Stereoselective addition of organometallic reagents to a chiral acyclic nitrone derived from L-erythrulose

Article abstract of DOI:10.1016/j.tetasy.2005.03.013

The additions of various organolithium and organomagnesium reagents to a chiral nitrone prepared from L-erythrulose took 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 acid additives: zinc bromide enhances the attack to the Si face of the C=N bond whereas diethyl aluminium chloride promotes attack to the Re face. The obtained adducts can be then 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:10.1016/j.tetasy.2005.03.013

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1807–1816
Stereoselective addition of organometallic reagents to a
chiral acyclic nitrone derived from L-erythrulose
a
a
a
b
Juan Murga,a, Raul Portoles, Eva Falomir, Miguel Carda and J. Alberto Marco
*
´
a
´
Depart. de Q. Inorganica y Organica, Univ. Jaume I, 12071 Castellon, Spain
Depart. de Q. Organica, Univ. de Valencia, 46100 Burjassot, Valencia, Spain
´
´
b
´
Received 22 February 2005; accepted 10 March 2005
Available online 14 April 2005
Abstract—The additions of various organolithium and organomagnesium reagents to a chiral nitrone prepared from L-erythrulose
took 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 acid additives: zinc bromide enhances the attack to the Si face of the C@N bond whereas
diethyl aluminium chloride promotes attack to the Re face. The obtained adducts can be then transformed into protected N-hydr-
oxy-a,a-disubstituted-a-amino acid derivatives as well as into the corresponding a,a-disubstituted a-amino acids.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
O
OBn
N
N
The addition of carbon nucleophiles to C@N bonds1,2 is
a synthetically important method of preparing many
types of biologically relevant nitrogen-containing com-
pounds, among them non-proteinogenic amino acids.
These are used, for example, in the synthesis of non-
natural peptides.3 One important class of non-proteino-
genic amino acids are a,a-disubstituted a-amino
carboxylic acids.4 Another class, also of interest as syn-
thetic targets, are N-hydroxy amino acids.5 In relation
with these synthetic goals, we reported several years
ago the stereoselective additions of organolithium re-
agents to the C@N bond of chiral E oximes 1 (P,
P0 = protecting groups),6 prepared from four-carbon
monosaccharide L-erythrulose.7 The obtained adducts
were then transformed into various a-substituted serine
derivatives (Scheme 1). As an alternative approach to
the same targets, we later reported on the stereoselective
additions of lithium and magnesium organometallics to
the C@N bond of the homochiral keto nitrone8 2, also
prepared from L-erythrulose.9
O
OP´
O
PO
PO
O
OP
2
1
Nu
Nu
HO
NHOBn
OP´
Nu
N
Nu
O
O
OP
O
Nu
NH2
HO
COOH
α-Substituted serines
Scheme 1. Nucleophillic additions to oximes 1 and nitrone 2.
2. Results and discussion
2.1. Preparation of chiral nitrone 3 and its reactions
with organometallic reagents
Even though organometallic additions to the C@N bond
of both 1 and 2 took place with good diastereoselectivity
(diastereomeric ratios, dr, were often >95:5), the overall
efficiency of the process suffered from unsatisfactory
yields in the preparation of the two chiral precursors.10
*
Corresponding author. Tel.: +34 964 728174; fax: +34 964 728214;
e-mail: jmurga@qio.uji.es
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.013

1808
J. Murga et al. / Tetrahedron: Asymmetry 16 (2005) 1807–1816
Table 1. Diastereomeric ratios (dr) in the reactions of nitrone 3 with
organomagnesium and orgamolithium reagentsa
We thus looked for another chiral nitrone, which could
not only be obtainable from L-erythrulose in good yield
but also undergo stereoselective reactions with organo-
metallic reagents. After some experimentation, we found
that the reaction of a known silylated L-erythrulose
derivative7 with N-benzyl hydroxyl amine gave rise to
nitrone 3 in good yield (Scheme 2, TPS = t-butyldiphen-
ylsilyl). Compound 3 was an oil and thus not amenable
to X-ray diffraction analysis but NOE measurements
permitted us to assign the configuration of the C@N
bond as Z.11,12
Entry Organometallic
reagent
Solvent Additive Yield %
(dr)b
1
MeMgCl
MeMgCl
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
None
None
ZnBr2
ZnBr2
63 (85:15)
65 (78:22)
72 (95:5)
2
3b
MeMgCl
MeMgCl
4
78 (88:12)
5
6b
MeMgCl
MeMgCl
Et2AlCl 69 (54:46)
Et2AlCl 66 (67:33)
7
EtMgBr
EtMgBr
None
None
ZnBr2
ZnBr2
74 (85:15)
60 (85:15)
79 (93:7)
8
9
EtMgBr
EtMgBr
10
11
12b
13
14
15b
16
17
18b
19
20
21b
22
23
24b
25
26
27b
28
29
30b
31
32
33b
34
35
36b
37
38
39b
40
41
42b
43
75 (89:11)
O
O
Bn
EtMgBr
EtMgBr
Et2AlCl 85 (47:53)
Et2AlCl 55 (65:35)
N
O
OTPS
OTPS
BnNHOH
nBuMgCl
nBuMgCl
nBuMgCl
nBuMgCl
nBuMgCl
nBuMgCl
CH2@CHMgBr
CH2@CHMgBr
CH2@CHMgBr
CH2@CHMgBr
CH2@CHMgBr
CH2@CHMgBr
CH2@CHCH2MgBr THF
CH2@CHCH2MgBr Et2O
CH2@CHCH2MgBr THF
CH2@CHCH2MgBr Et2O
CH2@CHCH2MgBr THF
CH2@CHCH2MgBr Et2O
None
None
ZnBr2
ZnBr2
75 (83:17)
65 (87:13)
75 (88:12)
72 (>95:5)
O
O
O
(78%)
3
Silylated L-erythrulose
acetonide
Et2AlCl 74 (50:50)
Et2AlCl 78 (31:69)
(Lewis acidic
additive)
RM, THF
None
None
ZnBr2
ZnBr2
75 (80:20)
63 (55:45)
80 (85:15)
80 (64:36)
R
R
N(OH)Bn
N(OH)Bn
OTPS
OTPS
O
O
O
+
O
Et2AlCl 78 (<5:95)
Et2AlCl 87 (<5:95)
4
5
None
None
ZnBr2
ZnBr2
84 (<5:95)
92 (50:50)
80 (80:20)
86 (90:10)
a R = Me
b R = Et
c R = nBu
d R = vinyl
e R = allyl f R = Ph
g R = ethynyl
Scheme 2. Preparation of 3 and its reactions with organometallic
reagents.
Et2AlCl 80 (15:85)
Et2AlCl 87 (20:80)
PhMgCl
PhMgCl
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
None
None
ZnBr2
ZnBr2
90 (>95:5)
85 (85:15)
85 (>95:5)
82 (80:20)
2.2. Determination of the configurations of the addition
products
PhMgCl
PhMgCl
PhMgCl
Et2AlCl 60 (30:70)
Et2AlCl 67 (39:61)
The reaction of nitrone 3 with several organometallic
reagents yielded mixtures of diastereoisomeric adducts
4 and 5 (see Scheme 2 and Table 1). For adducts 4a,
4c and 4f (Table 1, entries 3, 16 and 31), the configura-
tions were established by means of chemical correlations
as depicted in Scheme 3. Thus, reductive cleavage of the
N–O bond with the zinc–copper couple was followed by
acetonide hydrolysis, selective silylation of the primary
hydroxyl group and ring closure to oxazolidinones 6a,
6c and 6f. NOE measurements in the latter allowed
the establishment of the relative configurations of the
stereocentres.13 Adducts 4b and 4e (Table 1, entries 9
and 28) could be obtained as crystals amenable to
X-ray diffraction analysis.14 Where mixtures of 4 and 5
were formed, their NMR spectra were compared with
those of the pure adduct 4. Finally, the configurations
of the addition products 4d/5d or 4g/5g formed with
vinyl or ethynyl magnesium bromide, respectively, were
established by means of hydrogenation and spectral
comparison with the product mixtures 4b/5b generated
from ethyl magnesium bromide.
