Catalyst recognition of cis-1,2-diols enables site-selective functionalization of complex molecules

Article abstract of DOI:10.1038/nchem.1726

Carbohydrates and natural products serve essential roles in nature, and also provide core scaffolds for pharmaceutical agents and vaccines. However, the inherent complexity of these molecules imposes significant synthetic hurdles for their selective functionalization and derivatization. Nature has, in part, addressed these issues by employing enzymes that are able to orient and activate substrates within a chiral pocket, which increases dramatically both the rate and selectivity of organic transformations. In this article we show that similar proximity effects can be utilized in the context of synthetic catalysts to achieve general and predictable site-selective functionalization of complex molecules. Unlike enzymes, our catalysts apply a single reversible covalent bond to recognize and bind to specific functional group displays within substrates. By combining this unique binding selectivity and asymmetric catalysis, we are able to modify the less reactive axial positions within monosaccharides and natural products.

Full text of DOI:10.1038/nchem.1726

ARTICLES
PUBLISHED ONLINE: 11 AUGUST 2013 | DOI: 10.1038/NCHEM.1726
Catalyst recognition of cis-1,2-diols enables site-
selective functionalization of complex molecules
Xixi Sun, Hyelee Lee, Sunggi Lee and Kian L. Tan
*
Carbohydrates and natural products serve essential roles in nature, and also provide core scaffolds for pharmaceutical
agents and vaccines. However, the inherent complexity of these molecules imposes significant synthetic hurdles for their
selective functionalization and derivatization. Nature has, in part, addressed these issues by employing enzymes that are
able to orient and activate substrates within a chiral pocket, which increases dramatically both the rate and selectivity of
organic transformations. In this article we show that similar proximity effects can be utilized in the context of synthetic
catalysts to achieve general and predictable site-selective functionalization of complex molecules. Unlike enzymes, our
catalysts apply a single reversible covalent bond to recognize and bind to specific functional group displays within
substrates. By combining this unique binding selectivity and asymmetric catalysis, we are able to modify the less reactive
axial positions within monosaccharides and natural products.
eveloping site-selective catalysts1 for the functionalization of For most monosaccharides, an axial hydroxyl group tends to be
naturally occurring compounds offers an efficient means of inert kinetically, so selective modification of these groups has
D
accessing novel therapeutics2 as well as expediting the syn- proved more elusive using catalyst-controlled methodologies32.
thesis of complex molecular probes. These molecules are often poly-
Examining past triumphs for site-selective reactions, whether
hydroxylated, which creates a significant synthetic challenge in enzymatic or synthetic, reveals that proximity effects33 are a power-
which the catalyst is required to differentiate between multiple ful and reliable means of accessing less reactive sites in a molecule.
similar functional groups. The most prominent examples of these For example, Howell and co-workers elucidated the structure of
molecules are carbohydrates, which mediate a diverse array of bio- a-1,2-mannosyltransferase Kre2p/Mnt1p, which catalyses the man-
logical processes, including the control of cell-to-cell communi- nosylation of the C2-hydroxyl of mannose; in the active site multiple
cation via cell-surface oligosaccharides3 and the facilitation of hydrogen bonding and van der Waals interactions are used to orient
protein folding in the endoplasmic reticulum4. Reflecting their mannose, which allows for selective functionalization of the axial
diverse function, saccharides are incorporated in proteins, lipids hydroxyl (Fig. 1b)34. In most cases, enzymes require multiple non-
and DNA, as well as in clinically relevant natural products5,6 such covalent interactions to achieve substrate recognition, which
as digoxin. Although significant progress has been made in oligosac- enables highly selective reactions, but this high specificity often
charide synthesis7–10, the polyhydroxylated nature of these biomole- comes at the expense of broad substrate scope. A complementary
cules requires elaborate protecting group strategies to ensure the approach is to design catalysts that recognize a specific functional
appropriate spatial and temporal control during molecular assem- group motif rather than the entire molecule. Such a catalyst would
bly. Beyond carbohydrates, numerous natural products contain allow for site selectivity within a complex molecule, but would be
multiple hydroxyl groups (Fig. 1a), and therefore suffer from broadly and predictably applicable to substrates that contain the tar-
similar challenges in their selective derivatization. A suite of cata- geted functional group display. In this article we report the appli-
lysts that have the ability to target selectively and predictably specific cation of catalysts that have the ability to recognize a selected
functional group displays (that is, site selectivity) would be a power- functional group motif within polyol frameworks (Fig. 1). In a criti-
ful approach for manipulating complex molecules without imple- cal advance this chiral catalyst is able to overturn the substrate’s
menting complex protecting group sequences.
