Enantioselective rhodium enolate protonations. A new methodology for the synthesis of β2-amino acids

Article abstract of DOI:10.1021/ol050630b

(Chemical Equation Presented) Rhodium-catalyzed conjugate addition of an aryl boronic acid to α-methylamino acrylates followed by enantioselective protonation of the oxa-π-allylrhodium intermediate provides access to aryl-substituted β²-amino a

Full text of DOI:10.1021/ol050630b

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2571-2573
Enantioselective Rhodium Enolate
Protonations. A New Methodology for
the Synthesis of
â
2-Amino Acids
Mukund P. Sibi,* Hiroto Tatamidani, and Kalyani Patil
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105
mukund.sibi@ndsu.edu
Received March 23, 2005
ABSTRACT
Rhodium-catalyzed conjugate addition of an aryl boronic acid to
oxa- -allylrhodium intermediate provides access to aryl-substituted
the levels of enantioselectivity has been assessed.
r-methylamino acrylates followed by enantioselective protonation of the
â
π
2-amino acids. The impact of the different variables of the reaction on
Rhodium-catalyzed conjugate addition of organoboron,1
organosilicon,2 and organotin3 reagents to R,â-unsaturated
systems has seen tremendous advances in the past decade.
Hayashi, Miyaura, and others have developed highly efficient
enantioselective protocols for these conjugate additions that
allows for the establishment of a new chiral center at the
â-carbon.4 In contrast, use of this strategy to establish a
stereocenter at the R-carbon has met with limited success.5
Recently, several examples of enantioselective rhodium
enolate protonations leading to enantioenriched R-amino
acids and succinates have been reported.6
Development of new methods for the synthesis of â-amino
acids is important.7 There are a number of enantioselective
methods for the synthesis of â-substituted â-amino acids (â3-
amino acids).8 In contrast, there are few enantioselective
methods for the synthesis of R-substituted â-amino acids (â2-
amino acids).7 This substitution pattern is of interest since it
is present in naturally occurring amino acids as well as
compounds with potential therapeutic value.9
We have recently developed a novel method for the
synthesis of â2-amino acids using free radical chemistry.10
The stereochemistry in these reactions was established by
an enantioselective H-atom transfer after conjugate radical
(6) (a) Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004,
43, 719. (b) Reetz, M. T.; Moulin, D.; Gosberg, A. Org. Lett. 2001, 3,
4083. (c) Chapman, C. J.; Wadsworth, K. J.; Frost, C. G. J. Organomet.
Chem. 2003, 680, 206. (d) Moss, R. J.; Wadsworth, K. J.; Chapman, C. J.;
Frost, C. G. Chem. Commun. 2004, 1984. (e) For Co-mediated reduction/
protonation: Ohtsuka, Y.; Ikeno, T.; Yamada, T. Tetrahedron: Asymmetry
2003, 14, 967. Racemic reactions: (f) Chapman, C. J.; Frost, C. G. AdV.
Synth. Catal. 2003, 345, 353. (g) Huang, T.-S.; Li, C.-J. Org. Lett. 2001, 3,
2037.
(7) For a recent review, see: Liu, M.; Sibi, M. P. Tetrahedron 2002,
58, 7991. Also see: Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999,
6, 983.
(8) (a) Davies, H. M. L.; Venkataramani, C. Angew. Chem., Int. Ed. 2002,
41, 2197. (b) Eilitz, U.; Lessmann, F.; Seidelmann, O.; Wendisch, V.
Tetrahedron: Asymmetry 2003, 14, 189. (c) Duursma, A.; Minnaard, A.
J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125, 3700. (d) Mun˜oz-Mun˜iz,
O.; Juaristi, E. Tetrahedron 2003, 59, 4223. (e) Lee, H.-S.; Park, J.-S.; Kim,
B. M.; Gellman, S. H. J. Org. Chem. 2003, 68, 1575. (f) Seebach, D.;
Schaeffer, L.; Gessier, F.; Bindscha¨dler, P.; Ja¨ger, C.; Josien, D.; Kopp,
S.; Lelais, G.; Mahajan, Y. R.; Micuch, P.; Sebesta, R.; Schweizer, B. W.
HelV. Chim. Acta 2003, 86, 1852.
(9) Cryptophycins: (a) Subbaraju, G. V.; Golakoti, T.; Patterson, G. M.
