Synthesis of chiral β2,2,3-3-amino-2-hydroxyalkanoates and 3-alkyl-3-hydroxy-β-lactams by double asymmetric induction

Article abstract of DOI:10.1016/j.tet.2007.05.069

Reactions of chiral (2S)-enolates of dioxolan-4-ones, derived from lactic, mandelic, and phenyllactic acids, with aliphatic (S_S)- and (S_R)-tert-butylsulfinyl aldimines afforded conformationally restrained C2-disubstituted N,O-orthogo

Full text of DOI:10.1016/j.tet.2007.05.069

Tetrahedron 63 (2007) 7949–7969
Synthesis of chiral b2,2,3-3-amino-2-hydroxyalkanoates and
3-alkyl-3-hydroxy-b-lactams by double asymmetric induction
*
Andrea Guerrini, Greta Varchi, Rizzo Daniele, Cristian Samorı and Arturo Battaglia
*
`
Istituto CNR per la Sintesi Organica e Fotoreattivitaꢀ—‘I.S.O.F.’, Area della Ricerca di Bologna,
via P. Gobetti 101, 40129 Bologna, Italy
Received 14 February 2007; revised 2 May 2007; accepted 17 May 2007
Available online 24 May 2007
Abstract—Reactions of chiral (2S)-enolates of dioxolan-4-ones, derived from lactic, mandelic, and phenyllactic acids, with aliphatic (SS)-
and (SR)-tert-butylsulfinyl aldimines afforded conformationally restrained C2-disubstituted N,O-orthogonally protected 3-amino-2-hydr-
oxyalkanoates in the form of N-sulfinyl protected 10-aminodioxolan-4-ones. The product distribution showed that there is significant kinetic
selectivity, due to the presence of ‘matched’ and ‘mismatched’ components, between the (S)- or (R)-tert-butylsulfinyl aldimines and the (2S)-
enolates of the 1,3-dioxolan-4-ones. Selective methoxide-induced removal of the acetal group of the N-sulfinyl-10-aminodioxolanones yielded
the corresponding N-sulfinyl protected methyl alkanoates. In addition, the selective acid-induced removal of the sulfinyl group of the N-
sulfinyl-10-aminodioxolanones provided the corresponding N-unprotected 10-aminodioxolanones, whose base-induced cyclization afforded
the corresponding b-lactams.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
attractive for peptide synthesis, whose number of solution
conformations can be reduced by the presence of this addi-
tional substituent. As long as the biological activity is pre-
served, these less flexible analogs gain affinity toward the
receptor, primarily for entropic reasons.10 Moreover, the
presence of a tertiary alcohol in the transition-state mimick-
ing unit will possibly improve the membrane permeation
properties and decrease the enzymatic hydrolysis.11
3-Amino-2-hydroxyalkanoic acids find several applications
in medicinal chemistry due to the presence of the hydroxy-
ethylamine core structure, which mimics the tetrahedral
transition state of peptidase amide bond hydrolysis.1 This
family of b-amino acids exhibits a per se inhibitory activity
against aminopeptidase-2 (MetAP2), being useful for treat-
ing cancer conditions, which are exacerbated by angiogene-
sis.2 Moreover, these compounds can serve as building
blocks for the synthesis of oligopeptides, which are recog-
nized as displaying inhibitory activity against several prote-
ases, including renin,3 HIV retropepsins,4 plasmepsins,5
cathepsins,6 and pepsins7 involved in important pathologies
regarding blood pressure regulation such as HIV, malaria,
and Alzheimer’s disease. These b-amino acids are also em-
ployed as appendants for anti-neoplastic taxol analogs.8
Our previous investigations have focused on the reaction
between chiral enolates of 1,4-dioxolanones and N-BOC
aromatic and heteroaromatic aldimines12 and C-glyco-
sylsulfinyl aldimines.13 These reactions proved to be a
powerful method for the synthesis of 10-aminodioxolanones,
which can be considered as orthogonally N,O-protected
norstatines.
In continuing our studies on this subject, we considered the
synthesis of a-hydroxy-b-aminoalkanoic acids, which are
key scaffolds of many potent peptidomimetics. For this pur-
pose, we selected activated aliphatic chiral N-tert-butylsul-
finyl aldimines as the proper partners (Scheme 1), since
they happen to be more stable compared to their BOC pro-
tected counterparts, which can only be generated in situ.
However, the presence of a stereogenic center in the imine
skeleton provides an additional element of kinetic selectivity
with respect to the reactions performed with achiral N-BOC
substituted counterparts. In addition to a full account of the
synthetic results, we provide here a preliminary rationaliza-
tion of the stereochemical outcome, based on all ‘matching’
Our contribution in this field concerns the synthesis of chiral
a-hydroxy-b-amino acids, which are characterized by a con-
formational constraint due to the presence of an additional
substituent at the C2 carbon atom.9 The synthesis of
constrained analogs of biologically active molecules is
a widespread procedure to reduce the number of possible
conformations. This practice was shown to be particularly
Keywords: Dioxolan-4-ones; Double asymmetric induction; Aldimines;
a-Hydroxy-b-amino acids; 3-Hydroxy-b-lactams.
* Corresponding authors. Tel.: +39 051 6398283; fax: +39 051 6398349;
e-mail: g.varchi@isof.cnr.it
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.069

7950
A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
and ‘mismatching’ components. Qin and co-workers have
very recently demonstrated the key role of sulfur chirality
in terms of diastereoselectivity control in the addition of
(R)-tert-butylsulfinyl amines to achiral enolates of O-
BOC-a-hydroxy acetates.14 Based on this report, we decided
to evaluate the sulfur chirality effect on our product distribu-
tion, not only in reactions involving aliphatic sulfinyl imines
but also in a reaction involving a heteroaromatic imine
derived from thiophene-2-carbaldehyde.
that the enolate will predominantly approach the aldimine
from the less hindered diastereotopic face, so compounds
arising from TS-I and TS-II will be favored, while TS-III
and especially TS-IV will be highly disfavored because of
the severe steric repulsion between R3 and the tert-butyl
group of the dioxolanone ring9c (Scheme 3). Besides, simple
exo/endo selectivity will control the stereochemistry at the
newly formed C10 chiral center.
-O
R1
R3
R1
O
S
LiO
+
O
2S O
t
N
N
Bu
O
R2
+
O
t
R
Bu
R2
t
R
Bu
TS-III
TS-I
TS-IV
TS-II
THF
HMPA
O
t
Highly
S
Bu
Favored
Disfavored
Favored
Disfavored
O
S
HN
R1
R2
R2
N
R2
R2
N
H
R
O
R2
t
NH
O
Bu
R3
H
N
R3
N
H
2
H
R2
OR3
O
3
O
R3
R1 OH
R3
t
t
R
Bu
Bu
-O
R1
-O
R1
R
t
α-hydroxy-β-amino esters
Bu
O
O
O
O
O
O
-O
O
R1
R3
O
O
R2 = 2-thiophene; Alk
-O
t
t
Bu
Bu
R1
R
R
Scheme 1. General scheme for the a-hydroxy-b-amino acid synthesis.
R2NH
R1
R2NH
R1
R2NH
For this study, we selected the three 1,4-dioxolanones 1–3,
which are characterized by a different steric demand at
both the C2 and C5-position, in order to evaluate their reac-
tivity and stereochemical effect. These compounds are read-
ily available from acetalization of chiral a-hydroxy acids
with aldehydes or ketones.15 In particular, we selected natu-
rally occurring (2S)-lactic, benzyllactic and mandelic acids,
which were reacted with pivaldehyde or pinacolone
(Scheme 2).
R3
R1
R3
O
O
1'
1'
1'
O
R
5 O
O
5O
2
2
O
5 O
2
t
t
t
R
Bu
Bu
R
Bu
2S,5S,1'S
2S,5R,1'R
2S,5R,1'S
Scheme 3.
For our study the heteroaromatic aldimines16 (SS)-4 and
(SR)-4, derived from thiophene-2-carbaldehyde, and the ali-
phatic tert-butylsulfinyl aldimines (SS)-5–7 and (SR)-5–7,
derived from isovaleraldehyde, 2-phenylacetaldehyde, and
isobutyraldehyde, respectively, were employed (Fig. 1).
R1
R1
O
LiO
R1
CO2H
O
5O
O
+
O
O
2
t
R
Bu
OH
t
t
R
Bu
(2S,5S)-1-3
1, 1a: R=R1= Me; 2, 2a: R= H; R1= CH2Ph; 3, 3a: R=H; R1= Ph
R
Bu
These aldehydes were selected on the basis of the potential
biological activity of their resulting trisubstituted a-hy-
droxy-b-amino acids obtained by our enolate/aldimine
protocol (Chart 1).
(2S)-1a-3a
Scheme 2.
For example, a-hydroxy-b-amino acids bearing a heteroaro-
matic substituent at the C3-position, such as the 2-thienyl
group, are found as side chains of potent antitumor tax-
anes.11,17 The C2-methyl substituted analogs were obtained
by reaction of the enolate 1a with the 2-thienylaldimines
(SS)- and (SR)-4.
The (2S,5S)-1,3-dioxolan-4-one major isomers were isolated
as homochiral material, or in a very high diastereomeric
excess, by re-crystallization (de>98%). Treatment of the di-
oxolanones with lithiated bases afforded the corresponding
(2S)-chiral enolates 1a–3a. As shown in Scheme 3, the addi-
tion of chiral (2S)-enolates to aliphatic aldimines can in prin-
ciple give rise to the formation of four diastereoisomers,
arising from the different approach of the enolate to the ald-
imine (transition states: TS-I, TS-II, TS-III, and TS-IV). The
enantiomeric (2R)-enolates would provide their enantio-
mers. Since the (2R)-a-hydroxy acids can be readily ob-
tained from the corresponding (2R)-a-amino acids, this
feature is particularly useful in terms of biologically active
analogs synthesis. The final product distribution will be
the result of facial and simple selectivities. It is expected
S
S
S
S
N
O
N
O
N
O
N
O
S
Ph
(S )-6, (S )-6 (S )-5, (S )-5
(S )-4, (S )-4
(S )-5, (S )-5
S
R
S
R
S
R
S
R
Figure 1.

A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
7951
NH2
O
NH2
O
family30,31 and the low molecular weight peptide (HIV
PR) protease KI2.32
NH2
O
2
2
2
3
3
OH
OH
3
OH
R1 OH
AHMHA
R1 OH
AHMPA
R1 OH
AHPA
Finally, the analogs, which contain the 3-amino-2-hydroxy-
4-methylpentanoic acid (AHMPA) scaffold, were obtained
by reaction of 1a–3a with isobutyraldimines (SS)-7 and
(SR)-7. This scaffold is found in lapstatin, a potent APN/
CD13 inhibitor produced by Streptomyces rimosus.33
Chart 1. Scaffolds of the 3-amino-2-hydroxyalkanoic acid analogs.
The C2-analogs, which contain the aliphatic 3-amino-2-hy-
droxy-5-methylhexanoic [AHMHA] scaffold, were obtained
by reaction of enolates 1a–3a with isovaleraldimines (SS)-5
and (SR)-5. The chiral [AHMHA] scaffold is contained in
several aminopeptidases, such as amastatin,18 leuhistin,19
KRI-1230,20 renin,21 bombesin,22 and apstatin.23
2. Results and discussion
2.1. Reactions of the (2S)-enolates 1a–3a with hetero-
aromatic sulfinyl imines (SR)- and (SS)-4 and aliphatic
N-tert-butylsulfinyl azomethines (SR)- and (SS)-5–7
The C2-analogs, which contain the aliphatic 3-amino-2-
hydroxy-4-phenylbutanoic acid [AHPA] scaffold, were
obtained by reaction of enolates 1a–3a with 2-phenylacetal-
dimines (SS)-6 and (SR)-6. The AHPA scaffold is present
with different configurations in many inhibitors, such as
the BACE1 amyloid,24 bestatin,25,26 aminopeptidases P27
and N,28 and in some peptides, which exhibit enkephalinase
inhibitory activity.29 Moreover, AHPA-based scaffolds of
different configurations serve for the design of antiviral
drugs, which target retroviral polyproteins by human immu-
nodeficiency virus protease (HIV PR) and other aspartyl pro-
teases, such as in potent plasmepsin inhibitors of the KNI
Table 1 shows the product distribution for the reactions
between (SR)- and (SS)-sulfinyl aldimines 4–7 and (2S)-
enolates 1a–3a. In particular, entries 1–8 give the results
arising from the reactions of the lithium enolate (2S)-1a.
The major products of these reactions were the diastereo-
mers derived from TS-I, regardless of the stereochemistry
at the aldimine sulfur atom. In fact, the approach of the aldi-
mine to the less hindered enantiotopic face of the enolate
with the C-substituent exo to the dioxolanone ring was fa-
vored, due to the presence of the small methyl substituent
at the C5 carbon atom. At the same time, the methyl group
Table 1. Addition of imines 4–7 to chiral enolates 1a–3a
From: TS-II
O
From: TS-I
From: TS-III
O
O
S
R1
LiO
S
S
t
t
t
O
S
HN
O
Bu
HN
Bu
HN
Bu
R1
R1
R1
O
O
O
O
O
R2
N
R2
t
+
Bu
R2
R2
t
+
+
Bu
R
O
O
O
O
O
(S )-(S )-4: R2= 2-Thienyl
S
R
t
t
t
(S )-(S )-5: R2= CH2 Pr
i
R
Bu
R
Bu
R
Bu
(2S)-1a: R = R1 = Me
S
R
(S )-(S )-6: R2= CH2Ph
(2S)-2a: R = H; R1 = CH2Ph
(2S)-3a: R = H; R1 = Ph
S
R
9, 12, 14, 17, 20,
23, 26, 27, 28, 29
8, 11, 13, 16,
19, 22, 25
(S )-(S )-7: R2= Pr
i
S
R
10, 15, 18, 21, 24
Entry Enolate (R, R1)
Iminea (R2)
Isomers from [TS-I]a
(relative amount)
Isomers from [TS-II]a
(relative amount)
Isomer [TS-III]a
(relative amount)
Yieldb
(%)
1
2
3
4
5
6
7
8
(2S)-1a (R¼R1¼Me)
(2S)-1a (R¼R1¼Me)
(2S)-1a (R¼R1¼Me)
(2S)-1a (R¼R1¼Me)
(2S)-1a (R¼R1¼Me)
(2S)-1a (R¼R1¼Me)
(2S)-1a (R¼R1¼Me)
(2S)-1a (R¼R1¼Me)
(SR)-4 (2-Thienyl) (SR,2S,5R,10S)-8 (55.0)
(SR,2S,5R,10R)-9 (45.0)
(SS,2S,5R,10R)-9 (5.0)
(SR,2S,5R,10S)-12 (16.7)
(SS,2S,5R,10S)-12 (7.0)
(SR,2S,5R,10S)-14 (37.0)
—
—
79
(SS)-4 (2-Thienyl) (SS,2S,5R,10S)-8 (80.0)
(SS,2S,5S,10R)-10 (15.0) 82
i
(SR)-5 (CH2 Pr)
(SR,2S,5R,10R)-11 (83.3)
(SS,2S,5R,10R)-11 (93.0)
(SR,2S,5R,10R)-13 (63.0)
(SS,2S,5R,10R)-13 (79)
(SR,2S,5R,10R)-16 (89.0)
(SS,2S,5R,10R)-16 (ꢀ98.0)
(SR,2S,5R,10R)-19 (24.0)
(SS,2S,5R,10R)-19 (45.7)
(SR,2S,5R,10R)-22 (45.0)
(SS,2S,5R,10R)-22 (73.0)
(SR,2S,5R,10R)-25 (56.5)
(SS,2S,5R,10R)-25 (88.6)
—
—
—
—
84
80
78
75
88
93
77
i
(SS)-5 (CH2 Pr)
(SR)-6 (CH2Ph)
(SS)-6 (CH2Ph)
(SR)-7 (iPr)
(SS,2S,5S,10S)-15 (21)
(SR,2S,5S,10S)-18 (2.0)
—
(SR,2S,5R,10S)-17 (9.0)
—
(SS)-7 (iPr)
(2S)-2a (R¼H, R1¼CH2Ph) (SR)-5 (CH2 Pr)
(SR,2S,5R,10S)-20 (72.0)
—
(SR,2S,5R,10S)-23 (50.0)
—
(SR,2S,5R,10S)-26 (43.5)
(SS,2S,5R,10S)-26 (11.4)
(SR,2S,5R,10S)-27+
(SS,2S,5R,10S)-27 (100.0)
(SR,2S,5R,10S)-28+
(SS,2S,5R,10S)-28 (100.0)
(SS,2S,5R,10S)-29 (100.0)
(SR,2S,5S,10S)-21 (4.0)
i
9
(2S)-2a (R¼H, R1¼CH2Ph) (SS)-5 (CH2 Pr)
(SS,2S,5S,10S)-21 (54.3) 79
i
10
11
12
13
14
15
(2S)-2a (R¼H, R1¼CH2Ph) (SR)-6 (CH2Ph)
(2S)-2a (R¼H, R1¼CH2Ph) (SS)-6 (CH2Ph)
(2S)-2a (R¼H, R1¼CH2Ph) (SR)-7 (iPr)
(SR,2S,5S,10S)-24 (5.0)
58c
(SS,2S,5S,10S)-24 (27.0) 60
—
—
—
61
70
86
(2S)-2a (R¼H, R1¼CH2Ph) (SS)-7 (iPr)
(2S)-3a (R¼H, R1¼Ph)
(2S)-3a (R¼H, R1¼Ph)
(2S)-3a (R¼H, R1¼Ph)
(SSR)-5 (CH2 Pr)
(SSR)-6 (CH2Ph)
(SS)-7 (iPr)
i
16
—
—
—
—
75
80
17
a
In the (SR) or (SS) terms for the N-tert-butylsulfinyl aldimines and N-tert-butylsulfinyl-10-aminodioxolan-4-ones, the ‘S’ and ‘R’ in subscripts refer to the S or R
chirality of the sulfur atom (S).
Overall yields.
Yield refers to a 60% aldimine conversion.
b
c

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A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
at the C2 acetal center inhibits the competitive approach of
the aldimine according to TS-II, i.e., with the C-substituent
endo to the ring. However, with respect to the (SR)-aldi-
mines, the (SS)-configured aldimines favored the formation
of diastereomers derived from TS-I, as appears by a compar-
ison between entries 2, 4, 6, and 8 [where (SS)-configured
aldimines were employed] and entries 1, 3, 5, and 7 [which
employed (SR)-configured aldimines]. Sulfur chirality also
affects the product distribution for compounds derived
from TS-II and TS-III. Thus, the formation of isomers de-
rived from TS-II is favored in reactions involving (SR)-sulfi-
nyl aldimines, while the stereoisomers derived from TS-III
are strongly inhibited. For instance, the relative amounts of
(SR)-9 (45.0), (SR)-12 (16.7), (SR)-14 (37.0), and (SR)-17
(9.0) are greater than those of the corresponding (SS)-config-
ured isomers, namely (SS)-9 (5.0), (SS)-12 (7.0), (SS)-14 (no
formation), and (SS)-17 (no formation). Accordingly, the iso-
mers derived from TS-III are only favored when (SS)-sulfinyl
aldimines are the partners, such as in the reactions of entries
2 and 6, which afforded consistent amounts of (SS)-10 (15.0)
and (SS)-15 (21.0).
[compounds (SSR)-27 from (SSR)-5, and (SSR)-28 from (SSR)-
6], while the enantiomerically pure aldimine (SS)-7 provided
(SS)-29 exclusively.
2.2. Selective deprotection of the N-tert-butylsulfinyl-10-
aminodioxolanone moiety and stereoconfigurational
assessment
In order to prove the orthogonality between the acetal and
sulfinyl protecting groups, the N-tert-butylsulfinylamino
group of 10-aminodioxolanones 8–29 was selectively re-
moved by ethereal HCl treatment, affording the correspond-
ing free amines 30–50 in very good yields. This deprotection
reaction allowed the subsequent synthesis of chiral 3-
substituted 3-hydroxy-2-azetidinones, via base-induced
cyclization of the corresponding free amines. These com-
pounds represent an efficient carboxylate mimic,34 being
present in several pharmacologically active monobactams,
such as sulfazecin and related products,35 and in enzyme
inhibitors such as tabtoxin and its analogs.36 In addition,
the synthesis of the b-lactams provided an entry to the
absolute stereochemistry assignment at the 10-position of
the N-tert-butylsulfinyl-10-aminodioxolanones. In particu-
lar, the LHMDS-induced cyclization of free amines 30–50
provided the corresponding b-lactams 51–64, whose C4
stereochemistry, which corresponds to that of the C10 carbon
atom of the parent 10-aminodioxolanones, was assessed by
means of NOE experiments (see Table 2 and Section 4 for
details). On the other hand, the stereochemistry at the C5-
position was assigned by means of NOE experiments,
performed either on the 10-sulfinylamino-dioxolanones or
on their free amines. The orthogonality of the N-sulfinyl
and the acetal protecting groups was demonstrated by per-
forming selective acetal removal on compounds (SR)-13,
(SS)-16, (SS)-21, and (SS)-29, by base-induced methanolysis,
which afforded the corresponding N-tert-butylsulfinyl pro-
tected a-hydroxy-b-amino methyl esters (SR,2R,3R)-65,
(SS,2R,3R)-66, (SS,2S,3S)-67, and (SS,25R,3S)-68, respec-
tively, in good yields (Table 3).
Entries 9–14 show the product distribution for the reactions
of (2S)-2a with aldimines 5–7. Enolate (2S)-2a differs from
(2S)-1a by the presence of a smaller H-substituent at the C2
acetal center and a larger benzyl group at the C5 carbon
atom. Accordingly, the exo approach of the aldimine to the
dioxolanone ring is unfavorable, and thus a reduced forma-
tion of the (2S,5R,10R)-diastereomers is observed. The sulfur
chirality plays the same role already observed with enolate
(2S)-1a, and thus aldimines (SS)-5–7 favor the formation
of (2S,5R,10R)-diastereomers (from TS-I) more than their
(SR)-5–7 enantiomers. In addition, imines (SR)-5–7 more
selectively form the (2S,5R,10S)-isomers (SR)-20, (SR)-23,
and (SR)-26 (entries 9, 11, and 13) from TS-II, while the
(SS)-5 and (SS)-6 enantiomers favor the (2S,5S,10S)-dia-
stereomers (SS)-21 and (SS)-24 from TS-III. The effect of
the sulfur atom stereochemistry can be explained by an
unfavorable steric interaction between the sulfinyl substitu-
ents of (SR)-configured aldimines in TS-III, which point
toward the enolate ring. This interaction inhibits the
formation of the (SR,2S,5S,10S)-sulfinylamino-dioxolanones
(Fig. 2).
3. Conclusions
We have described here a versatile and general method for
the synthesis of enantiopure conformationally restrained
C2-disubstituted 3-amino-2-hydroxyalkanoates and steri-
cally congested trisubstituted 3-alkyl-3-hydroxy-b-lactams.
Both classes of compounds are very important building
blocks in medicinal chemistry. Moreover, the amino acids
are obtained in the form of N,O-orthogonally protected 10-
aminodioxolan-4-ones.
In entries 15–17 of Table 1 are given the product distri-
butions for the reactions of (2S)-3a with aldimines 5–7.
The sterically demanding C5 phenyl substituent of this
enolate plays a pivotal role in the diastereoselection, since
only the (2S,5R,10S)-enantiomers, derived from TS-II, were
formed regardless of sulfur chirality. Aldimines 5 and 6
were used as racemic mixtures [(SSR)-5 and (SSR)-6], while
aldimine 7 was used as a pure (SS)-enantiomer [(SS)-7].
Accordingly, the racemic aldimines 5 and 6 afforded a
mixture of (SS,2S,5R,10S)- and (SR,2S,5R,10S)-diastereomers
This methodology allows the insertion of bulky substituents,
such as the phenyl group, at the C2 carbon atom of the amino
acid and/or the corresponding b-lactam. These targets are
difficult to synthesize by other methodologies. Moreover,
it is possible to control, or at least to reduce, the number
of possible diastereomers since the formation of products
derived from TS-IV is precluded due to a severe repulsion
between the tert-butyl substituent of the enolate and that at
the carbon atom of the aldimines. Besides, the formation
of epimers derived from TS-III is almost suppressed by using
(SR)-configured N-tert-butylsulfinyl aldimines.
O
O
(S)
(R)
S
S
R
R
N
N
-O
-O
Alk
Alk
H
H
O
O
O
O
R1
R1
Figure 2.

