1′-Azido- and 1′-amino-1,3-dioxolan-4-ones

Article abstract of DOI:10.1016/S0957-4166(01)00173-2

1,3-Dioxolanone alcohols, prepared via the addition of chiral lithium enolates of 1,3-dioxolan-4-ones to aldehydes, are suitable intermediates for the synthesis of chiral trisubstituted isoserines or trisubstituted 3-hydroxy-β-lactams. In particular, the

Full text of DOI:10.1016/S0957-4166(01)00173-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1015–1023
1%-Azido- and 1%-amino-1,3-dioxolan-4-ones
Arturo Battaglia,* Gaetano Barbaro, Patrizia Giorgianni, Andrea Guerrini and Antonella Pepe
Istituto CNR dei Composti del Carbonio Contenenti Eteroatomi ‘I.Co.C.E.A.’, via Gobetti 101, I-40129 Bologna, Italy
Received 26 February 2001; accepted 18 April 2001
Abstract—1,3-Dioxolanone alcohols, prepared via the addition of chiral lithium enolates of 1,3-dioxolan-4-ones to aldehydes, are
suitable intermediates for the synthesis of chiral trisubstituted isoserines or trisubstituted 3-hydroxy-b-lactams. In particular, the
methyl ester of 2-methyl-3-(2-furyl)isoserinic acid and two 3-methyl-3-hydroxy-b-lactams bearing either a 2-furyl or a phenyl
substituent at C-(4) have been prepared. The (2R,3S) stereochemistry of the isoserine, and the (3R,4S) stereochemistry of the two
b-lactams is that required for the synthesis of taxoid analogues having the side-chain with the proper (2%R,3%S) configuration.
© 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
ing 1%-amino dioxolanones (path B), from which, by use
of suitable protocols, both isoserines and b-lactams can
be synthesized. Surprisingly, no methods have been
reported for the preparation of 1%-amino dioxolanones
whose structure places them as leading candidates as
building blocks for EPC syntheses of a special class of
b-peptides bearing in their skeleton a quaternary stereo-
genic center as a bend promoter.3 As the only excep-
Recently, we have developed a protocol for the synthe-
sis of (4S)/(4R) diastereomeric mixtures of (3R)-3-
hydroxy-b-lactams with a quaternary stereogenic center
at C-(3) by addition of imines to (2S)-lithium enolates
of (2S,5S)-1,3-dioxolan-4-ones in a mixed THF:HMPA
(4:1) solvent system.1 From a practical point of view the
(2S,5S)-1,3-dioxolan-4-one starting materials are easily
prepared from inexpensive and readily available (2S)-
hydroxy acids. A major pitfall of this protocol is that
the low reactivity of the imines requires the use of a
toxic HMPA co-solvent. Therefore, we considered
replacing the imines with the more reactive aldehydes,
which would represent a new approach to trisubstituted
isoserines and 3-hydroxy-b-lactams. Seebach’s dia-
stereoselectivity studies2 on the addition reactions of
(2S)-enolates of dioxolanones to aldehydes, which gave
dioxolanone alcohols I, seemed to us a good starting
point to explore the new methodology according to the
sequence of reactions depicted in Scheme 1. Access to
isoserines and 3-hydroxy-b-lactams requires the devel-
opment of new methodology for the stereoselective
conversion of 1%-hydroxy dioxolanones into 1%-azido
dioxolanones. These products can be directly trans-
formed into isoserines by removal of the acetal center
via base induced solvolysis followed by reduction of the
azido group (path A). Alternatively, the C-(1%)-N3
group can be transformed into an amino group afford-
O
OH
N3
O
O
O
1'
R
5
1'
R
R
(ii)
5
O
O
O
H
O
O
O
(i)
H
H
I
(iii)
NH2
Path B
O
Path A
1'
R
5
O
1: (v)
2: (iii)
O
(iv)
(v)
H
Path D
Path C
HO
R
H
NH2
O
3
4
2
OR1
OH
N
3
R
O
(i) Aldol addition; (ii) azidation; (iii) reduction; (iv) cyclization;
(v) alcoholysis
Scheme 1. Suggested protocol for the conversion of diox-
olanone alcohols into trisubstituted isoserines and 3-hydroxy-
b-lactams.
* Corresponding
battaglia@area.bo.cnr.it
author.
Fax:
(+39)51-6398349;
e-mail:
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00173-2

1016
A. Battaglia et al. / Tetrahedron: Asymmetry 12 (2001) 1015–1023
+Li-O
tion, we have recently described the synthesis of a
1%-amino dioxolan-4-one derived from the addition
reaction of the enolates of 1a to N-trimethylsilylphenyl
aldimine under special reaction conditions.1d Another
very important use of 1%-amino dioxolanones would be
the synthesis of a,a-disubstituted 2%-hydroxy-b-amino
acids (isoserines), intramolecularly protected both at
the carbonyl and adjacent OH substituent. Conse-
quently, the free 1%-amino group could be coupled with
the carboxylic function of another amino acid. Alterna-
tively, the 1%-amino dioxolanones can be transformed
into b-lactams (path C) for peptide synthesis via Oji-
ma’s ‘b-lactam synthon method’.4 Very important
targets from 1%-amino dioxolanones are also (3R,4S)-
trisubstituted b-lactams and (2R,3S)-a,a-disubstituted
isoserines with the correct stereochemistry to append to
the 13-OH of taxoids.5 Methodologies for the synthesis
of these highly functionalized appendants are still
scarce. Kant, Greene and Ojima independently devel-
oped approaches for the synthesis of suitable precursors
of these appendants such as N,O-protected trisubsti-
tuted (2R,3S)-isoserines and (3R,4S)-b-lactams.6 How-
ever, these intermediates were obtained in low yields via
multi-step processes, which require the use of expensive
chiral auxiliaries and several deprotection/reprotection
sequences.
R
2S
O
O
+
O
R1
2,3
1a,b
TS I
TS II
TS III
TS IV
+Li-O
O
+Li-O
+Li-O
+Li-O
O
R
O
O
R
O
H
H
R
H
R
X
O
O
O
O
O
O
O
R1
R1
R1
R1
OH
OH
OH
O
O
O
O
1'
1'
1'
R
R
R
5
5
5
O
O
O
2
2
2
O
O
R1
R1
R1
(2S,5S,1'S)
(2S,5R,1'R)
(2S,5R,1'S)
6a,b
5a,b
4a,b
i)
i)
i)
N3
N3
N3
The key step in the protocol outlined in Scheme 1 is the
azidation of the C-(1%) hydroxyl group and, herein, we
describe our attempts to carry out its conversion to an
azide moiety with inversion of configuration, and its
subsequent reduction to an amine functionality.7
O
O
O
1'
1'
1'
R
R
R
5
2
5
2
5
O
O
O
2
O
O
O
R1
R1
R1
(2S,5R,1'R)
(2S,5R,1'S)
(2S,5S,1'R)
7a,b
8a,b
9a
2. Results and discussion
1a: R1 = H; 1b: R1 = Me; 2: R = C6H5; 3: R = 2-furyl; 4a, 5a, 6a,
7a, 8a, 9a: R = 2-furyl, R1 = H; 4b, 5b, 6b, 7b, 8b: R = C6H5,
R1 = Me; i) ZnN6.2Py/PPh3/R2CO2-N=N-CO2R2 (R2: iPr, tBu)
The starting substrates tested for the development of
our methodology were the dioxolanone alcohols
obtained by the addition reactions of 2-furylaldehyde 3
to the lithium enolate 1a (ratio of (2S):(2R)=97:3) and
benzaldehyde 2 to the lithium enolate 1b (ratio of
(2S):(2R)=93:7),8 respectively (Scheme 2). Synthesis of
the dioxolanone alcohols lacked stereochemical control
at C-(5) and C-(1%)8 and mixtures of three isomers were
obtained (Scheme 2 and Table 1). The (2S,5R,1%S)
diastereoisomer formed via TS I, the (2S,5R,1%R)
diastereoisomer via TS II and the (2S,5S,1%S)
diastereoisomer, formed via TS IV. The aldol conden-
sation of aldehyde 2 with enolate 1b yielded a mixture
of (2S,5R,1%S)-4b, (2S,5R,1%R)-5b, and (2S,5S,1%S)-6b,
which were separated by flash chromatography.8 The
addition reaction of aldehyde 3 to the enolate 1a
yielded the dioxolanone alcohols (2S,5R,1%S)-4a,
(2S,5R,1%R)-5a, and (2S,5S,1%S)-6a. Chromatography
Scheme 2. Synthesis of 1%-azido dioxolanones by azidation of
dioxolanone alcohols.
