Towards a synthesis of epothilone A: Asymmetric synthesis of C(1)-C(6) and C(7)-C(15) fragments

Article abstract of DOI:10.1016/S0957-4166(02)00095-2

The asymmetric synthesis of protected C(1)-C(6) and C(7)-C(15) fragments of epothilone A starting from 1,3-cyclohexanedione and methyl L-hydroxy propionate, respectively, is described.

Full text of DOI:10.1016/S0957-4166(02)00095-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 261–268
Towards a synthesis of epothilone A: asymmetric synthesis of
C(1)ꢀC(6) and C(7)ꢀC(15) fragments†
S. Chandrasekhar* and Ch. Raji Reddy
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 24 January 2002; accepted 20 February 2002
Abstract—The asymmetric synthesis of protected C(1)–C(6) and C(7)–C(15) fragments of epothilone A starting from 1,3-cyclohex-
anedione and methyl L-hydroxy propionate, respectively, is described. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
several SAR studies3 and stitch them in a combinatorial
fashion towards pseudonatural products.4
The isolation of a new group of macrocyclic natural
products, the epothilones, has enabled research into
structure–activity relationships (SAR) in the stabiliza-
tion of microtubules to be conducted faster and more
efficiently. Epothilones A 1 and B 2 were first isolated
by Hofle’s group from the myxobacteria Sorangium
Cellulosum.1 Due to their very interesting biological
activities and novel structure, these biological analogues
of taxol immediately attracted much attention from
chemists and biologists and several groups have
reported their approaches to the epothilones.2 Herein,
we report our preliminary results for epothilone A
synthesis.
The retrosynthetic analysis of epothilone A indicated
that appropriately protected forms of the three frag-
ments 3, 4 and 5 would be key intermediates (based on
the literature)5 (Scheme 1). Herein, we wish to report
the asymmetric synthesis of C(1)–C(6) and C(7)–C(15)
fragments starting from 1,3-cyclohexanedione and
methyl 3-hydroxy-2-methyl-(2R)-propionate, respec-
tively.
2. Results and discussion
2.1. Synthesis of the C(1)–C(6) fragment
3-Methoxy-2-cyclohexenone 7 was treated with ethyl-
magnesium bromide followed by acidic workup to give
the enone 8. Alkylation of the ethyl cyclohexenone 8
using potassium tert-butoxide and methyl iodide in
THF yielded 9, which was reduced with oxazaboro-
lidine (Corey’s reagent)6 to furnish the chiral alcohol 10
with 92% e.e. On acetylation the alcohol 10 gave 11,
which on treatment with SeO2 furnished the allylic
hydroxy compound 12. Dihydroxylation of 12 with
osmium tetroxide then afforded the triol 13. Aldehyde
14 was obtained by sodium periodate cleavage of triol
13, which was further oxidized to give the required
fragment 3 (Scheme 2).
The objective of the present exercise is to synthesize the
fragments essential for biological activity as detailed in
2.2. Synthesis of the C(7)–C(15) fragment
After completion of the synthesis of the C(1)–C(6)
fragment, attempts were then directed towards the syn-
thesis of the C(7)–C(15) epothilone fragment, 4, whose
* Corresponding author. Tel./fax: +91-40-7160512; e-mail: srivaric@
iict.ap.nic.in
† IICT Communication No: 020112.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00095-2

262
S. Chandrasekhar, Ch. R. Reddy / Tetrahedron: Asymmetry 13 (2002) 261–268
OTBS
TBSO
8
15
7
X
4
X: -OBn
Epothilone A
+
4a X: =O
1
S
5
1
+
4
COOH
PO(OR)2
N
O
OAc
5
3
Scheme 1.
O
O
O
O
O
OMe
a
b
c
6
8
9
7
OAc
OAc
OH
g
f
d
e
10
11
OH
12
OAc
h
i
CHO
OH
COOH
O
OAc
O
OAc
HO
14
3
13
OH
Scheme 2. Reagents and conditions: (a) CH(OCH3)3, MeOH, PTSA (cat.) benzene, reflux, 80 min, 92%; (b) EtMgBr, THF, H+,
t
0°C, 2 h, 86%; (c) (i) BuOK, MeI, THF, −78°C, 5 h, 80%; (d) (S)-diphenylprolinol, BH3·DMS, THF, 45°C, 17 h, 81%; (e) Py.,
Ac2O, CH2Cl2, rt, 11 h, 90%; (f) SeO2, TBHP, CH2Cl2, rt, 5 h, 60%; (g) OsO4, NMO, acetone/H2O (8:2), rt, 16 h, 86%; (h) NaIO4,
t
SiO2, CH2Cl2/H2O (9:1), rt, 4 h, 77%; (i) NaClO2, NaH2PO4, BuOH, rt, 4 h, 76%.
retrosynthetic analysis is shown in Scheme 3. This
disconnection approach revealed two intermediates
viz., acetylene 15 and epoxide 16.
23, which upon alkylation with lithium acetylide fur-
nished the required acetylene 15 (Scheme 4).
