Synthesis of chiral 4-hydroxy-2,3-unsaturated carbonyl compounds from 3,4-epoxy alcohols by oxidation: Application in the formal synthesis of macrosphelide A

Article abstract of DOI:10.1016/j.tet.2003.09.070

An interesting transformation during the oxidation of 3,4-epoxy alcohols 1a-d, derived from the corresponding homoallylic alcohols, led to the formation of 4-hydroxy-2,3-unsaturated carbonyls 2a-d in very good yields. One of these products 2c was transfor

Full text of DOI:10.1016/j.tet.2003.09.070

Tetrahedron 59 (2003) 9127–9135
Synthesis of chiral 4-hydroxy-2,3-unsaturated carbonyl
compounds from 3,4-epoxy alcohols by oxidation: application in
the formal synthesis of macrosphelide A
*
Tushar K. Chakraborty, Subhas Purkait and Sanjib Das
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 12 June 2003; revised 26 August 2003; accepted 18 September 2003
Abstract—An interesting transformation during the oxidation of 3,4-epoxy alcohols 1a–d, derived from the corresponding homoallylic
alcohols, led to the formation of 4-hydroxy-2,3-unsaturated carbonyls 2a–d in very good yields. One of these products 2c was transformed
into the functionalised carboxylic acid 5, an advanced stage intermediate from which the total synthesis of macrosphelide A has been
reported.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric synthesis due to the easy availability of chiral
epoxides by the Sharpless asymmetric epoxidation method.3
Many of these reactions are used routinely by synthetic
organic chemists to construct a wide variety of structural
moieties en route to various natural products. During the
Ring-opening reactions of epoxides1,2 constitute an import-
ant class of methodologies developed and employed
extensively in organic synthesis, especially in the area of
Keywords: epoxy alcohols; Sharpless epoxidation; epoxide opening; macrosphelides.
*
Corresponding author. Tel.: þ914027193154; fax: þ914027193108; e-mail: chakraborty@iict.res.in
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.070

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T. K. Chakraborty et al. / Tetrahedron 59 (2003) 9127–9135
Scheme 3.
2. Results and discussion
The starting 3,4-epoxy alcohols 1a–d were prepared
following the routes shown in Schemes 1–4. The salient
feature of the common strategy adopted in these syntheses is
the construction of an appropriate intermediate in each case
that carries an allylic alcohol moiety at one end of the
molecule and a protected hydroxyl group in the homoallylic
position at the other terminal. While the former served as a
prerequisite template to introduce chirality in the molecule
by Sharpless asymmetric epoxidation, the deprotected
hydroxyl of the other end finally provided the required
3,4-epoxy alcohol moieties of the oxidation substrates
1a–d.
Scheme 1.
synthesis of such compounds, we encountered an unusual
transformation while oxidizing various 3,4-epoxy alcohols,
like 1a–d, derived from the corresponding homoallylic
alcohols. Under standard oxidation reaction conditions, this
led to the formation of unexpected products, 4-hydroxy-2,3-
unsaturated carbonyl compounds 2a–d, exclusively and in
good yields. These structural moieties are present in many
polyketide natural products, like cineromycins B4 (3) and
the related compounds, macrosphelides A-L5 (4). Our
present work provides a simple methodology for the
efficient synthesis of trans 4-hydroxy-2,3-unsaturated
carbonyl compounds in optically pure form. Finally, one
of these products 2c is transformed into an appropriately
protected form of (E)-(4R,5S)-4,5-dihydroxyhex-2-enoic
acid 5, the major structural component of highly potent
antitumor compounds, macrosphelides.5,6 Total synthesis
of macrosphelide A has already been achieved from 5.6i
Synthesis of 1a started with but-3-yn-1-ol 6 that was
silylated to give compound 7 in 97% yield (Scheme 1). The
Li-acetylide prepared from 7 using n-BuLi was reacted with
paraformaldehyde to furnish the addition product 8 in 93%
yield. Reduction of 8 with Red-Al provided the E-allylic
alcohol 9 that was subjected to Sharpless epoxidation using
(þ)-DET to give the chiral epoxy alcohol 10 (96% ee)7 in
Scheme 2.
Scheme 4.

T. K. Chakraborty et al. / Tetrahedron 59 (2003) 9127–9135
9129
97% yield. The primary hydroxyl group of 10 was protected
as a trityl ether to provide compound 11 in 98% yield.
Subsequent desilylation at the other end furnished the
requisite oxidation substrate 1a in 93% yield.
92% yield. Epoxidation of 21 by Sharpless method using
(þ)-DET led to the formation of chiral epoxy alcohol 22 as a
mixture of diastereomers in 96% yield. Routine reaction
sequences were followed next to convert 22 to the required
compound 1d in 85% yield.
The starting material for the synthesis of 1b was the
aldehyde 128 (Scheme 2), prepared from mono-PMB-
protected propane-1,3-diol by oxidation. Olefination of 12
with the stabilized ylide provided the a,b-unsaturated ester
13 in 90% yield with complete E-selectivity. No Z-isomer
was detected. Reduction of 13 with LAH gave the allylic
alcohol 14 in 88% yield. Sharpless epoxidation of 14 using
(þ)-DET furnished the chiral epoxy alcohol 15 (96% ee)7 in
95% yield. Routine functional group manipulations finally
led to the required epoxy alcohol 1b in two steps in 86%
yield from 15.
Having thus prepared the starting materials 1a–d, the stage
was now set to carry out their oxidation reactions.
Compound 1a was oxidized under four different reaction
conditions: (a) Swern oxidation using (COCl)2, DMSO,
Et3N in CH2Cl2; (b) PDC in CH2Cl2; (c) IBX in DMSO and
(d) TPAP, NMO in CH2Cl2. In all these reactions, the only
product that could be isolated after the work-up was
the 4-hydroxy-2,3-unsaturated aldehyde 2a. Presumably,
the aldehyde intermediate that was first formed during the
oxidation process underwent an in situ b-elimination
reaction leading to the formation of 2a in very good yields.
The results of these oxidation reactions are summarized in
Table 1. Oxidation of the other 3,4-epoxy alcohols 1b and
1c under Swern oxidation conditions led to the formation of
similar products (2b and 2c, respectively), exclusively and
in excellent yields. The keto intermediate that was formed
during the oxidation of 1d, under Swern oxidation method
and also with SO3-py/Et3N/DMSO, underwent the same
kind of b-elimination process, but only partially during the
reaction. However, the transformation was complete when
the crude oxidation product was subjected to purification by
column chromatography using a long silica gel column that
was eluted slowly with 5–20% EtOAc in petroleum ether or
simply by stirring in the presence of silica gel in the same
solvent system to furnish the corresponding g-hydroxy-a,b-
unsaturated keto product 2d in excellent yield.
Compound 1c was prepared starting from the same aldehyde
12 (Scheme 3) that was used in Scheme 2. Olefination of 12
provided an a,b-unsaturated ester that was reduced to an
allylic alcohol using DIBAL-H. Finally, Swern oxidation of
the allylic alcohol furnished the requisite aldehyde 16 in
87% overall yield in three steps from 12. Grignard addition
to 16 led to the allylic alcohol 17 (78% yield) that was
subjected to Sharpless catalytic kinetic resolution using
(þ)-DET to furnish the chiral epoxy alcohol 18 (94% ee by
Mosher ester method) in 40% yield. A two-step protection–
deprotection protocol converted 18 to the required product
1c in 80% yield.
