Total synthesis of 5-epi-Torrubiellutin C and its biological evaluation

Article abstract of DOI:10.1039/c3ra42127a

The total synthesis of 5-epi-Torrubiellutin C is described in a fully stereocontrolled manner and linear sequence involving high yielding steps. The synthetic strategy involves the dicyclohexylboron chloride mediated Paterson's aldol protocol, Horner-Emmo

Full text of DOI:10.1039/c3ra42127a

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Total synthesis of 5-epi-Torrubiellutin C and its
biological evaluation3
Cite this: RSC Advances, 2013, 3,
15917
Bodugam Mahipal,a Ashita Singh,b Ramesh Ummanni*b and Srivari Chandrasekhar*a
The total synthesis of 5-epi-Torrubiellutin C is described in a fully stereocontrolled manner and linear
sequence involving high yielding steps. The synthetic strategy involves the dicyclohexylboron chloride
mediated Paterson’s aldol protocol, Horner–Emmons olefination, TiCl4 mediated syn-aldol reaction and
ring closing metathesis (RCM) as the key steps. Furthermore, the resultant epimer was evaluated for
cytotoxicity against DU145 (prostate), MCF-7 (breast) and A549 (lung) cancer cell lines, and the results
showed that the 5-epi-Torrubiellutin C is as good as the natural product in bioassays.
Received 30th April 2013,
Accepted 25th June 2013
DOI: 10.1039/c3ra42127a
www.rsc.org/advances
The local disconnections based on this background allowed
us to initiate the synthesis starting from commercially
Introduction
Torrubiellutins are 15-membered macrocyclic amides grafted
on L-phenylalanine through ester–amide linkages. These
compounds were recently isolated by Pittayakhajonwut et al.
from the crude extract of the insect fungus; Torrubiella
luteorostrata BCC 12904.1 The crude extract exhibited low
micromolar inhibition of MCF-7 and human epidermoid
carcinoma (KB) cell lines. The further purification of this
extract resulted in isolation of three macrolides, viz.,
Torrubiellutins A–C (1–3, Fig. 1) along with the known pyrone
diterpene. While Torrubiellutin C (3) showed very good
cytotoxic activity, the pyrone exhibited good antimalarial
properties.
Besides their 15-membered macrocyclic feature, torrubiel-
lutins are enriched with seven asymmetric carbons, having an
a, b-unsaturated amide and tri-substituted olefin functional-
ities. These challenging functionalities and our interest in the
total synthesis of bioactive compounds2 prompted us to
embark on the endeavour of synthesizing this natural product.
To the best of our knowledge, to date no synthetic effort has
been reported towards the synthesis of torrubiellutins.
available (S)-Roche ester through the diol 8, aldehyde 7, which
could be further converted to the RCM precursor 4 via 6. This
may eventually be converted to the target molecule (Scheme 1).
In the next steps, (S)-Roche ester was silylated to 10,3 which
was converted to ethyl ketone 94 via Weinreb amide 11,
resulting in 87% yields over two steps. The asymmetric aldol
(Paterson’s aldol) reaction5 of 9 with acetaldehyde in the
presence of dicyclohexylboron chloride, followed by LiBH4
reduction, provided the diol 8 with perfect stereocontrol (>98%
dr ratio, the minor isomer was separated by column
chromatography). The resultant major diol 8 was correlated
with the data of reported compound 12 by replacing its silyl
ether with benzyl ether.6,7 The protective group manipula-
tions, viz., monobenzylation of 8, followed by silylation to 13
and selective 1u desilylation to 14 were highly predictable with
good yields. The compound 15 was oxidized using IBX and in
turn was subjected to (Z)-controlled olefination conditions
(Horner–Emmons olefination)8 to realize 16 in yields of over
83%. No trace of other trans-diastereomer was observed during
this transformation. The reduction of ester functionality in 16
Results and discussion
The asymmetric centres present in this macrocycle are tailor
made for ‘aldol chemistry’. Thus, we relied heavily on utilizing
asymmetric aldol reactions towards the target envisioned.
aDivision of Natural Products Chemistry, Hyderabad 500 007, India.
E-mail: srivaric@iict.res.in; Fax: +91-40-27160512
bCenter for Chemical Biology, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 007, India. E-mail: ummanni@iict.res.in
Electronic supplementary information (ESI) available: Copies of 1H NMR and
3
13C NMR spectra of all the new compounds. See DOI: 10.1039/c3ra42127a
Fig. 1 Structures of torrubiellutins.
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Scheme 1 Retrosynthetic analysis of Torrubiellutin C.
Scheme 2 Stereoselective synthesis of aldehyde 7.
was achieved using DIBAL-H to produce the alcohol 17, which
was oxidized using MnO2 to aldehyde 7 in a 98% yield
(Scheme 2).
The real challenge of anti-aldol addition of the propionic
amide (using auxiliaries 18a–d) under various reaction
conditions5f,9–12 on to aldehyde 7 was futile. Unfortunately,
no reaction was observed even after prolonged reaction times
(see Scheme 3 and Table 1).
As we achieved an advanced stage of synthesis, not looking
back, we attempted to form a syn-aldol13 product with the
known auxiliary 18e13a using TiCl4 and (2)-sparteine.
Interestingly, the reaction was very smooth with good ‘syn’
control (97 : 3 diastereomeric ratio) to give 19e in 84% yield,
after the minor isomer was separated by column chromato-
graphy (Scheme 4). The reason for the failure to obtain an anti-
aldol may be due to steric congestion during the transition
state (Fig. 2).
After successful construction of the aliphatic propionate
part 6a, it was esterified with N-methyl-N-Boc phenylalanine
514 using DCC and DMAP to realize the ester 23 in 88% yield
(Scheme 6). The desilylation of 23 to alcohol 24, which was
then acetylated to 25, were rather easy transformations and
were achieved in quantitative yields. The Boc group in 25 was
deprotected with TFA followed by immediate treatment with
acryloyl chloride and Et3N to produce acrylamide 4a in 90%
yield. The macrocyclization via RCM was accomplished rather
efficiently using HG-II catalyst15 (only 10% reaction conversion
Further attempts to invert the C-5 hydroxyl of the target
molecule in 19e were again not successful. Therefore, we
anticipated that this could be achieved after accomplishing
the macrocycle. Thus, we proceeded further by protecting the
free hydroxyl group in 19e as MOM ether 20, which was
followed by the removal of the auxiliary with LiBH4 to furnish
the primary alcohol 21 in 90% yield. One carbon homologation
of 21 to olefin 22 was achieved via IBX oxidation, followed by a
Wittig reaction with P+Ph3MeI2 in the presence of KOtBu. The
benzyl group in 22 was removed using Li/naphthalene to
provide 6a in 94% yield (Scheme 5).
Scheme 3 Trials attempted in favour of key fragment 6.
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Table 1 Anti-aldol reactions of aldehyde 7 with auxiliaries (18a–d) under various reaction conditions
Entry
Reaction conditions
Reaction progressa
no reaction
1
2
3
18a,9 MgBr2?OEt2 (10 mol%), aldehyde 7 (1.1 equiv.), Et3N (2 equiv.), TMSCl (1.5 equiv.),
0.4 M in EtOAc, 24 h; then 5 : 1 THF/1.0 N HCl.
18a,9 MgCl2 (10 mol%), aldehyde 7 (1.1 equiv.), Et3N (2 equiv.), TMSCl (1.1 equiv.),
0.4 M in EtOAc, 24 h; then 5 : 1 THF/1.0 N HCl.
no reaction
18b,10 c-Hex2BOTf (2.0 equiv.), Et3N (2.4 equiv.), 278 uC for 2 h; then aldehyde 7,
278 uC for 1 h, 0 uC–RT for 15 h.
,2% product
i
4
5
6
18c,11 TiCl4, Pr2NEt, then aldehyde 7, Bu2BOTf, CH2Cl2, 278 uC–RT, 12 h.
mixture of products
no reaction
no reaction
18d,5f,12 c-Hex2BCl, NMe2Et, 0 uC, 2 h; then aldehyde 7, 278 uC–RT, 10 h.
18d,5f,12 c-Hex2BCl, Et3N, 0 uC, 1.5 h; then aldehyde 7, 278 uC–RT, 12–15 h.
a
All reactions were performed according to known procedures.
showed that the cytotoxic effect of the tested compound on
prostate cancer (DU145) and breast cancer (MCF-7) cell lines is
comparable to that of the control drug doxorubicin, whereas it
was less effective in lung cancer (A549) cells compared to the
control. Previously, Pittayakhajonwut et al. reported cytotoxicity
for the natural product. However, in their reported assays,1 the
determined efficacy of the natural product (3) was 5 fold less
compared to the standard drug doxorubicin against MCF-7
(strong cytotoxicity compared to other cell types tested) cells.
