Asymmetric synthesis of chloroisothreonine derivatives via syn-stereoselective Mannich-type additions across N-sulfinyl-α- chloroimines

Article abstract of DOI:10.1039/c4ob00243a

Mannich-type reactions of O-Boc glycolic esters across chiral N-sulfinyl-α-chloroaldimines resulted in the efficient and syn-stereoselective synthesis of new γ-chloro-α-hydroxy-β-amino esters (dr > 99 : 1). The α-coordinating ability of the chlorine atom

Full text of DOI:10.1039/c4ob00243a

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Asymmetric synthesis of chloroisothreonine
derivatives via syn-stereoselective Mannich-type
additions across N-sulfinyl-α-chloroimines†
Cite this: Org. Biomol. Chem., 2014,
12, 3393
Gert Callebaut,‡a Filip Colpaert,§a Melinda Nonn,b Loránd Kiss,b Reijo Sillanpää,c
Karl W. Törnroos,d Ferenc Fülöp,b Norbert De Kimpea and Sven Mangelinckx*a
Mannich-type reactions of O-Boc glycolic esters across chiral N-sulfinyl-α-chloroaldimines resulted in
the efficient and syn-stereoselective synthesis of new γ-chloro-α-hydroxy-β-amino esters (dr > 99 : 1).
The α-coordinating ability of the chlorine atom was of great importance for the diastereoselectivity of the
Mannich-type reaction and overruled the chelation of the sulfinyl oxygen with the lithium ion of the
incoming E-enolate in the transition state model. These novel chloroisothreonine derivatives proved to be
excellent building blocks in asymmetric synthesis of novel syn-β,γ-aziridino-α-hydroxy esters and biologi-
cally relevant trans-oxazolidinone carboxylic esters.
Received 31st January 2014,
Accepted 17th March 2014
DOI: 10.1039/c4ob00243a
www.rsc.org/obc
Introduction
The enantioselective synthesis of β-amino acid derivatives, as
biologically active compounds, constituents of biologically
active natural products, chiral building blocks and monomers
aDepartment of Sustainable Organic Chemistry and Technology, Faculty of Bioscience
Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
E-mail: Sven.Mangelinckx@UGent.be; Fax: +32 (0)9 264 62 21;
Tel: +32 (0)9 264 59 51
Fig. 1 Biologically active compounds containing an α-hydroxy-β-amino
carboxylic acid unit.
bInstitute of Pharmaceutical Chemistry and Stereochemistry Research Group of the
Hungarian Academy of Sciences, H-6720, Szeged, Eötvös u. 6, Hungary
cDepartment of Chemistry, University of Jyväskylä, Fin-40351 Jyväskylä, Finland
dDepartment of Chemistry, University of Bergen, Allégt. 41, N-5007 Bergen, Norway
†Electronic supplementary information (ESI) available: General experimental
for the preparation of β-peptides, received a lot of attention
from organic chemists and biochemists.1 The incorporation of
conditions and copies of 1H NMR and 13C NMR spectra for ethyl (tert-butoxy- conformationally constrained α- and β-amino acids into bio-
carbonyloxy)acetate 3c, γ-chloro-α-hydroxy-β-amino esters (RS,2R,3R)-5 and
(SS,2S,3S)-5, N-tert-butanesulfinyl-β,γ-aziridino-α-hydroxy esters (RS,2R,2′S)-6, N-p-
logically active peptides gained great interest in the prepa-
ration of peptide-based drug molecules. In particular, much
toluenesulfinyl-β,γ-aziridino-α-hydroxy esters (SS,2S,2′R)-6,
O-deprotected
effort has been focused on synthetic methods towards
(RS,2R,3R)-γ-chloro-α-hydroxy-β-amino ester (RS,2R,3R)-7, N-deprotected esters
(2R,3R)-9, O,N-deprotected esters (2R,3R)-10 and oxazolidinones (4R,5R)-11.
α-hydroxy-β-amino carboxylic acid derivatives.2 This can be
Crystallographic data were collected at 123 K with a Nonius-Kappa CCD area explained by the fact that the α-hydroxy-β-amino carboxylic
detector diffractometer, using graphite-monochromatized Mo-Kα radiation (λ =
acid unit is present in a wide range of biologically active mole-
0.71073 Å). The structures were solved by direct methods by the use of the
cules, such as (−)-bestatin 1, which is an aminopeptidase
inhibitor,3 paclitaxel 2a and docetaxel 2b, both of which are
known for their anti-mitotic activity (Fig. 1).4 The α-hydroxy-
SHELXS-97 program and the full-matrix, least-squares refinements on F2 were
also performed using the SHELXL-97 program.26 The hydrogen atoms were
included at fixed distances with the fixed displacement parameters from their
host atoms. More details are presented in the Crystallographic Information β-amino carboxylic acid moiety is also present in the natural
product leuhistin, an inhibitor of aminopeptidase M.5
The synthesis of non-proteinogenic α-hydroxy-β-amino
acids, including norstatine, isoserine and isothreonine deriva-
Format (CIF) files for the X-ray crystal structure of compounds (SS,2S,3S)-5db,
(RS,2R,2′S)-6cc and (RS,2R,3R)-7ac. CCDC 977960–977962. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4ob00243a
‡Grant holder of the Agency for Innovation by Science and Technology in
tives, has attracted much attention, as these compounds give
access to new drug candidates and act as valuable biological
Flanders (IWT).
§Postdoctoral Fellow of the Research Foundation – Vlaanderen (FWO).
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probes. Norstatine and its analogues have been used in the
synthesis of peptide-based inhibitors of aspartyl proteases
Results and discussion
such as renin and HIV-1 protease.6 Halogenated analogues of According to the good results obtained in the diastereoselec-
these non-proteinogenic α-hydroxy-β-amino carboxylic acids tive synthesis of non-functionalized α-hydroxy-β-amino acid
are of great interest for the design of new protease inhibitors. derivatives,20c the addition of O-protected alkyl α-hydroxy-
Fluoroalkyl isoserine derivatives were synthesized via ring acetates 3 across N-sulfinyl-α-chloroimines 4 was investigated
opening of the corresponding cis-4-(fluoroalkyl)-3-hydroxy- (Scheme 1, Table 1) in view of providing access to γ-functiona-
azetidin-2-ones.7 The synthesis of γ-iodo-α-hydroxy-β-amino lized-α-hydroxy-β-amino acid building blocks, suitable for the
acid derivatives was also reported starting from aspartic acid synthesis of chloroisothreonine derivatives and functionalized
via a lactone intermediate.8 Nevertheless, γ-chloro-α-hydroxy- heterocyclic compounds. Therefore, the O-protected alkyl
β-amino acid derivatives are virtually unknown in the litera- α-hydroxyacetates 3,20c α-chloro N-tert-butanesulfinylaldimines
ture, with the exception of one racemic example of a γ-chloro- 4a–c,19f,g and α-chloro N-p-toluenesulfinylaldimines 4d–e14,17
γ,γ-difluoro-α-hydroxy-β-amino acid derivative.7 More recently, were synthesized via (modified) literature procedures.
in analogy with the synthesis of (3-fluoroalkyl)isoserinates,7
In the first step, O-Boc alkyl α-hydroxyacetates 3a–c were
our research group explored the use of 4-(chloroalkyl)-3-hydroxy- deprotonated using LiHMDS and subsequent addition of 0.20
azetidin-2-ones in the synthesis of chlorinated α-hydroxy- equivalents of (RS)-N-(tert-butanesulfinyl)-2-chloro-2,2-dimethyl-
β-amino acid derivatives.9 Unfortunately, the chlorinated acetaldimine (RS)-4a at −78 °C for 3 hours resulted in the
α-hydroxy-β-amino acid derivatives were only observed as inter- formation of Mannich-type addition products (RS)-5aa–ac in
mediates towards the corresponding ω-alkylaminopentenoates. good to excellent diastereomeric ratios (Scheme 1, Table 1,
Therefore, in an effort to synthesize regioisomeric derivatives entries 1–3). γ-Chloro-α-hydroxy-β-amino esters (RS,2R,3R)-5aa–
of the natural product 4-chloro-L-threonine, the present paper ac were isolated as single syn-diastereomers in high yields
deals with the asymmetric synthesis of γ-chloro-α-hydroxy- (75–88%) after purification via flash chromatography.
β-amino acid derivatives, i.e. chloroisothreonine derivatives,
Furthermore, to expand the scope, the use of N-(tert-butane-
via Mannich-type additions of O-Boc glycolic esters across sulfinyl)-α-chloroaldimines (RS)-4b–c was explored. Performing
enantiopure N-sulfinyl-α-chloroaldimines. 4-Chloro-L-threonine the Mannich-type addition with N-(tert-butanesulfinyl)-
is biologically active as a serine hydroxymethyltransferase 2-chloro-2,2-diethylacetaldimine (RS)-4b, the desired adducts
inhibitor,10 and as a herbicidal antimetabolite,11 and is also (RS)-5ba–bc were formed with excellent syn-diastereoselectivity
a constituent of naturally occurring syringomycins (antifungal (Table 1, entries 4–6). After purification via flash chromato-
compounds),12 and actinomycins (cytotoxic and antibacterial graphy, single syn-diastereomers of γ-chloro-α-hydroxy-β-amino
compounds).13
esters (RS)-5ba–bc were isolated, although in moderate yields
Generally, halogenated amino acid derivatives are biologi- (44–65%). These lower yields were obtained due to the con-
cally relevant compounds, which can also serve as very promis- comitant formation of the corresponding aziridines (RS)-6ba–bc,
ing building blocks in synthetic organic chemistry due to the resulting in a more tedious separation via flash chromato-
presence of leaving groups. Recently, our research group graphy. In the case of the Mannich-type adduct (RS)-5bb,
reported the stereoselective synthesis of γ-chloro α,β-diamino which was isolated in 44% yield, the corresponding aziridine
acid derivatives via Mannich-type additions of N-(diphenyl- (RS)-6bb was also isolated in 13% yield (Table 1, entry 5).
methylene)glycine esters across α-chloro-N-sulfinylimines,14
Surprisingly, when N-(tert-butanesulfinyl)-α-chloroaldimine
and α-chloro β-amino acid derivatives via Mannich-type reac- (RS)-4c was used in the Mannich-type addition with benzyl
tions of N-sulfinyl imidates with aromatic aldimines.15 Also ester 3a, formation of the desired Mannich-type adduct could
γ-chloro-α,β-diamino- and β,γ-aziridino-α-aminoacylpyrrolidines not be observed (Table 1, entry 7). The Mannich-type addition
and -piperidines, as potential dipeptidyl peptidase (DPP) of aldimine (RS)-4c with methyl and ethyl esters 3b–c occurred
inhibitors,16 were synthesized via stereoselective Mannich- with excellent syn-diastereoselectivity (Table 1, entries 8–9).
