Stereoselective synthesis of substituted oxocene cores by Lewis acid promoted cyclization

Article abstract of DOI:10.1021/acs.orglett.5b03411

Substituted oxocene derivatives have been synthesized by Lewis acid catalyzed reactions of ε-hydroxyalkene and substituted aromatic aldehydes. The Cu(OTf)₂-bis-phosphine catalyzed reaction typically provides substituted dihydropyran derivatives through an olefin migration followed by a Prins cyclization. The corresponding reaction catalyzed by TMSOTf or BF₃·OEt₂ provided eight-membered cyclic ethers (oxocenes), selectively. This methodology provides convenient access to a variety of 2,4,8-trisubstituted oxocenes in good yields and excellent diastereoselectivities.

Full text of DOI:10.1021/acs.orglett.5b03411

Letter
pubs.acs.org/OrgLett
Stereoselective Synthesis of Substituted Oxocene Cores by Lewis
Acid Promoted Cyclization
Arun K. Ghosh,* Anthony J. Tomaine, and Kelsey E. Cantwell
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana
47907, United States
S
* Supporting Information
ABSTRACT: Substituted oxocene derivatives have been
synthesized by Lewis acid catalyzed reactions of ε-hydrox-
yalkene and substituted aromatic aldehydes. The Cu(OTf)2-
bis-phosphine catalyzed reaction typically provides substituted
dihydropyran derivatives through an olefin migration followed
by a Prins cyclization. The corresponding reaction catalyzed by
TMSOTf or BF3·OEt2 provided eight-membered cyclic ethers (oxocenes), selectively. This methodology provides convenient
access to a variety of 2,4,8-trisubstituted oxocenes in good yields and excellent diastereoselectivities.
ubstituted medium-sized cyclic ethers, particularly eight-
membered oxocane and oxocene derivatives, are structural
Cu(OTf)2 and bis-phosphine complex provided the olefin
migration and Prins cyclization product 5 (55% yield) along
with a small amount of eight-membered cyclic ether 6 (11%
yield, Scheme 1).18,19 Presumably, the 2,8-substituents in 6 are in
S
features in a variety of bioactive natural products.1,2 This includes
lauthisan (1, Figure 1), helianane (2), laurencin (3), and
Scheme 1. Formation of THP and Oxocene Products
Figure 1. Structures of oxacyclic natural products.
others.3−6 As a result, stereoselective synthesis of these medium-
sized oxocyclic rings has been the subject of much interest over
the years.7 Unlike six-membered ring compounds, construction
of eight-membered rings from acyclic precursors is problematic
due to factors related to entropy, as well as developing
transannular and torsional strains.8,9 A number of methods
including cycloadditions,10 ring expansions,11,12 ring-closing
metathesis,13,14 and intramolecular acetal−alkene cycliza-
tions15,16 have been developed. A number of these methods
were utilized in the synthesis of bioactive molecules.7 A majority
of these synthetic approaches, however, involve intramolecular
reactions, especially in the case of the synthesis of oxocene core
structures.
a cis-relationship, as depicted, and the oxocene product was
formed by a nucleophilic attack of the olefin onto the
oxocarbenium ion 7, followed by elimination.
In an effort to access substituted oxocene derivatives, we
investigated this reaction with a variety of Lewis acids and
reaction conditions. Herein, we report the results of our
investigations leading to the synthesis of 2,4,8-trisubstituted
oxocenes in a highly diastereoselective manner. We initially
investigated the Lewis acid catalyzed cyclization using 6-
methylhept-6-en-2-ol (4) and p-nitrobenzaldehyde as the
model substrates, as shown in Scheme 2. The use of 10 mol %
of Sc(OTf)3 as the Lewis acid in CH2Cl2, in the presence of p-
TsOH and 4 Å molecular sieves at 23 °C, resulted in
tetrahydropyran derivative 8 as the major product and oxocene
An intermolecular reductive cyclization leading to oxocene
cores was reported by Solladie and co-workers.17 We recently
reported that the reaction of substituted alkenol 4 with
benzyloxyacetaldehyde in the presence of a catalytic amount of
Received: November 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03411
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Organic Letters
Letter
number of solvent systems.21 As it turns out, 1 equiv of TMSOTf
in a variety of solvents afforded cyclization product oxocene 9a as
the major product. The choice of diethyl ether in the presence of
molecular sieves at 0 °C for 15 min provided oxocene 9a in 60%
yield (entry 6). The presence of 4 Å molecular sieves did not
improve the yield of oxocene product, but it did improve the
endo/exo ratio (entries 5 and 6). The use of toluene resulted in a
lower endo/exo ratio. The reaction in DME provided a
comparable yield; however, cyclization products were obtained
in an 81:19 ratio (entry 8). These ratios were determined on the
basis of 1H NMR analysis of the benzylic protons, as the products
could not be separated by silica gel chromatography. This Prins-
type cyclization provided the best result when THF was used as
the solvent in the presence of 4 Å molecular sieves. As shown,
oxocene product 9a was obtained essentially as a single product
(mixture ratio 98:2) in 73% isolated yield (entry 9). The reaction
in a mixture of CH2Cl2 and THF also provided comparable yields
and mixture ratios (entries 10 and 11). The use of TMSOTf in t-
BuOMe provided a 46% yield (88:12) of oxocene product 9a
(entry 12).