Thus, in our currently reported assays, the 5-epi-Torrubiellutin C
(3a) showed better efficacy than the control drug doxorubicin on
the same cell line, MCF-7 (breast cancer cells), suggesting that 3a
is more effective than 3. Taken together, the present cytotoxic
results clearly showed that the ‘C-5 epimer’ synthesized as an
alternative to the original natural product is equally potent or
more cytotoxic in selected cell types (see Table 2).
Scheme 4 Syn-aldol reaction of aldehyde 7.
was observed when Grubbs’-II catalyst is used) in 95% yield
after several parameter corrections to realize the exclusive
trans-macrolactam 26. The MOM ether 26 was hydrolyzed
under LiBF4 conditions16 to generate 5-epi-Torrubiellutin C
(3a) (y213 mg), which has been thoroughly characterized (see
experimental).
Furthermore, several attempts to epimerize the C-5 hydroxyl
group in 3a under Mitsunobu or oxidation–reduction conditions
were not successful. This was rather disappointing taking into
account the efforts that had gone into achieving the target
molecule synthesis. Then, we anticipated that the resultant 5-epi-
Torrubiellutin C (3a), having the entire functionality of the natural
product, would be biologically useful. Thus, the epimer 3a was
subjected to screening for cytotoxic effects as reported.17,18
Interestingly, the results from cytotoxic assays clearly showed its
anti-cancer properties against the tested cell lines. The IC50 values
Conclusions
In summary, the total synthesis of the C-5 epimer of a cytotoxic
natural product, Torrubiellutin C, has been achieved with
Scheme 5 Synthesis of fragment 6a from syn-aldol adduct 19e.
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Fig. 2 Transition states during syn- and anti-aldol additions.
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b-naphthol for visualization. Column chromatography was
performed on silica gel (60–120 or 100–200 mesh) using
n-hexane and ethyl acetate as eluent. Evaporation of solvents
was conducted under reduced pressure at temperatures below
50 uC. IR spectra were recorded on Perkin–Elmer 683, Nicolet
Nexus 670 spectrometers. 1H and 13C NMR spectra were
recorded in CDCl3 solvent on 300 MHz, 400 MHz and 500 MHz
NMR spectrometers. Chemical shifts d and coupling constants
J are given in ppm (parts per million) and Hz (hertz),
respectively. Chemical shifts are reported relative to residual
1
solvent as an internal standard for H and 13C (CDCl3: d 7.26
ppm for 1H and 77.0 ppm for 13C). Mass spectra were obtained
on Finnigan MAT1020B, micromass VG 70–70H or LC/MSD
trapSL spectrometers operating at 70 eV using direct inlet
system.
Cytotoxicity evaluation against different cancer cell lines
Cellular viability was determined by MTT-microcultured
tetrazolium assay using the reported protocol with minor
modifications. Briefly, all three types of cell line were seeded to
a flat bottom 96 (10 000 cells/100 mL) well plate and cultured in
a medium containing 10% serum followed by incubation of
these cells for 24 h with a constant supply of 5% CO2 in a
humid incubator so that they adhered to the surface of the
plate. The synthesized epimer was resuspended in DMSO to
prepare stock concentrations. Different concentrations of test
compound and doxorubicin (as a standard control anti cancer
drug) were prepared in DMSO and added to achieve final
concentrations of 0 to 100 mM of compound to cells. Cells were
further allowed to grow for 48 h with a constant supply of 5%
CO2 in a humid incubator. 3-(4,5-Dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) was dissolved in PBS at 5
mg mL21 and filter sterilized MTT solution was added for
assay. After 48 h, MTT solution (10 mL per well) was added to
the culture plate. Cells were further incubated in the CO2
chamber for 2 h. Subsequently, the medium was removed and
100 mL of DMSO was added to cells. The absorbance of purple
colour obtained was measured at 562 nm in a multimode
microplate reader (Tecan GENios) is proportional to cell
growth. From the observed %age of growth with and without
test compound IC50 values were calculated. In this study, three
types of cancer cell lines, i.e. human lung cancer (A549);
human breast cancer (MCF-7) and prostate cancer (DU145) cell
lines were tested for the cytotoxic effect of the epimer
synthesized. The results presented are from three independent
experiments, each in triplicates. The calculated IC50 values ¡
standard deviation are presented in Table 2.
Scheme 6 Construction of 5-epi-torrubiellutin C (3a).
excellent stereocontrol, and it has also been proved that this
isomer is as good as the natural product in bioassays.
Experimental
General
Reactions were monitored by thin-layer chromatography
carried out on silica plates (silica gel 60 F254, Merck) using
UV-light and anisaldehyde or potassium permanganate or
Experimental details and analytical data for all the new
compounds and comparison data for the known compounds
are described below.
1-(tert-Butyldiphenylsilyloxy)-2-methylpentan-3-one (9). (a)
To a stirred solution of the silylated ester 10 (ref. 3) (17.0 g,
47.7 mmol) and N,O-dimethylhydroxylamine hydrochloride
(13.9 g, 143.2 mmol) in dry THF (200 mL) at 215 uC, was slowly
added iso-propylmagnesium chloride (12.2 g, 59.6 mL, 119.2
mmol, 2.0 M in Et2O). The reaction mixture was stirred for 1 h
at the same temperature. After completion of the reaction
(monitored by TLC), it was quenched with saturated NH4Cl
solution (80 mL) at 0 uC and diluted with EtOAc (180 mL). The
Table 2 IC50 values of 5-epi-Torrubiellutin C (3a)
IC50 value in mM
S. No Compounds
DU 145
MCF 7
A549
1
2
5-epi-Torrubiellutin 8.88 ¡ 0.05 5.58 ¡ 0.86 23.08 ¡ 2.28
C (3a)
Doxorubucin
6.30 ¡ 0.12 7.39 ¡ 0.41 6.54 ¡ 0.14
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organic layer was separated, washed with brine solution (120
mL), dried over anhydrous Na2SO4 and concentrated on a
rotary evaporator. The resultant amide 11 (16.9 g, 92%) was
used for the next step without purification.
(75 MHz, CDCl3): d 135.5, 135.4, 132.8, 132.5, 129.86, 129.80,
127.7, 79.9, 72.4, 69.4, 42.2, 36.0, 26.7, 20.9, 19.0, 12.6, 8.8; IR
(KBr): n 3403, 2963, 2931, 2859, 1467, 1427, 1109, 822, 740, 703,
611, 504 cm21; MS (ESI): m/z 401 (100) [M + H]+; HRMS (ESI):
[M + Na]+ C24H36NaO3Si: calcd. 423.2326; found, 423.2330;
[a]3D0: 273.0 (c 0.5, CHCl3).
(b) To the above crude Weinreb amide 11 (16.0 g, 41.5
mmol) dissolved in dry THF (160 mL), was slowly added
EtMgBr (16.7 g, 99.5 mL, 124.6 mmol, 2.0 M in Et2O) at 0 uC
under N2 atmosphere. The reaction mixture was stirred under
the same conditions for 1 h (reaction progress was monitored
by TLC). Then, it was quenched with aq. saturated NH4Cl
solution (70 mL), diluted with EtOAc (150 mL), the organic
layer was separated and the aqueous layer was washed with
EtOAc (2 6 80 mL). The combined organic layers were washed
with brine (90 mL), dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (2% EtOAc in hexanes) to afford the ethyl
ketone 9 (13.9 g, 95%) as a colourless liquid.
(2S,3R,4R,5S)-5-(Benzyloxy-1-(tert-butyldiphenylsilyloxy)-2,4-
dimethylhexan-3-ol (13). Diol 8 (11.0 g, 27.5 mmol) in dry THF
(50 mL) was slowly added to a stirred suspension of NaH (1.6 g,
41.2 mmol, 60% w/v in dispersion mineral oil) in dry THF (120
mL) at 0 uC under a nitrogen atmosphere. The reaction
mixture was stirred at the same temperature for 20 min and
benzyl bromide (5.6 g, 33.0 mmol) followed by TBAI (50 mg)
were added. The reaction was maintained at 0 uC for 6 h. After
completion of the reaction (monitored by TLC), it was
quenched with saturated NH4Cl solution (50 mL). The reaction
mass was diluted with EtOAc (120 mL) and stirred for 10 min.
