Asymmetric synthesis of 5-(1-hydroxyalkyl)-5-methyl-5H-furan-2-ones

Article abstract of DOI:10.1016/S0040-4020(03)00937-2

The reactivity of 5-methyl-4-(pyrrolidin-1-yl)-5H-furan-2-one with aldehydes and with acyl chlorides followed by reduction was studied. The aldol condensation gave predominantly the anti aldol product when the acylation-reduction sequence led exclusively to the syn product. The use of a chiral pyrrolidine, (S)-2-methoxymethylpyrrolidine (SMP), allowed the synthesis of enantio-enriched compounds, the acylation-reduction leading to the (R,R) addition product.

Full text of DOI:10.1016/S0040-4020(03)00937-2

Tetrahedron 59 (2003) 5879–5886
Asymmetric synthesis of
5-(1-hydroxyalkyl)-5-methyl-5H-furan-2-ones
a
Helene Bruyere, Stephanie Ballereau, Mohamed Selkti and Jacques Royer
a
b
a
,
*
´ `
`
´
a
´ ´ ´ ´
UMR 8638 CNRS/Universite Rene Descartes, Laboratoire de Chimie Therapeutique, Faculte de Pharmacie, 4 avenue de l’Observatoire,
75270 Paris Cedex 06, France
UMR 8015 CNRS/Universite Rene Descartes, Laboratoire de Cristallographie et RMN Biologiques, Faculte de Pharmacie,
4 avenue de l’Observatoire, 75270 Paris Cedex 06, France
b
´
´
´
Received 24 March 2003; revised 19 May 2003; accepted 12 June 2003
Abstract—The reactivity of 5-methyl-4-(pyrrolidin-1-yl)-5H-furan-2-one with aldehydes and with acyl chlorides followed by reduction was
studied. The aldol condensation gave predominantly the anti aldol product when the acylation–reduction sequence led exclusively to the syn
product. The use of a chiral pyrrolidine, (S)-2-methoxymethylpyrrolidine (SMP), allowed the synthesis of enantio-enriched compounds, the
acylation–reduction leading to the (R,R) addition product.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
very interesting cytotoxic activity with a mechanism of
action similar to paclitaxel.7 In an approach of the total
synthesis of eleutherobin and analogues, we have conducted
a model study in the aim of preparing 5,5-disubstituted-5H-
furan-2-ones. In this paper, we describe the results of this
study which represents a method to synthesize 5-(1-
hydroxyalkyl)-5-methyl-5H-furan-2-one of type 2 with the
control of relative and absolute configurations.
Over the last decade, a great number of new natural products
have been isolated from marine organisms.1,2 A lot of these
marine natural products contain a,a0-disubstituted
5-membered oxygenated heterocycles in their structures
and exhibit various biological activities. Some examples of
these compounds are shown in Figure 1: the cytotoxic
macrolides oscillariolide3 and pectenotoxin-2,4 clavidol,5 a
novel marine polyether and valdivone A6 which presents
anti-inflammatory activity.
2. Results and discussion
Eleutherobin 1 (Fig. 2), isolated from soft coral, possesses
Reactivity of 5H-furan-2-one and particularly of its
Figure 1.
Keywords: aldol reaction; acylation; furanones; stereoselectivity.
*
Corresponding author. Tel.: þ33-1-53-73-97-49; fax: þ33-1-43-29-14-03; e-mail: royer@pharmacie.univ-paris5.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00937-2

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5880
Scheme 2. Reagents and conditions: t-BuLi, THF, then RCHO, 2788C.
Figure 2.
separation of the two diastereomers. This diastereoselective
protection of the anti aldol adduct has already been
reported.17 However, to confirm this assignement, the
pyrrolidinyl group was removed from 6 (Scheme 3) via a
two-step Borch reduction–Cope elimination16 and the
alcohol function of 7 deprotected under acidic conditions
to give product 8. The spectral data of 8 were in agreement
with the anti product described by Redero et al.12
Elimination of the pyrrolidinyl group from compound 4b
2-silyloxyfuran derivatives towards aldol-type addition has
been largely used in organic synthesis and reviewed in the
literature.8–11 The silyloxyfurans are known to afford only
C5 adducts under Mukaiyama conditions.9 However, a
recent study of the reactivity of 5-methyl-2-silyloxyfuran in
Mukaiyama-aldol condensation12 showed that the C5
adducts cannot be obtained in satisfactory yields due to
the competitive reaction at C3. On the other hand, it has
been reported in the literature13 that the presence of an
electron-releasing group, such as an alkylamine, at the C4
position of 5H-furan-2-one favors the formation of C5
substituted derivatives. A pyrrolidinyl group at C4 not only
favors C5 addition but can also be a chiral auxiliary by using
asymmetric derivatives which could be easily removed to
afford a,b-unsaturated g-lactone.14–18
Taking these results into account, we decided to use
5-methyl-4-(pyrrolidin-1-yl)-5H-furan-2-one (3) as starting
material to study the syn–anti diastereoselectivity of the
addition reaction. This compound is obtained in two steps
from tetronic acid (Scheme 1) according to a protocol
described with (S)-2-methoxymethylpyrrolidine.19
Scheme 3. Reagents and conditions: (a) 2,6-lutidine, TBDMSOTf, CH2Cl2,
18 h, 74%; (b) (i) NaBH3CN, AcOH; (ii) mCPBA, CH2Cl2, aq. NaHCO3,
30% (two steps); (c) TFA–H2O, THF, quant.
Scheme 1. Reagents and conditions: (a) pyrrolidine, pTsOH, benzene,
reflux, 24 h; (b) t-BuLi, THF, 2788C then MeI, 89% (two steps).
We chose to conduct the addition reaction with the lithium
dienolate of 3 obtained by treatment with tert-butyllithium.
We studied the aldol condensation in THF at 2788C with
two different aldehydes: phenylacetaldehyde and propion-
aldehyde (Scheme 2). Under these conditions, the addition
was totally regioselective since only C5 adducts 4 and 5
were formed in 56 and 48% yields with phenylacetaldehyde
and propionaldehyde, respectively. A fair diastereo-
selectivity was observed (de¼40% for 4 and de¼60% for
5 determined by NMR) in favor of the diastereomers 4a and
5a.
In order to determine the relative configuration of the major
diastereomer, the 4a:4b mixture was subjected to a
silylation reaction. Under standard conditions, only the
isomer 4a was silylated which greatly facilitated the
Scheme 4. Reagents and conditions: (a) 2,6-lutidine, DMAP, TBDMSOTf,
CH2Cl2, 42 h, 95%; (b) (i) NaBH3CN, AcOH; (ii) mCPBA, CH2Cl2, aq.
NaHCO3, 94% (two steps); (c) TFA–H2O, THF, quant.

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5881
in 82 and 90% yields, respectively (Scheme 5). Reduction of
these ketones under Luche conditions22 provided diastereo-
selectively the syn addition products 4b and 5b in 98 and
87%, respectively. Reduction without CeCl3 furnished a
mixture of diastereoisomers with a de¼40%.
