Rhodium-catalyzed conjugate addition-enantioselective protonation: The synthesis of α,α′-dibenzyl esters

Article abstract of DOI:10.1021/ol070603g

α-Benzyl acrylates, which are conveniently prepared from the corresponding aldehydes, can be employed as substrates in a tandem rhodiumcatalyzed conjugate addition-enantioselective protonation protocol to afford enantiomerically enriched α,α′-dibenzyl est

Full text of DOI:10.1021/ol070603g

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2119-2122
Rhodium-Catalyzed Conjugate
Addition Enantioselective Protonation:
The Synthesis of
−
r,r′-Dibenzyl Esters
Christopher G. Frost,*,† Stephen D. Penrose,† Kim Lambshead,† Paul R. Raithby,†
John E. Warren,§ and Robert Gleave‡
Department of Chemistry, UniVersity of Bath, Bath, BA2 7AY, United Kingdom,
Neurology and Gastrointestinal Centre of Excellence for Drug DiscoVery,
GlaxoSmithKline, New Frontiers Science Park, Third AVenue, Harlow, Essex,
CM19 5AW, United Kingdom, and CCLRC Daresbury Laboratory, Daresbury,
Warrington WA4 4AD, United Kingdom
c.g.frost@bath.ac.uk
Received March 12, 2007
ABSTRACT
r
-Benzyl acrylates, which are conveniently prepared from the corresponding aldehydes, can be employed as substrates in a tandem rhodium-
catalyzed conjugate addition enantioselective protonation protocol to afford enantiomerically enriched r′-dibenzyl esters. The synergistic
effect of enantiopure ligand and proton source was rapidly optimized with use of a microwave reactor.
−
r,
Tandem catalytic reactions including enantioselective pro-
cesses have emerged as important methods for the formation
of new chemical bonds in an efficient manner.1 Within this
context, the stereoselective construction of C-C bonds with
the rhodium-catalyzed 1,4-addition of organometallics can
generate a reactive π-allylrhodium intermediate for further
C-C bond-forming reactions.2,3 An interesting and chal-
lenging variant of this type of process is the asymmetric
arylation of activated alkenes or allenes via enantioselective
protonation.4,5 This approach entails the selective protonation
of a chiral π-allylrhodium intermediate formed by the
reaction of a 1,1′-disubstituted substrate and an arylrhodium
species (Figure 1). In this circumstance, the combined effect
of the chiral rhodium complex, the nature of the organo-
metallic, and the structure of the proton source dictate the
overall enantioselectivity.6
† University of Bath.
‡ GlaxoSmithKline.
§ CCLRC Daresbury.
(1) (a) Pelissier, H. Tetrahedron 2006, 62, 2143-2173. (b) Pellissier,
H. Tetrahedron 2006, 62, 1619-1665. (c) Chapman, C. J.; Frost, C. G.
Synthesis 2007, 1-21 and references cited therein.
(2) For reviews see: (a) Hayashi, T. Synlett 2001, 879-887. (b) Hayashi,
T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829-2844. (c) Fagnou, K.;
Lautens, M. Chem. ReV. 2003, 103, 169-196. (d) Darses, S.; Geneˆt, J.-P.
Eur. J. Org. Chem. 2003, 4313-4327. (e) Hayashi, T. Bull. Chem. Soc.
Jpn. 2004, 77, 13-21.
(3) (a) Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 2002,
124, 10984-10985. (b) Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Org.
Chem. 2003, 68, 1901-1905. (c) Cauble, D. F.; Gipson, J. D.; Krische, M.
J. J. Am. Chem. Soc. 2003, 125, 1110-1111. (d) Bocknack, B. M.; Wang,
L. C.; Krische, M. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5421-5424.
(4) (a) Reetz, M. T.; Moulin, D.; Gosberg, A. Org. Lett. 2001, 3, 4083-
4085. (b) Chapman, C. J.; Wadsworth, K. J.; Frost, C. G. J. Organomet.
Chem. 2003, 680, 206-211. (c) Moss, R. J.; Wadsworth, K. J.; Chapman,
C. J.; Frost, C. G. Chem. Commun. 2004, 1984-1985. (d) Navarre, L.;
Darses, S.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723. (e)
Sibi, M. P.; Tadamidani, H.; Patil, K. Org. Lett. 2005, 7, 2571-2573. (f)
Hargrave, J. D.; Herbert, J.; Bish, G.; Frost, C. G. Org. Biomol. Chem.
2006, 4, 3235-3241. (g) Hargrave, J. D.; Bish, G.; Frost, C. G. Chem.
Commun. 2006, 4389-4391.
(5) Nishimura, T.; Hirabayashi, S.; Yasuhara, Y.; Hayashi, T. J. Am.
Chem. Soc. 2006, 128, 2556-2557.
(6) For a review on the enantioselective protonation of enolates, see:
Eames, J.; Weerasooriya, N. Tetrahedron: Asymmetry 2001, 12, 1-24.
10.1021/ol070603g CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/28/2007

