An iterative, facile stereoselective synthesis of C1-C11 fragment of borrelidin via enzymatic desymmetrization strategy

Article abstract of DOI:10.1039/c3ra22754e

A highly stereoselective and general method for the synthesis of the C1-C11 fragment of borrelidin has been achieved. The main feature of our synthetic route is enzymatic desymmetrization to create two methyl bearing chiral centres, use of Evans auxiliary to introduce two other methyl groups and creation of C3 stereocentre by regioselective opening of an epoxide arising from Sharpless epoxidation protocol. The synthesis of the C1-C11 subunit was achieved in gram scale by a linear synthetic sequence in an overall yield of 18.4%.

Full text of DOI:10.1039/c3ra22754e

RSC Advances
View Article Online
View Journal | View Issue
PAPER
An iterative, facile stereoselective synthesis of C1-C11
fragment of borrelidin via enzymatic desymmetrization
strategy3
Cite this: RSC Advances, 2013, 3,
4024
Jhillu Singh Yadav* and Nagendra Nath Yadav
A highly stereoselective and general method for the synthesis of the C1-C11 fragment of borrelidin has
been achieved. The main feature of our synthetic route is enzymatic desymmetrization to create two
methyl bearing chiral centres, use of Evans auxiliary to introduce two other methyl groups and creation of
C3 stereocentre by regioselective opening of an epoxide arising from Sharpless epoxidation protocol. The
synthesis of the C1-C11 subunit was achieved in gram scale by a linear synthetic sequence in an overall
yield of 18.4%.
Received 2nd November 2012,
Accepted 13th January 2013
DOI: 10.1039/c3ra22754e
www.rsc.org/advances
The first total synthesis was reported Morken and co-
workers,14 followed by efforts from various other groups for
Introduction
the total synthesis15,16 as well as formal synthesis.17,18 The
reported strategies are essentially based on chiral pool starting
materials, iterative catalytic approach, chiral-reagent based
strategy, chiral auxiliaries and kinetic resolution. Most recently
Minnaard reported the formal synthesis of borrelidin using
Cu/Josiphos-catalysed iterative asymmetric conjugate addition
of MeMgBr to create the methyl centres.18f In the retro-
Natural products derived from polydeoxypropionates are well
known to exhibit various biological activities for instance,
calcium ionophore ionomycin,1 which is responsible to
chelate various inorganic cations (especially Ca++) and to
transport them across lipid membranes, cytotoxic cyclodepsi-
peptide (–)-doliculide,2 immune response inducing agent
Sulfolipid-I (2,3,6,69-tetraacyltrehalose 29-sulfate),3 the phero-
mones hexamethyldocosane,4 vittatalactone,5 lardolure6 as
well as the cytotoxic metabolite borrelidin. Borrelidin (1) a
structurally unique 18-membered macrolide antibiotic posses-
sing anti-Borrelia activity was first isolated by Berger et al.7
from Streptomyces rochei in 1949. The planar structure of
borrelidin was assigned by Keller-Schierlein8 in 1967, and the
absolute configuration was determined by Anderson et al.9 by
the X-ray crystallography of a chiral solvate. Borrelidin (1)
exhibits many interesting biological activities such as anti-
viral,10 anti-angiogenesis,11 antibacterial activity which
involves selective inhibition of threonyl tRNA synthatase,7,12
and inhibitory activity towards cyclin-dependent kinase Cdc28/
Cln2 of Saccharomyces cerevisiae.13 The structural features of
borrelidin (1) includes the presence of deoxy propionate
moiety with four methyl groups at 4,6,8 and 10 positions in
a syn/syn/anti relationship, a Z/E cyanodiene unit at C12-C15,
and a cyclopentane carboxylic acid subunit at C17 (Fig. 1).
These complex structural features and interesting biological
activity of borrelidin has prompted many synthetic efforts
towards the total synthesis as well as formal synthesis.
synthetic analysis of Omura and co-workers,15c,e
1 was
disconnected into two fragments (2, 3), of which the upper
part was achieved by kinetic resolution, alkyne addition to
aldehyde, chelation-controlled carbotitanation of the homo-
allylic alcohol under slightly modified Thompson’s conditions
and hydrogenation using Rh[(nbd)dppb]BF4 catalyst as key
steps.
Our continuing interest in the total synthesis of biologically
active natural products by enzymatic desymmetrization stra-
tegy5e,19 and the inherent biological activity of borrelidin (1)
encouraged us to explore the synthesis of this molecule. We
herein, report a facile and general method for the stereo-
selective synthesis of C1-C11 (2) fragment of 1 using Evans
alkylation iteratively and regioselective opening of a chiral
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad, 500 607, India. E-mail: yadavpub@iict.res.in;
Fax: +91-40-27160512
Electronic supplementary information (ESI) available: spectral data of all the
3
Fig. 1 Chemical structure of Borrelidin (1).
new compounds. See DOI: 10.1039/c3ra22754e
4024 | RSC Adv., 2013, 3, 4024–4032
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Paper
Scheme 1 Retrosynthetic analysis of borrelidin 1.
epoxide to generate the three of the five stereogenic centres
with good diastereoselectivity.
Scheme 2 Synthesis of alcohol 6.
Results and discussion
The retrosynthetic approach to 1 is depicted in Scheme 1. The
target molecule 1 was envisioned to be obtained by coupling of
carboxylic acid 2 with the alcohol 3.15c,e Compound 2 can be
easily obtained from regioselective opening of epoxide 4.
Further, compound 4 can be obtained from 5 by a sequence of
reactions such as reduction with NaBH4, Wittig reaction,
DIBAL-H reduction and Sharpless asymmetric epoxidation.
NaBH4 in MeOH furnished alcohol 15. Protection of the
carbinol as its THP ether 16 followed by deprotection of the
silyl ether furnished the desired diastereoisomeric mixture of
alcohol 6, Scheme 2.
Alcohol 6 was subjected to oxidation followed by C2-Wittig
reaction to afford the E/Z mixture of a,b- unsaturated ester 17
in 92% for two steps. Reduction of the mixture of unsaturated
ester 17 followed by hydrolysis furnished acid 19 in 93% yield.
Coupling of acid 19 with the Evans chiral oxazolidinone and
diastereoselective methylation of 20 furnished the desired
compound 5 in 89% yield in good selectivity5d. Reduction of
compound 5 provided alcohol 21, which was further converted
to trans-unsaturated ester 22 (E/Z . 98 : 2 as confirmed by the
crude 1HNMR of 23) by means of oxidation and Wittig
olefination.
The ester 22 was then reduced to the corresponding allylic
alcohol 23 and subjected to Sharpless asymmetric epoxidation
using (2)-DET, Ti(OiPr)4 and TBHP in dichloromethane at
220 uC furnished the corresponding epoxide 4 in 90% yield.25
Reductive opening of epoxide afforded diol 24. Selective
protection of primary alcohol using TBDPSCl gave the
compound 25 in 94% yield. The secondary carbinol was then
protected as its TBDMS ether to afford 26 that was subjected to
selective deprotection of the TBDPS group using NH4F in
methanol26 to afford alcohol 27. Ultimately oxidation of
alcohol 27 with TEMPO-BAIB27 in acetone : water (4 : 1)
furnished the target C1-C11 fragment (2) of borrelidin in
95% yield (Scheme 3). Analytical data of 2 was compared and
found to be identical with the reported compound.15c,e
Compound
5 can in turn be obtained from a known
compound 7 via 6 by means of Wittig reaction followed by
stereoselective Evans methylation.
Our synthesis began with
a
known precursor 720,21
possessing two chiral centres which was synthesized by
desymmetrization of a meso-diol using porcine pancreatic
lipase (PPL) and vinyl acetate in THF at ambient temperature
in 47% yield (.95% ee) along with the meso-diacetate.22 It is
noteworthy to mention that the meso-diacetate obtained was
again converted back to the meso-diol by treatment with
CH3ONa in methanol in quantitative yield for further utiliza-
tion. Mono acetate 7 was oxidized and subjected to two carbon
extension by means of Wittig reaction to afford the E/Z mixture
of a,b-unsaturated ester 8 in 91% yield. The reduction of
double bond with NaBH4 in the presence of NiCl2?6H2O in
MeOH afforded the saturated ester 9 in 96% yield.23 Treatment
of acetate 9 with K2CO3 in ethanol gave the alcohol 10 which
was then protected as its silyl ether using TBSCl and imidazole
in dichloromethane to furnish compound 11.
Hydrolysis of ester 11 under basic conditions furnished the
corresponding carboxylic acid 12 in 91% yield. Coupling of
acid 12 with Evans chiral oxazolidinone using pivaloyl chloride
in presence of triethylamine and LiCl furnished the required
compound 13 in 95% yield.24 Diastereoselective methylation of
Na-enolate of compound 13 with MeI furnished the desired
compound 14 in 90% yield and in 98 : 25d dr which was
confirmed by HPLC analysis. Reduction of compound 14 with
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 4024–4032 | 4025

View Article Online
Paper
RSC Advances
tion at 1610 cm21. Samples were scanned neat, in KBr wafers
or in chloroform as a thin film. 1H NMR spectra were recorded
in CDCl3 on Bruker 300, Varian Unity 500 NMR spectrometer.
