Mechanistic, crystallographic, and computational studies on the catalytic, enantioselective sulfenofunctionalization of alkenes

Article abstract of DOI:10.1038/nchem.2109

The stereocontrolled introduction of vicinal heteroatomic substituents into organic molecules is one of the most powerful ways of adding value and function. Although many methods exist for the introduction of oxygen- and nitrogen-containing substituents,

Full text of DOI:10.1038/nchem.2109

ARTICLES
PUBLISHED ONLINE: 10 NOVEMBER 2014 | DOI: 10.1038/NCHEM.2109
Mechanistic, crystallographic, and computational
studies on the catalytic, enantioselective
sulfenofunctionalization of alkenes
Scott E. Denmark , Eduard Hartmann, David J. P. Kornfilt and Hao Wang
*
The stereocontrolled introduction of vicinal heteroatomic substituents into organic molecules is one of the most powerful
ways of adding value and function. Although many methods exist for the introduction of oxygen- and nitrogen-containing
substituents, the number of stereocontrolled methods for the introduction of sulfur-containing substituents pales by
comparison. Previous reports from our laboratories have described sulfenofunctionalizations of alkenes that construct
carbon–sulfur bonds vicinal to carbon–oxygen, carbon–nitrogen or carbon–carbon bonds with high levels of
diastereospecificity and enantioselectivity. This process is enabled by the concept of Lewis-base activation of Lewis acids,
which provides activation of Group 16 electrophiles. To provide a foundation for the expansion of substrate scope and
improved selectivities, we have undertaken a comprehensive study of the catalytically active species. Insights gleaned
from kinetic, crystallographic and computational methods have led to the introduction of a new family of sulfenylating
agents that provide significantly enhanced selectivities.
he importance of organosulfur compounds1,2 manifests itself providing access to enantiomerically enriched tetrahydropyrans
in the myriad constructive and functional manipulations and −furans21,22
.
T
involving these as building blocks as well as in the abundance
The generality of this catalytic system has been demonstrated using
of sulfur-containing natural products3. Among the variety of various nucleophiles (Fig. 1b). In addition to the use of hydroxyl
methods used for the introduction of sulfur groups, the vicinal groups in sulfenoetherification reactions21, electron-rich arenes have
sulfenofunctionalization of alkenes using electrophilic sulfur4 been deployed in carbosulfenylations of olefins, affording trans-
reagents is a powerful approach. Extensive studies on the tetrahydronaphthalenes with complete diastereospecificity and high
mechanism of this reaction have confirmed the intermediacy of enantiomeric ratios22–24. More recently, we have extended our proto-
thiiranium ions5,6, which are captured with inversion by a nucleo- col to tosyl-protected amines that can be engaged in sulfenoamination
phile, affording 1,2-difunctionalized products with defined relative reactions, yielding enantioenriched nitrogen heterocycles25.
configurations. However, despite the sound understanding of this
Despite these positive developments, further improvement of
transformation, asymmetric variants remain largely underdeveloped catalyst performance is desirable for some substrates. For instance,
and, for a long time, only two examples of direct enantioselective efficient discrimination between enantiotopic faces of terminal,
sulfenofunctionalization were known, both employing chiral 1,1-disubstituted and trisubstituted double bonds remains a chal-
reagents in stoichiometric amounts7,8.
lenge. Beyond an empirical attempt to solve this problem, the
Only recently have catalytic enantioselective sulfenylations of in-depth understanding of processes occurring during the sulfeno-
activated alkenes derived from aldehydes9,10 ketones11 and functionalization, as well as detailed knowledge about the structure
,
amides12 been reported, as well as the catalytic enantioselective of the active sulfenylating agent, can contribute substantially to the
sulfenoetherification of unactivated alkenes under chiral Brønsted rational design of a more selective catalytic system. Given that thi-
acid catalysis13. The necessity to generate enantioenriched thiira- iranium ions are the common intermediate, a more enantioselective
nium ions has been elegantly circumvented by asymmetric desym- preparation thereof would be beneficial to all conceivable substrate
metrization of meso-thiiranium ions, where ring-opening by a classes of this transformation. Therefore, to advance and further
nucleophile is the stereodetermining step14,15. This progress not- generalize this method, we undertook an in-depth study to elucidate
withstanding, there is a lack of methods that control the absolute the mechanism and to characterize the catalytically active species in
stereochemical outcome of 1,2-sulfenofunctionalizations, and this the Lewis base-catalysed sulfenofunctionalization of unactivated
pertains especially to isolated double bonds.
alkenes. Here, we report the results of kinetic, crystallographic as
During our endeavour to apply the concept of Lewis-base acti- well as computational investigations. The synthetic impact of our
vation of Lewis acids16 to reactions of main group elements, we findings is illustrated by the improvement in the enantioselectivity
have systematically investigated the stability of seleniranium17,18 of the process.
and thiiranium ions19,20 to establish boundary conditions for cataly-
tic, asymmetric chalcogen functionalizations. Our studies have Results
revealed that, under certain conditions, the thiiranium ions are Kinetic studies. A full investigation of the kinetic parameters was
configurationally stable19,20 and can be captured with various undertaken to identify the rate equation. The conversion of 1a
heteroatom nucleophiles without erosion of enantiomeric purity20. was monitored by 19F NMR spectroscopy (Fig. 2). Catalyst 3a was
On the basis of these findings, the first catalytic, enantioselective chosen, because the rates of reaction could be followed easily over
sulfenofunctionalization of unactivated alkenes was developed, a wide range of temperatures and concentrations. The order in
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois, 61801, USA. e-mail: sdenmark@illinois.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2109
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R
Nu
The activation parameters of the reaction were obtained by
carrying out an Arrhenius study in the temperature range −20 °C
to 20 °C. The enthalpy of the reaction was 8.9 0.2 kcal mol−1
and the entropic contribution was −52.7 0.6 e.u. (e.u. = entropy
units). At 298 K, the entropy term is the primary contributor to
the free energy of activation of 24.6 kcal mol−1.
