A Lemieux-Johnson oxidation of shikimic acid derivatives: Facile entry to small library of protected (2S,3S,4R)-2,3,4,7-tetrahydroxy-6-oxoheptanals

Article abstract of DOI:10.1007/s11696-016-0004-8

The Lemieux-Johnson oxidation was employed for the cleavage of the carbon-carbon double bond of shikimic acid derivatives. Through this procedure, a series of the sixteen novel (2S,3S,4R)-2,3,4,7-tetrahydroxy-6-oxoheptanals bearing three contiguous stereo

Full text of DOI:10.1007/s11696-016-0004-8

Chem. Pap.
DOI 10.1007/s11696-016-0004-8
ORIGINAL PAPER
A Lemieux–Johnson oxidation of shikimic acid derivatives: facile
entry to small library of protected (2S,3S,4R)-2,3,4,7-
tetrahydroxy-6-oxoheptanals
1
Miroslav Psotka1 Miroslava Martinkova Jozef Gonda1
•
•
´
Received: 24 July 2016 / Accepted: 16 September 2016
Ó Institute of Chemistry, Slovak Academy of Sciences 2017
Abstract The Lemieux–Johnson oxidation was employed
for the cleavage of the carbon–carbon double bond of
shikimic acid derivatives. Through this procedure, a series
of the sixteen novel (2S,3S,4R)-2,3,4,7-tetrahydroxy-6-ox-
oheptanals bearing three contiguous stereocentres have
been synthesized in excellent yields.
this effective methodology to a range of the shikimic acid
derivatives with the aim to build up diversely protected
keto-aldehydes substructures, as the chiral synthons. The
Lemieux–Johnson reaction (Pappo et al. 1956) was chosen
as a suitable procedure for this transformation.
Keywords Shikimic acid Á Lemieux-Jonson oxidation Á 6-
Experimental
oxoheptanals
All commercial reagents were used in the highest available
purity from Aldrich, Merck or Acros Organics, without
further purification. Solvents were dried and purified prior
to use following standard procedures. Kieselgel 60
(0.040–0.063 mm, Merck) was used for flash column
chromatography. Solvents for flash chromatography (hex-
ane, EtOAc, MeOH, CH2Cl2) were distilled prior to use.
Thin layer chromatography was performed using Merck
silica gel 60 F254 analytical plates; detection was carried
out with either ultraviolet light (254 nm) or spraying with a
solution of phosphomolybdic acid, a basic potassium per-
manganate solution, or a solution of concentrated H2SO4,
Introduction
(-)-Shikimic acid I is an interesting chiral building block
in the pharmaceutical and cosmetic industry (Ghosh et al.
2012; Rawat et al. 2013). It plays a key role in the con-
structions of important medicinal compounds such as
anticancer and antibacterial agents, and hormones (Blanco
´
et al. 2013, 2012; Dıaz et al. 2000). Specific derivatives
include oseltamivir (Bochkov et al. 2012; Magano 2009),
(-)-zeylenone (Zhang et al. 2006), dioxolamycin, peri-
cosine A, and cythiaformines (Sanchez-Abella et al. 2006)
and valiolamine, a potent a-glucosidase inhibitor (Quan
et al. 2013). It is well known that the oxidative fragmen-
tation of the carbon/carbon double bond of shikimic acid
1
with subsequent heating. H NMR and 13C NMR spectra
were recorded in CDCl3 on a Varian Mercury Plus 400 FT
NMR (400.13 MHz for 1H and 100.6 MHz for 13C) or on a
Varian Premium Compact 600 (599.87 MHz for 1H,
150.84 MHz for 13C) spectrometer using TMS as internal
reference. For the assignment of signals, homonuclear
COSY and heteronuclear 2D correlated (HSQC, HMBC)
techniques was used. Optical rotations were measured on a
P-2000 Jasco polarimeter and reported as follows: [a]D
(c in grams per 1000 mL, solvent). Melting points were
recorded on a Kofler hot block and are uncorrected. All
reactions were performed under a nitrogen atmosphere,
unless otherwise noted. Elemental analysis was performed
on a Perkin-Elmer CHN 2400 elemental analyser. The non-
´
with ozone has provided dicarbonyl compounds (Gonzalez-
Castro et al. 2015). In light of the aforementioned study
and recent synthetic developments, we set out to extend
& Jozef Gonda
jozef.gonda@upjs.sk
1
Department of Organic Chemistry, Institute of Chemical
ˇ
Sciences, P. J. Safarik University, Moyzesova 11,
´
040 01 Kosice, Slovak Republic
ˇ
123

Chem. Pap.
commercially available compounds, 2, 4, 6, 18, 21 (Liu
et al. 2004), 10 (Alves et al. 1999), 27, 29 (Cuelar et al.
2015), 28, 33, 35 (Grewe et al. 1956), were prepared
according to published procedures.
to afford 0.155 g (99%) of 7 as a colorless oil; [a]2D3 = –
53.3 (c 0.3, CHCl3). H NMR (400 MHz, CDCl3), d: 1.27
(s, 3 H, CH3), 1.29 (s, 3 H, CH3), 2.08 (s, 3 H, CH3), 2.28
(ddd, 1 H, J6,2 = 2.8 Hz, J6,5 = 10.3 Hz, J6,6 = 17.9 Hz,
H-6), 2.85 (dd, 1 H, J6,5 = 6.1 Hz, J6,6 = 17.6 Hz, H-6),
3.24 (s, 3 H, OCH3), 3.27 (s, 3 H, OCH3), 3.72 (dd, 1H,
J4,3 = 4.5 Hz, J4,5 = 11.0 Hz, H-4), 3.75 (s, 3 H, OCH3),
1
Isopropyl (3R,4S,5R)-3,4,5-trihydroxycyclohex-1-
enecarboxylate (3)
4.09 (ddd,
J5,4 = 11.0 Hz, H-5), 5.57 (dd, 1 H, J3,4 = 4.5 Hz,
J3,2 = 5.4 Hz, H-3), 6.82 (dd, H, J2,6 = 2.8 Hz,
J2,3 = 5.4 Hz, H-2). 13C NMR (100 MHz, CDCl3), d: 17.6
(CH3), 17.8 (CH3), 20.9 (CH3), 30.0 (C-6), 47.9 (OCH3),
48.0 (OCH3), 52.2 (OCH3), 62.9 (C-3), 66.1 (C-5), 68.8 (C-
4), 99.1 (Cq), 99.7 (Cq), 132.2 (C-2), 133.3 (C-1), 166.3
(C=O), 170.4 (C=O). Anal. Calcd for C16H24O8: C, 55.81;
H, 7.02. Found: C, 55.91; H, 7.15.
1
H, J5,6 = 6.1 Hz, J5,6 = 10.3 Hz,
Sulfuric acid (4 mL, 96%) was added dropwise to a solu-
tion of shikimic acid 1 (10 g, 57.42 mmol) inisopropanol
(300 mL). After stirring at 85 °C for 24 h, the solvent was
evaporated under reduced pressure, and the crude product 3
(11.2 g, 90%) was used without further purification.
1
Isopropyl (3R,4R,5R)-3-hydroxy-4,5-{[(20S,30S)-20,30-
dimetoxybutane-20,30-diyl]dioxy}cyclohex-1-
enecarboxylate (5)
Methyl (3R,4S,5R)-3-benzyloxy-4,5-{[(20S,30S)-20,30-
dimetoxybutane-20,30-diyl]dioxy}cyclohex-1-
enecarboxylate (8)
To a solution of ester 3 (5 g, 23 mmol) in MeOH (75 mL),
DMAP (9 mg, 0.07 mmol), trimethoxymethane (15 mL,
138 mmol) and butane-2,3-dione (5 mL, 55.66 mmol) were
successively added. The resulting mixture was stirred for 3 h
at 60 °C; then solid NaHCO3 (6 g) was added and stirring
was continued for another 30 min at room temperature. The
insoluble material was filtered off, the solvent was evapo-
rated, and the residue was chromatographed on silica gel
(hexane/EtOAc, ur = 3:1), to afford 1.25 g (25%) of 5 as
a purple oil; [a]D24 = ? 18.4 (c 1.3, CHCl3). 1H NMR
(400 MHz, CDCl3), d: 1.21 (m, 6 H, 2 9 CH3), 1.27 (s, 3 H,
CH3), 1.30 (s, 3 H, CH3), 2.25 (ddd, 1 H, J6,2 = 2.7 Hz,
J6,5 = 10.4 Hz, J6,6 = 17.6 Hz, H-6), 2.84 (dd, 1H,
J6,5 = 5.8 Hz, J6,6 = 17.6 Hz, H-6), 3.22 (s, 3 H, OCH3),
3.23 (s, 3 H, OCH3), 3.63 (dd, 1 H, J4,3 = 4.3 Hz,
J4,5 = 10.8 Hz, H-4), 4.11 (ddd, 1 H, J5,6 = 5.8 Hz,
J5,6 = 10.4 Hz, J5,4 = 10.8 Hz, H-5), 4.39 (dd, 1 H,
J3,4 = 4.3 Hz, J3,2 = 5.2 Hz, H-3), 5.06 (m, 1H, OCHiPr),
6.90 (dd, 1 H, J2,6 = 2.7 Hz, J2,3 = 5.2 Hz, H-2). 13C NMR
(100 MHz, CDCl3), d: 17.7 (CH3), 17.9 (CH3), 21.8
(2 9 CH3), 30.1 (C-6), 47.9 (OCH3), 48.0 (OCH3), 62.5 (C-
5), 65.1 (C-3), 68.4 (OCHiPr), 70.6 (C-4), 99.2 (Cq), 100.0
(Cq), 132.5 (C-1), 134.3 (C-2), 165.5 (C=O). Anal. Calcd for
C16H26O7: C, 58.17; H, 7.93. Found: C, 58.26; H, 7.89.
