Enantioselective Stereodivergent Nucleophile-Dependent Isothiourea-Catalysed Domino Reactions

Article abstract of DOI:10.1002/chem.201603318

α,β-Unsaturated acyl ammoniums generated from the reaction of α,β-unsaturated 2,4,6-trichlorophenol (TCP) esters bearing a pendent enone with an isothiourea organocatalyst are versatile intermediates in a range of enantioselective nucleophile-dependent domino processes to form complex products of diverse topology with excellent stereoselectivity. Use of either 1,3-dicarbonyls, acyl benzothiazoles, or acyl benzimidazoles as nucleophiles allows three distinct, diastereodivergent domino reaction pathways to be accessed to form various fused polycyclic cores containing multiple contiguous stereocentres.

Full text of DOI:10.1002/chem.201603318

DOI: 10.1002/chem.201603318
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&
Organic Chemistry
Enantioselective Stereodivergent Nucleophile-Dependent
Isothiourea-Catalysed Domino Reactions
Anastassia Matviitsuk, James E. Taylor, David B. Cordes, Alexandra M. Z. Slawin, and
Andrew D. Smith*[a]
Abstract: a,b-Unsaturated acyl ammoniums generated from
the reaction of a,b-unsaturated 2,4,6-trichlorophenol (TCP)
esters bearing a pendent enone with an isothiourea organo-
catalyst are versatile intermediates in a range of enantiose-
lective nucleophile-dependent domino processes to form
complex products of diverse topology with excellent stereo-
selectivity. Use of either 1,3-dicarbonyls, acyl benzothiazoles,
or acyl benzimidazoles as nucleophiles allows three distinct,
diastereodivergent domino reaction pathways to be ac-
cessed to form various fused polycyclic cores containing
multiple contiguous stereocentres.
Introduction
a planar-chiral DMAP catalyst and a,b-unsaturated acyl fluo-
rides in [3+2] annulations with silylated indenes to form highly
substituted diquinanes with good stereoselectivity (up to 92:8
d.r. and 89:11 e.r.).[7]
Domino reaction processes are one of the most useful strat-
egies for the rapid generation of molecular complexity in or-
ganic synthesis.[1] Enantioselective organocatalysis is particular-
ly suited to the development of complex tandem or domino
processes due to the wide range of distinct activation modes
accessible, the ease with which these can be combined, and
the high levels of chemo- and stereoselectivity often ob-
tained.[2]
Tertiary amine Lewis base-catalysed functionalisation of sub-
strates at the carboxylic acid oxidation level can provide direct
access to different catalytic intermediates that have a wide
range of applications (Figure 1). To this end, enantiomerically
pure catalysts based upon either the DMAP or PPY scaffolds,[3]
cinchona alkaloids,[4] or isothioureas[5] are the most widely
used. Of the intermediates directly accessible at the carboxylic
acid oxidation level using these catalysts, acyl ammonium and
ammonium enolates have been the most extensively studied
to date and can be utilised in a number of stereoselective pro-
cesses.[6] However, the use of a,b-unsaturated acyl ammonium
intermediates generated from stable a,b-unsaturated carboxyl-
ic acid derivatives has received comparatively little attention.
Seminal work in this area from Fu and co-workers used a,b-un-
saturated acyl ammonium intermediates generated from
Figure 1. Intermediates accessible from the carboxylic acid oxidation level
using tertiary amine Lewis base catalysts.
Building on this work, we reported the use of an isothiourea
catalyst and homoanhydrides as a,b-unsaturated acyl ammoni-
um precursors in Michael addition-lactonization reactions with
a range of 1,3-dicarbonyls to form functionalised dihydropyra-
nones 2, dihydropyridones, or esters (upon ring-opening) with
high enantioselectivity (Scheme 1a).[8a] Recent experimental
and computational analysis has revealed the importance of
non-bonding 1,5-S···O interactions in governing the chemo-
and enantioselectivity of annulations of benzothiazoles.[8b]
Romo and co-workers subsequently used acid chlorides as a,b-
unsaturated acyl ammonium precursors in enantioselective iso-
thiourea-catalysed domino Michael addition-aldol-lactonization
reactions using malonate derivatives as nucleophiles to form
functionalised cyclopentanes 4 with high stereoselectivity
(Scheme 1b).[9a] Romo has also used a- and b-aminomalonates
as di-nucleophiles in Michael addition-lactamization processes
with a,b-unsaturated acyl ammoniums to form substituted g-
lactams and piperidones.[9b] The a,b-unsaturated acyl ammoni-
um intermediate can also serve as an activated dienophile in
highly enantioselective organocatalytic Diels–Alder reactions to
form fused g- and d-lactones.[9c] Matsubara and co-workers
have recently prepared enantiomerically enriched 1,5-benzo-
[a] A. Matviitsuk, Dr. J. E. Taylor, Dr. D. B. Cordes, Prof. A. M. Z. Slawin,
Prof. A. D. Smith
EaStCHEM, School of Chemistry, University of St. Andrews
North Haugh, St. Andrews, Fife, KY16 9ST (UK)
E-mail: ads10@st-andrews.ac.uk
Homepage: http://ch-www.st-andrews.ac.uk/staff/ads/group/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201603318.
