Total synthesis of eustifolines A-D and glycomaurrol via a divergent Diels-Alder strategy

Article abstract of DOI:10.1021/ol070381m

The Diels-Alder reaction between a quinone monoimine and cyclic diene allows for the construction of substituted carbazoles in a regiospecific manner. This methodology has sucessfully been employed in a divergent strategy, culminating in the synthesis of

Full text of DOI:10.1021/ol070381m

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1883-1886
Total Synthesis of Eustifolines A
Glycomaurrol via a Divergent
−D and
Diels−Alder Strategy
Terry P. Lebold and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario,
London, Ontario, Canada N6A 5B7
makerr@uwo.ca
Received February 14, 2007
ABSTRACT
The Diels−Alder reaction between a quinone monoimine and cyclic diene allows for the construction of substituted carbazoles in a regiospecific
manner. This methodology has sucessfully been employed in a divergent strategy, culminating in the synthesis of eustifolines A
−D and
glycomaurrol.
The naturally occurring carbazoles glycomaurrol and gly-
comaurin (Figure 1) were isolated in 1989 from the stem
were isolated from the root bark of Murraya euchrestifolia,
a shrub growing in the central and southern parts of Taiwan;2
eustifoline A is in fact the same compound as glycomaurin.
Until this year, the only synthetic effort toward these
compounds has been the semisynthesis of glycomaurin by
Wickramasinghe and co-workers in 1989 in their efforts to
verify its structure.1 Very recently, the syntheses of two of
the members of this class (eustifoline D and glycomaurrol)
were reported by Kno¨lker and co-workers using an elegant
cross-coupling strategy to assemble the carbazole core of
the targets.3
The wide variety and important biological activity of
naturally occurring carbazoles have made them attractive
targets for organic synthesis.4 Although there are many useful
synthetic routes to some carbazoles, the regiocontrolled
preparation of these compounds with specific substitution
patterns remains a significant challenge to the synthetic
organic chemist.
Figure 1. Eustifolines A-D, glycomaurin, and glycomaurrol.
The substitution pattern represented by the title com-
pounds, namely, 5-alkyl-6-alkoxy (or hydroxyl), is particu-
bark of Glycosmis mauritiana, a small tree growing in the
dry zone of Sri Lanka.1 The following year, eustifolines A-D
(2) Ito, C.; Furukawa, H. Chem. Pharm. Bull. 1990, 38, 1548.
(3) Forke, R.; Krahl, M. P.; Krause, T.; Schlechtingen, G.; Kno¨lker, H.-
J. Synlett 2007, 268.
(1) Kumar, V.; Reisch, J.; Wickramasinghe, A. Aust. J. Chem. 1989,
42, 1375.
(4) Kno¨lker, H.-J.; Reddy, K. R. Chem. ReV. 2002, 102, 4303.
10.1021/ol070381m CCC: $37.00
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Published on Web 04/18/2007

