Organocatalytic Functionalization of carboxylic acids: Isothiourea- catalyzed asymmetric intra- and intermolecular Michael addition-lactonizations

Article abstract of DOI:10.1021/ja109975c

Tetramisole promotes the catalytic asymmetric intramolecular Michael addition-lactonization of a variety of enone acids, giving carbo- and heterocyclic products with high diastereo- and enantiocontrol (up to 99:1 dr, up to 99% ee) that are readily derivatized to afford functionalized indene and dihydrobenzofuran carboxylates. Chiral isothioureas also promote the catalytic asymmetric intermolecular Michael addition-lactonization of arylacetic acids and α-keto-β,γ-unsaturated esters, giving anti-dihydropyranones with high diastereo- and enantiocontrol (up to 98:2 dr, up to 99% ee).

Full text of DOI:10.1021/ja109975c

ARTICLE
pubs.acs.org/JACS
Organocatalytic Functionalization of Carboxylic Acids:
Isothiourea-Catalyzed Asymmetric Intra- and Intermolecular
Michael Addition-Lactonizations
Dorine Belmessieri, Louis C. Morrill, Carmen Simal, Alexandra M. Z. Slawin, and Andrew D. Smith*
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, U.K.
S Supporting Information
b
ABSTRACT:
Tetramisole promotes the catalytic asymmetric intramolecular Michael addition-lactonization of a variety of enone acids, giving
carbo- and heterocyclic products with high diastereo- and enantiocontrol (up to 99:1 dr, up to 99% ee) that are readily derivatized to
afford functionalized indene and dihydrobenzofuran carboxylates. Chiral isothioureas also promote the catalytic asymmetric
intermolecular Michael addition-lactonization of arylacetic acids and R-keto-β,γ-unsaturated esters, giving anti-dihydropyranones
with high diastereo- and enantiocontrol (up to 98:2 dr, up to 99% ee).
’ INTRODUCTION
An alternative but synthetically appealing strategy to generate
enolates in an organocatalytic fashion directly from carboxylic
acids has received relatively little attention to date. In this area,
Romo has elegantly shown that aldehyde- and keto-acids under-
go intramolecular cyclization using either cinchona alkaloids or
4-pyrrolidinylpyridine as the Lewis base promoter, giving the
corresponding β-lactones in good yields and stereoselectivities.18
This protocol has been extended to highly enantioselective intra-
molecular desymmetrizing aldol-lactonization events, initially
using stoichiometric tetramisole,19 and very recently to substoi-
chiometric homobenzotetramisole.20 Building upon these pre-
cedents, and our own interest in Lewis base catalysis,21 we report
herein the highly diastereo- and enantioselective intramolecular
Michael addition-lactonizationprocess22 of a range of enone-acid
substrates using isothioureas, introduced by Birman and utilized
extensively for asymmetric O-acylation procedures,23 to afford
indene and dihydrobenzofuran carboxylates after derivatization.24
The further application of this methodology to an intermolecular
Michael addition-lactonization strategy, allowing the direct asym-
metric functionalization of a range of arylacetic acids with R-keto-
β,γ-unsaturated esters, giving anti-dihydropyranones with excel-
lent diastereo- and enantiocontrol, is also detailed herein
(Figure 1).
