Study of the Lewis acid-promoted addition of silylenol ethers to imines derived from glyceraldehyde

Article abstract of DOI:10.1016/j.tetlet.2003.10.027

Chiral N-benzylimines derived from D-glyceraldehyde undergo Lewis acid-promoted asymmetric Mannich reactions with O-methyl-O-trimethylsilyl dimethylketeneacetal to give β-amino acid esters in good yields and with excellent diastereoselectivities.

Full text of DOI:10.1016/j.tetlet.2003.10.027

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9189–9192
Study of the Lewis acid-promoted addition of silylenol ethers to
imines derived from glyceraldehyde
Ramo´n Badorrey, Carlos Cativiela, Mar´ıa D. D´ıaz-de-Villegas* and Jose´ A. Ga´lvez*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias-Instituto de Ciencia de Materiales de Arago´n,
Universidad de Zaragoza-CSIC, E-50009 Zaragoza, Spain
Received 30 July 2003; revised 26 September 2003; accepted 6 October 2003
Abstract—Chiral N-benzylimines derived form
D-glyceraldehyde undergo Lewis acid-promoted asymmetric Mannich reactions
with O-methyl-O-trimethylsilyl dimethylketeneacetal to give b-amino acid esters in good yields and with excellent diastereoselec-
tivities.
© 2003 Elsevier Ltd. All rights reserved.
Since Ojima et al. first described1 the Lewis acid-pro-
moted condensation of silylenol ethers to imines, this
procedure has been widely used to obtain valuable
b-aminocarbonyl compounds such as b-amino acids
and b-lactams.2 Furthermore, the development of
diastereo-3 and enantioselective4 processes has become
an active area of investigation.
N-benzylimine derived from (R)-2,3-di-O-benzylglycer-
aldehyde with O-methyl-O-trimethylsilyl dimethylkete-
neacetal, as outlined in Scheme 1, and several reaction
factors such as the nature of the Lewis acid, solvent and
temperature were examined.
The study revealed that ZnI2 was the best Lewis Acid
promoter tested [BF3·OEt2, Et2AlCl, EtAlCl2, CeCl3,
MgBr2, ZnI2, SnCl4, Sc(OTf)3, Yb(OTf)3], yielding the
corresponding Mannich adduct 2 of 3R,4S configura-
tion together with a by-product characterised as olefin 3
in a ratio that depended on the reaction conditions. In
the presence of certain Lewis acids the O-benzyl pri-
mary group becomes a good leaving group and an
elimination reaction followed by the nucleophilic addi-
tion of O-methyl-O-trimethylsilyl dimethylketeneacetal,
giving rise to olefin 3, competes with the pure imine
nucleophilic addition.
In recent years we have been interested in the use of
chiral imines derived from suitably protected
D-glycer-
aldehyde as chiral precursors in the synthesis of amino
acids and other nitrogen-containing compounds
through cyanide5 or organometallic reagent additions6
and in the synthesis of piperidones through hetero
Diels–Alder reactions.6f,7 The excellent results obtained
in this area prompted us to investigate the reactivity of
these imines towards other interesting carbon-based
nucleophiles.
Initially, we searched for effective reaction conditions
for the Mannich reaction of chiral imines derived from
Different experimental conditions were tested with ZnI2
as promoter and the best results were observed when 1
equiv. of Lewis acid was used in acetonitrile as the
solvent at low temperature (−20°C); under these condi-
suitably protected
D-glyceraldehyde and silylenol
ethers. We selected as a model the reaction of the
Scheme 1. Asymmetric Mannich reaction of chiral imine 1 with O-methyl-O-trimethylsilyl dimethylketeneacetal.
Keywords: asymmetric synthesis; imines; Mannich reaction.
* Corresponding author. Tel.: +34-976-762274; fax: +34-976-761210; e-mail: loladiaz@unizar.es; jagl@unizar.es
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.027

