Isothiourea-mediated asymmetric Michael-lactonisation of trifluoromethylenones: A synthetic and mechanistic study

Article abstract of DOI:10.1039/c3sc51791h

HBTM-2.1 promotes the catalytic asymmetric intermolecular Michael-lactonisation of arylacetic acids and trifluoromethylenones in the presence of pivaloyl chloride, giving C(6)-trifluoromethyldihydropyranones with high diastereo- and enantiocontrol (up to

Full text of DOI:10.1039/c3sc51791h

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Isothiourea-mediated asymmetric Michael-lactonisation
of trifluoromethylenones: a synthetic and mechanistic
study†
Cite this: DOI: 10.1039/c3sc51791h
a
a
a
a
b
*
Louis C. Morrill, James Douglas, Tomas Lebl, Alexandra M. Z. Slawin, David J. Fox
a
*
and Andrew D. Smith
HBTM-2.1 promotes the catalytic asymmetric intermolecular Michael-lactonisation of arylacetic acids and
trifluoromethylenones in the presence of pivaloyl chloride, giving C(6)-trifluoromethyldihydropyranones
with high diastereo- and enantiocontrol (up to 95 : 5 dr and >99% ee) that are readily derivatised to
diverse synthetic building blocks containing trifluoromethyl-stereogenicity. Kinetic studies indicate the
reaction is first order with respect to both in situ formed mixed anhydride and catalyst concentration,
with a primary kinetic isotope effect observed using a,a-di-deuterio 4-fluorophenylacetic acid, consistent
with rate determining deprotonation of an intermediate acyl isothiouronium ion.
Received 26th June 2013
Accepted 1st August 2013
DOI: 10.1039/c3sc51791h
www.rsc.org/chemicalscience
stereospecicity of these reaction processes nor the rate deter-
mining step has not been detailed to date.
Introduction
The catalytic generation of C(1)-, C(2)- or C(3)-ammonium
enolates and their exploitation in asymmetric transformations
is a powerful synthetic strategy.1 Within this area, C(1)-ammo-
nium enolates are commonly prepared from a Lewis basic
tertiary amine and an acid chloride as a ketene precursor, or
through the use of isolable ketenes.2 As alternative precursors,
Romo has pioneered the in situ generation of ammonium
enolates from carboxylic acids and their application to a range
of NCAL processes.3 Building upon this work we have recently
utilised chiral isothioureas,4 initially introduced in catalysis by
Birman and Okamoto,5 to promote the intra- and intermolec-
ular asymmetric functionalisation of carboxylic acids through a
Michael-lactonisation sequence.6,7 Given the recognised chal-
lenge of utilising ketone derivatives in such formal hetero-
Diels–Alder [4 + 2] type processes,8 our intermolecular strategy
previously relied upon reactive a-keto-b,g-unsaturated esters,6
N-aryl-N-aroyldiazenes9 or N-tosyl-a,b-unsaturated ketimines10
as the Michael acceptor. Despite the synthetic power of these
strategies, these processes are mechanistically not well under-
stood. In particular, potential intermediates within this process
have not been isolated, while the reaction order with respect to
reactants has not been determined. Furthermore neither the
To investigate these mechanistic questions and further
demonstrate the synthetic utility of this methodology, the use of
triuoromethylenones within this organocatalytic Michael-lac-
tonisation process was probed. We envisaged that such a
process, coupled with simple derivatisation procedures, would
permit the efficient preparation of a range of triuoromethyl
containing stereogenic building blocks. The triuoromethyl
unit holds a privileged position in organic chemistry. It is widely
employed within both the pharmaceutical and agrochemical
industries, with the incorporation of this motif strategically
used to enhance binding selectivity and metabolic stability, as
well as increasing lipophilicity.11 In this context, the generation
of practical and efficient methodology capable of the selective
introduction of this unit into organic molecules has developed
widely,12 with a series of elegant strategies utilised toward these
aims.13–24
This manuscript demonstrates that the electron with-
drawing triuoromethyl unit within a series of 4-aryl- and
4-alkyltriuoromethylenones25 facilitates their compatibility
with this Michael-lactonisation process. Stereodened syn- or
anti-6-triuoromethyldihydropyranones can be generated
through stereospecic reaction with the (Z)- or (E)-enone
respectively with high diastereo- and enantiocontrol (up to
95 : 5 dr, >99% ee). These dihydropyranones are readily deri-
vatised using simple procedures into a variety of cyclic and
acyclic triuoromethyl-containing building blocks with high
stereocontrol (Fig. 1).26 Mechanistic studies generate insight
into the mechanism of this reaction and indicate rate deter-
mining deprotonation within this system.
aEaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews,
KY16 9ST, UK. E-mail: ads10@st-andrews.ac.uk
bDepartment of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV7
4AL, UK. E-mail: d.j.fox@warwick.ac.uk
† Electronic supplementary information (ESI) available: All spectroscopic data
and procedures for novel compounds. CCDC 907070, 907071, 907808 and
907809. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3sc51791h
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Fig. 1 Proposed catalytic route to CF3-containing stereogenic building blocks.
Reaction optimisation
The proposed Michael-lactonisation sequence was optimised
using phenylacetic acid 1 and triuoromethylenone 227 using
laboratory grade solvents as standard (Table 1, entries 1–8).28
Tetramisole hydrochloride 4 proved a competent precatalyst for
this transformation, giving 3 in promising diastereo- and
enantioselectivity (87 : 13 dr, 89% ee). Benzotetramisole 5
showed marginally reduced diastereo- and enantioselectivity
(entry 2), with HBTM-2.1 6 offering high enantiocontrol at rt
(85 : 15 dr, 95% ee). Further optimisation showed that lowering
the reaction temperature gave improved diastereo- and enan-
tiocontrol, with as low as 1 mol% of 6 delivering 3 with excellent
stereocontrol (90 : 10 dr, 99% ee).29,30
Scheme 1 Improved synthetic route to chiral isothiourea HBTM-2.1 6 and
representation of the X-ray crystal structure of 6.
have proved limited to scale-up in our hands, predominantly
due to a sealed tube coupling process in addition to the nal
two synthetic steps requiring chromatographic purication.
