Synthesis of the macrolactone core of (+)-neopeltolide by transannular cyclization

Article abstract of DOI:10.1039/c2ob25151e

The synthesis of the macrolactone core of (+)-neopeltolide has been achieved. The key synthetic strategy involves the highly diastereoselective synthesis of the 2,6-cis-disubstituted tetrahydropyran ring by a transannular cyclization of δ-hydroxy alkene using mercuric trifluoroacetate. Two of the six stereocenters C-5 and C-11 were realized from l-malic acid, while the remaining stereocenters C-3 (Sharpless asymmetric epoxidation), C-7 (transannular cyclization), C-9 (regioselective epoxide opening) and C-13 (chelation controlled reduction) were derived by asymmetric synthesis. The macrolactone ring was synthesized by macrocyclization using a RCM protocol.

Full text of DOI:10.1039/c2ob25151e

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PAPER
Synthesis of the macrolactone core of (+)-neopeltolide by transannular
cyclization†
Gangavaram V. M. Sharma,*a Sheri Venkat Reddya and Kallaganti V. S. Ramakrishnab
Received 19th January 2012, Accepted 5th March 2012
DOI: 10.1039/c2ob25151e
The synthesis of the macrolactone core of (+)-neopeltolide has been achieved. The key synthetic strategy
involves the highly diastereoselective synthesis of the 2,6-cis-disubstituted tetrahydropyran ring by a
transannular cyclization of δ-hydroxy alkene using mercuric trifluoroacetate. Two of the six stereocenters
C-5 and C-11 were realized from L-malic acid, while the remaining stereocenters C-3 (Sharpless
asymmetric epoxidation), C-7 (transannular cyclization), C-9 (regioselective epoxide opening) and C-13
(chelation controlled reduction) were derived by asymmetric synthesis. The macrolactone ring was
synthesized by macrocyclization using a RCM protocol.
Introduction
Results and discussion
(+)-Neopeltolide is a marine macrolide isolated from a deep-
water sponge of the family Neopeltidae off the north coast of
Jamaica in 2007 by Wright et al.1 The structural features of 1
include: a trisubstituted 2,6-cis tetrahydropyran moiety, within a
14-membered macrolide and 6-stereocenters (3R, 5R, 7R, 9S,
11S, 13S), besides the presence of an unsaturated oxazole-con-
taining side chain at C5 on the tetrahydropyran ring. Macrolide 1
exhibited significant and highly potent in vitro toxicity towards
several cancer cell lines, including A549 human lung adenocar-
cinoma, NCI/ADR-RES ovarian carcinoma and P388 murine
leukemia cell lines with an IC50 values of 1.2, 5.1 and 0.56 nM,
respectively. In addition, 1 has also exhibited potent antifungal
activity against pathogenic yeast Candida albicans with a MIC
of 0.63 μg mL−1, and cytostatic effects in PANC-1 pancreate cell
line and the DLD-1 colorectal adenocarcinoma cell line, besides
targeting the cytochrome bc1 complex. Due to the biological
activity and structural complexity of (+)-neopeltolide (1), several
groups have reported the total synthesis2 and formal synthesis.3
Herein, we report the formal synthesis of 1 by accomplishing the
synthesis of 2, through a transannular cyclization as the key step
in the construction of the 2,6-cis-disubstituted tetrahydropyran
ring.
Retrosynthetic analysis
Retrosynthetic analysis (Scheme 1) of 1 showed that the macro-
lactone 2 is the late stage intermediate, which could be
aOrganic and Biomolecular Chemistry Division, CSIR-Indian Institute
of Chemical Technology, Hyderabad-500 007, India. E-mail:
esmvee@iict.res.in
bNMR Group, CSIR-Indian Institute of Chemical Technology,
Hyderabad-500 007, India
†Electronic supplementary information (ESI) available: Experimental
details on the compounds – 9–16, 18, 19, 21–28, 31, 32, 34, 4, 37, 3,
38. See DOI: 10.1039/c2ob25151e
Scheme 1 The retrosynthetic strategy of neopeltolide 1.
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Scheme 2 Reagents and conditions: (a) (−)-DIPT, Ti(OiPr)4, cumene hydroperoxide, 4 Å molecular sieves, CH2Cl2, −20 °C; (b) Red-Al, THF,
0 °C–rt; (c) NaIO4, sat. NaHCO3, CH2Cl2, 0 °C–rt; (d) p-anisaldehyde dimethyl acetal, PPTS, CH2Cl2, 0 °C–rt; (e) DIBALH, CH2Cl2, 0 °C–rt; (f)
TBDPSCl, imidazole, CH2Cl2, 0 °C–rt; (g) CuCl2·2H2O, CH3CN, 0 °C–rt; (h) p-TsCl, Bu2SnO, Et3N, CH2Cl2; (i) K2CO3, MeOH, 0 °C–rt; ( j) vinyl-
magnesium bromide, CuI, THF, −20 °C; (k) MOMCl, DIPEA, DMAP, 0 °C–rt; (l) TBAF, THF, 0 °C–rt; (m) TEMPO, BAIB, CH2Cl2 : H2O (1 : 1).
