A novel domino reaction for the preparation of substituted non-racemic β-proline derivatives

Article abstract of DOI:10.1016/j.tet.2016.08.017

A novel domino reaction for the preparation of non-racemic β-proline derivatives is reported. The addition of a methyl 2-(oxetan-3-yl)acetate titanium enolate to chiral tert-butanesulfinyl ketimines followed by an intramolecular oxetane ring-opening provi

Full text of DOI:10.1016/j.tet.2016.08.017

Accepted Manuscript
A novel domino reaction for the preparation of substituted non-racemic β-proline
derivatives
Eric J. Gilbert, Andrew Brunskill, Jiaqiang Cai, Yaxian Cai, Xin-Jie Chu, Xing Dai,
Jinsong Hao, Jeffrey T. Kuethe, Zhong Lai, Hong Liu, Cuizhi Mu, Yan Qi, Jack D.
Scott, Brandon Taoka, Quang Truong, Shawn P. Walsh, Wen-Lian Wu, Jared N.
Cumming
PII:
S0040-4020(16)30775-X
10.1016/j.tet.2016.08.017
TET 27998
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 July 2016
Revised Date: 31 July 2016
Accepted Date: 4 August 2016
Please cite this article as: Gilbert EJ, Brunskill A, Cai J, Cai Y, Chu X-J, Dai X, Hao J, Kuethe JT, Lai
Z, Liu H, Mu C, Qi Y, Scott JD, Taoka B, Truong Q, Walsh SP, Wu W-L, Cumming JN, A novel domino
reaction for the preparation of substituted non-racemic β-proline derivatives, Tetrahedron (2016), doi:
10.1016/j.tet.2016.08.017.
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A novel domino reaction for the preparation
of substituted non-racemic β-proline
derivatives
Leave this area blank for abstract info.
Eric J. Gilbert*, Andrew Brunskill, Jiaqiang Cai, Yaxian Cai, Xin-Jie Chu, Xing Dai, Jinsong Hao,
Jeffrey T. Kuethe, Zhong Lai, Hong Liu, Cuizhi Mu, Yan Qi, Jack D. Scott, Brandon Taoka, Quang
Truong, Shawn P. Walsh, Wen-Lian Wu, Jared N. Cumming
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ, 07033, United States
X-ray structure of (–)-7a

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1
Tetrahedron
journal homepage: www.elsevier.com
A novel domino reaction for the preparation of substituted non-racemic β-proline
derivatives
Eric J. Gilberta , Andrew Brunskillb, Jiaqiang Caic, Yaxian Caic, Xin-Jie Chua, Xing Daia, Jinsong Haoa,
Jeffrey T. Kuethed, Zhong Laia, Hong Liua, Cuizhi Muc, Yan Qic, Jack D. Scotta, Brandon Taokaa, Quang
Truonga, Shawn P. Walsha, Wen-Lian Wua, Jared N. Cumminga ‡
aDepartment of Global Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ, 07033, United States
bDepartment of Process and Analytical Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, United States
cWuXi AppTec (Shanghai) Co., Ltd, 288 FuTe Zhong Road, Shanghai 200131, People’s Republic of China
dDepartment of Process Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, New Jersey 07033, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel domino reaction for the preparation of non-racemic β-proline derivatives is reported.
The addition of a methyl 2-(oxetan-3-yl)acetate titanium enolate to chiral tert-butanesulfinyl
ketimines followed by an intramolecular oxetane ring-opening provides the highly-substituted
pyrrolidine ring systems with three contiguous stereogenic centers.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
β-Proline
Oxetane
Domino reaction
tert-butanesulfinyl ketimine
1. Introduction
we describe a domino reaction that features a stereoselective
addition of the titanium enolate of methyl 2-(oxetan-3-yl)acetate
β-Amino acid building blocks offer unique properties for the
design of bioactive peptides and proteins,1 foldamers,2,3 and small
molecule therapeutics.4 As they are not recognized by proteases,
β-amino acids are less prone to metabolic degradation relative to
their α-amino acid counterparts.5 In addition, incorporation of a
β-amino acid into a peptide or protein can alter their secondary
and tertiary structures, which in turn has implications with regard
to ligand-receptor and protein-protein interactions.6-8
to tert-butanesulfinyl ketimines followed by an intramolecular
oxetane ring opening to form highly substituted non-racemic β-
proline derivatives (Scheme 1).
Scheme 1. General scheme for domino reaction to form β-
proline derivatives.
β-Proline and its derivatives have been of particular interest in
the asymmetric organocatalysis field as well.9,10 Importantly, the
use of a β-proline catalyst can provide results that are
complimentary to those obtained with L-proline catalysis. For
example, in the Mannich-type reaction between aldehydes and
iminoglyoxylates, a β-proline catalyst leads to anti amino acid
derivatives with high diastereoselectivity and enantioselectivity.11
In contrast, use of L-proline as a catalyst provides the syn
diastereomer.12
2. Results and Discussion
As part of an effort to support SAR (structure activity
relationship) exploration within one of our drug discovery
programs, compounds 3a and 3b were seen as attractive
intermediates (Scheme 2). To access these compounds, the tert-
butanesulfinyl ketimine 2 was treated with the titanium enolate of
methyl 2-(oxetan-3-yl)acetate 1 at −78 °C. Unexpectedly, the
major product of this reaction was pyrrolidine 4a, isolated in 46%
yield, representing formation of a highly substituted β-proline
Despite the importance of the β-proline scaffold, few methods
are available for the synthesis of substituted analogs.13-17 Herein
———
Corresponding author. Tel.: +1-908-740-4091; e-mail: eric.gilbert@merck.com
‡ This manuscript is dedicated to Professor Gary H. Posner on the occasion of his retirement and in celebration of his career of innovative
research and outstanding mentorship.

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2
Tetrahedron
derivative in one pot from commercial (e.g. acetate 1) and/or
readily-prepared (e.g. ketimine 2) starting materials. The relative
stereochemistry of the three contiguous stereogenic centers was
determined through NOE studies.
While the synthesis of substituted β-prolines utilizing an
enolate addition to activated imines is precedented, additional
chemical steps are required to form the pyrrolidine ring
system.18,19 Of note in the one pot transformation in Scheme 2 is
the formation of a pyrrolidine ring via an intramolecular oxetane
ring-opening with a nitrogen-based nucleophile, for which just a
few examples have been reported.20-22 To the best of our
knowledge, this is the first example of this transformation
through a domino reaction. The novelty of this process, coupled
with the potential utility of β-proline derivatives, prompted
further investigation into the scope of this reaction.
Fig. 1. X-ray crystal structure of (–)-2S,3S,4S-7a.
2.1. Mechanism
CO2Me
O
The observed relative and absolute stereochemistry of (–)-7a
is consistent with the initial adduct 6a being formed through a
Zimmerman-Traxler chair-like transition state model (TS-1) as
proposed by Ellman and coworkers (Scheme 4).18,23 Consistent
with the reported model, the phenyl group of the E-ketimine is in
the axial position allowing for chelation of the sulfoxide oxygen
to titanium and thereby shielding the Re face with the t-butyl
group. The approach of the E-enolate from the Si face of the
ketimine leads to 6a. Subsequent intramolecular nucleophilic
opening of the oxetane by the metallated tert-butanesulfinyl
amine forms the β-proline ring system. The trans C3-C4
arrangement found in (–)-7a arises from the oxetane ring-opening
occurring with the oxetane methine proton syn to the ester,
minimizing negative steric interactions between the oxetane and
ester groups.
Me
Ar
i. LDA (2.2 eq.), 78 °C
ii. ClTi(OiPr)3 (3.1 eq.)
CO2Me
HN
S
HO
O
3a
F
Me
CO2Me
O
t
Bu
N
S
N
1
iii.
F
CO2Me
F
N
O
O
tBu
2.1 eq.
Me
Ar
F
Me
tBu
4a
2
1 eq.
HN
S
N
S
O
3b
tBu
O
46% yield
Scheme 2. Initial observation of β-proline formation from
methyl 2-(oxetan-3-yl)acetate 1 and ketimine 2. Ar = 2,5-
difluoro-4-pyridine.
We rapidly identified conditions that, while unoptimized, were
fit-for-purpose to explore the mechanism and scope of the
transformation. Three equivalents of the ester enolate relative to
the ketimine were used, and LiHMDS was selected as the base.
A two-fold excess of ClTi(OiPr)3 relative to the ester was utilized
as this has been previously shown by Ellman and coworkers to
increase diastereomeric ratios during the addition of ester
enolates to tert-butanesulfinyl aldimines.23 When simple phenyl
ketimine 5 was treated under these conditions, first at −78 °C and
then with warming to room temperature overnight, 2S, 3S, 4S
diastereomer (–)-7a and 2S, 3R, 4R diastereomer (–)-7b were
obtained in 30% and 16% yields, respectively, after isolation and
purification.
Scheme 3. Addition of acetate 1 to ketimine 5 under
unoptimized conditions.
A single crystal X-ray structure of the major diastereomer (–)-
7a (Fig. 1) confirmed the relative stereochemistry of the three
contiguous stereogenic centers and also allowed for unambiguous
assignment of the absolute stereochemistry based on the chiral
auxiliary.24 This X-ray, along with additional NOE studies
supporting the structure of (–)-7b, provided a basis for the
mechanistic rationale of this transformation. The absolute
stereochemistry of subsequent reaction products were assigned
by analogy or by NOE studies.
Scheme 4. Transition states leading to cyclized products
(–)-7a and (–)-7b. M = Ti(OiPr)3

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3
The modest dr of the reaction suggests a competing reaction
Table 1. Scope of domino oxetane acetate ketimine
manifold is available for the E-enolate or there is contribution
from the Z-enolate of 1. Reaction of the E-enolate of 1 through a
boat-like transition (TS-2) would yield 6b followed by oxetane
ring-opening to provide the minor product (–)-7b (Scheme 4).
Alternatively, reaction of the Z-enolate of 1 through a chair-like
transition state (TS-3) would also lead to the minor product (–)-
7b (Fig. 2). While the kinetic deprotonation of 1 would be
expected to favor the E-enolate,25 formation of the Z-enolate at
the initial deprotonation step or through the equilibration of the
E-enolate under the reaction conditions cannot be ruled out and
will be the subject of further investigation.
addition/oxetane ring opening reaction.