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R. Badorrey et al. / Tetrahedron Letters 44 (2003) 9189–9192
Scheme 2. Synthesis of b,b-dimethyl aspartic acid derivative 6 from Mannich adduct 2.
tions the elimination reaction was avoided and com-
pound 28 was obtained as a single diastereoisomer in
78% isolated yield. Other reaction conditions, such as
the use of diethyl ether, toluene or THF as solvent, or
an increase in the temperature, did not improve the
results. It is worth noting that the use of 0.1 equiv. of
ZnI2 did not affect the stereochemical result although it
did give a slightly lower yield.
Figure 1. Determination of the relative configuration of cyclic
compound 7 by NOE measurements.
Compound 2 was successfully converted into suitably
protected b,b-dimethylaspartic acid. At the same time
the relative stereochemical assignment of a cyclic inter-
mediate was made and the absolute configuration of
compound 2 was unambiguously determined. Selective
benzylamine hydrogenolysis of the Mannich adduct in
the presence of (Boc)2O, using Pd(OH)2 on carbon as a
catalyst, afforded N-Boc derivative 4 in 87% overall
yield. Extensive hydrogenolysis of the resulting com-
pound, using Pd(OH)2 on carbon as a catalyst, cleanly
afforded the desired N-Boc aminodiol 5, whose imme-
diate treatment with an excess of sodium periodate in
the presence of ruthenium trichloride gave b,b-dimethyl-
aspartic acid derivative 69 in 56% yield from compound
4. On standing, compound 5 gave the cyclic compound
7 as outlined in Scheme 2. Attempts to remove all the
benzyl protecting groups in a single step using Pd(OH)2
on carbon as a catalyst in CH3OH/HCl led to the
formation of lactone 8.10
When the reaction was carried out at −20°C using 1
equiv. of ZnI2 in acetonitrile, a 92/8 mixture of
diastereoisomers was obtained from which compound
10 was obtained as a single diastereoisomer in 58%
isolated yield after column chromatography. This com-
pound was converted into cyclic derivative 7 by
hydrogenolysis of the N-benzyl group in the presence of
(Boc)2O using Pd(OH)2 on carbon as a catalyst (95%
yield), followed by hydrolysis of the isopropylidene
acetal with trifluoroacetic acid (92% yield). This latter
step allowed the unambiguous assignment of the abso-
lute configuration as 3R,4S (Scheme 3).
The excellent stereoselectivity observed in the Mannich
reaction is in accordance with that previously described
for the addition of thioesters to 4-methoxyphenylimines
derived from 2,3-isopropylidene-
D
-glyceraldehyde and
2,3-cyclohexylidene-
D-glyceraldehyde promoted by
The relative configuration of compound 7 was assigned
by analysis of difference NOE spectra. The specific
pattern of NOEs (Fig. 1) can be explained by the cis
relative configuration for compound 7, thus the abso-
lute configuration of the diastereoisomer formed in the
Mannich reaction is 3R,4S.
TiCl4.11
The preferential formation of compounds 2 and 10
(with a cis-configuration) can be explained in terms of
attack from the re-face of the silylenol ether to the
a-chelate formed by simultaneous coordination of zinc
both to the imine nitrogen and the a-alkoxy group (Fig.
2).
We have noticed previously that in the addition of
some organometallic reagents to N-benzylimines
derived from conveniently protected
D-glyceraldehyde,
In conclusion, chiral N-benzylimines derived from (R)-
2,3-di-O-benzylglyceraldehyde and (R)-2,3-O-isopropyl-
ideneglyceraldehyde react with O-methyl-O-trimethyl-
silyl dimethylketeneacetal in the presence of ZnI2. In
both cases the attack of the nucleophile occurs from the
re face, yielding the corresponding 3R,4S Mannich
the sense of asymmetric induction and the degree of
diastereoselectivity depend on the protecting group.6b,6g
For this reason we also tested the addition of O-
methyl-O-trimethylsilyl dimethylketeneacetal to the N-
benzylimine 9 derived from (R)-2,3-O-isopropylidene-
glyceraldehyde.

R. Badorrey et al. / Tetrahedron Letters 44 (2003) 9189–9192
9191
Scheme 3. Asymmetric Mannich reaction of chiral imine 9 with O-methyl-O-trimethylsilyl dimethylketeneacetal and conversion
into known compound 7.
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adduct with excellent diastereoselectivity. The resulting
Mannich adducts have proven to be useful precursors
for b,b-dimethyl aspartic acid.
The synthetic methodology described here can be
extended to include silylketene acetals capable of yield-
ing b-substituted aspartic acid precursors with two
stereogenic carbon atoms. This work is now in progress
and detailed results will be published in due course.
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Acknowledgements
This work was carried out with the financial support of
the Ministerio de Ciencia y Tecnolog´ıa and FEDER
(project PPQ2001-1834).
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8. A solution of N-benzylimine 1—derived from (R)-2,3-di-
O-benzylglyceraldehyde—(570 mg, 1.58 mmol) in dry
acetonitrile (20 mL) under argon was cooled to −20°C.
ZnI2 (506 mg, 1.58 mmol) was added and the reaction
mixture was stirred for 10 min at this temperature. O-
Methyl-O-trimethylsilyl dimethylketeneacetal (330 mg,
1.9 mmol) was then added to the solution. The reaction
was stirred overnight and then quenched with a saturated
solution of NH4Cl, extracted with ether and dried over
MgSO4. The solvent was evaporated and the residue was
purified by column chromatography eluting with
ether:hexane (1:4) to afford (3R,4S)-3-benzylamino-4,5-
bis-benzyloxy-2,2-dimethylpentanoic acid methyl ester
1
(2): Colourless oil, [h]2D5 +11.5 (c 0.98, CHCl3); H NMR
(CDCl3, 300 MHz) l 1.18 (s, 3H), 1.21 (s, 3H), 1.80 (brs,
1H), 2.99 (brs, 1H), 3.48–3.60 (m, 1H), 3.55 (s, 3H),
3.62–3.70 (m, 2H), 3.67 (d, 1H, J=13.2 Hz), 3.86 (d, 1H,