Divergent syntheses of L-733, 060 and CP-122721 from functionalized pieridinones made by one-pot tandem cyclization

Article abstract of DOI:10.1016/j.tet.2017.02.057

An efficient diastereoselective approach to access trans-5-hydroxy-6-substituted 2-piperidinones skeleton has been developed through one-pot intramolecular tandem process of O-benzyl protected aldimine 11 with Grignard reagents. The diastereoselectivity of substitution at C-6 position of 2-piperidinone was controlled by α-benzyloxy group. In addition, the utility of this straightforward cascade process is demonstrated by the asymmetric syntheses of (+)-L-733, 060 (2) and its 2-substituted analogue 3, as well as (+)-CP-122721 (5).

Full text of DOI:10.1016/j.tet.2017.02.057

Accepted Manuscript
Divergent syntheses of L-733, 060 and CP-122721 from functionalized pieridinones
made by one-pot tandem cyclization
Yi-Wen Liu, Zhuo-Ya Mao, Rui-Jun Ma, Jia-Hang Yan, Chang-Mei Si, Bang-Guo Wei
PII:
S0040-4020(17)30205-3
10.1016/j.tet.2017.02.057
TET 28498
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 January 2017
Revised Date: 22 February 2017
Accepted Date: 25 February 2017
Please cite this article as: Liu Y-W, Mao Z-Y, Ma R-J, Yan J-H, Si C-M, Wei B-G, Divergent syntheses
of L-733, 060 and CP-122721 from functionalized pieridinones made by one-pot tandem cyclization,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.02.057.
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Divergent syntheses of L-733, 060 and CP-
122721 from functionalized pieridinones
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Yi-Wen Liua, Zhuo-Ya Maoa, Rui-Jun Mab, Jia-Hang Yana, Chang-Mei Sia,* and Bang-Guo Weia,*
a Institutes of Biomedical Sciences and School of Pharmacy, Fudan University, 130 Dongan Road, Shanghai 200030, China
b Center for Gastrointestinal Endoscopy, Shanxi Provincial People’s Hospital, 29 Shuangta Road, Taiyuan 030012,China

1
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Tetrahedron
journal homepage: www.elsevier.com
Divergent syntheses of L-733, 060 and CP-122721 from functionalized pieridinones
made by one-pot tandem cyclization
Yi-Wen Liua, Zhuo-Ya Maoa, Rui-Jun Mab, Jia-Hang Yana, Chang-Mei Sia,* and Bang-Guo Weia,*
a
Institutes of Biomedical Sciences and School of Pharmacy, Fudan University, 130 Dongan Road, Shanghai 200030, China
Center for Gastrointestinal Endoscopy, Shanxi Provincial People’s Hospital, 29 Shuangta Road, Taiyuan 030012,China
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient diastereoselective approach to access trans-5-hydroxy-6-substituted 2-piperidinones
skeleton has been developed through one-pot intramolecular tandem process of O-benzyl
protected aldimine 11 with Grignard reagents. The diastereoselectivity of substitution at C-6
position of 2-piperidinone was controlled by α-benzyloxy group. In addition, the utility of this
straightforward cascade process is demonstrated by the asymmetric syntheses of (+)-L-733, 060
(2) and its 2-substituted analogue 3, as well as (+)-CP-122721 (5).
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
Asymmetric Synthesis
tandem process
2-piperidinone
(+)-L-733, 060
(+)-CP-122721
CF3
1. Introduction
R
The chiral cyclic 1, 2-amino alcohol motif exists in
numerous biologically relevant natural products1 and is a
common subunit in medicinal and pharmaceutical candidates or
O
H
N
CF3
drugs2.
Moreover, these structures and their ring-opened
N
H
OMe
N
Ph
fragments are widely used as chiral auxiliaries3 and catalysts for
asymmetric synthesis4. Among them, chiral functionalized cis-3-
hydroxy-2-substituted 6-piperidinone 1 (Figure 1) is one of the
most representative in synthetic and medicinal chemistry. Typical
examples include clinical agents (+)-L-733, 060 (2)5 and (+)-CP-
99994 (4)6 as well as (+)-CP-122721 (5)7, which are potent
neurokinin substance P receptor antagonists and display a variety
of biological activities including inhibition of neurogenic
inflammation, blocking of pain transmission and regulation of
immune response5-7. Other trans-3-hydroxy-2-substituted 6-
piperidinones examples are antimalarial (+)-febrifugine (6)8,
antibiotic and anesthetic Prosopis alkaloid (+)-prosophylline (7)9
(Figure 1). Moreover, the trans-2-alkyl-3-hydroxypiperidine unit
is also embedded in the bicyclic structure of hydroxylated
indolizidines, such as the α-mannosidase inhibitor (-)-
swainsonine (8)10. Accordingly, tremendous efforts have been
devoted to the development of stereospecific methods for the
construction of cyclic 1, 2-amino alcohol motif, and a number of
H
R
(+)-CP-99994 (4) (R=H)
(+)-L-733, 060 (2) (R=H)
3 (R=Me)
(+)-CP-122721 (5) (R=OCF3)
OH
OH
H
OH
OH
OH
X
N
R
N
X
N
R
Boc
Boc
X= O or 2H
(-)-Swainsonine (8)
cis-1
trans-1
OH
O
OH
O
N
N
MeC(CH2)9
OH
N
N
H
H
O
(+)-Prosophylline (7)
(+)-Febrifugine (6)
Figure 1. The structure of several bioactive molecules 1-8.
powerful approaches have been reported in past years1-4
.
Davis and Ellman’s chiral auxiliaries (e.g. p-
toluenesulfinamide and 2-methylpropane-2- sulfinamide) have
been widely used in organic synthesis11. In recent years, one of
our research interests is to utilize these popular chiral auxiliaries
in asymmetric synthesis of natural products12. We observed an
unusual 1,3-migration for the reaction of N-tert-butanesulfinyl
ester with functionalized organozinc reagents13, and developed an
———
Corresponding authors. E-mail address: sicm@fudan.edu.cn (C.-
M. Si); bgwei1974@fudan.edu.cn (B.-G. Wei).

2
Tetrahedron
OTES
intramolecular tandem process to trans-5-hydroxy-6-substituted
ACCEPTED MANUSCRIPT OTES
OH
2-piperidinones
or
trans-4-hydroxy-5-substituted
2-
a
b
OH
O
OTBS
pyrrolidinones skeleton by switching organozinc species to
Grignard reagents (Figure 2. eq.1)2i,2j,14. It is noteworthy that
different O-protective groups of α-chiral aldimine substrates
could lead to different stereoselectivities, sometimes, generate
reversed chirality for the addition products (Figure 2. eq.2)15. Cis-
5-hydroxy-6-substituted 2-piperidinones are also found in
numerous biologically relevant natural products and
O
OBn
OBn
Ph
13
14
15
O
O
O
R or S
c
S
e
MeO
N
MeO
OP
pharmaceutical candidates5-7
. Although the oxidation and
OBn
OBn
reduction of trans-1 provided an alternative approach to generate
cis-1 isomer, only a few direct methods for preparation of cis-1
(R,SR)-11
(R,SS)-11
16 (P=TBS)
17 (P=H)
d
have
been
developed,
appeared
with
moderate
enantioselectivities5-7. Encouraged by Ellman’s and our previous
results (Figure 2. eq.1 and 2), we decided to investigate on our
previous intramolecular tandem protocol through the addition-
cylization-deprotection process in one-pot using O-benzyl
protected aldimine 11 to react with Grignard reagents to afford 5-
hydroxy-6-substituted 2-piperidinones skeleton (Figure 2. eq. 3).
Herein we report our recent results for this intramolecular tandem
process, and the application in divergent syntheses of L-733, 060
(2) and CP-122721 (5).
Scheme 1. The preparation of aldimine 11. Reagents and conditions: a.
o
DIBAL-H, toluene, -78 C, 77%; b. (1) TBSCl, DMAP, TEA, DCM, rt; (2)
o
AcOH/DCM/H2O/MeOH, 0 C, 83% over two steps; c. (1) (COCl)2, DMSO,
.
TEA, DCM, -78 oC; (2) NaH2PO4 2H2O, NaClO2, 2-methyl-2-butene, tBuOH,
rt; (3) NaHCO3, MeI, DMF, 56% over three steps. d. CSA, DCM/MeOH, rt,
100%. e. (1) DMP, DCM; (2) (S)-2-methylpropane-2-sulfinamide, CuSO4,
DCM, 85% for (R, SR)-11 and 83% for (R, SS)-11 over two steps.
Thus, (R, SR)-11 was treated with phenylmagnesium bromide at –
o
78 C to room temperature to afford the corresponding lactam,
which was in turn treated with Boc anhydride, for the purpose of
convenient purification, to afford the N-Boc lactam 18a in 68%
yield with high diastereoselectivity (dr > 99:1) (Table 1 entry 1).