Synthesis of alcohol fragment 5
synthesized from 3, that in turn could be generated from bis
olefin 4. Ester 4 could be obtained from alcohol fragment 5 and
acid fragment 6. Both the alcohol 5 and acid 6 components
could be envisaged from L-malic acid using general chemical
transformations.
Thus, the key synthetic strategy is to construct the macrolide
ring through macrocyclization using a RCM protocol and finally
formation of the tetrahydropyran ring through mercuric trifluoro-
acetate-mediated cyclization within the macrolide ring.
Alcohol fragment 5 was synthesized from L-malic acid-derived
aldehyde 204a (Scheme 3). Accordingly, reaction of 20 with
n-propylmagnesium bromide in THF gave a diastereomeric
mixture of carbinols 21 (1.5 : 1) in 70% yield, which was sub-
jected to oxidation under Swern reaction conditions to give
ketone 22. Chelation controlled reduction of 22 with LiAlH4 and
LiI afforded the syn alcohol 23 in 81% yield (95% de),10 which
on reaction with TBDPS-Cl and imidazole afforded ether 24
(82%). Acetonide deprotection in 24 with CuCl2·2H2O afforded
diol6 25 in 75% yield. Regioselective protection of primary
alcohol in 25 with benzoyl chloride7 furnished 26 in 94% yield,
which on further reaction with Et3N and p-TsCl afforded 27.
Base (K2CO3) mediated reaction of 27 in methanol led to the
deprotection of the benzoyl ester in 27, which on concomitant
ring closure furnished epoxide 28 in 83% yield (for two steps).
Opening of the epoxide 28 with alkynyl borane reagent, gener-
Synthesis of acid fragment 6
The synthesis of the acid fragment 6 was initiated from L-malic
acid-derived allylic alcohol 84b (Scheme 2). Accordingly,
alcohol 8 on Sharpless asymmetric epoxidation with cumene
hydroperoxide, (−)-DIPT and Ti(OiPr)4 gave epoxy alcohol 9 in
85% yield. Regioselective reductive opening of epoxide 9 with
Red-Al5 at 0 °C in THF afforded 1,3-diol 10 (80%) along with
the corresponding 1,2-diol. The unwanted 1,2-diol was oxida-
tively cleaved with NaIO4 and the resultant aldehyde was
removed by column chromatography to give the pure 1,3-diol
10. Treatment of diol 10 with p-anisaldehyde dimethyl acetal
and PPTs gave 11 (79%), which on subsequent regioselective
reductive ring opening with DIBAL-H at 0 °C to room tempera-
ture for 4 h afforded alcohol 12 in 86% yield. Reaction of
alcohol 12 with TBDPS-Cl and imidazole afforded silyl ether 13
(92%), which on reaction with CuCl2·2H2O afforded diol6 14
(79%). A regioselective tosylation7 of diol 14 gave 15 in 95%
yield, which, on further reaction with K2CO3 in methanol furn-
ished epoxide 16 (83%).
11
ated in situ from 29, by the reaction with n-BuLi and BF3·OEt2
in THF at −78 °C, afforded the alcohol 30 in 67% yield. Treat-
ment of 30 with NaH and MeI gave ether 31 in 82% yield,
which on treatment with PPTS in methanol furnished 32 in 75%
yield. Stereospecific reduction of propargylic alcohol 32 with
Red-Al12 gave (E)-allylic alcohol 33 (94%), which on Sharpless
asymmetric epoxidation afforded the desired epoxy alcohol 34 in
75% yield. Regioselective opening of 34 with Me3Al13 in
hexane at 0 °C furnished 1,2-diol 35 in 85% yield, which on
subsequent reaction with Ph3P, imidazole and I2 gave olefin14 36
in 70% yield. Finally, treatment of TBDPS ether 36 with TBAF
afforded alcohol 5 in 84% yield.
To establish the relative configuration in 26, it was treated
with TBAF to give 26a (Scheme 4), which on reaction with 2,2-
dimethoxy propane and p-TsOH (cat.) in CH2Cl2 furnished ace-
tonide 26b. The 13C NMR of 26b revealed the presence of two
peaks corresponding to the two methyl groups of the acetonide:
at 19.7 ppm and 30.1 ppm, characteristic of a syn-1,3-diol
derivative.15
Treatment of epoxide 16 with vinylmagnesium bromide in the
presence of CuI8 in THF at −20 °C gave homoallylic alcohol 17
i
in 82% yield, which on reaction with MOM-Cl and Pr2NEt
afforded 18 (92%). Reaction of 18 with TBAF in THF furnished
alcohol 19 (85%), which on subsequent oxidation with TEMPO
and BAIB9 furnished acid 6 in 70% yield.
