NHC catalyzed enantioselective Coates-Claisen rearrangement: A rapid access to the dihydropyran core for oleuropein based secoiridoids

Article abstract of DOI:10.1039/c7nj04057a

We present the short synthesis of the suitably functionalized enantioselective dihydropyran core of secoiridoids using an N-heterocyclic carbene (NHC) catalyzed Coates-Claisen rearrangement mechanism. The key steps of the synthesis are (i) the highly enantioselective NHC catalyzed Coates-Claisen rearrangement for the dihydropyran core, (ii) the assembly of the target dihydropyran core structure of oleuropein from a highly diastereoselective exocyclic trans alkene, and (iii) the highly stereoselective assembly of a monoterpene elenolide core structure.

Full text of DOI:10.1039/c7nj04057a

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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DOI: 10.1039/C7NJ04057A
Journal Name
ARTICLE
NHC catalyzed enantioselective Coates-Claisen rearrangement : A
rapid access to the dihydropyran core for Oleuropein based
Secoiridoids
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
DOI: 10.1039/x0xx00000x
Seenuvasan Vedachalam,* Nithya Murugesh, Priyanka Chakraborty, Ramasamy Karvembu and
b
Xue-Wei Liu*
www.rsc.org/
"
We present a short synthesis of a suitably functionalized enantioselective dihydropyran core of Secoiridoids using N-
heterocyclic carbene (NHC) catalyzed Coates-Claisen rearrangment mechanism. Key steps of the synthesis are (i) the highly
enantioselective NHC catalyzed Coates-Claisen rearrangment for dihydropyran core (ii) the highly diastereoselective
exocyclic trans alkene for the assembly of the target dihydropyran core structure of Oleuropein (iii) highly stereoselective
assembly of monoterpene elenolide core structure."
and challenging structures of the Oleuropein based Secoiridoid
natural products immediately caught our attention and lead us
to initiate a program aiming to the total synthesis of
Introduction
Secoiridoids are monoterpenoid based natural products, they
have a unique dihydropyran based structural skeleton. Their
novel structures and potent biological activity makes these
scarcely available Secoiridoids acts as an attractive synthetic
target for the medicinal chemistry community. Oleuropein
based Secoiridoid natural products have a characteristic
Oleuropein and its structural analogues. However, no one has
been reported the total synthesis of Oleuropein yet. This can
lead us to the design of new synthetic strategy for the
acquirement of derivatives of Oleuropein analogues or other
Secoiridoids (Figure 1) by utilising a common key intermediate
approach. Recently, N-Heterocyclic carbene (NHC) catalysis has
emerged as one of the most promising areas of research and
has undergone significant developments and application in
dihydropyran ring with an unique stereo structural analogy
1
(
Figure 1). Similar natural products have also been identified,
2
consolidating to over 250 members in this family. This
unprecedented dihydropyran based structure of these
molecules have attracted considerable attention as it shows
similar structural skeleton with each other Secoiridoids. Also
Oleuropein and their analogues are biogenetically related to
each other by an oxidative ring contraction and functional
group modification to generate other Secoiridoids and
13
complex molecule synthesis. NHC catalysis provides efficient
routes to access a variety of nucleophilic species such as acyl
anion, homoenolate, enolate which are more attractive tactics
14
for carbon-carbon bond-formation.
3
Iridoids. Oleuropein (1a) possesses a wide spectrum of
4
5
biological activities such as antioxidant, anti-inflammatory,
6
7
8
9
anti-atherogenic, anti-cancer, antimicrobial, antiviral and
10
anti-HIV properties. Also it has enormous application towards
11
neurodegenerative diseases.
Oleuropein has a prime
dihydropyran-3-methylcarboxylate ring like structure with 1,1'-
glycosidic bond. In addition, it has an exo-cyclic trans alkene
bond and an ester linkage with the tyrosyl group (Figure 1, 1a).
Recently, we are interested in developing various bio-active
12
organic molecules for medicinal applications. The fascinating
Figure 1. Examples of Secoiridoids based natural products.
a.
Department of Chemistry, National Institute of Technology, Tiruchirappalli-
In addition, generation of an activated carboxylate species is
another attractive area for the delivery of ester and amide
6
20015, India, E-mail: vseenu@nitt.edu, seenuvasanv@gmail.com; Fax: +91-
b.4312500133; Tel: +91-4312503636.
1 Nanyang Link, Division of Chemistry and Biological Chemistry, School of
Physical & Mathematical Sciences, Nanyang Technological University, Singapore,
37371. E-mail: xuewei@ntu.edu.sg; Fax: +65-6791 1901; Tel: +65 6316 8901
2
15
bonds. Zeitler introduced redox esterification on alkynyl
1
6
6
aldehydes by providing an α,β-unsaturated ester. Later Bode,
Electronic supplementary information (ESI) available: Detailed experimental
procedures and characterization data See DOI: 10.1039/x0xx00000x
developed NHC-catalyzed Coates-Claisen rearrangement
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through one pot redox esterification with electron rich Kojic Table 1 Optimization of key step for dihydropyran based
View Article Online
DOI: 10.1039/C7NJ04057A
1
7
acid followed by 3,3’-sigmatropic rearrangement reaction. An lactone formation.
important aspect of this NHC catalyzed Coates-Claisen
rearrangement is that it leads us to design the possible
Oleuropein synthetic route and other Secoiridoids from easily
accessible starting materials such as
from homopropargyl alcohol and Meldrum acid respectively.
2 and 3 (Table 1) obtained
18
Herein, we report a short and efficient formal synthesis of
enantioselective Oleuropein and monoterpene elenolide, using
an organocatalytic strategy for the construction of the
dihydropyran core structure. This approach can produce
library of chiral fragment based on Secoiridoids natural
compounds
d
Solvent
(0.1 M)
Toluene
Toluene
Toluene
Toluene
Temp.
/ °C
20
Yield
(%)
Trace
‒
% of
ee
a
b
c
Entry
Catalyst
Base
e
1
2
A
B
C
DBU
DBU
‒
‒
20
3
DBU
20
‒
‒
Results and discussion
4
D
E
DBU
20
‒
‒
17
Retrosynthesis: Bode et al. discussed the challenges and
strategies for facilitating NHC catalyzed Coates-Claisen
rearrangement for the construction of dihydropyran based
lactone ring which could be a suitable method for Oleuropein
synthesis with modified starting materials. The retrosynthetic
5
DBU
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
20
‒
‒
6
F
DBU
20
‒
‒
7
G
H
G
G
G
G
G
DBU
20
35
33
45
52
62
51
‒
42
-41
50
79
82
79
‒
8
DBU
20
9
DIPEA
No base
No base
No base
No base
20
approach for Oleuropein synthesis is illustrated in Scheme 1
.
