Synthesis of highly substituted tetrahydropyrans: Preparation of the C20-C28 moiety of phorboxazoles

Article abstract of DOI:10.1016/j.tet.2003.08.056

A propionate-derived polyketide building block A whose 2-methyl-1,3-diol moiety was built by a Ti(III)-mediated ring opening reaction of a trisubstituted 2,3-epoxy alcohol precursor was employed as a common starting material for the syntheses of highly su

Full text of DOI:10.1016/j.tet.2003.08.056

Tetrahedron 59 (2003) 8613–8622
Synthesis of highly substituted tetrahydropyrans: preparation
of the C20–C28 moiety of phorboxazoles
*
Tushar K. Chakraborty, V. Ramakrishna Reddy and T. Jagadeshwar Reddy
Bioorganic Laboratory, Organic Division-III, Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500 007, India
Received 21 May 2003; revised 7 August 2003; accepted 29 August 2003
Abstract—A propionate-derived polyketide building block A whose 2-methyl-1,3-diol moiety was built by a Ti(III)-mediated ring opening
reaction of a trisubstituted 2,3-epoxy alcohol precursor was employed as a common starting material for the syntheses of highly substituted
tetrahydropyrans 1–5, the first one being the C20–C28 fragment of cytotoxic natural products, phorboxazoles.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
cyclic components.2 In this paper, we describe a new
strategy for the synthesis of highly substituted tetrahydro-
2H-pyrans3 1–5 starting from a common intermediate A, a
propionate-derived polyketide unit. Compound 1 constitutes
the C20–C28 moiety of phorboxazoles,4 the most cytotoxic
natural products that have attracted wide attention of
synthetic chemists.5
Saturated oxygen heterocycles are important structural
moieties of large number of organic natural products.1
Total synthesis of these natural products depend largely on
the efficient stereoselective construction of these essential
The salient feature of our strategy is the facile 6-exo SN2
type ring closure reaction mediated by different hydroxyl
groups present in the acyclic precursor A. By carefully
choosing the requisite nucleophilic oxygen and a suitable
leaving group at d-position, various tetrahydropyran frame-
works were constructed as shown in Scheme 1. For the
synthesis of the key building block A, a Ti(IV)-mediated
‘non-Evans’ Crimmins aldol reaction6 was employed to
construct its C5- and C6-stereocentres. The remaining chiral
centers at C3- and C4-positions were subsequently fixed
by Sharpless epoxidation7 followed by a radical-mediated
epoxide opening reaction, developed by us earlier for the
synthesis of 2-methyl-1,3-diols, using cp2Ti(III)Cl.8
2. Results and discussion
Scheme 2 outlines in detail the synthesis of tetrahydropyrans
1 and 2. Asymmetric aldol addition of the titanium enolate
derived from the N-propanoyl oxazolidinethione 6,9 to
aldehyde 710 gave the non-Evans syn aldol product 8 as the
only isolable diastereomer in 78% yield. The relative and
absolute stereochemistry of the product were assigned on
the basis of earlier reported work.6 The syn-relationship
between the C5-hydroxyl and C6-methyl groups was
supported by the relatively small value of the corresponding
vicinal coupling constant of 3.8 Hz. Reductive removal of
the chiral auxiliary using NaBH4 gave an intermediate
Scheme 1. Cyclization modes. (a) C3–OH!C7–OX; (b) C7–OH!
C3–OX; (c) C3–O2!C7–OX; (d) C5–O2!C1–OX (X¼Ms, Ts).
Keywords: epoxy alcohols; Sharpless epoxidation; epoxide opening;
2-methyl-1,3-diol; phorboxazoles.
*
Corresponding author. Tel.: þ91-4027193154; fax: þ91-4027193108;
e-mail: chakraborty@iict.res.in
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.056

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Scheme 2. Stereoselective synthesis of 1 and 2. Reagents and conditions: (a) 6 (1.3 equiv.), TiCl4 (2 equiv.), DIPEA (1.1 equiv.), CH2Cl2, 278–08C, 0.5 h,
then 7 (1 equiv.), 278–08C, 1 h, 78%; (b) NaBH4 (2 equiv.), EtOH, 08C, 15 min; (c) TBDPSCl (1.1 equiv.), Et3N (1.5 equiv.), DMAP (0.1 equiv.), CH2Cl2,
08C to room temperature, 4 h, 68% in 2 steps; (d) Ti(OiPr)4 (1 equiv.), (2)-DIPT (1.1 equiv.), TBHP (2.5 equiv.), CH2Cl2, 4 A MS, 2208C, 3 h, 81%;
˚
(e) cp2TiCl2 (3 equiv.), Zn (6 equiv.), ZnCl2 (3 equiv.), THF, 2208C to room temperature, 12 h; (f) H2, 10% Pd–C, CH3COONH4 (0.1 equiv.), MeOH, room
temperature, 0.5 h, 65% yield of 12 (combined, steps e and f); (g) H2, 10% Pd–C, MeOH, room temperature, 24 h; (h) 2,2-dimethoxypropane (1.1 equiv.), CSA
(0.1 equiv.), CH2Cl2, 08C, 1 h, 56% in 2 steps; (i) TBAF (1.5 equiv.), THF, 08C to room temperature, 4 h; (j) TBS-OTf (2.5 equiv.), 2,6-Lutidine (4 equiv.),
CH2Cl2, 08C, 0.5 h; (k) HF–py, THF, 08C to room temperature, 18 h, 58% in 3 steps; (l) SO3–py (5 equiv.), Et3N (5 equiv.) DMSO:CH2Cl2 (2:1.6), 08C, 0.5 h;
(m) (trimethylsilyl)acetylene (5 equiv.), n-BuLi (4 equiv.), THF, 2788C to room temperature, 1 h, then aldehyde (1 equiv.), 08C, 15 min, 76% in 2 steps;
(n) MsCl (1.5 equiv.), DMAP (0.1 equiv.), pyridine, 08C, 0.5 h; (o) CSA (0.1 equiv.), CH2Cl2, 08C to room temperature, 3 h, 37% of 1 and 21% of 2 (in 2 steps
from 15).
diol that was selectively protected at its primary hydroxyl as
tert-butyldiphenylsilyl (TBDPS) ether to furnish 9 in 68%
yield from 8. The E-allylic alcohol 9 was then subjected to
Sharpless asymmetric epoxidation7 using (2)-diisopropyl
tartrate (DIPT) in presence of Ti(OiPr)4 and tert-butyl-
and 23.8 ppm and that of ketal carbon at 100.3 ppm proved
3,5-anti relationship of the molecule,13 its 1H NMR
3
3
spectrum with J3H,4H¼4.0 Hz, J4H,5H¼9.7 Hz confirmed
the assigned stereochemistry of the C4–Me group having
the expected 3,4-syn and 4,5-anti orientations.14 Next,
debenzylation of 12 and selective acetonide protection of
the C1–C3 diol gave intermediate 13 in 56% yield from 12.
The small amount of C3–C5 acetonide formed during the
acetonide protection step could be easily separated. Routine
functional group manipulations transformed 13 into 14 in 3
steps in 58% overall yield. The primary hydroxyl group of
14 was then oxidized and the resulting aldehyde was treated
with lithium trimethylsilylacetylide to get the propargylic
alcohol 15 as a mixture of isomers. Finally, the C7–OH of
15 was mesylated and subsequently treated with a catalytic
amount of (^)-camphorsulphonic acid (CSA) to give the
desired products 1 and 2, in 37 and 21% yields (from 15),
respectively, which were separated easily by standard silica
gel column chromatography and fully characterized.
˚
hydroperoxide (TBHP) and 4 A molecular sieves in CH2Cl2
at 2208C furnishing the desired epoxy alcohol 10 in 81%
1
isolated yield and 83% de, determined by H NMR studies
of the crude product. With the trisubstituted chiral epoxide
10 in hand, the stage was now set to carry out the radical-
mediated ring opening reaction. However, treatment of 10
with cp2TiCl, generated in situ according to the procedure
reported by us earlier8 gave the desired ‘2-methyl-1,3-diol’
containing compound 12 along with an unexpected
b-hydrogen eliminated compound 11 as the major product.