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Scheme 3 Reagents and conditions: (a) n-propyl bromide, Mg, THF, 0 °C–rt; (b) (COCl)2, DMSO, Et3N, CH2Cl2, −78 °C; (c) LiAlH4, LiI, −40 to
−100 °C; (d) TBDPSCl, imidazole, CH2Cl2, 0 °C–rt; (e) CuCl2·2H2O, CH3CN, 0 °C–rt; (f ) BzCl, Bu2SnO, Et3N, CH2Cl2; (g) p-TsCl, DMAP, Et3N,
CH2Cl2, 0 °C–rt; (h) K2CO3, MeOH, 0 °C–rt; (i) n-BuLi, BF3·Et2O, THF, −78 °C; ( j) MeI, NaH, THF, 0 °C–rt; (k) PPTs, MeOH, 0 °C–rt; (l) Red-
Al, diethyl ether, −20 °C; (m) (−)-DIPT, Ti(OiPr)4, cumene hydroperoxide, 4 Å molecular sieves, CH2Cl2, −20 °C; (n) Me3Al, hexane, 0 °C–rt; (o)
Ph3P, I 2, imidazole, CH2Cl2, 0 °C–rt; (p) TBAF, THF, 0 °C–rt.
product, along with the major 2,6-trans isomer 38a. However,
alcohol 3 on oxymercuration20 with Hg(CF3OO)2 in dry CH2Cl2
at 0 °C (entry 3, Table 1) and treatment of the resultant organo-
mercurial acetate with saturated aqueous KBr solution gave the
2,6-cis-tetrahydropyran 39 as a single product in 84% yield. The
above results on the formation of a mixture of 38/38a on
iodoetherification and exclusive formation of 39 on oxymercura-
tion can be rationalized based on the conformational transition
state and steric factors, respectively, as evidenced from the
literature.21
Scheme 4 Reagents and conditions: (a) TBAF, THF, 0 °C–rt; (b)
Me2C(OMe)2, p-TsOH, CH2Cl2, 0 °C–rt.
Synthesis of macrolactone 2
The structures of 38, 38a and 39 were established by 1H
NMR (500 MHz, CDCl3) data and assignments were made with
the aid of TOCSY and NOESY experiments. The characteristic
NOE between C3H/C7H in 39 (Fig. 1) suggested that both the
protons are on the same face of the structure. This was further
supported by NOE correlation between C7H/C9H and C8H/
C11H, confirming the structure of 39 (Fig. 1(a)). The energy
minimized structure as shown in Fig. 1(b) is also in agreement
with the assigned structure from NMR data.
In a further study on the synthesis of 2 from segments 5 and 6,
alcohol 5 was subjected to esterification with acid 6 (Scheme 5)
using DCC and DMAP to give ester 4 in 67% yield. Ring
closing metathesis (RCM) of ester 4 under high dilution con-
ditions with 10 mol% of Grubb’s second generation catalyst
afforded the 14-membered macrolactone 37 in 65% yield,16
which on oxidative deprotection of PMB ether with DDQ gave
δ-hydroxy alkene 3 in 90% yield.
With the macrolactone 3 in hand, attention was directed
towards the construction of the 2,6-cis-tetrahydropyran ring17 by
transannular cyclization.18 In such a cyclization on δ-hydroxy
alkene 3, the presence of the C-9 methyl in the α-face adjacent
to the alkene was assumed to play a role in the attack of the
incoming electrophile from the less hindered β-face. Accord-
ingly, in order to construct the 2,6-cis-tetrahydropyran unit of 1,
initially we employed the iodocyclization19 reaction of 3
(Table 1), with iodine in acetonitrile19c (entry 1, Table 1) to give
a mixture of isomers 38 and 38a (60%) in a 15 : 85 ratio respect-
ively. In a further study, the attempted cyclization with NIS in
CH2Cl2 at 0 °C resulted in 38 and 38a (78%) with a slightly
increased isomeric ratio (30 : 70; entry 2, Table 1). Thus, the
desired 2,6-cis-tetrahydropyran 38 was obtained as the minor
Treatment of 39 with Bu3SnH and AIBN in toluene under
reflux conditions afforded 40 (Scheme 5) in 93% yield, which
on final deprotection of the MOM ether in 40 using conc. HCl in
MeOH gave 2 in 86% yield; the spectral and analytical data of 2
is in accordance with the data reported earlier.3e
Conclusion
In summary, an efficient synthesis of the 14-membered macrolac-
tone core of biologically potent neopeltolide was achieved by
RCM mediated macrocyclization and transannular cyclization
with Hg(CF3OO)2 to construct the 2,6-cis-disubstituted tetrahy-
dropyran ring of neopeltolide.
