Regioselective carbonylation of trans-disubstituted epoxides to β-lactones: A viable entry into syn-aldol-type products

Article abstract of DOI:10.1021/ja405151n

Two new catalysts are reported for the regioselective carbonylation of trans-disubstituted epoxides to cis-β-lactones. The two catalysts display high and opposing selectivities, which generally are difficult to achieve for this class of epoxides. The resulting β-lactones are well-defined precursors for a wide variety of aldol-type compounds. Altogether, carbonylation of disubstituted epoxides is established as a viable and economical entry into syn- and anti-aldol products.

Full text of DOI:10.1021/ja405151n

Communication
pubs.acs.org/JACS
Regioselective Carbonylation of trans-Disubstituted Epoxides to
β‑Lactones: A Viable Entry into syn-Aldol-Type Products
Michael Mulzer, Bryan T. Whiting, and Geoffrey W. Coates*
Baker Laboratory, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853-1301, United States
S
* Supporting Information
stereocontrol.3 Taken together, these attributes can be
ABSTRACT: Two new catalysts are reported for the
regioselective carbonylation of trans-disubstituted epoxides
to cis-β-lactones. The two catalysts display high and
opposing selectivities, which generally are difficult to
achieve for this class of epoxides. The resulting β-lactones
are well-defined precursors for a wide variety of aldol-type
compounds. Altogether, carbonylation of disubstituted
epoxides is established as a viable and economical entry
into syn- and anti-aldol products.
disadvantageous in terms of cost and operational simplicity.
An alternative approach to the same line of products utilizes
α,β-disubstituted β-lactones. Due to their inherent reactivities,
they can easily be converted into a wide variety of
stereochemically well-defined aldol compounds (Scheme 1),
or rearranged to structures otherwise inaccessible via aldol
reactions.4,5 Of the methods available for the synthesis of α,β-
disubstituted β-lactones,4 most require lactonization of a
corresponding acyclic precursor.6 However, these precursors
themselves are typically derived from aldol reactions.7 Another
popular approach is the catalyzed (formal) [2+2]-cycloaddition
of ketenes to carbonyl compounds. This transformation gives
β-lactones directly, often with excellent stereoselectivity.8
Drawbacks are the need to synthesize both reaction partners
separately, the use of stoichiometric amounts of an activating
agent, and careful control of the reaction parameters.
An attractive alternative method to obtain the β-lactones is
the carbonylation of vicinally disubstituted epoxides using
catalysts of the form [Lewis acid]+[Co(CO)4]− (Schemes 1 and
2).9,10 The epoxides are readily available in diastereo- and
enantioenriched forms,11 and the SN2 mechanism of the
carbonylation reaction transforms stereochemistry predict-
ably.12 However, known carbonylation catalysts show low
regioselectivity with vicinally disubstituted epoxides, leading to
he aldol reaction and its diverse array of products are of
T
great importance in the synthesis of complex molecules
and industrial processes.1 Noteworthy features of this trans-
formation are the formation of a C−C bond and the
concomitant creation of two contiguous stereocenters. Aldol
products derived from so-called propionate aldol reactions (R2 =
Me in Scheme 1) are of special interest,2 and thus many
Scheme 1. Epoxide Carbonylation with Subsequent β-
Lactone Functionalization as a Versatile Alternative to the
Aldol Reaction
Scheme 2. Simplified Mechanism of Epoxide Carbonylation
Using [Lewis Acid]+[Co(CO)4]− Catalysts, and the Problem
of Regioselectivity
excellent methods for their synthesis exist.3 A common
deficiency of these methods, however, is the use of
stoichiometric amounts of an activating agent, e.g. a base, to
facilitate the reaction. Furthermore, strict control of reaction
conditions and additional auxiliaries or catalysts are often
needed to induce high levels of relative and absolute
Received: May 22, 2013
Published: June 21, 2013
© 2013 American Chemical Society
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Communication
a mixture of products. This is attributed to an unselective SN2
reaction between the epoxide and the cobaltate anion (Scheme
2).
