Organocatalytic enantioselective tandem aldol-cyclization reaction of α-isothiocyanato imides and activated carbonyl compounds

Article abstract of DOI:10.1016/j.tetasy.2011.06.028

The organocatalytic enantioselective tandem aldol-cyclization reactions of α-isothiocyanato imides and activated carbonyl compounds, such as isatins, an α-ketolactone and a 1,2-dione, have been studied with cinchona alkaloid-derived thiourea-catalysts. Th

Full text of DOI:10.1016/j.tetasy.2011.06.028

Tetrahedron: Asymmetry 22 (2011) 1205–1211
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Organocatalytic enantioselective tandem aldol-cyclization reaction
of
a
-isothiocyanato imides and activated carbonyl compounds
⇑
Jie Guang, Cong-Gui Zhao
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0698, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The organocatalytic enantioselective tandem aldol-cyclization reactions of a-isothiocyanato imides and
activated carbonyl compounds, such as isatins, an a-ketolactone and a 1,2-dione, have been studied with
cinchona alkaloid-derived thiourea-catalysts. This methodology provided an easy way to access enanti-
omerically enriched spirobicyclic thiocarbamates with high yields and good to excellent stereoselectivity,
which have been demonstrated to be useful precursors for the synthesis of biologically active molecules.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 25 May 2011
Accepted 27 June 2011
Available online 4 August 2011
1. Introduction
tions for the asymmetric synthesis of molecules of biological signif-
icance.8 In this regard, we have recently reported the first quinine
Cyclic thiocarbamates are a very useful class of compounds in
modern organic synthesis.1 Moreover, many compounds containing
this structural motif show interesting biological and pharmacolog-
ical activities.2 Due to their importance, there has been a lot of
interest in developing an asymmetric synthesis of these heterocy-
cles and their derivatives in recent years.3 These interesting hetero-
cyclic compounds can be synthesized by the direct condensation of
carbon disulfide and b-aminoalcohols.4 Nevertheless, this method
cannot be made enantioselective. Since tandem reactions are a
powerful tool for assembling complex organic structures from rel-
atively simple starting materials,5 a better way to assemble these
heterocycles utilizes the tandem aldol6-cyclization reaction
between isothiocyanatoalkanes and aldehydes or ketones.7 Asym-
metric versions of the latter strategy have already been reporte-
d.3a–e For example, Willis et al. reported the first enantioselective
synthesis of cyclic thiocarbamates using Mg-PYBOX as the
catalyst.3a Recently, Shibasaki and co-workers developed a highly
enantioselective synthesis of these derivatives using Mg–Schiff
base complexes as catalysts.3b On the other hand, Seidel and
co-workers reported the first organocatalyzed tandem aldol-
thiourea-catalyzed cross aldol reaction of isatins and unactivated
ketones via an enolate mechanism, in which isatin was demon-
strated to be an excellent enolate acceptor in cross aldol reactions.8d
Inspired by the work of Siedel and co-workers and Wang and co-
workers on the reaction of
ers,3d,e we envisioned that an organocatalyzed tandem aldol-cycli-
zation reaction of -isothiocyanato imides and activated carbonyl
a-isothiocyanato imides and a-ketoest-
a
compounds, such as isatins, should lead to the enantioselective syn-
thesis of cyclic thiocarbamates with a spiro indolinone substituent,
a unique structural feature that may have interesting biological rel-
evance.9,10 Herein we report a cinchonidine thiourea-catalyzed11
tandem aldol-cyclization reaction for the highly stereoselective
synthesis of 20-thioxospiro[indoline-3,50-oxazolidin]-2-one deriva-
tives. It should be mentioned that, while our work was still under
progress, Wang and co-workers reported a rosin-derived thio-
urea-catalyzed synthesis of similar derivatives.10
2. Results and discussion
Amine thioureas, especially those derived from cinchona
alkaloids, have been proven to be powerful catalysts in a wide
range of asymmetric transformations involving enolate intermedi-
ates.11,12 These bifunctional catalysts are able to activate both
nucleophiles and electrophiles. Moreover, the thiourea moiety
can also help improve stereoselectivities by directing the approach
of the substrates with hydrogen bonding. We envisioned that these
thioureas should also be good catalysts for the present reaction.
Thus, several amine thioureas, mainly those derived from cinchona
alkaloids 6a–d, 6h, and 6i, (Fig. 1) were selected as catalysts for the
preliminary screening. For the sake of comparison, some cinchona
alkaloids 6e–g without the thiourea moiety were also screened
(Fig. 1).
cyclization reaction between
a-isothiocyanato imides and alde-
hydes for the enantioselective synthesis of cyclic thiocarbamates,
which may be used for the synthesis of enantiomerically enriched
a
-hydroxy-b-amino acids.3c Most recently, the tandem aldol-
cyclization reaction of
a-isothiocyanato imides and a-ketoesters
were also independently reported by Wang and co-workers and
Seidel and co-workers.3d,e
Our group is interested in using activated carbonyl compounds
as enamine or enol acceptors in novel organocatalyzed aldol reac-
⇑
Corresponding author. Tel.: +1 210 458 5432; fax: +1 210 458 7428.