L.; Moore, R. E. J. Nat. Prod. 1997, 60, 302. Biologically active
â-peptides: (b) Werder, M.; Hauser, H.; Abele, S.; Seebach, D. HelV. Chim.
Acta 1999, 82, 1774.
(1) (a) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T.;
Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579.
(2) Mori, A.; Danda, Y.; Fujii, T.; Hirabayashi, K.; Osakada, K. J. Am.
Chem. Soc. 2001, 123, 10774.
(3) (a) Oi, S.; Moro, M.; Ono, S.; Inoue, Y. Chem. Lett. 1998, 83. (b)
Oi, S.; Moro, M.; Ito, H.; Honma, Y.; Miyano, S.; Inoue, Y. Tetrahedron
2002, 58, 91.
(4) For recent reviews, see: (a) Hayashi, T. Synlett 2001, 879. (b)
Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829. (c) Fagnou, K.;
Lautens, M. Chem. ReV. 2003, 103, 169.
(5) For an example of addition to 1-nitrocyclohexene, see: Hayashi, T.;
Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716.
(10) Sibi, M. P.; Patil, K. Angew. Chem., Int. Ed. 2004, 43, 1235.
10.1021/ol050630b CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/18/2005

Scheme 1
Table 2. Identification of Optimal Chiral Ligand and Proton
Source for the Conversion of 5a to 6a
yield (SM), ee,
b
c
entry
ligand
(S)-BINAP
proton sourcea
%
%
1
2
2-methoxyphenol
2-acetylphenol
phthalimide
2-methoxyphenol
2-acetylphenol
2-methoxyphenol
31 (49)
84 (2)
81
77
82
73
77
36
nd
(S)-BINAP
3
4
5
6
7
8
9
10
11
12
13
14
15
(S)-BINAP
56 (34)
21 (39)
42 (40)
43 (31)
8 (80)
0 (95)
8 (87)
1 (73)
30 (67)
25 (50)
8 (83)
71 (15)
91 (0)
addition.11 One deficiency of the H-atom transfer methodol-
ogy was the inability to incorporate aromatic groups into
the targets. We surmised that a rhodium-catalyzed conjugate
addition of an aryl boronic acid to 1 followed by enantiose-
lective protonation of the oxa-π-allylrhodium intermediate
21 could provide access to aryl-substituted â2-amino acids
(Scheme 1).12 Recently, Frost and co-workers have reported
a racemic version of the transformation shown in Scheme
1.13 In this work, we have evaluated several variables for
the conversion of 1 to 3, including the nature of the proton
source, chiral ligand, catalyst, nitrogen protecting group, and
ester substituent, and report a reasonably efficient method
for the synthesis of enantioenriched â2-amino acids.
(S)-tol-BINAP
(S)-tol-BINAP
(S,S)-DIOP
(R,R)-CHIRAPHOS 2-methoxyphenol
(R,S)-JOSIPHOS
(S)-MethylBOPhoz
(S)-SYNPHOS
(S)-SYNPHOS
(S)-SYNPHOS
2-methoxyphenol
2-methoxyphenol
2-methoxyphenol
2-acetylphenol
phthalimide
nd
nd
71
70
nd
88
88
(S)-DIFLUORPHOS 2-methoxyphenol
(S)-DIFLUORPHOS 2-acetylphenol
(S)-DIFLUORPHOS phthalimide
a Performed with 1 equiv of the proton source. The reactions were carried
out at 50 °C using dioxane as a solvent and 2 mol % chiral rhodium catalyst.
b Isolated yields. Yields in parentheses are for recovered starting materials.
c Chiral HPLC analysis; nd ) not determined.
Our work began with the identification of an optimal rhod-
ium catalyst for the addition of phenylboronic acid to com-
pound 5a using BINAP as the chiral ligand and water as the
proton source. Our initial choice of catalyst, ligand, and pro-
ton source was based on the work of Hayashi,14 Genet,6a
Reetz,6b and Frost.6c Results from these experiments are pre-
sented in Table 1. The catalyst rhodium (acac)bisethylene
modest enantioselectivity (entry 1). The reactions were
effective at 50 °C. Increasing the reaction temperature to
100 °C did not improve the selectivity.15 Of the four other
variants tested, the catalyst derived from rhodium hydroxide
(entry 2) and rhodium chloride (entries 3 and 4) gave good
yields but only modest selectivity.
