An access to chiral β-benzyl-γ-butyrolactones and its application to the synthesis of enantiopure (+)-secoisolariciresinol, (-)-secoisolariciresinol, and (-)-enterolactone

Article abstract of DOI:10.1055/s-0030-1259982

Both enantiomers of secoisolariciresinol and enantiopure (-)-enterolactone were synthesized through a highly stereoselective convergent synthesis. An Evans diastereoselective alkylation followed by a substrate-induced diastereoselective -alkylation of the newly formed optically active β-benzyl-γ- butyrolactone gave the β-β′ linkage of the target skeleton. The (S,S)- and (R,R)-enantiomers of secoisolariciresinol and (-)-enterolactone were obtained in 12-14% (11 steps) and 20% (7 steps) overall yield, respectively. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259982

1456
PAPER
An Access to Chiral b-Benzyl-g-butyrolactones and Its Application to the
Synthesis of Enantiopure (+)-Secoisolariciresinol, (–)-Secoisolariciresinol,
and (–)-Enterolactone
Florent Allais,* Thomas J. L. Pla, Paul-Henri Ducrot*
INRA/AgroParisTech UMR1318 Institut Jean-Pierre Bourgin, INRA route de Saint-Cyr, 78026 Versailles Cedex, France
Fax +33(1)30833119; E-mail: florent.allais@versailles.inra.fr
Received 24 January 2011; revised 4 March 2011
optical purity. However, a main drawback in this synthetic
Abstract: Both enantiomers of secoisolariciresinol and enantiopure
route lies in the sensitivity of tert-butyl ester during the sa-
(–)-enterolactone were synthesized through a highly stereoselective
ponification of the oxazolidinone moiety. In fact, despite
convergent synthesis. An Evans diastereoselective alkylation fol-
careful control of the temperature during the workup, we
lowed by a substrate-induced diastereoselective a-alkylation of the
newly formed optically active b-benzyl-g-butyrolactone gave the b- were unable to reproduce their results as the tert-butyl es-
b¢ linkage of the target skeleton. The (S,S)- and (R,R)-enantiomers
of secoisolariciresinol and (–)-enterolactone were obtained in 12–
14% (11 steps) and 20% (7 steps) overall yield, respectively.
ter was partially cleaved, leading to an undesired diacid
intermediate.
Key words: total synthesis, natural product, lactones, asymmetry,
diastereoselective alkylation
R1
R1
O
O
O
Lignans form a large class of secondary metabolites wide-
ly encountered in plants.1,2 In 1936, the term lignan was
introduced by Harworth3 to describe a group of plant phe-
nols whose general structure was determined by the oxi-
dase-catalyzed b-b¢ radical coupling of two cinnamic acid
residues. Many lignans exhibit potent biological activi-
ties, mainly due to their antioxidant properties. Therefore,
lignans have not only been used in folk remedies for cen-
turies to treat a wide range of disorders but also remain to-
day as promising drug targets.4 Developing new synthetic
methods for lignans is therefore a challenge for synthetic
R2
R2
O
4
2
β
O
R1
R1
3
O
O
R1
O
O
R2
O
R2
5
6
chemists.1,2,5 Many methods for asymmetric synthesis of Figure 1 b-Benzyl-g-butyrolactones as key substructures in lignan
synthesis
chiral lignans involved the intermediacy of enantiomeri-
cally pure b-benzyl-g-butyrolactones (R)-3 and (S)-3
(Figure 1). They allowed – through diastereoselective re-
actions on (R)-3 and (S)-3 – the synthesis of dibenzylbu-
tyrolactones 2, dibenzylcyclooctadienes 4, aryltetralins 5,
and benzylidenebenzylbutyrolactones 6. Several synthetic
approaches for the preparation of optically active butyro-
lactones have been published.5i,6 Although these methods
have provided elegant routes to the preparation of lignan
intermediates, many issues remain. In fact, these methods
are limited either in terms of yields, number of steps,
enantiomeric purity, or reagents/reactants availability. In
1997, Charlton published a convenient and straightfor-
ward approach for the asymmetric synthesis of b-benzyl-
g-butyrolactones (R)-3 and (S)-3 using Evans diastereose-
lective alkylation through substituted oxazolidinone as
chiral auxilliaries.7 This versatile asymmetric synthesis
then allowed the formation of b-benzyl-g-butyrolactones
in a six-step procedure in 45% overall yield and in >95%
In the course of our studies dedicated to greener asymmet-
ric syntheses of lignans and phenolic natural substances, a
short, cost-limited, and efficient access to chiral b-benzy-
lated g-butyrolactones was devised and, to prove its utili-
ty, was applied to the enantioselective synthesis of
secoisolariciresinols 1 and enterolactone (2a). This new
methodology uses Evans diastereoselective alkylation (al-
lylation) as it allows the formation of both enantiomers in
excellent ee’s and the possible recovery of the oxazolidi-
nones (recycling).
Our retrosynthetic analysis of 1 and 2a relied on the con-
trol of the chirality of the b-b¢ bond via Evans diastereo-
selective alkylation followed by a substrate-induced
diastereoselective a-alkylation of the b-benzyl-g-butyro-
lactone intermediate 3 (Scheme 1). First, our efforts were
focused on the diastereoselective synthesis of the chiral b-
benzylated g-butyrolactones and the formation of the two
enantiomers of diol 1. Ferulic acid (9) was easily convert-
ed into its dihydrocinnamic acid derivative 10 in 77%
yield through a classical three-step sequence (catalytic hy-
SYNTHESIS 2011, No. 9, pp 1456–1464
x
x
.
x
x
.2
0
1
1
Advanced online publication: 01.04.2011
DOI: 10.1055/s-0030-1259982; Art ID: T14311SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Chiral b-Benzyl-g-butyrolactones
1457
OH
OH
MeO
HO
MeO
MeO
BnO
O
O
O
BnO
O
(S)-3a
MeO
(S,S)-1
MeO
(S,S)-2b
OH
OBn
O
O
O
MeO
MeO
MeO
BnO
OH
OH
N
O
HO
BnO
9
(R)-7a
8
Scheme 1 Retrosynthetic pathway for diol (S,S)-1
drogenation of the olefin over Pd/C, perbenzylation, and Therefore, KHMDS-generated enolates of 11 and 12 were
saponification of the benzyl ester). Acid 10 was then cou- alkylated with allyl iodide and provided the correspond-
pled with chiral oxazolidinones (S)-4-isopropyl-2-oxazo- ing optically active allyl adducts (S)-8 and (R)-13 in 86%
lidinone (A) and (R)-4-benzyl-2-oxazolidinone (B) using and 90% yield, respectively, and in excellent diastereo-
Evans procedure8 to provide enantiopure 11 and 12 (72% meric ratios (>97:3 dr) (Schemes 2 and 3).9a
yield) (Figure 2).
With the butyrolactone precursors in hand, the removal of
the chiral auxiliaries was achieved via LiBH4 reduction of
O
O
O
O
O
O
H
(R)-13 and (S)-8 providing, respectively, the optically ac-
tive primary alcohols (R)-7a and (S)-7a in 67 and 70%
yield, respectively, and in 98% ee.9b Both enantiomers of
7a were then efficiently transformed into the b-benzyl-g-
butyrolactones (S)-3a and (R)-3a in a two-step sequence:
the oxidative cleavage of the olefin in (R)-7a and (S)-7a
(OsO4, NaIO4, 2,6-lutidine, 1,4-dioxane–H2O) provided a
crude hemiacetal,10 which was directly oxidized into its
corresponding lactone with Fetizon’s reagent11 (silver car-
bonate on Celite) to give (S)-3a and (R)-3a in 73 and 77%
yield, respectively. In order to complete the synthesis of
diols (S,S)-1 and (R,R)-1, the next task was the diastereo-
selective benzylation of both enantiomers of 3a on the a-
position (Scheme 4). Thus, after deprotonation of (R)-3a
and (S)-3a with NaHMDS and treatment with substituted
benzyl iodide 14,12,13h the dibenzylated lactones (R,R)-2b
and (S,S)-2b were obtained in 66 and 64% yield, respec-
tively, and in >97:3 dr.9a Finally, secoisolariciresinols
H
H
N
N
N
Bn
Bn
B
A
C
Figure 2 Evans chiral oxazolidinones
At this stage, we searched for an alternative to Charlton’s
procedure in order to simplify the formation of butyrolac-
tone 3. Our main objective being a cost-efficient and
straightforward total synthesis of 1 and 2a, efforts were
directed towards the development of a new pathway to 3
using an acid- and base-resistant alkylating agent in order
to achieve a selective removal of the oxazolidinone
through saponification or reduction. Allyl iodide was cho-
sen as the alkylating agent, which besides its chemical re-
sistance, offered another benefit as it would serve as a
masked carbonyl group required latter on in the synthesis.
