Stereoselective synthesis of fully substituted δ-lactone; the C1-C8 fragment of discodermolide

Article abstract of DOI:10.3987/com-02-s46

Baeyer-Villiger reaction of (2R,3S,4R)-4-tert-butyldimethyl-silyloxy-2-tert-butyl dimethylsilyloxymethyl-3-methylcyclopentanone (5) gave (4R, 5S, 6R)-4-tert-butyldimethylsilyloxy-6-tert-butyldimethylsilyloxymethyl- 5-methyltetrahydropyran-2-one (3) in 96%

Full text of DOI:10.3987/com-02-s46

HETEROCYCLES, Vol. 59, No. 1, 2003, pp. 347 - 358, Received, 1st August, 2002
STEREOSELECTIVE SYNTHESIS OF FULLY SUBSTITUTED
†
δ
-LACTONE; THE C1-C8 FRAGMENT OF DISCODERMOLIDE
Takayuki Yakura, Tomoko Kitano, Masazumi Ikeda, and Jun'ichi Uenishi*
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan.
E-mail: juenishi@mb.kyoto-phu.ac.jp
Abstract — Baeyer-Villiger reaction of (2R,3S,4R)-4-tert-butyldimethyl-
silyloxy-2-tert-butyldimethylsilyloxymethyl-3-methylcyclopentanone (5) gave
(4R,5S,6R)-4-tert-butyldimethylsilyloxy-6-tert-butyldimethylsilyloxymethyl-5-
methyltetrahydropyran-2-one (3) in 96% yield, which was transformed into the
C1-C8 fragment (2) of discodermolide via (3R,4S,5S,6S)-6-allyl-4-tert-butyl-
dimethylsilyloxy-3,5-dimethyltetrahydropyran-2-one (4).
Considerable attention has recently been directed toward the stereoselective synthesis of lactones, since
they are structural components of a large number of natural products and used as variable intermediates for
the total syntheses.1 Highly substituted stereo-defined δ-lactones are very important units in such natural
products. The antitumor marine natural product (+)-discodermolide,2-6 which was isolated from the deep-
water Caribbean sponge Discodermia dissoluta by Gunasekera and co-workers in 1990,2 contains fully
substituted δ-lactone and a polyhydroxylated acyclic portion. As a part of our interests in the
stereoselective syntheses of functionalized cyclic compounds,7 we reported a novel stereoselective
synthesis of an optically active cyclopentanone (1).8 Since 1 has three consecutive stereocenters on the
cyclopentanone ring, we envisioned that 1 would be converted into an aldehyde (2), which is the C1-C8
intermediate9 in the total synthesis of discodermolide reported by Smith and co-workers.4 We describe
here the synthesis of highly substituted δ-lactone (2) in a stereoselective manner. Our retrosynthetic plan
for 2 is shown in Scheme 1. The key steps include the Baeyer-Villiger reaction, stereoselective
methylation, and the Sharpless asymmetric dihydroxylation.
TBDMSO
CHO
8
HO
O
O
O
CO2Me
O
O
OH O
NH2
1
OH
discodermolide
O
TBDMSO
OTBDMS
2
OH
1
†
This paper is dedicated to Professor Yuichi Kanaoka on the occasion of his 75th birthday.

7
OTBDMS
Sharpless
dihydroxylation
O
O
Stereoselective
methylation
O
O
2
1
2
Baeyer-
Villiger
OTBDMS
OTBDMS
reaction
4
3
Scheme 1
The starting optically active cyclopentanone [(+)-1] was prepared from (R)-malic acid according to the
procedure of the antipode [(–)-1].8 The following three-step sequence from (+)-1 gave the Baeyer-Villiger
precursor (5) shown in Scheme 2: (i) reduction of 1 with lithium aluminum hydride (LAH), (ii) selective
silylation of the primary alcohol with TBDMSCl and triethylamine in the presence of 4-(N,N-
dimethylamino)pyridine (DMAP), and (iii) oxidation by a catalytic amount of tetrapropylammonium
perruthenate (TPAP) with N-methylmorpholine N-oxide (NMO). Because of the steric hindrance around
the carbonyl group, the Baeyer-Villiger reaction of the optically active cyclopentanone (5) was
considerably slow under standard conditions. This difficulty has been overcome by improved solvent-free
conditions.10 Thus, treatment of 5 with m-chloroperbenzoic acid (m-CPBA) in the presence of sodium
bicarbonate under solvent-free conditions using a dissolution and evaporation technique every 3 h
produced 3 in 96% yield (Scheme 2).
O
OTBDMS
a-c
d
(+)-1
3
TBDMSO
5
Scheme 2 Reagents and conditions: a) LAH, THF, rt (quant.); b) TBDMSCl, Et3N, DMAP,
CH2Cl2, rt (88%); c) TPAP, NMO, MS 4A, CH2Cl2, rt (99%); d) m-CPBA, NaHCO3, rt (96%)
I
OTBDMS
OT BDMS
Me
O
O
O
O
c
H
a, b
3
2
LiO
O
Me
OLi
OH
6
OH
TBDMSO
8
H
7
Scheme 3 Reagents and conditions: a) TsOH, MeCN, rt (88%); b) TBDMSCl, imidazole, DMF,
rt (95%); c) LDA, THF-HMPA, –78 °C, then MeI, –78 °C (82%)
The stereoselective introduction of a methyl group at the C-2 position of 3 was achieved by methylation of
dianion (7). Desilylation of both the TBDMS ethers of 3 followed by selective silylation of the primary
alcohol gave β-hydroxy lactone (6) in 84% yield in 2 steps. Treatment of 6 with 2 equivalents of lithium
diisopropylamide (LDA) in tetrahydrofuran (THF) and hexamethylphosphamide (HMPA) (5:1) at –78 °C

afforded dianion (7), which was trapped with methyl iodide to furnish 8 as a sole product in 82% yield,
while a similar reaction without HMPA gave 8 in only 56% yield along with 24% of unreacted 6.11 At this
stage, all substituents and their stereocenters of 8 on the δ-lactone ring are properly arranged for the C1-
C8 portion of 1. These stereochemistries were confirmed by NOESY experiments; positive NOE effects
were observed among 2-Me protons, H-3 proton, and H-4 proton, respectively. This high stereoselectivity
was rationalized in terms of the axial attack of methyl iodide to 7 (Scheme 3).
