First asymmetric total synthesis of aspergillide D

Article abstract of DOI:10.1039/c6ob02435a

The first asymmetric total synthesis of a 16-membered macrolide, aspergillide D, is described. The chiral centers of the acid are derived from d-ribose and the alcohol subunit from 1,8-octane diol through Sharpless kinetic resolution, respectively. The other key reactions include Yamaguchi esterification, ring-closing metathesis reaction, and Shiina macrolactonization to construct the fully functionalized macrocycle.

Full text of DOI:10.1039/c6ob02435a

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ARTICLE TYPE
First Asymmetric Total Synthesis of Aspergillide D
Bighnanshu K. Jena, G. Sudhakar Reddy and Debendra K. Mohapatra*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
exhibited no antibacterial activity against both Escherichia coli
and Staphylococcus aureus. Compounds 1d and 1e showed
antiviral activity against H1N1 and H3N2, with IC50 values of 7.4
40 and 4.3 ꢁM for 1d and IC50 values of 36.0 and 12.0 ꢁM for 1e,
respectively. Furthermore, the exploration of structureꢀactivity
5
The first asymmetric total synthesis of 16-membered
macrolide aspergillide D is described. The chiral centers of
the acid is derived from D-ribose and the alcohol subunit
from 1,8-octane diol through Sharpless kinetic resolution,
respectively. The other key reactions include Yamaguchi
10 esterification, ring-closing metathesis reaction, and Shiina
macrolactonization to construct the fully functionalized
macrocycle.
OH
2
O
OH OH
HO
O
4
1
5
3
16
O
O
6
7
8
15
OCH3
13
11
OH
(R)-semivioxanthin
(1a)
aspergillide D
(1)
Introduction
O
HO
H
In 2013, Qi and coꢀworkers1 reported the isolation of aspergillide
15 D (1), a 16ꢀmembered macrolide along with two polyketones,
(R)ꢀsemivioxanthin (1a),2a (R)ꢀsemixanthomegnin (1b)2b and four
alkaloids, 5ꢀ(1Hꢀindolꢀ3ꢀylmethyl)ꢀimidazolidineꢀ2,4ꢀdione (1c),
9α,14ꢀdihydroxyꢀ6βꢀpꢀnitroꢀbenzoylcinnamolide (1d),2c 7α,14ꢀ
dihydroxyꢀ6βꢀpꢀnitroꢀbenzoylconfertifolin(1e),[2c] azonazine(1f)2d
20 from the extract of the gorgonianꢀassociated fungal stain
Aspergillus sp. SCSGAF 0076. The assignment of the gross
structure of aspergillide D (1) was allotted on account of 1H, 13C
NMR, and DEPT spectra, which confirmed the presence of one
methyl, eight aliphatic methylenes, α,βꢀunsaturated ester, four
25 oxygenated methines, two double bond equivalents including one
unsaturation and molecular formula by HRESIMS (m/z 323.1828
[M + Na]+). Elucidation of the relative configuration of the
natural product 1 was based on NOESY spectrum, large coupling
constant (J = 16 Hz) supporting Eꢀconfigured olefinic bond. 14ꢀ
30 and 16ꢀmembered macrolides isolated from fungi and bacteria
generally display antibacterial activity3,4 but this new macrolide
N
O
O
OH
O
O
NO2
H
O
N
O
H
HO
O
OCH3
NH
O
O
9
,14-dihydroxy-6 -p-nitro-
benzoylcinnamolide
(1d)
(R)-semixanthomegnin
5-(1H-indol-3-ylmethyl)-
imidazolidine-2,4-dione
(1b)
(1c)
O
O
O
N
N
H
OH
O
NO2
H
HO
O
N
O
O
O
H3C
7
,14-dihydroxy-6 -p-nitro-
benzoylconfertifolin
(1e)
azonazine
(1f)
Figure 1. Structure of aspergillide D (1), two polyketones (1a-b), four
45 alkaloids (1c-f).
relationships (SAR) of different macrolides have revealed that the
combination of macrolide core and side chain parts were effective
for the enhancement of biological activity of the natural product.5
Generally, the accumulative importance focussed on the aglycons
50 in the structureꢀactivity investigations on such molecules
sidelining the contribution of the corresponding carbohydrate
components whereas latter part’s inclusion can change the
solubility, absorption, and interactions with a defined biological
Natural Products Chemistry Division, CSIRꢀIndian Institute of Chemical
Technology, Hyderabad 500 007, India; Eꢀmail: mohapatra@iict.res.in
35 †Electronic Supplementary Information (ESI) available: [Scanned copies
of 1H, 13C NMR Spectra]. See DOI: 10.1039/b000000x/
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target and can be hampered to a great extent the other way
around.6 The biological activities of aspergillide D has not been
extensively explored, presumably due to the scarce natural
The synthesis of acid fragment 5 was commenced with
commercially available Dꢀribose (7) which was converted to
lactol 9 following a literature protocol,8 as shown in Scheme 2.
abundance which can be recouped by total synthesis for further 40 Lactol 9 was synthesized from Dꢀribose (7) by treating with
5
biological evaluation. The quest for improvement of biological
significance of aspergillide D with further structureꢀactivity
studies, along with its extremely limited supply, prompted us to
undertake its chemical synthesis. Herein, we report the first
asymmetric total synthesis of 1, relying on the Shiina
catalytic amount of H2SO4 and acetone, which produced 2,3ꢀ
acetonide, followed by reduction with NaBH4 and subsequent
oxidative cleavage of the resulting diol with NaIO4 afforded
lactol 9 in quantitative yield. The lactol 9 was then treated with
45
O
OH
(PPh3-CH3)+Br- , n-BuLi
Ref. 8
10 macrolactonization7 as the pivotal step.
D-ribose
THF, 0 °C to 50 °C
O
O
7
3 h, 81%
9
According to the retrosynthetic analysis of aspergillide D (1) as
shown in Scheme 1, macrolactone core 2 of aspergillide D could
be synthesized from secoꢀacid 3 via intramolecular Shiina
esterification. Secoꢀacid 3 which could be obtained from α,βꢀ
O
O
O
TEMPO, BAIB
O
CH2Cl2:H2O
r.t. 3 h, 82%.
O
OH
50
HO
Scheme 2. Synthesis of the acid fragment 5.
Derived from
Shiina
macrolactonization
15
D-Ribose
O
HO
PPh3=CH2 in THF at 50 oC to afford alcohol 10 in 81% yield. The
primary alcohol group was then transformed to its corresponding
carboxylic acid functionality by treating with BAIB in presence
O
O
HO
O
Sharpless
resolution
RCM & PtO2
reduction
O
O
OMOM
OH
2
Aspergillide D (1)
55 of TEMPO in a mixture of CH2Cl2 and water as solvent at room
O
Yamaguchi
esterification
temperature to furnish 5 in 82% yield.9
O
O
O
CO2H
HO
O
O
The synthesis of alcohol fragment
6 was initiated with
OMOM
3
commercially available 1,8ꢀoctane diol (8) and monoꢀPMB
protection with 4ꢀmethoxybenzyl alcohol in presence of
60 Amberlystꢀ15 in CH2Cl2 furnished PMB ether 11 in 89% yield.10
The primary alcohol 11 was oxidized under Swern conditions11 to
obtain the corresponding aldehyde, which was treated with
vinylmagnesium bromide in presence of CuI (catalytic),
immediately after purification through flash chromatography, to
65 afford racemic allylic alcohol 12 in 74% yield over two steps.
