Enantioselective H-atom transfer reactions: A new methodology for the synthesis of β2-amino acids

Article abstract of DOI:10.1002/anie.200353000

A radical step: The addition of radicals to amino acrylates and subsequent H-atom transfer in the presence of chiral Lewis acid activators provides β²-amino acids in high yields and enantiomeric purity (see scheme; Ln* = chiral ligands, Fmoc = 9-fluorenylmethoxycarbonyl).

Full text of DOI:10.1002/anie.200353000

Angewandte
Chemie
Amino Acid Synthesis
Enantioselective H-Atom Transfer Reactions: A
New Methodology for the Synthesis of b2-Amino
Acids**
Mukund P. Sibi* and Kalyani Patil
The development of new methods for the synthesis of b-
amino acids and their derivatives is important.[1] Several
enantioselective catalytic methods have been developed
recently for the synthesis of b-substituted b-amino acids (b3-
amino acids).[2] In contrast, there are very few reports on
enantioselective methods for the synthesis of a-substituted b-
amino acids (b2-amino acids).[3] This substitution pattern is of
interest since it is present in naturally occurring amino acids
as well as in compounds with potential therapeutic value.[4]
Enantioselective H-atom transfer,[5] an underdeveloped
complementary strategy to enolate protonation,[6] is well
suited to the preparation of b-amino acids. We showed
recently that a-amino acrylates undergo radical addition
followed by an enantioselective H-atom transfer in the
presence of a chiral Lewis acid (1!2, Scheme 1).[5d] In this
transformation, a stoichiometric amount of the Lewis acid is
required to achieve good selectivity because of the low
reactivity of the substrate. Development of a similar protocol
starting with b-amino acrylate would provide access to a-
substituted b-amino acids. At the outset, we were not certain
if substrate 3 would be suitable for the catalytic process
[*] Prof. M. P. Sibi, K. Patil
Department of Chemistry
North Dakota State University
Fargo, ND 58105-5516 (USA)
Fax: (+1)701-231-1057
E-mail: mukund.sibi@ndsu.nodak.edu
[**] This work was supported by the National Institutes of Health (Grant
no. NIH-GM-54656). We thank Dr. Kennosuke Ito and Dr. Craig
Jasperse for helpful discussions.
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 1235 –1235
DOI: 10.1002/anie.200353000
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1235

Communications
Enantioselective H-atom transfer reactions catalyzed
by chiral Lewis acids derived from bisoxazolines and
magnesium salts were evaluated.[11] Addition of an
isopropyl radical to 5 in the presence of 9a and MgI2
(100 mol%) gave the product in good yield and with
modest enantioselectivity (Table 2, entry 1). A change of
ligand to either 9b or 9c did not lead to improvements in
selectivity (entries 2 and 3). The effect of the H-atom
donor on the level of selectivity was also examined and
was found to have very little impact.[12] This trend is
similar to that observed in our previous work on a-amino
acids.[5d] The addition of a series of acyclic and cyclic
radicals to 5 was investigated with 9a as the ligand.
Scheme 1. Synthesis of amino acid derivatives from amino acrylates by radical addi-
tion and subsequent enantioselective H-atom transfer.
Table 2: Enantioselective H-atom transfer reactions with methyl ester 5.
because of its high reactivity towards conjugate addition. The
requirement of a very flexible eight-membered chelate[7] to
control the face selectivity posed an additional concern.
Herein, we report the successful development of catalytic
methods for the synthesis of b2-amino acids in high chemical
yield and with high enantioselectivity by radical addition[8]
followed by H-atom transfer.
We began our work by examining conjugate radical
additions to acrylates 5 and 6. These substrates were readily
prepared in good overall yields in three steps.[9] The addition
of various radicals was examined by using triethylborane/O2
as an initiator in the absence of any Lewis acid activation
(Table 1). As can be discerned from the results (entries 1–6),
Entry
RX
Ligand
Compd
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
isopropyl-I
isopropyl-I
isopropyl-I
CH3OCH2-Br
CH3CH2-I
9a
9b
9c
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
7a
7a
7a
7d
7e
7 f
7g
7h
7b
7c
7i
91
98
76
85
91
80
81
68
71
70
64
95
76
40
6
ꢀ6
30
40
55
20
60
79
75
27
20
40
Table 1: Radical addition to amino acrylates.[a]
MeC(O)Br
tert-butyl-I
cyclopentyl-Br
cyclohexyl-I
cycloheptyl-Br
1-adamantyl-I
isopropyl-I
cyclohexyl-I
9
10
11
12[c]
13[c]
Entry
R
R1
Compd
Yield [%],[b]
7a
7b
No Lewis acid MgI2 (1 equiv)
1
2
3
4
5
6
Me isopropyl-I
Me cyclohexyl-I
Me cycloheptyl-Br 7c
tBu isopropyl-I
tBu cyclohexyl-I
tBu cycloheptyl-I
7a
7b
99
95
94
99
99
91
78
80
85
86
77
80
[a] Yields of isolated products. 100 mol% catalyst was used. [b] Enantio-
meric excess determined by chiral HPLC analysis. A negative value
indicates that the enantiomer opposite to that of the startingmaterial is
favored. [c] Reaction with 30 mol% chiral Lewis acid.