A Grignard addition to the aldehyde 12 constituted the first
step in the synthesis of 1d as depicted in Scheme 4. The
resulting addition product 19 was next transformed into 20
in 80% yield following a two-step protection–deprotection
sequence.
Finally, the free hydroxyl group of compound 2c was
protected as MEM-ether to give the intermediate 23
(Scheme 5). The aldehyde function of 23 was next oxidized
to the acid to furnish the protected (E)-(4R,5S)-4,5-
dihydroxyhex-2-enoic acid 5. As the conversion of 5 to
macrosphelide A 4 is already reported,6i the present work
Oxidation of 20 was followed by olefination using stabilized
ylide to give the a,b-unsaturated ester in 82% yield.
Reduction using DIBAL-H gave the allylic alcohol 21 in
Table 1. Oxidation of 3,4-epoxy alcohols 1 under various conditions
Entry
3,4-Epoxy alcohols (1)
Products (2)
Oxidation conditionsa
Yield (%)
A
B
C
D
82
85
80
80
1
1a
1b
2a
2b
2
3
A
92
A
90
1c
2c
A
E
90
88
4
1d
2d
a
˚
A: (COCl)2 (1.5 equiv.), DMSO (3.2 equiv.), Et3N (5 equiv.), CH2Cl2, 278 to 08C; B: PDC (2 equiv.), 4 A MS, CH2Cl2, rt. C: IBX (2 equiv.), DMSO, 08C to
˚
rt. D: TPAP (0.05 equiv.), NMO (1.5 equiv.), 4 A MS, CH2Cl2, rt. E: SO3–py (5 equiv.), Et3N (5 equiv.), CH2Cl2–DMSO (0.8:1), 08C.

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T. K. Chakraborty et al. / Tetrahedron 59 (2003) 9127–9135
(1.65 g, 97%) as colorless oil. Rf 0.75 (silica gel, 20%
EtOAc in petroleum ether); IR (neat): nmax 3294, 3069,
2912, 2856, 1463, 1419, 1094, 694 cm21 1H NMR
;
(200 MHz, CDCl3): d 7.7–7.38 (m, 10H, aromatic), 3.75
(t, J¼6.1 Hz, 2H, C4–H2), 2.41 (dt, J¼6.1, 1.5 Hz, 2H, C3–
t
H2), 1.84 (t, J¼1.5 Hz, 1H, C1–H), 1.02 (s, 9H, Bu); 13C
NMR (75 MHz, CDCl3): d 135.6, 133.5, 129.7, 127.7,
81.4, 69.3, 62.3, 26.8, 22.6, 19.2; Mass (EI): m/z: 252
[M2isobutene]þ.
3.1.2. Synthesis of 8.9,10 To a stirred solution of 7 (1.53 g,
4.98 mmol) in dry THF (15 mL), n-BuLi (1.6 M in hexane,
3.42 mL, 5.4 mmol) was added at 2788C and the reaction
mixture was slowly warmed up to 08C in 1 h. Paraformalde-
hyde (448.6 mg, 14.94 mmol) was then added and the
reaction mixture was stirred at room temperature for 3 h. It
was quenched with saturated aqueous NH4Cl solution,
extracted with EtOAc. The combined organic extracts were
washed with brine, dried (Na2SO4) and concentrated in
vacuo. Purification of the residue by column chroma-
tography (SiO2, 10–15% EtOAc in petroleum ether eluant)
provided compound 8 (1.57 g, 93%) as a colorless oil. Rf 0.4
(silica gel, 20% EtOAc in petroleum ether); IR (neat): nmax
3369 (b), 3062, 2937, 1094, 694 cm21; 1H NMR (200 MHz,
CDCl3): d 7.74–7.33 (m, 10H, aromatic), 4.27–4.16 (m, 2H,
C1–H2), 3.70 (t, J¼6.8 Hz, 2H, C5–H2), 2.57–2.44 (m, 2H,
Scheme 5.
pertains to a formal total synthesis of the latter. Compound 5
synthesized here is identical in all respects with that
prepared earlier, having all spectroscopic data matching
with those reported.6i
The method described here for the synthesis of 4-hydroxy-
2,3-unsaturated carbonyl compounds should find useful
applications in the synthesis of many other natural products
that carry such structural moieties.
3. Experimental
C4–H2), 1.43 (t, J¼4.6 Hz, 1H, OH), 1.08 (s, 9H, tBu); 13
C
NMR (50 MHz, CDCl3): d 135.6, 133.7, 129.7, 127.6, 83.8,
79.7, 62.5, 51.3, 26.8, 22.9, 19.2; Mass (LSIMS): m/z: 320
[M2H2O]þ, 307 [M2CH2OH]þ.
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 homo-
geneous materials unless otherwise stated. IR spectra were
recorded as neat liquids or KBr pellets. NMR spectra were
recorded on 200, 300 and 400 MHz spectrometers at room
temperature of ,218C in CDCl3 using tetramethylsilane as
internal standard or the solvent signal as secondary standard
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 with complete
proton decoupling. Mass spectra were obtained under
electron impact (EI) and liquid secondary ion mass
spectrometric (LSIMS) techniques.
3.1.3. Synthesis of 9. To a stirred solution of compound 8
(1.44 g, 4.27 mmol) in dry ether (15 mL), Red-Al (3.5 M in
toluene, 2.44 mL, 8.54 mmol) was added slowly over a
period of 15 min at 08C. After being stirred for 3 h, the
solution was quenched by careful addition of saturated
aqueous NH4Cl solution and extracted with EtOAc. The
combined organic extracts were washed successively with
water (8 mL) and brine (6 mL), dried over Na2SO4 and
concentrated. The resulting oil was purified by column
chromatography (SiO2, 12–16% EtOAc in petroleum ether
eluant) to give compound 9 (1.02 g, 70%) as colorless oil.
Rf 0.4 (silica gel, 25% EtOAc in petroleum ether); IR (neat):
nmax 3306, 3912, 2850, 1094, 694 cm21
;
1H NMR
(200 MHz, CDCl3): d 7.68–7.38 (m, 10H, aromatic),
5.70–5.66 (m, 2H, olefinic), 4.10–4.01 (m, 2H, C1–H2),
3.72 (t, J¼6.0 Hz, 2H, C5–H2), 2.32 (dt, J¼11.4, 6.0 Hz,
2H, C4–H2), 1.05 (s, 9H, tBu); 13C NMR (75 MHz, CDCl3):
d 135.6, 133.9, 130.96, 129.6, 129.5, 127.6, 63.7, 63.4, 35.5,
26.8, 19.2; Mass (EI): m/z: 283 [MþH2isobutene]þ.
3.1.4. Synthesis of 10. To a suspension of activated
˚
3.1.1. Synthesis of 7.9,10 To a solution of compound 6
(0.42 mL, 5.53 mmol) in dry CH2Cl2 (20 mL), Et3N
(1.15 mL, 8.29 mmol) and TBDPSCl (1.57 mL,
6.08 mmol) were added sequentially at 08C, followed by
the addition of DMAP (67 mg, 0.55 mmol). 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 extracts were com-
bined, dried over Na2SO4, filtered and concentrated in
vacuo. The residue was purified by column chromatography
(SiO2, 2.5% EtOAc in petroleum ether eluant) to give 7
powdered 4 A molecular sieves (177 mg, 20 wt%) in
CH2Cl2 (10 mL), Ti(OiPr)4 (0.77 mL, 2.6 mmol) and
(þ)-DET (0.53 mL, 3.12 mmol) were added sequentially
at 2208C. After being stirred for 0.5 h, a solution of 9
(884 mg, 2.6 mmol) in CH2Cl2 (8 mL) was added and
stirring continued for another 0.5 h at the same temperature.