CO2H
CO2H
O
O
i) H2, Pd/C
ii) BnBr, K2CO3
acetone–MeCN,
Δ
Ar
N
i) Et3N, pivCl, THF, –78 °C
O
iii) KOH, H2O–MeOH
70 °C
ii) BuLi, oxazolidinone A
OMe
OMe
72%
OH
OBn
77%
11
9
10
KHMDS
allyl iodide
THF, –72 °C
86%
Ar = 4-BnO-3-MeOC6H3
O
O
i) OsO4, NaIO4, 2,6-lutidine
1,4-dioxane–H2O
LiBH4, MeOH, 0 °C to r.t.
70%
Ar
O
Ar
N
O
Ar
OH
ii) Ag2CO3–Celite, C6H6
77%11
O
(R)-3a
(S)-7a
8
Scheme 2 Diastereoselective synthesis of a-benzyl-g-butyrolactone (R)-3a
Synthesis 2011, No. 9, 1456–1464 © Thieme Stuttgart · New York

1458
F. Allais et al.
PAPER
O
O
O
O
i) Et3N, pivCl, THF, –78 °C
KHMDS, allyl iodide
THF, –72 °C
10
Ar
N
Ar
N
O
O
ii) BuLi, oxazolidinone B
Bn
Bn
72%
90%
12
13
Ar = 4-BnO-3-MeOC6H3
i) OsO4, NaIO4, 2,6-lutidine
1,4-dioxane–H2O
LiBH4, MeOH, 0 °C to r.t.
67%
Ar
Ar
O
OH
ii) Ag2CO3–Celite, C6H6
73%11
O
(R)-7a
(S)-3a
Scheme 3 Diastereoselective synthesis of a-benzyl-g-butyrolactone (S)-3a
OH
MeO
HO
i) H2, Pd/C
NaHMDS, 14
Ar
Ar
ii) LiAlH4, Et2O, –15 °C
THF, –54 °C
O
O
66%
83%
O
O
OH
Ar
(R)-3a
(R,R)-2b
MeO
OH
(R,R)-1
14 = ArCH2I
Ar = 4-BnO-3-MeOC6H3
OH
OH
MeO
HO
i) H2, Pd/C
NaHMDS, 14
Ar
Ar
ii) LiAlH4, Et2O, –15 °C
THF, –54 °C
O
O
64%
80%
O
O
Ar
(S,S)-2b
(S)-3a
MeO
OH
(S,S)-1
Scheme 4 Diastereoselective synthesis of secoisolariciresinols (S,S)-1 and (R,R)-1
(S,S)-1 and (R,R)-1 were successfully formed after remov- To evaluate the scope of this new access to b-benzyl-g-bu-
al of benzyl protecting groups via hydrogenation directly tyrolactones, the synthesis of the widely known lignan
followed by lithium aluminum hydride reduction of the (–)-enterolactone (2a) was undertaken, for which numer-
lactones [80–83% yield; (S,S)-1: 12% overall yield (11 ous total syntheses have been reported to
steps), (R,R)-1: 14% overall yield (11 steps)].
date.6a,b,12b,13According to the procedure described in
Scheme 2, commercially available 3-methoxydihydrocin-
CO2H
O
O
O
O
KHMDS, allyl iodide
THF, –72 °C
i) Et3N, pivCl, THF, –78 °C
Ar
N
Ar
N
O
O
ii) BuLi, oxazolidinone C
77%
Bn
Bn
OMe
88%
15
16
17
LiBH4
MeOH, 0 °C to r.t.
Ar = 3-MeOC6H3
71%
O
i) LiHMDS, ArCH2Br
THF, –78 °C
i) OSO4, NaIO4,2,6-lutidine
1,4-dioxane–H2O
Ar
Ar
OH
O
HO
O
ii) BBr3, CH2Cl2
0 °C to –18 °C
ii) Ag2CO3–Celite, C6H6
O
73%10
OH
59%
(R)-3b
2a
(S)-7b
Scheme 5 Stereoselective synthesis of (–)-enterolactone (2)
Synthesis 2011, No. 9, 1456–1464 © Thieme Stuttgart · New York

PAPER
Chiral b-Benzyl-g-butyrolactones
1459
tone–MeCN (1:1, 600 mL) under argon was added K2CO3 (39.6 g,
286.8 mmol) and BnBr (60 mL, 86.28 g, 504.5 mmol). The mixture
was refluxed until completion (TLC), filtered over Celite, and con-
centrated in vacuo to provide crude dibenzylated dihydroferulic
acid. To a solution of the crude dibenzylated dihydroferulic acid in
MeOH–H2O (58 mL/580 mL) was added KOH (78.6 g) and the so-
lution was stirred at 70 °C until completion. The mixture was then
cooled to r.t. and washed with CHCl3 (3 × 600 mL). The aqueous
layer was neutralized with concd HCl until pH 2 and extracted with
CHCl3 (5 × 600 mL). The combined organic layers were washed
with brine (400 mL), dried (MgSO4), filtered, and concentrated in
vacuo. The crude product was purified by flash chromatography
(cyclohexane–EtOAc, 3:7) to give 10 as a white solid (22.3 g, 77%).
All spectral data were consistent with those reported in the litera-
ture.14
namic acid (15) was coupled with chiral oxazolidinone
(S)-4-benzyl-2-oxazolidinone (C) (Figure 2) using Evans
procedure and provided enantiopure 16 (88%)
(Scheme 5). Diastereoselective alkylation of 16 was then
realized and gave the optically active allylated intermedi-
ate 17 in 77% yield and with >97/3 dr.9a LiBH4 reduction
of 17 gave the corresponding alcohol (S)-7b (98% ee)9b
which, after oxidative cleavage and oxidation, provided
the b-benzyl-g-butyrolactone (R)-3b in 52% yield. Final-
ly, after diastereoselective a-alkylation of (R)-3b and sub-
sequent O-demethylation,13l (–)-enterolactone (2a) was
obtained in 59% yield (20% overall yield, 7 steps) and its
spectral data were in good agreement with those reported
in the literature.6a,b,12b,13
(S)-3-[3-(4-Benzyloxy-3-methoxyphenyl)propanoyl]-4-isopro-
pyloxazolidin-2-one (11)
In conclusion, we have developed an efficient, short, and
easy access to enantiopure b-benzyl-g-butyrolactones via
Evans diastereoselective allylation and oxidative cleavage
of the allyl moiety as the key steps. This methodology was
then successfully applied to the synthesis of (–)-enterolac-
tone and both enantiomers of secoisolariciresinol in good
yields and with excellent stereoselectivity.