type additions of N-(diphenylmethylene)glycinamides across Nevertheless, the reaction time was limited to 1 hour, as
α-chloro-N-sulfinylimines.17
longer reaction times resulted in lower yields, due to the
Chiral N-sulfinylimines have already proven to be valuable instability of aldimine (RS)-4c. Single syn-diastereomers of
synthons for the preparation of a wide range of enantiopure chloroisothreonine derivatives (RS)-5cb–cc were isolated in
aliphatic and cyclic amines.18 In this study, α-chloro N-sulfinyl- moderate yield (42%) after purification via flash chromato-
aldimines were used as starting products as these imines are graphy (Table 1, entries 8–9).
known for their good reactivity and stereoselectivity by incor-
The high reactivity and syn-diastereoselectivity observed in
poration of chiral directing groups.19 In this context, addition the Mannich-type additions of Li-enolates derived from O-Boc
reactions across non-halogenated N-sulfinylimines were alkyl α-hydroxyacetates 3a–c across N-(tert-butanesulfinyl)-
already performed for the asymmetric synthesis of β-amino α-chloroaldimines (RS)-4 prompted the further investigation of
acid derivatives.20 In addition, nucleophilic additions across the Mannich-type additions across N-(p-toluenesulfinyl)-
α-chloroimines with different carbon and heteroatom nucleo- α-chloroaldimines (SS)-4d and (SS)-4e, which were reacted
philes have extensively been used in the past for the synthesis under similar conditions. Using (SS)-N-(p-toluenesulfinyl)-
of azaheterocyclic compounds.9,21
α-chloroaldimine (SS)-4d, the desired γ-chloro-α-hydroxy-
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Scheme 1 Synthesis of chloroisothreonine derivatives 5.
Table 1 Mannich-type addition reactions of α-hydroxyacetates 3 across (RS)-N-(tert-butanesulfinyl)-α-chloroaldimines 4a–c and (SS)-N-(p-toluene-
sulfinyl)-α-chloroaldimines 4d–e
Entry
R1
R2
X
4
Time (h)
syn/antia
Yield 5b (%)
1
2
3
4
5
6
7
8
Bn
Me
Et
Bn
Me
Et
Bn
Me
Et
Bn
Me
Et
Me
Me
Me
Et
Et
Et
H
H
H
Me
Me
Me
H
0.20
0.20
0.20
0.33
0.33
0.33
0.25
0.25
0.25
0.20
0.20
0.20
0.33
0.33
(RS)-4a
(RS)-4a
(RS)-4a
(RS)-4b
(RS)-4b
(RS)-4b
(RS)-4c
(RS)-4c
(RS)-4c
(SS)-4d
(SS)-4d
(SS)-4d
(SS)-4e
(SS)-4e
3
3
3
4
4
4
1–4
1
1
5
5
5
4
80/20
98/2
89/11
>99/1
>99/1
>99/1
—
>99/1
>99/1
95/5
87/13
82/18
—
(RS,2R,3R)-5aa (75)
(RS,2R,3R)-5ab (86)
(RS,2R,3R)-5ac (88)
(RS,2R,3R)-5ba (62)
(RS,2R,3R)-5bb (44)c
(RS,2R,3R)-5bc (65)
(RS,2R,3R)-5ca (−)
(RS,2R,3R)-5cb (42)
(RS,2R,3R)-5cc (42)
(SS,2S,3S)-5da (51)
(SS,2S,3S)-5db (83)
(SS,2S,3S)-5dc (75)
(SS,2S,3S)-5ea (−)
(SS,2S,3S)-5ec (35)
9
10
11
12
13
14
Bn
Et
H
4
>99/1
a Determined via 1H NMR analysis of the crude reaction mixture. b Isolated yield of a single diastereomer (dr > 99 : 1) after purification via flash
chromatography. c The corresponding aziridine 6bb was also formed and isolated in 13% yield.
β-amino esters (SS)-5da–dc were formed in good to excellent
diastereomeric ratios (Table 1, entries 10–12). Purification via
flash chromatography afforded the pure chloroisothreonine
derivatives (SS)-5da–dc as single syn-diastereomers in moderate
to high yields (51–83%).
When N-(p-toluenesulfinyl)-α-chloroaldimine (SS)-4e was
applied, again no formation of the desired adduct (SS)-5ea was
observed (Table 1, entry 13). Due to the high instability of ald-
imine (SS)-4e, the Mannich-type addition with ethyl ester 3c
afforded the desired γ-chloro-α-hydroxy-β-amino esters (SS)-5ec
in moderate yield, although with an excellent syn-diastereo-
Scheme 2 Synthesis of N-tert-butanesulfinyl-β,γ-aziridino-α-hydroxy
esters (RS,2R,2’S)-6.
selectivity (Table 1, entry 14).
The γ-chloro-α-hydroxy-β-sulfinylamino esters (RS,2R,3R)-5
and (SS,2S,3S)-5da–dc were subsequently cyclized to the corres-
ponding N-tert-butanesulfinyl-β,γ-aziridino-α-hydroxy esters
(RS,2R,2′S)-6 and N-p-toluenesulfinyl-β,γ-aziridino-α-hydroxy
esters (SS,2S,2′R)-6, respectively, upon treatment with K2CO3 in
acetone under reflux in good to excellent yields (47–96%)
and all with an excellent diastereoselectivity (dr > 99 : 1)
(Schemes 2 and 3).
Scheme 3 Synthesis of N-p-toluenesulfinyl-β,γ-aziridino-α-hydroxy
esters (SS,2S,2’R)-6.
In order to extend the potential applicability of the
synthesized (RS,2R,3R)-γ-chloro-α-hydroxy-β-amino esters
(RS,2R,3R)-5 as building blocks in biomedicinal chemistry, a
number of attempts were made to remove the protective (RS,2R,3R)-5bb were treated with trifluoroacetic acid (30% v/v)
groups of (RS,2R,3R)-5 under acidic conditions (Scheme 4). In in dichloromethane. After a basic workup with K2CO3, the
the first step, α-hydroxy-β-amino esters (RS,2R,3R)-5aa–ac and desired α-deprotected syn-γ-chloro-α-hydroxy-β-amino esters
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Scheme 4 Further transformations of chloroisothreonine derivatives (RS,2R,3R)-5 and synthesis of oxazolidinones (4R,5R)-11.
(RS,2R,3R)-7 were purified by crystallization in Et2O or by flash 0 °C to neutralize the trifluoroacetic acid salt (Scheme 4).
chromatography on silica gel (70–86% yield) (Scheme 4). Dropwise addition of triphosgene22 resulted in the formation
Hereby, a selective deprotection of the O-Boc-protecting group of the corresponding oxazolidinones (4R,5R)-11aa–ac in good
with TFA occurred in the presence of an N-tert-butanesulfinyl isolated yields (64–82%) (Scheme 4).
moiety. Moreover, the O-deprotected (RS,2R,3R)-γ-chloro-
α-hydroxy-β-amino ester (RS,2R,3R)-7ac was isolated as a crystal- synthesized
line product which allowed the implementation of X-ray dif- esters (RS)-5, based on 1H NMR analysis, it was observed
fraction analysis (vide infra). that the isolated major diastereomers were syn-adducts, by
Upon determination of the relative configuration of the
γ-chloro-α-hydroxy-β-N-tert-butanesulfinylamino
In the next step, the N-tert-butanesulfinyl group of the comparison of the characteristic vicinal coupling constants
O-deprotected chloroisothreonine derivatives (RS,2R,3R)-7aa (3JH2–H3,syn = 0–1.4 Hz), whereas the corresponding anti-
and 7ac was deprotected by reaction with a saturated HCl-solu- adducts have larger coupling constants (3JH2–H3,anti
>
tion in dioxane towards the N,O-deprotected γ-chloro- 2.5 Hz).20c Unfortunately, it was impossible to determine the
α-hydroxy-β-amino esters (RS,2R,3R)-8aa and 8ac (Scheme 4). absolute stereochemistry of these syn-adducts (RS)-5 by means
Unfortunately, intensive screening of different purification of an X-ray diffraction analysis as none of these compounds
techniques (crystallization, preparative TLC, acid–base extrac- were crystalline. Therefore, the corresponding (SS)-γ-chloro-
tion) in order to obtain the pure N,O-deprotected esters α-hydroxy-β-amino ester (SS)-5aa was synthesized by Mannich-
(RS,2R,3R)-8aa and 8ac in good yield was only partially success- type addition of the Li-enolate derived from the O-Boc benzyl
ful, affording 27–36% yield of (RS,2R,3R)-8aa and 8ac after α-hydroxyacetate 3a across (SS)-N-(tert-butanesulfinyl)-α-chloro-
crystallization in dichloromethane.
aldimine (SS)-4a under the same reaction conditions as
Alternatively, a selective deprotection of the N-tert-butane- described in Table 1 (Scheme 2). As the optical rotation of the
sulfinyl group of (RS,2R,3R)-γ-chloro-α-hydroxy-β-amino esters corresponding dehalogenated (SS,2R,3S)-α-hydroxy-β-amino
(RS,2R,3R)-5aa–ac was performed under mild acidic treatment ester (SS,2R,3S)-12aa is known from the literature,23 the reac-
with HCl in dioxane, leading to N-deprotected (2R,3R)- tion of compound (SS)-5aa with Bu3SnH and AIBN was
γ-chloro-α-hydroxy-β-amino esters (2R,3R)-9aa–ac in high yields attempted (Scheme 5). Unfortunately, this reaction failed to
(79–93%) (Scheme 4). In the next step, deprotection of the provide the desired dechlorinated compound (SS,2S,3R)-12aa,
O-Boc protective group of esters (2R,3R)-9aa–ac was realized by which would have allowed the determination of the absolute
stirring in dichloromethane/trifluoroacetic acid (30% v/v), stereochemistry of (SS)-5aa by comparison of the optical
resulting in the isolation of O,N-deprotected (2R,3R)-γ-chloro- rotation. Additionally, having both enantiomers (RS,2S,3R)-5aa
α-hydroxy-β-amino ester salts (2R,3R)-10aa–ac as pure products and (SS,2R,3S)-5aa in hand, an enantiomeric excess of >98%
in excellent yields (84–97% yield). In this way, a straight- for both enantiomers could be determined by chiral HPLC. In
forward route towards the enantioselective synthesis of the O,N- analogy with an enantiomeric excess of >98% for the commer-
deprotected chloroisothreonine derivatives (2R,3R)-10aa–ac cially available starting materials tert-butanesulfinamide and
starting from the esters (RS,2R,3R)-5 was developed (Scheme 4). p-toluenesulfinamide, an enantiomeric excess of >98% can be
Furthermore, additional reactions were performed in order concluded for all synthesized γ-chloro-α-hydroxy-β-amino acid
to synthesize oxazolidinones (4R,5R)-11. The N,O-deprotected derivatives 5.
ester salts (2R,3R)-10aa–ac were treated with N,N-diisopropyl-
However, the absolute stereochemistry of the chloro-
ethylamine (DIPEA) in dichloromethane for 15 minutes at isothreonine derivative (RS)-5ac was determined by means of
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Scheme 5 Synthesis of (SS)-γ-chloro-α-hydroxy-β-amino ester (SS,2S,3S)-5aa and an attempt for further dechlorination towards (SS,2S,3R)-12aa.