The organic layer was separated and the aqueous layer was
extracted with EtOAc (2 6 60 mL). The combined organic
layers were washed with brine (80 mL), dried over Na2SO4 and
concentrated on a rotary evaporator. The crude product was
chromatographed over silica gel (8–10% EtOAc/petroleum
ether) to provide the monobenzylated compound 13 (11.9 g,
89%) as a colourless liquid.
1H NMR (400 MHz, CDCl3): d 7.66–7.58 (m, 4H), 7.45–7.33
(m, 6H), 3.79 (dd, J = 7.3, 9.5 Hz, 1H), 3.62 (dd, J = 5.9, 9.5 Hz,
1H), 2.85–2.75 (m, 1H), 2.61–2.43 (m, 2H), 1.01 (t, J = 7.3 Hz,
3H), 1.03 (s, 9H), 1.01 (d, J = 6.6, 3H); 13C NMR (75 MHz,
CDCl3): d 214.0, 135.5, 133.3, 133.1, 129.6, 127.6, 66.3, 48.1,
35.7, 26.6, 19.1, 13.0, 7.4; IR (KBr): n 2934, 2860, 1715, 1466,
1428, 1386, 1110, 1087, 821, 740, 704 cm21; MS (ESI): m/z 377
(100) [M + Na]+; HRMS (ESI): [M + Na]+ C22H30NNaO2Si: calcd.
377.1907; found, 377.1928; [a]3D0: +31.3 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d 7.70–7.59 (m, 4H), 7.43–7.17
(m, 11H), 4.57 (d, J = 11.7 Hz, 1H), 4.47 (d, J = 11.4 Hz, 1H),
3.83–3.74 (m, 1H), 3.72–3.63 (m, 3H), 3.34 (bs, 1H), 1.95–1.83
(m, 1H), 1.80–1.70 (m, 1H), 1.18 (d, J = 6.2 Hz, 3H), 1.06 (s, 9H),
0.88 (d, J = 6.7 Hz, 3H), 0.76 (d, J = 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3): d 135.6, 135.5, 134.7, 129.6, 128.3, 127.6, 127.5,
127.4, 77.8, 75.3, 70.5, 68.5, 40.1, 36.6, 26.8, 19.1, 15.2, 10.9,
8.7; IR (KBr): n 3484, 2961, 2930, 2857, 1467, 1427, 1383, 1109,
822, 739, 702, 610, 504 cm21; MS (ESI): m/z 513 (100) [M + H]+;
HRMS (ESI): [M + Na]+ C31H42NaO3Si: calcd. 513.2795; found,
513.2813; [a]3D1: 220.5 (c 1.0, CHCl3).
(5R,6S)-5-((2S,3S)-3-(Benzyloxy)butan-2-yl)-2,2,3,3,6,10,10-
heptamethyl-9,9-diphenyl-4,8-dioxa-3,9-disilaundecane (14).
To a stirred solution of compound 13 (10.0 g, 20.4 mmol) in
CH2Cl2 (90 mL), was added 2,6-lutidine (5.4 g, 51.0 mmol) at
278 uC under N2 atmosphere. After stirring for 5 min, TBSOTf
(8.0 g, 30.6 mmol) was added to the above reaction mixture at
278 uC. The reaction temperature was raised to 220 uC and
stirred for 1 h. After completion of the reaction monitored by
TLC, it was diluted with water (60 mL), the organic layer was
separated and the aqueous layer was extracted with CH2Cl2 (2
6 50 mL). The combined organic layers were washed with
brine (80 mL), dried over anhydrous Na2SO4 and concentrated
in vacuo. The crude product was purified by column
chromatography (2% EtOAc/petroleum ether) to afford dis-
ilylated compound 14 (11.2 g, 94%) as a colourless oily liquid.
1H NMR (300 MHz, CDCl3): d 7.80–7.71 (m, 4H), 7.55–7.42
(m, 6H), 7.41–7.30 (m, 5H), 4.55 (dd, J = 11.9, 25.8 Hz, 2H), 3.90
(d, J = 7.7 Hz, 1H), 3.82–3.72 (m, 1H), 3.65 (t, J = 9.8 Hz, 1H),
3.52 (t, J = 7.1 Hz, 1H), 2.14–2.04 (m, 1H), 2.01–1.90 (m, 1H),
1.26–1.12 (m, 12H), 1.03–0.86 (m, 15H), 0.08 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 139.2, 135.5, 133.9, 129.4, 128.2, 127.5,
127.3, 127.1, 75.0, 72.4, 70.0, 66.9, 41.5, 38.2, 26.8, 26.1, 19.1,
18.4, 14.9, 10.4, 10.1, 23.9, 24.1; IR (KBr): n 3067, 2956, 2932,
(2S,3S,4R,5S)-6-(tert-Butyldiphenylsilyloxy)-3,5-dimethylhex-
ane-2,4-diol (8). To a stirred solution of dicyclohexylboron
chloride (11.5 g, 54.1 mL, 54.2 mmol, 1.0 M in diethyl ether) in
anhydrous Et2O (80 mL) at 0 uC under inert conditions, was
added Et3N (6.1 g, 8.8 mL, 61.0 mmol) followed by ethyl ketone
9 (12.0 g, 33.8 mmol) in diethyl ether (80 mL). After stirring for
2 h at 0 uC, the reaction mixture was cooled to 278 uC and
acetaldehyde (5.4 mL, 84.7 mmol) was added. The reaction was
maintained for 3 h at the same temperature. The reaction
mass was kept at 220 uC for 20 h. Then, the reaction
temperature was re-cooled to 278 uC, LiBH4 (3.7 g, 169.4
mmol, 84.5 mL, 2.0 M in THF) was added and the mixture was
stirred for 3 h. The temperature was raised to 0 uC and
quenched with aq. saturated NH4Cl solution (70 mL). The
mixture was diluted with diethyl ether (100 mL), and the
organic layer was separated and concentrated on a rotary
evaporator. The resultant residue was dissolved in MeOH (140
mL) and cooled to 0 uC. NaOH (90 mL, 10%) and followed by
H2O2 (31 mL, 30%) were added dropwise. After stirring for 3 h
at room temperature, the reaction mixture was diluted with
dichloromethane (200 mL). The organic layer was separated
and the aqueous layer was extracted with dichloromethane (2
6 100 mL). The combined organic layers were washed with
brine (120 mL), dried over Na2SO4 and concentrated under
reduced pressure to afford the crude compound in a 98 : 2
diasteriomeric ratio. This was chromatographed (the minor
isomer was separated) over silica gel (25% EtOAc/petroleum
ether) to provide the pure diol 8 (11.6 g, 86%) as a colourless
liquid.
1H NMR (300 MHz, CDCl3): d 7.73–7.60 (m, 4H), 7.53–7.33
(m, 6H), 3.92–3.71 (m, 3H), 3.69 (dd, J = 4.6, 9.8 Hz, 1H), 1.85–
1.74 (m, 1H), 1.67–1.52 (m, 1H), 1.19 (d, J = 6.0 Hz, 3H), 1.07 (s,
9H), 0.98 (d, J = 6.9 Hz, 3H), 0.71 (d, J = 6.6 Hz, 3H); 13C NMR
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2859, 1465, 1383, 1254, 1107, 832, 773, 737, 701, 613, 502
cm21; MS (ESI): m/z 627 (100) [M + Na]+; HRMS (ESI): [M + Na]+
C38H56NaO4Si: calcd. 627.3840; found, 627.3830; [a]3D0: 210.5 (c
1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d 7.33–7.18 (m, 5H), 5.76 (d, J =
10.1 Hz, 1H), 4.53 (d, J = 11.8 Hz, 1H), 4.36 (d, J = 11.9, 1H),
4.19–4.09 (m, 2H), 3.73 (dd, J = 4.7, 6.1 Hz, 1H), 3.62–3.54 (m,
1H), 1.97–1.86 (m, 1H), 1.84 (s, 3H), 1.29 (t, J = 6.9 Hz, 3H), 1.10
(d, J = 6.0 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 0.92–0.86 (m, 12H),
0.02 (s, 3H), 20.02 (s, 3H); 13C NMR (75 MHz, CDCl3): d 167.9,
147.0, 146.0, 139.3, 128.2, 127.1, 125.1, 76.1, 75.3, 69.8, 60.0,
43.0, 35.7, 26.1, 20.8, 18.3, 15.7, 14.2, 10.0, 23.9, 24.1; IR
(KBr): n 3448, 2957, 2930, 2858, 1713, 1626, 1452, 1376, 1256,
1216, 1172, 1133, 1086, 1029, 835, 772, 697 cm21; MS (ESI): m/z
449 (100) [M + H]+; HRMS (ESI): [M + Na]+ C26H44NaO4Si: calcd.