Entry Imine
R
Product
dra
Yieldb
67%
1
2
2
4a
6:1
5
7a
2:1
n.d.c
5:1
30%
21%
45%
30%
39%
41%
41%
29%
71%
44%
33%
3
8
9a
Fig. 2. Chair-like transition state model of the Z-enolate of 1 reacting
with ketimine 5 (M = Ti(OiPr)3, R = 3-oxetanyl, Rʹ = Ph).
4
10
12
14
16
18
20
22
24
26
11a
13a
15a
17a
19a
21a
23a
25a
27a
5
n.d.c
n.d.c
3:1
2.2. Substrate scope and additional mechanistic observations
Having examined the basic parameters of the reaction and
established the stereochemistry of the products from ketimine 5,
we next investigated the scope of the transformation by utilizing
different ketimine electrophiles (Table 1). For this study, the
general reaction conditions were adopted from Scheme 3. When
possible, the dr of the reaction was determined from the
6
7
1
integration of peaks in the H NMR spectrum of the crude
reaction mixture. The reported yields are for the purified major
diastereomers. In general, the dr of the reaction with aryl
ketimines remained modest, ranging from 2:1 (e.g. entries 2, 9,
13) to as high as 7:1 (e.g. entry 8) with a preference for the 3S, 4S
diastereomer. The methyl ketimine 30 was also tolerated and
showed a preference for the same diastereomer (entry 14).
Interestingly, reaction of the tetrahydropyranyl ketimine 32
resulted in a complete reversal of diastereoselectivity, with the
3R, 4R diastereomer 33b favored by greater than 10:1 (entry 15).
This is likely a result of destabilization of chair transition state
TS-4 with the E-enolate of 1 due to the gauche arrangement of
the non-planar oxetane and tetrahydropyran (Fig. 3). The boat-
like transition state TS-5 would avoid these unfavorable steric
interactions and lead to the observed major product 33b.
Contribution of the Z-enolate leading to the formation of 33b (i.e.
TS-3, Rʹ = 4-tetrahydropyranyl) cannot be ruled out, however.
8
7:1
9
2:1
10
11
12
3:1
5:1
3:1
13
28
29a
2:1
37%
14
15
30
32
31a
33b
3:1
41%
65%
>1:10
a Ratio of product a to product b. The diastereomeric ratio (dr) was
determined by integration in the 1H NMR of the crude reaction after workup.
b Isolated yield of the major diastereomer.
c n.d. = not determined. The complexity of the crude 1H NMR spectrum did
not allow for an accurate integration measurement.
Fig. 3. Newman projections, chair and boat-like transition state models of
the E-enolate addition of 1 to 4-tetrahydropyranyl (THP) ketimine 32.

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4
Tetrahedron
To further examine the effects of steric conflict between the
Table 2. Removal of the tert-butanesulfinyl chiral auxiliary.
enolate and ketimine on the product distribution, a substituted
oxetane, ethyl 2-(3-cyanooxetan-3-yl)acetate 34, and ketimine 22
were submitted to the general reaction conditions (Scheme 5).
From this coupling, the highly substituted β-proline 2S, 3R, 4R-
35b, possessing two quaternary centers amongst its three
contiguous stereogenic centers, was formed with a greater than
10:1 dr in 71% isolated yield. This diastereomer again
corresponded to the minor isomer observed in the examples with
less sterically demanding reactants. The C3-methine of 36b
showed strong NOE correlations between the C2-methyl and the
hydroxy-substituted C4-methylene providing evidence for the
relative stereochemistry. Given that the analogous reaction
between unsubstituted oxetane 1 and ketimine 22 produced the
major product 23a with the opposite C3 and C4 stereochemistry
(Table 1, entry 10), this result further highlights the effect of
sterics on product distribution.
Entry β-Proline
R
Product Yield
1
2
3
4
5
6
7
9a
37
38
39
40
41
42
43
55%
58%
45%
91%
88%
79%
92%
11a
13a
17a
19a
25a
27a
Scheme 5. Domino reaction with ethyl 2-(3-cyanooxetan-3-
yl)acetate 34 and ketimine 22.
2.3. Formation of N-H β-prolines
4. Experimental Section
Facile removal of the tert-butanesulfinyl chiral auxiliary was
demonstrated with several examples from Table 1. In each case,
treatment of the sulfinamides with 4N HCl in 1,4-dioxane
unmasked the pyrrolidine nitrogen providing the N-H β-proline
and a potential handle for further synthetic manipulations (Table
2). Yields were generally good with no evidence of scrambling
of the methyl carboxylate stereocenter.
4.1. Materials and methods
The oxetanyl acetates 1 (Advanced ChemBlocks Inc.) and 34
(Synthonix) were used as received. The (R)-tert-butanesulfinyl
ketimines 5 and 30 were purchased from Small Molecules, Inc.
and purified by silica gel chromatography prior to use. LiHMDS
(1.0 M in THF), ClTi(OiPr3) (1.0 M in hexane), n-BuLi (2.5 M in
hexanes), LDA (2 M in THF), MeMgBr (3 M in ether), and
Ti(OEt)4 (technical grade, ~20% Ti) were purchased from Sigma
3. Conclusion
Aldrich and used as received.
chromatography (TLC) was performed on Merck silica gel 60
Analytical thin layer
We have described herein the discovery and preliminary
characterization of a novel domino reaction that provides one pot
access to highly substituted non-racemic β-proline derivatives via
addition of the titanium enolate of an (oxetanyl)acetate to a chiral
tert-butanesulfinyl ketimine followed by intramolecular oxetane
ring-opening by the metallated tert-butanesulfinyl amine.
Diastereoselectivities are modest in the reaction between
unsubstituted methyl 2-(oxetan-3-yl)acetate 1 and an aryl or
methyl ketimine, while use of the more sterically demanding
F254 pre-coated plates. Plates were visualized using UV light
(254 nm), 1% aq. KMnO4, or an iodine chamber. H, 13C, and 19
F
1
NMR spectra were recorded on a Bruker 500 or 600 MHz
spectrometer in CDCl3 or MeOH-d4. Proton, carbon, and fluorine
chemical shifts are reported in parts per million (ppm; δ). NMR
data are reported as follows: chemical shift (multiplicity,
coupling constant(s) in Hz, integration). 13C and 19F NMR
spectra were recorded with proton decoupling. Carbon-fluorine
coupling (JF) in the 13C NMR is reported in Hz. Specific
rotations were obtained on a Perkin Elmer 341 polarimeter. High
resolution mass spectra were obtained using a Waters Acquity
UPLC followed by electrospray ionization into a Waters Xevo
G2 QTof mass spectrometer. Supercritical fluid chromatography
(SFC) was carried out using a Thar SFC Prep 80 system with a
Waters 2489 UV/Vis detector.
tetrahydropyranyl
(oxetanyl)acetate 34 leads to an increase in and reversal of
diastereoselectivity. Finally, the tert-butanesulfinyl chiral
ketimine
32
or
cyano-substituted
auxiliary was removed under acidic conditions for a number of
examples, providing the N-H β-proline derivatives.
4.2. General procedure for preparation of tert-butanesulfinyl
ketimines.

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5
The tert-butylsulfinyl ketimines were prepared from the
requisite ketone and (R)-tert-butanesulfinamide according to the
published procedure (Method C).26 The requisite methyl ketone
(1 eq.), (R)-2-methylpropane-2-sulfinamide (1.5 eq.), and
Ti(OEt)4 (technical grade, 20% Ti, ~2 eq.) in THF (1 M), were
stirred at reflux for 24-48 h. The reaction mixture was cooled to
RT and then added to an equal volume of ice water. EtOAc was
added and the mixture was stirred vigorously for 15 minutes after
which it was filtered through a pad of Celite. The filter cake was
washed with EtOAc. The filtrate was then washed with water
and brine, dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was purified by silica gel chromatography or
triturated with ether to provide the (R)-tert-butanesulfinyl
ketimine.
Hz), 156.4 (d, JF = 198.7 Hz), 128.9, 119.0 (dd, JF = 24.4, 9.2
Hz), 117.8 (dd, JF = 26.1, 8.3 Hz), 115.8 (dd, JF = 25.4, 3.2 Hz),
57.4, 23.2 (d, JF = 7.7 Hz), 22.2. 19F NMR (470 MHz, CDCl3) δ
−118.1, −117.5. m/z (ESI+) 260.5 [M+H]+.
4.2.3. (R,E)-N-(1-(2,4-difluorophenyl)ethylidene)-
2-methylpropane-2-sulfinamide (10)2 8
The general procedure was followed with 1-(2,4-
difluorophenyl)ethan-1-one (250 g, 1.60 mol), (R)-2-
methylpropane-2-sulfinamide (220 g, 1.67 mol), and technical
grade Ti(OEt)4 (1000 g, ~4 mol) in THF (2.65 L). Purification
by silica gel chromatography (10% EtOAc/PE) provided the title
1
compound 10 (255 g, 62%). H NMR (500 MHz, CDCl3) δ 7.76
(d, J = 8.5 Hz, 1H), 6.96−6.92 (m, 1H), 6.88 (ddd, J = 11.3, 8.7, 2
Hz, 1H), 2.78 (d, J = 3.7 Hz, 3H), 1.33 (s, 9H). 13C NMR (125
MHz, CDCl3) 174.7, 164.3 (dd, JF = 254.6, 12.3 Hz), 161.1 (dd,
JF = 256.5, 12.2 Hz), 131.3 (dd, JF = 10.0, 4.3 Hz), 124.4 (d, JF =
8.8 Hz), 111.6 (dd, JF = 21.3, 3.6 Hz), 104.5 (t, JF = 26.1 Hz),
57.1, 23.3 (d, JF = 7.3 Hz), 22.2. 19F NMR (470 MHz, CDCl3) δ
−106.9, −105.0. m/z (ESI+) 260.1 [M+H]+.