1
The H NMR spectrum of 11 showed the characteristic
methylene protons as two singlets at 5.15 and 5.20 ppm
with C3–H appearing as a triplet at d 4.22 (3J¼4.8 Hz) and
C5–H as a doublet at d 4.38 (3J¼2.4 Hz). The formation of
such olefins during the Ti(III)-mediated epoxide opening
reaction has been observed earlier by us in certain sterically
hindered substrates11 and also by others.12 Efforts to
suppress the unwanted b-hydrogen elimination using H2O
as additive according to a reported procedure,12 led to the
decomposition of the Ti(III)-species and the starting epoxy
alcohol 10 remained unchanged. Fortunately, diastereo-
selective reduction of the olefin moiety of 11 with H2 using
10% Pd/C as a catalyst in the presence of ammonium acetate
transformed it into the desired product 12 with the requisite
stereochemistry at the C4 methyl group leading to a
combined yield of 65% of 12. The stereochemistry of 12
was ascertained by NMR study of its acetonide. While the
13C NMR spectrum with acetonide methyl signals at 24.9
Although, our efforts to achieve diastereofacial selectivity
during the addition of trimethylsilylacetylide to the
aldehyde derived from 14 were not very successful,
subjection of the resulting mixture of alcohols 15 to a two
step process, oxidation followed by hydride reduction led to
the desired diastereoselectivity. The results of this study are
summarized in Table 1. While reduction with L-selectride
resulted in the best selectivity in favour of the anti isomer
with an a-hydroxyl group at C7, reduction with Zn(BH4)2
favored the formation of the syn isomer as the major
product. The formation of the anti isomer as the major
product using L-selectride and DIBAL-H can be explained
by non-chelate controlled Felkin–Anh model.15 A chelate

T. K. Chakraborty et al. / Tetrahedron 59 (2003) 8613–8622
8615
Table 1. Results of the diastereoselective hydride reduction of the C7-keto intermediate, derived from 14 by SO3–py oxidation, using various reagents
Hydride reagent
Solvent, temperature
Products
L-selectride
DIBAL-H
NaBH4
LiBH4
Zn(BH4)2
THF, 2788C
Toluene, 2788C
MeOH, 2788C
THF, 2788C
Et2O, 2308C
1
1
2
3
2
4
3
3
2
1
controlled six-membered transition state,16 on the other
hand, can rationalize the formation of the syn isomer during
the reduction with Zn(BH4)2.
confirmed the proposed structure of 1, representing
the C20–C28 moiety of phorboxazoles. Inversion of the
C7-center made the C7( TMS) group occupy axial
position in compound 2 (Fig. 1) with the other substituents
in the ring orienting in the same way in a chair conformation
as in 1. This is reflected in the 1H NMR signal of C7–H at d
1
The H NMR chemical shifts and coupling constants of 1
are comparable to those reported earlier for similar units
of phorboxazoles.5 In the energy-minimized17 chair con-
formation of 1 (Fig. 1), while the C4–Me occupied an axial
position, the remaining substituents on the tetrahydropyran
ring, C3–(C2–C1), C5–OTBS, C6–Me and C7( TMS),
were all in equatorial positions. This was supported by the
1H NMR spectrum of 1 where the C5–H signal appeared at
3
4.52 that showed a doublet with J6H,7H¼5.5 Hz. The dd
peak of C5–H at 3.75 ppm had coupling constants 3J5H,6H
¼
3
10.3 Hz (a,a) and J5H,4H¼4.9 Hz (a,e). The remaining
protons showed peaks in accordance with the structure.
For the synthesis of compounds 3 and 4, the intermediate
diol 12 was first debenzylated as shown in Scheme 3 and the
C1–C3 diol moiety was protected as PMP–acetal to furnish
16 in 63% yield from 12. Small amount of the other
benzylidene from C3–C5 diol was also formed that could be
easily separated chromatographically. The C5–OH was
protected next as Bn-ether by treating a solution of 16 and
3
3.33 ppm as a dd with coupling constants J5H,6H¼10.1 Hz
(a,a) and 3J5H,4H¼4.8 Hz (a,e). The chemical shift of C7–H
at 3.72 ppm was a doublet with a large (a,a) coupling,
3J6H,7H¼10.7 Hz. The C3–H signal at 3.57 ppm was a ddd
with 10.1, 3.1 and 2.0 Hz coupling constants. The chemical
shifts of the remaining protons and their splitting patterns
Scheme 3. Stereoselective synthesis of 3 and 4. Reagents and conditions:
(a) H2, 10% Pd–C, MeOH, room temperature, 24 h; (b) p-methoxy-
benzaldehyde dimethylacetal (1.1 equiv.), CSA (0.01 equiv.), CH2Cl2, 08C,
1 h, 63% in 2 steps; (c) BnBr (1.2 equiv.), NaHMDS (1.2 equiv.),
THF:DMF (2:1), 08C, 45 min, 85%; (d) NaCNBH3 (6 equiv.), TMS–Cl
˚
(6 equiv.) CH3CN, 4 A MS, 08C, 15 min, 62%; (e) MsCl (1.5 equiv.),
DMAP (0.1 equiv.), pyridine, 08C, 0.5 h; (f) TBAF (1.5 equiv.), THF, 08C
to room temperature, 24 h, 87% in 2 steps; (g) Ac2O (1.5 equiv.), Et3N
(1.5 equiv.), DMAP (0.1 equiv.), CH2Cl2, 08C to room temperature, 8 h;
(h) TBAF (1.5 equiv.), THF, 08C to room temperature, 5 h, 91% in 2 steps;
(i) TsCl (1.1 equiv.), Et3N (2 equiv.), 08C to room temperature 5 h;
(j) K2CO3 (3 equiv.), MeOH, 08C to room temperature, 24 h, 85% in 2 steps.
Figure 1. Energy-minimized structures of 1 (top-left), 2 (top-right), 3
(centre), 4 (bottom-left) and 5 (bottom-right).

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T. K. Chakraborty et al. / Tetrahedron 59 (2003) 8613–8622
BnBr with NaHMDS to furnish 17 in 85% yield. Reduction
of 17 with NaCNBH3 and TMS–Cl in anhydrous CH3CN
gave selectively the primary-protected substrate 18 in 62%
yield.18 The minor product with C3–OPMB could be easily
removed by column chromatography. Mesylation of the
C3–OH followed by deprotection of the TBDPS group
using TBAF led to a concomitant cycloetherification
reaction in which the C7–alkoxide ion intramolecularly
displaced the C3–OMs in SN2 fashion leading to the
formation of the tetrahydropyran 3 in 87% yield.
synthesis of many such natural products that contain similar
substituted tetrahydropyran moieties.
3. Experimental
3.1. General procedures
All reactions were carried out in oven or flame-dried
glassware with magnetic stirring under nitrogen atmosphere
using dry, freshly distilled solvents, unless otherwise noted.
Reactions were monitored by thin layer chromatography
(TLC) carried out on 0.25 mm silica gel plates with UV
light, I2, 7% ethanolic phosphomolybdic acid-heat and 2.5%
ethanolic anisaldehyde (with 1% AcOH and 3.3% conc.
H2SO4)-heat as developing agents. Silica gel finer than
200 mesh was used for flash column chromatography.
Yields refer to chromatographically and spectroscopically
homogeneous materials unless otherwise stated. Melting
points are uncorrected. IR spectra were recorded as neat
liquids or KBr pellets. Mass spectra were obtained under
electron impact ionisation (EI), liquid secondary ion mass
spectrometric (LSIMS) technique, electron spray ionisation
(ESI) and MALDI techniques. NMR spectra were recorded
on 500, 300 and 200 MHz spectrometers at 308C with
2–10 mM solutions in appropriate solvents using TMS as
internal standard or the solvent signals as secondary
standards and the chemical shifts are shown in d scales.