10
11
12
13
20
From the Oleuropein, dihydropyran based lactone ring (VII) is a
core structure which could be constructed first and further
functionalization can introduced such as alkene construction,
lactone reduction, glycosylation and esterification with tyrosyl
group. Enantioselective lactone ring can be constructed from
two aldehydes VIII and IX using a chiral NHC catalyst. The
lactone ring (VII) is further converted in to trans-alkene (VI) at
the ring diastereotropic carbon. Then the lactone ring
subsequently reduces to lactol which upon in situ acetylation
40
80
40
40
40
40
40
1
1
1
1
4
5
6
7
G
G
G
G
No base
No base
No base
No base
Hexane
o-Xylene
p-Xylene
‒
‒
32
38
35
81
77
78
3 6 5
CF C H
a
Unless otherwise specified, all of the reactions were carried out with freshly
b,c
produces aglycon (V). This acetyl protected aglycon (V) is distilled dry solvents at the specified temperature for 24 h. 0.1 equivalent. was
further subjected to 1,1' glycosylation with glycosyl acceptor used. Isolated yields. Determined by HPLC (IC column, solvent system: 99:1
d
e
R
hexanes:i-PrOH), t = 10.2 and 12.1 min. To get a racemic product, 1:1 mixture of
(IV) and esterification of tyrosyl unit (III) leads to formation of
G & H was used.
protected Oleuropein (II) which upon deprotection completes
the Oleuropein (
I) total synthesis.
The product obtained using catalyst
G furnishes the
stereochemistry of Oleuropein and it was predicted with the
1
8
aid of Bode's report (Entry 7). So we chose catalyst
further optimization of the reaction. The racemic compound of
is derived from the 1:1 mixture of and as this reaction
G for
4
G
H
does not work with any achiral catalyst which was screened
here. By exchanging the base from DBU to DIPEA leads to
slight increases in the yield and selectivity (Entry 9). Next the
reaction is carried out using the catalyst
base which furnishes the lactone product
G
without adding any
in 52% yield and
Scheme 1. Retrosynthetic analysis
4
NHC-catalyzed enantioselective key dihydropyran based 79% enantioselectivity at room temperature (Entry 10). The
lactone synthesis: To probe the feasibility of Coates-Claisen used base plays a dual role; activates the catalyst and
rearrangement to generate dihydropyran core of Oleuropein generates enol from
Secoiridoid using NHC catalysts orienting the selectivities were obtained from both DBU and DIPEA (Entries
experiments were carried out using two aldehydes and in 7–9). The counter (Cl) anion present in the catalyst
acts as a
:1.5 equivalent. The initial optimization was carried out using mild base which performs this dual role as it produces major
the NHC catalyst precursors ( ) (Table 1, entries 1–8) in 0.1 selectivity (79% ee), hence, the reaction condition was tested
3. Unfortunately, diminished yields and
(A‒H)
3
2
G
1
A–H
equiv. and 0.1 equiv. of DBU as base in (0.1 M) dry toluene at without base (Entry 10). In order to improve the yield of the
room temperature for 24 h. Among the tested catalysts, product, reaction was subjected to higher temperatures
catalyst
G
furnished the dihydropyran based lactone product
4
(Entries 11 and 12) such as 40
C resulted in 62% yield with 82% enantiomeric excess
(Entry 11). We expect that the compound is highly unstable
°C and 80 °C. It was found that,
in 35% yield and 42% enantioselectivity (Entry 7). The catalyst 40
°
H
gave similar results with the stereoisomer of
4
.
3
2
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at higher temperature as it needs to be stored at -78
loss of its composition was noted for a month. Next, the
reaction was carried out in different solvents and it was found
that the reaction is not feasible in THF, hexane (Entries 13, 14)
and the toluene mimic solvents such as o-xylene, p-xylene and
trifluro toluene afforded moderate yields (32, 38 & 35%
respectively) and selectivities (81, 77 & 78% ee respectively)
ARTICLE
°
C. No
View Article Online
DOI: 10.1039/C7NJ04057A
Scheme 3. Reduction of lactone 5
2
2
(
Entries 15-17). So the key dihydropyran based lactone solvent. The result consisted of two major products
7 (ring
synthesis was carried out using catalyst at 40
G
°
C in 0.1 M dry opened primary alcohol, 45% yield) and (ring opened α,β-
8
toluene for 24 h. If this reaction is carried out in a large scale, unsaturated aldehyde, 5 % yield) which is unlikely to be the
the catalyst can be recovered by column chromatography expected products based on the retrosynthetic analysis
followed by drying in high vacuum and reused for 3 to 4 times. (Scheme 1). But it resembles the core structural skeleton of
The possible transition state for stereoselective-outcome can Oleocanthal (1i) (Scheme 3). If the acetylation is not carried
be obtained through hemiacetal chair transition state (Shown out in one pot protocol, it leads to the allylic primary alcohol
in Table 1) adduct which undergoes 3, 3'-sigmatropic which further reacts with terminal aldehyde intramolecularly
rearrangement followed by ring closure to obtain
4
.
to form undesired lactol which further protected with an
acetyl group, it produces an undesired dihydropyran alkene
1
8
Alkene construction: Trans alkene construction on compound. Another significant reported procedure from
diastereotropic ring carbon of is an another key step due to Lupton group for the reduction of lactone to lactol using
the presence of various functional groups such as alkene, sodium borohydride in methanol produces over-reduced
lactone and tert-butyl ester. The initial approach was to product which was isolated as acetyl protected compound
in
construct trans alkene by using Horner-Wadsworth-Emmons 51% yield (Scheme 3).13h-i Then we decided to carry out the
HWE) reaction by preparing phosphate diastereomeric controlled DIBAL-H reduction reactions that needs to optimize
4
9
(
mixtures in ring diastereotopic carbon using Lithium selectively one product as the major one with good chemical
Diisopropylamide (LDA) as a base and acetaldehyde as a yield (Table 2). Initially reaction was carried out using 1.1 equiv
1
9
counter substrate. It leads to formation of complex mixtures of DIBAL-H at ‒78
even at both ‒78 and ‒40 C in dry THF which is unlike the product which upon subsequent acetylation, produced
expected trans alkene product ( ). Furthermore, the reaction
was subjected to Mukiyama aldol reaction and aldol Table 2 Optimization of lactone reduction and one pot
condensation with acetaldehyde using LDA as a base under acetylation.
