Synthesis of a highly functionalized γ-lactone as a precursor of 9- pentyl anthracyclines

Article abstract of DOI:10.1016/S0957-4166(98)00320-6

The synthesis of non racemic chiral γ-lactone 7 from α-D- isosaccharino-1,4-lactone (+)-8, as a precursor of the A-ring of the targeted 3'-morpholinyl-9-pentyl anthracycline 6, is described.

Full text of DOI:10.1016/S0957-4166(98)00320-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2999–3009
Synthesis of a highly functionalized γ-lactone as a precursor of
9-pentyl anthracyclines
Emmanuel Bertounesque, Fatima Millal, Philippe Meresse and Claude Monneret ∗
UMR 176 CNRS-Institut Curie, Section Recherche, 26 rue d’Ulm, 75248 Paris Cedex 05, France
Received 17 June 1998; accepted 7 August 1998
Abstract
The synthesis of non racemic chiral γ-lactone 7 from α-D-isosaccharino-1,4-lactone (+)-8, as a precursor of
the A-ring of the targeted 30-morpholinyl-9-pentyl anthracycline 6, is described. © 1998 Elsevier Science Ltd. All
rights reserved.
1. Introduction
The anthracycline antibiotics daunorubicin 1 and doxorubicin 2 are of primary importance in cancer
chemotherapy.1 In particular, doxorubicin has been used successfully to produce regression in dissem-
inated neoplastic diseases such as breast carcinoma, malignant lymphoma and sarcomas. The clinical
value of anthracyclines is limited by the development of multidrug resistance (MDR)1,2 which may be
due to one or several mechanisms, most notably P-glycoprotein (PGP) associated multidrug resistance
(MDR1) and alterations in topoisomerase II. One strategy to overcome this drawback is the classic
analogue development3,4 through structure–activity studies. In the case of doxorubicin and aclacinomycin
analogues, Coley et al.5 have evaluated 9-alkyl-modified anthracyclines on MDR cell lines on the basis of
P-glycoprotein overproduction and overexpression of the MDR1 gene, and were successful at addressing
the circumvention of multidrug resistance, most notably the 9-ethyl Ro 31-1966 3 and 13-methyl
aclacinomycin 4 (Fig. 1). This work showed a significant correlation between lipophilicity and MDR-
reversing ability, where lipophilic 9-alkyl groups are believed to increase the rate of cellular uptake. It is
noteworthy that other elements may be involved in the effectiveness of these compounds, such as affinity
for the membrane efflux pump PGP, intracellular distribution, endocytosis, and membrane trafficking.
Moreover, studies6 on morpholinyl anthracyclines have disclosed the essential role of the intramolecular
combination of 9-alkyl substitution and the 30-morpholinyl ring to obtain resistance factors (RF) close
to unity, and have confirmed the identification7 of MX2 5 as a promising antitumour agent.8 Additional
∗
Corresponding author. E-mail: Claude.Monneret@curie.fr
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00320-6
tetasy 2469 Article

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Fig. 1.
lipophilicity of the morpholinyl sugar unit would not be the only determinant favouring retention of
activity in P-glycoprotein-overexpressing MDR cells, indeed its enzymatic activation might lead to DNA
alkylation.9
As part of our program10 aimed at the reversal of anthracycline resistance, we have reported11 the
synthesis and activity of a 40-morpholino-9-methyl anthracycline demonstrating that the morpholino sub-
stitution in the sugar moiety is amenable at the C-40 position, but this appears to be of minor importance
from the observations reported by the Farmitalia group.3 It was of interest to undertake the synthesis
of the 30-morpholinyl-9-pentyl anthracycline 6 potentially endowed with higher lipophilic property than
the mentioned derivatives. In this account, we describe the synthesis of chiral 4-benzoyloxymethyl-2-
hydroxy-2-pentyl γ-lactone 7 from the readily available α-D-isosaccharino-1,4-lactone 8,12 which is a
key intermediate of our target compound 6 utilizing a strategy based upon aldol methodology A+BCD
as shown in the retrosynthetic analysis (Scheme 1).
Scheme 1.
2. Results and discussion
We first tried to construct13 the chiral tertiary hydroxy group of 3 and 5 in order to evaluate the
reactivity of the γ-lactone substrates such as 10, 15, and 17, prepared from 8, vis-à-vis substitution
reactions (Scheme 2).
Lactone 8 was converted into benzylidene 9 (PhCHO, ZnCl2, rt) as a 1:2 mixture of endo- and
exo-diastereoisomers in 88% overall yield. Several attempts14 were made to achieve this protection.