Having obtained a method to diastereoselectively synthesize
syn-5-(1-hydroxyalkyl)-5-methyl-5H-furan-2-one, we
further investigated the reaction in order to access to
enantio-enriched compounds. For this purpose, we intro-
duced a chiral pyrrolidine, (S)-2-methoxymethylpyrrolidine
(SMP), via tetronic acid and methylated the intermediate to
obtain 15 as a mixture of diastereomers (de¼40%) as
described in the literature.19
Compound 15 reacted with the same aldehydes and acyl
chlorides and according to the same protocols used in the
previous racemic series. The results obtained with SMP
derivative are resumed in Scheme 6.
Scheme 5. Reagents and conditions: (a) t-BuLi, TMSCl, THF, then
RCOCl, 2788C; (b) NaBH4, CeCl3, MeOH, 08C.
gave the syn product 920 (Scheme 3). The yields obtained for
the reduction–elimination procedure of enamine 6 or 4b
were not optimized. When the same sequence of reaction
was applied to compound 5b, with more drastic silylation
conditions,21 syn-5-(1-hydroxypropyl)-5-methyl-5H-furan-
2-one (12) was obtained with an overall yield of 89%
(Scheme 4).
The aldolisation furnished a mixture of two anti products
16a and 16b with phenylacetaldehyde and 17a and 17b with
propionaldehyde in a 1:1 ratio in both cases (determined by
NMR of the reaction mixtures). Under these conditions, no
diastereofacial selectivity was observed. The couple of
diastereomers could not be separated using standard
chromatography technique. Trace amounts of the syn
products could not be detected in the NMR spectra.
Direct elimination of pyrrolidinyl group from compound 5b
with the free hydroxyl was possible but the yield in desired
compound 12 was not satisfactory.
As in the racemic series, the two-step procedure of
acylation–reduction was much more stereoselective. In
both examples, ketones 18 and 19 (Scheme 6) were obtained
from the acylation reaction in 76 and 70% yields
respectively as an unseparable mixture of two diastereo-
mers. The HPLC analyses of these mixtures show a
de¼80%. After reduction, compounds 20 and 21 were
obtained in 91% yield each. NMR analysis of alcohols 20
and 21 showed that they both consisted of a 9:1
We also studied another route to obtain 5-(1-hydroxyalkyl)-
5-methyl-5H-furan-2-one, still using the 5-methyl-4-(pyrro-
lidin-1-yl)-5H-furan-2-one (3) as starting material. Com-
pound 3 was deprotonated with tert-butyllithium and treated
with chlorotrimethylsilane and then with either phenylace-
tyl or propionyl chloride. Ketones 13 and 14 were obtained
Scheme 6. Reagents and conditions: (a) t-BuLi, THF, then RCHO, 2788C; (b) t-BuLi, TMSCl, THF, then RCOCl, 2788C; (c) NaBH4, CeCl3, MeOH, 08C.

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5882
diastereomeric mixture indicating that the reduction step is
totally diastereoselective. This diastereoselectivity was
confirmed after elimination of the chiral auxiliary from 20
using a slightly modified procedure:23 only one diaster-
eomer exhibiting the same NMR data than 9 was obtained.
nitrogen atmosphere, and were monitored by thin-layer
chromatography with Merck 60F-254 precoated silica
(0.2 mm) on aluminium. Flash chromatography was per-
formed with SDS Silicagel 60 (35–70 mm); the solvent
systems were given v/v. Spectroscopic (1H and 13C NMR,
MS) and/or analytical data were obtained using chromato-
graphically homogeneous samples.
In order to determine the absolute configuration of the major
isomer 20a, the latter was separated from the mixture by
chromatography on silica gel. Compound 20a could be
crystallized and submitted to single crystal X-ray analysis.
This allowed us to confirm the syn relative configuration of
20a and to assign a (R,R) absolute configuration (Fig. 3) for
the two stereogenic centers created during the reaction
sequence.
4.1. 5-Methyl-4-(pyrrolidin-1-yl)-5H-furan-2-one (3)
To a solution of 4-(pyrrolidin-1-yl)-5H-furan-2-one25
(3.1 g, 20 mmol) in anhydrous THF (100 mL) at 2788C
was added dropwise t-BuLi (1.7 M in pentane, 14.2 mL,
24 mmol) and the solution was stirred for 1 h. Methyl iodide
(5.0 mL, 80 mmol) was slowly added. After 3 h stirring at
2788C, saturated ammonium chloride solution (100 mL)
was added to the reaction mixture. The resulting mixture
was extracted with Et2O (3£200 mL). The combined
organic extracts were dried over MgSO4 and evaporated
to dryness. Compound 3 (3.0 g, 89%) was obtained as a tan
solid. A sample was purified by column chromatography
(CH2Cl2/MeOH, 98:2): Rf 0.31 (EtOAc); mp 888C; 1H
3
NMR (CDCl3, 300 MHz) d 1.52 (d, J¼6.7 Hz, 3H, CH3),
1.8–2.2 (m, 4H, CH2Pyr), 3.0–3.6 (m, 4H, CH2Pyr), 4.47 (s,
3
1H, CHvC), 4.93 (q, J¼6.5 Hz, 1H, CHCH3); 13C NMR
(CDCl3, 75 MHz) d 18.8 (CH3), 24.7, 26.1, 48.3, 49.9
(CH2Pyr), 74.5 (CHCH3), 80.8 (CHvC), 170.6 (CqN),
174.41 (CvO); CIMS (NH3) m/z (%): 185 (MNHþ4 , 100),
168 (MHþ, 55); Anal. calcd for C9H13NO2: C, 64.65, H,
7.84, N, 8.38; found: C, 64.61, H, 7.96, N, 8.27.
Figure 3. X-Ray structure of compound 20a.24
4.2. (5S p,10R p)-5-(10-Hydroxy-20-phenylethyl)-5-methyl-
4-(pyrrolidin-1-yl)-5H-furan-2-one (4a)
3. Conclusion
To a solution of 5-methyl-4-(pyrrolidin-1-yl)-5H-furan-2-
one (3) (0.20 g, 1.20 mmol) in anhydrous THF (2.2 mL) at
2788C was added dropwise t-BuLi (1.7 M in pentane,
1.05 mL, 1.79 mmol) and the solution was stirred for 1 h at
2788C. Phenylacetaldehyde (0.17 mL, 1.43 mmol) was
added dropwise. After stirring for 1 h at 2788C and 3 h at
08C, the volatiles were removed under reduced pressure and
chromatography of the residue (EtOAc) afforded aldols 4a
and 4b as a 7:3 mixture (0.19 g, 56%). The following
spectroscopic properties for the major isomer 4a are given:
Rf 0.26 (EtOAc); IR (neat): n 3320 (OH), 1718 (CvO),
1588 (CvC) cm21; 1H NMR (CDCl3, 400 MHz) d 1.70 (s,
To summarize, the introduction of a pyrrolidinyl group at
the C4 position of 5H-furan-2-one allowed the regio-
selective double addition at the C5 position. With 5-methyl-
4-(pyrrolidin-1-yl)-5H-furan-2-one (3), the aldolisation
reaction furnished the anti product while the acylation–
reduction sequence gave exclusively the syn product. The
introduction of the SMP, as a chiral auxiliary, allowed a
diastereofacial selectivity in the acylation–reduction which
led to the (R,R) syn addition products 20a and 21a in good
yields, providing an efficient asymmetric method to
synthesize 5-(1-hydroxyalkyl)-5-methyl-5H-furan-2-ones.
