Enantioselective silyl protection of alcohols promoted by a combination of chiral and achiral Lewis basic catalysts

Article abstract of DOI:10.1038/nchem.1708

Catalytic enantioselective monosilylations of diols and polyols furnish valuable alcohol-containing molecules in high enantiomeric purity. These transformations, however, require high catalyst loadings (20-30 mol%) and long reaction times (2-5 days). Here, we report that a counterintuitive strategy involving the use of an achiral co-catalyst structurally similar to the chiral catalyst provides an effective solution to this problem. A combination of seemingly competitive Lewis basic molecules can function in concert such that one serves as an achiral nucleophilic promoter and the other performs as a chiral Bronsted base. On the addition of 7.5-20 mol% of a commercially available N-heterocycle (5-ethylthiotetrazole), reactions typically proceed within one hour, and deliver the desired products in high yields and enantiomeric ratios. In some instances, there is no reaction in the absence of the achiral base, yet the presence of the achiral co-catalyst gives rise to facile formation of products in high enantiomeric purity.

Full text of DOI:10.1038/nchem.1708

ARTICLES
PUBLISHED ONLINE: 28 JULY 2013 | DOI: 10.1038/NCHEM.1708
Enantioselective silyl protection of alcohols
promoted by a combination of chiral and achiral
Lewis basic catalysts
Nathan Manville, Hekla Alite, Fredrik Haeffner, Amir H. Hoveyda and Marc L. Snapper
*
*
Catalytic enantioselective monosilylations of diols and polyols furnish valuable alcohol-containing molecules in high
enantiomeric purity. These transformations, however, require high catalyst loadings (20–30 mol%) and long reaction times
(2–5 days). Here, we report that a counterintuitive strategy involving the use of an achiral co-catalyst structurally similar
to the chiral catalyst provides an effective solution to this problem. A combination of seemingly competitive Lewis basic
molecules can function in concert such that one serves as an achiral nucleophilic promoter and the other performs as a
chiral Brønsted base. On the addition of 7.5–20 mol% of a commercially available N-heterocycle (5-ethylthiotetrazole),
reactions typically proceed within one hour, and deliver the desired products in high yields and enantiomeric ratios. In
some instances, there is no reaction in the absence of the achiral base, yet the presence of the achiral co-catalyst gives
rise to facile formation of products in high enantiomeric purity.
n designing a catalytic process, a chemist might use a promoter
In contemplating the design of a more efficient catalytic enantio-
molecule that interacts with both reaction partners. Catalytic selective diol silylation, we were led to consider the use of two
units are often tethered so that the appropriate geometry can be heterocyclic Lewis base catalysts that are structurally similar but
I
achieved to ease the bond-forming event (bifunctional catalysis1). accomplish separate tasks. One chiral catalyst would have to serve
The attendant structural rigidity enhances stereoselectivity and dis- as the Brønsted base by association with the diol substrate, which
courages the promoter sites from interfering with one another. An enhances reactivity of one of the enantiotopic alcohol sites, and
alternative stratagem enlists independent and unattached co-cata- an achiral Lewis base would be exclusively the nucleophilic promo-
lysts2; repeated adjustment of connector chains is thus obviated, cat- ter, which generates an activated silyl species. Such a scenario is dis-
alyst candidates are less structurally complex and screening studies tinct from a recent approach in which a chiral Brønsted acid and an
can be performed expeditiously. Incorporation of more than one achiral nucleophile transform an anhydride into an activated acylat-
catalyst molecule in an enantioselective process when they are struc- ing complex that then reacts enantioselectively with meso-diamines6
turally and functionally similar, but only one is chiral, raises an or racemic amines7. In the latter system, again, the co-catalysts are
intriguing question. Can the two promoters be induced to unable to replace one another. It is improbable that structural altera-
perform distinct tasks so that adventitious diminution of stereose- tions would transform the nucleophilic promoter into a competing
lectivity is not caused by the achiral component?
achiral anion binder (versus the chiral Brønsted acid), bringing dim-
Enantioselective reactions that proceed through the shared action inution in enantioselectivity.
of two catalysts have been reported3, many of which are promoted
by a chiral Brønsted acid and an achiral Lewis acid (often a metal- Results
based complex4). Transformations catalysed by two different Catalytic enantioselective alcohol silylation and its shortcomings.