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Scheme 5 Reagents and conditions: (a) DCC, DMAP, CH2Cl2, 0 °C–rt; (b) Grubb’s 2nd generation catalyst, CH2Cl2, rt; (c) DDQ, CH2Cl2 : H2O
(19 : 1); (d) n-Bu3SnH, AIBN, toluene, reflux; (e) conc. HCl, MeOH, 0 °C–rt.
Table 1 Formation of cis-2,6-disubstituted tetrahydropyran unit of 1
in THF (15 mL) at −20 °C, vinylmagnesium bromide
from 3
(27.55 mL, 27.55 mmol, 1 M in THF) was added and stirred for
15 min. A solution of epoxide 16 (4.50 g, 9.18 mmol) in THF
(30 mL) was added and stirred at −40 °C for 30 min. The reac-
tion mixture was quenched with sat. aq. NH4Cl solution (10 mL)
and extracted with EtOAc (2 × 50 mL). The combined organic
layers were washed with water (50 mL), brine (50 mL) and dried
(Na2SO4). Solvent was evaporated and the crude residue purified
by column chromatography (60–120 mesh silica gel, 12% ethyl
acetate in pet. ether) to afford 17 (3.90 g, 82%) as a colourless
oil; [α]2D5 +57.3 (c 0.6, CHCl3); IR (neat): 3069, 2932, 2857,
Syn/
Yieldb
(%)
Entry Conditions
antia
1
2
3
I2, CH3CN, −40 °C–0 °C
15 : 85 60
30 : 70 78
100 : 0 84
NIS, CH2Cl2, 0 °C–rt
Hg(CF3COO)2, CH2Cl2, 0 °C, sat. KBr, rt
a Product ratio was determined by 1H NMR spectral analysis
(500 MHz). b Isolated yield.
1
1715, 1612, 1514, 1427, 1250, 1109, 821, 734, 704 cm−1; H
NMR (500 MHz, CDCl3): δ 7.63–7.61 (m, 4H), 7.41–7.33 (m,
6H), 7.12 (d, 2H, J = 8.8 Hz), 6.79 (d, 2H, J = 8.8 Hz),
5.82–5.71 (m, 1H), 5.05–5.02 (m, 2H), 4.45 (d, 1H, J = 11.0
Hz), 4.29 (d, 1H, J = 11.0 Hz), 3.82–3.67 (m, 4H), 3.77 (s, 3H),
2.18–2.07 (m, 2H), 1.96–1.86 (m, 1H), 1.74–1.68 (m, 1H),
1.60–1.52 (m, 2H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3): δ
159.2, 135.5, 134.9, 133.6, 129.9, 129.7, 129.5, 127.6, 117.3,
113.8, 77.0, 70.8, 70.4, 60.2, 55.2, 42.1, 40.6, 36.5, 26.8, 19.1;
HRMS (ESI): m/z calculated for C32H42O4Si (M + Na)+
541.2746, found 541.2750.
Experimental
General
Solvents were dried over standard drying agents prior to use.
Chemicals were purchased and used without further purification.
All column chromatographic separations were performed using
silica gel (Acme’s 60–120 mesh). Organic solutions were dried
over anhydrous Na2SO4 and concentrated below 40 °C in vacuo.
1H NMR (300 MHz, 500 MHz and 600 MHz) and, 13C NMR
(75 MHz and 125 MHz) spectra were measured with a Bruker
Avance 300 MHz, Inova-500 MHz and Bruker-600 MHz with
TMS as internal standard for solutions in deutero chloroform. J
values were given in Hz. IR-spectra were recorded on Perkin-
Elmer IR-683 spectrophotometer with NaCl optics. Optical
rotations were measured with JASCO DIP 300 digital polari-
meter at 25 °C. Mass spectra were recorded on direct inlet
system or LC by MSD trap SL (Agilent Technologies).
(3R,5R)-3-(4-Methoxybenzyloxy)-5-(methoxymethoxy)oct-7-
enoicacid (6). To a stirred solution of 19 (1.50 g, 4.63 mmol) in
1 : 1 solution of CH2Cl2–water (20 mL), BAIB (4.47 g,
13.89 mmol) and TEMPO (0.22 g, 1.39 mmol) were added and
stirred at room temperature for 1.5 h. The reaction mixture was
diluted with CHCl3 (20 mL) and washed with sat. Na2S2O3
(10 mL), brine (10 mL) and dried (Na2SO4). Solvent was evap-
orated and the residue purified by column chromatography
(60–120 mesh silica gel, 20% ethyl acetate in pet. ether) to
afford 6 (1.1 g, 70%) as a colourless oil; [α]2D5 −40.5 (c 0.7,
CHCl3); IR (neat): 2932, 1714, 1612, 1514, 1456, 1250, 1171,
(4R,6S)-8-(tert-Butyldiphenylsilyloxy)-6-(4-methoxybenzyloxy)-
oct-1-en-4-ol (17). To a suspension of CuI (1.75 g, 9.18 mmol)
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Fig. 1 (a) NOESY spectrum (in CDCl3) of 39 (the NOEs C3H/C7H, C7H/C9H and C8H/C11H are marked as 1, 2 and 3 respectively), (b) energy
minimized structure of 39.
