Matching Glycosyl Donor Reactivity to Sulfonate Leaving Group Ability Permits SN2 Glycosylations

Article abstract of DOI:10.1021/jacs.9b07022

Here we demonstrate that highly β-selective glycosylation reactions can be achieved when the electronics of a sulfonyl chloride activator and the reactivity of a glycosyl donor hemiacetal are matched. While these reactions are compatible with the acid- and base-sensitive protecting groups that are commonly used in oligosaccharide synthesis, these protecting groups are not relied upon to control selectivity. Instead, β-selectivity arises from the stereoinversion of an α-glycosyl arylsulfonate in an S_N2-like mechanism. Our mechanistic proposal is supported by NMR studies, kinetic isotope effect (KIE) measurements, and DFT calculations.

Full text of DOI:10.1021/jacs.9b07022

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Article
Matching Glycosyl Donor Reactivity to Sulfonate
Leaving Group Ability Permits SN2 Glycosylations
Ming-Hua Zhuo, David J Wilbur, Eugene E Kwan, and Clay S Bennett
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07022 • Publication Date (Web): 24 Sep 2019
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Matching Glycosyl Donor Reactivity to Sulfonate Leaving Group
Ability Permits SN2 Glycosylations
Ming-Hua Zhuo,† David J. Wilbur,† Eugene E. Kwan,*,‡ and Clay S. Bennett*,†
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†Department of Chemistry, Tufts University, 62 Talbot Avenue, Medford, Massachusetts 02155, United States
‡Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
ABSTRACT: Here we demonstrate that highly β-selective glycosylation reactions can be achieved when the electronics of a sul-
fonyl chloride activator and the reactivity of a glycosyl donor hemiacetal are matched. While these reactions are compatible with
the acid- and base-sensitive protecting groups that are commonly used in oligosaccharide synthesis, these protecting groups are not
relied upon to control selectivity. Instead, β-selectivity arises from the stereoinversion of an α-glycosyl arylsulfonate in an SN2-like
mechanism. Our mechanistic proposal is supported by NMR studies, kinetic isotope effect (KIE) measurements, and DFT calcula-
tions.
tion would be entirely determined by the stereochemical puri-
ty of the starting material. Since SN2 reactions generally re-
Introduction
quire good leaving groups, and electronegative substituents
strongly favor one stereoisomer through the anomeric effect,
obtaining purely α-configured starting materials is often
straightforward. Thus, glycosylation reactions proceeding via
an SN2 mechanism would have the potential to reduce or even
eliminate the reliance on protecting groups for controlling
selectivity.
Oligosaccharides carry out critical functions in a vast ar-
ray of biochemical processes.1 However, our understanding
of the molecular basis of carbohydrate function remains con-
strained by the challenges associated with synthesizing stere-
ochemically pure glycosides for study. In general, the diffi-
culty of controlling glycoside stereochemistry arises from the
existence of glycosylation reactions at the border between the
SN1 and SN2 mechanisms.2 Which mechanism dominates,
and consequently, what product distribution is observed, de-
pends on complex interactions between donor, acceptor, pro-
tecting groups, and reagents.3 While many useful methods
successfully leverage these interactions to generate certain
glycosidic linkages in a stereoselective manner,4−25 a general
solution for the construction of broad classes of linkages has
yet to emerge.26 Here, we show that by matching the electron-
ics of the leaving group to the reactivity of the glycosyl donor
it is possible to obtain SN2-type glycosylation, that afford
products with high β-selectivity for a range of acceptors.
A
OP
OP
O
PO
PO
ROH
SN
O
PO
PO
OR
2
PO
X
PO
β-product
LA
OP
OP
O
LA
ROH
SN
PO
PO
O
PO
PO
1
PO
X
X
PO
LA
OP
O
OP
ROH
SN
O
PO
PO
PO
PO
Glycosylation reactions reside at the SN1−SN2 boundary
because they involve nucleophilic attack on a secondary elec-
trophile with an adjacent oxygen atom that can stabilize adja-
cent positive charge. In many traditional approaches to gly-
cosylation, positive charge at C1 is generated by using a
Lewis acid to promote leaving group heterolysis (Figure 1A).
Although this strategy activates the donor towards nucleo-
philic attack, the resulting ion pair is also stereochemically
labile. As a result, controlling stereoselectivity typically re-
quires the use of specialized protecting groups to bias the
approach of the nucleophile to one face of the electrophile.
While the protecting group scheme can be tailored to synthe-
size either α- or β-glycosidic linkages, this solution greatly
reduces the efficiency of oligosaccharide synthesis.
X
LA
2
PO
PO
OR
α-product
B
OP
O
OP
OP
O
ArSO2Cl
Base
RO
SN
O
PO
PO
PO
PO
PO
PO
OR
2
PO
PO
PO
β-product
OH
OSO2Ar
Figure 1. A. Classical approaches to Lewis acid-mediated
glycosylation. B. This work. LA = Lewis acid.
To obtain a stereoinvertive process, we examined condi-
tions that are classically known to favor the SN2 mechanism:
a donor with an excellent leaving group, an alkoxide as a
strong nucleophile, and a polar aprotic solvent. We chose to
use sulfonate as the leaving group based on our previous ob-
servation that 2-deoxy-pyranose α-tosylates react with accep-
tor alkoxides to afford β-glycosides with excellent selectivi-
ty.27−29 However, we anticipated that extending this strategy
to conventional C2-substituted pyranoses might be challeng-
ing because C2-substituted sugars are more than 500 times
However, if the glycosyl donor could be activated to-
wards nucleophilic attack without the generation of a signifi-
cant amount of positive charge, then a classical SN2 process
might be possible in which displacement is purely stereoin-
vertive (Figure 1B). In such a scenario, the product distribu-
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less reactive than their 2-deoxy counterparts.30 As a result,
Page 2 of 12
fonates bearing electron-withdrawing substituents led to re-
1
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under conditions that are sufficiently activating to render the
SN2 pathway feasible, undesirable SN1 reactivity might be-
come competitive. Indeed, when glycosyl sulfonates have
previously been generated for use as donors,31−43 specialized
protecting groups were required to control selectivity. For
example, Schuerch demonstrated that a C2 sulfonate protect-
ing group was necessary to stabilize α-mannosyl trifluoro-
ethylsulfonates and tosylates for β-mannosylation and rham-
nosylation.36,38 More recently, Crich and co-workers demon-
strated the importance of the 4,6-O-benzylidene acetal in
stabilizing covalent α-triflates in their β-mannosylation reac-
tion.44−48
duced yields (4g−h), 3,5-bis(trifluoromethyl)benzenesulfonyl
chloride (4i) emerged as an effective promoter (entry 9).
