Enantioselective intermolecular [2 + 2 + 2] cycloadditions of ene-allenes with allenoates

Article abstract of DOI:10.1021/ol303024q

An enantioselective [2 + 2 + 2] cycloaddition of ene-allenes with allenoates is described, which transforms simple π-components into stereochemically complex carbocycles in a single step. The rhodium(I)-catalyzed cycloaddition proceeds with good levels of enantioselectivity, and with high levels of regio-, chemo-, and diastereoselectivity. Our results are consistent with a mechanism involving an enantioselective intermolecular allene-allene oxidative coupling.

Full text of DOI:10.1021/ol303024q

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Enantioselective Intermolecular
[2 þ 2 þ 2] Cycloadditions of
EneꢀAllenes with Allenoates
Andrew T. Brusoe, Rahul V. Edwankar, and Erik J. Alexanian*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599, United States
eja@email.unc.edu
Received November 3, 2012
ABSTRACT
An enantioselective [2 þ 2 þ 2] cycloaddition of eneꢀallenes with allenoates is described, which transforms simple π-components into
stereochemically complex carbocycles in a single step. The rhodium(I)-catalyzed cycloaddition proceeds with good levels of enantioselectivity,
and with high levels of regio-, chemo-, and diastereoselectivity. Our results are consistent with a mechanism involving an enantioselective
intermolecular alleneꢀallene oxidative coupling.
An important goal of chemical synthesis is the rapid
construction of valuable complex molecular architectures
from simple building blocks.1 Transition-metal-catalyzed
cycloadditions have proven to be remarkably useful in
accomplishing these goals.2 These processes provide effi-
cient access to a diverse set of carbocyclic and heterocyclic
compounds from simple π-systems in a single step with
perfect atom economy. The prototype for such a process is
the [2 þ 2 þ 2] cycloaddition,3 which constitutes a powerful
approach to carbocyclic,4 heterocyclic,5 aromatic,6 and
heteroaromatic7 systems.
Alkynes are commonly used as π-components in multi-
component cycloadditions. Despite the efficiency with which
they react in metal-catalyzed cycloadditions, alkynes in-
trinsically limit the stereochemical complexity of the carbo-
cyclic product (Scheme 1). For example, a cycloaddition
employing three alkynes affords a product containing no
stereocenters, whereas a cycloaddition involving three
alkenes could generate a cyclohexane possessing up to
six stereocenters in a single step. We demonstrated the
potential of alkene and allene π-systems to deliver com-
plex trans-fused hydrindanes with high levels of diastereo-
selectivity.8 Herein, we report the development of an en-
antioselective variant of this eneꢀalleneꢀallene [2 þ 2 þ 2]
cycloaddition. This reaction represents a rare enantioselec-
tive intermolecular [2 þ 2 þ 2] cycloaddition capable
(1) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197–201.
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r
10.1021/ol303024q
XXXX American Chemical Society

