1-Hydroxybenzotriazole-Assisted, N-Heterocyclic Carbene Catalyzed β-Functionalization of Saturated Carboxylic Esters: Access to Spirooxindole Lactones

Article abstract of DOI:10.1021/acs.joc.6b02032

A 1-hydroxybenzotriazole-assisted, N-heterocyclic carbene catalyzed direct β-functionalization of saturated carboxylic esters is disclosed. This formal [3 + 2] annulation reaction of carboxylic esters with isatins affords optically pure spirooxindole lactones (on gram scale) bearing two vicinal stereogenic centers. A dual role of HOBt is proposed based on controlled experiments to rationalize the enhancement of diastereoselectivity and enantioselectivity.

Full text of DOI:10.1021/acs.joc.6b02032

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Note
1-Hydroxybenzotriazole Assisted, N-Heterocyclic
Carbene Catalyzed beta-Functionalization of Saturated
Carboxylic Esters: Access to Spirooxindole Lactones
Jianfeng Xu, Shiru Yuan, Maozhong Miao, and Zhengkai Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02032 • Publication Date (Web): 06 Oct 2016
Downloaded from http://pubs.acs.org on October 8, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1-Hydroxybenzotriazole Assisted, N-Heterocyclic Carbene
Catalyzed β-Functionalization of Saturated Carboxylic
Esters: Access to Spirooxindole Lactones
Jianfeng Xu,* Shiru Yuan, Maozhong Miao, and Zhengkai Chen
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Department of Chemistry, Zhejiang SciꢀTech University, Hangzhou 310018, PR China
ABSTRACT: A 1ꢀhydroxybenzotriazole (HOBt) assisted, Nꢀheterocyclic carbene (NHC)
catalyzed direct βꢀfunctionalization of saturated carboxylic esters is disclosed. This
formal [3+2] annulation reaction of carboxylic esters with isatins affords optically pure
spirooxindole lactones (on gram scale) bearing two vicinal stereogenic centers. A dual
role of HOBt is proposed based on controlled experiments to rationalize the enhancement
of diastereoselectivity and enantioselectivity.
Saturated carbonyl compounds such as esters and aldehydes are unambiguously vital
building blocks for the preparation of pharmaceuticals, fine chemicals, and materials.
Therefore, it is not surprising that considerable efforts have been devoted to the direct
asymmetric functionalization of the carbonyl carbon and αꢀcarbon of those compounds.
However, the direct catalytic incorporation of useful units on the saturated inert carbons
1
2
remote from carbonyl group, such as the βꢀcarbon, is more challenging. Recently,
several research groups have accomplished the direct enantioselective βꢀfunctionalization
3
3b
of saturated carbonyl compounds through organocatalysis. In 2011, Wang and
3
c
Hayashi independently turned the βꢀcarbon of saturated aldehydes into an electrophilic
reactive carbon via oxidative amine catalysis. In 2013, Chi and coꢀworkers also formed
an electrophilic βꢀcarbon from saturated aldehydes mediated by an Nꢀheterocyclic
3
d
carbene (NHC) catalyst under oxidative condition. In 2013 and 2015, Chi group and
3
e,f
Yao group further successfully converted the saturated βꢀcarbon of esters,
3g,h
3i
anhydrides,
and acids into a nucleophilic reactive carbon via NHC catalysis. Despite
the progress has been achieved, the development of efficient strategies towards the direct
introduction of functional groups at the βꢀposition of saturated carbonyl compounds in a
diastereoꢀ and enantioselective manner is still in very high demand.
In the past several years, Nꢀheterocyclic carbenes (NHCs) have been exploited as
captivating organocatalysts for the activation of various substrates through many kinds of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
reaction modes to construct structurally complex and biologically active compounds.
Compared to oxygen sensitive aldehydes and easily hydrolysed anhydrides, carboxylic
esters are bench stable, readily available, and easy to handle substrates. We are
interested in the development of novel catalytic asymmetric reactions to synthesize
enantiomerically enriched heterocycles from inexpensive 4ꢀnitrophenol esters via NHC
catalysis. In 2013 we realized an NHC catalyzed direct γꢀfunctionalization of α,βꢀ
unsaturated carboxylic esters to prepare chiral δꢀlactams, which could be further
transformed to pipecolic acid derivatives (Scheme 1a). Very recently, we achieved an
NHC catalyzed formal [4+2] annulation reaction to furnish optically pure indoleꢀfused δꢀ
lactams by in situ generation of indoleꢀ2,3ꢀquinodimethanes from 2ꢀmethylꢀindoleꢀ3ꢀ
carboxylic esters (Scheme 1b). Herein we describe a HOBt assisted, NHC catalyzed
formal [3+2] annulation reaction to afford spirooxindole lactones bearing two vicinal
stereogenic centers through direct βꢀfunctionalization of saturated carboxylic esters
Scheme 1c). Notably, the employment of a catalytic amount of HOBt in our reaction
could dramatically improve the diastereoselectivity and enantioselectivity, which is
distinguished from other reactions in NHC catalysis where HOBt is simply used as a
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6a
6b
7
(
8
coupling reagent to form in situ generated activated benzotriazole esters.
Scheme 1. NHC Catalyzed Synthesis of Heterocycles from Carboxylic Esters
a. NHC catalyzed -functionalization of , -unsaturated carboxylic esters (ref 6a)
O
O
N
R'
NH
COOEt
O
O
OAr
H
R'
NH
N
NHC
[4+2]
+
COOEt
R
R
H
b. NHC catalyzed functionalization of 2-methyl-indole-3-carboxylic esters (ref 6b)
R
O
O
Boc
NBoc
OAr
R
N
NHC
[4+2]
+
O
N
N
N
N
Trt
Trt
O
H
PG
PG
c. NHC catalyzed -functionalization of saturated carboxylic esters (this work)
O
O
NHC
HOBt
H
O
O
R2
R1
+
O
R1
OAr
[3+2]
N
R2
O
N
Trt
Trt
We started our investigation by using ester 1a and isatin 2a as the model substrates,
and the key results are summarized in Table 1. As anticipated, when racemic NHC
precatalyst A was used, the [3+2] annulation product 3a was successfully formed in 66%
yield and 1:1 dr (Table 1, entry 1). LꢀLeucine derived NHC precatalyst B , which was
the optimal precatalyst for our previous ester γꢀfunctionalization, affording 3a in 84%
yield and 88% ee, but only with 2:1 dr (entry 2). When Lꢀphenylalanine derived NHC
precatalyst C was employed, spirooxindole lactone 3a was obtained in lower yield and
ee but slightly increased dr (entry 3). To our delight, when aminoindanol derived NHC
9
10
6a
1
1
1
2
precatalyst D was introduced, the desired product 3a could be furnished with an
encouraging 7:1 dr and similar yield and ee (entry 4). With D as the optimal catalyst, we
next set out to examine the solvent effect. 1,4ꢀDioxane could proceed this reaction
ACS Paragon Plus Environment

Page 3 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
smoothly, giving 3a in 82% yield, 8:1 dr, and 82% ee (entry 5). CH CN and EtOAc were
3
less effective, as the dr value in both reactions dropped to 3:1 (entries 6 and 7). Lewis
acids were previously proven to be able to improve diastereoselectivities and
1
3
enantioselectivites in NHC catalysis, so we tested Sc(OTf) and Mg(OTf) in our
3
2
reaction, but unfortunately only negative results were observed (entries 8 and 9). Finally,
when 20 mol % of HOBt was exploited as an additive, we were gratifyingly to isolate 3a
in 86% yield, >20:1 dr, and 93% ee (entry 10).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Table 1. Optimization of Reaction Conditions
c
entry conditions
yield
dr
ee
(%)
ꢀ
b
d
(
%)
1
2
3
4
5
6
7
8
9
1
A, THF, ꢀ
B, THF, ꢀ
C, THF, ꢀ
D, THF, ꢀ
66
84
72
1:1
2:1
3:1
88
64
86
82
78
80
76
82
89 (80) 7:1
D, 1,4ꢀdioxane, ꢀ
82
79
68
8:1
3:1
3:1
5:1
5:1
D, CH CN, ꢀ
3
D, EtOAc, ꢀ
D, THF, Sc(OTf)3 74
D, THF, Mg(OTf)2 73
0
D, THF, HOBt
91 (86) >20:1 93
a
Reaction conditions unless otherwise specified: 1a (0.15 mmol), 2a (0.1 mmol), NHC (10
mol %), Cs CO (0.2 mmol), additive (20 mol %), solvent (1 mL), 4 Å MS (100 mg, powder) at
room temperature for 12 h. Yield estimated via H NMR analysis using 1,3,5ꢀtrimethoxybenzene
as an internal standard, number in the parentheses is the isolated yield based on 2a.
