Non-bonding 1,5-S?O interactions govern chemo- and enantioselectivity in isothiourea-catalyzed annulations of benzazoles

Article abstract of DOI:10.1039/c6sc00940a

Isothiourea-catalyzed annulations between 2-acyl benzazoles and α,β-unsaturated acyl ammonium intermediates are selectively tuned to form either lactam or lactone heterocycles in good yields (up to 95%) and high ee (up to 99%) using benzothiazole or benzoxazole derivatives, respectively. Computation gives insight into the significant role of two 1,5-S?O interactions in controlling the structural preorganization and chemoselectivity observed within the lactam synthesis with benzothiazoles as nucleophiles. When using benzazoles the absence of a second stabilizing non-bonding 1,5-S?O interaction leads to a dominant C-H?O interaction in determining structural preorganization and lactone formation.

Full text of DOI:10.1039/c6sc00940a

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Non-Bonding 1,5-S•••O Interactions Govern Chemo- and
Enantioselectivity in Isothiourea-Catalyzed Annulations of
Benzazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Emily R. T. Robinson,a Daniel M. Walden,b Charlene Fallan,a Mark D. Greenhalgh,a Paul Ha-Yeon
Cheong,b* and Andrew D. Smitha*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Isothiourea-catalyzed annulations between 2-acyl benzazoles and α,β-unsaturated acyl ammonium intermediates are
selectively tuned to form either lactam or lactone heterocycles in good yields (up to 95%) and high ee (up to 99%) using
benzothiazole or benzoxazole derivatives, respectively. Computation gives insight into the significant role of two 1,5-
S•••O interactions in controlling the structural preorganization and chemoselectivity observed within the lactam synthesis
with benzothiazoles as nucleophiles. When using benzazoles the absence of a second stabilizing non-bonding 1,5-S•••O
interaction leads to a dominant C–H•••O interaction in determining structural preorganization and lactone formation.
symmetrical
functionalized esters in high ee after ring-opening through a
postulated Michael addition-lactonization/ring-opening
1,3-dicarbonyl
nucleophiles
generates
Introduction
Nitrogen-containing heterocycles are of wide-spread
importance in pharmaceutical, agrochemical and material
science industries.1 In particular, benzazoles have found broad-
reaching applications as bioactive compounds in medicinal
chemistry, with a range of therapeutic treatments exploiting
their anti-bacterial, anti-fungal, anti-parasitic and anti-cancer
properties.2 In addition, they are key components of useful
ligands3 as well as organic semiconductors and dyes.4 The
prevalence of the benzazole motif in these applications has led
the synthetic community to develop numerous methodologies
for the use of benzazole containing nucleophiles for the rapid
synthesis of complex heterocycles.5
process (17 examples, up to 96% ee). Notably, preliminary
results using unsymmetrical 2-phenacylbenzothiazole as a
nucleophile gave functionalized lactams preferentially (~85:15
lactam:lactone), resulting from preferential N- rather than O-
cyclization, through a Michael addition-lactamization process
in up to 86% ee in three isolated examples (Scheme 1, eq 2).
