A general strategy for the formal synthesis of (-)-trans-kumausyne and total synthesis of (5R)-Hagen's gland lactones from diacetone-D-glucose

Article abstract of DOI:10.1016/S0957-4166(99)00575-3

A general strategy for the formal synthesis of (-)-trans-kumausyne 1 via the bicyclic lactone (3aR,5R,6aR)-4 and total synthesis of (5R)-Hagen's gland lactones 2 and 3 via bicyclic lactone (3aR,5S,6aR)-5 starting from diacetone-D-glucose 6 is described. Syntheses of 4 and 5 were achieved by Wittig olefination-lactonization-Michael addition of the corresponding lactols 16 and 17, respectively. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00575-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 743–751
A general strategy for the formal synthesis of (−)-trans-
kumausyne and total synthesis of (5R)-Hagen’s gland lactones
from diacetone-D-glucose
Hari Babu Mereyala ∗ and Rajendrakumar Reddy Gadikota
Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 September 1999; accepted 30 November 1999
Abstract
A general strategy for the formal synthesis of (−)-trans-kumausyne 1 via the bicyclic lactone (3aR,5R,6aR)-4 and
total synthesis of (5R)-Hagen’s gland lactones 2 and 3 via bicyclic lactone (3aR,5S,6aR)-5 starting from diacetone-
D-glucose 6 is described. Syntheses of 4 and 5 were achieved by Wittig olefination–lactonization–Michael addition
of the corresponding lactols 16 and 17, respectively. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Natural products containing tetrahydrofurans have been of special interest due to their widespread
occurrence and their varied biological activities.1,2 Notable among them are (−)-trans-kumausyne 1 and
Hagen’s gland lactones 2 and 3. Compound 1 was isolated from the red alga Laurencia nipponica yamada
by Kurosawa and co-workers.3 Due to its unusual all cis-3-oxygenated-2,5-dialkyltetrahydrofuran core
and rich functionality it has been the subject of considerable synthetic efforts. Overman’s group ac-
complished the landmark total synthesis of (±)-1 from 2-cyclopentylidenecyclopentanone using a novel
Prins cyclization–pinacol rearrangement.4 Sugimura et al. have reported a total synthesis of 1 by stereo-
selective formation of substituted tetrahydrofurans in the BF3-promoted reaction of 2,3-O-isopropylidene
derivatives of aldehydes with allylsilanes.5 Martin et al. have disclosed a synthesis of 1 from propargyl
alcohol that employed brominative cyclization as a key step to obtain the tetrahydrofuran.6 Lee et al. have
reported the synthesis of 1 by use of radical cyclization of β-alkoxy acrylate as a key step to form the
tetrahydrofuran template.7 Boukouvalas et al. have reported an elegant synthesis of 1 by Pd(II) mediated
intramolecular alkoxycarbonylation–lactonization of an ene diol to generate tetrahydrofurofurone.8 More
recently, Fernandez de la Pradilla et al. have reported a formal synthesis of (+)-1 using a highly
∗
Corresponding author. E-mail: haribabu@iict.ap.nic.in
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00575-3
tetasy 3209

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H. B. Mereyala, R. R. Gadikota / Tetrahedron: Asymmetry 11 (2000) 743–751
stereoselective remote nucleophilic epoxidation of a sulfinyl diene moiety9 and Pd(II) mediated oxidative
cyclization of hydroxy(vinyl) furans to tetrahydrofurofurans, a methodology that was first developed
by us.10 Williams and co-workers have shown by chemical analysis that the glands of braconid wasps
Diachasmimorpha longicaudata contain two bicyclic lactones which were tentatively identified as
(3aα,5β,6aα)-5-butyl tetrahydrofuro-[3,2-b]fura-2-(3H)-one 2 and its corresponding 5-hexyl derivative
1
3 based on H NMR considerations.11 The absolute stereochemistry of these lactones was established
by Kitching et a1.12 based on the synthesis of a diastereomeric mixture by a Pd(II) mediated alkoxycar-
bonylation–lactonization protocol. We have recently reported a simple and general synthesis of Hagen’s
gland lactones 2 and 3 starting from D-glucose by a Wittig olefination–lactonization–Michael addition
protocol.13
2. Results and discussion
Earlier, several authors have reported the synthesis of (−)-trans-kumausyne 1 via the advanced inter-
mediate, bicyclic lactone 4.5,6,8 We have considered the preparation of bicyclic lactone (3aR,5R,6aR)-4
and also its diastereomer (3aR,5S,6aR)-5 for the synthesis of 1, 2 and 3, respectively, by a chiron approach
starting from diacetone-D-glucose 6, a general route which has potential for the synthesis of several other
C-15 lipid metabolites (Fig. 1).
