Synthesis of α2,2,β3-diamino acids by double stereodifferentiation aldol addition of oxazolidinone enolates to N-(tert-butylsulfinyl) imines

Article abstract of DOI:10.1002/ejoc.200800356

A novel application of Seebach's SRS synthetic principle works efficiently when conformationally restrained trisubstituted chiral α^2,2,β³-diamino acids are synthesized by double stereoinduction reactions of chiral oxazolidinone enolates with N-sulfinyl aldimines. Two stereoisomers were isolated in a form of 1′-(sulfinylamino) oxazolidinones and bicyclic 1H,3H-imidazo[1,5-c]oxazole-1,5(6H)-diones, from which the α^2,2,β³-diamino acids are obtained by selective deprotection methodologies. Among a variety of highly functionalized diamino acids, this highly diastereoselective protocol provides a synthetic route for yet unreported C-glycosyl and α-nucleoside diamino acids. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800356

FULL PAPER
DOI: 10.1002/ejoc.200800356
Synthesis of α2,2,β3-Diamino Acids by Double Stereodifferentiation Aldol
Addition of Oxazolidinone Enolates to N-(tert-Butylsulfinyl) Imines
Andrea Guerrini,*[a] Greta Varchi,*[a] Cristian Samorì,[a] and Arturo Battaglia[a]
Keywords: Amino acids / Oxygen heterocycles / Nitrogen heterocycles / Diastereoselectivity / Antifungal agents / Peptido-
mimetics
A novel application of Seebach’s “SRS” synthetic principle
works efficiently when conformationally restrained trisubsti-
tuted chiral α2,2,β3-diamino acids are synthesized by double
stereoinduction reactions of chiral oxazolidinone enolates
with N-sulfinyl aldimines. Two stereoisomers were isolated
in a form of 1Ј-(sulfinylamino)oxazolidinones and bicyclic
1H,3H-imidazo[1,5-c]oxazole-1,5(6H)-diones, from which the
α2,2,β3-diamino acids are obtained by selective deprotection
methodologies. Among a variety of highly functionalized di-
amino acids, this highly diastereoselective protocol provides
a synthetic route for yet unreported C-glycosyl and α-nucleo-
side diamino acids.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
creased lipophilicity.[10] To date, only a few disubstituted
α2,2-diamino acids[11] and trisubstituted α2,2,β3-diamino ac-
ids[9g,12] with a quaternary chiral center at the α position
have been synthesized.
Introduction
α,β-Diamino acids are key structural units of many natu-
ral products that are involved in a variety of biological
functions.[1] In particular, they are employed as building
blocks for peptidomimetic syntheses to improve their sta-
bility toward peptidases[2] and to induce, in some cases, spe-
cific conformations in peptide segments.[3] Their metal com-
plexing abilities have also been documented.[4] Among the
several procedures described for the enantioselective synthe-
sis of α,β-diamino acids,[5] the addition of glycine synthons
to imines is one of the most important. For example, Staud-
inger’s cycloaddition reactions of glycinyl chlorides to ald-
imines afford 3-amino-β-lactams, which are synthetic pre-
cursors of α,β-diamino acids.[6] However, enantioselective
Mannich-type additions of glycine enolates to aldimines[7]
are key methodologies that have been developed for several
asymmetric syntheses of disubstituted 1,2-diamino acids. In
the reaction between glycine enolates and electrophilically
activated N-sulfinyl imines,[8] the proper choice of the tert-
butylsulfinyl substituent stereochemistry serves as a chiral
directing group,[9] even though the synthesis of the corre-
sponding chiral diamino acid occurs with different degrees
of selectivity[9b–9d] and more often requires hardly repro-
ducible reaction conditions.[9a,9c]
We reasoned that, on the basis of Seebach’s “self-regener-
ation of stereocenters” (SRS) synthetic principle,[13] the
enolates of N-acyloxazolidinones could serve as directing
chiral partners in the reaction with electrophilically acti-
vated imines for the synthesis of trisubstituted α,β-diamino
acids. Apart from operational simplicity, this approach
shows a number of other favorable features, including the
use of easily attainable reagents such as natural α-amino
acids and aldimines. Moreover, the use of a rigid cyclic
enolate, unlike the corresponding alicyclic systems, could
provide an additional element that could be used to control
the stereochemical outcome. The present work proposes a
general methodology for the preparation of a wide range of
important molecular frameworks, including the synthesis of
the first glycosyl- and nucleoside-1,2-diamino acid conju-
gates connected through a carbon–carbon bond.
Results and Discussion
According to a modified version of Seebach’s methodol-
ogy,[14] enantiomeric lithium enolates (S)-8 and (R)-8 of
(2S,4S)-cis-4-methyl-1,3-oxazolidin-5-one (cis-7) and its
(2R,4S)-trans-diastereomer (trans-7), respectively, (Fig-
ure 1) were treated with a variety of electrophilically acti-
vated aldimines 1–6 to prove the broad applicability of our
protocol.
In our first attempt, performed with achiral N-(tert-bu-
toxycarbonyl)benzenemethanimine, we were discouraged by
the low reaction selectivity.[15] Therefore, we sought to im-
Trisubstituted homochiral 1,2-diamino acids are not
readily accessible. Even so, these highly substituted com-
pounds might find application in the preparation of β-pep-
tides with a restricted conformational flexibility and an in-
[a] Istituto CNR per la Sintesi Organica e la Fotoreattività
“ISOF”, Area della Ricerca di Bologna,
Via P. Gobetti 101, 40129 Bologna, Italy
E-mail: g.varchi@isof.cnr.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
3834
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3834–3844

α2,2,β3-Diamino Acids by a Stereodifferentiation Aldol Addition Reactions
Figure 1. Oxazolidinones cis-7, trans-7 and their corresponding lithium enolates (S)-8, (R)-8, and (SS)- and (SR)-(N-tert-butylsulfinyl)
aldimines 1–6.
prove the efficiency of the method by using chiral N-(tert-
Scheme 1 reports the stereochemistry of the addition of
butylsulfinyl) imines, as the tert-butylsulfinyl substituent af- an (S)- or (R)-configured sulfinamide to enolate (S)-8. Two
fords an additional element of kinetic selectivity with re- structurally different compounds, that is, the 1Ј-(sulfin-
spect to the achiral tert-butoxycarbonyl group.
ylamino)oxazolidinone or the bicyclic oxazoledione, were
In this respect, we recently reported the synthesis of chi- obtained. Regardless of the nature of the stereogenic centers
ral α-hydroxy-β-amino acids by asymmetric Mannich-type of the reagents, the enolate attacks the aldimine from the
additions of homochiral 1,3-dioxolanon-4-one enolates opposite side of the bulky tert-butyl group with 1,3-induc-
to homochiral N-(tert-butylsulfinyl) aldimines and ket- tion. In particular, the addition of (S)-8 to the (R)-config-
imines.[16] This methodology proved to be particularly use- ured N-sulfinyl imine affords, in principle, diastereomeric
ful for the synthesis of trisubstituted C-glycosyl isoseri- lithiated intermediates Ia and IIa, whereas the addition to
nes.[16a] Instead, to the best of our knowledge, no report the (S)-configured N-sulfinyl imine affords intermediates Ib
has been published concerning the synthesis of isosteric C- and IIb. Intermediates IIa and IIb, which only differ in the
glycosyl-α,β-diamino acids and their corresponding C-gly- stereochemistry at the sulfur atom, are derived from an exo
copeptides, in which the diamino acid side chain is con- approach of the imine to the enolate ring. In these interme-
nected to the sugar moiety through a carbon–carbon bond. diates, the N-sulfinyl amide substituents at the (1ЈR)-posi-
These compounds are expected to be more stable toward tion are syn to the carbamate group; thus, they undergo
glycosidases relative to their N- and O-linked analogs.[17] cyclization with concomitant elimination of allyl 2-methyl-
Thus, we exploited the above-mentioned approach to ob- propane-2-sulfinate to afford bicyclic oxazole derivatives.
tain these valuable building blocks. In particular, we consid- For intermediates Ia and Ib, which are derived from an endo
ered the “matching” and “mismatching” effects in the reac- approach of the imine to the enolate ring, the sulfinamide
tions involving enantiomeric pairs of aromatic, aliphatic, substituent of the (1ЈS)-position lays anti to the carbamate
and sugar aldimines.[18] Modification to Seebach’s protocol residue; thus, they afford the 1Ј-(sulfinylamino)-3-(allyloxy-
relies on the use of an orthogonal allyloxycarbonyl (Alloc) carbonyl)oxazolidinones upon treatment with 0.2  HCl.
protecting group to the oxazolidinone nitrogen atom.[18,19]
For aromatic and heteroaromatic aldimines we observed
Treatment of cis-7 (or trans-7) with lithium bis(trimethyl- that the pairs (2S)-8/(RS)-1, (2R)-8/(SS)-1, and (2S)-8/(RS)-
silyl)amide (LHMDS) affords nonracemic lithium enolates 2 were highly diasterocontrolled and afforded bicyclic imid-
(2S)-8 or (2R)-8, which can then be treated with aldimines azo[1,5-c]oxazole derivatives 9, ent-9, and 10 (Table 1, En-
at –78/–90 °C in THF/HMPA (85:15). An excess amount of tries 1, 3, and 4). The product distribution for the reactions
enolate (3.5–5.5 equiv.) and a very slow addition rate of the of lithium enolates (2R)-8 and (2S)-8 with (SS)- and (RS)-
imine were found to be crucial to minimize the competitive N-(tert-butylsulfinyl) aldimines 1–6 is reported in Table 1.
self-condensation of the N-sulfinyl imine under the basic
The (2S)-8/(SS)-1 pair afforded a mixture of bicyclic
and 1Ј-(sulfinylamino)oxazolidinone 11
(Table 1, Entry 2). Similarly, for the (2S)-8/(SS)-3 (Table 1,
reaction conditions,[20] and to ensure its complete consump- compound
9
tion.
Eur. J. Org. Chem. 2008, 3834–3844
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3835

A. Guerrini, G. Varchi, C. Samorì, A. Battaglia
FULL PAPER
Scheme 1.
