Catalytic asymmetric synthesis of geminal-dicarboxylates

Article abstract of DOI:10.1039/c8sc01786g

Stereogenic acetals, spiroacetals and ketals are well-studied stereochemical features that bear two heteroatoms at a common carbon atom. These stereocenters are normally found in cyclic structures while linear (or acyclic) analogues bearing two heteroatoms are rare. Chiral geminal-dicarboxylates are illustrative, there is no current way to access this class of compounds while controlling the stereochemistry at the carbon center bound to two oxygen atoms. Here we report a rhodium-catalysed asymmetric carboxylation of ester-containing allylic bromides to form stereogenic carbon centers bearing two different carboxylates with high yields and enantioselectivities. The products, which are surprisingly stable to a variety of acidic and basic conditions, can be manipulated with no loss of enantiomeric purity as demonstrated by ring closing metathesis reactions to form chiral lactones, which have been extensively used as building blocks in asymmetric synthesis.

Full text of DOI:10.1039/c8sc01786g

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Catalytic asymmetric synthesis of geminal-dicarboxylates
Nisha Mistry and Stephen P. Fletcher*a
Received 00th January 20xx,
Accepted 00th January 20xx
Stereogenic acetals, spiroacetals and ketals are well-studied stereochemical features that bear two heteroatoms at a
common carbon atom. These stereocenters are normally found in cyclic structures while linear (or acyclic) analogues
bearing two heteroatoms are rare. Chiral geminal-dicarboxylates are illustrative, there is no current way to access this
class of compounds while controlling the stereochemistry at the carbon center bound to two oxygen atoms. Here we
report a rhodium-catalyzed asymmetric carboxylation of ester-containing allylic bromides to form stereogenic carbon
centers bearing two different carboxylates with high yields and enantioselectivities. The products, which are surprisingly
stable to a variety of acidic and basic conditions, can be manipulated with no loss of enantiomeric purity as demonstrated
by ring closing metathesis reactions to form chiral lactones, which have been extensively used as building blocks in
asymmetric synthesis.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Stereocenters bearing two heteroatoms, including chiral
acetals, spiroacetals and ketals (Fig. 1a), are some of the most
prevalent structural motifs found in nature. These features are
present in virtually all carbohydrate derivatives such as starch
and cellulose, and in many small natural products including
pheromones, steroids, and polyketides.1 The ability to control
the stereochemistry of carbon centers featuring two
heteroatoms is also important in the development of
pharmaceuticals.1,2
For many years, stereocontrolled access to chiral acetal
derivatives relied on derivatisation of chiral starting
materials,3–8 metal mediated desymmetrisations,9–11 or kinetic
or thermodynamically controlled cyclisation of carbonyl
containing chiral-compounds.12–17 A recent approach to bis-
heteroatom containing stereogenic centers involves catalysis
with very sterically hindered chiral Brønsted acids. Though
generally envisaged to occur via oxocarbenium ion or imine
intermediates (Fig. 1b) which undergo stereoselective
addition, some reactions likely proceed via single-step
asynchronous pathways.18 This strategy has now been
sufficiently developed to allow the synthesis of chiral N,N–,19–
Figure 1. Common stereocenters bearing two heteroatoms and their catalytic
asymmetric formation, including this work. a) General Structures for O,O-
Acetals, spiroacetals, ketals and dicarboxylates. b) Formation of
a bis-
heteroatom bearing stereogenic center via an oxocarbenium ion intermediate
using Brønsted acid catalysis c) This work: Rh catalyzed asymmetric carboxylation
of heteroatom containing allyl bromides to form gem-dicarboxylates.
processes, including allylic substitutions, with oxygen, nitrogen
and carbon nucleophiles have been reported to form allylic
alcohols, amines, and tertiary or quaternary carbon
stereogenic centers.30–39 Carboxylic acids may be used as
nucleophiles, not only in rhodium-catalysed asymmetric
reactions,40 but also in processes catalysed by iridium,41
palladium,42,43 and ruthenium.44 However, only limited
examples of metal-catalysed asymmetric additions to make
stereogenic centres bearing two heteroatoms are known, and
no Rh-catalysed processes have been reported.45–48
22
N,O–,23 N,S–24,25 and O,O–acetals.26–29 Methods for the
stereocontrolled formation of analogous linear compounds are
less common.19,20,23,24
A variety of rhodium-catalysed asymmetric allylation-type
Here we report the stereocontrolled synthesis of geminal-
dicarboxylates (acylals) via a highly enantioselective rhodium-
catalysed carboxylation of allyl bromide derivatives bearing
ester groups. These allyl bromides have been used in copper-
catalysed additions of Grignard reagents to give allylic esters.49
The linear products described here feature a stereogenic
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As long as it is of high quality, it is possible to use LiOMe
instead of LiOt-Bu (Table 1, entry 6), however when switching
to non-Li bases, for example KOt-Bu, the ee drops significantly
(8% ee, Table 1, entry 7).