Fig. 1.
Retrosynthetic analysis (Scheme 1), derived by consideration of stereochemical flexibility, suggest-
ed that bicyclic lactones 4 and 5 could be derived from diacetone-D-glucose 6. It required the
configuration at C-4 to be inverted, deoxygenation of the C-3 hydroxyl group and Wittig olefina-
tion–lactonization–Michael addition at C1–C2 to obtain the advanced key intermediate 4. Retrosynthetic

H. B. Mereyala, R. R. Gadikota / Tetrahedron: Asymmetry 11 (2000) 743–751
745
analysis of 2 and 3 indicated that they could be derived from 6 which has appropriate stereogenic centres
at C-2, C-4 and requires deoxygenation of the C-3 hydroxyl group.
Scheme 1.
Thus, 6 was transformed to 3-deoxy-galacto-814 and glucofuranose 915 derivatives by well established
procedures (Scheme 2). Regioselective hydrolysis of the terminal isopropylidene groups of 8 and 9 with
60% aq. HOAc at room temperature for 4–6 h gave the corresponding diols 10 and 11, respectively,
in good yield. Oxidative cleavage of diols 10 and 11 with sodium metaperiodate followed by reduction
with sodium borohydride gave the corresponding alcohols 12 and 13, respectively. Benzylation of 12
and 13 with NaH–BnBr–DMF at 0°C gave the corresponding benzyl ethers 14 and 15, respectively,
in 90–95% yield. Acid catalyzed reaction of 14 and 15 with 40% aq. HOAc and cat. H2SO4 at 45°C
gave the corresponding lactols 16 and 17, respectively. Compounds 16 and 17 were characterized from
1
the H NMR spectrum by the appearance of anomeric protons at δ 5.08–5.5 (1H, α/β, mixture).
In order to build the required tetrahydrofurofuran moiety, lactols 16 and 17 were severally reacted
with carboethoxymethylene triphenylphosphorane in methanol at 10°C to afford the corresponding
bicyclic lactones 18 (58%) and 19 (66%) and trans-olefins 20 (18%) and 21 (15%), respectively. Due
to spontaneous lactonization and Michael ring closure16c formation of cis-olefins and corresponding
1
butenolides was not observed.16 Lactone 18 was characterized from the H NMR spectrum by the
appearance of characteristic H-3,30 protons at δ 2.60–2.80 (m, 2H) and H-6a proton at δ 4.98–5.10
(m, 1H) and 19 by the appearance of H-3,30 protons at δ 2.69–2.91 (m, 2H) and H-6a proton at δ 5.12
(dd, 1H, J=6.0, 4.7 Hz). Compounds 18 and 19 were also characterized from the IR spectra from the
C_O absorption at 1768–1770 cm−1. trans-Olefins 20 and 21 were characterized by the appearance of
olefinic protons at δ 6.10 (d, 1H, J=16.2 Hz) and δ 6.95 (dd, 1H, J=16.2, 3.8 Hz) and ethoxycarbonyl
protons at δ 1.30 (t, 3H) and δ 4.15 (q, 2H).
Hydrogenolysis of 18 and 19 with Pd/C and H2 (1 atm) gave the corresponding hydroxy lactones
22 and 5, respectively, in good yield. Silylation of 22 and 5 with tert-butyldiphenylsilyl chloride gave
the corresponding lactones 45,6,8 {[α]D 25.4 (c 0.8, CHCl3)} and 7 {[α]D 25.0 (c 0.84, CHCl3)},17
1
respectively. Lactone 4 was characterized from the H NMR and 13C NMR spectra which were in
complete agreement with the reported data.8,17 Since elaboration of 4 to (−)-trans-kumausyne 1 has
been earlier reported,5,6,8 a formal synthesis of 1 has thus been achieved. Compound 7 was characterized
by the appearance of protons at δ 1.11 (s, 9H), δ 2.55–2.80 (m, 2H, H-3,30) and δ 5.10 (dd, 1H, J=4.9,