metal complexes or an N-heterocyclic carbene and a metal salt In 2006, we reported the first instances of catalytic enantioselective
have been outlined as well. In other developments, chiral iminium silylations of diols (Fig. 1)8. Such processes are simple to operate and
ions, generated in situ, undergo further reaction with a Brønsted promoted by a readily accessible, robust and recyclable chiral
acid- or metal-activated partner. In the above cases, the co-catalysts, catalyst (1). Since then the utility of such processes9 has been
although at times possessing generally related attributes, are structurally illustrated in several contexts, including reactions with triols10,
disparate and realize independent tasks; as there is minimal overlay applications to natural product synthesis10,11 and kinetic
in their modes of action, their simultaneous presence does not pose resolutions12. Subsequently, alternative strategies were outlined;
a complication. For instance, a chiral proton donor that associates one involves an imidazole-based directing unit13 and in another a
preferentially with a heteroatomic site operates differently to a heterobicycle is used to effect kinetic resolution of cyclic aryl
gold-based complex with strong propensity towards interacting alcohols14. Despite the high enantiomeric ratio (e.r.) values, as
with Lewis basic p clouds5. It is much less probable that a represented in Fig. 1a, a severe drawback of the transformations
Brønsted acid can bind firmly to and activate an alkyne unit as promoted by 1 is the low efficiency: up to 30 mol% loadings and
the ‘softer’ transition-metal complex interacts with a heteroatom reaction times that span several days are needed. Based on the
in preference to a proton. The use of two Brønsted acids or two initial model, depicted in Fig. 1b, extensive investigations were
gold complexes, with fully differentiated roles, as collaborating carried out concerning alterations of the catalyst structure to
catalysts would be a proposition of greater difficulty.
render the silylation reactions more efficient; all efforts proved
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA. e-mail: amir.hoveyda@bc.edu;
*
marc.snapper@bc.edu
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1708
ARTICLES
tBu
a
b
H
H
H
Me
N
N
Me
tBu
N
N
N
N
H
30 mol%
H
H
O
N
O
N
H
O
OH
OTBS
OH
1
Me
Me
H
O
Cl
2.0 equiv. TBSCl, 1.2 equiv. iPr2EtN, THF
Si
OH
tBu
3
2
–40 °C, 120 h,
c
96% yield, 97.5:2.5 e.r.
Brønsted base activation
Cl–
NMe
+
N
OTBS
Me
Ph
OTBS
OH
H
HO
tBu
O
HO
OTBS
OH
Si
4
5
6
Nucleophilic activation
NMe
30 mol% 1,
–40 °C, 72 h,
30 mol% 1,
30 mol% 1,
–15 °C, 72 h,
N
–30 °C, 96 h,
75% yield, 97:3 e.r.
78% yield, 96.5:3.5 e.r.
70% conv., krel = 8
Figure 1 | Previously reported enantioselective alcohol silylations, the initially proposed model and the results of initial theoretical studies.
a, Representative details for the generation of chiral monosilyl derivatives of various cyclic and acyclic diols or triols that proceeds with exceptional
enantioselectivity, but requires high catalyst loadings and long reaction times. b, The initially proposed stereochemical model entails catalyst–substrate
association through two hydrogen bonds that involve the amide carbonyl and the amine linkage of the catalyst as well as activation of the silyl chloride by
the resident N-methylimidazole moiety. A wide range of catalyst modifications based on the aforementioned proposal did not lead to any increase in activity,
which casts doubt on the validity of the mechanistic model. c, Theoretical studies suggest a dual role for the Lewis basic heterocycle: silyl activation and
enhancement of substrate nucleophilicity.
unproductive, and kinetic studies were not fruitful because solution capable nucleophile. High enantioselectivities suggest that it is
heterogeneity led to variable and irreproducible data. more probable that, although 1 is a suitable chiral base for diols
i
Computational studies to locate the suggested transition structure (versus Pr2EtN), it is an inferior nucleophilic activator, which
`
(Fig. 1b) were similarly unsuccessful. Earlier investigations vis-a- leads to low silylation rates (Fig. 1a). If a second Lewis base were
vis the effect of structural changes on reactivity and, particularly, to perform as a co-catalyst that provides strong nucleophilic acti-
enantioselectivity8, suggested that 1 probably serves as a Brønsted vation alongside 1 (but without interfering as a Brønsted base)
base; for example, removal of the imidazole unit or its then a more facile and equally enantioselective transformation
replacement with a less basic pyridine or thiazole moiety results could become feasible.