Table 1. Asymmetric geminal-dicarboxylation and variations from standard conditions
Room temperature reactions proceed with excellent results
but to maintain reaction component solubility, adequate
stirring and reasonable reaction times, (particularly when
using other nucleophiles), 40 °C appears to be a suitable
temperature (Table 1, entries 8 and 9). The reaction can easily
be performed on a gram-scale while simultaneously reducing
the amount of rhodium to 0.5 mol % [Rh(COD)(Cl)]2, and ligand
to 1.2 mol % (Table 1, entry 11).
Entry
Variation from
Standard Conditions
None
Reaction
time
1.5 h
o/n[c]
o/n
Yield[a]
(%)
82
0
ee[b]
(%)
96
-
1
2
No Rh
3
No ligand
76
69
0
Rac
45
-
4
(S)-BINAP instead of A
No LiOt-Bu
o/n
For reaction scope, aliphatic carboxylic acids including bulky
tert-butyl (2b) and adamantyl groups (2c), provided the
corresponding products in excellent enantioselectivities (>93%
ee), however smaller nucleophiles such as formic and acetic
acid, (2e and 2f respectively) give lower yields and ee’s. In
addition to the reduced yield and ee, the reaction with formic
acid also gave small amounts of the achiral dibenzoyloxy
5
o/n
6
LiOMe instead of LiOt-Bu
KOt-Bu instead of LiOt-Bu
Room Temperature
60 °C
1 h
85
67
89
83
82
82
96
8
7
o/n
8
2 h
94
95
96
95
9
1 h
10
11[d]
1 eq. isobutyric acid
4 mmol scale
50 mins
2 h
derivative of
2 and under some conditions 1a may decompose
to benzoic acid, which then undergoes competitive Rh-
[a] All yields are isolated yields [b] Enantiomeric excesses determined by
SFC using a chiral non-racemic stationary phase [c] The reaction was stirred
catalysed carboxylation to the remaining 1a. We were not able
to separate this by-product from 2f
.
overnight [d] Gram-scale reaction, carried out using 0.5 mol
[Rh(COD)(Cl)]2 and 1.2 mol % ligand.
%
This method is compatible with carboxylic acids that contain a
terminal alkene (2g), terminal alkyne (2h) and an internal
alkene (2i). When racemic ibuprofen is used as a nucleophile, a
1:1 mixture of diastereoisomers is formed (both diastereomers
having 94% ee, 2j).
carbon center bearing two different carboxylates. Geminal-
dicarboxylates are an understudied class of compounds with
the exception of the diacetate and dipropionate derivatives,
which can protect aldehydes and are important substrates for
asymmetric Tsuji-Trost reactions.50,51
Aromatic carboxylic acids generally work well as nucleophiles.
2,4,6-Trimethylbenzoic acid (2k) and 4,5-dimethoxybenzoic (2l
)
Methods for the synthesis of 1,1-diacetates include protic and
Lewis acid catalysis,52,53 the action of I2,54 NBS,55 and various
heterogeneous catalysts.56 However, none of these methods
allow stereocontrol. As far as we are aware the only report of
asymmetric induction in gem-dicarboxylate formation involved
copper-catalysed allylic oxidation of an olefin in 23% yield and
10% ee.57
both gave high yields and ee’s over 90%. 4-Chloro- (2r), 2-
chloro- (2o) and 4-bromobenzoic acid (2s) also give good ee’s.
Interestingly the 2-bromo derivative (2p) was formed in
excellent yield (91%) but the ee drops to only 73%. Increasing
the electron withdrawing potential of ring substituents, for
example having fluoro (2r), trifluoromethyl (2v), nitro (2q and
2w) or multiple halogens (2m and 2n) tends to decrease the
yield and ee. Curiously 4-methoxybenzoic acid (2u) gives only a
34% yield and 83% ee, whereas 4,5-dimethoxybenzoic acid (2l
)
Results and Discussion
gave 88% yield and 93% ee.
