Enantioselective construction of sterically hindered tertiary α-aryl ketones: A catalytic asymmetric synthesis of isoflavanones

Article abstract of DOI:10.1039/c2cc36452b

A method for the catalytic asymmetric α-arylation of ketones bearing very sterically hindered aryl rings has been developed. This reaction occurs under mild conditions, in short reaction times and has been applied to the first catalytic asymmetric synthesis of isoflavanones.

Full text of DOI:10.1039/c2cc36452b

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COMMUNICATION
Enantioselective construction of sterically hindered tertiary a-aryl
ketones: a catalytic asymmetric synthesis of isoflavanonesw
Michael P. Carroll, Helge Muller-Bunz and Patrick J. Guiry*
¨
Received 4th September 2012, Accepted 25th September 2012
DOI: 10.1039/c2cc36452b
A method for the catalytic asymmetric a-arylation of ketones
bearing very sterically hindered aryl rings has been developed.
This reaction occurs under mild conditions, in short reaction
times and has been applied to the first catalytic asymmetric
synthesis of isoflavanones.
complexes and diaryliodonium salts. More recently, Zhou
reported an a-arylation of silyl ketene acetals with aryl triflates
using a Pd H8-BINOL catalyst system.9
Isoflavanones 1, such as Vestinone 2, constitute a class of plant
secondary metabolites which display a range of useful medicinal
properties including anti-cancer1a and immunosuppressant
activities.1b
While these examples consisted of a number of carbonyl
groups being arylated, reports of chiral tertiary a-aryl ketones
being catalytically generated are rare, limited to only one
report by Fu.6c Furthermore examples of catalytic asymmetric
arylations to form tertiary sterocentres on any type of carbonyl
with mono-ortho substitution are limited and with di-ortho
substitution almost non-existent.10
Despite the multitudinous approaches to isoflavanones,2 to
date only one asymmetric synthesis has been realised, which
employed the use of chiral auxiliaries.3 The catalytic asymmetric
alkylation of isoflavanones has been reported using chiral
phase transfer catalysis to afford the corresponding quaternary
stereocentres.4
The prevalence of a-aryl carbonyls in both nature and
pharmaceuticals drives the discovery and development of
further methods for their efficient asymmetric preparation.
Within the field of Pd-allyl chemistry, asymmetric decarboxyl-
ative allylations have recently emerged as a powerful transfor-
mation in organic synthesis,11 chiefly due to the pioneering
efforts of the Stoltz,12 Trost,13 and Tunge14 groups, among
others.15 In 2006 Stoltz reported an asymmetric protonation
whereby the intermediate enolate in the decarboxylative
allylation was intercepted with a proton (eqn (2)).16 Crucial
to the success of this reaction was the use of chiral P,N-ligands.
While this transformation was able to generate a-tertiary
ketones with a range of alkyl groups in excellent enantio-
selectivites and yields, there was no report of this methodology
being applied to the synthesis of an a-aryl ketone.
Recently catalytic asymmetric a-arylation of carbonyls has
emerged as an important C–C bond forming reaction in
organic synthesis, and in the case of the asymmetric synthesis
of quaternary a-aryl carbonyl sterocentres has been well
investigated.5 In contrast, the catalytic asymmetric construction
of tertiary a-aryl carbonyl compounds remains a prominent
challenge due to the ease at which such compounds may be
racemised. Recently, noticeable progress was made in this area
by Fu when he reported a series of nickel catalysed a-arylations.
By using a combination of NiII, a chiral ligand and an aryl
nucleophile a variety of a-halocarbonyls could be arylated in
excellent yields and enantioselectivities.6 Further elegant examples
followed with MacMillan combining organocatalysis with
CuII catalysis to enantioselectively a-arylate aldehydes with
diaryliodonium salts7 and the groups of both MacMillan8a and
Gaunt8b a-arylating N-acyloxazolidinones with Cu-bisoxazoline
Centre for Synthesis and Chemical Biology, School of Chemistry and
Chemical Biology, University College Dublin, Belfield, Dublin 4,
Ireland. E-mail: patrick.guiry@ucd.ie; Tel: +353 1 7162309
w Electronic supplementary information (ESI) available: Experimental
procedures, details of optimisation studies, and spectroscopic data for
all new compounds. CCDC 894384 (7c). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2cc36452b
Herein we report our efforts to develop a catalytic asymmetric
synthesis of isoflavanones an interest which was prompted
by a previously reported racemic synthesis by Donnelly.2c
c
11142 Chem. Commun., 2012, 48, 11142–11144
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Table 1 Arylation of b-ketoester 3 with aryllead triacetates
improve selectivity resulted in a sharp decrease in conversion.
This temperature limitation was overcome by using the
more electronically deficient (S)-(CF3)3-t-Bu PHOX 6 which
provided 20,40,60-trimethoxyisoflavanone 7c in 89% ee in 1 h at
0 1C (Table 2, entry 2). Further optimisation showed that a
marginal increase in selectivity could be obtained in a shorter
reaction time by running the reaction at 7 1C to give 7c in 92%
ee and an isolated yield of 92% (Table 2, entry 3).