Diastereomeric ratio of 3a, determined via H NMR analysis of crude reaction mixtures.
Enantiomeric excess of 3a, determined via chiral phase HPLC analysis.
2
3
b
1
c
1
d
To gain further insight of how HOBt function in this reaction, we next set out to
perform several additional experiments (Scheme 2). Similarly, when (1ꢀ
Bis(dimethylamino) methylene]ꢀ1Hꢀ1,2,3ꢀtriazolo[4,5ꢀb]pyridinium 3ꢀoxid hexafluoro
phosphate) (HATU) was used as an additive, the desired product 3a was isolated in good
yield with excellent diastereoselectivity and enantioselectivity (Scheme 2, eq 1, entry 3).
However, 4ꢀdimethylaminopyridine (DMAP), another commonly used coupling reagent
in peptide synthesis, only affording 3a in poor result (eq 1, entry 4). The use of methyl
substituted HOBt (MeOBt) also led to unsatisfactory outcome, suggesting that hydrogen
bonding may play a critical role in current reaction (eq 1, entry 5). Finally, preformed
[
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
benzotriazole ester 4 was employed as the ester substrate and the corresponding product
3
a was obtained in 88% yield, >20:1 dr, and 94% ee (eq 2).
Scheme 2. Controlled Experiments
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Based on the above observations, a plausible mechanism where HOBt plays a dual role
is depicted in Scheme 3. HOBt (role No. 1: as an ester activating reagent) first replaces
the 4ꢀnitrophenol moiety of 1a to afford activated benzotriazole ester 4, which is next
substituted by a chiral free NHC catalyst (formed by Cs CO mediated deprotonation of
2
3
NHC precatalyst D) to generate acyl azolium intermediate I. αꢀDeprotonation of
intermediate I furnishes enolate intermediate II, and subsequent proton transfer turns
3
eꢀf,14
enolate intermediates II to homoenolate intermediate III.
Due to the steric hindrance
of the bulky indanol moiety on NHC catalyst, isatin 2a would prefer to approach
intermediate III from the opposite face induced by hydrogen bonding from HOBt (role
No. 2: as a hydrogen bonding donor), this reorganization of reactive species (transition
state TS) may lead to the enhancement of diastereoselectivity and enantioselectivity. The
anion on the βꢀcarbon of intermediate III attacks isatin 2a from si face furnishes
intermediate IV, and lactonization of intermediate IV finally releases spirooxindole
lactone 3a as the annulation product and regenerate free NHC catalyst.
Scheme 3. Proposed Catalytic Cycle
ACS Paragon Plus Environment

Page 5 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
NHC D
Cs2CO3
1a
3a
O
N
HOBt
N
N
4
O
H
N
N
N
O
O
N
N
N
N
O
N
O
N
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
HOBt
O
N
H
H
I
Cs2CO3
IV
O
N
N
O
N
N
N
O
N
N
N
N
O
HO
O
H
III'
N
H
N
O
N
N
II
O
H
O
HOBt
O
N
N
TS
N
HO
2a
III
With the optimized reaction conditions in hand (Table 1, entry 10), we then evaluated
the scope of this formal [3+2] annulation reaction. As shown in Scheme 4, a broad range
of carboxylic esters with diverse electronic and steric properties were first explored. The
use of 4ꢀnitrophenyl 3ꢀphenylpropanoate (1a) provided the desired product 3a in 86%
yield with >20:1 dr and 93% ee. Esters with both electronꢀ donating substituents (4ꢀMe
and 4ꢀOMe) and electronꢀwithdrawing substituents (4ꢀF, 4ꢀCl, and 4ꢀBr) on their βꢀ
phenyl ring were all well tolerated, leading to the corresponding products 3b-f in similar
good yields, excellent diastereoselectivities and enantioselectivities. The introduction of a
sterically demanding substituent such as the 1ꢀnaphthyl group caused a decrease in both
yield and enantioselectivity (3g). Heteroaryl substituted carboxylic ester can be readily
accommodated, thus affording the corresponding 2ꢀfuryl substituted product 3h in 80%
yield, >20:1 dr, and 94% ee. It is worth noting that βꢀalkyl substituted carboxylic ester
was also compatible under the optimal conditions, furnishing product 3i in lower 41%
yield, >20:1 dr, and 98% ee. Modifications on the phenyl ring of the isatin substrates
were feasible. The use of 5ꢀMe and 5ꢀOMe substituted isatins achieved the desired
products 3j and 3k in good yields, excellent diastereoselectivities and enantioselectivities.
However, when electronꢀwithdrawing substituents (5ꢀF, 5ꢀCl, 5ꢀBr, and 5ꢀI) were
installed on the isatin phenyl ring, a slight drop in both yields and enantioselectivities
were observed (3l-o), the absolute configuration of the major enantiomer was assigned
1
5
based on Xꢀray structure of 3n. The substitution patterns on other positions of the isatin
phenyl ring were also investigated, and the use of 7ꢀMe, 7ꢀF, and 5,7ꢀdimethyl
substituted isatins gave the corresponding products 3p-r in good yields and excellent drs
and ees, respectively.
a
Scheme 4. Scope of Reactions
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reaction conditions: 1 (0.15 mmol), 2 (0.1 mmol), NHC D (10 mol %), Cs CO (0.2 mmol),
2
3
THF (1 mL), HOBt (20 mol %), 4 Å MS (100 mg, powder) at room temperature for 12 h;
Isolated yields based on 2; The drs were determined via H NMR analysis of crude reaction
mixtures; The ees were determined via chiral phase HPLC analysis.