4.2.1. (R,E)-N-(1-(2,5-difluoropyridin-4-
yl)ethylidene)-2-methylpropane-2-sulfinamide (2)
To a solution of 2,5-difluoropyridine (140 g, 1.22 mol) in THF
(730 mL) was added n-BuLi (2.5 M in hexanes, 584 mL, 1.46
mol) at -70 °C under N2. The system was stirred for 30 min. N-
methoxy-N-methylacetamide (188.7 g, 1.83 mol) was then added
dropwise at -70 °C. The reaction was warmed to room
temperature and stirred for 1 hour. The reaction was then
quenched with aq. NH4Cl solution (200 mL). The mixture was
extracted with EtOAc (3 x 300 mL), washed with brine (200
mL), dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel chromatography (3%
EtOAc/PE) to provide 1-(2,5-difluoropyridin-4-yl)ethan-1-one
(91 g, 48%). 1H NMR (500 MHz, CDCl3) δ 8.20 (t, J = 1.7 Hz,
1H), 7.28 (dd, J = 4.5, 3.1 Hz, 1H), 3.78 (s, 1H), 2.67 (d, J = 4.1
Hz, 3H), 1.17 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 194.5–
191.9 (m), 159.8 (dd, JF = 238.9, 2.0 Hz), 155.1 (dd, JF = 257.2,
5.1 Hz), 137.2 (dd, JF = 30.8, 15.5 Hz), 136.3 (dd, JF = 14.7, 7.2
Hz), 108.9 (d, JF = 41.9 Hz), 57.3, 56.0, 31.0 (d, JF = 6.4 Hz),
21.4. 19F NMR (470 MHz, CDCl3) δ −71.1, −131.7. m/z (ESI+)
158.09 [M+H]+. HRMS (ESI) m/z calcd for C7H5F2NO [M+H]+:
158.0417, found: 158.0421.
4.2.4. (R,E)-N-(1-(2-fluoro-5-
nitrophenyl)ethylidene)-2-methylpropane-2-
sulfinamide (12)2 9
The general procedure was followed with 1-(2-fluoro-5-
nitrophenyl)ethan-1-one (160 g, 0.87 mol), (R)-2-methylpropane-
2-sulfinamide (117 g, 0.96 mol), and technical grade Ti(OEt)4
(438 g, ~1.9 mol) in THF (1.0 L) with stirring at 50-55 °C for 12
h. Trituration of the crude material with ether provided the title
1
compound 12 (250 g, 90%). H NMR (500 MHz, CDCl3) δ 8.58
(dd, J = 6.3, 2.9 Hz, 1H), 8.34 (dt, J = 9.0, 3.5 Hz, 1H), 7.32 (t, J
= 9.5 Hz, 1H), 2.84 (d, J = 3.5 Hz. 3H), 1.36 (s, 9H). 13C NMR
(125 MHz, CDCl3) δ 172.8, 163.3 (d, JF = 263.5 Hz), 143.9,
127.2 (d, JF = 10.9 Hz), 125.5 (d, JF = 5.0 Hz), 117.9, 117.7,
57.7, 22.8 (d, JF = 6.3 Hz), 22.1. 19F NMR (470 MHz, CDCl3) δ
−102.0. m/z (ESI+) 287.2 [M+H]+.
4.2.5. (R,E)-N-(1-(5-bromo-2-
fluorophenyl)ethylidene)-2-methylpropane-2-
sulfinamide (14)3 0
A solution of 1-(2,5-difluoropyridin-4-yl)ethan-1-one (91 g,
0.58 mol), (R)-2-methylpropane-2-sulfinamide (195 g, 1.61 mol)
and technical grade Ti(OEt)4 (758 g, ~3 mol) in THF (800 mL)
was refluxed overnight. The reaction mixture was quenched with
ice-water (1 L) and filtered. The filter cake was washed with
EtOAc (3x200 ml). The combined filtrate solution was washed
with brine (200 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel
chromatography (3-10% EtOAc/PE) to provide the title
compound 2 (100 g, yield 66%) as yellow oil. 1H NMR (500
MHz, CDCl3) δ 8.14 (t, J = 1.8 Hz, 1H), 7.13 (dd, J = 4.7, 2.9 Hz,
1H), 2.78 (d, J = 3.1 Hz, 3H), 1.32 (s, 9H). 13C NMR (125 MHz,
CDCl3) δ 171.8, 159.4 (d, JF = 237.8 Hz), 154.3 (dd, JF = 256.2,
5.1 Hz), 139.6 (dd, JF = 12.6, 7.8 Hz), 136.5 (dd, JF = 30.0, 16.2
Hz), 108.5 (d, JF = 42.3 Hz), 58.3, 22.61 (d, JF = 5.8 Hz), 22.5.
19F NMR (470 MHz, CDCl3) δ −71.6, −133.6. m/z (ESI+) 261.2
[M+H]+. HRMS (ESI) m/z calcd for C11H14F2N2OS [M+H]+:
261.0873, found: 261.0872.
The general procedure was followed with 1-(5-bromo-2-
fluorophenyl)ethan-1-one (870 g, 4.0 mol), (R)-2-methylpropane-
2-sulfinamide (636 g, 5.2 mol), and technical grade Ti(OEt)4
(1650 g, ~7 mol) in THF (10 L). Purification by silica gel
chromatography (1-10% EtOAc/PE) provided the title compound
14 (660 g, 51%). 1H NMR (500 MHz, CDCl3) δ 7.76 (dd, J =
6.53, 2.59 Hz, 1H), 7.52−7.50 (m, 1H), 7.00 (t, J = 9.70 Hz, 1H),
2.74 (d, J = 3.52 Hz, 3H), 1.31 (s, 9 H). 13C NMR (125 MHz,
CDCl3) δ 174.3, 159.5 (d, JF = 253.8 Hz), 135.1 (d, JF = 8.8 Hz),
132.3 (d, JF = 3.1 Hz), 129.7 (d, JF = 13.0 Hz), 118.4 (d, JF = 24.6
Hz), 116.8, 57.6, 23.4, 22.3. 19F NMR (470 MHz, CDCl3) δ
−114.2. m/z (ESI+) 320.1 [M+H]+.
4.2.6. (R,E)-N-(1-(6-bromo-3-fluoropyridin-2-
yl)ethylidene)-2-methylpropane-2-sulfinamide
(16)2 7
The general procedure was followed with 1-(6-bromo-3-
fluoropyridin-2-yl)ethan-1-one (227 g, 1.04 mol), (R)-2-
methylpropane-2-sulfinamide (227 g, 1.87 mol), and technical
grade Ti(OEt)4 (475 g, ~2 mol) in THF (2.3 L) with stirring at
reflux for 3 h. Purification by silica gel chromatography (0-10%
EtOAc/PE) provided the title compound 16 (400 g, 60%). 1H
NMR (500 MHz, CDCl3) δ 7.55 (dd, J = 8.6, 3.1 Hz, 1H), 7.39 (t,
J = 9.2 Hz, 1H), 2.83 (s, 3H), 1.34 (s, 9H). 13C NMR (125 MHz,
CDCl3) δ 172.6 (d, JF = 6.8 Hz), 157.4 (d, JF = 270.9 Hz), 144.3
(d, JF = 7.2 Hz), 134.1 (d, JF = 3.4 Hz), 131.1 (d, JF = 5.2 Hz),
4.2.2. (R,E)-N-(1-(2,5-difluorophenyl)ethylidene)-
2-methylpropane-2-sulfinamide (8)2 7
The general procedure was followed with 1-(2,5-
difluorophenyl)ethan-1-one (260 g, 1.67 mol), (R)-2-
methylpropane-2-sulfinamide (220 g, 1.82 mol), and technical
grade Ti(OEt)4 (1030 g, ~4 mol.) in THF (1.2 L). Purification by
silica gel chromatography (10% EtOAc/PE) provided the title
compound 8 (300 g, 69%). 1H NMR (500 MHz, CDCl3) δ 7.40
(s, 1H), 7.14−7.08 (m, 2H), 2.79 (d, J = 3.73 Hz, 3H), 1.34 (s,
9H). 13C NMR (125 MHz, CDCl3) δ 174.5, 158.3 (d, JF = 193.7

ACCEPTED MANUSCRIPT
6
Tetrahedron
128.2 (d, JF = 22.2 Hz), 57.9, 22.3, 19.9. 19F NMR (470 MHz,
A solution of 1-(3-chloro-4-methylthiophen-2-yl)ethan-1-one
CDCl3) δ −120.4. m/z (ESI+) 453.2 [M+H]+.
(110 g, 0.63 mol), (R)-2-methylpropane-2-sulfinamide (115 g,
0.95 mol) and technical grade Ti(OEt)4 (438 g, ~1.9 mol) in THF
(1500 mL) was heated to reflux and stirred for 48 h. The reaction
mixture was poured into ice-water (2.5 L) and the mixture was
filtered. The filtrate was extracted with EtOAc (4 x 2L), and the
combined organic layers were washed with brine (3 x 2L), dried
over Na2SO4, filtered and concentrated in vacuo. The residue
was purified by a silica gel chromatography (2-20% EtOAc/PE)
to afford the title compound 22 (140 g, yield 80%) as a yellow
solid. 1H NMR (500 MHz, CDCl3) δ 7.16 (q, J = 1.0 Hz, 1H),
2.90 (s, 3H), 2.23 (d, J = 1.0 Hz, 3H), 1.33 (s, 9H). 13C NMR
(125 MHz, CDCl3) δ 171.4, 138.3, 137.6, 128.0, 125.5, 57.6,
29.7, 22.6, 15.1. m/z (ESI+) 278.18 [M+H]+. HRMS (ESI) m/z
calcd for C11H16ClNOS2 [M+H]+: 278.0440, found: 278.0448.
