An efficient method for the preparation of 3-hydroxyl-5-substituted 2-pyrrolidones and application in the divergent synthesis of (-)-preussin and its analogues

Article abstract of DOI:10.1016/j.tet.2014.05.037

An asymmetric method to (S,R)-α-hydroxyl-γ-amino alcohols 12 through a diastereoselective addition of Grignard reagents to β-chiral aldimines 11 is described. Subsequent oxidation/cyclization with Sarett reagent provided a novel approach to lactams 14, a flexible building block whose utility was demonstrated in the divergent synthesis of antifungal agent (-)-preussin 5 and its three analogues 23, 24, 25.

Full text of DOI:10.1016/j.tet.2014.05.037

Tetrahedron 70 (2014) 4799e4808
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An efficient method for the preparation of 3-hydroxyl-5-substituted
2-pyrrolidones and application in the divergent synthesis
of (ꢀ)-preussin and its analogues
,
,
b,
*
Qian-Ru Zhou a b, Xiao-Yun Wei a, You-Qin Li b, Danfeng Huang a , Bang-Guo Wei
*
a College of Chemistry and Chemical Engineering, Northwest Normal University, 967 Anning Road (E.), Lanzhou 730070, China
b Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric method to (S,R)-a-hydroxyl-g-amino alcohols 12 through a diastereoselective addition of
Grignard reagents to b-chiral aldimines 11 is described. Subsequent oxidation/cyclization with Sarett
reagent provided a novel approach to lactams 14, a flexible building block whose utility was demon-
strated in the divergent synthesis of antifungal agent (ꢀ)-preussin 5 and its three analogues 23, 24, 25.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 19 February 2014
Received in revised form 6 May 2014
Accepted 8 May 2014
Available online 16 May 2014
Keywords:
Imine
Alkaloid
Lactam
Asymmetric synthesis
Preussin
1. Introduction
Functionalized 5-substituted 2-pyrrolidones 1, 2 and their ring-
opened equivalents 3, 4 (Fig. 1) are found in pharmaceuticals and
numerous biologically active natural products.1,2 They are also
valuable chiral building blocks toward the divergent syntheses of
other pyrrolidine or indolizidine alkaloids, which include the an-
tifungal (þ)-preussin, isolated from the fermentation extracts of
Preussia sp. and Aspergillus ochraceus,3 and the pheromone
(þ)-monomorine I 6.4 Another example is hapalosin 8, which was
shown to have multidrug-resistance reversing activity in cancer
cells.5 From the practical point of view, one of the most straight-
forward ways to synthesize these natural products is the asym-
metric construction of 2-pyrrolidones 1, 2. Although a number of
powerful approaches have been reported for the synthesis of 2,2aek
to our best knowledge, only one indirect method could be adapted
for the preparation of building block 12l and several methods for
preparation its deprotective amide.2meo,15b
Chiral N-tert-butanesulfinamide, originally developed by Ellman
and Davis, is arguably one of the most efficient auxiliaries applied in
modern organic synthesis.6 One popular application of Ellman’s
Fig. 1. The structure of several bioactive molecules.
auxiliary is the asymmetric preparation of chiral amines by means
of addition to imines with organo-magnesium, lithium, zinc and
other anionic reagents.7 Excellent chemoselectivity was observed
in many of these reactions, including the unusual 1,3-migration we
* Corresponding authors. Tel.: (þ86) 931 7971 687 (D.H.); tel.: (þ86) 21 5423
7757 (B.-G.W.); e-mail addresses: huangdf@nwnu.edu.cn (D. Huang), bgwei1974@
fudan.edu.cn (B.-G. Wei).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.037

4800
Q.-R. Zhou et al. / Tetrahedron 70 (2014) 4799e4808
Table 1
observed in the reaction of N-tert-butanesulfinyl ester with func-
tionalized organo-magnesium reagents.8 Very recently, our group
also studied the chemical selectivity of the imine with aldehydes in
the presence of ester, ketone and sterically hindered long-chain
alkyl aldehydes.9
Addition of Grignard reagents to imines
Encouraged by Ellman’s pioneered work of Grignard reagents to
a
-chiral aldimines10, we decided to investigate the addition of
Grignard reagents to
vestigate the addition of Grignard reagents to
b
-chiral aldimines (Fig. 2). we decided to in-
-chiral aldimines. As
Entrya
11
R
12
Y %b
(S,R)/(R,R)c
b
1d
(R,R)
(R,R)
(S,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
Bne
Bne
Bne
Allyle
Phe
Phe
4-MePhe
4-MeePhe
CH2]CHe
CH2]CHe
CH^Ce
CH^Ce
CH3e
CH3e
Ete
n-C9H19e
n-C14
Isopropyle
Isopropyle
tert-Butyle
Cyclopropyle
Cyclopenyle
Cyclopenyle
Cyclohexyle
Cyclohexyle
12a
12a
12a
12b
12c
12c
12d
12d
12e
12e
12f
70
95
58
78
78
89
77
94
92
94
72
85
87
89
79
89
90
83
98
65
90
90
91
83
93
80:20
87:13
21:79
88:12
83:17
88:12
84:16
89:11
82:18
89:11
73:27
83:17
92:8
95:5
98:2
99:1
99:1
94:6
98:2
99:1
part of our continuous interests in pursuing the building blocks
used in the synthesis of piperidine alkaloids, depsipeptides, and
ceramides,2k,9,11 our aim is to develop a concise approach to 2,5-
disubstituted 3-hydroxy pyrrolidine alkaloids. Herein we report
a facile method for the preparation of 5-substituted 3-hydroxy
2e
3e
4e
5d
6e
7d
lactam
1 and its application in the divergent syntheses of
8e
(ꢀ)-preussin 5 and its analogous.
9d
10e
11d
12e
13d
14e
15e
16e
17e
18d
19e
20e
21e
22d
23e
24d
25e
12f
12g
12g
12h
12i
O
S
OTBS
OTBS
N
H
29e
12j
β-chiral aldimines
OTBS
OH
12k
12k
12l
12m
12n
12n
12o
12o
S
S
HN
O
R
N
O
TMEDA
R'MgX
R
R'
BocHN
85:15
74:26
82:18
99:1
Ref.10
OTBS
OTBS
Efficient oxidation/cyclization
OTBS
OTBS
chiral aldimines
R = Me
99:1
a
Reactions were performed with imines 11 (7.93 mmol), Grignard reagents
(23.8 mL, 1.0 M in THF) in dry solvent (40 mL) at ꢀ78 ꢁC to room temperature for
12 h.
Ellman's work.
R
O
Bn
R
N
N
Boc
lactam 1
b
Isolated yield.
dr was determined by isolated yields.
THF as solvent (40 mL).
preussin and
its analogues
c
d
This work
e
DCM as solvent (40 mL).
Fig. 2. Addition of nucleophiles to N-tert-butanesulfinyl ester.
room temperature and stirring for 12 h gave 12a in 70% yield with
80:20 diastereoselectivity (Table 1 entry 1). To improve the dia-
stereoselectivity of the reaction, different conditions were screened
(Table 1 entries 1e3). It was discovered that when the solvent was
changed to dichloromethane, diastereoselectivity and yields of
compounds 12a, ceg, k, n, o were slightly improved (Table 1 entries
2, 5e14, 18e19, 22e25). On the other hand, when the diastereomer
(S,R)-11 was applied to the reaction, (R,R)-12a was generated with
79:21 diastereoselectivity in 58% yield, indicating a mismatch be-
2. Results and discussion
Ester 10 was prepared from
D-malic acid via a known method in
73% overall yield.12 Reduction of 10 with DIBAL-H gave the corre-
sponding aldehyde in quantitative yield without further purifica-
tion, which was directly reacted with (R or S)-2-methyl-2-
propanesulfinamide in the presence of anhydrous copper sulfate
tween the chiral auxiliary and the substrate’s g-stereocenter (Table
to produce the corresponding
b-chiral aldimines 11 in good yields
(Scheme 1).13
1 entry 3). When allylmagnesium bromide was used as the nucle-
ophile, similar yield and diastereoselectivity of (S,R)-12b was ob-
tained (Table 1 entry 4). The effect of different Grignard reagents
was also investigated, and the result showed that alkyl Grignards in
general led to improved diastereoselectivity (up to 99:1, Table 1
entries 13e20, 24, 25). Unexpectedly, cyclopropyl and cyclopentyl
magnesium bromide led to moderate diastereoselectivity (Table 1
entries 21e23).
The stereochemistry of 12a derived from (R,R)-11 was ambigu-
ously confirmed by the following synthesis of (ꢀ)-preussin 5.
Therefore, the stereochemistry of 12a derived from (S,R)-11 was
confirmed by contrast the results of HPLC. The (S,R) and (R,R)-13a
were easily converted from (Rs,S,R) and (Rs,R,R)-12a, respectively.
The results of HPLC were obviously shown that (R,R)-11 mainly
produced (R,S,R)-12a, while (S,R)-11 mainly generated (S,R,R)-12a
(Scheme 2). According to similar process, treatment of (S,R)-12aeo
with HCl/Dioxane in ethanol and subsequent protection (Boc2O/
TEA) gave corresponding compounds 13aeo from 54% to 89%
yields.
Scheme 1. Reagents and conditions. a. (1) DIBAL-H, toluene, 0.5 h, quantitative yield;
(2) (R or S)-2-methyl-2-propanesulfinamid, CuSO4, PPTS, CH2Cl2, 24 h, 91% for (R,R)-11;
70% for (S,R)-11.
Next, several diastereoselective addition reactions to
b-chiral
aldimines 11 with Grignard reagents were surveyed (Table 1).
Treatment of compound 11 with 3.0 equiv of benzylmagnesium
bromide in THF at ꢀ78 ꢁC followed by warming up the mixture to

Q.-R. Zhou et al. / Tetrahedron 70 (2014) 4799e4808
4801
compound 14h with benzylmagnesium bromide to generate ring-
opened compound 15 in 82% yield (Scheme 3). The addition/ring-
opening process to convert pyrrolidones to its open chain form is
known to require rather harsh reaction conditions.20 We were
pleased to find that lactam 14h smoothly underwent addition/ring-
opening process to provide 15 in good yield. The coordination of
a magnesium cation with the ortho oxygen in 14 may account for
the success of this reaction. Deprotection of the Boc group in 15
with 2,2,2-trifluoroacetic acid and subsequent one-pot cyclization/
hydrogenation/methylation generated intermediate 16 in 59%
overall yield. Finally, 16 was treated with tetrabutylammonium
Scheme 2. Reagents and conditions: (a). HCl/dioxane, EtOH; (b). Boc2O, TEA, DCM, 57%
for (S,R)-13a and 53% for (R,R)-13a.
fluoride (TBAF) in tetrahydrofuran to give (ꢀ)-preussin
5
25
25
{[a]
ꢀ34.7 (c 0.5, CHCl3); lit.15l
[
a
]
þ32 (c 1.1, CHCl3)} in 95%
D
D
Next, we turned our attention to the preparation of lactams 14
from 13. Initially, the known intramolecular oxidative cyclization of
13 with pyridinium dichromate (PDC) was attempted.14 The alcohol
13c was treated with PDC in DMF to give lactam 14c in low yield
(Table 2, entry 1). To improve the yield of 14ael, different condi-
tions and substrates were screened, but the results showed that the
yields of 14c, e, hei were not improved (Table 2 entries 1e4).
Compared to the Oxidation/cyclization process of lactam 2,14 the
formation of lactams 14ael was more difficult. We speculated that
the bulky OTBS group of compound 13aeg, i, kem, o limited the
yield of the oxidative cyclization reaction. To improve the yield of
lactams 14, various conditions were investigated. Ultimately, when
Sarett reagent21 [CrO3$(C5H5)2] was used, the reaction proceeded
with good to excellent yield (Table 2 entries 5e16). To the best of
our knowledge, this is the first example for the synthesis of lactams
by oxidation/cyclization with Sarett reagent.
yield. The spectroscopic and physical data of the synthetic 5 were
identical to the reported data.15l
Scheme 3. Reagents and conditions: (a) BnMgBr, ꢀ78 ꢁC, 3 h, 72%; (b) 1. CF3COOH, rt,
3 h; NaOH, pH¼10e12; 2. H2, Pd/C, Pd(OH)2, (HCHO)n, rt, 16 h, two steps 59%; (c) TBAF,
THF, rt, 8 h, 95%.