A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
7953
Table 2. Deprotection of SS- and SR-N-tert-butylsulfinyl-10-aminodioxolanones 8–29, affording the corresponding 10-aminodioxolanones 30–50, and synthesis
of the corresponding b-lactams 51–64a
O
S
NH2
R2
t
R1
HN
Bu
O
R1
OH
R2
H
O
R1
R2
ii
i
O
O
N
O
O
O
t
R
Bu
t
R
Bu
30-50
51-64
8-29
Entry
R
R1
R2
8–29
30–50
(Yield, %)
51–64
(Yieldb, %)
1
2
4
5
6
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2-Thienyl
2-Thienyl
(SS,2S,5R,10S)-8
(SR,2S,5R,10S)-8
(SR,2S,5R,10R)-9
(SS,2S,5R,10R)-9
(SS,2S,5R,10R)-11
(SR,2S,5R,10R)-11
(SS,2S,5R,10S)-12
(SR,2S,5R,10R)-12
(SR,2S,5R,10R)-13
(Ss,2S,5R,10R)-13
(SR,2S,5R,10S)-14
(SS,2S,5S,10S)-15
(SS,2S,5R,10R)-16
(SR,2S,5R,10R)-16
(SS,2S,5R,10R)-19
(SR,2S,5R,10R)-19
(SR,2S,5R,10S)-20
(SS,2S,5S,10S)-21
(SR,2S,5R,10R)-22
(SS,2S,5R,10R)-22
(SS,2S,5S,10S)-24
(SS,2S,5R,10R)-25
(SR,2S,5R,10R)-25
(SR,2S,5R,10S)-26
(SS,2S,5R,10S)-26
(SR,2S,5R,10S)-27
(SS,2S,5R,10S)-27
(SR,2S,5R,10S)-28
(SS,2S,5R,10S)-28
(SS,2S,5R,10S)-29
(2S,5R,10S)-30 (82)
(2S,5R,10S)-30 (82)
(2S,5R,10R)-31 (86)
(2S,5R,10R)-31
(3R,4S)-51 (82)
(3R,4R)-52 (82)
(3R,4R)-53 (82)
(3R,4S)-54 (78)
(3R,4R)-55 (82)
i
CH2 Pr
(2S,5R,10R)-35 (73)
(2S,5R,10R)-35 (83)
(2S,5R,10S)-36 (86)
(2S,5R,10S)-36 (80)
(2S,5R,10R)-37 (91)
(2S,5R,10R)-37 (88)
(2S,5R,10S)-38 (85)
(2S,5S,10S)-39 (88)
(2S,5R,10R)-40 (85)
(2S,5R,10R)-40 (81)
(2S,5R,10R)-41 (91)
(2S,5R,10R)-41 (82)
(2S,5R,10S)-42 (85)
(2S,5S,10S)-43 (82)
(2S,5R,10R)-44 (90)
(2S,5R,10R)-44 (88)
(2S,5S,10S)-45 (83)
(2S,5R,10R)-46 (88)
(2S,5R,10R)-46
i
CH2 Pr
CH2Ph
7
8
9
Me
Me
Me
Me
Me
Me
CH2Ph
CH2Ph
iPr
—
—
(3R,4R)-56 (87)
i
CH2 Pr
10
H
CH2Ph
(3R,4R)-57 (85)
i
11
12
13
H
H
H
CH2Ph
CH2Ph
CH2Ph
CH2iPr
—
(3S,4S)-58 (78)
(3R,4R)-59 (88)
CH2 Pr
CH2Ph
14
15
H
H
CH2Ph
CH2Ph
CH2Ph
iPr
(3S,4S)-60 (81)
(3R,4R)-61 (87)
16
17
18
H
H
H
H
CH2Ph
Ph
iPr
(2S,5R,10S)-47 (90)
(2S,5R,10S)-47
(2S,5R,10S)-48 (92)
i
CH2 Pr
(3R,4S)-62 (90)
(3R,4S)-63 (71)
(3R,4S)-64 (88)
Ph
CH2Ph
iPr
(2S,5R,10S)-49 (72)
(2S,5R,10S)-50 (84)
19
Ph
a
Reagents and conditions: (i) 2 N HCl in 1/1 MeOH/Et2O; (ii) LHMDS/THF/HMPA.
Isolated yields.
b
4. Experimental
4.1. General experimental conditions
Table 3. Synthesis of N-tert-butylsulfinyl protected a-hydroxy-b-amino
methyl esters
All reactions were performed under an atmosphere of dry
nitrogen using oven-dried glassware. Tetrahydrofuran, tolu-
ene, and ethyl ether were distilled from sodium benzophe-
none ketal. Dichloromethane, HMPA, and acetonitrile
were distilled from calcium hydride. All other solvents
were of HPLC grade. Reactions were magnetically stirred
and monitored by thin layer chromatography (TLC) with
E. Merck silica gel 60-F254 plates. Flash column chromato-
graphy was performed with Merck silica gel (0.04–0.63 mm,
240–400 mesh) under high pressure. NMR spectra were re-
corded on 400 MHz spectrometer. Unless otherwise stated,
all NMR spectra were measured in CDCl3 solutions and ref-
erenced to the CHCl3 signal. All 1H and 13C shifts are given
in parts per million (s¼singlet; d¼doublet; t¼triplet;
dd¼quadruplet; dt¼doublet of triplets, m¼multiplet; br
s¼broad singlet). Coupling constants J are given in hertz.
Assignments of proton resonances were confirmed, when
possible, by selective homonuclear decoupling experiments
O
S
t
O
S
HN
O
Bu
R1
O
t
R2
Bu
NH
O
i
2
O
R2
OMe
3
R1 OH
R
(S )-65, (S )-66,
(S )-13, (S )-16,
R
S
R
S
(S )-67, (S )-68
(S )-21, (S )-29
S
S
S
S
Entry R1
R2
Substratea
Product
Yieldb
(%)
1
2
3
4
Me
Me
CH2Ph (SR,2S,5R,10R)-13 (SR,2R,3R)-65 75
iPr (SS,2S,5R,10R)-16 (SS,2R,3R)-66 90
i
CH2Ph CH2 Pr (SS,2S,5S,10S)-21 (SS,2S,3S)-67 83
Ph
iPr
(SS,2S,5R,10S)-29 (SS,2R,3S)-68 87
Reagents and conditions: (i) MeOꢁ/MeOH.
Isolated yields.
a
b

7954
A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
or by correlated spectroscopy. IR spectra were recorded on
a FTIR E.S.P. spectrometer as thin films on NaCl plates.
Mass spectra were recorded on an ion trap spectrometer
with an ionization potential of 70 eV. High-resolution mass
spectra (HRMS) were performed with a resolution of
10,000 against a suitable mass standard. The commercially
available reagents were used as received without further
purification. The tert-butylsulfinyl aldimines 4–7 were pre-
pared from the corresponding aldehydes and chiral or race-
mic tert-butanesulfinamides35 according to a literature
method.37 Dioxolanones (2S,5S)-1–3 were prepared from
the corresponding (S)-a-hydroxy acids according to a litera-
ture method.15
d 173.4, 140.7, 127.6, 126.8, 125.8, 115.7, 82.0, 59.9, 57.4,
38.9, 24.8, 22.5, 22.4, 20.3. Anal. Calcd for C18H29NO4S2:
C, 55.78; H, 7.54; N, 3.61. Found: C, 55.64; H, 7.66; N,
3.57. (SS,2S,5R,10R)-9: IR (CDCl3, cmꢁ1) 3200–3050,
1771; HRMS m/z calcd for C18H29NO4S2 [M]+: 387.1538,
1
m/z found: 387.1533; H NMR (CDCl3) d 7.26–7.22 (m,
1H, arom), 7.02–9.95 (m, 2H, arom), 5.12 (d, 1H,
J¼1.5 Hz, H-10), 5.04 (d, 1H, J¼1.0 Hz, NH), 1.71 (s, 3H,
Me), 1.34 (s, 3H, Me), 0.96 (s, 9H, 3Me), 0.70 (s, 9H,
3Me); 13C NMR (CDCl3) d 173.2, 142.1, 128.0, 127.1,
125.3, 116.8, 84.9, 60.9, 60.1, 39.2, 25.4, 24.2, 22.8, 21.9.
The (5R)-stereoconfiguration of (SS)-9 was assigned by
homonuclear NOE experiments (CDCl3). Upon irradiation
of the acetal tert-butyl group at 0.70 ppm, significant NOE
effects (3.2 and 5.5%) were observed on the CH3 protons
at 1.71 and 1.34 ppm, respectively.
4.2. General procedure for the synthesis of N-sulfinyl-10-
aminodioxolanones
Unless otherwise stated, a THF solution of dioxolanone
(2.0 mL of THFꢂ0.25 g of dioxolanone, 2.8 equiv) was
added dropwise at ꢁ78 ꢃC to a solution of LHMDS in
THF (2.8 equiv, 1.0 M). The solution was stirred at
ꢁ70 ꢃC for 30 min, then the temperature was lowered at
ꢁ90 ꢃC, and a THF solution of HMPAwas added (final ratio
THF/HMPA, 85/15). The temperature was raised to ꢁ78 ꢃC
and after 2 min, a THF solution of N-sulfinyl azomethine
(1.0 equiv) was slowly added. After complete addition, the
temperature was raised to ꢁ60 ꢃC during 1 h and stirred at
this temperature for additional 30 min. The reaction was
quenched with 1.0 N HCl and warmed under stirring to
room temperature. The reaction mixture was extracted
with EtOAc (3ꢂ15 mL) and then washed three times with
0.2 N HCl followed by saturated NH4Cl (2ꢂ10 mL). The or-
ganic phase was dried over Na2SO4 and after filtration the
solvent was removed under vacuum. The mixture of diaste-
reomers was purified, or separated when possible, by silica
gel flash chromatography. A slightly modified procedure
was adopted for the synthesis of the enolate (2S)-2a.
Namely, 4.0 mL of THFꢂ0.25 g of dioxolanone were slowly
added at ꢁ85/ꢁ80 ꢃC in 30 min to a solution of LHMDS in
THF (2.8 equiv, 1.0 M). Subsequently, a THF solution of
HMPA was very slowly added (20 min) at this temperature.
The THF solution of the imine was also added at this temper-
ature in 20 min. The reaction was quenched with 1.0 N HCl
and warmed under stirring to room temperature and then
worked up as already reported above. The crude material
was purified by silica gel flash column chromatography.
O
S
HN
O
S
O
O
(S , 2S, 5R, 1'R)-9
S
(SS,2S,5S,10R)-10: [a]D20 +76.0 (c 0.37, CHCl3); IR (CDCl3,
cmꢁ1) 3260, 3200–3050, 1778; mp 123–125 ꢃC; MS m/z
387, 282, 267, 215; 1H NMR (CDCl3) d 7.36–7.31 (m, 1H,
arom), 7.16–7.11 (m, 1H, arom), 7.07–7.01 (m, 1H, arom),
5.20 (s, 1H, NH), 5.04 (s, 1H, H-10), 1.55 (s, 3H, Me),
1.53 (s, 3H, Me), 1.30 (s, 9H, 3Me), 1.08 (s, 9H, 3Me);
13C NMR (CDCl3) d 175.3, 137.4, 128.5, 126.5, 126.1,
116.4, 78.8, 56.9, 56.0, 38.7, 24.9, 22.8, 22.7, 19.4. Anal.
Calcd for C18H29NO4S2: C, 55.78; H, 7.54; N, 3.61. Found:
C, 55.91; H, 7.47; N, 3.66.
4.2.2. Synthesis of (SR,2S,5R,10S)-8 and (SR,2S,5R,10R)-9.
The reaction of dioxolanone (2S,5S)-1 (300 mg, 1.74 mmol)
and imine (SR)-4 (136 mg, 0.63 mmol) afforded a 1.2/1 mix-
ture of (SR)-8/(SR)-9. Silica gel column chromatography pu-
rification (n-hexane/Et2O, 2/3) afforded compounds (SR)-8
(105 mg, 0.27 mmol, 43%) and (SR)-9 (87 mg, 0.22 mmol,
36%) as pale yellow oils. (SR,2S,5R,10S)-8: [a]D20 ꢁ62.0 (c
0.46, CHCl3); IR (CDCl3, cmꢁ1) 3270, 3200–3050, 1777;
1
mp 107 ꢃC; MS m/z 387, 282, 267, 215; H NMR (CDCl3)
4.2.1. Synthesis of (SS,2S,5R,10S)-8, (SS,2S,5R,10R)-9, and
(SS,2S,5S,10R)-10. The dioxolanone (2S,5S)-1 (420 mg,
2.44 mmol) was reacted with imine (SS)-4 (200 mg,
d 7.32–7.28 (m, 1H, arom), 7.07–6.97 (m, 2H, arom), 5.00
(d, 1H, J¼1.5 Hz, NH), 4.81 (d, 1H, H-10), 1.57 (s, 3H, Me),
1.47 (s, 3H, Me), 1.28 (s, 9H, 3Me), 0.96 (s, 9H, 3Me); 13C
NMR (CDCl3) d 175.0, 138.6, 128.4, 126.9, 126.1, 116.6,
80.5, 58.5, 56.4, 39.0, 24.9, 23.4, 22.9, 18.9. Anal. Calcd
per C18H29NO4S2: C, 55.78; H, 7.54; N, 3.61. Found: C,
55.91; H, 7.58; N, 3.55. (SR,2S,5R,10R)-9: [a]D20 ꢁ5.0 (c
0.42, CHCl3); IR (CDCl3, cmꢁ1) 3265, 3200–3050, 1776;
1
0.929 mmol). The H NMR analysis of the crude mixture
showed a product distribution of (SS)-8/(SS)-9/(SS)-10¼
16.0/1.0/3.0. Chromatography (SiO2, n-hexane/Et2O, 1/1),
afforded compounds (SS)-8 (236 mg, 0.61 mmol, 65.7%),
(SS)-10 (44 mg, 0.114 mmol, 12.3%), and (SS)-9 contami-
nated by trace amounts of impurities (15 mg, 0.0381 mmol,
4%) as pale oils. (SS,2S,5R,10S)-8: [a]D20 +100.0 (c 0.43,
CHCl3); IR (CDCl3, cmꢁ1) 3270, 3200–3050, 1776; mp
1
mp 177 ꢃC; MS m/z 387, 282, 267, 215; H NMR (CDCl3)
d 7.29–7.24 (m, 1H, arom), 7.20–7.14 (m, 1H, arom),
7.00–6.94 (m, 1H, arom), 4.79 (d, 1H, J¼8.5 Hz, NH),
3.33 (d, 1H, H-10), 1.66 (s, 3H, Me), 1.42 (s, 3H, Me),
1.19 (s, 9H, 3Me), 1.04 (s, 9H, 3Me); 13C NMR (CDCl3) d
173.6, 140.2, 133.9, 128.3, 127.1, 115.9, 84.0, 62.5, 56.9,
39.2, 25.4, 23.4, 23.2, 22.7. Anal. Calcd for C18H29NO4S2:
C, 55.78; H, 7.54; N, 3.61. Found: C, 55.85; H, 7.67; N, 3.68.
1
161 ꢃC; MS m/z 387, 282, 267, 215; H NMR (CDCl3)
d 7.28–7.24 (m, 1H, arom), 7.19–7.16 (m, 1H, arom),
7.02–6.97 (m, 1H, arom), 4.94 (d, 1H, J¼4.2 Hz, H-10),
4.19 (d, 1H, NH), 1.47 (s, 3H, Me), 1.26 (s, 3H, Me), 1.24
(s, 9H, 3Me), 0.98 (s, 9H, 3Me); 13C NMR (CDCl3)