Next, a two-carbon extension and introduction of a chiral hydroxy center were performed by the following
chemical transformations. Silylation of the C-3 secondary hydroxyl group of 8 with TBDMSOTf and 2,6-
lutidine gave bisTBDMSoxylactone (9) in 88% yield. Selective desilylation12 of the primary TBDMS ether
was accomplished by the use of camphorsulfonic acid (CSA) in acetonitrile to give a primary alcohol (10).
Since an attempt to substitute the hydroxyl group by a vinyl group via its tosylate or triflate13 failed, we
turned our attention to the Wittig reaction for elongation of the side chain. Oxidation of 10 with Dess-
Martin periodinane gave the corresponding aldehyde, which was treated with triphenylphosphoranylidene
acetaldehyde without purification to give α,β-unsaturated aldehyde (11) in 73% yield in 2 steps. Catalytic
hydrogenations of 11 followed by sodium borohydride reduction afforded a primary alcohol (12) in 90%
yield, which was converted to terminal alkene (4) in two steps via seleno ether (13) by the standard
procedure14 (Scheme 4).
CHO
OH
R
O
O
O
O
O
O
c, d
a
e
8
OTBDMS
OTBDMS
OT BDMS
11
12
9: R=OTBDMS
10: R=OH
b
NO2
Se
g
O
O
f
4
OTBDMS
13
Scheme 4 Reagents and conditions: a) TBDMSOTf, 2,6-lutidine, CH2Cl2, –78 °C (88%); b) CSA,
MeCN, rt (90%); c) Dess-Martin periodinane, CH2Cl2, rt; d) Ph3P=CHCHO, benzene, rt (73% in 2
steps); e) H2, Pd-C, EtOAc, rt, then NaBH4, MeOH, rt (90%); f) o-NO2C6H4SeCN, n-Bu3P, THF, rt
(95%); g) 30% H2O2, THF, rt (84%)
The Sharpless asymmetric dihydroxylation15 of the allylic portion of 4 with AD-mix-α in tert-butanol-
water (1:1) at 0 °C for 2 days afforded diols in 90% yield as a 4.8:116 inseparable mixture of desired (7S)-
1
diol (14) and undesired (7R)-diol (15). The ratio of 14 and 15 was determined by a H-NMR spectrum
(see the experimental section). Oxidation with AD-mix-β gave a 1:1.7 mixture of 14 and 15. The
stereochemistries of 14 and 15 were assumed on the basis of the empirical rule for dihydroxylation of
terminal alkene with AD-mix.17 After conversion of a mixture of the diols to bistriethylsilyl(TES) ether, an

attempt at selective oxidation of primary TES ether to the corresponding aldehyde under Swern oxidation
conditions18 resulted in the formation of a mixture of the aldehyde and ketone. Therefore, the mixture of
14 and 15 was silylated with TBDMSCl to give a mixture of 16 and 17 in 95% yield, and then selective
desilylation12 of the bisTBDMS ether was examined. Desilylation of the mixture of 16 and 17 with
pyridinium p-toluenesulfonate (PPTS) in acetonitrile at room temperature for 12 h and successive careful
separation gave a primary alcohol (18) (30%) and its (7R)-isomer (19) (6%), a mixture of unreacted 16
and 17 (50%), and recovery of diols (5%).19 Finally, oxidation of 18 with Dess-Martin periodinane gave
aldehyde (2) in 72% yield. The aldehyde was identical with the spectroscopic data of an authentic sample
reported by Smith's group4 (Scheme 5).
HO
TBDMSO
OH
OT BDMS
7
7
a
O
O
O
O
b
4
+ (7R)-isomer 15
+ (7R)-isomer 17
OTBDMS
OTBDMS
(14 : 15 = 4.8 : 1)
14
16
TBDMSO
TBDMSO
OH
OH
O
O
O
O
c
d
2
OTBDMS
OTBDMS
18
19
Scheme 5 Reagents and conditions: a) AD-mix-α, tert-BuOH-H2O (1:1), 0 °C (90%); b) TBDMSCl,
imidazole, DMF, rt (95%); c) PPTS, MeCN, rt (30% for 18, 6% for 19, 50% for recovered 16 and 17,
5% for 14 and 15); d) Dess-Martin periodinane, CH2Cl2, rt (72%)
In conclusion, trisubstituted cyclopentanone (1) was converted to a C1-C8 fragment (2) of discodermolide
by ring expansion by the Baeyer-Villiger reaction, stereoselective methylation at the C-2 position, and
introduction of the C-7 chiral center by the Sharpless asymmetric dihydroxylation as key steps.
ACKNOWLEDGEMENT
The authors wish to thank Prof. Yoshihiko Ito for his helpful discussions.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded using a JASCO FT/IR-410 spectrophotometer.
1H-NMR spectra were determined with a Varian XL-400 (400 MHz) and JEOL JNM-AL 300 (300 MHz)
spectrometers using CDCl3 as a solvent and tetramethylsilane as an internal standard. 13C-NMR spectra
were determined with a Varian XL-400 (100 MHz) and JEOL JNM-AL 300 (75 MHz) spectrometers
using CDCl3 as a solvent and an internal standard. Specific rotations were recorded on a JASCO DIP-360
polarimeter. HRMS spectra (Exact FAB-MS) were obtained with a JEOL JMS-SX 102A instrument.
Column chromatography was carried out on Silica gel 60 (0.063-0.200 mm) (Merck).

