Synthetic studies of carolacton: Enantioselective total synthesis of C1-C8 and C9-C19 fragments of the molecule

Article abstract of DOI:10.1055/s-0033-1339500

This paper describes synthetic studies towards carolacton, a highly potent antibiotic against dental caries and endocarditis related bacterium Streptococcus mutans. The synthesis of the 12-membered lactone with a diversely functionalized keto acid side chain was accomplished by utilizing a blend of chiral pool and aldol strategies. Carbon chain C1-C8 was derived by utilizing Paterson aldol methodology and a Corey-Fuchs reaction. The C9-C19 chain was prepared by means of iterative Evans asymmetric alkylations and an E-selective cross-metathesis reaction. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339500

PAPER
▌2745
paper
Synthetic Studies of Carolacton: Enantioselective Total Synthesis of C1–C8
and C9–C19 Fragments of the Molecule
Synthetic Studies of Carolacton
Kulakarni Sripad Rao, Subhash Ghosh*
Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
Fax +91(40)27193108; E-mail: sripadchem@gmail.com
Received: 16.06.2013; Accepted after revision: 12.07.2013
OH
Abstract: This paper describes synthetic studies towards carolac-
OH
ton, a highly potent antibiotic against dental caries and endocarditis
related bacterium Streptococcus mutans. The synthesis of the 12-
membered lactone with a diversely functionalized keto acid side
chain was accomplished by utilizing a blend of chiral pool and aldol
strategies. Carbon chain C1–C8 was derived by utilizing Paterson
aldol methodology and a Corey–Fuchs reaction. The C9–C19 chain
was prepared by means of iterative Evans asymmetric alkylations
and an E-selective cross-metathesis reaction.
O
O
O
OMe O
OH
Figure 1 Structure of carolacton
Key words: Streptococcus mutans, carolacton, antibiotic, Paterson
aldol reaction, cross metathesis
be obtained from olefinic alcohol 3 and the tert-butyl ester
4 by utilizing the Nozaki–Hiyama–Kishi reaction (similar
to the Kirschning approach). The olefinic fragment 3 with
E-configuration could be obtained from the two olefinic
fragments 5 and 6 by means of a cross-metathesis reac-
tion. The other fragment 4 could be obtained via Paterson
aldol reaction between 7 and 8 followed by functional
group interconversion (Scheme 1).
Streptococcus mutans biofilms on various body tissues,
medical devices, and implants1,2 are a matter of serious
concern due to their strong resistance to available anti-
biotics. These biofilms cause dental caries, periodontal
decay, and are found to be highly resistant3,4 compared to
when they are present in their natural habitat. Therefore,
the development of efficient antibiotics to eradicate these
biofilms formed via bacterial aggregation is an active area
of research. Recently Müller et al. isolated5a carolacton
(Figure 1) from the extracts of the Sorangium cellulosum
strain and this has the ability to destroy these biofilms5b at
considerably low concentrations. Structural assignment
based on NMR showed that it is a 12-membered macro-
lide with a highly functionalized keto acid side chain. Fur-
ther development of carolacton skeleton based motifs are
highly promising towards the elimination of Streptococ-
cus mutans biofilms and related complications. We have
undertaken the total synthesis of carolacton because of its
interesting biological functions and complex architecture.
Our approach is highly diversified so that, as it can be uti-
lized for the synthesis of various carolacton analogues and
subsequent biological evaluations. While this work was
still ongoing, the first total synthesis of carolacton was re-
ported by Kirschning et al.6a A synthetic study towards the
total synthesis of carolacton appeared in the literature dur-
ing preparation of this manuscript.6b In this paper we re-
port our efforts towards synthetic studies of carolacton.
O
O
CO2H
OPMB
OH
OMe O
1
Ot-Bu
2
O
O
OPMB
OMe
COOMe
O
+
Ot-Bu
OH
3
4
O
O
OTBDPS
O
PMBO
+
Structural analysis of carolacton (1) revealed that macro-
lactonization of the seco acid 2 followed by protecting
group deprotection and functional group manipulations
would provide the target molecule. The seco acid 2 could
O
8
CO2Me
7
5
+
SYNTHESIS 2013, 45, 2745–2751
Advanced online publication: 15.08.2013
OH
6
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339500; Art ID: SS-2013-T0411-OP
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic analysis of carolacton

2746
K. S. Rao, S. Ghosh
PAPER
Thus our synthesis commenced from the known com- hydroxy keto compound 15 (96%, dr > 99:1). Hydroxy-
pound 97 (Scheme 2), which on two-step oxidation8 directed keto reduction by using the Evans protocol18 pro-
afforded the known acid 10;9 coupling of the acid with vided the 1,3-anti-diol compound 16, which on oxidative
(R)-4-benzyloxazolidin-2-one provided compound 11.10 rearrangement with 2,3-dichloro-5,6-dicyano-1,4-benzo-
Methylation11 of 11 with iodomethane in the presence of quinone followed by O-methylation with iodomethane
sodium hexamethyldisilazanide in tetrahydrofuran at and sodium hydride in tetrahydrofuran provided globally
–78 °C followed by chiral auxiliary removal provided the protected compound 17. Opening of the 4-methoxyben-
known primary alcohol 12.12 Oxidation of the alcohol 12 zylidene ring with diisobutylaluminum hydride afforded
under Swern conditions provided an aldehyde, which on primary alcohol 18, which on oxidation19 followed by
one-carbon homologation with methylenetriphenyl- Corey–Fuchs20 reaction and methylation of the terminal
phosphorane followed by tetrabutylammonium fluoride alkyne with iodomethane afforded compound 19. TBDPS
mediated TBS deprotection furnished known compound deprotection of 19 furnished primary alcohol 20, which on
13.13 The alcohol 13 was oxidized to an acid by a two-step two-step oxidation followed by esterification of the resul-
oxidation protocol and then coupled with the chiral auxil- tant acid with tert-butyl trichloroacetimidate21 provided
iary to give 14, which on methylation with iodomethane known ester compound 4 (Scheme 3).
followed by removal of chiral auxiliary furnished alcohol
The key intermediates 3 and 4 were utilized by
6. The crucial cross-metathesis reaction14 between 6 and
Kirschning6a et al. in their total synthesis of carolacton,
the known compound 515 was achieved with Grubbs
thus we herewith demonstrate a formal total synthesis of
second-generation catalyst (Grubbs II) to afford the alco-
the molecule.
hol 3 with the required E-configured olefinic moiety in
In conclusion we have achieved the enantioselective total
73% yield.
synthesis of C1–C8 and C9–C19 fragments of carolacton.