butyl acrylate 1 in dioxane as solvent with variation of the
enantiopure ligand and proton source (selected examples are
shown in Table 1). For ease of operation and rapid evalu-
Table 1. Rhodium-Catalyzed Conjugate
Addition-Enantioselective Protonation; Optimization of Ligand
and Proton Sourcea
Figure 1. Rhodium-catalyzed conjugate addition-enantioselective
protonation strategy.
Given that the enantioselective protonation occurs via the
rhodium complex after the carbon-carbon bond-forming
step, this allows us to explore the construction of chiral
molecules with only subtle differences in their structural
features. Herein, we document the synthetic utility of this
method in a versatile catalytic, asymmetric synthesis of R,R′-
dibenzyl esters as shown in Scheme 1. At the outset it was
yieldb
(%) (3a:ent-3a)
erc
entry
1d (R,R)-Me-DUPHOS H2O
2d (R)-PROPHOS
H2O
3d (S,S)-CHIRAPHOS H2O
(R)-DIFLUORPHOS phthalimide
5d (S)-BINAP
H2O
ligandi
proton source
91
24
42
49
63
49:51
35:65
67:33
22:78
79:21
80:20
81:19
85:15
85:15
85:15
85:15
90:10
90:10
90:10
24:76
84:16
86:14
81:19
4
6
7
8
9
(S)-BINAP
(S)-BINAP
(S)-BINAP
(S)-BINAP
2-methoxyphenol 54
phthalimide
(R)-BINOL
(S)-BINOL
(rac)-BINOL
(rac)-BINOL
B(OH)3
57
47
48
45
55
65
78
84
76
54
71
69
Scheme 1. The Catalytic, Asymmetric Synthesis of
R,R′-Dibenzyl Esters
10 (S)-BINAP
11e (S)-BINAP
12 (S)-BINAP
13f (S)-BINAP
B(OH)3
B(OH)3
14g (S)-BINAP
15g (R,R,R)-dieneh
16g (S)-tol-BINAP
17g (S)-SYNPHOS
18g (S)-Xyl-BINAP
B(OH)3
B(OH)3
B(OH)3
B(OH)3
a Reaction conditions: 1 (1.0 equiv), phenylboronic acid 2a (4.0 equiv),
[Rh(acac)(C2H4)2] (4 mol %), dioxane, proton source (1.0 equiv), microwave
reactor (110 W, 100 °C). b Isolated yields. c Determined by HPLC analysis
with use of a Chiralcel OD-H column. d Dioxane:H2O (10:1). e With B(OH)3
(1.0 equiv). f B(OH)3 (3.0 equiv). g B(OH)3 (4.0 equiv). h (1R,4R,8R)-5-
Benzyl-8-methoxy-1,8-dimethyl-2-(2′-methylpropyl)-bicyclo[2.2.2]octa-2,5-
diene. i See Figure 2.
decided to employ a tert-butyl ester based on a precedent
for higher enantioselectivities in related additions and its ease
of deprotection.4e The requisite R-substituted tert-butyl
acrylates were straightforward to prepare via a Mannich-
type process employing a variant of the method reported by
Tsukamoto et al.7
Thus, an initial Knoevengal condensation of aldehyde and
Meldrum’s acid was followed by reduction with sodium
borohydride according to the procedure of Bigi et al.8 The
5-monosubstituted Meldrum’s acid derivatives were then
treated with Eschenmoser’s iodide salt in the presence of
tert-butanol to afford the R-substituted tert-butyl acrylates
in excellent isolated yield.9
ation, the rhodium-catalyzed addition was performed in
capped tubes under microwave irradiation (CEM Discover
model 045704 system at 100 °C for 1 h).10 It should be noted
that the reactions proceeded in similar yields and enantio-
selectivities by heating in an oil bath or heating block at
110 °C for 18-24 h. In line with previous rhodium-catalyzed
1,4-additions on R-substituted acrylates, higher enantio-
selectivities were observed when employing BINAP and
related analogues.4 The use of water as proton source
afforded the product with modest enantioselectivity (Table
1, entry 5). The combination of BINAP and 2-methoxyphenol
(Table 1, entry 6) as previously reported by Genet et al. (for
R-amino acids4d), or DIFLUORPHOS and phthalimide (Table
Our initial investigation focused on the addition of
phenylboronic acid (2a) to the thiophene-substituted tert-
(7) Hin, B.; Majer, P.; Tsukamoto, T. J. Org. Chem. 2002, 67, 7365-
7368.
(8) (a) Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori,
G. Tetrahedron Lett. 2001, 42, 5203-5205. (b) Maggi, R.; Bigi, F.; Carloni,
S.; Mazzacani, A.; Sartori, G. Green Chem. 2001, 3, 173-174.
(9) See the Supporting Information for full details.
(10) For selected accounts of the use of microwaves in organic synthesis
see: (a) Adam, D. Nature 2003, 421, 571-572. (b) Loupy, A. In
MicrowaVes in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2002.
(c) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250-6284. (d) Caddick,
S. Tetrahedron 1995, 51, 10403-10432.
2120
Org. Lett., Vol. 9, No. 11, 2007