Our standard reaction conditions involve 1.25 mol
%
For 4-hydroxybenzoic acid (2xa) we obtained good results
(75%, 91% ee) but a hydroxy at the 2-position (2xb) is
detrimental (45%, 37% ee), likely due to either chelation of 2xb
to Rh during the reaction or hydrogen (or lithium) bonding of
the 2-hydroxy group altering the nucleophilicity of the
carboxylic acid. A free hydroxyl group in (R)-2-hydroxy-2-
phenylacetic acid (used as a single enantiomer) entirely
suppressed reactivity and no product 2ya is observed, but if
acetylated (here the single S-enantiomer was arbitrarily used)
2yb can be obtained (43%, 78% ee).
[Rh(COD)(Cl)]2, 3 mol % of Ugi amine derived ligand A, 1 eq. of
LiOt-Bu and THF at 40 °C. Using ester substituted allyl bromide
1a, easily prepared by mixing benzoyl bromide and acrolein at
room temperature in CH2Cl2,58 we are able to add isobutyric
acid to give 2a in good yield and excellent ee (82%, 96% ee,
Table 1, entry 1).
Pleasingly, we also observe complete regioselectivity for the
SN2’ product over the SN2 product, which is a known challenge
in allylic substitution reactions (see SI for further details).
If we remove either the rhodium source or base from the
reaction, we obtain no product (Table 1, entries 2 and 5). A
Substrates containing free amino groups such as
enantiomerically pure proline (3a) and 4-aminobenzoic acid
reaction without ligand
A gave racemic product (Table 1, entry
(3c) give no product, but protected derivatives (single
3) and using (S)-BINAP instead of
A gave 45% ee (Table 1, entry
enantiomer Boc-proline and N,N-dimethyl-4-
4).
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Figure 2. Reaction scope. a) Scope of aliphatic carboxylic acids. b) Scope of aromatic carboxylic acids. c) 4-hydroxybenzoic acid and 2-hydroxybenzoic acid give very
different results. d) Protection of free–OH groups may allow an otherwise problematic reaction to occur. e) Nitrogen-containing and pyridyl substrates. f) Using
different carboxylic acid derived electrophiles. All reactions were carried out on a 0.4 mmol scale of the electrophile. All yields are isolated yields. Enantiomeric
excesses determined by SFC using a chiral non-racemic stationary phase.
aminobenzoic acid) allowed synthesis of 3b and 3d in 2–position of the pyridyl ring allowed moderate yields and
respectable yield with excellent enantioselectivity (>90% ee). enantioselectivities to be achieved in formation of 3f and 3g
.
3b was obtained as a ‘single diastereoisomer’ which exists as a This observation is consistent with previous Rh-catalysed
3:1 mixture of rotamers at room temperature, as observed by asymmetric processes,59 and overall these experiments
NMR spectroscopy (see SI for NOESY spectra). Nicotinic acid suggest that many other carboxylic acid bearing heterocycles
did not give product 3e, but addition of a chloro group in the
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The gem-dicarboxylates shown here have not previously been
described in the literature and since there has been no good
way to access these chiral compounds before, their chemistry
has not yet been explored. In order to demonstrate if the gem-
dicarboxylates may be useful we briefly examined their
conversion to other species using ring-closing metathesis. The
synthesis of cyclic small-ring esters is of considerable interest
as they frequently appear in natural products and show
important biological activity.60 Asymmetric γ–butenolides have
been widely studied but only acetyl esters in the γ–position
have been reported, and asymmetry is normally induced using
enzymes.61–64
Entry
Conditions(^)
1M HCl(aq)
Recovered starting material
88%, 93% ee
1
2
3
4
5
6
7
3M HCl(aq)/THF
2M NaOH(aq)/THF
2M KOH(aq)/THF
1M KOH(MeOH)
K2CO3/MeOH
Na2CO3/MeOH
quant. 93% ee
58%, 95% ee
64%, 94% ee
Decomposed
Decomposed
<72%, 95% ee(^^)
Using the terminal alkene formed during the Rh-catalysed
addition, we are able to access 5– and 7–membered lactones.