A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
7955
1
4.2.3. Synthesis of (SS,2S,5R,10R)-11 and (SS,2S,5R,10S)-
12. The reaction of dioxolanone (2S,5S)-1 (328 mg,
1.90 mmol) and imine (SS)-5 (128 mg, 0.676 mmol)
258, 177, 116, 87; H NMR (CDCl3) d 3.56–3.48 (m, 1H,
H-10), 2.82 (d, 1H, J¼3.2 Hz, NH), 2.04–1.88 (m, 1H,
Me2CH), 1.68–1.58 (m, 1H, CH2), 1.61 (s, 3H, Me), 1.41
(s, 3H, Me), 1.36–1.26 (m, 1H, CH2), 1.23 (s, 9H, 3Me),
0.99 (s, 9H, 3Me), 0.96 (d, 3H, J¼6.4 Hz, Me), 0.93 (d,
3H, J¼6.4 Hz, Me); 13C NMR (CDCl3) d 172.4, 114.8,
83.5, 60.7, 56.7, 40.2, 39.1, 25.0, 24.1, 23.5, 23.2, 22.9,
21.1, 20.26. Anal. Calcd for C18H35NO4S: C, 59.80; H,
9.76; N, 3.87. Found: C, 59.95; H, 9.83; N, 3.85.
afforded
a
15.0/1.0 mixture of (SS,2S,5R,10R)-11/
(SS,2S,5R,10S)-12. Silica gel purification (n-hexane/EtOAc,
2/1) afforded compounds (SS)-11 (184 mg, 0.51 mmol,
75%, sticky oil), and (SS)-12 (12 mg, 0.033 mmol, 5%,
sticky oil). (SS,2S,5R,10R)-11: [a]D20 +76.0 (c 0.43, CHCl3);
IR (CDCl3, cmꢁ1) 3492, 3126, 2963, 1792; mp 132 ꢃC;
1
MS m/z 361, 258, 177, 116, 87; H NMR (CDCl3) d 3.57–
3.48 (m, 1H, J1¼2.0 Hz, J2¼6.0 Hz, J3¼8.5 Hz, H-10),
3.23 (d, 1H, J¼3.2 Hz, NH), 2.02–1.92 (m, 1H, Me2CH),
1.54 (s, 3H, Me), 1.43 (s, 3H, Me), 1.60–1.46 (m, 2H,
CH2), 1.26 (s, 9H, 3Me), 0.99 (s, 9H, 3Me), 0.97 (d, 3H,
J¼3.4 Hz, Me), 0.94 (d, 3H, Me); 13C NMR (CDCl3)
d 173.9, 114.3, 80.9, 59.3, 56.9, 39.6, 39.2, 24.9, 24.1,
23.5, 23.4, 23.1, 21.2, 18.2. Anal. Calcd for C18H35NO4S:
C, 59.80; H, 9.76; N, 3.87. Found: C, 59.67; H, 9.68; N,
3.94. (SS,2S,5R,10S)-12: [a]D20 +49.0 (c 0.4, CHCl3); IR
(CDCl3, cmꢁ1) 3492, 3126, 2963, 1792; MS m/z 361, 258,
4.2.5. Synthesis of (SR,2S,5R,10R)-13 and (SR,2S,5R,10S)-
14. The reaction of dioxolanone (2S,5S)-1 (0.45 g,
2.61 mmol) with aldimine (SR)-6 (208 mg, 0.93 mmol) af-
forded a 1.6/1.0 mixture of (SR)-13/(SR)-14. Silica gel chro-
matographic purification (n-hexane/Et2O, 1.5/1) provided
compounds (SR)-13 (0.18 g, 0.45 mmol, 48%) and (SR)-14
(0.11 g, 0.28 mmol, 30%) as vitreous oils. (SR,2S,5R,10R)-
13: [a]2D0 ꢁ63.0 (c 0.84, CHCl3); IR (CDCl3, cmꢁ1) 2957,
1
1771, 1290, 1154; MS m/z 395, 193, 131, 91; H NMR
(CDCl3) d 7.28–7.16 (m, 5H, arom), 4.29 (d, 1H, NH),
3.87 (m, 1H, J1¼1.5 Hz, J2¼5.8 Hz, J3¼9.4 Hz, H-10),
3.01 (m, 2H, CH2–Ph), 1.57 (s, 3H, Me), 1.32 (s, 3H, Me),
1.15 (s, 9H, 3Me), 0.95 (s, 9H, 3Me); 13C NMR (CDCl3)
d 175.1, 138.6, 130.0, 128.5, 126.6, 116.1, 81.0, 60.6,
56.2, 39.0, 37.0, 25.0, 22.9, 22.8, 19.4. Anal. Calcd for
C21H33NO4S: C, 63.76; H, 8.41; N, 3.54. Found: C, 63.81;
H, 8.47; N, 3.60. The (5R)-configuration of (SR)-13 was as-
signed by homonuclear NOE experiments (CDCl3). Upon ir-
radiation of the acetal tert-butyl group at 0.95 ppm, relevant
NOE effects (5 and 6%) were observed on the methyl pro-
tons at 1.57 and 1.32 ppm, respectively.
1
177, 116, 87; H NMR (CDCl3) d 3.66 (d, 1H, J¼5.4 Hz,
NH), 3.57 (m, 1H, J1¼2.1 Hz, J2¼5.5 Hz, J3¼9.5 Hz, H-
10), 1.94–1.85 (m, 1H, Me2CH), 1.64 (s, 3H, Me), 1.74 (m,
1H, CH2), 1.43 (s, 3H, Me), 1.38 (m, 1H, CH2), 1.23 (s,
9H, 3Me), 1.01 (s, 9H, 3Me), 0.95 (d, 3H, J¼6.5 Hz, Me),
0.88 (d, 3H, J¼6.5 Hz, Me). 13C NMR (CDCl3) d 173.6,
115.1, 81.5, 58.6, 56.7, 40.0, 39.2, 25.4, 25.0, 24.0, 23.4,
22.9, 21.2, 18.1. Anal. Calcd for C18H35NO4S: C, 59.80;
H, 9.76; N, 3.87. Found: C, 59.72; H, 9.79; N, 3.76. The
(5R)-configuration of (SS,2S,5R,10S)-12 was assigned by
NOE experiments (CDCl3). Irradiation of the tert-butyl
group at 1.01 ppm produced significant NOE effects (9.2
and 5.1%) on the methyl groups at C2 (1.64 ppm) and C5
(1.43 ppm), respectively.
O
S
HN
O
O
S
O
O
HN
O
(S , 2S, 5R, 1'R)-13
R
O
O
(SR,2S,5R,10S)-14: [a]D20 ꢁ8.0 (c 0.50, CHCl3); IR (CDCl3,
(S , 2S, 5R, 1'S)-12
S
1
cmꢁ1) 2964, 1783, 1152; MS m/z 395, 193, 131, 91; H
NMR (CDCl3) d 7.32–7.22 (m, 5H, arom), 3.84 (m, 1H,
H-10), 3.35 (dd, 1H, J1¼5.5 Hz, J2¼14.5 Hz, CH2–Ph),
3.33 (d, 1H, J¼5.2 Hz, NH), 3.38 (m, 1H, J1¼5.4 Hz,
J2¼14.5 Hz, CH2–Ph), 1.49 (s, 3H, Me), 1.45 (s, 3H, Me),
1.14 (s, 9H, 3Me), 0.98 (s, 9H, 3Me); 13C NMR (CDCl3)
d 174.0, 136.4, 130.5, 128.6, 127.2, 115.1, 83.8, 61.8,
56.6, 39.1, 37.0, 25.1, 23.2, 22.8, 21.1. Anal. Calcd for
C21H33NO4S: C, 63.76; H, 8.41; N, 3.54. Found: C, 63.94;
H, 8.34; N, 3.58. The (5R)-configuration of (SR)-14 was as-
signed by homonuclear NOE experiments (CDCl3). Upon ir-
radiation of the acetal tert-butyl group at 0.98 ppm, relevant
4.2.4. Synthesis of (SR,2S,5R,10R)-11 and (SR,2S,5R,10S)-
12. The reaction of dioxolanone (2S,5S)-1 (386 mg,
2.24 mmol) and imine (SR)-5 (151 mg, 0.80 mmol) afforded
a 5/1 mixture of (SR,2S,5R,10R)-11 and (SR,2S,5R,10S)-12.
Silica gel purification (n-hexane/EtOAc, 2/1) provided com-
pounds (SR)-11 (201 mg, 0.56 mmol, 70%), and (SR)-12
(42 mg, 0.12 mmol, 14%) as sticky oils. (SR,2S,5R,10R)-11:
[a]D20 ꢁ65.0 (c 0.4, CHCl3); IR (CDCl3, cmꢁ1) 3220, 2960,
d 4.30 (d, 1H, J¼1.5 Hz, NH), 3.56–3.48 (m, 1H, H-10),
2.01–1.83 (m, 1H, Me2CH), 1.57–1.50 (m, 1H, CH2), 1.52
(s, 3H, Me), 1.48–1.42 (m, 1H, CH2), 1.43 (s, 3H, Me),
1.22 (s, 9H, 3Me), 0.97 (s, 9H, 3Me), 0.94 (d, 3H,
J¼3.4 Hz, Me), 0.90 (d, 3H, Me); 13C NMR (CDCl3)
d 175.1, 115.7, 81.0, 56.8, 56.3, 40.0, 39.0, 25.7, 25.0,
23.8, 23.5, 22.9, 22.1, 19.1. Anal. Calcd for C18H35NO4S:
C, 59.80; H, 9.76; N, 3.87. Found: C, 59.61; H, 9.65; N,
3.94. (SR,2S,5R,10R)-12: [a]D20 ꢁ25.0 (c 0.54, CHCl3); IR
(CDCl3, cmꢁ1) 3220, 2960, 1776; mp 95 ꢃC; MS m/z 361,
1
1777; MS m/z 361, 258, 177, 116, 87; H NMR (CDCl3)
O
S
HN
O
O
O
(S , 2S, 5R, 1'S)-14
R

7956
A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
NOE effects (3 and 4.5%) were observed on the methyl
protons at 1.49 and 1.45 ppm, respectively.
78%) and a 4.5/1 mixture of (SR)-17/(SR)-18 (25 mg,
0.074 mmol, 10%) as a colorless oil. This mixture was
used for the N-sulfinyl deprotection without any purification.
(SR,2S,5R,10R)-16: white solid (mp 102–104 ꢃC); [a]2D0
ꢁ102 (c 1.3, CHCl3); IR (Nujol, cmꢁ1): 3240, 2965, 1788,
1470, 1400; HRMS m/z calcd for C17H33NO4S [M]+:
4.2.6. (SS,2S,5R,10R)-13 and (SS,2S,5S,10S)-15. The reac-
tion of dioxolanone (2S,5S)-1 (0.41 g, 2.41 mmol) with aldi-
mine (SS)-6 (0.19 g, 0.86 mmol) yielded a 3.8/1.0 mixture of
(SS)-13/(SS)-15. Silica gel chromatographic purification (n-
hexane/EtOAc/CH2Cl2, 2/1/1) provided a 3.8/1.0 mixture
of compounds (SS)-13/(SS)-15 (0.25 g, 0.64 mmol, 75%) as
an oil. (SS,2S,5R,10R)-13: IR (CDCl3, cmꢁ1) 2957, 1771,
1290, 1154; MS m/z 395, 211, 193, 131, 91; 1H NMR
(CDCl3) d 7.25–7.10 (m, 5H, arom), 3.85–3.80 (m, 1H,
H-10), 3.72 (d, 1H, J1¼6.0 Hz, NH), 3.23 (dd, 1H,
J1¼4.5 Hz, J2¼14.5 Hz, CH2–Ph), 3.00 (dd, 1H, J1¼
8.0 Hz, J2¼14.5 Hz, CH2–Ph), 1.48 (s, 3H, Me), 1.43 (s,
3H, Me), 1.10 (s, 9H, 3Me), 0.97 (s, 9H, 3Me); 13C NMR
(CDCl3) d 174.1, 137.3, 130.0, 128.7, 127.1, 114.8, 80.7,
62.1, 57.0, 39.2, 36.3, 24.9, 23.4, 22.8, 18.2. The (5R)-
configuration of (SS)-13 was assigned by homonuclear
NOE experiments (CDCl3). Upon irradiation of the acetal
tert-butyl group at 0.97 ppm, relevant NOE effects (4.5
and 2.5%) were observed on the methyl protons at 1.48
and 1.43 ppm, respectively.
1
347.2130, m/z found: 347.2125; H NMR (CDCl3) d 4.35
(d, 1H, J1¼3.0 Hz, NH), 3.40 (t, 1H, J1¼J2¼3.0 Hz, H-10),
2.16 (m, 1H, CHMe2), 1.55 (s, 3H, Me), 1.43 (s, 3H, Me),
t
1.23 (s, 9H, 3Me, BuSO), 1.08 (d, 3H, J¼7.0 Hz, Me of
CHMe2), 1.00 (d, 3H, J¼7.0 Hz, Me of CHMe2), 0.96 (s,
9H, 3Me, tBuCH); 13C NMR (CDCl3) d 175.3, 115.8, 81.2,
62.4, 56.5, 38.9, 29.4, 25.0, 23.2, 23.1, 23.0, 20.2, 20.0.
Anal. Calcd for C17H33NO4S: C, 58.76; H, 9.57; N, 4.03.
1
Found: C, 58.65; H, 9.55; N, 3.96. (SR,2S,5R,10S)-17: H
NMR (CDCl3) d 3.38–3.26 (m, 2H, NH and H-10), 2.30
(m, 1H, CHMe2), 1.61 (s, 3H, Me), 1.49 (s, 3H, Me), 1.23
t
(s, 9H, 3Me, BuSO), 1.15 (d, 3H, J¼7.0 Hz, Me of
CHMe2), 1.01–0.98 (m, 12H, 1Me of CHMe2, and 3Me,
tBuCH); 1H NMR (C6D6) d 3.43 (dd, 1H, J1¼1.5 Hz,
J2¼8.8 Hz, H-10), 3.32 (d, 1H, J¼8.8 Hz, NH), 2.11 (m,
1H, CHMe2), 1.43 (s, 3H, Me), 1.27 (d, 3H, J¼7.0 Hz, Me
t
of CHMe2), 1.26 (s, 3H, Me), 1.19 (s, 9H, 3Me, BuSO),
0.97 (d, 3H, J¼7.0 Hz, Me of CHMe2), 0.85 (s, 9H, 3Me,
tBuCH); 13C NMR (CDCl3) d 175.3, 115.2, 81.2, 67.0,
65.1, 39.2, 27.3, 25.3, 23.4, 23.3, 23.0, 22.2, 17.3.
O
S
HN
1
(SR,2S,5S,10S)-18: H NMR (C6D6) relevant resonances at
O
d 3.62 (d, 1H, J¼8.5 Hz, NH), 3.54 (dd, 1H, J1¼2.8 Hz,
J2¼8.5 Hz, H-10), 2.35 (m, 1H, CHMe2), 1.38 (s, 3H, Me),
O
O
t
1.23 (s, 9H, 3Me, BuSO), 0.95 (d, 3H, J¼7.0 Hz, Me of
CHMe2), 0.86 (s, 9H, 3Me, tBuCH). The (5R)-configuration
of (SR)-17 was assigned by homonuclear NOE experiments
(C6D6). Irradiation of the acetal tert-butyl group at
0.85 ppm produced 3.0 and 2.0% NOE effects on the Me
protons at 1.43 and 1.26 ppm, respectively.
(S , 2S, 5R, 1'R)-13
S
(SS,2S,5S,10S)-15: IR (CDCl3, cmꢁ1) 2960, 1775, 1290,
1152; MS m/z 395, 211, 193, 131, 91; 1H NMR (CDCl3) rel-
evant resonances at d 7.25–7.10 (m, 5H, arom), 4.49 (d, 1H,
J1¼4.0 Hz, NH), 3.88–3.84 (m, 1H, H-10), 3.04–2.92 (m,
2H, CH2Ph), 1.62 (s, 3H, Me), 1.52 (s, 3H, Me), 1.10 (s,
9H, 3Me), 0.87 (s, 9H, 3Me); 13C NMR (CDCl3) d 175.5,
138.5, 129.6, 128.6, 126.7, 116.0, 80.5, 60.6, 56.3, 38.9,
37.0, 25.0, 23.0, 22.9, 21.0. The (5S)-configuration of
(SS)-15 was assigned by homonuclear NOE experiments
(CDCl3). Irradiation of the acetal tert-butyl group at
0.87 ppm produced a 1.5% NOE effect on the C2-methyl
protons at 1.62 ppm. No NOE effect on the C5-methyl
protons at 1.52 ppm was observed.
O
S
HN
O
O
O
(S , 2S, 5R, 1'S)-17
R
4.2.8. Synthesis of (SS,2S,5R,10R)-16. The reaction of
(2S,5S)-1 (300 mg, 1.74 mmol) and imine (SS)-7 (110 mg,
0.63 mmol) afforded (SS)-16. Traces of a second diastereo-
O
S
1
mer were observed by H NMR spectroscopy of the crude
HN
O
material, but we could not isolate it from impurities. Chro-
matography (SiO2, n-hexane/EtOAc, 4/3), gave the 10-sulfi-
nylimino dioxolanone (SS)-16 as a white solid (mp 138–
140 ꢃC) (214 mg, 0.618 mmol, 93%). [a]2D0 +63.1 (c 0.9,
CHCl3); IR (Nujol, cmꢁ1): 3244, 2963, 1790, 1470, 1395,
1282, 1251, 1153, 1049; HRMS m/z calcd for
C17H33NO4S [M]+: 347.2130, m/z found: 347.2121; 1H
NMR (C6D6) d 3.40 (dd, 1H, J1¼3.2 Hz, J2¼8.8 Hz, H-
10), 3.29 (d, 1H, J¼8.8 Hz, NH), 2.15 (m, 1H, CHMe2),
1.24 (s, 3H, Me), 1.18 (d, 3H, J¼7.0 Hz, Me of CHMe2),
O
O
(S , 2S, 5S, 1'S)-15
S
4.2.7. Synthesis of (SR,2S,5R,10R)-16, (SR,2S,5R,10S)-17,
and (SR,2S,5S,10S)-18. The reaction of (2S,5S)-1 (563 mg,
3.27 mmol) and imine (SR)-7 (206 mg, 0.756 mmol)
afforded (SR)-16/(SR)-17/(SR)-18 as a 89/9/2 mixture. Chro-
matography (SiO2, n-hexane/EtOAc, 4/3), gave the 10-
sulfinylimino dioxolanone (SR)-16 (206 mg, 0.593 mmol,
t
1.13 (s, 3H, Me), 1.12 (s, 9H, 3Me, BuSO), 0.84 (d, 3H,
t
J¼7.0 Hz, Me of CHMe2), 0.78 (s, 9H, 3Me, BuCH); 13C
NMR (C6D6) d 172.6, 113.1, 81.3, 65.8, 56.4, 38.9, 27.9,

A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
7957
24.6, 22.8, 22.6, 22.5, 18.9, 18.5. Anal. Calcd for
C17H33NO4S: C, 58.76; H, 9.57; N, 4.03. Found: C, 58.81;
H, 9.49; N, 4.09. The (5R)-configuration of (SS)-16 was
assigned by homonuclear NOE experiments (CDCl3). Irradi-
ation of the acetal tert-butyl group at 0.96 ppm produced 3.5
and 4.8% NOE effects on the Me protons at 1.24 and
1.13 ppm, respectively.
56.8, 56.3, 39.6, 36.9, 34.4, 24.2, 24.0, 23.3, 23.0, 21.1.
Anal. Calcd for C23H37NO4S: C, 65.21; H, 8.80; N, 3.31.
Found: C, 65.17; H, 8.68; N, 3.20. The (5R)-stereoconfigura-
tion of (SR)-20 was assigned by NOE experiments (CDCl3).
Irradiation of the tert-butyl group at C2-position (0.58 ppm)
produced an NOE effect of 2.0% on the aromatic protons of
the benzyl group, while irradiation of the hydrogen at C2-
position (5.20 ppm) caused NOE effects (1.5 and 3.0%) on
the NH (2.95 ppm) and H10 (3.68 ppm), respectively.
O
S
HN
O
S
H
O
HN
O
O
O
H
O
O
(SS, 2S, 5R, 1'R)-16
(S , 2S, 5R, 1'S)-20
R
4.2.9. Synthesis of (SR,2S,5R,10R)-19, (SR,2S,5R,10S)-20,
and (SR,2S,5S,10S)-21. The dioxolanone (2S,5S)-2 (335 mg,
1.43 mmol) was reacted with imine (SR)-5 (96 mg,
(SR,2S,5S,10S)-21: 1H NMR (CDCl3) relevant resonances at
d 5.22 (s, 1H, C2–H), 1.28 (s, 9H, BuS(O)), 0.67 (s, 9H,
t
1
3Me, tBuC2).
0.51 mmol). The H NMR analysis of the crude mixture
showed the presence of a 6.0/18.0/1.0 mixture of (SR)-19/
(SR)-20/(SR)-21. Silica gel purification (n-hexane/Et2O, 1/1)
afforded 119 mg of (SR)-20 (0.28 mmol, 55%) and 47 mg
of a (SR,)-19/(SR)-21¼6/1 mixture (0.11 mmol, 22%).
(SR,2S,5R,10R)-19: pale oil; IR (CDCl3, cmꢁ1) 1726;
HRMS m/z calcd for C23H37NO4S [M]+: 423.2443, m/z
4.2.10. Synthesis of (SS,2S,5R,10R)-19 and (SS,2S,5S,10S)-
21. The dioxolanone (2S,5S)-2 (525 mg, 2.24 mmol) was re-
acted with imine (SS)-5 (151 mg, 0.80 mmol). The 1H NMR
analysis of the crude compounds showed the presence of
a 0.84/1.0 mixture of (SS)-19/(SS)-21. Silica gel purification
(n-hexane/Et2O, 1/1) afforded (SS)-19 (122 mg, 0.29 mmol,
36%) and (SS)-21 (145 mg, 0.34 mmol, 43%) as sticky oils.
(SS,2S,5R,10R)-19: [a]D20 +48.1 (c 0.5, CHCl3); IR (CDCl3,
1
found: 423.2437; H NMR (CDCl3) d 7.25–7.20 (m, 5H,
arom), 5.33 (s, 1H, C2–H), 3.82 (d, 1H, J¼7.0 Hz, NH),
3.58 (m, 1H, H-10), 3.30 (d, 1H, J¼14.5 Hz, CH2–C6H5),
3.22 (d, 1H, J¼14.5 Hz, CH2–C6H5), 1.94–1.84 (m, 1H,
Me2CH), 1.66 (m, 1H, CH2–CHMe2), 1.50 (m, 1H, CH2–
cmꢁ1
)
3215, 2966, 1726; HRMS m/z calcd for
C23H37NO4S [M]+: 423.2443, m/z found: 423.2433; 1H
NMR (CDCl3) d 7.30–7.18 (m, 5H, arom), 5.21 (s, 1H,
C2–H), 3.59 (m, 1H, H-10), 3.23 (d, 1H, J¼14.0 Hz, CH2–
C6H5), 3.20 (d, 1H, J¼6.0 Hz, NH), 3.09 (d, 1H,
J¼14.0 Hz, CH2–C6H5), 1.94–1.84 (m, 1H, Me2CH),
t
CHMe2), 1.27 (s, 9H, BuS(O)), 0.95 (d, 3H, J¼6.5 Hz,
Me), 0.81 (d, 3H, J¼6.5 Hz, Me), 0.62 (s, 9H, 3Me,
tBuC2); 13C NMR (CDCl3) d 173.9, 134.7, 131.2, 128.6,
127.3, 109.8, 85.5, 57.3, 57.0, 41.2, 39.0, 34.5, 25.3, 24.0,
23.3, 23.1, 21.2. The (5R)-configuration of (SR,2S,5R,10R)-
19 was assigned by homonuclear NOE experiments
(CDCl3). Irradiation of the hydrogen at C2-position
(5.33 ppm) produced NOE effects (1.5 and 3.5%) on the
NH (3.82 ppm) and H10 (3.58 ppm), respectively.
t
1.68–1.50 (m, 1H, CH2–CHMe2), 1.28 (s, 9H, BuS(O)),
1.30–1.15 (m, 1H, CH2–CHMe2), 0.95 (d, 3H, J¼6.5 Hz,
Me), 0.80 (d, 3H, J¼6.5 Hz, Me), 0.67 (s, 9H, 3Me,
tBuC2); 13C NMR (CDCl3) d 173.3, 134.5, 131.0, 128.6,
127.4, 109.5, 85.9, 57.7, 56.9, 41.0, 39.0, 34.6, 24.2, 23.9,
23.4, 23.1, 20.9. Anal. Calcd for C23H37NO4S: C, 65.21;
H, 8.80; N, 3.31. Found: C, 65.07; H, 8.76; N, 3.37.
(SS,2S,5S,10S)-21: [a]D20 +10.0 (c 0.6, CHCl3); IR (CDCl3,
O
S
H
HN
O
Ph
O
cmꢁ1
)
3210, 2963, 1772; HRMS m/z calcd for
C23H37NO4S [M]+: 423.2443, m/z found: 423.2436; 1H
NMR (CDCl3) d 7.30–7.25 (m, 5H, arom), 4.10 (d, 1H,
J¼6.4 Hz, NH), 3.84 (s, 1H, C2–H), 3.58 (m, 1H, H-10),
3.57 (d, 1H, J¼14.0 Hz, CH2–C6H5), 3.12 (d, 1H,
J¼14.0 Hz, CH2–C6H5), 1.95–1.84 (m, 1H, Me2CH),
H
O
(S , 2S, 5R,1'R)-19
R
t
1.70–1.60 (m, 1H, CH2–CHMe2), 1.30 (s, 9H, BuS(O)),
(SR,2S,5R,10S)-20: pale oil; [a]D20 ꢁ16.8 (c 0.7, CHCl3); IR
1.37–1.25 (m, 1H, CH2–CHMe2), 0.94 (d, 3H, J¼6.4 Hz,
Me), 0.92 (d, 3H, J¼6.4 Hz, Me), 0.78 (s, 9H, 3Me,
tBuC2); 13C NMR (CDCl3) d 174.8, 134.8, 130.7, 128.8,
127.7, 109.9, 86.1, 59.3, 56.9, 41.5, 39.8, 34.5, 25.2, 24.0,
24.0, 23.2, 21.3. Anal. Calcd for C23H37NO4S: C, 65.21;
H, 8.80; N, 3.31. Found: C, 65.41; H, 8.88; N, 3.22. The
(5S)-configuration of (SS)-21 was assigned by homonuclear
NOE experiments (CDCl3). Upon irradiation of the aromatic
protons of the C5 benzyl group, significant NOE effect
(2.5%) was observed at the H2 acetal proton. ASIS effect
confirmed the structure: the shielding of the C2–H acetal
(CDCl3, cmꢁ1
) 3220, 1721; HRMS m/z calcd for
C23H37NO4S [M]+: 423.2443, m/z found: 423.2430; 1H
NMR (CDCl3) d 7.25–7.15 (m, 5H, arom), 5.20 (s, 1H,
C2–H), 3.68 (m, 1H, H-10), 3.12 (d, 1H, J¼12.0 Hz, CH2–
C6H5), 3.05 (d, 1H, J¼12.0 Hz, CH2–C6H5), 2.95 (d, 1H,
J¼5.0 Hz, NH), 1.96–1.85 (m, 1H, Me2CH), 1.69 (m, 1H,
CH2–CHMe2), 1.44 (m, 1H, CH2–CHMe2), 1.27 (s, 9H,
tBuS(O)), 0.99 (d, 3H, J¼6.5 Hz, Me), 0.92 (d, 3H,
t
J¼6.5 Hz, Me), 0.58 (s, 9H, 3Me, BuC2); 13C NMR
(CDCl3) d 173.2, 134.7, 131.2, 128.5, 127.3, 108.1, 86.5,