The strategy developed here is highly flexible and conver-
gent. The key features of the synthesis include a cross-
metathesis reaction, Evans asymmetric alkylation, and
The synthesis of alkyne compound 4 started with the ad-
dition of the enolate generated from the known ketone 716
under Paterson conditions17 to the aldehyde 8 and gave β-
Paterson aldol reaction.
i (b)
ii
R
OTBS
HO
OTBS
4
5
1H NMR and 13C NMR spectra were recorded on Bruker 300 MHz
(Avance), Varian Unity 500 MHz (Innova) and 700 MHz spectrom-
eters at r.t. in CDCl3 solvent by using TMS as internal standard.
FTIR spectra were recorded on an Alpha (Bruker) infrared spectro-
photometer. Horiba Sepa 300 polarimeter was used to record the op-
tical rotations. All the reactions were carried out under inert
atmosphere in flame dried glass apparatus. Freshly distilled anhyd
solvents were used to carry out the reactions. All the chemicals from
Aldrich were used as received. Column chromatography was car-
ried on silica gel (60–120 mesh) packed in glass columns.
O
9 R = CH2OH
10
i (a)
R = CHO
Bn
iv
iii
HO
O
N
OTBS
OTBS
5
4
O
O
12
11
Bn
7-(tert-Butyldimethylsiloxy)heptanal; Typical Procedure for
the Swern Oxidation
vi
v
N
O
To a cooled soln of (COCl)2 (1.57 mL, 18.25 mmol) in anhyd
CH2Cl2 (30 mL) at –78 °C was added anhyd DMSO (2.76 mL,
38.95 mmol) slowly under a N2 atmosphere. After 15 min, alcohol
9 (3 g, 12.17 mmol) in anhyd CH2Cl2 (10 mL) was added by cannu-
la. The mixture was stirred for 30 min at –78 °C, then Et3N (8.46
mL, 60.86 mmol) was added, and the mixture was stirred at this
temperature for 45 min. The mixture was quenched with sat. aq
NH4Cl soln (20 mL) and extracted with EtOAc (2 × 60 mL). The
combined organic extracts were washed sequentially with H2O (10
mL) and brine (10 mL), dried (Na2SO4), and concentrated in vacuo.
The residue was passed through a plug of silica gel and used in the
next step without characterization.
OH
3
4
13
O
O
14
5, vii
OH
3
6
Scheme 2 Synthesis of fragment 3: Reagents and conditions: (i) (a)
(COCl)2, DMSO, Et3N, CH2Cl2, –78 °C to 0 °C, 2 h; (b) NaClO2,
NaH2PO4, t-BuOH, H2O, 2-methylbut-2-ene, 0 °C to r.t., 1 h, 80%
over 2 steps; (ii) PivCl, Et3N, THF, –20 °C, 1 h, then LiCl, (R)-4-ben-
zyloxazolidin-2-one, –20 °C, 1 h, 0 °C, 2 h, 85%; (iii) (a) MeI, NaH-
MDS, THF, –78 °C, 3 h; (b) LiBH4, Et2O, H2O, 0 °C, 30 min, 81%
over 2 steps; (iv) (a) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C to 0 °C,
2 h; (b) Ph3P+MeI–, NaHMDS, THF, –78 °C to r.t., 2 h; (c) TBAF,
THF, 0 °C to r.t., 1 h, 86% over 3 steps; (v) (a) (COCl)2, DMSO, Et3N,
CH2Cl2, –78 °C to 0 °C, 2 h; (b) NaClO2, NaH2PO4, t-BuOH, H2O, 2-
methylbut-2-ene, 0 °C to r.t., 1 h; (c) PivCl, Et3N, THF, –20 °C, 1 h,
then LiCl, (S)-4-benzyloxazolidin-2-one, –20 °C, 1 h, 0 °C, 2 h, 81%
over 3 steps; (vi) (a) MeI, NaHMDS, THF, –78 °C, 4 h; (b) LiBH4,
Et2O, H2O, 0 °C, 30 min, 80% over 2 steps; (vii) Grubbs II (10 mol%),
CH2Cl2, reflux, 7 h, 73%.
7-(tert-Butyldimethylsiloxy)heptanoic Acid (10); Typical Proce-
dure for the Pinnick Oxidation
To a soln of 7-(tert-butyldimethylsiloxy)heptanal in t-BuOH (40
mL) at 0 °C 2-methylbut-2-ene (12.1 mL) was added; this was fol-
lowed, after 5 min, by the addition of NaClO2 (4.38 g, 48.69 mmol)
and NaH2PO4 (7.59 g, 48.69 mmol) dissolved in the minimum
amount of H2O. The resulting mixture was stirred at r.t. for 1 h. The
mixture pH was adjusted to 2 with 1 M HCl and extracted with
EtOAc (2 × 60 mL). The combined organic layers were washed se-
quentially with sat. aq NaHCO3 (10 mL), H2O (10 mL), and brine
(10 mL), concentrated in vacuo, and purified by column chromato-
Synthesis 2013, 45, 2745–2751
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthetic Studies of Carolacton
2747
O
O
OH OTBDPS
i
ii
PMBO
PMBO
15
7
PMP
O
OH OH
O
OMe
iii
PMBO
OTBDPS
OTBDPS
16
17
PMBO
OMe OTBDPS
PMBO
OMe OTBDPS
v
iv
HO
18
19
PMBO
OMe
PMBO
OMe O
vi
vii
Ot-Bu
OH
4
20
Scheme 3 Synthesis of fragment 4: Reagents and conditions: (i) Cy2BCl, Et3N, Et2O, –78 °C to 0 °C, 2.5 h, then 8, –78 °C to r.t., 12 h, 96%,
dr > 99:1; (ii) Me4NHB(OAc)3, AcOH–acetone (1:1), –20 °C, 24 h, 81%; (iii) (a) DDQ, 4 Å MS, CH2Cl2, –10 °C to 0 °C, 1 h; (b) MeI, NaH,
DMAP, THF, 0 °C to r.t., 3 h, 78% over 2 steps; (iv) DIBAL-H, CH2Cl2, –78 °C, 2 h, 74%; (v) (a) DMP, NaHCO3, CH2Cl2, 0 °C to r.t., 1 h;
(b) CBr4, Ph3P, CH2Cl2, 0 °C to r.t., 1 h; (c) BuLi, MeI, THF, –78 °C to r.t., 3 h, 70% over 3 steps; (vi) TBAF, THF, 0 °C to r.t., 1 h, 90%; (vii)
(a) DMP, NaHCO3, CH2Cl2, 0 °C to r.t., 1 h; (b) NaClO2, NaH2PO4, t-BuOH, H2O, 2-methylbut-2-ene, 0 °C to r.t., 1 h; (c) tert-butyl trichloro-
acetimidate, CSA, CH2Cl2, 0 °C to r.t., 24 h, 60% over 3 steps.
graphy to provide 10 (2.53 g, 80%) as a colorless oil; Rf = 0.3 (30%
H), 2.77 (dd, J = 14.0, 10.0 Hz, 1 H), 1.75–1.66 (m, 2 H), 1.58–1.49
EtOAc–petroleum ether).