Our improved synthesis (Scheme 1) utilises the (S)-proline cat-
alysed Mannich reaction between benzaldehyde-derived N-Boc
imine 731 and isovaleraldehyde 8. Based upon List’s procedure,32
this consistently provided multigram quantities of 9 (up to
78 g), in good yield (up to 94%) and with excellent diastereo- and
enantioselectivity (typically >99 : 1 dr, >99% ee). In the previous
synthesis, 12 equivalents of 4 M HCl in dioxane were required to
affect N-Boc deprotection. In this revised protocol, using only 5
equivalents of HCl allows the direct precipitation of the HCl salt
10 from solution and substantially lowers the cost associated
with this step. Coupling of amino alcohol 10 and chlor-
obenzothiazole 11 can be performed on a multi-gram scale in a
standard round-bottom ask using chlorobenzene as the
solvent, avoiding the previous requirement for sealed tubes in
this step. The resultant alcohol 12 can be puried by trituration,
with cyclisation using MsCl affording HBTM-2.1 6 that can be
obtained in analytically pure form via recrystallisation from
EtOAc, negating the need for any chromatographic purica-
tion.33 This procedure allows the synthesis of 40 g of enantio-
merically pure catalyst HBTM-2.1 6 in 38% overall yield.34
Table 1 Reaction optimisation
Entry Cat. (mol%) T (ꢀC) Time (h) dra
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
4 (10)
5 (10)
6 (10)
6 (10)
6 (10)
6 (5)
rt
rt
rt
ꢁ30
ꢁ78
ꢁ78
ꢁ78
ꢁ78
0.25
0.25
0.25
3
4
16
87 : 13 61
89 (ent)
77
82 : 18 76
85 : 15 73
86 : 14 79
90 : 10 83
90 : 10 80
90 : 10 79
90 : 10 79
95
96
99
99
99
99
6 (2)
6 (1)
16
16
Reaction generality and derivatisation of
functionalised
6-trifluoromethyldihydropyranones
a
Determined by 1H NMR spectroscopic analysis of the crude reaction
mixture. b Isolated yield of 3 ($95 : 5 dr). c Determined by HPLC analysis.
Upon identication of HBTM-2.1 6 as the optimal catalyst, an The generality of this asymmetric Michael-lactonisation process
improved multi-gram synthesis of this chiral isothiourea was was next investigated through variation of the arylacetic acid
developed. Our previous syntheses of HBTM-2.1 6 (ref. 4f and aa) component (Table 2). Using 5 mol% of 6 as standard, under
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Table 3 Variation of trifluoromethylenone component
optimised conditions this process readily tolerates heteroaryl, 3-
and/or 4-aryl substitution, including electron withdrawing and
donating substituents within the arylacetic acid.35 Notably,
incorporation of the strongly electron withdrawing 4-CF3C6H4
substituent leads to reduced enantioselectivity (product 24),36
while 1-naphthyl or N-Me-3-indole substitution leads to reduced
diastereoselectivity (products 25–27), although still giving the
major diastereoisomer in high ee in each case (up to 97% ee).
Table 2 Variation of acid component
a
Determined by 1H NMR spectroscopic analysis of the crude reaction
mixture. b Isolated yield ($95 : 5 dr). Determined by HPLC analysis.
c
extended aromatic substituents, all generate preferentially the
corresponding anti-dihydropyranones with good dr (up to
95 : 5) and ee (up to >99% ee). Anti-dihydropyranone 40 bearing
an alkyl substituent at C(4) was also obtained in excellent ee
(98%), albeit with slightly attenuated diastereoselectivity
(78 : 22 dr).
The synthetic versatility of these triuoromethyl-substituted
products was next demonstrated through a series of simple
derivatisation processes. Firstly, this reaction sequence is
readily applicable to scale up, with reaction of 3-tolylacetic acid
with enone 2 on a 7.5 mmol scale using isothiourea 6 (1 mol%)
generating >2 g of dihydropyranone 20 (85% yield, 94 : 6 dr,
a
Determined by 1H NMR spectroscopic analysis of the crude reaction
b
c
mixture. Isolated yield ($95 : 5 dr). Determined by HPLC analysis.
d
Isolated yield (92 : 8 dr). e Isolated yield (71 : 29 dr).
The generality of this procedure was further demonstrated 98% ee). Dihydropyranone 20 readily undergoes ring opening
through the functionalisation of phenylacetic acid with a range with methanol, allowing a tandem Michael-lactonisation/
of 4-aryltriuoromethylenones (Table 3). 2-, 3- and 4-Br ring opening sequence to be developed, giving tri-
substituents in the aryl unit are readily incorporated with high uoromethylketone 41 in 72% isolated yield, 92 : 8 dr and 97%
ee; incorporation of electron-withdrawing and electron- ee directly from 3-tolylacetic acid (Scheme 2).
donating substituents is tolerated, although 4-NO2 substitution
Alternative derivatisation methods focused upon the intro-
leads to decreased dr and ee. Heteroaryl substituents, as well as duction of CF3-stereogenicity from dihydropyranone 20. While
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Scheme 2 Scale-up of Michael-lactonisation process and tandem Michael-lac-
tonisation ring-opening. (a) Isolated yield of product at stated dr; (b) determined
by HPLC analysis.
hydrogenation of 20 with Pd/C proceeded with essentially no
stereocontrol (dr 47 : 53 (42 : 43)), chromatographic purica-
tion gave the readily separable diastereoisomers 42 and 4337 in
45% and 51% yield respectively and in $97% ee. Hydrogenation
using Wilkinson’s catalyst proceeded with high stereocontrol
(dr 4 : 96 (42 : 43)), giving 43 in 96% yield and 98% ee. Reduc-
tion of 42 and 43 with LiAlH4 gave the corresponding CF3-con-
taining diols 44 and 45 as single diastereoisomers in 96% ee
and 98% ee respectively, while ring opening of 43 with metha-
nol gave ester 46 in 90% yield and 98% ee (Scheme 3).