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This is an open access article under the terms of the Creative Commons At-
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medium, provided the original work is properly cited.
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thiazepines through reaction of 2-aminothiophenols with a,b-
unsaturated acyl ammoniums generated from mixed anhy-
drides and an isothiourea organocatalyst.[10]
Results and Discussion
Reactions using 1,3-dicarbonyls as nucleophiles
To date, these are the only reported examples investigating
the use of a,b-unsaturated acyl ammonium intermediates.[11]
Further studies into the reactivity and synthetic applicability of
these species using readily available tertiary amine based cata-
lysts are required to determine their versatility. To demonstrate
the potential of these intermediates, in this manuscript we en-
visioned that introducing a second Michael acceptor into an
a,b-unsaturated acyl ammonium precursor would allow for the
development of more complex domino reaction processes
(Scheme 1c). Addition of suitable nucleophiles into such an
a,b-unsaturated acyl ammonium would initiate a domino pro-
cess that can utilize the latent ammonium enolate and acyl
ammonium reactivity present within the system. Moreover,
using pro-nucleophiles that contain multiple potential sites of
reactivity may further increase the molecular complexity acces-
sible in these processes. In this case, the challenge is to gener-
ate highly chemo-, regio- and stereoselective processes that
favour one specific domino reaction pathway over all others.
This is particularly difficult given the multiple electrophilic and
nucleophilic sites within the reactants, and such domino pro-
cesses have not been previously investigated using tertiary
amine based catalysis.
Investigations into the isothiourea-catalysed domino process
began with the treatment of 1,3-diphenylpropane-1,3-dione 6
with a cinnamic acid derivative bearing an ortho-a,b-unsaturat-
ed ketone substituent. However, no cyclisation products were
observed under a range of conditions including the use of vari-
ous carboxylic acid “activating” agents (such as pivaloyl chlo-
ride), isothiourea catalysts and bases.[12] As in situ formation of
a reactive mixed anhydride from the carboxylic acid was un-
successful, attention turned to the use of activated esters as
a,b-unsaturated acyl ammonium precursors. While the use of
a 4-nitrophenol (PNP) ester gave only traces (<5%) of the ex-
pected cyclisation product,[13] treating bench-stable 2,4,6-tri-
chlorophenol (TCP) ester 5 with diketone 6 in the presence of
the isothiourea HyperBTM 1 (20 mol%) using polymer-support-
ed BEMP as a base gave isomeric fused indanes 7a and 7b as
a 75:25 mixture in 46% yield and excellent 97.5:2.5 e.r. for 7a
(Table 1, entry 1).[14–17] The minor isomer 7b was also formed
with high enantioselectivity (>99:1 e.r.).[18] Control experiments
on isolated samples of each isomer showed that the products
do not interconvert under the reaction conditions. Further op-
timisation of this domino process showed that isothioureas
such as tetramisole hydrochloride (TM·HCl) 8 and benzotetra-
misole (BTM) 9 were not competent catalysts, returning only
starting materials (Table 1, entries 2 and 3). Changing the sol-
vent and reaction stoichiometry had an impact on both yield
and selectivity (Table 1, entries 4–6), with the optimal condi-
tions using two equivalents of both diketone 6 and PS-BEMP
in THF at room temperature giving fused 1,2,3-substituted
indane 7a as a single diastereoisomer in 60% yield and >99:1
e.r. (Table 1, entry 6). Under these conditions, no base-promot-
ed background reaction was observed in the absence of the
catalyst (Table 1, entry 7). Reducing the catalyst loading (5 or
10 mol%) still gave 7a with excellent selectivity, but led to a re-
duction in isolated yield (48 and 53%, respectively). Finally, the
Herein the successful realisation of these ideas is reported
using an isothiourea-derived a,b-unsaturated acyl ammonium
generated from bench-stable activated ester precursors. To the
best of our knowledge, these processes are also the first dem-
onstration of using an activated ester as an a,b-unsaturated
acyl ammonium precursor. The exact domino reaction pathway
followed is dependent on the intrinsic reactivity within each
class of pro-nucleophile used, which has allowed three distinct
and stereodivergent processes to be developed. The fused
polycyclic products obtained contain multiple contiguous ster-
eocentres and have complex molecular topologies. Important-
ly, in each case the products are formed with high specificity
and stereoselectivity.