3
3H, CH3), 1.7–2.1 (m, 4H, CH2Pyr), 2.41 (bd, J¼10.6 Hz,
1H, OH), 2.76 (d, 3J¼6.3 Hz, 2H, CH2Ph), 3.1–3.6 (m, 4H,
CH2Pyr), 4.10 (dt, 3J¼10.4, 6.3 Hz, 1H, CHOH), 4.45 (s, 1H,
CHvC), 7.1–7.4 (m, 5H, Harom); 13C NMR (CDCl3,
100 MHz) d 20.7 (CH3), 26.0 (CH2Pyr), 38.8 (CH2Ph),
49.7 (CH2Pyr), 75.2 (CHOH), 83.3 (CHvC), 86.0 (CqCH3),
126.6, 128.5, 129.4 (CHarom), 137.9 (Cqarom), 170.1 (CqN),
173.2 (CvO); CIMS (NH3) m/z (%): 288 (MHþ, 100), 168
(13), 72 (10); HRMS calcd for C17H21NO3 (MHþ)
288.1600; found: 288.1588.
4. Experimental
General directions: Tetrahydrofuran (THF) was distilled
from sodium-benzophenone and dichloromethane (CH2Cl2)
from CaH2. IR spectra were recorded on a Nicolet 205-FT
infrared spectrophotometer. Only noteworthy IR absorp-
tions are listed. 1H and 13C NMR spectra were recorded on a
Bruker AC 300 or Bruker 400 Avance. Chemical shifts are
reported in d (ppm). Specific rotations were measured on a
Perkin Elmer 241C polarimeter with sodium (589 nm)
lamp. CIMS were recorded on Nermag R10-10C and HRMS
4.3. (5S p,10R p)-5-(10-Hydroxypropyl)-5-methyl-4-
(pyrrolidin-1-yl)-5H-furan-2-one (5a)
´
on Q-Tof 1 Micromass by the Laboratoire de Spectrometrie
de Masse de la Faculte de Pharmacie, Paris V. Elementary
analyses were performed at the Microanalysis Laboratory,
Paris VI. All reactions were carried out under argon or
The above protocol for 4a was used with propionaldehyde
(81 mL, 1.11 mmol) and 5-methyl-4-(pyrrolidin-1-yl)-5H-
furan-2-one (3) (0.15 g, 0.93 mmol). Chromatography of
´

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5883
the residue (cyclohexane/EtOAc, 1:9) afforded aldols 5a
and 5b as a 8:2 mixture (0.10 g, 48%). The following
spectroscopic properties for the major isomer 5a are given:
Rf 0.15 (EtOAc). IR (neat): n 3322 (OH), 1700 (CvO),
1594 (CvC) cm21; 1H NMR (CDCl3, 400 MHz) d 0.94 (t,
3J¼7.4 Hz, 3H, CH2CH3), 1.2–1.5 (m, 2H, CH2CH3), 1.64
(s, 3H, CH3Cq), 1.8–2.0 (m, 4H, CH2Pyr), 3.2–3.5 (m, 4H,
lactone 7 (26 mg, 30%) as a clear colorless oil: Rf 0.37
1
(cyclohexane/EtOAc, 8:2); H NMR (CDCl3, 300 MHz) d
20.64, 20.05 (2 s, 6H, SiCH3), 0.81 (s, 9H, SiC(CH3)3),
2
3
1.50 (s, 3H, CH3), 2.67 (dd, J¼13.8 Hz, J¼8.6 Hz, 1H,
2
3
CH2Ph), 3.13 (dd, J¼13.6 Hz, J¼2.5 Hz, 1H, CH2Ph),
3.93 (dd, 3J¼8.6, 2.9 Hz, 1H, CHOTBS), 6.00 (d,
3J¼5.7 Hz, 1H, CHCvO), 7.1–7.4 (m, 6H, containing at
3
3
CH2Pyr), 3.67 (bd, J¼5.9 Hz, 1H, CHOH), 4.38 (s, 1H,
7.27 (d, J¼5.7 Hz, 1H, CHvCHCvO) and CHarom); 13C
CHvC); 13C NMR (CDCl3, 75 MHz) d 10.3 (CH2CH3),
20.7 (CH3Cq), 24.5 (CH2CH3), 25.2, 49.6 (CH2Pyr), 75.3
(CHOH), 83.1 (CHvC), 86.5 (CqCH3), 170.4 (CqN), 173.3
(CvO); CIMS (NH3) m/z (%): 226 (MHþ, 100); HRMS
calcd for C12H19NO3þNa 248.1263; found: 248.1260.
NMR (CDCl3, 75 MHz) d 23.7 (SiCH3), 17.8 (CqSi), 19.5
(CH3Cq), 25.7 (C(CH3)3), 40.0 (CH2Ph), 76.4 (CHOTBS),
90.9 (CqCH3), 121.2 (CHCvO), 126.6, 128.3, 129.8
(CHarom), 137.8 (Cqarom), 158.6 (CHvCHCvO), 173.5
(CvO).
4.4. (5S p,10R p)-5-[10-(tert-Butyldimethylsilanyloxy)-20-
phenylethyl]-5-methyl-4-(pyrrolidin-1-yl)-5H-furan-2-
one (6)
4.6. (5S p,10R p)-5-(10-Hydroxy-20-phenylethyl)-5-methyl-
5H-furan-2-one (8)
The silyl ether 7 (26 mg, 0.08 mmol) was dissolved in TFA/
H2O/THF (9:1:1) (3 mL). After stirring for 2 h at room
temperature, the solvents were evaporated to dryness and
the residue was purified by chromatography to afford 5-(1-
hydroxy-2-phenylethyl)-5-methyl-5H-furan-2-one 8 (17 mg,
quant.) as a clear colorless oil: Rf 0.38 (cyclohexane/EtOAc,
1:1); 1H NMR (CDCl3, 300 MHz) d 1.55 (s, 3H, CH3), 2.65
(dd, 2J¼13.7 Hz, 3J¼10.4 Hz, 1H, CH2Ph), 3.02 (dd,
To a cooled (08C) solution of 7:3 mixture of alcohols 4a and
4b (100 mg, 0.35 mmol) in anhydrous CH2Cl2 (3.5 mL) was
added dropwise 2,6-lutidine (250 mL, 2.12 mmol) and tert-
butyldimethylsilyl trifluoromethanesulfonate (122 mL,
0.53 mmol). The reaction mixture was warmed to room
temperature and stirred overnight. Water was added and the
layers were separated. The aqueous solution was extracted
with Et2O (3£5 mL) and the combined organic extracts
were dried over MgSO4. The volatiles were removed under
reduced pressure and chromatography of the residue
(EtOAc) yielded silyl ether 6 (104 mg, 74%) as an oil and
unreacted alcohol 4b (15 mg, 11%). 6: Rf 0.44 (EtOAc); 1H
NMR (CDCl3, 400 MHz) d 20.11, 20.03 (2 s, 6H, SiCH3),
0.89 (s, 9H, SiC(CH3)3), 1.5–1.7 (m, 7H, containing at 1.55
(s, 3H, CH3) and CH2Pyr), 2.77 (dd, 2J¼14.5 Hz, 3J¼4.3 Hz,
1H, CH2Ph), 2.86 (dd, 2J¼14.5 Hz, 3J¼7.7 Hz, 1H,
CH2Ph), 2.9–3.1 (m, 4H, CH2Pyr), 4.2–4.4 (m, 2H,
containing at 4.28 (s, 1H, CHvC) and CHOTBS), 7.0–
7.3 (m, 5H, CHarom); 13C NMR (CDCl3, 100 MHz) d 23.7
(SiCH3), 18.3 (CqSi), 21.8 (CH3Cq), 25.2 (CH2Pyr), 26.0
(C(CH3)3), 39.3 (CH2Ph), 49.2 (CH2Pyr), 75.6 (CHOTBS),
84.4 (CHvC), 86.3 (CqCH3), 126.4, 128.2, 129.8 (CHarom),
138.5 (Cqarom), 169.9 (CqN), 174.1 (CvO); HRMS calcd
for C23H35NO3SiþNa 424.2284; found: 424.2292.