4.5 Hz, H-6a) in the 1H NMR spectrum.
To achieve the total synthesis of (5R)-Hagen’s gland lactones 2 and 3, alcohol 5 was subjected to
Swern oxidation to obtain the corresponding aldehyde which was immediately severally treated with
alkylidene triphenylphosphoranes (Ph3P+CH2CH2CH3Br−/Ph3P+CH2(CH2)3CH3Br−/NaNH2, THF) to
obtain the corresponding olefins (E/Z) 23 and 24 which were characterized from the 1H NMR spectrum
by the appearance of olefinic protons at δ 5.40–5.65 (m, 2H) (Scheme 3). Hydrogenation (Raney-Ni, H2,

746
H. B. Mereyala, R. R. Gadikota / Tetrahedron: Asymmetry 11 (2000) 743–751
Scheme 2. (a) 60% aq. HOAc, rt, 4–6 h; (b) NaIO4, CH2Cl2, satd NaHCO3 soln, rt, 1 h; (c) NaBH4, MeOH, 0°C–rt, 30 min;
(d) NaH, BnBr, DMF, 0°C, 30 min; (e) 40% aq. HOAc, H2SO4, 45°C, 6–8 h; (f) Ph3P_CHCOOEt, MeOH, 10°C, 8–12 h; (g)
Pd/C, MeOH, H2 (1 atm), rt, 3–5 h; (h) TBDPSCl, Py, 0°C, 2 h
EtOH) of olefins 23 and 24 gave the desired (5R)-Hagen’s gland lactones 2 and 3, respectively, in good
yield. Lactone 3 was characterized from the 1H NMR spectrum by the H-3,30 protons at δ 2.64 (dd, 1H,
J=19.1, 0.7 Hz), δ 2.75 (1H, dd, J=19.1, 6.4 Hz), H-3a proton at δ 4.80 (ddd, 1H, J=6.4, 4.5, 0.7 Hz) and
H-6a proton at δ 5.11 (dd, 1H, J=4.9, 4.5 Hz). 1H and 13C NMR data11,13 of 2 and 3 were consistent with
those reported in the literature.
Scheme 3. (a) Oxalyl chloride, DMSO, TEA, CH2Cl2, −78°C, 1 h; (b) Ph3P_CHCH2CH3/Ph3P_CH(CH2)3CH3, THF, −20°C,
1–2 h; (c) W-4 Raney-Ni, H2 (1 atm), EtOH, rt, 2–4 h
In conclusion, this general strategy has been demonstrated to be serviceable for stereoselective
construction of tetrahydrofuran and tetrahydrofurofuran core structure of several natural products by
a chiron approach. Further investigations into the application of this strategy to other brominated
tetrahydrofuran non-terpenoids isolated from the red alga of genus laurencia are under progress.
3. Experimental
All moisture sensitive reactions were performed under a nitrogen atmosphere using flame-dried
1
glassware. Solvents were dried over standard drying agents and freshly distilled prior to use. H NMR
spectra were measured with a Varian Gemini (200 MHz) spectrometer, with tetramethylsilane as an

H. B. Mereyala, R. R. Gadikota / Tetrahedron: Asymmetry 11 (2000) 743–751
747
internal standard for solutions in deuteriochloroform. J values are given in hertz. 13C NMR spectra
were taken with a Varian Gemini (50 MHz) spectrometer with CDCl3 as internal standard (δC 77.0)
for solutions in deuteriochloroform. Optical rotations were measured with a JASCO DIP-370 instrument,
and [α]D values are in units of 10−1 deg cm2 g−1. IR spectra were taken with a Perkin–Elmer 1310
spectrometer. Organic solutions were dried over anhydrous Na2SO4 and concentrated below 40°C in
vacuo.
3.1. 3-Deoxy-1,2-O-isopropylidene-L-arabinofuranose 12
To a solution of 10 (1.8 g, 8.8 mmol) at 0°C in dichloromethane (50 ml) and satd aqueous NaHCO3 (3
ml) was added in one portion sodium metaperiodate (3.6 g, 16 mmol) and the mixture stirred vigorously
at room temperature for 1 h. After completion of the reaction anhydrous Na2SO4 (10 g) was added to the
reaction mixture and filtered through a bed of Celite. The Celite bed was washed with dichloromethane
(2×50 ml), the filtrate was concentrated to a thick syrup and dissolved in methanol (50 ml), cooled to
0°C and sodium borohydride (0.33 g, 8.8 mmol) was added. The reaction mixture was stirred for 30 min
and then quenched with a few drops of acetic acid. The solvent was removed under reduced pressure to
obtain a residue which was extracted into ethyl acetate (2×75 ml). The combined organic extracts were
washed with brine (50 ml), water, dried (Na2SO4), filtered and concentrated to obtain a residue which
was filtered on a bed of silica gel (60–120 mesh; hexane:EtOAc, 1:1) to obtain the title compound 12
25
(1.29 g, 84%) as a colourless syrup. IR: νmax 3450 cm−1 (OH); [α]D −30.86 (c 1.0, CHCl3); 1H NMR
(200 MHz, CDCl3): δ 1.30, 1.53 (2s, 6H, 2×CH3), 1.9–2.3 (m, 2H, H-3), 3.58 (dd, 1H, J=4.1, Jgem=11.2
Hz, H-5), 3.75 (dd, J=4.2 Hz, 1H, H-50), 4.3 (m, 1H, H-4), 4.72 (dd, 1H, J=3.9, 4.2 Hz, H-2), 5.8 (d, 1H,
J=3.9 Hz, H-1). Anal. calcd for C8H14O4: C, 55.16; H, 8.10. Found: C, 55.08; H, 8.02.
