Synthesis of the tetracyclic core of the neomangicols using a late-stage indene alkylation

Article abstract of DOI:10.1021/ol9010008

A general approach to the tetracyclic core of the neomangicol natural products via a late-stage indene alkylation reaction is presented. This strategy sets the stage for access to the neomangicol family and, in addition, provides a potential biogeneticall

Full text of DOI:10.1021/ol9010008

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3128-3131
Synthesis of the Tetracyclic Core of the
Neomangicols Using a Late-Stage
Indene Alkylation
Jessica L. Wood, Brian G. Pujanauski, and Richmond Sarpong*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
rsarpong@berkeley.edu
Received May 8, 2009
ABSTRACT
A general approach to the tetracyclic core of the neomangicol natural products via a late-stage indene alkylation reaction is presented. This
strategy sets the stage for access to the neomangicol family and, in addition, provides a potential biogenetically inspired entry to the mangicol
natural products.
Historically, the carbon framework of terpenoid natural
products has proven to be a synthetic challenge due to the
lack of functional groups on these molecules that can direct
C-C bond formation.1 As a result, synthetic chemists must
design strategies for terpenoid syntheses that maximize
carbon-carbon bond formation. Enolate methodology has
been featured prominently in a wide range of C-C bond
forming cyclization tactics (e.g., intramolecular aldol and
Dieckmann reactions) en route to terpene natural products,
which often necessitate the removal of the enolate carbonyl
oxygen at a late stage. In the context of [5, 6] bicyclic ring-
containing terpene natural products, we envisioned that
indenes, which possess acidities comparable to carbonyl
compounds (e.g., ketones), could serve as enolate equivalents
in late-stage bond-forming events. In this communication,
Figure 1. Selected neomangicol and mangicol natural products.
we present the application of this tactic to the synthesis of
the tetracyclic core of the natural product neomangicol C
(2, Figure 1).
Fusarium, which possess varied bioactivity.2 For example,
neomangicols A and B (1a and 1b, Figure 1) have shown in
vitro cytotoxicity against human colon carcinoma.
Furthermore, neomangicol B (1b) has shown potency
against the Gram-positive bacterium Bacillus subtilis similar
Neomangicol C is a member of a group of rearranged
sesterterpenoids isolated from a marine fungus of the genus
(1) For a recent discussion on terpene synthesis, see: Hudlicky, T.; Reed,
J. The Way of Synthesis: EVolution of Design and Methods for Natural
Products Synthesis, 1st ed.; Wiley-VCH: Weinheim, 2007; pp 207-215.
(2) Renner, M. K.; Jensen, P. R.; Fenical, W. J. Org. Chem. 1998, 63,
8346–8354.
10.1021/ol9010008 CCC: $40.75
Published on Web 06/15/2009
 2009 American Chemical Society