PhMgCl
HC„CMgBrc
HC„CMgBrc
HC„CMgBrc
HC„CMgBrc
HC„CMgBrc
HC„CMgBrc
tBuMgCl
None
None
ZnBr2
ZnBr2
82 (33:67)
90 (40:60)
80 (52:48)
85 (40:60)
Et2AlCl 75 (19:81)
Et2AlCl 80 (28:72)
THF or Noned
No reaction
Et2O
44
45
46
47b
48
49
50
MeLi
MeLi
MeLi
Et2Oe
Et2Oe
Et2Oe
Et2Oe
Et2Oe
Et2Oe
Et2Oe
None
ZnBr2
55 (13:87)
77 (10:90)
Et2AlCl 80 (13:87)
nBuLi or tBuLi
PhLi
PhLi
Nonef
None
ZnBr2
Decomp.
63 (80:20)
65 (70:30)
PhLi
Et2AlCl 92 (23:77)
a For reaction conditions, see Experimental section.
b DrÕs were measured by high-field 1H and 13C NMR. Values such as
>95:5 or <5:95 indicate that the minor stereoisomer was not detected
with this technique.
c The reaction was performed at 0 ꢁC.
d With ZnBr2 or Et2AlCl as additives, no reaction was observed, either.
e In THF, decomposition was observed.
f With ZnBr2 or Et2AlCl as additives, decomposition was observed, as
well.
2.3. Mechanistic discussion
Inspection of Table 1 clearly shows that only the Grig-
nard reagents give useful results in reactions with
nitrone 3. The addition of organolithium derivatives
(entries 44–50) not only in general gave inferior yields
but also show lower degrees of diastereoselectivity.

J. Murga et al. / Tetrahedron: Asymmetry 16 (2005) 1807–1816
1809
MLn = metal cation and its associated ligands
OMLn
#
Bn
H
#
steric
O
N
H
N
O
crowding
Me
O
Re attack
Nu
O
OTPS
Me
H
Nu
H
LnM
O
Si attack
Bn
CH2OTPS
Cram´s chelated TS
Felkin-Anh´s TS
4
5
Scheme 4. Mechanistic proposals for the reactions of keto nitrone 3
with organometallic reagents.
stereoisomer 4 was the almost exclusive adduct with
phenylmagnesium bromide, 5 was the only isomer
detected in the case of the allylmagnesium reagent.
Whether this differential behaviour of the allyl reagent
is related to a different aggregation state of the
reagent, to an intrinsic preference for a non-chelated
cyclic TS of the metallo-ene type17 or to another cause
is still unclear.
When the addition was performed in the presence of
ZnBr2 (1 equiv),5d,15d,e,h a visible increase in the propor-
tion of 4 was observed, in several cases up to syntheti-
cally useful values (entries 3, 9 and 16). As commented
above, the addition of the phenyl Grignard reagent is al-
ready very stereoselective without the Lewis acid addi-
tive (entry 31) and remains so after adding ZnBr2
(entry 33). These results may be explained if we assume
that the bidentate Lewis acid ZnBr2 binds to the sub-
strate as the chelating species (MLn = ZnBr2 in the left
TS of Scheme 4) more tightly then the magnesium cation
present in the reaction mixture.
Scheme 3. Determination of the configurations of adducts 4 and 5 via
chemical correlations and ORTEP structure of 4b.
Furthermore, the high reactivity of these reagents cause
decomposition in some cases (entry 47), most likely
because of its extreme basicity. Grignard reagents, how-
ever, display an adequate level of reactivity except in
cases of steric crowding (entry 43). The use of either
Et2O or THF as solvent gave comparable results in
broad terms, even though the latter tends to perform
somewhat better in both yield and dr. Further changes
in either of these two features were observed when the
reactions were carried out in the presence of the Lewis
acid ZnBr2 or Et2AlCl.
In contrast, the addition of Et2AlCl (1 equiv) to the
reaction mixture always caused a marked increase in
the proportion of the Felkin–Anh isomer 5. However,
the stereochemical bias imposed by this Lewis acid
was not strong enough to cause a complete reversal of
the stereoselectivity5d,15d,e,h,i except in the case of vinyl
magnesium bromide, which proved highly stereoselec-
tive in the presence of Et2AlCl (entries 23 and 24) and
yielded only 5. Results of this type have previously been
observed in the additions of organometallics to a-oxy-
genated nitrones.5d,15 In order to explain such results,
it has been proposed that Et2AlCl acts as a monodentate
Lewis acid, which coordinates only with the negatively
charged oxygen atom of the nitrone, thus leading to a
Felkin–Anh-type TS (MLn = AlClEt2 in the right part
of Scheme 4). It is worth mentioning that Evans et al.
have shown that Me2AlCl and MeAlCl2 are exceptio-
nally strong chelating species if added in an excess of
at least 2–2.5 equiv.18 However, the results presented
in Table 1 were essentially the same with either 1 or
2.5 equiv of Et2AlCl added to the reaction mixture. This
and the preferred formation of stereoisomer 5 do not
lend support to the idea that chelates are formed here
in the presence of this Lewis acid. Perhaps the negatively
Various mechanistic models have been proposed to ex-
plain the stereochemical outcome of the additions of
organometallic reagents to the C@N bond of nitrones.
In almost all cases, such reactions have been performed
on functionalized nitrones derived from aldehydes.15 As
a matter of fact, the formation of either 4 or 5 can be
rationalized within the mechanistic frame of CramÕs a-
chelated (!4) versus Felkin–AnhÕs non-chelated (!5)
transition states (TS)6a (M = Mg or Li in Scheme 4). A
b-chelated TS should also lead to stereoisomer 5. How-
ever, our experience with organometallic additions to
various types of erythrulose derivatives6a,16 has led us
to consider this mechanistic alternative less likely here
(see also below). Very variable drÕs were observed when
no Lewis acidic additive was present, with only the addi-
tions of allyl and phenyl Grignard reagents being highly
stereoselective (entries 25 and 31). Interestingly, whereas

1810
J. Murga et al. / Tetrahedron: Asymmetry 16 (2005) 1807–1816
charged oxygen atom of the nitrone displaces the chlo-
rine atom and forms a C@N+-OAlEt2 species, where
the aluminium atom is possibly not Lewis acidic enough
to coordinate with one of the ketal oxygen atoms and
close the chelate ring.
the TPS group and nucleophilic substitution of the
hydroxyl function.
3. Conclusions
2.4. Synthesis of a,a-disubstituted a-amino acids
In summary, we have investigated the additions of sev-
eral organometallic reagents to a chiral nitrone 3 derived
from L-erythrulose. Under specific reaction conditions,
these additions have turned out to be very stereoselec-
tive. The better overall yield in the preparation of the
starting nitrone has led us to prefer its use to that of
our previous chiral precursors 1 and 2. We have also
reported a convenient methodology for the synthesis
of the enantiopure form of N-hydroxy a-substituted a-
amino acids and a-substituted a-amino acids, two types
of non-proteinogenic amino acids. This method can be
further applied to the preparation of aminopolyols bear-
ing tert-alkyl amine fragments, as well as of other nitro-
genated natural products of pharmacological interest.
