A new method for the synthesis of chiral β-branched α-amino acids

Article abstract of DOI:10.1021/ol071305m

A new method for the synthesis of chiral β-branched α-amino acids based on a copper-mediated directed allylic substitution reaction with Grignard reagents is reported. This is the first case in which a δ-stereogenic center is controlling the diastereosele

Full text of DOI:10.1021/ol071305m

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3881-3884
A New Method for the Synthesis of
Chiral -Branched -Amino Acids
â
r
Thomas Spangenberg,†,‡ Ange`le Schoenfelder,† Bernhard Breit,*,‡ and
Andre´ Mann*,†
De´partement de Pharmacochimie de la Communication Cellulaire UMR 7175-LC-1
ULP/CNRS, Faculte´ de Pharmacie 74 route du Rhin BP 60024, F-67401 Illkirch,
France, and Institut fu¨r Organische Chemie und Biochemie,
Albert-Ludwigs-UniVersita¨t Freiburg, Albertstrasse 21, D-79104 Freiburg, Germany
andre.mann@pharma.u-strasbg.fr; bernhard.breit@organik.chemie-freiburg.de
Received June 1, 2007
ABSTRACT
A new method for the synthesis of chiral
Grignard reagents is reported. This is the first case in which a
â
-branched
r
-amino acids based on a copper-mediated directed allylic substitution reaction with
-stereogenic center is controlling the diastereoselectivity of an o-DPPB-
δ
directed allylic substitution. Depending on the alkene geometry of the starting material either diastereomer, anti or syn, is accessible with
good levels of acyclic stereocontrol.
Synthesis of â-branched R-amino acids requires the control
over adjacent stereocenters. To achieve this goal three major
synthetic strategies have appeared in the literature: (i) the
azaenolate-Claisen rearrangement for the synthesis of syn
adducts;1,2 (ii) the Meerwein-Eschenmoser-Claisen rear-
rangement, an alternative to reach the anti diastereomers;3
and (iii) the Overman imidate rearrangement, requiring the
oxidation of an allylamine.4,5 In previous work we6 and
others7-9 have shown that the oxazolidine moiety in Garner’s
aldehyde is a useful control element to achieve high levels
of π-diastereofacial discrimination in the course of 1,4
conjugate addition. We also explored the use of Garner’s
aldehyde as a precursor for seco-kainic acid, isoleucine, or
ADDA.6,10 In this context, we were wondering whether it
would be possible to construct the two epimeric alkenyl-
oxazolidines 1 and 2 from the corresponding E and Z
allylalcohols 3 and 4, via a SN2′ displacement reaction
(Scheme 1). Indeed, deprotection of the aminoalcohol
function in 1 and 2 followed by oxidation could regenerate
the R-amino acid function and would represent a new
synthesis of â-branched R-amino acids equipped with an
additonal terminal alkene function, amenable for further
chemical elaborations.
† De´partement de Pharmacochimie de la Communication Cellulaire
UMR 7175-LC-1 ULP/CNRS.
(6) (a) Jako, I.; Uiber, P.; Mann, A.; Wermuth, C. G.; Boulanger, Th.;
Norberg, B.; Evrard, C.; Durant, F. J. Org. Chem. 1991, 56, 5729. (b)
D’Aniello, F.; Mann, A.; Taddei, M.; Wermuth, C. G. Tetrahedron Lett.
1994, 35, 7775. (c) D’Aniello, F.; Schoenfelder, A.; Mann, A.; Taddei, M.
Tetrahedron 1997, 53, 1447.
(7) Hannessian, S.; Sumi, K. Synthesis 1991, 1083.
(8) Flamant-Robin, C.; Wang, Q.; Sasaki, N. A. Tetrahedron Lett. 2001,
42, 8483.
(9) Rastogi, S. K.; Kornienko, A. Tetrahedron: Asymmetry 2006, 17,
3170.
(10) Jako, I.; Uiber, P.; Mann, A.; Taddei, M.; Wermuth, C. G.