8a
8b
8c
Reactions with the primary radicals methoxymethyl and ethyl
were chemically efficient but selectivities were low (entries 4
and 5). Addition of the acetyl radical was not highly selective
either (entry 6). The yield from the addition of the bulky tert-
butyl radical was high, but the reaction gave the product in
only 20% ee (entry 7). The observed trend of lower selectivity
with bulkier radicals is the same as that found in our previous
work on the synthesis of a-amino acids. Reactions with cyclic
radicals were more rewarding: the addition products were
formed in good yield and high ee values (entries 8–10).
Addition of the bulky adamantyl radical occurred with a
low enantioselectivity similar to that observed for the tert-
butyl radical (entry 11). Reactions in the presence of
30 mol% of the chiral Lewis acid gave lower ee values for
the products than when 100 mol% of the Lewis acid was used
[a] For detailed reaction conditions see the SupportingInformation.
[b] Yields are for column-purified, isolated materials.
both substrates are very reactive and undergo very efficient
uncatalyzed radical addition even at ꢀ788C. Reactions were
also carried out with a stoichiometric amount of MgI2 which
was present as a representative Lewis acid (Table 1, entries 1–
6).[10] The results show that the uncatalyzed reactions are
slightly more efficient than reactions mediated by a Lewis
acid. The results also suggest that the reactions catalyzed by
chiral Lewis acids have to be substantially faster than the
background reaction to achieve enantioselective H-atom
transfer.
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(compare entries 1 and 9 with entries 12 and 13, respectively).
These results clearly suggest that background reactions
compete with the catalyzed reactions.
products of the radical reaction can be converted into
compounds that can be employed in solid-phase peptide
synthesis.
In our next set of experiments we used the tert-butyl ester
6 as the substrate and investigated the addition of various
radicals of different size in the presence MgI2/9a as the chiral
Lewis acid catalyst. The results of these experiments are
presented in Table 3. The reactions with primary radicals
A stereochemical model for the H-atom transfer reactions
must be consistent with four key observations: 1) the effect of
the ester substituent (tert-butyl versus methyl) on selectivity,
2) the increased enantioselectivity observed with bulky rad-
icals and with 6 as the substrate, 3) the absolute stereo-
chemistry of the addition product,
Table 3: Enantioselective H-atom transfer reactions with tert-butyl ester 6.[a]
and 4) the effect of catalytic load-
ing on selectivity. We propose an
eight-membered chelate model
with a tetrahedrally coordinated
magnesium ion to account for
most of these observations
(Figure 1).[16] In this model, the
conformation of the ester substitu-
100 mol% LA[b]
30 mol% LA[b]
Entry
RX
Compd
Yield [%][c]
ee [%][d]
Yield [%][c]
ee [%][d]
ent (S-cis or S-trans) is dependent
on its size and is controlled by the
ligand.[17] Substrate 6, which has a
bulky tert-butyl ester substituent, is
predominantly in an S-trans
arrangement.[18] The conformation
of 5, which has a smaller methyl
ester substituent, is not fixed but is
predominantly S-trans. After radi-
cal addition from the top face (see
structure B), the face selectivity of
the H-atom transfer is dependent
1
2
3
4
5
6
7
8
9
CH3OCH2-Br
ClCH2-I
CH3CH2-I
isopropyl-I
tert-butyl-I
ClCH2CH2CH2(CH3)2C-Br
cyclopentyl-I
cyclohexyl-I
8d
8e
8 f
8a
8g
8h
8i
85
84
82
91
85
72
86
95
71
68
36
36
62
92
98
94
88
97
78
84
83
95
88
70
74
86
72
36
34
62
84
71
50
47
90
61
8b
8j
1-adamantyl-I
[a] For detailed reaction conditions see the SupportingInformation. [b] LA =Lewis acid. [c] Yields are for
column-purified, isolated materials. [d] ee values were determined by chiral HPLC.