To a solution of 10 (1.00 g, 3.49 mmol) in THF (9 mL) under argon
at –70 °C was successively added, dropwise, Et3N (0.56 mL, 407
mg, 4.02 mmol) and pivaloyl chloride (0.45 mL, 434 mg, 3.59
mmol). The mixture was then warmed to 0 °C, stirred at this tem-
perature for 1 h, and then recooled to –70 °C. n-BuLi (2.24 mL, 1.6
M in hexane, 3.59 mmol) was added dropwise to a solution of (S)-
4-isopropyl-2-oxazolidinone (451 mg, 3.49 mmol) in THF (20 mL)
under argon at –70 C. The resulting lithium salt was then transferred
to the above anhydride mixture via a cannula at –70 °C over a 10
min period. The resulting mixture was then stirred for 1 h, warmed
to 0 °C, and stirred for 35 min at this temperature. Quenching was
realized by adding sat. aq NH4Cl (2.8 mL). The mixture was con-
centrated in vacuo to remove THF, diluted with H2O (14 mL), and
extracted with EtOAc (4 × 15 mL). The organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo to give crude 11. Flash
chromatography on silica gel (cyclohexane–EtOAc, 8:2) provided
pure 11 as a thick oil (1.00 g, 72%); [a]D16 +53.9 (c 0.1, CHCl3).
CH2Cl2 (stabilized with amylene) was purified by distillation from
CaH2 under N2 immediately before use. THF and Et2O were puri-
fied by distillation from sodium/benzoquinone under N2. Moisture
and O2-sensitive reactions were carried out in flame-dried glass-
ware under N2. Evaporations were conducted under reduced pres-
sure at temp below 35 °C unless otherwise noted. Column
chromatography (CC) was carried out under positive N2 pressure
with 40–63 mm silica gel. Melting points are uncorrected. 1H Spec-
tra of samples in the indicated solvent were recorded at 300 MHz at
20 °C (1H NMR: CDCl3 residual signal at 7.26 ppm). 13C NMR
Spectra of samples in the indicated solvent were recorded at 75
MHz at 20 °C (13C NMR: CDCl3 residual signal at 77.26 ppm). All
reported yields are uncorrected and refer to purified products. As-
signments are given as per the labeling shown below (Figure 3).
IR (neat): 2965, 1778, 1699, 1514 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.44–7.25 (m, 5 H, C6H5), 6.81–
6.69 (m, 3 H, H-5, H-8, H-9, Ar), 5.12 (s, 2 H, H-11, OCH2Ph), 4.40
(app quint, J = 3.6 Hz, 1 H, H-3¢, NCH-i-Pr), 4.25–4.15 [m, 2 H, H-
2¢, NC(=O)CH2CH-i-Pr], 3.88 (s, 3 H, H-10, ArOCH3), 3.18 [m, H-
3, C(=O)CH2CH2Ar], 3.00–2.86 [m, 2 H, H-2, C(=O)CH2CH2Ar],
2.39–2.27 [m, 1 H, H-4¢, CH(CH3)2], 0.89 [d, J = 7.0 Hz, 3 H, H-5¢,
CH(CH3)2], 0.82 [d, J = 7.0 Hz, 3 H, H-5¢, CH(CH3)2].
13C NMR (75 MHz, CDCl3): d = 172.7 (s, C-1, carbon from amide),
154.3 (s, C-1¢, carbon from urethane), 149.9 (s, C-6, Ar), 146.9 (s,
C-7, Ar), 137.6 (s, C-12, C6H5), 134.0 (s, C-4, Ar), 128.7 (d, C-14,
C6H5), 127.9 (d, C-15, C6H5), 127.5 (d, C-13, C6H5), 120.6 (d, C-9,
Ar), 114.6 (d, C-5, Ar), 112.8 (d, C-8, Ar), 71.4 (t, C-11, OCH2Ph),
63.6 (d, C-3¢, NCH-i-Pr), 58.7 [t, C-2¢, NC(=O)CH2CH-i-Pr], 56.2
(q, C-10, ArOCH3), 37.3 [t, C-2, C(=O)CH2CH2Ar], 30.4 [d, C-4¢,
CH(CH3)2], 28.6 [t, C-3, C(=O)CH2CH2Ar], 18.1 [q, C-5¢,
CH(CH3)2], 14.8 [q, C-5¢, CH(CH3)2].
O
1
2
O
1
O
7
6
3
3
5
8
2
O
O
6
7
4
8
10
14
N
Me
12
1'
Me
O
4
O
5
3'
16
9
17
2'
O
4'
5'
9
11
10
18
11
12
13
15
O
1
O
13
3
5
8
2
O
6
4
10
N
1'
Me
12
O
3'
16
9
17
7
2'
6'
7'
O
4'
5'
11
18
HRMS (TOF, ES+): m/z calcd for C23H27NO5 + Na [M + Na]:
420.1787; found: 420.1789.
13
15
14
8'
(S)-3-[(S)-2-(4-Benzyloxy-3-methoxybenzyl)pent-4-enoyl]-4-
isopropyloxazolidin-2-one (8)
Figure 3 Numbering of the carbon atoms for NMR assignments
To a solution of 11 (1.00 g, 2.51 mmol) in THF (26 mL) under argon
at –72 °C was added KHMDS (5.3 mL, 0.5 M in hexane, 2.64
mmol) over a 10 min period. The mixture was stirred at this temper-
ature for 1 h, and then allyl iodide (0.69 mL, 1.27 g, 7.55 mmol) was
added over a 5 min period. The mixture was stirred at –72 °C for 2
h before quenching with sat. aq NH4Cl (10 mL). The mixture was
concentrated in vacuo to remove THF and extracted with EtOAc
(4 × 20 mL). The organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo to give crude 8. Flash chromatography on sil-
3-(4-Benzyloxy-3-methoxyphenyl)propanoic Acid (10)
To a solution of ferulic acid (9; 20.0 g, 103 mmol) in EtOAc (500
mL) under argon at r.t. was added 10% Pd/C and the solution was
placed under an atmosphere of H2 (1 atm). The mixture was stirred
at r.t. until completion (TLC), filtered over Celite and concentrated
in vacuo to afford dihydroferulic acid as a white solid (19.8 g, 98%).
To a solution of dihydroferulic acid (19.8 g, 100.9 mmol) in ace-
Synthesis 2011, No. 9, 1456–1464 © Thieme Stuttgart · New York

1460
F. Allais et al.
PAPER
ica gel (cyclohexane–EtOAc, 8:2) provided pure 8 as a thick oil
(942 mg, 86%); [a]D22 +75.5 (c 0.1, CH2Cl2).
IR (neat): 2967, 1775, 1697, 1513 cm–1.
dition of CH2Cl2 (15 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 20 mL); the combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. The crude hemiacetal
(lactol) was used directly without further purification. Ag2CO3 on
Celite11b (972 mg, 1.62 mmol) was added to a solution of crude lac-
tol in benzene (6.9 mL). The mixture was refluxed for 4 h, cooled
to r.t., filtered on Celite and concentrated in vacuo. The crude prod-
uct was purified by flash chromatography (cyclohexane–EtOAc,
6:4) to afford pure lactone (R)-3a as a thick oil (156 mg, 77%) with
1H NMR (300 MHz, CDCl3): d = 7.42–7.26 (m, 5 H, C6H5), 6.76 (d,
J = 7.5 Hz, 2 H, Ar), 6.63 (d, J = 7.2 Hz, 1 H, Ar), 5.81 (m, 1 H, H-
17, CH2CH=CH2), 5.12 (s, 2 H, H-11, OCH2Ph), 5.13–5.01 (m, 2 H,
H-18, CH2CH=CH2), 4.34 (m, 1 H, H-3¢, NCH-i-Pr), 4.16 [m, 1 H,
H-2, C(=O)CH2CH2Ar], 4.01 [d, J = 8.7 Hz,
1 H, H-2¢,
spectral data in good agreement with literature values;15 [a]D
20
NC(=O)CH2CH-i-Pr], 3.87 (s, 3 H, H-10, ArOCH3), 3.81 [app t,
J = 8.9 Hz, 1 H, H-2¢, NC(=O)CH2CH-i-Pr], 2.88–2.69 [m, 2 H, H-
3, C(=O)CH2CH2Ar], 2.50 (m, 1 H, H-16, CH2CH=CH2), 2.33–2.27
[m, 2 H, H-4¢, CH(CH3)2 and H-16, CH2CH=CH2], 0.85 [d, J = 7.0
Hz, 3 H, H-5¢, CH(CH3)2], 0.81 [d, J = 7.0 Hz, 3 H, H-5¢,
CH(CH3)2].