Despite
this
interest,
catalytic
enantioselective
functionalization of benzazole derivatives has received limited
attention, with only a small number of enantioselective
protocols developed to date.6 As a representative example of
such an approach, Lam has shown that benzazoles undergo
catalytic enantioselective nickel-catalyzed Michael-additions to
nitroalkenes, giving the desired products in high yields,
moderate to excellent dr and good to excellent
enantioselectivity (Scheme 1, eq 1).7 As part of our ongoing
research employing isothioureas8 in catalysis,9 we recently
developed an enantioselective annulation process utilizing α,β-
unsaturated acyl ammonium intermediates.10,11 In this
annulation process, reaction of this intermediate with
Scheme 1: Previous work using benzazoles in enantioselective catalysis. Eq 1 Nickel-
catalyzed Michael addition to nitroalkenes; Eq 2 isothiourea-catalyzed enantioselective
annulation with α,β-unsaturated acyl ammonium intermediates
This manuscript builds upon the intriguing chemoselectivity
observed in the preferential formation of lactams in this latter
process, and subsequently explores the effect of changing
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both carbonyl substitution and the heteroatom within a series (88:12 lactam 4A: lactone 4B), with 4A isolated in 86% yield
of acylbenzazole nucleophiles. As a result, we have developed and 83% ee that was recrystallized to give 4A in 68% yield and
a highly chemoselective method to access either lactam A or 97% ee. A small amount of the lactone constitutional isomer
heterocyclic products in excellent enantioselectivity 4B was also isolated (9% yield, 86% ee).16 The potential for
lactone
B
through use of acylbenzothiazole or acylbenzoxazole isomerization of lactone 4B to the lactam 4A) was investigated
derivatives respectively (Scheme 2). Furthermore, through under a range of conditions. Treatment of the minor lactone
computations, the role that non-bonding 1,5-S•••O product 4B with base, with base and HyperBTM, or to the
interactions and C–H•••O interactions play in governing the reaction conditions, led to no interconversion of lactone to
unusual regioselectivity of these processes is highlighted. The lactam, consistent with the observed product ratios arising
importance of non-bonding S•••O interactions has been from kinetic control (see SI for further details). The
widely recognized in structural and medicinal chemistry in the incorporation of electron donor benzothiazole amides and
solid state (commonly ascribed to a stabilizing nO to
σ
*
esters resulted in the exclusive formation of lactams 2A and 3A
interaction),12 and has been used as a key controlling element as single constitutional isomers in excellent ee (97% and 93%
to
rationalize
enantioselective
isothiourea-catalyzed ee) and in good yields respectively. Further studies probed the
reactions.13 While the origin of this interaction is still under effect of variation within the heterocyclic portion of the
debate,14 and is the focus of ongoing work within our research benzazole. While using 2-phenacylbenzothiazole leads to
groups, the demonstration of alternative examples of how preferential formation of lactam 4A
non-bonding S•••O interactions can facilitate selectivity in phenacylbenzoxazole afforded exclusively lactone product
catalysis could lead to its broader utilization, akin to the (>95:5 5B 5A) with the lactone 5B isolated in 95% yield and
,
remarkably, 2-
:
current widespread use of hydrogen bonding and other non- 98% ee. The seemingly trivial substrate change from
bonding interactions in synthesis.15 To the best of our benzothiazole to benzoxazole in this system promotes a
knowledge, S•••O interactions have not been invoked to change in chemoselectivity in the annulation process to
describe the origins of chemoselectivity in a catalytic reaction.
selectively facilitate lactone (O-cyclization) rather than
preferential lactam (N-cyclization) product formation.
This work: S•••O-controlled chemodivergence
O
R
O
O
LB*
iPr
Ph
N
O
R1
R1
N
R2
X
S
R
N
Lewis Base
Activation
= HyperBTM 1
Deprotonation
iPr
δ−
O
N
S
X
N
X
O
Ph
N
N
δ−
R2
1,5-S•••O
O
R
R1
R2
O
LB
R
R1
α,β-Unsaturated Acyl
1,4-addition
Annulation
Benzazole Nucleophile
Ammonium Electrophile
X = S
X = O
O
R
R2
X
X
R
Lactam A
Lactone B
N
R2
N
O
Scheme 3: Probing the effects of acyl and benzazole substituents on annulation chemo-
a
O
and enantioselectivity Ratio of constitutional isomers arising from either N- or O-
O
R1
R1
b
cyclization calculated from 1H NMR spectra of crude reaction product. ee values
> 30 examples
c
• High enantioselectivity (up to 99% ee)
• High chemoselectivity (up to >95:5) for lactam A or lactone B formation
obtained via chiral HPLC. Following a single recrystallization ee could be enhanced to
97%.
