Stereoselective total synthesis of FD-891

Article abstract of DOI:10.1021/jo302205t

FD-891, a structurally unique 16-membered macrolide having anticancer activity, was synthesized according to a strategy employing asymmetric allylation, Prins cyclization, cross-metathesis reaction, Yamaguchi lactonization, and Julia-Kocienski olefination

Full text of DOI:10.1021/jo302205t

Article
pubs.acs.org/joc
Stereoselective Total Synthesis of FD-891
J. S. Yadav,* Sukant Kishore Das, and G. Sabitha
Natural Products Chemistry Division I, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
S
* Supporting Information
ABSTRACT: FD-891, a structurally unique 16-membered macro-
lide having anticancer activity, was synthesized according to a
strategy employing asymmetric allylation, Prins cyclization, cross-
metathesis reaction, Yamaguchi lactonization, and Julia−Kocienski
olefination.
Scheme 1. Retrosynthetic Analysis
INTRODUCTION
■
FD-891 (1) is a novel macrolide isolated in 1994 by a Japanese
group from the fermentation broth of Streptomyces graminofa-
ciens A-8890.1 FD-891 exhibited a notable cytotoxic activity in
vitro against various cancer cell lines and also prevents both
perforin and FasL-dependent CTL-mediated killing pathways.2
More recently, it has been found to be the phytotoxic agent of
infections by Streptomyces spp. causing potato russet scab.3
Initially, the structure of FD-891 was found to be a 18-
membered macrolide, based on the results of chemical
degradations and X-ray diffraction analyses of some degradation
products, which was later revised as 16-membered macrolide
1,4 with no changes in stereochemistry, but one double bond
has now been moved from inside the ring to the side chain. The
limited availability of 1 together with its unique structural
feature and promising biological activity make it an attractive
synthetic target for total synthesis.5 As part of our continued
interest in the total synthesis of macrolides,6 we embarked on
the total synthesis of FD-891 (1). Herein, we describe an
efficient and stereoselective total synthesis of FD-891.
RESULTS AND DISCUSSION
■
Our retrosynthetic analysis of 1 is depicted in Scheme 1. The
target molecule 1 could be made from 2 and 3 by using Julia−
Kocienski olefination, whereas 2 could be realized from 4 and 5
by cross-metathesis reaction followed by Yamaguchi lactoniza-
tion (Scheme 1).
protected as its PMB ether to afford 12. Selective removal of
the primary TBS group in the presence of the secondary TBS
group was accomplished with PPTS in MeOH at 0 °C for 1 h
to furnish the required alcohol 13. The free alcohol was then
oxidized to the aldehyde, and subsequent Wittig olefination
provided ester 14. DIBAL-H reduction of ester gave allylic
alcohol 15, which was oxidized to the corresponding aldehyde
using MnO2 followed by Horner−Wadsworth−Emmons
olefination to provide the conjugated dienoate 16. Oxidative
removal of the PMB group in wet DCM using DDQ gave the
Our approach for the synthesis of fragment 4 (Scheme 2)
began with regioselective opening of known epoxy alcohol 67
with lithium dimethylcuprate to give an inseparable mixture of
1,3-diol and 1,2-diol products (3:1).7 After oxidative cleavage
with sodium periodate, the undesired 1,2-diol compound was
separated. Protection of the major 1,3-diol 7 as di-TBS ether 8,
followed by PMB group removal, furnished primary alcohol 9.
The resulting alcohol 9 was then oxidized to aldehyde with IBX
and subjected to Wittig olefination with two-carbon Wittig
ylide to provide ester 10, which on reduction with DIBAL-H
provided the allylic alcohol 11. The resulting alcohol was then
Received: October 8, 2012
Published: November 8, 2012
© 2012 American Chemical Society
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Scheme 2. Synthesis of Fragment 4
allylic alcohol 17 in 88% yield. Asymmetric Sharpless
epoxidation provided epoxy alcohol 18, which was converted
into the aldehyde and subjected to asymmetric allylation using
(+)-IPC2 allylborane to produce homoallyl alcohol 19 in 60%
overall yield as a 92:8 mixture of diastereoisomers.5b,8 After
purification by column chromatography the major diastereomer
19 was converted into the TBS ether to provide the desired
fragment 4.
The synthesis of fragment 5 (Scheme 3) began with the
known epoxy alcohol 20,9 which was opened with Me3Al in
pentane from −10 °C to rt to provide a mixture of two
inseparable 1,2-diol and 1,3-diol products.10 Fortunately,
separation by column chromatography proved possible after
acetonide protection (21, 70%). Hydrolysis of 21 with PTSA
and MeOH provided the required diol 23 in 85% yield. Diol 23
on treatment with tosyl imidazole in the presence of NaH at 0
°C gave the epoxide 24 in 70% yield. This epoxide was opened
with vinyl magnesium bromide in the presence of catalytic CuI
to give homoallyl alcohol 25 in 85% yield, and subsequent
removal of benzyl group and the selective protection of primary
hydroxyl group as TBS ether provided 5.
synthesis of sulfone began (Scheme 4) with the Prins
cyclization reaction of known homoallylic alcohol 27 and (S)-
3-(benzyloxy)-2-methylpropanal 28 in the presence of trifluoro-
acetic acid followed by hydrolysis of the resulting trifluor-
oacetate to afford the tetrasubstituted pyran 29.11 The
preparation of homoallyl alcohol 31 with the required chiral
centers was realized through selective tosylation of the primary
hydroxyl group in 29 followed by convertion into iodo
derivative and reductive ring-opening of pyran. Next, the 1,3-
diol was protected as an acetonide and removal of benzyl group
provided the primary alcohol 33, which was oxidized to the
aldehyde by Dess−Martin periodinane. Addition of 2 equiv of
methyl Grignard reagent to the aldehyde furnished the racemic
alcohol 34, which was without purification directly oxidized
with Dess−Martin periodinane to provide methyl ketone 35 in
85% yield over the two steps. Reduction of 35 under chelation
control conditions12 furnished the alcohol as a diastereomeric
mixture in 85:15 ratio. The required major isomer 36 was
separated by column chromatography and subjected to
methylation to give the corresponding methyl ether 37. The
double bond in compound 37 was then transformed to the
alcohol 38 by ozonolysis followed by reduction with NaBH4.
Introduction of the sulfide by Mitsunobu5c,13 reaction and
Generation of the 4 chiral centers in the side chain of 1 was
achieved through application of Prins cyclization. Thus,
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oxidation of the sulfide to sulfone5c,14 afforded the Julia−
Kocienski olefination substrate 3.
Scheme 3. Synthesis of Fragment 5
With both coupling partners 4 and 5 in hand, we could now
investigate the cross-metathesis reaction. Accordingly, Grubbs’
second generation catalyst15 in refluxing CH2Cl2 provided 39 in
65% yield. Hydrolysis of the ethyl ester produced seco-acid,
which readily lactonized under standard Yamaguchi5a,16
conditions to give the macrolactone 40 in 60% yield.
Selective cleavage of the primary TBS group followed by
Dess−Martin oxidation (Scheme 5) delivered the aldehyde 2
and set the stage for Julia-olefination reaction.
The aldehyde 2 was subjected to Julia−Kocienski olefinatio-
n5a with sulfone 3 as reported to provide the E-olefin 42 in 80%
yield (Scheme 6). The deprotection of two TBS groups and the
5a
acetonide was achieved in one- pot by using H2SiF6 to give
the cytotoxic macrolide FD-891 (1) in 90% yield.
The spectral data (1H NMR, 13C NMR), optical rotation
([α]25 +11.5, c 0.1, MeOH, lit.1,4 value [α]D +14.0, c 0.1,
D
MeOH), and HRMS data of synthetic (1) were in agreement
with those of the natural product.
CONCLUSION
■
We have described a stereoselective total synthesis of cytotoxic
macrolide FD-891. The key features of the synthesis are the use
of the asymmetric allylation, Prins cyclization, cross-metathesis
reaction, Yamaguchi lactonization, and Julia−Kocienski olefi-
nation.
Scheme 4. Synthesis of Fragment 3
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1
obtained using either a TOF or a double focusing spectrometer. H
Scheme 5. Synthesis of Fragment 2
NMR spectra were recorded at 300, 400, 500 and 13C NMR spectra 75
MHz in CDCl3 solution unless otherwise mentioned; chemical shifts
are 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, m = multiplet, br = broad.
(2R,3S)-4-(4-Methoxybenzyloxy)-2-methylbutane-1,3-diol
(7). To a stirred suspension of CuI (4.24 g, 22.3 mmol) in dry Et2O
(50 mL) was slowly added methyl lithium (27.9 mL, 1.6 M, 44.6
mmol) in ether at 0 °C under nitrogen atmosphere, and the resulting
solution was stirred for 15 min at 0 °C. Epoxy alcohol 6 (2.0 g, 8.92
mmol) in dry Et2O (20 mL) was then added dropwise at −40 °C.
Once the addition was completed, the reaction mixture was stirred at 0
°C for 3 h. The reaction was quenched by the addition of saturated
aqueous NH4Cl. The mixture was filtered through a Celite pad, and
the salts were washed several times with Et2O. The organic layer was
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure to provide a 3:1 mixture of the regioisomeric diols.
The crude mixture was dissolved in 10% aqueous THF (50 mL), and
NaIO4 (1.9 g, 8.92 mmol) was added at 0 °C to cleave the 1,2-diol.
The reaction was completed in 1 h. After the layers were separated, the
aqueous layer was extracted with Et2O. The organic layer was dried
over anhydrous Na2SO4, and solvent was removed under reduced
pressure. The crude residue was purified on silica gel column
chromatography (70% EtOAc/hexane) to provide the desired diol 7
1
(1.4 g, 68%) as a yellow oil. [α]25 +2.5, (c 1.5, CHCl3); H NMR
D
(CDCl3, 500 MHz) δ 7.25 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0 Hz,
2H), 4.49 (d, J = 3.0 Hz 2H), 4.0−3.95 (m, 1H), 3.80 (s, 3H), 3.67−
3.60 (m, 2H), 3.49 (d, J = 5.0 Hz, 2H), 2.77 (brs, 2H), 1.90−1.80 (m,
1H), 0.92 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 159.2,
129.8, 129.3, 113.7, 73.0, 72.2, 72.1, 65.9, 55.1, 37.3, 10.9; IR (neat)
3403, 2929, 1612, 1513, 1247, 1032, 820 cm−1; ESIMS m/z 263 [M +
Na]+.