The chiral epoxide 16 was prepared from acrolein 24,
which was treated with methyl magnesium iodide to
produce the alcohol 25. Alcohol 25 was subjected to
The synthesis of the acetylene 15 started from commer-
cially available methyl-3-hydroxy-2-methyl-(2R)-propi-
onate 17. The free hydroxyl group was protected as its
TBS ether to give 18. The ester 18 was reduced with
DIBAL-H to furnish the alcohol 19, which was oxi-
dized to aldehyde by PDC. The aldehyde thus obtained
was subjected to stabilised-ylide Wittig olefination with
carboethoxymethylenetriphenylphosphorane to give the
a,b-unsaturated ester 20. The double bond of 20 was
reduced with Mg in methanol to yield the ester 21.7
The ester 21 was reduced to alcohol 22 using LiCl–
NaBH4,8 followed by tosylation to give the compound
Sharpless
asymmetric
epoxidation
[(−)-DIPT,
Ti(iPrO)4] and subsequent protection of the alcohol as
benzyl ether furnished the epoxide 16. The epoxide 16
was ring-opened with acetylide 15, using the
Yamaguchi method9 to afford the propargyl alcohol
26, which was subjected to partial hydrogenation with
Lindlar’s catalyst to yield the cis-olefin 27. Protection
of the free hydroxyl group of 27 as its tert-
butyldimethylsilyl ether furnished the desired fragment
4 (Scheme 5).
Scheme 3.

S. Chandrasekhar, Ch. R. Reddy / Tetrahedron: Asymmetry 13 (2002) 261–268
263
a
b
HO
TBSO
TBSO
OH
COOMe
COOMe
TBSO
19
18
17
e
c
d
TBSO
COOMe
COOEt
21
20
g
f
TBSO
OTs
TBSO
TBSO
OH
23
22
15
Scheme 4. (a) Imidazole, TBDMSCl, CH2Cl2, 0°C, 6 h, 92%; (b) DIBAL-H, CH2Cl2, 0°C–rt, 2 h, 78%; (c) (i) PDC, CH2Cl2, rt,
15 min, 97%, (ii) PPh3ꢁCHCOOEt, benzene, rt, 12 h, 82% (two steps); (d) Mg/MeOH, rt, 4 h, 82%; (e) LiCl–NaBH4, EtOH/THF
(1:1), rt, 12 h, 92%; (f) Et3N, TsCl, CH2Cl2, rt, 10 h, 85%; (g) Li, liq. NH3, acetylene (gas), DMSO, −20°C–rt, 3 h, 73%.
O
a
b
CHO
OH
OBn
OBn
24
25
16
c
d
15 + 16
TBSO
26
OH
OH
OTBS
e
TBSO
TBSO
27
OBn
4
OBn
i
,
Scheme 5. (a) MeMgI, THF, rt, 1 h, 76%; (b) (i) (−)-DIPT, Ti( PrO)4, TBHP, 4 A MS, CH2Cl2, −20°C, 14 h, 50%, (ii) NaH, BnBr,
n
THF, 0°C, 6 h, 78%; (c) BuLi, BF3·Et2O, THF, −78°C, 30 min, 75%; (d) Pd–BaSO4/H2, EtOH, rt, 20 min, 95%; (e) imidazole,
TBDMSCl, CH2Cl2, 0°C–rt, 6 h, 88%.
3. Conclusion
most significant absorptions in cm−1 are indicated. All
solvents used were purified by a known procedure. All
reactions were carried out under an atmosphere of
nitrogen using dry glassware.
In conclusion, the asymmetric synthesis of two impor-
tant synthetic precursors of epothilone A, the C(1)–C(6)
and C(7)–C(15) fragments, was achieved from commer-
cially available starting materials.
4.1. 3-Methoxy-2-cyclohexen-1-one 7
A mixture of cyclohexane-1,3-dione 6 (5 g, 51.02
mmol), p-toluenesulfonic acid (0.21 mg), methanol (17
mL) and trimethyl orthoformate (5.2 mL) was heated
under reflux in benzene (85 mL) for 80 min. The cooled
reaction mixture was washed with a 10% aq. NaOH
solution (2×20 mL), brine (20 mL), dried and evapo-
rated in vacuo. Purified by distillation (bp=52–53°C,
0.7 mmHg) to give 7 in 92% yield (5.9 g). IR (neat): w
4. Experimental
Crude products were purified by column chromatogra-
phy on silica gel of 60–120 mesh. H and 13C NMR
1
spectra were recorded in CDCl3 solution on Varian
Gemini-200, AV-300 MHz spectrometer and chemical
shifts are reported in ppm unless otherwise stated. Mass
spectra were recorded on VG micromass-7070H (70
eV). HPLC analysis was performed on a Schimadzu
liquid chromatography LC-6A, equipped with a SCE-
6A, system controller, SPD-6A, fixed wavelength UV
monitor as detector and chromatograpac C-R4A data
processor as integrator. The column was 4.6×250 mm,
chiral cell OD column (Dia cell). The optical rotations
were recorded using a Jasco Dip 360 digital polarime-
ter. Infrared spectra were obtained neat and only the
1
1710 cm−1; H NMR (CDCl3, 200 MHz): l 5.32 (s, 1H,
–CO–CHꢁ), 3.69 (s, 3H, –OCH3), 2.45–2.23 (m, 4H,
–CO–CH2–, ꢁCH–CH2–), 2.06–1.89 (m, 2H, –CH2–
CH2–CH2–); EIMS (m/z): 126 (M+).