–16.0 (c 0.2, CHCl3) {Lit.2b [a]D20 –16.0 (c 0.4, CHCl3)}.
(R)-4-Benzyl-3-[3-(4-benzyloxy-3-methoxyphenyl)pro-
panoyl]oxazolidin-2-one (12)
To a solution of 10 (1.00 g, 3.49 mmol) in THF (9 mL) under argon
at –70 °C were successively added, dropwise, Et3N (0.56 mL, 407
mg, 4.02 mmol) and pivaloyl chloride (0.45 mL, 434 mg, 3.59
mmol). The mixture was then warmed to 0 °C and stirred at this
temperature for 1 h, then recooled to –70 °C. n-BuLi (2.24 mL, 1.6
M in hexane, 3.59 mmol) was added dropwise to a solution of (R)-
4-benzyl-2-oxazolidinone (618 mg, 3.49 mmol) in THF (20 mL)
under argon at –70 °C. The resulting lithium salt was then trans-
ferred to the above anhydride mixture via a canula at –70 °C over a
10 min period. The resulting mixture was then stirred for 1 h,
warmed to 0 °C, and stirred for 35 min at this temperature. Quench-
ing was realized by adding sat. aq NH4Cl (2.8 mL). The mixture was
concentrated in vacuo to remove THF, diluted with H2O (14 mL),
and extracted with EtOAc (4 × 15 mL). The organic extracts were
dried (MgSO4), filtered, and concentrated in vacuo to give crude 12.
Flash chromatography on silica gel (cyclohexane–EtOAc, 8:2) pro-
13C NMR (75 MHz, CDCl3): d = 175.5 (s, C-1, carbon from amide),
153.9 (s, C-1¢, carbon from urethane), 149.7 (s, C-6, Ar), 146.8 (s,
C-7, Ar), 137.5 (s, C-12, C6H5), 135.3 (d, C-17, CH2CH=CH2),
132.4 (s, C-4, Ar), 128.6 (d, C-14, C6H5), 127.9 (d, C-15, C6H5),
127.5 (d, C-13, C6H5), 121.2 (d, C-9, Ar), 117.3 (t, C-18,
CH2CH=CH2), 114.3 (d, C-5, Ar), 113.1 (d, C-8, Ar), 71.2 (t, C-11,
OCH2Ph), 63.3 (d, C-3¢, NCH-i-Pr), 58.8 [t, C-2¢, NC(=O)CH2CH-
i-Pr], 56.1 (q, C-10, ArOCH3), 44.0 [t, C-2, C(=O)CH2CH2Ar], 38.1
[t, C-3, C(=O)CH2CH2Ar], 36.6 (t, C-16, CH2CH=CH2), 28.8 [d, C-
4¢, CH(CH3)2], 18.1 [q, C-5¢, CH(CH3)2], 15.0 [q, C-5¢, CH(CH3)2].
HRMS (TOF, ES+): m/z calcd for C26H31NO5 + Na [M + Na]:
460.2100; found: 460.2121.
(S)-2-(4-Benzyloxy-3-methoxybenzyl)pent-4-en-1-ol [(S)-7a]
To a rapidly stirred solution of 8 (228 mg, 0.52 mmol) in Et2O (15
mL) were added LiBH4 (0.52 mL, 2.0 M, 1.04 mmol) and anhyd
MeOH (44 mL, 1.04 mmol) dropwise. After stirring at r.t. until com-
pletion, the reaction mixture was cooled to 0 °C and 1 M aq NaOH
(2 mL) and EtOAc (15 mL) were added. The organic layer was sep-
arated, washed with H2O (5 mL) and brine (5 mL), dried (MgSO4),
filtered, and concentrated in vacuo to give crude alcohol, which was
then purified by flash chromatography (cyclohexane–EtOAc, 6:4)
22
vided pure 12 as a thick oil (1.12 g, 72%); [a]D –52.9 (c 1,
CH2Cl2).
IR (neat): 2879, 1782, 1695, 1514 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.44–7.15 (m, 10 H, C6H5), 6.84–
6.72 (m, 3 H, Ar), 5.13 (s, 2 H, H-11, OCH2Ph), 4.65 (m, 1 H, H-3¢,
NCHCH2Ph), 4.16 [m, 2 H, H-2¢, NC(=O)CH2CHCH2Ph], 3.89 (s,
3 H, H-10, ArOCH3), 3.25 [m, 3 H, H-3, C(=O)CH2CH2Ar and H-
4¢, NCHCH2Ph], 2.96 [m, 2 H, H-2, C(=O)CH2CH2Ar], 2.74 (m, 1
H, H-4¢, NCHCH2Ph).
13C NMR (75 MHz, CDCl3): d = 172.6 (s, C-1, carbon from amide),
153.6 (s, C-1¢, carbon from urethane), 149.9 (s, C-6, Ar), 146.9 (s,
C-7, Ar), 137.6 (s, C-5¢, C6H5), 135.4 (s, C-12, C6H5), 133.9 (s, C-
4, Ar), 129.6 (d, C-7¢, C6H5), 129.1 (d, C-8¢, C6H5), 128.7 (d, C-14,
C6H5), 127.9 (d, C-15, C6H5), 127.6 (d, C-6¢, C6H5), 127.5 (d, C-13,
C6H5), 120.7 (d, C-9, Ar), 114.5 (d, C-5, Ar), 112.8 (d, C-8, Ar),
71.4 (t, C-11, OCH2Ph), 66.3 [t, C-2¢, NC(=O)CH2CHCH2Ph], 56.2
(q, C-10, ArOCH3), 55.3 (d, C-3¢, NCHCH2Ph), 38.0 (t, C-4¢,
NCHCH2Ph), 37.4 [t, C-2, C(=O)CH2CH2Ar], 30.2 [t, C-3,
C(=O)CH2CH2Ar].
25
providing pure (S)-7a as a thick oil (114 mg, 70%); [a]D –17.9
(c 0.1, CH2Cl2).
IR (neat): 3400, 2910, 1512 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.46–7.25 (m, 5 H, C6H5), 6.82–
6.63 (m, 3 H, Ar), 5.84 (m, 1 H, H-17, CH2CH=CH2), 5.12 (s, 2 H,
H-11, OCH2Ph), 5.13–5.00 (m, 2 H, H-18, CH2CH=CH2), 3.88 (s,
3 H, H-10, ArOCH3), 3.55 [d, J = 5.4 Hz, 2 H, H-1, ArCH2CH(al-
lyl)CH2OH], 2.57 [m, 2 H, H-3, ArCH2CH(allyl)CH2OH], 2.13
(app t, J = 6.0 Hz, 2 H, H-16, CH2CH=CH2), 1.89 [m, 1 H, H-2,
ArCH2CH(allyl)CH2OH], 1.58 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 149.9 (s, C-6, Ar), 146.8 (s, C-7,
Ar), 137.7 (s, C-12, C6H5), 137.1 (d, C-17, CH2CH=CH2), 134.0 (s,
C-4, Ar), 128.7 (d, C-14, C6H5), 128.0 (d, C-15, C6H5), 127.5 (d, C-
13, C6H5), 121.4 (d, C-9, Ar), 116.8 (t, C-18, CH2CH=CH2), 114.6
(d, C-5, Ar), 113.4 (d, C-8, Ar), 71.5 (t, C-11, OCH2Ph), 65.1 [t, C-
1, ArCH2CH(allyl)CH2OH], 56.3 (q, C-10, ArOCH3), 42.7 [d, C-2,
ArCH2CH(allyl)CH2OH], 37.2 [t, C-3, ArCH2CH(allyl)CH2OH],
35.8 (t, C-16, CH2CH=CH2).