3.2. 3-Deoxy-1,2-O-isopropylidene-α-D-ribofuranose 13
Prepared from the diol 11 (2.0 g, 9.8 mmol) as described for compound 12 to obtain the title compound
25
1
13 (1.43 g, 84%) as a white solid. Mp 82–84°C; [α]D −7.4 (c 0.7, CHCl3); H NMR (200 MHz,
CDCl3): δ 1.32, 1.42 (2s, 6H, 2×CH3), 1.8–2.1 (m, 2H, H-3,30), 3.52 (dd, 1H, Jgem=11.0, 3.8 Hz, H-5),
3.88 (dd, 1H, Jgem=11.0, 3.2 Hz, H-50), 4.22–4.4 (m, 1H, H-4), 4.72 (dd, 1H, J=4.4, 4.4, 4.6 Hz, H-2),
5.78 (d, 1H, H-1). Anal. calcd for C8H14O4: C, 55.16; H, 8.10. Found: C, 55.27; H, 8.19.
3.3. 5-O-Benzyl-3-deoxy-1,2-O-isopropylidene-L-arabinofuranose 14
To a solution of 12 (1.2 g, 6.9 mmol) in dry N,N-dimethylformamide (3 ml) sodium hydride (0.24
g, 10 mmol) was added at 0°C followed by benzyl bromide (1.75 g, 10.3 mmol). The reaction mixture
was stirred for 30 min at room temperature, poured into ice cold water and extracted into diethyl ether
(2×100 ml). The combined ether extracts were washed with water (100 ml), dried (Na2SO4), filtered and
concentrated to obtain a residue which was filtered on a bed of silica gel (60–120 mesh; hexane:EtOAc,
25
4:1) to obtain the title compound 14 (1.61 g, 88%) as a colourless syrup. [α]D −7.64 (c 0.95, CHCl3);
1H NMR (200 MHz, CDCl3): δ 1.98–2.2 (m, 2H, H-3,30), 3.48–3.70 (m, 2H, H-5,50), 4.22–4.4 (m, 1H,
H-4), 4.48–4.74 (m, 3H, H-2 and OCH2Ph), 5.78 (d, 1H, J=4.0 Hz, H-1), 7.2–7.40 (m, 5H, ArH). Anal.
calcd for C15H20O4: C, 68.16; H, 7.63. Found: C, 68.11; H, 7.57.

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H. B. Mereyala, R. R. Gadikota / Tetrahedron: Asymmetry 11 (2000) 743–751
3.4. 5-O-Benzyl-3-deoxy-1,2-O-isopropylidene-α-D-ribofuranose 15
Prepared from 13 (1.4 g, 8.0 mmol) as described for compound 14 to obtain the title compound 15
25
(1.92 g, 91%) as a syrup. [α]D −11.9 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3): δ 1.31, 1.50 (2s,
6H, 2×CH3), 1.65–1.84 (m, 1H, H-3), 2.3 (dd, 1H, Jgem=12.5, 4.6 Hz, H-30), 3.48–3.70 (m, 2H, H-5,50),
4.28–4.45 (m, 1H, H-4), 4.6 (s, 2H, OCH2Ph), 4.70 (dd, 1H, J=4.3, 4.6 Hz, H-2), 5.8 (d, 1H, H-1), 7.2–7.4
(m, 5H, ArH). Anal. calcd for C15H20O4: C, 68.16; H, 7.63. Found: C, 68.38; H, 7.69.