Scheme 4 LiAlH4 reduction to prepare CF3-lactols. (a) Isolated yield of product
(>98 : 2 dr); (b) determined by HPLC analysis; (c) enantioselectivity could not be
determined.
delivers CF3-lactols 48–53 as single diastereoisomers in >80%
yields and high ee (Scheme 4).
Mechanistic studies
To complement these synthetic studies, kinetic investigations
aimed at establishing the catalytic cycle were performed.
4-Fluorophenylacetic acid (preactivated with pivaloyl chloride
and Hunig’s base to prepare the mixed anhydride 54 in situ) and
triuoromethylenone 2 were used as model substrates in order
to measure reaction kinetics by in situ 19F NMR spectroscopic
analysis. The reactions were performed in CD2Cl2 at ꢁ78 ꢀC
using HBTM 2.1 6 (Scheme 5).
Scheme 5 Model reaction used for in situ 19F NMR spectroscopic analysis.
Scheme 3 Hydrogenation and ring-opening derivatisation procedures. (a) Iso-
Data were tted (MATLAB) using plots of log concentrations
of mixed anhydride 54 and enone 2 vs. time to give the observed
rst order rate constants kobs. Using one equivalent of enone
with respect to anhydride the reaction progress could be tted
to a rst-order rate expression for the concentration of the
mixed anhydride 54 or the enone 2 (see ESI†). Repeating the
analysis, varying the initial concentration of enone 2 (50 mM,
75 mM, 100 mM, 200 mM and 300 mM) showed that while the
reaction rate remained rst order with respect to anhydride the
lated yield of product (>98 : 2 dr); (b) determined by HPLC analysis.
Alternatively, reduction of dihydropyranone 20 with LiAlH4
gave the CF3-lactol 47 as a single diastereoisomer in 80% yield
and 97% ee aer purication.38,39 This simple procedure is
general and highly diastereoselective, tolerates various substi-
tution patterns at C(3)- and C(4)- in the dihydropyranone, and
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corresponding acyl isothiouronium ion 56. Deprotonation will
generate the (Z)-enolate 57, which undergoes stereoselective
Michael addition43 to the triuoromethylenone 58, followed by
intramolecular cyclisation, to generate the dihydropyranone 59
and regenerate the isothiourea 6 (Fig. 4). The kinetic studies
indicate that the rate-determining transition structure is con-
structed from the catalyst and the anhydride. While either the
N-acylation or deprotonation steps are consistent with this
requirement the deuterium kinetic isotope effect described
above is consistent with deprotonation being rate determining.
Such knowledge suggests that, within certain boundaries, the
reaction rate will not be limited by the choice of enone acceptor.
Fig. 2 Graph of the natural log of the observed rate constant against the natural
log of the initial concentration of the enone acceptor. The gradient of the best-fit
line (roughly zero) is indicative of the order of the rate with respect to the
concentration of the enone.
Fig. 3 Graph of the natural log of the observed rate constant against the natural
log of the initial concentration of the catalyst. The gradient of the best-fit line
(roughly one) is indicative of the order of the rate with respect to the concen-
tration of the catalyst.
Fig. 4 Proposed catalytic cycle for asymmetric Michael-lactonisation process.
The formation of an acyl isothiouronium ion such as 56 is
supported by the treatment of HBTM 2.1 6 with 4-uo-
rophenylacetyl chloride to give N-acyl isothiouronium chloride
60 (dF ꢁ116.3) in 92% isolated yield (Scheme 6). The validity of
60 as a plausible reaction intermediate was probed by its use as
a precatalyst (5 mol%). Treatment of 4-uorophenylacetic acid
with pivaloyl chloride and Hunig’s base, followed by addition of
triuoromethylenone 2 and acyl isothiouronium salt 60 as the
precatalyst gave dihydropyridone 13 in 88% isolated yield and
rate was essentially independent of the concentration of the
enone 2 (Fig. 2). Repeating the analysis, varying the initial
concentration of catalyst (0.25 mM, 0.5 mM and 1.0 mM)
showed a near linear rst order dependence of rate on catalyst
concentration (Fig. 3). Further kinetic studies revealed that
increasing to 8 equivalents of Hunig’s base led to minimal
change in reaction rate. Notably for the acetylation of alcohols
using DMAP Zipse et al. have demonstrated kinetically that
alcohol deprotonation is performed in a rate determining step
by acetate instead of
a trialkylamine auxiliary base in
dichloromethane.40 Extrapolation of these studies to the system
in this manuscript implicates potential deprotonation of an acyl
ammonium intermediate by pivalate and the use of Hunig’s
base as a shuttle base.41
Overall these results suggest that the reaction is most likely
to be rst order with respect to mixed anhydride 54 and catalyst
6 and zero order with respect to enone 2. When the reaction was
performed using a,a-di-deuterio 4-uorophenylacetic acid
(>99% d2) the observed rate (kobs) was approximately a quarter
of that for the equivalent reaction using 4-uorophenylacetic
acid (kobsH/kobsD ¼ 3.8).42 Based on these kinetic studies we
propose a catalytic cycle that proceeds via initial formation of
Scheme
6
Validation of acyl ammonium as a plausible intermediate; (a)
determined by 1H NMR spectroscopic analysis of the crude reaction mixture; (b)
the mixed anhydride 55, followed by generation of the isolated yield ($95 : 5 dr); (c) determined by HPLC analysis.
