Approaches towards the total synthesis of carolacton: Synthesis of C1-C16 fragment

Article abstract of DOI:10.1016/j.tetlet.2015.03.002

Abstract A stereoselective synthesis of the C1-C16 segment of biofilm inhibitor carolacton has been achieved. The synthetic strategy involves Sharpless asymmetric epoxidation, Roush crotylation, Steglich esterification, RCM reaction and selective reduction of a disubstituted olefin in the presence of a trisubstituted olefin using in situ generated diimide.

Full text of DOI:10.1016/j.tetlet.2015.03.002

Tetrahedron Letters 56 (2015) 2018–2022
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Approaches towards the total synthesis of carolacton: synthesis
of C1–C16 fragment
a
b
a
Sheri Venkata Reddy a, , K. Prasanna Kumar , Kallaganti V. S. Ramakrishna , Gangavaram V. M. Sharma
⇑
a Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b NMR Group, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective synthesis of the C1–C16 segment of biofilm inhibitor carolacton has been achieved. The
synthetic strategy involves Sharpless asymmetric epoxidation, Roush crotylation, Steglich esterification,
RCM reaction and selective reduction of a disubstituted olefin in the presence of a trisubstituted olefin
using in situ generated diimide.
Received 25 December 2014
Revised 25 February 2015
Accepted 1 March 2015
Available online 5 March 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Carolacton
Steglich esterification
Ring closing metathesis
Roush crotylation
Diimide reduction
Introduction
Results and discussion
Kirschning and Müller discovered carolacton 1 from the extract
of a Sorangium cellulosum strain So ce961 in 2010. Carolacton 1 has
shown high antibacterial activity against biofilms of Streptococcus
mutans. 1 also exhibited an activity against the antibiotic-sensitive
Retrosynthetically, carolacton would be obtained via the cross
metathesis (CM) of known 1,1-disubstituted olefin 2 (C7–C19)
and terminal olefin 3 (C1–C7). Fragment 3 was prepared from a
sequence of oxidation/Roush crotylation of alcohol 4. A series of
hydroboration and protecting group manipulations would give
alcohol 4 from olefin 5, which in turn was obtained from the
corresponding Roche ester 6 (Scheme 1).
Escherichia coli strain tolC, (MIC 0.06 lg/mL), besides minor
antifungal activity2 and other applications.3 Since the antibiotic
resistance of bacteria in biofilms is found to be approximately
1000-fold higher than in planktonic form, there is an urgent need
to develop new methods or tools to selectively destroy clinically
relevant biofilms.4
The known alcohol 7,8 on oxidation under Swern reaction and
the Wittig reaction in refluxing benzene for 30 min afforded ester
8 in 93% yield (Scheme 2).
Carolacton 1 is a 12-membered macrolide containing 8-stere-
ogenic centres in addition to trans-1,2-diol moiety at C17–C18 in
an open-chain conformation. It has a trans double bond at C15–
C16 and a trisubstituted olefin with E-configuration at C7–C8.
Besides the 12-membered macrolactone ring, 1 has a side chain
(C1–C8) containing three stereocentres at C3, C4 and C6, a keto car-
bonic acid. So far two groups have reported5 the total synthesis of
carolacton, while two other groups reported6 the synthesis of frag-
ments of carolacton. Recently our group reported7 the syntheses of
macrolactone moiety of 1, constituting the C7–C19 core. In con-
tinuation with our efforts on the total synthesis of 1, herein we
present our studies on the synthesis of C1–C16 fragment of 1.
DIBAL-H reduction of 8 in CH2Cl2 at 0 °C for 1 h furnished the
alcohol 9 in 82% yield. Sharpless asymmetric epoxidation of allylic
alcohol 9 with (+)-DIPT, Ti(OiPr)4 and cumene hydroperoxide at
À20 °C for 12 h gave epoxide 10 in 81% yield. Alcohol 10 was con-
verted to the corresponding iodide 10a using imidazole, Ph3P and
I29 in THF at 0 °C–rt for 15 min (94% yield), which on reaction with
NaI and zinc dust10 in MeOH at reflux for 2 h furnished allylic alco-
hol 11 in 79% yield. Treatment of 11 with MeI and NaH in THF at
0 °C to room temperature for 4 h gave methyl ether 5 in 91% yield.
Hydroboration of terminal olefin
5
with 9-BBN11 in THF
afforded the alcohol 12 (72%), which on treatment with PMB-Br
and NaH in THF for 6 h afforded the ether 13 in 80% yield.
Deprotection of silyl ether 13 using TBAF at 0 °C to room tempera-
ture for 3 h gave alcohol 4 in 78% yield, which on subjected to
Swern reaction conditions gave aldehyde 4a. Roush crotylation12
⇑
Corresponding author. Tel.: +91 40 27193158; fax: +91 40 27160757.
E-mail address: sheri.venkatreddy@gmail.com (S.V. Reddy).
http://dx.doi.org/10.1016/j.tetlet.2015.03.002
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