471.2901; found, 471.2896. [a]3D0: +10.5 (c 1.0, CHCl3).
(4S,5R,6S,7S,Z)-7-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-
2,4,6-trimethyl-oct-2-en-1-ol (17). DIBAL-H (2.21 g, 11.0 mL,
15.6 mmol, 20% in hexanes) was slowly added to a stirred
solution of a,b-unsaturated cis-ester 16 (3.5 g, 7.8 mmol) in
anhydrous dichloromethane (30 mL) at 278 uC under N2
atmosphere. The reaction temperature was slowly raised to 0
uC and stirred for 1.5 h and then 20% aq. solution of sodium
potassium tartarate (5 mL) was added. Then, it was diluted
with CH2Cl2 (60 mL) and allowed to stir at room temperature
for clear separation of the layers. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2 (2
6 30 mL). The combined organic layers were washed with
brine (50 mL), dried over anhydrous Na2SO4 and concentrated
in vacuo. The crude material was chromatographed over silica
gel (8% EtOAc/petroleum ether) to give the allyl alcohol 17 (3.0
g, 95%) as a pale yellow liquid.
(2S,3R,4R,5S)-5-(Benzyloxy-3-(tert-butyldimethylsilyloxy)-2,4-
dimethylhexan-1-ol (15). NH4F (11.0 g, 297.0 mmol) was added
to disilylated compound 14 (9.0 g, 14.8 mmol) dissolved in
methanol (120 mL). The reaction mixture was stirred at room
temperature for 48 h. After completion of the reaction
(reaction progress was monitored by TLC), it was quenched
with saturated NH4Cl solution (20 mL). The solvent was
removed under reduced pressure. The resultant crude product
was dissolved in EtOAc (120 mL). The organic layer was
washed with water (80 mL), brine (80 mL), dried over
anhydrous Na2SO4, and the solvent was removed under
reduced pressure. The resultant crude was chromatographed
over silica gel (7–8% EtOAc/petroleum ether) to give the
alcohol 15 (4.9 g, 88%) as a colourless gummy liquid.
1H NMR (300 MHz, CDCl3): d 7.37–7.24 (m, 5H), 4.56 (d, J =
11.8 Hz, 1H), 4.43 (d, J = 11.7 Hz, 1H), 3.87 (dd, J = 2.1, 6.6 Hz,
1H), 3.70–3.61 (m, 1H), 3.52–3.39 (m, 2H), 2.07–1.95 (m, 1H),
1.88–1.76 (m, 1H), 1.15 (d, J = 6.0 Hz, 3H), 0.92–0.83 (m, 15H),
0.06 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3): d 138.9,
128.2, 127.4, 127.3, 75.6, 72.8, 69.9, 66.4, 42.5, 38.2, 26.0, 18.2,
15.7, 11.3, 11.0, 24.0, 24.3; IR (KBr): n 3448, 2956, 2931, 2886,
2858, 1625, 1458, 1377, 1255, 1131, 1091, 1028, 836, 773, 697
cm21; MS (ESI): m/z 367 (100) [M + H]+; HRMS (ESI): [M + H]+
C21H39O3Si: calcd. 367.2663; found, 367.2662; [a]3D1: +18.5 (c
1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d 7.39–7.20 (m, 5H), 5.02 (d, J =
10.1 Hz, 1H), 4.56 (d, J = 11.3 Hz, 1H), 4.41 (d, J = 11.3 Hz, 1H),
3.89 (d, J = 11.8 Hz, 1H), 3.73–3.62 (m, 2H), 3.50–3.43 (m, 1H),
2.88–2.76 (m, 1H), 2.00–1.85 (m, 1H), 1.73 (s, 3H), 1.11 (d, J =
6.0 Hz, 3H), 0.98–0.82 (m, 15H), 0.07 (s, 3H), 0.04 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 138.6, 133.2, 132.8, 128.2, 127.9,
127.4, 79.4, 76.4, 70.6, 61.2, 42.3, 36.3, 26.2, 21.8, 18.5, 17.9,
16.9, 13.6, 23.5, 23.9; IR (KBr): n 3426, 2959, 2932, 2858, 1457,
1379, 1254, 1083, 1059, 1030, 835, 773, 736 cm21; MS (ESI): m/z
429 (100) [M + Na]+; HRMS (ESI) : [M + Na]+ C24H42NaO3Si:
calcd. 429.2795; found, 429.2817; [a]3D0: 215.3 (c 0.75, CHCl3).
(4S,5R,6S,7S,Z)-7-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-
2,4,6-trimethyloct-2-enal (7). To a solution of allyl alcohol 17
(2.8 g, 6.8 mmol) in anhydrous dichloromethane (40 mL), was
charged a half-portion of freshly prepared MnO2 (2.96 g, 34.0
mmol) under N2 atmosphere. The reaction mixture was stirred
for 15 h at room temperature. At this time, another half-
portion of MnO2 (2.96 g, 34.0 mmol) was charged and the
stirring was continued for 13 h. After completion of the
reaction (monitored by TLC), the solids were filtered through a
pad of Celite1 and washed with CH2Cl2 (100 mL). The filtrate
was reduced on a rotary evaporator and the crude material was
chromatographed over silica gel (5% EtOAc/petroleum ether)
to afford an a,b-unsaturated cis-aldehyde 7 (2.73 g, 98%) as a
pale yellow liquid.
(4S,5R,6S,7S,Z)-Ethyl-7-(benzyloxy)-5-(tert-butyldimethylsily-
loxy)-2,4,6-tri-methyloct-2-enoate (16). (a) To a stirred solution
of IBX (4.6 g, 16.3 mmol) in DMSO (7.0 mL) under N2
atmosphere, was added alcohol 15 (4.0 g, 10.9 mmol) in
anhydrous THF (35 mL) at room temperature. The reaction
mixture was stirred for 1 h and diluted with Et2O (70 mL). The
solids were removed through a pad of Celite1. The filtrate was
washed with saturated aq. NaHCO3 (3 6 50 mL) and dried
over anhydrous Na2SO4. The solvent was reduced in vacuo to
obtain the crude aldehyde (3.85 g, 97%) which was used
directly for the next reaction without further purification.
(b) K2CO3 (8.7 g, 62.6 mmol) and 18-crown-6 (33.0 g, 125.2
mmol) were charged into a 250 mL flask containing 75 mL of
anhydrous toluene under N2 atmosphere. The reaction
mixture was stirred at room temperature for 3 h before cooling
to 0 uC. Ethyl-2-(bis(perfluoroethoxy)-phosphoryl)propanoate
(4.3 g, 12.5 mmol) in toluene (20 mL) and the above aldehyde
(3.8 g, 10.4 mmol) in toluene (20 mL) were then slowly added
to the reaction mixture at 0 uC. The reaction was maintained at
the same temperature for 3 h. After complete consumption of
the starting material (the reaction progress was monitored by
TLC), it was quenched with saturated NH4Cl solution (30 mL).
The organic layer was separated and the aqueous layer was
extracted with EtOAc (2 6 40 mL). The combined organic
layers were washed with brine (60 mL), dried over anhydrous
Na2SO4 and concentrated in vacuo. The compound was
purified by column chromatography (3% EtOAc/petroleum
ether) to afford an a,b-unsaturated cis-ester 16 (4.0 g, 86%, no
other isomer detected) as a colourless liquid.
1H NMR (500 MHz, CDCl3): d 10.02 (s, 1H), 7.35–7.27 (m,
5H), 6.26 (d, J = 9.6 Hz, 1H), 4.58 (d, J = 11.5 Hz, 1H), 4.30 (d, J =
11.5 Hz, 1H), 3.77 (t, J = 5.7 Hz, 1H), 3.51–3.40 (m, 2H), 1.94–
1.88 (m, 1H), 1.70 (s, 3H), 1.12 (d, J = 5.7 Hz, 3H), 1.04 (d, J =
6.7 Hz, 3H), 0.94–0.86 (m, 12H), 0.05 (s, 3H), 0.04 (s, 3H); 13C
15922 | RSC Adv., 2013, 3, 15917–15927
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NMR (75 MHz, CDCl3): d 191.3, 153.6, 139.0, 133.7, 128.3,
127.3, 127.2, 76.3, 75.6, 69.8, 44.2, 33.9, 29.6, 26.0, 22.6, 16.4,
14.0, 11.1, 23.9, 24.2; IR (KBr): n 2927, 2856, 1741, 1681, 1459,
1378, 1255, 1084, 1030, 835, 774, 735 cm21; MS (ESI): m/z 427
(100) [M + Na]+; HRMS (ESI): [M + Na]+ C24H40NaO3Si: calcd.