Table 2
Preparation of 14ael by oxidation/cyclization
In light of our interest in diversity-oriented synthesis,11f we
prepared several analogues of (ꢀ)-preussin (Scheme 4). Following
the synthetic sequence described above, three analogues of
25
26
(ꢀ)-preussin 23 {[
a
]
þ6.98 (c 0.38, CHCl3)}, 24 {[
a]
ꢀ25.42 (c
D
D
25
0.63, CHCl3)}, 25 {[
a]
ꢀ36.53 (c 0.79, CHCl3)} were successfully
D
prepared in 19%, 34%, 8% respectively yields. The structures of an-
alogues 23, 24 and 25 were unambiguously confirmed by spec-
troscopic data.
Entrya
R
Oxidant
14
Yield %b
1
2
3
4
5
6
7
8
Phe
PDC
PDC
PDC
PDC
14c
14e
14h
14i
14a
14b
14c
14d
14e
14f
14g
14h
14i
41
35
53
48
58
34
72
81
45
57
52
72
81
76
70
55
CH2]CHe
n-C9H19e
Isopropyle
Bn
Allyle
Phe
4-MePhe
CH2]CHe
CH^Ce
Mee
n-C9H19e
Isopropyle
tert-Butyle
Cyclopropyle
Cyclohexyle
CrO3$(C5H5)2
CrO3$(C5H5)2
CrO3$(C5H5)2
CrO3$(C5H5)2
CrO3$(C5H5)2
CrO3$(C5H5)2
CrO3$(C5H5)2
CrO3$(C5H5)2
CrO3$(C5H5)2
CrO3$(C5H5)2
CrO3$(C5H5)2
CrO3$(C5H5)2
9
10
11
12
13
14
15
16
14j
14k
14l
a
The reactions were performed with amines 13 (2.44 mmol), Sarett reagent
(5 equiv) in dry DMF (5 mL) at rt for 24 h.
b
Isolated yield.
Scheme 4. Reagents and conditions. (a) BnMgBr, ꢀ78 ꢁC, 3 h, 64% for 17, 80% for 18,
39% for 19; (b) 1. CF3COOH, rt, 3 h; NaOH, rt, pH¼10e12; 2. H2, Pd/C, Pd(OH)2, (HCHO)n,
rt, 16 h, two steps 55% for 20, 69% for 21, 37% for 22; (c) TBAF, THF, rt, 24 h, 55% for 23,
61% for 24, 57% for 25.
With the chiral 2-pyridones 14ael in hand, we turned our at-
tention to the synthesis of (þ)-preussin,14e16 a pyrrolidinol alkaloid.
Recently, it was reported that (ꢀ)-preussin 5 could inhibit growth
of the bacteria Candida and filamentous fungi,3,17 induce apoptosis
in human tumor cells18 and inhibit cell growth of the fission yeast ts
mutants defective on cdc2-regulatory genes.16b,19 All of these re-
ported biological activities rendered preussin an attractive syn-
thetic target.14e16 Our synthesis started with the treatment of
3. Conclusions
In summary, an efficient method for the preparation of (S,R)-
hydroxy- -amino 12 by a diastereoselective addition of Grignard
reagents to -chiral aldimines 11 has been developed. Moreover,
a-
g
b

4802
Q.-R. Zhou et al. / Tetrahedron 70 (2014) 4799e4808
a novel approach for the synthesis of flexible building blocks 14 has
been achieved by oxidation/cyclization with Sarett reagent in
moderate to excellent yields. Using this strategy, (ꢀ)-preussin 5 and
its three analogues 23, 24 and 25 have been synthesized. Further
studies on this methodology’s application in the diversity-oriented
synthesis of other bioactive compounds are now in progress in our
laboratory.
CDCl3): d 7.33e7.26 (m, 4H), 7.25e7.20 (m, 1H), 3.82e3.72 (m, 2H),
3.51 (dd, J¼4.8, 10.0 Hz, 1H), 3.32 (dd, J¼6.8, 10.0 Hz, 1H), 3.23
(d, J¼9.6 Hz,1H), 3.11 (dd, J¼4.2,13.4 Hz,1H), 3.04 (dd, J¼7.4,13.4 Hz,
1H), 1.57e1.47 (m, 2H), 1.25e1.15 (m, 9H), 0.92e0.86 (m, 9H),
0.86e0.82 (m, 9H), 0.10e0.05 (m, 6H), 0.05e0.00 (m, 6H) ppm; 13
C
NMR (100 MHz, CDCl3):
d 137.1, 130.3, 128.3, 126.4, 70.4, 67.3, 56.2,
54.4, 43.7, 40.6, 25.9, 25.9, 22.8, 18.2, 18.1, ꢀ3.84, ꢀ4.42, ꢀ5.35,
ꢀ5.39 ppm; HRMS (ESI) calcd for [C27H53NO3SSi2þHþ]: 528.3363,
found: 528.3344.
4. Experimental section
4.1. General
(R,R)-12a (1.92 g, 58%) as a white solid. Mp 95e96 ꢁC.
[
a
]
25 þ17.37 (c 1.26, CHCl3); IR (film): nmax 3274, 2954, 2930, 2856,
D
1495, 1473, 1463, 1251, 1134, 1110, 1088, 1048, 1007, 955, 895, 834,
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 chromatog-
raphy was performed on silica gel (300e400 mesh) with Petro-
leum/EtOAc as eluent. Optical rotations were measured on
a polarimeter with a sodium lamp. HRMS were measured on an
LCMS-IT-TOF apparatus. IR spectra were recorded using film on
a Fourier Transform Infrared Spectrometer. NMR spectra were
recorded at 400 MHz or 500 MHz, and chemical shifts are reported
862, 814, 773, 753, 703 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
7.35e7.21 (m, 5H), 3.92e3.82 (m, 1H), 3.82e3.72 (m, 1H), 3.58 (dd,
J¼5.2, 10.0 Hz, 1H), 3.45 (dd, J¼6.0, 10.4 Hz, 1H), 3.25 (d, J¼8.0 Hz,
1H), 3.04 (dd, J¼6.4, 13.6 Hz, 1H), 2.97 (dd, J¼5.2, 13.6 Hz, 1H),
1.86e1.74 (m, 1H), 1.63e1.53 (m, 1H), 1.18 (s, 9H), 0.94e0.86
(m, 18H), 0.10e0.01 (m, 12H) ppm; 13C NMR (100 MHz, CDCl3):
d
136.9, 130.3, 128.4, 126.5, 70.5, 67.5, 55.8, 53.7, 42.1, 40.3, 29.7,
25.9, 25.8, 22.6, 18.4, 18.1, ꢀ4.2, ꢀ4.7, ꢀ5.4 ppm; HRMS (ESI) calcd
for [C27H53NO3SSi2þHþ]: 528.3363, found: 528.3372.
in
d (parts per million) referenced to an internal TMS standard for
1H NMR and CDCl3 (77.0 ppm) for 13C NMR.
4.2.2. (R)-N-((2R,4S)-1,2-Bis(tert-butyldimethylsilyloxy)hept-6-en-
4-yl)-2-methylpropane-2-sulfinamide (12b). 12b (2.69 g, 78%) as
26
4.1.1. (R,E)-N-((R/S)-3,4-Bis(tert-butyldimethylsilyloxy)butylidene)-
2-methylpropane-2-sulfinamide (11). A solution of 10 (30.54 g,
84.28 mmol) in toluene (200 mL) was cooled to ꢀ78 ꢁC and stirred
for 10 min. To this solution was added a solution of diisobutylalu-
minium hydride (101.2 mL, 101.2 mmol, 20% in hexane) dropwise
and the reaction mixture was stirred for 20 min. The mixture was
quenched with a solution of potassium sodium tartrate (1 M) and
warmed to room temperature. The crude aldehyde, which was
dissolved in DCM (200 mL). (R)-2-Methyl-2-propanesulfinamide
(7.89 g, 65.15 mmol), cupric sulfate anhydrous (23.11 g,
144.78 mmol), and PPTS (0.91 g, 3.62 mmol) were added to the
solution in one portion and the mixture was stirred for 19 h. The
resulting mixture was filtrated and the filtrate was concentrated to
give the crude product, which was purified by flash chromatogra-
phy on silica gel (PE/EA¼20/1) to give 11 (28.42 g) in 91% yield as
a yellow oil.
a white solid. Mp 71e72 ꢁC; [
a
]
ꢀ9.01 (c 1.12, CHCl3); IR (film):
D
nmax 3153, 2929, 2857,1471,1419,1389,1362,1255,1099,1043,1055,
941, 912 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
5.90e5.78 (m,1H), 5.24
(d, J¼5.2 Hz, 1H), 5.21 (br s, 1H), 3.92e3.82 (m, 1H), 3.65e3.52
(m, 2H), 3.41 (dd, J¼6.8, 10.0 Hz, 1H), 3.31 (d, J¼8.8 Hz, 1H),
2.63e2.46 (m, 2H), 1.76e1.67 (m, 1H), 1.67e1.55 (m, 1H), 1.35e1.25
(m, 9H), 1.07e0.85 (m, 18H), 0.22e0.17 (m, 6H), 0.17e0.00 (m, 6H)
ppm; 13C NMR (100 MHz, CDCl3):
d 133.8, 119.0, 70.4, 67.3, 56.0,
53.1, 41.8, 40.8, 25.9, 22.8, 18.3, 18.1, ꢀ3.9, ꢀ4.5, ꢀ5.3 ppm; HRMS
(ESI) calcd for [C23H51NO3SSi2þHþ]: 478.3206, found: 478.3208.
4.2.3. (R)-N-((1R,3R)-3,4-Bis(tert-butyldimethylsilyloxy)-1-
phenylbutyl)-2-methylpropane-2-sulfinamide (12c). 12c (3.19 g,
25
89%) as a colorless oil. [
a
]
ꢀ29.91 (c 0.99, CHCl3); IR (film): nmax
D
3399, 2954, 2928, 2857, 1664, 1655, 1648, 1638, 1459, 1400, 1071,
835, 766, 697 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
7.39e7.34 (m, 4H),
(R,R)-11 [
a
]
25 ꢀ121.29 (c 2.16, CHCl3); IR (film): nmax 3433, 2956,
7.32e7.25 (m, 1H), 4.60e4.52 (m, 1H), 3.82e3.74 (m, 1H), 3.64
(d, J¼6.0 Hz, 1H), 3.57 (dd, J¼5.2, 10.0 Hz, 1H), 3.43 (dd, J¼6.4,
10.0 Hz, 1H), 2.24 (ddd, J¼5.1, 8.3, 13.9 Hz, 1H), 1.85 (ddd, J¼5.9, 6.7,
14.1 Hz, 1H), 1.24e1.21 (m, 9H), 0.91e0.88 (m, 9H), 0.94e0.91
(m, 9H), 0.05e0.02 (m, 6H), 0.10e0.05 (m, 6H) ppm; 13C NMR
D
2929, 2854, 1638, 1473, 1459, 1387, 1368, 1253, 1084, 1004, 939, 835,
806, 776 cmꢀ1; 1H NMR (400 MHz, CDCl3):
4.02e4.07 (m, 1H), 3.62 (dd, J¼5.4, 10.2 Hz, 1H), 3.48 (dd, J¼7.0,
10.2 Hz, 1H), 2.85e2.75 (m, 1H), 2.72e2.60 (m, 1H), 1.25e1.15
(m, 9H), 0.85e0.85 (m, 18H), 0.10e0.05 (m, 12H) ppm; 13C NMR
d
8.15 (t, J¼4.8 Hz, 1H),
(100 MHz, CDCl3):
d 143.3, 128.7, 127.6, 127.0, 70.7, 67.1, 56.6, 56.0,
(100 MHz, CDCl3):
d
167.9, 70.9, 66.8, 56.5, 41.1, 25.9, 25.8, 22.4,
43.1, 26.0, 25.9, 22.7, 18.3, 18.1, ꢀ4.1, ꢀ4.6, ꢀ5.4 ppm; HRMS (ESI)
18.3, 18.1, ꢀ4.4, ꢀ4.8, ꢀ5.4 ppm; HRMS (ESI) calcd for
calcd for [C26H51NO3SSi2þHþ]: 514.3206, found: 514.3201.
[C20H45NO3SSi2þHþ]: 436.2737, found: 436.2737.