When the addition reaction was conducted at 0 oC to room
temperature for 12 h, the subsequent protected 18a was obtained
in 52% yield, and the diastereoselectivity remained essentially
unchanged (dr > 99:1) (Table 1 entry 2). To examine the effect of
auxiliary chirality on the intramolecular tandem reaction, O-
benzyl aldimine (R, SS)-11 was used to react with
phenylmagnesium bromide. As shown in table 1, both (R, SR)-11
and (R, SS)-11 afforded the same product 18a with high
diastereoselectivity (Table 1 entry 3), suggesting that the chiral
sulfinamide moiety was not involved in the stereocontrol of this
addition process. To further investigate this tandem reaction,
different solvents were also screened, and the results indicated
that the solvents did not affect the diastereoselectivity of 18a
(Table 1 entries 4-6).
Our previous work2i,2j,14
OTBS
O
O
S
R/S
RMgX
MeO
N
(1)
(2)
(3)
O
N
R
one-pot
H
OTBS
α-chiral aldimines 9
trans-2-piperidinones 10
dr up to 99:1
Ellman's previous work15
(S)
(S)
(S)
S
R
S
H
S
R
(S)
N
(S)
S
H
HN
O
+
N
O
HN
O
RMgBr
O
RMgBr
toluene
TMEDA
THF
OP
syn
OTBS
OP
anti
OBn
syn / anti = 99:1
P=Bn, TBS
syn / anti = 8:92
Table 1. The reactions with phenylmagnesium bromide in
deferent conditions.
This work
O
O
O
S
OBn
Ph
OBn
1. PhMgBr
Conditions
2. Boc2O
O
R/S
RMgX
One-Pot
S
MeO
N
MeO
N
O
N
O
N
R
OBn
OBn
H
Boc
2-piperidinones 12
α-chiral aldimine 11
18a
(R,SR)-11 and (R,SS)-11
Figure 2. Our strategy to 5-hydroxy-6-substituted 2-piperidinones 12.
Entry[a]
11
Conditions
Y%[b] trans/cis[c]
2. Results and Discussion
1
2
3
4
5
6
7
(R,SR)
(R,SR)
(R,SS)
(R,SR)
(R,SR)
(R,SR)
(R,SRS)
THF, -78 oC-rt
THF, 0 oC-rt
68
52
40
65
37
14
64
99:1
99:1
98:2
99:1
65:35
99:1
99:1
As shown in Scheme 1, α-chiral N-sulfinyl aldimine 11 was
first prepared through the following sequence. A known acetal
compound 1316 was treated with DIBAL-H17 in toluene at –78 oC
to give desired chiral alcohol 14 in 77% yield with high
chemoselectivity. Upon TBS protection of 14, the TES group
was selectively removed in AcOH/DCM/H2O/MeOH to afford
primary alcohol 15 in 83% overall yield. Swern oxidation19c 15
and subsequent Pinnick oxidation (NaH2PO4·2H2O, NaClO2)18
gave the crude acid, which was converted to its methyl ester 16 in
56% overall yield. Finally, upon CSA-mediated desilyation and
DMP oxidation19a,19b of 17, the resulting aldehyde was condensed
with sulfinamide in presence of anhydrous cupric sulphate20 to
afford the desired α-chiral N-sulfinyl aldimine 11 in 85% overall
yield.
THF, -78 oC-rt
THF/TMEDA,-78 oC
THF/AlMe3, -78 oC
Toluene, -78 oC
THF, -78 oC-rt
[a] The reaction was performed with aldimine 11 (0.60 mmol), PhMgBr(1.80
mmol) in solvent (2.5 mL) overnight. [b] Isolated yield. [c] trans/cis was
determined by 1H NMR.
Next, we turned our attention to investigate the scope and
limitation of various Grignard reagents for this tandem addition-
cyclization of O-benzyl protected α-chiral aldimine (R, SRS)-11.
As shown in Table 2, a variety of substituted aryl Grignard
reagents were examined under the above optimal conditions
To this end, the intramolecular tandem reaction of O-benzyl
protected aldimine 11 with Grignard reagents was investigated.

3
(Table 1 entry 1). Although the overall yields of 18 were
moderate, the diastereoselectivity in all cases were excellent (dr
> 98:2) (Table 2 entries 1-6). It is noteworthy to mention that β-
naphthyl Grignard reagent also afforded the desired product in
54% yield and with high diastereoselectivity (dr > 99:1) (Table 2
entry 3). When alkyl Grignard reagents were screened, the yields
slightly decreased, but the diastereoselectivities still maintained
(dr > 87:13) (Table 2 entries 7-8). As for substituted benzyl
Grignard reagent, the yield of desired product 18j was reduced to
31% (Table 2 entry 9).
(R, SR)-11, which was separately treated with phenylmagnesium
ACCEPTED MANUSCRIPT
bromide (PhMgBr) and m-methyl phenylmagnesium bromide (p-
CH3PhMgBr). The resulting lactams were treated with lithium
aluminum hydride (LAH) and subsequent protected with di-tert-
butyl dicarbonate (Boc2O) in the presence of triethylamine (TEA)
to give N-Boc piperidine 20a in 45% and 20b in 50% overall
yield, respectively. Hydrogenation [Pd/C, Pd(OH)2, H2] of
compounds 20a and 20b afforded secondary alcohols 21a in 90%
yield and 21b in 85% yield. The X-ray crystallography of 21a
further confirmed the formation of trans isomer during the
nucleophilic attack and cyclization step (see Supporting
Information). The reverse of the secondary hydroxy group was
achieved through oxidation and reduction sequence. Oxidation of
21a and 21b with Dess-Martin periodinane19 (DMP) and
subsequent reduction with NaBH4 generated the desired cis-
alcohols 22a and 22b in 85% and 71% yield, respectively.
Finally, the alcohols 22a and 22b were alkylated with substituted
benzyl bromide in the presence of sodium hydride (NaH) and
then treated with trifluoroacetic acid (TFA) to give desired (+)-L-
733, 060 (2) { [α]D23 = 46.5 (c 1.0, CHCl3), lit.21e [α]D20 = 55.0 (c
Table 2. Reactions with different Grignard reagents.
O
O
OBn
1. RMgBr
2. Boc2O
S
MeO
N
O
N
R
OBn
Boc
(R,SRS)-11
18b-k
Entry[a]
R
18b-k
18b
18c
18d
18e
18f
Y%[b] trans/cis[c]
1
2
p-CH3C6H4
m-CH3OC6H4
β-naphthyl
m-CH3C6H4
m-CF3C6H4
m-FC6H4
72
50
54
57
53
54
41
40
31
22
99:1
99:1
99:1
98:2
99:1
99:1
90:10
87:13
99:1
90:10
o
1.0, CHCl3)} in 56% isolated yield, and 3 { mp 181.3-182.3 C;
[α]D = 32.8 (c 1.0, CHCl3) in 50% isolated yield. The
spectroscopic and physical data of the synthetic (+)-L-733, 060
23
3
(2) were identical to the reported data21e
.
4
5
OH
OBn
a
6
18g
18h
18i
c
b
(R, SR)-11
N
N
7
CH3(CH2)4
CH3(CH2)8
m-CH3C6H4CH2
Ethenyl
Boc
Boc
R
R
8
21a (R=H)
20a (R=H)
9
18j
21b (R=Me)
20b (R=Me)
10
18k
CF3
OH
[a] The reaction was performed with aldimine 11 (0.60 mmol), Grignard
o
reagents (1.80 mmol) in THF (2.5 mL) overnight from -78 C-rt. [b] Isolated
O
d
yield. [c] trans/cis was determined by 1H NMR.
CF3
N
Boc
N
H
To confirm the relative configuration of the product, 18a
was converted to a known compound 10a. As shown in Scheme
2, O-benzyl protection was switched to O-TBS through
hydrogenation (Pd/C, HCOOH) of lactam 18a and subsequent
treatment with TBSCl. Removal of the N-Boc group with
R
22a (R=H)
R
(+)-L-733, 060 (2) (R=H)
22b (R=Me)
The X ray of 21a (R=H)
3 (R=Me)
23
trifluoroacetic acid (TFA) afforded amide 10a {[α]D = -18.9 (c
Scheme 3. The preparation of (+)-L-733, 060 (2) and its 2-substituted
0.63, CHCl3), lit2h [α]D23 = -16.9 (0.44, CHCl3) } in 81% overall
yield. The spectroscopic and physical data of 10a were identical
to the reported data2h, which unambiguously confirmed that the
one-pot intramolecular tandem process of O-benzyl protected
aldimine 11 with Grignard reagents generated trans-form
products 18.
o
analogue 3. Reagents and conditions: a. (1) Grignard reagents, THF, -78 C-
rt, overnight. (2) LAH, 60oC, 4 h; (3) Boc2O, DMAP, TEA, DCM, NaHCO3,
12 h, 45% over three steps of 20a and 50% over three steps of 20b; b. Pd/C,
Pd(OH)2, H2, MeOH, 2 h, 90% of 21a and 85% of 21b; c. (1) DMP, DCM;
(2) NaBH4, MeOH, 0 oC, 85% over two steps of 22a and 71% over two steps
of 22b; d. (1) NaH, DMF, overnight; (2) TFA, DCM, 24h , 56% over two
steps of (+)-L-733, 060 (2) and 50% over two steps of 3.