13C NMR spectra were recorded at 75 MHz in CDCl3 using
tetramethylsilane as a reference standard. Column chromato-
graphy was performed using silica gel (60–120 mesh) and the
column was usually eluted with a mixture of ethyl acetate–
petroleum ether. Visualization of the spots on TLC plates was
achieved either by exposure to iodine vapor or UV light or by
dipping the plates to ethanolic anisaldehyde–sulphuric acid–
acetic acid or to phosphomolybdic acid–sulphuric acid
solution and heating the plates at 120 uC. Mass spectra were
obtained on a Finnigan MAT1020B or Micromass VG 70-70H
spectrometer operating at 70 eV using a direct inlet system.
Optical rotations were recorded on PerkinElmer 241 polari-
meter in 1.0 dm, 1.0 mL cells.
(2S,4R)-5-Hydroxy-2,4-dimethylpentyl acetate (7). To a stir-
red solution of meso-diol (4.0 gm, 22.9 mmol) in THF (130 mL)
and water (170 mL) was added PPL (11.6 g) and vinyl acetate at
room temperature. The reaction mixture was stirred for 6 h at
room temperature. After complete conversion of the starting
material (as indicated by TLC), the reaction mixture was
filtered off through a pad of celite, washed with ethyl acetate,
dried over Na2SO4, concentrated in vacuo and purified by
chromatography on silica gel (1 : 5, EtOAc/hexane) to afford
the monoacetate 7 (2.47 g, 47%) as a colorless liquid. [a]D
=
+9.8 (c = 0.6, CHCl3). 1H NMR (300 MHz, CDCl3): d 3.97 (dd, J =
10.5, 5.2 Hz, 1H), 3.85 (dd, J = 10.5, 6.7 Hz, 1H), 3.49 (dd, J =
10.5, 6.0 Hz, 1H), 3.42 (dd, J = 10.5, 6.0 Hz, 1H), 2.05 (s, 3H),
1.82–1.96 (m, 1H), 1.64–1.78 (m, 1H), 1.43 (br, 1H), 1.39–1.49
(m, 1H), 1.15–1.30 (m, 1H), 0.96 (d, J = 6.7 Hz, 3H), 0.95 (d, J =
6.7 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d = 171.3, 69.1, 67.9,
37.2, 32.9, 29.9, 20.9, 17.8, 17.2 ppm.
Scheme 3 Synthesis of C1-C11 fragment of borrelidin 2.
Ethyl (E,4R,6S)-7-(acetyloxy)-4,6-dimethyl-2-heptenoate (8).
To a stirred solution of IBX (12.25 g, 43.6 mmol) in DMSO
(30 mL) at 25 uC, was added drop wise a solution of alcohol 7
(5.0 g, 29.07 mmol) in CH2Cl2 (40 mL). The resulting mixture
was stirred at 25 uC for 3 h. The solid was filtered and washed
with ether. The filtrate was diluted with ether, washed with
saturated aqueous NaHCO3 solution, water, brine and dried
over Na2SO4. The solvent was removed under reduced pressure
to furnish crude aldehyde. To the above crude mixture (4.94 g,
29.07 mmol) in CH2Cl2 (150 mL) was added (ethoxycarbonyl-
methylene) triphenyl phosphorane (25.29 g, 72.68 mmol) and
resulting mixture was stirred for 12 h at room temperature and
then quenched by the addition of water and extracted with
CH2Cl2 (3 6 100 mL). The combined organic layers were
washed with water, brine, dried (Na2SO4) and concentrated.
The crude was purified by silica gel column chromatography
(1 : 9 EtOAc/hexane) to afford yellow oil 8 in (6.40 g, 91%)
yield. [a]2D5 216.4 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3): d
6.74 (dd, J = 15.6, 8.3 Hz, 1H), 5.76 (d, J = 15.6 Hz, 1H), 4.17 (q,
J = 14.1, 7.1 Hz, 2H), 3.78–3.94 (m, 2H), 2.35–2.50 (m, 1H), 2.04
(s, 3H), 1.70–1.87 (m, 1H), 1.41–1.54 (m, 1H), 1.30 (t, J = 7.1 Hz,
3H), 1.12–1.24 (m, 1H), 1.09 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.6
Hz, 3H); 13C NMR (75 MHz, CDCl3): d 170.8, 166.4, 153.3,
119.9, 69.0, 59.9, 39.6, 33.8, 30.0, 20.6, 20.2, 16.3, 14.0; IR
(Neat): 2966, 1721, 1652, 1461, 1369, 1238, 1182, 1037, 986, 766
Conclusions
In conclusion, we have accomplished the facile and general
stereoselective synthesis of C1-C11 fragment of anti-angio-
genic polyketide borrelidin employing enzymatic desymme-
trization of a meso-diol, Wittig reaction, an iterative Evans
methylation, Sharpless asymmetric epoxidation and regiose-
lective opening of a chiral epoxide as key steps. The synthesis
follows a linear synthetic sequence with an overall yield of
18.4%.
Experimental section
General
All reactions were carried out under inert atmosphere of argon
or nitrogen using standard syringe, septa, and cannula
techniques unless otherwise mentioned. Commercial reagents
were used without further purification. All solvents were
purified by standard techniques. Infrared (IR) spectra were
recorded on a Perkin-Elmer 683 spectrometer using NaCl
optics. Spectra were calibrated against the polystyrene absorp-
4026 | RSC Adv., 2013, 3, 4024–4032
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Paper
cm21; MS (ESIMS): m/z 265 [M + Na]+; HRMS (ESI) calcd for
C13H22O4Na [M + Na]+: 265.1415, Found: 265.1410.
9.5, 6.3 Hz, 1H), 2.19–2.33 (m, 2H), 1.28–1.72 (m, 6H), 1.26 (t, J
= 7.1 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H), 0.88 (s, 9H), 0.87 (d, J =
6.3 Hz, 3H), 0.01 (s, 6H); 13C NMR (75 MHz, CDCl3): d 174.0,
68.1, 60.1, 40.7, 33.0, 31.8, 31.5, 29.6, 25.9, 19.9, 18.3, 17.3,
14.2, 25.4; IR (Neat): 2956, 1738, 1636, 1253, 1094, 772, 570
cm21; MS (ESIMS): m/z 339 [M + Na]+; HRMS (ESI) calcd for
C17H36O3NaSi [M + Na]+: 339.2331, Found: 339.2321.
Ethyl (4S,6S)-7-(acetyloxy)-4,6-dimethylheptanoate (9). To a
cooled (0 uC) solution of 8 (6.35 g, 26.23 mmol) and
NiCl2?6H2O (1.25 g, 5.25 mmol) in MeOH (200 mL), NaBH4
(1.95 g, 52.66 mmol) was added in small portions to the
solution. The reaction temperature was kept at 0 uC by ice
cooling. After complete addition of NaBH4 the reaction
mixture was stirred for 1 h at room temperature. The black
precipitate formed was filtered and washed with MeOH. The
solvent was removed under reduced pressure. Water (100 mL)
was added and the solution extracted with ethyl acetate (2 6
100 mL). The combined organic layers were washed with
water, brine and dried over anhydrous Na2SO4. Concentration
under reduced pressure and purification by silica gel column
chromatography using ethyl acetate and hexane (1 : 9)
afforded the pure compound 9 (6.15 g, 96%) as a colorless
(4S,6S)-7-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-4,6-dimethyl-
heptanoic acid (12). LiOH?H2O (1.97 g, 46.8 mmol) was added
portion wise to a cooled solution (0 uC) of ester 11 (7.4 g, 23.4
mmol) in CH3OH : H2O (3 : 1) and stirring was continued for 2
h at room temperature. The reaction mixture was concentrated
in vacuo and residue was diluted with EtOAc (80 mL) and
saturated aqueous NH4Cl, extracted with EtOAc (3 6 50 mL).
The combined organic layers was washed with brine, dried
over Na2SO4 and concentrated under reduced pressure.