E-mail address: cong.zhao@utsa.edu (C.-G. Zhao).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.028

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J. Guang, C.-G. Zhao / Tetrahedron: Asymmetry 22 (2011) 1205–1211
CF3
CF3
alkaloid catalysts 6e–g that did not carry a thiourea moiety all led
to poor enantioselectivities (Table 1, entries 7–9), although the de-
sired product was also obtained in high yields and with similar dia-
stereoselectivities. Takemoto’s thiourea 6h was also screened in
this reaction and good results were obtained (entry 10); nonethe-
less, the ee value obtained for the major diastereomer was slightly
inferior to that with catalyst 6d. In contrast, the less basic 1,10-
binaphthyl-2,20-diamine-derived thiourea catalyst 6i gave only
trace amounts of the product (entry 11). These results indicate that
the thiourea moiety is crucial for maintaining high enantioselectiv-
ity in this reaction. However, the diastereoselectivity of this reac-
tion is largely independent of the catalyst structure (e.g., catalyst
6i gives a similar dr as those cinchona alkaloid catalysts). With
the best catalyst in hand, the solvent used in this reaction was opti-
mized further. We found that the solvent did not have major influ-
ence on the enantioselectivity of the reaction (entries 12–18), but it
did show some influence on the diastereoselectivity and the reac-
tion rate. Among the common solvents screened, diethyl ether ap-
peared to be the best, in which the highest dr, ee, and the
reaction rate were obtained (entry 13). Conducting the reaction at
a lower temperature (5 °C) under the optimized conditions proved
to be counterproductive, since lower diastereoselectivity, enanti-
oselectivity, and reaction rates were observed (entry 19)
S
S
NH
F3C
N
H
HN
N
H
CF3
N
N
N
H
R
H
R
N
6a: R = OMe
6b: R = H
6c: R = OMe
6d: R = H
OH
CF3
NMe2
N
S
H
N
N
N
H
CF3
H
R
6e:
6h
R = H
6f: R = OH
6g:
R = OMe
The reaction of 2c with various isatin derivatives was then eval-
uated under optimized reaction conditions, and the results are
summarized in Table 2. As shown by the results in Table 2, besides
isatin 1a, a number of substituted isatins bearing either an elec-
tron-withdrawing or an electron-donating group all gave high ee
values of the desired products (P94% ee, entries 1–4; 6–9), with
the exception of 5-bromoisatin, which produced a slightly lower
ee value of 88% (entry 5). Furthermore, the product yields were
almost quantitative in most cases. Although the substituents on
the isatin aromatic ring did show some influence on the diastere-
oselectivity, the variation in diastereoselectivity is quite small.
According to the data, both the substituent position on the phenyl
ring and its electronic nature can exert some influence on the dia-
stereoselectivity. For example, 4-bromoisatin 1c (entry 3) gave a
slightly higher dr than 5-bromoisatin 1e (entry 5) and 6-bromoi-
satin 1g (entry 7). As an example of the electronic effects, 5-meth-
oxyisatin 1f (entry 6) leads to a higher dr value of the product than
5-bromoisatin 1e (entry 5) or 5-fluoroisatin 1d (entry 4). Lower
diastereoselectivity was obtained for the N-benzyl protected isatin
1i (entry 9), which might be due to the steric effects.
In addition to isatins, some other activated carbonyl compounds
were also studied (Scheme 1). The reaction of 4,4-dim-
ethyldihydrofuran-2,3-dione 7 and 2c under the optimized reac-
tion conditions led to a high yield (91%) of the desired product 8.
The stereoselectivity of this reaction was also excellent (92:8 dr,
94% ee, Scheme 1, top equation). 1,2-Cyclohexanedione 9 is also
an activated electrophile for enolate.14 Its reaction with 2c has also
been studied.15 Although the desired product 10 was obtained in a
lower yield (51%) and mediocre diastereoselectivity (65:35), the ee
value of the major enantiomer was excellent (90%, Scheme 1, lower
equation).
NMe2
H
H
N
N
CF3
S
CF3
6i
Figure 1. Catalysts screened for the tandem aldol-cyclization reaction of isatin 1a
and -isothiocyanatoacetate derivatives 2.
a
With isatin 1a as the substrate and quinidine thiourea 6a as the
catalyst, we first screened several -isothiocyanatoacetate deriva-
a
tives 2a–c. The results of this screen are collected in Table 1. As
shown in Table 1, under the catalysis of 6a, the reaction between
isatin 1a and methyl
a-isothiocyanatoacetate 2a in toluene at rt
for 24 h afforded the desired product 3 in 65% yield with a low
dr ratio of 56:44 and poor ee value of 35% (entry 1). Replacing
the methoxy group in 2a with an oxazolidinone group 2b13 led
to a dramatic improvement of the reactivity (entry 2); the reaction
time was reduced to 3 h and the yield for 4 was improved to 90%.
