Enantioselective synthesis of antibiotic (+)-rancinamycin III derivative and two protected carbasugars of the α-D-talo-series from furan

Article abstract of DOI:10.1016/S0957-4166(99)00358-4

The synthesis of (+)-1, a carbasugar related to rancinamycin III, has been achieved from diene (+)-3 in two steps using as the key step the transformation of alkyne (-)-2, obtained by resolution of alcohol 6, into diene (+)-3 by treatment with Na/MeOH. Moreover, reduction of the carbonyl group in (+)-1 affords diol (+)-19, in which different protection strategies of the hydroxy groups allows one to obtain, selectively, protected derivatives of α-D-carbatalopyranose (+)-4a and its 6-desoxy derivative (+)- 4b to be obtained selectively.

Full text of DOI:10.1016/S0957-4166(99)00358-4

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3431–3442
Enantioselective synthesis of antibiotic (+)-rancinamycin III
derivative and two protected carbasugars of the α-D-talo-series
from furan
Odón Arjona,∗ Fátima Iradier, Rocío Medel and Joaquín Plumet ∗
Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense, 28040 Madrid, Spain
Received 26 July 1999; accepted 13 August 1999
Abstract
The synthesis of (+)-1, a carbasugar related to rancinamycin III, has been achieved from diene (+)-3 in two
steps using as the key step the transformation of alkyne (−)-2, obtained by resolution of alcohol 6, into diene (+)-3
by treatment with Na/MeOH. Moreover, reduction of the carbonyl group in (+)-1 affords diol (+)-19, in which
different protection strategies of the hydroxy groups allows one to obtain, selectively, protected derivatives of α-
D-carbatalopyranose (+)-4a and its 6-desoxy derivative (+)-4b to be obtained selectively. © 1999 Elsevier Science
Ltd. All rights reserved.
1. Introduction
The term ‘carbasugar’ is commonly used for designing a class of compounds wherein the ring oxygen
atom of a cyclic monosaccharide is replaced by a methylene group.1 In some cases, a carbasugar might
be accepted by enzymes or biological systems in the place of a true sugar. Thus, some of them show
interesting biological activities in the area of enzyme inhibitors. In addition, several of them have been
used as sweeteners, antibiotics, antiviral and anticancer agents.2 Consequently, much attention has been
bestowed on devising methodologies for gaining rapid entry to carbasugars in a regio- and stereoselective
manner.3
2. Results and discussion
Within this research field, we have recently reported the synthesis, in racemic form, of the carbasugar
1 related to rancimamycin III.4 Rancinamycins5 are a group of secondary metabolites produced by
∗
Corresponding authors. E-mail: plumety@eucmax.sim.ucm.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00358-4

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Streptomyces lincolnensis in a sulfur-depleted culture medium. They have important antibiotic activity in
vitro against Proteus vulgaris, Proteus rettgeri and Staphylococcus aureus (Scheme 1).
Scheme 1.
The key step of this synthesis is the unprecedented transformation of alkynylcyclohexenylsulfones
such as 2 into dienylsulfone 3 by reaction with Na/MeOH (Scheme 2). This transformation involves in
one step a Michael addition, vinylsulfone isomerization and triple bond reduction.4
Scheme 2.
On the basis of this novel transformation, we envisioned diene 3 as a potential precursor to different
families of carbasugars. In this paper we wish to account for the synthesis, in enantiomerically pure
form, of carbasugar (+)-1, the protected derivative of α-D-carbatalopyranose (+)-4a and the protected
derivative of the hitherto unknown α-D-6-desoxycarbatalopyranose (+)-4b6 (Scheme 3), which were in
turn obtained from the 7-oxanorbornene derivative 5,7 the Diels–Alder adduct of furan and trans-1,2-bis-
(phenylsulfonyl)ethylene.8
Scheme 3.
Our starting material was the enantiomerically pure vinylsulfone (−)-9, prepared by resolution of
alcohol 6 (Scheme 4).9 Treatment of 6 with (1S)-(−)-camphanic acid chloride gave a 1:1 mixture of
diastereomeric esters (+)-7 and (−)-7, which were separated by column chromatography on silica gel.
Removal of the benzyl groups on (−)-7 with BF3·OEt2 and protection of the resulting diol as the
acetonide afforded camphanic derivative (−)-8. Elimination of the chiral auxiliary was performed with
K2CO3 giving vinylsulfone (−)-9.
Ring opening of (−)-9 with lithium trimethylsilylacetylide afforded compound (−)-2. Transformation
of (−)-2 into diene (+)-3 was performed by treatment with MeONa in MeOH at 0°C. A possible
mechanism proposed for this reaction4 involves deprotection of the acetylenic moiety to give the
tridentade anion 10. Reprotonation at the terminal allenic position gives 11, which after conjugate
addition of methoxide anion affords compound (+)-3 (Scheme 5).