1
Moreover, this reaction can be smoothly performed on a gram scale without loss of
diastereoselectivity and enantioselectivity (Scheme 5, eq 1). The trityl protecting group
on 3a can be readily removed by trifluoroacetic acid (TFA) to form spirooxindole lactone
1
6
5
, which could be further transformed to 3ꢀhydroxy oxindole 6 (Scheme 5, eq 2). It is
noteworthy that 3ꢀhydroxy oxindoles are widely found as core skeletons in a variety of
natural products and biologically active compounds.
1
7
Scheme 5. Gram-scale Preparation and Synthetic Transformation of 3a
ACS Paragon Plus Environment

Page 7 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In summary, we have developed a HOBt assisted, NHCꢀcatalyzed direct βꢀ
functionalization reaction of saturated carboxylic esters that undergoes a formal [3+2]
annulation with isatins in a highly efficient, diastereoselective, and enantioselective
manner to afford chiral spirooxindole lactones. This reaction can be easily scaled up and
the trityl protecting group could be readily removed under mild conditions to give
spirooxindole lactone which could be further converted to the biologically interesting 3ꢀ
hydroxy oxindole. A dual role of HOBt is proposed to rationalize the enhancement of
diastereoselectivity and enantioselectivity.
EXPERIMENTAL SECTION
1
General Information Commercially available materials were used as received. H and
13
CNMR spectra were recorded at 400 and 100 MHz, respectively. Chemical shifts were
recorded in parts per million (ppm, δ) relative to tetramethylsilane (δ = 0.00) or
chloroform (δ = 7.26). Highꢀresolution mass spectra were obtained on a HRMS/LCꢀMS
instrument using electrospray ionization (ESI) as the ionization method and an ion trap
mass analyzer. The determination of ee was performed via chiral HPLC analysis using IA
and IC columns (25 × 0.46 cm) on an HPLC instrument. Optical rotations were measured
rt
using a 1 mL cell with a 1 dm path length and are reported as follows: [α] D (c in g per
1
00 mL solvent). All reactions were monitored by TLC with GF 254 silica gel coated
plates. Flash column chromatography was carried out using 200−300 mesh silica gel,
Melting points are uncorrected.
General Procedure for the Catalytic Synthesis of Spirooxindole Lactones. To a dry
1
0 mL Schlenk tube equipped with a magnetic stir bar, was added 1 (0.15 mmol), 2 (0.1
mmol), Cs CO (0.2 mmol), HOBt (0.02 mmol), 4Å MS (100 mg), and chiral NHC preꢀ
2
3
catalyst D (0.01 mmol). The tube was sealed with a septum, evacuated and refilled with
nitrogen (3 cycles). Freshly distilled anhydrous THF (1 mL) was added and the reaction
mixture was allowed to stir for 12 hours at room temperature. After completion of the
reaction, the reaction mixture was concentrated under reduced pressure and the residue
was subjected to column chromatography using hexane/EtOAc = 5/1 as eluent to afford
the desired spirooxindole lactones 3. Note: The racemic catalyst that used for the
preparation of the corresponding racemic products for HPLC analysis was synthesized by
mixing chiral preꢀcatalyst D and entꢀD in a 1:1 ratio.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
4
2R,3S)-3-phenyl-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione
4.8 mg, 86% yield, >20:1 dr, white solid: mp 253ꢀ254 C. H NMR (400 MHz, CDCl )
(3a):
o
1
3
δ 7.47 (d, J = 7.6 Hz, 1H), 7.41ꢀ7.39 (m, 3H), 7.16ꢀ7.11 (m, 11H), 7.05 (t, J = 7.6 Hz,
1H), 6.94ꢀ6.92 (m, 7H), 6.13 (d, J = 8.4 Hz, 1H), 4.14 (dd, J = 14.0 Hz, J = 8.0 Hz, 1H),
3
NMR (100 MHz, CDCl ) δ 174.7, 174.3, 144.5, 140.9, 132.3, 129.6, 129.4, 128.9, 128.7,
1
calcd. for C H NO Na 544.1889, found 544.1891. [α] = ꢀ90.1 (c = 1.0 in CHCl3);
HPLC analysis: 93% ee , [CHIRALPAK IA column; 1 mL/min; solvent system: iꢀ
PrOH/hexane = 5:95; retention times: 16.6 min (minor), 21.6 min (major)].
1
2
1
3
.73 (dd, J = 16.8 Hz, J = 13.6 Hz, 1H), 2.86 (dd, J = 16.8 Hz, J = 8.0 Hz, 1H); C
1 2 1 2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
28.3, 127.5, 127.0, 124.9, 123.4, 123.0, 116.7, 86.0, 74.8, 51.3, 31.7; HRMS (ESI, m/z):
+
21
3
6
27
3
D
(2R,3S)-3-(p-tolyl)-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione
(3b):
7.1 mg, 88% yield, >20:1 dr, pale yellow solid: mp 245ꢀ246 C. H NMR (400 MHz,
CDCl ) δ 7.45 (d, J = 7.2 Hz, 1H), 7.21ꢀ7.10 (m, 11H), 7.03ꢀ6.91 (m, 10H), 6.11 (d, J =
o
1
4
3
8
1
.0 Hz, 1H), 4.09 (dd, J = 13.6 Hz, J = 8.0 Hz, 1H), 3.70 (dd, J = 16.8 Hz, J = 14.0 Hz,
1 2 1 2
13
H), 2.83 (dd, J = 17.2 Hz, J = 8.4 Hz, 1H), 2.34 (s, 3H); C NMR (100 MHz, CDCl )
1
2
3
δ 174.8, 174.3, 144.4, 140.9, 138.7, 129.6, 129.4, 129.3, 129.2, 128.1, 127.4, 127.0, 124.9,
123.4, 122.9, 116.6, 86.1, 74.8, 51.2, 31.7, 21.2; HRMS (ESI, m/z): calcd. for
C H NO Na 558.2045, found 558.2052. [α]
+
21
= ꢀ100.7 (c = 1.0 in CHCl ); HPLC
37
29
3
D
3
analysis: 94% ee , [CHIRALPAK IA column; 1 mL/min; solvent system: iꢀPrOH/hexane
5:95; retention times: 10.1 min (minor), 13.2 min (major)].