(m, 2 H), 1.44–1.35 (m, 4 H), 0.90 (s, 9 H), 0.05 (s, 6 H).
IR (neat): 2934, 1708, 1462, 1097, 833 cm–1.
13C NMR (75 MHz, CDCl3): δ = 173.2, 153.3, 135.2, 129.3, 128.8,
127.2, 66.0, 63.0, 55.0, 37.7, 35.3, 32.5, 28.8, 25.8, 25.5, 24.1, 18.2,
–5.3.
1H NMR (500 MHz, CDC13): δ = 3.59 (t, J = 7.3 Hz, 2 H), 2.32 (t,
J = 7.3 Hz, 2 H), 1.67–1.58 (m, 2 H), 1.54–1.46 (m, 2 H), 1.37–1.30
(m, 14 H), 0.87 (s, 9 H), 0.03 (s, 6 H).
HRMS (ESI): m/z [M + Na]+ calcd for C23H37NO4SiNa: 442.2389;
found: 442.2375.
13C NMR (75 MHz, CDCl3): δ = 179.8, 63.0, 33.9, 32.4, 28.7, 25.8,
25.3, 24.5, 18.1, -5.4.
HRMS (ESI): m/z [M + Na]+ calcd for C13H28O3SiNa: 283.1705;
(R)-4-Benzyl-3-[(R)-7-(tert-butyldimethylsiloxy)-2-methylhep-
tanoyl]oxazolidin-2-one; Typical Procedure
To a soln of 11 (3 g, 7.15 mmol) in anhyd THF (20 mL) at –78 °C,
1 M NaHMDS (107 mL, 10.7 mmol) was added slowly with stirring
under a N2 atmosphere. The mixture was stirred at –78 °C for 30
min, MeI (1.34 mL, 21.4 mmol) was added, and it was stirred for an
additional 3 h at –78 °C. The reaction was quenched with sat. aq
NH4Cl (10 mL), warmed to r.t., and extracted with EtOAc (2 × 30
mL). The combined organic extracts were washed sequentially with
H2O (10 mL) and brine (10 mL), dried (Na2SO4), evaporated under
reduced pressure, and purified by column chromatography to afford
the methylated product as a colorless oil.
found: 283.1700.
(R)-4-Benzyl-3-[7-(tert-butyldimethylsiloxy)heptanoyl]oxazoli-
din-2-one (11); Typical Procedure
To a stirred soln of acid 10 (2.5 g, 9.6 mmol) in anhyd THF (30 mL)
at –20 °C was added Et3N (3.33 mL, 24.0 mmol) followed by PivCl
(1.18 mL, 9.6 mmol). The mixture was stirred for 1 h at –20 °C, and
then LiCl (0.61 g, 14.4 mmol) followed by (R)-4-benzyloxazolidin-
2-one (1.7 g, 9.6 mmol) were added and stirring was continued for
1 h at –20 °C and then 2 h at 0 °C. The reaction was quenched with
sat. aq NH4Cl (10 mL) and extracted with EtOAc (2 × 60 mL). The
combined organic extracts were washed sequentially with H2O (10
mL) and brine (10 mL), dried (Na2SO4), and evaporated under re-
duced pressure to give a residue that was purified by column chro-
matography to yield 11 (3.42 g, 85%) as a colorless oil; Rf = 0.35
(20% EtOAc–petroleum ether).
(R)-7-(tert-Butyldimethylsiloxy)-2-methylheptan-1-ol (12);
Typical Procedure
To an ice-cooled soln of methylated compound (2.5 g, 5.7 mmol) in
Et2O (18 mL), containing 1 drop of H2O, was added LiBH4 (0.37 g,
17.3 mmol) portionwise. The mixture was stirred at r.t. for 30 min.
The reaction was quenched by slow dropwise addition of sat. aq
NH4Cl (10 mL) at 0 °C. The mixture was extracted with EtOAc (2
× 30 mL) and the combined organic layers were washed sequential-
ly with H2O (10 mL) and brine (10 mL), dried (Na2SO4), concen-
trated in vacuo, and purified by column chromatography to afford
12 (1.21 g, 81%) as a colorless oil; Rf = 0.4 (20% EtOAc–petroleum
ether).
[α]D24 –35.3 (c 4, CHCl3).
IR (neat): 2935, 2860, 1782, 1383, 1096 cm–1.
1H NMR (500 MHz, CDC13): δ = 7.36–7.30 (m, 2 H), 7.27 (m, 1
H), 7.22–7.19 (m, 2 H), 4.67 (m, 1 H), 4.22–4.13 (m, 2 H), 3.61 (t,
J = 7.0 Hz, 2 H), 3.29 (dd, J = 13.0, 3.0 Hz, 1 H), 3.01–2.85 (m, 2
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2745–2751

2748
K. S. Rao, S. Ghosh
PAPER
[α]D24 +6.7 (c 5, CHCl3).
IR (neat): 3347, 2930, 2860, 1464, 1098, 834 cm–1.
1H NMR (500 MHz, CDC13): δ = 3.60–3.55 (m, 2 H), 3.45 (m, 1
H), 3.37 (m, 1 H), 2.02 (br s, 1 H), 1.58 (m, 1 H), 1.53–1.46 (m, 2
H), 1.41–1.34 (m, 2 H), 1.33–1.25 (m, 3 H), 1.08 (m, 1 H), 0.88 (d,
J = 7.0 Hz, 3 H), 0.86 (s, 9 H), 0.02 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 68.0, 63.1, 35.5, 33.0, 32.6, 26.6,
26.0, 25.8, 18.2, 16.4, -5.3.
HRMS (ESI): m/z [M + Na]+ calcd for C14H32O2SiNa: 283.2099;
found: 283.2102.