Scheme 2. Formation of Oxocene Products
We then examined the substrate scope of this intermolecular
process. As shown in Table 2, a variety of alkyl substituents on
derivative 9a as the minor product in 36% combined yield. The
ratios of products (9a:8) were 9:91 by 1H NMR analysis.
With the aim of forming oxocene 9a as the major product
directly, we explored a number of oxophilic Lewis acids for this
cyclization. Overman and co-workers reported efficient con-
struction of medium-sized ring ethers by an intramolecular Prins-
type reaction of mixed acetals using BF3·OEt2 as the Lewis acid in
t-BuOMe.20 We first examined the reaction of alkenol 4 with p-
nitrobenzaldehyde using a catalytic amount of BF3·OEt2 in
CH2Cl2. As it turns out, BF3·OEt2-catalyzed cyclization provided
mainly oxocene product 9a. We have not been able to identify
a
Table 2. TMSOTf-Catalyzed Synthesis of Oxocenes
b
c
entry
R
R1
compd
ratio (9:10)
yield (%)
1
H
p-NO2Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
m-NO2Ph
o-NO2Ph
p-FPh
9b
9c
9d
9e
9a
9f
90:10
90:10
91:9
91:9
98:2
91:9
97:3
90:10
92:8
93:7
94:6
98:2
92:8
94:6
70
87
62
39
73
65
58
20
37
18
35
24
8
2
Et
3
i-Pr
Ph
1
any 6-membered Prins product 8 by H NMR analysis of the
4
crude products. The trace amount of minor product appeared to
be the exo-olefin product. As shown in Table 1, a catalytic amount
(20 mol %) of BF3·OEt2 in CH2Cl2 provided a 38% yield of
oxocene product 9a as the major product (entry 2). The use of 40
mol % of BF3·OEt2 resulted in a lower yield of oxocene
cyclization product 9a (entry 3). The use of BF3·OEt2 (3 equiv)
in t-BuOMe provided a 33% yield of oxocene product 9a (entry
4). To further improve yields, we then explored TMSOTf in a
5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
6
7
9g
9h
9i
8
9
p-CF3Ph
p-ClPh
10
11
12
13
14
15
9j
Ph(CH2)2
CH2OBn
m-MePh
2-naphth
p-F-m-NO2Ph
9k
6
9l
a
Table 1. BF3·OEt2- and TMSOTf-Catalyzed Reactions
9m
9n
16
41
91:9
yield
(%)
ratio
9a:10a
b
a
b
entry solvent
Lewis acid equiv
Reaction conditions are from entry 8, Table 1. The endo/exo ratio
c
1
c
was determined by H NMR. Isolated yield of combined products.
1
2
3
4
5
6
7
8
9
CH2Cl2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
0.1
0.2
0.4
3.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
14
38
21
33
60
60
98:2
98:2
98:2
76:24
95:5
98:2
c
c
c
c
CH2Cl2
CH2Cl2
the alkyl group of the alkenol substrate were accommodated
(entries 1−4). The structures of the major endo-products are
shown in Figure 2. The electron-withdrawing nitro group on the
ortho, meta, or para position of the benzene ring of the
benzaldehyde provided a good yield of oxocene product and
excellent endo/exo ratios (entries 5−7). Incorporation of p-F, p-
CF3, or p-Cl groups provided moderate yields of oxocene
derivatives, and the endo/exo ratio decreased at the same time
(entries 8−10). The reaction with dihydrocinnamaldehyde
afforded 35% yield of oxocene derivative 9k, and the endo/exo
olefin ratio was 94:6 (entry 11). Also, reaction with
benzyloxyacetaldehyde provided oxocene derivative 6 in 24%
yield (entry 12). However, 3-(4-methoxybenzyloxy)propanal
and 3-(tert-butyldimethylsilyloxy)propanal failed to provide any
oxocene product. The reaction with m-methyl- or 2-naphthalde-
t-BuOMe
Et2O
Et2O
d
toluene
68:32
DME
58
73
68
68
46
81:19
98:2
THF
10
11
12
CH2Cl2−THF (1:1)
CH2Cl2−THF (3:1)
t-BuOMe
98:2
98:2
88:12
a
Conditions: 1 equiv of 6-methylhept-6-en-2-ol, 1.2 equiv of p-
nitrobenzaldehyde, 0.1 M solution, 0 °C, 60 mg of molecular sieves,
b
c
ratio is endo/exo. equiv = equivalent of Lewis acid. No molecular
d
sieves were used. No purification was conducted because the crude
ratio was low.