Table 1. Effect of Sulfonylating Agenta
i. TTBP, KN(SiMe3)2, THF, -15 o
C
OBn
O
OBn
O
ii. sulfonylating agents 4a-k, THF
BnO
BnO
O
BnO
BnO
iii. KN(SiMe3)2, THF
OH
O
BnOBnO
BnO
OH
BnO
BnO
O
OMe
BnO
BnO
1
3
BnO
OMe
9
2
sulfonylating agents
4a, R = 4-Me
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4b, R = H
O
O
O
O
O
O
4c, R = 4-OMe
4d, R = 2, 4, 6-Me
4e, R = 2, 4, 6-iPr
4f, R = 2, 3, 4, 5, 6-Me
4g, R = 4-Br
2
5
To balance the benefit of activation against the risk of
creating stereochemical lability, we reasoned we could take
advantage of the tunability of arylsufonates as leaving
groups.49−51 For example, relatively unreactive donors might
be expected to require more electron-poor, and presumably
more activated, arylsulfonates. Conversely, for relatively
reactive donors, electron-rich arylsulfonates that would be
less prone to anomerization could be used. Indeed, as we
show below, there is an inverse relationship between the in-
trinsic reactivity of the donor (as measured by Wong’s rela-
tive reactivity values52,53) and the electronics of the optimal
arylsulfonate for each glycosylation.
S
S
S
3
4
Cl
Cl
Cl
6
N
N
R
4h, R = 4-NO2
4j
4a-i
4k
4i, R = 3, 5-CF3
entry
yield (%)b
β/α ratioc
sulfonylating
agent
4a
4b
4c
4d
4e
4f
27
29
29
36
27
36
29
18
46
15
17
β only
β only
β only
β only
β only
β only
β only
β only
β only
β only
β only
1
2
3
4
Furthermore, we reasoned that we could lessen the need
for strong electrophilic activation of the donor by using an
alkoxide as the nucleophilic acceptor.54 This prediction is
consistent with previous work by the Taylor,11 Kahne,55 Yo-
shida,56 and Walczak19 groups, which demonstrated that acti-
vating the acceptor through either borinic acid catalysis or in
situ generation of a tin ether can effect selective reactions
with glycosyl sulfonate donors.
5
6
4g
4h
4i
7
8
9
4j
10
11
An additional advantage of our strategy is that it elimi-
nates the need to synthesize and isolate potentially unstable
species such as glycosyl halides or imidates. By generating
the reactive donor in situ, through activation of the donor
hemiacetal as a glycosyl sulfonate, the electrophilic donor
sulfonate can react directly with the nucleophilic acceptor
alkoxide. As we demonstrate below, this strategy makes it
possible to engage C2 substituted sugars in SN2-like dis-
placements, thus accessing valuable β-glycoside products
(Figure 1B). Our mechanistic analysis confirms that the ma-
jor products obtained in these glycosylation reactions are the
result of a stereoinvertive and concerted reaction pathway.
4k
a0.20 mmol of glucosyl donor 1, 0.13 mmol of acceptor 2,
0.20 mmol of TTBP, 0.20 mmol of sulfonylating agent, THF
as the solvent, 2 hrs of activation time. Glycosylation [1] =
0.050M. Isolated yield. All selectivities based on H NMR
analysis of purified material (see SI). TTBP = 2,4,6-tri-tert-
butylpyrimidine.
b
c
1
Further improvements were gained by varying the coun-
terion, additives, and reaction conditions (Table 2). We
found that sodium, rather than lithium or potassium, was the
most effective alkoxide counterion (entries 1−3). Although
adding the acid scavenger 2,4,6-tri-tert-butylpyrimidine
(TTBP) was beneficial when the counterion was potassium, it
was deleterious when the counterion was sodium (entry 1 vs.
entries 3 and 4). Furthermore, increasing the donor to accep-
tor ratio from 1.5:1 to 2:1 and decreasing temperature to –30
°C led to the formation of the desired product 3 in 96% yield
as a single β-isomer (entry 5). Under these optimized condi-
tions, nosylate 4h was also found to be a competent promoter,
affording the desired product in slightly diminished yield
(85%, entry 6).
Results and Discussion
Our initial optimization efforts focused on selecting the
optimal sulfonate leaving group and reaction conditions for
the glycosylation between glucosyl donor 1 and acceptor 2
(Table 1). As expected, donor 1 was less reactive than its 2-
deoxy-sugar analogs towards nucleophilic displacement by
glucosyl acceptor 2. For example, the use of tosyl (4a) or
benzenesulfonyl (4b) chloride as the promoter required an
elevated reaction temperature of –15 °C (vs. –78 °C for 2-
deoxy-sugars).27,28 Although these conditions led to the for-
mation of product 3 as a single β-anomer, low yields were
observed (entries 1 and 2). Reasoning that the poor efficiency
was due to decomposition of the putative α-sulfonate inter-
mediate,57 we examined arenesulfonates bearing electron-
donating substituents (4c−f, j−k). Once again, β-isomers
were exclusively obtained, but with only somewhat improved
yields (entries 3−6). Interestingly, although many arenesul-
We next examined the scope of the reaction promoted by
both 4h and 4i (Table 3). Although both reagents promoted
reactions with acetonide-protected acceptor 11, 4h provided
the desired product with higher β-selectivity (entry 2). The
reaction also tolerated a variety of common protecting groups,
including 2-naphthylmethyl (Nap), benzoate (Bz), acetate
(Ac), and triisopropylsilyl (TIPS) ether (entries 3−7). How-
ever, the position of the benzoate ester protecting group did
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impact the observed yield. For example, C4-benzoates gave
tors, we observed a greater dependence on selectivity on the
identity of the promoter. For example, in the presence of 4i,
the hindered secondary acceptor 12 reacted with 29 to afford
33 in high yield and modest selectivity. By switching to
nosylate 4h as the promoter, however, we were able to obtain
33 in good yield and selectivity (73% yield, 11:1 β:α). As
with the corresponding glucosyl donor, acceptor 16 reacted
with galactosyl donor 29 to afford product 34, albeit with
attenuated selectivity. The β-selective glycosylation of 4,6-
O-benzylidene-protected galactopyranosyl donor 30 is note-
worthy because this system is intrinsically biased towards α-
products. For example, the triflate of 30 reacts with nucleo-
philes to afford products in moderate to high levels of α-
selectivity.44,45 In contrast, under the current conditions, the
β-anomer was the major product.