Scheme 2: Chemo- and enantioselective isothiourea-catalyzed annulation of
Scope and Generality
acylbenzazoles with α,β-unsaturated acyl ammonium intermediates
To demonstrate the generality of these chemo- and
enantioselective annulation processes, and facilitate direct
comparison across a range of substrates, the use of 2-
phenacylbenzothiazole, 2-phenacylbenzoxazole and 2-N,N-
dimethylacetamidobenzothiazole as nucleophiles was fully
investigated with a range of anhydrides (Table 1).
Results and Discussion
Probing the effects of acyl and benzazole substituents on
annulation chemo- and enantioselectivity
Initial investigations sequentially probed substituent effects on
the chemo- and enantioselectivity of this annulation process
within a series of acylbenzazoles, with variation of both the
acyl substituent and heterocycle tested (Scheme 3). Consistent
with our previous studies, using homoanhydrides as α,β-
unsaturated acyl ammonium precursors with isothiourea
HyperBTM
1
(5 mol%) in bench-grade THF, 2-
phenacylbenzothiazole gave preferentially lactam product 4A
2 | J. Name., 2012, 00, 1-3
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S
O
S
O
N
Ph
N
Ph
N
NMe2
S
O
N
Ph
O
O
O
O
O
O
O
O
O
O
OMe
6A, 53%,a 93% eeb
OMe MeO
MeO
8B, 74%,a 90% eeb
7A, 59%,a 85% eeb; 7B, 6%,a 89% eeb
7A:7B 88:12c
S
O
S
O
N
Ph
N
Ph
N
NMe2
S
O
N
Ph
O
O
O
O
CF3
CF3 F3
C
F3C
9A, 60%,a 97% eeb
78%,d 10A, 79% eeb; 10B, 90% eeb
11B, 36%,a 99% eeb
10A:10B 77:23c
S
O
S
O
N
Ph
N
Ph
N
NMe2
Br
S
O
N
Ph
O
O
Br
Br
Br
O
O
12A, 92%,a 96% eeb
86%,d 13A, 84% eeb; 13B, 84% eeb
13A:13B 87:13c
14B, 78%,a 98% eeb
S
O
S
O
N
Ph
N
NMe2
S
N
Ph
O
O
no reaction
O
O
Br
15A, 92%,a 96% eeb
Br
Br
62%,d 16A, 81% eeb; 16B, 31% eeb
16A:16B 87:13c
S
O
S
O
N
Ph
N
Ph
N
NMe2
Me
17A, 71%,a 92% eeb
S
O
N
Ph
Me
O
O
O
O
Me
O
Me
O
18A, 55%,a 86% eeb; 18B, 9%,a 92% eeb
18A:18B 82:18c
19B, 77%,a 93% eeb
S
O
N
Ph
N
O
Ph
S
O
N
NMe2
S
O
O
O
N
Ph
O
O
O
O
O
O
O
20A, 79%,a 95% eeb
22B, 83%,a 97% eeb
21A, 72%,a 80% eeb; 21B, 10%,a 80% eeb
21A:21B 88:12c
S
O
N
Ph
N
Ph
S
O
N
NMe2
O
O
S
O
O
N
Ph
O
O
O
O
O
O
O
O
O
23A, 53%,a 95% eeb
25B, 83%,a 97% eeb
24A, 40%,a 90% eeb; 24B, 5%,a 94% eeb
24A:24B 88:12c
S
O
N
Ph
N
Ph
S
O
N
NMe2
S
S
O
O
O
N
Ph
O
O
O
S
S
S
26A, 58%,a 96% eeb
28B, 45%,a 97% eeb
27A, 46%,a 82% eeb; 27B, 6%,a 85% eeb
27A:27B 87:13c
S
O
N
Ph
N
Ph
S
O
N
NMe2
CO2Et
29A, 77%,a 92% eeb
S
O
O
O
N
Ph
O
O
O
CO2Et
EtO2
C
EtO2C
30A, 50%,a 52% eeb; 30B, 5%,a 56% eeb
30A:30B 71:29c
68%,d 31B: 94% eeb; 31A 90% ee
31B:31A 97:3c
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a
b
c
Table 1: isolated yield of single constitutional isomer. ee values obtained via chiral HPLC. ratio of constitutional isomers calculated from 1H NMR spectra of crude reaction
product. d isolated yield of inseparable mixture of constitutional isomers.