larly elusive. Usually such compounds are prepared via a
Fischer indole synthesis with a cyclohexanone-derived hy-
drazone (and subsequent dehydrogenation),5 alkylation6
or Claisen rearrangement1 beginning with a 6-hydroxycar-
bazole, or annulation of an existing indole moiety.7 Draw-
backs to these methods include the lack of regiocontrol in
functionalizing an existing carbazole or the necessity to
prepare precursors with preexisting and extensive substitu-
tion.
in a number of ways to access the target molecules. Acid-
catalyzed ring closure of 10, for instance, yields eustifoline
D, whereas olefination of the aldehyde gives glycomaurrol.
Oxidative cyclization of glycomaurrol provides access to
eustifoline A (glycomaurin). Isopropenyl Grignard addition
to 10 and ketene acetal formation yield 11, which is a suitable
substrate for a Claisen rearrangement en route to eustifoline
C. Again, oxidative cyclization of eustifoline C can be
utilized to access eustifoline B.
We have recently reported a general synthesis of indoles8
which uses as its key transformation a Diels-Alder reaction
of a quinoid monoimine and subsequent Plieninger indoliza-
tion9 of the adducts (Scheme 1), as well as applications to
Scheme 3. Synthesis of Key Intermediates 13 and 14
Scheme 1. Synthesis of Indoles and Carbazoles
Our synthetic efforts commenced (Scheme 3) with the
readily available quinone imine 8 and diene 9 which
underwent a facile Diels-Alder cycloaddition in refluxing
CH2Cl2. Treatment of the resulting adducts with catalytic
DBU then afforded the desired aromatized species 12 as a
1:1 mixture of diastereomers in 91% overall yield.
The lack of diastereoselectivity in the formation of 12 was
of no concern because both stereocenters would later become
sp2 hybridized. The phenolic moiety was protected via
treatment with NaH and TIPSCl. Conversion of the dihy-
dronaphthalene to the tetrahydrocarbazole 13 was ac-
complished via oxidative cleavage of the double bond (via
the diol) followed by treatment of the resulting dicarbonyl
with acid to afford the desired tetrahydrocarbazole in 61%
yield over the four steps. Aldehyde reduction, tosyl removal,
and dehydrogenation yielded carbazole 14 in 89% yield over
the three steps. Tosyl removal was required to effect the
dehydrogenation. Reduction of the aldehyde was found
necessary to effect clean tosyl removal and dehydrogen-
ation.
target oriented synthesis.10 During our work, it occurred to
us that the use of a diene bearing a cyclohexyl ring fused at
the 1,2-positions would allow extension of this methodol-
ogy to the formation of carbazoles in a regiospecific
manner. In this communication, we illustrate the implemen-
tation of this strategy in the first total synthesis of eustifolines
A-C and alternative syntheses of glycomaurrol and eusti-
foline D.
Our divergent synthetic strategy has as its cornerstone the
synthesis of carbazole 10 or a closely related compound
(Scheme 2). The aldehyde group in 10 would be elaborated
Scheme 2. Synthetic Strategy
(5) Mulwad, V. V.; Dalvi, M. B.; Mahaddalkar, B. S. Indian J. Chem.,
Sect. B.: Org. Chem. Incl. Med. Chem. 2002, 41, 1477.
(6) Hall, T. J.; Jackson, A. H.; Oliviera-Campos, A. M. F.; Queiroz, M.
J. R. P.; Shannon, P. V. R. Heterocycles 1990, 31, 401.
(7) Duval, E.; Cuny, G. D. Tetrahedron Lett. 2004, 5411.
(8) (a) Banfield, S. C.; England, D. B.; Kerr, M. A. Org. Lett. 2001, 3,
3325. (b) Zawada, P. V.; Banfield, S. C.; Kerr, M. A. Synlett 2003, 971.
(c) England, D. B.; Kerr, M. A. J. Org. Chem. 2005, 70, 6519.
(9) (a) Plieninger, H.; Suhr, K. Chem. Ber. 1956, 89, 270. (b) Plieninger,
H.; Volkl, A. Chem. Ber. 1976, 109, 2121.
(10) (a) Jackson, S. K.; Banfield, S. C.; Kerr, M. A. Org. Lett. 2005, 7,
1215. (b) England, D. B.; Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8,
2209. (c) Leduc, A. B.; Kerr, M. A. Eur. J. Org. Chem. 2007, 237. (d)
Ganton, M. D.; Kerr, M. A. J. Org. Chem. 2007, 72, 574. (e) Jackson, S.
K.; Kerr, M. A. J. Org. Chem. 2007, 72, 1405-1411.
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Org. Lett., Vol. 9, No. 10, 2007

