A flexible approach to protected (4S,5S)-5-alkyl-1-benzyl-4-benzyloxy-2- pyrrolidinones

Article abstract of DOI:10.1080/00397911.2010.495827

We report in this paper a flexible approach to (4S,5S)-5-alkyl-1-benzyl-4- benzyloxy-2-pyrrolidinones 7 starting from the known 5-alkyl-1-benzyl-4- benzyloxy-5-hydroxy-2-pyrrolidinones 6. The method is based on TMSCl-mediated reductive dehydroxylation of 6 with Zn(BH₄)₂, which allows the synthesis of a variety of 2-pyrrolidinones 7 in 48-75% yields with cis=trans diastereoselectivities ranging from 58:42 to 90:10. Copyright

Full text of DOI:10.1080/00397911.2010.495827

Synthetic Communications1, 41: 2036–2043, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.495827
A FLEXIBLE APPROACH TO PROTECTED
(4S,5S)-5-ALKYL-1-BENZYL-4-BENZYLOXY-2-
PYRROLIDINONES
Zhen-Hua Xiao,1 Liang-Xian Liu,1,2 Cong Liu,1 and
Pei-Qiang Huang1
1Department of Chemistry and Key Laboratory for Chemical Biology of
Fujian Province, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen, Fujian, China
2Department of Chemistry and Biology, Ganan Teachers’ College,
Ganzhou, Jiangxi, China
GRAPHICAL ABSTRACT
Abstract We report in this paper a flexible approach to (4S,5S)-5-alkyl-1-benzyl-
4-benzyloxy-2-pyrrolidinones 7 starting from the known 5-alkyl-1-benzyl-4-benzyloxy-5-
hydroxy-2-pyrrolidinones 6. The method is based on TMSCl-mediated reductive
dehydroxylation of 6 with Zn(BH4)2, which allows the synthesis of a variety of 2-pyrrolidi-
nones 7 in 48-75% yields with cis=trans diastereoselectivities ranging from 58:42 to 90:10.
Keywords Diastereoselective reduction; 2-pyrrolidinone; Zn(BH4)2
Five-membered azacyclic systems are widely distributed in nature. Among them,
cis-2-alkyl-3-hydroxypyrrolidine is a structural feature found in many biologically
active hydroxylated pyrrolidines, pyrrolizidines, indolizidines, and azasugars.[1]
For example, imino-L-lyxitol (1) is a potent inhibitor of a-L-fucosidase;[2] anisomycin
(2) was isolated from Streptomyces griseolus and S. roseochromogenes[3] in the early
fifties and has become an important tool in molecular biology;[4] and (ꢀ)-platynecine
(3) was first isolated from Senecio platyphyllusis and is the necine base portion of
several pyrrolizidine alkaloids such as platyphyllin, neoplatyphilline, bulgarsenine,
Received August 9, 2009.
Address correspondence to Liang-Xian Liu and Pei-Qiang Huang, Department of Chemistry and
Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, Fujian 361005, P.R. China. E-mail: lxliu@xmu.edu.cn;
pqhuang@xmu.edu.cn
2036

DIASTEREOSELECTIVITE REDUCTIVE DEHYDROXYLATION
2037
Figure 1. Some cis-2-alkyl-3-hydroxypyrrolidine-containing alkaloids.
