Synthesis of α,α-disubstituted α-amino acid derivatives in enantiopure form via stereoselective addition of Grignard reagents to a chiral acyclic nitrone derived from L-erythrulose

Article abstract of DOI:10.1055/s-2002-25358

The additions of various Grignard reagents to a chiral nitrone prepared from L-erythrulose take place with variable diastereoselectivity. The degree and strength of the facial selectivity can be modified if the reaction is performed in the presence of Lewis acidic additives: zinc bromide enhances attack to the si face whereas diethyl aluminum chloride promotes attack to the re side. The obtained adducts can be then efficiently transformed into protected N-hydroxy α,α-disubstituted α-amino acid derivatives as well as into the corresponding α,α-disubstituted α-amino acids.

Full text of DOI:10.1055/s-2002-25358

LETTER
711
Synthesis of , -Disubstituted -Amino Acid Derivatives in Enantiopure Form
via Stereoselective Addition of Grignard Reagents to a Chiral Acyclic Nitrone
Derived from L-Erythrulose
Synthesis of
E
nan
a
tiopure
,
u
-Disubstitute
l
d
-Amino A
P
cid Derivativ
o
es rtolés,a Juan Murga,a Eva Falomir,a Miguel Carda,*a Santiago Uriel,a J. Alberto Marco*b
a
Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, Castellón, Spain
Fax +34(964)728214; E-mail: mcarda@qio.uji.es
b
Depart. de Q. Orgánica, Univ. de Valencia, c/D. Moliner, 50, 46100 Burjassot, Valencia, Spain
Fax +34(96)3864328; E-mail: alberto.marco@uv.es
Received 18 February 2002
Abstract: The additions of various Grignard reagents to a chiral ni-
trone prepared from L-erythrulose take place with variable dia-
stereoselectivity. The degree and strength of the facial selectivity
can be modified if the reaction is performed in the presence of
Lewis acidic additives: zinc bromide enhances attack to the si face
whereas diethyl aluminum chloride promotes attack to the re side.
The obtained adducts can be then efficiently transformed into pro-
tected N-hydroxy , -disubstituted -amino acid derivatives as well
as into the corresponding , -disubstituted -amino acids.
O
OBn
N
N
O
OP´
O
PO
O
OP
1
2
R
NH2
α-alkylated
Key words: Grignard reagents, chiral nitrone, erythrulose , -di-
substituted -aminoacids, N-hydroxy aminoacids
HO
serines
COOH
Scheme 1
The addition of carbon nucleophiles to C=N bonds1 is a
synthetically important method of preparing many types
of biologically relevant nitrogen-containing compounds,
among them non-proteinogenic amino acids. These are
used, for example, for the synthesis of non-natural pep-
tides.2 One important class of non-proteinogenic amino
acids are , -disubstituted -amino carboxylic acids.3 An-
other class, also interesting as synthetic targets, are N-hy-
droxy amino acids.4 In relation with these synthetic goals,
we described a few years ago the stereoselective additions
of organolithium reagents to the C=N bond of chiral E
oximes 1 (P, P = protecting groups),5 prepared from the
four-carbon monosaccharide L-erythrulose6 (Scheme 1).
The obtained adducts were then transformed into various
-substituted serine derivatives. As an alternative ap-
proach to the same targets, we later reported on the stereo-
selective additions of lithium and magnesium
organometallics to the C=N bond of the chiral keto
nitrone7 2, also prepared from L-erythrulose.8
reaction of a known silylated erythrulose derivative6 with
N-benzyl hydroxyl amine gave rise to nitrone 3 in a good
yield (Scheme 2). The compound was an oil and thus not
amenable to X-ray diffraction analysis but NOE measure-
ments permitted us to assign the configuration of the C=N
bond as Z.10,11
The results of the reactions of nitrone 312 with several
Grignard reagents in THF to yield a mixture of the dia-
stereoisomeric adducts 4 and 5 (Scheme 2) are indicated
in the Table.13 Various mechanistic models have been pro-
posed to explain the stereochemical outcome of such ad-
ditions, which have in most cases been performed on
functionalized nitrones derived from aldehydes.14 For in-
stance, the formation of either 4 or 5 can be rationalized
within the mechanistic frame of Cram’s -chelated ( 4)
vs. Felkin–Anh’s nonchelated ( 5) transition states5a
(MLn = MgBr in Scheme 2). According to our experience
with organometallic additions to various types of erythru-
lose derivatives5a,15
a -chelated TS, which should also
Even though the nucleophilic additions to the C=N bond
took place in both cases with an excellent diastereoselec-
tivity (diastereomeric ratios, dr, > 95:5 in many cases), the
overall efficiency of the process suffered from insatisfac-
tory yields in the preparation of precursors 1 and 2.9 We
thus looked for another chiral nitrone which should be ob-
tained from L-erythrulose with a good yield and show a
good diastereoselectivity in its reactions with carbon nu-
cleophiles. After due experimentation, we found that the
lead to stereoisomer 5, seems less likely here (see also be-
low). Variable dr were observed in THF,13 with the addi-
tions of allyl and phenyl Grignard reagents being
particularly stereoselective (entries 5 and 6). Stereoisomer
4 was the major or almost exclusive component of the
mixture except in the case of allylmagnesium bromide,
where 5 was the only isomer detected. Whether this differ-
ential behavior of the allyl reagent may be related to a dif-
ferent aggregation state of the reagent, to an intrinsic
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
1437-2096,E;2002,0,05,0711,0714,ftx,en;G04402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

