Gold-catalyzed Hosomi-Sakurai type reaction for the total synthesis of herboxidiene

Article abstract of DOI:10.1039/c6ob00321d

Total synthesis of herboxidiene/GEX1A/TAN-1609 has been accomplished in the 22 longest linear sequences starting from 2-butyne-1,4-diol following our recently developed gold-catalyzed Hosomi-Sakurai type of reaction on lactols with allyltrimethyl silane a

Full text of DOI:10.1039/c6ob00321d

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Gold-Catalyzed Hosomi-Sakurai Type Reaction for the
Total Synthesis of Herboxidiene
Received 00th May 20xx,
Accepted 00th May 20xx
Barla Thirupathi and Debendra K. Mohapatra*
DOI: 10.1039/x0xx00000x
Total synthesis of herboxidiene/GEX1A/TAN-1609 has been accomplished in 22 longest linear sequence starting from 2-
butyne-1,4-diol following our recently developed gold-catalyzed Hosomi-Sakurai type of reaction on lactols with
allyltrimethyl silane and Stille cross coupling to assemble the advanced fragment. The synthesis of C10-C19 fragment was
accomplished by means of Sharpless epoxidation and asymmetric alkylation reactions starting from (R)-methyl lactate.
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degradation, spectroscopic studies, X-ray analysis, and its
synthesis.9 The first total synthesis has been reported by Kocienski
et al.,10 subsequently Banwell et al. achieved the formal total
synthesis of herboxidiene.11 Edmunds and co-workers reported
simple aromatic hybrids of herboxidiene.12 In 2007, Panek et al.
published silane based total synthesis,13 Forsyth et al. reported the
total synthesis by utilizing Suzuki cross coupling,14 Ghosh presented
Introduction
Herboxidiene was initially isolated in 1992 by Issac and co-workers
from Streptomyces chromofuscus.1 Again in 2002, Yoshida et al.
isolated the series (GEX1) of six new polyketide natural products
from culture broth of Streptomyces sp,2 out of which, GEX1A was
identified as herboxidiene. Herboxidiene shows selective
phytotoxicity effect against a range of broadleaf annual weeds,
itself being harmless to wheat.1,3 It activates the gene transcription
of low-density lipoprotein (LDL) receptors which bind to the
cholesterol-rich lipoproteins in plasma and transport them into cells
thereby decreasing the cholesterol level in plasma4 and it also
induces both G1 and G2/M cell cycle arrest in human tumor cell line
WI-38.5 Recently, Mizukam et al. reported that herboxidiene targets
particularly the SAP155 protein,6 which is a subunit of SF3b,
responsible for pre-mRNA splicing. Herboxidiene/GEX1A series acts
as a novel splicing inhibitor that especially impairs SF3b function by
binding to SAP155 (like Spliceostatin A interacts with SAP130 or
SAP1557 and Pladienolide B binds to SAP1308). Splicing machinery
is a new target for antitumor drugs. Further modification on these
structures may lead to high efficiency drugs.6 Herboxidiene has
synthetically challenging structural features, including the tri-
substituted tetrahydropyran core, conjugated diene side chain
including nine stereogenic centers. The intriguing biological profile
O
OMe
O
HO
O
OH
Figure 1. Structure of Herboxidiene/GEX 1A.
convergent synthesis by utilizing Suzuki coupling reaction.15 In
2011, Romea and Urpi also reported the total synthesis by using
Suzuki coupling strategy.16 Thomas et al. have published the total
synthesis of herboxidiene, synthetic analogue 6-norherboxidiene
and its biological evaluation by following Diels
−Alder reacꢀon and a
Ferrier-type rearrangement.17 Recently, Yadav et al. published
formal total synthesis of herboxidiene by utilizing Prins cyclization
for the construction of the tetrahydropyran core while the
oxygenated side chain was synthesized following Sharpless
asymmetric dihydroxylation and Evan’s alkylation as key steps.18
and structural complexity has attracted the attention of several The typical dissection of herboxidiene provides two synthons,
synthetic chemists across the globe towards the total synthesis of
the natural product herboxidiene.
tetrahydropyran core 2 (C1-C9 unit) and the side chain 3 (C10-C19
unit). It was anticipated that Stille coupling can be employed to
stitch these two key fragments with ease as depicted in Scheme 1.
We have demonstrated that the 2,6-disubstituted tetrahydro-2H-
pyrans relevant to the C1-C8 fragment could be prepared by
following our recently developed Hosomi-Sakurai type of reaction
of lactol 5 with allyltrimethyl silane in the presence of AuCl3.19 The
catalysis of organic reactions by gold catalyst has recently been
shown to be a powerful tool in organic synthesis. After a phase of
methodology development20 and mechanistic studies,21-22 now gold
Initial structural assignment was carried out by chemical
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad-500007, India; E-mail: mohapatra@iict.res.in;
Tel: +91-40-27193128; Fax: +91-40-27160512.
†Electronic Supplementary Informaꢀon (ESI) available: [Scanned copy of
1H and 13C NMR, NOESY spectrum of compound
DOI: 10.1039/x0xx00000x
4]. See
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catalysts are regularly used in the total synthesis of complex natural The regioselective opening of epoxide was achieved by
products.23-25
trimethylaluminum28 at ‒40 oC to obtain compound 13 exclusively
in 92% yield (Scheme 2).
Vanadyl-oxo epoxidation
Asymmetric alkylation
The α,β-unsaturated double bond in 13 was reduced by using
NaBH4 and catalytic amount of NiCl2 in ethanol29 to furnish the
saturated ester which on treatment with camphor sulfonic acid
(CSA) obtained lactone 14 in 82% over two steps. Treatment of 14
with DIBAL-H at −78 oC furnished the lactol compound 5 in 83%
yield. Having lactol compound in hand allylation19 reaction was then
O
OMe
O
HO
O
OH
Stille coupling
Epimerizatin
Sharpless epoxidation
OMe
O
Bu3Sn
carried out. Compound
5 was then treated with allyltri-
I
EtO
O
OMOM
3
2
methylsilane and catalytic amount of AuCl3 (8.3 mol%) to afford
compound 15 in 87% yield (dr = 97:3, by HPLC). Following, Jin’s one-
step dihydroxylation–oxidation protocol,30 the terminal double
bond in 15 was oxidized to an aldehyde. Subsequent oxidation
under Pinnick conditions31 afforded carboxylic acid 16 in 90% yield.
O
OMe
O
EtO
EtO
O
OMOM
4
OPMB
OPMB
7
OH
DIBAL-H
NiCl2, NaBH4, EtOH
O
CH2Cl2
0 oC-rt, 1 h
HO
O
EtOOC
OPMB
O
O
MeO
-78 oC, 2 h
83%
CSA, rt, 4 h
OH
14
OPMB
OH
6
8
13
5
OH
82% for two steps
1. NaIO4, OsO4, 2,6-lutidine
1,4-dioxane, 0 oC-rt, 81%
SiMe3
Scheme 1. Retrosynthetic analysis for herboxidiene
O
HO
O
5
AuCl3, rt
3 h, 87%
2. NaClO2,NaH2PO4
OPMB
OPMB
15
t-BuOH, H2O
0 oC to rt, 1 h
90%
Lactol 5 could be prepared from readily available 2-Butyne-1,4-diol
(6). The stanane compound 3 could be obtained from 7 by following
asymmetric alkylation as a key reaction. The ester compound 7 in
turn could be obtained from readily available methyl lactate 8 by
following Sharpless epoxidation, regio- and stereoselective opening
of epoxide with trimethylaluminium.
BF3.OEt2
KH
THF
EtOH
0 oC to rt
2 h, 76%
O
O
rt, 4 h
84%
O
OPMB
OPMB
OPMB
O
OEt
17
O
OH
16
O
OEt
4
Scheme 3. Synthesis of the fragment 4
Results and discussion
The acid compound was easily converted ester in 84% yield. At this
stage the epimerization of trans-pyran to cis-pyran with t-BuOK as a
base in THF was carried out, but it suffered from low yield.
However, when the base was switched to potassium hydride (KH),
the compound 4 was obtained in 76% yield (Scheme 3).16,32 The
structure of compound 4 was also confirmed with the help of nOe
studies.
The synthesis of fragment 2 was initiated from commercially
available 2-butyne-1,4-diol (6). The primary hydroxy of diol 6 was
selectively protected as its PMB ether with Amberlyst-15 resin26 and
4-methoxy benzylalcohol to obtain mono-protected compound in
91% yield, which on treatment with Red-Al in THF afforded the
allylic alcohol 10 in 87% yield. Following Swern oxidation conditions
allylic alcohol group present in 10 was smoothly oxidized to
aldehyde 11 in 90% yield. The aldehyde 11 was then subjected
The PMB group present in 4 was smoothly deprotected with DDQ to
obtain compound 18 in 89% yield.33 The primary alcohol was
converted to aldehyde with Dess-Martin periodinane reagent
(DMP)34 and the treatment of aldehyde with methylmagnesium
OPMB
Red-Al, THF
Amberlyst-15 resin
PMBOH
HO
6
OPMB
0 oC-rt, 6 h
87%
CH2Cl2, 45 oC, 12 h
91%
10
9
OH
1. Proline Cat., H2O2
CH2Cl2, rt, 2 h
(COCl)2, DMSO, CH2Cl2
DDQ
O
DMP, CH2Cl2
0 oC-rt, 3 h
CH2Cl2, H2O
OPMB
-78 oC, Et3N, 2 h
90%
2. C-2 ylide,
-78 oC to rt, 1 h,
80%
O
O
11
0 oC to rt
2 h, 89%
OPMB
OH
MeMgBr, THF
-78 oC, 1 h
(73%) over two steps
O
OEt
O
OEt
18
4
Me3Al, CH2Cl2,
EtOOC
OPMB
EtOOC
OPMB
-40 oC to rt, 3 h,
92%
O
12
OH
13
DMP
CHI3, CrCl2
THF
CH2Cl2
Scheme 2. Synthesis of the fragment 13
O
O
O
I
rt, 3 h
93%
rt, 5 h, 72%
OH
O
O
OEt
19
O
OEt
20
O
OEt
to asymmetric epoxidation under standard Jørgensen’s conditions27
with H2O2 in the presence of a proline-derived catalyst (10 mol%) to
furnish an epoxy aldehyde, which on treatment with Ph3P=CHCO2Et
afforded epoxy ester 12 in 80% yield (ee 96%, by HPLC) (E/Z = 10:1).
2
Scheme 4. Synthesis of the fragment 2
2 | J. Name., 2016, 00, 1-15
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bromide at −78 oC produced the diastereomeric mixture (1:1) of iodide with lithium enolate (insitu generated using 29 in the
compound 19 in 73% yield (over two steps). The secondary hydroxyl presence of LiHMDS at −78 °C) afforded 30 as a single diastereomer.
in 19 was smoothly converted to its corresponding ketone 20 in
93% yield by using Dess-Martin periodinane (DMP). The ketone 20
O
OMe
OMe
DIBAL-H, CH2Cl2
was subjected to Takai olefination35 using CHI3, CrCl2 in THF to
obtain the corresponding vinyl iodide 2 in 72% yield (with E/Z ratio
= 9:1 by NMR).17
EtO
-78 to 0 oC, 2 h
86%
HO
OMOM
OMOM
7
28
Imid., PPh3, I2
Et2O,CH3CN, 0 o
,
O
OMe
O
LiBH4, Et2O, MeOH
0 oC, 30 min, 86%
OMOM
C
N
The synthesis of the side chain fragment vinyl stanane
3
O
LiHMDS, 29, -78 to -40 oC
commenced with masking of the hydroxy group of (R)-methyl
lactate 8 as its MOM ether to obtain compound 22 in 94% yield.