4.2.4. (R)-N-((1R,3R)-3,4-Bis(tert-butyldimethylsilyloxy)-1-p-tol-
4.2. General procedure for the synthesis of 12aeo
ylbutyl)-2-methylpropane-2-sulfinamide (12d). 12d (3.50 g, 94%) as
27
a colorless oil. [
a
]
D
ꢀ12.39 (c 0.89, CHCl3); IR (film): nmax 3351,
A solution of 11 (3.45 g, 7.93 mmol) in dry DCM (40 mL) was
treated with a solution of Grignard reagent (23.78 mL, 23.78 mmol,
1 M in THF) at ꢀ78 ꢁC. The reaction mixture was allowed to warm to
room temperature and stirred for 12 h. The mixture was quenched
with a solution of saturated NH4Cl and extracted with DCM
(50 mLꢂ3). The combined organic layers were washed with brine,
dried, and concentrated. The residue was purified by flash chro-
matography on silica gel (PE/EA¼6/1) to give 12aeo.
2945, 2833, 2601, 2519, 2043, 1450, 1410, 1108, 1031 cmꢀ1; 1H NMR
(400 MHz, CDCl3): 7.29e7.19 (m, 2H), 7.18e7.08 (m, 2H), 4.48
d
(dd, J¼6.4, 13.2 Hz, 1H), 3.80e3.70 (m, 1H), 3.60e3.50 (m, 2H), 3.38
(dd, J¼7.0, 9.4 Hz, 1H), 2.36e2.27 (m, 3H), 2.24e2.15 (m, 1H),
1.85e1.75 (m, 1H), 1.29e1.17 (m, 9H), 0.88e0.74 (m, 18H), 0.16e0.03
(m, 6H), 0.03e0.00 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3):
d
140.3, 137.2, 129.3, 126.9, 70.6, 67.1, 56.4, 55.9, 42.9, 25.9, 25.9,
22.7, 21.1, 18.3, 18.1, ꢀ4.1, ꢀ4.6, ꢀ5.4 ppm; HRMS (ESI) calcd for
[C27H53NO3SSi2þHþ]: 528.3363, found: 528.3361.
4.2.1. (R)-N-((2S,4R)-4,5-Bis(tert-butyldimethylsilyloxy)-1-
phenylpentan-2-yl)-2-methylpropane-2-sulfinamide
((S,R)-12a).
4.2.5. (R)-N-((3R,5R)-5,6-Bis(tert-butyldimethylsilyloxy)hex-1-en-3-
(S,R)-12a (3.48 g, 95%) as a colorless oil. [
a
]
D
24 þ47.38 (c 0.82, CHCl3);
yl)-2-methylpropane-2-sulfinamide (12e). 12e (3.07 g, 94%) as
IR (film): nmax 3136, 2954, 2928, 2856, 1655, 1460, 1363, 1251, 1138,
a white solid. Mp 115e116 ꢁC; [
nmax 3145, 2929, 2858, 1473, 1389, 1362, 1257, 1050, 998, 915, 835,
a
]
25 ꢀ20.23 (c 0.30, CHCl3); IR (film):
D
1098, 1044, 1033, 1004, 833, 777, 700 cmꢀ1
;
1H NMR (400 MHz,

Q.-R. Zhou et al. / Tetrahedron 70 (2014) 4799e4808
4803
777, 739 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
6.10e5.95 (m, 1H), 5.33
1H), 1.85e1.74 (m, 1H), 1.65e1.50 (m, 4H), 1.29e1.26 (m, 21H),
1.24e1.21 (m, 11H), 0.93e0.87 (m, 21H), 0.12e0.07 (m, 6H),
0.07e0.04 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3): 70.5, 67.4, 61.6,
41.4, 37.8, 35.0, 31.9, 29.7, 29.6, 29.5, 29.4, 26.2, 25.9, 25.7, 22.8, 22.8,
(dd, J¼0.8,17.2 Hz, 1H), 5.21 (dd, J¼1.2, 10.4 Hz, 1H), 4.05e3.95
(m, 1H), 3.95e3.85 (m, 1H), 3.63 (dd, J¼5.2, 10.0 Hz, 1H), 3.47
(dd, J¼6.8, 10.0 Hz, 1H), 3.33 (d, J¼8.0 Hz, 1H), 1.95e1.85 (m, 1H),
1.72e1.65 (m, 1H), 1.42e1.20 (m, 9H), 1.12e0.75 (m, 18H), 0.35e0.15
(m, 6H), 0.15e0.00 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3):
22.7, 18.3, 18.1, 14.1, ꢀ3.8, ꢀ4.4, 5.4
d ppm; HRMS (ESI) calcd for
[C34H75NO3SSi2þHþ]: 634.5084, found: 634.5042.
d
140.8, 115.6, 70.2, 67.1, 56.2, 56.0, 41.3, 25.9, 25.9, 22.7, 18.3, 18.1,
ꢀ4.0, ꢀ4.5, ꢀ5.4 ppm; HRMS (ESI) calcd for [C22H49NO3SSi2þHþ]:
4.2.11. (R)-N-((3R,5R)-5,6-Bis(tert-butyldimethylsilyloxy)-2-
464.3050, found: 464.3049.
methylhexan-3-yl)-2-methylpropane-2-sulfinamide
(12k). 12i
þ24.51 (c 1.06,
25
(3.66 g, 98%) as a white solid, mp 66e67 ꢁC. [
a
]
D
4.2.6. (R)-N-((3R,5R)-5,6-Bis(tert-butyldimethylsilyloxy)hex-1-yn-3-
CHCl3); IR (film): nmax 3399, 2949, 2855, 2841, 2382, 1653, 1457,
yl)-2-methylpropane-2-sulfinamide (12f). 12f (2.58 g, 85%) as
1252, 1021 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 3.82e3.75 (m, 1H),
26
a white solid. Mp 65e66 ꢁC. [
a
]
þ5.26 (c 1.02, CHCl3); IR (film):
3.57 (dd, J¼5.0, 9.8 Hz, 1H), 3.38e3.34 (m, 1H), 3.34e3.28 (m, 1H),
3.19 (d, J¼9.6 Hz, 1H), 2.20e2.08 (m, 1H), 1.56e1.38 (m, 2H), 1.24
(s, 9H), 0.95e0.87 (m, 24H), 0.12e0.04 (m, 12H) ppm; 13C NMR
D
nmax 3313, 3220, 2956, 2930, 2897, 2858, 1473, 1463, 1389, 1362,
1255, 1092, 1005, 939, 810 cmꢀ1 1H NMR (400 MHz, CDCl3):
4.30e4.25 (m, 1H), 4.02e3.95 (m, 1H), 3.70e3.57 (m, 2H), 3.50
;
d
(100 MHz, CDCl3): d 70.6, 67.5, 59.3, 56.2, 36.8, 33.4, 25.9, 22.9, 19.0,
(dd, J¼6.8, 10.0 Hz, 1H), 2.51e2.50 (m, 1H), 2.14e2.06 (m, 1H),
18.3, 18.1, 16.3, ꢀ3.7, ꢀ4.4, ꢀ5.3, ꢀ5.4 ppm; HRMS (ESI) calcd for
1.94e1.86 (m, 1H), 1.33e1.27 (m, 9H), 1.01e0.87 (m, 18H), 0.27e0.14
[C23H53NO3SSi2þHþ]: 480.3363, found: 480.3325.
(m, 6H), 0.14e0.00 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3):
d 84.4,
72.8, 70.0, 67.0, 56.4, 44.4, 42.5, 25.9, 25.9, 22.6, 18.3, 18.0, ꢀ4.2,
ꢀ4.5, ꢀ5.4 ppm; HRMS (ESI) calcd for [C22H47NO3SSi2þHþ]:
462.2893, found: 462.2885.
4.2.12. N-((3R,5R)-5,6-Bis(tert-butyldimethylsilyloxy)-2,2-
dimethylhexan-3-yl)-2-methylpropane-2-sulfinamide
(12l). 12l
þ3.84 (c 1.06,
27
(2.51 g, 65%) as a white solid, mp 95e96 ꢁC. [
a]
D
CHCl3); IR (film): nmax 3344, 2946, 2833, 2603, 2519, 2229, 2044,
4.2.7. (R)-N-((2S,4R)-4,5-Bis(tert-butyldimethylsilyloxy)pentan-2-
1658, 1452, 1417, 1118, 1031 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
yl)-2-methylpropane-2-sulfinamide (12g). 12g (3.03 g, 89%) as
d
3.90e3.80 (m, 1H), 3.58 (dd, J¼5.0, 9.8 Hz, 1H), 3.32 (dd, J¼7.2,
a white solid. Mp 104e105 ꢁC; [
a
]
26 þ3.67 (c 1.12, CHCl3); IR (film):
9.6 Hz, 1H), 3.23 (d, J¼8.0 Hz, 1H), 3.16e3.08 (m, 1H), 1.64e1.48
(m, 2H), 1.30e1.22 (m, 9H), 0.98 (s, 9H), 0.92e0.87 (m, 18H),
0.16e0.08 (m, 6H), 0.08e0.00 (m, 6H) ppm; 13C NMR (100 MHz,
D
nmax 3344, 2944, 2832, 2600, 2514, 2043, 1459, 1449, 1420 cmꢀ1; 1H
NMR (400 MHz, CDCl3): d3.82e3.75 (m,1H), 3.56e3.47(m, 2H), 3.33
(dd, J¼7.2, 9.2 Hz, 1H), 2.93 (d, J¼8.8 Hz, 1H), 1.73e1.64 (m, 1H),
1.49e1.40 (m, 1H), 1.32 (d, J¼6.0 Hz, 3H), 1.25e1.14 (m, 9H),
0.86e0.70 (m, 9H),1.05e0.86 (m, 9H), 0.12e0.04 (m, 6H), 0.04e0.00
CDCl3): d 70.8, 67.7, 62.8, 56.6, 38.3, 34.5, 29.7, 27.0, 26.0, 25.9, 23.1,
18.3, 18.1, ꢀ3.7, ꢀ4.2, ꢀ5.4 ppm; HRMS (ESI) calcd for
[C24H55NO3SSi2þHþ]: 494.3519, found: 494.3515.
(m, 6H) ppm; 13C NMR (100 MHz, CDCl3):
d 70.4, 67.3, 55.9, 50.3, 44.1,
25.9, 24.8, 22.7,18.3,18.1, ꢀ4.0, ꢀ4.5, ꢀ5.4 ppm; HRMS (ESI) calcd for
4.2.13. (R)-N-((1R,3R)-3,4-Bis(tert-butyldimethylsilyloxy)-1-
[C21H49NO3SSi2þHþ]: 452.3050, found: 452.3048.
cyclopropylbutyl)-2-methylpropane-2-sulfinamide
(12m). 12m
(2.90 g, 90%) as a white solid, mp 101e102 ꢁC. [
a
]
27 ꢀ26.31 (c 0.92,
D
4.2.8. (R)-N-((3S,5R)-5,6-Bis(tert-butyldimethylsilyloxy)hexan-3-yl)-
CHCl3); IR (film): nmax 3152, 3002, 2957, 2928, 2901, 2857, 1472,
2-methylpropane-2-sulfinamide (12h). 12h (2.86 g, 79%) as a white
1361, 1251, 1128, 1095, 1050, 998 cmꢀ1; 1H NMR (400 MHz, CDCl3):
solid. Mp 92e93 ꢁC; [
a]
25 þ5.79 (c 1.46, CHCl3); IR (film): nmax 3349,
d
3.95e3.87 (m, 1H), 3.61 ( dd, J¼5.2, 10.0 Hz, 1H), 3.44 (dd, J¼7.0,
D
2945, 2833, 2601, 2515, 2228, 2051, 1654, 1447, 1420, 1029 cmꢀ1; 1H
9.8 Hz, 1H), 3.27 (d, J¼8.0 Hz, 1H), 2.71e2.61 (m, 1H), 1.91e1.81
(m, 1H), 1.78e1.70 (m, 1H), 1.34e1.25 (m, 9H), 0.99e0.87 (m, 18H),
0.79e0.69 (m,1H), 0.69e0.61 (m,1H), 0.61e0.53 (m,1H), 0.34e0.25
(m, 1H), 0.18e0.00 (m, 12H) ppm; 13C NMR (100 MHz, CDCl3):
NMR (400 MHz, CDCl3):
d
3.85e3.76 (m, 1H), 3.55 (dd, J¼5.0, 9.8 Hz,
1H), 3.38 (dd, J¼3.0, 8.6 Hz,1H), 3.35e3.30 (m,1H), 3.07 (d, J¼8.8 Hz,
1H), 1.85e1.75 (m, 1H), 1.67e1.50 (m, 3H), 1.25e1.20 (m, 9H), 0.95
(t, J¼7.2 Hz, 3H), 0.92e0.87 (m, 18H), 0.10e0.07 (m, 6H), 0.07e0.05
d
70.3, 67.3, 59.5, 55.9, 42.1, 25.9, 25.9, 22.8, 18.6, 18.3, 18.1, 5.5, 4.4,
(m, 6H) ppm; 13C NMR (100 MHz, CDCl3) :
d
70.5, 67.4, 56.0, 55.8,
ꢀ3.9, ꢀ4.6, ꢀ5.4 ppm; HRMS (ESI) calcd for [C23H51NO3SSi2þHþ]:
40.9, 30.5, 25.9, 22.8,18.3,18.1, 9.9, ꢀ3.8, ꢀ4.4, ꢀ5.4 ppm; HRMS (ESI)
478.3206, found: 478.3207.
calcd for [C22H51NO3SSi2þHþ]: 466.3206, found: 466.3187.