The allylic alcohol 12 was transformed to the enantiomerically
rich epoxy alcohol 13 in 43% yield under Sharpless kinetic
resolution conditions by employing requisite equivalents of (−)ꢀ
DIPT and Ti(OiPr)4 in presence of 0.5 equivalent of tꢀBuOOH in
70 CH2Cl2 at −20 oC.12 The optical rotation of the compound 13 was
OMOM
20
4
O
OH
O
O
+
OH
OMOM
5
6
OH
D-ribose
7
OH
Scheme 1. Retrosynthetic analysis of Aspergillide D (1).
25 unsaturated ester through two carbon homologation on the
corresponding lactol of the 14ꢀmembered macrolactone with
controlled DIBALꢀH reduction, which in turn could be
constructed by ringꢀclosing metathesis reaction of the resulting
diene compound 4, followed by reduction of the unsaturated
30 macrolactone with PtO2. The diene could be prepared from the
coupling of the acid 5 and the alcohol 6 under Yamaguchi
coupling conditions. Acid fragment 5 would be obtained from Dꢀ
ribose following a reported protocol whereas alcohol fragment 6
could be accessed from 1,8ꢀoctane diol (8) through Sharpless
35 kinetic resolution as the key reaction (Scheme 1).
20
found to be [α]D −4.90 (c 2.1, CHCl3) and the enantiomeric
purity was determined by HPLC analysis. The free secondary
hydroxy functionality of 13 was masked as its MOM ether to
afford 14 in 93% yield by treating with MOMCl and N,Nꢀ
75 diisopropylethylamine (DIPEA) in CH2Cl2. The PMB protecting
group was oxidatively removed upon treatment with DDQ in
CH2Cl2:H2O (9:1) under phosphate buffer solution (pH = 7) to
Results and Discussion
2
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provide 15 in 92% yield.13 The primary group 15 was then
immediately subjected to Ph3P=CHCO2Et in refluxing benzene
after purification through a flash silica gel chromatography to
produce α,βꢀunsaturated ester 19 in 61% yield over two steps
45 (Scheme 7).19 The ester functionality of 19, was hydrolyzed under
converted to the corresponding terminal alkene by a two step
sequence involving oxidation to corresponding aldehyde with
PMB-OH, Amberlyst-15
OPMB
OH
OH
OH
5
CH2Cl2, reflux, 10 h, 89%
11
8
O
O
O
OH
(–)-DIPT, Ti(OiPr)4
TBHP, MS (4 Å)
2,4,6-Cl3C6H2COCl
(i) (COCl)2, DMSO, Et3N
CH2Cl2, –78 °C
O
OPMB
O
+
Et3N, DMAP
O
O
toluene, 7 h, 65%
(ii) VinylMgBr, CuI, THF
–30 °C, 2 h, 74% yield
over two steps
CH2Cl2, –23 °C
12 h, 43%
OH
OMOM
12
6
OH
5
4
OMOM
50
55
60
65
OPMB
O
O
MOMCl, i-Pr2EtN
O
OPMB
O
10
O
O
O
O
O
PtO2, H2
DMAP, 3 h, 0 °C
93%
14
Grubbs' II (cat.),
OMOM
MeOH, r.t.
3 h, 95%
O
13
OH
CH2Cl2, reflux
12 h, 73%
dr = 93:7
OMOM
OMOM
O
(i) DMP, CH2Cl2
NaHCO3, 0 °C to r.t., 3 h
18
17
DDQ, CH2Cl2:H2O (19:1)
OH
O
pH = 7 buffer, r.t., 1 h
92%
(ii) (PPh3-CH3)+Br-, nBuLi,
(i) DIBAL-H, CH2Cl2
–78 °C, 20 min
O
CO2Et
HO
OMOM THF, –78 °C to 0 °C, 3 h,
65% over two steps
15
LiOH, THF/H2O (3:2)
reflux, 12 h, 77%
(ii) Ph3P=CHCO2Et
benzene, reflux, 4 h
61% over two steps
OH
15
LiAlH4, THF
OMOM
O
19
–10 to 0 °C, 89%
OMOM
OMOM
O
6
O
16
O
O
O
CuCl2:2H2O
CO2H
HO
MNBA, DMAP
Scheme 3. Synthesis of the alcohol fragment 7.
O
MS (4 Å), toluene
r.t., 10 h, 66%
CH3CN, 0 °C
2 h, 90%
OMOM
OMOM
DessꢀMartin periodinane in CH2Cl2,14 followed by treatment with
2
3
PPh3=CH2 to produce alkene 16 in 65% yield over two steps
OH
OH
O
HO
O
HO
20 (Scheme 3). The terminal epoxide 16 was reductively cleaved
with LiAlH4 in THF at −10 oC to obtain 6 in 89% yield.
4N HCl, THF
r.t., 6 h, 72%
O
O
OH
OMOM
1
20
Having synthesized both the desired fragments in a simple and
efficient manner, we turned our attention to couple the acid 5 and
the alcohol 6 followed by crucial ringꢀclosing metathesis reaction
25 of the resulting diene 4. When the coupling was initially
attempted in the presence of DCC (dicyclohexyl carbodiimide)15
and EDCI (NꢀethylꢀN’ꢀ(dimethylaminopropyl)carbodiimide),16
DMAP in CH2Cl2, both the reaction conditions afforded product
with low yield and nonꢀreproducible, anticipating the
30 vulnerability of acid moiety 5. Pleasingly, under Yamaguchi
esterification17 conditions, the diene ester 4 was obtained in 65%
yield, which set the stage for RCM reaction to prepare 14ꢀ
membered unsaturated lactone 17. The diene ester was dissolved
in degassed CH2Cl2 and refluxed with Grubbs' 2nd generation
35 catalyst under high dilution conditions to furnish the desired
macrolactone 17 as major isomer in 73% yield.18 Hydrogenation
of unsaturated lactone compound 17 was effected in presence of
catalytic amount of PtO2 under H2 atmosphere in MeOH to afford
14ꢀmembered saturated lactone 18 in 95% yield. The reduction of
40 macrolactone 18 in CH2Cl2 was efficiently carried out with
DIBALꢀH at −78 oC into the corresponding lactol, which was
Scheme 4. Total synthesis of aspergillide D (1).
basic conditions with LiOH in THF/H2O (3:2) to afford the
70 requisite secoꢀacid 3 of aspergillide D, which set the stage for
crucial Shiina macrolactonization. The azeotropic secoꢀacid
moiety with anhydrous benzene, was macrocyclized under
Shiina’s protocol utilizing 2ꢀmethylꢀ6ꢀnitrobenzoic anhydride as
acid activating agent, to furnish the key fully functionalized
75 macrolactone 2 in 51% yield over two steps.7 Global deprotection
of
2
having acetonide group and MOMꢀether to the
corresponding hydroxy groups was attempted under different
acidic conditions, which led to the formation of inseparable
mixture of products along with decomposition of the starting
80 material. Then, it was planned to deprotect the acetonide group of
2 selectively in the presence of MOM ether by treating with 3
equivalents CuCl2·2H2O in CH3CN at 0 °C which produced the
diol 20 in 90% yield.20 Deprotection of MOMꢀprotecting group
was the remaining task to complete the synthesis of proposed
85 structure of aspergillide D. After achieving the acetonide
deprotection, the deprotection of MOM ether with CuCl2·2H2O in
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Conclusions
Table 1: 1H and 13C NMR data of natural and synthetic aspergillide D
In conclusion, the first asymmetric total synthesis of aspergillide
D was achieved in 18 longest linear step sequences. The
20 intramolecular Shiina coupling was successfully applied to the
synthesis of 16ꢀmembered macrolactone ring of aspergillide D.