The development of methods for the catalytic generation of
enolates or their equivalents is of widespread interest in asym-
metric catalysis. While the use of transition metals to generate
enolates is welldocumented,1 a variety of organocatalyticmethods,
such as the use of enamines,2 N-heterocyclic carbenes (NHCs),3
and cinchona alkaloid derivatives,4 have also been reported.5 Lewis
base catalysis encompasses a multitude of different catalyst types
and reactions,6 with the generation and reactivity of ammonium
enolates,7 typically formed from the interaction of a nucleophilic
tertiary amine with either a preformed or in situ generated ketene,
exploited for a range of asymmetric transformations.8 Among
these processes, the formal [4þ2] cycloadditions of ammonium
and azolium enolates, typically generated using cinchona alkaloids
from acid chlorides, or from enals or R-functionalized aldehydes
with NHCs, have been elegantly developed. For example,
Lectka has shown that cinchona alkaloid-derived ketene en-
olates undergo a variety of enantioselective [4þ2] cycloaddi-
tions with o-quinones,9 o-quinone diimides10 and quinone
imides,11 while Nelson has employed a similar pathway using
N-thioacyl imines.12,13 Bode has employed NHCs to catalyze
asymmetric [4þ2] cycloadditions, using azolium enolates gener-
ated from enals or R-chloroaldehydes to give syn-dihydropyra-
nones with exquisite diastereo- and enantiocontrol,14 while Ye has
shown that NHCs promote the [4þ2] cycloaddition of disub-
stituted ketenes with enones.15,16 An asymmetric [4þ2] approach
using enamine catalysis has also been reported by Jørgensen,17
generating anti-dihydropyranones after oxidation.
Received: November 6, 2010
Published: February 8, 2011
r
2011 American Chemical Society
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Table 1. Intramolecular Michael Addition-Lactonization:
Optimization Studies
entry activating agent Lewis base (equiv) yield (%)a
drb
ee (%)c
1
2
3
4
5
6
7
8
9
6
DMAP (1.0)
DHPB (1.0)
DHPB (0.5)
DHPB (0.2)
40
87
95
53
73
43
47
36
28
62
72
g95:5
g95:5
g95:5
g95:5
-
-
-
-
6
6
Figure 1. Proposed catalytic strategy: intra- and intermolecular Michael
addition-lactonizations.
6
6
4 HCl (0.5)
g95:5 97
g95:5 97
99:1 92
3
6
4 HCl (0.2)
3
’ RESULTS AND DISCUSSION
EDCI
PyBOP
DCC
4 HCl (0.2)
3
4 HCl (0.2)
99:1 97
Intramolecular Michael Addition-Lactonization Reac-
tions. Initial studies focused upon the demonstration of the
intramolecular Michael addition-lactonization strategy, with this
proposed reaction sequence optimized using the transformation of
model enone-acid 1 to polycyclic lactone 2 (Table 1). In the
racemic series, using Mukaiyama reagent 6 as the activating agent,
both DMAP and isothiourea DHPB 3 proved competent cata-
lysts for this transformation, giving 2 with high diastereocontrol
(99:1 dr). Tetramisole hydrochloride 4 proved a competent
enantioselective precatalyst for this transformation, giving 2 with
excellent diastereo- and enantiocontrol (g95:5 dr, 97% ee),25
although in only modest yields unless 50 mol % of the isothiourea
was used. Further optimization through variation of the activating
agent showed that pivaloyl chloride allowed the synthesis of 2
using20mol % of precatalyst 4 in an acceptable62% yield and high
stereoselectivity (99:1 dr, 97% ee). Isothiourea 5 also proved
catalytically active but gave 2 with reduced diastereo- and en-
antiocontrol. Consistent with the recent work of Romo and co-
workers,20 this study demonstrates the importance of the combi-
nation of activating agent and isothiourea in generating an efficient
catalytic process in such transformations.
3
4 HCl (0.2)
99:1 96
3
10 (CH3)3COCld
11 (CH3)3COCld
4 HCl (0.2)
99:1 97
3
5 (0.2)
80:20 70 (ent)
a Isolated yield. b Determined by H NMR spectroscopic analysis of
the crude reaction product. c Determined by HPLC analysis. d i-Pr2NEt
(3.6 equiv) was used.
1
Table 2. Scope of the Intramolecular Michael Addition-
Lactonization Process
With a working protocol in place, the generality of this domino
Michael addition-lactonization process was next exemplified
(Table 2). Utilizing the optimized conditions delineated above,
this protocol allows the incorporation of alkyl and both electron-
withdrawing and -donating aryl substituents within the enone,
substitution of the aromatic tether, as well as the use of aliphatic
substrates, giving the desired polycyclic products 7-12 in good
yield with high dr (up to 99:1) and ee (90-99% ee) in all cases.