Benzylidene acetal opening via the procedure of Hanessian15 (NBS, C6H6, NaHCO3, 80°C) delivered

E. Bertounesque et al. / Tetrahedron: Asymmetry 9 (1998) 2999–3009
3001
Scheme 2.
bromo-lactone (+)-10 in 59% yield but the yield was improved to reach 66% in the presence of benzoyl
peroxide as the catalyst.16 We next examined nucleophilic displacements of the neopentyl bromide 10.
Azidolysis (LiN3, DMF, 70°C) afforded the azido lactone (+)-11 in 60% yield, which could serve as
a useful chiron for the preparation of SM-588717 analogues wherein the A-ring contains an amino
group at the C-13 position. In contrast with the azide ion, introduction of the methyl group (MeMgI,
CuBr–SMe2, THF)18 was not effective. We then sought to prepare the tosylate derivative 15. Protection
of the neopentyl alcohol of (+)-8 as the TBDPS ether (TBDPSCl, imidazole, DMF, rt) gave the lactone
(+)-13 in 76% yield, along with a minor amount of the corresponding bis-silyl lactone (+)-14 (11%).
Tosylation of 13 (TsCl, Et3N, CH2Cl2, rt) then furnished (+)-15 in 43% yield. Attempts to displace
tosylate via copper-catalyzed Grignard reaction (MeMgI, CuBr–SMe2, THF) or cuprate reaction19
(Me2CuLi, THF, −20°C) were unsuccessful. Finally, we also briefly examined the possibility of forming
carbon–carbon bonds from spiroepoxy γ-lactone 17.20 To this end, treatment of (+)-13 according to
the Mitsunobu protocol21 provided the desired epoxy lactone (+)-17 in 85% yield. However, we were
unable to achieve nucleophilic opening of epoxide (+)-17 by the higher order cuprate Me2Cu(CN)Li222 or
Me2Cu(CN)Li2/BF3–Et2O.23 Importantly, reaction of 17 with Bu2Cu(CN)Li2 was attempted to obtain 18
but also failed. As we anticipated, the lack of substitution reaction presumably comes from the sterically
congested transition state due to the neopentylic systems24 and an unfavourable specific conformation25
towards the attack of an organometallic species from the β-face. Molecular modelling (Chem 3D Pro,
MM2 force field, dihedral driver, molecular dynamics) provided a possible minimum conformation for
17 (TBDPS modelled as TMS group). This model revealed high steric bias due to the close proximity
of the TMS group and the C2 centre of the epoxide moiety (d(O–C2)=3.23 Å) which should not lead to
β-face attack (Fig. 2). In addition, in the case of 10 and 15, the SN2 mechanism is currently known to be
retarded by proximal electron-withdrawing groups.26
As an alternative, we decided to examine the ring expansion of the known iodo-lactone (+)-1927
based on the methodology developed by Shibata et al.28 in order to investigate the feasibility of the
nucleophilic ring opening of a spiroepoxy δ-lactone system. Unexpectedly, treatment of (+)-19 with

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E. Bertounesque et al. / Tetrahedron: Asymmetry 9 (1998) 2999–3009
Fig. 2.
(Bu3Sn)2O provided γ-lactone (−)-20 in 47% yield (Scheme 3). The structure and the stereochemical
1
assignment were based on spectroscopic analysis (IR, H NMR, MS) and comparison with the α-D-
isosaccharino-1,4-lactone derivative (+)-26.29 The diastereoisomeric relationship was also confirmed by
1
comparison (IR, H NMR, MS) of esters 25 (52%) and 2730 prepared from γ-lactone 20 and epimeric
γ-lactone 26, respectively.
Scheme 3.
We speculate that the inversion of the C7 stereocentre in this reaction is established through the epoxide
intermediate 28 giving rise to 20 by 5-exo ring closure31 as generally observed32 (Scheme 4).
Scheme 4.

E. Bertounesque et al. / Tetrahedron: Asymmetry 9 (1998) 2999–3009
3003
Fig. 3.
The formation of the γ-lactone (−)-20 is also understandable on the basis of calculated heats of
formation of 20 and δ-lactone 29 (6-endo ring closure). They were calculated using the AM1 method
(Chem 3D Pro, MOPAC) (Fig. 3). The γ-lactone 20 is more stable (4.07 kcal/mol) than the δ-lactone 29.