Benzyl bromide (BnBr) (0.0065 mL, 0.546 mmol) and
Ag2O (0.172 g, 0.744 mmol) were added successively to a
solution of 4 (0.15 g, 0.496 mmol) in dry DCM (1.5 mL) and
the resulting mixture was stirred for 3.5 h at room temper-
ature. The insoluble parts were removed by filtration, the
filtrate was concentrated to dryness, and the residue was
purified by flash chromatography on silica gel (hexane/
EtOAc, ur = 5:1), to give 0.14 g(73%) of 8as white crystals
1
(from CH3OH); [a]D22 = -32.5 (c 4.0, CHCl3). H NMR
(400 MHz, CDCl3), d: 1.33 (s, 3 H, CH3), 1.37 (s, 3 H, CH3),
2.24 (ddd,
1
H, J6,2 = 2.8 Hz, J6,5 = 10.5 Hz,
J6,6 = 18.0 Hz, H-6), 2.83 (dd, 1 H, J6,5 = 5.9 Hz,
J6,6 = 18.0 Hz, H-6), 3.28 (s, 3 H, OCH3), 3.30 (s, 3 H,
OCH3), 3.68 (dd, 1 H, J4,3 = 3.9 Hz, J4,5 = 11.0 Hz, H-4),
3.71 (s, 3 H, OCH3), 4.17 (dd, 1 H, J3,4 = 3.9 Hz,
J3,2 = 5.6 Hz, H-3), 4.28 (ddd, 1 H, J5,6 = 5.9 Hz,
J5,6 = 10.5 Hz, J5,4 = 11.0 Hz, H-5), 4.67 (d, 1 H,
JH,H = 11.3 Hz, CH2Ph), 5.04 (d, 1 H, JH,H = 11.3 Hz,
CH2Ph), 6.82 (dd, 1 H, J2,6 = 2.8 Hz, J2,3 = 5.6 Hz, H-2),
7.26–7.47 (m, 5H, Ph). 13C NMR (100 MHz, CDCl3), d: 17.7
(CH3), 17.8 (CH3), 30.2 (C-6), 47.8 (2 9 OCH3), 51.8
(OCH3), 62.8 (C-3), 71.3 (OCH2Ph), 72.0 (C-5), 73.9 (C-4),
98.8 (Cq), 99.4 (Cq), 127.5 (CPh), 128.1 (2 9 CPh), 130.9 (C-
1), 134.4 (C-2), 138.7 (Ci), 166.4 (C=O). Anal. Calcd for
C21H28O7: C, 64.27; H, 7.19. Found: C, 64.32; H, 7.10.
Methyl (3R,4S,5R)-3-acetoxy-4,5-{[(20S,30S)-20,30-
dimetoxybutane-20,30-diyl]dioxy}cyclohex-1-
enecarboxylate (7)
Acetic anhydride (0.07 mL, 0.75 mmol) and DMAP
(12 mg, 0.10 mmol) were added successively to a solution
of 4 (0.15 g, 0.5 mmol) in dry pyridine (2.5 mL). After
stirring at room temperature for 30 min, the solvent was
evaporated under reduced pressure, and the residue was
chromatographed on silica gel (hexane/EtOAc, ur = 3:1),
Methyl (3R,4S,5R)-3-[(tert-butyldiphenylsilyl)oxy)]-
4,5-{[(20S,30S)-20,30-dimetoxybutane-20,30-
diyl]dioxy}cyclohex-1-enecarboxylate (9)
tert-Butyldiphenylsilyl chloride (TBDPSCl) (1 mL,
3.97 mmol) and imidazole (0.27 g, 3.97 mmol) were added
123

Chem. Pap.
successively to a solution of 4 (0.60 g, 1.985 mmol) in dry
DMF (2.4 mL) and the resulting mixture was stirred and
heated at 60 °C for 30 min. After cooling to room tem-
perature, the mixture was poured into water (5 mL), and
extracted with CH2Cl2 (2 9 10 mL). The combined
organic extracts were dried with anhydrous Na2SO4, the
solvent was evaporated in vacuo, and the residue was
subjected to flash chromatography on silica gel (hexane/
EtOAc, ur = 15:1), to afford 0.98 g (92%) of 9 as a vis-
cous oil; [a]2D8 = -35.4 (c 2.0, CHCl3). 1H NMR
(400 MHz, CDCl3), d: 1.08 (s, 9 H, 3 9 CH3), 1.24 (s, 3 H,
CH3), 1.31 (s, 3 H, CH3), 2.23 (ddd, 1 H, J6,2 = 2.4 Hz,
J6,5 = 10.1 Hz, J6,6 = 17.7 Hz, H-6), 2.85 (dd, 1 H,
J6,5 = 6.0 Hz, J6,6 = 17.7 Hz, H-6), 3.11 (s, 3 H, OCH3),
3.33 (s, 3 H, OCH3), 3.44 (dd, 1 H, J4,3 = 4.0 Hz,
J4,5 = 10.9 Hz, H-4), 3.73 (s, 3 H, OCH3), 4.32 (dd, 1 H,
J3,4 = 4.0 Hz, J3,2 = 5.3 Hz, H-3), 4.36 (ddd, 1 H,
J5,6 = 6.0 Hz, J5,6 = 10.1 Hz, J5,4 = 10.9 Hz, H-5), 6.63
(dd, 1 H, J2,6 = 2.4 Hz, J2,3 = 5.3 Hz, H-2), 7.34–7.89 (m,
10H, Ph). 13C NMR (100 MHz, CDCl3), d: 17.6 (CH3),
17.9 (CH3), 19.5 (Cq), 26.9 (3 9 CH3), 30.4 (C6), 47.7
(2 9 OCH3), 52.0 (OCH3), 62.6 (C-5), 66.4 (C-3), 70.8 (C-
4), 98.8 (Cq), 99.6 (Cq), 127.2 (CHPh), 127.4 (CHPh), 129.4
(CHPh), 129.6 (CHPh), 129.9 (C-1), 133.4 (Ci), 134.3 (Ci),
136.1 (CAr), 136.5 (CAr), 136.6 (C2), 167.0 (C=O). Anal.
Calcd for C30H40O7Si: C, 66.64; H, 7.46. Found: C, 66.49;
H, 7.53.
(dd, 1 H, J3,4 = 3.6 Hz, J3,2 = 5.5 Hz, H-3), 5.05 (m, 1 H,
OCHiPr), 6.75 (dd, 1 H, J2,6 = 2.2 Hz, J2,3 = 5.5 Hz, H-2).
13C NMR (100 MHz, CDCl3), d: -4.8 (CH3), -4.7 (CH3),
17.6 (CH3), 17.8 (CH3), 18.3 (Cq), 21.7 (2 9 CH3), 25.7
(3 9 CH3), 30.5 (C-6), 47.5 (OCH3), 47.7 (OCH3), 62.3
(C-5), 65.9 (C-3), 68.1 (OCHiPr), 70.8 (C-4), 98.6 (Cq),
99.4 (Cq), 130.4 (C-1), 136.1 (C-2), 165.9 (C=O). Anal.
Calcd for C22H40O7Si: C, 59.43; H, 9.07. Found: C, 59.41;
H, 9.15.
General procedure for the synthesis of keto-
aldehydes 12, 13, 14, 15, 16, 17, 24, 25, 26, 38, 39, 40,
41, 42, 43 and 44
A mixture of tert-butanol/water (ur = 1:1, 3.2 mL) was
added to vigorously stirred solution of esters 6–11, 19–22
and 31–37 (1 mmol) in CH2Cl2 (1.6 mL) and the resulting
mixture was then treated successively with K2OsO4.2H2O
(5 lmol) and NaIO4 (3 mmol). The resulting suspension
was stirred overnight (21–24 h) at room temperature. The
insoluble parts were filtered through a small pad of Celite,
and the solvent was removed under reduced pressure. The
resulting products were then characterized without further
purification.
Methyl (4R,5S,6S)-6-[(tert-butyldimethylsilyl)oxy]-
4,5-{[(20S,30S)-20,30-dimetoxybutane-20,30-
diyl]dioxy}-2,7-dioxoheptanoate (12)
Isopropyl (3R,4S,5R)-3-[(tert-
butyldimethylsilyl)oxy)]-4,5-{[(20S,30S)-20,30-
dimetoxybutane-20,30-diyl]dioxy}cyclohex-1-
enecarboxylate (11)
Following the general procedure, compound 6 (0.416 g,
1.0 mmol) was converted to 12 (0,45 g, 99%, dark oil);
[a]2D2 = ?142.5 (c 1.6, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 0.09 (s, 3 H, CH3), 0.12 (s, 3 H, CH3), 0.92 (s, 9 H,
3 9 CH3), 1.18 (s, 3 H, CH3), 1.24 (s, 3 H, CH3), 2.77 (dd, 1
H, J3,4 = 2.5 Hz, J3,3 = 17.0 Hz, H-3), 3.08 (dd, 1 H,
J3,4 = 10.2 Hz, J3,3 = 17.0 Hz, H-3), 3.23 (s, 3 H, OCH3),
3.25 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.92 (dd, 1 H,
Imidazole (137 mg, 2 mmol) was added to a solution of 5
(330 mg, 1 mmol) in dry DMF (1.0 mL). Then TBDMSCl
(226 mg, 1.5 mmol) was added and the resulting mixture
was stirred and heated at 70 °C for 30 min, under stirring.
After completion of the reaction, the mixture was allowed
to cool to room temperature, and then was poured into
water (3 mL), and extracted with CH2Cl2 (2 9 10 mL).
The combined organic layers were dried with anhydrous
Na2SO4, the solvent was removed under reduce pressure,
and the residue was purified by flash chromatography on
silica gel (hexane/EtOAc, ur = 9:1), to afford 0.36 g
(81%) of 11 as a colorless oil; [a]2D4 = -15.6 (c 1.8,
CHCl3). 1H NMR (400 MHz, CDCl3), d: 0.10 (s, 3 H,
CH3), 0.13 (s, 3 H, CH3), 0.89 (s, 9 H, 3 9 CH3), 1.25 (m,
6 H, 2 9 CH3), 1.28 (s, 3 H, CH3), 1.29 (s, 3 H, CH3), 2.22
(ddd, 1 H, J6,2 = 2.2 Hz, J6,5 = 10.6 Hz, J6,6 = 17.6 Hz,
H-6), 2.80 (dd, 1 H, J6,5 = 6.1 Hz, J6,6 = 17.6 Hz, H-6),
3.23 (s, 3 H, OCH3), 3.24 (s, 3 H, OCH3), 3.48 (dd, 1 H,
J4,3 = 3.6 Hz, J4,5 = 10.4 Hz, H-4), 4.12 (ddd, 1 H,
J5,6 = 6.1 Hz, J5,4 = 10.4 Hz, J5,6 = 10.6 Hz, H-5), 4.31
J5,6 = 3.9 Hz, J5,4 = 9.8 Hz, H-5), 4.10 (dd,
1 H,
J6,7 = 0.9 Hz, J6,5 = 3.9 Hz, H-6), 4.45 (ddd, 1 H,
J4,3 = 2.5 Hz, J4,5 = 9.8 Hz, J4,3 = 10.2 Hz, H-4), 9.68 (d,
1 H, J7,6 = 0.9 Hz, H-7). 13C NMR (100 MHz, CDCl3), d:
-5.0 (CH3), -4.9 (CH3), 17.3 (2 9 CH3), 18.2 (Cq), 25.7
(3 9 CH3), 40.5 (C-3), 48.1 (OCH3), 48.2 (OCH3), 52.9
(OCH3), 64.5 (C-4), 72.1 (C-5), 78.7 (C-6), 98.6 (Cq), 99.1
(Cq), 161.0 (COOMe), 191.0 (C-2), 201.6 (C-7). Anal. Calcd
for C20H36O9Si: C, 53.55; H, 8.09. Found: C, 53.61; H, 7.93.