inherent reactivity bias, which allows the functionalization of the
Early work by Breslow and co-workers11–13 demonstrated that axial positions within six-membered rings. Similar to enzymes,
steroids can be oxidized selectively using directing groups, and the control of site selectivity arises from proximity effects within a
more recent studies that used directing groups, reagents and cata- substrate-binding pocket (Fig. 1b,c). In contrast to an enzyme, the
lysts demonstrated the selective functionalization of a range of catalyst is not constrained to a single substrate but rather is appli-
natural products14–23. Over the past decade particular attention cable to a broad spectrum of biologically relevant molecules.
has been devoted to using synthetic catalysts to control selectivity Moreover, the high selectivity is achieved with a catalyst that is
in the modification and functionalization of carbohydrates24. The orders of magnitude smaller (molecular weight 307 g mol21) than
Kawabata25,26 and Miller27 groups demonstrated the catalyst-con- a typical enzyme.
trolled acylation of the C4 equatorial hydroxyl group of monosac-
charides. More recently, Taylor and co-workers demonstrated that Results and discussion
borinic ester catalysts effectively transfer a range of electrophiles As a first step towards developing this concept, our aim was to
to the equatorial position of a cis-1,2-diol within monosacchar- design a catalyst that selectively functionalized cis-1,2-diols, a preva-
ides28–31. Even with these successes, a major challenge in the area lent motif in biologically relevant molecules (Fig. 1a). We reported
of site-selective catalysis is the design and application of catalysts previously that scaffold 135,36 is an effective catalyst for the desym-
that can overturn the inherent kinetic preference of the substrate. metrization of cis-1,2-diols37 via silylation38–43. The catalyst binds
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA. e-mail: kian.tan.1@bc.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1726
ARTICLES
OH
a
O
N
O
O
HO
O
CO2H
( )8
NH
OH
H
O–
O
O
O
OH
OH
O
P
O
O
O
HO
HO
OH
Mupirocin (antibiotic)
O
H
OH
OH
O
O
O
OH
HO
O
O
O
O
H
O
Mannose
P
O
–O
OH
OH
OH
RNA
Digoxin (cardiac glycoside)
Covalent substrate
catalyst bond
b
Trp 325
c
OMe
His 323
OTBS
OMe
OH
GDP
N
O
OTBS
OH
O
OH
N
H
O
O
P
O
P
O
O
N
H
O
O
N
–O
–O
O
O
iPr
OMe
N
HO
OMe
O
H
N
OH
iPr
Mn2+
N
OH
R
–
O
HOMe
N
R
O
OH
H
N
Me
Selective activation
HO
H
+
Me
cis-1,2-diol
(–)-1 R = iPr
(–)-2 R = cyclopentyl
NH
Mannose
Glu 279
H2N
OMe
H
HO
E
OTBS
O
Arg 358
H
HO
OH
OE
Tyr 220
Figure 1 | The role of selectively modified polyols in naturally occurring compounds and approaches to their site-selective functionalization
a, Representative biologically relevant molecules that contain a cis-1,2-diol structural motif. b, Representation of the active site interactions between Kre2p/
Mnt1p a-1,2-mannosyltransferase and mannose. c, Proposed mode of substrate activation for scaffolding catalyst and methyl-a-L-mannose. E, electrophile.
to the substrate through a single reversible-formed covalent bond44–47
,
hydroxyl; moreover, a dramatic loss of activity was observed for
which minimizes the number of interactions needed for effective both catalysts (,10% yield, Table 1, entries 4 and 5). The inability
substrate localization and enables the desired proximity effects to achieve axial functionalization and the decreased catalyst
(Fig. 1c). The catalyst contains a catalytically active imidazole ring
that is connected to the substrate-binding site via a chiral organic
scaffold. We reasoned that, although the catalyst can bind to mul-
tiple sites within the substrate, it would only functionalize the site
with the appropriate geometric and proximity constraints.
Table1 | Functionalization of mannose derivative.