Multiplicities of NMR signals are designated as s (singlet), d
(doublet), t (triplet), q (quartet), br (broad), m (multiplet,
for unresolved lines), etc. 13C NMR spectra were recorded
on 75 and 50 MHz spectrometers with complete proton
decoupling.
The small vicinal coupling constants, 3.0 and 1.2 Hz, of its
C7-protons with C6–H suggest an equatorial disposition
of the latter as shown in its energy-minimized structure in
Figure 1. This, in turn, leads to an equatorial orientation of
the adjacent C5–H as reflected in the absence of any large
diaxial coupling in its chemical shift at 3.24 ppm. Protection
of the C3–OH of 18 as an acetate and subsequent silyl
deprotection gave the intermediate 19 in 91% yield from 18.
The primary hydroxyl of 19 was then tosylated and finally
base-catalyzed cyclization furnished the desired product 4 in
85% yield. In compound 4, the C3, C5 and C6 substituents
occupy equatorial positions with an axial orientation of the
C4–Me (Fig. 1). This is reflected in the large vicinal diaxial
coupling of 11.2 Hz of the C7–H(axial) that resonated at
2.96 ppm. The dd peak of its C5–H at 3.12 ppm with
3
3
coupling constants J5H,6H¼10.3 Hz (a,a) and J5H,4H
¼
4.9 Hz (a,e) further corroborated the structure.
The PMP–acetal 16 served as the starting material for the
synthesis of 5 as outlined in Scheme 4. Reduction of 16 with
NaCNBH3 and TMS–Cl gave the diol 20 as the minor
product in 35% yield. The major product had the primary
hydroxyl group PMB-protected. Uses of other hydride
reagents did not help in reversing the selectivity. Selective
tosylation of the primary hydroxyl of 20 was followed by
facile intramolecular cyclization initiated by the C5–O2
leading to the expected product 5 in 65% yield. In
compound 5, all the three substituents on the ring occupy
equatorial positions in a chair conformation as shown in its
energy-minimized structure in Figure 1. The C5–H
(numberings according to A) signal at 3.69 ppm with large
diaxial vicinal coupling of 9.1 Hz points to its axial
position. The dt peak at 3.11 ppm belonged to C3–H that
showed two diaxial couplings of 10.3 Hz and one (a,e)-
coupling of 4.8 Hz providing further supports for the
proposed structure.
3.1.1. Synthesis of 8. To a solution of N-propanoyl
oxazolidinethione 69 (2.54 g, 10.19 mmol) in CH2Cl2
(40 mL) at 08C, TiCl4 (1.67 mL, 15.69 mmol) was added
dropwise. After 5 min, DIPEA (1.5 mL, 8.63 mmol) was
slowly added and stirring was continued for another
20 min at 08C. It was cooled to 2788C, aldehyde 710
(1.6 g, 7.84 mmol) in CH2Cl2 (20 mL) was added and
stirred at 2788C for 1 h. The reaction mixture was warmed
to 08C and quenched with saturated aqueous NH4Cl
solution. It was diluted with CH2Cl2, washed with brine,
dried (Na2SO4) and concentrated in vacuo. Purification by
column chromatography (SiO2, 15–18% EtOAc in petro-
leum ether eluant) gave pure compound 8 (2.77 g, 78%) as
colorless oil. Rf¼0.4 (silica gel, 25% EtOAc in petroleum
ether). [a]2D0¼þ80.1 (c 1.8, CHCl3); IR (neat): nmax 3446,
2928, 2860, 1707, 1453, 1321, 1196, 1095, 960, 775, 741,
1
702 cm21; H NMR (CDCl3, 300 MHz): d 7.37–7.18 (m,
10H, aromatic), 5.62 (br t, J¼7.2 Hz, 1H, olefinic), 5.05
(dq, J¼6.8, 3.8 0Hz, 1H, CHCvO), 4.96 (ddt, J¼10.2, 6.4,
3.8 Hz, 1H, C4 –H), 4.53 (m, 1H, allylic CHOH), 4.496
(s, 2H, OCH2Ph), 4.33–4.26 (m, 2H, C50 –H2), 3.50 (t,
J¼7.2 Hz, 2H, BnOCH2–), 3.28 (dd, J¼13.2, 3.8 Hz, 1H,
PhCH), 2.704 (dd, J¼13.2, 10.2 Hz, 1H, PhCH0), 2.638
(d, J¼3.4 Hz, 1H, OH), 2.406 (m, 2H, allylic CH2), 1.70
(s, 3H, vCCH3), 1.15 (d, J¼6.8 Hz, 3H, CHCH3); 13C
NMR (CDCl3, 75 MHz): d 185.08, 177.79, 138.43, 135.65,
135.17, 129.27, 128.99, 128.29, 127.56, 127.45, 127.40,
122.56, 96.08, 75.15, 72.86, 70.17, 69.71, 59.90, 40.40,
37.71, 28.35, 13.62, 10.75; MS (LSIMS): m/z (%): 436 (38)
Scheme 4. Stereoselective synthesis of 5. Reagents and conditions:
˚
(a) NaCNBH3 (6 equiv.), TMS–Cl (6 equiv.), CH3CN, 4 A MS, 08C,
15 min, 35%; (b) TsCl (1.1 equiv.), Et3N (2 equiv.), CH2Cl2, 08C to room
temperature, 3 h; (c) NaH (6 equiv.), toluene, 08C to reflux, 3 h, 65% in 2
steps.
In conclusion, a versatile synthon A has been successfully
and very efficiently exploited to construct a wide variety of
structurally diverse chiral tetrahydropyran frameworks,
including the one that bears the C20–C28 unit 1 of
phorboxazoles. The protocol will be very useful in the

T. K. Chakraborty et al. / Tetrahedron 59 (2003) 8613–8622
8617
[MþH–H2O]þ; HRMS (LSIMS): calcd for C26H32NO4S
C3–H), 2.07 (br s, 1H, OH), 1.89 (m, 3H, C2–H2, C6–H),
1.24 (s, 3H, C4–CH3), 1.06 (s, 9H, tBu), 0.79 (d, J¼6.8 Hz,
3H, C6–CH3); 13C NMR (CDCl3, 75 MHz): d 138.10,
135.52, 133.70, 133.59, 129.55, 128.29, 127.58, 73.09,
71.19, 67.39, 66.79, 61.77, 56.66, 37.02, 28.86, 26.83,
19.17, 15.17, 9.44; MS (MALDI): m/z (%): 542 (48)
[MþHþNa]þ, 558 (19) [MþHþK]þ.
[MþH]þ: 454.2052, found: 454.2074.
3.1.2. Synthesis of 9. To a solution of 8 (8.86 g,
19.55 mmol) in EtOH (120 mL), NaBH4 (1.48 g,
39.1 mmol) was added at 08C and stirred at the same
temperature for 15 min. The reaction mixture was quenched
with saturated NH4Cl solution, extracted with EtOAc,
washed with brine, dried (Na2SO4) and concentrated in
vacuo. The resulting alcohol was used directly in the next
step. It was dissolved in CH2Cl2 (60 mL), Et3N (4.08 mL,
29.32 mmol) and TBDPSCl (5.51 mL, 21.5 mmol) were
added sequentially at 08C. Next, a catalytic amount of
DMAP (239 mg, 1.95 mmol) was added to the reaction
mixture. After being stirred for 4 h at room temperature the
reaction mixture was quenched with saturated aqueous
NH4Cl solution and extracted with CH2Cl2. The organic
extract was dried (Na2SO4) and concentrated in vacuo.