Methyl (4R,5S,6S)-6-acetoxy-4,5-{[(20S,30S)-20,30-
dimetoxybutane-20,30-diyl]dioxy}-2,7-
dioxoheptanoate (13)
Using the general procedure, compound 7 (0.35 g,
1.0 mmol) was converted to 13 (0.34 g, 91%, dark oil);
123

Chem. Pap.
[a]2D2 = ?110.0 (c 0.6, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 1.20 (s, 3 H, CH3), 1.25 (s, 3 H, CH3), 2.17 (s, 3
H, CH3), 2.91 (dd, 1 H, J3,4 = 3.4 Hz, J3,3 = 17.1 Hz,
H-3), 3.18 (dd, 1 H, J3,4 = 9.2 Hz, J3,3 = 17.1 Hz, H-3),
3.21 (s, 3 H, OCH3), 3.28 (s, 3 H, OCH3), 3.87 (s, 3 H,
OCH3), 4.15 (dd, 1 H, J6,4 = 5.8 Hz, J6,5 = 10.5 Hz, H-6),
4.40 (dd, 1 H, J5,6 = 10.5 Hz, J5,4 = 10.8 Hz, H-5), 4.50
(dddd, 1 H, J4,3 = 3.4 Hz, J4,6 = 5.8 Hz, J4,3 = 9.2 Hz,
J4,5 = 10.8 Hz, H-4), 9.68 (s, 1 H, H-7). 13C NMR
(100 MHz, CDCl3), d: 17.2 (CH3), 17.3 (CH3), 20.4 (CH3),
40.5 (C-3), 48.2 (OCH3), 48.4 (OCH3), 53.1 (OCH3), 64.9
(C-4), 71.4 (C-5), 76.4 (C-6), 98.9 (Cq), 99.1 (Cq), 160.9
(C=O), 169.7 (C=OAc), 190.7 (C-2), 196.3 (C-7). Anal.
Calcd for C16H24O10: C, 51.06; H, 6.43. Found: C, 51.14;
H, 6.54.
26.8 (3 9 CH3), 40.0 (C-3), 48.1 (OCH3), 48.2 (OCH3),
53.0 (OCH3), 63.8 (C-4), 73.3 (C-5), 78.5 (C-6), 98.6 (Cq),
99.1 (Cq), 127.8 (CPh), 127.9 (CPh), 130.1 (CPh), 130.2
(CPh), 132.1 (Ci), 132.6 (Ci), 135.8 (CAr), 136.1 (CAr),
160.8 (C = O), 190.8 (C=O, C-2), 201.6 (C-7). Anal.
Calcd for C30H40O9Si: C, 62.91; H, 7.04. Found: C, 63.10;
H, 7.15.
Methyl (4R,5S,6S)-6-benzoyloxy-4,5-{[(20S,30S)-20,30-
dimetoxybutane-20,30-diyl]dioxy}-2,7-
dioxoheptanoate (16)
Following the general procedure, derivative 10 (0.40 g,
1.0 mmol) was converted to 16 (0.42 g, 96%, dark oil);
[a]2D2 = ?59.0 (c 2.0, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 1.28 (s, 6 H, 2 9 CH3), 3.01 (dd, 1 H,
J3,4 = 3.7 Hz, J3,3 = 17.1 Hz, H-3), 3.16 (dd, 1 H,
J3,4 = 10.2 Hz, J3,3 = 17.1 Hz, H-3), 3.25 (s, 3 H, OCH3),
3.30 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 4.18 (dd, 1 H,
J5,6 = 4.9 Hz, J5,4 = 9.9 Hz, H-5), 4.58 (ddd, 1 H,
J4,3 = 3.7 Hz, J4,5 = 9.9 Hz, J4,3 = 10.2 Hz, H-4), 5.21
(d, 1 H, J6,5 = 4.9 Hz, H-6), 7.39–7.46 (m, 2 H, Ph),
7.55–7.60 (m, 1 H, Ph), 7.98–8.03 (m, 2 H, Ph), 9.75 (s, 1
H, H-7). 13C NMR (100 MHz, CDCl3), d: 17.2 (CH3), 17.3
(CH3), 40.5 (C-3), 48.2 (OCH3), 48.4 (OCH3), 53.0
(OCH3), 65.0 (C-4), 71.8 (C-5), 78.2 (C-6), 99.0 (Cq), 99.2
(Cq), 128.4 (CHPh), 130.1 (CHPh), 133.6 (CHPh), 133.8
(Ci), 165.3 (C=OBz), 170.8 (C=O), 190.6 (C=O, C-2), 196.6
(C-7). Anal. Calcd for C21H26O10: C, 57.53; H, 5.98.
Found: C, 57.44; H, 6.12.
Methyl (4R,5S,6S)-6-benzyloxy-4,5-{[(20S,30S)-20,30-
dimetoxybutane-20,30-diyl]dioxy}-2,7-
dioxoheptanoate (14)
Following the general procedure, compound 8 (0.39 g,
1.0 mmol) was transformed to 14 (0.32 g, 75%, dark oil);
[a]2D2 = ?97.2 (c 4.3, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 1.21 (s, 3 H, CH3), 1.26 (s, 3 H, CH3), 3.05 (m,
2 H, 2 9 H3), 3.21 (s, 3 H, OCH3), 3.28 (s, 3 H, OCH3),
3.75 (s, 3 H, OCH3), 3.91 (dd, 1 H, J6,5 = 6.5 Hz,
J6,7 = 1.8 Hz, H-6), 3.98 (dd,
1 H, J5,6 = 6.5 Hz,
J5,4 = 9.6 Hz, H-5), 4.45 (m, 2 H, OCH2Ph, H-4), 4.63 (d,
1 H, JH,H = 11.3 Hz, OCH2Ph), 7.27–7.36 (m, 5H, Ph),
9.73 (d, 1 H, J7,6 = 1.8 Hz, H-7). 13C NMR (100 MHz,
CDCl3), d: 17.2 (CH3), 17.3 (CH3), 41.1 (C-3), 48.2
(OCH3), 48.3 (OCH3), 52.9 (OCH3), 65.5 (C-4), 71.3
(OCH2Ph), 72.5 (C-5), 82.1 (C-6), 98.8 (Cq), 98.9 (Cq),
128.1 (CAr), 128.2 (CAr), 128.5 (CAr), 136.5 (Ci), 160.7
(C=O), 190.8 (C-2), 200.4 (C-7). Anal. Calcd for
C21H28O9: C, 59.43; H, 6.65. Found: C, 59.53; H, 6.52.
Isopropyl (4R,5S,6S)-6-[(tert-
butyldimethylsilyl)oxy]-4,5-{[(20S,30S)-20,30-
dimetoxybutane-20,30-diyl]dioxy}-2,7-
dioxoheptanoate (17)
Using the general procedure, derivative 11 (0.44 g,
1.0 mmol) was converted to 17 (0.47 g, 99%, dark oil);
[a]2D2 = ?141.0 (c 1.8, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 0.09 (s, 3 H, CH3), 0.11 (s, 3 H, CH3), 0.92 (s, 9
H, 3 9 CH3), 1.19 (s, 3 H, CH3), 1.24 (s, 3 H, CH3), 1.32
(m, 6 H, 2 9 CH3), 2.78 (dd, 1 H, J3,4 = 2.5 Hz,
J3,3 = 17.1 Hz, H-3), 3.08 (dd, 1 H, J3,4 = 10.3 Hz,
J3,3 = 17.1 Hz, H-3), 3.23 (s, 3 H, OCH3), 3.29 (s, 3 H,
OCH3), 3.92 (dd, 1 H, J5,6 = 3.9 Hz, J5,4 = 10.1 Hz, H-5),
4.10 (dd, 1 H, J6,7 = 0.9 Hz, J6,5 = 3.9 Hz, H-6), 4.45
(ddd, 1 H, J4,3 = 2.5 Hz, J4,5 = 10.1 Hz, J4,3 = 10.3 Hz,
H-4), 5.11 (m, 1 H, OCHiPr), 9.68 (d, 1 H, J7,6 = 0.9 Hz,
H-7). 13C NMR (100 MHz, CDCl3), d: -5.0 (CH3), -4.9
(CH3), 17.3 (CH3), 17.4 (CH3), 18.2 (Cq), 21.6 (CH3), 21.8
(CH3), 25.7 (3 9 CH3), 40.5 (C-3), 48.1 (OCH3), 48.3
(OCH3), 64.4 (C-4), 70.7 (OCHiPr), 72.0 (C-5), 78.5 (C-6),
98.6 (Cq), 99.1 (Cq), 160.1 (C=O), 191.5 (C=O, C-2), 201.6
Methyl (4R,5S,6S)-6-[(tert-butyldiphenylsilyl)oxy]-
4,5-{[(20S,30S)-20,30-dimetoxybutane-20,30-
diyl]dioxy}-2,7-dioxoheptanoate (15)
Using the general procedure, compound 9 (0.54 g,
1.0 mmol) was converted to 15 (0.54 g, 95%, dark oil);
[a]2D2 = -41.9 (c 2.1, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 1.14 (s, 3 H, CH3), 1.18 (s, 3 H, CH3), 1.27 (s, 9
H, 3 9 CH3), 2.45 (dd, 1 H, J3,4 = 2.6 Hz, J3,3 = 16.4 Hz,
H-3), 2.92 (dd, 1 H, J3,4 = 10.4 Hz, J3,3 = 16.4 Hz, H-3),
3.23 (s, 3 H, OCH3), 3.25 (s, 3 H, OCH3), 3.84 (s, 3 H,
OCH3), 3.89 (dd, 1 H, J5,6 = 1.7 Hz, J5,4 = 10.0 Hz, H-5),
4.07 (d, 1 H, J6,5 = 1.7 Hz, H-6), 4.58 (ddd, 1 H,
J4,3 = 2.6 Hz, J4,5 = 10.0 Hz, J4,3 = 10.4 Hz, H-4),
7.35–7.75 (m, 10H, Ph), 9.49 (s, 1 H, H-7). 13C NMR
(100 MHz, CDCl3), d: 17.3 (CH3), 17.4 (CH3), 19.3 (Cq),
123

Chem. Pap.