of generating multiple stereocenters.9 In addition, our
studies have revealed a number of interesting mech-
anistic details of this multicomponent cycloaddition
process.
with temperature changes (45 to 120 °C, entries 1, 7, and 8).
Silver(I) ions do not inhibit the reaction (entry 9), but the use
of noncationic complexes gives poor results (entry 10). Other
silver(I) salts (entries 11ꢀ13) can increase enantioselectivity
substantially (up to 92:8 er). The conditions in entry 1 were
chosen as our standard conditions because they provide the
best combination of yield and enantioselectivity and are
general toward all substrates investigated.
Scheme 1. Prototypical [2 þ 2 þ 2] Cycloadditions Constructing
Six-Membered Carbocycles
A number of addition reaction parameters were evalu-
ated. These include reactant stoichiometry, concentration,
rate of addition, metal to ligand ratios, and the presence of
Lewis acidic and basic additives (e.g., pyridines). These
changes were found to have no major impact on the
enantioselectivity, and several modifications resulted in
decreased reaction efficiency. A screen of 39 ligands con-
firmed the H8-BINAP family as the optimal choice for our
studies (see the Supporting Information).
As no alternative ligand to (R)-H8-BINAP proved cap-
able of increasing reaction enantioselectivity, we system-
atically studied the effects of H8-BINAP structure modifica-
tion on the reaction (Scheme 2, using benzyl allenoate 2b).10
Our prior studies demonstrated the ability of [Rh-
(C2H4)2Cl]2, H8-BINAP, and AgOTf to facilitate highly
diastereoselective eneꢀalleneꢀallene [2 þ 2 þ 2] cycload-
ditions. The development of an asymmetric variant of the
cycloaddition began by using (R)-H8-BINAP as a ligand,
which led to an efficient [2 þ 2 þ 2] cycloaddition between
eneꢀallene 1 and commercially available ethyl allenoate 2a
delivering product 3a in 79% yield with a promising 81:19 er
(Table 1, entry 1), which could be recrystallized to 95:5 er. We
screened a variety of different reaction conditions to increase
the enantioselectivity of the transformation. Representative
results are summarized in Table 1. Solvents and precatalysts
did not significantly impact enantioselectivity (entries 2ꢀ6).
Surprisingly, the enantioselectivity of the reaction is constant
Scheme 2. Ligand Structure Studies on Enantioselectivity
Table 1. Optimization Studies of the [2 þ 2 þ 2] Cycloaddition
Specifically, we sought tounderstand the influence of steric
and electronic modifications of the biaryl phosphine
groups on reaction enantioselectivity, which required the
preparation of four new (R)-H8-BINAP derivatives.11
The use of moderately electron-withdrawing12 (R)-p-Cl-H8-
BINAP L1 decreased the yield and enantioselectivity.
Substituting the phenyl rings for larger aromatic systems
gave lower enantioselectivities. We also prepared two new
H8-BINAP derivatives lacking C2 symmetry to determine
the effects of an unsymmetrical catalyst structure.13 However,
electronic and steric modification in this manner was unable
to increase reaction enantioselectivities.
entry
1
precatalyst
additive
AgOTf
solvent
toluene
yielda
79%
er
[Rh(C2H4)2Cl]2
81:19
(55%)b (95:5)b
standard conditions
2
3
4
5
6
[Rh(C2H4)2Cl]2
[Rh(C2H4)2Cl]2
[Rh(C2H4)2Cl]2
[Rh(C2H4)2Cl]2
[Rh(COD)Cl]2
AgOTf
AgOTf
mesitylene
benzene
75%
66%
32%
52%
70%
67%
35%
59%
26%
49%
53%
51%
84:16
81.19
71:29
81:19
81:19
81:19
81:19
81:19
79:21
80:20
88:12
92:8
AgOTf ClCH2CH2Cl
AgOTf
AgOTf
AgOTf
AgOTf
ꢀ
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
7c [Rh(C2H4)2Cl]2
8d [Rh(C2H4)2Cl]2
9
[Rh(COD)2][OTf]
We next explored the substrate scope of the enantio-
selective [2 þ 2 þ 2] cycloaddition (Table 2). Overall, the
10 [Rh(C2H4)2Cl]2
11 [Rh(C2H4)2Cl]2
12 [Rh(C2H4)2Cl]2
ꢀ
AgPF6
AgBF4
(10) Benzyl allenoate was used due to its decreased volatility.
(11) Larionov, O. V.; Corey, E. J. Org. Lett. 2010, 12, 300–302.
(12) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
3694–3703.
(13) Pfaltz, A.; Drury, W. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5723–5726.
13 [Rh(C2H4)2Cl]2 AgOMs
a Isolated yield. b After single recrystallization. c Reaction at 120 °C.
d Reaction at 45 °C.
B
Org. Lett., Vol. XX, No. XX, XXXX

reaction proceeded with moderate to good levels of en-
antioselectivity across a range of substrates. Steric or elec-
tronic modification of the ester had little effect on the reac-
tion (entries 1ꢀ3). Styrenyl eneꢀallene substrate 8 delivers
9 with similar yields and selectivities to those obtained
using enoate substrates. Notably, the cycloaddition is
also capable of the enantioselective construction of qua-
ternary stereocenters. Reactions involving 1,1-disubsti-
tuted alkenes deliver products possessing quaternary
stereocenters at the ring junction (entries 5ꢀ6). The use
of trisubstituted alkene π-components also produces
cycloadducts containing quaternary stereocenters with
good yields and enantioselectivities (entries 7ꢀ8). In addi-
tion to malonates, sulfonamide and 1,2-disubstituted aryl
tethers were tolerated in this reaction. The sulfonamide
derived product 17 can be easily recrystallized to excellent
levels of enantiopurity (98:2 er). The final reaction para-
meter we evaluated was the use of alternative allenoates.
In general, the reaction enantioselectivity was not sensi-
tive to modifications of the ester of 2, which allows
postreaction differentiation of the adjacent esters. Using
other allenes gave either low yields or poor enantioselec-
tivities (e.g., phenylallene, not shown). In contrast to
reactions with eneꢀallene 1 as the substrate, the use of
other silver salts and solvents to increase the enantio-
selectivity of these reactions further was not successful.
Further studies of substrate scope demonstrated that
alkenes capable of more strongly coordinating to the metal
gave lower enantioselectivity.14 We present additional
substrates to show the inverse correlation between coordi-
nating ability and enantioselectivity. Substituting the en-
oate with a fumarate (eq 1, compare with Table 2, entry 9)
or an aryl enone (eq 2, compare with Table 2, entries 1ꢀ3)
results in lower enantioselectivities. In addition, chang-
ing the geometry of the alkene (eq 3, compare with
Table 2, entry 1) also has a deleterious effect on
reaction enantio- and diastereoselectivity. The catalyst
is expected to coordinate more strongly with these
substrates, and these results suggest that this increase
significantly lowers enantioselectivity. With the excep-
tion of (Z)-alkene 24, all substrates gave excellent
diastereoselectivity.
Table 2. Substrate Scope of the [2 þ 2 þ 2] Cycloaddition
a Isolated yield. b Reaction with benzyl allenoate, 2b. c After single
recrystallization.
We present two plausible mechanisms in Figure 1. In
catalytic cycle A, initial oxidative coupling of the allenes15
yields 27. Insertion of the alkene then gives metallacyclo-
heptane 28, which undergoes reductive elimination to afford
Org. Lett., Vol. XX, No. XX, XXXX
C