3
3
2J¼13.8 Hz, J¼2.4 Hz, 1H, CH2Ph), 3.78 (dd, J¼10.4,
3
2.3 Hz, 1H, CHOH), 6.08 (d, J¼5.7 Hz, 1H, CHCvO),
7.1–7.4 (m, 5H, CHarom), 7.52 (d, 3J¼5.7 Hz, 1H,
CHvCHCvO); 13C NMR (CDCl3, 75 MHz) d 18.9
(CH3Cq), 38.5 (CH2Ph), 76.1 (CHOH), 90.1 (CqCH3),
121.0 (CHCvO), 126.8, 128.6, 129.2 (CHarom), 137.3
(Cqarom), 159.1 (CHvCHCvO), 172.3 (CvO); HRMS
calcd for C13H14O3þNa 241.0841; found: 241.0844.
4.7. (5S p,10S p)-5-(10-Hydroxy-20-phenylethyl)-5-methyl-
5H-furan-2-one (9)
The protocol described for compound 7 was applied to
alcohol 4b to afford 9:20 Rf 0.34 (cyclohexane/EtOAc, 1:1);
1H NMR (CDCl3, 400 MHz) d 1.59 (s, 3H, CH3), 1.99 (d,
2
3
3J¼3.3 Hz, 1H, OH), 2.55 (dd, J¼13.7 Hz, J¼10.2 Hz,
1H, CH2Ph), 2.91 (dd, 2J¼13.7 Hz, 3J¼3.0 Hz, 1H,
3
CH2Ph), 3.93 (dt, J¼10.2, 2.9 Hz, 1H, CHOH), 6.11 (d,
4.5. (5S p,10R p)-5-[10-(tert-Butyldimethylsilanyloxy)-20-
phenylethyl]-5-methyl-5H-furan-2-one (7)
3J¼5.7 Hz, 1H, CHCvO), 7.1–7.4 (m, 5H, CHarom), 7.40
(d, 3J¼5.7 Hz, 1H, CHvCHCvO); 13C NMR (CDCl3,
75 MHz) d 20.2 (CH3), 37.9 (CH2Ph), 76.3 (CHOH), 90.5
(CqCH3), 121.6 (CHCvO), 127.0, 128.8, 129.2 (CHarom),
137.2 (Cqarom), 158.2 (CHvCHCvO), 172.0 (CvO);
HRMS calcd for C13H14O3þNa 241.0841; found: 241.0842.
To a solution of lactone 6 (104 mg, 0.26 mmol) in glacial
acetic acid (3 mL), was added sodium cyanoborohydride
(330 mg, 5.2 mmol) in portions over 2 h. Aqueous NaOH
(25 mL of a 2 M solution) was added slowly at 08C and the
solution was extracted with Et2O (4£30 mL). The combined
organic extracts were dried over MgSO4 and the volatiles
were removed under reduced pressure. Purification on a
short pad of silica gel (cyclohexane/EtOAc, 1:1) furnished
unreacted lactone 6 (65 mg) and saturated lactone which
was dissolved in CH2Cl2 (1 mL). Then m-CPBA (60% w/w,
30 mg, 0.11 mmol) was added. The reaction mixture was
stirred for 10 min, then sat. aq. NaHCO3 (2 mL) was added
at 08C and stirring was continued for 20 min. The solution
was extracted with CH2Cl2 (3£5 mL) and the combined
organic extracts were dried over MgSO4. The volatiles were
removed under reduced pressure and chromatography of the
residue (cyclohexane/EtOAc, 1:1) afforded a,b-unsaturated
4.8. (5S p,10S p)-5-[10-(tert-Butyldimethylsilanyloxy)-
propyl]-5-methyl-4-(pyrrolidin-1-yl)-5H-furan-2-one (10)
To a cooled (08C) solution of alcohol 5b (1.85 g,
8.22 mmol) in anhydrous CH2Cl2 (10 mL) was added
dropwise 2,6-lutidine (5.75 mL, 49.3 mmol), DMAP
(0.5 g, 4.11 mmol) and tert-butyldimethylsilyl trifluoro-
methanesulfonate (3.8 mL, 16.44 mmol). The reaction
mixture was warmed to room temperature and stirred
overnight. DMAP (0.5 g, 4.11 mmol) and tert-butyl-
dimethylsilyl
trifluoromethanesulfonate
(1.89 mL,
8.22 mmol) were added again. After 18 h stirring, water
was added and the layers were separated. The aqueous

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3
solution was extracted with Et2O (3£50 mL) and the
combined organic extracts were dried over MgSO4. The
volatiles were removed under reduced pressure and
chromatography of the residue (cyclohexane/EtOAc, 1:9)
yielded silyl ether 10 (2.68 g, 95%) as an oil: Rf 0.46
(EtOAc); 1H NMR (CDCl3, 400 MHz) d 0.06, 0.07 (2 s, 6H,
SiCH3), 0.7–1.0 (m, 12H, SiC(CH3)3 and CH2CH3), 1.39
(dq, J¼14.3 Hz, J¼7.2 Hz, 1H, CH2CH3), 1.5–1.7 (m,
4H, containing at 1.53 (s, 3H, CH3Cq) and CH2CH3), 1.8–2.1
(m, 4H, CH2Pyr), 3.1–3.4 (m, 4H, CH2Pyr), 3.85 (t, 3J¼5.0 Hz,
1H, CHOTBS), 4.38 (s, 1H, CHvC); 13C NMR (CDCl3,
100 MHz) d 24.1 (SiCH3), 10.2 (CH2CH3), 18.3 (CqSi), 21.9
(CH3Cq),24.9(CH2Pyr),25.5(C(CH3)3),29.8(CH2CH3),50.2
(CH2Pyr), 76.8 (CHOTBS), 83.7 (CHvC), 87.1 (CqCH3),
170.7(CqN), 173.2 (CvO); CIMS (NH3) m/z(%):340 (MHþ,
100), 300 (35), 282 (10); Anal. calcd for C18H33NO3Si: C,
63.67, H, 9.80, N, 4.13; found: C, 63.57, H, 9.87, N, 3.94.