The stereochemical configuration of (+)-3 (Scheme 5) was established on the basis on the multiplicity
1
of the signal of H-4, which appears as a singlet in the H NMR spectrum. The absence of coupling

O. Arjona et al. / Tetrahedron: Asymmetry 10 (1999) 3431–3442
3433
Scheme 4.
between H-4 and H-5 suggests that the dihedral angle between both protons is near 90°. The s-trans
configuration of the diene was deduced from the absence of an NOE effect between the H-trans of the
vinyl group and the aromatic protons of the phenylsulfonyl substituent.
In order to achieve the synthesis of our target molecules, we accomplished first the oxidation of the
exocyclic double bond in 3 to the related aldehyde 14. In this way, bishydroxylation of 3 afforded a 12:1
mixture of compounds 12 and 13. Oxidation of 12 with NaIO4 gave aldehyde 14. This compound could
be prepared in a one-pot procedure by treatment of diene 3 with NaIO4 and RuCl310 (Scheme 6).
At this stage, desulfonylation of 14 was not possible because of extensive decomposition of starting
material under a variety of experimental conditions. Therefore, in order to obtain carbatalopyranose
derivatives, we decided to carry out a total reduction of aldehyde 14 by transformation into alcohol
15 followed by 1,4-hydride addition to the vinylsulfone moiety.11 This new strategy would involve the
desulfonylation process in a further step of the synthesis. Reduction of 14 was performed using different
conditions (NaBH4, CeCl3·7H2O; LiAlH4; NaBH4; LiEt3BH; DIBALH). In all cases the isolated final
product was alcohol 15 instead of the desired fully reduced product 16 (Scheme 7).
Completion of the synthesis of compounds 4 from alcohol 15 would require desulfonylation and
hydrogenation of the double bond. However, treatment of 15 with Na–Hg or H2, Pd/C did not produce
the expected products. Compounds 12–15 were not obtained in enantiomerically pure form.
Finally, the synthesis was completed as follows (Scheme 8). Desulfonylation of (+)-3 afforded diene
(+)-17. Oxidation of the exocyclic double bond in (+)-17 to obtain aldehyde (+)-1 was carried out
by reaction with NaIO4 and RuCl3. This transformation was also achieved by bishydroxylation of the
exocyclic double bond in (+)-17 and oxidation of the remittant diol (+)-18 with NaIO4.
Thus, we have obtained the general structure of rancinamycin III with a well defined stereochemistry
of the four stereogenic centers and in enantiomerically pure form.
To synthesize α-D-carbatalopyranose, we decided to reduce the α,β-unsaturated system in (+)-1.

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Scheme 5.
Scheme 6.

O. Arjona et al. / Tetrahedron: Asymmetry 10 (1999) 3431–3442
3435
Scheme 7.
Scheme 8.
However, using reagents for this transformation such as NaBH4 or NaCNBH3, complex mixtures of
products were obtained. With other reducing reagents only diol (+)-19 was observed. The best conditions
for this transformation were found on treating (+)-1 with LiAlH4 in THF at 0°C (Scheme 9). At this
stage, appropriate protection of diol (+)-19 allowed us to obtain selectively the carbasugars 4a or 4b.
Thus, when (+)-19 was protected as a diacetonide, the hydrogenation of the resulting product (+)-20a
afforded the α-D-carbatalopyranose derivative (+)-4a. In contrast, protection of diol with Ac2O afforded
(+)-20b, which, after catalytic hydrogenation (Pd/C 10% as catalyst), produced the 6-desoxy derivative
(+)-4b. This result has a precedent in the literature12 and can be explained admitting hydrogenolysis of
the acetoxy group, catalyzed by Pd, followed by hydrogenation of the alkene moiety.
In summary, the synthesis of a protected derivative of α-D-carbatalopyranose (+)-4a, α-D-6-
desoxycarbatalopyranose (+)-4b and one stereoisomer of rancinamycin III (+)-1 has been accomplished
from furan and trans-1,2-bis-(phenylsulfonyl)ethylene.

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Scheme 9.
3. Experimental
3.1. General methods
Reagents and solvents were handled by using standard syringe techniques. THF was distilled over
Na/benzophenone; CH2Cl2, PhMe, Et3N, pyridine and Ac2O were distilled over CaH2 before use. The
remaining solvents and chemicals were commercial and used as received. 1H NMR and 13C NMR were
recorded at 300 MHz and 75 MHz, respectively. Chemical shifts (δ) are reported in ppm from internal
(CH3)4Si. Flash chromatography was performed using 230–400 mesh silica gel. Analytical TLC was
carried out on silica gel plates. Melting points are uncorrected. Elemental analyses were performed at the
Universidad Complutense de Madrid.