Scheme 1. a,b-Unsaturated acyl ammoniums in domino organocatalytic processes.
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Table 1. Optimisation of Domino Michael-Michael-lactonization reactio-
n.[a]
Table 2. Variation of the dicarbonyl nucleophile.[a–e]
Entry
Cat.
5/6/PS-BEMP
Solvent
Yield
[%][b]
7a/7b[c]
e.r.
(7a)[d]
1
2
3
4
5
6
7
8[e]
1
8
9
1
1
1
–
1
1:1:1
1:1:1
1:1:1
1:1:1
1:2:2
1:2:2
1:2:2
1:2:2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeCN
THF
46
75:25
–
–
86:14
91:9
>95:5
–
97.5:2.5
–
–
96.5:2.5
95.5:4.5
>99:1
–
trace
trace
62
70
60
THF
THF
–
57
>95:5
>99:1
[a] Reactions performed on 0.1 mmol scale. [b] Combined yield. [c] The a/
1
b ratio was determined by H NMR spectroscopic analysis of the crude re-
action product. [d] Determined by HPLC analysis. [e] Reaction performed
on a 5 mmol scale.
practicality of the process was demonstrated by performing
the reaction on a 5 mmol scale, providing 1.2 g of indane 7a
as a single stereoisomer (Table 1, entry 8).
The scope and limitations of the domino process was first
explored through variation of the nucleophile (Table 2). Sym-
metrical aryl substituted diketones bearing electron-rich, halo-
gen and heterocyclic substituents worked well under the previ-
ously optimised conditions, giving fused indanes 10a–12a in
good yields and excellent diastereo- and enantioselectivity.
The absolute and relative configuration of 12a was con-
firmed by X-ray crystallographic analysis, with all other prod-
ucts in this series assigned by analogy.[19] The use of non-aryl
substituted diketones such as acetylacetone led to a slight
drop in product selectivity and a significant reduction in enan-
tioselectivity for 13a (62.5:37.5 e.r.), although the diastereose-
lectivity remained high. A control experiment in the absence
of HyperBTM 1 did not lead to product formation, demonstrat-
ing that a racemic base-promoted background reaction is not
responsible for the observed drop in enantioselectivity. Malo-
nates are also competent nucleophiles in this process, selec-
tively forming fused products 14a and 15a with high diaste-
reoselectivity, but with slightly reduced enantioselectivity. The
treatment of 5 with non-symmetrical ethyl benzoylacetate
gave indane 16 in 74% yield, although the additional stereo-
genic centre was only modestly controlled leading to a 75:25
mixture of diastereoisomers.
[a] Reactions performed on 0.1 mmol scale. [b] Combined yield. [c] The a/
b ratio was determined by H NMR spectroscopic analysis of the crude re-
action product. [d] The d.r. was determined by 1H NMR spectroscopic
analysis. [e] The e.r. was determined by HPLC analysis. [f] Reaction per-
formed by using (Æ)-HyperBTM 1. [g] The d.r. at additional stereocentre.
1
ing steps from the corresponding substituted 2-bromobenzal-
dehyde. Substitution around the benzenoid ring is tolerated,
with polycyclic products 17a–19a formed with excellent ste-
reoselectivity. Various alkyl and aryl enone substituents were
also successfully incorporated. Aryl rings bearing electron-do-
nating, electron-withdrawing and halogen substituents all
worked well, giving indanes 22a–25a with high product selec-
tivity in good yields (up to 69%) and excellent stereoselectivity
in all cases (>95:5 d.r., up to >99:1 e.r.). Combinations of sub-
stituted a,b-unsaturated TCP esters with different aryl 1,3-dike-
tones were also performed, forming functionalised products
26a–28a in good yields with the same high selectivity.
The reaction mechanism using 1,3-dicarbonyls as nucleo-
philes is proposed to proceed through a domino Michael-Mi-
chael-lactonization process (Scheme 2a). Nucleophilic addition
of HyperBTM 1 into TCP ester 5 generates an a,b-unsaturated
acyl ammonium intermediate 29. Michael addition of the eno-
late of 1,3-dicarbonyl 6 onto 29 generates ammonium enolate
30, which undergoes intramolecular Michael addition onto the
pendent enone. Lactonization of the resulting enolate onto
Next, a wide range of substituted a,b-unsaturated TCP
esters was subjected to the previously optimised reaction con-
ditions using aryl 1,3-diketones as nucleophiles (Table 3). The
various TCP esters were readily synthesised in four high-yield-
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Table 3. Variation of the Michael acceptor with 1,3-diketones.[a–e]
[a] Reactions performed on 0.1 mmol scale. [b] Combined yield. [c] The a/b ratio was determined by 1H NMR spectroscopic analysis of the crude reaction
1
product. [d] The d.r. was determined by H NMR spectroscopic analysis. [e] The e.r. was determined by HPLC analysis.