7958
A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
proton of (SS)-21 by the aromatic substituent (3.84 ppm)
causes an upfield effect respect to that of (SS)-19
(5.21 ppm). Accordingly, the C2-tert-butyl substituent of
(SS)-21 (0.78 ppm) was down-fielded respect to the one of
(SS)-19 (0.67 ppm). The (5R)-stereoconfiguration of the epi-
mer (SS)-19 was assessed by homonuclear NOE experi-
ments. Upon irradiation of the tert-butyl group of the
sulfinyl substituent at 1.28 ppm, a consistent NOE effect
(5%) was observed at the H2 acetal proton at 5.21 ppm.
(SR,2S,5R,10S)-23: sticky oil; IR (CDCl3, cmꢁ1) 3218, 2960,
1725; HRMS m/z calcd for C26H35NO4S [M]+: 457.2287,
m/z found: 457.2295; H NMR (CDCl3) d 7.40–7.18 (m,
1
10H, arom), 5.11 (s, 1H, C2–H), 4.00 (m, 1H, H-10), 3.39
(dd, 1H, J1¼5.0 Hz, J2¼14.5 Hz, CH2–C6H5), 3.30 (d, 1H,
J¼5.6 Hz, NH), 3.18 (m, 2H, CH2–C6H5), 2.93 (dd, 1H,
J1¼8.0 Hz, J2¼14.5 Hz, CH2–C6H5), 1.16 (s, 9H, tBuS(O)),
0.55 (s, 9H, 3Me, tBuC2); 13C NMR (CDCl3) d 173.3, 136.0,
134.6, 131.2, 130.2, 129.1, 129.0, 128.6, 127.4, 108.5, 86.8,
58.3, 56.6, 37.7, 36.8, 34.3, 23.2, 22.7. The (5R)-stereocon-
figuration of (SR)-23 was assigned by homonuclear NOE
experiments (CDCl3). Irradiation of the C2–H acetal proton
(5.11 ppm) produced an NOE effect of 7.0% on the proton at
the 10-position (4.0 ppm) and 3.0% on the NH proton
(3.30 ppm).
O
S
O
S
C6H5
O
C6H5
O
HN
HN
H
H
O
O
O
O
O
S
HN
H
(S , 2S, 5R, 1'R)-19
(S , 2S, 5S, 1'S)-21
O
S
S
t
t
ASIS: H-2: 5.21 ppm; Bu-2: 0.67ppm
ASIS: H-2: 3.84 ppm; Bu-2: 0.78 ppm
H
O
O
NOE: 5 %
NOE: 2.5 %
Legend:
Aromatic Solvent-Induced Effect (ASIS):
(S , 2S, 5R, 1'S)-23
R
Nuclear Overhauser Effect (NOE)
:
(SR,2S,5S,10S)-24: 1H NMR (CDCl3) relevant resonances at
d 5.21 (s, 1H, C2–H), 1.06 (s, 9H, BuS(O)), 0.72 (s, 9H,
t
4.2.11. Synthesis of (SR,2S,5R,10R)-22, (SR,2S,5R,10S)-
23, and (SR,2S,5S,10S)-24. The dioxolanone (2S,5S)-2
(765 mg, 4.02 mmol) was reacted with imine (SR)-6 (259 mg,
1.17 mmol). The reaction was quenched after 60% conver-
sion of the aldimine 6. The 1H NMR analysis of the crude re-
action mixture showed the presence of a (SR)-22/(SR)-23/(SR)-
24¼9.0/10.0/1.0 mixture. Silica gel purification (n-hexane/
Et2O, 1/1) afforded (SR)-22 (145 mg, 0.318 mmol, 27.0%)
and a (SR)-23/(SR)-24¼10/1 mixture (178 mg, 0.389 mmol).
(SR,2S,5R,10R)-22: white solid (mp 98 ꢃC); [a]2D0 +2.0 (c
0.8, CHCl3); IR (CDCl3, cmꢁ1) 3218, 2960, 1731; HRMS
m/z calcd for C26H35NO4S [M]+: 457.2287, m/z found:
3Me, BuC2); 13C NMR (CDCl3) relevant resonances at
d 136.4, 135.0, 130.9, 109.6, 85.4, 58.6, 57.1, 39.3, 37.0,
34.7, 23.5, 22.6.
t
4.2.12. Synthesis of (SS,2S,5R,10R)-22 and (SS,2S,5S,10S)-
24. The dioxolanone (2S,5S)-2 (942 mg, 4.02 mmol) was re-
acted with imine (SS)-6 (319 mg, 1.44 mmol). The 1H NMR
analysis of the crude material showed the presence of a 2.7/
1.0 mixture of (SS)-22/(SS)-24. Silica gel purification (n-hex-
ane/Et2O, 1/1) afforded (SS)-22 (291 mg, 0.629 mmol,
43.7%) and (SS)-24 (107 mg, 0.233 mmol, 16.3%) as pale
oils. (SS,2S,5R,10R)-22: [a]D20 +72.5 (c 0.6, CHCl3); IR
(CDCl3, cmꢁ1) 3215, 2960, 1722; HRMS m/z calcd for
C26H35NO4S [M]+: 457.2287, m/z found: 457.2269; 1H
NMR (CDCl3) d 7.35–7.18 (m, 8H, arom), 7.14 (m, 2H,
arom), 5.21 (s, 1H, C2–H), 3.93 (m, 1H, H-10), 3.44 (d,
1H, J¼4.8 Hz, NH), 3.32 (dd, 1H, J1¼4.8 Hz, J2¼14.4 Hz,
10-CH2–C6H5), 3.39 (d, 1H, J¼14.4 Hz, CH2–C6H5), 3.10
(d, 1H, J¼14.4 Hz, CH2–C6H5), 3.07 (dd, 1H, J1¼4.8 Hz,
1
457.2274; H NMR (CDCl3) d 7.40–7.15 (m, 8H, arom),
7.00 (m, 2H, arom), 5.61 (s, 1H, C2–H), 3.80 (m, 1H, H-
10), 3.57 (d, 1H, J¼7.5 Hz, NH), 3.35 (s, 2H, 10-CH2–
C6H5), 3.23 (dd, 1H, J1¼4.0 Hz, J2¼14.5 Hz, CH2–C6H5),
2.88 (dd, 1H, J1¼10.4 Hz, J2¼14.5 Hz, CH2–C6H5), 0.88
t
t
(s, 9H, BuS(O)), 0.76 (s, 9H, 3Me, BuC2); 13C NMR
(CDCl3) d 174.0, 138.0, 134.6, 131.0, 129.5, 128.9, 128.8,
127.6, 127.0, 110.5, 85.3, 61.6, 56.9, 40.0, 37.7, 34.8, 23.5,
22.4. Anal. Calcd for C26H35NO4S: C, 68.24; H, 7.71; N,
3.06. Found: C, 68.36; H, 7.65; N, 3.14. The (5R)-stereoconfi-
guration of (SS)-22 was assigned by homonuclear NOE exper-
iments (CDCl3). Irradiation of the C2–H acetal proton
(5.61 ppm) produced an NOE effect of 5.0% on the proton at
the 10-position (3.8 ppm), 3.0% on the NH proton (3.57 ppm),
and 4.0% on the H proton of CH2–C6H5 at 2.88 ppm.
t
J2¼14.4 Hz, 10-CH2–C6H5), 1.07 (s, 9H, BuS(O)), 0.72 (s,
t
9H, 3Me, BuC2); 13C NMR (CDCl3) d 173.2, 136.4,
134.5, 130.8, 129.9, 129.0, 128.8, 127.6, 127.4, 109.6,
85.4, 58.6, 56.6, 39.3, 37.0, 34.7, 23.5, 22.7. Anal. Calcd
for C26H35NO4S: C, 68.24; H, 7.71; N, 3.06. Found: C,
68.41; H, 7.78; N, 2.98. The (5R)-stereoconfiguration of
(SS)-22 was assigned by homonuclear NOE experiments
(CDCl3). Irradiation of the C2–H acetal proton (5.21 ppm)
O
O
S
S
HN
HN
H
H
O
O
H
H
H
H
O
O
O
O
(S , 2S, 5R, 1'R)-22
R
(S , 2S, 5R, 1'R)-22
S

A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
7959
produced an NOE effect of 4.0% on the proton at the 10-
position (3.93 ppm).
(CDCl3). Irradiation of the tert-butyl group at the C2-posi-
tion (0.66 ppm) produced an NOE effect of 1.2% on the
CH of the CH2–C6H5 centered at 3.21 ppm and at the 10-po-
sition centered at 2.87 ppm and an NOE effect of 1.5% on
the aromatic protons.
(SS,2S,5S,10S)-24: [a]D20 ꢁ5.3 (c 0.4, CHCl3); IR (CDCl3,
cmꢁ1
)
3215, 2960, 1725; HRMS m/z calcd for
C26H35NO4S [M]+: 457.2287, m/z found: 457.2294; 1H
NMR (CDCl3) d 7.35–7.10 (m, 10H, arom), 3.94–3.88 (m,
3H, 1H of C2–H and 2H of 10-CH2–C6H5), 3.71 (d, 1H,
J¼14.0 Hz, CH2–C6H5), 3.18 (d, 1H, J¼14.0 Hz, CH2–
C6H5), 3.03 (d, 1H, J¼13.5 Hz, NH), 2.87 (m, 1H, H-10),
(SR,2S,5R,10S)-26: [a]D20 ꢁ25.5 (c 0.6, CHCl3); IR (CDCl3,
cmꢁ1
)
3210, 2955, 1726; HRMS m/z calcd for
C22H35NO4S [M]+: 409.2287, m/z found: 409.2272; 1H
NMR (CDCl3) d 7.30–7.18 (m, 5H, arom), 5.14 (s, 1H,
C2–H), 3.45 (m, 2H, NH and H-10), 3.15 (d, 1H, J¼14.4 Hz,
CH2–C6H5), 3.10 (d, 1H, J¼14.4 Hz, CH2–C6H5), 2.37 (m,
1H, CHMe2), 1.26 (s, 9H, tBuS(O)), 1.14 (d, 3H, J¼6.0 Hz,
Me), 1.03 (d, 3H, J¼6.0 Hz, Me), 0.61 (s, 9H, 3Me,
tBuC2); 13C NMR (CDCl3) d 173.8, 134.6, 131.2, 128.6,
127.4, 109.4, 87.5, 65.3, 57.0, 39.9, 34.5, 27.4, 23.3, 23.0,
.22.1, 17.1. The (5R)-stereoconfiguration of (SR)-26 was
assigned by homonuclear NOE experiments (CDCl3). Irradi-
ation of the tert-butyl group at the C2-position (0.66 ppm)
produced an NOE effect of 0.7% on the two protons of
CH2–C6H5 centered at 3.15 and 3.10 ppm, respectively,
and an NOE effect of 1.7% on the aromatic protons.
t
t
1.02 (s, 9H, BuS(O)), 0.80 (s, 9H, 3Me, BuC2); 13C
NMR (CDCl3) d 176.0, 138.2, 134.7, 130.8, 129.9, 128.9,
128.7, 127.8, 126.9, 110.1, 86.3, 63.1, 56.8, 40.2, 38.7,
34.5, 23.9, 22.7. Anal. Calcd for C26H35NO4S: C, 68.24;
H, 7.71; N, 3.06. Found: C, 68.11; H, 7.80; N, 3.14. The
(5S)-stereoconfiguration of (SS)-24 was assigned by NOE
experiments (CDCl3). Irradiation of the tert-butyl group at
C2-position (0.80 ppm) produced an NOE effect of 1.8%
on the proton at the 10-position centered at 2.87 ppm and
a cumulative NOE effect of 9.0% on the H-2 acetal proton
and the 10-CH2–C6H5 protons (3.95–3.88 ppm).
O
S
O
S
HN
H
O
HN
O
H
O
O
O
O
(S , 2S, 5S, 1'S)-24
S
(S , 2S, 5R, 1'S)-26
R
4.2.13. Synthesis of (SR,2S,5R,10R)-25 and (SR,2S,5R,10S)-
26. The dioxolanone (2S,5S)-2 (565 mg, 2.41 mmol) was re-
acted with imine (SR)-7 (150 mg, 0.861 mmol). The 1H
NMR analysis of the crude material showed the presence
of a 1.3/1.0 mixture of (SR)-25/(SR)-26. Silica gel purifica-
tion (n-hexane/Et2O, 1/1) afforded (SR)-25 as a sticky oil,
contaminated by trace amounts of impurities (122 mg,
0.297 mmol, 34.5%), and (SR)-26 (93 mg, 0.228 mmol,
26.5%) as a pale sticky oil. (SR,2S,5R,10R)-25: IR (CDCl3,
4.2.14. Synthesis of (SS,2S,5R,10R)-25 and (SS,2S,5R,10S)-
26. The dioxolanone (2S,5S)-2 (984 mg, 4.20 mmol) was
reacted with imine (SS)-7 (262 mg, 1.50 mmol). H NMR
1
analysis of the crude material showed the presence of a
7.75/1.0 mixture of (SS)-25/(SS)-26. Silica gel purification
(n-hexane/Et2O, 1/1) afforded (SS)-25 (380 mg, 0.930 mmol,
62.0%) and (SS)-26 (50 mg, 0.120 mmol, 8%) as a mixture
with impurities. (SS,2S,5R,10R)-25: white sticky solid; [a]2D0
+32 (c 1.0, CHCl3); IR (CDCl3, cmꢁ1) 3200, 2955, 1728;
HRMS m/z calcd for C22H35NO4S [M]+: 409.2287, m/z
cmꢁ1
)
3200, 2950, 1734; HRMS m/z calcd for
C22H35NO4S [M]+: 409.2287, m/z found: 409.2266; 1H
NMR (CDCl3) d 7.23–7.18 (m, 5H, arom), 5.39 (s, 1H,
C2–H), 3.75 (d, 1H, J¼8.0 Hz, NH), 3.41 (dd, 1H,
J1¼2.4 Hz, J2¼8.0 Hz, H-10), 3.34 (d, 1H, J¼14.8 Hz,
CH2–C6H5), 3.21 (d, 1H, J¼14.8 Hz, CH2–C6H5), 2.16
1
found: 409.2298; H NMR (CDCl3) d 7.26–7.18 (m, 5H,
arom), 5.16 (s, 1H, C2–H), 3.55 (d, 1H, J¼8.8 Hz, NH),
3.44 (dd, 1H, J1¼2.0 Hz, J2¼8.8 Hz, H-10), 3.19 (d, 1H,
J¼14.4 Hz, CH2–C6H5), 3.14 (d, 1H, J¼14.8 Hz, CH2–
t
C6H5), 2.20 (m, 1H, CHMe2), 1.31 (s, 9H, BuS(O)), 1.12
t
(m, 1H, CHMe2), 1.28 (s, 9H, BuS(O)), 1.00 (d, 3H,
(d, 3H, J¼6.8 Hz, Me), 1.07 (d, 3H, J¼6.8 Hz, Me), 0.59
t
(s, 9H, 3Me, BuC2); 13C NMR (CDCl3) d 173.0, 134.7,
J¼6.8 Hz, Me), 0.97 (d, 3H, J¼6.8 Hz, Me), 0.66 (s, 9H,
t
3Me, BuC2); 13C NMR (CDCl3) d 173.8, 134.7, 131.3,
131.2, 128.6, 127.4, 108.9, 87.0, 64.5, 57.2, 39.1, 34.4,
29.1, 23.3, .23.2, 22.4, 18.2. The (5R)-stereoconfiguration
of (SS)-25 was assigned by homonuclear NOE experi-
ments (CDCl3). Irradiation of the tert-butyl group at the
128.6, 127.4, 109.5, 86.1, 64.5, 57.5, 40.6, 34.6, 29.8,
23.4, .23.3, 23.0, 17.7. The (5R)-stereoconfiguration of
(SR)-25 was assigned by homonuclear NOE experiments
O
O
S
S
HN
HN
O
O
O
O
O
O
(S , 2S, 5R, 1'R)-25
R
(S , 2S, 5R, 1'R)-25
S

