Modular synthesis of the pentacyclic core of batrachotoxin and select batrachotoxin analogue designs

Article abstract of DOI:10.1039/c2sc21723f

Pentacyclic analogues of the potent voltage-gated sodium ion channel agonist batrachotoxin can be accessed through an intermediate furan by exploiting Diels-Alder cycloaddition reactions with ring-strained dienophiles. The use of 3-bromofuran as a 1,2-dianion equivalent, the application of carbamate reductive N-alkylation for homomorpholine ring assembly, and the demonstration of CsF as an effective reagent for generating benzyne, cyclohexyne, and related dienophiles underscore this work.

Full text of DOI:10.1039/c2sc21723f

Chemical Science
View Article Online
View Journal
EDGE ARTICLE
Modular synthesis of the pentacyclic core of
batrachotoxin and select batrachotoxin analogue
Cite this: DOI: 10.1039/c2sc21723f
designs†
*
A. Sloan Devlin and J. Du Bois
Pentacyclic analogues of the potent voltage-gated sodium ion channel agonist batrachotoxin can be
accessed through an intermediate furan by exploiting Diels–Alder cycloaddition reactions with ring-
strained dienophiles. The use of 3-bromofuran as a 1,2-dianion equivalent, the application of carbamate
reductive N-alkylation for homomorpholine ring assembly, and the demonstration of CsF as an effective
reagent for generating benzyne, cyclohexyne, and related dienophiles underscore this work.
Received 11th October 2012
Accepted 9th November 2012
DOI: 10.1039/c2sc21723f
www.rsc.org/chemicalscience
NaV modulators.11 To our knowledge, no reports of the prepa-
ration of the C/D/E skeleton have appeared, in spite of the fact
Introduction
Batrachotoxin (BTX, 1), homobatrachotoxin, and batrachotox-
inin A comprise a small family of complex steroidal alkaloids
originally isolated in sparing amounts from the skin of
Colombian poison dart frogs of the genus Phyllobates (Fig. 1).1,2
Batrachotoxin acts as a selective agonist of voltage-gated
sodium channels (NaVs) and is among the most potent non-
peptidic toxins known (LD50 in mice ¼ 2 mg kgꢀ1).3,4 BTX
binding to NaVs results in a remarkably complex array of
responses, including hyperpolarization of threshold activation,
elimination of inactivation gating, and reduction of single
channel conductance.5 While there exist other small molecule
modulators of NaVs, arguably none show activity that is as
multifaceted as BTX. Severely limited quantities of BTX,
however, frustrate any efforts to evaluate structure–function
relationships and to utilize BTX or select analogues to interro-
gate mechanisms of ion selectivity and channel gating.6,7 Such
interests have motivated the synthetic studies described herein.
Batrachotoxin offers numerous intriguing challenges to the
chemist interested in de novo synthesis.8 The E-ring homo-
morpholine is unique among secondary metabolite structures,
and the 9a-hydroxy 3b-hemiketal, C16–C17 unsaturation, and
20a pyrrole ester do not appear in other steroidal natural
products. To date, only a single de novo route to (ꢁ)-batracho-
toxinin A has been disclosed.9,10 The impressiveness of this
achievement notwithstanding, the length and linear nature of
the synthesis does not provide a viable means to BTX analogues.
Other reports describe preparations of A/B/C ring system vari-
ants; those that have been tested show modest to little effect as
that mouse lethality and electrophysiology data indicate that
variations to the C, D, or E rings dramatically alter BTX
activity.12 Homology modelling and protein mutagenesis data
suggest that BTX binds to the inner pore region of NaV through
primary contacts with the C/D/E ring unit.13,14 With an interest
in understanding how toxin binding alters NaV function, we
have xed on the preparation of molecular probes that conserve
the C/D/E ring system of BTX and the pendant pyrrole ester. Our
synthetic efforts have culminated in a synthesis of a furan-
derived C/D/E ring intermediate, which is appropriately
congured to enable access to both BTX and A/B ring BTX
derivatives. The versatility of this furan structure is demon-
strated below for the synthesis of the pentacyclic core of the
natural product and related analogues.
Results and discussion
Our retrosynthetic plan for preparing BTX is depicted in Fig. 2.