°C in dichloromethane to form the reduced
°
7
and 8
5
20
standard reaction condition which obtain complex mixture.
a
DIBAL-H
solvent
[0.1 M]
Yield
7 (%)
Yield
8 (%)
Recv
5 (%)
Scheme 2. Trans alkene construction through aldol reactions
Entry
Time/h
b,c
b,c
b,c,
(equiv)
1
2
3
4
5
6
7
8
9
1.1
2
2
2
2
2
2
2
2
4
4
CH
CH
CH
2
2
2
Cl
2
45
20
70
80
79
52
51
72
76
46
5
10
5
25
50
10
5
Next, we turned our attention to carry out aldol reaction with
acetaldehyde using Lithium hexamethyldisilane (LiHMDS) as a
base that resulted in a diastereomeric mixture of aldol
products which is similar in core structure of Alpignoside and
0.5
1.5
2.0
2.5
1.1
1.1
2.0
2.0
1.1
Cl
2
2
Cl
CH
2
Cl
2
5
21
was isolated as
a
diastereomeric mixtures.
This
CH
2
Cl
2
0
0
diastereomeric mixture was then subjected to mesylation
followed by elimination using DBU as a base to obtain the
Toluene
THF
15
10
5
10
15
5
requisite alkenes
5) and Cis (
5
and
6 in 72% yield (trans:cis-95:5). Trans
(
6
) alkenes were separated via column
Toluene
chromatography. The obtained major trans alkene was
subjected to one pot protocol of lactone to lactol reduction
followed by acetyl protection that leads to the formation of
CH
CH
2
Cl
2
2
5
5
1
0
2
Cl
5
10
a
Unless otherwise specified, all of the reactions were carried out with freshly
distilled dry solvents at ‒78 °C and used 1 M DIBAL-H in toluene as a
reducing agent. Isolated yield. After the mentioned reduction time the
following reagents were added at the same temperature (‒78 °C) in the
following order 2 equiv of pyridine, 1.1 equiv of DMAP in dichloromethane,
expected glycosyldonor (V) (Scheme 1).
Lactone reduction: The vast number of reports have been
devised from lactone to lactol at lower temperature using
DIBAL-H as a reducing agent followed by one pot acetyl
protection. For this we have subjected Rychnovsky method's
b
c
4
equiv of acetic anhydride and stirred for 12 h.
for one pot DIBAL-H reduction of lactone (
5) to lactol followed
by acetylation at -78 C using dry dichloromethane as a
°
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in 45% & 5% yields respectively (Table 2, Entry 1). If the DIBAL- with excess amount of Trifluoroacetic acid (10 equiv) in
View Article Online
DOI: 10.1039/C7NJ04057A
H quantity was reduced to 0.5 equiv,
7 was obtained in 20% dichloromethane at 0 °C to form corresponding acid 14 in 30
yield indicating that, after the formation of lactol subsequently mins which further undergoes methylation using
it undergoes ring opening forms of α,β- unsaturated aldehyde Timethylsilydiazomethane to obtain 15 in 95 and 86% yields. In
which further undergoes reduction instead of reducing both the reaction, the products were obtained in quantitative
another molecule of lactone (5) (Entry 2). Also it provides 50% yield and the obtained acid 14 reaction mixture was subjected
unreacted lactone which emphasises the reaction with lower to remove the excess trifluroaceticacid followed by tituration
amount of reducing agent also leads to ring opened over with hexane and high vacuum drying before methylation. In
reduced product
expected lactol product from the retro-synthetic analysis corresponding methyl 3-oxopropanoate as a starting material
Scheme 1). If the DIBAL-H quantity was increased to 1.5, 2 for the initial lactone formation instead of tert-butyl 3-
and 2.5 equiv, it results in increasing yields of 70, 80, 79% oxopropanoate ( ), but the synthesis and stability of this
respectively (Entries 3-5). From that we concluded more than aldehyde is very poor. Compound 15 shows similar core
equiv. of DIBAL-H leads to slight decrease in the product structural analogues for monoterpene elenolide (1g) and
yield, so we chose 2 equiv which is an ideal amount of Vallesiachotamine (1h). Furthermore, the compound 15 was
reducing agent for getting compound as the major product. subjected to NaOMe/MeOH that delivers deprotection of
Next, reactions were carried out in different solvents such as acetate group as well as ring opened methyl ester product was
7 as a major product which is unlike the this functional group interconversion, we could use the
(
3
2
7
18
THF and toluene that yielded similar ring opened product were obtained. In this protocol, we find the resulting chiral
obtained with diminished yield of (Entries 6‒8). intermediates shows interesting structural features which
7
Furthermore, reduction reaction time was increased to 4 h allows anyone can develop other Secoiridoids.
producing similar results which was obtained from 2 and 1.1
equiv of DIBAL-H in 2 h period (Entries 9 and 10). In conclusion,
the detail obtained from optimization table for reduction of
lactone (
ring opened product
5
) to lactol followed by one pot acetylation leads to
as a major one which is unlike the result
7
obtained from the retrosynthetic analysis. Part of our aim of
this project is to develop the synthesis of other Secoiridoids
Scheme 5. Synthesis of monoterpene elenolide core
(
Figure 1) which can be compatible with this method. So we
decided to use the over reduced acetyl protected compound
as key starting material for the synthesis of
diastereoselective monoterpene elenolide core. The In conclusion, we have developed a novel chemical approach
compound
was subjected to TBS deprotection by using for the synthesis of Oleuropein based Secoiridoids core using
7
Conclusions
a
7
Tetrabutyl ammonium fluoride (TBAF) leads to the acetyl NHC catalyzed Coates-Claisen rearrangement reaction.
group deprotection which further undergoes an undesired Furthermore, an aldol reaction with acetaldehyde that takes
lactol formation with allylic primary alcohol and terminal place at the diastereotropic ring carbon using LiHMDS which
1
8
aldehyde. So, the deprotection of TBS group of
out in acidic condition using 1.5 equiv of Trifluroacetic acid at product (major). This approach can produce a library of
C for 10 min. to obtain the selective TBS deprotected compounds by using diverse aldehydes. Although the selective
alcohol (10) (Scheme 4) in 84% yield. Furthermore, compound reduction of lactone to lactol by DIBAL-H leads to formation of
was oxidized to aldehyde 11 using Desmartin periodide and over reduced ring opened product instead of the anticipated
acid 12 using Pinnick oxidation, that delivered 88% and 92% lactol product creates a new type of chiral fragment which can
7
was carried resulted in an exocyclic trans ethyleneic double bonded
0
°
1
0
yields respectively (Scheme 4).
further be used by other synthetic organic community. The
ring opened product is successfully exploited for functional
group transformation which produces diastereoselective
monoterpene elenolide core structure. The synthetic strategy
developed here is flexible and can be extended towards the
synthesis of numerous stereochemical analogues of the
Secoiridoid natural products or medicinally active fragments.