4.2.14. N-((1R,3R)-3,4-Bis(tert-butyldimethylsilyloxy)-1-
4.2.9. (R)-N-((2R,4S)-1,2-Bis(tert-butyldimethylsilyloxy)tridecan-4-
yl)-2-methylpropane-2-sulfinamide (12i). 12i (3.94 g, 89%) as a col-
cyclopentylbutyl)-2-methylpropane-2-sulfinamide
(12n). 12n
þ4.03 (c 0.79,
25
(2.99 g, 91%) as a white solid, mp 92e93 ꢁC. [
a
]
D
27
orless oil. [
a]
þ2.96 (c 0.47, CHCl3); IR (film): nmax 3386, 2944,
CHCl3); IR (film): nmax 3251, 2954, 2928, 2858, 1252, 1131, 1097,
D
2949, 2836, 1655, 1459, 1449, 1407 cmꢀ1
CDCl3):
;
1H NMR (400 MHz,
1052, 834 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 3.88e3.78 (m, 1H),
d
3.85e3.76 (m, 1H), 3.65e3.60 (m, 0.4H), 3.53 (dd, J¼5.2,
3.55 (dd, J¼5.2, 10.0 Hz, 1H), 3.40e3.28 (m, 2H), 3.16 (d, J¼8.0 Hz,
1H), 2.25e2.12 (m, 1H), 1.85e1.70 (m, 2H), 1.67e1.50 (m, 6H),
1.40e1.27 (m, 2H), 1.22 (s, 9H), 0.95e0.85 (m, 18H), 0.12e0.02
10.0 Hz, 1H), 3.42e3.30 (m, 2H), 3.04 (d, J¼8.8 Hz, 1H), 1.85e1.67
(m, 2H), 1.62e1.47 (m, 3H), 1.42e1.22 (m, 16H), 1.22e1.17 (m, 8H),
0.87e0.82 (m, 10H), 0.90e0.87 (m, 8H), 0.20e0.05 (m, 6H),
(m, 12H) ppm; 13C NMR (100 MHz, CDCl3):
d 70.7, 67.6, 57.9, 56.1,
0.05e0.00 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3):
d
70.4, 67.4,
45.8, 39.8, 29.7, 28.6, 25.9, 25.7, 25.5, 22.9, 18.3, 18.1, ꢀ3.7, ꢀ4.4,
ꢀ5.4 ppm; HRMS (ESI) calcd for [C25H55NO3SSi2þHþ]: 506.3519,
found: 506.3518.
56.0, 54.4, 41.3, 37.8, 31.8, 29.5, 29.5, 29.4, 29.3, 25.9, 25.6, 22.8, 22.6,
18.3, 18.0, 14.1, ꢀ3.9, ꢀ4.5, ꢀ5.4 ppm; HRMS (ESI) calcd for
[C29H65NO3SSi2þHþ]: 564.4302, found: 564.4294.
4.2.15. (R)-N-((1R,3R)-3,4-BIS(tert-butyldimethylsilyloxy)-1-
4.2.10. (R)-N-((2R,4S)-1,2-Bis(tert-butyldimethylsilyloxy)octadecan-
cyclohexylbutyl)-2-methyl-propane-2-sulfinamide
(12o). 12o
þ18.36 (c 0.89,
25
4-yl)-2-methylpropane-2-sulfinamide (12j). 12j (4.47 g, 90%) as
(3.79 g, 93%) as a white solid, mp 91e92 ꢁC. [
a
]
D
a colorless oil. [
a
]
D
25 ꢀ3.49 (c 0.98, CHCl3); IR (film): nmax 3351, 2945,
CHCl3); IR (film): nmax 3258, 2955, 2929, 2856, 2739, 2709, 2662,
2833, 2600, 2521, 2219, 2039, 1452, 1412, 1117, 1028 cmꢀ1; 1H NMR
1472, 1450, 1414, 1389, 1362, 1252, 1230, 1181, 1095, 1051, 994,
(400 MHz, CDCl3):
3.45e3.37 (m, 1H), 3.35 (dd, J¼3.0, 8.2 Hz, 1H), 3.04 (d, J¼8.4 Hz,
d
3.90e3.76 (m, 1H), 3.55 (dd, J¼5.0, 9.8 Hz, 1H),
974, 940, 893, 835, 775, 742, 714, 662 cmꢀ1 1H NMR (400 MHz,
;
CDCl3):
d
3.78e3.70 (m, 1H), 3.59 (dd, J¼5.2, 10.0 Hz, 1H),

4804
Q.-R. Zhou et al. / Tetrahedron 70 (2014) 4799e4808
3.32e3.22 (m, 2H), 3.18 (d, J¼9.6 Hz, 1H), 1.78e1.68 (m, 3H),
1.68e1.58 (m, 3H), 1.55e1.38 (m, 2H), 1.32e1.22 (m, 2H), 1.19
(s, 9H), 1.16e0.97 (m, 3H), 0.86 (s, 9H), 0.85 (s, 9H), 0.07e0.00
[
a
]
24 þ34.70 (c 0.64, CHCl3); IR (film): nmax 3346, 2945, 2833, 2597,
D
2515, 2343, 2339, 2039, 1653, 1462, 1450, 1430, 1029 cmꢀ1; 1H NMR
(400 MHz, CDCl3, rotamers):
d 7.20e7.10 (m, 4H), 5.30e5.10 (s, 9/
(m, 12H) ppm; 13C NMR (100 MHz, CDCl3):
d
70.6, 67.5, 59.0, 56.1,
10H), 5.10e5.00 (s, 1/10H), 4.75e4.60 (s, 9/10H), 4.60e4.50 (s, 1/
10H), 3.85e3.75 (m,1H), 3.65e3.58 (m,1H), 3.58e3.50 (m,1H), 2.35
(s, 3H), 1.98e1.90 (m, 2H), 0.97e0.92 (m, 9H), 0.95 (s, 9H),
0.10e0.07 (m, 3H), 0.15e0.10 (m, 3H) ppm; 13C NMR (100 MHz,
43.8, 37.9, 29.5, 27.2, 26.6, 26.3, 26.2, 25.9, 22.8, 18.2, 18.0, ꢀ3.8,
ꢀ4.4, ꢀ5.4 ppm; HRMS (ESI) calcd for [C26H57NO3SSi2þHþ]:
520.3676, found: 520.3681.
CDCl3):
d 155.1, 140.2, 136.7, 129.3, 125.9, 79.3, 70.3, 66.3, 51.8, 41.3,
4.3. General procedure for synthesis of 13aeo
28.4, 25.9, 21.1, 18.0, ꢀ4.5, ꢀ4.8 ppm; HRMS (ESI) calcd for
[C22H39NO4SiþNaþ]: 432.2546, found: 432.2543.
A solution of 12 (3.79 mmol) in EtOH (5 mL) was cooled to 0 ꢁC.
A solution of HCl/dioxane (3.8 mL) was added and the reaction was
stirred for 30 min. The mixture was concentrated and the residue
was dissolved in DCM (50 mL). Boc2O (0.99 g, 4.55 mmol) and TEA
(2.6 mL, 18.95 mmol) were added to the solution and the mixture
was stirred overnight. The mixture was quenched with a saturated
aqueous solution of NH4Cl and resulting layers were separated. The
aqueous layer was extracted with DCM for three times and the
combined organic layers were washed with brine, dried, filtered,
and concentrated. The residue was purified by flash chromatogra-
phy on silica gel (PE/EA¼4/1) to give 13aeo.
4.3.5. tert-Butyl (3R,5R)-5-(tert-butyldimethylsilyloxy)-6-hydroxy-
hex-1-en-3-yl-carbamate (13e). 13e (1.16 g, 78%) as a colorless oil.
25
[a
]
ꢀ2.51 (c 0.60, CHCl3); IR (film): nmax 3349, 2945, 2833, 2597,
D
2520, 2228, 2044, 1684, 1450, 1418, 1114, 1031 cmꢀ1
;
1H NMR
(400 MHz, CDCl3, rotamers): 6.05e5.90 (m, 1/5H), 5.85e5.70
d
(m, 3/5H), 5.30e5.08 (m, 3/2H), 5.00e4.75 (m, 1/2H), 4.25e4.10
(m, 1/2H), 4.05e3.80 (m, 1H), 3.65e3.45 (m, 13/10H), 3.42 (dd,
J¼6.8, 10.0 Hz, 1/5H), 3.20 (d, J¼8.4 Hz, 1/5H), 2.10e1.95 (m, 3/5H),
1.88e1.75 (m, 1H), 1.75e1.60 (m, 1H), 1.55e1.35 (m, 6H), 1.35e1.05
(m, 3H), 0.95e0.85 (m, 9H), 0.15e0.05 (m, 6H) ppm; 13C NMR
(100 MHz, CDCl3):
d 155.3, 139.0, 115.6, 79.2, 70.3, 66.5, 50.2, 41.4,
4.3.1. tert-Butyl (2S,4R)-4-(tert-butyldimethylsilyloxy)-5-hydroxy-1-
38.9, 28.4, 25.9, 22.7, 18.0, ꢀ4.0, ꢀ4.4, ꢀ4.8, ꢀ5.4 ppm; HRMS (ESI)
phenylpentan-2-yl-carbamate ((S,R)-13a). (S,R)-13a (0.885 g, 57%)
calcd for [C17H35NO4SiþNaþ]: 368.2233, found: 368.2232.
24
as a colorless oil. [
a]
þ17.23 (c 1.50, CHCl3); IR (film): nmax 3400,
D
2929, 2857, 1691, 1498, 1391, 1366, 1253, 1171, 1047, 836, 777,
4.3.6. tert-Butyl (3R,5R)-5-(tert-butyldimethylsilyloxy)-6-hydroxy-
700 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
7.32e7.27 (m, 2H), 7.25e7.16
hex-1-yn-3-yl-carbamate (13f). 13f (1.32 g, 89%) as a colorless oil.
(m, 3H), 4.67 (d, J¼6.8 Hz,1H), 3.98e3.79 (m, 2H), 3.60e3.40 (m, 2H),
2.95 (dd, J¼3.8, 13.0 Hz, 1H), 2.71 (dd, J¼7.8, 13.0 Hz, 1H), 1.95 (br s,
1H), 1.86e1.62 (m, 2H), 1.46e1.40 (m, 9H), 0.90 (m, 9H), 0.10e0.05
[a
]
25 þ73.55 (c 1.01, CHCl3); IR (film): nmax 3346, 2945, 2833, 2600,
D
2526, 2225, 2048, 1476, 1452, 1415, 1032 cmꢀ1; 1H NMR (400 MHz,
CDCl3): d 5.17 (br s,1H), 4.50 (br s,1H), 4.15e4.05 (m,1H), 3.68e3.60
(m, 6H) ppm; 13C NMR (100 MHz, CDCl3):
d
155.3,138.1,129.6,128.3,
(m,1H), 3.58e3.50 (m,1H), 2.30 (d, J¼2.4 Hz,1H),1.98e1.90 (m, 3H),
126.3, 79.1, 70.3, 66.7, 49.1, 41.9, 37.7, 28.4, 25.9,18.0, ꢀ4.5, ꢀ4.9 ppm;
HRMS (ESI) calcd for [C22H39NO4SiþNaþ]: 432.2546, found:
432.2545. The results of HPLC (Waters 2535 Quaternary Gradient
Module, Waters 2707 Autosampler and Waters 2489 UV/Visible
Detector; PC-3 column (19ꢂ250 mm), n-hexane/i-propanol¼90/10,
0.7 mL/min, rt: 5.23 min).
1.46e1.43 (m, 9H), 0.95e0.88 (m, 9H), 0.17e0.15 (m, 3H), 0.14e0.13
(m, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d 154.8, 83.4, 79.8, 71.1,
70.3, 66.2, 40.2, 39.1, 28.3, 25.9, 18.0, ꢀ4.4, ꢀ4.7 ppm; HRMS (ESI)
calcd for [C17H33NO4SiþNaþ]: 366.2077, found: 366.2075.