TBHP (3.5 M in toluene, 2.22 mL, 7.8 mmol) was then
added to it and stirred for 3 h at 2208C. The reaction was
quenched by adding water (15 mL) and allowed to come to
room temperature where it was stirred for 1 h. After
re-cooling it to 08C, an aqueous solution of NaOH (30%

T. K. Chakraborty et al. / Tetrahedron 59 (2003) 9127–9135
9131
w/v, 5 mL), saturated with NaCl was added to it and stirred
at 08C for 10 min. CH2Cl2 was removed under reduced
pressure and the compound was extracted with ether,
washed with brine, dried (Na2SO4), filtered and concen-
trated in vacuo. Purification by column chromatography
(SiO2, 25–30% EtOAc in petroleum ether eluant) afforded
pure 10 (898 mg, 97%) as a syrupy liquid. Rf 0.4 (silica gel,
40% EtOAc in petroleum ether); [a]2D2¼219.4 (c 1.37,
CHCl3); IR (neat): nmax 3437, 3075, 2931, 2856,1469,1431,
1094, 694 cm21; 1H NMR (200 MHz, CDCl3): d 7.68–7.29
(m, 10H, aromatic), 4.93–3.51 (m, 4H, C1–H2, C5–H2),
3.08 (dt, J¼5.8, 1.8 Hz, 1H, C3–H), 2.92 (m, 1H,
C2–H),1.77 (q, J¼5.8 Hz, 2H, C4–H2); 1.53 (m, 1H,
room temperature and the reaction mixture stirred for 3 h.
Solvent was evaporated under reduced pressure and the
residue was purified by column chromatography (SiO2, 6%
EtOAc in petroleum ether eluant) to yield 13 (1.06 g, 90%)
as a syrup. Rf 0.6 (silica gel, 30% EtOAc in petroleum
ether); IR (neat): nmax 2938, 2856, 1700, 1506, 1240, 1090,
1
825 cm21; H NMR (400 MHz, CDCl3): d 7.20 (d, J¼
8.5 Hz, 2H, aromatic), 6.83 (d, J¼8.5 Hz, 2H, aromatic),
6.72 (t, J¼7.2 Hz, 1H, olefinic), 4.43 (s, 2H, OCH2Ar),
4.176 (q, J¼6.7 Hz, 2H, CO2CH2CH3), 3.79 (s, 3H, PMB–
OCH3), 3.49 (t, J¼7.2 Hz, 2H, PMBOCH2), 2.53 (q, J¼
7.2 Hz, 2H, allylic), 1.84 (s, 3H,¼CCH3), 1.30 (t, J¼6.7 Hz,
3H, CO2CH2CH3); 13C NMR (CDCl3, 200 MHz): d 159.2,
138.2, 130.3, 129.4, 129.2, 113.8, 72.6, 68.3, 60.4, 55.2,
29.4, 14.2, 12.5; Mass (EI): m/z: 278 [M]þ, 234
[M2CH3CHO]þ, 205 [M2CO2Et]þ.
t
OH), 1.04 (s, 9H, Bu); 13C NMR (75 MHz, CDCl3): d
135.5, 133.5, 129.6, 127.6, 61.7, 60.7, 58.6, 53.7, 34.7, 26.7,
19.1; Mass (LSIMS): m/z: 357 [MþH]þ.
3.1.5. Synthesis of 11. A solution of alcohol 10 (812 mg,
2.28 mmol), Et3N (0.48 mL, 3.42 mmol) and DMAP
(28 mg, 0.23 mmol) in CH2Cl2 (10 mL) at 08C was treated
with TrCl (763 mg, 2.74 mmol). The reaction was stirred at
ambient temperature for 12 h and then quenched with
saturated aqueous NH4Cl solution, extracted with ether. The
combined organic extracts were washed with water, brine,
dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (SiO2,
2–4% EtOAc in petroleum ether eluant) to give 11 (1.34 g,
98%) as a white solid. Rf 0.4 (silica gel, 10% EtOAc in
petroleum ether); [a]D22¼7.28 (c 1.2, CHCl3); IR (CHCl3):
3.1.8. Synthesis of 14. Ester 13 (945 mg, 3.4 mmol) was
taken in dry ether (12 mL), cooled at 08C and to it LAH
(258 mg, 6.8 mmol) was added portion wise and stirred at
that temperature for 15 minutes. The reaction was then
quenched with saturated aqueous Na2SO4 solution (5 mL) at
08C and stirred for 15 minutes. Precipitated solid was
filtered through a short pad of Celite and the filter cake was
washed with ether. The filtrate and washings were combined
and washed with brine, dried (Na2SO4) and concentrated
in vacuo. After column chromatography (SiO2, 24–30%
EtOAc in petroleum ether eluant), the product 14 (706 mg,
88%) was obtained as syrupy liquid. Rf 0.4 (silica gel, 50%
EtOAc in petroleum ether); IR (neat): nmax 3426, 2850,
1
nmax 3069, 2944, 2875, 1435, 1094, 694 cm21; H NMR
(200 MHz, CDCl3): d 7.68–7.12 (m, 25H, aromatic), 3.86–
3.72 (m, 2H, –CH2–O–), 3.32 (dd, J¼10.1, 2.2 Hz, 1H,
–CH–O–), 3.15 (t, J¼10.1 Hz, 1H, –CH–O–), 3.05 (m,
1H, C3–H), 2.88 (m, 1H, C1–H), 1.87–1.68 (m, 2H,
1600, 1506, 1238, 1088, 1027, 825 cm21 1H NMR
;
(200 MHz, CDCl3): d 7.20 (d, J¼8.8 Hz, 2H, aromatic),
6.83 (d, J¼8.8 Hz, 2H, aromatic), 5.30 (br t, J¼7.2 Hz, 1H,
olefinic), 4.41 (s, 2H, OCH2Ar), 3.96 (br s, 2H, C1–H2),
3.79 (s, 3H, PMB–OCH3), 3.42 (t, J¼7.2 Hz, 2H,
PMBOCH2), 2.32 (q, J¼7.2 Hz, 2H, allylic), 1.66 (s,
3H¼CCH3), 1.43 (br s, 1H, OH); 13C NMR (CDCl3,
75 MHz): d 159.0, 136.6, 130.3, 129.1, 121.7, 113.6, 72.4,
69.3, 68.4, 55.1, 28.1, 13.6; Mass (LSIMS): m/z: 236 [M]þ,
235 [M2H]þ.
t
C4–H2), 1.04 (s, 9H, Bu); 13C NMR (75 MHz, CDCl3): d
143.8, 135.5, 133.6, 133.5, 129.6, 128.6, 127.8, 127.6,
127.0, 86.6, 77.2, 64.2, 60.7, 57.4, 53.7, 35.0, 26.8, 19.1;
Mass (LSIMS): m/z: 597 [M2H]þ, 355 [M2CPh3]þ, 243
[CPh3]þ.
3.1.6. Synthesis of 1a. To a solution of compound 11
(1.27 g, 2.12 mmol) in dry THF (9 mL), TBAF (1 M
solution in THF, 2.54 mL, 2.54 mmol) was added under
nitrogen atmosphere, at 08C. After stirring for 3 h at room
temperature, the reaction was quenched with saturated
aqueous NH4Cl solution, extracted with EtOAc, washed
with brine, dried over Na2SO4 and concentrated in vacuo.