Catalyst, 2–4 h
3% DIPEA·HCl
1.2 equiv. E-Cl
OTBS
OTBS
OH
O
OR
O
4: R, R = H; R
5: R, R = H; R
6: R, R = H; R
a: TES
= b: Ac
c: Ms
4
4
HO
HO
RO
RO
We investigated the effectiveness of the scaffolding catalyst in the
context of a methyl-a-D-mannose derivative. Using N-methylimi-
dazole (NMI) as a control catalyst demonstrated that in silyl transfer
the C3 hydroxyl is approximately four times more reactive than the
C4 hydroxyl and about 15 times more reactive than the C2 hydroxyl
(Table 1, entry 1). Silyl transfer with catalyst (þ)-1 reversed the
selectivity so that the major product is the protected C2 axial
hydroxyl (C2-OH:C3-OH ¼ 90:10, Table 1, entry 2), allowing for
isolation of practical quantities of 4a (76% yield). At high conver-
sion (95%), a minimal amount of bis-silylation (9%) was observed
in the reaction, even though the more reactive C3 hydroxyl
remained available in the product. The suppression of a second sily-
lation event is attributed to the absence of a cis-1,2-diol in 4a, such
that the scaffolding catalyst cannot effectively activate the substrate
for an additional electrophile-transfer reaction. Switching to catalyst
(2)-2, a pseudo-enantiomer of (þ)-1, resulted in a highly site-selec-
tive reaction for silylation of the C3 hydroxyl (98% yield, Table 1,
entry 3). The excellent site selectivity is ascribed to the C3 hydroxyl
being both the inherently most reactive site as well as the stereoche-
mically preferred site for catalyst (2)-2 (that is, the matched case
between substrate and catalyst). Functionalizations of both the C3
and C2 hydroxyls were also carried out on a more synthetically
useful scale (4 mmol/1.2 g) to afford comparable selectivities and
yields for the desired products (Table 1, entries 2 and 3). To
probe the mechanism of catalysis, we performed two reactions
with control catalysts (þ)-1b and (2)-2b with substrate-binding
sites excised. Both catalysts prefer functionalization at the C3
1.2 equiv. DIPEA
t-amyl-OH or THF
–15 °C or 4 °C
2
3
2
3
3
OMe
OMe
O
N
O
O
O
OMe
OMe
N
N
iPr
iPr
N
N
N
N
iPr
N
N
iPr
iPr
iPr
N
N
N
c–pentyl
c–pentyl
Me
Me
Me
Me
(+)-1
(–)-2
( )-1b
+
(–)-2b
Entry
Electrophile (E)
Catalyst
C2:C3:C4*
Yield (%)†,‡
1
2
3
TESCl§
TESCl§
TESCl§
TESCl§
TESCl§
AcCl§
AcCl§
AcCl§
MsClꢀ
MsClꢀ
MsClꢀ
20% NMI
20% (þ)-1
5% (2)-2
20% (þ)-1b
20% (2)-2b
20% NMI
20% (þ)-1
5% (2)-2
20% NMI
20% (þ)-1
5% (2)-2
5:78:17
90:10:–
–:100:–
3:92:5
2:92:6
9:84:7
84:15:1
1:99:–
77
84 (76/74})
(.98/.98})
4
5
6
7
8
9
10
11
7
9
39
74
(96)
68
(80)
(97)
22:56:22
91:8:1
–:100:–
Detailed reaction conditions are given in the Supplementary Information. *‘-’ indicates the isomer
was not observed by the mode of detection used. †Isolated yield of the isomeric mixture. ‡Yields
in parentheses are of the isolated major isomer. §Selectivity determined by 1H NMR spectroscopy.
ꢀSelectivity determined by gas chromatography (GC). }Reactions performed on a 4 mmol scale
(1.2 g) of substrate, selectivity matched small-scale reaction. DIPEA, N,N-diisopropylethylamine;
TESCl, triethylsilyl chloride; AcCl, acetyl chloride, MsCl, methane sulfonyl chloride.
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1726
Table 2 | Site-selective functionalization of methyl-a-
ARTICLES
L-rhamnose and methyl-b-L-arabinose.