Column chromatography using (1 : 9, EtOAc/hexane) afforded
the 12 as a viscous liquid (6.14 g, 91%). [a]2D5 22.7 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): d 3.29–3.44 (m, 2H), 2.23–
2.42 (m, 2H), 1.47–1.75 (m, 4H), 1.28–1.45 (m, 2H), 0.90 (d, J =
6.7 Hz, 3H), 0.88 (s, 9H), 0.86 (d, J = 6.0 Hz, 3H), 0.01 (s, 6H);
13C NMR (75 MHz, CDCl3): d 180.5, 68.1, 40.6, 33.0, 31.6, 31.2,
29.6, 25.9, 19.9, 18.7, 17.4, 25.4; IR (Neat): 2956, 2930, 2858,
1711, 1464, 1414, 1253, 1094, 938, 839, 775, 667 cm21; MS
1
liquid. [a]2D5 21.2 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3): d
4.07 (q, J = 14.6, 7.3 Hz, 2H), 3.89 (dd, J = 10.9, 5.8 Hz, 1H),3.77
(dd, J = 10.9, 6.5 Hz, 1H), 2.18–2.37 (m, 2H), 2.04 (s, 3H), 1.83–
1.93 (m, 1H), 1.62–1.74 (m, 1H), 1.48–1.60 (m, 1H), 1.28–1.41
(m, 2H), 1.24 (t, J = 7.3 Hz, 3H), 0.97–1.05 (m, 1H), 0.93 (d, J =
6.5 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H)); 13C NMR (75 MHz,
CDCl3): d 173.7, 171.0, 69.1, 60.0, 40.7, 31.7, 31.3, 29.7, 29.4,
20.7, 19.6, 17.4, 14.0; IR (Neat): 2961, 1737, 1372, 1239, 1176,
1036, 606 cm21; MS (ESIMS): m/z 267 [M + Na]+; HRMS (ESI)
calcd for C13H24O4Na [M + Na]+: 267.1572, Found: 267.1564.
Ethyl (4S,6S)-7-hydroxy-4,6-dimethylheptanoate (10). To a
solution of 9 (6.1 g, 25 mmol) in ethanol (150 mL) at room
temperature was added K2CO3 (8.62 g, 62.5 mmol) and the
reaction was stirred under nitrogen atmosphere for 12 h. The
resulting mixture was vacuum filtered through celite and the
filter cake was washed well with CH2Cl2 and the filtrate was
concentrated under reduced pressure. Purification of the
resulting residue by the column chromatography (1.2 : 8.8,
EtOAc/hexane) afforded 10 (5.05 g, 98%) as a colorless liquid.
[a]2D5 28.6 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 4.10 (q, J
= 14.1, 7.1 Hz, 2H), 3.32–3.50 (m, 2H), 2.19–2.37 (m, 2H), 1.61–
1.78 (m, 2H), 1.45–1.61 (m, 2H), 1.31–1.45 (m, 2H), 1.26 (t, J =
6.9 Hz, 3H), 0.93 (d, J = 4.5 Hz, 3H), 0.90 (d, J = 4.3 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 174.0, 67.9, 60.1, 40.4, 32.9, 31.7,
31.3, 29.4, 19.8, 17.1, 14.1; IR (Neat): 3424, 2957, 2923, 1733,
1460, 1375, 1255, 1176, 1109, 1037, 767 cm21; MS (ESIMS): m/z
225 [M + Na]+; HRMS(ESI) calcd for C11H22O3Na [M + Na+]:
225.1466, Found: 225.1476.
Ethyl (4S,6S)-7-[1-(tert-butyl)-1,1-dimethylsilyl]oxy-4,6-
dimethylheptanoate (11). To a cold (0 uC) solution of alcohol
10 (5.0 g, 24.75 mmol) in dry CH2Cl2 (80 mL) was added
imidazole (3.36 g, 49.5 mmol) and tert-butyldimethylsilylchlor-
ide. The resulting reaction mixture was stirred at room
temperature for 3 h. After completion of reaction as indicated
by TLC, the mixture was quenched with saturated aqueous
NH4Cl, extracted with CH2Cl2 (3 6 50 mL). The combined
organic layers was washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. Column chromatogra-
phy using (1 : 30, EtOAc/hexane) afforded 11 (7.66 g, 98%).
[a]2D5 22.7 (c 1.2, CHCl3); 1H NMR (500 MHz, CDCl3): d 4.07 (q, J
= 14.3, 7.1 Hz, 2H), 3.40 (dd, J = 9.5, 5.5 Hz, 1H), 3.33 (dd, J =
(ESIMS): m/z 311 [M
+
Na]+; HRMS (ESI) calcd for
C15H32O3NaSi [M + Na]+: 311.2018, Found: 311.2028.
(4S)-4-Benzyl-3-((4S,6S)-7-[1-(tert-butyl)-1,1-dimethylsily-
l]oxy-4,6-dimethylheptanoyl)-1,3-oxazolan-2-one (13). To a stir-
red solution of acid 12 (6.1 g, 21.2 mmol) in THF (90 mL) at
220 uC was added Et3N (7.43 mL, 53 mmol) followed by PivCl
(2.64 mL, 21.2 mmol). After stirring for 1 h at 220 uC, LiCl
(1.35 g, 31.8 mmol), (S)-oxazolidinone (3.76 g, 21.2 mmol) was
added to the above mixture at the same temperature. The
stirring was continued for 1 h at 220 uC and then 2 h at 0 uC.
The reaction mass was then quenched with saturated NH4Cl
solution (50 mL) and extracted with ethyl acetate (2 6 80 mL).
The combined organic layers were washed with brine (30 mL),
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography using ethyl acetate and hexane (1 : 16) to gave
13 (9.0 g, 95%) as a viscous liquid. [a]2D5 + 27.1 (c 1.2, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.15–7.37 (m, 5H), 4.56–4.69 (m,
1H), 4.08–4.22 (m, 2H), 3.25–3.49 (m, 3H), 2.90 (t, J = 7.7 Hz,
2H), 2.71 (dd, J = 13.2, 10.0 Hz, 1H), 1.28–1.84 (m, 6H), 0.94 (d,
J = 6.6 Hz, 3H), 0.90 (d, J = 6.0 Hz, 3H), 0.89 (s, 9H), 0.03 (s, 6H);
13C NMR (75 MHz, CDCl3): d 173.6, 153.3, 135.2, 129.3, 128.8,
127.2, 68.2, 66.0, 55.1, 40.8, 37.8, 33.1, 33.0, 30.8, 29.7, 25.9,
20.0, 18.2, 17.4, 25.3; IR (Neat): 2954, 2928, 2857, 1784, 1700,
1461, 1386, 1353, 1251, 1208, 1093, 839, 772, 701, 591 cm21
;
MS (ESIMS): m/z 470 [M + Na]+; HRMS (ESI) calcd for
C25H41NO4SiNa [M + Na]+: 470.2702, Found: 470.2714.
(4S)-4-Benzyl-3-((2S,4R,6S)-7-[1-(tert-butyl)-1,1-dimethylsily-
l]oxy-2,4,6-trimethylheptanoyl)-1,3-oxazolan-2-one (14). To a
solution of 13 (8.7 g, 19.5 mmol) in dry THF (80 mL) at 278
uC, NaHMDS (1 M solution, 29.25 mL, 29.25 mmol) was added
slowly with stirring under nitrogen atmosphere. After stirring
at 278 uC for 30 min, MeI (3.62 mL, 58.3 mmol) was added
drop wise into the reaction mixture and stirred for an
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 4024–4032 | 4027

View Article Online
Paper
RSC Advances
additional 2 h at 278 uC. Then the reaction mixture was
quenched with saturated NH4Cl (50 mL), warmed to room
temperature and extracted with ethyl acetate (2 6 100 mL).
The combined organic extracts were washed with brine (50
mL), dried (Na2SO4) and concentrated under reduced pressure.
The crude product was purified by silica gel column
chromatography using ethyl acetate and hexane (1 : 19) to
afford 14 as a colorless liquid (8.0 g, 90%). [a]2D5 + 30.0 (c 1.0,
CHCl3); HPLC Hibar Lichrospher 5 mm, 4.6 6 250 mm (C18)
column, acetonitrile/water 85 : 15, flow rate = 1 mL min21, 20
uC, detection at 254 nm, PDA detector, t1 = 10.89 min (minor),
t2 = 11.63 min (major). 1H NMR (300 MHz, CDCl3): d 7.15–7.36
(m, 5H), 4.55–4.66 (m, 1H), 4.09–4.19 (m, 2H), 371–3.86 (m,
1H), 3.41 (dd, J = 9.0, 5.2 Hz, 1H), 3.23–3.34 (m, 2H), 2.70 (dd, J
= 13.5, 9.8 Hz, 1H), 1.50–1.5 (m, 2H), 1.38–1.46 (m, 3H), 1.23–
1.35 (m, 1H), 1.18 (d, J = 6.0 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H),
0.88 (s, 9H), 0.86 (d, J = 6.7 Hz, 3H), 0.02 (s, 6H); 13C NMR (75
MHz, CDCl3): d 177.6, 152.9, 135.3, 129.4, 128.8, 127.2, 68.3,
65.9, 55.3, 41.6, 40.1, 37.8, 35.4, 32.9, 27.7, 25.9, 19.8, 18.3,
17.3, 16.6, 25.3; IR (Neat): 2956, 2928, 2857, 1783, 1699, 1460,
1385, 1351, 1249, 1208, 1096, 839, 774, 700 cm21; MS (ESIMS):
m/z 484 [M + Na]+; HRMS (ESI) calcd for C26H43O4SiNa [M +
Na]+: 484.2859, Found: 484.2875.
