Asymmetric Synthesis of Deoxypropionate Derivatives via Catalytic Hydrogenolysis of Enantioenriched Z-Ketene Heterodimers

Article abstract of DOI:10.1021/acs.orglett.5b01391

A diastereoselective approach to deoxypropionate derivatives through Pd/C-catalyzed hydrogenolysis of enantioenriched ketene heterodimers is described. Catalytic hydrogenolysis of the Z-isomer of ketene heterodimers facilitates access to anti-deoxypropion

Full text of DOI:10.1021/acs.orglett.5b01391

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of Deoxypropionate Derivatives via Catalytic
Hydrogenolysis of Enantioenriched Z‑Ketene Heterodimers
Shi Chen,† Ahmad A. Ibrahim,†,§ Mukulesh Mondal,† Anthony J. Magee,† Adam J. Cruz,†
Kraig A. Wheeler,‡ and Nessan J. Kerrigan*,†
†Department of Chemistry, Oakland University, 2200 North Squirrel Road, Rochester, Michigan 48309-4477, United States
‡Department of Chemistry, Eastern Illinois University, 600 Lincoln Avenue, Charleston, Illinois 61920-3099, United States
S
* Supporting Information
ABSTRACT: A diastereoselective approach to deoxypropionate derivatives
through Pd/C-catalyzed hydrogenolysis of enantioenriched ketene heterodimers
is described. Catalytic hydrogenolysis of the Z-isomer of ketene heterodimers
facilitates access to anti-deoxypropionate derivatives (10 examples with dr 7:1 to
>20:1). Transfer of chirality from the Z-ketene heterodimer to an acid product
was good to excellent in most cases (78−99% ee for 12 examples).
eoxypropionate stereotriad units are compelling targets in
synthesis, as they are integral structural features of many
alkaloid-catalyzed asymmetric methylketene homodimerization,
coupled with diastereoselective aldol reactions, can be applied
to the synthesis of deoxypropionate natural products, such as
siphonarienal, siphonarienedione, and siphonarienolone.5 How-
ever, Calter’s elegant methodology for polypropionate synthesis
requires additional deoxygenation steps in order to access
deoxypropionate units.5 Most synthetic strategies for deoxy-
polypropionates follow a linear-iterative concept, with new
deoxypropionate units being successively added to a growing
chain.2,6 This approach, although conceptually simple, can lead
to rather lengthy syntheses of complex molecules. Recently,
some highly diastereoselective catalytic asymmetric approaches,
which are not limited to iterative synthetic plans, have been
introduced.7−9 One especially noteworthy method was
introduced by the Burgess group.7 They demonstrated that a
chiral Ir(I) complex could be used to catalyze the double
diastereoselective hydrogenation of enantioenriched trisubsti-
tuted olefins, with good to excellent levels of diastereoselection
being observed. However, Burgess’s approach is dependent
upon the availability of appropriate enantioenriched olefin
substrates, which can often require lengthy multistep
procedures to assemble (e.g., 6 steps for spongidepsin
deoxypropionate unit).9
D
biologically active molecules (Figure 1).1,2 Many of these
Figure 1. Deoxypropionate natural products.
In contrast ketene heterodimerization has remained a
relatively unexplored field in the context of complex molecule
synthesis.10,11 Recently we reported the first catalytic
asymmetric ketene heterodimerization reaction, which provided
access to ketene heterodimer β-lactones with excellent enantio-
and regioselectivity (Scheme 1).12,13
molecules contain an anti-deoxypropionate unit, e.g. (−)-bor-
relidin, ionomycin, and 4,6,8,10,16,18-hexamethyldocosane.1,2
Access to deoxypropionates has largely relied on methods
involving chiral auxiliary-controlled enolate alkylations and
conjugate additions, as well as substrate-controlled conjugate
additions and allylic alkylations.2 Feringa’s and Negishi’s groups
have also reported catalytic asymmetric iterative approaches to
deoxypropionates, although in Negishi’s case with only
moderate diastereoselectivity for syn-deoxypropionates.3,4 In
addition, Calter and co-workers have demonstrated that
A fundamentally different approach to deoxypropionate
synthesis would involve the use of an enantioselective ketene
Received: May 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01391
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3).15 Thereafter, we proceeded to optimize the process
in order to favor direct formation of deoxypropionate 3a.