the cycloadduct. In catalytic cycle B, oxidative coupling of the
eneꢀallene would generate trans-metallacycle 29.16 Insertion
of allenoate 2a could then occur, followed by reductive
elimination. Typically, intramolecular oxidative coupling
of 1,5-eneꢀallenes form cis-metallacycles,17 likely because
they are less strained (the strain energy for trans-bicyclo-
[3.3.0]octane is 6.4 kcal/mol higher than that of the cis
isomer).18 Should our reaction operate by path B, one
would expect a preference for the formation of a cis ring
junction. Based on the stereochemical outcome of our
system, we propose catalytic cycle A to be operative.
Additional insight into the operative pathway in the
[2 þ 2 þ 2] cycloaddition was provided by a reaction in-
volving eneꢀallene substrate 31 containing an unsaturated
lactone (Figure 2). Instead of undergoing the [2 þ 2 þ 2]
cycloaddition, it participates in a formal [4 þ 2] cycloaddi-
tion involving the allene and allenoate π-components to
deliver 34. A plausible mechanism for the formation of this
product is shown in Figure 2. Initial alleneꢀallenoate
oxidative coupling forms metallacycle 32, which contains
a carbon-bound rhodium enolate.19 Isomerization of this
metallacycle to an oxygen-bound rhodium enolate (33)
allows CꢀO reductive elimination to provide a benzyl-enol
ether; loss of the benzyl group gives lactone 34. Impor-
tantly, this [4 þ 2] product is formed during the time frame
for our standard cycloadditions. Furthermore, such un-
saturated lactones have been identified as minor bypro-
ducts (<5%) in our standard cycloadditions (e.g., 1 to 3b).
This suggests that alleneꢀallenoate coupling is a kineti-
cally viable process and can occur on the same time scale as
the cycloaddition. Moreover, lactone 34, which likely does
not coordinate as strongly to the metal center as our
standard substrates, is formed with somewhat higher en-
antioselectivity than any [2 þ 2 þ 2] cycloaddition studied,
which is consistent with the inverse relationship between
the coordinating ability of the alkene and enantioselec-
tivity (vide supra). The formation of product 34 is consis-
tent with catalytic cycle A, involving an intermolecular
alleneꢀallenoate coupling. Notably, such an enantioselec-
tive alleneꢀallene coupling is unprecedented.20
Figure 1. Plausible mechanisms for the [2 þ 2 þ 2] cycloaddition.
Figure 2. Unexpected [4 þ 2] cycloadduct demonstrates alleneꢀ
allenoate coupling as a kinetically viable process.
carbocyclic rings, and up to four contiguous stereocenters
in a single step with excellent levels of reaction regio-,
chemo-, and diastereoselectivity. A catalyst system com-
prised of a rhodium(I) precatalyst, a silver(I) salt, and a
bidentate phosphine, delivers the carbocyclic products with
good levels of enantioselectivity. Our studies are consistent
with a mechanism involving an enantioselective alleneꢀ
allenoate oxidative coupling, followed by insertion of the
alkene. Wehave alsodiscovered anenantioselective formal
alleneꢀallenoate [4 þ 2] cycloaddition as an alternative
reaction pathway.
In conclusion, we have developed an intermolecular en-
antioselective [2 þ 2 þ 2] cycloaddition of eneꢀallenes and
allenoates for the synthesis of enantioenriched carbocycles
possessing multiple stereocenters. This reaction represents
a rare example of an intermolecular cycloaddition af-
fording carbocyclic products containing multiple stereo-
genic centers. This reaction generates three σ-bonds, two
Acknowledgment. Financial support was provided by
the NSF CAREER program (CHE-1054540). Acknowl-
edgement is also made to the donors of the ACS PRF
(50245-DNI) for partial support of this research.
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Supporting Information Available. Experimental details
and spectroscopic data is available for all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) We cannot exclude the possibility of πꢀσꢀπ isomerization
contributing to the enantioselectivity of this process.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX