Synthetic studies toward the citrinadin A and B core architecture

Article abstract of DOI:10.1021/ol402177a

The core architecture of the citrinadin alkaloids has been prepared in racemic form by utilizing a strategy that exploits the alkylation of 2-methoxypyridines. An initially planned indolizidine to quinolizidine transformation to build the D/E rings was unsuccessful. Success was ultimately gained by a direct alkylation to establish the citrinadin core architecture.

Full text of DOI:10.1021/ol402177a

ORGANIC
LETTERS
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Vol. XX, No. XX
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Synthetic Studies toward the Citrinadin
A and B Core Architecture
Devon A. Mundal and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California 94720,
United States
rsarpong@berkeley.edu
Received July 31, 2013
ABSTRACT
The core architecture of the citrinadin alkaloids has been prepared in racemic form by utilizing a strategy that exploits the alkylation of
2-methoxypyridines. An initially planned indolizidine to quinolizidine transformation to build the D/E rings was unsuccessful. Success was
ultimately gained by a direct alkylation to establish the citrinadin core architecture.
Citrinadins A (1, Figure 1) and B (2) are oxindole
alkaloid natural products that were isolated from Penicillium
citrinum by Jun’ichi Kobayashi and co-workers in 2004 and
2005, respectively.1,2 Recently, highly elegant total syntheses
of alkaloids 1 and 2 have been completed by the groups of
Martin and Wood, respectively.3,4 These contributions have
resulted in the revision of the relative stereochemistry of
the citrinadins to the representations shown for 1 and 2 in
Figure 1. These stereochemical revisions now bring the
structures of the citrinadins in line with the related PF1270
spiro-oxindole natural products (AÀC, 3À5), which were
isolated from Penicillum waksmanii (strain PF1270) by
Figure 1. Citrinadins and PF1270 alkaloids.
Kushida et al.5
Synthetic interest in the citrinadins has been driven by
their unusual structures, which feature a substituted qui-
nolizidine and a cyclopentane ring replete with four tetra-
substituted carbon atoms, two of which are quaternary.
In addition to their challenging structural attributes, which
may inspire new synthetic strategies and tactics, 1 and 2,
as well as related spiro-oxindoles such as 3À5, possess
notable biological activity (e.g., cytotoxicity against mu-
rine leukemia L1210 cells for 1 (IC50 = 6.2 μg/mL) and 2
(1) Tsuda, M.; Kasai, Y.; Komatsu, K.; Sone, T.; Tanaka, M.;
Mikami, Y.; Kobayashi, J. Org. Lett. 2004, 6, 3087.
(2) Mugishima, T.; Tsuda, M.; Kasai, Y.; Ishiyama, H.; Fukushi, E.;
Kawabata, J.; Watanabe, M.; Akao, K.; Kobayashi, J. J. Org. Chem.
2005, 70, 9430.
(IC50 = 10 μg/mL), whereas 3À5 are potent agonists of rat
and human histamine receptor H3). As such, the syntheses
of 1 and 2 or 3À5 could offer opportunities for a more
(3) Bian, Z.; Marvin, C. C.; Martin, S. F. J. Am. Chem. Soc. 2013,
comprehensive examination of their anticancer activity
135, 10886.
and their effects on the central nervous system. This is
especially significant given the limited availability of these
materials from their natural sources. It is therefore not
surprising that, in addition to the recently completed total
(4) Kong, K.; Enquist, J. A., Jr.; McCallum, M. E.; Smith, G. M.;
Matsumaru, T.; Menhaji-Klotz, E.; Wood, J. L. J. Am. Chem. Soc. 2013,
135, 10890.
(5) Kushida, N.; Watanabe, N.; Okuda, T.; Yokoyama, F.; Gyobu,
Y.; Yaguchi, T. J. Antibiot. 2007, 60, 667.
r
10.1021/ol402177a
XXXX American Chemical Society