of the crude mixture gave (2S,5S,1%S)-6a and a mixture
of (2S,5R,1%R)-5a and (2S,5R,1%S)-4a. Quantities of
pure 5a were isolated by fractional crystallization of
this mixture. The diastereoisomer 4a was isolated as the
major of a 9:1 (2S,5R,1%S)/(2S,5R,1%R) diastereoiso-
meric mixture by recrystallization. Alternatively, an
exploratory investigation showed that all the isomers
could be efficiently separated by preparative HPLC.
The stereochemistry of 4b, 5b, and 6b has been assigned
previously.8 In particular, the stereochemistry of
Table 1. Relative product distribution of dioxolanone alcoholsa,b
Entry
Product
(2S,5S,1%S)
(2S,5R,1%R)
(2S,5R,1%S)
Total yield (%)
1
2
a
b
4: 19
4: 19
5: 46
5: 63
6: 35
6: 18
80
89
a THF at −78°C.
b Determined by 1H NMR directly on the crude reaction mixture.

A. Battaglia et al. / Tetrahedron: Asymmetry 12 (2001) 1015–1023
1017
zinc azide-mediated Mitsonobu azidation.11 This proto-
col uses zinc azide (in the form of its more stable
bis-pyridine complex) as the nucleophilic partner of the
dioxolanone alcohol, electrophilically activated by the
bis-iso-propylazodicarboxylate/Ph3P system. The azida-
tion of dioxolanone alcohols (2S,5R,1%R)-5a,b and
(2S,5S,1%S)-6a occurred with inversion of configuration
at the C-(1%) stereogenic center, yielding the 1%-azido
dioxolanones (2S,5R,1%S)-8a, (2S,5R,1%S)-8b and
(2S,5S,1%R)-9a, respectively. The azidation of
R1
R1
R1
O
O
O
O
O
O
R
2
2
2
5
5
5
O
H
O
H
O
H
H
R
H
R
1'
1'
1'
O
O
O
H
(2S,5R,1'S)-4a,b
a: R = 2-furyl, R1 = H; b: R = C6H5, R1 = Me
(2S,5R,1'R)-5a,b
(2S,5S,1'S)-6a,b
Figure 1. Five-membered ring chelate structures of diox-
olanone alcohols (2S,5R,1%S)-4a,b, (2S,5R,1%R)-5a,b, and
(2S,5S,1%S)-6a,b.
(2S,5R,1%R)-5a
also
afforded
the
carbonate
Boc
NH
O
(2S,5S,1%S)-6b was established by X-ray structural anal-
ysis. The stereochemistry of (2S,5R,1%R)-5b, and
(2S,5R,1%S)-4b were assigned by chemical correlation
with the corresponding methyl (2R,3R)- and (2R,3S)-
2,3-dihydroxy-2-methyl-3-phenylpropanoates. The 1H
and 13C NMR spectral data are consistent with the
assumption that the main conformers exists in an
intramolecular hydrogen bonded form of a five-mem-
bered ring structure (Fig. 1) that have been suggested to
rationalize the 1H and 13C NMR spectral data of
alicyclic 2,3-dihydroxy-a-methylcarbonyl compounds.9
The diastereoisomers 4a, 5a, and 6a showed consistent
trends for the C-(2)H and C-(5)Me 1H NMR reso-
nances with those observed for 4b, 5b, and 6b and other
dioxolanone alcohols.8 In fact, a trans relationship
between the 2-furyl substituent at C-(1%) and the C-(2)
proton is seen for both the (2S,5S,1%S) and (2S,5R,1%S)
isomers in the five-membered ring structures, whereas a
cis relationship exists in the (2S,5R,1%R) isomer.
Accordingly, the C-(2)H signal of the (2S,5R,1%R) iso-
mer (l=4.84 ppm) resonated at higher field than that
of the (2S,5R,1%S) isomer (l=5.48 ppm) and the
(2S,5S,1%S) isomer (l=5.21 ppm). Similarly, the 2-furyl
substituent at C-(1%) and the methyl group at C-(5) are
trans to each other in the (2S,5S,1%S) and (2S,5R,1%R)
isomers, while a cis relationship is seen for the
(2S,5R,1%S) isomer. The C-(5)Me resonance of the
(2S,5R,1%S) isomer absorbed at higher field (l=1.20
ppm) with respect to that of the (2S,5S,1%S) isomer
(l=1.37 ppm) and (2S,5R,1%R) (l=1.43 ppm). An
identical trend was observed for the resonances of the
C-(5)Me signals in 13C NMR. It is also notable that the
1H NMR signal for the C-(2) proton of the (2S,5S,1%S)
isomer was seen within the narrow range of l=5.20–
5.21 ppm, which is typical of a number of relevant
(2S,5S,1%S)-dioxolanone alcohols we have already
synthesized.8,10
13
OMe
N3
OH
O
ii)
N3
O
1'
5
i)
R
(2R,3S)-15
O
2
O
R
OMe
Bz
O
OH
R1
NH
O
(2R,3S)-12, 13
12
OMe
(2S,5R,1'S)
8a,b
OH
iii), iv)
(2R,3S)-14
R2
C6H5
O
N
H
O
3
2
O
R2 = 2,4-MeO-C6H3
O
OMe
(2R,3S)-16
i) MeO-/MeOH; ii) H2/Pd/C/Boc2O; iii) H2/Pd/C; iv) BzCl/NaHCO3
8b, 13: R = C6H5, R1 = Me; 8a, 12: R = 2-furyl, R1 = H
Scheme 3. Synthesis of isoserines from 1%-azido dioxolanones.
(2S,5S,1'R)
(2S,5R,1'R)
(2S,5R,1'S)
9a
7b
8a,b
i)
i)
i)
NH2
NH2
NH2
O
O
O
1'
1'
R
1'
R
R
5
2
5
2
5
2
O
O
O
O
O
O
R1
R1
R1
(2S,5R,1'R)
(2S,5R,1'S)
(2S,5S,1'R)
18b
17a,b
19a
ii)
ii)
ii)
B:
B:
B:
HO
R
HO
R
R
The azido dioxolanones 7–9 which were used as tem-
plates for the synthesis of methyl isoserinates (path A of
Scheme 1, and Scheme 3) and b-lactams (path B of
Scheme 1, and Scheme 4) were targets of this prelimi-
nary investigation. In particular, the b-lactam (3R,4S)-
20b and the isoserinate (2R,3S)-14, are opportunely
protected to be appended to taxoid derivatives accord-
ing to standard methodologies. Regardless of the stereo-
chemistry of the dioxolanone alcohol, the one-pot
C-(1%) hydroxyl to azide conversion was achieved via
HO
N
N
N
O
H
O
H
O
H
(3R,4S)
20a,b
(3S,4R)
(3R,4R)
21b
22a
a: R= 2-Furyl, R1 = H; b: R = C6H5, R1= Me
i) H2O/PPh3; ii) B: = MeMgBr or LHMDS
Scheme 4. Synthesis of b-lactams from 1%-azido dioxolanones.