Fig. 2 X-ray crystal structure of (RS,2R,3R)-γ-chloro-α-hydroxy-
β-amino ester (RS,2R,3R)-7ac.
Scheme 6 Proposed transition state model for rationalization of the
enolate geometry of O-Boc alkyl α-hydroxyacetates 3.
rationalized on the basis of the enolate geometry of the anions
derived from the deprotonation of O-Boc alkyl α-hydroxy-
acetates 3. Enolates obtained via deprotonation of O-Boc alkyl
α-hydroxyacetates 3 with LiHMDS in THF were expected to
have the E-geometry (Scheme 6).20c,24 As commonly performed
in the assignment of enolate geometry, in contrast to the con-
ventional E/Z-nomenclature, the highest priority designation
was allocated to the O-metal group of the enolate substituents.
Fig. 3 X-ray crystal structure of N-tert-butanesulfinyl-β,γ-aziridino-
The stereoselective formation of the E-enolates has been
α-hydroxy ester (RS,2R,2’S)-6cc.
rationalized with the Ireland model,24 which showed that
deprotonation of O-Boc alkyl α-hydroxyacetates 3 with LiHMDS
X-ray diffraction analysis (Fig. 2) of the corresponding crystal-
line (RS,2R,3R)-O-deprotected derivative (RS,2R,3R)-7ac (vide
supra). The (RS,2R,3R)-stereochemistry of the synthesized (RS)-
γ-chloro-α-hydroxy-β-amino esters (RS)-5aa–ab was deduced
via the transition state TS-1A induced adverse steric
interactions of the axial TMS group and the O-Boc group. For
this reason, the deprotonation proceeded via the transition
state TS-1B and afforded the corresponding E-enolate
(Scheme 6).
3
from the vicinal coupling constant JH2–H3,syn = 1.0–1.3 Hz and
the 1H NMR chemical shift of H3 (4.01 ppm; CDCl3), which
were in the same range as for the (RS)-γ-chloro-α-hydroxy-
β-amino ester (RS)-5ac. Also a (RS,2R,3R)-stereochemistry could
be ascribed to 4,4-diethyl-substituted (RS)-γ-chloro-α-hydroxy-
β-amino esters (RS)-5ba–bc in analogy with their 4,4-dimethyl
substituted derivatives (RS)-5aa–ac.
The same absolute (RS,2R,3R)-stereochemistry was con-
firmed for chloroisothreonine derivatives (RS)-5cb–cc (R2 = H)
by means of an X-ray diffraction analysis of the corresponding
crystalline N-tert-butanesulfinyl-β,γ-aziridino-α-hydroxy ester
(RS,2R,2′S)-6cc (Fig. 3).
Reaction of the E-enolates of 3 via a six/four-membered
Li-chelated bicyclic chairlike transition state model TS-2A,
which was valid for Mannich-type additions across non-
functionalized N-sulfinyl imines,20c would have resulted in
the formation of (RS,2S,3S)-γ-chloro-α-hydroxy-β-amino esters
(RS,2S,3S)-5 (Scheme 7). However, this transition state model
TS-2A, which proceeded via a Si-face attack, lacked the impor-
tant chelation between the α-coordinating chlorine atom and
the lithium atom.
The formation of the (RS,2R,3R)-γ-chloro-α-hydroxy-β-amino
esters (RS,2R,3R)-5 can be explained by a six/six-membered
di-metal-chelated bicyclic chairlike transition state model
TS-2B,25 or by a six-membered Li-chelated cyclic chairlike
The stereochemical outcome of the Mannich-type reaction
across (RS)-N-(tert-butanesulfinyl)-α-chloroaldimine (RS)-4a was
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isothreonine derivative (SS)-5db by means of X-ray diffraction
analysis proved this assumption (Fig. 4). The (SS,2S,3S)-stereo-
chemistry of the other (SS)-γ-chloro-α-hydroxy-β-amino esters
(SS)-5da and (SS)-5dc was again confirmed by comparison
3
1
of the vicinal coupling constant JH2–H3 = 1.10 Hz and the H
NMR chemical shift of H3 (4.00 ppm), which were in the same
range as for the (SS)-γ-chloro-α-hydroxy-β-amino ester (SS)-5db.
The absolute (SS,2S,3S)-stereochemistry could be also
ascribed for (SS)-γ-chloro-α-hydroxy-β-amino esters (SS)-5eb–ec
(R2 = H) in analogy with the assigned stereochemistry of (RS)-
γ-chloro-α-hydroxy-β-amino esters (RS)-5cb–cc (R2 = H).
Conclusions
In conclusion, it was demonstrated that new (RS,2R,3R)- and
(SS,2S,3S)-N-sulfinyl-γ-chloro-α-hydroxy-β-amino esters were
synthesized in high yields and excellent diastereomeric ratios
(dr > 99 : 1) via stereoselective Mannich-type reactions of O-Boc
glycolic esters across chiral N-sulfinyl-α-chloroimines. In these
reactions, the influence of the imine on the Mannich-type
addition, i.e. N-(tert-butanesulfinyl)-α-chloroaldimines or N-(p-
toluenesulfinyl)-α-chloroaldimines, did not cause significant
differences in the obtained yields and diastereoselectivities.
Furthermore, the γ-chloro-α-hydroxy-β-amino esters, as
novel chloroisothreonine derivatives, proved to be versatile
building blocks in asymmetric synthesis of novel syn-β,γ-
aziridino-α-hydroxy esters and trans-alkyl oxazolidinone-5-
carboxylates.
Scheme 7 Proposed transition state model for the Mannich-type
addition reactions of O-Boc alkyl α-hydroxyacetates 3 across (RS)-N-
(tert-butanesulfinyl)-α-chloroaldimine (RS)-4a.
transition state model TS-2C both of which proceeded via a
Re-face attack of the E-enolate (Scheme 7).
In the transition state model TS-2B, the α-coordinating
ability of the chlorine atom overrides the chelation of the sulfi-
nyl oxygen with the lithium ion of the incoming E-enolate and
induced chelation of the sulfinyl oxygen with an extra Li-cation
to form a six/six-membered di-Li-chelated bicyclic chairlike
transition state model. In an alternative transition state model
TS-2C, the coordinating ability of the chlorine atom overrules
the chelation of the sulfinyl oxygen as well and an extra stabi-
lizing effect is attained by the fact that the N-sulfinyl imine
(RS)-4a in this transition state is present in the energetically
favoured s-cis configuration.18b
Experimental section
Synthesis of alkyl (tert-butoxycarbonyloxy)acetates 3
Benzyl and methyl (tert-butoxycarbonyloxy)acetates 3a–b were
synthesized according to the literature starting from the corres-
ponding benzyl and methyl α-hydroxyacetates.20c In a flame
dried round-bottomed 250 mL flask, ethyl α-hydroxyacetate
(1.0 equiv., 4.00 g, 38.42 mmol) was dissolved in acetonitrile
(150 mL). Subsequently, DMAP (0.1 equiv., 0.43 g, 3.84 mmol)
and Boc2O (3.0 equiv., 10.90 g, 49.95 mmol) were added and
the mixture was stirred for 18 hours at room temperature. The
reaction mixture was poured into brine (300 mL) and the
aqueous phase was extracted with diethyl ether (3 × 200 mL).
The combined organic phases were dried (MgSO4), filtered and
evaporated in vacuo to yield 7.68 g (37.65 mmol, 98%) of ethyl
(tert-butoxycarbonyloxy)acetate 3c. Ethyl (tert-butoxycarbonyl-
oxy)acetate 3c was stored with molecular sieves for further
use.
Concerning the γ-chloro-α-hydroxy-β-N-tert-butanesulfinyl-
amino esters (RS)-5, the major diastereomers of γ-chloro-
α-hydroxy-β-N-p-toluenesulfinylamino esters (SS)-5 were
1
assigned as syn-adducts based on H NMR analysis. According
to these transition state models TS-2B and TS-2C (Scheme 7),
it was assumed that the Mannich-type addition products (SS)-5
would have an (SS,2S,3S)-stereochemistry. Indeed, determi-
nation of the absolute stereochemistry of the crystalline chloro-
Ethyl (tert-butoxycarbonyloxy)acetate 3c. Brown oil, 98%
(7.68 g). IR (cm−1): 1745, 1H NMR (300 MHz, CDCl3): δ 1.29
(3H, t, J = 7.15 Hz), 1.51 (9H, s), 4.25 (2H, q, J = 7.15 Hz), 4.56
(2H, s). 13C NMR (75 MHz, CDCl3): δ 14.1, 27.7 (3C), 61.5, 62.8,
83.2, 153.0, 167.9, MS (ES+): m/z (%): 527 (100), 427 (77), 222
(M + NH4 , 50). HRMS (ES) calcd for C9H16O5: 205.1071 MH+;
+
Fig. 4 X-ray crystal structure of (SS,2S,3S)-γ-chloro-α-hydroxy-β-amino
ester (SS,2S,3S)-5db.
found: 205.1082.