Table 1. Evaluation of Carbonylation Catalysts for the
Regioselective Carbonylation of trans-Epoxide 2a
a
Opening unbiased vicinally disubstituted epoxides regiose-
lectively using an intermolecular SN2 reaction is generally very
challenging.13 Consequently, very few selective catalysts exist
for such a reaction.14,15 With the intent to address these
problems, we herein report two new carbonylation catalysts
that carbonylate trans-disubstituted epoxides with good to
excellent regioselectivities. The catalysts display opposing
selectivities, allowing the synthesis of either regioisomer of
the β-lactone. Overall, this method provides access to a large
group of more complex α,β-disubstituted β-lactones starting
from epoxides and CO, and as such is a convenient and
economical entry into a large variety of syn- and anti-aldol-type
products (Scheme 1).
b
b
entry
1
linker
R1
R2
catalyst
ratio 3a:4a
conv (%)
L1
L2
L1
L1
L3
L4
L5
L1
L1
L3
tBu
tBu
Me
Me
Me
Me
Me
Me
Me
Me
tBu
tBu
Me
Ar1
Ar1
Ar1
Ar1
Ar2
Ar3
Ar3
1a
1b
1c
1d
1e
1f
1:1.6
1:4.0
5
>95
9
c
2
3
1.4:1
4
10.1:1
11.5:1
2.3:1
40
5
23
6
87
7
1g
1h
1i
6.7:1
71
8
11.5:1
11.5:1
10.1:1
40
Initial studies focused on identifying a ligand framework for
the Lewis acidic metal ion that could impart high degrees of
regioselectivity in the carbonylation of trans-epoxides (Chart
1). Methyl-substituted epoxides such as 2a were chosen as
9
>95
35
10
1j
a
b
1
Conditions: [2a] = 0.5 M, 22 °C, 20 h. Determined by H NMR/
GC analysis from crude reaction mixture. Benzene as solvent and 7.5
c
mol % 1b used. See Supporting Information for complete table.
Chart 1. [Lewis Acid]+[Co(CO)4]− Catalysts Explored in
This Study
production of 4a, yet a carbonylation catalyst that would
strongly favor formation of regioisomer 3a was still more
desirable. A first indication of how this could be achieved came
in the form of catalyst 1c (entry 3). The small size of the
substituents R1 and R2 in this catalyst gave rise to a small shift
in selectivity toward 3a. A subsequent adjustment of the steric
hindrance in R2 then gave rise to very good selectivity, yet
catalyst activity was still only moderate (entry 4). Variation of
the diamine linker yielded unsatisfactory results (entries 5−7).
However, fine-tuning the steric size of the aryl group in R2
(entries 8 and 9) led to catalyst 1i, which in THF showed the
best activity and selectivity in producing 3a.16 Although only
low-quality X-ray crystals of 1i could be obtained to date (R =
0.0707, wR2 = 0.1832), their analysis indicates that the ligand
coordinates in the salen-typical trans-planar geometry around
the Al3+ ion, albeit in a rather distorted fashion.16,17 Lastly,
changing the diamine linker in 1i to L3 resulted in lower activity
(entry 10).
Catalysts 1b and 1i were subsequently tested for the
regioselective carbonylation of a variety of trans-disubstituted
epoxides 2 (Tables 2 and 3). GC or 1H NMR analysis of crude
reaction mixtures indicated full conversion of starting material
to lactone with both catalysts in almost all cases. The resulting
regioisomeric β-lactone products 3 and 4 could be separated
from one another either directly via column chromatography or
after their conversion into the corresponding ester derivatives 5
and 6 by quenching the reaction with MeOH/NaOMe. The
latter approach showcases how the obtained β-lactones can
readily be converted into related aldol moieties with well-
defined stereochemistry.