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identical diastereo- and enantioselectivity (90 : 10 dr and >99%
ee) to that employing HBTM-2.1 6 directly in this protocol.44
To experimentally test the hypothesis of epimerisation,
treatment of the 91 : 9 mixture of (3R,4S)-64 (99% ee):(3R,4R)-3
Notably, for all cases in this kinetic analysis monitoring the (54% ee) with DHPB (10 mol%) at rt for 16 h gave a 12 : 88
product distribution with reaction progress indicated that the mixture of (3R,4S)-64 (86% ee):(3S,4S)-3 (85% ee), consistent
product diastereoselectivity increased with time, with typically with epimerisation at C(3) of the syn-dihydropyranone (3R,4S)-
an 83 : 17 anti–syn ratio observed aer 5 min, and a 90 : 10 anti– 64 to the anti-dihydropyanone (3S,4R)-3 (Scheme 9).46 This
syn ratio observed at the end of the kinetic experiments (typi- observation is in agreement with both proton/deuterium
cally 4–6 hours). Furthermore, product 61 derived from a,a-di- exchange at C(3) (Scheme 7) and the observed increase in
deuterio 4-uorophenylacetic acid 62 (>99% d2) contained product diastereoselectivity over time in the kinetic
around 30% H at C(3) (Scheme 7). These observations imply in experiments.
situ equilibration and epimerisation at C(3) during the reaction
and prompted an investigation regarding the stereospecicity
of this process through the employment of the (Z)-enone 6345 as
the Michael acceptor.
Scheme 7 Reaction using a,a-di-deuterio 4-fluorophenylacetic acid 62 (>99%
d2); (a) determined by 1H NMR spectroscopic analysis of the crude reaction
mixture; (b) isolated yield ($95 : 5 dr).
Initial studies with 3,4-dihydro-2H-pyrimido[2,1-b]benzothia-
zole (DHPB) as the isothiourea catalyst and (Z)-enone 63 using
Scheme 9 Epimerisation study; (a) determined by HPLC analysis.
standard reaction conditions at rt gave an 87 : 13 anti–syn mixture
of dihydropyranones aer 16 hours, essentially identical to the
observed 86 : 14 anti–syn product ratio observed using DHPB
from the (E)-enone (Scheme 8). At lower temperature (ꢁ78 ꢀC) a
47 : 53 anti–syn mixture of dihydropyranones was generated,
suggesting epimerisation of the initially formed syn-isomer to the
thermodynamically preferred anti-isomer. In the asymmetric
With syn-dihydropyranone 64 (dr 91 : 9) in hand, treatment
with LiAlH4 generates the CF3-lactol 65 (dr 91 : 9) in 76% iso-
lated yield and 99% ee aer purication (Scheme 10).47 This
protocol thus allows access to stereoisomeric product tri-
uoromethyl lactols by judicious choice of enone geometry.
ꢀ
series, the use of HBTM 2.1 6 at ꢁ78 C with (Z)-enone 63 gave
preferentially the syn-dihydropyranone 64 with good diaster-
eoselectivity (85 : 15 dr), with purication giving a 91 : 9 mixture
of (3R,4S)-64 (99% ee): (3R,4R)-3 (54% ee) in 74% yield.
Scheme 10 Syn-diastereoisomer derivatisation; (a) determined by 1H NMR
spectroscopic analysis of the crude reaction mixture; (b) isolated yield (94 : 6 dr);
(c) determined by HPLC analysis.
Conclusions
In conclusion, the isothiourea-mediated Michael-lactonisation
process of arylacetic acids and either (E)- or (Z)-4-aryl-tri-
uoromethylenones proceeds readily using HBTM 2.1 6 at low
catalyst loadings (1–5 mol%). This process is stereospecic and
proceeds with high diastereo- and enantiocontrol (up to 95 : 5
dr, >99% ee), giving anti-dihydropyranones preferentially from
(E)-enones and syn-dihydropyranones from (Z)-enones. The
Scheme 8 Reaction stereospecificity; (a) determined by 1H NMR spectroscopic
analysis of the crude reaction mixture; (b) isolated yield (91 : 9 dr); (c) determined
by HPLC analysis.
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product C(6)-triuoromethyldihydropyranones are readily
derivatised to a range of triuoromethyl containing synthetic
building blocks under scalable and operationally simple
experimental conditions. Kinetic studies indicate this process is
rst order with respect to both in situ formed anhydride and
catalyst concentration, with a primary kinetic isotope effect
observed using a,a-di-deuterio 4-uorophenylacetic acid.
Current research from this laboratory is directed toward
developing alternative applications of isothioureas in asym-
metric catalysis.
Tetrahedron, 2009, 65, 2232; (f) D. Belmessieri,
C. Joannesse, P. A. Woods, C. MacGregor, C. Jones,
´
C. D. Campbell, C. P. Johnston, N. Duguet, C. Concellon,
R. A. Bragg and A. D. Smith, Org. Biomol. Chem., 2011, 9,
559; (g) X. Li, H. Jiang, E. W. Uffman, L. Guo, Y. Zhang,
X. Yang and V. B. Birman, J. Org. Chem., 2012, 77, 1722; (h)
X. Yang, V. D. Bumbu, P. Liu, X. Li, H. Jiang,
E. W. Uffman, L. Guo, W. Zhang, X. Jiang, K. N. Houk and
V. B. Birman, J. Am. Chem. Soc., 2012, 134, 17605; (i)
A. J. Wagner, J. G. David and S. D. Rychnovsky, Org. Lett.,
2011, 13, 4470; (j) M. A. Perry, J. V. Trinidad and
S. D. Rychnovsky, Org. Lett., 2013, 15, 472; (k) A. J. Wagner
and S. D. Rychnovsky, J. Org. Chem., 2013, 78, 4594; (2) For
kinetic resolutions using carboxylic acids as acylating
agents utilising in situ formation of a reactive mixed
anhydride see: (l) I. Shiina and K. Nakata, Tetrahedron Lett.,
2007, 48, 8314; (m) I. Shiina, K. Nakata, M. Sugimoto,
Y. Onda, T. Iizumi and K. Ono, Heterocycles, 2009, 77, 801;
(n) X. Yang and V. B. Birman, Adv. Synth. Catal., 2009, 351,
2301; (o) I. Shiina and K. Nakata, Heterocycles, 2010, 80,
169; (p) I. Shiina, K. Nakata and Y. Onda, Eur. J. Org.