Purification by column chromatography (SiO2, 8–10%
EtOAc in petroleum ether eluant) gave pure compound 9
(6.68 g, 68% in 2 steps) as clear oil. Rf¼0.5 (silica gel, 15%
EtOAc in petroleum ether); [a]2D0¼þ7.2 (c 2.22, CHCl3);
IR (neat): nmax 3444, 3072, 2941, 2858, 1475, 1423, 1368,
3.1.4. Synthesis of 12. To a suspension of cp2TiCl2
(5.018 g, 20.16 mmol) in dry THF (90 mL) at room
temperature, freshly fused ZnCl2 (2.75 g, 20.16 mmol), Zn
powder (2.63 g, 40.3 mmol) were added under N2 atmos-
phere and stirred at room temperature for 1 h. To the above
solution, epoxy alcohol 10 (3.48 g, 6.72 mmol) in dry THF
(10 mL) was added at 08C. The reaction mixture was
warmed to room temperature and stirred for 10–12 h. The
reaction was quenched by slow addition of 1N HCl and
extracted with EtOAc. The combined organic extracts were
washed with water, dried (Na2SO4) and concentrated in
vacuo. Purification by column chromatography (SiO2,
18–35% EtOAc in petroleum ether eluant) eluted first
compound 12 (735 mg, 21%) followed by 11 (2.62 g, 75%)
as colorless oils.
1107, 1004, 815, 738, 691 cm21
;
1H NMR (CDCl3,
500 MHz): d 7.67–7.27 (m, 15H, aromatic), 5.47 (t, J¼
6.8 Hz, 1H, olefinic), 4.50 (s, 2H, OCH2Ph), 4.2 (d, J¼
3.7 Hz, 1H, C5–H), 3.65 (dd, J¼10.5, 4.9 Hz, 1H, C7–H),
3.63 (dd, J¼10.5, 5.6 Hz, 1H, C7–H0), 3.46 (t, J¼6.8 Hz,
2H, C1–H2), 2.37 (m, 2H, C2–H2), 1.84 (m, 1H, C6–H),
1.55 (s, 3H, C4–CH3), 1.06 (s, 9H, tBu), 0.89 (d, J¼6.8 Hz,
3H, C6–CH3); 13C NMR (CDCl3, 75 MHz): d 138.41,
137.39, 135.57, 135.49, 133.29, 133.15, 129.66, 129.64,
128.26, 127.63, 127.56, 127.43, 121.13, 77.77, 72.80, 69.80,
67.66, 37.67, 28.25, 26.79, 19.14, 13.14, 10.60; MS
(LSIMS): m/z (%): 503 (5) [MþH]þ.
Data for 12. Rf¼0.45 (silica gel, 30% EtOAc in petroleum
ether); [a]2D0¼þ12.7 (c 2.62, CHCl3); IR (neat): nmax 3439,
3055, 2949, 2918, 2850, 1485, 1436, 1381, 1107, 811, 735,
1
699 cm21; H NMR (CDCl3, 500 MHz): d 7.67–7.27 (m,
15H, aromatic), 4.53 (ABq, J¼12.4 Hz, 2H, OCH2Ph),
4.03 (br d, J¼10.5 Hz, 1H, C5–H), 3.9 (dd, J¼9.3, 1.2 Hz,
1H, C3–H), 3.76 (dd, J¼9.9, 4.3 Hz, 1H, C7–H), 3.75–
3.68 (m, 3H, C1–H2, C7–H0), 3.61 (br s, 1H, OH), 3.52
(br s, 1H, OH), 1.98–1.91, 1.84–1.77, 1.75–1.72 and 1.66–
1.62 (m, 4H, C2–H2, C4–H, C6–H), 1.06 (s, 9H, tBu), 0.96
(d, J¼6.8 Hz, 3H, CH3), 0.78 (d, J¼6.8 Hz, 3H, CH3); 13
C
NMR (CDCl3, 75 MHz): d 138.04, 135.64, 135.52, 133.17,
133.00, 129.74, 128.37, 127.69, 127.64, 75.70, 73.26, 69.70,
69.00, 39.78, 36.63, 32.57, 29.64, 26.84, 19.14, 11.97, 9.35;
MS (MALDI): m/z (%): 543 (13) [MþNa]þ, 559 (5)
[MþK]þ; HRMS (LSIMS): calcd for C32H45O4Si [MþH]þ:
521.3087, found: 521.3077.
3.1.3. Synthesis of 10. To a suspension of activated
˚
powdered 4 A molecular sieves (1.06 g, 20 wt%) in
CH2Cl2 (25 mL), Ti(OiPr)4 (3.13 mL, 10.52 mmol) and
(2)-DIPT (2.46 mL, 11.57 mmol) were added sequentially
at 2208C. After being stirred for 20 min, TBHP (3.73 M
solution in toluene, 7.05 mL, 26.3 mmol) was added
and stirring continued for another 30 min at the same
temperature. To the above solution, compound 9 (5.28 g,
10.52 mmol) in CH2Cl2 (10 mL) was added and stirred for
3 h at 2208C. The reaction mixture was quenched with
water (60 mL), warmed to room temperature and stirred for
1 h. After re-cooling to 08C, an aqueous solution of NaOH
(30% (w/v), 16 mL), saturated with NaCl, was added to it
and stirred at 08C for 10 min. CH2Cl2 was removed under
reduced pressure, the compound was extracted with ether,
washed with brine, dried (Na2SO4), filtered and concen-
trated in vacuo. Purification by column chromatography
(SiO2, 10–13% EtOAc in petroleum ether eluant) afforded
pure compound 10 in 83% de (4.41 g, 81%) as colorless oil.
Rf¼0.6 (silica gel, 15% EtOAc in petroleum ether); [a]2D0¼
20.5 (c 1.89, CHCl3); IR (neat): nmax 3470, 3059, 2957,
2929, 2855, 1486, 1439, 1393, 1341, 1258, 1211, 1107,
1004, 815, 735, 694 cm21; 1H NMR (CDCl3, 500 MHz): d
7.68–7.27 (m, 15H, aromatic), 4.52 (ABq, J¼11.8 Hz, 2H,
OCH2Ph), 4.02 (d, J¼1.2 Hz, 1H, C5–H), 3.74 (dd, J¼9.9,
8.0 Hz, 1H, C7–H), 3.64 (t, J¼6.2 Hz, 2H, C1–H2) 3.61
(dd, J¼9.9, 5.6 Hz, 1H, C7–H0), 3.28 (t, J¼6.2 Hz, 1H,
To a solution of 11 (2.62 g, 5.05 mmol) in MeOH (5 mL),
10% Pd–C and catalytic amount of NH4OAc (38 mg,
0.5 mmol) were added and the mixture was hydrogenated
using a H2-filled balloon for 0.5 h. It was then filtered
through a short pad of Celite and the filter cake was washed
with MeOH. The filtrate and washings were combined and
concentrated. Purification by column chromatography
(SiO2, 18–22% EtOAc in petroleum ether eluant) eluted
compound 12 (1.54 g, 58%) as colorless oil.
3.1.5. Synthesis of 13. To a solution of 12 (2.07 g,
3.98 mmol) in MeOH (5 mL), 10% Pd–C was added
and the mixture was hydrogenated using a H2-filled
balloon for 24 h. It was then filtered through a short pad
of Celite and the filter cake was washed with MeOH.
The filtrate and washings were combined and concen-
trated in vacuo. The residue was used directly in the
next step.
It was dissolved in dry CH2Cl2 (12 mL), 2,2-dimethoxy-
propane (0.54 mL, 4.37 mmol) and CSA (92 mg,

8618
T. K. Chakraborty et al. / Tetrahedron 59 (2003) 8613–8622
0.39 mmol) were added sequentially at 08C. After being
stirred for 1 h at the same temperature, the reaction mixture
was quenched with saturated aqueous NaHCO3 solution,
extracted with EtOAc, washed with brine, dried (Na2SO4),
and concentrated in vacuo. Purification by column chroma-
tography (SiO2, 14–16% EtOAc in petroleum ether eluant)
gave the compound 13 (1.05 g, 56% in 2 steps) as clear oil.