To exemplify the synthetic utility of these products, lactones 2,
7, and 8 were readily derivatized with either methanol or iso-
propylamine, generating the corresponding indene carboxylate
derivatives in excellent yield and ee (Scheme 1).
Having demonstrated the suitability of this process for the pre-
paration of carbocyclic products, we further applied this process to
the synthesis of dihydrobenzofuran derivatives (Table 3). A range
of substituted aryloxyacetic acids, readily prepared from salicylal-
dehyde derivatives,26 proved susceptible to the tetramisole-catalyzed
intramolecular Michael addition-lactonization process. Substituent
a Isolated yield. b Determined by 1H NMR spectroscopic analysis of the crude
reaction product. c Determined by HPLC analysis. d Reaction time 16 h.
variation within the enone and the aromatic tether was readily
tolerated, with short reaction times employed. In each case, in situ
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Scheme 1. Lactone Derivatizations To Give Indene Carbox-
ylates
Table 4. Intermolecular Michael Addition-Lactonization:
Optimization Studies
entry isothiourea (mol %) T (°C) time (h) yield (%)a drb ee (%)c
1
3 (20)
4 (20)
27 (20)
5 (20)
5 (20)
5 (20)
5 (20)
5 (20)
5 (10)
5 (5)
rt
rt
1
3
64
60
55
52
55
60
55
60
68
68
55
95:5 -
2
94:6 86 (ent)
96:4 83
96:4 91
95:5 93
94:6 97
96:4 95
98:2 96
95:5 97
95:5 96
94:6 96
3
rt
3
4
rt
3
Table 3. Further Scope of the Intramolecular Michael
Addition-Lactonization Process
5
-10
-30
-50
-78
-30
-30
-30
3
6
3
7
3
8
3
9
16
24
72
10
11
5 (2)
a Isolated yield of major diastereoisomer of 1 (>98:2 dr) unless other-
wise stated. b Determined by H NMR spectroscopic analysis of the
1
crude reaction product. c Determined by HPLC analysis.
reaction times, in this series the catalyst loading could be readily
reduced to 5 mol % without compromising diastereo- and ena-
ntioselectivity while maintaining a short reaction time.
Intermolecular Michael Addition-Lactonization Reac-
tions. Subsequent studies focused upon demonstrating the chal-
lenging intermolecular Michael addition-lactonization strategy,
with this reaction sequence optimized using phenylacetic acid
(Table 4). In the racemic series, using pivaloyl chloride, i-Pr2NEt,
isothiourea DHPB 3, and chalcone as the Michael acceptor gave
no conversion to the desired product, while the use of an R-keto-
β,γ-unsaturated ester readily gave anti-dihydropyranone 26 with
high diastereocontrol (95:5 dr). Tetramisole hydrochloride 4 proved
a competent enantioselective precatalyst for this transformation,
giving 26 in promising diastereo- and enantioselectivity (94:6 dr,
86% ee). Variation of the isothiourea showed that 5 offered the
highest levels of enantiocontrol at room temperature (96:4 dr, 91%
ee), although for optimal enantioselectivity lowering the temperature
was necessary, giving 26 with excellent enantiocontrol (up to 97%
ee). The catalyst loading of 5 could also be lowered to 2 mol %
without compromising the diastereo- and enantiocontrol of this
transformation, although longer reaction times were required.