1
2
3
4
5
6
7
8
consistently higher yields than C3-benzoates (entries 4 vs. 5),
with this effect being more pronounced with 4h than 4i.
Nonetheless, promoter 4i was still able to activate the C3-
benzoate 7 for glycosylation to give a synthetically useful
yield.
Table 2. Optimization of Glycosylation Conditionsa
O
O
S
i. TTBP, base, THF, -15 o
C
Cl
9
OBn
O
OBn
O
ii. 4h or 4i, THF
O2
N
BnO
BnO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
4h
BnO
BnO
O
BnOBnO
BnO
iii. base, THF
OH
O
O
OH
BnO
BnO
F3C
S
OMe
Cl
O
BnO
1
3
BnO
BnO
OMe
CF3
4i
2
Reasoning that a better mechanistic understanding of the
reaction would help guide us in improving the yields of unse-
lective reactions, we turned to VT-NMR spectroscopy. Upon
activating the glucosyl hemiacetal 1 with 4i in THF-d8 under
conditions that were otherwise identical to those employed in
the synthetic reaction (SI section 4.2), we observed a single
anomeric doublet corresponding to the α-sulfonate (1H NMR
6.28 ppm, J = 3.3 Hz; 13C NMR 100.3 ppm).38,58 Similarly,
the analogous reaction using 4h afforded a single α-linked
glycosyl sulfonate (1H NMR 6.18 ppm (s); 13C NMR 100.0
ppm). This selectivity is not surprising, given the established
tendency of anomeric alkoxides to react with electrophiles at
low temperature to form α-anomers,59 and the propensity for
glycosyl sulfonates to adopt an α-configuration.34,36
sulfonylat-
ing agent
entry base
yield
(%)b
β/α
ratioc
KN(SiMe3)2
4i
4i
4i
4i
4i
4h
46
NR
69
81
96
85
β only
NR
1
LiN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
2
β only
β only
β only
β only
3
4d
5d,e
6d,e
a0.20 mmol of glucosyl donor 1, 0.13 mmol of acceptor
2, 0.20 mmol of TTBP, 0.20 mmol of sulfonylating
agent, THF as the solvent, 2 hrs of activation time. Gly-
coslyation was run at −15 oC. Glycosylation [1] =
0.050M. bThe yield and selectivity was determined by
While the nosylate derived from 4h is stable to room
temperature, the sulfonate obtained from with the reaction
°
with 4i decomposes above 0 C (SI section 4.2). This rela-
c
isolated yield.. All selectivities based on 1H NMR analysis
tive stability fits with the observation that 4h provides higher
selectivity than 4i in reactions with hindered acceptors (e.g.,
Table 3, entry 12). This led us to consider that it should be
possible to improve less selective reactions, such as the one
between galactose donor 29 and acceptor 16 through the use
of a less reactive sulfonate. Indeed, the selectivity of this
reaction could be improved to 11:1 β:α using the 4-
bromobenzenesulfonyl chloride promoter 4g (Table 4, entry
4).
of purified material (see SI). dWithout adding TTBP.
e0.20 mmol of 1, 0.1 mmol of acceptor 2, glycosylation
[1] = 0.059M. Glycoslyation was run at −30 oC. TTBP =
2,4,6-tri-tert-butylpyrimidine. NR = No Reaction.
Glycosylation of the hindered secondary glycosyl accep-
tors 12−15 also proved to be feasible, and the corresponding
disaccharides 23−26 were isolated in 42−63% yields. The
selectivities ranged from 10:1 β:α to exclusively β regardless
of whether 4h or 4i was used as the promoter (Table 3, en-
tries 8−11). In contrast, reactions with less nucleophilic ac-
ceptors were more sensitive to the electronics of the sulfonyl
chloride. For example, the union of hindered acceptor 16
with donor 1 to afford disaccharide 27 gave a much higher
selectivity with 4i than 4h (entry 12). This latter result
demonstrates the importance of having ready access to a col-
lection of promoters. In addition, lactosyl donor 10 was
also a competent donor in the reaction and behaved similarly
to the glucosyl donors (entry 13).
To examine further the relationship between the electron-
ics of the sulfonyl promoter and the stereoselectivity of gly-
cosylation, we examined fucose donor 36 in detail. Because
this donor is approximately 27 times more reactive than glu-
cose,52,53 it provides an opportunity to study a system in
which the corresponding sulfonates are relatively unstable.
As before, when donor 36 was reacted with primary acceptor
2, we obtained the product as a single β-isomer, regardless of
which sulfonate was used. Interestingly, higher yields were
obtained with less reactive sulfonates (Table 5, entries 1−3).
However, when the more hindered acceptor 12 was used,
only modest levels of selectivity were observed with 4g−4i.
To improve this yield, we next examined the relatively elec-
tron-rich promoter 4m (Hammett σp = 0.06). As predicted,
the use of this promoter improved the selectivity of the reac-
tion (11:1 β:α), further demonstrating the impact of sulfonate
electronics on the stereochemical outcome of the reaction.