nemorensine, and mulgediifoline[5] (Fig. 1). A number of methods have been
developed for the synthesis of this class of alkaloids.[6]
Starting from multifunctional (S or R)-malimide 5, we have previously
established an asymmetric reductive alkylation approach to trans-5-alkyl-4-
benzyloxy-2-pyrroli-dinones 4, which are ready precursors of pyrrolidines and
b-hydroxy c-amino acids (Scheme 1).[7] The utility of this approach has been demon-
strated by the asymmetric synthesis of several bioactive pyrrolidines, b-hydroxy
c-amino acids, and natural products.[8] To extend the scope of this methodology,
we were engaged in the development of approaches to cis-(4S,5S)-5-alkyl-4-
hydroxy-2-pyrrolidinones 7 starting from 5-alkyl-1-benzyl-4-benzyloxy-5-hydroxy-
2-pyrrolidinones 6, which resulted in a highly cis-diastereoselective two-step
approach.[9] We now report direct access to cis-lactams 7 via a new reductive
dehydroxylation of 6.[7,8]
In our previous work, the BF3 ꢁ OEt2-mediated reductive dehydroxylation of
diastereomeric mixture of a-hydroxylactams 6 has been shown to give excellent
trans-diastereoselectivity.[7,8] To obtained the corresponding cis-diastereomers 7,
we elected to use zinc borohydride as a reducing agent[10] and chlorotrimethylsilane
as an additive,[11] because both Zn(BH4)2
and the Zn(BH4)2=TMSCl system[12b]
[12a]
have been used for the reductive cleavage of hemi-azaketal[12a] and acatals,[12b] as
well as the higher homologs of a-hydroxylactam 6.[13] In the event when a CH2Cl2
Scheme 1. Diastereodivergent approach to (4S,5R)- and (4S,5R)-5-alkyl-4-hydroxy-2-pyrrolidinones.

2038
Z.-H. XIAO ET AL.
Table 1. Reductive dehydroxylation of hemi-azaketals 6a–i
Entry
R in 6
Yield of 7a
cis=trans ratiob
1
2
3
4
5
6
7
8
9
CH3 (6a)
C2H5 (6b)
7a (70)
7b (66)
7c (75)
7d (58)
7e (48)
7f (61)
7g (73)
7h (70)
7i (68)
84:16
90:10c
81:19c
71:29
58:42c
74:26
67:33
64:36
66:34
n-C3H7 (6c)
n-C4H9 (6d)
i-C4H9 (6e)
n-C5H11 (6f)
n-C8H17 (6g)
n-C12H25 (6h)
n-C16H33 (6i)
aIsolated yield.
bRatio determined by column chromatographyic separation.
cDetermined by 1H NMR analysis.
solution of hemi-azaketal 6a (1 equiv.) was treated with TMSCl (2.5 equiv.) and
Zn(BH4)2 (5 equiv.), lactam 7a was obtained with the cis=trans diastereoselectivity
1
of 84:16 cis=trans diastereoselectivity according to H NMR analysis. The reductive
dehydroxylation of hemi-azaketals 6b–i were investigated, and the results are
summarized in Table 1.
As can be seen from Table 1, modest cis-selectivities were obtained for all
hemi-azaketals tested, and mediocre cis-selectivity was obtained in the case where
hemi-azaketals 6 had a bulkier C-5 alkyl group (e.g., Table 1, entry 5). The cis=trans
stereochemistry of compounds 7 was assigned according to the observed vicinal
coupling constants[14,7] (J4,5 ¼ 6.3 Hz for cis-7a and J4,5 ¼ 2.5 Hz for trans-4a;
J4,5 ¼ 5.8 Hz for cis-7d and J4,5 ¼ 1.5 Hz for trans-4d; J4,5 ¼ 5.8 Hz for cis-7e and
J4,5 ¼ 2.7 Hz for trans-4e).
Starting from a trans-enriched diastereomeric mixture of a-hydroxylactam 6,[15]
cis-diastereomer 7 was obtained in modest selectivity, which is in accordance with an
N-acyliminium ion-based mechanism. It was envisioned that in the presence of
TMSCl, the reaction between the hydroxy group of 6 and TMSCl led to the formation
of an N-acyliminium intermediate 8 (Scheme 1). The chelation between the C-4 oxygen
atom and TMSCl directed the hydride to approach the C-5 carbon from the opposite
side of the bulky C-4 benzyloxy substituent, thus producing the cis-isomer.
In summary, we demonstrated that the diastereoselection for the reductive
dehydroxylation of a-hydroxylactam 6 can be controlled by changing the reagent
system. A flexible approach to cis-5-alkyl-1-benzyl-4-benzyloxy-2-pyrrolidinones
was established. Although the diastereoselectivities are only modest for most cases,
the ready separation of diastereomers in most cases makes this method of synthetic
value. As such, this method is complementary, in part, to our previously established
trans-diastereoselective method.