Table 1. Product distribution for the reactions of lithium enolates (2R)-8 and (2S)-8 with (SS)- and (RS)-N-(tert-butylsulfinyl) aldimines
1–6.
Entry
Imine
Enolate
R
Products
% de[a]
% Yield
1
2
3
4
5
6
7
8
(RS)-1
(SS)-1
(SS)-1
(RS)-2
(SS)-3
(RS)-3
(RS)-3
(SS)-4
(RS)-4
(SS)-5
(SS)-5
(RS)-5
(RS)-5
(SS)-6
(2S)-8
(2S)-8
(2R)-8
(2S)-8
(2S)-8
(2R)-8
(2S)-8
(2S)-8
(2R)-8
(2S)-8
(2R)-8
(2S)-8
(2R)-8
(2S)-8
phenyl
phenyl
phenyl
2-thiophene
2-isobutyl
2-isobutyl
2-isobutyl
isopropyl
(3S,7R,7aR)-9
Ͼ96
0
Ͼ96
Ͼ96
76
76
–
Ͼ96
Ͼ96
Ͼ96
–
Ͼ96
90
80
80
81
83
89
83
Trace
82
83
59
(SS,2S,4R,1ЈS)-11/(3S,7R,7aR)-9
ent-9
(3S,7S,7aR)-10
(SS,2S,4R,1ЈS)-12/(3S,7R,7aR)-13
ent-12/ent-13
(3S,7R,7aR)-13
(SS,2S,4R,1ЈS)-14
ent-14
9
isopropyl
10
11
12
13
14
O-tetrabenzyl glucose
O-tetrabenzyl glucose
O-tetrabenzyl glucose
O-tetrabenzyl glucose
di-OTBDMS-uridine
(SS,2S,4R,1ЈR)-15
[b]
Ͻ15
63
(RS,2S,4R,1ЈR)-16
(3R,7S,7aR)-17
(SS,2S,4R,1ЈR)-18
79[c]
89
Ͼ96
1
[a] Calculated on the crude reaction mixture by H NMR spectroscopic analysis. [b] Inseparable mixture of addition products. [c] Trace
amounts (5%) of the opened compound were detected (See Experimental Section).
Entry 5) and (2R)-8/(RS)-3 (Table 1, Entry 6) pairs involv-
1Ј-(Sulfinylamino)oxazolidinones 12 and ent-12 were ob-
ing aliphatic branched sterically demanding N-isopentyl tained as the major products in a 88:12 ratio along with
aldimines, the (sulfinylamino)oxazolidinone is favored over minor amounts of bicyclic adducts 13 and ent-13, respec-
the bicyclic adduct.
tively. Accordingly, upon treatment of aldimine (RS)-3 with
3836
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3834–3844

α2,2,β3-Diamino Acids by a Stereodifferentiation Aldol Addition Reactions
(2S)-8, the formation of bicyclic adduct 13 should be favored
(Table 1, Entry 7). Actually, we found that the bulkiness of
the imine C-substituent inhibited the formation of the bicy-
clic compound, which was anyway detected as the sole prod-
uct but in very low yield. The greater steric bulkiness of the
isopropyl group of aldimines (RS)- and (SS)-4 relative to that
of aldimine 3 further enhanced the endo selectivity in the re-
actions of (2S)-8 with (SS)-4 and (2R)-8 with (RS)-4, which
gave homochiral 1Ј-(sulfinylamino)oxazolidinones 14 and
ent-14 exclusively. These results demonstrate that the tert-bu-
tylsulfinyl substituent introduces an additional element of ki-
netic selectivity due to matching/mismatching interactions be-
tween the two chiral partners. In particular, when the (RS)-
imine endo approaches the (S)-8 enolate, the sterically encum-
bered tert-butyl substituent points towards the enolate ring,
whereas when it approaches in an exo manner, the tert-butyl
group points outwards the ring (Scheme 1). Consequently,
Figure 2. Spatial view of (SS,2S,4R,1ЈR)-18.
the last pathway, which leads to the formation of the bicyclic
oxazole-1,5-dione, is strongly favored. Alternatively, when an
(SS)-configured imine reacts with enolate (S)-8, the tert-butyl
substituent points outwards in the endo approach and in-
wards in the exo one so that the 1Ј-(sulfinylamino)oxazolid-
inone may compete for the product distribution. Besides the
stereochemistry of the tert-butylsulfinyl group, the size of the
substituent at the imine carbon atom also strongly influences
the chemical yields and product distributions. For instance,
the bulky sugar moiety (aldimines 5 and 6) exerts a key role
in terms of endo diastereoselectivity when treated with (2S)-
8, leading to 1Ј-(sulfinylamino)oxazolidinones 15, 16, and 18
as sole products (Table 1, Entries 10, 12, and 14).[21] Instead,
exo selectivity was observed in the reaction of enolate (2R)-8
with (RS)-5, which affords bicyclic compound 17 along with
trace amounts (Ͻ5%) of the opened compound (Table 1, En-
try 13). Only trace amounts of an inseparable mixture of ad-
dition products were detected in the crude mixture for the
reaction involving imine (SS)-5 and (2R)-8 (Table 1, En-
try 11).
The absolute stereochemistry of 15 was assigned by
chemical correlation methods (see compound 24). However,
nOe analysis of 15 was performed in order to compare this
result with that obtained from nOe analysis of 18 (Fig-
ure 3). In detail, irradiation of the C2-tBu group (δ
=1.00 ppm) produces a 7.0% nOe effect on C4-Me (δ
=1.90 ppm) and a 22% effect on C2-H, which thus suggests
(R) stereoconfiguration of the C4 carbon atom. Irradiation
of the C4-Me group produces an 8.0% nOe effect on the H-
C1Ј position, which suggests a C1Ј (R) configuration. Other
Nuclear Overhauser effect (nOe) experiments allowed the
assessment of the C4 stereocenter of the 1Ј-(sulfinylamino)-
oxazolidinones and that at the C7a center of the bicyclic
oxazole-1,5-diones, by selective irradiation of the tBu
substituent. Moreover, by means of nOe experiments it
was possible to assign the absolute configuration of bicyclic
adducts 9, 10, 13, 17, and uridine derivative 18, which
adopts a restricted (4R,1ЈR)-conformation (Figure 2). In
detail, irradiation of the tBu-C2 group (δ =0.75 ppm) pro-
vided a 1.3% nOe effect on the C4 methyl group at δ =
1.69 ppm and 6.0% on the H1, which thus suggests (R) ste-
reoconfiguration at the C4 carbon atom. Selective irradia-
tion of the C4-Me group produced an 11% nOe effect on
H1Ј, which suggests (1ЈR) conformation. Other significant
nOe effects, which would further confirm the restricted con-
formation of 18, were observed between the tert-butyl
group on the sulfur atom and NH (1.0%), H7 (1.0%), and
H6 (3%). Furthermore, irradiation of one the methyl
protons attached to the silicon atom, centered at δ =
0.37 ppm, induced a 2.2% nOe effect on H3Ј and a 4.2%
effect on H1Ј.
Figure 3. Spatial view of (SS,2S,4R,1ЈR)-15.
Eur. J. Org. Chem. 2008, 3834–3844
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3837

A. Guerrini, G. Varchi, C. Samorì, A. Battaglia
FULL PAPER
Table 2. Nitrogen sulfinyl deprotection and cyclizations of free amines 19–21.
Entry
1Ј-(Sulfinylamino)-
oxazolidinones
R
1Ј-Amino-
oxazolidinones
% Yield
Imidazo[1,5-c]oxazoles
% Yield
1
2
3
4
(SS,2S,4R,1ЈS)-12
(SS,2S,4R,1ЈS)-14
(SS,2S,4R,1ЈR)-15
(RS,2S,4R,1ЈR)-16
isobutyl
isopropyl
O-tetrabenzyl glucose
O-tetrabenzyl glucose
(2S, 4R, 1ЈS)-19
(2S, 4R, 1ЈS)-20
(2S,4R,1ЈR)-21
(2S,4R,1ЈR)-21
90
85
90
90
(3S,7R,7aS)-22
(3S,7R,7aS)-23
(3S,7R,7aR)-24
–
80
40
40
–
significant nOe effects, which would further confirm this
configuration, are observed between the tBu group on the
S(O) moiety and NH (12%) and C3-H (8%).
1Ј-(Sulfinylamino)oxazolidinones can be considered as
orthogonally N1,N2-protected-α,β-diamino acids. This fea-
ture was confirmed by a number of deprotection experi-
ments of compounds 12, 14, 15, and 16. Treatment with
ethereal 2  HCl in anhydrous MeOH afforded the corre-
sponding N-unprotected 1-aminooxazolidinones 19, 20,
and 21 in good yields. Subsequent LHMDS-induced cycli-
zation of compounds 19–21 afforded bicyclic derivatives
22–24, whose stereochemistry assessment (n.O.e. experi-
ments; see Experimental Section) served also to assign the
stereoconfiguration of their precursors 12, 14–16 (Table 2
and Experimental Section for details).
Selective Alloc-group deprotection was accomplished un-
der neutral conditions on derivatives 12, 14, 15, and 18 by
catalyzed hydrogen transfer with the use of tetrakis(triphen-
ylphosphane)palladium(0) catalyst and PhSiH3. By stand-
ing at 20 °C for 3 h in THF/water, the free NH cyclic com-
pounds smoothly afforded the corresponding NH-sulfinyl
protected syn amino acids 25–28 (Table 3 and Experimental
Section). This soft deprotection methodology, which can be
applied to sensitive substrates such as nucleosides and
sugars, proved the orthogonality between the two nitrogen
protecting groups.
Scheme 2.
Conclusions
We developed a simple and general protocol for the syn-
thesis of homochiral trisubstituted α2,2,β3-diamino acids.