To extend the utility of the ‘intramolecular tandem process’
to access trans-3-hydroxy-2-substituted 6-piperidinones 1, the
synthesis of (+)-CP-122721 (5)22 was also performed. As shown
in Scheme 4, alcohol 21a was converted to cis-2, 3-disubstituted
OBn
OH
OTBS
b
a
O
N
Ph
O
N
Ph
O
N
H
Ph
Boc
18a
Boc
OCF3
10a
19
Scheme 2. Synthesis of lactam 10a. Reagents and conditions: a. Pd/C,
MeOH, HCOOH; b. (1) TBSCl, imid., DMF, DMAP; (2) TFA, DCM, 81%
over three steps.
NH2
Ph
H
N
b
a
With chiral lactam 18a in hand, we focused on the synthesis
of (+)-L-733, 060 (2) and its 2-substituted analogue 3. In past
decades, tremendous efforts have been devoted to the
development of concise method to 2, and a number of powerful
approaches have been reported21. However, among these known
powerful methods, its 2-substituted analogue was scarcely
explored. As a continuation of our program for asymmetric
21a
N
OMe
N
Ph
Boc
H
23
(+)-CP-122721 (5)
Scheme 4. The preparation of (+)-CP-122721 (5). Reagents and conditions:
a. (1) DMP, DCM; (2) NH2OMe.HCl, pyridine; (3) BH3 DMS, THF, MeOH,
.
reflux,
72%
over
three
steps;
b.
(1)
2-methoxy-5-
synthesis
of
nitrogen-containing heterocyclic compounds
(trifluoromethoxy)benzaldehyde, DCM, 4Å MS, ZnCl2; (2) NaBH4, MeOH;
(3) HCl/MeOH, 85% over three steps.
including L-733, 060(2), our synthesis started with the aldimine

4
Tetrahedron
ACCEPTED MANUSCRIPT
amine 23 in three steps: oxidation by DMP, oxime formation
CHCl3); IR (film): νmax 2941, 2877, 1584, 1508, 1397, 1344,
with O-methyl hydroxyamine hydrochloride (NH2OMeꢀHCl) and
subsequent reduction with borane. This synthetic sequence
afforded 23 with high diastereoselectivity (dr = 95:5) in 72%
overall yield22a,b. The introduction of substituted benzyl group
was accomplished by the reaction of 2-methoxy-5-
(trifluoromethoxy)benzaldehyde with Sodium borohydride
(NaBH4) in the presence of zinc chloride (ZnCl2). Finally, the N-
Boc protective group was cleaved with hydrogen chloride in
1316, 1109, 1014, 730 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.36-
7.24 (m, 5H), 4.64-4.60 (m, 1H), 4.56-4.52 (m, 1H), 3.72-3.65
(m, 1H), 3.63-3.58 (m, 2H), 3.57-3.52 (m, 2H), 2.01 (brs, 1H),
1.73-1.56 (m, 4H), 0.98-0.91 (m, 9H), 0.63-0.54 (m, 6H) ppm;
13C NMR (100 MHz, CDCl3) δ 138.8, 128.5, 128.0, 127.7, 79.8,
72.4, 65.6, 63.1, 28.8, 28.3, 26.0, 18.4, -5.2, -5.3 ppm; HRMS
(ESI-Orbitrap) m/z: [M + H]+ Calcd for C12H18O2: 194.1301,
found: 194.1303.
o
22
methanol to give (+)-CP-122721 (5) {mp 86.5-88.5 C; [α]D
=
4.4. (R)-4-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)pentan-1-
+7.0 (c 0.5, CHCl3); (+)-CP-122721.2HCl, lit.22b mp 275-276 oC;
ol 15.
[α]D26 +75.6 (c 1.0, CH3OH) } in 85% yield.
Compound 14 (27.0 g，0.14 mol), TBSCl (31.5 g，0.21
mol) and DMAP (855 mg，7 mmol) were stirred in DCM (400
mL) at 0 °C, and then TEA (38.7 ml，0.28 mol) was added in
one portion. After stirring for 12 h at room temperature, the
mixture was quenched with a saturated aqueous solution of
NH4Cl and separated. The aqueous layer was extracted with
DCM (400 mL × 3) and the combined organic layers were
washed with brine, dried and concentrated. Without further
purification, the above crude compound was dissolved in a
mixture of DCM (60 mL)/MeOH (60 mL)/AcOH(180
mL)/H2O(120 mL) at 0 °C. After being stirred for 0.5h, the
mixture was quenched with a saturated aqueous solution of
NaHCO3 and extracted with EtOAc (300 mL × 3). The combined
organic layers were washed with brine, dried, filtrated and
concentrated. The residue was purified by flash chromatography
on silica gel (PE/EA = 5/1) to give alcohol 15 (37.6 g，83%) as a
3. Conclusions
In summary, we established a high diastereoselective
method to trans-5-hydroxy-6-substituted 2-piperidinones
skeleton by one-pot intramolecular tandem process of O-benzyl
protected aldimine 11 with Grignard reagents. The stereogenic
center of C-6 was solely controlled by α- benzyloxy substitution.
In addition, the utility of chiral δ-lactams 20a/b in the
enantioselective synthesis of specific targets, has been
demonstrated by a concise synthetic route to (+)-L-733, 060 (2)
and its 2-substituted analogue 3, as well as (+)-CP-122721 (5).
4. Experimental Section
4.1. General Methods.
THF was distilled from sodium/benzophenone. Reactions
were monitored by thin layer chromatography (TLC) on glass
plates coated with silica gel with fluorescent indicator. Flash
chromatography was performed on silica gel (300−400) with
Petroleum/EtOAc as eluent. Optical rotations were measured on a
polarimeter with a sodium lamp. HRMS were measured on LTQ-
Orbit. IR spectra were recorded using film on a Fourier
Transform Infrared Spectrometer. NMR spectra were recorded at
400 or 600 MHz, and chemical shifts are reported in δ (ppm)
24
light yellow oil. [α]D = +19.3 (c 1.00, CHCl3); IR (film): νmax
2928, 2858, 1578, 1463, 1406, 1253, 1106, 1063, 831, 778, 735
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 4.74-4.69
(m, 1H), 4.59-4.54 (m, 1H), 3.75-3.69 (m, 1H), 3.63-3.57 (m,
3H), 3.53-3.47 (m, 1H), 1.91 (brs, 1H), 1.74-1.50 (m, 4H), 0.90
(s, 9H), 0.06 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 138.8,
128.5, 128.0, 127.7, 79.8, 77.5, 77.2, 76.8, 72.4, 65.6, 63.0, 28.7,
28.3, 26.0, 18.4, -5.2, -5.3 ppm; HRMS (ESI-Orbitrap) m/z: [M +
H]+ Calcd for C18H33O3Si: 325.2194, found: 325.2194.
1
referenced to an internal TMS standard for H NMR and CDCl3
(77.16 ppm) for 13C NMR.
4.5.
(R)-Methyl
4-(benzyloxy)-5-(tert-
butyldimethylsilyloxy)pentanoate 16.
4.2.
Triethyl(3-((4R)-2-phenyl-1,3-dioxolan-4-
yl)propoxy)silane 13.
(COCl)2 (20.6 mL, 0.24 mol) was stirred in DCM (240 mL)
at -78°C, and then a solution of DMSO (34.1 mL, 0.48 mol) in
DCM (120 mL) was slowly added dropwise. After the mixture
was stirred for 1 h, a solution of 15 (38.9 g, 0.12 mol) in DCM
(120 mL) was added dropwise, and the resulting mixture was
stirred for 3 h. Once TEA (99.6 mL, 0.72 mol) was added
dropwise, the mixture was allowed to warm to room temperature,
and the reaction was quenched with a saturated aqueous solution
of NH4Cl. The organic layer was separated, and the aqueous
layer was extracted with DCM (200 mL × 2). The combined
organic layers were washed with brine, dried, filtered, and
concentrated to give crude aldehyde without further purification.
The above aldehyde was dissolved in anhydrous isopentene (240
mL) / tBuOH (240 mL) and cooled to 0 °C, and then a solution of
an aqueous solution of NaH2PO4 (56.4 g) and NaClO2 (32.6 g)
was slowly dropped under an argon atmosphere. After being
stirred 3h, the mixture was diluted with EtOAc (300 mL) and
separated. The aqueous layer was extracted with EtOAc (300 mL
× 2) and the combined organic layers were washed with brine,
dried and concentrated to give crude acid, which was directly
dissolved in dry DMF (240 mL). Then NaHCO3 (20 g, 0.24 mol)
was added and MeI (37 mL, 0.60 mol) was dropped at 0 °C and
the mixture was stirred for 36 h. The mixture was quenched with
water and extracted with EtOAc (200 mL × 4). The combined
organic layers were washed with water (20 mL × 2) and brine,
dried, filtrated and concentrated. The residue was purified by
Compound 13 was prepared through the known method.16
Colorless oil. IR (film): νmax 2954, 2876, 2349, 2336, 1582, 1509,
1458, 1409, 1109, 1015, 741 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.49-7.44 (m, 2H), 7.40-7.31 (m, 3H), 5.92 (s, 1H), 4.28-4.21 (m,
2H), 3.70-3.64 (m, 2H), 3.63-3.60 (m, 1H), 1.82-1.60 (m, 4H),
0.99-0.91 (m, 9H), 0.64-0.56 (m, 6H) ppm; 13C NMR (150 MHz,
CDCl3) δ 138.7, 129.2, 128.5, 126.5, 103.2, 76.5, 70.9, 62.6, 29.9,
29.2, 6.9, 4.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd
for C12H16O2: 192.1145, found: 192.1143.