4.2.7. (R,E)-N-(1-(5-bromo-2-fluoropyridin-3-
yl)ethylidene)-2-methylpropane-2-sulfinamide
(18)3 1
The general procedure was followed with 1-(5-bromo-2-
fluoropyridin-3-yl)ethan-1-one (72 g, 0.33 mol), (R)-2-
methylpropane-2-sulfinamide (44 g, 0.36 mol), and technical
grade Ti(OEt)4 (151 g, ~0.7 mol) in THF (1.4 L) with stirring at
reflux for 12 h. Purification by silica gel chromatography (2-
1
20% EtOAc/PE) provided the title compound 18 (90 g, 85%). H
NMR (500 MHz, CDCl3) δ 8.34 (d, J = 2.1 Hz, 1H), 8.21 (dd, J =
8.2, 2.5 Hz, 1H), 2.77 (d, J = 3.6 Hz, 3H), 1.32 (s, 9H). 13C
NMR (125 MHz, CDCl3) δ 172.4, 159.2 (d, JF = 244.3 Hz), 150.3
(d, JF = 16.1 Hz), 142.7 (d, JF = 3.8 Hz), 124.0 (d, JF = 27.5 Hz),
116.8, 58.0, 22.8 (d, JF = 6.9 Hz), 22.5. 19F NMR (470 MHz,
CDCl3) δ −67.1. m/z (ESI+) 321.2 [M+H]+.
4.2.10. (R,E)-N-(1-(3-fluorothiophen-2-
yl)ethylidene)-2-methylpropane-2-sulfinamide
(24)2 7
4.2.8. (R,E)-N-(1-(5-bromo-3-chlorothiophen-2-
yl)ethylidene)-2-methylpropane-2-sulfinamide
(20)3 2
The general procedure was followed with 1-(3-fluorothiophen-2-
yl)ethan-1-one (250 g, 1.74 mol), (R)-2-methylpropane-2-
sulfinamide (421 g, 3.84 mol), and technical grade Ti(OEt)4 (750
ml, ~3 mol) in THF (2.5 L) with stirring at reflux for 12 h.
Purification by silica gel chromatography (3-10% EtOAc/PE)
provided the title compound 24 (181 g, 43%). 1H NMR (500
MHz, CDCl3) δ 7.39 – 7.31 (m, 1H), 6.82 (dd, J = 5.6, 1.4 Hz,
1H), 2.76 (dd, J = 2.4, 1.4 Hz, 3H), 1.28 (d, J = 1.2 Hz, 9H). 13C
NMR (125 MHz, CDCl3) δ 170.0 (d, JF = 4.7 Hz), 158.0 (d, JF =
272.4 Hz), 129.9 (d, JF = 10.8 Hz), 118.7, 118.5, 57.2, 22.1, 20.8
(d, JF = 6.9 Hz). 19F NMR (470 MHz, CDCl3) δ −116.9. m/z
(ESI+) 248.2 [M+H]+.
The general procedure was followed with 1-(5-bromo-3-
chlorothiophen-2-yl)ethan-1-one (2.0 kg, 8.3 mol), (R)-2-
methylpropane-2-sulfinamide (1.0 kg, 8.3 mol), and technical
grade Ti(OEt)4 (3.8 kg, ~16 mol) in THF (20 L) with stirring at
reflux for 5 h. Trituration of the crude material with PE (5L)
provided the title compound 20 (1.1 kg, 40%) as a yellow solid.
1H NMR (500 MHz, CDCl3) δ 6.98 (s, 1H), 2.86 (s, 3H), 1.31 (s,
9H). 13C NMR (125 MHz, CDCl3) δ 170.5, 139.7, 133.8, 126.4,
119.1, 56.7, 22.0, 20.3. m/z (ESI+) 342.1 [M+H]+.
4.2.9. (R,E)-N-(1-(3-chloro-4-methylthiophen-2-
yl)ethylidene)-2-methylpropane-2-sulfinamide (22)
4.2.11. (R,E)-N-(1-(4-bromo-5-methylthiophen-2-
yl)ethylidene)-2-methylpropane-2-sulfinamide (26)
To a solution of 3-chloro-4-methylthiophene-2-carboxylic
acid33 (150 g, 0.85 mol) in pyridine (1500 mL) was added N,O-
dimethylhydroxylamine hydrochloride (165 g, 1.71 mol) and 1-
ethyl-3-(3-dimethylaminopropyl) carbodiimide (326 g, 1.71 mol)
at 0 °C. After addition, the mixture was stirred at room
temperature (30 °C) for 20 h. TLC (30% EtOAc/PE) showed the
To a mixture of 1-(4-bromo-5-methylthiophen-2-yl)ethan-1-
one34 (109 g, 498 mmol) and (R)-2-methylpropane-2-sulfinamide
(63.2 g, 523 mmol) in THF (1 L) was added technical grade
Ti(OEt)4 (227.1 g, ~1 mol). The resulting mixture was stirred at
70 °C for 2 days. The reaction mixture was poured into brine (1
L). The precipitate was filtered and washed with EtOAc (1 L).
The combined organic layers were washed with brine (1 L), dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue solid was washed with ether (200 mL) and dried to afford
the title compound 26 (101 g, 63%) as yellow solid. 1H NMR
(500 MHz, CDCl3) δ 7.34 (s, 1H), 2.68 (s, 3H), 2.43 (s, 3H), 1.30
(s, 9H). 13C NMR (125 MHz, CDCl3) δ 169.3, 142.1, 132.1,
109.9, 57.7, 22.5, 22.3, 18.9, 15.5. m/z (ESI+) 322.16 [M+H]+.
HRMS (ESI) m/z calcd for C11H16BrNOS2 [M+H]+: 321.9935,
found: 321.9940.
starting material was consumed.
The mixture was then
concentrated in vacuo. The residue was diluted with EA (4 L)
and washed with 1N HCl (3 x 1L), aqueous NaHCO3 (2 x 800
mL), brine (3 x 800 mL), dried over Na2SO4, filtered and
concentrated in vacuo to afford 3-chloro-N-methoxy-N,4-
dimethylthiophene-2-carboxamide (180 g, 96%) as dark yellow
1
oil. H NMR (500 MHz, CDCl3) δ 7.12 (d, J = 1.0 Hz, 1H), 3.70
(s, 3H), 3.35 (s, 3H), 2.24 (s, 3H). 13C NMR (CDCl3, 125 MHz)
δ 161.7, 136.3, 130.6, 125.1, 124.2, 61.5, 33.4, 14.5. m/z (ESI+)
220.10 [M+H]+. HRMS (ESI) m/z calcd for C8H10ClNO2S
[M+H]+: 220.0199, found: 220.0201.
4.2.12. (R,E)-N-(1-(7-bromo-3-chlorothieno[2,3-
c]pyridin-2-yl)ethylidene)-2-methylpropane-2-
sulfinamide (28)3 5
The general procedure was followed with 1-(7-bromo-3-
chlorothieno[2,3-c]pyridin-2-yl)ethan-1-one (58 g, 1.74 mol),
(R)-2-methylpropane-2-sulfinamide (421 g, 3.84 mol), and
technical grade Ti(OEt)4 (750 g, ~3 mol) in THF (2.5 L) with
To a solution of 3-chloro-N-methoxy-N,4-dimethylthiophene-
2-carboxamide (150 g, 0.68 mol) in anhydrous THF (1500 mL)
was added CH3MgBr (3.0 M in ether, 300 mL, 900 mmol)
dropwise at 0 °C under N2. The mixture was allowed to warm to
room temperature and stirred for 1.5 h. TLC (20% EtOAc/PE)
showed the starting material was consumed. The reaction
mixture was poured into NH4Cl-ice-water (NH4Cl, 200 g; H2O, 1
L; ice, 1000 g) and extracted with EA (3 x 1L). The combined
organic layers were washed with brine (3 x 1L), dried over
Na2SO4, filtered, and concentrated in vacuo to afford 1-(3-chloro-
4-methylthiophen-2-yl)ethan-1-one (117 g, 98 %) as yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.27 (q, J = 1.0 Hz, 1H), 2.66 (s,
3H), 2.23 (d, J = 1.0 Hz, 3H). 13C NMR (CDCl3, 125 MHz) δ
190.0, 138.2, 137.5, 129.5, 127.4, 29.7, 14.9. m/z (ESI+) 175.03
[M+H]+. HRMS (ESI) m/z calcd for C7H7ClOS [M+H]+:
174.9984, found: 174.9992.
stirring at reflux for 12 h.
Purification by silica gel
chromatography (3-10% EtOAc/PE) provided the title compound
16 (181 g, 43%). 1H NMR (CDCl3, 500 MHz) δ 8.41 (d, J = 5.5
Hz, 1H), 7.75 (d, J = 5.5 Hz, 1H), 3.05 (s, 3H), 1.40 (s, 9H). 13C
NMR (CDCl3, 125 MHz) δ 170.5, 144.5, 144.3, 144.1, 136.5,
135.8, 121.6, 116.5, 58.8, 22.3, 22.1. m/z (ESI+) 394.8 [M+H]+.
4.2.13. (R,E)-2-methyl-N-(1-(tetrahydro-2H-pyran-
4-yl)ethylidene)propane-2-sulfinamide (32)3 6

ACCEPTED MANUSCRIPT
7
The general procedure was followed with 1-(tetrahydro-2H-
pyran-4-yl)ethanone (1.0 g, 7.8 mmol), (R)-2-methylpropane-2-
sulfinamide (1.4 g, 11.5 mmol), and technical grade Ti(OEt)4 (2.0
g, ~8 mmol) in THF (7.8 mL) with stirring at reflux for 24 h.
Purification by silica gel chromatography (0-50% EtOAc/hex)
provided the title compound 32 (0.99 g, 55%). 1H NMR (500
MHz, CDCl3) δ 4.05 (m, 2H), 3.45 (ddd, J = 14.1, 11.7, 2.4 Hz,
2H), 2.50 (m, 1H), 2.36 (s, 3H), 1.84-1.65 (m, 4H), 1.26 (s, 9H).
13C NMR (CDCl3, 125 MHz) δ 185.9, 67.4, 67.3, 56.5, 47.8,
29.7, 29.6, 22.1, 21.1. m/z (ESI+) 232 [M+H]+.