The generality of this intermolecular Michael addition-
lactonization process catalyzed by isothiourea 5 was first exemplified
through variation of the arylacetic acid component (Table 5).29
Under optimized conditions this protocol tolerates 2-, 3-, and 4-aryl
substitution and allows the incorporation of electron-withdrawing
and -donating substituents on the aryl unit, as well as heteroaryl
substituents within the arylacetic acid,30 giving the anti-dihydro-
pyranones 28-36 in good yield with high dr (up to 96:4 after
chromatography) and ee (up to 99% ee).31,32
a Isolated yield. b Determined by 1H NMR spectroscopic analysis of the
crude reaction product. c Determined by HPLC analysis. d Using 5 mol %
4 HCl, reaction time 15 min.
3
methanolysis or amidation was used to directly generate the
corresponding dihydrobenzofuran esters and amides 16-25 in
good to excellent yields and with high stereocontrol (dr up to
99:1, up to 96% ee).27,28 While 20 mol % of 4 HCl is necessary in
3
the carbocyclic series for optimal reactivity and to avoid long
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Table 5. Scope of the Intermolecular Michael Addition-
Lactonization: Variation of the Acid Component
Table 6. Further Scope of the Intermolecular Michael
Addition-Lactonization: Variation of the r-Keto-β,
γ-unsaturated Ester Component
a Isolated yield of major diastereoisomer (>98:2 dr) unless otherwise
1
stated. b Determined by H NMR spectroscopic analysis of the crude
reaction product. c Determined by HPLC analysis. d isolated yield of
product of 97:3 dr. e isolated yield of product of 95:5 dr.
To further demonstrate the generality of this procedure,
phenylacetic acid was functionalized using a range of γ-alkyl-
and γ-aryl-substituted R-keto-β,γ-unsaturated esters (Table 6).
Variation of the ester group is readily tolerated in this Michael
addition-lactonization process, as is substitution of the γ-aryl
unit with electron-withdrawing and -donating substituents as
well as γ-heteroaryl substituents, giving anti-dihydropyranones
37-45 with high dr (up to 98:2) and ee (up to 99% ee). γ-Alkyl-
substituted R-keto-β,γ-unsaturated esters are also readily incor-
porated, albeit with reduced diastereoselectivity, generating anti-
dihydropyranones 46 and 47 with excellent enantioselectivity.
To exemplify the synthetic utility of this intermolecular reac-
tion protocol, a domino Michael addition-lactonization followed
by in situ ring opening with MeOH was developed. Preparation of
26 using isothiourea 5 under standard conditions, followed by
direct addition of MeOH to the crude reaction mixture, gave 48
directly in 92% isolated yield, 95:5 dr, and 96% ee (Scheme 2).
We assume that both of these transformations proceed via
related catalytic pathways, involving the initial in situ formation of
a transient mixed anhydride, 49 or 54, from the corresponding
acid,33 with N-acylation of the isothiourea with this activated
carboxylate giving an acyl ammonium species, 50 or 55. Depro-
tonation is expected to generate the (Z)-ammonium enolate 51
or 56,34 with subsequent intra- or intermolecular asymmetric
Michael addition to the relevant acceptor in the s-cis conforma-
a Isolated yield of major diastereoisomer (>98:2 dr) unless otherwise
1
stated. b Determined by H NMR spectroscopic analysis of the crude
reaction product. c Determined by HPLC analysis. d isolated yield of
product of 97:3 dr. e isolated yield of product of 92:8 dr. f Reaction time
40 h. g 91:9 dr. h Reaction temperature -78 °C. i 90:10 dr.
Scheme 2. Tandem Michael Addition-Lactonization and
Ring Opening
tion,35 followed by lactonization, giving the desired product in
high dr and ee and regenerating the isothiourea (Figure 2).