Rf¼0.6 (silica gel, 20% EtOAc in petroleum ether);
[a]2D0¼þ8.9 (c 2.0, CHCl3); IR (neat): nmax 3486, 3070,
2965, 2921, 2847, 1459, 1422, 1374, 1196, 1102, 968, 818,
3.1.7. Synthesis of 15. To a solution of 14 (115 mg,
0.33 mmol) in dry CH2Cl2 (1 mL) and DMSO (0.8 mL),
Et3N (0.23 mL, 1.66 mmol) and SO3–py complex
(264.5 mg, 1.66 mmol) were added sequentially at 08C
under N2 atmosphere. After 30 min of stirring at 08C, the
reaction mixture was quenched with saturated NH4Cl
solution and extracted with petroleum ether. The organic
extract was dried (Na2SO4) and concentrated in vacuo. The
residue was used directly in the next step.
1
740, 692 cm21; H NMR (CDCl3, 200 MHz): d 7.66–7.25
To a solution of (trimethylsilyl)acetylene (0.23 mL,
1.66 mmol) in dry THF (5 mL), n-BuLi (1.6 M in hexane,
0.83 mL, 1.32 mmol) was added at 2788C. After stirring for
30 min at 2788C, the reaction mixture was warmed to room
temperature and stirred for another 30 min. It was then
cooled to 08C and the above aldehyde in THF (1 mL) was
added to it. After 15 min, it was quenched with saturated
aqueous NH4Cl solution at 08C, extracted with EtOAc,
washed with brine, dried (Na2SO4) and concentrated
in vacuo. Purification by column chromatography (SiO2,
6–8% EtOAc in petroleum ether eluant) afforded compound
15 (112 mg, mixture of isomers, 76% in 2 steps) as clear oil.
Rf¼0.5 (silica gel, 15% EtOAc in petroleum ether);
IR (neat): nmax 3420, 2949, 2926, 2842, 2647, 2173,
(m, 10H, aromatic), 4.18 (dd, J¼11.9, 2.2 Hz, 1H, C5–H),
3.99–3.74 and 3.69–3.64 (m, 5H, C1–H2, C7–H2, C3–H),
3.29 (br s, 1H, OH), 1.97–1.76 and 1.75–1.62 and 1.32–
1.17 (m, 4H, C2–H2, C4–H, C6–H), 1.45 (s, 3H, acetonide
t
Me), 1.35 (s, 3H, acetonide Me), 1.06 (s, 9H, Bu), 0.86
(d, J¼6.8 Hz, 3H, CH3), 0.78 (d, J¼6.8 Hz, 3H, CH3); 13C
NMR (CDCl3, 50 MHz): d 135.63, 135.57, 133.83, 133.69,
129.58, 127.61, 98.49, 72.78, 71.25, 67.69, 60.17, 39.12,
37.52, 29.92, 26.91, 26.45, 19.23, 19.05, 11.35, 9.31; MS
(MALDI): m/z (%): 494 (10) [MþHþNa]þ; HRMS
(LSIMS): calcd for C28H43O4Si [MþH]þ: 471.2931,
found: 471.2956.
1
3.1.6. Synthesis of 14. To a solution of 13 (658 mg,
1.4 mmol) in dry THF (5 mL), TBAF (1 M in THF, 2.1 mL,
2.1 mmol) was added at 08C. The reaction mixture was
warmed to room temperature and stirred for 4 h. It was
quenched with saturated aqueous NH4Cl solution, extracted
with EtOAC, washed with brine, dried (Na2SO4) and
concentrated in vacuo. The residue was used directly in
the next step.
1448, 1381, 1239, 1075, 1007, 831, 768 cm21; H NMR
(CDCl3, 200 MHz, mixture of isomers): d 4.19–3.71 (m,
5H, CH–O), 2.06–2.01 and 1.85–1.58 (m, 4H, C2–H2,
C4–H, C6–H), 1.41 (s, 3H, acetonide CH3), 1.31 (s, 3H,
acetonide CH3), 1.01 (d, J¼6.8 Hz, 3H, CH3), 0.94 (d, J¼
t
6.8 Hz, 3H, CH3), 0.88 and 0.878 (two s, 9H, Bu), 0.16,
0.15 and 0.07 (three s, 15H, SiMe); 13C NMR (CDCl3,
75 MHz): d 106.92, 106.65, 98.16, 90.84, 90.00, 77.21,
72.72, 70.98, 70.14, 66.74, 66.11, 59.79, 45.07, 44.87,
42.52, 41.69, 29.87, 29.61, 29.56, 25.97, 19.54, 18.31,
18.26, 11.75, 10.72, 10.67, 10.37, 20.14, 20.23, 24.03,
24.11, 24.32, 24.39; MS (ESIMS): m/z (%): 465 (100)
[MþNa]þ.
It was dissolved in CH2Cl2 (5 mL), 2,6-lutidine (0.65 mL,
5.6 mmol) and TBS–OTf (0.8 mL, 3.5 mmol) were added at
08C. After being stirred for 0.5 h at the same temperature,
the reaction mixture was quenched with saturated aqueous
NaHCO3 solution, extracted with EtOAc, washed with
saturated aqueous CuSO4 solution, water, brine, dried over
Na2SO4 and concentrated in vacuo. The residue was
dissolved in dry THF (5 mL) and treated with HF–py
complex (40%, 0.17 mL) at 08C. It was warmed to room
temperature and stirred for 18 h. The reaction mixture was
cautiously poured into aqueous NaHCO3 solution and
extracted with EtOAc. The combined extracts were washed
with brine, dried (Na2SO4), and concentrated in vacuo.
Purification by column chromatography (SiO2, 16–18%
EtOAc in petroleum ether) afforded compound 14 (281 mg,
58% in 3 steps) as clear oil. Rf¼0.5 (silica gel, 20% EtOAc
in petroleum ether); [a]D20¼þ5.5 (c 1.48, CHCl3); IR (neat):
3.1.8. Synthesis of 16. To a solution of 12 (1.268 g,
2.44 mmol) in MeOH (5 mL), 10% Pd–C was added and
the mixture was hydrogenated using a H2-filled balloon for
24 h. It was then filtered through a short pad of Celite and
the filter cake was washed with MeOH. The filtrate and
washings were combined and concentrated in vacuo. The
residue was used directly in the next step.
It was dissolved in dry CH2Cl2 (8 mL), p-methoxybenz-
aldehyde dimethylacetal (0.5 mL, 2.7 mmol) and CSA
(6 mg, 0.024 mmol) were added sequentially at 08C. After
being stirred for 1 h at the same temperature, the reaction
mixture was quenched with saturated aqueous NaHCO3
solution, extracted with EtOAc, washed with brine, dried
(Na2SO4) and concentrated in vacuo. Purification by column
chromatography (SiO2, 16–18% EtOAc in petroleum ether
eluant) gave the compound 16 (842 mg, 63% in 2 steps) as
colorless oil. Rf¼0.6 (silica gel, 20% EtOAc in petroleum
ether); [a]2D0¼25.2 (c 1.185, CHCl3); IR (neat): nmax 3502,
3062, 2952, 2929, 2844, 2714, 1593, 1502, 1467, 1420,
1384, 1289, 1242, 1107, 1011, 984, 823, 738, 702 cm21; 1H
NMR (CDCl3, 200 MHz): d 7.65–7.33 (m, 10H, aromatic),
7.34, 6.84 (two d, J¼8.2 Hz, 4H, PMP ortho and meta-H),
5.47 (s, 1H, CHPMP), 4.34–4.18, 4.02–3.86 and 3.75–3.62
(m, 6H, C1–H2, C3–H, C5–H, C7–H2), 3.79 (s, 3H,
n
max 3455, 2952, 2925, 2855, 2746, 1455, 1368, 1242, 1193,
1
1083, 1028, 968, 826, 757, 670 cm21; H NMR (CDCl3,
500 MHz): d 3.94 (dt, J¼12.4, 3.1 Hz, 1H, C1–H), 3.89 (dd,
J¼4.9, 1.8 Hz, 1H, C5–H), 3.825 (m, 2H, C1–H0, C3–H),
3.43 (dd, J¼10.5,0 8.6 Hz, 1H, C7–H), 3.38 (dd, J¼10.5,
5.6 Hz, 1H, C7–H ), 1.78, 1.7–1.58 and 1.40–1.35 (m, 4H,
C2–H2, C4–H, C6–H), 1.37 (s, 3H, acetonide Me), 1.29
(s, 3H, acetonide Me), 0.91 (d, J¼6.8 Hz, 3H, CH3), 0.84
(s, 9H, tBu), 0.81 (d, J¼6.8 Hz, 3H, CH3), 0.011 and 0.001
(two s, 6H, SiMe2); 13C NMR (CDCl3, 50 MHz): d 98.08,
72.39, 69.99, 66.49, 59.81, 44.65, 38.16, 29.81, 29.55,
25.92, 19.48, 18.23, 11.67, 10.69, 24.19, 24.51; MS
(LSIMS): m/z (%): 347 (8) [MþH]þ.