(2S,4S,6S)-7-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-2,4,6-tri-
methylheptan-1-ol (15). To a stirred solution of 14 (7.8 g, 17.1
mmol) in MeOH (50 mL) at 0 uC was added NaBH4 (1.95 g, 51.3
mmol) portionwise. The reaction mixture was allowed to stir
for 30 min at same temperature. Reaction mixture was then
quenched with drop wise addition of saturated aqueous
NH4Cl. MeOH was removed under vacuum and residue was
extracted with ethyl acetate. The combined organic extracts
were dried over Na2SO4 and concentrated under reduced
pressure. Crude was purified by silica gel column chromato-
graphy (1 : 19, EtOAc/hexane) to afford the pure product 15
(4.53 g, 93%) as a viscous liquid. [a]2D5 217.7 (c 1.0, CHCl3); 1H
NMR (300 MHz, CDCl3): d 3.29–3.48 (m, 4H), 1.54–1.78 (m,
3H), 1.22–1.34 (m, 1H), 1.03–1.19 (m, 3H), 0.83–0.91 (m, 18H),
0.02 (s, 6H); 13C NMR (75 MHz, CDCl3): d 69.1, 68.3, 41.9, 40.2,
33.1, 32.9, 27.1, 25.9, 20.1, 18.3, 17.3, 16.1, 25.3; IR (Neat):
3351, 2956, 2928, 2858, 1465, 1383, 1253, 1098, 1040, 838, 775,
667 cm21; MS (ESIMS): m/z 289 [M + H]+; HRMS (ESI) calcd for
C16H36O2SiNa [M + Na]+: 311.2382, Found: 311.2398.
98.6, 73.8, 73.6, 68.39, 68.33, 62.1, 61.9, 42.0, 41.9, 40.7, 32.9,
30.8, 30.7, 30.6, 27.1, 25.8, 25.4, 20.0, 19.5, 19.4, 17.3, 16.7,
16.6, 25.4; IR (Neat): 2953, 2857, 1464, 1379, 1253, 1097, 1032,
838, 774, 667 cm21; MS (ESIMS): m/z 395 [M + Na]+; HRMS
(ESI) calcd for C21H44O3NaSi [M + Na]+: 395.2957, Found:
395.2960.
(2S,4R,6S)-2,4,6-Trimethyl-7-(tetrahydro-2H-2-pyranyloxy)-
heptan-1-ol (6). To a stirred solution of silyl ether 16 (5.2 g,
13.9 mmol) in dry THF (30 mL) at 0 uC was added drop wise a
solution of TBAF (21 mL, 21 mmol) in THF. The reaction
mixture was allowed to warm to 25 uC and stirred for 12 h.
Reaction mixture was then quenched with addition of water
and extracted with ethyl acetate (2 6 100 mL). The combined
organic extracts were dried over Na2SO4 and concentrated
under reduced pressure and crude was purified by silica gel
column chromatography (1 : 9, EtOAc/hexane) to afford the
pure product 6 (3.35 g, 93%) as a viscous liquid. [a]2D5 217.4 (c
1
1.05, CHCl3); H NMR (300 MHz, CDCl3): d 4.47–4.58 (m, 1H),
3.66–3.87 (m, 2H), 3.32–3.57 (m, 3H), 3.04–3.21 (m, 1H), 1.40–
1.92 (m, 10H), 1.24–1.39 (m, 1H), 1.05–1.18 (m, 2H), 0.84–0.96
(m, 9H); 13C NMR (75 MHz, CDCl3): d 99.0, 98.6, 73.8, 73.6,
68.9, 68.1, 62.2, 62.1, 62.0, 42.2, 41.5, 41.4, 40.6, 40.5, 32.9,
32.8, 30.7, 30.6, 27.1, 27.0, 25.4, 20.1, 20.0, 19.5, 19.4, 17.1,
16.8, 16.7; IR (Neat): 3448, 2925, 2854, 1632, 1437, 1196, 765,
646 cm21; MS (ESIMS): m/z 281 [M + Na]+; HRMS (ESI) calcd
for C15H30O3Na [M + Na]+: 281.2092, Found: 281.2096.
Ethyl (E,4S,6R,8S)-4,6,8-trimethyl-9-(tetrahydro-2H-2-pyrany-
loxy)-2-nonenoate (17). To a stirred solution of IBX (5.37 g, 19.2
mmol) in DMSO (15 mL) at 25 uC, was added drop wise a
solution of alcohol 6 (3.3 g, 12.8 mmol) in CH2Cl2 (30 mL). The
resulting mixture was stirred at 25 uC for 3 h. The solid was
filtered and washed with ether. The filtrate was diluted with
ether, washed with saturated aqueous NaHCO3 solution,
water, brine and dried over Na2SO4. The solvent was removed
under reduced pressure to furnish crude aldehyde. To the
above crude mixture (3.27 g, 12.8 mmol) in CH2Cl2 (100 ml)
was added (ethoxycarbonylmethylene) triphenyl phosphorane
(11.14 g, 32 mmol) and resulting mixture was stirred for 12 h at
room temperature and then quenched by the addition of water
and extracted with CH2Cl2 (3 6 100 mL). The combined
organic layers were washed with water, brine, dried (Na2SO4)
and concentrated. The crude product was purified by silica gel
column chromatography (1 : 19 EtOAc/hexane) giving 17 (3.84
g, 92%) as colorless liquid. [a]2D5 + 3.8 (c 1.05, CHCl3); 1H NMR
(300 MHz, CDCl3): d 6.76 (dd, J = 15.8, 8.3 Hz, 1H), 5.74 (d, J =
15.8 Hz, 1H), 4.47–4.57 (m, 1H), 4.16 (q, J = 14.3, 6.7 Hz, 2H),
3.79 (t, J = 9.0 Hz, 1H), 3.38–3.56 (m, 2H), 3.01–3.18 (m, 1H),
2.33–2.51 (m, 1H), 0.75–1.92 (m, 24H); 13C NMR (75 MHz,
CDCl3): d 166.7, 154.5, 119.5, 98.9, 98.6, 73.6, 73.4, 62.1, 61.9,
60.0, 44.4, 41.2, 34.0, 30.6, 27.4, 25.4, 20.1, 19.5, 19.4, 19.0,
16.9, 16.8, 14.1; IR (Neat): 2956, 2872, 1721, 1651, 1459, 1372,
1269, 1179, 1033, 981, 724 cm21; MS (ESIMS): m/z 349 [M +
Na]+; HRMS (ESI) calcd for C19H34O4Na [M + Na]+: 349.2354,
Found: 349.2359.
tert-Butyl(dimethyl)[(2S,4S,6S)-2,4,6-trimethyl-7-(tetrahydro-
2H-2-pyranyloxy)heptyl]oxysilane (16). To the solution of above
alcohol 15 (4.5 g, 15.6 mmol) and DHP (2.14 mL, 23.4 mmol) in
dry CH2Cl2 (60 mL) at 0 uC were added catalytic amount of
p-toluene sulfonic acid. It was allowed to stir at this
temperature for 15 min. The reaction mixture was diluted
with DCM, washed with saturated NaHCO3 solution, water,
brine successively. The organic layer was dried over anhydrous
Na2SO4 and concentrated in vacuo. The crude obtained was
purified through column chromatography (1 : 33, EtOAc/
hexane) afforded the pure 16 (5.29 g, 91%) as a colorless oil.
[a]2D5 210.8 (c 1.15, CHCl3); 1H NMR (500 MHz, CDCl3): d 4.50–
4.56 (m, 1H), 3.77–3.84 (m, 1H), 3.39–3.54 (m, 3H), 3.28–3.36
(m, 1H), 3.05–3.18 (m, 1H), 1.76–1.89 (m, 2H), 1.46–1.71 (m,
8H), 1.24–1.32 (m, 1H), 1.03–1.18 (m, 2H), 0.89 (s, 9H), 0.83–
0.92 (m, 9H)), 0.02 (s, 6H); 13C NMR (75 MHz, CDCl3): d 98.9,
Ethyl (4R,6R,8S)-4,6,8-trimethyl-9-(tetrahydro-2H-2-pyrany-
loxy)nonanoate (18). The procedure was analogous to that
used for the preparation of 9. From the unsaturated ester 17
(3.8 g, 11.66 mmol), NiCl2?6H2O (0.55 g, 2.33 mmol) and
4028 | RSC Adv., 2013, 3, 4024–4032
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Paper
NaBH4 (0.88 g, 23.32 mmol) was obtained saturated ester 18
0.94 (m, 9H); 13C NMR (75 MHz, CDCl3): 177.1, 152.8, 135.1,
129.3, 128.7, 127.2, 98.9, 98.5, 73.7, 73.6, 65.8, 62.1, 61.9, 55.1,
45.8, 40.7, 40.5, 37.7, 35.1, 30.6, 27.8, 26.9, 25.4, 20.2, 19.8,
19.4, 18.4, 16.8; IR (Neat): 2962, 2085, 1769, 1643, 1454, 1383,
743, 701 cm21; MS (ESI): m/z 496 [M + Na]+; HRMS (ESI) calcd
for C28H43O5Na [M + Na]+: 496.3038, found: 496.3044.
