Concise, stereocontrolled synthesis of the citrinadin B core architecture

Article abstract of DOI:10.1021/ol2020362

A concise, stereocontrolled synthesis of the citrinadin B core architecture from scalemic, readily available starting materials is disclosed. Highlights include ready access to both cyclic tryptophan tautomer and trans-2,6- disubstituted piperidine fragme

Full text of DOI:10.1021/ol2020362

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5164–5167
Concise, Stereocontrolled Synthesis of
the Citrinadin B Core Architecture
Carlos A. Guerrero† and Erik J. Sorensen*
Frick Laboratory, Department of Chemistry, Princeton University, Princeton,
New Jersey 08544, United States
ejs@princeton.edu
Received July 27, 2011
ABSTRACT
A concise, stereocontrolled synthesis of the citrinadin B core architecture from scalemic, readily available starting materials is disclosed.
Highlights include ready access to both cyclic tryptophan tautomer and trans-2,6-disubstituted piperidine fragments, an efficient, stereoretentive
mixed Claisen acylation for the coupling of these halves, and further diastereoselective carbonyl addition and oxidative rearrangement for
assembly of the core.
In complex, small molecule synthesis, the adoption of
reagent- or substrate-directed strategies to achieve stereo-
control ꢀ or a combination thereof ꢀ depends on the
particular challenges posed by the synthesis target of
interest. In the case of citrinadin B1 (1, Figure 1) ꢀ a
scarce, cytotoxic, marine meroterpene alkaloid ꢀ the
density of stereocenters in the center of the molecule would
seem to favor a strategy wherein a merger of prefabricated,
scalemic fragments would permit the management of
remote stereochemical relationships. The central cyclopen-
tane has four fully substituted carbon atoms, three of
which are centers of asymmetry. However, the establish-
ment of such stereocenters by enantioselective methods
lags behind those methods that set tertiary carbon
stereocenters,2 and pre-existing elements of complexity
may render predictions of the stereochemical course diffi-
cult. In contrast, the advantages of relative stereocontrol
mentioned above might be realized in the context of a
synthesis of the citrinadin B core architecture; the success-
ful implementation of this strategy is reported herein.3
Figure 1. Structures of the citrinadins and PF1270AꢀC.
The citrinadins1,4 (1 and 2) and PF1270AꢀPF1270C5,6
(see Figure 1) comprise a tryptophan portion, a piperidine
fragment, and two isoprene units, one bonded peripherally
toC7 (heterocycle numbering) of the oxindole, whereas the
other isdeeplyembeddedsuchthat a carbonꢀcarbon bond
is expressed to all three central carbons of this isoprene
† Present address: Department of Chemistry and Biochemistry, University
of California, San Diego, 9500 Gilman Drive #0358, Pacific Hall Room
5100C, La Jolla, CA 92093-0358.
(1) Mugishima, T.; Tsuda, M.; Kasai, Y.; Ishiyama, H.; Fukushi, E.;
Kawabata, J.; Watanabe, M.; Akao, K.; Kobayashi, J. J. Org. Chem.
2005, 70, 9430–9435.
(2) (a) Liao, X.; Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc.
2011, 133, 2088. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5363. (c) The 2001 Nobel Prize in Chemistry recog-
nized enantioselective hydrogenation and oxidation reactions, yet the
former obviously cannot be used for the establishment of quaternary
stereocenters starting from π-systems.
(3) For a previous report from our laboratory directed toward the
citrinadin B structure, see: Chandler, B. D.; Roland, J. T.; Li, Y.;
Sorensen, E. J. Org. Lett. 2010, 12, 2746.
(4) Tsuda, M.; Kasai, Y.; Komatsu, K.; Sone, T.; Tanaka, M.;
Mikami, Y; Kobayashi, J. Org. Lett. 2004, 6, 3087.
r
10.1021/ol2020362
Published on Web 09/06/2011
2011 American Chemical Society

unit. As the isoprene units are small, their installation
allows for considerable flexibility. In contrast, we opted
to commence with tryptophan and piperidine fragments
and find suitable means for their stereocontrolled synthesis
and union.
