A rapid, asymmetric synthesis of the decahydrofluorene core of the hirsutellones

Article abstract of DOI:10.1021/ol802768p

(Chemical Equation Presented) A tandem ketene-trapping/Diels-Alder cyclization sequence was the pivotal transformation in an efficient, asymmetric synthesis of a decahydrofluorene tricyclic structure possessing eight stereogenic centers and key features o

Full text of DOI:10.1021/ol802768p

ORGANIC
LETTERS
2009
Vol. 11, No. 3
701-703
A Rapid, Asymmetric Synthesis of the
Decahydrofluorene Core of the
Hirsutellones
S. David Tilley, Keith P. Reber, and Erik J. Sorensen*
Department of Chemistry, Princeton UniVersity, Frick Chemical Laboratory, Princeton,
New Jersey 08544
ejs@princeton.edu
Received December 1, 2008
ABSTRACT
A tandem ketene-trapping/Diels-Alder cyclization sequence was the pivotal transformation in an efficient, asymmetric synthesis of a
decahydrofluorene tricyclic structure possessing eight stereogenic centers and key features of the hirsutellone class of antitubercular natural
products. The hirsutellone-like ꢀ-keto ester that was fashioned by this sequence (13 steps; 6% overall yield) demonstrated significant inhibitory
activity against Mycobacterium tuberculosis. The mechanism of action of this antitubercular compound is not yet known.
Tuberculosis is an infectious pulmonary disease caused by
the pathogenic species Mycobacterium tuberculosis. Ap-
proximately one-third of the world’s population is infected
with the tuberculosis bacterium, resulting in over 1.5 million
deaths each year.1 Given the global impact of this devastating
illness, there has been a renewed interest in finding new
antitubercular agents to combat the significant issues of drug
resistance and mycobacterial persistence.2 In their search for
new antibacterial metabolites, Isaka et al. reported the
isolation of six bioactive polyketides from the fungus
Hirsutella niVea BCC 2594 in 2005.3 The hirsutellone family
of natural products exhibits antimicrobial activity against M.
tuberculosis, with minimum inhibitory concentration (MIC)
values in the range 0.78-3.125 µg/mL.3 The intriguing
polycyclic architecture of the hirsutellones features an
unusual 13-membered p-cyclophane ether, a succinimide or
γ-lactam ring, and a decahydrofluorene ring system contain-
ing eight stereocenters, of which seven are contiguous. The
degree of structural complexity exhibited by these natural
products combined with their strong antitubercular properties
make the hirsutellones compelling objectives for chemical
synthesis.
We reasoned that a thermal, retro-Diels-Alder fragmenta-
tion of the 2,2-dimethyl-1,3-dioxinone heterocycle of a
compound of type 1 (Figure 1) would cause the formation
of a transient acyl ketene.4 This reactive species might then
be capable of triggering both a lactam ring formation and
an intramolecular Diels-Alder cycloaddition (see arrows in
2) to give pentacycle 3, a compound possessing key elements
of the structure of hirsutellone B (4). While the ordering of
the proposed lactamization and Diels-Alder events implied
in intermediate 2 seemed unclear, this plan for rapidly
forming the hirsutellone molecular architecture is supported
by several published examples of nucleophilic trappings of
(1) World Health Organization, Fact Sheet 104, March 2007.
(2) Sacchettini, J. C.; Rubin, E. J.; Freundlich, J. S. Nat. ReV. Microbiol.
2008, 6, 41.
(4) (a) Ja¨ger, G.; Wenzelburger, J. Liebigs Ann. Chem. 1976, 1689. (b)
Sato, M.; Ogasawara, H.; Yoshizumi, E.; Kato, T. Chem. Pharm. Bull. 1983,
31, 1902. (c) Hyatt, J. A.; Feldman, P. L.; Clemens, R. J. J. Org. Chem.
1984, 49, 5105.
(3) Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.; Prabpai, S.;
Thebtaranonth, Y. Tetrahedron 2005, 61, 5577.
10.1021/ol802768p CCC: $40.75
Published on Web 01/02/2009
2009 American Chemical Society