We have also investigated the conversion of the ob-
tained adducts into derivatives of non-proteinogenic
amino acids of the type mentioned in the introduction.
For synthetic purposes, it proved much better to quench
the reaction mixture with acetic anhydride at ꢀ78 ꢁC in-
stead of the aqueous work-up. In this way, we have ob-
tained N-acetoxy derivatives 7a, 7b, 7c, 7f and 8d, which
were more stable than their deacetylated counterparts,
as well as easier to purify by means of chromatography
(Scheme 5). Subsequent functional manipulations trans-
form 7 or 8 into the N-acetoxy a-amino esters 9 or ent-9,
which are protected forms of N-hydroxy a-substituted
a-amino acids.
The a,a-disubstituted a-amino acids themselves can also
be made available by means of this methodology, as
shown in Scheme 5 for the case of (R)-2-methylserine.
Compound 9a was first desilylated with TBAF in THF
to hydroxy ester 10 and then subjected to hydrogeno-
lysis in the presence of PearlmanÕs catalyst. This caused
both debenzylation and reductive cleavage of the N–O
bond to yield (R)-(ꢀ)-2-methyl serine methyl ester,
which was then uneventfully hydrolyzed to (R)-(ꢀ)-2-
methyl serine.6b Further amino acids with other a-sub-
stituents may also be prepared through desilylation of
4. Experimental
4.1. General
NMR spectra were measured at 400 or 500 MHz in
CDCl3 solution at 25 ꢁC. The signals of the deuterated
solvent (CDCl3) were taken as the reference (the singlet
at d 7.25 for 1H NMR and the triplet centred at
77.00 ppm for 13C NMR data). The multiplicities of
the 13C NMR signals were determined with the DEPT
pulse sequence. Mass spectra were run by the electron
impact (EIMS, 70 eV) or with the fast atom bombard-
ment mode (FABMS, m-nitrobenzyl alcohol matrix)
on a VG AutoSpec mass spectrometer. IR data are given
only for compounds with relevant functions (OH, C@O)
and were recorded as oily films on NaCl plates (oils) or
as KBr pellets (solids). Optical rotations were measured
at 25 ꢁC. Reactions which required an inert atmosphere
were carried out under N2 with flame-dried glassware.
Et2O and THF were freshly distilled from sodium-ben-
zophenone ketyl. Dichloromethane was freshly distilled
from CaH2. Commercially available reagents were used
as received. Unless detailed otherwise, Ôwork-upÕ means
pouring the reaction mixture into 5% aq NaHCO3 (if
the reaction was carried out in an acidic medium) or into
satd aq NH4Cl (if it was carried out in a basic medium),
extracting with the indicated solvent, then washing
again the organic layer with brine, drying over anhy-
drous Na2SO4 or MgSO4 and elimination of the solvent
in vacuo. When the solutions were filtered through a
Celite pad, the pad was additionally washed with the
same solvent, and the washing liquids incorporated to
the main organic layer. The obtained material was then
chromatographed on a silica gel column (60–200 l) with
the indicated eluent.
OAc
NBn
OAc
NBn
RM, -78ºC,
then quench
with Ac2O
R
or
3
O
O
O
OTPS
O
OTPS
8d
7a,b,c,f
OAc
NBn
1: H5IO6
2: NaClO2
3: CH2N2
R
OTPS
7a,b,c,f
MeO2C
9a,b,c,f
OAc
NBn
1: H5IO6
2: NaClO2
3: CH2N2
OTPS
MeO2C
8d
ent-9d
OAc
NBn
OH
OAc
NBn
OTPS
TBAF / THF
MeO2C
MeO2C
10
9a
1: H2, Pd(OH)2 (70 psi)
2: NaOH/EtOH
NH2
OH
4.2. General reaction conditions for organometallic
additions to nitrone 3 with aqueous work-up
HOOC
(R)-(-)-2-methylserine
The preparation and physical data of nitrone 3 have
been previously described.11 A solution of 3 (504 mg,
Scheme 5. Conversion of adducts into protected a-substituted
N-hydroxy a-amino acids and synthesis of R-(ꢀ)-2-methylserine.

J. Murga et al. / Tetrahedron: Asymmetry 16 (2005) 1807–1816
1811
1 mmol) in the appropriate solvent (5 mL) was cooled
under N2 to ꢀ78ꢁC and treated with the appropriate
organometal reagent (5 mmol). After stirring for 5 h at
the same temperature, the reaction mixture was
worked-up (extraction with EtOAc). The organic layers
were then dried over anhyd Na2SO4 and concentrated in
vacuo. Column chromatography of the oily residue on a
silica gel column (hexanes–EtOAc 4:1) afforded adducts
4/5 (for relative proportions and chemical yields, see
Table 1). Additions in the presence of Lewis acid addi-
tives were performed in the same way except that the
Lewis acid (1 mmol) was added to a ice-cooled solution
of 3; the solution was then stirred for 15 min and cooled
to ꢀ78 ꢁC, prior to addition of the organometal reagent.
In the case of Et2AlCl, the reactions were also per-
formed in the presence of 2.5 equiv of the Lewis acid.
The results, however, were essentially the same as with
1 equivalent of the Lewis acid. Physical and spectral
data are given hereafter for compounds, which were
only isolated in a pure state.
(125 MHz, CDCl3) d 139.6, 133.0, 132.8, 108.1, 66.2,
19.1 (C), 135.7, 135.6, 129.6, 129.5, 128.7, 128.1, 127.7,
127.6, 127.5, 126.8, 77.1 (CH), 65.6, 65.0, 57.8, 22.2
(CH2), 26.9 (·3), 26.4, 25.0, 7.8 (CH3). HR FABMS
m/z 534.3044 [M+H+], calcd for C32H44NO4Si,
534.3039. Anal. Calcd for C32H43NO4Si: C, 72.00; H,
8.12. Found, C, 72.01; H, 8.08.
4.6. (1R)-N-Benzyl-N-[1-(tert-butyldiphenylsilyloxy-
methyl)-1-(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-pentyl]-
hydroxylamine, 4c
Oil, [a]D = ꢀ4.1 (c 0.5, CHCl3); IR mmax (cmꢀ1) 3410
(br, OH); dH (500 MHz, CDCl3) 7.80–7.75 (4H, m),
7.50–7.30 (11H, m), 5.00 (1H, br s, OH), 4.68 (1H, t,
J = 7.5 Hz), 4.33 (1H, dd, J = 8, 7 Hz), 4.20
1H, d, J = 14 Hz), 4.09 (1H, dd, J = 8, 7 Hz), 4.03
(1H, d, J = 14 Hz), 4.00, 3.93 (2H, AB system,
J = 10.7 Hz), 1.75–1.65 (2H, m), 1.42 (3H, s), 1.41
(3H, s), 1.45–1.25 (4H, m), 1.13 (9H, s), 0.92 (3H, t,
J = 7.2 Hz); dC (100 MHz, CDCl3) d 139.6, 133.0,
132.8, 108.2, 66.3, 19.2 (C), 135.8, 135.7, 129.8, 129.6,
128.8, 128.3, 127.8, 127.7, 127.5, 126.8, 77.3 (CH),
65.7, 65.3, 57.9, 29.6, 25.2, 23.8 (CH2), 27.0 (·3), 26.4,
25.0, 14.2 (CH3). HR FABMS m/z 562.3364 [M+H+],
calcd for C34H48NO4Si, 562.3352.