1099, 1033, 918, 821 cm−1
;
1H NMR (500 MHz, CDCl3): δ
layers were washed with brine (25 mL), dried (Na2SO4), evapor-
ated and the residue purified by column chromatography
(60–120 mesh silica gel, 12% ethyl acetate in pet. ether) to
furnish 33 (1.70 g, 94%) as a colourless oil; [α]2D5 +29.20 (c
0.25, CHCl3); IR (neat): 3401, 3073, 2957, 2932, 2859, 1589,
7.20 (d, 2H, J = 8.4 Hz), 6.80 (d, 2H, J = 8.4 Hz), 5.78–5.70
(m, 1H), 5.05–5.02 (m, 2H), 4.62 (d, 1H, J = 6.7 Hz), 4.56 (d,
1H, J = 6.7 Hz), 4.46 (d, 1H, J = 10.9 Hz), 4.45 (d, 1H, J = 10.9
Hz), 3.99 (m, 1H), 3.76 (s, 3H), 3.71–3.66 (m, 1H), 3.33 (s,
3H), 2.60–2.58 (m, 2H), 2.27–2.24 (m, 2H), 1.93–1.87 (m, 1H),
1.70–1.65 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 176.5, 159.2,
134.0, 130.0, 129.4, 117.6, 113.7, 95.3, 73.7, 72.4, 70.9, 55.7,
55.2, 39.3, 38.8, 38.4; HRMS (ESI): m/z calculated for
C18H26O6 (M + Na)+ 361.1614, found 361.1627.
1462, 1427, 1381, 1186, 1109, 821, 704 cm−1 1H NMR
;
(500 MHz, CDCl3): δ 7.71–7.63 (m, 4H), 7.44–7.31 (m, 6H),
5.64–5.45 (m, 2H), 4.02–4.0 (m, 2H), 3.94–3.87 (m, 1H),
3.28–3.2 (m, 1H), 3.04 (s, 3H), 2.11–2.07 (m, 2H), 1.54–1.50
(m, 2H), 1.41–1.17 (m, 4H), 1.03 (s, 9H), 0.72 (t, 3H, J = 7.2
Hz); 13C NMR (75 MHz, CDCl3): δ 135.9, 134.6, 131.7, 129.4,
128.2, 127.4, 76.9, 70.5, 63.6, 55.9, 41.5, 39.8, 35.8, 27.0, 19.4,
17.7, 14.0; HRMS (ESI): m/z calculated for C27H40O3Si
(M + Na)+ 463.2644, found 463.2638.
(5S,7S)-7-(tert-Butyldiphenylsilyloxy)-1-(tetrahydro-2H-pyran-
2-yloxy)dec-2-yn-5-ol (30). To a stirred solution of 29 (1.83 g,
13.04 mmol) in dry THF (20 mL), n-BuLi (5.22 mL,
13.04 mmol, 2.5 M in hexane) was added at −78 °C and stirred
for 30 min. BF3·Et2O (1.50 mL, 11.96 mmol) was added slowly
and stirred for 10 min followed by the addition of epoxide 28
(4.0 g, 10.86 mmol) in THF (20 mL). After 2 h at −78 °C, it
was quenched with sat. aq. NH4Cl solution (10 mL) and
extracted with EtOAc (3 × 50 mL). The combined organic layers
were washed with brine (50 mL) and dried (Na2SO4). Solvent
was evaporated and the residue purified by column chromato-
graphy (60–120 mesh silica gel, 7% ethyl acetate in pet. ether)
to furnish 30 (3.70 g, 67%) as a colourless oil; [α]2D5 +18.33 (c
0.65, CHCl3); IR (neat): 3447, 2986, 2934, 1794, 1745, 1645,
(2S,3S,5S,7S)-7-(tert-Butyldiphenylsilyloxy)-5-methoxy-3-methyl-
decane-1,2-diol (35). To a stirred solution of 34 (1.20 g,
2.63 mmol) in dry hexane (6 mL), Me3Al (3.94 mL, 7.89 mmol,
2 M in toluene) was added at 0 °C and allowed to stir for
10 min. Reaction mixture was quenched with sat. aq. NH4Cl sol-
ution (1 mL) and extracted with EtOAc (2 × 10 mL). The com-
bined organic layers were washed with brine (3 mL), dried
(Na2SO4), evaporated and the residue purified by column chrom-
atography (60–120 mesh silica gel, 25% ethyl acetate in pet.