4.3.7. tert-Butyl (2S,4R)-4-(tert-butyldimethylsilyloxy)-5-hydroxy-
pentan-2-yl-carbamate (13g). 13g (1.09 g, 74%) as a colorless oil.
26
4.3.2. tert-Butyl (2R,4S)-2-(tert-butyldimethylsilyloxy)-1-hydroxy-
[
a
]
þ8.10 (c 0.84, CHCl3); IR (film): nmax 3345, 2944, 2593, 2509,
D
hept-6-en-4-yl-carbamate (13b). 13b (0.858 g, 57%) as a colorless oil.
2227, 2039,1684,1455,1415,1031 cmꢀ1; 1H NMR (400 MHz, CDCl3):
4.82e4.70 (m, 1H), 4.00e3.88 (m, 1H), 3.79 (br s, 1H), 3.70e3.60
[
a]
25 þ18.90 (c 0.45, CHCl3); IR (film): nmax 3353, 2945, 2833, 2601,
d
D
2526, 2343, 2231, 2048, 1450, 1425, 1110, 1030 cmꢀ1
;
1H NMR
(m, 1H), 3.60e3.58 (m, 1H), 1.80e1.60 (m, 1H), 1.50 (s, 9H), 1.25
(d, J¼6.4 Hz, 3H), 0.98 (s, 9H), 0.25e0.00 (m, 6H) ppm; 13C NMR
(400 MHz, CDCl3, rotamers): d 5.82e5.70 (m,1H), 5.15e5.00 (m, 2H),
4.55 (d, J¼7.8 Hz,1/5H), 4.64 (d, J¼7.8 Hz, 4/5H), 3.98e3.92 (m,1/5H),
3.88e3.82 (m, 4/5H), 3.79e3.63 (m,1H), 3.58 (d, J¼10.4 Hz,1H), 3.46
(d, J¼9.6 Hz, 1H), 2.35e2.16 (m, 2H), 2.12e1.92 (m, 1H), 1.77e1.68
(m, 1H), 1.60e1.35 (m, 9H), 1.10e0.75 (m, 9H), 0.25e0.00 (m, 6H)
(100 MHz, CDCl3): d 155.3, 78.9, 70.3, 66.5, 43.8, 41.0, 28.4, 25.8,
21.9, 18.0, ꢀ4.5, ꢀ4.8 ppm; HRMS (ESI) calcd for
[C17H33NO4SiþNaþ]: 356.2233, found: 356.2232.
ppm; 13C NMR (100 MHz, CDCl3):
d
155.3,134.3,117.8, 79.0, 71.9, 70.2,
4.3.8. tert-Butyl (2R,4S)-2-(tert-butyldimethylsilyloxy)-1-hydroxy-
tridecan-4-ylcarbamate (13i). 13i (1.17 g, 74%) as a colorless oil. [a]
þ9.30 (c 1.08, CHCl3); IR (film): nmax 3369, 2920, 2855, 1719, 1691,
1500, 1460, 1366, 1252, 1173, 1055, 837, 777 cmꢀ1 1H NMR
(400 MHz, CDCl3):
25
66.6, 47.3, 40.1, 38.3, 28.4, 25.8, 18.0, ꢀ4.5, ꢀ4.6, ꢀ4.8 ppm; HRMS
D
(ESI) calcd for [C18H37NO4SiþNaþ]: 382.2390, found: 382.2390.
;
4.3.3. tert-Butyl (1R,3R)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-1-
d
4.60 (d, J¼8.8 Hz, 9/10H), 4.52 (d, J¼8.8 Hz, 1/
phenylbutyl-carbamate (13c). 13c (1.34 g, 87%) as a colorless oil.
10H), 3.85 (dd, J¼4.4, 7.6 Hz, 1H), 3.68e3.54 (m, 2H), 3.52e3.45
(m, 1H), 2.32e2.15 (m, 1H), 1.75e1.65 (m, 1H), 1.46e1.40 (m, 11H),
1.35e1.20 (m, 15H), 0.95e0.85 (m, 12H), 0.14e0.10 (m, 3H),
[
a]
25 þ25.25 (c 0.93, CHCl3); IR (film): nmax 3349, 2945, 2833, 2597,
D
2520, 2228, 2044, 1684, 1450, 1418, 1114, 1031 cmꢀ1
;
1H NMR
(400 MHz, CDCl3, rotamers):
d
7.25e7.20 (m,1H), 7.38e7.26 (m, 4H),
0.10e0.08 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d 155.5, 78.9,
5.54 (s, 1/5H), 5.29 (s, 3/5H), 4.74 (br s, 4/5H), 4.58 (br s, 1/5H), 3.85
(br s, 1H), 3.65e3.50 (m, 2H), 2.06 (d, J¼13.2 Hz, 1H), 2.00e1.90
(m, 1H), 1.42 (s, 9H), 1.27 (t, J¼13.2, 2H), 0.95 (s, 9H), 0.16e0.10
(m, 3H), 0.10e0.06 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3):
72.4, 70.4, 66.8, 59.4, 48.0, 39.2, 36.2, 31.9, 29.6, 29.6, 29.3, 28.4,
25.9, 25.8, 22.7, 18.0, 14.1, ꢀ4.4, ꢀ4.6, ꢀ4.8 ppm; HRMS (ESI) calcd
for [C24H51NO4SiþNaþ]: 468.3485, found: 468.3489.
d
155.1, 143.3, 128.5, 127.1, 126.0, 79.3, 70.2, 66.4, 52.0, 41.4, 28.3,
4.3.9. tert-Butyl (3R,5R)-5-(tert-butyldimethylsilyloxy)-6-hydroxy-2-
25.9, 18.0, ꢀ4.5, ꢀ4.9 ppm; HRMS (ESI) calcd for
methylhexan-3-yl-carbamate (13k). 13k (1.22 g, 81%) as a colorless
25
[C21H37NO4SiþNaþ]: 418.2390, found: 418.2396.
oil. [a
]
þ19.85 (c 1.10, CHCl3); IR (film): nmax 3399, 2949, 2927,
D
2855, 2841, 1655, 1459, 1252, 1110, 1023 cmꢀ1; 1H NMR (400 MHz,
CDCl3, rotamers):
4.48 (d, J¼8.8 Hz, 4/5H), 4.35e4.25 (m, 1/5H),
3.90e3.80 (m, 1H), 3.64e3.44 (m, 3H), 2.05e1.95 (m, 1H), 1.87e1.75
4.3.4. tert-Butyl (1R,3R)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-1-
p-tolylbutyl-carbamate (13d). 13d (0.838 g, 54%) as a colorless oil.
d

Q.-R. Zhou et al. / Tetrahedron 70 (2014) 4799e4808
4805
(m, 1H), 1.74e1.65 (m, 1H), 1.50e1.42 (m, 9H), 0.95e0.90 (m, 9H),
0.90e0.85 (m, 6H), 0.16e0.12 (m, 3H), 0.12e0.09 (m, 3H) ppm; 13
NMR (100 MHz, CDCl3): 155.5, 78.8, 70.5, 66.8, 52.4, 35.9, 32.5,
a colorless oil. [
a
]
25 þ99.6 (c 0.72, CHCl3); IR (film): nmax 3056, 2956,
D
C
2930, 2857, 1788, 1755, 1720, 1473, 1463, 1370, 1346, 1306, 1265,
d
1155, 1088, 974 cmꢀ1
;
1H NMR (400 MHz, CDCl3, rotamers):
29.6, 28.3, 25.8,18.1, 17.9, 17.8, ꢀ4.6, ꢀ4.9 ppm; HRMS (ESI) calcd for
d
5.80e5.65 (m, 1H), 5.30e5.25 (m, 1/5H), 5.15e5.05 (m, 9/5H),
[C18H39NO4SiþNaþ]: 384.2546, found: 384.2535.
4.30e4.25 (m, 1/10H), 4.25e4.15 (m, 9/10H), 4.05e3.95 (m, 1H),
2.77e2.67 (m, 1H), 2.47e2.37 (m, 1H), 2.27e2.17 (m, 1H), 1.80e1.70
4.3.10. tert-Butyl (3R,5R)-5-(tert-butyldimethylsilyloxy)-6-hydroxy-
(m, 1H), 1.62e1.40 (m, 9H), 0.89 (s, 9H), 0.25e0.00 (m, 6H) ppm; 13
C
2,2-dimethylhexan-3-ylcarbamate (13l). 13l (1.11 g, 73%) as a white
NMR (100 MHz, CDCl3): d 172.7, 150.1, 133.1, 118.6, 83.1, 71.2, 54.9,
27
solid, mp 81e83 ꢁC. [
a
]
þ12.97 (c 0.64, CHCl3); IR (film): nmax
39.0, 32.2, 28.0, 25.7, 18.1, ꢀ4.6, ꢀ5.3 ppm; HRMS (ESI) calcd for
D
3358, 2946, 2834, 2593, 2517, 2225, 2043, 1689, 1652, 1642, 1457,
[C18H33NO4SiþNaþ]: 378.2077, found: 378.2078.
1415, 1028 cmꢀ1 1H NMR (400 MHz, CDCl3, rotamers):
;
d
4.30
(d, J¼9.8 Hz, 4/5H), 4.18 (d, J¼9.8 Hz, 1/5H), 3.82e3.74 (m, 1H),
3.62e3.54 (m, 1H), 3.50e3.42 (m, 9/5H), 3.36e3.28 (m, 1/5H),
2.01e1.90 (m, 1H), 1.79 (ddd, J¼14.4, 7.6, 1.6 Hz, 1H), 1.71 (br s, 1H),
4.4.3. (3R,5R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-oxo-5-
phenylpyrrolidine-1-carboxylate (14c). 14c (723 mg, 73%) as a col-
25
orless oil. [
a
]
D
þ66.14 (c 0.92, CHCl3); IR (film): nmax 3357, 2945,
1.50e1.20 (m, 9H), 1.10e0.60 (m, 18H), 0.25e0.00 (m, 6H) ppm; 13
C
2833, 2585, 2519, 2223, 2046, 1782, 1655, 1450, 1417, 1111,
NMR (100 MHz, CDCl3):
d
171.2, 155.8, 78.8, 71.0, 67.0, 55.8, 35.6,
1031 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
7.26e7.23 (m, 5H), 4.81
35.2, 29.7, 28.4, 26.2, 25.9, 18.0, ꢀ4.6, ꢀ4.7 ppm; HRMS (ESI) calcd
(dd, J¼6.2, 9.4 Hz, 1H), 4.39 (dd, J¼7.0, 10.2 Hz, 1H), 2.75e2.65
(m, 1H), 1.88e1.78 (m, 1H), 1.28e1.22 (m, 2H), 1.20e1.15 (m, 7H),
0.90e0.82 (m, 9H), 0.22e0.00 (m, 6H) ppm; 13C NMR (100 MHz,
for [C19H41NO4SiþNaþ]: 398.2703, found: 398.2710.
4.3.11. tert-Butyl (1R,3R)-3-(tert-butyldimethylsilyloxy)-1-cyclopro-
CDCl3): d 173.3,149.2,142.4,128.6,127.6,125.7, 82.9, 70.9, 58.2, 38.3,
pyl-4-hydroxybutyl-carbamate (13m). 13m (1.19 g, 79%) as a color-
29.7, 27.5, 25.6, 18.2, ꢀ4.5, ꢀ5.3 ppm; HRMS (ESI) calcd for
less oil. [
a]
27 ꢀ24.39 (c 0.64, CHCl3); IR (film): nmax 3354, 2945, 2833,
[C21H33NO4SiþNaþ]: 414.2077, found: 414.2078.