=
(2R,3S)-3-(4-methoxyphenyl)-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-
o
1
dione (3c): 47.4 mg, 86% yield, >20:1 dr, pale yellow solid: mp 229ꢀ230 C. H NMR
400 MHz, CDCl ) δ 7.44 (d, J = 7.2 Hz, 1H), 7.16ꢀ7.11 (m, 9H), 7.05ꢀ6.89 (m, 12H),
(
3
6.12 (d, J = 8.4 Hz, 1H), 4.08 (dd, J = 13.6 Hz, J = 8.0 Hz, 1H), 3.77 (s, 3H), 3.67 (dd,
J = 16.8 Hz, J = 14.0 Hz, 1H), 2.82 (dd, J = 16.8 Hz, J = 8.0 Hz, 1H); C NMR (100
MHz, CDCl ) δ 174.8, 174.3, 160.0, 144.4, 140.9, 129.5, 129.4, 129.3, 127.4, 127.0,
1
calcd. for C H NO Na 574.1994, found 574.1993. [α]
HPLC analysis: 94% ee , [CHIRALPAK IA column; 1 mL/min; solvent system: iꢀ
PrOH/hexane = 5:95; retention times: 15.9 min (minor), 18.3 min (major)].
1
2
13
1
2
1
2
3
24.8, 124.1, 123.4, 123.0, 116.6, 114.0, 86.1, 74.7, 55.3, 50.8, 31.9; HRMS (ESI, m/z):
+
21
37 29
4
D
= ꢀ105.9 (c = 1.0 in CHCl3);
(2R,3S)-3-(4-fluorophenyl)-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione
1
(3d): 45.3 mg, 84% yield, >20:1 dr, viscous solid. H NMR (400 MHz, CDCl ) δ 7.46 (d,
3
J = 6.8 Hz, 1H), 7.17ꢀ7.12 (m, 9H), 7.07ꢀ7.03 (m, 5H), 6.96ꢀ6.93 (m, 7H), 6.12 (d, J =
8
1
174.0, 162.9 (d, JC-F = 247 Hz), 144.5, 140.8, 130.0 (d, JC-F = 8 Hz), 129.7, 129.4, 128.1
(d, JC-F = 2 Hz), 127.5, 127.1, 124.4, 123.4, 123.1, 116.8, 115.6 (d, JC-F = 21 Hz), 85.6,
.4 Hz, 1H), 4.10 (dd, J = 13.6 Hz, J = 8.0 Hz, 1H), 3.67 (dd, J = 16.8 Hz, J = 14.0 Hz,
1 2 1 2
13
H), 2.86 (dd, J = 16.8 Hz, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 174.4,
1
2
3
+
7
5
4.8, 50.8, 32.0; HRMS (ESI, m/z): calcd. for C H NO FNa 562.1794, found
3
6
26
3
21
62.1790. [α] = ꢀ77.9 (c = 1.0 in CHCl ); HPLC analysis: 94% ee , [CHIRALPAK IA
D
3
column; 1 mL/min; solvent system: iꢀPrOH/hexane = 5:95; retention times: 10.9 min
(minor), 13.2 min (major)].
(2R,3S)-3-(4-chlorophenyl)-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione
o
1
(3e): 48.3 mg, 87% yield, >20:1 dr, pale yellow solid: mp 209ꢀ211 C. H NMR (400
MHz, CDCl ) δ 7.46 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.18ꢀ7.13 (m, 9H),
3
ACS Paragon Plus Environment

Page 9 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7
3
.07ꢀ6.91 (m, 10H), 6.11 (d, J = 8.0 Hz, 1H), 4.08 (dd, J = 13.6 Hz, J = 8.0 Hz, 1H),
1
2
1
3
.67 (dd, J = 16.8 Hz, J = 14.0 Hz, 1H), 2.85 (dd, J = 16.8 Hz, J = 8.4 Hz, 1H); C
1
2
1
2
NMR (100 MHz, CDCl ) δ 174.3, 173.9, 144.6, 140.8, 134.9, 130.9, 129.8, 129.7, 129.4,
128.8, 127.5, 127.1, 124.3, 123.4, 123.1, 116.8, 85.8, 74.9, 50.8, 31.9; HRMS (ESI, m/z):
calcd. for C H NO Cl 556.1679, found 556.1670. [α] = ꢀ97.5 (c = 1.0 in CHCl3);
HPLC analysis: 92% ee , [CHIRALPAK IA column; 1 mL/min; solvent system: iꢀ
3
+
21
3
6
27
3
D
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
PrOH/hexane = 5:95; retention times: 11.1 min (minor), 14.0 min (major)].
(
2R,3S)-3-(4-bromophenyl)-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione
o
1
(3f): 51.0 mg, 85% yield, >20:1 dr, white solid: mp 224ꢀ225 C. H NMR (400 MHz,
CDCl ) δ 7.47 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.19ꢀ7.14 (m, 9H), 7.05 (t, J
3
= 7.2 Hz, 1H), 6.97ꢀ6.91 (m, 9H), 6.11 (d, J = 8.0 Hz, 1H), 4.07 (dd, J = 13.6 Hz, J =
1
2
8
1
1
.0 Hz, 1H), 3.67 (dd, J = 16.8 Hz, J = 14.0 Hz, 1H), 2.85 (dd, J = 16.8 Hz, J = 8.0 Hz,
1 2 1 2
1
3
H); C NMR (100 MHz, CDCl ) δ 174.3, 173.9, 144.5, 140.8, 131.8, 130.4, 130.0,
3
29.8, 129.4, 127.5, 127.1, 124.3, 123.4, 123.1, 123.0, 116.8, 85.7, 74.9, 50.8, 31.9;
81
+
21
HRMS (ESI, m/z): calcd. for C H NO BrNa 624.0973, found 624.0963. [α] = ꢀ
3
6
26
3
D
96.7 (c = 1.0 in CHCl ); HPLC analysis: 93% ee , [CHIRALPAK IA column; 1 mL/min;
3
solvent system: iꢀPrOH/hexane = 5:95; retention times: 11.7 min (minor), 15.1 min
(major)].
(2R,3S)-3-(naphthalen-1-yl)-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-
o
1
dione (3g): 33.1 mg, 58% yield, >20:1 dr, pale yellow solid: mp 262ꢀ263 C. H NMR
400 MHz, CDCl ) δ 7.95 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.2
(
3
Hz, 1H), 7.58ꢀ7.64 (m, 2H), 7.52ꢀ7.45 (m, 2H), 7.18 (t, J = 8.0 Hz, 1H), 7.11ꢀ7.05 (m,
4
1
3
H), 7.02ꢀ6.98 (m, 6H), 6.80 (t, J = 8.0 Hz, 1H), 6.59ꢀ6.57 (m, 6H), 5.85 (d, J = 8.0 Hz,
H), 5.04 (dd, J = 13.6 Hz, J = 8.4 Hz, 1H), 3.89 (dd, J = 17.2 Hz, J = 13.6 Hz, 1H),
1
2
1
2
13
.00 (dd, J = 16.8 Hz, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 174.8, 174.7,
1
2
3
144.1, 140.7, 134.2, 131.9, 129.4, 129.2, 129.0, 128.9, 128.3, 127.3, 126.8, 125.9, 125.8,
25.7, 125.6, 125.2, 123.3, 123.2, 122.8, 116.8, 86.2, 74.6, 45.7, 33.1; HRMS (ESI, m/z):
1
+
21
calcd. for C H NO Na 594.2045, found 594.2039. [α] = +28.0 (c = 1.0 in CHCl3);
4
0
29
3
D
HPLC analysis: 88% ee , [CHIRALPAK ID column; 1 mL/min; solvent system: iꢀ
PrOH/hexane = 10:90; retention times: 24.4 min (minor), 32.5 min (major)].