The utility of cyclic tautomers of tryptophan7,8 in the
stereoselective synthesis of amino acid derivatives has been
studied.9,10 Chain-to-ring tautomerism gives structures
with a pronounced folded topology; in the wake of en-
olization events, trappings with electrophiles would occur
on the convex face of the molecule.11,12 We relied on this
propensity to stereoselectively join two halves of roughly
equal complexity. Subsequent chemo- and/or diastereose-
lective transformations were then used to complete a
synthesis of the citrinadin B core.
efficient carbonꢀcarbon bond formation and suppresses
byproduct formation with allyl bromide as an electrophile;
strict temperature control is required for desirable diaster-
eoselectivity favoring piperidine 6.16 Two-step oxidative
cleavage by initial dihydroxylation with substoichiometric
OsO4 and 1,4-diazabicyclo-[2.2.2]octane using K3Fe(CN)6
as a terminal oxidant followed by cleavage with substoi-
chiometric RuCl3 and excess NaIO4 furnishes acid 7. At
this point, electrophile 8 is formed by simple dehydrative
esterification of acid 7 with di-isopropylcarbodiimide and
pentafluorophenol.
Scheme 2. Preparation of Ester 8a
Scheme 1. Preparation of tert-Butyl Ester 4a
a DMAP = 4-(dimethylamino)pyridine.
Readily available acid 313 is esterified in good yield
though the intermediacy of an in situ generated mixed
carbonate, giving tert-butyl ester 4 (see Scheme 1).
The piperidine portion (see Scheme 2) is generated in
scalemic form starting with a classical resolution of (()-2-
methylpiperidine.14 Neutralization/carbamoylation then
gives N-tert-butoxycarbonyl-(R)-2-methylpiperidine (5).
This material is alkylated stereoselectively by modifying
conditions originally reported by Beak and co-workers.15
In particular, transmetalation to a Cu(I) salt promotes
a s-BuLi = sec-butyllithium; DABCO = 1,4-diazabicyclo[2.2.2]-
octane; DIC = di-isopropylcarbodiimide; TMEDA = N,N,N0,N0-tetra-
methylethylenediamine; THF = tetrahydrofuran.
The fragment union is accomplished by the following
sequence: (1) initial enolization of a slight excess of tert-
butyl ester 4 using lithium bis(trimethylsilyl)amide in cold
THF; (2) subsequent addition of hexamethylphosphora-
mide; (3) addition by cannula of a cold solution of penta-
fluorophenylester 8; and(4) cold-temperaturequenchwith
acetic acid (see Scheme 3).17 The delayed addition of
hexamethylphosphoramide minimizes deprotonation at
the benzylic site of the ester 4 (i.e., “lateral” deprotonation)
foundtooccur inoptimization studiesofthisreaction. This
mixed Claisen acylation generates β-keto ester 9 in 77%
isolated yield and with high diastereoselectivity. The great-
est erosion of diastereoselectivity arises if the reaction
mixture is not quenched cold with glacial acetic acid, which
leads to epimerization at C16 (citrinadin B numbering),
ostensibly by a β-eliminationꢀ1,4-addition mechanism.
Compound 9 is converted toβ-keto lactam 10by a three-
stage process wherein the following occurs: (1) the Boc
group is selectively removed using in situ-generated HCl;
(2) after evaporation to dryness of the methanolic mixture,
the resultant residue is taken up in anhydrous toluene and
treated with excess POCl3, and the mixture is heated at
(5) Kushida, N.; Watanabe, N.; Okuda, T.; Yokoyama, F.; Gyobu,
Y.; Yaguchi, T. J. Antiobiot. 2007, 60, 667.
(6) (a) Kushida, N.; Watanabe, N.; Yaguchi, T.; Yokoyama, F.;
Tsujiuchi, G.; Okuda, T. Novel Physiologically Active Substances
PF1270A, B and C. Eur. Pat. Appl. 1612273, 2004. (b) Kushida, N.;
Watanabe, N.; Yaguchi, T.; Yokoyama, F.; Tsujiuchi, G.; Okuda, T. U.S.