D
2598, 2512, 2344, 2226, 2047, 1473, 1449, 1413, 1117, 1029 cmꢀ1; 1H
NMR (400 MHz, CDCl3):
d
3.95e3.85 (m, 1H), 3.61 (dd, J¼5.0, 9.4 Hz,
4.4.4. (3R,5R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-oxo-5-p-
1H), 3.43 (dd, J¼7.0, 9.8 Hz, 1H), 3.27 (d, J¼8.0 Hz, 1H), 2.70e2.62
(m, 1H), 1.92e1.82 (m, 1H), 1.77e1.68 (m, 1H), 1.35e1.22 (m, 9H),
0.97e0.92 (m, 11H), 0.80e0.70 (m, 1H), 0.68e0.60 (m, 1H),
0.60e0.52 (m, 1H), 0.35e0.25 (m, 1H), 0.14e0.12 (m, 3H), 0.12e0.11
tolylpyrrolidine-1-carboxylate (14d). 14d (802 mg, 81%) as a white
solid; mp 94e96 ꢁC. [
a]
24 þ55.44 (c 1.05, CHCl3); IR (film): nmax 3408,
D
3338, 2954, 2928, 2856,1697,1514,1461,1390,1366,1253,1172,1108,
1045, 1010, 838, 808, 777, 739 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
(m, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d
70.3, 67.3, 59.5, 55.9, 42.1,
d
7.20e7.08 (m, 4H), 4.77 (dd, J¼6.2, 9.4 Hz, 1H), 4.37 (dd, J¼7.4,
25.9, 25.8, 22.8,18.6, 5.5, 4.4, ꢀ3.9, ꢀ4.6, ꢀ5.4 ppm; HRMS (ESI) calcd
10.2 Hz, 1H), 2.72e2.60 (m, 1H), 2.33 (s, 3H), 1.85e1.75 (m, 1H),
for [C18H37NO4SiþNaþ]: 382.2390, found: 382.2389.
1.28e1.18 (m, 9H),0.90e0.85 (m, 9H), 0.20e0.05 (m, 6H) ppm; 13C
NMR (100 MHz, CDCl3): d 173.3,149.3,139.4,137.2,129.2,125.7, 82.9,
4.3.12. tert-Butyl (1R,3R)-3-(tert-butyldimethylsilyloxy)-1-
70.9, 57.9, 38.4, 27.6, 25.7, 21.1, 18.2, ꢀ4.5, ꢀ5.3 ppm; HRMS (ESI)
cyclohexyl-4-hydroxybutyl-carbamate (13o). 13o (1.34 g, 87%) as
calcd for [C22H35NO4SiþNaþ]: 428.2233, found: 428.2234.
a colorless oil. [
a
]
25 þ13.76 (c 1.29, CHCl3); IR (film): nmax 3358, 2928,
D
2854, 1686, 1528, 1509, 1450, 1391, 1366, 1251, 1173 cmꢀ1
;
1H NMR
4.4.5. (3R,5R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-oxo-5-
(400 MHz, CDCl3):
d
4.57 (d, J¼9.2 Hz, 1H), 3.85e3.77 (m, 1H),
vinylpyrrolidine-1-carboxylate (14e). 14e (445 mg, 45%) as a color-
3.60e3.40 (m, 3H), 2.15e2.05 (m, 1H), 1.78e1.60 (m, 6H), 1.47e1.37
(m, 11H), 1.27e1.05 (m, 4H), 1.00e0.93 (m, 1H), 0.88 (s, 9H), 0.10
less oil. [
a
]
D
27 þ10.53 (c 1.14, CHCl3); IR (film): nmax 3086, 2956, 2931,
2887, 2858, 1790, 1725, 1648, 1473, 1463, 1423, 1393, 1305, 1156,
(s, 3H), 0.06 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d
155.6, 78.8,
1078 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 5.98e5.85 (m, 1H), 5.28
70.6, 66.7, 52.1, 42.9, 36.4, 28.4, 26.5, 26.3, 25.9,18.0, ꢀ4.6, ꢀ4.8, ppm;
(d, J¼17.2 Hz, 1H), 5.21 (d, J¼10.0 Hz, 1H), 4.45 (dd, J¼7.4, 14.2 Hz,
1H), 4.31 (dd, J¼6.8, 7.6 Hz, 1H), 2.54e2.44 (m, 1H), 1.82e1.72
(m, 1H), 1.56 (s, 9H), 0.97 (s, 9H), 0.28e0.12 (m, 6H) ppm; 13C NMR
HRMS (ESI)calcd for[C21H43NO4SiþNaþ]:402.3040, found:402.3028.
4.4. General procedure for synthesis of 14ael
(100 MHz, CDCl3): d 172.7, 149.8, 138.5, 116.2, 83.1, 70.9, 57.7, 35.1,
28.0, 25.7, 18.2, ꢀ4.6, ꢀ5.3 ppm; HRMS (ESI) calcd for
To a solution of compound 13 (2.44 mmol) in anhydrous DMF
(5 mL) was added CrO3$2Py (3.15 g, 12.22 mmol). After being stirred
for24hatroom temperature, themixturewasdilutedwithwater, and
extracted with EtOAc (30 mLꢂ5). The combined organic layers were
washed with brine, dried, and concentrated. The residue was purified
by flash chromatography on silica gel (PE/EA¼2/1) to give 14ael.
[C17H31NO4SiþNaþ]: 364.1920, found: 364.1919.
4.4.6. (3R,5R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-ethynyl-2-
oxopyrrolidine-1-carboxylate (14f). 14f (563 mg, 57%) as a color-
25
less oil. [
a
]
þ105.35 (c 1.32, CHCl3); IR (film): nmax 3429, 3310,
D
2957, 2931, 2887, 2841, 2858, 1701, 1499, 1392, 1367, 1254, 1170,
1109, 1047, 1007 cmꢀ1 1H NMR (400 MHz, CDCl3, rotamers):
;
4.4.1. (3R,5S)-tert-Butyl 5-benzyl-3-(tert-butyldimethylsilyloxy)-2-
d
4.60e4.52 (m, 9/10H), 4.32 (d, J¼5.2 Hz, 1/10H), 4.23 (t, J¼7.2 Hz,
oxopyrrolidine-1-carboxylate (14a). 14a (574 mg, 58%) as a color-
4/5H), 2.92 (dd, J¼5.2, 17.2 Hz, 1/5H), 2.64e2.53 (m, 4/5H), 2.43
(d, J¼2.0 Hz, 1/5H), 2.42e2.32 (m, 4/5H), 2.10e2.00 (m, 1H),
27
less oil. [
a]
þ48.66 (c 1.00, CHCl3); IR (film): nmax 3338, 2945,
D
2832, 2594, 2517, 2235, 1448, 1408, 1111, 1028 cmꢀ1
;
1H NMR
1.74e1.35 (m, 9H), 0.97e0.75 (m, 9H), 0.20e0.00 (m, 6H) ppm; 13
C
(400 MHz, CDCl3): 7.37e7.28 (m, 2H), 7.26e7.17 (m, 3H),
d
NMR (100 MHz, CDCl3): d 171.5, 149.2, 83.8, 81.8, 72.0, 70.3, 45.3,
4.25e4.12 (m, 2H), 3.45 (dd, J¼3.2, 12.8 Hz, 1H), 2.80 (dd, J¼10.0,
13.2 Hz, 1H), 2.05e1.95 (m, 1H), 1.77e1.70 (m, 1H), 1.65e1.50
(m, 9H), 0.95e0.80 (m, 9H), 0.20e0.00 (m, 6H) ppm; 13C NMR
35.0, 29.6, 27.9, 25.6, 18.1, ꢀ4.6, ꢀ5.3 ppm; HRMS (ESI) calcd for
[C17H29NO4SiþNaþ]: 362.1764, found: 362.1761.
(100 MHz, CDCl3):
d
172.7, 150.1, 137.6, 129.4, 128.6, 126.6, 83.2, 71.5,
4.4.7. (3R,5S)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-methyl-2-
57.6, 41.0, 31.8, 29.7, 28.1, 25.7, 18.2, ꢀ4.6, ꢀ5.3 ppm; HRMS (ESI)
oxopyrrolidine-1-carboxylate (14g). 14g (514 mg, 52%) as a color-
calcd for [C22H35NO4SiþNaþ]: 428.2233, found: 428.2234.
less oil. [
a]
27 þ47.36 (c 1.08, CHCl3); IR (film): nmax 3406, 2955, 2923,
D
2841, 1652, 1014 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
4.25e4.15
4.4.2. (3R,5S)-tert-Butyl 5-allyl-3-(tert-butyldimethylsilyloxy)-2-
oxo-pyrrolidine-1-carboxylate (14b). 14b (336 mg, 34%) as
(m, 1H), 4.05e3.95 (m, 1H), 2.45e2.30 (m, 1H), 1.60e1.45 (m, 10H),
1.45e1.35 (m, 3H), 0.92e0.80 (m, 9H), 0.18e0.00 (m, 6H) ppm; 13
C

4806
Q.-R. Zhou et al. / Tetrahedron 70 (2014) 4799e4808
NMR (100 MHz, CDCl3):
d
172.9, 150.2, 82.9, 71.2, 51.3, 35.7, 28.0,
(6.80 mL, 1 M in Et2O) was slowly added. After being stirred for 3 h
at room temperature, the mixture was quenched with saturated
aqueous solution of NH4Cl and warmed to room temperature. The
resulted mixture was extracted with EtOAc (20 mLꢂ3) and the
combined organic layers were washed with brine, dried, and con-
centrated. The residue was purified by flash chromatography on
silica gel (PE/EA¼2/1) to give 15, 17e19.
25.7, 21.7, 18.1, ꢀ4.6, ꢀ5.3 ppm; HRMS (ESI) calcd for
[C16H31NO4SiþHþ]: 352.1920, found: 352.1917.
4.4.8. (3R,5R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-oxo-5-
vinylpyrrolidine-1-carboxylate (14h). 14h (713 mg, 72%) as a color-
less oil. [
a
]
25 þ10.35 (c 0.91, CHCl3); IR (film): nmax 3433, 2958, 2925,
D
2849, 2102, 1640, 1250, 1172, 1015 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
4.50 (d, J¼8.4 Hz, 1H), 3.87e3.80 (m, 1H), 3.65e3.52 (m, 2H),
4.5.1. tert-Butyl (3R,5S)-3-(tert-butyldimethylsilyloxy)-2-oxo-1-
3.50e3.40 (m, 1H), 1.72e1.60 (m, 1H), 1.45e1.37 (m, 10H), 1.25e1.20
phenyltetradecan-5-ylcarbamate (15). 15 (991 mg, 82%) as a color-
(m, 13H), 0.90e0.80 (m, 12H), 0.10e0.00 (m, 6H) ppm; 13C NMR
less oil. [
a
]
27 þ47.36 (c 1.08, CHCl3); IR (film): nmax 3338, 2944, 2833,
D
(100 MHz, CDCl3):
d
171.2,155.5, 78.9, 70.4, 66.8, 47.9, 39.2, 36.2, 31.9,
2599, 2515, 2232, 2043, 1450, 1415, 1112, 1028 cmꢀ1
;
1H NMR
29.6, 29.5, 29.3, 28.4, 25.9, 22.7, 18.0, 14.1, ꢀ4.5, ꢀ4.8 ppm; HRMS
(400 MHz, CDCl3, rotamers): d 7.39e7.31 (m, 2H), 7.31e7.27 (m, 1H),
(ESI) calcd for [C24H47NO4SiþNaþ]: 464.3172, found: 464.3176.
7.24e7.19 (m, 1H), 4.55 (d, J¼8.4 Hz, 1H), 4.30 (dd, J¼3.0,9.0 Hz, 1H),
3.94 (d, J¼16.8 Hz, 1H), 3.82 (d, J¼16.8 Hz, 1H), 3.76e3.62 (m, 1H),
1.84e1.74 (m, 4/5H), 1.72e1.68 (m, 1/5H), 1.64e1.57 (m, 1H),
1.47e1.42 (m, 9H), 1.32e1.22 (m, 16H), 1.02e0.95 (m, 9H),
0.92e0.85 (m, 3H), 0.19e0.00 (m, 6H) ppm; 13C NMR (100 MHz,
4.4.9. (3R,5R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-isopropyl-
2-oxopyrrolidine-1-carboxylate (14i). 14i (801 mg, 81%) as a white
25
solid; mp 63e64 ꢁC. [
a
]
þ156.27 (c 0.77, CHCl3); IR (film): nmax
D
3348, 2945, 2833, 2600, 2231, 2046, 1774, 1447, 1412, 1108,
CDCl3): d 210.5,155.3,133.9,129.8,128.5,127.0, 78.9, 76.3, 47.8, 44.3,
1031 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
4.26 (dd, J¼6.8, 10.0 Hz,
39.5, 36.1, 31.9, 29.7, 29.6, 29.5, 29.5, 29.3, 28.4, 25.8, 22.7, 18.0, 14.1,
ꢀ4.8, ꢀ5.3 ppm; HRMS (ESI) calcd for [C31H55NO4SiþNaþ]:
556.3798, found: 556.3734.