Purification by column chromatography (SiO2, 40–50%
EtOAc in petroleum ether eluant) afforded 1a (708 mg,
93%) as a syrupy liquid. Rf 0.4 (Silica gel, 40% EtOAc
in petroleum ether). [a]2D2¼29.76 (c 0.815, CHCl3); IR
(CHCl3): nmax 3419, 3021, 2912, 1488, 1444, 1056,
3.1.9. Synthesis of 15. The allylic alcohol 14 (597 mg,
2.53 mmol) was subjected to Sharpless asymmetric epoxi-
dation following the same procedure as described for the
preparation of 10. Purification by column chromatography
(SiO2, 25–40% EtOAc in petroleum ether eluant) afforded
the epoxide 15 (606 mg, 95%). Rf 0.3 (silica gel, 50%
EtOAc in petroleum ether); [a]2D2 215.5 (c 2.0, CHCl3);
IR(neat): nmax 3450, 2928, 2856, 1612, 1508, 1452, 1237,
1093, 1038, 820 cm21; 1H NMR (400 MHz, CDCl3): d 7.20
(d, J¼8.6 Hz, 2H, aromatic), 6.83 (d, J¼8.6 Hz, 2H,
aromatic), 4.41 (s, 2H, OCH2Ar), 3.80 (s, 3H, PMB–
OCH3), 3.66–3.50 (m, 4H), 3.13 (t, J¼6. 1 Hz, 1H, epoxy-
H), 1.94–1.74 (m, 2H), 1.68 (br m, 1H, OH), 1.27 (s, 3H,
C2CH3); 13C NMR (CDCl3, 75 MHz): d 159.1, 130.2,
129.1, 113.7, 72.6, 67.0, 65.4, 60,8, 57.9, 55.1, 28.8, 14.2;
Mass (LSIMS): m/z: 252 [M]þ, 251 [M2H]þ.
700 cm21 1H NMR (200 MHz, CDCl3): d 7.49–7.13
;
(m, 15H, aromatic), 3.73 (t, J¼7.6 Hz, 2H, CH2OH), 3.28
(dd, J¼10.5, 3.8 Hz, 1H, –CHOTr), 3.14 (dd, J¼10.5,
4.7 Hz, 1H, –CH?OTr), 3.05–2.92 (m, 2H, epoxyH), 1.81–
1.6 (m, 3H, CH2, OH); 13C NMR (75 MHz, CDCl3): d
143.7, 128.6, 127.8, 127.0, 86.7, 64.2, 59.8, 56.6, 54.3, 33.9;
Mass (LSIMS): m/z: 360 [M]þ, 243 [CPh3]þ.
3.1.10. Synthesis of 1b. The epoxy alcohol 15 (479 mg,
1.90 mmol) was subjected to TBDPS-protection following
the same procedure as described above for the preparation
of 7. Chromatographic purification (SiO2, 5–7% EtOAc in
petroleum ether eluant) provided the silylated intermediate
3.1.7. Synthesis of 13. To a solution of the aldehyde 12
(820 mg, 4.23 mmol) in CH2Cl2 (15 mL), stabilized ylide
Ph3PvC(CH3)CO2Et (1.83 g, 5.07 mmol) was added at

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T. K. Chakraborty et al. / Tetrahedron 59 (2003) 9127–9135
(890 mg, 98%) as colorless syrupy liquid that was used
directly in the next step.
chromatography (SiO2, 16–20% EtOAc in petroleum ether
eluant) to give 16 (3.15 g, 92%) as a syrupy liquid. Rf 0.4
(silica gel, 40% EtOAc in petroleum ether); IR (neat): nmax
1
To a solution of the silyl ether prepared above (763 mg,
1.60 mmol) and DDQ (555 mg, 2.4 mmol) in CHCl3–H2O
(32 mL:1.6 mL) buffered by using 0.2 M aqueous solutions
of Na2HPO4 and NaH2PO4 (5.8:4.2, 8 mL) was stirred at
room temperature for 0.5 h. The reaction mixture was
quenched with saturated aqueous NaHCO3 solution (40 mL)
and the layers were separated. The aqueous phase was
extracted with ethyl acetate. The combined organic phases
were washed with water, brine, dried (Na2SO4), filtered and
concentrated in vacuo. The residue was purified by column
chromatography (SiO2, 30–40% EtOAc in petroleum ether
eluant) to give 1b (521 mg, 88%) as colorless syrupy liquid.
Rf¼0.4 (silica gel, 40% EtOAc in petroleum ether);
[a]2D2¼24.27 (c 2.9, CHCl3); IR (neat): nmax 3447, 2930,
2850, 1687, 1602, 1513, 1251, 1099, 813 cm21; H NMR
(200 MHz, CDCl3): d 9.48 (d, J¼8.2 Hz, 1H, CHO), 7.19
(d, J¼8.8 Hz, 2H, aromatic), 6.83 (d, J¼8.8 Hz, 2H,
aromatic), 6.82 (dt, J¼16.3, 6.2 Hz, 1H, CHvCHCHO),
6.13 (ddt, J¼16.3, 8.2, 1.5 Hz, 1H, CHvCHCHO), 4.43
(s, 2H, OCH2Ar), 3.79 (s, 3H, PMB–OCH3), 3.56 (t, J¼
6.2 Hz, 2H, PMBOCH2–), 2.59 (dq, J¼6.2, 1.5 Hz, 2H,
allylic); 13C NMR (50 MHz, CDCl3): d 193.7, 159.3, 155.0,
134.0, 129.9, 129.2, 113.8, 72.7, 67.5, 55.2, 33.0; Mass (EI):
m/z: 220 [M]þ.
3.1.12. Synthesis of 17. To a solution of 16 (3.047 mg,
13.85 mmol) in dry Et2O (40 mL) at 08C, MeMgI (1 M in
Et2O, 20.8 ml, 20.8 mmol) was added drop-wise with
stirring under nitrogen atmosphere. After stirring at the
same temperature for 1 h, the reaction mixture was
quenched with saturated aqueous NH4Cl solution and the
mixture was extracted with EtOAc. The combined organic
extracts were washed with brine, dried (Na2SO4) and
concentrated in vacuo. Column chromatography (SiO2,
25–30% EtOAc in petrolium ether eluant) afforded pure 17
(2.55 g 78%) as a colorless syrupy liquid. Rf 0.3 (silica gel,
40% EtOAc in petroleum ether); IR (neat): nmax 3446, 2920,
1
2853, 1410, 1112, 808, 698 cm21; H NMR (200 MHz,
CDCl3): d 7.70–7.30 (m, 10H, aromatic), 3.81 (m, 2H, C5–
H2), 3.66 and 3.59 (Abq, 2H, C1–H2), 2.92 (dd, J¼7.5,
5.2 Hz, 1H, epoxy-H), 1.90–1.60 (m, 2H, C4–H2), 1.35 (s,
t
3H, C2–CH3), 1.08 (s, 9H, Bu); 13C NMR (CDCl3;
75 MHz): d 135.6, 135.5, 133.3, 133.2, 129.7, 127.7,
76.6, 68.3, 60.6, 60.5, 58.9, 31.0, 26.7, 19.2, 14.5; Mass
(ESI): m/z: 393 [MþNa]þ.
1
3.1.11. Synthesis of 16. To a solution of the aldehyde 12
(3.34 g 17.2 mmol) in CH2Cl2 (55 mL), the stabilized ylide
Ph3PvCHCO2Et (8.99 g, 25.8 mmol) was added at room
temperature and the reaction mixture was stirred for 3 h.