1018
A. Battaglia et al. / Tetrahedron: Asymmetry 12 (2001) 1015–1023
(2S,5R,1%R)-10 (Fig. 2) (with
a
(2S,5R,1%S)-8a/
2.2. Synthesis of b-lactams (Scheme 4)
(2S,5R,1%R)-10 ratio of 1.7:1). The formation of this
undesired side-product was substantially reduced to
Catalytic hydrogenation of 1%-azido dioxolanones in the
presence of Pd–C failed. Instead, (2S,5R,1%S)-8a,b,
(2S,5R,1%R)-7b, and (2S,5S,1%R)-9a were reduced to the
corresponding 1%-amino dioxolanones (2S,5R,1%S)-
17a,b, (2S,5R,1%R)-18b, and (2S,5S,1%R)-19a with Ph3P/
H2O.13 The treatment of 1%-amino dioxolanones with
bases caused the simultaneous cyclization and elimina-
tion of the acetal center with the formation of the
corresponding b-lactams. Two bases were probed.
Namely, the reaction of (2S,5R,1%S)-17b and MeMgBr
under Birkofer’s conditions14 gave the b-lactam
(3R,4S)-20b,15 while the lithium bis(trimethylsilyl)amide
(LHMDS) induced cyclization of (2S,5R,1%R)-18b,
(2S,5R,1%S)-17a, and (2S,5S,1%R)-19a, yielded the b-lac-
tams (3R,4R)-21b, (3R,4S)-20a, and (3S,4R)-22a,
respectively. The analytical data for (3R,4S)-20a, and
(3R,4S)-20b were consistent with the literature data16
giving further proof of the configuration of the parent
1%-azido dioxolanones (2S,5R,1%S)-17a and 17b and 1%-
amino dioxolanones (2S,5R,1%S)-8a and 8b. Similarly,
the stereochemistry of (2S,5R,1%R)-7b and (2S,5R,1%R)-
18b was further assessed via chemical correlation with
the b-lactam (3R,4R)-21b.16 Finally, the stereochem-
istry of 1%azido dioxolanone (2S,5S,1%R)-9a and 1%-
amino dioxolanone (2S,5S,1%R)-19a was established via
chemical correlation with the b-lactam (3S,4R)-22a
55%
when
bis-iso-propylazodicarboxylate
was
replaced by the more sterically demanding bis-tert-
butylazodicarboxylate. Partial loss of selectivity at the
C-(1%) stereocenter occurred during the azidation of the
(2S,5R,1%S) diastereomers of 4a and 4b. In fact, the
azidation of a (2S,5R,1%S)-4a/(2S,5R,1%R)-5a (9:1 mix-
ture) gave a 3:1 mixture of (2S,5R,1%R)-7a/(2S,5R,1%S)-
8a, (2S,5R,1%S)-4b gave a 12:1 mixture of azido
derivatives (2S,5R,1%R)-7b/(2S,5R,1%S)-8b and the car-
bonate (2S,5R,1%S)-11 (Fig. 2). The formation of this
undesired side product was avoided when the azidation
of (2S,5R,1%S)-4b was carried out with the bis-tert-
butylazodicarboxylate/Ph3P system.
The enantiomeric excess (e.e.) of all dioxolanone alco-
hols and 1%-azido dioxolanones (2S,5R,1%S)-8a,b and
(2S,5S,1%R)-9a was determined by H NMR analysis in
the presence of the chiral shift reagent Yt(hfc)3 and
corresponded to the diastereomeric excess (d.e.) of the
parent dioxolanones 1a and 1b. Namely, an e.e. of 94%
was found for 4a, 5a, 6a, 8a, and 9a and an e.e. of 86%
was determined for 4b, 5b, 6b, and 8b.
1
2.1. Synthesis of isoserines
1
whose H and 13C NMR spectral data were identical to
those of its enantiomer (3R,4S)-20a.16
Methoxide-induced removal of the auxiliary of
(2S,5R,1%S)-azido dioxolanones 8a and 8b (Scheme 3)
gave the corresponding (2R,3S)-2-azido methyl esters
12 and 13, respectively. Catalytic hydrogenation of
(2R,3S)-13 using Pd–C in the presence of bis-tert-
butyldicarbonate (Boc2O) gave the protected methyl
isoserinate (2R,3S)-15 which was already synthesized
via an independent route.12 This chemical correlation
allowed the assignment of configuration of (2S,5R,1%S)-
8b. Sequential catalytic hydrogenation of (2R,3S)-12
and N-benzoylation under Schotten–Baumann condi-
tions gave the methyl N-benzoylisoserinate (2R,3S)-14.
2,4-Dimethoxybenzylidene protection of (2R,3S)-14
with 2,4-dimethoxybenzaldehyde dimethyl acetal6b in
the presence of pyridinium toluene-p-sulfonate (PTS) in
toluene at 110°C followed by LiOH induced hydrolysis
afforded the oxazolidine carboxylic acid (2R,3S)-16 as
a 4:1 epimeric mixture, ready to be appended to taxoid
derivatives.
3. Conclusion
We have developed a route for the one step transforma-
tion of dioxolanone alcohols into 1%-azido diox-
olanones. The conversion occurs with clean inversion of
configuration at the 1%-position when a cis relationship
exists between the C-(5) methyl group and the C-(1%)
hydroxyl substituent, as in the (2S,5R,1%R) and
(2S,5S,1%S) isomers. 1%-Azido dioxolanones are useful
building blocks for the synthesis of other interesting
compounds.17 As an application, we have probed their
potential as intermediates for the synthesis of isoserines
and 1%-amino dioxolanones, from which b-lactams were
synthesized. The synthesis of these important chiral
intermediates is achieved in a few very simple steps and
does not require the use of chiral auxiliaries or expen-
sive protection/deprotection sequences with sterically
hindered protecting groups in order to improve the
diastereoselectivity.
O
O
4. Experimental
4.1. General
O
O
1'
1'
CHMe2
CHMe2
O
O
O
O
5
5
O
O
H
O
O
O
2
2
1H and 13C NMR spectra were recorded on a 400 MHz
spectrometer with Me4Si or CHCl3 (in CDCl3) as inter-
nal standards. Mass spectra were recorded on an ion
trap spectrometer with an ionization potential of 70 eV.
Gas liquid chromatography (GC) was carried out on a
(2S,5R,1'R)-10
(2S,5R,1'S)-11
Figure 2. Carbonates (2S,5R,1%R)-10 and (2S,5R,1%S)-11.

A. Battaglia et al. / Tetrahedron: Asymmetry 12 (2001) 1015–1023
1019
1
GC–mass spectrometer (ion trap, 70 eV). Infrared spec-
tra were recorded on a Fourier-transform IR spectrom-
eter. Preparative HPLC chromatography used an
Hypersil column (10 mm CN CPS, 250×10.0 mm, n-hex-
ane/MeOH, 88.5:1.5). Finally, a Chiracel OD column
(Daicel 25×0.46 cm i.d.) was used for the enantioselec-
tive analysis of the 1%-amino-1,3-dioxolan-4-ones and
b-lactams.