4.3. (R)-2-(Benzyloxy)-5-(triethylsilyloxy)pentan-1-ol 14.
Compound 13 (36.0 g，0.19 mol) was dissolved in toluene
(500 mL) and cooled to -78 °C, and then a solution of DIBAl-H
（380 ml，0.38 mol）was slowly dropped under an argon
atmosphere. After being stirred for 1 h at -78 °C, the mixture was
warmed to 0 °C. After stirring for another 0.5 h, the resulting
mixture was carefully quenched with EtOAc (100 mL) at -78 °C,
and then warmed to room temperature. After being stirred for 1h,
the resulting mixture was quenched with a saturated aqueous
solution of seignette salt. The mixture was diluted with EtOAc
(300 mL) and separated. The aqueous layer was extracted with
EtOAc (500 mL × 3) and the combined organic layers were
washed with brine, dried and concentrated. The residue was
purified by flash chromatography on silica gel (PE/EA = 5/1) to
23
give 14 (28.2 g，77%) as a colorless oil. [α]D = -6.4 (c 0.50,

5
1
flash chromatography on silica gel (PE/EA = 25/1) to give 16
(23.7 g，56%) as a light yellow oil. [α]D = +26.6 (c 1.00,
698 cm-1; H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 4.4 Hz,
ACCEPTED MANUSCRIPT
24
1H), 7.38-7.27 (m, 5H), 4.72-4.66 (m, 1H), 4.47-4.42 (m, 1H),
4.28-4.23 (m, 1H), 3.64 (s, 3H), 2.52-2.46 (m, 2H), 2.09-1.97 (m,
2H), 1.22 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 173.4,
169.6, 137.5, 128.6, 128.2, 79.1, 72.2, 57.2, 51.8, 29.7, 28.3, 22.6
CHCl3); IR (film): νmax 2957, 2933, 2855, 1741, 1580, 1253,
1
1090, 837, 778, 731 cm-1; H NMR (400 MHz, CDCl3) δ 7.35-
7.23 (m, 5H), 4.71-4.66 (m, 1H), 4.55-4.51 (m, 1H), 3.73-3.68
(m, 1H), 3.62 (s, 3H), 3.61-3.57 (m, 1H), 3.52-3.46 (m, 1H),
2.47-2.33 (m, 2H), 1.97-1.87 (m, 1H), 1.83-1.72 (m, 1H), 0.90 (s,
9H), 0.06 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.3,
138.8, 128.4, 127.9, 127.6, 78.8, 72.4, 65.5, 51.6, 30.1, 27.0, 26.0,
18.4, -5.2, -5.3, -5.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+
Calcd for C19H33O4Si: 353.2143, found: 353.2143.
ppm; HRMS (ESI-Orbitrap) m/z: [M
C17H26NO4S: 340.1577, found: 340.1576.
+ H]+ Calcd for
4.8. General Procedure for Synthesis of 18a-k.
To a solution of compound 11 ( 203 mg, 0.60 mmol) in
anhydrous THF (2.5 mL) was treated with a solution of Grignard
reagents (1.8 mL, 1 M in THF) at −78 °C to rt overnight. The
mixture was quenched with a saturated aqueous solution of
NH4Cl and extracted with EtOAc (20 mL × 3). The combined
organic layers were washed with brine, dried, filtrated and
concentrated. The crude, Boc2O (196 mg, 0.90 mmol) and
DMAP (73 mg, 0.60 mmol) were stirred in DMF (2.5 mL) before
TEA (0.3 mL, 1.80 mmol) was added, then the reaction mixture
was stirred for 24 h. The mixture was quenched with a saturated
aqueous solution of NH4Cl and extracted with EtOAc (20 mL ×
4). The combined organic layers were washed with water (10 mL
× 2) and brine, dried, filtrated and concentrated. The residue was
purified by flash chromatography on silica gel (PE/EA = 5/1) to
give 18a−k.
4.6. (R)-Methyl 4-(benzyloxy)-5-hydroxypentanoate 17.
Compound 16 (23.7 g, 67.20 mmol) was dissolved in
anhydrous DCM (130 mL) and MeOH (130 mL) and treated with
CSA (3.1 g, 13.44 mmol) for 4h at room temperature. The
resulting mixture was quenched with TEA (3.7 mL, 26.88 mmol)
and concentrated. The residue was dissolved in EtOAc (100 mL)
and water (100 mL). The resulting mixture was separated and the
aqueous layer was extracted with EtOAc (150 mL × 3). The
combined organic layers were washed with brine, dried, filtrated
and concentrated. The residue was purified by flash
chromatography on silica gel (PE/EA = 3/1) to give ester 17
23
(16.0 g, 100%) as a colorless oil. [α]D = +8.5 (c 1.00, CHCl3);
IR (film): νmax 2924, 1735, 1454, 1343, 1169, 1101, 1056, 745
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.46-7.24 (m, 5H), 4.58-4.54
(m, 2H), 3.73-3.67 (m, 1H), 3.66-3.63 (s, 3H), 3.58-3.52 (m, 2H),
2.44-2.37 (m, 2H), 2.18-2.05 (brs, 1H), 2.00-1.85 (m, 2H) ppm;
13C NMR (100 MHz, CDCl3) δ 174.1, 138.3, 128.6, 127.9, 78.4,
71.8, 63.8, 51.7, 29.7, 26.0 ppm; HRMS (ESI-Orbitrap) m/z: [M
+ H]+ Calcd for C13H19O4: 239.1278, found: 239.1281.
4.8.1.
(2S,3R)-tert-Butyl
3-(benzyloxy)-6-oxo-2-
phenylpiperidine-1-carboxylate 18a.
Colorless oil, (153 mg, 68%), [α]D24 = -46.0 (c 1.00, CHCl3);
IR (film): νmax 2938, 1770, 1719, 1454, 1369, 1251, 1148, 1074,
702 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40-7.23 (m, 8H), 7.18-
7.14 (m, 2H), 5.44-5.42 (m, 1H), 4.71-4.63 (m, 2H), 3.82 (dd, J =
6.4, 3.2 Hz, 1H), 2.87-2.76 (m, 1H), 2.61-2.53 (m, 1H), 1.87-1.83
(m, 2H), 1.28 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.2,
152.0, 140.2, 137.8, 128.8, 128.6, 128.0, 127.7, 127.6, 125.9,
83.1, 75.8, 70.7, 63.9, 29.8, 27.7, 20.6 ppm; HRMS (ESI-
Orbitrap) m/z: [M + H]+ Calcd for C23H28NO4: 382.2013, found:
382.2013.
4.7. General Procedure for Synthesis of (R, SR)-11 and (R, SS)-
11.
A solution of 17 (16.0 g, 67.20 mmol) in dry DCM (250 mL)
was treated with DMP (34.2 g, 80.64 mmol) at room temperature
for 0.5 h. The reaction mixture was carefully quenched with a
saturated aqueous solution of NaHCO3 and solid Na2S2O3, then
the mixture was separated and then aqueous layer was extracted
with DCM (150 mL × 3). The combined organic layers were
washed with brine, dried and concentrated to give a crude middle
compound without further purification. The above crude product
was dissolved in dry DCM (250 mL) and treated with CuSO4
(21.4 g, 134.40 mmol), PPTS (1.7 g, 6.72 mmol) and (R)-(+)-2-
Methyl-2- propanesulfinamide (8.1 g, 67.20 mmol) or (S)-(+)-2-
Methyl-2- propanesulfinamide (8.1 g, 67.20 mmol) in one
portion. After stirring for 24 h, the mixture was filtrated and
concentrated. The residue was purified by flash chromatography
on silica gel (PE/EA = 5/1) to give (R, SR)-11 (19.4 g, 85%) or (R,
SS)-11 (18.9 g, 83%).
4.8.2.
(2S,3R)-tert-Butyl
3-(benzyloxy)-6-oxo-2-p-
tolylpiperidine-1-carboxylate 18b.
Colorless oil, (171 mg, 72%), [α]D23 = -38.6 (c 2.00, CHCl3);
IR (film): νmax 2975, 2922, 1770, 1718, 1582, 1512, 1455, 1368,
1250, 1148, 1078, 739 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40-
7.27 (m, 5H), 7.15-7.10 (m, 2H), 7.05-7.01 (m, 2H), 5.41-5.39
(m, 1H), 4.70-4.61 (m, 2H), 3.78 (dd, J = 6.4, 3.2 Hz, 1H), 2.85-
2.74 (m, 1H), 2.58-2.50 (m, 1H), 2.31 (s, 3H), 1.86-1.80 (m, 2H),
1.29 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 170.6, 151.4,
137.2, 136.6, 136.5, 128.8, 127.9, 127.3, 127.0, 125.1, 82.3, 75.1,
70.0, 62.9, 29.1, 27.1, 20.4, 20.0 ppm; HRMS (ESI-Orbitrap) m/z:
[M + H]+ Calcd for C24H30NO4: 396.2169, found: 396.2168.
4.8.3. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-(3-methoxyphenyl)-
6-oxopiperidine-1-carboxylate 18c.
4.7.1. (R, E)-Methyl 4-(benzyloxy)-5-((R)-2-methylpropan-2-
ylsulfinamido)pentanoate (R, R)-11.
