Lewis Acid Catalyzed [3+3] Annulation of Donor–Acceptor Cyclopropanes with γ-Hydroxyenones: Access to Highly Functionalized Tetrahydropyrans

Article abstract of DOI:10.1002/ejoc.201601305

Donor–acceptor cyclopropanes were engaged in a [3+3]-annulation reaction with γ-hydroxyenones. Sc(OTf)₃was found to be the best catalyst, and 2,4,4,5-tetrasubstituted tetrahydropyran products were obtained in good yields under mild reaction con

Full text of DOI:10.1002/ejoc.201601305

A Journal of
Accepted Article
Title: Lewis Acid Catalyzed [3 + 3]-Annulation of Donor-Acceptor
Cyclopropanes with γ-Hydroxyenones: Access to Highly
Functionalized Tetrahydropyrans
Authors: Subhas Chandra Pan and Keshab Mondal
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601305
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601305
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10.1002/ejoc.201601305
European Journal of Organic Chemistry
COMMUNICATION
Lewis Acid Catalyzed [3 + 3]-Annulation of Donor-Acceptor
Cyclopropanes with γ-Hydroxyenones: Access to Highly
Functionalized Tetrahydropyrans
Keshab Mondal and Subhas Chandra Pan*[a]
Dedication ((optional))
Abstract: Donor-acceptor cyclopropanes are engaged in [3 + 3]
annulation reaction with γ-hydroxyenones. Sc(OTf)3 was found to be
have been engaged in this important transformation. However,
literature analysis reveals only one report of the tetrahydropyran
ring formation using DA cyclopropanes as disclosed by Kerr group
utilizing propargylic alcohols (Scheme 1).[10h] To date, allylic
alcohols have never been used in the reaction with DA
cyclopropanes. We envisioned that γ-hydroxyenones could be
suitable as 1,3 conjunctive reagent which can undergo tandem
nucleophilic addition–Michael reaction. Realizing the importance
of highly functionalized tetrahydropyran ring in natural products
and other compounds, we wish to report an easy synthesis of
2,4,4,5-tetrasubstituted tetrahydropyran rings having two
stereogenic centres employing γ-hydroxyenones and DA
cyclopropanes (Scheme 1).
the best catalyst and
2,4,4,5-tetrasubstituted tetrahydropyran
products are obtained in good yields under mild reaction conditions.
The generality of the reaction permitted the synthesis of
tetrasubstituted tetrahydropyrans bearing aryl, alkyl and
heteroaromatic groups. The catalytic asymmetric variant of this
process was also studied preliminary with chiral PyBOX ligand.
Tetrahydropyran ring is an important structural motif present in a
wide range of natural products such as antibiotics, pheromones
and marine toxins.[1] Also tetrahydropyran moiety is prevalent in
many carbohydrates as well as in their oligomers and polymers
which play vital role in living organisms.[2] Due to the impressive
biological activities, enormous emphasis has been put for the
efficient construction of a variety of tetrahydropyrans.[3] The
processes include the Prins cyclizations,[4] the hetero-Diels-Alder
cyclizations,[5] ring opening of epoxides,[6] radical cyclizations,[7]
oxa-Michael additions[8] and many others. Given the diversity of
tetrahydropyran units in natural products and in other compounds,
new methods are still required for proficient synthesis of
substituted tetrahydropyrans from easily available starting
materials.
Previous work: with propargylic alcoholos
CO2Me
MeO2C
R
Lewis acid (cat)
base (cat)
R
OH
CO2Me
CO2Me
+
O
Kerr et al.
2-stereogenic
This work: with allylic alcohols
CO2Me
MeO2C
O
R1
R2
O
CO2Me
CO2Me
Lewis acid (cat)
OH
R1
+
O
R2
In the last decade, donor-acceptor cyclopropanes (DA
cyclopropane) have served as important synthetic intermediate in
organic chemistry and a wide range of annulation reactions have
been developed.[9] Among the [3 + n] annulation reactions, [3 + 3]
annulation reaction affords quick access to valuable six
membered rings.[10], [11] For this purpose a stable 1,3-zwitterions
or substrate that can produce dipolar species is required which
can react with in situ generated reactive 1,3 dipole from DA
cyclopropane. Since the initial work of Kerr in 2003 on [3 + 3]
annulation reaction with nitrones, a variety of [3 + 3] annulation
reactions have been reported with DA cyclopropanes. Besides
nitrones, other 1,3 dipoles such as azides, azomethine imines,
nitrile imines, indole derivatives, mercaptoacetaldehydes etc.