712
R. Portolés et al.
LETTER
lective without Lewis acid additive (entry 6) and remained
so after adding ZnBr2. These results may be explained if
we assume that the bidentate Lewis acid ZnBr2 binds to
the substrate as the chelating species (MLn = ZnBr in
Scheme 2) more tightly that the magnesium salt present in
the reaction mixture. In contrast with this, addition of
Et2AlCl (1 equiv) to the reaction mixture caused consis-
tently a marked increase in the proportion of the Felkin–
Anh isomer 5 (except for entry 5). However, the stere-
ochemical bias imposed by this Lewis acid was not strong
enough to cause a complete reversal of the stereoselectiv-
ity except in the case of vinyl magnesium bromide, which
proved highly stereoselective in the presence of Et2AlCl
(entry 4) and yielded only 5.
O
O
Bn
N
O
OTPS
OTPS
O
O
O
BnNHOH
(78%)
3
Silylated L-erythrulose
acetonide
RMgX, THF (LA)
R
R
N(OH)Bn
OTPS
N(OH)Bn
OTPS
O
O
+
O
O
Findings of this type have previously been observed in the
additions of organometallics to -oxygenated ni-
trones.4d,14b In order to explain such results, it has been
proposed that Et2AlCl acts as monodentate Lewis acid
which coordinates only with the negatively charged oxy-
gen atom of the nitrone, thus leading to a Felkin–Anh-type
transition state. It is worth mentioning here that Evans and
co-workers have shown that Me2AlCl and MeAlCl2 are
exceptionally strong chelating species if added in an ex-
cess of 2–2.5 equivalents.17 However, the results present-
ed in the Table were essentialy the same, no matter
whether 1 or 2.5 equivalents of Et2AlCl were added to the
reaction mixture. This and the preferent formation of ste-
reoisomer 5 do not lend support to the idea that chelates
are formed here in the presence of this Lewis acid. Per-
haps the negatively charged oxygen atom of the nitrone
displaces the chlorine atom and forms a C=N+–OAlEt2
species, where the aluminum atom is possibly not enough
Lewis acidic to coordinate with the ketal oxygen atom.
4
5
ML
n
= metal cation and its
associated ligands
OML
n
Bn
#
H
#
steric
crowding
O
N
H
N
O
Me
O
Re attack
O
OTPS
Nu
Me
H
Nu
H
CH2OTPS
LnM
O
Si attack
Bn
Cram´s chelated TS
Felkin-Anh´s TS
Scheme 2
preference for a non-chelated cyclic transition state of the
metallo-ene type16 or to another cause is unclear.
Interestingly, addition in the presence of ZnBr2 (1 equiv)
led to an increase in the proportion of 4, in some cases to
synthetically useful values (entries 1 and 2). The addition
of the phenyl Grignard reagent was already very stereose-
We have also investigated the conversion of the obtained
adducts into derivatives of non-proteinogenic amino acids
of the type mentioned in the introduction. For synthetic
purposes, it proved better to quench the Grignard reaction
mixture with acetic anhydride at –78 °C instead of the
aqueous work-up.13 This yielded N-acetoxy derivatives 6
(and/or their epimers epi-6) which were both more stable
and easier to purify by means of chromatography
(Scheme 3). Subsequent functional manipulations trans-
formed 6 (epi-6) into the N-acetoxy -amino esters 7 (ent-
7), which constitute a protected form of N-hydroxy , -
disubstituted -amino acids.
