total synthesis of (+)-galbulin via organocatalytic domino Michael-Michael-aldol condensation

Article abstract of DOI:10.1039/c2cc16682h

A concise and practical enantioselective synthesis of (+)-galbulin has been achieved using organocatalytic domino Michael-Michael-aldol condensation and organocatalytic kinetic resolution as the key steps. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc16682h

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COMMUNICATION
Enantioselective total synthesis of (+)-galbulin via organocatalytic
domino Michael–Michael–aldol condensationwz
Bor-Cherng Hong,*a Che-Sheng Hsua and Gene-Hsiang Leeb
Received 28th October 2011, Accepted 29th November 2011
DOI: 10.1039/c2cc16682h
A concise and practical enantioselective synthesis of (+)-galbulin
has been achieved using organocatalytic domino Michael–Michael–
aldol condensation and organocatalytic kinetic resolution as the
key steps.
The tetrahydronaphthalene carbon skeleton is prevalent in
Scheme 1 Retrosynthetic analysis of galbulin (1).
many lignans, a class of secondary metabolites widely found in
plants which are derived biosynthetically from the oxidative
Whitby14 and Charlton15 described the stereoselective synthesis
dimerization of two phenylpropanoid (cinnamic acid) units.
of (ꢀ)-galbulin using a metal-mediated cyclization of a 1,7-diene
The lignans possess a vast array of biological activities and
and acid-catalyzed cyclizations of E,E-dibenzylidenesuccinate
have been used as folk remedies in treating an assortment of
esters, respectively. However, the enantioselective total synthesis
maladies. Contemporarily, the significant pharmacological
of galbulin has not yet been realized. Herein, we describe the
activities of lignans include anti-inflammatory, antioxidant,
application of organocatalysis in the first enantioselective total
anti-tumor, antiviral, cardiovascular, anti-HIV, and immuno-
suppression properties, and are of immense interest to scientists.1
synthesis of (+)-galbulin.
At the outset, a suspension of 3,4-dihydro-2-methoxy-4-
The significant bioactivities and structural diversity of lignans
have driven many efforts for the total synthesis of lignans,2
methyl-2H-pyran (5) in H2O was treated with concentrated
especially the tetrahydronaphthalenes (THN)3 and the dihydro-
aqueous HCl solution and stirred for 2 h until the solution
naphthalenes (DHN).4 The most prominent examples of these
turned clear. The solution was then neutralized by slow
compounds include the anti-cancer drugs: podophyllotoxin,5
addition of NaHCO3 powder until the pH value reached 7.
To the solution of crude 3-methylpentanedial16,17 was slowly
added a solution of 1-triphenylphosphoranylidene-2-propanone
in CH2Cl2 over 1.5 h and the mixture was stirred for an
additional 14 h at ambient temperature to give (E)-3-methyl-7-
oxooct-5-enal (3) in 54% overall yields for the two consecutive
reactions (Scheme 2). At the outset of the study of the key
reaction of the synthesis, i.e., the organocatalytic double
Michael reaction, a nearly 1 : 1 ratio of ketoaldehyde 3 and
aldehyde 418 was reacted with Jørgensen–Hayashi catalyst I
(20 mol%) and acetic acid in CH3CN. After many days of
reaction, the reaction reached only B50% conversion without
further progress. Thus, ketoaldehyde 3 and aldehyde 4 were
then reacted in a ratio of 2.4 : 1 under the same reaction
conditions for 3 days until the complete consumption of
aldehyde 4, followed by the addition of p-TsOH with stirring
for an additional 5 h to give the adduct (+)-2 as the only
observable stereoisomer in 82% yield.19 This result supports
the idea that a kinetic asymmetric transformation (KAT) of
racemic 3 took place, and the proposed mechanism is depicted
in Scheme 3 to account for the resulting stereoselectivity
in KAT. The initial Michael addition of (S)-3 to aldehyde
4-iminium activated from the Re face under the control of
catalyst, via the transition state TS A, gives intermediate I-1,
which cyclizes by the second Michael reaction to afford I-2.
etoposide,6 and conidendrin.7 Despite these synthetic advances,
enantioselective total synthesis of the THN lignans by organo-
catalysis has not been reported. Nevertheless, inspired by the
burgeoning number of organocatalytic and cascade reactions,8
elegant applications of organocatalysis in natural product syntheses
have recently been demonstrated.9 In continuing our efforts in
exploring new organocatalytic annulations,10,11 we envisioned an
approach to this system via a domino Michael–Michael–aldol
condensation (Scheme 1) that targeted galbulin, a natural lignan
first isolated from Himantandra baccata and Himantandra
belgraveana.12 Although syntheses of galbulin have been reported,
most of them start from other known lignans of similar structure
and proceed by stepwise interconversion reactions.13
a Department of Chemistry and Biochemistry,
National Chung Cheng University, Chia-Yi 621, Taiwan, R.O.C.
E-mail: chebch@ccu.edu.tw; Fax: +886 5 2721040;
Tel: +886 5 2428174
b Instrumentation Center, National Taiwan University, Taipei, 106,
Taiwan, R.O.C.
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
details, spectroscopic characterization and HPLC analysis. CCDC 844400.
For ESI and crystallographic data in CIF or other crystallographic data see
DOI: 10.1039/c2cc16682h
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2385–2387 2385