MeOH was found to be the best solvent for favoring formation
of hydrogenolysis product 3a, and with good diastereoselectiv-
ity (dr 4:1). We speculate that the use of a polar protic solvent
allows for stabilization of the transition state leading to a
palladium carboxylate intermediate to a greater extent than
transition states containing just Pd−C bonds, thus favoring
formation of the carboxylic acid product. The anti-diastereomer
was formed as the major diastereomer as determined by X-ray
crystal structure analysis of a derivative of 3a (see Supporting
Information (SI) for details).
Scheme 1. Catalytic Asymmetric Heterodimerization of
Ketenes
We then proceeded to evaluate the substrate scope of the
reaction (Table 1). The ketene heterodimers examined had a
heterodimerization reaction followed by a diastereoselective
catalytic hydrogenation reaction. Romo’s group had previously
demonstrated that the use of catalytic hydrogenation provided
an efficient diastereoselective route for the synthesis of fully
reduced cis-β-lactones from simple enantioenriched ketene
homodimers.14 We proposed a route whereby catalytic
hydrogenation of a highly substituted ketene heterodimer 1
followed by regioselective ring opening of 2 would provide
access to deoxypropionate unit 3 (Scheme 2).
Table 1. Substrate Scope of Catalytic Hydrogenolysis of Z-
a
Ketene Heterodimers
Scheme 2. Initial Plan for the Catalytic Synthesis of
Deoxypropionate Molecules
c
d
entry ((S)- or
% ee yield
ee
b
e
(R)-1)
R1
Me
R3
Z-1
(%)
(%)
dr
3
f
1 (S)-1a
2 (R)-1a
3 (S)-1b
4 (R)-1b
5 (S)-1c
6 (R)-1c
7 (S)-1d
8 (R)-1d
9 (S)-1e
10 (R)-1e
11 (S)-1f
12 (R)-1f
13 (S)-1g
14 (R)-1g
15 (S)-1h
16 (R)-1h
17 (S)-1i
18 (R)-1i
19 (S)-1j
Me
Me
Et
95
93
98
73
96
96
99
99
95
70
95
72
94
74
95
76
95
97
95
79
75
73
55
92
73
98
87
84
83
96
94
79
92
94
86
96
95
86
78
99
80
4:1
4:1
7:1
7:1
(+)-3a
Me
(−)-3a
(+)-3b
(−)-3b
(+)-3c
(−)-3c
(+)-3d
(−)-3d
(+)-3e
(−)-3e
Me
Me
Et
Me
Ph
Ph
Me
Me
Et
Me
Et
4:1
4:1
9:1
Et
Et
Et
Et
13:1
g
We began our optimization of the proposed catalytic
hydrogenation methodology with methylphenylketene-derived
heterodimer Z-1a as the substrate (Scheme 3). Careful
n-Pr
n-Pr
n-Bu
n-Bu
n-Bu
n-Bu
n-Hex
n-Hex
Me
Et
45
>20:1 (+)-3f
>20:1 (−)-3f
>20:1 (+)-3g
Et
66
79
72
68
h
Me
Me
Et
>20:1 (−)-3g
>20:1 (+)-3h
>20:1 (−)-3h
(−)-3i
Scheme 3. Optimization of Catalytic Hydrogenolysis of
Ketene Heterodimers
a
g
Et
54
H
71
70
H
(+)-3i
i
Me
0
3j
a
b
Z/E = 3:1 to >20:1 (see SI for individual details). Absolute
c
configuration of heterodimer. Isolated yield for both diastereomers of
3. ee of major diastereomer of 3, determined by chiral GC of methyl
ester derivative in most cases (by chiral HPLC for entries 5 and 6). dr
determined by GC-MS or by H NMR analysis of crudes. Sign of
specific rotation. 15−20% of 2 as well. ee not determined for entries
13−18. Complex mixture with no acid 3.