Moreover, although the dr was not much improved, the ee value of
the product improved to 75% (entry 2). Higher diastereoselectivity
(78:22) was achieved when two methyl groups were introduced
onto the oxazolidinone moiety at the C4 position (2c, entry 3).
The ee value of product 5a was also improved to 88% (entry 3).
Thus, among the three a-isothiocyanatoacetate derivatives, isothi-
ocyanato imide 2c provided the best stereocontrol in this reaction.
A similar trend was also observed by Siedel and co-workers.3c Since
2c yielded the best results, it was chosen as the model substrate in
our further screening (Table 1).
The absolute configuration of the major enantiomer of com-
pound 5a obtained in the reactions between isatin 1a and a-isoth-
Next, the other amine thiourea catalysts were screened. Cincho-
nine-derived thiourea 6b gave very similar results to 6a (entry 4).
Quinine thiourea 6c, the pseudo enantiomer of 6a, gave almost ex-
actly the same results as 6a, with the exception that the major
enantiomer obtained was the opposite to that obtained with 6a (en-
try 5). Among these cinchona alkaloid thiourea congeners, cincho-
nidine thiourea 6d was found to be superior to the other catalysts
in terms of both the diastereoselectivity and enantioselectivity ob-
tained for the product: 5a was obtained in a dr ratio of 81:19 with
95% ee for the major diastereomer (entry 6). In contrast, cinchona
iocyanato imide 2c was determined to be (3R,40S) by X-ray
crystallography analysis (Fig. 2).17 The stereochemistry of the other
products was assigned on the basis of the reaction mechanism.
On the basis of the stereochemistry of the major stereoisomer
obtained herein and the previously reported mechanisms10,16 for
these bifunctional cinchona alkaloid-derived thioureas, a plausible
mechanism of this reaction was proposed. As shown in Scheme 2,
the tertiary amine in the cinchonidine-thiourea catalyst backbone
first deprotonates one of the acidic
a-protons from the imide 2c.
After deprotonation, 2c closely associates with the catalyst through

J. Guang, C.-G. Zhao / Tetrahedron: Asymmetry 22 (2011) 1205–1211
1207
Table 1
Catalyst screening and optimization of the reaction conditionsa
S
O
O
NH
*
O
O
O
O
cat. (10 mol %)
*
2a/3: R = OMe;
2b/4: R =
N
O
; 2c/5a: R =
O
SCN
R
N
O
+
R
solvent, rt
N
H
O
N
H
1a
2a-2c
3, 4, 5a
Entry
a
-Isothiocyanato derivative
Catalyst
Solvent
Time (h)
Yieldb (%)
drc
eed (%)
Configuratione
1
2
3
4
5
6
7
8
2a
2b
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
6a
6a
6a
6b
6c
6d
6e
6f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
Et2O
Benzene
CH2Cl2
DME
THF
1,4-Dioxane
Et2O
24
3
3
3
3
3
5
5
5
2
24
6
2
2
2
5
3
5
65
90
98
99
99
99
90
98
99
99
0h
97
99
99
99
97
98
99
98
56:44
64:36
78:22
76:24
77:23
81:19
74:26
83:17
73:27
80:20
—
75:25
85:15
83:17
70:30
85:15
81:19
84:16
79:21
35
75
88
86
88
95
43
52
51
90
—
93
95
94
95
95
89
95
91
ndf
(3S,40R)g
(3S,40R)
(3S,40R)
(3R,40S)
(3R,40S)
(3R,40S)
(3R,40S)
(3R,40S)
(3S,40R)
—
9
6g
6h
6i
10
11
12
13
14
15
16
17
18
19i
6d
6d
6d
6d
6d
6d
6d
6d
(3R,40S)
(3R,40S)
(3R,40S)
(3R,40S)
(3R,40S)
(3R,40S)
(3R,40S)
(3R,40S)
24
a
b
c
d
e
f
Unless otherwise specified, all reactions were performed with 2 (0.050 mmol), 1 (0.060 mmol, 1.2 equiv), and the catalyst (10 mol %) in the specified solvent (1.0 mL) at rt.
Combined yield of both diastereomers after column chromatography.
Determined by 1H NMR analysis of the crude product.
Determined by HPLC analysis using a ChiralCel OD-H column.
Unless otherwise indicated, the absolute configuration of the product was determined by X-ray crystallography.
Not determined.
The absolute configuration of this product was assigned based on the reaction mechanism.
Only trace amounts of the product were detected.