7960
A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
C2-position (0.59 ppm) produced an NOE effect of 1.6% on
the aromatic protons.
reacted with imine (SRS)-6 (0.35 g, 1.56 mmol). Chromato-
graphy of the crude reaction mixture (SiO2, n-hexane/
EtOAc, 2/2) afforded a 13.0/1.0 mixture of (SR,2S,5R,10S)-
28 and (SS,2S,5R,10S)-28 (0.24 g, 0.53 mmol, 75%). IR
(CDCl3, cmꢁ1) 3270–3201, 2961, 1793; MS m/z 443, 284,
193, 121, 105. 1H NMR (CDCl3) d 7.88–7.84 (m, 2H,
arom, minor), 7.82–7.68 (m, 2H, arom, major), 7.50–7.00
(m, 16H, arom, minor and major), 5.62 (s, 1H, H-2, minor),
5.30 (s, 1H, H-2, major), 4.30–4.16 (m, 1H, J1¼5.8 Hz,
J2¼8.2 Hz, J3¼11.4 Hz, H-10, major), 4.0–4.14 (m, 1H, H-
10, minor), 3.53 (d, 1H, NH, major), 3.25 (d, 1H, NH, minor),
2.96–2.82 (dd, 1H, CH2–Ph, major), 2.80–2.66 (dd, 1H,
CH2–Ph, major), 2.41–2.28 (dd, 2H, CH2–Ph, minor), 1.16
(s, 9H, 3Me, major), 0.99 (s, 9H, 3Me, minor), 0.93 (s,
9H, 3Me, major), 0.82 (s, 9H, 3Me, minor); 13C NMR
(CDCl3) relevant resonances at d 172.9 (major), 136.2 (ma-
jor), 136.1 (major), 130.7 (major), 129.5 (minor), 128.7 (ma-
jor), 128.4 (major), 126.9 (major), 126.1 (minor), 125.7
(major), 111.0 (major), 110.8 (minor), 86.7 (major), 65.2
(major), 57.0 (minor), 56.6 (major), 36.5 (major), 35.5 (ma-
jor), 23.9 (minor), 23.8 (major), 22.7 (major), 22.1 (minor).
Anal. Calcd for C25H33NO4S: C, 67.69; H, 7.50; N, 3.16.
Found: C, 67.65; H, 7.57; N, 3.21.
(SS,2S,5R,10S)-26: IR (CDCl3, cmꢁ1) 3210, 2950, 1731;
HRMS m/z calcd for C22H35NO4S [M]+: 409.2287, m/z
found: 409.2297; H NMR (CDCl3) d 7.45 (m, 2H, arom),
1
7.30–7.20 (m, 3H, arom), 5.21 (s, 1H, C2–H), 4.44 (d, 1H,
J¼8.5 Hz, NH), 3.53 (dd, 1H, J1¼2.0 Hz, J2¼8.5 Hz, H-
10), 3.38 (d, 1H, J¼14.0 Hz, CH2–C6H5), 3.27 (d, 1H,
J¼14.0 Hz, CH2–C6H5), 2.15 (m, 1H, CHMe2), 1.31 (s,
t
9H, BuS(O)), 0.94 (d, 3H, J¼6.8 Hz, Me), 0.88 (d, 3H,
t
J¼6.8 Hz Me), 0.80 (s, 9H, 3Me, BuC2); 13C NMR
(CDCl3) d 175.2, 134.7, 131.6, 128.5, 127.3, 110.0, 82.0,
64.3, 57.6, 39.8, 34.8, 28.6, 23.6, .23.3, 22.6, 16.2. The
(5R)-stereoconfiguration of (SS)-25 was assigned by homo-
nuclear NOE experiments (CDCl3). Irradiation of the
tert-butyl group at the C2-position (0.80 ppm) produced
an NOE effect of 0.8% on one of the two protons of
CH2–C6H5 centered at 3.27 ppm and an NOE effect of 5.8%
on the aromatic protons at 7.45 ppm.
O
S
HN
O
4.2.17. Synthesis of (SS,2S,5R,10S)-29. The reaction of
dioxolanone (2S,5S)-3 (394 mg, 1.79 mmol) and imine
(SS)-7 (112 mg, 0.638 mmol) afforded compound
(SS,2S,5R,10S)-29 as a white solid (0.20 mg, 0.51 mmol,
80%). Mp 118–120 ꢃC; [a]D20 +2.8 (c 0.5, CHCl3); IR (Nujol,
cmꢁ1): 2960, 1793, 1202, 1081; HRMS m/z calcd for
C21H33NO4S [M]+: 395.5560, m/z found: 395.5566; 1H
NMR (CDCl3) d 7.70 (m, 2H, arom), 7.40–7.28 (m, 3H,
arom), 5.52 (s, 1H, H-2), 3.77 (dd, 1H, J1¼1.6 Hz,
J2¼10.4 Hz, H-10), 3.55 (d, 1H, J¼10.4 Hz, NH), 1.60–
O
O
(S , 2S, 5R, 1'S)-26
S
4.2.15. Synthesis of (SR,2S,5R,10S)-27 and (SS,2S,5R,10S)-
27. The dioxolanone (2S,5S)-3 (143 mg, 0.65 mmol) was
reacted with imine (SSR)-5 (272 mg, 1.44 mmol). Silica gel
column chromatography of the crude compound (n-hex-
ane/EtOAc, 2/1) afforded a 1.5/1.0 mixture (229 mg,
0.56 mmol, 86%) of (SR,2S,5R,10S)-27 and (SS,2S,5R,10S)-
27. IR (CDCl3, cmꢁ1) 3210, 1721; HRMS m/z calcd for
C22H35NO4S [M]+: 409.2287, m/z found: 409.2278. 1H
NMR (CDCl3) d 7.80–7.71 (m, 2H, arom, minor), 7.70–
7.60 (m, 2H, arom, major), 7.41–7.23 (m, 3H, arom, major
and minor), 5.52 (s, 1H, CH-2, minor), 5.45 (s, 1H, CH-2,
major), 3.89–3.81 (m, 1H, H-10, minor), 3.80–3.72 (m, 1H,
H-10, major), 3.35 (d, 1H, J¼9.2 Hz, NH, minor), 3.08 (d,
1H, NH, major), 1.74–1.84 (m, 1H, Me2CH, major), 1.72–
1.62 (m, 1H, Me2CH, minor), 1.42–1.26 (m, 4H, 2 CH2,
major and minor), 1.24 (s, 9H, 3Me, minor), 1.20 (s, 9H,
3Me, major), 0.95 (s, 9H, 3Me, minor), 0.94 (s, 9H, 3Me,
major), 0.80 (d, 3H, J¼6.4 Hz, Me, minor), 0.77 (d, 3H,
J¼6.8 Hz, Me, major), 0.67 (d, 3H, Me, minor), 0.63 (d,
3H, Me, major); 13C NMR (CDCl3) relevant resonances at d
173.0 (major), 172.6 (minor), 136.3 (major), 135.7 (minor),
128.6 (major), 128.4 (minor), 126.2 (minor), 125.5 (major),
111.0 (major), 110.2 (minor), 86.7 (major), 85.0 (minor),
63.7 (major), 60.6 (minor), 57.2 (minor), 56.7 (major),
39.7 (major), 39.4 (minor), 35.7 (major), 35.5 (minor),
24.4 (minor), 23.9 (minor), 23.8 (major), 23.1 (major),
22.9 (major), 22.8 (minor), 21.0 (major), 20.8 (minor).
Anal. Calcd for C22H35NO4S: C, 64.51; H, 8.61; N, 3.42.
Found: C, 64.55; H, 8.67; N, 3.48.
t
1.52 (m, 1H, CHMe2), 1.26 (s, 9H, 3Me, BuSO), 0.94 (s,
t
9H, 3Me, BuCH), 0.80 (d, 3H, Me, CHMe2, J¼7.0 Hz),
0.74 (d, 3H, Me, CHMe2, J¼7.0 Hz); 13C NMR (CDCl3)
d 173.3, 137.4, 128.6, 128.4, 125.4, 111.2, 85.7, 67.3,
57.4, 35.5, 28.6, 24.0, 23.0, 22.0, 15.6. Anal. Calcd for
C21H33NO4S: C, 63.76; H, 8.41; N, 3.54. Found: C, 63.93;
H, 8.35; N, 3.42. The (5R)-configuration of 29 was assigned
by homonuclear NOE experiments (CDCl3). Irradiation of
the C2-tert-butyl group at 0.94 ppm produced a 2.5% NOE
effect on the two ortho aromatic protons of the phenyl
(7.70 ppm), while irradiation of H-2 at 5.52 ppm induced
2.0 and 2.5% NOE effects on the H-10 and NH protons at
3.77 and 3.55 ppm, respectively.
O
H
S
H
HN
O
H
H
O
O
(S , 2S, 5R, 1'S)-29
S
4.3. General procedure for the synthesis of
10-aminodioxolanones
4.2.16. Synthesis of (SR,2S,5R,10S)-28 and (SS,2S,5R,10S)-
28. The dioxolanone (2S,5S)-3 (0.16 g, 0.71 mmol) was
Unless otherwise stated, to an MeOH solution of the N-
sulfinylaminodioxolanone (2 mLꢂ0.03 g of substrate) was

A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
7961
added an ethereal solution of 2 N HCl (16 equiv), under
nitrogen and at 0 ꢃC.38 After 30 min, the temperature was
raised to 25 ꢃC and stirred for additional 2 h. The solvent
was removed under vacuum and the residue was treated
with a saturated aqueous solution of NaHCO3, diluted with
H2O, and extracted three times with ethyl acetate. The or-
ganic phase was dried over Na2SO4 and the solvent removed
under vacuum. Silica gel column chromatography of the
residue yielded pure 10-aminodioxolanones.
on the CH3 protons at C2 (1.79 ppm) and C5 (1.35 ppm),
respectively.
NH2
O
S
O
O
(2S, 5R, 1'R)-31
4.3.1. Synthesis of (2S,5R,10S)-30. (i) Deprotection of
(SS,2S,5R,10S)-8: a solution of (SS)-8 (60 mg, 0.15 mmol)
was reacted with 1.25 mL of 2.0 N HCl (16.0 equiv). Chro-
matography of the crude reaction mixture (SiO2, n-hexane/
Et2O, 1/1) provided (2S,5R,10S)-30 as an oil (36 mg,
0.13 mmol, 82%). (ii) Deprotection of (SR,2S,5R,10S)-8:
the HCl-induced sulfinyl deprotection of (SR)-8 (75 mg,
0.19 mmol) afforded (2S,5R,10S)-30 (47 mg, 0.17 mmol,
4.3.3. Synthesis of (2S,5S,10R)-32. A MeOH solution of
(SS,2S,5S,10R)-10 (80 mg, 0.2 mmol) was reacted with
1.6 mL of 2 N HCl (16 equiv). Silica gel column chromato-
graphy purification of the crude reaction mixture (n-hexane/
Et2O, 1/1) afforded (2S,5S,10R)-32 as a sticky foam (49 mg,
0.17 mmol, 83%). [a]D20 ꢁ22.5 (c 0.68, CHCl3); IR (CDCl3,
1
cmꢁ1) 3390, 2959, 1780; MS m/z 283; H NMR (CDCl3)
82%). [a]2D0 +82.0 (c 0.26, CHCl3); IR (CDCl3, cmꢁ1
)
d 7.28–7.23 (m, 1H, arom), 7.19–7.14 (m, 1H, arom),
7.04–7.00 (m, 1H, arom), 4.67 (s, 1H, H-10), 1.99–1.50 (b,
2H, NH2), 1.55 (s, 3H, Me), 1.49 (s, 3H, Me), 1.09 (s, 9H,
3Me); 13C NMR (CDCl3) d 175.5, 142.7, 126.5, 125.4,
124.8, 115.2, 80.0, 56.1, 38.8, 24.8, 22.7, 18.0. Anal. Calcd
for C14H21NO3S: C, 59.34; H, 7.47; N, 4.94. Found: C,
59.11; H, 7.39; N, 5.01. The (5S)-stereoconfiguration of
(2S,5S,10R)-32, hence of (SS,2S,5S,10R)-10 by chemical cor-
relation, was assigned by homonuclear NOE experiments
(CD3COCD3). This compound showed a significant NOE
effect (5.0%) with the Me proton at C2 (1.55 ppm) upon ir-
radiation of the C2-tert-butyl group at 1.09 ppm. Instead, no
NOE effect was detected with the Me protons at C5
(1.49 ppm).
1
3390, 2959, 1782; MS m/z 283; H NMR (CDCl3) d 7.27–
7.22 (m, 1H, arom), 7.12–7.08 (m, 1H, arom), 7.04-7.0 (m,
1H, arom), 4.62 (s, 1H, H-10), 1.92–1.85 (b, 2H, NH2),
1.49 (s, 3H, Me), 1.45 (s, 3H, Me), 1.01 (s, 9H, 3Me); 13C
NMR (CDCl3) d 175.0, 143.4, 126.6, 125.5, 124.8, 115.2,
81.6, 57.2, 38.9, 24.8, 23.0, 17.8. Anal. Calcd for
C14H21NO3S: C, 59.34; H, 7.47; N, 4.94. Found: C, 59.60;
H, 7.50; N, 4.86. The (5R)-stereoconfiguration of
(2S,5R,10S)-30, hence of the parent compounds (SR)- and
(SS)-8, was assigned by homonuclear NOE experiments
(CDCl3). Upon irradiation of the C2-tert-butyl group at
1.01 ppm, significant NOE effects (5.5 and 3.5%) were
observed on the Me protons at C2 (1.49 ppm) and C5
(1.47 ppm), respectively.
NH2
O
NH2
S
O
S
O
O
O
O
(2S, 5S, 1'R)-32
(2S,5R,1'S)-30
4.3.4. Synthesis of (2S,5R,10R)-35. (i) Deprotection of com-
pound (SS,2S,5R,10R)-11: a solution of (SS)-11 (90 mg,
0.25 mmol) was reacted with 2.0 mL of 2.0 N HCl
(16 equiv). Silica gel chromatography of the crude reaction
mixture (n-hexane/Et2O, 1/1) afforded (2S,5R,10R)-35
(47 mg, 0.19 mmol, 73%). (ii) Deprotection of compound
(SR,2S,5R,10R)-11: HCl-induced sulfinyl deprotection of
(SR)-11 (80 mg, 0.22 mmol) provided (2S,5R,10R)-35
(47 mg, 0.18 mmol, 83%). Mp 98–101 ꢃC; [a]D20 +36.0 (c
0.36, CHCl3); IR (CDCl3, cmꢁ1) 3349, 2965, 1775; mp
92 ꢃC; MS m/z 257, 156, 130, 86. Anal. Calcd for
C14H27NO3: C, 65.33; H, 10.57; N, 5.44. Found: C, 65.51;
4.3.2. Synthesis of (2S,5R,10R)-31. (i) Deprotection of
(SR,2S,5R,10R)-9: a MeOH solution of (SR)-9 (45 mg,
0.12 mmol) was reacted with 0.09 mL of 2.0 N HCl
(16.0 equiv). Silica gel column chromatography purification
of the crude reaction mixture (n-hexane/Et2O, 1/1) gave (2S,
5R, 10R)-31 as a sticky oil (28 mg, 0.10 mmol, 86%). (ii) De-
protection of (SS,2S,5R,10R)-9: after the HCl-induced depro-
tection of 10 mg of an MeOH solution of (Ss)-9, the 1H NMR
spectrum (CDCl3) of the crude reaction mixture revealed the
presence of (2S,5R,10R)-31. [a]D20 +49.0 (c 0.4, CHCl3); IR
(CDCl3, cmꢁ1) 3388, 1778; MS m/z 283; 1H NMR
(CDCl3) d 7.28–7.25 (m, 1H, arom), 7.05–7.00 (m, 1H,
arom), 6.95–6.90 (m, 1H, arom), 4.43 (s, 1H, H-10), 1.80–
1.70 (b, 2H, NH2), 1.79 (s, 3H, Me), 1.35 (s, 3H, Me),
1.03 (s, 9H, 3Me); 13C NMR (CDCl3) d 175.0, 143.7,
126.2, 126.1, 125.4, 115.8, 83.7, 57.2, 39.0, 25.1, 22.3,
22.2. Anal. Calcd for C14H21NO3S: C, 59.34; H, 7.47; N,
4.94. Found: C, 59.18; H, 7.41; N, 4.96. The (5R)-stereocon-
figuration of 31 was assigned by homonuclear NOE experi-
ments (CDCl3). Irradiation of the C2-tert-butyl group at
1.03 ppm produced significant NOE effects (5.2 and 4.4%)
1
H, 10.68; N, 5.46. H NMR (CDCl3) d 3.06 (dd, 1H, J1¼
10.8 Hz, J2¼2.2 Hz, H-10), 1.92–1.72 (m, 1H, Me2CH), 1.52
(s, 3H, Me), 1.46–1.42 (b, 2H, NH2), 1.39 (s, 3H, Me), 1.32–
1.12 (m, 2H, CH2), 0.99 (s, 9H, 3Me), 0.96 (d, 3H, J¼6.8 Hz,
Me), 0.89 (d, 3H, J¼6.8 Hz, Me); 13C NMR (CDCl3) d 175.5,
114.3, 81.4, 54.8, 39.6, 38.9, 24.7, 24.6, 24.0, 23.1, 21.1,
16.3. The (5R)-configuration of (SR)-15 was assigned by
homonuclear NOE experiments. Irradiation of the acetal
tert-butyl group at 0.99 ppm produced a 4.0 and 2.0% NOE
effects on the Me protons at 1.52 and 1.39 ppm, respectively.

7962
A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
reaction mixture yielded a 3.8/1 mixture of (2S,5R,10R)-
NH2
O
37/(2S,5S,10S)-39 (0.069 g, 0.24 mmol, 88%). (2S,5S,10S)-
39: IR (CDCl3, cmꢁ1) 1784, MS m/z 291; 1H NMR
(CDCl3) d 7.30–7.20 (m, 2H, arom), 7.23–7.18 (m, 3H,
arom), 3.33 (m, 1H, H-10), 3.10 (dd, 1H, J1¼2.0 Hz,
J2¼13.0 Hz, CH2–Ph), 2.40 (dd, 1H, J1¼10.5 Hz,
J2¼13.2 Hz, CH2–Ph), 1.61 (s, 3H, Me), 1.60 (s, 3H, Me),
1.56–1.50 (b, 2H, NH2), 1.08 (s, 9H, 3Me); 13C NMR
(CDCl3) d 175.9, 139.1, 129.5, 128.9, 126.8, 115.0, 81.7,
57.8, 39.0, 37.2, 25.1, 23.1, 18.1.
O
O
(S , 2S, 5R, 1'R)-35
S
4.3.5. Synthesis of (2S,5R,10S)-36. (i) Deprotection of com-
pound (SS,2S,5R,10S)-12: an MeOH solution of (SS)-12
(91 mg, 0.25 mmol) was reacted with 2.0 mL of 2.0 N HCl
(16 equiv). Silica gel column chromatography of the crude
reaction mixture (n-hexane/Et2O, 1/1) provided
(2S,5R,10S)-36 (56 mg, 0.22 mmol, 86%). (ii) HCl-induced
sulfinyl deprotection of (SS,2S,5R,10S)-12 (88 mg,
0.24 mmol) afforded (2S,5R,10S)-36 as a sticky oil (50 mg,
0.19 mmol, 80%). [a]D20 +4.0 (c 0.35, CHCl3); IR (CDCl3,
4.3.9. Synthesis of (2S,5R,10R)-40. (i) Deprotection of com-
pound (SS,2S,5R,10R)-16: an MeOH solution of (SS)-16
(180 mg, 0.52 mmol) was reacted with 4.1 mL of 2.0 N
HCl (16 equiv). The crude reaction mixture (107 mg,
0.44 mmol, 85%) of (2S,5R,10R)-40 was used for the next
step without any further purification. (ii) Deprotection of
compound (SR,2S,5R,10R)-16: an MeOH solution of (SR)-
16 (120 mg, 0.35 mmol) was reacted with 2.7 mL of 2.0 N
HCl (16 equiv) to afford 68 mg (0.28 mmol, 81%) of
(2S,5R,10R)-40 as a white solid (mp 103–105 ꢃC); HRMS
m/z calcd for C13H25NO3 [M]+: 243.1834, m/z found:
243.1839; IR (CDCl3, cmꢁ1) 2982, 1781; 1H NMR
(CDCl3) d 2.83 (d, 1H, J¼4.8 Hz, H-10), 2.03 (m, 1H,
CHMe2), 1.52 (s, 3H, Me), 1.44 (s, 3H, Me), 1.44–1.38 (b,
2H, NH2), 1.04 (d, 3H, J¼6.8 Hz, Me of CHMe2), 1.00 (s,
cmꢁ1) 3349, 2965, 1775; MS m/z 257, 156, 130, 86; H
1
NMR (CDCl3) d 3.05 (dd, 1H, J1¼10.5 Hz, J2¼2.5 Hz,
H-10), 1.89–1.62 (m, 1H, Me2CH), 1.62 (s, 3H, Me), 1.58–
1.30 (m, 4H, 2CH2+NH2), 1.36 (s, 3H, Me), 1.01 (s, 9H,
3Me), 0.96 (d, 3H, J¼6.6 Hz, Me), 0.87 (d, 3H, Me); 13C
NMR (CDCl3) d 175.3, 114.8, 68.4, 55.0, 40.1, 39.2, 25.1,
24.9, 24.4, 23.1, 21.3, 18.7. Anal. Calcd for C14H27NO3:
C, 65.33; H, 10.57; N, 5.44. Found: C, 65.51; H, 10.61; N,
5.52.
t
9H, 3Me, BuCH), 0.99 (d, 3H, J¼6.8 Hz, Me of CHMe2);
4.3.6. Synthesis of (2S,5R,10R)-37. A MeOH solution of
(SR)-13 (0.10 g, 0.25 mmol) was reacted with 2.0 N HCl
(16 equiv). Chromatography of the crude reaction mixture
(SiO2, n-hexane/EtOAc, 5/2+2% of isopropylamine) yielded
(2S,5R,10R)-37 as a white solid (mp 79 ꢃC) (0.066 g,
0.227 mmol, 91%). [a]2D0 +7.44 (c 0.39, CHCl3); IR
(CDCl3, cmꢁ1) 2964, 1780, 1152; MS m/z 291, 232, 120,
92; 1H NMR (CDCl3) d 7.30–7.20 (m, 5H, arom), 3.30 (m,
1H, H-10), 3.14 (dd, 1H, J1¼2.0 Hz, J2¼13.2 Hz, CH2–
Ph), 2.42 (dd, 1H, J1¼10.8 Hz, J2¼13.2 Hz, CH2–Ph),
1.62 (s, 3H, Me), 1.54 (s, 3H, Me), 1.56–1.50 (b, 2H,
NH2), 1.04 (s, 9H, 3Me); 13C NMR (CDCl3) d 175.4,
139.3, 129.4, 128.9, 126.8, 115.0, 81.7, 59.1, 39.2, 37.4,
25.0, 23.5, 17.1. Anal. Calcd for C17H25NO3: C, 70.07; H,
8.65; N, 4.81. Found: C, 70.02; H, 8.60; N, 4.75.
13C NMR (CDCl3) d 176.0, 114.6, 82.3, 61.4, 39.0, 29.1,
25.0, 23.3, 22.7, 18.5, 17.5.
4.3.10. Synthesis of (2S,5R,10R)-41. (i) Deprotection of
compound (SS,2S,5R,10R)-19: HCl-induced sulfinyl depro-
tection of (SS)-19 (194 mg, 0.46 mmol) afforded
(2S,5R,10R)-41 (133 mg, 0.42 mmol, 91%). (ii) Deprotec-
tion of compound (SR,2S,5R,10R)-19: HCl-induced sulfinyl
deprotection of (SR)-19 (164 mg, 0.39 mmol) provided
(2S,5R,10R)-41 (102 mg, 0.32 mmol, 82%). The crude oil
41 was used for the next step without any further purifica-
tions. (2S,5R,10R)-41: IR (CDCl3, cmꢁ1) 3355, 2965,
1772; HRMS m/z calcd for C19H29NO3 [M]+: 319.2147,
1
m/z found: 319.2158; H NMR (CDCl3) d 7.27–7.20 (m,
5H, arom), 5.34 (s, 1H, C2–H), 3.22 (d, 1H, J¼14.5 Hz,
CH2–C6H5), 3.11 (dd, 1H, J1¼10.5 Hz, J2¼3.5 Hz, H-10),
3.02 (d, 1H, J¼14.0 Hz, CH2–C6H5), 1.78–1.66 (m, 1H,
Me2CH), 1.54–1.25 (m, 4H, 2H of CH2–CHMe2 and 2H of
NH2), 0.98 (d, 3H, J¼6.5 Hz, Me), 0.78 (d, 3H, J¼6.5 Hz,
Me), 0.73 (s, 9H, 3Me, tBuC2); 13C NMR (CDCl3)
d 174.6, 135.3, 131.0, 128.5, 127.2, 110.1, 86.6, 53.7,
40.8, 38.2, 34.7, 25.1, 24.4, 23.5, 21.1.
4.3.7. Synthesis of (2S,5R,10S)-38. An MeOH solution of
(SR,2S,5R,10S)-14 (0.16 g, 0.41 mmol) was reacted with
2.0 N HCl (16 equiv). Chromatography (SiO2, n-hexane/
EtOAc, 5/2+2% isopropylamine) yielded (2S,5R,10S)-38 as
a sticky oil (0.10 g, 0.34 mmol, 85%). [a]2D0 ꢁ17.5 (c 0.40,
CH2Cl2); IR (CDCl3, cmꢁ1) 2964, 1783, 1152; MS m/z
1
291, 232, 120, 92; H NMR (CDCl3) d 7.53–7.25 (m, 2H,
arom), 7.23–7.18 (m, 3H, arom), 3.32–3.17 (m, 2H, 1 of
H-10 and 1H of CH2–Ph), 2.36 (dd, 1H, J1¼5.4 Hz,
J2¼6.6 Hz, CH2–Ph), 1.66 (s, 3H, Me), 1.52 (s, 3H, Me),
1.42–1.31 (b, 2H, NH2), 1.04 (s, 9H, 3Me); 13C NMR
(CDCl3) d 175.8, 139.0, 129.4, 128.9, 126.8, 115.3, 83.4,
58.5, 39.2, 37.6, 25.2, 22.9, 19.2. Anal. Calcd for
C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C, 70.12;
H, 8.71; N, 4.86.
4.3.11. Synthesis of (2S,5R,10S)-42. HCl-induced sulfinyl
deprotection of (SR,2S,5R,10S)-20 (126 mg, 0.30 mmol) af-
forded (2S,5R,10S)-42 (81 mg, 0.25 mmol, 85%). The crude
oil 42 was used for the next step without any further purifi-
cations. (2S,5R,10S)-42: [a]D20 ꢁ30.0 (c 0.6, CHCl3); IR
(CDCl3, cmꢁ1) 3355, 2960, 1778; HRMS m/z calcd for
C19H29NO3 [M]+: 319.2147, m/z found: 319.2140; 1H
NMR (CDCl3) d 7.27–7.20 (m, 5H, arom), 5.28 (s, 1H,
C2-H), 3.17 (dd, 1H, J1¼10.5 Hz, J2¼2.5 Hz, H-10), 3.08
(s, 2H, CH2–C6H5), 1.85–1.66 (m, 1H, Me2CH), 1.54–1.20
(m, 4H, 2H of CH2–CHMe2 and 2H of NH2), 0.99 (d, 3H,
J¼6.5 Hz, Me), 0.87 (d, 3H, J¼6.5 Hz, Me), 0.61 (s, 9H,
4.3.8. Synthesis of (2S,5S,10S)-39. An MeOH solution of
a 3.8/1.0 mixture of (SS,2S,5R,10R)-13/(SS,2S,5S,10S)-15
(0.11 g, 0.27 mmol) was reacted with 2.0 N HCl (16 equiv).
Chromatography (SiO2, n-hexane/EtOAc, 2/1) of the crude
t
3Me, BuC2); 13C NMR (CDCl3) d 174.7, 135.3, 131.1,