Colorless oil, (123 mg, 50%), [α]D24 = -54.4 (c 1.00, CHCl3);
IR (film): νmax 2932, 1769, 1720, 1602, 1585, 1454, 1368, 1269,
1250, 1147, 1073, 696 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40-
7.20 (m, 6H), 6.82-6.65 (m, 3H), 5.42-5.37 (m, 1H), 4.70-4.64
(m, 2H), 3.85-3.80 (m, 1H), 3.77 (s, 3H), 2.85-2.75 (m, 1H),
2.60-2.51 (m, 1H), 1.87-1.83 (m, 2H), 1.31 (s, 9H) ppm; 13C
NMR (100 MHz, CDCl3) δ 171.2, 160.1, 152.2, 142.0, 137.9,
130.0, 128.7, 128.1, 127.8, 118.2, 112.9, 111.9, 83.2, 75.7, 70.8,
63.8, 55.4, 29.9, 27.8, 20.9 ppm; HRMS (ESI-Orbitrap) m/z: [M
+ H]+ Calcd for C24H30NO5P: 412.2119, found: 412.2122.
24
Light yellow oil. [α]D = -80.0 (c 1.00, CHCl3); IR (film):
νmax 2951, 2868, 1738, 1620, 1581, 1514, 1169, 1085, 743, 696
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 4.8 Hz, 1H),
7.39-7.27 (m, 5H), 4.71-4.66 (m, 1H), 4.47-4.42 (m, 1H), 4.29-
4.22 (m, 1H), 3.65 (s, 3H), 2.53-2.46 (m, 2H), 2.11-2.02 (m, 2H),
1.25 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 173.3, 169.4,
137.4, 128.5, 128.0, 127.9, 78.8, 72.0, 56.9, 51.7, 29.5, 28.0, 22.5
ppm; HRMS (ESI-Orbitrap) m/z: [M
C17H26NO4S: 340.1577, found: 340.1575.
+ H]+ Calcd for
4.7.2. (R, E)-Methyl 4-(benzyloxy)-5-((S)-2-methylpropan-2-
ylsulfinamido)pentanoate (R, S)-11.
Light yellow oil. [α]D24 = +183.1 (c 1.00, CHCl3); IR (film):
νmax 2952, 2871, 1737, 1622, 1455, 1361, 1173, 1085, 1028, 735,
4.8.4. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-(naphthalen-2-yl)-6-
oxopiperidine-1-carboxylate 18d.

6
Tetrahedron
25
Colorless oil, (140 mg, 54%), [α]D = -44.5 (c 1.00,
4.8.9.
(2S,3R)-tert-Butyl
3-(benzyloxy)-2-nonyl-6-
ACCEPTED MANUSCRIPT
CHCl3); IR (film): νmax 2359, 2333, 1773, 1716, 1559, 1507,
oxopiperidine-1-carboxylate 18i.
1147 cm-1; H NMR (400 MHz, CDCl3) δ 7.85-7.78 (m, 3H),
1
Colorless oil, (104 mg, 40%), [α]D22 = +7.0 (c 1.00, CHCl3);
IR (film): νmax 2929, 2858, 1716, 1583, 1151, 1111, 739 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.40-7.25 (m, 5H), 4.63-4.52 (m, 2H),
4.45-4.39 (m, 1H), 3.71 (dd, J = 6.0, 3.2 Hz, 1H), 2.75-2.65 (m,
1H), 2.46-2.37 (m, 1H), 2.07-1.96 (m, 2H), 1.52 (s, 9H), 1.35-
1.20 (m, 16H), 0.91-0.86 (m, 3H) ppm; 13C NMR (150 MHz,
CDCl3) δ 171.3, 153.0, 138.1, 128.6, 127.8, 127.6, 82.8, 72.3,
70.1, 58.5, 34.4, 32.0, 30.0, 29.6, 29.4, 28.1, 26.4, 22.8, 22.4,
14.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
C26H42NO4: 432.3108, found: 432.3112.
7.63-7.60 (m, 1H), 7.53-7.45 (m, 2H), 7.40-7.22 (m, 6H), 5.63-
5.59 (m, 1H), 4.75-4.65 (m, 2H), 3.94 (dd, J = 6.0, 2.8 Hz, 1H),
2.92-2.80 (m, 1H), 2.67-2.57 (m, 1H), 1.91-1.83 (m, 2H), 1.26 (s,
9H) ppm; 13C NMR (150 MHz, CDCl3) δ 171.3, 152.2, 137.8,
137.8, 133.4, 132.8, 128.8, 128.7, 128.0, 127.8, 126.7, 126.3,
124.6, 124.0, 83.2, 75.7, 70.9, 64.0, 30.0, 27.8, 20.8 ppm; HRMS
(ESI-Orbitrap) m/z: [M + H]+ Calcd for C27H30NO4: 432.2169,
found 432.2175.
4.8.5.
(2S,3R)-tert-Butyl
3-(benzyloxy)-6-oxo-2-m-
tolylpiperidine-1-carboxylate 18e.
4.8.10. (2S,3R)-tert-Butyl 2-(2-methylbenzyl)-3-(benzyloxy)-6-
Colorless oil, (135 mg, 57%), [α]D25 = -55.0 (c 1.00, CHCl3);
IR (film): νmax 2928, 1769, 1719, 1608, 1365, 1251, 1147, 1076,
706 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40-6.92 (m, 9H), 5.42-
5.38 (m, 1H), 4.70-4.61 (m, 2H), 3.85-3.79 (m, 1H), 2.88-2.74
(m, 1H), 2.61-2.51 (m, 1H), 2.32 (s, 3H), 1.88-1.83 (m, 2H), 1.29
(s, 9H) ppm; 13C NMR (150 MHz, CDCl3) δ 171.2, 152.1, 140.2,
138.6, 137.9, 128.7, 128.6, 128.4, 128.0, 127.7, 126.6, 123.0,
83.0, 75.9, 70.7, 63.8, 29.9, 27.8, 21.5, 20.7 ppm; HRMS (ESI-
Orbitrap) m/z: [M + H]+ Calcd for C24H30NO4: 396.2169, found:
396.2170.
oxopiperidine-1-carboxylate 18j.
26
Colorless oil, (76 mg, 31%), [α]D = -5.0 (c 1.00, CHCl3);
IR (film): νmax 2365, 2298, 1767, 1715, 1582, 1510, 1455, 1395,
1
1368, 1289, 1143, 1110 cm-1; H NMR (400 MHz, CDCl3) δ
7.30-7.09 (m, 9H), 4.79-4.72 (m, 1H), 4.46-4.32 (m, 2H), 3.60
(dd, J = 6.0, 3.6 Hz, 1H), 3.03-2.97 (m, 1H), 2.81-2.63 (m, 2H),
2.55-2.46 (m, 1H), 2.32 (s, 3H), 2.22-2.10 (m, 1H), 2.04-1.95 (m,
1H), 1.44 (s, 9H) ppm; 13C NMR (150 MHz, CDCl3) δ 171.3,
152.9, 137.9, 136.5, 135.4, 130.8, 130.0, 128.5, 127.8, 127.7,
127.1, 126.4, 83.0, 71.4, 70.2, 58.7, 37.6, 30.1, 28.0, 22.7, 19.7
ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C25H32NO4:
410.2326, found: 410.2325.
4.8.6.
(2S,3R)-tert-Butyl
3-(benzyloxy)-6-oxo-2-(3-
(trifluoromethyl)phenyl)piperidine-1-carboxylate 18f.
Colorless oil, (143 mg, 53%), [α]D26 = -47.5 (c 1.00, CHCl3);
IR (film): νmax 2951, 2868, 1738, 1581, 1512, 1455, 1171, 1085,
1027, 743, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.56-7.44 (m,
2H), 7.40-7.29 (m, 7H), 5.41-5.38 (m, 1H), 4.72-4.59 (m, 2H),
3.82-3.77 (m, 1H), 2.89-2.76 (m, 1H), 2.63-2.54 (m, 1H), 1.95-
1.77 (m, 2H), 1.28 (s, 9H) ppm; 13C NMR (150 MHz, CDCl3) δ
170.8, 152.0, 141.6, 137.5, 131.4 (q, J = 32.2 Hz), 129.5, 129.3,
128.8, 128.2, 127.8, 124.0 (q, J = 271.2 Hz), 124.3 (d, J = 3.2
Hz), 123.0 (d, J = 3.3 Hz), 83.6, 75.7, 71.0, 63.9, 29.9, 29.8, 27.7,
21.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
C24H27F3NO4: 450.1887, found: 450.1884.
4.8.11.
(2S,3R)-tert-Butyl
3-(benzyloxy)-6-oxo-2-
vinylpiperidine-1-carboxylate 18k.