Patent 7,501,431, March 10, 2009.
(7) (a) Ohno, M.; Spande, T. F.; Witkop, B. J. Am. Chem. Soc. 1968,
90, 6521. (b) Ohno, M.; Spande, T. F.; Witkop, B. J. Am. Chem. Soc.
1970, 92, 343.
(8) Hino, T.; Taniguchi, M. J. Am. Chem. Soc. 1978, 100, 5564.
(9) Hino, T.; Nakagawa, M. Chemistry and Reactions of Cyclic
Tautomers of Tryptamines and Tryptophans. In The Alkaloids: Chem-
istry and Pharmacology; Brossi, A., Ed.; Academic Press, Inc.: San Diego,
1988; Vol. 34, pp 1ꢀ75.
(10) Crich, D.; Banerjee, A. Acc. Chem. Res. 1997, 40, 151.
(11) Crich, D.; Davies, J. W. Chem. Commun. 1989, 1418.
(12) Crich, D.; Bruncko, M. Tetrahedron Lett. 1992, 33, 6251.
(13) Prepared by saponification of the corresponding methyl ester.
See Supporting Information for experimental procedure. The starting
methyl ester has been reported (formerly available from Aldrich); see:
Chan, C.-O.; Crich, D.; Natarajan, N. Tetrahedron Lett. 1992, 33, 3405.
(14) Craig, J. C.; Pinder, A. R. J. Org. Chem. 1971, 36, 3648. A
modified procedure was employed, the details of which are provided in
the Supporting Information.
(16) Dieter, R. K.; Oba, G.; Chandupatla, K. R.; Topping, C. M.; Lu,
K.; Watson, R. T. J. Org. Chem. 2004, 69, 3076.
(17) For a similar strategic union via mixed Claisen acylation, see:
(15) (a) Beak, P.; Lee, W.-K. Tetrahedron Lett. 1989, 30, 1187. (b)
Beak, P.; Lee, W.-K. J. Org. Chem. 1993, 58, 1109.
Vaswani, R. G.; Chamberlin, A. R. J. Org. Chem. 2008, 73, 1661.
Org. Lett., Vol. 13, No. 19, 2011
5165

Scheme 3. Toward Citrinadin B: Attainment of the Core Architecturea
a HMPA = hexamethylphosphoramide; Tf = trifluoromethansulfonyl; TMS = trimethylsilyl; rt = room temperature.
reflux; (3) the resultant mixture is evaporated to dryness,
dissolved in neat TFA, and stirred for two days.10 After
neutralization, workup, and flash column chromatogra-
phy, lactam 10is obtainedin 59% overall yield from β-keto
ester 9. This sequence of operations constitutes a refined
process for lactamization and ring-to-chain tautomerism
as the pyrroloindoline topology of 4 is superfluous after
fragment coupling and the original indole structure must
be restored. Numerous other methods for unimolecular
amide bond formation were surveyedbut provided inferior
results on scale due to the propensity of the intermediate
β-keto acid to undergo decarboxylation, a process driven
by favorable entropic gains and release of strain. The use of
POCl3 directly on a tert-butyl ester of type 9 had a twofold
motivation: (1) the interaction between the ester carbonyl
and oxophilic POCl3 might induce ionization of the tert-
butyl group, rendering a separate hydrolysis step unneces-
sary, and (2) the resulting acyl phosphate intermediate
might mimic the reactivity seen with the intermediates
invoked in phosphonium-based amide bond-forming
reactions;18 neutralization of the secondary amine would
then lead to spontaneous lactamization. In practice, cycli-
zation occurs spontaneously without an exogenous base
during treatment with POCl3 in boiling toluene. The
reaction mixture that results contains mostly the ring
tautomer of 10; this material is easily converted to 10 as
described above.