4.2. 3-Ethyl-2-cyclohexen-1-one 8
The Grignard reagent was prepared from magnesium
(2.37 g, 98.94 mmol), ethyl bromide (10.68 g, 22.1 mL,

264
S. Chandrasekhar, Ch. R. Reddy / Tetrahedron: Asymmetry 13 (2002) 261–268
98.94 mmol) and dry THF (75 mL). To this a solution
of 3-methoxy-2-cyclohexen-1-one (5.66 g, 44.97
122.1, 96.2, 74.6, 38.9, 32.8, 29.7, 26.2, 26, 21.8, and
12.2; EIMS (m/z): 154 (M+); HRMS: calcd 154.2516;
found: 154.2530; [h]D=−15.9 (c 1, CHCl3).
7
mmol) in dry THF (15 mL) was added and the mixture
was stirred for 2 h. After the Grignard complex was
decomposed with dilute sulfuric acid, the mixture was
extracted with ether. The ether solution was washed
with dilute NaHCO3, water and dried over Na2SO4.
After evaporation of volatiles, the crude product was
purified by silica gel column chromatography to give 8
4.5. (1S)-3-Ethyl-2,2-dimethyl-3-cyclohexenyl acetate
11
To a solution of alcohol 10 (4 g, 25.9 mmol) in dry
CH2Cl2 (60 mL) containing dry pyridine (2.3 mL, 28.57
mmol) was added a solution of acetic anhydride (3.17 g,
31.16 mmol) in CH2Cl2 (8 mL) at 0°C under nitrogen.
The reaction mixture was stirred for 10 h at room
temperature then washed with a saturated CuSO4 solu-
tion (2×40 mL) and extracted with CH2Cl2 (50 mL).
The organic phase was washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography
to afford the acetate 11 (4.58 g, 90%). IR (neat): w 3624,
1
in 86% yield (4.8 g). IR (neat): w 1708 cm−1; H NMR
(CDCl3, 200 MHz): l 5.79 (s, 1H, ꢁCH–CO–), 2.39–2.1
(m, 6H, –CH2–CH2–CH2–), 1.96 (q, J=12.8, 6 Hz, 2H,
CH3–CH2–), 1.06 (t, J=6.8 Hz, 3H, CH3–CH2–); EIMS
(m/z): 124 (M+).
4.3. 3-Ethyl-2,2-dimethyl-3-cyclohexen-1-one 9
To a solution of 3-ethyl-2-cyclohexen-1-one 8 (4.66 g,
37.63 mmol) in dry THF (75 mL) was added potassium
tert-butoxide (12.63 g, 112.9 mmol) at −78°C under a
nitrogen atmosphere. After 15 min, methyl iodide
(11.66 mL, 188.2 mmol) was slowly added to the reac-
tion mixture at the same temperature. After 5 h, the
reaction mixture was cooled to room temperature and
extracted with ether (2×50 mL). The extracts were
washed with water (30 mL), brine (30 mL), dried over
Na2SO4 and the volatiles were evaporated on a rotary
evaporator. The crude product was purified by column
chromatography to give 9 in 80% yield (4.57 g). IR
1
1736 cm−1; H NMR (CDCl3, 200 MHz): l 5.3 (broad
s, 1H, ꢁCH–), 4.95 (broad s, 1H, –CH(OAc)–), 2.1–1.9
(s and m, 7H, CH3–CO–, CH3–CH2, –CHꢁCH2–), 1.61–
1.3 (m, 2H, ꢁCH–CH2–CH2–), 1.1–0.95 (m, 3H, CH3–
CH2–), 0.9 (s, 6H, 2×–CH3); EIMS (m/z): 196 (M+);
[h]D=−24.7 (c 0.5, CHCl3).
4.6. (1S)-3-Ethyl-5-hydroxy-2,2-dimethyl-3-cyclohexenyl
acetate 12
A solution of acetate 11 (3 g, 15.3 mmol) in CH2Cl2 (60
mL) was stirred at 35°C with SeO2 (0.849 g, 7.6 mmol)
and dry tert-butylhydroperoxide (6.887 g, 76.5 mmol).
The reaction mixture was extracted with CH2Cl2 (50
mL), extracts were washed with 10% aq. KOH (2×25
mL), and the organic phase was dried and the solvent
was evaporated under reduced pressure. The crude
product was purified by column chromatography to
afford the allylic hydroxyl compound 12 (1.94 g, 60%).
1
(neat): w 1725 cm−1; H NMR (CDCl3, 200 MHz): l
5.79 (m, 1H, ꢁCH–CH2), 2.41–2.19 (m, 4H, CH3–CH2–,
ꢁCH–CH2–), 1.86 (t, J=6.89 Hz, 2H, –CH2–CH2–CO–
), 1.24–1.10 (m, 9H, CH3–CH2–, 2×CH3); EIMS (m/z):
152 (M+); HRMS: calcd 152.2354; found: 152.2356.