We currently favor a stepwise Michael addition-lactonization
mechanism over a concerted [4þ2] hetero-Diels-Alder reaction
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Figure 2. Proposed catalytic pathways and transition states.
pathway, although at the moment we cannot distinguish these
mechanistic possibilities. Assuming the Michael addition-
lactonization pathway, a simplistic rationale consistent with the
observed absolute configurations of the products for these
transformations can be achieved by assuming that the Michael
addition proceeds with the two prostereogenic centers adopting
an approximately staggered array in order to minimize unfavor-
able nonbonding interactions. In the intramolecular manifold,
this leads to a preferred transition state such as 52, while in the
intermolecular process, Michael addition proceeds preferentially
via transition state 57 by analogy to Heathcock’s model.36 Nota-
bly, both of these proposed transition-state arrangements place
the enolate oxygen syn to the S atom within the isothiourea, pos-
sibly allowing a stabilizing no-to-σ*C-S interaction. Such interac-
tions have previously been envoked by Nagao and co-workers in
(acylimino)thiadiazoline derivatives,37 and also by both Birman38
and Romo20 in reaction processes utilizing isothioureas.
In summary, tetramisole catalyzes the highly diastereo- and
enantioselective intramolecularMichael addition-lactonization of
enone-acids, generating carbo- and heterocyclic products that are
readily derivatized to functionalized indene and dihydrobenzofur-
an carboxylates. Isothiourea 5 promotes the highly diastereo- and
enantioselective intermolecular Michael addition-lactonization
of arylacetic acids and R-keto-β,γ-unsaturated esters, generating
anti-dihydropyranones with good diastereoselectivity (up to 98:2 dr)
and enantioselectivity (up to 99% ee). Ongoing studies within this
laboratory are currently directed toward demonstrating alternative
uses of isothioureas in asymmetric catalysis.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures;
b
X-ray structural data for 21 and 32 (CIF); spectral and HPLC
data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
ads10@st-andrews.ac.uk
’ ACKNOWLEDGMENT
We thank the Royal Society for a University Research Fellow-
ship (A.D.S.), The Carnegie Trust for the Universities of Scotland
(L.C.M.), and the EU (Marie-Curie Intra-European Fellow-
ship for Career Development, C.S.) for funding, and the EPSRC
National Mass Spectrometry Service Centre (Swansea). We also
acknowledge the assistance of Stuart Leckie in the preparation of
a number of R-keto-β,γ-unsaturated esters.
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(12) Xu, X.; Wang, K.; Nelson, S. G. J. Am. Chem. Soc. 2007, 129,
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(13) For an alternative [4 þ 2] strategy, utilizing the reaction of vinyl
ketenes with aldehydes see: (a) Tiseni, P. S.; Peters, R. Angew. Chem., Int.
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of azolium enolates with azadienes see: (d) He, M.; Struble, J. R.; Bode,
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(24) Related intramolecular Michael addition-lactonization pro-
cesses using NHCs to generate enolates from enals have been reported:
(a) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 3107–3110. (b) Li, Y.; Wang, X.-Q.; Zheng, C;
You, S.-L. Chem. Commun. 2009, 5823–5825.
(25) The absolute configuration of 2 was assigned by comparison of
the HPLC and specific rotation data with that contained in ref 24a. Ring
opening of 2 with MeOH to give 14, and comparison of its specific
rotation contained in ref 24b, also confirmed the absolute configuration
and stereochemical integrity of the products of this transformation (see
SI for full details).
(26) See SI for full experimental details.
(27) The relative and absolute configuration of 21 was confirmed by
X-ray crystal structure analysis, with all other dihydrobenzofuran
derivatives assigned by analogy. See SI for further details. Crystal-
lographic data for 21 have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication number CCDC
799331.
(15) Zhang, Y.-R.; Lv, H.; Zhou, D.; Ye, S. Chem. Eur. J. 2008, 14,
8473–8476.
(16) For the asymmetric Michael lactonization of silyl ketene
acetals and enones utilizing chiral ammonium phenoxides see: Tozawa,
T.; Nagao, H.; Yamane, Y.; Mukaiyama, T. Chem. Asian J. 2007, 2, 123–
134.
(28) ThelactoneproductsarisingfromMichaeladdition-lactonization
in this series proved susceptible to degradation upon attempted isolation
by chromatography, so direct ring opening with MeOH or i-PrNH2 was
followed.