The remaining three carbon atoms of the central iso-
prene unit and another fully substituted stereocenter are
incorporated by a diastereoselective carbonyl addition of
iso-propenylmagnesium bromide to the ketocarbonyl of
lactam 10. Predictably higher diastereoselectivity is ob-
served with lower reaction temperatures (10:1 at ꢀ78 °C).
There are two noteworthy aspects of this outcome. First, in
a control experiment, the cyclic tautomer of 10 furnished
no products of ketocarbonyl addition, providing circum-
stantial evidence for a directed process19,20 when chain
tautomer 10 is subjected to the reaction conditions. Sec-
ond, although no affirming correlations could be discerned
in the NOESY spectrum of carbinol 11, its C18 epimer
(citrinadin B numbering; see structure SI-3 in the Support-
ing Information) bore a correlation between both termini
of the isopropenyl group and C16ꢀH, thus establishing
structure 11 by a process of elimination.
Although citrinadin B has a central cyclopentane core,
we addressed this element indirectly by oxidative rearran-
gement of a 2,3-disubstituted indole to a 3,3-disubstituted
oxindole for two reasons: first, given the high density of
fully substituted carbons, it seemed logical to rearrange
hindered, pre-existing bonds rather than attempting to
generate such bonds to already-crowded centers directly;
second, the factors giving rise to diastereoselection dur-
ing oxidative rearrangement appeared predictable and
(19) For an authoritative review of directed reactions, see: Hoveyda,
A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
(20) Paquettehas reported similar directivity: Hilmey, D. G.; Galluci,
J. C.; Paquette, L. A. Tetrahedron 2005, 61, 11000.
ꢀ
(18) Coste, J.; Frerot, E.; Jouin, P. J. Org. Chem. 1994, 59, 2437.
5166
Org. Lett., Vol. 13, No. 19, 2011

possibly amenable to substrate control. Thus, carbinol 11
is reductively deprotected with Mg powder in methanol
buffered with solid NH4Cl furnishing a free indole that
readily undergoes a formalcycloisomerization with a slight
excess of Hg(O2CCF3)2 followed by reductive demercura-
tion of the resultant CꢀHg σ-bond. Pentacycle 12 is iso-
lated in 90% overall yield starting from pure carbinol 11.
Notably, the use of mixtures of 11 and its carbinol epimer
at C18 is of no consequence since only the desired, pre-
dominant diastereomer undergoes mercurative cyclization.
Earlier investigations pointed to a protecting group
liability during attempted oxidative rearrangement.
Though the details are beyond the scope of this Letter,
NMR and MS data suggest azetidine or cyclic imidate
products from such reactions when the N25 atom or a
carbamate group bonded to it has any appreciable nucleo-
philicity. The electrophilicity at C3 of indole during pina-
col-like rearrangement may thus be diverted at the expense
of oxindole formation. To address this difficulty, a protect-
ing group exchange of carbamate for azide is performed.
The methyl carbamate-protected nitrogen of 12 is depro-
tected with remarkable chemoselectivity with excess
BBr3•S(CH3)2 at ambient temperature, furnishing amine
13 in 96% isolated yield, and this material is converted to
azido amine 14 by a two-step sequence involving reduction
of the lactam function by sodium bis(2-methoxyethoxy)-
aluminum hydride and conversion of the primary amine to
an azide upon treatment with trifluoromethanesulfonyl
azide.21 Finally, carbamoylation of the indole nitrogen
occurs upon treatment with stoichiometric 4-(dimethyl-
amino)pyridine and excess di-tert-butyl dicarbonate at
55 °C furnishing azido carbamate 15 in 47% isolated yield.
The desired oxidative rearrangement22,23 was achieved
by sequential treatment of azido carbamate 15 with (1) a
slight excess of trifluoroacetic acid to protonate and there-
fore protect the tertiary amine from oxidation; (2) at least 3
equiv of anhydrous, exogenously generated trifluoroper-
acetic acid;24 and (3) 10 equiv of dimethyl sulfide to quench
the unconsumed oxidant. After neutralization, workup,
and purification, oxindole 16 is isolated in 33% yield.