Of the strategies considered for assembling the A/B ring system
from an advanced intermediate, a Diels–Alder sequence was
selected using furan 3 as the diene component. The choice of
this heterocycle as a B-ring surrogate offers exibility in terms of
dienophile selection and is expected to facilitate analogue
production. Furan 3 is further deconstructed by unraveling the
Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA. E-mail:
jdubois@stanford.edu
† Electronic supplementary information (ESI) available: General experimental
protocols, characterization data, and NMR spectra for all new compounds. See
DOI: 10.1039/c2sc21723f
Fig. 1 Structure of batrachotoxin and related compounds.
This journal is ª The Royal Society of Chemistry 2012
Chem. Sci.

View Article Online
Chemical Science
Edge Article
subsequent attempts to add nucleophiles to the masked alde-
hyde have been unfruitful. Efforts to protect the nitrogen center
in 10 using various alkylating agents (e.g., MeI or Me2SO4) and
bases (e.g., NaH or KHMDS) resulted in retro-Mannich reaction.
Fortunately, the application of a recently developed protocol for
N-methoxymethyl (MOM) protection of carbamates using
paraformaldehyde and MeOH successfully affords 11 in 80%
yield (Scheme 1).17 Subsequent alkene cleavage with O3 gives the
desired aldehyde 12, a critical component of our synthetic plan.
As originally conceived, sequential addition of a vicinal
dianion nucleophile to 12 would make possible diaster-
eoselective C-ring formation through a meso-breaking desym-
metrization event (Fig. 3). While several potential dianion
surrogates were considered at this stage of planning, 3-bromo-
furan appeared optimal in the rst-generation design of our
synthesis. Selective C2-lithiation of 3-bromofuran is possible
using LiNiPr2; elimination to the heteroaryne does not occur at
reduced temperature.18 Addition of this anion to the aldehyde
moiety in 12 was expected to furnish 2ꢂ alcohol 15 (R]H).
Following alcohol protection, metal–halogen exchange would
trigger cyclization to establish the cis-fused C/D ring junction.
In theory, the intermediate furyl anion could add to either
ketone group to generate diasteromeric products. A preferred
transition structure in which the C11-alkoxy group is disposed
in a pseudo-equatorial arrangement should favor the desired
stereoisomer 16.
Fig. 2 Retrosynthetic analysis of batrachotoxin 1.
homomorpholine unit. Latent symmetry elements appear in the
resulting tricyclic structure 4 that are revealed in ketone 5. The
preparation of 5 follows from dione 6 and a suitably derived
furan. In this context, the furan is intended to serve as a 1,2-
vicinal dianion equivalent.
Installation of the C13 quaternary carbon center is per-
formed in the initial stages of the BTX synthesis through a
three-step sequence from 1,3-cyclopentadione (Scheme 1).
Mannich reaction with this diketone and a suitable imine or
iminium electrophile are problematic, as the product readily
reverts to starting materials under acidic or basic conditions.15
The use of sulfone 8 as an imine precursor, however, enables
formation of the N-Boc-protected Mannich product 9 in 86%
yield.16 Both sulfone 8 and the dione product 9 are easily
prepared on multigram scales. Subsequent allylation of 9 under
basic conditions does not induce retro-Mannich or b-elimina-
tion of the NHBoc group; instead, a 2 : 1 mixture of O- and C-
allylated products is furnished. The choice of base has little
inuence on product selectivity; however, the mixture of
isomers converges to the desired C-allylated product 10 upon
heating in toluene (98%, two steps).
Addition of 2-lithio-3-bromofuran to diketo-aldehyde 12
occurs exclusively at C11 to afford a 3 : 2 diastereomeric mixture
of hemiacetals 18 rather than alcohol 17 (Scheme 2). Attempts
to promote hemiacetal ring opening and 2ꢂ alcohol protection,
however, did not prove successful; instead, use of MOMCl and
amine base gives the unusual bis-acetal structures 19 in a
slightly improved 2 : 1 diastereomeric ratio.19 Although this
intermediate was not conceived in our original retrosynthetic
analysis, the value of the major diastereomer 19-endo for
generating the C/D ring system of BTX is evident. Treatment of
ꢂ
19 with n-BuLi at ꢀ78 C results in selective lithium–halogen
Ozonolysis of alkene 10 to reveal the tricarbonyl species 13,
while successful, gives exclusively hemi-aminal 14 (eqn (1)). All
exchange, and intramolecular anion addition to the C14-ketone
(BTX numbering) furnishes the bridged tetracycle 20.20 Access
to 19-endo thus enables C/D ring formation with perfect control
of relative stereochemistry between the C11 and C14 centers.
