Stereoselective synthesis of two new trihydroxylated pyrrolidines using a meyer-schuster rearrangement

Article abstract of DOI:10.1080/00397911.2010.503003

The synthesis of two new trihydroxylated pyrrolidines, in a highly diastereoselective manner, has been developed using the Meyer-Schuster rearrangement as a key step.

Full text of DOI:10.1080/00397911.2010.503003

Synthetic Communications1, 41: 2435–2445, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.503003
STEREOSELECTIVE SYNTHESIS OF TWO NEW
TRIHYDROXYLATED PYRROLIDINES USING A
MEYER–SCHUSTER REARRANGEMENT
Nalivela Kumara Swamy and Stephen G. Pyne
School of Chemistry, University of Wollongong, Wollongong, Australia
GRAPHICAL ABSTRACT
Abstract The synthesis of two new trihydroxylated pyrrolidines, in a highly diastereoselec-
tive manner, has been developed using the Meyer–Schuster rearrangement as a key step.
Keywords Meyer–Schuster rearrangement; polyhydroxylated pyrrolidine
INTRODUCTION
The polyhydroxylated pyrrolidine, piperidine, indolizidine, pyrrolizidine, and
nortropane alkaloids have glycosidase inhibitory activities and thus have potential
utility as antiviral, anticancer, antidiabetic, and antiobesity drugs.[1] These poten-
tially useful biological properties, along with novel structures, have made these com-
pounds and their analogs attractive and important synthetic targets.[1] A large
majority of the polyhydroxylated bioactive alkaloids or azasugars contain a pyrroli-
dine ring moiety decorated with one or two hydroxyl group functionalities (Fig. 1).
The polyhydroxylated pyrrolidines include the 1,4-dideoxy-1,4-imino hexitols A
and B (Fig. 1). In many other azasugar compounds the pyrrolidine ring is part of
Received May 31, 2010.
Address correspondence to Stephen G. Pyne, School of Chemistry, University of Wollongong,
Wollongong, NSW, 2522, Australia. E-mail: spyne@uow.edu.au
2435

2436
N. K. SWAMY AND S. G. PYNE
Figure 1. Some polyhydroxylated pyrrolidine ring–containing natural products.
Scheme 1. Target trihydroxylated pyrrolidines 2 and 3.
a bicyclic heterocyclic system, such as that found in the polyhydroxylated indolizi-
dine and pyrrolizidine alkaloids. Well-known examples include swainsonine C,
castanospermine D, and australine E (Fig. 1).
During our synthetic studies on the Stemona alkaloids, we unexpectedly pre-
pared the novel Meyer–Schuster rearrangement product the enal 1.[2] Intermediate
1 has an a,b-unsaturated aldehyde moiety, which could be potentially useful for
the synthesis of polyhydroxylated pyrrolidines, pyrrolizidines, and indolizidines.
Here we report the diastreoselective synthesis of the two new trihydroxylated pyrro-
lidines 2 and 3 from the aldehyde 1 (Scheme 1).
RESULTS AND DISCUSSION
Our synthetic approach started from enantiopure imide 4, which can be readily
synthesized from (ꢀ)-malic acid.[3] Imide 1 was alkynylated with lithium trimethylsi-
lylacetylide, which was prepared from trimethylsilane (TMS)–acetylene (1.5 equiv)
and nBuLi (1.5 equiv). The crude reaction mixture was treated with LiOH, to remove
the TMS group and give a mixture (6:4) of diastereomeric hydroxy lactams 2 in 74%

TRIHYDROXYLATED PYRROLIDINES
2437
yield. This mixture was treated with borontrifluoride-etherate (1 equiv), which
rapidly (2–5 min) gave the Meyer–Schuster rearrangement product 1 as a single
E-isomer in excellent yield (86%). The E-geometry of 1 was established from a
nuclear Overhauser effect spectroscopic (NOESY) study that showed a cross peak
between the N-benzyl methylene protons and the alkene proton. The E-isomer
was also expected from the work of Huang on related compounds.[4] The aldehyde
1 was reduced to the alcohol 6 using NaBH4 in MeOH, followed by hydroxyl group
protection with tert-butyldiphenylsilyl (TBDPS) chloride=imidazole in CH2Cl2 to
give the TBDPS ether 7 as shown in Scheme 2.
Having first investigated the stereoselective dihydroxylation of 7 using the
Sharpless asymmetric dihydroxylation reaction conditions,[5] we discovered high
trans diastereoselectivites at the pyrrolidine ring (C-4=C-5) but only 1:1 anti=syn dia-
stereoselectivites at the pyrrolidine ring (C-5) and exocyclic stereogenic center (C-10).
However, when we used K2OsO4 ꢁ 2H2O=NMO in acetone and H2O (2:1), high trans
diastereoselectivites at the pyrrolidine ring (C-4=C-5) and also high 5:95 anti=syn dia-
stereoselectivites at the pyrrolidine ring (C-5) and exocyclic stereogenic center (C-10)
were observed. This resulted in isolation of the diol 8 in 72% yield (Scheme 3).[6] The
configuration at the aminol carbon (C-5) was not unequivocally established.
Reductive of 8 with Et3SiH=BF3 ꢁ OEt2 gave only the trans diastereomer 9 in 77%
yield. The stereochemical outcomes of this reaction was expected because of the
stereodirecting effect of the C-3 pyrrolidine substituent in 8.[4] Evidence for the con-
figuration of 9 was obtained from NOESY NMR experiments, which showed a sig-
nificant correlation between H-5 and H-10 and no correlation between H-4 and H-5
(Fig. 2). Further, J4,5 was 0 Hz, consistent with the 4,5-trans configuration.[7] Lactam
9 was reduced to the pyrrolidine 10 using LiAlH4 in 83% yield. Finally, debenzyla-
tion of 10 by hydrogenolysis over PdCl2 gave the hydrochloride salt of 2 in nearly
quantitative yield (Scheme 3).
Hydroboration of 7 using BH3 ꢁ SMe2 in tetrahydrofuran (THF) and sub-
sequent oxidative workup using H2O2[6] in alkaline solution resulted in the formation
of an unidentified ultraviolet (UV)–inactive side product and gave the desired
Scheme 2. Reagents and conditions: (a) HCCSiMe3, nBuLi (1.5 eq)=THF, ꢀ78 ꢂC, 1 h and then LiOH,
(74%), (b) BF3 ꢁ OEt2, CH2Cl2, 0 ꢂC, 2–5 min (86%), (c) NaBH4=MeOH, 0 ꢂC, 30 min (97%), and (d)
TBDPSCl, imidazole, CH2Cl2, rt, 2 h (83%).