For larger scale, we prepared directly γ-lactone (−)-21 in 46% yield (2 steps). Acidic hydrolysis of 21
and epoxidation of 22 gave the spiroepoxy γ-lactone (−)-23. Molecular mechanics minimization of the
geometry of 23 showed a possible conformation33 which would serve to direct approaching nucleophiles
to β-face. To our delight, the reaction of Me2Cu(CN)Li2 and Bu2Cu(CN)Li2 afforded (−)-24 and the
suitable γ-lactone (−)-7 in 52% and 50% yields, respectively.
In summary, the synthesis of (−)-7 as an A-ring precursor of 30-morpholinyl-9-pentyl anthracycline 6
reveals the continuing pivotal role of α-D-isosaccharino-1,4-lactone 8 in anthracycline chemistry.
3. Experimental
3.1. General procedures
1H NMR spectra were recorded on Bruker AM-200, 250 and 270 instruments. IR spectra were
recorded on a Perkin–Elmer 1710 infrared spectrophotometer. Optical rotations were measured with
a Perkin–Elmer 241 polarimeter. Melting points were determined on either a Kofler hot-stage instrument
or an electrothermal digital melting point apparatus and are not corrected. Mass spectra (MS) were reg-
istered on a Nermag R10-10C mass spectrometer under chemical ionization (CI) conditions. Elemental
analyses were performed by the ‘Service d’Analyse du CNRS, Vernaison, France’. All reactions were
monitored by thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-
254) using UV light and 20% methanolic sulfuric acid, heat was used as a developing agent. E. Merck
silica gel (particle size 0.040–0.063 mm) was used for flash column chromatography.34 All reactions were
carried out under an argon atmosphere with dry, freshly distilled solvents under anhydrous conditions
unless otherwise noted. Yields refer to chromatographically and spectroscopically pure compounds
unless otherwise stated.
3.2. (5S,8S)-8-Hydroxymethyl-2-phenyl-1,3,7-trioxaspiro[4.4]nonan-6-one 9
To a solution of lactone 8 (200 mg, 1.23 mmol) in benzaldehyde (4 mL) was added dry zinc chloride
(195 mg, 1.43 mmol). The mixture was stirred for 1.5 h at room temperature and then diluted with ethyl
acetate. The ethyl acetate extracts were washed successively with saturated aqueous NaHCO3 and water,
dried over MgSO4, and concentrated in vacuo. Flash chromatography, with cyclohexane:acetone (8:1)
as eluent, afforded a separable mixture of two diastereoisomeric forms of 9 in a 2:1 ratio (265 mg, 88%

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overall yield). The major compound was an oil: [α]D22=+47 (c 0.8, CHCl3). 1H NMR (250 MHz, CDCl3)
δ 7.55 (m, 2H, aryl), 7.40 (m, 3H, aryl), 5.90 (s, 1H, H-2), 4.72 (m, 1H, H-8), 4.60 (d, J=9.5 Hz, 1H,
H-4), 4.02 (d, J=9.5 Hz, 1H, H-4), 4.00 (dd, J=12.7, 2.5 Hz, 1H, H-10), 3.60 (dd, J=12.7, 3 Hz, 1H,
H-10), 2.91 (s, 1H, OH), 2.59 (dd, J=13.9, 7.3 Hz, 1H, H-9), 2.35 (dd, J=13.9, 6.7 Hz, 1H, H-9). MS
(DCI, NH3) m/e 251 [M+H]+, 268 [M+NH4]+.
The minor compound was a solid: mp 72–74°C. [α]D22=+55.1 (c 0.8, CHCl3). IR (CDCl3): 3606,
1
3471, 2949, 2887, 1778, 1607 cm−1. H NMR (250 MHz, CDCl3) δ 7.50 (m, 2H, aryl), 7.30 (m, 3H,
aryl), 6.07 (s, 1H, H-2), 4.75 (m, 1H, H-8), 4.37 (d, J=8.9 Hz, 1H, H-4), 4.30 (dd, J=8.9 Hz, 1H, H-
4), 4.00 (dd, J=12.8, 2.5 Hz, 1H, H-10), 3.60 (dd, J=12.8, 3 Hz, 1H, H-10), 2.91 (bs, 1H, OH), 2.58
(dd, J=14, 7.5 Hz, 1H, H-9), 2.47 (dd, J=14, 6.4 Hz, 1H, H-9). MS (DCI, NH3) m/e 251 [M+H]+, 268
[M+NH4]+. Anal. calcd for C13H14O5: C, 62.39; H, 5.63. Found: C, 62.58; H, 5.62.
