Diastereoselectivity of the reactions of organolithium reagents with protected erythrulose oximes

Article abstract of DOI:10.1016/S0957-4166(98)00145-1

The addition of organolithium reagents to the C=N bond of several erythrulose-derived chiral (E)- and (Z)-ketoxime ethers has been shown to be highly diastereoselective in the case of the (E)-isomers. Chelated and nonchelated transition states have been proposed to rationalize these results, with additional support of computational methods.

Full text of DOI:10.1016/S0957-4166(98)00145-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1679–1701
Diastereoselectivity of the reactions of organolithium reagents
with protected erythrulose oximes
J. A. Marco,a,∗ M. Carda,b,∗ J. Murga,b S. Rodríguez,b E. Falomir b and M. Olivac
aDepart. de Q. Orgánica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
bDepart. de Q. Inorgánica y Orgánica, Univ. Jaume I, Castellón, E-12080 Castellón, Spain
cDepart. de Ciencias Experimentales, Univ. Jaume I, Castellón, E-12080 Castellón, Spain
Received 3 March 1998; accepted 7 April 1998
Abstract
The addition of organolithium reagents to the C_N bond of several erythrulose-derived chiral (E)- and
(Z)-ketoxime ethers has been shown to be highly diastereoselective in the case of the (E)-isomers. Chelated
and nonchelated transition states have been proposed to rationalize these results, with additional support of
computational methods. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The addition of carbon nucleophiles to C_N bonds1 is a synthetically important method of prepar-
ing many types of nitrogen-containing compounds of biological importance. Among these, the non-
proteinaceous amino acids are particularly worth mentioning. This class of amino acids, which are used,
for example, for the synthesis of modified peptides,2 comprises a variety of structural types, one of them
being the α,α-disubstituted α-amino carboxylic acids.3 The latter are characterized by a quaternary
carbon atom, to which the carboxyl function, the amino group and two alkyl/aryl residues are bonded.
There are few methods for preparing such compounds in enantiopure form. Most of them rely on the
alkylation of amino acid enolate anion equivalents.3 This fact places some limits on their applicability,
as certain α-amino acids such as those with α-tert-alkyl or α-aryl substituents cannot be easily, if at
all, prepared in this way. In contrast, there are fewer alternative synthetic methods based on nucleophilic
alkylation of amino acid enolate cation equivalents. Indeed, reports on diastereoselective nucleophilic
additions to the C_N bond of chiral ketone imino derivatives are not frequent in the literature and usually
involve reduction processes.4 Diastereoselective additions of carbon nucleophiles have been investigated
in a limited number of cases.5–7
∗
Corresponding authors. E-mail: alberto.marco@uv.es
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00145-1

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(1)
We have previously reported on the diastereoselective addition of organometallic reagents to the C_O
bond of O-protected L-erythrulose derivatives 1a–d.8 Through reaction with O-benzyl hydroxylamine,
these four ketones have now been converted into E/Z mixtures of the corresponding ketoxime ethers
2a–d (Eq. 1), which were then separated into pure geometric isomers by column chromatography.
These oximes were at least 98% enantiomerically pure, as confirmed by NMR analysis of their Mosher
derivatives.9 The configurational assignments of the C_N bond were based on 1H and 13C NMR data,10
and supported by NOE measurements.
We now report that additions of organolithium reagents to the C_N bond of chiral ketoxime ethers (E)-
and (Z)-2a–d often take place with high stereocontrol to yield the differentially protected, stereoisomeric
amino polyols 3/4 (Eqs 2 and 3).11a The results are presented in Tables 1 and 2. As shown in the following
article,11b these amino alcohols can be subsequently converted into enantiopure α,α-disubstituted α-
amino acids, including those not easily available by previous methodologies.
(2)
(3)
2. Results and discussion
In our initial report,11a we used oximes 2a/2b, which bear a t-butyldiphenylsilyl (TPS) group bonded
to the hydroxyl at C-1. In search of an alternative and less expensive protecting group, we have also tested
the reactivity of the structurally analogous oximes 2c/2d, in which a trityl moiety replaces the TPS group.
As shown by Tables 1 and 2, the trityl group provides essentially the same results as the similarly bulky
TPS group, with the added advantage of its introduction requiring a cheaper reagent.12 We have also
investigated oximes with a 1-O-t-butyldimethylsilyl (TBS) group but its results were inferior to those of
the other protecting groups (lower stereoselectivity) and are thus not reported here.
Nucleophilic additions to C_N bonds face some difficulties when compared with additions to the
related C_O bond. The less polar imino group has a comparatively low reactivity and it often happens
that side reactions, such as deprotonation or reduction, take precedence over the desired nucleophilic
addition.1,5 In fact, ketoximes 2a–d were not very reactive, a circumstance most likely due to steric
hindrance to the approach of nucleophiles to the imino carbon atom. Many types of organometallic
reagents were essayed on the compounds under study and found to be unreactive. Only organolithium

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Table 1
Stereoisomer distribution in additions of organolithium reagents to oximes 2a/2ba
derivatives eventually met with success. In almost all cases where these reagents were used, an addition
took place with subsequent formation of N-tert-alkyl O-benzyl hydroxyl amines 3/4. The main exceptions
were reactions involving t-butyllithium (entries 9–12 in both tables), which usually led to decomposition.
It is not known whether this lack of success is due to steric hindrance to the approach of the reagent
to the C_N bond, to competitive deprotonation of the oxime by the highly basic reagent or to some
type of retroaldol-like process. Only oximes (E)-2a and (E)-2c (entry 9 in both Tables) reacted with the
aforementioned reagent with a fair yield and an excellent diastereoisomeric ratio (d.r.). In any case, this
represents an interesting result, as these reactions give rise to the appendage of a bulky tert-alkyl group
to a crowded tertiary position. The reactions involving phenyllithium (entries 13–16) are also interesting
as they open the possibility of synthesizing enantiopure α-aryl-α-alkyl-α-amino acids.

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Table 2
Stereoisomer distribution in additions of organolithium reagents to oximes 2c/2da
In addition to these positive results, we have observed some negative findings which are also worth
mentioning. For instance, aside from the aforementioned organolithium reagents we have essayed
chloromethyllithium, generated from chloroiodomethane and n-butyllithium.13 No reaction was observed
with this reagent, even at 0°C. The same result was observed after treating the oximes in toluene at
−20°C with methyl- or n-butyllithium in the presence of BF3. This and other Lewis acids such as ZnCl2
or TiCl4 were not able to promote the addition of Grignard reagents, even at room temperature. Either
methyllithium in the presence of TiCl4 or preformed14 MeTiCl3 caused only decomposition at 0°C, with
no reaction being observed at lower temperatures. These facts show the relatively low reactivity of the
C_N bond in the compounds under study.
The configuration of the new stereogenic centre in stereoisomers 3a–d was established with the series

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of reactions illustrated below. Compounds 3a were desilylated to amino alcohols 5, which were then
converted as indicated into oxazolidinones of general formula 6 (R0 and R00=Tr, TPS or TBS, according
to ease of preparation). In each of these oxazolidinones, a characteristic NOE (7–10%) was observed
between H-5 (heterocycle numbering) and the proximal protons of the R group at C-4 (CH2 protons
for R=nBu and allyl, CH3 protons for R=Me and tBu, ortho protons of the aromatic ring for R=Ph).
The observation of this NOE unequivocally settled the configuration at C-4 as depicted. In the case of
3a (R=Ph), the aromatic hydrogen signals of the protecting groups TPS and OBn interfered with the
measurement of the NOE. For this reason, TBS was selected as the protecting group and the benzyl
group was eliminated by hydrogenolysis.
Configurational assignments for compounds 3b were made by desilylation to 7 and subsequent
conversion into the perbenzylated derivatives 8, also obtained from 5 as indicated below. Configurational
assignments in 3c and 3d were established by detritylation to yield 5 and 7, respectively.
As shown by the data in Tables 1 and 2, the reactions of the (E)-isomers were markedly faster than
those of their (Z)-counterparts. As a matter of fact, most additions to the C_N bond of (E)-oximes
take place at −78°C, whereas those involving the (Z)-oximes had to be conducted at 0°C (except for
allyllithium, entries 19 and 20). For the sake of comparison of the relative reactivity of both isomeric
oximes, the reaction of (E)-2a with 1.1 equiv. of MeLi is complete in less than 5 min at 0°C. The obtained
addition product displays the same diastereoisomeric composition as that obtained after 1 h at the same
temperature. In contrast, the reaction of (Z)-2a with the same reagent is still incomplete after 15 min.
The difference was still more evident in the case of the reaction of (E)-2a with nBuLi (1.1 equiv.), which
was complete in less than 5 min at −78°C, while (Z)-2a required almost 1 h at 0°C. A further interesting
feature is that the highest diastereoselectivities are observed in the reactions of the (E)-oximes, whereby
stereoisomer 3 is always predominantly or exclusively formed (exclusive formation means that the minor
diastereoisomer was not detectable by high-field NMR spectroscopy; this has been indicated in the last
column of Tables 1 and 2 with d.r. >95:5).
The aforementioned compounds can also be prepared with the enantiomeric configuration by using D-
erythrulose precursors as the starting materials.8e As a matter of fact, reaction of ent-1a8e with O-benzyl
hydroxylamine afforded a mixture of the stereoisomeric oximes ent-(E)-2a and ent-(Z)-2a. As expected,
these oximes reacted with organolithium reagents with the same yield and diastereoselectivity as their
enantiomers.

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Diastereoselective additions of carbon nucleophiles to chiral aldoximes have been often investigated.15
In contrast, related studies on ketoximes are scarce.16 In some cases, the stereochemical outcome of
nucleophilic additions has been shown to be dependent on the configuration of the C_N bond. When
oxygen atoms are present in the vicinity of the C_N bond, a differential chelation ability of either isomer
has been claimed to be at the origin of the diverging stereochemical behaviour.15b In the present case,
we believe that the higher reactivity and stereoselectivity of the (E)-oximes are due to the formation of
a five-membered α-chelate involving the lithium, nitrogen and oxygen atoms of the α-OR group (see
the following scheme).1d,5,17 This allows the prediction of a preferred approach from the less hindered
Si face of the C_N bond and the predominant formation of amino polyols 3a–d, in good agreement
with observations. Moreover, the participation of the nitrogen atom in a chelate is expected to increase
the electrophilicity of the imino carbon atom of the oxime, with a concomitant increase in the reactivity
of the C_N bond.18 In the previous paragraph, we have commented on the fact that the reactions of
the (E)-oximes are complete in a very short time, even if only 1.1 equiv. of the organolithium reagent
is added. This suggests that a chelate between the (E)-oxime and the organolithium reagent is rapidly
formed, followed by an internal magnesium-to-carbon 1,3-transfer within the chelate.18,19 Most likely,
the (Z)-isomers react through a non-chelated transition state of the Felkin–Anh type,1d,5,20 which should
lead predominantly to stereoisomers 4a–d.
Although many quantum-mechanical calculations on nucleophilic additions to carbonyl groups have
been published, there are few theoretical investigations on additions to C_N bonds.21 We have thus
performed computational studies with the aim of providing the aforementioned mechanistic models with
a more firm basis. We will show here only preliminary results centred on a reaction with the synthetically
more useful (E)-isomer. In order to reduce the calculation time, we have studied the simplified model 9, in
which the O-benzyl group has been replaced by an O-methyl group and the two acetonide methyl groups
have been replaced by hydrogen atoms. Furthermore, a methyl group substitutes for the bulky CH2OTPS
group, a simplification justified on the basis that the CH2OTPS fragment may be assumed to play the
role of an inert spectator which does not participate in the chelation process.18 Methyllithium was the
model reagent (no new stereogenic centre is created in the addition of MeLi to 9 but this does not affect

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1685
the calculation of transition state energies). With the assumption of the alternative Cram’s chelation and
Felkin–Anh models, four different transition states (TS-1 to TS-4, represented below) may be proposed
according to whether the organolithium reagent approaches the imino carbon atom from the Re or from
the Si face. Attack from the Re face leads to stereoisomer 11, which corresponds to stereoisomers
4a/4d in the actual reaction. These may be formed through either Cram’s TS-2 or Felkin–Anh’s TS-
4. Correspondingly, attack from the Si face leads to stereoisomer 10, which is the model equivalent of
stereoisomers 3a/3d. The latter may arise through either Cram’s TS-1 or Felkin–Anh’s TS-3:
With the aid of ab initio methods,22 it has been shown that Cram’s TS-1, which explains the formation
of the major stereoisomer (3a/3d) in the reactions of the (E)-oximes, is in fact the most favourable
transition state, its energy contents being well below that of the alternative ones.

