The efficient desymmetrization of glycerol using scaffolding catalysis

Article abstract of DOI:10.1039/c2cc33633b

Glycerol is an ideal building block for the synthesis of complex molecules, because it is inexpensive and highly functionalized. We report the desymmetrization of glycerol through silyl transfer, using a chiral organic catalyst in high yield and enantioselectivity.

Full text of DOI:10.1039/c2cc33633b

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The efficient desymmetrization of glycerol using scaffolding catalysiswz
Zachary X. Giustra and Kian L. Tan*
Received 20th May 2012, Accepted 27th June 2012
DOI: 10.1039/c2cc33633b
Glycerol is an ideal building block for the synthesis of complex
molecules, because it is inexpensive and highly functionalized. We
report the desymmetrization of glycerol through silyl transfer,
using a chiral organic catalyst in high yield and enantioselectivity.
catalyst that directly desymmetrizes glycerol in a single step
through silylation with state-of-the-art yield and enantioselectivity
(>99 : 1 er, Table 1).
Previous work in our laboratories6 has shown that catalyst 4
is effective in the desymmetrization and kinetic resolution of
1,2-diols via silyl transfer.7–10 Glycerol poses a more challenging
substrate class because it contains two reactive primary alcohols,
such that suppression of over-addition is critical to obtain high
yield and enantioselectivity of the monofunctionalized product.
Catalyst 4 has a unique mode of action in which it covalently
bonds to alcohol-based substrates and then, through either
intramolecular general base catalysis or electrophile transfer,
functionalizes the unbound alcohol. We have termed this mode
of action scaffolding catalysis,11 because a primary function of the
catalyst is to hold several reacting partners in close proximity
to one another. The intramolecular nature of the catalyst
There is an abundance of natural products and biologically
active compounds that can be derived from glycerol (Fig. 1).1
Although glycerol is an achiral compound, the majority of
natural products derived from glycerol are chiral. This fact has
led many research groups to investigate reaction sequences
that efficiently access a desymmetrized variant of glycerol. One
of the most successful methods for accessing these compounds is a
multiple step sequence that uses mannitol, a chiral pool material.2
Because glycerol is a commodity chemical (a by-product of
biodiesel production), it would be desirable to develop methods
that can directly convert glycerol into chiral building blocks.
Enzymatic esterases have been shown to selectively hydrolyse
the meso diester of glycerol;3 however, there are a limited
number of methods that can directly desymmetrize glycerol in
a single step with high enantioselectivity. The most successful
desymmetrizations are in the area of enzymatic reactions,4 and
the only reported synthetic catalysts for the desymmetrization
of glycerol use derivatives that are functionalized at the
C2-hydroxyl.5 In this communication, we report an organic
Table 1 Optimization of glycerol desymmetrization
Catalyst
loading (%)
Yield
2a (%)
Yield
3a (%)
Entry
Catalyst
erb
1c
2c
3c
20
20
20
4a
4b
4c
68
74
14
12
12
3 : 97
98 : 2
>99 : 1
(>99 : 1)e
99 : 1
99 : 1
(96 : 4)e
50 : 50
82 (78)e
4d
5d
10
5
4c
4c
66
66 (65)e
20
10
Fig. 1 Biologically active glycerol derived products.
6c
20
5
52
8
Boston College, Merkert Chemistry Center, 2609 Beacon,
St. Chestnut Hill, MA, USA 02467-3860. E-mail: kian.tan.1@bc.edu;
Fax: +1 617-552-2705; Tel: +1 617-552-2705
w This article is part of the ChemComm ‘Emerging Investigators 2013’
themed issue.
a
1
Yields determined by H NMR by comparison to internal standard
b
1,3,5-trimethoxybenzene. er’s determined by HPLC analysis after
c
derivatization with 1-naphthoyl chloride. Reaction time 12 h.
d
e
Reaction time 26 h. Isolated yield and er of products on a 1 mmol
scale and an average of two runs.
z Electronic supplementary information (ESI) available: Experimental
details and compound characterization. See DOI: 10.1039/c2cc33633b
c
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Chem. Commun.