2438
N. K. SWAMY AND S. G. PYNE
Scheme 3. Reagents and conditions: (a) K2OsO4 ꢁ 2H2O, NMO, acetone=H2O, rt, 3 h (72%), (b) Et3SiH=
BF3 ꢁ OEt2, CH2Cl2, rt, 12 h (77%), (c) LiAlH4=THF, rt, 12 h (83%), and (d) PdCl2=H2, MeOH, rt, 12 h
(99%).
Figure 2. NOESY correlations for compounds 9 and 11.
Scheme 4. Reagents and conditions: (a) BH3-Me2S, THF, rt, 12 h, then EtOH, NaBO3 ꢁ 4H2O, reflux, 3 h
(50%), (b) BH3-Me2S, THF rt, 12 h, then EtOH reflux, 2 h (72%), and (c) PdCl2=H2, MeOH, rt 12 h (99%).

TRIHYDROXYLATED PYRROLIDINES
2439
product 11 in an unsatisfactory yield of 32% (Scheme 4). However, when the alter-
native oxidant, NaBO3 ꢁ 4H2O,[8] was used, the yield of 11 was more satisfactory
(50%). The configuration of 11 was established by NOESY NMR experiments
(Fig. 2). Further, J4,5 was 6.0 Hz, consistent with the 4,5-cis configuration.[7] Lactam
11 was reduced to the pyrrolidine 12 using BH3-Me2S in 72% yield. Finally, deben-
zylation of 12 by hydrogenolysis over PdCl2 gave the hydrochloride salt of 3 in
nearly quantitative yield (Scheme 4).
CONCLUSIONS
The synthesis of two new trihydroxylated pyrrolidines, in a highly diastereose-
lective manner, has been developed using the Meyer–Schuster rearrangement as a
key step. The trihydroxylated pyrrolidine 2 was obtained as its hydrochloride salt
in eight synthetic steps from 4 in 23% overall yield, while the hydrochloride salt of
3 was obtained in seven synthetic steps and 18% overall yield from 4. This method-
ology could, in principle, be extended to the synthesis of natural and synthetic
polyhydroxylated pyrollizidines and indolizidines.
EXPERIMENTAL
General methods were as previously described.[7]
(S)-1-Benzyl-4-(benzyloxy)-5-ethynyl-5-hydroxy pyrrolidin-2-one (5)
To a solution of trimethylsilyl acetylene (0.50 g, 5.08 mmol) in dry THF
(10 mL) was added dropwise 2.5 M n-butyllithium solution (2.40 mL) at ꢀ78 ꢂC
under N2 atm, and the mixture was stirred for 30 min. Then cyclic imide 4 (1 g,
3.39 mmol) dissolved in dry tetrahydrofuran (THF; 10 mL) was added dropwise.
Stirring was continued for 30 min at ꢀ78 ꢂC, and the reaction was monitored via
thin-layer chromatography (TLC). The reaction mixture was quenched with satu-
rated aqueous ammonium chloride solution and extracted with EtOAc (3 ꢃ 50 mL).
The combined organic layers were washed with brine, dried over MgSO4, and con-
centrated in vacuo. The residue was dissolved in THF (10 mL) and treated with satu-
rated LiOH solution (2 mL) to cleave the TMS group. The mixture was then diluted
with water and extracted with EtOAc (3 ꢃ 50 mL). The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in vacuo. The crude pro-
duct was chromatographed on silica gel (2:1 EtOAc=petrol) to afford a 60:40 mixture
of two diastereomeric products as an pale yellow gum (0.80 g, 74%).
21
Major isomer. Rf ¼ 0.28 (7:3 EtOAc=petrol); ½aꢄD þ 20:0 (c 1.40, CHCl3); IR
(neat, nmax=cmꢀ1) 3278, 2115, 1686, 1403, 1124, 968, 743, 702; dH (500 MHz, CDCl3)
7.37–7.19 (m, 10ArH), 4.73 (1H, d, J ¼ 11.5 Hz), 4.66 (1H, d, J ¼ 11.5 Hz), 4.65 (1H,
d, J ¼ 15.0 Hz), 4.50 (1H, d, J ¼ 15.0 Hz), 4.24 (1H, t, J ¼ 6.5 Hz, H-4), 2.65 (1H, dd,
J ¼ 6.0, 17.0 Hz, H-3), 2.63 (1H, s, H-20), 2.50 (1H, dd, J ¼ 6.0, 17.0 Hz, H-3); dC
(125 MHz, CDCl3) 171.0 (CO), 137.4 (ArC), 136.3 (ArC), 128.5 (ArCH), 128.3
(ArCH), 128.2 (ArCH), 128.1 (ArCH), 127.9 (ArCH), 127.1 (ArCH), 83.97 (C-20),
80.87 (C-10), 78.02 (C-4), 75.0 (C-5), 72.64 (C-40), 43.7 (C-30), 32.2 (C-3); ESIMS