in complete loss of activity. Furthermore, we judged that less
tenable is the scenario in which an achiral base (iPr2EtN) is
Examination of achiral co-catalysts. To establish feasibility, the
operative and 1 acts as a chiral nucleophilic catalyst that induces
enantioselectivity from a position distal to the reacting diol. We
became doubtful, however, as to whether 1 can operate as a
nucleophilic activator and a Brønsted base.
experiments summarized in Table 1 were carried out. We set a
limit of six hours; 20 mol% 1 was used at 240 8C with 1.25 equiv.
iPr2EtN to neutralize the generated HCl. With only 1 present
there is 9% conversion into 3 (entry 1, Table 1), whereas the
reaction is significantly more efficient (69% conversion) in
Mechanistic analysis. We began with a computational study forming rac-3 with NMI (7) (entry 2, Table 1).
of
a
model transformation: silylation of MeOH with
We then chose to probe the reaction under an unusual set of con-
t-butyldimethylsilyl chloride (TBSCl) and imidazole,
a
ditions. We attempted silylation with 20 mol% 1 and 20 mol% NMI,
combination based on the original report15 regarding formation of an achiral and more-active catalyst (entry 3, Table 1). This is a com-
silyl ethers with the same reagent and catalyst (used in bination that chemists in search of attaining maximum enantios-
stoichiometric amounts) in dimethylformamide (DMF) as the electivity are unlikely to consider. Avoiding ‘background reactions’
solvent. To understand better the role of the heterocyclic catalyst, by achiral catalyst competitors is a principle strictly adhered to in
we probed the system without DMF, which can serve as a weak enantioselective catalysis. Nonetheless, with 20 mol% of the more
nucleophilic catalyst, and because enantioselective silylation is strongly activating achiral Lewis base 7 present alongside 20 mol%
performed in its absence. Theoretical investigations supported the of less potent chiral Lewis basic 1, remarkably, silyl ether 3 is
critical notion that there are two imidazole molecules involved obtained more rapidly and in 78:22 e.r. (entry 3, Table 1).
(Fig. 1c): one generates a highly electrophilic silyl complex and Analysis of the findings in entries 1–3 of Table 1 reveals two
the other plays the role of Brønsted base, which enhances alcohol crucial points:
nucleophilicity (see the Supplementary Information for details)16.
An implication of the model in Fig. 1c is the anti-orientation of † First, the higher efficiency in entry 3 as opposed to lower conver-
the promoter molecules; therefore, because of severe geometric con-
straints, 1 cannot serve as an effective bifunctional catalyst.
Accordingly, we surmised that high enantioselectivities might orig-
inate from efficient enantiotopic group differentiation arising when
sions in entries 2 and 3 indicates that the combination of 1,
which almost certainly serves as an effective chiral base, and
NMI, which probably provides nucleophilic activation, leads to
a more-efficient process than when one of these is absent.
1 plays the role of a chiral Brønsted base (see Fig. 1b). We judged, † Second, the chiral NMI-substituted 1 emerges as a superior
however, that diol silylation through involvement of two molecules
of N-methylimidazole (NMI)-substituted 1 might be relatively
unfavourable because nucleophilicity is sensitive to steric factors
(versus proton removal) and 1 might be too hindered to be a
Brønsted base compared to NMI and the more abundant
iPr2EtN (20 mol% versus 1.25 equiv.); otherwise, higher conver-
sion and appreciable enantioselectivity would not be observed in
entry 3 versus entry 2 (Table 1).
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1708
ARTICLES
NMI 9 has noteworthy implications regarding the inefficiency of
silylations with 1 as the catalyst (see Fig. 1a): if a methyl substituent
hampers the ability of an NMI moiety as a nucleophilic activator,
the sterically more-demanding amino acid-based moiety of the
chiral variant does so as well, and probably to a larger extent.