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activation encouraged us to test glycerol as a substrate as a
means of suppressing over-silylation. Implementing catalyst 4a
with TBSCl as the electrophile yields the desired silylated
product in 68% yield by 1H NMR and 97 : 3 er also with
formation of 14% of the bis-silylated product 3 (Table 1, entry 1).
Upon optimizing the R group proximal to the imidazole, catalyst
4c was found to deliver (R)-2 in 78% yield and >99 : 1 er
(Table 1, entry 3). The bis-silyated product 3 also forms in the
reaction in 12% yield. The origin of 3 is believed to be a catalysed
process rather than background reaction (vida infra). Reducing
the catalyst loading to 5 mol% results in only a small decrease in
yield and er (er = 96 : 4, Table 1, entry 5). In a control reaction,
catalyst 5, which does not have a covalent substrate-binding site,
was employed to afford 2 in 52% yield as a racemic mixture
(Table 1, entry 6). An additional control experiment with
2-methyl-1,3-propanediol, which lacks a secondary hydroxyl, also
resulted in low yield and enantioselectivity of the mono-silylated
product (eqn (1)). These results are consistent with covalent
bonding between the secondary hydroxyl of the substrate and
catalyst being essential for enantioselectivity.
Fig. 2 Time course of selectivity and yield of desymmetrization.
Fig. 3 Mechanism of secondary kinetic resolution.
ð1Þ
however, (S)-2 is stereochemically matched to catalyst 4c.
A secondary kinetic resolution occurs in which (S)-2 reacts
at a faster rate than (R)-2 (k3 > k4, Fig. 3). Consequently, the
formation of 3 is still a scaffold-catalysed process, which helps
to increase the enantioselectivity of the desired product (R)-2.
The desymmetrization of glycerol has proven to be a
challenging problem in asymmetric catalysis. By employing a
catalyst that uses reversible covalent bonding, a highly efficient
desymmetrization is achieved. In this case, the power of
intramolecularity helps to avoid intermolecular processes that
lead to undesired by-product formation. We are continuing
to explore modifications of the catalyst structure to improve
catalyst activity, and we are investigating the expansion of the
scope of the reaction to other electrophiles.
With the optimal conditions in hand we investigated the
range of silyl chlorides that can be employed in the reaction.
Both TIPSCl and TBDPSCl provide the mono-silylated
product in high yield and enantioselectivity (eqn (2)). These
silylating reagents generally require extended reaction times
(24 h) in order to achieve high conversions. Employing the
more reactive TESCl results in a complex mixture of products.
In this case, both the bis-silylated product, in which the
secondary hydroxyl is protected, and the secondary hydroxyl
mono-silylated product are observed.y
We are grateful for the financial support from NSF
(CHE-1150393) and NIGMS (RO1GM087581). We also thank
Xixi Sun and Amanda Worthy for experimental assistance.
ð2Þ
Notes and references
The formation of 3 with TBSCl was unusual for catalyst 4
since in the desymmetrization of cis-1,2-diols bis-silylated
products were not observed in significant quantities.6b To
determine the origin of the over-silylation the yield and
enantioselectivity were monitored as a function of time. As
Fig. 2 shows, the initial enantioselectivity of the reaction is
90 : 10 er with 45% yield of 2 after 1 h. Over time the
enantioselectivity increases to >99 : 1 er with concomitant
formation of 3. These results are consistent with a secondary
resolution occurring on the mono-silylated product.12
Rephrasing these results in terms of kinetics, the formation of
(R)-2 is approximately 9ꢀ faster than (S)-2 (k2 > k1, Fig. 3).
Notably, both (S)-2 and (R)-2 can still bind to the catalyst;
y The functionalization of the secondary hydroxyl is consistent with
previously published results (ref. 6a), which demonstrate the regio-
divergent resolution of terminal 1,2-diols.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.