Scheme 6. Synthesis of FD-891 (1)
(5S,6R)-5-((4-Methoxybenzyloxy)methyl)-2,2,3,3,6,9,9,10,10-
nonamethyl-4,8-dioxa-3,9-disilaundecane (8). The diol 7 (1.0 g,
4.16 mmol) was dissolved in CH2Cl2 (10 mL), and then imidazole
(0.84 g, 12.48 mmol) was added followed by TBDMSCl (1.56 g, 10.4
mmol). After 16 h the reaction was washed with water (1 × 10 mL),
and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL), dried
over Na2SO4, and concentrated. Purification by silica gel chromatog-
raphy (5% EtOAc/hexane) provided the silyl ether 8 (1.8 g, 95%) as a
yellow oil. [α]25D −3.9, (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 7.25 (d, J = 7.5 Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 4.49−4.37 (m,
2H), 4.02−3.96 (m, 1H), 3.81 (s, 3H), 3.56−3.34 (m, 4H), 1.86−1.76
(m, 1H), 0.89(s, 9H), 0.87(s, 9H), 0.80 (d, J = 6.8 Hz, 3H), 0.03 (s,
12H), 13C NMR (CDCl3, 75 MHz) δ 159.0, 129.1, 113.6, 72.9, 72.7,
70.6, 65.2, 55.2, 38.8, 25.9, 18.2, 10.3, −4.1, −5.0, −5.3; IR (neat)
2954, 2930, 2857, 1250, 1093, 836, 775 cm−1; ESI HRMS m/z calcd
for C25H48O4NaSi2 [M + Na]+ 491.29833, found 491.29739.
(2S,3R)-2,4-Bis(tert-butyldimethylsilyloxy)-3-methylbutan-1-
ol (9). To a solution of the compound 8 (1.7 g, 3.62 mmol) in CH2Cl2
(10 mL) and pH 7 buffer solution (1 mL) was added DDQ (1.84 g,
5.44 mmol) at 0 °C, and the mixture was allowed to stir for 2 h at
room temperature. The reaction mixture was quenched with saturated
NaHCO3 solution (10 mL) and diluted with CH2Cl2 (10 mL). The
two layers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layer was washed with
brine (2 × 20 mL), dried over anhydrous Na2SO4, and evaporated to
give a red crude product, which on purification by silica gel column
chromatography (15% EtOAc/hexane) provided the desired primary
EXPERIMENTAL SECTION
■
All reactions were performed under inert atmosphere, if argon
mentioned. All glassware apparatus used for reactions were perfectly
oven/flame-dried. Anhydrous solvents were distilled prior to use: THF
from Na and benzophenone; CH2Cl2, DMSO from CaH2; MeOH
from Mg cake. Commercial reagents were used without purification.
Column chromatography was carried out by using silica gel (60−120
mesh) unless otherwise mentioned. Analytical thin layer chromatog-
raphy (TLC) was run on silica gel 60 F254 precoated plates (250 μm
thickness). Optical rotations [α]D were measured on a polarimeter and
given in 10−1 deg cm2 g−1. Infrared spectra were recorded in CHCl3/
KBr (as mentioned) and reported in wavenumber (cm−1). Mass
spectral data were obtained using MS (EI) ESI, HRMS mass
spectrometers. High resolution mass spectra (HRMS) [ESI+] were
alcohol 9 (1.2 g, 95%) as a colorless liquid. [α]25 −3.0, (c 1.0,
D
1
CHCl3); H NMR (CDCl3, 300 MHz) δ 3.76−3.69 (m, 1H), 3.61−
3.48 (m, 4H), 1.85−1.74 (m, 1H), 0.91(s, 9H), 0.89 (s, 9H), 0.89 (d, J
= 6.8 Hz, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05 (s, 6H); 13C NMR
(CDCl3, 75 MHz) δ 74.0, 64.8, 64.7, 39.4, 25.8, 18.1, 12.4, −4.4, −4.8,
−5.5; IR (neat) 3419, 2954, 2930, 2858, 1253, 1053, 837, 774 cm−1;
ESI HRMS m/z calcd for C17H41O3Si2 [M + H]+ 349.25887, found
349.25946.
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(4R,5R,E)-Ethyl 4,6-Bis(tert-butyldimethylsilyloxy)-5-methyl-
hex-2-enoate (10). To an ice-cooled solution of 2-(iodooxy)benzoic
acid (1.2 g, 4.3 mmol) in anhydrous DMSO (1.2 mL, 14.3 mmol) was
added a solution of alcohol 9 (1.0 g, 2.86 mmol) in anhydrous CH2Cl2
(20 mL). The mixture was stirred at room temperature for 3 h, then
filtered through a Celite pad, and washed with Et2O (2 × 10 mL). The
combined organic filtrates were washed with H2O (2 × 5 mL) and
brine, dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The crude product was immediately dissolved in C6H6 (20
mL), and stable two-carbon Wittig yilide (3.0 g, 8.58 mmol) was
added. The reaction mixture was refluxed for 3 h and then allowed to
cool to rt. The solvent was removed under reduced pressure, and the
compound was purified by silica gel column chromatography (5%
was quinched with solid NaHCO3, and methanol was removed under
reduced pressure. Water was added and extracted with EtOAc (3 × 10
mL). The combined organic layer was dried over anhydrous Na2SO4
and concentrated under vacuum. The residue was purified on silica gel
column chromatography (20% EtOAc/hexane) to provide 13 (0.5 g,
1
85%) as colorless oil. [α]25 −2.8, (c 0.6, CHCl3); H NMR (CDCl3,
D
300 MHz) δ 7.25 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 5.79−
5.75 (m, 2H), 4.44 (s, 2H), 4.32−4.27 (m, 1H), 4.02 (d, J = 3.0 Hz,
2H), 3.81 (s, 3H), 3.70−3.62 (m, 1H), 3.49 (dd, J = 10.6, 3.8 Hz, 1H),
2.09−1.92 (m, 1H), 0.90 (s, 9H), 0.81 (d, J = 7.5 Hz, 3H), 0.09 (s,
3H), 0.05 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 159.1, 132.5, 130.2,
129.2, 128.1, 113.7, 76.1,71.4, 69.6, 65.5, 55.1, 40.9, 25.7, 18.0, 12.2,
−4.4, −5.2; IR (neat) 3429, 2955, 2931, 2857, 1612, 1513, 1465, 1250,
1094, 1037, 836, 776 cm−1; ESI HRMS m/z calcd for C21H36O4NaSi
[M + Na]+ 403.22751, found 403.22661.
EtOAc/hexane) to provide 10 (1.06 g, 90%) as pale yellow oil. [α]25
D
−7.3, (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 6.93 (dd, J = 4.5,
15.1 Hz, 1H), 5.95 (d, J = 17.4 Hz, 1H), 4.52−4.47 (m, 1H), 4.19 (q, J
= 6.8 Hz, 2H), 3.56−3.38 (m, 2H), 1.76−1.67 (m, 1H), 1.29 (t, J = 7.5
Hz, 3H), 0.91(s, 9H), 0.88 (s, 9H), 0.80 (d, J = 6.8 Hz, 3H), 0.06 (s,
3H), 0.04 (s, 6H), 0.01 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 166.5,
150.8, 120.2, 71.0, 64.3, 60.1, 41.8, 25.8, 18.1, 14.1, 10.3, −4.4, −5.2,
−5.4; IR (neat) 2956, 2932, 2858, 1724, 1256, 1101, 838, 776 cm−1;
ESI HRMS m/z calcd for C21H44O4NaSi2 [M + Na]+ 439.26703,
found 439.26569.
(2E,4R,5R,6E)-Ethyl 5-(tert-Butyldimethylsilyloxy)-8-(4-me-
thoxybenzyloxy)-2,4-dimethylocta-2,6-dienoate (14). To an
ice-cooled solution of 2-(iodooxy)benzoic acid (0.475 g, 1.77 mmol)
in anhydrous DMSO (0.47 mL, 5.9 mmol) was added a solution of
alcohol 13 (0.45 g, 1.18 mmol) in CH2Cl2 (10 mL). The mixture was
stirred at room temperature for 4 h, then filtered through a Celite pad,
and washed with Et2O (2 × 10 mL). The combined organic filtrates
were washed with H2O (2 × 5 mL) and brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude product
was immediately dissolved in CH2Cl2 (20 mL), and Ph3C(CH3)-
CO2Et Wittig yilide (1.63 g, 3.5 mmol) was added. The reaction
mixture was refluxed for 15 h and then allowed to cool to room
temperature. The solvent was removed under reduced pressure, and
the compound was purified by silica gel column chromatography (10%
(4R,5R,E)-4,6-Bis(tert-butyldimethylsilyloxy)-5-methylhex-2-
en-1-ol (11). To a solution of 10 (1 g, 2.4 mmol) in CH2Cl2 (10 mL)
was added 3.44 mL of DIBAL-H (1.76 M in hexane, 6.0 mmol) at 0
°C. The solution was stirred for 1 h at the same temperature and then
quenched by addition of saturated Na/K tartrate at 0 °C. The solution
was warmed to room temperature and stirred for 3 h until two clear
layers were observed. The layers were separated, and the aqueous layer
was further extracted with CH2Cl2 (2 × 20 mL). The combined
organic layers were dried over anhydrous Na2SO4, and solvent was
evaporated under reduced pressure. The crude residue was purified by
EtOAc/hexane) to provide 14 (0.462 g, 85%). [α]25 +2.0, (c 0.5,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.25 (d, J = 9.0 Hz, 2H), 6.88
(d, J = 8.3 Hz, 2H), 6.66 (dq, J = 10.5, 1.5 Hz, 1H), 5.72−5.67 (m,
2H), 4.41 (s, 2H), 4.29−4.11 (m, 2H), 4.04 (t, J = 5.3 Hz, 1H), 4.01−
3.97 (m, 2H), 3.80 (s, 3H), 2.63−2.53 (m, 1H), 1.83 (d, J = 1.4 Hz,
3H), 1.27 (t, J = 6.8 Hz, 3H), 1.0 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H),
0.05 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 168.2,
159.1, 144.3, 134.4, 129.2, 127.5, 113.7, 75.7, 71.2, 69.6, 60.3, 55.2,
40.2, 25.8, 18.1, 17.2, 14.7, 14.2, 12.6, −4.1, −5.0; IR (neat) 2956,
2931, 2856, 1711, 1513, 1465, 1249, 1102, 1035, 836, 776 cm−1;
ESIMS m/z 485 [M + Na]+.
silica gel column chromatography (20% EtOAc/hexane) to provide 11
1
(0.82 g, 92%) as colorless oil. [α]25 −1.9, (c 0.6, CHCl3); H NMR
D
(CDCl3, 300 MHz) δ 5.77−5.68 (m, 2H), 4.30−4.25 (m, 1H), 4.19−
4.10 (m, 2H), 3.59−3.51 (m, 1H), 3.40 (dd, J = 6.8, 9.8 Hz, 1H),
1.68−1.59 (m, 1H), 0.89 (s, 9H), 0.88 (s, 9H), 0.83 (d, J = 6.8 Hz,
3H), 0.04 (s, 3H), 0.03 (s, 6H), 0.0 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 134.2, 128.8, 72.3, 64.8, 63.2, 42.4, 25.9, 18.2, 10.9, −4.1,
−5.0, −5.4; IR (neat) 3358, 2955, 2931, 2858, 1467, 1253, 1090, 837,
775 cm−1; ESI HRMS m/z calcd for C19H42O3NaSi2 [M + Na]+
397.25647, found 397.25752.