the acyl ammonium releases polycyclic product 7a and regen-
erates the catalyst. The observed stereochemical outcome is
proposed to arise from an initial Michael addition onto the Re-
face of a,b-unsaturated acyl ammonium 29, which is confor-
mationally locked due to a stabilising non-bonding O–S inter-
action (nO to s*C–S), with the Si-face effectively blocked by the
stereodirecting groups on the catalyst.[20] Evidence for such an
O–S interaction has previously been obtained both in the
solid-state, through X-ray analysis of an a,b-unsaturated acyl
isothiourea salt,[8] and computationally through DFT calcula-
tions of possible transition states for a Diels–Alder reaction
using an a,b-unsaturated acyl ammonium.[9c] Subsequent intra-
molecular Michael addition of ammonium enolate 30 proceeds
under substrate control, with the 1,3-dicarbonyl, ammonium
enolate and enone all adopting pseudo-equatorial positions in
the five-membered pre-transition state assembly 32
(Scheme 2b). Cyclisation under catalyst control is presumably
disfavoured due to the presence of A1,3 strain between the 1,3-
dicarbonyl substituent and the ammonium enolate.[21]
Scheme 2. a) Proposed domino Michael-Michael-lactonization using 1,3-di-
carbonyls. b) Stereochemical rationale.
Reactions using acyl benzothiazoles as nucleophiles
Having explored the use of various 1,3-dicarbonyls, the use of
acyl benzothiazoles as an alternative pro-nucleophile class in
the domino process was investigated. Reacting a,b-unsaturat-
ed TCP ester 5 with 2-phenacyl benzothiazole 34 under the
previously optimised conditions using HyperBTM 1 (20 mol%)
as the catalyst gave a separable 89:11 mixture of functionalised
polycyclic products 35a and 35b in 53% yield (Scheme 3). In
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this case, major product 35a results from preferential cyclisa-
tion through the benzothiazole nitrogen, which is consistent
with previous observations using this class of nucleophile.[8] In-
terestingly, while the diastereo- and enantioselectivity of this
process remain high (>95:5 d.r., 94:6 e.r.), the relative configu-
ration around the fused indane 35a is different to that ob-
served within the major product from the reaction using 1,3-
dicarbonyls. The relative configuration of minor product 35b
could not be determined, although it is formed as a racemate
suggesting that it may arise from a base-mediated background
process. A control experiment in the absence of HyperBTM
1 confirmed the presence of a base-promoted reaction in this
case.[22]
Scheme 3. Reaction with 2-phenacyl benzothiazole 34.
tive and absolute configuration of 41a was confirmed by X-ray
crystallographic analysis,[23] with all other products assigned by
analogy. Various 2-arylacyl benzothiazole substituents were
also tolerated, forming polycyclic products 42a–44a with high
product selectivity and with good diastereo- and enantiocon-
trol.
Intrigued by the change in constitution and configuration
within the major product, the scope of the domino process
using various acyl benzothiazoles as nucleophiles was explored
(Table 4). Substitution within the benzenoid ring of the a,b-un-
saturated ester was possible, although the presence of
a methyl substituent led to lower enantioselectivity (82:18 e.r.
for 36a). The presence of an aryl enone substituent worked
particularly well, forming indane 38a in 83% yield with high
selectivity (93:7 a/b) and excellent stereoselectivity (>95:5 d.r.,
97:3 e.r.). Within the acyl benzothiazole, halogen substitution
around the benzenoid ring gave products 39a and 40a in
good yields and high stereoselectivity. A lower yield was ob-
tained for 41a bearing an electron-donating methoxy substitu-
ent (20%), although the stereocontrol remained high. The rela-
The stereodivergence observed in the major products ob-
tained from the reactions using 2-acyl benzothiazoles com-
pared with 1,3-dicarbonyls can be rationalised through the op-
eration of an alternative domino Michael-lactamization-Michael
pathway (Scheme 4a). After initial Michael addition onto a,b-
unsaturated acyl ammonium 29 the resulting ammonium eno-
late 45 undergoes preferential proton transfer to give acyl am-
monium 46. Lactamization of the benzothiazole nitrogen onto
the acyl ammonium generates dihydropyridone 47 and releas-
Table 4. Substrate scope using acyl benzimidazoles as nucleophiles.[a–e]
[a] Reactions performed on 0.1 mmol scale. [b] Combined yield. [c] The a/b ratio was determined by 1H NMR spectroscopic analysis of the crude reaction
1
product. [d] The d.r. was determined by H NMR spectroscopic analysis. [e] The e.r. was determined by HPLC analysis. [f] The e.r. was obtained upon single
recrystallisation.
