Polymer supported synthesis of a natural product-inspired oxepane library

Article abstract of DOI:10.1016/j.bmc.2014.05.039

Natural product inspired compound collections are prevalidated due to the evolutionary selection of the natural product scaffolds. Their synthesis requires the development of novel strategies amenable to formats suitable for library build-up. We describe

Full text of DOI:10.1016/j.bmc.2014.05.039

Accepted Manuscript
Polymer Supported Synthesis of a Natural Product-Inspired Oxepane Library
Sudipta Basu, Herbert Waldmann
PII:
S0968-0896(14)00388-5
DOI:
http://dx.doi.org/10.1016/j.bmc.2014.05.039
BMC 11600
Reference:
Bioorganic & Medicinal Chemistry
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Accepted Date:
25 March 2014
14 May 2014
16 May 2014
Please cite this article as: Basu, S., Waldmann, H., Polymer Supported Synthesis of a Natural Product-Inspired
Oxepane Library, Bioorganic & Medicinal Chemistry (2014), doi: http://dx.doi.org/10.1016/j.bmc.2014.05.039
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Polymer Supported Synthesis of a Natural Product-Inspired Oxepane
Library
Sudipta Basu and Herbert Waldmann*
* Prof. Dr. H. Waldmann, Dr. Sudipta Basu
Max-Planck-Institut für molekulare Physiologie,
Otto-Hahn Strasse 11, 44227 Dortmund (Germany) and
Technische Universität Dortmund, Fachbereich Chemische Biologie,
Otto-Hahn-Str. 6, 44227 Dortmund, Germany
Fax: (+49) 321-133-2499
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
Abstract
Natural product inspired compound collections are prevalidated due to the evolutionary
selection of the natural product scaffolds. Their synthesis requires the development of
novel strategies amenable to formats suitable for library build-up. We describe a method
for the synthesis of an oxepane library inspired by the core structure of oxepane natural
products endowed with multiple bioactivities. Core aspects of the strategy are the
establishment of a one-pot method employing different immobilized scavengers, the
employment of an enyne ring closing reaction and diversification by means of different
transformations, e. g. cycloadditions and cross-metathesis reactions. In total, a collection
of 115 oxepanes was obtained in 5-6-step reaction sequences.
1

Introduction
Biologically active natural products are a source of inspiration for the development of
compound libraries based on prevalidated scaffolds.1,2 In this context, the canonical
solution synthesis of compound libraries using solid supported reagents and scavengers is
a powerful technique for chemical biology and medicinal chemistry research. 2
The oxepane scaffold occurs widely in natural products with a broad range of interesting
biological activities (Figure 1). For instance, the Heliannual family contains benzoxepane
systems having allelopathic and phytotoxic activities,3 the sodwanone family, isolated
from marine organisms, contains dimeric keto oxepane scaffolds and shows activity
against human tumor cell lines.4 The halogenated marine toxins regioloxepane A and
isolaurepinnacin are representative memberes of the Laurencia-derived C15 acetogenins
containing α, α’-disubstituted oxepane rings.5 (+)-Zoapatanol is one of the numerous
diterpenoid oxepanes isolated from leaves of the Mexican plant Montanoa tomentosa.6
Tea prepared from extracts of the leaves has long been used as a contraceptive in ancient
time and recent studies indicate that zoapatanol metabolites might be responsible for the
antifertility activity.7 Due to the manifold biological activities of these compounds, their
underlying structural architectures may be regarded as biologically pre-validated and as
promising guiding scaffolds for natural product inspired compound library development.
In developing the concept of Biology Oriented Synthesis (BIOS)8, we have devised
synthesis methods that give efficient access to natural product inspired compound
collections.9 Among these, the oxepane scaffold had attracted our attention as well.9e
2

O
HO
O
O
HO
HO
H
H
OH
O
O
OH
Sodwanone S
OH
Heliannuol C
Heliannuol B
Allelopathic and Phytotoxic
Active aginst Human Tumor Cell Lines
OR1
HO
O
R
O
O
H
H
H
H
Br
Cl
Br
Cl
O
1
(+)-Regioloxepane A
Isolaurepinnacin
Marine Toxin
R = (CH ) C=CHCH -
3 2
, R = H, Zoapatanol
2
Antifertility activity
R = (CH3)2CHC(CH3)=CH-, R1 = H, Montanol
R = (CH3)2C(OH)CH=CH-, R1 = Ac, Tomentol
R = H2C=C(CH3)CH(CH3)CH2-, R1 = H, Tomentanol
Figure 1: Natural products having different biological activities containing oxepane scaffold.
Here we report in full detail the development of a practical and efficient polymer-
supported solution phase parallel synthetic route to a compound library focused on the
highly substituted oxepane scaffold. The key step of the method includes a ring-closing
enyne metathesis reaction.10
Results and discussion
The retrosynthetic analysis of the oxepane library 1 is shown in the Scheme 1. It was
planned to access the oxepane core 1 by ring-closing enyne metathesis from the open
chain precursors 2 as key transformation. The open chain enyne precursors 2, homoallyl
alcohols, can be obtained from the aldehydes 3, in diastereomerically pure form using the
asymmetric Brown allylation. Aldehydes 3 could be generated from the esters 4 by
controlled reduction. Intermediates 4 can be synthesized from the easily available
building blocks 5 and 6, which are the starting points of the synthetic route.
3

