B rings of aconitine. Our efforts to implement this strategy
on an advanced model system of the natural product are
highlighted herein.
table product mixture. By contrast, silyl ether 8 furnished
the desired spirocycle 11 in 68% yield and as a single
diastereomer, as determined by proton NMR of the un-
purified reaction mixture (Figure 3). Other Lewis acids tested,
Prior work from our lab has demonstrated that chemo-
selective C-H insertion of a Rh-stabilized nitrene into an
R-ethereal center can be utilized to generate oxathiazinane
N,O-acetal heterocycles such as 3 (Figure 2). In the presence
Figure 3. A spirodienone is formed from an oxathiazinane N,O-
acetal.
Figure 2. A C-H amination route to the aconitine skeleton.
including Sc(OTf)3 and AlCl3, gave similar results, albeit at
a cost to the isolated yield of 11. While we did not explore
alternative phenolic protecting groups at this stage of
planning, these two data points were quite informative and
suggest that deblocking of the phenol must prestage the
addition event.
of a Lewis acid and a nucleophilic agent, these novel N,O-
acetal derivatives function as electrophiles to make available
substitutionally complex oxathiazinane products.6 To capital-
ize on these findings for an aconitine synthesis, a late-stage
C-H amination reaction was envisioned that would afford
3. Treatment of 3 with a Lewis acid would result in the
subsequent addition of the pendant aromatic ring to generate
spirodienone 2. The successful implementation of this
strategy would make possible installation of both the C17
nitrogen and C11 tetrasubstituted stereocenters (aconitine
numbering) as well as the B ring of the carbon skeleton in
a single C-C bond-forming event. Importantly, the oxa-
thiazinane moiety serves as a controlling element to ensure
the proper stereochemical outcome in the iminium ion
addition (vide infra). While prior studies from our lab have
shown that allyl silanes, silyl enol ethers, and alkynyl zinc
species are effective nucleophiles when employed in coupling
reactions with oxathiazinane N,O-acetals, at the onset of this
study, we were uncertain if electron-rich arene groups could
function analogously.7 To test the viability of this plan, two
model substrates have been examined.
The isolation of 11 as a single diastereomer out of a
possible mixture of four is rather striking and deserves
comment.8 We have found that heating 11 in warm MeOH
results in C-C bond scission to return the N,O-acetal and
re-aromatized side chain (i.e., 11f9). On the basis of this
observation, we speculate that BF3‚OEt2/CH2Cl2 provides a
medium for reversible arene-iminium ion addition and that
thermodynamic biases are responsible for controlling the
product stereochemistry in 11.9 For the purpose of utilizing
this reaction sequence in the aconitine synthesis, the relative
stereochemistry between C7 and C17 in 11 is, however,
incorrect. Accordingly, we wondered whether specific geo-
metrical constraints could be imposed on the linker between
the N,O-acetal heterocycle and the arene ring to force the
requisite cis-stereochemistry at positions C7 and C17. The
challenge of assembling the rigid C/D ring skeleton of
aconitine was therefore assumed. To facilitate the testing of
these ideas, a partially deoxygenated form of the C/D bicycle
was targeted.
The bicyclooctane frame in 12 restricts the various
trajectories by which the arene ring may attack the reactive
iminium ion. Based on an analysis of computational models,
we reasoned that only one face of the iminium π-bond would
be properly aligned with the aryl moiety to enable successful
C-C bond formation. Reaction through this conformer, 12,
affords the requisite cis-oxathiazinane 13. Rotation around
the C7-C8 bond (i.e., 15) exposes the alternative dia-
stereoface of the iminium ion to the nucleophilic arene. In
The first oxathiazinane N,O-acetal having a tethered
aromatic group was formed in straightforward fashion from
an available pentanoic acid derivative. Although such a
substrate lacks both the C and D ring elements, ease of
synthesis rendered it an optimal starting point for our
investigations. Oxidative intramolecular C-H insertion of
either 5 or 6 under the action of 2 mol % Rh2(OAc)4 and
1.1 equiv of PhI(OAc)2 afforded the corresponding N,O-
acetals in quantitative conversion and with outstanding
chemoselectivity. Subsequent exposure of 7 and 8 to
BF3‚OEt2 (CH2Cl2, -78 to 23 °C), however, resulted in
considerably disparate outcomes. N,O-Acetal 7, having both
phenolic oxygens blocked as methyl ethers, gave an intrac-
(8) The structure and stereochemistry of 11 have been assigned through
1H and 13C HMBC, as well as 1H NOE studies, see the Supporting
Information for details.
(6) Fleming, J. J.; Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2003,
125, 2028.
(7) Fiori, K. W.; Fleming, J. J.; Du Bois, J. Angew. Chem., Int. Ed. 2004,
43, 4349.
(9) If the addition reaction were under kinetic control, it is likely that a
cis-configuration between C7 and C17 would be favored in accord with
predictive models for nucleophilic additions to cyclic iminium ions: Stevens,
R. V. Acc. Chem. Res. 1984, 17, 289.
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Org. Lett., Vol. 9, No. 26, 2007