( 2R, 3S, 4R)-4-tert-Butyldimethylsilyloxy-2-tert-butyldimethylsilyloxymethyl-3-methyl-
cyclopentanone (5). A solution of (+)-1 (500 mg, 1.75 mmol) [mp 62.0-63.0 °C (pentane), [α]D
24
+43.1 ° (c 1.00, CHCl3)]8 in THF (10 mL) was added to a suspension of LAH (199 mg, 5.24 mmol) in
THF (33 mL) at 0 °C under a nitrogen atmosphere. After the mixture was stirred at rt for 2 h, 5% aqueous
NaOH solution was added to it. The resulting mixture was dried (MgSO4) and concentrated to give 4-tert-
butyldimethylsilyloxy-2-hydroxymethyl-3-methylcyclopentanol, which was used without further
purification in the next step. A mixture of the crude diol, TBDMSCl (389 mg, 2.59 mmol), Et3N (209 mg,
2.07 mmol), and DMAP (21 mg, 0.17 mmol) in CH2Cl2 (12 mL) was stirred at rt overnight. The mixture
was diluted with Et2O and washed with saturated aqueous NH4Cl solution, dried (MgSO4), and
concentrated. The residue was chromatographed on silica gel (5% in EtOAc in hexane) to give 4-tert-
butyldimethylsilyloxy-2-tert-butyldimethylsilyloxymethyl-3-methylcyclopentanol (580 mg, 88% from 1)
as a colorless oil: 1H-NMR δ: 0.05 (3H, s), 0.07 (3H, s), 0.09 (3H, s), 0.10 (3H, s), 0.88 (9H, s), 0.90
(9H, s), 1.02 (3H, d, J = 6.8 Hz), 1.65-1.70 (1H, m), 1.70-1.85 (1H, m), 1.85-1.95 (2H, m), 2.94 (1H,
m), 3.52 (1H, dd, J = 9.9, 5.6 Hz), 3.78 (1H, dd, J = 9.9, 4.4 Hz), 3.99 (1H, br), 4.13 (1H, m). A
mixture of the cyclopentanol (570 mg, 1.52 mmol), TPAP (160 mg, 0.46 mmol), MS 4A (100 mg), and
NMO (445 mg, 3.80 mmol) in CH2Cl2 (20 mL) was stirred at rt for 2 h. The mixture was filtered through
short silica gel pad and the filtrate was concentrated. The residue was chromatographed on silica gel (10%
24
EtOAc in hexane) to give 5 (561 mg, 99%) as colorless crystals: mp <30 °C (hexane). [α]D +31.7 °(c =
1
1.06, CHCl3). IR (neat) cm–1: 1750. H-NMR (300 MHz) δ: 0.01 (3H, s), 0.03 (3H, s), 0.04 (3H, s),
0.07 (3H, s), 0.84 (9H, s), 0.86 (9H, s), 1.11 (3H, d, J = 6.8 Hz), 1.94-2.02 (1H, m), 2.23-2.27 (2H,
m), 2.31-2.42 (1H, m), 3.63 (1H, dd, J = 10.1, 3.1 Hz), 4.02 (1H, dd, J = 10.1, 3.1 Hz), 4.29-4.34
(1H, m). 13C-NMR (75 MHz) δ: –5.6 (2), –5.0, –4.7, 13.8, 18.1, 18.2, 25.7 (3), 25.8 (3), 38.5, 49.8,
54.2, 59.5, 71.5, 218.0. Exact FAB-MS m/z: 373.2600, Calcd for C19H41O3Si2: 373.2594.
( 4R, 5S, 6R)-4-tert-Butyldimethylsilyloxy-6-tert-butyldimethylsilyloxymethyl-5-methyl-
tetrahydropyran-2-one (3). To a solution of 5 (3.0 g, 8.05 mmol) and m-CPBA (2.8 g, 16.1 mmol)
in CH2Cl2 (3 mL) was added NaHCO3 (676 mg, 8.05 mmol) and then the suspension was concentrated
under reduced pressure to give a solid residue. After 3 h, a small amount of CH2Cl2 was added to the
mixture and the solvent was removed. This process (a dissolution and evaporation) was repeated twice
every 3 h. After 10 h, EtOAc was added to the reaction mixture. The mixture was washed with saturated
aqueous Na2S2O3 solution, saturated aqueous NaHCO3 solution, and brine, dried (MgSO4), and
concentrated. The residue was chromatographed on silica gel (10% EtOAc in hexane) to give 3 (3.0 g,
96%) as a white solid, mp 84-85 °C (hexane). [α]D26 –6.6 °(c = 1.01, CHCl3). IR (KBr) cm–1: 1727. H-
1
NMR (300 MHz) δ: 0.06 (3H, s), 0.07 (6H, s), 0.08 (3H, s), 0.88 (18H, s), 1.01 (3H, d, J = 6.8 Hz),
2.08-2.11 (1H, m), 2.54 (1H, dd, J = 17.5, 3.1 Hz), 2.62 (1H, dd, J = 17.5, 3.1 Hz), 3.74 (1H, dd, J =
11.9, 2.4 Hz), 3.91 (1H, dd, J = 11.9, 2.2 Hz), 4.05 (1H, dd, J = 5.0, 3.1 Hz), 4.31 (1H, dt, J = 10.1,
13
2.2 Hz). C-NMR (75 MHz) δ: –5.5, –5.3, –4.9, –4.5, 13.9, 18.0, 18.3, 25.7 (3), 25.8 (3), 33.3, 39.9,
62.8, 68.8, 81.8, 170.1. Exact FAB-MS m/z: 389.2536, Calcd for C19H41O4Si2: 389.2543. Anal. Calcd
for C19H40O4Si2: C, 58.71; H, 10.37. Found: C, 58.49; H, 10.31.

