DBU-Promoted Dynamic Kinetic Resolution in Rh-Catalyzed Asymmetric Transfer Hydrogenation of 5-Alkyl Cyclic Sulfamidate Imines: Stereoselective Synthesis of Functionalized 1,2-Amino Alcohols

Article abstract of DOI:10.1021/acs.joc.8b01892

Dynamic kinetic resolution (DKR)-driven asymmetric transfer hydrogenation of 5-alkyl cyclic sulfamidate imine produces the corresponding sulfamidate with excellent levels of diastereo- and enantioselectivity by employing a HCO₂H/DBU mixture as

Full text of DOI:10.1021/acs.joc.8b01892

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Article
DBU-Promoted Dynamic Kinetic Resolution in Rh-Catalyzed Asymmetric
Transfer Hydrogenation of 5-Alkyl Cyclic Sulfamidate Imines:
Stereoselective Synthesis of Functionalized 1,2-Amino Alcohols
Hyeong Rae Kim, Raghavendra Achary, and Hyeon-Kyu Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01892 • Publication Date (Web): 10 Sep 2018
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DBU-Promoted Dynamic Kinetic Resolution in Rh-Catalyzed
Asymmetric Transfer Hydrogenation of 5-Alkyl Cyclic Sulfamidate
Imines: Stereoselective Synthesis of Functionalized 1,2-Amino
Alcohols
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Hyeong Rae Kim,†,‡ Raghavendra Achary† and HyeonꢀKyu Lee†,‡*
†Korea Chemical Bank, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong, Daejeon 305-
600, Korea; ‡Department of Medicinal Chemistry and Pharmacology, University of Science and Technology,
113 Gwahango, Yuseong, Daejeon 305-333, Korea.
leehk@krict.re.kr
ABSTRACT
Dynamic kinetic resolution (DKR)ꢀdriven asymmetric transfer hydrogenation of 5ꢀalkyl cyclic
sulfamidate imine produces the corresponding sulfamidate with excellent levels of diastereoꢀ and
enantioselectivity by employing a HCO2H/DBU mixture as the hydrogen source in the presence of the
Noyoriꢀtype chiral Rhꢀcatalyst at room temperature for 1 h. In this process, DKR was induced by
DBUꢀpromoted rapid racemization of the substrate. Stereoselective transformations of the resulting
cyclic sulfamidates to functionalized enantiomerically enriched 1,2ꢀamino alcohol and chiral amine
substances are also described.
INTRODUCTION
1,2ꢀAmino alcohols are important structural motifs in a wide range of natural products and
pharmacologically active compounds.1 Furthermore, the relative and absolute stereochemistry of the
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1,2ꢀamino alcohols is an important factor governing their biological activities. Optically active 1,2ꢀ
amino alcohols have also been used as both chiral auxiliaries and ligands in synthetically important
asymmetric transformations. Therefore, the development of methods for stereoselective synthesis of
members of this family has received considerable attention.1
Dynamic kinetic resolution (DKR), which combines a kinetic resolution process with in situ
equilibration or racemization of a configurationally labile substrate, has become an important method
to generate enantiomerically enriched/pure compounds from racemic substrates in a theoretically
quantitative yield.2
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Asymmetric transfer hydrogenation (ATH) reactions, using hydrogen sources other than molecular
hydrogen, have proven to be among the most powerful methods for asymmetric reduction of ketones
and imines. These processes, which yield the corresponding chiral alcohols and amines, have
advantages associated with operational simplicity, ready availability of hydrogen sources, and use of
readily accessible and less sensitive catalysts.3
In a recent study in this area, we uncovered a new procedure for DKRꢀdriven ATH reactions of
prochiral cyclic sulfamidate imines, which utilizes a mixture of HCO2H/Et3N as the hydrogen source
and base, along with a wellꢀdefined Noyoriꢀtype chiral Rhꢀcatalyst (Scheme 1ꢀa).4
Scheme 1. ATH of cyclic sulfamate imines accompanied by DKR
(a) Substrate-acidity control to promote DKR (previous studies)
O
O
O
O
O
O
0.5 mol%
(R,R)-Rh-cat
S
S
S
N
4
O
5
HN
4
O
5
HN
4
O
5
+
HCO2H/Et3N, EtOAc
25oC, 0.5 h
Ph
racemic
H
R
Ph
(4S,5R)-2a
R
Ph
(4R,5S)-2a
R
1a: R = Me
major (75% ee)
minor
(4S,5R)-4a
(4R,5S)-4a
3a: R = Ph
major (98% ee)
minor
(4S,5S)-6a
(4R,5R)-6a
5a: R = CO2Me
major (98% ee)
minor
(b) Base-strength control to promote DKR (this study)
O
O
O
O
O
O
0.5 mol%
(S,S)-Rh-cat
S
S
S
N
4
O
5
HN
4
O
5
HN
4
O
5
+
HCO2H/Base, EtOAc
25oC, 1.0 h
Ph
H
CH3
Ph
CH3
Ph
CH3
racemic-1a
(4R,5S)-2a
(4S,5R)-2a
Base = Et3N
major (75% ee)
Base = DBU major (99% ee)
Ts
Ph
N
Rh
N
Cl
Ph
H2
(S,S)-Rh-cat
In the effort, we showed that ATH reactions of 4,5ꢀdisubstituted cyclic sulfamidate imines, possessing
configurationally labile stereogenic centers (C5) are accompanied by DKR.4 We also observed that
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DKR is caused by Et3N promoted racemization at the acidic C5 stereogenic position under the
reaction conditions. As a consequence, a drastic improvement in the stereoselectivity of this process
occurs when the sulfamidate imine substrates contain H5 acidity enhancing aryl (3a)4d or carboxylate
groups (5a)4b instead of a methyl group (1a)4e at C5 (eg., 98% ee for 4a and 6a vs 75% ee for 2a,
Scheme 1ꢀa). However, compare to the excellent stereoselectivities (98% ee) in the ATH of cyclic
imine 3a or 5a, stereoselectivity in the ATH of 5ꢀmethyl cyclic imine 1a to 5ꢀmethyl cyclic
sulfamidate 2a (75% ee) remains to be improved.
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While considering other strategies to improve the stereoselectivity of ATH reactions of 5ꢀalkyl
substituted cyclic imine 1a, we envisioned that employing stronger bases than triethylamine5 could
also facilitate rapid racemization of 1a and, as a result, would lead to higher degrees of
stereoselectivity in reaction of 5ꢀalkyl substituted substrate 1a. In the literature search for strong bases
suitable for this study, we found that readily available DBU [pKa(CH3CN) = 24.34] is much stronger
organic base than Et3N [pKa(CH3CN) = 18.82] and might serve well in this role.8 Below, we describe
the results of investigation exploring the use of DBU as the base for ATH reactions of 5ꢀalkyl
substituted cyclic imines 1 (Scheme 1ꢀb).
RESULTS AND DISCUSSION
The racemic 5ꢀalkyl cyclic imines 1, used in this study, were prepared starting with αꢀhydroxy
acetophenone derivatives (B)9 and sulfamoyl chloride by using a previously described procedure
(Scheme 2).4c
Scheme 2. Synthesis of 5ꢀalkyl cyclic sulfamidate imine 1
In the first phase of this effort, racemic 4ꢀphenylꢀ5ꢀmethyl cyclic imine 1a was subjected to ATH
reaction conditions employing 2 eqiv of HCO2H as the hydrogen source and 2 eqiv of Et3N or DBU in
the presence of the Rhꢀcatalyst [(S,S)ꢀClRhCp*(TsDPEN)].10
Table 1. Optimization of the ATHꢀDKR reaction of 1aa
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Cat. amt
(mol%)
Convn
drc
(%)b (cis:trans)
Entry
FA/Base(ratio)
Solvent
%eed
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1
2
0.5
0.5
0.5
0.5
1.0
1.0
0.5
0.1
HCO2H/Et3N(5:2) EtOAc >99
HCO2H/Et3N(1:1) EtOAc >99
HCO2H/Et3N(5:2) CH3CN >99
HCO2H/Et3N(1:1) CH3CN >99
HCO2H/DBU(1:1) EtOAc >99
HCO2H/DBU(1:1) CH3CN >99
HCO2H/DBU(1:1) CH3CN >99
HCO2H/DBU(1:1) CH3CN >99
>25:1
>25:1
>25:1
>25:1
>25:1
75
80
87
98
99
3
4
5
6
>25:1 >99
>25:1 >99
>25:1 >99
7
8
9
0.5 HCO2H/DABCO(1:1) CH3CN >99
>25:1
95
94
ꢀ
10
11e
0.5 HCO2H/iꢀPr2NEt(1:1) CH3CN >99
>25:1
0.5 HCO2H/Pyridine(1:1) CH3CN
HCO2H only CH3CN
0
ꢀ
12 1.0
0
ꢀ
ꢀ
a Reaction conditions: 1a (0.2 mmol), (S,S)ꢀRhꢀcat [(S,S)ꢀClRhCp*(TsDPEN)] (0.1ꢀ1.0 mol%), HCO2H/Base (2
eqiv.), solvent (2 mL), rt, 1 h. Determined by 1H NMR analysis of crude products. c Only 4,5ꢀcis products were
b
detected by using H NMR analysis of crude product mixtures. d Determined by using chiral HPLC. Reaction
1
e
time: 12 h.
The results, summarized in Table 1, show that replacement of Et3N by DBU in the reaction of 1a in
EtOAc leads to a dramatic improvement in the degree of enantioselectivity of the ATH reaction,
which produces (4R,5S)ꢀ2a with a 99% ee and a dr >25:1 (Table 1, entries 1ꢀ2 and 5). The
observations also show that solvent has a strong effect on the stereoselectivity of this process (eg.,
CH3CN is better solvent than EtOAc, Table 1, entries 2 and 4). In addition, replacement of Et3N by
other bases such as DABCO or i-Pr2NEt in the ATH reaction of 1a leads to a slight decrease of
enantioselectivities of (4R,5S)ꢀ2a (Table 1, entries 9 and 10). Interestingly, when pyridine was
employed instead of Et3N, the ATH reaction was not proceeded at all and 1a was recovered
quantitatively even with longer reaction of 12 h (Table 1, entry 11). The exact role the base plays is
not clear yet but the ATH reaction does not proceed in the absence of added base (Table 1, entry 12).
We believe that the high level of stereoselectivity observed in the ATHꢀDKR reaction of 1a is a result
of rapid racemization of the configurationally labile C5ꢀcenter promoted by the strong base DBU. To
demonstrate this proposal, optically active imine (5S)ꢀ1a (93% ee) was prepared from optically active
(S)ꢀ2ꢀhydroxypropiophenone4e and subjected to reaction with DBU in CH3CN at room temperature for
1 min (Scheme 3).
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Scheme 3. Baseꢀmediated racemization of (5S)ꢀ1a
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Analysis of the reaction mixture, generated by acid quenching after 1 min, showed that the reduction
product 2a is not formed and that the starting imine (5S)ꢀ1a is recovered in nearly quantitative yield
with only a 0.4% ee (see, Scheme 3 and SI). However, when (5S)ꢀ1a (93% ee) was subjected to the
reaction with Et3N for 1 min, (5S)ꢀ1a was recovered with 9.1% ee. These findings show that both
DBU and Et3N promote racemization of (5S)ꢀ1a but that racemization promoted by DBU takes place
more rapidly (krac for DBU >> krac for Et3N in Scheme 4) and, consequently, the ATHꢀDKR reaction
using DBU occurs with a higher stereoselectivity (base = DBU: 99% ee for 2a, base = Et3N: 75% ee
for 2a). DABCO and i-Pr2NEt also induced racemization of (5S)ꢀ1a but slightly slower than Et3N or
DBU in CH3CN solvent (after 1 min., base = DABCO: 15% ee for recovered (5S)ꢀ1a, base = i-Pr2NEt:
18.5% ee for recovered (5S)ꢀ1a, Scheme 3). Interestingly, when pyridine and (5S)ꢀ1a (93% ee) were
allowed to react for 1 min. in CH3CN, (5S)ꢀ1a was recovered with almost no racemization (92% ee
for recovered (5S)ꢀ1a, Scheme 3).