CH2CH3), 2.12 (bs, 1H, OH), 3.53 (dd, J¼10.2, 2.2 Hz,
3
1H, CHOH), 6.08 (d, J¼5.7 Hz, 1H, CHCvO), 7.41 (d,
3J¼5.7 Hz, 1H, CHvCHCvO); 13C NMR (CDCl3,
75 MHz)
d 10.6 (CH2CH3), 19.0 (CH3Cq), 24.6
(CH2CH3), 77.1 (CHOH), 91.4 (CqCH3), 121.5 (CHCvO),
158.5 (CHvCHCvO), 172.2 (CvO); HRMS calcd for
C8H12O3þNa 179.0684; found: 179.0691.
2
3
4.11. 5-Methyl-5-phenylacetyl-4-(pyrrolidin-1-yl)-5H-
furan-2-one (13)
To a solution of 5-methyl-4-(pyrrolidin-1-yl)-5H-furan-2-
one (3) (0.30 g, 1.80 mmol) in anhydrous THF (3.3 mL) at
2788C was added dropwise t-BuLi (1.7 M in pentane,
1.58 mL, 2.69 mmol) and the solution was stirred for 1 h at
2788C. Chlorotrimethylsilane (0.27 mL, 2.15 mmol) was
added dropwise. The reaction mixture was stirred at 2788C
for 30 min and at 08C for 30 min. After recooling to 2788C,
phenylacetyl chloride (0.28 mL, 2.15 mmol) was added
dropwise. After stirring for 1 h at 2788C and 3 h at 08C, the
volatiles were removed under reduced pressure and
chromatography of the residue (cyclohexane/EtOAc, 3:7)
afforded ketone 10 (0.42 g, 82%): Rf 0.34 (cyclohexane/
4.9. (5S p,10S p)-5-[10-(tert-Butyldimethylsilanyloxy)-
propyl]-5-methyl-5H-furan-2-one (11)
To a solution of lactone 10 (950 mg, 2.75 mmol) in glacial
acetic acid (27 mL), was added sodium cyanoborohydride
(3.46 g, 55 mmol) in portions over 2 h. Aqueous NaOH
(250 mL of a 2 M solution) was slowly added at 08C and the
solution was extracted with Et2O (4£250 mL). The
combined organic extracts were dried over MgSO4 and
the volatiles were removed under reduced pressure. The
residue was dissolved in CH2Cl2 (6 mL), then m-CPBA
(60% w/w, 1.05 g, 3.57 mmol) was added. The reaction
mixture was stirred for 10 min, then sat. aq. NaHCO3
(17 mL) was added at 08C and stirring was continued for
20 min. The solution was extracted with CH2Cl2 (3£50 mL)
and the combined organic extracts were dried over MgSO4.
The volatiles were removed under reduced pressure and
chromatography of the residue (cyclohexane/EtOAc, 1:1)
afforded a,b-unsaturated lactone 11 (700 mg, 94%) as a
EtOAc, 3:7); IR (neat): n 1725 (CvO), 1602 (CvC) cm21
1H NMR (CDCl3, 300 MHz) d 1.65 (s, 3H, CH3), 1.7–1.9
;
2
(m, 4H, CH2Pyr), 2.8–3.3 (m, 4H, CH2Pyr), 3.69 (d, J¼
2
14.7 Hz, 1H, CH2Ph), 3.91 (d, J¼14.7 Hz, 1H, CH2Ph),
4.55 (s, 1H, CHvC), 7.1–7.3 (m, 5H, Harom); 13C NMR
(CDCl3, 75 MHz) d 18.9 (CH3), 24.1, 25.9 (CH2Pyr), 42.2
(CH2Ph), 47.6, 50.7 (CH2Pyr), 82.9 (CHvC), 86.9 (CqCH3),
127.2, 128.5, 129.5 (CHarom), 133.3 (Cqarom), 167.1 (CqN),
173.3 (OCvO), 202.5 (CH2CvO); CIMS (NH3) m/z (%):
286 (MHþ, 100), 244 (36), 168 (6), 72 (14); Anal. calcd for
C17H19NO3: C, 71.56, H, 6.71, N, 4.91; found: C, 71.98, H,
6.60, N, 4.53.
4.12. 5-Methyl-5-propionyl-4-(pyrrolidin-1-yl)-5H-
furan-2-one (14)
1
clear colorless oil: Rf 0.43 (cyclohexane/EtOAc, 1:1); H
NMR (CDCl3, 400 MHz) d 0.04, 0.09 (2 s, 6H, SiCH3),
0.7–1.0 (m, 12H, SiC(CH3)3 and CH2CH3), 1.4–1.7 (m,
5H, containing at 1.39 (s, 3H, CH3Cq) and CH2CH3), 3.53
The above protocol for 13 was reproduced with propionyl
chloride (63 mL, 0.72 mmol) and 5-methyl-4-(pyrrolidin-1-
yl)-5H-furan-2-one (3) (0.10 g, 0.60 mmol). Chroma-
tography of the residue (EtOAc) afforded ketone 14
(0.11 g, 82%): Rf 0.44 (EtOAc); IR (neat): n 1727
3
3
(dd, J¼7.5, 3.9 Hz, 1H, CHOTBS), 6.00 (d, J¼5.6 Hz,
3
1H, CHCvO), 7.34 (d, J¼5.6 Hz, 1H, CHvCHCvO);
13C NMR (CDCl3, 100 MHz) d 24.1 (SiCH3), 11.0
(CH2CH3), 18.3 (CqSi), 20.2 (CH3Cq), 26.0 (C(CH3)3),
26.3 (CH2CH3), 78.1 (CHOTBS), 91.7 (CqCH3), 121.6
(CHCvO), 159.1 (CHvCHCvO), 173.2 (CvO); CIMS
(NH3) m/z (%): 288 (MNHþ4 , 100), 271 (MHþ, 22), 186
(33); Anal. calcd for C14H26O3Si: C, 62.18, H, 9.69; found:
C, 62.16, H, 9.78.
1
(CvO), 1602 (CvC) cm21; H NMR (CDCl3, 400 MHz)
3
d 1.00 (t, J¼7.0 Hz, 3H, CH2CH3), 1.67 (s, 3H, CH3Cq),
1.8–2.0 (m, 4H, CH2Pyr), 2.43 (dq, 2J¼18.6 Hz, 3J¼6.9 Hz,
1H, CH2CH3), 2.74 (dq, 2J¼18.7 Hz, 3J¼7.0 Hz, 1H,
CH2CH3), 3.1–3.5 (m, 4H, CH2Pyr), 4.53 (s, 1H, CHvC);
13C NMR (CDCl3, 100 MHz) d 7.6 (CH3CH2), 19.1
(CH3Cq), 24.2, 26.3 (CH2Pyr), 28.9 (CH2CH3), 47.9, 51.0
(CH2Pyr), 82.2 (CHvC), 87.1 (CqCH3), 167.5 (CqN), 173.3
(OCvO), 208.2 (CH2CvO); CIMS (NH3) m/z (%): 224
(MHþ, 100); Anal. calcd for C12H17NO3: C, 64.55, H, 7.67,
N, 6.27; found: C, 64.71, H, 7.84, N, 6.07.