Tetrahedron Lett. 1990, 31, 1011.
‡ Albert-Ludwigs-Universita¨t Freiburg.
(1) Bartlett, P. A.; Barstow, J. F. J. Org. Chem. 1982, 47, 3933.
(2) (a) Kazmaier, U. Angew. Chem., Int. Ed. 1994, 33, 998. (b) Kazmaier,
U.; Maier, S. J. Org. Chem. 1999, 64, 4574. (c) Kazmaier, U.; Deska, J.;
Watzler, A. Angew. Chem., Int. Ed. 2006, 45, 4855.
(3) (a) Qu, H.; Gu, X.; Min, B. J.; Llu, Z.; Hruby, V. J. Org. Lett. 2006,
8, 4215. (b) Coats, B.; Montgomery, D.; Sterenson, P. J. Tetrahedron Lett.
1994, 50, 4025.
(4) Jamieson, A. G.; Sutherland, A.; Willis, C. L. Org. Biomol. Chem.
2004, 2, 808.
(5) Overman, L. E. Angew. Chem., Int. Ed. 1984, 23, 579.
10.1021/ol071305m CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/06/2007

from either face of the π-system in allylic o-DPPB esters
such as 7 or 8.20
Scheme 1. Approach toward â-Branched R-Amino Acids
Preparation of allylic substrates 7 and 8 commenced from
(R)-Garner’s aldehyde.21,22 Conversion to enoates 5 and 6
was achieved employing either a modified Horner-Wad-
sworth-Emmons reaction for the E isomer (6)6,23 or the
Stille-Gennari procedure for the Z isomer (5).7,24 Chemose-
lective ester reduction occurred upon treatment with DIBAL.
Finally esters 7 and 8 were obtained using Steglich’s
esterification conditions with o-DPPB acid (Scheme 2).25
The allylic substitution with organocopper reagents is an
attractive operation since in contrast to many other transition-
metal catalyzed allylic substitutions it allows the introduction
of hard nucleophiles such as alkyl, alkenyl, and aryl
substituents.11 However, the simultaneous control of regio-
and stereochemistry is still a difficult problem, and only a
few successful examples are known.12,13 One solution to this
problem makes use of reagent-directing leaving groups which
control the trajectory of the incoming copper nucleophile to
occur as an exclusive γ-attack.14,15 Additionally, a directing
leaving group reverses the stereochemical course of the
allylic substitution to occur as a syn process as opposed to
the natural anti attack relative to the leaving group.16 In this
regard the o-diphenylphosphanyl benzoate (o-DPPB) has
proved to be an efficient controller of regio- and stereo-
chemistry in the course of the allylic substitution reaction
with secondary and primary allylic substrates.17 Excellent
SN2′ selectivity and perfect levels of 1,3-syn chirality transfer
have been observed in many cases for cyclic and acyclic
derivatives.18,19 However, it was unknown whether a stereo-
genic center in δ-position of a primary allylic substrate would
exert any influence on the stereochemical course of the
intramolecular delivery of the organometallic nucleophile
Scheme 2
In a first series of experiments allylic o-DPPB esters 7
and 8, respectively, were subjected to the reaction conditions
of the directed allylic substitution with methyl magnesium
bromide in the presence of 0.5 equiv of CuBr‚SMe2 in
diethylether (Table 1). In accordance with previous inves-
tigations, optimal results were obtained upon slow syringe
pump addition of the Grignard reagent to a solution of the
allylic o-DPPB ester precomplexed with copper(I). Thus, for
E-substrate 7 under optimized conditions excellent SN2′
selectivity and a remarkable diastereoselectivity in favor of
the anti-SN2′ product 1a (dr 85:15) was obtained (Table 1,
entry 3). Even better, and most interestingly, opposite
diastereoselectivity was observed for Z-substrate 8 (dr 95:
5) in favor of syn-SN2′ product 2a. Hence, depending on
alkene geometry both diastereomeric allylic substitution
products 1a and 2a are accessible with good levels of acyclic
stereocontrol exerted by a stereogenic center in δ-position.