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es the catalyst. Subsequent base-mediated cyclisation of 47
generates the observed polycyclic indane 35a. In this case, the
intramolecular Michael addition occurs through the conforma-
tionally restricted enolate of dihydropyridone 47, with the
enone adopting a pseudo-equatorial position in the forming
indane ring (Scheme 4b).
Reactions using acyl benzimidazoles as nucleophiles
As acyl benzothiazoles had given a distinct domino reaction
pathway, the use of alternative acyl benzazoles was investigat-
ed. While treatment of 2-phenyacyl benzoxazole with a,b-unsa-
turated TCP ester 5 under the previously optimised conditions
led to a complex isomeric mixture, reaction with 2-phenyacyl
benzimidazole 53 gave a single major product isolated in 83%
yield (Scheme 6). Further characterisation revealed its structure
to be fused polycycle 54 containing three contiguous stereo-
centres, including one quaternary stereocentre. Although 54
was formed as a single diastereoisomer, the enantioselectivity
was low (62:38 e.r.).
Scheme 6. Reaction with 2-phenacyl benzimidazole 53.
Scheme 4. a) Proposed domino Michael-lactamization-Michael using acyl
benzothiazoles. b) Stereochemical rationale.
Intrigued by this observation and the possibility of accessing
another distinct domino pathway, the reaction with 2-phenacyl
benzimidazole 53 was optimised (Table 5). A control experi-
ment in the absence of catalyst also led to product 54 in 79%
yield and >95:5 d.r. (Table 5, entry 1), with X-ray crystallo-
graphic analysis confirming the structural assignment and rela-
tive configuration.[24] The presence of a significant racemic
base-promoted background reaction accounts for the low
enantioselectivity observed in the presence of HyperBTM 1.
Consequently, the racemic base-promoted domino reaction of
5 with 53 was first studied. Weaker organic bases such as
iPr2NEt led to no product formation, but addition of DMAP
(20 mol%) gave 31% of 54 (Table 5, entries 2 and 3). The use
of the amidine base DBU led to a complex mixture (Table 5,
entry 4), therefore PS-BEMP was chosen for further study. The
domino process was more efficient in CH2Cl2 compared with
either THF or MeCN and the reaction stoichiometry could be
reduced to 1.5 equivalents of both 53 and PS-BEMP, giving 54
in 90% yield as a single diastereoisomer (Table 5, entries 5–7).
The reaction could be performed on a 3.5 mmol scale, leading
to the isolation of 1.3 g of fused polycycle 54 in 84% yield
(Table 5, entry 8).
Consistent with this alternative mechanism, treatment of
TCP ester 5 with acyl benzothiazole 50 using only 1.5 equiv
PS-BEMP gave dihydropyridone 51 as the major product (77%
yield, 88:12 e.r.), with only 11% of cyclised product 52 isolated
with comparable levels of stereocontrol (Scheme 5). Treating
isolated dihydropyridone 51 with PS-BEMP in the absence of
catalyst promoted further cyclisation into 52, which was ob-
tained in 86% yield as a single diastereoisomer in 92:8 e.r. This
demonstrates that 51 is a viable precursor to indane 52 and
the stereochemical outcome of the stepwise cyclisation is con-
sistent with that observed in the domino processes.
The scope and limitations of this process were explored
through variation of both the acyl benzimidazole and the a,b-
unsaturated TCP ester (Table 6). Various 2-arylacyl benzimida-
zoles containing either electron-donating, electron-withdraw-
ing or halogen substituents were tolerated, forming fused in-
danes 55–60 in generally good yield and excellent diastereose-
lectivity. Introduction of a 2-furyl substituent gave product 61
in 68% yield, although the diastereoselectivity was reduced
Scheme 5. Formation of pre-cyclised dihydropyridone 51.
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the a,b-unsaturated TCP ester gave the corresponding prod-
ucts 65 and 66 in excellent yield as single diastereoisomers. In
contrast with the reactions using acyl benzothiazoles, only an
electron-rich aryl enone substituent could be incorporated,
forming product 68 in 80% yield. The presence of either elec-
tron-withdrawing or halogen substituted aromatic rings on the
enone led to mixtures of products and low yields. Notably, the
pendent enone could be replaced with an a,b-unsaturated
methyl ester, giving the corresponding indane 69 in 79% yield
with excellent selectivity.