2,5-stereogenic
(major)
Scheme 1. Tetrahydropyran synthesis using donor-acceptor cyclopropanes.
We initiated our investigation by performing a model reaction
between 3-benzoylprop-2-en-1-ol (1a) and dimethyl 2-p-
tolylcyclopropane 1,1-dicarboxylate (2a) in CH2Cl2 at 35 oC (Table
1). However, only trace amount of [3 + 3] annulation product was
observed with Lewis acids such as Cu(OTf)2, Zn(OTf)2, SnCl2,
BF3.Et2O, MgBr2, Sn(OTf)2, TiCl4. Interestingly Yb(OTf)3 provided
50% combined yield of the [3 + 3] annulation products 3a (cis) and
3a' (trans) which were obtained in 2:1 diastereomeric ratio (entry
1). The relative structures of 3a and 3a' were determined by 2D
NMR studies. Gratifyingly, the yield was further enhanced to 85%
with Sc(OTf)3 and identical diastereomeric ratio was observed
(entry 2).Though other halogenated solvent such as DCE
afforded decent yield of the products (entry 3), moderate yield
were obtained with CHCl3 (entry 4). Also, good yields were
observed with toluene, CH3CN and THF (entries 5-7). Other
solvents such as DMF, MeOH and 1,4-dioxane provided only
traces of the desired products. Then we focused on decreasing
the catalyst loading of Sc(OTf)3 to 10 mol% and 5 mol% in CH2Cl2
but only less yields were detected (entries 8-9).
[a]
K. Mondal, Prof. Dr. S. C. Pan
Department of Chemistry
Indian Institute of Technology Guwahati
Assam, 781039, India
E-mail: span@iitg.ernet.in
[b]
This work is supported by Science and Engineering Research Board
(SERB) (Grant No. EMR/2015/001034) of the Department of
Science and Technology (DST), India. We thank CIF of Indian
Institute of Technology Guwahati for the instrumental facility.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Table 1: Catalyst Screening and Optimization of Reaction Conditions
Table 2: Scope of Tetrahydropyran with Different γ-Hydroxyenones
Me
Me
CO2Me
Ar
MeO2C
Lewis acid
(20 mol%)
CO2Me
Ar
MeO2C
O
Ph
O
Sc(OTf)3
(20 mol%)
R
CO2Me
CO2Me
O
CO2Me
CO2Me
OH
O
+
Ph
OH
O
+
solvent, 35 o
24h
C
R
O
CH2Cl2, 35 o
C
Ar = 4-MeC6H4
3a: cis, 3a': trans
1a
2a
Ar = 4-MeC6H4
3a-k: cis, 3a'-k': trans
1a-k
2a
Entry[a]
Catalyst
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Solvent
Yield[b]
50
dr[c]
2:1
Entry[a]
R
3
Time (h)
24
Yield[b]
dr[c]
1
CH2Cl2
CH2Cl2
(CH2Cl)2
CHCl3
1
Ph
3a/3a’
3b/3b’
3c/3c’
3d/3d’
3e/3e’
3f/3f’
3g/3g’
3h/3h’
3i/3i’
85
93
64
65
61
79
71
83
59
72
48
2:1
2
85
2:1
2
4-OMeC6H4
4-MeC6H4
4-FC6H4
24
2.2:1
2.4:1
2:1
3
80
1.8:1
2:1
3
36
4
54
4
24
5
toluene
CH3CN
THF
74
1.7:1
2.1:1
2:1
5
4-ClC6H4
16
1.9:1
1.6:1
1.8:1
1.6:1
2.1:1
1.5:1
1.1:1
6
71
6
4-BrC6H4
24
7
73
7
3-MeC6H4
3-ClC6H4
36
8[d]
9[e]
CH2Cl2
CH2Cl2
75
2:1
8
24
45
2:1
9
2-MeC6H4
1-naphthyl
Hydrocinnamyl
40
[a] Reaction conditions: Unless otherwise mentioned 0.1 mmol of 1a and 0.2
mmol of 2a in 0.5 mL solvent using 20 mol% catalyst at 35 oC for 24h. [b] Isolated
yield after silica gel column chromatography. [c]Determined by 1H NMR. [d] With
10 mol% catalyst. [e] With 5 mol% catalyst.
10
11
3j/3j’
24
3k/3k’
16
[a] Reaction was carried out with 20 mol% of Sc(OTf)3 in CH2Cl2 at 35 oC. [b]
The combined yields reported are isolated after silica gel column
chromatography. [c] Determined by 1H NMR.