syntheses of 1 and 2, there have been several approaches to
these compounds that are each characterized by a creative,
unique strategy to address the core architecture of these
molecules.6
Particularly intriguing in our proposed approach to 2 is
the conversion of 7 to 6. At the time that we initiated our
studies, no direct precedent existed for this particular
transformation. As such, a plan to study this conversion
on a model system (12, Scheme 2) was hatched. It was
expected that appropriate activation of the primary hydro-
xyl group of 12 would lead to aziridinium intermediate 13,
which would form upon engaging the tertiary amine
group. At that stage, the introduction of an appropriate
nucleophile would lead to quinolizidine 14 by a SN1-like or
an asynchronous SN2-like process capable of delivering the
requisite stereochemistry (either via substrate or reagent
control). While we cannot exclude the possibility of a the
direct SN2 opening of aziridinium intermediate138b (which
would lead tothe stereochemistry opposite tothat depicted
in compound 14), ourhypothesisis supported by the recent
reports from the Wood group, where the conversion of 15
to 17 may pass through an intermediate (16) where the
tertiary amine offers a level of anchimeric assistance.4,8
In this communication, we report our own synthetic
studies toward the citrinadins, which is prompted by the
recentdisclosuresofthe Martinand Woodsyntheses3,4 of 1
and 2, respectively, withwhich our approach shares several
strategic features. As outlined in Scheme 1, we envisioned
the citrinadins, particularly citrinadin B (2), arising (as was
achieved in the Wood synthesis of 2) from functionaliza-
tion at C-7 of oxindole 6 (where X = Br or I). In one of the
key transformationsofthe synthesis, quinolizidine6 would
arise from indolizidine 7 (discussed in more detail in
Scheme 2 below). It was imagined that alkylation of the
2-methoxypyridine portion of 8 by the epoxide functional
group would provide eventual access to indolizidine 7.
2-Methoxypyridines offer several strategic advantages in
complex molecule synthesis, which we have exploited in the
past in the syntheses of several complex alkaloid natural
products.7 For example, they are excellent surrogates for
piperidine groups where the basic nitrogen atom is in
essence protected given the mitigated basicity of the
methoxypyridine nitrogen. As a corollary of this reduced
basicity/nucleophilicity of the 2-methoxypyridine nitrogen,
alkylation of the 2-methoxypyridine group is not general,
especially using electrophiles other than alkyl triflates or
halides. Thus, the annulation strategy proposed herein (i.e.,
8 to 7) would serve to extend the scope of annulation
reactions of 2-methoxypyridines. Fused indole tricycle 8
would in turn arise from hydrazine 9 (where X = Br or I),
ketoester 10 (enol form shown), and 2-methoxypicoline 11.
Scheme 2. Proposed Indolizidine to Quinolizidine Conversion
via an Aziridinium Intermediate
Our synthesis of the model indolizidine compound 12 com-
menced with the preparation of 24 as outlined in Scheme 3.
Commercially available 2,2-dimethylcyclohexane-1,3-dione
(18)9 was converted to monoketal 19, which was subjected
to a Claisen reaction to afford 10. A standard triflation
of 10 followed by Negishi cross-coupling10 with freshly
prepared 21 smoothly affords the expected adduct, which
upon hydrolysis of the ketal group yields ketone 22.
Fischer indolization11 of 22 via the intermediacy of
hydrazone 23 affords dihydrocarbazole derivative 24
(following Boc protection of the indole nitrogen).
Scheme 1. Retrosynthetic Analysis of Citrinadin B
Access to 24 set the stage for the synthesis of the
indolizidone derivative 27 as outlined in Scheme 4. Reduc-
tion of ester 24 with DIBAL produces an allylic alcohol,
(8) (a) The Wood group has also demonstrated this epoxide opening
on C-7 substituted derivatives of 15. See: Smith, G. M. Progress toward
the Total Synthesis of the Citrinadins, Ph.D. Thesis, Colorado State
University, Fort Collins, CO, 2012. (b) The work of Wonjacynska et al. has
shown that aziridinium openings may proceed with retention of stereochem-
istry, which supports the possible intermediacy of 16: Wojaczynska, E.;
Turowska-Tryk, I.; Skarzewski, J. Tetrahedron 2012, 68, 7848–7854.
(9) For a recent application of 18 in synthesis, see ref 3.
(10) For an early account, see: Negishi, E. Acc. Chem. Res. 1982, 15,
340.
(11) For a review on the Fischer indole synthesis, see: Martin, M. J.;
Dorn, L. J.; Cook, J. M. Heterocycles 1993, 36, 157.
(6) (a) Pettersson, M.; Knueppel, D.; Martin, S. F. Org. Lett. 2007, 9,
4623. (b) McIver, A. L.; Deiters, A. Org. Lett. 2010, 12, 1288. (c)
Chandler, B. D.; Roland, J. T.; Li, Y.; Sorensen, E. J. Org. Lett. 2010,
12, 2746. (d) Guerrero, C. A.; Sorensen, E. J. Org. Lett. 2011, 13, 5164.
(e) Albertshofer, K.; Tan, B.; Barbas, C. F. Org. Lett. 2012, 14, 1834.
(7) (a) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008, 130,
7222. (b) Larson, K. K.; Sarpong, R. J. Am. Chem. Soc. 2009, 131, 13244.
(c) Bisai, V.; Sarpong, R. Org. Lett. 2010, 12, 2551. (d) Murphy, R. A.;
Sarpong, R. Org. Lett. 2012, 14, 632. (e) Newton, J. N.; Fischer, D. F.;
Sarpong, R. Angew. Chem., Int. Ed. 2013, 52, 1726.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Synthesis of Dihydrocarbazole Derivative 24
Scheme 5. Synthesis of Spiro-oxindole Indolizidine 12
model compound tostudy the proposed key indolizidine to