2440
N. K. SWAMY AND S. G. PYNE
m=z 343.89 [(M þ Naþ) 100%]; HRESIMS calcd. for C20H19NO3Na, (M þ Na)þ
344.1272, found: 344.1263.
22
Minor isomer. Rf ¼ 0.24 (7:3 EtOAc=petrol); ½aꢄD ꢀ 30:0 (c 1.40, CHCl3); IR
(neat, nmax=cmꢀ1) 3278, 2115, 1686, 1403, 1124, 968, 743, 702; dH (500 MHz, CDCl3)
7.32–7.16 (m, 10ArH), 4.84 (1H, d, J ¼ 11.5 Hz), 4.70 (1H, d, J ¼ 15.0 Hz), 4.60 (1H,
d, J ¼ 11.5 Hz), 4.40 (1H, d, J ¼ 15.0 Hz), 4.00 (1H, apparent t, J ¼ 6.5 Hz, H-4), 2.69
(1H, s, H-20), 2.67 (1H, dd, J ¼ 6.0, 17.0 Hz, H-3), 2.40 (1H, dd, J ¼ 6.0, 17.0 Hz,
H-3); dC (125 MHz, CDCl3) 172.2 (CO), 137.3 (ArC), 137.29 (ArC), 128.32 (ArCH),
128.3 (ArCH), 128.1 (ArCH), 128.0 (ArCH), 127.7 (ArCH), 127.6 (ArCH), 127.2
(ArCH), 88.4 (C-20), 80.4(C-10), 78.6 (C-4), 77.4 (C-5), 72.4 (C-40), 43.4 (C-30), 36.0
(C-3); ESIMS m=z 343.88 [(M þ Na)þ 100%]; HRESIMS calcd. for C20H19NO3Na,
(M þ Na)þ 344.1251, found: 344.1263.
(S,E)-2-(1-Benzyl-3-(benzyloxy)-5-oxopyrrolidin-
2-ylidene)acetaldehyde (1)
BF3-Et2O (0.31 g, 2.18 mmol) was added to a solution of 5 (0.70 g, 2.18 mmol)
in dichloromethane (10 ml) cooled to 0 ꢂC dropwise at 0 ꢂC under N2 atm. The reac-
tion mixture was stirred for 2–5 min at 0 ꢂC. After completion of reaction, the reac-
tion mixture was quenched with saturated NaHCO3 solution, and the aqueous phase
was extracted with dichloromethane (3 ꢃ 50 mL). The combined organic layers were
dried over MgSO4, and the solvent was removed in vacuo. The crude product was
chromatographed on silica gel (1:1 EtOAc=petrol) to give the title compound as col-
24
orless gum (0.60 g, 86%). Rf ¼ 0.60 (7:3 EtOAc=petrol); ½aꢄD þ 78:3 (c 0.83, CHCl3);
IR (neat, nmax=cmꢀ1) 2919, 1716, 1622, 1403, 1149, 968, 743, 707; dH (500 MHz,
CDCl3) 9.75 (1H, d, J ¼ 8.0 Hz, CHO), 7.38–7.18 (m, 10ArH), 5.54 (1H, d,
J ¼ 8.0 Hz, H-10), 5.17 (1H, dd, J ¼ 2.5, 7.5 Hz, H-3), 4.37 (2H, s, H-30), 4.64
(1H, d, J ¼ 11.0 Hz), 4.55 (1H, d, J ¼ 11.0 Hz), 2.89 (1H, dd, J ¼ 7.5, 18.5 Hz,
H-4), 2.80 (1H, dd, J ¼ 2.5, 18.5 Hz, H-4); dC (125 MHz, CDCl3), 189.3 (CHO),
173.2 (CO), 160.1 (C-2), 135.8 (ArC), 133.8 (ArC), 128.9 (ArCH), 128.8 (ArCH),
128.7 (ArCH), 128.5 (ArCH), 128.4 (ArCH), 128.3 (ArCH), 128.1 (ArCH), 128.0
(ArCH), 127.2 (ArCH), 126.9 (ArCH), 107.0 (C-þ2), 71.3 (C-40), 70.0 (C-3), 44.2
(C-30), 35.1 (C-4); ESIMS m=z 321.9 [(M þ H) 30%]; HRESIMS calcd. for
C20H20NO3, (M þ H)þ 322.1458, found: 322.1443.
(S,E)-1-Benzyl-4-(benzyloxy)-5-(2-hydroxyethylidene)pyrrolidin-
2-one (6)
NaBH4 (0.21 g, 5.6 mmol) was added in portions to a solution of 1 (0.6 g,
1.86 mmol) in MeOH (10 mL) at 0 ꢂC under a N2 atmosphere. After the addition
was completed (4 min), the reaction was stirred at 0 ꢂC for 30 min. Then it was
quenched with saturated NaHCO3 solution and extracted with EtOAc (3 ꢃ 40 mL).
The combined extracts were washed with brine, dried over MgSO4, and concentrated
in vacuo. The crude product was chromatographed on silica gel (2:1 EtOAc=petrol)
to give the title compound as colorless gum (0.59 g, 97%). Rf ¼ 0.28 (2:1 EtOAc=
24
petrol); ½aꢄD þ 56:5 (c 0.92, CHCl3); IR (neat, nmax=cmꢀ1) 3380, 2924, 1669, 1419,