(2E,4R,5R,6E)-5-(tert-Butyldimethylsilyloxy)-8-(4-methoxy-
benzyloxy)-2,4-dimethylocta-2,6-dien-1-ol (15). To a solution of
14 (0.45 g, 0.97 mmol) in CH2Cl2 (15 mL) was added 1.38 mL of
DIBAL-H (1.76 M in hexane, 2.435 mmol) at 0 °C. The solution was
stirred for 1 h and quenched by addition of saturated Na/K tartrate at
0 °C. The solution was warmed to room temperature and stirred for 3
h until two clear layers were observed. The layers were separated, and
the aqueous layer was further extracted with CH2Cl2 (2 × 20 mL).
The combined organic layers were dried over anhydrous Na2SO4, and
solvent was evaporated under reduced pressure. The crude product
was purified by silica gel column chromatography (10% EtOAc/
(5R,6R)-5-((E)-3-(4-Methoxybenzyloxy)prop-1-enyl)-
2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecane
(12). To a suspension of 60% sodium hydride (0.11 g, 4.675 mmol)
dispersion in mineral oil in THF (10 mL) at 0 °C (0.7 g, 1.87 mmol)
was slowly added alcohol 11. The resulting mixture was stirred at 0 °C.
After 1 h freshly prepared p-methoxybenzylbromide (0.55 g, 2.8
mmol) was added, and stirring at room temperature was continued for
10 h. The mixture was carefully quenched by addition of water (10
mL). The resulting layers were separated, and the aqueous portion was
extracted with EtOAc (2 × 10 mL), washed with brine (10 mL), and
dried over anhydrous Na2SO4. The solvent was evaporated under
reduced pressure to afford the crude product, which was purified by
silica gel column chromatography (10% EtOAc/hexane) to provide 12
(0.855 g, 93%) as colorless oil. [α]25D −2.0, (c 0.6, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 7.25 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 9.0 Hz,
2H), 5.72−5.68 (m, 2H), 4.43 (s, 2H), 4.30−4.26 (m, 1H), 4.0 (d, J =
3.7 Hz, 2H), 3.81 (s, 3H), 3.60−3.50 (m, 1H), 3.43−3.36 (dd, J = 6.8,
9.8 Hz, 1H), 1.69−1.59 (m, 1H), 0.90 (s, 9H), 0.89 (s, 9H), 0.84 (d, J
= 6.8 Hz, 3H), 0.04 (s, 3H), 0.03 (s, 6H), 0.02 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 159.1, 135.7, 130.4, 129.2, 126.4, 113.7, 72.4,71.3,
69.9, 64.8, 55.1, 42.5, 25.9, 18.1, 10.9, −4.1, −5.0, −5.4; IR (neat)
2954, 2930, 2857, 1513, 1466, 1250, 1097, 837, 775 cm−1; ESI HRMS
m/z calcd for C27H50O4NaSi2 [M + Na]+ 517.31398, found 517.31533.
(2R,3R,E)-3-(tert-Butyldimethylsilyloxy)-6-(4 methoxybenzy-
loxy)-2-methylhex-4-en-1-ol (13). To a stirred solution of 12 (0.8
g, 1.615 mmol) in MeOH (0.08 g, 0.32 mmol) was added PPTS, and
the mixture was stirred for 1 h at 0 °C. After completion of reaction, it
hexane) to provide 15 (0.38 g, 93%) as colorless oil. [α]25 −12, (c
D
1
0.4, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.25 (m, 2H), 6.88 (m,
2H), 5.66−5.64 (m, 2H), 5.25 (d, J = 10.0 Hz, 1H), 4.42 (s, 2H),
4.01−3.90 (m, 5H), 3.81 (s, 3H), 2.53−2.43 (m, 1H), 1.65 (s, 3H),
0.97 (d, J = 7.0 Hz, 3H), 0.90 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 159.1, 135.6, 134.5, 130.2, 129.3, 129.0,
126.7, 113.7, 77.0, 71.4, 69.8, 69.0, 55.2, 39.1, 25.8, 18.2, 16.3, 14.1,
−4.1, −4.8; IR (neat) 3446, 2955, 2929, 2856, 1613, 1513, 1463, 1249,
1037, 835, 773 cm−1; ESIMS m/z 443 [M + Na]+.
(2E,4E,6R,7R,8E)-Ethyl 7-(tert-Butyldimethylsilyloxy)-10-(4-
methoxybenzyloxy)-2,4,6-trimethyldeca-2,4,8-trienoate (16).
Activated MnO2 (1.08 g, 12.45 mmol) was added to a solution of
15 (0.35 g, 0.83 mmol) in dry CH2Cl2 (25 mL), and the mixture was
refluxed for 3 h and then allowed to cool to room temperature. The
reaction mixture was filtered through a Celite pad with CH2Cl2, and
removal of solvent under reduced pressure provided the crude
aldehyde, which was used in the next step.
At 0 °C, 0.9 mL of n-BuLi (1.6 M, 1.42 mmol) was added to the
solution of phosphonate (0.35 mL, 1.63 mmol) in dry THF. The
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mixture was stirred for 15 min at 0 °C, and the crude aldehyde
dissolved in dry THF was added dropwise. The stirring was continued
for 16 h at 0 °C. The reaction was quenched by the addition of
saturated aqueous NH4Cl, and the aqueous portion was extracted with
EtOAc (2 × 20 mL). The residue was purified by silica gel column
chromatography (20% EtOAc/hexane) to provide 16 (0.35 g, 84%) as
colorless oil. [α]25D +20, (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 7.18 (d, J = 8.3 Hz, 2H), 7.03 (s, 1H), 6.81 (d, J = 9 Hz, 2H), 5.68−
5.64 (m, 2H), 5.40 (d, J = 9.8 Hz, 1H), 4.38 (s, 2H), 4.18 (q, J = 7.5
Hz, 2H), 3.99−3.90 (m, 2H), 3.79 (s, 3H), 2.63−2.51 (m, 1H), 1.95
(s, 3H), 1.82 (s, 3H), 1.31 (t, J = 6.8 Hz, 3H), 1.0 (d, J = 6.8 Hz, 3H),
0.91 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3, 75 MHz)
δ 169.0, 159.0, 142.9, 138.2, 134.6, 131.6, 130.4, 129.2, 127.4, 125.5,
113.7, 76.6, 71.3, 69.7, 60.5, 55.2, 40.0, 38.4, 25.8, 18.1, 16.7, 16.3,
14.3, 14.0, −4.0, −4.8; IR (neat) 2956, 2930, 2856, 1706, 1249, 1111,
1036, 835, 773 cm−1; ESI HRMS m/z calcd for C29H46O5NaSi [M +
Na]+ 525.30067, found 525.29846.
min at −78 °C. After addition of Et3N (0.5 mL, 3.7 mmol), the
mixture was stirred for 15 min at −78 °C and then for 20 min at 0 °C.
Workup with CH2Cl2 gave a crude aldehyde, which was used for the
next step without further purification.
A solution of (+)-IPC2B(allyl) (1.0 M in pentane, 0.6 mL, 1.2
mmol) in Et2O (5 mL) was cooled to −100 °C, and a solution of the
above crude aldehyde in 20 mL of diethyl ether was added slowly. The
mixture was stirred at −100 °C for 2 h and then warmed to 0 °C. The
reaction was quenched by the dropwise addition of 1 mL of 30% H2O2
(aq) and 0.5 mL of 1 N NaOH. The mixture was diluted with 10 mL
of ethyl acetate, and the layers were separated. The aqueous layer was
extracted with (3 × 10 mL) ethyl acetate. The combined organic layers
were washed with brine, dried over Na2SO4, filtered, and concentrated.
The crude reaction mixture was further purified by silica gel column
chromatography (5% EtOAc/hexane) to give homoallyl alcohol 19 as
a 92:8 diastereomeric mixture (98 mg, 60%). [α]25 +8.9, (c 0.5,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.10 (s, 1H), 5.93−5.78 (m,
1H), 5.53 (d, J = 9.8 Hz, 1H), 5.20−5.10 (m, 2H), 4.20 (q, J = 6.8 Hz,
2H), 3.73−3.58 (m, 2H), 3.08−3.0 (m, 2H), 2.76−2.64 (m, 1H), 2.38
(t, J = 7.5 Hz, 2H), 2.0 (s, 3H), 1.85 (s, 3H), 1.30 (t, J = 6.8 Hz, 3H),
1.06 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 169.0, 142.5, 137.7, 133.4, 132.0, 125.9,
118.5, 73.3, 68.8, 60.6, 57.4, 56.8, 39.5, 37.6, 25.8, 18.2, 16.5, 15.7,
14.3, 14.0, −4.2, −4.9; IR (neat) 3481, 2930, 2858, 1704, 1253, 1115,
835, 774 cm−1; ESI HRMS m/z calcd for C24H42O5NaSi [M + Na]+
461.26917, found 461.27017.