Scheme 4. Proposed mechanism for DKR in ATH of 1a
In addition, the results of 1H NMR spectroscopic analysis show that the 4,5ꢀtransꢀisomer of
sulfamidate 2a is not present in the crude product mixture produced by ATH reaction of 1a. Thus, as
describe previously,4b,4d hydrogen addition in the (S,S)ꢀClRhCp*(TsDPEN)ꢀcatalyzed reaction of 1a
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occurs exclusively from the less sterically hindered face of the cyclic imine. Moreover, the catalyst
loading in this process can be reduced to 0.1 mol% without deterioration of efficiency and
stereoselectivity (Table 1, entry 8).
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Utilizing the optimal reaction conditions developed in the preliminary studies, we investigated the
scope of the ATHꢀDKR reaction using a variety of 5ꢀalkyl substituted cyclic sulfamidate imines
(Table 2).
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Table 2. Sulfamidate imine scope of the ATHꢀDKR reactiona
Substrate 1,
Product 2
Yield
(%)c
Entry
R1
R2
% eed
1
2b
a
a
b
c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
90
92
96
97
94
92
96
91
97
96
91
90
92
97
92
90
93
99
99
90
95
95
94
93
91
99.7
ꢀ99.2b
99.8
99.8
99.8
99.3
95.6
99.7
92.3
99.4
95.8
99.7
53.4
99.4
99.6
88.1
99.6
99.5
99.7
99.6
98.2
99.9
99.3
99.6
95.2f
Me
3
Et
4
nꢀPr
5
d
e
iꢀPr
6
Bn
7
f
nꢀOctyl
CH2OMe
CH2OBn
Allyl
8
g
h
i
9
10
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17
18
19
20
21
22
23
24
25
j
4ꢀOMeꢀPh Allyl
4ꢀOMeꢀPh Bn
k
l
2ꢀClꢀPh
3ꢀClꢀPh
4ꢀClꢀPh
2ꢀMeꢀPh
3ꢀMeꢀPh
4ꢀMeꢀPh
4ꢀFꢀPh
Me
Me
Me
Me
Me
Me
Me
m
n
o
p
q
r
s
4ꢀOMeꢀPh Me
t
4ꢀCNꢀPh
4ꢀCF3ꢀPh
2ꢀThienyl
Me
Me
Me
u
v
w
y
2ꢀNaphthyl Me
nꢀButyl Me
a Reaction conditions: 1 (0.2 mmol), (S,S)ꢀRhꢀcat (0.5 mol%), HCO2H/DBU (2 eqiv), CH3CN (2 mL), rt, 1 h. b
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(R,R)ꢀRhꢀcat was used and (4S,5R)ꢀ2a was formed c Yields of isolated and purified products. d Determined by
e
using chiral HPLC. Absolute configuration of 2a was determined by comparing the sign of the optical rotation
and chiral HPLC retention time with those of the known compound (ref. 4e). f ee of N-Cbz derivative of 2y.
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As the data in Table 2 show, almost all of the substrates undergo complete ATHꢀDKR reactions within
1 h at room temperature with high efficiencies and stereoselectivities. For example, ATH reactions of
cyclic imines bearing ethyl, nꢀpropyl, iꢀpropyl, allyl and benzyl groups in CH3CN occur with high
efficiencies and excellent levels of stereoselectivity (Table 2, entries 1ꢀ6, 8, and 10, >99% ee).
Moreover, cyclic imines containing long chain alkyl groups at C5 such as nꢀoctyl (1f) or
benzyoxymethyl (1h, CH2OBn) also react smoothly to produce products in high yields but with
slightly decreased levels of enantioselectivity (entries 7 and 9, 92ꢀ96% ee). Furthermore, ATH
reactions of 4ꢀarylꢀ5ꢀmethyl cyclic imines bearing either electronꢀwithdrawing or electronꢀdonating
groups at the metaꢀ or paraꢀpositions of the Cꢀ4 phenyl ring lead to production of the corresponding
4ꢀarylꢀ5ꢀmethyl cyclic sulfamidates in high yields and excellent levels of stereoselectivity. However,
ATH reactions of 5ꢀmethyl cyclic imines possessing C4 orthoꢀsubstituted phenyl groups (1l: 2ꢀClꢀPh
and 1o: 2ꢀMeꢀPh) generate the corresponding sulfamidates in high yields but only moderate levels of
enantioselectivity (53ꢀ88% ee, entries 13 and 16). The results show that cyclic imines containing 4ꢀ
thiophene or 4ꢀnaphthalene substituents also serve as suitable substrates for the ATHꢀDKR reaction
(entries 23 and 24). ATH reaction of the 4ꢀ(nꢀbutyl)ꢀ5ꢀmethyl cyclic imine 1y also occurs to produce
the corresponding sulfamidate 2y in high yield (91%) but with slightly decreased ee (95% ee, entry
25). Finally, ATH reaction of 1a, employing the (R,R)ꢀRhꢀcatalyst under the same conditions,
produces the enantiomeric sulfamidate (4S,5R)ꢀ2a with the same efficiency and stereoselectivity as
those of the reaction using the (S,S)ꢀRhꢀcatalyst (entries 1 and 2).
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It is interesting to note that under the standard ATH reaction conditions, 5ꢀ(2ꢀchloroethyl) substituted
cyclic imine 1x reacts to form the bicyclic sulfamidate 7 in a good yield and an excellent % ee. This
product, whose structure and absolute stereochemistry were unambiguously determined by using Xꢀ
ray crystallography analysis (see SI, CCDC1835266), is likely produced through cyclization of the
initially formed 5ꢀ(2ꢀchloroethyl) cyclic sulfamidate 2x under the reaction conditions (Scheme 5).
Scheme 5. ATH of 1x to bicyclic sulfamidate 7
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Because the highly enantioꢀenriched cyclic sulfamidates 2 produced in these ATHꢀDKR reactions
contain both a stereogenic carbon bearing an amine moiety and a reactive cyclic sulfamidate group,
they are potentially valuable intermediates for the synthesis of chiral 1,2ꢀfunctionalized amines and
1,2ꢀamino alcohols.11
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Scheme 6. Stereoselective transformation of sulfamidatesa
aReaction conditions: (a) (tꢀBoc)2O, cat. DMAP, CH3CN, 92%. (b) PhCO2H/CsF, DMF, 60 C, 3 h, 71%. (c)
o
KCN, MeOH, rt, 3h, 66%. (d) ref. 12. (e) Propagyl bromide, NaH, DMF, rt, 3 h, 82%. (f) i) NaN3, DMF, 60 oC,
3 h, ii) 1N HCl, Et2O, 92%. (g) Benzyl bromide, NaH, DMF, rt, 5 h, 89%. (h) i) NaN3, DMF, rt, 3 h, ii) 1N HCl,
o
o
Et2O, 93%. (i) Chloroacetyl chloride, Et3N, CH2Cl2, 0 C, 91%. (j) PPh3, MeOH, 80 C, 5 h, 85%. (k) NaN3,
DMF/CH3CN, 60 oC, 36 h. (l) (tꢀBoc)2O, rt, 3 h (66% from 7).
As part of an effort to demonstrate this potential, (4S,5R)ꢀ4ꢀphenylꢀ5ꢀallyl cyclic sulfamidate (2i),
formed by ATHꢀDKR reaction of 1i, was converted to its NꢀBoc derivative, which upon treatment
with PhCO2H/CsF undergoes sulfamidate ring opening to form the protected 1,2ꢀamino alcohol (S,S)ꢀ
8 (Scheme 6). Selective removal of the Oꢀbenzyl group in this substance using KCN in MeOH
produces the N-Boc derivative (S,S)ꢀ9, which serves as a precursor to piperidineꢀ3ꢀol (S,S)ꢀ10 that is
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reported to be a key intermediate in the synthesis of the nonpeptide neurokinin NK1 receptor agonists,
(+)ꢀLꢀ733,060 and (+)ꢀCPꢀ99,994.12 In addition, NaN3 treatment of (4R,5S)ꢀNꢀpropagylꢀ4ꢀphenylꢀ5ꢀ
methyl cyclic sulfamidate (11), which is prepared from 2a, generates the azidoꢀamine 12 that is
converted by intramolecular [3+2] cycloaddition reaction13 under the reaction conditions to the
triazolopiperazine 13 in good yield. Moreover, the Nꢀbenzyl cyclic sulfamidate 14 produced from 2a
undergoes NaN3 ring opening to form the aminoꢀazide 15. Treatment of this substance with
chloroacety chloride produces amide 16, which is transformed to (R,R)ꢀ1ꢀbenzylꢀ5ꢀmethylꢀ6ꢀ
phenylpiperazinꢀ2ꢀone (17) by PPh3 promoted azide reduction. A final example showing the utility of
the enantioꢀenriched cyclic sulfamidates generated by using the ATHꢀDKR process is found in the
NaN3 promoted conversion of bicyclic sulfamidate (1R,4S,7R)ꢀ7 to the (R,R)ꢀN-Bocꢀ3ꢀazidoꢀ2ꢀ
phenylpyrrolidine 19 (Scheme 6).
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CONCLUSION
In the effort described above, we developed a convenient and highly stereoselective method for the
preparation of 4ꢀarylꢀ5ꢀalkyl cyclic sulfamidates 2. The process, involving asymmetric transfer
hydrogenation (ATH), employs HCO2H/DBU as the hydrogen source and the Noyoriꢀtype chiral Rh
catalysts (S,S)ꢀ or (R,R)ꢀCp*RhCl(TsDPEN). Dynamic kinetic resolution takes place in this process
through DBUꢀpromoted rapid racemization of the configurationally labile cyclic imine substrates. In
addition, selected stereoselective transformations of the cyclic sulfamidates, generated by the ATHꢀ
DKR process, were carried out to demonstrate the use of this method in producing synthetically
valuable functionalized chiral amines and 1,2ꢀamino alcohols.
EXPERIMENTAL SECTION
General
All commercial reagents were used as obtained from commercial sources unless otherwise noted.
