Site-selective catalysis: Toward a regiodivergent resolution of 1,2-diols

Article abstract of DOI:10.1021/ja3027086

This paper demonstrates that the secondary hydroxyl can be functionalized in preference to the primary hydroxyl of a 1,2-diol. The site selectivity is achieved by using an enantioselective organic catalyst that is able to bond to the diol reversibly and covalently. The reaction has been parlayed into a divergent kinetic resolution on a racemic mixture, providing access to highly enantioenriched secondary-protected 1,2-diols in a single synthetic step.

Full text of DOI:10.1021/ja3027086

Communication
pubs.acs.org/JACS
Site-Selective Catalysis: Toward a Regiodivergent Resolution of 1,2-
Diols
Amanda D. Worthy, Xixi Sun, and Kian L. Tan*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
can be used to functionalize sugars selectively.6 We report a
ABSTRACT: This paper demonstrates that the secondary
hydroxyl can be functionalized in preference to the
primary hydroxyl of a 1,2-diol. The site selectivity is
achieved by using an enantioselective organic catalyst that
is able to bond to the diol reversibly and covalently. The
reaction has been parlayed into a divergent kinetic
resolution on a racemic mixture, providing access to
highly enantioenriched secondary-protected 1,2-diols in a
single synthetic step.
chiral organic catalyst that uses reversible covalent bonding
between the catalyst and the substrate to functionalize a
secondary alcohol in preference to an adjacent primary alcohol.
Because the catalyst is chiral, the enantiomers of a racemic
mixture react at different rates, resulting in a regiodivergent
silylation of a racemic mixture (eq 1). This delivers the
elective manipulation of multiple similar functional groups
S
within a molecular ensemble is a significant challenge in
chemical synthesis. This problem is generally addressed by
employing reaction sequences wherein the more reactive
groups are functionalized first.1 The ability to functionalize a
less reactive position in the presence of a more reactive group
may enable new synthesis strategies. The challenge of such a
transformation is that most synthetic catalysts cannot change
the energetics of the reaction coordinate sufficiently to
overcome inherent biases in substrate reactivity.
protected secondary alcohol product with excellent enantiose-
lectivity in a single synthetic step (up to >98% ee; see Table
2).7,8
We thought that a scaffolding catalyst previously developed
for the desymmetrization of 1,2-diols9 could be used to perform
the site-selective functionalization of a secondary hydroxyl over
a primary hydroxyl. As shown in Scheme 1, each enantiomer of
Notable exceptions are enzymes that routinely functionalize
less reactive sites within a complex molecule.2 Enzymes are able
to achieve these dramatic changes in selectivity by binding
substrates in a specific orientation that places the target
functional group near a catalytic residue. The entropic price for
this exquisite control is paid through multiple enthalpically
favored interactions between the substrate and the amino acids
that line the substrate binding pocket. In analogy to enzymes,
synthetic catalysts are able to functionalize less reactive sites
when they use noncovalent substrate binding as a critical
component in determining the overall selectivity.3 For example,
both Miller3f and Kawabata3c have reported catalysts that
functionalize glucose at the C4 position. In both cases it is
postulated that noncovalent interactions are used to bind to the
more accessible primary hydroxyl, which directs the reaction to
the more hindered site. The size of these organocatalysts is
relatively large (although significantly smaller than enzymes),
reflecting the need to have a well-defined array of noncovalent
interactions to overturn the inherent reactivity. As a
complementary method, using reversible covalent bonding4,5
instead of noncovalent interactions would allow for efficient
substrate−catalyst association through a single point of contact,
minimizing the catalyst architecture devoted to substrate
binding while retaining the proximity effects necessary to
achieve site selectivity. Recent work by Taylor and co-workers
has shown that covalent interactions in boron-based catalysts
Scheme 1. Curtin−Hammett Kinetics as a Basis for Site and
Enantioselectivity
the diol has an independent site selectivity based on both the
affinity of the 1° or 2° hydroxyl for the catalyst (Keq and Ke′q)
and the relative rates of functionalization (k1 vs k2 and k3 vs
k4).10 We hypothesized that one of the enantiomers of the diol
would allow us to combine the binding selectivity and
stereoselectivity effectively to overturn the large inherent
Received: March 20, 2012
Published: April 19, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a
substrate bias for primary functionalization. In this report, we
show that the scaffolding catalyst gives dramatically different
site selectivities for the enantiomers of the diol, resulting in an
effective divergent kinetic resolution.