13C NMR (75 MHz, CDCl3): δ = 173.3, 153.4, 144.5, 135.2, 129.3,
128.8, 127.2, 112.4, 66.0, 55.0, 37.8, 37.6, 36.2, 35.4, 26.9, 26.7,
24.2, 20.1.
HRMS (ESI): m/z [M + Na]+ calcd for C19H25NO3Na: 338.1732;
found: 338.1730.
(2S,6R)-2,6-Dimethyloct-7-en-1-ol (6)
Compound 14 (0. 5 g, 1.6 mmol) was subjected to Evans methyla-
tion according to the typical procedure for (R)-4-benzyl-3-[(R)-7-
(tert-butyldimethylsiloxy)-2-methylheptanoyl]oxazolidin-2-one to
provide the methylated product as clear oil.
The methylated compound was treated with LiBH4 according to the
typical procedure for 12 to yield 6 (0.11 g, 80%) as a colorless oil;
Rf = 0.4 (20% EtOAc–petroleum ether).
[α]D24 –29.6 (c 0.5, CHCl3).
(R)-6-Methyloct-7-en-1-ol (13)
Compound 12 (1 g, 3.84 mmol) was subjected to Swern oxidation
following the typical procedure for 7-(tert-butyldimethylsil-
oxy)heptanal to yield (R)-7-(tert-butyldimethylsiloxy)-2-methyl-
heptanal, which was used directly in the next step without
characterization.
IR (neat): 3316, 2923, 1696, 1519, 1207 cm–1.
1H NMR (500 MHz, CDC13): δ = 5.68 (m, 1 H), 4.98–4.86 (m, 2
H), 3.49 (m, 1 H), 3.41 (m, 1 H), 2.11 (m, 1 H), 1.66 (m, 1 H), 1.42–
1.31 (m, 2 H), 1.31–1.23 (m, 3 H), 1.10 (m, 1 H), 0.97 (d, J = 6.2
Hz, 3 H), 0.90 (d, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 144.8, 112.2, 62.9, 37.6, 36.5,
32.7, 26.9, 25.7, 20.1.
To a suspension of methyltriphenylphosphonium iodide (3.41 g,
8.44 mmol) in anhyd THF (8 mL) at 0 °C was added 1 M NaHMDS
(7.68 mL, 7.68 mmol) slowly. The mixture was stirred at this tem-
perature for 30 min, then it was cooled to –78 °C, and (R)-7-(tert-
butyldimethylsiloxy)-2-methylheptanal dissolved in THF (4 mL)
was added slowly. The mixture was allowed to reach r.t. over a pe-
riod of 2 h. H2O (10 mL) was added to the mixture, and it was ex-
tracted with EtOAc (2 × 30 mL). The combined organic extracts
were washed sequentially with brine (10 mL), dried (Na2SO4), and
concentrated in vacuo. Purification by column chromatography
yielded (R)-8-(tert-butyldimethylsiloxy)-3-methylocta-1,8-diene as
a clear oil.
MS (EI): m/z = 156 (M+).
Methyl (4R,5R)-5-[(3R,7S,E)-8-Hydroxy-3,7-dimethyloct-1-
enyl]-2,2-dimethyl-1,3-dioxolane-4-carboxylate (3)
To a degassed soln of 5 (0.089 g, 0.48 mmol) and 6 (0.05 g, 0.32
mmol) in anhyd CH2Cl2 (2 mL) was added Grubbs II catalyst (5 mg,
10 mol%) at r.t. under a N2 atmosphere. The resulting pale purple
color soln was heated to reflux (40 °C) for 7 h. After complete con-
sumption of the starting material, the solvent was removed under
vacuo. The resulting crude residue was purified by column chroma-
tography to afford 3 (0.73 g, 73%) as a clear oil; Rf = 0.2 (20%
EtOAc–petroleum ether).
To a stirred soln of (R)-8-(tert-butyldimethylsiloxy)-3-methylocta-
1,8-diene in anhyd THF (9 mL), 1 M TBAF (2.7 mL, 2.7 mmol) was
added at 0 °C and the mixture was allowed to reach r.t. After 1 h the
reaction was quenched with sat. aq NH4Cl (5 mL) and extracted
with EtOAc (2 × 20 mL). The combined organic layers were
washed sequentially with H2O (5 mL) and brine (5 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. Chromatographic pu-
rification of the residue provided alcohol 13 (0.368 g, 86%) as a liq-
uid; Rf = 0.3 (20% EtOAc–petroleum ether).
[α]D24 –15.79 (c 1, CHCl3).
IR (neat): 3327, 2926, 1642, 1054, 910 cm–1.
1H NMR (300 MHz, CDC13): δ = 5.69 (m, 1 H), 5.0–4.87 (m, 2 H),
3.63 (t, J = 6.8 Hz, 2 H), 2.11 (m, 1 H), 1.63–1.51 (m, 2 H), 1.38–
1.24 (m, 6 H), 0.98 (d, J = 6.8 Hz, 3 H).
[α]D24 –54.87 (c 0.8, CH2Cl2).
IR (neat): 3563, 2925, 1647, 1516, 1204 cm–1.
1H NMR (500 MHz, CDC13): δ = 5.74 (dd, J = 15.0, 8.0 Hz, 1 H),
5.27 (dd, J = 16.0, 8.0 Hz, 1 H), 4.76 (t, J = 8.0 Hz, 1 H), 4.63 (d,
J = 7.0 Hz, 1 H), 3.70 (s, 3 H), 3.47 (m, 1 H), 3.41 (m, 1 H), 2.15
(m, 1 H), 1.82 (br s, 1 H), 1.62 (s, 3 H), 1.59 (m, 1 H), 1.39 (s, 3 H),
1.37–1.22 (m, 5 H), 1.12–1.07 (m, 1 H), 0.96 (d, J = 7.0 Hz, 3 H),
0.90 (d, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.1, 142.8, 122.1, 110.9, 78.9,
77.8, 68.1, 51.7, 36.7, 36.2, 35.6, 33.1, 26.9, 25.5, 24.5, 20.1, 16.5.
13C NMR (75 MHz, CDCl3): δ = 144.8, 112.2, 62.9, 37.6, 36.5,
32.7, 26.9, 25.7, 20.1.
MS (EI): m/z = 142 (M+).
HRMS (ESI): m/z [M + Na]+ calcd for C17H30O5Na: 337.1990;
found: 337.1984.