After identifying the optimized conditions, the scope of the
reaction was studied. Initially, a variety of γ-hydroxyenones 1 was
examined with cyclopropane 1,1-diester 2a (Table 2). Pleasingly,
different electron-withdrawing and electron-donating groups can
be embedded in the ortho-, meta- and para-position of the aryl
group. An excellent yield of 93% was achieved for the
diastereomeric products 3b/3b' having p-anisyl group (Table 2,
entry 2). Enone 1c having p-tolyl motif provided the corresponding
products in relatively less yields (entry 3). 4-Halo substituted aryl
groups containing enones were also screened and the products
were attained in acceptable yields (entries 4-6). Next different
meta-substitutions were explored and the products were similarly
obtained in good yields with comparable diastereoselectivities
(entries 7-8). O-Substitution of the aryl group was also tolerated
and products 3i/3i' were obtained in 59% combined yield (entry
9). 1-Naphthyl group containing enone 1j could also be employed
in our reaction condition delivering products 3j/3j' in 72% yield
(entry 10). To our delight, the methodology is also suitable for
aliphatic enone such as employment of the hydrocinnamyl
substituted enone 1k resulted in the formation of the products
3k/3k' albeit less yields were observed (entry 11). Unfortunately,
other aliphatic substituted enones (cyclohexyl, tbutyl etc.) did not
deliver product under the reaction condition.
(Table 3). Though a variety of substitutions on the aryl group was
tolerated but traces of products were obtained with electron poor
aryl groups. Thus we thought to synthesize a range of
cyclopropane 1,1-diesters bearing electron-rich aryl and
heteroaromatic groups. Phenyl containing cyclopropane 1,1-
diester 2b delivered products 3l/3l' in 40 % yield (entry 1) but
pleasingly higher yield of 70% was achieved for products 3m/3m'
having p-anisyl substituent in short time (entry 2). Moderate yield
was attained with 2d having p-ethoxyphenyl substituent after 3h
as running the reaction for longer time resulted in undesired side
products (entry 3). Similarly, m-tolylsubstituted diester 2e
underwent the reaction delivering the product 3o/3o' in less yield
due to side product formation though the outcome was better with
o-anisylsubstituted diester 2f (entries 4-5). Gratifyingly, 2-
naphthylsubstituted diester 2g could also be employed in our
reaction albeit lower yield was observed (entry 6). Finally, a
heteroaromatic thiopene containing diester 2h was engaged in
the reaction and decent yield of 79% was attained in a short
reaction time with a higher diastereomeric ratio (entry 7).
Afterward we focused on the possibility for the asymmetric version
of this reaction (Scheme 2).[12] Accordingly 1a was treated with
The next phase of attention was to enhance the generality of the
reaction by incorporating a range of cyclopropane 1,1-diesters.
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10.1002/ejoc.201601305
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COMMUNICATION
Table 3: Scope of Tetrahydropyran with Different Cyclopropane 1,1-diesters
4/4' were isolated in 74% yield with 2.7:1 diastereomeric ratio. The
structure of the major diastereomer 4 was determined by 2D NMR
studies. Similarly sodium borohydride reduction was performed
CO2Me
MeO2C
Sc(OTf)3
Ph
(20 mol%)
o
Ar
O
on 3a in methanol solvent at 0 C. Interestingly, besides normal
CO2Me
CO2Me
OH
O
+
alcohol products 5/5', a lactol 6 was also formed in 2:1 ratio. The
structure of lactol 6 was unamiguously confirmed by X-ray
crystallography.[13] Presumably lactol 6 is formed from a lactone
and thus it is an unusual reduction by sodium borohydride since
sodium borohydride generally does not reduce lactones.
Ph
O
Ar
CH2Cl2, 35 o
C
1a
2
3l-r: cis, 3l'-r': trans
Entry[a]
Ar
Ph
3
Time (h)
Yield[b]
40
dr[c]
CO2Me
O
CO2Me
1
2
3
4
5
6
7
3l/3l’
16
7
2:1
MeO2C
O
Ph
Ph
LiCl (3 eq)
4-OMeC6H4
4-OEtC6H4
3-MeC6H4
2-OMeC6H4
2-naphthyl
2-thienyl
3m/3m’
3n/3n’
3o/3o’
3p/3p’
3q/3q’
3r/3r’
70
43
36
68
25
79
1.7:1
1.9:1
1.8:1
1:1.3
1.8:1
3.5:1
O
O
DMSO/H2O
110 oC, 48h
3
Me
4 (major)
3a
Me
74% combined yield
2.7:1 dr
24
14
20
4
NaBH4 (2 eq)
MeOH
0 oC-RT, 8h
60% yield
Ph
O
OH
CO2Me
MeO2C
OH
CO2Me
Ph
+
O
O
[a] Reaction was carried out with 20 mol% of Sc(OTf)3 in CH2Cl2 at 35 oC. [b]
The combined yields reported are isolated after silica gel column
chromatography. [c] Determined by 1H NMR.
