Rh-catalyzed carbonyl hydroacylation: an enantioselective approach to lactones

Article abstract of DOI:10.1021/ja7109025

This communication describes the design and execution of a novel approach to forming chiral lactones via C-H bond activation. The strategy features an unprecedented enantioselective Rh-catalyzed hydroacylation of carbon-oxygen double bonds. Representative keto-aldehydes (derived from salicylaldehyde) undergo cyclization with complete regioselectivity to afford seven-membered lactones in great enantiomeric excess (≥99% ee). The basicity of the phosphine ligand is shown to play a critical role in promoting hydroacylation over competitive decarbonylation. Copyright

Full text of DOI:10.1021/ja7109025

Published on Web 02/16/2008
Rh-Catalyzed Carbonyl Hydroacylation: An Enantioselective Approach to
Lactones
Zengming Shen, Hasan A. Khan, and Vy M. Dong*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
Received December 10, 2007; E-mail: vdong@chem.utoronto.ca
Scheme 2. Proposal for Tishchenko versus Benzoin
Hydroacylation
The ester is a prevalent motif found in diverse synthetic and
biological architectures, from fatty acid triesters to macrolide
antibiotics. Nature uses enzymes (e.g., polyketide synthase) to form
ester bonds by coupling alcohols to activated thioesters.1 The
majority of synthetic approaches to constructing esters involve this
same natural carbon-oxygen bond formation. For example, many
stoichiometric reagents, including Corey-Nicolaou’s PySSPy and
Yamaguchi’s acid chloride, have been developed to activate car-
boxylic acids and achieve macrolactonizations.2 We envisioned a
fundamentally different approach to lactonization based on the
ability of Rh(I) complexes to activate the C-H bond of aldehydes
(Scheme 1). Herein, we report a novel and atom economical strategy
for making chiral lactones starting from keto-aldehydes. In contrast
to conventional strategies, this ester synthesis features an unprec-
edented regio- and enantioselective carbonyl hydroacylation.
Scheme 3. Competing Transformations for Model Substrate
Scheme 1. An Atom Economical Strategy for Lactonization
While the Rh-catalyzed hydroacylation of alkenes and alkynes
has been reported,3 the analogous hydroacylation of carbonyl com-
pounds, specifically prochiral ketones, has been virtually unex-
plored.4 Since Tsuji’s discovery,5 it has become well-established
that Rh(I) complexes can undergo oxidative addition of aldehydes
1 to form acyl-Rh(III) intermediates 2 (Scheme 2).6 We hypoth-
esized that, in the presence of a ketone, intermediate 2 could react
via two regio-divergent pathways: a “Tishchenko-type”7 or a “ben-
zoin-type” hydroacylation.8 In the Tishchenko-type hydroacylation,
2 undergoes hydrometalation of ketone 3 to form organorhodium
intermediate 4. Subsequent reductive elimination from 4 would yield
the desired chiral ester 5. Conversely, intermediate 2 could undergo
acylmetalation of carbonyl 3 to form a rhodium-alkoxide 6.
Reductive elimination from 6 would generate R-hydroxy ketone 7,
the formal benzoin product.
For our initial investigation of the proposed lactonization, we
chose readily available keto-aldehyde 8a as the test substrate
(Scheme 3).9 Intramolecular hydroacylation of 8a could yield a
seven-membered ring lactone 9a and/or the six-membered ring
chromanone 10a.10 The Rh-promoted decarbonylation of 8a to form
benzene derivative 11a would be a competing and nonproductive
pathway. Based on previous studies,11 we considered that the
coordinating ability of the ether-oxygen in 8a could help suppress
decarbonylation and facilitate hydroacylation.
120 °C. An illustrative study of six chiral diphosphine ligands is
shown in Table 1. These ligands are listed in order of increasing
basicity to highlight a trend between phosphine basicity and catalyst
selectivity (cf entry 1-6). (R)-Ph-MeOBIPHEP (12) (the least basic
phosphine in this series) was ineffective at promoting hydroacy-
lation. Use of ligand 12 resulted in complete decarbonylation (98%
yield 11a, entry 1). (R)-Ar-MeOBIPHEP 13 is structurally related
to 12, except that 13 is more basic and sterically encumbering due
to the presence of the substituted-aryl rings on phosphine (Ar )
3,5-t-Bu-4-MeOC6H2). Remarkably, catalyst [Rh(13)]BF4 trans-
formed 8a into lactone 9a in 63% yield and 95% ee. While formal
benzoin product 10a was not observed, decarbonylated product 11a
was formed in 31% yield (entry 2). By using the more electron-
rich biphenyl-phosphine ligand (R)-DTBM-SEGPHOS 14, hydro-
acylation efficiency was improved without compromising enan-
tioselectivity (76% yield 8a, 96% ee, no 10a, and 22% yield 11a,
entry 3).
Based on this trend, we studied several alkyl-substituted phos-
phine ligands which were expected to further improve reaction
