A new approach to 3-hydroxyprolinol derivatives by samarium diiodide-mediated reductive coupling of chiral nitrone with carbonyl compounds

Article abstract of DOI:10.1039/b906224f

A flexible diastereoselective approach to trans-(3S)-hydroxyprolinol derivatives is described, which is based on the samarium diiodide-mediated reductive coupling of the chiral 1-pyrroline N-oxide (nitrone)(S)-10 with carbonyl compounds. The reductive hyd

Full text of DOI:10.1039/b906224f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A new approach to 3-hydroxyprolinol derivatives by samarium
diiodide-mediated reductive coupling of chiral nitrone with
carbonyl compounds†
Shao-Feng Wu, Xiao Zheng,* Yuan-Ping Ruan and Pei-Qiang Huang*
Received 30th March 2009, Accepted 27th April 2009
First published as an Advance Article on the web 2nd June 2009
DOI: 10.1039/b906224f
A flexible diastereoselective approach to trans-(3S)-hydroxyprolinol derivatives is described, which is
based on the samarium diiodide-mediated reductive coupling of the chiral 1-pyrroline N-oxide
(nitrone)(S)-10 with carbonyl compounds. The reductive hydroxyalkylation of nitrone 10 with ketones
and aromatic aldehydes is highly diastereoselective in establishing the C-2 chiral center of the
pyrrolidine ring.
Introduction
Prolinol is the key structural feature of many azasugars (e.g. 1 and
2 in Fig. 1) and organocatalysts (e.g. 3a,b in Fig. 1). Azasugars
(also known as iminosugars) are polyhydroxylated alkaloids with
either five or six-membered ring structures.1 Many azasugars
exhibit potent inhibitory activity toward carbohydrate-processing
enzymes,1 that make them promising both for the treatment
Fig. 1 Structure of prolinol-containing azasugars and organocatalysts.
of metabolite disorder-associated diseases, and as invaluable
molecular tools for the study of the mechanism of action of
carbohydrate-processing enzymes. For example, Miglitol2 and
Zavesca3 (Miglustat) are in clinical use as drugs for the treatment
of Type II diabetes and Gaucher’s disease, respectively, and MBI-
3253 (celgosivir) a derivative of castanospermine, is in Phase II
clinical trials for the treatment of patients with chronic HCV.4
The synthesis of azasugars, their stereoisomers, and analogues
has attracted considerable attention, and a number of methods
have been developed.1,5
Prolinol derivatives (e.g. 3a and 3b in Fig. 1) are structurally
related, but less hydroxylated molecules, which are gaining pop-
ularity as versatile organocatalysts for a number of asymmetric
reactions.6,7 The rapid development of organocatalysis as a
promising field in organic chemistry calls for the development
of novel organocatalysts. On the basis of these considerations, we
were interested in the synthesis of heterocycles of generic structure
A. It was considered that such molecules, combining in a molecule
both hydrophilic and lipophilic groups, would be beneficial for
both inhibitory activity and asymmetric catalytic profile.
Scheme 1 Three possible approaches for the synthesis of b-hydroxy-
prolinol derivatives.
For a flexible synthesis of molecules of type A, although a
number of methods can be envisioned,8 such as that shown
in path A9 (Scheme 1), a disconnection at the C1–C1¢ bond
(Path B) is quite attractive for its flexibility in the synthesis
of diversely substituted prolinols. However, the execution of
such a strategy is challenging, because it involves the realiza-
tion of synthon C, which is either prone to b-elimination (for
O-protected derivatives),10 or gives the wrong regioselectivity (in
the deprotonation of 4).11 Recently, we have developed direct12
and indirect13 as well as synthetic equivalent-based14 approaches
to realize synthon C. Among these approaches, the SmI2-mediated
method12 is straightforward, because it allows direct access to
differently substituted pyrrolidines in one step.
The widespread application of nitrones15–19 as versatile elec-
trophiles over the last thirty years led us to consider them as suit-
able components for the synthesis of hydroxylated prolinol deriva-
tives of type A. A survey of the literature showed that while chiral
non-racemic cyclic nitrones15 have served as versatile building
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: pqhuang@
xmu.edu.cn; Fax: 86-592-2186400
† Electronic supplementary information (ESI) available: NMR spectra of
6, 7, 8, 10, 11, 12a–l, 13, 14. See DOI: 10.1039/b906224f
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Table 1 Optimization of the reductive coupling reaction
Entry
Mol. equiv. of acetophenone
Proton source (eq)
Equiv. of SmI2
T (◦C)
Time (h)
Yield (%)a
d.r.b
1
2
3
4
5
6
1.5
1.5
1.5
1.1
1.1
3
—
3
3
3
3
3
6.5
-78
-78
-78
-50
-20
-78
4
4
4
3
4
1.5
48
50
64
59
36
84
59:41
62:38
71:29
72:28
60:40
79:21
t-BuOH (2)
H2O (8)
H2O (8)
H2O (8)
H2O (78)
a Isolated yields. b Ratio determined by 1H NMR.
blocks, the methods used for the carbon–carbon bond formation
at the N a-position were limited to 1,3-dipolar cycloadditions,16
nucleophilic additions,17 and SmI2-induced nitrones coupling
with activated olefins.18g–j In 2002, Py, Valle´e and co-workers
reported the first SmI2-mediated19 coupling of achiral alicyclic
nitrones with aldehydes.20 While our work was in progress, Py
and co-workers reported the SmI2-mediated coupling of carbonyl
compounds with achiral pyrrolidine nitrone.21 We now report
the first asymmetric coupling22 of chiral non-racemic pyrroline
N-oxides D with aldehydes/ketones, which allows a flexible and
high-yielding access to hydroxylated prolinol derivatives of type A
(Scheme 1).
As the first phase of our investigation, and in combination
with our interest in the development of malic acid-based synthetic
methodology,23 nitrone (S)-10 was selected as the starting point
for our study, which is available from (S)-malic acid. The
hitherto unknown nitrone15,24 (S)-10 was synthesized as shown in
Scheme 2. Diethyl L-malate 5 was converted to bis-mesylate 8 by
O-benzylation (BnBr, Ag2O, EtOAc, r.t.), lithium aluminium
hydride reduction (LAH, THF, refl.), and bis-mesylation (MsCl,
NEt3, CH2Cl2, r.t.). In the presence of triethylamine, treatment of
bis-mesylate 8 with hydroxylamine hydrochloride at reflux gave the
O-benzyl-N-hydroxy-3-pyrrolidinol 9, which upon oxidation with
freshly prepared manganese dioxide25a in dichloromethane gave
the desired nitrone (S)-10 and its regioisomer (S)-11 in 88:12 ratio
with a combined yield of 79% over two steps. Noteworthy is that
acceptable yield and regioselectivity were obtained with MnO2,25a–c
which replaced the commonly used highly toxic oxidant HgO.24
The structural assignment was made on the basis of the coupling
24a,c
=
pattern of the HC N
proton in the 1H-NMR spectra (d 6.87,
quintet, J = 1.6 Hz for 10, and d 6.85, broad multiplet for 11).
The nitrone 10 exhibited reasonable stability and could be stored
for several weeks at -20 ◦C under an inert atmosphere.
With the desired nitrone (S)-10 in hand, we turned our attention
to investigate its reductive coupling with carbonyl compounds.
Initial attempts to couple nitrone 10 with n-butanal by Py and
Valle´e’s protocol20 gave the desired coupling product in only
32% yield, along with some unreacted starting material. The
observation of a higher reactivity of acetophenone in the coupling
reaction led us to select it for the optimization of the reaction.