With these results at hand, we set out to determine the
optimal chiral ligand and proton source for the formation of
6a. Results from these experiments are presented in Table
2. Several different proton sources have been evaluated by
Genet and co-workers in their work on the synthesis of
R-amino acids.6a In our experiments, three different proton
sources and several commercially available phosphine ligands
were evaluated.16 Changing the proton source from water to
2-methoxyphenol led to a decrease in the yield of 6a.
However, there was a large improvement in enantioselectivity
(entry 1).17 This observation is similar to that made by
Genet.6a The use of 2-acetylphenol as a proton source was
very beneficial, providing 6a in 84% yield and 77% ee (entry
Table 1. Evaluation of Different Rhodium Complexesa
entry
catalyst
yield (SM), %a ee, %b
1
2
3
4
5
Rh(acac)(ethylene)2
Rh(OH)(COD)2
[RhCl(COD)]2/NaHCO3
[RhCl(norbornadiene)]2/NaHCO3
[RhCl(COD)]2/AgPF6
76 (0)
65 (12)
80 (0)
76 (2)
2 (91)
41
30
13
25
nd
a Isolated yields. Yields in parentheses are for recovered starting materials.
(12) For recent reviews on enantioselective protonations, see: (a) Eames,
J.; Weerasooriya, N. Tetrahedron: Asymmetry 2001, 12, 1. (b) Duhamel,
L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron: Asymmetry 2004, 15, 3653.
Also see: (c) Mun˜oz-Mun˜iz, O.; Juaristi, E. Tetrahedron Lett. 2003, 44,
2023.
(13) Wadsworth, K. J.; Wood, F. K.; Chapman, C. J.; Frost, C. G. Synlett
2004, 2022. For Heck reactions with R-methylamino acrylates, see: Huck,
J.; Receveur, J.-M.; Roumestant, M.-L.; Martinez, J. Synlett 2001, 1467.
(14) Takaya, Y.; Ogasawara, M.; Hayashi, T. Chirality 2000, 12, 469.
(15) For example, reaction using Rh(acac)(ethylene)2 complex at 100
°C gave the product in 66% yield and 42% ee. We have also observed that
prolonged heating of the tert-butyl ester at 100 °C leads to decomposition
of the starting material.
b Chiral HPLC analysis; nd ) not determined.
complex gave a good yield of the addition product with
(11) For recent reviews on enantioselective H-atom transfer, see: (a)
Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. ReV. 2003, 103, 3263. (b)
Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163. For examples of
chiral Lewis acid-mediated H-atom transfer, see: (c) Sibi, M. P.; Asano,
Y.; Sausker, J. B. Angew. Chem., Int. Ed. 2001, 40, 1293. (d) Sibi, M. P.;
Sausker, J. B. J. Am. Chem. Soc. 2002, 124, 984.
2572
Org. Lett., Vol. 7, No. 13, 2005

Table 3. Effect of Nitrogen Protecting Group and Ester
Substituent on Selectivitya
Table 4. Preparation of Different â2-Amino Acids
entry
R
yield (SM), %a ee, %b
yield (SM), ee,
a
b
1
2
3
4
5
6
phenyl 6a
91
88
84
63
86
90
91
entry nitrogen PG
ester R
phthalimide tert-butyl 5a Ph 6a
phthalimide methyl 5b Ph 6b
phthalimide cyclohexyl 5c Ph 6c
phthalimide benzyl 5d Ph 6d
succinimide tert-butyl 5e Ph 6e
R1
%
%
4-chlorophenyl 6h
4-methylphenyl 6i
4-methoxyphenyl 6j
3,5-bistrifluoromethylphenyl 6k
2-naphthyl 6l
71 (10)
16 (62)
84
1
2
3
4
5
6
7
91
35 (35)
0
88
10
70 (23)
95
85
61
86
23 (67)
20
71
81
84
a Isolated yields. Yields in parentheses are for recovered starting materials.
b Chiral HPLC analysis.
tosyl
tosyl
tert-butyl 5f Ph 6f
tert-butyl 5f 4-BrPh 6g
a Isolated yields. Yields in parentheses are for recovered starting materials.
b Chiral HPLC analysis.
phenylboronoic acid addition were employed for these
studies. In general, the enantioselectivity in these experiments
was high (entries 1, 2, and 4-6). However, the chemical
yield for the reaction was variable. For example, while reac-
tion with 4-methoxyphenylboronic acid was highly efficient
(entry 4), reaction with 4-methylphenylboronic acid gave the
product in only 16% yield (entry 3). Of the different sub-
strates evaluated, reaction with 2-naphthylboronic acid gave
the highest chemical yield and enantioselectivity (entry 6).