The reaction was carried out at 5 °C.
g
h
i
Table 2
Reaction of isatin derivatives and 2c as catalyzed by 6da
S
O
NH
O
O
O
O
SCN
6d (10 mol %)
R1
O
N
+
N
O
R1
Et2O, rt, 2 h
O
O
N
N
R2
O
R2
1
2c
5
Entry
R1
R2
1/5
Yieldb (%)
drc
eed
1
2
3
4
5
6e
7
8
9
H
H
H
H
H
H
H
H
H
Bn
a
b
c
d
e
f
g
h
i
98
95
99
98
90
90
98
96
99
85:15
78:22
85:15
78:22
81:19
86:14
80:20
85:15
70:30
95
98
95
95
88
97
95
96
94
4-Cl
4-Br
5-F
5-Br
5-OMe
6-Br
4,7-diCl
H
a
b
c
All reactions were conducted with 2 (0.050 mmol), 1 (0.060 mmol, 1.2 equiv), and catalyst 6d (10 mol %) in Et2O (1.0 mL) at rt.
Combined yield of both diastereomers after column chromatography.
Determined by 1H NMR analysis of the crude product.
Determined by HPLC analysis on a ChiralCel OD-H column.
Reaction was carried out with 2 equiv of 1f.
d
e
ionic interactions between the imide moiety and the ammonium.
Simultaneously, two hydrogen bonds are formed between the
two carbonyl groups of isatin and the thiourea moiety of the cata-
lyst. In addition to activating the ketone group toward enolate at-
tack, these hydrogen bonds also direct the orientation of isatin.
Amongst the two possible orientations, the si face orientation is fa-

1208
J. Guang, C.-G. Zhao / Tetrahedron: Asymmetry 22 (2011) 1205–1211
S
O
O
O
NH
O
O
SCN
O
O
6d (10 mol %)
N
+
O
Et2O, rt, 2 h
N
O
O
O
O
7
2c
8
91% yield, 92:8 dr, 94% ee
S
O
O
O
O
NH
O
SCN
O
6d (10 mol %)
N
+
O
Et2O, rt, 4 d
N
O
O
10
O
9
2c
51% yield, 65:35 dr, 90% ee
Scheme 1. Tandem aldol-cyclization reaction of activated carbonyl compounds with 2c catalyzed by 6d.
various activated carbonyl compounds is a facile method for the
enantioselective synthesis of spirobicyclic thiocarbamates, which
may be used for the synthesis of biologically active spiroindoline
phytoalexin analogues.10 The desired products can be obtained
in high yields, excellent enantioselectivities, and with good
diastereoselectivities.
4. Experimental
4.1. General
Unless otherwise noted, 1H, and 13C NMR spectra were recorded
on a 300 MHz spectrometer (75 MHz for 13C). Melting points were
recorded in open capillaries and are uncorrected. TLC was per-
formed with silica gel GF254 precoated on plastic plates and spots
were visualized with UV. Flash column chromatography was per-
formed on silica gel. HPLC analysis was performed on a Shimadzu
HPLC instrument equipped with a UV–Vis detector. ChiralCel and
ChiralPak HPLC columns were purchased from Daicel Chemical
Industry, Ltd Microanalyses were conducted by Atlantic Microlab,
Inc (6180 Atlantic Blvd. Suite M, Norcross, Georgia 30071, USA).
Compounds used herein were purchased from Aldrich, Alfa-Aesar,
Figure 2. ORTEP drawing of compound 5a (THF solvate).
or TCI and were used as received. Catalysts 6a–d,18 h,19 20 and iso-
i
thiocyanate 2b,3c c3c were prepared according to the literature
procedures.
vored (Scheme 2, top left) since unfavorable interactions between
the isatin benzene ring and the oxazolidinone moiety of 2c is
avoided. The attack of the
a-isothiocyanato imide from the back
4.2. Representative procedure for the enantioselective tandem
onto the re face of the isatin produces the product with the ob-
served configuration (3R,40S). In contrast, the re face orientation
of the isatin (Scheme 1, bottom left) is disfavored due to the steric
interactions. An intramolecular reaction between the hydroxy
group of the resulting aldol intermediate and the isothiocyanate
group affords the observed spirocyclic product 5a. The observed
aldol-cyclization reaction of
isatins 1 using cinchonidine thiourea 6d as the catalyst
a-isothiocyanato imide 2c with
a
-Isothiocyanato imide 2c (10.7 mg, 0.050 mmol) and catalyst
6d (2.8 mg, 0.005 mmol, 10 mol %) were dissolved in diethyl ether
(1.0 mL) in glass vial while stirring. Isatin 1a (8.8 mg,
a
improvement in the ee values of the products when the a-isothio-
0.060 mmol) was added and the mixture was further stirred at
room temperature for 2 h. The reaction progress was monitored
by TLC analysis. Upon completion, the solvent was removed under
reduced pressure and the crude product was purified by flash col-
umn chromatography on silica gel (1:1 hexane/ethyl acetate) to
give the desired product.
cyanato imide is introduced with two methyl groups at the 4-posi-
tion of the five-membered ring (Table 1, entries 2 and 3) may be
rationalized with these proposed transition states, since an in-
crease of the steric bulk at the oxazolidinone moiety further disfa-
vors the si face attack.