a
Brønsted acid
chiral Lewis base
H
Nu
PhS
R
NuH
R
S
R
SPh
R´2N–SPh
Ph
Nu
Enantiomerically
enriched
Isolation of the catalytically active species. Because thiiranium ion
formation is most probably the enantiodetermining step, detailed
knowledge about the stereostructure of the presumed catalytically
active species [(R2N)3P = Se–SPh]+X− could help understanding
the origin of enantioselectivity. Accordingly, the isolation and
crystallographic characterization of [(R2N)3P = Se–SPh]+X−
was performed.
b
R
O
R
OH
Sulfenoetherification
PhS
O
O
O
To generate [(R2N)3P = Se–SPh]+X− without any by-products
that would disrupt the crystallization process, a binaphthyl-
derived selenophosphoramide was combined with the S-phenyl
transfer agent [PhS(SMe2)]SbCl6 (ref. 26):
Carbosulfenylation
Sulfenoamination
O
SPh
R
R
Ts
N
R
NHTs
R
(R2N)3P==Se + [PhS(SMe2)]+SbCl6−
[(R2N)3P==Se−SPh]+SbCl6−
(1)
PhS
−SMe2
c
2a (1.05 equiv.)
MsOH (1.0 equiv.)
3a (0.10 equiv.)
O
F
F
(For more details on the actual catalyst structure, see Supplementary
Information, pp. 14–19.) Formation of the active species was
O
HO
+
N
SPh
CDCl3
a
BArF24
O
PhS
Me
1a
2a
4a
Me
Me
SPh
N
Se
PhSCl (1.0 equiv.)
NaBArF24 (1.0 equiv.)
Me
Me
N
N
S
P
S
N
P
P
N
NiPr2
CH2Cl2
RT
90%
NiPr2
N
N
Me
Me
Me
1st order in 1a
0th order in 2a
1st order in 3a
3a
(
)-3b
( )-5b
31P NMR: 65.8 ppm
(X-ray crystal structure)
Arrhenius activation parameters:
ΔH = 8.9 0.2 kcal mol–1
ΔS = –52.7 0.6 e.u.
Rate = kobs [1a][MsOH]x
kobs = k [3a]
ΔGact(298) = 24.6 kcal mol–1
H
Ph
O
Ph
O
Figure 1 | Lewis-base catalysed, enantioselective sulfenofunctionalization
of unactivated alkenes. a, Generic reaction pathway for the
1b
PhS
(
1,2-sulfenofunctionaliaztion of alkenes. Initial formation of an
CDCl3, RT
17 h
90% conv.
)-4b
enantiomerically enriched thiiranium ion is followed by stereospecific
(invertive) capture with a nucleophile in an intra- or intermolecular fashion.
b, Substrate and nucleophile scope of the Lewis-base catalysed,
enantioselective sulfenofunctionalization. c, Model reaction for kinetic
analysis of the Lewis-base catalysed sulfenofunctionalization.
b
each substrate was determined by the method of initial rate kinetics.
Reactions were followed to 10% conversion, and the initial rates
were plotted against concentration to obtain straight lines
(Supplementary Information, pages 11–13). The reaction was
found to be first order in both catalyst and substrate. No order in
the electrophile was observed. Interestingly, when the acid
(MsOH) dependence was investigated, the rate dependence was
found to be curved with a maximum at 0.6 equiv.
S2
C1
S1
N2
P1
C29
N3
N1
C32
These results suggest that transfer of the sulfenium ion to the
alkene occurs from the sulfenylated selenophosphoramide
[(R2N)3P = Se–SPh]+X−, constituting the turnover-limiting step of
the reaction. The catalytically active species [(R2N)3P =
Se–SPh]+X−, in turn, is generated upon the MsOH-mediated reac-
tion of 2a with Lewis base 3 and represents the resting state of the
catalyst. Its existence is supported by 31P NMR spectroscopy, in
which the diagnostic signal for 3 (80–90 ppm, depending on the cat-
alyst structure) disappears and a new resonance at ∼60 ppm is
observed. This value is in accord with previously reported, analo-
gous compounds of the type [(R2N)3P = Se–YAr]+X− (refs 18, 22).
Figure 2 | Synthesis of catalytically active species ( )-5b and its X-ray
crystal structure. a, Catalytically active species ( )-5b was prepared from
3b, PhSCl and NaBArF24. Its sulfenylating potential is demonstrated by
reaction with alkene 1b. b, Ortep plot of ( )-5b X-ray crystal structure
(35% thermal ellipsoids, BArF24− counteranion omitted for clarity).
S(2)–S(1)–P(1) = 103.5°, C(1)–S(2)–S(1) = 104.1°, P(1)–S(1)–S(2)–C(1) = 96.0°,
N(3)–P(1)–S(1)–S(2) = 175.1°.