Scheme 1 Reagents and conditions: (a) PhSO2Na, aq. CH2]O, HCO2H, MeOH,
78%; (b) 1,3-cyclopentadione, DBU, THF, 86%; (c) allyl bromide, K2CO3; toluene,
110 ꢂC, (98%, 2 steps); (d) Me3SiCl, paraformaldehyde, CH2Cl2, 0 ꢂC; 9 : 1 MeOH/
Et3N, 5 ꢂC, 80%; (e) O3, CH2Cl2, ꢀ78 ꢂC; Me2S, 83%. DBU ¼ 1,8-diazabicyclo[5.4.0]
undec-7-ene.
Fig. 3 Predicted stereochemical outcome of furyl anion meso-breaking addition.
This journal is ª The Royal Society of Chemistry 2012
Chem. Sci.

View Article Online
Edge Article
Chemical Science
using i-Bu2AlH as the hydride source. In this reaction, we
speculate that the 2ꢂ carbamate may serve as a stereochemical
controlling element to favor preferential addition to the si-face
of the ketone. Exclusive formation of the b-congured C20-
alcohol 24, as required for completing the C/D/E ring synthesis,
is consistent with the putative chelate addition model.22
Starting from alcohol 24, homomorpholine ring synthesis is
achieved through an efficient reductive amination sequence
(Scheme 3). Despite the weakly nucleophilic nature of the
carbamate moiety, condensation of this group with the inter-
mediate aldehyde 25 is favorable under the action of acetic acid
and MgSO4. In situ iminium ion reduction occurs with
NaCNBH3 to afford the bridging 7-membered ring structure 26
in 74% yield.23,24 The success of this cyclization reaction is
attributed to both the highly electrophilic character of the a-
alkoxyaldehyde and the geometric constraints of the C/D ring
fusion. Following a second metal hydride reaction, this one
employing LiAlH4 to reduce the N-Boc group, assembly of the
fully functionalized C/D/E core 27 of the natural product is
accomplished.
We have explored a variety of Diels–Alder reactions with
furan 26 in an effort to complete the synthesis of BTX and to
evaluate dienophile reactivity for BTX analogue design.25
Cycloaddition reactions with electron-decient alkynes showed
encouraging preliminary results and revealed several important
reactivity trends (Table 1, entries 1–3).26 First, the substituted
furan diene strongly biases regiochemical control in reactions
with unsymmetrical alkyne dienophiles, as all three Diels–Alder
adducts were formed as single constitutional isomers. The
steric and electronic inuence of C8–C9 substitution on the
furanyl unit favors bond formation between C6 and the most
electrophilic site on the dienophile. Second, in all cases exam-
ined, approach of the dienophile occurs from the desired b-face
of the furan, albeit not with the degree of selectivity anticipated
from analysis of molecular models. The modest diastereomeric
ratios may be reective of thermodynamic energy differences
between the oxo-norbornadiene products, as these alkyne–
furan Diels–Alder reactions are reversible.27
Scheme 2 Reagents and conditions: (a) 3-bromofuran, LiNiPr2, THF, ꢀ78 ꢂC, 3 : 2
dr, 89%; (b) MOMCl, i-PrNEt2, 2 : 1 endo/exo, 80%; (c) n-BuLi, THF, ꢀ78 ꢂC, 89%
based on 19-endo starting material.
Having established a preparative route to 20, a three-step
sequence makes possible elaboration of this structure to tricycle
22 (Scheme 3). High yielding, 3ꢂ alcohol allylation is effected
using a biphasic reaction protocol with 50% aqueous NaOH and
n-Bu4NI as a phase-transfer agent.21 Subsequent acetal hydro-
lysis reveals the C17 ketone, which is smoothly transformed to
the corresponding vinyl triate. Stille cross-coupling with (1-
ethoxyvinyl)tributyltin followed by aqueous acid treatment
affords methyl ketone 23 (81% yield over three steps). Notably,
strong acid hydrolysis also cleaves the N-MOM group. Finally,
diastereoselective 1,2-reduction of the C20 enone is achieved
The modest reactivity of furan as a diene for [4 + 2] cyclo-
additions and the proclivity of the oxo-bridged bicyclic products
to undergo cycloreversion have foiled attempted reactions with
several other common dienophiles.28 We have, therefore,
investigated reactions of 26 with highly strained dienophiles,
which have been shown to cycloadd irreversibly with furan and
simple furan derivatives. Benzyne, cyclohexyne, and cyclo-
propene derivatives react productively with 26 to give the
expected Diels–Alder adducts (entries 4–6, Table 1).29–31 Each of
these structures comprises the pentacyclic framework of BTX.