3.3. (3S,5S)-3-Benzoyloxy-3-bromomethyl-5-hydroxymethyl-2-oxotetrahydrofuran 10
To a solution of 9 (220 mg, 0.88 mmol) in benzene (20 mL) were added N-bromosuccinimide (180
mg, 1.01 mmol) and a few granules of benzoyl peroxide. The resultant mixture was heated to reflux
for 1.5 h. The mixture was then diluted with ethyl acetate, washed with saturated aqueous NaHCO3,
saturated Na2S2O3 and brine, dried over MgSO4, and concentrated in vacuo. Flash chromatography,
with cyclohexane:ethyl acetate (3:1) as eluent, gave 193 mg (66%) of 10 as a solid: mp 89–91°C.
[α]D22=+34.8 (c 0.79, CHCl3). IR (CDCl3): 3477, 3073, 2962, 2879, 1780, 1724, 1602 cm−1. 1H NMR
(270 MHz, CDCl3) δ 8.05 (dd, J=7.5, 1.5 Hz, 2H, aryl), 7.60 (t, J=7.5 Hz, 1H, aryl), 7.45 (m, 2H, aryl),
5.05 (m, 1H, H-5), 4.06 (dd, J=13.5, 2.5 Hz, 1H, H-6), 3.95 (d, J=10.5 Hz, 1H, H-30), 3.86 (d, J=10.5
Hz, 1H, H-30), 3.70 (dd, J=13.3, 3 Hz, 1H, H-6), 2.75 (dd, J=14.5, 6 Hz, 1H, H-4), 2.60 (dd, J=14.5,
8.5 Hz, 1H, H-4), 2.53 (s, 1H, OH). MS (DCI, NH3) m/e 329 ([M+H]+, 79Br), 331 ([M+H]+, 81Br), 346
([M+NH4]+, 79Br), 348 ([M+NH4]+, 81Br). Anal. calcd for C13H13O5Br: C, 47.43; H, 3.98. Found: C,
47.64; H, 4.01.
3.4. (3S,5S)-3-Azidomethyl-3-benzoyloxy-5-hydroxymethyl-2-oxotetrahydrofuran 11
To a solution of 10 (100 mg, 0.30 mmol) in DMF (15 mL) was added LiN3 (38 mg, 0.76 mmol). After
3.5 h at 70°C, the mixture was diluted with ethyl acetate, washed with brine, dried over MgSO4, and
concentrated in vacuo. Flash chromatography, with cyclohexane:ethyl acetate (2:1) as eluent, provided
53 mg (60%) of 11 as a solid: mp 113–115°C. [α]D22=+88.7 (c 0.8, CHCl3). IR (CDCl3): 3628, 2934,
2108, 1779, 1723, 1602 cm−1. 1H NMR (270 MHz, CDCl3) δ 8.08 (dd, J=8, 1.5 Hz, 2H, aryl), 7.66 (t,
J=8 Hz, 1H, aryl), 7.50 (dd, J=8 Hz, 2H, aryl), 5.05 (m, 1H, H-5), 4.08 (dd, J=12, 2 Hz, 1H, H-6), 3.97
(d, J=13 Hz, 1H, H-30), 3.70 (dd, J=12, 3 Hz, 1H, H-6), 3.68 (d, J=13 Hz, 1H, H-30), 2.70 (dd, J=15, 6
Hz, 1H, H-4), 2.60 (dd, J=15, 9 Hz, 1H, H-4), 2.10 (s, 1H, OH). MS (DCI, NH3) m/e 292 [M+H]+, 309
[M+NH4]+.
3.5. (3S,5S,)-5-(tert-Butyldiphenylsilyloxy)methyl-3-hydroxy-3-hydroxymethyl-2-oxotetrahydrofuran 13
and (3S,5S)-3,5-di-(tert-butyldiphenylsilyloxy)methyl-3-hydroxy-2-oxotetrahydrofuran 14
To a solution of 8 (2 g, 12.5 mmol) in DMF (10 mL) were added imidazole (42 mg, 0.62 mmol) and
tert-butyldiphenylsilyl chloride (3.2 mL, 12.6 mmol). The solution was stirred at room temperature for 2
h before being diluted with H2O. The mixture was extracted with ethyl acetate, washed with brine, dried

E. Bertounesque et al. / Tetrahedron: Asymmetry 9 (1998) 2999–3009
3005
over MgSO4, and concentrated in vacuo. Flash chromatography, with cyclohexane:ethyl acetate (3:1) as
eluent, furnished 3.8 g (76%) of 13 as a solid and 900 mg (11%) of 14 as an oil.