d
e
f
1
g
h
a
conv = conversion, determined by GC-MS analysis of crude product;
i
1
dr determined by GC-MS and corroborated by H NMR analysis.
evaluation of a range of heterogeneous hydrogenation catalysts
(Pd/C, Pt/C, Rh/C, Ru/C, PtO2, Pd/alumina, Pd/BaSO4, and
Lindlar’s catalyst among others) revealed that Pd/C was the
optimal catalyst in terms of conversion of ketene heterodimer
to reduction products (Scheme 3).14 To our surprise, analysis
of the reduction products revealed a mixture of fully reduced β-
lactone 2a and acid 3a (formed through hydrogenolysis,
Z/E ratio of 3:1 to >20:1 in most cases. In general it was found
that when Z-ketene heterodimers were subjected to catalytic
hydrogenolysis conditions, carboxylic acids 3 were formed as
the major product, in good yield, and with moderate to
excellent diastereoselectivity (Table 1). Minor amounts of
reduced β-lactone 2 (typically 5−20%) were formed in most
cases. Simple substrate modification (substituting Et for Me at
B
DOI: 10.1021/acs.orglett.5b01391
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
R3; 1b) led to an improvement in diastereoselectivity (dr 7:1,
entry 3, Table 1). The best levels of diastereoselectivity (dr
>20:1) were observed when two moderately large alkyl
substituents were employed (e.g., n-Pr and Et, entries 11 and
12, Table 1). We surmise that moderate diastereoselectivity for
some examples (e.g., entries 1 and 2) may be due to
equilibration of a Z-olefin intermediate (see Scheme 5). The
ee of the acid was assayed for a selection of examples, and good
to excellent transfer of chirality from ketene heterodimer to
acid 3 was observed (78 to 99% ee for 12 examples analyzed).
It should be noted that the reaction is not strictly
stereospecific; the minor E-isomer of ketene heterodimer
does undergo hydrogenolysis to contribute the acid product as
a mixture of anti- and syn-diastereomers. Occasional differences
in diastereoselectivity resulting from enantiomeric ketene
heterodimers were attributed to differing levels of E-ketene
heterodimer in the starting material (e.g., for entry 9, dr 9:1
from (S)-1e with Z/E = 6:1 vs entry 10, dr 13:1 from (R)-1e
with Z/E = 10:1).
From the data in Table 1, it is clear that an anion stabilizing
group (e.g., Ph or SiMe3) must be present at the olefin carbon
furthest from the ring (the exocyclic olefin carbon) in order for
the reaction to favor acid 3 rather than β-lactone 2. When only
alkyl substituents are present at this carbon, a complex product
mixture containing none of 3 results (entry 19, Table 1). We
hypothesize that hydropalladation regioselectivity is responsible
for this divergency. Specifically, regioselective hydropalladation
of the exocyclic olefin enabled by the presence of a Ph/SiMe3
substituent would provide access to an intermediate with Pd
bonded to the exocyclic carbon. This hydropalladated
intermediate could subsequently undergo β-elimination and
ultimately provide access to acid 3 (see Scheme 5).