2
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confirmed by the appearance of a diagnostic 31P NMR resonance at enantioselectivity of the process is to change the sulfenylating
60.4 ppm. Unfortunately, during crystallization attempts, a dispro- agent. Insights gained from the X-ray crystal structure of 5b suggest
portionation reaction occurred, reducing the sulfenyl group to that electronic and particularly steric properties of the arylsulfenyl
PhSSPh while oxidizing the selenophosphoramide to the dicationic group could impact the stereochemical outcome of the reaction.
dimer [(R2N)3P==Se−Se==P(NR2)3]2+ 2SbCl6−:
2[(R2N)3P==Se−SPh]+SbCl6−
To test this hypothesis, a variety of electronically and sterically
disparate N-arylsulfenylphthalimides 2a–n were synthesized and
evaluated in the sulfenoetherification of hydroxyl-substituted
alkene 1b using selenophosphoramide (R)-3c as the catalyst
(Table 1). The enantiomeric ratios of the resulting tetrahydropyrans
4bb–4bn were compared against the enantiomeric ratio obtained
for the phenylsulfenyl-substituted product 4ba (95.3:4.7 e.r.,
−PhSSPh
[(R2N)3P==Se−Se==P(NR2)3]2+2SbCl6−
(2)
(For an X-ray crystal structure see Supplementary Fig. 1, p. 93.)
To avoid the disproportionation reaction caused by the lability entry 1). Neither the rate nor the selectivity of the reaction was per-
of the Se–SPh bond, the donor atom of the catalyst was replaced turbed significantly in response to changes in the electronic proper-
with a sulfur atom. Thiophosphoramides are comparably selective ties of the ring (entries 2–4).
in sulfenoetherification reactions21. However, when a thiophosphor-
To evaluate the influence of steric effects, different ortho-substi-
amide Lewis base was combined with [PhS(SMe2)]SbCl6, an tuents were installed into the arylsulfenyl moiety, 2e–j. The presence
equilibrium between the reactants was established, complicating of an ortho-methyl group increased the enantioselectivity of the
the crystallization:
reaction to 97.2:2.8 e.r. for tetrahydropyran 4be (entry 5).
Essentially the same ratio of enantiomers was obtained for
product 4bf containing two ortho-methyl substituents (entry 6).
Surprisingly, the rate of formation of product 4bf was faster than
for 4be, probably owing to the electron-donating effect of the
methyl groups. Further increasing the steric bulk around the
sulfur atom by incorporating ethyl substituents again led to a
slight enhancement in enantioselectivity (entries 7 and 8)
Logically, the impact of ortho-isopropyl groups was next investi-
gated (2i, 2j). Whereas monoisopropyl-substituted product 4bi
(R2N)3P==S + [PhS(SMe2)]+SbCl6−
[(R2N)3P==S−SPh]+SbCl6− + SMe2
(3)
To overcome the reversible formation of the active species, thio-
phosphoramide ( )-3b was combined with PhSCl and sodium tet-
rakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF24) to furnish
( )-5b as a pale yellow, air-stable solid (Fig. 2a). This approach
not only enabled the irreversible generation of the active species
( )-5b, but also allowed for the introduction of the weakly coordi- was obtained with somewhat diminished enantiomeric purity
−
nating BArF24 counteranion26, which greatly improved the solubi-
lity properties of complex ( )-5b. The formation of ( )-5b was
initially confirmed by its 31P NMR chemical shift (65.8 ppm), as
well as its kinetic competency to stoichiometrically sulfenylate sub-
strate 1b to afford thioetherification product ( )-4b (Fig. 2a).
Ultimately, crystals suitable for X-ray analysis were obtained by
slow evaporation of a saturated solution of ( )-5b in dichloro-
methane. The molecular structure was confirmed by the X-ray
crystal structure analysis of ( )-5b (Fig. 2b, (S)-enantiomer
shown). Several features of this structure are noteworthy. First, the
diisopropylamino group is rotated such that the C(32)–N(3) bond
(96.3:3.7 e.r., entry 9), the sulfenoetherification with 2j bearing
two isopropyl groups produced tetrahydropyran 4bj with a remark-
ably high enantiomeric ratio of >99:1 at −20 °C (entry 10). In this
scenario, the reactivity gain from electron donation is obviously out-
weighed by the steric encumbrance, leading to a slow conversion at
−20 °C. Gratifyingly, at 0 °C the reaction proceeded at a reasonable
rate (80% conversion after 24 h), accompanied by only a marginal
erosion of the enantiomeric ratio (entry 11). Even at room tempera-
ture a high level of enantiocontrol was achieved (entry 12).
For the sake of completeness, other N-arylsulfenylphthalimides
2k–n w
ere inspected (entries 13–16), all of which were inferior to
occupies a nearly antiperiplanar orientation to the S(1)–P(1) sulfenylating agent 2j. Finally, N-alkylsulfenylphthalimides were
bond, while the C(29)–N(3) bond is synperiplanar to this. examined; however, these sulfenylating agents afforded slow conver-
Torsion angles of 169.1° for S(1)–P(1)–N(3)–C(32) and −15.0° for sion or no reaction at all.