(S)-4-Benzyl-3-[(R)-6-methyloct-7-enoyl]oxazolidin-2-one (14)
Compound 13 (0.35 g, 2.46 mmol) was subjected to the Swern oxi-
dation following the typical procedure for 7-(tert-butyldimethylsil-
oxy)heptanal followed by Pinnick oxidation following the typical
procedure for 10 to provide the acid as a clear oil.
(2R,4R,5R)-7-(tert-Butyldiphenylsiloxy)-5-hydroxy-1-(4-meth-
oxybenzyloxy)-2,4-dimethylheptan-3-one (15)
To a cooled soln of Cy2BCl (19 mL, 19 mmol) in anhyd Et2O (30
mL) at –78 °C were added sequentially dropwise Et3N (3.17 mL,
22.8 mmol) and ketone 7 (3 g, 12.7 mmol) in Et2O (10 mL). The
milky mixture was stirred at 0 °C for 2.5 h. The soln was again
cooled to –78 °C before slow addition of 3-(tert-butyldiphenylsil-
oxy)propanal (8, 5.98 g, 19 mmol) and the resulting soln was stirred
for 2 h at this temperature. Then the mixture was kept at –25 °C for
overnight and after that it was stirred at 0 °C for 30 min. The reac-
tion was quenched successively with MeOH (38 mL), pH 7 buffer
(38 mL), and 30% H2O2 (38 mL), and it was stirred for 30 min at r.t.
The organic layer was extracted with EtOAc (2 × 80 mL). The com-
bined organic extracts were washed sequentially with H2O (20 mL)
and brine (20 mL), dried (Na2SO4), concentrated in vacuo, and pu-
rified by column chromatography to provide the β-hydroxy ketone
15 (6.68 g, 96%) as a colorless oil; Rf = 0.3 (20% EtOAc–petroleum
ether).
The above acid was treated with (S)-4-benzyloxazolidin-2-one ac-
cording to the typical procedure for 11 to yield 14 (0.43 g, 81%) as
a colorless oil; Rf = 0.3 (20% EtOAc–petroleum ether).
[α]D24 +41.0 (c 1.2, CHCl3).
IR (neat): 2924, 2859, 1780, 1699, 1205 cm–1.
1H NMR (300 MHz, CDC13): δ = 7.38–7.26 (m, 3 H), 7.24–7.18
(m, 2 H), 5.69 (m, 1 H), 5.01–4.88 (m, 2 H), 4.68 (m, 1 H), 4.24–
4.13 (m, 2 H), 3.29 (dd, J = 13.6, 3.0 Hz, 1 H), 3.04–2.83 (m, 2 H),
2.77 (dd, J = 13.6, 9.8 Hz, 1 H), 2.14 (m, 1 H), 1.77–1.63 (m, 2 H),
1.23 (s, 4 H), 0.99 (d, J = 6.8 Hz, 3 H).
Synthesis 2013, 45, 2745–2751
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthetic Studies of Carolacton
IR (neat): 2940, 1615, 1246, 1080 cm–1.
2749
[α]D24 –6.14 (c 1.4, CHCl3).
IR (neat): 3463, 2936, 1704, 1513, 1097 cm–1.
1H NMR (300 MHz, CDC13): δ = 7.74–7.62 (m, 4 H), 7.48–7.32
(m, 8 H), 6.88 (d, J = 8.3 Hz, 2 H), 5.48 (s, 1 H), 4.13 (dd, J = 11.3,
4.5 Hz, 1 H), 3.90–3.72 (m, 3 H), 3.80 (s, 3 H), 3.60–3.46 (m, 2 H),
3.33 (s, 3 H), 2.14–1.92 (m, 2 H), 1.86 (m, 1 H), 1.62 (m, 1 H), 1.06
(s, 9 H), 0.90 (d, J = 7.0 Hz, 3 H), 0.74 (d, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.6, 135.9, 135.5, 133.8, 131.5,
129.4, 127.5, 127.1, 113.4, 100.5, 81.9, 78.8, 73.2, 60.3, 58.3, 55.2,
37.7, 34.7, 30.3, 26.7, 19.1, 11.9, 9.3.
1H NMR (300 MHz, CDC13): δ = 7.72–7.65 (m, 4 H), 7.47–7.35
(m, 6 H), 7.21 (d, J = 8.5 Hz, 2 H), 6.86 (d, J = 8.5 Hz, 2 H), 4.43
(d, J = 12.0 Hz, 1 H), 4.38 (d, J = 12.0 Hz, 1 H), 4.02 (m, 1 H),
3.92–3.80 (m, 2 H), 3.79 (s, 3 H), 3.64 (t, J = 8.5 Hz, 1 H), 3.42 (m,
1 H), 3.07 (m, 1 H), 2.78 (m, 1 H), 1.82–1.57 (m, 2 H), 1.09–1.03
(m, 15 H).
13C NMR (75 MHz, CDCl3): δ = 217.3, 159.1, 135.5, 133.28,
133.22, 129.9, 129.7, 129.1, 127.6, 113.7, 72.9, 72.2, 72.0, 62.1,
55.2, 51.9, 45.8, 36.0, 26.8, 19.0, 13.5, 12.9.
HRMS (ESI): m/z [M
585.3009.2099; found: 585.3004.
+
Na]+ calcd for C34H46O5SiNa:
HRMS (ESI): m/z [M + Na]+ calcd for C33H44O5SiNa: 571.2855;
found: 571.2865.
(2R,3R,4R,5R)-7-(tert-Butyldiphenylsiloxy)-5-methoxy-3-(4-
methoxybenzyloxy)-2,4-dimethylheptan-1-ol (18)
To a soln of 17 (2 g, 3.55 mmol) in anhyd CH2Cl2 (11 mL) at –78
°C, a 1 M DIBAL-H (10.6 mL, 10.6 mmol) was added dropwise and
the mixture was stirred at this temperature for 2 h. The reaction was
then quenched by slow addition of few drops of anhyd MeOH fol-
lowed by sat. aq sodium potassium tartrate soln (10 mL). The mix-
ture was stirred (~2 h) until two clear layers separated. The aqueous
layer was extracted with EtOAc (2 × 25 mL) and the combined or-
ganic extracts were washed sequentially with H2O (5 mL) and brine
(5 mL), dried (Na2SO4), and concentrated in vacuo. Purification by
column chromatography of the residue provided alcohol 18 (1.48 g,
74%) as a colorless liquid; Rf = 0.3 (20% EtOAc–petroleum ether).