(4R, 5R, 6R)-4-Hydroxy-6-hydroxymethyl-5-methyltetrahydropyran-2-one. A mixture of
3 (669 mg, 1.72 mmol) and TsOH·H2O (646 mg, 3.40 mmol) in MeCN (5 mL) was stirred at rt for 3 h,
then powdered NaHCO3 (314 mg, 3.73 mmol) was added. The mixture was concentrated, and the residue
was chromatographed on silica gel (EtOAc) to give (4R,5R,6R)-4-hydroxy-6-hydroxymethyl-5-methyl-
tetrahydropyran-2-one (242 mg, 88%) as colorless crystals: mp 109.5-110 °C (EtOAc-hexane). IR (KBr)
1
cm–1: 3420, 1685. H-NMR (300 MHz) δ: 1.11 (3H, d, J = 7.6 Hz), 2.02-2.18 (3H, m), 2.69 (1H, dd, J
= 18.1, 3.8 Hz), 2.77 (1H, dd, J = 18.1, 2.7 Hz), 3.70 (1H, ddd, J = 12.3, 7.9, 4.0 Hz), 3.96 (1H, ddd,
J = 12.3, 6.0, 3.0 Hz), 4.10-4.16 (1H, br), 4.47 (1H, dt, J = 10.5, 3.0 Hz). 13C-NMR δ: 13.4, 32.7,
39.4, 62.6, 68.0, 81.2, 169.8. Exact FAB-MS m/z: 161.0818, Calcd for C7H13O4: 161.0814. Anal.
Calcd for C7H12O4: C, 52.49; H, 7.55. Found: C, 52.44; H, 7.63.
(4R, 5R, 6R)-6-tert-Butyldimethylsilyloxy-4-hydroxy-5-methyltetrahydropyran-2-one (6).
A mixture of (4R,5R,6R)-4-hydroxy-6-hydroxymethyl-5-methyltetrahydropyran-2-one (460 mg, 2.87
mmol), TBDMSCl (433 mg, 2.87 mmol), and imidazole (293 mg, 4.31 mmol) in DMF (30 mL) was
stirred at rt overnight. The mixture was poured into H2O and the mixture was extracted with Et2O. The
combined extracts were washed with brine, dried (MgSO4), and concentrated. The residue was
chromatographed on silica gel (50% EtOAc in hexane) to give 6 (750 mg, 95%) as colorless crystals: mp
25
1
74.5-75.5 °C (hexane). [α]D +6.6 ° (c = 1.45, CHCl3). IR (KBr) cm–1: 3444, 1717. H-NMR (300
MHz) δ: 0.06 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.09 (3H, d, J = 6.6 Hz), 2.11-2.25 (1H, m), 2.60
(1H, dd, J = 17.8, 3.7 Hz), 2.62 (1H, br s), 2.71 (1H, dd, J = 17.6, 3.0 Hz), 3.75 (1H, dd, J = 11.7,
2.6 Hz), 3.92 (1H, dd, J = 11.7, 2.2 Hz), 4.10 (1H, br s), 4.36 (1H, dt, J = 10.3, 2.4 Hz). 13C-NMR
(75 MHz) δ: –5.5, –5.3, 13.4, 18.3, 25.8 (3), 32.6, 39.4, 62.8, 67.9, 81.5, 170.3. Exact FAB-MS m/z:
275.1674, Calcd for C13H27O4Si: 275.1678. Anal. Calcd for C13H26O4Si: C, 56.90; H, 9.55. Found: C,
56.62; H, 9.49.
( 3R, 4S, 5R, 6R)-6-tert-Butyldimethylsilyloxymethyl-4-hydroxy-3,5-dimethyltetrahydro-
pyran-2-one (8). A solution of 6 (350 mg, 1.28 mmol) in THF-HMPA (5:1, 4 mL) was added to a
solution of LDA in THF-HMPA (5:1, 20 mL), prepared from diisopropylamine (671 mg, 6.63 mmol) and
butyllithium (1.6 M in hexane, 4.11 mL, 6.38 mmol), at –78 °C under a nitrogen atmosphere and the
mixture was stirred for 1 h. Then MeI (1.81 g, 12.75 mmol) was added to the solution of the dianion at
the same temperature. The whole mixture was stirred for 1 h, and then saturated aqueous NH4Cl
solution was added at the same temperature. After the mixture was warmed to rt, it was diluted with Et2O
and washed with H2O and brine, dried (MgSO4), and concentrated. The residue was chromatographed on
silica gel (30% EtOAc in hexane) to give 8 (303 mg, 82%) as colorless crystals: mp 93.5-94.5 °C (EtOAc-
hexane). [α]D25 +5.5 °(c = 0.75, CHCl3). IR (KBr) cm–1: 3853, 1697. H-NMR (300 MHz) δ: 0.07 (3H,
1
s), 0.08 (3H, s), 0.89 (9H, s), 1.09 (3H, d, J = 7.0 Hz), 1.31 (3H, d, J = 7.3 Hz), 1.73 (1H, br), 2.37
(1H, dqd, J = 9.9, 7.0, 3.0 Hz), 2.69 (1H, qd, J = 7.3, 3.0 Hz), 3.75 (1H, dd, J = 11.7, 2.5 Hz), 3.81
(1H, t, J = 3.0 Ηz), 3.91 (1Η, dd, J = 11.7, 2.5 Hz), 4.30 (1H, dt, J = 9.9, 2.5 Hz). 13C-NMR (75
MHz) δ: –5.9, –5.3, 12.8, 15.8, 18.3, 25.8 (3), 29.4, 43.4, 62.8, 73.5, 81.2, 173.8. Exact FAB-MS

m/z: 289.1841, Calcd for C14H29O4Si: 289.1835. Anal. Calcd for C14H28O4Si: C, 58.29; H, 9.78. Found:
C, 58.37; H, 9.92.