4.3. (1R)-N-Benzyl-N-[2-(tert-butyldiphenylsilyloxy)-1-
(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-1-methylethyl]-
hydroxylamine, 4a
Oil, [a]D = +17.8 (c 0.5, CHCl3); IR mmax (cmꢀ1) 3410
(br, OH); dH (500 MHz, CDCl3) 7.85–7.80 (4H, m),
7.50–7.30 (11H, m), 5.10 (1H, br s, OH), 4.75 (1H, t,
J = 7 Hz), 4.30–4.10 (4H, m), 4.06, 3.97 (2H, AB system,
J = 11 Hz), 1.48 (3H, s), 1.44 (3H, s), 1.18 (9H, s), 1.16
(3H, s); dC (125 MHz, CDCl3) d 139.5, 133.0, 132.7,
108.4, 66.0, 19.1 (C), 135.6, 135.5, 129.6, 129.5, 128.7,
128.1, 127.7, 127.6, 127.5, 126.8, 76.1 (CH), 66.0, 65.4,
58.0 (CH2), 26.8 (·3), 26.2, 24.9, 13.7 (CH3). HR
FABMS m/z 520.2873 [M+H+], calcd for C31H42NO4Si,
520.2883.
4.7. (1S)-N-Benzyl-N-[1-(tert-butyldiphenylsilyloxy-
methyl)-1-(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-allyl]-
hydroxylamine, 5d
Oil, [a]D = ꢀ13.2 (c 1, CHCl3); IR mmax (cmꢀ1) 3410 (br,
OH); dH (400 MHz, CDCl3) 7.80–7.75 (4H, m), 7.50–
7.30 (11H, m), 6.10 (1H, dd, J = 17.7, 11.6 Hz), 5.50–
5.40 (2H, m), 4.90 (1H, br s, OH), 4.65 (1H, t,
J = 7.5 Hz), 4.18 (1H, d, J = 14 Hz), 4.15–4.05 (4H,
m), 4.03 (1H, d, J = 14 Hz), 1.43 (3H, s), 1.41 (3H, s),
1.16 (9H, s); dC (100 MHz, CDCl3) d 139.8, 133.0,
132.9, 108.6, 68.8, 19.3 (C), 135.8 (·2), 135.3, 129.9,
128.9, 128.2, 127.8, 127.7, 126.8, 77.9 (CH), 118.6,
66.2, 63.6, 58.0 (CH2), 27.0 (·3), 26.4, 25.3 (CH3). HR
FABMS m/z 532.2895 [M+H+], calcd for C32H42NO4Si,
532.2881.
4.4. (1S)-N-Benzyl-N-[2-(tert-butyldiphenylsilyloxy)-1-
(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-1-methylethyl]-
hydroxylamine, 5a
Oil, [a]D = ꢀ10.5 (c 0.9, CHCl3); IR mmax (cmꢀ1) 3410
(br, OH); dH (400 MHz, CDCl3) 7.80–7.75 (4H, m),
7.50–7.30 (11H, m), 4.60 (1H, br s, OH), 4.49 (1H, dd,
J = 8, 7 Hz), 4.15–4.05 (3H, m), 4.00 (1H, t, J = 8 Hz),
3.90, 3.87 (2H, AB system, J = 11 Hz), 1.42 (6H, s),
1.26 (3H, s), 1.17 (9H, s); dC (100 MHz, CDCl3) d
139.9, 133.2 (·2), 108.6, 65.7, 19.3 (C), 135.9, 135.8,
129.7, 129.1, 128.3, 128.2, 127.8, 127.6, 126.9, 78.5
(CH), 65.9, 65.4, 57.9 (CH2), 27.0 (·3), 26.4, 25.4, 14.2
(CH3).
4.8. (1R)-N-Benzyl-N-[1-(tert-butyldiphenylsilyloxy-
methyl)-1-(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-but-3-
enyl]-hydroxylamine, 4e
Solid, mp 66–67 ꢁC; [a]D = ꢀ0.1 (c 0.4, CHCl3); IR mmax
(cmꢀ1) 3410 (br, OH); dH (500 MHz, CDCl3) 7.80–7.75
(4H, m), 7.50–7.30 (11H, m), 6.00 (1H, m), 5.10 (1H, br
d, J = 17 Hz), 5.05 (1H, br d, J = 10 Hz), 4.80 (1H, br
s, OH), 4.67 (1H, t, J = 7.5 Hz), 4.30 (2H, m), 4.10–
4.00 (4H, m), 2.60 (1H, dd, J = 14.5, 6.5 Hz), 2.50
(1H, dd, J = 14.5, 7.5 Hz), 1.43 (3H, s), 1.39 (3H, s),
1.14 (9H, s); dC (125 MHz, CDCl3) d 139.6, 133.0,
132.8, 108.0, 65.3, 19.2 (C), 135.8, 135.7, 134.6, 129.9,
129.8, 128.8, 128.2, 127.8, 127.7, 126.8, 76.8 (CH),
117.2, 66.7, 65.6, 58.0, 33.9 (CH2), 27.0 (·3), 26.4,
25.0 (CH3). HR FABMS m/z 546.3048 [M+H+], calcd
for C33H44NO4Si, 546.3039. Anal. Calcd for
C33H43NO4Si: C, 72.62; H, 7.94. Found, C, 72.57; H,
8.08.
4.5. (1R)-N-Benzyl-N-[1-(tert-butyldiphenylsilyloxy-
methyl)-1-(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-propyl]-
hydroxylamine, 4b
Solid, mp 68–69 ꢁC; [a]D = ꢀ1.6 (c 0.5, CHCl3); IR mmax
(cmꢀ1) 3410 (br, OH); dH (500 MHz, CDCl3) 7.80–7.75
(4H, m), 7.50–7.30 (11H, m), 5.00 (1H, br s, OH), 4.73
(1H, t, J = 7.3 Hz), 4.35 (1H, t, J = 8 Hz), 4.25 (1H, d,
J = 14 Hz), 4.10 (2H, m), 4.03, 4.00 (2H, AB system,
J = 10.7 Hz), 1.90–1.75 (2H, m), 1.46 (3H, s), 1.44
(3H, s), 1.18 (9H, s), 1.02 (3H, t, J = 7.5 Hz); dC

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J. Murga et al. / Tetrahedron: Asymmetry 16 (2005) 1807–1816
4.9. (1S)-N-Benzyl-N-[1-(tert-butyldiphenylsilyloxy-
methyl)-1-(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-but-3-
enyl]-hydroxylamine, 5e
with MeOH (20 mL) and treated carefully with solid
Na2CO3 until evolution of CO2 ceased. The reaction
mixture was then filtered through Celite, evaporated in
vacuo and chromatographed on silica gel (hexanes–
EtOAc 1:1) to afford the corresponding aminopolyol.
Chemical yields: 80% (R = Me), 82% (R = nBu), 85%
(R = Ph).