Solvent was evaporated under reduced pressure and the
residue was chromatographed (SiO2, 10–12% EtOAc in
petroleum ether eluant) the desired a,b-unsaturated ester
(4.45 g, 98%) as a syrupy liquid that was used directly in the
next step.
1615, 1218, 1069 cm21; H NMR (200 MHz, CDCl3): d
7.20 (d, J¼8.9 Hz, 2H, aromatic), 6.83 (d, J¼8.9 Hz, 2H,
aromatic), 5.73–5.48 (m, 2H, olefinic), 4.42 (s, 2H,
OCH2Ar), 4.23 (dq, J¼6.0 Hz, 1H, CH(OH)CH3), 3.81 (s,
3H, OCH3), 3.45 (t, J¼6.7 Hz, 2H, PMBOCH2–) 2.31 (q,
J¼6.7 Hz, 2H, allylic), 1.55 (m, 1H, OH), 1.25 (d, J¼
6.0 Hz, 3H, CH(OH)CH3); 13C NMR (75 MHz, CDCl3): d
159.1, 136.0, 130.3, 129.2, 126.9, 113.7, 72.4, 69.3, 68.6,
55.2, 32.4, 23.2; Mass (LSIMS): m/z: 236 [M]þ.
To a solution of the above ester (4.35 g, 16.5 mmol) in dry
toluene at 2788C, DIBAL-H (1.2 M solution in toluene,
28.8 mL, 34.6 mmol) was added. After 15 minutes the
reaction mixture was quenched by adding methanol and
saturated aqueous K–Na-tartrate solution and allowed to
warm to room temperature. The layers were separated and
the aqueous layer was extracted with EtOAc. The combined
organic layers were washed with water, brine, dried
(Na2SO4) concentrated in vacuo. The crude product was
purified by column chromatography (SiO2, 30–40% EtOAc
in petroleum ether eluant) to give compound an allylic
alcohol intermediate (3.55 g, 97%) as a colorless oily liquid
that was used directly in the next step for oxidation.
3.1.13. Synthesis of 18. Compound 17 (2.46 g, 10.4 mmol)
was subjected to Sharpless asymmetric epoxidation follow-
ing the same procedure as described above for the
preparation of 10. Purification by column chromatography
(SiO2, 35–40% EtOAc in petroleum ether eluant) afforded
epoxide 18 (1.05 g, 40%) as a colorless syrupy liquid. Rf 0.4
(silica gel, 50% EtOAc in petrolium ether); [a]2D2¼22.58 (c
1.4, CHCl3); IR (neat): nmax 3437, 2921, 2845, 1598, 1506,
1236, 1088, 1020, 800 cm21; 1H NMR (200 MHz, CDCl3):
d 7.20 (d, J¼8.9 Hz, 2H, aromatic), 6.83 (d, J¼8.9 Hz,
2H, aromatic), 4.43 (ABq, 2H, OCH2Ar), 3.89 (m, 1H,
CH(OH)CH3), 3.79 (s, 3H, OCH3), 3.54 (t, J¼6.0 Hz, 2H,
PMBOCH2–), 3.07 (dt, J¼6.0, 2.2 Hz, 1H, epoxy-H), 2.75
(dd, J¼3.8, 2.2 Hz, 1H, epoxy-H), 1.83 (q, J¼6.0 Hz, 2H,
PMBOCH2CH2–), 1.80 (m, 1H, OH), 1.22 (d, J¼6.7 Hz,
3H, CH(OH)CH3); 13C NMR (50 MHz, CDCl3): d 159.2,
130.3, 129.2, 113.8, 72.7, 66.6, 64.99, 61.6, 55.2, 52.9, 32.1,
18.7; Mass (EI): m/z: 252 [M]þ.
To a solution of oxalyl chloride (2.02 ml, 23.32 mmol) in
dry CH2Cl2 (50 ml) at 2788C, DMSO (3.53 ml,
49.76 mmol) was added slowly and drop-wise with stirring
under nitrogen atmosphere. After 15 min, the allylic alcohol
(3.45 g, 15.55 mmol), prepared as above and dissolved in
dry CH2Cl2 (20 mL), was added to the reaction mixture.
After stirring for 0.5 h at 2788C, Et3N (10.84 mL,
77.75 mmol) was added and stirred for another 0.5 h at
the same temperature and then for 1 h at 08C. The reaction
mixture was then quenched with saturated aqueous NH4Cl
solution and extracted with ether. The combined organic
layers were washed with water, brine, dried (Na2SO4) and
concentrated in vacuo. The residue was purified by column
3.1.14. Synthesis of 1c. To a solution of 18 (950 mg,
3.77 mmol) in dry CH2Cl2 (12 mL), 2,6-lutidine (0.88 mL,
7.54 mmol) and TBSOTf (1.03 mL, 4.52 mmol) were added
sequentially at 08C. After 0.5 h, the reaction was quenched
by saturated aqueous NH4Cl solution, extracted with
EtOAc, washed thoroughly with saturated aqueous CuSO4
solution, water, brine, dried (Na2SO4) and concentrated in
vacuo. Column chromatography (SiO2, 5–6% EtOAc in

T. K. Chakraborty et al. / Tetrahedron 59 (2003) 9127–9135
9133
petrolium ether eluant) gave pure silyl ether intermediate
(1.35 g, 98%) as a colorless syrupy liquid that was used
directly in the next step.
petroleum ether); IR (neat): nmax 3420, 2952, 2926, 2808,
1
1445, 1349, 1051, 718, 682 cm21; H NMR (200 MHz,
CDCl3): d 7.29 (m, 5H, aromatic), 4.63–4.42 (ABq, 2H,
PhCH2), 3.74 (m, 3H, CH2OH, CH(OBn)CH3), 2.32 (m, 1H,
OH), 1.75 (q, J¼5.7 Hz, 2H, –CH2CH2OH), 1.25 (d, J¼
6.0 Hz, 3H, CH(OBn)CH3); 13C NMR (CDCl3, 50 MHz): d
138.4, 128.4, 127.6, 127.6, 74.4, 70.4, 60.6, 38.8, 19.3; Mass
(LSIMS): m/z: 181 [MþH]þ.
The silyl ether (1.296 g, 3.54 mmol), thus prepared, was
subjected to PMB-deprotection following the same pro-
cedure described above in the second step during the
synthesis of 1b from 15. Chromatographic purification
(SiO2, 18–24% EtOAc in petroleum ether eluant) provided
1c (714 mg, 82%) as an oily liquid. Rf 0.3 (silica gel, 10%
EtOAc in petroleum ether); [a]2D2¼29.76 (c 2.1, CHCl3); IR
(neat): nmax 3449, 2925, 2830, 1460, 1225, 1073, 824,
3.1.17. Synthesis of 21. To a solution of compound 20
(674 mg, 3.74 mmol) in dry CH2Cl2 (6 mL) was added with
stirring, DMSO (7.48 mL), Et3N (2.60 mL, 18.7 mmol) and
portion wise SO3–py complex (2.97 g, 18.7 mmol) at 08C
and under nitrogen atmosphere. After 1 h, the reaction
mixture was quenched with saturated aqueous NH4Cl
solution. The layers were separated and the aqueous phase
extracted with EtOAc. The combined organic extracts were
washed with water and brine (15 mL), dried (Na2SO4) and
concentrated in vacuo. The aldehyde thus obtained was
directly subjected to the next step without purification.