3.5. 5-O-Benzyl-3-deoxy-L-arabinofuranose 16
A solution of 14 (1.4 g, 5.3 mmol) in 40% aq. acetic acid (7 ml) and a drop of concd H2SO4 was stirred
at 45°C for 6 h. After completion of the reaction, it was cooled to 10°C and neutralized with sodium
hydrogen carbonate and extracted into ethyl acetate (2×100 ml). The organic phase was separated,
washed with water (Na2SO4), filtered and concentrated to a residue which was purified on a bed of
silica gel (60–120 mesh; hexane:EtOAc, 1:1) to obtain the title compound 16 (0.94 g, 80%) as a thick
syrup. IR: νmax 3450 cm−1 (OH); 1H NMR (200 MHz, CDCl3): δ 1.72–2.6 (m, 2H, H-3,30), 3.35–4.60
(m, 5H, H-2,4,5,50 and OCH2Ph), 4.7 (d, 1H, J=11.6 Hz, OCH2Ph), 5.08–5.15 (br.s, 0.5H, H-1), 5.3 (s,
0.5H, H-1), 7.2–7.43 (m, 5H, ArH). Anal. calcd for C12H16O4: C, 64.27; H, 7.19. Found: C, 64.33; H,
7.16.
3.6. 5-O-Benzyl-3-deoxy-α/β-D-ribofuranose 17
Prepared from 15 (1.8 g, 6.8 mmol) as described for compound 16 to obtain the title compound 17
1
(1.29 g, 85%) as a syrup. H NMR (200 MHz, CDCl3): δ 1.7–2.2 (m, 2H, H-3,30), 2.7–3.0 (br.s, 1H,
OH), 3.3–3.5 (m, 7H, H-1,2,4,5,50 and OCH2Ph), 7.08–7.41 (m, 5H, ArH). Anal. calcd for C12H16O4:
C, 64.27; H, 7.19. Found: C, 64.22; H, 7.13.
3.7. (3aR,5R,6aR)-5-Benzyloxymethylperhydrofuro[3,2-b]furan-2-one 18 and [E,4R,6R]-ethyl-7-ben-
zyloxy-4,6-dihydroxy-2-heptenoate 20
To a solution of lactol 16 (0.3 g, 1.3 mmol) in methanol (10 ml) was added carboethoxymethylene
triphenylphosphorane (0.91 g, 2.6 mmol) at 10°C and the reaction mixture was stirred for 8 h at 10°C.
After completion of the reaction, solvent was removed under reduced pressure to obtain a residue which
25
was chromatographed to elute first 20 (0.072 g, 18%) as a syrup. [α]D −17.1 (c 0.3, CHCl3); IR: νmax
1718 cm−1; 1H NMR (200 MHz, CDCl3): δ 1.3 (t, 3H, OCH2CH3), 1.4–1.8 (m, 2H, H-5,50), 3.2–3.80
(m, 3H, H-6,7,70) 4.02–4.1 (m, 1H, H-4), 4.15 (q, 2H, OCH2CH3), 4.55 (s, 2H, OCH2Ph), 6.1 (d, 1H,
J=16.5 Hz, H-2), 6.9 (dd, 1H, J=16.5, 6.2 Hz, H-3), 7.2–7.4 (m, 5H, ArH). Anal. calcd for C16H22O5:
25
C, 65.29; H, 7.53. Found: C, 65.34; H, 7.58. This was followed by 18 (0.19 g, 57%) as a syrup. [α]D
+38.8 (c 0.39, CHCl3); IR: νmax 1770 cm−1; H NMR (200 MHz, CDCl3): δ 2.12 (ddd, 1H, J=13.6,
1
7.8, 6.0 Hz, H-6), 2.4 (ddd, 1H, J=13.6, 6.0, 5.55 Hz, H-60), 2.6–2.8 (m, 2H, H-3,30), 3.38–3.6 (m, 2H,
CH2OBn), 4.22 (m, 1H, H-5), 4.48–4.7 (m, 3H, H-3a and OCH2Ph), 4.98–5.1 (m, 1H, H-6a), 7.2–7.4
(m, 5H, ArH). Anal. calcd for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.89; H, 6.58.