Colorless oil, (44 mg, 22%), [α]D23 = +75.2 (c 0.25, CHCl3);
IR (film): νmax 2935, 2360, 2339, 1770, 1723, 1582, 1510, 1409,
1111 cm-1; H NMR (400 MHz, CDCl3) δ 7.40-7.25 (m, 5H),
1
6.13-6.04 (m, 1H), 5.40-5.33 (m, 1H), 5.24-5.15 (m, 1H), 5.03-
4.95 (m, 1H), 4.68-4.59 (m, 2H), 3.90-3.83 (m, 1H), 2.75-2.57
(m, 1H), 2.53-2.41 (m, 1H), 2.03-1.84 (m, 2H), 1.50 (s, 9H) ppm;
13C NMR (150 MHz, CDCl3) δ 170.7, 152.2, 137.8, 133.5, 128.7,
128.1, 127.8, 127.7, 117.5, 83.4, 74.4, 71.3, 58.4, 31.8, 28.1, 23.3
ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C19H26NO4:
332.1856, found: 332.1856.
4.8.7. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-(3-fluorophenyl)-6-
oxopiperidine-1-carboxylate 18g.
4.9. (2S,3R)-tert-Butyl 3-hydroxy-6-oxo-2-phenylpiperidine-1-
Colorless oil, (129 mg, 54%), [α]D25 = -57.6 (c 1.00, CHCl3);
IR (film): νmax 2937, 1582, 1510, 1376, 1279, 1176, 1131, 704
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.42-7.25 (m, 6H), 7.00-6.93
(m, 2H), 6.90-6.85 (m, 1H), 5.41-5.38 (m, 1H), 4.71-4.61 (m,
2H), 3.83-3.77 (m, 1H), 2.88-2.76 (m, 1H), 2.60-2.50 (m, 1H),
1.93-1.76 (m, 2H), 1.32 (s, 9H) ppm; 13C NMR (150 MHz,
CDCl3) δ 170.9, 164.0, 162.4, 152.1, 143.1, 143.0, 137.6, 130.6,
130.5, 128.7, 128.2, 127.8, 121.5, 114.7, 114.6, 113.2, 113.1,
83.4, 75.6, 70.9, 63.5, 29.8, 27.8, 20.9 ppm; HRMS (ESI-
Orbitrap) m/z: [M + H]+ Calcd for C23H27FNO4: 400.1919, found
400.1915.
carboxylate 19.
To a solution of 18a (158 mg, 0.41mmol) and (10%) Pd/C
(150 mg) was stirred in MeOH (10 mL) under hydrogen
atmosphere for 10 min. Then HCOOH (0.8 mL) was carefully
dropped and the mixture was stirred at room temperature for 2 h.
The resulting mixture was filtered and concentrated. The residue
was purified by flash chromatography on silica gel (PE/EA =2/1)
o
to give 19 (119 mg, 100%) as a white solid. M.p. 140-142 C;
21
[α]D = +21.2 (c 0.25, CHCl3); IR (film): νmax 2931, 1778, 1697,
1583, 1513, 1409, 1367, 1110 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.39-7.26 (m, 5H), 5.45-5.37 (m, 1H), 4.95-4.87 (m, 1H), 4.77-
4.72 (m, 1H), 2.32-2.21 (m, 2H), 1.96-1.74 (m, 2H), 1.42 (s, 9H)
ppm; 13C NMR (150 MHz, CDCl3) δ 176.9, 155.1, 136.3, 129.0,
128.5, 128.2, 81.6, 80.3, 57.8, 28.4, 27.7, 24.0 ppm; HRMS (ESI-
Orbitrap) m/z: [M + H]+ Calcd for C16H22NO4: 292.1543, found:
292.1545.
4.8.8.
(2S,3R)-tert-Butyl
3-(benzyloxy)-6-oxo-2-
pentylpiperidine-1-carboxylate 18h.
21
Colorless oil, (92 mg, 41%), [α]D = +6.2 (c 1.00, CHCl3);
IR (film): νmax 2932, 2871, 1769, 1710, 1582, 1509, 1408, 1153,
741 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40-7.23 (m, 5H), 4.62-
4.53 (m, 2H), 4.45-4.39 (m, 1H), 3.72-3.69 (m, 1H), 2.75-2.64
(m, 1H), 2.46-2.37 (m, 1H), 2.05-1.95 (m, 2H), 1.53 (s, 9H),
1.35-1.22 (m, 8H), 0.90-0.83 (m, 3H) ppm; 13C NMR (150 MHz,
CDCl3) δ 171.3, 153.0, 138.1, 128.7, 128.6, 128.0, 127.9, 127.8,
127.6, 82.8, 72.2, 70.1, 58.5, 34.4, 31.7, 30.0, 28.1, 26.0, 22.6,
22.4, 14.0 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
C22H34NO4: 376.2482, found: 376.2488.
4.10.
(5R,6S)-5-(tert-Butyldimethylsilyloxy)-6-
phenylpiperidin-2-one 10a.
To a solution of compound 19 (100 mg, 0.34 mmol) in dry
DMF (0.8 mL) was treated with TBSCl (78 mg, 0.51 mmol),
imidazole (69 mg, 1.02 mmol) and DMAP (41 mg, 0.34 mmol) at
0 oC. After stirred for 24 h at room temperature, the mixture was
quenched with a saturated aqueous solution of NH4Cl and
extracted with EtOAc (40 mL × 3). The combined organic layers

7
were washed with brine, dried and concentrated to give a white
solid. Without purification, the solid was dissolved in cooled (0
oC) DCM (1.2 mL) and treated with TFA (0.1 mL) for 1.5 h. The
resulting mixture was quenched with a saturated aqueous solution
of NaHCO3 and extracted with EtOAc (10 mL × 3). The
combined organic layers were washed with brine, dried and
concentrated. The residue was purified by flash chromatography
on silica gel (PE/EA =3/1) to give amide 10a (84 mg, 81%) as a
colorless oil. [α]D24 = -18.9 (c 0.63, CHCl3); IR (film): νmax 3211,
3060, 2950, 2925, 2852, 1669, 1467, 1402, 1350, 1253, 1111,
128.4, 127.6, 126.4, 79.6, 74.1, 70.4, 55.7, 39.9, 28.5, 24.5,
ACCEPTED MANUSCRIPT
21.0, 19.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
C24H32NO3: 382.2377, found: 382.2378.
4.12. General Procedure for Synthesis of 21a or 21b.
Compound 20a (1.35 g, 3.67 mmol) or 20b (1.40 g, 3.67
mmol), 10% Pd/C (200 mg) and Pd(OH)2 (200 mg) were stirred
in MeOH (50 mL) under hydrogen atmosphere for 2 h. Then the
mixture was filtered and concentrated. The residue was purified
by flash chromatography on silica gel (PE/EA =15/1) to give 21a
(0.91 g, 90%) or 21b (0.91 g, 85%).
1090, 883, 832, 773 cm-1; H NMR (400 MHz, CDCl3) δ 7.40-
1
7.26 (m, 5H), 5.94 (brs, 1H), 4.39-4.36 (m, 1H), 3.86-3.81 (m,
1H), 2.67-2.57 (m, 1H), 2.51-2.41 (m, 1H), 1.97-1.91 (m, 1H),
1.87-1.75 (m, 1H), 0.82 (s, 9H), -0.07 (s, 3H), -0.24 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 171.9, 140.4, 128.8, 128.3, 127.3,
71.5, 64.5, 28.3, 27.3, 25.8, 18.0, -4.9, -5.3 ppm; HRMS (ESI-
Orbitrap) m/z: [M + H]+ Calcd for C17H28NO2Si: 306.1884,
found: 306.1883.
4.12.1. (2S,3R)-tert-Butyl 3-hydroxy-2-phenylpiperidine-1-
carboxylate 21a.
White solid. M.p. 130-132 oC; [α]D22 = +6.2 (c 1.00, CHCl3);
IR (film): νmax 2933, 1692, 1666, 1580, 1412, 1365, 1127, 984
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 2H), 7.28-7.17
(m, 3H), 5.40-5.35 (m, 1H), 4.55-4.47 (m, 1H), 4.13-4.05 (m,
1H), 2.91-2.82 (m, 1H), 2.16-2.13 (m, 1H), 1.99-1.85 (m, 1H),
1.79-1.73 (m, 1H), 1.66-1.56 (m, 1H), 1.45 (s, 9H), 1.43-1.35 (m,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ 156.8, 138.3, 128.8,
127.0, 126.4, 80.2, 67.6, 60.4, 40.0, 29.8, 28.5, 26.1, 19.0 ppm;
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C16H24NO3:
278.1750, found: 278.1749.
4.11. General Procedure for Synthesis of 20a or 20b.
To a solution of aldaldimine 11 (3.0 g, 8.84 mmol) in
anhydrous THF (27 mL) was treated with a solution of PhMgBr
o
or p-MePhMgBr (26.5 mL, 1 M in THF) at −78 C to room
temperature overnight. The mixture was quenched with a
saturated aqueous solution of NH4Cl and extracted with EtOAc
(50 mL × 3). The combined organic layers were washed with
brine, dried, filtrated and concentrated. After that, LAH (671 mg,
17.68 mmol) was carefully treated with anhydrous THF (35 mL)
at 0 oC, then a solution of the above crude imine in THF (35 mL)
4.12.2. (2S,3R)-tert-Butyl 3-hydroxy-2-p-tolylpiperidine-1-
carboxylate 21b.