Reactions were performed with reagent grade solvents except dichloromethane (DCM), ether, THF
which were dried and purified using a solvent purification system. The progress of reactions was
monitored using thin layer chromatography (TLC) and visualized using UV light and by staining with
ethanolic phosphomolybdic acid (PMA) solution or KMnO4 solution followed by heating. Flash
column chromatography was carried out on silica gel (38ꢀ75 ꢁm). Analytical thin layer
chromatography (TLC) was performed on Merck silica gel 60 F254 plates. Preparative thin layer
chromatography (PLC) was performed on Merck silica gel 60 F254 2mm plates. Nuclear magnetic
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resonance (NMR) spectra were recorded using Bruker 500 MHz NMR instrument (1H NMR at 500
MHz and 13C NMR at 125 MHz) or Bruker 300 MHz NMR instrument (1H NMR at 300 MHz and 13
C
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NMR at 75 MHz). H NMR data are reported as follows: chemical shift (δ, ppm), multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), integration, coupling constants
(Hz). Data for 13C NMR are reported in terms of chemical shift (δ, ppm). High performance liquid
chromatography (HPLC) was carried out on a Young Lin HPLC system (7725i Injector, SDV 30 Plus
Solvent Degassor & Valve Module (Helium Sparging), SP930D Solvent Delivery Pump, UV 730D
Absorbance Detector) equipped with a Chiralpak IA, IB, IC, ID or Chiralpak ADꢀH, Chiralcel ODꢀH
column. Specific rotations were measured on a Rudolph Autopol IV (Automatic polarimeter). Highꢀ
resolution mass spectra and elemental analysis were obtained from the Korea Research Institute of
Chemical Technology. HRꢀMS were measured with electron impact (EI) or fast atom bombardment
(FAB) ionization via double focusing mass analyzer (magnetic and electric fields) or electrospray
ionization (ESI) via time of flight (TOF) analyzer. (R,R)ꢀ and (S,S)ꢀClRhCp*(TsDPEN) catalysts were
prepared according to the literature procedures.10
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1. General procedure for the synthesis of cyclic imine from αꢀhydroxy acetophenone derivatives
To a solution of 2ꢀhydroxyꢀ1ꢀphenylpropanꢀ1ꢀone (500 mg, 3.33 mmol) in DMA (10 mL) was added
sulfamoyl chloride (769 mg, 6.66 mmol) at 0 oC. The reaction mixture was stirred at rt for 2 h, diluted
with EtOAc, and washed with saturated NaCl (aq). The organic layer was dried over MgSO4 and the
solvent was evaporated under reduced pressure. The residue was reꢀdissolved in toluene (10 mL) and
o
catalytic amount of pꢀTSA was added. The mixture was heated for 1 h at 110 C, cooled to room
temperature, diluted with EtOAc (50 mL), and washed with saturated NaCl (aq). The organic layer
was separated, dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude
residue was purified on silica gel column chromatography using EtOAc/hexanes (1:9 to 1:3) as an
eluent to afford the title compound as a white solid.
5ꢀMethylꢀ4ꢀphenylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1a)
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yield: 61% (470 mg as a white solid); mp: 107.0ꢀ107.9 C; H NMR (500 MHz,
CDCl3) δ 7.94 (dd, J = 8.5, 1.3 Hz, 2H), 7.80ꢀ7.71 (m, 1H), 7.65ꢀ7.57 (m, 2H),
5.98 (q, J = 7.0 Hz, 1H), 1.79 (d, J = 7.0 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ
179.4, 135.4, 129.7, 129.6, 127.0, 83.9, 20.1.; HRMS (EI, double focusing) m/z:
[M]+ Calcd for C9H9NO3S 211.0303; Found 211.0290.
5ꢀEthylꢀ4ꢀphenylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1b)
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yield: 68% (650 mg as a white solid); mp: 87.0ꢀ88.3 C; H NMR (500 MHz,
CDCl3) δ 7.95ꢀ7.90 (m, 2H), 7.77ꢀ7.71 (m, 1H), 7.63ꢀ7.57 (m, 2H), 5.91 (dd, J =
7.3, 3.4 Hz, 1H), 2.26ꢀ2.16 (m, 1H), 2.04ꢀ1.94 (m, 1H), 1.08 (t, J = 7.4 Hz, 3H).;
13C NMR (125 MHz, CDCl3) δ 178.6, 135.3, 129.6, 129.4, 127.4, 89.0, 27.22, 9.0.;
HRMS (EI, double focusing) m/z: [M]+ Calcd for C10H11NO3S 225.0460; Found 225.0446.
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4ꢀPhenylꢀ5ꢀpropylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1c)
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yield: 88% (710 mg as a white solid); mp: 63.8ꢀ65.0 C; H NMR (500 MHz,
CDCl3) δ 7.94ꢀ7.90 (m, 2H), 7.77ꢀ7.72 (m, 1H), 7.63ꢀ7.58 (m, 2H), 5.92 (dd, J =
8.6, 3.0 Hz, 1H), 2.11ꢀ2.06 (m, 1H), 1.97ꢀ1.87 (m, 1H), 1.71ꢀ1.60 (m, 1H), 1.58ꢀ
1.43 (m, 1H), 0.99 (t, J = 7.4 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 178.9,
135.3, 129.6, 129.5, 127.3, 87.9, 35.8, 18.5, 13.4.; HRMS (EI, double focusing)
m/z: [M]+ Calcd for C11H13NO3S 239.0616; Found 239.0614.
5ꢀIsopropylꢀ4ꢀphenylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1d)
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yield: 82% (187 mg as an ivory solid); mp: 107.5ꢀ112.0 C; H NMR (500 MHz,
CDCl3) δ 7.95ꢀ7.87 (m, 2H), 7.77ꢀ7.70 (m, 1H), 7.64ꢀ7.56 (m, 2H), 5.86 (d, J = 2.3
Hz, 1H), 2.48ꢀ2.35 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H).; 13C
NMR (125 MHz, CDCl3) δ 178.6, 135.1, 129.5, 129.3, 127.7, 92.9, 32.5, 20.1,
14.5.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C11H13NO3S 239.0616;
Found 239.0613.
5ꢀBenzylꢀ4ꢀphenylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1e)
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yield: 38% (500 mg as a white solid); mp: 150.7ꢀ153.2 C; H NMR (500
MHz, CDCl3) 7.99ꢀ7.90 (m, 2H), 7.81ꢀ7.73 (m, 1H), 7.67ꢀ7.59 (m, 2H),
7.39ꢀ7.30 (m, 3H), 7.24ꢀ7.20 (m, 2H), 6.05 (dd, J = 8.7, 3.3 Hz, 1H), 3.37
(dd, J = 15.0, 3.3 Hz, 1H), 3.23 (dd, J = 15.0, 8.7 Hz, 1H).; 13C NMR (125
MHz, CDCl3) δ 178.0, 135.4, 134.00, 129.7, 129.6, 129.4, 128.9, 127.9,
127.4, 88.0, 40.0.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C15H13NO3S 287.0616; Found
287.0612.
5ꢀOctylꢀ4ꢀphenylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1f)
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yield: 70% (495 mg as a colorless oil); H NMR (500 MHz, CDCl3) δ
7.95ꢀ7.89 (m, 2H), 7.79ꢀ7.70 (m, 1H), 7.65ꢀ7.57 (m, 2H), 5.90 (dd, J =
8.6, 3.0 Hz, 1H), 2.13ꢀ2.03 (m, 1H), 1.98ꢀ1.86 (m, 1H), 1.68ꢀ1.55 (m,
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1H), 1.54ꢀ1.41 (m, 1H), 1.40ꢀ1.20 (m, 10H), 0.89 (t, J = 7.0 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ
178.9, 135.3, 129.6, 129.5, 127.4, 88.1, 33.9, 31.7, 29.1, 29.0, 28.8, 25.00, 22.6, 14.1.; HRMS (EI,
double focusing) m/z: [M]+ Calcd for C16H23NO3S 309.1399; Found 309.1396.
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5ꢀ(Methoxymethyl)ꢀ4ꢀphenylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1g)
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yield: 58% (650 mg as a yellow solid); mp: 149.5ꢀ151.2 C; H NMR (500
MHz, CDCl3) δ 7.99ꢀ7.93 (m, 2H), 7.78ꢀ7.71 (m, 1H), 7.65ꢀ7.57 (m, 2H),
5.99 (dd, J = 4.0, 2.8 Hz, 1H), 3.99ꢀ3.87 (m, 2H), 3.38 (s, 3H).; 13C NMR
(125 MHz, CDCl3) δ 176.3, 135.4, 129.5, 129.5, 127.4, 87.4, 71.9, 60.1.;
HRMS (EI, double focusing) m/z: [M]+ Calcd for C10H11NO4S 241.0409;
Found 241.0398.
5ꢀ((Benzyloxy)methyl)ꢀ4ꢀphenylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1h)
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yield: 47% (110 mg as a white solid); mp: 131.5ꢀ135.0 C; H NMR
(300 MHz, CDCl3) δ 7.94ꢀ7.86 (m, 2H), 7.77ꢀ7.69 (m, 1H), 7.61ꢀ7.51
(m, 2H), 7.32ꢀ7.23 (m, 3H), 7.21ꢀ7.11 (m, 2H), 5.98 (dd, J = 3.9, 2.8 Hz,
1H), 4.65ꢀ4.46 (m, 2H), 4.02ꢀ3.87 (m, 2H).; 13C NMR (125 MHz, CDCl3)
δ 176.3, 136.5, 135.3, 129.5, 129.4, 128.5, 128.0, 127.7, 127.4, 87.4,
73.7, 68.8.; HRMS (EI, double focusing) m/z: [M]+ Calcd for
C16H15NO4S 317.0722; Found 317.0709.
5ꢀAllylꢀ4ꢀphenylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1i)
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yield: 67% (523 mg as an ivory solid); mp: 94.7ꢀ95.6 C; H NMR (300 MHz,
CDCl3) δ 7.96ꢀ7.87 (m, 2H), 7.79ꢀ7.71 (m, 1H), 7.66ꢀ7.56 (m, 2H), 6.00ꢀ5.92 (m,
1H), 5.90ꢀ5.73 (m, 1H), 5.27ꢀ5.18 (m, 1H), 5.15ꢀ5.05 (m, 1H), 2.97ꢀ2.84 (m, 1H),
2.76ꢀ2.62 (m, 1H).; 13C NMR (125 MHz, CDCl3) δ 178.2, 135.4, 129.6, 129.5,
127.3, 120.8, 87.0, 67.1, 37.8.; HRMS (EI, double focusing) m/z: [M]+ Calcd for
C11H11NO3S 237.0460; Found 237.0453.
5ꢀAllylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1j)
yield: 77% (150 mg as a yellow solid); mp: 133.1ꢀ134.5 oC; 1H NMR (500
MHz, CDCl3) δ 7.89 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 5.92ꢀ
5.88 (m 1H), 5.87ꢀ5.78(m 1H), 5.22 (dd, J = 10.2, 1.3 Hz, 1H), 5.12 (dd, J
= 17.0, 1.3 Hz, 1H), 3.95 (s, 3H), 2.93ꢀ2.85 (m, 1H), 2.73ꢀ2.65 (m, 1H).;
13C NMR (125 MHz, CDCl3) δ 177.1, 165.4, 132.00, 129.8, 120.6, 119.4,
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115.1, 86.8, 55.8, 38.3.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C12H13NO4S 267.0565;
Found 267.0561
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5ꢀBenzylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1k)
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yield: 50% (500 mg as a yellow solid); mp: 130.5ꢀ132.0 C; H
NMR (500 MHz, CDCl3) δ 7.96ꢀ7.88 (m, 2H), 7.39ꢀ7.31 (m, 3H),
7.28ꢀ7.21 (m, 2H), 7.12ꢀ7.06 (m, 2H), 5.98 (dd, J = 8.9, 3.2 Hz, 1H),
3.97 (s, 3H), 3.35 (dd, J = 15.1, 3.2 Hz, 1H), 3.24 (dd, J = 15.1, 8.9
Hz, 1H).; 13C NMR (125 MHz, CDCl3) δ 177.0, 165.5, 134.3, 132.1,
129.4, 128.9, 127.8, 119.5, 115.1, 87.8, 55.9, 40.41.; HRMS (EI, double focusing) m/z: [M]+ Calcd for
C16H15NO4S 317.0722; Found 317.0736.