764 cm21
;
1H NMR (200 MHz, CDCl3): d 3.76 (t, J¼
6.0 Hz, 2H, CH2OH), 3.66 (m, 1H, CH(OTBS)CH3), 2.99
(ddd, J¼6.0, 4.5, 2.2 Hz, 1H, epoxy-H), 2.69 (dd, J¼4.5,
2.2 Hz, 1H, epoxy-H), 2.05–1.62 (m, 2H, –CH2CH2OH),
t
1.23 (d, J¼6.0 Hz, 3H, CH(OTBS)CH3), 0.88 (s, 9H, Bu),
0.048 and 0.041 (two s, 6H, SiMe2); 13C NMR (75 MHz,
CDCl3): d 67.8, 61.4, 59.88, 54.8, 34.0, 25.7, 20.8, 18.0,
24.75, 24.8; Mass (LSIMS): m/z: 247 [MþH]þ.
3.1.15. Synthesis of 19. Compound 19 was prepared from
12 (2.165 g, 11.16 mmol) following the same procedure as
described above for the preparation of 17. Purification by
column chromatography (SiO2, 25–30% EtOAc in petro-
leum ether eluant) afforded compound 19 (1.87 g, 80%) as
colorless oily liquid. Rf 0.2 (silica gel, 30% EtOAc in
petroleum ether); IR (neat): nmax 3451, 2925, 2828, 1620,
To the crude aldehyde in dry CH2Cl2 (15 mL),
Ph3PvCHCO2Et (1.95 g, 5.61 mmol) was added at room
temperature and the reaction mixture was stirred for 3 h.
Solvent was evaporated under reduced pressure and the
residue was purified by column chromatography (SiO2,
6–7% EtOAc in petroleum ether) to give the a,b-un-
saturated ester intermediate as an oily liquid. The ester was
subjected directly to DIBAL-H reduction following the
same procedure used earlier for the preparation of 16.
Chromatographic purification (SiO2, 25–30% EtOAc in
petroleum ether eluant) gave compound 21 (632 mg, 82%)
as an oily colourless liquid. Rf 0.3 (silica gel, 30% EtOAc in
petroleum ether); IR (neat): nmax 3422, 2926, 2862, 1448,
1
1510, 1242, 1076, 1005, 820 cm21; H NMR (300 MHz,
CDCl3): d 7.20 (d, J¼8.8 Hz, 2H, aromatic), 6.83 (d, J¼
8.8 Hz, 2H, aromatic), 4.43 (s, 2H, OCH2Ar), 3.95 (m, 1H,
CH(OH)CH3), 3.79 (s, 3H, OCH3), 3.69–3.52 (m, 2H,
PMBOCH2–), 2.74 (br s, 1H, OH), 1.79–1.60 (m, 2H,
CH2), 1.18 (d, J¼6.0 Hz, 3H, CH(OH)CH3); 13C NMR
(75 MHz, CDCl3): d 159.1, 130.0, 129.2, 113.7, 72.80, 68.6,
67.4, 55.1, 38.0, 23.2; Mass (LSIMS): m/z: 210 [M]þ, 209
[Mþ2H].
1373, 1080, 968, 738, 698 cm21 1H NMR (300 MHz,
;
CDCl3): d 7.4–7.2 (m, 5H, aromatic), 5.7 (m, 2H, olefin),
4.55 (ABq, 2H, OCH2Ph), 4.1 (m, 2H, CH2OH), 3.6 (m, 1H,
CHCH3), 2.4–2.2 (m, 2H, allylicH), 1.2 (d, J¼6.7 Hz, 3H,
CH3); 13C NMR (CDCl3, 75 MHz): d 138.7, 131.5, 128.7,
128.2, 127.7, 127.6, 127.4, 74.4, 70.3, 63.5, 39.0, 19.4; Mass
(LSIMS): m/z: 206 [M]þ.
3.1.16. Synthesis of 20. Sodium hydride (60% dispersion in
oil, 501.6 mg, 12.54 mmol) was added portion wise to a
solution of 19 (1.756 g, 8.36 mmol) in THF (24 mL) at 08C
under nitrogen atmosphere. After the addition was com-
plete, the reaction mixture was stirred at 08C for 15 minutes.
Then BnBr (1.49 mL, 12.54 mmol) was added slowly to the
stirred reaction mixture followed by the addition of TBAI
(308.8 mg, 0.836 mmol). After stirring for 12 h at room
temperature, the reaction mixture was quenched slowly by
the addition of saturated aqueous NH4Cl solution. THF was
removed on a rotary evaporator and the product was
extracted from the aqueous layer with EtOAc. The
combined organic layers were washed with brine, dried
(Na2SO4), filtered and concentrated in vacuo. Purification
by column chromatography (SiO2, 4–5% EtOAc in
petroleum ether eluant) afforded the benzyl ether inter-
mediate as a colorless liquid that was used directly in the
next step.
3.1.18. Synthesis of 22. The allylic alcohol 21 (426 mg,
2.07 mmol) was subjected to Sharpless asymmetric epoxi-
dation following the same procedure described for the
preparation of 10. Purification by column chromatography
(SiO2, 30–45% EtOAc inpetroleum ether eluant) afforded
compound 22 (441 mg, 96%), an oily liquid, as a mixture
of diastereomers (1:1). Rf 0.5 (silica gel, 50% EtOAc in
petroleum ether); IR (neat): nmax 3418, 2977, 2914, 2873,
1496, 1453, 1378, 1342, 1218, 1130, 1069, 1026, 902, 859,
1
770, 698 cm21; H NMR (200 MHz, CDCl3, mixture of
diastereomers): d 7.29 (m, 5H, aromatic), 4.65–4.38 (two
ABq, 2H, PhCH2O–), 3.91–3.49 (m, 3H, CH(OBn),
CH2OH), 3.12–2.99 (m, 1H, epoxy-H), 2.92–2.81 (m,
1H, epoxy-H), 1.92–1.45 (m, 2H, CH2), 1.57 (1H), 1.28 and
1.25 (two d, J¼6.0 Hz, 3H, CH3). 13C NMR (50 MHz,
CDCl3, mixture of isomers 1:1): d 138.6, 128.3, 127.6,
127.5, 72.7, 72.3, 70.6, 70.2, 61.7, 58.8, 58.1, 53.4, 53.2,
39.2, 38.4, 19.9, 19.6; Mass (LSIMS): m/z: 223 [MþH]þ.
Compound 20 was prepared from the above benzyl ether
(1.665 g, 5.55 mmol) following the same procedure as
described above during the preparation of 1b from 15.
Chromatographic purification (SiO2, 35–45% EtOAc in
petroleum ether eluant) provided compound 20 (800 mg,
80% from 19) as a liquid. Rf 0.2 (silica gel, 20% EtOAc in
3.1.19. Synthesis of 1d. Compound 22 (353 mg,
1.59 mmol) was subjected to TBDPS protection following

9134
T. K. Chakraborty et al. / Tetrahedron 59 (2003) 9127–9135
the same procedure described for the preparation of 7.
Chromatographic purification (SiO2, 4–5% EtOAc in
petroleum ether eluant) gave the silylated intermediate as
colorless oily liquid that was used directly in the next step.
was subjected to Swern oxidation following the same
procedure described for the preparation of 16, Purification
by column chromatography (SiO2, 14–16% EtOAc in
petroleum ether eluant) afforded 2c (569 mg, 90%) as an
oily liquid. Rf 0.2 (silica gel, 20% EtOAc in petroleum
ether); [a]2D2¼40.9 (c 2.2, CHCl3); IR (neat): nmax 3450,
The silyl ether, thus obtained, was dissolved in MeOH–
EtOAc (2:1, 3 mL). Pd(OH)2 on C (10%, 200 mg) was
added and subjected to hydrogenation under atmospheric
pressure using a H2-filled balloon. After 1 h, the reaction
mixture was 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.