A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
7963
128.4, 127.1, 109.3, 87.2, 52.7, 40.2, 37.5, 34.4, 25.1, 24.3,
23.4, 21.2.
1H NMR (CDCl3) d 7.26–7.18 (m, 5H, arom), 5.25 (s, 1H,
C2–H), 3.29 (d, 1H, J¼14.4 Hz, CH2–C6H5), 3.06 (d, 1H,
J¼14.8 Hz, CH2–C6H5), 2.93 (d, 1H, J¼4.2 Hz, H-10),
2.07 (m, 1H, CHMe2), 1.05 (d, 3H, J¼6.8 Hz, Me), 1.03
4.3.12. Synthesis of (2S,5S,10S)-43. Sulfinyl deprotection
of (SS,2S,5S,10S)-21 (169 mg, 0.40 mmol) afforded (2S,5S,
10S)-43 (104 mg, 0.33 mmol, 82%). The crude 43 was
used for the next step without any further purifications.
(2S,5S,10S)-43: IR (CDCl3, cmꢁ1) 3360, 1774; HRMS m/z
calcd for C19H29NO3 [M]+: 319.2147, m/z found:
t
(d, 3H, J¼6.8 Hz, Me), 0.62 (s, 9H, 3Me, BuC2); 13C
NMR (CDCl3) d 174.7, 135.4, 131.2, 128.5, 127.1, 108.9,
87.0, 59.3, 37.6, 34.4, 29.8, 23.3, 22.4, 18.2. The (5R)-ste-
reoconfiguration of (SS)-25 was assigned by NOE experi-
ments (CDCl3). Irradiation of the tert-butyl group at the
C2-position (0.62 ppm) produced an NOE effect of 1.3%
on the aromatic protons.
1
319.2133; H NMR (CDCl3) d 7.30–7.25 (m, 5H, arom),
4.01 (s, 1H, C2–H), 3.24 (d, 1H, J¼14.0 Hz, CH2–C6H5),
3.08 (m, 1H, H-10), 3.04 (d, 1H, J¼14.0 Hz, CH2–C6H5),
1.85–1.75 (m, 1H, Me2CH), 1.82–1.75 (b, 2H, NH),
1.60–1.50 (m, 1H, CH2–CHMe2), 1.50–1.47 (m, 1H,
CH2–CHMe2), 0.98 (d, 3H, J¼6.2 Hz, Me), 0.88 (d,
NH2
O
t
3H, J¼6.2 Hz, Me), 0.81 (s, 9H, 3Me, BuC2); 13C NMR
O
O
(CDCl3) d 175.3, 135.2, 130.6, 128.8, 127.6, 109.3, 54.9,
40.4, 37.2, 34.6, 25.0, 24.4, 23.8, 21.2.
4.3.13. Synthesis of (2S,5R,10R)-44. Sulfinyl deprotection
of an MeOH solution of (SS,2S,5R,10R)-22 (150 mg,
0.325 mmol) with 2.6 mL of 2.0 N HCl (16 equiv) afforded
(2S,5R,10R)-44 as a sticky oil (0.100 mg, 0.286 mmol, 88%).
The crude 44 was used for the next step without any further
purifications. (2S,5R,10R)-44: IR (CDCl3, cmꢁ1) 3360, 1768;
HRMS m/z calcd for C22H27NO3 [M]+: 353.1991, m/z found:
(2S, 5R, 1'R)-46
4.3.16. Synthesis of (2S,5R,10S)-47. (i) Deprotection of
(SR,2S,5R,10S)-26: sulfinyl deprotection of an MeOH solu-
tion of (SR)-26 (67 mg, 0.162 mmol) with 1.4 mL of
2.0 N HCl (16 equiv) afforded (2S,5R,10S)-47 (42 mg,
0.146 mmol, 90%). (ii) Deprotection of (SS,2S,5R,10S)-26;
after the HCl-induced deprotection of 15 mg of an MeOH
solution of (SS)-26, the 1H NMR spectrum (CDCl3) of
the crude reaction mixture revealed the presence of
(2S,5R,10S)-47. IR (CDCl3, cmꢁ1) 3360, 1720; HRMS m/z
calcd for C18H27NO3 [M]+: 305.1991, m/z found:
1
353.1983; H NMR (CDCl3) d 7.40–7.20 (m, 8H, arom),
7.08 (m, 2H, arom), 5.43 (s, 1H, C2–H), 3.36–3.28
(m, 2H, 1H of 10-CH2–C6H5 and 1H of 5-CH2–C6H5),
3.22–3.14 (m, 2H, 1H of 10-CH2–C6H5 and 1H of 5-CH2–
t
C6H5), 2.68 (m, 1H, H-10), 0.82 (s, 9H, 3Me, BuC2);
13C NMR (CDCl3) d 174.4, 138.6, 135.3, 130.9, 129.3,
129.0, 128.7, 127.4, 126.9, 110.6, 86.2, 57.4, 39.0, 38.0,
34.9, 23.6.
305.1979; H NMR (CDCl3) d 7.25–7.18 (m, 5H, arom),
1
5.33 (s, 1H, C2–H), 3.11 (d, 1H, J¼14.0 Hz, CH2–C6H5),
3.07 (d, 1H, J¼14.0 Hz, CH2–C6H5), 2.96 (d, 1H,
J¼2.5 Hz, H-10), 2.22 (m, 1H, CHMe2), 0.99 (d, 3H,
J¼6.8 Hz, Me), 0.98 (d, 3H, J¼6.8 Hz, Me), 0.62 (s, 9H,
4.3.14. Synthesis of (2S,5S,10S)-45. Sulfinyl deprotection
of an MeOH solution of (SS,2S,5S,10S)-24 (95 mg,
0.207 mmol) with 1.7 mL of 2.0 N HCl (16 equiv) afforded
(2S,5S,10S)-45 (0.60 mg, 0.172 mmol, 83%). The crude oil
45 was used for the next step without any further puri-
fications. (2S,5S,10S)-45: IR (CDCl3, cmꢁ1) 3368, 1776;
HRMS m/z calcd for C22H27NO3 [M]+: 353.1991, m/z
3Me, BuC2); 13C NMR (CDCl3) d 175.9, 135.4, 131.2,
t
128.5, 127.2, 110.3, 87.9, 60.5, 40.0, 34.4, 28.0, 23.4,
22.2, 15.5.
4.3.17. Synthesis of (2S,5R,10S)-48. Deprotection of the
1.5/1.0 mixture of compounds (SR,2S,5R,10S)-27 and
(SR,2S,5R,10S)-27 (166 mg, 0.41 mmol), followed by silica
gel column chromatography purification (n-hexane/Et2O,
1/1) afforded (2S,5R,10S)-48 as a white solid (mp 99–
103 ꢃC) (114 mg, 0.37 mmol, 92%). [a]2D0 ꢁ14.5 (c 1.05,
1
found: 353.2004; H NMR (CDCl3) d 7.35–7.20 (m, 10H,
arom), 4.14 (s, 1H, C2–H), 3.37 (d, 1H, J¼8.5 Hz, 5-CH2–
C6H5), 3.32 (d, 1H, J¼8.0 Hz, 10-CH2–C6H5), 3.37 (d,
1H, J¼8.5 Hz, 5-CH2–C6H5), 3.14 (d, 1H, J¼8.0 Hz, 10-
CH2–C6H5), 2.72 (m, 1H, H-10), 0.86 (s, 9H, 3Me, tBuC2);
13C NMR (CDCl3) d 174.9, 138.9, 135.1, 130.7, 129.5,
128.9, 128.8, 127.6, 126.9, 109.5, 86.2, 58.4, 38.0, 37.4,
34.6, 23.8.
CHCl3); IR (CDCl3, cmꢁ1); MS m/z 305, 220, 105, 77; H
1
NMR (CDCl3) d 7.80–7.60 (m, 2H, arom), 7.41–7.20
(m, 3H, arom), 5.59 (s, 1H, CH-2), 3.32 (dd, 1H, J1¼2.8 Hz,
J2¼11.6 Hz, H-10), 1.78–1.58 (m, 1H, Me2CH), 1.42–1.28
(b, 2H, NH2), 1.28–1.16 (m, 2H, CH2), 0.96 (s, 9H, 3Me),
0.82 (d, 3H, J¼6.8 Hz, Me), 0.66 (d, 3H, Me); 13C NMR
(CDCl3) d 174.5, 137.0, 128.3, 128.1, 125.5, 111.3, 87.4,
58.3, 39.8, 35.7, 24.4, 24.1, 23.9, 20.8. Anal. Calcd for
4.3.15. Synthesis of (2S,5R,10R)-46. (i) Deprotection of
(Ss,2S,5R,10R)-25: sulfinyl deprotection of an MeOH solu-
tion of (SS,2S,5R,10R)-25 (150 mg, 0.366 mmol) with
3.0 mL of 2.0 N HCl (16 equiv) afforded (2S,5R,10R)-46
(0.98 mg, 0.322 mmol, 88%). The crude oil 46 was used
for the next step without any further purifications. (ii) Depro-
tection of (SR,2S,5R,10R)-25: after the HCl-induced depro-
H
NH2
O
H
1
tection of 15 mg of an MeOH solution of (SS)-25, the H
NMR spectrum (CDCl3) of the crude reaction mixture
O
O
revealed the presence of (2S,5R,10R)-46 (2S,5R,10R)-46:
IR (CDCl3, cmꢁ1
)
3375, 1742; HRMS m/z calcd
for C18H27NO3 [M]+: 305.1991, m/z found: 305.1987;
(2S, 5R, 1'S)-48

7964
A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
C18H27NO3: C, 70.79; H, 8.91; N, 4.59. Found: C, 70.85; H,
8.83; N, 4.65. The (5R)-configuration of (2S,5R,10S)-48 was
assigned by NOE experiments (CDCl3). Irradiation of the
tert-butyl group at the C2-position (0.96 ppm) produced
NOE effect (4.5%) on the aromatic protons of the phenyl
group (region between 7.27 and 7.20 ppm), while irradiation
of the hydrogen at the C2-position (5.59 ppm) caused an
NOE effect (3.0%) on the H10 protons at 3.32 ppm.
stirring to room temperature. The reaction mixture was
extracted with ethyl acetate (3ꢂ20 mL) and dried over
Na2SO4. The solvent was removed under vacuum, after
filtration of the salts. The residue was purified by silica gel
column chromatography to afford the b-lactam.
4.4.1. Synthesis of (3R,4S)-51. The reaction of compound
(2S,5R,10S)-30 (50 mg, 0.18 mmol) was performed accord-
ing to the reported standard procedure. Purification by silica
gel column chromatography of the crude reaction mixture
(EtOAc/n-pentane, 12/8) afforded the b-lactam (3R,4S)-51
as a sticky oil (26 mg, 0.14 mmol, 81%). HRMS m/z calcd
4.3.18. Synthesis of (2S,5R,10S)-49. Deprotection of the
13.0/1.0 mixture of compounds (SR,2S,5R,10S)-28 and
(SR,2S,5R,10S)-28 (0.19 g, 0.43 mmol) followed by chroma-
tography purification (SiO2, n-hexane/EtOAc, 5/1) yielded
(2S, 5R, 10S)-49 as a foaming sticky solid (0.11 g,
0.31 mmol, 72%). [a]D20 +3.7 (c 0.33, CHCl3); IR (CDCl3,
cmꢁ1) 2961, 1788, 1202; MS m/z 339, 324, 232, 120, 92.
1H NMR (CDCl3) d 7.81–7.74 (m, 2H, arom), 7.47–7.35
(m, 3H, arom), 7.27–7.18 (m, 3H, arom), 7.07–7.02 (m,
2H, arom), 5.68 (s, 1H, H-2), 3.58 (dd, 1H, J1¼2.4 Hz,
J2¼11.0 Hz, H-10), 2.64–2.52 (dd, 1H, CH2–Ph), 2.42–
2.30 (dd, 1H, CH2–Ph), 1.40–1.18 (b, 2H, NH2), 1.00 (s,
9H, 3Me); 13C NMR (CDCl3) d 174.1, 138.8, 137.0,
129.3, 128.8, 128.5, 128.3, 126.7, 125.5, 111.6, 86.7, 61.9,
37.4, 35.6, 23.9. Anal. Calcd for C21H25NO3: C, 74.31; H,
7.42; N, 4.13. Found: C, 74.27; H, 7.35; N, 4.09. The
(5R)-configuration of (2S,5R,10S)-49 was assigned by homo-
nuclear NOE experiments (CDCl3). Irradiation of the hydro-
gen at the C2-position (5.68 ppm) caused an NOE effect
(3.5%) on the H10 protons at 3.58 ppm.
1
for C8H9NO2S [M]+: 183.0354, m/z found: 183.0346; H
NMR (CDCl3) d 7.45–7.40 (m, 2H, arom), 7.02–7.10 (m,
2H, arom), 6.50–6.65 (br s, 1H, NH), 4.90 (s, 1H, H-4),
1.19 (s, 3H, Me); lit.9b relevant resonances at d 4.91, 1.19;
13C NMR (CD3COCD3) d 173.2, 138.5, 127.5, 124.8,
124.7, 62.0, 54.3, 18.2. Homonuclear NOE experiments
(CDCl3) did not show any enhancement of the C4–H
(4.90 ppm) upon irradiation of C3–Me at 1.19 ppm. There-
fore, the stereochemistry of the b-lactam is (3R,4S). This
allowed the stereochemical assessment of the parent
dioxolanones (SR,2S,5R,10S)-8 and (SS,2S,5R,10S)-8.
S
OH
3 4
NH
H
O
(3R,4S)-51
H
NH2
O
4.4.2. Synthesis of (3R,4R)-52. The reaction of compound
(2S,5R,10R)-31 (45 mg, 0.159 mmol) was performed accord-
ing to the reported standard procedure. Purification by silica
gel column chromatography of the crude reaction mixture
(SiO2, EtOAc/n-pentane, 12/8) afforded b-lactam (3R,4R)-
52 as a white solid (24 mg, 0.13 mmol, 82%). Mp 190–
192 ꢃC; HRMS m/z calcd for C8H9NO2S [M]+: 183.0354,
H
O
O
(2S, 5R, 1'S)-49
1
4.3.19. Synthesis of (2S,5R,10S)-50. An MeOH solution of
(SS,2S,5R,10S)-29 (140 mg, 0.354 mmol) was reacted with
2.8 mL of 2.0 N HCl (16 equiv). The crude reaction mixture
of the oil (2S,5R,10S)-50 (87 mg, 0.3 mmol, 84%) was
used for the next step without any further purification.
HRMS m/z calcd for C17H25NO3 [M]+: 291.1834, m/z found:
291.1846; IR (Nujol, cmꢁ1) 2958, 1784; 1H NMR (CDCl3)
d 7.70–7.60 (m, 2H, arom), 7.42–7.30 (m, 3H, arom), 5.57
(s, 1H, H-2), 3.27 (d, 1H, J¼2.0 Hz, H-10), 1.58–1.44 (m,
1H, CHMe2), 1.36–1.26 (m, 2H, NH2), 0.96 (s, 9H, 3Me,
tBuCH), 0.82 (d, 3H, Me, CHMe2, J¼6.8 Hz), 0.76 (d, 3H,
Me, CHMe2, J¼6.8 Hz); 13C NMR (CDCl3) d 175.0,
137.5, 128.4, 128.0, 125.3, 111.3, 87.9, 64.2, 35.5, 27.6,
23.9, 21.8, 15.1.
m/z found: 183.0356; H NMR (CDCl3) d 7.00–7.50 (m,
3H, arom), 6.40–6.55 (br s, 1H, NH), 4.84 (s, 1H, H-4),
2.70–2.78 (br s, 1H, OH), 1.64 (s, 3H, Me); lit.9b 7.00–
7.50, 6.45–6.60, 4.83, 3.20–3.30, 1.63; 13C NMR (CDCl3)
d 172.0, 140.0, 127.9, 126.4, 126.2, 86.2, 61.6, 21.3; lit:9b
172.0, 139.9, 127.7, 126.1, 126.0, 86.0, 61.6, 21.2. Homo-
nuclear NOE experiments (CDCl3) performed on compound
52 showed, upon irradiation of CH3 at C3 carbon atom
(1.64 ppm), an enhancement of 4.8% of the hydrogen at
the C4-position (4.84 ppm). Therefore, the stereochemistry
of the b-lactam is (3R,4R). This allowed the stereochemical
assessment of the parent dioxolanones (SR,2S,5R,10R)-9
and (SS,2S,5R,10R)-9. Moreover, the stereochemical assess-
ment of compounds (SS,2S,5R,10S)-8 (from TS-I) and
(SS,2S,5R,10R)-9 (from TS-II), obtained by reaction of
4.4. General procedure for the synthesis of b-lactams
The b-lactams were prepared according to a modified liter-
ature procedure. The aminodioxolanone was dissolved in
THF (1.0 mLꢂ0.03 g of dioxolanone) at ꢁ30 ꢃC. HMPA
(0.1 mLꢂ0.030 g of dioxolanone) was added dropwise, fol-
lowed by LHMDS (4.0 equiv, 1 M THF solution). The tem-
perature was raised to ꢁ5 ꢃC during 3 h. The reaction was
quenched with few drops of HCl (1.0 N) and warmed under
S
OH
3 4
NH
H
O
(3R,4R)-52