( 3R, 4S, 5S, 6R)-4-tert-Butyldimethylsilyloxy-6-tert-butyldimethylsilyloxymethyl-3,5-di-
methyltetrahydropyran-2-one (9). A mixture of 8 (100 mg, 0.35 mmol), 2,6-lutidine (89 mg, 0.83
mmol), and TBDMSOTf (183 mg, 0.69 mmol) in CH2Cl2 (5 mL) was stirred at –78 °C for 1 h. Then H2O
was added to the mixture at the same temperature and allowed to warm to rt. The aqueous layer was
extracted with Et2O and the combined organic layers were washed with H2O and brine, dried (MgSO4),
and concentrated. The residue was chromatographed on silica gel (20% EtOAc in hexane) to give 9 (123
mg, 88%) as colorless crystals: mp 70.5-71 °C (hexane). [α]D25 +8.8 °(c = 1.10, CHCl3). IR (KBr) cm-1:
1
1722. H-NMR (300 MHz) δ: 0.02 (3H, s), 0.04 (3H, s), 0.07 (3H, s), 0.08 (3H, s), 0.88 (9H, s), 0.89
(9H, s), 1.01 (3H, d, J = 6.9 Hz), 1.26 (3H, d, J = 7.5 Hz), 2.35 (1H, dqd, J = 9.7, 6.6, 2.8 Hz), 2.64
(1H, qd, J = 7.5, 2.8 Hz), 3.72 (1H, t, J = 2.8 Hz), 3.73 (1H, dd, J = 11.7, 2.2 Hz), 3.90 (1H, dd, J =
13
11.7, 2.2 Hz), 4.27 (1H, dt, J = 9.7, 2.2 Hz). C-NMR (75 MHz) δ: –5.6, –5.3, –4.9, –4.5, 13.6, 16.0,
17.9, 18.2, 25.7 (3), 25.8 (3), 28.9, 43.9, 62.7, 74.4, 81.7, 174.0. Exact FAB-MS m/z: 403.2694,
Calcd for C20H43O4Si2: 403.2700. Anal. Calcd for C20H42O4Si2: C, 59.65; H, 10.51. Found: C, 59.31; H,
10.48.
( 3R, 4S, 5S, 6R)-4-tert-Butyldimethylsilyloxy-6-hydroxymethyl-3,5-dimethyltetrahydro-
pyran-2-one (10). A mixture of 9 (243 mg, 0.60 mmol) and CSA (140 mg, 0.60 mmol) in MeCN (8
mL) was stirred at rt overnight, then powdered NaHCO3 (50 mg, 0.60 mmol) was added. The mixture
was concentrated, the residue was chromatographed on silica gel (50% EtOAc in hexane) to give 10 (157
25
mg, 90%) as colorless crystals: mp 87.5-88.5 °C (hexane). [α]D +2.0 ° (c = 0.85, CHCl3). IR (KBr)
1
cm–1: 3175, 1725. H-NMR (300 MHz) δ: 0.08 (3H, s), 0.09 (3H, s), 0.89 (9H, s), 1.02 (3H, d, J = 6.6
Hz), 1.29 (3H, d, J = 7.7 Hz), 1.98-2.16 (1H, br), 2.22 (1H, dqd, J = 10.5, 6.6, 2.6 Hz), 2.68 (1H, qd,
J = 7.7, 2.6 Hz), 3.68 (1H, dd, J = 12.8, 4.0 Hz), 3.70 (1H, t, J = 2.6 Hz), 3.92 (1H, dd, J = 12.8, 2.6
13
Hz), 4.39 (1H, ddd, J = 10.5, 4.0, 2.6 Hz). C-NMR (75 MHz) δ: –4.8, –4.5, 13.7, 16.3, 17.9, 25.7
(3), 29.3, 44.2, 62.6, 74.5, 81.7, 174.1. Exact FAB-MS m/z: 289.1829, Calcd for C14H29O4Si:
289.1835. Anal. Calcd for C14H28O4Si: C, 58.29; H, 9.78. Found: C, 58.06; H, 10.06.
3-[(2S, 3S, 4S, 5R)-4-tert-Butyldimethylsilyloxy-3,5-dimethyl-6-oxotetrahydropyran-2-
yl]-(E)-propenal (11). A mixture of 10 (380 mg, 1.32 mmol) and Dess-Martin periodinane (559 mg,
2.64 mmol) in CH2Cl2 (13 mL) was stirred at rt overnight. The mixture was diluted with EtOAc (25 mL),
washed with 10% aqueous NaHSO3 solution, saturated aqueous NaHCO3 solution, H2O, and brine, dried
(MgSO4) and concentrated to give crude 4-tert-butyldimethylsilyloxy-3,5-dimethyl-6-oxotetrahydropyran-
2-carbaldehyde (500 mg), which was used without further purification in the next step. A mixture of the
crude aldehyde (500 mg) and Ph3P=CHCHO (401 mg, 1.32 mmol) in benzene (13 mL) was stirred at rt.
After 3 h, the mixture was concentrated and the residue was chromatographed on silica gel (20% EtOAc in
1
hexane) to give 11 (301 mg, 73% from 10) as a pale yellow oil: IR (neat) cm–1: 1741, 1697. H-NMR

(300 MHz) δ: 0.09 (3H, s), 0.10 (3H, s), 0.90 (9H, s), 1.07 (3H, d, J = 6.6 Hz), 1.30 (3H, d, J = 7.7
Hz), 2.03 (1H, dqd, J = 10.0, 6.6, 2.5 Hz), 2.73 (1H, qd, J = 7.7, 2.5 Hz), 3.73 (1H, t, J = 2.5 Hz),
5.04 (1H, br dd, J = 10.0, 5.5 Hz), 6.40 (1H, ddd, J = 15.8, 7.5, 1.1 Hz), 6.78 (1H, dd, J = 15.8, 5.5
Hz), 9.62 (1H, d, J = 7.5 Hz). 13C-NMR (75 MHz) δ: –4.8, –4.5, 13.5, 16.3, 18.0, 25.7 (3), 34.3,
44.0, 74.0, 79.1, 133.0, 151.2, 172.5, 192.5. Exact FAB-MS m/z: 335.1650, Calcd for C16H28O4NaSi:
335.1654.