to that of the aminoglycoside gentamycin and may prove to
be of general utility as an antibiotic.2 Preliminary studies
have not identified significant bioactivity for neomangicol
C (2), and there is evidence that suggests it may be an
isolation artifact arising from the net loss of HCl or HBr
from 1a or 1b, respectively.2
aspect of our approach was that the indene cyclization
precursor 5 could be readily constructed in a convergent
manner from vinyl triflate 6 and boronic ester 7.
Our synthetic studies commenced with the preparation of
boronic ester 7 as illustrated in Scheme 2. The sequence
To date, there have been no reports of synthetic work
toward the neomangicols. However, studies by Uemura3 and
Paquette4 have recently begun to address the synthesis of
the related mangicols5 (e.g., mangicol A (3) and B (4), Figure
1). Mangicol A is of interest as a unique structural motif
that possesses anti-inflammatory activity.
Scheme 2. Synthesis of Indene Precursor 7
A series of feeding studies has demonstrated that the
neomangicols may arise from a rearrangement of the
mangicol skeleton (see B f A, Figure 1).5 We envisioned
that our model studies on the neomangicols would offer an
opportunity to test the reverse of the biosynthetic proposal
by employing a semipinacol/Wagner-Meerwein6 ring con-
traction (see A f B, Figure 1) to construct the mangicol
skeleton.
Despite their relatively small size, the neomangicols and
mangicols possess several challenging features from a
synthetic standpoint. For example, these natural product
families possess nine and eleven stereocenters, respectively.
Additionally, the vinyl halide moiety present in neomangicols
A and B is highly unusual in sesterterpene natural products.
Our initial studies have focused on the neomangicols and
specifically the tetracyclic core of neomangicol C. This
presents an opportunity to investigate the potential application
of indene alkylation chemistry to the synthesis of these highly
complex rearranged sesterterpenoids. Importantly, the core
of neomangicol C will serve as a starting point for the
synthesis of neomangicols A and B, as well as the mangicols.
Our retrosynthetic analysis of 2 (Scheme 1) features a late-
stage disconnection to indene 5, which offers a potential
began with Knoevenagel condensation of 2-bromo-5-meth-
oxybenzaldehyde (8)7 and the sodium salt of Meldrum’s acid
(9), which provided adduct 10 in 85% yield.8 Of note,
numerous attempts to effect the Knoevenagel condensation
using the conditions of Fillion (cat. pyrrolidinium acetate),9
which work well for electron-rich aryl aldehydes, resulted
in lower yields. A conjugate reduction of alkylidene 10 was
effected with sodium triacetoxyborohydride (STAB), and the
resulting Meldrum’s acid derivative was methylated under
standard conditions (K2CO3, MeI). At this stage, a formal
Friedel-Crafts acylation using polyphosphoric acid (PPA)
proceeded with concomitant loss of acetone and carbon
dioxide to yield indanone 11 in 80% yield over the three
steps.10
Reduction of indanone 11 upon treatment with DIBAL-H
gave an inconsequential diastereomeric mixture (3:1 dr) of
indanol products,11 which was immediately protected to
afford MOM ether 12. Installation of the boronic ester moiety
was accomplished via halogen-metal exchange with t-BuLi
at -78 °C followed by a quench of the resulting aryl anion
with dioxaborolane 13 to give 7 in 93% yield. The overall
sequence for the preparation of boronic ester 7 can be
routinely performed on gram scale.
Scheme 1. Retrosynthetic Analysis of Neomangicol C
Having established reliable access to 7, we turned our
attention to the preparation of vinyl triflate 6 (eq 1). This
(7) Tietze, L. F.; Brasche, G.; Grube, A.; Bo¨hnke, N.; Stadler, C.
Chem.sEur. J. 2007, 13, 8543–8563.
(8) Margaretha, P.; Polansky, O. E. Tetrahedron Lett. 1969, 57, 4983–
4986.
solution to the construction of terpenoid frameworks that
incorporate a fused [5, 6] bicyclic ring system. An appealing
(9) Dumas, A. M.; Seed, A.; Zorzitto, A. K.; Fillion, E. Tetrahedron
Lett. 2007, 48, 7072–7074.
(10) The success of the Friedel-Crafts reaction using PPA was significant,
given that earlier attempts with Lewis acids such as Sc(OTf)3 returned
carboxylic acid i whereas AlCl3 did effect cyclization, but also led to the
cleavage of the methyl ether to yield ii.
(3) Araki, K.; Saito, K.; Arimoto, H.; Uemura, D. Angew. Chem., Int.
Ed. 2004, 43, 81–84.
(4) (a) Pichlmair, S.; de Lera Ruiz, M.; Basu, K.; Paquette, L. A.
Tetrahedron 2006, 62, 5178–5194. (b) Pichlmair, S.; de Lera Ruiz, M.;
Vilotijevic, I.; Paquette, L. A. Tetrahedron 2006, 62, 5791–5802.
(5) Renner, M. K.; Jensen, P. R.; Fenical, W. J. Org. Chem. 2000, 65,
4843–4852.
(6) For a review, see: Hanson, J. R. Wagner-Meerwein Rearrangements.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 3, pp 705-719.
(11) Reduction also proceeded efficiently with Li(Ot-Bu)3AlH, NaBH4,
and LiEt3BH with equal but opposite diastereocontrol.
Org. Lett., Vol. 11, No. 14, 2009
3129