427.2639; found, 427.2658; [a]3D0: +16.5 (c 1.0, CHCl3).
(2R,3R,6S,7R,8S,9S,Z)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-
yl)-9-(benzyloxy)-(7-tert-butyldimethylsilyloxy-3-hydroxy-
2,4,6,8-tetramethyldec-4-en-1-one (19e). In a 50 mL round-
bottom flask was dissolved N-propanoyl thiazolidinethione
dichloromethane (2 6 40 mL). The combined organic layers
were washed with brine (50 mL), dried over anhydrous Na2SO4
and concentrated in vacuo. The crude product was purified by
column chromatography (7% EtOAc/petroleum ether) to afford
the MOM ether 20 (2.97 g, 93%) as a yellowish gummy liquid.
1H NMR (300 MHz, CDCl3): d 7.37–7.16 (m, 10H), 5.50–5.25
(m, 3H), 4.75 (d, J = 9.8 Hz, 1H), 4.58 (d, J = 6.7 Hz, 1H), 4.51–
4.47 (m, 2H), 4.42 (d, J = 6.2 Hz, 1H), 3.82–3.77 (m, 1H), 3.48–
3.43 (m, 1H), 3.36 (s, 3H), 3.34–3.25 (m, 1H), 3.03–2.95 (m, 3H),
2.79 (d, J = 11.3 Hz, 1H), 2.11–1.98 (m, 1H), 1.63 (s, 3H), 1.34
(d, J = 6.7 Hz, 3H), 1.05 (d, J = 6.0 Hz, 3H), 0.96 (d, J = 6.7 Hz,
3H), 0.92 (d, J = 6.0 Hz, 3H), 0.84 (s, 9H), 20.03 (s, 3H), 20.13
(s, 3H); 13C NMR (75 MHz, CDCl3): d 201.0, 175.0, 139.5, 139.4,
136.4, 129.3, 128.9, 128.8, 128.2, 127.3, 127.2, 127.1, 92.4, 74.3,
73.4, 69.9, 68.5, 55.2, 41.4, 40.4, 37.1, 33.3, 30.6, 29.6, 26.2,
18.5, 18.2, 15.7, 13.9, 12.1, 9.5, 23.2, 23.7; IR (KBr): n 2928,
2855, 1694, 1455, 1346, 1254, 1135, 1097, 1062, 1030, 834, 771,
741, 701 cm21; MS (ESI): m/z 736 (100) [M + Na]+; HRMS (ESI):
[M + Na]+ C39H59NO5S2SiNa: calcd. 736.3496; found, 736.3435;
[a]3D0: 214.5 (c 0.5, CHCl3).
[(S)-1-(4-benzyl-2-thioxothiazolidin-3-yl)-propan-1-one]
18e
(1.63g, 6.1 mmol) in 30 mL of anhydrous dichloromethane
(CH2Cl2). TiCl4 (1.17 g, 3.0 mL, 6.1 mmol, 2.0 M in CH2Cl2) was
added to the above bright yellow solution which had been
previously cooled down to 0 uC and the suspension was stirred
at the same temperature for 15 min. To this resulting
homogeneous orange solution was added (2)-sparteine (1.44
g, 6.1 mmol) at 0 uC. The brick-red solution was stirred at the
same temperature for 30 min. This titanium enolate solution
was re-cooled to 278 uC and aldehyde 7 (2.5 g, 6.1 mmol) in
CH2Cl2 (15 mL) was added dropwise with rapid stirring. After
stirring for 2 h, the reaction mixture was quenched by pouring
into 15 mL of saturated aq. NH4Cl solution. The organic layer
was separated and aqueous portion was extracted with CH2Cl2
(3 6 25 mL). The combined organic layers were washed with
brine solution (30 mL), dried over Na2SO4 and concentrated in
vacuo. The diastereomeric ratio (97 : 3) was determined by
HPLC (using a Waters HR C18 column and acetonitrile–water
as eluent). The mixture of the two diastereomers were slowly
separated by column chromatography (10% EtOAc/hexanes)
and the major isomer 19e (3.4 g, 84%) was afforded in pure
form as a yellow gummy liquid.
(2R,3R,6S,7R,8S,9S,Z)-9-(Benzyloxy)-7-(tert-butyldimethyl-
silyloxy)-3-(methoxymethoxy)-2,4,6,8-tetramethyldec-4-en-1-ol
(21). To a stirred solution of MOM protected aldol adduct 20
(2.8 g, 3.92 mmol) in a 30 mL mixture of Et2O : MeOH (1 : 1
ratio), was added lithium borohydride (172 mg, 7.84 mmol) in
portions at 0 uC. The reaction mixture was allowed to stir for 2
h at room temperature. After completion of the reaction
(monitored by TLC), it was acidified with saturated aq.
NaHSO4 solution (pH y 5). The reaction mixture was extracted
with CH2Cl2 (60 mL), the combined organic layers were
washed with brine (50 mL), dried over anhydrous Na2SO4 and
concentrated in vacuo. The crude residue was chromato-
graphed over silica gel (12% EtOAc/petroleum ether) to give
the alcohol 21 (1.8 g, 90%) as a colourless gummy liquid.
1H NMR (300 MHz, CDCl3): d 7.35–7.18 (m, 5H), 5.45 (d, J =
9.8 Hz, 1H), 4.55–4.39 (m, 4H), 4.31 (d, J = 8.3 Hz, 1H), 3.77–
3.67 (m, 1H), 3.53–3.44 (m, 2H), 3.40–3.31 (m, 4H), 2.78–2.66
(m, 1H), 2.00–1.82 (m, 1H), 1.62 (s, 3H), 1.05 (d, J = 5.3 Hz, 3H),
1.03 (d, J = 6.0 Hz, 3H), 0.92–0.88 (m, 12H), 0.86 (d, J = 6.7 Hz,
3H), 0.02 (s, 3H), 20.07 (s, 3H); 13C NMR (75 MHz, CDCl3): d
137.51, 137.50, 131.0, 128.2, 127.3, 127.2, 93.0, 77.4, 75.0, 74.7,
69.9, 65.5, 55.3, 41.3, 38.6, 33.4, 26.2, 18.5, 14.5, 13.7, 10.11,
10.10, 23.5, 23.7; IR (KBr): n 3449, 3307, 2930, 2856, 1625,
1H NMR (300 MHz, CDCl3): d 7.43–7.15 (m, 10H), 5.36–5.23
(m, 1H), 4.97–4.82 (m, 1H), 4.60–4.36 (m, 3H), 3.77–3.64 (m,
1H), 3.45–3.39 (m, 1H), 3.28 (dd, J = 7.3, 11.3 Hz, 1H), 3.13–
2.88 (m, 3H), 2.78 (d, J = 11.3 Hz, 1H), 2.06–1.88 (m, 1H), 1.62
(s, 3H), 1.14 (d, J = 6.0 Hz, 3H), 1.05–0.81 (m, 18H), 0.10 (s, 3H),
0.06 (s, 3H); 13C NMR (75 MHz, CDCl3): d 200.7, 176.3, 138.5,
136.5, 133.7, 133.4, 129,3, 128.8, 128.3, 128.2, 127.5, 127.1,
80.7, 71.0, 70.0, 68.5, 42.2, 42.1, 36.89, 36.80, 30.9, 29.6, 26.3,
19.2, 18.5, 17.9, 17.4, 15.0, 14.4, 23.3, 23.8; IR (KBr): n 3449,
3307, 2929, 2855, 1694, 1626, 1580, 1451, 1375, 1354, 1258,
1171, 1133, 836, 772, 700 cm21; MS (ESI): m/z 692 (100) [M +
Na]+; HRMS (ESI): [M
+
Na]+ C37H55NNaO4S2Si: calcd.
1581, 1450, 1375, 1259, 1170, 1134, 1030, 836, 770, 698 cm21
;
692.3234; found, 692.3261; [a]3D0: 22.5 (c 0.5, CHCl3).
MS (ESI): m/z 531 (100) [M + Na]+; HRMS (ESI): [M + Na]+
C29H52O5SiNa: calcd. 531.3476; found, 531.3412; [a]3D0: +45.0 (c
1.0, CHCl3).
(2R,3R,6S,7R,8S,9S,Z)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-
yl)-9-(benzyloxy)-(7-tert-butyldimethylsilyloxy-3-(methoxy-
methoxy)-2,4,6,8-tetramethyldec-4-en-1-one (20). To a stirred
solution of syn-aldol compound 19e (3.0 g, 4.47 mmol) in
CH2Cl2 (40 mL), was added di-isopropylethylamine (DIPEA)
(1.73 g, 2.4 mL, 13.4 mmol) at 0 uC. After stirring for 15 min, it
was treated with methoxymethyl chloride (MOMCl) (0.7 g, 8.9
mmol) at the same temperature. The reaction suspension was
stirred at room temperature under N2 atmosphere for 12 h.