4.10. (5S p,10S p)-5-(10-Hydroxypropyl)-5-methyl-5H-
furan-2-one (12)
The silyl ether 11 (27 mg, 0.1 mmol) was dissolved in TFA/
H2O/THF (9:1:1) (3 mL). After 2 h stirring, the solvents
were evaporated to dryness and the residue was purified by
chromatography to afford 5-(1-hydroxypropyl)-5-methyl-
5H-furan-2-one (12) (15 mg, quant.) as a clear colorless oil:
Rf 0.26 (cyclohexane/EtOAc, 1:1); 1H NMR (CDCl3,
4.13. (5S p,10S p)-5-(10-Hydroxy-20-phenylethyl)-5-
methyl-4-(pyrrolidin-1-yl)-5H-furan-2-one (4b)
To a solution of 5-methyl-5-phenylacetyl-4-(pyrrolidin-1-
yl)-5H-furan-2-one (13) (0.30 g, 1.05 mmol) in MeOH
(7.6 mL) at 08C was added cerium(III) chloride (0.39 g,
1.58 mmol). Sodium borohydride (0.16 g, 4.21 mmol) was
3
400 MHz) d 1.03 (t, J¼7.3 Hz, 3H, CH2CH3), 1.39 (dqd,
3
2J¼14.3 Hz, J¼7.2, 2.9 Hz, 1H, CH2CH3), 1.49 (s, 3H,
CH3Cq), 1.58 (dqd, 2J¼14.5 Hz, 3J¼7.4, 2.5 Hz, 1H,

`
H. Bruyere et al. / Tetrahedron 59 (2003) 5879–5886
5885
added portionwise. The reaction mixture was stirred at room
4.16. (5R p,10S p,200S)-5-(10-Hydroxypropyl)-4-(200-
temperature to completion. The volatiles were removed
under reduced pressure and filtration of the residue over
silica gel (EtOAc) afforded alcohol 4b (0.30 g, 98%) as a
light yellow solid: Rf 0.24 (EtOAc); mp 1448C; IR (neat): n
methoxymethylpyrrolidin-100-yl)-5-methyl-5H-furan-2-
one (17)
The protocol for 4 was used0on propionaldehyde (0.12 mL,
1.70 mmol) and (20S)-4-(2 -methoxymethylpyrrolidin-10-
yl)-5-methyl-5H-furan-2-one (15) (0.30 g, 1.42 mmol).
Chromatography of the residue (CH2Cl2/MeOH, 98:2)
afforded aldols 17a and 17b as a 1:1 mixture (0.23 g,
59%). The following spectroscopic properties for the
mixture are given: Rf 0.15 (CH2Cl2/MeOH, 98:2). IR
(neat): n 3424 (OH), 1707 (CvO), 1586 (CvC) cm21; 1H
NMR (CDCl3, 300 MHz) d 0.98 (t, 3J¼7.4 Hz, 6H,
CH2CH3), 1.3–1.8 (m, 10H, containing at 1.65, 1.68 (2 s,
6H, CH3Cq) and CH2CH3), 1.8–2.1 (m, 8H, CH2Pyr), 3.1–
3.8 (m, 18H, containing at 3.29, 3.31 (2 s, 6H, OCH3), and
CH2Pyr, CHOH, CHN, CH2O), 4.52, 4.53 (2 s, 2H, CHvC);
13C NMR (CDCl3, 100 MHz) d 10.3, 10.5 (CH2CH3), 20.4,
21.4 (CH3Cq), 24.1, 24.6 (CH2Pyr), 28.0 (CH2CH3), 49.4,
49.7 (CH2Pyr), 59.3 (OCH3), 61.1 (CHN), 70.9 (CH2O),
75.1, 76.0 (CHOH), 84.1 (CHvC), 87.1 (CqCH3), 170.2,
170.7 (CqN), 173.5 (CvO); CIMS (NH3) m/z (%): 270
(MHþ, 22), 116 (100), 72 (29).
1
3283 (OH), 1686 (CvO), 1584 (CvC) cm21; H NMR
(CDCl3, 300 MHz) d 1.62 (s, 3H, CH3), 1.8–2.0 (m, 4H,
2
3
CH2Pyr), 2.4–2.5 (m, 1H, OH), 2.74 (dd, J¼14.1 Hz, J¼
2
3
10.2 Hz, 1H, CH2Ph), 3.03 (dd, J¼14.1 Hz, J¼2.1 Hz,
1H, CH2Ph), 3.3–3.6 (m, 4H, CH2Pyr), 4.03 (bd, 3J¼9.5 Hz,
1H, CHOH), 4.44 (s, 1H, CHvC), 7.1–7.3 (m, 5H, Harom);
13C NMR (CDCl3, 75 MHz) d 21.2 (CH3), 25.3 (CH2Pyr),
38.1 (CH2Ph), 49.6 (CH2Pyr), 75.0 (CHOH), 83.2 (CHvC),
86.5 (CqCH3), 126.6, 128.6, 129.4 (CHarom), 138.2
(Cqarom), 170.8 (CqN), 173.6 (CvO); CIMS (NH3) m/z
(%): 288 (MHþ, 100), 168 (10); HRMS calcd for
C17H21NO3þNa 310.1419; found: 310.1418.
4.14. (5S p,10S p)-5-(10-Hydroxypropyl)-5-methyl-4-
(pyrrolidin-1-yl)-5H-furan-2-one (5b)
The protocol for 4b was carried out using 5-methyl-5-
propionyl-4-(pyrrolidin-1-yl)-5H-furan-2-one (14) (50 mg,
0.22 mmol). Filtration of the residue (EtOAc) afforded
alcohol 5b (44 mg, 87%): Rf 0.30 (CH2Cl2/MeOH, 98:2); IR
(neat): n 3306 (OH), 1694 (CvO), 1588 (CvC) cm21; 1H
NMR (CDCl3, 300 MHz) d 1.01 (t, 3J¼7.4 Hz, 3H,
CH2CH3), 1.50 (dqd, 2J¼14.3 Hz, 3J¼7.1, 3.0 Hz, 1H,
4.17. (20S)-4-(20-Methoxymethylpyrrolidin-10-yl)-5-
methyl-5-phenylacetyl-5H-furan-2-one (18)
The protocol for 13 was carried out using phenylacetyl
chloride (2.25 mL, 1.70 mmol) and (20S)-4-(20-
methoxymethylpyrrolidin-10-yl)-5-methyl-5H-furan-2-one
(15) (0.30 g, 1.42 mmol). Chromatography of the residue
(cyclohexane/EtOAc, 3:7) afforded ketone 18 as a 9:1
mixture of diastereoisomers (0.36 g, 73%). The following
spectroscopic properties for the major isomer are given:
Rf 0.49 (EtOAc); IR (neat): n 1725 (CvO), 1594
2
CH2CH3), 1.53 (s, 3H, CH3Cq), 1.73 (dqd, J¼14.4 Hz,
3J¼7.5, 2.5 Hz, 1H, CH2CH3), 1.9–2.1 (m, 4H, CH2Pyr),
3.2–3.5 (m, 4H, CH2Pyr), 3.72 (bt, 3J¼4.3 Hz, 1H, CHOH),
4.42 (s, 1H, CHvC); 13C NMR (CDCl3, 75 MHz) d 10.7
(CH2CH3), 20.8 (CH3Cq), 24.5 (CH2CH3), 25.2, 49.6
(CH2Pyr), 75.1 (CHOH), 83.2 (CHvC), 86.7 (CqCH3),
171.1 (CqN), 173.7 (CvO); CIMS (NH3) m/z (%): 226
(MHþ, 100), 186 (16), 166 (8); Anal. calcd for C12H19NO3:
C, 63.98, H, 8.50, N, 6.22; found: C, 63.48, H, 8.50, N, 5.81.