Chem., 2008, 5887; (q) I. Shiina, K. Nakata, K. Ono,
M. Sugimoto and A. Sekiguchi, Chem.–Eur. J., 2010, 16, 167;
(r) K. Nakata, Y. Onda, K. Ono and I. Shiina, Tetrahedron
Lett., 2010, 51, 5666; (s) I. Shiina, K. Ono and K. Nakata,
Chem. Lett., 2011, 40, 147; (t) I. Shiina, K. Nakata, K. Ono,
Y.-S. Onda and M. Itagaki, J. Am. Chem. Soc., 2010, 132,
11629; (u) K. Nakata, A. Sekiguchi and I. Shiina,
Tetrahedron, 2011, 22, 1610; (v) I. Shiina, K. Nakata, K. Ono
and T. Mukaiyama, Helv. Chim. Acta, 2012, 95, 1891. For
the kinetic resolution of b-lactams see (w) V. D. Bumbu
and V. B. Birman, J. Am. Chem. Soc., 2011, 133, 13902. For
desymmetrisation processes see: (x) X. Yang, G. Lu and
V. B. Birman, Org. Lett., 2010, 12, 892; (y) X. Yang and
V. B. Birman, Angew. Chem., Int. Ed., 2011, 50, 5553. For
metal mediated processes see (z) J. A. Kalow and
A. G. Doyle, J. Am. Chem. Soc., 2010, 132, 3268; For
asymmetric C-acylation and C-carboxylation reaction
processes see: (aa) C. Joannesse, C. P. Johnston,
Acknowledgements
We thank the Royal Society for a University Research Fellow-
ships (A.D.S) and The Carnegie Trust for the Universities of
Scotland (L.C.M) for funding. The research leading to these
results has received funding from the European Research
Council under the European Union’s Seventh Framework Pro-
gramme (FP7/2007–2013)/ERC grant agreement no. 279850. We
also thank the EPSRC National Mass Spectrometry Service
Centre (Swansea).
Notes and references
1 M. J. Gaunt and C. C. C. Johansson, Chem. Rev., 2007, 107,
5596.
2 For a comprehensive review on the generation and utility of
ammonium enolates generated from ketenes and acid
chlorides see D. H. Paull, A. Weatherwax and T. Lectka,
Tetrahedron, 2009, 65, 6771.
3 (a) G. S. Cortez, R. L. Tennyson and D. Romo, J. Am. Chem.
Soc., 2001, 123, 7945; (b) G. S. Cortez, S. H. Oh and
D. Romo, Synthesis, 2001, 1731; (c) S. H. Oh, G. S. Cortez
and D. Romo, J. Org. Chem., 2005, 70, 2835; (d) H. Henry-
Riyad, C. Lee, V. C. Purohit and D. Romo, Org. Lett., 2006,
8, 4363; (e) G. Ma, H. Nguyen and D. Romo, Org. Lett.,
2007, 9, 2143; (f) H. Nguyen, G. Ma and D. Romo, Chem.
Commun., 2010, 46, 4803; (g) K. A. Morris, K. M. Arendt,
S. H. Oh and D. Romo, Org. Lett., 2010, 12, 3764; (h)
H. Nguyen, G. Ma, T. Gladysheva, T. Fremgen and
D. Romo, J. Org. Chem., 2011, 76, 2; (i) V. C. Purohit,
A. S. Matla and D. Romo, J. Am. Chem. Soc., 2008, 130,
10478; (j) C. Leverett, V. C. Purohit and D. Romo, Angew.
Chem., Int. Ed., 2010, 49, 9479; (k) G. Liu, M. E. Shirley and
D. Romo, J. Org. Chem., 2012, 77, 2496; (l) G. Liu and
D. Romo, Angew. Chem., Int. Ed., 2011, 50, 7537.
4 For a recent review detailing the use of isothioureas in
nucleophilic catalysis see J. E. Taylor, S. D. Bull and
J. M. J. Williams, Chem. Soc. Rev., 2012, 41, 2109. For a
representative selection of manuscripts detailing the
diverse abilities of isothioureas in asymmetric catalysis see
(1). For kinetic resolutions using anhydrides as acylating
agents: (a) V. B. Birman and X. Li, Org. Lett., 2006, 8, 1351;
(b) V. B. Birman and L. Geo, Org. Lett., 2006, 8, 4859; (c)
V. B. Birman and X. Li, Org. Lett., 2008, 10, 1115; (d)
X. Yang and V. B. Birman, Adv. Synth. Catal., 2009, 351,
2525; (e) Q. Xu, H. Zhou, X. Geng and P. Chen,
´
C. Concellon, C. Simal, D. Philp and A. D. Smith, Angew.
Chem., Int. Ed., 2009, 48, 8914; (ab) C. Joannesse,
L. C. Morrill, C. D. Campbell, A. M. Z. Slawin and
A. D. Smith, Synthesis, 2011, 1865; (ac) B. Viswambharan,
T. Okimura, S. Suzuki and S. Okamoto, J. Org. Chem., 2011,
76, 6678; (ad) P. A. Woods, L. C. Morrill, R. A. Bragg and
A. D. Smith, Chem.–Eur. J., 2011, 17, 11060; (ae)
E. R. T. Robinson, C. Fallan, C. Simal, A. M. Z. Slawin and
A. D. Smith, Chem. Sci., 2013, 4, 2193.
5 For pioneering work see: (a) V. B. Birman, H. Jiang, X. Li,
V. Geo and E. W. Uffman, J. Am. Chem. Soc., 2006, 128,
6536; (b) M. Kobayashi and S. Okamoto, Tetrahedron Lett.,
2006, 47, 4347.
6 D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin and
A. D. Smith, J. Am. Chem. Soc., 2011, 133, 2714.
7 For selectedother examples of Lewis base catalysed reaction
processes from this laboratory see: (a) J. E. Thomson, K. Rix
and A. D. Smith, Org. Lett., 2006, 8, 3785; (b) J. E. Thomson,
This journal is ª The Royal Society of Chemistry 2013
Chem. Sci.