A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
7965
(2S)-1a with (SS)-4, allowed the assessment of configuration
of the third epimer (SS,2S,5S,10R)-10 derived from TS-III.
n-pentane, 3/13) afforded (3R,4R)-55 as a white solid
(0.045 mg, 0.23 mmol, 82%). Mp 172 ꢃC; [a]D20 +66.75
(c 0.65, CD3COCD3); IR (CDCl3, cmꢁ1) 3321, 1757, 1234;
MS m/z 191, 133, 105, 91; 1H NMR (CD3COCD3) d 7.34–
7.12 (b, 1H, NH), 7.34–7.12 (m, 5H, arom), 5.04 (s, 1H,
OH), 3.76 (dd, 1H, J1¼5.5 Hz, J2¼8.8 H-4), 3.02 (dd,
1H, J1¼5.5 Hz, J2¼14.4 Hz, CH2–Ph), 2.77 (dd, 1H,
J1¼8.8 Hz, J2¼14.4 Hz, CH2–Ph), 1.38 (s, 3H, Me); 13C
NMR (CD3COCD3) d 171.4, 138.9, 129.0, 128.7, 126.4,
84.5, 63.5, 37.2, 17.1. Anal. Calcd for C11H13NO2: C,
69.09; H, 6.85; N, 7.32. Found: C, 69.14; H, 6.81; N, 7.38.
Homonuclear NOE experiments (CD3COCD3). Irradiation
of C3–Me at 1.38 ppm produced an enhancement of 2.8
and 4.5% on CHs of CH2–Ph centered at 3.02 and
2.77 ppm, respectively. Accordingly, irradiation of OH at
5.04 ppm induced a 2.3% NOE effect on the CH-4 at
3.76 ppm. Moreover, irradiation of one of the two CH pro-
tons of the benzylic group centered at 2.77 ppm produced
a 1.5% enhancement on the C3–Me, while no NOE effect
was observed on the OH group. Therefore, the stereo-
chemistry of the b-lactam is (3R,4R). This allowed the
stereochemical assessment of the parent dioxolanones
(SR,2S,5R,10R)-13 and (SS,2S,5R,10R)-13. Consequently,
the stereochemistry of compounds (SR,2S,5R,10S)-14 and
(SS,2S,5S,10S)-15 was also ascertained. In fact, both di-
oxolanones (SR,2S,5R,10R)-13 and (SR,2S,5R,10S)-14 were
formed by reaction of (2S)-1a with aldimine (SR)-6. These
compounds only differed in their stereochemistry at the 10-
position since NOE experiments showed an identical (R)-
stereoconfiguration at the 5-position. Instead, compounds
(SS,2S,5R,10R)-13 and (SS,2S,5S,10S)-15 were formed by
reaction of (2S)-1a with aldimine (SS)-6. Since a (5S)-stereo-
configuration was assigned by NOE experiments to (SS)-15,
this compound is derived from TS-III. For this reason, a
(S)-stereochemistry is found at the 10-position.
4.4.3. Synthesis of (3R,4R)-53. LHMDS-induced cycliza-
tion of (2S,5R,10R)-35 (60 mg, 0.23 mmol) afforded, after
silica gel column chromatography purification (EtOAc/
n-hexane, 12/8), compound (3R,4R)-53 as a pale yellow solid
(30 mg, 0.19 mmol, 82%). Mp 136 ꢃC; [a]D20 +123.0 (c
0.44, CHCl3); IR (CDCl3, cmꢁ1) 3339, 1748; MS m/z 157,
1
149, 86, 71; H NMR (CD3COCD3) d 7.25–7.15 (b, 1H,
NH), 4.91 (s, 1H, OH), 3.54 (dd, 1H, J1¼8.0 Hz,
J2¼4.0 Hz, H-4), 1.74–1.65 (m, 1H, Me2CH), 1.49 (m, 1H,
J1¼4.8 Hz, J2¼7.6 Hz, J3¼14.8 Hz, CH2), 1.38 (m, 1H,
CH2), 1.27 (s, 3H, Me), 0.95 (d, 3H, J¼6.0 Hz, Me), 0.93
(d, 3H, Me); 13C NMR (CDCl3) d 172.6, 84.7, 61.7, 39.6,
26.4, 23.3, 22.5, 17.7. Anal. Calcd for C8H15NO2: C,
61.12; H, 9.62; N, 8.91. Found: C, 61.24; H, 9.55; N, 8.87.
Homonuclear NOE experiments (CD3COCD3). Irradiation
of OH at 4.91 ppm produced a 6.0% NOE effect on the
CH-4 at 3.54 ppm. Therefore, the stereochemistry of the
b-lactam is (3R,4R). This allowed the stereochemical assess-
ment of the parent dioxolanones (SR,2S,5R,10R)-11 and
(SR,2S,5R,10R)-11.
HO
H
3 4
N
O
H
(3R, 4R)-53
4.4.4. Synthesis of (3R,4S)-54. Cyclization of (2S,5R,10S)-
36 (82 mg, 0.32 mmol) afforded, after purification by silica
gel column chromatography of the crude reaction mixture
(EtOAc/cyclohexane, 3/1), the b-lactam (3R,4S)-54 as a
white solid (39 mg, 0.25 mmol, 78%). Mp 135 ꢃC; [a]D20
+19.5 (c 0.5, CHCl3); IR (CDCl3, cmꢁ1) 3340, 1752;
HRMS m/z calcd for C8H15NO2 [M]+: 157.1103, m/z found:
157.1107; 1H NMR (CD3COCD3) d 7.25–7.10 (b, 1H, NH),
4.80 (s, 1H, OH), 3.48 (dd, 1H, J1¼8.0 Hz, J2¼6.0, H-4),
1.76–1.64 (m, 1H, Me2CH), 1.60–1.40 (m, 2H, CH2), 1.42
(s, 3H, Me), 0.94 (d, 3H, J¼6.0 Hz, Me), 0.92 (d, 3H,
Me); 13C NMR (CDCl3) d 173.3, 83.2, 61.3, 39.2, 25.9,
23.3, 22.7, 22.3. Anal. Calcd for C8H15NO2: C, 61.12; H,
9.62; N, 8.91. Found: C, 60.95; H, 9.53; N, 9.00. Homonu-
clear NOE experiments (CD3COCD3). Irradiation of Me at
the C3-position (1.42 ppm) produced a 6% NOE effect on
the hydrogen at C4-position (3.48 ppm). Accordingly, no
NOE effect was detected on the hydrogen at C4-position
upon irradiation of OH at 4.80 ppm, thus confirming the
(3R,4S) b-lactam stereochemistry. This allowed the stereo-
chemical assessment of the parent dioxolanones (SR,2S,
5R,10S)-12 and (SR,2S,5R,10S)-12.
H
H
HO
H
N
O
H
(3R, 4R)-55
4.4.6. Synthesis of (3R,4R)-56. LHMDS-induced cycliza-
tion of (2S,5R,10R)-40 (102 mg, 0.42 mmol) followed by
silica gel chromatography of the residue (n-hexane/EtOAc,
1/1) afforded the b-lactam (3R,4R)-40 as a white solid
(52 mg, 0.37 mmol, 87%). [a]2D0 +23.8 (c 0.5, CH3COCH3);
mp 179–181 ꢃC; IR (Nujol, cmꢁ1) 3400–3250, 1755; HRMS
m/z calcd for C7H13NO2 [M]+: 143.0946, m/z found:
143.0958; 1H NMR (CD3COCD3) d 7.45–7.38 (b, 1H,
NH), 4.99 (s, 1H, OH), 3.08 (d, 1H, J¼10.4 Hz, H-4),
1.72–1.64 (m, 1H, CHMe2), 1.35 (s, 1H, Me), 0.95 (d, 3H,
J¼6.0 Hz, 1Me of CHMe2), 0.93 (d, 3H, J¼6.0 Hz, 1Me
of CHMe2); 13C NMR (CD3COCD3) d 172.0, 83.9, 69.3,
29.8, 19.7, 18.9, 17.2. Anal. Calcd for C7H13NO2: C,
58.72; H, 9.15; N, 9.78. Found: C, 58.64; H, 9.22; N, 9.90.
Homonuclear NOE experiments (CD3COCD3). Irradiation
of OH at 4.99 ppm produced a 6.5% NOE effect on the
CH-4 at 3.08 ppm. Accordingly, the irradiation of C3–Me
at 1.35 ppm induced a 2.5% enhancement of the CH
of CHMe2 centered at 1.68 ppm. Therefore, the stereochem-
istry of the b-lactam is (3R,4R). This allowed the
HO
H
3 4
N
O
H
(3R, 4S)-54
4.4.5. Synthesis of (3R,4R)-55. LHMDS-induced cycliza-
tion of (2S,5R,10R)-37 (0.082 g, 0.28 mmol) followed by
chromatography purification of the residue (SiO2, EtOAc/

7966
A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
stereochemical assessment of the parent dioxolanone
(SR,2S,5R,10R)-16. Consequently, the absolute configuration
of (SR,2S,5R,10S)-17 was also assessed since these epimers
only differed in the stereochemistry at the 10-position being
both formed by reaction of (2S)-1a with aldimine (SR)-7 via
TS-I and TS-II, respectively.
as a white solid (73 mg, 0.274 mmol, 88%). [a]2D0 +7ꢁ3.15
(c 0.4, CD3COCD3); mp 139–140 ꢃC; IR (CDCl3, cm
)
3336, 1755; HRMS m/z calcd for C17H17NO2 [M]+:
267.1259, m/z found: 267.1245; 1H NMR (CD3COCD3)
d 7.49 (m, 2H, arom), 7.35–7.25 (b, 1H, NH), 7.30–7.15
(m, 8H, arom), 5.03 (s, 1H, OH), 3.84 (dd, 1H, J1¼4.5 Hz,
J2¼10.5 Hz, H-4), 3.26 (d, 1H, J¼14.8 Hz, 3-CH2–C6H5),
3.10 (d, 1H, J¼14.8 Hz, 3-CH2–C6H5), 3.06 (dd, 1H,
J1¼4.5 Hz, J2¼14.0 Hz, 4-CH2–C6H5), 2.84 (dd, 1H,
J1¼10.5 Hz, J2¼14.0 Hz, 4-CH2–C6H5); 13C NMR
(CDCl3) d 170.5, 138.9, 136.9, 130.9, 129.0, 128.8, 127.9,
126.5, 126.3, 86.5, 64.2, 37.7, 37.6. Anal. Calcd for
C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.24;
H, 6.35; N, 5.27. Homonuclear NOE experiments
(CD3COCD3). Irradiation of OH at 5.03 ppm produced
a 5.0% NOE effect on the hydrogen at C4-position
(3.84 ppm). Therefore, the stereochemistry of the b-lactam
is (3R,4R). This allowed the stereochemical assessment of
the parent 10-sulfinylamino-dioxolanone (SR,2S,5R,10R)-22.
H
Me
Me
H
HO
3 4
N
O
H
(3R, 4R)-56
4.4.7. Synthesis of (3R,4R)-57. Cyclization of (2S,5R,10R)-
41 (85 mg, 0.27 mmol) afforded, after purification by silica
gel column chromatography of the crude reaction mixture
(EtOAc/n-pentane, 12/8), the b-lactam (3R,4R)-57 as
a sticky oil (53 mg, 0.23 mmol, 85%). [a]2D0 +71 (c 0.5,
CD3COCD3); IR (CDCl3, cmꢁ1) 3336, 1747; HRMS m/z
calcd for C14H19NO2 [M]+: 233.1416, m/z found:
1
HO H
(R)
233.1414; H NMR (CD3COCD3) d 7.46–7.30 (m, 3H, 2H
(R)
arom and NH), 7.28–7.15 (m, 3H, arom), 4.91 (s, 1H,
OH), 3.64 (dd, 1H, J1¼4.8 Hz, J2¼9.2 Hz, H-4), 3.11 (d,
1H, J¼14.8 Hz, CH2–C6H5), 2.99 (d, 1H, J¼14.8 Hz,
CH2–C6H5), 1.72–1.60 (m, 1H, Me2CH), 1.55–1.45 (m,
2H, CH2–CH), 0.95 (d, 3H, J¼6.5 Hz, Me), 0.92 (d, 3H,
J¼6.5 Hz, Me); 13C NMR (CDCl3) d 171.0, 137.0, 130.8,
127.8, 126.2, 86.6, 61.5, 40.1, 37.8, 26.0, 23.1, 21.5. Anal.
Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found:
C, 72.24; H, 8.15; N, 6.07. Homonuclear NOE experiments
(CD3COCD3). Irradiation of OH at 4.91 ppm produced
a 3.6% NOE effect on the hydrogen at C4-position
(3.64 ppm). Accordingly, no NOE effect was observed on
the C4–H hydrogen at 3.64 ppm upon irradiation of CH of
CH2–C6H5 (3.11 ppm and 2.99 ppm). Therefore, the stereo-
chemistry of the b-lactam is (3R,4R). This allowed the stereo-
chemical assessment of the parent 10-aminodioxolanones
(SR,2S,5R,10R)-19 and (SS,2S,5R,10R)-19. Consequently, the
stereochemistry of compound (SR,2S,5R,10S)-20 was also
assessed. In fact, NOE experiments showed a (5R)-stereo-
chemistry for both (SR,2S,5R,10R)-19 and (SR,2S,5R,10S)-
20, derived from the same reaction. Hence, the two epimers
differ in the stereochemistry at the 10-position.
N
O
H
(3R, 4R)-59
4.4.10. Synthesis of (3S,4S)-60. Cyclization of (2S,5S,10S)-
45 (80 mg, 0.226 mmol) afforded, after purification by silica
gel column chromatography of the crude reaction mixture
(EtOAc/n-pentane, 12/8), the b-lactam (3S,4S)-60 as a white
solid (48 mg, 0.180 mmol, 81%). Mp 148–160 ꢃC; [a]D20
ꢁ74.1 (c 0.4, CD3COCD3); Spectral data were identical to
those reported for compound (3R,4R)-60. This allowed the
stereochemical assessment of the parent 10-sulfinylamino-
dioxolanone (SS,2S,5S,10S)-24.
HO
H
N
O
H
(3S, 4S)-60
4.4.11. Synthesis of (3R,4R)-61. LHMDS-induced cycliza-
tion of (2S,5R,10R)-46 (110 mg, 0.360 mmol), followed by
silica gel chromatography of the residue (n-hexane/EtOAc,
1:/1), the b-lactam (3R,4R)-61 as a sticky oil (68 mg,
0.310 mmol, 87%). [a]2D0 +28 (c 0.5, CH3COCH3); IR (Nu-
jol, cmꢁ1) 1747; HRMS m/z calcd for C13H17NO2 [M]+:
219.1259, m/z found: 219.1258; 1H NMR (CD3COCD3)
d 7.44–7.40 (m, 3H, 2H arom and NH), 7.44–7.40 (m, 3H,
arom), 4.93 (s, 1H, OH), 3.17 (d, 1H, J¼10.4 Hz, H-4),
3.16 (d, 1H, J¼14.4 Hz, CH2–C6H5), 3.08 (d, 1H,
J¼14.4 Hz, CH2–C6H5), 1.84–1.78 (m, 1H, CHMe2), 0.94
(d, 6H, J¼6.4 Hz, 2Me of CHMe2); 13C NMR (CD3COCD3)
d 171.0, 136.9, 130.9, 127.7, 126.3, 86.1, 69.8, 38.4, 19.8,
19.2. Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N,
6.39. Found: C, 71.34; H, 7.92; N, 6.24. Homonuclear
NOE experiments (CD3COCD3). Irradiation of OH at
4.93 ppm produced a 6.5% NOE effect on the CH-4 at
3.17 ppm. Therefore, the stereochemistry of the b-lactam
is (3R,4R). This allowed the stereochemical assessment of
HO
H
N
H
H
O
H
(3R, 4R)-57
4.4.8. Synthesis of (3S,4S)-58. LHMDS-induced cycliza-
tion of (2S,5S,10S)-43 (105 mg, 0.34 mmol) afforded
b-lactam (3S,4S)-58 (62 mg, 0.27 mmol, 78%). Spectral
data were identical to those reported for compound
(3S,4S)-58. [a]2D0 ꢁ69 (c 0.5, CD3COCD3). This allowed
the stereochemical assessment of the parent 10-sulfinyl-
amino-dioxolanone (SR,2S,5S,10S)-21.
4.4.9. Synthesis of (3R,4R)-59. Cyclization of (2S,5R,10R)-
44 (110 mg, 0.311 mmol) afforded, after purification by
silica gel column chromatography of the crude reaction
mixture (EtOAc/n-pentane, 12/8), the b-lactam (3R,4R)-59

A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
7967
the parent 10-sulfinylamino-dioxolanones (SS,2S,5R,10R)-25
and (SR,2S,5R,10R)-25. Consequently, the stereochemistry
of (SR,2S,5R,10S)-26 and (SS,2S,5R,10S)-26 were also as-
sessed. In fact, both dioxolanones (SR,2S,5R,10R)-25 and
(SR,2S,5R,10S)-26 were formed by reaction of (2S)-1a with
aldimine (SR)-7. These compounds only differed in their
stereochemistry at the 10-position since NOE experiments
showed an identical (R)-stereoconfiguration at the 5-position.
Similarly, dioxolanones (SS,2S,5R,10R)-25 and (SS,2S,5R,10S)-
26 were formed by reaction of (2S)-1a with aldimine (SS)-7.
These compounds only differed in their stereochemistry at
the 10-position since NOE experiments showed an identical
(S)-stereoconfiguration at the 5-position.
127.9, 126.4, 125.8, 64.6, 64.4, 37.1. Anal. Calcd for
C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C, 75.91;
H, 5.92; N, 5.58. Homonuclear NOE experiments
(CD3COCD3). Irradiation of the OH group at 5.79 ppm pro-
duced 5 and 6% NOE effects on the two CH benzylic protons
at 3.25 and 2.95 ppm, respectively. Irradiation of the H-4
proton at 3.91 ppm caused a 2.0% enhancement on the or-
tho–ortho0 protons of the C3-phenyl group (7.49 ppm).
Therefore, the stereochemistry of the b-lactam is (3R,4S).
This allowed the stereochemical assessment of the parent
10-sulfinylamino-dioxolanones
(SR,2S,5R,10S)-28
and
(SS,2S,5R,10S)-28.
H
HO H
HO
H
N
N
O
H
H
O
H
(3R, 4S)-63
(3R, 4R)-61
4.4.14. Synthesis of (3R,4S)-64. LHMDS-induced cycliza-
tion of (2S,5R,10S)-50 (121 g, 0.41 mmol) followed by silica
gel chromatography of the residue (SiO2, n-hexane/EtOAc,
1/1), afforded b-lactam (3R,4S)-64 as a white solid
(75 mg, 0.36 mmol, 88%). [a]2D0 +57.2 (c 0.4, CH3COCH3);
mp 206–208 ꢃC; IR (Nujol, cmꢁ1) 3400–3250, 2956, 1746;
HRMS m/z calcd for C12H15NO2 [M]+: 205.1103, m/z found:
205.1094; 1H NMR (CD3COCD3) d 7.84–7.75 (b, 1H, NH),
7.58–7.50 (m, 2H, arom), 7.32–7.25 (m, 1H, arom), 5.56 (s,
1H, OH), 3.23 (d, 1H, J¼10.0 Hz, NH–CH), 2.10–2.00 (m,
4.4.12. Synthesis of b-lactam (3R,4S)-62. LHMDS-in-
duced cyclization of (2S,5R,10S)-48 (114 mg, 0.37 mmol)
afforded b-lactam (3R,4S)-62 as a white solid (74 mg,
0.34 mmol, 90%). [a]2D0 ꢁ2.9 (c 0.4, CD3COCD3); IR
(CDCl3, cmꢁ1) 3350–3290, 1743; mp 218–220; m/z 219,
1
176, 133, 55; H NMR (CD3COCD3) d 7.76–7.58 (b, 1H,
NH), d 7.48 (m, 2H, arom), 7.39–7.20 (m, 3H, arom), 4.53
(s, 1H, OH), 3.73 (dd, 1H, J1¼11.6 Hz, J2¼15.2 Hz, H-4),
1.74–1.65 (m, 1H, CH2), 2.05 (m, 2H, CH2), 1.84–1.58
(m, 1H, Me2CH), 0.95 (d, 3H, J¼6.8 Hz, Me), 0.91 (d,
3H, Me); 13C NMR (CDCl3) d 169.9, 141.2, 128.5, 127.8,
125.6, 61.8, 39.6, 25.4, 22.8, 22.2. Anal. Calcd for
C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.24;
H, 7.86; N, 6.44. Homonuclear NOE experiments
(CD3COCD3). Irradiation of the two ortho protons of the
phenyl group at 7.48 ppm produced a 4% NOE effect on
the hydrogen at C4-position (3.73 ppm). Accordingly, no
NOE effect was observed on C4–H upon irradiation of OH
at 4.53 ppm. Therefore, the stereochemistry of the b-lactam
is (3R,4S). This allowed the stereochemical assessment of
the parent 10-sulfinylamino-dioxolanones (SR,2S,5R,10S)-27
and (SS,2S,5R,10S)-27.
1H, CHMe2), 1.00 (d, 6H, J¼6.4 Hz, 2Me of CHMe2); 13
C
NMR (CD3COCD3) d 170.0, 141.4, 128.5, 127.7, 125.7,
87.2, 69.6, 29.5, 19.0, 18.6. Anal. Calcd for C12H15NO2:
C, 70.22; H, 7.37; N, 6.82. Found: C, 70.04; H, 7.42; N,
6.90. Homonuclear NOE experiments (CD3COCD3). Irradi-
ation of H-4 at 3.23 ppm produced a 2.5% NOE on the reso-
nances of the two ortho aromatic protons at 7.54 ppm.
Therefore, the stereochemistry of the b-lactam is (3R,4S).
This allowed the stereochemical assessment of the parent
10-sulfinylamino-dioxolanone (SS,2S,5R,10S)-29.
H
HO H
H
H
N
OH
H
N
O
H
H
(3R, 4S)-64
O
H
H
(3R,4S)-62
4.5. General procedure for the synthesis of methyl
b-sulfinylaminopropionates
4.4.13. Synthesis of b-lactam (3R,4S)-63. LHMDS-in-
duced cyclization of (2S,5R,10S)-49 (0.065 g, 0.19 mmol)
followed by chromatography purification of the residue
(SiO2, n-hexane/EtOAc, 1/1) afforded b-lactam (3R,4S)-63
as a pale yellow solid (0.034 mg, 0.14 mmol, 71%). [a]D20
+14.6 (c 0.5, CD3COCD3); IR (CDCl3, cmꢁ1) 3320–3280,
To a solution of 10-sulfinylamino-dioxolanone in dry metha-
nol (3.0 mLꢂ0.1 g) were added 1.5 equiv of an MeOH
solution of MeOꢁ (1.5 M). The solution was stirred under
nitrogen at 65 ꢃC until disappearance of the starting material,
which was monitored by TLC analysis. After cooling, the re-
action mixture was quenched with 0.1 M HCl and extracted
with ethyl acetate (3ꢂ15 mL). The combined organic phases
were dried over Na2SO4 and after filtration the solvent was
removed under vacuum. The residue was purified by silica
gel flash column chromatography (SiO2, EtOAc/n-hexane,
1/2) to afford the corresponding amino esters.
1
1745, 1452; mp 181 ꢃC; m/z 253, 210, 192, 105, 77; H
NMR (CD3COCD3) d 7.66 (s, 1H, NH), 7.52–7.46 (m, 2H,
arom), d 7.38–7.19 (m, 8H, arom), 5.79 (s, 1H, OH), 3.91
(dd, 1H, J1¼6.4 Hz, J2¼7.0 Hz, H-4), 3.25 (dd, 1H,
J2¼14.4 Hz, CH2–Ph), 2.95 (dd, 1H, CH2–Ph); 13C NMR
(CDCl3) d 170.9, 140.8, 138.75, 129.5, 128.6, 128.5,