TRIHYDROXYLATED PYRROLIDINES
2441
1347, 1147, 1070, 736, 707; dH (500 MHz, CDCl3) 7.38–7.16 (m, 10ArH), 5.14 (1H, t,
J ¼ 7.5 Hz, H-10), 4.83 (1H, apparent bd, J ca. 7 Hz, H-4), 4.70 (1H, d, J ¼ 15.5 Hz),
4.64 (1H, d, J ¼ 15.5 Hz), 4.58 (1H, d, J ¼ 11.5 Hz), 4.47 (1H, d, J ¼ 11.5 Hz), 4.13
(1H, dd, J ¼ 7.5, 12.5 Hz, H-20), 3.99 (1H, dd, J ¼ 7.5, 12.5 Hz, H-20), 2.80 (1H,
dd, J ¼ 8.0, 18.0 Hz, H-3), 2.70 (1H, dd, J ¼ 2.5, 18.0 Hz, H-3); dC (125 MHz, CDCl3)
172.98 (CO), 143.6 (C-5), 136.3 (ArC), 135.3 (ArC), 128.7 (ArCH), 128.6 (ArCH),
128.5 (ArCH), 128.4 (ArCH), 128.39 (ArCH), 128.35 (ArCH), 127.9 (ArCH),
127.4 (ArCH), 127.0 (ArCH), 105.3 (C-10), 71.0 (C-40), 70.2 (C-4), 57.7 (C-20), 43.6
(C-30), 35.8 (C-3); ESIMS m=z 345.9 [(M þ Na)þ 100%]; HRESIMS calcd. for
C20H21NO3Na, (M þ Na)þ 346.1425, found: 346.1419.
(S,E)-1-Benzyl-4-(benzyloxy)-5-(2-(tert-
butyldiphenylsilyloxy)ethylidene)pyrrolidin-2-one (7)
DMAP (0.037 g, 0.31 mmol), Et3N (0.47 g, 4.64 mmol), and TBDPSCl (1.98 g,
1.85 mmol) were added to a solution of 6 (0.50 g, 1.54 mmol) in dry CH2Cl2 (10 ml) at
rt under N2 atmosphere, and the solution was stirred at rt for 2 h under N2 atmos-
phere until the disappearance of starting material as shown by thin-layer chromato-
graphy (TLC). The reaction mixture diluted with water (10 ml) and extracted with
EtOAc (3 ꢃ 30 mL). The organic layers were combined and dried over MgSO4,
and the solvent was concentrated in vacuo. The crude product was chromatographed
on silica gel (1:2 EtOAc=petrol) give the title compound as a colorless liquid (0.72 g,
)
24
83%). Rf ¼ 0.84 (2:1 EtOAc=petrol); ½aꢄD þ 56:5 (c 0.92, CHCl3); IR (neat, nmax=cmꢀ1
2929, 1685, 1429, 1112, 830, 743 and 707; dH (500 MHz, CDCl3) 7.59–7.08 (m,
20ArH), 4.98 (1H, dd, J ¼ 4.5, 9.0 Hz, H-10), 4.65 (1H, d, J ¼ 15.5 Hz), 4.55 (1H,
d, J ¼ 15.5 Hz), 4.32 (1H, dd, J ¼ 4.5,12.5 Hz, H-20), 4.27 (1H, d, J ¼ 11.5 Hz),
4.15 (1H, dd, J ¼ 3.0, 12.5 Hz, H-20), 4.12 (1H, d, J ¼ 11.5 Hz), 3.89 (1H, d,
J ¼ 3.0 Hz, H-4), 2.46 (2H, d, J ¼ 2.5 Hz, H-3); dC (125 MHz, CDCl3) 173.1
=
(C O), 140.7 (C-5), 136.8 (ArC), 135.8 (ArC), 135.6 (ArC), 135.57 (ArC),
135.45 (ArCH), 135.43 (ArCH), 135.3 (ArCH), 134.8 (ArCH), 133.7 (ArCH),
133.6 (ArCH), 129.6 (ArCH), 129.5 (ArCH), 128.6 (ArCH), 128.5 (ArCH), 128.44
(ArCH), 128.4 (ArCH), 128.2 (ArCH), 128.0 (ArCH), 127.9 (ArCH), 127.85
(ArCH), 127.8 (ArCH), 127.6 (ArCH), 127.4 (ArCH), 127.3 (ArCH), 106.2 (C-10),
70.0 (C-40), 69.7 (C-4), 59.9 (C-20), 43.5 (C-30), 36.2 (C-3), 26.7 (3Me-tBu),
19.0 (C-tBu); ESIMS m=z 583.8 [(M þ Na)þ 100%]; HRESIMS calcd. for
C36H39NO3NaSi (M þ Na)þ 584.2611, found: 584.2597.
(4S,5R)-1-Benzyl-4-(benzyloxy)-5-((R)-2-(tert-
butyldiphenylsiloxy)-1-hydroxyethyl)-5-hydroxypyrrolidin-2-one (8)
K2OsO4 ꢁ 2H2O (8.5 mg, 0.023 mmol) and NMO (0.13 g, 1.11 mmol) were
added to a solution of 7 (0.26 g, 0.46 mmol) in a mixture of acetone (6 mL) and water
(4 mL). The solution was stirred at rt for 3 h until disappearance of starting material
as shown by TLC. The reaction mixture was quenched with saturated potassium
bisulfite solution (5 mL), stirred for 10 min, diluted with water (5 mL), and extracted
with EtOAc (3 ꢃ 10 mL). The organic layers were combined and dried over MgSO4,
and the solvent was concentrated in vacuo. The crude product was chromatographed