After complete consumption of the starting material (reaction
progress was monitored by TLC), it was quenched with
saturated aq. NaHCO3 solution (20 mL). The organic layer
was layer separated and aqueous layer was extracted with
(5R,8S,9R,Z)-9-((2S,3S)-3-(Benzyloxy)butan-2-yl)-5-((S)-but-3-
en-2-yl)-6,8,11,11,12,12-hexamethyl-2,4,10-trioxa-11-silatridec-
6-ene (22). (a) To a stirred solution of IBX (1.41 g, 5.01 mmol)
in DMSO (2.5 mL) under N2 atmosphere was added alcohol 21
(1.7 g, 3.3 mmol) in anhydrous THF (10 mL) at room
temperature. The reaction mixture was stirred for 45 min at
the same temperature and diluted with Et2O (20 mL). The
solids were filtered through a Celite1 pad, the filtrate was
washed with saturated aq. NaHCO3 solution (2 6 20 mL) and
dried over anhydrous Na2SO4. The solvent was reduced in
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437 (100) [M + Na]+; HRMS (ESI): [M + Na]+ C23H46NaO4Si:
calcd.437.3058; found, 437.3038; [a]3D0: +51.5 (c 1.0, CHCl3).
(S)-(2S,3S,4R,5S,8R,9S,Z)-4-(tert-Butyldimethylsilyloxy)-8-
(methoxymethoxy)-3,5,7,9-tetramethylundeca-6,10-dien-2-yl)-2-
(tert-butoxycarbonyl(methyl)amino)-3-phenylpropanoate (23).
To a suspension of Boc-N-Me-L-phenylalanine 5 (1.0 g, 3.86
mmol) and DCC (0.73 g, 3.86 mmol) in anhydrous dichlor-
omethane (7 mL) was added DMAP (43 mg, 0.386 mmol) at 0
uC. The reaction mixture was stirred at 0 uC for 10 min and
alcohol 6a (0.8 g, 1.93 mmol) in CH2Cl2 (3.0 mL) was added
slowly to the above reaction mixture. The reaction was
maintained for 1 h at 0 uC and another 2 h at room
temperature. Upon completion of the reaction (monitored by
TLC), H2O (5 mL) was added and stirred for 10 min. The
reaction mixture was diluted with a 20 mL mixture of CH2Cl2/
hexanes (1 : 2 ratio) and cooled to 0 uC. The resulting white
precipitate was filtered off and washed with CH2Cl2/hexanes
(1 : 2 ratio, 20 mL). The filtrate was washed with saturated aq.
NaHCO3 solution (20 mL), washed with brine solution (20 mL),
dried over Na2SO4 and concentrated on a rotary evaporator.
The crude product was chromatographed over silica gel (6%
EtOAc/petroleum ether) to afford the desired ester 23 (1.14 g,
88%) as a colourless gummy liquid. The NMR spectra of this
compound showed a mixture of rotamers (60 : 40 ratio).
1H NMR (300 MHz, CDCl3): d 7.33–7.13 (m, 5H), 5.68–5.53
(m, 1H), 5.39 (d, J = 10.5 Hz, 1H), 5.29–5.13 (m, 1H), 5.07–4.91
(m, 2H), 4.59 (d, J = 6.8 Hz, 1H), 4.45 (d, J = 6.8 Hz, 1H), 4.08 (d,
J = 9.8 Hz, 1H), 3.48–3.39 (m, 1H), 3.34 (s, 3H), 3.28 (dd, J = 6.0,
15.8 Hz, 1H), 3.09–2.93 (m, 2H), 2.78–2.68 (m, (NMe) 3H),
2.66–2.52 (m, 1H), 2.48–2.35 (m, 1H), 1.92–1.78 (m, 1H), 1.60
(s, 3H), 1.40–1.30 (m, (Boc protons) 9H), 1.19–1.07 (m, 6H),
0.93 (s, 9H), 0.88–0.81 (m, 6H), 0.09 (s, 3H), 0.04 (s, 3H); 13C
NMR (75 MHz, CDCl3): ‘‘M’’ for major rotamer and ‘‘m’’ for
minor rotamer, d 170.4 (m), 170.1 (M), 155.6 (m), 155.1 (M),
140.0, 137.8 (M), 137.7 (m), 136.0, 130.7, 128.9, 128.4 (M),
128.3 (m), 126.5 (M), 126.3 (m), 114.1, 92.7, 80.1, 79.6, 77.1,
72.5, 61.4 (M), 59.9 (m), 55.1, 42.1 (M), 41.9 (m), 40.3, 35.2 (M),
35.0 (m), 33.1, 32.1 (m), 31.9 (M), 29.6, 28.2, 26.2, 18.5 (m), 17.8
(M), 16.8, 14.6 (m), 14.4 (M), 14.09 (M), 14.00 (m), 10.0, 23.5,
23.8; IR (KBr): n 2958, 2928, 1732, 1701, 1457, 1388, 1368,
1263, 1141, 1035, 837, 772, 745 cm21; MS (ESI): m/z 698 (100)
[M + Na]+; HRMS (ESI): [M + Na]+ C38H65NNaO7Si: calcd.
698.4423; found, 698.4392; [a]3D0: +10.5 (c 1.0, CHCl3).
vacuo to obtain the aldehyde (1.62 g, 96%), which was directly
used for the next reaction without purification.
(b) To a 50 mL, two necked round-bottom flask, PPh3MeI
(3.56 g, 8.89 mmol) and KOtBu (0.83 g, 7.41 mmol) followed by
20 mL of anhydrous THF were charged and cooled to 0 uC
under nitrogen atmosphere. After stirring for 1 h at the same
temperature, the above aldehyde (1.5 g, 2.96 mmol) in 10 mL
of dry THF was added dropwise. The reaction mixture was left
at 0 uC for 15 min. Then, it was quenched by adding saturated
aq. NH4Cl solution (10 mL) and diluted with EtOAc (30 mL).
The organic layer was separated and the aqueous portion was
extracted with EtOAc (2 6 10 mL). The combined organic
layers were washed with brine solution (30 mL), dried over
Na2SO4 and concentrated on a rotary evaporator. The crude
residue was chromatographed over silica gel (3% EtOAc/
petroleum ether) to give the olefin 22 (1.31 g, 92%) as a
colourless liquid.
1H NMR (300 MHz, CDCl3): d 7.43–7.26 (m, 5H), 5.72–5.58
(m, 1H), 5.49 (d, J = 10.9 Hz, 1H), 5.12–4.97 (m, 2H), 4.63 (d, J =
6.6 Hz, 1H), 4.56 (q, J = 12.2, 17.7 Hz, 2H), 4.48 (d, J = 6.6 Hz,
1H), 4.15 (d, J = 9.6 Hz, 1H), 3.86–3.78 (m, 1H), 3.55 (dd, J = 2.7,
8.3 Hz, 1H), 3.42 (s, 3H), 2.79–2.66 (m, 1H), 2.54–2.40 (m, 1H),
2.12–1.97 (m, 1H), 1.66 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H), 1.13 (d,
J = 6.4 Hz, 3H), 1.02–0.88 (m, 15H), 0.10 (s, 6H); 13C NMR (75
MHz, CDCl3): d 140.0, 137.2, 128.9, 128.2, 128.1, 127.3, 127.1,
114.0, 92.7, 82.3, 74.5, 72.2, 69.9, 55.1, 41.1, 40.3, 33.2, 26.2,
17.8, 16.8, 14.3, 13.2, 10.3, 9.9, 23.4, 23.7; IR (KBr): n 3429,
2931, 1640, 1458, 1376, 1253, 1095, 1033, 835, 771, 735 cm21
;
MS (ESI): m/z 527 (100) [M + Na]+; HRMS (ESI): [M + Na]+
C30H52NaO4Si: calcd. 527.3527; found, 527.3484; [a]3D0: +49.1 (c
1.0, CHCl3).
(2S,3S,4R,5S,8R,9S,Z)-4-(tert-Butyldimethylsilyloxy)-8-(meth-
oxymethoxy)-3,5,7,9-tetramethylundeca-6, 10-dien-2-ol (6a).