Oil, [a]D = ꢀ4.3 (c 0.9, CHCl3); IR mmax (cmꢀ1) 3410
(br, OH); dH (500 MHz, CDCl3) 7.80–7.75 (4H, m),
7.50–7.30 (11H, m), 6.03 (1H, m), 5.15 (1H, br d,
J = 17 Hz), 5.09 (1H, br d, J = 10 Hz), 4.80 (1H, br s,
OH), 4.50 (1H, t, J = 7.5 Hz), 4.16 (2H, m), 4.07-4.00
(3H, m), 3.90 (1H, d, J = 10.5 Hz), 2.65 (2H, br d,
J = 7 Hz), 1.39 (3H, s), 1.37 (3H, s), 1.12 (9H, s); dC
(125 MHz, CDCl3) d 139.6, 133.0, 132.8, 107.9, 63.8,
19.2 (C), 135.8, 135.7, 134.8, 129.8, 128.9 128.2, 127.8,
127.7, 126.8, 77.7 (CH), 117.3, 67.1, 65.8, 57.8, 34.6
(CH2), 27.0 (·3), 26.4, 25.0 (CH3).
4.11.3. Selective silylation. A solution of the amino
alcohol from above, triethyl amine (182 lL, 1.3 mmol)
and N,N-dimethylaminopyridine (6 mg, 0.05 mmol) in
dry CH2Cl2 (3 mL) was treated dropwise under an inert
atmosphere with TPS chloride (260 lL, 1 mmol). The
reaction mixture was stirred overnight at room temper-
ature and worked-up (extraction with CH2Cl2). Column
chromatography on silica gel (hexanes–EtOAc 9:1) gave
rise to the desired silyl derivative. Chemical yields: 66%
(R = Me), 72% (R = nBu), 65% (R = Ph).
4.10. (1R)-N-Benzyl-N-[2-(tert-butyldiphenylsilyloxy)-1-
(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-1-phenylethyl]-
hydroxylamine, 4f
4.11.4. Oxazolidinone formation. The silylated com-
pound from above was dissolved under an inert atmo-
sphere in dry CH2Cl2 (4 mL) and treated sequentially
with triethyl amine (280 lL, 2 mmol) and triphosgene
(296 mg, 1 mmol). The reaction mixture was then stirred
at room temperature for 2 d. Work-up (extraction with
CH2Cl2) followed by column chromatography on silica
gel (hexanes–EtOAc 9:1) yielded the desired oxazolid-
inones 6. Chemical yields: 6a, 73%; 6c, 78%; 6f, 70%.
Solid, mp 53–54 ꢁC, [a]D = +4.2 (c 0.6, CHCl3); IR mmax
(cmꢀ1) 3410 (br, OH); dH (500 MHz, CDCl3) 7.80–7.75
(4H, m), 7.50–7.40 (12H, m), 7.30–7.20 (4H, m), 6.10
(1H, br s, OH), 5.20 (1H, t, J = 7 Hz), 4.80 (1H, d,
J = 10.6 Hz), 4.39 (1H, d, J = 10.6 Hz), 4.20–4.05 (4H,
m), 1.36 (3H, s), 1.10 (9H, s), 0.80 (3H, s); dC
(125 MHz, CDCl3) d 138.9, 138.2, 132.4, 132.1, 108.8,
69.3, 19.2 (C), 135.8, 135.7, 130.0, 129.9, 129.8, 128.8,
128.2, 127.8, 127.7, 126.9, 76.1 (CH), 66.6, 65.6, 58.5
(CH2), 27.0 (·3), 25.6 (·2) (CH3). HR FABMS m/z
582.3032 [M+H+], calcd for C36H44NO4Si, 582.3039.
Anal. Calcd for C36H43NO4Si: C, 74.32; H, 7.45. Found,
C, 74.37; H, 7.59.
4.12. (4R,5R)-3-Benzyl-4,5-bis-(tert-butyldiphenylsilyl-
oxymethyl)-4-methyloxazolidin-2-one, 6a
Oil, [a]D = ꢀ43 (c 0.3, CHCl3); IR mmax (cmꢀ1) 1756
(C@O); dH (400 MHz, CDCl3) 7.70–7.65 (6H, m), 7.55
(2H, m), 7.50–7.35 (12H, m), 7.25 (3H, m), 7.15 (2H,
m), 4.58 (1H, d, J = 16 Hz), 4.28 (1H, t, J = 6 Hz),
4.18 (2H, m), 3.75 (1H, d, J = 11.5 Hz), 3.60 (1H, d,
J = 11.5 Hz), 3.48 (1H, d, J = 16 Hz), 1.07 (9H, s),
1.04 (9H, s), 0.95 (3H, s); dC (100 MHz, CDCl3) d
158.3, 133.0, 132.8, 132.6, 132.3, 63.9, 19.1, 19.0 (C),
136.1, 135.8, 135.5, 130.2, 130.0, 128.4, 128.0, 127.9,
127.8, 127.5, 127.3, 82.9 (CH), 63.4, 61.9, 44.1 (CH2),
26.9 (·3), 26.8 (·3), 21.8 (CH3). HR FABMS m/z
728.3623 [M+H+], calcd for C45H54NO4Si2, 728.3591.
4.11. Determination of the configurations of adducts
4 via chemical correlations
4.11.1. Reductive cleavage of the N–O bond. Activated
Zn powder (654 mg, 10 mmol) was added under an inert
atmosphere to
a solution of Cu(OAc)2 (36 mg,
0.2 mmol) in acetic acid (3 mL). The mixture was then
stirred at room temperature for 15 min followed by
the addition of a solution of adduct 4 (2 mmol) in acetic
acid (3 mL). The reaction mixture was stirred at 70 ꢁC
(bath temp) for 35 min. After this time, the mixture
was cooled to room temperature and treated with tetra-
sodium ethylendiamintetraacetate (Na4EDTA, 2 g,
5.3 mmol) followed by stirring for 10 min. The solution
was then treated with 3 M NaOH until its pH value was
above 10, followed by a threefold extraction with
EtOAc. The organic layers were washed once again with
Na4EDTA and brine, dried over anhyd Na2SO4, filtered
and concentrated in vacuo. The oily residue was sub-
jected to column chromatography on silica gel (hex-
anes–EtOAc 9:1) to yield the corresponding tert-alkyl
N-benzylamine. Chemical yields: 70% (R = Me), 69%
(R = nBu), 72% (R = Ph).
4.13. (4R,5R)-3-Benzyl-4-butyl-4,5-bis-(tert-butyldiphen-
ylsilyloxymethyl)-oxazolidin-2-one, 6c
Oil, [a]D = ꢀ14.6 (c 0.2, CHCl3); IR mmax (cmꢀ1) 1755
(C@O); dH (400 MHz, CDCl3) 7.70–7.65 (6H, m), 7.55
(2H, m), 7.50–7.35 (12H, m), 7.25 (3H, m), 7.15 (2H,
m), 4.50 (1H, d, J = 15.7 Hz), 4.32 (1H, t, J = 6 Hz),
4.13 (1H, dd, J = 11.3, 6 Hz), 4.08 (1H, dd, J = 11.3,
6 Hz), 3.72 (1H, d, J = 11.5 Hz), 3.59 (1H, d,
J = 11.5 Hz), 3.49 (1H, d, J = 15.7 Hz), 1.25 (2H, m),
1.04 (9H, s), 1.01 (9H, s), 1.00–0.70 (4H, m), 0.60 (3H,
t, J = 6.5 Hz); dC (100 MHz, CDCl3) d 158.8, 133.0,
132.8, 132.6, 132.3, 66.6, 19.1, 19.0 (C), 136.1, 135.8,
135.5, 130.2, 130.0, 128.4, 128.0, 127.9, 127.8, 127.5,
127.3, 79.5 (CH), 63.5, 62.5, 44.5, 33.3, 24.7, 22.7
(CH2), 26.9 (·3), 26.8 (·3), 13.6 (CH3). HR FABMS
m/z 770.4094 [M+H+], calcd for C48H60NO4Si2,
770.4060.