EXPERIMENTAL
Melting points were determined on a Yanaco MP-500 micromelting-point
apparatus and were uncorrected. Infrared (IR) spectra were measured with a Nicolet

DIASTEREOSELECTIVITE REDUCTIVE DEHYDROXYLATION
2039
Avatar 330 Fourier transform (FT)–IR spectrometer using film KBr pellet technique.
1H NMR spectra were recorded in CDCl3 on a Bruker 400 or a Varian unity þ500
spectrometer with tetramethylsilane (TMS) as an internal standard. Chemical shifts
are expressed in d (ppm) units downfield from TMS. Mass spectra were recorded
with Bruker Dalton Esquire 3000 plus LC-MS apparatus. Optical rotations were
measured with a Perkin-Elmer 341 automatic polarimeter. High-resolution mass
spectra (HRMS) were recorded on a Bruker APEX II FT mass spectrometer.
Elemental analysis were carried out on a Perkin-Elmer 240B instrument. Flash-
column chromatography was carried out with silica gel (300–400 mesh).
Tetrahydrofuran (THF) was distilled over sodium. Dichloromethane (DCM) was
distilled over P2O5.
General Procedure for the Reductive Dehydroxylation of a-
Hydroxylactams 6 with TMSCl/Zn(BH4)2
A solution of TMSCl (2.5 equiv.) in anhydrous CH2Cl2 (1 mL) and a solution
of Zn(BH4)2 (5 equiv.) in anhydrous Et2O (0.25 M) were added dropwise and succes-
sively to a cooled (ꢀ78 ꢂC) solution of hemi-azaketal 6 (1 equiv.) in anhydrous
CH2Cl2 (0.1 M) under N2. After stirring at ꢀ78 ꢂC for 2 h, the mixture was allowed
to warm slowly to room temperature and stirred at room temperature overnight. The
reaction was quenched with saturated aqueous NH4Cl, and the resultant mixture
was extracted with CH2Cl2. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (eluent: EtOAc=
PE ¼ 1:4) to yield lactam 7.
(4S,5S)-1-Benzyl-4-benzyloxy-5-methyl-2-pyrrolidinone (7a)
25
Yield: 70%, cis=trans ¼ 84:16. Colorless oil. ½aꢃD ꢀ 28:5 (c 1.0, CHCl3) [lit.[7b]
22
½aꢃD ꢀ 28:1 (c 0.5, CHCl3)]. IR (film) nmax: 2960, 2930, 1692, 1454, 1420, 1095cmꢀ1
.
1H NMR (500 MHz, CDCl3): d 1.18 (d, J ¼ 6.4 Hz, 3H, CH3), 2.58 (dd, J ¼ 16.9,
6.4 Hz, 1H, H-3), 2.61 (dd, J ¼ 16.9, 6.4 Hz, 1H, H-3), 3.65 (dq, J ¼ 6.3, 6.4 Hz,
1H, H-5), 3.92 (d, J ¼ 15.1 Hz, NCH2), 4.10 (ddd, J ¼ 6.4, 6.4, 6.3 Hz, 1H, H-4),
4.45 (d, J ¼ 11.8 Hz, 1H, OCH2), 4.55 (d, J ¼ 11.8 Hz, 1H, OCH2), 5.05 (d,
J ¼ 15.1 Hz, 1H, NCH2), 7.20–7.38 (m, 10H, Ph-H). 13C NMR (125 MHz, CDCl3):
d 12.41, 36.37, 43.65 (NCH2), 55.87 (OCH2), 71.23, 73.39, 127.36 (2C), 127.69
=
(2C), 127.82 (2C), 128.33 (2C), 128.54 (2C), 136.45, 137.52, 171.86 (C O). MS
(ESI): 296 (M þ Hþ, 100). Anal. calcd. for C19H21NO2: C, 77.26; H, 7.17; N, 4.74.