Compound 13: mp 106–107°C. [α]D22=+37.5 (c 0.81, CHCl3). IR (CDCl3): 3537, 3450, 3075, 1767
cm−1. 1H NMR (200 MHz, CD3COCD3) δ 7.72 (m, 4H, aryl), 7.44 (m, 6H, aryl), 4.90 (s, 1H, OH), 4.75
(m, 1H, H-5), 4.13 (dd, J=6.3, 5.1 Hz, 1H, OH), 3.92 (dd, J=11.5, 3.4 Hz, 1H, H-6), 3.78 (dd, J=11.5,
5.4 Hz, 1H, H-6), 3.74 (dd, J=10.5, 6.3 Hz, 1H, H-30), 3.59 (dd, J=10.7, 5.1 Hz, 1H, H-30), 2.52 (dd,
J=13.6, 9 Hz, 1H, H-4), 2.13 (dd, J=13.6, 6.5 Hz, 1H, H-4), 1.10 (s, 9H, C(CH3)3). MS (DCI, NH3) m/e
418 [M+NH4]+. Anal. calcd for C22H28O5Si: C, 66.97; H, 7.04. Found: C, 67.16; H, 7.07.
Compound 14: [α]D22=+16.2 (c 0.81, CHCl3). IR (CDCl3): 3674, 3563, 3074, 2956, 1780, 1590 cm−1
.
1H NMR (270 MHz, CDCl3) δ 7.75 (m, 5H, aryl), 7.45 (m, 15H, aryl), 4.80 (m, 1H, H-5), 3.87 (dd, J=10,
4 Hz, 1H, H-6), 3.83 (d, J=10 Hz, 1H, H-30), 3.77 (dd, J=10, 3.4 Hz, 1H, H-6), 3.74 (d, J=10 Hz, 1H,
H-30), 3.07 (s, 1H, OH), 2.37 (dd, J=14, 8 Hz, 1H, H-4), 2.30 (dd, J=14, 7.5 Hz, 1H, H-4), 1.15 (s, 9H,
C(CH3)3), 1.10 (s, 9H, C(CH3)3). MS (DCI, NH3) m/e 656 [M+NH4]+.
3.6. (3S,5S)-5-(tert-Butyldiphenylsilyloxy)methyl-3-hydroxy-2-oxo-3-(para-toluenesulfonyl-oxy)
methyltetrahydrofuran 15
To a solution of 13 (500 mg, 1.25 mmol) in methylene chloride (30 mL) were added p-toluenesulfonyl
chloride (248 mg, 1.3 mmol) and triethylamine (180 µL, 1.3 mmol). The solution was stirred at room
temperature for 16 h. At the end of this time, the mixture was diluted with ethyl acetate, washed with
brine, dried over MgSO4, and concentrated in vacuo. Flash chromatography, with cyclohexane:ethyl
acetate (4:1) as eluent, gave 300 mg (43%) of tosylate 15 as an oil: [α]D22=+17.5 (c 0.79, CHCl3). IR
(CDCl3): 3457, 3073, 2932, 2860, 1778, 1600 cm−1. 1H NMR (270 MHz, CDCl3) δ 7.80 (d, J=7.5 Hz,
2H, aryl), 7.60 (m, 4H, aryl), 7.45 (m, 6H, aryl), 7.35 (d, J=7.5 Hz, 2H, aryl), 4.75 (m, 1H, H-5), 4.23
(d, J=10 Hz, 1H, H-30), 4.14 (d, J=10 Hz, 1H, H-30), 3.94 (dd, J=12, 3.5 Hz, 1H, H-6), 3.74 (dd, J=12,
4 Hz, 1H, H-6), 2.92 (s, 1H, OH), 2.50 (m, 4H, H-4 and CH3), 2.32 (dd, J=14, 7 Hz, 1H, H-4), 1.10 (s,
9H, C(CH3)3). MS (DCI, NH3) m/e 572 [M+NH4]+.