(2R,3S)-3-(furan-2-yl)-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione (3h):
1
4
0.9 mg, 80% yield, >20:1 dr, viscous solid. H NMR (400 MHz, CDCl ) δ 7.41ꢀ7.39 (m,
3
2
H), 7.20ꢀ7.11 (m, 15H), 7.03 (t, J = 7.6 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.44ꢀ6.42 (m,
1H), 6.28ꢀ6.26 (m, 1H), 6.24ꢀ6.22 (m, 1H), 4.18 (dd, J = 13.2 Hz, J = 8.4 Hz, 1H), 3.60
1
2
1
3
(dd, J = 17.2 Hz, J = 13.6 Hz, 1H), 2.92 (dd, J = 17.2 Hz, J = 8.4 Hz, 1H); C NMR
1 2 1 2
(
100 MHz, CDCl ) δ 174.0, 173.9, 148.2, 144.4, 142.8, 141.2, 129.6, 129.3, 127.5, 127.0,
3
1
25.0, 123.4, 123.0, 116.6, 110.8, 108.7, 84.5, 74.7, 44.8, 31.8; HRMS (ESI, m/z): calcd.
+
21
for C H NO Na 534.1681, found 534.1683. [α]
= ꢀ64.7 (c = 1.0 in CHCl ); HPLC
3
3
4
25
4
D
analysis: 94% ee , [CHIRALPAK ID column; 1 mL/min; solvent system: iꢀPrOH/hexane
10:90; retention times: 19.0 min (minor), 20.6 min (major)].
=
(
2R,3R)-3-propyl-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione (3i): 19.9
1
mg, 41% yield, >20:1 dr, viscous solid. H NMR (400 MHz, CDCl ) δ 7.42ꢀ7.40 (m, 6H),
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
.30ꢀ7.20 (m, 11H), 7.02ꢀ6.96 (m, 2H), 6.31 (d, J = 6.8 Hz, 1H), 2.90 (dd, J = 15.6 Hz,
1
J = 12.0 Hz, 1H), 2.79ꢀ2.72 (m, 1H), 2.67 (dd, J = 15.6 Hz, J = 7.6 Hz, 1H), 1.43ꢀ1.36
2
1
2
1
3
(m, 1H), 1.26ꢀ1.15 (m, 2H), 1.07ꢀ1.00 (m, 1H), 0.79 (t, J = 7.2 Hz, 3H); C NMR (100
MHz, CDCl ) δ 175.5, 174.3, 144.5, 141.4, 129.6, 129.3, 127.8, 127.1, 125.7, 123.8,
1
3
23.0, 116.4, 85.1, 75.0, 46.0, 33.9, 30.6, 21.4, 14.0; HRMS (ESI, m/z): calcd. for
+
21
C H NO Na 510.2045, found 510.2053. [α]
= +41.9 (c = 1.0 in CHCl ); HPLC
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
33 29
3
D
analysis: 98% ee , [CHIRALPAK IA column; 1 mL/min; solvent system: iꢀPrOH/hexane
5:95; retention times: 8.3 min (minor), 9.9 min (major)].
=
(2R,3S)-5'-methyl-3-phenyl-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione
o
1
(3j): 49.2 mg, 92% yield, >20:1 dr, pale yellow solid: mp 259ꢀ260 C. H NMR (400
MHz, CDCl ) δ 7.41ꢀ7.38 (m, 3H), 7.28 (s, 1H), 7.14ꢀ7.10 (m, 11H), 6.93ꢀ6.92 (m, 6H),
3
6
1
2
.71 (d, J = 8.4 Hz, 1H), 6.01 (d, J = 8.4 Hz, 1H), 4.13 (dd, J = 13.6 Hz, J = 8.0 Hz,
1 2
H), 3.72 (dd, J = 16.8 Hz, J = 14.0 Hz, 1H), 2.84 (dd, J = 16.8 Hz, J = 8.0 Hz, 1H),
1
2
1
2
1
3
.26 (s, 3H); C NMR (100 MHz, CDCl ) δ 174.7, 174.3, 142.0, 141.0, 132.7, 132.4,
3
130.1, 129.4, 128.9, 128.7, 128.3, 127.4, 126.9, 124.8, 124.0, 116.4, 86.1, 74.7, 51.2, 31.7,
+
21
2
1
0.8; HRMS (ESI, m/z): calcd. for C H NO Na 558.2045, found 558.2039. [α] = ꢀ
37 29 3 D
21.0 (c = 1.0 in CHCl ); HPLC analysis: 94% ee , [CHIRALPAK IA column; 1 mL/min;
3
solvent system: iꢀPrOH/hexane = 5:95; retention times: 13.3 min (minor), 16.1 min
(major)].
(2R,3S)-5'-methoxy-3-phenyl-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-
o
1
dione (3k): 47.4 mg, 86% yield, >20:1 dr, pale yellow solid: mp 241ꢀ242 C. H NMR
400 MHz, CDCl ) δ 7.42ꢀ7.39 (m, 3H), 7.15ꢀ7.10 (m, 11H), 7.03 (s, 1H), 6.94ꢀ6.91 (m,
(
3
6H), 6.47 (d, J = 9.2 Hz, 1H), 6.03 (d, J = 9.2 Hz, 1H), 4.12 (dd, J = 13.6 Hz, J = 8.0
Hz, 1H), 3.77ꢀ3.70 (m, 4H), 2.85 (dd, J = 16.8 Hz, J = 8.0 Hz, 1H); C NMR (100
MHz, CDCl ) δ 174.7, 174.1, 155.8, 141.0, 137.5, 132.3, 129.4, 128.9, 128.7, 128.3,
1
calcd. for C H NO Na 574.1994, found 574.1987. [α] = ꢀ128.5 (c = 1.0 in CHCl3);
HPLC analysis: 94% ee , [CHIRALPAK IC column; 1 mL/min; solvent system: iꢀ
PrOH/hexane = 10:90; retention times: 46.2 min (major), 56.3 min (minor)].