3.2. (1S,2R,3R,4R,5S,6S)-2-exo-Camphanoyloxy-5,6-exo-(isopropylidene-dioxy)-3-endo-phenyl-
sulfonyl-7-oxabicyclo[2.2.1]heptane, (−)-8
To a solution of (−)-7 (1.37 g, 2.12 mmol) in EtSH (6.4 ml), BF3·OEt2 (0.78 ml, 6.36 mmol) was
added. The mixture was stirred for 15 min and then H2O was added. The crude was extracted with
AcOEt, the organic layer was dried over MgSO4, filtered and then the solvent was evaporated under
reduced pressure. The solid obtained was dissolved in acetone (21.0 ml) and 2,2-dimethoxypropane
(0.52 ml, 4.24 mmol) and p-TsOH (catalytic amounts) were added. After 30 min of stirring, solvent
was eliminated in vacuo. The crude product was purified by column chromatography (hexane:AcOEt
1
2:1) to produce (−)-8 (0.87 g, 81%) as a white solid. [α]D −41.0 (c 1.4, CHCl3). Mp: 224–225°C. H
NMR (CDCl3, 300 MHz): δ 0.67 (s, 3H), 0.91 (s, 3H), 1.05 (s, 3H), 1.36 (s, 3H), 1.47 (s, 3H), 1.62–2.07
(m, 4H), 3.69 (dd, 1H, J=3.4, 5.4 Hz), 4.42 (s, 1H), 4.59 (d, 1H, J=5.4 Hz), 4.80 (dd, 1H, J=1.8, 5.4 Hz),

O. Arjona et al. / Tetrahedron: Asymmetry 10 (1999) 3431–3442
3437
5.24 (d, 1H, J=5.9 Hz), 5.31 (d, 1H, J=3.4 Hz), 7.60 (t, 2H, J=7.3 Hz), 7.70 (t, 1H, J=7.3 Hz), 7.92 (d,
2H, J=6.8 Hz). 13C NMR (CDCl3, 75 MHz): δ 9.7, 16.4, 16.6, 25.0, 25.6, 28.7, 30.3, 54.2, 54.6, 69.1,
74.0, 78.3, 79.3, 86.0, 90.1, 112.7, 128.0, 129.8, 134.6, 136.6, 139.1, 166.5, 177.4. IR (KBr): ν 1790,
1440, 1105 cm−1. Anal. calcd for C25H30O9S: C, 59.29; H, 5.93. Found: C, 59.16; H, 5.88.
3.3. 5,6-exo-(Isopropylidenedioxy)-2-phenylsulfonyl-7-oxabicyclo[2.2.1]hept-2-ene, (−)-9
To a solution of (−)-8 (160 mg, 0.32 mmol) in a mixture of THF:H2O 20:1 (3.20 ml of THF, 0.10
ml of H2O), K2CO3 (190 mg, 1.58 mmol) was added. The mixture was stirred at room temperature for
2 days and then quenched with H2O. The crude was extracted with AcOEt, organic layers were dried
over MgSO4, filtered and solvent was evaporated in vacuo. The crude product was purified by column
chromatography (hexane:AcOEt 5:1) to afford sulfone (−)-9 (69 mg, 71%) as a white solid. [α]D −39.1
(c 0.8, CHCl3). Mp: 112–114°C. 1H NMR (CDCl3, 300 MHz): δ 1.30 (s, 3H), 1.45 (s, 3H), 4.44 (d, 1H,
J=5.1 Hz), 4.55 (d, 1H, J=5.1 Hz), 4.77 (d, 1H, J=0.6 Hz), 4.94 (dd, 1H, J=0.6, 2.0 Hz), 7.05 (d, 1H,
J=2.0 Hz), 7.58 (t, 2H, J=7.0 Hz), 7.66 (d, 1H, J=7.5 Hz), 7.90 (d, 2H, J=7.5 Hz). 13C NMR (CDCl3, 75
MHz): δ 25.6, 31.5, 79.2, 79.5, 81.2, 83.1, 116.5, 127.9, 129.6, 134.3, 138.4, 143.3, 150.4. IR (KBr): ν
3050, 1520, 1420 cm−1. Anal. calcd for C15H16O5S: C, 58.44; H, 5.20. Found: C, 58.40; H, 5.13.
3.4. (1S,2R,5R,6S)-5,6-(Isopropylidenedioxy)-2-(trimethylsilylethynyl)-3-phenyl-sulfonylcyclohex-
3-enol, (−)-2
To a solution of trimethylsilylacetylene (0.27 ml, 1.94 mmol) in THF (5 ml), n-BuLi (1.46 ml, 2.33
mmol) was added dropwise at 0°C. After 30 min of stirring, lithium trimethylsilylacetylide was added
via cannula over a solution of (−)-9 (200 mg, 0.65 mmol) in PhMe (13 ml) cooled at 0°C. The mixture
was stirred for 5 min, quenched with saturated aqueous solution of NH4Cl and extracted with AcOEt.