Table Dr (ratio 4:5) in the Reactions of 3 with Grignard Reagents
RMgCl in THFa
En-
try
R
Lewis Acid Additive (LA, 1 equiv added)
None
ZnBr2
Et2AlClc
1
2
3
4
5
6
Me
85:15 (63%)
> 95:5 (72%)
93:7 (79%)
54:46 (69%)
47:53 (85%)
50:50 (74%)
< 5:95 (78%)
15:85 (80%)
70:30 (60%)
Etb
85:15 (74%)
83:17 (75%)
80:20 (75%)
< 5:95 (84%)
> 95:5 (90%)
The , -disubstituted -amino acids themselves can also
be made available by means of this methodology, as
shown in Scheme 4 in the case of 2-methyl serine. Com-
pound 7 (R = Me) was first desilylated with TBAF in THF
and then subjected to hydrogenolysis in the presence of
Pearlman’s catalyst. This caused both debenzylation and
reductive cleavage of the N–O bond to yield 2-methyl
serine methyl ester, which was then uneventfully hydrol-
yzed to R-(–)-2-methyl serine.5b Further amino acids with
other -substituents may also be prepared through desilyl-
ation of the TPS group and nucleophilic substitution of the
hydroxyl function.
n-Bu
vinylb
allylb
Ph
88:12 (75%)
85:15 (80%)
80:20 (80%)
> 95:5 (85%)
a Dr values (measured by high field 1H and 13C NMR) are followed
by chemical yields in parentheses (dr > 95:5 or < 5:95 means that
the minor stereoisomer was not detected). When the same reactions
were performed in Et2O, the dr were markedly lower.
b RMgBr instead of RMgCl.
c With 2.5 equiv of Et2AlCl the results changed only slightly.
Synlett 2002, No. 5, 711–714 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Enantiopure , -Disubstituted -Amino Acid Derivatives
(4) For a general review on this class of compounds, see:
713
OAc
NBn
(a) Ottenheijm, H. C. J.; Herscheid, J. D. M. Chem. Rev.
1986, 86, 697. (b) See also: Kolasa, T.; Sharma, S. K.;
Miller, M. J. Tetrahedron 1988, 44, 5431. (c) Jin, Y.; Kim,
D. H. Tetrahedron: Asymmetry 1997, 8, 3699. (d) Merino,
P.; Castillo, E.; Franco, S.; Merchán, S. L.; Tejero, T. J. Org.
Chem. 1998, 63, 2371. (e) N-Hydroxy amino acids have
been found as components of depsipeptide antibiotics:
Lorca, M.; Kurosu, M. Tetrahedron Lett. 2001, 2431. (f)
Another N-hydroxy compound which displays useful
pharmacological properties is the 5-lipoxygenase inhibitor
Zileuton: Brooks, D. W.; Bell, R. L.; Carter, G. W.; Dube, L.
M.; Rubin, P. D. Drugs Future 1993, 18, 616.
R
OAc
NBn
R
O
OTPS
O
OTPS
MeO2C
RMgX, -78 °C,
then quench
with Ac2O
1: HIO4
6
7
2: NaClO2
3: CH2N2
(50-70%
overall)
OAc
NBn
3
50-96%
R
OAc
NBn
R
O
OTPS
O
OTPS
MeO2C
(5) (a) Marco, J. A.; Carda, M.; Murga, J.; Rodríguez, S.;
Falomir, E.; Oliva, M. Tetrahedron: Asymmetry 1998, 9,
1679. (b) Carda, M.; Murga, J.; Rodríguez, S.; González, F.;
Castillo, E.; Marco, J. A. Tetrahedron: Asymmetry 1998, 9,
1703.
epi-6
ent-7
Scheme 3
(6) (a) Marco, J. A.; Carda, M.; González, F.; Rodríguez, S.;
Murga, J. Liebigs Ann. Chem. 1996, 1801. (b) Carda, M.;
Rodríguez, S.; Murga, J.; Falomir, E.; Marco, J. A.; Röper,
H. Synth. Commun. 1999, 29, 2601.
OAc
NBn
OAc
NBn
TBAF / THF
87%
(7) (a) Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates
in Organic Synthesis; VCH: , 1988. (b) Confalone, P. N.;
Huie, E. M. Org. React. 1988, 36, 1. (c) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(8) (a) Marco, J. A.; Carda, M.; Murga, J.; Portolés, R.; Falomir,
E.; Lex, J. Tetrahedron Lett. 1998, 3237. (b) 1,3-Dipolar
cycloadditions of this nitrone have also been investigated:
Carda, M.; Portolés, R.; Murga, J.; Uriel, S.; Marco, J. A.;
Domingo, L. R.; Zaragozá, R. J.; Röper, H. J. Org. Chem.