were efficient but their enantioselectivity was modest
(entries 1–3). Interestingly, addition of the ethyl radical
occurred more selectively with substoichiometric amounts
of the Lewis acid (ee = 62%, entry 3) than with 100 mol% of
the Lewis acid. The isopropyl radical behaved similarly and
led to a higher ee value of 84% when 30 mol% of the catalyst
was used (entry 4).[13] Substrate 6, a tert-butyl ester, reacted
with higher selectivity than the corresponding methyl ester
(compare entry 5 in Table 3 with entry 7 in Table 2). Reac-
tions with tertiary and cyclic radicals gave excellent yields and
proceeded with high enantioselectivity (entries 5–9). The
functionalized tertiary radical gave the highest selectivity
(98%, entry 6). These results demonstrate that a variety of b2-
Figure 1. Stereochemical model.
amino acids can be prepared with high levels of selectivity by
employing a novel enantioselective H-atom transfer reaction.
Disappointingly, there was no clear correlation between the
catalytic loading and level of selectivity.[14]
The absolute stereochemistry of 8a was assigned by
converting it into a known b2-amino acid[15] by using standard
reactions (Scheme 2). This sequence also establishes that the
upon the size of the ester substituent as well as that of the
radical fragment. The high enantioselectivities observed in
reactions between bulky radicals and 6 suggests that the local
conformation of the substituent at the carbon atom b to the
radical center[19] has a large impact on
the selectivity. Metzger and co-work-
ers.[7a] also noted unusual relationships
between selectivity and the size of the
radical fragment. Steric interactions
between the tert-butyl ester and the
radical fragment in the complex force
the radical to adopt the orientation
shown in Figure 1A. H-atom transfer
Scheme 2. Conversion of 8a into a b2-amino acid. Fmoc=9-fluorenylmethoxycarbonyl, Py=pyr-
idine, TFA=trifluoroacetic acid.
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Communications
Kobayashi, F. Sato, J. Org. Chem. 1995, 60, 3576; d) M. P. Sibi, Y.
Asano, J. B. Sausker, Angew. Chem. 2001, 113, 1333; Angew.
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Chem. Soc. 2002, 124, 984; for selected examples of enantiose-
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f) M. Blumenstein, K. Schwarzkopf, J. O. Metzger, Angew.
Chem. 1997, 109, 245; Angew. Chem. Int. Ed. Engl. 1997, 36,
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Asymmetry 1996, 7, 2417; i) D. Dakternieks, K. Dunn, V. T.
Perchyonok, C. H. Schiesser, Chem. Commun. 1999, 1665; j) for
general information on radical reactions, see: Radicals in
Organic Synthesis (Eds.: P. Renaud, M. P. Sibi), Wiley-VCH,
Weinheim, 2001.
then occurs anti to the radical fragment. This analysis is
consistent with the dependence of the level of enantioselec-
tivity on the steric bulk of the radical fragment. In reactions
with 5, steric interactions between the methyl group of the
ester and the radical fragment are less demanding (both
models A and B are feasible) but reactions occur predom-
inantly through model A.
The absolute stereochemistries of 8a and 7a were
determined to be S (see above). The proposed model predicts
the correct face selectivity (S) for H-atom transfer in
reactions with both 5 and 6. In the methyl ester (5) series,
the lower selectivity of reactions with 30 mol% of the catalyst
suggests that background reactions compete effectively with
the catalyzed process. In contrast, there is no discernable
relationship between catalytic loading and selectivity in the
reactions with 6. The broad range of results observed with
these reactions is more difficult to explain and further work is
required.
[6] a) O. Muꢀoz-Muꢀiz, E. Juaristi, Tetrahedron Lett. 2003, 44, 2023,
and references cited therein; b) for a recent review, see: J.
Eames, N. Weerasooriya, Tetrahedron: Asymmetry 2001, 12, 1.
[7] For reports on seven- and eight-membered metal chelates in
stereoselective radical reactions, see: a) A. Hayen, R. Koch, W.
Saak, D. Haase, J. Metzger, J. Am. Chem. Soc. 2000, 122, 12458;
b) A. Hayen, R. Koch, J. O. Metzger, Angew. Chem. 2000, 112,
2898; Angew. Chem. Int. Ed. 2000, 39, 2758; c) H. Nagano, H.
Ohkouchi, T, Yajima, Tetrahedron 2003, 59, 3649; d) H.
Nagano, T. Hirasawa, T. Yajima, Synlett 2000, 1073.