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As a matter of fact, Cram’s transition state TS-2, which leads to the minor stereoisomer (4a/4d) in the
reaction of the (E)-oximes, is around 3.33 kcal/mol higher than TS1. In accordance with this energy
difference, a very high d.r. (10:11 >99:1) is expected.23
Felkin–Anh transition states TS-3 and TS-4 lie 9.54 and 6.74 kcal/mol, respectively, above TS-1.
This shows once again that chelation is able to decrease to an important extent the energy contents of
transition states.8d,17,18 Moreover, TS-4 has a markedly lower energy content (2.8 kcal/mol) than TS-3,
which means that the predicted d.r. 10/11 (i.e. 3/4) would be about 1:99,23 in clear disagreement with
experimental data. Therefore, we are able to conclude that the proposed preference for Cram’s chelation
mechanism is also well founded from the theoretical point of view.
Inspection of the data contained in Tables 1 and 2 clearly reveals that only the (E)-oximes display
a good synthetic utility. For this reason, we have investigated ways of converting the less desirable
(Z)-oximes into their (E)-isomers. One practical procedure for achieving this purpose has turned out
to be a photochemical method.24 By UV irradiation of the (Z)-oximes, a photostationary equilibrium was
reached in which a ca. 1:1 mixture of both isomers was present. Through chromatographic separation,
additional amounts of the more useful (E)-isomers were secured.
The methodology we have described in this communication may be very useful for the preparation
of chiral, nitrogen-containing compounds in general, and α,α-disubstituted α-amino acids in particular.
Examples of the practical application of this methodology are presented in the following article.11b
3. Experimental
NMR spectra were measured in CDCl3 solution at 22°C with a Varian Unity 400 NMR spectrometer
1
(400 and 100 MHz resonance frequencies for H and 13C, respectively). Mass spectra were run either
by the electron impact mode (EIMS, 70 eV), by the chemical ionization mode (CIMS, CH4) or by
the fast atom bombardment mode (FABMS) on a VG AutoSpec mass spectrometer. IR spectra were
recorded as films on NaCl plates (oils) or as KBr pellets (solids). Optical rotations were measured
at 22°C. Reactions which required an inert atmosphere were performed under argon with flame-dried
glassware. Commercial reagents (Aldrich or Fluka) were used as received. Et2O was freshly distilled
under argon from sodium–benzophenone ketyl. Dichloromethane was distilled from P2O5 and stored
over 4 Å molecular sieves (4 Å MS). Triethylamine was distilled from CaH2. Trityl chloride (TrCl) was
crystallized from isooctane prior to use. Unless detailed otherwise, ‘work-up’ means pouring the reaction
mixture into brine, extraction with the indicated solvent, additional washing with 5% aq NaHCO3 (if
acids had been utilized in the reaction) or with 5% aq HCl (if bases had been utilized), then again
with brine, drying over anhydrous Na2SO4 or MgSO4 and elimination of the solvent in vacuo. The
obtained material was then chromatographed on a silica gel column (Süd-Chemie AG, 60–200 µ) with
the indicated eluent.
3.1. (E)- and (Z)-O-Benzyloximes of 1-O-t-butyldiphenylsilyl-3,4-O-isopropylidene-L-erythrulose,
(E)- and (Z)-(2a)
Erythrulose derivative 1a8e (4.783 g, 12 mmol) was dissolved in MeOH (40 ml) and treated with
pyridine (1 ml) and O-benzyl hydroxylamine hydrochloride (1.95 g, 12.2 mmol). The reaction mixture

J. A. Marco et al. / Tetrahedron: Asymmetry 9 (1998) 1679–1701
1687
was heated at reflux under Ar for 30 min. Work-up (CH2Cl2) and column chromatography (hex-
ane:EtOAc=19:1) afforded (Z)-2a (1.94 g, 32%) and (E)-2a (2.57 g, 42%). The respective enantiomeric
oximes ent-(Z)-2a and ent-(E)-2a were prepared in the same way from ent-1a8e as the starting material.
(Z)-2a: oil, [α]D −45.4 (CHCl3, c 3.1); IR νmax cm−1: 3071, 3031, 1589 (C_N); CIMS, m/z 504.2561
(M+H+). Calcd for C30H38NO4Si, M=504.2570; 1H NMR: δ 7.70–7.65 (4H, m, arom.), 7.40–7.30 (11H,
m, arom.), 5.11 (1H, dd, J=8, 7.5 Hz, H-3), 5.07 (2H, s, NOCH2Ph), 4.44 (1H, d, J=13 Hz, H-1), 4.34
(1H, d, J=13 Hz, H-10), 4.32 (1H, dd, J=8, 7.5 Hz, H-4), 3.64 (1H, t, J=8 Hz, H-40), 1.32, 1.31 (2×3H,
2×s, acetonide Me), 1.03 (9H, s, SitBu); 13C NMR: δ 158.1 (C-2), 137.7, 133.5, 133.2 (arom. C), 135.7,
135.6, 129.6, 128.4, 128.1, 127.9, 127.6 (arom. CH), 109.3 (acetonide C), 76.4 (NOCH2Ph), 71.7 (C-3),
67.9 (C-4), 61.6 (C-1), 26.7 (SiCMe3), 25.8, 25.3 (2×acetonide Me), 19.2 (SiCMe3). Anal. calcd for
C30H37NO4Si: C, 71.53; H, 7.40; N, 2.78. Found: C, 71.60; H, 7.49; N, 2.67.
(E)-2a: oil, [α]D −6.7 (CHCl3, c 6.3); IR νmax cm−1: 3071, 3031, 1589 (C_N); CIMS, m/z 504.2563
(M+H+). Calcd for C30H38NO4Si, M=504.2570; 1H NMR: δ 7.70–7.65 (4H, m, arom.), 7.40–7.20 (11H,
m, arom.), 5.03 (2H, s, NOCH2Ph), 5.00 (1H, dd, J=7, 6.5 Hz, H-3), 4.53 (2H, s, H-1, H-10), 4.21 (1H,
dd, J=8.5, 7 Hz, H-4), 4.19 (1H, dd, J=8.5, 6.5 Hz, H-40), 1.41, 1.39 (2×3H, 2×s, acetonide Me), 1.03
(9H, s, SitBu); 13C NMR: δ 156.9 (C-2), 137.5, 132.8, 132.5 (arom. C), 135.6, 135.5, 129.9, 129.8,
128.2, 128.1, 127.8, 127.7 (arom. CH), 109.8 (acetonide C), 76.3 (NOCH2Ph), 74.0 (C-3), 67.1 (C-4),
57.6 (C-1), 26.7 (SiCMe3), 26.2, 25.7 (2×acetonide Me), 19.1 (SiCMe3). Anal. calcd for C30H37NO4Si:
C, 71.53; H, 7.40; N, 2.78. Found: C, 71.31; H, 7.61; N, 2.87.
3.2. (E)- and (Z)-O-Benzyloximes of 1-O-t-butyldiphenylsilyl-3,4-O-isopropylidene-D-erythrulose,
ent-(E)- and ent-(Z)-(2a)
Prepared as above from ent-1a8e: ent-(Z)-2a: [α]D +45.5 (CHCl3, c 2.7); ent-(E)-2a: [α]D +6.4
(CHCl3, c 5.9). Other physical properties identical to those of (Z)- and (E)-2a.
3.3. (E)- and (Z)-O-Benzyloximes of 1-O-t-butyldiphenylsilyl-3,4-di-O-benzyl-L-erythrulose, (E)- and
(Z)-(2b)
Obtained as described above from 1b8e using similar molar amounts. Work-up (CH2Cl2) and column
chromatography (hexane:EtOAc=19:1) provided (Z)-2b (39%) and (E)-2b (46%).
(Z)-2b: oil, [α]D −20.1 (CHCl3, c 8.2); IR νmax cm−1: 3087, 3067, 3031, 1589 (C_N); FABMS,
1
m/z 644.3228 (M+H+). Calcd for C41H46NO4Si, M=644.3196; H NMR: δ 7.70–7.60 (4H, m, arom.),
7.40–7.20 (21H, m, arom.), 5.13 (1H, dd, J=8, 2.5 Hz, H-3), 5.08, 5.05 (2H, AB system, J=12 Hz,
NOCH2Ph), 4.53, 4.50 (2H, AB system, J=12 Hz, OCH2Ph), 4.46, 4.43 (2H, AB system, J=12 Hz,
OCH2Ph), 4.43 (1H, d, J=12 Hz, H-1), 4.14 (1H, d, J=12 Hz, H-10), 3.85 (1H, dd, J=11, 8 Hz, H-4), 3.62
(1H, dd, J=11, 2.5 Hz, H-40), 1.00 (9H, s, SitBu); 13C NMR: δ 157.7 (C-2), 138.4, 138.0, 137.8, 133.1
(arom. C), 135.7, 129.7, 129.6, 128.3, 128.2, 128.1, 127.8, 127.7, 127.6, 127.5, 127.4 (arom. CH), 76.2
(NOCH2Ph), 74.2 (C-3), 73.1, 72.5 (2×OCH2Ph), 71.5 (C-4), 62.0 (C-1), 26.7 (SiCMe3), 19.2 (SiCMe3).
Anal. calcd for C41H45NO4Si: C, 76.48; H, 7.04; N, 2.18. Found: C, 76.28; H, 7.30; N, 2.17.
(E)-2b: oil, [α]D −23.7 (CHCl3, c 3.7); IR νmax cm−1: 3088, 3062, 1589 (C_N); FABMS, m/z
1
644.3182 (M+H+). Calcd for C41H46NO4Si, M=644.3196; H NMR: δ 7.65–7.60 (4H, m, arom.),
7.40–7.20 (21H, m, arom.), 5.04 (2H, s, NOCH2Ph), 4.62 (1H, dd, J=7.5, 4 Hz, H-3), 4.60–4.50 (4H,
m, 2×OCH2Ph), 4.54 (1H, d, J=14.3 Hz, H-1), 4.40 (1H, d, J=14.3 Hz, H-10), 3.89 (1H, dd, J=10.5, 7.5
Hz, H-4), 3.82 (1H, dd, J=10.5, 4 Hz, H-40), 0.99 (9H, s, SitBu); 13C NMR: δ 157.1 (C-2), 138.4, 138.3,
137.7, 132.8, 132.7 (arom. C), 135.6, 129.7, 128.3, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.4 (arom.