OMe
OMe
OH
OH
O
O
4
4
Me
HO
Me
HO
O
O
2
2
HO
RO
OH
OMe
3
2
2
3
3
3
4
4
OH
OR
OH
OR
OH
O
4
OR
Me
HO
OMe
OMe
O
12a–12c
13a–13c
8a–8c
9a–9c
HO
2
OR
OMe
2
3
3
4
OH
OH
OH
O
4
a: R = TES
b: R = Ac
c: R = Ms
a: R = TES
b: R = Ac
c: R = Ms
Me
RO
OMe
O
11
HO
7
2
2
3
3
4
OH
OH
OH
OMe
14a–14c
10a–10c
Entry
Electrophile
Catalyst
C2:C3:C4*
Yield (%)†,‡
Entry
Electrophile
Catalyst
C2:C3:C4*
Yield (%)†,‡
1
TESCl
TESCl
TESCl
AcCl
AcCl
AcCl
MsCl
MsCl
MsCl
20% NMI
7:79:14
89:11:–
–:100:–
12:79:9
84:14:2
1:99:–
24:57:19
92:8:–
1:99:–
78
88
(.98)
83
73
(98)
72
(82)
(.98)
10
11
TESCl
TESCl
TESCl
AcCl
AcCl
AcCl
MsCl
MsCl
MsCl
20% NMI
20% (2)-1
5% (þ)-1
20% NMI
20% (2)-1
5% (þ)-1
20% NMI
20% (2)-1
5% (þ)-1
27:14:59
–:3:97
–:98:2
22:72:6
5:9:86
3:96:1
68:23:9
3:10:87
1:92:7
39
2
20% (2)-2
5% (þ)-1
20% NMI
20% (2)-2
5% (þ)-1
20% NMI
20% (2)-2
5% (þ)-1
(92)
(97)
6
61
(83)
27
3§
4
12
13
14}
15
16
17
18
5
6
7ꢀ
8ꢀ
9ꢀ
93
(91)
.
The monosaccharides were functionalized with catalysts as listed, 3 mol% DIPEA HCl, 1.2 equiv. electrophile and 1.2 equiv. DIPEA, 4 h. Reactions were performed in tert-amyl-OH or THFat 4 8C. Detailed reaction
conditions are given in the Supplementary Information. *‘–’ indicates the isomer was not observed by the mode of detection used. Selectivities were determined by 1H NMR spectroscopy. †Isolated yields of the
isomeric mixture. ‡Yields in parentheses are of the isolated major isomer. §Reaction time 20 h. ꢀSelectivity determined by GC. }Reaction time 8 h.
performance are consistent with the hypothesis that reversible
covalent bonding is necessary for the observed catalysis.
The critical test of the functional group recognition strategy was
the application to other compounds that contain a cis-1,2-diol.
The scaffold-catalysed transfer of a triethylsilyl group enables the Rhamnose is a monosaccharide prevalent as a glycone in natural
selective protection of either the C2 or C3 hydroxyl groups within products. Control reactions with NMI and the three electrophiles
the mannose derivative through the appropriate choice of catalyst. revealed that all three hydroxyls of methyl-a-L-rhamnose are acces-
To expand further the utility of this method we investigated the trans- sible, with the C3 hydroxyl being the most reactive position
fer of both acetyl and mesyl groups. Acyl transfer offers both an (Table 2, entries 1, 4 and 7). Application of the scaffolding catalyst
orthogonal protecting group and a means of functionalizing monosac- collection to methyl-a-L-rhamnose allowed for modification of
charides, whereas a sulfonylating reagent can serve to activate the both hydroxyls of cis-1,2-diol with all three electrophiles
hydroxyl, which provides an avenue for further chemical manipu- (Table 2, entries 1–9). As expected, catalyst (2)-2 provided 5:1 to
lation. Catalysts (þ)-1 and (2)-2 were effective in performing both 11:1 selectivity, depending on the electrophile for the C2 axial
acyl and sulfonyl transfer to the C2 and C3 hydroxyls, respectively. hydroxyl, which demonstrates that inherent substrate bias can be
For catalyst (2)-2, the acyl- and sulfonylated products were formed overturned via catalyst control (Table 2, entries 2, 5 and 8).