(C-7). Anal. Calcd for C22H40O9Si: C, 55.44; H, 8.46.
Found: C, 55.53; H, 8.37.
J6,5 = 10.4 Hz, J6,6 = 17.1 Hz, H-6), 2.33 (dd, 1 H,
J6,5 = 6.2 Hz, J6,6 = 17.1 Hz, H-6), 3.23 (s, 3 H, OCH3),
3.24 (s, 3 H, OCH3), 3.49 (dd, 1 H, J4,3 = 3.8 Hz,
J4,5 = 10.8 Hz, H-4), 4.16 (ddd, 1 H, J5,6 = 6.2 Hz,
J5,6 = 10.4 Hz, J5,4 = 10.8 Hz, H-5), 4.20 (dd, 1 H,
[(1R,5R,6S)-3-[(Benzyloxy)methyl]-5,6-{[(20S,30S)-
20,30-dimetoxybutane-20,30-diyl]dioxy}cyclohex-2-en-
1-yl)oxy](tert-butyl)dimethylsilane (19)
J3,4 = 3.8 Hz, J3,2 = 5.4 Hz, H-3), 4.45 (d,
1 H,
J7,7 = 12.9 Hz, H-7), 4.50 (d, 1 H, J7,7 = 12.9 Hz, H-7),
5.69 (dd, 1 H, J2,6 = 1.3 Hz, J2,3 = 5.4 Hz, H-2). 13C
NMR (100 MHz, CDCl3), d: -4.8 (CH3), -4.6 (CH3), 17.7
(CH3), 17.9 (CH3), 18.4 (Cq), 20.8 (CH3), 25.8 (3 9 CH3),
31.9 (C-6), 47.7 (2 9 OCH3), 62.5 (C-5), 66.3 (C-7), 67.2
(C-3), 71.0 (C-4), 98.7 (Cq), 99.5 (Cq), 125.6 (C-2), 133.6
(C-1), 170.6 (C=O). Anal. Calcd for C21H38O7Si: C, 58.57;
H, 8.89. Found: C, 58.64; H, 8.93.
To a solution of 18 (0.15 g, 0.39 mmol) in dry THF
(2 mL) pre-cooled to 0 °C NaH (19 mg, 0.772 mmol, 60%
dispersion in mineral oil) was added, followed by succes-
sive addition of TBAI (2 mg, 4 lmol) and BnBr (0.07 mL,
0.58 mmol). The reaction mixture was stirred for 6 h at
0 °C and the poured into water (2 mL) and extracted with
Et2O (2 9 10 mL). The combined organic layers were
dried with anhydrous Na2SO4, the solvent was evaporated
in vacuo, and the residue was subjected to flash chro-
matography on silica gel (hexane/EtOAc, ur = 11:1), to
afford 0.175 g (95%) of 19 as a colorless oil; [a]2D2 = ?1.1
(c 1.88, CHCl3). 1H NMR (400 MHz, CDCl3), d: 0.09 (s, 3
H, CH3), 0.11 (s, 3 H, CH3), 0.90 (s, 9 H, 3 9 CH3), 1.28
(s, 3 H, CH3), 1.29 (s, 3 H, CH3), 2.14 (ddd, 1 H,
J6,2 = 2.0 Hz, J6,5 = 10.5 Hz, J6,6 = 17.1 Hz, H-6), 2.39
(dd, 1 H, J6,5 = 6.2 Hz, J6,6 = 17.1 Hz, H-6), 3.23 (s, 3 H,
OCH3), 3.25 (s, 3 H, OCH3), 3.51 (dd, 1 H, J4,3 = 3.8 Hz,
J4,5 = 10.7 Hz, H-4), 3.92 (s, 2 H, H-7), 4.16 (ddd, 1 H,
J5,6 = 6.2 Hz, J5,6 = 10.5 Hz, J5,4 = 10.7 Hz, H-5), 4.21
(dd, 1 H, J3,4 = 3.8 Hz, J3,2 = 5.3 Hz, H-3), 4.46 (d, 1 H,
J7,7 = 12.0 Hz, H-7), 4.49 (d, 1 H, J7,7 = 12.0 Hz, H-7),
tert-Butyl{[(3R,4S,5R)-3-[(tert-
butyldimethylsilyl)oxy]-4,5-{[(20S,30S)-20,30-
dimetoxybutane-20,30-diyl]dioxy}cyclohex-1-ene-1-
yl]methoxy}dimethylsilane (22)
A solution of 18 (1 g, 2.6 mmol) in dry DMF (6.5 mL) was
successively treated with imidazole (0.356 g, 5.2 mmol) and
TBDMSCl (0.59 g, 3.9 mmol), and the stirred reaction
mixture was heated for 30 min at 70 °C. After completion of
the reaction, the mixture was poured into water (8 mL), and
extracted with CH2Cl2 (2 9 20 mL). The combined organic
layers were dried with anhydrous Na2SO4, stripped of sol-
vent, and the residue was passed through a small pad of silica
gel (hexane/EtOAc, ur = 11:1), to afford 1.29 g (98%) of 22
5.71 (dd,
1 H, J2,6 = 2.0 Hz, J2,3 = 5.3 Hz, H-2),
1
7.33–7.34 (m, 5H, Ph). 13C NMR (100 MHz, CDCl3), d:
-4.8 (CH3), -4.6 (CH3), 17.7 (CH3), 17.9 (CH3), 18.4
(Cq), 25.9 (3 9 CH3), 32.0 (C-6), 47.6 (OCH3), 47.7
(OCH3), 62.7 (C-3), 66.5 (C-5), 71.3 (OCH2Ph), 71.9 (C-
7), 73.2 (C-4), 98.7 (Cq), 99.4 (Cq), 124.7 (C-2), 127.6
(CAr), 127.7 (CAr), 128.4 (CAr), 135.6 (C-1), 138.2 (Ci).
Anal. Calcd for C26H42O6Si: C, 65.24; H, 8.84. Found: C,
65.31; H, 8.91.
as a colorless oil; [a]2D6 = ?14.2 (c 0.7, CHCl3). H NMR
(400 MHz, CDCl3), d: 0.05 (s, 3 H, CH3), 0.06 (s, 3 H, CH3),
0.08 (s, 3 H, CH3), 0.10 (s, 3 H, CH3), 0.88 (s, 9 H, 3 9 CH3),
0.90 (s, 9 H, 3 9 CH3), 1.28 (s, 6 H, 2 9 CH3), 2.06 (ddd, 1
H, J6,2 = 2.0 Hz, J6,5 = 10.1 Hz, J6,6 = 16.8 Hz, H-6),
2.26 (dd, 1 H, J6,5 = 6.1 Hz, J6,6 = 16.8 Hz, H-6), 3.23 (s, 3
H, OCH3), 3.24 (s, 3 H, OCH3), 3.49 (dd, 1 H, J4,3 = 3.8 Hz,
J4,5 = 10.7 Hz, H-4), 4.02 (s, 2 H, H-7), 4.14 (ddd, 1 H,
J5,6 = 6.1 Hz, J5,6 = 10.1 Hz, J5,4 = 10.7 Hz, H-5), 4.21
(dd, 1 H, J3,4 = 3.8 Hz, J3,2 = 5.0 Hz, H-3), 5.68 (dd, 1 H,
J2,6 = 2.0 Hz, J2,3 = 5.0 Hz, H-2). 13C NMR (100 MHz,
CDCl3), d: -5.4 (CH3), -5.3 (CH3), -4.8 (CH3), -4.6
(CH3), 17.7 (CH3), 17.9 (CH3), 18.3 (Cq), 18.4 (Cq), 25.8
(3 9 CH3), 25.9 (3 9 CH3), 31.4 (C-6), 47.6 (OCH3), 47.7
(OCH3), 62.8 (C-5), 66.0 (C-7), 66.5 (C-3), 71.4 (C-4), 98.7
(Cq), 99.4 (Cq), 121.6 (C-2), 138.0 (C-1). Anal. Calcd for
C25H50O6Si2: C, 59.72; H, 10.02. Found: C, 59.76; H, 10.11.
[(3R,4S,5R)-3-[(tert-Butyldimethylsilyl)oxy]-4,5-
{[(20S,30S)-20,30-dimetoxybutane-20,30-
diyl]dioxy}cyclohex-1-ene-1-yl)]methyl acetate (20)
Acetic anhydride (0.11 mL, 0.579 mmol) and DMAP
(9 mg, 0.070 mmol) were added successively to a solution
of 18 (0.15 g, 0.386 mmol) in dry pyridine (2.3 mL). After
stirring at room temperature for 30 min, the solvent was
evaporated in vacuo, and the residue was flash-chro-
matographed through a short column of silica gel (hexane/
EtOAc, ur = 5:1), to furnish 0.16 g (96%) of 20 as
(4R,5S,6S)-6-[(tert-Butyldimethylsilyl)oxy]-4,5-
{[(20S,30S)-20,30-dimetoxybutane-20,30-diyl]dioxy}-
2,7-dioxoheptyl acetate (24)
a colorless oil; [a]D22 = ?30.0 (c 1.0, CHCl3). H NMR
1
(400 MHz, CDCl3), d: 0.08 (s, 3 H, CH3), 0.10 (s, 3 H,
CH3), 0.89 (s, 9 H, 3 9 CH3), 1.28 (s, 3 H, CH3), 1.29 (s, 3
H, CH3), 2.06 (s, 3 H, CH3), 2.12 (ddd, 1 H, J6,2 = 1.3 Hz,
Following the general procedure, compound 20 (0.43 g,
1.0 mmol) was converted to 24 (0.45 g, 98%, dark oil);
123

Chem. Pap.
