Diastereoselective rhodium-catalyzed ene-cycloisomerization reactions of alkenylidenecyclopropanes: Total synthesis of (-)-α-kainic acid

Article abstract of DOI:10.1021/ja210804r

The rhodium-catalyzed ene-cycloisomerization of alkenylidenecyclopropanes provides an atom-economical approach to five-membered carbo- and heterocycles that contain two new stereogenic centers. A key and striking feature of this protocol is that the alkene geometry does not impact the efficiency and diastereocontrol, which provides excellent synthetic versatility. For instance, (E)- and (Z)-allylic alcohols furnish the corresponding aldehydes with similar efficiency and selectivity. This process facilitates the construction of a key intermediate in an eight-step total synthesis of (-)-α-kainic acid.

Full text of DOI:10.1021/ja210804r

Communication
pubs.acs.org/JACS
Diastereoselective Rhodium-Catalyzed Ene-Cycloisomerization
Reactions of Alkenylidenecyclopropanes: Total Synthesis of (−)-α-
Kainic Acid
P. Andrew Evans* and Phillip A. Inglesby
Department of Chemistry, The University of Liverpool, Crown Street, Liverpool L69 7ZD, United Kingdom
S
* Supporting Information
Scheme 1. Rhodium-Catalyzed Ene-Cycloisomerization of
ACPs for the Construction of Functionalized Five-
Membered Carbo- and Heterocycles
ABSTRACT: The rhodium-catalyzed ene-cycloisomeriza-
tion of alkenylidenecyclopropanes provides an atom-
economical approach to five-membered carbo- and
heterocycles that contain two new stereogenic centers. A
key and striking feature of this protocol is that the alkene
geometry does not impact the efficiency and diastereocon-
trol, which provides excellent synthetic versatility. For
instance, (E)- and (Z)-allylic alcohols furnish the
corresponding aldehydes with similar efficiency and
selectivity. This process facilitates the construction of a
key intermediate in an eight-step total synthesis of (−)-α-
kainic acid.
improvements in efficiency, since the conversion mirrored the
yield. Although changing the solvent from acetonitrile to
tetrahydrofuran (THF) and then to toluene provided modest
improvements in the yield (entries 2 and 3 vs entry 1),
increasing the reaction temperature proved critical for driving
this reaction to completion (entry 4 vs 3). Additional studies
illustrated that minor modifications of the ligand further
improved the efficiency (entry 5 vs 4).7 The next phase of the
study focused on the impact of the olefin geometry on this
reaction, since related rhodium-catalyzed reactions with 1,6-
enynes are particularly sensitive to the alkene geometry. For
example, the E isomers are particularly poor substrates for this
transformation.3a Treatment of (E)-1a under the optimal
conditions furnished 2a with analogous reactivity and selectivity
(entry 6 vs 5). Additionally, the fact that the two geometries
provide the same diastereoisomer with similar efficiencies
simplifies the preparation of the alkene precursors, since they
do not have to be stereodefined, thereby making this a more
convenient process for synthetic applications.
Table 2 outlines the application of the optimized reaction
conditions (Table 1, entries 5 and 6) to a range of carbon- and
heteroatom-tethered ACPs to demonstrate the synthetic scope
of this novel transformation. Interestingly, the diastereoselec-
tivity and efficiency of this process is independent of the nature
of the ACP tether, alkene geometry and substitution, which
provides outstanding versatility. For example, the ene-cyclo-
isomerizations of carbon- (entries 9−12) and heteroatom-
tethered (entries 1−8) ACPs with allylic alcohol and 1,2-
disubstituted alkene substitutents provide aldehydes 2 and
dienes 3, respectively, with analogous efficiencies and
selectivities (entries 1/2, 5/6, 9/10 vs 3/4, 7/8, 11/12).
Additionally, the cycloisomerization of trisubstituted alkenes
provides products with quaternary carbon stereogenic centers
(entries 2, 4, 6, 8, 10, and 12), which further demonstrates the
ransition-metal-catalyzed ene-cycloisomerization reactions
T
represent an important class of reactions due to their
ability to construct cyclic scaffolds with a high degree of
molecular complexity in an atom-economical fashion.1 In this
context, the ene-cycloisomerization of 1,6-dienes has not been
extensively examined in comparison with the analogous process
involving 1,6-enynes, which may be attributed to the low
reactivity of alkenes with unsaturated transition-metal com-
plexes.1−3 Nevertheless, both substrates provide the same type
of product, which has a new stereogenic center and an exocyclic
alkene. In a program directed toward the development of
metal-catalyzed carbocyclization reactions, we have recently
described the merit of alkenylidenecyclopropanes (ACPs) in
the context of a rhodium-catalyzed [(3+2)+2] carbocyclization
reaction with activated alkynes for the diastereoselective
construction of bicycloheptadienes.4 We envisioned that the
omission of the exogenous 2π component, namely, the alkyne,
would promote β-hydride elimination of the intermediary
metallacycle to facilitate the construction of highly functional-
ized five-membered rings with two new stereogenic centers and
an array of functionality, namely, aldehydes and alkenes.5,6
Herein, we now describe the metal-catalyzed ene-cyclo-
isomerization of ACPs 1 for the stereoselective construction
of the five-membered carbo- and heterocyclic aldehydes 2 and
dienes 3 (Scheme 1).