HRMS (TOF, ES+): m/z calcd for C27H27NO5 + Na [M + Na]:
468.1787; found: 468.1795.
(R)-4-Benzyl-3-[(S)-2-(4-benzyloxy-3-methoxybenzyl)pent-4-
enoyl]oxazolidin-2-one (13)
To a solution of 12 (1.12 g, 2.51 mmol) in THF (26 mL) under argon
at –72 °C was added KHMDS (5.3 mL, 0.5 M in hexane, 2.64
mmol) over a 10 min period. The mixture was stirred at this temper-
ature for 1 h, then allyl iodide (0.69 mL, 1.27 g, 7.55 mmol) was
added over a 5 min period. The mixture was stirred at –72 °C for 2
h before quenching with sat. aq NH4Cl (10 mL). The mixture was
concentrated in vacuo to remove THF, and extracted with EtOAc
(4 × 20 mL). The combined organic extracts were dried (MgSO4),
filtered, and concentrated in vacuo to give crude 15. Flash chroma-
tography on silica gel (cyclohexane–EtOAc, 9:1) provided pure 13
as a thick oil (1.10 g, 90%); [a]D21 –89.7 (c 1, CH2Cl2).
HRMS (TOF, ES+): m/z calcd for C20H24O3 + Na [M + Na]:
335.1623; found: 335.1637.
(R)-4-(4-Benzyloxy-3-methoxybenzyl)dihydrofuran-2(3H)-one
[(R)-3a]
To a solution of (S)-7a (203 mg, 0.65 mmol) in 1,4-dioxane–H2O
mixture (3:1, 5.4 mL/1.8 mL) at r.t. were successively added OsO4
(0.013 mmol), 2,6-lutidine (0.15 mL, 1.29 mmol), and NaIO4 (555
mg, 2.59 mmol). The solution was stirred at r.t. until completion,
then quenched by the addition of H2O (10 mL) followed by the ad-
Synthesis 2011, No. 9, 1456–1464 © Thieme Stuttgart · New York

PAPER
Chiral b-Benzyl-g-butyrolactones
1461
IR (neat): 2908, 1776, 1696, 1513 cm–1.
layers were dried (MgSO4), filtered, and concentrated in vacuo. The
crude hemiacetal (lactol) was used directly without further purifica-
tion. Ag2CO3 on Celite11b (1.54 g, 2.57 mmol) was added to a solu-
tion of crude lactol in benzene (11 mL). The mixture was refluxed
for 4 h, cooled to r.t., filtered on Celite, and concentrated in vacuo.
The crude product was purified by flash chromatography (cyclo-
hexane–EtOAc, 6:4) to afford pure lactone (S)-3a as a thick oil (235
mg, 73%) with spectral data in good agreement with literature val-
ues;15 [a]D20 +16.2 (c 0.3, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.43–7.16 (m, 10 H, C6H5), 6.80–
6.63 (m, 3 H, Ar), 5.86 (m, 1 H, H-17, CH2CH=CH2), 5.12 (s, 2 H,
H-11, OCH2Ph), 5.16–5.01 (m, 2 H, H-18, CH2CH=CH2), 4.36 [m,
2 H, H-2, C(=O)CH(allyl)CH2Ar and H-3¢, NCHCH2Ph], 3.96 [d,
J = 6.9 Hz, 1 H, H-2¢, NC(=O)CH2CHCH2Ph], 3.87 (s, 3 H, H-10,
ArOCH3), 3.72 [app t, J = 8.4 Hz,
1
H, H-2¢,
NC(=O)CH2CHCH2Ph], 3.21 (dd, J = 2.7, 13. 2 Hz, 1 H, H-4¢,
NCHCH2Ph), 2.91–2.76 [m, 2 H, H-3, C(=O)CH(allyl)CH2Ar],
2.68–2.49 (m, 2 H, H-4¢, NCHCH2Ph and H-16, CH2CH=CH2),
2.40–2.30 (m, 1 H, H-16, CH2CH=CH2).
1-Benzyloxy-4-(iodomethyl)-2-methoxybenzene (14)
To a solution of vanillin (7.70 g, 50.67 mmol) in EtOH (40 mL) was
added K2CO3 (7.90 g, 57.35 mmol) and BnBr (6.0 mL, 50.67
mmol), and the mixture was stirred at r.t. overnight. The reaction
mixture was filtered through Celite and the filtrate concentrated in
vacuo. The residue was redissolved in CH2Cl2 (250 mL), washed
with aq 5% w/v NaOH (2 × 100 mL) and the organic layer was dried
(MgSO4), filtered, and concentrated in vacuo. The recrystallization
of the residue obtained from EtOH gave 4-benzyloxy-3-methoxy-
benzaldehyde as a white powder (11.2 g, 91%); mp 63–64 °C.
1H NMR (300 MHz, CDCl3): d = 9.82 (s, 1 H, H-1, CHO), 7.42–
7.36 (m, 7 H, C6H5, H-6, H-7, Ar), 6.98 (d, J = 8.1 Hz, 1 H, H-3,
Ar), 5.23 (s, 2 H, H-9, OCH2Ph), 3.93 (s, 3 H, H-8, ArOCH3).
13C NMR (75 MHz, CDCl3): d = 191.0 (s, C-1, CHO), 153.9 (s, C-
5, Ar), 150.4 (s, C-4, Ar), 136.3 (s, C-10, C6H5), 130.6 (s, C-2, Ar),
128.9 (d, C-12, C6H5), 128.4 (d, C-13, C6H5), 127.4 (d, C-11, C6H5),
126.7 (d, C-7, Ar), 112.8 (d, C-6, Ar), 109.8 (d, C-3, Ar), 71.1 (t, C-
9, OCH2Ph), 56.3 (q, C-8, ArOCH3).
13C NMR (75 MHz, CDCl3): d = 175.6 (s, C-1, carbon from amide),
153.3 (s, C-1¢, carbon from urethane), 149.8 (s, C-6, Ar), 146.9 (s,
C-7, Ar), 137.5 (s, C-5¢, C6H5), 135.6 (d, C-17, CH2CH=CH2),
135.3 (s, C-12, C6H5), 132.3 (s, C-4, Ar), 129.6 (d, C-7¢, C6H5),
129.1 (d, C-8¢, C6H5), 128.7 (d, C-14, C6H5), 128.0 (d, C-15, C6H5),
127.5 (d, C-6¢, C-13, C6H5), 121.2 (d, C-9, Ar), 117.5 (t, C-18,
CH2CH=CH2), 114.3 (d, C-5, Ar), 113.1 (d, C-8, Ar), 71.3 (t, C-11,
OCH2Ph), 66.0 [t, C-2¢, NC(=O)CH2CHCH2Ph], 56.2 (q, C-10,
ArOCH3), 55.8 (d, C-3¢, NCHCH2Ph), 44.1 [t, C-2, C(=O)CH(al-
lyl)CH2Ar], 38.4 [t, C-4¢, NCHCH2Ph or C-3, C(=O)CH(al-
lyl)CH2Ar], 38.3 [t, C-3, C(=O)CH2CH2Ar or C-4¢, NCHCH2Ph],
36.6 (t, C-16, CH2CH=CH2).
HRMS (TOF, ES+): m/z calcd for C30H31NO5 + Na [M + Na]:
508.2100; found: 508.2109.