efficiency due to their increased phosphine basicity. As anticipated,
achiral ligand 1,3-bis(diphenylphosphino)propane (dppp) enabled
Rh-catalyzed hydroacylation of 8a to yield 9a exclusively in 96%
yield. However, a chiral analogue of dppp, (S,S)-BDPP 15, gave
only 4% ee and 67% yield of 9a (entry 4). (R,R)-Me-Duphos 16
also afforded lactone 9a with excellent efficiency (95% yield) albeit
in 82% ee (entry 5). (R,R)-Me-BPE 17, the most basic ligand in
this series, appears to be too electron-rich, affording sluggish
A number of catalysts were examined to achieve regio- and
enantioselective hydroacylation of 8a, including the use of cationic
Rh(I) salts and various phosphine ligands, in dichloroethane at
9
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J. AM. CHEM. SOC. 2008, 130, 2916-2917
10.1021/ja7109025 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Phosphine Effect on Catalytic Selectivitya
and excellent enantioselectivities (entries 2 and 3). Aliphatic ketones
bearing substituents of varying sizes were also transformed with
remarkable efficiency. The methyl substituted ketone underwent
hydroacylation to form lactone 9d in 91% yield and 99% ee (entry
4). Notably, n-butyl, benzyl, i-Pr, and tert-butyl substituted lactones
were isolated in high yields (g93%) as essentially single enan-
tiomers (>99% ee, entries 5-8). Single-crystal X-ray analysis of
chloro-substituted lactone 9b reveals the absolute configuration to
be the S-configuration as depicted.
In summary, we have designed and executed a new approach to
forming chiral lactones. This C-H bond functionalization strategy
involves an unprecedented Rh-catalyzed hydroacylation of ketones.
The basicity of the phosphine ligand plays a critical role in
promoting hydroacylation over competitive decarbonylation. In-
tramolecular hydroacylation of keto-aldehydes 8 occurs with
complete regiocontrol to yield formal Tishchenko lactones in large
enantiomeric excess. Further scope and mechanistic studies are
underway to determine the origin of regio- and enantioselectivity
in this transformation.
Acknowledgment. Financial support provided by the University
of Toronto, the Canadian Foundation of Innovation, Ontario
Research Foundation, and NSERC. We thank Merck Frosst for an
unrestricted research grant. Professors Mark Lautens, Robert Morris,
Robert Batey, and Andrei Yudin are gratefully acknowledged for
their support.
a General conditions: 8a, 5 mol % [Rh(Ligand)]BF4, dichloroethane,
120 °C, 3 d in a sealed tube. Yields based on integration by 1H NMR.
Formal benzoin product 10a was not observed under these conditions.
Enantiomeric excess determined by chiral HPLC.
Supporting Information Available: Experimental procedures,
X-ray crystallographic data, and spectroscopic data for new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Table 2. Intramolecular Hydroacylation of Various Ketones
References
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entry
R
lactone
time (d)
% yielda
% eeb
% decarbon.c
(3) For a review, see: Fu, G. C. In Modern Rhodium-Catalyzed Reactions;
Evans, P. A., Ed.; Wiley-VCH: New York, 2005; pp 79-91 and
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1
2
3
4
5
6
7
8
Ph
9a
9b
9c
9d
9e
9f
3
2
2
2
92
89
85
91
99
93
98
94
99
99
99
7
7
9
6
0
0
0
0
4-Cl-Ph
2-naphthyl
Me
n-Bu
Bn
(4) To our knowledge, there are no other transition metal-catalyzed ketone
hydroacylations. For Rh- and Ru-catalyzed aldehyde hydroacylation,
see: (a) Fuji, K.; Morimoto, T.; Tsutsumi K.; Kakiuchi, K. Chem.
Commun. 2005, 3295. (b) Horino, H.; Ito, T.; Yamamoto, A. Chem. Lett.
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99
2
>99
>99
>99
>99
3.5
1.5
1.5
i-Pr
t-Bu
9g
9h
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a Isolated yields. b Determined by chiral HPLC. c Decarbonylated product
yields based on H NMR integration relative to product peaks.
1
(7) (a) For a Tishchenko review, see: Mahrwald, R. Curr. Org. Chem. 2003,
7, 1713. (b) For an asymmetric Tishchenko, see: Hsu, J. L.; Fang, J. M.
J. Org. Chem. 2001, 66, 8573.
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reactivity (46% yield 9a, 6% yield 11a) and moderate enantiose-
lectivity (76% ee) (entry 6).
By varying the solvent and temperature, we found that use of
catalyst [Rh((R)-(14)]BF4 in dichloromethane at room temperature
afforded optimal results. Under these conditions, lactone 9a was
formed in 92% yield and 99% enantiomeric excess, while decar-
bonylated product 11a was formed in only 7% yield (Table 2, entry
1). Next, we investigated the scope of the reaction by varying the
substituents on the prochiral ketone component (Table 2). Other
aromatic ketones (e.g., R ) 4-Cl-Ph and 2-naphthyl) were
hydroacylated to form the corresponding lactones in good yields
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