Asymmetric
Brown Allylation
Ring-closing
enyne metathesis
O
HO
R3
HO
R3
O
H
R2
R1
R2
R1
R2
R3
O
R1
O
1
3
2
Reduction
O
O
Coupling
HO
O
Br
O
O
+
R2
R2
R1
R3
R3
R1
5
6
4
Scheme 1: Retrosynthetic analysis of focused oxepane core 1.
Strategy for the synthesis of oxepane library 1
Keeping the retro-synthetic blue print in mind, the synthesis commenced by coupling of
the substituted propargyl alcohols 6 and the substituted α-bromo ethyl acetates 5 (Scheme
2). When the alcohols 6 were deprotonated using sodium hydride as base in THF at 0 oC
and coupled with 5, the ethers 4 were formed in 70-80 % yield depending on the building
blocks 5 and 6 used.11 The ethers 4 were purified by means of silica gel chromatography.
The ethyl ester in 4 was reduced in a controlled manner using diisobutyl
o
aluminiumhydride (DIBAL-H) in diethyl ether at -78 C for 20 minutes to afford the
aldehydes 3. Application of THF or CH2Cl2 for this reduction proved to be unsuitable
because in those solvents a 1:1 mixture of the desired aldehydes 3 and over reduced
alcohols were formed. The over reduced alcohols were removed by chromatography. All
attempts to oxidize the alcohols to the desired aldehydes 3 were unsuccessful due to
decomposition. The aldehydes 3 were then allylated using Brown’s asymmetric allylation
procedure.12 The chiral allyl borane reagent was prepared in situ by treating either (+)- or
(-)- B-chlorodiisopinocampheylborane (DIPCl) and allyl magnesium chloride at -78 oC to
room temperature. When either of (+)- or (-)- diisopinocampheylallyl borane (Ipc2B-
o
allyl) reagents was treated with aldehydes 3 in THF at -78 C, the homoallyl alcohols 2
were formed stereoselectively. As soon as the reaction was complete (determined by
4

TLC), the excess allylmagnesium chloride was scavenged using polystyrene supported
sulfonic acid resin 7 or the cation exchange sulfonic acid resin DOWEX® 50WX8-200
(8).13 The resin was filtered and the crude products 2 were obtained after evaporating the
1
solvent. The diastereomeric excess was determined by means of H NMR spectroscopy
of the crude products. With aldehyde 3a (R1 = n-pentyl, R2 = H, R3 = H) and using (+)-
DIPCl, the expected homoallyl alcohol 2a was obtained in 8:1 diastereomeric ratio
(syn:anti = 8:1). Under the same conditions (-) –DIPCl yielded the other diastereomer in
only 2.5:1 diastereomeric ratio (anti:syn = 2.5:1). It was assumed at this point that the
Brown asymmetric allylation proceeded with the expected stereoselectivity as predicted
by Brown et al12 and confirmed later by the nOe measurements of a particular member of
the oxepane library (Figure 2). Thus, use of the chiral allylborane formed from (+) -
DIPCl is a “matched” case and from (-)-DIPCl is a “mismatched” case for aldehyde 3a.
It was also observed that the polymer bound sulfonic acid resin 7 gave better results than
the DOWEX® 50WX8-200 cation exchange resin 8. Impurities in the commercially
available resin 8 contaminated the product mixture and had to be removed by
chromatography before proceeding to the next reactions. But in the case of polymer
bound sulfonic acid resin 7, the impurities were negligible and the product was
sufficiently pure to proceed for the next reactions. The following reactions were carried
out using the isomeric mixtures of the homoallyl alcohols without any further
purification.
5