(2S,5R,1%S)-4a: H NMR (CDCl3): l 0.96 (s, 9H), 1.36
(s, 3H), 2.70 (bs, 1H), 4.91 (s, 1H), 5.30 (s, 1H), 6.40
(m, 1H), 6.46 (m, 1H), 7.43 (m, 1H); 13C NMR
(CDCl3): l 20.8, 23.5, 34.9, 72.3, 82.2, 109.4, 110.9,
111.1, 142.9, 151.8, 175.0.
4.4. General procedure for azidation of dioxolanone
alcohols
4.2. General procedure of synthesis of dioxolanone
alcohols
A toluene solution of di-iso-propyl- or di-tert-butyl-
azodicarboxylate was added to a stirred solution of the
appropriate dioxolanone alcohol, PPh3, and ZnN6·2Py
in toluene (10.0 mL) at 25°C. The mixture was soni-
cated, filtered on Celite, and the solvent was evaporated
in vacuo. Flash chromatography (SiO2, n-hexane/ethyl
acetate) provided pure 1%-azido dioxolanones.
A solution of the dioxolanone (1.0 equiv.) in THF was
added to a cooled (−78°C) stirred solution of LDA (1.5
equiv.) and the mixture was stirred for 15 min at
−78°C. The aldehyde (1.5–2.0 equiv.) was added.
Unless otherwise stated, the reaction mixture was
allowed to warm to −15°C with continuous stirring
over a 3 h period. The reaction solution was quenched
by the addition of saturated NH4Cl solution (10 mL)
and extracted with ethyl acetate. The extracts were
combined, dried, and concentrated under reduced pres-
sure. The diastereomeric composition of the diox-
olanone alcohols was established directly in the crude
4.5. (2S,5R,1%S)-1%-(Azidophenylmethyl)-2-tert-butyl-2,5-
dimethyl-[1,3]-dioxolan-4-one (2S,5R,1%S)-8b
Di-iso-propylazodicarboxylate (0.40 g, 2.0 mmol), PPh3
(0.55 g, 2.1 mmol), (2S,5R,1%R)-5b (0.22 g, 0.8 mmol),
and ZnN6·2Py (0.24 g, 0.8 mmol) gave, after 3 h,
(2S,5R,1%S)-8b (0.22 g, 0.72 mmol, 90%): mp 84–86°C;
IR (CDCl3, cm−1): 2109, 1793; [h]2D0=+163.8 (c 0.6,
CHCl3); MS (m/z): 303 (M+), 276, 245, 133, 115, 101,
77; 1H NMR (400 MHz, CDCl3): l 0.94 (s, 9H), 1.26 (s,
3H), 1.83 (s, 3H), 4.67 (s, 1H), 7.30–7.40 (m, 5H); 13C
NMR (100 MHz, CDCl3): l 22.1, 22.2, 25.0, 39.0, 69.6,
81.9, 116.3, 128.5, 129.1, 129.3, 133.7, 173.7. Anal.
calcd for C16H21N3O3: C, 63.35; H, 6.98; N 13.85.
Found: C, 63.62; H, 6.79; N, 13.80%.
1
reaction mixture by H NMR. The mixture of diox-
olanone alcohols was subjected to a first purification by
flash chromatography on silica, which allowed the
determination of overall yields. No variation of the
product distribution was observed after this
chromatography.
4.3. 2-tert-Butyl-5-(furan-2-yl-hydroxymethyl)-5-methyl-
[1,3]-dioxolan-4-ones
4.6. (2S,5R,1%R)-1%-(Azidophenylmethyl)-2-tert-butyl-
2,5-dimethyl-[1,3]-dioxolan-4-one (2S,5R,1%R)-7b
The reaction of dioxolanone 1a (1.0 g, 6.3 mmol) and
furan-2-carbaldehyde 3 (0.91 g, 9.5 mmol) at −90°C
over 90 min gave a 19:46:35 mixture of (2S,5S,1%S)-6a/
(2S,5R,1%R)-5a/(2S,5R,1%S)-4a. (1.28 g, 5.04 mmol,
80%). Chromatography (SiO2, n-pentane/Et2O/EtOAc,
15.0:4.0:1.0) gave pure (2S,5S,1%S)-6a (0.13 g, 0.51
Di-tert-butylazodicarboxylate (0.46 g, 2.0 mmol), PPh3
(0.52 g, 2.0 mmol), (2S,5R,1%S)-4b (0.20 g, 0.72 mmol)
and ZnN6·2Py (0.24 g, 0.8 mmol) were reacted at 25°C
for 24 h. Chromatography of the crude reaction mix-
ture gave (2S,5R,1%R)-7b (0.10 g, 0.34 mmol, 47%) and
(2S,5R,1%S)-8b (0.01 g, 0.03 mmol, 4.0%) and unreacted
(2S,5R,1%S)-4b (0.07 g, 0.27 mmol). In another experi-
ment (2S,5R,1%S)-4b (0.2 g, 0.72 mmol) was reacted
with di-iso-propylazodicarboxylate (0.40 g, 2.0 mmol),
PPh3 (0.52 g, 2.0 mmol), and ZnN6·2Py (0.24 g, 0.8
mmol) at 25°C for 15 h. Chromatography gave
(2S,5R,1%R)-7b (0.12 g, 0.42 mmol, 58%), (2S,5R,1%S)-
8b (0.012 g, 0.04 mmol, 6%) and the carbonate
(2S,5R,1%S)-11 (0.69 g, 0.19 mmol, 26%). (2S,5R,1%R)-
7b: mp 97–99°C; IR (CDCl3, cm−1): 2110, 1790; [h]D20=
−86.8 (c 0.7, CHCl3); MS (m/z): 303 (M+), 276, 245,
mmol) and
a
mixture of (2S,5R,1%R)-5a and
(2S,5R,1%S)-4a. Recrystallization of the mixture from
n-hexane gave pure (2S,5R,1%R)-5a (0.46 g, 1.82 mmol,
29%) and a mixture of (2S,5R,1%S)-4a/(2S,5R,1%R)-5a=
9:1 (0.40 g, 1.56 mmol, 25%). Alternatively, it was
possible to separate the three stereoisomers by prepara-
tive HPLC column (Hypersil, 10 mm CN CPS, 250×10.0
mm, n-hexane/EtOH, 98.5:1.5); IR (CDCl3, cm−1):
3600–3500, 1789, 1484; MS (m/z): 254 (M+), 210, 197,
168. Anal. calcd for C13H18O5: C, 61.40; H, 7.14.
Found: C, 61.64; H, 6.96%.
1
1
(2S,5S,1%S)-6a: [h]2D0=−12.5 (c 1.5, CHCl3); H NMR
133, 115, 101; H NMR (400 MHz, CDCl3): l 0.97 (s,
(CDCl3): l 0.84 (s, 9H), 1.50 (s, 3H), 2.70 (bs, 1H), 4.91
(s, 1H), 5.16 (s, 1H), 6.34 (m, 2H), 7.38 (m, 1H); 13C
NMR (CDCl3): l 15.6, 23.3, 34.0, 71.1, 81.6, 108.1,
108.6, 110.5, 142.2, 150.8, 174.2.