3398 | Org. Biomol. Chem., 2014, 12, 3393–3405
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Synthesis of γ-chloro-α-hydroxy-β-amino esters 5
(RS,2R,3R)-Methyl 2-(tert-butoxycarbonyloxy)-4-chloro-4-methyl-
3-(tert-butanesulfinylamino)pentanoate 5ab. Rf = 0.28 (pet-
roleum ether–EtOAc: 5/4). Yellow solid, 86% (0.89 g). [α]D −6.5
The synthesis of (RS,2R,3R)-benzyl 2-(tert-butoxycarbonyloxy)-
4-chloro-4-methyl-3-(tert-butanesulfinylamino)pentanoate 5aa
is a representative. A similar procedure was used for the syn-
thesis of γ-chloro-α-hydroxy-β-amino esters 5, using the
amounts of reagents and the exact reaction time as depicted
in Table 1. In a flame dried round-bottomed 250 mL flask,
benzyl (tert-butoxycarbonyloxy)acetate 3a (1.0 equiv., 3.00 g,
11.13 mmol) was dissolved in anhydrous THF (40 mL) under a
N2 atmosphere. Subsequently, the reaction mixture was cooled
to −78 °C and a 1 M solution of LiHMDS in THF (1.0 equiv.,
11.13 mL, 11.13 mmol) was added dropwise and the mixture
was stirred for 1 hour at −78 °C. After deprotonation, N-(tert-
butanesulfinyl)-α-chloroaldimine (RS)-4a (0.20 equiv., 0.34 g,
2.26 mmol) in THF (10 mL) was added dropwise. The reaction
mixture was stirred for 3 hours at −78 °C and quenched at
−78 °C with a saturated aqueous solution of NH4Cl (50 mL).
After 2 minutes, the cooling bath was removed and the temp-
erature was slowly increased to room temperature. The
aqueous phase of the mixture was extracted with EtOAc
(3 × 100 mL). The combined organic phases were dried
(MgSO4), filtered and evaporated in vacuo. The crude product
1
(c 0.3, CHCl3). Mp. 118.5–118.9 °C. IR (cm−1): 1733. H NMR
(300 MHz, CDCl3): δ 1.20 (9H, s), 1.51 (9H, s), 1.68 (3H, s), 1.82
(3H, s), 3.76 (3H, s), 3.94 (1H, d, J = 10.5 Hz), 4.01 (1H, d × d,
J = 10.5, 1.0 Hz), 5.64 (1H, d, J = 1.0 Hz). 13C NMR (75 MHz,
CDCl3): δ 22.6 (3C), 27.7 (3C), 29.7, 31.5, 52.7, 57.2, 66.1, 70.5,
74.2, 83.6, 152.3, 168.9. MS (ES+): m/z (%): 400/402 (M + H+,
100). Anal. Calcd for C16H30ClNO6S: C 48.05; H 7.56; N 3.50,
Found: C 48.27; H 7.83; N 3.59.
(RS,2R,3R)-Ethyl 2-(tert-butoxycarbonyloxy)-4-chloro-4-methyl-
3-(tert-butanesulfinylamino)pentanoate 5ac. Rf = 0.34 (pet-
roleum ether–EtOAc: 5/4). Yellow solid, 88% (0.77 g). [α]D −2.3
(c 0.4, CHCl3). Mp. 73.6–74.4 °C. IR (cm−1): 3325, 1743, 1726.
1H NMR (300 MHz, CDCl3): δ 1.20 (9H, s), 1.30 (3H, t, J =
7.2 Hz), 1.50 (9H, s), 1.68 (3H, s), 1.82 (3H, s), 3.96 (1H, d, J =
10.5 Hz), 4.00 (1H, d × d, J = 10.5, 1.1 Hz), 4.19 (1H, d × q, J =
10.9, 7.2 Hz), 4.21 (1H, d × q, J = 10.9, 7.2 Hz), 5.59 (1H, d, J =
1.1 Hz). 13C NMR (75 MHz, CDCl3): δ 14.1, 22.6 (3C), 27.7 (3C),
29.7, 31.5, 57.2, 62.0, 66.0, 70.6, 74.2, 83.4, 152.3, 168.4. MS
(ES+): m/z (%): 414/416 (M + H+, 100). Anal. Calcd for
C17H32ClNO6S: C 49.32; H 7.79; N 3.38. Found: C 49.66;
H 7.87; N 3.51.
(RS,2R,3R)-Benzyl 2-(tert-butoxycarbonyloxy)-4-chloro-4-ethyl-
3-(tert-butanesulfinylamino)hexanoate 5ba. Rf = 0.27 (pet-
roleum ether–EtOAc: 5/1). Yellow oil, 62% (0.85 g). [α]D −17.8
(c 0.3, CHCl3). IR (cm−1): 1737, 1280, 1241, 1046. 1H NMR
(300 MHz, CDCl3): δ 0.98 (3H, t, J = 7.2 Hz), 1.03 (3H, t, J =
7.2 Hz), 1.13 (9H, s), 1.47 (9H, s), 1.87–2.11 (4H, m), 4.09 (1H,
d, J = 10.2 Hz), 4.17 (1H, d, J = 10.2 Hz), 5.10 (1H, d, J = 12.1
Hz), 5.22 (1H, d, J = 12.1 Hz), 5.54 (1H, s (br)), 7.31–7.39 (5H,
m). 13C NMR (75 MHz, CDCl3): δ 8.6 (2C), 22.6 (3C), 29.7 (3C),
30.0, 30.3, 57.1, 62.2, 67.7, 73.6, 79.1, 83.4, 128.5 (2C), 128.6
(3C), 134.8, 152.5, 168.5, MS (ES+): m/z (%): 504/506 (M + H+,
100). HRMS (ES) calcd for C24H38ClNO6S: 504.2175 MH+;
found: 504.2177/506.2148.
was purified via flash chromatography to yield 0.80
(1.70 mmol, 75%) of pure (RS,2R,3R)-benzyl 2-(tert-butoxy-
carbonyloxy)-4-chloro-4-methyl-3-(tert-butanesulfinylamino)-
pentanoate 5aa.
(RS,2R,3R)-Benzyl 2-(tert-butoxycarbonyloxy)-4-chloro-4-methyl-
g
3-(tert-butanesulfinylamino)pentanoate 5aa. Rf = 0.20 (pet-
roleum ether–EtOAc: 5/4). Brown oil, 75% (0.80 g). [α]D −8.5
(c 0.4, CHCl3). ee > 98%, HPLC Daicel Chiralcel OD-H column:
hexane (99%)–EtOH (1%), 1.0 mL min−1, 35 °C, tR (RS,2R,3R)-
5aa = 21.77 min, (SS,2S,3S)-5aa = 29.27 min. IR (cm−1): 3333,
1
1745, H NMR (300 MHz, CDCl3): δ 1.13 (9H, s), 1.47 (9H, s),
1.67 (3H, s), 1.81 (3H, s), 3.96 (1H, d, J = 10.5 Hz), 4.01 (1H, d × d,
J = 10.5, 1.3 Hz), 5.12 (1H, d, J = 12.1 Hz), 5.19 (1H, d, J =
12.1 Hz), 5.65 (1H, d, J = 1.3 Hz), 7.33–7.39 (5H, m). 13C NMR
(75 MHz, CDCl3): δ 22.6 (3C), 27.7 (3C), 29.8, 31.5, 57.2, 66.0,
67.7, 70.6, 74.3, 83.6, 128.5 (2C), 128.7 (3C), 134.7, 152.3,
168.3. MS (ES+): m/z (%): 476/478 (M + H+, 100). HRMS (ES)
calcd for C22H34ClNO6S: 476.1862 MH+; found: 476.1876/
478.1847.
(RS,2R,3R)-Methyl 2-(tert-butoxycarbonyloxy)-4-chloro-4-ethyl-
3-(tert-butanesulfinylamino)hexanoate 5bb. Rf = 0.22 (pet-
roleum ether–EtOAc: 5/1). Yellow solid, 44% (0.70 g).
[α]D −39.4 (c 0.6, CHCl3). Mp. 78.5–81.5 °C. IR (cm−1): 1736,
(SS,2S,3S)-Benzyl 2-(tert-butoxycarbonyloxy)-4-chloro-4-methyl- 1247, 1077. 1H NMR (300 MHz, CDCl3): δ 0.99 (3H, t, J =
3-(tert-butanesulfinylamino)pentanoate 5aa. Rf = 0.20 (pet- 7.2 Hz), 1.04 (3H, t, J = 7.2 Hz), 1.21 (9H, s), 1.50 (9H, s),
roleum ether–EtOAc: 5/4). Brown oil, 75% (0.47 g). [α]D +7.2 1.86–2.14 (4H, m), 3.76 (3H, s), 4.09 (1H, d, J = 9.9 Hz), 4.16
(c 0.3, CHCl3). ee > 98%, HPLC Daicel Chiralcel OD-H column: (1H, d, J = 9.9 Hz), 5.54 (1H, s (br)). 13C NMR (75 MHz, CDCl3):
hexane (99%)–EtOH (1%), 1.0 mL min−1, 35 °C, tR (RS,2R,3R)- δ 8.6 (2C), 22.7 (3C), 27.7 (3C), 30.0, 30.3, 53.0, 57.1, 62.2, 73.5,
5aa = 21.77 min, (SS,2S,3S)-5aa = 29.27 min. IR (cm−1): 1745. 79.0, 83.4, 152.6, 169.2, MS (ES+): m/z (%): 428/430 (M + H+,
1H NMR (300 MHz, CDCl3): δ 1.13 (9H, s), 1.47 (9H, s), 100). HRMS (ES) calcd for C18H34ClNO6S: 428.1862 MH+;
1.67 (3H, s), 1.81 (3H, s), 3.96 (1H, d, J = 10.5 Hz), 4.02 (1H, d × d, found: 428.1849/430.1820.
J = 10.5, 1.4 Hz), 5.12 (1H, d, J = 12.1 Hz), 5.20 (1H, d, J =
(RS,2R,3R)-Ethyl 2-(tert-butoxycarbonyloxy)-4-chloro-4-ethyl-
12.1 Hz), 5.65 (1H, d, J = 1.4 Hz), 7.33–7.39 (5H, m). 13C NMR 3-(tert-butanesulfinylamino)hexanoate 5bc. Rf = 0.19 (pet-
(75 MHz, CDCl3): δ 22.6 (3C), 27.7 (3C), 29.8, 31.5, 57.2, 66.0, roleum ether–EtOAc: 3/1). Yellow oil, 65% (1.20 g). [α]D −36.7
67.7, 70.6, 74.3, 83.6, 128.5 (2C), 128.7 (3C), 134.7, 152.2, (c 0.8, CHCl3). IR (cm−1): 1737, 1240, 1046. 1H NMR (300 MHz,
168.3. MS (ES+): m/z (%): 476/478 (M + H+, 100). HRMS (ES) CDCl3): δ 0.99 (3H, t, J = 7.2 Hz), 1.04 (3H, t, J = 7.2 Hz), 1.22
calcd for C22H34ClNO6S: 476.1862 MH+; found: 476.1883/ (9H, s), 1.30 (3H, t, J = 7.2 Hz), 1.50 (9H, s), 1.86–2.13 (4H, m),
478.1854.