Other key features of the synthesis include the preparation of both
desired fragments from commercial available cheaper starting
materials in a concise and convergent manner and the successful
25 use of Sharpless resolution, Yamaguchi esterification, and RCM
reaction. Hopefully, the current synthesis will provide
considerable flexibility to a variety of structural analogues of
aspergillide D for further biological studies.
Position
Natural
Synthetic
Position
Natural
Synthetic
δH (J in
Hz)
δH (J in
Hz)
δC
δC
Hꢀ2
Hꢀ3
6.08,
(dd, 1.5,
15.5)
6.11, (dd,
1.7, 15.9)
Cꢀ1
Cꢀ2
166.0
122.0
165.6
122.5
6.93,
(dd, 5.0,
16.0)
6.92, (dd,
5.2, 15.7)
Hꢀ15
Hꢀ4
4.81, m
4.87, m
4.50, m
Cꢀ3
Cꢀ4
146.6
74.0
145.8
74.02
4.44,
(ddd,
1.3, 2.6,
4.7)
Experimental Section
Hꢀ5
3.69, m
1.58, m
3.74, m
Cꢀ5
Cꢀ6
74.1
31.8
74.5
32.1
Hꢀ6a,
Hꢀ13a
1.66ꢀ1.52,
m
30 General Remarks: Air and/or moisture sensitive reactions were
carried out in anhydrous solvents under an atmosphere of argon
in an oven or flameꢀdried glassware. All anhydrous solvents were
distilled prior to use: THF, benzene, toluene, diethyl ether from
Na and benzophenone; CH2Cl2, DMSO, DMF, hexane from
35 CaH2; MeOH, EtOH from Mg cake. Commercial reagents were
used without purification. Column chromatography was carried
out by using silica gel (60–120 mesh). Specific optical rotations
[α]D are given in 10−1 degcm2g−1. Infrared spectra were recorded
in CHCl3/neat (as mentioned) and reported in wave number
40 (cm−1). TOF analyzer type was used for the HRMS measurement.
1H and 13C NMR chemical shifts are reported in ppm downfield
from tetramethylsilane and coupling constants (J) are reported in
hertz (Hz). The following abbreviations are used to designate
signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet,
45 m = multiplet, br = broad.
Hꢀ7~ Hꢀ
12
1.45ꢀ
1.13, m
1.44ꢀ1.14,
m
Cꢀ7
27.8
27.9
Hꢀ14
Hꢀ6b
Hꢀ16
3.47, m
1.32, m
3.54, m
1.48, m
Cꢀ8
Cꢀ9
27.5
23.2
22.9
27.6
23.4
23.0
1.38, (d,
6.0)
1.36, (d,
6.3)
Cꢀ10
Hꢀ13b
1.26, m
−
Cꢀ11
Cꢀ12
Cꢀ13
Cꢀ14
Cꢀ15
Cꢀ16
26.1
26.0
29.7
73.8
73.7
17.6
26.3
26.3
30.0
73.97
73.7
17.6
CH3CN at room temperature was investigated which led to
furnish the requisite product along with the decomposition
product. Finally, treatment of the MOMꢀether 20 with 4N HCl in
THF, successfully afforded aspergillide D in 72% yield. The
5
8-((4-Methoxybenzyl)oxy)octan-1-ol (11): To a stirred solution
of 1,8ꢀoctanediol (8) (18.0 g, 123.29 mmol) and catalytic amount
of Amberlystꢀ15 resin (1.8 g, 10% w/w) in CH2Cl2 (100 mL) was
added 4ꢀmethoxybenzyl alcohol (15.28 mL, 123.29 mmol) at
50 room temperature and heated to reflux at 50 °C for 10 h. After
completion of the reaction (monitored by TLC), it was filtered
through a pad of Celite. The residue was washed with CH2Cl2 (2
× 40 mL). The combined organic layer was dried over anhydrous
Na2SO4, concentrated under reduced pressure. The crude residue
55 was purified by silica gel column chromatography
(EtOAc/hexane = 1:3) to obtain the desired alcohol 11 (29.19 g,
20
specific rotation {[α]D = −9.42 (c 0.1, MeOH)} of synthetic
compound 1 was in good agreement with the data reported1 for
20
10 the natural product {[α]D = −11.1 (c 0.1, MeOH)} and the
spectral data (1H NMR and 13C NMR taken at 40 oC as the
compound was partially soluble in CDCl3) were also in good
agreement with the natural product data except few chemical
shifts differs to a little extent (Table 1), thus, represents the first
15 asymmetric total synthesis of 16ꢀmembered macrolactone
aspergillide D.
4
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89%) as a colorless liquid. IR (neat): 3409, 2930, 2855, 1612,
5.09 (td, J = 1.4, 10.4 Hz, 1H), 4.42 (s, 2H), 4.07 (m, 1H), 3.80
(s, 3H), 3.42 (t, J = 6.7 Hz, 2H), 1.62ꢀ1.56 (m, 2H), 1.54ꢀ1.46 (m,
1
1513, 1247, 1095, 1036, 821 cm−1; H NMR (400 MHz, CDCl3):
δ 7.26 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.43 (s, 2H), 45 2H), 1.39ꢀ1.27 (m, 8H); 13C NMR (125 MHz, CDCl3): δ 159.0,
3.80 (s, 3H), 3.62 (t, J = 6.6 Hz, 2H), 3.43 (t, J = 6.7 Hz, 2H),
1.65ꢀ1.50 (m, 5H), 1.40ꢀ1.27 (m, 7H) ppm; 13C NMR (100 MHz,
CDCl3): δ 159.0, 130.7, 129.2, 113.7, 72.5, 70.1, 62.9, 55.2, 32.7,
29.7, 29.4, 29.3, 26.1, 25.6 ppm; HRMS (ESI): m/z calcd for
C16H26O3Na [M + Na]+ 289.1774; Found: 289.1766.
141.3, 130.7, 129.2, 114.4, 113.7, 73.1, 72.4, 70.1, 55.2, 36.9,
29.7, 29.4, 29.3, 26.1, 25.2; HRMS (ESI) calcd for C18H28O3Na
[M + Na]+ 315.1931; Found: 315.1939.
