S. V. Reddy et al. / Tetrahedron Letters 56 (2015) 2018–2022
2019
OH
O
OH
OH
O
OH
O
TBSO
OMe
OH
Grubbs II catalyst
CH2Cl2, reflux
O
+
OPMB
X
OH
18
16
14
3
2
2
O
O
9
O
5
OMe O
7
+
8
4
OH
3
1
OH
10
OH
2
OMe
TBSO
N
Mes
Ph
Mes
N
Carolacton (1)
Cl
TBSO
OMe
OPMB
O
O
Ru
PCy3
Cl
3
OPMB
Grubbs II catalyst
15
OMe
OMe
Scheme 3. Synthesis of segment 15.
3
HO
OPMB
TBDPSO
4
5
O
O
O
HO
O
6
OMe O
OMe
O
O
TBSO
Carolacton (1)
Scheme 1. Retrosynthetic analysis of carolacton 1.
16
OH
OPMB
O
O
OMe
OTBS
HO
a, b
ref. 8
BzO
TBDPSO
OH
HO
O
O
6
18
7
9
O
+
d
c
TBDPSO
OH
OMe O
OH
TBSO
TBDPSO
OMe
OPMB
3
8
H
17
H
19
O
H
O
e
f
TBDPSO
TBDPSO
I
OH
Scheme 4. Retrosynthetic analysis of carolacton 1.
H
10a
OMe
10
OH
g
h
TBDPSO
TBDPSO
5
OH
OPMB
11
OH
OPMB
HO
OMe
a
OMe
BzO
i
j
18
20
TBDPSO
a
TBDPSO
OPMB
OH
13
12
OMe
OMe
TBSO
TBSO
OMe
OMe
b
c
k
OPMB
OH
HO
OPMB
O
OPMB
21
3
4
4a
O
O
OH OMe
OMe
OMe
TBSO
TBSO
l
d
COOH
OPMB
OPMB
OMe
14
3
19
19a
Scheme 2. Synthesis of segment 3. Reagents and conditions: (a) (COCl)2, DMSO,
CH2Cl2, À78 °C, 1 h and then Et3N; (b) Ph3P@CHCOOMe, benzene, reflux, 30 min,
93%; (c) DIBAL-H, CH2Cl2, 0 °C–rt, 1 h, 82%; (d) (+)-DIPT, Ti(OiPr)4, cumenehydro-
peroxide, 4 Å molecular sieves, CH2Cl2, À20 °C, 12 h, 81%; (e) imidazole, Ph3P, I2,
0 °C–rt, THF, 15 min, 94%; (f) NaI, Zinc dust, MeOH, reflux, 2 h, 79%; (g) MeI, NaH,
THF, 0 °C–rt, 4 h, 91%; (h) (i) 9-BBN, THF; (ii) 4 N NaOH, 30% H2O2, THF, 0 °C–rt, 7 h,
72%; (i) NaH, PMBBr, THF, 0 °C–rt, 6 h, 80%; (j) TBAF, THF, 0 °C–rt, 3 h, 78%; (k) (i)
trans-2-butene, KOtBu, n-BuLi, B(OiPr)3, THF then 1 N HCl, (À)-DIPT; (ii) 4 Åmolecu-
lar sieves, toluene, À78 °C, 8 h, 84%; (l) TBSOTf, 2,6-lutidine, 0 °C–rt, 2 h, 91%.
Scheme 5. Synthesis of 19a. Reagents and conditions: (a) BzCl, Bu2SnO, Et3N,
CH2Cl2, rt, 30 min, 81%; (b) DDQ, CH2Cl2/H2O (19:1), 0 °C–rt, 1 h, 97%; (c) TEMPO,
BAIB, CH2Cl2/H2O (1:1), 0 °C–rt, 1.5 h, 74%; (d) 1 N HCl, MeOH, rt, 1.5 h, 85%.
CH2Cl2 was unsuccessful to provide 15 at room temperature as
well as at reflux temperature.
After failing to obtain tri-substituted olefin 15 via Grubbs cross
metathesis reaction, a new route was envisioned. It was proposed
to create a segment with trisubstituted double bond (C7–C8) by
RCM reaction.14 Thus, in a new retroanalysis, by two iterative
esterifications and RCM reactions, 1 was envisaged from 16 by
RCM reaction, while 16 in turn would be synthesized from the lac-
tone 17, which in turn could be realized from known diol 187 and
acid 19 by esterification and RCM. 19 in turn was planned from 3
(Scheme 4).
of aldehyde 4a using in situ generated (E)-crotyl boronate, gener-
ated from trans-2-butene, KOt-Bu, n-BuLi, B(OiPr)3 and (À)-DIPT,
afforded the alcohol 14 exclusively in 84% yield. Silylation of 14
with TBSOTf and 2,6-lutidine in CH2Cl2 for 2 h furnished ether 3
in 91% yield.
According to the retrosynthetic strategy, introduction of the
trisubstituted olefin (C7–C8) accomplished by subjecting 2 and 3
to cross metathesis13 (Scheme 3) by using Grubbs II catalyst in