Analysis of the crude reaction mixture reveals that the
desired product is the predominant species (see Supporting
Information); the identity of the remaining products,
however, remains to be determined. The refined protocol
for oxidative rearrangement was identified based on
previously observed complications and the finding that
trifluoroperacetic acid is uniquely effective at converting
carbamate 15 to oxindole 16. This oxidant was chosen not
only because other, less electrophilic peracids were found
to be incapable of oxidation of the Boc-protected indole
nucleus but also because the heightened acidity of this
reagent might enable a substrate-directable chemical re-
action wherein the tertiary hydroxyl group serves as a
hydrogen bond acceptor, as opposed to a donor as seen
with other hydroxyl-directed epoxidations.25 Although
this hypothesis served as a design element, more rigorous
studies are required before such a conclusion can be firmly
established. Nonetheless, the production of oxindole 16
demonstrates that the highly substituted, stereochemically
rich core of citrinadin B is accessible via oxidative rearran-
gement of a 2,3-disubstituted indole.
The chemistry described herein serves as a milestone in
our effort to synthesize citrinadin B.26 Apart from the
brevity and operational simplicity of our route, other points
of note include (1) utilization of the stereochemistry of L-
tryptophan in an overall “self-reproduction of chirality”
event; (2) ready access to scalemic piperidine fragment 8;
(3) an efficient mixed Claisen acylation union; and
(4) designed, diastereoselective carbonyl addition and oxi-
dative rearrangement reactions to address remaining pro-
blems of stereocontrol in the citrinadin B context. These
investigations place the projected completion of our synth-
esis on a firm foundation and may allow more general
questions to be answered with regard to the physiological
performance of this potential antileukemic agent.
Acknowledgment. We gratefully acknowledge financial
support from the National Institutes of Health (R01-
GM065483 to E.J.S.; F32-GM086035 to C.A.G.).27 We
ꢀ
thank Drs. Istvan Pelczer and John Eng (both of Princeton
University) for spectroscopic assistance. Graham Hone
(Princeton University) is acknowledged for reproduction
of experimental procedures.
Supporting Information Available. Detailed experi-
mental procedures, characterization data, and spectra
of isolated and purified intermediates. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(21) Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-Lomas, M. Helv.
Chim. Acta 1991, 74, 2073.
(22) Martin disclosed a similar oxidative ring contraction strategy
toward citrinadin A: Pettersson, M.; Knueppel, D.; Martin, S. F. Org.
Lett. 2007, 9, 4623.
(23) Both Martin’s and our own work were based on Foote’s
observation that indoles bearing electron-withdrawing groups at N1
rearrange to oxindoles spontaneously upon epoxidation in contrast to
ring opening to C3-hydroxyindolenines when the indole is unprotected:
Zhang, X.; Foote, C. S. J. Am. Chem. Soc. 1993, 115, 8867.
(24) Generation of solutions of trifluoroperacetic acid: Ballini, R.;
Marcantoni, E.; Petrini, M. Tetrahedron Lett. 1992, 33, 4835.
(25) McKittrick, B. A.; Ganem, B. Tetrahedron Lett. 1985, 26, 4895.
(26) For recent disclosures from other groups: (a) McIver, A. L.;
Deiters, A. Org. Lett. 2010, 6, 1288. (b) At the 2011 Grasmere Hetero-
cyclic and Synthesis Symposium (May 5ꢀ9, 2011) Prof. Stephen Martin
presented a lecture describing his laboratory’s synthesis of the penacyclic
core structure of citrinadin B. (c) Kong, K.; Smith, G. M.; Wood, J. L.
“Progress Towards the Total Synthesis of Citrinadins A & B.” 42nd
National Organic Symposium, June 6ꢀ9, 2011, Princeton, NJ.
(27) Research toward a synthesis of citrinadin B was conducted by
CAG from February 2009 to April 2011.
Org. Lett., Vol. 13, No. 19, 2011
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