Table 1 summarizes the preliminary studies to determine the
feasibility of this transformation using ACP 1a (X = O, R = H).
Treatment of (Z)-1a (Y = CH2OH, Z = H) with [Rh(COD)-
Cl]2 modified with triphenyl phosphite in acetonitrile at 60 °C
furnished only a trace of 2a, albeit with excellent
diastereoselectivity (entry 1). We envisioned that variations in
solvent, temperature, and catalyst would provide further
Received: November 16, 2011
Published: February 15, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a
Table 1. Optimization of the Ene-Cycloisomerization of ACPs (Scheme 1; 1a, X = O, R = H)
ACP 1a
b
c
entry
Y
Z
ligand
temp (°C)
solvent
yield (%)
ds 2a
1
2
3
4
5
6
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
H
H
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OTol)3
P(OTol)3
60
60
MeCN
THF
3
17
21
89
99
99
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
H
H
H
60
PhMe
PhMe
PhMe
PhMe
100
100
100
H
CH2OH
a
All reactions were carried out on a 0.25 mmol reaction scale (0.05 M) utilizing [Rh(COD)Cl]2 (4 mol %) modified with the triaryl phosphite (16
b
c
1
mol %). GC yields. Ratios of diastereoisomers were determined by 500 MHz H NMR analyses of the crude reaction mixtures.
a
Table 2. Scope of the Diastereoselective Rhodium-Catalyzed Ene-Cycloisomerization of ACPs (Scheme 1)
ACP 1
b
c
entry
X
R
Y
Z
E/Z
yield (%)
ds 2/3
1
2
O
O
H
Me
H
CH2OH
H
CH2OH
Me
Z
E
E
E
Z
E
E
E
Z
E
E
E
2a
2b
3c
3d
2e
2f
97
93
80
89
81
80
92
84
89
80
96
93
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
H
3
O
H
4
O
Me
H
H
Me
5
NTs
CH2OH
H
6
NTs
Me
H
H
CH2OH
Me
7
NTs
H
3g
3h
2i
8
NTs
Me
H
H
Me
9
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
CH2OH
H
10
11
12
Me
H
H
H
H
CH2OH
Me
2j
3k
3l
Me
Me
a
All reactions were carried out on a 0.25 mmol reaction scale using [Rh(COD)Cl]2 (4 mol %) modified with tri-p-tolyl phosphite (16 mol %) in
b
c
1
toluene at 100 °C (0.05 M). Isolated yields. Determined by 500 MHz H NMR analyses of the crude reaction mixtures.
synthetic utility of this process for target-directed synthesis.
Overall, this work provides diastereoselective access to functional-
ized five-membered carbo- and heterocyclic rings, which are present
in an array of important bioactive agents.
Scheme 2 provides support for the proposed catalytic cycle
for this ene-cycloisomerization. Treatment of the ACP d2-(Z)-
cycle iv (or the η3-allyl intermediate), which can undergo
selective β-hydride elimination at the terminal position to
afford the metal deuteride/enol v.5,9 Tautomerization of v and
concomitant reductive elimination provides the aldehyde d2-2a
with ≥95% incorporation of the deuterium in the aldehyde and
β-isopropenyl groups.
To showcase the synthetic utility of this new transformation,
we elected to devise a concise total synthesis of (−)-α-kainic
acid (9), a member of the kainoid family of natural products,
which are structurally related non-proteinogenic amino acids.10
Kainic acid was isolated in 1953 from the Japanese marine algae
Digenea simplex and exhibits potent anthelmintic and neuro-
excitatory activity, making it a biologically important target.11
Moreover, it has an estimated market value of $1 billion per
annum,12 which provides the impetus for the development of a
practical synthesis of this agent.13 We envisioned that the
distinctive anti,syn-2,3,4-trisubstituted pyrrolidine ring could be
installed with a diastereoselective rhodium-catalyzed ene-
cycloisomerization reaction, using the C2 substituent to direct
the diastereoselectivity in a manner analogous to that for 1,6-
enynes.