Inclusion of relatively basic 10 (entry 10, Table 1) does not lead
to rate acceleration, probably as a result of the formation of the
Table 1 | The effect of heterocyclic co-catalysts on silylation
of diol 2.
tBu
H
Me
N
Me
tBu
N
N
H
N
O
1 (0–20 mol%)
+ 0–20 mol% co-catalyst
i
derived HCl salt (that is, 10 competes effectively with Pr2EtN). In
OH
OH
OTBS
OH
contrast, with 4,5-dicyanoimidazole (11) (entry 11, Table 1)
present, there is 45% conversion in three hours and 3 is generated
with the same enantioselectivity as obtained without a co-catalyst
(96:4 versus 97.5:2.5 e.r. (see Fig. 1a)). Reaction with 7.5 mol% tet-
razole (12) (entry 12, Table 1) leads to a similar rate acceleration and
selectivity. The silylation proceeds to completion in three hours and
3 is obtained in 97:3 e.r. when 5-ethylthiotetrazole (13) (entry 13,
Table 1) is introduced. Similar roles (Brønsted base and nucleophilic
activation) are assigned to the imidazole moieties of histidine resi-
dues within bifunctional polypeptide catalysts used for enantioselec-
2.0 equiv. TBSCl, 1.25 equiv. iPr2EtN,
THF, –40 °C
2
3
Co-catalysts examined
NMe2
Me
N
H
N
Me
N
Me
N
N
N
N
tive conversion of various alcohol families to carboxylic19,20
,
7
8
9
10
phosphoryl ester21 or sulfinate derivatives22. In such instances,
Lewis base promoters perform their expected tasks as dictated by
the geometrical constraints imposed by the structure of the bifunc-
tional catalyst. Furthermore, examination of different promoter
units in the aforementioned context requires the preparation of
enantiomerically pure a-amino acid residues and subsequent syn-
thesis of each polypeptide catalyst candidate.
H
N
H
N
H
N
NC
N
N
N
N
SEt
N
N
N
NC
11
12
13
Entry
1
Co-catalyst
(mol%)
Time
(h)
Conv.
(%)*
e.r.†
(mol%)
Enantioselective alcohol silylation with improved catalytic
efficiency. The positive influence of 13 as a co-catalyst for
enantioselective diol silylation is general (Table 2).
Transformations depicted in entries 1–14 of Table 2 proceed with
lower catalyst loadings (20 mol% versus 30 mol%; see below for
further data) at the same or slightly lower temperature (entries 13
versus 14, Table 2) and in substantially shorter periods of time
(one hour versus 2–5 days) through the simple expediency of
1
2
3
4
5
6
7
8
9
10
11
12
13
20
0
None; NA
7; 20
7; 20
7; 15
7; 10
7; 7.5
7; 5.0
8; 7.5
9; 7.5
10; 7.5
11; 7.5
12; 7.5
13; 7.5
6.0
6.0
6.0
6.0
6.0
6.0
6.0
3.0
3.0
3.0
3.0
3.0
3.0
9
93.5:6.5
NA
78:22
81.5:18.5
83:17
85.5:14.5
86.5:13.5
93:7
90.5:9.5
86:14
69
92
88
79
71
49
13
5
20
20
20
20
20
20
20
20
20
20
20
incorporating
7.5 mol%
of
5-ethylthiotetrazole
(13).
8
Monosilylated diols are obtained in nearly identical yields and e.r.
values as those when only the chiral catalyst 1 is used. In one
instance that involved enantioselective synthesis of acyclic silyl
ether 18 (entries 15 and 16, Table 2), there was minimal reaction
in the absence of 13 (,10% yield after 24 hours at 230 8C);
when the co-catalyst is present, the desired product is obtained
within 12 hours in 93% yield and 95:5 e.r.
47
45
.98
96:4
98:2
97:3
Reactions were carried out in a sealed vessel in air (see the Supplementary Information for details).
NA, not applicable.
*Conversion (conv.) was determined by GC analysis; the variance of values is estimated to be less
than+2%. † Values determined by GC analysis; the variance of values is estimated to be less than
+2%. (See the Supplementary Information for details.)