Consistent with the model studies, chemoselective leading to cyclized lactam product 35 containing a stereogenic
formation of either lactam or lactone products (>95:5 ratio of quaternary trifluoromethyl group in moderate yield but 96%
constitutional isomers) was achieved by using the 2-N,N- ee. Notably no lactone products were observed in this
dimethylacetamidobenzothiazole or 2-phenacylbenzoxazole, annulation process, although 1,2-addition product 36 was
with excellent enantioselectivity (90-99% ee) observed across isolated in 13% yield as a side-product.
a range of anhydrides. Using 2-phenacylbenzothiazole led to Scale-up and Derivatizations:
preferential lactam formation (typically ~85:15 lactam:
To demonstrate the potential further utility of the heterocyclic
lactone), albeit with reduced enantioselectivity (typically >80%
products obtained, scale-up and derivatization through
ee). For all acylbenzazole nucleophiles, variation of aryl
palladium-catalyzed cross-coupling reactions was tested. 3-
substitution within the anhydride was tolerated, including
BrC6H4-substituted lactam 14A was readily prepared on gram
electron donating (4-MeOC6H4), electron withdrawing (4-
scale in high yield and enantioselectivity (1.15 g, 75%, 96% ee).
CF3C6H4), and 3-BrC6H4 substitution. Sterically demanding 2-
Subjecting lactam 14A to Suzuki coupling generated 37 in 70%
BrC6H4 substitution led to no reaction with 2-
yield with no erosion of enantioselectivity; similarly, Heck
phenacylbenzoxazole,
while
reactions
using
2-N,N-
reaction of 14A with methyl acrylate afforded 38 in 89% yield
dimethylacetamidobenzothiazole or 2-phenacylbenzothiazole
gave acceptable to good product yields, with excellent
enantioselectivity in the amide series. Heteroaryl (2-furyl, 3-
furyl, and 3-thiophenyl) substituents were also successfully
incorporated (90-99% ee), as were methyl and ester
substitution. In the 2-phenacylbenzothiazole derived series,
the ee of lactam and lactone products were approximately
and 97% ee (Scheme 5).
S
O
N
NMe2
Br
O
(HO)2B
OMe
14A
CO2Me
(5 eq)
(1.5 eq)
Pd(OAc)2 (5 mol%),
dppf (10 mol%),
Na2CO3 (2 eq),
dioxane/H2O (9:1),
100 oC, 15 h
NEt3 (1.25 eq)
Pd(OAc)2 (5 mol%),
P(o-tolyl)3 (10 mol%),
DMF,
equivalent, except for 16A/16B (81% and 31% ee respectively)
bearing a 2-Br substituent. The origin of this variation in ee is
currently unexplained, despite extensive synthetic and
computational investigations.17
125 oC, 15 h
S
O
S
O
OMe
Excited by the high chemo- and enantiocontrol observed,
the scope of this process was expanded to the synthesis of
challenging all-carbon quaternary centers (Scheme 4).
N
NMe2
N
NMe2
CO2Me
O
O
37, 70%,a 99% eeb
38, 89%,a 97% eeb
Trisubstituted homoanhydrides were used as α,β
-
unsaturated acyl ammonium precursors, allowing limited
access to stereogenic quaternary centers for the first time in
this methodology. Initial studies employed 3-methylbut-2-
enoic anhydride 32 and gave the expected achiral lactam
product 33 in good yield (Scheme 4).
a
Scheme 5: Product derivatization through cross coupling. isolated yield. ee values
b
obtained via chiral HPLC.