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4ꢀ(2ꢀChlorophenyl)ꢀ5ꢀmethylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1l)
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yield: 69% (60 mg as a yellow solid); mp: 88.3ꢀ89.7 C; H NMR (500 MHz,
CDCl3) δ 7.93ꢀ7.89 (m, 1H), 7.65ꢀ7.61 (m, 1H), 7.60ꢀ7.56 (m, 1H), 7.52ꢀ7.48 (m,
1H), 6.36 (q, J = 7.0 Hz, 1H), 1.64 (d, J = 7.0 Hz, 3H).; 13C NMR (125 MHz,
CDCl3) δ 180.5, 134.8, 133.5, 132.6, 131.5, 127.9, 127.2, 85.9, 18.3.; HRMS (EI,
double focusing) m/z: [M]+ Calcd for C9H8ClNO3S 244.9913; Found 244.9920.
4ꢀ(3ꢀChlorophenyl)ꢀ5ꢀmethylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1m)
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yield: 47% (310 mg as a white solid); mp: 118.8ꢀ120.1 C; H NMR (500
MHz, CDCl3) δ 7.95ꢀ7.93 (m, 1H), 7.82ꢀ7.78 (m, 1H), 7.74ꢀ7.70 (m, 1H),
7.59ꢀ7.54 (m 1H), 5.94 (q, J = 7.0 Hz, 1H), 1.79 (d, J = 7.0 Hz, 3H).; 13C
NMR (125 MHz, CDCl3) δ 178.3, 136.0, 135.3, 130.9, 129.5, 128.6, 127.6,
83.8, 20.0.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C9H8ClNO3S 244.9913; Found
244.9912.
4ꢀ(4ꢀChlorophenyl)ꢀ5ꢀmethylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1n)
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yield: 45% (300 mg as a white solid); mp: 145.7ꢀ148.3 C; H NMR (500
MHz, CDCl3) δ 7.94ꢀ7.85 (m, 2H), 7.65ꢀ7.57 (m, 2H), 5.93 (q, J = 6.9 Hz,
1H), 1.78 (d, J = 6.9 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 178.2, 142.3,
130.9, 130.1, 125.4, 83.7, 20.1.; HRMS (EI, double focusing) m/z: [M]+ Calcd
for C9H8ClNO3S 244.9913; Found 244.9914.
5ꢀMethylꢀ4ꢀ(oꢀtolyl)ꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1o)
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yield: 40% (171 mg as a white solid); mp: 124.3ꢀ126.9 C; H NMR (300 MHz,
CDCl3) δ 7.61ꢀ7.53 (m, 1H), 7.49ꢀ7.35 (m, 3H), 5.99 (q, J = 7.0 Hz, 1H), 2.70 (s,
3H), 1.66 (d, J = 7.0 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 179.9, 141.8, 133.8,
133.1, 129.7, 126.5, 126.1, 85.1, 22.3, 19.4.; HRMS (EI, double focusing) m/z:
[M]+ Calcd for C10H11NO3S 225.0460; Found 225.0446.
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5ꢀMethylꢀ4ꢀ(mꢀtolyl)ꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1p)
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yield: 67% (508 mg as a slightly yellow solid); mp: 72.1ꢀ74.2 C; H NMR
(500 MHz, CDCl3) δ 7.78 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 7.7
Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 5.97 (q, J = 7.0 Hz, 1H), 2.48 (s, 3H), 1.77
(d, J = 7.0 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 179.8, 139.8, 136.3,
130.1, 129.4, 126.9, 126.9, 84.0, 21.3, 20.2.; HRMS (EI, double focusing) m/z: [M]+ Calcd for
C10H11NO3S 225.0460; Found 225.0455.
5ꢀMethylꢀ4ꢀ(pꢀtolyl)ꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1q)
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yield: 61% (378 mg as an ivory solid); mp: 120.9ꢀ122.7 C; H NMR (500
MHz, CDCl3) δ 7.83 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 5.95 (q, J
= 7.0 Hz, 1H), 2.51 (s, 3H), 1.78 (d, J = 7.0 Hz, 3H).; 13C NMR (125 MHz,
CDCl3) δ 179.3, 147.1, 130.3, 129.8, 124.2, 83.9, 22.0, 20.3.; HRMS (EI,
double focusing) m/z: [M]+ Calcd for C10H11NO3S 225.0460; Found
225.0449.
4ꢀ(4ꢀFluorophenyl)ꢀ5ꢀmethylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1r)
yield: 74% (503 mg as a white solid); mp: 100.3ꢀ101.2 oC; 1H NMR (300 MHz,
CDCl3) δ 8.05ꢀ7.92 (m, 2H), 7.37ꢀ7.23 (m, 2H), 5.95 (q, J = 7.0 Hz, 1H), 1.78
(d, J = 7.0 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 178.1, 167.0 (d, J = 260.0
Hz), 132.4 (d, J = 10.9 Hz), 123.3, 117.2 (d, J = 22.2 Hz), 83.7, 20.1.; HRMS
(EI, double focusing) m/z: [M]+ Calcd for C9H8FNO3S 229.0209; Found
229.0209.
4ꢀ(4ꢀMethoxyphenyl)ꢀ5ꢀmethylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1s)
yield: 59% (393 mg as a yellow solid); mp: 129.7ꢀ130.5 oC; 1H NMR (500
MHz, CDCl3) δ 7.91 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 5.92 (q,
J = 6.9 Hz, 1H), 3.95 (s, 3H), 1.79 (d, J = 6.9 Hz, 3H).; 13C NMR (125
MHz, CDCl3) δ 178.4, 165.5, 132.1, 119.2, 115.1, 83.6, 55.8, 20.5.;
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HRMS (EI, double focusing) m/z: [M]+ Calcd for C10H11NO4S 241.0409; Found 241.0408.
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yield: 69% (60 mg as a yellow solid); mp: 160.9ꢀ162.3 C; H NMR (300
MHz, CDCl3) δ 8.06 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 8.7 Hz, 2H), 5.97 (q, J
= 7.0 Hz, 1H), 1.78 (d, J = 7.0 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ
177.7, 133.2, 130.7, 130.0, 118.6, 117.1, 83.7, 19.7.; HRMS (EI, double
focusing) m/z: [M]+ Calcd for C10H8N2O3S 236.0256; Found 236.0228.
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5ꢀMethylꢀ4ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1u)
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yield: 80% (513 mg as a white solid); mp: 144.7ꢀ145.5 C; H NMR (500
MHz, CDCl3) δ 8.07 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H), 6.01 (q, J
= 7.0 Hz, 1H), 1.79 (d, J = 7.0 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ
178.4, 136.5 (q, J = 33.3 Hz), 130.2, 130.0, 126.6 (q, J = 3.4 Hz), 123.1 (q, J
= 273.2 Hz), 83.9, 19.8.; HRMS (EI, double focusing) m/z: [M]+ Calcd for
C10H8F3NO3S 279.0177; Found 279.0162.
5ꢀmethylꢀ4ꢀ(thiophenꢀ2ꢀyl)ꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1v)
yield: 64% (384 mg as a yellow solid); mp: 94.4ꢀ96.5 oC; 1H NMR (500 MHz, CDCl3)
7.94 (d, J = 5.0 Hz, 1H), 7.78 (d, J = 3.9 Hz, 1H), 7.31 (dd, J = 5.0, 3.9 Hz, 1H), 5.83
(q, J = 6.9 Hz, 1H), 1.88 (d, J = 6.9 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 172.9,
137.4, 135.7, 130.7, 129.4, 83.7, 20.9.; HRMS (EI, double focusing) m/z: [M]+ Calcd
for C7H7NO3S2 216.9867; Found 216.9857.
5ꢀMethylꢀ4ꢀ(naphthalenꢀ2ꢀyl)ꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1w)
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yield: 77% (670 mg as a slightly yellow solid); mp: 142.1ꢀ143.6 C; H
NMR (500 MHz, CDCl3) δ 8.39ꢀ8.35 (m, 1H), 8.06ꢀ7.92 (m, 4H), 7.77ꢀ7.62
(m, 2H), 6.12 (q, J = 6.9 Hz, 1H), 1.86 (d, J = 6.9 Hz, 3H).; 13C NMR (125
MHz, CDCl3) δ 179.4, 136.4, 132.4, 132.0, 130.1, 129.7, 129.6, 128.1, 127.8,
124.3, 124.3, 84.0, 20.4.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C13H11NO3S 261.0460;
Found 261.0460.
5ꢀ(2ꢀChloroethyl)ꢀ4ꢀphenylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide(1x)
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yield: 57% (253.5 mg as a yellow solid); mp: 109.7ꢀ110.5 C; H NMR (500
MHz, CDCl3) δ 8.02ꢀ7.89 (m, 2H), 7.81ꢀ7.72 (m, 1H), 7.63 (t, J = 7.9 Hz, 2H),
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6.20 (dd, J = 10.3, 2.3 Hz, 1H), 3.91ꢀ3.79 (m, 2H), 2.52ꢀ2.30 (m, 2H).; 13C NMR (125 MHz, CDCl3) δ
178.3, 135.8, 129.8, 129.7, 126.8, 84.1, 40.5, 37.0.; HRMS (EI, double focusing) m/z: [M]+ Calcd for
C10H10ClNO3S 259.0070; Found 259.0045
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4ꢀButylꢀ5ꢀmethylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide (1y)
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1y was prepared from 2ꢀhydroxyꢀ3ꢀheptanone14 and sulfamoyl chloride.
yield: 76% (2.2 g as a colorless oil); 1H NMR (300 MHz, CDCl3) δ 5.28 (q, J =
7.0 Hz, 1H), 2.74ꢀ2.42 (m, 2H), 1.85ꢀ1.71 (m, 2H), 1.66 (d, J = 7.0 Hz, 3H),
1.56ꢀ1.37 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ
188.0, 86.1, 30.8, 27.4, 22.5, 18.2, 14.0.; HRMS (EI, double focusing) m/z:
[M]+ Calcd for C7H13NO3S 191.0616; Found 191.0614.
2. General procedure for the asymmetric transfer hydrogenation reaction of 1 to 2
To a solution of 5ꢀmethylꢀ4ꢀphenylꢀ5Hꢀ1,2,3ꢀoxathiazole 2,2ꢀdioxide (1a, 50 mg, 0.24 mmol), in
CH3CN (2 mL) was added a solution of DBU (72 mg, 0.48 mmol) and HCO2H (29 mg, 0.48 mmol) in
CH3CN (1 mL) followed by (S,S)ꢀClRhCp*(TsDPEN) catalyst (1.5 mg, 0.5 mol%). The reaction
mixture was stirred at room temperature for 1 h, diluted with EtOAc (10 mL), and washed with water
and saturated NaCl(aq) solution successively. The organic layer was separated, dried over MgSO4 and
the solvent was removed under reduced pressure. The crude residue was purified on silica gel column
chromatography using EtOAc/hexanes (1:9 to 1:2) as an eluent to afford the title compound as a white
solid.
(4R,5S)ꢀ5ꢀMethylꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2a)
Yield: 90% (45 mg as a white solid); mp: 78.2ꢀ79.5 oC; 99.7% ee (Chiralcel ODꢀH,
20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(major) = 8.9 min, tR(minor) = 14.1
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min); [α]D = ꢀ38.2 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.48ꢀ7.37 (m,
5H), 5.26ꢀ5.32 (m, 1H), 5.03 (s, 1H), 4.99 (d, J = 6.1 Hz, 1H), 1.15 (d, J = 6.5 Hz,
3H).; 13C NMR (125 MHz, CDCl3) δ 134.8, 129.2, 129.1, 127.3, 82.5, 63.6, 16.0.; HRMS (EI, double
focusing) m/z: [M]+ Calcd for C9H11NO3S 213.0460; Found 213.0460.