S(1)–P(1)–N(3)–C(29), respectively, define this arrangement. The
The general superiority of sterically demanding N-arylsulfenyl-
sum of the angles about the N(3) atom is >359.8°, indicating imides for the highly enantioselective sulfenoetherification of other
near-perfect planarity. This alignment is most probably a conse- substrate classes was next evaluated (Table 2). First, reaction of 1b
quence of a generalized anomeric effect in which the N(3) was conducted on a preparative scale with 2a, 2f, 2h and 2j to
non-bonding electron pair is delocalized into the P(1)–N(1) and confirm the results from the initial survey (entries 1–4)21. Because
P(1)–N(2) σ* orbitals27,28
.
a different selenophosphoramide had been used under the originally
To avoid destabilizing steric interactions with the diisopropyla- reported conditions, in the following, reactions of alkenes 1c–1e
mino group, the S–SPh subunit is oriented back towards the with the parent sulfenylating agent 2a and catalyst (R)-3c were
binaphthyl backbone, as evidenced by a 175.1° torsion angle of run in parallel to provide a valid comparison with 2j. A significant
the N(3)–P(1)–S(1)–S(2) subunit. On the basis of the X-ray improvement of enantioselectivity was seen in the reaction of term-
crystal structures of neutral 10–S–3 compounds29,30 and by inal alkene 1c with 2j as compared to 2a (entry 5 versus 6). Despite
analogy with the well-known 10–Se–3 T-shaped charge transfer the already high enantiopurity of product 4da obtained from an
complexes31, the active sulfenylating agent was anticipated to be a intermolecular sulfenoetherification of 4-octene (1d), 2a and
bent ion pair complex (8–S–2), which is now verified crystallo- MeOH, the enantiopurity of the corresponding product 4dj was
graphically by the S(1)–S(2)–C(1) angle of 104.1°.
further increased by using 2j (entry 7 versus 8). The suitability of a
terminal double bond was also showcased in an intermolecular func-
Improvement of enantioselectivity. To date, the most selective tionalization with 1-octene (1e) and MeOH as the nucleophile (entry 9
catalyst for the sulfenofunctionalization is the 1,1′-binaphthyl- versus 10). Product 4ej was accessed with an excellent enantiomeric
2,2′-diamine-derived selenophosphoramide 3c (Table 1). Previous ratio (98.6:1.4), whereas 4ea gave only a moderate selectivity. Apart
optimization studies identified the importance of a methyl from the sulfenoetherification, we were able to demonstrate the
substituent on the internal nitrogen atoms as well as the isopropyl benefit of 2j in a sulfenoamination reaction25 using alkenyl sulfona-
groups on the external nitrogen18,21. Attempts to further enhance mide 1f. Again, an enhanced enantioselectivity was noticed, with 2j
the catalyst performance by modifying the biaryl backbone have forming product 4fj in 94.3:5.7 enantiomeric ratio (entry 11 versus
not been successful so far. An alternative approach to improve the 12). Although enantiotopic face differentiation was improved for
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Table 1 | Influence of the sulfenylating agent on enantioselectivity in the sulfenoetherification reaction.
O
Me
MsOH (1.0 equiv.)
(R)-3c (0.1 equiv.)
H
O
Ph
O
N
Ph
Se
+
N
SAryl
P
CDCl3
–20 °C
ArylS
NiPr2
N
O
Me
(R)-3c
1b
2a−n
(1.05 equiv.)
4ba−bn
Entry Product
Conversion
(time)
e.r.*
Entry Product
Conversion
(time)
e.r.*
Entry Product
Conversion e.r.*
(time)
Ph
O
Ph
S
O
Ph
S
O
1
93% (24 h)
95.3:4.7
6
93% (21 h)
97.1:2.9 13
80% (24 h) 98.0:2.0
S
Me
Me
iPrO
OiPr
4bf
4bk
4ba
Ph
O
O
O
Ph
S
O
Ph
S
O
2
100% (24 h) 95.1:4.9
7
>95% (42 h) 97.5:2.5 14
80% (48 h) 94.0:6.0
95% (21 h) 92.6:7.4
90% (48 h) 91.8:8.2
S
Et
iPr
iPr
4bg
OMe
4bl
4bb
Ph
S
Ph
S
O
Ph
S
O
3
>95% (24 h) 95.6:4.4
8
>95% (24 h) 98.0:2.0 15
Et
Et
4bh
CF3
4bm
4bc
Ph
S
Ph
S
O
Ph
S
O
4
88% (51 h)
95.7:4.3
9
67% (48 h)
96.3:3.7 16
iPr
4bi
NO2
4bd
4bn
Ph
S
O
Ph
S
O
5
>95% (21 h)
97.2:2.8 10
70% (65 h)
99.1:0.9
11
12
80%†(24 h) 99.0:1.0
100%‡(12 h) 98.0:2.0
Me
iPr
iPr
4be
4bj
General reaction conditions: 5 mm NMR tube, 1b (70.0 µmol), 2 (74.0 µmol), MsOH (70.0 µmol), (R)-3c (10 mol%), CDCl3 (0.11 M), −20 °C. Conversion was determined by assuming that, besides small
quantities of the respective tetrahydrofuran (<5%), 1b was converted only to 4, as no other significant product was detected by 1H NMR spectroscopy. *Determined by CSP–SFC analysis. †Reaction
conducted at 0 °C. ‡Reaction conducted at room temperature.
terminal and E-1,2-disubstituted alkenes, 1,1-disubstituted and dependence was observed for both catalyst 3a and substrate 1a,
trisubstituted double bonds did not respond to this modification, implying a simple bimolecular turnover-limiting step. In addition,
affording results comparable with 2a and 2j (not shown).
the zeroth-order dependence of the rate on the concentration of
electrophile 2a (even at only 3 equiv. 2a with respect to catalyst)
implies that the catalytically active sulfenylating agent (5, Fig. 3)
Discussion
The kinetic studies undertaken here have allowed for a better under- is at a saturated equilibrium concentration22. When the reaction
standing of the reaction mechanism (Fig. 3). A first-order was tested at different acid concentrations, no overall linear
4
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Table 2 | Scope of sulfenofunctionalization using sterically demanding sulfenylating reagents.
