Carbonylative enantioselective meso-desymmetrization of cis-epoxides to trans-β-lactones: Effect of salen-ligand electronic variation on enantioselectivity

Article abstract of DOI:10.1039/c4cc04397a

Carbonylation catalysts for the desymmetrization of meso-epoxides yielding enantioenriched trans-β-lactones are reported. Fine-tuning the electronic properties of the ligand further improved enantioselectivity. The sterics of the substrate dictated whether a given electronic variation decreased or increased enantioenrichment, revealing an unexpected relationship between the substrate's steric environment and the electronic nature of the optimal catalyst.

Full text of DOI:10.1039/c4cc04397a

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Carbonylative enantioselective
meso-desymmetrization of cis-epoxides to
trans-b-lactones: effect of salen-ligand
electronic variation on enantioselectivity†
Cite this: Chem. Commun., 2014,
50, 9842
Received 9th June 2014,
Accepted 5th July 2014
Michael Mulzer, Jessica R. Lamb, Zachary Nelson and Geoffrey W. Coates*
DOI: 10.1039/c4cc04397a
www.rsc.org/chemcomm
Carbonylation catalysts for the desymmetrization of meso-epoxides
yielding enantioenriched trans-b-lactones are reported. Fine-tuning
the electronic properties of the ligand further improved enantio-
selectivity. The sterics of the substrate dictated whether a given
electronic variation decreased or increased enantioenrichment,
revealing an unexpected relationship between the substrate’s steric
environment and the electronic nature of the optimal catalyst.
The utility and inherent high reactivity of b-lactones has prompted
the synthetic community to explore the usage of this class of
compounds in numerous applications. Examples include new
drug design,1 protein labeling,2 polyester synthesis,3 and the
production of aldol-type moieties in small molecules.4
Enantioenriched trans-3,4-disubstituted b-lactones are of special
interest due to their occurrence as structural motifs in drugs and
many natural products.5 Furthermore, they can easily be converted
into valuable enantioenriched anti-aldol-type products.6 However,
only a few methods provide direct access to enantioenriched trans-
b-lactones;7 one of the best approaches being (formal) [2+2]-
cycloadditions of ketenes with aldehydes.8 Disadvantages of this
route include the need for multiple reagents and careful control of
the reaction conditions.
Fig. 1 Catalysts and carbonylation reactions investigated for the enantio-
selective synthesis of trans-b-lactones from cis-epoxides.
Carbonylative ring-expansion of cis-2,3-disubstituted epox-
ides to trans-b-lactones has some distinct advantages such as
Our group recently reported the regiodivergent carbonylation
readily available starting materials, mild reaction conditions, of racemic cis-epoxides using salen-type catalysts (Fig. 1a).11
and a well-defined SN2-mechanism.9 Unfortunately, the develop- Building on the structure of catalyst (R)-1a, we found that
ment of enantioselective epoxide carbonylation reactions has salen-ligands bearing bulky aryl substituents positioned ortho
been slow and remains a challenge to the present day.10 to the phenoxide moiety, as in catalysts (R)-1b and 1c, were
Significant progress came in 2012 from Ibrahim and coworkers, required to form highly enantioenriched trans-b-lactones. These
who reported moderate ee’s (11–56%) in the carbonylative lactones were then elaborated to the corresponding anti-aldol-
desymmetrization of alicyclic meso-epoxides.10c Other classes type products in a one-pot procedure. In light of these findings,
of aliphatic epoxides have yet to be studied extensively.
we hypothesized that these new enantiopure catalysts could also
induce enantioenrichment in the carbonylation of meso-epoxides
(Fig. 1b). In addition, we were interested to see if electronic
variation of catalyst (R)-1c would have an impact on enantio-
selectivity in this reaction. Electronic variation of related salen-
based catalytic systems has led to improved selectivity as well as
mechanistic insights.12 Moreover, the modular nature of the
Department of Chemistry and Chemical Biology, Baker Laboratory,
Cornell University, Ithaca, NY 14853-1301, USA. E-mail: gc39@cornell.edu;
Fax: +1 607-255-4137; Tel: +1 607-255-5447
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data for all new compounds, expanded Tables S1–S4.