Table 5. Reaction optimisation.[a]
Entry
Base
Solvent 5/53/base
t [h] Yield [%][b] d.r.[c]
1
2
3[d]
4
PS-BEMP
iPr2NEt
THF
THF
THF
THF
1:2:2
1:2:2
1:2:2
1:2:2
16
16
16
16
16
24
40
40
79
trace
31
–
56
>95:5
–
>95:5
–
>95:5
>95:5
>95:5
>95:5
Having demonstrated a wide scope for the diastereoselec-
tive domino process using benzimidazoles as nucleophiles, the
possibility of an isothiourea-catalysed enantioselective variant
was revisited.[25] The reaction of TCP ester 5 and benzimidazole
53 under the previously optimised conditions with the addi-
tion of HyperBTM 1 (20 mol%) gave product 54 as a single dia-
stereoisomer, but with low enantioselectivity (Table 7, entry 1).
Lowering the temperature to 08C led to an improvement, with
54 formed in 70.5:29.5 e.r. (Table 7, entry 2). Changing the
base used also had an impact on enantioselectivity. While DBU
gave a complex mixture, the use of 2,6-lutidine gave product
54 in an enhanced 83:17 e.r. (Table 7, entries 3 and 4). Finally,
iPr2NEt
DBU
5
6
7
8[f]
PS-BEMP
PS-BEMP
PS-BEMP
PS-BEMP
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
1:2:2
1:2:2
1:1.5:1.5
1:1.5:1.5
90
97 (90)[e]
(84)[e]
[a] Reactions performed on 0.1 mmol scale. [b] NMR yield using 1,4-dini-
trobenzene as an internal standard. [c] Determined by 1H NMR spectro-
scopic analysis. [d] Reaction using 20 mol% DMAP. [e] Isolated yield in pa-
rentheses. [f] Reaction performed on a 3.5 mmol scale.
i
(70:30 d.r.). Substitution around the benzimidazole ring was
also well tolerated, giving selective access to polycycles 62–64.
The introduction of substituents within the benzenoid ring of
using Pr2NEt allowed 54 to be isolated in 60% yield as a single
diastereoisomer in 88:12 e.r. (Table 7, entry 5).
Table 6. Substrate scope using acyl benzimidazoles as nucleophiles.[a,b]
1
[a] Reactions performed on 0.1 mmol scale. [b] The d.r. was determined by H NMR spectroscopic analysis.
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the products in generally good yields with excellent diastereo-
selectivity and comparable levels of enantioselectivity in each
case. The absolute and relative configuration of fused indane
55 was confirmed through X-ray crystallographic analysis of
a recrystallised sample (98.5:1.5 e.r.),[26] with all other products
assigned by analogy.
Table 7. Optimisation of enantioselective reaction.[a]
Mechanistically, the reactivity and stereoselectivity observed
for the reactions using benzimidazoles can be rationalised by
the Michael-lactamization-Michael domino pathway depicted
in Scheme 7a. Michael addition occurs on the Re-face of a,b-
unsaturated acyl ammonium 29, with subsequent proton
transfer and lactamization of the resulting acyl ammonium 71
generating fused dihydropyridone 72 and releasing the cata-
lyst.
Entry
Base
T [8C]
Yield [%][b]
d.r.[c]
e.r.[d]
1
2
3
4
5
PS-BEMP
PS-BEMP
DBU
2,6-lutidine
iPr2NEt
RT
0
0–10
0–10
0–10
97
65
–
70
>95:5
>95:5
–
>95:5
>95:5
57:43
70.5:29.5
–
83:17
88:12
68 (60)[e]
[a] Reactions performed on 0.1 mmol scale. [b] NMR yield using 1,4-dini-
trobenzene as an internal standard. [c] Determined by 1H NMR spectro-
scopic analysis. [d] Determined by HPLC analysis. [e] Isolated yield in pa-
rentheses.
The newly optimised conditions for the HyperBTM 1-cata-
lysed reaction using benzimidazoles were applied to the enan-
tioselective synthesis of a subset of the fused polycycles made
previously (Table 8). Structural variation within both the benzi-
midazole and a,b-unsaturated TCP ester was tolerated, forming
Table 8. Scope of the enantioselective process.[a–c]
Scheme 7. a) Proposed domino Michael-lactamization-Michael using acyl
benzimidazoles. b) Stereochemical rationale.
Deprotonation of the benzimidazole followed by intramolec-
ular Michael addition of the enolate formed onto the pendent
a,b-unsaturated ketone gives the observed product 54 con-
taining three contiguous stereocentres, including one all-
carbon quaternary stereocentre. The diastereoselectivity is ra-
tionalised by the enone adopting a sterically favoured pseudo-
equatorial position in the forming indane ring during the intra-
molecular Michael addition (Scheme 7b). An alternative path-
way in which the intramolecular Michael addition occurs from
acyl ammonium 71 prior to lactamization cannot be ruled out,
however the Michael-lactamization-Michael pathway is current-
ly favoured by drawing analogy with the reactions using acyl
benzothiazoles.