exclusively at the C3 hydroxyl, consistent with a matched relationship Catalyst (þ)-1 favours functionalization of the C3 hydroxyl in
between the substrate and catalyst (Table 1, entries 8 and 11). excellent yields (.97%) for the three electrophiles (Table 2,
Switching to catalyst (þ)-1, the site selectivity in acylation altered entries 3, 6 and 9); in these cases the other constitutional
to favour the axial position (C2-OH:C3-OH:C4-OH ¼ 84:15:1, isomers were observed in trace quantities in the crude reaction
Table 1, entry 7). Similarly mesylation occurred at the C2 hydroxyl mixture. Similarly, catalysts (þ)-1 and (2)-1 were applied to the
with 91:8:1 selectivity (C2-OH:C3-OH:C4-OH, Table 1, entry 10) functionalization of methyl-b-L-arabinose, which allowed for
and in an isolated yield of 80% of 4c.
toggling of the functionalization between both the C3 and C4
Table 3 | Site-selective functionalization of galactose derivative and 1,6-anhydro-b-D-galactose.
OTBS
OTBS
O
O
OH
OH
HO
O
RO
O
O
O
4
4
2
2
OTBS
O
HO
RO
HO
HO
OH
O
3
3
2
2
4
4
3
3
HO
O
OR
OH
4
OR
OH
OMe
OMe
16a–16c
17a–17c
20a–20c
21a–21c
HO
2
HO
OTBS
O
OR
O
3
2
3
4
HO
OH
4
a: R = TES
b: R = Ac
c: R = Ms
a: R = TES
b: R = Ac
c: R = Ms
OH
OMe
O
3
15
19
HO
RO
2
2
3
4
OH
OH
OMe
22a–22c
18a–18c
Entry
Electrophile
Catalyst
C2:C3:C4*
Yield(%)†,‡
Entry
Electrophile
Catalyst
C2:C3:C4*
Yield(%)†,‡
1
TESCl
TESCl
AcCl
AcCl
MsCl
MsCl
20% NMI
86:14:–
6:94:–
42:58:–
19:81:–
76:24:–
–:100:–
77
95
26
96
62
7
8
9
10
11
12
TESCl
TESCl
AcCl
AcCl
MsCl
MsCl
20% NMI
5% (2)-2
20% NMI
5% (2)-2
20% NMI
5% (2)-2
91:–:9
1:–:99
75:8:17
–:3:97
75:6:19
–:1:99
51
(98)
53
(93)
50
(88)
2
3
4
5
6
20% (þ)-1
20% NMI
20% (þ)-1
20% NMI
20% (þ)-1
(74)
.
The monosaccharides were functionalized with catalysts as listed, 3 mol% DIPEA HCl, 1.2 equiv. electrophile, and 1.2 equiv. DIPEA, 4 h. Reactions were performed in tert-amyl-OH or THF at 215 8C or 4 8C.
Detailed reaction conditions are given in the Supplementary Information. *‘–’ indicates the isomer was not observed by the mode of detection used. Selectivities were determined by 1H NMR spectroscopy.
†Isolated yields of the isomeric mixture. ‡Yields in parentheses are of the isolated major isomer.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1726
ARTICLES
5% catalyst,
3% DIPEA·HCl
1.2 equiv. TES-Cl
the result implies that the scaffolding catalyst can bind to an equa-
torial position and then functionalize the axial hydroxyl (see
Supplementary Fig. S1a). The result does not preclude the possi-
bility that sugars able to undergo chair flipping (for example,
methyl-a-D-mannose) react through a minor conformer in which
the scaffolding catalyst binds to the axial position and functionalizes
the equatorial position followed by interconversion back to the most
stable conformer (see Supplementary Fig. S1b).
To test further the capabilities of the scaffolding catalysts, we
investigated the functionalization of other biologically and thera-
peutically important compounds that contain cis-1,2-diols. We
tested the site-selective functionalization of the monosaccharide
Helicid, which contains a cis,cis-1,2,3-triol. In this case (2)-2 and
(þ)-2 afford silylation of the C2 and C4 hydroxyls, respectively
(Fig. 2). These results suggest that, potentially, the scaffolding cata-
lysts can be applied to the derivatization of other cis,cis-1,2,3-triols,
such as myo-inositol. Suitably protected ribonucleoside monomers
are required for the automated synthesis of RNA. It is common to
use monomers with the 2′-hydroxyl protected with a tert-butyldi-
OTBS
OTBS
4
4
O
O
2
HO
RO
O
O
1.2 equiv. DIPEA
THF, 4 °C
2
3
3
OH
OR
OH
OR
CHO
CHO
23
24: R = TES, R, R = H
25: R = TES, R, R = H
26: R = TES, R, R = H
Catalyst:
NMI = 24:25:26 = 65:3:32; 29%
(–)-2 = 24:25:26 = 95:5:–; 90% 24
(+)-2 = 24:25:26 = 10:13:77; 63% 26
Figure 2 | The site-selective modification of both the C2 and C4 hydroxyls
of Helicid. Achiral catalyst NMI leads to an approximately 2:1 mixture of
both C2- and C4-protected products. In contrast, use of catalyst (2)-2 gives
almost entirely the C2-protected product with no detectable C4 protection.