(2E,4E,6R,7R,8E)-Ethyl 7-(tert-Butyldimethylsilyloxy)-10-hy-
droxy-2,4,6-trimethyldeca-2,4,8-trienoate (17). To a solution of
the compound 16 (0.325 g, 0.646 mmol) in CH2Cl2 (10 mL) and
water (1 mL) was added DDQ (0.215 g, 0.97 mmol) at 0 °C, and the
mixture was allowed to stir for 2 h at room temperature. The reaction
mixture was quenched with saturated NaHCO3 solution (5 mL) and
diluted with CH2Cl2 (10 mL). The two layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layer was washed with brine (2 × 10 mL), dried over
anhydrous Na2SO4, and evaporated to give the crude product, which
was purified by column chromatography (5% EtOAc/hexane) to
(2E,4E,6R,7S)-Ethyl 7-(tert-Butyldimethylsilyloxy)-7-((2R,3R)-
3-((R)-1-(tert-butyldimethylsilyloxy)but-3-enyl)oxiran-2-yl)-
2,4,6-trimethylhepta-2,4-dienoate (4). 2,6-Lutidine (28 μL, 0.24
mmol) was added to a solution of alcohol 19 (70 mg, 0.16 mmol) in
dry CH2Cl2 (5 mL). The reaction mixture was stirred for 10 min at
room temperature, followed by dropwise addition of TBSOTf (46.5
μL, 0.19 mmol). The mixture was stirred for 1 h at room temperature
and quenched by addition of water. The aqueous layer was extracted
with CH2Cl2, dried over Na2SO4, and concentrated. The crude
reaction mixture was purified by silica gel column chromatography
provide the desired alcohol 17 (0.21 g, 85%) as a colorless oil. [α]25
+22, (c 0.6, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.08 (s, 1H),
D
1
5.81−5.62 (m, 2H), 5.41 (d, J = 9.8 Hz, 1H), 4.2 (q, J = 6.8 Hz, 2H),
4.16−4.10 (m, 2H), 3.98 (t, J = 6.1 Hz, 1H), 2.64−2.52 (m, 1H), 1.98
(s, 3H), 1.81 (s, 3H), 1.30 (t, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz,
3H), 0.89 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 169.1, 142.9, 138.0, 133.0, 131.6, 129.7, 125.5, 76.5, 63.1,
60.5, 40.0, 25.8, 18.1, 16.7, 16.2, 14.3, 14.0, −4.1, −4.8; IR (neat)
3451, 2956, 2931, 2858, 1706, 1253, 1114, 1028, 837, 776 cm−1; ESI
HRMS m/z calcd for C21H38O4NaSi [M + Na]+ 405.2431, found
405.2424.
(2E,4E,6R,7S)-Ethyl 7-(tert-Butyldimethylsilyloxy)-7-((2R,3S)-
3-(hydroxymethyl)oxiran-2-yl)-2,4,6-trimethylhepta-2,4-dien-
oate (18). Powdered 4 Å MS (50 mg) were suspended in dry CH2Cl2
(5 mL) and cooled to −23 °C. Titanium-tetraisopropoxide (146.5 μL,
0.52 mmol) and L-(+)-DET (96 μL, 0.52 mmol) were added at the
same temperature followed by the alcohol 17 (0.2 g, 0.52 mmol) in
dry CH2Cl2. The reaction mixture was stirred at −23 °C for 20 min
followed by addition of tert-butylhydroperoxide (0.52 mL, 5 M in
DCM, 2.6 mmol), and stirring was continued for 24 h at −23 °C. The
reaction was quenched with water (1 mL) and stirring for 30 min at
room temperature, then addition of 30% aq NaOH (0.5 mL) and
further stirring for 30 min. Workup with CH2Cl2 and purification by
column chromatography (30% EtOAc/hexane) provided the desired
epoxy alcohol 18 (0.175 g, 85%) as a colorless oil. [α]25D +5.0, (c 1.9,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.05 (s, 1H), 5.51 (d, J = 9.6
Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.90 (brs, 1H, OH), 3.65−3.55 (m,
3H), 3.08 (dt, J = 3.0, 1.5 Hz, 1H), 2.97 (dd, J = 3.6, 2.2 Hz, 1H),
2.76−2.62 (m, 1H), 1.98 (s, 3H), 1.85 (s, 3H), 1.31 (t, J = 7.0 Hz,
3H), 1.07 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H);
13C NMR (CDCl3, 75 MHz) δ 169.0, 142.5, 137.7, 131.9, 125.8, 73.4,
(5% EtOAc/hexane) to provide the desired product 4 (83 mg, 95%) as
1
a colorless oil. [α]25 +11.0, (c 0.5, CHCl3); H NMR (CDCl3, 300
D
MHz) δ 7.10 (s, 1H), 5.82 (ddt, J = 17.4, 10.6, 6.8 Hz, 1H), 5.55 (d, J
= 9.8 Hz, 1H), 5.14−5.02 (m, 2H), 4.20 (q, J = 6.8 Hz, 2H), 3.63−
3.58 (m, 1H), 3.50−3.44 (m, 1H), 2.95 (dd, J = 5.3, 2.2 Hz, 1H), 2.88
(dd, J = 3.8, 2.2 Hz, 1H), 2.74−2.60 (m, 1H), 2.27 (t, J = 6.8 Hz, 2H),
2.0 (d, J = 1.5 Hz, 3H), 1.85 (d, J = 1.5 Hz, 3H), 1.30 (t, J = 6.8 Hz,
3H), 1.05 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.08 (s, 3H),
0.04 (s, 6H), 0.01 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 169.0,
142.6, 138.1, 134.4, 131.8, 125.8, 117.3, 73.5, 72.9, 60.6, 58.4, 57.1,
39.4, 37.6, 25.9, 25.9, 18.2, 18.1, 16.5, 15.7, 14.3, 14.0, −4.2, −4.4,
−4.8, −4.9; IR (neat) 2957, 2931, 2858, 1709, 1252, 1113, 836, 775
cm−1; ESI HRMS m/z calcd for C30H56O5NaSi2 [M + Na]+
575.35585, found 575.35658.
(R)-4-((S)-4-(Benzyloxy)butan-2-yl)-2,2-dimethyl-1,3-dioxo-
lane (21). To a stirred solution of epoxy alcohol 20 (1.5 g, 7.21
mmol) in dry CH2Cl2 (20 mL) and dry n-pentane (6 mL) was added
Me3Al (10.8 mL, 2 M in toluene, 21.6 mmol) dropwise at −10 °C
under N2 atmosphere. The reaction mixture was stirred for 8 h at
room temperature, diluted with CH2Cl2, quenched slowly with 1 N
HCl (aq) (dropwise) at 0 °C, and extracted with EtOAc (3 × 20 mL).
The combined organic fraction was dried over anhydrous Na2SO4, and
the solvent was removed under reduced pressure to give the
inseparable mixture of 1,2-diol and 1,3-diol. The crude reaction
mixture was used for the next reaction. To the above crude mixture in
dry acetone was added a catalytic amount of PTSA, and the mixture
was stirred for 24 h at room temperature under N2 atmosphere. Then
reaction mixture was quenched with saturated NaHCO3 (aq) solution,
and the acetone was removed from the reaction mixture under reduced
pressure. Water was added to the residue and extracted with EtOAc (3
× 20 mL). The combined organic fraction was dried over anhydrous
Na2SO4, solvent was removed, and the crude residue was purified by
silica gel column chromatography using (2% EtOAc/hexane) to afford
acetonide 21 as an oil (1.33 g, 70% for two steps). [α]25D −11.4, (c 1.0,
61.1, 60.6, 56.4, 55.5, 37.6, 25.8, 18.2, 16.5, 15.5, 14.2, 14.0, −4.2,
−4.9; IR (neat) 3454, 2957, 2930, 2857, 1706, 1253, 1115, 1030, 836,
777 cm−1; ESI HRMS m/z calcd for C21H38O5NaSi [M + Na]+
421.23862, found 421.2366.
(2E,4E,6R,7S)-Ethyl 7-(tert-Butyldimethylsilyloxy)-7-((2R,3S)-
3-((R)-1-hydroxybut-3-enyl)oxiran-2-yl)-2,4,6-trimethylhepta-
2,4-dienoate (19). Oxalyl chloride (82 μL, 0.925 mmol) was added
dropwise at −78 °C to a solution of DMSO (132 μL, 1.85 mmol) in
dry CH2Cl2 (5 mL). The mixture was stirred for 5 min at this
temperature. A solution of epoxy alcohol 18 (150 mg, 0.37 mmol) in
dry CH2Cl2 (2 mL) was added. The reaction mixture was stirred for 15
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1
CHCl3); H NMR (CDCl3, 300 MHz) δ 7.42−7.23 (m, 5H), 4.5 (s,
2H), 1.85−1.66 (m, 2H), 1.55−1.48 (m, 1H), 0.92 (d, J = 6.9 Hz,
3H); 13C NMR (CDCl3, 75 MHz) δ 135.5, 117.5, 73.7, 60.3, 38.1,
35.9, 35.2, 13.8; IR (neat) 3355, 2933, 1055, 997, 772 cm−1; ESIMS
m/z 167 [M + Na]+.
(4S,5S)-7-(tert-Butyldimethylsilyloxy)-5-methylhept-1-en-4-
ol (5). To a solution of diol 26 (200 mg, 1.39 mmol) in CH2Cl2 (10
mL) at 0 °C under nitrogen atmosphere were added imidazole (188.5
mg, 2.77 mmol) and TBSCl (208 mg, 1.39 mmol). After 17 h of
stirring for at room temperature, water was added. The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2 (2 ×
25 mL). The combined organic extracts were dried over Na2SO4,
filtered, and concentrated in a rotary evaporator. Purification by silica
2H) 4.04−3.87 (m, 2H), 3.66−3.47 (m, 3H), 1.86−1.60 (m, 3H), 1.40
(s, 3H), 1.35 (s, 3H), 0.97 (d, J = 6.6, 3H); 13C NMR (CDCl3, 75
MHz) δ 138.4, 128.2, 127.5, 108.5, 79.8, 72.8, 67.9, 67.4, 33.2, 32.6,
26.5, 25.3, 15.3; IR (neat) 2927, 1112, 1065 cm−1; ESI HRMS m/z
calcd for C16H24O3Na [M + Na]+ 287.16177, found 287.16208.
(2R,3S)-5-(Benzyloxy)-3-methylpentane-1,2-diol (23). To a
stirred solution of acetonide 21 (1.25 g, 4.725 mmol) in MeOH was
added PTSA (0.8 g, 4.725 mmol), and the mixture was stirred for 24 h
at room temperature. After completion of reaction, it was quenched
with solid NaHCO3, and the methanol was removed under reduced
pressure. Water was added and extracted with EtOAc (3 × 25 mL).
The combined organic fraction was dried over anhydrous Na2SO4, and
solvent was removed under reduced pressure. The residue was purified
gel column chromatography (10% EtOAc/hexane) gave primary
1
protected alcohol 5 (280 mg, 80%). [α]25 +2.0, (c 0.3, CHCl3); H
D
on silica gel column chromatography (30% EtOAc/hexane) to afford
NMR (CDCl3, 300 MHz) δ 5.90−5.75 (m, 1H), 5.15−5.03 (m, 2H),
3.78−3.53 (m, 3H), 2.20 (t, J = 6.8 Hz, 2H), 1.80−1.62 (m, 2H),
1.50−1.42 (m, 1H), 0.91 (d, J = 6.9 Hz, 3H), 0.90 (s, 9H), 0.06 (s,
6H); 13C NMR (CDCl3, 75 MHz) δ 135.9, 117.0, 73.6, 61.2, 38.6,
36.4, 35.4, 25.9, 13.5, −5.4; IR (neat) 3432, 2955, 2931, 2859, 1095,
834, 776 cm−1; ESI HRMS m/z calcd for C14H31O2Si [M + H]+
259.20878, found 259.20887.