2000, 65, 7000.
OH
OTPS
MeO2C
MeO2C
8
7 (R=Me)
1: H2, Pd(OH)2 (70 psi)
2: NaOH/EtOH
NH2
OH
HOOC
(64% overall)
R-(-)-2-methylserine
(9) The oximes 1 were obtained as E/Z mixtures,5 from which
only the E isomers showed a good stereoselectivity.
Moreover, nitrone 2 was obtained together with a
Scheme 4
structurally close dioxazine,8 which was, however,
unreactive towards organometallics..
In summary, we have reported a convenient method for
the preparation of two types of non-proteinogenic amino
acids in enantiopure form. Application of this method to
the synthesis not only of amino acids but also of various
nitrogenated natural products of pharmacological interest
is being currently developed within our group and will be
reported in due course.
(10) A distinct NOE was detected between the N-benzylic
hydrogens and the methylene protons of the CH2OTPS
group.
(11) We have studied the formation of the nitrone with the aid of
quantum-mechanical ab initio methods. The non-isolated E
nitrone was found to be more stable than the Z isomer by
more than 3 kcal/mol. This indicates that the formation of the
Z nitrone is subjected to kinetic control. Preliminary results
of studies on possible transition states suggest that that
leading to the isolated Z nitrone is lower in energy than the
alternative transition state leading to the E isomer
(unpublished results with S. Safont).
(12) Preparation of Nitrone 3. 1-O-t-butyldiphenylsilyl-3,4-O-
isopropylidene-L-erythrulose6 (19.93 g, 50 mmol) and N-
benzyl hydroxylamine (6.16 g, 50 mmol) were dissolved in
CH2Cl2 (150 mL). Anhyd MgSO4 (10 g) was added to the
mixture and the suspension was stirred under Ar for 48 h at
r.t. The reaction mixture was then filtered through Celite,
and the Celite pad was subsequently washed twice with
CH2Cl2 (2 30 mL). After complete solvent removal in
vacuo, the oily residue was chromatographed on silica gel
(hexanes–EtOAc, 7:3). This furnished nitrone 3 as a dense
oil (19.65 g, 78%), which could not be induced to crystallize:
[ ]D25 –20.6 (CHCl3, c 3.7). IR max(film): 3052, 2986, 2934,
2892, 2860, 1577, 1472, 1455, 1428, 1382, 1266, 1212,
1181, 1154, 1112, 1058, 738, 704 cm–1. HRMS (EI): m/z
(rel. int.) = 503.2504 (0.5) [M+], 488(10) [M+ – Me], 446(16)
[M+ – t-Bu], 388(45), 341(88), 199(100), 101(96). Calcd for
C30H37NO4Si, M = 503.2492. 1H NMR (CDCl3, 500 MHz):
= 7.80–7.20 (15 H, m), 5.27 (1 H, t, J = 7 Hz), 5.06 (2 H,
Acknowledgement
Financial support has been granted by the Spanish Ministry of Sci-
ence and Technology (project PB98-1438) and by BANCAJA (pro-
ject P1B99-18). One of the authors (J. M.) further thanks the
Spanish Ministry of Science and Technology for a Ramón y Cajal
fellowship. The authors also thank Dr. Harald Roeper, from Erida-
nia Béghin-Say, R&D Center, Vilvoorde, Belgium, for his very
generous gift of erythrulose.
References
(1) (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997,
8, 1895. (b) Bloch, R. Chem. Rev. 1998, 98, 1407.
(c) Adams, J. P.; Box, D. S. J. Chem. Soc., Perkin Trans. 1
1999, 749.
(2) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(3) (a) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225.
(b) Cativiela, C.; Díaz de Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517. (c) Cativiela, C.; Díaz de
Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645.
Synlett 2002, No. 5, 711–714 ISSN 0936-5214 © Thieme Stuttgart · New York

714
R. Portolés et al.
LETTER
AB system, J = 11 Hz), 4.53 (1 H, dd, J = 8.5 and 7 Hz), 4.46
(2 H, AB system, J = 12.5 Hz), 3.77 (1 H, dd, J = 8.5 and 7
Hz), 1.35 (3 H, s), 1.29 (3 H, s), 1.10 (9 H, s). 13C NMR
(CDCl3, 125 MHz): = 148.1, 133.2, 132.3, 132.2, 109.7,
19.3 (C), 135.7, 135.6, 135.5, 130.0, 129.1, 128.8, 128.6,
128.5, 128.3, 128.2, 127.8, 127.7, 73.2 (CH), 68.3, 64.5,
56.3 (CH2), 27.0, 26.0, 24.7 (CH3).