4.4. (1S)-3-Ethyl-2,2-dimethyl-3-cyclohexen-1-ol 10
1
To a solution of BH3·Me2S (9.6 mL of 2 M solution in
toluene, 19.2 mmol) was added a solution of (S)-
diphenyl prolinol (0.373 g, 1.5 mmol) in THF (12 mL)
and the reaction mixture was stirred at 45°C for 16 h
under nitrogen. To the resulting turbid solution of
oxazaborolidine, a solution of 3-ethyl-2,2-dimethyl-3-
cyclohexen-1-one 9 (4.5 g, 29.6 mmol) in anhydrous
THF (20 mL) was added dropwise over a period of
30–40 min. After completion of the addition, the reac-
tion mixture was continued to stir at the same tempera-
ture for 15 min. It was then cooled to room
temperature and cautiously quenched with MeOH (6
mL). The solvent was evaporated and the residue was
dissolved in ether. The ether phase was washed with
1 M HCl followed by brine and dried over anhydrous
Na2SO4. The residue obtained after removal of ether
was purified by column chromatography to afford the
alcohol 10 (3.69 g, 81% yield). The optical purity was
determined by a chiral HPLC column (Schimadzu liq-
uid chromatography LC-6A) as benzoate and found to
IR (neat): w 3624, 1736 cm−1; H NMR (CDCl3, 200
MHz): l 5.26–5.2 (m, 1H, ꢁCH–), 5.16–5.09 (m, 1H,
–CH(OAc)–), 4.25–4.1 (broad m, 1H, ꢁCH–CH(OH)–),
2.25–2.1 (m, 2H, CH3–CH2), 2.06 (s, 3H, CH3–CO–),
1.51–1.36 (m, 2H, CH(OH)–CH2–), 1.04 (t, J=7.0 Hz,
3H, CH3–CH2–), 0.98, 089 (2×s, 6H, 2×–CH3); EIMS
(m/z): 212 (M+); HRMS: calcd 212.2870; found:
212.2867; [h]D=−12.62 (c 0.8, CHCl3).
4.7. (1S)-3-Ethyl-3,4,5-trihydroxy-2,2-dimethylcyclo-
hexyl acetate 13
To a solution of 12 (1 g, 4.68 mmol) in acetone/water
(16:4) was added a catalytic amount of OsO4 (0.05 mL,
0.02 M solution). After 15 min, N-methyl morpholine
oxide (0.828 g, 6.12 mmol) was added and the mixture
was stirred overnight at ambient temperature. After the
reaction was completed, the solvent was removed and a
sat. sodium metabisulfite solution (15 mL) was added
to the residue. The resulting mixture was stirred for 30
min. The reaction mixture was extracted with ethyl
acetate (2×25 mL) and the extracts were washed with
brine, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography to
afford the triol 13 (1 g, 86%). IR (neat): w 3624, 3612,
1738 cm−1; 1H NMR (D2O exchange, 200 MHz): l
1
be 92% e.e. IR (neat): w 3622 cm−1; H NMR (CDCl3,
200 MHz): l 5.38 (broad s, 1H, ꢁCH–CH2–), 3.68
(broad s, 1H, –CH2–CH (OH)–), 2.05–1.86 (m, 4H,
CH3–CH2, –CH=CH2–), 1.60–1.20 (m, 2H, ꢁCH–CH2–
CH2–), 1.07–0.94 (m, 3H, CH3–CH2–), 0.90 and 0.88
(2×s, 2×3H, 2×–CH3); 13C NMR (CDCl3, 200 MHz): l

S. Chandrasekhar, Ch. R. Reddy / Tetrahedron: Asymmetry 13 (2002) 261–268
265
4.99–4.84 (m, 1H, –CH(OAc)–), 4.4–4.24 (m, 1H,
–CH(OH)–CH(OH)–), 4.18–4.0 (m, 1H, –CH(OH)–
CH2–), 2.07 (s, 3H, –CO–CH3), 1.36–1.16 (m, 4H,
CH3–CH2–, –CH2–CH(OAc)–), 1.1–0.8 (m, 9H, CH3–
CH2–, 2×CH3); EIMS (m/z): 246 (M+); [h]D=−6.0 (c
1, CHCl3).
(m, 1H, –CH2–CH(CH3)–CO–), 1.12 (d, J=6.8 Hz,
3H, CH3–CH–), 0.88 (s, 9H, (CH3)3C–Si–), 0.2 (s, 6H,
(CH3)2Si–); EIMS (m/z): 232 (M+); [h]D=+17.7 (c 1.7,
CHCl3).
4.11. (2S)-3-tert-Butyldimethylsilyloxy-2-methyl-
propanol 19
4.8. (5S)-5-Acetoxy-7-formyl-4,4-dimethyl-3-heptanone
14
To a stirred solution of 18 (5 g, 21.6 mmol) in dry
CH2Cl2 (75 mL) at −10°C was added DIBAL-H (7.65
g, 53.9 mmol, 2 M solution in hexane) under nitrogen.
The reaction mixture was stirred at 0°C for 30 min
and allowed to warm to room temperature and further
stirred for an additional 2 h. After the excess DIBAL-
H was decomposed with methanol (3 mL), the mixture
was poured into a sodium potassium tartrate solution
(10 g in 100 mL water) with vigorous stirring until the
layers were separated. The aqueous layer was
extracted with ether (2×60 mL) and the combined
organic extracts were washed with brine (50 mL),
dried over Na2SO4 and concentrated. The crude
product was purified by column chromatography to
afford 19 as a colorless viscous oil (3.43 g, 78%). IR
To a stirred solution of triol 13 (0.3 g, 1.219 mmol) in
CH2Cl2:H2O (9:1) was added NaIO4 (0.782 g, 3.6
mmol) and SiO2 (0.3 g) at room temperature. After 4
h, the reaction mixture was filtered through a sintered
funnel and extracted with DCM (2×15 mL). The com-
bined organic layer was washed with water (15 mL),
brine (15 mL), dried over Na2SO4, and the solvent was
evaporated by rotary evaporator, and the residue was
purified by column chromatography to afford alde-
hyde 14 (0.2 g, 77%). IR (neat): w 1740, 1724, 1710
cm−1; 1H NMR (CDCl3, 200 MHz): l 9.74 (s, 1H,
–CHO), 5.18 (dd, J=9, 3 Hz, 1H, –CH(OAc)–), 2.48
(q, J=8.8 Hz, 2H, CH3–CH2–CO–), 2.06 (s, 3H,
–CO–CH3), 1.98–1.78 (m, 2H, –CH2–CHO), 1.22
(broad s, 9H, CH3–CH2–, 2×CH3); EIMS (m/z): 214
(M+); [h]D=−2.5 (c 2, CHCl3).