Table 2. Substrate Scope for Regiodivergent RRM
To simplify this complex problem, the site-selective silylation
of a single enantiomer of terminal 1,2-diol (S)-1a was
investigated (Table 1). As expected, a control reaction
2
3
entry
R
yield (%)
ee (%)
yield (%)
ee (%)
b
1
Cy
52
54
53
48
46
56
44
53
52
50
81
79
82
70
80
74
78
57
90
91
41
40
40
36
40
40
32
37
45
41
97
98
98
92
96
99
96
91
97
98
Table 1. Catalyst Screening for 2° Alcohol Protection
c
2
(CH2)3CH3
CH2CH(CH3)2
CH3
b
3
d
4
e
5
CH2Ph
c
6
CH2OBn
CH2OPh
CHCH2
CH2Cl
f
7
d
8
b
9
b
10
CH2Br
a
Yields and ee’s are averages of two runs; ee's were determined by GC
or HPLC analysis. In all cases, 2 and 3 were separable by SiO2 column
chromatography, so the isolated yields are of the pure constitutional
b
isomers. Run with 15% 6b, 1.3 eq triethylsilyl chloride (TESCl) and
a
a
a
entry
catalyst
yield of 4a (%)
2a:3a
yield of 3a (%)
c
diisopropylethylamine (DIPEA) for 45 min. Run with 10% 6a, 1.2 eq
TESCl and DIPEA for 1.5 h. Run with 15% 6b, 1.2 eq TESCl and
d
1
2
3
4
5
9
5
5
8
7
98:2
18:82
12:88
91:9
<2
58
e
6a
6b
7
DIPEA for 25 min. Run with 10% 6b, 1.2 eq TESCl and DIPEA for
b
f
76 (74 )
45 min. Run with 15% 6a, 1.4 eq TESCl and DIPEA for 45 min.
<1
<2
c
5
6b
>98:2
category of a regiodivergent reaction on a racemic mixture
(regiodivergent RRM).11−13
a
GC yields and selectivities based on an internal standard
(trimethoxybenzene). Isolated yield of 3a. (R)-1a was used as the
b
c
Investigation of the substrate scope for the resolution
revealed that the reaction is permissive of both sterically
demanding groups14 such as cyclohexyl and sec-butyl (Table 2,
entry 3) and smaller alkyl groups such as butyl (Table 2, entry
2). In most cases, the enantioselectivity of the secondary-
protected product was found to be ≥96% ee; exceptions
included Me and vinyl substituents (92 and 91% ee,
respectively; Table 2, entries 4 and 8). The methyl and vinyl
substrates highlight the importance of stereoselectivity as a
means of controlling site selectivity, because as the smallest
substituents they are the most challenging to differentiate. Both
vinyl and OPh groups also pose the additional challenge that
the secondary alcohol is electronically deactivated toward
silylation. Consequently, background silylation (including bis-
silylation) becomes more competitive with 2° alcohol
functionalization, lowering the overall yield of 3. When R is
benzyl or OBn, the reaction proceeds in good yield (40%) with
high enantioselectivity (96 and 99% ee; Table 2, entries 5 and
6). Additionally, both Cl and Br substituents are tolerated
under the reaction conditions and provide excellent enantio-
selectivities for 3 (Table 2, entries 9 and 10).
The divergent resolution allows for access to (S)-3a−j with
high ee, but the formation of (R)-2a−j occurs with more
modest enantioselectivities. The lower enantioselectivities for
(R)-2a−j directly result from the site selectivity observed for
the (S)-diol (Table 1, entry 3; also see the boxes in Scheme 1).