4.09–4.29 (4H, m), 5.49 (1H, s (br)). 13C NMR (75 MHz, CDCl3):
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δ 8.6 (2C), 14.1, 22.8 (3C), 27.7 (3C), 30.0, 30.3, 53.0, 57.2, 62.0, s), 1.51 (3H, s), 1.60 (3H, s), 2.42 (3H, s), 4.02 (1H, d × d, J =
62.2, 73.5, 79.1, 83.3, 152.6, 168.6, MS (ES+): m/z (%): 442/444 10.7, 1.1 Hz), 4.30 (1H, d × q, J = 10.7, 7.2 Hz), 4.36 (1H, d × q,
(M + H+, 100). HRMS (ES) calcd for C19H36ClNO6S: 442.2019 J = 10.7, 7.2 Hz), 4.82 (1H, d, J = 10.5 Hz), 5.63 (1H, d, J =
MH+; found: 442.2027/444.1998.
1.1 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.59 (2H, d, J = 8.3 Hz).
(RS,2R,3R)-Methyl 2-(tert-butoxycarbonyloxy)-4-chloro-3-(tert- 13C NMR (75 MHz, CDCl3): δ 14.2, 21.4, 27.7 (3C), 29.4, 31.3,
butanesulfinylamino)butanoate 5cb. Rf
= 0.25 (petroleum 62.2, 63.4, 70.2, 73.7, 83.5, 125.9 (2C), 129.6 (2C), 141.6, 141.8,
ether–EtOAc: 5/1). Yellow oil, 42% (0.60 g). [α]D −37.4 (c 0.6, 152.1, 168.5. MS (ES+): m/z (%): 448/450 (M + H+, 100). Anal.
CHCl3). IR (cm−1): 1738, 1241, 1046. 1H NMR (300 MHz, Calcd for C20H30ClNO6S: C 53.62; H 6.75; N 3.13. Found:
CDCl3): δ 1.17 (9H, s), 1.52 (9H, s), 3.62 (2H, t, J = 11.0 Hz), C 53.25; H 6.40; N 2.79.
3.76 (3H, s), 3.92–4.19 (2H, m), 5.43 (1H, d, J = 1.7 Hz).
(SS,2S,3S)-Ethyl 2-(tert-butoxycarbonyloxy)-4-chloro-3-(p-toluene-
13C NMR (75 MHz, CDCl3): δ 22.4 (3C), 27.6 (3C), 42.6, 52.6, sulfinylamino)butanoate 5ec. Rf = 0.18 (petroleum ether–
56.8, 59.7, 72.9, 84.0, 152.1, 168.3, MS (ES+): m/z (%): 394/396 EtOAc: 2/1). Yellow oil, 35% (0.70 g). [α]D +5.6 (c 0.2, CHCl3). IR
(M + Na+, 100). HRMS (ES) calcd for C14H26ClNO6S: 372.1236 (cm−1): 1744, 1251, 1093. 1H NMR (300 MHz, CDCl3): δ 1.35
MH+; found: 372.1254/374.1225.
(3H, t, J = 7.2 Hz), 1.49 (9H, s), 2.42 (3H, s), 3.52 (1H, t, J =
(RS,2R,3R)-Ethyl 2-(tert-butoxycarbonyloxy)-4-chloro-3-(tert- 11.0 Hz), 3.66 (1H, d × d, J = 11.0, 4.4 Hz), 4.03–4.19 (1H, m),
butanesulfinylamino)butanoate 5cc. Rf 0.31 (petroleum 4.23–4.41 (2H, m), 4.59 (1H, d, J = 11.0 Hz), 5.38 (1H, d, J =
=
ether–EtOAc: 5/1). Yellow oil, 35% (0.60 g). [α]D −21.3 (c 0.9, 2.2 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.50 (2H, d, J = 8.0 Hz).
CHCl3). IR (cm−1): 1739, 1248, 1046. 1H NMR (300 MHz, 13C NMR (75 MHz, CDCl3): δ 14.2, 21.4, 27.6 (3C), 42.9, 56.6,
CDCl3): δ 1.18 (9H, s), 1.29 (3H, t, J = 7.2 Hz), 1.52 (9H, s), 3.62 62.2, 73.1, 83.9, 125.5 (2C), 129.7 (2C), 141.1, 142.0, 152.0,
(2H, t, J = 11.0 Hz), 3.96 (1H, d × d, J = 11.0, 4.4 Hz), 4.00–4.10 167.9, MS (ES+): m/z (%): 420/422 (M + H+, 100). HRMS (ES)
(1H, m), 4.21 (2H, q, J = 7.2 Hz), 5.39 (1H, d, J = 2.8 Hz). calcd for C18H26ClNO6S: 420.1236 MH+; found: 420.1246/
13C NMR (75 MHz, CDCl3): δ 14.1, 22.4 (3C), 27.6 (3C), 42.7, 422.1217.
56.8, 59.7, 61.9, 72.9, 83.9, 152.1, 168.3. MS (ES+): m/z (%): 386/
Synthesis of β,γ-aziridino-α-hydroxy esters 6
388 (M + H+, 100). HRMS (ES) calcd for C15H28ClNO6S:
386.1392 MH+; found: 386.1409/388.1380.
The synthesis of (RS,2R,2′S)-benzyl 2-(tert-butoxycarbonyloxy)-
(SS,2S,3S)-Benzyl 2-(tert-butoxycarbonyloxy)-4-chloro-4-methyl- 2-(3,3-dimethyl-1-tert-butanesulfinylaziridin-2-yl)acetate 6aa is
3-(p-toluenesulfinylamino)pentanoate 5da. Rf 0.63 (pet- a representative. To a solution of (RS,2R,3R)-benzyl 2-(tert-
=
roleum ether–EtOAc: 5/4). White solid, 51% (0.68 g). [α]D +85.2 butoxycarbonyloxy)-4-chloro-4-methyl-3-(tert-butanesulfinylamino)-
(c 0.4, CHCl3). Mp. 127.2–127.6 °C. IR (cm−1): 3301, 1747, pentanoate 5aa (0.18 g, 0.38 mmol) in acetone (10 mL) was
1
1722. H NMR (300 MHz, CDCl3): δ 1.46 (9H, s), 1.47 (3H, s), added K2CO3 (3.0 equiv., 1.13 mmol, 0.16 g) at room tempera-
1.53 (3H, s), 2.40 (3H, s), 4.00 (1H, d × d, J = 10.5, 1.1 Hz), 4.84 ture. The reaction mixture was allowed to stir for 24 hours at
(1H, d, J = 10.5 Hz), 5.24 (1H, d, J = 12.1 Hz), 5.35 (1H, d, J = reflux temperature. After 24 hours, the K2CO3 was filtered off
12.1 Hz), 5.69 (1H, d, J = 1.1 Hz), 7.23 (2H, d, J = 8.3 Hz), and the solvent was evaporated in vacuo. The resulting oil
7.31–7.42 (5H, m), 7.49 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz, was redissolved in EtOAc (10 mL) and washed with water
CDCl3): δ 21.4, 27.6 (3C), 29.3, 31.3, 62.9, 67.9, 70.2, 73.8, 83.6, (2 × 5 mL). The organic phase was dried (MgSO4), filtered and
125.8 (2C), 128.5, 128.6 (4C), 129.5 (2C), 135.0, 141.4, 141.7, evaporated in vacuo. The crude product was purified by
152.1, 168.3. MS (ES+): m/z (%): 510/512 (M + H+, 100). Anal. flash chromatography to yield 0.13 g (0.26 mmol, 68%) of
Calcd for C25H32ClNO6S: C 58.87; H 6.32; N 2.75. Found: (RS,2R,2′S)-benzyl
2-(tert-butoxycarbonyloxy)-2-(3,3-dimethyl-
C 58.92; H 6.60; N 2.64.
1-tert-butanesulfinylaziridin-2-yl)acetate 6aa.
(SS,2S,3S)-Methyl 2-(tert-butoxycarbonyloxy)-4-chloro-4-methyl-
(RS,2R,2′S)-Benzyl 2-(tert-butoxycarbonyloxy)-2-(3,3-dimethyl-
3-(p-toluenesulfinylamino)pentanoate 5db. Rf
= 0.20 (pet- 1-tert-butanesulfinylaziridin-2-yl)acetate 6aa. Rf = 0.43 (pet-
roleum ether–EtOAc: 3/1). White solid, 51% (0.91 g). [α]D +95.8 roleum ether–EtOAc: 5/4). Brown oil, 68% (0.13 g). [α]D −54.8
1
(c 0.4, CHCl3). Mp. 149.4–149.8 °C. IR (cm−1): 3283, 1748, (c 0.4, CHCl3). IR (cm−1): 1744. H NMR (300 MHz, CDCl3): δ
1
1720, H NMR (300 MHz, CDCl3): δ 1.47 (3H, s), 1.50 (9H, s), 1.25 (9H, s), 1.33 (3H, s), 1.47 (9H, s), 1.50 (3H, s), 2.72 (1H, d,
1.54 (3H, s), 2.42 (3H, s), 3.88 (3H, s), 3.98 (1H, d × d, J = 10.5, J = 9.6 Hz), 4.76 (1H, d, J = 9.6 Hz), 5.13 (1H, d, J = 12.1 Hz),
1.4 Hz), 4.86 (1H, d, J = 10.5 Hz), 5.66 (1H, d, J = 1.4 Hz), 7.32 5.33 (1H, d, J = 12.1 Hz), 7.30–7.41 (5H, m). 13C NMR (75 MHz,
(2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz). 13C NMR (75 MHz, CDCl3): δ 22.1, 22.8 (3C), 23.3, 27.8 (3C), 46.6, 48.6, 56.9, 67.7,
CDCl3): δ 21.5, 27.8 (3C), 29.5, 31.3, 53.0, 62.8, 70.4, 73.7, 83.7, 74.5, 83.5, 128.6 (2C), 128.8 (3C), 134.9, 152.7, 167.8. MS (ES+):
125.9 (2C), 129.7 (2C), 141.4, 142.0, 152.2, 169.0, MS (ES+): m/z m/z (%): 440 (M + H+, 50), 384 (100). HRMS (ES) calcd for
(%): 434/436 (M + H+, 100). Anal. Calcd for C19H28ClNO6S: C22H33NO6S: 440.2095 MH+; found: 440.2119.