The efficiency of this method relies on the possibility to
obtain a wide pool of aromatic, heteroaromatic, aliphatic,
glycosyl, and nucleoside homochiral diamino acids by using
relatively inexpensive reagents, such as chiral N-sulfinyl ald-
imines and oxazolidinones. Moreover, we reported the first
C-glycosyl-α,β-diamino acids bearing either a sugar moiety
or a nucleobase, which can potentially serve as new building
blocks for the synthesis of important biologically active
compound analogs, such as antibiotics,[22] antifungals,[23]
and peptidomimetics.[2] In particular, compound 28 can be
considered as a new analog of polyoxin C; thus, it could
function as an antifungal agent as is, or as a versatile build-
ing block for the preparation of a new family of polyoxin
C isosters[23a] (Figure 4).
Table 3. Alloc Removal and amino acid formation.
Entry
Reagent
R
Product
% Yield
Figure 4. Polyoxin C and compound 28.
1
2
3
4
12
14
15
18
isobutyl
isopropyl
(SS,2R,3S)-25
(SS,2R,3S)-26
98
98
98
98
O-tetrabenzyl glucose (SS,2R,3R)-27
di-OTBDMS-uridine (SS,2R,3R)-28
Experimental Section
Compounds 9, 10, and 11 were deprotected in refluxing
6  HCl, which provided the corresponding anti amino ac-
ids 29, 30, and syn-(2R,3S)-31, respectively, in 98% yield
(Scheme 2).
General: All reactions were performed under an atmosphere of dry
nitrogen by using oven-dried glassware. Tetrahydrofuran, toluene,
and ethyl ether were distilled from sodium benzophenone ketal.
Dichloromethane and acetonitrile were distilled from calcium hy-
3838
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3834–3844

α2,2,β3-Diamino Acids by a Stereodifferentiation Aldol Addition Reactions
tion was assessed by homonuclear nOe experiments (CD3COCD3).
dride. All other solvents were HPLC grade. Reactions were magnet-
ically stirred and monitored by thin-layer chromatography (TLC)
with E. Merck silica gel 60-F254 plates. Flash column chromatog-
raphy was performed with Merck silica gel (0.04–0.63 µm, 240–
400 mesh) under high pressure. NMR spectra were recorded with
a 400 MHz spectrometer. Unless otherwise stated, all NMR spectra
were measured in CDCl3 solutions and referenced to the CHCl3
signal. All 1H and 13C shifts are given in ppm (s = singlet; d =
doublet; t = triplet; dd = quadruplet; dt = doublet of triplets, m =
multiplet; br. = broad signal). Coupling constants J are given in
Hz. Assignments of proton resonances were confirmed, when pos-
sible, by selective homonuclear decoupling experiments or by corre-
lated spectroscopy. IR spectra were recorded with an FTIR E.S.P.
spectrometer as thin films on NaCl plates. Mass spectra were re-
corded with an ion trap spectrometer with an ionization potential
of 70 eV. High-resolution mass spectra (HRMS) were performed
with a Finnigan MAT 8230 with a resolution of 10000. The com-
mercially available reagents were used as received without further
purification.
Upon irradiation of the C3-tBu group (δ =0.98 ppm), a 23.8% nOe
effect was registered at the C3-H proton (δ =5.22 ppm) and a 5.2%
effect on the Me group at the C7a position (δ =1.79 ppm), which
thus confirms the (R) stereoconfiguration for the 7a stereocenter.
In addition, irradiation of the C7a-Me protons produced a 14.6%
nOe effect on the proton at the C7 position.
(3S,7S,7aR)-10: Reaction between (2S)-8 and (RS)-2 afforded com-
pound 10 in 83% yield as a white solid after crystallization from
hexane/diethyl ether, 5:1. [α]2D0 = –10.2 (c = 0.6, CHCl3). M.p. 158–
160 °C. 1H NMR (400 MHz, CDCl3): δ = 7.24–7.20 (m, 1 H), 6.95–
6.90 (m, 2 H), 5.40 (s, 1 H, NH), 5.15 (s, 1 H, C3-H), 4.73 (s, 1 H,
C7-H), 1.69 (s, 3 H, Me), 0.91 (s, 9 H, 3 Me) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.7, 164.4, 141.1, 128.0, 126.7, 126.1,
General Procedure for the Reactions of Lithium Enolates (2R)- and
(2S)-8 with (SS)- and (RS)-N-(tert-Butylsulfinyl) Aldimines 1–6: To
a solution of LHMDS (4.5 equiv. for aromatic sulfinamides and
3.5 equiv. for aliphatic ones; 1  in THF) in THF (16 mL), cooled
to –78 °C, was dropwise added a solution of oxazolidin-5-one
(4.5 equiv. for aromatic aldimines and 3.5 equiv. for aliphatic ones)
in THF (3.5 mL). After 20 min, the reaction mixture was further
cooled to –85 to –90 °C and a solution of THF/HMPA (2 mL of
THF and 3 mL of HMPA) was added dropwise. The selected sulfi-
namide (0.53 mmol, 1 equiv.) in THF (4.5 mL) was then added to
the reaction mixture by a syringe pump (addition rate: 1.5 mL/h)
keeping the temperature below –75 °C (not lower than –80 °C).
Once the addition was over, the temperature was raised to –60 °C
in 1 h and 0.2  HCl was added. The solution was brought to room
temperature, and the organic phase was extracted with EtOAc
(2ϫ). The organic layer was than washed with HCl (0.2 , 2ϫ) and
saturated NH4Cl (1ϫ) and then dried with Na2SO4. Filtration of
the salt and solvent removal afforded the crude material, which was
purified by flash column chromatography (Table 1).
98.1, 68.5, 63.6, 36.3, 25.8, 24.7 ppm. IR (neat): ν = 2973, 1790,
˜
1724, 1190 cm–1. C14H18N2O3S (294.37): calcd. C 57.12, H 6.16, N
9.52; found C 57.24, H 6.09, N 9.59. The (3S,7R,7aS) stereoconfig-
uration was assigned by homonuclear nOe experiments (CDCl3).
Upon irradiation of the Me group at δ = 1.69 ppm, a 16% nOe
effect was observe on the proton at the C7 position (4.73 ppm).
Irradiation of the Me3C group at δ = 0.91 ppm only produced a
2.0% nOe effect on the Me group at δ = 1.69 ppm.
(3S,7R,7aR)-9 and (SS,2S,4R,1ЈS)-11: Reaction between (2S)-8 and
(SS)-1 afforded a mixture (80%) of (SS,2S,4R,1ЈS)-11 and 9 in a
1:1 ratio, which was separated by flash column chromatography
(hexane/CHCl3/EtOAc, 10:8:2). Compound 11 was isolated as
sticky oil, slightly contaminated by an inseparable byproduct. Data
for 11: 1H NMR (400 MHz, CDCl3, 55 °C): δ = 7.30–7.20 (m, 3
H, arom.), 7.20–7.05 (m, 2 H, arom.), 6.20–5.80 (br. m, 1 H), 5.50–
5.20 (br. m, 3 H), 5.05 (m, 1 H), 4.85–4.40 (br. m, 2 H), 4.55 (s, 1
H, CH-NH), 2.03 (s, 3 H, Me), 1.11 (s, 9 H, tBuS), 0.86 (s, 9 H,
tBuCH) ppm. 13C NMR (100 MHz, CDCl3, 55 °C; relevant reso-
nances): δ = 174.5, 153–150 (br.), 139–138 (br.), 131.7, 128.7, 127.5,
119.7, 95.3, 74.8, 66.7, 65.5, 56.4, 38.5, 25.6, 22.6 ppm. IR (CDCl3):
(SS,2S,4R,1ЈS)-12 and (3S,7R,7aR)-13: Reaction between (2S)-8
and (SS)-3 afforded a mixture of 12 and 13 (89% overall yield) in
a 88:12 ratio, which was separated by flash column chromatography
(cyclohexane/CHCl3/Et2O, 7:8:5) as a white solid. Data for 12:
1
[α]2D0 = +12.5 (c = 0.5, CHCl3). M.p. 162 °C. H NMR (400 MHz,
CD3COCD3): δ = 6.03 (m, 1 H, CH=CH2), 5.64 (s, 1 H, C2 H),
5.44 (d, J = 17.0 Hz, 1 H, CH=CH2), 5.29 (dd, J = 1.2 Hz, J =
10.5 Hz, 1 H, CH=CH2), 4.84–4.72 (br., 1 H, O-CH2), 4.64 (d, J =
8.5 Hz, 1 H, NH), 4.58 (dd, J = 6.0 Hz, J = 13.2 Hz, 1 H, O-CH2),
4.40–4.20 (br., 1 H, C1Ј-H), 1.87 (s, 3 H, Me), 1.90–1.80 (m, 1 H,
CHMe2), 1.23 (s, 9 H, tBu-S), 1.20–1.15 (m, 1 H, CH-CH2), 0.98
(s, 9 H, tBu-C2), 1.00–0.90 (m, 1 H, CH-CH2), 0.88 (d, J = 6.5 Hz,
3 H, Me), 0.82 (d, J = 6.5 Hz, 3 H, Me) ppm. 13C NMR (100 MHz,
CD3OD, 58 °C): δ = 174.9, 156.0–154.0 (br.), 131.9, 118.5, 95.9,
66.8, 64.4, 60.0–58.0 (br.), 57.3, 41.4, 38.2, 24.7, 24.0, 23.0, 22.2,
ν = 2962, 1775, 1715, 1394, 1325 cm–1. HRMS: calcd. for
˜
C22H34N2O5S [M]+ 450.2188; found 450.2177. The (5R) stereocon-
figuration was assessed by homonuclear nOe experiments (CDCl3).
A nOe effect of 2.8% was observed on the Me group at C5 position
(δ =2.03 ppm) upon irradiation of the tBu-C2 signal at δ =
0.86 ppm. Data for 9: [α]2D0 = –38.3 (c = 0.6, CHCl3). M.p. 224–
226 °C. 1H NMR (400 MHz, CDCl3): δ = 7.42–7.30 (m, 3 H), 7.20– 21.5, 20.0 ppm. MS: m/z = 431 [M]+, 241, 196, 156, 135. IR (neat):
7.10 (m, 2 H), 5.65 (s, 1 H, NH), 5.21 (s, 1 H, C3-H), 4.56 (s, 1 H,
ν = 2960, 1778, 1720, 1389, 1339 cm–1. C H N O S (430.6): calcd.