2442
N. K. SWAMY AND S. G. PYNE
on silica gel (3:1 EtOAc=petrol) to give the title compound as a colorless liquid (0.2 g,
)
22
72%). Rf ¼ 0.48 (7:3 EtOAc=petrol); ½aꢄD þ 6:20 (c 3.64, CHCl3); IR (neat, nmax=cmꢀ1
3421, 2929, 1675, 1434, 1112, 825, 748 and 702; dH (500 MHz, CDCl3) 7.60–7.15
(m, 20ArH), 4.56 (1H, d, J ¼ 15.5 Hz), 4.54 (1H, d, J ¼ 11.5 Hz), 4.43 (1H, d,
J ¼ 15.5 Hz), 4.35 (1H, d, J ¼ 11.5 Hz), 4.14 (1H, d, J ¼ 5.0 Hz, H-10), 3.96 (1H,
s, OH), 3.84–3.79 (m, 2H, H-20, H-4), 3.52 (1H, dd, J ¼ 7.0, 10.0 Hz, H-20), 2.76
(1H, dd, J ¼ 7.0, 17.0 Hz, H-3), 2.46 (1H, d, J ¼ 17.0 Hz, H-3), 2.46 (1H, s, OH),
=
1.02 (9H, s, 3Me); dC (125 MHz, CDCl3) 172.9 (C O), 138.7 (ArC), 136.7
(ArC), 135.8 (ArC), 135.7 (ArC), 133.2 (ArCH), 132.9 (ArCH), 130.2 (ArCH),
130.1 (ArCH), 128.8 (ArCH), 128.7 (ArCH), 128.5 (ArCH), 128.1 (ArCH), 128.0
(ArCH), 127.9 (ArCH), 127.4 (ArCH), 92.2 (C-5), 72.8 (C-10), 72.0 (C-40), 71.88
(C-4), 64.1 (C-20), 42.3 (C-30), 37.3 (C-3), 27.1 (3Me-tBu), 19.4 (C-tBu); ESIMS
m=z 595.7 [(M þ H)þ 100%]; HRESIMS calcd. for C36H42NO5Si (M þ H)þ
596.2853, found: 596.2832.
(4S,5R)-1-Benzyl-4-(benzyloxy)-5-((S)-2-(tert-
butyldiphenylsiloxy)-1-hydroxyethyl)pyrrolidin-2-one (9)
BF3 ꢁ Et2O (0.19 g, 1.34 mmol) was added to a solution of 8 (0.20 g, 0.33 mmol)
in dry CH2Cl2 (6 mL) followed by Et3SiH (0.39 g, 3.36 mmol) at 0 ꢂC under a N2
atmosphere. The solution was stirred at 0 ꢂC under N2 atmosphere for 15 min and
then at rt for 12 h until disappearance of starting material was shown by TLC.
The reaction mixture was quenched with saturated NaHCO3 solution (5 mL), stirred
for 10 min, diluted with water (5 ml), and extracted with CH2Cl2 (3 ꢃ 20 mL). The
organic layers were combined and dried over MgSO4, and the solvent concentrated
in vacuo. The crude product was chromatographed (3:1 EtOAc=petrol) to give the
title compound as a colorless liquid (0.15 g, 77%). Rf ¼ 0.56 (6:4 EtOAc=petrol);
24
½aꢄD þ 26:70 (c 2.65, CHCl3); IR (neat, nmax=cmꢀ1) 3334, 2929, 1670, 1424, 1112,
819, 748 and 707; dH (500 MHz, CDCl3) 7.60–7.11 (m, 20 ArH), 5.10 (1H, d,
J ¼ 15.5 Hz), 4.32 (2H, s), 4.13 (1H, d, J ¼ 6.5 Hz, H-4), 4.05 (1H, d, J ¼ 15.5 Hz),
3.97–3.96 (1H, m, H-10), 3.67 (1H, s, H-5), 3.65 (1H, dd, J ¼ 7.0, 10.5 Hz, H-20),
3.56 (1H, dd, J ¼ 7.0, 10.5 Hz, H-20), 3.29 (1H, d, J ¼ 3.0 Hz, OH), 2.77 (1H, dd,
J ¼ 6.5, 17.5 Hz, H-3), 2.46 (1H, d, J ¼ 17.5 Hz, H-3), 0.98 (9H, s, 3Me); dC
=
(125 MHz, CDCl3) 174.0 (C O), 137.5 (ArC), 136.0 (ArC), 135.47 (ArC), 135.46
(ArC), 132.8 (ArCH), 132.76 (ArCH), 129.95 (ArCH), 129.93 (ArCH), 128.7
(ArCH), 128.3 (ArCH), 127.83 (ArCH), 127.81 (ArCH), 127.67 (ArCH), 127.5
(ArCH), 71.9 (C-4), 70.3 (C-40), 68.65 (C-10), 64.8 (C-5), 64.3 (C-20), 44.1 (30), 38.5
(C-3), 26.8 (3Me-tBu), 19.1 (C-tBu); ESIMS m=z 580.3 [(M þ H)þ 100%]; HRESIMS
calcd. for C36H42NO4Si (M þ H)þ 580.2892, found: 580.2883.
(S)-1-((2R,3S)-1-Benzyl-3-(benzyloxy)pyrrolidin-2-yl)ethane-
1,2-diol (10)
LiAlH4 (0.039 g, 1.03 mmol) was added to a solution of 9 (0.15 g, 0.26 mmol) in
dry THF (5 mL) at rt under a N2 atmosphere. The solution was stirred at rt for 12 h
until disappearance of starting material was shown by TLC. The reaction mixture
was quenched with saturated ammonium chloride solution until a precipitate was