7.32 (m, 2H), 7.25 (m, 1H), 4.05 (m, 1H), 3.74 (s (br), 2H),
3.50 (s, 3H), 3.23 (d, J = 10.5 Hz, 1H), 2.99 (m, 2H), 1.88 (s (br),
1H), 1.74 (s, 3H), 1.08 (s, 9H). 13C NMR (125 MHz, CDCl3) δ
171.5, 144.3, 127.8, 127.3, 127.2, 71.4, 63.5, 58.8, 57.9, 51.8,
42.5, 41.5, 24.4, 20.0. m/z (ESI+) 354.31 [M+H]+. HRMS (ESI)
m/z calcd for C18H27NO4S [M+H]+: 354.1739, found: 354.1745.
20
(–)-7b: [α]D −66.1° (c = 0.51, MeOH). 1H NMR (500 MHz,
CDCl3) δ 7.27 (m, 4H), 7.23 (m, 1H), 3.73 (m, 2H), 3.63 (dd, J =
11.2, 5.3 Hz, 1H), 3.41 (m, 1H), 3.38 (s, 3H), 2.94 (d, J = 10.9
Hz, 1H), 2.89 (m, 1H), 2.61 (s (br), 1H), 2.12 (s, 3H), 1.19 (s,
9H). 13C NMR (125 MHz, CDCl3) δ 171.1, 143.5, 127.8, 127.3,
126.5, 72.8, 63.0, 58.7, 58.1, 51.6, 44.0, 41.0, 26.9, 24.3. m/z
(ESI+) 354.3 [M+H]+. HRMS (ESI) m/z calcd for C18H27NO4S
[M+H]+: 354.1739, found: 354.1748.
4.3. Methyl (2S,3S,4S)-1-((R)-tert-butylsulfinyl)-2-(2,5-
difluoropyridin-4-yl)-4-(hydroxymethyl)-2-methylpyrrolidine-3-
carboxylate (4a)
To methyl 2-(oxetan-3-yl)acetate (4.60 g, 35.3 mmol) in THF
(150 mL) at −78 °C was added LDA (18.6 mL, 2.0 M in THF,
37.1 mmol). After 30 minutes at −78 °C, ClTi(OiPr)3 (1M in
hexane, 53 mL, 53 mmol) was added. The reaction was stirred
for 30 minutes followed by the addition of (R,E)-N-(1-(2,5-
difluoropyridin-4-yl)ethylidene)-2-methylpropane-2-sulfinamide
2 (4.60 g, 17.7 mmol) in THF (100 mL). The reaction was stirred
for 4 h at −78 °C and then quenched with saturated aq. NH4Cl
(60 mL). After warming to room temperature, the mixture was
extracted with EtOAc (3 x 200 mL). The combined organic
layers were washed with water (2 x 100 mL) and brine (100 mL),
dried (Na2SO4), filtered, and concentrated in vacuo. The crude
material was purified by silica gel chromatography (33%
EtOAc/PE) to provide the title compound 4a (4.0 g, 46%). 1H
NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 6.93 (s, 1H), 4.09 (t, J =
9.4 Hz, 1H), 3.76 (m, 2H), 3.62 (d, J = 11.2 Hz, 1H), 3.57 (s,
3H), 3.04 (t, J = 9.7 Hz, 1H), 2.99–2.87 (m, 1H), 1.74 (s, 3H),
1.05 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 170.7, 159.5 (d, JF
= 236.6 Hz), 155.5 (dd, JF = 252.8, 4.5 Hz), 146.3 (d, JF = 7.3
Hz), 135.5 (dd, JF = 31.1, 16.3 Hz), 109.0 (d, JF = 42.4 Hz), 68.9,
62.8, 57.9, 54.3, 54.2, 52.2, 42.9, 41.6, 23.7, 20.5. m/z (ESI+)
391.4 [M+H]+. HRMS (ESI) m/z calcd for C17H24F2N2O4S
[M+H]+: 391.1503, found: 391.1511.
4.5. General procedure for the condensation of (oxetanyl)acetate
and tert-butanesulfinyl ketimine.
To (oxetanyl)acetate (3 mmol) in THF (16 mL) at −78 °C was
added LiHMDS (1.0 M in THF, 3.1 mmol). After 15-30 minutes,
ClTi(OiPr)3 in hexane (6.2 mmol) was added. The mixture was
stirred for 30 minutes after which the tert-butanesulfinyl ketimine
(1.0 mmol) in THF (4 mL) was added. The cold bath was
allowed to expire while stirring overnight. Saturated aqueous
NH4Cl (30 mL) was added followed by EtOAc (50 mL) and the
mixture was stirred vigorously for 15 minutes. The mixture was
then extracted with EtOAc (3 x 25 mL). The combined organic
layers were washed with water (30 mL) and brine (30 mL), dried
1
(MgSO4), filtered, and concentrated in vacuo. A H NMR was
obtained on the crude material to determine the dr of the reaction.
The residue was then purified by silica gel chromatography to
isolate the major diastereomer.
4.5.1. Methyl (2S,3S,4S)-1-((R)-tert-butylsulfinyl)-
2-(2,5-difluoropyridin-4-yl)-4-(hydroxymethyl)-2-
methylpyrrolidine-3-carboxylate (4a)
Following the general procedure, the title compound 4a was
obtained as a white foam (265 mg, 67%). 1H NMR (500 MHz,
CDCl3) δ 8.00 (s, 1H), 6.93 (s, 1H), 4.09 (t, J = 9.4 Hz, 1H), 3.76
(m, 2H), 3.62 (d, J = 11.2 Hz, 1H), 3.57 (s, 3H), 3.04 (t, J = 9.7
Hz, 1H), 2.99–2.87 (m, 1H), 1.74 (s, 3H), 1.05 (s, 9H). 13C NMR
(125 MHz, CDCl3) δ 170.7, 159.5 (d, JF = 236.6 Hz), 155.5 (dd,
JF = 252.8, 4.5 Hz), 146.3 (d, JF = 7.3 Hz), 135.5 (dd, JF = 31.1,
16.3 Hz), 109.0 (d, JF = 42.4 Hz), 68.9, 62.8, 57.9, 54.3, 54.2,
52.2, 42.9, 41.6, 23.7, 20.5. m/z (ESI+) 391.4 [M+H]+. HRMS
(ESI) m/z calcd for C17H24F2N2O4S [M+H]+: 391.1503, found:
391.1511.
4.4. (–)-methyl (2S,3S,4S)-1-((R)-tert-butylsulfinyl)-4-
(hydroxymethyl)-2-methyl-2-phenylpyrrolidine-3-carboxylate
(7a) and (–)-methyl (2S,3R,4R)-1-((R)-tert-butylsulfinyl)-4-
(hydroxymethyl)-2-methyl-2-phenylpyrrolidine-3-carboxylate
(7b)
To methyl 2-(oxetan-3-yl)acetate 1 (0.39 g, 3.0 mmol) in THF
(16 mL) at −78 °C was added LiHMDS (3.1 mL, 1.0 M in THF,
3.1 mmol) dropwise. The reaction mixture was then stirred for
15 minutes after which ClTi(OiPr)3 (6.2 mL, 1.0 M in hexane, 6.2
mmol) was added. The mixture was stirred at −78 °C for an
additional 30 minutes after which (R,E)-2-methyl-N-(1-
phenylethylidene)propane-2-sulfinamide 5 (0.22 g, 1.0 mmol) in
THF (4 mL) was added. The cold bath was allowed to expire
while stirring for 16 hours. Saturated aqueous NH4Cl (30 mL)
was added to the reaction followed by EtOAc (50 mL) and the
mixture was stirred vigorously for 15 min. The mixture was
filtered through a plug of Celite washing with EtOAc (2 x 25
mL). The filtrate was then washed with EtOAc (2 x 30 mL).
The combined organic layers were washed with water and brine,
dried (MgSO4), filtered, and concentrated in vacuo. The residue
was purified by silica gel chromatography (gradient elution, 0-
95% EtOAc/hex over 30 min.) to provide the product as a 1.7 : 1
mixture of (–)-7a and (–)-7b (0.23 g, 64%). The mixture was
separated by SFC (Regis Whelk-01(S,S), 21 x 250 mm, 50 g/min,
20% acetonitrile/MeOH 1:1 modifier, 120 barr, 35 °C, 210 nm)
to provide the slower eluting (–)-7a (105 mg, 30%) and the faster
4.5.2. methyl-(2S,3S,4S)-1-((R)-tert-butylsulfinyl)-
2-(2,5-difluorophenyl)-4-(hydroxymethyl)-2-
methylpyrrolidine-3-carboxylate (9a)
Following the general procedure and purification by silica gel
chromatography (0-10% MeOH/DCM) afforded the title
compound 9a (81 mg, 21%) as a white solid. 1H NMR (500
MHz, CDCl3) δ 7.11-7.07 (m, 1H), 7.03-6.98 (m, 2H), 4.10 (t, J
= 8.5 Hz, 1H,), 3.80 (d, J = 5.1 Hz, 2H), 3.71-3.69 (m,1H), 3.59
(s, 3H), 3.01-2.92 (m, 2H), 1.74-1.70 (s, 3H), 1.06 (s, 9H). 13C
NMR (125 MHz, CDCl3) δ 171.5, 158.5 (d, JF = 175.1 Hz), 156.6
(d, JF = 238.0 Hz), 133.6, 117.4 (dd, JF = 26.4, 8.6 Hz), 115.6
(dd, JF = 23.9, 3.8 Hz), 115.5 (dd, JF = 25.2, 1.3 Hz), 69.3, 63.5,
57.7, 54.7(d, JF = 6.3 Hz), 52.0, 42.8, 41.7, 23.7, 21.1 19F NMR
(470 MHz, CDCl3) δ −118.4, −113.7. m/z (ESI+) 390.66 [M+H]+.
HRMS (ESI) m/z calcd for C18H25F2NO4S [M+H]+: 390.1550,
found: 390.1558.
