Scheme 2. The Analgesic Alkaloid (-)-Epibatidine (5) and an
Iterative StReCH Based Synthetic Plan To Access It
Scheme 3. Enantioselective Synthesis of Chlorosulfoxides 12
this nascent technology could be directed to the synthesis
of all manner of acyclic targets; however, it may also be
potentially applied to access cyclic compounds providing
that the carbenoid building blocks used during iterative
assembly bear functionalized substituents. In this manner,
following production of an acyclic precursor, annulation
processes involving the embedded side-chain functional
groups could be triggered to yield some cyclic motif of
interest. Herein, we reportanexploration of thisstrategyas
it relates to the synthesis of congeners of the analgesic alka-
loid (-)-epibatidine using a functionalized R-chloroalk-
yllithium formed by sulfoxide-ligand exchange.8
(-)-Epibatidine (5) was first identified by Daly and co-
workers as a trace component of the skin extract of the
poison tree frog Epipedobates tricolor.9 Isolation of 5 was
guided by a mouse Straub-tail bioassay, a response usually
associated with opiate induced analgesia. The analgesic ac-
tion of 5 (estimated to be >200 times that of morphine)
was later tracked to its agonism of nicotinic acetylcholine
receptors (nAChR’s).10 Given the interesting biological
activity of 5 and its intriguing 7-azabicyclo[2.2.1]heptane
core, epibatidine has become an inspirational and popular
synthetic target11 and many artificial analogs have been
prepared to determine SAR.12 We desired a versatile route
to epibatidine that would enable any of its stereoisomeric
forms, and related congeners, to be accessed in a concise
fashion. Thus, it was envisioned that sequential StReCH
reactions from commercially available pinacol boronate 7
using functionalized scalemic carbenoids 8 would afford
an acyclic precursor to epibatidine (6) containing preset C1
and C2 stereogenic centers (Scheme 2). Formation of the
desired azanorbornane could then be accomplished by en-
gaging the latent reactivity placed at C4 and C5 with a het-
eroatom (X) at C1, derived from the final site of the boron
atom. Four different functional group possibilities (i.e.,
FG in 8) were surveyed in pursuit of this aim: FG = ethenyl,
ethynyl, benzyloxy, and 1,3-dioxolan-2-yl; only the last
one will be detailed in this initial report.
To access a dioxolane substituted chloroalkyllithium,
appropriate chlorosulfoxide precursors 12 were prepared
from thioether 9 (Scheme 3). A Jackson-Ellman-Bolm13
catalytic enantioselective sulfoxidation was used as the source
of stereochemistry for downstream carbenoids by provid-
ing the key asymmetric progenitor 11. Electrophilic chlor-
ination of this sulfoxide occurred with inversion of stere-
ochemistry on sulfur14 to provide syn-H-12 which was
recrystallized to improve isomeric purity. Curious as to
what advantages, if any, anti chlorosulfoxides may offer
over their better studied syn isomers, we prepared anti-H-
12 and anti-D-12 by epimerization of syn-H-12. The ab-
solute and relative stereochemical outcome of all reactions
involved in the synthesis of anti-12 from 9 was confirmed
by anomalous scattering XRD analysis.
(7) For a substrate-controlled approach to synthesis based on itera-
tive homologation of boronic esters, see ref 6a and: (a) Matteson, D. S.
Tetrahedron 1998, 54, 10555–10607. For recent applications of the
Matteson chain extension method, see: (b) Hiscox, W. C.; Matteson,
D. S. J. Organomet. Chem. 2000, 614-615, 314. (c) Davoli, P.; Spaggiari,
A.; Castagnetti, L.; Prati, F. Org. Biomol. Chem. 2004, 2, 38–47.
(8) For seminal work concerning the generation of scalemic carbe-
noids via sulfoxide-ligand exchange, see: Hoffmann, R. W.; Nell, P. G.;
Leo, R.; Harms, K. Chem.;Eur. J. 2000, 6, 3359–3365.
(9) (a) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh,
H. J. C.; Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475–
3478. (b) Daly, J. W.; Tokuyama, T.; Fujiwara, T.; Highet, R. J.; Karle,
I. L. J. Am. Chem. Soc. 1980, 102, 830–836.
The pivotal sulfoxide-ligand exchange (SLE) process
was examined in isolation for each of the three forms of
12 in hand (Table 1). Syn and anti isomers of H-12 were
treated with PhLi15 as indicated followed soon thereafter
by a deuterium quench to track the final site of lithiation
(entries 1 and 2). In each case, the product of SLE (sulf-
oxide 13) was found alongside chlorosulfoxide 12 and an
(10) Damaj, M. I.; Creasy, K. R.; Grove, A. D.; Rosecrans, J. A.;
Martin, B. R. Brain Res. 1994, 664, 34–40.
(11) There are over 50 published syntheses of epibatidine. For recent
efforts and a review, see: (a) Lee, C.-L. K.; Loh, T.-P. Org. Lett. 2005, 7,
2965–2967. (b) Aggarwal, V. K.; Olofsson, B. Angew. Chem., Int. Ed.
2005, 44, 5516–5519. (c) Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe, H.;
Takemoto, Y. Tetrahedron 2006, 62, 365–374. (d) Armstrong, A.;
Bhonoah, Y.; Shanahan, S. E. J. Org. Chem. 2007, 72, 8019–8024.
(e) Bexrud, J.; Lautens, M. Org. Lett. 2010, 12, 3160–3163. Review:
(f) Olivo, H. F.; Hemenway, M. S. Org. Prep. Proced. Int. 2002, 34, 1–26.
(12) (a) Carroll, F. I. Heterocycles 2009, 79, 99–120. (b) Garraffo,
H. M.; Spande, T. F.; Williams, M. Heterocycles 2009, 79, 207–217.
(13) (a) Drago, C.; Caggiano, L.; Jackson, R. F. W. Angew. Chem.,
Int. Ed. 2005, 44, 7221–7223. (b) Cogan, D. A.; Liu, G.; Kim, K.; Backes,
B. J.; Ellman, J. A. J. Am. Chem. Soc. 1998, 120, 8011–8019. (c) Bolm, C.;
Bienewald, F. Angew. Chem., Int. Ed. 1995, 34, 2640–2642.
(14) Stereochemical inversion in this reaction is well precedented; see:
(a) Calzavara, P.; Cinquini, M.; Colonna, S.; Fornasier, R.; Montanari,
F. J. Am. Chem. Soc. 1973, 95, 7431–7436. (b) Satoh, T.; Oohara, T.;
Ueda, Y.; Yamakawa, K. Tetrahedron Lett. 1988, 29, 313–316.
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