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CH), 77.2 (C-3), 76.2 (NOCH2Ph), 73.3, 71.5 (2×OCH2Ph), 71.9 (C-4), 57.3 (C-1), 26.7 (SiCMe3), 19.1
(SiCMe3). Anal. calcd for C41H45NO4Si: C, 76.48; H, 7.04; N, 2.18. Found: C, 76.34; H, 7.25; N, 2.10.
3.4. (E)- and (Z)-O-Benzyloximes of 1-O-trityl-3,4-O-isopropylidene-L-erythrulose, (E)- and (Z)-(2c)
Obtained as described above from 1c8d using similar molar amounts. Work-up (CH2Cl2) and column
chromatography (hexane:EtOAc=19:1) provided (Z)-2c (44%) and (E)-2c (40%).
(Z)-2c: oil, [α]D −45.3 (CHCl3, c 3.1); IR νmax cm−1: 3086, 3060, 3032, 1598 (C_N); CIMS,
1
m/z 508.2479 (M+H+). Calcd for C33H34NO4, M=508.2488; H NMR: δ 7.70–7.60 (6H, m, arom.),
7.55–7.20 (14H, m, arom.), 5.35 (1H, t, J=7.5 Hz, H-3), 5.30 (2H, s, NOCH2Ph), 4.52 (1H, dd, J=8, 7.5
Hz, H-4), 4.05 (1H, d, J=11.7 Hz, H-1), 3.99 (1H, d, J=11.7 Hz, H-10), 3.96 (1H, t, J=8, 7.5 Hz, H-40),
1.44, 1.35 (2×3H, 2×s, acetonide Me); 13C NMR: δ 157.9 (C-2), 144.0, 137.8 (arom. C), 128.9, 128.6,
128.5, 128.2, 128.1, 128.0, 127.8, 127.2 (arom. CH), 109.6 (acetonide C), 87.7 (CPh3), 76.7 (NOCH2Ph),
71.7 (C-3), 68.3 (C-4), 62.0 (C-1), 26.0, 25.4 (2×acetonide Me). Anal. calcd for C33H33NO4: C, 78.08;
H, 6.55; N, 2.76. Found: C, 78.31; H, 6.27; N, 2.52.
(E)-2c: oil, [α]D −18.5 (CHCl3, c 6.8); IR νmax cm−1: 3086, 3060, 3031, 1598 (C_N); FABMS,
1
m/z 508.2492 (M+H+). Calcd for C33H34NO4, M=508.2488; H NMR: δ 7.50–7.40 (6H, m, arom.),
7.40–7.20 (14H, m, arom.), 5.11, 5.08 (2H, AB system, J=12 Hz, NOCH2Ph), 4.90 (1H, dd, J=7, 6.5
Hz, H-3), 4.20 (1H, d, J=12.5 Hz, H-1), 4.16 (1H, dd, J=8.5, 6.5 Hz, H-4), 4.05 (1H, dd, J=8.5, 7 Hz,
H-40), 3.86 (1H, d, J=12.5 Hz, H-10), 1.40, 1.25 (2×3H, 2×s, acetonide Me); 13C NMR: δ 155.2 (C-2),
143.4, 137.4 (arom. C), 128.97, 128.3, 128.2, 127.9, 127.8, 127.2 (arom. CH), 109.8 (acetonide C), 87.5
(CPh3), 76.4 (NOCH2Ph), 74.8 (C-3), 66.8 (C-4), 56.6 (C-1), 26.1, 25.7 (2×acetonide Me). Anal. calcd
for C33H33NO4: C, 78.08; H, 6.55; N, 2.76. Found: C, 78.22; H, 6.38; N, 2.62.
3.5. (E)- and (Z)-O-Benzyloximes of 1-O-trityl-3,4-di-O-benzyl-L-erythrulose, (E)- and (Z)-(2d)
Obtained as described above from 1d8d using similar molar amounts. Work-up (CH2Cl2) and column
chromatography (hexane:EtOAc=19:1) provided (Z)-2d (30%) and (E)-2d (42%).
(Z)-2d: oil, [α]D −33.4 (CHCl3, c 1.8); IR νmax cm−1: 3062, 3030, 1597 (C_N); FABMS, m/z
648.3093 (M+H+). Calcd for C44H42NO4, M=648.3114; 1H NMR: δ 7.45–7.40 (6H, m, arom.),
7.40–7.20 (24H, m, arom.), 5.15 (1H, dd, J=8, 2.5 Hz, H-3), 5.15, 5.13 (2H, AB system, J=12.4 Hz,
NOCH2Ph), 4.54, 4.50 (2H, AB system, J=12 Hz, OCH2Ph), 4.41 (2H, s, OCH2Ph), 3.91 (1H, dd, J=11,
8 Hz, H-4), 3.85 (1H, d, J=11 Hz, H-1), 3.70 (1H, dd, J=11, 2.5 Hz, H-40), 3.69 (1H, d, J=11 Hz, H-10);
13C NMR: δ 157.0 (C-2), 143.7, 138.3, 137.9, 137.7 (arom. C), 128.8, 128.7, 128.3, 128.2, 128.0, 127.9,
127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 127.2, 127.0 (arom. CH), 87.5 (CPh3), 76.3 (NOCH2Ph), 74.0
(C-3), 73.1, 72.5 (2×OCH2Ph), 71.2 (C-4), 62.0 (C-1). Anal. calcd for C44H41NO4: C, 81.58; H, 6.38;
N, 2.16. Found: C, 81.66; H, 6.40; N, 2.23.
(E)-2d: oil, [α]D −15.5 (CHCl3, c 2.4); IR νmax cm−1: 3062, 3033, 1597 (C_N); FABMS, m/z
648.3116 (M+H+). Calcd for C44H42NO4, M=644.3114; 1H NMR: δ 7.45–7.40 (6H, m, arom.),
7.40–7.20 (24H, m, arom.), 5.11, 5.09 (2H, AB system, J=12 Hz, NOCH2Ph), 4.57 (1H, dd, J=7.2,
4.4 Hz, H-3), 4.57, 4.50 (2H, AB system, J=12 Hz, OCH2Ph), 4.52, 4.48 (2H, AB system, J=12 Hz,
OCH2Ph), 4.06 (1H, d, J=12.6 Hz, H-1), 3.89 (1H, d, J=12.6 Hz, H-10), 3.77 (1H, dd, J=10.5, 7.5 Hz, H-
4), 3.71 (1H, dd, J=10.5, 4.5 Hz, H-40); 13C NMR: δ 155.7 (C-2), 143.4, 138.3, 138.2, 137.7 (arom. C),
128.7, 128.3, 128.2, 128.0, 127.8, 127.7, 127.6, 127.4, 127.0 (arom. CH), 87.4 (CPh3), 77.5 (C-3), 76.1
(NOCH2Ph), 73.2, 71.4 (2×OCH2Ph), 71.5 (C-4), 56.8 (C-1). Anal. calcd for C44H41NO4: C, 81.58; H,
6.38; N, 2.16. Found: C, 81.75; H, 6.44; N, 2.28.

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3.6. General experimental procedure for organolithium additions to oximes 2a–d
Substrate, temperature, reaction time and yield are indicated in Tables 1 and 2. Careful exclusion
of oxygen and moisture is assumed in all cases. Allyllithium was generated according to a described
procedure25 and used immediately in situ.
A solution of the appropriate oxime (1 mmol) in dry Et2O (5 ml) was cooled to the indicated
temperature. The required organolithium reagent (2 mmol) was then added dropwise, and the reaction
mixture was stirred for 1 h. Work-up (Et2O) and column chromatography (hexane:EtOAc=9:1) yielded
the expected addition product with the indicated yield and diastereoisomeric composition. In the case of
allyllithium, a solution of the oxime in dry Et2O was added to a solution of the freshly generated reagent.
The mixtures of diastereoisomers 3/4 formed in these reactions are practically inseparable with normal
chromatographic systems based on silica gel. For this reason, spectral data and optical rotations are given
below only for diastereoisomers 3 in such cases where a high stereoisomeric purity (>95% d.r.) was
achieved.
3.6.1. (2R,3R)-1-O-t-Butyldiphenylsilyl-3,4-O-isopropylidene-2-(N-benzyloxyamino)-2-methylbutane-
1,3,4-triol (3a, R=Me)
Oil, [α]D −6.2 (CHCl3, c 6.8); IR νmax cm−1: 3350 (br, NH); CIMS, m/z (% rel. int.): 520.2888
(M+H+). Calcd for C31H42NO4Si, M=520.2883; 1H NMR: δ 7.75–7.70 (4H, m, arom.), 7.45–7.30 (11H,
m, arom.), 4.67 (2H, s, NOCH2Ph), 4.23 (1H, t, J=6.9 Hz, H-3), 4.03 (1H, dd, J=8.5, 6.9 Hz, H-4),
3.96 (1H, dd, J=8.5, 6.9 Hz, H-40), 3.83 (1H, d, J=9.7 Hz, H-1), 3.63 (1H, d, J=9.7 Hz, H-10), 1.40,
1.34 (2×3H, 2×acetonide Me), 1.06 (9H, s, SitBu), 1.05 (3H, s, MeC2); 13C NMR: δ 137.8, 133.4, 134.3
(arom. C), 135.7, 135.6, 129.6, 129.5, 128.3, 128.2, 127.7, 127.6, 127.5 (arom. CH), 108.5 (acetonide C),
76.7 (NOCH2Ph), 76.1 (C-3), 65.4 (C-4), 64.8 (C-1), 62.2 (C-2), 26.8 (SiCMe3), 26.3, 24.9 (2×acetonide
Me), 19.4 (SiCMe3), 13.9 (MeC2). Anal. calcd for C31H41NO4Si: C, 71.64; H, 7.95; N, 2.69. Found: C,
71.77; H, 8.05; N, 2.61.
3.6.2. (2S,3S)-1-O-t-Butyldiphenylsilyl-3,4-O-isopropylidene-2-(N-benzyloxyamino)-2-methylbutane-
1,3,4-triol (ent-3a, R=Me)
Oil, [α]D +6.0 (CHCl3, c 1.6). Other physical properties identical to those of 3a (R=Me). Anal. calcd
for C31H41NO4Si: C, 71.64; H, 7.95; N, 2.69. Found: C, 71.80; H, 7.90; N, 2.57.
3.6.3. (2R,3R)-1-O-t-Butyldiphenylsilyl-3,4-O-isopropylidene-2-(N-benzyloxyamino)-2-n-butylbutane-
1,3,4-triol (3a, R=nBu)
Oil, [α]D −7.0 (CHCl3, c 1.2); IR νmax cm−1: 3350 (br, NH), 3051; FABMS, m/z 562.3372 (M+H+).
Calcd for C34H48NO4Si, M=562.3352; 1H NMR: δ 7.75–7.65 (4H, m, arom.), 7.45–7.25 (11H, m, arom.),
4.64 (2H, s, NOCH2Ph), 4.32 (1H, dd, J=8.2, 7 Hz, H-3), 4.09 (1H, t, J=8.2 Hz, H-4), 3.95 (1H, dd, J=8.2,
7.0 Hz, H-40), 3.77 (1H, d, J=10 Hz, H-1), 3.69 (1H, d, J=10 Hz, H-10), 1.60–1.50 (2H, m, CH2-C3H7),
1.39, 1.35 (2×3H, 2×acetonide Me), 1.35–1.20 (4H, m, CH2CH2Me), 1.04 (9H, s, SitBu), 0.88 (3H, t,
J=7 Hz, CH2Me); 13C NMR: δ 137.8, 133.3, 133.1 (arom. C), 135.7, 135.6, 129.7, 129.6, 128.3, 128.2,
127.7, 127.6, 127.5 (arom. CH), 107.9 (acetonide C), 77.5 (C-3), 76.7 (NOCH2Ph), 65.6 (C-4), 63.9 (C-
1), 63.2 (C-2), 29.5 (CH2–C3H7), 26.8 (SiCMe3), 26.3, 25.1 (2×acetonide Me), 25.4, 23.8 (CH2CH2Me),
19.3 (SiCMe3), 14.1 (CH2Me). Anal. calcd for C34H47NO4Si: C, 72.69; H, 8.43; N, 2.49. Found: C,
72.77; H, 8.25; N, 2.60.