We next examined galactosyl donors, which are approxi-
mately 6 times more reactive than their glucosyl counterparts
(Table 4).52,53 With both promoters 4h and 4i, the primary
acceptor 2 reacted smoothly with 29 to afford disaccharide 31
in good yields and stereoselectivities. Acceptor 11, which
bears acetonides, afforded product 32 in good to high yields
and excellent stereoselectivities. Again, with hindered accep-
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1
2
3
4
5
Table 3. Scope of the reaction between glucosyl donor and acceptors to afford β-linked saccharidesa
OP
OP
i. NaN(SiMe3)2, temp, THF
O
ii. ArSO2Cl, temp, THF
O
O
O
PO
PO
PO
iii. NaN(SiMe3)2 or KN(SiMe3)2
OH
O
HO
6
PO
7
8
9
β:α ratio
β:α ratio
yield
yield
O
O
O
O
CF3
S
S
Cl
Cl
entry
acceptor
β-linked disaccharides
donor
O2
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CF3
4i
4h
OBn
OBn
O
ONa
O
O
BnO
BnO
BnO
BnO
BnO
O
BnO
1
85%, β only
96%, β only
BnO
O
BnO
BnO OH
BnO
OMe
BnO
1
2
BnO
3
OMe
OBn
O
ONa
O
OBn
O
O
BnO
BnO
BnO
BnO
O
O
O
O
2
BnO
OH
71%, 17:1b
92%, 10:1b
O
BnO
O
O
O
O
17
1
11
OBn
O
OBn
O
ONa
O
NapO
BnO
O
NapO
BnO
BnO
BnO
3
4
5
6
7
O
54%, β only
82%, β only
33%, β only
72%, β only
52%, β only
69%, β only
90%, β only
65%, β only
83%, β only
57%, β only
BnO
BnO
BnO
OH
BnO
BnO
OMe
BnO
OMe
18
2
5
OBn
O
ONa
O
OBn
O
BzO
BnO
BzO
BnO
BnO
BnO
O
BnO
O
BnO
BnO OH
BnO
OMe
BnO
19
BnO
6
2
OMe
OBn
O
OBn
O
ONa
BnO
BzO
O
O
BnO
BzO
BnO
BnO
O
BnO
BnO
BnO OH
BnO
OMe
BnO
20
BnO
OMe
2
7
OBn
O
OBn
O
ONa
O
AcO
BnO
AcO
BnO
O
BnO
BnO
O
BnO
BnO
BnO
BnO OH
BnO
OMe
BnO
8
2
21
OMe
OBn
O
OBn
O
ONa
TIPSO
BnO
O
O
TIPSO
BnO
BnO
BnO
O
BnO
BnO
BnO
OH
BnO
BnO
2
OMe
BnO
OMe
22
9
Ph
OBn
O
OBn
O
Ph
O
O
O
O
O
O
BnO
BnO
BnO
BnO
KO
8
9
O
60%, 14:1b
55%, 11:1b
48%, 12:1b,d
58%, 14:1b,c
63%, 10:1b
54%, 12:1b,c
BnO
BnO OH
OMe
BnO
23
BnO
OMe
12
1
OBn
O
Ph
OBn
Ph
O
O
O
O
OMe
BnO
BnO
O
O
KO
O
BnO
BnO
BnO
BnO OH
O
BnO
13
OMe
BnO
24
1
OBn
O
OBn
O
OBn
O
BnO
O
BnO
BnO
BnO
BnO
OBn
O
BnO
KO
10
BnO OH
BnO
BnO
OMe
BnO
OMe
25
14
1
Ph
O
O
OBn
O
Ph
O
BnO
OBn
O
BnO
BnO
O
BnO
O
45%, β onlyb,d 42%, β onlyb,d
11
BnO OH
NaO
OMe
O
BnO
BnO
O
OMe
BnO
15
1
26
OBn
OBn
O
OBn
O
BnO
BnO
O
O
BnO
16
BnO
BnO
KO
BnO
OBn
BnO
38%, 16:1b
40%, 6:1b,c
BnO
12
BnO OH
O
OMe
27
BnO
OMe
1
OBn
O
BnO
BnO
OBn
O
BnO
BnO
ONa
OBn
O
OBn
O
O
BnO
BnO
O
BnO
O
BnO
O
13
71%, β only
90%, β only
BnO
O
BnO
BnO
OH
BnO BnO
BnO
BnO
OMe
BnO
OMe
28
10
2
aReaction was run at -30 oC. The donor to acceptor ratio is 2:1. Isolated yield. All selectivities based on 1H
NMR analysis of purified material (see SI). bThe donor to acceptor ratio is 3:1. cReaction was run at -40 oC.
dReaction was run at -15 oC.
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Journal of the American Chemical Society
Table 4. Examining the scope of the reaction between galatosyl donor and acceptors to afford β-linked disaccharidesa
1
2
3
4
5
6
O
O
O
O
CF3
S
S
Cl
Cl
i. NaN(SiMe3)2, temp, THF
ii. promoter (ArSO2Cl)
O
O
O
O2N
O
OH
4h
CF3 4i
iii. NaN(SiMe3)2 or KN(SiMe3)2
O
O
PO
PO
O
S
PO
Cl
OH
Br
PO
4g
7
8
9
entry
1
acceptor
β-linked disaccharides
promoter
yield
β:α ratio
donor
OBn
BnO
ONa
OBn
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
BnO
12:1
10:1
62%
85%
4h
4i
O
O
O
BnO
29
BnO
BnO
O
BnO
BnO
BnO
OMe
O
BnO
OH
BnO
BnO
BnO
2
OMe
31
OBn
O
BnO
BnO
ONa
O
O
4h
4i
β only
β only
OBn
O
58%b
92%c
BnO
BnO
O
O
O
O
2
OBn
O
O
OH
BnO
O
O
O
29
32
11
Ph
OBn
O
OBn
BnO
BnO
BnO
Ph
O
11:1
5:1
4h
4i
73%
O
O
O O
O
O
BnO
33
KO
BnO
BnO
3
OMe
OH
BnO
O
91%c
12
BnO
MeO
29
OBn
BnO
BnO
4h
67%
6:1
5:1
OBn
O
OBn
BnO
BnO
O
O
BnO
O
BnO
16
KO
BnO
71%c
OBn
O
BnO
4i
4
OH
BnO
OMe
BnO
MeO
29
51%c,d
34
4g
11:1
Ph
Ph
ONa
O
O
O
9.5:1
6:1
44%
64%
O
BnO
BnO
4h
4i
O
O
O
BnO
O
BnO
BnO
5
OMe
BnO
BnO
O
BnO
OH
BnO
BnO
OMe
30
2
35
1
o
aReaction was run at -30 C. The donor to acceptor ratio is 3:1. Isolated yield. All selectivities based on H
NMR analysis of purified material (see SI). bReaction was run at -15 oC. cReaction was run at -40 oC. dThe
donor to acceptor ratio is 4:1.