C 52.29; H 6.50; N 3.23. Found: C 52.59; H 6.59; N 3.41.
(RS,2R,2′S)-Methyl 2-(tert-butoxycarbonyloxy)-2-(3,3-dimethyl-
(SS,2S,3S)-Ethyl 2-(tert-butoxycarbonyloxy)-4-chloro-4-methyl- 1-tert-butanesulfinylaziridin-2-yl)acetate 6ab. Rf = 0.46 (pet-
3-(p-toluenesulfinylamino)pentanoate 5dc. Rf = 0.24 (petroleum roleum ether–EtOAc: 5/4). Brown oil, 88% (0.15 g). [α]D −11.5
ether–EtOAc: 3/1). White solid, 75% (1.03 g). [α]D +85.1 (c 0.4, (c 0.4, CHCl3). IR (cm−1): 1745. 1H NMR (300 MHz, CDCl3):
CHCl3). Mp. 98.2–98.8 °C. IR (cm−1): 3280, 1745, 1714. δ 1.27 (9H, s), 1.42 (3H, s), 1.50 (9H, s), 1.63 (3H, s), 2.76 (1H,
1H NMR (300 MHz, CDCl3): δ 1.34 (3H, t, J = 7.2 Hz), 1.50 (9H, d, J = 9.4 Hz), 3.81 (3H, s), 4.78 (1H, d, J = 9.4 Hz). 13C NMR
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(75 MHz, CDCl3): δ 22.2, 22.7 (3C), 23.2, 27.7 (3C), 46.4, 48.7, CHCl3). Mp. 88.0–90.0 °C. IR (cm−1): 1740, 1250, 1079.
52.8, 56.8, 74.2, 83.5, 152.6, 168.4. MS (ES+): m/z (%): 364 1H NMR (300 MHz, CDCl3): δ 1.22 (9H, s), 1.51 (9H, s), 2.10
(M + H+, 99), 308 (100). HRMS (ES) calcd for C16H29NO6S: (1H, d, J = 3.9 Hz), 2.54–2.60 (1H, m), 2.72 (1H, d, J = 7.2 Hz),
364.1782 MH+; found: 364.1771.
3.79 (3H, s), 4.82 (1H, d, J = 6.6 Hz). 13C NMR (75 MHz,
(RS,2R,2′S)-Ethyl 2-(tert-butoxycarbonyloxy)-2-(3,3-dimethyl- CDCl3): δ 22.1, 22.6 (3C), 27.6 (3C), 32.4, 53.0, 57.4, 74.5,
1-tert-butanesulfinylaziridin-2-yl)acetate 6ac. Rf = 0.41 (pet- 83.7, 152.5, 168.0, MS (ES+): m/z (%): 358 (M + Na+, 100).
roleum ether–EtOAc: 5/4). Brown oil, 67% (0.12 g). [α]D −83.4 HRMS (ES) calcd for C14H25NO6S: 336.1469 MH+; found:
(c 0.4, CHCl3). IR (cm−1): 1744. 1H NMR (300 MHz, CDCl3): 336.1459.
δ 1.26 (9H, s), 1.29 (3H, t, J = 7.2 Hz), 1.41 (3H, s), 1.48 (9H, s),
(RS,2R,2′S)-Ethyl 2-(tert-butoxycarbonyloxy)-2-(1-tert-butane-
1.61 (3H, s), 2.73 (1H, d, J = 9.4 Hz), 4.21 (1H, d × q, J = 11.0, sulfinylaziridin-2-yl)acetate 6cc. Rf = 0.24 (petroleum ether–
7.2 Hz), 4.29 (1H, d × q, J = 11.0, 7.2 Hz), 4.72 (1H, d, J = 9.4 EtOAc: 3/1). Yellow solid, 64% (0.50 g). [α]D −212.8 (c 1.1,
Hz). 13C NMR (75 MHz, CDCl3): δ 14.2, 22.3, 22.8 (3C), 23.4, CHCl3). Mp. 119.0–121.0 °C. IR (cm−1): 1739, 1244, 1117.
27.8 (3C), 46.6, 48.6, 56.9, 62.0, 74.5, 83.4, 152.7, 167.9. MS 1H NMR (300 MHz, CDCl3): δ 1.22 (9H, s), 1.29 (3H, t, J =
(ES+): m/z (%): 378 (M + H+, 100), 322 (76). HRMS (ES) calcd for 7.2 Hz), 1.51 (9H, s), 2.10 (1H, d, J = 3.9 Hz), 2.58 (1H, d × d × d,
C17H31NO6S: 378.1939 MH+; found: 378.1958.
J = 7.2, 6.9, 3.9 Hz), 2.72 (1H, d, J = 7.2 Hz), 4.16–4.32
(RS,2R,2′S)-Benzyl 2-(tert-butoxycarbonyloxy)-2-(3,3-diethyl- (2H, m), 4.79 (1H, d, J = 6.9 Hz). 13C NMR (75 MHz, CDCl3):
1-tert-butanesulfinylaziridin-2-yl)acetate 6ba. Rf = 0.37 (pet- δ 14.2, 22.0, 22.6 (3C), 27.7 (3C), 32.4, 57.4, 61.8, 74.4,
roleum ether–EtOAc: 3/1). Yellow oil, yield 79% (0.35 g). 83.5, 152.5, 167.4, MS (ES+): m/z (%): 372 (M + Na+, 100).
[α]D −75.6 (c 1.0, CHCl3). IR (cm−1): 1756, 1734, 1298, 1112, HRMS (ES) calcd for C15H27NO6S: 350.1626 MH+; found:
1
861. H NMR (300 MHz, CDCl3): δ 0.79 (3H, t, J = 7.2 Hz), 1.01 350.1640.
(3H, t, J = 7.2 Hz), 1.24 (9H, s), 1.46 (9H, s), 1.45–1.50 (1H, m),
1.60–1.75 (1H, m), 1.79–1.91 (1H, m), 2.10–2.23 (1H, m), 2.70 1-p-toluenesulfinylaziridin-2-yl)acetate 6da. Rf
(SS,2S,2′R)-Benzyl 2-(tert-butoxycarbonyloxy)-2-(3,3-dimethyl-
0.31 (pet-
=
(1H, d, J = 9.4 Hz), 4.80 (1H, d, J = 9.4 Hz), 5.18 (1H, d, J = roleum ether–EtOAc: 3/1). Yellow oil, 96% (0.16 g). [α]D −50.5
11.7 Hz), 5.26 (1H, d, J = 11.7 Hz), 7.29–7.38 (5H, m). 13C NMR (c 2.1, CHCl3). IR (cm−1): 1743, 1252, 1099. 1H NMR
(75 MHz, CDCl3): δ 9.0, 11.1, 22.1 (3C), 24.5, 25.6, 27.6 (3C), (300 MHz, CDCl3): δ 1.24 (3H, s), 1.34 (3H, s), 1.44 (9H, s),
49.8, 54.8, 57.2, 67.7, 74.1, 83.4, 128.6 (2C), 128.7, 128.8 (2C), 2.42 (3H, s), 2.77 (1H, d, J = 9.4 Hz), 4.72 (1H, d, J = 9.4 Hz),
134.7, 152.5, 167.8. MS (ES+): m/z (%): 468 (M + H+, 100). 5.08 (1H, d, J = 12.1 Hz), 5.33 (1H, d, J = 12.1 Hz), 7.26–7.37
HRMS (ES) calcd for C24H37NO6S: 468.2414 MH+; found: (7H, m), 7.65 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3):
468.2425.
δ 20.5, 21.5, 23.1, 27.6 (3C), 44.4, 49.1, 67.5, 74.0, 83.2, 125.4
(RS,2R,2′S)-Methyl 2-(tert-butoxycarbonyloxy)-2-(3,3-diethyl- (2C), 128.5 (2C), 128.5, 128.6 (2C), 129.5 (2C), 134.9, 141.6,
1-tert-butanesulfinylaziridin-2-yl)acetate 6bb. Rf
=
0.41 142.0, 152.5, 167.7. MS (ES+): m/z (%): 474 (M + H+, 100).
(petroleum ether–EtOAc: 3/1). White solid, 66% (0.15 g). HRMS (ES) calcd for C25H31NO6S: 474.1945 MH+; found:
[α]D −118.9 (c 0.2, CHCl3). Mp. 99.0–101.0 °C. IR (cm−1): 1736, 474.1934.
1252, 1089. 1H NMR (300 MHz, CDCl3): δ 0.99 (3H, t, J =
(SS,2S,2′R)-Methyl 2-(tert-butoxycarbonyloxy)-2-(3,3-dimethyl-
7.2 Hz), 1.06 (3H, t, J = 7.2 Hz), 1.25 (9H, s), 1.49 (9H, s), 1-p-toluenesulfinylaziridin-2-yl)acetate 6db. Rf = 0.41 (pet-
1.55–1.59 (2H, m), 1.90–2.05 (1H, m), 2.17–2.32 (1H, m), 2.71 roleum ether–EtOAc: 5/4). Brown oil, 68% (0.14 g). [α]D +149.4
1
(1H, d, J = 9.4 Hz), 3.80 (3H, s), 4.80 (1H, d, J = 9.4 Hz). (c 0.4, CHCl3). IR (cm−1): 1744. H NMR (300 MHz, CDCl3): δ
13C NMR (75 MHz, CDCl3): δ 9.0, 11.3, 22.1 (3C), 24.4, 25.6, 1.33 (3H, s), 1.47 (3H, s), 1.48 (9H, s), 2.43 (3H, s), 2.81 (1H, d,
27.7 (3C), 49.8, 52.6, 54.7, 57.2, 73.9, 83.4, 152.5, 168.4, MS J = 9.4 Hz), 3.79 (3H, s), 4.73 (1H, d, J = 9.4 Hz), 7.31 (2H, d, J =
(ES+): m/z (%): 392 (M + H+, 100). HRMS (ES) calcd for 8.3 Hz), 7.67 (2H, d, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3):
C18H33NO6S: 392.2095 MH+; found: 392.2112.