Controlled reduction of 21 with DIBAL-H in CH2Cl2 at −78 °C
afforded the corresponding aldehyde which on treatment with
phosponate 2236 in THF at −78 °C furnished unsaturated ester 23 in
81% yield (cis/trans = 9:1 by HPLC) and the isomers were separated
by silica gel column chromatography. Exposure of 23 to DIBAL-H in
CH2Cl2 afforded the allyl alcohol 24 in 86% yield. Alcohol 24 was
subjected to Sharpless asymmetric epoxidation37 with Ti(iPrO)4 (15
mol%) and tert-butylhydroperoxide (TBHP) in the presence of (−)-
DET (20 mol%) to yield epoxide 25 in 87% yield (dr = 10:1 by HPLC).
The epoxy alcohol 25 was oxidized with DMP and the resultant
aldehyde was used for next step without further purification. Thus,
Wittig reaction with Ph3P=CH(CH3)COOEt in benzene at 50 oC
furnished a mixture of trans:cis (12:1 by NMR) unsaturated ester 26
30
5 h, (65%) over two steps
Ph
OMe
OH
K2CO3, 33
OMe
O
DMP, CH2Cl2
MeOH
-78 oC, 5 h
0
oC-rt, 3 h
96%
OMOM
OMOM
88%
32
31
OMe
OMe
n-Bu3SnH, THF Bu3Sn
PdCl2(PPh3)2
0 oC to rt
15 min
OMOM
OMOM
34
3
O
O
O
O
P
N
O
OMe
OMe
N2
29
Ph
33
Scheme 6: Synthesis of the fragment 3
The reductive cleavage of the chiral auxiliary in 30 was achieved
with LiBH4 in Et2O at 0 oC to afford the alcohol 31 in 86% yield. DMP
oxidation of alcohol 31 to its corresponding aldehyde was then
transformed into the terminal alkyne 34 under modified Ohira-
Bestmann conditions41 to give the alkyne 34 in 88% yield. Finally,
palladium catalyzed hydrostannation42 of alkyne 34 provided vinyl
stanane 3 (Scheme 6).
DIBAL-H, CH2Cl2
-78 oC, 1 h
O
O
MOMCl, DIPEA
O
O
CH2Cl2, 0 oC to rt
10 h, 94%
NaH, THF, 22
-78 oC, 2 h
81% over two steps
OMOM
OH
8
21
(-)-DET, Ti(iOPr)4
DIBAL-H, CH2Cl2
EtO
-78 to 0 oC, 1 h
86%
TBHP, -40 oC, 48 h
87%
OMOM
OH
OMOM
O
23
24
(Z/E: 9:1)
DMP, CH2Cl2
0 oC-rt, 3 h
O
O
Me3Al, CH2Cl2
Having both the key fragments 2 and 3 in hand, the stage was ready
for their crucial coupling reaction.43 Accordingly, the reaction was
carried out under Stille conditions to yield the coupled product in
OMOM -40 oC, 4 h
83%
Ph3PCH(CH3)COOEt
EtO
OH
OMOM
25
benzene, reflux, 1 h,
(72%) over two steps
26
O
(dr: 10:1)
Me3OBF4
O
P
O
OEt
OMe
OEt
OH
O
O
proton sponge
OMe
O
O
Bu3Sn
O
CH2Cl2,0 oC- rt, 3 h
O
EtO
O
I
OMOM
OMOM
90%
OMOM
22
2
27
7
3
Scheme 5: Synthesis of the fragment 7
1. Pd2(dba)3, LiCl, Ph3As
NMP, rt, 48 h, 71%
O
OMe
OH
in 82% yield, which were separated by silica gel column
chromatography. Then, the epoxide opening was planned
regioselectively following Miyashita’s protocol38 with excess
trimethylaluminium (TMA) (8 equiv.)/H2O (6 equiv.) at −40 oC to
afford the requisite product 27 (regioselectivity = 19:1) in 83% yield.
The secondary hydroxy group in 27 was converted to its methyl
ether with Meerwein's salt (Me3OBF4)39 to afford 7 in 90% yield
(Scheme 5).
EtO
O
2. 2N HCl, MeOH
-15 oC, 4 h 86%
35
36
VO(acac)2, TBHP
CH2Cl2
O
OMe
OH
O
EtO
O
-25 oC, 24 h, 51%
O
OMe
OH
K2CO3, MeOH, 45 o
4 h, 85%
C
O
HO
O
Herboxidiene (1)
Reduction of ester 7 using DIBAL-H in CH2Cl2 at 0 °C afforded the
allylic alcohol 28 in 86% yield. Alcohol 28 was converted into its
corresponding iodide by treating with PPh3, imidazole and iodine in
Et2O/CH3CN (1:2) at 0 °C for 15 min, then Evan’s alkylation40 of the
Scheme 7: Total synthesis of herboxidiene (1)
71% yield. The MOM group was deprotected with 2 N HCl to afford
the deprotected compound 35 in 86% yield (Scheme 7). Regio and
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stereoselective epoxidation of C14-C15 olefin using vanadyl-oxo Celite pad, the pad was additionally washed with the same solvent
1
epoxidation conditions furnished 36 in 51% yield with traces of
used, and the washings incorporated to the main organic layer. H
other diastereomeric epoxide as previously reported.10,13 Finally,
and 13C NMR chemical shifts are reported in ppm downfield from
saponification of the ester group using K2CO3 in methanol yielded
herboxidiene (1) in 85% yield. The spectroscopic data (1H, 13C NMR)
tetramethylsilane and coupling constants (J) are reported in hertz
20
and analytical data {(HRMS and [α]D +4.2 (c 0.2, MeOH)} were in
(Hz). High resolution mass spectra were run by the electron impact
accordance with the previously reported values.
mode (ESIMS, 70 eV) or by the FAB mode (m-nitrobenzyl alcohol
Conclusions
matrix), using an orbitrap mass analyzer. IR data were measured
with oily films on NaCl plates (oils) or KBr pellets (solids) and are
given only for molecules with relevant functional groups (OH, C=O).
Specific optical rotations [α]D are given in 10-1 degcm2g-1 and were
measured at 25°C. The following abbreviations are used to
designate signal multiplicity: s = singlet, d = doublet, t = triplet, q =
quartet, quin = quintet, m = multiplet, br = broad.
In summary, we have achieved the total synthesis of herboxidiene
(1) in an efficient manner with high stereoselectivity starting from
commercially available 2-butyne1,4-diol and by taking the
advantage of the gold-(III) catalyzed diastereoselective C-C bond
formation of a cyclic hemiacetal with allyltrimethylsilane as a
nucleophile via the formation of an oxocarbenium ion intermediate
as the key reaction. The protocol offers an operationally simple
approach to 2,6-disubstituted tetrahydropyrans, and features
ambient temperature conditions, good diastereoselectivity and
protecting group tolerance compare to earlier methods. The
present strategy proceeds in good to excellent yield without pre-
functionalization or via alkyne assistance, in contrast to the
previous approaches, with a less nucleophilic carbon. The other
highlight of our synthetic strategy is the demonstration of Stille
coupling reaction for the introduction of the diene system. The
other key steps of the synthesis were introduction of terminal
alkyne under modified Ohira-Bestmann conditions, epoxide group
4-(4-Methoxybenzyloxy)but-2-yn-1-ol (9): To a stirred solution of
butyne-1,4-diol (6) (10.0 g, 116.2 mmol), catalytic amount of
Amberlyst-15 resin (1.0 g, 10% w/w) in anhydrous in CH2Cl2 (100
mL) was added 4-methoxybenzyl alcohol (16.0 g, 116.2 mmol) at
room temperature and heated to reflux at 45 oC for 12 h. After
completion of the reaction (monitored by TLC), it was filtered
through a pad of Celite. The filtrate was washed with CH2Cl2 (2 × 50
following Jørgensen’s asymmetric epoxidation and vanadyl-oxo mL). The combined organic layer was dried over anhydrous Na2SO4,
epoxidation conditions. The simple reactions and flexible synthetic
concentrated under reduced pressure to get a brown oil, which on
strategy offers an additional platform for the generation of
purification by silica gel column chromatography (ethyl
synthetic analogues for further biological studies.
acetate/hexane = 1:1) afforded 9 (21.7 g, 91%) as colourless liquid.
Experimental
IR (neat): 3397, 3011, 2839, 2371, 2040, 1612, 1514, 1464, 1302,
1175, 1031 cm−1 1H NMR (300 MHz, CDCl3): δ 7.28 (d, J = 8.7 Hz,
;
General methods
2H), 6.88 (d, J = 8.7 Hz, 2H), 4.52 (s, 2H), 4.31 (s, 2H), 4.17 (t, J = 1.8
Hz, 2H), 3.80 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 159.2, 129.6,
129.1, 113.7, 84.9, 81.2, 71.1, 56.9, 55.1, 50.6 ppm; HRMS (ESI): m/z
calcd. for C12H14O3Na [M + Na]+: 229.0835; found: 229.0846.
Experiments which required an inert atmosphere were carried out
under argon in flame-dried glassware. Et2O and THF were freshly
distilled from sodium/benzophenone ketyl and transferred via
syringe. Dichloromethane was freshly distilled from CaH2. Tertiary
amines were freshly distilled over KOH. Commercially available
reagents were used as received. Unless detailed otherwise, "work-
up" means pouring the reaction mixture into brine, followed by
extraction with the solvent indicated in parenthesis. If the reaction
medium was acidic (basic), an additional washing with 5% aqueous
NaHCO3 (aqueous NH4Cl) was performed. Washing with brine,
drying over anhydrous Na2SO4 and evaporation of the solvent under
reduced pressure followed by chromatography on a silica gel
column (60-120 mesh) with the indicated eluent furnished the
corresponding products. Where solutions were filtered through a
(E)-4-(4-Methoxybenzyloxy)but-2-en-1-ol (10): Red-Al (15.8 mL,
51.0 mmol, 65% in toluene) was added to a solution of compound 9
(5.1 g, 20.4 mmol) in anhydrous THF (70 mL) at 0 oC and allowed to
stir at room temperature for 6 h. After complete consumption of
the starting material (monitored by TLC), it was quenched with
saturated solution of sodium potassium tartrate (100 mL) at 0 oC
and diluted with ethyl acetate (100 mL). The organic layer was
separated and the aqueous layer extracted with ethyl acetate (2 ×
75 mL). The combined organic layers were washed with brine (2 ×
100 mL), dried over anhydrous Na2SO4 and evaporated under
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reduced pressure. The crude product was purified by silica gel another 1 h at room temperature. After completion of the reaction
column chromatography (ethyl acetate/hexane = 2:1) to furnish the (monitored by TLC), solvent was removed under reduced pressure.
desired compound 10 (4.8 g, 87%) as a colorless liquid. IR (neat): The residue was purified by silica gel column chromatography (ethyl
3396, 3011, 2839, 2371, 2909, 2433, 1612, 1464, 1249, 1218, 1036, acetate/hexane = 1:8) to give the desired epoxy compound 12 (3.69
27
1010 cm−1; 1H NMR (300 MHz, CDCl3): δ 7.26 (d, J = 8.5 Hz, 2H), 6.87 g, 80%) as a colorless liquid. [α]D −13.2 (c 0.8, CHCl3); IR (neat):
(d, J = 8.5 Hz, 2H), 5.91-5.78 (m, 2H), 4.44 (s, 2H), 4.12 (d, J = 4.7 3445, 2928, 2862, 1715, 1657, 1613, 1367, 1302, 1183, 1097, 1035
Hz, 2H), 3.99 (d, J = 6.9 Hz, 2H), 3.79 (s, 3H), 2.06 (br s, 1H) ppm; 13
C
cm−1; 1H NMR (300 MHz, CDCl3): δ 7.26 (d, J = 8.5 Hz, 2H), 6.88 (d, J
NMR (75 MHz, CDCl3): δ 158.7, 132.3, 129.7, 129.0, 126.7, 113.4, = 8.5 Hz, 2H), 6.66 (dd, J = 15.7, 7.3 Hz, 1H ), 6.14 (d, J = 15.7 Hz,
71.4, 69.5, 61.9, 54.8 ppm; HRMS (ESI): m/z calcd. for C12H16O3Na 1H), 4.50 (s, 2H), 4.20 (q, J = 14.3, 7.2 Hz, 2H), 3.80 (s, 3H), 3.73 (dd,
[M + Na]+: 231.0991; found: 231.1004.