The influence of 5-ethylthiotetrazole on catalytic kinetic resol-
utions23 is similarly notable (Table 3). Whereas transformations
We presumed that the lowering of e.r. is partly because NMI (7) that afford the silyl ethers shown in entries 1, 3 and 5 of Table 3
competitively serves as a Brønsted base (see Fig. 1c). Accordingly, require 24–72 hours to proceed to 55–70% conversion, when
silylations with reduced amounts of 7 were probed. As the concen- 7.5 mol% 13 is introduced a conversion of 47–54% is attained in
tration of 7 is decreased (entries 4–7, Table 1), silyl ether 3 is formed one hour (entries 2, 4 and 6, Table 3), in many cases despite a
in higher enantioselectivity; with 20 mol% 1 and 5.0 mol% NMI lower loading of 1 and fewer equivalents of TBSCl. Faster rates
(entry 7), there is nearly 50% conversion after six hours and the were achieved on two occasions despite lower reaction temperature
desired product is generated in 86.5:13.5 e.r. The latter findings (entries 3 versus 4 and 5 versus 6, Table 3). Moreover, the catalytic
i
show that Pr2EtN, present in excess amounts, performs as a kinetic resolution that delivers silyl ether 6 is more enantioselective
weaker Brønsted base than NMI.
when both 1 and 13 are utilized (entries 5 and 6, Table 3); such an
To establish whether the efficiency and enantioselectivity might improvement is probably because, in the presence of the co-catalyst,
be further improved, we investigated the effectiveness of several the reaction is sufficiently facile to be performed at 240 8C (versus
other N-heterocycles. We chose to carry out reactions with 215 8C). The presence of 20 mol% 13 facilitates silylation leading to
7.5 mol% of a co-catalyst and measure progress within a span of mono-protected tertiary alcohol 21 such that it proceeds to 39%
three hours (versus six hours with 7). Representative findings are conversion in 12 hours with a relative rate of reaction by enantio-
shown in entries 8–13 of Table 1. Neither imidazole (8) (entry 8, mers (krel) .25 (entry 8, Table 3); this process hardly occurs in the
Table 1) nor 1,2-dimethylimidazole (9) (entry 9, Table 1) offer an absence of the achiral co-catalyst (entry 7).
improvement. The former probably generates an N-silylimidazole
An advantage of the catalytic system is that reactions reach com-
that is an inferior nucleophilic catalyst because of steric and elec- pletion within a few hours with lower catalyst loadings; two
tronic deactivation (the C–Si s* orbital serves as an electron accep- examples are presented in Fig. 2. With 5.0 mol% 1 and 5.0 mol%
tor17,18), whereas the latter is less effective due to its larger size 13, one gram of diol 2 can be converted into silyl ether 3 in 96%
(versus NMI). The low activity exhibited with 2-methyl-substituted yield and 96.5:3.5 e.r.; .98% conversion is observed in eight
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1708
ARTICLES
Table2 | Catalytic enantioselective silylation of various diols with and without 5-ethylthiotetrazole (13) as the co-catalyst.
Entry
Product
1 (mol%)
13 (mol%)
Time (h)
Temp. (8C)
Yield (%)*
e.r.†
OTBS
1
2
30
20
None
7.5
60
1
240
240
96
97
94:6
95.5:4.5
14
OH
OTBS
3
4
30
20
None
7.5
120
1
240
240
82
93
96:4
97:3
15
4
OH
OTBS
5
6
30
20
None
7.5
72
1
240
240
75
82
97:3
97.5:2.5
OH
OTBS
7
8
30
20
None
7.5
120
1
240
240
93
93
96.5:3.5
96.5:3.5
16
3
OH
OTBS
9
10
30
20
None
7.5
120
1
240
240
96
96
97.5:2.5
97.5:2.5
OH
OH
TBSO
11
12
30
20
None
7.5
48
1
278
278
82
78
98:2
94:6
17
5
HO
tBu
tBu
13
14
30
20
None
7.5
96
1
230
240
78
74
96.5:3.5
96:4
HO
HO
OTBS
OTBS
HO
15
16
18
30
20
None
7.5
24
12
230
240
,10
93
ND
95:5
Reactions were carried out in a sealed vessel in air (see the Supplementary Information for details). ND, not determined; Temp., temperature.