4.11.2. Acetonide hydrolysis. The product from the
previous reaction was dissolved in MeOH (10 mL),
and treated with 2 M HCl (10 mL). The mixture was
then heated at reflux for 30 min and then for a further
30 min at room temperature, after which it was diluted

J. Murga et al. / Tetrahedron: Asymmetry 16 (2005) 1807–1816
1813
4.14. (4R,5R)-3-Benzyl-4,5-bis-(tert-butyldiphenylsilyl-
oxymethyl)-4-phenyloxazolidin-2-one, 6f
4.18. (1R)-N-Acetoxy-N-benzyl-N-[1-(tert-butyldiphen-
ylsilyloxymethyl)-1-(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-
pentyl]amine, 7c
Oil, [a]D = ꢀ7.5 (c 0.3, CHCl3); IR mmax (cmꢀ1) 1756
(C@O); dH (500 MHz, CDCl3) 7.65 (2H, m), 7.55 (2H,
m), 7.45 (2H, m), 7.45–7.30 (16H, m), 7.20–7.10 (5H,
m), 7.00 (3H, m), 4.50 (3H, m), 4.19 (1H, d,
J = 11 Hz), 4.10 (2H, m), 3.59 (1H, d, J = 15.5 Hz),
Oil, [a]D = +7.5 (c 1.3, CHCl3); IR mmax (cmꢀ1) 1769
(C@O); dH (500 MHz, CDCl3) 7.75–7.70 (4H, m),
7.50–7.25 (11H, m), 4.58 (1H, t, J = 7.5 Hz), 4.44 (1H,
br d, J = 14.4 Hz), 4.18 (1H, br d, J = 14.4 Hz), 4.04
(2H, m), 3.95 (1H, dd, J = 8, 7.5 Hz), 3.77 (1H, d,
J = 11 Hz), 1.85 (1H, m), 1.59 (3H, s), 1.55–1.45 (3H,
m), 1.33 (3H, s), 1.29 (3H, s), 1.30–1.20 (2H, m), 1.09
(9H, s), 0.88 (3H, t, J = 7.2 Hz); dC (125 MHz, CDCl3)
d 169.5 (br), 137.7, 133.1, 133.0, 108.3, 68.0, 19.3 (C),
135.9, 135.8, 129.9, 129.8, 129.4, 128.1, 127.9, 127.7,
127.3, 77.7 (CH), 65.6, 63.5, 58.0, 30.2, 24.9, 23.7
(CH2), 27.0 (·3), 26.4, 24.8, 19.0, 13.9 (CH3). HR
FABMS m/z 604.3438 [M+H+], calcd for C36H50NO5Si,
604.3458.
1.02 (9H, s), 0.87 (9H, s); d
(125 MHz, CDCl3) d
C
158.9, 138.6, 137.5, 132.7, 132.6, 132.4, 132.1, 69.1,
19.0 (·2) (C), 136.2, 135.8, 130.2, 129.9, 129.8, 128.8,
128.2, 127.8, 127.7, 126.9, 84.5 (CH), 62.0, 61.9, 45.7
(CH2), 26.8 (·3), 26.6 (·3) (CH3). HR FABMS m/z
790.3745 [M+H+], calcd for C50H56NO4Si2, 790.3748.
4.15. General reaction conditions for organometallic
additions to nitrone 3 with acetylation quench
For the preparation of amino acid derivatives, the reac-
tion was performed as described in Paragraph 4.2 except
that acetic anhydride (190 lL, 2 mmol) was added at
ꢀ78 ꢁC to the reaction mixture. The cooling bath was
removed and the mixture stirred for 30 min at room
temperature. After quenching with satd aq NH4Cl
(2 mL), the reaction mixture was stirred for a further
15 min, poured into brine, worked-up and chromato-
graphed on silica gel (hexanes–EtOAc 9:1). Chemical
yields: 7a, 74%; 7b, 70%; 7c, 80%; 7f, 96%; 8d, 65%.
4.19. (1R)-N-Acetoxy-N-Benzyl-N-[2-(tert-butyldiphen-
ylsilyloxy)-1-(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-1-phen-
ylethyl]amine, 7f
Solid, 104–105 ꢁC, [a]D = +0.2 (c 0.6, CHCl3); IR mmax
(cmꢀ1) 1767 (C@O); dH (500 MHz, CDCl3) 7.80–7.75
(6H, m), 7.50–7.20 (14H, m), 4.79 (2H, m), 4.30 (1H,
d, J = 15 Hz), 4.26 (1H, d, J = 11.7 Hz), 4.18 (1H, d,
J = 15 Hz), 3.62 (1H, m), 3.42 (1H, m), 1.75 (3H, s),
1.22 (3H, s), 1.10 (9H, s), 1.08 (3H, s); dC (125 MHz,
CDCl3) d 169.4 (br), 138.1, 137.9, 133.0, 132.9, 109.2,
71.6, 19.2 (C), 135.9, 135.8, 129.9, 129.8, 128.7, 128.4,
128.0, 127.9, 127.7, 127.0, 79.9 (CH), 66.4, 61.4, 58.5
(CH2), 27.0 (·3), 25.9, 24.9, 19.1 (CH3). HR FABMS
m/z 624.3169 [M+H+], calcd for C38H46NO5Si,
624.3145. Anal. Calcd for C38H45NO5Si: C, 73.16; H,
7.27. Found, C, 73.30; H, 7.39.
4.16. (1R)-N-Acetoxy-N-benzyl-N-[2-(tert-butyldiphenyl-
silyloxy)-1-(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-1-methyl-
ethyl]amine, 7a
Oil, [a]D = +10.5 (c 5.7, CHCl3); IR mmax (cmꢀ1) 1765
(C@O); dH (500 MHz, CDCl3) 7.80–7.75 (4H, m),
7.50–7.25 (11H, m), 4.44 (1H, br d, J = 14 Hz), 4.35–
4.30 (2H, m), 4.21 (1H, br t, J = 7.5 Hz), 4.06 (1H, dd,
J = 8.5, 7 Hz), 4.00 (1H, m), 3.91 (1H, m), 1.70 (3H,
s), 1.40 (3H, s), 1.31 (3H, s), 1.18 (3H, s), 1.12 (9H, s);
dC (125 MHz, CDCl3) d 169.6 (br), 137.6, 133.2, 133.1,
108.8, 67.1, 19.3 (C), 135.9, 135.7, 129.8, 129.7, 129.4,
128.1, 127.7, 127.6, 127.3, 75.9 (CH), 65.7, 64.9, 58.3
(CH2), 26.9 (·3), 26.2, 24.8, 19.0, 14.3 (CH3). HR
FABMS m/z 562.3006 [M+H+], calcd for C33H44NO5Si,
562.2989.