T. K. Chakraborty et al. / Tetrahedron 59 (2003) 8613–8622
8619
t
OCH3), 3.02 (br s, 1H, OH), 2.17–1.96, 1.75–1.61 and
1.32–1.25 (m, 4H, C2–H2, C4–H, C6–H), 1.07 (s, 9H,
tBu), 0.91 (d, J¼6.7 Hz, 3H, CH3), 0.87 (d, J¼6.7 Hz, 3H,
CH3); 13C NMR (CDCl3, 75 MHz): d 159.81, 135.65,
135.52, 133.41, 133.23, 131.42, 129.68, 129.63, 127.64,
127.30, 113.51, 101.22, 77.61, 73.01, 68.39, 67.19, 55.21,
40.04, 36.71, 27.38, 26.87, 19.15, 10.86, 8.93; MS (LSIMS):
m/z (%): 549 (4) [MþH]þ; HRMS (LSIMS): calcd for
C33H45O5Si [MþH]þ: 549.3036, found: 549.3018.
C2–H2, C4–H, C6–H), 1.07 (s, 9H, Bu), 0.923 (d, J¼
6.9 Hz, 3H, CH3), 0.913 (d, J¼6.8 Hz, 3H, CH3); 13C NMR
(CDCl3, 50 MHz): d 159.16, 138.81, 135.56, 133.75,
130.42, 129.58, 129.15, 128.29, 127.62, 127.42, 113.79,
82.61, 75.20, 72.77, 69.65, 68.77, 66.75, 55.21, 40.32,
38.37, 34.91, 26.94, 19.27, 11.21, 10.93; MS (MALDI): m/z
(%): 664 (30) [MþHþNa]þ, 680 (8) [MþHþK]þ; HRMS
(LSIMS): calcd for C40H53O5Si [MþH]þ: 641.3662, found:
641.3656.
3.1.9. Synthesis of 17. To a solution of 16 (338 mg,
0.616 mmol) in THF:DMF (2:1, 3 mL), benzyl bromide
(0.088 mL, 0.74 mmol) was added. The reaction mixture
was cooled to 08C and treated by dropwise addition of
NaHMDS (2 M in THF, 0.37 mL, 0.74 mmol). After being
stirred for 45 min at 08C, it was quenched with saturated
aqueous NH4Cl solution and extracted with EtOAc. The
combined organic extracts were washed with brine, dried
(Na2SO4) and concentrated in vacuo. Purification by column
chromatography (SiO2, 6–8% EtOAc in petroleum ether
eluant) afforded compound 17 (334 mg, 85%) as colorless
oil. Rf¼0.7 (silica gel, 20% EtOAc in petroleum ether);
[a]2D0¼258.1 (c 0.86, CHCl3); IR (neat): nmax 3439, 3070,
2960, 2925, 2842, 1608, 1514, 1475, 1381, 1234, 1157,
3.1.11. Synthesis of 19. To a solution of 18 (126 mg,
0.196 mmol) in dry CH2Cl2 (1 mL), Et3N (0.04 mL,
0.294 mmol), Ac2O (0.027 mL, 0.294 mmol), catalytic
amount of DMAP (2.4 mg, 0.02 mmol) were added at
08C. After being stirred for 8 h at room temperature, the
reaction mixture was quenched with saturated aqueous
NH4Cl solution, extracted with EtOAc, washed with brine,
dried (Na2SO4) and concentrated in vacuo. The residue was
used directly in the next step.
It was dissolved in dry THF (1 mL), TBAF (1 M in THF,
0.294 mL, 0.294 mmol) was added at 08C, the reaction
mixture was warmed to room temperature and stirred for
5 h. It was quenched with saturated aqueous NH4Cl
solution, extracted with EtOAc, washed with brine, dried
(Na2SO4) and concentrated in vacuo. Purification by column
chromatography (SiO2, 30% EtOAc in petroleum ether
eluant) afforded compound 19 (80 mg, 91% in 2 steps) as a
clear oil. Rf¼0.5 (silica gel, 40% EtOAc in petroleum
ether); [a]2D0¼þ7.1 (c 1.01, CHCl3); IR (neat): nmax 3439,
3289, 2937, 2866, 1744, 1615, 1525, 1368, 1239, 1083,
1023, 850, 773, 702 cm21; 1H NMR (CDCl3, 300 MHz): d
7.34–7.21 (m, 5H, aromatic), 7.174 and 6.761 (two d,
J¼9.5 Hz, 4H, PMP ortho and meta-H), 5.41 (m, 1H, C3–
H), 4.565 and 4.45 (ABq, J¼10.7 Hz, 2H, OCH2Ar), 4.35
(ABq, J¼11.8 Hz, 2H, OCH2Ar), 3.758 (s, 3H, OMe),
3.601–3.514 and 3.494–3.376 (m, 5H, C1–H2, C7–H2,
C5–H), 2.0 (s, 3H, OCOCH3), 2.02–1.73 (m, 4H, C2–H2,
C4–H, C6–H), 1.7 (br s, 1H, OH), 0.91 (d, J¼6.8 Hz, 3H,
CH3), 0.86 (d, J¼6.7 Hz, 3H, CH3); 13C NMR (CDCl3,
50 MHz): d 170.84, 159.05, 138.81, 130.46, 129.22, 128.22,
127.74, 127.36, 113.68, 79.99, 74.35, 72.68, 71.61, 67.17,
65.95, 55.21, 39.46, 37.67, 33.39, 21.24, 10.35, 10.19; MS
(ESIMS): m/z (%): 445 (3.3) [MþH]þ, 467 (12.5)
[MþNa]þ, 483 (7) [MþK]þ; HRMS (LSIMS): calcd for
C26H37O6 [MþH]þ: 445.2590, found: 445.2580.
1102, 1036, 815, 733, 694 cm21
;
1H NMR (CDCl3,
200 MHz): d 7.68–7.20 (m, 15H, aromatic), 7.40 and 6.85
(two d, J¼8.9 Hz, 4H, PMP ortho and meta-H), 5.37 (s, 1H,
CHPMP), 4.60 (ABq, J¼11.1 Hz, 2H, OCH2Ph), 4.32–4.16
and 4.04–3.88 (m, 4H, C7–H2, C5–H, C3–H), 3.82 (s, 3H,
OCH3), 3.705 (t, J¼9.7 Hz, 1H, C1–H), 3.57 (dd, J¼9.7,
5.9 Hz, 1H, C1–H0), 2.2–1.84, 1.77–1.61 and 1.26–1.21
(m, 4H, C2–H2, C4–H, C6–H), 1.06 (s, 9H, tBu), 0.95 (d,
J¼6.7 Hz, 3H, CH3), 0.79 (d, J¼6.7 Hz, 3H, CH3); 13C
NMR (CDCl3, 50 MHz): d 159.34, 139.26, 135.53, 133.81,
131.79, 129.53, 128.24, 127.59, 127.48, 127.26, 127.10,
113.47, 100.44, 78.42, 75.83, 74.76, 67.25, 66.52, 55.23,
40.32, 37.56, 28.52, 26.91, 19.24, 10.51, 9.22; MS (LSIMS):
m/z (%): 639 (6) [MþH]þ; HRMS (LSIMS): calcd for
C40H51O5Si [MþH]þ: 639.3506, found: 639.3527.