The organic layer was dried over MgSO4 and evaporated under reduced pressure. Compound (−)-2 (163
mg, 63%) was obtained as a colorless oil after purification by column chromatography (hexane:AcOEt
1
5:1). [α]D −6.4 (c 0.9, CHCl3). H NMR (CDCl3, 300 MHz): δ −0.08 (s, 9H), 1.22 (s, 3H), 1.32 (s,
3H), 2.85 (d, 1H, J=12.4 Hz), 3.82 (ddd, 1H, J=2.4, 6.4, 12.4 Hz), 4.00 (d, 1H, J=6.4 Hz), 4.47 (dd, 1H,
J=2.4, 5.7 Hz), 4.78 (t, 1H, J=2.5 Hz), 6.99 (d, 1H, J=3.7 Hz), 7.51 (t, 2H, J=7.7 Hz), 7.62 (t, 1H, J=7.4
Hz), 7.93 (d, 2H, J=7.7 Hz). 13C NMR (CDCl3, 75 MHz): δ 0.0, 0.2, 0.3, 26.3, 27.8, 31.0, 67.8, 72.6,
75.4, 98.9, 110.8, 111.6, 128.9, 129.3, 130.1, 134.0, 135.5, 139.6. IR (CHCl3): ν 3600, 3050, 1425 cm−1.
Anal. calcd for C20H26O5SSi: C, 59.26; H, 6.17. Found: C, 59.18; H, 6.09.
3.5. (1S,4R,5S,6S)-5,6-(Isopropylidenedioxy)-4-methoxy-3-phenylsulfonyl-2-vinyl-cyclohex-2-enol,
(+)-3
To a solution of MeONa (1 M, 3.3 ml) cooled at 0°C, sulfone (−)-2 (267 mg, 0.66 mmol) dissolved
in MeOH (3.3 ml) was added and stirred for 20 min. The reaction was quenched with saturated aqueous
solution of NaCl and extracted with AcOEt. The organic layer was dried over MgSO4 and solvent was
evaporated under reduced pressure. The resulting crude product was purified by column chromatography
(hexane:AcOEt 5:1) to afford 163 mg of (+)-3 (71%) as a white solid. [α]D +158.9 (c 0.9, CHCl3). Mp:
1
131–132°C. H NMR (CDCl3, 300 MHz): δ 0.84 (s, 3H), 1.26 (s, 3H), 2.23 (d, 1H, J=10.0 Hz), 3.44
(s, 3H), 4.59 (bs, 1H), 4.60 (bs, 1H), 4.72 (bs, 1H), 4.75 (d, 1H, J=10.0 Hz), 5.44 (dd, 1H, J=1.5, 18.0
Hz), 5.55 (dd, 1H, J=1.5, 12.0 Hz), 6.79 (dd, 1H, J=12.0, 18.0 Hz), 7.47 (t, 2H, J=8.0 Hz), 7.55 (d, 1H,
J=7.8 Hz), 7.89 (d, 2H, J=7.5 Hz). 13C NMR (CDCl3, 75 MHz): δ 24.2, 25.4, 57.6, 68.8, 74.0, 74.5,

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O. Arjona et al. / Tetrahedron: Asymmetry 10 (1999) 3431–3442
76.3, 109.5, 123.7, 128.3, 128.6, 129.5, 129.6, 133.1, 135.2, 141.6. IR (KBr): ν 3500, 3000, 1450, 1390
cm−1. Anal. calcd for C18H22O6S: C, 59.00; H, 6.05. Found: C, 58.87; H, 6.17.
3.6. (1S*,4R*,5S*,6S*,10R*)-2-(10,20-Dihydroxyethyl)-5,6-(isopropylidenedioxy)-4-methoxy-3-phenyl-
sulfonylcyclohex-2-enol 12 and (1R*,2S* or 2R*,5S*,6S*,10S*)-2-(10,20-dihydroxyethyl)-5,6-(iso-
propylidenedioxy)-4-methoxy-3-phenylsulfonylcyclohex-3-en-1,2-diol, 13
To a solution of 3 (55 mg, 0.15 mmol) in acetone:H2O 8:1 (0.8 ml of acetone, 0.1 ml of H2O)
Me3NO·2H2O (23 mg, 0.20 ml) and OsO4 (2.5% t-BuOH) (0.04 ml, 3.10−3 mmol) were added. The
mixture was stirred for 25 min. The reaction was quenched with NaHSO3 and solvent was evaporated
in vacuo. The crude product was subjected to column chromatography (hexane:AcOEt 5:1) to afford 12
(42 mg, 70%) as a white solid and 13 (4 mg, 6%) as a colorless oil. Compound 12: mp: 120–122°C. 1H
NMR (CDCl3, 300 MHz): δ 1.15 (s, 3H), 1.31 (s, 3H), 3.25 (s, 3H), 3.52 (dd, 1H, J=3.7, 11.9 Hz), 3.76
(dd, 1H, J=5.8, 11.9 Hz), 3.91–3.99 (m, 3H), 4.54–4.59 (m, 2H), 4.63–4.67 (m, 1H), 4.94 (d, 1H, J=3.5
Hz), 5.81 (dd, 1H, J=3.8, 5.7 Hz), 7.55 (t, 2H, J=7.5 Hz), 7.63 (t, 1H, J=7.3 Hz), 7.94 (d, 2H, J=7.5 Hz).