Scheme 1
Figure 1. Proposed cascade for rapid construction of the polycyclic
core of hirsutellone B.
transient acyl ketenes.4 To the best of our knowledge, there
is no published example of a tandem intramolecular ketene-
capture/Diels-Alder cyclization; however, the laboratories
of Roush and Boeckman have described impressive examples
of tandem intermolecular acyl ketene-trapping/intramolecular
Diels-Alder reactions in complex natural product synthesis.5
In the course of pursuing a synthesis of hirsutellone B (4),
we achieved a solvolytic capture of an acyl ketene intermedi-
ate and a fully stereocontrolled synthesis of the decahydrof-
luorene core architecture of the hirsutellone class of natural
products. This compound possesses promising inhibitory
activity against the M. tuberculosis strain mc27000. Our
synthesis of this tricyclic ꢀ-keto ester is described in this
report.
The construction of the hirsutellone decahydrofluorene
tricycle began with a stereoface-selective Diels-Alder reac-
tion (Scheme 1). Use of Seebach’s DIOZ chiral auxiliary6
(derived from D-valine) gave complete diasteroselectivity in
the reaction of 5 with excess isoprene, which was complete
within 20 min at -40 °C. This observation stood in marked
contrast to reactions using other oxazolidinone auxiliaries
which provided much lower diastereomeric ratios and
required longer reaction times.7 After several unsuccessful
attempts to excise the DIOZ auxiliary by direct reduction,
we retreated to an efficient two-step procedure involving the
conversion of imide 6 to benzyl ester 7,6 followed by a
complete reduction of the ester moiety to alcohol 8 with
diisobutylaluminum hydride (DIBAL-H). By this sequence,
alcohol 8 was available in >99% ee.8
hydrogenation of the alkene formed in the initial Diels-Alder
construction. Thus, we were pleased to discover that a
hydroxyl-directed hydrogenation of 8 using Crabtree’s cata-
lyst9 at 0 °C afforded compound 9 as a single diastereomer.
To set the stage for a needed one carbon homologation,
alcohol 9 was oxidized to the corresponding aldehyde by
the Swern method.10 A subsequent Wittig reaction11 with
the phosphorane derived from phosphonium salt 10 produced
a 1:6 mixture of geometrically isomeric vinyl ethers in 84%
yield from 9; for clarity, only the major, trans-vinyl ether
isomer 11 is shown.
As shown in Scheme 2, when the mixture of isomeric vinyl
ethers was dihydroxylated by the Upjohn method (OsO4/
NMO),12 an electrophilic R-hydroxy aldehyde 12 was
generated and subsequently intercepted with the known
phosphorane 13,13 resulting in the exclusive formation of
trans-alkene 14 in 50% yield and as a 4:1 mixture of
separable alcohol epimers. In order to establish the identity
of the major diastereomer, a short sequence was carried out
to generate a rigid structure from which the stereochemistry
could be determined by nuclear Overhauser effect (NOE)
correlations (Scheme 2). First, removal of the silyl protecting
group with acetic acid in aqueous THF afforded the desired
diol. Treatment of this compound with triphosgene in the
presence of pyridine and 4Å molecular sieves afforded the
cyclic carbonate 15 in 85% yield over the two steps. NMR
It was our intent to establish the methyl-bearing stereo-
genic center of the goal structure by a face-selective
(5) (a) Roush, W. R.; Brown, B. B. J. Org. Chem. 1993, 58, 2162. (b)
Boeckman, R. K., Jr.; Shao, P.; Wrobleski, S. T.; Boehmler, D. J.;
Heintzelman, G. R.; Barbosa, A. J. J. Am. Chem. Soc. 2006, 128, 10572.
(6) Hintermann, T.; Seebach, D. HelV. Chim. Acta 1998, 81, 2093.
(7) Reactions utilizing the chiral auxiliary (R)-4-benzyl-2-oxazolidinone
gave 3:1 dr and required 12 h at -30 °C.
(9) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
(10) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(11) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
(12) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973.
(13) Bodurow, C.; Carr, M. A.; Moore, L. L. Org. Prep. Proc. Int. 1990,
22, 109.
(8) See the Supporting Information for details.
702
Org. Lett., Vol. 11, No. 3, 2009