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3.6.4. (2S,3S)-1-O-t-Butyldiphenylsilyl-3,4-O-isopropylidene-2-(N-benzyloxyamino)-2-n-butylbutane-
1,3,4-triol (ent-3a, R=nBu)
Oil, [α]D +6.5 (CHCl3, c 1.4). Other physical properties identical to those of 3a (R=nBu). Anal. calcd
for C34H47NO4Si: C, 72.69; H, 8.43; N, 2.49. Found: C, 72.82; H, 8.35; N, 2.44.
3.6.5. (2R,3R)-1-O-t-Butyldiphenylsilyl-3,4-O-isopropylidene-2-(N-benzyloxyamino)-2-t-butylbutane-
1,3,4-triol (3a, R=tBu)
Oil, [α]D −8.8 (CHCl3, c 2.9); IR νmax cm−1: 3400 (br, NH), 3071; FABMS, m/z 562.3343 (M+H+).
Calcd for C34H48NO4Si, M=562.3352; 1H NMR: δ 7.65–7.60 (4H, m, arom.), 7.50–7.10 (11H, m, arom.),
4.48 (1H, dd, J=8.5, 6.3 Hz, H-3), 4.42 (2H, s, NOCH2Ph), 3.97 (1H, dd, J=8.5, 7.5 Hz, H-4), 3.96 (1H,
d, J=10.7 Hz, H-1), 3.62 (1H, dd, J=7.5, 6.3 Hz, H-40), 3.56 (1H, d, J=10.7 Hz, H-10), 1.32, 1.30 (2×3H,
2×acetonide Me), 1.12 (9H, s, tBu), 1.08 (9H, s, SitBu); 13C NMR: δ 137.8, 133.0, 132.8 (arom. C),
136.0, 135.9, 129.8, 129.7, 128.4, 128.1, 127.7, 127.6, 127.5 (arom. CH), 107.7 (acetonide C), 77.6 (C-
3), 76.8 (NOCH2Ph), 66.2 (C-4), 64.7 (C-1), 64.5 (C-2), 37.5 (CMe3), 28.1 (CMe3), 27.1 (SiCMe3),
26.4, 25.5 (2×acetonide Me), 19.1 (SiCMe3). Anal. calcd for C34H47NO4Si: C, 72.69; H, 8.43; N, 2.49.
Found: C, 72.80; H, 8.30; N, 2.45.
3.6.6. (2S,3S)-1-O-t-Butyldiphenylsilyl-3,4-O-isopropylidene-2-(N-benzyloxyamino)-2-t-butylbutane-
1,3,4-triol (ent-3a, R=tBu)
Oil, [α]D +8.0 (CHCl3, c 2). Other physical properties identical to those of 3a (R=tBu). Anal. calcd
for C34H47NO4Si: C, 72.69; H, 8.43; N, 2.49. Found: C, 72.77; H, 8.55; N, 2.61.
3.6.7. (2R,3R)-1-O-t-Butyldiphenylsilyl-3,4-O-isopropylidene-2-(N-benzyloxyamino)-2-phenylbutane-
1,3,4-triol (3a, R=Ph)
Oil, [α]D +1.1 (CHCl3, c 1.3); IR νmax cm−1: 3400 (br, NH), 3054; FABMS, m/z 582.3036 (M+H+).
Calcd for C36H44NO4Si, M=582.3040; 1H NMR: δ 7.75–7.50 (6H, m, arom.), 7.45–7.25 (14H, m, arom.),
6.50 (1H, br s, NH), 4.84 (2H, s, NOCH2Ph), 4.54 (1H, dd, J=8.2, 6.7 Hz, H-3), 4.35 (1H, d, J=9.6 Hz,
H-1), 4.04 (1H, d, J=9.6 Hz, H-10), 3.97 (1H, dd, J=8.2, 6.7 Hz, H-4), 3.67 (1H, t, J=8.2 Hz, H-40), 1.35,
1.13 (2×3H, 2×acetonide Me), 0.98 (9H, s, SitBu); 13C NMR: δ 137.7, 137.6, 133.3, 133.1 (arom. C),
135.7, 135.6, 129.7, 129.6, 128.5, 128.4, 128.1, 127.9, 127.6, 127.5, 127.2 (arom. CH), 108.5 (acetonide
C), 76.1 (C-3, NOCH2Ph), 67.6 (C-2), 66.1 (C-4), 63.7 (C-1), 26.7 (SiCMe3), 26.0, 25.2 (2×acetonide
Me), 19.3 (SiCMe3). Anal. calcd for C36H45NO4Si: C, 74.06; H, 7.77; N, 2.40. Found: C, 73.97; H, 7.90;
N, 2.48.
3.6.8. (2S,3S)-1-O-t-Butyldiphenylsilyl-3,4-O-isopropylidene-2-(N-benzyloxyamino)-2-phenylbutane-
1,3,4-triol (ent-3a, R=Ph)
Oil, [α]D −1.5 (CHCl3, c 2.1). Other physical properties identical to those of 3a (R=Ph). Anal. calcd
for C36H45NO4Si: C, 74.06; H, 7.77; N, 2.40. Found: C, 74.10; H, 7.88; N, 2.51.
3.6.9. (2R,3R)-1-O-t-Butyldiphenylsilyl-3,4-di-O-benzyl-2-(N-benzyloxyamino)-2-methylbutane-1,3,4-
triol (3b, R=Me)
Oil, [α]D −4.2 (CHCl3, c 2.6); IR νmax cm−1: 3400 (br, NH), 3058, 3031; FABMS, m/z 660.3521
(M+H+). Calcd for C42H50NO4Si, M=660.3509; 1H NMR: δ 7.70–7.60 (4H, m, arom.), 7.40–7.15 (21H,
m, arom.), 4.90, 4.52 (2H, AB system, J=11.5 Hz, OCH2Ph), 4.68, 4.62 (2H, AB system, J=11.5 Hz,
NOCH2Ph), 4.58 (2H, s, OCH2Ph), 4.09 (1H, dd, J=10, 1.5 Hz, H-4), 3.84 (1H, dd, J=7.5, 1.5 Hz, H-3),
3.77 (1H, d, J=9.5 Hz, H-1), 3.75 (1H, dd, J=10, 7.5 Hz, H-40), 3.70 (1H, d, J=9.5 Hz, H-10), 1.05 (9H, s,

J. A. Marco et al. / Tetrahedron: Asymmetry 9 (1998) 1679–1701
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SitBu), 1.03 (3H, s, MeC2); 13C NMR: δ 139.0, 138.7, 138.1, 133.3, 133.2 (arom. C), 135.7, 135.6, 129.6,
129.5, 128.4, 128.3, 128.2, 128.1, 127.6, 127.5, 127.4, 127.2 (arom. CH), 79.4 (C-3), 76.6 (NOCH2Ph),
74.0, 73.3 (2×OCH2Ph), 72.9 (C-4), 64.0 (C-1), 63.6 (C-2), 26.9 (SiCMe3), 19.3 (SiCMe3), 15.0 (MeC2).
Anal. calcd for C42H49NO4Si: C, 76.44; H, 7.48; N, 2.12. Found: C, 76.80; H, 7.31; N, 2.15.
3.6.10. (2R,3R)-1-O-t-Butyldiphenylsilyl-3,4-di-O-benzyl-2-(N-benzyloxyamino)-2-n-butylbutane-
1,3,4-triol (3b, R=nBu)
Oil, [α]D +5.1 (CHCl3, c 1.3); IR νmax cm−1: 3350 (br, NH), 3067, 3031; CIMS, m/z (% rel. int.):
1
702.3960 (M+H+). Calcd for C45H56NO4Si, M=702.3978; H NMR: δ 7.70–7.60 (4H, m, arom.),
7.40–7.20 (21H, m, arom.), 4.95, 4.55 (2H, AB system, J=11.5 Hz, OCH2Ph), 4.66, 4.59 (2H, AB system,
J=11.5 Hz, NOCH2Ph), 4.56 (2H, s, OCH2Ph), 4.06 (1H, dd, J=10, 1 Hz, H-4), 3.93 (1H, d, J=7.5, 1 Hz,
H-3), 3.84 (1H, dd, J=10, 7.5 Hz, H-40), 3.75 (1H, d, J=10 Hz, H-1), 3.66 (1H, d, J=10 Hz, H-10), 1.50
(2H, m, CH2C3H7), 1.45–1.20 (4H, m, CH2CH2Me), 1.04 (9H, s, SitBu), 0.89 (3H, t, J=7 Hz, CH2Me);
13C NMR: δ 139.3, 138.6, 138.0, 133.3, 133.2 (arom. C), 135.7, 129.6, 129.5, 128.3, 128.2, 128.1, 127.7,
127.6, 127.5, 127.4, 127.1 (arom. CH), 80.4 (C-3), 76.3 (NOCH2Ph), 74.1, 73.5 (2×OCH2Ph), 73.3 (C-
4), 65.3 (C-2), 62.4 (C-1), 29.9 (CH2C3H7), 26.9 (SiCMe3), 25.8, 23.8 (CH2CH2Me), 19.3 (SiCMe3),
14.1 (CH2Me). Anal. calcd for C45H55NO4Si: C, 76.99; H, 7.90; N, 2.00. Found: C, 76.88; H, 7.71; N,
2.10.
3.6.11. (2R,3R)-1-O-t-Butyldiphenylsilyl-3,4-di-O-benzyl-2-(N-benzyloxyamino)-2-phenylbutane-
1,3,4-triol (3b, R=Ph)
Oil, [α]D −8.5 (CHCl3, c 3.1); IR νmax cm−1: 3350 (br, NH), 3065, 3031; CIMS, m/z (% rel.
1
int.): 722.3667 (M+H+). Calcd for C47H52NO4Si, M=722.3665; H NMR: δ 7.60–7.45 (6H, m, arom.),
7.40–7.15 (24H, m, arom.), 4.90, 4.57 (2H, AB system, J=11.5 Hz, OCH2Ph), 4.76 (2H, s, NOCH2Ph),
4.44, 4.41 (2H, AB system, J=12 Hz, OCH2Ph), 4.30 (1H, d, J=10 Hz, H-1), 4.19 (1H, d, J=10 Hz,
H-10), 4.18 (1H, dd, J=7.5, 1.5 Hz, H-3), 4.02 (1H, dd, J=10.5, 1.5 Hz, H-4), 3.24 (1H, dd, J=10.5, 7.5
Hz, H-40), 0.92 (9H, s, SitBu); 13C NMR: δ 139.0, 138.7, 138.6, 137.8, 133.4, 133.1 (arom. C), 135.8,
135.6, 129.5, 128.5, 128.4, 128.1, 127.7, 127.6, 127.5, 127.4, 127.2, 127.1, 126.9 (arom. CH), 79.7 (C-
3), 76.4 (NOCH2Ph), 74.2, 74.0 (2×OCH2Ph), 73.2 (C-4), 68.1 (C-2), 63.2 (C-1), 26.8 (SiCMe3), 19.3
(SiCMe3). Anal. calcd for C47H51NO4Si: C, 78.19; H, 7.12; N, 1.94. Found: C, 78.00; H, 7.31; N, 2.00.
3.6.12. (2R,3R)-1-O-t-Butyldiphenylsilyl-3,4-di-O-benzyl-2-(N-benzyloxyamino)-2-allylbutane-
1,3,4-triol (3b, R=allyl)
Oil, [α]D +7.0 (CHCl3, c 2.9); IR νmax cm−1: 3350 (br, NH), 3067; FABMS, m/z 686.3674 (M+H+).
Calcd for C44H52NO4Si, M=686.3665; 1H NMR: δ 7.65–7.60 (4H, m, arom.), 7.40–7.20 (21H, m, arom.),
5.94 (1H, ddt, J=17.3, 10.2, 7.5 Hz, CH_CH2), 5.02 (1H, br dd, J=17.3, 2 Hz, CH_CH2), 4.99 (1H, br
dd, J=10.2, 2 Hz, CH_CH2), 4.92, 4.52 (2H, AB system, J=11.5 Hz, OCH2Ph), 4.63, 4.59 (2H, AB
system, J=11.5 Hz, NOCH2Ph), 4.51 (2H, s, OCH2Ph), 4.00 (1H, dd, J=10, 1 Hz, H-4), 3.90 (1H, dd,
J=8, 1 Hz, H-3), 3.83 (1H, dd, J=10, 8 Hz, H-40), 3.72 (1H, d, J=10 Hz, H-1), 3.62 (1H, d, J=10 Hz,
H-10), 2.35 (2H, br d, J=7.5 Hz, CH2C_C), 1.01 (9H, s, SitBu); 13C NMR: δ 139.2, 138.6, 137.8, 133.2,
133.1 (arom. C), 134.6 (CH_CH2), 135.7, 129.5, 128.3, 128.2, 128.1, 127.6, 127.5, 127.4, 127.1 (arom.
CH), 117.0 (CH_CH2), 80.2 (C-3), 76.3 (NOCH2Ph), 74.1, 73.2 (2×OCH2Ph), 73.1 (C-4), 65.5 (C-2),
62.7 (C-1), 34.9 (CH2C_C), 26.9 (SiCMe3), 19.2 (SiCMe3). Anal. calcd for C44H51NO4Si: C, 77.04; H,
7.49; N, 2.04. Found: C, 77.00; H, 7.32; N, 1.92.