4.20. (1S)-N-Acetoxy-N-Benzyl-N-[1-(tert-butyldiphenyl-
silyloxymethyl)-1-(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-
allyl]amine, 8d
Oil, [a]D = ꢀ17.4 (c 0.3, CHCl3); IR mmax (cmꢀ1) 1766
(C@O); dH (500 MHz, CDCl3) 7.70–7.65 (4H, m),
7.50–7.20 (11H, m), 6.05 (1H, dd, J = 18, 11.2 Hz),
5.45–5.40 (2H, m), 4.15 (1H, m), 4.10–3.90 (6H, m),
1.60 (3H, s), 1.31 (3H, s), 1.28 (3H, s), 1.09 (9H, s); dC
(125 MHz, CDCl3) d 169.5 (br), 137.5, 134.6, 132.9,
132.8, 108.6, 70.0, 19.3 (C), 135.9, 135.8, 130.0, 129.8,
129.5, 128.0, 127.9, 127.7, 127.4, 77.5 (CH), 119.1,
66.0, 63.4, 58.2 (CH2), 27.0 (·3), 26.2, 24.8, 19.2
(CH3). HR FABMS m/z 574.2975 [M+H+], calcd for
C34H44NO5Si, 574.2989.
4.17. (1R)-N-Acetoxy-N-benzyl-N-[1-(tert-butyldiphenyl-
silyloxymethyl)-1-(2,2-dimethyl-[1,3]dioxolan-4(R)-yl)-
propyl]amine, 7b
Oil; [a]D = +9.7 (c 1.1, CHCl3); IR mmax (cmꢀ1) 1766
(C@O); dH (400 MHz, CDCl3) 7.75–7.65 (4H, m),
7.45–7.20 (11H, m), 4.59 (1H, t, J = 7.5 Hz), 4.43
(1H, br d, J = 14 Hz), 4.16 (1H, d, J = 14 Hz), 4.05–
3.95 (3H, m), 3.77 (1H, d, J = 11 Hz), 1.90 (1H, m),
1.61 (3H, s), 1.60 (1H, m), 1.34 (3H, s), 1.30 (3H, s),
1.09 (9H, s), 1.00 (3H, t, J = 7.5 Hz); dC (100 MHz,
CDCl3) d 169.5 (br), 137.6, 133.0, 132.9, 108.3, 67.8,
19.3 (C), 135.8, 135.7, 129.9, 129.8, 129.4, 128.1,
127.8, 127.7, 127.3, 77.3 (CH), 65.5, 63.3, 57.9, 23.0
(CH2), 27.0 (·3), 26.4, 24.9, 19.1, 7.7 (CH3). HR
FABMS m/z 576.3133 [M+H+], calcd for C34H46NO5Si,
576.3145.
4.21. General procedure for the conversion of adducts 7
and 8 into N-hydroxy a,a-disubstituted amino acid
derivatives 9 and ent-9
Compound 7 or 8 (1.5 mmol) was dissolved in Et2O
(10 mL)19 and treated with H5IO6 (800 mg, ca.
3.5 mmol). The reaction mixture was stirred under Ar
at room temperature until consumption of the starting
material (ca. 4 h, TLC monitoring). After this time,
the mixture was filtered through a pad of Celite. The

1814
J. Murga et al. / Tetrahedron: Asymmetry 16 (2005) 1807–1816
organic layers were then concentrated in vacuo to yield a
crude aldehyde, which was used directly in the next
reaction.
135.7, 129.9, 129.8, 129.5, 128.1, 127.9, 127.7, 127.5
(CH), 63.1, 58.0, 31.0, 25.4, 23.3 (CH2), 51.7, 27.0
(·3), 18.7, 14.0 (CH3). HR FABMS m/z 562.2998
[M+H+], calcd for C33H44NO5Si, 562.2988.
The crude product of the previous reaction was dis-
solved in acetonitrile (5 mL) and treated dropwise with
an aqueous solution of NaClO2 (2.5 mmol). The mixture
was cooled in an ice bath and treated with a phosphate
buffer solution (prepared dissolving 50 mg of NaH2 PO4
in 2 mL of water) and 30% aqueous hydrogen peroxide
(0.2 mL, 1.75 mmol). The reaction mixture was then stir-
red for 4 h while maintaining the temperature below
10 ꢁC. After this time, sodium sulfite (15 mg, 0.12 mmol)
was added, followed by 10% aqueous HCl until a
pH ꢁ 3. The reaction mixture was then extracted with
CH2Cl2, and the organic layer dried over anhyd Na2SO4
and concentrated in vacuo to yield a crude carboxylic
acid, which was dissolved in Et2O and treated with ex-
cess diazomethane. Elimination of all volatiles in vacuo
and column chromatography of the residue on silica gel
(elution with hexanes–EtOAc 9:1) afforded the protected
N-hydroxy aminoester 9. Overall chemical yields: 9a,
70%; 9b, 62%; 9c, 63%; 9f, 60%; ent-9d, 60%.
4.25. Methyl (2R)-2-(N-acetoxy-N-benzylamino)-3-(tert-
butyldiphenylsilyloxy)-2-phenylpropionate, 9f
Oil, [a]D = +12.3 (c 1.3, CHCl3); IR mmax (cmꢀ1) 1770,
1731 (C@O); dH (400 MHz, CDCl3) 7.65–7.55 (4H, m),
7.45–7.20 (16H, m), 4.48 (1H, d, J = 10 Hz), 4.29 (1H,
d, J = 14.5 Hz), 4.24 (1H, br d, J = 10 Hz), 4.17 (1H,
br d, J = 14.5 Hz), 3.83 (3H, s), 1.54 (3H, s), 0.97 (9H,
s); dC (100 MHz, CDCl3) d 170.0, 169.4 (br), 137.6,
137.1, 133.0, 132.9, 78.1, 19.2 (C), 135.7, 135.6, 129.9,
129.8, 128.7, 128.4, 128.0, 127.9, 127.7, 127.0 (CH),
67.1, 58.6 (CH2), 51.8, 26.8 (·3), 18.7 (CH3). HR
FABMS m/z 582.2672 [M+H+], calcd for C35H40NO5Si,
582.2676.
4.26. Methyl (2S)-2-(N-acetoxy-N-benzylamino)-2-(tert-
butyldiphenylsilyloxymethyl)-but-3-enoate, ent-9d
Oil, [a]D = +0.7 (c 0.2, CHCl3); IR mmax (cmꢀ1) 1763,
1740 (C@O); dH (500 MHz, CDCl3) 7.70–7.65 (4H, m),
7.50–7.20 (11H, m), 6.15 (1H, dd, J = 17.7, 11.2 Hz),
5.50 (1H, br d, J = 17.7 Hz), 5.43 (1H, br d,
J = 11.2 Hz), 4.29 (1H, d, J = 14 Hz), 4.20 (1H, br d,
J = 10 Hz), 4.15 (1H, br d, J = 14 Hz), 4.04 (1H, d,
J = 10 Hz), 3.76 (3H, s), 1.63 (3H, s), 1.02 (9H, s); dC
(125 MHz, CDCl3) d 170.1, 169.0 (br), 136.8, 133.0,
132.9, 75.8, 19.3 (C), 135.8, 135.7, 134.2, 129.8, 129.6,
128.2, 127.7, 127.5 (CH), 119.3, 66.3, 58.6 (CH2), 52.0,
26.8 (·3), 18.9 (CH3). HR FABMS m/z 532.2532
[M+H+], calcd for C31H38NO5Si, 532.2519.