The formation of (R)-2a−j is faster than that of (S)-3a−j,
suggesting that silylation of the primary alcohol is also catalyzed
by 6.15 Therefore, analogous to a standard kinetic resolution,
the enantioselectivity for (R)-2 can be increased by lowering
the overall conversion. However, unlike a traditional kinetic
resolution, which generally is effective at providing starting
material in high ee,16,17 the divergent resolution makes it
possible to isolate the products in high yield with high ee. For
example, using 0.6 equiv of TESCl leads to the isolation of (R)-
substrate.
examining silylation with triethylsilyl chloride and catalysis
with N-methylimidazole resulted in silylation of the primary
alcohol (2a:3a = 98:2; Table 1, entry 1). Preliminary studies
showed that under acetal exchange conditions, primary alcohols
have ∼8-fold higher affinity for 6a than secondary alcohols do
(see the Supporting Information), suggesting that the binding
selectivity alone would not be sufficient to overturn the
inherent substrate bias (98:2). Using 6a in the silylation of (S)-
1a resulted in a dramatic change in selectivity, with the
secondary-protected product being favored (2a:3a = 18:82;
Table 1, entry 2). Furthermore, switching to scaffold 6b
increased the selectivity to 2a:3a = 12:88 (Table 1, entry 3)
with an isolated yield of 74% for (S)-3a. The net site selectivity
change is between 2 and 3 orders of magnitude relative to N-
methylimidazole. A second control reaction using as the catalyst
compound 7, which does not have a substrate binding site,
resulted in selective formation of the primary-protected product
(2a:3a = 91:9; Table 1, entry 4), demonstrating the necessity of
covalent bonding between the substrate and the catalyst. This
reaction was also the only one that suffered from low
conversion (33% conv), consistent with the fact that covalent
bonding to the catalyst is also necessary for rate acceleration.
Application of 6b to (R)-1a resulted in a complete reversal in
site selectivity, with silylation of the primary alcohol occurring
almost exclusively (Table 1, entry 5).
These foregoing results suggested that kinetic resolution of
the racemic substrate could be achieved. When the racemic
substrate was silylated under the standard conditions, both the
primary- and secondary-silylated products were enantioen-
riched, with 3a forming in 97% ee in favor of the S
configuration and 2a in 81% ee favoring the R configuration
(Table 2, entry 1). Such a kinetic resolution falls under the
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Communication
(2) For examples of site-selective enzymatic reactions, see:
2a (R = Cy) in 47% yield with 92% ee (eq 2) versus 52% yield
with 81% ee using 1.3 equiv of TESCl (Table 2, entry 1). From
(a) Thibodeaux, C. J.; Melanco
Ed. 2008, 47, 9814. (b) Thibodeaux, C. J.; Melanco
̧
n, C. E.; Liu, H. Angew. Chem., Int.
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Nature 2007, 446, 1008. (c) Koeller, K. M.; Wong, C.-H. Chem. Rev.
2000, 100, 4465.
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Angew. Chem., Int. Ed. 2006, 45, 5616. (f) Griswold, K. S.; Miller, S. J.
Tetrahedron 2003, 59, 8869.
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a practical perspective, these results mean that either the 1°- or
2°-protected products can be accessed in high enantioselectivity
simply by adjusting the amount of TESCl employed.
The synthesis of enantioenriched diols is a process that has
been achieved using several noteworthy enantioselective
reactions, including asymmetric dihydroxylation of olefins,18
hydrolytic kinetic resolution of terminal epoxides,19 and
asymmetric diboration/oxidation of olefins and alkynes.20
However, accessing compounds where a secondary alcohol is
protected in the presence of a primary alcohol would require an
additional 2−3 synthetic steps from the enantiopure diol. Using
the regiodivergent RRM not only resolves the enantiomers of
the starting material but also chemically differentiates the
primary and secondary alcohols. This procedure can also be
used for selective functionalization of the secondary over the
primary hydroxyl of enantioenriched 1,2-diols in a single step.
The ability to overturn the large substrate bias is made possible
by implementing a catalyst that is highly stereoselective and has
a preference for binding less hindered hydroxyls covalently. We
believe that exploiting binding selectivity and proximity will be
a productive means of functionalizing inherently less reactive
sites on complex molecules.