H. B. Mereyala, R. R. Gadikota / Tetrahedron: Asymmetry 11 (2000) 743–751
749
3.8. (3aR,5S,6aR)-5-Benzyloxymethylperhydrofuro[3,2-b]furan-2-one 19 and [E,4R,6S]-ethyl-7-ben-
zyloxy-4,6-dihydroxy-2-heptenoate 21
Prepared from 17 (0.9 g, 4 mmol) as described for compounds 18 and 20 to obtain the title compounds
25
19 (0.66 g, 66%) and 21 (0.18 g, 15%). Analytical data of 19: mp 74–75°C; [α]D +35.3 (c 1.35,
CHCl3); IR: νmax 1769 cm−1; 1H NMR (200 MHz, CDCl3): δ 2.02–2.2 (ddd, 1H, J=13.9, 9.0, 4.65 Hz,
H-6), 2.35 (ddd, 1H, Jgem=13.9, 6.0, 1.5 Hz, H-60), 2.68 (m, 2H, H-3,30), 3.45 (dd, 1H, Jgem=11.6, 4.65
Hz, CH2OBn), 3.60 (dd, 1H, J=4.1 Hz, CH2OBn), 4.25–4.45 (m, 1H, H-5), 4.55 (s, 2H, OCH2Ph), 4.81
(ddd, J=4.6, 0.7, 6.1 Hz, H-3a), 5.12 (dd, 1H, J=4.7 Hz, H-6a), 7.18–7.40 (m, 5H, ArH); 13C NMR (50
MHz, CDCl3): δ 176.2 (C-2), 127.5–137.0 (aromatic), 84.7 (C-6a), 78.4 (C-3a), 77.8 (OCH2Ph), 73.4
(C-5), 71.5 (CH2OBn), 36.6 (C-3), 32.2 (C-6). Anal. calcd for C14H16O4: C, 67.73; H, 6.50. Found: C,
67.71; H, 6.48. Spectral data of 21: [α]D +6.1 (c 0.4, CHCl3); IR: νmax 1718 cm−1; 1H NMR (200 MHz,
CDCl3): δ 1.28 (t, 3H, J=8.2 Hz, OCH2CH3), 1.5–2.2 (m, 2H, H-5,50), 3.38–3.78 (m, 3H, H-6,7,70), 4.25
(q, 2H, J=8.0 Hz, OCH2CH3), 4.5–4.7 (m, 3H, H-4 and OCH2Ph), 6.15 (d, J=16.2 Hz, H-2), 6.95 (dd,
1H, J=16.0, 3.8 Hz, H-3), 7.2–7.4 (m, 5H, ArH). Anal. calcd for C16H22O5: C, 65.29; H, 7.53. Found: C,
65.38; H, 7.62.
3.9. (3aR,5R,6aR)-Hydroxymethylperhydrofuro[3,2-b]furan-2-one 22
To a solution of 18 (0.18 g, 0.72 mmol) in methanol (10 ml) was added 10% Pd/C (10 mg) and the
mixture was stirred under hydrogen atmosphere (1 atm) for 3 h at room temperature. The catalyst was
filtered off and the solvent removed under reduced pressure to obtain the title compound 22 (0.11 g, 93%)
as a thick syrup; [α]D25 +34.2 (c 0.3, MeOH); IR: 1771 cm−1; 1H NMR (200 MHz, CDCl3): δ 1.9–2.45
(m, 2H, H-6,60), 2.65–2.9 (m, 2H, H-3,30), 3.5–4.3 (m, 3H, H-5, CH2OH), 4.5 (br.s, 1H, OH), 4.55–4.65
(m, 1H, H-3a), 4.95–5.1 (m, 1H, H-6a). Anal. calcd for C7H10O4: C, 53.16; H, 6.37. Found: C, 53.27; H,
6.32.
3.10. (3aR,5S,6aR)-Hydroxymethylperhydrofuro[3,2-b]furan-2-one 5
Prepared from 19 (0.6 g, 2.4 mmol) as described for compound 22 to obtain the title compound 5 (0.36
25
g, 95%) as a syrup. [α]D 41.7 (c 1.4, CHCl3); IR: νmax 1769 cm−1; 1H NMR (200 MHz, CDCl3): δ
1.75 (br.s, 1H, OH), 2.02–2.24 (ddd, H, J=14.1, 4.2, 1.8 Hz, H-6), 2.38 (dd, 1H, Jgem=14.1, 4.85 Hz, H-
60), 2.6–2.9 (m, 2H, H-3,30), 3.6 (dd, 1H, Jgem=14.0, 5.8 Hz, CH2OH), 3.9 (dd, 1H, J=5.4 Hz, CH2OH),
4.2–4.42 (m, 1H, H-5), 4.88 (ddd, 1H, J=6.1, 0.6, 4.7 Hz, H-3a), 5.16 (dd, 1H, J=6.1, 4.85 Hz, H-6a); 13
C
NMR (50 MHz, CDCl3): δ 33.8 (C-6), 38.7 (C-3), 63.3 (CH2OH), 78.3 (C-5), 79.0 (C-3a) 85.0 (C-6a),
75.0 (C-2). Anal. calcd for C7H10O7: C, 53.16; H, 6.37. Found: C, 53.12; H, 6.32.