(2R,3R,4R,5R)-7-(tert-Butyldiphenylsiloxy)-1-(4-methoxyben-
zyloxy)-2,4-dimethylheptane-3,5-diol (16)
Compound 15 (6 g, 10.9 mmol) was taken up in AcOH–acetone
(1:1, 34 mL) and the soln was cooled to –20 °C. Then
Me4NHB(OAc)3 (7.19 g, 27.3 mmol) was added very quickly to the
mixture and it was stirred at this temperature for 24 h. After com-
pletion of the reaction it was quenched with sat. sodium potassium
tartrate soln (25 mL) and the mixture was stirred at r.t. for 3 h. The
organic layer was extracted with EtOAc (2 × 80 mL). The combined
organic extracts were washed sequentially with H2O (20 mL) and
brine (20 mL), and dried (Na2SO4). The organic soln was concen-
trated in vacuo and purified by column chromatography provided
16 (4.87 g, 81%) as a colorless oil; Rf = 0.25 (20% EtOAc–petro-
leum ether).
[α]D24 +2.35 (c 0.85, CHCl3).
IR (neat): 3445, 2938, 1513, 1094 cm–1.
1H NMR (300 MHz, CDC13): δ = 7.70–7.64 (m, 4 H), 7.45–7.34
(m, 6 H), 7.27 (d, J = 8.3 Hz, 2 H), 6.86 (d, J = 8.3 Hz, 2 H), 4.55
(dd, J = 10.5, 2.2 Hz, 2 H), 3.82–3.75 (m, 2 H), 3.79 (s, 3 H), 3.71–
3.59 (m, 2 H), 3.56 (dd, J = 6.7, 3.7 Hz, 1 H), 3.39 (m, 1 H), 3.25 (s,
3 H), 2.82 (br s, 1 H), 1.98–1.86 (m, 2 H), 1.81 (m, 1 H), 1.69 (m, 1
H), 1.05 (s, 9 H), 0.92 (d, J = 7.5 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.1, 135.5, 133.6, 130.5, 129.5,
129.2, 127.5, 113.7, 83.9, 78.9, 74.6, 66.1, 60.0, 55.9, 55.1, 38.3,
37.7, 32.7, 26.7, 19.1, 14.7, 10.2.
[α]D24 –10.19 (c 2, CHCl3).
IR (neat): 3451, 2930, 1612, 1079 cm–1.
1H NMR (300 MHz, CDC13): δ = 7.71–7.64 (m, 4 H), 7.47–7.34
(m, 6 H), 7.25 (d, J = 8.3 Hz, 2 H), 6.87 (d, J = 8.3 Hz, 2 H), 4.48
(d, J = 11.3 Hz, 1 H), 4.43 (d, J = 11.3 Hz, 1 H), 4.03 (br s, 1 H),
3.94–3.84 (m, 4 H), 3.83–3.77 (m, 1 H), 3.79 (s, 3 H), 3.54 (d,
J = 6.7 Hz, 2 H), 2.03–1.81 (m, 2 H), 1.72 (m, 1 H), 1.58 (m, 1 H),
1.05 (s, 9 H), 0.97 (d, J = 7.5 Hz, 3 H), 0.76 (d, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.2, 135.4, 133.2, 133.1, 129.9,
129.6, 129.2, 127.6, 113.7, 75.7, 75.2, 74.8, 73.0, 63.3, 55.2, 39.0,
37.1, 35.9, 26.7, 19.0, 13.1, 9.8.
HRMS (ESI): m/z [M + Na]+ calcd for C33H46O5SiNa: 573.3012;
found: 573.3007.
HRMS (ESI): m/z [M + Na]+ calcd for C34H48O5SiNa: 587.3168;
found: 587.3150.
(2R,3R,4R,5R)-7-(tert-Butyldiphenylsiloxy)-5-methoxy-3-(4-
methoxybenzyloxy)-2,4-dimethylheptanal; Typical Procedure
for the Dess–Martin Periodinane Oxidation
To a soln of 18 (1 g, 1.77 mmol) in anhyd CH2Cl2 (6 mL) were add-
ed NaHCO3 (0.59 g, 7.08 mmol) and Dess–Martin periodinane
(DMP) (1.5 g, 3.54 mmol) sequentially at 0 °C. The mixture was
stirred at r.t. for 1 h and then quenched with sat. aq NaHCO3 soln (2
mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 ×
10 mL), and the combine organic extracts were washed sequentially
with H2O (2 mL) and brine (2 mL), dried (Na2SO4), and concentrat-
ed in vacuo. The residue was passed through a short bed of silica gel
and used directly in the next step without characterization.
tert-Butyl{(3R,4R)-3-methoxy-4-[(4R,5R)-2-(4-methoxyphe-
nyl)-5-methyl-1,3-dioxan-4-yl]pentyloxy}diphenylsilane (17)
To a soln of 16 (4 g, 7.26 mmol) and 4Å molecular sieves (5.2 g, 1.3
equiv with respect to weight) in anhyd CH2Cl2 (22 mL), DDQ (1.64
g, 7.26 mmol) was added at –10 °C and the mixture was kept at this
temperature for 60 min and then warmed slowly to 0 °C over a pe-
riod of 1 h. After complete consumption of the starting material the
reaction was quenched with sat. aq NaHCO3 (10 mL) and extracted
with EtOAc (2 × 50 mL). The combined organic extracts were
washed sequentially with H2O (10 mL) and brine (10 mL), dried
(Na2SO4), concentrated in vacuo, and purified by column chroma-
tography to provide the rearranged compound as a colorless liquid.
tert-Butyl[(3R,4R,5R,6R)-3-methoxy-5-(4-methoxybenzyloxy)-
4,6-dimethylnon-7-ynyloxy}diphenylsilane (19)
To an ice cooled soln of Ph3P (1.99 g, 7.08 mmol) in CH2Cl2 (6 mL)
was added CBr4 (1.17 g, 3.54 mmol). The resulting mixture was
stirred at r.t. for 30 min. The mixture was again cooled to 0 °C and
(2R,3R,4R,5R)-7-(tert-butyldiphenylsiloxy)-5-methoxy-3-(4-meth-
oxybenzyloxy)-2,4-dimethylheptanal was added by cannula to the
mixture. The mixture was stirred at r.t. for ~30 min. Then the mix-
ture was diluted with petroleum ether and passed through a plug of
silica gel and used directly in the next step.
