α-ketophosphonates as ester surrogates: Isothiourea-catalyzed asymmetric diester and lactone synthesis

Article abstract of DOI:10.1021/ol500873s

Isothiourea HBTM-2.1 catalyzes the asymmetric Michael addition/ lactonization of aryl- and alkenylacetic acids using α-keto-β, γ-unsaturated phosphonates as α,β-unsaturated ester surrogates, giving access to a diverse range of stereodefined lactones or enantioenriched functionalized diesters upon ring-opening.

Full text of DOI:10.1021/ol500873s

Letter
pubs.acs.org/OrgLett
α‑Ketophosphonates as Ester Surrogates: Isothiourea-Catalyzed
Asymmetric Diester and Lactone Synthesis
Siobhan R. Smith,† Stuart M. Leckie,† Reuben Holmes,† James Douglas,† Charlene Fallan,†
Peter Shapland,‡ David Pryde,§ Alexandra M. Z. Slawin,† and Andrew D. Smith*,†
†EaStCHEM, School of Chemistry, University of St. Andrews, North Haugh, St. Andrews KY16 9ST, U.K.
‡GSK, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
§Pfizer Neusentis, The Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, U.K.
S
* Supporting Information
ABSTRACT: Isothiourea HBTM-2.1 catalyzes the asymmet-
ric Michael addition/lactonization of aryl- and alkenylacetic
acids using α-keto-β,γ-unsaturated phosphonates as α,β-
unsaturated ester surrogates, giving access to a diverse range
of stereodefined lactones or enantioenriched functionalized
diesters upon ring-opening.
ewis base organocatalysis has developed as a powerful tool
Lfor the enantioselective construction of carbon−carbon
bonds.1 Within this area, the asymmetric addition of enolates
and their derivatives via the use of cinchona alkaloids,2
enamines,3 and azolium enolates4 generated with N-hetero-
cyclic carbenes (NHCs)5 to electron-deficient alkenes has
received widespread attention in recent years. Catalytic
asymmetric conjugate additions employing enones and enals
is well established,6 although the use of α,β-unsaturated esters
and amides remains challenging due to the intrinsic decreased
reactivity of these motifs. Efforts to circumvent this issue have
used N-acylpyrroles,7 2-acylimidazoles,8 and activated imides9
as ester surrogates, while Evans10 and Jørgensen11 have
pioneered the use of α-keto-β,γ-unsaturated phosphonates as
ester equivalents. Using transition metal and organocatalysts,
respectively, these methods activate the α-ketophosphonate for
nucleophilic attack via bidentate coordination of a Lewis acid or
hydrogen bonding to a thiourea catalyst architecture (Scheme
1).
Building on Romo’s pioneering nucleophile-catalyzed aldol
lactonization (NCAL) strategy,12 we have previously studied
the isothiourea13-catalyzed asymmetric functionalization of
carboxylic acids14 via ammonium enolates.15 This process
requires highly electron-deficient alkene components in
Michael−lactonization reactions, with α,β-unsaturated esters
inert to typical reaction conditions. This manuscript explores α-
ketophosphonates as α,β-unsaturated ester equivalents,16
affording stereodefined diesters upon ring-opening that are
suitable for further synthetic manipulations.
Initial investigations employed phenylacetic acid 1 and α-
ketophosphonate 2 in a model system and assessed a range of
isothiourea Lewis base catalysts (5−7, Table 1). In situ
formation of the mixed anhydride with pivaloyl chloride and i-
Pr2NEt, followed by treatment with isothiourea 5, gave anti-
lactone 3 in 66% isolated yield with modest ee (entry 1). A
screen of isothioureas revealed HBTM-2.1 7 as the optimum
catalyst, providing lactone 3 in 86% ee (entry 3). This catalyst
was then examined using toluene and THF as the solvent,
affording decreased isolated yields but with high diastereocon-
trol (entries 4 and 5). Lowering the temperature to −78 °C
(entry 6) led to improved isolated yield, dr, and ee.
Gratifyingly, a catalyst loading of only 1 mol % at −78 °C
gave the product in good yield with excellent stereocontrol
(entry 7). Finally, in situ methanolysis of lactone 3 gave diester
4 and provided proof of principle that α-ketophosphonates act
as ester surrogates in this system (entry 8).