Substrate
Ar
Yielda (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-MeOC6H4
63
60
80
78
80
86
84
75
70
80
89
The sense of stereoinduction was ascertained by referring to
the optical rotation of naturally occurring isoflavanones19 and
we obtained an X-ray crystal structure which gave unambiguous
evidence for the (R)-enantiomer.20
2,4-(MeO)2C6H3
2,4,6-(MeO)3C6H2
(3,4)-OCH2O–C6H3
2,3,4-(MeO)3C6H2
2,6(MeO)2C6H3
2,3,6-(MeO)3C6H2
2-MeO,4,6-(Me)2C6H2
2,6-(Me)2C6H3
With optimised conditions in hand further substrates were then
synthesised to further understand the effect substitution on the
aryl ring would have upon this transformation and to broaden the
substrate scope. From the results obtained it was possible to
deduce a relationship between the substitution on the aryl ring
and the enantioselectivity observed in the product isoflavanone
(Table 3). Under the new optimized conditions isoflavanone 7b
was obtained in an improved ee of 35%. An additional methoxy
group on the aryl ring in the 30-position gave 7e in 51% ee. These
results suggest that increasing the electron richness of the aryl ring
can have a positive influence on enantioselectivity.
4j
4k
2-BnOC10H6
2-MeOC10H6
a
Refers to isolated yield after column chromatography.
This consisted of a lead mediated arylation of a b-keto ester
followed by a Pd-catalysed decarboxylative protonation to give
the product isoflavanone (eqn (3)). Thus our synthesis began with
the arylation of b-keto ester 3 with a variety of aryllead triacetates
to give substrates 4a–k for catalysis (Table 1).17 At the commence-
ment of our investigations we chose allyl-3-(4-methoxyphenyl)-
4-oxochroman-3-carboxylate 4a as our model substrate and
screened it with several classes of P,N-type ligands.18 The
isoflavanone precursor 4a proved to be a highly active sub-
strate for the decarboxylative protonation with full consump-
tion of starting material observed within 1 h.
Isoflavanone 7d, which lacks substitution in the ortho-
positions of the aryl ring, gave a 23% ee. Conversely, 4f
bearing two methoxy groups in the 20- and 60-positions
provided 7f in an ee of 85% underlining the importance of
sterics upon the selectivity of the reaction. An additional
methoxy group in the 30-position provided 7g with an identical
level of enantioinduction. The importance of an ortho-ethereal
substituent was probed by sequential replacement by methyl
groups. Products 7h and 7i were obtained in lower enantio-
selectivities of 73 and 71%, respectively. Substituting the aryl
ring for a naphthyl ring was shown to still give excellent
enantioselectivities with the 20-benzyloxy substituted 7j being
obtained in 87% ee and the 20-methoxy substituted 7k being
afforded in an ee of 89%. In all of the above cases regardless of
the steric bulk around the aryl ring, the isoflavanones were
obtained in good to excellent yields (72–93%).
Disappointingly however, the product isoflavanone, 7a, was
obtained in poor enantioselectivities regardless of the P,N
ligand class employed. In an effort to probe what effect steric
bulk on the aryl ring would have upon the transformation the
20,40-dimethoxy substituted substrate 4b was tested. This led to
an increase in selectivity to 19% ee with (S)-t-Bu PHOX 5.
Encouraged by this we further increased the steric bulk on the
aryl ring with the 20,40,60-trimethoxy substituted substrate 4c.
Table 2 Optimisation of enantioselective decarboxylative protonation
Table 3 Scope of the decarboxylative protonation reaction in the
synthesis of isoflavanones
Isoflavanone
Ar
Yielda %
eeb %
7a
7b
7d
7e
7f
7g
7h
7i
4-MeOC6H4
98
87
72
87
83
90
93
86
81
89
7
35
23
51
85
85
73
71
87
89
Entry Ligand Substrate Temp (1C) Time (h) Conv.a eeb
2,4-(MeO)2C6H3
(3,4)-OCH2O–C6H3
2,3,4,(MeO)3C6H2
2,6(MeO)2C6H3
2,3,6-(MeO)3C6H2
2-MeO,4,6-(Me)2C2H2
2,6-(Me)2C6H3
1
2
3
5
6
6
4c
4c
4c
rt
0
7
1
1
0.5
100
100
100
78 (R)c
89 (R)c
92 (R)c
a
b
Determined by HPLC or 1H NMR spectroscopy. Determined by
c
chiral phase HPLC. Determined by X-ray crystallography.