5
(R)-8-((4-Methoxybenzyl)oxy)-1-((S)-oxiran-2-yl)octan-1-ol
50 (13): At first, 4 Å molecular sieves (12.7 g) and CH2Cl2 (90 mL)
were placed in a twoꢀnecked 250 mL round bottomed flask,
followed by the addition of Ti(OiPr)4 (2.45 mL, 8.24 mmol) and
(−)ꢀdiisopropyltartrate (2.0 mL, 9.50 mmol) at –25 °C under
nitrogen and the resulting mixture was stirred for 30 min. The
10-((4-Methoxybenzyl)oxy)dec-1-en-3-ol (12): To
a stirred
10 solution of anhydrous dimethyl sulfoxide (19.67 mL, 277.44
mmol) in CH2Cl2 (120 mL), was added oxalyl chloride (16.8 mL,
184.96 mmol) dropꢀwise at –78 °C under N2 atmosphere. The
reaction mixture was stirred for 30 min before alcohol 11 (24.6 g, 55 allylic alcohol 12 (18.5 g, 63.36 mmol) was then added and
92.84 mmol) in CH2Cl2 (80 mL) was added slowly. The reaction
15 mixture was stirred for 45 min at same temperature. Then
triethylamine (51.50 mL, 369.92 mmol) was added dropꢀwise and
allowed to stir for 1 h at −78 °C. The reaction was allowed to stir
stirred for 30 min, after which tꢀBuOOH (4.9 mL, 31.68 mmol)
(6.5 M in toluene) was added over 20 min at the same
temperature. Then the reaction mixture was stirred for 12 h at the
same temperature. After monitoring resolution of the racemic
at room temperature for additional 1 h. After completion of the 60 alcohol (monitored by TLC), the reaction mixture was warmed to
reaction (monitored by TLC), the reaction mixture was quenched
20 with water. The aqueous phase was extracted with CH2Cl2 (3 ×
100 mL). The combined organic layer was washed with brine
(100 mL), dried over Na2SO4 and evaporated to dryness under
0
oC and whole reaction mixture was filtered through sintered
funnel. Then quenched by water (40 mL) and stirred vigorously
for 30 min and the filtrate were again stirred along with 20%
aqueous NaOH solution (15 mL). The biphasic solution was
reduced pressure. The crude aldehyde was purified by flash 65 separated and aqueous layer was extracted with CH2Cl2 (3 × 60
chromatography and immediately used in the next reaction
25 without further characterization.
mL). The combined organic extracts were dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The crude
residue was purified by silica gel column chromatography
(EtOAc/hexane = 2:3) to afford pure epoxy alcohol 13 (8.39 g,
70 43%) as a colorless liquid. [α]D20 −4.90 (c 2.1, CHCl3); IR (neat):
3426, 2925, 2854, 1610, 1512, 1461, 1247, 1093, 1034, 823 cm−1;
1H NMR (400 MHz, CDCl3): 7.26 (d, J = 8.7 Hz, 2H), 6.87 (d, J
= 8.7 Hz, 2H), 4.42 (s, 2H), 3.86ꢀ3.77 (m, 4H), 3.43 (t, J = 6.6
Hz, 2H), 3.00 (m, 1H), 2.79 (m, 1H), 2.72 (dd, J = 4.0, 5.0 Hz,
75 1H), 1.65ꢀ1.44 (m, 4H), 1.43ꢀ1.23 (m, 8H); 13C NMR (125 MHz,
CDCl3): δ 159.0, 130.7, 129.2, 113.7, 72.5, 70.1, 68.4, 55.2, 54.5,
43.4, 33.4, 29.7, 29.5, 29.3, 26.1, 25.2; HRMS (ESI) calcd for
C18H28O4Na [M + Na]+ 331.1880; Found: 331.1891.
Vinyl magnesium bromide (122.16 mL, 122.16 mmol) (1 M
solution in THF) was added dropwise to a solution of CuI (1.55 g,
8.14 mmol) in THF (130 mL) at −20 °C. The mixture was stirred
for 30 min. and aldehyde (21.5 g, 81.44 mmol) in THF (60 mL)
30 was added dropwise to the above mixture at the same
temperature. After 2 h, the reaction (monitored by TLC) was
quenched with a saturated NH4Cl solution (75 mL) and diluted
with ethyl acetate (100 mL). The organic layer was separated and
the aqueous layer extracted with ethyl acetate (3 × 50 mL). The
35 combined organic layer was washed with brine (70 mL), dried
over anhydrous Na2SO4 and concentrated under reduced pressure
to give the crude mass. Purification by silica gel column
(S)-2-((R)-8-((4-Methoxybenzyl)oxy)-1-(methoxymethoxy)oct-
chromatography (EtOAc/hexane = 3:7) afforded the desired allyl 80 yl)oxirane (14): To a stirred solution of compound 13 (8.1 g,
alcohol 12 (19.98 g, 74% yield over two steps) as a colorless
26.30 mmol) in CH2Cl2 (60 mL), was added diisopropyl
ethylamine (13.74 mL, 78.9 mmol) and stirred for 30 min at 0 oC
under N2 atmosphere. Methoxymethyl chloride (3.0 mL, 39.45
mmol) was added to the reaction mixture at same temperature.
40 liquid. IR (neat): 3438, 2931, 2855, 1611, 1513, 1463, 1247,
1
1096, 821 cm−1; H NMR (500 MHz, CDCl3): 7.26 (d, J = 8.7
Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.85 (m, 1H), 5.21 (m, 1H),
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The reaction was continued to stir for 3 h at room temperature.
After completion of the reaction (monitored by TLC), it was
(10.97 g, 25.86 mmol). The reaction mixture was stirred at 0 °C
for 3 h. After completion of the reaction (monitored by TLC), it
quenched with water (30 mL). The organic layer was separated 45 was quenched with saturated aqueous NaHCO3 solution (30 mL)
and the aqueous layer extracted with CH2Cl2 (2 × 50 mL). The
combined organic layer was dried over anhydrous Na2SO4 and
removed under reduced pressure. The crude mass was purified by
and stirred for another 30 min. The organic layer was separated
and the aqueous layer extracted with CH2Cl2 (3 × 30 mL). The
combined organic layer was evaporated under reduced pressure to
afford a crude residue which was immediately used for the next
5
silica gel chromatography (EtOAc/hexane = 1:3) to afford 14
20
(8.61 g, 93%) as a colorless liquid. [α]D +6.81 (c 1.60, CHCl3); 50 reaction.
IR (neat): 2931, 2855, 1612, 1513, 1461, 1247, 1099, 1035, 802
Methyltriphenylphosphonium bromide (15.04 g, 42.13 mmol)
10 cm−1; 1H NMR (500 MHz, CDCl3): 7.26 (d, J = 8.6 Hz, 2H), 6.87
(d, J = 8.7 Hz, 2H), 4.65 (ABq, J = 6.9, 66.8 Hz, 2H), 4.43 (s,
2H), 3.80 (s, 3H), 3.43 (t, J = 6.7 Hz, 2H), 3.39 (m, 1H), 3.36 (s,
was dissolved in THF (50 mL) and cooled to –78 ºC. nꢀ
Butyllithium (14.04 mL, 2.5 M in hexane, 35.11 mmol) was
added drop wise to the above stirred solution which turned into
3H), 2.90 (m, 1H), 2.78 (dd, J = 4.0, 5.2 Hz, 1H), 2.72 (dd, J = 55 light orange solution. It was then warmed to 0 ºC for 45 min and
2.6, 5.3 Hz, 1H), 1.68ꢀ1.55 (m, 4H), 1.49 (m, 1H), 1.40ꢀ1.28 (m,
15 7H); 13C NMR (75 MHz, CDCl3): δ 159.0, 130.7, 129.1, 113.7,
95.9, 76.2, 72.4, 70.1, 55.4, 55.2, 53.2, 45.5, 32.8, 29.7, 29.5,
29.3, 26.1, 25.0; ESIꢀHRMS Calcd for C20H32O5Na [M + Na]+
375.2142; found: 375.2150.
again cooled to –78 ºC. The crude aldehyde (3.23 g, 14.04 mmol)
in THF (20 mL) was added to the reaction mixture drop wise.
