.
Angewandte
Communications
[
18]
[15b]
addition product 20 (3:1 d.r.).
Thermolysis of 20 (N,N-
allylations is well-known.
Accordingly, we prepared the
diisopropylethylamine, acetonitrile, 1008C) induced [3,3]-
endo-trimethylsilyl enyne 27 (Scheme 5); however the cycli-
zation precursor derived from 27 underwent ring closure with
similar efficiency (30%), thus suggesting other factors may
influence the efficiency of this transformation.
[
19]
rearrangement
to provide the formate 21. The formyl
group was cleaved (ammonia, methanol) to produce the
[20]
hemiketal 22. Oxidation of 22 (Dess–Martin periodinane)
formed a vinylogous a-diketone (not shown) that was
selectively reduced (sodium borohydride, ethanol, > 20:1
d.r., H NMR analysis) to yield the penultimate intermediate
The oxidation of 17 to the enedione 18 was attempted only
after extensive efforts to effect nucleophilic addition to the
C10 position of the dechloroenone 28 (Scheme 5; formed by
selective allylic oxidation of the corresponding diol) failed.
Oxygen-based nucleophiles (e.g., sodium hydrogen peroxide,
various carboxylate salts, primary alcohols, and water) did not
add to 28, and sulfur-based adducts (formed by addition of
thiophenol or butanethiol) reverted to 28 on attempted S-
functionalization. Presumably, the vicinal dicarbonyl func-
tional group of 18 lowers the kinetic barrier to formation and
increases the thermodynamic stability of the C10 addition
products.
In exploratory studies, we found that the dechloro
intermediate 29 (Scheme 5) underwent stereoretentive ipso
substitution of the thiomethyl substituent on treatment with
mercury acetate in formic acid. However, these conditions
failed when applied to the chlorinated substrate 19, and the
oxidative substitution process we developed (19!20) pro-
ceeds with distinct stereo- and site-selectivity. These changes
in selectivity may be due to shielding introduced by the
chlorine atom; this shielding is apparent on inspection of
molecular models, and this same effect also presumably leads
to the favorable diastereoselectivity obtained in the borohy-
dride reduction step. The remaining carbonyls in 23 are
vinylogous esters, and this may underscore the site-selectivity
in the reduction.
1
dehydroacutumine (23, 28% over five steps). Homogeneous
[
21]
hydrogenation
of 23 ([Rh(nbd)(dppb)]BF , 300 psi H )
4
2
provided synthetic (ꢀ)-acutumine (1, 17%), which was
[22]
1
13
identical to a natural sample by H and C NMR spectros-
copy, IR spectroscopy, HRMS, TLC in eight solvent systems,
UPLC/MS coinjection, and optical rotation. Alternatively,
heterogeneous hydrogenation of 23 (H , Pd/C) provided
2
synthetic (ꢀ)-dechloroacutumine (2, 60%), which was iden-
[
2]
1
13
tical to natural material by H and C NMR spectroscopy,
IR spectroscopy, HRMS, and optical rotation.
Several steps in these sequences are worthy of additional
comment. Acetylide-based nucleophiles were uniquely effec-
tive in the iminium ion addition step (4!13). Alkyl, allyl, and
vinyl-based nucleophiles undergo 1,2-addition to the carbonyl
group, cleave the N-methyl substituent of 4, or lead to
intractable mixtures of decomposition products.
The selectivity of the hydrostannylation step (14!15) is
attributed to more favorable insertion of the alkyne 14 into
3
a palladium hydride to form an intermediate with h -allyl
character. The steric congestion arising from the fully
substituted C5 atom in 14 may also disfavor palladium–
carbon bond formation at the 6-position. Attempts to
chlorodestannylate the cyclization precursor 15 led to erosion
of the exocyclic olefin stereochemistry.
Many different intermediates were examined as sub-
strates for construction of the C8ꢀC9 bond; a selection of
Finally, selective hydrogenations of vinyl halides to alkyl
[23]
halides are known, but are often accompanied by hydro-
dehalogenation. We found that (ꢀ)-acutumine (1) was
formed exclusively at low conversions of dehydroacutumine
(23, 17% yield of 1 at 30% conversion of 23), and other
these are shown in Scheme 5. These studies revealed a close
relationship between the nucleophilicity of the cyclopente-
none ring and the products formed. For example, attempts to
trigger ring closure by 1,4-addition to the cyclopentenone 24
led to products arising from cleavage of the C5ꢀN bond and
1
hydrogenation isomers could not be detected ( H NMR
analysis). This result suggests that the reduction of 23 is
directed by coordination of the amine and/or alcohol groups
to the catalyst, as anticipated based on inspection of
molecular models. Attempts to achieve higher conversions
aromatization of the cyclohexanedienone. Alternatively, the
b-methoxyenone groups of 25 and 26 were not sufficiently
nucleophilic to initiate ring closure (thermal or Lewis acid
activation). The preference for an anti arrangement of the
carbon–silicon bond and the electrophile in Hosomi–Sakurai
of 23 by using [Rh(nbd)(dppb)]BF , or application of a broad
4
variety of heterogeneous catalysts, led to the formation of
(ꢀ)-dechloroacutumine (2) exclusively.
In summary, we have described a concise and unified
pathway to prepare (ꢀ)-acutumine (1) and (ꢀ)-dechloroacu-
tumine (2). Notable features of the syntheses include the
strategic application of 5-trimethylsilylcyclopentadiene as
a stabilization and stereocontrol element, a stereo- and
regioselective hydrostannylation of
a complex enyne,
a Hosomi–Sakurai cyclization to fom the two contiguous
quaternary centers of the targets, utilization of an allylic
formate rearrangement to establish the oxygenation pattern
of the spirocyclopentenone rings, and execution of a selective
hydrogenation to construct the alkyl chloride functional
group of (ꢀ)-acutumine (1). The full scope of the chemistry
developed in these syntheses, as well as application to other
related natural products, will be reported in due course.
Scheme 5. Key intermediates that contributed to the development of
the successful syntheses.
3
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 3642 –3645
King, Sandra M.