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

2020
S. V. Reddy et al. / Tetrahedron Letters 56 (2015) 2018–2022
and lactonization reaction. The structure of 19a was established by
O
1H NMR (500 MHz, CDCl3) data and assignments were made using
TOCSY and NOESY experimental data. The characteristic NOE
correlation between C3-H/C5-H in 19a [Fig. 1a] suggested that
both protons are 1,3-diaxial. The energy minimized structure as
shown in Figure 1b is also in agreement with the assigned struc-
ture from NMR data.
1
O
5
6
4
3
O
8
19a
a
b
Further, Steglich esterification of acid 19 with alcohol 20 using
DCC and DMAP in CH2Cl2 at room temperature for 12 h furnished
bis-olefin 22 in 69% yield (Scheme 6). However, diene 22 on treat-
ment either with Grubbs II generation catalyst or with Hoveyda–
Grubbs II generation catalyst in CH2Cl2 as well as in toluene at
reflux for 12 h failed to give the required lactone 20. Having been
unsuccessful in introducing the trisubstituted olefin at the C7–C8
position, we sought to perform a Wittig olefination to overcome
the unreactivity.
According to the modified retroanalysis (Scheme 7), 1 could be
obtained from acid 237 and alcohol 24, while 24 in turn could be
synthesized from the eight membered lactone 25. Esterification
of acid 26 with alcohol 27 and followed by RCM of the resulting
ester would give 25, while 27 would be synthesized from 3.
Accordingly, olefin 3 subjected to ozonolysis16 in CH2Cl2 at
À78 °C for 15 min gave aldehyde, which on treatment with
Ph3P@C(Me)CO2Et17 in refluxing benzene for 1 h afforded 28 in
90% yield (Scheme 8). Reduction of ester 28 using DIBAL-H in dry
CH2Cl2 at 0 °C for 1 h furnished allylic alcohol 29 in 87% yield,
which upon subjected to Swern oxidation gave aldehyde 29a.
Roush crotylation of 29a using in situ generated (E)-crotyl boro-
nate (generated from trans-2-butene, KOt-Bu, n-BuLi, B(OiPr)3
and (+)-DIPT) afforded alcohol 27 in 67% yield.
Figure 1. (a) The NOE correlation between C3-H/C5-H of 19a, (b) energy minimized
structure of 19a.
O
OMe
TBSO
OTBS
OMe
a
O
OPMB
COOH
BzO
19
22
O
O
OMe
OTBS
BzO
N
N
Mes
Mes
b
Cl
X
Ru
O
Cl
OPMB
17
Hoveyda grubbs II
catalyst
Scheme 6. Synthesis of segment 17. Reagents and conditions: (a) 23, DCC, DMAP,
CH2Cl2, 0 °C–rt, 12 h, 69%; (b) Grubbs II generation catalyst, CH2Cl2/toluene, reflux
or Hoveyda Grubbs II generation catalyst, CH2Cl2/toluene, reflux.
Steglich esterification of known chiral acid 2618 with alcohol 27
using DCC and DMAP in CH2Cl2 at room temperature for 12 h fur-
nished the bis-olefin 30 in 91% yield (Scheme 9). RCM reaction of
diene 30 with Hoveyda Grubbs II generation catalyst19 in toluene
at reflux for 18 h afforded eight membered lactone 25 in 35% yield.
The addition of 10 equiv of 1,4-benzoquinone as additive acceler-
ated the RCM reaction and the diene was completely consumed
in 3 h to give lactone 25 in 66% yield (Scheme 9).
Accordingly, known diol 18 on mono benzoylation with benzoyl
chloride, Bu2SnO and Et3N in CH2Cl2 at room temperature for
30 min furnished benzoate 20 in 81% yield (Scheme 5). For the syn-
thesis of acid 19, compound 3 was treated with DDQ in CH2Cl2/H2O
(19:1) at room temperature for 1 h to afford alcohol 21 (97%),
which upon oxidation using TEMPO and iodobenzene diacetate15
in CH2Cl2/H2O (1:1) at room temperature for 1.5 h furnished acid
19 in 74% yield.
After having eight membered ring in the hand the next target
was selective reduction of disubstituted olefin in the presence of
a trisubstituted olefin in 25, thermal decomposition of 2,4,6-
To establish the configuration in 19, the acid treated with 1 N
HCl in MeOH gave lactone 19a (85%) by a concomitant desilylation
O
O
OH
OH
18
16
14
23
O
OH
+
O
O
9
O
5
OMe O
7
OH
OMe
TBSO
8
4
3
1
OH
10
2
OPMB
Carolacton (1)
24
O
O
O
HO
OH
OMe
TBSO
26
TBSO
+
OMe
OPMB
OPMB
25
27
OMe
TBSO
OPMB
3
Scheme 7. Retrosynthetic analysis of carolacton 1.