See DOI: 10.1039/c4cc04397a
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Table 2 Scope of the carbonylative enantioselective desymmetrization of
meso-epoxides 3 using catalysts (R)-1b and 1ca
Table 1 Evaluation of enantiopure carbonylation catalysts and solvents
for the enantioselective desymmetrization of meso-epoxide 3a
b-Lactone
R
Catalyst
(mol%)
Isol. yield
(%)
eec
(%)
b-Lactone 4ab
Entry
Catalystb
Entry
Catalysta
Solvent
Conv. (%)
ee (%)
1
2
3
4
5
6
7
8
Me (4b)
Et (4c)
(R)-1c
(R)-1c
(R)-1c
(R)-1c
(R)-1b
(R)-1b
(R)-1b
(R)-1b
2.5
4
7
8
2.5
6
95d
70
77
72
94d
74
76
72
83
96
94
92
83
98
97
91
1
2
3
4
5
6
7
8
(R)-1c
(S,S)-2
(R)-1a
(R)-1b
(R)-1c
(R)-1c
(R)-1c
(R)-1c
THF
THF
THF
THF
THP
1,4-Dioxane
DME
70
43
89
42
78
98
7
94
16
58
97
73
70
24
43
nPr (4a)
nBu (4d)
Me (4b)
Et (4c)
nPr (4a)
nBu (4d)
10
12
Toluene
98
a
b
All reactions gave full conversion by GC analysis. Catalysts (R)-1b
c
a
b
and 1c were generated in situ (LnAlCl + NaCo(CO)4). Enantiomeric
excess determined by GC analysis. Yield determined by GC analysis
(method of standard addition). See ESI for expanded Table S2.
Catalysts (R)-1a–c were generated in situ (LnAlCl + NaCo(CO)4). Con-
version to b-lactone 4a and enantiomeric excess determined by GC
analysis. See ESI for expanded Table S1.
d
salen-ligand in catalyst (R)-1 facilitates electronic variation at the This substrate may be too small to be influenced by the
R1-position while keeping the required steric bulk at the ortho- additional steric bulk of (R)-1b. For larger substrates, improved
position. Herein we report the application of enantiopure chiral enantiomeric excess of the b-lactone product was obtained, but
catalysts for the carbonylative enantioselective desymmetriza- again higher catalyst loadings were required (entries 6 and 7).
tion13 of meso-epoxides 3 and describe the effect of electronic
While aliphatic meso-epoxides were active with catalysts
variation of the salen-ligand on this transformation (catalysts (R)-1b and 1c, no activity was observed with alicyclic meso-
(R)-1c–f). epoxides under standard reaction conditions. This is note-
Initially, we focused on the carbonylation of cis-4-octene worthy because the majority of reported desymmetrization
oxide (3a) using catalysts (R)-1a–c (Table 1). The best results in reactions of meso-epoxides utilize alicyclic meso-epoxides.16
terms of activity and enantioselectivity were obtained with Nonetheless, the carbonylative meso-desymmetrization of ali-
catalyst (R)-1c in THF (entry 1). Control reactions using (R)-1a phatic epoxides using catalysts (R)-1b and 1c complements the
and (S,S)-2 demonstrated that while the 2,20-diamino-1,10- previous work on alicyclic meso-epoxides carried out by Ibrahim
binaphthalene (DABN)14 backbone improved selectivity to and coworkers.10c
some extent, the bulky aryl-substituents at the ortho-position
With the goal of further improving the activity and enantio-
(R2) were essential for achieving satisfactory levels of enantio- selectivity of catalyst (R)-1c, electronic variations at the para-
enrichment (entries 2 and 3). Increasing the steric bulk around position (R1) of the phenoxide were analyzed (Fig. 2 and Table 3).
the Lewis acidic metal center further improved selectivity but
simultaneously decreased activity (catalyst (R)-1b, entry 4).
Other solvents gave no further benefit to enantioselectivity
(entries 5–8).
Once the catalyst and reaction conditions had been established,
the scope of the carbonylative enantioselective desymmetrization
of meso-epoxides was explored (Table 2). Of the meso-epoxides
tested with catalyst (R)-1c, each resulted in yields greater than 70%
and good to excellent levels of enantioenrichment (entries 1–4).
Moreover, an inverse correlation between the steric size of the
substrate and the activity of (R)-1c was observed, with bulkier
epoxides requiring higher catalyst loadings (cf. entries 1 and 4).
Interestingly, increasing the steric size of the epoxide also
led to larger amounts of ketone side-products,15 which stem
from rearrangement reactions of the epoxide.9d In addition,
meso-epoxides with longer alkyl substituents such as 3a, c,
and d gave substantially higher % ee’s than cis-2-butene oxide
(3b, entries 1–4).
Use of the bulkier catalyst (R)-1b gave results and trends
similar to those seen with (R)-1c. In the case of epoxide 3b, the
same % ee was observed with either catalyst (entries 1 and 5).