1
23 (0.9 g, 85%) as yellow oil. [α]25 −2.9, (c 0.5, CHCl3); H NMR
D
(CDCl3, 300 MHz) δ 7.35−7.22 (m, 5H), 4.50 (s, 2H), 3.72−3.40 (m,
5H), 1.84−1.69 (m, 2H), 1.64−1.49 (m, 1H), 0.90 (d, J = 6.8 Hz,
3H); 13C NMR (CDCl3, 75 MHz) δ 137.8, 128.4, 127.7, 75.1, 73.1,
68.1, 64.7, 33.3, 33.2, 14.2; IR (neat) 3405, 2930, 2871, 1078, 740, 698
cm−1; ESIMS m/z 225 [M + H]+.
(R)-2-((S)-4-(Benzyloxy)butan-2-yl)oxirane (24). To a stirred
solution of 60% sodium hydride dispersion in mineral oil (0.24 g, 9.75
mmol) in THF was added the diol 23 (0.875 g, 3.9 mmol) followed by
tosyl-imidazole (1.73 g, 7.8 mmol), and the mixture was stirred for 30
min at 0 °C. After completion of reaction, water was added and
extracted with EtOAc (3 × 20 mL). The combined organic fraction
was dried over anhydrous Na2SO4, and solvent was removed under
reduced pressure. The residue was purified on silica gel column
chromatography (10% EtOAc/hexane) to afford the epoxide 24 (0.56
(2S,3R,4S,6S)-2-((R)-1-(Benzyloxy)propan-2-yl)-6-(hydroxy-
methyl)-3-methyltetrahydro-2H-pyran-4-ol (29). Trifluoroacetic
acid (27.6 mL) was added slowly to a solution of homoallylic alcohol
27 (2.0 g, 17.24 mmol) and (S)-3-(benzyloxy)-2-methylpropanal 28
(9.18 g, 51.7 mmol) in CH2Cl2 (30 mL) at room temperature under
nitrogen atmosphere. The reaction mixture was stirred for 3 h, then
saturated aqueous sodium hydrogen carbonate solution (30 mL) was
added, and the pH was adjusted to >7 by addition of triethylamine.
The layers were separated, the aqueous layer was extracted with
CH2Cl2 (3 × 30 mL), the organic layers were combined, and the
solvent was removed under reduced pressure. The residue was
dissolved in methanol (20 mL) and stirred with potassium carbonate
(1.05 g) for 0.5 h. The methanol was then removed under reduced
pressure, and water (15 mL) was added. The mixture was extracted
with dichloromethane (3 × 20 mL), the combined organic layers were
dried (Na2SO4), and the solvent was removed under reduced pressure.
Purification by silica gel column chromatography (30% EtOAc/
g, 70%) as colorless oil. [α]25 +2.0, (c 1.2, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 7.38−7.25 (m, 5H), 4.49 (s, 2H), 3.60−3.09 (m,
2H), 2.83−2.67 (m, 1H), 2.55−2.40 (m, 1H), 2.37−2.28 (m, 1H),
2.16−1.91 (m, 1H), 1.78−1.40 (m, 2H), 1.04 (d, J = 6.8 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ 138.3, 128.3, 127.5, 72.9, 67.8, 56.6, 46.7,
33.3, 33.1, 16.9; IR (neat) 2925, 2861, 1101, 740 cm−1; ESIMS m/z
224 [M+NH4]+.
(4S,5S)-7-(Benzyloxy)-5-methylhept-1-en-4-ol (25). A freshly
prepared vinyl magnesium bromide (4.85 mL, 4.85 mmol) (1 M
solution in THF) was added dropwise to a solution of CuI (45 mg,
0.24 mmol) in THF (10 mL) at −20 °C. The mixture was stirred for
30 min, and chiral epoxide 24 (0.5 g, 2.4 mmol) was added in THF
(10 mL) dropwise. After 2 h, the reaction was quenched with saturated
solution of NH4Cl (10 mL) and diluted with Et2O (25 mL). The two
layers were separated, and the aqueous layer was extracted with Et2O
(3 × 25 mL). The combined organic layer was washed with brine (2 ×
10 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The crude mass was purified by silica gel column
chromatography (15% EtOAc/hexane) to afford the desired homoallyl
alcohol 25 (0.45 g, 85%) as a colorless oil. [α]25D +6.8, (c 0.6, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 7.35−7.20 (m, 5H), 5.89−5.71 (m,
1H), 5.15−5.01 (m, 2H), 4.48 (s, 2H), 3.60−3.42 (m, 3H), 2.22−2.12
(m, 2H), 1.82−1.67 (m, 1H), 0.89 (d, J = 6.6 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 135.7, 128.3, 127.7, 127.6, 117.2, 73.4, 73.0, 68.2,
38.8, 35.3, 33.3, 13.4; IR (neat) 3446, 2928, 2863, 1096, 738, 698
cm−1; ESI HRMS m/z calcd for C15H22O2Na [M + Na]+ 257.15120,
found 257.15161.
hexane) gave 29 (3.04 g, 60%) as a colorless oil. [α]25 −8.5 (c 1.8,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.36−7.16 (m, 5H), 4.55−
4.39 (m, 2H), 3.72−3.18 (m,7H), 2.21−2.03 (m, 1H), 1.87−1.75 (m,
1H), 1.47−1.20 (m, 2H), 0.95 (d, J = 6.2 Hz, 3H), 0.84 (d, J = 6.9 Hz,
3H), 13C NMR (75 MHz, CDCl3) δ 138.5, 128.2, 127.5, 127.4, 79.4,
75.4, 73.0, 71.4, 70.4, 67.4, 40.4, 36.7, 34.1, 12.0, 9.5; IR (neat) 3407,
2926, 2863, 1095, 744 cm−1; ESIMS m/z 317 [M + Na]+.
((2S,4S,5R,6S)-6-((R)-1-(Benzyloxy)propan-2-yl)-4-hydroxy-5-
methyltetrahydro-2H-pyran-2-yl)methyl 4-Methylbenzenesul-
fonate (30). To a solution of diol 29 (3.0 g, 10.17 mmol) in dry
CH2Cl2 (15 mL) was added triethylamine (5.6 mL, 40.67 mmol) at 0
°C, followed by addition of tosyl chloride (2.31 g, 12.2 mmol) over 2
h. The reaction mixture was allowed to warm to room temperature
and was stirred for 5 h. The reaction mixture was treated with aqueous
1 N HCl (1 mL) and extracted with CH2Cl2 (3 × 20 mL). The organic
layer was washed with saturated aqueous NaHCO3 (6 mL) solution
and water (6 mL). The combined organic phases were dried over
Na2SO4 and concentrated under reduced pressure. Purification by
silica gel column chromatography (20% EtOAc/hexane) gave 30 (3.87
1
(3S,4S)-3-Methylhept-6-ene-1,4-diol (26). To a stirred solution
of naphthalene (1.15 g, 9 mmol) in THF (10 mL) at room
temperature were added lithium granules (62.5 mg, 9 mmol), and the
solution was stirred at room temperature for 45 min to generate
lithium naphthalenide. To the resulting dark green solution was added
benzyl ether 25 (0.425 g, 1.8 mmol) at −20 °C, and the mixture was
allowed the mixture to stir at the same temperature for 30 min and
then was quenched with aqueous NH4Cl, extracted into EtOAc (3 ×
20 mL), dried over Na2SO4, concentrated in a rotary evaporator, and
purified on silica gel column chromatography (40% EtOAc/hexane) to
g, 85%) as a gummy liquid. [α]25 −10.1 (c 0.7, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 7.72 (d, J = 4.1 Hz, 2H), 7.44−7.15 (m, 7H),
4.43(d, J = 4.1 Hz, 2H), 4.18−3.75 (m, 2H), 3.63−3.43 (m, 1H),
3.43−3.03 (m, 4H), 2.43 (s, 3H), 2.19−1.79 (m, 2H), 1.66 (brs, 1H,
OH), 1.52−1.07 (m, 2H), 0.90 (d, J = 6.5 Hz, 3H), 0.74 (d, J = 6.5 Hz,
3H), 13C NMR (75 MHz, CDCl3) δ 144.7, 138.6, 132.8, 129.7, 128.3,
127.8, 127.5, 127.4, 79.4, 73.1, 73.0, 72.8, 72.4, 71.9, 40.1, 36.8, 34.0,
21.6, 11.9, 9.3; IR (neat) 3448, 2927, 2862, 1364, 1178, 1092, 979, 670
cm−1; ESI MS m/z 627 [M + Na]+.
(2R,3S,4R,5S)-1-(Benzyloxy)-2,4-dimethyloct-7-ene-3,5-diol
(31). NaI (25.4 g, 169.4 mmol) was added to a solution of 30 (3.8 g,
8.47 mmol) in acetone (50 mL), and the mixture was heated to reflux
for 24 h. Acetone was removed under reduced pressure. Water (20
give diol 26 (220 mg, 85%) as colorless oil. [α]25 +10.6, (c 0.6,
D
1
CHCl3); H NMR (CDCl3, 300 MHz) δ 5.85−5.75 (m, 1H), 5.15−
5.08 (m, 2H), 3.76−3.69 (m, 1H), 3.65−3.58 (m, 2H), 2.26−2.16 (m,
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mL) was added to the residue and extracted with EtOAc (2 × 30 mL).
The organic layer was separated, dried over Na2SO4, and without
isolation treated with commercial zinc dust (10.78 g, 169.4 mmol) in
ethanol. The mixture was refluxed for 1 h and then cooled to 25 °C.
Addition of solid ammonium chloride (1 g) and Et2O (20 mL)
followed by stirring for 5 min gave a gray suspension. The suspension
was filtered through Celit, and the filtrate was concentrated under
reduced pressure. Purification by silica gel column chromatography
(30% EtOAc/hexane) gave 31 (1.88 g, 80%) as a colorless liquid.
[α]25D −12 (c 0.3, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.37−7.24
(m, 5H), 5.91−5.72 (m, 1H), 5.14−5.04 (m, 2H), 4.50 (d, J = 2.3 Hz,
2H), 3.89−3.76 (m, 2H), 3.57−3.50 (m, 2H), 2.36−2.03 (m, 2H),
2.0−1.71 (m, 2H), 0.99 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H);
13C NMR (CDCl3, 75 MHz) δ 136.9, 134.8, 128.5, 128.0, 127.5, 118.2,
78.2, 75.5, 74.7, 73.7, 38.5, 36.5, 34.8, 12.3, 10.0; IR (neat) 3443, 2970,
2927, 1455, 1096, 746, 698 cm−1; ESI HRMS m/z calcd for C17H27O3
[M + H]+ 279.09602, found 279.09379.