Found C, 77.34; H, 7.32; N, 4.71.
(4S,5S)-1-Benzyl-4-benzyloxy-5-ethyl-2-pyrrolidinone (7b)
Yield: 66%, cis=trans ¼ 90:10. White solid, mp 78–79 ꢂC (EtOAc=PE ¼ 1=2).
1H NMR (400 MHz, CDCl3): d 0.88 (t, J ¼ 7.4 Hz, 3H, CH3), 1.64–1.82 (m, 2H,
CH2), 2.57 (dd, J ¼ 16.8, 6.4 Hz, 1H, H-3), 2.63 (dd, J ¼ 16.8, 4.5 Hz, 1H, H-3),
3.48 (ddd, J ¼ 6.0, 4.0, 2.9 Hz, 1H, H-5), 3.97 (d, J ¼ 15.1 Hz, NCH2), 4.13 (ddd,
25
½aꢃD þ 12:7 (c 0.6, CHCl3). IR (film) nmax: 2968, 2932, 1693, 1454, 1421, 1068 cmꢀ1
.

2040
Z.-H. XIAO ET AL.
J ¼ 6.4, 6.0, 4.5 Hz, 1H, H-4), 4.02 (d, J ¼ 11.7 Hz, 1H, OCH2), 4.57 (d, J ¼ 11.7 Hz,
OCH2), 5.02 (d, J ¼ 15.1 Hz, 1H, NCH2), 7.20–7.40 (m, 10H, Ph-H). 13C NMR
(100 MHz, CDCl3): d 9.65, 19.92, 37.08, 43.96 (NCH2), 61.62 (OCH2), 71.31,
72.79, 127.41 (2C), 127.52 (2C), 127.79 (2C), 128.41 (2C), 128.61 (2C), 136.59,
þ
=
137.62, 172.84 (C O). MS (ESI): 310 (M þ H , 100). Anal. calcd. for C20H23NO2:
C, 77.67; H, 7.44; N, 4.53. Found: C, 77.37; H, 7.64; N, 4.62.
(4S,5S)-1-Benzyl-4-benzyloxy-5-(n-propyl)-2-pyrrolidinone (7c)
Yield: 75%, cis=trans ¼ 81:19, inseparable by column chromatography. IR
1
(film) nmax: 2968, 2932, 1693, 1454, 1421, 1068 cmꢀ1. H NMR (400 MHz, CDCl3):
d 0.88 (t, J ¼ 7.2 Hz, 3H, CH3), 1.15–1.38 (m, 2H), 1.53–1.63 (m, 1H), 1.67–1.80 (m,
1H), 2.55 (dd, J ¼ 16.8, 6.2 Hz, 1H, H-3), 2.62 (dd, J ¼ 16.8, 4.4 Hz, 1H, H-3), 3.51
(ddd, J ¼ 5.9, 4.0, 2.0 Hz, 1H, H-5), 3.97 (d, J ¼ 15.1 Hz, NCH2), 4.10 (ddd,
J ¼ 6.2, 5.9, 4.4 Hz, 1H, H-4), 4.41 (d, J ¼ 11.7 Hz, 1H, OCH2), 4.57 (d, J ¼ 11.7 Hz,
OCH2), 5.03 (d, J ¼ 15.1 Hz, 1H, NCH2), 7.20–7.40 (m, 10H, Ph-H). 13C NMR
(100 MHz, CDCl3): d14.31, 18.64, 29.10, 37.04, 44.04 (NCH2), 60.45 (OCH2),
71.32, 73.03, 127.40 (2C), 127.54 (2C), 127.82 (2Cþ), 128.44 (2C), 128.61 (2C),
=
136.66, 137.68, 172.80 (C O). MS (ESI): 324 (M þ H , 100). HRESIMS calcd. for
[C21H25NO2þH]þ: 324.1964; found: 324.1966.