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Fig. 1 Stereo plot of the X-ray crystal structure of (+)-2: C, gray;
O, red, and the ORTEP diagram (thermal ellipsoids drawn at the 30%
probability level).
(MnO2, CH2Cl2, rt, 12 h) to give alcohol 6 in 98% overall yield
for the two consecutive reactions (Scheme 2). The subsequent
attempts at the introduction of the hydroxy group on the ring
system and aromatization were tricky and many efforts to
complete the transformation were futile. Finally, the transforma-
tion was achieved via a reaction sequence of epoxidation, oxida-
tion, and aromatization. Specifically, epoxidation of 6 with H2O2
in aqueous methanolic NaOH solution for 2 h gave 80% yield of
the epoxide 7. We purified a small amount of epoxide 7 for
analysis, but in general, the product was unstable upon silica gel
chromatography. In the routine process, epoxide 7 was obtained
but not purified and was used as the crude product for the next
reaction step. Aromatization of 7 to 9 required a special reaction
condition and was achieved in a two-step reaction sequence.
A solution of 7 in MeOH and KOH (3.5 equiv.) was heated to
reflux for 10 min to afford enone 8, followed by evaporation
of the major part of MeOH to give a sticky residue21 and the
mixture was then heated to 120 1C for 50 min to provide the
methoxyphenol 9 in 44% yield. Methylation of alcohol 9 with
methyl iodide and K2CO3 in acetone at room temperature for
12 h produced 95% yield of dimethoxytetrahydronaphthalene
10. Finally, treatment of alcohol 10 with MsCl in Et3N and
CH2Cl2 gave the corresponding mesylate which was reduced by
superhydride, lithium triethylborohydride, in THF to afford the
(+)-galbulin (1) in 80% yield.22
Scheme 2 Total synthesis of galbulin (1).
In summary, we have achieved the first enantioselective
synthesis of (+)-galbulin in 11% overall yield through 12 reaction
steps with 7 isolations and purifications of the intermediates.
Noteworthy features of the synthesis include: (1) the highly
stereoselective organocatalyzed domino Michael–Michael–
aldol condensation, which was effective for constructing the
skeleton, (2) an unusual kinetic resolution of (ꢀ)-3 with a
remote stereocenter, (3) special operation and mild conditions
in the oxidation and aromatization of the cyclohexenone
system. The synthesis demonstrated a successful strategy and
provides a venue for the application of organocatalyzed domino
Michael–Michael–aldol condensations to a natural product
synthesis. Further applications of this protocol in the synthesis
of other elaborate natural products are currently underway.
We acknowledge the financial support for this study from
the National Science Council (NSC), Taiwan, R.O.C. Thanks
to the National Center for High-Performance Computing
(NCHC) for their assistance in literature searching, and the
instrument center of NSC for compounds analysis. Initial study
Scheme 3 Proposed mechanisms for the organocatalytic domino
Michael–Michael–aldol condensation.
After the addition of p-TsOH, aldol reaction of I-2 followed
by dehydration to provide the hexahydronaphthalenone (+)-2
took place. Alternatively, Michael addition of (R)-3 to aldehyde
4-iminium via the transition state TS B suffers a severe steric
hindrance and hampers the subsequent reactions, and results in
the observation of kinetic resolution of (ꢀ)-3. The structure of
(+)-2 was assigned unambiguously by the X-ray analysis (Fig. 1).
Thus, the origin of the stereoselectivity in this Michael–Michael
reaction of 3 to 4 by the Jørgensen–Hayashi catalyst was identical
to that observed in the similar examples of our earlier study in the
organocatalytic domino Michael–Michael–aldol condensation.20
Reduction of (+)-2 with NaBH4 and CeCl3ꢁ7H2O in methanol
at 0 1C for 2 h gave the corresponding diol, without further
purification, which was subjected to selective allylic oxidation
c
2386 Chem. Commun., 2012, 48, 2385–2387
This journal is The Royal Society of Chemistry 2012

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of the organocatalytic domino Michael–Michael–aldol conden-
sation by Dr Roshan Y. Nimje, help in the HPLC analysis by
Mr Nitin S. Dange, and the help from Miss Wan-Chen Chang
are all acknowledged.
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19 Adduct (+)-2 was the only observed isomer, dr 4 20 : 1, 99% ee.
20 See ref. 10g; in the previous study, the absolute configurations of
the products were assigned based on the X-ray analysis of the
adducts; with the subtle differences in the substituents on 3 and 4,
(+)-2 should have the same enantioselectivity as the previous
examples. In fact, the subsequent transformation of (+)-2 to
(+)-galbulin further supports the conclusion, vide infra.
21 A small amount, but not too much, of MeOH is necessary in the
beginning of the reaction to dissolve KOH and 8.
10 For our recent efforts in exploring new organocatalytic annula-
tions, see: (a) B.-C. Hong, P. Kotame and G.-H. Lee, Org. Lett.,
2011, 13, 5758; (b) B.-C. Hong, R. Y. Nimje, C.-W. Lin and
J.-H. Liao, Org. Lett., 2011, 13, 1278; (c) B.-C. Hong, N. S.
Dange, C.-S. Hsu, J.-H. Liao and G.-H. Lee, Org. Lett.,
22 The synthetic material was identical in all respects (1H, 13C NMR)
to the literature data, see ESIz for details.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2385–2387 2387