[a]2D5 = ?140.0 (c 0.9, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 0.09 (s, 3 H, CH3), 0.13 (s, 3 H, CH3), 0.93 (s, 9
H, 3 9 CH3), 1.22 (s, 3 H, CH3), 1.24 (s, 3 H, CH3), 2.15
(s, 3 H, CH3), 2.30 (dd, 1 H, J5,4 = 2.6 Hz, J5,5 = 14.8 Hz,
H-5), 2.53 (dd, 1 H, J5,4 = 10.1 Hz, J5,5 = 17.0 Hz, H-5),
3.19 (s, 3 H, OCH3), 3.24 (s, 3 H, OCH3), 3.89 (dd, 1 H,
H-5), 2.51 (dd, 1 H, J5,4 = 3.0 Hz, J5,5 = 15.7 Hz, H-5),
3.24 (s, 3 H, OCH3), 3.26 (s, 3 H, OCH3), 3.30 (m, 2 H,
H-7), 3.91 (dd, 1 H, J3,2 = 3.3 Hz, J3,4 = 9.9 Hz, H-3),
4.10 (dd, 1 H, J2,1 = 0.7 Hz, J2,3 = 3.3 Hz, H-2), 4.32
(ddd, 1 H, J4,5 = 3.0 Hz, J4,5 = 9.7 Hz, J4,3 = 9.9 Hz,
H-4), 9.54 (d, 1 H, J2,1 = 0.7 Hz, H-1). 13C NMR
(100 MHz, CDCl3), d: -5.5 (CH3), -5.4 (CH3), -5.0
(CH3), -4.9 (CH3), 17.3 (CH3), 17.4 (CH3), 18.1 (Cq), 18.4
(Cq), 25.7 (3 9 CH3), 25.8 (3 9 CH3), 31.1 (C-5), 48.0
(OCH3), 48.1 (OCH3), 64.7 (C-4), 70.5 (C-7), 72.5 (C-3),
78.6 (C-2), 98.4 (Cq), 99.1 (Cq), 201.8 (C-6), 201.9 (C-1).
Anal. Calcd for C25H50O8Si2: C, 56.14; H, 9.42. Found: C,
56.06; H, 9.47.
J3,2 = 3.3 Hz, J3,4 = 9.8 Hz, H-3), 4.10 (d,
J2,3 = 3.3 Hz, H-2), 4.36 (ddd, 1 H, J4,5 = 2.6 Hz,
J4,3 = 9.8 Hz, J4,5 = 10.1 Hz, H-4), 4.66 (d, H,
1 H,
1
J7,7 = 17.2 Hz, H-7), 4.71 (d, 1 H, J7,7 = 17.2 Hz, H-7),
9.65 (s, 1 H, H-1). 13C NMR (100 MHz, CDCl3), d: -5.0
(2 9 CH3), 17.3 (CH3), 17.4 (CH3), 18.2 (Cq), 20.4 (CH3),
25.7 (3 9 CH3), 40.0 (C-5), 48.1 (2 9 OCH3), 65.1 (C-4),
69.2 (C-7), 72.2 (C-3), 78.7 (C-2), 98.6 (Cq), 99.2 (Cq),
170.0 (C=OAc), 200.9 (C-6), 201.9 (C=O, C-1). Anal.
Calcd for C21H28O9Si: C, 54.52; H, 8.28. Found: C, 54.46;
H, 8.33.
(1R,5R,6S)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-
5,6-(isopropylidenedioxy)cyclohex-3-enol (30)
To a solution of 28 (1.0 g, 4.99 mmol) in dry CH2Cl2
(27 mL) pre-cooled to 0 °C, Et3N (0.9 mL, 6.49 mmol)
and DMAP (92 mg, 0.75 mmol) were added dropwise,
under stirring. The resulting mixture was stirred at the
same temperature for 10 min and then TBDMSCl (979 mg,
6.49 mmol) was added and stirring vas continued at room
temperature for 1 h. The reaction was monitored by TLC.
At the end, the mixture was poured into water, the organic
layer was separated, and the aqueous phase was then
washed with CH2Cl2 (3 9 15 mL). The combined organic
extracts were dried with anhydrous Na2SO4, stripped of
solvent, and the residue was subjected to flash chro-
matography on silica gel (hexane/EtOAc, ur = 4:1), to
give 1.5 g (96%) of 30 as a colorless oil; [a]2D7 = -60.8
(4R,5S,6S)-6-[(tert-Butyldimethylsilyl)oxy]-4,5-
{[(20S,30S)-20,30-dimetoxybutane-20,30-diyl]dioxy}-
2,7-dioxoheptyl benzoate (25)
Following the general procedure, compound 21 (0.49 g,
1.0 mmol) was converted into 25 (0.49 g, 93%, dark oil);
[a]2D5 = ?67.7 (c 1.8, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 0.09 (s, 3 H, CH3), 0.12 (s, 3 H, CH3), 0.92 (s, 9
H, 3 9 CH3), 1.24 (s, 6 H, 2 9 CH3), 2.39 (dd, 1
H,J5,4 = 2.6 Hz, J5,5 = 14.9 Hz, H-5), 2.63 (dd, 1 H,
J5,4 = 10.2 Hz, J5,5 = 14.9 Hz, H-5), 3.21 (s, 3 H, OCH3),
3.24 (s, 3 H, OCH3), 3.92 (dd, 1 H, J3,2 = 3.2 Hz,
J3,4 = 9.8 Hz, H-3), 4.11 (dd,
J2,3 = 3.2 Hz, H-2), 4.40 (ddd, 1 H, J4,5 = 2.6 Hz,
J4,5 = 9.8 Hz, J4,3 = 10.2 Hz, H-4), 4.92 (s, H,
1 H, J2,1 = 0.6 Hz,
1
(c 1.3, CHCl3). H NMR (400 MHz, CDCl3), d: 0.07 (s, 6
2
H, 2 9 CH3), 0.91 (s, 9 H, 3 9 CH3), 1.40 (s, 3 H, CH3),
1.49 (s, 3 H, CH3), 2.00 (ddd, 1 H, J6,2 = 1.7 Hz,
J6,5 = 10.0 Hz, J6,6 = 16.4 Hz, H-6), 2.27 (dd, 1 H,
J6,5 = 4.6 Hz, J6,6 = 16.4 Hz, H-6), 3.81 (ddd, 1 H,
J5,6 = 4.6 Hz, J5,4 = 8.5 Hz, J5,6 = 10.0 Hz, H-5), 3.97
(dd, 1 H, J4,3 = 6.3 Hz, J4,5 = 8.5 Hz, H-4), 4.07 (s, 2 H,
H-7), 4.66 (dd, 1 H, J3,2 = 3.7 Hz, J3,4 = 6.3 Hz, H-3),
5.86 (dd, 1 H, J2,6 = 1.7 Hz, J2,3 = 3.7 Hz, H-2). 13C
NMR (100 MHz, CDCl3), d: -5.4 (2 9 CH3), 18.3 (Cq),
25.9 (3 9 CH3), 25.9 (CH3), 28.4 (CH3), 31.2 (C-6), 65.5
(C-5), 69.6 (C-7), 72.9 (C-3), 79.6 (C-4), 109.3 (Cq), 116.8
(C-2), 141.0 (C-1). Anal. Calcd for C16H30O4Si: C, 61.11;
H, 9.61. Found: C, 61.17; H, 9.56.
H-7),7.42–7.45 (m, 2 H, Ph), 7.54–7.59 (m, 1 H, Ph),
8.06–8.08 (m, 2 H, Ph), 9.66 (d, 1 H, J1,2 = 0.6 Hz,
H-1).13C NMR (100 MHz, CDCl3), d: -5.0 (2 9 CH3),
17.3 (CH3), 17.4 (CH3), 18.1 (Cq), 25.6 (3 9 CH3), 40.1
(C-5), 48.1 (2 9 OCH3), 65.1 (C-4), 69.5 (C-7), 72.2 (C-
3), 78.7 (C-2), 98.6 (Cq), 99.1 (Cq), 128.4 (CHPh), 129.2
(Ci), 129.9 (CHPh), 133.3 (CHPh), 165.6 (C=OBz), 200.9
(C=O, C-6), 201.9 (C-1). Anal. Calcd for C26H40O9Si: C,
59.52; H, 7.68. Found: C, 59.55; H, 7.72.
(2S,3S,4R)-2,7-Bis[(tert-butyldimethylsilyl)oxy]-3,4-
{[(20S,30S)-20,30-dimetoxybutane-20,30-diyl]dioxy}-6-
oxoheptanal (26)
[(3R,4R,5R)-5-[(tert-butyldimethylsilyl)oxy]-3,4-
(isopropylidenedioxy)cyclohex-1-en-1-yl]methyl
acetate (31)
Following the general procedure, compound 22 (0.50 g,
1.0 mmol) was converted to 26 (0.52 g, 97%, dark oil);
[a]2D4 = ?97.2 (c 1.7, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 0.10 (s, 9 H, 3 9 CH3), 0.13 (s, 3 H, CH3), 0.91
(s, 9 H, 3 9 CH3), 0.93 (s, 9 H, 3 9 CH3), 1.25 (s, 6 H,
2 9 CH3), 2.38 (dd, 1 H, J5,4 = 9.7 Hz, J5,5 = 15.7 Hz,
A solution of 29 (0.6 g, 1.908 mmol) in dry pyridine
(10 mL) was successively diluted, with DMAP (47 mg,
0.382 mmol) and Ac2O (0.3 mL, 2.862 mmol). After
123

Chem. Pap.