13C NMR (CDCl3, 75 MHz): δ 24.2, 25.6, 57.9, 66.1, 70.6, 71.7, 73.8, 74.5, 76.6, 109.8, 128.0, 129.4,
133.9, 135.6, 140.8, 156.8. IR (KBr): ν 3400, 1430, 1370 cm−1. Anal. calcd for C18H24O8S: C, 51.90;
H, 5.77. Found: C, 51.79; H, 5.65. Compound 13: 1H NMR (CDCl3, 300 MHz): δ 0.78 (s, 3H), 1.21 (s,
3H), 3.41 (s, 3H), 4.21–4.26 (m, 4H), 4.50 (t, 1H, J=7.9 Hz), 4.54–4.61 (m, 3H), 5.25 (t, 1H, J=7.2 Hz),
7.60 (t, 2H, J=7.7 Hz), 7.68 (d, 1H, J=7.3 Hz), 7.96 (d, 2H, J=7.7 Hz). 13C NMR (CDCl3, 75 MHz):
δ 23.7, 25.4, 58.7, 69.3, 73.0, 75.3, 75.7, 76.6, 101.8, 109.6, 128.4, 129.6, 134.6, 136.1, 138.8, 158.5.
IR (CHCl3): ν 3460, 3020, 1450, 1390 cm−1. Anal. calcd for C18H24O9S: C, 51.92; H, 5.77. Found: C,
51.83; H, 5.66.
3.7. (3R*,4S*,5S*,6S*)-6-Hydroxy-4,5-(isopropylidenedioxy)-3-methoxy-2-phenyl-sulfonylcyclohex-
1-enecarbaldehyde, 14
3.7.1. Procedure A
To a solution of 12 (39 mg, 0.10 mmol) in THF:H2O 1:1 (0.5 ml of H2O, 0.5 ml of THF), NaIO4 (31
mg, 0.15 mmol) was added. The mixture was stirred for 1 h and was then quenched with H2O. The crude
was extracted with AcOEt, and the organic layers were dried over MgSO4, filtered and concentrated
under reduced pressure. Aldehyde 14 (26 mg, 71%) was obtained as a colorless oil.
3.7.2. Procedure B
To a solution of 3 (163 mg, 0.44 mmol) in CH3CN:CCl4:H2O 3:3:4 (2.5 ml of CH3CN, 2.5 ml of
CCl4, 3.4 ml of H2O), NaIO4 (188 mg, 0.88 ml) was added. After 5 min of stirring, RuCl3·H2O (4 mg,
0.02 mmol) was added. The mixture was stirred for 30 min, quenched with saturated aqueous solution of
NaHCO3 and extracted with CH2Cl2. Organic layers were dried over MgSO4, filtered and concentrated
in vacuo. Purification by column chromatography afforded aldehyde 14 (108 mg, 67%) as a colorless oil.
1H NMR (CDCl3, 300 MHz): δ 0.82 (s, 3H), 1.20 (s, 3H), 2.98 (d, 1H, J=10.5 Hz), 3.40 (s, 3H), 4.31
(d, 1H, J=2.7 Hz), 4.51 (dd, 1H, J=2.7, 7.1 Hz), 4.57 (dd, 1H, J=4.0, 7.1 Hz), 4.87 (dd, 1H, J=3.9, 10.1
Hz), 7.56 (t, 2H, J=7.7 Hz), 7.64 (t, 1H, J=7.1 Hz), 7.86 (d, 2H, J=7.7 Hz), 10.45 (s, 1H). 13C NMR
(CDCl3, 75 MHz): δ 24.2, 25.3, 58.3, 68.1, 73.6, 74.4, 75.6, 110.0, 128.8, 129.4, 134.2, 139.1, 139.8,
152.9, 194.0. IR (CHCl3): ν 3400, 3020, 1715 cm−1. Anal. calcd for C17H20O7S: C, 55.43; H, 5.43.
Found: C, 55.59; H, 5.56.

O. Arjona et al. / Tetrahedron: Asymmetry 10 (1999) 3431–3442
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3.8. (1S*,4R*,5S*,6S*)-2-(Hydroxymethyl)-5,6-(isopropylidenedioxy)-4-methoxy-3-phenylsulfonyl-
cyclohex-2-enol, 15
To a solution of CeCl3·7H2O (201 mg, 0.54 mmol) in MeOH (1.4 ml) at −78°C, NaBH4 (12 mg,
0.32 mmol) was added. After 5 min, 14 (101 mg, 0.27 mmol) dissolved in MeOH (1.4 ml) was added
dropwise. The mixture was stirred for 3.5 h, quenched with H2O and extracted with AcOEt. The organic
layer was dried over MgSO4 and evaporated under reduced pressure. The crude was purified by column
chromatography (hexane:AcOEt, 1:1) to afford 15 (66 mg, 66%) as a white solid. Mp: 105–106°C. 1H
NMR (CDCl3, 300 MHz): δ 0.92 (s, 3H), 1.28 (s, 3H), 2.65 (m, 1H), 3.19 (d, 1H, J=9.2 Hz), 3.37 (s,
3H), 4.58 (dd, 1H, J=2.6, 7.4 Hz), 4.62–4.66 (m, 2H), 4.71–4.78 (m, 2H), 4.86 (dd, 1H, J=6.3, 12.9 Hz),
7.55 (t, 2H, J=7.0 Hz), 7.62 (t, 1H, J=7.0 Hz), 7.94 (d, 2H, J=7.0 Hz). 13C NMR (CDCl3, 75 MHz): δ
24.1, 25.3, 57.4, 57.6, 69.3, 74.0, 74.1, 75.8, 109.6, 127.8, 129.1, 133.5, 136.6, 141.1, 156.5. IR (KBr):
ν 3250, 2930, 1420 cm−1. Anal. calcd for C17H22O7S: C, 55.13; H, 5.95. Found: C, 55.24; H, 5.83.