Thus treatment of acetophenone with nitrone 10 at -78 ◦C for
2 h gave the desired product 12a as a diastereomeric mixture in
a 59:41 ratio with a 48% combined yield (Table 1, entry 1). In
view of the well documented beneficial effects of proton sources
such as alcohols19–22,26,27 and water19–22,28 as promoters for the SmI2-
mediated reactions, we then tested their effects on the reaction. The
results summarized in Table 1 showed that addition of 2.0 molar
equiv. of t-butanol (Table 1, entry 2) or 8.0 equiv. of water (Table 1,
entry 3) could speed up the coupling reaction, but the yields were
not significantly improved. Higher reaction temperatures led to
lower yields (Table 1, entries 3–5). After extensive studies, it was
found that when 78 molar equiv. of water, 6.5 molar equiv. of SmI2
and 3.0 molar equiv. of acetophenone were used, the coupling with
nitrone (S)-10 produced the desired product 12a in a significantly
improved yield of 84%. Moreover, the diastereoselectivity was also
improved to 79:21 (Table 1, entry 6).
Under the optimized conditions, the coupling reaction of the
nitrone (S)-10 with other carbonyl compounds was investigated,
and the results are summarized in Table 2. As can be seen from
Table 2, the reductive hydroxyalkylation of 10 with symmetric
ketone (benzophenone) gave only one diastereomer 12b (Table 2,
entry 2); and when unsymmetrical ketones or aromatic aldehydes
were used, only two diastereomers were obtained in each case
(Table 2, entries 1, 3–9); the coupling with aliphatic aldehydes
produced a total of four diastereomers in each case (Table 2,
Scheme 2 Synthesis of the chiral nitrone 10.
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Table 2 The reductive coupling of nitrone 10 with carbonyl compounds
Entry
Carbonyl compounds
Time (h)
Product (% yield)a
d.r.b
1
2
3
acetophenone
benzophenone
2,3-dihydroinden-1-one
benzaldehyde
4-methoxybenzaldehyde
piperonal
2-chlorobenzaldehyde
4-chlorobenzaldehyde
2,4-dichlorobenzaldehyde
butyraldehyde
isobutyraldehyde
hexanal
1.5
1.2
1.2
1.2
1.5
1
1.2
1.3
1.2
1.2
1.5
0.8
12a (84)
12b (83)
12c (91)
12d (93)
12e (95)c
12f (74)
12g (72)
12h (95)
12i (93)
12j (80)
12k (88)
12l (88)
79:21
—
72:28
61:39
62:38
61:39
67:33
63:37
4
5c
6
7
8
9
10
11
12
61:39
43:36:11:10
45:36:19
40:35:10:15
a Isolated yields, based on nitrone 10. b Ratio determined by 1H NMR. c 31% of 13 was obtained based on the starting 4-methoxybenzaldehyde.
entries 10–12). These results clearly indicate that the reductive a-
hydroxyalkylation of 10 with ketones and aromatic aldehydes was
highly diastereoselective in establishing the C-2 stereocenter of the
pyrrolidine ring, and the diastereo-isomerism arose from the newly
formed exocyclic chiral carbinol center; while the reaction with
Fig. 3 Structure of the pinacol coupling product 13.
aliphatic aldehydes gave low diastereoselectivities at the two newly
formed stereocenters. The stereochemistry of the product was
determined as 2,3-trans on the basis of 2D NOESY experiments
undertaken on the major diastereomers of 12a and 12c (Fig. 2).
The J2,3 of 12a (2.3 Hz) is also consistent with the pyrrolidines that
possess a 2,3-trans stereochemical relationship.29 The stereochem-
istry of the exocyclic chiral center was not determined. The same
diastereoselection was assumed to be retained for benzophenone
and aromatic aldehydes. For aliphatic aldehydes (entries 10–12,
Scheme 3 Cleavage of the N–O bond.
Table 2), obviously it is different.
Conclusions
To summarize, we demonstrated that in the presence of a large
excess of water, the samarium diiodide-mediated chemoselective
reductive coupling of optically active pyrrolidine nitrone 10 with
aldehydes/ketones underwent a smooth reaction to give the cor-
responding coupling products 12a–12l in good to excellent yields.
This proves that nitrone D is an effective synthetic equivalent of
synthon C, and thus paves a flexible approach to enantio-enriched
hydroxylated prolinol derivatives as exhibited by the synthesis of
prolinol derivative 14.
Fig. 2 NOE correlations on the major diastereomers of 12a and 12c.
Experimental
Regarding the mechanism of the reductive coupling, Py and
Valle´e proposed an aminoxyl radical-based mechanism in which
a ketyl radical was excluded as an intermediate.20 In our case,
General
the observation of pinacol coupling products such as 13 (Fig. 3)
suggested that the ketyl radical might be involved in the reaction.
As a demonstration of the suitability of the method for the
Melting points were determined on a Yanaco MP-500 micro
melting point apparatus and were uncorrected. Infrared spectra
were measured with a Nicolet Avatar 360 FT-IR spectrometer
using film KBr pellet techniques. 1H NMR spectra were recorded
in CDCl3 on a Bruker 400 spectrometer with tetramethylsilane as
an internal standard. Chemical shifts are expressed ind (ppm) units
downfield from TMS. 13C NMR spectra were determined at
synthesis of prolinol derivatives, the coupling product 12b was
18j,21,30,31
treated with an excess of SmI2
at -78 ◦C for 1 h, then
allowed to warm up and was stirred at rt overnight. The pyrrolidine
14 was obtained in 77% yield (Scheme 3).
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100 MHz. Mass spectra were recorded on a Bruker Dalton ESquire
3000 plus liquid chromatography-mass spectrum (direct injection).
HRMS spectra were recorded on a Shimadzu LCMS-IT-TOF
apparatus. Optical rotations were measured with a Perkin-Elmer
341 automatic polarimeter. Silica gel (300–400 mesh) was used for
flash column chromatography, eluting (unless otherwise stated)
with an ethyl acetate/petroleum ether (PE) (60–90 ◦C) mixture.
Ether and THF were distilled over sodium benzophenone ketyl
under N2. Dichloromethane was distilled over calcium hydride
under N2. Water used as the additive in the coupling reactions was
doubly distilled and deaerated with argon for 24 h prior to use. Sm
was purchased from Yuelong New Materials Co. Ltd. (China).
to 0 ◦C and treated with saturated aqueous NH4Cl (14 mL). The
two phases were separated and the aqueous phase extracted with
CH2Cl2 (100 mL). The combined organic phases were washed
with brine (5 mL), dried over Na2SO4, filtered and concentrated in
vacuum. The residue was purified by column chromatography on
silica gel (eluent: EtOAc: PE = 2: 3) to give compound 8 (2.81 g,
92%) as a colorless oil. Rf 0.42 (EtOAc: PE = 3: 1); [a]20 -42.4
D
(c 3.0 in CHCl3); nmax/cm-1: 1455, 1352, 1174, 1125, 1059, 1027;
dH 7.34–7.21 (5H, m, Ph-H), 4.63 (1H, d, J = 11.3 Hz, PhCH2),
4.49 (1H, d, J = 11.3 Hz, PhCH2), 4.35–4.21, 4.17–4.10 (4H, 2
m, -CH2OMs), 3.84–3.77 (1H, m, -CHOBn), 2.94 (3H, s, -CH3),
2.88 (3H, s, -CH3), 2.01–1.87 (2H, m, -OCHCH2CH2-); dC 137.3,
128.5 (2C), 128.1 (3C), 72.7, 72.4, 69.8, 65.9, 37.5, 37.2, 31.3; m/z
(ESI) 375 (M + Na+, 100%), 391 (M + K+, 40); Found: C, 44.07;
H, 5.32. Calc. for C13H20O7S2: C, 44.30; H, 5.72%.