3. Conclusion
4.2.1. (3R,40S)-Ethyl 2-oxo-20-thioxospiro[indoline-3,50-
oxazolidine]-40-carboxylate 3
In conclusion, we have demonstrated that the cinchonidine
thiourea-catalyzed tandem aldol-cyclization reaction between
3-(2-isothiocyanatoacetyl)-4,4-dimethyloxazolidin-2-one 2c and
White solid; yield: 9.0 mg (65%); mp 108–111 °C; Mixture of
two diastereomers: 1H (300 MHz, acetone-d6): d = 3.41 and 3.56
(s, 3H), 5.08 and 5.29 (s, 1H), 7.01–7.69 (m, 4H), 9.61, 9.79 and

J. Guang, C.-G. Zhao / Tetrahedron: Asymmetry 22 (2011) 1205–1211
1209
CF3
O
S
O
N
N
H
CF3
HN
N
C
S
O
O
favored
N
H
Ar
O
O
O
O
HN
O
HN
NCS
N
O
O
S
O
N
NH
O
NH
O
O
O
C
S
N
O
O
O
N
H
O
HN
CF3
S
S
N
H
HN
CF3
NH
O
O
N
H
disfavored
Ar
N
O
O
O
O
O
O
N
O
NH
H
NCS
N
O
Ar =
N
Scheme 2. Proposed transition states of the tandem aldol-cyclization reaction between isatin and 2c.
9.94 (br, 2H); mixture of two diastereomers: 13C (75 MHz, acetone-
d6): d = 52.5 and 52.6, 64.3 and 64.5, 85.8 and 86.4, 111.2 and
111.4, 123.3 and 123.6, 125.4 and 125.8, 126.0, 132.5 and 132.6,
95% ee. Enantiomeric excess of the product was determined by chi-
ral stationary phase HPLC analysis using ChiralCel OD-H (hexanes:
i-PrOH 90:10 at 1.0 mL/min), major isomer: tR = 47.0 min, minor
isomer: tR = 97.5 min. HRMS calcd. for C16H15N3O5S: 362.0811
(M+1); found: 362.0807.
143.0 and 143.3, 167.2, 171.8 and 172.3, 188.2 and 188.7; mmax
:
1103, 1169, 1470, 1618, 1728, 1756, 3234 cmꢀ1. ½a D25
¼ ꢀ34:7 (c
ꢁ
0.27, MeOH), 35% ee. Anal. calcd for C12H10N2O4S: C, 51.79; H,
3.62; N, 10.07. Found: C, 52.01; H, 3.72; N, 9.87.
4.2.4. (3R,40S)-4-Chloro-40-(4,4-dimethyl-2-oxooxazolidine-3-
carbonyl)-20-thioxospiro[indoline-3,50-oxazolidin]-2-one 5b
White solid; yield: 18.8 mg (95%); mp 188–190 °C; 1H
(300 MHz, acetone-d6): d = 1.58 (d, J = 6.3 Hz, 6H), 4.16 (s, 2H),
5.67 (s, 1H), 6.91–7.39 (m, 3H), 9.42 (s, 1H), 9.96 (s, 1H); 13C
(75 MHz, acetone-d6): d = 23.7, 23.9, 61.1, 64.0, 76.4, 87.5, 109.7,
4.2.2. (3R,40S)-40-(2-Oxooxazolidine-3-carbonyl)-20-
thioxospiro[indoline-3,50-oxazolidin]-2-one 4
White solid; yield: 15.1 mg (90%); mp 203–205 °C; 1H
(300 MHz, DMSO-d6): d = 3.79–4.03 (m, 2H), 4.37–4.52 (m, 2H),
5.48 (s, 1H), 6.88–7.39 (m, 4H), 10.88 (br, 2H); 13C = (75 MHz,
DMSO-d6): d = 42.38, 63.4, 63.9, 86.2, 110.6, 122.7, 123.0, 127.3,
123.7, 125.5, 130.7, 132.8, 144.8, 154.9, 166.6, 169.4, 188.3; mmax
:
.
1096, 1174, 1240, 1308, 1515, 1621, 1730, 1764, 3291 cmꢀ1
131.4, 141.9, 154.1, 165.8, 169.3, 187.8; ½a D25
ꢁ
¼ þ129:1 (c 0.18,
½
a 2D5
ꢁ
¼ þ63:1 (c 1.04, THF), 98% ee. Enantiomeric excess of the
MeOH), 75% ee.
m
max: 1033, 1173, 1241, 1398, 1470, 1538, 1734,
product was determined by chiral stationary phase HPLC analysis
using ChiralCel OD-H (hexanes/i-PrOH 90:10 at 1.0 mL/min), major
isomer: tR = 50.4 min, minor isomer: tR = 84.8 min. HRMS calcd for
1762, 3216 cmꢀ1. HRMS calcd for C14H12N3O5S: 334.0498 (M+H);
found: 334.0490.
C
16H15ClN3O5S: 396.0421 (M+H); found: 396.0372.