O
NaH, THF, 0 oC to rt,
10h, 70-80%
O
DIBAL-H, Et2O, -78 oC
20 min
HO
R1
O
O
O
H
R2
R2
R2
R3 R1
R3
O
R1
6
Br
O
4
3
3a = R1 = -(CH2)4CH3,
R2 = -H, R3 = -H
R3
5
O
R4 N C O
or
18
R4
19
Cl
MgCl
then
7 or 8
(+) DIPCl or (-) DIPCl
Py, THF, rt, 6h
then 14, rt, 6h
rt, 5h
THF, -78 oC to rt
4h
9
1. CDI, CH2Cl2, 10h
CH2Cl2, reflux,
18h
OH
R4
X
2. K2CO3, THF: DMF (4:1)
R5R4NH (17), rt, 5h
O
or
O
HO
R2
R5
R2
R1
R2
R1
R3
R1
10
then 7 or 8
rt, 4h
O
R3
R3
O
O
CH2Cl2, Reflux,
3h-18h
2
1
2a = R1 = -(CH2)4CH3,
12: X = -CH2-
13: X = -NH-
then 11, rt, 10h
R2 = -H, R3 = -H
(d.r. = 8:1)
OH
Toluene, 70 oC, 3h-10h
Y
O
O
2b = R1 = -(CH2)4CH3,
15% to 50% after 5 or 6 steps
R2 = -H, R3 = -H
20
(d.r. = 2.5:1)
PCy3
OH
Cl
DOWEX
50WX8-200
O
H
Y
SO3H
Ru
O
Cl
H
8
7
PCy3
R4
X
H
9
PCy3
O
R2
R1
Cl
Cl
R5
PPh2
Ru
O
R3
O
Ph
N
PPh2
NH2
PCy3
15: X = -CH2-
16: X = -NH-
14
11
10
Oxepane Library 1
NH2
5a: R3 = -H
NH2
NH2
Y
O
O
5b: R3 =
CH3
HN
Z
NH2
n
5c: R3 =
CH3
20
R
n
n = 5 (17g) Z = CH2 (17j)
n = 10 (17h)
n = 11 (17i)
Y = NH (20a)
Y = NPh (20b)
Y = O (20c)
O
n = 1 (17e)
n = 2 (17f)
6a: R1 = -(CH2)4CH3,
R2 = -H
6b: R1 = R2 = -(CH2)5-
6c: R1 = R2 = -CH3
6d: R1 = R2 = -H
Z = O (17k)
Z = N-4-FPh (17l)
R = -H (17a)
R = 3-Cl (17b)
R = 3-F (17c)
O
17d
NCO NCO
O
CO2Me
R
COCl
n
R
COCl
n = 8 (19h)
n = 12 (19i)
COCl
COCl
CO2Me
R = -H (19a)
18a
R = -H (18b)
R = 4-Cl (18c)
R = 2,4- di-OMe (18d)
O
R = 4-OMe (19b)
R = 2-F (19c)
R = 4-Me (19d)
20e
20d
19g
19f
R = 3,4- di-Cl (19e)
Scheme 2. Synthesis of Oxepane Library 1.
6

The crude enyne precursors 2 were then subjected to the decisive enyne metathesis
reaction. When intermediates 2 were treated with polymer supported 1st generation
Grubbs catalyst 914 (loading = 0.11 mmol/g, 2 x 40 mol%) in refluxing CH2Cl2, the
oxepanes 1 were formed. After the reaction was complete (monitored by TLC), the resin
was filtered and the solvent was evaporated to obtain the colorless crude products 1. In
this reaction the catalyst loading is too low (0.11 mmol/g) for the synthesis of an entire
library. So an alternative method was implemented to scavenge the ruthenium. Precursors
2 were treated with 1st generation Grubbs catalyst 10 (20 mol%) in refluxing CH2Cl2. As
soon as the reaction was complete (monitored by TLC), the resin 1115 (20 equiv. relative
to the metal catalyst used) was added to scavenge the ruthenium. After filtration through
a silica gel pad the solvent was evaporated to furnish the colorless crude products 1. The
strategy to scavenge ruthenium from the metathesis reaction developed by Breinbauer et.
al.15 turned out to be efficient and inexpensive for library generation. The oxepanes 1
were formed in the same diastereomeric ratio already displayed the precursors 2 which
indicates that the configuration of the enyne precursor 2 was translated into the cyclic
product 1 after the ring-closing enyne metathesis. The diastereomeric excess was
determined by means of 1H NMR spectroscopy of the crude products.
At this point, the oxepane scaffold was ready for diversification to generate a fully
functionalized oxepane library 1. The free alcohol in 1 was functionalized as ester and
carbamate. Hence oxepane 1 was treated with different commercially available
carboxylic acids (3 equiv. relative to the alcohol 1) in CH2Cl2 using either dicyclohexyl-
carbodiimide (DCC) or its solid supported analogue, N-cyclohexyl-carbodiimide, N’-
methyl polystyrene, dimethylamino pyridine (DMAP) as catalyst,16 but esters 12 were not
formed. As more reactive coupling partners, acid chlorides were then chosen. When
alcohol 1 was treated with commercially available acid chlorides 19 (3 equiv relative to
the alcohol 1) in THF in the presence of pyridine as base, the esters 12 were formed. The
same reaction conditions were used to synthesize the carbamates 13 from alcohol 1 using
different commercially available isocyanates 18 (3 equiv relative to the alcohol).17 In
both cases excess acid chlorides and isocyanates were scavenged from the reaction
mixture using aminomethylated polystyrene scavenger 14 (6 equiv. relative to the acid
chlorides and 3 equiv relative to the isocyanate). Esters or carbamates were not formed in
7