*Yield of isolated product after purification; the variance of values is estimated to be less than+2%. All reactions proceeded to .98% conversion (except for entry 15). †Values determined by GC analysis; the
variance of values is estimated to be less than+2%. (See the Supplementary Information for details.)
Table 3 | Effect of ethylthiotetrazole on catalytic kinetic resolution through enantioselective silylation.
tBu
H
N
H
Me
N
N
Me
tBu
N
N
N
SEt
H
N
O
N
1
13
R2
R1
OH
OH
R2
R1
OH
OH
R2
R1
OTBS
OH
R2
R1
OH
OH
20–30 mol%
7.5–20 mol%
i
0.6–1.0 equiv. TBSCl, 1.25 equiv. Pr2EtN,
THF, –15 to –40 °C, 0.6–1.0 h
R
R
R
R
Racemic
Enantiomerically enriched
Entry
Silylation product
1 (mol%);
13 (mol%)
TBSCI
(equiv.)
Time
(h)
Te mp .
(8C)
Conv.
(%)*
Recovered substrate
Product
Yield (%)†
krel
Yield (%)†
e.r.‡
e.r.‡
OTBS
1
2
20; none
20; 7.5
1.0
1.0
24
1.0
78
78
55
54
25
41
92:8
91:9
55
49
84:16
85:15
14
14
rac-19
rac-20
EtO
EtO
Me
OH
OTBS
3
4
30; none
20; 7.5
1.0
0.6
24
1.0
30
40
55
47
44
52
.98:2
89.5:10.5
52
35
90:10
95:5
.25
.25
EtO
EtO
Me
OH
OTBS
5
6
30; none
20; 7.5
1
0.6
72
1.0
15
40
70
52
30
47
98:2
96:4
68
52
69.5:30.5
93:7
8
.25
rac-6
Ph
OH
OTBS
7
8
30; none
20; 20
1
0.6
24
12
30
40
,5
39
.95%
62
ND
78.5:21.5
,5%
36
ND
95:5
NA
.25
rac-21
OH
Me
Reactions were carried out in THF in a sealed vessel in air. ND, not determined; NA, not applicable.
*Conversion into the desired product as measured by GC analysis of unpurified mixtures; krel was measured based on a previously reported method23; the variance of values is estimated to be less than+2%.
†Yield of isolated product after purification; the variance of values is estimated to be less than+2%. ‡Values determined by GC analysis; the variance of values is estimated to be less than+2%. (See the
Supplementary Information for details.)
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1708
ARTICLES
tBu
Mechanism and stereochemical models. The modes of reaction
illustrated in Fig. 3, based on and supported by theoretical studies
(see the Supplementary Information), put forth a plausible
rationale for the enantioselectivity trends. Reaction via complex I
leads to the major enantiomer; involvement of II entails
unfavourable steric repulsion and less-effective activation of the
diol substrate by the chiral base (see below).
H
N
H
Me
N
Me
tBu
N
N
N
N
SEt
H
N
O
N
1
13
5.0 mol%
OH
OH
OTBS
OH
5.0 mol%
2.0 equiv. TBSCl, 1.25 equiv. iPr2EtN, THF,
–40 °C, 8.0 h
Deprotonated 13, generated through reaction with i-Pr2EtN,
probably serves as the nucleophilic co-catalyst. The anionic
species is turned exceptionally reactive towards a silyl chloride
because of its high-energy highest occupied molecular orbital,
caused by its several neighbouring heteroatoms24, and the avail-
ability of a sterically accessible site for chloride displacement
(dotted circle in Table 1). Deprotonated 13 is the more-effective
nucleophilic promoter despite exhibiting the lowest degree of ther-
modynamic Brønsted basicity among those shown in Table 1 (pKa
values for 11, 12 and 13 (in 50% EtOH) ¼ 5.2, 4.9 and 4.2, respect-
ively25,26); the reason for such a trend rests in the distinction between
basicity and nucleophilicity functions of a Lewis base. Supplanting a
leaving group and forming an active electrophilic intermediate,
unlike proton transfer, is not readily reversible. A nucleophilic cat-
alyst is unable to serve as an effective Brønsted base because,
although it might be rapidly converted into its conjugate acid, the
resulting species would be short-lived (swift proton loss).