3.1.10. Synthesis of 18. To a solution of 17 (307 mg,
0.48 mmol) in dry CH3CN (10 mL), activated and powered
˚
molecular sieves (4 A, 62 mg) were added at room
temperature. After being stirred for 5 min, the reaction
mixture was cooled to 08C and NaCNBH3 (181 mg,
2.89 mmol) and TMS–Cl (0.37 mL, 2.89 mmol) were
added sequentially. The resulting solution was stirred for
15 min before quenching with saturated aqueous NH4Cl
solution and extracted with EtOAc, washed with brine, dried
(Na2SO4), filtered and concentrated in vacuo. Purification
by column chromatography (SiO2, 13–15% EtOAc in
petroleum ether eluant) provided compound 18 (191 mg,
62%) as a clear oil. Rf¼0.6 (silica gel, 30% EtOAc in
petroleum ether); [a]D20¼22.3 (c 1.76, CHCl3); IR (neat):
3.1.12. Synthesis of 20. To a solution of 16 (340 mg,
0.62 mmol) in dry CH3CN (13 mL), activated and powered
˚
molecular sieves (4 A, 70 mg) were added at room
temperature. After being stirred for 5 min, the reaction
mixture was cooled to 08C; to the above solution, NaCNBH3
(234 mg, 3.72 mmol) and TMS–Cl (0.47 mL, 3.72 mmol)
were added sequentially. After being stirred for 15 min the
reaction mixture was quenched with saturated aqueous
NH4Cl solution, extracted with EtOAc, washed with brine,
dried (Na2SO4), filtered and concentrated in vacuo.
Purification by column chromatography (SiO2, 25–30%
EtOAc in petroleum ether eluant) provided compound 20
(119 mg, 35%) as a clear oil. Rf¼0.4 (silica gel, 35% in
petroleum ether); [a]2D0¼þ26.5 (c 1.13, CHCl3); IR (neat):
n
max 3499, 3039, 2960, 2930, 2839, 1607, 1510, 1447, 1234,
1102, 823, 746, 699 cm21; 1H NMR (CDCl3, 500 MHz): d
7.66–7.24 (m, 15H, aromatic), 7.22 and 6.84 (two d,
J¼8.7 Hz, 4H, PMP ortho and meta-H), 4.625 (ABq, J¼
11.2 Hz, 2H, OCH2Ar), 4.407 (ABq, J¼11.8 Hz, 2H,
OCH2Ar), 4.09 (br d, J¼9.3 Hz, 1H, C5–H), 3.78 (s, 3H,
OCH3), 3.734 (dd, J¼7.4, 4.3 Hz, 1H, CH–O), 3.662 (dd,
J¼10.5, 7.4 Hz, 1H, CH–O), 3.606–3.531 (m, 3H, CH–O),
3.08 (br s, 1H, OH), 1.98, 1.86, 1.66, 1.52 (four m, 4H,
n
max 3451, 3070, 2960, 2925, 2834, 1607, 1502, 1420, 1242,
1107, 1047, 811, 730, 694 cm21
;
1H NMR (CDCl3,

8620
T. K. Chakraborty et al. / Tetrahedron 59 (2003) 8613–8622
300 MHz): d 7.7–7.33 (m, 10H, aromatic), 7.27 and 6.87
(two d, J¼8.4 Hz, 4H, PMP ortho- and meta-H), 4.65, 4.48
(ABq, J¼11.2 Hz, 2H, OCH2PMP), 3.78 (s, 3H, OCH3),
3.95–3.89 and 3.76–3.64 (m, 6H, C1–H2, C3–H, C5–H,
C7–H2), 3.64 (br s, 1H, OH), 2.11 (br s, 1H, OH), 1.99–
1.85 and 1.8–1.74 and 1.71–1.61 (m, 4H, C2–H2, C4–H,
C6–H), 1.06 (s, 9H, tBu), 0.9 (d, J¼6.8 Hz, 3H, CH3), 0.78
(d, J¼6.8 Hz, 3H, CH3); 13C NMR (CDCl3, 75 MHz): d
159.32, 135.61, 135.53, 133.66, 133.50, 130.18, 129.64,
129.61, 127.63, 113.88, 79.65, 73.30, 71.93, 67.94,
60.62, 55.21, 37.15, 37.07, 33.25, 26.86, 19.21, 11.87,
8.71; MS (ESIMS): m/z (%): 551 (17) [MþH]þ; HRMS
(LSIMS): calcd for C33H47O5Si [MþH]þ: 551.3193, found:
551.3189.
(s, 3H, SiMe); 13C NMR (CDCl3, 75 MHz): d 101.90, 93.65,
73.65, 73.43, 70.85, 61.62, 40.01, 34.87, 34.76, 25.84,
18.13, 13.92, 5.79, 20.09, 24.29, 24.84; MS (LSIMS): m/z
(%): 386 (33) [MþH]þ; HRMS (LSIMS): calcd for
C20H41O3Si2 [MþH]þ: 385.2594, found: 385.2594.
3.1.14. Synthesis of 3. To a solution of compound 18
(105 mg, 0.164 mmol) in dry pyridine (1 mL), MsCl
(0.02 mL, 0.246 mmol) and DMAP (2 mg, 0.0164 mmol)
were added sequentially at 08C. After being stirred for 0.5 h
at the same temperature, the reaction mixture was quenched
with saturated aqueous NH4Cl solution, extracted with
EtOAc, washed with saturated aqueous CuSO4 solution,
water, brine, dried (Na2SO4) and concentrated in vacuo. The
residue was used directly in the next step.
3.1.13. Synthesis of 1 and 2. To a solution of compound
15 (72 mg, 0.162 mmol) in dry pyridine (1 mL), MsCl
(0.08 mL, 0.244 mmol) and DMAP (2 mg, 0.016 mmol)
were added sequentially at 08C. After being stirred for
30 min at the same temperature, the reaction mixture was
quenched with saturated aqueous NH4Cl solution, extracted
with EtOAc, washed with saturated aqueous CuSO4
solution, water, brine, dried (Na2SO4) and concentrated in
vacuo. It was used directly in the next step.
It was dissolved in dry THF (1 mL) and TBAF (1 M in THF,
0.246 mL, 0.246 mmol) was added at 08C. Reaction mixture
was warmed to room temperature and stirred for 24 h. It was
quenched with saturated aqueous NH4Cl solution, extracted
with EtOAc, washed with brine, dried (Na2SO4) and
concentrated in vacuo. Purification by column chromato-
graphy (SiO2, 12–14% EtOAc in petroleum ether) afforded
compound 3 (55 mg, 87% in 2 steps) as a clear oil. Rf¼0.6
(silica gel, 20% EtOAc in petroleum ether); [a]2D0¼224.8 (c
1.83, CHCl3); IR (neat): nmax 3030, 2855, 1612, 1512, 1458,
The residue was dissolved in dry MeOH (1 mL), CSA
(3.8 mg, 0.016 mmol) was added at 08C under nitrogen
atmosphere. The reaction mixture was warmed to room
temperature and stirred for 3 h. It was quenched with
saturated aqueous NaHCO3 solution, extracted with EtOAc,
washed with brine, dried (Na2SO4) and concentrated in
vacuo. Purification by column chromatography (SiO2,
7–8% EtOAc in petroleum ether eluant) eluted first
compound 2 (13 mg, 21% in 2 steps) and followed by 1
(23 mg, 37% in 2 steps).