We have found dienophile generation to be most effective using
CsF to promote elimination of a vicinally substituted silyl-vinyl
triate or -vinyl halide, and reaction efficiency is excellent for
Scheme 3 Reagents and conditions: (a) allyl bromide, n-Bu4NI, CH2Cl2, 50% aq.
NaOH, 89%; (b) MeC(O)Cl, MeOH, 0 ꢂC, 92%; (c) MOMCl, i-PrNEt2, CH2Cl2, 40 ꢂC, two of the examples shown. With these [4 + 2] additions,
92%; (d) KN(SiMe3)2, N-(5-chloro-2-pyridyl)triflimide, THF, ꢀ78 ꢂC, 95%; (e)
however, facial selectivities across the furan diene are compa-
rable to those obtained with alkyne dienophiles and only
slightly in favor of the desired product.
While Diels–Alder cycloadditions with furan 26 have provided
a collection of structurally unique analogues possessing the
tributyl(1-ethoxyvinyl)tin, 10 mol% Pd(PPh3)4, CuCl, DMSO, 65 ꢂC; 4N aq. HCl,
EtOAc, 0 ꢂC, 85%; (f) i-Bu2AlH, toluene, ꢀ78 ꢂC, 76%; (g) t-BuMe2SiOTf, 2,6-
lutidine, CH2Cl2, ꢀ78 ꢂC, 99%; (h) 14 mol% OsO4, NMO, H2O/THF; (i) Pb(OAc)4,
CH2Cl2, 91% (over 2 steps); (j) MgSO4, CH3CO2H, DCE; NaBH3CN, 74%; (k) LiAlH4,
THF, 65 ꢂC, 73%. NMO ¼ N-methylmorpholine N-oxide.
This journal is ª The Royal Society of Chemistry 2012
Chem. Sci.

View Article Online
Chemical Science
Edge Article
Table 1 Late-stage Diels–Alder cycloaddition reactions with furan 26
investigated reactions of furan 21 with dienophiles, including
cyclohexyne and a substituted benzyne (Fig. 4). The three-
dimensional topology of this tetracyclic structure effectively
precludes approach of the dienophile from the a face of the
furan, and the desired products 29 and 30 are furnished with
>20 : 1 stereoselectivity. The utility of the CsF-promoted method
for generating strained dienophiles is illustrated in these exam-
ples, as treatment of 21 with a cyclohexenyl phenyliodonium salt,
a known cyclohexyne precursor, gives none of the desired cyclo-
adduct.32 Products such as 29 and 30 should facilitate access to
BTX analogues with alternative D-ring and/or homomorpholine
congurations than those highlighted in Table 1, and may allow
for preparation of the natural product itself.
Conclusions
We have outlined a synthetic plan that makes available novel
pentacyclic forms of BTX possessing the fully elaborated C/D/E
ring core. Highlights of this work include the application of
sulfone 8 for Mannich addition with cyclopentadione, the use of
3-bromofuran as a vicinal dianion equivalent, desymmetriza-
tion of dione 17 through bis-acetal formation, Li–Br exchange
for C-ring formation, and homomorpholine assembly through
reductive alkylation. In addition, Diels–Alder reactions with
furans 21 and 26 and ring-strained dienophiles have been
examined for introduction of the A-ring moiety. Use of CsF to
trigger benzyne, cyclohexyne, and cyclopropene formation from
corresponding trimethylsilyl starting materials has proven to be
a general and effective method, affording in most cases high
yields of the desired cycloadducts. The evaluation of these
unique toxin derivatives as modulators of voltage-gated sodium
channels is currently underway in our laboratory.
a
A
regioisomeric Diels–Alder product having C6 (S), C9 (R)
b
stereochemistry is also obtained. The cyclopropane stereochemistry
in B is inverted from that depicted (i.e., C5 (S), C10 (R)). In addition, a
third product having C5 (S), C6 (S), C9 (R), C10 (R) stereochemistry is
also obtained, see ESI.†
Acknowledgements
We are grateful to the National Institutes of Health (R01
NS045684) for partial support of this work and to Pzer, Inc. for
a generous gi. ASD acknowledges the nancial support of
Novartis, Lieberman and Stanford Graduate Fellowships.
pentacyclic core of BTX, our inability to improve levels of dia-
stereoinduction in these reactions has challenged us to recon-
sider elements of our synthetic strategy. To this end, we have
Notes and references
1 (a) F. Marki and B. Witkop, Experientia, 1963, 19, 329; (b)
J. W. Daly, B. Witkop, P. Bommer and K. Biemann, J. Am.
Chem. Soc., 1965, 87, 124.