4.5.3. methyl (2S,3S,4S)-1-((R)-tert-butylsulfinyl)-
2-(2,4-difluorophenyl)-4-(hydroxymethyl)-2-
methylpyrrolidine-3-carboxylate (11a)
20
eluting (–)-7b (57 mg, 16%). (–)-7a: [α]D −47.2° (c 0.55,
1
MeOH). H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 7.5 Hz, 2H),

ACCEPTED MANUSCRIPT
8
Tetrahedron
Following the general procedure, the title compound 11a
(ESI) m/z calcd for C17H24BrFN2O4S [M+H]+: 451.0702, found:
was obtained as a colorless oil (175 mg, 44.9%). 1H NMR (500
MHz, CDCl3) δ 7.33 (td, J = 9.1, 6.3 Hz, 1H), 6.88-6.78 (m, 2H)
4.07 (t, J = 9.1 Hz, 1H), 3.79 (dd, J =10.8, 5.0 Hz, 1H), 3.72 (dd,
J = 10.8, 5.7 Hz 1H), 3.55 (s, 3H), 3.63-3.61 (m, 1H), 3.02 (t, J =
9.5 Hz, 1H), 3.48 (s, 1H), 2.97-2.93 (m, 1H), 1.75 (s, 3H), 1.04
(s, 9H). 13C NMR (125 MHz, CDCl3) δ 171.5, 162.6 (dd, JF =
188.0, 12.1 Hz), 160.6 (dd, JF = 191.3, 12.2 Hz), 129.4 (dd, JF =
9.5, 5.1 Hz), 127.8 (dd, JF = 7.1, 4.1 Hz), 110.6 (dd, JF = 20.5,
3.6 Hz), 104.9 (dd, JF = 27.2, 25.1 Hz), 69.3 (d, JF = 3.6 Hz),
63.4, 57.6, 54.5 (d, JF = 6.5 Hz), 51.9, 42.8, 41.7, 23.7, 21.4. 19F
NMR (470 MHz, CDCl3) δ −111.1, −103.2. m/z (ESI+) 390.2
[M+H]+. HRMS (ESI) m/z calcd for C18H25F2NO4S [M+H]+:
390.1550, found: 390.1556.
451.0703.
4.5.7. Methyl (2S,3S,4S)-2-(6-bromo-3-
fluoropyridin-2-yl)-1-((R)-tert-butylsulfinyl)-4-
(hydroxymethyl)-2-methylpyrrolidine-3-carboxylate
(19a)
Following the general procedure, the title compound 19a was
obtained as a white foam (184 mg, 41%). 1H NMR (500 MHz,
CDCl3) δ 8.21 (dd, J = 2.4, 1.5 Hz, 1H), 7.87 (dd, J = 8.8, 2.4 Hz,
1H), 4.08 (t, J = 9.3 Hz, 1H), 3.79 (td, J = 5.3, 2.9 Hz, 2H), 3.61
(dd, J = 11.2, 1.7 Hz, 1H), 3.59 (s, 3H), 3.01 (d, J = 9.6 Hz, 1H),
2.88 (s, 1H), 1.74 (s, 3H), 1.05 (s, 9H). 13C NMR (125 MHz,
CDCl3) δ 170.6, 159.4 (d, JF = 243.8 Hz), 147.0 (d, JF = 16.6 Hz),
141.6 (d, JF = 4.4 Hz), 129.0 (d, JF = 22.3 Hz), 116.2 (d, JF = 4.4
Hz), 68.6 (d, JF = 6.8 Hz), 62.3, 57.8, 53.8 (d, JF = 5.8 Hz), 52.0,
43.1, 41.6, 23.7, 20.8. 19F NMR (470 MHz, CDCl3) δ −62.2. m/z
(ESI+) 451 [M+H]+. HRMS (ESI) m/z calcd for C17H24BrFN2O4S
[M+H]+: 451.0702, found: 451.0706.
4.5.4. Methyl (2S,3S,4S)-1-((R)-tert-butylsulfinyl)-
2-(2-fluoro-5-nitrophenyl)-4-(hydroxymethyl)-2-
methylpyrrolidine-3-carboxylate (13a)
Following the general procedure, the resulting crude material
was purified by silica gel chromatography (0-10% MeOH/DCM)
followed by SFC (IC-H column, 4.6x250mm, 20% MeOH/CO2,
2.1 mL/min, 100 barr, 254 nm, 40 °C) to afford the title
compound 13a as a white solid (96 mg, 23%). 1H NMR (500
MHz, CDCl3) δ 8.35 (dd, J = 6.9, 2.8 Hz, 1H), 8.26 (dd, J = 8.9,
3.3 Hz, 1H), 7.23 (dd, J = 11.4, 8.9 Hz, 1H), 4.13 (t, J = 9.1 Hz,
1H), 3.82 (d, J = 5.1 Hz, 2H), 3.65 (d, J = 11.0 Hz, 1H), 3.59 (s,
3H), 2.99 (d, J = 9.7 Hz, 1H), 1.86 (s, 3H), 3.07-3.01 (m, 2H),
1.07 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 170.8, 164.3 (d, JF
= 261.5 Hz), 143.9, 133.7 (d, JF = 8.8 Hz), 125.4 (d, JF = 11.4
Hz), 124.8 (d, JF = 5.4 Hz), 117.7 (d, JF = 26.4 Hz), 69.5 (d, JF =
3.8 Hz), 62.8, 57.8, 54.5 (d, JF = 6.0 Hz), 52.1, 42.9, 41.6, 23.7,
21.2 19F NMR (470 MHz, CDCl3) δ −96.7. m/z (ESI+) 417.7
[M+H]+. HRMS (ESI) m/z calcd for C18H25FN2O6S [M+H]+:
417.1495, found: 417.1504.
4.5.8. Methyl (2S,3S,4S)-2-(5-bromo-3-
chlorothiophen-2-yl)-1-((R)-tert-butylsulfinyl)-4-
(hydroxymethyl)-2-methylpyrrolidine-3-carboxylate
(21a)
Following the general procedure, the title compound 21a was
obtained as a white foam (120 mg 29%). 1H NMR (500 MHz,
CDCl3) δ 6.91 (1H, s), 4.08 (t, J = 9.5 Hz, 1H), 4.00 (d, J = 11.1
Hz, 1H), 3.78 (, s, 2H), 3.66 (s, 3H), 2.99 (t, J = 9.7 Hz, 1H),
2.88 (d, J = 10.8 Hz, 1H), 1.81 (s, 3H), 1.15 (s, 9H). 13C NMR
(125 MHz, CDCl3) δ: 171.3, 142.4, 132.2, 121.3, 109.9, 69.3,
63.5, 58.2, 53.7, 52.3, 42.8, 41.8, 24.5, 22.7. m/z (ESI+) 472
[M+H]+. HRMS (ESI) m/z calcd for C16H23BrClNO4S2 [M+H]+:
472.0018, found: 472.0018.
4.5.9. Methyl (2S,3S,4S)-1-(tert-butylsulfinyl)-2-(3-
chloro-4-methylthiophen-2-yl)-4-(hydroxymethyl)-2-
methylpyrrolidine-3-carboxylate (23a)
4.5.5. Methyl (2S,3S,4S)-2-(5-bromo-2-
fluorophenyl)-1-((R)-tert-butylsulfinyl)-4-
(hydroxymethyl)-2-methylpyrrolidine-3-carboxylate
(15a)
Following the general procedure, the title compound 23a was
obtained as a white foam (290 mg, 71%). 1H NMR (500 MHz,
CDCl3) δ 6.90 (d, J = 1.3 Hz, 1H), 4.07 (m, 2H), 3.78 (m, 2H),
3.62 (s, 3H), 3.04 (t, J = 9.8 Hz, 1H), 2.90 (m, 1H), 2.19 (d, J =
1.1 Hz, 3H), 1.84 (s, 3H), 1.09 (s, 9 H). 13C NMR (125 MHz,
CDCl3) δ 171.7, 140.3, 137.2, 122.7, 118.3, 69.1, 63.6, 58.0,
53.3, 52.1, 43.1, 41.9, 23.8, 22.7, 15.2. m/z (ESI+) 408.6 [M+H]+.
HRMS (ESI) m/z calcd for C17H26ClNO4S2 [M+H]+: 408.1070,
found: 408.1081.
Following the general procedure, the title compound 15a was
obtained as a white foam (220 mg, 39%). 1H NMR (500 MHz,
CDCl3) δ 7.49-7.41 (m, 2H), 6.95 (dd, J = 12.2, 8.6 Hz, 1H), 4.10
(t, J = 8.5 Hz, 1H), 3.79 (d, J = 5.0 Hz, 2H), 3.64 (d, J = 10.54
Hz, 1H), 3.02-2.98 (m, 2H), 3.60 (s, 3H), 1.76 (s, 3H), 1.07 (s, 9
H). 13C NMR (125 MHz, CDCl3) δ 171.4, 159.98 (d, JF = 250.3
Hz), 134.0 (d, JF = 8.3 Hz), 132.4 (d, JF = 9.3 Hz), 131.7 (d, JF =
3.6 Hz), 118.3 (d, JF = 25.2 Hz), 116.5 (d, JF = 3.2 Hz), 69.5 (d,
JF = 3.5 Hz), 63.4, 57.8, 54.8 (d, JF = 6.3 Hz), 52.1, 42.9, 41.8,
23.8, 21.3. 19F NMR (470 MHz, CDCl3) δ −109.7. m/z (ESI+)
452.6 [M+H]+. HRMS (ESI) m/z calcd for C18H25BrFNO4S
[M+H]+: 450.0750, found: 450.0761.
4.5.10. Methyl (2S,3S,4S)-1-((R)-tert-butylsulfinyl)-
2-(3-fluorothiophen-2-yl)-4-(hydroxymethyl)-2-
methylpyrrolidine-3-carboxylate (25a)
Following the general procedure, the title compound 25a was
obtained as a white foam (168 mg, 44%). 1H NMR (500 MHz,
CDCl3) δ 7.09 (dd, J = 5.6, 3.7 Hz, 1H), 6.75 (d, J = 5.5 Hz, 1H),
4.02 – 3.94 (m, 1H), 3.75 (td, J = 5.3, 3.0 Hz, 2H), 3.62 (s, 3H),
3.51 (d, J = 10.7 Hz, 1H), 2.95 – 2.84 (m, 2H), 1.75 (s, 3H), 1.11
(s, 9H). 13C NMR (125 MHz, CDCl3) δ 171.3, 154.3 (d, JF =
259.8 Hz), 122.0 (d, JF = 11.0 Hz), 118.3, 118.1, 68.5, 63.7, 57.9,
55.9 (d, JF = 3.2 Hz), 52.1, 42.1, 41.0, 24.0, 21.6 (d, JF = 2.6 Hz).