Carbonylation of trans-epoxides 2 with catalyst 1b gave good
preference for β-lactones 4 (Table 2), with ratios 3:4 falling in
the range from 1:3.0 to 1:4.6. Interestingly, 1b displayed an
almost steady increase in regioselectivity for epoxides 2a−e
(Table 2, entries 1−5). This seems counterintuitive because
longer alkyl chains should shield their side of the epoxide more
from nucleophilic attacks than shorter ones. In line with this
expectation, epoxides with sterically more demanding sub-
stituents R such as 2f gave no formation of any lactone when
exposed to 1b (entry 6). Nevertheless, the contrasteric
selectivities achieved with 1b are without precedence for this
substrates because the resulting β-lactones 3 and 4 are both of
interest. Lactone class 3 serves as a precursor for biologically
important propionate aldol products.2 Lactones 4 give aldol-
type products based on acetaldehyde, which can be a
troublesome electrophile in aldol reactions due to its suspected
carcinogenicity and propensity to hydrate or oligomerize. The
salen framework seemed to be a good starting point for ligand
development because of its highly modular nature and known
ability to form complexes that catalyze carbonylation
reactions.9,12b Previously reported salen-based carbonylation
catalysts, however, showed poor activity at ambient temper-
ature, and a modest contrasteric preference for β-lactone 4a
(Table 1, entry 1).16 Consequently, a redesign of the ligand was
necessary. Changing the ligand structure from the salen-type to
a salalen-type (L2) increased the preference for 4a to more
synthetically useful levels (entry 2). Use of a salalen ligand also
allowed for the incorporation of an additional pyridine donor
ligand. Based on prior mechanistic studies,12b this was expected
to facilitate the rate-determining step in the catalytic cycle, thus
improving the low activity of catalysts such as 1a at room
temperature. Catalyst 1b proved useful for the enhanced
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Communication
even better selectivities toward β-lactones 3 (entries 6−9). In
the cases of 2h,i, this additional bias was strong enough to form
lactones 3h,i almost exclusively, with only trace amounts of 4h,i
being detected via 1H NMR spectroscopy. However, placement
of steric bulk immediately adjacent to the epoxy group (2j,
entry 10) gave a mixture of 3 and 4 and relatively poor
conversion. Likewise, trans-epoxides with sterically very similar
substituents such as trans-2-butyl-3-ethyloxirane (2k) gave
rather low selectivities when using 1i.18
Given the good performance of 1i, its ability to
regioselectively carbonylate enantioenriched trans-epoxides
was investigated next. The use of enantioenriched epoxides is
very attractive because several excellent methods for their
preparation exist,11 and stereochemistry is reliably converted
during carbonylation reactions.12 A potential pitfall, however,
lies in the fact that 1i is typically used as a racemate. This can
lead to matched/mismatched combinations19 between the
enantioenriched epoxide and the two enantiomers of the
racemic catalyst, thus potentially diminishing the good
selectivities observed before with racemic epoxides. To explore
this scenario, highly enantioenriched (S,S)-2e (>95% ee) and
(S,S)-2i (99% ee) were synthesized and carbonylated using
racemic versions of 1i (Table 4). Good regioselectivities and
Table 2. Regioselective Carbonylation of trans-Disubstituted
Epoxides to β-Lactones Using 1b
a
isolated
product
isolated
yield (%)
b
entry
R (epoxide)
ratio 3:4
c
1
Et (2b)
1:3.0
1:3.7
1:3.5
1:4.0
1:4.6
n.d.
5b
4c
4d
4a
4e
4f
63
60
65
68
71
2
nPr (2c)
c
3
nBu (2d)
nPent (2a)
nHex (2e)
4
5
6
b
(CH2)3OTBS (2f)
<5
a
Conditions: [2] = 0.5 M, 22 °C, 22 h. All reactions gave full
1
conversion (GC or H NMR analysis), except for 2f (<5%). Yields
b
refer to isolated products. Determined by 1H NMR analysis of crude
c
reaction mixture. 5 mol % of 1b used. n.d. = not determined. TBS =
tBuMe2Si.
group of epoxides, and cannot readily be explained by invoking
an inherent steric or electronic bias.
In comparison to 1b, catalyst 1i generally showed higher
regioselectivities in the carbonylation of trans-epoxides 2, with
ratios 3:4 typically exceeding 10.0:1 in favor of 3 (Table 3).
Table 4. Regioselective Carbonylation of Enantioenriched
a
trans-Disubstituted Epoxides (S,S)-2e,i
Table 3. Regioselective Carbonylation of trans-Disubstituted
a
Epoxides to β-Lactones Using 1i
b
b
entry
R (epoxide)
catalyst
ratio 3:4
conv (%)
1
2
3
4
5
6
nHex (S,S-2e)
nHex (S,S-2e)
nHex (S,S-2e)
CH2Ph (S,S-2i)
CH2Ph (S,S-2i)
CH2Ph (S,S-2i)
rac-1i
13.3:1
1.6:1
>95
80
(S,S)-1i
(R,R)-1i
rac-1i
32.3:1
>50:1
13.4:1
>50:1
>95
>95
56
isolated
product
isolated
b
entry
R (epoxide)
ratio 3:4
yield (%)
(S,S)-1i
(R,R)-1i
1
2
3
4
5
6
Et (2b)
nPr (2c)
nBu(2d)
nPent (2a)
6.1:1
11.5:1
13.3:1
11.5:1
13.3:1
19.0:1
24.0:1
>50:1
>50:1
10.1:1
6b
6c
6d
6a
6e
6f
60
68
74
79
85
75
81
92
84
>95
a
b
Conditions: [2] = 0.5 M, 22 °C, 20 h. Conversion to lactone,
determined by H NMR analysis of crude reaction mixture.