Scheme 4. Synthesis of acid (12)
The compound 12 was further subjected to intramolecular DCC
coupling in the presence of DMAP that leads to compound 13
in 81% yield (Scheme 5). In this case, acetyl protected vinyl
group of 12 was selectivley deprotected and in situ
intramolecular lactonization produces compound 13 which is
Experimental
General methods: All the reactions were carried out in a flame
or oven dried glassware under an argon or nitrogen
atmosphere with freshly distilled dry solvents under anhydrous
conditions unless otherwise indicated. Evaporation of organic
solutions was achieved by rotary evaporation with a water
23
the structural skeleton of monoterpene elenolide (Figure 1,
). Next, tert-butyl ester of 13 was converted into
corresponding methyl ester. Tert-butyl ester of 13 was treated
1
i
bath temperature below 40 °C. Product purification by flash
4
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column chromatography was accomplished using silica gel 60 reaction mixture was quenched with a solution of saturated
View Article Online
DOI: 10.1039/C7NJ04057A
(
0.010–0.063 nm). Chromatograms were visualized by NH Cl (2 mL) at room temperature, diluted with EtOAc,
4
fluorescence quenching with UV light at 254 nm or by staining washed with sat. NaHCO , and brine, dried over MgSO , and
3
4
using base solution of potassium permanganate. Technical concentrated in vacuum to give a residue, which was passed
grade solvents were used for chromatography and were through a silica gel column (Hexane−EtOAc; 3:2) gave a
distilled prior to use. NMR spectra were recorded at room mixture of diastereomers (0.42 g, 75%) which was used for
temperature on 300 MHz Bruker ACF 300, 400 MHz Bruker next steps. (ii) The above obtained mixture of alcohols (0.42 g,
DPX 400, 500 MHz Bruker AMX 500, and 400 MHz JEOL ECA 10.5 mmol) was dissolved in pyridine (8 mL), and to this
4
00 NMR spectrometers. The residual solvent signals were solution methane sulfonyl chloride (0.16 mL, 21.0 mmol) was
1
taken as the reference (7.26 ppm for H NMR spectra and 77.0 added at room temperature with vigorous stirring. After 1 h,
ppm for C NMR spectra in CDCl , 2.5 ppm for H NMR spectra the reaction mixture was concentrated in high vacuum
and 39.5 ppm for C NMR spectra in DMSO-d . Sometimes the distillation, diluted with EtOAc (20 mL), washed with H O (2x10
TMS signal at 0.0 ppm was used an internal standard for H mL), and brine (10 mL), dried over MgSO , and concentrated in
13
1
3
13
6
2
1
4
NMR spectra. Chemical shift () is reported in ppm, coupling vacuum to gave a crude mixture of diastereomers (0.46 g,
constants (J) are given in Hz. The following abbreviations 85%). (iii) The mixture of mesylates (0.46 g, 0.97 mmol) was
classify the multiplicity: s = singlet, d = doublet, t = triplet, m = dissolved in THF (5 mL) and added DBU (0.29 mL, 1.95 mmol)
multiplet or unresolved, br = broad signal. HR-MS (ESI) spectra and stir at room temperature. After 10 min. stirring, the
TM
were recorded on
spectrometer.
a
Waters Q-Tof premier
mass reaction mixture was diluted with EtOAc, washed with sat.
NH Cl, sat. NaHCO , brine and dried over MgSO , and
4
3
4
Materials: All solvents were distilled under argon from the concentrated in vacuum to give a mixture of E and Z-
following drying agents immediately before use: geometrical isomers as viscous oil. The mixture was
tetrahydrofuran
(THF)
was
distilled
from chromatographed on a silica gel column. Elution with Hexane-
23
1
sodium/benzophenone ketyl; dichloromethane was distilled EtOAc (98:2); (0.26 g, 72%); [α] = ‒34.0 (c = 0.5, CHCl ); H
D
3
from calcium hydride. All the starting materials were NMR (400 MHz, CDCl ): δ 7.39 (s, 1H), 7.05 (qd, J = 7.2 Hz, J =
3
1
2
purchased from commercial suppliers and used without 0.9 Hz, 1H), 3.86 (dd, J = 7.4 Hz, J = 4.9 Hz, 1H), 3.62‒3.47 (m,
1
2
further purification. All the NHC catalyses were purchased 2H), 1.91 (d, J = 7.3 Hz, 3H), 1.82‒1.61 (m, 2H), 1.50 (s, 9H),
1
3
from commercial suppliers and catalyst
from standard literature procedure.
G
and
H
was prepared 0.86 (s, 9H), 0.06 (s, 6H); C NMR (100 MHz, CDCl ): δ 164.3,
3
162.9, 148.7, 143.1, 127.3, 115.6, 81.3, 59.5, 37.4, 30.1, 28.1,
25.9, 18.3, 14.5, ‒5.3; HRMS (ESI) m/z [M+H] : calcd. for
+
(S)-tert-Butyl-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-
3
,4-dihydro-2H-pyran-5-carboxylate (4):
C H O Si: 383.2260, found: 383.2256.