1H), 3.96e3.88 (m, 1H), 2.60e2.45 (m, 1H), 2.25e2.15 (m, 1H),
1.70e1.57 (m, 1H), 1.58e1.48 (m, 9H), 0.95e0.87 (m, 12H), 0.79
(d, J¼6.8 Hz, 3H), 0.20e0.15 (m, 3H), 0.15e0.10 (m, 3H) ppm; 13C
NMR (100 MHz, CDCl3):
d
173.2, 150.5, 83.0, 70.6, 58.6, 29.7, 28.4,
4.5.2. tert-Butyl (1R,3R)-3-(tert-butyldimethylsilyloxy)-4-oxo-1,5-
28.0, 27.5, 25.8, 18.5, 18.3, 14.7, ꢀ4.5, ꢀ5.2 ppm; HRMS (ESI) calcd
diphenylpentyl-carbamate(17). 17 (791 mg, 64%) as a colorless
25
for [C18H35NO4SiþNaþ]: 380.2233, found: 380.2227.
oil. [
a
]
ꢀ7.98 (c 1.09, CHCl3); IR (film): nmax 3441, 3029, 2928,
D
2856, 1713, 1367, 1310, 1255, 1147, 1088, 1029, 837, 699 cmꢀ1
;
1H
4.4.10. (3R,5R)-tert-Butyl
5-tert-butyl-3-(tert-butyldimethylsily-
NMR (400 MHz, CDCl3, rotamers): 7.47e7.28 (m, 8H), 7.26e7.22
d
loxy)-2-oxopyrrolidine-1-carboxylate (14j). 14j (752 mg, 76%) as
(m, 1H), 7.17e7.07 (m, 1H), 4.70e4.58 (m, 4/5H), 4.55e4.45 (m, 1/
5H), 4.12e4.02 (m, 4/5H), 3.98e3.88 (m, 1/5H), 3.82e3.70 (m, 4/
5H), 3.68e3.58 (m, 1/5H), 3.34 (d, J¼13.6 Hz, 1H), 2.52e2.40 (m, 1/
5H), 2.17 (d, J¼13.6 Hz, 7/10H), 2.07 (dd, J¼4.8,14.0 Hz, 4/5H), 1.58
(br s, 4/5H), 1.45e1.38 (m, 1H), 1.34e1.26 (m, 1H), 1.26e1.18
(m, 1H), 1.16 (s, 6H), 1.05e0.95 (m, 6H), 0.95e0.77 (m, 3H),
a colorless oil. [
a
]
25 þ31.84 (c 0.84, CHCl3); IR (film): nmax 3422, 2955,
D
2925, 2847, 1647, 1371, 1288, 1260, 1157 cmꢀ1
;
1H NMR (400 MHz,
CDCl3, rotamers):
d
4.37e4.31 (m, 1/10H), 4.28 (dd, J¼3.2, 10.0 Hz, 9/
10H), 4.08 (dd, J¼2.8, 9.6 Hz, 1H), 2.43e2.32 (m, 4/5H), 2.23e2.14
(m, 1/5H), 1.80e1.72 (m, 1H), 1.56e1.53 (m, 7H), 1.51e1.48 (m, 2H),
0.95e0.94 (m, 9H), 0.93e0.89 (m, 9H), 0.18e0.11 (m, 6H) ppm; 13C
0.22e0.00 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3):
d 206.0,
NMR (100 MHz, CDCl3):
d
173.4,151.2, 83.1, 82.8, 70.3, 63.0, 36.1, 29.0,
154.9, 141.9, 137.7, 130.9, 129.4, 128.7, 128.4, 128.0, 127.8, 127.1,
126.3, 126.1, 93.2, 80.4, 73.2, 45.3, 41.1, 28.3, 28.0, 26.0, 25.8, 25.7,
18.2, ꢀ4.7, ꢀ4.7 ppm; HRMS (ESI) calcd for [C28H41NO4SiþNaþ]:
506.2703, found: 506.2703.
28.3, 27.9, 27.3, 26.5, 25.7, 18.2, ꢀ4.5, ꢀ5.3 ppm; HRMS (ESI) calcd for
[C19H37NO4SiþNaþ]: 394.2390, found: 394.2392.
4.4.11. (3R,5R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-5-cycloprop-
yl-2-oxopyrrolidine-1-carboxylate (14k). 14i (692 mg, 70%) as a col-
4.5.3. tert-Butyl (3R,5R)-5-(tert-butyldimethylsilyloxy)-2-methyl-6-
25
orless oil. [
a
]
þ43.15 (c 2.00, CHCl3); IR (film): nmax 2955, 2931,
oxo-7-phenylheptan-3-ylcarbamate (18). 18 (1.01 g, 80%) as a color-
D
25
2887, 2857, 1786, 1755, 1724, 1369, 1342, 1301, 1257, 1159, 1082, 843,
less oil. [
a
]
ꢀ26.08 (c 1.35, CHCl3); IR (film): nmax 3356, 2959,
D
781, 745 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
4.18 (dd, J¼5.2, 7.6 Hz,
2930, 2895, 2858, 1697, 1497, 1472, 1390, 1365, 1253, 1172, 1088,
1H), 3.55e3.47 (m, 1H), 2.30e2.18 (m, 1H), 1.72e1.64 (m, 1H),
1.55e1.48 (m, 9H), 1.27e1.17 (m, 1H), 0.90e0.85 (m, 9H), 0.62e0.52
(m, 2H), 0.50e0.40 (m, 1H), 0.23e0.15 (m, 1H), 0.15e0.09 (m, 6H)
1009, 838, 779 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
7.39e7.32
(m, 2H), 7.31e7.27 (m, 1H), 7.24e7.19 (m, 2H), 4.47 (d, J¼9.2 Hz, 1H),
4.25 (dd, J¼2.4, 8.8 Hz, 1H), 3.96 (d, J¼16.4 Hz, 1H), 3.82
(d, J¼16.4 Hz, 1H), 3.65e3.57 (m, 1H), 1.88e1.78 (m, 1H), 1.74e1.66
(m, 1H), 1.48e1.43 (m, 9H), 0.99 (s, 9H), 0.90e0.82 (m, 6H),
ppm; 13C NMR (100 MHz, CDCl3):
d 171.7,149.5, 81.9, 70.1, 58.5, 32.6,
27.0, 24.7, 17.1, 15.2, 4.9, 0.0, ꢀ5.6, ꢀ6.3 ppm; HRMS (ESI) calcd for
[C18H33NO4SiþNaþ]: 378.2077, found: 378.2072.
0.12e0.05 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3):
d 210.8, 155.5,
133.9, 129.8, 128.5, 127.0, 78.9, 76.3, 52.2, 44.4, 36.5, 32.5, 28.4, 28.0,
25.8, 18.1, 18.0, 18.0, 14.2, ꢀ4.8, ꢀ5.3 ppm; HRMS (ESI) calcd for
[C25H43NO4SiþHþ]: 450.3040, found: 450.3033.
4.4.12. (3R,5R)-tert-Butyl-3-(tert-butyldimethylsilyloxy)-5-
cyclohexyl-2-oxopyrrolidine-1-carboxylate (14l). 14l (544 mg, 55%)
25
as a colorless oil. [
a
]
þ55.67 (c 1.66, CHCl3); IR (film): nmax 3346,
D
2945, 2833, 2606, 2517, 2048, 1450, 1417, 1118, 1031 cmꢀ1; H NMR
(400 MHz, CDCl3):
4.5.4. tert-Butyl (1R,3R)-3-(tert-butyldimethylsilyloxy)-1-cyclo-pro-
1
d
4.21 (t, J¼8.0 Hz,1H), 3.87 (dd, J¼7.2,12.4 Hz,1H),
pyl-4-oxo-5-phenyl-pentylcarbamate (19). 19 (491 mg, 39%) as
25
2.24e2.08 (m, 2H), 1.80e1.63 (m, 4H), 1.60e1.45 (m, 11H), 1.27e1.07
(m, 3H),1.05e0.92 (m, 2H), 0.89 (s, 9H), 0.15 (s, 3H), 0.11 (s, 3H) ppm;
a colorless oil. [
a]
ꢀ47.86 (c 1.00, CHCl3); IR (film): nmax 3361,
D
3005, 2955, 2930, 2857, 1716, 1497, 1472, 1391, 1366, 1253, 1172,
1092, 1044, 838, 780, 699 cmꢀ1 1H NMR (400 MHz, CDCl3):
7.38e7.32 (m, 2H), 7.31e7.26 (m, 1H), 7.23e7.19 (m, 2H),
13C NMR (100 MHz, CDCl3):
d
173.2, 150.5, 82.9, 70.8, 58.5, 39.4, 29.2,
;
28.0, 26.5, 26.4, 25.9, 25.7, 25.7, 18.2, ꢀ4.5, ꢀ5.3. ppm; HRMS (ESI)
d
calcd for [C21H39NO4SiþNaþ]: 420.2546, found: 420.2553.
4.67e4.53 (m, 1H), 4.32 (dd, J¼3.6, 8.8 Hz, 1H), 3.94 (d, J¼16.8 Hz,
1H), 3.85 (d, J¼16.8 Hz, 1H), 2.00e1.88 (m, 1H), 1.82e1.70 (m, 1H),
1.46 (s, 9H), 0.99e0.92 (m, 9H), 0.85e0.75 (m, 1H), 0.52e0.38
(m, 3H), 0.25e0.17 (m, 1H), 0.12e0.07 (m, 3H), 0.07e0.04 (m, 3H)
4.5. General procedure for synthesis of 15, 17e19
To a solution of compound 14 (2.27 mmol) in anhydrous Et2O
(12 mL) was cooled to ꢀ78 ꢁC. Then a solution of Grignard reagent
ppm; 13C NMR (100 MHz, CDCl3):
d
210.4, 155.5, 133.9, 129.8, 128.5,
126.9, 79.0, 76.1, 51.5, 44.2, 40.1, 29.7, 28.7, 28.6, 28.4, 28.1, 25.8,

Q.-R. Zhou et al. / Tetrahedron 70 (2014) 4799e4808
4807
25.6, 21.1, 18.0, 17.0, 14.2, 3.0, ꢀ4.8, ꢀ5.2 ppm; HRMS (ESI) calcd for
[C25H41NO4SiþNaþ]: 470.2703, found: 470.2712.
(m, 1H), 2.35 (s, 3H), 2.26 (dd, J¼6.8, 13.6 Hz, 1H), 1.70e1.60 (m, 1H),
1.38e1.22 (m, 2H), 0.90 (s, 9H), 0.67e0.57 (m, 1H), 0.47e0.37
(m, 1H), 0.30e0.20 (m, 1H), 0.06e0.01 (m, 1H), ꢀ0.02 (s, 3H), ꢀ0.09
4.6. General procedure for synthesis of 16, 20e22
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d 140.5, 128.8, 127.9, 125.5,
73.2, 71.1, 70.7, 41.3, 40.3, 33.7, 29.5, 25.9, 20.9, 18.3, 18.0, 5.0, 0.0,
ꢀ4.5, ꢀ5.2 ppm; HRMS (ESI) calcd for [C21H35NOSiþHþ]: 346.2566,
found: 346.2588.
Compound 15 (or 17e19) (0.47 mmol) was dissolved in
CF3COOH (6 mL) and stirred for 1 h, then the mixture was alkal-
ized with 30% aqueous solution of NaOH to pH to 10e12. The
resulted mixture was extracted with CHCl3 (20 mLꢂ5) and the
combined organic layers were washed with brine. The solvent was
dried and concentrated to give crude intermediate. The crude
material along with 10% (wt) Pd/C and 20% (wt) Pd(OH)2/C were
stirred in MeOH (20 mL) under H2 atmosphere for 8 h. The re-
action mixture was then treated with paraformaldehyde (250 mg).
After being stirred for 3 h, the mixture was filtered and purified by
flash chromatography on silica gel (CH2Cl2/CH3OH¼40/1) to give
16, 20e22.
4.7. General procedure for synthesis of ent-5, 23e25
Compound 16 (or 20e22) (0.12 mmol) was dissolved in THF
(1 mL) and stirred for 10 min at 0 ꢁC. Then, a solution of TBAF
(0.2 mL, 1 M in THF) was added in one portion. After being stirred
for overnight, the mixture was diluted with water and extracted
with EtOAc (20 mLꢂ3). The combined organic layers were washed
with brine, dried, and concentrated. The residue was purified by
flash chromatography on silica gel (CH2Cl2/CH3OH¼40/1) to give
(ꢀ)-preussin ent-5, 23e25.