3.9. (1S,4S,5R,6S)-5,6-(Isopropylidenedioxy)-4-methoxy-2-vinylcyclohex-2-enol, (+)-17
To a solution of (+)-3 (333 mg, 0.90 mmol) in anhydrous MeOH (1 ml), Na2HPO4 (505 mg, 3.55
mmol) was added. After cooling the mixture to −20°C, Na–Hg 6% (2.28 g, 2.5 g/mmol) was added. The
mixture was stirred for 3.5 h, quenched with H2O and extracted with Et2O. The organic layer was dried
over MgSO4 and solvent was evaporated under reduced pressure to afford (+)-17 as a colorless oil (164
mg, 80%). [α]D +15.4 (c 0.02, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 1.42 (s, 3H), 1.57 (s, 3H), 2.59
(s, 1H), 3.52 (s, 3H), 4.21 (m, 2H), 4.33 (s, 1H), 4.71 (s, 1H), 5.17 (d, 1H, J=11.1 Hz), 5.43 (d, 1H,
J=17.5 Hz), 5.94 (s, 1H), 6.41 (dd, 1H, J=11.1, 17.5 Hz). 13C NMR (CDCl3, 75 MHz): δ 24.1, 26.4,
57.5, 62.6, 75.0, 78.5, 79.9, 110.2, 113.9, 132.3, 135.2, 137.4. IR (CHCl3): ν 3420, 2920, 1480 cm−1.
Anal. calcd for C12H18O4: C, 63.72; H, 7.96. Found: C, 63.61; H, 8.08.
3.10. (1S,4S,5R,6S,10R)-2-(10,20-Dihydroxyethyl)-5,6-(isopropylidenedioxy)-4-methoxycyclohex-
2-enol, (+)-18
To a solution of (+)-17 (74 mg, 0.33 mmol) in acetone:H2O 8:1 (2.64 ml of acetone, 0.33 ml of H2O),
Me3NO·2H2O (73 mg, 0.66 ml) and OsO4 (2.5% t-BuOH) (0.09 ml, 6.6×10−3 mmol) were added. The
mixture was stirred for 1 h. The reaction was quenched with NaHSO3 and solvent was evaporated in
vacuo. The crude product was subjected to column chromatography (hexane:AcOEt 1:1) to afford (+)-18
(52 mg, 61%) as a white solid. [α]D +56.5 (c 0.01, CHCl3). Mp: 92–94°C. 1H NMR (CDCl3, 300 MHz):
δ 1.40 (s, 3H), 1.50 (s, 3H), 3.45 (s, 3H), 3.72–3.79 (m, 4H), 4.13 (t, 1H, J=3.5 Hz), 4.28–4.34 (m, 2H),
4.37–4.39 (m, 1H), 4.51 (s, 1H), 4.57 (d, 1H, J=3.5 Hz), 5.98 (d, 1H, J=2.9 Hz). 13C NMR (CDCl3, 300
MHz): δ 24.3, 26.4, 57.4, 64.4, 66.0, 72.6, 74.1, 75.6, 77.9, 110.0, 128.7, 140.8. IR (KBr): ν 3600–3200,
2920, 1160 cm−1. Anal. calcd for C12H20O6: C, 55.38; H, 7.69. Found: C, 55.27; H, 7.59.
3.11. (3S,4R,5S,6S)-6-Hydroxy-4,5-(isopropylidendioxy)-3-methoxycyclohex-1-ene-carbaldehyde,
(+)-1
3.11.1. Procedure A
To a well-stirred solution of (+)-17 (32 mg, 0.14 mmol) in a mixture of CH3CN (0.4 ml), CCl4 (0.4 ml)
and H2O (0.6 ml), NaIO4 (60 mg, 0.28 mmol) was added. The resulting mixture was allowed to stir for
5 min and then RuCl3·H2O (1.3 mg, 0.01 mmol) was added. The mixture turned black and was stirred

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O. Arjona et al. / Tetrahedron: Asymmetry 10 (1999) 3431–3442
for 50 min. The reaction was quenched with saturated aqueous solution of NaHCO3 and extracted with
CH2Cl2. The organic layer was dried over MgSO4 and solvent was evaporated in vacuo. After purification
by column chromatography (hexane:AcOEt 5:1), (+)-1 was obtained as a colorless oil (16 mg, 50%).