2 4b-Hydroxybatrachotoxin and 4b-hydroxyhomobatrachotoxin
were also isolated as minor components, see: T. Tokuyama
and J. W. Daly, Tetrahedron, 1983, 39, 41.
3 T. Tokuyama, J. W. Daly and B. Witkop, J. Am. Chem. Soc.,
1969, 91, 3931.
4 E. X. Albuquerque, J. W. Daly and B. Witkop, Science, 1971,
172, 995.
5 (a) S. Y. Wang and G. K. Wang, Cell. Signalling, 2003, 15, 151;
(b) F. N. Quandt and T. Narahashi, Proc. Natl. Acad. Sci. U. S.
A., 1982, 79, 6732.
6 The sacrice of over 10 000 Colombian poison dart frogs,
which are now endangered, resulted in the isolation of 180
Fig. 4 Highly selective cyclohexyne and benzyne Diels–Alder reactions with
furan 21.
Chem. Sci.
This journal is ª The Royal Society of Chemistry 2012

View Article Online
Edge Article
Chemical Science
mg of BTX and 100 mg of hBTX. H. M. Garraffo and 17 D. M. Barnes, J. Barkalow and D. J. Plata, Org. Lett., 2009, 11,
T. F. Spande, Heterocycles, 2009, 79, 195. 273.
7 Frogs raised in captivity do not produce the toxin. J. W. Daly, 18 N. D. Ly and M. Schlosser, Helv. Chim. Acta, 1977, 60, 2085.
C. W. Myers, J. E. Warnick and E. X. Albuquerque, Science, 19 The preference for isomer 19-endo, in which the furan unit is
1980, 208, 1383.
8 (a) T. Tokuyama, J. Daly, B. Witkop, I. L. Karle and J. Karle, J.
Am. Chem. Soc., 1968, 90, 1917; (b) I. L. Karle and J. Karle,
located on the concave face of the bicyclic, may be the result
of a stereoelectronic preference for O-lone pair / s*(C11–
C9) delocalization.
Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem., 20 Lithium–halogen exchange is performed on a 2 : 1 19-endo/
1969, 25, 428; (c) R. D. Gillardi, Acta Crystallogr., Sect. B:
Struct. Crystallogr. Cryst. Chem., 1970, 26, 440.
9 M. Kurosu, L. R. Marcin, T. J. Grinsteiner and Y. Kishi, J. Am.
Chem. Soc., 1998, 120, 6627.
exo mixture to give 60% isolated yield of 20 (89% based on
theoretical maximum) and 30% of the proto-debrominated
exo product.
21 A. Goto, K. Fujiwara, A. Kawai, H. Kawai and T. Suzuki, Org.
Lett., 2007, 9, 5373.
10 Imhof and co-workers completed a partial synthesis of an
analog of (ꢀ)-batrachotoxinin A in which the stereochemistry 22 Crystallographic analysis of an analogue structure conrms
of the C20 alcohol was inverted (S instead of R). (a)
the C20-b-conguration. M. M. Logan, J. Du Bois,
¨
R. Imhof, E. Gossinger, W. Graf, L. Berner-Fenz, H. Berner,
manuscript in preparation.
R. Schaufelberger and H. Wehrli, Helv. Chim. Acta, 1973, 56, 23 For a related N-Boc pyrrolidine synthesis, see: K. Sakaguchi,
¨
139; (b) R. Imhof, E. Gossinger, W. Graf, H. Berner,
M. Ayabe, Y. Watanabe, T. Okada, K. Kawamura, T. Shiada
L. Berner-Fenz and H. Wehrli, Helv. Chim. Acta, 1972, 55, 1151.
and Y. Ohfune, Org. Lett., 2008, 10, 5449.
11 (a) R. R. Schumaker and J. F. W. Keana, J. Chem. Soc., Chem. 24 The major byproduct of this reaction results from reduction
Commun., 1972, 622; (b) J. F. W. Keana and R. R. Schumaker,
J. Org. Chem., 1976, 41, 3840; (c) P. Magnus, T. Leapheart and
C. Walker, J. Chem. Soc., Chem. Commun., 1985, 1185; (d)
P. Hudson, G. Pairaudeau, P. J. Parsons, A. W. Jahans and
of aldehyde 25 to a primary alcohol. Mesylation of this
alcohol and subsequent intramolecular SN2 displacement
gives 26, increasing the overall yield of homomorpholine
ring closure to 84%. See ESI† for details.