Computational Details and Mechanism:
Computations were undertaken to provide insight into the
observed chemoselectivity when using the benzoxazole and
benzothiazole nucleophiles (X = O or S, respectively). For this
purpose, we have specifically computed the intermediate and
transition structures involved in the formation of products 4A
(lactam) and 4B (lactone) using 2-phenacylbenzothiazole, and
5B (lactone) using 2-phenacylbenzoxazole. All energy
refinements and geometries were computed in solution using
the implicit polarizable continuum model PCM with
tetrahydrofuran
as
solvent
(M06-2X/6-
31+G(d,p)/PCM(THF)//M06-2X/6-31G(d)/PCM(THF)19).20 The
M06-2X DFT method has been successfully used to rationalize
mechanisms and selectivities of synthetic reactions by us and
others.21 Given the zwitterionic nature of many of the
intermediates in the reaction, we also took into account the
Scheme 4: Generation of all-carbon quaternary centresa
Unfortunately, when (2E)-3-phenylbut-2-enoic anhydride ability of M06-2X to accurately evaluate dispersion-heavy and
was examined under the same conditions, no reaction was ionic systems relative to the less computationally expensive
observed. The use of (2E)-4,4,4-trifluoro-3-methylbut-2-enoic B3LYP method.22 The catalytic cycle is shown in Figure 1.23
anhydride 34 proved compatible with this methodology,18 Stepwise N-acylation of HyperBTM leads to the α,β-
4 | J. Name., 2012, 00, 1-3
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unsaturated acyl ammonium intermediate. Stereodetermining and the incoming nucleophile, dramatically simplifying the
1,4-addition of the anionic benzazole nucleophile and proton stereochemical model. Nucleophilic 1,4-addition occurs anti to
transfer leads to the pre-cyclization intermediate, which can the catalyst stereodirecting groups on the less hindered re-
either lactamize of lactonize. Restoration of the carbonyl π- face. The computed enantioselectivities of 99% in both cases
bond releases the product and regenerates HyperBTM
Me
1.
are in reasonable agreement with experiments (83% and 98%
ee for 4A and 5B, respectively, Scheme 3).
Benzoxazole Nucleophile
Me
N
20.0#
S
O1
O
N
O
Lactam
Lactone
Ph
LB
N
=
HyperBTM 1
Homo
O
16.0#
12.0#
8.0#
2
4
2
4
N
O
Ph
Ph
Syn 3
1 Anti 3
R
Anhydride
X
R
R'
O
O
R
X
O
N
iPr
Ph
N
R'
N
O
O
O
4.0#
S
N
LB
LB
0.0#
α,β-Unsaturated
0#
20#
40#
60#
80#
100# 120# 140# 160# 180#
TS-N-Elimination
TS-O-Elimination
Acyl Ammonium
Dihedral ∠1,2,3,4 (° )
R
Benzothiazole Nucleophile
O
X
X
O
S1
O
N
O
X
R'
N
R'
N
R'
N
20.0#
O
O
O
2
4
2
4
N
S
Ph
Ph
Syn 3
1 Anti 3
R
S
N
O
R
16.0#
12.0#
8.0#
N
R
LB
LB
TS-Lactonization
Ph
Me
TS-1,4-Addition
TS-Lactamization
Lactamization
Me
4.0#
Proton Transfer
0.0#
X
O
Lactonization
0#
20#
40#
60#
80#
100# 120# 140# 160# 180#
N
R'
O
Dihedral ∠1,2,3,4 (° )
R
Pre-Cyclization
Intermediate
Figure 2. Conformational preferences of anionic benzoxazole and benzothiazole
nucleophiles.25
LB
Figure 1. Catalytic cycle of the isothiourea-catalyzed annulations between 2-acyl
benzazoles and homoanhydrides to form the lactam (left) or the lactone (right) using
benzothiazole (X=S) or benzoxazole (X=O) derivatives, respectively.