The absolute stereochemistry of the enolate protonation
product 6a derived from reaction with phenylboronic acid
and phthalimide as a proton donor was determined to be (S)-
by converting it into a known compound.21 A catalytic cycle
as postulated by Hayashi and Miyaura1b appears to be
operative in our experiments also. Genet observed a strong
correlation between the level of enantioselectivity and the
nature of the proton donor.6a A functionality capable of
coordinating the rhodium which is located ortho to the proton
donor was optimal in their work. In our experiments we
suggest that phthalimide containing a carbonyl donor coor-
dinates the rhodium and transfers a proton to the oxa-π-allyl
complex. The present work and the prior results in the
literature suggest that enantioselective rhodium enolate
protonations require a proper matching of all the variables,
and development of a general protocol is yet to be achieved.
In conclusion, we have developed a reasonably practical
method for the preparation of â2-amino acids. Furthermore,
we have also demonstrated that enantioselective rhodium
enolate protonations can be carried out with good selectivity.
The extension of the present protocol to more complex
susbtrates is underway in our laboratory.
2). Phthalimide, with a reasonably acidic N-H, was also
functional as a proton source, providing the highest ee for
the product with moderate yield (entry 3).18 The chemical
efficiency of the reaction was modest using tol-BINAP as a
ligand, but the selectivity was high (entries 4 and 5). Of the
several other ligand/proton source combinations tested
(entries 6-12), Synphos19 gave good levels of enantiose-
lectivity (entries 11 and 12). More promising results were
obtained using a bisphosphine, DIFLUORPHOS, recently
introduced by Genet,20 as a ligand (entries 13-15). A
combination of this ligand and phthalimide as the proton
source gave the product in excellent chemical yield and
enantioselectivity (entry 15).
Having identified an optimal ligand/proton source com-
bination, we evaluated the effect of the nitrogen protecting
group and the ester substituent on efficiency and selectivity
(Table 3). These two variables had a significant impact on
the course of the reaction. Changing the ester substituent
from tert-butyl to others with a phthalimido nitrogen protect-
ing group led to either inefficient reactions or low selectivity
(entries 1-4). Thus, a bulky ester substituent is essential for
obtaining high selectivity. Succinimide and tosyl protecting
groups seem promising (entries 5 and 6).
We have preliminarily carried out work on the scope of
the aryl boronic acid component in the enantioselective proto-
nation experiments, and these results are shown in Table 4.
The reaction conditions which were found to be best for
Acknowledgment. We thank the NSF and NIH for
financial support of our research programs.
(16) JOSIPHOS ) 1-[2-(diphenylphosphino)ferrocenyl]ethyl dicyclo-
hexyl phosphine; MethylBOPhoz ) (R)-N-methyl-N-diphenylphosphino-
1-[S-2-(diphenylphosphino)ferrocenyl]ethylamine; SYNPHOS ) [(5,6),-
(5′,6′)-bis(ethylenedioxy)biphenyl-2,2′-diyl]bis(diphenylphosphine); DIFLUOR-
PHOS ) [(4,4′-bi-2,2-difluoro-1,3-benzodioxole)-5,5′diyl]bis(diphenylphos-
phine).
(17) Product does not racemize under the reaction conditions.
(18) Increasing the amount of phthalimide did not lead to enhancement
of the chemical yield or selectivity.
Supporting Information Available: Characterization
data for compounds and experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Genet,
J.-P.; Champion, N.; Dellis, P. PNAS 2004, 101, 5799.
(20) Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Genet,
J.-P.; Champion, N.; Dellis, P. Angew. Chem., Int. Ed. 2004, 43, 320.
OL050630B
(21) Guichard, G.; Abele, S.; Seebach, D. HelV. Chim. Acta 1998, 81,
187.
Org. Lett., Vol. 7, No. 13, 2005
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