Scheme 2. Proposed Catalytic Cycle for the
Diastereoselective Rhodium-Catalyzed Ene-
Cycloisomerization Reaction
The synthesis of 9 commenced with a one-pot sequential
oxidation/homologation reaction (Scheme 3). Dess−Martin
oxidation of commercially available amino alcohol 4 followed
by a concomitant Wittig homologation furnished the
conjugated ester in 77% yield.14 Palladium-catalyzed allylic
amination of 1-vinylcyclopropyl tosylate afforded 5 in 84%
yield.15 Interestingly, the order of the reactions in this sequence
was important to reduce epimerization of the C2 substituent.13c
DIBAL-H reduction of the α,β-unsaturated ester 5 in the
presence of BF3·OEt16 afforded allylic alcohol 6, which set the
1a under the optimized reaction conditions provided the
aldehyde d2-2a in 93% yield, which is consistent with a type-I
process involving the formation of a metallacycle intermedia-
te.1b For example, oxidative addition of i into the distal bond of
ACP d2-(Z)-1a presumably generates the metallacyclobutene ii,
which undergoes rearrangement to afford iii.8 Stereoselective
carbometalation of the alkene provides the cis-fused metalla-
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Journal of the American Chemical Society
Communication
Scheme 3. Asymmetric Total Synthesis of (−)-α-Kainic Acid
ASSOCIATED CONTENT
■
Using a Rhodium-Catalyzed Ene-Cycloisomerization of an
S
* Supporting Information
a
Alkenylidenecyclopropane
Experimental procedures and spectral data for all new
compounds, including NOE data and CIF files for 3g and
derivatives of 2e and 2f. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
Andrew.Evans@liverpool.ac.uk
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
a
■
Reagents: (a) DMP, pyridine, Ph3PCHCO2Et, DCM/MeCN, 40 °C,
We sincerely thank AstraZeneca (Alderley Park) for a
studentship (P.A.I.) through the EPSRC-Pharma Managed
Programme for (Synthetic) Organic Chemistry and Dr. Sam
Butterworth (AstraZeneca) for his support and helpful
discussions. We further acknowledge the Royal Society for a
Wolfson Research Merit Award (P.A.E.), and we are grateful to
the EPSRC National Mass Spectrometry Service Centre
(Swansea, U.K.) for high-resolution mass spectrometry.
77%. (b) 1-Vinylcyclopropyl tosylate, cat. Pd(PPh3)4, THF, then
pronucleophile, NaH, THF, RT, 84%. (c) DIBAL-H, BF3·OEt, DCM,
−78 °C to RT, 70%. (d) [Rh(COD)Cl]2 (4 mol %), tri-p-tolyl
phosphite (24 mol %), THF, 135 °C (sealed tube), 69%. (e) PDC,
DMF, MeOH, RT, 73%. (f) NaOMe, MeOH, 0 °C to RT, 83%. (g)
i
Jones reagent (8 N), acetone, 0 °C to RT. (h) LiOH, PrOH/H2O,
120 °C then H+ (Dowex-50WX8), 85% over two steps.
stage to examine the key rhodium-catalyzed ene-cycloisomeri-
zation reaction. Treatment of 6 with the rhodium complex
derived from [Rh(COD)Cl]2 modified with tri-p-tolyl
phosphite in THF at 135 °C furnished the key anti,syn-2,3,4-
trisubstituted pyrrolidine skeleton 7 in good yield with excellent
diastereocontrol (ds ≥19:1).17 Interestingly, the optimized
reaction conditions utilized in Table 2 resulted in a lower yield
and significantly lower diastereoselectivity for the formation of
7 (ds = 4:1), which will be the subject of further investigation.
Oxidation of the aldehyde using a modified Corey procedure
furnished the known methyl ester 8 in 73% yield.18 Although
this constitutes a formal synthesis of kainic acid, we elected to
convert the methyl ester to the natural product 9 using a
modified sequence that was originally developed by Mont-
gomery and co-workers.13c Sodium methoxide-mediated ring
opening of the carbamate followed by oxidation of the primary
alcohol to the carboxylic acid and concomitant global
deprotection furnished 9 in 71% overall yield from 8. Hence,
the total synthesis of (−)-α-kainic acid (9) was accomplished in
eight steps from commercially available amino alcohol 4 in 17%
overall yield. Notably, this strategy provides a synthesis that
constructs the fully functionalized skeleton with loss of only
methanol, ethanol, and carbon dioxide, which makes this a
particularly atom-economical synthesis of this important agent.
Finally, this total synthesis represents one of the most concise
and efficient developed to date, which may be suitable for
commercialization.
In conclusion, we have developed a highly diastereoselective
rhodium-catalyzed ene-cycloisomerization reaction of carbon-
and heteroatom-tethered ACPs. This protocol provides the
same diastereoisomer with similar efficiency irrespective of the
alkene geometry, which simplifies the preparation of the alkene
precursor. The synthetic utility of this approach was highlighted
in the concise eight-step total synthesis of (−)-α-kainic acid (9)
in 17% overall yield. Hence, we envision that this methodology
will provide a convenient atom-economical approach to an
array of five-membered carbo- and heterocyclic structures in the
context of target-directed synthetic applications.
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