(14) See, for example: (a) Chang, Z.-Y.; Coates, R. M. J. Org.
Chem. 1990, 55, 3464. (b) Dondoni, A.; Franco, S.;
Merchán, S. L.; Merino, P.; Tejero, T. Synlett 1993, 78.
(c) Basha, A.; Henry, R.; McLaughlin, M. A.; Ratajczyk, J.
D.; Wittenberger, S. J. J. Org. Chem. 1994, 59, 6103.
(d) Dondoni, A.; Franco, S.; Junquera, F.; Merchán, F. L.;
Merino, P.; Tejero, T.; Bertolasi, V. Chem.–Eur. J. 1995, 1,
505. (e) Merino, P.; Lanaspa, A.; Merchán, F. L.; Tejero, T.
J. Org. Chem. 1996, 61, 9028. (f) Dhavale, D. D.; Desai, V.
N.; Sindkhedkar, M. D.; Mali, R. S.; Castellari, C.;
Trombini, C. Tetrahedron: Asymmetry 1997, 8, 1475.
(15) (a) Marco, J. A.; Carda, M.; González, F.; Rodríguez, S.;
Castillo, E.; Murga, J. J. Org. Chem. 1998, 63, 698.
(b) Carda, M.; Castillo, E.; Rodríguez, S.; González, F.;
Marco, J. A. Tetrahedron: Asymmetry 2001, 12, 1417.
(16) Oppolzer, W. In Comprehensive Organic Synthesis, Vol. 5;
Trost, B. M.; Fleming, I.; Paquette, L. A., Eds.; Pergamon
Press: Oxford, 1991, Chap. 1.2.
(13) General Reaction Conditions for Grignard Additions to
Nitrone 3 with Aqueous Work-up. A solution of 3 (1
mmol) in THF (5 mL) was cooled under Ar to –78 °C and
treated with the appropriate Grignard reagent (5 mmol of a
commercial solution in THF). After stirring for 5 h at the
same temperature, the reaction mixture was quenched with
sat. aq NH4Cl (2 mL); the reaction mixture was stirred for
further 5 min, poured into brine and extracted with EtOAc.
The organic layers were then dried on anhyd Na2SO4 and
concentrated in vacuo. Column chromatography of the oily
residue on silica gel (hexane–EtOAc mixtures) afforded the
corresponding adducts (Table). Additions in the presence of
Lewis acid additives were performed in the same way except
that the Lewis acid (1 mmol) was added to an ice-cooled
solution of 3; the solution was then stirred for 15 min and
cooled to –78 °C, prior to addition of the Grignard reagent.
Grignard Additions to Nitrone 3 with acetylating Work-
up. For the preparation of amino acid derivatives, the
reaction was performed as above except that acetic
anhydride (190 L, 2 mmol) was added dropwise at –78 °C
to the reaction mixture. The cooling bath was removed and
the mixture was stirred for 30 min at r.t. After quenching
with sat. aq NH4Cl (2 mL), the reaction mixture was stirred
for further 15 min, poured into brine and worked up as
above.
(17) (a) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E.
J. Am. Chem. Soc. 2001, 123, 10840. (b) The strong
chelating ability of Me2AlCl is attributed to a bimolecular
interchange where the anion (Me2AlCl2)– is formed together
with formal transfer of the chelating, highly Lewis acidic
species Me2Al+ to the substrate. Obviously, two equivalents
of Me2AlCl are required.
The configuration of the newly formed stereogenic center
was determined by straightforward conversion of adducts 4
into oxazolidinones i (Scheme 5) and observation of suitable
NOE’s in the latter. Additional support was given by X-ray
diffraction analyses of 4 (R = Et), 4 (R = allyl) and 6
(R = Ph). The crystallographic data of these three com-
pounds have been deposited at the Cambridge Crystallo-
graphic Data Centre (deposition numbers, CCDC-177985 to
CCDC–177987).
TPSO
OTPS
R
N(OH)Bn
OTPS
1: Zn/Cu, AcOH
2: H3O+
R
H
O
N
O
Bn
3: TPSCl, base
4: triphosgene
O
O
4
i
Scheme 5
Synlett 2002, No. 5, 711–714 ISSN 0936-5214 © Thieme Stuttgart · New York