Scheme 4. Mechanistic Experiments
intermediate in the hydrogenolysis reaction. Subjecting
heterodimer 1a to deuteriolysis (15 atm D2) revealed that no
olefin migration occurs, as only the β- and γ-carbons (with
respect to the carboxyl group) became labeled with D (Scheme
4).17 In addition, when deuteriolysis (15 atm D2) of 1i was
stopped before all of the heterodimer was consumed, no
evidence for equilibration of olefin geometry in the starting
heterodimer was observed (see SI for further details).18
Palladium catalysis typically involves syn β-eliminations,
although there have been a few reports of anti β-eliminations
in molecules where a good leaving group is present.19
Hydrogenation of the Z-isomer of alkene 5 via TS1, in which
the A1,3 strain is minimized, predicts formation of the anti-
isomer as the major diastereomer of 3a (Scheme 5).20,21
Scheme 5. Possible Mechanism for Catalytic Hydrogenolysis
of Ketene Heterodimer
A great advantage of the system is that both enantiomers of
the deoxypropionate units can be readily obtained due to the
availability of both antipodes of each ketene heterodimer
(prepared through use of the appropriate pseudoenantiomer of
a quinine/quinidine derivative in the alkaloid-catalyzed ketene
heterodimerization reaction).12
The deoxypropionate derivatives 3 described here can be
utilized effectively in the synthesis of natural products, as ably
demonstrated by Negishi and co-workers.4,16 The phenyl
substituent of 3a−3h can be treated as a protecting group and
oxidized to a carboxyl group at an appropriate stage of a
synthesis plan, allowing for extension of the deoxypropionate
chain.4 Aggarwal’s group has also recently demonstrated how
similar deoxypropionate units may be incorporated via an
iterative lithiation−borylation−protodeboronation strategy into
a growing polydeoxypropionate chain.6
The formation of carboxylic acid 3a from Z-ketene
heterodimer 1a could potentially be accomplished by a number
of different mechanisms. To probe the mechanism of the
hydrogenolysis reaction, we prepared β-lactone 2a from ketene
heterodimer Z-1a. This was done by carrying out the catalytic
hydrogenation in EtOAc. The desired β-lactone 2a was
obtained as a mixture of two diastereomers (30%, dr 1.3:1, cis
and trans β-lactone isomers). The mixture, as well as each
diastereomer separately, was exposed to the catalytic hydro-
genolysis conditions (5 mol % Pd/C, MeOH, 30 min). 3a was
not formed from either of the two isolated diastereomers of β-
lactone 2a, and so we tentatively infer that 2a does not function
as an intermediate in the formation of acid 3a (Scheme 4).
However, at this point we cannot definitively rule out the
possibility that another (unisolated) diastereomer of 2a is an
Alternatively, if anti β-elimination occurs, the E-isomer of
alkene 5 would be formed. Hydrogenation of E-5 would lead to
formation of anti-3a, providing the carboxyl/carboxylate group
(rather than Me) is the large substituent in an allylic strain-
minimized conformation. Delivery of hydrogen to the less
sterically hindered face would provide access to the anti-isomer
of 3a.20 Mechanisms involving direct insertion into the
heterodimer ring could also be possible.22 Studies to distinguish
between these mechanistic pathways are ongoing.
C
DOI: 10.1021/acs.orglett.5b01391
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In summary, we have developed a catalytic asymmetric
synthetic method of wide substrate scope that provides access
to deoxypropionate derivatives with moderate to excellent
diastereoselectivity (10 examples with dr ≥7:1, up to >20:1)
from enantioenriched ketene heterodimers. Studies are
currently underway to examine other hydrometalation tech-
nologies and to examine applications in complex molecule
synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectroscopic data, and chromato-
grams for all new compounds, and CIF for derivative (+)-6.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01391.
59, 3545−3565. (d) Marques
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(14) Purohit, V. C.; Richardson, R. D.; Smith, J. W.; Romo, D. J. Org.
Chem. 2006, 71, 4549−4558.
AUTHOR INFORMATION
Corresponding Author
■
(15) (a) Roll, L. J.; Adams, R. J. Am. Chem. Soc. 1931, 53, 3469−
*E-mail: kerrigan@oakland.edu.
Present Address
§Wayne State University, MI, USA.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support has been provided by the National Science Foundation
and the National Institutes of Health: Grant Nos. CHE-
1213638 and R15GM107800 to N.J.K, CHE-0722547 to
K.A.W., CHE-0821487 for NMR facilities at Oakland
University, and CHE-1048719 for LC-MS facilities at Oakland
University.
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