Scheme 2
Scheme 3
analysis of 15 allowed for an unambiguous assignment of
the (R)-configuration at the hydroxyl-bearing stereogenic
center in compound 14 (Scheme 2).
From alcohol 14, the substrate for the pivotal ketene-
trapping/intramolecular Diels-Alder sequence could be
fashioned in four steps (Scheme 3). Thus, protection of the
secondary hydroxyl group of 14 was accomplished by
deprotonation with n-butyllithium followed by addition of
methyl chloroformate to give methyl carbonate 16. Acid-
induced cleavage of the silyl protecting group then afforded
a primary alcohol, which was subsequently oxidized to
aldehyde 17 by the action of the Dess-Martin periodinane
(DMP)14 in 74% yield over the two steps. The required triene
chain was then introduced by a Wittig reaction between
aldehyde 17 and the phosphorane derived from phosphonium
salt 18.15 We found that biphasic reaction conditions (Scheme
3)16 were uniquely successful for carrying out this Wittig
reaction, which produced triene 19 in 66% yield.
We were pleased to observe that heating of triene 19 to
110 °C in an 8:1 mixture of toluene/methanol17 gave rise to
the desired tricycle 20 in 85% yield. NOE correlation data
was used to assign the relative stereochemistry of 20 (Scheme
3); the stereochemical relationships in compound 20 cor-
respond to those found in the decahydrofluorene core
structure of the hirsutellone natural products. Our interest
in the design and synthesis of new compounds with activity
against tuberculosis prompted us to submit samples of
compound 20 to the Sacchetini laboratory at Texas A&M
University for a study of its performance in assays for
antitubercular activity. While its mode of action is not yet
known, compound 20 demonstrated an MIC of 1.21 µg/mL
versus M. tuberculosis mc27000.18 Efforts to elucidate the
origin of biological activity of the hirsutellone-like tricycle
20 are currently underway.
The design for synthesis described herein guided the
development of an expedient construction of the tricyclic
core of the hirsutellone class of natural products in 6% overall
yield over 13 steps from R,ꢀ-unsaturated imide 5. The high
yield and diastereoselectivity of the tandem ketene-trapping/
Diels-Alder sequence lends credence to the possibility of
generating even more complexity in a single step through
an intramolecular capture of a putative acyl ketene interme-
diate. Efforts to realize this more ambitious chemical
objective are currently underway.
Acknowledgment. We gratefully acknowledge Princeton
University, the Merck Research Laboratories, and Boe-
hringer-Ingelheim for supporting this work. Additionally, we
thank our collaborators at Texas A&M University for
conducting the biological testing of compound 20.
Supporting Information Available: Experimental pro-
cedures and full characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(15) Na¨f, F.; Decorzant, R.; Thommen, W.; Willhalm, B.; Ohloff, G.
HelV. Chim. Acta 1975, 58, 1016.
OL802768P
(16) Tagaki, W.; Inoue, I.; Yano, Y.; Okonogi, T. Tetrahedron Lett.
1974, 15, 2587–2590.
(17) Munakata, R.; Katakai, H.; Ueki, T.; Kurosaka, J.; Takao, K.;
Tadano, K. J. Am. Chem. Soc. 2004, 126, 11254.
(18) Krieger, I.; Lai Hing, S.; Freundlich, J. S.; Sacchettini, J. C. Texas
A&M, College Station, TX. Unpublished work, 2008.
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