Lactamization vs. Lactonization: The interplay between S•••O
and C–H•••O interactions26 (between the anionic nucleophile
atoms and C–H
α-to the positively-charged nitrogen of the
S•••O Interaction: Considering this mechanistic scheme,
within all key reactive intermediates and transition states
where S- and O-atoms contain 1,5-connectivity (such as from
the carbonyl C=O and isothiourea S within the acylammonium
intermediate, or 2-phenacylbenzothiazole carbonyl-O and
benzothiazole-S), these atoms are co-planar. The internuclear
distances (within the range of 2.53–2.70 Å) are significantly
less than the sum of the van der Waals radii (3.4 Å).24 These
observations are consistent with an attractive force between
the S- and O-atoms and in line with previous computations by
Tantillo and Romo13b as well as by Houk and Birman.13c Unique
to this system, however, is how this interaction dominates the
structural preorganization of all key reactive intermediates and
transition states of this annulation process.
acylated HyperBTM) governs cyclization regioselectivity. Figure
3 shows computed model complexes analogous to the pre-
cyclization intermediate, featuring truncated simplified
structures of both HyperBTM catalyst and benzazole
nucleophiles. In the oxazole model system, the conformation
with one S•••O and one C–H•••O interaction is favored by 2.5
kcal/mol over the conformation featuring the unfavorable
O•••O. However, in the thiazole model, the conformation
featuring two S•••O interactions, rather than one S•••O and
one C–H•••O, is preferred by 3.7 kcal/mol.
S•••O Interaction in the Enantiocontrol of 1,4-Addition: All
stable conformations of the α,β-unsaturated acyl ammonium
intermediate exhibit coplanarity of the 1,5-O and S atoms. This
is corroborated by the crystal structure of this intermediate
which show the S–O being coplanar at a distance of 2.48 Å.10a
In addition, both anionic nucleophiles prefer the planar
arrangement (Figure 2), with the 1,5-S–O syn conformation
favored by ~7 kcal/mol in the case of benzothiazole. Taken
together, these factors rigidify and planarize both the
electrophilic α,β-unsaturated acyl ammonium intermediate
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Model Benzothiazole
structure anti to the catalyst stereodirecting groups (phenyl
and isopropyl) to minimize steric occlusion. The Favored-
Lactonization-(X=O)-TS is preferred over the Disfavored-
2.58
2.59
O
O
H
S
S
S
N
N
N
N
Lactamization-(X=O)-TS (∆G‡
= 11.1 and 14.3 kcal/mol,
N
Me
O
respectively) due to a stabilizing C–H•••O involving the ortho
N
Me
O
S
2.08
2.76
C–H of the catalyst and the incoming oxygen atom. In the
Dual S•••O
∆∆G = 0.0
S•••O + C–H•••O
∆∆G = 3.7
latter, a β-C–H is involved in a repulsive interaction with the
incoming benzoxazole. The computed selectivity of 99:1
2.58
2.59
O
O
S
S
matches well with the experimental selectivity of 98:2 seen
O
N
N
N
N
with lactone 5B
.
N
The benzothiazole lactone closure occurs exactly as the
benzoxazole case through the Disfavored-Lactonization-(X=S)-
TS (ΔG‡ = 11.7 kcal/mol). The Favored-Lactamization-(X=S)-TS
has a lower barrier (ΔG‡ = 10.6 kcal/mol), and the computed
selectivity of 88:12 matches experiments. Interestingly,
lactamization occurs on the re-face, the same face as the
catalyst stereodirecting groups, previously thought to be
untenable due to the steric occlusion.