, J = 11.5, 3.2 Hz, 1H), 3.55 (dd, J = 11.5, 4.9 Hz, 1H), 3.40 (dd, J =
7.2, 1.5 Hz, 1H), 3.14 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H) ppm; 13C NMR
(75 MHz, CDCl3): δ 165.1, 159.0, 143.6, 129.4, 129.1, 123.9, 113.5,
72.7, 68.5, 60.3, 59.2, 54.8, 53.3, 13.8 ppm; HRMS (ESI): m/z calcd.
for C16H21O5 [M + H]+: 293.1383; found: 293.1389.
(E)-4-(4-Methoxybenzyloxy)but-2-enal (11): To a stirred solution of
oxalyl chloride (3.27 mL, 38.46 mmol) in CH2Cl2 (30 mL), was added
DMSO (5.45 mL, 76.92 mmol) at –78 oC. After 20 min, alcohol 10
(4.0 g, 19.23 mmol) in CH2Cl2 (30 mL) was added to the reaction
o
mixture and stirred at –78 C for 45 min. Then triehtylamine (20.21 (4S,5S,E)-Ethyl-6-(benzyloxy)-5-hydroxy-4-methylhex-2-enoate
mL, 153.84 mmol) was added to the reaction mixture and stirred at (13): The epoxy compound 12 (5.0 g, 17.1 mmol) was taken in a 250
the same temperature for further 45 min. After completion of the mL RB and to it CH2Cl2 (70 mL) was added under nitrogen
reaction (monitored by TLC), it was quenched with saturated atmosphere. The reaction mixture was cooled to −40 °C. Trimethyl
aqueous solution of NH4Cl (50 mL) and the layers were separated. aluminum (68.5 mL, 136.9 mmol, 2M in toluene) was slowly added
The aqueous layer was extracted with CH2Cl2 (2 × 75 mL). The under nitrogen atmosphere at the same temperature. After 30 min,
combined organic layer was washed with water (100 mL) and brine H2O (1.8 mL, 102.7 mmol) was added very carefully and slowly so
(40 mL), dried over anhydrous Na2SO4 and concentrated, that the internal temperature should not change. After
evaporated to dryness and then purified by silica gel column effervescence ceased, it was allowed to stir for further 3 h at −40 oC
chromatography (ethyl acetate/hexane = 1:6) to get the desired and TLC showed the complete consumption of the starting material.
product11 (3.56 g, 90%) as a colorless oil; IR (neat): 2850, 1689, It was then quenched very slowly with saturated NH4Cl solution (50
1
1612, 1514, 1462, 1247, 1177, 1106, 1032 cm−1; H NMR (300 MHz, mL) and diluted with CH2Cl2 (100 mL). HCl (1 N, 100 mL) was added
CDCl3): δ 9.57 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 6.89 (d, J = and vigorously stirred until a clear separation of the two layers took
8.3 Hz, 2H), 6.82 (t, J = 3.4 Hz, 1H), 6.39 (dd, J = 9.8, 1.5 Hz, 1H), 4.52 place. The organic layer was separated and the aqueous layer
(s, 2H), 4.26 (dd, J = 3.4, 1.5 Hz, 2H), 3.81 (s, 3H) ppm; 13C NMR (75 extracted with CH2Cl2 (2 × 100 mL). The combined organic layer was
MHz, CDCl3): δ193.0, 159.0, 153.2, 131.2, 129.0, 113.5, 72.2, 67.9, washed with brine (2 × 150 mL), dried over anhydrous Na2SO4, and
54.8 ppm; HRMS (ESI): m/z calcd. for C12H14O3Na [M + Na]+: evaporated under reduced pressure. The crude was purified by
229.0835; found: 229.0847.
silica gel column chromatography (ethyl acetate/hexane = 1:5) to
27
get the desired product 13 (4.8 g, 92%) as a colorless liquid. [α]D
(E)-Ethyl 3-((2R,3R)-3-((4-methoxybenzyloxy)methyl)oxiran-2-yl)
acrylate (12): To a stirred solution of α,β-unsaturated aldehyde 11
(3.9 g, 18.93 mmol) in CH2Cl2 (40 mL) at 0 °C was added TMS-
protected diphenyl prolinol catalyst (0.46 g, 1.90 mmol) followed by
H2O2 (35 % aq., 1.23 mL, 18.23 mmol). The reaction mixture was
stirred vigorously at room temperature until total consumption of
the starting material (monitored by TLC). Then Ph3P=CHCO2Et (8.46
g, 24.6 mmol) was added in one portion at 0 °C and stirred for
+10.8 (c 0.8, CHCl3); IR (Neat): 3464, 2921, 1711, 1652, 1610, 1513,
1
1250, 1177, 1034 cm−1; H NMR (300 MHz, CDCl3): δ7.26 (d, J = 9.1
Hz, 2H), 7.00 (dd, J = 15.9, 9.1 Hz, 1H), 6.88 (d, J = 9.1 Hz, 2H), 5.84
(dd, J = 15.8, 1.5 Hz, 1H ), 4.46 (s, 2H), 4.18 (q, J = 14.3, 7.5 Hz, 2H),
3.81 (s, 3H), 3.72 (m, 1H), 3.49 (dd, J = 9.8, 3.8 Hz, 1H), 3.37 (dd, J =
9.1, 7.5 Hz, 1H), 2.50 (dd, J = 13.6, 8.3 Hz, 1H), 2.26 (br s, 1H), 1.28
(t, J = 7.5 Hz, 3H), 1.08 (d, J = 7.5 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3): δ 166.3, 159.0, 150.0, 129.6, 129.2, 121.4, 113.5, 72.9, 72.7,
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71.9, 60.0, 54.9, 39.2, 15.5, 13.9 ppm; HRMS (ESI): m/z calcd. for mL). The combined organic layer was washed with brine (2 × 100
C
17H28NO5 [M + NH4]+: 326.1962; found: 326.1967.
mL), dried over anhydrous Na2SO4 and evaporated under reduced
pressure. The crude was purified by silica gel column
chromatography (ethyl acetate/hexane = 1:7) to afford the desired
(5S,6S)-6-((4-Methoxybenzyloxy)methyl)-5-methyltetrahydro-2H-
pyran-2-one (14): NiCl2.6H2O (0.6 g, 2.59 mmol) was dissolved in
EtOH (20 mL) and to it, NaBH4 (1.28 g, 33.7 mmol) was added at 0
oC. The solution was turned green to black. The α,β-unsaturated
ester 13 (8.0 g, 25.9 mmol) was dissolved in EtOH (20 mL) was
subsequently added to the above solution under nitrogen
atmosphere. The reaction was mixture was stirred for 1 h at
ambient temperature. After completion of the reaction (monitored
by TLC), CSA (0.64 g, 2.59 mmol) was added and stirring was
continued for further 4 h at room temperature, EtOH was removed
under reduced pressure and residual black material was diluted
with ethyl acetate (20 mL) and filtered through Celite bed. The
filtrate was washed with ethyl acetate (2 × 100 mL), brine (2 × 100
mL), dried over Na2SO4 and concentrated under reduced pressure.
The crude product so obtained was purified by silica gel column
25
lactol 5 (4.2 g, 83%). [α]D −17.6 (c 2.3, CHCl3); IR (Neat): 3420,
2928, 2863, 1731, 1612, 1512, 1459, 1247, 117, 1102, 1033 cm−1; 1H
NMR (300 MHz, CDCl3): δ 7.27 (m, 2H), 6.88 (m, 2H), 5.35 (br d, J =
1.9 Hz, 0.5 H ), 4.70 (m, 0.5H), 4.55 (m, 1H), 4.49−4.43 (m, 2H), 4.04
(m, 0.4 H), 3.80 (m, 3H), 3.69−3.56 (m, 1H), 3.56−3.43 (m, 1H),
3.29−3.23 (m, 0.5 H), 2.65−2.57 (m, 0.5 H), 2.52−2.44 (m, 0.5 H),
2.05 (dd, J = 9.6, 1.7 Hz, 0.5 H), 1.94−1.87 (m, 0.6 H), 1.74−1.70 (m,
0.5 H), 1.62−1.48 (m, 1.5 H), 1.28−1.24 (m, 1H), 0.99 (dd, J = 6.6, 1.8
Hz, 1H), 0.81 (dd, J = 6.1, 1.8 Hz, 1H), 0.79 (dd, J = 6.5, 1.9 Hz, 1H)
ppm; 13C NMR (75 MHz, CDCl3): δ 175.5, 171.5, 159.0, 129.8, 129.3,
129.2, 113.7, 113.5, 96.4, 91.3, 85.1, 80.9, 73.6, 73.0, 72.9, 70.5,
69.4, 55.1, 32.7, 31.1, 30.7, 29.8, 29.5, 28.6, 27.4, 25.9, 17.7, 17.1,
16.9 ppm; HRMS (ESI): m/z calcd. for C15H22O4Na [M + Na]+:
289.1410; found: 289.1411.
chromatography (ethyl acetate/hexane = 1:7) to afford 14 (5.4 g,
26
72% over two steps) colourless liquid. [α]D +9.1 (c 2.0, CHCl3); IR (2S,3S,6S)-6-Allyl-2-((4-methoxybenzyloxy)methyl)-3-methyltetra
(neat): 3010, 2935, 1729, 1612, 1513, 1460, 1363, 1216, 1247, hydro-2H-pyran (15): To a stirred solution of lactol 5 (3.2 g, 12.0
1092, 1033 cm−1 1H NMR (300 MHz, CDCl3): δ 7.26 (d, J = 8.7 Hz, mmol) and allyltrimethylsilane (2.0 mL, 18.0 mmol) in CH2Cl2 (50
;
2H), 6.88 (d, J = 8.7 Hz, 2H), 4.55 (d, J = 1.7 Hz, 1H ), 4.46 (d, J = 1.7 mL), was added AuCl3 (0.26 g, 0.1 mmol) at 0 oC and allowed to
Hz, 1H ), 4.06−4.02 (m, 1H), 3.80 (s, 3H), 3.66 (dd, J = 10.9, 2.7 Hz, warm to room temperature slowly. After completion of the reaction
1H), 3.61 (dd, J = 11.3, 3.6 Hz, 1H), 2.61 (dddd, J = 13.5, 6.2, 4.2, 2.1 (monitored by TLC), it was quenched with saturated solution of
Hz, 1H), 2.52−2.43 (m, 1H), 2.10−2.00 (m, 1H), 1.93−1.85 (m, 1H), NaHCO3 (20 mL) and the organic layer was separated. The aqueous
1.59−1.49 (m, 1H), 0.99 (d, J = 6.5 Hz, 3H) ppm; 13C NMR (75 MHz, layer was extracted with CH2Cl2 (2 × 50 mL), the combined organic
CDCl3): δ 171.3, 159.2, 129.8, 129.2, 113.7, 85.1, 73.1, 69.6, 55.1, layer was dried over anhydrous Na2SO4 and concentrated under
29.5, 28.7, 27.4, 17.1 ppm; HRMS (ESI): m/z calcd. for C15H20O4Na reduced pressure to give a pale yellow oil which on purification by
[M + Na]+: 287.1246; found: 287.1254.
silica gel column chromatography (ethyl acetate/hexane = 1:20)
25
produced the desired allylated compound 15 (3.0 g, 87%). [α]D
(5S,6S)-6-((4-Methoxybenzyloxy)methyl)-5-methyltetrahydro-2H-
pyran-2-ol (5): Lactone 14 (5.0 g, 18.9 mmol) was dissolved in
CH2Cl2 (60 mL) and cooled to −78 °C under nitrogen atmosphere.