(S)-Diethyl 2-benzyloxysuccinate (6). To a suspension of di-
ethyl (S)-malate 5 (2.15 g, 11.3 mmol) and silver oxide (7.90 g,
34.1 mmol) in 30 mL of EtOAc was added benzyl bromide
(2.70 mL, 22.6 mmol). The mixture was stirred at dark for two days
at rt. The resulting mixture was filtered through Celite and
concentrated in vacuo. Short column chromatography purification
afforded diethyl (S)-2-benzyloxysuccinate 632 (2.22 g, 70%). Rf
(S)-3-Benzyloxy-1-pyrroline N-oxide (10) and (S)-4-benzyloxy-
1-pyrroline N-oxide (11). A suspension of compound 8 (1.14 g,
3.3 mmol) and hydroxylamine hydrochloride (993 mg, 14.3 mmol)
in Et3N (17 mL) was heated at reflux for 6 h under N2 atmosphere.
The solvent was then evaporated and the resulting yellow solid
was washed thoroughly with diethyl ether. Ethereal extracts were
concentrated to give the crude N-hydroxypyrrolidine 9, which was
used in the next step without further purification.
To a CH2Cl2 (11 mL) solution of the crude N-hydroxypyrro-
lidine 9 was added portionwise active manganese dioxide (390 mg,
3.9 mmol) at 0 ◦C and under a N2 atmosphere. The suspension was
stirred at rt overnight. The resultant mixture was filtered through
Celite and concentrated under reduced pressure. Chromatography
purification of the residue on silica gel (eluent: ethyl acetate: EtOH,
5: 1) yielded two regioisomeric nitrones 10 and 11 in 88:12 ratio
(combined yield: 79%).
0.31 (EtOAc: PE = 1: 10); colorless oil; [a]20 -59.9 (c 6.8 in
D
CHCl3); nmax/cm-1: 1738, 1454, 1373, 1274, 1176, 1123 and 1028;
dH 7.38–7.27 (5H, m, Ph-H), 4.77 (1H, d, J = 11.4 Hz, PhCH2),
4.54 (1H, d, J = 11.4 Hz, PhCH2), 4.39 (1H, dd, J = 5.1, 7.8 Hz,
-CHOBn), 4.27–4.19 (2H, m, CH3CH2O-), 4.19–4.11 (2H, m,
CH3CH2O-), 2.85–2.72 (2H, m, -OCHCH2CO-), 1.30, 1.24 (6H,
2t, J = 7.15, 7.15 Hz, CH3CH2O-); dC 171.4, 170.1, 137.3, 128.3
(2C), 128.1 (2C), 127.9, 74.6, 73.0, 61.2, 60.9, 38.1, 14.1, 14.1; m/z
(ESI) 303 (M + Na+, 100%), 281 (M + H+, 34); Found: C, 64.35;
H, 7.38. Calc. for C15H20O5: C, 64.27; H, 7.19%.
(S)-2-(Benzyloxy)butane-1,4-diol (7). A THF solution (45 mL)
of diester 6 (6.18 g, 22.1 mmol) was added dropwise to a suspension
of LiAlH4 (1.98 g, 52 mmol) in THF (20 mL) under a N2
atmosphere. The white suspension was vigorously stirred and
(S)-10 (major isomer). 431 mg, yield: 70%; Rf 0.23 (EtOAc);
colorless oil; [a]20 -97.6 (c 2.7 in CHCl3); nmax/cm-1: 1582, 1455,
D
1359, 1257, 1089, 1070, 1044, 1028; dH 7.33–7.22 (5H, m, Ph-H),
6.87 (1H, quintet, J = 1.6 Hz, H-2), 4.72–4.66 (1H, m, -CHOBn),
4.51 (1H, d, J = 11.6 Hz, PhCH2), 4.46 (1H, d, J = 11.6 Hz,
PhCH2), 4.18–4.03 (1H, m, H-5), 3.85–3.74 (1H, m, H-5), 2.54–
2.41 (1H, m, H-4), 2.24–2.12 (1H, m, H-4); dC 137.2, 133.5, 128.6
(2C), 128.1, 127.8 (2C), 78.2, 71.5, 61.3, 27.6; m/z (ESI) 214
(M + Na+, 100%), 192 (M + H+, 72); Found: C, 69.29; H, 7.07; N,
7.38. Calc. for C11H13NO2: C, 69.09; H, 6.85; N, 7.32%.
(S)-11 (minor isomer). 59 mg, yield: 9%; Rf 0.05 (EtOAc);
colorless oil; nmax/cm-1: 1592, 1453, 1357, 1270, 1228, 1206, 1159,
1089, 1028; dH 7.40–7.28 (m, 5H, Ph-H), 6.87–6.82 (br m, 1H,
H-2), 4.54–4.51 (m, 2H, PhCH2), 4.45–4.37 (m, 1H, -CHOBn),
4.16–4.08 (m, 1H, H-5), 4.02–3.95 (m, 1H, H-5), 3.05–2.95 (m,
1H, H-4), 2.85–2.76 (m, 1H, H-4); dC 136.8, 132.8, 128.5 (2C),
128.0, 127.7 (2C), 72.1, 71.1, 67.6, 36.4; m/z (ESI) 214 (M + Na+,
100%), 192 (M + H+, 75).
◦
refluxed for 5 h. The mixture was cooled to 0 C, and quenched
by successive dropwise addition of H2O (2 mL), 10% NaOH
solution (4 mL) and H2O (6 mL). After diluting with ethanol
(60 mL) the mixture was refluxed for 3 h. The suspension was
filtered through Celite and washed with ethanol several times.
The combined organic phases were dried over Na2SO4, filtered
and concentrated in vacuum. The residue was purified by column
chromatography on silica gel (eluent: EtOAc: PE, 2: 1) to give the
known diol 7 (3.620 g, 84%) as a colorless oil. Rf 0.38 (EtOAc:
PE = 2: 1); [a]20 -15.6 (c 2.0 in CHCl3) {lit.33a +15.0 (c 1.0 in
D
CHCl3) for (R)-enantiomer}; [a]20 -41.7 (c 1.6 in ethanol) (lit.33b
D
-37.9); nmax/cm-1: 3382, 3031, 2933, 2878, 1454, 1400, 1350, 1208,
1055; dH 7.38–7.25 (5H, m, Ph-H), 4.59 (1H, d, J = 11.6 Hz,
PhCH2), 4.55 (1H, d, J = 11.6 Hz, PhCH2), 3.77–3.62 (4H, m,
-CH2OH), 3.58–3.48 (1H, m, -CHOBn), 3.07–2.96 (2H, br, OH),
1.89–1.68 (2H, m, -OCHCH2CH2-); dC 138.1, 128.4 (2C), 127.8,
127.8 (2C), 77.7, 71.5, 63.7, 59.2, 33.9; m/z (ESI) 219 (M + Na+,
100%), 197 (M + H+, 10); Found: C, 67.18; H, 7.99. Calc. for
C11H16O3: C, 67.32; H, 8.22%.