Nu
R2
O
MsOH
(R)-3c (0.1 equiv.)
R1
R2
HNu
R1
+
N
S
S
CH2Cl2
T, t
R2
O
R2
1b−f
4ba, bf, bh, bj and
4ca−4fa and 4cj−1fj
2a,f,h,j
(1.05 equiv.)
Entry
1
2
3
4
Alkene
Sulfenylating agent
Temp (°C)
Time (h)
Product
4ba*
4bf
4bh
4bj
Yield§ (%)
78
e.r*
1b
1b
1b
1b
2a
2f
2h
2j
−20
−20
−20
0
36
36
36
48
95.6:4.4‡‡
97.6:2.4‡‡
98.4:1.6††,j
99.3:0.7††,j
84
87||
87¶
O
5
6
2a
2j
0
0
36
36
4ca (R = H)*
4cj (R = iPr)*
83
94
88.9:11.1‡‡
OH
R
98.6:1.4§§
1c
1d
S
R
OMe
7
8
2a
2j
−20
48
36
4da (R = H)*,†
4dj (R = iPr)†
77
85
97.4:2.6§§
99.2:0.8§§
nPr
Me
nPr
Me
0
R
S
R
OMe
nHex
9
2a
2j
23
23
24
24
4ea (R = H)*,†
4ej (R = iPr)†
75#
84#
87.8:12.2‡‡
98.6:1.4§§
Me
R
10
1e
1f
S
R
O
Ts
N
11
2a
2j
0
48
24
4fa (R = H)‡
4fj (R = iPr)‡
85
72
83.7:16.3‡‡
94.3:5.7§§
Ph
O
Ph
NHTs
12
23
S
R
R
General reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), MsOH (1.0 mmol), (R)-3c (10 mol%), CH2Cl2 (0.2 M). *Reaction of literature described compounds21 conducted on 0.2 mmol scale. †MeOH used as
external nucleophile. ‡0.5 equiv. MsOH used. §Yield of isolated products. ∥Combined yield of a 97:3 mixture of tetrahydropyran/-furan. ¶Combined yield of a 93:7 mixture of tetrahydropyran/-furan. #Combined
yield of a 4:1 mixture of 4e and its constitutional isomer (see Supplementary Information). **Absolute configuration assigned by comparison and in analogy to literature described compounds. ††e.r. of the major
isomer. ‡‡Determined by CSP-SFC analysis. §§Determined by HPLC analysis.
relationship was found. Instead, the rate appeared to be dependent formation as the only possibility for the enantiodetermining step.
on two competing processes at low and high acid concentrations. At The formation of thiiranium ion i (Fig. 3) thereby constitutes the
concentrations corresponding to the catalyst-unsaturated system irreversible setting of both stereocentres, which are not affected by
(<4 equiv. MsOH with respect to 3a), a first-order dependence on downstream processes. The observed improvements in enantio-
acid concentration is observed. In contrast, the rate dependence of selectivity of the overall reaction when more hindered sulfenylating
the catalyst-saturated system (≥6 equiv. MsOH with respect to agents are employed further support this conclusion, as avoidance
3a) is an inverse dependence with a slope of −0.35. In this of increased steric interactions leads to better differentiated
scenario, the excess acid protonates the nucleophile, retarding the transition states.
opening of the thiiranium ion, which now presumably becomes
rate-determining.
The activation parameters of ΔH‡ = 8.9 kcal mol−1 and
ΔS‡ = −52.7 e.u. imply a highly ordered transition state in which
The enantiodetermining step of the sulfenylation is most the reaction barrier is primarily entropy-dominated. This profile
likely an irreversible step, as the high selectivity precludes a results from the organizational requirement wherein the alkene
dynamic process that can interconvert the enantiomers. The must approach the catalyst in a highly restricted conformational
capture of the thiiranium ion formed from 1b, for example, in the landscape. In fact, the entropic barrier is comparable to those of
presence of excess MsOH, is known to be reversible, even at low other highly conformationally restricted bimolecular transition
temperatures21. Isolation of tetrahydropyranyl and -furanyl thio states such as those of Diels–Alder reactions32, Morita–Baylis–
ethers followed by resubjection to the reaction conditions resulted Hillman reactions33 or the Lewis base-promoted aldol addition of
in no change in the enantiomeric composition, although the ratio trichlorosilyl enolates34. Such highly restricted transition states
of constitutional isomers was affected21. It is therefore unlikely bode well for computational analysis, as the degrees of freedom of
that capture can be rate-determining, leaving thiiranium ion the reaction partners are significantly reduced.
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MsOH
+
O
To further refine this picture, two assumptions were made with
regard to the directionality of the alkene approach. First, to maxi-
mize orbital overlap between the lowest unoccupied molecular
orbital (LUMO) of the electrophile and the highest occupied mol-
ecular orbital (HOMO) of the alkene, an approach of the bonding
–
MsO
OH
N
SPh
N
SPh
MsOH
+
O
O
Nu
Me
R2
π-orbital of the alkene along the S–Se σ*-orbital is expected38,39
.