the presence of polymer-supported pyridine as base. Excellent reactivity was observed
using aromatic isocyanates (e.g. naphthyl 18a and phenyl isocyanate 18b), but a sluggish
reaction was experienced in case of 2,4-dimethoxy phenyl isocyanate 18d. Tertiary-butyl
isocyanate and tertiary-butyl isothiocyanate were unreactive under these reaction
conditions. In case of ester formation, aliphatic acid chlorides (19f-i) are more reactive
than the aromatic acid chlorides (19a-e). Among the aromatic acid chlorides, the ortho-
substituted acid chloride 19c showed lower reactivity due to steric hindrence. Electron
donating substituents on the aromatic ring (19b and 19d) reduced reactivity whereas
electron withdrawing substituents (19e) led to higher reactivity.
To introduce higher diversity in the oxepane library a two step carbamate synthesis
protocol was implemented. To this end, alcohol 1 was treated with 1,1’-
carbonyldiimidazole (CDI) in CH2Cl2 to obtain a imidazolyl carbamate intermediate
o
which was immediately heated in a sealed tube at 40 C with commercially available
primary amines in CH2Cl2, using triethylamine and catalytic amounts of DMAP. The
carbamates 13 were formed after 48h.18 As this reaction appeared to be sluggish, a
stronger base (K2CO3) was used with different primary and secondary amines 17 in
THF:DMF (4:1) at room temperature for 5h (determined by TLC). The excess potassium
carbonate and amines were scavenged by polymer-supported sulfonic acid resin 7 or 8.
After filtration of the resin and evaporation of the solvent the crude carbamates 13 were
obtained. In this scavenging technique again the sulfonic acid resin 7 was preferable over
8 because of the described impurity problem. This two step protocol appeared to be
suitable because a wide range of primary and secondary amines can be used. All primary
and secondary amines showed similar reactivity in this reaction. It was noted that the
secondary amines (17j-l) are slightly less reactive than the primary amines (17a-i)
because of steric hindrance.
For diversification of the crude diene esters 12 and carbamates 13 were treated separately
o
with different dienophiles 20 in toluene at 70 C to afford the fully substituted oxepanes
15 and 16 respectively in 15-50% overall yield after 5 steps (for 15) or 6 steps (for 16).
The products were isolated by column chromatography as single isomers (entries 11-14,
21-30, 32, 34, 35, 39, 40, 42, 44-46, 49-51, 56-58, 62-64, 66, 67, 74-76 in Table 1) as
well as the inseparable mixtures of two isomers (entries 1-10, 15-20, 31, 33, 36-38, 41,
8

43, 47, 48, 52-55, 59-61, 65, 68-73 in Table 1) . The isomeric ratios of the oxepanes were
1
determined by means of H NMR spectroscopy (see the Supporting Information). All
oxepanes prepared as shown in Scheme 2 are given in Table 1.
Among the different commercially available dienophiles used, the maleimide (20a), N-
phenyl maleimide (20b) and maleic anhydride (20c) reacted very fast and the reactions
were complete within 3h of heating in toluene. But in the case of p-benzoquinone (20d)
and dimethyl acetylene dicarboxylate (20e), the reactions were sluggish (complete after
10h of heating). Using p-benzoquinone (20d) as dienophile, the hydroquinone product
was obtained after purification, which suggests that the initial Diels-Alder adduct was
aromatized in the reaction condition.
9

Table 1. Oxepane Library 1.
Y
H
H
H
R4
R3
R2
O
R1
Entry
R1
R2
R3
R4
Y
Yielda
34 %
H
H
-(CH2)5-
-(CH2)5-
-H
1.
COOH
(after 6 steps)
d.r. = 4:1
N
O
O
COOH
O
O
O
H
N
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-H
-H
-H
32%
(after 6 steps)
d.r. = 8:1
2.
H
N
Ph
5
H
H
O
H
N
O
40%
(after 6 steps)
d.r. = 7.5:1
3.
4.
Ph
Cl
O
N
Ph
O
H
O
H
15%
(after 6 steps)
d.r. = 5:1
COOH
COOH
O
HN
H
O
O
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-H
-H
32%
(after 6 steps)
d.r. = 8:1
5.
6.
H
N
O
N
Ph
Ph
O
H
H
O
O
O
32%
(after 6 steps)
d.r. = 8:1
O
N
H
N
O
H
H
O
O
O
-(CH2)5-
-(CH2)5-
-H
34%
(after 6 steps)
d.r. = 8:1
7.
O
N
O
N
Ph
O
H
O
10

Cl
O
-(CH2)5-
-(CH2)5-
-H
32%
(after 6 steps)
d.r. = 6:1
8.
H
H
N
Ph
HN
O
O
O
H
H
-(CH2)5-
-(CH2)5-
-CH3
-(CH2)5-
-(CH2)5-
-CH3
-H
-H
-H
20%
(after 6 steps)
d.r. = 4:1
9.
COOH
COOH
COOH
Ph
N
O
O
H
H
H
N
15%
(after 6 steps)
d.r. = 7:1
10.
11.
O
5
O
COOH
O
H
30%
(after 6 steps)
O
H
N
N
O
NH
O
H
H
O
O
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-H
-H
-H
22%
(after 6 steps)
12.
13.
14.
O
O
NH
O
O
H
H
O
O
H
N
20%
(after 6 steps)
Ph
NH
H
H
O
O
Cl
16%
(after 6 steps)
NH
HN
O
H
H
O
O
O
O
H
N
-CH3
-CH3
-H
31%
(after 6 steps)
d.r. = 3:1
15.
NH
5
O
H
O
O
H
-(CH2)5-
-CH3
-(CH2)5-
-CH3
-H
-H
29%
(after 6 steps)
d.r. = 3:1
16.
17.
H
O
Ph
N
N
Ph
O
H
O
Cl
O
22%
(after 6 steps)
d.r. = 4:1
H
NH
HN
O
H
O
O
11