6
5/5'
Me
Me
(2:1)
(X-ray)
Scheme 3. Synthetic Transformations of the Products.
cyclopropane diester 2a in the presence of catalytic amounts of
different chiral ligands and Sc(OTf)3. BINOL and t-leucine derived
BOX catalyst L1 provided the product in very poor
enantioselectivities (<5% ee). However, gratifyingly, we found that
promising result could be attained using PyBOX catalyst L2. With
20 mol% L2 and 20 mol% Sc(OTf)3, the major diastereomer was
obtained with 49% ee (minor 36% ee) in 40% overall yield
(Scheme 2).
In summary, we have developed an interesting [3 + 3]-annulation
reaction between γ-hydroxyenones and cyclopropane 1,1-
diesters catalyzed by commercially available Sc(OTf)3.
Preliminary experiment for the catalytic asymmetric variant has
been performed with a PyBOX ligand and 49% ee was achieved
for the major cis diastereomer. The tetrahydropyran products
having two stereogenic centres are significant in pharmaceuticals
and for natural product synthesis. Further developments of
related [3 + 3]-annulation reactions as well as for a more
enantioselective version of the current process are in progress in
our laboratory.
Sc(OTf)3
(20 mol%)
Ligand
Me
CO2Me
MeO2C
O
Ph
O
CO2Me
CO2Me
(20 mol%)
OH
+
Ph
O
Ar
CH2Cl2, RT
5d
Ar = 4-MeC6H4
1a
2a
.
O
O
O
O
N
OH
OH
N
N
N
N
Experimental Section
CMe3
Me3C
L2
L1
General procedure for the formation of 3: Under argon atmosphere,
compound 1 (0.1 mmol), cyclopropyl diester (2) (0.2 mmol) and catalyst
Sc(OTf)3 (20 mol%) were placed in a 10 mL round bottom flask and 0.5
mL DCM solvent was added to it. Then the reaction mixture was stirred at
35% yield
40% yield
20% yield
3a:3a' = 2:1
ee (3a) = 49%
ee (3a') = 36%
3a:3a' = 2:1
ee (3a) = 5%
3a:3a' = 2:1
ee (3a) = 0%
o
35 C. After the reaction was completed monitored by TLC, the reaction
mixture was directly subjected to silica gel column chromatography using
10% EtOAc/hexane as an eluent to obtain the desired product.
Scheme 2. Asymmetric version of the Method.
Further, to demonstrate the synthetic utility of our method, we
Acknowledgements ((optional))
carried out few reactions on our products (Scheme 3). Purified cis
o
3a was thus treated with LiCl in DMSO/H2O at 110 C. To our
Acknowledgements Text.
delight, the desired 2,4,5-trisubstituted tetrahydropyran products
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10.1002/ejoc.201601305
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COMMUNICATION
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Keywords: cyclopropane diester• γ-hydroxyenones •Lewis acid•
tetrahydropyran • enantioselectivity
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[7]
[8]
[9]
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[13] CCDC 1487919 contains the crystallographic data for 6 (available also
in Supporting Information). The data can be obtained from the
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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COMMUNICATION
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COMMUNICATION
CO2Me
MeO2C
Keshab Mondal, Subhas Chandra Pan*
Sc(OTf)3
R
Ar
O
Chiral version:
49% ee for major diastereomer
(20 mol%)
CO2Me
CO2Me
OH
O
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R
O
Ar
CH2Cl2, 35 o
C
up to 93% yield
up to 3.5:1 dr
R = Ar, Alk
Lewis Acid Catalyzed [3 + 3]-
Annulation of Donor-Acceptor
Cyclopropanes with γ-
18 examples
Hydroxyenones: Access to Highly
Functionalized Tetrahydropyrans
A highly efficient [3 +3] annulation reaction has been developed between donor-
acceptor cyclopropanes and γ-hydroxyenones using scandium triflate as the
catalyst. Biologically important 2,4,4,5-tetrasubstituted tetrahydropyran products
were obtained in high yields with moderate to good diastereomeric ratios. An
asymmetric version has also been reported and moderate enantiomeric excess has
been achieved.
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