TRIHYDROXYLATED PYRROLIDINES
2443
formed. The solution was filtered, and the solids were washed with EtOAc. The
organic layer was dried over MgSO4, and the solvent was concentrated in vacuo.
The crude product was chromatographed (3:1 EtOAc=petrol) to give the title com-
pound as
a
colorless liquid (0.07 g, 83%). Rf ¼ 0.31 (4:1 EtOAc=petrol);
23
½aꢄD ꢀ 16:80 (c 0.77, CHCl3); IR (neat, nmax=cmꢀ1) 3370, 2934, 1659, 1444, 1050,
748 and 707; dH (500 MHz, CDCl3) 7.37–7.25 (m, 10ArH), 4.54 (1H, d, J ¼ 11.5 Hz),
4.30 (1H, d, J ¼ 11.5 Hz), 4.15–4.00 (1H, m, H-3), 4.08 (1H, d, J ¼ 13.0 Hz), 3.89
(1H, dd, J ¼ 5.5, 8.5 Hz, H-2), 3.74–3.65 (2H, m, H-20), 3.41 (1H, d, J ¼ 13.0 Hz),
2.93 (1H, t, J ¼ 8.5 Hz, H-5), 2.80 (1H, apparent t, J ¼ 3.5 Hz, H-10), 2.56 (1H, dd,
J ¼ 7.0, 17.0 Hz, H-5), 1.90 (1H, dd, J ¼ 7.0, 13.0 Hz, H-4), 1.84–1.68 (1H, m,
H-4); dC (125 MHz, CDCl3) 138.5 (ArC), 137.8 (ArC), 128.8 (ArCH), 128.52
(ArCH), 128.45 (ArCH), 128.0 (ArCH), 127.3 (ArCH), 79.1 (C-3), 72.6 (C-10),
71.1 (C-40), 69.2 (C-2), 64.4 (C-20), 59.04 (C-30), 52.1 (C-5), 30.1 (C-4); ESIMS
m=z 328.1 [(M þ H)þ 100%]; HRESIMS calcd. for C20H26NO3, (M þ H)þ
328.1909, found: 328.1913.
(2S,3S)-2-((S)-1,2-Dihydroxyethyl)pyrrolidin-3-ol-hydrochloride (2)
PdCl2 (0.043 g, 0.21 mmol) was added to a solution of 10 (0.07 g, 0.21 mmol) in
MeOH (5 mL) at rt under a N2 atmosphere. Then the reaction mixture was flushed
with H2 (balloon), and the solution was stirred at rt under a H2 atmosphere for 12 h.
After completion of the reaction, the reaction mixture was filtered through a celite
bed and washed with MeOH. The solvent was concentrated in vacuo, and then resi-
due was triturated with ether for several times to get rid of all nonpolar impurities.
This gave the pure title compound as a colorless gum (0.039 g, 99%). Rf ¼ 0.18 (1:9
22
MeOH=EtOAc); ½aꢄD þ 4:7 (c 4.0, MeOH); IR (neat, nmax=cmꢀ1) 3409, 3365, 2924,
2484, 1634, 1420, 1091, and 1045; dH (500 MHz, CD3OD) 4.45 (1H, apparent t,
J ¼ 2.5 Hz, H-3), 3.77 (1H, dd, J ¼ 5.0, 9.5 Hz, H-10), 3.63 (1H, dd, J ¼ 5.0,
11.0 Hz, H-20), 3.65 (1H, dd, J ¼ 5.0, 11.0 Hz, H-20), 3.45 (1H, bs, H-2), 3.30 (2H,
apparent t, J ¼ 7.5 Hz, H-5), 2.18–2.10 (1H, m, H-4), 1.91–1.85 (1H, m, H-4); dC
(125 MHz, CDCl3) 70.76 (C-3), 69.8 (2C-C-2 and C-10), 64.5 (C-20), 45.34 (C-5),
34.5 (C-4); ESIMS m=z 148.1 [(M þ H)þ 100%]; HRESIMS calcd. for C6H14NO3
(M þ H)þ 148.0952, found: 148.0974.
(4S,5S)-1-Benzyl-4-(benzyloxy)-5-((S)-2-(tert-
butyldiphenylsiloxy)-1-hydroxyethyl)pyrrolidin-2-one (11)
A 1 M solution of borane-dimethylsulfide in CH2Cl2 (0.36 mL, 0.35 mmol) was
added dropwise to a solution of 7 (0.20 g, 0.35 mmol) in THF (4 mL) at 0 ꢂC under a
N2 atmosphere. The reaction mixture was stirred at rt for 12 h. The reaction mixture
was quenched with ethanol (1.2 mL) and treated with NaBO3 ꢁ 4H2O (0.032 g,
0.21 mmol) at 0 ꢂC. The reaction mixture was then heated at reflux for 3 h. After
being cooled, the reaction mixture was poured into ice water and was extracted with
EtOAc (3 ꢃ 20 mL). The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on
silica gel (2:1 EtOAc=petrol) to give the title compound as a colorless gum
24
(0.103 g, 50%). Rf ¼ 0.48 (6:4 EtOAc=petrol); ½aꢄD ꢀ 0:90 (c 5.40, CHCl3); IR (neat,