[(3R,4S,5R)-5-(benzoyloxy)-3,4-
(isopropylidenedioxy)cyclohex-1-en-1-yl]methyl
benzoate (34)
stirring for 30 min at room temperature, the solvent was
evaporated, and the residue was passed through a small
pad of silica gel (hexane/EtOAc, ur = 7:1), to give
0.6 g (88%) of 31 as a colorless oil; [a]2D6 = -53.7
1
A solution of 28 (0.83 g, 4.161 mmol) in dry CH2Cl2
(17 mL) was successively treated with DMAP (0.3 g,
(c 1.6, CHCl3). H NMR (400 MHz, CDCl3), d: 0.07 (s,
3 H, CH3), 0.10 (s, 3 H, CH3), 0.88 (s, 9 H, 3 9 CH3),
1.38 (s, 3 H, CH3), 1.43 (s, 3 H, CH3), 2.08 (dd, 1 H,
J6,5 = 7.3 Hz, J6,6 = 16.8 Hz, H-6), 2.07 (s, 3 H, CH3),
2.22 (dd, 1 H, J6,5 = 4.6 Hz, J6,6 = 16.8 Hz, H-6), 3.93
(ddd, 1 H, J5,6 = 4.6 Hz, J5,4 = 4.8 Hz, J5,6 = 7.3 Hz,
H-5), 4.00 (dd, 1 H, J4,5 = 4.8 Hz, J4,3 = 6.4 Hz, H-4),
4.49 (s, 2 H, H-7), 4.63 (dd, 1 H, J3,2 = 3.6 Hz,
J3,4 = 6.4 Hz, H-3), 5.78 (d, 1 H, J2,3 = 3.6 Hz, H-2).
13C NMR (100 MHz, CDCl3), d: -4.8 (CH3), -4.6
(CH3), 18.0 (Cq), 20.8 (CH3), 25.8 (3 9 CH3), 26.1
(CH3), 28.1 (CH3), 32.2 (C-6), 66.8 (C-5), 69.3 (C-7),
72.6 (C-3), 77.9 (C-4), 109.0 (Cq), 121.6 (C-2), 134.4
(C-1), 170.6 (C=O). Anal. Calcd for C18H32O5Si: C,
60.63; H, 9.05. Found: C, 60.56; H, 9.11.
2.497 mmol)
and benzoyl
chloride
(1.95 mL,
16.484 mmol), and the mixture was stirred at ambient
temperature for 3.5 h. After completion of the reaction,
a saturated NaHCO3 solution (10 mL) was added, and
mixture was extracted with CH2Cl2 (2 9 15 mL). The
combined organic extracts were dried with anhydrous
Na2SO4, striped of solvent, and the residue was flash-
chromatographed through a short column of silica gel
(hexane, then hexane/EtOAc, ur = 7:1), to give 1.60 g
(94%) of 34 as a colorless oil; [a]2D4 = -75.6 (c 1.8,
CHCl3). 1H NMR (400 MHz, CDCl3), d: 1.41 (s, 3 H,
CH3), 1.50 (s, 3 H, CH3), 2.32 (ddd, 1 H, J6,2 = 1.7 Hz,
J6,5 = 8.0 Hz, J6,6 = 17.0 Hz, H-6), 2.68 (dd, 1 H,
J6,5 = 4.8 Hz, J6,6 = 17.0 Hz, H-6), 4.39 (dd, 1 H,
J4,3 = 6.1 Hz, J4,5 = 7.5 Hz, H-4), 4.77 (dd,
1 H,
[(3R,4R,5R)-5-[(tert-butyldimethylsilyl)oxy]-3,4-
(isopropylidenedioxy)cyclohex-1-en-1-yl]methyl
benzoate (32)
J3,2 = 3.3 Hz, J3,4 = 6.1 Hz, H-3), 4.81 (s, 2 H, H-7), 5.41
(ddd, 1 H, J5,6 = 4.8 Hz, J5,4 = 7.5 Hz, J5,6 = 8.0 Hz,
H-5), 6.03 (dd, 1 H, J2,6 = 1.7 Hz, J2,3 = 3.3 Hz, H-2),
7.40–7.50 (m, 4 H, Ph), 7.53–7.64 (m, 2 H, Ph), 8.02–8.13
(m, 4 H, Ph). 13C NMR (100 MHz, CDCl3), d: 26.1 (CH3),
28.0 (C-6), 29.0 (CH3), 66.8 (C-7), 71.1 (C-5), 72.3 (C-3),
75.0 (C-4), 109.8 (Cq), 121.6 (C-2), 128.3 (CHPh), 128.4
(CHPh), 129.6 (CHPh), 129.7 (CHPh), 130.2 (Ci), 133.1
(CHPh), 133.2 (CHPh), 133.7 (Ci), 134.8 (C-1), 165.9
(2 9 C=O). Anal. Calcd for C24H24O6: C, 70.57; H, 5.92.
Found: C, 70.63; H, 5.99.
Benzoyl chloride (BzCl) (0.35 mL, 2.862 mmol) and
DMAP (0.035 g, 0.286 mmol) were added successively
to a solution of 29 (0.6 g, 1.908 mmol) in dry pyridine
(12 mL). The reaction mixture was stirred at room
temperature for 30 min, then poured into water (10 mL),
and extracted with CH2Cl2 (3 9 10 mL). The combined
organic phases were dried with anhydrous Na2SO4, the
solvent was evaporated in vacuo, and the residue was
purified by flash chromatography on silica gel (hexane/
EtOAc, ur = 11:1), to afford 0.73 g (97%) of 32 as
(1R,5R,6S)-3-{[(tert-butyldimethylsilyl)oxy]methyl}-
5,6-(isopropylidenedioxy)cyclohex-3-en-1-yl
benzoate (36)
a colorless oil; [a]D27 = -50.0 (c 1.7, CHCl3). H NMR
1
(400 MHz, CDCl3), d: 0.07 (s, 3 H, CH3), 0.10 (s, 3 H,
CH3), 0.88 (s, 9 H, 3 9 CH3), 1.39 (s, 3 H, CH3), 1.45
Using the procedure as for the preparation of 32, compound
30 (0.5 g, 1.59 mmol) was converted into 36 (0.6 g, 90%,
colorless oil, hexane/EtOAc, ur = 11:1); [a]2D7 = -92.3
(s,
3 H, CH3), 2.11 (ddd, 1 H, J6,2 = 1.5 Hz,
J6,5 = 7.2 Hz, J6,6 = 17.0 Hz, H-6), 2.32 (dd, 1 H,
J6,5 = 4.5 Hz, J6,6 = 17.0 Hz, H-6), 3.97 (ddd, 1 H,
J5,6 = 4.5 Hz, J5,4 = 6.7 Hz, J5,6 = 7.2 Hz, H-5), 4.04
(dd, 1 H, J4,3 = 6.0 Hz, J4,5 = 6.7 Hz, H-4), 4.67 (dd, 1
H, J3,2 = 3.0 Hz, J3,4 = 6.0 Hz, H-3), 4.75 (s, 2 H,
H-7), 5.90 (dd, 1 H, J2,6 = 1.5 Hz, J2,3 = 3.0 Hz, H-2),
7.42–7.48 (m, 2 H, Ph), 7.55–7.59 (m, 1 H, Ph),
8.04–8.06 (m, 2 H, Ph). 13C NMR (100 MHz, CDCl3), d:
-4.8 (CH3), -4.5 (CH3), 18.1 (Cq), 25.8 (3 9 CH3),
26.1 (CH3), 28.2 (CH3), 32.3 (C-6), 67.1 (C-7), 69.3 (C-
5), 72.7 (C-3), 78.0 (C-4), 109.0 (Cq), 121.5 (CHPh),
128.4 (CHPh), 129.6 (CHPh), 129.9 (Ci), 133.1 (C-2),
134.6 (C-1), 166.1 (C=O). Anal. Calcd for C23H34O5Si:
C, 65.99; H, 8.19. Found: C, 66.06; H, 8.25.
1
(c 1.3, CHCl3). H NMR (400 MHz, CDCl3), d: 0.07 (s, 6
H, 2 9 CH3), 0.90 (s, 9 H, 3 9 CH3), 1.40 (s, 3 H, CH3),
1.49 (s, 3 H, CH3). 2.15 (dd, 1 H, J6,5 = 8.8 Hz,
J6,6 = 16.8 Hz, H-6), 2.47 (dd, 1 H, J6,5 = 5.0 Hz,
J6,6 = 16.8 Hz, H-6), 4.09 (s, 2 H, H-7), 4.33 (dd, 1 H,
J4,3 = 6.2 Hz, J4,5 = 8.0 Hz, H-4), 4.75 (dd,
1 H,
J3,2 = 4.4 Hz, J3,4 = 6.2 Hz, H-3), 5.32 (ddd, 1 H,
J5,6 = 5.0 Hz, J5,4 = 8.0 Hz, J5,6 = 8.8 Hz, H-5), 5.92 (d,
1 H, J2,3 = 4.4 Hz, H-2), 7.41–7.45 (m, 2 H, Ph),
7.53–7.56 (m, 1 H, Ph), 8.04–8.08 (m, 2 H, Ph). 13C NMR
(100 MHz, CDCl3), d: -5.4 (2 9 CH3), 18.3 (Cq), 25.8
(3 9 CH3), 26.1 (CH3), 28.1 (CH3), 28.9 (C-6), 65.4 (C-7),
123

Chem. Pap.
71.7 (C-5), 72.7 (C-3), 75.7 (C-4), 109.5 (Cq), 117.3
(CHPh), 128.3 (CHPh), 129.7 (CHPh), 130.1 (Ci), 133.0 (C-
2), 139.7 (C-1), 166.0 (C=O). Anal. Calcd for C23H34O5Si:
C, 65.99; H,; 8.19. Found: C, 66.06; H, 8.24.
H, 3 9 CH3), 1.35 (s, 3 H, CH3), 1.54 (s, 3 H, CH3), 2.61
(dd, 1 H, J5,4 = 6.0 Hz, J5,5 = 16.1 Hz, H-5), 2.87 (dd, 1
H, J5,4 = 5.6 Hz, J5,5 = 16.1 Hz, H-5), 4.38 (ddd, 1 H,
J4,5 = 5.6 Hz, J4,5 = 6.0 Hz, J4,3 = 8.7 Hz, H-4),
4.41–4.46 (m, 2 H, H-7), 4.80–4.94 (m, 2 H, H-2, H-3),
7.40–7.44 (m, 2 H, Ph), 7.53–7.57 (m, 1 H, Ph), 8.04–8.07
(m, 2 H, Ph), 9.72 (d, 1 H, J1,2 = 1.2 Hz, H-1). 13C NMR
(100 MHz, CDCl3), d: -4.6 (2 9 CH3), 17.9 (Cq), 24.9
(CH3), 25.7 (3 9 CH3), 26.7 (CH3), 42.2 (C-5), 66.9 (C-3),
69.0 (C-7), 80.6 (C-2), 80.8 (C-4), 110.6 (Cq), 128.3
(CHPh), 129.0 (Ci), 129.8 (CHPh), 133.3 (CHPh, 165.6
(C=OBz), 200.1 (C-1), 201.3 (C-6). Anal. Calcd for C23-
H34O7Si: C, 61.31; H, 7.61. Found: C, 61.36; H, 7.64.