7968
A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
4.5.1. Synthesis of methyl 3-tert-butylsulfinyl-amino-2-
hydroxy-2-methyl-4-phenylbutanoate ((SR,2R,3R)-65).
The MeOꢁ-induced methanolysis of (SR,2S,5R,10R)-13
(100 mg, 0.25 mmol) provided (SR,2R,3R)-65 as a white
solid (62 mg, 0.189 mmol, 75%). [a]2D0 +39.8 (c 0.5,
CHCl3); mp 198–200 ꢃC; IR (CDCl3, cmꢁ1) 3400, 1771,
1381, 1045; HRMS m/z calcd for C16H25NO4S [M]+:
23.4, 22.2, 15.9. Anal. Calcd for C17H27NO4S: C, 59.80;
H, 7.97; N, 4.10. Found: C, 59.64; H, 7.88; N, 4.02.
References and notes
1. (a) Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359–
1472; (b) Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med.
Chem. 2000, 43, 305–341; (c) Datta, A.; Veeresa, G. J. Org.
Chem. 2000, 65, 7609–7611; (d) Dash, C.; Aarohi Kulkarni,
A.; Dunn, B.; Rao, M. Crit. Rev. Biochem. Mol. Biol. 2003,
38, 89–119; (e) Cooper, J. B. Curr. Drug Targets 2002, 3,
155–173.
1
327.1504, m/z found: 327.1501; H NMR (CDCl3) d 7.30–
7.10 (m, 5H, arom), 4.80–4.20 (b, 1H, OH), 4.06 (d, 1H,
J¼9.5 Hz, NH), 3.78 (s, 3H, OMe), 3.63 (m, 1H, H-3),
2.87 (dd, 1H, J1¼3.5 Hz, J2¼14.0 Hz, CH2Ph), 2.62 (dd,
1H, J1¼3.5 Hz, J2¼14.0 Hz, CH2Ph), 1.61 (s, 3H, Me),
t
0.93 (s, 9H, 3Me, BuS(O)); 13C NMR (CDCl3) d 175.8,
138.3, 129.6, 128.6, 126.7, 76.4, 67.0, 56.4, 53.0, 39.0,
24.3, 22.6. Anal. Calcd for C16H25NO4S: C, 58.69; H,
7.70; N, 4.28. Found: C, 58.64; H, 7.54; N, 4.22.
2. BaMaung, N. Y.; Niles, I. L.; Craig, R. A.; Henkin, J.; Kawai,
M.; Searle, X. B.; Sheppard, G. S.; Wang, J. Int. Pub. N. WO
2004/013085 A1, 12.02.2004.
3. Fisher, N. D. L.; Hollenberg, N. K. J. Am. Soc. Nephrol. 2005,
16, 592–599.
4.5.2. Synthesis of (SS,2R,3R)-66. The MeOꢁ-induced
methanolysis of (SS,2S,5R,10R)-16 (90 mg, 0.26 mmol) pro-
vided (SS,2R,3R)-66 as a white solid (65 mg, 0.23 mmol,
90%). [a]2D0 +23.4 (c 0.3, CHCl3); mp 127–129 ꢃC; IR
(CDCl3, cmꢁ1) 3400, 1774, 1375, 1044; HRMS m/z calcd
4. (a) Craig, L.; Senese, C. L.; Hopfinger, A. J. J. Chem. Inf.
Comput. Sci. 2003, 43, 1297–1307; (b) Murcko, M. A.; Rao,
B. G.; Gomperts, R. J. Comput. Chem. 1997, 18, 1151–1166;
(c) Vega, S.; Kang, L.-W.; Velazquez-Campoy, A.; Kiso, Y.;
Amzel, L. M.; Freire, E. Proteins: Struct., Funct., Bioinform.
1
for C12H25NO4S [M]+: 279.1504, m/z found: 279.1521; H
ꢁ
NMR (CDCl3) d 7.68–7.60 (m, 2H, arom), 7.42–7.25 (m,
3H, arom), 3.10 (s, 1H, NH), 3.78 (s, 3H, OMe), 3.64 (d,
1H, J¼9.5 Hz, NH), 3.26 (d, 1H, J¼9.5 Hz, H-4), 3.58–
3.50 (b, 1H, OH), 1.76–1.68 (m, 1H, CHMe2), 1.39 (s, 3H,
Me), 1.27 (s, 9H, 3Me, tBuSO), 1.07 (d, 3H, J¼6.8 Hz, Me
of CHMe2), 0.93 (d, 3H, J¼6.8 Hz, Me of CHMe2); 13C
NMR (CDCl3) d 176.8, 78.8, 67.5, 57.2, 53.2, 30.3, 25.2,
23.3, 22.1, 17.8. Anal. Calcd for C12H25NO4S: C, 51.59;
H, 9.02; N, 5.01. Found: C, 51.64; H, 9.10; N, 5.02.
2004, 55, 594–602; (d) Tam, T. F.; Carriere, J.; MacDonald,
I. D.; Castelhano, A. L.; Pliura, D. H.; Dewdney, N. J.;
Thomas, E. M.; Bach, C.; Barnett, J.; Chan, H.; Krantz, A.
J. Med. Chem. 1992, 35, 1319–1320.
5. Kiso, A.; Hidaka, K.; Kimura, T.; Hayashi, Y.; Nezami, A.;
Freire, E.; Kiso, Y. J. Pept. Sci. 2004, 10, 641–647 and refer-
ences therein.
6. Hoover, D. J.; Lefker, B. A.; Rosati, R. L.; Wester, R. T.;
Kleinman, E. F.; Bindra, J. S.; Holt, W. F.; Murphy, W. R.;
Mangiapane, M. L.; Hockel, G. M.; Williams, I. H.; Smith,
W. H.; Gumkowski, M. J.; Shepard, R. M.; Gardner, M. J.;
Nocerini, M. R. Adv. Exp. Med. Biol. 1995, 362, 167–180.
7. Badasso, M. O.; Dhanaraj, V.; Wood, S. P.; Cooper, J. B.;
Blundell, T. L. Acta Crystallogr. 2004, D60, 770–772.
8. See, for example: (a) Gueritte-Voegelein, F.; Guenard, D.;
Lavelle, F.; Le Goff, M. T.; Mangatal, L.; Potier, P. J. Med.
Chem. 1991, 34, 992–998; (b) Ojima, I.; Lin, S.; Wang, T.
Curr. Med. Chem. 1999, 6, 927–954; (c) Fang, W.-S.; Liang,
X.-T. Mini Rev. Med. Chem. 2005, 5, 1–12.
9. (a) Battaglia, A.; Guerrini, A.; Bertucci, C. J. Org. Chem. 2004,
69, 9055–9062 and references therein; (b) Barbaro, G.;
Battaglia, A.; Guerrini, A.; Bertucci, C. J. Org. Chem. 1999,
64, 4643–4651; (c) Battaglia, A.; Barbaro, G.; Giorgianni, P.;
Guerrini, A.; Bertucci, C.; Geremia, S. Chem.—Eur. J. 2000,
6, 3551–3557.
10. For selected examples of biologically active constrained nor-
statines, which bear an aromatic substituent at the C3 carbon
atom and a methyl at the C2, see: (a) 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; (b) Ojima, I.; Wang, T.; Delaloge, F. Tetrahedron Lett.
1998, 39, 3663–3666; (c) Battaglia, A.; Ralph, J.; Bernacki,
R. J.; Bertucci, C.; Bombardelli, E.; Cimitan, S.; Ferlini, C.;
Fontana, G.; Guerrini, A.; Riva, A. J. Med. Chem. 2003, 46,
4822–4825.
11. (a) Ashwood, A. V.; Field, M. J.; Horwell, D. C.; Julien-Larose,
C.; Lewthwaite, R. A.; McCleary, S.; Pritchard, M. C.; Raphy,
J.; Singh, L. J. Med. Chem. 2001, 44, 2276–2285; (b) Ekegren,
J. K.; Unge, T.; Safa, M. Z.; Wallberg, H.; Samuelsson, B.;
Hallberg, A. J. Med. Chem. 2005, 48, 8098–8102;
4.5.3. Synthesis of (SS,2S,3S)-67. The MeOꢁ-induced
methanolysis of (SS,2S,5S,10S)-21 (174 mg, 0.41 mmol) pro-
vided (SS,2S,3S)-67 as a sticky oil (0.13 g, 0.34 mmol, 83%).
[a]D20 +18.2 (c 0.6 CHCl3); IR (CDCl3, cmꢁ1) 3400, 2925,
1765, 1359, 1057; HRMS m/z calcd for C19H31NO4S [M]+:
1
369.1974, m/z found: 369.1985; H NMR (CDCl3) d 7.25–
7.15 (m, 5H, arom), 3.99 (d, 1H, J¼9.2 Hz, NH), 3.74 (s,
1H, OH), 3.72 (s, 3H, Me), 3.48 (m, 1H, H-3), 3.37 (d,
1H, J¼14.0 Hz, CH2–C6H5), 3.10 (d, 1H, J¼14.0 Hz,
CH2–C6H5), 3.12 (d, 1H, J¼14.0 Hz, CH2–C6H5), 1.80–
1.66 (m, 1H, Me2CH), 1.51 (m, 1H, CH2–CHMe2), 1.27
t
(s, 9H, BuS(O)), 0.95 (m, 1H, CH2–CHMe2), 0.89 (d, 3H,
J¼6.8 Hz, Me), 0.79 (d, 3H, J¼6.4 Hz, Me); 13C NMR
(CDCl3) d 174.9, 136.0, 130.5, 128.3, 127.0, 80.6, 61.7,
57.0, 52.7, 41.5, 43.0, 42.1, 25.2, 24.4, 24.1, 23.2, 20.9.
Anal. Calcd for C19H31NO4S: C, 61.76; H, 8.46; N, 3.79.
Found: C, 61.71; H, 8.39; N, 3.82.
4.5.4. Synthesis of (SS,2R,3S)-68. The MeOꢁ-induced
methanolysis of (SS,2S,5R,10S)-29 (110 mg, 0.28 mmol) pro-
vided (SS,2R,3S)-68 as a white solid (82 mg, 0.24 mmol,
87%). [a]2D0 +87.8 (c 0.5, CHCl3); mp 159–161 ꢃC; IR
(CDCl3, cmꢁ1) 3400, 1781, 1355, 1060; HRMS m/z calcd
1
for C17H27NO4S [M]+: 341.1661, m/z found: 341.1647; H
NMR (CDCl3) d 7.68–7.60 (m, 2H, arom), 7.42–7.25 (m,
3H, arom), 4.22–4.18 (b, 1H, OH), 4.10 (s, 1H, NH), 3.87
(s, 3H, Me), 1.60–1.48 (m, 1H, CHMe2), 1.27 (s, 9H, 3Me,
tBuSO), 0.82 (d, 3H, Me, CHMe2, J¼7.2 Hz), 0.73 (d, 3H,
Me, CHMe2, J¼13.5 Hz); 13C NMR (CDCl3) d 174.7,
139.8, 128.6, 128.1, 125.6, 82.7, 65.9, 57.4, 54.5, 29.0,

A. Guerrini et al. / Tetrahedron 63 (2007) 7949–7969
7969
(c) Ekegren, J. K.; Ginman, N.; Johansson, A.; Wallberg, H.;
Larhed, M.; Samuelsson, B.; Unge, T.; Hallberg, A. J. Med.
Chem. 2006, 49, 1828–1832.
J. Antibiot. 1978, 31, 636–638; (c) Hanson, H.; Frohne, M.
Methods Enzymol. 1976, 45, 504–521.
26. Orning, L.; Krivis, G.; Fitzpatrick, F. A. J. Biol. Chem. 1991,
266, 1375–1378.
12. For the synthesis of BOC aldimines, see for example: (a)
Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org. Chem.
1994, 59, 1238–1240; (b) Wenzel, A. G.; Jacobsen, E. N.
J. Am. Chem. Soc. 2002, 124, 12964–12965.
13. Guerrini, A.; Varchi, G.; Battaglia, A. J. Org. Chem. 2006, 71,
6785–6795.
€
27. Stockel-Maschek, A.; Stiebitz, B.; Koelsch, R.; Neubert, K.
Bioorg. Med. Chem. 2005, 13, 4806–4820.
28. Bauvois, B.; Dauzonne, D. Med. Res. Rev. 2006, 26, 88–130.
29. Matsuoka, Y.; Satoh, S.; Uruno, T.; Kubota, K. Jpn. J.
Pharmacol. 1988, 46, 205–210.
14. Wang, Y.; He, Q.-F.; Wang, H.-W.; Zhou, X.; Huang, Z.-Y.;
Qin, Y. J. Org. Chem. 2006, 71, 1588–1591.
15. (a) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40,
1313–1324; (b) Ortholand, J. Y.; Greiner, A. Bull. Soc. Chim.
Fr. 1993, 130, 133–142.
16. An inversion for the descriptor of the 10-position of 10-amino-
dioxolanones which bear the heteroaromatic 2-thienyl substit-
uent occurs, with respect to other dioxolanones, due to the
priority rule at this stereocenter.
17. (a) Georg, G. I.; Harriman, G. C. B.; Vander Velde, D. G.;
Boge, T. C.; Cheruvallath, Z. S.; Datta, A.; Hepperle, M.;
Park, H.; Himes, R. H.; Jayasinghe, L. Taxane Anticancer
Agents: Basic Science and Current Status; Georg, G. I.,
Chen, T. C., Ojima, I., Vyas, D. M., Eds.; ACS Symposium
Series 583; American Chemical Society: Washington, DC,
1995; pp 217–232; (b) Holton, R. A.; Nadizadeh, H.;
Beidiger, R. J. Fury1 and Thienyl Substituted Taxanes as
Antitumor Agents. EP 0534708A1, 1993; (c) Holton, R. A.;
Chai, K.-B. Idmoumaz, H.; Nadizadeh, H.; Rengan, K.;
Suzuki, Y.; Tao, C. U.S. Patent 6,794,523, September 21, 2004.
18. (a) Rich, D. H.; Moon, B. J.; Boparai, A. S. J. Org. Chem. 1980,
45, 2288–2290; (b) Rich, D. H.; Moon, B. J.; Harbeson, S.
J. Med. Chem. 1984, 27, 417–420.
30. (a) Sohma, Y.; Hayashi, Y.; Ito, T.; Matsumoto, H.; Kimura, T.;
Kiso, Y. J. Med. Chem. 2003, 46, 4124–4135; (b) Baldwin,
E. T.; Bhat, T. N.; Gulnik, S.; Liu, B.; Topol, I. A.; Kiso, Y.;
Mimoto, T.; Mitsuya, H.; Erickson, J. W. Structure 1995, 3,
581–590; (c) Kageyama, S.; Mimoto, T.; Murakawa, Y.;
Momizu, M.; Ford, H., Jr.; Shirasaka, T.; Gulnik, S.;
Erickson, J.; Takada, K.; Hayashi, H.; Broder, S.; Kiso, Y.;
Mitsuya, H. Antimicrob. Agents Chemother. 1993, 810–817;
(d) Huang, X.; Xu, L.; Luo, X.; Fan, K.; Ji, R.; Pei, G.;
Chen, K.; Jiang, H. J. Med. Chem. 2002, 45, 333–343; (e)
See Ref. 4a.
31. (a) Nezami, A.; Luque, I.; Kimura, T.; Kiso, Y.; Freire, E.
Biochemistry 2002, 41, 2273–2280; (b) Abdel-Rahman,
H. M.; Kimura, T.; Hidaka, K.; Kiso, A.; Nezami, A.; Freire,
E.; Yoshio Hayashi, Y.; Kiso, Y. Biol. Chem. 2004, 385,
1035–1039.
32. Brynda, J.; Rezacova, P.; Fabry, M.; Horejsi, M.; Stouracova,
R.; Sedlacek, J. J. Med. Chem. 2004, 47, 2030–2036.
33. Repic Lampret, B.; Kidric, J.; Kralj, B.; Vitale, L.; Pokorny,
M.; Renko, M. Arch. Microbiol. 1999, 171, 397–404.
34. (a) Unkefer, C. J.; London, R. E.; Durbin, R. D.; Uchytil, T. F.;
Langston-Unkefer, P. J. J. Biol. Chem. 1987, 262, 4994–4999;
(b) Meek, T. D.; Villafranca, J. V. Biochemistry 1980, 19,
5513–5519; (c) Sinden, S. L.; Durbin, R. D. Nature 1968,
219, 379–380.
19. Yoshida, S.; Naganawa, H.; Aoyagi, T.; Takeuchi, T.; Takeuchi,
Y.; Kodama, Y. J. Antibiot. 1991, 44, 579–581.
20. Izuka, K.; Kamijo, T.; Kubota, T.; Akahane, K.; Umeyama, H.;
Kiso, Y. J. Med. Chem. 1988, 31, 701–703.
35. Imada, A.; Kitano, K.; Kintana, K.; Muroi, M.; Asai, M. Nature
1981, 289, 590.
21. Johnson, R. L. J. Med. Chem. 1982, 25, 605–610.
22. (a) Llinares, M.; Devin, C.; Chaloin, O.; Azay, J.; Noel-Artis,
A.-M.; Bernad, N.; Fehrentz, J.-A.; Marttinez, J. J. Pept. Res.
1999, 53, 275–283; (b) Kim, S. H.; Taylor, J. E.; Jensen,
R. T.; Coy, D. H.; Bogden, A. E.; Moreau, J.-P. Peptides,
Chemistry, Structure and Biology; Rivier, J. E., Marshall,
G. R., Eds.; Escom: Leiden, 1990; pp 181–184.
23. Maggiora, L. L.; Orawski, A. T.; Simmons, W. H. J. Med.
Chem. 1999, 42, 2394–2402.
24. (a) Asai, M.; Hattori, C.; Iwata, N.; Saido, T. C.; Sasagawa, N.;
36. (a) Dolle, R. E.; Hughes, M. J.; Li, C.-S.; Kruse, L. I. J. Chem.
Soc., Chem. Commun. 1989, 1448–1449; (b) Greenlee, W. J.;
Springer, J. P.; Patchett, A. A. J. Med. Chem. 1989, 32, 165–
170; (c) Baldwin, J. E.; Otsuka, M.; Wallace, P. M.
Tetrahedron 1986, 42, 3097–3110; (d) Stewart, W. W. Nature
1971, 229, 174–177.
37. For the synthesis of N-(S)-tert-butylsulfinyl adimines, see: (a)
Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60,
8003–8030; (b) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang,
T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278–1284; (c)
Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A.
J. Am. Chem. Soc. 1998, 120, 8011–8019; (d) Ellman, J. A.
Pure Appl. Chem. 2003, 75, 39–46; For the preparation of a-
sulfonyl carbamates, see: Pearson, W. H.; Lindbeck, A. C.;
Kampf, J. W. J. Am. Chem. Soc. 1993, 115, 2622–2636.
38. (a) Tang, T. P.; Ellmann, J. A. J. Org. Chem. 1999, 64, 12–13;
(b) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.;
Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051–2052.
ꢁ
Szabo, B.; Hashimoto, Y.; Maruyama, K.; Tanuma, S.-C.; Kiso,
Y.; Ishiura, S. J. Neurochem. 2006, 96, 533–540; (b) Shuto, D.;
Kasai, S.; Kimura, T.; Liu, P.; Hidaka, K.; Hamada, T.;
Shibakawa, S.; Hayashi, Y.; Hattori, C.; Szabo, B.; Ishiura,
S.; Kiso, Y. Bioorg. Med. Chem. Lett. 2003, 13, 4273–4276.
25. (a) Burley, S. K.; David, P. R.; Lipscomb, W. N. Proc. Natl.
Acad. Sci. U.S.A. 1991, 88, 6916–6920; (b) Aoyagi, T.; Tobe,
H.; Kojima, F.; Hamada, M.; Takeuchi, T.; Umezawa, H.