˜
21 38 2 5
C7-H), 1.79 (s, 3 H, Me), 0.98 (s, 9 H, 3 Me) ppm. 13C NMR C 58.57, H 8.89, N 6.51; found C 58.70, H 8.82, N 6.45. The (4R)
(100 MHz, CDCl3): δ = 171.8, 165.0, 137.5, 129.5, 129.1, 126.1, stereoconfiguration was assessed by homonuclear nOe experiments
97.9, 68.1, 67.6, 36.0, 26.2, 24.5 ppm. IR (CDCl ): ν = 2972, 1789,
(CD3COCD3). A 2.8% nOe effect was observed on the C5-Me pro-
1723, 1188 cm–1. C16H20N2O3 (288.34): calcd. C 66.65, H 6.99, N tons (1.87 ppm) upon irradiation of the tBu-C2 signal at δ =
9.72; found C 66.72, H 6.91, N 9.77. The (7R,7aR) stereoconfigura-
0.98 ppm. Data for 13: [α]2D0 = +67.0 (c = 0.4, CHCl3). M.p. 198–
˜
3
Eur. J. Org. Chem. 2008, 3834–3844
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3839

A. Guerrini, G. Varchi, C. Samorì, A. Battaglia
FULL PAPER
200 °C. 1H NMR (400 MHz, CDCl3): δ = 5.57–5.42 (br., 1 H, NH),
5.19 (s, 1 H, C3-H), 3.53 (dd, J = 3.0 Hz, J = 11.5 Hz, 1 H, C7-
H), 1.70–1.60 (m, 1 H, CHMe2), 1.62 (s, 3 H, Me), 1.62–1.52 (m,
(SS,2S,4R,1ЈR)-15: Reaction between (2S)-8 and (SS)-5 afforded
compound 15, which was separated by silica-gel flash column
chromatography (cyclohexane/CH2Cl2/Et2O, 6:3:1), as a sticky oil.
1 H, CHCH2), 1.18–1.10 (m, 1 H, CHCH2), 0.98 (s, 9 H, 3 Me), Yield: 59%, Ͼ96% de. [α]2D0 = +36.0 (c = 0.6, CHCl3). 1H NMR
0.93 (d, J = 6.5 Hz, 3 H, Me), 0.89 (d, J = 6.5 Hz, 3 H, Me) ppm.
13C NMR (100 MHz, CDCl3): δ = 173.4, 164.5, 98.6, 65.9, 61.3, 5.80–5.50 [br., 2 H, (CH=CH2) + (tBuCH)], 5.18 (br., 1 H, NH),
41.7, 36.1, 26.3, 24.8, 24.7, 24.0, 20.9 ppm. IR (neat): ν = 1785, 5.25–4.50 [m, 12 H (C=CH2) + 10 H (3ϫ CH2C6H5)], 4.65–4.55
1713, 1243 cm–1. C14H24N2O3 (268.35): calcd. C 62.66, H 9.01, N [br., 1 H, (CHNH)], 3.90 (dd, J = 2.8 Hz, J = 11.5 Hz, 1 H,
(400 MHz, CD3COCD3, 53 °C): δ = 7.42–7.20 (m, 20 H, arom.),
˜
10.44; found C 62.58, H 9.03, N 10.47. The (7R,7aR) stereoconfig-
uration for the major product was assessed by means of homonu-
clear nOe experiments (CDCl3). A 3.0% nOe effect was observed
on the Me group at the C7a position (δ =1.62 ppm) upon irradia-
tion of the tBu group centered at δ = 0.98 ppm, and a 11.0% nOe
effect was detected on the C7a-Me signal upon irradiation of the
C7-H proton centered at δ = 3.53 ppm, which thus confirms the
(R) stereoconfiguration both at the 7 and 7a stereocenters. Reac-
tion between sulfinamide (RS)-3 and enolate (2R)-8 afforded a mix-
ture of ent-12 and ent-13 (76% de) in an 83% overall yield. NMR
and IR spectroscopic data and mass analysis for ent-12 and ent-13
are identical to those of 12 and 13, respectively. ent-12: [α]2D0 = –12.8
(c = 0.5, CHCl3). ent-13: –67.2 (c 0.4, CHCl3).
OCH2CH=CH2), 3.75 (dd, J = 1.63 Hz, J = 11.5 Hz, 1 H,
OCH2CH=CH2), 3.80–3.65 (m, 1 H, H4), 3.69 (t, J = 8.8 Hz, 1 H,
H5), 3.61 (t, J = 8.8 Hz, 1 H, H3), 3.52 (d, J = 9.2 Hz, 1 H, H6),
3.23 (d, J = 8.8 Hz, 1 H, H2), 1.90 (s, 3 H, Me), 1.27 (s, 9 H, tBu-
S), 1.00 (s, 9 H, tBu-CH) ppm. 13C NMR (100 MHz, CD3COCD3,
58 °C, relevant resonances): δ = 174.3, 153.2, 139.4, 139.1, 139.0,
138.9, 132.7, 128.4–127.3 (arom.), 117.5, 95.1, 87.6, 79.7, 78.3, 77.3,
77.2, 75.2, 74.6, 73.7, 68.5, 66.3, 59.9, 57.0, 38.5, 25.2, 22.9,
22.6 ppm. IR (neat):
ν =
˜
1778, 1716, 1454, 1334 cm–1.
C51H64N2O10S (897.13): calcd. C 68.28, H 7.19, N 3.12; found C
68.21, H 7.25, N 3.18. The absolute stereochemistry of 15 was as-
signed by chemical correlation methods (see compound 24). How-
ever, n.O.e. analysis of 15 was performed in order to compare this
result with that obtained from n.O.e. analysis of 18. In detail, irra-
diation of the C2-tBu group (δ =1.00 ppm) produces a 7.0% nOe
effect on C4-Me (δ =1.90 ppm) and a 22% effect on C2-H, which
thus suggests an (R) stereoconfiguration of the C4 carbon atom.
Irradiation of the C4-Me group produces an 8.0% nOe effect on
the H-C1Ј position, which suggests a C1Ј (R) configuration. Other
significant nOe effects that further confirm this configuration are
observed between the tBu group of the SO moiety and the NH
(12%) group and the C3-H (8%) proton; furthermore, irradiation
of H1 centered at δ = 4.61 ppm produces a 3.0% nOe effect on H2
(δ =3.23 ppm).
(SS,2S,4R,1ЈS)-14: Reaction between (2S)-8 and (SS)-4 afforded
compound 14 as a sticky oil, which crystallized upon standing, in
82% isolated yield. [α]2D0 = +32.0 (c = 0.8, CHCl3). 1H NMR
(400 MHz, CD3COCD3, 50 °C): δ = 6.03 (dq, J = 6.0 Hz, J =
10.5 Hz, J = 17.2 Hz, 1 H, CH=CH2), 5.71 (s, 1 H, C2 H), 5.43 (d,
J = 17.2 Hz, 1 H, CH=CH2), 5.30 (d, J = 10.5 Hz, 1 H, CH=CH2),
4.78 (m, 1 H, O-CH2), 4.76 (m, 1 H, O-CH2), 4.80–4.60 (br., 1 H,
NH), 4.20–4.0 (br., 1 H, C1Ј-H), 1.85 (s, 3 H, Me), 1.75–1.64 (m,
1 H, CHMe2), 1.27 (s, 9 H, tBu-S), 1.02 (s, 9 H, tBu-C2), 0.90 (d,
J = 6.5 Hz, 3 H, Me), 0.77 (d, J = 6.5 Hz, 3 H, Me) ppm. 1H NMR
(400 MHz, CDCl3, relevant resonances): δ = 1.86 (s, 3 H, Me), 0.99
(s, 9 H, tBu-C2) ppm. 13C NMR (100 MHz, CD3COCD3, 50 °C):
δ = 175.3, 156.0–154.0 (br.), 132.5, 118.6, 95.6, 66.6, 63–62 (br.),
(RS,2S,4R,1ЈR)-16: Reaction between (2S)-8 and (RS)-5 afforded
compound 16, which was separated by silica-gel flash column
chromatography (cyclohexane/CH2Cl2/Et2O, 6:3:1). Yield: 63%,
62.8, 56.8, 38.4, 28.5, 25.1, 22.7, 22.1, 14.5 ppm. IR (neat): ν =
˜
2960, 1781, 1725, 1390, 1336 cm–1. C20H36N2O5S (416.57): calcd.
C 57.66, H 8.71, N 6.72; found C 57.52, H 8.80, N 6.79.
1
Ͼ96% de (still contaminated by impurities). H NMR (400 MHz,
CDCl3, 55 °C): δ = 7.40–7.20 (m, 20 H, arom.), 5.43 (s, 1 H,
tBuCH), 5.60–5.20 (br., 1 H, CH=CH2), 5.10–4.90 (m, 5 H), 4.82–
4.75 (m, 2 H), 4.66–4.58 (m, 3 H), 4.50–4.40 (m, 3 H), 4.10 (t, J =
9.2 Hz, 1 H), 3.82 (dd, J = 2.8 Hz, J = 11.2 Hz, 1 H), 3.78 (t, J =
9.6 Hz, 1 H), 3.72–3.60 (m, 3 H), 3.36 (d, J = 9.2 Hz, 1 H, H6),
3.12 (d, J = 9.6 Hz, 1 H, H2), 1.74 (s, 3 H, Me), 1.29 (s, 9 H, tBu-
S), 0.96 (s, 9 H, tBu-CH) ppm. 13C NMR (100 MHz, CDCl3, 58 °C,
relevant resonances): δ = 172.6, 139.6, 138.9, 138.8, 138.70, 132.3,
128.4–127.3 (arom.), 117.5 (b), 94.9, 88.3, 79.8, 77.9, 77.4, 76.3,
76.1, 75.2, 75.1, 74.6, 74.0, 68.6, 66.6, 60.2, 57.5, 38.9, 25.6, 23.2,
General Procedure for the Addition of Sugar Aldimines to Enolates
cis- and trans-8: To a solution of LHMDS (5.5 equiv.; 1  in THF)
in THF (15 mL), cooled to –78 °C, was dropwise added a solution
of oxazolidin-5-one (5.5 equiv.) in THF (3.0 mL). After 20 min, the
reaction mixture was further cooled to –85 to –90 °C and a solution
of THF/HMPA (2 mL of THF and 3 mL of HMPA) was added
dropwise. The selected sulfinamide (0.23 mmol, 1 equiv.) in THF
(4.0 mL) was then added to the reaction mixture by a syringe pump
(addition rate: 1.5 mL/h) keeping the temperature below –75 °C
(not lower than –80 °C). Once the addition was over, the tempera-
ture was raised to –60 °C in 1 h and 0.2  HCl was added. The
solution was brought to room temperature, and the organic phase
was extracted with EtOAc (2ϫ). The organic layer was than washed
with 0.2  HCl (2ϫ) and saturated NH4Cl (1ϫ) and then dried
with Na2SO4. Filtration of the salt and solvent removal afforded
the crude material, which was purified by flash column chromatog-
raphy.