Accordingly, there is minimal reaction when only 13 and 1.25
2
3
(1.0 g)
96% yield, 96.5:3.5 e.r.
OTBS
OH
Me
tBu
H
EtO
H
Me
N
N
Me
tBu
N
N
N
N
SEt
H
EtO
N
O
N
20
42% yield, 93:7 e.r.
1
13
5.0 mol%
OH
OH
Me
5.0 mol%
EtO
EtO
rac-22
OH
OH
Me
1.0 equiv. TBSCl, 1.25 equiv. iPr2EtN, THF,
–40 °C, 2.0 h; 52% conv.; krel > 25
EtO
EtO
(S,S)-22
38% yield, 96:4 e.r.
i
Figure 2 | Examples of the catalytic system. In the presence of
commercially available 5-ethylthiotetrazole (13) as the co-catalyst,
enantioselective silylation of alcohols, or the related kinetic resolution
processes, can be performed with 5.0 mol% of chiral catalyst 1; the desired
conversion levels (.98% and ꢀ50%, respectively) are achieved within eight
hours. As exemplified through enantioselective preparation of silyl ether 3,
the catalytic reactions are amenable to gram-scale operations. (See the
Supplementary Information for experimental details.)
equiv. Pr2EtN are present (,5% conversion after six hours at
240 8C). The above considerations point to 1 as the enabling and
enantiodifferentiating base.
Why is 1 such a capable Brønsted base for the diol substrates, and
i
why does it outperform Pr2EtN, which is available in much larger
amounts? The NMI-containing 1 is an effective Brønsted base cata-
lyst because it can readily associate with diols by hydrogen bonding.
Proximity-induced reactivity enhancement is an acknowledged
principle in catalysis27–30. Appropriate spatial fit that involves the
basic heteroatomic sites within the catalyst (nitrogen of imidazole
and the amine side chain) and substrate hydroxyl groups gives rise
to activation of one of the enantiotopic alcohol groups. NMI or
derivatives of 1 that lack the heterocyclic moiety are thus ineffective
in generating sufficient Brønsted basicity. Whereas NMI readily cat-
alyses silylation of alcohols (as well as diols), 1 does not; association
of 1 with an alcohol necessary for Brønsted base activation is weaker
(only one point of contact). Unlike imidazole-containing entities
hours, which constitutes an improvement in turnover frequency
of nearly two orders of magnitude compared to the transformation
in Fig. 1a. The longer time required as a result of diminished catalyst
loading supports the critical role of chiral 1 in what is probably
the turnover-limiting step. In the kinetic resolution of rac-22,
52% conversion is observed in two hours; silyl ether 20 and the
recovered diol were isolated in 42% and 38% yield and 93:7 and
96:4 e.r., respectively.
‡
‡
H
H
N
N
H
H
N
N
N
t-Bu
O
N
O
Steric
repulsion
N
t-Bu
O
H
N
O
H
H
H
H
H
O
O
Si
t-Bu
Si
t-Bu
N
N
N
N
N
N
II
N
N
I
SEt
SEt
Computed ΔΔG‡ ≈ 4.8 kcal mol–1
Major enantiomer
Minor enantiomer
Figure 3 | Mechanistic models to account for the observed sense and levels of enantioselectivity (deprotonated 13 serves as the nucleophilic co-catalyst).
Proper juxtaposition of the two basic units of the chiral co-catalyst, namely the imidazole and the secondary amine side chain, with the hydroxyl groups of
the diol substrate leads to efficient binding and activation of one of the enantiotopic hydroxyl groups for silylation. Computational (DFT) studies reveal that
the proposed transition structures are further stabilized by an ion–dipole interaction that involves the carbonyl amide and the transferring proton. In the
competing complex II, there is a significant destabilizing steric interaction between the bound substrate and the co-catalyst backbone, thus resulting in a high
degree of enantioselectivity. (See the Supplementary Information for details of the computational studies.).