O
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-H
-H
-H
15%
(after 6 steps)
d.r. = 3:2
18.
19.
20.
H
O
N
N
O
O
NH
O
O
H
H
O
O
15%
(after 6 steps)
d.r. = 3.8:1
NH
H
H
O
O
O
30%
(after 6 steps)
d.r. = 3:1
O
NH
H
N
O
H
O
O
H
H
-CH3
-H
-CH3
-H
-H
-H
16%
(after 6 steps)
21.
22.
COOH
N
O
O
COOH
O
H
20%
(after 6 steps)
H
N
O
NH
O
H
H
O
O
H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
26%
(after 6 steps)
23.
24.
25.
26.
27.
O
N
NH
O
H
H
O
O
30%
(after 6 steps)
O
O
N
NH
O
H
H
O
O
H
N
20%
(after 6 steps)
O
NH
5
O
H
H
O
O
16%
(after 6 steps)
(CH2)4CH3
(CH2)4CH3
O
N
O
NH
O
H
O
OH
F
15%
(after 6 steps)
O
HN
O
OH
12

O
O
-H
-H
-H
-H
16%
(after 6 steps)
28.
29.
(CH2)4CH3
H
H
O
NH
H
N
O
O
O
OH
H
N
15%
(after 6 steps)
(CH2)4CH3
O
5
O
OH
OH
Cl
-H
-H
15%
(after 6 steps)
30.
(CH2)4CH3
HN
O
OH
O
O
H
O
-H
-H
-H
-H
16%
(after 6 steps)
d.r. = 25:1
31.
32.
(CH2)4CH3
(CH2)4CH3
H
N
NH
O
H
O
OH
Cl
Cl
F
20%
(after 6 steps)
HN
HN
O
O
O
O
O
O
OH
H
-H
-H
-H
-H
15%
(after 6 steps)
d.r. = 3:2
33.
34.
(CH2)4CH3
COOH
COOH
H
H
20%
(after 6 steps)
(CH2)4CH3
COOH
COOH
HN
O
H
H
N
O
-H
-H
-H
-H
23%
(after 6 steps)
35.
36.
(CH2)4CH3
(CH2)4CH3
H
O
NH
10
H
O
H
N
H
41%
(after 6 steps)
d.r. = 3:2
COOH
Ph
O
O
COOH
H
13

F
H
H
-CH3
-CH3
-H
25%
(after 6 steps)
d.r. = 6:1
37.
COOH
COOH
N
N
O
O
H
O
-H
-H
-H
-H
-H
-H
-H
-H
29%
(after 6 steps)
d.r. = 2.6:1
38.
39.
40.
41.
(CH2)4CH3
(CH2)4CH3
(CH2)4CH3
(CH2)4CH3
H
N
O
NH
5
O
H
H
O
O
H
N
31%
(after 6 steps)
O
NH
O
H
H
O
O
H
N
24%
(after 6 steps)
O
NH
11
O
H
O
O
H
15%
(after 6 steps)
d.r. = 4:1
COOH
O
H
N
O
COOH
H
O
O
-H
-H
-H
-H
20%
(after 6 steps)
42.
43.
(CH2)4CH3
(CH2)4CH3
H
N
O
NH
O
H
O
OH
Cl
30%
(after 5 steps)
d.r. = 4:1
Cl
O
O
OH
OH
H
-H
-H
-H
-H
20%
(after 5 steps)
44.
45.
(CH2)4CH3
N
O
O
O
OH
O
12
O
44%
(after 5 steps)
(CH2)4CH3
O
O
O
14

O
-H
-H
70%
(after 5 steps)
46.
47.
CH3
CH3
H
H
OH
(CH2)4CH3
(CH2)4CH3
N
Ph
O
O
32%
(after 5 steps)
d.r. = 8:1
O
O
O
HN
O
O
O
-H
-H
50%
(after 5 steps)
d.r. = 8:1
48.
49.
CH3
CH3
H
(CH2)4CH3
(CH2)4CH3
O
H
N
O
N
Ph
O
H
H
O
O
O
60%
(after 5 steps)
N
Ph
O
HN
H
O
O
O
-H
-H
26%
(after 5 steps)
50.
51.
CH3
(CH2)4CH3
O
O
O
O
O
OH
Cl
-H
60%
(after 5 steps)
(CH2)4CH3
Cl
O
O
OH
H
F
-H
-H
-H
-H
-H
-H
21%
(after 6 steps)
d.r. = 8:1
52.
53.
54.
(CH2)4CH3
(CH2)4CH3
(CH2)4CH3
COOH
O
COOH
COOH
COOH
COOH
COOH
O
H
H
12
25%
(after 6 steps)
d.r. = 9:1
O
O
H
H
Cl
24%
(after 6 steps)
d.r. = 6.5:1
Cl
O
H
H
O
-H
-H
20%
(after 6 steps)
d.r. = 6:1
55.
(CH2)4CH3
COOH
COOH
O
O
H
15