General procedure for the SmI2 mediated a-hydroxyalkylation of
nitrone 10. To a slurry of Sm powder (flame dried under Ar
atmosphere, 826 mg, 5.5 mol) in THF (50 mL) was added I2
(1.270 g, 5.0 mmol) at rt, and the mixture was stirred for 2 h
at 45 ◦C to give a SmI2 (0.1 M in THF) reagent as a dark blue
solution.18h
To a stirring and carefully deoxygenated solution of nitrone 10
(95 mg, 0.50 mmol) and a carbonyl compound (1.50 mmol) in
THF (10 mL) was added H2O (0.70 mL, 39 mmol) under an Ar
(S)-2-(Benzyloxy)-1,4-bis(methanesulfonyloxy)butane (8). To
a cooled (0 ◦C) CH2Cl2 (12 mL) solution of compound 7
(1.70 g, 8.7 mmol) and Et3N (7.5 mL, 52.0 mmol) was added
dropwise methanesulfonyl chloride (2.9 mL, 37.0 mmol) under a
N2 atmosphere. The mixture was stirred at rt for 7 h, then cooled
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atmosphere. The mixture was cooled to -78 ◦C, to which was
added a freshly prepared THF solution of SmI2 (0.1 mol·L-1,
32 mL, 3.2 mmol). After the reaction was judged to be completed
by TLC, saturated aqueous solutions of Na2S2O3 (30 mL) and
NaHCO3 (40 mL) were added successively. The yellow mixture
was extracted with EtOAc (3 ¥ 40 mL), and the combined organic
layers were washed with brine, dried over Na2SO4 and filtered.
After concentration in vacuum, the residue was purified by flash
chromatography on silica gel to yield the coupling product 12.
diastereomers in 72:28 ratio (determined by H NMR, dH 3.80-
3.50) (eluent: EtOAc: PE = 1: 4; combined yield: 91%). Major
isomer: 106 mg, yield: 66%; Rf 0.21 (EtOAc: PE = 1: 4); colorless
1
wax; [a]20 53.0 (c 1.93 in CHCl3); nmax/cm-1: 3383, 3028, 2939,
D
2854, 1677, 1605, 1454, 1355, 1206, 1093, 1062, 1028; dH 7.43 (1H,
d, J = 7.4 Hz, Ph-H), 7.26–7.10 (8H, m, Ph-H), 4.30 (1H, d, J =
11.7 Hz, PhCH2), 4.20 (1H, d, J = 11.7 Hz, PhCH2), 3.79–3.73
(1H, m, H-3), 3.30 (1H, d, J = 3.3 Hz, H-2), 3.26–3.19 (1H, m, H-
5), 3.08 (1H, ddd, J = 12.5, 9.2, 6.4 Hz, H-5), 2.88 (1H, ddd, J =
16.3, 8.6, 3.9 Hz, PhCH2CH2), 2.75–2.65 (1H, m, PhCH2CH2),
2.51 (1H, ddd, J = 13.1, 8.6, 3.9 Hz, PhCH2CH2), 2.04–1.94 (1H,
m, PhCH2CH2), 1.85 (1H, dd, J = 13.4, 6.4 Hz, H-4), 1.69–1.57
(1H, m, H-4); dC 144.9, 143.9, 138.0, 128.4, 128.3 (2C), 127.7
(2C), 127.6, 126.4, 124.8, 124.6, 84.2, 79.6, 78.8, 70.5, 56.6, 38.2,
29.4, 28.4; m/z (ESI) 348 (M + Na+, 100%), 326 (M + H+, 45);
HRMS (ESI) calcd for C20H24NO3 [M + H+]: 326.1756; found:
326.1745.
(2S,3S)-3-Benzyloxy-2-(1-hydroxy-1-phenylethyl)-N-hydroxy-
pyrrolidine (12a). Following the general procedure, the SmI2-
mediated a-hydroxyalkylations of 10 with acetophenone gave
12a as a mixture of two separable diastereomers in 79:21 ratio
1
(determined by H NMR, dH 4.45, 3.81) (eluent: EtOAc: PE =
1: 8; combined yield: 84%). Major isomer: 103 mg, yield: 66%;
Rf 0.34 (EtOAc: PE = 1: 4); colorless wax; [a]20 5.44 (c 0.84 in
D
CHCl3); nmax/cm-1: 3229, 2925, 2853, 1728, 1598, 1462, 1447, 1119;
dH 7.45–7.42 (2H, m, Ph-H), 7.31–7.26 (2H, m, Ph-H), 7.22–7.13
(4H, m, Ph-H), 6.91–6.88 (2H, m, Ph-H), 3.81 (1H, d, J = 11.5 Hz,
PhCH2), 3.71 (1H, d, J = 11.5 Hz, PhCH2), 3.54 (1H, dd, J =
5.6, 2.3 Hz, H-3), 3.31 (1H, d, J = 2.3 Hz, H-2), 3.32–3.25 (1H,
m, H-5), 3.23–3.14 (1H, m, H-5), 1.76 (1H, dd, J = 13.2, 5.6 Hz,
H-4), 1.64–1.53 (1H, m, H-4), 1.59 (3H, s, CH3); dC 145.2, 138.1,
128.1 (2C), 128.1 (2C), 127.6 (2C), 127.3, 126.7, 125.2 (2C), 82.2,
79.4, 74.5, 70.5, 57.5, 29.6, 28.9; m/z (ESI) 336 (M + Na+, 100%),
314 (M + H+, 96); Found: C, 72.88; H, 7.74; N, 4.56. Calc. for
C19H23NO3: C, 72.82; H, 7.40; N, 4.47%.
Minor isomer: 41 mg, yield: 25%; Rf 0.16 (EtOAc: PE = 1:
4); colorless wax; [a]20 1.35 (c 4.9 in CHCl3); nmax/cm-1: 3348,
D
3029, 2929, 2854, 1679, 1604, 1454, 1358, 1204, 1093, 1060, 1028;
dH 7.41–7.38 (1H, m, Ph-H), 7.22–7.14 (6H, m, Ph-H), 7.06–7.03
(2H, m, Ph-H), 4.17 (1H, d, J = 11.6 Hz, PhCH2), 4.04 (1H, d,
J = 11.6 Hz, PhCH2), 3.64–3.58 (1H, m, H-3), 3.33 (1H, d, J =
3.1 Hz, H-2), 3.24–3.30 (1H, m, H-5), 3.11 (1H, ddd, J = 12.1, 6.4,
5.6 Hz, H-5), 2.95 (1H, ddd, J = 16.1, 9.2, 7.1 Hz, PhCH2CH2),
2.79–2.68 (1H, m, PhCH2CH2), 2.32–2.23 (1H, m, PhCH2CH2),
2.13–2.03 (1H, m, PhCH2CH2), 1.88 (1H, dd, J = 13.7, 6.4 Hz,
H-4), 1.80–1.69 (1H, m, H-4); dC 145.7, 143.2, 137.9, 128.6, 128.3
(2C), 127.6 (2C), 127.5, 126.8, 125.2, 123.7, 84.7, 80.7, 79.1, 70.8,
56.6, 36.7, 29.7, 28.5; m/z (ESI) 348 (M + Na+, 100%), 326
(M + H+, 35).
Minor isomer: 27 mg, yield: 18%; Rf 0.37 (EtOAc: PE = 1: 4);
colorless wax; [a]20D 46.3 (c 1.82 in CHCl3); nmax/cm-1: 3229, 2925,
2852, 1670, 1601, 1494, 1447, 1093; dH 7.42 (2H, d, J = 7.4 Hz,
Ph-H), 7.30–7.15 (8H, m, Ph-H), 4.45 (1H, d, J = 11.5 Hz,
PhCH2), 4.35 (1H, d, J = 11.5 Hz, PhCH2), 4.12–4.05 (1H, m,
H-3), 3.37 (1H, d, J = 2.5 Hz, H-2), 3.23–3.13 (1H, m, H-5), 3.04
(1H, ddd, J = 12.6, 9.6, 6.4 Hz, H-5), 1.88 (1H, dd, J = 13.5,
6.4 Hz, H-4), 1.76–1.66 (1H, m, H-4), 1.46 (3H, s, CH3); dC 147.2,
138.1, 128.4 (2C), 128.2 (2C), 127.8 (2C), 127.7, 126.7, 125.1 (2C),
82.3, 78.9, 74.2, 71.0, 56.2, 29.7, 28.1; m/z (ESI) 336 (M + Na+,
100%), 314 (M + H+, 84).