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3.6.13. (2R,3R)-1-O-Trityl-3,4-O-isopropylidene-2-(N-benzyloxyamino)-2-methylbutane-1,3,4-triol
(3c, R=Me)
Oil, [α]D −4.7 (CHCl3, c 7.2); IR νmax cm−1: 3400 (br, NH), 3060, 3030; CIMS, m/z (% rel. int.):
1
524.2807 (M+H+). Calcd for C34H38NO4, M=524.2800; H NMR (200 MHz): δ 7.60–7.50 (6H, m,
arom.), 7.50–7.20 (14H, m, arom.), 6.10 (1H, br s, NH), 4.70 (2H, s, NOCH2Ph), 4.34 (1H, t, J=7 Hz,
H-3), 4.10–3.90 (2H, m, H-4, H-40), 3.45 (1H, d, J=8.8 Hz, H-1), 3.18 (1H, d, J=8.8 Hz, H-10), 1.40
(6H, 2×acetonide Me), 1.17 (3H, s, MeC2); 13C NMR: δ 144.1, 137.9 (arom. C), 129.2, 129.1, 129.0,
128.4, 128.3, 128.0, 127.9, 127.4, 127.1 (arom. CH), 108.6 (acetonide C), 86.6 (CPh3), 77.3 (C-3), 76.8
(NOCH2Ph), 65.4 (C-4), 64.3 (C-1), 61.7 (C-2), 26.4, 25.2 (2×acetonide Me), 15.6 (MeC2). Anal. calcd
for C34H37NO4: C, 77.98; H, 7.12; N, 2.67. Found: C, 78.11; H, 7.30; N, 2.42.
3.6.14. (2R,3R)-1-O-Trityl-3,4-O-isopropylidene-2-(N-benzyloxyamino)-2-n-butylbutane-1,3,4-triol
(3c, R=nBu)
Oil, [α]D −9.6 (CHCl3, c 2.2); IR νmax cm−1: 3300 (br, NH), 3061, 3031; FABMS, m/z 566.3257
1
(M+H+). Calcd for C37H44NO4, M=566.3270; H NMR: δ 7.50–7.40 (6H, m, arom.), 7.40–7.20 (14H,
m, arom.), 4.57 (2H, s, NOCH2Ph), 4.30 (1H, dd, J=8.2, 6.8 Hz, H-3), 3.98 (1H, t, J=8.2 Hz, H-4), 3.83
(1H, dd, J=8.2, 6.8 Hz, H-40), 3.33 (1H, d, J=9 Hz, H-1), 3.12 (1H, d, J=9 Hz, H-10), 1.60–1.50 (2H, m,
CH2C3H7), 1.33, 1.32 (2×3H, 2×acetonide Me), 1.30–1.10 (4H, m, CH2CH2Me), 0.83 (3H, t, J=7 Hz,
CH2Me); 13C NMR: δ 143.8, 137.8 (arom. C), 128.8, 128.3, 128.2, 128.0, 127.9, 127.7, 127.0 (arom.
CH), 108.0 (acetonide C), 86.7 (CPh3), 78.2 (C-3), 76.7 (NOCH2Ph), 65.5 (C-4), 63.0 (C-2), 62.8 (C-1),
30.9 (CH2C3H7), 26.3, 25.2 (2×acetonide Me), 25.2, 23.7 (CH2CH2Me), 14.1 (CH2Me). Anal. calcd for
C37H43NO4: C, 78.55; H, 7.66; N, 2.48. Found: C, 78.43; H, 7.39; N, 2.41.
3.6.15. (2R,3R)-1-O-Trityl-3,4-O-isopropylidene-2-(N-benzyloxyamino)-2-t-butylbutane-1,3,4-triol
(3c, R=tBu)
Oil, [α]D −2.5 (CHCl3, c 1.7); IR νmax cm−1: 3400 (br, NH), 3060, 3029; FABMS, m/z 566.3257
1
(M+H+). Calcd for C37H44NO4, M=566.3270; H NMR: δ 7.50–7.40 (6H, m, arom.), 7.35–7.20 (14H,
m, arom.), 4.47 (2H, s, NOCH2Ph), 4.44 (1H, dd, J=8.2, 6.5 Hz, H-3), 3.93 (1H, t, J=8.2 Hz, H-4),
3.57 (1H, dd, J=8.2, 6.5 Hz, H-40), 3.46 (1H, d, J=10 Hz, H-1), 3.33 (1H, d, J=10 Hz, H-10), 1.31 (6H,
2×acetonide Me), 1.05 (9H, s, tBu); 13C NMR: δ 143.4, 137.9 (arom. C), 129.1, 128.7, 128.6, 128.3,
128.1, 127.9, 127.8, 127.7, 127.4, 127.2, 127.1, 126.8 (arom. CH), 107.6 (acetonide C), 87.8 (CPh3),
77.9 (C-3), 76.7 (NOCH2Ph), 66.3 (C-4), 64.9 (C-2), 63.5 (C-1), 37.8 (CMe3), 27.9 (CMe3), 26.4, 25.4
(2×acetonide Me). Anal. calcd for C37H43NO4: C, 78.55; H, 7.66; N, 2.48. Found: C, 78.62; H, 7.49; N,
2.61.
3.6.16. (2R,3R)-1-O-Trityl-3,4-O-isopropylidene-2-(N-benzyloxyamino)-2-phenylbutane-1,3,4-triol
(3c, R=Ph)
Oil, [α]D −16.0 (CHCl3, c 4.3); IR νmax cm−1: 3400 (br, NH), 3060, 3030; FABMS, m/z 586.2960
1
(M+H+). Calcd for C39H40NO4, M=586.2957; H NMR: δ 7.40–7.20 (25H, m, arom.), 4.72 (2H, s,
NOCH2Ph), 4.51 (1H, t, J=7.2 Hz, H-3), 3.83 (1H, dd, J=8, 7.2 Hz, H-4), 3.82 (1H, d, J=8.8 Hz, H-1),
3.61 (1H, t, J=8 Hz, H-40), 3.49 (1H, d, J=8.8 Hz, H-10), 1.26, 1.01 (2×3H, 2×acetonide Me); 13C NMR:
δ 143.7, 138.0, 137.6 (arom. C), 128.8, 128.3, 128.2, 127.9, 127.7, 127.6, 127.4, 127.1, 126.9 (arom.
CH), 108.5 (acetonide C), 86.5 (CPh3), 76.7 (C-3), 76.1 (NOCH2Ph), 66.9 (C-2), 65.8 (C-4), 62.9 (C-1),
25.8, 25.2 (2×acetonide Me). Anal. calcd for C39H39NO4: C, 79.97; H, 6.71; N, 2.39. Found: C, 80.08;
H, 6.72; N, 2.63.

J. A. Marco et al. / Tetrahedron: Asymmetry 9 (1998) 1679–1701
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3.6.17. (2R,3R)-1-O-Trityl-3,4-di-O-benzyl-2-(N-benzyloxyamino)-2-methylbutane-1,3,4-triol
(3d, R=Me)
Oil, [α]D −10.6 (CHCl3, c 0.4); IR νmax cm−1: 3400 (br, NH), 3061, 3030; FABMS, m/z 664.3398
1
(M+H+). Calcd for C45H46NO4, M=664.3426; H NMR: δ 7.40–7.20 (30H, m, arom.), 4.79, 4.38 (2H,
AB system, J=11.5 Hz, OCH2Ph), 4.63, 4.58 (2H, AB system, J=11.5 Hz, NOCH2Ph), 4.48 (2H, s,
OCH2Ph), 3.91 (1H, dd, J=10.2, 1.8 Hz, H-4), 3.82 (1H, dd, J=7.7, 1.8 Hz, H-3), 3.61 (1H, dd, J=10.2,
7.7 Hz, H-40), 3.27 (1H, d, J=8.8 Hz, H-1), 3.18 (1H, d, J=8.8 Hz, H-10), 1.02 (3H, s, MeC2); 13C NMR:
δ 144.0, 139.0, 138.6, 137.9 (arom. C), 129.8, 128.3, 128.2, 128.1, 128.0, 127.7, 127.6, 127.5, 127.4,
127.1, 126.8 (arom. CH), 86.4 (CPh3), 80.1 (C-3), 76.6 (NOCH2Ph), 74.0, 73.2 (2×OCH2Ph), 72.5 (C-
4), 63.5 (C-1), 63.1 (C-2), 16.3 (MeC2). Anal. calcd for C45H45NO4: C, 81.42; H, 6.83; N, 2.11. Found:
C, 81.28; H, 6.72; N, 2.23.
3.6.18. (2R,3R)-1-O-Trityl-3,4-di-O-benzyl-2-(N-benzyloxyamino)-2-n-butylbutane-1,3,4-triol
(3d, R=nBu)
Oil, [α]D −1.6 (CHCl3, c 3.8); IR νmax cm−1: 3400 (br, NH), 3088, 3061, 3032; FABMS, m/z 706.3878
1
(M+H+). Calcd for C48H52NO4, M=706.3896; H NMR: δ 7.45–7.20 (30H, m, arom.), 4.90, 4.50 (2H,
AB system, J=11.5 Hz, OCH2Ph), 4.68, 4.62 (2H, AB system, J=11.5 Hz, NOCH2Ph), 4.52 (2H, s,
OCH2Ph), 3.93 (2H, m, H-3, H-4), 3.73 (1H, dd, J=10.5, 8 Hz, H-40), 3.24 (2H, s, H-1, H-10), 1.50–1.40
(2H, m, CH2C3H7), 1.30–1.00 (4H, m, CH2CH2Me), 0.83 (3H, t, J=7 Hz, CH2Me); 13C NMR: δ 143.9,
139.3, 138.6, 138.0 (arom. C), 128.9, 128.8, 128.3, 128.2, 128.1, 128.0, 127.7, 127.6, 127.5, 127.4, 127.3,
127.0, 126.8 (arom. CH), 86.6 (CPh3), 80.8 (C-3), 76.4 (NOCH2Ph), 74.2, 73.2 (2×OCH2Ph), 73.1 (C-
4), 64.9 (C-2), 61.6 (C-1), 30.6 (CH2C3H7), 25.5, 23.7 (CH2CH2Me), 14.0 (CH2Me). Anal. calcd for
C48H51NO4: C, 81.67; H, 7.28; N, 1.98. Found: C, 81.48; H, 7.44; N, 2.13.
3.6.19. (2R,3R)-1-O-Trityl-3,4-di-O-benzyl-2-(N-benzyloxyamino)-2-phenylbutane-1,3,4-triol
(3d, R=Ph)
Oil, [α]D −18.8 (CHCl3, c 2.6); IR νmax cm−1: 3350 (br, NH), 3060, 3030; FABMS, m/z 726.3617
1
(M+H+). Calcd for C50H48NO4, M=726.3583; H NMR: δ 7.60–7.20 (35H, m, arom.), 6.70 (1H, br
s, NH), 4.78, 4.42 (2H, AB system, J=11.5 Hz, OCH2Ph), 4.69, 4.66 (2H, AB system, J=11.5 Hz,
NOCH2Ph), 4.37, 4.34 (2H, AB system, J=12 Hz, OCH2Ph), 4.15 (1H, dd, J=7.7, 1.5 Hz, H-3), 3.88
(1H, br d, J=10.2 Hz, H-4), 3.74 (2H, s, H-1, H-10), 3.18 (1H, dd, J=10.2, 7.7 Hz, H-40); 13C NMR: δ
143.7, 138.9, 138.6, 137.8 (arom. C), 128.9, 128.3, 128.0, 127.6, 127.5, 127.4, 127.3, 127.1, 127.0, 126.8
(arom. CH), 86.5 (CPh3), 80.5 (C-3), 76.4 (NOCH2Ph), 74.2, 73.1 (2×OCH2Ph), 73.4 (C-4), 67.5 (C-2),
62.5 (C-1). Anal. calcd for C50H47NO4: C, 82.73; H, 6.53; N, 1.93. Found: C, 82.49; H, 6.44; N, 2.15.
3.7. General desilylation procedure
A solution of the substrate (1 mmol) in dry THF (15 ml) was treated with solid tetra-n-butylammonium
fluoride trihydrate (331 mg, 1.05 mmol) and stirred at room temperature for 2 h. After adding water (1
ml), the volatiles were totally eliminated at reduced pressure. Column chromatography of the residue
(hexane/EtOAc mixtures) provided the desilylation product with yields in the range 75–95%.
3.8. General benzylation procedure
An 80% suspension of NaH in mineral oil (45 mg, ca. 1.5 mmol of sodium hydride) was washed three
times under Ar with dry hexane. Dry THF (1 ml) was then added, followed by a solution of the substrate