12
O
O
-H
-H
-H
-H
28%
(after 5 steps)
56.
57.
(CH2)4CH3
O
O
O
O
O
16%
(after 5 steps)
(CH2)4CH3
O
O
HN
O
O
O
O
-H
-H
-H
-H
-H
-H
32%
(after 5 steps)
58.
59.
60.
(CH2)4CH3
(CH2)4CH3
(CH2)4CH3
O
O
O
O
O
O
25%
(after 5 steps)
d.r. = 4:1
O
O
O
O
O
O
25%
(after 5 steps)
d.r. = 8:1
O
O
O
O
O
H
H
H
-H
-H
-H
-H
26%
(after 6 steps)
d.r. = 6:1
61.
62.
(CH2)4CH3
(CH2)4CH3
COOH
N
O
O
COOH
O
Cl
H
N
32%
(after 5 steps)
H
O
N
Ph
O
H
H
O
O
-H
-H
-H
-H
30%
(after 5 steps)
63.
64.
(CH2)4CH3
N
Ph
HN
O
H
O
O
OH
O
17%
(after 5 steps)
(CH2)4CH3
O
O
OH
16

O
-H
-H
-H
60%
(after 4 steps)
d.r. = 8:1
65.
66.
67.
H
CH3
CH3
OH
OH
(CH2)4CH3
(CH2)4CH3
(CH2)4CH3
N
Ph
Ph
H
H
O
O
70%
(after 4 steps)
N
H
O
12
O
OH
-H
23%
(after 5 steps)
O
OH
O
-H
-H
-H
-H
65%
(after 4 steps)
d.r. = 20:1
68.
69.
70.
H
OH
OH
OH
(CH2)4CH3
(CH2)4CH3
(CH2)4CH3
N
Ph
H
H
O
O
50%
(after 4 steps)
CH3
N
Ph
H
O
O
55%
(after 4 steps)
d.r. = 2.8:1
CH3
O
O
O
H
H
-H
-CH3
-(CH2)5-
-H
-H
27%
(after 6 steps)
d.r. = 4:1
71.
72.
73.
74.
(CH2)4CH3
COOH
COOH
COOH
COOH
COOH
N
O
O
5
H
H
H
N
-CH3
-H
-H
-H
20%
(after 6 steps)
d.r. = 6:1
O
O
10
H
H
-(CH2)5-
10%
(after 6 steps)
d.r. = 4:1
O
N
O
O
COOH
O
H
H
N
-H
25%
(after 6 steps)
H
O
NH
O
O
H
17

F
O
-H
-H
-H
-H
-H
-H
-H
28%
(after 6 steps)
75.
76.
77.
H
H
N
NH
N
O
O
O
OH
20%
(after 5 steps)
(CH2)4CH3
O
O
OH
O
F
22%
(after 6 steps)
(CH2)4CH3
H
H
N
NH
N
O
O
O
aIsolated yield after column chromatography, d.r. = diastereomeric ratio.
18

The Diels-Alder adduct with electron withdrawing dienophiles 20 was formed with endo-
selectivity. The relative stereochemistry of one of the library members was determined by
nOe experiments as shown in Figure 2.
nOe
nOe
H
N
H
O
O
H
H
O
H
O
11
O
4
11
5
H
9
9
3
H
6
HN
O
7
10
10
H
O
H
6
2
8
H
O
1
5 4
O
N
H
O
8
H
3
HN
2
7
O
1
O
O
H
O
nOe
endo-product
endo-product
Figure 2. nOe study of a oxepane library member.
In this nOe experiment protons H2, H4 and H6 were irradiated in their resonance
frequency and the signal enhancements observed are shown in Table 2.
Table 2. nOe irradiation and intensity of the protons.
Irradiation at
Signal enhancements of protons
H4 (5.0%), H5 (3.0 %)
H6
H4
H2
H6 (6.0%), H11 (3.0%), H5 (3.0%)
H8 (4.0%), H7 (2.0%)
From the nOe experiment it was evident that the Brown asymmetric allylation proceeded
with the expected stereochemistry. The Diels-Alder reaction also proceeded with endo-
selectivity. Based on this experiment the configuration of the other library members was
assigned by analogy. In the Diels-Alder reaction the diene can react through four possible
transition states (a, b, c, d, Scheme 3) with the dienophile. When the Diels-Alder reaction
proceeds through exo-transition state d, the dienophile approaches from the less sterically
hindered and more favorable face of the diene, giving rise to the exo-adduct D. When the
19

dienophile approaches from the face occupied by the bulky n-pentyl group, steric
hindrance renders the exo-transition state c less favorable.
Y
O
H
Y
O
H
O
O
H
H
R
R
H
H
HN
O
HN
O
H
O
H
O
O
O
B
A
endo-product
endo-product
H
N
O
H
R
O
O
Y
O
Y
O
O
H
N
H
H
O
R
H
O
O
O
O
H
H
Y
H
H
b
O
a
R
endo-TS
HN
O
endo-TS
more favorable TS
less favorable TS
H
O
O
H
N
O
H
R
O
O
Y
O
H
N
H
H
O
O
R
H
O
O
O
H
H
O
O
H
Y
Y
H
c
exo-TS
O
d
exo-TS
more favorable TS
less favorable TS
Y
O
H
O
O
H
Y
O
H
R
H
H
R
HN
O
H
HN
O
H
O
O
H
O
O
C
D
exo-product
exo-product
Scheme 3. Endo-transition state for the Diels-Alder reaction.
20