2
0 35 5
In an oven dried 10.0 mL round bottom flask, tert-butyl (S,Z)-tert-Butyl-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-
formylacetate ( ) (100 mg, 0.69 mmol, 1.0 equiv) and (R,S) ethylidene-2-oxo-3,4-dihydro-2H-pyran-5-carboxylate
triazolium precatalyst (
followed by 4.0 mL of toluene (0.1 M) and ((tert- (s, 1H), 6.35 (q, J = 7.2 Hz, 1H), 3.65-3.51 (m, 3H), 2.11 (d, J =
Butyldimethylsilyl)oxy)pent-2-ynal ( ) (220.0 mg, 1.04 mmol, 7.2 Hz, 3H), 1.94‒1.82 (m, 1H), 1.51 (s, 9H), 1.51‒1.46 (m, 1H),
3
(6)
:
23
D
1
G
) (26.7 mg, 0.10 equiv) were added, [α] = ‒74.7 (c = 1.6, CHCl ); H NMR (400 MHz, CDCl ): δ 7.37
3
3
2
13
1
.50 equiv) in a nitrogen atmosphere. The resulting solution 0.90 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); C NMR (100 MHz,
was heated to 40 °C and stirred for 24 h. Toluene was CDCl ): δ 164.1, 161.0, 148.3, 144.9, 125.3, 117.2, 81.2, 59.0,
3
+
evaporated and the residue was purified by column 37.2, 36.9, 28.1, 25.9, 18.2, 16.2, ‒5.3; HRMS (ESI) m/z [M+H] :
chromatography to obtained (4) as a viscous oil. (Note: In calcd. for C H O Si: 383.2260, found: 383.2274.
20 35 5
higher scale, catalyst was recovered by column DIBAL-H reduction: (S,1E,4E)-2-(tert-Butoxycarbonyl)-3-(2-
2
3
D
chromatography and reused) (153 mg, 62%). [α] = +10.7 (c = ((tertbutyldimethylsilyl) oxy)ethyl)-4-ethylidene pent-1-ene-
1
0
.9, CHCl ); H NMR (400 MHz, CDCl ): δ 7.45 (s, 1H), 3.71‒3.66 1,5-diyldiacetate (7):
3 3
(
m, 2H), 3.09‒3.03 (m, 1H), 2.88 (dd, J = 16.0 Hz, J = 1.6 Hz, To a 10 mL flame-dried round bottom flask (
5
) (0.1 g, 0.26
1
2
1
0
1
‒
3
9
H), 2.66 (dd, J = 16.0 Hz, J = 7.2 Hz, 1H), 1.80‒1.76 (m, 12H), mmol) was placed and dissolved in 3 mL of dry CH Cl under
1
2
3
2
2
1
.91 (s, 9H), 0.06 (s, 6H); C NMR (100 MHz, CDCl ): δ 166.8, nitrogen atmosphere. After the mixture was cooled to ‒78 °C
3
64.3, 149.7, 117.2, 81.4, 60.5, 35.9, 33.0, 28.2, 25.9, 18.3, cool bath, DIBAL-H (1.0 M in toluene, 0.52 mL, 0.52 mmol, 2
+
5.3, ‒5.3; HRMS (ESI) m/z [M+H] : calcd. for C H O Si: equiv) was added drop wise. After being stirred for 2 h the
18 33 5
57.2097, found: 357.2102. 82% ee as determined by HPLC (IC, reaction mixture was treated with pyridine (62 mg, 0.063 mL,
9:1 hexanes:i-PrOH), t = 9.3 min. (major) and 12.1 min. 0.78 mmol, 3.0 equiv), and then a solution of DMAP (35 mg,
R
(minor).
0.28 mmol, 1.1 equiv) in 1 mL of dry CH Cl was slowly added.
2 2
(
S,E)-tert-Butyl-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-
Finally, aceticanhydride (26 mg, 0.025 mL, 1.0 mmol, 4.0 equiv)
was added drop wise, and the mixture was stirred under
ethylidene-2-oxo-3,4-dihydro-2H-pyran-5-carboxylate (5):
(
i) LiN(SiMe ) (1.68 mL, 1.68 mmol, 1M in hexane) was added nitrogen atmosphere for 12 h. The reaction vessel was packed
3 2
to the solution of (4) (0.5 g, 1.4 mmol) in dry THF (5 mL) at -78 in a Dewar flask containing dry ice-acetone mixture was
C with stirring under nitrogen atmosphere. After 10 min. a warmed to −20 C and the reaction was quenched by adding
°
°
solution of acetaldehyde (0.78 mL, 14.0 mmol) in dry THF (5 saturated NH Cl (5 mL) solution. The reaction mixture was
4
mL) was added to this mixture, and stirred for 15 min. The stirred for 30 mins, allowed to warm to room temperature,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Pl eNa es we dJ oo u nr no at l ao df jCu hs et mm i as tr rgy ins
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ARTICLE
Journal Name
and then extracted with dichloromethane (3 x 5 mL). Trifluoroacetic acid (0.36 g, 3.19 mmol, 244 µL, 1.5 equiv) was
View Article Online
DOI: 10.1039/C7NJ04057A
Aluminum salts formed emulsions, they were disrupted by added slowly at 0 °C. Then the mixture was stirred for 10 min.
adding a saturated solution of Rochelle’s salt (10 mL) with and then removed the solvents using low temperature rota-
vigorous stirring. The combined dichloromethane extracts vapour and the residue was neutralized with saturated
were washed with ice-cold 1 N NaHSO (2 x 5 mL), saturated solution of sodium bicarbonate (10 ml) and extract with
4
NaHCO (3 mL), and brine (1 mL). After drying (anhydrous dichloromethane (3x30 mL). The residue was purified by flash
3
Na SO ) and evaporation of dichloromethane extracts, the silica gel column chromatography using a mixture of hexane
2
4
residue obtained was purified by flash chromatography on and EtOAc (20:1 to 6:1) to afford corresponding compound
2
1
1
silica gel to give compound (7) as a viscous oil. Yield (0.1 g,
8
(10). Yield (0.64 g, 84%); [α] = +26.3 (c = 1.3, CHCl ); H NMR
D 3
23
1
0%); [α] = +53.0 (c = 1.6, CHCl ); H NMR (400 MHz, CDCl ): (400 MHz, CDCl ): δ 8.16 (s, 1H), 5.71 (q, J = 6.8 Hz, 1H), 4.69
D 3 3 3
δ 8.17 (s, 1H), 5.69 (q, J = 6.8 Hz, 1H), 4.58 (s, 2H), 4.24 (t, J = (d, J = 12.4 Hz, 1H), 4.59 (d, J = 12.4 Hz, 1H), 4.16 (t, J = 7.6 Hz,
7
2
9
1
6
.8 Hz, 1H), 3.60‒3.50 (m, 2H), 2.22 (s, 3H), 2.21‒2.11 (m, 1H), 1H), 3.64‒3.58 (m, 2H), 2.24 (s, 3H), 2.19‒2.08 (m, 1H), 2.05 (s,
.05 (s, 3H), 2.02‒1.94 (m, 1H), 1.77 (d, J = 6.8 Hz, 3H) 1.51 (s, 3H), 2.04‒2.02 (m, 1H), 1.85 (bs, 1H), 1.73 (d, J = 6.8 Hz, 3H)
13
13
H), 0.86 (s, 9H), 0.06 (s, 6H); C NMR (100 MHz, CDCl ): δ 1.50 (s, 9H); C NMR (100 MHz, CDCl ): δ 170.8, 166.8, 166.4,
3
3
70.8, 166.5, 166.2, 144.2, 135.0, 127.8, 119.2, 80.9, 66.7, 144.1, 135.0, 128.3, 119.5, 81.4, 66.7, 60.8, 33.5, 32.7, 28.1
+
0.8, 34.1, 32.4, 28.1, 25.8, 21.1, 20.7, 18.1, 13.4, ‒5.1; HRMS (3C), 21.1, 20.7, 13.4; HRMS (ESI) m/z [M+H] : calcd. for
+
(ESI) m/z [M+H] : calcd. for C H O SiNa: 493.2598, found: C H O Na: 379.1733, found: 379.1716.