The reaction mixture was stirred at the same temperature for 1 h
then warmed to 0 °C for 2 h. After complete consumption of the
60 starting material (monitored by TLC), the reaction was quenched
with saturated NH4Cl solution (30 mL) and warmed to room
temperature. The organic phase was separated and the aqueous
phase extracted with ethyl acetate (2 × 30 mL). The combined
organic layers were washed with brine (25 mL), dried over
65 Na2SO4 and concentrated under reduced pressure. Purification by
silica gel column chromatography (EtOAc/hexane = 1:4) afforded
the desired compound 16 (2.56 g, 65% over two steps) as a
(R)-8-(Methoxymethoxy)-8-((S)-oxiran-2-yl)octan-1-ol (15):
20 To a stirred solution of PMB ether 14 (7.4 g, 21.02 mmol) in
CH2Cl2 (50 mL), was added phosphate buffer (pH7) solution (3
mL) at 0 oC followed by DDQ (7.16 g, 31.53 mmol). The reaction
mixture was continued to stir for 1 h at room temperature. After
completion of the reaction (monitored by TLC), it was quenched
25 with saturated NaHCO3 solution (40 mL). The organic layer was
separated and the aqueous layer extracted with CH2Cl2 (2 × 50
mL). The combined organic layer was washed with brine (50
mL), dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure to obtain the crude product which on
30 purification by silica gel column chromatography (EtOAc/hexane
= 2:3) furnished the corresponding diol 15 (4.49 g, 92%) as
20
colorless liquid. [α]D +9.48 (c 0.5, CHCl3); IR (neat): 2927,
1
2855, 1741, 1641, 1150, 1104, 1038, 916, 557 cm−1; H NMR
70 (500 MHz, CDCl3): 5.80 (m, 1H), 4.99 (dd, J = 1.5, 17.1 Hz, 1H),
4.92 (dd, J = 1.2, 10.2 Hz, 1H), 4.64 (ABq, J = 6.9, 66.2 Hz, 2H),
3.39 (m, 1H), 3.36 (s, 3H), 2.89 (m, 1H), 2.77 (dd, J = 4.0, 5.2
Hz, 1H), 2.71 (dd, J = 2.6, 5.2 Hz, 1H), 2.07ꢀ2.00 (m, 2H), 1.69ꢀ
1.56 (m, 2H), 1.50 (m, 1H), 1.44ꢀ1.28 (m, 7H) ppm; 13C NMR
75 (75 MHz, CDCl3): δ 139.1, 114.2, 96.0, 76.3, 55.4, 53.3, 45.6,
33.7, 32.9, 29.5, 29.0, 28.8, 25.1 ppm; ESIꢀHRMS Calcd for
C13H24O3Na [M + Na]+ 251.1618; found: 251.1627.
20
colorless liquid. [α]D +8.73 (c 1.5, CHCl3); IR (neat): 3444,
1
2930, 2856, 1465, 1366, 1149, 1103, 1034, 919, 755 cm−1; H
NMR (500 MHz, CDCl3): 4.65 (ABq, J = 6.9, 65.3 Hz, 2H), 3.63
35 (t, J = 6.7 Hz, 2H), 3.41ꢀ3.36 (m, 4H), 2.90 (m, 1H), 2.78 (m,
1H), 2.72 (m, 1H), 1.69ꢀ1.46 (m, 5H), 1.42ꢀ1.30 (m, 7H); 13C
NMR (100 MHz, CDCl3): δ 95.9, 76.3, 62.8, 55.4, 53.3, 45.6,
(2S,3R)-3-(Methoxymethoxy)undec-10-en-2-ol (6): To
a
stirring suspension of LiAlH4 (0.38 g, 10.83 mmol) in dry THF
32.9, 32.7, 29.5, 29.2, 25.6, 25.0 ppm; ESIꢀHRMS Calcd for 80 (10 mL) was dropwise added a solution of epoxide 16 (1.9 g, 8.33
C12H25O4 [M + H]+ 233.1747; found: 233.1755.
mmol) in dry THF (30 mL) at 0 ºC. The reaction mixture was
allowed to warm to room temperature, and stirred for 3 h. The
reaction was quenched by the addition of water (20 mL). The
mixture was filtered with a pad of Celite and washed with ethyl
85 acetate (3 × 40 mL), washed with brine (15 mL), and dried over
40 (S)-2-((R)-1-(Methoxymethoxy)non-8-en-1-yl)oxirane (16): To
a stirred solution of primary alcohol 15 (4.0 g, 17.24 mmol) in
CH2Cl2 (45 mL) at 0 oC, was added DessꢀMartin periodinane
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Na2SO4. The combined organic layers were concentrated under
reduced pressure. The crude product was purified by silica gel
orange solution. It was then warmed to 0 ºC for 45 min and again
cooled to –78 ºC. The crude aldehyde 9 (2.0 g, 12.5 mmol) in
column chromatography (EtOAc/hexane = 3:7) to afford 6 (1.71 45 THF (15 mL) was added to the reaction mixture drop wise. The
20
o
g, 89%) as a colorless liquid. [α]D −10.29 (c 0.6, CHCl3); IR
reaction mixture was stirred at 0 C for 1 h and then warmed to
5
(neat): 3430, 2926, 2854, 1640, 1460, 1147, 1100, 1034, 910
50 °C. After complete consumption of the starting material
(monitored by TLC), the reaction was quenched with saturated
NH4Cl solution (20 mL) and warmed to room temperature. The
1
cm−1; H NMR (500 MHz, CDCl3): 5.81 (m, 1H), 5.03ꢀ4.92 (m,
2H), 4.70 (ABq, J = 6.9, 47.3 Hz, 2H), 3.75 (m, 1H), 3.50 (m,
1H), 3.44 (s, 3H), 3.13 (bs, 1H), 2.04 (q, J = 6.7 Hz, 2H), 1.55ꢀ 50 organic phase was separated and the aqueous phase extracted
1.43 (m, 2H), 1.42ꢀ1.35 (m, 3H), 1.34ꢀ1.26 (m, 5H), 1.14 (d, J =
with ethyl acetate (2 × 50 mL). The combined organic layers
were washed with brine (50 mL), dried over Na2SO4 and
concentrated under reduced pressure. Purification by silica gel
column chromatography (EtOAc/hexane = 1:6) afforded the
10 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 139.0, 114.1, 97.5,
85.1, 68.9, 55.7, 33.7, 30.9, 29.4, 28.9, 28.7, 25.9, 17.0; HRMS
(ESI) calcd for C13H30O3N [M + NH4]+ 248.2220; Found:
248.2233.