4.2.3. (3R,40S)-40-(4,4-Dimethyl-2-oxooxazolidine-3-carbonyl)-
20-thioxospiro[indoline-3,50-oxazolidin]-2-one 5a
4.2.5. (3R,40S)-4-Bromo-40-(4,4-dimethyl-2-oxooxazolidine-3-
carbonyl)-20-thioxospiro[indoline-3,50-oxazolidin]-2-one 5c
White solid; yield: 21.8 mg (99%); mp 208–210 °C; 1H
(300 MHz, acetone-d6): d = 1.58 (d, J = 8.1 Hz, 6H), 4.16 (dd,
J = 10.5, 8.7 Hz, 2H), 5.72 (s, 1H), 6.94–7.31 (m, 3H), 9.41 (s, 1H),
9.95 (s, 1H); 13C (75 MHz, acetone-d6): d = 24.2, 24.5, 61.7, 64.6,
76.9, 88.6, 110.7, 119.3, 127.5, 127.8, 133.4, 145.6, 155.3, 167.1,
White solid; yield: 17.8 mg (98%); m.p.167–169 °C; 1H
(300 MHz, acetone-d6): d = 1.60 (d, J = 6.3 Hz, 6H), 4.15 (d, J = 8.7
Hz, 1H), 4.20 (d, J = 8.7 Hz, 1H), 5.49 (s, 1H), 6.95–7.48 (m, 4H),
9.42 (s, 1H), 9.70 (s, 1H); 13C (75 MHz, acetone-d6): d = 23.7,
24.0, 61.1, 65.1, 76.4, 87.3, 110.8, 123.1, 123.4, 128.3, 131.6,
142.5, 155.2, 166.9, 169.6, 189.7;
mmax: 1025, 1095, 1254, 1304,
1511, 1622, 1735, 1770, 3255 cmꢀ1. ½a D25
ꢁ
¼ þ89:0 (c 0.87, THF)
170.0, 188.8; mmax: 1105, 1174, 1251, 1446, 1536, 1716, 1774,

1210
J. Guang, C.-G. Zhao / Tetrahedron: Asymmetry 22 (2011) 1205–1211
3150 cmꢀ1. ½a 2D5
ꢁ
¼ þ73:7 (c 0.99, MeOH), 95% ee. Enantiomeric ex-
4.2.10. (3R,40S)-4,7-Dichloro-40-(4,4-dimethyl-2-oxooxazoli-
dine-3-carbonyl)-20-thioxospiro[indoline-3,50-oxazolidin]-2-
one 5h
cess of the product was determined by chiral stationary phase
HPLC analysis using ChiralCel OD-H (hexanes/i-PrOH 90:10 at
1.0 mL/min), major isomer: tR = 58.9 min, minor isomer:
tR = 95.1 min. Anal. calcd for C16H14BrN3O5S: C, 43.65; H, 3.21; N,
9.54. Found: C, 43.41; H, 3.03; N, 9.35.
White solid; yield: 20.5 mg (96%); mp 214–216 °C; 1H
(300 MHz, acetone-d6): d = 1.58 (d, J = 9.0 Hz, 6H), 4.18 (s, 2H),
5.68 (s, 1H), 7.14–7.47 (m, 2H), 9.50 (s, 1H), 10.33 (s, 1H); 13C
(75 MHz, DMSO-d6): d = 23.7, 23.8, 60.6, 63.5, 75.8, 86.7, 113.8,
4.2.6. (3R,40S)-40-(4,4-Dimethyl-2-oxooxazolidine-3-carbonyl)-
5-fluoro-20-thioxospiro[indoline-3,50-oxazolidin]-2-one 5d
White solid; yield: 18.6 mg (98%); mp 194–196 °C; 1H
(300 MHz, DMSO-d6): d = 1.51 (d, J = 9.0 Hz, 6H), 4.15 (dd,
J = 19.5, 9.0 Hz, 2H), 5.39 (s, 1H), 6.87–7.21 (m, 3H), 10.79 (b,
1H), 10.83 (s, 1H); 13C (75 MHz, DMSO-d6): d = 23.6, 23.7, 60.5,
64.0, 75.7, 86.2, 110.7, 111.1, 111.5, 111.6, 117.6, 117.9, 128.5.
124.3, 124.8, 126.1, 128.2, 142.2, 154.5, 165.8, 169.3, 186.6; mmax
:
.
1107, 1163, 1249, 1317, 1507, 1613, 1772, 3241 cmꢀ1
½
a 2D5
ꢁ
¼ þ78:3 (c 0.54, THF), 96% ee. Enantiomeric excess of the
product was determined by chiral stationary phase HPLC analysis
using ChiralCel OD-H (hexanes/i-PrOH 92:8 at 1.0 mL/min), major
isomer: tR = 69.5 min, minor isomer: tR = 107.6 min. HRMS calcd
for C16H14Cl2N3O5S: 430.0031 (M+H); found: 430.0026.