24
42
7
18 28 7
4
93.2608.
(S,1E,4E)-2-(tert-Butoxycarbonyl)-4-ethylidene-3-(2-
oxoethyl)pent-1-ene-1,5-diyldiacetate (11):
(S,2E,4E)-tert-Butyl-2-(acetoxymethylene)-3-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-4-formylhex-4-enoate (8):
In an oven dried 10 mL round bottom flask (10) (1 g, 2.6 mmol,
Obtained from Table 5.2, entry 4 condition (6 mg, 5% not able 1 equiv) was taken and dissolved in dichloromethane (10 mL),
22
D
1
to isolate in pure form); [α] = ‒39.6 (c = 1.2, CHCl ); H NMR Dess-martin periodide (1.68 g, 3.9 mmol, 1.5 equiv) was added
3
(
400 MHz, CDCl ): δ 9.41 (s, 1H), 8.10 (s, 1H), 6.63 (q, J = 7.2 slowly and then stirred for 3 h. Then the reaction mixtures
3
Hz, 1H), 4.20 (t, J = 7.8 Hz, 1H), 3.62‒3.50 (m, 2H), 2.23 (s, 3H), passed though celite bed and wash the celite bed with
2
1
.22‒2.11 (m, 1H), 2.05 (d, J = 7.2 Hz, 3H), 2.03‒2.01 (m, 1H), dichloromethane (3x10 mL). The filtrate was concentrated and
.49 (s, 9H), 0.90 (s, 9H), 0.04 (s, 6H); HRMS (ESI) m/z [M+H] : purified by flash silica gel column chromatography using a
+
calcd. for C H O SiNa: 449.2245, found: 449.2233.
mixture of hexane and EtOAc (20:1 to 6:1) to afford
2
2 38 6
(
3R,E)-2-(tert-Butoxycarbonyl)-3-(2-((tert-butyldimethylsilyl)
oxy)ethyl)-4-ethylidene pentane-1,5-diyl diacetate (9):
A magnetically stirred solution of (5) (0.1 g, 0.26 mmol) in δ 9.69 (s, 1H), 8.13 (s, 1H), 5.70 (q, J = 6.8 Hz, 1H), 4.59-4.49
CH OH (1 mL) was cooled to 0 C then treated with NaBH (1 (m, 3H), 3.07 (dd, J = 17.2 Hz, 8.4 Hz, 1H), 2.88 (dd, J = 17.2 Hz,
corresponding compound (11) as a viscous liquid. Yield (0.87 g,
21
1
88%); [α] = +18.2 (c = 0.5, CHCl ); H NMR (400 MHz, CDCl ):
D
3
3
°
3
4
ml of a 0.1 M solution in CH OH). The reaction was stirred at 0 7.6 Hz, 1H), 1.77 (s, 3H), 1.75 (s, 3H), 1.71 (d, J = 6.8 Hz, 3H),
3
1
3
°
C for 10 min. then quenched with H O (1 ml) and extracted 1.46 (s, 9H); C NMR (100 MHz, CDCl ): δ 201.1, 170.6, 166.2,
2
3
with CH Cl (3 x 3 ml). The combined organic layers were dried 165.8, 144.3, 133.8, 129.3, 118.0, 81.5, 66.9, 45.0, 30.7, 28.1,
2
2
+
(
Na SO ) and concentrated in high vacuum. The crude reaction 21.0, 20.7, 13.5; HRMS (ESI) m/z [M+H] : calcd. for C H O :
2
4
1
8
2
7
7
mixture was used for acetylation step. The crude reaction 355.1757, found: 355.1757.
mixture was dissolved in CH Cl treated with pyridine (62 mg, (S,E)-3-((E)-1-Acetoxy-3-(tert-butoxy)-3-oxoprop-1-en-2-yl)-4-
2
2
0
.63 mL, 0.78 mmol, 3.0 equiv), and then a solution of DMAP (acetoxymethyl)hex-4-enoic acid (12):
(
35 mg, 0.28 mmol, 1.1 equiv) in 2 mL of dry CH Cl was slowly A solution of of NaClO (432 mg, 4.80 mmol) in 1 mL of water
2
2
2
added by syringe at 0 °C. Finally, Ac O (0.1 mg, 0.1 mL, 1.0 was added drop wise in 2 h to a stirred mixture of (11) (1 g,
2
mmol, 4.0 equiv) was added drop wise and stir for 2 h. After 2 2.82 mmol) in 2 mL of acetonitrile and NaH PO (67 mg, 0.56
2
4
h, the reaction mixture was quenched by adding saturated mmol) of in 0.5 mL of water and 35% H O (283 µL, 4.23 mmol)
2
2
NH Cl (5 mL) solution and extract with dichloromethane (5 x 3 of keeping the temperature at 10 °C with ice-water cooling.