22.8 ppm. IR (neat): ν = 1778, 1716, 1454, 1334 cm–1. HRMS:
˜
calcd. for C51H64N2O10S [M]+ 896.4282; found 896.4294.
(3R,7S,7aS)-17: Reaction between (2R)-8 and (RS)-5 afforded com-
pound 17 as a white solid, along with trace amounts (5%) of the
opened compound. The mixture was separated by silica-gel flash
column chromatography (cyclohexane/CH2Cl2/Et2O, 6:3:1). Over-
all yield: 79%, 90% de. [α]2D0 = –90.0 (c = 1.0, CHCl3). M.p. 83–
3840
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3834–3844

α2,2,β3-Diamino Acids by a Stereodifferentiation Aldol Addition Reactions
85 °C. 1H NMR (400 MHz, CD3COCD3): δ = 7.22–7.42 (m, 20 H,
arom.), 6.63 (br., 1 H, NH), 5.09 (s, 1 H, C3H), 4.96 (d, J = 11.0 Hz,
1 H, OCH2), 4.94 (d, J = 11.0 Hz, 1 H, OCH2), 4.89 (d, J =
11.0 Hz, 1 H, OCH2), 4.81 (d, J = 11.0 Hz, 1 H, OCH2), 4.78 (d,
J = 11.0 Hz, 1 H, OCH2), 4.68 (d, J = 11.0 Hz, 1 H, OCH2), 4.63
(d, J = 12.5 Hz, 1 H, OCH2), 4.54 (d, J = 12.5 Hz, 1 H, OCH2),
3.85 (d, J = 1.5 Hz, 1 H, C7H), 3.81 (dd, J = 3.2 Hz, J = 11.6 Hz,
1 H, C3-CH2), 3.76–3.68 (m, 3 H, C4H + C5H + C6H), 3.62 (dd,
J = 2.0 Hz, J = 11.6 Hz, 1 H, C3-CH2), 3.56–3.52 (m, 1 H, C2H),
3.29 (m, J = 3.2 Hz, J = 2.0 Hz, J = 9.5 Hz, 1 H, C3H), 1.58 (s, 3
H, Me), 0.93 (s, 9 H, tBu-C3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 174.0, 164.4, 138.7 (C arom.), 138.5 (C arom.), 138.4 (C arom.),
General Procedure for Nitrogen Sulfinyl Deprotection and Cycliza-
137.8 (C arom.), 129.1 (2 CH), 129.0 (2 CH), 128.9 (CH), 128.7 (2
CH), 128.6 (2 CH), 128.5 (2 CH), 128.0 (2 CH), 127.9 (2 CH),
127.8 (2 CH), 127.7 (CH), 127.6 (2 CH), 97.8, 87.6, 78.7, 78.1, 75.7,
75.6, 75.0, 74.8, 74.4, 73.4, 67.8, 63.8, 62.0, 35.7, 26.5, 24.7 ppm. IR
tion of the Corresponding Free Amines 19–21: Unless otherwise
stated, a MeOH solution of the 1Ј-(sulfinylamino)oxazolidinone
(2 mL per 0.03 g of dioxolanone) was added to an ethereal 2  HCl
solution (16 equiv.) under a nitrogen atmosphere at 0 °C. After
30 min, the temperature was raised to 25 °C, and the mixture was
stirred for 2 h. The solvent was removed under vacuum, and the
residue was treated with a 10% aqueous solution of NaHCO3, di-
luted with H2O, and extracted with ethyl acetate (3ϫ). The organic
phase was dried with Na2SO4 and concentrated under vacuum. The
residue was placed in a 50-mL two-necked round-bottom flask,
equipped with a nitrogen inlet, an injection septum, and a magnetic
stirring bar, and diluted with freshly distilled THF (1.0 mL per
0.03 g of starting material). The reaction mixture was cooled to
–30 °C, and a solution of LHMDS (4 equiv.; 1  in THF) and
HMPA (4 equiv.) was added dropwise. The reaction mixture was
warmed to –5 °C over 3 h and then quenched with 1.0  HCl. The
bicyclic compounds were isolated according to the following stan-
dard procedure: the reaction mixture was extracted with ethyl ace-
tate (3ϫ20 mL), and the collected organic phase was washed with
saturated NH4Cl and then dried with Na2SO4. After filtration, the
solvent was removed under vacuum, and the residue was purified
by flash column chromatography (Table 2).
(neat): ν = 3030, 2871, 1784, 1719, 1249, 1096 cm–1. C H N O
˜
44 50
2
8
(734.88): calcd. C 71.91, H 6.86, N 3.81; found C 71.83, H 6.90, N
3.87. The stereochemistry of 17 was determined by n.O.e. experi-
ments. In detail, irradiation of C7-H (3.85 ppm) produced a 3%
n.O.e. effect on the C7a methyl group (δ =1.58 ppm). Irradiation
of the tBu group (δ =0.93 ppm) furnished a 2.5% n.O.e. effect on
the C7a methyl group and a 25% effect on C3-H. Relevant reso-
nances for the opened compound: 1H NMR (400 MHz, CD3Cl3,
55 °C): δ = 0.98 (s, 9 H, tBu), 1.18 (s, 9 H, tBu), 1.77 (s, 3 H, Me),
3.45 (m, 1 H), 3.99 (m, 1 H), 5.45 (br. s, 1 H) ppm.
(SS,2S,4R,1ЈR)-18: Reaction between (2S)-8 and (SS)-6 afforded
compound 18, which was purified by silica-gel flash column
chromatography (cyclohexane/ethyl acetate, 7:3) to obtain a sticky
oil. Overall yield: 89%, Ͼ96% de. [α]2D0 = +24.0 (c = 0.5, CHCl3).
1H NMR (400 MHz, C6D6, 75 °C): δ = 8.75 (br., 1 H, NH-CO,
(2S,4R,1ЈS)-19 and (3S,7S,7aR)-22: Reaction of 12 (0.2 g,
0.46 mmol) with 2.0  HCl (3.7 mL) afforded 19 (0.13 g,
0.42 mmol, 90%). Treatment of 19 (crude compound) with
LHMDS (1  in THF, 1.7 mL) afforded, after silica-gel flash
H8Ј), 7.68 (br., 1 H, HC=CH-C=O, H6Ј), 6.10 (br., 1 H, H5Ј), chromatography (cyclohexane/ethyl acetate, 5:1), 22 (0.096 g,
5.80–5.64 (m, 1 H, CH=CH2, H12Ј), 5.62 (m, 1 H, NH, H9Ј), 5.60– 0.35 mmol, 80%) as a white solid. Data for 19: 1H NMR
5.45 (m, 1 H, HC=CH-C=O, H7Ј), 5.49 (s, 1 H, CHtBu, H10Ј), (400 MHz, CDCl3): δ = 5.93 (dq, J = 6.2 Hz, J = 10.8 Hz, J =
5.10 (d, J = 17.2 Hz, 1 H, CH=CH2, H13Ј), 5.00 (d, J = 10.4 Hz,
1 H, CH=CH2, H13Ј), 4.72 (t, J = 5.6 Hz, 1 H, H3Ј), 4.47 (t, J =
17.6 Hz, 1 H, CH=CH2), 5.52 (s, 1 H, C2 H), 5.34 (dd, J = 1.2 Hz,
J = 17.6 Hz, 1 H, CH=CH2), 5.27 (dd, J = 1.2 Hz, J = 10.8 Hz, 1
4.8 Hz, 1 H, H4Ј), 4.30–4.15 (m, 3 H, 2 H, OCH2CH=CH2 + H2Ј), H, CH=CH2), 4.78–4.64 (m, 1 H, O-CH2), 4.80 (m, 1 H, O-CH2),
4.20 (d, J = 10.0 Hz, 1 H, CH-NH), 1.69 (s, 3 H, Me), 1.12 (s, 9
H, tBuS), 1.02 (s, 9 H, tBuSi), 0.94 (s, 9 H, tBuSi), 0.75 (s, 9 H,
tBuCH), 0.37 (s, 3 H, Me), 0.19 (s, 3 H, Me), 0.15 (s, 3 H, Me),
0.14 (s, 3 H, Me) ppm. 13C NMR (100 MHz, C6D6, 58 °C, relevant
resonances): δ = 173.0, 162.1, 154.7, 150.4, 142.0, 131.8, 118.9,
3.80–3.40 (br., 1 H, C1Ј-H), 1.80–1.60 (m, 1 H, CHMe2), 1.78 (s, 3
H, Me), 1.55–1.45 (br., 2 H, NH2), 1.00–0.85 (m, 2 H, CHCH2),
0.98 (s, 9 H, tBu-C2), 0.91 (d, J = 6.5 Hz, 3 H, Me), 0.80 (d, J =
6.5 Hz, 3 H, Me) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.2,
154.5, 132.0, 119.1, 95.1, 66.7, 65.9, 56.0–54.0 (br.), 41.5, 38.7, 29.9,
102.9, 94.8, 92.0, 84.5, 74.0, 72.9, 66.8, 66.6, 65.0, 57.3, 38.4, 26.1, 25.5, 25.0, 24.3, 21.2 ppm. IR (neat): ν = 2958, 1770, 1715, 1389,
˜
26.0, 25.5, 23.1, 21.6, 18.1 ppm. IR (neat): ν = 1798, 1702, 1698,
1339 cm–1. Data for 22: [α]2D0 = –32.0 (c = 0.5, CHCl3). M.p. 194–
˜
1463, 1389 cm–1. C37H66N4O10SSi2 (815.17): calcd. C 54.52, H 8.16, 196 °C. 1H NMR (400 MHz, CDCl3): δ = 5.26 (s, 1 H, C3-H),
N 6.87; found C 54.66, H 8.09, N 6.83. The stereochemistry of 18
was determined by n.O.e. experiments. In detail, irradiation of the
tBu-C2 group (δ =0.75 ppm) showed a 1.3% nOe effect on C4-Me
at δ = 1.69 ppm and 6.0% with H1, which thus suggests the (R)
stereoconfiguration for the C4 carbon atom. Selective irradiation
of C4-Me produced an 11% nOe effect on H1Ј, which suggests
an (1ЈR) conformation. Other significant nOe effects that further
confirm the restricted conformation of 18 were observed between
tBuS and CH-NH (1.0%), H7 (1.0%), and H6 (3%) and between
one of the methyl protons of Me2Si centered at δ = 0.37 ppm and
H3Ј (2.2%) and CH-NH (4.2%).