We therefore decided to evaluate further proton sources
including BINOL, which is commercially available as a
racemate or in either enantiomeric form. Interestingly, the
inclusion of BINOL resulted in an improved enantioselec-
tivity but the configuration of the proton source had no affect
on the enantiomeric ratio (Table 1, entries 8-10). After
further investigation the optimal proton source proved to be
boric acid, which afforded the product with good enantio-
selectivity and excellent yield (Table 1, entries 12-14).
Interestingly, the omission of boric acid resulted in a very
low conversion to product. A range of other enantiopure
ligands were tested in conjunction with boric acid as proton
source; however, none surpassed the efficiency and selectiv-
ity of the system with BINAP (Table 1, entries 15-18).
With the optimized set of reaction conditions, we next
explored the scope of the process with respect to the boronic
acid; in all cases the thiophene-substituted tert-butyl acrylate
1 was employed as substrate. The yield and enantioselectivity
was consistently good for a range of boronic acids (Table
2). It is useful to note that both electron-donating and
electron-withdrawing substituents are tolerated. The suc-
cessful incorporation of thiomethyl, halogen, and aldehyde
functionality demonstrates the versatility of the catalytic
process (Table 2, entries 2, 6, and 7).
Figure 2. Ligands used.
1, entry 4) as previously reported by Sibi et al. (for â2-amino
acids4e) imparted similar results.
Table 2. Rhodium-Catalyzed Conjugate
Addition-Enantioselective Protonation: Scope of Boronic Acida
The biphenyl-substituted product 3f was deprotected by
treatment with trifluoroacetic acid to furnish the carboxylic
acid 4f as a crystalline solid. Recrystallization of 4f resulted
in an enhancement of enantiopurity (>97:3 er). The absolute
configuration of 4f was determined to be (S) by X-ray
crystallography.11 The mechanism of the rhodium-catalyzed
1,4-addition of boronic acids to enones has been docu-
mented12 but there is little detail on the mode of protonation.
However, more recent observations from Hayashi et al.
suggest that protonation of a related chiral π-allylrhodium
intermediate occurs on the same face as rhodium.5 The
proximity of coordinating functionality in the optimal proton
sources utilized by Genet et al. (2-methoxyphenol) and Sibi
et al. (phthalimide) supports the notion of protonation taking
place via prior coordination to rhodium. In the presented
Scheme 2. Deprotection of 3f
a Reaction conditions: 1 (1.0 equiv), boronic acid 2 (4.0 equiv),
[Rh(acac)(C2H4)2] (4 mol %), dioxane, boric acid (4.0 equiv), microwave
reactor (110 W, 100 °C). b Isolated yields. c Determined by HPLC analysis
with use of a Chiralcel OD-H column.
Org. Lett., Vol. 9, No. 11, 2007
2121

The broad synthetic potential of this protocol arises from
the ready availability of the two key reagents: boronic acids
and aryl aldehydes. This has been established for a diverse
range of substrate-boronic acid permutations, examples of
which are shown in Scheme 3. A good illustration of the
versatility of this method is the synthesis of either 9 or ent-9
with use of the same enantiopure catalyst and proton source,
simply by switching the functional groups on the boronic
acid and starting aryl aldehyde.
Scheme 3. Scope of Rhodium-Catalyzed Conjugate
Addition-enantioselective Protonation
In conclusion, we have demonstrated that R-substituted
tert-butyl acrylates are efficient substrates for a tandem
rhodium-catalyzed conjugate addition-enantioselective pro-
tonation process. The method can tolerate a variety of
reactive functional groups on both substrate and boronic acid
to deliver highly functionalized products. The adducts are
obtained in good yields, and in general with very good levels
of enantioselectivity.
Acknowledgment. This work was supported by the
EPSRC and GlaxoSmithKline. The EPSRC Mass Spectrom-
etry Service at the University of Wales Swansea is also
thanked for their assistance.
Supporting Information Available: Experimental pro-
cedures and full characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL070603G
(11) The crystal structure of 4f was determined by using single crystal
X-ray data collected on Station 9.8 at the SRS, CCLRC Daresbury
Laboratory. Crystal data: C20H18O2S, M ) 322.4, monoclinic, space group
P21, a ) 8.1857(13) Å, b ) 5.4937(9) Å, c ) 17.963(3) Å, â ) 92.876(1)°,
system, it is proposed that the high enantioselectivity arises
in a similar manner, by prior coordination of the boric acid
to rhodium. An intriguing precedent for this is provided by
the recent isolation and characterization of a series of
pertinent rhodium boronate complexes by Hartwig et al.13
V ) 806.8(2) Å3, Z ) 2, T ) 150(2) K, 8927 measured reflections (Rint
0.056), R1 ) 0.073, wR2 ) 0.217, Flack parameter ) 0.10(13).
)
(12) For a discussion of the mechanism, see: Hayashi, T.; Takahashi,
M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052-5058.
(13) Zhao, P.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2007,
129, 1876-1877.
2122
Org. Lett., Vol. 9, No. 11, 2007