In transition state b the dienophile approaches from the side occupied by the bulky pentyl
group, encountering a steric hindrance and hence making b a less favorable transition
state. In transition state a, the dienophile approaches from the face opposite to the bulky
n-pentyl group. Thus, transition state a is less sterically hindered and more favorable
giving rise to the desired product A. The nOe study described above rules out the
possibility of the exo-transition states (c and d) and also the more sterically hindered
transition state b. Hence the only product A was obtained from this Diels-Alder reaction
through the more favorable endo-transition state a. Interestingly, we did not detect any
thermodynamically stable exo-product (D) through transition state d. We anticipate that
kinetically controlled endo-product (A) formation was more favorable as the oxepane
diene is not electronically rich leading to slow reaction kinetics even at 70 oC for 10h.19
Synthesis of oxepane library 2 by cross metathesis
Further diversification was achieved by cross metathesis including the diene group
embedded in 1(Scheme 4). Diene 1 was refluxed in CH2Cl2 with methyl acrylate in the
presence of either 2nd generation Grubbs catalyst 2120a (15 mol%) or 2nd generation
Hoveyda-Grubbs catalyst 2220b (20 mol%) for 18 h. When the reaction was complete
(determined by TLC), the ruthenium scavenger resin 11 was added.
O
R4
18
N C O
R4
Cl
or
O
Ha
O
Ha
19
THF, Py, rt, 6h
R4
X
O
O
O
then 14
O
Hb
O
HO
R3
HO
R3
R2
R1
R5
Hb
R2
R1
R2
R1
O
R3
O
or
21 or 22
CH2Cl2, reflux, 18h
O
O
1. CDI, CH2Cl2, rt, 10h
2. K2CO3, THF:DMF (4:1)
R5R4NH (17), rt, 5h
24: X = -CH2-
25: X = -NH-
1
23
then 11
rt,10h
Oxepane Library 2
then 7, rt, 6h
25% to 75%
after 5 or 6 steps
N
N
N
N
Cl
Cl
Cl
Ru
O
Ru
Ph
Cl
PCy3
21
22
Scheme 4. Synthesis of the oxepane library 2.
21

In this cross metathesis strategy it was realized that the 2nd generation Grubbs catalyst 21
showed higher reactivity than the 2nd generation Hoveyda-Grubbs catalyst 22. The free
alcohol was functionalized to give esters 24 and carbamates 25 in 47%-57% (after 5
steps) and 25%-75% (after 5 or 6 steps) isolated overall yield respectively. In the
products 24 and 25, the newly formed olefin after the cross metathesis reaction was E-
configured exclusively as was evident from the coupling constant (JHa-Hb = 16.0 Hz, (see
1
also the Supporting Information) between Ha and Hb in the H NMR spectrum. The
oxepanes synthesized by means of this procedure are shown in Table 3.
22

Table 3. Oxepane library 2.
R3
R4
R2
R1
O
Entry
1.
R1
-CH3
R2
-CH3
R3
-H
R4
Yielda
40%
(after 5 steps)
F
N
N
O
O
H
-CH3
-CH3
-CH3
-CH3
-H
-H
25%
(after 5 steps)
2.
3.
O
N
5
O
O
O
29%
(after 5 steps)
N
O
-CH3
-CH3
-H
40%
(after 5 steps)
4.
O
N
O
H
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-H
45%
(after 5 steps)
5.
6.
7.
O
N
O
O
O
H
N
35%
(after 6 steps)
O
O
O
O
36%
(after 6 steps)
O
N
O
O
O
F
-CH3
-CH3
-CH3
-CH3
38%
(after 6 steps)
8.
9.
O
O
N
N
O
O
O
H
N
35%
(after 6 steps)
O
O
23

O
O
H
N
-CH3
-CH3
-CH3
-CH3
35%
(after 6 steps)
10.
11.
O
O
O
O
5
O
O
30%
(after 6 steps)
N
12
O
-H
47%
(after 5 steps)
12.
(CH2)4CH3
O
O
O
O
O
O
-H
-H
30%
(after 5 steps)
13.
14.
(CH2)4CH3
(CH2)4CH3
O
O
H
N
75%
(after 5 steps)
O
O
Cl
O
O
H
N
-H
-H
47%
(after 5 steps)
15.
16.
(CH2)4CH3
(CH2)4CH3
O
O
O
O
40%
(after 5 steps)
HN
O
O
-H
-H
-H
-H
-H
-H
60%
(after 3 steps)
d.r. = 8:1
60%
(after 3 steps)
d.r. = 2.5:1
57%
17.
18.
19.
OH
OH
(CH2)4CH3
(CH2)4CH3
(CH2)4CH3
Cl
Cl
(after 4 steps)
d.r. = 8:1
O
O
H
N
-H
-H
65%
(after 4 steps)
d.r. = 8:1
20.
(CH2)4CH3
O
O
Cl
H
N
-H
-H
-H
40%
(after 4 steps)
d.r. = 8:1
21.
22.
(CH2)4CH3
(CH2)4CH3
O
O
O
45%
(after 4 steps)
OH
O
aIsolated yield after column chromatography, d.r. = diastereomeric ratio.
24