(RS,2R,2′S)-Ethyl
δ 20.6, 21.5, 23.1, 27.6 (3C), 44.3, 49.2, 52.8, 73.9, 83.2, 125.4
2-(tert-butoxycarbonyloxy)-2-(3,3-diethyl- (2C), 129.5 (2C), 141.6, 142.1, 152.5, 168.3. MS (ES+): m/z (%):
1-tert-butanesulfinylaziridin-2-yl)acetate 6bc. Rf = 0.35 (pet- 398 (M + H+, 65), 342 (95), 288 (100). HRMS (ES) calcd for
roleum ether–EtOAc: 3/1). Yellow oil, 47% (0.28 g). [α]D −80.2 C19H27NO6S: 398.1626 MH+; found: 398.1644.
(c 1.2, CHCl3). IR (cm−1): 1744, 1252, 1089. 1H NMR (300 MHz,
(SS,2S,2′R)-Ethyl 2-(tert-butoxycarbonyloxy)-2-(3,3-dimethyl-
CDCl3): δ 1.00 (3H, t, J = 7.2 Hz), 1.08 (3H, t, J = 7.2 Hz), 1.26 1-p-toluenesulfinylaziridin-2-yl)acetate 6dc. Rf 0.33 (pet-
=
(9H, s), 1.33 (3H, t, J = 7.2 Hz), 1.49 (9H, s), 1.52–1.60 (2H, m), roleum ether–EtOAc: 3/1). Yellow oil, 82% (0.50 g). [α]D +18.0
1.90–2.04 (1H, m), 2.20–2.32 (1H, m), 2.71 (1H, d, J = 9.4 Hz), (c 2.8, CHCl3). IR (cm−1): 1737, 1241, 1045, 1H NMR (300 MHz,
4.26 (2H, q, J = 7.2 Hz), 4.76 (1H, d, J = 9.4 Hz). 13C NMR CDCl3): δ 1.28 (3H, t, J = 7.2 Hz), 1.34 (3H, s), 1.46 (3H, s), 1.48
(75 MHz, CDCl3): δ 9.0, 11.4, 14.1, 22.1 (3C), 24.5, 25.7, 27.7 (9H, s), 2.43 (3H, s), 2.81 (1H, d, J = 9.4 Hz), 4.11–4.35 (2H, m),
(3C), 49.9, 54.7, 57.2, 62.0, 74.0, 83.3, 152.5, 167.9. MS (ES+): 4.70 (1H, d, J = 9.4 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.67 (2H, d, J =
m/z (%): 406 (M + H+, 100). HRMS (ES) calcd for C19H35NO6S: 8.3 Hz). 13C NMR (75 MHz, CDCl3): δ 14.1, 20.7, 21.6, 23.2,
406.2252 MH+; found: 406.2271.
27.7 (3C), 44.4, 49.2, 61.9, 74.1, 83.2, 125.5 (2C), 129.6 (2C),
(RS,2R,2′S)-Methyl 2-(tert-butoxycarbonyloxy)-2-(1-tert-buta- 141.6, 142.2, 152.6, 167.8. MS (ES+): m/z (%): 412 (M + H+, 100).
nesulfinylaziridin-2-yl)acetate 6cb. Rf = 0.35 (petroleum ether– HRMS (ES) calcd for C20H29NO6S: 412.1788 MH+; found:
EtOAc: 3/1). Yellow solid, 70% (0.70 g). [α]D −179.4 (c 0.5, 412.1781.
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Synthesis of O-deprotected (RS,2R,3R)-γ-chloro-α-hydroxy-
β-amino esters (RS,2R,3R)-7
4.14 (1H, d, J = 9.7 Hz), 4.71 (1H, s (br)). 13C NMR (75 MHz,
CDCl3): δ 8.7 (2C), 22.7 (3C), 29.9, 30.4, 53.1, 57.2, 62.7, 70.5,
80.4, 174.0, MS (ES+): m/z (%): 328/330 (M + H+, 100). HRMS
The synthesis of (RS,2R,3R)-benzyl 4-chloro-2-hydroxy-4-methyl- (ES) calcd for C13H26ClNO4S: 328.1338 MH+; found: 328.1348/
3-(tert-butanesulfinylamino)pentanoate 7aa is a representative. 330.1319.
To a solution of (RS,2R,3R)-benzyl 2-(tert-butoxycarbonyloxy)-
4-chloro-4-methyl-3-(tert-butanesulfinylamino)pentanoate 5aa
(1.0 equiv., 0.61 g, 1.29 mmol) in CH2Cl2 (7 mL) was added
Synthesis of N-deprotected (2R,3R)-γ-chloro-α-hydroxy-
β-amino esters (2R,3R)-9
dropwise trifluoroacetic acid (3 mL) at room temperature. The The synthesis of (2R,3R)-benzyl 3-amino-2-(tert-butoxycarbonyl-
reaction mixture was stirred for one hour at room temperature oxy)-4-chloro-4-methylpentanoate hydrochloride 9aa is
a
and subsequently poured in water (7 mL) and quenched with representative. To a solution of (RS,2R,3R)-benzyl 2-(tert-butoxy-
K2CO3 until pH = 7. The aqueous phase was extracted with carbonyloxy)-4-chloro-4-methyl-3-(tert-butanesulfinylamino)-
CH2Cl2 (3 × 10 mL) and the combined organic phases were pentanoate 5aa (1.0 equiv., 0.69 g, 1.45 mmol) in dioxane
dried (MgSO4), filtered and evaporated in vacuo. The crude (60 mL) was added a saturated solution of HCl in dioxane
product was purified via flash chromatography to yield 0.36 g (15 mL) at room temperature. The reaction mixture was stirred
(0.96 mmol, 75%) of pure (RS,2R,3R)-benzyl 4-chloro-2-hydroxy- for one hour at room temperature and subsequently the
4-methyl-3-(tert-butanesulfinylamino)pentanoate 7aa. Com- solvent was evaporated in vacuo. Precipitation in dry Et2O
pound 7ac was purified by crystallization in diethyl ether.
afforded 0.47 g (1.15 mmol, 79%) of pure (2R,3R)-benzyl
(RS,2R,3R)-Benzyl 4-chloro-2-hydroxy-4-methyl-3-(tert-buta- 3-amino-2-(tert-butoxycarbonyloxy)-4-chloro-4-methylpentanoate
nesulfinylamino)pentanoate 7aa. Rf = 0.27 (petroleum ether– hydrochloride 9aa.
EtOAc: 1/1). Yellow oil, 75% (0.36 g). [α]D +6.3 (c 2.0, CHCl3).
(2R,3R)-Benzyl 3-amino-2-(tert-butoxycarbonyloxy)-4-chloro-
IR (cm−1): 3266, 1739. 1H NMR (300 MHz, CDCl3): δ 1.09 (9H, s), 4-methylpentanoate hydrochloride 9aa. Yellow solid, 79%
1.68 (3H, s), 1.82 (3H, s), 3.48 (1H, s (br)), 3.88 (1H, d × d, J = (0.47 g). [α]D +5.3 (c 0.4, CHCl3). Mp 150.9–151.7 °C. IR (cm−1):
9.9, 1.1 Hz), 4.04 (1H, d, J = 9.9 Hz), 4.86 (1H, d, J = 1.1 Hz), 3232, 1752, 1728. 1H NMR (300 MHz, CDCl3): δ 1.34 (9H, s),
5.16 (1H, d, J = 12.1 Hz), 5.24 (1H, d, J = 12.1 Hz), 7.35–7.40 1.86 (6H, s), 4.48 (1H, s (br)), 5.25 (1H, d, J = 12.1 Hz), 5.33
(5H, m). 13C NMR (75 MHz, CDCl3): δ 22.6 (3C), 28.8, 31.5, (1H, d, J = 12.1 Hz), 5.76 (1H, s (br)), 7.20–7.37 (5H, m), 8.92
57.1, 66.7, 68.1, 70.8, 71.8, 128.7 (4C), 128.8, 134.5, 173.5. MS (3H, s (br)). 13C NMR (75 MHz, CDCl3): δ 27.6 (3C), 29.9, 31.1,
(ES+): m/z (%): 376/378 (M + H+, 100). HRMS (ES) calcd for 59.4, 68.1, 68.9, 70.7, 84.3, 128.4, 128.5 (2C), 128.6 (2C), 135.0,
C17H26ClNO4S: 376.1344 MH+; found: 376.1345/378.1311.
151.8, 167.5. MS (ES+): m/z (%): 372/374 (M + H+ − HCl, 100).
(RS,2R,3R)-Methyl 4-chloro-2-hydroxy-4-methyl-3-(tert-buta- Anal. Calcd for C18H27Cl2NO5: C 52.95; H 6.67; N 3.43. Found:
nesulfinylamino)pentanoate 7ab. Rf = 0.29 (petroleum ether– C 53.12; H 6.93; N 3.52.
EtOAc: 1/2). White crystals, 80% (0.27 g). [α]D −27.1 (c 2.0,
(2R,3R)-Methyl 3-amino-2-(tert-butoxycarbonyloxy)-4-chloro-
CHCl3). Mp. 113.1–115.1 °C. IR (cm−1): 3293, 1742, 1H NMR 4-methylpentanoate hydrochloride 9ab. White solid, 93%
(300 MHz, CDCl3): δ 1.17 (9H, s), 1.70 (3H, s), 1.85 (3H, s), 3.23 (0.44 g). [α]D −13.0 (c 2.2, CHCl3). Mp 147.2–151.2 °C.
(1H, s (br)), 3.82 (3H, s), 3.86 (1H, d, J = 9.9 Hz), 3.97 (1H, d, IR (cm−1): 2980, 1752, 1727. 1H NMR (300 MHz, CDCl3): δ 1.50
J = 9.9 Hz), 4.86 (1H, s). 13C NMR (75 MHz, CDCl3): δ 22.6 (3C), (9H, s), 1.87 (6H, s (br)), 3.89 (3H, s), 4.26 (1H, s (br)), 5.73
28.8, 31.5, 53.1, 57.1, 66.6, 70.7, 71.8, 174.1. MS (ES+): m/z (%): (1H, s (br)), 9.01 (3H, s (br)). 13C NMR (75 MHz, CDCl3): δ 27.8
300/302 (M + H+, 100). HRMS (ES) calcd for C11H22ClNO4S: (3C), 30.4, 31.3, 54.2, 59.8, 67.8, 70.8, 84.3, 151.8, 167.7. MS
300.1031 MH+; found: 300.1024/302.0995.
(ES+): m/z (%): 296/298 (M + H+ − HCl, 100). HRMS (ES) calcd
(RS,2R,3R)-Ethyl 4-chloro-2-hydroxy-4-methyl-3-(tert-butane- for C12H22ClNO5: 296.1259 MH+ − HCl; found: 296.1259/
sulfinylamino)pentanoate 7ac. White crystals, 86% (0.24 g). 298.1229.