(5) For a recent example of a catalyst that uses temporary
intramolecularity in enantioselective catalysis, see: MacDonald, M.
J.; Schipper, D. J.; Ng, P. J.; Moran, J.; Beauchemin, A. M. J. Am. Chem.
Soc. 2011, 133, 20100.
(6) (a) Gouliaras, C.; Lee, D.; Chan, L.; Taylor, M. S. J. Am. Chem.
Soc. 2011, 133, 13926. (b) Lee, D.; Taylor, M. S. J. Am. Chem. Soc.
2011, 133, 3724. (c) Chan, L.; Taylor, M. S. Org. Lett. 2011, 13, 3090.
(7) For examples of catalyzed silyl transfer, see: (a) Rodrigo, J. M.;
Zhao, Y.; Hoveyda, A. H.; Snapper, M. L. Org. Lett. 2011, 13, 3778.
(b) Grajewksa, A.; Oestreich, M. Synlett 2010, 2482. (c) Yan, H.; Jang,
H. B.; Lee, J.-W.; Kim, H. K.; Lee, S. W.; Yang, J. W.; Song, C. E.
Angew. Chem., Int. Ed. 2010, 49, 8915. (d) You, Z.; Hoveyda, A. H.;
Snapper, M. L. Angew. Chem., Int. Ed. 2009, 48, 547. (e) Yu, Z.; Mitra,
A. W.; Hoveyda, A. H.; Snapper, M. L. Angew. Chem., Int. Ed. 2007, 46,
8471. (f) Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature
2006, 443, 67. (g) Isobe, T.; Fukuda, K.; Araki, Y.; Ishikawa, T. Chem.
Commun. 2001, 243.
(8) For a review of Si−O coupling reactions, including metal-
catalyzed reactions, see: Weickgenannt, A.; Mewald, M.; Oestreich, M.
Org. Biomol. Chem. 2010, 8, 1497.
(9) Sun, X.; Worthy, A. D.; Tan, K. L. Angew. Chem., Int. Ed. 2011,
50, 8167.
(10) For a review of Curtin−Hammett and Winstein−Holness
kinetics, see: Seeman, J. I. Chem. Rev. 1983, 83, 83.
(11) For reviews of divergent kinetic resolutions, see: (a) Miller, L.
C.; Sarpong, R. Chem. Soc. Rev. 2011, 40, 4550. (b) Kumar, R. R.;
Kagan, H. B. Adv. Synth. Catal. 2010, 352, 231. (c) Vedejs, E.; Jure, M.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, compound characterization, equilibrium
data, and estimations of site selectivities for (R)- and (S)-diols
from Table 2. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
kian.tan.1@bc.edu
■
(12) For an example of a regiodivergent RRM using silyl transfer, see
ref 7a.
Notes
(13) In this case, the formation of constitutional isomers is derived
from site selectivity, so a more appropriate term maybe site-divergent
RRM. Regioselectivity generally refers to differentiation of positions
within the same functional group; in this case, we are differentiating
the same type of functional group within the same molecule, which is
site selectivity.
(14) Attempts at silylating 3,3-dimethyl-1,2-butanediol (R = t-Bu)
resulted in no protection of the secondary hydroxyl. These results
suggest that the current catalyst system is unable to overcome the large
substrate bias for primary alcohol protection for this substrate.
(15) Reacting (R)-1a with control catalyst 7 resulted in modest
conversion (60% conv) and a low yield of (R)-2a (16%), suggesting
that covalent bonding between 6b and (R)-1a is necessary for efficient
catalysis.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We dedicate this paper to Robert G. Bergman on the occasion
of his 70th birthday. We thank Omar DePaolis for experimental
support and the Alfred P. Sloan Foundation (K.L.T.), the
LaMattina Fellowship (X.S. and A.D.W.), NSF (CHE-
1150393), and NIGMS (R01GM087581) for funding of this
project. Mass spectrometry instrumentation at Boston College
is supported by funding from the NSF (DBI-0619576).
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■
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