4
mL). The combined organic layer was dried over sodium Oxygen evolved from the solution was monitored until the end
sulphate and concentrated in vacuo. The residue was purified of the reaction (about 1h) with a bubbler connected to the
by column chromatography to give (9) as a viscous liquid. apparatus. A small amount (~0.05 g) of Na SO was added to
2 3
2
3
D
1
Yield: (62 mg, 51%); [α] = ‒63.0 (c = 0.3, CHCl ); H NMR (400 destroy the unreacted HOCl and H O . Acidification with 10%
3
2 2
MHz, CDCl ): δ 5.85 (q, J = 7.2 Hz, 1H), 4.54‒4.46 (m, 2H), 4.25 aqueous ammonium chloride (20 mL) which was extracted
3
(
dd, J = 10.4 Hz, J = 4.4 Hz, 1H), 4.0 (t, J = 10.4 Hz, 1H), with ethylacetate (3x10 mL) and evaporate the organic layer to
1 2
3
.56‒3.41 (m, 2H), 3.13‒3.11 (m, 1H), 2.75‒2.71 (m, 1H), 2.07 afforded of (12) 960 mg (92%), as viscous liquid. The acid was
21
(s, 3H), 2.02 (s, 3H), 1.73 (d, J = 6.8 Hz, 3H), 1.68‒1.61 (m, 2H), used for next step without purification. [α] = +9.3 (c = 1.6,
D
+
1
1
.51 (s, 9H), 0.86 (s, 9H), 0.06 (s, 6H); HRMS (ESI) m/z [M+H] : CHCl3); H NMR (400 MHz, CDCl ): δ 8.16 (s, 1H), 5.73 (q, J =
3
calcd. for C H O SiNa: 495.2723, found: 495.2719.
6.8 Hz, 1H), 4.61–4.46 (m, 3H), 3.03 (dd, J = 16.4 Hz, 8.4 Hz,
1H), 2.87 (dd, J = 16.4 Hz, 7.8 Hz, 1H), 2.22 (s, 3H), 2.03 (s, 3H),
1.78 (d, J = 6.8 Hz, 3H), 1.48 (s, 9H); C NMR (100 MHz, CDCl3):
24 44 7
(
S,1E,4E)-2-(tert-Butoxycarbonyl)-4-ethylidene-3-(2-
hydroxyethyl)pent-1-ene-1,5-diyl diacetate (10):
In an oven dried 10 mL round bottom flask ( ) (1g, 2.12 mmol, δ 177.6, 170.6, 166.3, 165.8, 144.3, 133.6, 129.9, 118.2, 81.4,
equiv) was taken and dissolved in dichloromethane (10 mL).
13
7
1
6
| J. Name., 2012, 00, 1-3
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Page 7 of 9
Pl eNa es we dJ oo u nr no at l ao df jCu hs et mm i as tr rgy ins
Journal Name
ARTICLE
+
6
7.1, 35.9, 32.7, 28.1, 21.1, 20.6, 13.5; HRMS (ESI) m/z [M+H] : India for financial support and gratefully acknowledged. We
View Article Online
DOI: 10.1039/C7NJ04057A
calcd. for C H O : 371.1706, found: 371.1706.
also thank Department of chemistry, National Institute of
18 27 8
(R,E)-tert-Butyl-4-(1-acetoxybut-2-en-2-yl)-2-oxo-3,4-dihydro- Technology-Tiruchirappalli for providing Infrastructure and
2
H-pyran-5-carboxylate (13) :
To a mixture of (12) (800 mg, 2.16 mmol) and DMAP (290 mg,
.37 mmol) in dichloromethane (8 mL), DCC (467 mg, 2.27
Instrumentation facilities.
2
Notes and references
mmol) was added in one portion. The reaction mixture stirred
at room temperature for 24 h. Evaporate dicholoromethane
and then add water (10 mL) and extract with diethylether
1
2
M. Guiso and C. Marra, Nat. Prod. Res., 2005, 19, 105.
(a) B. Dinda, D. R. Chowdhury and B. C. Mohanta, Chem.
Pharm. Bull., 2009, 57, 765; (b) B. Dinda, S. Debnath and Y.
Harigaya, Chem. Pharm. Bul., 2007, 55, 159; (c) B. Dinda, S.
Debnath and Y. Harigaya, Chem. Pharm. Bull., 2007, 55, 689;
(3X30 mL). The combined organic layer was dried and purified
by flash column chromatography (10% Ethylacetate and
Hexane) to obtained 13 as viscous oil. Yield (0.54 g, 81%);
(
d) C. A. Boros and F. R. Stermitz, J. Nat. Prod., 1991, 54
,
,
,
21
D
1
[
α] = +65.8 (c = 1.0, CHCl3); H NMR (400 MHz, CDCl ): δ
1173. (e) L. J. El-Naggar and J. L. Beal, J. Nat. Prod. 1980, 43
649; (f) B. Shasha and J. Leibowitz, J. Org. Chem., 1961, 26
3
7
.58 (s, 1H), 5.80 (q, J = 6.8 Hz, 1H), 4.40 (d, J = 12 Hz, 1H), 4.32
1
948.
(d, J = 12 Hz, 1H), 4.10 (d, J = 9.6 Hz, 1H), 2.91 (dd, J = 16.4 Hz,
3
(a) K. Miettinen, L. Dong, N. Navrot, T. Schneider, V. Burlat, J.
Pollier, L. Woittiez, S. van der Krol, R. Lugan, T. Ilc, R.
Verpoorte, K.-M. Oksman-Caldentey, E. Martinoia, H.
Bouwmeester, A. Goossens, J. Memelink and D. Werck-
9
6
1
2
3
.6 Hz, 1H), 2.67 (d, J = 16.4 Hz, 1H), 2.03 (s, 3H), 1.80 (d, J =
1
3
.8 Hz, 3H), 1.48 (s, 9H); C NMR (100 MHz, CDCl ): δ 170.8,
3
65.6, 164.2, 150.9, 134.5, 130.1, 112.6, 81.6, 68.0, 34.3, 30.2,
+
8.1, 20.8, 13.2; HRMS (ESI) m/z [M+H] : calcd. for C H O :
Reichhart, Nat. Commun., 2014,
Clastre, V. Courdavault and S. E. O’Connor, PNAS, 2015, 112
205.
F. Visioli, A. Poli and C. Gall, Med. Res. Rev., 2002, 22, 65.
F. Visioli, S. Bellosta and C. Galli, Life Sci., 1998, 62, 541.
M. A. Carluccio, L. Siculella, M. A. Ancora, M. Massaro, E.
Scoditti, C. Storelli, F. Visioli, A. Distante and R. De Caterina,
Arterioscler. Thromb. Vasc. Biol., 2003, 23, 622.
5, 3606; (b) S. Brown, M.
1
6 23 6
,
11.1495, found: 311.1502.