B
DOI: 10.1021/acs.orglett.5b03411
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Organic Letters
Letter
Scheme 3. Preparation of exo-Oxocene Isomer 10f
Figure 2. Structure of major isomer.
a
Scheme 4. Synthesis and X-ray Structure of 13
hyde provided only 8% and 16% yields of the corresponding
oxocene derivatives, respectively (entries 13 and 14). The
reaction with 4-fluoro-3-nitrobenzaldehyde resulted in reduction
of yield over the 3-nitrobenzaldehyde (entry 15). This condition
was also utilized in the preparation of nearly 0.5 g quantity of
oxocene derivative 9f.22
Separation of endo and exo isomers proved difficult by silica
gel chromatography or via HPLC methods. In order to confirm
the identity of the exo derivative, we exposed the mixture of
products from entry 6 (Table 2) to ozonolytic cleavage at −78 °C
in a mixture (1:1) of methanol and CH2Cl2 (Scheme 3). The
resulting products were separated by silica gel chromatography.
Ketone 12 was then subjected to Wittig olefination with
methylene triphenylphosphorane to provide pure exo-olefin
derivative 10f. The 1H NMR and 13C NMR of 10f obtained in
this manner matched completely with the minor product in the
spectra containing the mixtures.
To determine the X-ray crystal structure, the main product 9a
(entry 6) was subjected to reduction with Zn dust in acetic acid as
shown in Scheme 4.23 The resulting aromatic amine was reacted
with p-bromobenzenesulfonyl chloride in the presence of
aqueous sodium bicarbonate solution to provide sulfonamide
derivative 13. This was recrystallized from ether/pentane at 23
°C for 48 h. The single-crystal X-ray analysis (Scheme 4) further
supports the assignment of cis-stereochemistry.24,25
a
White = hydrogen, black = carbon, red = oxygen, blue = nitrogen,
yellow = sulfur, brown = bromine.
As shown in Table 2, the endo-olefin product was typically the
major isomer observed by H and 13C NMR analysis. The
1
stereochemical assignment of these compounds was carried out
by 1H NMR NOESY experiments of compound 9a (Figure 3).
The depicted conformation is chosen on the basis of the X-ray
crystal structure. The observed strong NOESY correlation
between HE and HD provided evidence of the assigned cis-
relationship between the alkyl and aromatic ring in 9a. Additional
NOESY correlations between HE−HC, HC−HL, HD−HJ, HJ−
HH, and HF−HG are due to a preferred conformation of the eight-
membered oxocene ring.26
Figure 3. 1H NMR NOESY of compound 9a.
The stereochemical outcome of the current Prins-type
cyclization, which provided cis-oxocene derivatives, can be
C
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Organic Letters
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4. The TMSOTf-catalyzed reactions of alkenol 4 and an aromatic
aldehyde would lead to the formation of oxocarbenium ion
intermediates 14a and 14b.
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Figure 4. Stereochemical analysis for cis-oxocene products.
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Subsequent cyclization followed by proton elimination is
unlikely to proceed through transiton state 14b as it shows
unfavorable steric interactions. The cyclization is likely to
proceed through transition state 14a leading to cis-product 15a.
The formation of trans-product 15b was not observed.
In summary, we have developed an unprecedented TMSOTf-
catalyzed intermolecular Prins-type cyclization for the synthesis
of a variety of oxocene derivatives. The use of various 1-alkyl-5-
methylhex-5-en-l-ol and an appropriate aromatic aldehyde
afforded a range of oxocene endo-olefin derivatives. A stereo-
chemical model also provided explanation for the selective
formation of 2,8-cis-oxocene derivatives in up to 87% yields and
excellent diastereoselectivity for disubstituted derivatives.
Mechanistic studies and application of these substituted oxocene
derivatives are in progress in our laboratory.
(21) Ullapu, P. R.; Kim, Y. S.; Lee, J. K.; Pae, A. N.; Kim, Y.; Min, S.-J.;
Cho, Y. S. Chem. - Asian J. 2011, 6, 2092−2100.
(22) For experimental details, see the Supporting Information.
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Encyclopedia of Industrial Chemistry; John Wiley & Sons: New York,
2007.
(24) Single-crystal X-ray analysis was performed in our X-ray
crystallography laboratory by Dr. Phil Fanwick, Department of
Chemistry, Purdue University, West Lafayette, IN.
(25) CCDC 1437986 contains the supplementary crystallographic
data for compound 13. This data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(26) Rhee, H. J.; Beom, H. Y.; Kim, H.-D. Tetrahedron Lett. 2004, 45,
8019−8022.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03411.
Experimental procedures and 1H and 13C NMR spectra for
all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: akghosh@purdue.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the National Institutes of Health is
gratefully acknowledged. We thank Dr. Jorden Kass (Purdue
University) for preliminary experimental assistance.
REFERENCES
(1) Majumdar, K. C. RSC Adv. 2011, 1, 1152−1170.
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DOI: 10.1021/acs.orglett.5b03411
Org. Lett. XXXX, XXX, XXX−XXX