4.22. Methyl (2R)-2-(N-acetoxy-N-benzylamino)-3-(tert-
butyldiphenylsilyloxy)-2-methylpropionate, 9a
Oil, [a]D = ꢀ2 (c 0.4, CHCl3); IR mmax (cmꢀ1) 1774, 1742
(C@O); dH (400 MHz, CDCl3) 7.65 (4H, m), 7.50–7.25
(11H, m), 4.21 (1H, d, J = 13.8 Hz), 4.11 (1H, d,
J = 9.7 Hz), 4.02 (1H, br d, J = 13.8 Hz), 3.78 (1H, d,
J = 9.7 Hz), 3.75 (3H, s), 1.64 (3H, s), 1.56 (3H, s),
1.04 (9H, s); dC (100 MHz, CDCl3) d 171.5, 169.6 (br),
136.4, 132.9, 132.8, 72.1, 19.2 (C), 135.7, 135.6, 129.8,
129.7, 128.1, 127.7, 127.6, 127.5 (CH), 66.9, 58.2
(CH2), 52.0, 26.8 (·3), 18.7, 17.3 (CH3). HR FABMS
m/z 520.2507 [M+H+], calcd for C30H38NO5Si,
520.2519.
4.27. Conversion of 9a into (R)-(ꢀ)-2-methylserine
Compound 9a (230 mg, 0.6 mmol) was dissolved in dry
THF (5 mL) and treated with tetra-n-butylammonium
fluoride trihydrate (189 mg, 0.6 mmol). The reaction
mixture was then stirred under Ar for 1 h. After this
time, the reaction mixture was quenched into satd aq
NH4Cl (10 mL), stirred for 5 min and extracted with
CH2Cl2. The organic layer was dried over anhyd
Na2SO4, evaporated in vacuo and chromatographed
on silica gel (elution with hexanes–EtOAc 7:3) to yield
b-hydroxy ester 10 (160 mg, 87%): oil, dH (500 MHz,
CDCl3) 7.30–7.25 (5H, m), 5.70 (1H, br s, OH), 4.78
(1H, d, J = 11.5 Hz), 4.22 (1H, d, J = 11.5 Hz), 4.01
(2H, AB system, J = 14 Hz), 3.79 (3H, s), 2.12 (3H, s),
1.45 (3H, s); dC (125 MHz, CDCl3) d 172.2, 171.5,
138.8, 69.1 (C), 128.5, 128.2, 127.0 (CH), 66.1, 56.8
(CH2), 52.0, 20.9, 17.8 (CH3).
4.23. Methyl (2R)-2-(N-acetoxy-N-benzylamino)-2-(tert-
butyldiphenylsilyloxymethyl)butyrate, 9b
Oil; [a]D = ꢀ4.3 (c 1.5, CHCl3); IR mmax (cmꢀ1) 1769,
1732 (C@O); dH (400 MHz, CDCl3) 7.70–7.65 (4H, m),
7.45–7.20 (11H, m), 4.29 (1H, d, J = 14 Hz), 4.10–4.00
(3H, m), 3.72 (3H, s), 2.15–1.95 (2H, m), 1.61 (3H, s),
1.06 (9H, s), 0.97 (3H, t, J = 7.4 Hz); dC (100 MHz,
CDCl3) d 171.5, 169.5 (br), 136.8, 132.9, 132.8, 74.4,
19.3 (C), 135.7, 135.6, 129.8, 129.7, 129.5, 128.1, 127.7,
127.6, 127.4 (CH), 62.6, 58.0, 24.1 (CH2), 51.8, 26.8
(·3), 18.7, 8.0 (CH3). HR FABMS m/z 534.2683
[M+H+], calcd for C31H40NO5Si, 534.2675.
4.24. Methyl (2R)-2-(N-acetoxy-N-benzylamino)-2-(tert-
butyldiphenylsilyloxymethyl)hexanoate, 9c
Compound 10 obtained above and PearlmanÕs catalyst
(31 mg) were dissolved in MeOH (10 mL) and stirred
at room temperature under an H2 atmosphere (70 psi)
for 5 d. The mixture was then filtered, concentrated in
vacuo, dissolved in EtOH (5 mL) and treated with an
aqueous solution of NaOH 2 M (5 mL). The mixture
was then stirred at room temperature for 1 h. The pH
value was then adjusted to 1 by adding 1 M HCl. After
Oil, [a]D = ꢀ3.6 (c 0.4, CHCl3); IR mmax (cmꢀ1) 1775,
1734 (C@O); dH (500 MHz, CDCl3) 7.70–7.65 (4H, m),
7.45–7.20 (11H, m), 4.30 (1H, d, J = 14 Hz), 4.10–4.00
(3H, m), 3.71 (3H, s), 2.10–1.90 (2H, m), 1.61 (3H, s),
1.45 (1H, m), 1.35–1.20 (3H, m), 1.07 (9H, s), 0.90
(3H, t, J = 7.4 Hz); dC (125 MHz, CDCl3) d 171.5,
169.5 (br), 136.9, 133.1, 133.0, 74.3, 19.3 (C), 135.8,

J. Murga et al. / Tetrahedron: Asymmetry 16 (2005) 1807–1816
1815
´
M.; Rodrıguez, S.; Murga, J.; Falomir, E.; Marco, J. A.;
Ro¨per, H. Synth. Commun. 1999, 29, 2601–2610.
8. (a) Torssell, K. B. G. Nitrile Oxides, Nitrones and
Nitronates in Organic Synthesis; VCH, 1988; (b) Conf-
alone, P. N.; Huie, E. M. Org. React. 1988, 36, 1–173; (c)
Lombardo, M.; Trombini, C. Synthesis 2000, 759–
774.
solvent removal, the remaining residue was purified via
ion interchange chromatography with Dowex 50WX8-
400 (the resin was previously washed with water, 1 M
HCl and again with water until neutral pH). R-(ꢀ)-2-
methylserine (40 mg, 64% overall yield)6b was eluted
with aqueous ammonia, first 0.02 M and then 0.1 M.
´
9. Marco, J. A.; Carda, M.; Murga, J.; Portoles, R.; Falomir,
E.; Lex, J. Tetrahedron Lett. 1998, 3237–3240; 1,3-Dipolar
cycloadditions of this nitrone have also been investigated:
Acknowledgements
´
Carda, M.; Portoles, R.; Murga, J.; Uriel, S.; Marco, J. A.;
Domingo, L. R.; Zaragoza, R. J.; Roeper, H. J. Org.
´
Financial support has been granted by the Spanish Min-
istry of Science and Technology (project BQU2002-
00468), by the BANCAJA-UJI foundation (Project
PI-1B2002-06), and by the AVCyT (Project Grupos03/
180). One of the authors (J.M.) thanks the Spanish Min-
Chem. 2000, 65, 7000–7009.
10. Oximes 1 were obtained as E/Z mixtures,6 from which
only the E isomers showed a good stereoselectivity.
Nitrone 2 was obtained together with a structurally
close dioxazine,9 which was unreactive towards
organometallics.
´
istry of Science and Technology for a Ramon y Cajal
11. A distinct NOE was detected between the N-benzyl
hydrogens and the methylene protons of the CH2OTPS
group. For a preliminary account of the results described
fellowship. The authors also thank Dr. Harald Roeper,
Cargill TDC Food Europe, Cerestar Vilvoorde R&D
Centre, Belgium, for his very generous gift of L-
erythrulose.
´
here, see: Portoles, R.; Murga, J.; Falomir, E.; Carda, M.;
Uriel, S.; Marco, J. A. Synlett 2002, 711–714.
12. 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 over 3 kcal/mol. This indicates that the
formation of the Z-nitrone is subject 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).
13. An exception was oxazolidinone 6f, where unequivocal
NOE measurements were not possible due to overlapping
of the key signals. In this case, however, the configuration
was unequivocally determined by means of X-ray diffrac-
tion analysis of product 7f.
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