3.7. (3S,6S)-6-(tert-Butyldiphenylsilyloxy)methyl-1,5-dioxaspiro[2.4]heptan-4-one 17
To a solution of diol 13 (1.9 g, 4.75 mmol) in benzene (50 mL) were added successively 4 Å molecular
sieves (1.9 g), PPh3 (1.37 g, 5.23 mmol) and DEAD (860 µL, 5.46 mmol). After 3 h at reflux, the reaction
mixture was filtered, and the filtrate was diluted with ether. The organic solution was washed with 5%
aqueous HCl, saturated aqueous NaHCO3 and brine, and dried over MgSO4. Following concentration in
vacuo, the residue was purified by flash chromatography, with cyclohexane:ethyl acetate (5:1) as eluent,
to provide 1.55 g (85%) of epoxide 17 as a solid: mp 72–73°C. [α]D22=+44.5 (c 0.81, CHCl3). IR
(CDCl3): 3074, 2962, 2933, 2861, 1790, 1590 cm−1. 1H NMR (270 MHz, CDCl3) δ 7.70 (dd, J=7, 1.5
Hz, 4H, aryl), 7.45 (m, 6H, aryl), 4.85 (m, 1H, H-6), 4.04 (dd, J=11.5, 3 Hz, 1H, H-8), 3.75 (dd, J=11.5,
2.5 Hz, 1H, H-8), 3.28 (d, J=6 Hz, 1H, H-2), 3.09 (d, J=6 Hz, 1H, H-2), 2.65 (dd, J=14, 9 Hz, 1H,
H-7), 2.55 (dd, J=14, 4 Hz, 1H, H-7), 1.10 (s, 9H, C(CH3)3). HRMS (DCI, CH4) calcd for C22H27O4Si
(M+H)+: 383.1679. Found: 383.1677.
3.8. (5S,8R)-8-Hydroxymethyl-2,2-dimethyl-1,3,7-trioxaspiro[4.4]nonan-6-one 20
A solution of 19 (970 mg, 3.11 mmol) in bis(tributyltin) oxide (1.6 mL) was heated to 80°C for 2
h and then quenched by addition of methanol. Repeated flash chromatography, with cyclohexane:ethyl

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acetate (4:1 then 3:1) as eluent, furnished 296 mg (47%) of γ-lactone 20 as an oil: [α]D22=−30.6 (c 0.81,
CHCl3). IR (CDCl3): 3598, 2993, 1785, 1670 cm−1. 1H NMR (300 MHz, CDCl3) δ 4.49 (m, 1H, H-8),
4.22 (d, J=8.6 Hz, 1H, H-4), 4.08 (d, J=8.6 Hz, 1H, H-4), 3.91 (dd, J=12.6, 2.9 Hz, 1H, H-10), 3.71 (d,
J=12.6, 5.3 Hz, 1H, H-10), 3.70 (d, J=7.6 Hz, 1H, H-9), 2.02 (m, 1H, OH), 1.54 (s, 3H, Me), 1.47 (s,
3H, Me). MS (DCI, NH3) m/e 203 [M+H]+, 220 [M+NH4]+. Anal. calcd for C9H14O5: C, 53.46; H, 6.98.
Found: C, 53.41; H, 7.01.
3.9. (5S,8R)-8-Benzoyloxymethyl-2,2-dimethyl-1,3,7-trioxaspiro[4.4]nonan-6-one 21
A solution of 19 (4 g, 13 mmol) in bis(tributyltin) oxide (7 mL) was heated to 80°C. After 6 h, benzoyl
chloride (1.5 mL, 13 mmol) and a mixture of methylene chloride:pyridine (9:1) were added at room
temperature. The resultant mixture was stirred for 24 h at room temperature, quenched by the addition of
methanol (2 mL) and concentrated in vacuo. Flash chromatography, with cyclohexane:ethyl acetate (5:1)
as eluent, followed by recrystallization with cyclohexane, gave 1.81 g (46%) of 21 as a solid: mp 94°C.
[α]D22=−50 (c 0.82, MeOH). IR (KBr): 3060, 1770, 1719, 1601 cm−1. 1H NMR (270 MHz, CDCl3) δ
8.10 (d, J=7 Hz, 2H, aryl), 7.60 (m, 1H, aryl), 7.50 (m, 2H, aryl), 4.78 (m, 1H, H-8), 4.62 (dd, J=12, 3.4
Hz, 1H, H-10), 4.52 (dd, J=12, 6 Hz, 1H, H-10), 4.29 (d, J=9 Hz, 1H, H-4), 4.11 (d, J=9 Hz, 1H, H-4),
2.55 (dd, J=14.7 Hz, 1H, H-9), 2.40 (dd, J=14, 8 Hz, 1H, H-9), 1.60 (s, 3H, CH3), 1.50 (s, 3H, CH3).