Chromatographic purification (SiO2, 20–24% EtOAc in
petroleum ether eluant) gave compound 1d (500 mg, 85%
from 22), a colorless liquid, as a mixture of diastereomers.
Rf 0.2 (silica gel, 25% EtOAc in petroleum ether); IR (neat):
1
2927, 2845, 1681, 1230, 1085, 975, 825, 773 cm21; H
NMR (200 MHz, CDCl3): d 9.56 (d, J¼6.35 Hz, 1H, CHO),
6.72 (dd, J¼16.9, 4.2 Hz, 1H, C3–H), 6.32 (ddd, J¼16.9,
6.35, 1.27 Hz, 1H, C2–H), 4.28 and 3.92 (two sets of m, 2H,
C4–H and C5–H), 2.37 (d, J¼5.1 Hz, 1H, OH), 1.12 (d, J¼
6.3 Hz, 3H, C5–CH3), 0.91 (s, 9H, t-butyl), 0.08 (s, 6H,
Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 193.3, 154.6,
132.3, 75.0, 70.8, 25.7, 18.2, 18.0, 24.5, 24.9; Mass
(LSIMS): m/z: 227 [M2OH]þ,
n
max 3435, 3069, 2933, 2861, 1467, 1428, 1387, 1111, 947,
;
3.1.23. Synthesis of 2d. Compound 1d (352 mg,
0.95 mmol) was subjected to Swern oxidation following
the same procedure described for the preparation of 16.
Purification by column Chromatography (SiO2, 18–24%
EtOAc in petroleum ether eluant) afforded 2d (315 mg,
90%) as an oily liquid. Rf 0.3 (silica gel, 25% EtOAc in
petroleum ether); [a]D22¼30.6 (c 0.72, CHCl3); IR (neat):
824, 743, 703, 614, 505 cm21 1H NMR (200 MHz,
CDCl3): d 7.72–7.30 (m, 10H, aromatic), 3.98 (m, 1H,
CH(OH)CH3), 3.75 (d, J¼4.0 Hz, 2H, –CH2OTBDPS),
3.04–2.84 (m, 2H, epoxy-Hs), 1.85–1.42 (m, 2H, CH2),
1.25 and 1.22 (two d, J¼6.0 Hz, 3H, CH(OH)CH3), 1.05 (s,
9H, tBu); 13C NMR (75 MHz, CDCl3, mixture of isomers):
d 135.6, 135.5, 133.2, 129.7, 127.7, 77.2, 66.5, 65.4, 64.0,
63.9, 58.0, 57.9, 54.3, 54.0, 40.6, 39.8, 26.7, 23.5, 23.4,
19.2; Mass (LSIMS): m/z: 393 [MþNa]þ.
n
max 3437, 3071, 3050, 2931, 2859, 1677, 1632, 1470, 1427,
1
1362, 1257, 1111, 980, 824, 742, 704, 612, 506 cm21; H
NMR (200 MHz, CDCl3): d 7.6–7.32 (m, 10H, aromatic),
6.64 (dd, J¼16.8, 3.44 Hz, 1H, C3–H), 6.32 (dd, J¼16.8,
1.9 Hz, 1H, C4–H), 4.4 (m, 1H, C2–H), 3.78 (dd, J¼9.09,
3.82 Hz, 1H, C1–H), 3.59 (dd, J¼9.9, 6.2 Hz, 1H, C1–H ),
2.7 (d, J¼3.9 Hz, 1H, OH), 2.24 (s, 3H, C5–CH3), 1.1 (s,
9H, t-butyl); 13C NMR (75 MHz, CDCl3): d 198.0, 144.5,
135.5, 132.7, 130.6, 130.0, 127.8, 71.5, 67.0, 27.3, 26.8,
19.2; Mass (LSIMS): m/z: 391 [MþNa]þ, 351 [M2OH]þ.
3.1.20. Synthesis of 2a. Compound 1a (497 mg,
1.38 mmol) was subjected to Swern oxidation following
the same procedure described for the preparation of 16.
Purification by column Chromatography (SiO2, 25–30%
EtOAc in petroleum ether eluant) afforded 2a (405 mg,
82%) as an oily liquid. Rf 0.5 (silica gel, 40% EtOAc in
petroleum ether); [a]D22¼12.75 (c 2.3, CHCl3); IR (neat):
n
max 3445, 3063, 3025, 2905, 2855, 1680, 1480, 1433, 1208,
3.1.24. Synthesis of 23. To a stirred solution of 2c (464 mg,
1.9 mmol) in dry CH2Cl2 (8 mL) at 08C, DIPEA (3.30 mL,
19 mmol) followed by MEMCl (1.73 mL, 15.2 mmol) were
added under nitrogen atmosphere. Then the reaction mixture
was allowed to come to room temperature and stirred for
12 h. The reaction was quenched with saturated aqueous
NH4Cl solution and extracted with EtOAc. The organic
extracts were combined and washed with brine, dried
(Na2SO4) and concentrated in vacuo. Purification by column
chromatography (SiO2, 13–16% EtOAc in petroleum ether
eluant) gave compound 23 (606 mg, 96%) as an oily liquid.
Rf 0.33 (silica gel, 20% EtOAc in petroleum ether);
[a]2D2¼226.3 (c 4.2, CHCl3); IR (neat): nmax 2925, 1687,
;
1H NMR
1075, 964, 750, 705 cm21; H NMR (200 MHz, CDCl3):
d 9.49 (d, J¼6.9 Hz, 1H, CHO), 7.44–7.12 (m, 15H,
aromatic), 6.64 (dd, J¼17.1, 3.9 Hz, 1H, C3–H), 6.3 (ddd,
J¼17.1, 6.9, 2.1 Hz, 1H, C2–H), 4.46 (m, 1H, C4–H), 3.34
(dd, J¼10.57, 4.2 Hz, 1H, C5–H), 3.21 (dd, J¼10.57,
6.8 Hz, 1H, C5–H0), 2.49 (d, J¼4.3 Hz, 1H, OH); 13C NMR
(75 MHz, CDCl3): d 193.3, 155.0, 143.3, 131.9, 128.5,
127.9, 127.2, 87.2, 70.4, 66.4; Mass (LSIMS): m/z: 281
[M2Ph]þ, 243 [CPh3]þ.
1
3.1.21. Synthesis of 2b. Compound 1b (400 mg,
1.08 mmol) was subjected to Swern oxidation following
the same procedure described for the preparation of 16.