3
(
5
R,E)-4-(1-Acetoxybut-2-en-2-yl)-2-oxo-3,4-dihydro-2H-pyran-
-carboxylic acid (14):
To a stirred solution of (13) (500 mg, 1.61 mmol) in
dichloromethane (5 mL) at 0 C, trifluoaceticacid (5 mL) was
4
5
6
°
added slowly, the reaction mixture was stirred for another 1 h
at room temperature. Evaporated the reaction mixture and
the obtained acid was washed with hexane for several times
and then dry to give (14) which was used further step without
purification. Yield (389 mg, 95%); H NMR (400 MHz, CDCl ): δ
7
4
1
7
8
R. W. Owen, A. Giacosa, W. E. Hull, R. Haubner, G. Wartele,
B. Spiegelhalder and H. Bartsch, Lanc. Oncol. 2000, 1, 107.
E. Tripoli, M. Giammanco, G. Tabacchi, D. Di Majo, S.
Giammanco and M. La Guardia, Nutr. Res. Rev., 2005, 18, 98.
W. R. Fredrickson, U.S. Patent., 2000, 117, 884.
0 S. Lee-Huang, P. L. Huang, D. Zhang, J. W. Lee, J. Bao, Y. Sun,
Y.-T. Chang, J. Zhang and P. L. Huang, Biochem. Biophys. Res.
Commun., 2007, 354, 879.
1
9
1
3
.78 (s, 1H), 5.83 (q, J = 6.8 Hz, 1H), 4.42 (d, J = 11.7 Hz, 1H),
.37 (d, J = 11.9 Hz, 1H), 4.15 (d, J = 9.6 Hz, 1H), 2.95 (dd, J =
6.4 Hz, 9.6 Hz, 1H), 2.73 (d, J = 16 Hz, 1H), 2.04 (s, 3H), 1.81
1
1 (a) W. Li, J. B. Sperry, A. Crowe, J. Q. Trojanowski, A. B. Smith
III and V. M. Y. Lee, J. Neurochem., 2009, 110, 1339; (b) M. C.
Monti, L. Margarucci, A. Tosco, R. Riccio and A. Casapullo,
Food Funct., 2011, 2, 423; (c) M. C. Monti, L. Margarucci, R.
Riccio and A. Casapullo, J. Nat. Prod., 2012, 75, 1584–1588.
2 (a) F. Ding, R. William, S. M. Kock, M. Leow and X.-W. Liu,
Chem. Commun., 2015, 51, 4639; (b) F. Ding, M. Leow, J. Ma,
(d, J = 6.8 Hz, 3H).
(R,E)-Methyl-4-(1-acetoxybut-2-en-2-yl)-2-oxo-3,4-dihydro-
2
H-pyran-5-carboxylate (15):
To a stirred solution of crude (14) (200 mg, 0.78 mmol) in
dichloromethane (5 mL) at 0 C, Trimethylsilyldiazomethane
0.39 mL 2M solution in hexane, 0.86 mmol, 1.1 equiv,) was
1
°
(
R. William, H. Liao and X.-W. Liu, Chem. Asian J., 2014, 9,
added slowly and the reaction mixture stirred for another 2 h
at room temperature. Quench the reaction mixture with
saturated solution of sodium bicarbonate (10 mL) and extract
with dicholormethane (3X20 mL). The combined organic layer
was dried and purified by flash column chromatography (15%
Ethylacetate and Hexane) to obtain 15 as a viscous liquid. Yield
2548; (c) J. Zeng, Y. J. Tan, J. Ma, M. L. Leow, D. Tirtorahardjo
and X.-W. Liu, Chem. Eur. J., 2014, 20, 405; (d) F. Ding, R.
William, M. L. Leow, H. Chai, J. Z. M. ong and X.-W. Liu, Org.
Lett., 2014, 16, 26; (e) R. Lorpitthaya, S. B. Suryawanshi, S.
Wang, K. K. Pasunooti, S. Cai, J. Ma and X.-W. Liu, Angew.
Chem. Int. Ed., 2011, 50, 12054; (f) S. Vedachalam, B.-H.
Choi, K. K. Pasunooti, K. M. Ching, K. Lee, H. S. Yoon and X.-
21
1
W. Liu, Med. Chem. Commun., 2011,
William, F. Wang, J. Ma, L. Ji and X.-W. Liu, Org. Lett., 2011,
, 652; (h) J. Zeng, S. Vedachalam, S. Xiang and X.-W.Liu,
2, 371; (g) F. Ding, R.
(
181 mg, 86%) [α] = +26.1 (c = 1.1, CHCl3); H NMR (400
D
MHz, CDCl ): δ 7.68 (s, 1H), 5.82 (q, J = 6.8 Hz, 1H), 4.40 (d, J =
3
1
3
1
3
2.4 Hz, 1H), 4.34 (d, J = 12 Hz, 1H), 4.17 (d, J = 9.2 Hz, 1H),
.77 (s, 3H), 2.92 (dd, J = 16.8 Hz, 9.6 Hz, 1H), 2.71 (dd, J = 16.6
Org. Lett., 2011, 13, 42; (i) J. Ma, Y. Zhao, S. Ng, J. Zhang, J.
Zeng, A. Than, P. Chen and X.-W. Liu, Chem. Eur. J., 2010, 16
,
Hz, 1.2 Hz, 1H), 2.03 (s, 3H), 1.82 (dd, J = 7.2 Hz, 1.2 Hz, 3H);
4533.
13
1
3 (a) B. M. Trost, C. D. Shuey and F. DiNinno, J. Am. Chem. Soc.,
C NMR (100 MHz, CDCl ): δ 170.7, 165.5, 165.3, 151.5, 133.8,
3
1
979, 101, 1284; (b) B. D. Roth, C. J. Blankley, A. W.
1
30.8, 111.2, 67.8, 52.0, 34.1, 30.1, 20.8, 13.3; HRMS (ESI) m/z
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New Journal of Chemistry
View Article Online
DOI: 10.1039/C7NJ04057A
Table of Content:
NHC catalyzed enantioselective Coates-Claisen rearrangement : A rapid
access to the dihydropyran core for Oleuropein based Secoiridoids
a
a
a
a
b
Seenuvasan Vedachalam,* Nithya Murugesh, Priyanka Chakraborty, Ramasamy Karvembu and Xue-Wei Liu *
A simple protocol for the synthesis of dihydropyran core structure of Secoiridoid using NHC catalyzed Coates-Claisen rearrangement is
described. Further functional group conversion was carried out to generate monoterpene elenolide core structure