( 3R, 4S, 5S, 6S)-4-tert-Butyldimethylsilyloxy-6-(3-hydroxypropyl)-3,5-dimethyltetra-
hydropyran-2-one (12). A mixture of 11 (62 mg, 0.20 mmol) and 10% Pd-C (10 mg) in EtOAc (2
mL) was stirred under H2 (1 atm) at rt for 1 h. The mixture was diluted with EtOAc (20 mL), and the
catalyst was filtered off. The filtrate was concentrated to give crude 3-(4-tert-butyldimethylsilyloxy-3,5-
dimethyl-6-oxotetrahydropyran-2-yl)propanal (66 mg), which was used without further purification in the
next step. A mixture of the crude aldehyde (66 mg) and NaBH4 (7.5 mg, 0.20 mmol) in MeOH (2 mL)
was stirred at rt. After 2 h, the mixture was diluted with Et2O, washed with H2O and brine, dried (MgSO4),
and concentrated. The residue was chromatographed on silica gel (20% EtOAc in hexane) to give 12 (57
mg, 90% from 11) as a colorless oil: [α]D24 –15.8 ° (c = 0.85, CHCl3). IR (neat) cm-1: 3438, 1730. H-
1
NMR (300 MHz) δ: 0.07 (3H, s), 0.08 (3H, s), 0.89 (9H, s), 1.00 (3H, d, J = 7.0 Hz), 1.27 (3H, d, J =
7.7 Hz), 1.55-1.98 (6H, m), 2.65 (1H, qd, J = 7.3, 2.9 Hz), 3.64-3.74 (3H, m), 4.33-4.41 (1H, m).
13C-NMR (75 MHz) δ: –4.8, –4.5, 13.9, 16.3, 18.0, 25.7 (3), 27.8, 29.6, 33.7, 43.9, 62.6, 74.4, 80.6,
174.2. Exact FAB-MS m/z: 317.2140, Calcd for C16H33O4Si: 317.2148.
( 3R, 4S, 5S, 6S)-4-tert-Butyldimethylsilyloxy-3,5-dimethyl-6-[3-(2-nitrophenylseleno)-
propyl]tetrahydropyran-2-one (13). A mixture of 12 (120 mg, 0.38 mmol), o-nitrophenylcyano
selenide (138 mg, 0.61 mmol), and tributylphosphine (123 mg, 0.61 mmol) in THF (4 mL) was stirred at
rt. After 3 h, the mixture was concentrated, the residue was chromatographed on silica gel (50% EtOAc in
1
hexane) to give 13 (180 mg, 95%) as a pale yellow oil: IR (neat) cm–1: 1734, 1514. H-NMR (300 MHz)
δ: 0.07 (3H, s), 0.08 (3H, s), 0.88 (9H, s), 0.99 (3H, d, J = 7.0 Hz), 1.26 (3Η, δ, J = 7.7 Hz), 1.65-
2.16 (5H, m), 2.65 (1H, qd, J = 7.7, 2.5 Hz), 2.90-3.05 (2H, m), 3.66 (1H, t, J = 2.5 Hz), 4.38 (1H,
ddd, J = 10.8, 8.2, 2.5 Hz), 7.28-7.37 (1H, m), 7.53-7.58 (2H, m), 8.29 (1H, d, J = 8.4 Hz). 13C-
NMR (75 MHz) δ: –4.8, –4.5, 14.0, 16.4, 17.9, 23.6, 25.7 (3), 25.8, 33.4, 33.7, 44.0, 74.5, 80.0,
125.4 (2), 126.5, 129.0, 133.3, 133.7, 174.0. Exact FAB-MS m/z: 502.1518, Calcd for
C22H36O5NSeSi: 502.1528.
( 3R, 4S, 5S, 6S)-6-Allyl-4-tert-butyldimethylsilyloxy-3,5-dimethyltetrahydropyran-2-one
(4). A 30% aqueous solution of hydrogen peroxide (0.5 mL, 4.4 mmol) was added to a solution of 13
(180 mg, 0.36 mmol) in THF (4 mL) at rt and the mixture was stirred for 3 h. Then the mixture was
diluted with Et2O and washed with 5% aqueous Na2CO3 solution and brine, dried (MgSO4), and
concentrated. The residue was chromatographed on silica gel (20% EtOAc in hexane) to give 4 (90 mg,
23
23
84%) as colorless crystals: mp 63-64.5 °C (hexane). [α]D +14.5 ° (c = 0.95, CHCl3). [lit.,4 [α]D

1
+14.2 °(c = 0.12, CHCl3)]. IR (KBr) cm–1: 2925, 1720, 1463, 1086, 832. H-NMR (300 MHz) δ: 0.06
(3H, s), 0.08 (3H, s), 0.89 (9H, s), 0.98 (3H, d, J = 6.9 Hz), 1.25 (3H, d, J = 7.6 Hz), 1.95 (1H, dqd,
J = 9.9, 6.9, 2.3 Hz), 2.23-2.36 (1H, m), 2.51-2.63 (1H, m), 2.64 (1H, qd, J = 7.6, 3.0 Hz), 3.65 (1H,
t, J = 2.5 Hz), 4.41 (1H, ddd, J = 9.9, 5.6, 4.3 Hz), 5.16-5.21 (2H, m), 5.88 (1H, dddd, J = 17.5, 9.8,
7.9, 6.3 Hz). 13C-NMR (75 MHz) δ: –4.8, –4.5, 13.6, 16.3, 17.9, 25.7 (3), 32.4, 37.0, 43.9, 74.5,
80.1, 118.6, 132.6, 174.1. Exact FAB-MS m/z: 299.2035, Calcd for C16H31O3Si: 299.2042. Anal. Calcd
for C16H30O3Si: C, 64.38; H, 10.13. Found: C, 64.27; H, 9.98.