(4S,5R)ꢀ5ꢀMethylꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(entꢀ2a)
Yield: 92% (39.2 mg as a white solid); mp: 78.2ꢀ79.5 oC; 99.2% ee (Chiralcel ODꢀH,
20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(minor) = 8.9 min, tR(major) = 14.1
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min); [α]D 20 = +31.6 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.48ꢀ7.37 (m, 5H), 5.26ꢀ5.32 (m,
1H), 5.03 (s, 1H), 4.99 (d, J = 6.1 Hz, 1H), 1.15 (d, J = 6.5 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ
134.8, 129.2, 129.1, 127.3, 82.4, 63.7, 16.0.; HRMS (EI, double focusing) m/z: [M]+ Calcd for
C9H11NO3S 213.0454; Found 213.0460.
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(4R,5S)ꢀ5ꢀEthylꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2b)
Yield: 96% (48 mg as a white solid); mp: 46.0ꢀ46.9 oC; 99.8% ee (Chiralcel ODꢀH,
20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(major) = 8.34min, tR(minor) = 13.9
min); [α]D 20 = ꢀ59.5 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) 7.46ꢀ7.33 (m, 5H),
5.03ꢀ4.97 (m, 1H), 4.95ꢀ4.91 (m, 1H), 4.88 (s, 1H), 1.48ꢀ1.36 (m, 1H), 1.30ꢀ1.21 (m,
1H), 0.95 (t, J = 7.4 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 135.2, 129.2, 129.1, 127.5, 87.5, 63.5,
23.9, 10.2.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C10H13NO3S 227.0616; Found 227.0609.
(4R,5S)ꢀ4ꢀPhenylꢀ5ꢀpropylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2c)
Yield: 97% (48.5 mg as a white solid); mp: 79.3ꢀ80.1 oC; 99.8% ee (Chiralcel ODꢀH,
20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(major) = 7.7 min, tR(minor) = 13.3
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min); [α]D = ꢀ40.8 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.49ꢀ7.37 (m,
5H), 5.14ꢀ5.10 (m, 1H), 4.96ꢀ4.93 (m, 1H), 4.85 (s, 1H), 1.57ꢀ1.44 (m, 1H), 1.46ꢀ
1.24 (m, 2H), 1.23ꢀ1.14 (m, 1H), 0.87 (t, J = 7.2 Hz, 3H).; 13C NMR (125 MHz,
CDCl3) δ 135.3, 129.2, 129.1, 127.5, 86.0, 63.6, 32.3, 19.0, 13.5.; HRMS (EI, double focusing) m/z:
[M]+ Calcd for C11H15NO3S 241.0773; Found 241.0765.
(4R,5S)ꢀ5ꢀIsopropylꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2d)
o
Yield: 94% (45.5 mg as a white solid); mp: 133.3ꢀ134.5 C; 99.8% ee (Chiralcel
ODꢀH, 20% IPA/nꢀhexanes, 1.0 mL/min, 215 nm, tR(major) = 7.3 min, tR(minor) =
16.3 min); [α]D 20 = +5.3 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.53ꢀ7.34 (m,
5H), 4.92 (s, 1H), 4.82ꢀ4.76 (m, 1H), 4.73ꢀ4.65 (m, 1H), 1.70ꢀ1.51 (m, 1H), 1.03 (d,
J = 6.5 Hz, 3H), 0.76 (d, J = 6.5 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 135.9, 129.3, 129.1, 128.29,
90.3, 64.0, 28.4, 19.7, 17.2.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C11H15NO3S 241.0773;
Found 241.0771.
(4R,5S)ꢀ5ꢀBenzylꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2e)
o
Yield: 92% (53.1 mg as a white solid); mp: 181.5ꢀ184.0 C; 99.3% ee
(Chiralpak IC, 20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(major) = 7.8
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min, tR(minor) = 9.8 min); [α]D 20 = ꢀ51.5 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.49ꢀ7.37 (m,
5H), 7.30ꢀ7.21 (m, 3H), 7.07ꢀ7.01 (m, 2H), 5.33ꢀ5.27 (m, 1H), 5.00 ꢀ 4.97 (m, 1H), 4.83 (s, 1H), 2.78
(dd, J = 14.9, 9.5 Hz, 1H), 2.48 (dd, J = 14.9, 4.3 Hz, 1H).; 13C NMR (125 MHz, CDCl3) δ 135.0,
134.9, 129.5, 129.2, 129.1, 128.7, 127.7, 127.2, 86.0, 63.4, 36.6.; HRMS (EI, double focusing) m/z:
[M]+ Calcd for C15H15NO3S 289.0773; Found 289.0775.
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(4R,5S)ꢀ5ꢀOctylꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2f)
Yield: 96% (59.6 mg as a colorless oil); 95.6% ee (Chiralpak IC, 20%
EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(minor) = 6.4 min, tR(major) =
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6.8 min); [α]D = ꢀ20.2 (c 0.9, CHCl3); H NMR (500 MHz, CDCl3) δ
7.48ꢀ7.37 (m, 5H), 5.15ꢀ5.03 (m, 2H), 4.96ꢀ4.92 (mz, 1H), 1.49ꢀ1.34 (m,
2H), 1.32ꢀ1.15 (m, 12H), 0.88 (t, J = 7.1 Hz, 3H).; 13C NMR (125 MHz,
CDCl3) δ 135.3, 129.1, 129.0, 127.5, 86.4, 63.5, 31.7, 30.4, 29.2, 29.0,
29.0, 25.6, 22.6, 14.1.; HRMS (EI, double focusing) m/z: [M]+ Calcd for
C16H25NO3S 311.1555; Found 311.1552.
(4R,5R)ꢀ5ꢀ(Methoxymethyl)ꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2g)
Yield: 91% (44.5 mg as a white solid); mp: 139ꢀ141.9 oC; 99.7% ee (Chiralpak
ADꢀH, 20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(minor) = 12.8 min,
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tR(major) = 14.6 min); [α]D = ꢀ124.4 (c 1.0, CHCl3); H NMR (500 MHz,
CDCl3) δ 7.48ꢀ7.40 (m, 3H), 7.38ꢀ7.34 (m, 2H), 5.24 (d, J = 8.7 Hz, 1H), 5.16
(dd, J = 8.7, 6.1 Hz, 1H), 5.12 (ddd, J = 6.1, 4.3, 3.2 Hz, 1H), 3.39 (dd, J = 11.3, 3.2 Hz, 1H), 3.27 (dd,
J = 11.3, 4.3 Hz, 1H), 3.20 (s, 3H).; 13C NMR (125 MHz, CDCl3) δ 133.2, 129.1, 129.0, 126.6, 85.0,
70.7, 61.8, 59.4.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C10H13NO4S 243.0565; Found
243.0567
(4R,5R)ꢀ5ꢀ((Benzyloxy)methyl)ꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2h)
Yield: 97% (31.0 mg as a white solid); mp: 107.1ꢀ109.5 oC; 99.5% ee
(Chiralpak ADꢀH, 20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(minor) =
12.4 min, tR(major) = 14.0 min); [α]D 20 = ꢀ122.5 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.48ꢀ7.37 (m, 3H), 7.38ꢀ7.26 (m, 6H), 7.22ꢀ7.12 (m,
2H), 5.25ꢀ5.07 (m, 3H), 4.34 (q, J = 11.8 Hz, 2H), 3.51 (dd, J = 11.1, 3.2
Hz, 1H), 3.41 (dd, J = 11.1, 3.4 Hz, 1H).; 13C NMR (125 MHz, CDCl3) δ
136.7, 133.0, 129.0, 129.0, 128.5, 128.0, 127.7, 126.5, 85.0, 73.8, 68.3, 61.8.; HRMS (EI, double
focusing) m/z: [M]+ Calcd for C16H17NO4S 319.0878; Found 319.0873.
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(4R,5S)ꢀ5ꢀAllylꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2i)
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Yield: 96% (45.2 mg as a white solid); mp: 73.7ꢀ76.0 C; 99.4% ee (Chiralpak
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ID, 20% IPA/nꢀhexanes, 0.8 mL/min, 215 nm, tR(minor) = 8.1 min, tR(major) =
8.6 min); [α]D 20 = ꢀ38.5 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.49ꢀ7.37
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(m, 5H), 5.75ꢀ5.59 (m, 1H), 5.19ꢀ5.09 (m, 2H), 5.09ꢀ4.90 (m, 3H), 2.31ꢀ2.15 (m,
1H), 2.05ꢀ1.94 (m, 1H).; 13C NMR (125 MHz, CDCl3) δ 134.9, 131.2, 129.4, 129.1, 127.5, 119.4, 85.0,
63.3, 34.6.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C11H13NO3S 239.0616; Found 239.0623.
(4R,5S)ꢀ5ꢀAllylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2j)
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Yield: 91% (49.1 mg as an ivory solid); mp: 116.1ꢀ117.5 C; 95.8% ee
(Chiralpak ID, 20% IPA/nꢀhexanes, 0.8 mL/min, 215 nm, tR(minor) = 10.9
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min, tR(major) = 12.0 min); [α]D = ꢀ29.6 (c 1.0, CHCl3); H NMR (300
MHz, CDCl3) δ 7.33 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 5.75ꢀ5.59
(m, 1H), 5.17ꢀ5.00 (m, 3H), 4.95ꢀ4.89 (m, 1H), 4.83 (s, 1H), 3.85 (s, 3H),
2.34ꢀ2.17 (m, 1H), 2.08ꢀ1.93 (m, 1H).; 13C NMR (125 MHz, CDCl3) δ 160.3, 131.3, 128.9, 126.9,
119.3, 114.4, 85.1, 63.0, 55.4, 34.6.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C12H15NO4S
269.0722; Found 269.0724.
(4R,5S)ꢀ5ꢀBenzylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2k)
Yield: 90% (57.2 mg as a white solid); mp: 188.5ꢀ191.2 oC; 99.7% ee
(Chiralpak ADꢀH, 20% IPA/nꢀhexanes, 1.0 mL/min, 215 nm, tR(minor)
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= 11.8 min, tR(major) = 14.8 min); [α]D = ꢀ22.7 (c 1.0, CHCl3); H
NMR (500 MHz, CDCl3) δ 7.38ꢀ7.32 (m, 2H), 7.32ꢀ7.24 (m, 3H),
7.10ꢀ7.05 (m, 2H), 7.01ꢀ6.96 (m, 2H), 5.30 (ddd, J = 9.4, 5.8, 4.4 Hz,
1H), 4.94 (dd, J = 5.8, 3.8 Hz, 1H), 4.79 (d, J = 3.8 Hz, 1H), 3.88 (s, 3H), 2.83 (dd, J = 14.9, 9.4 Hz,
1H), 2.52 (dd, J = 14.9, 4.4 Hz, 1H).; 13C NMR (125 MHz, CDCl3) δ 160.4, 135.1, 129.1, 129.0,
128.6, 127.2, 126.9, 114.5, 86.2, 63.1, 55.4, 36.6.; HRMS (EI, double focusing) m/z: [M]+ Calcd for
C16H17NO4S 319.0878; Found 319.0879
(4R,5S)ꢀ4ꢀ(2ꢀChlorophenyl)ꢀ5ꢀmethylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2l)
Yield: 92% (22.8 mg as a colorless oil); 53.4% ee (Chiralpak ADꢀH, 20% IPA/nꢀ
hexanes, 1.0 mL/min, 215 nm, tR(minor) = 6.3 min, tR(major) = 7.4 min); [α]D 20 = ꢀ
36.6 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.77ꢀ7.72 (m, 1H), 7.46ꢀ7.38 (m,
2H), 7.38ꢀ7.32 (m, 1H), 5.61 (d, J = 6.5 Hz, 1H), 5.43 (p, J = 6.5 Hz, 1H), 5.20 (s,
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1H), 1.19 (d, J = 6.5 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 132.8, 132.6, 130.1, 129.7, 128.7,
127.7, 82.0, 59.6, 15.7.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C9H10ClNO3S 247.0070;
Found 247.0057.