To a stirred ice cooled soln of the rearranged compound in anhyd
THF (14 mL) was added NaH (0.45 g, 11.4 mmol). After 15 min,
MeI (0.85 mL, 13.7 mmol) and DMAP (0.055 g, 0.46 mmol) were
added to the mixture at 0 °C. The mixture was stirred for 12 h at r.t.,
and then the reaction was quenched with sat. aq NH4Cl (10 mL) at
0 °C and extracted with EtOAc (2 × 25 mL). The combined organic
extracts were washed sequentially with H2O (10 mL) and brine (10
mL), dried (Na2SO4), concentrated in vacuo, and purified by col-
umn chromatography to provide 17 (2.1 g, 78%) as a clear oil;
Rf = 0.55 (10% EtOAc–petroleum ether).
To a soln of the above compound in anhyd THF (6 mL) cooled to
–78 °C, was added 1.6 M BuLi (2.76 mL, 4.4 mmol); the resulting
soln was stirred for 2 h at –78 °C. MeI (1 mL, 7.08 mmol) was added
to the mixture at –78 °C and it was stirred for ~2–3 h at r.t. The re-
sulting soln was quenched with sat. aq NH4Cl (4 mL) and extracted
[α]D24 –21.15 (c 2.5, CHCl3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2745–2751

2750
K. S. Rao, S. Ghosh
PAPER
with EtOAc (2 × 10 mL). The combined organic extracts were
washed sequentially with H2O (2 mL) and brine (2 mL), dried
(Na2SO4), concentrated in vacuo, and purified by column chroma-
tography to afford 19 (0.709 g, 70%) as a clear oil; Rf = 0.4 (10%
EtOAc–petroleum ether).
[α]D24 +1.20 (c 3, CHCl3).
IR (neat): 2934, 2866, 2360, 1513, 1094 cm–1.
1H NMR (500 MHz, CDC13): δ = 7.75–7.66 (m, 4 H), 7.46–7.36
(m, 6 H), 7.32 (d, J = 9.0 Hz, 2 H), 6.88 (d, J = 8.0 Hz, 2 H), 4.73
(d, J = 11.0 Hz, 1 H), 4.53 (d, J = 11.0 Hz, 1 H), 3.86–3.76 (m, 2 H),
3.80 (s, 3 H), 3.52 (m, 1 H), 3.34 (t, J = 6.0 Hz, 1 H), 3.29 (s, 3 H),
2.75 (m, 1 H), 2.19 (m, 1 H), 1.79 (d, J = 2.0 Hz, 3 H), 1.73 (m, 1
H), 1.64 (m, 1 H), 1.18 (d, J = 7.0 Hz, 3 H), 1.09 (s, 9 H), 0.92 (d,
J = 7.0 Hz, 3 H).
1H NMR (500 MHz, CDC13): δ = 7.29 (d, J = 8.0 Hz, 2 H), 6.87 (d,
J = 8.0 Hz, 2 H), 4.76 (d, J = 11.0 Hz, 1 H), 4.46 (d, J = 11.0 Hz, 1
H), 3.80 (s, 3 H), 3.68 (m, 1 H), 3.42 (dd, J = 7.0, 4.0 Hz, 1 H), 3.34
(s, 3 H), 2.74 (m, 1 H), 2.43 (dd, J = 15.0, 4.0 Hz, 1 H), 2.34 (dd,
J = 15.0, 7.0 Hz, 1 H), 2.12 (m, 1 H), 1.79 (d, J = 2.0 Hz, 3 H), 1.46
(s, 9 H), 1.15 (d, J = 7.0 Hz, 3 H), 0.91 (d, J = 7.0 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 171.4, 159.0, 131.0, 129.3, 113.6,
81.9, 81.5, 80.3, 79.7, 77.2, 73.7, 56.8, 55.2, 37.9, 37.6, 29.6, 28.0,
17.5, 9.5, 3.6.
HRMS (ESI): m/z [M + Na]+ calcd for C24H36O5Na: 427.2460;
found: 427.2458.
Acknowledgement
13C NMR (75 MHz, CDCl3): δ = 158.9, 135.4, 134.7, 133.8, 131.0,
129.5, 129.2, 127.5, 113.5, 82.6, 81.1, 78.3, 74.0, 60.3, 56.2, 55.2,
37.4, 32.8, 29.6, 26.7, 19.1, 17.8, 9.7, 3.6.
Author (K.S.R.) is thankful to CSIR, New Delhi, India, for a re-
search fellowship.
HRMS (ESI): m/z [M + Na]+ calcd for C36H48O4SiNa: 595.3219;
found: 595.3210.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
(3R,4R,5R,6R)-3-Methoxy-5-(4-methoxybenzyloxy)-4,6-di-
methylnon-7-yn-1-ol (20)
References and Notes
To a stirred soln of 19 (0.5 g, 0.88 mmol) in anhyd THF (3 mL), 1
M TBAF (0.88 mL, 0.88 mmol) was added at 0 °C and the mixture
was allowed to reach r.t. After 1 h the mixture was quenched by ad-
dition of sat. aq NH4Cl (2 mL) and extracted with EtOAc (2 × 10
mL). The combined organic extracts were washed sequentially with
H2O (2 mL) and brine (2 mL), dried (Na2SO4), filtered, and concen-
trated in vacuo. Chromatography purification of the residue provid-
ed 20 (0.26 g, 90%) as a colorless oil; Rf = 0.3 (30% EtOAc–
petroleum ether).
(1) (a) Costerton, J. W.; Stewart, P. S.; Greenberg, E. P. Science
(Washington, D.C.) 1999, 284, 1318. (b) Costerton, J. W.;
Montanaro, L.; Arciola, C. R. Int. J. Artif. Organs 2007, 30,
757.
(2) (a) Lynch, A. S.; Robertson, G. T. Annu. Rev. Med. 2008, 59,
415. (b) Hall-Stoodley, L.; Costerton, J. W.; Stoodley, P.
Nat. Rev. Microbiol. 2004, 2, 95. (c) Parcek, M. R.; Singh,
P. K. Annu. Rev. Microbiol. 2003, 57, 677.
[α]D24 –2.54 (c 2, CHCl3).
IR (neat): 3397, 2924, 2359, 1512, 1040 cm–1.
(3) (a) Kolenbrander, P. E.; Palmer, R. J. Jr.; Rickard, A. H.;
Jakubovics, N. S.; Chalmers, N. I.; Diaz, P. I.
Periodontology 2000 2006, 42, 47. (b) Kolenbrander, P. E.
Annu. Rev. Microbiol. 2000, 54, 413. (c) Stewart, P. S.;
Costerton, J. W. Lancet 2001, 358, 135.