Although these experiments established that these reac-
tions proceed via the quantitative generation of a glycosyl
sulfonate intermediate, further studies were required to un-
derstand the mechanism of the reaction. One possibility is
that of a classical SN2 process: concerted and stereospecific
inversion of the sulfonate by the acceptor alkoxide, with the
development of relatively little positive charge in the transi-
tion state. Alternatively, a stereoinvertive SN1 process
might occur: initial ionization of the sulfonate to form a
contact ion pair, followed by highly stereoselective nucleo-
philic attack from the face opposite the leaving group. In
this latter case, the intermediate would be a formal oxo-
carbenium ion, and the rate-determining transition structure
would be expected to bear a significant degree of positive
charge at C1.
transition state is expected to be relatively symmetric, and
thus the predicted isotope effect at C1 would be large
(>1.02). In a typical SN1 reaction, where formation of the
high-energy oxocarbenium ion is both rate-limiting and
isotope-determining, a very late transition state is expected,
and the predicted isotope effect at C1 would be small
(~1.00). This near-unity isotope effect reflects the balanc-
ing of two opposing effects: the loss of vibrational energy
from leaving group heterolysis (a normal effect) and the
gain of vibrational energy from hyperconjugation of neigh-
boring σ bonds into π* system of the oxocarbenium ion (an
inverse effect).60
While the KIE at C1 reflects the degree to which the
nucleophile is associated with the transition state, the KIEs
at C2 and C5 reflect the degree of charge buildup in the
donor ring. In an SN2 reaction, the loss of negative charge
caused by leaving group departure is balanced by the gain
of negative charge caused by nucleophilic attack. Accord-
To determine where this reaction lies along the SN2−SN1
continuum, we measured the 12C/13C kinetic isotope effects
(KIEs) with respect to the donor. In an SN2 reaction, the
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Journal of the American Chemical Society
Page 6 of 12
ingly, at sites removed from the reactive center (C1), the and a magnetization transfer delay of 3.357 ms (effective
1JCH = 148.9 Hz). We also found that the addition of 0.5
mM Cr(acac)3 to the NMR samples appreciably reduced the
T1 relaxation times of the methine protons, without signifi-
cantly increasing T2 relaxation.64,65 This strategy allowed
many more scans to be taken and increased the precision of
the measurement. We recommend that concentrations of
0.5–2 mM Cr(acac)3 be used in all future applications of the
DEPT methodology.
1
2
3
4
5
6
7
8
bonding is relatively unchanged, and the predicted isotope
effects are small (1.007 for C2 and 1.006 for C5). In an SN1
reaction, the buildup of positive charge at C1 weakens the
bonding at adjacent sites through hyperconjugation. Thus,
the expected isotope effects at C2 and C5 are normal (~1.02
at both sites). Together, the KIEs at C1, C2, and C5 are
highly diagnostic of where any given glycosylation reaction
lies on the SN2−SN1 mechanistic continuum (Figure 2).
9
products
late
Table 5. The scope of the reaction between fucosyl donor
and acceptors to afford β-linked disaccharidesa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
i. NaN(SiMe3)2, THF, temp
ii. ArSO2Cl
RO
X
OH
O
O
O
OBn
36
O
O
OBn
PO
OBn
iii. NaN(SiMe3)2 or KN(SiMe3)2
OBn
BnO
BnO
RO
O
HO
PO
central TS =
maximum
C1 KIE
entry
1
promoter
yield
45%
β:α ratio
β only
disaccharide
O
O
SN2
S
Cl
O2N
CF3
4h
SN1
early
O
O
cationic =
C2, C5 KIE
S
O
O
Cl
OBn
BnO
BnO
O
OBn
β only
2
54%
H
BnO
BnO
starting
materials
OMe
CF3
37
H
C–X bond cleavage
O
4i
SN1
O
O
RO
S
Cl
β only
3
4
Figure 2. The SN1−SN2 continuum in glycosylations. The
KIE at C1 measures how early or late the transition state is,
while the KIEs at C2 and C5 measure how much positive
charge is present.
60%
45%
Br
4g
4h
O
O
S
S
Cl
4:1
O2N
CF3
O
O
Cl
Table 6. Measured Glycosylation KIEsa
5
59%
3:1
OBn
O
CF3
CF3
OBn
O
NaN(SiMe3)2, -60 o
C
4i
BnO
BnO
BnO
BnO
SO2Cl
O
O
THF
Ph
O
O
BnO
OH
BnO
O
OSO2Ar
S
CF3
O
O
Cl
6
7
8
42%
41%
34%
3:1
6:1
1
4i
OBn
BnO
OMe
OBn
CF3
BnO
OH
O
38
4l
C5
C4
BnO
MeO
MeO
O
O
OBn
O
C1
S
MeO
OMe
Cl
39
O
BnO
C3
Br
NaN(SiMe3)2, -60 oC, THF
BnO
O
MeO
MeO
C2
4g
MeO
OMe
O
O
40
S
Cl
11:1
KIE
KIE
F
position
average KIE
4m
measurement 1 measurement 2
aIsolated yield. All selectivities based on crude 1H NMR analysis.
C1
C2
C4
C5
1.032
1.004
1.001
0.997
1.035
1.005
1.002
0.998
1.034
1.005
1.002
0.998
To measure the required 12C/13C KIEs at natural abun-
dance, we employed our previously reported DEPT meth-
odology.61,62 Two glycosylation reactions using donor 1 and
acceptor 39 were carried to 22% and 23% conversion at –60
°C, with 39 as the limiting reagent.63 To determine the iso-
topic fractionation in these partial conversion samples, the
area of the peak of interest was divided by the area of a
reference peak remote from the reaction center (C3). This
isotopic ratio compared to the corresponding ratio in the
samples fully converted to 40.
a12C/13C isotopic fractionations were determined via DEPT
relative to C3. The estimated standard error in these KIEs is
0.004 at all positions. 1H/2H isotopic fractionations were
measured over 3 trials by H NMR. The H/2H KIE in 3
measurements are 1.168, 1.154, 1.160.