DIBAL-H (13.5 mL, 18.9 mmol, 1.4 M in toluene) was slowly added
to it over a period of 15 min at −78 °C. Aꢁer 30 min of sꢀrring at the
same temperature, TLC was checked which showed complete
consumption of starting material. It was quenched by slow addition
of saturated solution of sodium potassium tartrate (50 mL), diluted
with CH2Cl2 (40 mL) and allowed to stir at room temperature for
another 2 h to get a clear two separated layers. The organic layer
was separated and the aqueous layer extracted with CH2Cl2 (3 × 50
−19.6 (c 1.0, CHCl3); IR (neat): 3450, 3071, 2929, 2859, 1733, 1612,
1512, 1460, 1247, 1097, 1034, 913 cm−1; 1HNMR (300 MHz, CDCl3) δ
7.27 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.89−5.72 (m, 1H),
5.06 (td, J = 17.0, 3.0 Hz, 2H), 3.95−3.86 (m, 1H), 3.80 (s, 3H),
3.53−3.48 (m, 2H), 3.44 (dt, J = 7.5, 5.3, 3.4 Hz, 1H), 2.48 (dd, J
=14.2, 6.9 Hz, 1H), 2.24 (dd, J = 14.2, 6.9 Hz, 1H), 1.74−1.57 (m, 4H),
1.54−1.46 (m, 1H), 1.41−1.22 (m, 2H).88 (d, J = 6.6 Hz, 3H) ppm; 13
C
NMR (75 MHz, CDCl3): δ 159.0, 135.4, 130.6, 129.2, 116.4, 113.6,
75.5, 72.8, 71.8, 70.5, 55.2, 36.2, 30.5, 26.9, 26.6, 18.0 ppm; HRMS
(ESI): m/z calcd. for C18H26O3Na [M + Na]+: 313.1774; found:
313.1777.
6 | J. Name., 2016, 00, 1-15
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2-((2S,5S,6S)-6-((4-Methoxybenzyloxy)methyl)-5-methyltetrahydro 1.83−1.45 (m, 3H), 1.40−1.24 (m, 2H), 0.95 (d, J = 6.0, 3H) ppm; 13C
-2H-pyran-2-yl)acetald- ehyde (15a): 2,6-Lutidine (2.1 mL, 15.16 NMR (75 MHz, CDCl3): δ 175.3, 159.1, 130.2, 129.3, 113.7, 76.1,
mmol), OsO4 (1.80 mL, 2% in toluene, 0.14 mmol), and NaIO4 (6.46 72.8, 69.8, 68.6, 55.1, 37.3, 29.5, 27.2, 26.3, 17.9 ppm; HRMS (ESI):
g, 30.32 mmol) were added to a stirred solution of compound 15 m/z calcd. for C17H24O5Na [M + Na]+: 331.1516; found: 331.1518.
(2.2 g, 7.58 mmol) in dioxane and water (3:1, 30 mL). The reaction
Ethyl-2-((2S,5S,6S)-6-((4-methoxybenzyloxy)methyl)-5-methyltetra
mixture was stirred at room temperature and monitored by TLC.
hydro-2H-pyran-2-yl) acetate (17): To a stirred solution of acid 16
After completion of the reaction (monitored by TLC), water (30 mL)
(1.0 g, 3.24 mmol) in ethanol was added BF3.OEt2 (0.12 mL, 0.97
and CH2Cl2 (50 mL) were added. The organic layer was separated
mmol) at room temperature. The reaction mixture was stirred for 4
and the aqueous layer extracted with CH2Cl2 (2 × 50 mL). The
h at ambient temperature. After completion of the reaction
combined organic layer was washed with water (2 × 100 mL), brine
(monitored by TLC), it was quenched with triethylamine (3 mL).
(2 × 100 mL) and dried over Na2SO4. The solvent was removed
Solvent was evaporated under reduced pressure and the crude
under reduced pressure and then purified by silica gel column
product was purified by silica gel chromatography (ethyl
chromatography (ethyl acetate/hexane = 1:7) to get the desired
acetate/hexane = 1:7) to afford ester 17 (920 mg, 84%) as colorless
27
product 15a (1.90 g, 81%) as a colorless liquid. [α]D +14.3 (c 1.2,
27
liquid. [α]D +26.4 (c 1.0, CHCl3); IR (neat): 3020, 2983, 2937, 2421,
CHCl3); IR (neat): 3008, 2933, 2860, 2365, 2388, 1724, 1612, 1513,
2374, 1726, 1513, 1215, 1175, 1034 cm−1 1H NMR (300 MHz,
;
1458, 1301, 1216 cm−1; H NMR (300 MHz, CDCl3): δ 9.78 (d, J = 5.3
1
CDCl3): δ 7.26 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 4.53 (d, J =
11.7 Hz, 1H), 4.43 (d, J = 11.7 Hz, 1H), 4.40−4.35 (m, 1H), 4.12 (q, J =
14.3, 9.8 Hz, 2H ), 3.79 (s, 3H), 3.51 (dd, J = 4.7, 3.3 Hz, 2H),
3.46−3.41 (m, 1H), 2.75 (dd, J = 14.5, 8.1 Hz, 1H), 2.45 (dd, J = 14.5,
6.6 Hz, 1H), 1.84−1.77 (m, 1H), 1.72−1.63 (m, 2H), 1.53−1.48 (m,
1H), 1.36−1.31 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H), 0.88 (d, J = 6.6 Hz,
3H) ppm; 13C NMR (75 MHz, CDCl3): δ 171.3, 158.9, 131.6, 129.2,
113.5, 75.7, 72.7, 70.3, 69.2, 60.3, 55.1, 37.3, 30.2, 27.4, 26.5, 17.8,
14.0 ppm; HRMS (ESI): m/z calcd. for C19H28O5Na [M + Na]+:
359.1829; found: 360.1830.
Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 4.53 (d, J =
11.3 Hz, 1H), 4.42 (d, J = 11.3 Hz, 1H), 3.80 (s, 3H), 3.52 (dd, J = 10.6,
5.3 Hz, 1H), 3.47−3.39 (m, 1H), 2.85 (dddd, J = 11.3, 9.1, 8.3, 3.0 Hz,
1H), 2.46 (dddd, J = 15.8, 7.5, 5.3, 2.2 Hz, 1H), 1.88−1.74 (m, 1H),
1.75−1.64 (m, 2H), 1.50 (dd, J = 9.8, 4.5 Hz, 1H), 1.39−1.26 (m, 3H),
0.89 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 201.3,
159.1, 130.3, 129.2, 113.7, 75.9, 72.9, 70.0, 67.5, 55.2, 45.9, 30.0,
27.6, 26.1, 17.9 ppm; HRMS (ESI): m/z calcd. for C17H24O4Na [M +
Na]+: 315.1566; found: 315.1583.
2-((2S,5S,6S)-6-((4-Methoxybenzyloxy)methyl)-5-methyltetrahydro
-2H-pyran-2-yl) acetic acid (16): To a solution of aldehyde 15a (1.2
g, 4.10 mmol) in tert-butyl alcohol (20 mL) was added the solution
of sodium dihydrogen phosphate (1.57 g, 13.15 mmol) and sodium
Ethyl-2-((2R,5S,6S)-6-((4-methoxybenzyloxy)methyl)-5-methyltetra
hydro-2H-pyran-2-yl) acetate (4): To
a stirred solution of
compound 17 (900 mg, 2.67 mmol) in THF (10 mL) was added
potassium hydride (0.53 g, 13.33 mmol) at 0 oC. The reaction
o
chlorite (0.74 g, 8.21 mmol) in water (10 mL) at 0 C. It was allowed
mixture was stirred for
2 h at ambient temperature. After
to stir for 3 h at room temperature. After completion of the
reaction (monitored by TLC), it was extracted with ethyl acetate (3 ×
40 mL). The combined organic layers were washed with brine, dried
over anhydrous Na2SO4 and evaporated under reduced pressure.
The crude product was purified by silica gel chromatography (ethyl
acetate/hexane = 2:5) to afford acid 16 (1.13 g, 88%) as a colorless
completion of reaction (monitored by TLC), it was quenched with
water (10 mL) and diluted with ethyl acetate (25 mL) were added.
The organic layer was separated and the aqueous layer extracted
with ethyl acetate (2 × 25 mL). The combined organic layer was
washed water (50 mL), brine (2 × 50 mL) and dried over Na2SO4. The
solvent was removed under reduced pressure and then purified by
silica gel column chromatography (ethyl acetate/hexane = 1:8) to
27
liquid. [α]D +79.1 (c 1.0, CHCl3); IR (neat): 3433, 2934, 1708, 1610,
1
1512, 1458, 1366, 1250, 1170, 1080, 1033 cm−1; H NMR (300 MHz,
27
get the desired product 4 (684 mg, 76%) as a light yellow oil [α]D
CDCl3): δ 7.26 (d, J = 9.1 Hz, 2H), 6.88 (d, J = 9.1 Hz, 2H), 4.49 (dd, J =
20.4, 11.3 Hz, 2H), 4.28−4.19 (m, 1H), 3.80 (s, 3H), 3.62−3.47 (m,
2H), 2.80 (dd, J = 15.8, 9.8 Hz, 2H), 2.44 (dd, J = 15.8, 4.5 Hz, 1H),
−10.1 (c 0.7, CHCl3); IR (neat): 2923, 1735, 1609, 1511, 1452, 1244,
1088 cm−1; 1H NMR (300 MHz, CDCl3): δ 7.26 (d, J = 8.2 Hz, 2H), 6.86
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(d, J = 8.2 Hz, 2H), 4.55 (d, J = 11.9 Hz, 1H), 4.45 (d, J = 11.9 Hz, 1H), removed under reduced pressure. The crude mass was purified by
4.12 (q, J = 14.3, 7.2 Hz, 2H ), 3.80 (s, 3H), 3.78−3.72 (m, 1H), 3.57 flash chromatography (ethyl acetate/hexane = 1:5) to afford the
(dd, J = 11.0, 5.0 Hz, 1H), 3.47 (dd, J = 11.0, 5.0 Hz, 1H), 3.15 (dddd, J corresponding aldehyde as a pale yellow liquid. The aldehyde was
=10.1, 7.2, 4.8, 2.1 Hz, 1H), 2.62 (dd, J = 15.1, 7.0 Hz, 1H), 2.41 (dd, J used for the next reaction without further characterization.
= 15.1, 6.1 Hz, 1H), 1.79 (dd, J = 12.9, 3.2 Hz, 1H), 1.70−1.63 (m, 1H),
To a stirred solution of aldehyde (230 mg, 1.07 mmol) in THF (5 mL)
1.61−1.52 (m, 1H), 1.41−1.31 (m, 1H), 1.27−1.25 (m, 1H), 1.24 (t, J =
was added methyl magnesium bromide (0.8 mL, 1.07 mmol, 1.4 M
7.2 Hz, 3H), 0.79 (d, J = 6.5 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ
in toluene) at −78 oC and stirred at the same temperature for 1 h.