Treatment of 4c and 2i with the 1st generation Grubbs catalyst
in refluxing CH2Cl2 overnight gave 5-membered lactones 5a
and 5b, which have a γ-stereogenic center. We assign the
absolute stereochemistry of all gem-dicarboxylate products
here, including diastereomeric mixture 2j, and single
diastereoisomers 2yb and 3b, by comparing the optical
rotation of lactone 5a with that quoted in the literature.62 This
is the first report of an asymmetric synthesis of compound
5b 65
. Using electrophile 1c specifically, the combination of Rh-
catalysed carboxylation followed by RCM has the potential to
give access to a range of new chiral γ–butenolides. Attempts to
use the Grubbs I catalyst to form a 7-membered ring did not
give the desired 5c, but the 2nd generation Grubbs catalyst
gave 43% yield and 5c was obtained as a solid with >99% ee.
Conclusions
Figure 3. Stability and derivatization of gem-dicarboxylates. (a) (^) 25 mg of 2a stirred
In conclusion, we have developed a method to form chiral
in 1 mL of a 1:1 mixture of solvents for 1 hour. (^^) Complete decomposition observed
overnight. (aq) – aqueous, (MeOH) – methanolic solution. (b) Ring closing metathesis of gem-dicarboxylates by Rh-catalysed asymmetric carboxylation.
gem-dicarboxylates to lactones. Isolated yields. Enantiomeric excesses determined by
Many different carboxylic acid nucleophiles can be used to
SFC.
give novel gem-dicarboxylates in good yields with high
enantioselectivity. The products are remarkably stable to a
and heteroatoms would be compatible with this method if
variety of acidic and basic conditions. We have demonstrated
appropriate protecting group strategies are used.
We then examined different allylic bromides 1b and 1c58 with
that the products can be used to form other chiral acetal
derivatives using the terminal alkene formed in the reaction in
isobutyric acid which gave 4a and 4b with good yields and
subsequent RCM reactions to access novel cyclic products
excellent ee’s. We note that acetic acid in combination with 1a
including valuable γ–butenolides. We anticipate that these
gave 48% yield and 74% ee however with 1c much better
gem-dicarboxylates may have many other potential uses and
results (84%, 92% ee) are observed.
now that we have described an efficient synthesis, this
To investigate the stability of the gem-dicarboxylates, we
chemistry can now be explored more fully.
subjected 2a to various conditions for 1 hour at room
More generally, linear products, chiral by virtue of
a
temperature. 2a is remarkably stable to a range of conditions;
in aqueous acidic solutions of up to 3M HCl, there is a
negligible loss in the yield and ee of 2a (Table 3, entries 1-2). In
aqueous basic solutions of up to 2M NaOH or KOH we see
some loss of yield, there is no change in ee (Table 3, entries 1–
4). Unsurprisingly, the products were unstable to methanolic
basic solutions in combination with potassium salts, and under
these conditions complete decomposition was observed (Table
stereogenic carbon bearing two differentiated hetereoatoms,
can be obtained by metal catalysed asymmetric additions to
appropriately substituted electrophiles. The ease of synthesis
and stability of the products suggests that a broad range of
new chemical species may be accessible by developing
strategies to form stereogenic carbon centers featuring
different combinations of hetereoatoms.
3, entries
5 and 6). Using Na2CO3 and MeOH trace
Experimental Procedures
decomposition was observed after
decomposition occurs overnight.
1 h, and complete
General procedure for asymmetric carboxylation reaction to
give chiral gem-dicarboxylates: In a flame-dried 10 mL round
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bottomed flask [Rh(COD)(Cl)]2 (2.5 mg, 0.0050 mmol, 0.0125 15
eq), Ligand (5.3 mg, 0.012 mmol, 0.030 eq) and LiOt-Bu (32
M. J. Gaunt, D. F. Hook, H. R. Tanner and S. V. Ley, Org.
A
Lett., 2003, 5, 4815–4818.
mg, 0.40 mmol, 1.0 eq) were stirred in THF (2 mL) at 60 °C for 16
30 mins. The reaction was cooled to 40 °C then a solution of
the allylic bromide (1a-c, 0.40 mmol, 1.0 eq) and the carboxylic 17
acid (0.80 mmol, 2.0 eq) in THF (1.5 mL) was added via syringe
and the flask rinsed with THF (0.5 mL). The resulting mixture 18
was then stirred at 40 °C until the reaction was complete by
TLC. SiO2 was added and the solvent was then carefully
evaporated. The resulting solid was directly loaded onto a 19
chromatographic column and eluted with Et2O/pentane to
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20
Conflicts of interest
21
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