1H NMR (500 MHz, CDC13): δ = 7.28 (d, J = 8.2 Hz, 2 H), 6.87 (d,
J = 8.2 Hz, 2 H), 4.71 (d, J = 11.0 Hz, 1 H), 4.45 (d, J = 11.0 Hz, 1
H), 3.79 (s, 3 H), 3.79–3.71 (m, 2 H), 3.49 (m, 1 H), 3.35 (s, 3 H),
3.32 (t, J = 5.5 Hz, 1 H), 2.86 (br s, 1 H), 2.73 (m, 1 H), 2.24 (m, 1
H), 1.78 (d, J = 2.7 Hz, 3 H), 1.73–1.68 (m, 2 H), 1.19 (d, J = 7.3
Hz, 3 H), 0.92 (d, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.0, 130.7, 129.2, 113.5, 82.0,
82.0, 81.1, 73.6, 61.0, 56.1, 55.1, 51.6, 36.6, 31.0, 29.2, 17.3, 9.6,
3.5.
(4) (a) Fux, C. A.; Costerton, J. W.; Stewart, P. S.; Stoodley, P.
Trends Microbiol. 2005, 13, 34. (b) Donlan, R. M.;
Costerton, J. W. Clin. Microbiol. Rev. 2002, 15, 167.
(5) (a) Jansen, R.; Irschik, H.; Schummer, D.; Steinmertz, H.;
Bock, M.; Schmidt, T.; Kirschning, A.; Müller, R. Eur. J.
Org. Chem. 2010, 7, 1284. (b) Kunze, B.; Reck, M.; Dotsch,
A.; Lemme, A.; Schummer, D.; Irschik, H.; Steinmertz, H.;
Wagner-Döbler, I. BMC Microbiol. 2010, 10, 199.
(6) (a) Schmidt, T.; Kirschning, A. Angew. Chem. Int. Ed. 2012,
51, 1063. (b) Sabitha, G.; Shankaraiah, K.; Prasad, M. N.;
Yadav, J. S. Synthesis 2013, 45, 251.
(7) (a) Liu, L.; Floreancig, P. E. Org. Lett. 2009, 11, 3152.
(b) Hulme, A. N.; Howells, G. E. Tetrahedron Lett. 1997,
38, 8245.
(8) (a) Maucuro, A. J.; Haung, S. L.; Swern, D. J. Org. Chem.
1978, 43, 2480. (b) Balkrishna, S. B.; Childers, W. B.;
Pinnick, H. W. Tetrahedron 1981, 37, 2091.
(9) Nicolaou, K. C.; Hwang, C. K.; Marron, B. E.; DeFrees, S.
A.; Couladouros, E. A.; Abe, Y. J. Am. Chem. Soc. 1990,
112, 3040.
(10) (a) Ho, G. J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271.
(b) Paterson, I.; Yeung, K.; Watson, C.; Wallace, R. A.
Tetrahedron 1998, 54, 11935. (c) Vanderwal, C. D.;
Vosburg, D. A.; Sorenson, E. J. Org. Lett. 2001, 2, 4307.
(11) (a) Chakraborty, T. K.; Suresh, V. R. Chem. Lett. 1997, 565.
(b) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem.
Soc. 1982, 104, 1737.
HRMS (ESI): m/z [M + Na]+ calcd for C20H30O4Na: 357.2041;
found: 357.2038.
tert-Butyl (3R,4R,5R,6R)-3-methoxy-5-(4-methoxybenzyloxy)-
4,6-dimethylnon-7-ynoate (4)
Compound 20 (0.1 g, 0.3 mmol) was subjected to Dess–Martin
periodinane oxidation following the typical procedure for
(2R,3R,4R,5R)-7-(tert-butyldiphenylsiloxy)-5-methoxy-3-(4-meth-
oxybenzyloxy)-2,4-dimethylheptanal and then Pinnick oxidation
following the typical procedure for 10 to afford the acid as a color-
less oil.
To an ice-cooled soln of the acid in anhyd CH2Cl2 (2 mL) was added
tert-butyl trichloroacetimidate (0.062 g, 0.28 mmol) in CH2Cl2 (2
mL). After 5 min CSA (3 mg, 0.01 mmol) was added. The resulting
mixture was stirred at r.t. for ~24 h. After complete consumption of
the starting material, the mixture was quenched with sat. aq
NaHCO3 (1 mL) and extracted with EtOAc (2 × 5 mL). The com-
bined organic extracts were washed sequentially with H2O (1 mL)
and brine (1 mL), dried (Na2SO4), concentrated in vacuo, and puri-
fied by column chromatography to yield 4 (0.029 g, 60%) as a clear
oil; Rf = 0.5 (10% EtOAc–petroleum ether).
(12) Fürstner, A.; Bonnekessel, M.; Blank, J. T.; Radkowski, K.;
Ing, G. S.; Lacombe, F.; Gabor, B.; Mynott, R. Chem. Eur.
J. 2007, 13, 8762.
[α]D24 –7.22 (c 0.1, CH2Cl2).
IR (neat): 2925, 1714, 1512, 1250 cm–1.
Synthesis 2013, 45, 2745–2751
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthetic Studies of Carolacton
2751
(13) Krishna, P. R.; Srinivas, P. Tetrahedron: Asymmetry 2012,
23, 769.
(14) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.;
Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 58.
(18) (a) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986,
27, 5939. (b) Evans, D. A.; Chapman, K. T.; Carriera, E. M.
J. Am. Chem. Soc. 1988, 110, 3560.
(19) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(20) (a) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13,
3769. (b) Hu, T.; Panek, J. S. J. Am. Chem. Soc. 2002, 124,
11368.
(15) (a) Palmer, A. M.; Jager, V. Eur. J. Org. Chem. 2001, 1293.
(b) Jager, V.; Hafele, B. Synthesis 1987, 801.
(16) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister,
M. A. J. Am. Chem. Soc. 1994, 116, 11287.
(17) (a) Paterson, I.; Goodman, J. M. Tetrahedron Lett. 1989, 30,
7121. (b) Cowden, C. J.; Paterson, I. Org. React. 1997, 51,
1. (c) Williams, D. R.; Shamim, K. Org. Lett. 2005, 7, 4161.
(21) (a) Lampe, T.; Kast, R.; Stoll, F.; Schuhmacher, J. US
2011054017, 2011. (b) Lampe, T.; Hahn, M.; Stasch, J.-P.;
Schlemmer, K.-H.; Wunder, F.; Heitmeier, S.; Griebenow,
N.; El Sheikh, S.; Li Volkhart, M.-J.; Becher, E.-M.; Stoll,
F.; Knorr, A. US 28971A1, 2012.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2745–2751