1
(neat): w 3538 cm−1; H NMR (CDCl3, 200 MHz): l
3.78–3.48 (m, 4H, TBSO–CH2–, –CH2–OH), 2.0–1.8
(m, 1H, –CH2–CH(CH3)–CH2–), 0.95 (s, 9H,
(CH3)3C–Si–), 0.83 (d, J=7.0 Hz, CH3–CH–), 0.4 (s,
6H, (CH3)2Si–); EIMS (m/z): 204 (M+); [h]D=+20.6 (c
0.8, CHCl3).
4.9. (3S)-3-Acetoxy-4,4-dimethyl-5-oxoheptanoic acid 3
t
A mixture of aldehyde 14 (0.15 g, 0.7 mmol), BuOH
(10 mL), isobutylene (5 mL in 5 mL THF), H2O (1
mL), sodium hypochlorite NaClO2 (0.19 g, 2.1 mmol)
and sodium dihydrogenphosphate (NaH2PO4) (0.126 g,
1.05 mmol) was stirred at room temperature for 4 h.
The reaction mixture was concentrated under reduced
pressure, and the residue was subjected to silica gel
column chromatography to produce the pure keto acid
4.12. Ethyl (4S)-(E)-5-tert-butyldimethylsilyloxy-4-
methyl-2-pentenoate 20
Chromium trioxide (5.88 g, 58.8 mmol) was added to
a stirred solution of dry pyridine (9.29 g, 117.6 mmol)
in dry CH2Cl2 (80 mL). The solution was stirred for
15 min at room temperature and then treated with a
solution of alcohol 19 (4 g, 19.6 mmol) in CH2Cl2 (10
mL). After stirring for an additional 15 min at room
temperature, the solution was decanted from the mix-
ture and the residue was filtered through a silica gel
pad, eluting with ether (100 mL). The filtrate was
concentrated on a rotary evaporator to give the alde-
hyde (3.86 g, 97%).
1
3 (0.12 g, 76%). IR (neat): w 3350, 1722, 1700 cm−1; H
NMR (CDCl3, 200 MHz): l 10.9–10.68 (broad m,
–COOH), 5.2 (dd, J=8, 2.3 Hz, 1H, –CH(OAc)–),
2.66–2.44 (m 2H, CH3–CH2–CO–), 2.15–1.78 (s and
m, 5H, –CO–CH3, –CH2–COOH), 1.4–1.04 (m, 9H,
CH3–CH2–, 2×CH3); 13C NMR (CDCl3, 200 MHz): l
198.6, 176.8, 163.4, 73.5, 52.2, 39.4, 29.7, 25.8, 20.8,
20.5 and 18.2; EIMS (m/z): 230 (M+); HRMS: calcd
214.2608; found: 214.2603; [h]D=+12.4 (c 1, CHCl3).
The above aldehyde (3.86 g, 19.1 mmol) was immedi-
ately dissolved in benzene (70 mL), and the solution
treated with carboethoxymethylenetriphenylphospho-
rane (6.33 g, 18.14 mmol). The reaction mixture was
stirred overnight at room temperature. After concen-
tration, the residue was purified by column chro-
matography to afford compound 20 as a viscous liquid
(4.26 g, 82%). IR (neat): w 1722 cm−1; 1H NMR
(CDCl3, 400 MHz): l 6.9 (dd, J=14.4, 5.8 Hz, 1H,
EtOOC–CHꢁCH–), 5.8 (d, J=17.3 Hz, 1H, EtOOC–
CHꢁCH–), 4.2 (q, J=15.6, 7.8 Hz, 2H, CH3–CH2O–
CO–), 3.6–3.44 (m, 2H, TBSO–CH2–) 2.48–2.42 (m,
1H, –CH2–CH(CH3)–), 1.26 (t, J=3.8 Hz, 3H, CH3–
CH2O–CO–), 1.05 (d, J=4.3 Hz, 3H, –CH(CH3)–), 0.9
(s, 9H, (CH3)3C–Si–), 0.4 (s, 6H, (CH3)2Si–); EIMS
(m/z): 272 (M+); HRMS: calcd 272.4577; found:
272.4574; [h]D=+12.8 (c 1.3, CHCl3).
4.10. Methyl-(2R)-3-tert-butyldimethylsilyloxy-2-
methylpropanoate 18
To a stirred solution of 17 (5 g, 42.4 mmol) and
imidazole (4.32 g, 63.6 mmol) in CH2Cl2 (125 mL) was
added TBDMS-Cl (6.35 g, 42.4 mmol) portion wise at
0°C. The reaction mixture was stirred at the same
temperature for 6 h and then quenched with water.