3.11. (3aR,5R,6aR)-5-tert-Butyldiphenylsilyloxymethylperhydro[3,2-b]furan-2-one 4
To a solution of 22 (0.24 g, 0.5 mmol) in pyridine (1 ml) at 0°C was added tert-butyldiphenylsilyl
chloride (0.2 g, 0.76 mmol) and the mixture stirred for 2 h at room temperature. After completion of the
reaction, it was diluted with water (50 ml) and extracted into diethyl ether (2×75 ml). Combined ethereal
extracts were dried (Na2SO4), filtered and concentrated to obtain a residue which was filtered on a bed
of silica gel (60–120 mesh, hexane:EtOAc, 4:1) to obtain the title compound 4 (0.51 g, 85%) as a syrup.
[α]D25 +25.4 (c 0.8, CHCl3); IR: νmax 1771 cm−1; 1H NMR (200 MHz, CDCl3):8,16 δ 1.2 (s, 9H, CMe3),
2.1–2.42 (m, 2H, H-6,60), 2.65 (d, 2H, J=4.0 Hz, H-3,30), 3.58–3.8 (m, 2H, CH2OSiPh2t-Bu), 4.0–4.2

750
H. B. Mereyala, R. R. Gadikota / Tetrahedron: Asymmetry 11 (2000) 743–751
(m, 1H, H-5), 4.55 (dd, 1H, J=3.6, 4.1 Hz, H-3a), 4.9–5.05 (m, 1H, H-6a), 7.3–7.8 (m, 10H, ArH); 13
C
NMR (50 MHz, CDCl3): δ 19.0, 26.2 (CMe3), 34.0 (C-6), 36.6 (C-3), 65.8 (CH2OTBDPS), 78.8 (C-5),
80.7 (C-3a), 84.2 (C-6a), 127.0–136.0 (aromatic), 175.1 (C-2). Anal. calcd for C23H28O4Si: C, 69.66; H,
7.12. Found: C, 69.78; H, 7.21.
3.12. (3aR,5S,6aR)-5-tert-Butyldiphenylsilyloxymethylperhydro[3,2-b]furan-2-one 7
Prepared from 5 (0.3 g, 1.9 mmol) as described for compound 4 to obtain the title compound 7 (0.66
25
1
g 88%) as a syrup. [α]D +25.0 (c 0.8 CHCl3); IR: νmax 1771 cm−1; H NMR (200 MHz, CDCl3):
δ 1.1 (s, 9H, CMe2), 2.1–2.45 (m, 2H, H-6,60), 2.55–2.8 (m, 2H, H-3,30), 3,7 (dd, 1H, J=9.2, 4.0 Hz,
CH2OSiPh2t-Bu), 3.9 (dd, 1H, CH2OSiPh2t-Bu), 4.2–4.39 (m, 1H, H-5), 4.72–4.84 (m, 1H, H-3a), 5.1
(dd, 1H, J=4.5, 4.9 Hz, H-6a), 7.3–7.75 (m, 10H, ArH). Anal. calcd for C23H28O4Si: C, 69.66; H, 7.12.
Found: C, 69.71; H, 7.12.
3.13. 5-[(E/Z)-1-Butenyl]-(3aR,5S,6aR)-perhydrofuro[3,2-b]furan-2-one 23
Dry dichloromethane (5 ml) containing dimethylsulfoxide (0.25 g, 2.4 mmol) was added to solution
of oxalyl chloride (0.26 g, 2.0 mmol) in dry dichloromethane (5 ml) at −78°C and the resulting solution
was stirred for 20 min. A solution of lactone 5 (0.25 g, 1.6 mmol) in dry dichloromethane was added to
the above reaction mixture and the whole was stirred for 45 min followed by the addition of triethylamine
(0.48 g, 4.7 mmol). The reaction mixture was brought gradually to room temperature and diluted with
dichloromethane (40 ml). The organic layer was washed with brine (2×25 ml), dried (Na2SO4) and
evaporated to obtain the aldehyde as a thick syrup, which was immediately treated with a solution of
propylidenetriphenylphosphorane [generated in situ from nC3H7P+Ph3Br− (1.13 g, 2.94 mmol), NaNH2
(0.1 g, 2.6 mmol), THF (2.5 ml)] under a nitrogen atmosphere for 1.5 h at −20°C. The reaction mixture
was then quenched with satd aq. ammonium chloride (25 ml) and extracted into diethyl ether (2×30 ml).