Fig. 2 Electronic effects on the meso-desymmetrization of epoxides 3
using catalysts (R)-1c–f (see Table 3 for % ee values).
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Table 3 Change in enantioselectivity for a given meso-epoxide when
using catalysts (R)-1c–fa
the nature of the substrate. Nonetheless, the linear trends
observed in Fig. 2 seem to indicate that each substrate under-
goes carbonylation with a consistent mechanism for all cata-
lysts tested.
To test the effect of lowered temperature, each substrate was
carbonylated with the optimal catalyst at 0 1C. For each system,
the % ee increased by about 1% but reduced activity was also
observed (Table 4). In addition, less ketone side-product was
observed at the lower temperature.15
In conclusion, we report catalysts (R)-1b and 1c for the
carbonylative enantioselective desymmetrization of aliphatic
meso-epoxides. The resulting trans-3,4-disubstituted b-lactones
were isolated in good yields and displayed high levels of
enantioenrichment. In addition, electronic variation of the
ligand framework as well as a lower reaction temperature
resulted in improved enantioselectivity for all substrates. The
opposing LFER of epoxide 3b when compared with the trends
for the other substrates investigated indicates an unexpected
relationship between the sterics of the substrate and the
electronic properties of the catalyst. A better understanding of
this relationship may provide insight into the mode of stereo-
induction with these catalysts and will guide design of future
catalysts with improved activity and selectivity. Studies towards
these goals are currently under way.
Catalyst used and observed % eeb
b-Lactone
R
(R)-1d
(R)-1c
(R)-1e
(R)-1f
Entry
(R1 = OMe)
(R1 = Me)
(R1 = F)
(R1 = Cl)
1
2
3
4
Me (4b)
Et (4c)
86
95
92
90
83
96
94
92
76
96
94
93
76
97
96
96
nPr (4a)
nBu (4d)
a
Average conversion to b-lactone was 89%. See ESI for individual
conversion data, catalyst loadings, and expanded Table S3. Catalysts
b
(R)-1c–f were generated in situ (LnAlCl + NaCo(CO)4). Enantiomeric
excess determined by GC analysis.
Although the meso-desymmetrization of the small epoxide 3b
was unaffected by increased steric bulk around the chiral pocket
(vide supra), a higher enantioselectivity (86% ee, Table 3, entry 1)
was observed using electronic variation. The observed negative
linear free energy relationship (LFER) in the case of 3b indicates
higher selectivity with more electron-donating substituents
(Fig. 2, blue line).
An opposite electronic effect was observed for the larger
epoxides 3a, c, and d (entries 2–4). In these cases, LFERs with
positive slopes (r) indicate enhanced enantioselectivity with
more electron-withdrawing substituents. While the observed
r values are only modestly positive (+0.48 to +0.71), this change
is enough to greatly affect the observed enantiomeric ratio.
Notably, the selectivity for 4d increased from 19 : 1 to 48 : 1 by
changing this electronic parameter (entry 4). Catalysts (R)-1e
(R1 = F) and 1f (R1 = Cl) were also generally more active
and yielded less ketone side-products than their electron-rich
counterparts.15 The highest % ee with all catalysts (R)-1c–f was
always obtained with meso-epoxide 3c.
We are grateful to the Department of Energy (DE-FG02-
05ER15687) and the National Science Foundation (DGE-1144153,
fellowship to J.R.L.) for funding.
Notes and references
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unexpected interplay between the size of the substrate and the
electronic properties of the catalyst. This observation suggests
the possibility of different reaction mechanisms depending on
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Conv.b (%)
0 1C 22 1C
eec (%)
b-Lactone
R
Entry
Catalyst
0 1C
22 1C
1d
2
Me (4b)
Et (4c)
(R)-1d
(R)-1f
(R)-1f
(R)-1f
97
85
32
58
94
96
95
84
88
98
97
97
86
97
96
96
3
nPr (4a)
nBu (4d)
4e
a
Catalysts (R)-1d and 1f were generated in situ (LnAlCl + NaCo(CO)4).
b
[3] = 0.5 M (22 1C) or 1.5 M (0 1C). Conversion to b-lactone 4
determined by 1H NMR (entry 1) or GC analysis (entries 2–4). Enantio-
c
d
meric excess determined by GC analysis. 3 mol% (0 1C) and 4 mol%
e
(22 1C) catalyst were used. 5 mol% (0 1C) and 4 mol% (22 1C) catalyst
were used. See ESI for expanded Table S4.
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This journal is ©The Royal Society of Chemistry 2014
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