4.6.1. (2R,3R,5S)-2-Benzyl-3-(tert-butyldimethylsilyloxy)-1-methyl-
5-nonylpyrrolidine(16). 16 (119 mg, two steps 59%) as a colorless
4.7.1. (2R,3R,5S)-2-Benzyl-1-methyl-5-nonylpyrrolidin-3-ol((þ)-pre-
24
oil. [
a
]
ꢀ45.99 (c 1.05, CHCl3); IR (film): nmax 3344, 2944, 2833,
ussin ent-5). (þ)-preussin ent-5 (35 mg, 95%) as a pale yellow oil.
D
24
2600, 2512, 2225, 2038, 1455, 1417, 1028 cmꢀ1
;
1H NMR
[
a
]
ꢀ34.71 (c 0.51, CHCl3); IR (film): nmax 3357, 2944, 2833,
D
(400 MHz, CDCl3): 7.30e7.24 (m, 4H), 7.22e7.15 (m, 1H),
d
2598, 2517, 2227, 2048, 1655, 1460, 1449, 1420, 1402, 1113,
4.22e4.12 (m, 1H), 3.09 (dd, J¼8.0, 14.4 Hz, 1H), 2.81 (d, J¼4.0,
14.0 Hz, 1H), 2.57e2.45 (m, 1H), 3.25 (s, 3H), 2.14e2.04 (m, 1H),
1.80e1.68 (m, 1H), 1.50e1.42 (m, 1H), 1.35e1.25 (m, 16H),
0.92e0.87 (m, 12H), 0.03e0.00 (m, 6H) ppm; 13C NMR (100 MHz,
1031 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
7.40e7.29 (m, 4H),
7.26e7.20 (m, 1H), 3.87e3.81 (m, 1H), 2.93 (dd, J¼10.0, 13.2 Hz,
1H), 2.87 (dd, J¼5.0, 13.4 Hz, 1H), 2.38 (s, 3H), 2.34e2.28 (m, 1H),
2.26e2.18 (m, 1H), 2.11e2.01 (m, 1H), 1.78e1.70 (m, 1H), 1.48e1.42
(m, 1H), 1.35e1.26 (m, 16H), 0.92e0.87 (m, 3H) ppm; 13C NMR
CDCl3):
d 140.7, 129.1, 128.1, 125.7, 73.4, 71.2, 66.0, 40.7, 40.4, 34.6,
34.1, 31.9, 30.0, 29.7, 29.6, 29.6, 29.4, 26.7, 26.0, 22.7, 18.2, 14.1,
ꢀ4.3, ꢀ5.0 ppm; HRMS (ESI) calcd for [C27H49NOSiþHþ]:
432.3662, found: 432.3645.
(100 MHz, CDCl3): d 139.4, 129.4, 128.4, 126.1, 73.7, 70.4, 65.9,
39.3, 38.6, 31.9, 31.9, 29.9, 29.7, 29.7, 29.6, 29.4, 29.3, 26.3, 22.7,
14.1 ppm; HRMS (ESI) calcd for [C21H35NOþHþ]: 318.2797, found:
318.2806.
4.6.2. (2R,3R,5R)-2-Benzyl-3-(tert-butyldimethylsilyloxy)-1-methyl-
5-phenylpyrrolidine(20). 20 (108 mg, two steps 55%) as a colorless
4.7.2. (2R,3R,5R)-2-Benzyl-1-methyl-5-phenylpyrrolidin-3-ol
25
25
oil. [
a
]
ꢀ10.19 (c 1.26, CHCl3); IR (film): nmax 3297, 3027, 2955,
(23). 23 (19 mg, 55%) as a pale yellow oil. [
a
]
þ6.98 (c 0.38,
D
D
2928, 2856, 1495, 1455, 1254, 1068, 836, 775, 699 cmꢀ1
;
1H NMR
CHCl3); IR (film): nmax 3375, 3026, 2926, 2375, 1651, 1455,1098, 745,
(400 MHz, CDCl3): 7.44e7.29 (m, 4H), 7.26e7.21 (m, 4H),
d
699 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
7.36e7.26 (m, 5H),
7.20e7.16 (m, 1H), 7.10 (d, J¼6.8 Hz, 1H), 3.78e3.70 (m, 1H), 2.88
(d, J¼6.0 Hz, 1H), 2.84e2.77 (m, 1H), 2.64e2.54 (m, 1H),
2.54e2.46 (m, 1H), 2.41 (s, 3H), 2.25e2.14 (m, 1H), 1.80e1.70
(m, 1H), 1.02e0.95 (m, 9H), 0.12e0.01 (m, 6H) ppm; 13C NMR
7.24e7.16 (m, 4H), 7.10 (d, J¼7.6 Hz, 1H), 3.49e3.42 (m, 1H), 2.89
(dd, J¼6.2, 14.2 Hz, 1H), 2.79e2.75 (m, 1H), 2.74e2.70 (m, 1H),
2.54e2.46 (m, 1H), 2.39 (dd, J¼10.4 Hz, 1H), 2.30 (s, 3H), 1.87e1.77
(m,1H),1.60e1.45 (m,1H) ppm; 13C NMR (100 MHz, CDCl3):
d 142.5,
(100 MHz, CDCl3):
d
142.4, 141.7, 129.2, 129.1, 128.5, 128.3, 128.2,
140.6, 129.0, 128.6, 128.5, 128.4, 128.3, 128.2, 126.1, 125.6, 69.9, 43.2,
40.7, 36.1, 31.9, 31.5, 26.1 ppm; HRMS (ESI) calcd for
[C18H21NOþNHþ3 ]: 284.1889, found: 284.2006.
126.3, 125.8, 125.6, 73.1, 67.7, 43.1, 35.8, 32.4, 30.0, 26.1, 18.2, ꢀ3.9,
ꢀ4.5 ppm; HRMS (ESI) calcd for [C24H35NOSiþNHþ3 ]: 398.2753,
found: 398.2883.
4.7.3. (2R,3R,5R)-2-Benzyl-5-isopropyl-1-methylpyrrolidin-3-
26
4.6.3. (2R,3R,5R)-2-Benzyl-3-(tert-butyldimethylsilyloxy)-5-
ol(24). 24 (20 mg, 61%) as a pale yellow oil. [
a]
ꢀ25.42 (c 0.63,
D
isopropyl-1-methylpyrroli-dine (21). 21 (133 mg, two steps 69%) as
CHCl3); IR (film): nmax 3419, 2957, 2871, 2784, 1495, 1454, 1386,
26
a colorless oil. [
a
]
D
ꢀ13.63 (c 2.03, CHCl3); IR (film): nmax 3370,
1125, 1110, 1030, 700 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
7.34e7.27
2956, 2929, 2894, 2857, 2783, 1463, 1386, 1361, 1253, 1127, 1044,
(m, 4H), 7.25e7.17 (m, 1H), 3.80e3.70 (m, 1H), 2.83 (m, 2H), 2.31
(s, 3H), 2.23e2.15 (m, 1H), 2.00e1.85 (m, 2H), 1.54e1.44 (m, 1H),
972, 837, 775, 742, 698 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
7.30e7.26 (m, 4H), 7.22e7.16 (m, 1H), 4.19 (dd, J¼6.0, 11.6 Hz, 1H),
1.32e1.25 (m, 1H), 0.97e0.92 (m, 1H), 0.92e0.84 (m, 6H) ppm; 13
C
3.01 (dd, J¼7.2, 14.0 Hz, 1H), 2.71 (d, J¼6.0, 14.0 Hz, 1H), 2.58
(dd, J¼6.4, 12.8 Hz, 1H), 2.20e2.14 (m, 1H), 2.13 (s, 3H), 1.95e1.85
(m, 1H), 1.60e1.50 (m, 1H), 0.95e0.91 (m, 11H), 0.91e0.87 (m, 4H),
NMR (100 MHz, CDCl3): d 139.6, 129.5, 128.3, 126.0, 73.7, 70.3, 70.0,
38.4, 33.7, 32.9, 27.8, 20.0, 15.1 ppm; HRMS (ESI) calcd for
[C15H23NOþHþ]: 234.1858, found: 234.1861.
0.06e0.00 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3):
d 141.1, 129.3,
128.0, 125.5, 72.9, 71.1, 70.3, 41.1, 35.1, 34.1, 28.7, 26.0, 25.9, 20.5,
18.2, 16.0, ꢀ4.2, ꢀ5.1 ppm; HRMS (ESI) calcd for [C21H37NOSiþHþ]:
348.2723, found: 348.2749.
4.7.4. (2R,3R,5R)-2-Benzyl-5-cyclopropyl-1-methylpyrrolidin-3-ol
25
(25). 25 (19 mg, 57%) as a pale yellow solid, mp 98e100 ꢁC. [
a]
D
ꢀ36.53 (c 0.79, CHCl3); IR (film): nmax 3334, 3027, 2999, 2559, 2931,
2850, 2768, 1670, 1495, 1454, 1427, 1347, 1198, 1144, 1122, 1030, 929,
4.6.4. (2R,3R,5R)-2-Benzyl-3-(tert-butyldimethylsilyloxy)-5-
748, 701 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 7.32e7.26 (m, 4H),
cyclopropyl-1-methylpyrrolidine(22). 22 (71 mg, two steps 37%) as
7.23e7.17 (m, 1H), 3.85e3.75 (m, 1H), 2.92e2.85 (m, 2H), 2.44
(s, 3H), 2.30e2.20 (m, 2H), 2.15 (d, J¼8.8 Hz, 1H), 1.65e1.55 (m, 1H),
1.45e1.35 (m, 1H), 0.85e0.75 (m, 1H), 0.65e0.55 (m, 1H), 0.45e0.35
(m, 1H), 0.30e0.20 (m, 1H), 0.05e0.00 (m, 1H) ppm; 13C NMR
26
a colorless oil. [
a
]
ꢀ47.69 (c 1.40, CHCl3); IR (film): nmax 3445,
D
2955, 2922, 2851, 2359, 1738, 1464, 1377 cmꢀ1; 1H NMR (400 MHz,
CDCl3): 7.32e7.23 (m, 4H), 7.22e7.15 (m, 1H), 4.19e4.11 (m, 1H),
3.10 (dd, J¼8.4, 14.4 Hz, 1H), 2.83 (dd, J¼4.4, 14.4 Hz, 1H), 2.52e2.42
d
(100 MHz, CDCl3):
d 139.4, 129.4, 128.4, 126.1, 73.7, 70.9, 70.2, 39.9,

4808
Q.-R. Zhou et al. / Tetrahedron 70 (2014) 4799e4808
39.0, 33.5, 15.3, 5.2, 0.0 ppm; HRMS (ESI) calcd for [C15H21NOþHþ]:
A, 2010. (c) Huang, W.; Ye, J.-L.; Zheng, W.; Dong, H.-Q.; Wei, B.-G. J. Org. Chem.
2013, 78, 11229.
9. (a) Liu, R.-C.; Wei, J.-H.; Wei, B.-G.; Lin, G.-Q. Tetrahedron: Asymmetry 2008, 19,
2731; (b) Xarnod, C.; Huang, W.; Ren, R.-G.; Liu, R.-C.; Wei, B.-G. Tetrahedron
2012, 68, 6688.
232.1701, found: 232.1730.
Acknowledgements
10. Evans, J. W.; Ellman, J. A. J. Org. Chem. 2003, 68, 9948.
11. (a) Liu, R.-C.; Huang, W.; Ma, J.-Y.; Wei, B.-G.; Lin, G.-Q. Tetrahedron Lett. 2009,
50, 4046; (b) Wang, X.-L.; Huang, W.-F.; Lei, X.-S.; Wei, B.-G.; Lin, G.-Q. Tetra-
hedron 2011, 67, 4919; (c) Huang, W.-F.; Li, Q.-R.; Chao, L.-M.; Lei, X.-S.; Wei, B.-
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J. Org. Chem. 2013, 78, 10747; (g) Feng, T.; Si, C.-M.; Liu, R.-C.; Fan, X.; Wei, B.-G.
Chin. J. Org. Chem. 2013, 33, 1291.
We thank the National Natural Science Foundation of China
(21272041, 21072034, 20832005), and Key Laboratory of Synthetic
Chemistry of Natural Substances, SIOC of Chinese Academy of Sci-
ences for financial support. The authors also thank Prof. Yu-Lai Hu
for helpful suggestions.
12. (a) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T. Tetrahedron 1992,
Supplementary data
ꢁ
ꢀ
48, 4067; (b) Pospísil, J.; Marko, I. E. Tetrahedron Lett. 2008, 49, 1523; (c) Yakura,
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X.; Yin, B.; Hu, Z.; Liao, C.; Liu, J.; Li, S.; Li, Z.; Nicklaus, M. C.; Zhou, G.; Jiang, S.
Org. Lett. 2010, 12, 1368.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.05.037.
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