1
(CvC) cm21; H NMR (CDCl3, 400 MHz) d 1.67 (s, 3H,
CH3Cq), 1.7–2.0 (m, 4H, CH2Pyr), 3.1–3.3 (m, 7H,
containing at 3.24 (s, 3H, OCH3) and CH2Pyr, CH2O),
3.67 (bs, 1H, CHN), 3.81 (bs, 2H, CH2Ph), 4.66 (s, 1H,
CHvC), 7.0–7.3 (m, 5H, Harom); 13C NMR (CDCl3,
75 MHz) d 19.2 (CH3Cq), 24.1, 28.0 (CH2Pyr), 41.9
(CH2Ph), 48.8 (CH2Pyr), 59.1 (OCH3), 61.5 (CHN), 70.4
(CH2O), 83.9 (CHvC), 87.7 (CqCH3), 127.1, 128.5, 129.5
(CHarom), 133.3 (Cqarom), 167.0 (CqN), 173.3 (OCvO),
203.0 (CH2CvO); CIMS (NH3) m/z (%): 330 (MHþ, 100),
288 (16); Anal. calcd for C14H21NO4: C, 62.90, H, 7.92, N,
5.24; found: C, 62.96, H, 7.98, N, 5.05.
4.15. (5R p,10S p,200S)-5-(10-Hydroxy-20-phenylethyl)-4-
(200-methoxymethylpyrrolidin-100-yl)-5-methyl-5H-
furan-2-one (16)
The protocol for 4 was used on (20S)-4-(20-methoxymethyl-
pyrrolidin-10-yl)-5-methyl-5H-furan-2-one (15) (0.30 g,
1.42 mmol). Chromatography of the residue (CH2Cl2/
MeOH, 98:2) afforded aldols 16a and 16b as a 1:1 mixture
(0.25 g, 53%). The following spectroscopic properties for
the mixture are given: Rf 0.28 (CH2Cl2/MeOH, 95:5); IR
(neat): n 3448 (OH), 1718 (CvO), 1584 (CvC) cm21; 1H
NMR (CDCl3, 300 MHz) d 1.68, 1.72 (2 s, 6H, CH3Cq),
1.8–2.2 (m, 8H, CH2Pyr), 2.60 (dd, 2J¼14.0 Hz, 3J¼
4.18. (20S)-4-(20-Methoxymethylpyrrolidin-10-yl)-5-
methyl-5-propionyl-5H-furan-2-one (19)
3
10.4 Hz, 1H, CH2Ph), 2.75 (d, J¼7.0 Hz, 2H, CH2Ph),
The protocol for 13 was carried out using propionyl chloride
(0.15 mL, 1.70 mmol) and (20S)-4-(20-methoxymethylpyr-
rolidin-10-yl)-5-methyl-5H-furan-2-one (15) (0.30 g,
1.42 mmol). Chromatography of the residue (cyclohexane/
EtOAc, 3:7) afforded ketone 19 as a 9:1 mixture of
diastereoisomers (0.27 g, 70%). The following spectro-
scopic properties for the major isomer are given: Rf 0.31
(cyclohexane/EtOAc, 3:7); IR (neat): n 1724 (CvO), 1594
2.79 (dd, 2J¼13.7 Hz, 3J¼2.4 Hz, 1H, CH2Ph), 3.2–3.8 (m,
16H, containing at 3.25, 3.29 (2 s, 6H, OCH3) and CH2Pyr
,
3
CHN, CH2O), 3.94 (bd, J¼9.1 Hz, 1H, CHOH), 4.12 (bt,
3J¼6.3 Hz, 1H, CHOH), 4.58 (s, 2H, CHvC), 7.1–7.3 (m,
10H, Harom); 13C NMR (CDCl3, 100 MHz) d 20.3, 21.3
(CH3Cq), 24.0, 27.7, 28.0 (CH2Pyr), 37.8, 38.6 (CH2Ph),
49.2, 50.0 (CH2Pyr), 59.3 (OCH3), 61.1 (CHN), 70.6
(CH2O), 74.6, 75.7 (CHOH), 84.2 (CHvC), 86.8
(CqCH3), 126.5, 126.6, 128.5, 129.4, 129.5 (CHarom),
137.9, 138.6 (Cqarom), 170.1, 170.3 (CqN), 173.4 (CvO);
CIMS (NH3) m/z (%): 332 (MHþ, 100), 212 (52), 138 (16).
(CvC) cm21 1H NMR (CDCl3, 400 MHz) d 0.91 (t,
;
3J¼7.2 Hz, 3H, CH2CH3), 1.59 (s, 3H, CH3Cq), 1.7–2.0
2
3
(m, 4H, CH2Pyr), 2.33 (dq, J¼18.5 Hz, J¼7.2 Hz, 1H,
CH2CH3), 2.60 (dq, 2J¼18.6 Hz, 3J¼7.3 Hz, 1H, CH2CH3),

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H. Bruyere et al. / Tetrahedron 59 (2003) 5879–5886
5886
3.2–3.5 (m, 7H, containing at 3.18 (s, 3H, OCH3) and
CH2Pyr, CH2O), 3.66 (bs, 1H, CHN), 4.55 (s, 1H, CHvC);
13C NMR (CDCl3, 75 MHz) d 7.5 (CH2CH3), 19.0
(CH3Cq), 24.1 (CH2Pyr), 28.1 (CH2CH3), 28.4, 48.8
(CH2Pyr), 59.0 (OCH3), 61.2 (CHN), 70.4 (CH2O), 83.6
(CHvC), 87.5 (CqCH3), 167.2 (CqN), 173.3 (OCvO),
206.1 (CH2CvO); CIMS (NH3) m/z (%): 268 (MHþ, 100),
226 (10); Anal. calcd for C19H23NO4: C, 69.28, H, 7.04, N,
4.25; found: C, 69.22, H, 7.22, N, 4.18.
Acknowledgements
We are grateful to La Ligue Nationale Contre le Cancer for
financing HB.
References
1. Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–48.
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2002; pp 57–98.