3.11.2. Procedure B
To a solution of (+)-18 (39 mg, 0.10 mmol) in a mixture THF:H2O 1:1 (0.5 ml of THF, 0.5 ml of
H2O), NaIO4 (31 mg, 0.15 mmol) was added. After 1 h of stirring, crude was hydrolyzed with H2O and
extracted with AcOEt. Organic layer was dried over MgSO4, filtered and solvent was evaporated under
reduced pressure. Compound (+)-1 (26 mg, 71%) was obtained as a colorless oil.
[α]D +49.5 (c 0.01, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 1.42 (s, 3H), 1.57 (s, 3H), 2.68 (s, 1H),
3.57 (s, 3H), 4.17 (dd, 1H, J=3.7, 8.4 Hz), 4.29 (dd, 1H, J=5.3, 8.6 Hz), 4.51 (dd, 1H, J=1.3, 5.5 Hz), 4.96
(d, 1H, J=3.8 Hz), 6.98 (s, 1H), 9.56 (s, 1H). 13C NMR (CDCl3, 75 MHz): δ 24.2, 26.5, 58.1, 60.0, 74.7,
78.9, 80.3, 111.0, 140.6, 153.8, 189.8. IR (CHCl3): ν 3560, 3045, 1700 cm−1. Anal. calcd for C11H16O5:
C, 57.89; H, 7.02. Found: C, 57.78; H, 6.90.
3.12. (1S,4S,5R,6R)-2-(Hydroxymethyl)-5,6-(isopropylidenedioxy)-4-methoxycyclohex-2-enol, (+)-19
To a solution of (+)-1 (23 mg, 0.10 mmol) in THF (1.0 ml), LiAlH4 was added (10 mg, 0.25 mmol)
at 0°C. The mixture was stirred for 20 min and quenched with H2O. The aqueous layer was extracted
with AcOEt. The organic layer was dried over MgSO4, evaporated under reduced pressure and purified
by column chromatography (hexane:AcOEt 1:5) to afford (+)-19 (21 mg, 93%) as a colorless oil. [α]D
+23.3 (c 0.01, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 1.38 (s, 3H), 1.45 (s, 3H), 3.40 (s, 3H), 4.07 (t,
1H, J=3.8 Hz), 4.25 (s, 2H), 4.34 (dd, 1H, J=3.9, 7.7 Hz), 4.43 (dd, 1H, J=4.1, 7.8 Hz), 4.48 (d, 1H,
J=3.5 Hz), 5.94 (d, 1H, J=3.5 Hz). 13C NMR (CDCl3, 75 MHz): δ 24.3, 26.3, 57.1, 64.4, 66.3, 67.8,
75.7, 76.3, 109.7, 125.3, 142.2. IR (CHCl3): ν 3500, 2880, 1380 cm−1. Anal. calcd for C11H18O5: C,
57.39; H, 7.83. Found: C, 57.28; H, 7.70.
3.13. (3S,4R,5S,6S)-1-(Hydroxymethyl)-10,6;4,5-bis-(isopropylidenedioxy)-3-methoxy-cyclohexene,
(+)-20a
To a solution of diol (+)-19 (32 mg, 0.14 mmol), p-TsOH (catalytic amount) and 2,2-
dimethoxypropane (0.02 ml, 0.28 mmol) were added. After stirring for 1 h, saturated aqueous
solution of NaHCO3 was added. The mixture was extracted with AcOEt, and then the organic layer
was dried under MgSO4, filtered and solvent was eliminated in vacuo. The crude product was purified
by column chromatography on silica gel (hexane:AcOEt 1:2) to produce (+)-20a (32 mg, 85%) as a
colorless oil. [α]D +20.5 (c 0.7, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 1.36 (s, 6H), 1.45 (s, 3H), 1.49
(s, 3H), 3.33 (s, 3H), 3.79 (dd, 1H, J=1.5, 5.5 Hz), 4.18 (d, 1H, J=13.6 Hz), 4.38 (dt, 1H, J=1.8, 13.9
Hz), 4.46 (dt, 1H, J=1.1, 6.6 Hz), 4.58 (dd, 1H, J=2.2, 4.0 Hz), 4.70 (dd, 1H, J=4.0, 6.7 Hz), 5.73 (dd,
1H, J=4.0, 6.7 Hz). 13C NMR (CDCl3, 75 MHz): δ 23.4, 24.6, 25.7, 26.2, 56.6, 61.8, 66.3, 74.5, 75.2,
76.0, 115.8, 142.6. IR (CHCl3): ν 3040, 1420, 1210 cm−1. Anal. calcd for C14H22O5: C, 62.22; H, 8.15.
Found: C, 62.14; H, 8.06.