1
nHex (2e)
activities were retained with both enantioenriched epoxides
when using rac-1i (Table 4, entries 1 and 4). These results
document that rac-1i is well suited for the regioselective
carbonylation of enantioenriched trans-epoxides, which ulti-
mately leads to enantioenriched aldol-type products. The use of
enantiopure catalysts also allowed for the identification of
matched/mismatched pairs between the epoxide and the
carbonylation catalyst. As Table 4 shows, trans-epoxides with
(S,S)-configuration constitute a mismatched pair with (S,S)-1i,
leading to significantly reduced selectivity and activity (entries 2
and 5). The matched case with (R,R)-1i, however, improved
further on the already good selectivity and produced the
preferred regioisomer 3 almost exclusively (entries 3 and 6).
It is currently unclear why (R,R)-1i preferentially interacts
with (S,S)- instead of (R,R)-trans-epoxides, and how the
catalyst is able to induce such high levels of regioselectivity.
Steric interactions presumably play a major role in both
processes. Moreover, it is reasonable to assume that, once the
epoxide is bound to the Lewis acid, the movement of its
substituent R is conformationally restricted. This restriction
(CH2)3OTBS (2f)
(CH2)2OTBS (2g)
CH2OTBS (2h)
CH2Ph (2i)
iPr (2j)
c
7
d
6g
3h
3i
8
9
b
b
10
3j + 4j
45
a
Conditions: [2] = 0.5 M, 22 °C, 20 h. All reactions gave full
1
conversion (GC or H NMR analysis), except for 2j (45%). Yields
b
refer to isolated products. Determined by 1H NMR analysis of crude
c
d
reaction mixture. 7.5 mol % 1i used. 10 mol % 1i used. TBS =
tBuMe2Si.
Only epoxide 2b gave a lower ratio of 6.1:1 (entry 1). Given the
similarity of the epoxide substituents in 2b (Me vs Et), this is
still a very good ratio, and underscores the ability of 1i to
effectively enhance even small degrees of steric bias contained
in 2. In contrast to the trend observed with 1b, epoxides 2a,c−e
showed little variation in regioselectivity as the length of the
alkyl chain was altered (entries 2−5). As expected, trans-
epoxides 2 with sterically more demanding substituents R gave
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Communication
(a) Mulzer, J.; Kerkmann, T. J. Am. Chem. Soc. 1980, 102, 3620−
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then probably confines R to positions that shield its
corresponding epoxy methine carbon from nucleophilic attacks,
thus favoring ring-opening of the epoxide at the observed
position.
In summary, two new carbonylation catalysts 1b and 1i are
reported that convert trans-disubstituted epoxides 2 into the
corresponding regioisomeric β-lactones 3 and 4. Due to the
regioselectivities displayed by 1b and 1i, only one of the two β-
lactone regioisomers is predominantly produced in these
reactions. Moreover, the two catalysts show opposing
regioselectivities, and thus provide access to a large variety of
α,β-disubstituted β-lactones starting from readily available
epoxides and carbon monoxide. In addition, these features
are retained with enantiopure epoxides, and regioselectivity can
be improved even further by matching the right enantiomers of
catalyst and epoxide. Lastly, this work constitutes a major
advance toward regioselective intermolecular SN2 ring-opening
reactions of vicinally disubstituted epoxides. Current work
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for the synthesis of enantioenriched β-lactones.20
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and spectra of
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
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Org. Lett. 2011, 13, 3142−3145. (b) Ganji, P.; Ibrahim, H. Chem.
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AUTHOR INFORMATION
Corresponding Author
gc39@cornell.edu
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the U.S. Department of Energy
(DE-FG02-05ER15687).
■
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