[α]D −9.3 (c 2.1, CHCl3). Mp 96.3–100.3 °C. IR (cm−1): 3288,
(2R,3R)-Ethyl 3-amino-2-(tert-butoxycarbonyloxy)-4-chloro-
1738. 1H NMR (300 MHz, CDCl3): δ 1.18 (9H, s), 1.34 (3H, t, J = 4-methylpentanoate hydrochloride 9ac. White solid, 92%
7.2 Hz), 1.70 (3H, s), 1.85 (3H, s), 3.29 (1H, d, J = 3.9 Hz), 3.85 (0.43 g). [α]D +14.0 (c 0.3, CHCl3). Mp 140.0–142.0 °C.
(1H, d × d, J = 9.9, 1.1 Hz), 3.99 (1H, d, J = 9.9 Hz), 4.16–4.35 IR (cm−1): 3198, 1751, 1729. 1H NMR (300 MHz, CDCl3): δ 1.32
(2H, m), 4.82 (1H, d × d, J = 3.9, 1.1 Hz). 13C NMR (75 MHz, (3H, t, J = 6.9 Hz), 1.50 (9H, s), 1.83 (3H, s), 1.89 (3H, s), 4.25
CDCl3): δ 14.2, 22.6 (3C), 28.8, 31.6, 57.0, 62.6, 66.6, 70.7, 71.8, (1H, s (br)), 4.34 (2H, q, J = 6.9 Hz), 5.67 (1H, s (br)), 8.94 (3H,
173.7. MS (ES+): m/z (%): 314/316 (M + H+, 100). HRMS (ES) s (br)). 13C NMR (75 MHz, CDCl3): δ 13.9, 27.7 (3C), 29.8, 31.2,
calcd for C12H24ClNO4S: 314.1187 MH+; found: 314.1176/ 59.4, 63.2, 67.9, 70.7, 84.1, 151.7, 167.1. MS (ES+): m/z (%): 310/
316.1147.
312 (M + H+ − HCl, 100). Anal. Calcd for C13H25Cl2NO5:
(RS,2R,3R)-Methyl 4-chloro-4-ethyl-2-hydroxy-3-(tert-butane- C 45.10; H 7.28; N 4.05. Found: C 45.12; H 7.19; N 3.99.
sulfinylamino)hexanoate 7bb. Rf = 0.58 (petroleum ether–
Synthesis of N,O-deprotected (2R,3R)-γ-chloro-α-hydroxy-
β-amino ester trifluoroacetic acid salts (2R,3R)-10
EtOAc: 1/2). Yellow oil, 70% (0.19 g). [α]D −12.5 (c 0.2, CHCl3).
IR (cm−1): 3341, 2976, 1737, 1212, 1044. 1H NMR (300 MHz,
CDCl3): δ 1.02 (3H, t, J = 7.2 Hz), 1.08 (3H, t, J = 7.2 Hz), 1.20 The synthesis of (2R,3R)-benzyl 3-amino-4-chloro-2-hydroxy-
(9H, s), 1.94–2.18 (5H, m), 3.82 (3H, s), 4.00 (1H, d, J = 9.7 Hz), 4-methylpentanoate trifluoroacetate 10aa is a representative.
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To a solution of (2R,3R)-benzyl 3-amino-2-(tert-butoxycarbonyl-
(4R,5R)-Benzyl 4-(2-chloro-2-propyl)oxazolidin-2-one-5-car-
oxy)-4-chloro-4-methylpentanoate hydrochloride 9aa (0.35 g, boxylate 11aa. White solid, 82% (0.06 g). [α]D −16.1 (c 0.8,
0.86 mmol) in CH2Cl2 (6 mL) was added trifluoroacetic acid CHCl3). Mp. 66.0–70.0 °C. IR (cm−1): 3262, 1761, 1209, 1096.
(2.7 mL) at room temperature. The reaction mixture was stirred 1H NMR (300 MHz, CDCl3): δ 1.57 (6H, s), 3.93 (1H, d, J =
for one hour at room temperature and subsequently evapor- 3.3 Hz), 4.91 (1H, d, J = 3.3 Hz), 5.26 (1H, d, J = 12.1 Hz), 5.28
ated in vacuo, affording 0.32 g of pure (2R,3R)-benzyl 3-amino- (1H, d, J = 12.1 Hz), 7.02 (1H, s (br)), 7.28–7.47 (5H, m).
4-chloro-2-hydroxy-4-methylpentanoate trifluoroacetate 10aa 13C NMR (75 MHz, CDCl3): δ 27.6, 27.8, 65.1, 68.1, 69.2, 75.0,
(0.83 mmol, 97%).
128.5 (2C), 128.9 (3C), 134.6, 158.3, 168.4. MS (ES+): m/z (%):
+
(2R,3R)-Benzyl 3-amino-4-chloro-2-hydroxy-4-methylpentano- 315/317 (M + NH4 , 100). HRMS (ES) calcd for C14H16ClNO4:
ate trifluoroacetate 10aa. Yellow oil, 97% (0.32 g). [α]D −4.5 298.0841 MH+; found: 298.0844/300.0815.
(c 1.3, CHCl3). IR (cm−1): 3038, 1739, 1665, 1142. 1H NMR
(4R,5R)-Methyl 4-(2-chloro-2-propyl)oxazolidin-2-one-5-car-
(300 MHz, CDCl3): δ 1.70 (3H, s), 1.76 (3H, s), 3.95 (1H, s), 4.65 boxylate 11ab. White solid, 76% (0.08 g). [α]D −23.1 (c 0.9,
(1H, s), 5.12 (1H, d, J = 12.1 Hz), 5.29 (1H, d, J = 12.1 Hz), CHCl3). Mp. 125.4–129.4 °C. IR (cm−1): 3297, 1746, 1720, 1240,
1
7.26–7.35 (5H, m), 8.21 (4H, s (br)). 13C NMR (75 MHz, CDCl3): 1116. H NMR (300 MHz, CDCl3): δ 1.60 (6H, s), 3.86 (3H, s),
δ 28.1, 29.9, 61.9, 67.1, 68.9, 69.2, 128.7 (2C), 128.9 (2C), 129.1, 3.97 (1H, d × d, J = 3.3, 1.1 Hz), 4.89 (1H, d, J = 3.3 Hz), 6.89
134.1, 171.6. MS (ES+): m/z (%): 272/274 (M + H+ − TFA, 100). (1H, s (br)). 13C NMR (75 MHz, CDCl3): δ 27.6, 27.7, 53.4, 65.1,
HRMS (ES) calcd for C13H18ClNO3: 272.1048 MH+ − TFA; 69.2, 74.9, 158.1, 169.1. MS (ES+): m/z (%): 239/241 (M + NH4 ,
+
found: 272.1058/274.1029.
100). HRMS (ES) calcd for C8H12ClNO4: 222.0528 MH+; found:
(2R,3R)-Methyl 3-amino-4-chloro-2-hydroxy-4-methylpenta- 222.0530/224.0502.
noate trifluoroacetate 10ab. Yellow oil, 84% (0.37 g).
(4R,5R)-Ethyl 4-(2-chloro-2-propyl)oxazolidin-2-one-5-carboxy-
[α]D −18.4 (c 2.0, CHCl3). IR (cm−1): 2961, 1669, 1183, 1135, late 11ac. White solid, 64% (0.06 g). [α]D −23.0 (c 0.5, CHCl3).
1H NMR (300 MHz, CDCl3): δ 1.72 (3H, s), 1.78 (3H, s), 3.79 Mp 140.1–144.1 °C. IR (cm−1): 3251, 1754, 1728, 1238, 1110.
(3H, s), 3.91 (1H, s), 4.66 (1H, s), 7.60 (4H, s (br)). 13C NMR 1H NMR (300 MHz, CDCl3): δ 1.34 (3H, t, J = 7.2 Hz), 1.60 (6H,
(75 MHz, CDCl3): δ 28.2, 29.7, 53.6, 61.8, 67.0, 69.0, 172.4. MS s), 3.96 (1H, d, J = 3.3 Hz), 4.31 (2H, q, J = 7.2 Hz), 4.86 (1H, d,
(ES+): m/z (%): 196/198 (M + H+ − TFA, 100). HRMS (ES) J = 3.3 Hz), 6.95 (1H, s (br)). 13C NMR (75 MHz, CDCl3): δ 14.1,
calcd for C7H14ClNO3: 196.0735 MH+ − TFA; found: 196.0740/ 27.6, 27.7, 62.7, 65.2, 69.3, 75.0, 158.2, 168.6. MS (ES+): m/z
+
198.0707.
(%): 253/255 (M
+
NH4 , 100). HRMS (ES) calcd for
(2R,3R)-Ethyl 3-amino-4-chloro-2-hydroxy-4-methylpentano- C9H14ClNO4: 236.0684 MH+; found: 236.0685/238.0658.
ate trifluoroacetate 10ac. Yellow oil, 96% (0.27 g). [α]D −14.7
(c 1.0, CHCl3). IR (cm−1): 2987, 1734, 1668, 1184, 1135,
1H NMR (300 MHz, CDCl3): δ 1.30 (3H, t, J = 7.2 Hz), 1.73 (3H,
Acknowledgements
s), 1.80 (3H, s), 3.90 (1H, s (br)), 4.16–4.36 (2H, m), 4.62 (1H,
s (br)), 6.96 (4H, s (br)). 13C NMR (75 MHz, CDCl3): δ 13.8,
The authors are indebted to the Research Foundation – Flan-
28.1, 29.9, 61.9, 63.5, 67.0, 69.2, 171.9. MS (ES+): m/z (%): 210/
ders (FWO – Vlaanderen), the Agency for Innovation by Science
212 (M + H+ − TFA, 100). HRMS (ES) calcd for C8H16ClNO3:
and Technology in Flanders (IWT), Ghent University (BOF) and
210.0891 MH+ − TFA; found: 210.0896/212.0866.
COST action CM0803 (STSM to M. N.) for financial support.
Synthesis of (4R,5R)-alkyl 4-(2-chloro-2-propyl)oxazolidin-
2-one-5-carboxylates (4R,5R)-11
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