O. Arjona et al. / Tetrahedron: Asymmetry 10 (1999) 3431–3442
3441
3.14. (3S,4R,5S,6S)-1-(Acetoxymethyl)-4,5-(isopropylidenedioxy)-3-methoxycyclo-hexen-1-ylacetate,
(+)-20b
To a solution of diol (+)-19 (13 mg, 0.06 mmol) in pyridine (0.30 ml), DMAP (catalytic amount)
and Ac2O (0.02 ml, 0.18 mmol) were added. The mixture was stirred for 1 h and then the solvent was
evaporated off under reduced pressure to afford (+)-20b (17 mg, 89%) as a colorless oil. [α]D +8.4 (c
0.02, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 1.36 (s, 3H), 1.45 (s, 3H), 2.07 (s, 3H), 2.11 (s, 3H), 3.46
(s, 3H), 4.12–4.13 (m, 1H), 4.33 (dd, 1H, J=4.0, 8.1 Hz), 4.40 (dd, 1H, J=4.0, 8.1 Hz), 4.65 (s, 2H), 5.58
(d, 1H, J=4.0 Hz), 6.05 (d, 1H, J=2.9 Hz). 13C NMR (CDCl3, 75 MHz): δ 20.8, 24.6, 26.1, 26.1, 57.2,
64.3, 67.4, 74.2, 77.7, 77.7, 110.2, 130.7, 134.4, 170.3. IR (CHCl3): ν 2940, 1750, 1720 cm−1. Anal.
calcd for C15H21O7: C, 57.32; H, 6.69. Found: C, 57.46; H, 6.55.
3.15. α-D-2,3;4,6-O-Diisopropylidene-1-O-methylcarbatalopyranose, (+)-4a
A solution of (+)-20a (17 mg, 0.06 mmol) and Pd/C 10% (67 mg, 0.06 mmol) in MeOH (1.2 ml)
was hydrogenated (30 psi) for 1.5 h. The reaction mixture was filtered through a short path of SiO2 with
MeOH to afford (+)-4a as a colorless oil (7 mg, 41%). [α]D +3.6 (c 0.2, CHCl3). 1H NMR (CDCl3, 300
MHz): δ 1.37 (s, 3H), 1.42 (s, 3H), 1.44 (s, 3H), 1.52 (s, 3H), 1.48–1.57 (m, 1H), 1.70–1.75 (m, 1H),
2.08 (ddd, 1H, J=4.1, 6.1, 13.4 Hz), 3.45 (s, 3H), 3.63 (dd, 1H, J=2.9, 11.7 Hz), 3.99 (q, 1H, J=4.1 Hz),
4.08 (dd, 1H, J=3.7, 11.7 Hz), 4.13–4.16 (m, 3H). 13C NMR (CDCl3, 75 MHz): δ 19.3, 25.6, 25.7, 25.8,
28.6, 29.1, 56.9, 64.9, 66.1, 75.4, 76.9, 77.6, 98.8, 109.5. IR (CHCl3): ν 1458, 1200 cm−1. Anal. calcd
for C14H24O5: C, 62.22; H, 8.89. Found: C, 62.17; H, 8.92.
3.16. α-D-4-O-Acetyl-6-deoxy-2,3-O-isopropylidene-1-O-methylcarbatalopyranose, (+)-4b
A solution of (+)-20b (17 mg, 0.05 mmol) and Pd/C 10% (58 mg, 0.05 mmol) in MeOH (1 ml) was
hydrogenated (30 psi) for 2 h. The reaction mixture was filtered through a short path of SiO2 with MeOH.
The resulting crude was purified by column chromatography (hexane:AcOEt 5:1) to afford (+)-4b (6 mg,
43%) as a colorless oil. [α]D +10.9 (c 0.01, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 1.05 (d, 3H, J=3.0
Hz), 1.35 (s, 3H), 1.51 (s, 3H), 1.60–1.65 (m, 1H), 1.72–1.81 (m, 2H), 2.14 (s, 3H), 3.44 (s, 3H), 3.61
(dt, 1H, J=4.8, 8.0 Hz), 4.12 (dd, 1H, J=5.5, 6.6 Hz), 4.30 (dd, 1H, J=4.0, 7.0 Hz), 5.20 (t, 1H, J=4.0
Hz). 13C NMR (CDCl3, 75 MHz): δ 16.9, 26.9, 27.5, 29.6, 29.7, 30.8, 70.9, 74.7, 77.1, 77.2, 77.3, 109.3,
170.1. IR (CHCl3): ν 1740, 1545, 1460 cm−1. Anal. calcd for C13H22O5: C, 60.46; H, 8.53. Found: C,
60.31; H, 8.64.
Acknowledgements
This research was supported by D.G.I.C.Y.T. (Ministerio de Educación y Cultura, grant no. PB96-
0064). Fátima Iradier and Rocío Medel thank the Universidad Complutense de Madrid and Ministerio de
Educación y Cultura, respectively, for a predoctoral fellowship.
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