Switching to catalyst (þ)-2 leads to selective protection of the C4 hydroxyl
with an approximately 8:1:1 ratio of products.
hydroxyls of the cis-1,2-diol and for minimizing the reaction at the methylsilyl group (TBS) and the 5′-hydroxyl with a dimethoxytrityl
C2 hydroxyl (Table 2, entries 10–18).
group (DMTr), but leave the C3′-hydroxyl available for coupling.
The substrate scope was expanded further to the derivatization of Direct silylation of DMTr-protected ribonucleosides leads to a
galactose, in which the C2 equatorial hydroxyl is generally the most mixture of silylated products at the C3′- and C2′-hydroxyls; there-
reactive site. Catalyst (þ)-1 provided access to functionalization of fore, multistep protecting group sequences are often used to
the C3 hydroxyl with all three electrophiles (Table 3, entries 2, 4 obtain the desired monomers48. Using scaffold catalyst (2)-2, a
and 6); however, attempts to functionalize the axial C4 hydroxyl TBS group was transferred efficiently to the C2′-OH of uridine
were unsuccessful. In the control reaction with the galactose deriva- with minimal amounts of C3′-OH protection (93% yield,
tive no axially silylated product was observed, which suggests that C2′-OH:C3′-OH ¼ .98: , 2, Fig. 3a). Digoxin, a natural product
this position is inherently at least 100-fold less reactive than in the produced by Digitalis lanta, is a cardiac glycoside used in the treat-
other hydroxyls. Although scaffolding catalyst (2)-2 is unable to ment of congestive heart failure49. Starting from commercially avail-
overturn this large substrate bias, simply employing 1,6-anhydro- able digoxin, which contains six free hydroxyls, we attempted to
1
b-D-galactose, in which the substrate is constrained into the C4 synthesize both a- and b-acetyl digoxin (also therapeutics for con-
chair, enables the functionalization of the C4 hydroxyl (Table 3, gestive heart failure) without the use of protecting groups. Applying
entries 8, 10 and 12). In the case of 1,6-anhydro-b-D-galactose, catalyst (þ)-2 resulted in the formation of b-acetyl digoxin in
use of catalyst (þ)-2 afforded mesylation of the axial C3-OH as 90% yield as a single isomer (Fig. 3b). Switching to catalyst (2)-1
the major product (see Supplementary Information for details). allowed the functionalization of the less reactive axial hydroxyl,
As 1,6-anhydro-b-D-galactose is unable to undergo a chair flip, yielding a-acetyl digoxin in 56% yield (a:b ¼ 91:9, Fig. 3b). We
O
OMs
a
c
O
20% (–)-2
3% DIPEA·HCl
HO
6
NH
NH
7
10% (−)-2
3% DIPEA·HCl
DMTrO
O
MsCl, DIPEA
–15 °C, 20 h
THF
DMTrO
N
O
N
O
O
O
OH
6
33
TBSCl, DIPEA
r.t., THF, 24 h
27
28
82% yield of 33
33:34 = >98:<2
2'
OH OH
HO
O
CO2Me
3'
( )8
OH OTBS
7
O
O
O
OH
2':3'
>98:<2
93% yield
20% (+)-1
3% DIPEA·HCl
MsO
OH
Mupirocin methyl ester (32)
6
7
MsCl, DIPEA
−15 °C,20 h
THF
O
34
57% yield of 34
33:34 = 18:82
30% (+)-2
3% DIPEA·HCl
Me
b
O
O
O
AcO
O
90% yield
α: β = <2:>98
AcCl, DIPEA
16 h, THF, 4°C
OH
H
OH
β-acetyldigoxin (30)
Me
O
30% (–)-1
3% DIPEA·HCl
H
OH
HO
O
O
O
O
56% yield
α: β = 91:9
O
HO
O
O
AcCl, DIPEA
16 h, THF, 4°C
H
OAc
α-acetyldigoxin (31)
OH
Digoxin (29)
OH
OH
Figure 3 | Expansion of scaffolding-catalysed electrophile transfer beyond monosaccharides. a, Silyl protection of the C2′-OH of uridine, an efficient
synthesis of an appropriately protected uridine for automated RNA synthesis. b, Site-selective acylation of digoxin towards a synthesis of a- and b-acetyl
digoxin devoid of protecting groups. c, Site-selective mesylation of mupirocin methyl ester, a means of derivatizing antibiotics. r.t., room temperature.