Conclusions
[a] Reactions performed on 0.1 mmol scale. [b] The d.r. was determined
by 1H NMR spectroscopic analysis. [c] The e.r. was determined by HPLC
analysis. [d] The e.r. was obtained upon single recrystallisation.
a,b-Unsaturated acyl ammonium intermediates generated
from an isothiourea catalyst and bench-stable a,b-unsaturated
TCP esters bearing pendent Michael acceptors undergo various
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enantioselective nucleophile-dependent domino reactions.
Three divergent processes are observed by using either 1,3-di-
carbonyls, acyl benzothiazoles, or acyl benzimidazoles as pro-
nucleophiles, forming a range of complex fused polycycles
containing multiple contiguous stereocentres with high selec-
tivity and stereocontrol. The different domino processes make
use of multiple catalytic intermediates, including a,b-unsaturat-
ed acyl ammonium, ammonium enolate and acyl ammoniums
and rely on the intrinsic differences in reactivity within each
class of pro-nucleophile to form the products with high selec-
tivity. Current work in this laboratory is aimed at further devel-
oping Lewis base-catalysed enantioselective transformations.
General procedure for the enantioselective Michael-lactami-
zation-Michael reaction with acyl benzimidazoles
The appropriate acyl benzimidazole (2 equiv), HyperBTM
i
1 (20 mol%), and Pr2NEt (2.0 equiv) were added to a solution of
the appropriate a,b-unsaturated TCP ester in anhydrous CH2Cl2
(0.4m) at 08C. The reaction was allowed to warm to 108C and
stirred for 48 h. The reaction was quenched with 0.1m HCl and ex-
tracted with CH2Cl2 (ꢁ3). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered and con-
centrated in vacuo. The crude product was purified by column
chromatography (petrol/EtOAc) on silica gel to give products of
approximately 95% purity. Analytically pure samples could be ob-
tained through
CH2Cl2 as eluent.
a second chromatographic purification using
Experimental Section
Acknowledgements
General
We thank the European Research Council under the European
Union’s Seventh Framework Programme (FP7/2007-2013) ERC
grant agreement no. 279850 (J.E.T.) and the EPSRC (EP/
J018139/1, A.M.). A.D.S. thanks the Royal Society for a Wolfson
Research Merit Award. We also thank the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
For the synthesis of starting materials, full characterisation data,
NMR spectra, and HPLC traces, see the Supporting Information.
The research data underpinning this publication can be accessed
at DOI: http://dx.doi.org/10.17630/9488831e-1495-4e96-bede-
7e3b4f252018.
General procedure for the Michael-Michael-lactonization re-
action with 1,3-dicarbonyls
Keywords: domino reactions · enantioselective synthesis ·
Lewis base · organocatalysis · a,b-unsaturated acyl ammonium
HyperBTM 1 (20 mol%), PS-BEMP (2 equiv), and the appropriate
1,3-dicarbonyl (2 equiv) were added to a solution of the appropri-
ate a,b-unsaturated TCP ester in anhydrous THF (0.4m) at room
temperature. The reaction mixture was stirred for 48 h before
being filtered to remove the base and concentrated in vacuo. The
crude product was purified by column chromatography (petrol/
EtOAc) on silica gel to give products of approximately 95% purity.
Analytically pure samples could be obtained through a second
chromatographic purification using CH2Cl2 as eluent.
[1] For reviews on domino reaction processes, see: a) L. F. Tietze, Chem.
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[7] E. Bappert, P. Muller, G. C. Fu, Chem. Commun. 2006, 2604–2606.
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HyperBTM 1 (20 mol%), PS-BEMP (2 equiv), and the appropriate
acyl benzothiazole (2 equiv) were added to a solution of the ap-
propriate a,b-unsaturated TCP ester in anhydrous THF (0.4m) at
room temperature. The reaction mixture was stirred for 48 h
before being filtered to remove the base and concentrated in
vacuo. The crude product was purified by column chromatography
(petrol/EtOAc) on silica gel to give products of approximately 95%
purity. Analytically pure samples could be obtained through
a second chromatographic purification using CH2Cl2 as eluent.
[10] Y. Fukata, K. Asano, S. Matsubara, J. Am. Chem. Soc. 2015, 137, 5320–
5323.
General procedure for the diastereoselective Michael-lac-
tamization-Michael reaction with acyl benzimidazoles
[11] These intermediates have also been suggested with the use of selected
hydrogen-bonding catalysts, see: a) S. Goudedranche, X. Bugaut, T. Con-
stantieux, D. Bonne, J. Rodriguez, Chem. Eur. J. 2014, 20, 410–415; b) Y.