(4S,5S)-1-Benzyl-4-benzyloxy-5-(n-butyl)-2-pyrrolidinone (7d)
25
Yield: 58%, cis=trans ¼ 71:29. Wax solid. ½aꢃD þ 13:1 (c 1.2, CHCl3). IR (film)
1
n
max: 2955, 2930, 1693, 1454, 1420, 1094 cmꢀ1. H NMR (400 MHz, CDCl3): d 0.85
(t, J ¼ 6.7 Hz, 3H, CH3), 1.12–1.30 (m, 4H), 1.62 (m, 1H), 1.75 (m, 1H), 2.55 (dd,
J ¼ 16.8, 6.4 Hz, 1H, H-3), 2.63 (dd, J ¼ 16.8, 4.5 Hz, 1H, H-3), 3.50 (ddd, J ¼ 5.8,
3.9, 1.9 Hz, 1H, H-5), 3.97 (d, J ¼ 15.2 Hz, 1H, NCH2), 4.11 (ddd, J ¼ 6.4, 5.8,
4.5 Hz, 1H, H-4), 4.39 (d, J ¼ 11.7 Hz, 1H, OCH2), 4.57 (d, J ¼ 11.7 Hz, OCH2),
5.04 (d, J ¼ 15.2 Hz, 1H, NCH2), 7.20–7.40 (m, 10H, Ph-H). 13C NMR (100 MHz,
CDCl3): d 13.95, 22.91, 26.59, 27.38, 37.08, 44.04 (NCH2), 60.62 (OCH2), 71.30,
72.95, 127.45 (2C), 127.62 (2C), 127.86 (2C), 128.44 (2C), 128.65 (2C), 136.66,
þ
=
137.66, 172.85 (C O). MS (ESI): 338 (M þ H , 100). Anal. calcd. for C22H27NO2:
C, 78.34; H, 8.01; N, 4.15. Found: C, 78.01; H, 8.23; N, 4.24.
(4S,5S)-1-Benzyl-4-benzyloxy-5-(i-butyl)-2-pyrrolidinone (7e)
Yield: 48%, cis=trans ¼ 58:42, inseparable by column chromatography. IR
1
(film) nmax: 2955, 2929, 1692, 1454, 1419, 1095 cmꢀ1. H NMR (400 MHz, CDCl3):
d0.80 (d, J ¼ 6.6 Hz, 3H, CH3), 0.90 (d, J ¼ 6.6 Hz, 3H, CH3), 1.30–1.44 (m, 1H),
1.52–1.66 (m, 1H), 1.75–1.85 (m, 1H), 2.54 (dd, J ¼ 16.6, 6.0 Hz, 1H, H-3), 2.64
(dd, J ¼ 16.6, 3.8 Hz, 1H, H-3), 3.54 (ddd, J ¼ 5.8, 4.4, 1.0 Hz, 1H, H-5), 3.93 (d,
J ¼ 15.2 Hz, 1H, NCH2), 4.08 (ddd, J ¼ 6.0, 5.8, 3.8 Hz, 1H, H-4), 4.38 (d,
J ¼ 11.7 Hz, 1H, OCH2), 4.56 (d, J ¼ 11.7 Hz, 1H, OCH2), 5.06 (d, J ¼ 15.1 Hz,
NCH2), 7.20–7.40 (m, 10H, Ph-H). 13C NMR (100 MHz, CDCl3): d21.80, 23.68,
24.68, 35.32, 36.96, 43.97 (NCH2), 61.42 (OCH2), 71.13, 73.06, 127.41 (2C),
=
127.53 (2C), 127.83 (2C), 128.38 (2C), 128.58 (2C), 136.57, 137.59, 172.86 (C O).

DIASTEREOSELECTIVITE REDUCTIVE DEHYDROXYLATION
2041
MS (ESI): 338 (M þ Hþ, 100). HRESIMS calcd. for [C22H27NO2 þ H]þ: 338.2120;
found: 338.2125.