9H), 1.21 (s, 3H), 1.44 (s, 3H), 4.81 (s, 1H), 7.30–7.45
(m, 5H); 13C NMR (100 MHz, CDCl3): l 22.4, 22.5,
25.3, 39.2, 71.3, 82.5, 116.1, 128.9, 129.1, 129.3, 135.2,
173.0. Anal. calcd for C16H21N3O3: C, 63.35; H, 6.98; N
13.85. Found: C, 63.67; H, 7.12; N, 13.72%.
(2S,5R,1%R)-5a: [h]D20=−4.72 (c 0.53, CHCl3); mp 99–
1
100°C; H NMR (CDCl3): l 0.93 (s, 9H), 1.49 (s, 3H),
(2S,5R,1%S)-7b: IR (CDCl3, cm−1): 1810, 1755; [h]D20=
+51 (c 1.1, CHCl3); MS (m/z): 364 (M+), 307, 221, 179,
2.70 (bs, 1H), 4.89 (s, 1H), 4.87 (s, 1H), 6.40 (m, 2H),
7.43 (m, 1H); 13C NMR (CDCl3): l 20.5, 23.3, 34.7,
72.2, 82.5, 108.4, 109.7, 142.2, 151.2, 172.9.
1
172, 133, 115, 105; H NMR (400 MHz, CDCl3): l 1.01
(s, 9H), 1.18 (d, 3H, J=6.4 Hz), 1.23 (d, 3H, J=6.4

1020
A. Battaglia et al. / Tetrahedron: Asymmetry 12 (2001) 1015–1023
Hz), 1.30 (s, 3H), 1.84 (s, 3H), 4.76 (m, 1H), 5.59 (s,
1H), 7.37–7.40 (m, 3H), 7.40–7.45 (m, 2H); 13C NMR
(100 MHz, CDCl3): l 21.5, 21.7, 21.8, 21.9, 25.3, 39.2,
72.7, 80.6, 82.2, 116.6, 128.4, 129.1, 129.2, 134.8, 153.4,
173.7. Anal. calcd for C20H28O6: C, 65.91; H, 7.74.
Found: C, 65.57; H, 7.64%.
8 h gave (2S,5S,1%R)-9a (0.18 g, 0.65 mmol, 65%). IR
(CDCl3, cm−1): 2142; [h]D20=−138 (c 0.6, CHCl3); MS
1
(m/z): 279 (M+), 237, 183, 167, 149, 94; H NMR (400
MHz, CDCl3): l 1.02 (s, 9H), 1.31 (s, 3H), 4.75 (s, 1H),
5.20 (s, 1H), 6.40 (m, 1H), 6.53 (m, 1H), 7.47 (m, 1H);
13C NMR (100 MHz, CDCl3): l 17.6, 23.8, 34.5, 61.9,
81.7, 108.2, 111.0, 111.3, 143.8, 147.1, 173.14. Anal.
calcd for C13H17N3O4: C, 55.91; H, 6.14; N, 15.05.
Found: C, 55.54; H, 6.31; N, 14.60%.
4.7. (2S,5R,1%S)-1%-(Azidofuran-2-yl-methyl)-2-tert-
butyl-5-methyl-[1,3]-dioxolan-4-one (2S,5R,1%S)-8a
Di-tert-butylazodicarboxylate (0.46 g, 2.0 mmol), PPh3
(0.55 g, 2.1 mmol), (2S,5R,1%R)-5a (0.23 g, 0.83 mmol),
and ZnN6·2Py (0.24 g, 0.8 mmol) gave, after 20 h,
(2S,5R,1%S)-8a (0.18 g, 0.65 mmol, 78%). In another
experiment (2S,5R,1%R)-5a (0.23 g, 0.83 mmol) was
reacted with di-iso-propylazodicarboxylate (0.4 g, 2.0
mmol), PPh3 (0.55 g, 2.1 mmol), and ZnN6·2Py (0.24 g,
0.8 mmol) in 15 h. Chromatography gave (2S,5R,1%S)-
8a (0.13 g, 0.45 mmol, 54%) and the carbonate deriva-
tive (2S,5R,1%R)-10 (0.09 g, 0.27 mmol, 33%).
(2S,5R,1%S)-8a: IR (CDCl3, cm−1): 2142; [h]D20=−1.98 (c
0.53, CHCl3); MS (m/z): 279 (M+), 237, 183, 167, 149,
94; 1H NMR (400 MHz, CDCl3): l 0.99 (s, 9H), 1.35 (s,
3H), 4.80 (s, 1H), 5.40 (s, 1H), 6.40 (m, 1H), 6.60 (m,
1H), 7.50 (m, 1H); 13C NMR (100 MHz, CDCl3): l
21.5, 23.5, 35.0, 63.4, 81.6, 110.9, 111.0, 111.1, 143.8,
147.5, 173.8. Anal. calcd for C13H17N3O4: C, 55.91; H,
6.14, N, 15.05. Found: C, 55.54; H, 6.29; N, 14.68%.
4.10. (2R,3S)-3-Azido-2-hydroxy-2-methyl-3-phenylpro-
pionic acid methyl ester (2R,3S)-13
A solution of (2S,5R,1%S)-8b (0.27 g, 0.9 mmol) in
MeOH (2.0 mL) and a solution of MeONa (0.1 M, 3.0
mL 0.30 mmol) was stirred at 60°C under argon for 45
min. The reaction mixture was diluted with saturated
NH4Cl solution (5.0 mL) and extracted with EtOAc.
The organic solvent was dried and evaporated to obtain
of (2R,3S)-13 (0.18 g, 0.76 mmol, 85%): IR (CDCl3,
cm−1): 2109, 1739; [h]D20=+114.5 (c 0.7, CHCl3); MS
1
(m/z): 235 (M+), 208, 193, 158, 148, 133, 106; H NMR
(400 MHz CDCl3): l 1.17 (s, 3H), 3.59 (b, 1H), 3.87 (s,
3H), 4.71 (s, 1H), 7.3–7.5 (m, 5H); 13C NMR (100
MHz, CDCl3): l 22.8, 53.3, 70.8, 76.8, 128.5, 129.0,
129.3, 133.9, 175.5. Anal. calcd for C11H13N3O3: C,
56.16; H, 5.57; N, 17.86. Found: C, 55.94; H, 5.68; N,
17.72%.
(2S,5R,1%R)-10: IR (CDCl3, cm−1): 2980, 1806, 1756;
1
4.11. (2R,3S)-3-(tert-Butoxycarbonylamino)-2-hydroxy-
2-methyl-3-phenylpropionic acid methyl ester (2R,3S)-15
MS (m/z): 340 (M+), 283, 172; H NMR (400 MHz,
CDCl3): l 0.94 (s, 9H), 1.30 (d, 3H), 1.33 (d, 3H), 1.48
(s, 3H), 4.90 (m, 1H, J=6.4 Hz), 4.95 (s, 1H), 5.85 (s,
1H), 6.38 (m, 1H), 6.52 (m, 1H), 7.42 (m, 1H); 13C
NMR (100 MHz, CDCl3): l 20.6, 21.7, 21.8, 23.3, 34.7,
73.0, 75.4, 80.6, 109.6, 110.0, 110.1, 142.8, 147.6, 153.2,
171.5. Anal. calcd for C17H24O7: C, 59.99; H, 7.11.
Found: C, 59.74; H, 7.28%.