View Article Online
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Edge Article
´
C. D. Campbell, C. Concellon, N. Duguet, K. Rix,
A. M. Z. Slawin and A. D. Smith, J. Org. Chem., 2008, 73,
2784; (c) C. D. Campbell, N. Duguet, K. A. Gallagher,
J. E. Thomson, A. G. Lindsay, A. O’Donoghue and
A. D. Smith, Chem. Commun., 2008, 3528; (d) N. Duguet,
C. D. Campbell, A. M. Z. Slawin and A. D. Smith, Org.
2008, 62, 260; (j) K. Stanek, R. Koller and A. Togni, J. Org.
Chem., 2008, 73, 7678; (k) S. Noritake, N. Shibata,
S. Nakamura, T. Toru and M. Shiro, Eur. J. Org. Chem.,
2008, 3465; (l) A. Matsnev, S. Noritake, Y. Nomura,
E. Tokunaga, S. Nakamura and N. Shibata, Angew. Chem.,
2010, 122, 582; Angew. Chem., Int. Ed., 2010, 49, 572.
Biomol. Chem., 2008, 6, 1108; (e) J. E. Thomson, A. F. Kyle, 15 For a selection of radical triuoromethylation strategies see:
´
C. Concellon, K. A. Gallagher, P. Lenden, L. C. Morrill,
(a) K. Miura, M. Taniguchi, K. Nozaki, K. Oshima and
K. Utimoto, Tetrahedron Lett., 1990, 31, 6391; (b) Y. Itoh
and K. Mikami, Org. Lett., 2005, 7, 4883; (c) Y. Itoh and
K. Mikami, Tetrahedron, 2006, 62, 7199.
A. J. Miller, C. Joannesse, A. M. Z. Slawin and A. D. Smith,
Synthesis, 2008, 17, 2805; (f) C. Joannesse, C. Simal,
C. Concellon, J. E. Thomson, C. D. Campbell,
A. M. Z. Slawin and A. D. Smith, Org. Biomol. Chem., 2008, 16 For
´
a
selection of nucleophilic triuoromethylation
´
´
6, 2900; (g) C. Concellon, N. Duguet and A. D. Smith, Adv.
strategies see: (a) R. Barhdadi, M. Troupel and J. Perichon,
Chem. Commun., 1998, 1251; (b) D. W. Nelson, R. A. Easley
and B. N. V. Pintea, Tetrahedron Lett., 1999, 40, 25; (c)
S. Large, N. Roques and B. R. Langlois, J. Org. Chem., 2000,
65, 8848; (d) D. W. Nelson, J. Owens and D. Hiraldo, J. Org.
Chem., 2001, 66, 2572; (e) J. J. Song, Z. Tan, J. T. Reeves,
F. Gallou, N. K. Yee and C. H. Senanayake, Org. Lett., 2005,
7, 2193; (f) T. Mukaiyama, Y. Kawano and H. Fujisawa,
Chem. Lett., 2005, 34, 88; (g) Y. Kawano, N. Kaneko and
T. Mukaiyama, Bull. Chem. Soc. Jpn., 2006, 79, 1133; (h)
S. Mizuta, N. Shibata, T. Sato, H. Fujimoto, S. Nakamura
and T. Toru, Synlett, 2006, 267.
Synth. Catal., 2009, 351, 3001; (h) P. A. Woods,
L. C. Morrill, R. A. Bragg and A. D. Smith, Org. Lett., 2010,
12, 2660; (i) J. Douglas, K. B. Ling, C. Concellon,
G. Churchill, A. M. Z. Slawin and A. D. Smith, Eur. J. Org.
Chem., 2010, 5863; (j) K. B. Ling and A. D. Smith, Chem.
Commun., 2011, 47, 373; (k) C. D. Campbell, C. J. Collett,
J. E. Thomson, A. M. Z. Slawin and A. D. Smith, Org.
Biomol. Chem., 2011, 9, 4205; (l) J. Douglas, J. E. Taylor,
G. Churchill, A. M. Z. Slawin and A. D. Smith, J. Org.
Chem., 2013, 78, 3925.
´
8 K. A. Jørgensen, Eur. J. Org. Chem., 2004, 2093.
9 L. C. Morrill, T. Lebl, A. M. Z. Slawin and A. D. Smith, Chem. 17 For a selection of manuscripts detailing catalytic asymmetric
Sci., 2012, 3, 2088.
10 C. Simal, T. Lebl, A. M. Z. Slawin and A. D. Smith, Angew.
Chem., Int. Ed., 2012, 51, 3653.
11 For select reviews see: (a) P. Kirsch, Modern Fluoroorganic
Chemistry, Wiley VCH, Weinheim, Germany, 2004; (b)
nucleophilic additions to CF3 ketones see: (a) R. Motoki,
D. Tomita, M. Kanai and M. Shibasaki, Tetrahedron Lett.,
2006, 47, 8083; (b) R. Motoki, M. Kanai and M. Shibasaki,
Org. Lett., 2007, 9, 2997; (c) S. L. X. Martina, R. B. C. Jagt,
J. G. de Vries, B. L. Feringa and A. J. Minnaard, Chem.
Commun., 2006, 4093; (d) A. Bøgevig, K. V. Gothelf and
K. A. Jørgensen, Chem.–Eur. J., 2002, 8, 5652; (e) F. Tur and
¨
K. Muller, C. Faeh and F. Diederich, Science, 2007, 317,
1881; (c) S. Purser, P. R. Moore, S. Swallow and
V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320; (d)
W. K. Hagmann, J. Med. Chem., 2008, 51, 4359.
´
J. M. Saa, Org. Lett., 2007, 9, 5079; (f) M. Shi, X.-G. Liu,
Y.-W. Guo and W. Zhang, Tetrahedron, 2007, 63, 12731.
12 For select reviews see: (a) J.-A. Ma and D. Cahard, Chem. Rev., 18 A. E. Allen and D. W. C. MacMillan, J. Am. Chem. Soc., 2010,
2004, 104, 6119; (b) J.-A. Ma and D. Cahard, J. Fluorine Chem., 132, 4986.