(4S,5R,6S)-4-Allyl-6-((R)-1-(benzyloxy)propan-2-yl)-2,2,5-tri-
methyl-1,3-dioxane (32). To a solution of compound 31 (1.8 g,
6.46 mmol) in dry CH2Cl2 (5 mL) were added 2,2-dimethoxypropane
(1.85 mL, 12.92 mmol) and a catalytic amount of PPTS. The mixture
was stirred at room temperature for 10 h, then aqueous NaHCO3
solution was added to neutralize PPTS, and the mixture was filtered.
Removal of solvent and purification by silica gel column chromatog-
solution. The organic layer was separated, and the compound from the
aqueous layer was extracted with ethyl acetate (2 × 20 mL). The
combined organic layers were washed with water and brine solution,
dried over Na2SO4, and concentrated under reduced pressure. The
crude mass was purified by silica gel column chromatography (20%
EtOAc/hexane) to afford a racemic mixture (0.81 g, 85%) as a viscous
liquid.
(S)-3-((4R,5R,6S)-6-Allyl-2,2,5-trimethyl-1,3-dioxan-4-yl)-
butan-2-one (35). To a solution of the above racemic alcohol (0.8 g,
3.3 mmol) in dry CH2Cl2 (10 mL) were added Dess−Martin
periodinane (2.81 g, 6.6 mmol) and NaHCO3 (0.55 g, 6.6 mmol) at 0
°C under nitrogen atmosphere. The turbid solution was allowed to
warm to room temperature and was stirred for 2 h. The reaction was
diluted with CH2Cl2 (10 mL) and quenched with saturated aqueous
NaHCO3 (10 mL) and saturated aqueous Na2S2O3 (10 mL). The
mixture was vigorously stirred until a clear solution was formed. The
organic layer was separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 10 mL). The combined organic extracts were washed
with brine (1 × 15 mL), dried over anhydrous Na2SO4, filtered,
concentrated, and purified by silica gel column chromatography (20%
EtOAc/hexane) to afford methyl ketone 35 (0.68 g, 85%) as a viscous
1
liquid. [α]25 +8.8 (c 0.6, CHCl3), H NMR (CDCl3, 500 MHz) δ
D
5.74 (ddt, J = 17., 10.0, 7.9 Hz, 1H), 5.10−4.99 (m, 2H), 3.78−3.72
(m, 1H), 3.62−3.57 (m, 1H), 2.58−2.50 (m, 1H), 2.23−2.16 (m, 2H),
2.15 (s, 3H), 2.08−2.01 (m, 1H), 1.86−1.79 (m, 1H), 1.28 (s, 3H),
1.25 (s, 3H), 1.12 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 5.9 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ 210.8, 135.0, 116.5, 100.5, 75.0, 69.0, 50.1,
36.1, 35.1, 29.6, 28.9, 25.0, 23.6, 12.1, 10.4; IR (neat) 2983, 2931,
1713, 1379, 1225 cm−1; ESI HRMS m/z calcd for C14H24O3Na [M +
Na]+ 263.16177, found 263.16246.
raphy (10% EtOAc/hexane) gave acetonide 32 (1.75 g, 85%) as a clear
1
liquid. [α]25 −11.8 (c 0.3, CHCl3); H NMR (CDCl3, 500 MHz) δ
D
7.30−7.19 (m, 5H), 5.76 (ddt, J = 17.0, 10.0, 7.0 Hz, 1H), 5.09−4.96
(m, 2H), 4.46 (s, 2H), 3.78−3.73 (m, 1H), 3.44−3.37 (m, 2H), 3.31−
3.26 (m, 1H), 2.22−2.14 (m, 1H), 2.09−2.02 (m, 1H), 1.86−1.76 (m,
2H), 1.25 (s, 6H), 0.90 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H);
13C NMR (CDCl3, 75 MHz) δ 138.6, 135.4, 128.2, 127.5, 127.5, 116.3,
(2S,3R)-3-((4S,5R,6S)-6-Allyl-2,2,5-trimethyl-1,3-dioxan-4-yl)-
butan-2-ol (36). To a solution of methyl-ketone 35 (0.6 g, 2.49
mmol) in MeOH (10 mL) at 0 °C under N2 atmosphere were added
cerium chloride hepatehydrate (0.29 g, 2.49 mmol) and NaBH4 (0.294
g, 2.49 mmol). After 1 h of stirring at 0 °C, saturated NH4Cl was
added. The organic layer was separated, and the aqueous layer was
extracted twice with CH2Cl2. The combined organic extracts were
dried over Na2SO4, filtered, and concentrated under reduced pressure,
to gave a mixture of alcohols in the ratio of 85:15. Purification by silica
gel column chromatography (20% EtOAc/hexane) gave the required
100.3, 73.9, 73.0, 72.9, 69.2, 36.3, 36.1, 35.1, 25.0, 23.5, 11.8, 11.1; IR
(neat) 2928, 2855, 1224 cm−1; ESI HRMS m/z calcd for C20H30O3Na
[M + Na]+ 341.20872, found 341.20955.
(R)-2-((4S,5R,6S)-6-Allyl-2,2,5-trimethyl-1,3-dioxan-4-yl)-
propan-1-ol (33). To a stirred solution of naphthalene (3.39 g, 26.7
mmol) in THF (10 mL) were added lithium granules (0.19 g, 26.7
mmol) at room temperature, and the solution was allowed to stir at
room temperature for 45 min to generate Li naphthalenide. To the
resulting dark green solution was added benzyl ether 32 (1.7 g, 5.33
mmol) at −10 °C, and the mixture was allowed to stir at the same
temperature for 30 min, quenched with aqueous NH4Cl, extracted into
EtOAc (3 × 20 mL), dried over Na2SO4, concentrated, and purified on
alcohol 36 (0.38 g, 75%). [α]25 −5.2 (c 1.0, CHCl3), 1H NMR
D
(CDCl3, 300 MHz) δ 5.75 (ddt, J = 17.2, 10.6, 6.6 Hz, 1H), 5.12−4.98
(m, 2H), 3.99−3.90 (m, 1H), 3.82−3.73 (m, 1H), 3.50−3.45 (m, 1H),
2.81 (s, 1H), 2.26−1.99 (m, 2H), 1.92−1.78 (m, 1H), 1.36 (s, 3H),
1.31 (s, 3H), 1.13 (d, J = 6.2 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 0.84
(d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 135.0, 116.6,
100.6, 80.0, 72.5, 69.2, 40.2, 36.1, 35.0, 24.9, 23.8, 20.7, 11.9, 5.4; IR
(neat) 3453, 2979, 2934, 1380, 1224, 1016 cm−1; ESI HRMS m/z
calcd for C14H26O3Na [M + Na]+ 265.17742, found 265.17819.
(4S,5R,6S)-4-Allyl-6-((2R,3S)-3-methoxybutan-2-yl)-2,2,5-tri-
methyl-1,3-dioxane (37). To a suspension of NaH (60%) (0.04 g,
1.8 mmol) in THF (3 mL) at 0 °C under N2 atmosphere was added a
solution of alcohol 36 (0.3 g, 1.2 mmol) in THF (2 mL). The mixture
was stirred for 1 h at room temperature, and MeI (0.56 mL, 9.0 mmol)
was added. After 5 h of stirring at room temperature, saturated NH4Cl
was added. The organic layer was separated, and the aqueous layer was
extracted twice with EtOAc. The combined organic extracts were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification by silica gel column chromatography (10% EtOAc/
hexane) gave 37 (0.25 g, 80%). [α]25D −8.3 (c 1.5, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 5.76 (ddt, J = 16.6, 10.4, 6.2 Hz, 1H), 5.12−4.95
(m, 2H), 3.82−3.69 (m, 1H), 3.39−3.30 (m, 1H), 3.29 (s, 3H), 3.22−
3.10 (m, 1H), 2.26−2.12 (m, 1H), 2.11−1.99 (m, 1H), 1.81−1.70 (m,
1H), 1.57−1.47 (m, 1H), 1.29 (s, 3H), 1.26 (s, 3H), 1.09 (d, J = 6.2
Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 135.3, 116.2, 100.1, 78.8, 73.7, 69.1, 56.2, 41.4,
36.7, 35.1, 25.1, 23.6, 16.1, 11.8, 10.1; IR (neat) 2978, 2933, 1378,
1224, 1099 cm−1; ESI HRMS m/z calcd for C15H28O3Na [M + Na]+
279.19307, found 279.19350.
silica gel (30% EtOAc/hexane) to give alcohol 33 (1.0 g, 90%). [α]25
−16.8 (c 0.5, CHCl3); H NMR (CDCl3, 300 MHz) δ 5.76 (ddt, J =
D
1
17.0, 10.4, 6.8 Hz, 1H), 5.13−4.98 (m, 2H), 3.84−3.74 (m, 1H),
3.63−3.57 (m, 2H), 3.52−3.47 (m, 1H), 2.26−2.01 (m, 2H), 1.92−
1.73 (m, 2H), 1.34 (s, 3H), 1.30 (s, 3H), 0.96 (d, J = 7.1 Hz, 3H), 0.86
(d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 135.0, 116.5,
100.5, 77.3, 69.3, 67.0, 37.3, 35.5, 35.1, 25.1, 23.6, 12.2, 10.6; IR (neat)
3421, 2980, 2935, 1380, 1224, 1020 cm−1; ESI HRMS m/z calcd for
C13H24O3Na [M + Na]+ 251.16177, found 251.16250.
(R)-3-((4S,5R,6S)-6-Allyl-2,2,5-trimethyl-1,3-dioxan-4-yl)-
butan-2-ol. To a solution of alcohol 33 (0.9 g, 3.94 mmol) in dry
CH2Cl2 (20 mL) were added Dess−Martin periodinane (3.1 g, 7.28
mmol) and NaHCO3 (0.61 g, 7.28 mmol) at 0 °C under nitrogen
atmosphere. The turbid solution was allowed to warm to room
temperature and was stirred for 2 h. The reaction was diluted with
CH2Cl2 (15 mL) and quenched with saturated aqueous NaHCO3 (10
mL) and saturated aqueous Na2S2O3 (10 mL). The mixture was
vigorously stirred until a clear solution was formed. The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2 (2 ×
20 mL). The combined organic extracts were washed with brine (1 ×
20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to
give a crude aldehyde, which was used for the next step without further
purification
MeMgBr (2.4 mL, 3M, 7.28 mmol) was added dropwise to a stirred
solution of the aldehyde in dry THF (15 mL) at 0 °C. After addition
was completed, the reaction mixture was allowed to stir at room
temperature for 1 h and then quenched with saturated aqueous NH4Cl
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2-((4S,5R,6S)-6-((2R,3S)-3-Methoxybutan-2-yl)-2,2,5-trimeth-
yl-1,3-dioxan-4-yl)ethanol (38). To a solution of alkene 37 (0.22 g,
0.85 mmol) in CH2Cl2 (5 mL) and MeOH (1 mL) under N2
atmosphere at −78 °C was added O3. After the solution turned
blue, argon was bubbled into the solution until it turned colorless.