An ethyl acetate solution (3.0 mL) of (2R,3S)-13 (0.04
g, 0.17 mmol), di-tert-butyldicarbonate (0.05 g, 0.28
mmol), and Pd–C (5%, 0.005 g) was stirred under
hydrogen (balloon pressure) for 48 h. The reaction
mixture was filtered through Celite, the solvent evapo-
rated and the residue chromatographed (SiO2, n-hex-
ane/ethyl acetate, 5:1) to afford (2R,3S)-15 (0.04 g, 0.14
mmol, 80%) whose analytical data were consistent with
those reported in the literature.6b (2R,3S)-15: IR
(CDCl3, cm−1): 3500, 2970, 1730; [h]2D0=−5.5 (c 0.7,
CHCl3); MS (m/z): 310 (MH+), 271, 254, 210, 193, 105;
1H NMR (400 MHz CDCl3): l 1.19 (s, 3H), 1.38 (s,
9H), 3.54 (b, 1H), 3.84 (s, 3H), 4.95 (d, 1H, J=10 Hz),
5.48 (d, 1H), 7.3–7.35 (m, 5H) [lit.:6b 1.20, 1.38, 3.51,
3.84, 4.95, 5.45, 7.28–7.35]; 13CNMR (100 MHz,
CDCl3): l 29.9, 28.5, 53.6, 59.9, 79.9, 128.1, 128.5,
128.7, 137.9, 155.0, 176.9. Anal. calcd for C16H23NO5:
C, 62.12; H, 7.49; N, 4.53. Found: C, 61.94; H, 7.58; N,
4.72%.
4.8. (2S,5R,1%R)-1%-(Azidofuran-2-yl-methyl)-2-tert-
butyl-5-methyl-[1,3]-dioxolan-4-one (2S,5R,1%R)-7a
Di-tert-butylazodicarboxylate (0.41 g, 1.8 mmol), PPh3
(0.50 g, 1.9 mmol), ZnN6·2Py (0.23 g, 0.75 mmol), and
a (2S,5R,1%S)-4a/(2S,5R,1%R)-5a (9:1 mixture; 0.19 g,
0.75 mmol) at 15°C in 10 h gave, after chromatogra-
phy, a (2S,5R,1%R)-7a/(2S,5R,1%S)-8a=2.8:1 mixture
(0.13 g, 0.48 mmol, 64%) and unreacted (2S,5R,1%S)-4a
(0.02 g, 0.08 mmol). (2S,5R,1%S)-8a: IR (CDCl3, cm−1):
1
2140; MS (m/z): 279 (M+), 237, 183, 167, 149, 94; H
NMR (400 MHz, CDCl3): l 0.93 (s, 9H), 1.51 (s, 3H),
4.67 (s, 1H), 4.97 (s, 1H), 6.42 (m, 1H), 6.51 (m, 1H),
7.46 (m, 1H); 13C NMR (100 MHz, CDCl3): l 21.9,
23.4, 34.9, 64.0, 82.1, 110.1, 110.7, 111.2, 143.5, 147.9,
172.5. Anal. calcd for C13H17N3O4: C, 55.91; H, 6.14;
N, 15.05. Found: C, 56.42; H, 6.20; N, 15.35%.
4.12. (2R,3S)-3-Azido-3-furan-2-yl-2-hydroxy-2-methyl-
propionic acid methyl ester (2R,3S)-12
A MeOH (4.0 mL) solution of (2S,5R,1%S)-8a (0.86 g,
3.1 mmol) and 6.2 mL of 1.0 M solution of MeONa
(6.2 mmol) was stirred at 50°C under argon for 2 h.
The reaction mixture was diluted with 5.0 mL of satu-
rated NH4Cl solution and extracted with ethyl acetate.
The extract was dried and concentrated under reduced
pressure to obtain (2R,3S)-12 (0.88 g, 0.29 mmol, 95%).
4.9. (2S,5S,1%R)-1%-(Azidofuran-2-yl-methyl)-2-tert-
butyl-5-methyl-[1,3]-dioxolan-4-one (2S,5S,1%R)-9a
Di-tert-butylazodicarboxylate (0.23 g, 1.00 mmol),
PPh3 (0.26 g, 1.0 mmol), (2S,5S,1%S)-6a (0.10 g, 0.41
mmol), and ZnN6·2Py (0.12 g, 0.41 mmol) at 15°C over

A. Battaglia et al. / Tetrahedron: Asymmetry 12 (2001) 1015–1023
1021
IR (CDCl3, cm−1): 2110, 1739; [h]2D0=+86.0 (c 1.0,
CHCl3); MS (m/z): 225 (M+), 183, 147, 129, 111, 83; 1H
NMR (400 MHz, CDCl3): l 1.30 (s, 3H), 3.52 (s, 1H),
3.87 (s, 3H), 4.69 (s, 1H), 6.40 (m, 1H), 6.60 (m, 1H),
7.45 (m, 1H); 13C NMR (100 MHz, CDCl3): l 23.1,
53.7, 63.9, 77.4, 110.9, 111.0, 143.4, 147.9, 175.3. Anal.
calcd for C9H11N3O4: C, 48.00; H, 4.92; N, 18.66.
Found: C, 48.26; H, 4.79; N, 18.48.
4.15. General procedure for the reduction of 1%-azido
dioxolanones to 1%-amino dioxolanones by using Ph3P/
H2O
The 1%-azido dioxolanone (1.0 equiv.) and Ph3P (1.5
equiv.), in the presence of few drops of H2O, was
heated at 60°C in THF. After addition of ethyl ether,
the reaction mixture was extracted three times with 1.0 N
aqueous HCl. The aqueous solution was washed with
ethyl ether. The aqueous phase was treated with solid
NaHCO3 and extracted with EtOAc. The organic layer
was dried over Na2SO4, the solvent evaporated under
reduced pressure and chromatographed (SiO2, n-hex-
ane/ethyl acetate, 1:1) to afford the corresponding 1%-
amino dioxolanone.
4.13. (2R,3S)-3-Benzoylamino-3-furan-2-yl-2-hydroxy-2-
methylpropionic acid methyl ester (2R,3S)-14
An ethyl acetate solution (10.0 mL) of (2R,3S)-12 (0.88
g, 2.9 mmol) and 0.12 g of 5% Pd–C was stirred under
hydrogen for 15 h. After the reaction mixture was
filtered and mixed with ethyl acetate (10 mL) and
saturated NaHCO3 solution (10 mL), benzoyl chloride
(0.42 g, 3.0 mmol) was added over 10 min. The organic
phase was separated and the aqueous phase was
extracted with ethyl acetate. The combined organic
phase was extracted with brine, dried and concentrated
under reduced pressure to obtain (2R,3S)-14 (0.70 g,
2.3 mmol, 80%). IR (CDCl3, cm−1): 1730; [h]D20=−3.76
(c 1.38, CHCl3); MS (m/z): 303 (M+), 288, 198; 1H
NMR (400 MHz, CDCl3): l 1.41 (s, 3H), 3.67 (bs, 1H),
3.81 (s, 3H), 5.68 (d, 1H), 6.35 (m, 1H), 6.43 (m, 1H)
7.01 (d, 1H), 7.4–7.8 (m, 6H, 1H); 13C NMR (100
MHz, CDCl3 relevant resonances): l 23.2, 53.0, 53.4,
76.6, 109.1, 110.2, 166.4, 175.3. Anal. calcd for
C16H17NO5: C, 63.36; H, 5.65; N, 4.62. Found: C,
62.62; H, 5.88; N, 4.50%.
4.16. (2S,5R,1%S)-1%-(Aminophenylmethyl)-2-tert-butyl-
2,5-dimethyl-[1,3]-dioxolan-4-one (2S,5R,1%S)-17b
The 1%-azido dioxolanone (2S,5R,1%S)-8b (0.25 g, 0.83
mmol) gave the 1%-amino dioxolanone (2S,5R,1%S)-17b
(0.21 g, 0.75 mmol, 90%). IR (CDCl3, cm−1): 3500–
3400, 1780; [h]2D0=+49.0 (c 0.7, CHCl3); MS (m/z): 277
1
(M+), 263, 220, 132, 106, 91, 79; H NMR (CDCl3): l
1.02 (s, 9H, 3 Me), 1.28 (s, 3H, Me), 1.76 (s, 3H, Me),
4.07 (s, 1H, HꢀCꢀN), 7.25–7.45 (m, 5H, arom.); 13C
NMR (CDCl3): l 22.3, 22.4, 25.1, 39.0, 61.2, 84.0,
115.5, 127.7, 127.9, 128.3, 141.2, 175.5. Anal. calcd for
C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C,
69.50; H, 8.49; N, 4.82%.