M. G. B. Drew, Tetrahedron Lett., 1993, 34, 7295; (e) 25 For a review of furan Diels–Alder reactions: C. O. Kappe,
S. Trudeau and P. Deslongchamps, J. Org. Chem., 2004, 69, S. S. Murphree and A. Padwa, Tetrahedron, 1997, 53, 14179.
832; (f) P. Lacrouts, P. J. Parsons, C. S. Penkett and 26 (a) J. Leroy, Tetrahedron Lett., 1992, 33, 2969; (b) A. Gorgues,
A. R. Raza, Synlett, 2005, 2767; (g) S. R. Schow,
D. P. Rossignol, A. E. Lund and M. E. Schnee, Bioorg. Med.
Chem. Lett., 1997, 7, 181.
A. Simon, A. Le Coq, A. Hercouet and F. Corre, Tetrahedron,
1986, 42, 351; (c) S. Albert, A. Soret, L. Blanco and S. Deloisy,
Tetrahedron, 2007, 63, 2888; (d) M. Shen and A. G. Schultz,
Tetrahedron Lett., 1981, 22, 3347.
12 (a) B. I. Khodorov, E. A. Yelin, L. D. Zaborovskaya,
M. Z. Maksudov, O. B. Tikhomirova and V. N. Leonov, Cell. 27 Re-subjecting the puried products to the reaction
Mol. Neurobiol., 1992, 12, 59; (b) J. E. Warnick, conditions results in cycloreversion to starting materials.
E. X. Albuquerque, R. Onur, S. Jansson, J. Daly, T. Tokuyama 28 Other alkyne and alkene substrates tested include
and B. Witkop, J. Pharmacol. Exp. Ther., 1975, 193, 232.
13 (a) D. B. Tikhonov and B. S. Zhorov, FEBS Lett., 2005, 579,
4207; (b) Y. Du, D. P. Garden, L. Wang, B. S. Zhorov and
K. Dong, J. Biol. Chem., 2011, 286, 13151.
ethyl propiolate and 2-bromo-4-ethoxycyclohexa-1,3-
dienecarbaldehyde. Use of high pressure conditions (>6
kbar) with methyl maleic anhydride also resulted in no
reaction.
14 (a) S. Y. Wang and G. K. Wang, Biophys. J., 1999, 76, 3141; (b) 29 S. Akai, T. Ikawa, S. Takayanagi, Y. Morikawa, S. Mohri,
S. Y. Wang and G. K. Wang, Proc. Natl. Acad. Sci. U. S. A.,
1998, 95, 2653; (c) S. Y. Wang, D. B. Tikhonov,
M. Tsubakiyama, M. Egi, Y. Wada and Y. Kita, Angew.
Chem., Int. Ed., 2008, 47, 7673.
B. S. Zhorov, J. Mitchell and G. K. Wang, Pugers Arch., 30 (a) W. C. Shakespeare and R. P. Johnson, J. Am. Chem. Soc.,
´
1990, 112, 8578; (b) N. Atanes, S. Escudero, D. Perez,
2007, 454, 277; (d) Y. Du, J. E. Lee, Y. Nomura, T. Zhang,
B. S. Zhorov and K. Dong, Biochem. J., 2009, 419, 377; (e)
´
E. Guitian and L. Castedo, Tetrahedron Lett., 1998, 39, 3039.
S. Y. Wang, M. Barile and G. K. Wang, Mol. Pharmacol., 31 G. E. Collis, D. Jayatilaka and D. Wege, Aust. J. Chem., 1997,
2001, 59, 1100; (f) S. Y. Wang, D. B. Tikhonov, J. Mitchell,
B. S. Zhorov and G. K. Wang, Channels, 2007, 1, 179.
15 C. C. McComas, J. B. Perales and D. L. Van Vranken, Org.
Lett., 2002, 4, 2337.
50, 505.
32 (a) M. Fujita, W. H. Kim, Y. Sakanishi, K. Fujiwara,
S. Hirayama, T. Okuyama, Y. Ohki, K. Tatsumi and
Y. Yoshioka, J. Am. Chem. Soc., 2004, 126, 7548; (b)
C. M. Gampe and E. M. Carreira, Angew. Chem., Int. Ed.,
2011, 50, 2962.
16 For the development of a related sulfone see: X. Guinchard,
´
Y. Vallee and J. N. Denis, Org. Lett., 2005, 7, 5147.
This journal is ª The Royal Society of Chemistry 2012
Chem. Sci.