5.20–5.15 (br., 1 H, NH), 4.03 (dd, J = 4.5 Hz, J = 19.6 Hz, 1 H,
C7-H), 1.68–1.60 (m, 1 H, CHMe2), 1.60–1.48 (m, 2 H, CHCH2),
1.51 (s, 3 H, Me), 1.01 (s, 9 H, 3 Me), 0.99 (d, J = 6.5 Hz, 3 H,
Me), 0.93 (d, J = 6.5 Hz, 3 H, Me) ppm. 13C NMR (100 MHz,
CDCl3): δ = 175.6, 164.9, 99.5, 64.3, 58.7, 39.4, 36.0, 25.8, 25.0,
24.7, 21.5, 19.3 ppm. IR (neat): ν = 1785, 1716, 1240 cm–1.
˜
C14H24N2O3 (268.35): calcd. C 62.66, H 9.01, N 10.44; found C
62.61, H 9.07, N 10.50. The (7S,7aR) stereoconfiguration was as-
sessed by homonuclear nOe experiments. An nOe effect of 7.0%
was observed with the C7a-Me protons at δ = 1.51 ppm upon irra-
diation of the C3-tBu signal at δ = 1.01 ppm.
Eur. J. Org. Chem. 2008, 3834–3844
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3841

A. Guerrini, G. Varchi, C. Samorì, A. Battaglia
FULL PAPER
J = 12.5 Hz, 1 H, OCH2), 4.20 (br., 1 H, NH), 3.99 (d, J = 1.2 Hz,
1 H, C7H), 3.76 (t, J = 8.0 Hz, 1 H, C5H), 3.63 (d, J = 10.0 Hz, 1
H, C2-H), 3.54–3.40 (m, 3 H, C4-H + C2-H), 3.37 (dd, J = 1.2 Hz,
J = 9.0 Hz, 1 H, C2-H), 3.21 (dd, J = 8.0 Hz, J = 9.0 Hz, 1 H, C6-
H), 1.59 (s, 3 H, Me), 0.97 (s, 9 H, tBu-C3) ppm. 13C NMR
(100 MHz, CDCl3, relevant resonances): δ = 176.4, 165.3, 138.5,
138.4, 138.0, 137.1, 129.3, 129.2, 129.1, 128.8, 128.7, 128.6, 128.1,
128.0, 127.9, 127.7, 127.6, 101.9, 87.5, 79.4, 78.7, 75.9, 75.8, 75.7,
(2S,4R,1ЈS)-20 and (3S,7S,7aR)-23: Reaction of (SS,2S,4R,1ЈS)-14
(0.2 g, 0.48 mmol) with 2.0  HCl (3.84 mL) afforded 20 (0.13 g,
0.40 mmol, 85%). Treatment of 20 (crude compound) with
LHMDS (1  in THF, 1.63 mL) afforded, after silica-gel flash
chromatography (cyclohexane/Et2O, 3:1), 23 (0.04 g, 0.16 mmol,
75.3, 74.5, 73.6, 69.1, 64.5, 56.4, 35.5, 26.5, 25.5 ppm. IR (neat): ν
˜
= 3030, 2871, 1784, 1719, 1249, 1096 cm–1. C44H50N2O8 (734.88):
calcd. C 71.91, H 6.86, N 3.81; found C 71.86, H 6.91, N 3.88. The
(7aR,7R) stereoconfiguration was assessed by homonuclear nOe ex-
periments. Selective irradiation of the C2-tBu group at δ =
0.97 ppm produced a 2.1% n.O.e. effect on C7a-Me and a 25.5%
effect on C3-H. Irradiation of the C7a-Me (δ =1.58 ppm) protons
produced a 1.6% enhancement on the tBu group (δ =0.97 ppm)
and 3.5% on C2-H. Irradiation of C2-H induced a 4% n.O.e. effect
on C7a-Me, a 5.5% effect on C5-H, and an 8.8% effect on C7-H.
Irradiation of C7-H induced a 5.5% enhancement of the C2-H sig-
nal, and a 3.0% effect on the NH proton. No nOe effect was de-
tected on C7a-Me.
1
40%) as a white solid. Data for 20: H NMR (400 MHz, CDCl3):
δ = 5.93 (dq, J = 6.2 Hz, J = 10.8 Hz, J = 17.6 Hz, 1 H, CH=CH2),
5.52 (br. s, 1 H, C2H), 5.34 (dd, J = 1.2 Hz, J = 17.6 Hz, 1 H,
CH=CH2), 5.27 (dd, J = 1.2 Hz, J = 10.8 Hz, 1 H, CH=CH2),
4.78–4.64 (m, 1 H, O-CH2), 4.80 (m, 1 H, O-CH2), 3.80–3.40 (br.,
1 H, C1Ј-H), 1.78 (s, 3 H, Me), 1.55–1.45 (br., 2 H, NH2), 1.30 (br.
s, 1 H), 0.98 (s, 9 H, tBu-C2), 0.91 (d, J = 6.5 Hz, 3 H, Me), 0.80
(d, J = 6.5 Hz, 3 H, Me) ppm. 13C NMR (100 MHz, CDCl3): δ =
174.4, 154.5, 132.0, 119.9, 119.6, 95.1, 66.7, 65.9, 56.0–54.0 (br.),
41.5, 38.7, 29.9, 25.5, 25.0, 24.3, 21.2 ppm. IR (neat): ν = 1790,
˜
1715 cm–1. Data for 23: [α]2D0 = –21 (c = 0.3, CHCl3). M.p. 191–
193 °C. 1H NMR (400 MHz, CDCl3): δ = 5.27 (s, 1 H, C3-H),
4.72–4.68 (br., 1 H, NH), 3.55 (dd, J = 1.2 Hz, J = 9.5 Hz, 1 H,
C7-H), 2.10–1.96 (m, 1 H, CHMe2), 1.58 (s, 3 H, Me), 1.07 (d, J
= 5.0 Hz, 3 H, Me), 1.01 (s, 9 H, 3 Me), 0.98 (d, J = 5.0 Hz, 3 H,
Me) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.1, 166.6, 99.0,
67.2, 64.7, 36.0, 28.3, 25.0, 20.4, 20.1, 19.1 ppm. IR (neat): ν =
˜
1787, 1714, 1242 cm–1. C13H22N2O3 (254.32): calcd. C 61.39, H
8.72, N 11.01; found C 61.28, H 8.78, N 11.10. The (7aR,7S) ste-
reoconfiguration was assessed by homonuclear nOe experiments
(CDCl3). An nOe effect of 3.6% was observed on the CHMe2 sig-
nal at 2.10–1.96 ppm upon irradiation of the 7a-Me signal at δ =
1.58 ppm.
General Procedure for Nitrogen Alloc-Group Deprotection and Sub-
sequent Hydrolysis to the Corresponding Sulfinyl-Protected Amino
Acids 25–28: To a solution of 1Ј-(sulfinylamino)oxazolidinone
(1 equiv.) in CH2Cl2 (1.0 mL per equiv.) was added Ph3SiH
(6 equiv.) followed by Pd(PPh3)4 (10 mol-%). The reaction course
was monitored by TLC analysis, and after approximately 2 h, the
solvent was removed under vacuum and THF and water were
added (few drops each). The solution was left to stand at room
temperature for 3 h, dried, and the free amino acids were purified
by crystallization or column chromatography (Table 3).
(SS,2S,3S)-25: Reaction of (SS,2S,4R,1ЈS)-12 (0.08 g, 0.19 mmol)
with Ph3SiH (1.12 mmol) and Pd(PPh3)4 (0.019 mmol) in CH2Cl2
(0.2 mL) followed by treatment with water and THF afforded 25
(0.052 g, 98%) after crystallization (Et2O). [α]2D0 = +17.5 (c = 0.3,
(2S,4R,1ЈR)-21 and (3S,7R,7aR)-24: Reaction of (SS,2S,4R,1ЈR)-15
(0.2 g, 0.23 mmol) with 2.0  HCl (1.82 mL) afforded 21 (0.16 g,
0.20 mmol, 90%). Treatment of 21 (crude compound) with
LHMDS (1  in THF, 0.8 mL) afforded, after silica-gel flash
chromatography (cyclohexane/Et2O, 1:1), 24 (0.06 g, 40%) as a
1
MeOH). H NMR (400 MHz, CD3OD, 45 °C): δ = 3.36 (dd, J =
11.6 Hz, J = 11.6 Hz, 1 H, C1Ј-H), 1.85–1.76 (m, 1 H, CHMe2),
1.52 (s, 3 H, Me), 1.49–1.40 (m, 1 H of CH2), 1.38–1.29 (m, 1 H,
of CH2), 1.29 (s, 9 H, tBu-S), 0.93 (d, J = 6.5 Hz, 3 H, Me), 0.91
(d, J = 6.5 Hz, 3 H, Me) ppm. 13C NMR (100 MHz, CD3OD,
54 °C): δ = 173.7, 62.7, 60.4, 57.0, 40.8, 24.1, 23.0, 22.3, 20.4,
19.8 ppm. C12H26N2O3S (278.17): calcd. C 51.77, H 9.41, N 10.06;
found C 51.69, H 9.46, N 10.11.