MS (DCI, NH3) m/e 307 [M+H]+, 324 [M+NH4]+. Anal. calcd for C16H18O6: C, 62.74; H, 5.92. Found:
C, 62.88; H, 5.89.
3.10. (3S,5R)-5-Benzoyloxymethyl-3-hydroxy-3-hydroxymethyl-2-oxotetrahydrofuran 22
Trifluoroacetic acid (9 mL) and water (1 mL) were added to a solution of 21 (1 g, 3.27 mmol) in
methylene chloride (10 mL) at 0°C. The reaction mixture was stirred for 1.5 h at 0°C, then diluted with
toluene, and concentrated in vacuo. Flash chromatography, with cyclohexane:ethyl acetate (2:1) as eluent,
afforded 22 (quant.): mp 101–102°C. [α]D22=−45.5 (c 0.79, MeOH). IR (KBr): 3405, 3069, 1746, 1719,
1601 cm−1. 1H NMR (270 MHz, CD3COCD3) δ 8.00 (dd, J=7.5 Hz, 2H, aryl), 7.55 (m, 1H, aryl), 7.40
(m, 2H, aryl), 4.80 (m, 1H, H-5), 4.52 (dd, J=12, 3 Hz, 1H, H-6), 4.38 (dd, J=12, 6 Hz, 1H, H-6), 3.74 (d,
J=10.5 Hz, 1H, H-30), 3.62 (d, J=10.5 Hz, 1H, H-30), 2.77 (s, 1H, OH), 2.72 (s, 1H, OH), 2.70 (dd, J=13,
7 Hz, 1H, H-4), 2.14 (dd, J=13, 7 Hz, 1H, H-4). MS (DCI, NH3) m/e 267 [M+H]+, 284 [M+NH4]+.
3.11. (3S,6R)-6-Benzoyloxymethyl-1,5-dioxaspiro[2.4]heptan-4-one 23
To a solution of diol 22 (332 mg, 1.25 mmol) in benzene (12 mL) were added successively 4 Å
molecular sieves (332 mg), PPh3 (358 mg, 1.36 mmol) and DEAD (232 µL, 1.47 mmol). After 25 min
at reflux, the reaction mixture was diluted with ethyl acetate, washed with 5% aqueous HCl, saturated
aqueous NaHCO3 and brine, and dried over MgSO4. Following concentration in vacuo, the residue was
purified by flash chromatography, with cyclohexane:ethyl acetate (2:1) as eluent, to provide 285 mg
(92%) of 23 as a solid: mp 81°C. [α]D22=−28.5 (c 0.81, CHCl3). IR (CDCl3): 2952, 1795, 1724, 1603
cm−1. 1H NMR (300 MHz, CDCl3) δ 8.09 (m, 2H, aryl), 7.59 (m, 1H, aryl), 7.46 (m, 2H, aryl), 5.03 (m,
1H, H-6), 4.67 (dd, J=12.4, 2.8 Hz, 1H, H-8), 4.52 (dd, J=12.4, 4.5 Hz, 1H, H-8), 3.31 (d, J=6 Hz, 1H,
H-2), 3.14 (d, J=6 Hz, 1H, H-2), 2.74 (dd, J=14.3, 7.8 Hz, 1H, H-7), 2.44 (dd, J=14.3, 6.6 Hz, 1H, H-7).
HRMS (DCI, CH4) calcd for C13H13O5 (M+H)+: 249.0763. Found: 249.0769.

E. Bertounesque et al. / Tetrahedron: Asymmetry 9 (1998) 2999–3009
3007
3.12. (3R,5R)-5-Benzoyloxymethyl-3-ethyl-3-hydroxy-2-oxotetrahydrofuran 24
The cuprate Me2Cu(CN)Li2 was prepared from CuCN (23.4 mg, 0.261 mmol) in THF (1 mL), to which
was added 1.0 M MeLi (522 mL, 0.522 mmol) at −78°C and the resultant mixture was stirred at this
temperature for 20 min. To this mixture was added the epoxy γ-lactone 23 (50 mg, 0.201 mmol). Stirring
for 30 min was followed by quenching and extractive workup (ethyl acetate). Flash chromatography
with methylene chloride:methanol (95:5) furnished 27.7 mg (52%) of 24 as an oil: [α]D22=−31 (c 0.29,
CHCl3). IR (CDCl3): 3566, 2977, 1781, 1723, 1603 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=7.8
Hz, 2H, aryl), 7.58 (t, J=7.3 Hz, 1H, aryl), 7.45 (t, J=7.7 Hz, 2H, aryl), 4.71 (m, 1H, H-5), 4.61 (dd,
J=12.5, 2.8 Hz, 1H, H-6), 4.42 (dd, J=12.5, 6.5 Hz, 1H, H-6), 2.77 (s, 1H, OH), 2.50 (dd, J=13.3, 6.6
Hz, 1H, H-4), 2.21 (dd, J=13.3, 8.8 Hz, 1H, H-4), 1.82 (q, J=7.4 Hz, 2H, CH2–CH3), 1.05 (t, J=7.4 Hz,
3H, CH2–CH3). MS (DCI, NH3) m/e 265 [M+H]+, 282 [M+NH4]+.