Scheme 1. Initial Concept
The scope and limitations of this process were next probed,
initially to generate a small range of stereodefined lactones
(Table 2, conditions A). Pleasingly, both electron-rich and
electron-deficient arylacetic acids were suitable ammonium
enolate precursors, and the functionalized lactones (3, 8−10)
Received: March 24, 2014
Published: April 15, 2014
© 2014 American Chemical Society
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Table 1. Optimization
Table 2. Reaction Scope
a
catalyst
(mol %)
time
(h)
yield
b
c
entry
product
(%)
dr
ee (%)
1
2
3
5 (10)
6 (10)
7 (10)
7 (10)
7 (10)
7 (10)
7 (1)
3
3
3
3
3
3
3
4
2
1
66
39
51
41
10
67
83
63
84:16
74:26
88:12
89:11
87:13
90:10
>95:5
60 (ent)
56
1
86
d
4
2
97
e
5
24
24
24
24
62
f
6
f
98
7
98
8
7 (1)
92:8
97
a
b
Isolated yield of product following chromatography. Determined by
1H NMR spectroscopic analysis of the unpurified reaction mixture.
c
d
e
Determined by chiral HPLC analysis. Reaction in toluene. Reaction
f
in THF. Reaction at −78 °C.
were isolated following Lewis base catalysis in good yield with
high diastereo- and enantiocontrol. The ability of the
phosphonate group to act as a masked ester/amide equivalent
was assessed with a range of arylacetic acids and α-
ketophosphonates using a low catalyst loading of 1 mol %.
The lactones were ring-opened in situ with a range of
nucleophiles to reveal 1,5-diester or-diamide products (Table
2, conditions B) in high yield with excellent stereocontrol.
Arylacetic acids containing both electron-withdrawing and
electron-donating substituents in the meta and para positions
were incorporated in high yield while maintaining excellent
levels of enantio- and diastereoselectivity (4, 11−21).17
Extended aromatic systems were also well tolerated (16).
Additionally, α-ketophosphonates containing electron-rich and
electron-deficient aromatic substitution were competent in this
process (17 and 18), and significantly, aliphatic substitution
was also tolerated with good isolated yield and high levels of
selectivity (19). Finally, allyl alcohol and i-PrNH2 were
employed in lactone ring-opening, providing diester 20 and
diamide 21, respectively, in excellent yields, with high enantio-
and diastereocontrol.
Single-crystal X-ray structure analysis of diester 15 allowed
unambiguous determination of the relative and absolute
configuration as (2R,3R) (Figure 1).18 All other diesters within
this series were assigned by analogy.
Variation of the α-ketophosphonate was also explored using
isopropyl phosphonate 22 (Table 3). The improved prepara-
tion and isolation of 22,19 in addition to its increased bench
stability over methyl phosphonate 2, allowed further examina-
a
b
Isolated yield of product following chromatography. Determined by
1H NMR spectroscopic analysis of the unpurified reaction mixture.
c
d
Determined by chiral HPLC analysis. 1 mol % of catalyst 7
employed.
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ality was achieved by treating 4 with LiAlH4 (1 equiv) in THF
at 0 °C, giving diol 28 in quantitative yield and 99% ee
(Scheme 2A). Additionally, selective reduction of the least
Scheme 2. Derivatizations
Figure 1. Representation of the single-crystal X-ray structure of diester
15.
Table 3. Substrate Scope Using Isopropyl Phosphonate 22
a
b
Isolated yield of product following chromatography. Determined by
1H NMR spectroscopic analysis of the unpurified reaction mixture.
c
Determined by chiral HPLC analysis.
hindered ester in 4, 12, and 14 was achieved by careful control
of reaction conditions with DIBAL-H (2.2 equiv) in THF at 0
°C giving alcohols 29−31, respectively.20 Subsequent acid-
catalyzed lactonization of 29−31 was achieved with TFA giving
the enantiomerically enriched lactones 32−34 in good yield
over two steps (Scheme 2B).21 Such aryl-substituted δ-lactones
are of medicinal and synthetic interest.22
The proposed mechanism of the process begins with N-
acylation of HBTM-2.1 7 with mixed anhydride 35 formed in
situ (Scheme 3). Subsequent deprotonation of 36 generates
(Z)-ammonium enolate 37, which undergoes Michael addition
to α-ketophosphonate 2. Lactonization regenerates the
Scheme 3. Proposed Mechanism
a
b
Isolated yield of product following chromatography. Determined by
1H NMR spectroscopic analysis of the unpurified reaction mixture.