2a
N
N
Se
R1
O
P
Second, for such group-transfer reactions, two limiting transition-
state geometries must be considered. In the planar transition state
(Fig. 4a, left) the alkene double bond is located in the plane
defined by the Caryl–S–Se subunit, whereas in the spiro transition
state (Fig. 4a, right) the double bond is positioned perpendicular
to this plane. By analogy to the oxygen atom transfer to alkenes
with dioxiranes and peracids (epoxidation), the spiro transition
state is favoured due to a stabilizing interaction of a sulfur lone
SPh
NR2
NH
Me
O
3
31P NMR for 3c: 81.1 ppm
Me
H
SPh
Se
MsO
MsO
R2
Nu
N
R1
P
NR2
N
PhS
pair with the π*-orbital of the alkene40–42
.
Me
3
Combining these considerations, four limiting transition states
for the formation of the thiiranium ion can be formulated
(Fig. 4b). For the purposes of calculating their energies, the coordi-
nates from the X-ray crystal structure of active species 5b were
employed wherein the sulfur donor atom of the Lewis base was
replaced by a selenium atom (5c) to more accurately reflect the
active species generated from the most selective catalyst 3c (note
that the (S)-enantiomer of the catalyst was used for the calculations).
With regard to the arylsulfenyl moiety, the parent phenysulfenyl
group (R = H, H-TS) was compared to the 2,6-dimethylphenylsulfe-
nyl group (R = Me, Me-TS) to secure greater insight into the
observed differences in enantioselectivity between different
sulfenylating agents (Table 1 and Table 2). For the alkene, trans
β-methylstyrene was chosen as a surrogate for substrate 1b to
embody the energetic contributions of aryl and alkyl substituents
with the active species. All the transition states were investigated at
the B3LYP level using the 6-31G(d) basis set43,44, and the results are
summarized in Fig. 4b and Table 3 (for full structures of all transition
states see Supplementary Information, pages 75 and 83). Solvation free
5c
31P NMR: 59.9 ppm
R2
R1
R1
R2
S
NuH
3
Ph
MsO
i
Figure 3 | Proposed catalytic cycle of Lewis-base catalysed
sulfenofunctionalization. The catalytic cycle commences with the
sulfenylation of Lewis base 3 mediated by MsOH to generate catalytically
active species 5, which is the resting state of the catalyst with a diagnostic
31P NMR chemical shift at 59.9 ppm for 5c. Subsequently, in the turnover-
limiting and stereo-determining step, the arylsulfenyl group is transferred to
the alkene, forming the enantiomerically enriched thiiranium ion. Its
stereospecific capture by an internal or external nucleophile delivers the
sulfenofunctionalized product and regenerates catalyst 3.
Computational studies on the formation of thiiranium ions are energy corrections were computed by singlet point Conductor
virtually non-existent, which is surprising given the fact that this Polarized Continuum Model (CPCM)45,46 calculations on gas-
event constitutes the enantiodetermining step of the sulfenofunctio- phase optimized geometries, Universal Force Field (UFF) atomic
nalization unless a meso-thiiranium ion is generated14,15. Radom35–37 radii were used and dichloromethane was specified as the solvent.
and Modena38,39 have calculated the transfer of a sulfenium ion from
For R = H, the lowest calculated transition state H-TS-major1
a thiiranium ion to both σ- and π-nucleophiles, which represents the (Fig. 4c, left) accounts for the formation of the (2S,3R)-enantiomer
microscopic reverse of the process. However, the availability of of 4ba, which is in agreement with the experimental findings using
X-ray crystallographic structural information for the catalytically catalyst (S)-3c. Transition state H-TS-major2 is 1.1 kcal mol−1 less
active species 5b enables a detailed examination of the forward reac- stable than H-TS-major1 and leads to the same enantiomer of 4ba.
tion (namely the formation of the thiiranium ion) with the aid of
computational methods, to gain a more quantitative understanding site face of the alkene reveals that the more stable H-TS-minor1
of the origin of enantioselectivity.
(Fig. 4c, middle left) is 1.4 kcal mol−1 (≅94.2:5.8 e.r.) higher in
Inspection of the two transition states for reaction on the oppo-
Initial clues to understanding the origin of enantioselectivity are energy than H-TS-major1, which correlates well with the enantio-
provided by the solid-state structure of the active species 5b. As selectivity observed (95.6:4.4 e.r.; ΔΔG† ≅ 1.55 kcal mol−1) for 4ba
already implied, the plane defined by the C(32)–N(3)–C(29) at −20 °C (Table 2, entry 1). The least stable of the four transition
atoms of the diisopropylamino group is coincident with the states is H-TS-minor2 (2.3 kcal mol−1), in which the phenyl ring
P(1)–S(1) bond. This anomerically stabilized conformation is positioned in the proximity of the binaphthyl backbone.
positions the two isopropyl groups such that rotation of the P
Computational analysis also provided insights into the origin of
(1)–S(1)–S(2)-phenyl subunit around the P(1)–S(1) bond is improved enantioselectivity with bulkier arylsulfenyl groups
restricted. As a consequence, the transferable S-phenyl group is (Table 1). To probe this feature, transition-state energies were calcu-
oriented towards the binaphthyl backbone, which is reflected lated using 4f, which bears methyl groups at the ortho positions of
in the N(3)–P(1)–S(1)–S(2) torsion angle of 175.1°. This orientation the sulfenylating agent. This modification enhances the steric inter-
dictates a specific approach vector for the incoming alkene and actions between the alkene and the S-aryl moiety in the transition
contributes to the enantiotopic face discrimination. In contrast, if states, leading to an increased energy difference of 2.2 kcal mol−1
the steric demand of the dialkylamino substituent of the catalyst (Fig. 4b, Me-TS-major1 versus Me-TS-minor1). Although the
is decreased, as is the case with a piperidinyl group, the arylsulfenyl experimentally observed enantiomeric composition of 4bf
moiety can rotate away from the binaphthyl backbone. This (97.6:2.4 e.r.; ΔΔG† = 1.86 kcal mol–1, Table 2, entry 2) is slightly
increased flexibility now leads to reduced steric interactions below the predicted value of 98.7:1.3, the trend of higher enantio-
between the approaching alkene and the active species during thiir- selectivity with increased steric demand of the arylsulfenyl group
anium ion formation and is ultimately responsible for the moderate is satisfactorily reflected by the calculations.