1
2
13
1
2
3
27.4, 126.9, 126.0, 117.5, 115.0, 109.3, 86.2, 74.7, 55.6, 51.4, 31.7; HRMS (ESI, m/z):
+
21
3
7
29
4
D
(2R,3S)-5'-fluoro-3-phenyl-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione
1
(3l): 41.5 mg, 77% yield, >20:1 dr, viscous solid. H NMR (400 MHz, CDCl ) δ 7.43ꢀ
3
7.41 (m, 3H), 7.22ꢀ7.11 (m, 12H), 6.92ꢀ6.90 (m, 6H), 6.67ꢀ6.62 (m, 1H), 6.09ꢀ6.05 (m,
1
2
H), 4.09 (dd, J = 13.6 Hz, J = 8.0 Hz, 1H), 3.72 (dd, J = 16.8 Hz, J = 13.6 Hz, 1H),
1 2 1 2
.86 (dd, J = 16.8 Hz, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 174.3, 174.1,
13
1
2
3
158.9 (d, JC-F = 243 Hz), 140.6, 140.3 (d, JC-F = 2 Hz), 131.9, 129.3, 129.1, 128.8, 128.3,
27.6, 127.1, 126.4 (d, JC-F = 8 Hz), 117.7 (d, JC-F = 7 Hz), 116.3 (d, JC-F = 22 Hz), 111.0
1
+
(d, JC-F = 25 Hz), 85.7, 74.9, 51.5, 31.6; HRMS (ESI, m/z): calcd. for C H NO FNa
36 26 3
21
5
62.1794, found 562.1791. [α]
= ꢀ77.4 (c = 1.0 in CHCl ); HPLC analysis: 88% ee ,
D 3
[CHIRALPAK IA column; 1 mL/min; solvent system: iꢀPrOH/hexane = 5:95; retention
times: 10.7 min (minor), 16.5 min (major)].
ACS Paragon Plus Environment

Page 11 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(
2R,3S)-5'-chloro-3-phenyl-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione
o
1
(3m): 45.0 mg, 81% yield, >20:1 dr, white solid: mp 220ꢀ222 C. H NMR (400 MHz,
CDCl ) δ 7.46ꢀ7.42 (m, 4H), 7.17ꢀ7.11 (m, 11H), 6.91ꢀ6.89 (m, 7H), 6.05 (d, J = 8.8 Hz,
3
1
2
1
H), 4.11 (dd, J = 13.6 Hz, J = 8.0 Hz, 1H), 3.70 (dd, J = 17.2 Hz, J = 14.0 Hz, 1H),
1 2 1 2
13
.86 (dd, J = 17.2 Hz, J = 8.4 Hz, 1H); C NMR (100 MHz, CDCl ) δ 174.2, 173.9,
1
2
3
43.0, 140.6, 131.9, 129.6, 129.3, 129.1, 128.8, 128.7, 128.3, 127.6, 127.2, 126.6, 123.7,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
117.7, 85.6, 75.0, 51.4, 31.6; HRMS (ESI, m/z): calcd. for C H NO ClNa 578.1499,
found 578.1503. [α]
[
3
6
26
3
21
= ꢀ120.8 (c = 1.0 in CHCl ); HPLC analysis: 90% ee ,
3
D
CHIRALPAK ID column; 1 mL/min; solvent system: iꢀPrOH/hexane = 10:90; retention
times: 16.1 min (minor), 18.4 min (major)].
(2R,3S)-5'-bromo-3-phenyl-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione
o
1
(3n): 49.1 mg, 82% yield, >20:1 dr, white solid: mp 228ꢀ230 C. H NMR (400 MHz,
CDCl ) δ 7.59 (s, 1H), 7.43ꢀ7.42 (m, 3H), 7.17ꢀ7.11 (m, 11H), 7.04 (d, J = 8.8 Hz, 1H),
6
(dd, J = 16.8 Hz, J = 13.6 Hz, 1H), 2.86 (dd, J = 16.8 Hz, J = 8.0 Hz, 1H); C NMR
3
.91ꢀ6.88 (m, 6H), 6.00 (d, J = 8.4 Hz, 1H), 4.11 (dd, J = 14.0 Hz, J = 8.4 Hz, 1H), 3.70
1 2
1
3
1
2
1
2
(100 MHz, CDCl ) δ 174.2, 173.8, 143.5, 140.5, 132.5, 131.9, 129.3, 129.1, 128.8, 127.9,
3
1
27.6, 127.2, 127.0, 126.6, 118.1, 116.0, 85.5, 75.0, 51.4, 31.6; HRMS (ESI, m/z): calcd.
+
21
for C H NO BrNa 622.0994, found 622.0992. [α]
= ꢀ122.4 (c = 1.0 in CHCl3);
D
HPLC analysis: 88% ee , [CHIRALPAK IC column; 1 mL/min; solvent system: iꢀ
PrOH/hexane = 10:90; retention times: 25.4 min (major), 34.8 min (minor)].
36 26
3
(2R,3S)-5'-iodo-3-phenyl-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione
o
1
(3o): 49.2 mg, 76% yield, >20:1 dr, white solid: mp 262ꢀ264 C. H NMR (400 MHz,
CDCl ) δ 7.76 (s, 1H), 7.44ꢀ7.42 (m, 3H), 7.25ꢀ7.11 (m, 12H), 6.90ꢀ6.88 (m, 6H), 5.89 (d,
J = 8.4 Hz, 1H), 4.11 (dd, J = 14.0 Hz, J = 8.0 Hz, 1H), 3.70 (dd, J = 16.8 Hz, J =
1
1
127.1, 118.5, 86.0, 85.4, 75.0, 51.3, 31.5; HRMS (ESI, m/z): calcd. for C H NO INa
6
[
3
1
2
1
2
13
4.0 Hz, 1H), 2.86 (dd, J = 16.8 Hz, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ
1 2 3
74.2, 173.6, 144.3, 140.5, 138.4, 132.3, 131.9, 129.3, 129.1, 128.8, 128.3, 127.6, 127.2,
+
3
6
26
3
2
1
70.0855, found 670.0834. [α] = ꢀ143.9 (c = 1.0 in CHCl ); HPLC analysis: 84% ee ,
D 3
CHIRALPAK IC column; 1 mL/min; solvent system: iꢀPrOH/hexane = 10:90; retention
times: 27.2 min (major), 37.4 min (minor)].
(2R,3S)-7'-methyl-3-phenyl-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione
1
(3p): 48.2 mg, 90% yield, >20:1 dr, viscous solid. H NMR (400 MHz, CDCl ) δ 7.47 (d,
J = 6.4 Hz, 1H), 7.34ꢀ7.33 (m, 3H), 7.22ꢀ7.05 (m, 12H), 6.92ꢀ6.83 (m, 7H), 4.13 (dd, J =
1
3
1
4.0 Hz, J = 8.0 Hz, 1H), 3.66 (dd, J = 16.8 Hz, J = 14.0 Hz, 1H), 2.81 (dd, J = 16.4
2 1 2 1
1
3
Hz, J = 8.0 Hz, 1H), 1.03 (s, 3H); C NMR (100 MHz, CDCl ) δ 174.8, 174.4, 144.2,
2
3
1
8
5
43.3, 136.9, 132.1, 129.4, 128.9, 128.7, 128.6, 127.4, 127.1, 126.0, 124.4, 123.8, 110.0,
+
5.1, 74.9, 52.1, 32.4, 22.6; HRMS (ESI, m/z): calcd. for C H NO Na 558.2045, found
3
7
29
3
21
58.2043. [α] = ꢀ79.6 (c = 1.0 in CHCl ); HPLC analysis: 94% ee , [CHIRALPAK IA
D
3
column; 1 mL/min; solvent system: iꢀPrOH/hexane = 5:95; retention times: 11.3 min
minor), 17.7 min (major)].