(2R,3S)-3-Benzyloxy-2-(hydroxy-phenyl-methyl)-N -hydroxy-
pyrrolidine (12d). Following the general procedure, the SmI2
mediated a-hydroxyalkylations of 10 with benzaldehyde gave 12d
as a mixture of two separable diastereomers in 61:39 (by 1H NMR,
PhCH, 5.10, 4.69) ratio (eluent: EtOAc: PE = 1: 3; combined
yield: 93%). Major isomer: 84 mg, yield: 57%; Rf 0.46 (EtOAc:
PE = 1 : 2); colorless wax; [a]20D 24.0 (c 1.38 in CHCl3); nmax/cm-1:
3395, 3030, 2930, 2862, 1604, 1496, 1452, 1400, 1064; dH 7.40–7.35
(2H, d, J = 7.5 Hz, Ph-H), 7.32–7.27 (2H, t, J = 7.9 Hz, Ph-H),
7.25–7.17 (1H, m, Ph-H), 7.14–7.10 (3H, m, Ph-H), 6.80–6.76 (2H,
m, Ph-H), 5.10 (1H, d, J = 2.4 Hz, PhCH), 3.89 (1H, dd, J = 5.1,
4.1 Hz, H-3), 3.84 (1H, d, J = 11.4 Hz, PhCH2), 3.73 (1H, d, J =
11.4 Hz, PhCH2), 3.24 (1H, dd, J = 8.6, 7.1 Hz, H-5), 3.18 (1H,
dd, J = 4.1, 2.4 Hz, H-2), 3.10 (1H, ddd, J = 12.3, 8.6, 7.1 Hz,
H-5), 1.93–1.86 (1H, m, H-4), 1.85–1.74 (1H, m, H-4); dC 140.6,
137.9, 128.4 (2C), 128.1 (2C), 127.5 (2C), 127.4, 127.3, 125.8 (2C),
80.4, 75.8, 70.6, 70.5, 56.3, 28.9; m/z (ESI) 322 (M + Na+, 100%),
300 (M + H+, 78); Found: C, 72.12; H, 6.81; N, 4.60. Calc. for
C18H21NO3: C, 72.22; H, 7.07; N, 4.68%.
Minor isomer: 54 mg, yield: 36%; Rf 0.28 (EtOAc: PE = 1: 2);
colorless wax; [a]20D 53.9 (c 0.93 in CHCl3); nmax/cm-1: 3354, 3030,
2925, 2858, 1633, 1495, 1454, 1399, 1060; dH 7.44–7.13 (8H, m,
Ph-H), 6.92–6.88 (2H, m, Ph-H), 4.69 (1H, d, J = 8.6 Hz, PhCH),
4.03 (1H, d, J = 11.5 Hz, PhCH2), 3.93 (1H, d, J = 11.5 Hz,
PhCH2), 3.73–3.66 (1H, m, H-3), 3.39 (1H, dd, J = 8.6, 4.0 Hz,
H-2), 3.31–3.24 (1H, m, H-5), 3.24–3.15 (1H, m, H-5), 2.02–1.85
(2H, m, H-4); dC 141.3, 137.7, 128.5 (2C), 128.2 (2C), 128.0, 127.6
(2S,3S)-3-Benzyloxy-2-(diphenylhydroxymethyl)-N -hydroxy-
pyrrolidine (12b). Following the general procedure, the SmI2
mediated a-hydroxyalkylations of 10 with benzophenone gave 12b
as a single diastereomer (eluent: EtOAc: PE = 1: 6; 155 mg, yield:
83%). Colorless wax. Rf 0.24 (EtOAc: PE = 1: 6); [a]20 76.1
D
(c 0.93 in CHCl3); nmax/cm-1: 3415, 3060, 2935, 1598, 1493, 1449,
1353, 1060; dH 7.55–7.48 (4H, m, Ph-H), 7.27–7.07 (11H, m, Ph-
H), 4.19 (1H, br d, J = 2.3 Hz, H-3), 4.14 (1H, d, J = 11.1 Hz,
PhCH2), 3.90 (1H, d, J = 11.1 Hz, PhCH2), 3.77 (1H, br s, H-2),
3.21–3.14 (2H, m, H-5), 1.88–1.81 (1H, m, H-4), 1.68–1.55 (1H,
m, H-4); dC 146.4, 144.4, 138.1, 128.3 (2C), 128.2 (2C), 128.2
(2C), 127.8 (2C), 127.6, 126.8, 126.7, 125.9 (2C), 125.8 (2C), 81.1,
80.6, 77.9, 71.1, 56.3, 28.0; m/z (ESI) 398 (M + Na+, 100%), 376
(M + H+, 61); Found: C, 76.55; H, 6.60; N, 3.89. Calc. for
C24H25NO3: C, 76.77; H, 6.71; N, 3.73%.
(2S,3S)-3-Benzyloxy-2-(1-hydroxy-2,3-dihydro-1H-inden-1-yl)-
N-hydroxypyrrolidine (12c). Following the general procedure,
the SmI2 mediated a-hydroxyalkylations of 10 with 2,3-
dihydroinden-1-one gave 12c as a mixture of two separable
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(2C), 127.5, 127.1 (2C), 80.0, 79.4, 75.2, 71.0, 56.7, 29.1; m/z (ESI)
5.4, 1.4 Hz, H-2), 3.22–3.08 (2H, m, H-5), 1.97–1.78 (2H, m, H-4);
dC 147.8, 147.3, 137.7, 135.2, 128.2 (2C), 127.5 (2C), 127.5, 120.6,
108.0, 107.6, 101.0, 79.9, 79.5, 75.1, 71.1, 56.7, 29.0; m/z (ESI)
366 (M + Na+, 100%), 344 (M + H+, 71).
322 (M + Na+, 100%), 300 (M + H+, 88).
(2R,3S)-3-Benzyloxy-2-[hydroxy-(4-methoxyphenyl)methyl]-N-
hydroxypyrrolidine (12e). Following the general procedure,
the SmI2 mediated a-hydroxyalkylations of 10 with 4-
methoxybenzaldehyde gave 12e as a mixture of two separable
(2R,3S)-3-Benzyloxy-2-[(2-chlorophenyl)hydroxymethyl]-N-hy-
droxypyrrolidine (12g). Following the general procedure, the
SmI2 mediated a-hydroxyalkylations of 10 with 2-chlorobenzal-
dehyde gave 12g as a mixture of two separable diastereomers
1
diastereomers in 62:38 ratio (determined by H NMR, dH 3.93,
4.06) (eluent: EtOAc: PE = 1: 1; combined yield: 95%). Major
1
isomer: 96 mg, yield: 59%; Rf 0.39 (EtOAc: PE = 2: 1); colorless
in 67:33 ratio (determined by H NMR, dH 5.44, 5.16) (eluent:
wax; [a]20 30.9 (c 0.99 in CHCl3); nmax/cm-1: 3345, 2924, 2854,
EtOAc: PE = 1: 4; combined yield: 72%). Major isomer: 80 mg,
D
1611, 1513, 1452, 1363, 1173, 1029; dH 7.29–7.27 (2H, m, Ph-H),
7.15–7.12 (3H, m, Ph-H), 6.85–6.81 (4H, m, Ph-H), 5.01 (1H, d,
J = 2.8 Hz, PhCH), 3.93 (1H, d, J = 11.5 Hz, PhCH2), 3.88 (1H,
dd, J = 6.7, 3.9 Hz, H-3), 3.82 (1H, d, J = 11.5 Hz, PhCH2), 3.73
(3H, s, CH3), 3.32–3.28 (1H, m, H-5), 3.20 (1H, dd, J = 3.9, 3.1 Hz,
H-3), 3.06–3.11 (1H, m, H-5), 1.81 (1H, dd, J = 13.5, 6.5 Hz, H-4),
1.77–1.67 (2H, m, H-4); dC 158.8, 138.0, 132.7, 128.1 (2C), 127.5
(2C), 127.4, 127.0 (2C), 113.7 (2C), 80.2, 76.0, 70.7, 70.4, 56.3,
55.3, 28.8; m/z (ESI) 330 (M + H+, 100%), 352 (M + Na+, 41).