4.19. (5R,10R,200S)-5-(10-Hydroxy-20-phenylethyl)-4-(200-
methoxymethylpyrrolidin-100-yl)-5-methyl-5H-furan-2-
one (20a)
The protocol for 4b was0 reproduced with (20S)-4-(20-
methoxymethylpyrrolidin-1 -yl)-5-methyl-5-phenylacetyl-
5H-furan-2-one (18) (50 mg, 0.15 mmol). Filtration of the
residue (CH2Cl2/MeOH, 8:2) afforded alcohols 20a and 20b
as a 9:1 mixture (46 mg, 91%). Chromatography of a sample
of the mixture (CH2Cl2/MeOH, 98:2) allowed the separation
of isomer 20a which could be crystallized (Isopropylether):
Rf 0.28 (EtOAc); mp 1328C; [a]2D0¼þ72.8 (c 0.5, CHCl3);
3. Murakami, M.; Matsuda, H.; Makabe, K.; Yamagushi, K.
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´
5. Souto, M. L.; Manriquez, C. P.; Norte, M.; Fernandez, J. J.
Tetrahedron 2002, 58, 8119–8125.
6. Lin, Y.; Bewley, C. A.; Faulkner, D. J. Tetrahedron 1993, 49,
7977–7984.
IR (neat): n 3356 (OH), 1694 (CvO), 1575 (CvC) cm21
;
7. Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza,
A. M.; Carboni, J. M.; Fairchild, C. R. J. Am. Chem. Soc. 1997,
119, 8744–8745.
1H NMR (CDCl3, 300 MHz) d 1.65 (s, 3H, CH3Cq), 1.8–
2.0 (m, 4H, CH2Pyr), 2.50 (d, 3J¼6.1 Hz, 1H, OH), 2.70 (dd,
2J¼13.9 Hz, 3J¼10.3 Hz, 1H, CH2Ph), 2.98 (dd, 2J¼
14.0 Hz, 3J¼2.3 Hz, 1H, CH2Ph), 3.2–3.5 (m, 6H, contain-
ing at 3.27 (s, 3H, OCH3) and CHN, CH2O), 3.6–3.9 (m,
8. Casiraghi, G.; Rassu, G. Synthesis 1995, 607–626.
9. Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem.
Rev. 2000, 100, 1929–1972.
3
2H, CH2Pyr), 3.98 (ddd, J¼10.2, 6.1, 2.3 Hz, 1H, CHOH),
10. Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Synlett
1999, 9, 1333–1350.
4.58 (s, 1H, CHvC), 7.1–7.3 (m, 5H, Harom); 13C NMR
(CDCl3, 75 MHz) d 20.9 (CH3Cq), 24.2, 28.0 (CH2Pyr), 37.6
(CH2Ph), 49.5 (CH2Pyr), 59.1 (OCH3), 61.0 (CHN), 70.6
(CH2O), 75.2 (CHOH), 85.0 (CHvC), 86.7 (CqCH3),
126.6, 128.6, 129.4 (CHarom), 138.4 (Cqarom), 169.7 (CqN),
173.5 (CvO); CIMS (NH3) m/z (%): 332 (MHþ, 100), 212
(20); Anal. calcd for C19H25NO4: C, 68.86, H, 7.60, N, 4.23;
found: C, 68.19, H, 7.65, N, 3.55.
11. Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem. Soc.
Rev. 2000, 29, 109–118.
12. Redero, E.; Sandoval, C.; Bermejo, F. Tetrahedron 2001, 57,
9597–9605.
13. Martin, M. R.; Mateo, A. I. Tetrahedron: Asymmetry 1995, 6,
1621–1632.
14. Schlessinger, R. H.; Iwanowicz, E. J.; Springer, J. P.
Tetrahedron Lett. 1988, 29, 1489–1492.
4.20. (5R,10R,200S)-5-(10-Hydroxypropyl)-4-(200-methoxy-
methylpyrrolidin-100-yl)-5-methyl-5H-furan-2-one (21a)
15. Dankwardt, S. M.; Dankwardt, J. W.; Schlessinger, R. H.
Tetrahedron Lett. 1998, 39, 4971–4974.
16. Dankwardt, S. M.; Dankwardt, J. W.; Schlessinger, R. H.
Tetrahedron Lett. 1998, 39, 4975–4978.
The above protocol for 20 was used with (20S)-4-(20-
methoxymethylpyrrolidin-10-yl)-5-methyl-5-propionyl-5H-
furan-2-one (19) (50 mg, 0.19 mmol). Filtration of the
residue (CH2Cl2/MeOH, 8:2) afforded alcohols 21a and 21b
as a 9:1 mixture (49 mg, 91%). The following spectroscopic
properties for the major isomer 21a are given: Rf 0.31
(CH2Cl2/MeOH, 98:2); IR (neat): n 3335 (OH), 1696
(CvO), 1578 (CvC) cm21; 1H NMR (CDCl3, 300 MHz) d
17. Dankwardt, J. W.; Dankwardt, S. M.; Schlessinger, R. H.
Tetrahedron Lett. 1998, 39, 4979–4982.
18. Dankwardt, J. W.; Dankwardt, S. M.; Schlessinger, R. H.
Tetrahedron Lett. 1998, 39, 4983–4986.
19. Nishide, K.; Aramata, A.; Kamanaka, T.; Inoue, T.; Node, M.
Tetrahedron 1994, 50, 8337–8346.
20. The NMR spectral data of 9 were slightly different from those
described in Ref. 12. The data for the syn adduct in Ref. 12 were
mistakenly reported: the 1H and 13C spectra kindly sent by Pr.
Bermejo are identical to those we describe in the present paper.
21. Silylation of syn diastereoisomer 5b required longer reaction
time than for the anti aldol and 3 equiv. of tert-butyldimethyl-
silyl trifluoromethanesulfonate were necessary to lead the
reaction to completion.
3
2
0.99 (t, J¼7.4 Hz, 3H, CH2CH3), 1.45 (dqd, J¼14.2 Hz,
3J¼7.3, 2.9 Hz, 1H, CH2CH3), 1.55 (s, 3H, CH3Cq), 1.66
2
3
(dqd, J¼14.3 Hz, J¼7.5, 2.4 Hz, 1H, CH2CH3), 1.8–2.1
(m, 4H, CH2Pyr), 2.50 (d, 3J¼7.8 Hz, OH), 3.2–3.5 (m, 7H,
containing at 3.28 (s, 3H, OCH3) and CH2Pyr, CH2O), 3.66
(td, 3J¼7.8, 2.3 Hz, 1H, CHOH), 3.76 (bs, 1H, CHN), 4.55
(s, 1H, CHvC); 13C NMR (CDCl3, 75 MHz) d 10.9
(CH2CH3), 20.6 (CH3Cq), 24.0, 24.2 (CH2Pyr), 28.0
(CH2CH3), 49.4 (CH2Pyr), 59.1 (OCH3), 60.9 (CHN),
70.6 (CH2O), 75.4 (CHOH), 85.0 (CHvC), 87.0
(CqCH3), 170.1 (CqN), 173.6 (CvO); CIMS (NH3) m/z
(%): 270 (MHþ, 100), 226 (7), 212 (13); Anal. calcd for
C14H23NO4: C, 62.43, H, 8.61, N, 5.20; found: C, 62.61, H,
8.67, N, 5.06.
22. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
23. Schlessinger, R. H.; Pettus, L. H. J. Org. Chem. 1998, 63,
9089–9094.
24. The crystal structure has been deposited at the Cambridge
Crystallographic Data Centre; deposition number CCDC 206620.
25. Momose, T.; Toyooka, N.; Nishi, T.; Takeuchi, Y.
Heterocycles 1988, 27, 1907–1923.