2007, 128, 975; (c) N. Shibata, A. Matsnev and D. Cahard, 19 D. A. Nagib, M. E. Scott and D. W. C. MacMillan, J. Am. Chem.
Beilstein J. Org. Chem., 2010, 6, 65. Soc., 2009, 131, 10875.
13 For the incorporation of the CF3 group into aromatic 20 For selected organocatalytic processes utilising CF3-carbonyl
compounds see E. J. Cho, T. D. Senecal, T. Kinzel,
Y. Zhang, D. A. Watson and S. L. Buchwald, Science, 2010,
328, 1679.
derivatives see: (a) M. Bandini, R. Sinisi and A. Umani-
Ronchi, Chem. Commun., 2008, 4360; (b) M. Rueping,
T. Theissmann, A. Kuenkel and R. M. Koenigs, Angew.
Chem., Int. Ed., 2008, 47, 6798; (c) J.-L. Zhao, L. Liu,
C.-L. Gu, D. Wang and Y.-J. Chen, Tetrahedron Lett., 2008,
49, 1476; (d) X.-N. Wang, P.-L. Shao, H. Lv and S. Ye, Org.
Lett., 2009, 11, 4029.
14 For
a
selection of electrophilic triuoromethylation
strategies see: (a) T. Umemoto and S. Ishihara, Tetrahedron
Lett., 1990, 31, 3579; (b) T. Umemoto and S. Ishihara, J.
Am. Chem. Soc., 1993, 115, 2156; (c) J. J. Yang,
R. L. Kirchmeier and J. M. Shreeve, J. Org. Chem., 1998, 63, 21 For asymmetric addition to aldehydes see: (a) K. Iseki,
2656; (d) J.-A. Ma and D. Cahard, J. Org. Chem., 2003, 68,
8726; (e) J.-C. Blazejewski, M. P. Wilmshurst, M. D. Popkin,
C. Wakselman, G. Laurent, D. Nonclercq, A. Cleeren,
Y. Ma, H.-S. Seoc and G. Leclercq, Bioorg. Med. Chem.,
2003, 11, 335; (f) P. Eisenberger, S. Gischig and A. Togni,
Chem.–Eur. J., 2006, 12, 2579; (g) I. Kieltsch, P. Eisenberger
and A. Togni, Angew. Chem., 2007, 119, 768; Angew. Chem.,
Int. Ed., 2007, 46, 754; (h) P. Eisenberger, I. Kieltsch,
N. Armanino and A. Togni, Chem. Commun., 2008, 1575; (i)
I. Kieltsch, P. Eisenberger, K. Stanek and A. Togni, Chimia,
T. Nagai and Y. Kobayashi, Tetrahedron Lett., 1994, 35,
3137; (b) T. Hagiwara, T. Kobayashi and T. Fuchigami,
Nippon Kagaku Kaishi, 1997, 12, 869; (c) T. Hagiwara,
T. Kobayashi and T. Fuchikami, Main Group Chem., 1997,
2, 13; (d) Y. Kuroki and K. Iseki, Tetrahedron Lett., 1999,
40, 8231; (e) S. Caron, S. M. Do, P. Arpin and A. Larrive,
Synthesis, 2003, 1693; (f) S. Mizuta, N. Shibata, T. Sato,
H. Fujimoto, S. Nakamura and T. Toru, Synlett, 2006, 267;
(g) S. Mizuta, N. Shibata, M. Hibino, S. Nagano,
S. Nakamura and T. Toru, Tetrahedron, 2007, 63, 8521; (h)
Chem. Sci.
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H. Nagao, Y. Yamane and T. Mukaiyama, Chem. Lett., 2007, 29 The relative and absolute conguration of 15 was conrmed
36, 666; (i) H. Zhao, B. Qin, Z. Liu and Z. Feng,
Tetrahedron, 2007, 63, 6822; (j) S. Mizuta, N. Shibata,
by X-ray crystal structure analysis, with all other derivatives
assigned by analogy. See ESI† for further details.
S. Akiti, H. Fujimoto, S. Nakamura and T. Toru, Org. Lett., 30 The minor (syn) diastereoisomer was formed in 34% ee and
2007, 9, 3707; (k) X. Hu, J. Wang, W. Li, L. Lin, X. Liu and
X. Feng, Tetrahedron Lett., 2009, 50, 4378; (l) H. Kawai,
was determined to have (3S,4R) absolute conguration. See
ESI† for full details.
A. Kusuda, S. Mizuta, S. Nakamura, Y. Funahashi, 31 See ESI† for full details of the two step synthetic route
H. Masuda and N. Shibata, J. Fluorine Chem., 2009, 130, towards imine 7.
762; (m) H. Kawai, K. Tachi, E. Tokunaga, M. Shiro and 32 J. W. Yang, S. C. Pan and B. List, Org. Synth., 2009, 86, 11.
N. Shibata, Org. Lett., 2010, 12, 5104; for asymmetric 33 See ESI.†
additions to azomethine imines see (n) H. Kawai, 34 Racemic HBTM-2.1 (ꢂ)-6 (>20 g scale) was also prepared
A. Kusuda, S. Nakamura, M. Shiro and N. Shibata, Angew.
Chem., 2009, 121, 6442; Angew. Chem., Int. Ed., 2009, 48,
6324.
following this method, using (DL)-proline as catalyst for the
Mannich reaction.
35 The use of 2-tolylacetic acid and a variety of alkylacetic acids
in this reaction protocol led to only modest conversion to the
desired products (<10%) upon extended reaction times and
so were not pursued further.
22 (a) G. K. S. Prakash, R. Krishnamurti and G. A. Olah, J. Am.