The combined ethereal layers were washed with water, dried (Na2SO4) and concentrated to a residue
which was chromatographed [SiO2, 60–120 mesh, hexane:EtOAc, 4:1] to obtain the title compound 23
25
1
(0.13 g, 45%) as a colourless oil. [α]D −21.2 (c 0.9, CHCl3); IR: νmax 1769 cm−1; H NMR (200
MHz, CDCl3): δ 1.1 (t, 3H, J=8.0 Hz, CH3CH2), 1.6–2.5 (m, 4H, H-6,60 and CH3CH2), 2.6–2.9 (m,
2H, H-3,30), 4.40–4.52 (m, 1H, H-3a), 4.8–4.92 (m, 1H, H-5), 5.01–5.15 (m, 1H, 6a), 5.28–5.70 (m, 2H,
n-C4H7 olefinic). Anal. calcd for C10H14O3: C, 65.92; H, 7.74. Found: C, 65.95; H, 7.81.
3.14. 5[(E/Z)-1-Hexenyl]-(3aR,5S,6aR)-perhydrofuro[3,2-b]furan-2-one 24
Prepared from 5 (0.2 g, 1.2 mmol) as described for compound 23 to obtain the title compound 24
25
(0.13 g, 49%) as a thick syrup. [α]D −18.9 (c 0.6, CHCl3); 1H NMR (200 MHz, CDCl3): δ 1.1 (t, 3H,
J=8.0 Hz, CH3CH2), 1.3–2.5 (m, 8H, H-6,60 and CH3(CH2)3), 2.6–2.9 (m, 2H, H-3,30), 4.40–4.52 (m,
1H, H-3a), 4.8–4.92 (m, 1H, H-5), 5.01–5.15 (m, 1H, H-6a), 5.28–5.70 (m, 2H, n-C4H7 olefinic). Anal.
calcd for C12H18O3: C, 68.55; H, 8.63. Found: C, 68.60; H, 8.69.
3.15. (3aR,5R,6aR)-5-Butylperhydrofuro[3,2-b]furan-2-one 2
A solution of ene 23 (0.12 g) in ethanol (10 ml) was subjected to hydrogenation with W-4 Raney-Ni
catalyst (approximately 0.1 g) for 2 h. The catalyst was filtered off and the filtrate was concentrated to
obtain the title compound 2 (0.11 g, 92%) as a syrup. [α]D25 +51.1 (c 1.0, CHCl3); IR: νmax 1771 cm−1
;

H. B. Mereyala, R. R. Gadikota / Tetrahedron: Asymmetry 11 (2000) 743–751
751
1H NMR (200 MHz, CDCl3): δ 0.8–1.8 (m, 10H, H-6 and n-C4H9), 2.38 (dd, 1H, J=14.8, 4.2 Hz, H-6),
2.64 (dd, 1H, J=19.1, 0.7 Hz, H-3), 2.75 (dd, 1H, J=19.1, 6.4 Hz, H-3), 4.07 (4d, 1H, J=10.0, 7.2, 5.2, 4.2
Hz, H-5), 4.80 (ddd, 1H, J=6.4, 4.5, 0.7 Hz, H-3), 5.11 (dd, 1H, J=4.9, 4.5 Hz, H-6a); 13C NMR 50 MHz,
CDCl3): δ 13.8, 12.5, 28.0, 34.2, 36.5, 38.6, 77.2, 78.1, 84.8, 175.9 (C_O). Anal. calcd for C10H16O3:
C, 65.19; H, 8.75. Found: C, 65.27; H, 8.81.
3.16. (3aR,5R,6aR)-5-Hexylperhydrofuro[3,2-b]furan-2-one 3
25
Prepared from 24 as described for compound 2 in 94% yield. [α]D +49.7 (c 1.0, CHCl3); IR: νmax
1771 cm−1; 1H NMR (200 MHz, CDCl3): δ 0.8–1.8 (m, 14H, H-6 and n-C6H13), 2.38 (dd, 1H, J=14.8,
4.2 Hz, H-6), 2.64 (dd, 1H, J=19.1, 0.7 Hz, H-3), 2.75 (dd, 1H, J=19.1, 6.4 Hz, H-3), 4.07 (4d, 1H,
J=10.0, 7.2, 5.2, 4.2 Hz, H-5), 4.80 (ddd, 1H, J=6.4, 4.5, 0.7 Hz, H-3), 5.11 (dd, 1H, J=4.9, 4.5 Hz,
H-6a). Anal. calcd for C12H20O3: C, 67.89; H, 9.50. Found: C, 67.97; H, 9.58.
Acknowledgements
RRG thanks the University Grants Commission, New Delhi, for financial assistance in the form of a
Senior Research Fellowship.
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