CH2Cl2 layer was separated and the aq. layer was
extracted with additional CH2Cl2 (2×30 mL). The
combined CH2Cl2 layer was washed with water, brine
and dried (Na2SO4). The solvent was removed in
vacuo and the residue was purified by column chro-
matography to give 18 (9 g, 92%). IR (neat): w 1744
1
cm−1; H NMR (CDCl3, 200 MHz): l 3.82–3.54 (s and
dd (unresolved), 5H, TBSO-CH2–, –OCH3), 2.7–2.52

266
S. Chandrasekhar, Ch. R. Reddy / Tetrahedron: Asymmetry 13 (2002) 261–268
4.13. (4S)-Methyl-5-tert-butyldimethylsilyloxy-4-
(m, 4H, –CH2–CH2–CH2OTs), 1.1–1.02 (m, 1H,
–CH(CH3)–), 0.94–0.78 (m, 12H, –CH(CH3)–,
(CH3)3C–Si–), 0.2 (s, 6H, (CH3)2Si–); EIMS (m/z): 386
(M+); [h]D=+6.6 (c 0.6, CHCl3).
methylpentanoate 21
To a stirred solution of the ester 20 (3 g, 11 mmol) in
dry methanol (60 mL) was added magnesium turnings
(0.795 g, 33.1 mmol) and the mixture was stirred for 4
h at room temperature under nitrogen. The reaction
mixture was taken into water (30 mL) to which dilute
acetic acid was added and the resulting mixture was
stirred vigorously to give a clear solution. The mixture
was treated with an NH4OH solution to adjust the pH
to 8.5 and extracted with ether (75 mL). The total
extracts were washed with water (20 mL), a saturated
NaHCO3 solution (20 mL) and dried over Na2SO4. The
solvent was removed under vacuum to give the crude
oily compound. Purification by column chromatogra-
phy afforded the pure methyl ester 21 (2.35 g, 82%). IR
4.16. (6S)-7-tert-Butyldimethylsilyloxy-6-methyl-1-hep-
tyne 15
In a two necked round bottomed flask fitted with a
condenser, a KOH guard tube and a septum, liq. NH3
(40 mL) was collected and small pieces of freshly cut
lithium (0.181 g, 25.9 mmol) were introduced to the
reaction mixture with stirring until the blue color per-
sisted for 10 min. Acetylene gas was bubbled into the
reaction mixture for 45 min at −20°C, then a solution
of the tosylate 23 (2 g, 5.18 mmol) in dry DMSO was
added slowly and the reaction mixture was stirred for 2
h at 0°C. The reaction was quenched with solid NH4Cl.
Ammonia was allowed to escape and crushed ice was
added to the reaction mixture, which was then
extracted with ether (2×50 mL). The organic layer was
washed with brine, dried over Na2SO4, concentrated
and purified by column chromatography to give 15 (0.9
1
(neat): w 1724 cm−1; H NMR (CDCl3, 200 MHz): l
3.64 (s, 3H, –COOCH3), 3.22 (d, 2H, TBSO–CH2–
CH(CH3)–), 2.4–2.22 (m, 2H, –CH2–CH2–COOCH3),
1.83–1.52 (m, 2H, –CH(CH3)–CH2–CH2–), 1.4–1.12 (m,
1H, –CH(CH3)–), 0.98–0.82 (m, 12H, –CH(CH3)–,
(CH3)3C–Si–), 0.2 (s, 6H, (CH3)2Si–); EIMS (m/z): 260
(M+); [h]D=+11.6 (c 1.1, CHCl3).
1
g, 73%). H NMR (CDCl3, 200 MHz): l 3.46–3.32 (m,
2H, TBSO–CH2–CH(CH3)–), 2.22–2.1 (m, 2H, –CH2–
Cꢁ) 1.9–1.82 (m, 1H,–CꢁCH), 1.7–1.4 (m, 4H, –CH2–
CH2–CH2–Cꢁ), 1.22–1.1 (m, 1H, –CH(CH3)–),
0.96–0.82 (m, 12H, –CH(CH3)–, (CH3)3C–Si–), 0.2 (s,
6H, (CH3)2Si–); 13C NMR (CDCl3, 400 MHz): l 84.3,
68.2, 68.0, 35.4, 32.3, 29.6, 25.9, 25.9, 18.7, 18.3 and
16.6; EIMS (m/z): 240 (M+); HRMS: calcd 240.4577;
found: 240.4579; [h]D=+5.2 (c 0.5, CHCl3).