(R)-2-(4-Benzyloxy-3-methoxybenzyl)pent-4-en-1-ol [(R)-7a]
To a rapidly stirred solution of 13 (320 mg, 0.66 mmol) in Et2O (19
mL) were added LiBH4 (0.66 mL, 2.0 M, 1.32 mmol) and anhyd
MeOH (56 mL, 1.32 mmol) dropwise. After stirring at r.t. until com-
pletion, the reaction mixture was cooled to 0 °C and 1 M aq NaOH
(2.5 mL) and EtOAc (19 mL) were added. The organic layer was
separated, washed with H2O (6 mL) and brine (6 mL), dried
(MgSO4), filtered, and concentrated in vacuo to give crude alcohol,
which was then purified by flash chromatography (cyclohexane–
EtOAc, 6:4) providing pure (R)-7a as a thick oil (138 mg, 67%);
[a]D25 +18.2 (c 0.3, CH2Cl2).
To a solution of 4-benzyloxy-3-methoxybenzaldehyde (5.00 g,
20.64 mmol) in anhyd CH2Cl2 (25 mL) was added a suspension of
NaBH4 (0.97 g, 25.59 mmol) in MeOH (12 mL), and the mixture
was stirred at r.t. until completion (ca. 1 h). The mixture was care-
fully poured into H2O (50 mL), extracted with CH2Cl2 (3 × 50 mL)
and the combined extracts were dried (MgSO4). Concentration in
vacuo gave a white residue. Recrystallization from Et2O–petroleum
ether provided 4-(benzyloxy)-3-methoxyphenyl)methanol as color-
less needles (4.91 g, 97%); mp 72–73 °C.
IR (neat): 3400, 2910, 1512 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.43–7.19 (m, 5 H, C6H5), 6.94 (s,
1 H, H-3, Ar), 6.84–6.82 (m, 2 H, H-6, H-7, Ar), 5.15 (s, 2 H,
CH2Ph), 4.59 (d, J = 4.2 Hz, 2 H, H-1, ArCH2OH), 3.89 (s, 3 H, H-
8, ArOCH3), 1.70 (d, J = 4.2 Hz, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 150.1 (s, C-4, Ar), 147.9 (s, C-5,
Ar), 137.4 (s, C-10, C6H5), 134.5 (s, C-2, Ar), 128.7 (d, C-12, C6H5),
128.0 (d, C-13, C6H5), 127.5 (d, C-11, C6H5), 119.5 (d, C-7, Ar),
114.4 (d, C-3, Ar), 111.3 (d, C-6, Ar), 71.4 (t, OCH2Ph), 65.4 (t, C-
1, ArCH2OH), 56.2 (q, C-8, ArOCH3).
1H NMR (300 MHz, CDCl3): d = 7.46–7.25 (m, 5 H, C6H5), 6.82–
6.63 (m, 3 H, Ar), 5.84 (m, 1 H, H-17, CH2CH=CH2), 5.12 (s, 2 H,
H-11, OCH2Ph), 5.13–5.00 (m, 2 H, H-18, CH2CH=CH2), 3.88 (s,
3 H, H-10, ArOCH3), 3.55 [d, J = 5.4 Hz, 2 H, H-1, ArCH2CH(al-
lyl)CH2OH], 2.57 [m, 2 H, H-3, ArCH2CH(allyl)CH2OH], 2.13
(app t, J = 6.0 Hz, 2 H, H-16, CH2CH=CH2), 1.89 [m, 1 H, H-2,
ArCH2CH(allyl)CH2OH], 1.58 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 149.9 (s, C-6, Ar), 146.8 (s, C-7,
Ar), 137.7 (s, C-12, C6H5), 137.1 (d, C-17, CH2CH=CH2), 134.0 (s,
C-4, Ar), 128.7 (d, C-14, C6H5), 128.0 (d, C-15, C6H5), 127.5 (d, C-
13, C6H5), 121.4 (d, C-9, Ar), 116.8 (t, C-18, CH2CH=CH2), 114.6
(d, C-5, Ar), 113.4 (d, C-8, Ar), 71.5 (t, C-11, OCH2Ph), 65.1 [t, C-
1, ArCH2CH(allyl)CH2OH], 56.3 (q, C-10, ArOCH3), 42.7 [d, C-2,
ArCH2CH(allyl)CH2OH], 37.2 [t, C-3, ArCH2CH(allyl)CH2OH],
35.8 (t, C-16, CH2CH=CH2).
To a stirred solution of (4-benzyloxy-3-methoxyphenyl)methanol
(2.33 g, 9.54 mmol) in THF (50 mL) at 0 °C was added I2 (2.68 g,
10.56 mmol), imidazole (0.85 g, 12.49 mmol), and PPh3 (2.82 g,
10.75 mmol). The mixture was stirred for 50 min at 0 °C before the
addition of a solution of Na2S2O3·5H2O (1.90 g) in H2O (15mL) fol-
lowed by Et2O (50 mL). The organic phase was separated and the
aqueous layer extracted with Et2O (2 × 50 mL). The combined or-
ganic extracts were then washed with aq Na2S2O3 (11% w/v, 15
mL), dried (MgSO4), and concentrated in vacuo. Purification by
flash chromatography (cyclohexane–EtOAc, 20:1) gave the com-
pound 14 as white needles (2.70 g, 80%) with spectral data in good
agreement with literature values;12c mp 82–83 °C.
HRMS (TOF, ES+): m/z calcd for C20H24O3 + Na [M + Na]:
335.1623; found: 335.1626.
(4S)-4-(4-Benzyloxy-3-methoxybenzyl)tetrahydrofuran-2-ol
[(S)-3a]
To a solution of (R)-7a (322 mg, 1.03 mmol) in 1,4-dioxane–H2O
mixture (3:1, 8.6 mL/2.9 mL) at r.t. were successively added OsO4
(0.021 mmol, 0.02 equiv), 2,6-lutidine (0.24 mL, 2.05 mmol, 2
equiv), and NaIO4 (880 mg, 4.11 mmol, 4 equiv). The solution was
stirred at r.t. until completion, then quenched by addition of H2O (16
mL), followed by the addition of CH2Cl2 (24 mL). The aqueous lay-
er was extracted with CH2Cl2 (3 × 32 mL), the combined organic
(3R,4R)-3,4-Bis(4-benzyloxy-3-methoxybenzyl)dihydrofuran-
2(3H)-one [(R,R)-2b]
To a solution of lactone (R)-3a (550 mg, 1.76 mmol) in THF (6.5
mL) cooled to –78 °C was added NaHMDS (2.64 mL, 1.0 M in
THF, 2.64 mmol) dropwise over a period of 5 min under N2. After
stirring at this temperature for 1.25 h, a solution of 3-methoxyben-
Synthesis 2011, No. 9, 1456–1464 © Thieme Stuttgart · New York

1462
F. Allais et al.
PAPER
zyl iodide (14; 941 mg, 3.17 mmol) in THF (3.2 mL) was added
dropwise over a period of 5 min. The reaction mixture was then
warmed up to –54 °C and stirred at this temperature for 22 h. The
reaction was quenched with sat. aq NaHCO3 (5 mL) and extracted
with Et2O (3 × 15 mL). The combined organic layers were washed
with brine (10 mL), dried (MgSO4), and concentrated in vacuo. The
crude product was purified by flash chromatography (cyclohexane–
EtOAc, 8:2) to afford the alkylated product (R,R)-2b as a pale yel-
low oil (626 mg, 66%) with spectral data in good agreement with lit-
(S)-4-Benzyl-3-[3-(3-methoxyphenyl)propanoyl]oxazolidin-2-
one (16)
To a solution of 15 (629 mg, 3.49 mmol) in THF (9 mL) under argon
at –70 °C were successively added dropwise, Et3N (0.56 mL, 407
mg, 4.02 mmol) and pivaloyl chloride (0.45 mL, 434 mg, 3.59
mmol). The mixture was then warmed to 0 °C and stirred at this
temperature for 1 h, then recooled to –70 °C. n-BuLi (2.24 mL, 1.6
M in hexane, 3.59 mmol) was added dropwise to a solution of (4S)-
benzyl-2-oxazolidinone (618 mg, 3.49 mmol) in THF (20 mL) un-
der argon at –70 °C. The resulting lithium salt was then transferred
to the above anhydride mixture via a canula at –70 °C over a 10 min
period. The resulting mixture was then stirred for 1 h, warmed to
0 °C, and stirred for 35 min at this temperature. Quenching was re-
alized by adding sat. aq NH4Cl (2.8 mL). The mixture was concen-
trated in vacuo to remove THF, diluted with H2O (14 mL), and
extracted with EtOAc (4 × 15 mL). The combined organic extracts
were dried (MgSO4), filtered, and concentrated in vacuo to give
crude 16. Flash chromatography on silica gel (cyclohexane–EtOAc,
erature values;16,17 [a]D –14.5 (c 0.1, CHCl3) {Lit.16 [a]D –14.0
(c 0.5, CHCl3)}.