Minor isomer: 59 mg, yield: 36%; Rf 0.30 (EtOAc: PE = 2 : 1);
colorless wax; [a]20D 58.3 (c 1.16 in CHCl3); nmax/cm-1: 3332, 2925,
2855, 1612, 1514, 1455, 1356, 1176, 1029; dH 7.25 (2H, d, J =
8.7 Hz, Ph-H), 7.16 (3H, dd, J = 5.0, 1.8 Hz, Ph-H), 6.92–6.87
(2H, m, Ph-H), 6.84–6.79 (2H, m, Ph-H), 4.53 (1H, d, J = 8.1 Hz,
PhCH), 4.06 (1H, d, J = 11.5 Hz, PhCH2), 3.95 (1H, d, J =
11.5 Hz, PhCH2), 3.74 (3H, s, CH3), 3.66–3.61 (1H, m, H-3),
3.31 (1H, dd, J = 8.2, 3.8 Hz, H-2), 3.27–3.20 (1H, m, H-5),
3.19–3.09 (1H, m, H-5), 1.92–1.84 (2H, m, H-4); dC 159.4, 137.8,
133.3, 128.4 (2C), 128.1 (2C), 127.6 (2C), 127.5, 113.9 (2C), 80.0,
79.5, 71.0, 56.6, 55.3, 29.1; m/z (ESI) 330 (M + H+, 100%), 352
(M + Na+, 99); Found: C, 69.38; H, 6.83; N, 4.10. Calc. for
C19H23NO4: C, 69.28; H, 7.04; N, 4.25%.
yield: 48%; Rf 0.42 (EtOAc: PE = 1: 2); colorless wax; [a]20
D
10.6 (c 2.36 in CHCl3); [a]20 4.33 (c 1.10, CHCl3); nmax/cm-1:
D
3405, 3030, 2925, 2860, 1595, 1496, 1454, 1441, 1356, 1093, 1049;
dH 7.60 (1H, dd, J = 7.6, 1.9 Hz, Ph-H), 7.30 (1H, dd, J = 7.5,
1.6 Hz, Ph-H), 7.21–7.14 (2H, m, Ph-H), 7.13–7.09 (3H, m, Ph-H),
6.80–6.74 (2H, m, Ph-H), 5.44 (1H, d, J = 1.7 Hz, PhCH), 3.96–
3.89 (1H, m, H-3), 3.80 (1H, d, J = 11.4 Hz, PhCH2), 3.72 (1H,
d, J = 11.4 Hz, PhCH2), 3.45–3.41 (1H, m, H-2), 3.28–3.24 (1H,
m, H-5), 3.16–3.09 (1H, m, H-5), 1.83–1.77 (2H, m, H-4); dC
138.2, 137.8, 131.9, 129.4, 128.6, 128.1 (2C), 127.5, 127.5 (2C),
127.4, 127.0, 77.1, 75.5, 70.5, 67.8, 56.5, 29.1; m/z (ESI) 356
(M + Na+, 100%), 334 (M + H+, 76); Found: C, 64.65; H, 5.90; N,
3.96. Calc. for C18H20ClNO3: C, 64.77; H, 6.04; N, 4.20%.
Minor isomer: 39 mg, yield: 24%; Rf 0.34 (EtOAc: PE = 1: 2);
colorless wax; [a]20D 35.0 (c 0.80 in CHCl3); nmax/cm-1: 3374, 3031,
2924, 2856, 1594, 1496, 1454, 1440, 1356, 1093, 1057; dH 7.55–
7.52 (1H, m, Ph-H), 7.30–7.11 (6H, m, Ph-H), 7.04–6.99 (2H, m,
Ph-H), 5.16 (1H, d, J = 6.2 Hz, PhCH), 4.22 (1H, d, J = 11.8 Hz,
PhCH2), 4.18 (1H, d, J = 11.8 Hz, PhCH2), 3.92–3.86 (1H,
m, H-3), 3.45 (1H, dd, J = 6.2, 3.7 Hz, H-2), 3.29–3.24 (1H,
m, H-5), 3.15 (1H, dd, J = 18.5, 9.4 Hz, H-5), 1.94–1.87 (2H, m,
H-4); dC 139.2, 137.7, 132.3, 129.6, 128.9, 128.4, 128.2 (2C), 127.6
(2C), 127.5, 127.2, 79.2, 79.0, 71.0, 70.7, 56.6, 29.2; m/z (ESI) 356
(M + Na+, 100%), 334 (M + H+, 79).
(2R,3S)-2-{(Benzo[d][1,3]dioxol-5-yl)hydroxymethyl)}-3-benzy-
loxy-N-hydroxypyrrolidine (12f). Following the general proce-
dure, the SmI2 mediated a-hydroxyalkylations of 10 with piperonal
gave 12f as a mixture of two separable diastereomers in 61:39 ratio
(2R,3S)-3-Benzyloxy-2-[(4-chlorophenyl)hydroxymethyl]-N-hy-
droxypyrrolidine (12h). Following the general procedure, the
SmI2 mediated a-hydroxyalkylations of 10 with 4-chlorobenzal-
dehyde gave 12h as a mixture of two separable diastereomers
1
(determined by H NMR, dH 4.09, 4.00) (eluent: EtOAc: PE =
1 : 2; combined yield: 74%). Major isomer: 77 mg, yield: 45%;
Rf 0.35 (EtOAc: PE = 1: 1); colorless wax; [a]20 37.6 (c 1.69
in 63:37 ratio (determined by H NMR, dH 4.11, 4.05) (eluent:
1
D
in CHCl3); nmax/cm-1: 3404, 3030, 2872, 1504, 1490, 1444, 1241,
1095, 1040; dH 7.20–7.13 (3H, m, Ph-H), 6.93–6.87 (3H, m, Ph-H),
6.81 (1H, d, J = 8.4 Hz, Ph-H), 6.72 (1H, d, J = 8.0 Hz, Ph-H),
5.87–5.84 (2H, m, OCH2O), 4.98 (1H, d, J = 2.6 Hz, PhCH), 4.00
(1H, d, J = 11.5 Hz, PhCH2), 3.87 (1H, d, J = 11.5 Hz, PhCH2),
3.88–3.84 (1H, m, H-3), 3.27–3.20 (1H, m, H-5), 3.10 (1H, dd, J =
2.6, 3.7 Hz, H-3), 3.10–3.04 (1H, m, H-5), 1.81 (1H, dd, J = 13.5,
6.6 Hz, H-4), 1.79–1.67 (1H, m, H-4); dC 147.6, 146.6, 137.8, 134.6,
128.1 (2C), 127.5 (2C), 127.4, 118.9, 108.1, 106.5, 100.9, 80.3,
75.7, 70.7, 70.3, 56.3, 28.7; m/z (ESI) 344 (M + H+, 100%), 366
(M + Na+, 51); Found: C, 66.34; H, 6.46; N, 3.95. Calc. for
C19H21NO5: C, 66.46; H, 6.16; N, 4.08%.