2444
N. K. SWAMY AND S. G. PYNE
n
max=cmꢀ1) 3390, 2939, 1680, 1424, 1112, 819, 753, and 712; dH (500 MHz, CDCl3)
7.61–7.13 (m, 20ArH), 5.10 (1H, d, J ¼ 15 Hz), 4.43 (1H, d, J ¼ 12.0 Hz), 4.23 (1H, d,
J ¼ 12.0 Hz), 4.20 (1H, d, J ¼ 15.0 Hz), 4.13–4.10 (1H, m, H-10), 4.00 (1H, apparent q
(ddd), J ¼ 6.0 Hz, H-4), 3.74–3.69 (2H, m, H-20), 3.64 (1H, apparent t, J ¼ 6.0 Hz,
H-5), 2.67 (s, OH), 2.66 (1H, dd, J ¼ 6.0, 16.0 Hz, H-3), 2.53 (1H, dd, J ¼ 6.0,
=
16.0 Hz, H-3); dC (125 MHz, CDCl3) 173.1 (C O), 136.94 (ArC), 135.5 (ArC),
132.9 (ArC), 132.8 (ArC), 129.89 (ArCH), 129.86 (ArCH), 128.5 (ArCH), 128.4
(ArCH), 127.9 (ArCH), 127.77 (ArCH), 127.7 (ArCH), 127.5 (ArCH), 127.2
(ArCH), 73.7 (C-4), 71.4 (C-40), 70.7 (C-10), 65.2 (C-20), 60.6 (C-5), 45.5 (C-30),
36.8 (C-3), 26.8 (3Me), 19.1 (tBuC); ESIMS m=z 602.1 [(M þ Na)þ 100%];
HRESIMS calcd. for C36H41NO4SiNa (M þ Na)þ 602.2780, found: 602.2703.
(S)-1-((2S,3S)-1-Benzyl-3-(benzyloxy)pyrrolidin-2-yl)-2-(tert-
butyldiphenylsiloxy)ethanol (12)
A 1 M solution of borane-dimethylsulfide in CH2Cl2 (0.69 mL, 0.69 mmol) was
added dropwise to a solution of 11 (0.10 g, 0.17 mmol) in anhydrous THF (5 mL) at
0 ꢂC under a N2 atmosphere. The reaction mixture was stirred at rt for 12 h. The
reaction mixture was quenched with ethanol (1 mL). The resulting mixture was
heated at reflux for 2 h. After cooling, the reaction mixture was poured into ice water
and extracted with EtOAc (3 ꢃ 20 mL). The combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue
was chromatographed on silica gel (2:1 EtOAc=petrol) to give the title compound
24
as colorless gum (0.07 g, 72%). Rf ¼ 0.62 (6:4 EtOAc=petrol); ½aꢄD þ 11:0 (c 2.08,
CHCl3); IR (neat, nmax=cmꢀ1) 3359, 2929, 2858, 1429, 1110, 738 and 702; dH
(500 MHz, CDCl3) 7.69–7.23 (m, 20ArH), 4.52 (1H, d, J ¼ 12.0 Hz), 4.45 (1H, d,
J ¼ 12.0 Hz), 4.10–4.04 (3H, m, H-2, H-3, PhCH), 3.75 (1H, dd, J ¼ 6.0, 10.0 Hz,
H-20), 3.69 (1H, dd, J ¼ 7.5, 10.0 Hz, H-20), 3.54 (1H, d, J ¼ 14.0), 3.33 (1H, dd,
J ¼ 3.0, 8.0 Hz, H-10), 3.01–2.97 (1H, m, H-5), 2.38–2.36 (1H, m, H-5), 1.97–1.94
(1H, m, H-4), 1.86–1.85 (1H, m, H-4); dC (125 MHz, CDCl3) 138.2 (ArC), 135.6
(ArC), 134.7 (ArC), 133.5 (ArC), 129.7 (ArCH), 129.6 (ArCH), 128.8 (ArCH),
128.5 (ArCH), 128.4 (ArCH), 128.35 (ArCH), 128.34 (ArCH), 128.1 (ArCH),
127.8 (ArCH), 127.6 (ArCH), 127.5 (ArCH), 127.3 (ArCH), 127.2 (ArCH), 126.9
(ArCH), 78.9 (C-3), 71.5 (C-40), 68.0 (C-2), 65.8 (C-20), 64.0 (C-10), 61.3 (C-30),
50.3 (C-5), 30.6 (C-4), 26.8 (3Me, tBu), 19.2 (tBuC); ESIMS m=z 566.1 [(M þ H)þ
100%]; HRESIMS calcd. for C36H44NO3Si (M þ H)þ 566.3107, found: 566.3090.
(2R,3S)-2-((S)-1,2-Dihydroxyethyl)pyrrolidin-3-ol-hydrochloride (3)
PdCl2 (47 mg, 0.26 mmol) was added to a solution of 12 (0.05 g, 0.088 mmol) in
MeOH (4 mL) at rt under a N2 atmosphere. Then the reaction mixture was flushed
with H2 (balloon), and the solution was stirred at rt under a H2 atmosphere for 12 h.
After completion of the reaction, the reaction mixture was filtered through a celite
bed and washed with MeOH. The solvent was concentrated in vacuo, and then
the residue was triturated several times with ether to get rid of all nonpolar impuri-
ties. This gave the pure title compound as a colorless gum (0.016 g, 99%). Rf ¼ 0.18
23
(1:9 MeOH=EtOAc); ½aꢄD þ 5:7 (c 4.0, MeOH); IR (neat, nmax=cmꢀ1) 3409, 3365,