(11) (a) Yamamoto, Y. Methods of Organic Chemistry (Houben-Weyl);
Thieme: Stuttgart, Germany, 1995; Vol. E21, pp 2011-2040. (b) Breit,
B.; Demel, P. In Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; pp 188-223.
(12) (a) Ibuka, T.; Tanaka, M.; Nishii, S.; Yamamoto, Y. J. Chem. Soc.
Chem. Commun. 1987, 1596. (b) Ibuka, T.; Akimoto, N.; Tanaka, M.; Nishii,
S.; Yamamoto, Y. J. Org. Chem. 1989, 54, 4055. (c) Harrington-Frost, N.;
Leuser, H.; Calaza, M. I.; Kneisel, F. F.; Knochel, P. Org. Lett. 2003, 5,
2111. (d) Leuser, H.; Perrone, S.; Liron, F.; Kneisel, F. F. Angew. Chem.,
Int. Ed. 2005, 44, 4627. (e) For a review on the progress in enantioselective
catalysis with chiral copper catalysts see: Yorimitsu, H.; Oshima, K. Angew.
Chem. 2005, 117, 4509; Angew. Chem., Int. Ed. 2005, 44, 4435-4439.
(13) Orientating experiments with other leaving groups such as OAc,
Cl, or PO(OEt)2 have shown that in these cases the SN2 product is formed
preferentially.
(14) (a) Gallina, C. Tetrahedron Lett. 1982, 23, 3094. (b) Goering, H.
L.; Kantner, S. S.; Tseng, C. C. J. Org. Chem. 1983, 48, 715. (c) Smitrovich,
J. H.; Woerpel, K. A. J. Am. Chem. Soc. 1998, 120, 12998. (d) Smitrovich,
J. H.; Woerpel, K. A. J. Org. Chem. 2000, 65, 1601.
(15) (a) Barsanti, P.; Calo`, V.; Lopez, L.; Marchese, G.; Naso, F.; Pesce,
G. J. Chem. Soc., Chem. Commun. 1978, 1085. (b) Calo`, V.; Lopez, L.;
Carlucci, W. F. J. Chem. Soc., Perkin Trans. 1 1983, 2953. (c) Valverde,
S.; Bernabe´, M.; Garcia-Ochoa, S.; Go´mez, A. M. J. Org. Chem. 1990, 55,
2294.
(16) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063.
(17) (a) Breit, B.; Demel, P. AdV. Synth. Catal. 2001, 343, 429. (b) Demel,
P.; Keller, M.; Breit, B. Chem. Eur. J. 2006, 12, 6669.
(18) (a) Breit, B.; Demel, P.; Studte, C. Angew. Chem., Int. Ed. 2004,
43, 3786. (b) Breit, B.; Demel, P.; Grauer, D.; Studte, C. Chem. Asian J.
2006, 1, 586.
(19) (a) Breit, B.; Herber, C. Angew. Chem., Int. Ed. 2004, 43, 3790.
(b) Herber, C.; Breit, B. Chem. Eur. J. 2006, 12, 6684. (c) Herber, C.;
Breit, B. Angew. Chem., Int. Ed. 2005, 44, 5267.
(20) So far only two reports have addressed stereoinduction from a
stereocenter located in δ-position relative to the leaving group of an allylic
substrate. (a) Arai, M.; Kawasuji, T.; Nakamura, E. J. Org. Chem. 1993,
58, 5121. (b) Belelie, J.; Chong, M. J. J. Org. Chem. 2002, 67, 3000.
(21) Garner, P.; Park, J. M. J. Org. Chem. 1990, 55, 3772.
(22) For a review on the use of Garner’s aldehyde see: Liang, X.;
Andersch, J.; Bobs, M. J. Chem. Soc., Perkin Trans 1, 2001, 2137.
(23) Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624.