128.6, 138.4, 154.4, 166.1, 169.3, 187.6; mmax: 1047, 1097, 1165,
1253, 1486, 1510, 1731, 1768, 3224 cmꢀ1. ½a D25
¼ þ95:2 (c 0.45,
ꢁ
4.2.11. (3R,40S)-1-Benzyl-40-(4,4-dimethyl-2-oxooxazolidine-3-
carbonyl)-20-thioxospiro[indoline-3,50-oxazolidin]-2-one 5i
White solid; yield: 22.3 mg (99%); mp 124–125 °C; 1H
(300 MHz, acetone-d6): d = 1.62 (d, J = 8.7 Hz, 6H), 4.18 (dd,
J = 12.9, 8.7 Hz, 2H), 4.96 (dd, J = 27.3, 15.9 Hz, 2H), 5.57 (s, 1H),
6.91–7.53 (m, 9H), 9.33 (s, 1H), 13C (75 MHz, acetone-d6):
d = 25.0, 25.2, 45.3, 62.3, 66.1, 66.2, 77.7, 88.2, 111.6, 124.5,
125.0, 128.9, 129.0, 130.1, 132.8, 137.0, 144.7, 155.4, 168.1,
THF), 95% ee. Enantiomeric excess of the product was determined
by chiral stationary phase HPLC analysis using ChiralCel OD-H
(hexanes/i-PrOH 92:8 at 1.0 mL/min), major isomer: tR = 60.0 min,
minor isomer: tR = 92.4 min. Anal. calcd for C16H14FN3O5SꢂCH3OH:
C, 49.63; H, 4.31; N, 10.31. Found: C, 49.44; H, 3.93; N, 10.67.
4.2.7. (3R,40S)-5-Bromo-40-(4,4-dimethyl-2-oxooxazolidine-3-
carbonyl)-20-thioxospiro[indoline-3,50-oxazolidin]-2-one 5e
White solid; yield: 19.8 mg (90%); mp 209–211 °C; 1H
(300 MHz, acetone-d6): d = 1.59 (d, J = 2.7 Hz, 6H), 4.16 (dd, J =
15.0, 8.7 Hz), 5.55 (s, 1H), 6.95–7.62 (m, 3H), 9.34 (s, 1H), 9.87 (s,
1H); 13C (75 MHz, acetone-d6): d = 24.3, 24.5, 61.7, 65.5, 77.0,
87.3, 113.4, 115.3, 127.0, 130.9, 135.0, 142.4, 155.8, 167.2, 169.8,
169.9, 190.8; mmax
:
1030, 1154, 1245, 1611, 17034, 1766,
3240 cmꢀ1. ½a 2D5
ꢁ
¼ þ87:0 (c 0.87, THF), 94% ee. Enantiomeric ex-
cess of the product was determined by chiral stationary phase
HPLC analysis using ChiralCel OD-H (hexanes/i-PrOH 85:15 at
1.0 mL/min), major isomer: tR = 31.0 min, minor isomer:
tR = 50.5 min. Anal. calcd for C23H21N3O5S: C, 61.18; H, 4.69; N,
9.31. Found: C, 60.96; H, 4.66; N, 9.20.
189.8; mmax
:
1025, 1183, 1254, 1472, 1508, 1731, 1765,
¼ þ58:7 (c 0.78, THF), 88% ee. Enantiomeric ex-
3229 cmꢀ1. ½a 2D5
ꢁ
cess of the product was determined by chiral stationary phase
HPLC analysis using ChiralCel OD-H (hexanes/i-PrOH 90:10 at
1.0 mL/min), major isomer: tR = 35.5 min, minor isomer:
tR = 54.5 min. Anal. calcd for C16H14BrN3O5S: C, 43.65; H, 3.21; N,
9.54. Found: C, 43.41; H, 3.03; N, 9.28.
4.2.12. (4S,5R)-4-(4,4-Dimethyl-2-oxooxazolidine-3-carbonyl)-
8,8-dimethyl-2-thioxo-1,7-dioxa-3-aza-spiro[4.4]nonan-6-one 8
White solid; yield: 15.6 mg (91%); mp 208–210 °C; 1H
(300 MHz, acetone-d6): d = 1.24 (s, 3H), 1.39 (s, 3H), 1.57 (s, 6H),
4.22 (m, 4H), 5.76 (s, 1H), 9.05 (s, 1H); 13C (75 MHz, acetone-d6):
d = 21.7, 21.8, 24.0, 24.5, 44.5, 61.9, 62.1, 76.8, 77.7, 92.9, 155.4,
4.2.8. (3R,40S)-40-(4,4-Dimethyl-2-oxooxazolidine-3-carbonyl)-
5-methoxy-20-thioxospiro[indoline-3,50-oxazolidin]-2-one 5f
White solid; yield: 17.6 mg (90%); mp 209–211 °C; 1H
(300 MHz, acetone-d6): d 1.59 (d, J = 5.1 Hz, 6H), 3.78 (s, 3H),
4.15 (dd, J = 13.5, 8.7 Hz, 2H), 5.51 (s, 1H), 6.86–7.07 (m, 3H),
9.22 (s, 1H), 9.53 (s, 1H); 13C (75 MHz, acetone-d6): d = 24.3, 24.6,
56.2, 61.6, 65.6, 77.0, 88.2, 110.9, 112.0, 116.7, 129.8, 136.2,
168.1, 170.3, 190.1; mmax: 1009, 1091, 1156, 1240, 1348.16, 1499,
1705, 1787, 3201 cmꢀ1. ½a D25
¼ þ62:3 (c 0.90, THF), 94% ee. Enan-
ꢁ
tiomeric excess of the product was determined by chiral stationary
phase HPLC analysis using ChiralCel OD-H (hexanes/i-PrOH 92:8 at
1.0 mL/min), major isomer: tR = 65.4 min, minor isomer:
tR = 56.8 min. Anal. calcd for C14H18N2O6S: C, 49.11; H, 5.30; N,
8.18. Found: C, 49.14; H, 5.29; N, 8.07.
155.7 156.9, 167.5, 170.1, 190.2;
m
max: 1186, 1254, 1397, 1509,
1700, 1770, 3256 cmꢀ1. ½a D25
ꢁ
¼ þ95:8 (c 0.51, THF), 97% ee. Enan-
tiomeric excess of the product was determined by chiral stationary
phase HPLC analysis using ChiralCel OD-H (hexanes/i-PrOH 85:15
at 1.0 mL/min), major isomer: tR = 24.4 min, minor isomer:
tR = 39.0 min. Anal. calcd for C17H17N3O6S: C, 52.07; H, 4.38; N,
10.74. Found: C, 51.66; H, 4.46; N, 10.35.
4.2.13. (4S,5R)-4-(4,4-Dimethyl-2-oxooxazolidine-3-carbonyl)-
8,8-dimethyl-2-thioxo-1,7-dioxa-3-aza-spiro[4.4]nonan-6-one 10
Foam; yield: 8.5 mg (52%); 1H (300 MHz, CDCl3): d = 0.88–2.78
(m, 14H), 4.10 (dd, J = 17.4, 8.3 Hz, 1H), 4.93 (s, 1H), 7.81 (s, 1H);
13C (75 MHz, CDCl3): d = 20.8, 23.8, 25.0, 26.2, 38.8, 39.8, 61.5,
64.3, 76.4, 95.7, 154.8, 169.9, 187.8, 201.0;
m
max: 1030, 1180,
4.2.9. (3R,40S)-6-Bromo-40-(4,4-dimethyl-2-oxooxazolidine-3-
carbonyl)-20-thioxospiro[indoline-3,50-oxazolidin]-2-one 5g
White solid; yield: 21.6 mg (98%); mp 211–212 °C; 1H
(300 MHz, acetone-d6): d = 1.62 (d, J = 2.7 Hz, 6H), 4.16 (dd,
J = 15.6, 8.4 Hz, 2H), 5.51 (s, 1H), 7.16–7.43 (m, 3H), 9.34 (s, 1H),
9.93 (s, 1H); 13C (75 MHz, acetone-d6): d = 24.3, 24.5, 61.6, 65.5,
77.0, 87.2, 114.6, 125.2, 125.7, 126.5, 128.1, 144.6, 155.8, 167.2,
1240, 1377, 1497, 1707, 1767 cmꢀ1. ½a D25
ꢁ
¼ þ47:9 (c 1.04, THF),
90% ee. Enantiomeric excess of the product was determined by chi-
ral stationary phase HPLC analysis using ChiralCel OD-H (hexanes/
i-PrOH 90:10 at 1.0 mL/min), major isomer: tR = 26.3 min, minor
isomer: tR = 56.1 min. HRMS calcd for C14H19N2O5S: 327.1015
(M+H); found: 327.1009.
170.0, 190.0; mmax: 1100, 1188, 1246.48, 1499, 1610, 1732, 1779,
3143 cmꢀ1. ½a 2D5
¼ þ117:4 (c 0.45, THF), 97% ee. Enantiomeric ex-
ꢁ
Acknowledgments
cess of the product was determined by chiral stationary phase
HPLC analysis using ChiralCel OD-H (hexanes/i-PrOH 90:10 at
1.0 mL/min), major isomer: tR = 48.8 min, minor isomer:
tR = 81.5 min. Anal. calcd for C16H14BrN3O5S: C, 43.65; H, 3.21; N,
9.54. Found: C, 43.40; H, 3.05; N, 9.45.
The authors thank the generous financial support from the
Welch Foundation (Grant No. AX-1593) and the NIH SCORE pro-
gram (Grant No. SC1GM082718). We also thank Dr. Hadi Arman
for crystallographic analysis.

J. Guang, C.-G. Zhao / Tetrahedron: Asymmetry 22 (2011) 1205–1211
1211
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M.; Shirata, A. Phytochemistry 1995, 39, 581.
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latter compounds are known to possess potent antimicrobial, antitumor, and