compound was available in short order by enolate formation
and triflation starting from easily obtained ꢀ-ketoester 13.12
Of note, 13 can be prepared in highly enantioenriched form,13
which presents an avenue for the enantioselective synthesis
of these natural products.
(Scheme 3) set the stage for the key indenide anion-
mediated C-C bond formation to forge the tetracyclic core
of neomangicol C.
Deprotonation of indenes and subsequent reactions of the
resulting anions have been studied in great detail.15 In line
with literature precedent, we investigated a range of bases
such as t-BuLi, KOt-Bu and the amide base LiTMP (see
Table 1, entries 1-3, respectively) to effect deprotonation
Table 1. Optimization of the Tetracyclization Stepa
Subsequent screening revealed an optimal set of condi-
tions for the Suzuki cross-coupling of 6 with boronic ester
7 (Scheme 3; 10 mol % PdCl2(PPh3)2, 1:1 i-PrOH/2 M
entry
1
conditions
time
result
t-BuLi (16 equiv)
THF, -78 °C
15 min
SM + decomp.
2
KOt-Bu (6 equiv)
MeOH, 23 to 50 °C
LiTMP (3 equiv)
THF, -78 to 23 °C
Triton B (8 equiv)
DMSO, 23 °C
Triton B (1 equiv)
DMF, -42 °C
Triton B (1 equiv)
DMF, -60 °C
12 h
Indene isomerization
+ decomp.
Indene isomerization
Scheme 3. Preparation of the Neomangicol Tetracycle
3
5 h
4
2 min
10 min
40 min
50% yield of 16
+ byproducts
60% yield of 16
+ byproducts
92% yield of 17
5b
6b c
,
a Standard protocol involved addition a solution of Triton B in methanol
to a solution of 5 in the indicated solvent (0.04 M). b Reverse addition of
the substrate (5) to a solution of the Triton B was used. c Yield was
determined following oxidation of the crude product (16) with Dess-Martin
periodinane.
of indene 5. The use of t-BuLi was ineffective and returned
starting material along with significant decomposition (entry
1). Both KOt-Bu and LiTMP led to isomerization of the
indene double bond (entries 2-3), suggesting that deproto-
nation was occurring; however, none of the desired tetracycle
was observed.
On the basis of the pioneering studies of Sprinzak, we
were drawn to the use of hydroxide bases such as Triton B
to effect indene alkylations.16 Gratifyingly, subjecting indenyl
aldehyde 5 to Triton B (8 equiv) in DMSO at rt over 2 min
provided a 50% yield of alcohol 16 as a 2:1 mixture of
epimers, which could be separated by column chromatog-
raphy with some difficulty, along with several unidentified
byproducts (entry 4).
aq. Na2CO3), which afforded 14 in 80% yield.14 At this
juncture, two-stage reduction of the ethyl ester moiety
followed by elimination of the MOM ether using pyri-
dinium p-toluenesulfonate (PPTS) gave indene conjugate
15. Attempted removal of the MOM ether group using
other protic conditions (e.g., KHSO4 in PhMe at >60 °C)
resulted in formation of a tetrasubstituted double bond
(see 18 f 19, Scheme 4), presumably via the mechanism
Encouraged by this initial result, we embarked on opti-
mization studies of the Triton B-mediated cyclization of 5
by varying the solvent, temperature and reaction times.
Ultimately, we identified a set of optimal conditions which
utilized 1 equiv of Triton B in DMF at -60 °C (entry 6).
The crude allylic alcohol product (16) was oxidized
immediately following workup to enone 17, which served
Scheme 4. Proposed Deformylation Pathway
(15) (a) Cedheim, L.; Eberson, L. Synthesis 1973, 3, 159. (b) Makosza,
M. Tetrahedron Lett. 1966, 38, 4621–4624. For applications in organome-
tallic chemistry, see: (c) Bringtzinger, H. H.; Fischer, D.; Mu¨lhaupt, R.;
Rieger, B.; Waymouth, R. M. Angew. Chem., Int. Ed. 1995, 34, 1143–
1170. For enantioenriched indenide anions, see: (d) Hoppe, I.; Marsch, M.;
Harms, K.; Buchi, G.; Hoppe, D. Angew. Chem., Int. Ed. 1995, 34, 2158–
2160.
as shown. Oxidation of the primary hydroxyl group of 15
(12) Barco, A.; Beretti, S.; Pollini, G. P. Synthesis 1973, 316.
(13) (a) Saigo, K.; Koda, H.; Nohira, H. Bull. Chem. Soc. Jpn. 1979,
52, 3119–3120. (b) Ramachandran, P. V.; Chen, G. M.; Brown, H. C. J.
Org. Chem. 1996, 61, 95–99.
(14) Initial attempts to prepare adducts related to 14 using a Grignard
reagent generated from 12 and addition to ꢀ-ketoester 13 gave low returns
of the desired product.
(16) (a) Ghera, E.; Sprinzak, Y. J. Am. Chem. Soc. 1960, 82, 4945–
4952. (b) Avramoff, M.; Sprinzak, Y. J. Am. Chem. Soc. 1960, 82, 4953–
4955.
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1
to significantly simplify H and 13C NMR analysis. This
terpenes. Current efforts are focused on advancing 17 to
neomangicols A-C.
compound possesses functional handles in the A and B rings
that make it an attractive precursor to the neomangicol natural
products.17
In summary, we report the first synthesis of the tetracyclic
core of the neomangicols via an efficient indene alkylation
strategy. This design provides a starting point for the
syntheses of the biosynthetically related neomangicol and
mangicol natural products by utilizing a powerful alternative
to enolate chemistry in the synthesis of this subset of
Acknowledgment. We are grateful to UC Berkeley, the
NIH (NIGMS RO1 GM84906-01), and the American Cancer
Society (RSG-09-017-01-CDD) for generous financial sup-
port. B.G.P. thanks the CA•TRDRP for a Thesis Fellowship
Award. We are indebted to Eric Simmons (UC Berkeley)
for discussions and suggestions. R.S. is a 2009 Alfred P.
Sloan Foundation Fellow and a 2009 Camille Dreyfus
Teacher-Scholar.
(17) Initial attempts to prepare tetracycle 17 from indene ester iii by
employing the optimized conditions for the cyclization of 5, or the conditions
of Birman,18 resulted in the recovery of iii or the corresponding indene
double-bond isomer.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Birman, V. B.; Zhao, Z.; Guo, L. Org. Lett. 2007, 9, 1223–1225.
OL9010008
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