( 3R, 4S, 5S, 6S)-4-tert-Butyldimethylsilyloxy-6-[(2S)-2,3-dihydroxypropyl]-3,5-di-
methyltetrahydropyran-2-one (14) and (3R, 4S, 5S, 6S)-4-tert-Butyldimethylsilyloxy-6-
[(2R)-2, 3-dihydroxypropyl]-3, 5-dimethyltetrahydropyran-2-one (15). A mixture of 4 (90
mg, 0.3 mmol) and AD-mix-α (422 mg) in t-BuOH-H2O (1:1, 1. 5 mL) was stirred at rt. After 15 min, the
mixture was cooled to 0 °C and stirred at the same temperature for 2 days. Then Na2SO3 (1.2 g) was added
to the reaction mixture. The whole mixture was allowed to warm to rt and stirred for further 20 min. The
mixture was diluted with EtOAc, washed with H2O and brine, and concentrated, the residue was
chromatographed on silica gel (50% EtOAc in hexane) to give a 4.8:1 mixture of 14 and 15 (90 mg, 90%)
1
as a colorless oil: IR (neat) cm–1: 3410, 1714. H-NMR (400 MHz) for the major isomer δ: 0.07 (3H, s),
0.08 (3H, s), 0.89 (9H, s), 1.01 (3H, d, J = 6.8 Hz), 1.27 (3H, d, J = 7.7 Hz), 1.58 (1H, ddd, J = 14.5,
10.5, 2.8 Hz), 1.79-1.96 (2H, m), 2.62-2.70 (1H, br), 2.66 (1H, qd, J = 7.6, 3.2 Hz), 3.00 (1H, br s),
3.45-3.56 (1H, m), 3.65-3.72 (2H, m), 4.08-4.15 (1H, m), 4.60 (1H, td, J = 10.2, 2.0 Hz). Selected
signals for the minor isomer δ: 1.28 (3H, d, J = 7.5 Hz), 4.01-4.08 (1H, m), 4.50 (1H, td, J = 9.4, 3.1
Hz). The ratio of stereoisomers (14 and 15) was estimated from the integrated intensity of peak heights of
the signals due to the 6-protons at δ 4.60 (td) and 4.50 (td), respectively. 13C-NMR (100 MHz) for the
major isomer δ: –4.7, –4.5, 13.9, 16.2, 18.0, 25.7 (3), 34.6, 37.0, 43.8, 66.9, 67.9, 74.2, 78.0, 174.2.
Exact FAB-MS m/z: 333.2094, Calcd for C16H33O5Si: 333.2097.
( 3R, 4S, 5S, 6S)-6-[(2S)-2,3-Bis-tert-butyldimethylsilyloxypropyl]-4-tert-butyldimethyl-
silyloxy-3, 5-dimethyltetrahydropyran-2-one (16) and (3R, 4S, 5S, 6S)-6-[(2R)-2, 3-Bis-
tert-butyldimethylsilyloxypropyl]-4-tert-butyldimethylsilyloxy-3,5-dimethyltetrahydro-
pyran-2-one (17). A mixture of 14 and 15 (90 mg, 0.27 mmol), TBDMSCl (122 mg, 0.81 mmol),
and imidazole (66 mg, 0.97 mmol) in DMF (2.5 mL) was stirred at rt overnight. The mixture was poured
into H2O and the mixture was extracted with Et2O. The extract was washed with brine, dried (MgSO4),
and concentrated. The residue was chromatographed on silica gel (5% EtOAc in hexane) to give a mixture
1
of 16 and 17 (144 mg, 95%) as a colorless oil: IR (neat) cm–1: 1737. H-NMR (400 MHz) for the major
isomer δ: 0.039 (3H, s), 0.042 (3H, s), 0.06 (3H, s), 0.07 (3H, s), 0.08 (3H, s), 0.09 (3H, s), 0.86
(9H, s), 0.88 (18H, s), 0.98 (3H, d, J = 6.8 Hz), 1.26 (3H, d, J = 7.7 Hz), 1.59-1.75 (2H, m), 1.80-
1.91 (1H, m), 2.63 (1H, qd, J = 7.7, 2.9 Hz), 3.39 (1H, dd, J = 10.0, 6.3 Hz), 3.57 (1H, dd, J = 10.0,
4.9 Hz), 3.66 (1H, t, J = 2.7 Hz), 4.02-4.09 (1H, m), 4.51 (1H, td, J = 10.4, 2.0 Hz). 13C-NMR (100
MHz) for the major isomer δ: –5.4, –5.3, –4.85, –4.83, –4.6, –4.2, 14.0, 16.4, 17.9, 18.0, 18.4, 25.7

(3), 25.9 (3), 26.0 (3), 34.6, 38.8, 43.9, 67.9, 68.4, 74.6, 77.1, 173.8. Exact FAB-MS m/z: 561.3822,
Calcd for C28H61O5Si3: 561.3827.
