Communications
Scheme 2. Proposed mechanism of the [2+2+2] cycloaddition.
subsequent CO migration process via II to arrive at III. The
À
migratory insertion of the pendant alkene into the Rh N
bond and subsequent reductive elimination gives rise to
cycloadducts 3. The selectivity in the formation of two initial
metalacycles (I versus IV) is reflected in the product
selectivity between 3 and 4. Despite the low yield and poor
ee value, the fundamental difference in product selectivity
prompted additional investigation into the binol-derived
phosphoramidites. Ligands possessing substitution at both
the 3- and 3’-position of the binol backbone positively impact
the reaction efficiency toward the desired indolizinone 3a.
Additional exploration led to the discovery of guiphos
((R)-L3). This TMS-substituted phosphoramidite (R)-L3
provides a much improved reaction having product selectivity
of approximately 4:1, good chemical yield, and most impor-
tantly an excellent 96% ee for 3a (Table 1, entry 3). Although
the TMS-substituted biphenol-derived phosphoramidite
(R)-L4 behaves no differently than guiphos (Table 1,
entry 4), the corresponding ligand possessing tert-butyl
groups at the 3,3’-positions ((R)-L5)[9,10] proved superior.
The precatalyst [{Rh(C2H4)2Cl}2], modified with (R)-L5,
provides a clean reaction to furnish the desired indolizinone
3a with a good product ratio (6.2:1) in excellent yield and
enantioselectivity (Table 1, entry 5).
Indolizidine 209D belongs to a family of 22 natural
products, commonly referred to as gephyrotoxins, isolated
from the skin secretions of neotropical frogs.[11] Along with
indolizidine 167B (Scheme 1), these two structurally simpler
alkaloids have only been isolated in minute quantities from
unidentified dendrobatid frogs found in a single population.
Over the years, they have attracted much interest from the
synthetic community, both to prepare them in greater
quantities, and as a tool to validate new methodologies.[12]
The key intermediate 5-hexyl indolizinone 3a can be pre-
pared conveniently by the cycloaddition protocol in one step
and is suitable for scale-up (Scheme 3). The resulting vinyl-
ogous amide functionality readily undergoes a diastereose-
lective hydrogenation to afford enantioenriched amino alco-
hol 5 as a single diastereomer. Barton–McCombie deoxygen-
ation via 6 completes the four-step enantioselective synthesis
of (À)-209D, which also confirms the absolute configuration
of 3a: [a]2D2 = À66.58 (c = 1.0 g per 100 mL, CH2Cl2); lit.[10a]
[a]2D6 = À80.48 (c = 1.0 g per 100 mL, CH2Cl2). Considering
that alkenyl isocyanate 2 can be prepared in one step from
commercially available 5-hexenoic acid, this constitutes the
shortest synthesis of 209D reported to date.[10]
Scheme 3. Synthesis of indolizidine (À)-209D. [a] See entry 1 of Table 2
for the reaction conditions. Im=imidazole, DMAP=4-dimethylamino-
pyridine, AIBN=2,2’-azobis(isobutyronitrile).
all react smoothly to afford cycloadducts in good product
ratios and excellent enantioselectivities (Table 2, entries 2–7).
The cycloaddition is highly sensitive to both electronic and
steric effects on the alkyne partner. The product selectivity
shifts more toward formation of the bicyclic lactams 4 when
electron-withdrawing substituents are closer to the alkynyl
center. For example, cycloaddition of 3-phenyl-1-propyne
(1h) gave a product ratio of 3:1 favoring the benzyl-
substituted indolizinone 3h, instead of the 5:1 ratio obtained
using 1g (Table 2, entry 8 versus entry 7). In a more extreme
case, the cycloaddition of the TIPS-protected propargyl
alcohol 1i furnishes a 1.6:1 product mixture slightly favoring
the indolizinone 3i (Table 2, entry 9). In contrast, the reaction
with the more sterically hindered alkyne 1j improves the
product selectivity to provide the desired cycloadduct 3j in a
high yield and excellent enantioselectivity (Table 2, entry 10).
In fact, bulky alkynes such as cyclohexyl and cyclopentyl
acetylenes are among the best cycloaddition partners. The
corresponding indolizinone products 3k and 3l can be
obtained in high yields and enantioselectivities with excellent
product ratios of 14:1 (Table 2, entries 11 and 12). Even more
impressively, the rhodium catalyst modified by ligand (R)-L5
promotes the cycloaddition of tertiary alkyl-substituted
alkynes to gain access to highly congested 5-alkyl indolizi-
nones (Table 2, entries 13 and 14). For example, the MOM-
protected cyclopentanol-substituted cycloadduct 3m can be
produced in 60% yield with a slightly diminished 81%
enantioselectivity as the only product. In general, cyclo-
addition with the tert-butyl-substituted phosphoramidite
(R)-L5 produces the best product selectivity and high overall
reactivity, whereas the use of guiphos ((R)-L3) usually gives
the best level of enantiocontrol. Although guiphos ((R)-L3)
displays low reactivity toward most sterically hindered
alkynes (3k: 44% yield, 95% ee; 3m: 23% yield, 80% ee),
it does provide an efficient cycloaddition for the formation of
tert-butyl-substituted indolizinone 3n in a good chemical yield
and enantioselectivity (Table 2, entry 15). This protocol can
also be applied to the synthesis of 5,9-dialkyl indolizinones
[Eq. (1)]. 1,1-Disubstituted alkenyl isocyanate 7 participates
in the cycloaddition with 1-octyne (1a) quite efficiently to
provide the corresponding cycloadduct 8 in good product
ratio and yield of the isolated product. Interestingly, whereas
the product selectivity stays relatively unchanged as those
The newly developed Rh/phosphoramidite (R)-L5 cata-
lyst promotes the enantioselective synthesis of 5-alkyl indo-
lizinones very efficiently (Table 2). Alkyl alkynes bearing an
array of functional groups including ester, chloride, silyl ether,
Weinreb amide, unprotected terminal alkyne, and phenyl ring
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 2379 –2382
Yu, Robert T.