1355, 1301, 1244, 1175, 1093, 1037, 839, 745, 699 cm21
;
1H NMR (CDCl3, 500 MHz, numbering as in A): d 7.34–
7.27 (m, 5H, aromatic), 7.25 and 6.86 (two d, J¼8.5 Hz, 4H,
PMP), 4.61 and 4.42 (ABq, J¼12.1 Hz, 2H, OCH2Ar), 4.43
(ABq, J¼12.7 Hz, 2H, OCH2Ar), 3.88 (dd, J¼11.5, 3.0 Hz,
1H, C7–H), 3.79 (s, 3H, OCH3), 3.62–3.52 (m, 3H, C1–H2,
C3–H), 3.44 (dd, J¼11.5, 1.2 Hz, 1H, C7–H0), 3.24 (t, J¼
3 Hz, 1H, C5–H), 1.95, 1.88, 1.78 and 1.65 (four m, 4H,
C2–H2, C4–H, C6–H), 1.05 (d, J¼6.8 Hz, 3H, CH3), 0.91
(d, J¼6.7 Hz, 3H, CH3); 13C NMR (CDCl3, 75 MHz): d
159.01, 139.01, 130.75, 129.17, 128.18, 127.38, 127.31,
113.66, 81.17, 75.42, 72.59, 71.21, 67.37, 67.01, 55.17,
34.97, 33.11, 31.72, 15.25, 14.00; MS (ESIMS): m/z
(%): 385 (17) [MþH]þ, 407 (25) [MþNa]þ; HRMS
(LSIMS): calcd for C24H33O4 [MþH]þ: 385.2379, found:
385.2389.
Data for compound 1. Rf¼0.4 (20% EtOAc in petroleum
ether); [a]2D0¼þ54.8 (c 0.22, CHCl3); IR (neat): nmax 3426,
2941, 2841, 2158, 1468, 1384, 1252, 1084, 1052, 843,
771 cm21; 1H NMR (CDCl3, 500 MHz, numbering as in A):
d 3.76 (t, J¼5.6 Hz, 2H, C1–H2), 3.72 (d, J¼10.7 Hz, 1H,
C7–H), 3.57 (ddd, J¼10.1, 3.1, 2.0 Hz, 1H, C3–H), 3.33
(dd, J¼10.1, 4.8 Hz, 1H, C5–H), 2.17 (br s, 1H, OH), 1.95,
1.74, 1.68 and 1.49 (four m, 4H, C2–H2, C4–H, C6–H),
0.97 (d, J¼6.5 Hz, 3H, CH3), 0.93 (d, J¼6.8 Hz, 3H, CH3),
0.88 (s, 9H, tBu), 0.14 (s, 9H, SiMe3), 0.037 (s, 3H, SiMe),
0.017 (s, 3H, SiMe); 13C NMR (CDCl3, 75 MHz): d 103.37,
89.96, 78.56, 76.85, 73.52, 61.23, 39.94, 38.42, 35.25,
25.80, 18.09, 14.34, 6.10, 20.14, 24.15, 24.85; MS
(LSIMS): m/z (%): 385 (31) [MþH]þ; HRMS (LSIMS):
calcd for C20H41O3Si2 [MþH]þ: 385.2594, found:
385.2584.
3.1.15. Synthesis of 4. To a solution of 19 (84 mg,
0.189 mmol) in CH2Cl2 (1 mL), Et3N (0.053 mL,
0.378 mmol) and TsCl (39.7 mg, 0.2 mmol) were added
sequentially at 08C under nitrogen atmosphere. The reaction
mixture was warmed to room temperature and stirred for
5 h. It was quenched with saturated aqueous NH4Cl
solution, extracted with EtOAc, washed with brine, dried
(Na2SO4) and concentrated in vacuo. The residue was used
directly in the next step.
Data for compound 2. Rf¼0.45 (20% EtOAc in petroleum
ether); [a]2D0¼þ104.6 (c 0.66, CHCl3); IR (neat): nmax 3453,
2951, 2169, 1463, 1388, 1335, 1253, 1076, 973, 844, 777,
674 cm21; 1H NMR (CDCl3, 500 MHz, numbering as in A):
d 4.52 (d, J¼5.5 Hz, 1H, C7–H), 4.215 (dt, J¼10.9, 2.4 Hz,
1H, C3–H), 3.76 (t, J¼5.5 Hz, 2H, C1–H2), 3.75 (dd, J¼
10.3, 4.9 Hz, 1H, C5–H), 2.24 (br s, 1H, OH), 1.97–1.85,
1.74 and 1.54–1.49 (m, 4H, C2–H2, C4–H, C6–H), 0.93
(d, J¼6.7 Hz, 3H, CH3), 0.92 (d, J¼6.8 Hz, 3H, CH3), 0.91
It was dissolved in dry MeOH (1 mL), K2CO3 (78.4 mg,
0.567 mmol) was added at 08C under nitrogen atmosphere.
The reaction mixture was allowed to room temperature and
stirred for 24 h. It was quenched with saturated aqueous
NH4Cl solution, extracted with EtOAc, washed with brine,
dried (Na2SO4) and concentrated in vacuo. Purification by
column chromatography (SiO2, 13–15% EtOAc in petro-
leum ether eluant) afforded compound 4 (62 mg, 85% in 2
steps) as a clear oil. Rf¼0.6 (silica gel, 20% EtOAc in
petroleum ether); [a]D20¼þ83.1 (c 1.5, CHCl3); IR (neat):
t
(s, 9H, Bu), 0.19 (s, 9H, SiMe3), 0.07 (s, 3H, SiMe), 0.05

T. K. Chakraborty et al. / Tetrahedron 59 (2003) 8613–8622
8621
n
max 2947, 2911, 2853, 1612, 1513, 1458, 1359, 1302, 1246,
References
1177, 1093, 955, 820, 739, 698 cm21; H NMR (CDCl3,
500 MHz, numbering as in A): d 7.35–7.27 (m, 5H,
aromatic), 7.25 and 6.88 (two d, J¼9.1 Hz, 4H, PMP
ortho and meta-H), 4.62 and 4.34 (ABq, J¼11.5 Hz, 2H,
OCH2Ar), 4.44 (ABq, J¼11.5 Hz, 2H, OCH2Ar), 3.80 (dd,
J¼11.2, 5.5 Hz, 1H, C7–H), 3.79 (s, 3H, OCH3), 3.57–
3.494 (m, 2H, C1–H2), 3.475–3.445 (m, 1H, C3–H), 3.12
(dd, J¼10.3, 4.9 Hz, 1H, C5–H), 2.96 (t, J¼11.2 Hz, 1H,
C7–H0), 2.04, 1.89 and 1.66 (m, 4H, C2–H2, C4–H, C6–
H), 0.92 (d, J¼6.7 Hz, 3H, CH3), 0.86 (d, J¼6.7 Hz, 3H,
CH3); 13C NMR (CDCl3, 75 MHz): d 159.08, 138.58,
130.54, 129.16, 128.24, 127.61, 127.41, 113.69, 83.76,
76.16, 72.90, 72.57, 69.57, 66.69, 55.14, 34.44, 33.36,
31.41, 13.46, 5.75; MS (EIMS): m/z (%): 293 (10)
[Mþ291], 384 (4.3) [M]þ; HRMS (LSIMS): calcd for
C24H33O4 [MþH]þ: 385.2379, found: 385.2365.
1
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It was dissolved in dry toluene (5 mL), NaH (35 mg,
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0.925 (d, J¼6.7 Hz, 3H, CH3), 0.775 (d, J¼6.8 Hz, 3H,
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113.79, 80.70, 80.27, 70.19, 66.27, 65.75, 55.24, 38.85,
36.52, 31.97, 26.89, 19.28, 12.72, 9.17; MS (ESIMS): m/z
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´
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Acknowledgements
Authors wish to thank Drs A. C. Kunwar and M. Vairamani
for NMR and mass spectroscopic assistance, respectively;
CSIR, New Delhi for research fellowship (R. R.).
7. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;

8622
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