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(4R,5S)ꢀ4ꢀ(3ꢀChlorophenyl)ꢀ5ꢀmethylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2m)
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Yield: 97% (48.6 mg as a white solid); mp: 104.1ꢀ105.5 oC; 99.4% ee (Chiralcel
ODꢀH, 20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(major) = 8.2 min,
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tR(minor) = 10.4 min); [α]D = ꢀ63.1 (c 1.0, CHCl3); H NMR (500 MHz,
CDCl3) δ 7.43ꢀ7.36 (m, 3H), 7.35ꢀ7.30 (m, 1H), 5.32ꢀ5.25 (m, 1H), 5.06 (s, 1H),
4.96 (d, J = 6.1 Hz, 1H), 1.17 (d, J = 6.5 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 137.0, 135.1, 130.4,
129.4, 127.5, 125.5, 82.1, 63.0, 16.1.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C9H10ClNO3S
247.0070; Found 247.0069.
(4R,5S)ꢀ4ꢀ(4ꢀChlorophenyl)ꢀ5ꢀmethylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2n)
Yield: 92% (46.1 mg as a white solid); mp: 114.5ꢀ116.2 oC; 99.6% ee (Chiralcel
ODꢀH, 20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(major) = 7.6 min,
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tR(minor) = 11.1 min); [α]D = ꢀ40.5 (c 1.0, CHCl3); H NMR (500 MHz,
CDCl3) δ 7.43 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 5.33ꢀ5.23 (m, 1H),
5.03 (s, 1H), 4.96 (d, J = 6.0 Hz, 1H), 1.15 (d, J = 6.5 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 135.2,
133.5, 129.3, 128.8, 82.2, 63.1, 16.0.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C9H10ClNO3S
247.0070; Found 247.0069.
(4R,5S)ꢀ5ꢀMethylꢀ4ꢀ(oꢀtolyl)ꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2o)
Yield: 90% (41.0 mg as a white solid); mp: 80.9ꢀ82.7 oC; 88.1% ee (Chiralpak ADꢀH,
20% IPA/nꢀhexanes, 1.0 mL/min, 215 nm, tR(minor) = 6.7 min, tR(major) = 7.5 min);
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[α]D = ꢀ86.2 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 7.62ꢀ7.51 (m, 1H),
7.37ꢀ7.29 (m, 2H), 7.25ꢀ7.18 (m, 1H), 5.43ꢀ5.37 (m, 1H), 5.36ꢀ5.25 (m, 1H), 4.78 (s,
1H), 2.34 (s, 3H), 1.14 (d, J = 6.4 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ δ 135.0, 132.6, 130.9,
128.9, 127.0, 126.4, 81.7, 59.2, 19.5, 16.0.; HRMS (EI, double focusing) m/z: [M]+ Calcd for
C10H13NO3S 227.0616; Found 227.0602.
(4R,5S)ꢀ5ꢀMethylꢀ4ꢀ(mꢀtolyl)ꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2p)
Yield: 93% (42.5 mg as a colorless oil); 99.6% ee (Chiralpak ADꢀH, 30%
IPA/nꢀhexanes, 1.0 mL/min, 215 nm, tR(minor) = 5.1 min, tR(major) = 5.6
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min); [α]D = ꢀ44.5 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.37ꢀ7.30 (m, 1H), 7.26ꢀ7.20 (m,
1H), 7.21ꢀ7.15 (m, 2H), 5.30ꢀ5.23 (m, 1H), 4.97ꢀ4.93 (m, 1H), 4.88 (s, 1H), 2.41 (s, 3H), 1.16 (d, J =
6.5 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 139.0, 134.7, 130.0, 129.0, 127.8, 124.3, 82.4, 63.6, 21.5,
16.0.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C10H13NO3S 227.0616; Found 227.0598.
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(4R,5S)ꢀ5ꢀMethylꢀ4ꢀ(pꢀtolyl)ꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2q)
Yield: 99% (45.0 mg as a white solid); mp: 73.9ꢀ74.5 oC; 99.5% ee (Chiralcel
ODꢀH, 20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(major) = 8.1 min,
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tR(minor) = 20.7 min); [α]D = ꢀ50.2 (c 1.0, CHCl3); H NMR (500 MHz,
CDCl3) δ 7.31ꢀ7.20 (m, 4H), 5.29ꢀ5.22 (m, 1H), 4.97ꢀ4.91 (m, 1H), 4.82 (s,
1H), 2.40 (s, 3H), 1.15 (d, J = 6.5 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 139.2, 131.8, 129.8, 127.2,
82.5, 63.5, 21.2, 16.0.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C10H13NO3S 227.0616;
Found 227.0621.
(4R,5S)ꢀ4ꢀ(4ꢀFluorophenyl)ꢀ5ꢀmethylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2r)
Yield: 99% (45.8 mg as a white solid); mp: 100.5ꢀ101.8 oC; 99.7% ee (Chiralcel
ODꢀH, 20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(major) = 6.6 min,
tR(minor) = 8.8 min); [α]D 20 = ꢀ28.6 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.46ꢀ7.32 (m, 2H), 7.23ꢀ7.05 (m, 2H), 5.35ꢀ5.20 (m, 1H), 5.13 (s, 1H), 5.04ꢀ
4.87 (m, 1H), 1.14 (d, J = 6.5 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 163.1 (d, J = 248.2 Hz), 130.8
(d, J = 3.5 Hz), 129.2 (d, J = 8.3 Hz), 116.1 (d, J = 21.4 Hz), 82.4, 63.0, 16.0.; HRMS (EI, double
focusing) m/z: [M]+ Calcd for C9H10FNO3S 231.0365; Found 231.0358.
(4R,5S)ꢀ4ꢀ(4ꢀMethoxyphenyl)ꢀ5ꢀmethylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2s)
o
Yield: 90% (44.0 mg as a white solid); mp: 141.5ꢀ142.9 C; 99.6% ee
(Chiralcel ODꢀH, 20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(major) =
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10.6 min, tR(minor) = 14.8 min); [α]D = ꢀ36.1 (c 1.0, CHCl3); H NMR
(500 MHz, CDCl3) δ 7.32 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H),
5.30ꢀ5.20 (m, 1H), 4.94ꢀ4.89 (m, 1H), 4.83 (s, 1H), 3.85 (s, 3H), 1.16 (d, J = 6.5 Hz, 3H).; 13C NMR
(125 MHz, CDCl3) δ 160.2, 128.6, 126.8, 114.5, 82.5, 63.4, 55.4, 16.0.; HRMS (EI, double focusing)
m/z: [M]+ Calcd for C10H13NO4S 243.0565; Found 243.0567.
4ꢀ((4R,5S)ꢀ5ꢀMethylꢀ2,2ꢀdioxidoꢀ1,2,3ꢀoxathiazolidinꢀ4ꢀyl)benzonitrile(2t)
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Yield: 95% (22.7 mg as a white solid); mp: 142.2ꢀ144.5 C; 98.2% ee
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(Chiralpak ADꢀH, 20% EtOH/nꢀhexanes, 1.0 mL/min, 215 nm, tR(minor) =
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12.0 min, tR(major) = 20.3 min); [α]D = ꢀ14.3 (c 1.0, CHCl3); H NMR
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(500 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H),
5.37ꢀ5.28 (m, 1H), 5.08ꢀ4.96 (m, 2H), 1.15 (d, J = 6.5 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 140.2,
132.8, 128.3, 118.0, 113.3, 81.7, 63.1, 16.1.; HRMS (EI, double focusing) m/z: [M]+ Calcd for
C10H10N2O3S 238.0412; Found 238.0406.
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(4R,5S)ꢀ5ꢀMethylꢀ4ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2u)
o
Yield: 95% (53.4 mg as a white solid); mp: 86.1ꢀ88.3 C; 99.9% ee
(Chiralpak ODꢀH, 20% IPA/nꢀhexanes, 1.0 mL/min, 215 nm, tR(major) =
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9.7 min, tR(minor) = 11.6 min); [α]D = ꢀ34.1 (c 1.0, CHCl3); H NMR
(500 MHz, CDCl3) δ 7.72 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H),
5.37ꢀ5.28 (m, 1H), 5.16ꢀ4.97 (m, 2H), 1.16 (d, J = 6.5 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ
139.00, 131.5 (q, J = 32.9 Hz), 127.9, 126.0 (q, J = 3.6 Hz), 123.7 (q, J = 272.0 Hz), 82.1, 63.1, 16.1.;
HRMS (EI, double focusing) m/z: [M]+ Calcd for C10H10F3NO3S 281.0333; Found 281.0331.
(4S,5S)ꢀ5ꢀMethylꢀ4ꢀ(thiophenꢀ2ꢀyl)ꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2v)
Yield: 94% (41.2 mg as a brown oil); 99.3% ee (Chiralpak ADꢀH, 40% IPA/nꢀ
hexanes, 0.8 mL/min, 215 nm, tR(minor) = 6.5 min, tR(major) = 7.0 min); [α]D 20 = ꢀ
1
40.5 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 7.38 (dd, J = 5.1, 1.2 Hz, 1H),
7.18 (dd, J = 3.6, 1.2 Hz, 1H), 7.08 (dd, J = 5.1, 3.6 Hz, 1H), 5.30ꢀ5.18 (m, 2H), 5.16
(s, 1H), 1.29 (d, J = 6.0 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 137.2, 127.5, 127.3, 126.6, 82.6,
59.9, 15.7.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C7H9NO3S2 219.0024; Found 219.0022.
(4R,5S)ꢀ5ꢀMethylꢀ4ꢀ(naphthalenꢀ2ꢀyl)ꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide(2w)
Yield: 93% (49.1 mg as a white solid); mp: 124.1ꢀ126.6 oC; 99.6% ee
(Chiralpak ADꢀH, 20% IPA/nꢀhexanes, 1.0 mL/min, 215 nm, tR(minor) = 8.6
min, tR(major) = 10.2 min); [α]D 20 = ꢀ46.5 (c 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.98ꢀ7.80 (m, 4H), 7.63ꢀ7.51 (m, 2H), 7.55ꢀ7.41 (m, 1H), 5.44ꢀ5.28
(m, 1H), 5.21ꢀ5.08 (m, 1H), 1.17 (d, J = 6.5 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 133.4, 133.1,
132.2, 129.1, 128.1, 127.8, 126.9, 126.8, 124.4, 82.5, 63.8, 16.1.; HRMS (EI, double focusing) m/z:
[M]+ Calcd for C13H13NO3S 263.0616; Found 263.0616.
4ꢀButylꢀ5ꢀmethylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide (2y)
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Yield: 91% (35.2 mg as a colorless oil); [α]D = +16.2 (c 0.2, CHCl3); 1H NMR
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(300 MHz, CDCl3) δ 5.06ꢀ4.91 (m, 1H), 4.52 (d, J = 8.4 Hz, 1H), 4.01ꢀ3.84 (m,
1H), 1.77ꢀ1.62 (m, 1H), 1.60ꢀ1.47 (m, 2H), 1.45 (d, J = 6.6 Hz, 3H), 1.42ꢀ1.26 (m,
3H), 0.95 (t, J = 7.0 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 84.9, 60.2, 28.7,
28.6, 22.8, 14.9, 14.2.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C7H15NO3S 193.0773;
Found 193.0780.