1
sticky solid. Data for 21: H NMR (400 MHz, CDCl3, 53 °C): δ =
7.35–7.20 (m, 20 H, arom.), 5.90–5.50 (br., 1 H), 5.41 (s, 1 H),
5.20–5.05 (m, 2 H), 4.90–4.75 (m, 5 H), 4.75–4.60 (m, 5 H), 4.50
(d, J = 12.0 Hz, 1 H), 4.20–4.00 (br., 1 H), 3.90–3.75 (m, 3 H),
3.75–3.60 (m, 3 H), 3.35 (m, 1 H), 3.07 (d, J = 9.5 Hz, 1 H), 1.77
(s, 3 H, Me), 1.60–1.45 (br., 2 H, NH2), 0.97 (s, 9 H, tBu-CH) (SS,2R,3S)-26: Reaction of (SS,2S,4R,1ЈS)-14 (0.08 g, 0.19 mmol)
ppm. 13C NMR (100 MHz, CDCl3, 53 °C, relevant resonances): δ
with Ph3SiH (1.12 mmol) and Pd(PPh3)4 (0.019 mmol) in CH2Cl2
= 173.6, 139.1, 139.0, 138.9, 138.7, 132.3, 128.4–127.3 (arom.), (0.2 mL) followed by treatment with water and THF afforded 26
118.0 (br.), 94.6, 87.7, 80.3, 78.4, 77.8, 77.7, 75.5, 75.0, 74.8, 74.2,
(0.05 g, 98%) as a white solid after crystallization (EtOAc). [α]2D0
+25.5 (c = 0.5, H2O). M.p. 241–243 °C. 1H NMR (400 MHz,
=
68.8, 66.6, 63.0, 38.7, 29.8, 25.7 ppm. Data for 24: 1H NMR
(400 MHz, CDCl3): δ = 7.20–7.40 (m, 20 H, arom.), 5.20 (s, 1 H, CD3OD, 62 °C): δ = 4.54 (br. s, 3 H, NH2 + OH), 3.41 (dd, J =
C3H), 4.95 (d, J = 11.0 Hz, 1 H, OCH2), 4.90 (d, J = 11.0 Hz, 1 11.6 Hz, J = 2.4 Hz, 1 H, C1Ј-H), 1.85–1.76 (m, 1 H, CHMe2),
H,OCH2), 4.84 (d, J = 11.5 Hz, 1 H, OCH2), 4.80 (d, J = 11.0 Hz, 1.52 (s, 3 H, Me), 1.29 (s, 9 H, tBu-S), 0.96 (d, J = 6.5 Hz, 3 H,
1 H, OCH2), 4.63 (d, J = 11.5 Hz, 1 H, OCH2), 4.58 (d, J =
11.0 Hz, 1 H, OCH2), 4.55 (d, J = 12.5 Hz, 1 H, OCH2), 4.51 (d,
Me), 0.87 (d, J = 6.5 Hz, 3 H, Me) ppm. 13C NMR (100 MHz,
D2O, 40 °C): δ = 176.95, 66.38, 60.64, 57.90, 28.86, 23.97, 22.99,
3842
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3834–3844

α2,2,β3-Diamino Acids by a Stereodifferentiation Aldol Addition Reactions
21.58, 14.20 ppm. C11H24N2O3S (264.38): calcd. C 49.97, H 9.15,
N 10.60; found C 49.88, H 9.20, N 10.68.
58.8, 20.8 ppm. C10H16Cl2N2O2 (267.15): calcd. C 44.96, H 6.04,
N 10.49; found C 44.89, H 6.10, N 10.41.
(SS,2R,3R)-27: Reaction of (SS,2S,4R,1ЈR)-15 (0.08 g, 0.091 mmol)
with Ph3SiH (0.54 mmol) and Pd(PPh3)4 (0.009 mmol) in CH2Cl2
(0.1 mL) followed by treatment with water and THF afforded 27
(0.07 g, 98%) as a sticky solid after purification by silica-gel flash
column chromatography (CHCl3/MeOH, 8.5:1.5). [α]2D0 = +17.5 (c
= 0.5, acetone). 1H NMR (400 MHz, CD3COCD3, 51 °C): δ =
7.36–7.27 (m, 20 H, arom.), 5.17 (d, J = 9.2 Hz, 1 H, NH), 4.97
(d, J = 11.2 Hz, 2 H), 4.89–4.84 (m, 2 H), 4.78–4.69 (m, 3 H), 4.57
(d, J = 12.5 Hz, 1 H), 4.12 (d, J = 9.0 Hz, 1 H), 3.86 (dd, J =
3.9 Hz, J = 11.2 Hz, 1 H), 3.79 (t, J = 8.8 Hz, 1 H), 3.74 (dd, J =
1.5 Hz, J = 11.5 Hz, 1 H), 3.72–3.60 (m, 3 H), 3.54–3.49 (m, 1 H,
O-CH-CH2-O), 1.60 (s, 3 H, Me), 1.31–1.23 (br., 9 H, tBu-CH)
ppm. 13C NMR (100 MHz, CD3COCD3, 51 °C): δ = 176.9, 139.4,
139.3, 139.1 (2 C), 128.4–127.3 (12 CH), 87.5, 79.0, 78.7, 77.9, 76.6,
75.1, 74.6, 74.4, 73.6, 69.1, 62.0, 61.2, 56.8, 25.6, 22.9 ppm.
C42H52N2O8S (744.94): calcd. C 67.72, H 7.04, N 3.76; found C
67.83, H 6.99, N 3.71.
Supporting Information (see footnote on the first page of this arti-
1
cle): Selected H and 13C NMR spectra.
[1] a) J. Tamariz, Enantioselective Synthesis of β-Amino Acids (Ed.:
E. Juaristi), Wiley, New York, 1997, p. 45; b) A. Viso, R.
Fernández de la Pradilla, A. Ana García, A. Flores, Chem. Rev.
2005, 105, 3167–3196.
[2] a) J. K. Kretsinger, J. P. Schneider, J. Am. Chem. Soc. 2003,
125, 7907–7913; b) J. P. Schneider, J. D. Lear, W. F. DeGrado,
J. Am. Chem. Soc. 1997, 119, 5742–5743.
[3] a) D. Seebach, A. Studer, E. Pfammatter, H. Widmer, Helv.
Chim. Acta 1994, 77, 2035–2050; b) D. Obrecht, H. Karaji-
annis, C. Lehmann, P. Schönholzer, C. Spiegler, K. Müller,
Helv. Chim. Acta 1995, 78, 703–714.
[4] a) M. Schnabelrauch, S. Wittmann, K. Rahn, U. Möllmann,
R. Reissbrodt, L. Heinisch, Biometals 2000, 13, 333–348; b) B.
Geisser, R. Alsfasser, Eur. J. Inorg. Chem. 1998, 957–963; c)
E. A. Enyedy, H. Csoka, L. Lázár, G. Micera, E. Garriba, E.
Farkas, J. Chem. Soc., Dalton Trans. 2002, 2632.
(SS,2R,3R)-28: Reaction of (SS,2S,4R,1ЈR)-18 (0.08 g, 0.09 mmol)
with Ph3SiH (0.59 mmol) and Pd(PPh3)4 (0.01 mmol) in CH2Cl2
(0.1 mL) followed by treatment with water and THF afforded 28
(0.64 g, 98%) as a white solid after after crystallization (CH3CN/
Et2O, 1:4). [α]2D0 = –31.0 (c = 0.4, THF). 1H NMR (400 MHz,
CD3COCD3, 53 °C): δ = 7.65 (d, J = 7.2 Hz, 1 H, HC=CH-C=O),
5.68 (d, J = 8.0 Hz, 1 H, H5Ј), 5.56 (m, J = 10.0 Hz, 1 H, NHSO),
5.47 (m, J = 7.2 Hz, 1 H, HC=CH-C=O), 4.88 (m, 1 H), 4.64 (m,
1 H), 4.41 (m, 1 H), 3.51 (dd, J = 10.0 Hz, J = 1.5 Hz, 1 H, CH-
NH), 1.44 (s, 3 H, Me), 1.342 (s, 9 H, tBuS), 0.96 (s, 9 H, tBuSi),
0.90 (s, 9 H, tBuSi), 0.21 (s, 3 H, Me), 0.17 (s, 3 H, Me), 0.14 (s,
3 H, Me), 0.04 (s, 3 H, Me) ppm. 13C NMR (100 MHz, 58 °C,
CD3COCD3): δ = 177.1, 162.2, 151.1, 145.2, 102.6, 95.9, 87.0, 74.0,
71.1, 66.6, 63.4, 57.4, 25.7, 25.6, 25.2, 23.1, 17.9, 17.7, –4.6, –4.7
(2 C), –5.6 ppm. C28H54N4O8SSi2 (662.99): calcd. C 50.72, H 8.21,
N 8.45; found C 50.81, H 8.17, N 8.41.
[5] For a summary review of the existing literature, see ref.[1b] For
selected references, see: a) K. R. Knudsen, T. Risgaard, N. Ni-
shiwaki, K. V. Gothelf, K. A. Jørgensen, J. Am. Chem. Soc.
2001, 123, 5843–5844; b) A. J. Robinson, C. Y. Lim, L. He, P.