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(1 mmol) in dry THF (3 ml). The solution was stirred at room temperature for 30 min. Benzyl bromide
(0.15 ml, 1.2 mmol) was then added dropwise, followed by nBu4N+I− (37 mg, 0.1 mmol). The reaction
mixture was then heated at reflux for 3 h. Work-up (Et2O) and column chromatography (hexane/EtOAc
mixtures) furnished the desired benzylation product. For compounds having three free hydroxyl groups,
the proportions of NaH and benzyl bromide were increased to 4.5 and 3.5 equiv., respectively. Yields
were usually about 80–85% in the monobenzylations and about 50–55% in the tribenzylations.
3.9. General acetonide hydrolysis procedure
The substrate (1 mmol) was dissolved in a MeOH:H2O (9:1) mixture (5 ml). After addition of PPTS
(25 mg, 0.1 mmol), the solution was heated at reflux for 12 h. After cooling the reaction mixture to room
temperature, solid Na2CO3 (15 mg) was added. The reaction mixture was then filtered through Celite, the
reaction flask and the Celite were washed two times with EtOAc. The organic phases were evaporated
at reduced pressure and the oily residue was chromatographed on silica gel (hexane/EtOAc mixtures) to
afford the desired hydrolysis product with yields in the range 70–90%.
3.10. General detritylation procedure26
A 1.8 M solution of trifluoroacetic acid/trifluoroacetic anhydride was prepared by dissolving these
reagents in the appropriate amount of dry CH2Cl2. The substrate (1 mmol) was then dissolved under Ar
in dry CH2Cl2 (2 ml) and treated dropwise at room temperature with the aforementioned solution (1.6
ml, ca. 7.5 equiv.). The reaction mixture turned yellow and was then cooled to 0°C, followed by addition
of triethylamine (1.25 ml, 9 mmol). After stirring for 5 min, the reaction mixture was poured into MeOH
(25 ml). Stirring was continued for 30 min at room temperature. After removal of all solvents at reduced
pressure, the residue was chromatographed (hexane/EtOAc mixtures) to yield the desired detritylation
product with yields in the range 70–80%.
3.11. Formation of oxazolidinones 6
A solution of the appropriate amino alcohol (0.2 mmol) in dry CH2Cl2 (2 ml) was successively
treated under Ar with Et3N (80 µl, ca. 0.6 mmol) and triphosgene (60 mg, ca. 0.2 mmol). The reaction
mixture was then stirred at room temperature for 2 days. Work-up (CH2Cl2) and column chromatography
(hexane/EtOAc mixtures) furnished oxazolidinones 6 with yields in the range 40–50%.
3.11.1. (2R,3R)-3,4-O-Isopropylidene-2-(N-benzyloxyamino)-2-methylbutane-1,3,4-triol (5, R=Me)
Oil, [α]D −8.2 (CHCl3, c 5); IR νmax cm−1: 3450 (br, OH), 3088, 3064, 3031; FABMS, m/z 282.1703
1
(M+H+). Calcd for C15H24NO4, M=282.1705; H NMR: δ 7.40–7.30 (5H, m, arom.), 4.64 (2H, s,
NOCH2Ph), 4.18 (1H, t, J=6.8 Hz, H-3), 3.91 (1H, dd, J=8.5, 6.8 Hz, H-4), 3.89 (1H, dd, J=8.5, 6.8
Hz, H-40), 3.65 (1H, d, J=11.5 Hz, H-1), 3.57 (1H, d, J=11.5 Hz, H-10), 1.40, 1.31 (2×3H, 2×acetonide
Me), 0.99 (3H, s, MeC2); 13C NMR: δ 137.4 (arom. C), 128.6, 128.4, 128.0 (arom. CH), 108.9 (acetonide
C), 77.5 (C-3), 77.1 (NOCH2Ph), 65.2, 65.1 (C-1, C-4), 61.4 (C-2), 26.2, 24.8 (2×acetonide Me), 15.1
(MeC2). Anal. calcd for C15H23NO4: C, 64.04; H, 8.24; N, 4.98. Found: C, 64.39; H, 8.44; N, 5.14.
3.11.2. (2R,3R)-3,4-O-Isopropylidene-2-(N-benzyloxyamino)-2-n-butylbutane-1,3,4-triol (5, R=nBu)
Oil, [α]D −16.0 (CHCl3, c 0.7); IR νmax cm−1: 3450 (br, OH), 3088, 3064, 3031; CIMS, m/z (% rel.
1
int.): 324.2168 (M+H+). Calcd for C18H30NO4, M=324.2174; H NMR: δ 7.40–7.30 (5H, m, arom.),

J. A. Marco et al. / Tetrahedron: Asymmetry 9 (1998) 1679–1701
1695
6.00 (1H, br s, NH), 4.66 (2H, s, NOCH2Ph), 4.22 (1H, dd, J=7.7, 6.6 Hz, H-3), 3.93 (2H, m, H-4,
H-40), 3.62 (2H, br s, H-1, H-10), 2.50 (1H, br s, OH), 1.60–1.20 (6H, m, CH2CH2CH2), 1.40, 1.31
(2×3H, 2×acetonide Me), 0.90 (3H, t, J=7.5 Hz, Me); 13C NMR: δ 137.5 (arom. C), 128.5, 128.4, 127.9
(arom. CH), 108.5 (acetonide C), 78.3 (C-3), 76.7 (NOCH2Ph), 65.2 (C-4), 64.2 (C-1), 62.6 (C-2), 29.9
(CH2–C3H7), 26.3, 24.9 (2×acetonide Me), 25.2, 23.5 (CH2CH2Me), 14.1 (CH2Me). Anal. calcd for
C18H29NO4: C, 66.84; H, 9.04; N, 4.33. Found: C, 66.55; H, 8.93; N, 4.13.
3.11.3. (2R,3R)-3,4-O-Isopropylidene-2-(N-benzyloxyamino)-2-t-butylbutane-1,3,4-triol (5, R=tBu)
Oil, [α]D −40.0 (CHCl3, c 0.7); IR νmax cm−1: 3440 (br, OH), 3086, 3065, 3030; CIMS, m/z (% rel.
1
int.): 324.2177 (M+H+). Calcd for C18H30NO4, M=324.2174; H NMR: δ 7.40–7.30 (5H, m, arom.),
4.71, 4.69 (2H, AB system, J=11.5 Hz, NOCH2Ph), 4.34 (1H, dd, J=9, 5.7 Hz, H-3), 4.09 (1H, dd, J=8.5,
5.7 Hz, H-4), 4.00 (1H, dd, J=9, 8.5 Hz, H-40), 3.84 (1H, br d, J=12 Hz, H-1), 3.58 (1H, br dd, J=12,
7 Hz, H-10), 2.20 (1H, br s, OH), 1.36, 1.33 (2×3H, 2×acetonide Me), 1.02 (9H, s, tBu); 13C NMR:
δ 137.3 (arom. C), 128.7, 128.5, 128.1 (arom. CH), 106.6 (acetonide C), 78.4 (C-3), 76.7 (NOCH2Ph),
66.8 (C-4), 65.6 (C-2), 63.2 (C-1), 37.4 (CMe3), 27.2 (CMe3), 26.5, 25.7 (2×acetonide Me). Anal. calcd
for C18H29NO4: C, 66.84; H, 9.04; N, 4.33. Found: C, 66.63; H, 9.15; N, 4.29.
3.11.4. (2R,3R)-3,4-O-Isopropylidene-2-(N-benzyloxyamino)-2-phenylbutane-1,3,4-triol (5, R=Ph)
Oil, [α]D −22.0 (CHCl3, c 2.9); IR νmax cm−1: 3330 (br, OH), 3085, 3066, 3030; FABMS, m/z
1
344.1855 (M+H+). Calcd for C20H26NO4, M=344.1862; H NMR: δ 7.55 (2H, m, arom.), 7.40–7.20
(8H, m, arom.), 6.50 (1H, br s, NH), 4.66 (2H, s, NOCH2Ph), 4.38 (1H, t, J=7.2 Hz, H-3), 4.28 (1H, br
d, J=11.5 Hz, H-1), 4.14 (1H, br d, J=11.5 Hz, H-10), 3.70–3.60 (2H, m, H-4, H-40), 2.50 (1H, br s, OH),
1.28, 1.27 (2×3H, 2×acetonide Me); 13C NMR: δ 138.0, 137.4 (arom. C), 128.5, 128.4, 128.1, 127.9,
127.4 (arom. CH), 109.5 (acetonide C), 78.3 (C-3), 76.7 (NOCH2Ph), 66.6 (C-2), 65.7 (C-4), 63.2 (C-1),
26.0, 24.8 (2×acetonide Me). Anal. calcd for C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found: C, 69.65;
H, 7.53; N, 4.15.
3.11.5. (4R,5R)-3-Benzyloxy-4-methyl-4,5-bis(trityloxymethyl)-1,3-oxazolidin-2-one (6, R=Me,
R0=R00=Tr, P=Bn)
Colourless needles (from hexane/CH2Cl2), mp 242–246°C (dec.), [α]D +5.8 (CHCl3, c 0.4); IR νmax
cm−1: 3059, 3031, 1787 (C_O); EIMS, m/z (% rel. int.): 751 (M+, 0.5), 478 (M+−CH2OTr, 20), 243
1
(Ph3C+, 100). Calcd for C51H45NO5, M=751; H NMR: δ 7.50–7.10 (35H, m, arom.), 5.24, 4.85 (2H,
AB system, J=10.2 Hz, NOCH2Ph), 4.03 (1H, dd, J=8.7, 3.3 Hz, H-5), 3.52 (1H, dd, J=10.6, 8.7
Hz, C5–CH2OTr), 3.42 (1H, d, J=10.2 Hz, C4–CH2OTr), 2.66 (1H, dd, J=10.6, 3.3 Hz, C5–CH2OTr),
2.52 (1H, d, J=10.2 Hz, C4–CH2OTr), 0.82 (3H, s, Me–C4); 13C NMR: δ 158.7 (C_O), 143.3, 142.8,
135.3 (arom. C), 129.8, 128.9, 128.7, 128.6, 128.4, 127.8, 127.7, 127.0, 126.8 (arom. CH), 87.7, 86.9
(2×CPh3), 80.3 (C-5), 79.1 (NOCH2Ph), 64.6 (C-4), 61.7 (C4–CH2OTr), 60.3 (C5–CH2OTr), 19.8
(Me–C4). Anal. calcd for C51H45NO5: C, 81.47; H, 6.03; N, 1.86. Found: C, 81.65; H, 6.20; N, 2.01.
3.11.6. (4R,5R)-3-Benzyloxy-4-n-butyl-4,5-bis(trityloxymethyl)-1,3-oxazolidin-2-one (6, R=nBu,
R0=R00=Tr, P=Bn)
Colourless needles (from hexane/Et2O), mp 270–275°C (dec.), [α]D +18.7 (CHCl3, c 1.2); IR
νmax cm−1: 3059, 3031, 2930, 1785 (C_O); FABMS, m/z 794.3881 (M+H+). Calcd for C54H52NO5,
M=794.3846; 1H NMR: δ 7.50–7.00 (35H, m, arom.), 5.30, 4.85 (2H, AB system, J=10 Hz, NOCH2Ph),
4.28 (1H, dd, J=8.6, 2 Hz, H-5), 3.58 (1H, dd, J=10.2, 8.6 Hz, C5–CH2OTr), 3.42 (1H, d, J=10
Hz, C4–CH2OTr), 2.54 (1H, dd, J=10.2, 2 Hz, C5–CH2OTr), 2.51 (1H, d, J=10 Hz, C4–CH2OTr),