21
20
(3S,4S)-3,4-Bis(4-benzyloxy-3-methoxybenzyl)dihydrofuran-
2(3H)-one [(S,S)-2b]
To a solution of lactone (S)-3a (678 mg, 2.17 mmol) in THF (8 mL)
cooled to –78 °C was added NaHMDS (3.25 mL, 1.0 M in THF,
3.25 mmol) dropwise over a period of 5 min under N2. After stirring
at this temperature for 1.25 h, a solution of 3-methoxybenzyl iodide
(14; 1.16 g, 3.91 mmol) in THF (4 mL) was added dropwise over a
period of 5 min. The reaction mixture was then warmed up to
–54 °C and stirred at this temperature for 22 h. The reaction was
quenched with sat. aq NaHCO3 (6 mL) and extracted with Et2O (3
× 18 mL). The combined organic layers were washed with brine (12
mL), dried (MgSO4), and concentrated in vacuo. The crude product
was purified by flash chromatography (cyclohexane–EtOAc, 8:2) to
afford the alkylated product (S,S)-2b as a pale yellow oil (748 mg,
64%) with spectral data in good agreement with literature val-
ues;16,17 [a]D21 +14.3 (c 0.1, CHCl3).
28
8:2) provided pure 16 as a thick oil (1.00 g, 88%); [a]D +35.9 (c
0.6, CHCl3).
IR (neat): 2835, 1778, 1699, 1601, 1490 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.33–7.19 (m, 6 H, C6H5 + Ar),
6.89–6.75 (m, 3 H, Ar), 4.67 (m, 1 H, H-3¢, NCHCH2Ph), 4.17 [m,
2 H, H-2¢, NC(=O)CH2CHCH2Ph], 3.82 (s, 3 H, H-10, ArOCH3),
3.30–3.21 [m, 3 H, H-3, C(=O)CH2CH2Ar and H-4¢, NCHCH2Ph],
3.01 [m, 2 H, H-2, C(=O)CH2CH2Ar and H-4¢, NCHCH2Ph], 2.77
[app t, J = 10.0 Hz, 1 H, H-2, C(=O)CH2CH2Ar].
13C NMR (75 MHz, CDCl3): d = 172.6 (s, C-1, carbon from amide),
160.0 (s, C-6, Ar), 153.6 (s, C-1¢, carbon from urethane), 142.3 (s,
C-4, Ar), 135.4 (s, C-5¢, C6H5), 129.7 (d, C-8, Ar), 129.2 (d, C-6¢,
C-7¢, C6H5), 127.6 (d, C-8¢, C6H5), 121.2 (d, C-9, Ar), 114.5 (d, C-
5, Ar), 112.0 (d, C-7, Ar), 66.4 [t, C-2¢, NC(=O)CH2CHCH2Ph],
55.4 (q, C-10, ArOCH3 and d, C-3¢, NCHCH2Ph), 38.1 (s, C-4¢,
NCHCH2Ph), 37.3 [t, C-2, C(=O)CH2CH2Ar], 30.6 [t, C-3,
C(=O)CH2CH2Ar].
(2R,3R)-2,3-Bis(4-hydroxy-3-methoxybenzyl)butane-1,4-diol
[(R,R)-1]
To a solution of lactone (R,R)-2b (700 mg, 1.30 mmol) in EtOAc
(26 mL) under argon at r.t. was added 10% Pd/C (138 mg) and the
solution was placed under an atmosphere of H2 (1 atm). The mixture
was stirred at r.t. until completion (TLC), filtered over Celite, and
concentrated in vacuo. The crude product was then redissolved in
anhyd THF (50 mL) and a suspension of LiAlH4 (0.78 mL, 2.0 M
in THF, 1.56 mmol) was added at –15 °C. The mixture was stirred
at the same temperature for 2 h. Then the reaction was quenched
with H2O (10 mL), extracted with EtOAc (3 × 40 mL), and the com-
bined organic layers were washed with brine (20 mL) and dried
(MgSO4). The solvent was evaporated in vacuo and the residue was
purified by column chromatography (cyclohexane–EtOAc, 5:5) to
give (R,R)-1 (391 mg, 83%). All spectral data were consistent with
HRMS (TOF, ES+): m/z calcd for C20H21NO4 + Na [M + Na]:
362.1368; found: 362.1374.
(S)-4-Benzyl-3-[(S)-2-(3-methoxybenzyl)pent-4-enoyl]oxazoli-
din-2-one (17)
To a solution of 16 (852 mg, 2.51 mmol) in THF (26 mL) under ar-
gon at –72 °C was added KHMDS (5.3 mL, 0.5 M in hexane, 2.64
mmol) over a 10 min period. The mixture was stirred at this temper-
ature for 1 h, then allyl iodide (0.69 mL, 1.27 g, 7.55 mmol) was
added over a 5 min period. The mixture was stirred at –72 °C for 2
h before quenching with sat. aq NH4Cl (10 mL). The mixture was
concentrated in vacuo to remove THF, and extracted with EtOAc
(4 × 20 mL). The combined organic extracts were dried (MgSO4),
filtered, and concentrated in vacuo to give crude 17. Flash chroma-
tography on silica gel (cyclohexane–EtOAc, 9:1) provided pure 17
as a thick oil (734 mg, 77%); [a]D20 +99.2 (c 0.1, CH2Cl2).
25
those reported in the literature;18 [a]D –32.2 (c 0.1, acetone)
{Lit.18e [a]D25 –32.0 (c 0.1, acetone)].
(2S,3S)-2,3-Bis(4-hydroxy-3-methoxybenzyl)butane-1,4-diol
[(S,S)-1]
To a solution of lactone (S,S)-2b (580 mg, 1.08 mmol) in EtOAc (22
mL) under argon at r.t. was added 10% Pd/C (115 mg) and the so-
lution was placed under an atmosphere of H2 (1 atm). The mixture
was stirred at r.t. until completion (TLC), filtered over Celite, and
concentrated in vacuo. The crude product was then redissolved in
anhyd THF (41 mL) and a suspension of LiAlH4 in THF (0.65 mL,
2.0 M, 1.29 mmol) was added at –15 °C. The mixture was stirred at
the same temperature for 2 h. Then, the reaction was quenched with
H2O (12 mL), extracted with EtOAc (3 × 50 mL), and the combined
organic layers were washed with brine (25 mL), and dried (MgSO4).
The solvent was evaporated in vacuo and the residue was purified
by column chromatography (cyclohexane–EtOAc, 5:5) to give
(S,S)-1 (313 mg, 80%). All spectral data were consistent with those
reported in the literature;18 [a]D25 +32.3 (c 0.1, acetone).