171.2, 158.9, 139.2, 130.4, 129.1, 113.4, 83.3, 74.2, 72.7, 70.5, 60.1,
After completion of the reaction (monitored by TLC), it was
54.9, 41.3,. 32.3, 31.3, 31.1, 17.3, 14.0 ppm; HRMS (ESI): m/z calcd.
quenched with saturated solution of NH4Cl (5 mL) and diluted with
for C19H28O5Na [M + Na]+: 359.1829; found: 359.1839.
ethyl acetate (10 mL). The organic layer was separated and the
Ethyl-2-((2R,5S,6S)-6-(hydroxymethyl)-5-methyltetrahydro-2H-
aqueous layer extracted with ethyl acetate (2 × 20 mL). The
pyran-2-yl)acetate (18): To a stirred solution of PMB-ether 4 (0.5 g, combined organic layer was washed with brine (40 mL), dried over
1.48 mmol) in CH2Cl2 (10 mL) and water (1 mL) at room anhydrous Na2SO4 and evaporated under reduced pressure. The
temperature, was added DDQ (506 mg, 2.23 mmol) and allowed to crude product was purified by silica gel chromatography (ethyl
stir for 2 h at the same temperature. After completion of the acetate/hexane = 1:6) to afford diastereomeric mixture 19 (181 mg,
25
reaction (monitored by TLC), it was quenched with saturated 73% over two steps) as a colorless liquid. [α]D +4.1 (c 0.5, CHCl3);
NaHCO3 (15 mL) solution. The organic compound was extracted IR (neat): 3442, 2924, 2852, 1755, 1636, 1458, 1387, 1187, 1088
with CH2Cl2 (2 × 25 mL). The combined organic layer was washed cm−1 1H NMR (300 MHz, CDCl3): δ 4.14 (q, J = 14.2, 7.0 Hz, 2H),
;
with brine (50 mL), dried over anhydrous Na2SO4 and evaporated to 3.88−3.82 (m, 1H), 3.82−3.72 (m, 2H), 2.80 (dd, J = 9.9, 1.4 Hz, 1H),
give red colored crude product which on purification by silica gel 2.56−2.47 (m, 1H), 2.46−2.38 (m, 1H), 1.86−1.76 (m, 1H), 1.73−1.62
column chromatography (ethyl acetate/hexane = 1:4) afforded the (m, 2H), 1.39−1.29 (m, 1H), 1.26 (t, J = 7.0 Hz, 3H), 1.20 (d, J = 6.4
desired primary alcohol 18 (280 mg, 89%) as a colorless liquid. Hz, 2.6 H), 1.12 (d, J = 6.4 Hz, 0.4 H), 0.86 (d, J = 6.5, 2.6H), 0.82 (d, J
27
[α]D +11.5 (c 0.7, CHCl3); IR (neat): 3680, 2929, 2266, 1735, 1195, = 6.7 Hz, 0.4H) ppm; 13C NMR (75 MHz, CDCl3): δ 177.0, 171.4, 85.8,
1084 cm−1; 1H NMR (300 MHz, CDCl3): δ 4.34−4.27 (m, 1H), 4.16 (q, J 85.6, 83.4, 74.4, 74.0, 67.0, 66.2, 63.7, 60.3, 51.5, 41.5, 41.2, 32.3,
= 14.1, 7.2 Hz, 2H ), 3.74 (dd, J = 11.6, 8.2 Hz, 1H) 3.57 (dd, J = 11.6, 32.1, 31.8, 31.5, 30.5, 29.6, 29.5, 20.6, 17.2, 17.0, 16.4, 14.2, 14.0
3.3 Hz, 1H), 3.46 (dt, J = 7.8, 3.0 Hz, 1H), 2.73 (dd, J = 15.4, 9.6 Hz, ppm; HRMS (ESI): m/z calcd. for C12H23O4 [M + H]+: 231.1590; found:
1H), 2.43 (dd, J = 15.4, 4.7 Hz, 1H), 1.75−1.67 (m, 2H), 1.58−1.51 (m, 231.1590.
2H), 1.42−1.35 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H), 0.97 (d, J = 6.8 Hz,
Ethyl-2-((2R,5S,6S)-6-acetyl-5-methyltetrahydro-2H-pyran-2-yl)
3H) ppm; 13C NMR (75 MHz, CDCl3): δ 171.1, 83.4, 74.0, 63.6, 60.3,
acetate (20): To a stirred solution alcoholic compound 19 (100 mg,
41.3, 32.0, 31.4, 31.0, 17.0, 14.0 ppm; HRMS (ESI): m/z calcd. for
0.434 mmol) in CH2Cl2 (2 mL) at 0 oC, was added Dess-Martin
C11H20O4Na [M + Na]+: 239.1253; found: 239.1254.
periodinane (275 mg, 0.65 mmol). The reaction mixture was stirred
Ethyl-2-((2R,5S,6S)-6-(1-hydroxyethyl)-5-methyltetrahydro-2H-
at room temperature for 3 h. After completion of reaction
pyran-2-yl)acetate (19): To a stirred solution of primary alcohol 18 (monitored by TLC), the reaction mixture was filtered through a
(0.25 g, 1.15 mmol) in CH2Cl2 (10 mL) at 0 oC, was added Dess- filter paper. The filtrate was washed with saturated NaHCO3 (2 × 10
Martin periodinane (586 mg, 1.38 mmol). The reaction mixture was mL). The aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The
stirred at 0 oC for 3 h. After completion of reaction (monitored by combined organic layer was dried over anhydrous Na2SO4 and
TLC), the reaction mixture was filtered through a filter paper. The solvent was removed under reduced pressure. The crude mass was
filtrate was washed with saturated NaHCO3 (2 × 10 mL). The purified by flash chromatography (ethyl acetate/hexane = 1:6) to
aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The combined afford the corresponding ketone 20 (92 mg, 93%) as light yellow
27
organic layer was dried over anhydrous Na2SO4 and solvent was liquid. [α]D −89.1 (c 0.5, CHCl3); IR (neat): 3020, 2364, 2094, 1719,
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1
1637, 1457, 1356, 1215, 1079, 1025, 893 cm−1; H NMR (300 MHz, the reaction (monitored by TLC), it was quenched with water (50
CDCl3): δ 4.14 (q, J = 15.4, 8.2 Hz, 2H), 3.83−3.76 (m, 1H), 3.42 (d, J = mL). The organic layer was separated and the aqueous layer
10.4 Hz, 1H), 2.56 (dd, J = 15.1, 7.6 Hz, 1H), 2.45 (dd, J = 15.1, 5.3 extracted with CH2Cl2 (3 × 75 mL). The combined organic layer was
Hz, 1H), 2.15 (s, 3H), 1.92−1.85 (m, 1H), 1.74−1.68 (m, 1H), dried over anhydrous Na2SO4 and solvent removed under reduced
1.60−1.50 (m, 1H), 1.46−1.37 (m, 1H), 1.33−1.28 (m, 1H), 1.25 (t, J = pressure. The crude mass was purified by silica gel chromatography
7.2 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ (ethyl acetate/hexane = 1:10) to afford MOM ether 21 (8.5 g, 94%)
25
207.9, 171.0, 88.9, 73.8, 60.4, 41.4, 32.2, 31.8, 31.0, 25.8, 16.9, 14.2 as colorless liquid. [α]D +77.0 (c 1.0, CHCl3); IR (neat): 2954, 2070,
ppm; HRMS (ESI): m/z calcd. for C12H21O4 [M + H]+: 229.1434; found: 1751, 1638, 1449, 1272, 1207, 1157, 1122, 1045 cm−1; 1H NMR (300
229.1436.
MHz, CDCl3): δ 4.70 (ABq, J = 7.0, 2.6 Hz, 2H), 4.25 (q, J = 13.7, 6.9
Hz, 1H), 3.75 (s, 3H), 3.39 (s, 3H), 1.44 (d, J = 6.9 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3): δ 173.3, 95.6, 71.2, 55.6, 51.7, 18.3 ppm.
Ethyl-2-((2R,5S,6S)-6-((E)-1-iodoprop-1-en-2-yl)-5-methyltetra
hydro-2H-pyran-2-yl) acetate (2): Powdered CrCl2 (260 mg, 2.2
mmol) was gently heated under vacuum for 5 min, then the (R,Z)-Ethyl-4-(methoxymethoxy)pent-2-enoate (23): To a stirred
solution of ketone 20 (50 mg, 0.22 mmol), CHI3 (172 mg, 0.43 solution of compound 21 (8.0 g, 54.0 mmol) in CH2Cl2 (100 mL), was
mmol) in THF (4 mL) was added via cannula. The resulting dark red- added DIBAL-H in toluene (38.6 mL, 1.4 M, 54.0 mmol) at −78 oC,
brown mixture was stirred at room temperature for 5 h. After and stirred for 1 h at same temperature. After completion of the
completion of the reaction (monitored by TLC), it was quenched by reaction (monitored by TLC), the reaction was treated with
addition of water (10 mL) and diluted with Et2O (15 mL). The layers saturated solution of sodium potassium tartarate and allowed to
were separated and the aqueous layer was extracted with Et2O (3 × stir for 4 h. The organic layer was separated and the aqueous layer
15 mL). The combined organic extracts were washed with brine (2 × extracted with CH2Cl2 (3 × 100 mL). The combined organic layer was
30 mL), dried over Na2SO4 and concentrated under reduced dried over anhydrous Na2SO4 and solvent was removed under
pressure. The crude product was purified by column reduced pressure. The crude aldehyde was used for next reaction
chromatography (ethyl acetate/hexane = 1/25) to afford the without characterization.
corresponding vinyl iodide 2 (72 mg, 72%, E/Z = 9:1) as pale yellow
To a suspension of NaH (2.2 g, 55.9 mmol, 60% w/v dispersion in
25
liquid. [α]D +10.5 (c 0.5, CHCl3); IR (neat): 3020, 2983, 2400, 2367,
mineral oil) in anhydrous THF (50 mL) was added dropwise solution
1726, 1426, 1215, 1044 cm−1; 1H NMR (300 MHz, CDCl3): δ 6.20 (d, J
of phosponate 22 (23.0 g, 66.1 mmol) in THF (50 mL) at 0 oC and the
= 0.9 Hz, 1H), 4.13 (q, J = 14.2, 7.0 Hz, 2H), 3.81−3.74 (m, 1H), 3.51
stirring was continued for 30 min at the same temperature. The
(d, J = 9.8 Hz, 1H), 2.55 (dd, J = 15.2, 6.7 Hz, 1H), 2.39 (dd, J = 15.1,
reaction mixture was then cooled to −78 °C and the crude aldehyde
6.4 Hz, 1H), 1.88−1.82 (m, 1H), 1.79 (d, J = 1.1 Hz, 3H), 1.71−1.66
(6.0 g, 50.8 mmol) dissolved in dry THF (20 mL) was added. The
(m, 1H), 1.55−1.46 (m, 1H), 1.41−1.31 (m, 1H), 1.29−1.27 (m, 1H),
reaction was allowed to stir for 2 h at −78 °C. Aꢁer compleꢀon of
1.24 (t, J = 7.0 Hz, 3H), 0.70 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (75
the reaction (monitored by TLC), it was carefully quenched with
MHz, CDCl3): δ 171.1, 147.1, 89.0, 80.1, 74.2, 60.3, 41.4, 32.6, 32.1,
small crushed ice flakes until a clear solution (biphasic) has formed.
31.4, 19.5, 17.4, 14.1 ppm; HRMS (ESI): m/z calcd. for C13H22O3I [M
The reaction mixture was extracted with ethyl acetate (3 × 100 mL).
+ H]+: 353.0608; found: 353.0615.
The organic extracts were washed with water (100 mL), brine (100
(R)-Methyl 2-(methoxymethoxy)propanoate (21): To
a stirred mL), dried over anhydrous Na2SO4, and the solvent was evaporated
solution of (R)-methyl lactate (8) (6.0 g, 57.7 mmol) in CH2Cl2 (60 under reduced pressure. The crude was purified by silica gel column
mL), was added diisopropylethylamine (15.6 mL, 12.72 mmol) and chromatography (ethyl acetate/hexane = 1:12) to afford 23 (8.2 g,
stirred for 30 min at
0
oC under nitrogen atmosphere. 81% over two steps) as colorless liquid. [α]D27 +22.1 (c 3.0, CHCl3); IR
1H NMR (300 MHz,
Methoxymethyl chloride (6.2 mL, 69.2 mmol) was added to the (neat): 3386, 293, 2351, 1718, 1034 cm−1
;
reaction mixture in CH2Cl2 (10 mL) at same temperature. Stirring CDCl3): δ 6.19 (dd, J = 11.7, 7.9 Hz, 1H), 5.79 (dd, J = 11.7, 1.1 Hz,
was continued for 10 h at room temperature. After completion of 1H), 5.32 (m, 1H), 4.63 (dq, J = 11.1, 6.8 Hz, 2H), 4.17 (q, J = 14.3,
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7.2 Hz, 2H), 3.37 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H), 1.29 (t, J = 7.0 Hz, was purified by silica gel column chromatography (ethyl
3H) ppm; 13C NMR (75 MHz, CDCl3): δ 165.6, 151.3, 119.4, 95.0, acetate/hexane = 1:2) to get epoxy alcohol 25 (4.98 g, 87%) as
25
69.5, 60.1, 55.2, 20.4, 14.0 ppm.
colourless liquid. [α]D +40.1 (c 2.7, CHCl3); IR (neat): 3409, 3025,
2960, 2925, 1487, 1453, 1374, 1148, 1031 cm−1; 1H NMR (300 MHz,
CDCl3): δ 4.86 (d, J = 6.8 Hz, 1H), 4.68 (d, J = 6.8 Hz, 1H), 3.86 (dd, J =
12.6, 3.6 Hz, 1H), 3.75−3.63 (m, 1H), 3.40 (s, 3H), 3.17 (m, 1H), 3.07
(dd, J = 8.7, 5.1 Hz, 1H), 2.11 (br s, 1H), 1.24 (d, J = 6.6 Hz, 3H) ppm;
13C NMR (75 MHz, CDCl3): δ 94.9, 71.1, 60.4, 60.3, 55.3, 55.3, 17.6
ppm; HRMS (ESI): m/z calcd. for C7H15O4 [M + H]+: 163.0964; found:
163.0968.