Colorless oil. [α]D23 = +31.1 (c 1.00, CHCl3); IR (film): νmax
3444, 3374, 2977, 2933, 1690, 1514, 1418, 1365, 1276, 1168,
1128, 986 cm-1; 1H NMR (400 MHz, CDCl3, mixture of rotamers)
δ 7.49-7.45 (m, 0.5H), 7.31-7.27 (m, 0.5H), 7.18-7.14 (m, 1.5H),
7.10-7.05 (m, 1.5H), 5.36-5.31 (m, 1H), 4.52-4.47 (m, 1H), 4.11-
4.07 (m, 1H), 2.90-2.81 (m, 1H), 2.41 (s, 0.7H), 2.33 (s, 2.3H),
2.28-2.25 (m, 1H), 1.99-1.86 (m, 1H), 1.78-1.71 (m, 1H), 1.66-
1.56 (m, 1H), 1.46 (s, 7H), 1.42-1.34 (m, 1H), 1.16 (s, 2H) ppm;
13C NMR (100 MHz, CDCl3, mixture of rotamers) δ 156.8, 141.6,
136.7, 136.5, 135.2, 129.4, 129.2, 126.4, 126.3, 80.1, 67.5, 60.1,
55.7, 39.9, 28.5, 26.0, 22.8, 21.5, 21.0, 19.0 ppm; HRMS (ESI-
Orbitrap) m/z: [M + H]+ Calcd for C17H26NO3: 292.1907, found:
292.1908.
o
was carefully dropped. After being stirred at 60 C for 6 h, the
o
mixture was cooled to 0 C and diluted with THF (50 mL). The
resulting mixture was carefully treated with Na2S2O3ꢀ10H2O and
filtered, concentrated to give crude intermediate without
purification. The above crude product was dissolved in dry DCM
(35 mL), then Boc2O (2.12 g, 9.72 mmol), TEA (1.2 mL, 8.84
mmol) and a 2M aqueous solution of NaHCO3 (1.5 mL) was
added in one portion. After stirred for 12 h, the mixture was
quenched with a saturated aqueous solution of NH4Cl and
extracted with EtOAc (50 mL × 3). The combined organic layers
were washed with brine, dried, filtrated and concentrated. The
residue was purified by flash chromatography on silica gel
(PE/EA = 3/1) to give 20a (1.46 g, 45%) or 20b (1.69 g, 50%).
4.13. General Procedure for Synthesis of 22a or 22b.
To a solution of 21a (785 mg, 2.83 mmol) or 21b (825 mg,
2.83 mmol) in dry DCM (8 mL) was treated with DMP (2.40 g,
5.66 mmol) at room temperature for 0.5 h. The reaction was
carefully quenched with a saturated aqueous solution of NaHCO3
and solid Na2S2O3, then the mixture was separated and the
aqueous layer was extracted with DCM (40 mL × 3). The
combined organic layers were washed with brine, dried and
concentrated to give crude middle compound without further
purification. The above crude was dissolved in cooled (0 °C)
MeOH (23 mL) and treated with NaBH4 (118 mg, 3.11 mmol) in
one portion. After stirred for 20 min, the mixture was
concentrated and the residue was dissolved in EtOAc (30 mL)
and water (30 mL). The resulting mixture was separated and the
aqueous layer was extracted with EtOAc (40 mL × 3). The
combined organic layers were washed with brine, dried and
concentrated. The residue was purified by flash chromatography
on silica gel (PE/EA = 5/1) to give 22a (667 mg, 85%) or 22b
(584 mg, 71%).
4.11.1. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-phenylpiperidine-1-
carboxylate 20a.
Colorless oil. [α]D22 = +44.2 (c 1.00, CHCl3); IR (film): νmax
2928, 1690, 1583, 1497, 1417, 1365, 1142, 1127, 1029, 700 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.42-7.15 (m, 10H), 5.65-5.58 (m,
1H), 4.77-4.73 (m, 1H), 4.64-4.58 (m, 1H), 4.16-4.07 (m, 2H),
2.92-2.83 (m, 1H), 2.07-1.93 (m, 1H), 1.90-1.81 (m, 1H), 1.60-
1.50 (m, 1H), 1.44 (s, 9H), 1.37-1.34 (m, 1H) ppm; 13C NMR
(150 MHz, CDCl3) δ 156.3, 139.2, 138.8, 128.7, 128.5, 127.6,
126.8, 126.6, 79.7, 74.2, 70.4, 56.1, 40.1, 28.6, 24.6, 19.5 ppm;
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C23H30NO3:
368.2220, found: 368.2216.
4.11.2. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-p-tolylpiperidine-1-
carboxylate 20b.
Colorless oil. [α]D22 = +60.7 (c 1.00, CHCl3); IR (film): νmax
2930, 2863, 1691, 1514, 1454, 1417, 1365, 1277, 1171, 1128,
739, 700 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.42-7.24 (m, 5H),
7.16-7.12 (m, 2H), 7.08-7.04 (m, 2H), 5.63-5.53 (m, 1H), 4.77-
4.73 (m, 1H), 4.62-4.57 (m, 1H), 4.15-4.07 (m, 2H), 2.90-2.81
(m, 1H), 2.33 (s, 3H), 2.05-1.91 (m, 1H), 1.87-1.81 (m, 1H),
1.60-1.50 (m, 1H), 1.44 (s, 9H), 1.31-1.25 (m, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ 156.3, 138.8, 136.4, 135.9, 129.4,
4.13.1. (2R,3R)-tert-Butyl 3-hydroxy-2-phenylpiperidine-1-
carboxylate 22a.
Colorless oil. [α]D24 = +44.7 (c 1.00, CHCl3); IR (film): νmax
2973, 2870, 1691, 1665, 1582, 1413, 1367, 1169, 1146, 1080,
965, 698 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.50-7.42 (m, 2H),
7.38-7.23 (m, 3H), 5.37-5.31 (m, 1H), 4.14-4.04 (m,1H), 4.03-

8
Tetrahedron
3.95 (m, 1H), 3.09-2.96 (m, 1 H), 1.88-1.62 (m, 5H), 1.37 (s,
Orbitrap) m/z: [M + H]+ Calcd for C21H22F6NO: 418.1600, found:
ACCEPTED MANUSCRIPT
9H) ppm; 13C NMR (150 MHz, CDCl3) δ 155.6, 138.6, 128.6,
128.5, 127.3, 80.0, 70.2, 59.4, 39.6, 28.4, 27.8, 23.2 ppm; HRMS
(ESI-Orbitrap) m/z: [M + H]+ Calcd for C16H24NO3: 278.1751,
found: 278.1751.
418.1601.
4.15.
carboxylate 23.
(2S,3S)-tert-Butyl
3-amino-2-phenylpiperidine-1-
To a solution of 21a (580 mg, 2.11 mmol) in dry DCM (8
mL) was treated with DMP (1.34 g, 3.17 mmol) at room
temperature for 0.5 h. The reaction was carefully quenched with
a solution of NaHCO3 and Na2S2O3, then the mixture was
separated and the aqueous layer was extracted with DCM (30 mL
× 3). The combined organic layers were washed with brine, dried
and concentrated to give crude product which was dissolved in
pyridine (10 mL), and then NH2OMe·HCl (211 mg, 2.53 mmol)
was added. After being stirred for 6 h, the reaction was diluted
4.13.2. (2S,3S)-tert-Butyl 3-hydroxy-2-p-tolylpiperidine-1-
carboxylate 22b.
Colorless oil. [α]D22 = +52.8 (c 0.25, CHCl3); IR (film): νmax
1
2932, 1607, 1582, 1407, 1366, 1275, 1143, 1111, 763 cm-1; H
NMR (400 MHz, CDCl3) δ 7.36-7.31 (m, 2H), 7.15-7.11 (m, 2H),
5.34-5.27 (m, 1H), 4.07-3.93 (m, 2H), 3.05-2.96 (m, 1H), 2.33 (s,
3H), 1.86-1.59 (m, 5H), 1.38 (s, 9H) ppm; 13C NMR (100 MHz,
CDCl3) δ 155.5, 136.8, 135.3, 129.1, 128.5, 80.0, 70.2, 58.9, 39.5,
28.4, 27.8, 23.4, 21.1 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+
Calcd for C17H26NO3: 292.1907, found: 292.1913.
.
with THF (8 mL) and treated with BH3 SMe2 (0.6 mL, 1M in
o
THF) at 50 C for 12 h. The reaction was concentrated and the
crude was stirred in anhydrous MeOH (15 mL) for another 2 h at
90 C. The resulting mixture was concentrated and purified by
4.14. General Procedure for Synthesis of (+)-L-733, 060 2 or 3.
o
To a cooled mixture of sodium hydride (60% dispersion in
mineral oil, 51 mg, 2.14 mmol) and dry DMF (2 mL) was added
a solution of 22a (297 mg, 1.07 mmol) or 22b (311 mg, 1.07
mmol) in dry DMF (2 mL) slowly under nitrogen atmosphere.
After being stirred for 0.5 h at room temperature, a solution of 1-
(bromomethyl)-3,5-bis(trifluoromethyl)benzene (655 mg, 2.14
mmol) in dry DMF (1 mL) was added and the resulting mixture
was stirred for 24 h. The mixture was quenched with water (5 mL)
and extracted with Et2O (10 mL × 3). The combined organic
layers were washed with brine, dried, filtered and concentrated.