Lithium metal (166 mg, 23.8 mmol) was added in portions
to a solution of naphthalene (3.65 g, 28.5 mmol) suspended in
anhydrous THF (20 mL) under N2 atmosphere. The mixture
was stirred at room temperature for 2 h and the resulting dark
green mixture was cooled to 220 uC. Then, benzylated
compound 22 (1.2 g, 2.38 mmol) in dry THF (10 mL) was
added dropwise to the above generated naphthalide solution
at 220 uC. The reaction mixture was stirred at the same
temperature for 15 min. Then, it was quenched with saturated
aq. NH4Cl solution (10 mL) and diluted with Et2O (40 mL). The
organic layer was separated and the aqueous layer was
extracted with Et2O (2 6 15 mL). The combined organic
layers were dried over anhydrous Na2SO4 and removed under
reduced pressure. The crude was purified by column chroma-
tography (6% EtOAc/petroleum ether) to afford the key alcohol
6a (0.926 g, 94%) as a colourless gummy liquid.
(S)-(2S,3R,4R,5S,8R,9S,Z)-4-Hydroxy-8-(methoxymethoxy)-
3,5,7,9-tetramethyl-undeca-6,10-dien-2-yl)-2-(tert-butoxycarbo-
nyl(methyl)amino)-3-phenylpropanoate (24). Tetra-n-butylam-
monium fluoride (TBAF) (0.77 g, 3.0 mL, 1 M in THF, 2.96
mmol) was slowly added to the silylated ester 23 (1.0 g, 1.48
mmol) dissolved in anhydrous THF (10 mL) at 25 uC. The
reaction mixture was allowed to stir for 48 h at the same
temperature (25 uC). Upon completion of the reaction
(monitored by TLC), it was quenched with saturated aq.
NH4Cl solution (5 mL). The reaction mixture was charged with
EtOAc (10 mL), the organic layer was separated and aqueous
layer was extracted with EtOAc (2 6 5 mL). The combined
organic layers were dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude compound
was subjected to silica gel column chromatography (12%
1H NMR (300 MHz, CDCl3): d 5.65–5.50 (m, 1H), 5.43 (d, J =
9.8 Hz, 1H), 5.06–4.91 (m, 2H), 4.61 (d, J = 6.8 Hz, 1H), 4.44 (d,
J = 6.8 Hz, 1H), 4.09 (d, J = 9.8 Hz, 1H), 3.71–3.49 (m, 2H), 3.38
(s, 3H), 2.71–2.57 (m, 1H), 2.50–2.36 (m, 1H), 1.59 (s, 3H), 1.17
(d, J = 6.0 Hz, 3H), 1.13 (d, J = 6.0 Hz, 3H), 0.94 (s, 9H), 0.90 (d, J
= 6.8 Hz, 3H), 0.85 (d, J = 7.5 Hz, 3H), 0.08 (s, 3H), 0.07 (s, 3H);
13C NMR (75 MHz, CDCl3): d 140.0, 137.0, 129.6, 114.2, 92.5,
79.0, 76.5, 69.0, 55.3, 45.6, 40.2, 34.8, 29.6, 26.1, 20.9, 17.8,
16.8, 15.3, 14.1, 23.7, 24.2; IR (KBr): n 3681, 2959, 2931, 1464,
1378, 1253, 1095, 1034, 950, 914, 834, 773 cm21; MS (ESI): m/z
15924 | RSC Adv., 2013, 3, 15917–15927
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EtOAc/hexanes) to afford the alcoholic ester 24 (0.756 g, 91%)
as a colourless liquid. The NMR spectra of this compound
showed a mixture of rotamers (55 : 45 ratio).
nyl propanoate (4a). The stirred solution of Boc-protected ester 25
(0.5g, 0.82 mmol) in anhydrous CH2Cl2 (8 mL) at 0 uC under N2
atmosphere, was treated with CF3COOH (2 mL). The reaction
temperature was raised to 25–30 uC and maintained for 1 h. The
solvent and TFA were removed under reduced pressure. The
resultant salt was dissolved in anhydrous dichloromethane (6 mL)
and treated with triethylamine (167 mg, 0.24 mL, 1.65 mmol) at
210 uC. After stirring for 5 min, acryloyl chloride (110 mg, 0.11 mL,
1.24 mmol) was added dropwise at 210 uC. The reaction was
maintained at the same temperature for 15 min. After completion
of the reaction, it was diluted with H2O (4 mL). The compound was
extracted in dichloromethane (2 6 10 mL), the separated organic
layer was dried over anhydrous Na2SO4 and concentrated on a
rotary evaporator. The crude compound was purified by column
chromatography (30% EtOAc/petroleum ether) to afford the
N-acroylated product 4a (415 mg, 90%) as a colourless liquid.
1H NMR (300 MHz, CDCl3): d 7.33–7.09 (m, 5H), 6.53–6.37
(m, 1H), 6.30–6.06 (m, 1H), 5.71–5.40 (m, 2H), 5.36–5.22 (m,
1H), 5.16 (d, J = 9.8 Hz, 1H), 5.09–4.86 (m, 3H), 4.75 (dd, J = 2.6,
9.8 Hz, 1H), 4.68 (d, J = 6.8 Hz, 1H), 4.42 (d, J = 6.8 Hz, 1H),
4.05 (d, J = 9.8 Hz, 1H), 3.43–3.27 (m, 4H), 3.12–2.98 (m, 1H),
2.92 (s, 3H), 2.80–2.66 (m, 1H), 2.50–2.34 (m, 1H), 2.12–1.94
(m, 4H), 1.57(s, 3H), 1.19–1.06 (m, 6H), 0.95–0.76 (m, 6H); 13C
NMR (75 MHz, CDCl3): d 170.6, 169.9, 166.9, 139.8, 137.1,
133.5, 132.2, 128.7, 128.4, 127.5, 126.9, 126.6, 114.2, 92.6, 76.9,
76.0, 71.9, 58.7, 55.1, 39.9, 38.2, 34.7, 31.8, 29.6, 20.9, 17.9,
16.8, 13.8, 13.5, 10.1; IR (KBr): n 2929, 1736, 1654, 1616, 1452,
1414, 1375, 1237, 1132, 1098, 1032, 957, 914, 700 cm21; MS
(ESI): m/z 580 (100) [M + Na]+; HRMS (ESI): [M + Na]+
C32H47NNaO7: calcd. 580.3245; found, 580.3236; [a]3D0: +12.1 (c
0.25, CHCl3).
(3S,6E,8S,9R,10Z,12S,13R,14S,15S)-3-Benzyl-9-(methoxy-
methoxy)-4,8,10,12,14,15-hexa-methyl-2,5-dioxo-1-oxa-4-azacy-
clopentadeca-6,10-dien-13-yl acetate (26). Hoveyda–Grubbs
second generation catalyst HG II (20 mg, 5 mol%) was added
to a stirred solution of amide 4a (0.35 g, 0.628 mmol) in
anhydrous toluene (650 mL) in which air had been previously
replaced by passing N2 gas. The reaction mixture was heated to
100 uC and maintained for 8 h at the same temperature until
TLC analysis indicated complete consumption of the starting
material. The solvent was removed on a rotary evaporator and
the resulting dark green residue was subjected to silica gel
column chromatography (25% EtOAc/petroleum ether) to
afford the exclusive ring closed trans-macrolactam 26 (315
mg, 95%) as a colourless semi-solid.
1H NMR (300 MHz, CDCl3): d 7.36–7.10 (m, 5H), 5.70–5.46
(m, 2H), 5.42–5.26 (m, 1H), 5.10–4.90 (m, 2H), 4.59 (d, J = 6.8
Hz, 1H), 4.45 (d, J = 6.8 Hz, 1H), 4.25–3.90 (m, 2H), 3.42–3.20
(m, 5H), 3.12–2.91 (m, 1H), 2.75 and 2.70 (s,s, equal to 3H of
rotamers), 2.53–2.35 (m, 1H), 1.99–1.76 (m, 2H), 1.63 (s, 3H),
1.38 and 1.35 (s,s, equal to 9H of rotamers, Boc protons), 1.21–
1.10 (m, 6H), 0.93–0.78 (m, 6H); 13C NMR (75 MHz, CDCl3):
‘‘M’’ for major rotamer and ‘‘m’’ for minor rotamer, d 170.6
(m), 170.3 (M), 155.7 (m), 155.1 (M), 139.7, 137.6, 134.5 (m),
134.3 (M), 132.0 (M), 131.8 (m), 128.9, 128.4 (M), 128.3 (m),
126.5 (M), 126.4 (m), 114.2, 92.8, 80.1 (M), 79.8 (m), 77.1, 72.9,
68.1 (m), 67.6 (M), 61.3, 60.0, 55.1, 39.9, 35.2 (M), 34.9 (m),
33.4, 32.1 (m), 31.8 (M), 28.2, 17.9, 16.8, 13.9 (m), 13.7 (M),
12.9, 10.4 (m), 10.0 (M); IR (KBr): n 3455, 2951, 2931, 1710,
1698, 1453, 1390, 1325, 1227, 1148, 1032, 949, 751, 698 cm21
;
MS (ESI): m/z 584 (100) [M + Na]+; HRMS (ESI): [M + Na]+
C32H51NNaO7: calcd. 584.3558; found, 584.3584; [a]3D2: +56.0 (c
0.25, CHCl3).