(R,Z)-4-(Methoxymethoxy)pent-2-en-1-ol (24): In a 500 mL of a dry
single necked R.B, α,β-unsaturated ester 23 (8.0 g, 42.55 mmol) was
dissolved in CH2Cl2 (100 mL) and cooled to −78 oC under nitrogen
atmosphere. DIBAL-H (76 mL 106.38 mmol, 1.4M in toluene) was
slowly added to it over a period of 40 min. After 1 h at 0 oC, TLC was
checked which showed complete consumption of starting material.
It was quenched by slow addition of a saturated solution of sodium
potassium tartrate (100 mL) and then stirred at room temperature (E)-Ethyl3-((2R,3S)-3-((R)-1-(methoxymethoxy)ethyl)oxiran-2-yl)-2-
for 2 h to get a clear separation of the two layers. The organic layer methylacrylate (26): To a stirred solution of epoxy alcohol 25 (4.1
was separated and the aqueous layer extracted with CH2Cl2 (2 × 100 g, 25.30 mmol) in dry CH2Cl2 (50 mL), was added Dess-Martin
mL). The combined organic layer was washed with brine (2 × 200 periodinane (12.81 g, 30.37 mmol) at
0 °C under nitrogen
mL), dried over Na2SO4, and evaporated under reduced pressure. atmosphere and stirred for 3 h. After completion of the reaction
The crude product was purified by silica gel column (monitored by TLC), it was quenched with water (25 mL) and
chromatography (ethyl acetate/hexane = 1:4) to obtain the desired filtered through a small bed of Celite. The organic layer was
27
alcohol 24 (5.33 g, 86%) as colorless liquid. [α]D
+60.5 (c 1.3, separated and the aqueous layer extracted with CH2Cl2 (2 × 50 mL).
CHCl3); IR (neat): 3420, 2975, 2935, 2343, 2077, 1653, 1444, 1402, The combined organic layer was washed with saturated aqueous
1157, 1098 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.82 (m, 1H), 5.41 (t, J sodium thiosulphate solution (2 × 100 mL), saturated aqueous
= 9.6 Hz, 1H), 4.71 (d, J = 7.0 Hz, 1H), 4.55 (d, J = 7.0 Hz, 1H), 4.58 NaHCO3 solution (2 × 100) and dried over anhydrous Na2SO4.
(m, 1H), 4.30 (dd, J = 14.2, 7.7 Hz, 1H), 4.05 (dd, J =13.8, 7.7 Hz, H), Solvent was removed under reduced pressure and the crude
3.38 (s, 3H), 1.26 (d, J = 6.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): product was used for the next reaction without further purification.
δ 133.0, 131.3, 93.3, 66.7, 57.9, 55.0, 21.3 ppm.
To a stirred solution of crude aldehyde (4.52 g, 28.25 mmol) in
((2R,3S)-3-((R)-1-(Methoxymethoxy)ethyl)oxiran-2-yl)methanol
benzene (50 mL), was added C-3 Wittig ylide (18.93 g, 56.52 mmol)
(25): In a 250 mL of two necked RB, dried molecular sieve (6.0 g, 4Ǻ) at room temperature. The reaction mixture was stirred at 50 oC for
and the allyl alcohol 24 (5.2 g, 35.61 mmol) was charged under 3 h. After completion of the reaction (monitored by TLC), solvent
nitrogen atmosphere in anhydrous CH2Cl2 (100 mL). It was cooled to was removed under reduced pressure. The crude mass was purified
−45 oC and vigorously stirred. To it, Ti(OiPr)4 (1.58 mL, 5.34 mmol) by silica gel chromatography (ethyl acetate/hexane = 1:10) to
followed by (−)-DET (1.42 mL, 7.12 mmol) was added under furnish 26 (3.92 g, 63% over two steps) as a light yellow liquid.
27
nitrogen atmosphere at the same temperature. After 30 min of [α]D −25.6 (c 1.8, CHCl3); IR (neat): 3488, 2982, 2935, 1713, 1322,
vigorous stirring, TBHP (6.52 mL, 39.17 mmol, and 6 M solution in 1246, 1156, 1109, 1034, 921 cm−1; 1H NMR (300 MHz, CDCl3): δ 6.47
toluene) was slowly added and allowed to stir for further 12 h at (d, J = 8.3 Hz, 1H), 4.86 (d, J = 6.8 Hz, 1H), 4.71 (d, J = 6.8 Hz, 1H),
o
−45 C. After completion of the reaction (monitored by TLC), it was 4.22 (m, 2H), 3.67 (dd, J = 8.3, 4.5 Hz, 1H), 3.57 (dd, J = 8.3, 6.8 Hz,
quenched with H2O (15 mL) and stirred with 10% solution of NaOH 1H), 3.41 (s, 3H), 3.21 (dd, J = 8.3, 4.5 Hz, 1H), 1.99 (s, 3H), 1.31 (t, J
(30 mL) to get a clear solution. It was filtered through a Celite pad = 6.8 Hz, 3H), 1.17 (d, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 166.7,
and washed with CH2Cl2 (50 mL). The organic layer was separated 134.4, 133.5, 95.1, 71.9, 62.0, 60.9, 55.4, 51.6, 17.2, 14.2, 12.9 ppm;
and the aqueous layer extracted with CH2Cl2 (2 × 60 mL). The HRMS (ESI): m/z calcd. for C12H21O5 [M + H]+: 245.1383; found:
combined organic layer was washed with brine (2 × 100 mL), dried 245.1389.
over Na2SO4, and concentrated under reduced pressure. The crude
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(4S,5R,6R,E)-Ethyl 5-hydroxy-6-(methoxymethoxy)-2,4-dimethyl product 7 (0.93 g, 90%) as colorless liquid. [α]D27 +8.1 (c 2.4, CHCl3);
hept -2-enoate (27): To a stirred solution of the epoxy compound IR (neat): 3429, 3020, 2360, 1710, 1448, 1369, 1215, 1034 cm−1; 1H
26 (3.5 g, 14.34 mmol) in dry CH2Cl2 (70 mL), trimethyl aluminum NMR (300 MHz, CDCl3): δ 6.68 (d, J = 9.8 Hz, 1H), 4.68 (d, J = 6.8 Hz,
(57.37 mL, 114.75 mmol, 2M in toluene) was slowly added under 1H), 4.61 (d, J = 6.8 Hz, 1H), 4.19 (q, J = 14.3, 7.2 Hz, 2H), 3.69 (m,
nitrogen atmosphere at −40 °C. After 30 min, H2O (1.54 mL, 86.06 1H), 3.51 (s, 3H), 3.36 (s, 3H), 2.92 (dd, J = 6.9, 3.9 Hz, 1H),
mmol) was added very carefully and slowly so that the internal 2.87−2.78 (m, 1H), 1.85 (s, 3H), 1.33−1.22 (m, 6H), 1.06 (d, J = 6.6
temperature did not change. After effervescence ceased, it was Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 167.9, 144.1, 126.5, 87.7,
allowed to stir for further 4 h at −40 oC and TLC showed the 74.6, 61.1, 60.2, 55.2, 35.0, 17.3, 15.1, 14.0, 12.2 ppm; HRMS (ESI):
complete consumption of the starting material. It was quenched m/z calcd. for C14H28O5 [M + H]+: 275.1853; found: 275.1848.
very slowly with saturated NH4Cl (50 mL) and diluted with CH2Cl2
(4S,5R,6R,E)-5-Methoxy-6-(methoxymethoxy)-2,4-dimethylhept-2-
(100 mL). HCl (1.0 N, 50 mL) was added and vigorously stirred until
en-1-ol (28): To a stirred solution of ester 7 (1.5 g, 54.74 mmol) in
a clear separation of the two layers took place. The organic layer
CH2Cl2 (40 mL), DIBAL-H (9.77 mL, 13.68 mmol, 1.4M in toluene)
was separated and the aqueous layer extracted with CH2Cl2 (2 × 100
was added slowly at −78 oC. After 2 h of stirring at the same
mL). The combined organic layer was washed with brine (2 × 100
temperature, TLC was checked which showed complete
mL), dried over anhydrous Na2SO4 and evaporated under reduced
consumption of the starting material. It was quenched by slow
pressure. The crude was purified by silica gel column
addition of a saturated solution of sodium potassium tartarate (30
chromatography (ethyl acetate/hexane = 1:5) to get the desired
mL) and then stirred at room temperature for 2 h to get a clear
product 27 (3.1 g, 83%) as colorless liquid. (dr = 19:1). [α]D26 −16.3 (c
separation of the two layers. The organic layer was separated and
1.4, CHCl3); IR (neat): 3473, 2929, 1709, 1648, 1499, 1368, 1272,
the aqueous layer extracted with CH2Cl2 (2 × 50 mL). The combined
1217, 1146, 1101, 1035, 985 cm−1; 1H NMR (300 MHz, CDCl3): δ 6.69
organic layer was washed with brine (2 × 50 mL), dried over Na2SO4,
(d, J = 10.0 Hz, 1H), 4.66 (ABq, J = 25.1, 6.6 Hz, 2H), 4.19 (q, J = 14.2,
and evaporated under reduced pressure. The crude product was
7.2 Hz, 2H), 3.63 (dd, J = 10.6, 4.91 Hz, 1H), 3.38 (s, 3H), 3.29−3.21
purified by silica gel column chromatography (ethyl acetate/hexane
(m, 1H), 2.76−2.63 (m, 1H), 2.57 (br s, 1H), 1.86 (s, 3H), 1.30 (t, J =
27
= 1:5) produced desired alcohol 28 (1.1 g, 86%). [α]D +23.8 (c 1.1,
7.2 Hz, 3H), 1.25 (d, J = 6.2 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H) ppm; 13C
CHCl3); IR (neat): 3433, 2940, 2360, 1630, 1457, 1034 cm−1; 1H NMR
NMR (75 MHz, CDCl3): δ 168.1, 144.0, 127.2, 96.0, 77.8, 75.4, 60.5,
(300 MHz, CDCl3): δ 5.33 (d, J = 9.6, 1.4 Hz, 1H), 4.68 (d, J = 6.7 Hz,
55.6, 30.1, 17.5, 14.8, 14.2, 12.9 ppm; HRMS (ESI): m/z calcd. for
1H), 4.62 (d, J = 6.7 Hz, 1H), 3.99 (s, 2H), 3.72 (m, 1H), 3.50 (s, 3H),
C13H24O5Na [M + Na]+: 283.1516; found: 283.1517.
3.37 (s, 3H), 2.83 (dd, J = 7.0, 4.1 Hz, 1H), 2.72 (m, 1H), 1.92 (br s,
(4S,5R,6R,E)-Ethyl-5-methoxy-6-(methoxymethoxy)-2,4-dimethyl
1H), 1.68 (s, 3H), 1.23 (d, J = 6.4 Hz, 3H), 1.01(d, J = 6.9 Hz, 3H) ppm;
hept-2-enoate (7): The secondary alcohol 27 (1.0 g, 3.84 mmol) was 13C NMR (75 MHz, CDCl3): δ 134.1, 128.9, 96.2, 88.8, 74.9, 68.6,
dissolved in CH2Cl2 (20 mL) and cooled to 0 °C. To this solution was 61.3, 55.4, 34.1, 17.7, 16.2, 13.7 ppm; HRMS (ESI): m/z calcd. for
added proton sponge (4.12 g, 19.2 mmol) and Me3OBF4 (2.84 g, C12H24O4Na [M + Na]+: 255.1566; found: 255.1561.