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1708
ARTICLES
i
with CH2Cl2 (15 ml) and washed with 20 ml of a 10 wt% solution of aqueous citric
acid; the aqueous layer was washed with CH2Cl2 (2 × 15 ml) and the combined
organic layers were dried over anhydrous MgSO4. The solids were removed by
filtration and the solution was concentrated in vacuo to give yellow oil, which was
purified by silica gel chromatography to afford silyl ether 3 (1.72 g, 6.66 mmol, 96%
yield); gas chromatography (GC) analysis (Supelco Beta or Gamma Dex 120
column) indicated a 96.5:3.5 e.r. To recover (.98%) the chiral catalyst (1), the
aqueous layer was treated with an aqueous solution of 3.0 N NaOH until the pH
reached 12, and was then washed with three 15 ml portions of CH2Cl2. The
combined organic layers were dried over MgSO4, solids were removed by filtration
and the solution was concentrated in vacuo to afford 1 as white solid.
(for example, 1 or NMI), Pr2EtN cannot delocalize the positive
charge generated through protonation in a nonpolar medium and
is therefore an inferior base.
In the models in Fig. 3 one substrate hydroxyl group, rendered
more basic by the NMI moiety of 1, can deprotonate and enhance
the basicity of the chiral co-catalyst’s secondary amine, empowering
it, together with the Lewis basic amide carbonyl, to activate the adja-
cent carbinol for silylation. Density functional theory (DFT) calcu-
lations suggest that, alternatively, the secondary amine of the
catalyst, with assistance from the Lewis basic amide terminus,
might be the initial base that deprotonates the alcohol unit to be
silylated. The resulting ammonium group is then either neutralized
by an external molecule of the general base iPr2NEt or internally by
the neighbouring imidazole unit. The considerably lower activity
furnished by the carboxylic ester or thioamide derivatives of 1
(ref. 8) is partly because the less Lewis-basic carbonyl oxygens are
ineffective relative to an amide, which can establish a stabilizing
electrostatic interaction with the nearby alcohol proton (ion-
dipole stabilization (Fig. 3)). Such an association generates
2.4 kcal mol21 more transition-state stabilization than that of an
ester group (see the Supplementary Information for details). Thus,
overall, the significant improvement in efficiency of enantioselective
catalytic silylation is the culmination of substituted imidazole 1, the
Received 18 March 2013; accepted 13 June 2013;
published online 28 July 2013
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Procedure for enantioselective alcohol silylation with 5-ethylthiotetrazole as
co-catalyst. A mixture of cyclooctane diol 2 (1.00 g, 6.93 mmol), chiral catalyst
1 (107 mg, 0.347 mmol) and co-catalyst 5-ethylthiotetrazole 13 (45.2 mg,
0.347 mmol) was placed in a 25 ml round-bottom flask, to which
diisopropylethylamine (DIPEA) (1.5 ml, 8.67 mmol) was added. The contents were
dissolved in 5.5 ml tetrahydrofuran (THF), the flask was capped with a rubber
septum and the solution was allowed to cool to 240 8C (CryoCool apparatus). In a
separate vessel, TBSCl (2.09 g, 13.9 mmol) was dissolved in 4.8 ml THF (total
volume ꢀ10.3 ml) and the solution was allowed to cool to 240 8C, after which it was
added to the first mixture, which was allowed to stir for eight hours (at 240 8C). The
reaction was quenched by the addition of DIPEA (1.21 ml, 6.93 mmol) followed by
methanol (578 ml). The resulting mixture was allowed to warm to 22 8C, diluted
6
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© 2013 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1708
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Acknowledgements
This research was supported by the US National Institutes of Health, Institute of General
Medical Sciences (Grant GM-57212). We thank D. Silverio, V. Rendina and B. Potter for
many helpful discussions and experimental assistance and Boston College for providing
access to computational facilities.
Author contributions
N.M. and H.A. were involved in the development of the catalytic protocol. F.H. designed
and performed the theoretical studies. M.L.S. and A.H.H. directed the investigations.
A.H.H. wrote the manuscript with revisions provided by the other authors.
Additional information
Supplementary information is available in the online version of the paper. Reprints and
permissions information is available online at www.nature.com/reprints. Correspondence and
requests for materials should be addressed to A.H.H. and M.L.S.
30. Kennan, A. J. & Whitlock, H. W. Host-catalyzed isoxazole ring opening: a
rationally designed artificial enzyme. J. Am. Chem. Soc. 118, 3027–3028 (1996).
Competing financial interests
The authors declare no competing financial interests.
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