Purification by column Chromatography (SiO2, 15% EtOAc
in petroleum ether eluant) afforded 2b (366 mg, 92%) as an
oily liquid. Rf 0.48 (silica gel, 40% EtOAc in petroleum
ether); [a]2D2¼45.3 (c 1.4, CHCl3); IR (neat): nmax 3370,
1443, 1325, 1230, 1100, 1025, 818 cm21
(200 MHz, CDCl3): d 9.58 (d, J¼8.2 Hz, 1H, CHO), 6.80
(dd, J¼15.6, 6.0 Hz, 1H, olefinic), 6.27 (dd, J¼15.6, 8.2 Hz,
1H, olefinic), 4.74 (ABq, 2H, –OCH2O–), 4.18 (t, J¼
6.0 Hz, 1H, –CH(OMEM)–), 3.89 (dq, J¼6.0 Hz, 1H,
–CH(OTBS)CH3), 3.82–3.48 (m, 4H, –OCH2–CH2O–),
3.37 (s, 3H, OCH3), 1.18 (d, J¼6.0 Hz, 3H,
3060, 2926, 2824, 1686, 1474, 1436, 1005, 696, 494 cm21
;
1H NMR (400 MHz, CDCl3): d 9.52 (d, J¼7.1 Hz, 1H,
CHO), 7.68–7.37 (m, 10H, aromatic), 6.7 (dd, J¼17.3 Hz,
1H, C3–H), 6.37 (dd, J¼17.3, 7.1 Hz, 1H, C2–H), 3.64 (s,
2H, C5–H2), 2.84 (s, 1H, OH), 1.3 (s, 3H, C4–CH3), 1.08
(s, 9H, t-butyl); 13C NMR (75 MHz, CDCl3): d 193.3, 160.6,
135.6, 135.5, 132.6, 132.5, 130.9, 130.1, 130.0, 127.8, 77.4,
73.5, 70.3, 29.6, 26.8, 23.4, 19.2; Mass (LSIMS): m/z: 369
[MþH]þ, 351 [M2OH]þ.
t
CH(OTBS)CH3), 0.87 (s, 9H, Bu), 0.056 and 0.033 (two
s, 6H, SiMe2); 13C NMR (75 MHz, CDCl3): d 193.2, 154.5,
133.5, 94.2, 79.9, 71.5, 70.5, 67.3, 58.9, 25.6, 20.1, 17.9,
24.6, 24.8; Mass (LSIMS): m/z: 333 [MþH]þ.
3.1.25. Synthesis of 5. The aldehyde 23 (495 mg,
1.49 mmol) was taken in tBuOH/2-methyl-2-butene (3:1,
40 mL) and to it a solution of NaClO2 (539 mg, 5.96 mmol)
and NaH2PO4.H2O (1.39 g, 8.9 mmol) in water (2 mL) was
3.1.22. Synthesis of 2c. Compound 1c (638 mg, 2.59 mmol)

T. K. Chakraborty et al. / Tetrahedron 59 (2003) 9127–9135
9135
3. (a) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1–299.
(b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109,
5765–5780.
added at room temperature. After being stirred for 1 h, the
solvent was removed in rotary evaporator, under reduced
pressure. Residue was taken in ethyl acetate, washed with
brine, dried (Na2SO4), filtered and concentrated in vacuo.
Purification by column chromatography (SiO2, 30–50%
EtOAc in petroleum ether eluant) afforded compound 5
(498 mg, 96%) as a colorless oily liquid. Rf 0.3 (silica gel,
60% EtOAc in petroleum ether); [a]2D2¼226.8 (c 2.4,
CHCl3); IR (neat): nmax 2933, 1702, 1257, 1107, 1040, 835,
4. (a) Schiewe, H. J.; Zeeck, A. J. Antibiot. 1999, 52, 635–642.
(b) Taddei, A.; Zeeck, A. J. Antibiot. 1997, 50, 526–528.
(c) Furumai, T.; Nagahama, N.; Okuda, T. J. Antibiot. 1968,
21, 85–91. (d) Miyairi, N.; Takashima, M.; Shimizu, K.;
Sakai, H. J. Antibiot. 1966, 19, 56–62.
1
774 cm21; H NMR (200 MHz, CDCl3): d 6.98 (dd, J¼
5. (a) Yamada, T.; Iritani, M.; Minoura, K.; Numata, A.;
Kobayashi, Y.; Wang, Y.-G. J. Antibiot. 2002, 55, 147–154.
(b) Yamada, T.; Iritani, M.; Doi, M.; Minoura, K.; Ito, T.;
Numata, A. J. Chem. Soc., Perkin Trans. 1 2001, 3046–3053.
(c) Fukami, A.; Taniguchi, Y.; Nakamura, T.; Rho, M.-C.;
Kawaguchi, K.; Hayashi, M.; Komiyama, K.; Omura, S.
J. Antibiot. 1999, 52, 501–504. (d) Numata, A.; Iritani, M.;
Yamada, T.; Minoura, K.; Matsumura, E.; Yamori, T.; Tsuruo,
T. Tetrahedron Lett. 1997, 38, 8215–8218. (e) Takamatsu, S.;
Hiraoka, H.; Kim, Y.-P.; Hayashi, M.; Natori, M.; Komiyama,
K.; Omura, S. J. Antibiot. 1997, 50, 878–880. (f) Takamatsu,
S.; Kim, Y.-P.; Hayashi, M.; Hiraoka, H.; Natori, M.;
Komiyama, K.; Omura, S. J. Antibiot. 1996, 49, 95–98.
(g) Hayashi, M.; Kim, Y.-P.; Hiraoka, H.; Natori, M.;
Takamatsu, S.; Kawakubo, T.; Masuma, R.; Komiyama, K.;
Omura, S. J. Antibiot. 1995, 48, 1435–1439.
15.6, 6.0 Hz, 1H, olefinic), 6.02 (d, J¼15.6 Hz, 1H,
olefinic), 4.74 (ABq, 2H, –OCH2O–), 4.10 (t, J¼6.0 Hz,
1H, –CH(OMEM)–), 3.84 (dq, J¼6.0 Hz, 1H,
–CH(OTBS)CH3), 3.82–3.48 (m, 4H, –OCH2–CH2O–),
3.38 (s, 3H, OCH3), 1.17 (d, J¼6.0 Hz, 3H,
t
CH(OTBS)CH3), 0.87 (s, 9H, Bu), 0.05 and 0.03 (two s,
6H, SiMe2); 13C NMR (50 MHz, CDCl3): d 170.9, 148.3,
122.5, 94.2, 80.0, 71.7, 70.6, 67.3, 58.9, 25.7, 19.9, 18.0,
24.6, 24.8; Mass (LSIMS): m/z: 349 [MþH]þ.
Acknowledgements
Authors wish to thank Drs A. C. Kunwar and M. Vairamani
for NMR and mass spectroscopic assistance, respectively;
CSIR (S. P.) and UGC (S. D.), New Delhi for research
fellowships.
6. For earlier works on the syntheses of macrosphelides see:
(a) Sharma, G. V. M.; Mouli, C. C. Tetrahedron Lett. 2002, 43,
9159–9161. (b) Nakamura, H.; Ono, M.; Shida, Y.; Akita, H.
Tetrahedron: Asymmetry 2002, 13, 705–713. (c) Nakamura,
H.; Ono, M.; Makino, M.; Akita, H. Heterocycles 2002, 57,
327–336. (d) Kobayashi, Y.; Acharya, H. P. Tetrahedron Lett.
2001, 42, 2817–2820. (e) Kobayashi, Y.; Kumar, B. G.;
Kurachi, T.; Acharya, H. P.; Yamazaki, T.; Kitazume, T.
J. Org. Chem. 2001, 66, 2011–2018. (f) Ono, M.; Nakamura,
H.; Konno, F.; Akita, H. Tetrahedron: Asymmetry 2000, 11,
2753–2764. (g) Kobayashi, Y.; Kumar, B. G.; Kurachi, T.
Tetrahedron Lett. 2000, 41, 1559–1563. (h) Kobayashi, Y.;
Nakano, M.; Kumar, G. B.; Kishihara, K. J. Org. Chem. 1998,
63, 7505–7515. (i) Sunazuka, T.; Hirose, T.; Harigaya, Y.;
Takamatsu, S.; Hayashi, M.; Komiyama, K.; Omura, S. J. Am.
Chem. Soc. 1997, 119, 10247.
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