19.2 mmol). The reaction was allowed to warm to room
(R)-4-Benzyl-3-((2S,6S,7R,8R,E)-7-methoxy-8-(methoxymethoxy)-2,
temperature and stirred for 3 h at the same temperature. After
4,6-trimethylnon-4-enoyl)oxazolidin-2-one (30): To
a stirred
completion of reaction (monitored by TLC), it was diluted with
diethyl ether (50 mL), filtered through Celite, and washed with
diethyl ether (50 mL). The organic layer was washed with saturated
aqueous NaHCO3 (50 mL), 0.5 M NaHSO4 (2 × 50 mL), saturated
aqueous NaHCO3 (50 mL) and brine (50 mL). The organic layer was
dried over anhydrous Na2SO4, and evaporated under reduced
pressure. The crude product was purified by silica gel column
chromatography (ethyl acetate/hexane = 1:10) to afford the desired
solution of alcohol 28 (0.5 g, 2.15 mmol) was dissolved in
diethylether (16 mL) and CH3CN (4 mL) and the solution was cooled
to 0 °C. Triphenylphosphine (734 mg, 2.79 mmol), imidazole (190
mg, 2.79 mmol), and iodine (711 mg, 2.79 mmol) were added to the
solution. TLC showed the complete consumption of the starting
material. It was quenched with saturated aqueous Na2S2O3 solution
(20 mL) and the mixture was stirred for 15 min. The layers were
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separated and the aqueous layer was extracted with diethyl ether completion of the reaction (monitored by TLC), it was quenched
(3 × 25 mL). The organic layers were combined, washed with water with saturated aqueous NaHCO3 (10 mL) and diluted with ethyl
(50 mL), brine (50 mL), dried over Na2SO4, and concentrated. The acetate (20 mL). The organic layer was separated and the aqueous
crude was purified by column chromatography (ethyl layer extracted with ethyl acetate (3 × 20 mL). The combined
acetate/hexane = 1:20) to obtain the product (720 mg) as pale organic layer was dried over anhydrous Na2SO4 and evaporated
yellow liquid, which was used for the next reaction without further under reduced pressure. The crude mass was purified over silica gel
characterization.
column chromatography (ethyl acetate/hexane = 1:6) to afford
25
31(158 mg, 86%) as colourless liquid. [α]D +38.1 (c 0.5, CHCl3); IR
To a stirred solution of auxiliary 29 (735 mg, 3.15 mmol) in dry THF
(20 mL) LiHMDS (2.94 mL, 2.94 mmol, 1M in THF) was added over a
period of 10 min at −78 oC under nitrogen atmosphere and the
resulting solution was stirred for 1 h at the same temperature.
Freshly prepared iodo compound (720 mg, 2.10 mmol) was
dissolved in dry THF (10 mL) and added to the lithiated auxiliary via
a cannula. After 2 h stirring at −78 oC, the reaction was allowed to
stir for 3 h at −45 oC. TLC showed complete consumption of the
starting material. It was quenched with saturated NH4Cl (20 mL),
and diluted with ethyl acetate (50 mL). The organic layer was
(neat): 3439, 2930, 2134, 1753, 1636, 1453, 1216, 1057, 1088, 1036
cm−1; 1H NMR (300 MHz, CDCl3): δ 5.09 (d, J = 9.2 Hz, 1H), 4.66 (dd, J
= 15.8, 6.8 Hz, 2H), 3.71 (dd, J = 6.4, 4.1 Hz, 1H), 3.50 (s, 3H),
3.49−3.40 (m, 2H), 3.37 (s, 3H), 2.80 (dd, J = 6.8, 4.1 Hz, 1H), 2.68
(m, 1H), 2.08 (m, 1H), 1.90−1.77 (m, 2H), 1.62 (d, J = 0.9 Hz, 3H),
1.24 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.4 Hz,
3H) ppm; 13C NMR (75 MHz, CDCl3): δ 133.0, 130.0, 96.3, 89.2, 75.2,
68.3, 61.3, 55.4, 34.5, 33.7, 29.7, 17.8, 16.8, 16.2, 16.1 ppm; HRMS
(ESI): m/z calcd. for C15H31O4 [M + H]+: 275.2216; found: 275.2212.
separated and the aqueous layer extracted with ethyl acetate (2 × (2S,6S,7R,8R,E)-7-Methoxy-8-(methoxymethoxy)-2,4,6-trimethyl
50 mL). The combined organic layers were washed with brine (2 × non-4-enal (32): To a stirred solution of primary alcohol 31 (100 mg,
75 mL), dried over Na2SO4 and evaporated under reduced pressure. 0.36 mmol) in CH2Cl2 (10 mL) at 0 oC was added Dess-Martin
The crude was purified by silica gel column chromatography (ethyl periodinane (310 mg, 0.73 mmol). The reaction mixture was stirred
acetate/hexane = 1:7) to furnish the desired alkylated product 30 at ambient temperature for 3 h. After completion of reaction
27
(639 mg, 62% over two steps) as gummy syrup. [α]D −11.8 (c 2.0, (monitored by TLC), it was diluted with CH2Cl2 (10 mL) and then
CHCl3); IR (neat): 3530, 2979, 2932, 1779, 1719, 1702, 1479, 1453, filtered through a filter paper. The filtrate was washed with
1363, 1388, 1215, 1083, 1039 cm−1 1H NMR (300 MHz, CDCl3): δ saturated NaHCO3 (2 × 15 mL). The aqueous layer was extracted
;
7.38−7.25 (m, 3H), 7.25−7.18 (m, 2H), 5.15 (d, J = 9.4 Hz, 1H), 4.66 with CH2Cl2 (2 × 20 mL). The combined organic fraction was dried
(dd, J = 15.0, 6.8 Hz, 2H), 4.73−4.60 (m, 3H), 3.99 (dd, J = 14.5, 6.6 over anhydrous Na2SO4 and evaporated under reduced pressure.
Hz, 1H), 3.70 (dd, J = 6.2, 4.5 Hz, 1H), 3.49 (s, 3H), 3.36 (s, 3H), 3.32 The crude mass was purified by flash chromatography (ethyl
(m, 1H), 2.80 (m, 1H), 2.74−2.63 (m, 2H), 2.56 (dd, J = 13.2, 6.2 Hz, acetate/hexane = 1:6) to afford the aldehyde 32 (95 mg, 96%) as
26
1H), 2.01 (dd, J = 13.2, 8.2 Hz, 1H), 1.68 (s, 3H), 1.22 (d, J = 6.4 Hz, pale yellow liquid. [α]D +31.1 (c 0.5, CHCl3); IR (Neat): 2935, 2353,
1
3H), 1.13 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H) ppm; 13C NMR 2093, 1643, 1454, 1216, 1035 cm−1; H NMR (300 MHz, CDCl3): δ
(75 MHz, CDCl3): δ 176.9, 153.0, 135.3, 131.3, 131.1, 129.3, 128.8, 9.61 (s, 1H), 5.11 (d, J = 9.1 Hz, 1H), 4.65 (dd, J = 17.4, 6.8 Hz, 2H),
127.2, 96.3, 89.0, 75.0, 65.9, 61.3, 55.3, 43.8, 38.0, 35.6, 34.5, 17.8, 3.70 (dd, J = 6.0, 3.8 Hz, 1H), 3.49 (s, 3H), 3.37 (s, 3H), 2.79 (dd, J =
16.4, 16.1, 15.7 ppm; HRMS (ESI): m/z calcd. for C25H37O6 NNa [M + 6.8, 4.5 Hz, 1H), 2.67 (m, 1H), 2.52 (m, 1H), 2.43 (dd, J = 13.6, 6.8
Na]+: 470.2513; found: 470.2521.
Hz, 1H), 2.01 (m, 1H), 1.63 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H), 1.06 (d, =
6.8 Hz, 3H)1, 0.97 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3):
δ 205.0, 131.2, 130.7, 96.2, 89.0, 75.0, 61.3, 55.4, 44.4, 40.8, 34.5,
17.8, 16.1, 13.2 ppm; HRMS (ESI): m/z calcd. for C15H28O4Na [M +
Na]+: 295.1879; found: 295.1885.
(2S,6S,7R,8R,E)-7-Methoxy-8-(methoxymethoxy)-2,4,6-trimethyl
non-4-en-1-ol (31): To a stirred solution of compound 30 (300 mg,
0.67 mmol) in diethylether (10 mL), was added MeOH (0.1 mL, 3.35
mmol), LiBH4 (17.72 mg, 0.80 mmol) at 0 oC under nitrogen
o
atmosphere. Reaction mixture was stirred for 30 min at 0 C. After
12 | J. Name., 2016, 00, 1-15
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Journal Name
(3S,7S,8R,9R,E)-8-Methoxy-9-(methoxymethoxy)-3,5,7-trimethyl
View Article Online
DOI: 10.1039/C6OB00321D
ARTICLE
Ethyl-2-((2R,5S,6S)-6-((2E,4E,6S,8E,10S,11R,12R)-11-methoxy-12-
dec-5-en-1-yne (34): To a solution of K2CO3 (13 mg, 0.24 mmol) in (methoxymethoxy)-6,8,10-trimethyltrideca-2,4,8-trien-2-yl)-5-
MeOH (2 mL) was added Ohira-Bestmann reagent 33 (53 mg, 0.24 methyltetrahydro-2H-pyran-2-yl)acetate (35a): To a solution of and
mmol) in MeOH (1 mL) at –78 oC under nitrogen atmosphere. The vinyl iodide 3 (22 mg, 0.062 mmol) and stanane 2 (42 mg, 0.075
resulting bright yellow solution was stirred for 15 min and a mmol) in freshly distilled degassed N-methyl pyrrolidinone (NMP)
solution of the aldehyde 32 (50 mg, 0.18 mmol) in THF (3 mL) was was added Pd2(dba)3 (5.7 mg, 0.0062 mmol), PPh3As (28 mg, 0.093
o
added via cannula. The reaction mixture was stirred for 5 h at –78 mmol), LiCl (5.3 mg, 0.12 mmol) (freshly dried by heating to 200 C
oC. After completion of reaction (monitored by TLC), it was at 0.2 mm/Hg vacuum for 15 min ) simultaneously in one portion.
quenched with saturated NH4Cl (10 mL) and extracted with ethyl The resultant dark green solution was stirred for 24 h at which point
acetate (3 × 15 mL). The combined organic layers were dried over an additional Pd2(dba)3 (5.7 mg, 0.0062 mmol) and Ph3As (28 mg,
anhydrous Na2SO4 and evaporated removed under reduced 0.093 mmol) were added. After stirring for an additional 24 h at
pressure. The crude mass was purified by flash chromatography room temperature, the reaction was quenched with water (10 mL).