Fukata, T. Omamura, K. Asano, S. Matsubara, Org. Lett. 2014, 16, 2184–
2187.
[12] For further details of the reaction optimisation, see the Supporting In-
formation.
[13] For examples of using PNP esters in asymmetric organocatalysis, see:
a) L. Hao, Y. Du, H. Lv, X. K. Chen, H. S. Jiang, Y. L. Shao, Y. R. Chi, Org.
Lett. 2012, 14, 2154–2157; b) T. H. West, D. S. B. Daniels, A. M. Z. Slawin,
A. D. Smith, J. Am. Chem. Soc. 2014, 136, 4476–4479.
PS-BEMP (1.5 equiv), and the appropriate acyl benzothiazole
(2 equiv) were added to a solution of the appropriate a,b-unsatu-
rated TCP ester in anhydrous CH2Cl2 (0.4m) at room temperature.
The reaction mixture was stirred for 40 h before being filtered to
remove the base and concentrated in vacuo. The crude product
was purified by column chromatography (petrol/EtOAc) on silica
gel to give products of approximately 95% purity. Analytically pure
samples could be obtained through a second chromatographic pu-
rification using CH2Cl2 as eluent.
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
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[14] An additional advantage of using TCP esters is the reduced toxicity of
2,4,6-trichlorophenol compared with 4-nitrophenol.
Birman, X. Li, Z. Han, Org. Lett. 2007, 9, 37–40; c) P. Liu, X. Yang, V. B.
Birman, K. N. Houk, Org. Lett. 2012, 14, 3288–3291.
[21] This is similar to the stereochemical model proposed by Romo and co-
workers for an Aldol-lactonization reaction to form substituted cyclo-
pentanes, see: G. Liu, M. E. Shirley, D. Romo, J. Org. Chem. 2012, 77,
2496–2500.
[22] The base-mediated background process gave a complex mixture that
contained both products 35a and 35b.
[15] The indane core is found within many natural products and biologically
active compounds, see: M. Vilums, J. Heuberger, L. H. Heitman, A. P. Ij-
zerman, Med. Res. Rev. 2015, 35, 1097–1126.
[16] For a comprehensive recent review on the enantioselective synthesis of
indanes, see: C. Borie, L. Ackermann, M. Nechab, Chem. Soc. Rev. 2016,
45, 1368–1386.
[23] CCDC 1452337 (41a) contains the supplementary crystallographic data
for this paper. These data are provided free of charge by The Cam-
bridge Crystallographic Data Centre.
[24] CCDC 1473024 ((Æ)-54) contains the supplementary crystallographic
data for this paper. These data are provided free of charge by The Cam-
bridge Crystallographic Data Centre.
[25] For further details of the reaction optimisation, see the Supporting In-
formation.
[26] CCDC 1473025 (55) contains the supplementary crystallographic data
for this paper. These data are provided free of charge by The Cam-
bridge Crystallographic Data Centre.
[17] Studer has reported the formation of related fused indanes using N-
heterocyclic carbene (NHC) catalysis from enals under oxidative condi-
tions but observed an alternative stereochemical outcome, see: A.
Biswas, S. D. Sarkar, R. Frçhlich, A. Studer, Org. Lett. 2011, 13, 4966–
4969.
[18] The relative configuration of minor product 7b was determined by
NOE experiments.
[19] CCDC 1452336 (12a) contains the supplementary crystallographic data
for this paper. These data are provided free of charge by The Cam-
bridge Crystallographic Data Centre.
[20] Noncovalent S–O interactions have recognised importance in medicinal
chemistry, see: a) B. R. Beno, K.-S. Yeung, M. D. Bartberger, L. D. Penning-
ton, N. A. Meanwell, J. Med. Chem. 2015, 58, 4383–4438. For discussions
of S–O interactions in isothiourea-catalysed reactions, see: b) V. B.
Received: July 13, 2016
Published online on && &&, 0000
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FULL PAPER
&
Organic Chemistry
A. Matviitsuk, J. E. Taylor, D. B. Cordes,
A. M. Z. Slawin, A. D. Smith*
&& – &&
One after another: Enantioselective,
stereodivergent isothiourea-catalysed
domino reactions utilising a,b-unsatu-
rated acyl ammonium, ammonium eno-
late and acyl ammonium intermediates
generate complex polycyclic products
with excellent enantioselectivity.
Enantioselective Stereodivergent
Nucleophile-Dependent Isothiourea-
Catalysed Domino Reactions
Chem. Eur. J. 2016, 22, 1 – 11
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11
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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