quinolizidine conversion that would deliver the citrinadin
skeleton (see 12 to 14, Scheme 2).13
Despite numerous attempts using a wide selection of
conditions(Table 1) and the encouraging related precedent
of Wood,4,14 we have so far not had success in accomplish-
ing the conversion of 12 to 14. For example, treatment of
12 under Cossy’s conditions15 (entry 1) with trifluoroacetic
anhydride and triethylamine results in the formation of
an intermediate trifluoroacetate. However, quinolizidine
formation did not occur, but instead, the starting material
was recovered (presumably after base-promoted hydroly-
sis of the trifluoroacetate). Other conditions that combine
hydroxyl activation followed by the introduction of a
nucleophile simply result in the decomposition of 12. Thus,
while it would appear (from the precedent of Wood) that a
quinolizidine structural motif may result if an aziridinium
intermediate is accessed, our studies thus far suggest that
indolizidine 12 may not represent the ideal substrate to
access the requisite aziridinium species.
which upon epoxidation gives epoxide 25. After a protracted
optimization, conversion of 25 to 26 could be effected with
MgCl2 as the Lewis acid and NaI to accomplish the requisite
demethylation. At this stage, hydrogenation of the pyridine
occurs with good levels of diastereoselectivity to afford
pentacycle 27, the structure of which was unambiguously
confirmed by single-crystal X-ray analysis.12
Scheme 4. Synthesis of Pentacycle 27
Table 1. Attempted Indolizidine to Quinolizidine Conversion
The next task was to convert fused pentacycle 27 to
spirocyclic oxindole 28 (Scheme 5), which is readily ac-
complished with high levels of diastereocontrol using in
situ generated dimethyldioxirane (DMDO; from oxone
and acetone). The excellent diastereoselectivity can in part
be attributed to a convex face approach of the DMDO,
which may also be directed to the R face of 27 by hydrogen
bond interactions with the primary hydroxyl group at
the C/D ring fusion. Sequential removal of the Boc and
amide carbonyl groups in 28 gives 12, which is the requisite
(13) For examples of prolinol to piperidine ring expansions via
aziridinium intermediates, see: (a) Cossy, J.; Dumas, C.; Pardo, D. G.
Eur. J. Org. Chem. 1999, 1693. (b) Cochi, A.; Pardo, D. G.; Cossy, J. Eur.
J. Org. Chem. 2012, 2023. (c) Wojaczynska, E.; Turowska-Tyrk, I.;
Skarzewski, J. Tetrahedron 2012, 68, 7848. (d) Abe, H.; Aoyagi, S.;
Kibayashi, C. J. Am. Chem. Soc. 2005, 127, 1473. (e) Jarvis, S. B. D.;
Charette, A. B. Org. Lett. 2011, 13, 3830.
(12) CYLView depictions of the X-ray crystal structures are shown.
Thermal ellipsoids shown at 50% probability. Most hydrogens removed
for clarity. See the Supporting Information for more details.
(14) Also see ref 8.
(15) See refs 13a and 13b.
Org. Lett., Vol. XX, No. XX, XXXX
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of which was unambiguously supported by single-crystal
X-ray analysis (see CYLView in Scheme 6).12 Although the
relative stereochemistry at C-3 and C-16 (citrinadin
numbering) in 32 is as desired, the C-18 stereocenter will
require inversion. Studies to effect the inversion of the C-18
stereochemistry as well as nucleophilic opening of the
epoxide group in 32 and derivatives thereof at C-8 are the
subject of our ongoing studies.
Scheme 6. Synthesis of Spiro-oxindole 32
In conclusion, we have applied a methoxypyridine alkyl-
ation strategy to the synthesis of the pentacyclic carbon
skeleton of the citrinadin natural products. A planned
indolizidine ring expansion/nucleophile trapping via an
aziridinium intermediate has thus far not been successful
despite encouraging literature precedent from the work of
Wood et al. An alternative methoxypyridine alkylation has
enabled access to the citrinadin pentacyclic core and sets
thestageforfuturestudiestoconstructthefullysubstituted
pentacyclic core of the citrinadin natural products.
Acknowledgment. We thank the NIH (NIGMS R01
086374 and F32CA167908-01) for financial support, and
a Ruth L. Kirschstein NRSA postdoctoral fellowship to
D.A.M. R.S. is a Camille Dreyfus Teacher-Scholar. We
thank Dr. Antonio DiPasquale (UC Berkeley) for solving
the crystal structures of 27, 28, and 32 and acknowledge
the CYLView program (developed by Prof. Claude Y.
Despite the disappointing observations in the attempted
conversion of 12 to 14, our synthetic studies have identified
an alternative sequence to access the carbon skeleton of the
citrinadins bearing a quinolizidone framework (Scheme 6).
Thus, treatment of a solution of epoxy alcohol 25 with
triflic anhydride in the presence of 2,6-di-tert-butylpyridine
(2,6-DTBP) yields pyridinium salt 29. Aqueous workup of
this salt followed by treatment with sodium iodide in reflux-
ing acetonitrile gives pentacyclic pyridone 30 in 75% yield
over the two steps. Catalytic hydrogenation of pyridone 30
proceeds with excellent diastereoselectivity (>20:1) to give
epoxy quinolizidone 31 in 82% yield. At this stage, oxidation
of indole 31 with dimethyldioxirane (generated in situ from
oxone and acetone) gives spiro-oxindole 32, the structure
ꢀ
Legault, Dept. of Chemistry, Universite Sherbrooke) for
X-ray depictions.
Supporting Information Available. Experimental details
and copies of 1H and 13C spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
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