NaBH4 was added at −78 °C, and the mixture was warmed to room
temperature. Saturated NH4Cl was added, then the organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (2 × 20
mL). The combined organic extracts were dried over Na2SO4, filtered,
and concentrated. Purification by column chromatography (30%
4,10,12-trien-9-one (40). To a solution of ester 39 (50 mg, 0.063
mmol) in THF (5 mL) was added TMSOK (81 mg, 0.63 mmol). After
17 h of stirring, a solution of citric acid 0.5 N was added. The aqueous
layer was extracted with EtOAc (2 × 20 mL). The combined organic
extracts were dried over Na2SO4, filtered, and concentrated.
Purification through a plug of silica gave the acid. The compound
was used immediately for the next step.
To a solution of the acid (45 mg, 0.062 mmol) in THF (3 mL)
were added Et3N (43 μL, 0.31 mmol) and 2,4,6-tricholorbenzoyl
chloride (18.6 μL, 0.124 mmol). After stirring for 17 h, the solution
was passed through a plug of Celite and rinsed with hexanes. The
solvent was removed, and the corresponding anhydride was dissolved
in toluene (3 mL), which was added to a solution of DMAP (72.6 mg,
0.62 mmol) in toluene via a syringe pump (0.35 mL/h). After 17 h of
stirring, saturated NH4Cl was added, and the aqueous layer was
extracted twice with Et2O. The combined organic extracts were dried
over Na2SO4, filtered, and concentrated in vacuo. Purification by silica
EtOAc/hexane) gave primary alcohol 38 (0.17 g, 80%). [α]25 +7.8;
D
1H NMR (CDCl3, 300 MHz) δ 4.06−3.97 (m, 1H), 3.80−3.73 (m,
1H), 3.72−3.65 (m, 1H), 3.42−3.36 (m, 1H), 3.31 (s, 3H), 3.26−3.20
(m, 1H), 1.88−1.73 (m, 2H), 1.68−1.55 (m, 2H), 1.34 (s, 3H), 1.32
(s, 3H), 1.13 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.84 (d, J =
6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 100.2, 78.8, 73.6, 69.8,
61.9, 56.2, 41.2, 37.2, 25.3, 23.6, 16.1, 12.2, 10.1; IR (neat) 3399, 2931,
1378, 1226, 1056 cm−1; ESIMS m/z 261 [M + H ]+.
gel column chromatography (20% EtOAc/hexane) gave macrocycle
1
40 in 60% yield for 2 steps. [α]25 +12.0 (c 0.3, CHCl3); H NMR
5-(2-((4S,5R,6S)-6-((2R,3S)-3-Methoxybutan-2-yl)-2,2,5-tri-
methyl-1,3-dioxan-4-yl)ethylsulfonyl)-1-phenyl-1H-tetrazole
(3). A solution of alcohol 38 (0.15 g, 0.57 mmol) and 1-phenyl-1H-
tetrazole-5-thiol (0.2 g, 1.14 mmol) in dry THF (10 mL) was cooled
to 0 °C under N2 and treated sequentially with n-Bu3P (0.35 mL, 1.42
mmol) and DIAD (0.28 mL, 1,42 mmol). After 90 min of stirring at 0
°C, the reaction was quenched by addition of H2O (1 mL) and then
stirred vigorously for 2 min. Workup with EtOAc and purification by
silica gel column chromatography (10% EtOAc/hexanes) provided the
intermediate sulphide (0.2 g, 90%) as a colorless oil.
A solution of the sulfide from above (0.15 g, 0.34 mmol) in EtOH
(10 mL) was treated with Mo7O24(NH4)6·4H2O (0.12 mg, 0.1 mmol)
and 30% aq H2O2 (0.1 mL, 3.4 mmol) at 0 °C. After stirring at room
temperature for 16 h, the reaction mixture was poured into a saturated
aqueous solution of sodium thiosulphate, stirred for 5 min, and
extracted with EtOAc. The combined organic phases were washed
with brine, dried over Na2SO4, and filtered. Solvent removal under
reduced pressure, and the residue was purified by silica gel column
D
(CDCl3, 500 MHz) δ 7.38 (s, 1H), 5.63−5.56 (m, 3H), 4.86−4.78 (m,
1H), 4.08−4.04 (m, 1H), 3.78−3.71 (m, 1H), 3.69−3.62 (m, 1H),
3.40−3.35 (m, 1H), 3.10 (dd, J = 7.0, 2.0 Hz, 1H), 2.92−2.85 (m,
2H), 2.52−2.40 (m, 3H), 2.27−2.18 (m, 1H), 2.06 (s, 3H), 1.97 (s,
3H), 1.83−1.73 (m, 1H), 1.38−1.21 (m, 2H), 1.08 (d, J = 6.9 Hz,
3H), 0.91 (s, 9H), 0.89 (d, J = 7.9 Hz, 3H), 0.86 (s, 9H), 0.84 (s, 9H),
0.07 (s, 6H), 0.05(s, 3H), 0.05(s, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 169.7, 144.7, 142.1, 134.6, 129.6, 126.8,
124.0, 77.1, 74.1, 72.4, 60.5, 56.7, 54.9, 38.8, 38.1, 35.5, 34.4, 31.1,
29.7, 25.9, 25.7, 18.2, 18.1, 16.9, 16.0, 15.5, 13.4, −4.5, −4.9, −5.0,
−5.1, −5.3, −5.4; IR (neat) 3452, 2930, 1700, 1634, 1251, 1112, 835,
769 cm−1; ESI HRMS m/z calcd for C40H76O6Si3Na [M + Na]+
759.48419, found 759.48451.
(1R,2R,4E,7S,10E,12E,14R,15S,16R)-2,15-Bis(tert-butyldime-
thylsilyloxy)-7-((S)-4-hydroxybutan-2-yl)-10,12,14-trimethyl-
8,17-dioxabicyclo[14.1.0]heptadeca-4,10,12-trien-9-one (41).
To a solution of 40 (20 mg, 0.027 mmol) in MeOH (2 mL) was
added PPTS (2.0 mg, 0.008 mmol). After 17 h of stirring, MeOH was
removed under reduced pressure, and saturated NaHCO3 was added.
The aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The
combined organic extracts were dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification by silica gel column
chromatography (30% EtOAc/hexane) gave primary alcohol 41 (13.8
mg, 82%). [α]25D +13.1 (c 0.7, CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 7.37 (s, 1H), 5.64−5.54 (m, 3H), 4.88−4.81 (m, 1H), 4.04 (d, J =
4.0 Hz, 1H), 3.85−3.63 (m, 2H), 3.41−3.31 (m, 1H), 3.13−3.06 (m,
1H), 2.94−2.85 (m, 2H), 2.51−2.39 (m, 3H), 2.35−2.23 (m, 1H),
2.04 (s, 3H), 1.97 (s, 3H), 1.88−1.76 (m, 1H), 1.47−1.38 (m, 2H),
1.08 (d, J = 8.0 Hz, 3H), 0.94 (d, J = 6.0 Hz, 3H), 0.86 (s, 9H), 0.84
(s, 9H), 0.07 (s, 3H), 0.05(s, 3H), 0.04(s, 3H), 0.03 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 169.5, 144.8, 142.1, 134.6, 130.0, 126.6,
123.9, 76.8, 74.1, 72.5, 60.6, 56.7, 55.0, 38.8, 38.2, 35.4, 34.4, 31.7,
31.4, 29.6, 25.8, 25.7, 18.2, 18.1, 17.0, 16.0, 15.5, 13.4, −4.5, −4.9,
−5.0, −5.1; IR (neat) 3451, 2929, 2857, 1698, 1251, 1118, 836, 776
cm−1; ESI HRMS m/z calcd for C34H62O6Si2Na [M + Na]+
645.39771, found 645.39835.
Dioxabicyclo[14.1.0]heptadeca-4,10,12-trien-7-yl)butanal:
(1R,2R,4E,7S,10E,12E,14R,15S,16R)-2,15-Bis(tert-butyldimethyl-
silyloxy)-7-((S,E)-6-((4S,5R,6S)-6-((2R,3S)-3-methoxybutan-2-
yl)-2,2,5-trimethyl-1,3-dioxan-4-yl)hex-4-en-2-yl)-10,12,14-tri-
methyl-8,17-dioxabicyclo[14.1.0]heptadeca-4,10,12-trien-9-
one (42). To a solution of alcohol 41 (8 mg, 0.012 mmol) in CH2Cl2
(2 mL) were added NaHCO3 (3.2 mg, 0.036 mmol) and Dess−Martin
periodinane (8 mg, 0.018 mmol). After 30 min of stirring, saturated
Na2SO3 was added. The mixture was stirred for 30 min, and then the
aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The combined
organic extracts were dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification through a plug of silica gave
aldehyde 2. The aldehyde was immediately used for the next step.
To a solution of sulfone 3 (11 mg, 0.024 mmol) in THF (0.5 mL)
at −78 °C was added KHMDS (24 μL, 0.024 mmol). The mixture was
chromatography (10% EtOAc/hexane) to afford sulphone 3 (0.13 g,
1
85%) as a dense oil. [α]25 −1.6 (c 0.8, CHCl3); H NMR (CDCl3,
D
300 MHz) δ 7.74−7.59 (m, 5H), 3.96−3.84 (m, 2H), 3.81−3.73 (m,
1H), 3.43−3.37 (m, 1H), 3.31 (s, 3H), 3.26−3.20 (m, 1H), 2.16−1.91
(m, 3H), 1.90−1.79 (m, 1H), 1.32 (s, 3H), 1.29 (s, 3H), 1.20 (d, J =
6.2 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ 131.4, 129.7, 125.0, 100.5, 78.7, 73.5, 67.7,
56.2, 53.7, 41.2, 37.1, 29.7, 25.2, 23.9, 16.1, 11.9, 10.1; IR (neat) 2925,
1344, 1151, 764 cm−1; ESI HRMS m/z calcd for C21H32O5N4NaS [M
+ Na]+ 475.19856, found 475.19945.