c
Determined by chiral HPLC analysis.
tion of the substrate scope in this process. Using phosphonate
22, this methodology was amenable to large-scale synthesis, and
diester 4 was obtained in 87% isolated yield (0.95 g, 5 mmol
scale) with excellent stereocontrol. Again, a range of diester
products using arylacetic acids were synthesized in excellent
isolated yields, with high diastereo- and enantiocontrol (12 and
14). Notably, the substrate scope was expanded to include
heteroarylacetic and alkenylacetic acids, giving functionalized
diesters 23−27 in high yield. However, the styrene 27 was
isolated with diminished levels of enantiocontrol (27% ee).
To demonstrate the potential utility of this methodology,
synthetic transformations of the diester products were
investigated. First, complete reduction of the diester function-
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Chem. 2005, 70, 2835−2838. (c) Henry-Riyad, H.; Lee, C.; Purohit, V.
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isothiourea catalyst and delivers lactone 3, which can be ring-
opened in situ to afford diester 4.
In conclusion, we have demonstrated the Michael addition/
lactonization of a range of acetic acids with α-keto-β,γ-
unsaturated phosphonates as masked α,β-unsaturated ester
equivalents. The synthetic utility of the lactone and diester
products has been demonstrated through a variety of product
manipulations, affording a range of stereodefined building
blocks. Further studies within our laboratory are directed
toward the development of isothioureas in catalysis.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and 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
■
(14) Robinson, E. R. T.; Fallan, C.; Simal, C.; Slawin, A. M. Z.;
Smith, A. D. Chem. Sci. 2013, 4, 2193−2200.
(15) (a) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M. Z.;
Smith, A. D. J. Am. Chem. Soc. 2011, 133, 2714−2720. (b) Morrill, L.
C.; Lebl, T.; Slawin, A. M. Z.; Smith, A. D. Chem. Sci. 2012, 3, 2088−
*E-mail: ads10@st-andrews.ac.uk.
Notes
The authors declare no competing financial interest.
́
2093. (c) Simal, C.; Lebl, T.; Slawin, A. M. Z.; Smith, A. D. Angew.
Chem., Int. Ed. 2012, 51, 3653−3657. (d) Belmessieri, D.; Cordes, D.
B.; Slawin, A. M. Z.; Smith, A. D. Org. Lett. 2013, 15, 3472−3475.
ACKNOWLEDGMENTS
■
́
(e) Morrill, L. C.; Douglas, J.; Lebl, T.; Slawin, A. M. Z.; Fox, D. J.;
We thank the Royal Society for a University Research
Fellowship (A.D.S.) the EPSRC and GSK (CASE award to
S.R.S.), Pfizer (CASE award to S.M.L.), and EU for funding
(C.F.). We also thank the European Research Council under
the European Union’s Seventh Framework Programme (FP7/
2007-2013) ERC Grant Agreement No. 279850 and thank the
EPSRC UK National Mass Spectrometry Facility at Swansea
University.
Smith, A. D. Chem. Sci. 2013, 4, 4146−4155. (f) Stark, D. G.; Morrill,
L. C.; Yeh, P.-P.; Slawin, A. M. Z.; O’Riordan, T. J. C.; Smith, A. D.
Angew. Chem., Int. Ed. 2013, 52, 11624−11646. (g) Morrill, L. C.;
Ledingham, L. A.; Couturier, J.-P.; Bickel, J.; Harper, A. D.; Fallan, C.;
Smith, A. D. Org. Biomol. Chem. 2014, 12, 624−636. (h) Yeh, P.-P.;
Daniels, D. S. B.; Cordes, D. B.; Slawin, A. M. Z.; Smith, A. D. Org.
Lett. 2014, 16, 964−967. (i) Smith, S. R.; Douglas, J.; Prevet, H.;
Shapland, P.; Slawin, A. M. Z.; Smith, A. D. J. Org. Chem. 2014, 79,
1626−1639. (j) Morrill, L. C.; Smith, S. M.; Slawin, A. M. Z.; Smith, A.
D. J. Org. Chem. 2014, 79, 1640−1655. (k) West, T. H.; Daniels, D. S.
B.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2014, 136, 4476−
4479.
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