3.13. (3R,5R)-5-Benzoyloxymethyl-3-hydroxy-3-pentyl-2-oxotetrahydrofuran 7
The cuprate Bu2Cu(CN)Li2 was prepared from CuCN (23.4 mg, 0.261 mmol) in THF (1 mL), to which
was added 2.5 M BuLi (208 µL, 0.522 mmol) at −78°C. The heterogeneous mixture was allowed to warm
up to 0°C and was then cooled once again to −78°C. The epoxy γ-lactone 23 (50 mg, 0.201 mmol) in
THF (0.6 mL) was added at −78°C, stirred at that temperature for 10 min and gradually warmed to
−20°C. Quenching, extractive workup (ethyl acetate) and flash chromatography with cyclohexane:ethyl
acetate (4:1) as eluent, gave 31.1 mg (50%) of 7 as a solid: mp 58–60°C. [α]D22=−25 (c 0.48, CHCl3).
IR (CDCl3): 3567, 2935, 2862, 1781, 1723, 1603 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=7.5
Hz, 2H, aryl), 7.59 (t, J=7.4 Hz, 1H, aryl), 7.45 (t, J=7.6 Hz, 2H, aryl), 4.72 (m, 1H, H-5), 4.62 (dd,
J=12.4, 3 Hz, 1H, H-6), 4.42 (dd, J=12.4, 6.6 Hz, 1H, H-6), 2.51 (dd, J=13.2, 6.6 Hz, 1H, H-4), 2.23 (dd,
J=13.2, 8.8 Hz, 1H, H-4), 1.83–1.26 (m, 8H, alkyl), 0.90 (t, J=6.5 Hz, 3H, alkyl). MS (DCI, NH3) m/e
307 [M+H]+, 324 [M+NH4]+. Anal. calcd for C17H22O5: C, 66.65; H, 7.24. Found: C, 66.92; H, 7.25.
3.14. 3-Deoxy-2-C-(methoxycarbonyl)-1,2:4,5-bis-O-(1-methylethylidene)-D-erythro-pentitol 25
To a solution of lactone 20 (100 mg, 0.49 mmol) in methanol (2 mL) were added α,α-
dimethoxypropane (5 mL) and 178 mg of Amberlyst 15 ion-exchange resin. The mixture was stirred for
23 h at room temperature, then filtered on Celite, and concentrated in vacuo. Flash chromatography, with
cyclohexane:ethyl acetate (7:1) as eluent provided 71.4 mg (52%) of 25 as a liquid: [α]D22=−2.5 (c 1,
CHCl3). IR (CDCl3): 2990, 2955, 1750, 1455 cm−1. 1H NMR (250 MHz, CDCl3) δ 4.34 (d, J=9.1 Hz,
1H, H-1), 4.29 (m, 1H, H-4), 4.10 (d, J=9.1 Hz, 1H, H-1), 4.01 (dd, J=8, 5.6 Hz, 1H, H-5), 3.75 (s, 3H,
CO2Me), 3.50 (t, J=8 Hz, 1H, H-5), 2.15 (dd, J=14.5, 6.5 Hz, 1H, H-3), 2.04 (dd, J=14.5, 5.4 Hz, 1H,
H-3), 1.43 (s, 6H, CH3), 1.32 (s, 3H, CH3). HRMS (DCI, CH4) calcd for C13H23O6 (M+H)+: 275.1495.
Found: 275.1475.
Acknowledgements
The authors thank Ms. Geneviève Flad for her excellent assistance in NMR spectroscopy. This work
was financially supported by the Centre National de la Recherche Scientifique and the Institut Curie,
Section Recherche, France. Thanks are also due to the referees for critical reading of the manuscript in
its first version.

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