In conclusion, we have developed a novel and efficient
enantioselective H-atom transfer process to prepare a-
substituted b-amino acids (b2-amino acids) in high enantio-
meric purity. Work is underway to develop more efficient
catalytic reactions and to extend the methodology to more
complex substrates.
[8] For a report on radical additions to acrylates leading to racemic
products, see: J. Huck, J.-M. Receveur, M.-L. Roumestant, J.
Martinez, Synlett 2001, 1467.
[9] For the synthesis of substrates and details on experimental
conditions, see the Supporting Information and D. Basavaiah, M.
Krishnamacharyulu, J. Rao, Synth. Commun. 2000, 30, 2061.
[10] Several other Lewis acids were evaluated. They gave similar
results to those obtained with MgI2. The details of these
experiments will be reported in a separate full account.
[11] Several ligand–Lewis acid combinations were also evaluated. Of
these, magnesium salts with ligand 9a gave the best results.
[12] Of the three H-atom donors tested (Bu3SnH, Ph3SnH, and
(TMS)3SiH; TMS = trimethylsilyl), tributyltin hydride gave the
addition products most efficiently (clean with very few byprod-
ucts) and with the highest enantioselectivity.
[13] The catalytic loading was varied from 10 to 100 mol%. The
enantioselectivity remained nearly constant (ca. 80% ee) for
loadings between 20 and 75 mol%.
[14] The higher enantioselectivities observed for 8a and 8 f at
30 mol% catalytic loading are not an experimental artifact.
Further experimentation is required to identify the origin(s) of
this anomaly.
[15] P. E. Coffey, K. Drauz, S. M. Roberts, J. Skidmore, J. A. Smith,
Chem. Commun. 2001, 2330. See also ref. [3e]. Product 7a also
has the S configuration (see the Supporting Information). By
analogy, we assume that the face selectivity is the same for the
other substrates.
[16] This model is similar to that proposed by Metzger and co-
workers in their work on diastereoselective H-atom transfer
reactions with methylene glutarates (see ref. [7a]).
[17] At the present time we do not have a clear picture of the
influence of the chiral ligand on the rotamer geometry of the
ester substituent and its impact on the observed enantioselec-
tivity.
Received: October 2, 2003 [Z53000]
Keywords: amino acids · asymmetric catalysis · enantioselective
.
H-atom transfer · Lewis acids · radical reactions
[1] For a recent review, see: M. Liu, M. P. Sibi, Tetrahedron 2002, 58,
7991; see also: E. Juaristi, H. Lopez-Ruiz, Curr. Med. Chem.
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[2] For selected recent examples, see: a) W. Tang, W. Wang, Y. Chi,
X. Zhang, Angew. Chem. 2003, 115, 973; Angew. Chem. Int. Ed.
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2, 3393; e) J. K. Myers, E. N. Jacobsen, J. Am. Chem. Soc. 1999,
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Chem. Soc. 1998, 120, 6615; g) M. P. Sibi, N. Prabagaran, S. G.
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[3] a) H. M. L. Davies, C. Venkataramani, Angew. Chem. 2002, 114,
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Josien, S. Kopp, G. Lelais, Y. R. Mahajan, P. Micuch, R. Sebesta,
B. W. Schweizer, Helv. Chim. Acta 2003, 86, 1852.
[4] Cryptophycins: a) G. V. Subbaraju, T. Golakoti, G. M. L. Pat-
terson, R. E. Moore, J. Nat. Prod. 1997, 60, 302; biologically
active b-peptides: b) M. Werder, H. Hausre, S. Abele, D.
Seebach, Helv. Chim. Acta 1999, 82, 1774.
[5] For recent reviews on enantioselective radical processes, see:
a) M. P. Sibi, S. Manyem, J. Zimmerman, Chem. Rev. 2003, 103,
3263; M. P. Sibi, N. A. Porter, Acc. Chem. Res. 1999, 32, 163; for
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b) M. Murakata, H. Tsutsui, N. Takeuchi, O. Hoshino, Tetrahe-
dron 1999, 55, 10295; c) H. Urabe, K. Yamashita, K. Suzuki, K.
[18] For the conformations of the ester substituents, see: A. G.
Pinkus, E. Y. Lin, J. Mol. Struct. 1975, 24, 9.
[19] The size of the exocyclic substituent has been shown to have an
impact on H-atom transfer reactions: B. Giese, W. Damm, T.
Witzel, H.-G. Zeitz, Tetrahedron Lett. 1993, 34, 7053.
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