ether) to afford 35 (1.05 g, 85%) as a colourless oil; [α]2D5 −37.0
(c 0.2, CHCl3); IR (neat): 3401, 3063, 2932, 2866, 1686, 1593,
1454, 1373, 1217, 1159, 1059, 841 cm−1; H NMR (500 MHz,
1
CDCl3): δ 7.68–7.64 (m, 4H), 7.43–7.34 (m, 6H), 4.75 (t, 1H, J
= 3.0 Hz), 4.26–4.11 (m, 1H), 4.0–3.96 (m, 2H), 3.82–3.74 (m,
1H), 3.50–3.45 (m, 1H), 3.08–3.07 (s, 1H), 2.42–2.22 (m, 2H),
1.86–1.21 (m, 10H), 1.06 (s, 9H), 0.66 (t, 3H, J = 7.2 Hz); 13C
NMR (75 MHz, CDCl3): δ 135.9, 134.7, 129.8, 127.6, 96.6,
82.9, 72.2, 67.1, 61.9, 54.5, 40.1, 37.9, 30.2, 22.8, 26.9, 25.3,
19.0, 18.4, 13.7; HRMS (ESI): m/z calculated for C31H44O4Si
(M + Na)+ 531.2906, found 531.2931.
1464, 1427, 1362, 1109, 823, 741, 702 cm−1 1H NMR
;
(300 MHz, CDCl3): δ 7.72–7.67 (m, 4H), 7.46–7.39 (m, 6H),
3.83–3.79 (m, 1H), 3.72–3.55 (m, 1H), 3.46 (dd, 1H, J = 7.5,
11.0 Hz), 3.34–3.29 (m, 1H), 3.27–3.21 (m, 1H), 3.16 (s, 3H),
2.0 (br. s, 2H), 1.82 (td, 1H, J = 6.0, 12.5 Hz), 1.66–1.57 (m,
1H), 1.55–1.16 (m, 7H), 1.05 (s, 9H), 0.83 (d, 3H, J = 6.5 Hz),
0.78 (t, 3H, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3): δ 135.9,
134.4, 129.5, 127.4, 77.1, 76.4, 70.7, 64.6, 56.0, 41.6, 39.3,
38.8, 33.6, 27.0, 17.8, 17.1, 14.0; HRMS (ESI): m/z calculated
for C28H44O4Si (M + Na)+ 495.2906, found 495.2926.
(5S,7S,E)-7-(tert-Butyldiphenylsilyloxy)-5-methoxydec-2-en-1-
ol (33). To a solution of 32 (1.80 g, 4.11 mmol) in dry ether
(20 mL), Red-Al (3.56 mL, 12.33 mmol, 70% w/w in toluene)
was added dropwise at 0 °C and allowed to stir for 2 h. The reac-
tion mixture was quenched with sat. aq. NH4Cl solution (2 mL)
and extracted with EtOAc (2 × 25 mL). The combined organic
tert-Butyl((4S,6S,8S)-6-methoxy-8-methyldec-9-en-4-yloxy)diphe-
nylsilane (36). To a stirred solution of 35 (1.0 g, 2.11 mmol) in
dry CH2Cl2 (10 mL), Ph3P (2.21 g, 8.44 mmol), imidazole
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(0.57 g, 8.44 mmol) and I2 (1.60 g, 6.36 mmol) were added at
0 °C and allowed to stir for 30 min. The reaction mixture was
quenched with sat. aq. NaOH (1 mL) and extracted with CH2Cl2
(2 × 5 mL). The combined organic layers were washed with
brine (3 mL), dried (Na2SO4), evaporated and the residue
purified by column chromatography (60–120 mesh silica gel,
5% ethyl acetate in pet. ether) to furnish 36 (0.65 g, 70%) as a
colourless oil; [α]2D5 +23.27 (c 0.3, CHCl3); IR (neat): 3468,
3072, 2959, 2932, 2858, 1641, 1585, 1462, 1427, 1379, 1259,
(d, 3H, J = 6.5 Hz), 0.92 (t, 3H, J = 7.5 Hz); 13C NMR
(75 MHz, CDCl3): δ 171.0, 95.2, 77.2, 76.1, 75.6, 70.1, 69.7,
56.3, 55.6, 42.5, 40.8, 40.0, 39.2, 36.6, 35.7, 34.1, 29.7, 21.7,
19.2, 13.8; HRMS (ESI): m/z calculated for C20H35O6BrHg
(M + Na)+ 675.1220, found 675.1221.