Without purification, the crude product was dissolved in
anhydrous DCM (5 mL) and cooled to 0 °C, and then a solution
of TFA (0.8 mL, 10.70 mmol) was slowly dropped under an
argon atmosphere. After being stirred for 24 h at room
temperature, the mixture was concentrated and the residue was
dissolved in DCM (10 mL). An aqueous solution of 3 M NaOH
(10 mL) was added to pH=9. The resulting mixture was separated
and the aqueous layer was extracted with DCM (10 mL × 3). The
combined organic layers were washed with brine, dried and
concentrated. The residue was purified by flash chromatography
on silica gel (DCM/MeOH/NH4OH = 100/3/1) to give (+)-L-733,
060 (2) (242 mg, 56%) or 3 (223 mg, 50%).
flash chromatography on silica gel (DCM/MeOH/NH4OH =
25
100/4/1) to give 23 (358 mg, 72%) as a light yellow oil. [α]D
=
+17.3 (c 1.00, CHCl3); IR (film): νmax 3369, 2975, 2932, 2866,
1690, 1475, 1454, 1412, 1391, 1365, 1300, 1270, 1252, 1175,
1
1148, 881, 867, 773, 702 cm-1; H NMR (400 MHz, CDCl3) δ
7.37-7.24 (m, 5H), 3.87-3.83 (m, 1H), 3.80-3.77 (m, 1H), 3.24-
3.16 (m, 1H), 2.84-2.75 (m, 1H), 2.30-2.10 (m, 2H), 2.07-1.98
(m, 1H), 1.95-1.83 (m, 1H), 1.75-1.65 (m, 1H), 1.54-1.46 (m, 1H)
ppm; 13C NMR (150 MHz, CDCl3) δ 155.4, 139.2, 129.5, 128.3,
127.3, 79.8, 60.6, 51.2, 39.9, 29.3, 28.4, 24.4 ppm; HRMS (ESI-
Orbitrap) m/z: [M + H]+ Calcd for C16H25N2O2: 277.1901, found:
277.1912.
4.16.
(2S,3S)-N-(2-Methoxy-5-(trifluoromethoxy)benzyl)-2-
phenylpiperidin-3-amine (+)-CP-122721 (5)
To a solution of 23 (339 mg, 1.05 mmol), 4Å MS (300 mg)
and 2-methoxy-5-(trifluoromethoxy)benzaldehyde (693 mg, 3.15
mmol) in dry DCM (4.2 mL) was added ZnCl2 (6 mL, 0.5 M in
THF ) and stirred for 24 h. The mixture was concentrated and
dissolved in MeOH (4.2 mL), then NaBH4 (238 mg, 6.29 mmol)
was added in one portion and the mixture was stirred for 3 h at
room temperature. The reaction was quenched with saturated
aqueous solution of NaHCO3 (10 mL) and extracted with DCM
(10 mL × 3) and the combined organic layers were washed with
brine, dried and concentrated. Without purification, the residue
was dissolved in MeOH (2 mL) and 6M HCl (2 mL). After being
stirred for 4 h, the mixture was concentrated and the residue was
dissolved in DCM (10 mL). An aqueous solution of 3 M NaOH
(10 mL) was added to pH=9. The resulting mixture was separated
and the aqueous layer was extracted with DCM (10 mL × 4). The
combined organic layers were washed with brine, dried and
concentrated. The residue was purified by flash chromatography
on silica gel (DCM/MeOH/NH4OH = 100/9/1) to give (+)-CP-
4.14.1.
(2R,3R)-3-(3,5-Bis(trifluoromethyl)benzyloxy)-2-
phenylpiperidine (+)-L-733, 060 (2).
Colorless oil. [α]D23 = +46.5 (c 1.00, CHCl3); IR (film): νmax
2924, 1769, 1721, 1590, 1455, 1369, 1269, 1250, 1148, 1071 cm-
1; 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.50-7.42 (m, 2H),
7.37-7.23 (m, 5H), 4.53-4.47 (m, 1H), 4.15-4.08 (m, 1H), 3.85-
3.82 (m, 1H), 3.69-3.65 (m, 1H), 3.31-3.24 (m, 1H), 2.87-2.78
(m, 1H), 2.25-2.16 (m, 1H), 1.94-1.80 (m, 2H), 1.74-1.64 (m,
1H), 1.55-1.48 (m, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ
142.0, 141.4, 131.4 (q, J = 33.0 Hz), 128.3, 127.6, 127.3, 126.9,
123.4 (q, J = 271.0 Hz), 121.3, 120.7, 77.4, 70.2, 64.4, 47.2, 28.6,
20.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
C20H20F6NO: 404.1444, found: 404.1436.
22
122721 (5) (280 mg, 85%) as a white solid. M.p. 86-88 oC; [α]D
= +7.0 (c 1.00, CHCl3); IR (film): νmax 2930, 1582, 1497, 1463,
1423, 1148, 1112, 1032, 700 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.32-7.20 (m, 5H), 7.01-6.94 (m, 1H), 6.86-6.82 (m, 1H), 6.63-
6.59 (m, 1H), 3.89-3.87 (m, 1H), 3.66-3.61 (m, 1H), 3.49 (s, 3H),
3.40-3.35 (m, 1H), 3.28-3.23 (m, 1H), 2.84-2.75 (m, 2H), 2.13-
2.05 (m, 1H), 1.97-1.83 (m, 1H), 1.80-1.65 (brs, 1H), 1.64-1.55
(m, 1H), 1.45-1.38 (m, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ
156.0, 142.6, 142.3, 130.5, 128.3, 126.8, 126.4, 122.5, 120.7 (q, J
= 254.2 Hz), 120.1, 110.3, 64.3, 55.4, 55.2, 47.9, 46.1, 28.5, 20.4
4.14.2.
(2S,3S)-3-(3,5-Bis(trifluoromethyl)benzyloxy)-2-p-
tolylpiperidine 3.
23
White solid. M.p. 181-183 oC; [α]D = +32.8 (c 1.00,
CHCl3); IR (film): νmax 2937, 1588, 1506, 1402, 1278, 1129, 620
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.45-7.42 (m,
2H), 7.27-7.23 (m, 2H), 7.16-7.11 (m, 2H), 4.57-4.53 (m, 1H),
4.18-4.13 (m, 1H), 3.84-3.79 (m, 1H), 3.67-3.63 (m, 1H), 3.32-
3.24 (m, 1H), 2.88-2.77 (m, 1H), 2.34 (s, 3H), 2.27-2.16 (m, 2H),
1.95-1.81 (m, 1H), 1.73-1.62 (m, 1H), 1.55-1.48 (m, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ 141.4, 138.7, 136.9, 131.4 (q, J =
33.0 Hz), 129.0, 127.6, 126.8, 123.4 (q, J = 271.0 Hz), 121.3,
77.4, 70.1, 64.1, 47.2, 28.5, 21.1, 20.5 ppm; HRMS (ESI-
ppm; HRMS (ESI-Orbitrap) m/z: [M
C20H24F3N2O2: 381.1784, found: 381.1785.
+ H]+ Calcd for

9
Nagahisa, A.; Nakane, M.; Lowe, J. A. Bioorg. Med. Chem. Lett.
1998, 8, 281-284.
Acknowledgements
ACCEPTED MANUSCRIPT
8. a) Koepfli, J. B.; Mead, J. F.; Brockman, J. A. J. Am. Chem. Soc.
1947, 69, 1837-1837; b) Koepfli, J. B.; Mead, J. F.; Brockman, J.
A. J. Am. Chem. Soc. 1949, 71, 1048-1054.
9. a) Ratle, G.; Monseur, X.; Das, B. C.; Yassi, J.; Khuong-Huu, Q.;
Goutarel, R. Bull. Soc. Chem. Fr. 1966, 9, 2945-2947; b) Khuong-
Huu, Q.; Ratle, G.; Monseur, X.; Gouratel, R. Bull. Soc. Chim.
Belg. 1972, 81,425-441.
We thank the National Natural Science Foundation of China
(21472022, 21272041 and 21072034) for financial support. The
authors also thank Dr. Han-Qing Dong (Arvinas, Inc.) for helpful
suggestions.
Supplementary data
10. a) Guengerich, F. P.; DiMari, S. J.; Broquist, H. P. J. Am. Chem.
Soc. 1973, 95, 2055-2056; b) Schneider, M. J.; Ungemach, F. S.;
Broquist, H. P.; Harris, T. M. Tetrahedron 1983, 39, 29-32.
11. For selected recent reviews on p-toluenesulfinimines; see: a)
Zhou, P.; Chen, B. C.; Davis, F. A. Tetrahedron 2004, 60, 8003-
8030; b) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62,
8869-8905. For selected reviews on the chemistry of t-BS-imines;
see: c) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
2002, 35, 984-995; d) Lin, G. Q.; Xu, M. H.; Zhong, Y. W.; Sun,
X. W. Acc. Chem. Res. 2008, 41, 831-840; e) Ferreira, F.; Botuha,
C.; Chemla, F.; Perez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162-
1186; f) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev.
2010, 110, 3600-3740.
12. a) Liu, R. C.; Wei, J. H.; Wei, B. G.; Lin, G. Q. Tetrahedron:
Asymmetry 2008, 19, 2731-2734; b) Xarnod, C.; Huang, W.; Ren,
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Supplementary data associated with this article can be found
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version,
at
http://dx.doi.org/10.1016/j.tet.2016.10.047.
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