4.14. (4S)-5-tert-Butyldimethylsilyloxy-4-methylpentan-
1-ol 22
To a cooled solution of NaBH4 (0.877 g, 23.07 mmol)
and LiCl (0.98 g, 23.07 mmol) in EtOH (20 mL), a
solution of the ester 21 (2 g, 7.69 mmol) in THF (20
mL) was added dropwise over 30 min at 0°C. The
reaction mixture was stirred at room temperature for 12
h. The mixture was filtered and the filtrate was evapo-
rated in vacuo. The crude residue was dissolved in ethyl
acetate and treated with saturated NH4Cl, the solvent
was then evaporated. Purification by column chro-
matography afforded the alcohol 23 (0.82 g, 92%). IR
4.17. 3-Butene-2-ol 25
Magnesium (1.92 g, 80.35 mmol) was taken in dry ether
(60 mL) and methyl iodide (11.4 g, 80.35 mmol) was
added dropwise slowly to the mixture in ether (10 mL)
under nitrogen. After all the magnesium was dissolved,
acrolein 24 (3 g, 53.57 mmol) was added dropwise and
stirred for 1 h. The reaction mixture was quenched with
a saturated NH4Cl solution and extracted with ether
(2×20 mL). The organic layer was dried over Na2SO4,
and evaporation of ether (without vacuum) resulted in
1
(neat): w 3500 cm−1; H NMR (CDCl3, 200 MHz): l
3.62–3.54 (m, 2H, –CH2–CH2–OH), 3.46–3.34 (m, 2H,
TBSO–CH2–CH(CH3)–), 1.64–1.40 (m, 4H, –CH2–
CH2–CH2OH), 1.2–1.08 (m, 1H, –CH(CH3)–), 0.94–
0.82 (m, 12H, –CH(CH3)–, (CH3)3C–Si–), 0.2 (s, 6H,
(CH3)2Si–); EIMS (m/z): 232 (M+); [h]D=+9.8 (c 1,
CHCl3).
1
the alcohol 25 (2.1 g, 70%). IR (neat): w 3622 cm−1; H
NMR (CDCl3, 200 MHz): l 5.96–5.72 (m, 1H,
CH2ꢁCH–), 5.06 (dd, J=26.9, 16.8 Hz, 2H, CH2ꢁCH–),
4.22 (p, 1H, ꢁCH–CH(OH)–CH3), 1.2 (d, J=6.3 Hz,
3H, –CH(OH)–CH3).
4.15. (4S)-5-tert-Butyldimethylsilyloxy-4-methylpentyl-
4-methyl-1-benzenesulfonate 23
To a solution of compound 22 (1.6 g, 6.9 mmol) in dry
CH2Cl2 (30 mL) containing dry Et3N (0.58 g, 10.34
mmol) was added p-toluene sulfonyl chloride (1.31 g,
6.89 mmol) in CH2Cl2 (5 mL) at 0°C under nitrogen.
The reaction mixture was stirred for 10 h at room
temperature, then washed with water (15 mL) and
extracted with CH2Cl2 (25 mL). The organic phase was
dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column
chromatography to afford the tosylate 23 (2.28 g, 85%).
1H NMR (CDCl3, 200 MHz): l 7.78 (d, J=7.8 Hz, 2H,
Ar–), 7.32 (d, J=7.8 Hz, 2H, Ar–), 3.98 (t, J=6.8 Hz,
2H, –CH2–CH2–OTs), 3.36 (d, J=5.4 Hz, 2H, TBSO–
CH2–CH(CH3)–), 2.46 (s, 3H, Ar–CH3) 1.79–1.32
4.18. (1R,2S)-2-(1-Benzyloxyethyl)oxirane 16
,
To a stirred suspension of activated powdered 4 A
molecular sieves (1 g) in dry CH2Cl2 (50 mL) were
added (−)-diisopropyl tartrate (DIPT) (5.84 g, 24.9
mmol), Ti(iPrO)4 (5.9 g, 20.8 mmol) and the allyl
alcohol 25 (1.5 g, 20.8 mmol) at −20°C under nitrogen.
Then tert-butyl hydroperoxide (TBHP) (1.12 g, 12.5
mmol) was added and the homogenous reaction mix-
ture was maintained at −20°C (in a freezer) overnight.
The cold reaction mixture was poured into a precooled
(−20°C) solution containing acetone (20 mL) and water
(10 mL). The resulting mixture was stirred and allowed

S. Chandrasekhar, Ch. R. Reddy / Tetrahedron: Asymmetry 13 (2002) 261–268
267
to warm to room temperature; stirring was continued
until filtration gives a clear solution. The filtrate was
concentrated and the crude was purified by column
chromatography to afford the epoxy alcohol. IR (neat):
filtered, the solvent was evaporated and the residue was
filtered through a short column of silica gel to give 27
(0.47 g, 95%). IR (neat): w 3632 cm−1; 1H NMR
(CDCl3, 300 MHz): l 7.35–7.25 (m, 5H, Ph–), 5.46–5.4
(m, 2H, –CH2–CHꢁCHꢁCH2–), 4.62 (d, J=12 Hz, 2H,
1
w 3620 cm−1; H NMR (CDCl3, 200 MHz): l 3.72–3.64
(m, 1H, –CH(OH)–), 3.54–3.46 (m, 1H, CH2–O–
CH(CH–)–)), 2.88 (d, J=1 Hz, 3H, –CH2–O–
CH(CH–)–), 1.26 (d, J=2.6 Hz, 3H, –CH(OH)–CH3);
[h]D=−16.4 (c 1, MeOH).
PhCH2O–),
3.46–3.25
(m,
4H,
TBSO–CH2–,
–CH(OH)–CH(OBn)–), 1.5–1.2 (m, 9H, –(CH3)CH–
CH2–CH2–CH2–CHꢁCH–CH2–), 1.15 (d, J=4.8 Hz,
3H, –(OBn)CH–CH3), 0.94–0.76 (m, 12H, (CH3)3C–Si–,
–CH(CH3)–), 0.2 (s, 6H, (CH3)2Si–); EIMS (m/z): 420
(M+); [h]D=+14.8 (c 1.6, CHCl3).