IR (neat): 2977, 1777, 1697, 1489 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.33–7.15 (m, 6 H, Ar + C6H5),
6.84–6.74 (m, 3 H, Ar), 5.89 (m, 1 H, H-17, CH2CH=CH2), 5.19–
5.09 (m, 2 H, H-18, CH2CH=CH2), 4.49 (m, 1 H, H-3¢,
NCHCH2Ph), 4.36 [m, 1 H, H-2, C(=O)CH(allyl)CH2Ar], 4.28 [app
d, J = 6.9 Hz, 1 H, H-2¢, NC(=O)CH2CHCH2Ph], 3.86 [app d,
J = 7.8 Hz, 1 H, H-2¢, NC(=O)CH2CHCH2Ph], 3.78 (s, 3 H, H-10,
ArOCH3), 3.24 (app d, J = 11.1 Hz, 1 H, H-4¢, NCHCH2Ph), 3.01–
2.80 [m, 2 H, H-3, C(=O)CH(allyl)CH2Ar], 2.72–2.50 (m, 2 H, H-
4¢, NCHCH2Ph and H-16, CH2CH=CH2), 2.41–2.35 (m, 1 H, H-16,
CH2CH=CH2).
13C NMR (75 MHz, CDCl3): d = 175.3 (s, C-1, carbon from amide),
159.7 (s, C-6, Ar), 153.1 (s, C-1¢, carbon from urethane), 140.6 (s,
C-4, Ar), 135.5 (s, C-5¢, C6H5), 135.2 (d, C-17, CH2CH=CH2),
Synthesis 2011, No. 9, 1456–1464 © Thieme Stuttgart · New York

PAPER
Chiral b-Benzyl-g-butyrolactones
1463
129.5 (d, C-7¢, C6H5), 129.4 (d, C-8, Ar), 129.0 (d, C-6¢, C6H5),
127.4 (d, C-8¢, C6H5), 121.5 (d, C-9, Ar), 117.4 (t, C-18,
CH2CH=CH2), 114.6 (d, C-5, Ar), 112.2 (d, C-7, Ar), 66.0 [t, C-2¢,
NC(=O)CH2CHCH2Ph], 55.6 (q, C-10, ArOCH3), 55.2 (d, C-3¢,
NCHCH2Ph), 43.9 [d, C-2, C(=O)CH(allyl)CH2Ar], 38.4 (t, C-4¢,
NCHCH2Ph), 38.1 [t, C-3, C(=O)CH(allyl)CH2Ar], 36.4 (t, C-16,
CH2CH=CH2).
and extracted with Et2O (3 × 20 mL). The combined organic layers
were washed with brine (15 mL), dried (Na2SO4), and concentrated
to provide crude dibenzyl lactone. To a rapidly stirred solution of
the crude lactone in anhyd CH2Cl2 (17 mL) at 0 °C was added BBr3
(3.3 mL, 1.0 M in CH2Cl2, 3.3 mmol) dropwise during 5 min. The
stirring was continued at 0 °C for 1 h and then at –18 °C. After 10
h, the reaction mixture was quenched with H2O (10 mL), the
CH2Cl2 layer was separated, and the aqueous layer was extracted
Et2O. The CH2Cl2 layer and the combined Et2O layers were sepa-
rately washed with brine, combined, dried (Na2SO4), and the sol-
vent was evaporated in vacuo. The crude product was purified by
flash chromatography (Et2O–CH2Cl2) to provide 2a as a colorless
semisolid (171 mg, 59%). All spectral data were consistent with
those reported in the literature;13 [a]D25 –38.4 (c 0.2, CHCl3) {Lit.13l
[a]D27 –38.5 (c 0.5, CHCl3)}.
HRMS (TOF, ES+): m/z calcd for C23H25NO4 + Na [M + Na]:
402.1681; found: 402.1665.
(S)-2-(3-Methoxybenzyl)pent-4-en-1-ol [(S)-7b]
To a rapidly stirred solution of 17 (797 mg, 2.1 mmol) in Et2O (60
mL) were added LiBH4 (2.1 mL, 2.0 M, 4.2 mmol) and anhyd
MeOH (178 mL, 4.2 mmol) dropwise. After stirring at r.t. until com-
pletion, the reaction mixture was cooled to 0 °C and 1 M aq NaOH
(8 mL) and EtOAc (60 mL) were added. The organic layer was sep-
arated, washed with H2O (10 mL) and brine (10 mL), dried
(MgSO4), filtered, and concentrated in vacuo to give crude alcohol,
which was then purified by flash chromatography (cyclohexane–
EtOAc, 6:4) providing pure (S)-7b as a thick oil (308 mg, 71%);
[a]D21 –22.8 (c 0.1, CH2Cl2).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
IR (neat): 3393, 2913, 1600, 1488 cm–1.
The authors would like to thank the INRA for financial support.
1H NMR (300 MHz, CDCl3): d = 7.25–7.19 (m, 1 H, H-8, Ar), 6.82–
6.66 (m, 3 H, H-5, H-7, H-9, Ar), 5.84 (m, 1 H, H-17,
CH2CH=CH2), 5.13–5.05 (m, 2 H, H-18, CH2CH=CH2), 3.80 (s, 3
H, H-10, ArOCH3), 3.54 [d, J = 5.1 Hz, 2 H, H-1, ArCH2CH(al-
lyl)CH2OH], 2.63 [m, 2 H, H-3, ArCH2CH(allyl)CH2OH], 2.35 (br
s, 1 H, OH), 2.15 (m, 2 H, H-16, CH2CH=CH2), 1.93 [m, 1 H, H-2,
ArCH2CH(allyl)CH2OH].
13C NMR (75 MHz, CDCl3): d = 159.7 (s, C-6, Ar), 142.3 (s, C-4,
Ar), 136.9 (d, C-17, CH2CH=CH2), 129.4 (d, C-8, Ar), 121.8 (d, C-
9, Ar), 116.6 (t, C-18, CH2CH=CH2), 115.1 (d, C-5, Ar), 111.3 (d,
C-7, Ar), 64.6 [t, C-1, ArCH2CH(allyl)CH2OH], 55.2 (q, C-10,
ArOCH3), 42.4 [d, C-2, ArCH2CH(allyl)CH2OH], 37.3 [t, C-3,
ArCH2CH(allyl)CH2OH], 35.4 (t, C-16, CH2CH=CH2).
References
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(R)-4-(3-Methoxybenzyl)dihydrofuran-2(3H)-one [(R)-3b]
To a solution of (S)-7b (134 mg, 0.65 mmol) in 1,4-dioxane–H2O
mixture (3.1, 5.4 mL/1.8 mL) at r.t. were successively added OsO4
(0.013 mmol), 2,6-lutidine (0.15 mL, 1.29 mmol), and NaIO4 (555
mg, 2.59 mmol). The solution was stirred at r.t. until completion,
then quenched by the addition of H2O (10 mL), followed by the ad-
dition of CH2Cl2 (15 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 20 mL), the combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. The crude hemiacetal
(lactol) was used directly without further purification. Ag2CO3 on
Celite11b (972 mg, 1.618 mmol) was added to a solution of crude
lactol in benzene (6.9 mL). The mixture was refluxed for 4 h, cooled
to r.t., filtered on Celite and concentrated in vacuo. The crude prod-
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6:4) to afford pure lactone (R)-3b as a thick oil (148 mg, 73%) with
spectral data in good agreement with literature values;13 [a]D25 +6.5
(c 0.2, CHCl3) {Lit.13l [a]D25 +6.4 (c 1.0, CHCl3)}.
(3R,4R)-3,4-Bis(3-hydroxybenzyl)dihydrofuran-2(3H)-one (2a)
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in THF (4 mL) under argon atmosphere was added dropwise LiH-
MDS (1.45 mL, 1.0 M in THF, 1.45 mmol) over a period of 5 min.
After stirring at that temperature for 1 h, a solution of 3-methoxy-
benzyl bromide (1.746 mmol, 351 mg) in THF (2 mL) was added
dropwise over a period of 5 min. The reaction mixture was then
slowly warmed up to –54 °C and stirred at this temperature for 20
h. The reaction mixture was quenched with sat. aq NaHCO3 (5 mL)
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Synthesis 2011, No. 9, 1456–1464 © Thieme Stuttgart · New York

1464
F. Allais et al.
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Synthesis 2011, No. 9, 1456–1464 © Thieme Stuttgart · New York