(1R,5R,6S)-3-{[(tert-butyldimethylsilyl)oxy]methyl}-
5,6-(isopropylidenedioxy)cyclohex-3-en-1-yl acetate
(37)
Using the procedure as for the preparation of 31, compound
30 (0.15 g, 0.477 mmol) was converted into 37 (0.12 g,
72%, hexane/EtOAc, ur = 9:1); [a]2D7 = -84.6 (c 1.33,
CHCl3). 1H NMR (400 MHz, CDCl3), d: 0.03 (s, 6 H,
2 9 CH3), 0.89 (s, 9 H, 3 9 CH3), 1.35 (s, 3 H, CH3), 1.43
(s, 3 H, CH3), 1.96 (dd, 1 H, J6,5 = 9.2 Hz, J6,6 = 16.7 Hz,
H-6), 2.05 (s, 3 H, CH3), 2.31 (dd, 1 H, J6,5 = 5.0 Hz,
J6,6 = 16.7 Hz, H-6), 4.02 (s, 2 H, H-7), 4.12 (dd, 1 H,
(4R,5S,6S)-5,6-(Isopropylidenedioxy)-2,7-
dioxoheptane-1,4-diyl diacetate (40)
J4,3 = 6.2 Hz, J4,5 = 8.8 Hz, H-4), 4.64 (d,
J3,4 = 6.2 Hz, H-3), 4.99 (ddd, 1 H, J5,6 = 5.0 Hz,
J5,4 = 8.8 Hz, J5,6 = 9.2 Hz, H-5), 5.82 (m, 1 H, H-2). 13
1
H,
Following the general procedure, compound 33 (0.28 g,
1.0 mmol) was converted to 40 (0.3 g, 96%, dark oil);
[a]2D7 = -25.2 (c 1.9, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 1.34 (s, 3 H, CH3), 1.55 (s, 3 H, CH3), 1.97 (s, 3
H, CH3), 2.12 (s, 3 H, CH3), 2.78 (dd, 1 H, J5,4 = 4.7 Hz,
J5,5 = 16.8 Hz, H-5), 2.90 (dd, 1 H, J5,4 = 8.3 Hz,
J5,5 = 16.8 Hz, H-5), 4.41 (dd, 1 H, J2,1 = 1.9 Hz,
C
NMR (100 MHz, CDCl3), d: -5.5 (2 9 CH3), 18.2 (Cq),
21.1 (CH3), 25.8 (3 9 CH3), 25.9 (CH3), 28.0 (CH3), 28.8
(C-6), 65.3 (C-7), 71.2 (C-5), 72.5 (C-3), 75.7 (C-4), 109.3
(Cq), 117.1 (C-2), 139.7 (C-1), 170.4 (C=O). Anal. Calcd
for C18H32O5Si: C, 60.63; H, 9.05. Found: C, 60.64; H,
9.06.
J2,3 = 8.1 Hz, H-2), 4.60 (dd,
1 H, J3,4 = 2.4 Hz,
J3,2 = 8.1 Hz, H-3), 4.62 (s, 2 H, H-7), 5.15 (ddd, 1 H,
J4,3 = 2.4 Hz, J4,5 = 4.7 Hz, J4,5 = 8.3 Hz, H-4), 9.59 (d,
1 H, J1,2 = 1.9 Hz, H-1). 13C NMR (100 MHz, CDCl3), d:
20.3 (CH3), 20.8 (CH3), 24.7 (CH3), 26.4 (CH3), 39.4 (C-
5), 66.8 (C-4), 67.9 (C-7), 78.4 (C-3), 80.0 (C-2), 110.8
(Cq), 169.3 (C=O), 170.0 (C=O), 200.4 (C-1), 200.7 (C-6).
Anal. Calcd for C14H20O8: C, 53.16; H, 6.37. Found: C,
53.11; H, 6.41.
(4R,5R,6S)-4-[(tert-Butyldimethylsilyl)oxy]-5,6-
(isopropylidenedioxy)-2,7-dioxoheptyl acetate (38)
Following the general procedure, compound 31 (0.36 g,
1.0 mmol) was converted to 39 (0.37 g, 96%, dark oil);
[a]2D7 = ?42.6 (c 1.5, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 0.05 (s, 3 H, CH3), 0.09 (s, 3 H, CH3), 0.86 (s, 9
H, 3 9 CH3), 1.38 (s, 3 H, CH3), 1.57 (s, 3 H, CH3), 2.17
(s, 3 H, CH3), 2.53 (dd, 1 H, J5,4 = 6.0 Hz, J5,5 = 16.0 Hz,
H-5), 2.79 (dd, 1 H, J5,4 = 5.6 Hz, J5,5 = 16.0 Hz, H-5),
4.39 (m, 1 H, H-4), 4.42–4.43 (m, 2 H, H-2, H-3), 4.60 (d, 1
H, J7,7 = 17.1 Hz, H-7), 4.70 (d, 1 H, J7,7 = 17.1 Hz,
H-7), 9.74 (m, 1 H, H-1). 13C NMR (100 MHz, CDCl3), d:
-4.5 (2 9 CH3), 18.0 (Cq), 20.4 (CH3), 25.0 (CH3), 25.8
(3 9 CH3), 26.9 (CH3), 42.2 (C-5), 67.0 (C-3), 68.7 (C-7),
80.6 (C-2), 81.0 (C-4), 110.7 (Cq), 170.1 (C=OAc), 200.2
(C-1), 201.4 (C-6). Anal. Calcd for C18H32O7Si: C, 55.64;
H, 8.30. Found: C, 55.59; H, 8.35.
(4R,5S,6S)-5,6-(Isopropylidenedioxy)-2,7-
dioxoheptane-1,4-diyl dibenzoate (41)
Following the general procedure, compound 34 (0.41 g,
1.0 mmol) was converted to 41 (0.33 g, 75%, dark oil);
[a]2D2 = -25.0 (c 1.6, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 1.42 (s, 3 H, CH3), 1.70 (s, 3 H, CH3), 3.07 (dd,
1 H, J5,4 = 4.4 Hz, J5,5 = 17.0 Hz, H-5), 3.16 (dd, 1 H,
J5,4 = 8.5 Hz, J5,5 = 17.0 Hz, H-5), 4.54 (dd, 1 H,
J2,1 = 1.5 Hz, J2,3 = 8.2 Hz, H-2), 4.83 (dd,
1 H,
J3,4 = 2.1 Hz, J3,2 = 8.2 Hz, H-3), 4.93 (s, 2 H, H-7), 5.42
(ddd, 1 H, J4,3 = 2.1 Hz, J4,5 = 4.4 Hz, J4,5 = 8.5 Hz,
H-4), 7.42–7.46 (m, 4 H, Ph), 7.54–7.59 (m, 2 H, Ph),
8.00–8.09 (m, 4 H, Ph), 9.59 (d, 1 H, J1,2 = 1.5 Hz, H-1).
13C NMR (100 MHz, CDCl3), d: 24.6 (CH3), 26.5 (CH3),
39.4 (C-5), 67.8 (C-4), 68.4 (C-7), 78.3 (C-3), 80.0 (C-2),
110.8 (Cq), 128.4 (CHPh), 128.5 (CHPh), 129.0 (Ci), 129.2
(Ci), 129.6 (CHPh), 129.8 (CHPh), 133.4 (CHPh), 133.5
(CHPh), 164.8 (C=O), 165.7 (C=O), 200.3 (C-1), 201.0 (C-
(4R,5R,6S)-4-[(tert-Butyldimethylsilyl)oxy]-5,6-
(isopropylidenedioxy)-2,7-dioxoheptyl benzoate (39)
Using the general procedure, compound 32 (0.42 g,
1.0 mmol) was converted to 39 (0.43 g, 95%, dark oil);
[a]2D7 = ?0.03 (c 1.7, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 0.04 (s, 3 H, CH3), 0.06 (s, 3 H, CH3), 0.85 (s, 9
123

Chem. Pap.
6). Anal. Calcd for C24H24O8: C, 65.45; H, 5.49. Found: C,
65.50; H, 5.53.
4.53 (dd, 1 H, J2,1 = 1.5 Hz, J2,3 = 8.2 Hz, H-2), 4.84 (dd,
1 H, J3,4 = 2.1 Hz, J3,2 = 8.2 Hz, H-3), 5.41 (ddd, 1 H,
J4,3 = 2.1 Hz, J4,5 = 4.5 Hz, J4,5 = 8.5 Hz, H-4),
7.44–7.47 (m, 2 H, Ph), 7.55–7.58 (m, 1 H, Ph), 8.00–8.03
(m, 2 H, Ph), 9.61 (d, 1 H, J1,2 = 1.5 Hz, H-1). 13C NMR
(100 MHz, CDCl3): d -5.6 (CH3), -5.5 (CH3), 18.2 (Cq),
24.7 (CH3), 25.7 (3 9 CH3), 26.6 (CH3), 39.0 (C-5),
68.1(C-3), 69.3 (C-7), 78.5 (C-2), 80.1 (C-4), 110.7 (Cq),
128.5 (CHPh), 129.7 (CHPh), 130.1 (Ci), 133.4 (CHPh),
164.8 (C=O), 200.3 (C-1), 207.9 (C-6). Anal. Calcd for
C23H34O7Si: C, 61.31; H, 7.61. Found: C, 61.26; H, 7.67.