20
55 desired compound 10 (1.6 g, 81%) as a colorless liquid. [α]D
−26.09 (c 0.5, CHCl3); IR (neat): 3384, 2924, 2854, 1717, 1461,
(3aS,6aS)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol
15 (9): To a stirred solution of Dꢀribose monoacetonide (3.5 g, 18.42
mmol) in dry methanol (30 mL), NaBH4 (1.05 g, 27.63 mmol)
was added in small portions at 0 ºC, then the resulting reaction
mixture was stirred at room temperature for 1 h. After complete
consumption of the starting material (monitored by TLC), the
20 solvent was evaporated under reduced pressure. The crude
residue was dissolved in tꢀBuOH:H2O (30:20 mL), NaIO4 (15.76
g, 73.68 mmol) was added in small portions at 0 ºC. Then the
resulting reaction mixture was stirred at room temperature for 10
h until complete consumption of stirring material (monitored by
25 TLC). The reaction mixture was filtered to remove solid residue,
washed with ethyl acetate (2 × 30 mL) and quenched by the
addition of saturated NaHCO3 solution (30 mL). The filtrate was
extracted with ethyl acetate (2 × 40 mL), dried over Na2SO4, and
concentrated under reduced pressure. Purification of the crude
30 product by silica gel column chromatography (EtOAc/hexane =
1:3) afforded 9 (2.27 g, 77%) as a colorless liquid. [α]D20 −73.8 (c
1.9, CHCl3); IR (neat): 3448, 2923, 2854, 1631, 1465, 1219, 770
cm−1; 1H NMR (400 MHz, CDCl3) δ = 5.43 (s, 1H), 4.84 (m, 1H),
4.58 (d, J = 6.0 Hz, 1H), 4.08ꢀ3.99 (m, 2H), 1.48 (s, 3H), 1.33 (s,
35 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 112.2, 101.5, 85.0,
79.8, 71.6, 26.0, 24.6 ppm; ESIꢀHRMS Calcd for C7H12O4Na [M
+ Na]+ 183.0628; found: 183.0649.
1
1376, 1215, 1075, 1045, 930 cm−1; H NMR (500 MHz, CDCl3):
5.87 (m, 1H), 5.40 (dt, J = 1.4, 17.2 Hz, 1H), 5.28 (dt, J = 1.4,
10.4 Hz, 1H), 4.65 (m, 1H), 4.27 (m, 1H), 3.60ꢀ3.57 (m, 2H),
60 1.51 (s, 3H), 1.40 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 132.9,
119.0, 108.9, 78.3, 78.2, 62.0, 27.8, 25.2; HRMS (ESI) calcd for
C8H14O3Na [M + Na]+ 181.0835; Found: 181.0841.
(4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolane-4-carboxylic acid
(5): To a stirred solution of 10 (1.7 g, 10.76 mmol) in
65 MeCN:H2O (2:1, 24 mL) were added PhI(OAc)2 (8.66 g, 26.90
mmol) and TEMPO (0.336 g, 2.15 mmol). The reaction mixture
was stirred at room temperature for 3 h. After completion of the
reaction (monitored by TLC), it was extracted with ethyl acetate
(3 × 20 mL). The combined organic layers were washed with
70 brine (40 mL), dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The crude product was purified by silica
gel column chromatography (EtOAc/hexane = 1:1) to afford
desired acid 5 (1.52 g, 82%) as a colorless liquid. [α]D20 −2.78 (c
2.8, CHCl3); IR (neat): 2927, 2855, 1733, 1420, 1377, 1215,
75 1165, 1091, 875 cm−1; 1H NMR (500 MHz, CDCl3): 5.79 (ddd, J
= 7.0, 10.4, 17.2 Hz, 1H), 5.46 (d, J = 17.1 Hz, 1H), 5.31 (d, J =
10.4 Hz, 1H), 4.85 (t, J = 7.2 Hz, 1H), 4.69 (d, J = 7.5 Hz, 1H),
1.62 (s, 3H), 1.41 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 174.0,
131.6, 119.8, 111.3, 78.5, 77.2, 26.8, 25.3; HRMS (ESI) calcd for
80 C8H12O4Na [M + Na]+ 195.0628; Found: 195.0621.
((4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)methanol
(10): Methyltriphenylphosphonium bromide (13.40 g, 37.5
40 mmol) was dissolved in THF (30 mL) and cooled to –78 ºC. nꢀ
Butyllithium (12.5 mL, 2.5 M in hexane, 31.25 mmol) was added
drop wise to the above stirred solution which turned into light
(4R,5R)-(2S,3R)-3-(Methoxymethoxy)undec-10-en-2-yl-2,2-
dimethyl-5-vinyl-1,3-dioxolane-4-carbo xylate (4): To a stirred
solution of the acid 5 (1.15 g, 6.70 mmol) in dry toluene (15 mL),
Et3N (1.0 mL, 7.17 mmol) followed by 2,4,6ꢀtrichlorobenzoyl
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chloride (1.12 mL, 7.17 mmol) was added at 0 °C under N2
110.7, 95.6, 78.6, 78.3, 77.5, 72.5, 55.7, 30.3, 29.2, 27.1, 26.4,
atmosphere and continued to stir for 45 min at room temperature. 45 26.2, 25.6, 25.3, 20.9, 15.7 ppm; ESIꢀHRMS Calcd for
DMAP (0.58 g, 4.78 mmol) and alcohol 6 (1.1 g, 4.78 mmol)
dissolved in dry toluene (20 mL) was added to reaction mixture
dropwise at 0 °C and allowed to stir for 7 h at room temperature.
After completion of the reaction (monitored by TLC), it was
quenched with water (20 mL). The reaction mixture was
extracted with ethyl acetate (3 × 40 mL). The combined organic
layers were washed with brine (50 mL), dried over anhydrous
C19H36O6N [M + NH4]+ 374.2537; found: 374.2564.
(3aR,6S,7R,15aR)-7-(Methoxymethoxy)-2,2,6-trimethyldeca-
hydro-3aH-[1,3]dioxolo[4,5-c][1]oxa-cyclotetradecin-4(6H)-
one (18): A catalytic amount of PtO2 was added in one portion to
50 a solution of 17 (270 mg, 0.76 mmol) in ethyl acetate (5 mL). The
reaction vessel was evacuated under vacuum and placed under H2
balloon pressure. The reaction mixture was allowed to stir at
room temperature for 3 h until complete consumption of the
starting material (monitored by TLC). The reaction was filtered
55 through a small pad of Celite and washed with ethyl acetate (2 ×
15 mL). The combined organic layer was concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel (EtOAc/hexane = 1:9) to provide
5
10 Na2SO4 and solvent evaporated under reduced pressure. The
crude mass was purified by silica gel column chromatography
(EtOAc/hexane = 1:9) to furnish 4 (1.19 g, 65%, based on the
20
starting alcohol) as a colorless liquid. [α]D +2.34 (c 0.45,
CHCl3); IR (neat): 2925, 2853, 2311, 1756, 1377, 1194, 1096,
1
15 1038, 918 cm−1; H NMR (400 MHz, CDCl3) δ = 5.77 (m, 2H),
5.41 (d, J = 17.0 Hz, 1H), 5.25 (d, J = 10.3 Hz, 1H), 5.07ꢀ4.89
(m, 3H), 4.78 (t, J = 7.2 Hz, 1H), 4.70 (d, J = 6.7 Hz, 1H), 4.65
(d, J = 7.2 Hz, 1H), 4.60 (d, J = 6.7 Hz, 1H), 3.60 (m, 1H), 3.36
(s, 3H), 2.07ꢀ1.99 (m, 2H), 1.62 (s, 3H), 1.53ꢀ1.25 (m, 13H), 1.17
20 (d, J = 6.5 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.8,
139.0, 132.4, 119.4, 114.2, 111.0, 96.1, 78.9, 78.5, 77.3, 73.0,
55.7, 33.7, 30.8, 29.4, 28.9, 28.8, 27.0, 25.6, 25.5, 14.5 ppm; ESIꢀ
HRMS Calcd for C21H40O6N [M + NH4]+ 402.2850; found:
402.2871.