(1R,5S,7S,9S,11R,13R)-7-Methoxy-13-(methoxymethoxy)-9-
methyl-5-propyl-4,15-dioxabicyclo[9.3.1]pentadecan-3-one (40).
To a stirred solution of 39 (15 mg, 0.02 mmol) in dry toluene
(3 mL), AIBN (5 mg) was added and the resulting mixture was
heated at reflux under a nitrogen atmosphere. Bu3SnH (14 μL,
0.05 mmol) was added to the reaction mixture and continued
stirring for 3 h. Toluene was evaporated and the residue purified
by column chromatography (60–120 mesh silica gel, 15% ethyl
acetate in pet. ether) to afford 40 (8.0 mg, 93%) as a colourless
oil; [α]2D5 +7.0 (c = 0.20, CHCl3); IR (neat): 2924, 2854, 1743,
1463, 1436, 1378, 1259, 1195, 1071 cm−1; 1H NMR (500 MHz,
CDCl3): δ 5.22–5.15 (m, 1H), 4.68 (s, 2H), 4.17–4.09 (m, 1H),
4.05–4.0 (m, 1H), 3.65–3.56 (m, 2H), 3.38 (s, 3H), 3.31 (s, 3H),
2.58 (dd, 1H, J = 4.0, 14.6 Hz), 2.38–2.28 (m, 3H), 1.90–1.75
(m, 1H), 1.73–1.47 (m, 6H), 1.45–1.32 (m, 4H), 1.19–1.03 (m,
2H), 0.98 (d, 3H, J = 6.8 Hz), 0.88 (t, 3H, J = 7.3 Hz); 13C
NMR (125 MHz, CDCl3): δ 171.0, 94.9, 75.7, 75.4, 72.9, 70.1,
69.6, 56.2, 55.4, 44.3, 42.6, 42.3, 40.2, 37.2, 37.0, 31.9, 29.4,
22.7, 18.9, 14.1; HRMS (ESI): m/z calculated for C20H36O6
(M + Na)+ 395.24046, found 395.24041.
1184, 1109, 1041, 912, 821, 730, 702 cm−1
;
1H NMR
(300 MHz, CDCl3): δ 7.67–7.60 (m, 4H), 7.39–7.30 (m, 6H),
5.66–5.56 (m, 1H), 4.93–4.83 (m, 2H), 3.92–3.86 (m, 1H),
3.34–3.24 (m, 1H), 3.06 (s, 3H), 2.16–2.08 (m, 1H), 1.56–1.43
(m, 2H), 1.40–1.11 (m, 6H), 1.03 (s, 9H), 0.93 (d, 3H, J = 6.8
Hz), 0.68 (t, 3H, J = 7.3 Hz); 13C NMR (75 MHz, CDCl3): δ
144.4, 135.9, 134.8, 129.4, 127.3, 112.5, 75.7, 70.4, 55.6, 42.0,
40.7, 39.6, 34.2, 27.0, 20.5, 19.4, 17.7, 14.0; HRMS (ESI): m/z
calculated for C28H42O2Si (M
461.2860.
+
Na)+ 461.2851, found
(4S,6S,8S)-6-Methoxy-8-methyldec-9-en-4-ol (5). To a stirred
and cooled (0 °C) solution of 36 (0.60 g, 1.37 mmol) in dry
THF (0.5 mL) TBAF (2.05 mL, 2.05 mmol, 1 M in THF) was
added and stirred for 3 h. The reaction mixture was diluted with
water (2 mL) and extracted with EtOAc (3 × 5 mL). The com-
bined organic layers were washed with brine (2 mL), dried
(Na2SO4), evaporated and the residue purified by column chrom-
atography (60–120 mesh silica gel, 7% ethyl acetate in pet.