(
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
2R,3S)-7'-fluoro-3-phenyl-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione
1
(3q): 38.3 mg, 71% yield, >20:1 dr, viscous solid. H NMR (400 MHz, CDCl ) δ 7.41ꢀ
3
7
.36 (m, 4H), 7.18ꢀ7.09 (m, 12H), 6.90ꢀ6.88 (m, 6H), 6.77ꢀ6.72 (m, 1H), 4.13 (dd, J =
1
14.0 Hz, J = 8.4 Hz, 1H), 3.71 (dd, J = 16.8 Hz, J = 13.6 Hz, 1H), 2.86 (dd, J = 16.8
Hz, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 174.3, 173.8, 146.5 (d, J = 250
Hz), 142.4 (d, JC-F = 2 Hz), 131.9, 131.5 (d, JC-F = 8 Hz), 129.2, 129.0, 128.8, 128.3,
1
2
1
2
1
1
3
2
3
C-F
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
27.8, 127.3, 126.3, 125.1 (d, JC-F = 7 Hz), 120.2 (d, JC-F = 24 Hz), 119.8 (d, JC-F = 4 Hz),
+
8
5.6 (d, JC-F = 2 Hz), 75.6, 52.0, 31.9; HRMS (ESI, m/z): calcd. for C H NO FNa
36
26
3
2
1
562.1794, found 562.1807. [α] = ꢀ105.8 (c = 1.0 in CHCl ); HPLC analysis: 97% ee ,
[CHIRALPAK ID column; 1 mL/min; solvent system: iꢀPrOH/hexane = 10:90; retention
times: 16.5 min (minor), 19.3 min (major)].
D
3
(2R,3S)-5',7'-dimethyl-3-phenyl-1'-trityl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-
1
dione (3r): 49.9 mg, 91% yield, >20:1 dr, viscous solid. H NMR (400 MHz, CDCl ) δ
7
6
Hz, 1H), 2.80 (dd, J = 16.8 Hz, J = 8.4 Hz, 1H), 2.31 (s, 3H), 0.98 (s, 3H); C NMR
(100 MHz, CDCl ) δ 174.9, 174.5, 143.4, 141.7, 137.4, 133.4, 132.3, 129.5, 129.2, 128.8,
1
m/z): calcd. for C H NO Na 572.2202, found 572.2215. [α] = ꢀ82.7 (c = 1.0 in
CHCl ); HPLC analysis: 96% ee , [CHIRALPAK IC column; 1 mL/min; solvent system:
iꢀPrOH/hexane = 10:90; retention times: 35.4 min (major), 41.6 min (minor)].
3
.34ꢀ7.32 (m, 3H), 7.28 (s, 1H), 7.21ꢀ7.18 (m, 4H), 7.14ꢀ7.07 (m, 7H), 6.91ꢀ6.89 (m, 6H),
.64 (s, 1H), 4.12 (dd, J = 14.0 Hz, J = 8.0 Hz, 1H), 3.64 (dd, J = 16.8 Hz, J = 14.0
1
2
1
2
1
3
1
2
3
28.7, 127.3, 127.0, 126.0, 124.0, 122.7, 85.3, 74.7, 52.0, 32.5, 22.4, 20.4; HRMS (ESI,
+
21
3
8
31
3
D
3
Transformation of 3a to 5. To a stirred solution of 3a (104.2 mg, 0.2 mmol, 93% ee) in
ClCH CH Cl (2 mL) was carefully added TFA (154 ꢁL, 2 mmol) at room temperature
and the reaction mixture was stirred at 50˚C for another 6 hours. After completion of the
reaction (monitored by TLC), the reaction mixture was cooled to room temperature and
quenched by saturated NaHCO aq. (4 mL). The aqueous phase was extracted
2
2
3
withCH Cl , and the combined organic phase was washed with brine, dried over Na SO .
2
2
2
4
Filtration and removal of solvent under reduced pressure gives a residue, which was
purified by column chromatography using hexane/EtOAc = 4/1 as eluent to afford the
desired product 5.
(2R,3S)-3-phenyl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione (5): 42.9 mg, 77%
1
yield, >20:1 dr, white solid. H NMR (400 MHz, CDCl ) δ 7.83 (br, 1H), 7.52 (d, J = 7.6
Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.26ꢀ7.14 (m, 4H), 6.94 (d, J = 7.6 Hz, 2H), 6.73 (d, J =
7
3
.6 Hz, 1H), 4.10 (dd, J = 13.6 Hz, J = 8.0 Hz, 1H), 3.76 (dd, J = 16.8 Hz, J = 14.0 Hz,
1 2 1 2
13
1H), 2.91 (dd, J = 17.2 Hz, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 174.9,
1
2
3
1
3
6
74.5, 141.4, 131.9, 131.3, 128.6, 128.3, 127.6, 124.9, 124.5, 123.5, 110.6, 86.5, 50.7,
+
21
2.1; HRMS (ESI, m/z): calcd. for C H NO Na 302.0793, found 302.0791. [α] = ꢀ
1
7
13
3
D
0.1 (c = 1.0 in CHCl ); HPLC analysis: 93% ee , [CHIRALPAK IC column; 0.8 mL/min;
3
solvent system: iꢀPrOH/hexane = 20:80; retention times: 32.8 min (major), 38.7 min
minor)].
(
ASSOCIATED CONTENT
Supporting Information
ACS Paragon Plus Environment

Page 13 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The Supporting Information is available free of charge on the ACS Publications website
at DOI:
H, C NMR, and HPLC spectra for all new compounds (PDF)
Xꢀray data for 3n (CIF)
AUTHOR INFORMATION
1
13
Corresponding Author
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
*Eꢀmail: jfxu@zstu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the National Natural Science Foundation of China (Grant No.
2
1302169, 21602203), the Natural Science Foundation of Zhejiang Province (Grant No.
LQ16B020001), the Natural Science Foundation of Zhejiang SciꢀTech University (Grant
No. 1206820ꢀY, 1206821ꢀY, 15062018ꢀY), as well as the Zhejiang Provincial Top Key
Academic Discipline of Chemical Engineering and Technology of Zhejiang SciꢀTech
University for financial support.
REFERENCES
(1) Watson, A. J. B.; Macmillan, D. W. C.; Wang, Y.; Deng, L.; Shirakawa, S.; Maruoka,
K. in: Catalytic Asymmetric Synthesis, 3rd ed., Chapter 2 (Ed.: I. Ojima), John Wiley &
Sons, New Jersey, 2010, pp. 37ꢀ117.
(2) For recent reviews on nonꢀasymmetric direct βꢀfunctionalization of carbonyl
compounds, see: (a) Yan, G.; Borah, A. J. Org. Chem. Front. 2014, 1, 838ꢀ842. (b)
Huang, Z.; Dong. G. Tetrahydron Lett. 2014, 55, 5869ꢀ5889.