(S)-(2S,3S,4R,5S,8R,9S,Z)-4-Acetoxy-8-(methoxymethoxy)-3,
5,7,9-tetramethylundeca-6,10-dien-2-yl)-2-(tert-butoxycarbo-
nyl(methyl)amino)-3-phenylpropanoate (25). Diisopropyl-ethy-
lamine (DIPEA) (230 mg, 0.3 mL, 1.78 mmol) and DMAP (5.4
mg, 0.04 mmol) were added to alcoholic ester 24 (0.5g, 0.89
mmol) dissolved in anhydrous dichloromethane (8 mL) at 0
uC. The reaction mixture was stirred for 10 min and Ac2O (136
mg, 1.33 mmol) was added dropwise at 0 uC. The reaction
mixture was left at room temperature for 1 h. Upon completion
of the reaction (monitored by TLC), H2O (4 mL) was added.
The organic layer was separated and aqueous layer extracted
with CH2Cl2 (2 6 5 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column chroma-
tography (9% EtOAc/petroleum ether) to afford acetylated
product 25 (526 mg, 98%) as a colourless liquid. The NMR
spectra of this compound showed a mixture of rotamers
(55 : 45 ratio).
1H NMR (300 MHz, CDCl3): d 7.36–7.11 (m, 5H), 5.66–5.49
(m, 1H), 5.17 (d, J = 9.8 Hz, 1H), 5.10–4.87 (m, 3H), 4.86–4.55
(m, 3H), 4.42 (d, J = 6.8 Hz, 1H), 4.05 (d, J = 9.8 Hz, 1H), 3.35 (s,
3H), 3.32–3.21 (m, 1H), 3.08–2.92 (m, 1H), 2.83–2.66 (m, 4H),
2.50–2.35 (m, 1H), 2.10 (s, 3H), 2.07–1.95 (m, 1H), 1.57 (s, 3H),
1.38 and 1.34 (s,s, equal to 9H of rotamers, Boc protons), 1.20–
1.07 (m, 6H), 0.96–0.81 (m, 6H); 13C NMR (75 MHz, CDCl3):
‘‘M’’ for major rotamer and ‘‘m’’ for minor rotamer, d 170.6
(M), 170.2 (m), 155.7 (m), 155.0 (M), 139.8, 137.6 (M), 137.5
(m), 133.5, 132.2 (M), 132.1 (m), 128.9, 128.4, 128.3, 126.5 (M),
126.4 (m), 114.2, 92.5, 80.1 (M), 79.7 (m), 77.0, 75.9, 71.8 (M),
71.6 (m), 61.3, 59.9, 55.1, 39.8, 38.4 (M), 38.2 (m), 35.2 (M), 35.0
(m), 32.0 (m), 31.8 (M), 28.2, 20.9, 17.9, 16.8, 13.79 (m), 13.70
(M), 13.4, 9.9; IR (KBr): n 2973, 2931, 1739, 1700, 1452, 1389,
1370, 1237, 1148, 1098, 1031, 964, 700 cm21; MS (ESI): m/z 626
(100) [M + Na]+; HRMS (ESI): [M + Na]+ C34H53NNaO8: calcd.
626.3663; found, 626.3687; [a]3D0: +51.3 (c 0.25, CHCl3).
(S)-(2S,3S,4R,5S,8R,9S,Z)-4-Acetoxy-8-(methoxymethoxy)-3,5,7,9-
tetramethylundeca-6,10-dien-2-yl)-2-(N-methylacrylamido)-3-phe-
1H NMR (500 MHz, CDCl3): d 7.24–7.07 (m, 5H), 5.92–5.74
(m, 3H), 4.98 (d, J = 11.0 Hz, 1H), 4.82–4.70 (m, 1H), 4.48–4.33
(m, 3H), 4.20–4.08 (m, 1H), 3.46 (dd, J = 5.1, 14.4 Hz, 1H), 3.33–
3.21 (m, 4H), 2.97–2.83 (m, 2H), 2.79 (s, 3H), 1.93–1.82 (m, 4H),
1.65 (s, 3H), 1.16 (d, J = 6.0 Hz, 3H), 0.98 (d, J = 6.0 Hz, 3H),
0.86 (d, J = 7.6 Hz, 3H), 0.77 (d, J = 6.0 Hz, 3H); 13C NMR (75
MHz, CDCl3): d 171.2, 170.1, 168.0, 145.6, 137.0, 131.2, 130.8,
128.7, 128.3, 126.5, 121.9, 94.9, 80.4, 80.1, 73.6, 68.0, 55.7,
55.4, 39.2, 36.2, 34.4, 31.2, 29.6, 20.6, 18.8, 18.1, 16.9, 13.0; IR
(KBr): n 2923, 2851, 1734, 1640, 1453, 1371, 1236, 1102, 1029,
771 cm21; MS (ESI): m/z 552 (100) [M + Na]+; HRMS (ESI): [M +
Na]+ C30H43NNaO7: calcd. 552.2932; found, 552.2917; [a]3D2:
221.5 (c 1.0, CHCl3).
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(3S,6E,8S,9R,10Z,12S,13R,14S,15S)-3-Benzyl-9-hydroxy-
RSC Advances
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deca-6,10-dien-13-yl acetate (3a). A solution of MOM-protected
compound 26 (0.25 g, 0.472 mmol) in a 5 mL mixture of
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mmol). The reaction mixture was heated to reflux and
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(monitored by TLC), the mixture was cooled to room
temperature, then it was poured into 3 mL of water and the
organic solvent (CH3CN) was removed under reduced pres-
sure. Aqueous layer was extracted with EtOAc (3 6 15 mL). The
combined organic layers were washed with water (15 mL),
brine (20 mL), dried over Na2SO4, filtered and concentrated in
vacuo. The crude residue was chromatographed over silica gel
(25% EtOAc in PE) to afford the 5-epi-torrubiellution C (3a)
(213 mg, 93% yield, 99.8% purity in HPLC) as a white solid.
1H NMR (300 MHz, CDCl3): d 7.25–7.07 (m, 5H), 5.87 (dd, J =
5.4, 10.3 Hz, 1H), 5.81–5.76 (m, 2H), 4.88 (d, J = 10.9 Hz, 1H),
4.82–4.71 (m, 1H), 4.47–4.35 (m, 2H), 3.47 (dd, J = 5.2, 14.9 Hz,
1H), 3.30–3.17 (m, 1H), 2.94–2.80 (m, 2H), 2.77 (s, 3H), 2.02–
1.93 (m, 1H), 1.92–1.79 (m, 4H), 1.72 (s, 3H), 1.14 (d, J = 6.0 Hz,
3H), 0.95 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H), 0.77 (d, J =
6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 171.2, 170.1, 168.0,
144.4, 137.6, 136.8, 128.8, 128.6, 128.3, 126.5, 123.1, 80.3, 76.5,
73.5, 55.4, 39.4, 38.1, 36.3, 34.4, 31.6, 29.6, 20.6, 19.5, 18.1,
16.8, 11.9; IR (KBr): n 3448, 2923, 1734, 1626, 1581, 1452, 1376,
1259, 1172, 1133, 1020, 991, 771, 700 cm21; MS (ESI): m/z 508
(100) [M + Na]+; HRMS (ESI): [M + H]+ C28H40NO6: calcd.
486.2826; found, 486.2846; Mp: 82–83 uC. [a]3D0: 236.1 (c 1.0,
CHCl3).
¯
6 The silyl ether 8 on treatment with TBAF in THF provided
the triol, which underwent the selective protection with
benzyl bromide and NaH conditions to afford the benzyl
ether 12. The analytical data of this resultant compound
was indistinguishabe with the reported data.
Acknowledgements
The authors thank the Council of Scientific and Industrial
Research (CSIR)-New Delhi for the award of a fellowship to
BM.
7
Dedicated to Prof. Goverdhan Mehta on the occasion of his
70th birthday.
Notes and references
For the data of known compound 12, see: I. Paterson, G.
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