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Benzyl 4ꢀbutylꢀ5ꢀmethylꢀ1,2,3ꢀoxathiazolidineꢀ3ꢀcarboxylate 2,2ꢀdioxide (N-Cbzꢀ2y)
To the solution of 2y (30 mg, 0.16 mmol) in THF (1 mL) was added tꢀBuOK in THF (1 M soln,
0.23 mL, 0.23 mmol). The reaction mixture was stirred for 1 h at rt. Benzyl chloroformate (55 ꢁL,
0.39 mmol) was then added slowly and stirred at rt for 2 h. The reaction mixture was diluted with
EtOAc (20 mL), washed with water and saturated NaCl (aq). The organic layer was separated, dried
over MgSO4 and the solvent was evaporated under reduced pressure. The crude residue was purified
on silica gel column chromatography using EtOAc/hexanes (EA:nꢀHex=1:9 to 1:4) as an eluent to
afford the title compound (41 mg, 69%) as a colorless oil.
Yield: 69% (41 mg as a colorless oil); 99.7% ee (Chiralcel ODꢀH, 5% IPA/nꢀ
hexanes, 0.8 mL/min, 215 nm, tR(major) = 21.7 min, tR(minor) = 24.5 min); [α]D
20 = +24.5 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.49ꢀ7.31 (m, 5H), 5.43ꢀ
5.26 (m, 2H), 5.15ꢀ5.05 (m, 1H), 4.40ꢀ4.28 (m, 1H), 1.78 (p, J = 7.5, 6.7 Hz, 2H),
1.53 (d, J = 6.5 Hz, 3H), 1.44ꢀ1.29 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ
150.6, 135.0, 129.1, 129.0, 128.4, 81.0, 69.8, 62.4, 28.7, 27.7, 23.1, 14.8, 14.2.; HRMS (EI, double
focusing) m/z: [M]+ Calcd for C15H21NO5S 327.1140; Found 327.1139.
(1R,4S,7R)ꢀ7ꢀPhenylꢀ3ꢀoxaꢀ2ꢀthiaꢀ1ꢀazabicyclo[2.2.1]heptane 2,2ꢀdioxide(7)
Yield: 82% (18.4 mg as a white solid); mp: 134.9ꢀ136.2 oC; 99.9% ee (Chiralpak IC, 10%
IPA/nꢀhexanes, 1.0 mL/min, 215 nm, tR(minor) = 22.2 min, tR(major) = 25.4 min); [α]D
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= +4.2 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 7.50ꢀ7.35 (m, 3H), 7.35ꢀ7.25
(m, 2H), 5.62 (s, 1H), 5.49 (s, 1H), 3.87ꢀ3.71 (m, 1H), 3.30ꢀ3.13 (m, 1H), 2.28ꢀ2.11 (m,
1H), 1.87ꢀ1.72 (m, 1H).; 13C NMR (125 MHz, CDCl3) δ 131.7, 129.2, 128.8, 125.8, 89.6, 70.9, 45.9,
27.1.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C10H11NO3S 225.0460; Found 225.0449.
3. Synthesis of tertꢀbutyl (4S,5R)ꢀ5ꢀallylꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidineꢀ3ꢀcarboxylate
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2,2ꢀdioxide (N-Bocꢀ2i)
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To a solution of (4S,5R)ꢀ5ꢀallylꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide (2i, 150 mg, 0.63 mmol)
in CH3CN (5 mL) was added diꢀtertꢀbutyl dicarbonate (273 mg, 1.25 mmol) followed by DMAP(cat.)
and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc
(20 mL), washed with water and saturated NaCl (aq). The organic layer was separated, dried over
MgSO4 and the solvent was evaporated under reduced pressure. The crude residue was purified on
silica gel column chromatography using EtOAc/hexanes (EA:nꢀHex=1:9 to 1:4) as an eluent to afford
the title compound (195 mg, 92%) as a white solid.
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yield: 92% (195 mg as a white solid); mp: 109.7ꢀ111.4 C; [α]D = +6.5 ; 1H
NMR (30 MHz, CDCl3) δ 7.51ꢀ7.34 (m, 5H), 5.77ꢀ5.57 (m, 1H), 5.24ꢀ5.11 (m,
3H), 5.14ꢀ5.00 (m, 2H), 2.18ꢀ1.98 (m, 2H), 1.47 (s, 9H).; 13C NMR (125 MHz,
CDCl3) δ 148.2, 134.1, 130.4, 129.2, 128.9, 127.7, 119.8, 85.5, 81.9, 64.7, 34.1,
27.7.; HRMS (EI, double focusing) m/z: [M]+ Calcd for C16H22NO5S 340.1218;
Found 340.1199.
4. Synthesis of (1S,2S)ꢀ1ꢀ(tꢀBocꢀamino)ꢀ1ꢀphenylpentꢀ4ꢀenꢀ2ꢀyl benzoate (8)
To a solution of (4S,5R)ꢀN-Bocꢀ2i (170 mg, 0.5 mmol) in DMF (5 mL) was added benzoic acid (122
mg, 1.0 mmol) followed by CsF (152 mg, 1.0 mmol) and the mixture was stirred at 60 ℃ for 3 h.
The reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with water
and saturated NaCl (aq). The organic layer was separated, dried over MgSO4 and the solvent was
evaporated under reduced pressure. The crude residue was purified on silica gel column
chromatography using EtOAc/hexanes (EA:nꢀHex=1:9 to 1:3) as an eluent to afford the title
compound (134 mg, 71%) as colorless oil.
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yield: 71% (134 mg as a colorless oil); [α]D = +31.7 ; H NMR (300 MHz,
CDCl3) δ 8.05 (d, J = 7.6 Hz, 2H), 7.64ꢀ7.55 (m, 1H), 7.51ꢀ7.41 (m, 2H), 7.39ꢀ
7.29 (m, 5H), 5.94ꢀ5.75 (m, 1H), 5.46 (q, J = 6.3 Hz, 1H), 5.24 (d, J = 9.4 Hz,
1H), 5.18ꢀ5.06 (m, 2H), 5.07ꢀ4.93 (m, 1Hrlagudf1), 2.44 (t, J = 6.5 Hz, 2H), 1.33
(s, 9H).; 13C NMR (125 MHz, CDCl3) δ 166.3, 155.2, 139.4, 133.1, 132.7, 129.9,
129.7, 128.8, 128.4, 127.9, 127.0, 118.8, 79.7, 75.8, 57.0, 36.1, 28.2.; HRMS (FAB, double focusing)
m/z: [M+H]+ Calcd for C23H28NO4 382.2018; Found 382.2034.
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5. Synthesis of (1S,2S)ꢀtꢀbutyl (2ꢀhydroxyꢀ1ꢀphenylpentꢀ4ꢀenꢀ1ꢀyl)carbamate (9)
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To a solution of (1S,2S)ꢀ1ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ1ꢀphenylpentꢀ4ꢀenꢀ2ꢀyl benzoate (8, 73 mg,
0.19 mmol) in MeOH (5 mL) was added KCN (6.5 mg, 0.1 mmol) and the mixture was stirred at
room temperature for 3 h. The solvent was evaporated under reduced pressure, diluted with EtOAc
(10 mL), washed with water, and saturated NaCl (aq). The organic layer was separated, dried over
MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified on silica gel
column chromatography using EtOAc/hexanes (EA:nꢀHex=1:9 to 1:1) as an eluent to afford title
compound (35 mg, 66%) as a white solid.
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o
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yield: 66% (35 mg as a white solid); mp: 95.5ꢀ96.2 C; [α]D = +13.1 (c 1.0
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.42ꢀ7.34 (m, 2H), 7.34ꢀ7.29 (m, 3H),
5.97ꢀ5.80 (m, 1H), 5.39 (s, 1H), 5.25ꢀ5.19 (m, 1H), 5.16 (d, J = 3.9 Hz, 1H), 4.71
(s, 1H), 3.91 (s, 1H), 2.44ꢀ2.24 (m, 2H), 1.98 (s, 1H), 1.45 (s, 9H).; 13C NMR
(125 MHz, CDCl3) δ 156.0, 136.8, 134.0, 128.7, 127.5, 126.58, 118.6, 79.7, 74.3,
58.1 38.7, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C16H24NO3 278.1756; Found
278.1748.
6. Synthesis of (4R,5S)ꢀ5ꢀmethylꢀ4ꢀphenylꢀ3ꢀ(propꢀ2ꢀynꢀ1ꢀyl)ꢀ1,2,3ꢀoxathiazolidine 2,2ꢀ
dioxide (11)
To a solution of 60% NaH (59 mg, 1.46 mmol) in DMF (3 mL) was added (4R,5S)ꢀ5ꢀmethylꢀ4ꢀ
o
phenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide (2a, 260 mg, 1.22 mmol) at 0 C. After stirring for 30
o
minutes at 0 C, propagyl bromide (218 mg, 1.83 mmol) was added to the reaction mixture. The
mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (10
mL), washed with water, and saturated NaCl (aq). The organic layer was dried over MgSO4 and the
solvent was evaporated under reduced pressure. The residue was purified on silica gel column
chromatography using EtOAc/hexanes (EA:nꢀHex=1:9 to 1:3) as an eluent to afford the title
compound (250 mg, 82%) as a colorless oil.
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yield: 82% (250 mg as a colorless oil); [α]D = ꢀ180.5 (c 1.0 CHCl3); H NMR
(500 MHz, CDCl3) δ 7.50 – 7.35 (m, 5H), 5.26ꢀ5.17 (m, 1H), 4.94 (d, J = 6.7 Hz,
1H), 4.13 (d, J = 18.0 Hz, 1H), 3.70 (d, J = 17.8 Hz, 1H), 2.38 (s, 1H), 1.15 (d, J =
6.4 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 133.0, 129.5, 129.2, 128.3, 80.3, 75.9,
74.8, 65.7, 34.4, 16.6.; HRMS (EI, double focusing) m/z: [M]+ Calcd for
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C12H13NO3S 251.0616; Found 251.0617.
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7. Synthesis of (6R,7R)ꢀ7ꢀmethylꢀ6ꢀphenylꢀ4,5,6,7ꢀtetrahydroꢀ[1,2,3]triazolo[1,5ꢀ
a]pyrazine (13)
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To a solution of (4R,5S)ꢀ5ꢀmethylꢀ4ꢀphenylꢀ3ꢀ(propꢀ2ꢀynꢀ1ꢀyl)ꢀ1,2,3ꢀoxathiazolidine 2,2ꢀ
dioxide (11, 100 mg, 0.40 mmol) in DMF (2 mL) was added NaN3 (52 mg, 0.80 mmol) and the
o
mixture was stirred at 60 C for 3 h. Upon completion, the reaction mixure was cool to room
temperature and contents were diluted with Et2O (4 mL), treated with 1N aqueous HCl (4 mL), and
allowed to stir for an additional 12 h at room temperature. Once this operation was completed, the
reaction mixture was poured into saturated NaHCO3 solution and extracted EtOAc (10 mL x 3). The
combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure.
The residue was purified on silica gel column chromatography using MeOH/DCM
(MeOH:DCM=1:19) as an eluent to afford the title compound (78 mg, 92%) as a white solid.
o
20
yield: 92% (78 mg as a white solid); mp: 149.4ꢀ151.1 C; [α]D = ꢀ103.1 (c
1
1.0 CHCl3); H NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 7.48ꢀ7.38 (m, 5H),
4.49 (p, J = 6.9 Hz, 1H), 4.36 (d, J = 15.1 Hz, 1H), 4.22 (d, J = 15.2 Hz, 1H),
3.78 (d, J = 9.3 Hz, 1H), 2.05 (s, 1H), 1.60 (d, J = 6.4 Hz, 3H).; 13C NMR
(125 MHz, CDCl3) δ 139.1, 131.8, 129.2, 129.0, 128.0, 66.0, 59.4, 41.6, 16.8.; HRMS (EI, double
focusing) m/z: [M]+ Calcd for C12H14N4 214.1218; Found 214.1208.