Me
N
O
H
Me
O
2.06
O
2.79
S•••O + S•••O
∆∆G = 2.5
S•••O + C–H•••O
∆∆G = 0.0
Model Benzoxazole
Figure 3. Model systems probing the relative energetic values (in kcal/mol) between
S•••O and C–H•••O nonbonding interactions.26
These preferences carry over to the cyclization transition
structures (Figure 4). In the benzoxazole case, both
annulations occur via a boat-like six-membered transition
Figure 4. Computed chemoselectivity determining cyclization transition structures for benzoxazole and thiazole nucleophiles. All transition structures are stepwise
(tetrahedral intermediate formation followed by HBTM release) except for Favored-Lactamization-(X=S)-TS (see supporting information for computed reaction
coordinates). Forming bonds shown in grey. S•••O interactions shown in orange, C–H•••O highlighted in green, and van der Waals repulsion shown in red. Aromatic
interaction shaded in purple. Relative energy values given in kcal/mol. Structure images rendered using CYLview.28
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ARTICLE
Reactions, Syntheses, and Applications, 2nd ed, Wiley-VCH,
Weinheim, Germany, 2003.
Two key stabilizing interactions are present in
benzothiazole lactamization that are not found in
lactonization: (1) π-stacking of the catalyst phenyl and the
fused benzene of the benzothiazole ring,27 and (2) a second
1,5-S•••O interaction within the former benzothiazole
nucleophile. The switch in chemoselectivity in favor of lactam
formation using the benzothiazole is attributed to the penalty
of breaking the 1,5-S•••O present within the benzothiazole
nucleophile for the lactonization process to proceed.
2
3
(a) R. S. Keri, M. R. Patil, S. A. Patil and S. Budagumpi, Eur. J.
Med. Chem., 2015, 89, 207–251. (b) S. Noel, S. Cadet, E. Gras
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2014, 97, 778–785.
(a) J. Kuwabara, T. Namekawa, M.-A. Haga and T. Kanbara,
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Hu, D.-Y. Wang and Z. Zheng, Org. Lett., 2010, 12, 5542–
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4
5
F. S. Rodembusch, F. P. Leusin, L. F. da Costa Medina, A.
Brandelli and V. Stefani, Photochem. Photobiol. Sci. 2005, 4,
254–259.
For selected recent examples, see: (a) Q. Cai, Z. Li, J. Wei, L.
Fu, C. Ha, D. Pei and K. Ding, Org. Lett., 2010, 12, 1500–1503.
(b) H. De Silva, S. Chatterjee, W. P. Henry and C. U. Pittman
Jr., Synthesis, 2012, 44, 3453–3464.
Conclusions
To conclude, we have demonstrated the scope and limitations
of the organocatalytic enantioselective functionalization of a
range of benzazole nucleophiles using the isothiourea
HyperBTM
1 and α,β-unsaturated homoanhydrides as α,β-
unsaturated acyl ammonium precursors. The chemoselectivity
observed during the cyclization is influenced by the nature of
the benzazole and the carbonyl employed within the
acylbenzazole, with benzothiazole preferentially using the ring-
nitrogen to extrude the catalyst, whereas the benzoxazole
moiety prefers to cyclize through the β-carbonyl substituent.
Computations elucidated the importance of non-covalent 1,5-
S•••O interactions in determining the chemoselectivity within
these processes. Specifically, the use of benzothiazole
nucleophiles allows two stabilizing 1,5-S•••O interactions in
the preferred lactamization transition structure, while
benzoxazole contains one stabilizing 1,5-S•••O and one C–
H•••O interaction in the lactonization transition structure.
Future research within our laboratories is aimed at harnessing
the collaboration between theory and experiments towards
the development of isothiourea Lewis base catalysts in new
enantioselective transformations.
6
(a) L. M. Stanley and J. F. Hartwig, J. Am. Chem. Soc., 2009,
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7
8
For seminal work on isothiourea catalysis see: (a) V. B.
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,
9
For selected examples see (a) D. Belmessieri, L. C. Morrill, C.