Ma, H.-Y. Li, J. Org. Chem. 2001, 66, 4141–4147; c) J. Kobaya-
shi, Y. Yamashita, S. Kobayashi, Chem. Lett. 2005, 34, 268–
269; d) P. Merino, A. Lanaspa, F. L. Merchan, T. Tejero, Tetra-
hedron: Asymmetry 1998, 9, 629–646.
[6] a) B. Alcaide, P. Almendros, Chem. Soc. Rev. 2001, 30, 226–
240; b) C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide,
Curr. Med. Chem. 2004, 11, 1837–1872; c) P. J. Colson, L. S.
Hegedus, J. Org. Chem. 1993, 58, 5918–5924.
[7] For selected references, see: a) V. A. Soloshonok, D. V. Avilov,
V. P. Kukhar, L. V. Meervelt, N. Mischenko, Tetrahedron Lett.
1997, 38, 4671–4674; b) L. Bernardi, A. S. Gothelf, R. G. Haz-
ell, K. A. Jørgensen, J. Org. Chem. 2003, 68, 2583–2591; c)
M. E. Bunnage, A. J. Burke, S. G. Davies, N. L. Millican, R. L.
Nicholson, P. M. Roberts, A. D. Smith, Org. Biomol. Chem.
2003, 1, 3708–3715; d) H. Han, J. Juyoung Yoon, K. D. Janda,
J. Org. Chem. 1998, 63, 2045–2048; e) C. Palomo, M. Oiarbide,
A. Aitor Landa, M. C. González-Rego, M. J. Garcìa, A.
Gonzàlez, J. M. Odriozola, M. Martìn-Pastor, A. Linden, J.
Am. Chem. Soc. 2002, 124, 8637–8643; f) A. J. Robinson, C. Y.
Lim, L. He, P. Ma, H.-Y. Li, J. Org. Chem. 2001, 66, 4141–
4147; g) S. Rojas-Lima, O. Téllez-Zenteno, H. López-Ruiz, L.
Loubet-González, A. Alvarez-Hernandez, Heterocycles 2005,
65, 59–75.
[8] For reviews on sulfinamides, see: a) P. Zhou, B.-C. Chen, F. A.
Davis, Tetrahedron 2004, 60, 8003–8030; b) J. A. Ellman, T. D.
Owens, T. P. Tang, Acc. Chem. Res. 2002, 35, 984–995. See also:
c) D. J. Weix, J. A. Ellman, Org. Lett. 2003, 5, 1317–1320; d)
J. A. Ellman, Pure Appl. Chem. 2003, 75, 39–46; e) T. P. Tang,
J. A. Ellman, J. Org. Chem. 2002, 67, 7819–7832; f) G. Borg,
M. Chino, J. A. Ellman, Tetrahedron Lett. 2001, 42, 1433–1436;
g) H. M. Peltier, J. P. McMahon, A. W. Patterson, J. A. Ellman,
J. Am. Chem. Soc. 2006, 128, 16018–16019.
(2R,3R)-29: (3S,7R,7aR)-9 (100 mg, 0.35 mmol) was heated at re-
flux for 2 h in 6  HCl (2 mL). Upon crystallization (MeOH/Et2O,
2:1), 29 was isolated from the reaction mixture in quantitative yield
as a solid. Data for (2R,3R)-29·2HCl: [α]2D0 = +22.0 (c = 0.5,
MeOH). 1H NMR (400 MHz, CD3OD): δ = 7.60–7.50 (br., 5 H,
ArH), 4.98 (s, 1 H, C3-H), 1.74 (s, 3 H, CH3) ppm. 13C NMR
(100 MHz, CD3OD): δ = 170.4, 130.7, 130.6, 129.8, 129.5, 60.9,
57.9, 17.7 ppm. C10H16Cl2N2O2 (267.15): calcd. C 44.96, H 6.04,
N 10.49; found C 44.88, H 6.09, N 10.53.
(2R,3S)-30: (3S,7S,7aR)-10 (100 mg, 0.34 mmol) was heated at re-
flux for 2 h in 6  HCl (2 mL). Upon crystallization (MeOH/Et2O,
2:1), 30 was isolated from the reaction mixture in quantitative yield
as a solid. Data for (2R,3S)-30·2HCl: [α]2D0 = +29.0 (c = 0.5,
1
MeOH). H NMR (400 MHz, CD3OD): δ = 7.71 (d, J = 7.1 Hz, 1
H, ArH), 7.57–7.59 (m, 1 H, ArH), 7.21–7.24 (m, 1 H, ArH), 5.39
(s, 1 H), 1.81 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CD3OD):
δ = 169.80, 130.96, 130.50, 128.98, 128.12, 61.04, 53.73, 17.82 ppm.
C8H14Cl2N2O2S (273.18): calcd. C 35.17, H 5.17, N 10.25; found
C 35.11, H 5.15, N 10.22.
[9] a) F. A. Davis, J. Deng, Org. Lett. 2004, 6, 2789–2792; b) F. A.
Davis, J. Deng, Org. Lett. 2005, 7, 621–623; c) F. A. Davis, Y. F.
Zhang, H. Qiu, Org. Lett. 2007, 9, 833–836; d) B.-F. Li, K.
Yuan, M.-J. Zhang, H. Wu, L.-X. Dai, Q. R. Wang, X.-L. Hou,
J. Org. Chem. 2003, 68, 6264–6267; e) A. Viso, R.
Fernández de la Pradilla, A. García, C. Guerrero-Strachan, M.
Alonso, A. Flores, M. Martínez-Ripoll, I. Fonseca, I. André,
A. Rodríguez, Chem. Eur. J. 2003, 9, 2867–2876; f) A. Viso,
R. Fernández de la Pradilla, A. Flores, A. García, Tetrahedron
2007, 63, 8017–8026; g) A. Viso, R. Fernández de la Pradilla,
M. L. López-Rodríguez, A. García, A. Flores, M. Alonso, J.
Org. Chem. 2004, 69, 1542–1547.
(2R,3S)-31: (SS,2S,4R,1ЈR)-11 (100 mg, 0.23 mmol) was heated at
reflux for 2 h in 6  HCl (2 mL). Upon crystallization (MeOH/
Et2O, 2:1), 31 was isolated from the reaction mixture in quantitative
yield as a solid, slightly contaminated by impurities. Data for
1
(2R,3S)-31·2HCl: H NMR (400 MHz, CD3OD): δ = 7.55 (br. s, 5
H, ArH), 4.85 (s, 1 H, C3-H), 1.91 (s, 3 H, CH3) ppm. 13C NMR
(100 MHz, CD3OD): δ = 169.9, 130.9, 130.7, 129.9, 128.4, 60.8,
Eur. J. Org. Chem. 2008, 3834–3844
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3843

A. Guerrini, G. Varchi, C. Samorì, A. Battaglia
FULL PAPER
[10] M. Goodman, S. Ro, Burger’s Medicinal Chemistry and Drug
Discovery, 5th ed. (Ed.: M. Wolff), Wiley and Sons, New York,
1995, pp. 803–861.
[11] a) E. Castellanos, G. Reyes-Rangel, E. Juaristi, Helv. Chim.
Acta 2004, 87, 1016–1034; b) K. Upender, U. K. Nadir, R. V.
Krishna, A. Singh, Tetrahedron Lett. 2005, 46, 479–482; c) P.-
J. Colson, L. S. Hegedus, J. Org. Chem. 1993, 58, 5918–5924;
d) R. Badorrey, C. Cativiela, M. D. Diaz-de-Villegas, J. A.
Gálvez, Tetrahedron: Asymmetry 1995, 6, 2787–2796; e) W.
Hartwig, J. Mittendorf, Synthesis 1991, 939–941.
[12] I. Ojima, Acc. Chem. Res. 1995, 28, 383–389.
[13] D. Seebach, A. R. Sting, M. Hoffmann, Angew. Chem. Int. Ed.
Engl. 1996, 35, 2708–2748.
[14] D. Seebach, A. Fadel, Helv. Chim. Acta 1985, 68, 1243–1250.
[15] The reaction of lithium enolate (R)-8 (1.0 equiv.) and N-(tert-
butoxycarbonyl)benzenemethanimine (1.5 equiv.) obtained in
situ from the corresponding carbamoyl sulfone at –80 °C in
THF/HMPA (85:15) yielded an inseparable 2.8:1 mixture of
two compounds whose structures have not yet been clarified.
A. Battaglia, unpublished results.
Guerrini, G. Varchi, D. Rizzo, C. Samorì, A. Battaglia, Tetra-
hedron 2007, 63, 7949–7969; c) A. Guerrini, G. Varchi, C.
Samorì, D. Rizzo, A. Battaglia, Tetrahedron Lett. 2007, 48,
5081–5085.
A. Dondoni, A. Marra, Chem. Rev. 2000, 100, 4395–4422.
A. B. Smith III, A. Pasternak, A. Yokoyama, R. Hirschmann,
[17]
[18]
Tetrahedron Lett. 1994, 35, 8977–8990.
[19]
A. B. Smith III, R. Hirschmann, A. Pasternak, M. C. Guzman,
A. Yokoyama, P. A. Sprengeler, P. L. Darke, E. A. Emini, W. A.
Schleif, J. Am. Chem. Soc. 1995, 117, 11113–11123.
[20]
L. B. Schenkel, J. A. Ellman, Org. Lett. 2004, 6, 3621–3624.
[21] This approach is probably preferred to avoid any repulsion of
the (R)-configured anomeric hydrogen atom of the rigid sugar
moiety with the methyl substituent of the enolate. In this ap-
proach, this hydrogen points towards the plane of the enolate.
[22] S. Knapp, Chem. Rev. 1995, 95, 1859–1876.
[23] a) A. G. M. Barret, S. Lebold, J. Org. Chem. 1990, 55, 3853–
3857; b) P. Bhaket, C. S. Stauffer, A. Datta, J. Org. Chem. 2004,
69, 8594–8601.
Received: April 7, 2008
Published Online: June 25, 2008
[16] For recent applications of our protocol, see: a) A. Guerrini, G.
Varchi, A. Battaglia, J. Org. Chem. 2006, 71, 6785–6795; b) A.
3844
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3834–3844