1
(3.75 g, 98%) as colorless liquid. [a]2D5 210.6 (c 1.2, CHCl3); H
NMR (500 MHz, CDCl3): d 4.50–4.57 (m, 1H), 4.10 (q, J = 13.6,
6.8 Hz, 2H), 3.80 (t, J = 9.7 Hz, 1H), 3.42–3.56 (m, 2H), 3.05–
3.17 (m, 1H), 2.18–2.33 (m, 2H), 1.75–1.89 (m, 2H), 1.46–1.73
(m, 8H), 1.31–1.41 (m, 1H), 1.26 (t, J = 6.8 Hz, 3H), 1.16–1.24
(m, 1H), 0.95–1.16 (m, 3H), 0.83–0.92 (m, 9H); 13C NMR (75
MHz, CDCl3): 173.9, 98.9, 98.5, 73.7, 73.5, 62.1, 61.9, 60.0, 45.5,
40.7, 31.9, 31.7, 30.77, 30.71, 30.6, 29.4, 27.05, 27.03, 25.4,
19.8, 19.6, 17.0, 14.1; IR (Neat): 2954, 2925, 2872, 1737, 1459,
1375, 1175, 1122, 1031, 976, 905, 770 cm21; MS (ESIMS): m/z
351 [M + Na]+; HRMS (ESI) calcd for C19H36O4Na [M + Na]+:
351.2511, Found: 351.2517.
(2S,4S,6R,8S)-2,4,6,8-Tetramethyl-9-(tetrahydro-2H-2-pyrany-
loxy)nonan-1-ol (21). The procedure was analogous to that
used for the preparation of 15. From the compound 5 (3.8 g,
8.03 mmol) and NaBH4 (0.92 g, 24.0 mmol) was obtained 21
1
(2.24 g, 93%) as colorless liquid. [a]2D5 221.2 (c 1.2, CHCl3); H
NMR (300 MHz, CDCl3): d 4.49–4.57 (m, 1H), 3.74–3.87 (m,
1H), 3.29–3.58 (m, 4H), 3.02–3.22 (m, 1H), 0.95–1.93 (m, 16H),
0.92 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.0 Hz, 3H), 0.87 (d, J = 6.0
Hz, 3H), 0.85 (d, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
98.9, 98.5, 73.8, 73.6, 68.0, 62.1, 61.9, 45.7, 41.2, 40.3, 32.9,
30.7, 30.64, 30.6, 27.2, 27.07, 27.02, 25.4, 20.7, 20.2, 19.5, 19.3,
19.2, 17.4, 16.75, 16.7; IR (Neat): 3422, 2953, 2920, 2872, 1459,
1377, 1124, 1031, 977, 550 cm21; MS (ESIMS): m/z 323 [M +
Na]+; HRMS (ESI) calcd for C18H36O3Na [M + Na]+: 323.2562,
Found: 323.2570.
Ethyl (E,4S,6S,8R,10S)-4,6,8,10-tetramethyl-11-(tetrahydro-
2H-2-pyranyloxy)-2-undecenoate (22). The procedure was ana-
logous to that used for the preparation of 17. From the alcohol
21 (2.2 g, 7.33 mmol), IBX (3.08 g, 11.0 mmol), and
(ethoxycarbonylmethylene) triphenyl phosphorane (6.38 g,
18.3 mmol) was obtained 22 (2.48 g, 92%) as colorless liquid.
[a]2D5 + 2.8 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3): d 6.76 (d, J
= 15.6, 8.3 Hz, 1H), 5.74 (d, J = 15.6 Hz, 1H), 4.47–4.58 (m, 1H),
4.16 (q, J = 14.1, 6.9 Hz, 2H), 3.73–3.86 (m, 1H), 3.37–3.57 (m,
2H), 3.02–3.19 (m, 1H), 2.31–2.49 (m, 1H), 1.24–1.93 (m, 12H),
1.30 (t, J = 6.9 Hz, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.92–1.24 (m,
3H), 0.76–0.93 (m, 9H); 13C NMR (75 MHz, CDCl3): 166.7,
154.4, 119.6, 98.9, 98.5, 73.7, 73.5, 62.1, 61.9, 60.0, 46.1, 43.6,
40.7, 34.1, 30.7, 30.6, 27.5, 26.9, 25.4, 20.4, 19.8, 19.4, 16.7,
14.1; IR (Neat): 2956, 2922, 2873, 1721, 1651, 1459, 1373, 1269,
1178, 1033, 980, 723 cm21; MS (ESIMS): m/z 391 [M + Na]+;
HRMS (ESI) calcd for C22H40O4Na [M + Na]+: 391.2824, Found:
391.2822.
(4R,6R,8S)-4,6,8-Trimethyl-9-(tetrahydro-2H-2-pyranyloxy)-
nonanoic acid (19). The procedure was analogous to that used
for the preparation of 12. From the ester 13 (3.7 g, 11.28 mmol)
and LiOH?H2O (0.95 g, 22.56 mmol) was obtained carboxylic
acid 19 (3.14 g, 93%) as colorless liquid. [a]2D5 211.2 (c 1.05,
CHCl3); 1H NMR (300 MHz, CDCl3): d 4.50–4.58 (m, 1H), 3.75–
3.87 (m, 1H), 3.40–3.56 (m, 2H), 3.04–3.20 (m, 1H), 2.24–2.42
(m, 2H), 0.92–1.91 (m, 15H), 0.90 (d, J = 6.4 Hz, 3H), 0.88 (d, J =
6.6 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 179.8, 99.0, 98.6, 73.8, 73.6, 62.2, 62.0, 45.4, 40.7, 31.6, 31.4,
30.7, 30.6, 29.4, 27.0, 25.4, 19.8, 19.6, 19.4, 16.8; IR (Neat):
2954, 2924, 2873, 1710, 1459, 1379, 1177, 1029, 904, 810 cm21
;
MS (ESIMS): m/z 323 [M + Na]+; HRMS (ESI) calcd for
C17H32O4Na [M + Na]+: 323.2198, Found: 323.2206.
(4S)-4-Benzyl-3-[(4R,6R,8S)-4,6,8-trimethyl-9-(tetrahydro-
2H-2-pyranyloxy)nonanoyl]-1,3-oxazolan-2-one (20). The proce-
dure was analogous to that used for the preparation of 13.
From the carboxylic acid 19 (3.0 g, 10.0 mmol), Et3N (3.50 mL,
25 mmol), PivCl (1.24 mL, 10 mmol), LiCl (0.64 g, 15 mmol)
and (S)-oxazolidinone (1.77 g, 10.0 mmol) was obtained 20
1
(4.27 g, 93%) as colorless liquid. [a]2D5 + 21.8 (c 1.0, CHCl3); H
NMR (300 MHz, CDCl3): d 7.15–7.37 (m, 5H), 4.57–4.66 (m,
1H), 4.51 (q, J = 6.7, 3.7 Hz, 1H), 4.09–4.21 (m, 2H), 3.75–3.86
(m, 1H), 3.41–3.57 (m, 2H), 3.31 (dd, J = 13.5, 3.7 Hz,1H), 3.05–
3.20 (m, 1H), 2.76–3.03 (m, 2H), 2.70 (dd, J = 13.5, 9.8 Hz, 1H),
1.35–1.94 (m, 12H), 1.19–1.33 (m, 1H), 0.99–1.18 (m, 2H), 0.92
(d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 6.7 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 173.6, 135.2, 129.3, 128.8,
127.2, 99.0, 98.6, 73.8, 73.6, 66.0, 62.2, 62.0, 55.1, 45.6, 40.7,
37.8, 33.2, 31.1, 30.6, 29.5, 27.0, 25.4, 19.8, 19.7, 19.5, 19.4,
16.8, 16.7; IR (Neat): 2952, 2923, 1783, 1700, 1454, 1384, 1352,
1208, 1029, 702 cm21; MS (ESIMS): m/z 482 [M + Na]+; HRMS
(ESI) calcd for C27H41NO5Na [M + Na]+: 482.2882, Found:
482.2871.