(17) Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498–
(29) Preliminary unoptimized experiments show only modest con-
1501.
version (around 30%) using hydrocinnamic acid as the acid component.
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Journal of the American Chemical Society
ARTICLE
(30) Dihydropyranone 36 proved susceptible to isomerization upon
extended exposure to isothioureas DHPB or 5. See SI for further
information.
(31) The relative and absolute configuration of 32 was confirmed by
X-ray crystal structure analysis, with all other derivatives assigned by
analogy. See SI for further details. Crystallographic data for 32 have been
deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 799871.
(32) Although this intermolecular process was routinely carried out
on an analytical scale (0.2 mmol), this reaction process has been scaled
to a 2 mmol scale, giving 26 in 66% yield and 99% ee. This reaction can
also be performed in an open flask using bench-grade solvents without
degradation of reactivity and enantioselectivity.
(33) Shiina and co-workers have utilised a trans-acylation procedure
to generate reactive mixed anhydrides from acids and anhydrides for
applications in kinetic resolutions catalyzed by isothioureas. See ref 23g
and also the following: (a) Shiina, I.; Nakata, K. Tetrahedron. Lett. 2007,
48, 8314–8317. (b) Shiina, I.; Nakata, K.; Sugimoto, M.; Onda, Y.;
Iizumi, T.; Ono, K. Heterocycles 2009, 77, 801–810. (c) Shiina, I.; Nakata,
K. Heterocycles 2010, 80, 169–175. (d) Shiina, I.; Nakata, K.; Onda, Y.
Eur. J. Org. Chem. 2008, 5887–5890. (e) Shiina, I.; Nakata, K.; Ono, K.;
Sugimoto, M.; Sekiguchi, A. Chem. Eur. J. 2010, 16, 167–172. (f) Nakata,
K.; Onda, Y.; Ono, K.; Shiina, I. Tetrahedron. Lett. 2010, 51, 5666–5669.
(34) We have considered the possibility that these reaction pro-
cesses proceed via the enol tautomer of the acyl ammonium species,
rather than the ammonium enolate, although we currently favor the
enolate pathway due to the assumed attenuated nucleophilicity of the
enol. An alternative reaction process, involving the in situ generation of a
ketene from the mixed anhydride, followed by nucleophilic addition of
an isothiourea to generate the ammonium enolate, cannot be ruled out at
this time, although we favor the mechanisms depicted in Figure 2.
Further mechanistic investigations of these reaction pathways are
currently under investigation. We thank a reviewer for helpful comments
on this matter.
(35) Using the assumption of a stepwise Michael addition-
lactonization pathway over a concerted [4þ2] hetero-Diels-Alder reac-
tion manifold, the high observed diastereoselectivity in these processes may
arise due to reversible Michael addition, followed by an irreversible lactoni-
zation process occurring preferentially through one diastereoisomer.
(36) For an excellent overview of this area see: (a) Oare, D. A.;
Heathcock, C. H. Topics Stereochem. 1989, 19, 227–407. For select
representative examples of enolate additions to Michael acceptors see:
(b) Heathcock, C. H.; Henderson, M. A.; Oare, D. A.; Sanner, M. A.
J. Org. Chem. 1985, 50, 3019–3022. (c) Oare, D. A.; Henderson, M. A.;
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(d) Yamaguchi, M.; Tsukamoto, M.; Tanaka, S.; Hirao, I. Tetrahedron
Lett. 1984, 25, 5661–5664. For a recent computational investigation of
intermolecular Michael reactions see: (e) Kwan, E. E.; Evans, D. A. Org.
Lett. 2010, 12, 5124–5127.
(37) Nagao, Y.; Hirata, T.; Goto, S.; Sano, S.; Kakehi, A.; Iizuka, K.;
Shiro, M. J. Am. Chem. Soc. 1998, 120, 3104–3310.
(38) Birman, V. B.; Li, X.; Han, Z. Org. Lett. 2007, 9, 37–40.
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