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1.30–1.10 (2H, m, CH2–C3H7), 1.00–0.75 (4H, m, CH2CH2Me), 0.69 (3H, t, J=7.4 Hz, CH2Me); 13C
NMR: δ 159.1 (C_O), 143.3, 142.7, 135.2 (arom. C), 129.7, 128.9, 128.7, 128.6, 128.5, 127.9, 127.7,
127.6, 126.9, 126.8 (arom. CH), 87.7, 86.8 (2×CPh3), 78.7 (C-5), 78.6 (NOCH2Ph), 67.1 (C-4), 615
(C4–CH2OTr), 60.7 (C5–CH2OTr), 32.8 (CH2–C3H7), 25.1, 22.9 (CH2CH2Me), 13.7 (CH2Me). Anal.
calcd for C54H51NO5: C, 81.69; H, 6.47; N, 1.76. Found: C, 81.61; H, 6.27; N, 1.63.
3.11.7. (4R,5R)-3-Benzyloxy-4-t-butyl-4-(t-butyldiphenylsilyloxymethyl)-5-(trityloxymethyl)-1,3-
oxazolidin-2-one (6, R=tBu, R0=Tr, R00=TPS, P=Bn)
Colourless needles (from hexane/CH2Cl2), mp 251–255°C (dec.), [α]D +39.1 (CHCl3, c 2.5); IR
νmax cm−1: 3058, 2957, 2858, 1785 (C_O); CIMS, m/z (% rel. int.): 790.3938 (M+H+). Calcd for
C51H56NO5Si, M=790.3928; 1H NMR: δ 7.50–7.10 (30H, m, arom.), 5.46, 4.90 (2H, AB system, J=8.8
Hz, NOCH2Ph), 4.46 (1H, d, J=7.5 Hz, H-5), 4.00 (1H, d, J=11 Hz, CH2OTPS), 3.96 (1H, dd, J=11,
7.5 Hz, CH2OTr), 3.01 (1H, d, J=11 Hz, CH2OTPS), 2.80 (1H, d, J=11 Hz, CH2OTr), 0.94 (9H, s,
SitBu), 0.66 (9H, s, C4-tBu); 13C NMR δ 159.8 (C_O), 143.5, 135.0, 132.7, 131.7 (arom. C), 136.2,
135.8, 130.0, 129.6, 127.9, 127.8, 127.7, 127.3, 127.1, 127.0 (arom. CH), 86.5 (CPh3), 78.8 (C-5),
76.9 (NOCH2Ph), 72.6 (C-4), 63.5, 58.4 (CH2OTr, CH2OTPS), 34.8 (C4–CMe3), 26.8 (C4–CMe3), 26.4
(SiCMe3), 18.7 (SiCMe3). Anal. calcd for C51H55NO5Si: C, 77.53; H, 7.02; N, 1.77. Found: C, 77.66;
H, 7.24; N, 1.88.
3.11.8. (4R,5R)-3-Benzyloxy-4-phenyl-4,5-bis(t-butyldimethylsilyloxymethyl)-1,3-oxazolidin-2-one
(6, R=Ph, R0=R00=TBS, P=Bn)
Colourless needles (from hexane/CH2Cl2), mp 110–112°C, [α]D +55.3 (CHCl3, c 0.9); IR νmax
cm−1: 3065, 3034, 2950, 2928, 2887, 2856, 1788 (C_O); FABMS, m/z 558.3064 (M+H+). Calcd for
C30H48NO5Si2, M=558.3071; 1H NMR: δ 7.50–7.20 (10H, m, arom.), 5.20, 4.74 (2H, AB system, J=10
Hz, NOCH2Ph), 4.49 (1H, t, J=6.3 Hz, H-5), 4.25, 4.23 (2H, AB system, J=10.5 Hz, C4–CH2OTBS),
4.08 (2H, m, C5–CH2OTBS), 0.89, 0.80 (2×9H, 2×s, 2×SitBu), 0.03, 0.01, −0.01, −0.03 (4×3H, 4×s,
SiMe); 13C NMR: δ 158.9 (C_O), 138.2. 135.3 (arom. C), 129.0, 128.6, 128.4, 128.3, 128.1, 126.4
(arom. CH), 82.2 (C-5), 78.0 (NOCH2Ph), 70.2 (C-4), 61.0, 60.6 (2×CH2OTBS), 25.7 (2×SiCMe3),
18.2 (2×SiCMe3), −5.4, −5.6, −5.7, −6.0 (4×SiMe). Anal. calcd for C30H47NO5Si2: C, 64.59; H, 8.49;
N, 2.51. Found: C, 64.64; H, 8.34; N, 2.80.
3.12. Hydrogenolysis of 6 (R=Ph, R0=R00=TBS, P=Bn)
A 10% Pd/C hydrogenation catalyst (15 mg) was suspended in MeOH (1 ml) and stirred for 10 min
under an H2 atmosphere. The substrate (0.1 mmol) was dissolved in MeOH (2 ml) and added via syringe
to the catalyst suspension. The reaction mixture was then stirred for 48 h at room temperature. After this
time, the mixture was filtered through Celite, the reaction flask and the Celite were washed two times
with EtOAc, and the organic layers were concentrated at reduced pressure. Column chromatography of
the oily residue (hexane:EtOAc=4:1) furnished the hydrogenolysis product 6 (R=Ph, R0=R00=TBS, P=H)
as an oil, [α]D +20.4 (CHCl3, c 0.5); IR νmax cm−1: 3220 (br, OH), 1764 (C_O); FABMS, m/z 468.2596
1
(M+H+). Calcd for C23H42NO5Si2, M=468.2601; H NMR: δ 7.50–7.30 (5H, m, arom.), 4.40 (1H, dd,
J=6.5, 6 Hz, H-5), 4.26 (1H, dd, J=11, 6 Hz, C5–CH2OTBS), 4.20 (1H, d, J=10.8 Hz, C4–CH2OTBS),
4.17 (1H, dd, J=11, 6.5 Hz, C5–CH2OTBS), 4.12 (1H, d, J=10.8 Hz, C4–CH2OTBS), 0.90, 0.87 (2×9H,
2×s, 2×SitBu), 0.10, 0.08, 0.07, 0.05 (4×3H, 4×s, SiMe); 13C NMR: δ 161.3 (C_O), 137.8 (arom. C),
128.9, 128.2, 125.9 (arom. CH), 82.3 (C-5), 71.4 (C-4), 61.2 (2×CH2OTBS), 25.8, 25.7 (2×SiCMe3),
18.3, 18.1 (2×SiCMe3), −5.4, −5.5, −5.6, −6.0 (4×SiMe). Anal. calcd for C23H41NO5Si2: C, 59.06;

J. A. Marco et al. / Tetrahedron: Asymmetry 9 (1998) 1679–1701
1697
H, 8.83; N, 2.99. Found: C, 58.88; H, 8.84; N, 3.11. The NOE measurements described in the text were
performed on this debenzylation product.
3.12.1. (4R,5R)-3-Benzyloxy-4-allyl-4-(t-butyldiphenylsilyloxymethyl)-5-(t-butyldimethylsilyloxymethyl)-
1,3-oxazolidin-2-one (6, R=allyl, R0=TBS, R00=TPS, P=Bn)
Oil, IR νmax cm−1: 1791 (C_O); FABMS, m/z 588.2606 (M−tBu)+. Calcd for C33H42NO5Si2,
M=588.2601; 1H NMR: δ 7.70–7.20 (15H, m, arom.), 5.76 (1H, dddd, J=17.5, 10, 8.5, 6 Hz, CH_CH2),
5.26, 4.89 (2H, AB system, J=9.8 Hz, NOCH2Ph), 5.14 (1H, br d, J=10 Hz, CH_CH2), 5.06 (1H, br d,
J=17.5 Hz, CH_CH2), 4.34 (1H, t, J=6.5 Hz, H-5), 4.00–3.85 (3H, m, C5–CH2OTBS, C4–CH2OTPS),
3.44 (1H, d, J=11 Hz, CH2OTPS), 2.28 (1H, dd, J=15, 6 Hz, CH2C_C), 2.14 (1H, dd, J=15, 8.5
Hz, CH2C_C), 1.04 (9H, s, SitBu), 0.79 (9H, s, SitBu), −0.02, −0.11 (2×3H, 2×s, SiMe); 13C
NMR: δ 158.8 (C_O), 135.0. 132.7, 131.9 (arom. C), 136.0, 135.7, 129.9, 129.6, 129.5, 128.6, 128.5,
127.8, 127.3 (arom. CH), 131.6 (CH_CH2), 119.8 (CH_CH2), 78.4 (NOCH2Ph), 77.3 (C-5), 68.1 (C-
4), 62.4 (C4–CH2OTPS), 60.9 (C5–CH2OTBS), 36.3 (CH2C_C), 26.6, 25.8 (2×SiCMe3), 18.8, 18.1
(2×SiCMe3), −5.6, −5.7 (2×SiMe). Anal. calcd for C37H51NO5Si2: C, 68.80; H, 7.96; N, 2.17. Found:
C, 68.81; H, 7.89; N, 2.01.
3.12.2. (2R,3R)-3,4-Di-O-benzyl-2-(N-benzyloxyamino)-2-methylbutane-1,3,4-triol (7, R=Me)
Oil, [α]D +24.4 (CHCl3, c 1); IR νmax cm−1: 3400 (br, OH), 3088, 3063, 3031; FABMS, m/z 422.2342
1
(M+H+). Calcd for C26H32NO4, M=422.2331; H NMR: δ 7.40–7.20 (15H, m, arom.), 4.78, 4.57 (2H,
AB system, J=11.3 Hz, NOCH2Ph), 4.66 (2H, br s, OCH2Ph), 4.53 (2H, s, OCH2Ph), 3.90 (1H, dd,
J=5.8, 4 Hz, H-3), 3.82 (1H, dd, J=10.3, 4 Hz, H-4), 3.66 (1H, d, J=11 Hz, H-10), 3.64 (1H, dd, J=10.3,
5.8 Hz, H-40), 3.58 (1H, d, J=11 Hz, H-10), 1.02 (3H, s, MeC2); 13C NMR: δ 138.3, 137.8, 137.5 (arom.
C), 128.4, 128.3, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6 (arom. CH), 79.6 (C-3), 77.0 (NOCH2Ph),
73.8, 73.5 (2×OCH2Ph), 70.3 (C-4), 65.4 (C-1), 63.2 (C-2), 16.2 (MeC2). Anal. calcd for C26H31NO4:
C, 74.08; H, 7.41; N, 3.32. Found: C, 73.96; H, 7.59; N, 3.16.
3.12.3. (2R,3R)-3,4-Di-O-benzyl-2-(N-benzyloxyamino)-2-n-butylbutane-1,3,4-triol (7, R=nBu)
Oil, [α]D +16.1 (CHCl3, c 2.1); IR νmax cm−1: 3440 (br, OH), 3088, 3063, 3030; FABMS, m/z
1
464.2778 (M+H+). Calcd for C29H38NO4, M=464.2800; H NMR: δ 7.40–7.25 (15H, m, arom.), 4.80,
4.56 (2H, AB system, J=11.3 Hz, OCH2Ph), 4.68, 4.65 (2H, AB system, J=11.5 Hz, NOCH2Ph), 4.57,
4.53 (2H, AB system, J=11.5 Hz, OCH2Ph), 3.94 (1H, dd, J=5.5, 3.4 Hz, H-3), 3.84 (1H, dd, J=10.5, 3.4
Hz, H-4), 3.68 (1H, dd, J=10.5, 5.5 Hz, H-40), 3.64 (2H, br s, H-1, H-10), 3.00 (1H, br s, OH), 1.50–1.20
(6H, m, CH2CH2CH2), 0.89 (3H, t, J=7.5 Hz, Me); 13C NMR: δ 138.4, 137.9, 137.8 (arom. C), 128.5,
128.4, 128.3, 127.8, 127.7, 127.6 (arom. CH), 80.3 (C-3), 76.5 (NOCH2Ph), 73.9, 73.5 (2×OCH2Ph),
70.4 (C-4), 64.6 (C-2), 64.1 (C-1), 30.2 (CH2C3H7), 25.3, 23.5 (CH2CH2Me), 14.1 (Me). Anal. calcd for
C29H37NO4: C, 75.13; H, 8.04; N, 3.02. Found: C, 74.99; H, 8.19; N, 3.11.
3.12.4. (2R,3R)-3,4-Di-O-benzyl-2-(N-benzyloxyamino)-2-phenylbutane-1,3,4-triol (7, R=Ph)
Oil, [α]D −1.0 (CHCl3, c 0.7); IR νmax cm−1: 3440 (br, OH), 3088, 3062, 3030; FABMS, m/z 484.2493
1
(M+H+). Calcd for C31H34NO4, M=484.2487; H NMR: δ 7.50 (5H, m, arom.), 7.40–7.20 (15H, m,
arom.), 4.76, 4.55 (2H, AB system, J=11.3 Hz, OCH2Ph), 4.60 (2H, s, NOCH2Ph), 4.37, 4.34 (2H, AB
system, J=12 Hz, OCH2Ph), 4.26 (1H, dd, J=11.3, 5 Hz, H-1), 4.15 (1H, dd, J=11.3, 7 Hz, H-10), 4.05
(1H, dd, J=6, 3.8 Hz, H-3), 3.55 (1H, dd, J=10.3, 3.8 Hz, H-4), 3.37 (1H, dd, J=10.3, 6 Hz, H-40), 2.60
(1H, br t, J=6.5 Hz, 1-OH); 13C NMR: δ 139.0, 138.2, 137.8, 137.5 (arom. C), 128.4, 128.3, 128.2,
128.1, 128.0, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2 (arom. CH), 81.0 (C-3), 76.5 (NOCH2Ph), 74.1,