(E,4S,6S,8R,10S)-4,6,8,10-Tetramethyl-11-(tetrahydro-2H-2-
pyranyloxy)-2-undecen-1-ol (23). To a cooled (0 uC) solution of
22 (2.4 g, 6.52 mmol) in dry CH2Cl2 (20 mL), DIBAL-H (9.78
mL, 9.78 mmol, 1 M solution in toluene) was added slowly for
15 min and stirred for 1 h at 0 uC, before being quenched with
methanol (1 mL) and sodium potassium tartarate solution (20
mL). The reaction mixture was passed through a short pad of
celite. The filtrate was concentrated and the residue was
purified by column chromatography (1 : 9, EtOAc/hexane) to
furnish allylic alcohol 23 (2.02 g, 95%) as a colorless liquid.
(4S)-4-Benzyl-3-[(2S,4S,6R,8S)-2,4,6,8-tetramethyl-9-(tetrahy-
dro-2H-2-pyranyloxy)nonanoyl]-1,3-oxazolan-2-one (5). The
procedure was analogous to that used for the preparation of
14. From the compound 20 (4.2 g, 9.15 mmol), NaHMDS (1 M
solution, 13.72 mL, 13.72 mmol) and MeI (1.71 mL, 27.45
1
[a]2D5 21.3 (c 1.05, CHCl3); H NMR (300 MHz, CDCl3): d 5.39–
5.64 (m, 2H), 4.49–4.57 (m, 1H), 3.99–4.09 (m, 2H), 3.75–3.86
(m, 1H), 3.39–3.57 (m, 2H), 3.02–3.19 (m, 1H), 2.13–2.32 (m,
1H), 1.34–1.93 (m, 10H), 0.86–1.32 (m, 8H), 0.97 (d, J = 6.7 Hz,
3H), 0.83 (d, J = 6.0 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 138.7, 127.3, 99.0, 98.5, 73.8, 73.6, 63.6,
62.1, 61.9, 46.2, 44.4, 40.8, 33.8, 30.6, 27.4, 26.9, 25.4, 21.4,
20.0, 19.9, 19.5, 19.4, 16.8; IR (Neat): 3409, 2954, 2920, 2871,
1458, 1377, 1123, 1029, 974, 904, 759 cm21; MS (ESIMS): m/z
mmol) was obtained 5 (3.85 g, 89%) as colorless liquid. [a]D25
+
27.3 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.15–7.37 (m,
5H), 4.59–4.69 (m, 1H), 4.49–4.58 (m, 1H), 4.09–4.23 (m, 2H),
3.73–3.92 (m, 2H), 3.39–3.59 (m, 2H), 3.27 (dd, J = 13.0, 3.5 Hz,
1H), 3.04–3.21 (m, 1H), 2.70 (dd, J = 13.2, 10.0 Hz, 1H), 1.42–
1.97 (m, 9H), 0.94–1.36 (m, 6H), 1.20 (d, J = 6.7 Hz, 3H), 0.82–
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 4024–4032 | 4029

View Article Online
Paper
RSC Advances
349 [M + Na]+; HRMS (ESI) calcd for C20H38O3Na [M + Na]+:
349.2718, Found: 349.2728.
of 10 min. The reaction mixture was stirred at room
temperature for 2 h and then diluted with CH2Cl2 and washed
with water and brine. The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated. The crude
product was purified by flash silica gel column chromato-
graphy using ethyl acetate and hexane (0.5 : 9.5) to afford
TBDPS protected alcohol 25 (2.62 g, 94%) as a colorless oil.
(2R,3R)-3-[(1S,3S,5R,7S)-1,3,5,7-Tetramethyl-8-(tetrahydro-
2H-2-pyranyloxy)octyl]oxiran-2-ylmethanol (4). To a solution of
(2)-DET (0.32 mL, 1.84 mmol) in dry CH2Cl2 (20 mL) at 230 uC
containing MS 4 Å (0.7 (g), was added sequentially, Ti(OiPr)4
(0.47 mL, 1.6 mmol) and TBHP (6.13 mL, 18.39 mmol, 3 M
solution in toluene) and stirred for 30 min. A solution of
alcohol 23 (2.0 g, 6.13 mmol) in CH2Cl2 (10 mL) was added and
stirred for 10 h at 230 uC and then reaction mixture was kept
frozen for an additional 12 h. It was then quenched with 45 mL
of water, 30% aqueous NaOH solution saturated with NaCl (20
mL) and the resulting mixture stirred vigorously for another 30
min at room temperature. The resulting mixture was vacuum
filtered through celite and the filter cake was washed well with
CH2Cl2. The organic phase was separated and the aqueous
phase was extracted with CH2Cl2 (3 6 100 mL). Combined
organic phases were washed with brine and dried over Na2SO4.
Removal of solvent under reduced pressure and purification by
column chromatography (3 : 7, EtOAc/hexane) afforded 4 (1.88
g, 90%) as a viscous liquid. [a]2D5 + 2.6 (c 1.35, CHCl3); 1H NMR
(300 MHz, CDCl3): d 4.46–4.58 (m, 1H), 3.73–3.90 (m, 2H),
3.37–3.64 (m, 3H), 3.02–3.22 (m, 1H), 2.87–2.94 (m, 1H), 2.56–
2.69 (m, 1H), 1.24–1.92 (m, 12H), 0.94–1.22 (m, 4H), 1.01 (d, J =
6.7 Hz, 3H), 0.81–0.93 (m, 9H); 13C NMR (75 MHz, CDCl3): d
98.9, 98.6, 73.7, 73.5, 62.1, 61.8, 60.9, 60.6, 58.6, 45.9, 41.4,
40.5, 32.7, 30.6, 30.5, 27.2, 26.9, 25.3, 20.3, 19.9, 19.5, 17.8,
16.7, 16.6; IR (Neat): 3446, 2955, 2922, 2872, 1460, 1378, 1122,
1029, 901, 868, 586 cm21; MS (ESIMS): m/z 365 [M + Na]+;
HRMS (ESI) calcd for C20H38O4Na [M + Na]+: 365.2667, Found:
365.2676.
1
[a]2D5 213.1 (c 1.5, CHCl3); H NMR (300 MHz, CDCl3): d 7.56–
7.72 (m, 4H), 7.28–7.50 (m, 6H), 4.49–4.58 (m, 1H), 3.64–3.94
(m, 4H), 3.38–3.62 (m, 2H), 3.01–3.22 (m, 1H), 2.64–2.78 (br,
1H), 1.14–1.90 (m, 16H), 1.05 (s, 9H), 0.94–1.15 (m, 2H), 0.78–
0.95 (m, 12H); 13C NMR (75 MHz, CDCl3): d 135.4, 133.0, 129.7,
127.6, 98.9, 98.5, 74.1, 73.9, 73.7, 63.6, 62.1, 61.9, 45.5, 40.9,
40.2, 35.9, 35.6, 30.8, 30.6, 27.2, 27.0, 26.7, 25.4, 20.8, 20.3,
19.5, 19.4, 18.9, 16.7, 16.6, 14.5; IR (Neat): 3484, 3070, 2954,
1655, 1443, 1380, 1111, 1029, 975, 703, 504 cm21; MS (ESIMS):
m/z 605 [M + Na]+; HRMS (ESI) calcd for C36H58O4Na [M + Na]+:
605.4002, Found: 605.4002.
tert-Butyl[(3S,4S,6S,8R,10S)-3-[1-(tert-butyl)-1,1-dimethylsi-
lyl]oxy-4,6,8,10-tetramethyl-11-(tetrahydro-2H-2-pyranyloxy)un-
decyl]oxydiphenylsilane (26). 2,6-Lutidine (1.25 mL, 10.7
mmol) was added drop wise to a cooled solution (0 uC) of
alcohol 25 (2.5 g, 4.29 mmol) in dry CH2Cl2 (15 mL). After 10
min
tert-butyldimethylsilyltrifluoromethane
sulfonate
(TBSOTf, 1.48 mL, 6.4 mmol) was added drop wise and
stirring was continued for 2 h at 0 uC. The reaction mixture
was diluted with CH2Cl2 (20 mL) and washed with NaHCO3,
water and brine. The organic layer was dried over anhydrous
Na2SO4 and concentrated in vacuo. The residue was purified by
column chromatography (1 : 40, EtOAc/hexane) to afford TBS
ether 26 as a colorless oil (2.92 g, 98%). [a]2D5 224.1 (c 1.05,
CHCl3); 1H NMR (300 MHz, CDCl3): d 7.56–7.68 (m, 4H), 7.27–
7.45 (m, 6H), 4.50–4.57 (m, 1H), 3.74–3.86 (m, 2H), 3.66 (t, J =
6.0 Hz, 2H), 3.40–3.57 (m, 2H), 3.03–3.18 (m, 1H), 0.94–1.93
(m, 18H), 1.04 (s, 9H), 0.73–0.92 (m, 12H), 0.84 (s, 9H), 0.02 (s,
3H), 20.02 (s, 3H); 13C NMR (75 MHz, CDCl3): d 135.5, 133.9,
129.5, 127.5, 98.9, 98.6, 74.03, 73.8, 72.3, 62.1, 61.9, 61.2, 45.8,
40.7, 40.0, 36.4, 35.03, 30.9, 30.8, 30.7, 27.4, 27.1, 26.8, 25.9,
25.5, 20.77, 20.70, 19.57, 19.50, 19.1, 18.1, 16.6, 15.0, 24.6; IR
(Neat): 3070, 2955, 2929, 2858, 1464, 1380, 1253, 1110, 1032,
835, 703, 504 cm21; MS (ESIMS): m/z 719 [M + Na]+; HRMS
(ESI) calcd for C42H72O4NaSi2 [M + Na]+: 719.4866, Found:
719.4869.