ether) to furnish 5 (0.23 g, 84%) as a colourless oil; [α]2D5 +91.9
(c 0.2, CHCl3); IR (neat): 3450, 2927, 2857, 1725, 1631, 1461,
(1R,5S,7S,9S,11R,13R)-13-Hydroxy-7-methoxy-9-methyl-5-
propyl-4,15-dioxabicyclo[9.3.1] pentadecan-3-one (2). To
a
1379, 1255, 1112, 1031, 763, 702, 607, 502, 408 cm−1 1H
;
stirred solution of 40 (8.0 mg, 0.02 mmol) in MeOH (0.50 mL),
conc. HCl (20 μL) was added at 0 °C. After stirring at 0 °C for
0.5 h and for 24 h at room temperature, the reaction mixture was
quenched with saturated aq. NaHCO3 solution (2 mL) and
extracted with EtOAc (4 × 5 mL). The organic layers were
washed with brine (5 mL), dried (Na2SO4), evaporated and the
residue purified by column chromatography (60–120 mesh silica
gel, 20% ethyl acetate in pet. ether) to furnish 2 (6.0 mg, 86%)
as a colorless oil; [α]D25 +27.3 (c 0.1, CHCl3); Lit.3e [α]2D5 +24.5
(c 0.1, CHCl3); IR (neat): 3448, 2922, 2853, 1728, 1645, 1462,
NMR (300 MHz, CDCl3): δ 5.71–5.59 (m, 1H), 4.99–4.89 (m,
2H), 3.88–3.80 (m, 1H), 3.52–3.41 (m, 1H), 3.33 (s, 3H),
2.30–2.33 (m, 1H), 2.23–2.04 (m, 1H), 1.78–1.63 (m, 2H),
1.54–1.23 (m, 6H), 1.02 (d, 3H, J = 6.6 Hz), 0.93 (t, 3H, J = 7.0
Hz); 13C NMR (300 MHz, CDCl3): δ 144.0, 112.9, 77.8, 68.5,
56.4, 39.9, 39.7, 38.6, 34.8, 20.8, 18.9, 14.1; HRMS (ESI): m/z
calculated for C12H24O2 (M + Na)+ 223.1673, found 223.1685.
((1R,5S,7S,9S,10R,11S,13S)-7-Methoxy-13-(methoxymethoxy)-
9-methyl-3-oxo-5-propyl-4,15-dioxabicyclo[9.3.1]pentadecan-10-
yl)mercury(II) bromide (39). To a stirred solution of 3 (15 mg,
0.04 mmol) in CH2Cl2 (0.6 mL), mercury trifluoroacetate
(34 mg, 0.08 mmol) was added at 0 °C and allowed the reaction
mixture to stir at room temperature for 1 h. The reaction mixture
was treated with KBr solution (1 mL) and extracted with CH2Cl2
(3 × 5 mL). The combined organic layers were washed with
water (2 × 3 mL), brine (2 × 3 mL) and dried (Na2SO4). Solvent
was evaporated and the residue purified by column chromato-
graphy (60–120 mesh silica gel, 12% ethyl acetate in pet. ether)
to furnish 39 (22 mg, 84%) as a colourless oil; [α]2D5 +44.6 (c
0.21, CHCl3); IR (neat): 3452, 2923, 2854, 1725, 1642, 1459,
1
1379, 1219, 1082, 771 cm−1; H NMR (600 MHz, CDCl3): δ
5.12 (dt, 1H, J = 4.5, 9.5 Hz), 4.18 (t, 1H, J = 2.5 Hz), 4.12 (qt,
1H, J = 2.0, 10.5 Hz), 3.61 (td, 1H, J = 2.1, 11.0 Hz), 3.53 (t,
1H, J = 10.0 Hz), 3.24 (s, 3H), 2.52 (dd, 1H, J = 4.0, 14.5 Hz),
2.28 (dd, 1H, J = 11.0, 14.5 Hz), 1.79 (dd, 1H, J = 11.0, 13.5
Hz), 1.65–1.58 (m, 2H), 1.54–1.40 (m, 5H), 1.38–1.33 (m, 5H),
1.08 (dt, 1H, J = 2.0, 10.5 Hz), 0.91 (d, 3H, J = 7.0 Hz), 0.84 (t,
3H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3): δ 171.2, 75.9,
75.1, 73.1, 69.3, 65.2, 56.4, 44.4, 42.5, 40.4, 39.6, 38.5, 37.2,
31.6, 29.9, 25.9, 19.1, 14.1; HRMS (ESI): m/z calculated for
C18H32O5 (M + Na)+ 351.2147, found 351.2133.
1382, 1269, 1148, 1037, 761 cm−1 1H NMR (500 MHz,
;
CDCl3): δ 4.83–4.74 (m, 1H), 4.69 (d, 1H, J = 6.5 Hz), 4.67 (d,
1H, J = 6.5 Hz), 4.19–4.10 (m, 1H), 4.08–4.05 (m, 1H),
3.91–3.79 (m, 1H), 3.43–3.35 (m, 1H), 3.39 (s, 3H), 3.33 (s,
3H), 2.71 (dd, 1H, J = 2.5, 10.0 Hz), 2.55 (dd, 1H, J = 5.0, 13.0
Hz), 2.29 (dd, 1H, J = 10.0, 13.0 Hz), 2.18–2.03 (m, 2H),
1.96–1.82 (m, 2H), 1.67–1.41 (m, 4H), 1.38–1.22 (m, 4H), 1.16
Acknowledgements
The authors are thankful for financial support from MLP-0010
of CSIR, New Delhi. S.V.R. is thankful to CSIR, New Delhi for
the research fellowship.
3694 | Org. Biomol. Chem., 2012, 10, 3689–3695
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