(4S,5S)-1-Benzyl-4-benzyloxy-5-(n-pentyl)-2-pyrrolidinone (7f)
25
Yield: 61%, cis=trans ¼ 74:26. Wax solid. ½aꢃD þ 14:3 (c 1.8, CHCl3). IR (film)
1
n
max: 2929, 2858, 1686, 1453, 1420, 1096 cmꢀ1. H NMR (400 MHz, CDCl3): d 0.86
(t, J ¼ 6.4 Hz, 3H, CH3), 1.08–1.27 (m, 6H), 1.48–1.58 (m, 1H), 1.62–1.75 (m, 1H),
2.49 (dd, J ¼ 16.8, 6.4 Hz, 1H, H-3), 2.55 (dd, J ¼ 16.8, 4.6 Hz, 1H, H-3), 3.43 (ddd,
J ¼ 5.8, 3.9, 1.9 Hz, 1H, H-5), 3.90 (d, J ¼ 15.1 Hz, 1H, NCH2), 4.03 (ddd, J ¼ 6.4,
5.8, 4.6 Hz, 1H, H-4), 4.33 (d, J ¼ 11.7 Hz, 1H, OCH2), 4.50 (d, J ¼ 11.7 Hz, 1H,
OCH2), 4.95 (d, J ¼ 15.1 Hz, 1H, NCH2), 7.10–7.35 (m, 10H, Ph-H). 13C NMR
(100 MHz, CDCl3): d 13.95, 22.44, 24.87, 26.80, 31.95, 37.02, 44.00 (NCH2), 60.59
(OCH2), 71.26, 72.92, 127.39 (2C), 127.57 (2C), 127.82 (2þC), 128.38 (2C), 128.60
=
(2C), 136.62, 137.61, 172.77 (C O). MS (ESI): 352 (M þ H , 100). Anal. calcd. for
C23H29NO2: C, 78.59; H, 8.32; N, 3.99. Found: C, 78.32; H, 8.53; N, 3.91.
(4S,5S)-1-Benzyl-4-benzyloxy-5-(n-octyl)-2-pyrrolidinone (7g)
Yield: 73%, cis=trans ¼ 67:33. White solid, mp 41–42 ꢂC (EtOAc=PE ¼ 1=3).
25
½aꢃD þ 11:0 (c 2.0, CHCl3). IR (film) nmax: 2926, 2855, 1694, 1454, 1420, 1099 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 0.88 (t, J ¼ 6.9 Hz, 3H, CH3), 1.18–1.31 (m, 12H),
1.55–1.68 (m, 1H), 1.70–1.78 (m, 1H), 2.54 (dd, J ¼ 16.8, 6.2 Hz, 1H, H-3), 2.63
(dd, J ¼ 16.8, 4.4 Hz, 1H, H-3), 3.50 (ddd, J ¼ 5.9, 3.9, 1.5 Hz, 1H, H-5), 3.96 (d,
J ¼ 15.1 Hz, 1H, NCH2), 4.09 (ddd, J ¼ 6.2, 5.9, 4.4 Hz, 1H, H-4), 4.39 (d,
J ¼ 11.7 Hz, 1H, OCH2), 4.57 (d, J ¼ 11.7 Hz, OCH2), 5.02 (d, J ¼ 15.1 Hz, NCH2),
7.20–7.40 (m, 10H, Ph-H). 13C NMR (100 MHz, CDCl3): d 14.08, 22.60, 25.18,
26.81, 29.16, 29.36, 29.76, 31.80, 37.02, 44.00 (NCH2), 60.58 (OCH2), 71.26, 72.92,
127.39 (2C), 127.56 (2C), 127.82 (2C), þ128.38 (2C), 128.60 (2C), 136.61, 137.61,
=
172.78 (C O). MS (ESI): 394 (M þ H , 100). Anal. calcd. for C26H35NO2: C,
79.39; H, 8.91; N, 3.56. Found: C, 79.26; H, 9.12; N, 3.64.
(4S,5S)-1-Benzyl-4-benzyloxy-5-(n-heptadecanyl)-2-pyrrolidinone
(7h)
Yield: 70%, cis=trans ¼ 64:36. White solid, mp 47–48 ꢂC (EtOAc=PE ¼ 1=3).