(24) (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405. (b)
Shimamoto, K.; Ohfune, Y. J. Med. Chem. 1996, 39, 407. (c) Sakai, N.;
Ohfune, Y. J. Am. Chem. Soc.1992, 114, 998.
(25) Ho¨fle, G.; Steglich, W.; Vorgru¨ggen, H. Angew. Chem., Int. Ed.
1978, 17, 569.
3882
Org. Lett., Vol. 9, No. 20, 2007

Table 1. Results of Copper-Mediated Directed Allylic
Substitution of Allylic o-DPPB Esters 7 and 8 with Methyl
Magnesium Bromide: Influence of Reaction Conditions
Table 2. Results of Copper-Mediated Directed Allylic
Substitution of Allylic o-DPPB Esters 7 and 8 with Grignard
Reagents
RMgBr
R
syn/antib
(products)
yield
(%)c
SN2′/SN2
1a + 2a/ syn/anti
10 + 11b 2a/1ac
entrya
1
cpd
SN2′/SN2
entrya cpd
equiv [MR]
7(E)
Me
98/2
15/85
78
(2a/1a)
15/85 (2b:1b)
17/83
(2c/1c)
7/93
(2d/1d)
97/3
(2a/1a)
97/3
(2b/1b)
98/2
(2c/1c)
95/5
1
2
3
4
5
6
7
8
9
10
7(E) 0.5 CuBr.SMe2/1.6 MeMgBr
7(E) 0.5 CuBr.SMe2/1.6 MeMgBr
7(E) 0.5 CuBr.SMe2/1.6 MeMgBr
7(E) 0.5 CuBr.SMe2/2 MeMgBr
7(E) 0.5 CuBr.SMe2/2 MeMgBr
7(E) 1 CuBr.SMe2/2 MeMgBr
7(E) 0.5 CuI/2 MeMgBr
7(E) 0.5 CuCN/2 MeMgBr
8(Z) 0.5 CuBr.SMe2/1.6 MeMgBr
8(Z) 0.5 CuBr.SMe2/2 MeMgBr
95/5 25/75
69/31 33/67
2
3
7(E)
7(E)
Et
nBu
96/4
98/2
91
97
98/2
96/4
92/8
93/7
84/16
89/11
98/2
97/3
15/85
21/79
18/82
24/76
22/78
28/72
95/5
4
5
6
7
8
7(E)
8(Z)
8(Z)
8(Z)
8(Z)
iPr
Me
Et
98/2
96/4
99/1
98/2
95/5
97
86
98
96
98
95/5
nBu
iPr
a All reactions were performed in Et2O, except for entry 1 which was
run in DCM. The reactions were performed at 20 °C, except for entries 2
and 4, run at 0 and 35 °C, respectively. In all cases the concentration of the
reaction was 0.02 M, MeMgBr 1.0 M in Et2O was added by syringe pump
(300 µL/h). b The SN2′/SN2 ratio was determinated by GC, the observed
SN2 adducts 10 and 11 were prepared from Garner’s aldehyde via a Wittig
olefination (E/Z: 7/93 with Ph3PdCHMe) and were employed for
identification purposes in the crude reaction mixture by GC/MS. c Complete
conversion of 7 or 8 was observed.
(2d/1d)
a RMgBr (2 equiv) at 0.1 M was added at a rate of 3 mL/h to a solution
of 7 or 8 precomplexed with of CuBr-Me2S (0.5 equiv) in Et2O at rt (0.01
M). b Configuration of 1b-d and 2b-d assigned on analogy with 1a and
2a by GC/MS. c Isolated products after column chromatography.
Assignment of the absolute configuration of 1a and 2a
was achieved upon transformation to known N-Boc isoleu-
cine and N-Boc allo-isoleucine (Scheme 3).
Regioselectivity toward the SN2′ product was high in all
cases. Furthermore, it proved generally that from E-substrate
7 anti-diastereomers 1a-d were formed preferentially,
whereas the corresponding Z-substrate 8 furnished the syn
diastereomers 2a-d diastereoselectively. Interestingly, dia-
stereoselectivity was more or less independent from the
nature of the Grignard reagent employed.