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1726
ARTICLES
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further applied our scaffolding catalysts to the activation of the C6-
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targets transfer RNA synthetase51. Scaffolding catalysts (2)-2 and
(þ)-1 provide access to both mesylated hydroxyls of the cis-1,2-
diol (Fig. 3c). In particular, the axial C7 hydroxyl was mesylated
with a site selectivity of 18:82 (33:34) with an isomerically pure iso-
lated yield of 57%.
Conclusion
In this article we demonstrate that chiral catalysts that use reversible
covalent bonding to the substrate are able to functionalize selectively
multiple sites within complex molecules, including sites that are
naturally kinetically less reactive. Similar to enzymes, this is
achieved by properly leveraging proximity effects within a chiral
binding pocket. In the future, we envision (through the appropriate
choice of the scaffold) that the catalytic residue could be reoriented
to activate other sites within polyfunctional molecules. Moreover,
the catalysts could be reappropriated to perform transformations
beyond electrophile transfer simply through the judicious choice
of the catalytic residue. A library of these catalysts, in which each
catalyst targets a specific functional group array, would allow for
the general reengineering of complex molecular architectures
devoid of using sophisticated protecting group strategies.
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Methods
In a dry box, a solution of 3 (62 mg, 0.20 mmol), catalyst (þ)-1 (11 mg, 0.040 mmol,
20 mol%) and N,N-diisopropylethylamine hydrochloride (1.0 mg, 0.0060 mmol,
3 mol%) in anhydrous tert-amyl alcohol (1.0 ml, distilled over CaH2 before use) was
prepared in a glass reaction vial (4 ml, oven dried). The solution was brought out of
the dry box, and N,N-diisopropylethylamine (42 ml, 0.24 mmol, 1.2 equiv., distilled
over CaH2 before use) was added to the stirring reaction at room temperature. The
reaction was stirred at 4 8C for ten minutes, followed by dropwise addition of
chlorotriethylsilane (40 ml, 0.24 mmol, 1.2 equiv., distilled over CaH2 before use).
The reaction was stirred at 4 8C for two hours. MeOH (50 ml, reagent grade) was
added to quench the reaction. The mixture was filtered through a Pasteur pipette
packed with silica gel, followed by flush with EtOAc (15 ml, reagent grade). The
solvent was removed under reduced pressure. Column chromatography
(hexane/EtOAc ¼ 20/1 to 1/1) afforded the bisfunctionalized products (10 mg, 9%),
substrate 3 (3 mg, 5%) and a mixture of monofunctionalized products (71 mg, 84%).
1H NMR spectroscopy of the mixture afforded the selectivity (C2:C3:C4 ¼ 90:10:–).
A second column chromatography (hexane/EtOAc ¼ 20:1 to 5:1) was performed to
isolate the pure product 4a (64 mg, 76%).
Received 28 March 2013; accepted 3 July 2013;
published online 11 August 2013
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© 2013 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1726
Acknowledgements
This research was supported by the National Institutes of Health (RO1-GM087581),
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Author contributions
K.L.T. and X.S. were involved in the design and discovery of the catalysts; X.S. was
responsible for the data obtained with methyl-a-D-mannose, arabinose, galactose and
digoxin; H.L. was responsible for the data obtained with methyl-a-L-rhamnose and
mupirocin; S.L. was responsible for the data obtained with uridine; K.L.T. conceived and
directed the investigation and wrote the manuscript.
Additional information
Supplementary information and chemical compound information are 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 K.L.T.
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Competing financial interests
The authors declare no competing financial interests.
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