( 3R, 4S, 5S, 6S)-4-tert-Butyldimethylsilyloxy-6-[(2S)-2-tert-butyldimethylsilyloxy-3-
hydroxypropyl]-3, 5-dimethyltetrahydropyran-2-one (18) and (3R, 4S, 5S, 6S)-4-tert-
Butyldimethylsilyloxy-6-[(2R)-2-tert-butyldimethylsilyloxy-3-hydroxypropyl]-3,5-di-
methyltetrahydropyran-2-one (19). A mixture of 16 and 17 (140 mg, 0.25 mmol) and PPTS (63
mg, 0.25 mmol) in MeCN (3 mL) was stirred at rt overnight. Then the mixture was diluted with Et2O,
washed with H2O and brine, dried (MgSO4), and concentrated. The residue was chromatographed on
silica gel (5% EtOAc in hexane). The first fraction gave a mixture of 16 and 17 (70 mg, 50%). The
1
second fraction gave 19 (7 mg, 6%) as a colorless oil: IR (neat) cm–1: 3434, 1725. H-NMR (400 MHz)
δ: 0.06 (3H, s), 0.08 (3H, s), 0.09 (3H, s), 0.10 (3H, s), 0.89 (9H, s), 0.90 (9H, s), 1.00 (3H, d, J =
6.8 Hz), 1.27 (3H, d, J = 7.7 Hz), 1.59 (1H, br s), 1.71 (1H, ddd, J = 14.5, 10.3, 3.7 Hz), 1.88 (1H,
dqd, J = 9.9, 6.8, 2.4 Hz), 2.00 (1H, ddd, J = 14.5, 8.7, 2.1 Hz), 2.65 (1H, qd, J = 7.7, 3.1 Hz), 3.58
(1H, dd, J = 11.8, 4.1 Hz), 3.63-3.69 (1H, m), 3.66 (1H, t, J = 2.7 Hz), 4.12 (1H, dq, J = 8.6, 3.8 Hz),
13
4.42 (1H, td, J = 10.2, 2.0 Hz). C-NMR (100 MHz) δ: –4.8, –4.7, –4.6, –4.5, 14.0, 16.3, 18.0, 21.4,
25.7 (3), 25.8 (3), 34.5, 37.5, 43.9, 64.8, 69.1, 74.3, 77.8, 173.7. The third fraction gave 18 (33 mg,
1
30%) as a colorless oil: IR (neat) cm–1: 3451, 1732. H-NMR (400 MHz) δ: 0.07 (3H, s), 0.08 (3H, s),
0.115 (3H, s), 0.118 (3H, s), 0.89 (9H, s), 0.90 (9H, s), 1.00 (3H, d, J = 6.8 Hz), 1.27 (3H, d, J = 7.7
Hz), 1.54 (1H, ddd, J = 14.3, 11.2, 2.2 Hz), 1.80-1.85 (1H, br), 1.86 (1H, dqd, J = 10.3, 6.8, 2.2 Hz),
1.98 (1H, ddd, J = 14.3, 10.3, 1.6 Hz), 2.65 (1H, qd, J = 7.7, 2.7 Hz), 3.42-3.49 (1H, m), 3.63-3.69
13
(1H, m), 3.66 (1H, t, J = 2.5 Hz), 4.14-4.20 (1H, m), 4.46 (1H, td, J = 10.7, 1.6 Hz). C-NMR (100
MHz) δ: –4.9, –4.8, –4.54, –4.51, 14.1, 16.5, 17.9 (2), 25.7 (3), 25.8 (3), 34.4, 38.3, 44.1, 67.0,
68.0, 74.7, 77.4, 173.7. Exact FAB-MS m/z: 447.2957, Calcd for C22H47O5Si2: 447.2962. The fourth
fraction gave a mixture of 1 4 and 1 5 (4 mg, 5%)
( 2S)-2-tert-Butyldimethylsilyloxy-3-[(2S, 3S, 4S, 5R)-4-tert-butyldimethylsilyloxy-3,5-
dimethyl-6-oxotetrahydropyran-2-yl]propanal (2). A mixture of 18 (14 mg, 0.03 mmol) and
Dess-Martin periodinane (27 mg, 0.06 mmol) in CH2Cl2 (0.3 mL) was stirred at rt overnight. The mixture
was diluted with Et2O (25 mL), washed with 10% aqueous NaHSO3 solution, saturated aqueous NaHCO3
solution, H2O, and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel
(5% EtOAc in hexane) to give a mixture of 2 (10 mg, 72%) as a white solid: mp 57-59.5 °C (hexane).
23
[lit.,4 mp 58-60 °C (hexane)]. [α]D26 –57.1 °(c = 0.48, CHCl3). [lit.,4 [α]D –55.5 °(c = 1.46, CHCl3)].
1
IR (neat) cm–1: 1738. H-NMR (400 MHz) δ: 0.07 (3H, s), 0.09 (3H, s), 0.11 (3H, s), 0.13 (3H, s),
0.89 (9H, s), 0.92 (9H, s), 0.99 (3H, d, J = 6.6 Hz), 1.28 (3H, d, J = 7.7 Hz), 1.78 (1H, ddd, J = 14.1,
10.5, 2.3 Hz), 1.87 (1H, ddd, J = 14.1, 10.5, 2.6 Hz), 1.92 (1H, dqd, J = 10.5, 6.6, 2.5 Hz), 2.66 (1H,
qd, J = 7.7, 2.5 Hz), 3.67 (1H, t, J = 2.5 Hz), 4.46 (1H, ddd, J = 10.1, 2.6, 0.7 Hz), 4.53 (1H, td, J =
13
10.6, 2.3 Hz), 9.67 (1H, d, J = 0.7 Hz). C-NMR (100 MHz) δ: –5.2, –4.9, –4.6, –4.5, 14.0, 16.5,
17.9, 18.1, 25.67 (3), 25.73 (3), 34.1, 36.1, 44.2, 73.6, 74.6, 76.0, 173.2, 203.4. Exact FAB-MS m/z:

445.2802, Calcd for C22H45O5Si2: 445.2806. These data were identical to those reported for an authentic
sample.4
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THF without HMPA.6
12. T. D. Nelson and R. D. Crouch, Synthesis, 1996, 1031.
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16. Smith and co-workers reported that attempts of dihydroxylation of 4 led, at best, a 3:1 mixture of
diols.4
17. Eventually, the stereochemistry of the isomer (14) was confirmed after the conversion to the known
aldehyde (2).
18. A. Rodríguez, M. Nomen, B. W. Spur, and J. J. Godfroid, Tetrahedron Lett., 1999, 4 0, 5161.
19. A longer reaction time and use of CSA or TsOH instead of PPTS led to increase the yield of diols
(1 4 and 1 5).