Scheme 3. Assignment of the Absolute Stereochemistry
As a rationale for the stereochemical outcome of these
reactions, we assume that the reaction follows the pathway
of a directed allylic substitution based on previous extensive
control experiments17 (Figure 1). Thus, for E-substrate 7 it
With the optimized reaction conditions in hand, we decided
to probe the influence of more spatially demanding nucleo-
philes on the regio- and diastereoselectivity of the directed
allylic substitution. Thus, the reaction of substrates 7 and 8
with a series of alkyl Grignard reagents was studied. Results
are summarized in Table 2. In all cases (R ) Et, nBu, and
iPr) complete conversion and almost quantitative yields of
allylic substitution product were obtained 1a-d and 2a-d
(Table 2, entries 1-8).
Figure 1. Rationale for the regio- and stereocontrol.
is plausible that reactive conformations (7A) or (7A′) are
accounting for the observed stereochemical outcome. Both
conformations are in agreement with stereoelectronic re-
Org. Lett., Vol. 9, No. 20, 2007
3883

quirements for the SN2′ reaction16 and minimize allylic A1,3
strain.26 Directed attack from the least hindered Si alkene
face provides the anti diastereomer preferentially.
with TFA in methanol and subsequent oxidation of the
primary alcohol toward the carboxylic acid with HIO4 and
CrO3 furnished the Boc-protected amino acid 14 in good
overall yield. Cleavage of the Boc group under standard
conditions yielded the desired â-branched amino acid 15
quantitatively (dr 9:1).
Employing the o-DPPB group as a reagent-directing
leaving group, chemo-, regio-, and diastereoselective allylic
substitution of allylic alcohols 3 and 4 derived from Garner’s
aldehyde is possible. This is the first case in which a
δ-stereogenic center is controlling the diastereoselectivity of
a o-DPPB-directed allylic substitution. Depending on the
alkene geometry of the starting material either diastereomer,
syn or anti, is accessible with good levels of acyclic
stereocontrol. A rational has been proposed including reactive
conformations minimizing A1,3 strain. The allylic substitution
products 1a-d or 2a-d constitute valuable building blocks
for the construction of natural and unnatural â-branched
R-amino acids as demonstrated with the synthesis of natural
(2S,3S)-2-amino-3-cyclopropylbutanoic acid.
In the case of Z-substrate 8, conformation (8B) with deliv-
ery of the alkyl nucleophile to the sterically less-hindered
Re face could explain the preferred formation of the syn
diastereomer. The pronounced A1,3 strain expected for a cis
disubstituted alkene could be responsible for the higher
diastereoselectivities observed for the Z-o-DPPB ester 8.
Our methodology has been applied toward the synthesis
of (2S,3S)-2-amino-3-cyclopropylbutanoic acid (15), isolated
from the mushroom Amanita castanopsidis Hongo, a natu-
rally occurring amino acid.27 As its absolute configuration
is related to iLeu, we started from substitution product 1a
(dr 85:15) (Scheme 4). Cyclopropanation of 1a occurred
Scheme 4
Acknowledgment. This work was supported by the
Ministe`re de´le´gue´ a` l’Enseignement Supe´rieur et a` la
Recherche (T.S.), by the Fonds der Chemischen Industrie
(B.B.) and the Krupp-Award for Young University Teachers
(B.B.).
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL071305M
(26) Hoffmann, R. W. Chem. ReV. 1989, 89, 1844.
(27) Morimoto, Y.; Takaishi, M.; Kinoshita, T.; Sakaguchi, K.; Shibata,
K. Chem. Commun. 2002, 42.
upon treatment with diazomethane in the presence of a
catalytic amount of palladium acetate to furnish fully pro-
tected amino acid precursor 12.28 Cleavage of the acetonide
(28) Suda, M. Synthesis 1981, 714.
3884
Org. Lett., Vol. 9, No. 20, 2007