1
1
Optimizing the DEPT parameters as previously report-
ed61 for the methines of the donor gave a tip angle of 60.25°
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Journal of the American Chemical Society
(b) bridging sodium
(c) sodium bound to sulfonate
(a) sodium bound to alkoxide
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(e) comparison with experiment
(d) distribution of energies and geometries
Figure 3. Computed glycosylation transition states (B3LYP-D3(BJ)/6-31G*/PCM(THF) at –60 °C). Lowest-energy transition
structures with the sodium ion: (a) bound to the alkoxide (red); (b) bridging the alkoxide and the sulfonate (green); and (c) bound to
the sulfonate (blue). The sodium ion is purple. A dimethyl ether is bound to the sodium. (d) The 106 transition states found
spanned a wide range of energies and geometries. (The lowest energy transition states depicted in a-c are circled.) (e) Most bridging
(type b) transition states gave KIE predictions at C1 that were within experimental error (highlighted), while all type a and c struc-
tures were inconsistent with experiment.
The measured KIEs are shown in Table 6. The KIE at
C1 of 1.034 is relatively large for a glycosylation reaction
and is consistent with an SN2 mechanism. For example,
Crich et al. obtained a KIE of 1.023 in an SN2-like β-
mannosylation reaction,66 while Chan, Bennet, and co-
workers reported a primary 13C KIE of 1.024 for the classi-
cal SN2 reaction between a glycosyl fluoride and azide
ion.67 Similarly, the concerted enzymatic hydrolysis of me-
thyl β-glucopyranoside gives KIEs of 1.026−1.032.68−70 The
KIE at C1 is also much larger than the KIEs that are pre-
dicted for an SN1 reaction (1.00–1.01, see DFT calculations
below). Conversely, the KIEs at C2 and C5 are much
smaller than would be expected for an SN1 reaction (1.02
for both sites, also regardless of DFT method).
flect the stiffness of the out-of-plane bending mode and this
stiffness is diagnostic of concertedness.
In an SN2 reaction, the hybridization at C1 remains ap-
proximately sp3 as nucleophile-C1 bonding largely replaces
C1-leaving-group bonding as the reaction progresses. As a
result, the out-of-plane mode weakens only somewhat, and
the isotope effect is expected to be small. In an SN1 reac-
tion, C1 becomes sp2-hybridized in the oxocarbenium ion.
This substantially weakens the out-of-plane mode and the
isotope effect is expected to be large.
However, glycosylation reactions naturally lie at the
boundary between the SN2 and SN1 mechanisms, making
clear interpretations challenging.73,74 For example, loose but
concerted displacements are also expected to give large
H/D isotope effects.75 Furthermore, H/D isotope effects are
much more challenging to predict quantitatively through
computational methods, in part due to the substantially in-
creased role of tunneling.76 Here, the SN2 glycosyation is
roughly predicted to give H/D isotope effects of 1.3–1.5
compared to 1.5–1.7 for the SN1 process (the ranges reflect
conformational effects). Thus, although the experimental
Further support for an SN2-like mechanism comes from
secondary H/D KIE measurements at C1 of 1. Here, we
measured an average secondary KIE value of 1.16 at –60
°C. This value is similar to other secondary KIE values
measured for SN2-like glycosylations, such as the results
reported by Crich (1.12)71,72 and Jacobsen (1.12−1.16).14
The canonical interpretation of these KIEs is that they re-
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Journal of the American Chemical Society
Page 8 of 12
H/D KIE of 1.16 qualitatively supports the interpretation of cies can be due to deficiencies in the electronic structure
1
2
3
4
5
6
7
8
an SN2 process, a definitive interpretation requires computa-
tional analysis of the 12C/13C KIEs, which are far more
amenable to quantitative prediction.
method, solvation protocol, or perhaps the operation of an
unknown mechanism.
Interestingly, while the 12C/13C KIE at C1 is relatively
large for a glycosylation reaction, this KIE is actually much
smaller than what is observed for many simple SN2 dis-
placements at aliphatic centers (often 1.07 or larger near
room temperature).77 To understand this discrepancy, and to
gain atomistic-level insight into the reaction, we turned to
density functional theory (DFT) calculations. To develop a
realistic model of the reaction capable of capturing its many
possible degrees of freedom, while maintaining good accu-
racy, we chose the standard method B3LYP-D3(BJ)/6-
31G*/PCM. (Further analysis indicates that many other
standard methods would have been acceptable; see SI sec-
tion 6 for details.) Additionally, the benzyl protecting
groups on the donor were simplified to methyl groups,
while the sodium counterion was explicitly solvated with
one dimethyl ether ligand. A comprehensive search over the
conformational, donor-acceptor, and solvent degrees of
freedom found 106 distinct transition states. These transi-
tion states could be clustered into three classes (Figure 3) in
which the sodium counterion was (a) bound to the alkoxide
nucleophile (34 structures); (b) bridging the alkoxide and
the sulfonate leaving group (46 structures); or (c) bound
only to the sulfonate (26 structures).
Table 7. Predicted vs. Experimental Isotope Effectsa
OBn
O
CF3
CF3
OBn
O
NaN(SiMe3)2, -60 o
C
BnO
BnO
BnO
BnO
SO2Cl
THF
BnO
OH
BnO
OSO2Ar
9
1
4i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
O
C5
C4
BnO
MeO
MeO
OBn
O
C1
MeO
OMe
39
O
BnO
C3
NaN(SiMe3)2, -60 oC, THF
BnO
O
MeO
MeO
C2
MeO
OMe
40
SN1 EIEs
SN2 KIEs
type b
type a
type c
expt.