(3) For a recent highlight, see: (a) Wang, L.; Xiao, J.; Loh, T. P. ChemCatChem 2014, 6,
1
183ꢀ1185. For selected examples, see: (b) Zhang, S. L.; Xie, H. X.; Zhu, J.; Li, H.;
Zhang, X. S.; Li, J.; Wang, W. Nat. Commun. 2011, 2, 211ꢀ217. (c) Hayashi, Y.; Itoh, T.;
Ishikawa, H. Angew. Chem., Int. Ed. 2011, 50, 3920ꢀ3924. (d) Mo, J.; Shen, L.; Chi, Y. R.
Angew. Chem., Int. Ed. 2013, 52, 8588ꢀ8591. (e) Fu, Z.; Xu, J.; Zhu, T.; Leong, W.W. Y.;
Chi, Y. R. Nat. Chem. 2013, 5, 835ꢀ839. (f) Fu, Z.; Jiang, K.; Zhu, T.; Torres, J.; Chi, Y.
R. Angew. Chem., Int. Ed. 2014, 53, 6506ꢀ6510. (g) Jin, Z,; Chen, S.; Wang, Y.; Zheng,
P.; Yang, S.; Chi, Y. R. Angew. Chem., Int. Ed. 2014, 53, 13506ꢀ13509. (h) Jin, Z.; Jiang,
K.; Fu, Z.; Torres, J.; Zheng, P.; Yang, S.; Song, B. –A.; Chi, Y. R. Chem. Eur. J. 2015,
2
1, 9360ꢀ9363. (i) Xie, Y.; Yu, C.; Li, T.; Tu, S.; Yao, C. Chem. Eur. J. 2015, 21, 5355ꢀ
5
359.
(4) For selected recent reviews on NHC catalysis, see: (a) Enders, D.; Niemeier, O.;
Henseler, A. Chem. Rev. 2007, 107, 5606ꢀ5655. (b) Mahatthananchai, J.; Bode, J. W. Acc.
Chem. Res. 2014, 47, 696ꢀ707. (c) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius,
F. Nature 2014, 510, 485ꢀ496. (d) Flanigan, D. M.; RomanovꢀMichailidis, F.; White, N.
A.; Rovis, T. Chem. Rev. 2015, 115, 9307ꢀ9387.
(5) For a recent highlight, see: (a) Chauhan, J.; Enders, D. Angew. Chem., Int. Ed.
2
014, 53, 1485ꢀ1487. For selected examples, see: (b) Ryan, S. J.; Candish, L.; Lupton, D.
W. J. Am. Chem. Soc. 2009, 131, 14176ꢀ14177. (c) Hao, L.; Chen, S.; Xu. J.; Tiwari, B.;
Fu, Z.; Li, T.; Lim, J.; Chi, Y. R. Org. Lett. 2013, 15, 4956ꢀ4959. (d) West, T. H.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Daniels, D. S. B.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2014, 136, 4476ꢀ
4
479. (e) Zhang, Z.; Zeng, X.; Xie, D.; Chen, D.; Ding, L.; Wang, A.; Yang, L.; Zhong.
G. Org. Lett. 2015, 17, 5052ꢀ5055. (f) Que, Y. Li, T.; Yu, C.; Wang, X.; Yao, C. J. Org.
Chem. 2015, 80, 3289ꢀ3294. (g) Chen. X.; Fong, J. Z. M.; Xu, J.; Mou, C.; Lu, Y.; Yang,
S.; Song, B.ꢀA.; Chi, Y. R. J. Am. Chem. Soc. 2016, 138, 7212ꢀ7215.
(
6) (a) Xu, J.; Jin. Z.; Chi, Y. R. Org. Lett. 2013, 15, 5028ꢀ5031. (b) Xu, J.; Yuan, S.;
Miao, M. Org. Lett. 2016, 18, 3822ꢀ3825.
7) For other preparation of spirooxindole lactones using α,βꢀunsaturated aldehydes as
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
substrates via NHC catalysis, see: (a) Sun, LꢀH.; Shen, LꢀT.; Ye, S. Chem. Commun.
2011, 47, 10136–10138. (b) DugalꢀTessier , J.; O'Bryan , E. A.; Schroeder , T. B. H.;
Cohen , D. T.; Scheidt , K. A. Angew. Chem., Int. Ed. 2012, 51, 4963– 4967. (c) Okano,
T. Heterocyclic Commun. 2013, 15, 311–326. (d) Zheng, C.; Yao, W.; Zhang, Y.; Ma, C.
Org. Lett. 2014, 16, 5028–5031. (e) Zhang, Y.; Lu, Y.; Tang, W.; Lu, T.; Du, D. Org.
Biomol. Chem. 2014, 12, 3009ꢀ3015. (f) Tang, W.; Du, D. Chem. Rec. 2016, 16, 1489ꢀ
1
500.
(8) (a) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796ꢀ13797. (b) Kuwano, S.;
Harada, S.; Orieza, R.; Yamada, K. Chem. Commun. 2012, 48, 145ꢀ147. (c) Zhu, L.; Yu,
C.; Li, T.; Wang, Y.; Lu, Y.; Wang, W.; Yao, C. Org. Biomol. Chem., 2016, 14, 1485ꢀ
1
(
491.
9) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873ꢀ3876.
(10) Chiang, P. C.; Rommel, M.; Bode, J. W. J. Am. Chem. Soc. 2009, 131, 8714ꢀ8718.
11) Piel, I.; Steinmetz, M.; Hirano, K.; Fröhlich, R.; Grimme, S.; Glorius, F. Angew.
(
Chem., Int. Ed. 2011, 50, 4983ꢀ4987.
(12) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418ꢀ8420.
(13) For selected examples, see: (a) Raup, D. E. A.; CardinalꢀDavid, B.; Holte, D.;
Scheidt, K. A. Nat. Chem. 2010, 2, 766ꢀ771. (b) Rong, Z.ꢀQ.; Jia, M. ꢀQ.; You, S. ꢀL. Org.
Lett. 2011, 13, 4080ꢀ4083. (c) Mo, J.; Chen, X.; Chi, Y. R. J. Am. Chem. Soc. 2012, 134,
8810ꢀ8813. (d) Xiao, Z.; Yu, C.; Li, T.; Wang, X.; Yao, C. Org. Lett. 2014, 16, 3632ꢀ
3
635.
(
(
14) Wang, Y.; Wei, D.; Wang, Y.; Zhang, W.; Tang, M. ACS Catal. 2016, 6, 279−289.
15) CCDC 1454941 contains the supplementary crystallographic data for 3n. These data
can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(16) Bergonzini, G.; Melchiorre, P. Angew. Chem. Int. Ed. 2012, 51, 971ꢀ974.
(17) (a) Popp, F. D. J. Heterocycl. Chem. 1982, 19, 589ꢀ592. (b) Hibino, S.; Choshi, T.
Nat. Prod. Rep. 2001, 18, 66ꢀ87. (c) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20ꢀ38.
(d) Chowdhury, S.; Chafeev, M.; Liu, S.; Sun, J.; Raina, V.; Chui, R.; Young, W.; Kwan,
R.; Fu, J.; Cadieux, J. A. Bioorg. Med. Chem. Lett. 2011, 21, 3676ꢀ3681.
ACS Paragon Plus Environment