Chem. Soc., 1989, 111, 393; (b) I. Ruppert, K. Schlich and
W. Volbach, Tetrahedron Lett., 1984, 25, 2195; (c)
G. K. S. Prakash and A. K. Yudin, Chem. Rev., 1997, 97, 757. 36 The reduction in enantioselectivity may be attributed to the
23 (a) J. Joubert, S. Roussel, C. Christophe, T. Billard,
B. R. Langlois and T. Vidal, Angew. Chem., 2003, 115, 3241;
Angew. Chem., Int. Ed., 2003, 42, 3133; (b) S. Roussel,
T. Billard, B. R. Langlois and L. Saint-James, Chem.–Eur. J.,
2005, 11, 939.
presence of a racemic background reaction between the in
situ formed mixed anhydride and the triuoromethyl
enone, which may be accelerated when arylacetic acids
bearing strongly electron withdrawing substituents are used.
1
37 H NMR coupling constant analysis and modelling studies
24 For
a
stoichiometric guanidine catalysed asymmetric
were used to conrm the relative congurations within 42
and 43. See ESI† for further details.
electrophilic triuoromethylation procedure see (a)
S. Noritake, N. Shibata, Y. Nomura, Y. Huang, A. Matsnev, 38 The relative conguration within 48 was conrmed by X-ray
S. Nakamura, T. Toru and D. Cahard, Org. Biomol. Chem.,
2009, 7, 3599. For an alternative asymmetric strategy see
(b) T. Umemoto and K. Adachi, J. Org. Chem., 1994, 59,
5692.
crystal structure analysis, with the absolute conguration
based upon that proven for dihydropyranone 15. All other
derivatives were assigned by analogy. The relative
conguration within 47 was also conrmed through a
combination of NMR spectroscopic investigations using
nOe and coupling constant analysis. See ESI† for further
details.
25 Somewhat related asymmetric organocatalytic processes
that utilise triuoromethylenones have been reported
previously (a) For an enamine promoted asymmetric
inverse-electron-demand hetero-Diels–Alder reaction see 39 For selected alternative protocols that prepare CF3-lactols
Y. Zhao, X.-J. Wang and J.-T. Liu, Synlett, 2008, 1017; (b)
For bifunctional thioureas-promoted Michael additions of
a-cyanoketones see P. Li, Z. Chi, S.-L. Zhao, Y.-Q. Yang,
see: (a) P. Munier, D. Picq and D. Anker, Tetrahedron Lett.,
1993, 34, 8241; (b) D. Sevenard and E. J. Lork, J. Fluorine
Chem., 2004, 125, 125.
H.-F. Wang, C.-W. Zheng, Y.-P. Cai, G. Zhao and S.-Z. Zhu, 40 S. Xu, I. Held, B. Kempf, H. Mayr, W. Steglich and H. Zipse,
Chem. Commun., 2009, 7369. For stoichiometric Chem.–Eur. J., 2005, 11, 4751.
diastereoselective three component inverse-electron- 41 For another isothiourea-related process where pivalate has
a
demand aza Diels–Alder reaction see (c) P. Li, L.-J. Liu and
J.-T. Liu, Org. Biomol. Chem., 2011, 9, 74.
been postulated to act as a base, see K. Nakata, K. Gotoh,
K. Ono, K. Futami and I. Shiina, Org. Lett., 2013, 15, 1170.
26 For the biological activity of CF3-substituted pyran 42 Lectka and co-workers reported a kinetic isotope effect (kH/
derivatives see: (a) Y. Takagi, K. Nakai, T. Tsuchiya and
T. Takeuchi, J. Med. Chem., 1996, 39, 1582; (b) K. Nakai,
Y. Takagi, S. Ogawa and T. Tsuchiya, Carbohydr. Res., 1999,
320, 8.
kD ¼ 3.12) when using a,a-dideuteriophenylacetylchloride
in a related process involving the catalytic, enantioselective
a-uorination of acid chlorides. They use this as evidence
for dehydrohalogenation being the rate-determing step in
the process: J. Erb, D. H. Paull, T. Dudding, L. Belding and
T. Lectka, J. Am. Chem. Soc., 2011, 133, 7536.
27 All 4-aryl-triuoromethylenones utilised in this manuscript
were prepared following the methods previously developed
by Yuan and co-workers. See: (a) W. S. Huang and 43 We postulate that this process proceeds via a Michael
C. Y. Yuan, J. Chem. Soc., Perkin Trans. 1, 1995, 741; (b)
D. Zhang and C. Y. Yuan, Eur. J. Org. Chem., 2007, 3916.
28 Racemic (ꢂ)-3 was prepared using the achiral isothiourea
DHPB (3,4-dihydro-2H-pyrimido[2,1-b]benzothiazole), giving
(ꢂ)-3 (86 : 14 dr) in 66% isolated yield (96 : 4 dr aer
purication). Racemic samples of all products were made
using DHPB as a catalyst.
addition-lactonisation process rather than a concerted
hetero-Diels–Alder type mechanism. Computational
calculations are underway to validate this hypothesis.
Although computational calculations shown that a related
NHC-catalysed reaction process proceeds via the hetero-
Diels–Alder pathway (S. E. Allen, J. Mahatthananchai,
J. W. Bode and M. C. Kozlowski, J. Am. Chem. Soc., 2012,
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134, 12098) we postulate that the isothiourea promoted
pathway is distinct.
reaction, may be basic enough to produce enolate and
further reaction such as Claisen-type self-condensation.
44 Treatment of the HBTM-2.1 6 with the mixed anhydride 45 (Z)-Enone 63, made by reduction of the corresponding
without enone acceptor 2 does not produce a single
product, as happens with the acid chloride, but rather a
complex mixture which seemingly included a signicant
alkyne using Lindlar’s hydrogenation conditions, must
be used immediately to avoid isomerisation to the (E)-
enone 2.
proportion of unreacted catalyst. This result suggests that, 46 Epimerisation at C(3) is also observed when HBTM-2.1 6 is
while the reaction with the acid chloride proceeds to used, although this occurs at a slightly reduced rate.
completion and then stops because chloride is not 47 The relative conguration within 65 was conrmed by X-ray
particularly basic, pivalate, generated in the anhydride crystal structure analysis.†
Chem. Sci.
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