25
½aꢃD þ 21:2 (c 1.0, CHCl3). IR (film) nmax: 2924, 2853, 1696, 1454, 1420, 1102 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 0.88 (t, J ¼ 6.8 Hz, 3H, CH3), 1.15–1.33 (m, 20H),
1.55–1.65 (m, 1H), 1.70–1.80 (m, 1H), 2.59 (dd, J ¼ 17.0, 6.2 Hz, 1H, H-3), 2.66
(dd, J ¼ 17.0, 4.1 Hz, 1H, H-3), 3.52 (ddd, J ¼ 5.6, 3.9, 1.5 Hz, 1H, H-5), 3.98 (d,
J ¼ 15.1 Hz, 1H, NCH2), 4.11 (ddd, J ¼ 6.2, 5.6, 4.1 Hz, 1H, H-4), 4.39 (d,
J ¼ 11.6 Hz, OCH2), 4.57 (d, J ¼ 11.6 Hz, OCH2), 5.03 (d, J ¼ 15.1 Hz, 1H, NCH2),
7.16–7.38 (m, 10H, Ph-H). 13C NMR (100 MHz, CDCl3): d 14.10, 22.67, 25.16,
26.66, 29.33, 29.40, 29.52 (2C), 29.60, 29.63, 29.74, 31.90, 36.95, 44.19 (NCH2),
61.00 (OCH2), 71.29, 72.76, 127.56 (2C), 127.61 (2C), 127.82 (2C)þ, 128.42 (2C),
=
128.69 (2C), 136.15, 137.46, 173.64 (C O). MS (ESI): 450 (M þ H , 100). Anal.
calcd. for C30H43NO2: C, 80.18; H, 9.58; N, 3.12. Found: C, 79.92; H, 9.97; N, 3.17.

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Z.-H. XIAO ET AL.
(4S,5S)-1-Benzyl-4-benzyloxy-5-(n-hexadecyl)-2-pyrrolidinone (7i)
Yield: 68%, cis=trans ¼ 66:34. White solid, mp 52–53 ꢂC (EtOAc=PE ¼ 1=3).
25
½aꢃD þ 14:9 (c 0.9, CHCl3). IR (film) nmax: 2923, 2852, 1696, 1454, 1419, 1098 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 0.88 (t, J ¼ 6.6 Hz, 3H, CH3), 1.16–1.35 (m, 28H),
1.55–1.65 (m, 1H), 1.68–1.78 (m, 1H), 2.55 (dd, J ¼ 16.8, 6.3 Hz, 1H, H-3), 2.62
(dd, J ¼ 16.8, 4.5 Hz, 1H, H-3), 3.50 (ddd, J ¼ 5.7, 4.7, 1.5 Hz, 1H, H-5), 3.95 (d,
J ¼ 15.2 Hz, 1H, NCH2), 4.10 (dd, J ¼ 6.3, 5.7, 4.5 Hz, 1H, H-4), 4.40 (d, J ¼ 11.7 Hz,
1H, OCH2), 4.57 (d, J ¼ 11.7 Hz, 1H, OCH2), 5.12 (d, J ¼ 15.2 Hz, 1H, NCH2), 7.18–
7.38 (m, 10H, Ph-H). 13C NMR (100 MHz, CDCl3): d 14.13, 22.70, 25.24, 26.86,
29.38, 29.46, 29.57 (6C), 29.68, 29.72, 29.82, 31.94, 37.06, 44.06 (NCH2), 60.65
(OCH2), 71.31, 72.97, 127.44, 127.61(2C), 127.82 (2C), 127þ.87, 128.43 (2C), 128.65
=
(2C), 136.66, 137.66, 172.85 (C O). MS (ESI): 506 (M þ H , 100). Anal. calcd. for
C34H51NO2: C, 80.79; H, 10.10; N, 2.77. Found: C, 80.40; H, 10.42; N, 2.66.
ACKNOWLEDGMENTS
The authors are grateful to the National Science Foundation (NSF) of China
(Grant No. 20772099) and National Fund for Fostering Talents of Basic Science
(NFFTBS) (No. J0630429) for financial support.
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