19F NMR (470 MHz, CDCl3) δ −123.7. m/z (ESI+) 378 [M+H]+.
HRMS (ESI) m/z calcd for C16H24FNO4S2 [M+H]+: 378.1209,
found: 378.1218.
4.5.6. Methyl (2S,3S,4S)-2-(6-bromo-3-
fluoropyridin-2-yl)-1-((R)-tert-butylsulfinyl)-4-
(hydroxymethyl)-2-methylpyrrolidine-3-carboxylate
(17a)
Following the general procedure, the title compound 17a was
obtained as a white foam (185 mg, 41%). 1H NMR (500 MHz,
CDCl3) δ 7.43 (dd, J = 8.4, 2.9 Hz, 1H), 7.29-7.27 (m, 1H), 4.10
(t, J = 8.9 Hz, 1H), 3.81-3.75 (m, 2H), 3.70 (d, J = 11.1 Hz, 1H),
3.57 (s, 3H), 3.01 (t, J = 9.5 Hz, 1H), 2.94 (d, J = 11.1 Hz, 1H),
2.48 (t, J = 5.26 Hz, 1H), 1.80 (s, 3H), 1.04 (s, 9 H). 13C NMR
(125 MHz, CDCl3) δ 171.1, 157.6 (JF = 261 Hz), 151.0 (JF = 8.1
Hz), 133.6 (JF = 2.7 Hz), 128.7 (JF = 4.5 Hz), 127.1 (JF = 22.7
Hz), 63.1, 57.7, 54.1, 54.0, 52.0, 43.2, 41.5, 23.7, 20.3. 19F NMR
(470 MHz, CDCl3) δ −118.8. m/z (ESI+) 451.20 [M+H]+, HRMS
4.5.11. Methyl-(2S,3S,4S)-2-(4-bromo-5-
methylthiophen-2-yl)-1-(tert-butylsulfinyl)-4-
(hydroxymethyl)-2-methylpyrrolidine-3-carboxylate
(27a)
Following the general procedure, the title compound 27a was
obtained as a white foam (140 mg, 33%). 1H NMR (500 MHz,

ACCEPTED MANUSCRIPT
9
CDCl3) δ 6.82 (s, 1H), 3.97 (t, J = 8.4 Hz, 1H), 3.74 (s, 2H), 3.64
[M+H]+. HRMS (ESI) m/z calcd for C19H27ClN2O4S2 [M+H]+:
(s, 3H), 3.17 (d, J = 10.3 Hz, 1H), 2.91 (t, J = 9.1 Hz, 2H), 2.38
(s, 3H), 1.16 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 170.9,
146.8, 133.8, 128.4, 108.5, 69.2, 63.3, 59.2, 58.5, 51.8, 42.2,
41.1, 24.2, 22.0, 14.5. m/z (ESI+) 452 [M+H]+. HRMS (ESI) m/z
calcd for C17H26BrNO4S2 [M+H]+: 452.0565, found: 452.0573.
447.1179, found: 447.1187.
4.6. General procedure for the removal of the tert-butanesulfinyl
group.
To the (2S, 3S, 4S)-methyl 2-(aryl)-4-(hydroxymethyl)-2-
methylpyrrolidine-3-carboxylate (1 equiv) in DCM (0.1M) at
room temperature was added 4N HCl in dioxane (10 equiv). The
reaction was stirred overnight or until starting material was
consumed. The mixture was concentrated in vacuo and purified
by silica gel chromatography (EtOAc/NH4OH or EtOAc/7N NH3
in MeOH) to provide the title compound.
4.5.12. Methyl-(2S,3S,4S)-2-(7-bromo-3-
chlorothieno[2,3-c]pyridin-2-yl)-1-((R)-tert-
butylsulfinyl)-4-(hydroxymethyl)-2-
methylpyrrolidine-3-carboxylate (29a)
Following the general procedure, the title compound 29a was
obtained as a colorless oil (192 mg, 37%). 1H NMR (500 MHz,
CDCl3) δ 8.39 (d, J = 5.5 Hz, 1H), 7.70 (d, J = 5.5 Hz, 1H), 4.17
(t, J = 9.9 Hz, 1H), 4.07 (d, J = 11.0 Hz, 1H), 3.83 (d, J = 5.1 Hz,
2H), 3.64 (s, 3H), 3.13 (t, J = 9.9 Hz, 1H), 2.96-3.00 (m, 1H),
2.01 (s, 3H), 1.15 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 170.9,
150.2, 144.9, 144.1, 135.3, 134.5, 117.8, 115.4, 69.8, 58.6, 54.2,
52.3, 43.4, 52.0, 24.0, 22.7. m/z (ESI+) 523.3 [M+H]+. HRMS
(ESI) m/z calcd for C19H24BrClN2O4S2 [M+H]+: 523.0127, found:
523.0136.
4.6.1. (2S,3S,4S)-methyl 2-(2,5-difluorophenyl)-4-
(hydroxymethyl)-2-methylpyrrolidine-3-carboxylate
(37)
Following the general procedure, 9a (40 mg, 0.1 mmol) in
DCM (1 mL) was treated with 4N HCl in dioxane (0.3 mL, 1.0
mmol) to provide the title compound 37 (16 mg, 55%) as a
colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.47 (ddd, J = 9.9,
6.3, 3.3 Hz, 1H), 7.02 (ddd, J = 10.8, 8.9, 4.5 Hz, 1H), 6.95-6.90
(m, 1H), 3.78 (s, 3H), 3.43 (dd, J = 12.1, 8.5 Hz, 1H), 3.34 (qd, J
= 10.6, 6.9 Hz, 2H), 3.27 (d, J = 5.0 Hz,1H), 2.86-2.82 (m, 1H),
2.72 (dd, J = 12.1, 7.2 Hz,1H), 1.48 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 174.3, 158.8 (d, JF = 241.7 Hz), 156.2 (d, JF =
241.6 Hz), 117.4 (dd, JF = 26.2, 8.6 Hz), 115.2 (dd, JF = 24.4, 9.1
Hz), 114.7 (d, JF = 4.8 Hz), 114.5 (d, JF = 4.6 Hz), 67.2, 64.3,
56.3 (d, JF = 3.8 Hz), 51.9, 48.3, 47.3, 23.7 (d, JF = 3.5 Hz). 19F
NMR (470 MHz, CDCl3) δ −118.3, −117.9. m/z (ESI+) 286.22
[M+H]+. HRMS (ESI) m/z calcd for C14H17F2NO3 [M+H]+:
286.1254, found: 286.1259.
4.5.13. Methyl (3S,4S)-1-((R)-tert-butylsulfinyl)-4-
(hydroxymethyl)-2,2-dimethylpyrrolidine-3-
carboxylate (31a)
Following the general procedure, the title compound 31a was
obtained as a colorless oil (120 mg, 41%). 1H NMR (600 MHz,
CDCl3) δ 3.75 – 3.70 (m, 1H), 3.69 (d, J = 1.6 Hz, 4H), 3.60 –
3.53 (m, 2H), 3.24 – 3.19 (m, 1H), 2.76 (dd, J = 9.5, 2.4 Hz, 1H),
1.58 (s, 4H), 1.15 (d, J = 1.5 Hz, 12H), 1.08 (d, J = 1.5 Hz, 4H).
13C NMR (150 MHz, CDCl3) δ 172.2, 68.0, 63.6, 57.2, 56.0,
51.8, 42.5, 42.2, 26.6, 25.9, 23.6. m/z (ESI+) 292.2 [M+H]+.
HRMS (ESI) m/z calcd for C13H25NO4S [M+H]+: 292.1582,
found: 292.1590.
4.6.2. (2S,3S,4S)-methyl-2-(2,4-difluorophenyl)-4-
(hydroxymethyl)-2-methylpyrrolidine-3-carboxylate
(38)
4.5.14. Methyl (2R,3R,4R)-1-((R)-tert-
butylsulfinyl)-4-(hydroxymethyl)-2-methyl-2-
(tetrahydro-2H-pyran-4-yl)pyrrolidine-3-
carboxylate (33b)
Following the general procedure, 11a (175 mg, 0.45 mmol) in
DCM (5 mL) was treated with 4N HCl in dioxane (1.1 mL, 4.5
mmol) to provide the title compound 38 (75 mg, 58%) as a
colorless film. 1H NMR (500 MHz, CDCl3) δ 7.69 (td, J = 9.1,
6.7 Hz, 1H), 6.87-6.79 (m, 2H), 3.76 (s, 3H), 3.41 (dd, J = 12.1,
8.6 Hz, 1H), 3.34-3.27 (m, 2H), 3.23 (d, J =5.0 Hz, 1H), 2.85-
2.81 (m, 1H), 2.70 (dd, J = 12.06, 7.04 Hz, 1H), 1.92 (br s, 2H),
1.46 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 174.9, 162.1 (dd, JF
= 208.2, 11.9 Hz), 160.1 (dd, JF = 209.1, 11.9 Hz), 129.3 (d, JF =
11.2, 3.8 Hz), 128.5 (dd, JF = 9.2, 5.8 Hz), 110.8 (dd, JF = 20.4,
3.4 Hz), 104.5 (dd, JF = 27.3, 25.1 Hz), 66.8 (d, JF = 3.1 Hz),
64.4, 56.9 (d, JF = 3.5 Hz), 51.7, 48.5, 47.7, 24.0 (d, JF = 3.2 Hz).
m/z (ESI+) 286.13 [M+H]+. HRMS (ESI) m/z calcd for
C14H17F2NO3 [M+H]+: 286.1254, found: 286.1257.