Methyl (4R,5S,6S)-4-benzoyloxy-5,6-
(isopropylidenedioxy)-2,7-dioxoheptanoate (42)
Using the general procedure, compound 35 (0.33 g,
1.0 mmol) was converted to 42 (0.35 g, 97%, dark oil);
[a]2D5 = -72.6 (c 2.6, CHCl3). 1H NMR (400 MHz, CDCl3),
d: 1.25 (s, 6 H, 2 9 CH3), 3.36 (m, 2 H, 2 9 H-3), 3.84 (s, 3
H, OCH3), 4.55 (dd, 1 H, J6,7 = 1.4 Hz, J6,5 = 8.2 Hz, H-6),
4.77 (dd, 1 H, J5,4 = 2.0 Hz, J5,6 = 8.2 Hz, H-5), 5.35 (ddd,
1 H, J4,5 = 2.0 Hz, J4,3 = 5.5 Hz, J4,3 = 6.0 Hz, H-4),
7.40–7.45 (m, 2 H, Ph), 7.53–7.58 (m, 1 H, Ph), 7.97–8.07
(m, 2 H, Ph), 9.59 (d, 1 H, J7,6 = 1.4 Hz, H-7). 13C NMR
(100 MHz, CDCl3), d: 24.7 (CH3), 26.5 (C-6), 30.9 (CH3),
53.2 (OCH3), 66.3 (C-4), 78.8 (C-5), 80.1 (C-6), 111.0 (Cq),
128.5 (CHPh), 128.6 (CHPh), 129.7 (Ci), 130.1 (CHPh), 160.5
(C=OBz), 165.2 (C=O), 190.0 (C=O, C-7), 200.4 (C=O, C-2).
Anal. Calcd for C18H20O8: C, 59.34; H, 5.53. Found: C,
59.39; H, 5.59.
(2S,3S,4R)-7-[(tert-Butyldimethylsilyl)oxy]-2,3-
(isopropylidenedioxy)-1,6-dioxoheptan-4-yl acetate
(44)
Following the general procedure, compound 37 (0.36 g,
1.0 mmol) was converted to 44 (0.35 g, 89%, dark oil);
[a]2D7 = ?11.6 (c 1.8, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 0.05 (s, 3 H, CH3), 0.06 (s, 3 H, CH3), 0.88 (s, 9
H, 3 9 CH3), 1.34 (s, 3 H, CH3), 1.56 (s, 3 H, CH3), 1.98
(s, 3 H, CH3), 2.84 (dd, 1 H, J5,4 = 4.7 Hz, J5,5 = 17.5 Hz,
H-5), 3.02 (dd, 1 H, J5,4 = 8.3 Hz, J5,5 = 17.5 Hz, H-5),
4.14 (s, 2 H, H-7), 4.41 (dd, 1 H, J2,1 = 1.8 Hz,
(2S,3S,4R)-7-[(tert-Butyldimethylsilyl)oxy]-2,3-
(isopropylidenedioxy)-1,6-dioxoheptan-4-yl benzoate
(43)
J2,3 = 8.1 Hz, H-2), 4.67 (dd,
J3,2 = 8.1 Hz, H-3), 5.19 (ddd, 1 H, J4,3 = 2.2 Hz,
J4,5 = 4.7 Hz, J4,5 = 8.3 Hz, H-4), 9.60 (d, H,
1 H, J3,4 = 2.2 Hz,
Following the general procedure, compound 36 (0.42 g,
1.0 mmol) was transformed to 43 (0.18 g, 40%, dark oil);
[a]2D7 = -16.8 (c 1.8, CHCl3). 1H NMR (400 MHz,
CDCl3), d: 0.07 (s, 3 H, CH3), 0.09 (s, 3 H, CH3), 0.90 (s, 9
H, 3 9 CH3), 1.41 (s, 3 H, CH3), 1.70 (s, 3 H, CH3), 3.03
(dd, 1 H, J5,4 = 4.5 Hz, J5,5 = 17.6 Hz, H-5), 3.16 (dd, 1
H, J5,4 = 8.5 Hz, J5,5 = 17.6 Hz, H-5), 4.20 (s, 2 H, H-7),
1
J1,2 = 1.8 Hz, H-1). 13C NMR (100 MHz, CDCl3), d: -5.6
(2 9 CH3), 18.2 (Cq), 20.9 (CH3), 24.9 (CH3), 25.7
(3 9 CH3), 26.6 (CH3), 39.2 (C-5), 67.1 (C-4), 69.3 (C-7),
78.7 (C-3), 80.2 (C-2), 110.8 (Cq), 169.4 (C=O), 200.3 (C-
1), 207.9 (C-6). Anal. Calcd for C18H32O7Si: C, 55.64; H,
8.30. Found: C, 55.70; H, 8.39.
Scheme 1 Synthesis of 12–17. Reagents and conditions: (1)
methanol, HCl, 5 h, 60 °C, 88%; (2) isopropanol, H2SO4, 24 h,
85 °C, 90%; (3) butane-2,3-dione, DMAP, MeOH, reflux 40 h, 4,
67%, 5, 25%; (4) TBDMSCl, imidazole, DMF, 70 °C, 0.5 h, 6, 85%
from 2, 11, 81% from 5; (5) Ac2O, pyridine, DMAP, 7, 99%; vi)
benzyl bromide, Ag2O, CH2Cl2, 3.5 h, 8, 73%; (6) TBDPSCl,
imidazole, DMF, 0.5 h, 60 °C, 9, 92%; (7) benzoyl chloride, pyridine,
DMAP, 10, 84%; (8) K2OsO4.2H2O, NaIO4, CH2Cl2, rt, 24 h, 12,
99%, 13, 91%, 14, 75%, 15, 95%, 16, 96%, 17, 99%
123

Chem. Pap.
Scheme 2 Synthesis of 23–26. Reagents and conditions: (1) DIBAL-
H, CH2Cl2, 0 °C, 0.5 h, 18, 95%; (2) benzyl bromide, NaH, TBAI,
THF, 0 °C, 6 h, 19, 95%; (3) Ac2O, pyridine, DMAP, rt, 0.5 h, 20,
96%; (4) benzoyl chloride, pyridine, DMAP, rt, 1 h, 21, 98%; (5)
TBDMSCl, imidazole, DMF, 70 °C, 0.5 h, 98%; (6) K2OsO4.2H2O,
NaIO4, CH2Cl2, rt, 24 h, 23, decomposition, 24, 98%, 25, 93%, 26,
97%
With the aim to extend the spectrum of the final com-
pounds and to demonstrate the general utility of the oxi-
dation protocol, the shikimic acid derivative 6 was
subjected to DIBAl-H reduction to produce the allylic
alcohol 18 in 77% (Scheme 2). To continue the synthesis,
the primary hydroxyl group of 18 was successively blocked
to accomplish derivatives 19–22. Thus, its classical ben-
zylation (NaH, BnBr, DMF), acetylation (Ac2O, pyridine,
DMAP), benzoylation (BzCl, pyridine, DMAP) and sily-
lation (TBDMSCl, imidazole, DMF) afforded in very good
yields the required protected compounds 19 (95%), 20
(96%), 21 (98%) and 22 (98%), respectively (Scheme 2).
Then, the Lemieux–Johnson reaction conditions as
employed for the conversion of 7–11 to 12–17 were
applied to 19–22 to give the corresponding (2S,3S,4R)-
2,3,4,7-tetrahydroxy-6-oxoheptanals 24–26 in good yields.
Attempts to oxidize compounds 19–23, resulted in the
complete decomposition of the starting material. We also
tried the various temperatures to enhance the efficiency of
this key step; but the oxidation realized at room tempera-
ture was found to be the most optimal.
Results and discussion
The starting protected derivatives 6–11 were prepared from
(-)-shikimic acid (SA, 1) as shown in Scheme 1. First, we
pursued the conversion of 1 into methyl ester 2 (Liu et al.
2004) and isopropyl ester 3 by treatment of 1 with the
corresponding alcohols, in the presence of catalytic
amounts of sulfuric acid. Compounds 2 and 3 were used
without chromatographic purification. Small amounts of
crude 2 and 3 were flash-chromatographed through a short
column of silica gel (hexane/EtOAc, ur = 9:1) to provide
analytical samples.
Exposure of both 2 and 3 to butane-2,3-dione and
trimethyl orthoformate in the presence of DMAP in
DMF led to the protected derivatives 4 and 5 in 67% and
25% yields, respectively (Scheme 1). Protection of their
hydroxyl groups at C-3 position provided silyl ethers 6
(85%, Liu et al. 2004) and 11 (81%) employing tert-
butyldimethylsilyl chloride and imidazole in DMF. In
parallel, ester 4 was also converted into 3-O-protected
derivatives 7–10. As shown in Scheme 1, applying a
general procedure of acetylation with Ac2O in pyridine,
the desired acetate 7 was obtained in 99% yield. Treat-
ment of 4 with BnBr and Ag2O in DMF resulted in the
formation of 8 (73%). Silylation of 4 with TBDPSCl,
produced IX in 92% yield. Finally, the conversion of 4
into 10 (84%) was achieved with benzoyl chloride in
pyridine. With the protected shikimate esters 6–11 in
hand, our next task was to explore the oxidative ring-
opening conditions required for the creation of the target
functionalized keto-aldehydes 12–17. The Lemieux–
Johnson reaction was chosen as the efficient transfor-
mation for this purpose when esters 6–11 were exposed
to K2OsO4.2H2O and NaIO4 in a mixture of CH2Cl2/tert-
butanol/water (ur = 1:2:2) at room temperature, the
dicarbonyl compounds 12–17 (Scheme 1) were formed
in excellent yields (from 75 to 99%).
According to the similar sequence described in
Schemes 1 and 2, compounds 38–44 were also prepared
(Scheme 3), starting from the isopropylidene derivatives
27 and 28. The Lemieux–Johnson reaction of 31–37, which
was carried out under aforementioned conditions resulted
in the formation of the functionalized keto-aldehydes 38–
44 isolated in good yields.
Conclusions
We have shown that the Lemieux–Johnson oxidation can
be utilized for oxidative fragmentation of the carbon–car-
bon double bond of a range several shikimic acid deriva-
tives. Through this process, a small library of the
functionalized
(2S,3S,4R)-2,3,4,7-tetrahydroxy-6-
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Scheme 3 Synthesis of 38–44. Reagents and conditions: (1) DIBAH,
29, 87%; (2) TBDMSCl, Et3N, DMAP, CH2Cl2, XXXI, 96%; (3)
benzoyl chloride, DMAP, CH2Cl2, 34, 94%, 36, 90%; (4) acetyl
chloride, pyridine, DMAP, 31, 88%, 37, 72%; (5) benzoyl chloride,
pyridine, DMAP, CH2Cl2, 32, 97%; (6) K2OsO4.2H2O, NaIO4,
CH2Cl2, rt, 24 h
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Acknowledgements The present work was supported by the Grant
Agency (Grant No. 1/0398/14) of the Ministry of Education, Slovak
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