C1
C2
1.001
1.020
1.082
1.004
1.036
1.007
1.066
1.001
1.034
1.005
C3
1.000b
1.007
1.001
1.002
0.999
C4
C5
1.005
1.018
1.001
1.001
1.002
1.006
1.000
1.002
1.002
0.998
aOnly the type b SN2 transition states gave KIE predictions that
were in good agreement with experiment. Predictions for the
lowest-energy representative of each class are shown. These
predictions include a Bell tunneling correction. bThe KIE at C3
positon is assumed 1.000.
While these structures spanned a range of energies (Fig-
ure 3d) and geometries (Figure 3e), the predicted isotope
effects within each class were relatively consistent. Inter-
estingly, type a (sodium bound to alkoxide) and type c (so-
dium bound to sulfonate) transition states gave predicted
KIEs at C1 that were too high (1.06–1.08) vs. experiment
(1.034). In contrast, type b (bridging) transition states gave
KIEs that were very close to experiment. Specifically, the
predicted KIEs at C1 for 16 of the 24 type b structures were
found to be within experimental error (highlighted points in
Figure 3e).
In the constrained transition state approach, the focus
shifts from using energetic criteria to locate transition struc-
tures to finding non-stationary geometries that best repro-
duce experimental isotope effects. In an explicit “grid”
approach, the transition structure is defined as a function of
a small number of geometric parameters, such as the form-
ing and breaking bond distances in a nucleophilic substitu-
tion. (This approach has been employed in several glyco-
sylation studies.67,80,81) After fixing these distances at regu-
lar intervals on a pre-defined grid, all other geometric pa-
rameters are allowed to relax, and the isotope effects at
each grid point are calculated. The “experimental” transi-
tion state can then be derived explicitly, by taking the grid
point that most closely matches experiment. Alternatively,
an implicit “regression” approach might be used in which
the geometric parameters of a number of known uncon-
strained transition states are used as features to predict the
isotope effects. The experimental transition state can then
be found by optimizing the parameters of the linear model.
The type b transition states were asynchronous, with a
longer forming bond distance of 2.49 Å and a shorter break-
ing bond distance of 2.16 Å in the lowest energy structure
(Figure 3b). Type b transition states were also relatively
central when compared to the type a and c transition states,
with longer breaking bond distances, but similar forming
bond distances. Although more central transition states
might be expected to give larger isotope effects, the bridg-
ing sodium ion enforces a non-linear nucleophile-C1-
leaving group angle of 138°. Additionally, the donor oxy-
gen-C1-nucleophile angle is 117° and the geometry at C1 is
planar. These geometric features are similar to those of
nucleophilic additions to carbonyl groups and the modest
oxocarbenium character is reflected in the slightly normal
predicted isotope effects at C2 and C5. Overall, it appears
that the sodium may both coordinate the alkoxide and acti-
vate the sulfonate for displacement.
Both approaches were tested here. To test the explicit
approach, we conducted a retrospective analysis in which
we imagined that only the type a transition states were
known. Since none of these transition states give isotope
effect predictions that are consistent with experiment, one
might attempt to identify the experimental transition struc-
ture by adjusting the geometric parameters of the available
structures to match the observed KIEs. To determine
whether such a strategy could conceivably be successful,
we assumed that the lowest-energy type b transition state is
the experimental transition state. Then, we took the lowest-
energy type a structure as a template and set the forming
The large number of transition states discovered here
offers a unique opportunity to examine the technique of
using constrained transition states.78,79 In the unconstrained
transition state approach employed above, each transition
structure represents a true first-order saddle point on the
potential energy surface. However, it is often the case that
none of the located unconstrained structures satisfactorily
reproduces the observed isotope effects. These discrepan-
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Journal of the American Chemical Society
and breaking bond distances to those of the lowest-energy
breaking bond is 2.2±0.2 Å long, and the sodium ion bridg-
es the acceptor and sulfonate oxygens.
1
2
3
4
5
6
7
8
type b transition state. The predicted isotope effects for this
constrained type a transition state did not agree with exper-
iment (see SI section 6.3 for details). For example, the pre-
dicted KIE at C1 for the constrained type a structure is
1.065, in stark contrast to the predicted KIE of 1.036 for the
unconstrained type b structure that the constrained structure
is intended to mimic. The reverse process is similarly un-
successful: constraining the lowest-energy type b structure
to the forming and breaking bond distances of the lowest
type a structure gives a predicted KIE at C1 of 1.059 vs. the
unconstrained KIE of 1.082 for unconstrained type a.
Therefore, in the event that only type a (or type b) transition
states were to be available, the explicitly constrained transi-
tion state would not identify the correct transition state ge-
ometry.
CONCLUSION
These studies demonstrate that by matching the intrinsic
reactivity of a glycosyl donor with the electronics of the
sulfonate leaving group (Figure 4) it is possible to obtain
highly β-selective glycosylation reactions without tailored
protecting group schemes. Depending on the nature of the
acceptor, achieving highly efficient β-glycosylation in this
SN2 manifold can require a balance between the reactivities
of the donor and arylsulfonyl activator. When relatively
reactive primary acceptors are employed, the desired SN2
pathway outcompetes all others, and high levels of β-
selectivity result, regardless of arylsulfonate substitution.
However, when less reactive secondary acceptors are used,
the selectivity between the desired SN2 and undesired SN1
pathways depends on both the reactivity and stability of the
α-sulfonate intermediate. With more reactive donors, more
stabilized, electron-rich arylsulfonates give more selective
reactions.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The finding that constrained transition states do not give
the same predicted KIEs as their unconstrained counterparts,
even when their key geometric parameters are the same,
requires that the KIE be dependent on other factors. This
inference is confirmed by a multiple linear regression anal-
ysis. The predicted isotope effect at C1 for the uncon-
strained type a transition states are described well by a four-
parameter model that incorporates an intercept, the forming
bond distance, the breaking bond distance, and the imagi-
nary frequency (adjusted R2 = 0.95, RMS prediction error =
0.002). However, when this model was used to predict the
isotope effects for the unconstrained type b structures, the
KIE at C1 was significantly overpredicted by 0.01–0.02
units.