TRIHYDROXYLATED PYRROLIDINES
2445
2924, 2484, 1634, 1420, 1091, and 1045; dH (500 MHz, CD3OD) 4.41 (1H, bs, H-3),
4.05–4.03 (1H, m, H-10), 3.73 (1H, dd, J ¼ 1.50, 11.5 Hz H-20), 3.65 (1H, dd, J ¼ 3.5,
11.5 Hz, H-20), 3.45 (1H, bs, H-2), 3.43 (1H, bs, H-5), 3.25 (1H, bs, H-5), 2.18–2.16
(1H, m, H-4), 2.10–2.05 (1H, m, H-4); dC (125 MHz, CDCl3) 70.7 (C-3), 69.6 (C-10),
67.5 (C-2), 64.7 (C-20), 44.0 (C-5), 34.9 (C-4); ESIMS m=z 148.1 [(M þ H)þ 100%];
HRESIMS calcd. for C6H14NO3 (M þ H)þ 148.0991, found: 148.0984.
ACKNOWLEDGMENTS
We thank the Australian Research Council and the University of Wollongong
for financial support.
REFERENCES
1. (a) Asano, N. In Modern Alkaloids: Structure, Isolation, Synthesis, and Biology; E.
Fattorusso, O. Taglialatela-Scafati (Eds.); Wiley-VCH: Weinheim, 2008; pp. 11–138; (b)
Asano, N. In Glycoscience: Chemistry and Chemical Biology; B. O. Fraser-Reid, K. Tatsuta,
J. Thiem (Eds.); Springer: Berlin, 2008; pp. 1887–1911.
2. For a recent review on the Meyer–Schuster rearrangement, see Engel, D. A.; Dudley, G. B.
The Meyer–Schuster rearrangement for the synthesis of a,b-unsaturated carbonyl com-
pounds. Org. Biom. Chem. 2009, 7, 4149–4158.
3. (a) Chamberlin, A. R.; Chung, J. Y. Synthesis of optically active pyrrolizidinediols:
(þ)-Heliotridine. J. Am. Chem. Soc. 1983, 105, 3653–3656; (b) Choi, J.-K.; Hart, D. J. Free
radical cyclizations in alkaloid synthesis: (þ)-Heliotridine and (þ)-hastanecine. Tetra-
hedron 1985, 41, 3959–3971.
4. (a) Zhou, X.; Huang, P.-Q. A versatile approach to protected (4S,5R)-4-hydroxy-
5-(a-hydroxyalkyl)-2-pyrrolidinones. Synlett 2006, 1235–1239; (b) Zhou, X.; Zhang,
P.-Y.; Ye, J.-L.; Huang, P.-Q.
A versatile approach to (4S,5R)-4-benzyloxy-5-
(a-hydroxyalkyl)-2-pyrrolidinones: Experimental evidence to the computational predic-
tions. Compt. Rend. Chim. 2008, 11, 5–18.
5. (a) Dugisaki, C. H.; Carroll, P. J.; Correia, R. D. Differential oxidation of endocyclic
enecarbamates: Synthesis of cyclic b-hydroxy-a-amino acids. Tetrahedron Lett. 1998, 39,
3413–3416; (b) Sunose, M.; Anderson, K. M.; Orpen, A. G.; Gallagher, T.; Macdonald,
S. J. F. Synthesis of 3-hydroxy and 3-amino 2-substituted N-heterocycles via enamine
oxidation and aziridination. Tetrahedron Lett. 1998, 39, 8885–8888.
6. Huang has prepared related compounds from the oxidation of similar enamides with
oxone=MeOH or mCPBA=MeOH. See Ref. 4b; Zhou, X.; Liu, W.-J.; Ye, J.-L.; Huang,
P.-Q. Complementary stereocontrolled approaches to 2-pyrrolidinones bearing a vicinal
amino diol subunit with three continuous chiral centers: A formal asymmetric synthesis
of (ꢀ)-detoxinine. J. Org. Chem. 2007, 72, 8904–8909.
7. Morgan, I. R.; Yazici, A.; Pyne, S. G. Metal-catalysed cycloisomerization reactions of cis-
4-hydroxy-5-alkynylpyrrolidinones and cis-5-hydroxy-6-alkynylpiperidinones: Synthesis of
furo[3,2-b]pyrroles and furo[3,2-b]pyridines. Tetrahedron 2008, 64, 1409–1419.
8. Winqvist, A.; Stromberg, R. Stereoselectivity in the synthesis of 30-deoxy-30-C-(hydroxy-
methyl)uridines by hydroboration and conversion into a building block for various
30-deoxy-30-C-(methylene)uridine analogues. Eur. J. Org. Chem. 2001, 4305–4311.

Copyright of Synthetic Communications is the property of Taylor & Francis Ltd and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.