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73.3 (2×OCH2Ph), 70.9 (C-4), 67.8 (C-2), 63.5 (C-1). Anal. calcd for C31H33NO4: C, 76.99; H, 6.88; N,
2.90. Found: C, 77.10; H, 7.00; N, 2.77.
3.12.5. (2R,3R)-3,4-O-Di-O-benzyl-2-(N-benzyloxyamino)-2-allylbutane-1,3,4-triol (7, R=allyl)
Oil, [α]D +19.5 (CHCl3, c 1.6); IR νmax cm−1: 3440 (br, OH), 3064, 3030; FABMS, m/z 448.2495
1
(M+H+). Calcd for C28H34NO4, M=448.2487; H NMR: δ 7.40–7.20 (15H, m, arom.), 5.94 (1H, ddt,
J=17.5, 10, 7 Hz, CH_CH2), 5.06 (1H, br d, J=10 Hz, CH_CH2), 5.03 (1H, br d, J=17.5 Hz, CH_CH2),
4.80, 4.56 (2H, AB system, J=11 Hz, OCH2Ph), 4.69, 4.65 (2H, AB system, J=11.5 Hz, NOCH2Ph),
4.54 (2H, s, OCH2Ph), 3.93 (2H, dd, J=5.5, 3.4 Hz, H-3), 3.86 (1H, dd, J=10.5, 3.4 Hz, H-4), 3.67
(1H, dd, J=10.5, 5.5 Hz, H-40), 3.66 (2H, s, H-1, H-10), 2.80 (1H, br s, OH), 2.34 (1H, dd, J=14, 7 Hz,
CH2C_C), 2.20 (1H, dd, J=14, 7 Hz, CH2C_C); 13C NMR: δ 138.3, 137.8, 137.6 (arom. C), 133.9
(CH_CH2), 128.5, 128.4, 128.3, 127.8, 127.7, 127.6 (arom. CH), 117.8 (CH_CH2), 80.0 (C-3), 76.6
(NOCH2Ph), 73.8, 73.5 (2×OCH2Ph), 70.2 (C-4), 64.7 (C-2), 64.2 (C-1), 35.1 (CH2C_C). Anal. calcd
for C28H33NO4: C, 75.14; H, 7.43; N, 3.13. Found: C, 75.10; H, 7.60; N, 3.22.
3.12.6. (2R,3R)-1,3,4-Tri-O-benzyl-2-(N-benzyloxyamino)-2-methylbutane-1,3,4-triol (8, R=Me)
Oil, [α]D +7.3 (CHCl3, c 1.7); IR νmax cm−1: 3320 (br, NH), 3063, 3030; FABMS, m/z 512.2794
1
(M+H+). Calcd for C33H38NO4, M=512.2801; H NMR: δ 7.40–7.20 (20H, m, arom.), 4.88, 4.55 (2H,
AB system, J=11.5 Hz, OCH2Ph), 4.63, 4.60 (2H, AB system, J=11.5 Hz, NOCH2Ph), 4.53, 4.52 (2H,
AB system, J=12 Hz, OCH2Ph), 4.50 (2H, s, OCH2Ph), 3.95 (1H, dd, J=10.5, 2 Hz, H-4), 3.80 (1H, dd,
J=7.5, 2 Hz, H-3), 3.68 (1H, dd, J=10.5, 7.5 Hz, H-40), 3.54, 3.50 (2H, AB system, J=9 Hz, H-1, H-10),
1.04 (3H, s, MeC2); 13C NMR: δ 139.1, 138.5, 138.0 (arom. C), 128.4, 128.3, 128.2, 128.1, 127.6, 127.5,
127.4, 127.3 (arom. CH), 79.6 (C-3), 76.6 (NOCH2Ph), 74.1, 73.3, 73.2 (4×OCH2Ph), 72.4 (C-4), 70.8
(C-1), 63.0 (C-2), 15.6 (MeC2). Anal. calcd for C33H37NO4: C, 77.47; H, 7.29; N, 2.74. Found: C, 77.30;
H, 7.41; N, 2.90.
3.12.7. (2R,3R)-1,3,4-Tri-O-benzyl-2-(N-benzyloxyamino)-2-n-butylbutane-1,3,4-triol (8, R=nBu)
Oil, [α]D +5.8 (CHCl3, c 0.8); IR νmax cm−1: 3350 (br, NH), 3063, 3030; FABMS, m/z 554.3276
1
(M+H+). Calcd for C36H44NO4, M=554.3270; H NMR: δ 7.40–7.25 (20H, m, arom.), 4.96, 4.60 (2H,
AB system, J=11.5 Hz, OCH2Ph), 4.66, 4.63 (2H, AB system, J=11.5 Hz, NOCH2Ph), 4.58, 4.53 (2H,
AB system, J=12 Hz, OCH2Ph), 4.49 (2H, s, OCH2Ph), 3.98 (1H, dd, J=10.2, 2 Hz, H-4), 3.91 (1H, dd,
J=7.5, 2 Hz, H-3), 3.80 (1H, dd, J=10.2, 7.5 Hz, H-40), 3.56, 3.51 (2H, AB system, J=8.8 Hz, H-1, H-10),
1.60–1.20 (6H, m, CH2CH2CH2), 0.91 (3H, t, J=7.5 Hz, Me); 13C NMR: δ 139.3, 138.7, 138.6, 138.1
(arom. C), 128.3, 128.2, 128.1, 127.6, 127.5, 127.4, 127.3 (arom. CH), 80.5 (C-3), 76.5 (NOCH2Ph), 74.3
(C-1), 73.3, 73.2, 73.1 (3×OCH2Ph), 69.3 (C-4), 64.7 (C-2), 30.3 (CH2–C3H7), 25.7, 23.6 (CH2CH2Me),
14.1 (Me). Anal. calcd for C36H43NO4: C, 78.09; H, 7.83; N, 2.53. Found: C, 78.00; H, 7.91; N, 2.60.
3.12.8. (2R,3R)-1,3,4-Tri-O-benzyl-2-(N-benzyloxyamino)-2-phenylbutane-1,3,4-triol (8, R=Ph)
Oil, [α]D −12.5 (CHCl3, c 2.2); IR νmax cm−1: 3350 (br, NH), 3064, 3031; FABMS, m/z 574.2947
1
(M+H+). Calcd for C38H40NO4, M=574.2957; H NMR: δ 7.50 (5H, m, arom.), 7.40–7.20 (25H, m,
arom.), 4.87, 4.57 (2H, AB system, J=11.5 Hz, OCH2Ph), 4.67 (2H, s, NOCH2Ph), 4.55, 4.45 (2H, AB
system, J=12.0 Hz, OCH2Ph), 4.40, 4.35 (2H, AB system, J=12.0 Hz, OCH2Ph), 4.15–3.95 (3H, m, H-1,
H-10, H-3), 3.85 (1H, dd, J=10.5, 2 Hz, H-4), 3.25 (1H, dd, J=10.5, 7.7 Hz, H-40); 13C NMR: δ 139.2,
139.0, 138.6, 138.4, 138.0 (arom. C), 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.3,
127.2, 127.0 (arom. CH), 80.2 (C-3), 76.2 (NOCH2Ph), 74.4, 73.5, 73.3, 73.2 (C-1, 3×OCH2Ph), 69.6

J. A. Marco et al. / Tetrahedron: Asymmetry 9 (1998) 1679–1701
1699
(C-4), 67.7 (C-2). Anal. calcd for C38H39NO4: C, 79.55; H, 6.85; N, 2.44. Found: C, 79.76; H, 7.00; N,
2.50.
3.12.9. (2R,3R)-1,3,4-Tri-O-benzyl-2-(N-benzyloxyamino)-2-allylbutane-1,3,4-triol (8, R=allyl)
Oil, [α]D +2.0 (CHCl3, c 0.6); IR νmax cm−1: 3350 (br, NH), 3064, 3031; FABMS, m/z 538.2963
1
(M+H+). Calcd for C35H40NO4, M=538.2957; H NMR: δ 7.40–7.20 (20H, m, arom.), 5.95 (1H, ddt,
J=17.5, 10, 7 Hz, CH_CH2), 5.05 (1H, br d, J=10 Hz, CH_CH2), 5.03 (1H, br d, J=17.5 Hz, CH_CH2),
4.92, 4.56 (2H, AB system, J=11 Hz, OCH2Ph), 4.66, 4.62 (2H, AB system, J=11.5 Hz, NOCH2Ph), 4.51,
4.49 (2H, AB system, J=11 Hz, OCH2Ph), 4.44 (2H, s, OCH2Ph), 3.95–3.85 (2H, m, H-3, H-4), 3.78 (1H,
dd, J=10.5, 7.5 Hz, H-40), 3.50 (2H, AB system, J=9 Hz, H-1, H-10), 2.35 (2H, d, J=7 Hz, CH2C_C);
13C NMR: δ 139.4, 138.7, 138.0 (arom. C), 134.7 (CH_CH2), 128.5, 128.4, 128.3, 127.7, 127.6, 127.5,
127.4 (arom. CH), 117.2 (CH_CH2), 80.2 (C-3), 76.4 (NOCH2Ph), 74.3, 73.2 (3×OCH2Ph), 72.8 (C-1),
69.6 (C-4), 64.9 (C-2), 35.4 (CH2C_C). Anal. calcd for C35H39NO4: C, 78.18; H, 7.31; N, 2.60. Found:
C, 78.05; H, 7.21; N, 2.48.
3.13. Photochemical conversion of (Z)-2a–d to (E)-2a–d
An ice-cooled solution of any of the oximes (Z)-2 (1 mmol) in MeOH (30 ml) was irradiated for 6
h with a UV lamp. Solvent removal in vacuo afforded an oil which was found by NMR to be a ca. 1:1
mixture of (E)- and (Z)-2. Column chromatography on silica gel (hexane:EtOAc=19:1) afforded both
isomeric oximes in almost 50% yield each.
Acknowledgements
This research has been financially supported by the Spanish Ministry of Education and Science
(DGICYT projects PB95-1089 and PB96-0760) and by BANCAJA (project P1B95-21). E.F. thanks the
Conselleria de Educaciò de la Generalitat Valenciana for a pre-doctoral fellowship.
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9. In order to ascertain whether partial racemization took place during either the formation of the oximes or their reactions
with organolithium reagents, we have prepared the Mosher derivatives of the 1-O-deprotected oximes 2a–d and addition
products 3a–b.
The Mosher derivatives obtained in this way were at least 98% diastereoisomerically pure, as judged by high-field 1H and
13C NMR measurements. Consequently, no detectable racemization took place in either step.
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11. (a) Murga, J., Ph.D. Thesis, Univ. Jaume I, 1996. A preliminary report of the present work has already appeared: Marco,
J. A.; Carda, M.; Murga, J.; González, F.; Falomir, E. Tetrahedron Lett. 1997, 1841–1844. (b) Carda, M.; Murga, J.;
Rodríguez, S.; González, F.; Castillo, E.; Marco, J. A. Tetrahedron: Asymmetry 1998, 9, 1703–1712.
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19. This result is to be compared with those observed for ketones 1b,d with organomagnesium reagents, where three
equivalents of the latter were necessary for a fast reaction.8d We have interpreted this behaviour by assuming that two
molecules of the Grignard reagent participate in the transition state, one of them forming the chelate and the second one
adding to the C_O bond.

J. A. Marco et al. / Tetrahedron: Asymmetry 9 (1998) 1679–1701
1701
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22. The study has been made at the HF/3-21G theoretical level using the GAUSSIAN94 package of programs, revision B.1:
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.; Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T.;
Petersson, G. A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J. V.; Foresman, J.
B.; Cioslowski, J.; Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.;
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here have been performed in vacuo, without consideration of the role played by solvation. Complete calculations for both
(E)- and (Z)-oximes, with inclusion of solvent molecules, are presently being performed and will be the subject of a
separate publication.
23. The diastereomeric ratios 10/11 have been calculated with the assumption of a Boltzmann distribution of the TSs leading
to either diastereoisomer. See: Frenking, G.; Köhler, K. F.; Reetz, M. T. Tetrahedron 1991, 47, 9005–9018.
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contained in these two papers.
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