Simal, A. M. Z. Slawin and A. D. Smith, J. Am. Chem. Soc.,
2011, 133, 2710-2714. (b) D. Belmessieri, D. B. Cordes, A. M.
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Acknowledgements
We thank the Royal Society (URF to ADS), the EPSRC (ERTR –
grant code EP/J500549/1) and the European Research Council
under the European Union’s Seventh Framework Programme
(FP7/2007-2013) ERC grant agreement n° 279850 (CF). We also
thank the EPSRC UK National Mass Spectrometry Facility at
Swansea University. PHYC is the Vicki & Patrick F. Stone
Scholar of Oregon State University and gratefully
acknowledges financial support from the Stone Family & the
National Science Foundation (NSF, CHE-1352663), and the
computing infrastructure in part provided by the NSF Phase-2
CCI, Center for Sustainable Materials Chemistry (NSF CHE-
1102637). DMW also acknowledges financial support from the
Johnson Research Fellowship.
O'Riordan and A. D. Smith, Angew. Chem. Int. Ed., 2013, 52
,
11642-11646. (d) S. R. Smith, C. Fallan, J. E. Taylor, R.
McLennan, D. S. B. Daniels, L. C. Morrill, A. M. Z. Slawin and
A. D. Smith, Chem. Eur. J., 2015, 21, 10530-10536.
10 (a) E. R. T. Robinson, C. Fallan, C. Simal, A. M. Z. Slawin and A.
D. Smith, Chem. Sci., 2013, , 2193-2200; for other examples
4
of related work using α,β-unsaturated acyl ammonium
intermediates, see: (b) E. Bappert, P. Müller and G. C. Fu,
Chem. Commun., 2006, 2604–2606. (c) S. Vellalath, K. N. Van
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(d) G. Liu, M. E. Shirley, K. N. Van, R. L. McFarlin and D.
Romo, Nature Chem., 2013, 5, 1049–1057. (e). S.
Goudedranche, X. Bugaut, T. Constantieux, D. Bonne and J.
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,
Notes and References
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11 For a recent review of related work using α,β-unsaturated
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W. Lupton, Synthesis, 2014, 46, 1823–1835.
5
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Journal Name
12 (a) B. R. Beno, K.-S. Yeung, M. D. Bartberger, L. D. Pennington 23 See Supporting Information for reaction coordinates,
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13 For the initial postulate of 1,5-S•••O interactions as a
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25 All geometries, energies, and thermal corrections obtained
using MO6-2X/6-31+G(d,p)/PCM(THF)//MO6-2X/6-
31G(d)/PCM(THF). Distances in Ångstroms (Å); energies in
kcal/mol.
manuscripts of interest see (b) M. E. Abbasov, B. M. Hudson, 26 (a) D. M. Walden, O. M. Ogba, R. C. Johnston, P. H.-Y.
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16 The absolute configurations of all products are based upon
previous reports of annulations using α,β-unsaturated acyl
ammonium intermediates (see ref. 10,11).
17 Synthetic investigations showed no change in the %ee of
lactone 16B over the course of the reaction, and no
racemization of the isolated product under standard reaction
conditions. QM computations reveal that this particular case
is a unique exception to all other cases discussed in the
manuscript. The enantioselectivity in this case does not
simply derive from the 1,4-addition step. Computed
enantioselectivity is 1.7 kcal/mol for both the lactam and
lactone based on the computed 1,4-addition transition
structures. This compares favorably for the experimental
enantioselectivity of the lactam at 1.1 kcal/mol, but
compares poorly to the enantioselectivity of the lactone at
0.4 kcal/mol. See SI for further details.
18 The corresponding acid (E:Z ratio 89:11) was prepared
following a literature procedure (P. Tarrant and R. E. Taylor,
J. Org. Chem., 1959, 24, 1888–1890). The anhydride was
prepared from this mixture, presumably as a statistical ratio
of stereoisomers, and used without purification (see SI for
further information).
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