Following the general procedure, the title compound 33b was
obtained as a colorless oil (236 mg, 65%). 1H NMR (500 MHz,
CDCl3) δ 3.97 (ddd, J = 15.6, 11.5, 4.1 Hz, 2H), 3.77 (dd, J =
10.8, 4.0 Hz, 1H), 3.72 (s, 3 H), 3.69 (dd, J = 12.0, 6.6 Hz, 1H),
3.59 (dd, J = 11.2, 4.4 Hz, 1H), 3.30 (m, 2H), 3.17 (dd, J = 11.1,
9.2 Hz, 1H), 2.98 (m, 1H), 2.87 (d, J = 11.5 Hz, 1H), 1.69 (m,
2H), 1.66 (s, 3H), 1.52 (ddd, J = 12.1, 12.1, 4.4 Hz, 1H), 1.40
(ddd, J = 13.1, 13.1, 4.4 Hz, 1H), 1.33 (m, 1H), 1.25 (s, 9H). 13C
NMR (125 MHz, CDCl3) δ 172.0, 74.0, 68.4, 68.1, 63.6, 58.9,
56.3, 52.0, 43.6, 43.1, 42.4, 28.6, 28.4, 24.5, 22.5. m/z (ESI+)
362 [M+H]+. HRMS (ESI) m/z calcd for C17H31NO5S [M+H]+:
362.2001, found: 362.2011.
4.6.3. (2S,3S,4S)-methyl 2-(2-fluoro-5-nitrophenyl)-
4-(hydroxymethyl)-2-methylpyrrolidine-3-
carboxylate (39)
4.5.15. Ethyl (2S,3R,4R)-1-((R)-tert-butylsulfinyl)-
2-(3-chloro-4-methylthiophen-2-yl)-4-cyano-4-
(hydroxymethyl)-2-methylpyrrolidine-3-carboxylate
(36b)
Following the general procedure, 13a (30 mg, 0.07 mmol) in
DCM (0.7 mL) was treated with 4N HCl in dioxane (0.18 mL,
0.7 mmol) to provide the title compound 39 (16 mg, 45%) as a
colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.73 (dd, J = 6.9,
2.9 Hz, 1H), 8.18 (dt, J = 8.90, 3.47 Hz, 1H), 7.24-7.19 (t, J =
8.90 Hz, 1H), 3.79-3.77 (m, 3H), 3.49-3.41 (m, 2H), 3.35 (dd, J =
10.6, 6.9 Hz, 1H), 3.24 (d, J = 5.76 Hz, 1H), 2.91-2.87 (m, 1H),
2.75 (dd, J = 12.05, 7.65 Hz, 1H), 1.53 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 178.6, 163.9 (d, JF = 258.3 Hz), 144.4, 124.7 (d,
JF = 10.6 Hz), 124.4 (d, JF = 6.3 Hz), 117.4 (d, JF = 26.4 Hz),
111.5, 67.0, 64.1, 56.7 (d, JF = 3.7 Hz), 52.0, 48.4, 47.9, 23.9 (d,
JF = 3.6 Hz). 19F NMR (470 MHz, CDCl3) δ −100.8. m/z (ESI+)
313.16 [M+H]+. HRMS (ESI) m/z calcd for C14H17FN2O5
[M+H]+: 313.1199, found: 313.1197.
Following the general procedure, ethyl 2-(3-cyanooxetan-3-
yl)acetate 34 (0.38 g, 0.75 mmol) was treated with LiHMDS
(2.35 mL, 2.3 mmol) and ClTi(iOPr3) (4.6 mL, 4.6 mmol)
followed ketimine 22 (0.20 g, 0.75 mmol) to provide the title
compound 36b as a colorless oil (0.24g, 71%). 1H NMR (500
MHz, CDCl3) δ 6.95 (s, 1H), 4.16 (d, J = 11.9 Hz, 1H), 4.13-4.04
(m, 2H), 3.91 (d, J = 11.5 Hz, 1H), 3.81 (dd, J = 11.7, 2.8 Hz,
2H), 3.26 (s, 1H), 2.79 (br s, 1H) 2.30 (s, 3H), 2.17 (s, 3H), 1.35
(s, 9H), 1.22 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
167.2, 139.4, 137.4, 122.1, 120.3, 119.8, 72.7, 63.8, 61.6, 60.2,
59.2, 48.2, 46.4, 26.4, 24.5, 15.3, 13.6. m/z (ESI+) 446.98

ACCEPTED MANUSCRIPT
10
Tetrahedron
4.6.4. (2S,3S,4S)-methyl 2-(6-bromo-3-
Acknowledgements
fluoropyridin-2-yl)-4-(hydroxymethyl)-2-
methylpyrrolidine-3-carboxylate (40)
The authors thank Nobuyoshi Yasuda of Merck & Co., Inc for
helpful discussions during the preparation of this manuscript.
Following the general procedure, 17a (110 mg, 0.24 mmol) in
DCM (3 mL) was treated with 4N HCl in dioxane (0.61 mL, 2.4
mmol) to provide the title compound 40 (77 mg, 91%) as a
colorless film. 1H NMR (500 MHz, CDCl3) δ 7.41 (dd, J = 8.4,
3.0 Hz, 1H), 5.32 (s, 1H,), 3.73 (s, 3H), 3.63 (dd, J = 10.7, 5.9
Hz, 1H), 3.54 (dd, J = 10.8, 6.6 Hz, 1H), 3.48 (s, 3H), 3.35 (dd, J
= 10.9, 8.3 Hz, 1H), 3.25 (d, J = 7.9 Hz, 1H), 2.99 (d, J = 7.6 Hz,
1H), 2.84 (dd, J = 10.9, 7.6 Hz, 1H), 2.60 (br s, 3H), 1.40 (s, 3H).
13C NMR (125 MHz, CDCl3) δ 173.5, 157.3 (d, JF = 259 Hz),
152.6 (d, JF = 13 Hz), 133.7 (d, JF = 3 Hz), 128.3 (d, JF = 5 Hz),
127.5 (d, JF = 23.1 Hz), 67.8 (d, JF = 6 Hz), 63.9, 55.7 (d, JF = 2
Hz), 51.8, 47.5, 45.8, 22.2 (d, JF = 6 Hz). m/z (ESI+) 347.1
[M+H]+. HRMS (ESI) m/z calcd for C13H16BrFN2O3 [M+H]+:
347.0406, found: 347.0407.
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4.6.5. Methyl (2S,3S,4S)-2-(5-bromo-2-
fluoropyridin-3-yl)-4-(hydroxymethyl)-2-
methylpyrrolidine-3-carboxylate (41)
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1408.
Following the general procedure, 19a (140 mg, 0.31 mmol) in
DCM (3 mL) was treated with 4N HCl in dioxane (2.0 mL, 8
mmol) to provide the title compound 41 (95 mg, 88%) as a
colorless film. 1H NMR (500 MHz, CDCl3) δ 8.26 (dd, J = 8.7,
2.5 Hz, 1H), 8.11–8.08 (m, 1H), 3.73 (s, 3H), 3.42–3.25 (m, 3H),
3.13 (d, J = 5.7 Hz, 1H), 2.87 – 2.74 (m, 1H), 2.59 (dd, J = 12.1,
7.7 Hz, 1H), 2.17 (s, 2H), 1.42 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 174.4, 159.6 (d, JF = 240.4 Hz), 146.4 (d, JF = 15.7 Hz),
141.2 (d, JF = 5.4 Hz), 130.9 (d, JF = 27.7 Hz), 116.9 (d, JF = 4.3
Hz), 66.3 (d, JF = 6.3 Hz), 63.8, 56.3 (d, JF = 3.3 Hz), 51.9, 48.4,
48.0, 23.7 (d, JF = 3.6 Hz). m/z (ESI+) 347.1, [M+H]+. HRMS
(ESI) m/z calcd for C13H16BrFN2O3 [M+H]+: 347.0406, found:
347.0408.
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factors) for the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
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4.6.6. Methyl (2S,3S,4S)-2-(3-fluorothiophen-2-yl)-
4-(hydroxymethyl)-2- methylpyrrolidine-3-
carboxylate (42)
Following the general procedure, 25a (140 mg, 0.37 mmol) in
DCM (3 mL) was treated with 4N HCl in dioxane (2.0 mL, 8
mmol) to provide the title compound 42 (80 mg, 79%) as a
colorless film. 1H NMR (500 MHz, CDCl3) δ 7.00 (dd, J = 5.6,
3.7 Hz, 1H), 6.73 (d, J = 5.6 Hz, 1H), 3.72 (s, 3H), 3.48 (dd, J =
6.4, 3.9 Hz, 2H), 3.42 – 3.34 (m, 1H), 3.23 (d, J = 5.9 Hz, 1H),
2.91 – 2.83 (m, 2H), 2.06 (s, 2H), 1.49 (d, J = 0.7 Hz, 3H). 13C
NMR (125 MHz, CDCl3) δ 173.5, 153.1 (d, JF = 257.0 Hz), 121.9
(d, JF = 10.8 Hz), 118.6, 118.4, 65.7 (d, JF = 3.3 Hz), 64.5, 56.7
(d, JF = 2.8 Hz), 52.0, 48.1, 46.0, 23.9 (d, JF = 2.7 Hz). m/z
(ESI+) 274 [M+H]+. HRMS (ESI) m/z calcd for C12H16FNO3S
[M+H]+: 274.0913, found: 274.0911.
4.6.7. (2S,3S,4S)-methyl-2-(4-bromo-5-
methylthiophen-2-yl)-4-(hydroxymethyl)-2-
methylpyrrolidine-3-carboxylate (43)
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Following the general procedure, 27a (130 mg, 0.29 mmol) in
DCM (1.5 mL) was treated with 4N HCl in dioxane (2.5 mL, 10
mmol) to provide the title compound 43 (92 mg, 92%) as a
yellow oil (92%). 1H NMR (500 MHz, CDCl3) δ 6.83 (s, 1H),
3.77 (s, 3H), 3.63-3.55 (m, 2H), 3.35 (dd, J = 11.3, 7.9 Hz, 1H),
3.10 (d, J = 7.2 Hz, 1H), 2.91-2.87(m, 1H), 2.81 (dd, J = 11.3,
7.5Hz, 1H), 2.36 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 173.8,
151.2, 132.7, 125.5, 108.1, 66.4, 64.4, 58.9, 52.0, 48.6, 47.1,
26.6, 14.6. m/z (ESI+) 348 [M+H]+. HRMS (ESI) m/z calcd for
C13H18BrNO3S [M+H]+: 348.0269, found: 348.0265.
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