(ethyl acetate/hexane = 1:19) to afford 34 (33 mg, 62%) as pale The recation mixture was extracted with ethyl acetate (3 × 15 mL).
yellow liquid. [α]D25 +20.1 (c 0.8, CHCl3); IR (neat): 3309, 2934, 2344, The organic layers were combined, washed with water (30 mL),
1
1058, 757 cm−1; H NMR (300 MHz, CDCl3): δ 5.13 (dd, J = 9.5, 1.1 brine (30 mL), dried over anhydrous Na2SO4, and concentrated
Hz, 1H), 4.66 (dd, J = 18.6, 6.7 Hz, 2H), 3.75−3.70 (m, 1H), 3.50 (s, under reduced pressure. The crude mass was purified by flash
3H), 3.36 (s, 3H), 2.80 (dd, J = 7.0, 4.1 Hz, 1H), 2.69 (m, 1H), chromatography (ethyl acetate/hexane
=
1:10) to afford the
27
2.62−2.56 (m, 1H), 2.17 (dd, J = 13.7, 8.8 Hz, 1H), 2.07 (dd, J = 13.5, compound 35a (21.8 mg, 71%) as colorless liquid. [α]D −9.5 (c 1.4,
7.0 Hz, 1H), 2.03 (d, J = 2.4 Hz, 1H), 1.63 (d, J = 1.2 Hz, 3H), 1.24 (d, J CHCl3); IR (neat): 3453, 3423, 2925, 2360, 1632, 1457, 1040 cm−1; 1H
= 6.4 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H) ppm; NMR (300 MHz, CDCl3): δ 6.19 (dd, J = 15.1, 10.4 Hz, 1H), 5.90 (d, J =
13C NMR (75 MHz, CDCl3): δ 131.5, 130.7, 96.4, 89.3, 88.9, 75.2, 10.9 Hz, 1H), 5.54 (dd, J = 15.1, 7.4 Hz, 1H), 5.02 (d, J = 9.2 Hz, 1H),
68.3, 61.4, 55.3, 46.7, 34.6, 24.3, 20.6, 18.0, 16.3, 16.2 ppm; HRMS 4.65 (ABq, J = 14.2, 6.6 Hz, 2H), 4.12 (q, J = 14.3, 7.2 Hz, 2H),
(ESI): m/z calcd. for C16H29O3 [M + H]+: 269.2111; found: 269.2108.
3.82−3.64 (m, 2H), 3.49 (s, 3H), 3.36 (s, 3H), 3.40−3.25 (m, 1H), 2.78
(dd, J = 6.8, 4.1 Hz, 1H), 2.70−2.52 (m, 2H), 2.45−2.29 (m, 2H), 2.03
(dd, J = 12.8, 6.8 Hz, 1H), 1.94−1.80 (m, 2H), 1.70 (s, 3H), 1.69−1.63
(m , 2H), 1.58 (s, 3H), 1.36−1.29 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.22
(d, J = 6.9 Hz, 3H), 0.95 (d, J = 7.2 Hz, 6H), 0.70 (d, J = 6.4 Hz, 3H)
ppm; 13C NMR (75 MHz, CDCl3): δ 171.4, 140.3, 134.3, 132.6, 130.1,
128.2, 123.9, 96.4, 90.4, 89.4, 75.3, 61.4, 60.2, 55.3, 47.5, 41.6,
34.9, 29.3, 22.6, 20.0, 18.0, 17.7, 16.2, 16.2, 14.2, 12.3 ppm; HRMS
(ESI): m/z calcd. C29H50O6Na [M + Na]+: 517.3506; found: 517.3501.
Tributyl-((1E,3S,5E,7S,8R,9R)-8-methoxy-9-(methoxymethoxy)-
3,5,7-trimethyldeca-1,5-dienyl)stannane (3): To
a solution of
alkyne compound 34 (20 mg, 0.074 mmol) in degassed THF (1 mL)
was added PdCl2(PPh3)2 (1 mg, 0.014 mmol). To the resulting yellow
solution was added Bu3SnH (30 µL, 0.107 mmol) (upon complete
addition of Bu3SnH, the solution became brown colour). After 15
min at room temperature, TLC showed complete consumption of
the starting material. The reaction mass was concentrated and
filtered quickly through a plug of silica gel basified with Et3N to 14,15-Desoxy-Herboxidiene ethyl ester (35): To a stirred solution
afford stanane 3 (32 mg) as colorless liquid which was used of MOM protected compound 35a (20 mg, 0.04 mmol) in MeOH (3
immediately for the next reaction. 1H NMR (300 MHz, CDCl3): δ 5.82 mL) was added 2N hydrochloric acid (0.3 mL, 0.64 mmol) at −15 °C.
(dd, J = 4.1, 1.1 Hz, 1H), 5.02 (d, J = 8.5 Hz, 1H), 4.70−4.61 (m, 3H), The reaction mixture was stirred for 4 h at 0 °C. After completion of
3.74−3.65 (m, 1H), 3.50 (s, 3H), 3.36 (s, 3H), 2.78 (dd, J = 6.8, 1.5 Hz, the reaction (monitored by TLC), ethyl acetate (10 mL) and
1H), 2.26 (m, 1H), 2.32 (m, 1H), 2.02 (dd, J = 13.4, 5.7 Hz, 1H), 1.89 saturated aqueous NaHCO3 (10 mL) were added. The layers were
(m, 1H), 1.59 (d, J = 0.9 Hz, 1H), 1.53−1.41 (m, 11H), 1.36−1.20 (m, separated and the aqueous layer extracted with ethyl acetate (3 ×
9H), 1.01−0.82 (m, 18H) ppm; HRMS (ESI): m/z calcd. for 10 mL). The combined organic layers were washed with brine (25
C28H56O3SnNa [M + Na]+: 583.3143; found: 583.3153.
mL), dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude mass was purified by flash chromatography
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Journal Name
(ethyl acetate/hexane = 1:7) to afford the compound 35 (15 mg, 11.7 ppm. HRMS (ESI): m/z calcd. for C27H46O6Na [M + Na]+:
27
86%) as colorless liquid. [α]D +12.0 (c 0.5, CHCl3); IR (neat): 3453, 489.3186; found: 489.3179.
2925, 2859, 1734, 1606, 1454, 1375, 1150, 1091, 1035 cm−1 1H
;
Herboxidiene/GEXIA (1): To a solution of herboxidiene ethyl ester
36 (3.5 mg, 7.51 µmol) in MeOH (1 mL), water (0.1 mL) was added
potassium carbonate (5.2 mg, 37.55 µmol). The reaction mixture
was stirred at 45 ºC for 4 h. After completion of the reaction
(monitored by TLC), it was diluted with ethyl acetate (5 mL) and
water (3 mL). The inorganic phase was carefully acidified with 1N
HCl up to pH = 4−5. The organic layer was separated and the
aqueous layer extracted with ethyl acetate (5 × 5 mL). The
combined organic layers were washed with brine (10 mL), dried
over Na2SO4, and concentrated under pressure. The crude product
was purified by silica gel column chromatography (5% MeOH/CHCl3)
NMR (300 MHz, CDCl3): δ 6.18 (dd, J = 14.9, 10.4 Hz, 1H), 5.90 (br d,
J = 10.8 Hz, 1H), 5.52 (dd, J = 15.1, 7.4 Hz, 1H), 4.97 (d, J = 9.1 Hz,
1H), 4.12 (q, J = 14.2, 7.2 Hz, 2H), 3.82−3.67 (m, 2H), 3.51 (s, 3H),
3.32 (d, J = 9.8 Hz, 1H), 2.74−2.52 (m, 3H), 2.44−2.30 (m, 2H), 2.01
(dd, J = 13.2, 6.8 Hz, 1H), 1.93 (d, J = 7.4 Hz, 1H), 1.84 (dd, J = 12.5,
3.2 Hz, 1H), 1.70 (s, 3H), 1.70−1.65 (m, 1H), 1.61 (s, 3H), 1.55−1.47
(m, 1H), 1.40−1.31 (m, 2H), 1.19 (d, J = 6.4 Hz, 3H), 1.24 (t, J = 7.1
Hz, 3H), 0.95 (d, J = 6.4 Hz, 6H), 0.68 (d, J = 6.6 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3): δ 171.4, 140.2, 134.4, 133.7, 129.6, 128.2,
124.0, 90.4, 89.8, 73.9, 67.9, 61.4, 60.3, 47.5, 41.6, 34.8, 34.7, 32.4,
32.2, 31.6, 20.4, 19.9, 17.7,16.5, 16.3, 14.2, 12.3 ppm.; HRMS (ESI):
m/z calcd. for C27H48O5 [M + H]+: 451.3418; found: 451.3425.
27
to furnish 1 (2.7 mg, 85%) as colorless liquid. [α]D +4.2 (c 0.2,
MeOH); IR (neat): 3447, 2924, 2856, 1732, 1457, 1375, 1077, 1018
Herboxidiene ethyl ester (36): To a solution of compound 35 (9.0 cm−1; 1H NMR (300 MHz, CD3OD): δ 6.30 (dd, J = 15.1 , 10.8 Hz, 1H),
mg, 0.02 mmol) in dry CH2Cl2 (1 mL), was added VO(acac)2 (1.06 mg, 5.92 (d, J = 10.8 Hz, 1H), 5.48 (dd, J = 15.1, 9.1 Hz, 1H), 3.79 (q, J =
4.0 μmol) was added followed by very slow addition of tert-butyl 8.7, 6.5 Hz, 1H), 3.81−3.75 (m, 1H), 3.64 (br s, 1H), 3.53 (s, 3H), 3.35
hydrogen peroxide (t-BuOOH) (≈ 6 M in Toluene, 13 μL) in dropwise (d, J = 9.8 Hz, 1H), 2.98 (dd, J = 6.2, 4.3 Hz, 1H), 2.66 (d, J = 9.5 Hz,
manner. The dark brown reaction mixture was stirred at −25 ºC for 1H), 2.46 (m, 1H), 2.48-2.43 (m, 1H), 2.39 (dd, J = 15.4, 5.3 Hz, 1H),
24 h. After completion of the reaction (monitored by TLC), CH2Cl2 (5 1.93 (dd, J = 13.4, 4.3 Hz, 1H), 1.89-1.84 (m, 1H), 1.74−1.72 (m, 1H),
mL) and saturated aqueous NaCl (3 mL) were added. The layers 1.70 (s, 3H), 1.62−1.47 (m, 2H), 1.39−1.32 (m, 1H), 1.28 (s, 3H),
were separated and the aqueous layer extracted with CH2Cl2 (3 × 5 1.27−1.15 (m, 1H), 1.19−1.16 (m, 1H), 1.11 (d, J = 6.5 Hz, 3H), 1.05
mL). The combined organic layer was dried over anhydrous Na2SO4 (d, J = 6.5 Hz, 3H), 0.83 (d, J = 7.0 Hz, 3H), 0.69 (d, J = 6.5 Hz, 3H)
and concentrated under reduced pressure. The crude mass was ppm; 13C NMR (125 MHz, CD3OD): δ 175.4, 140.7, 136.2, 129.7,
purified by flash chromatography (ethyl acetate/hexane = 1:4) to 126.6, 92.2, 88.6, 75.6, 69.9, 67.9, 62.7, 61.9, 48.1, 42.3, 36.6, 36.5,
27
afford the compound 36 (4.6 mg, 51%) clear liquid. [α]D +6.8 (c 33.5, 33.4, 32.8, 22.7, 19.9, 18.1, 16.8, 12.1, 11.6 ppm; HRMS (ESI):
0.4, CHCl3); IR (Neat): 3449, 2923, 2853, 1735, 1458, 1254, 1069 m/z calcd. for C25H46O6N [M + NH4]+: 456.3319; found: 456.3333.
1
cm−1; H NMR (300 MHz, CDCl3): δ 6.23 (dd, J = 15.1, 10.6 Hz, 1H),
Acknowledgements
5.89 (br d, J = 10.6 Hz, 1H), 5.43 (dd, J = 15.1, 8.3 Hz, 1H), 4.12 (q, J =
13.6, 6.8 Hz, 2H), 3.89−3.72 (m, 2H), 3.55 (s, 3H), 3.32 (d, J = 9.8 Hz,
Authors thank the CSIR, New Delhi, India, for financial support as
1H), 2.97 (t, J = 5.3 Hz, 1H), 2.58 (dd, J = 15.1, 6.0 Hz, 1H), 2.55 (d, J
part of XII Five Year plan programme under title ORIGIN (CSC-0108).
= 9.1 Hz, 1H), 2.54 (br s, 1H), 2.45−2.38 (m, 1H), 2.38 (dd, J = 15.1,
B.T. thanks the University Grants Commission (UGC), New Delhi,
7.5 Hz, 1H), 1.89 (dd, J = 13.6, 4.5 Hz, 1H), 1.84−1.81 (m, 1H), 1.70
India for financial assistance in the form of fellowships.
(s, 3H), 1.71−1.66 (m , 1H), 1.56−1.48 (m, 2H), 1.39−1.31 (m, 1H),
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