Scheme 4. Synthesis of Glycomaurrol and Eustifolines A and
Scheme 5. Synthesis of Eustifolines B and C
D
The preparation of glycomaurrol, as well as eustifolines
D and A, required reoxidation of 14 to the corresponding
aldehyde (Scheme 4). This, however, proved more challeng-
ing than expected with a variety of common methods (Swern,
Dess-Martin, Ley, and PDC oxidations) giving undesired
side products and unsatisfactory yields. Although treatment
with IBX in DMSO appeared to provide clean oxidation (by
TLC), it suffered from low isolated yields and longer reaction
times. Finally, it was found that treatment with IBX in
refluxing EtOAc afforded the desired aldehyde in excellent
yield.11 Olefination of the crude aldehyde with a triphen-
ylphosphonium isopropyl ylide followed by desilylation with
TBAF yielded glycomaurrol in 86% yield over the three
steps. Cyclization of glycomaurrol with PhSeCl followed by
oxidation with H2O2 afforded eustifoline A in 50% yield over
the two steps. Eustifoline D was prepared by oxidizing
carbazole 14 and subjecting the resulting aldehyde to
desilylation with TBAF followed by treatment with acid to
effect benzofuran formation in 53% yield over the three
steps.
Upon the successful syntheses of eustifolines A and D and
glycomaurrol, we turned our attention to the more elaborate
eustifolines B and C (Scheme 5). It should be noted that, at
the outset, we initially sought to advance carbazole 14 (via
oxidation to its corresponding aldehyde) to these target
molecules. However, upon oxidation of 14 with IBX to the
aldehyde, many of the transformations in Scheme 5 resulted
in low yields, undesired side products, and difficult purifica-
tions. The reasons for this are unclear. We, therefore, turned
our attention to tetrahydrocarbazole 13 as our step-off point
for the formation of eustifolines B and C.
78% overall yield. With the geranyl side chain installed,
attention was turned to the dehydrogenative conversion of
the tetrahydrocarbazole to the desired carbazole. N-Tosyl
removal was effected with magnesium metal in methanolic
aqueous ammonium chloride. Use of the previously proven
Pd/C in mesitylene to promote dehydrogenation to 17 failed
to produce the desired product, possibly due to transfer
hydrogenation to the terpenoid side chain. Success was
realized by using DDQ in dioxane albeit in less than optimal
yields (however not atypical to literature precedent4). A
substantial effort was put forth to improve the efficiency of
dehydrogenation; however, the geranyl side chain proved
incompatible with most methods. A strategy which would
allow the use of the higher-yielding palladium-catalyzed
oxidation would have required a severe sacrifice of step
economy. In the end, we settled on the DDQ-mediated
process which gave 17 in 21% yield over the two steps.
Desilylation gave eustifoline C in 64% yield. Oxidative
cyclization, this time using Pd(OAc)2, generated eustifoline
B in 64% yield.12
In conclusion, we have presented a general, regioselective
synthesis of carbazoles resulting in the syntheses of five
natural products, three of which represent the inaugural
syntheses. The yields are excellent providing glycomaurrol
in 42% overall yield and eustifolines A, B, C, and D in 21%,
3%, 4%, and 26% overall yields, respectively. The methods
described here are applicable to the preparation of a wide
variety of substituted carbazoles of both academic and
medicinal interest.
Treatment of 13 with isopropenyl magnesium bromide
followed by in situ generation of a ketene acetal en route to
a Johnson-Claisen rearrangement led to the formation of
ester 15 with the desired E geometry about the double bond
in 86% overall yield. Reduction to the aldehyde using
DIBAL and olefination with triphenylphosphonium isopropyl
ylide gave 16 bearing the requisite isopropylidine moiety in
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for funding.
(12) Koh, J. H.; Mascarenhas, C.; Gagne, M. R. Tetrahedron 2004, 60,
7405.
(11) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
Org. Lett., Vol. 9, No. 10, 2007
1885

Acknowledgment is made to the Donors of the American
Chemical Society Petroleum Research Fund for partial
support of this research. We thank Mr. Doug Hairsine of
the University of Western Ontario mass spectrometry facil-
ity for performing MS analyses. T.P.L. is a CGS-D awar-
dee.
Supporting Information Available: Full experimental
procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL070381M
1886
Org. Lett., Vol. 9, No. 10, 2007