S. V. Reddy et al. / Tetrahedron Letters 56 (2015) 2018–2022
2021
TBSO
OMe
TBSO
OMe
at À78 °C for 30 min to afford the lactol 31a (90%), which on
one carbon homologation by the subsequent reaction with
(methylene)triphenyl phosphorane in THF at À20 °C for 3 h gave
24 in 55% yield.
a
OPMB
O
OPMB
3a
3
O
Thus, the synthesis of 24 constitutes the synthesis of the
C1–C16 fragment of carolacton 1. Esterification of 24 and
macrocyclization of the resulting ester followed by deprotection
would give the target molecule carolacton 1.
OMe
TBSO
b
c
EtO
OPMB
O
28
OMe
TBSO
OMe
TBSO
d
HO
OPMB
OPMB
Conclusions
29
29a
In summary, our stereoselective synthesis of the C1–C16 seg-
ment began from (S)-Roche ester. The synthetic strategy involved
Sharpless asymmetric epoxidation, Roush crotylation, RCM reac-
tion, Steglich esterification and diimide reduction of a disubsti-
tuted olefin in the presence of a trisubstituted olefin as the key
reactions.
OH
OMe
TBSO
e
OPMB
27
Scheme 8. Synthesis of segment 27. Reagents and conditions: (a) O3, CH2Cl2, Me2S,
À78 °C, 15 min; (b) Ph3P@C(Me)CO2Et, benzene, reflux, 1 h, 90%; (c) DIBAL-H,
CH2Cl2, 0 °C, 1 h, 87%; (d) (COCl)2, DMSO, Et3N, CH2Cl2, À78 °C, 1 h; (e) trans-2-
butene, KOtBu, n-BuLi, B(OiPr)3, 1 N HCl, (+)-DIPT, 4 Å molecular sieves,
toluene,À78 °C, 7 h, 67%.
Acknowledgements
The authors are thankful to Council of Scientific and Industrial
Research, New Delhi, India for the financial support (ORIGIN).
S.V.R. thanks University Grants Commission (CSIR), New Delhi,
India, for the award of research fellowship.
O
OH
OMe
TBSO
a
HO
+
OPMB
Supplementary data
26
27
Supplementary data (full experimental procedures, character-
ization data, and 1H and 13C NMR spectra for new compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.03.002.
O
O
O
O
OTBS
c
b
OTBS
R
R
References and notes
30
25
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O
O
OH
OTBS
R
d
e
O
OTBS
R
31
31a
OH
OMe
TBSO
1
OPMB
24
NH2
HN
S
O
O
OMe
R =
OPMB
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Scheme 9. Synthesis of 24. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, 0 °C–
rt, 12 h, 91%; (b) Hoveyda Grubbs II Generation catalyst, 1,4-benzoquinone, toluene,
reflux, 3 h, 66%; (c) 2,4,6-triisopropylbenzenesulphonyl hydrazide, Et3N, 1,2-
dichloro ethane, 60 °C, 65%; (d) DIBAL-H, CH2Cl2, À78 °C, 30 min, 90%; (e) PPh3–
CH3Br, n-BuLi, THF, 0 °C–rt, 3 h, 55%.
triisopropylbenzenesulfonyl hydrazide20 in the presence of Et3N in
1,2-dichloroethane at 80 °C gave the expected product 31 in 65%
yield. In order to introduce the terminal olefin, lactone 31 was
subjected to reduction using 1 equiv of DIBAL-H21 in dry CH2Cl2

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S. V. Reddy et al. / Tetrahedron Letters 56 (2015) 2018–2022
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