4.17. (3R,4S)-4-Phenyl-3-hydroxy-3-methylazetidin-2-
one (3R,4S)-20b
4.14. Methyl (2S,3R)-3-Benzoyl-2-(2,4-dimethoxy-
phenyl)-4-furan-2-yl-5-methyloxazolidine-5-carboxylate
(2R,3S)-16
An ethereal solution of MeMgBr (3.0 M, 2.4 mmol)
was added to an ethereal solution of (2S,5R,1%S)-17b
(0.21 g, 0.75 mmol) at 0°C. The mixture was stirred at
25°C for 60 min. The reaction was quenched with a
saturated aqueous solution of ammonium chloride and
extracted with ethyl acetate. The organic layer was
dried over Na2SO4, and the solvent evaporated under
reduced pressure. Chromatography of the residue
(SiO2, EtOAc/n-hexane, 2:1) gave (3R,4S)-20b (0.11 g,
0.61 mmol, 81%) with analytical data consistent with
those reported in the literature.1d,6c (3R,4S)-20b: mp
171–173°C; IR (CDCl3, cm−1): 3650–3400, 1771; [h]D20=
+101 (c 0.5, CD3COCD3); MS (m/z): 177 (M+), 134;
A mixture of (2R,3S)-14 (0.43 g, 1.42 mmol), 1-
dimethoxymethyl-2,4-dimethoxybenzene (0.61 g, 2.85
mmol), and pyridinium toluene-p-sulfonate (0.04 g,
0.15 mmol) in toluene (15 mL) was refluxed for 1 h.
The solvent was evaporated, the residue was dissolved
in CH2Cl2 and extracted with water. The organic phase
was dried. Evaporation of the solvent and chromatog-
raphy (SiO2, CH2Cl2/EtOAc, 29:1) gave 16 (0.56 g, 1.24
mmol, 75%) as a 4:1 epimeric mixture. IR (CDCl3,
cm−1): 2980–2900, 1735, 1700; MS (m/z): 451 (M+),
1
106; H NMR (CD3COCD3): l 0.89 (s, 3H), 2.75–2.85
1
392, 286, 285, 267, 165; H NMR (major diastereoiso-
(b, 1H), 4.64 (s, 1H), 7.20–7.60 (m, 6H); 13C NMR
(CD3COCD3): l 22.7, 65.6, 86.8, 128.2, 128.8, 139.1,
172.1. Anal. calcd for C10H11NO2: C, 67.78; H, 6.26; N
7.90. Found: C, 68.04; H, 6.44; N, 8.05%.
mer) (400 MHz, CDCl3): l 1.15 (s, 3H, Me), 3.73 (s,
6H, OMe), 3.80 (s, 3H, OMe), 6.22 (bs, 1H), 6.32 (bs,
1H), 6.35 (m, 1H), 6.42 (m, 1H), 6.68 (s, 1H), 7.10–7.25
(bs, 4H), 7.20–7.35 (bs, 1H), 7.42 (s, 1H), 7.60 (m, 1H);
13C NMR (100 MHz, CDCl3): l 19.6, 29.9, 53.4, 55.6,
56.0, 61.4, 85.6, 98.6, 104.6, 110.6, 110.8, 117.8, 127.2,
128.2, 128.9, 130.4, 136.1, 142.9, 151.5, 159.4, 161.8,
173.2, 173.3. 1H NMR (minor diastereoisomer) (400
MHz, DMSO, 55°C): l 1.15 (bs, 3H, Me), 3.43 (s, 3H,
OMe), 3.65–3.85 (bs, 6H, 2 OMe), 5.8–5.9 (bs, 1H),
6.25–6.38 (bs, 1H), 6.40–6.58 (bs, 2H), 6.80 (s, 1H),
6.9–7.10 (bs, 1H), 7.20–7.40 (bs, 5H), 7.57 (b, 1H).
Anal. calcd for C25H25NO7: C, 66.51; H, 5.58; N, 3.10.
Found: C, 66.85; H, 5.72; N, 3.38%.
4.18. (2S,5R,1%R)-1%-(Aminophenylmethyl)-2-tert-butyl-
2,5-dimethyl-[1,3]-dioxolan-4-one (2S,5R,1%R)-18b
The 1%-azido dioxolanone (2S,5R,1%R)-7b (0.13 g, 0.44
mmol) gave, after 18 h, the 1%-amino dioxolanone
(2S,5R,1%R)-18b (0.11 g, 0.39 mmol, 88%). IR (CDCl3,
cm−1): 3500–3400, 1780; [h]D20=+51.0 (c 0.5, CHCl3);
1
MS (m/z): 277 (M+), 263, 220, 132, 106, 91, 79; H
NMR (CDCl3): l 0.97 (s, 9H), 1.42 (s, 3H), 1.47 (s,
3H), 4.39 (s, 1H), 7.30–7.45 (m, 5H); 13C NMR

1022
A. Battaglia et al. / Tetrahedron: Asymmetry 12 (2001) 1015–1023
(CDCl3): l 18.8, 23.0, 24.9, 38.8, 60.5, 82.1, 115.1,
127.9, 128.3, 128.5, 139.5, 175.2. Anal. calcd for
C16H23NO3: C, 69.29; H, 8.36; N 5.05. Found: C, 69.44;
H, 8.24; N, 5.15%.
Battaglia, A.; Barbaro, G.; Guerrini, A.; Bertucci, C.;
Geremia, S. Tetrahedron: Asymmetry 1998, 9, 3401–3409;
(c) Battaglia, A.; Barbaro, G.; Guerrini, A.; Bertucci, C.
J. Org. Chem. 1999, 64, 4643–4651; (d) Battaglia, A.;
Barbaro, G.; Di Giuseppe, F.; Giorgianni, P.; Guerrini,
A.; Bertucci, C.; Geremia, S. Tetrahedron: Asymmetry
1999, 10, 2765–2773.
4.19. (3R,4R)-4-Phenyl-3-hydroxy-3-methylazetidin-2-
one (3R,4R)-21b
2. (a) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2708–2748; (b) Seebach,
D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40, 1313–
1324.
3. See for example: (a) Seebach, D.; Abele, S.; Sifferlen, T.;
Ha¨nggi, M.; Gruner, S.; Seiler, P. Helv. Chim. Acta 1998,
81, 2218–2243 and references cited therein; (b) Hayashi,
Y.; Katada, J.; Harada, T.; Tachiki, A.; Iijima, K.;
Takiguchi, Y.; Muramatsu, M.; Miyazaki, H.; Asari, T.;
Okazaki, T.; Sato, Y.; Yasuda, E.; Yano, M.; Uno, I.;
Ojima, I. J. Med. Chem. 1998, 41, 2345–2360.
4. Ojima, I.; Acc. Chem. Res. 1995, 28, 383–389. According
to this protocol the carbonyl group of an N-unsubsti-
tuted b-lactam is coupled to the amino group of an
amino acid after acylation of the nitrogen atom of the
b-lactam.