Our mechanistic analysis confirms that the glycosylation
reactions reported here proceed via the quantitative genera-
tion of an α-glycosyl arylsulfonate, which is then stereoin-
vertively displaced by a sodium alkoxide. By using a good
leaving group and a strong nucleophile, an SN2-like process
is favored. Kinetic isotope studies and DFT calculations
indicate a concerted but asynchronous process in which
only a small amount of charge develops at C1 in the transi-
tion state. Furthermore, the sodium counterion bridges the
alkoxide and sulfonate oxygens in the transition state.
Thus, Lewis acid activation of the sodium for displacement
occurs, but only in the desired SN2 pathway, leading to a
favorable tradeoff between reactivity and selectivity.
In hindsight, it is not surprising that the dependence of
the KIE on geometric parameters can change significantly
when the mechanism changes. The results presented here
demonstrate that even subtle changes in mechanism, such
as changes to the solvation sphere, are sufficient to cause
the constrained transition state to give erroneous results.
Therefore, constrained transition state approaches should be
applied with caution in the future, particularly in glycosyla-
tion reactions.
This mechanistic analysis relied on the use of DEPT
methodology to measure multiple KIEs simultaneously and
at natural abundance as well as the use of unconstrained
transition state calculations to rationalize the observed KIEs.
In general, the KIE at C1 indicates whether a given glyco-
sylation proceeds via an associative or dissociative mecha-
nism, while the KIEs at C2 and C5 reflect the degree of
positive charge development. We anticipate that this strat-
egy will prove useful for studying other glycosylation reac-
tions in the future.
donors
glucose
galactose
2-deoxyglucose
fucose
OBn
O
BnO
OH
OBn
OBn
O
OBn
O
O
more
reactive
BnO
BnO
BnO
BnO
BnO
OBn
BnO
BnO OH
OH
BnO OH
RRV
1
6
27
376
Overall, we have shown that highly β-selective glyco-
sylations in an SN2 manifold are feasible when the electron-
ics of the leaving group are matched to the reactivity of the
glycosyl donor. By systematically correlating the reactivity
of the glycosyl donor, its leaving group, and the stereo-
chemical outcome, we have identified conditions that favor
clean and efficient stereoinversion. We hope that the in-
sights about reactivity and selectivity gained here will prove
useful for the rational design of next-generation glycosyla-
tion methodology.
Hammett σ
0.778
0.232
0.062
-0.170
O
O
O
O
O
O
O
O
electron-
rich
S
S
S
S
Cl
Cl
Cl
Cl
O2N
H3C
Br
F
optimal activators
Figure 4. More reactive donors require more electron-rich
sulfonyl chloride activators. RRV = Relative Reactivity
Value.52,53
Furthermore, this analysis highlights the power of an
unconstrained transition state approach when many degrees
of freedom are possible and can be explored with reasona-
ble coverage. In addition to rationalizing the observed
KIEs, the set of experimentally consistent transition states
defines the precision of the experimental transition state.
Specifically, the 19 highlighted points in Figure 3e define a
relatively central, but asynchronous transition state in which
the forming bond is approximately 2.5±0.1 Å long, the
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental details, computational analysis, and characteriza-
tion data (PDF).
AUTHOR INFORMATION
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 12
(17) Singh, Y.; Wang, T.; Geringer, S. A.; Stine, K. J.; Demchenko,
A. V. Regenerative Glycosylation. J. Org. Chem. 2018, 83, 374–
381.
Corresponding Authors
1
clay.bennett@tufts.edu, eugene.kwan@merck.com
2
3
4
5
6
7
8
9
(18) Tanaka, M.; Nakagawa, A.; Nishi, N.; Iijima, K.; Sawa, R.;
Takahashi, D.; Toshima, K. Boronic-Acid-Catalyzed Regioselec-
tive and 1,2-cis-Stereoselective Glycosylation of Unprotected
Sugar Acceptors via SNi-Type Mechanism. J. Am. Chem. Soc.
2018, 140, 3644−3651.
(19) Yang, T.; Zhu, F.; Walczak, M. A. Stereoselective Oxidative
Glycosylation of Anomeric Nucleophiles with Alcohols and Car-
boxylic Acids. Nature Commun. 2018, 9, 3650.
(20) Levi S. M.; Li, Q.; Rötheli, A. R.; Jacobsen, E. N. Catalytic
Activation of Glycosyl Phosphates for Stereoselective Coupling
Reactions. PNAS 2019, 116, 35–39.
(21) Meng, L.; Wu, P.; Fang, J.; Xiao, Y.; Xiao, X.; Tu, G.; Ma, X.;
Teng, S.; Zeng, J.; Wan, Q. Glycosylation Enabled by Successive
Rhodium (II) and Brønsted Acid Catalysis. J. Am. Chem. Soc. DOI:
10.1021/jacs.9b04619.
(22) Zeng, J.; Wang, R.; Zhang, S.; Fang, J.; Liu, S.; Sun, G.; Xu,
B.; Xiao, Y.; Fu, D.; Zhang, W.; Hu, Y.; Wan Q. Hydrogen-
Bonding-Assisted Exogenous Nucleophilic Reagent Effect for
β Selective Glycosylation of Rare 3-Amino Sugars. J. Am. Chem.
Soc. 2019, 141, 8509−8515.
(23) Hoang, K. M.; Lees, N. R.; Herzon, S. B. Programmable
Synthesis of 2 Deoxyglycosides. J. Am. Chem. Soc. 2019, 141,
8098−8103.
ORCID
Clay S. Bennett: 0000-0001-8070-4988
Eugene E. Kwan: 0000-0001-7037-0531
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
The authors thank the NIH for financial support (grant U01-
GM120414).
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O
O
S
O
Cl
HO
O
PO
O
O
O
R
PO
α
O
PO
PO
PO
OH
OSO2Ar
β
SN2 glycosylation
NMR identification 13C KIE and H/D KIE
DFT calculations
donors
BnO
BnO
OBn
OBn
O
OBn
O
OH
OBn
O
O
BnO
BnO
BnO
BnO
donors
OBn
BnO
BnO OH
OH
BnO OH
more reactive
RRV
1
6
27
376
–0.170
Hammett σ
electron-rich
optimal activators
0.062
O
0.778
0.232
O
O
O O
S
O
O
O
S
S
S
Cl
Cl
Cl
Cl
O2
N
H3C
Br
F
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