To a suspension of sodium hydride (0.27 g, 11.36
mmol, 60% in paraffin oil) in dry THF (25 mL) was
added the epoxy alcohol (0.5 g, 5.68 mmol) at 0°C
under a nitrogen atmosphere. After stirring for 30 min,
benzyl bromide (0.97 g, 5.68 mmol) was slowly added
at 0°C and the mixture was stirred for 6 h. After
completion of the reaction (monitored by TLC), the
reaction mixture was quenched with ice-cold water (15
mL), extracted with ether (2×20 mL), washed with
brine (15 mL), dried over Na2SO4 and evaporated in
vacuo. Silica gel column chromatography afforded 16
4.21. (1R,2S,9S)-(4Z)-1-[2,10-Di(tert-butyldimethylsilyl-
oxy)-1,9-dimethyl-4-decenyloxymethyl]benzene 4
To a stirred solution of 27 (0.4 g, 0.95 mmol) and
imidazole (0.085 g, 1.42 mmol) was added TBDMS-Cl
(0.157 g, 1.04 mmol) portionwise at 0°C. The reaction
mixture was stirred at the same temperature for 6 h and
then quenched with water. The CH2Cl2 layer was sepa-
rated and the aqueous layer was extracted with addi-
tional CH2Cl2 (2×30 mL). The combined CH2Cl2 layer
was washed with water, brine, and dried (Na2SO4). The
solvent was removed in vacuo and the residue was
purified by column chromatography to afford 4 (0.44 g,
1
(0.78 g, 78%). H NMR (CDCl3, 200 MHz): l 7.38–
7.18 (m, 5H, Ph-), 4.66–4.34 (m, 2H, PhCH2O–), 3.46–
3.14 (m, 4H, –CH2–O–CH(CHOBn)–), 1.34–1.2 (m,
3H, –CH(OBn)–CH3); EIMS (m/z): 178 (M+); HRMS:
calcd 178.2296; found: 178.2299; [h]D=+4.5 (c 1.56,
EtOH).
1
88%). H NMR (CDCl3, 200 MHz): l 7.38–7.24 (m,
5H, Ph–), 5.45–5.38 (2H, –CH2–CHꢁCHꢁCH2–), 4.62
(d, J=13.3 Hz, 2H, PhCH2O–), 3.47–3.25 (m, 4H,
TBSO–CH2–, –CH(OH)–CH(OBn)–), 1.48–1.24 (m,
9H, –(CH3)CH–CH2–CH2–CH2–CHꢁCH–CH2–), 1.05
(d, J=5.5 Hz, 3H, –(OBn)CH–CH3), 0.94–0.88 (2×s,
21H, 2×(CH3)3C–Si–, –CH(CH3)–), 0.1–0.15 (2×s, 12H,
2×(CH3)2Si–); 13C NMR (CDCl3, 300 MHz): l 139.2,
128.3, 127.6, 127.4, 76.6, 74, 71, 32.2, 31.1, 26.2, 26.1,
25.7, 22.8, 18.3, 17, 14.3, 13.9, −4.2, −4.4, −5.1;
FABMS: m/z 534 (M+); HRMS: calcd 536.9672; found:
536.9668; [h]D=+9.8 (c 0.8, CHCl3).
4.19. (2R,3S,10S)-2-Benzyloxy-11-tert-butyldimethyl-
silyloxy-10-methyl-5-undecyn-3-ol 26
Under a nitrogen atmosphere, a solution of n-butyl
lithium in hexane (1.4 M solution, 2 mL, 2.5 mmol,)
was added to a dry THF solution (20 mL) of the
acetylene 15 (0.4 g, 1.7 mmol) at −78°C and the mixture
was stirred for 10 min. Boron trifluoride etherate (0.2
mL) was added to the above solution and stirring was
continued for 10 min at −78°C and a THF solution of
the epoxide 16 (0.296 g, 1.7 mmol) was added. After
stirring for 30 min at −78°C, the reaction mixture was
quenched with aqueous ammonium chloride. The
organic layers were extracted with ethyl acetate (2×20
mL) and dried over Na2SO4. After removal of the
solvents, and purification by silica gel column chro-
matography, the propargylic alcohol 26 was obtained
(0.52 g, 75%). IR (neat): w 3628 cm−1; 1H NMR
(CDCl3, 200 MHz): l 7.36–7.26 (m, 5H, Ph–), 4.7–4.42
(m, 2H, PhCH2O–), 3.76–3.3 (m, 4H, TBSO–CH2–,
–CH(OH)–CH(OBn)–), 2.46–2.34 (m, 2H, ꢁC–CH2–
CH(OH)–), 2.18–2.08 (m, 2H, –CH2–CH2–Cꢁ), 1.56–
1.4 (m, 4H, –CH2–CH2–CH2–), 1.3–1.18 (m, 4H,
–CH(CH3), –CH(OBn)–CH3), 0.96–0.82 (m, 12H,
(CH3)3C–Si–, –CH(CH3)–), 0.2 (s, 6H, (CH3)2Si–);
EIMS (m/z): 418 (M+); [h]D=+7.9 (c 1, CHCl3).
Acknowledgements
C.R.R. and S.C. thanks CSIR, New Delhi for financial
assistance in the form of a Senior Research Fellowship
and research grant (EMR-006), respectively. Help in
the form of useful discussion is acknowledged to Dr. J.
S. Yadav.
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