enantioselectivity seen, for example, with a piperidinyl-substituted
In both systems, careful inspection of the competing transition
structures failed to identify any obvious interactions that would
catalyst (79:21 e.r.)21.
6
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2109
ARTICLES
R2
a
R2
R2
R1
R2
R1
R
R1
R1
R
S
S
R
S
R
S
Se
Se
Me
LB
LB
Me
R
R
P
P
R
N
N
R
NiPr2
N
N
NiPr2
Me
Me
Planar
Spiro
TS-spiro
TS-planar
Me
Ph
Me
R
Ph
b
Ph
Me
Ph
Me
R
R
R
S
S
S
S
Se
Se
P
Se
Se
Me
Me
Me
Me
R
R
R
R
P
P
P
N
N
N
N
N
N
N
N
NiPr2
NiPr2
NiPr2
NiPr2
Me
Me
Me
Me
H-TS-major1
H-TS-major2
H-TS-minor1
H-TS-minor2
R = H
ΔΔG = 0.0 (0.0)
ΔΔG = 1.5 (1.1)
ΔΔG = 1.7 (1.4)
ΔΔG = 3.0 (2.3)
kcal mol–1
kcal mol–1
kcal mol–1
kcal mol–1
Me-TS-major1
ΔΔG = 0.0 (0.0)
kcal mol–1
Me-TS-major2
ΔΔG = 1.8 (1.0)
kcal mol–1
Me-TS-minor1
ΔΔG = 3.5 (2.2)
kcal mol–1
Me-TS-minor2
ΔΔG = 5.4 (4.6)
kcal mol–1
R = Me
c
2.53
2.83
2.11
2.19
2.61
2.83
2.44
2.11
2.46
2.96
2.17
2.88
H-TS-major1
H-TS-minor1
Me-TS-major1
Me-TS-minor1
Figure 4 | Calculations of transition states leading to formation of the thiiranium ion. a, Limiting transition-state geometries are shown wherein the spiro
transition state is favoured over the planar transition state due to a stabilizing interaction of a sulfur lone pair with the π*-orbital of the alkene in the former.
b, Free energies of the four transition states with two different arylsulfenyl groups are given for the reaction at −20 °C. Data given in parentheses have been
computed using the CPCM solvent model (UFF radii, CH2Cl2). c, Four transition states are presented to illustrate steric interactions between the alkene and
the catalytically active species during thiiranium ion formation. Both transition states that lead to the respective minor enantiomer (H-TS-minor1 and Me-TS-
minor1, respectively) suffer from destabilizing distortions as a result of the alkene approach vector.
Table 3 | Distortion interaction and NBO analysis (B3LYP/6-31G(d) energies at 253.15 K in kcal mol−1).
ΔEdist_A*
ΔEdist_B†
ΔEd
ΔEi
ΔE‡act
ΔH
ΔG
π(C=C)–σ*(S–Se)§
H-TS-major1
H-TS-major2
H-TS-minor1
H-TS-minor2
Me-TS-major1
Me-TS-major2
Me-TS-minor1
Me-TS-minor2
9.6
10.7
10.4
13.3
7.8
9.0
9.4
9.1
26.1
27.4
28.1
33.5
22.8
27.2
28.6
29.9
35.7
38.1
−24.8
−25.6
−25.9
−32.2
−19.9
−22.4
−23.0
−23.6
10.9 (0.0)
12.5 (1.6)
12.6 (1.7)
14.6 (3.7)
10.8 (0.0)
13.7 (2.9)
15.0 (4.2)
15.4 (4.6)
11.9 (0.0)
13.5 (1.6)
13.6 (1.7)
15.2 (3.3)
11.2 (0.0)
14.7 (3.5)
15.3 (4.1)
15.5 (4.3)
23.9 (0.0)
25.4 (1.5)
25.6 (1.7)
26.9 (3.0)
25.0 (0.0)
26.8 (1.8)
28.5 (3.5)
30.4 (5.4)
63.3 (6.7)
57.5 (0.9)
64.2 (7.6)
56.6 (0.0)
61.7 (7.3)
55.9 (1.5)
62.1 (7.7)
54.4 (0.0)
38.5
46.8
30.7
36.1
38.0
39.0
*A = β-methylstyrene. †B = 5c (H = C6H5; Me = 2,6-Me2C6H3). ‡ΔEact = ΔEd + ΔEi; ΔEd = ΔEdist_A + ΔEdist_B. §π(C=C)–σ*(S–Se) orbital interaction energy is calculated by NBO analysis.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2109
ARTICLES
with a septum and placed into an iPrOH bath, which was cooled to 0 °C using a
cryocool unit. The temperature of the mixture was monitored by a thermocouple
digital temperature probe. Once the temperature had stabilized, MsOH (65 µl,
1.0 mmol, 1.0 equiv.) was added via syringe and the mixture was allowed to stir for
48 h at 0 °C. On completion of the reaction (monitoring by thin-layer
chromatography), the mixture was quenched while cold by the addition of Et3N
(0.20 ml). The mixture was poured into aqueous HCl (1.0 M, 20 ml) in a separatory
funnel, CH2Cl2 (30 ml) was added, and the layers were thoroughly mixed. The
organic layer was poured into aqueous NaOH (1.0 M, 20 ml), and the layers were
thoroughly mixed and then separated. The acidic layer was back-extracted with
CH2Cl2 (30 ml), which was poured into the basic layer and used to extract that layer
disfavour H-TS-major1 or Me-TS-major1 with respect to H-TS-
minor1 or Me-TS-minor1. The highly unsymmetrical transition
states allow for a significant distance between the aryl residue and
the catalytically active species, obviating any severe non-
bonding interactions.