EtOAc: PE = 1: 3; combined yield: 95%). Major isomer: 99 mg,
yield: 60%; Rf 0.23 (EtOAc: PE = 1: 2); colorless wax; [a]20 56.1
D
(c 0.59 in CHCl3); nmax/cm-1: 3361, 3030, 2865, 1597, 1492, 1453,
1408, 1355, 1089, 1058, 1027; dH 7.30–7.22 (7H, m, Ph-H), 6.93–
6.82 (2H, m, Ph-H), 4.73–4.54 (1H, br s, PhCH), 4.11 (1H, d, J =
11.5 Hz, PhCH2), 3.91 (1H, d, J = 11.5 Hz, PhCH2), 3.68–3.57
(1H, m, H-3), 3.30 (1H, dd, J = 9.0, 4.4 Hz, H-5), 3.27–3.21 (1H,
m, H-2), 3.21–3.14 (1H, m, H-5), 1.98–1.83 (2H, m, H-4); dC 139.6,
137.3, 133.8, 128.7 (2C), 128.6 (2C), 128.2 (2C), 127.6 (2C), 127.6,
79.7, 79.0, 71.1, 56.7, 28.8; m/z (ESI) 356 (M + Na+, 100%), 334
(M + H+, 36); HRMS (ESI) calcd for C18H21ClNO3 [M + H+]:
334.1210; found: 334.1212.
Minor isomer: 49 mg, yield: 29%; Rf 0.17 (EtOAc: PE = 1:
Minor isomer: 58 mg, yield: 35%; Rf 0.38 (EtOAc: PE = 1: 2);
colorless wax; [a]20D 38.1 (c 1.30 in CHCl3); nmax/cm-1: 3435, 3030,
2941, 2862, 1596, 1492, 1454, 1401, 1359, 1200, 1090, 1027; dH
7.36–7.28 (4H, m, Ph-H), 7.26–7.19 (3H, m, Ph-H), 6.85–6.78 (2H,
m, Ph-H), 5.15–5.10 (1H, m, PhCH), 4.05 (1H, d, J = 11.4 Hz,
PhCH2), 4.00–3.89 (1H, m, H-3), 3.86 (1H, d, J = 11.4 Hz,
PhCH2), 3.32–3.24 (1H, pseudo t, J = 7.5 Hz, H-2), 3.23–3.18
1); colorless wax; [a]20 53.8 (c 1.10 in CHCl3); nmax/cm-1: 3332,
D
3030, 2881, 1503, 1488, 1443, 1245, 1096, 1039, 737; dH 7.20-7.14
(3H, m, Ph-H), 6.96–6.89 (2H, m, Ph-H), 6.86–6.65 (5H, m, Ph-
H), 5.85 (2H, dd, J = 1.4, 5.5 Hz, OCH2O), 4.51 (1H, d, J =
5.4 Hz, PhCH), 4.09 (1H, d, J = 11.6 Hz, PhCH2), 3.94 (1H, d,
J = 11.6 Hz, PhCH2), 3.64–3.57 (1H, m, H-3), 3.25 (1H, dd, J =
2972 | Org. Biomol. Chem., 2009, 7, 2967–2975
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(1H, m, H-5), 3.18–3.10 (1H, m, H-5), 1.93–1.71 (2H, m, H-4);
dC 139.0, 137.4, 132.9, 128.4 (2C), 128.2 (2C), 127.5 (2C), 127.5,
127.1 (2C), 80.2, 75.2, 70.8, 69.6, 56.3, 28.4; m/z (ESI) 356 (M +
Na+, 100%), 334 (M + H+, 56).
Found: C, 67.54; H, 8.65; N, 5.19. Calc. for C15H23NO3: C, 67.90;
H, 8.74; N, 5.28%.
(3S)-3-Benzyloxy-2-(1-hydroxyhexyl)-N -hydroxypyrrolidine
(12l). Following the general procedure, the SmI2 mediated
a-hydroxyalkylations of 10 with hexanal gave 12l as a mixture
of four inseparable diastereomers in 40:35:10:15 (ratio determined
by 1H NMR, dH 4.35, 4.34, 4.24, 4.22) (eluent: EtOAc: PE = 2: 1;
128 mg, combined yield: 88%). Colorless wax. Rf 0.25 (EtOAc:
PE = 2: 1); nmax/cm-1: 3317, 3031, 2929, 2858, 1497, 1454, 1352,
1091, 1064; dH (three isomers) 7.31–7.20 (5H, m, Ph-H), 4.49,
4.45 (1H, 2d, J = 11.5 Hz, PhCH2), 4.34 (1H, overlapped, 2d,
J = 11.5 Hz, PhCH2), 3.99, 3.85 (1H, 2 m, CHOH), 3.60–
3.30 (1H, m, H-3), 3.20–2.95 (2H, m, CHNCH2), 2.91–2.81
(1H, m, CHNCH2), 1.95–1.65 (2H, m, H-4), 1.51–1.35 (3H, m,
CH2CH2CH2CH2Me), 1.32–1.15 (5H, m, CH2CH2CH2CH2Me),
0.82 (3H, t, CH3); dC 138.1, 137.9, 128.6, 128.4 (2C), 128.4 (2C),
127.8 (2C), 127.8 (2C), 127.7, 127.7, 80.0, 78.3, 78.2, 77.2, 75.7,
71.3, 71.1, 68.6, 56.8, 56.1, 34.7, 33.4, 31.9, 31.8, 28.7, 28.0, 25.8,
25.3, 22.6, 22.6, 14.1; m/z (ESI) 316 (M + Na+, 100%), 294
(M + H+, 90); Found: C, 69.33; H, 9.12; N, 4.76. Calc. for
C17H27NO3: C, 69.59; H, 9.28; N, 4.77%.
(2R,3S)-3-Benzyloxy-2-[(2,4-dichlorophenyl)hydroxymethyl]-
N-hydroxypyrrolidine (12i). Following the general procedure,
the SmI2 mediated a-hydroxyalkylations of 10 with 2,4-
dichlorobenzaldehyde gave 12i as a mixture of two inseparable
1
diastereomers in 61:39 ratio (determined by H NMR, dH 5.40-
5.15) (eluent: EtOAc: PE = 1: 4; 170 mg, combined yield: 93%).
Colorless wax. Rf 0.52 (EtOAc: PE = 1: 2); nmax/cm-1: 3390, 3031,
2863, 1590, 1562, 1470, 1454, 1383, 1357, 1101, 1057; dH 7.57–6.77
(8H, m, Ph-H), 5.43, 5.14 (1H, 2 m, PhCH), 4.33, 4.21, 4.03, 3.94–
3.84 (3H, d (min., J = 11.7 Hz), d (min., J = 11.7 Hz), d (maj.,
J = 11.4 Hz), m, PhCH2, PhCH2, PhCH2, PhCH2 and H-3), 3.42
(1H, dd, J = 6.4, 4.0 Hz), 3.34–3.25 (1H, m), 3.24–3.10 (1H, m,
H-5), 2.02–1.67 (2H, m, H-4); dC 137.4, 137.3, 136.9, 134.1, 133.6,
133.0, 132.3, 129.2, 129.0, 128.3, 128.3, 128.2 (2C), 127.6, 127.6,
127.5, 127.4 (2C), 127.2, 79.0, 78.5, 75.0, 70.5, 67.2, 56.7, 56.3,
28.5; m/z (ESI) 391 (M + Na+, 100%), 369 (M + H+, 74); Found:
C, 58.51; H, 5.22; N, 3.72. Calc. for C18H20ClNO3: C, 58.71; H,
5.20; N, 3.80%.
1,2-Bis(4-methoxyphenyl)ethane-1,2-diol (13) (meso and dl).