(3S,4S,6S,8R,10S)-4,6,8,10-Tetramethyl-11-(tetrahydro-2H-2-
pyranyloxy)undecane-1,3-diol (24). To a stirred solution of
epoxy alcohol 4 (1.85 g, 5.4 mmol) in THF was added Red-Al
(0.6 g, 1.12 mmol) under nitrogen atmosphere at 0 uC. The
reaction mixture was stirred for 3 h at room temperature, then
cooled to uC and quenched with drop wise addition of
saturated aqueous Na2SO4. The precipitate formed was filtered
and washed with ethyl acetate. The combined organic extracts
were dried over Na2SO4 and concentrated under reduced
pressure and crude product was purified by silica gel column
chromatography (1 : 3, EtOAc/hexane) to afford the pure
product 24 (1.69 g, 91%) as a viscous liquid. [a]2D5 226.5 (c
1
1.2, CHCl3); H NMR (500 MHz, CDCl3): d 4.50–4.58 (m, 1H),
(3S,4S,6S,8R,10S)-3-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-
4,6,8,10-tetramethyl-11-(tetrahydro-2H-2-pyranyloxy)undecan-
1-ol (27). To a stirred solution of 26 (2.8 g, 4.02 mmol) in
methanol (20 mL) was added ammonium fluoride (1.49 g, 40.2
mmol) at room temperature. The reaction mixture was
warmed at 60 uC for 8 h. After completion of reaction as
indicated by TLC, reaction mixture was quenched with
NaHCO3. The product was extracted with ethyl acetate and
purified by flash column chromatography (1 : 19, EtOAc/
hexane) to afford alcohol 27 (1.63 g, 89%) as colorless oil.
3.64–3.87 (m, 4H), 3.41–3.58 (m, 2H), 3.03–3.21 (m, 1H), 2.56–
2.78 (br, 2H), 1.76–1.89 (m, 2H), 1.46–1.76 (m, 10H), 1.33–1.42
(m, 1H), 1.17–1.28 (m, 1H), 0.89–1.15 (m, 4H), 0.82–0.93 (m,
12H); 13C NMR (75 MHz, CDCl3): d 99.0, 98.5, 74.9, 74.8, 73.9,
73.6, 62.2, 61.9, 61.8, 45.3, 40.9, 40.1, 35.9, 35.5, 30.7, 30.6,
27.2, 27.1, 27.0, 25.4, 20.8, 20.4, 19.5, 19.3, 16.7, 14.4; IR (Neat):
3677, 3404, 2954, 2923, 1654, 1459, 1378, 1120, 1029, 975, 759,
668 cm21; MS (ESIMS): m/z 367 [M + Na]+; HRMS (ESI) calcd
for C20H40O4Na [M + Na]+: 367.2824, Found: 367.2835.
(3S,4S,6S,8R,10S)-1-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-
4,6,8,10-tetramethyl-11-(tetrahydro-2H-2-pyranyloxy)undecan-
3-ol (25). To a stirred solution of diol 24 (1.65 g, 4.8 mmol) and
imidazole (0.98 g, 14.4 mmol) in CH2Cl2 (20 mL) was added
drop wise TBDPS-Cl (1.38 mL, 5.2 mmol) at 0 uC over a period
1
[a]2D0 241.5 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3): d 4.49–
4.58 (m, 1H), 3.75–3.86 (m, 1H), 3.61–3.74 (m, 3H), 3.39–3.57
(m, 2H), 3.03–3.20 (m, 1H), 0.95–1.91 (m, 18H), 0.90 (s, 9H),
0.78–0.95 (m, 12H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (75
MHz, CDCl3): d 98.9, 98.6, 74.7, 74.0, 73.8, 62.1, 61.9, 60.5,
4030 | RSC Adv., 2013, 3, 4024–4032
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Paper
K. Thirumala, V. S. Dubey, H. Sprecher and P.
E. Kolattukudy, J. Biol. Chem., 2001, 276, 16833–16839.
4 (a) M. T. Fletcher, S. Chow, L. K. Lambert, O. P. Gallagher,
B. W. Cribb, P. G. Allsopp, C. J. Moore and W. Kitching,
Org. Lett., 2003, 5, 5083; (b) G. Zhu, B. Liang and E. Negishi,
Org. Lett., 2008, 10, 1099; (c) C. Herber and B. Breit, Angew.
Chem., Int. Ed., 2005, 44, 5267; (d) J. Zhou, Y. Zhu and
K. Burgess, Org. Lett., 2007, 9, 1391.
5 (a) B. D. Morris, R. R. Smyth, S. P. Foster, M. P. Hoffmann,
W. L. Roelofs, S. Franke and W. Francke, J. Nat. Prod., 2005,
68, 26; (b) Y. Schmidt and B. Breit, Org. Lett., 2009, 11, 4767;
(c) Y. Schmidt, K. Lehr, U. Breuninger, G. Brand, T. Reiss
and B. Breit, J. Org. Chem., 2010, 75, 4424; (d) C. F. Weise,
M. Pischl, A. Pfaltz and C. Schneider, Chem. Commun.,
2011, 47, 3248; (e) J. S. Yadav, N. N. Yadav, T. S. Rao, B. V.
S. Reddy and A. A. K. A. Ghamdi, Eur. J. Org. Chem., 2011,
4603–4608.
6 (a) K. Mori and S. Kuwahara, Tetrahedron, 1986, 42, 5539;
(b) M. Kaino, Y. Naruse, K. Ishihara and H. Yamamoto, J.
Org. Chem., 1990, 55, 5814; (c) R. Des Mazery, M. Pullez,
F. Lopez, S. R. Harutyunyan, A. J. Minnaard and B.
L. Feringa, J. Am. Chem. Soc., 2005, 127, 9966.
7 J. Berger, L. M. Jampolsky and M. W. Goldberg, Arch.
Biochem., 1949, 22, 476.
8 W. Keller-Schierlein, Helv. Chim. Acta, 1967, 50, 731.
9 B. F. Anderson, A. J. Herlt, R. W. Rickards and G.
B. Robertson, Aust. J. Chem., 1989, 42, 717.
45.5, 40.06, 40.03, 35.5, 34.9, 30.8, 30.6, 27.6, 27.2, 25.9, 25.5,
21.1, 20.7, 19.5, 19.4, 18.0, 16.6, 16.5, 15.9, 24.2, 24.5; IR
(Neat): 3444, 2954, 2928, 2856, 1632, 1461, 1378, 1254, 1061,
1031, 835, 773, 665 cm21; MS (ESIMS): m/z 481 [M + Na]+;
HRMS (ESI) calcd for C26H54O4NaSi [M + Na]+: 481.3689,
Found: 481.3683.
(3S,4S,6S,8R,10S)-3-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-
4,6,8,10-tetramethyl-11-(tetrahydro-2H-2-pyranyloxy)undeca-
noic acid (2). To a vigorously stirred solution of alcohol 27
(1.63 g, 3.55 mmol) in acetone (16 mL) and water (4 mL) was
added TEMPO (0.05 g, 0.35 mmol) and BAIB (2.52 g, 7.8
mmol). Stirring was allowed until TLC indicated complete
conversion of the starting material to product. The reaction
mixture was quenched by addition of saturated Na2S2O3
solution (10 mL). The reaction mixture was then extracted
with ethyl acetate (3 6 20 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated. The
crude acid was purified by silica gel column chromatography
using ethyl acetate and hexane (1 : 19) to get pure acid 2 (1.59
g, 95%) as a colorless liquid. [a]2D5 231.5 (c 0.6, CHCl3); 1H
NMR (300 MHz, CDCl3): d 4.52–4.62 (m, 1H), 4.01–4.12 (m,
1H), 3.76–3.89 (m, 1H), 3.41–3.59 (m, 2H), 3.03–3.22 (m, 1H),
2.42 (d, J = 6.0 Hz, 2H), 1.33–1.92 (m, 11H), 0.97–1.32 (m, 3H),
0.77–0.96 (m, 23H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (75
MHz, CDCl3): d 177.8, 98.9, 98.5, 73.9, 73.7, 72.4, 62.1, 61.9,
45.6, 40.3, 40.0, 39.2, 35.9, 30.8, 30.7, 30.6, 27.4, 27.1, 25.7,
25.4, 20.79, 20.76, 20.6, 19.4, 19.3, 18.0, 16.6, 16.5, 15.18,
15.15, 24.5, 24.6; IR (Neat): 3422, 2953, 1715, 1621, 1462,
1384, 1255, 1118, 1030, 867, 772, 703, 505 cm21; MS (ESIMS):
m/z 495 [M + Na]+; HRMS (ESI) calcd for C26H52O5NaSi [M +
Na]+: 495.3481, Found: 495.3492.