20
the desired product 18 (255 mg, 95%) as a colorless oil. [α]D
60 −6.12 (c 0.65, CHCl3); IR (neat): 2927, 2853, 2310, 1732, 1457,
1375, 1219, 1044, 772 cm−1; H NMR (500 MHz, CDCl3) δ =
1
4.90 (m, 1H), 4.72 (d, J = 6.9, Hz, 1H), 4.65 (d, J = 6.9, Hz, 1H),
4.51 (d, J = 6.6 Hz, 1H), 4.27 (m, 1H), 3.67 (m, 1H), 3.37 (s, 3H),
1.53 (s, 3H), 1.49ꢀ1.37 (m, 7H), 1.36ꢀ1.20 (m, 15H) ppm; 13C
65 NMR (100 MHz, CDCl3) δ = 170.4, 110.6, 95.3, 79.0, 77.9, 77.4,
70.8, 55.8, 27.72, 27.67, 27.1, 26.6, 25.7, 25.5, 23.5, 22.4, 21.9,
18.0, 17.6 ppm; HRMS (ESI) calcd for C19H34O6Na [M + Na]+
381.2248; Found: 381.2259.
25 (3aR,6S,7R,15aR,E)-7-(Methoxymethoxy)-2,2,6-trimethyl-
6,7,8,9,10,11,12,13-octahydro-3aH-[1,3]dioxolo[4,5-c][1]oxa
cyclotetradecin-4(15aH)-one (17):
A
flameꢀdried roundꢀ
(E)-Ethyl-3-((4S,5R)-5-((9R,10S)-10-hydroxy-9-(methoxymeth
70 oxy)undecyl)-2,2-dimethyl-1,3-diox- olan-4-yl)acrylate (3): To
a stirred solution of lactone 18 (140 mg, 0.39 mmol) in CH2Cl2
(15 mL), DIBALꢀH (0.36 mL, 1.4 M solution in toluene, 0.51
bottomed flask was charged with a solution of ester 4 (0.6 g, 1.6
mmol) in CH2Cl2 (500 mL). The solution was degassed for 20
30 min under argon atmosphere. Grubbs’ 2nd generation catalyst
(132 mg, 0.16 mmol) was subsequently added to the solution,
which was again degassed for 15 min. The reaction mixture was
stirred for 12 h under refluxing conditions. After completion of
the reaction (monitored by TLC), solvent was evaporated under
35 reduced pressure. Purification of the crude residue by silica gel
column chromatography (EtOAc/hexane = 1:9) afforded 17 (404
mg, 73%) as a colorless liquid. [α]D20 +29.53 (c 0.35, CHCl3); IR
(neat): 2926, 2856, 1728, 1457, 1246, 1193, 1091, 1035, 976, 722
o
mmol) was added slowly at −78 C under nitrogen atmosphere.
The solution was stirred for 20 min at same temperature and
75 allowed to warm to 0 oC slowly. After completion of the reaction
(monitored by TLC), MeOH (0.2 mL) was added slowly followed
by the addition of cold aqueous saturated sodium potassium
tartrate (15 mL). The biphasic mixture was stirred for further 2 h
and separated. The aqueous layer was extracted with CH2Cl2 (3 ×
80 20 mL). The combined organic phase was dried over Na2SO4 and
concentrated under reduced pressure. The crude residue (111 mg,
79%) was used for the next step without further purification.
1
cm−1; H NMR (500 MHz, CDCl3) δ = 5.86 (m, 1H), 5.48 (dd, J
40 = 6.9, 15.5 Hz, 1H), 5.10 (m, 1H), 4.82 (t, J = 7.0 Hz, 1H), 4.77
(d, J = 6.7 Hz, 1H), 4.72ꢀ4.68 (m, 2H), 3.72 (q, J = 5.3 Hz, 1H),
3.41 (s, 3H), 2.17ꢀ2.04 (m, 2H), 1.65ꢀ1.55 (m, 5H), 1.49ꢀ1.22 (m,
14H) ppm; 13C NMR (100 MHz, CDCl3) δ = 169.3, 136.0, 124.2,
The lactol compound (111 mg, 0.31 mmol) in benzene (10 mL),
was added Ph3P=CHCO2Et (0.161 mg, 0.46 mmol) at room
85 temperature. The reaction mixture was heated to 90 °C for 4 h.
8
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After completion of the reaction (monitored by TLC), the
reaction mixture was concentrated under reduced pressure.
IR (neat): 2917, 1636, 1430, 1373, 1337, 1163, 1115, 1061, 898
1
cm−1; H NMR (500 MHz, CDCl3): 6.82 (dd, J = 7.2, 15.7 Hz,
Purification by silica gel column chromatography (EtOAc/hexane 45 1H), 6.03 (dd, J = 1.1, 15.7 Hz, 1H), 5.02 (m, 1H), 4.66 (dd, J =
= 3:7) afforded α,βꢀunsaturated ester 3 (102 mg, 77%; 61% over
6.9, 11.1 Hz, 2H), 4.61 (m, 1H), 4.21 (dd, J = 6.3, 13.6 Hz, 1H),
3.56 (m, 1H), 3.38 (s, 3H), 1.63ꢀ1.48 (m, 7H), 1.47ꢀ1.35 (m, 7H),
1.33ꢀ1.14 (m, 11H); 13C NMR (125 MHz, CDCl3): δ 164.7,
142.7, 124.1, 108.6, 95.9, 79.1, 78.4, 77.3, 71.0, 55.8, 29.7, 29.6,
20
5
two steps) as a colorless liquid. [α]D +7.18 (c 0.3, CHCl3); IR
(neat): 2925, 2854, 1731, 1608, 1459, 1382, 1272, 1038, 721
cm−1; 1H NMR (400 MHz, CDCl3) δ = 6.82 (dd, J = 6.2, 15.7 Hz,
1H), 6.04 (dd, J = 1.5, 15.7 Hz, 1H), 4.73 (d, J = 7.0 Hz, 1H), 50 29.5, 28.0, 27.8, 26.9, 26.6, 25.4, 23.2, 22.5, 17.7 ppm; HRMS
4.65ꢀ4.60 (m, 2H), 4.24ꢀ4.16 (m, 3H), 3.74 (m, 1H), 3.48 (m,
(ESI) calcd for C21H36O6Na [M + Na]+ 407.2404; Found:
10 1H), 3.42 (s, 3H), 1.74 (br s, 1H), 1.52ꢀ1.40 (m, 7H), 1.39ꢀ1.33
(m, 5H), 1.32ꢀ1.20 (m, 13H), 1.12 (d, J = 6.6 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ = 166.0, 143.8, 122.9, 108.7, 97.6,
85.1, 78.3, 77.3, 69.0, 60.5, 55.8, 31.0, 30.4, 29.6, 29.41, 29.39,
28.0, 26.3, 26.0, 25.5, 17.1, 14.2 ppm; ESIꢀHRMS Calcd for
15 C23H42O7Na [M + Na]+ 453.2823; found: 453.2824.
407.2410.