Compound 1334,35 was obtained as a side product from the
coupling of nitrone 10 with 4-methoxybenzaldehyde. 63 mg, yield:
31%, based on the starting 4-methoxybenzaldehyde. White solid;
(3S)-3-Benzyloxy-2-(1-hydroxybutyl)-N -hydroxypyrrolidine
(12j). Following the general procedure, the SmI2 mediated a-
hydroxyalkylations of 10 with butyraldehyde gave 12j as a mixture
of four inseparable diastereomers in 43:36:11:10 ratio (determined
by 1H NMR, dH 4.54, 4.51, 4.29, 4.27) (eluent: EtOAc: PE = 1: 2;
105 mg, combined yield: 80%). Colorless wax. Rf 0.41 (EtOAc:
PE = 1: 1); nmax/cm-1: 3356, 3030, 2957, 2870, 1605, 1497, 1454,
1432, 1357, 1093, 1067; dH (two isomers) 7.38–7.25 (5H, m, Ph-H),
4.56, 4.52 (1H, 2d, J =11.5 Hz, PhCH2), 4.41 (1H, overlapped, 2d,
J = 11.5 Hz, PhCH2), 3.99 (1H, m, CHOH), 3.75–3.67 (1H, m,
H-3), 3.26–3.21 (1H, m, CHNCH2), 3.20–3.02 (1H, m,
CHNCH2), 2.99–2.86 (1H, m, CHNCH2), 2.07–1.70 (2H, m, H-
4), 1.61–1.32 (4H, m, CH3CH2CH2), 0.91 (3H, overlapped, 2t, J =
7.1 Hz, CH3); dC 138.1, 137.9, 128.6, 128.4 (2C), 128.4 (2C), 128.1,
127.8 (2C), 127.8 (2C), 127.7, 127.7, 79.9, 78.3, 78.3, 71.2, 71.1,
68.1, 56.7, 47.4, 36.9, 35.4, 27.9, 19.4, 18.9, 14.1; m/z (ESI) 266
(M + H+, 100%), 288 (M + Na+, 51); Found: C, 67.91; H, 8.84; N,
5.17. Calc. for C15H23NO3: C, 67.90; H, 8.74; N, 5.28%.
◦
mp 164–165 C (EtOAc/PE) (lit.34 mp 167 ◦C, meso and dl,
determined by thermal analysis); Rf 0.64 (EtOAc: PE = 2: 1);
n
max/cm-1: 3354, 2901, 2836, 1611, 1585, 1515, 1460, 1246, 1177,
1032; dH (isomer 1): 7.08–7.01 (4H, m, Ph-H), 6.80–6.74 (4H, m,
Ph-H), 4.63 (2H, s, PhCH), 3.77 (6H, s, OCH3), 2.82 (2H, br s,
OH); dH (isomer 2): 7.18–7.24 (4H, m, Ph-H), 6.90–6.84 (4H, m,
Ph-H), 4.73 (2H, s, PhCH), 3.80 (6H, s, OCH3), 2.12 (2H, br s,
OH); dC 159.4, 159.2, 132.1, 132.0, 128.3 (2C), 128.1 (2C), 113.7
(2C), 113.5 (2C), 78.8, 77.8, 55.3, 55.2; m/z (ESI) 297 (M + Na+,
100%), 313 (M + K+, 10).
(2S,3S)-3-Benzyloxy-2-(diphenylhydroxymethyl)pyrrolidine (14).
A stirred and carefully deoxygenated solution of coupling product
12b (108 mg, 0.28 mmol) in THF (10 mL) was cooled to -78 ◦C
under an Ar atmosphere. A freshly prepared THF solution of
SmI2 (0.1 mol·L-1, 11.5 mL, 1.15 mmol) was then added. After
◦
stirring at -78 C for 1 h, the temperature was allowed to warm
(3S)-3-Benzyloxy-2-(1-hydroxy-2-methylpropyl)-N-hydroxypy-
rrolidine (12k). Following the general procedure, the SmI2 medi-
ated a-hydroxyalkylations of 10 with isobutyraldehyde gave 12k
as a mixture of three inseparable diastereomers in 45:36:19 ratio
up overnight. The reaction was then quenched by introduction of
air, and then a saturated aqueous solution of Na2S2O3 (4 mL) and
NaHCO3 (15 mL) were added successively. The yellow mixture
was extracted with EtOAc (3 ¥ 20 mL), and the combined organic
layers were washed with brine and dried over Na2SO4 and filtered.
After concentration in vacuum, the residue was purified by flash
chromatography on silica gel (eluent: EtOAc: PE, 2: 1) to yield
the pyrrolidine 14 (77.4 mg, yield: 77%) as a colorless wax. Rf
0.25 (EtOAc); [a]20D -24.2 (c 1.16, CHCl3); nmax/cm-1: 3283, 3060,
3030, 2924, 1598, 1449, 1385, 1357, 1097, 1061; dH 7.63–7.55 (4H,
m, Ph-H), 7.34–7.25 (7H, m, Ph-H), 7.21–7.14 (2H, m, Ph-H),
7.08–7.01 (2H, m, Ph-H), 4.45–4.41 (1H, m, H-3), 4.02 (1H, d,
J = 11.3 Hz, PhCH2), 3.94 (1H, d, J = 5.7 Hz, H-2), 3.91
(1H, d, J = 11.3 Hz, PhCH2), 3.10 (1H, ddd, J = 5.7, 9.5,
12.3 Hz, H-5), 2.87–2.75 (1H, m, H-5), 1.91 (1H, dd, J = 5.7,
13.4 Hz, H-4), 1.82–1.74 (1H, m, H-4); dC 144.2, 137.9, 128.6 (2C),
1
(determined by H NMR, dH 4.34, 4.32, 4.24) (eluent: EtOAc:
PE = 1: 2; 116 mg, combined yield: 88%). Colorless wax. Rf 0.24
(EtOAc: PE = 1: 2); nmax/cm-1: 3358, 3031, 2959, 2870, 1604, 1496,
1454, 1363, 1092, 1065; dH (two isomers) 7.38–7.27 (5H, m, Ph-H),
4.54 (1H, overlapped, 2d, J = 11.5 Hz, PhCH2), 4.42, 4.38 (1H,
2d, J = 11.5 Hz, PhCH2), 4.06, 3.85 (1H, 2 m, CHOH), 3.60–3.30
(1H, m, H-3), 3.31–3.05 (3H, m, CHNCH2), 2.18–1.97 (2H, m,
H-4), 1.97–1.77 (2H, m, H-5), 1.71–1.55 (1H, m, CHMe2), 1.07–
1.03, 1.01–0.96 (6H, 2m, 2CH3); dC 138.1, 138.0, 128.5, 128.4 (2C),
128.3, 128.1, 127.9, 127.7 (2C), 127.6, 80.3, 77.2, 76.4, 75.8, 74.1,
71.8, 71.2, 56.8, 55.9, 32.0, 31.0, 30.7, 27.8, 27.6, 20.1, 19.9, 19.5,
19.0, 16.6; m/z (ESI) 266 (M + H+, 100%), 288 (M + Na+, 44);
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128.3 (2C), 128.2 (2C), 127.8 (2C), 127.6, 126.9, 126.8 (2C), 125.9
(2C), 125.7 (2C), 80.5, 77.6, 71.7, 71.1, 45.5, 31.8; m/z (ESI) 360
(M + H+, 100); Found: C, 80.54; H, 7.33; N, 3.70. Calc. for
C15H20O5: C, 80.19; H, 7.01; N, 3.90%.
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The authors are grateful to the NSF of China (20832005), the
program for Innovative Research Team in Science & Technology
(University) in Fujian Province and the Program for New Century
Excellent Talents in Xiamen University for financial support.
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