8. Synthesis of (4R,5S)ꢀ3ꢀbenzylꢀ5ꢀmethylꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide (14)
To a solution of 60% NaH (366 mg, 9.1 mmol) in DMF (10 mL) was added (4R,5S)ꢀ5ꢀmethylꢀ4ꢀ
phenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide (2a, 1.3 g, 6.1 mmol) at 0 oC. After stirring for 30 minutes
at 0 oC, benzyl bromide (1.6 g, 9.1 mmol) was added to the reaction mixture. The mixture was stirred
at room temperature for 5 h. The reaction mixture was diluted with EtOAc (20 mL), washed with
water, and saturated NaCl (aq). The combined organic layers were dried over MgSO4 and the solvent
was removed under reduced pressure. The residue was purified on silica gel column chromatography
using EtOAc/hexanes (EA:nꢀHex=1:9 to 1:3) as an eluent to afford the title compound (1.65 g, 89%)
as a colorless oil.
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yield: 89% (1.65 g as a colorless oil); [α]D = ꢀ102.7 (c 0.5 CHCl3); H NMR
(500 MHz, CDCl3) 7.46 – 7.39 (m, 3H), 7.36 – 7.28 (m, 5H), 7.29 – 7.24 (m, 2H),
5.18 (p, J = 6.4 Hz, 1H), 4.54 (d, J = 14.8 Hz, 1H), 4.45 (d, J = 6.2 Hz, 1H), 3.96
(d, J = 14.8 Hz, 1H), 1.09 (d, J = 6.5 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ
134.4, 133.2, 129.2, 129.0, 128.9, 128.7, 128.4, 128.3, 79.8, 66.2, 48.1, 16.2.;
HRMS (EI, double focusing) m/z: [M]+ Calcd for C16H17NO3S 303.0929; Found
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303.0927.
9. Synthesis of (1R,2R)ꢀ2ꢀazidoꢀNꢀbenzylꢀ1ꢀphenylpropanꢀ1ꢀamine (15)
To a solution of (4R,5S)ꢀ3ꢀbenzylꢀ5ꢀmethylꢀ4ꢀphenylꢀ1,2,3ꢀoxathiazolidine 2,2ꢀdioxide (14, 1.1 g,
3.51 mmol) in DMF (5 mL) was added NaN3 (456 mg, 7.02 mmol) and the mixture was stirred at 60
oC for 3 h. Upon completion, the reaction mixture was cool to room temperature and diluted with Etꢀ
2O (8 mL), treated with 1N aqueous HCl (8 mL), and allowed to stir for an additional 12 h at room
temperature. Once this operation was completed, the reaction mixture was poured into saturated
NaHCO3 solution and extracted with EtOAc (15 mL x 3). The combined organic layers were dried
over MgSO4 and the solvent was removed under reduced pressure. The residue was purified on silica
gel column chromatography using EtOAc/hexanes (EA:nꢀHex=1:9 to 1:3) as an eluent to afford the
title compound (868 mg, 93%) as a colorless oil
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1
yield: 93% (868 mg as a colorless oil); [α]D = ꢀ81.1 (c 0.5 CHCl3); H NMR
(300 MHz, CDCl3) δ 7.44 – 7.27 (m, 10H), 3.72 – 3.56 (m, 2H), 3.50 (s, 1H), 3.46
(d, J = 4.2 Hz, 1H), 2.26 (br, 1H), 1.09 (d, J = 6.5 Hz, 3H).; 13C NMR (125 MHz,
CDCl3) δ 140.2, 140.1, 128.6, 128.4, 128.2, 128.1, 127.9, 126.9, 67.1, 62.9, 51.2,
16.5.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C16H18N4 267.1610;
Found 267.1613.
10. Synthesis of Nꢀ((1R,2R)ꢀ2ꢀazidoꢀ1ꢀphenylpropyl)ꢀNꢀbenzylꢀ2ꢀchloroacetamide (16)
To a solution of (1R,2R)ꢀ2ꢀazidoꢀNꢀbenzylꢀ1ꢀphenylpropanꢀ1ꢀamine (15, 266 mg, 1.0 mmol) in
CH2Cl2 (5 mL) was added Et3N (0.28 mL, 2.0 mmol) followed by chloroacetyl chloride (124 mg, 1.1
mmol) at 0 oC and the mixture was stirred for 2 h at that temperature. Upon completion, the reaction
mixture was poured into saturated NaHCO3 solution and extracted with CH2Cl2 (10 mL x 3). The
combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure.
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The residue was purified on silica gel column chromatography using EtOAc/hexanes (EA:nꢀHex=1:9
to 1:3) as an eluent to afford the title compound (256 mg, 91%) as a colorless oil.
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9
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yield: 91% (256 mg as a colorless oil); [α]D = ꢀ119.5 (c 1.0 CHCl3); H
NMR (500 MHz, CDCl3) δ 7.44ꢀ7.30 (m, 5H), 7.27ꢀ7.17 (m, 3H), 7.12 (d, J =
7.2 Hz, 0.6H), 7.01 (d, J = 6.5 Hz, 1.4H), 5.14 (d, J = 10.1 Hz, 0.7H), 4.90 (d, J
= 17.8 Hz, 0.3H), 4.79 (d, J = 10.9 Hz, 0.3H), 4.73 (d, J = 10.0 Hz, 0.3H), 4.60
(s, 1.4H), 4.56 – 4.46 (m, 0.7H), 4.32 (d, J = 12.0 Hz, 0.3H), 4.07 – 3.86 (m,
2H), 1.23 (d, J = 6.3 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 168.2, 136.7,
136.4, 129.3, 129.0, 129.0, 128.7, 128.5, 127.9, 127.7, 126.5, 65.3, 57.3, 50.0, 42.7, 18.0.; HRMS
(FAB, double focusing) m/z: [M+H]+ Calcd for C18H20ClN4O 343.1326; Found 343.1311.
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11. Synthesis of (5R,6R)ꢀ1ꢀbenzylꢀ5ꢀmethylꢀ6ꢀphenylpiperazinꢀ2ꢀone (17)
To a solution of Nꢀ((1R,2R)ꢀ2ꢀazidoꢀ1ꢀphenylpropyl)ꢀNꢀbenzylꢀ2ꢀchloroacetamide (16, 100 mg, 0.29
o
mmol) in MeOH (2 mL) was added PPh3 (153 mg, 0.58 mmol) and the mixture was stirred at 80 C
for 5 h. Upon completion, the reaction mixture was cooled to room temperature and solvent was
removed under reduced pressure. The reaction mixture was dissolved in EtOAc (10 mL) and washed
with saturated NaHCO3 solution. The separated saturated NaHCO3 solution was reꢀextracted with
EtOAc (10 mL x 3). The combined organic layers were dried over MgSO4 and the solvent was
removed under reduced pressure. The residue was purified on silica gel column chromatography using
MeOH/CH2Cl2 (MeOH: CH2Cl2=1:19) as an eluent to afford the title compound (70 mg, 85%) as a
white soidd.
o
20
yield: 85% (70 mg as a white solid); mp: 102.7ꢀ104.2 C; [α]D = ꢀ23.7 (c 1.0
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.45ꢀ7.34 (m, 3H), 7.34ꢀ7.25 (m, 4H), 7.17
(d, J = 7.3 Hz, 2H), 7.11 (d, J = 7.2 Hz, 2H), 5.54 (d, J = 14.6 Hz, 1H), 3.98 (d, J =
7.2 Hz, 1H), 3.78 (q, J = 17.8 Hz, 2H), 3.35 (d, J = 14.6 Hz, 1H), 3.09ꢀ2.98 (m, 1H),
1.05 (d, J = 6.4 Hz, 3H).; 13C NMR (125 MHz, CDCl3) δ 169.0, 139.0, 136.8, 129.1,
128.7, 128.4, 127.8, 127.5, 67.1, 55.8, 49.2, 46.7, 18.4.; HRMS (EI, double
focusing) m/z: [M]+ Calcd for C18H20N2O 280.1576; Found 280.1567.
12. Synthesis of tertꢀbutyl (2R,3R)ꢀ3ꢀazidoꢀ2ꢀphenylpyrrolidineꢀ1ꢀcarboxylate (19)
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NaN3 (43 mg, 0.67 mmol) was added in a single portion to a solution of (1R,4S,7R)ꢀ7ꢀphenylꢀ3ꢀoxaꢀ2ꢀ
thiaꢀ1ꢀazabicyclo[2.2.1]heptane 2,2ꢀdioxide (7, 50 mg, 0.22 mmol) in mixture of DMF and CH3CN (4
mL, 1:1) at room temperature. The resulting mixture was warmed to 60 °C and stirred for 36 h. Upon
completion, the reaction mixture was cooled to room temperature and the contents were evaporated
under reduced pressure. The crude mixture was dissolved in CH2Cl2, treated with 1N aqueous HCl (3
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mL), and allowed to stir for an additional 30 min at 60 C. Once this operation was completed, the
reaction mixture was poured into saturated NaHCO3 (aq) and extracted with EtOAc (2 x 25 mL). The
combined organic layers were then washed with water, dried (MgSO4), and concentrated. The
resulting solid was dissolved in CH2Cl2 and cooled to 0 oC. (tꢀBoc)2O (58 mg, 0.27 mmol), Et3N (0.06
mL, 0.44 mmol), and DMAP (cat) were added to this solution. The reaction mixture was stirred at rt
for 3 h, quenched with saturated NaHCO3 (aq) and extracted with EtOAc (2 x 25 mL). The combined
organic layers were then washed with water, dried (MgSO4), and concentrated and the residue was
purified on silica gel column chromatography using EtOAc/hexanes as an eluent to afford 15 (42 mg,
66%) as a white solid.
yield: 66% (42 mg as a white solid); mp: 71.2ꢀ72.8 oC; [α]D 23 = ꢀ23.6 (c 1.0, CHCl3);
1H NMR (500 MHz, (CD3)2CO) δ 7.38ꢀ7.25 (m, 5H), 5.04 (br, 1H), 4.41 (br, 1H),
3.70 (br, 1H), 3.64ꢀ3.59 (m, 1H), 2.29ꢀ2.23 (m, 1H), 2.04ꢀ1.98 (m, 1H), 1.43 (s, br,
3H), 1.13 (s, br, 6H); 13C NMR (125 MHz, CDCl3) δ 154.2, 138.7, 128.2, 127.6,
127.0, 79.9, 64.1, 63.6, 44.5, 28.3, 28.0.; HRMS (FAB, double focusing) m/z: [M+H]+ calcd for C15Hꢀ
20N4O2 289.1665, found 289.1653.
13. Base (DBU, Et3N, DABCO, iꢀPr2NEt, and pyridine)ꢀmediated racemization of (S)ꢀ1a
(5S)ꢀ1a (50 mg, 0.24 mmol, 93% ee) was dissolved in CH3CN (2 mL) and base (0.48 mmol) was
added in one portion. After stirring for 1 min at room temperature, the reaction mixture was quickly
quenched with 1N HCl solution (5 mL) and diluted with EtOAc (10 mL). The organic layer was
separated and washed with water, saturated NaHCO3 solution, and dried over MgSO4. The solvent
was removed under reduced pressure to give crude (5S)ꢀ1a (quantitative recovery). The residue was
subjected to chiral HPLC analysis. (Chiralpak ADꢀH, 5% isopropanol/hexanes, 1.0 mL/min, 215 nm)
Recovered (5S)ꢀ1a: 0.4% ee with DBU, 9.1% ee with Et3N, 15.0% ee with DABCO, 18.5% ee with iꢀ
Pr2NEt, 92% ee with pyridine.
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