(2Z,4E,6R,7S)-Ethyl 7-(tert-Butyldimethylsilyloxy)-7-((2R,3R)-
3-((5R,10S,11S,E)-10-hydroxy-2,2,3,3,11,15,15,16,16-nona-
methyl-4,14-dioxa-3,15-disilaheptadec-7-en-5-yl)oxiran-2-yl)-
2,4,6-trimethylhepta-2,4-dienoate (39). To a solution of ester 4
(60 mg, 0.108 mmol) and Grubb,s second-generation catalyst (16.2
mg, 0.02 mmol) in CH2Cl2 (2 mL) at reflux was added slowly (0.7
mL/h) a solution of alkene 5 (36.2 mg, 0.140 mmol) in CH2Cl2 (2
mL) using a syringe pump. After 8 h of stirring at reflux, the solvent
was removed, and the residue was purified by silica gel column
chromatography (30% EtOAc/hexane) to give the coupling product
39 (55 mg, 65%). [α]25D +4.5 (c 1.0, CHCl3); 1H NMR (CDCl3, 300
MHz) δ 7.05 (s, 1H), 5.60−5.44 (m, 3H), 4.19 (q, J = 7.5 Hz, 2H),
3.82−3.35 (m, 5H), 2.94−2.79 (m, 2H), 2.72−2.60 (m, 1H), 2.45−
2.06 (m, 4H), 1.99 (s, 3H), 1.87 (s, 3H), 1.76−1.60 (m,2H), 1.52−
1.41 (m, 2H), 1.32 (t, J = 7.5 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H), 0.94
(d, J = 6.8 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s,
6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 169.1, 142.7, 138.2, 132.1, 130.0, 128.4, 127.0, 126.0, 73.9,
73.5, 72.8, 61.2, 60.6, 58.5, 56.8, 38.3, 37.9, 36.5, 35.5, 35.2, 29.7, 25.8,
18.2, 18.1, 16.6, 15.5, 14.3, 14.0, 13.4, −4.1, −4.5, −4.8, −4.9, −5.1; IR
(neat) 2955, 2929, 2856, 1253, 1108, 835, 776 cm−1; ESI HRMS m/z
calcd for C42H82O7Si3Na [M + Na]+ 805.52606, found 805.52376.
(1R,2R,4E,7S,10E,12E,14R,15S,16R)-2,15-Bis(tert-butyldime-
thylsilyloxy)-7-((S)-4-(tert-butyldimethylsilyloxy)butan-2-yl)-
10,12,14-trimethyl-8,17-dioxabicyclo[14.1.0]heptadeca-
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The Journal of Organic Chemistry
Article
stirred at −78 °C for 5 min, and a solution of aldehyde 2 (5 mg,
0.0082 mmol) in THF (0.5 mL) was added. After 45 min of stirring at
−78 °C, saturated NH4Cl was added. The aqueous layer was extracted
with EtOAc (2 × 10 mL). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
(3) Natsume, M.; Komiya, M.; Koyanagi, F.; Tashiro, N.; Kawaide,
H.; Abe, H. J. Gen. Plant Pathol. 2005, 71, 364−369.
(4) (a) Eguchi, T.; Kobayashi, K.; Uekusa, H.; Ohashi, Y.; Mizoue,
K.; Matsushima, Y. K.; Kakinuma, Y. K. Org. Lett. 2002, 4, 3383−3386.
(b) Eguchi, T.; Yamamoto, K.; Mizoue, K.; Kakinuma, K. J. Antibiot.
2004, 57, 156−157.
Purification by silica gel column chromatography (20% EtOAc/
1
hexane) gave 42 in (5.4 mg, 80%). [α]25 +7.5 (c 0.4, CHCl3); H
(5) (a) Crimmins, M. T.; Caussanel, F. J. Am. Chem. Soc. 2006, 128
(10), 3128−3129. (b) Fortanet, J. G.; Murga, J.; Carda, M.; Marco, J.
A.; Matesanz, R.; Diaz, J. F.; Barasoain, I. Chem.Eur. J. 2007, 13,
5060−5074. (c) Fortanet, J. G.; Murga, J.; Carda, M.; Marco, J. A. Org.
Lett. 2006, 8 (13), 2695−2698. (d) Fragment synthesis: Marco, J. A.;
Murga, J.; Fortanet, J. G.; Carda, M. Synlett 2004, 15, 2530−2832.
(6) (a) Yadav, J. S; Reddy, Ch. S. Org. Lett. 2009, 11 (8), 1705−1708.
(b) Yadav, J. S.; Pattanayak, M. R.; Das, P. P.; Mohapatra, D. K. Org.
Lett. 2011, 13 (7), 1710−1713. (c) Yadav, J. S.; Reddy, C. N.; Sabitha,
G. Tetrahedron Lett. 2012, 53 (20), 2504−2507. (d) Yadav, J. S.;
Reddy, K. B.; Sabitha, G. Tetrahedron 2008, 64, 1971−1982.
(7) Trost, B. M.; Wrobleski, S. T.; Chisholm, J. D.; Harrington, P. E.;
Jung, M. J. Am. Chem. Soc. 2005, 127 (39), 13589−13597.
(8) (a) Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem.
1995, 500, 1−19. (b) Ramachandran, P. V. Aldrichimica Acta 2002, 35,
23−35.
D
NMR (CDCl3, 300 MHz) δ 7.36 (s, 1H), 5.63−5.42 (m, 5H), 4.85−
4.75 (m, 1H), 4.04 (d, J = 3.2 Hz, 1H), 3.81−3.71 (m, 1H), 3.41−3.34
(m, 2H), 3.31 (s, 3H), 3.28−3.18 (m, 1H), 3.09 (dd, J = 7.4, 1.3 Hz,
1H), 2.93−2.83 (m, 2H), 2.53−2.37 (m, 4H), 2.32−2.12 (m, 4H),
2.06 (s, 3H), 1.96 (s, 3H), 1.94−1.77 (m, 3H), 1.62−1.52 (m, 3H),
1.31 (s, 3H), 1.28 (s, 3H), 1.12 (d, J = 6.2 Hz, 3H), 1.07 (d, J = 7.2
Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 5.7 Hz, 3H), 0.86 (s,
9H), 0.83 (s, 9H), 0.07 (s, 3H), 0.04(s, 3H), 0.03 (s, 6H); 13C NMR
(CDCl3, 75 MHz) δ 169.5, 144.7, 142.1, 134.6, 129.9, 129.1, 129.0,
126.6, 123.9, 100.1, 78.8, 76.7, 73.7, 72.3, 69.5, 56.6, 56.2, 54.9, 41.4,
38.8, 38.1, 36.7, 36.0, 34.2, 34.0, 29.6, 25.7, 25.2, 23.7, 18.2, 18.1, 17.0,
16.2, 16.1, 15.5, 13.4, 11.9, 10.2, −4.5, −4.9, −5.0, −5.1; IR (neat)
2928, 2855, 1701, 1250, 1115, 836, 776 cm−1; ESI HRMS m/z calcd
for C48H86O8Si2Na [M + Na]+ 869.57589, found 869.57438.
( 1 S , 2 R , 4 E , 7 S , 1 0 E , 1 2 E , 1 4 R , 1 5 S , 1 6 S ) - 7 -
((2S,7S,8R,9R,10S,11S,E)-7,9-Dihydroxy-11-methoxy-8,10-di-
methyldodec-4-en-2-yl)-2,15-dihydroxy-10,12,14-trimethyl-
8,17-dioxabicyclo[14.1.0]heptadeca-4,10,12-trien-9-one (1).
To a solution of 42 (4.0 mg, 0.0047 mmol) in MeCN (1 mL) was
added fluorosilic acid 20−25 wt % solution in water (0.2 mL). After 3
days of stirring at room temperature, saturated NaHCO3 was added,
and the aqueous layer was extracted with EtOAc (2 × 10 mL). The
combined organic extracts were dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification by silica gel column
(9) Schomaker, J. M.; Pulgam, V. R.; Borhan, B. J. Am. Chem. Soc.
2004, 126, 13600.
(10) (a) Mori, K.; Sku, Y. B. Tetrahedron 1988, 44, 1035−1038.
(b) Okamura, H.; Kuroda, S.; Ikegami, S.; Tomita, K.; Sugimoto, Y.-I.;
Sakaguchi, Y.-I.; Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron 1993,
49, 10531−10554.
(11) Yadav, J. S.; Ather, H.; Rao, N. V.; Reddy, M. S.; Prasad, A. R.
Synlett 2010, 8, 1205−1208.
(12) Ancerewicz, J.; Vogel, P. Helv. Chim. Acta 1996, 79, 1393.
(13) (a) Mitsunobu, O. Synthesis 1981, 1−28. (b) Hughes, D. L. Org.
React 1992, 42, 335−656. (c) Valentine, D., Jr; Hillhouse, J. H.
Synthesis 2003, 317−334.
(14) Masuda, T.; Osako, K.; Shimizu, T.; Nakata, T. Org. Lett. 1999,
1, 941−944.
(15) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
(16) Inanada, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
chromatography gave FD-891 (1) in (2.0 mg, 90%). [α]25 +11.5 (c
D
0.1, MeOH); 1H NMR (CDCl3, 500 MHz) δ 7.30 (s, 1H), 5.83−5.72
(m, 1H), 5.64−5.43 (m, 4H), 4.88−4.81 (m, 1H), 4.20−4.10 (m, 1H),
3.88 (d, J = 4.9 Hz, 1H), 3.81(d, J = 7.9 Hz, 1H), 3.63−3.56 (m, 2H),
3.34 (s, 3H), 3.27−3.23 (m, 1H), 3.16−3.09 (m, 2H), 2.58−2.43 (m,
1H), 2.37−2.28 (m, 3H), 2.25−2.14 (m, 1H), 2.09 (s, 3H), 2.02 (s,
3H), 1.90−1.53 (m, 7H), 1.19 (d, J = 6.9 Hz, 3H), 1.13 (d, J = 6.9 Hz,
3H), 0.92 (d, J = 7.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H), 0.79 (d, J = 6.9
Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 168.8, 144.0, 141.7, 135.8,
130.4, 130.0, 129.9, 128.0, 124.6, 82.6, 78.4, 76.4, 73.2, 71.0, 70.8, 56.1,
56.0, 55.3, 55.0, 39.6, 39.5, 38.1, 37.0, 35.9, 35.8, 34.8, 34.0, 33.9, 16.5,
16.4, 16.3, 15.5, 13.6, 11.6, 4.9; IR (neat) 3417, 2923, 1704, 1117,
cm−1; ESI HRMS m/z calcd for C33H54O8Na [M + Na]+ 601.37109,
found 601.36988.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yadavpub@iict.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.K.D. thank UGC, New Delhi for the award of fellowship.
REFERENCES
■
(1) Seki-Asano, M.; Tsuchida, Y.; Hanada, K.; Mizoue, K. J. Antibiot.
1994, 47, 1234−1241.
(2) Kataoka, T.; Yamada, A.; Bando, M.; Honna, T.; Mizoue, K.;
Nagai, K. Immunology 2000, 100, 170.
11118
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