10 L. Dickinson, A. J. Griffiths, C. G. Mason and R. F. Mills,
Nature, 1965, 206, 265.
11 T. Wakabayashi, R. Kageyama, N. Naruse, N. Tsukahara,
Y. Funahashi, K. Kitoh and Y. Watanabe, J. Antibiot., 1997,
50, 671.
12 S. K. Singh, S. Gurusiddaiah and J. W. Whalen, Antimicrob.
Agents Chemother., 1985, 27, 239.
13 E. Tsuchiya, M. Yukawa, T. Miyakawa, K. Kimura and
H. Takahashi, J. Antibiot., 2001, 54, 84.
14 M. O. Duffey, A. LeTiran and J. P. Morken, J. Am. Chem.
Soc., 2003, 125, 1458.
Acknowledgements
N. N. Y thank CSIR, New Delhi for the financial support in the
form of a fellowship.
15 (a) S. Hanessian, Y. Yang, S. Giroux, V. Mascitti, J. Ma and
F. Raeppel, J. Am. Chem. Soc., 2003, 125, 13784; (b) B.
G. Vong, S. H. Kim, S. Abraham and A. E. Theodorakis,
Angew. Chem., Int. Ed., 2004, 43, 3947; (c) T. Nagamitsu,
D. Takano, T. Fukuda, K. Otoguro, I. Kuwajima,
Y. Harigaya and S. Omura, Org. Lett., 2004, 6, 1865; (d)
T. Nagamitsu, Y. Harigaya and S. Omura, Proc. Jpn. Acad.,
Ser. B, Phys. Biol. Sci., 2005, 81, 244; (e) T. Nagamitsu,
D. Takano, K. Marumoto, T. Fukuda, K. Furuya,
K. Otoguro, K. Takeda, I. Kuwajima, Y. Harigaya and
S. Omura, J. Org. Chem., 2007, 72, 2744.
References
1 (a) M. C. Liu and T. E. Hermann, J. Biol. Chem., 1978, 253,
5892; (b) W. C. Liu, D. S. Slusarchyk, G. Astle, W. H. Trejo,
W. E. Brown and E. Meyers, J. Antibiot., 1978, 31, 815; (c) J.
S. Hanessian, N. G. Cooke, B. DeHoff and Y. Saikito, J. Am.
Chem. Soc., 1990, 112, 5276; (d) D. A. Evans, R. L. Dow, T.
L. Shih, J. M. Takacs and R. Zahler, J. Am. Chem. Soc., 1990,
112, 5290; (e) M. Lautens, J. T. Colucci, S. Hiebert, N.
D. Smith and G. Bouchain, Org. Lett., 2002, 4, 1879.
´
16 (a) C. Olano, B. Wilkinson, C. Sanchez, S. J. Moss, A.
˜
´
F. Brana, C. Mendez, P. F. Leadlay and J. A. Salas, Chem.
2 (a) H. Ishiwata, M. Nemoto, M. Ojika and K. Yamada, J.
Org. Chem., 1994, 59, 4710; (b) H. Ishiwata, H. Sone,
H. Kigoshi and K. Yamada, Tetrahedron, 1994, 50, 12853; (c)
A. K. Ghosh and C. Liu, Org. Lett., 2001, 3, 635.
Commun., 2003, 2780; (b) C. Olano, B. Wilkinson,
´
C. Sanchez, S. J. Moss, R. Sheridan, V. Math, A.
˜
J. Weston, A. F. Brana, C. J. Martin, M. Oliynyk,
´
C. Mendez, P. F. Leadlay and J. A. Salas, Chem. Biol.,
3 (a) M. Gilleron, S. Stenger, Z. Mazorra, F. Wittke,
2004, 11, 87.
¨
S. Mariotti, G. Bohmer, J. Prandi, L. Mori, G. Puzo and
17 (a) N. Haddad, M. Grishko and A. Brik, Tetrahedron Lett.,
1997, 38, 6075; (b) N. Haddad, A. Brik and M. Grishko,
Tetrahedron Lett., 1997, 38, 6079; (c) C. V. Krishna,
S. Maitra, R. V. Dev, K. Mukkanti and J. Iqbal,
Tetrahedron Lett., 2006, 47, 6103; (d) C. V. Krishna, V.
´
G. De Libero, J. Exp. Med., 2004, 199, 649–659; (b) M. Daffe,
F. Papa, A. Laszlo and H. L. David, J. Gen. Microbiol., 1989,
135, 2759–2766; (c) M. W. Schelle and C. R. Bertozzi,
ChemBioChem, 2006, 7, 1516–1524; (d) T. D. Sirakova, A.
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 4024–4032 | 4031

View Article Online
Paper
R. Bhonde, A. Devendar, S. Maitra, K. Mukkanti and
RSC Advances
(c) J. C. Anderson, S. V. Ley and S. P. Marsden, Tetrahedron
Lett., 1994, 35, 2087; (d) K. Fujita and K. Mori, Eur. J. Org.
Chem., 2001, 493; (e) G. D. McAllister and R. J. K. Taylor,
Tetrahedron Lett., 2004, 45, 2551; (f) the enantiomeric
excess has been determined by the comparison of [a]D
rotation with the value reported in the literature, see ref.
21d,e.
J. Iqbal, Tetrahedron Lett., 2008, 49, 2013–2017.
18 (a) T. Novak, Z. Tan, B. Liang and E.-I. Negishi, J. Am. Chem.
Soc., 2005, 127, 2838; (b) M. Theurer, Y. E. Baz,
K. Koschorreck, V. B. Urlacher, G. Rauhut, A. Baro and
S. Laschat, Eur. J. Org. Chem., 2011, 4291; (c) B. G. Vong,
S. Abraham, A. X. Xiang and E. A. Theodorakis, Org. Lett.,
2003, 5, 1617; (d) C. Herber and B. Breit, Chem.–Eur. J.,
2006, 12, 6684–6691; (e) J. S. Yadav, B. Padmavani and
C. Venugopal, Tetrahedron Lett., 2009, 50, 3772–3775; (f) A.
V. R. Madduri and A. J. Minnaard, Chem.–Eur. J., 2010, 16,
11726.
23 T. Satoh, K. Nanba and S. Suzuki, Chem. Pharm. Bull., 1971,
19, 817.
24 (a) D. A. Evans, M. D. Ennis and D. J. Mathre, J. Am. Chem.
Soc., 1982, 104, 1737; (b) T. K. Chakraborty and V.
R. Suresh, Tetrahedron Lett., 1998, 39, 7775.
19 (a) J. S. Yadav, T. S. Rao, N. N. Yadav, K. V. R. Rao, B. V.
S. Reddy and A. K. Ghamdi, Synthesis, 2012, 44, 788–792;
(b) J. S. Yadav, S. Sengupta, N. N. Yadav, D. N. Chary and A.
A. Al Ghamdi, Tetrahedron Lett., 2012, 53, 5952.
20 (a) J. J. Miller and P. L. De Benneville, J. Org. Chem., 1957,
22, 1268; (b) G. Stork and V. Nair, J. Am. Chem. Soc., 1979,
101, 1315.
25 (a) M. G. Finn and K. B. Sharpless, Asymmetric Synthesis, ed.
J. D. Morrison, Academic Press, New York, 1985, Vol. 5,
Chapter 8, 247; (b) B. E. Rossiter, Asymmetric Synthesis, ed.
J. D. Morrison, Academic Press, New York, 1985, Vol. 5,
Chapter 7, 193; (c) A. Pfenninger, Synthesis, 1986, 89.
26 W. Zhang and M. J. Robins, Tetrahedron Lett., 1992, 33,
177–1180.
21 M. L. Wolfrom and J. M. Bobbitt, J. Am. Chem. Soc., 1956,
78, 2489.
22 (a) K. Tsuji, Y. Terao and K. Achiwa, Tetrahedron Lett., 1989,
30, 6189; (b) G. Lin and W. Xu, Tetrahedron, 1996, 52, 5907;
27 (a) A. D. Mico, R. Margarita, L. Parlanti, A. Vescovi,
G. Piancatelli, D. A. Evans, M. D. Ennis and D. J. Mathre,
J. Org. Chem., 1997, 62, 6974–6977; (b) J. B. Epp and T.
S. Widlanski, J. Org. Chem., 1999, 64, 293–295.
4032 | RSC Adv., 2013, 3, 4024–4032
This journal is ß The Royal Society of Chemistry 2013