5. Structure–activity relationship (SAR) studies have shown
that taxoids bearing an additional methyl substituent at
C-(2) of the (2%R,3%S)-a,a-disubstituted isoserine appen-
dant display higher cytotoxic activity compared to the
parent docetaxel and paclitaxel when evaluated in vitro
assays. See: Kant, J.; Schwartz, W. S.; Fairchild, C.; Gao,
Q.; Huang, S.; Long, B. H.; Kadow, J. F.; Langley, D.
R.; Farina, V.; Vyas, D. Tetrahedron Lett. 1996, 37,
6495–6498.
6. See: (a) Ref. 5; (b) Denis, J.-N.; Fkyerat, A.; Gimbert, Y.;
Coutterez, C.; Mantellier, P.; Jost, S.; Greene, A. E. J.
Chem. Soc., Perkin Trans. 1 1995, 1811–1816; (c) Ojima,
I.; Wang, T.; Delaloge, F. Tetrahedron Lett. 1998, 39,
3663–3666.
7. The azidation of the C-(1%)-OH group can also be carried
out in a two step process which involves the conversion
of the C-(1%)-OH into a bromide followed by azidation.
The net result is retention of configuration.
8. The enolates 1a (2S/2R=97:3) and 1b (2S:2R=93:7)
were obtained by treatment of the corresponding (2S,5S)/
(2R,5S)=97:3 and (2S,5S)/(2R,5S)=93:7 mixtures of 2-
tert-butyl-2,5-dimethyl-[1,3]-dioxolan-4-one and 2-tert-
butyl-5-methyl-[1,3]-dioxolan-4-one, respectively, with
lithium di-iso-propylamide (LDA). See: Battaglia, A.;
Barbaro, G.; Giorgianni, P.; Guerrini, A.; Bertucci, C.;
Geremia, S. Chem. Eur. J. 2000, 6, 3551–3557.
A solution of (2S,5R,1%R)-18b (0.07 g, 0.25 mmol) in
THF (2.0 mL) was added at −50°C to a stirred THF
solution (4 mL) of LHMDS (1.8 equiv.). The reaction
mixture was allowed to warm to −25°C with continuous
stirring over 3 h. The reaction solution was quenched by
the addition of acetic acid, concentrated under reduced
pressure. Chromatography of the residue (SiO2, EtOAc/
n-hexane, 2:1) gave the b-lactam (3R,4R)-21b (0.04 g,
0.23 mmol, 91%) whose analytical data are consistent
with those reported in the literature.1d (3R,4R)-21b: mp
191–193°C; IR (CDCl3, cm−1): 3650–3400, 1771; [h]D20=
−37.5 (c 0.5, CD3COCD3); MS (m/z): 177 (M+), 134; 106;
1H NMR (CD3COCD3): l 0.90 (s, 3H), 2.85–2.90 (b,
1H), 4.64 (s, 1H), 7.20–7.45 (m, 5H), 7.60 (b, 1H); 13C
NMR (CD3COCD3): l 19.0, 66.3, 88.0, 126.8, 128.3,
129.3, 139.2, 172.3. Anal. calcd for C10H11NO2: C, 67.78;
H, 6.26; N 7.90. Found: C, 67.43; H, 6.10; N, 7.75%.
4.20. (3R,4S)-4-Furan-2-yl-3-hydroxy-3-methylazetidin-
2-one (3R,4S)-20a
The 1%-azido dioxolanone (2S,5R,1%S)-8a (0.26 g, 0.92
mmol) was reduced using the Ph3P/H2O reduction pro-
tocol to yield the corresponding 1%-amino dioxolanone
(2S,5R,1%S)-17a. The solution of crude (2S,5R,1%S)-17a
in 4.0 mL of THF was added at −50°C to a stirred THF
solution (8 mL) of 1.1 mmol of LHMDS. The reaction
temperature was raised to −25°C with continuous stirring
over 2 h. The reaction solution was quenched by the
addition of acetic acid and concentrated under reduced
pressure. Chromatography of the residue (SiO2, EtOAc/
n-hexane, 2:1) gave (3R,4S)-20a (0.10 g, 0.57 mmol, 62%)
which has analytical data consistent with those reported
in the literature.1c (3R,4S)-20a: mp 127–129°C; [h]2D2=
1
+ 70 (c 0.3, CH3COCH3); H NMR (CDCl3): l 1.64 (s,
3H), 2.90–3.00 (br s, 1H), 4.62 (s, 1H), 6.30–6.45 (m, 2H),
6.60–6.70 (br s, 1H), 7.45–7.50 (m, 1H). Anal. calcd for
C8H9NO3: C, 57.48; H, 5.43; N, 8.38. Found: C, 57.32;
H, 5.38; N, 8.46%.
4.21. (3S,4R)-4-Furan-2-yl-3-hydroxy-3-methylazetidin-
2-one (3S,4R)-22a
9. For a description of the five-membered ring chelate struc-
ture suggested for the main conformers of alicyclic 2,3-
The b-lactam (3S,4R)-22a was prepared in 54% yields
from the 1%-azido dioxolanone (2S,5S,1%R)-9a under
identical conditions reported in Section 4.20. The com-
pound showed identical properties to its enantiomer
(3R,4S)-20a except for the sign of the optical rotation:
[h]2D0=−70.6 (c 0.4, CH3COCH3).
dihydroxy-a-methylcarbonyl
compounds,
see:
(a)
Heathcock, C. H.; Pirrung, M. C.; Sohn, J. E. J. Org.
Chem. 1979, 44, 4294–4299; (b) Heathcock, C. H.; Pir-
rung, M. C.; Young, S. D.; Hagen, J. P.; Jarvi, E. T.;
Badertscher, U.; Ma¨rki, H. P.; Montgomery, S. H. J. Am.
Chem. Soc. 1984, 106, 8161–8174; (c) See also: Ref. 8.
10. An alternative six-membered hydrogen bonded ring
structure has been suggested for the main conformers of
dioxolanone alcohols in Ref. 2b. However, this structure
References
cannot account for the observed trends in the H and 13C
1
1. (a) Battaglia, A.; Barbaro, G.; Guerrini, A.; Bertucci, C.
NMR spectral data of dioxolanone alcohols. For a
detailed discussion on this topic, see: Ref. 8.
Tetrahedron: Asymmetry 1997, 8, 2527–2531; (b)

A. Battaglia et al. / Tetrahedron: Asymmetry 12 (2001) 1015–1023
1023
11. Viaud, M. C.; Rollin, P. Synthesis 1990, 130–
132.
tion of the 3-hydroxyl group with TESCl and N-
acylation, as the key intermediate to append to 7-TES
baccatin III. See: Ref. 5.
12. See: Ref. 6b. This ester was transformed into the corre-
sponding 2-(2,4-dimethoxyphenyl)oxazolidine carboxylic
acid which was then appended to a derivative of 7,10-
deacetylbaccatin III according to the procedure described
in Ref. 6b.
13. Staundiger, H. Helv. Chim. Acta 1919, 2, 635.
14. Birkofer, L.; Schramm, J. Liebigs. Ann. Chem. 1975, XX,
2195.
16. The independent synthesis of b-lactams (3R,4S)-20a,b
and (3R,4R)-21a,b was achieved via addition reactions of
(2S)-enolates of dioxolanones 1a,b to phenyltrimethyl-
silylimine1d and 2-furyltrimethylsilylimine.1c The synthesis
of (3R,4S)-20b is also reported in Ref. 6c.
17. For example, it is possible to transform the azido group
in other interesting functional groups, such as NꢁCꢁO,
NꢁCꢁS, and NꢁSꢁO.
15. The chiral b-lactam (3R,4S)-20b was used, after protec-
.