7j
7k
2-BnOC10H6
2-MeOC10H6
This substrate provided a significant increase in enantio-
selectivity and gave the product isoflavanone 7c in 78% ee
(Table 2, entry 1). Decreasing the temperature in an attempt to
a
b
Refers to isolated yield after column chromatography. Determined
by chiral phase HPLC.
c
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9900–9901; (e) S. Ge and J. F. Hartwig, J. Am. Chem. Soc., 2011,
133, 16330–16333. For a review of catalytic asymmetric a-arylations
see: (f) A. C. B. Burtoloso, Synlett, 2009, 320.
6 (a) X. Dai, N. A. Strotman and G. C. Fu, J. Am. Chem. Soc., 2008,
130, 3302–3303; (b) P. M. Lundin, J. Esquivias and G. C. Fu,
Angew. Chem., Int. Ed., 2009, 48, 154–156; (c) S. Lou and G. C. Fu,
J. Am. Chem. Soc., 2010, 132, 1264–1266; (d) P. M. Lundin and
G. C. Fu, J. Am. Chem. Soc., 2010, 132, 11027–11029; (e) E. C. Lee
and G. C. Fu, J. Am. Chem. Soc., 2007, 129, 12066–12067.
7 A. E. Allen and D. W. C. MacMillan, J. Am. Chem. Soc., 2011,
133, 4260–4263.
8 (a) J. S. Harvey, S. P. Simonovich, C. R. Jamison and D. W. C.
MacMillan, J. Am. Chem. Soc., 2011, 133, 13782–13785;
(b) A. l. Bigot, A. E. Williamson and M. J. Gaunt, J. Am. Chem.
Soc., 2011, 133, 13778–13781.
9 Z. Huang, Z. Liu and J. Zhou, J. Am. Chem. Soc., 2011, 133,
15882–15885.
Fig. 1 Proposed transition state in asymmetric protonation.
When we attempted to apply substrate 4c in an asymmetric
decarboxylative allylation we obtained an essentially racemic
product.21 This result is consistent with earlier reports by Stoltz
where an a-phenyl substrate provided low levels of enantio-
selectivity in the decarboxylative asymmetric allylation.12b
We propose that the key intermediate in this reaction is
likely to consist of a prochiral palladium enolate. One of the
ortho-methoxy groups and the t-Bu group of the ligand
combine to block the Re-face of the enolate and ensure
protonation occurs at the Si-face (Fig. 1).
10 Enantioselective arylations to form tertiary a-aryl carbamates and
ester derivatives with mono-ortho substitution on the aryl ring have
been reported, see ref. 6e and 9. It should be noted that the nature
of the carbonyl has a pronounced effect on the pKa of the a proton
and in the case of a-aryl esters is B22.7 compared to B19.7 for a-
aryl ketones. For a comparison of various a-aryl proton acidities
see: (a) F. G. Bordwell and H. E. Fried, J. Org. Chem., 1981, 46,
4327–4331; (b) F. G. Bordwell and J. A. Harrelson Jr, Can. J.
Chem., 1990, 68, 1714–1718.
11 For reviews in this area see: (a) J. T. Mohr and B. M. Stoltz,
Chem.–Asian J., 2007, 2, 1476–1491; (b) J. D. Weaver, A. Recio,
A. J. Grenning and J. A. Tunge, Chem. Rev., 2011, 111, 1846–1913.
12 (a) J. T. Mohr, D. C. Behenna, A. M. Harned and B. M. Stoltz,
Angew. Chem., Int. Ed., 2005, 44, 6924–6927; (b) D. C. Behenna,
J. T. Mohr, N. H. Sherden, S. C. Marinescu, A. M. Harned,
In summary we have reported the first catalytic asymmetric
synthesis of 8 novel and 3 previously known isoflavanones. We
have shown that this process is influenced by both the sterics
and the electronics on the a-aryl ring of the isoflavanone.
Enantioselectivities of up to 92% have been achieved for very
sterically hindered a-aryl ketones using this methodology.
We believe this method of constructing tertiary a-aryl
carbonyl centres is likely to complement existing methods
where sterically hindered substrates can lead to reduced yields
and enantioselectivites. Whereas previous methods focused on
installing the aryl ring in the enantiodetermining step, the
methodology in this report has a bulky aryl group already
present on the substrate, leading to higher levels of enantio-
discrimination in the protonation step.
K. Tani, M. Seto, S. Ma, Z. Novak, M. R. Krout,
´
R. M. McFadden, J. L. Roizen, J. A. Enquist, D. E. White,
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M.P.C. acknowledges financial support from the Higher
Education Authority’s Programme for Research in Third-level
Institutions (PRTLI), Cycle 4. We thank Prof. Brian M. Stoltz
for a helpful suggestion to test electronically deficient ligand 6.
Notes and references
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18 For details of the reaction optimisation see ESIw.
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20 See ESIw for X-ray structure.
21 Substrate 4c was applied in the asymmetric decarboxylative
allylation and despite proceeding in full conversion, was essentially
racemic.
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11144 Chem. Commun., 2012, 48, 11142–11144
This journal is The Royal Society of Chemistry 2012