(5S,6R,15R,16S,E)-5,6-Dihydroxy-15-(methoxymethoxy)-16-
methyloxacyclohexadec-3-en-2-one (20): To a stirred solution
55 of 2 (13 mg, 0.034 mmol) in CH3CN (8 mL), was added
CuCl2·2H2O (9 mg, 0.050 mmol) at 0 °C. The reaction mixture
was allowed to stir for 2 h at the same temperature. After
complete conversion (monitored by TLC), the reaction was
quenched by a saturated NaHCO3 solution (5 mL). The aqueous
(3aS,8S,9R,17aR,E)-9-(Methoxymethoxy)-2,2,8-trimethyl-
9,10,11,12,13,14,15,16,17,17a-decahydro-3aH-[1,3]dioxolo-
[4,5-e][1]oxacyclohexadecin-6(8H)-one (2): To
a
stirred 60 layer extracted with ethyl acetate (3 × 10 mL), the combined
solution of the ester 3 (64 mg, 0.15 mmol) in THF (8 mL), was
20 added aqueous solution of LiOH (37 mg, 0.9 mL, 0.89 mmol) at
room temperature. The reaction mixture was allowed to stir at 70
°C for 12 h. After completion of the reaction (monitored by
organic layer were washed with brine (10 mL) and dried over
anhydrous Na2SO4. The combined organic solvent was removed
under reduced pressure. The residue was purified by column
chromatography with silica gel (EtOAc/hexane = 2:3) to give 20
TLC), it was cooled to 0 °C. The reaction mixture was acidified 65 (10 mg, 90%) as a clear liquid. [α]D20 −4.08 (c 0.3, CHCl3); IR
with 1 M HCl until pH = 5.0 and diluted with ethyl acetate (15
25 mL). The aqueous layer extracted with ethyl acetate (3 × 15 mL).
The combined organic layer were washed with brine (30 mL),
dried over anhydrous Na2SO4 and evaporated to dryness under
(neat): 3414, 2923, 2855, 1716, 1628, 1457, 1393, 1096, 1028,
1
767 cm−1; H NMR (400 MHz, CDCl3): 6.93 (dd, J = 4.8, 15.8
Hz, 1H), 6.11 (dd, J = 1.7, 15.8 Hz, 1H), 5.00 (m, 1H), 4.66 (d, J
= 2.5 Hz, 2H), 4.50 (m, 1H), 3.77 (m, 1H), 3.55 (m, 1H), 3.38 (s,
reduced pressure. The crude mass was dried through azeotropic 70 3H), 2.56 (br s, 1H), 2.13 (br s, 1H), 1.68ꢀ1.52 (m, 3H), 1.50ꢀ1.16
mixture with dry benzene to afford 19 (46 mg, 77%) as a
(m, 16H) ppm; 13C NMR (100 MHz, CDCl3): δ 165.3, 145.6,
122.3, 95.9, 79.4, 73.8, 73.5, 71.3, 55.8, 29.9, 29.6, 28.3, 27.3,
26.5, 26.1, 23.1, 22.6, 17.7 ppm; HRMS (ESI) calcd for
C18H32O6Na [M + Na]+ 367.2091; Found: 367.2097.
30 colorless liquid.
4 Å molecular sieves (114 mg) and toluene (50 mL) were placed
in a twoꢀnecked 250 mL round bottomed flask, followed by the
addition of DMAP (70 mg, 0.57 mmol) and MNBA (59 mg, 0.17
mmol) at 0 °C under nitrogen atmosphere. The crude secoꢀacid
35 19 (azeotroped with benzene two times) (46 mg, 0.114 mmol)
was dissolved in toluene (20 mL) and added to the above mixture
for 10 h with the help of syringe pump at room temperature. After
75 (5S,6R,15R,16S,E)-5,6,15-Trihydroxy-16-methyloxacyclohex-
adec-3-en-2-one (1): Compound 20 (6.5 mg, 0.019 mmol) was
dissolved in THF (2 mL) and aqueous 4 N HCl (9 ꢁL, 0.038
mmol) was added at 0 °C. The reaction mixture was stirred at
room temperature for 6 h and then quenched with saturated
completion of the reaction (monitored by TLC), MS 4 Å was 80 aqueous NaHCO3 solution. The aqueous layer was extracted with
removed by filtration and the filtrate was evaporated under
40 reduced pressure. The resulting residue was purified by flash
chromatography (EtOAc/hexane = 1:9) to provide macrolactone 2
(29 mg, 66%) as a colorless liquid. [α]D20 −3.28 (c 0.5, CHCl3);
ethyl acetate (3 × 5 mL) and the combined organic layer was
washed with brine (10 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure. Purification of the crude
residue by silica gel column chromatography (EtOAc/hexane =
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DOI: 10.1039/C6OB02435A
1:1) afforded 1 (4.1 mg, 72%) as a amorphous solid. [α]D20 −9.42
(c 0.1, CHCl3); IR (neat): 3447, 2923, 2853, 1716, 1461, 1376,
1251, 1170, 1099, 771 cm−1; 1H NMR (at 40 oC as the compound
was not completely soluble in CDCl3) (500 MHz, CDCl3): 6.92
(dd, J = 5.2, 15.7 Hz, 1H), 6.11 (dd, J = 1.7, 15.9 Hz, 1H), 4.87
(m, 1H), 4.50 (m, 1H), 3.74 (m, 1H), 3.54 (m, 1H), 2.38 (br s,
1H), 2.00 (br s, 1H), 1.66ꢀ1.52 (m, 2H), 1.48 (m, 1H), 1.40 (m,
1H), 1.36 (d, J = 6.3 Hz, 3H), 1.38ꢀ1.14 (m, 12H) ppm; 13C NMR
(at 40 oC as the compound was not completely soluble in CDCl3)
40
5
6
7
M. Ueda, M. Yamaura, Y. Ikeda, Y. Suzuki, K. Yoshizato, I.
Hayakawa and H. Kigoshi, J. Org. Chem. 2009, 74, 3370–3377.
X. M. Yu, H. Han and B. S. J. Blagg, J. Org. Chem. 2005, 70, 5599ꢀ
5605.
5
a) I. Shiina, M. Kubota and R. Ibuka, Tetrahedron Lett. 2002, 43,
7535ꢀ7539; b) I. Shiina, M. Kubota, H. Oshiumi and M. Hashizume,
J. Org. Chem. 2004, 69, 1822−1830; c) A. Parenty, X. Moreau and
J. M. Champagne, Chem. Rev. 2006, 106, 911–939.
45
50
55
10 (125 MHz, CDCl3): δ 165.6, 145.8, 122.5, 74.5, 74.02, 73.97,
73.7, 32.1, 30.0, 27.9, 27.6, 26.3, 23.4, 23.0, 17.6 ppm; HRMS
(ESI) calcd for C16H28O5Na [M + Na]+ 323.1829; Found:
323.1847.
8
9
L. Nagarapu, S. Karnakanti and R. Bannu, Tetrahedron 2012, 68,
5829ꢀ5832.
J. B. Epp and T. S. Widlanski, J. Org. Chem. 1999, 64, 293ꢀ295.
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Acknowledgements
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A. J. Mancuso, S.ꢀL. Huang and D. Swern, J. Org. Chem. 1978,
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15 The authors thank Council of Scientific & Industrial Research
(CSIR), New Delhi, India for financial support as part of XII Five
Year plan programme under title ORIGIN (CSCꢀ0108). B.J.
thanks the CSIR, New Delhi, India, for financial assistance in the
form of fellowships.
12
V. S. Martin, S. S. Woodward, T. Katsuki, Y. Yamada, M. Ikeda
and K. B. Sharpless, J. Am. Chem. Soc. 1981, 103, 6237.
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DOI: 10.1039/C6OB02435A
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