To provide additional insight into the origin of enantioselectivity,
distortion-interaction47 and natural bond order (NBO)48 analyses
were carried out (Table 3). These results mirror those from density
functional theory (DFT) analysis and suggest that a more subtle
effect may be operative. As shown in Table 3, H-TS-major1 possesses as well. Both organic portions were combined, dried over MgSO4, filtered through
the lowest activation energy, 1.7 kcal mol−1 lower than H-TS-
glass wool and concentrated in vacuo (20–23 °C, 20 mmHg). Purification by flash
column chromatography (SiO2, 65 g, 35 mm diameter, hexane/methyl-tert-butyl
ether = 60:1) afforded 310 mg (87%) of a 93:7 mixture of 4bj and the corresponding
tetrahydrofurane (4bj′) as a pale yellow oil. Partial separation of isomers was
accomplished by flash column chromatography using high-porosity silica gel (SiO2,
minor1. Interestingly, although H-TS-minor1 benefits from a
greater interaction energy (ΔΔEi = −1.1 kcal mol−1), this advantage
is offset by a greater distortion energy (ΔΔEd = 2.8 kcal mol−1).
65 g, 35 mm diameter, hexane/methyl-tert-butyl ether = 80:1 → 5:1), yielding
271 mg of a 97:3 mixture of 4bj and 4bj′ and 30 mg of a 60:40 mixture of 4bj and 4bj′.
The enantiomeric ratio of 4bj was determined to be 99.3:0.7 by chiral stationary
phase-supercritical fluid chromatographic analysis of the chromatographically
homogeneous material.
The greater interaction energy associated with H-TS-minor1 was
substantiated by the NBO analysis, which provided the stabilization
energies arising from orbital overlap from the π-bond of the alkene
to the antibonding (σ*) orbital of the sulfur–selenium bond.
The stabilization energy for H-TS-minor1 is slightly greater
(0.9 kcal mol−1) than for H-TS-major1, indicating similar levels
of orbital overlap. However, to achieve those levels of overlap
requires greater distortion of the orbitals in H-TS-minor1 (probably
resulting from the non-ideal approach of the alkene). Thus, whereas
unfavourable steric interactions are not the apparent cause of the
enantioselectivity, it is likely that the avoidance of unfavourable
steric interactions leads to a non-ideal approach of the alkene that
manifests in the greater distortion energy contribution to that
transition state.
Exactly the same trends are seen for the corresponding transition
states calculated for the 2,6-dimethyl-substituted sulfenylating
agent, but with a much greater energy differences throughout.
Interestingly, Me-TS-minor1 has a significantly greater interaction
energy (ΔΔEi = −3.1 kcal mol−1) and marginally larger orbital
overlap energy (0.4 kcal mol−1), but at a much greater cost in distor-
tion energy (ΔΔEd = 7.3 kcal mol−1), consistent with a more drastic
change in the approach vector for the alkene to avoid non-bonding
interactions with the methyl substituents.
X-ray crystallographic data. CCDC 1006824 contains the crystallographic data for
the dimer in equation (2) and CCDC 1006831 contains the crystallographic data for
compound 5b. These data can be obtained free of charge from the Cambridge
Crystallographic Data Center (www.ccdc.cam.ac.uk).
Received 26 June 2014; accepted 30 September 2014;
published online 10 November 2014
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Acknowledgements
The authors acknowledge financial support from the National Institutes of Health (GM
R01-085235). E.H. thanks the Deutscher Akademischer Austauschdienst for a postdoctoral
fellowship. D.J-P.K. thanks the University of Illinois for a Seemon H. Pines Graduate
Fellowship in Synthetic Organic Chemistry. The authors thank L.M. Wolf (MPI-
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Author contributions
E.H. planned and carried out the experimental work and obtained the X-ray structure of 5b.
D.J-P.K. carried out the kinetic analysis and H.W. performed the transition state
calculations. S.E.D. initiated and directed the project. E.H. wrote the manuscript with the
assistance of the other authors.
34. Denmark, S. E. & Pham, S. M. Kinetic analysis of the divergence of
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pair donors and unsaturated hydrocarbons. Chem. Eur. J. 7, 1516–1524 (2001).
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thiirenium and thiiranium ions feasible? An ab initio investigation. Chem. Eur. J.
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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 S.E.D.
37. Sølling, T. I., Wild, S. B. & Radom, L. Are the approach directions of σ and π
nucleophiles to the sulfur atom of thiiranium and thiirenium ions different?
Chem. Eur. J. 6, 590–591 (2000).
Competing financial interests
The authors declare no competing financial interests.
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