Synthesis of keto oxepanes
The Sodwanones are a family of marine natural products displaying activity against
different human cancer cell lines (Figure 3).5
HO
O
O
O
O
O
O
O
O
H
OH
O
H
OH
O
O
O
O
O
H
H
H
H
O
OH
Sodwanone S
OH
Sodwanone A
O
Sodwanone H
Sodwanone G
Figure 3. Few representatives of Sodwanone family natural products
The Sodwanone family contains the keto oxepane scaffold. Inspired by this marine
natural product family and its anti cancer activity, a small keto oxepane collection was
synthesized.
o
Aldehydes 26 were treated with allylmagnesium chloride in THF at 0 C to room
temperature for 2h to obtain the enyne metathesis precursors 27 as a 1:1 mixture of two
inseparable isomers after scavenging the excess allylmagnesium chloride with the
polymer supported sulfonic acid resin 7 (Scheme 5). These crude enyne metathesis
precursors were treated with 1st generation Grubbs catalyst 10 in refluxing CH2Cl2 for
18h. When the reaction was complete (monitored by TLC), the ruthenium metal was
scavenged using the metal chelating resin 11. After filtering the resin and removal of
solvent, a 1:1 mixture of colorless crude oxepanes 28 was obtained. The crude alcohols
28 were then oxidized to the ketones 29 using pyridinium chlorochromate (PCC) in
CH2Cl2 at room temperature for 10h. After total consumption of the starting alcohols 28
(monitored by TLC), the reaction mixtures were filtered through a Celite pad to remove
the chromium metal from the reaction mixture.
25

10
CH2Cl2, reflux, 18h
O
HO
MgCl
O
O
R2
R1
H
HO
THF, 0 oC to rt, 2h
then 11, rt, 10h
O
R2
R2
R1
R1
then 7, rt, 6h
26
27
28
PCC, CH2Cl2,
rt, 10h
R3O-NH2. HCl
O
Y
O
H
Y
Y
O
31
R3 = Me (31a)
R3 = Bn (31b)
O
O
R3
H
O
H
O
H
O
H
H
20
R2
R1
N
O
O
Toluene, 70 oC, 3h-10h
10%-25%overall yield
(after 5 steps)
R2
R1
EtOH: H2O (2:1)
rt, 10h
10%-15% overall yield
(after 6 steps)
R2
O
O
R1
29
30
32
Oxepane Library 4
Oxepane Library 3
Scheme 5. Synthesis of keto-oxepane library 3 and oxime library 4.
After the keto oxepane scaffold was formed the diene moiety of 29 was functionalized by
means of Diels-Alder reactions. When crude 29 was treated with different commercially
o
available dienenophiles 20 in the minimum volume of toluene necessary at 70 C for 3h
to 10h (depending on the dienophile used) the crude adducts 30 were formed. The crude
products 30 were purified by silica gel chromatography to obtain pure keto oxepanes in
10% to 25% overall yield after 5 steps for the major isomer. In this case also, it was
assumed that the endo-adduct had been formed based on the nOe study described above.
1
The isomeric ratios of the individual keto oxepanes were determined by means of H
NMR spectroscopy and are shown in the Supporting Information and Table 4.
Crude 30 were further treated with either O-methyl hydroxylamine hydrochloride salt
(31a) or O-benzyl hydroxylamine hydrochloride salt (31b) in ethanol:water (2:1) mixture
at room temperature for 10h.21 After the reaction was complete (monitored by TLC) the
solvent was evaporated and the crude 32 were purified by preparative thin layer
chromatography (PTLC) to afford the pure oximes in 10% to 15% overall yield after 6
steps. O-Benzylhydroxyl amine (31b) gave better yields than O-methylhydroxyl amine
(31a). The structures, yields and isomeric ratios of the oximes are shown in Table 4.
26

Table 4. Oxepane libraries with keto-/and oxime functional groups.
Y
H
H
H
X
R2
R1
O
Entry
1.
R1
R2
X
Y
O
Yield
30%a
(after 5 steps)
-H
O
(CH2)4CH3
O
O
O
-H
O
O
25%a
(after 5 steps)
O
2.
(CH2)4CH3
H
O
H
O
25%a
(after 5 steps)
O
-H
3.
4.
5.
H
(CH2)4CH3
-(CH2)5-
N
Ph
H
H
O
O
-(CH2)5-
-(CH2)5-
10%b
(after 6 steps)
OBn
N
N
Ph
H
O
-(CH2)5-
-(CH2)5-
-(CH2)5-
12%b
(after 6 steps)
OBn
N
O
H
NH
H
H
O
O
-(CH2)5-
-(CH2)5-
O
O
15%a
(after 5 steps)
6.
7.
NH
H
O
O
10%a
(after 5 steps)
H
N
Ph
H
O
27

O
O
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
O
15%a
(after 5 steps)
8.
9.
O
O
10%b
(after 6 steps)
d.r. = 8:1
OH
OMe
N
OH
O
-CH3
-CH3
-CH3
-CH3
O
O
12%a
(after 5 steps)
10.
11.
H
H
N
Ph
O
15%a
(after 5 steps)
O
H
NH
H
H
O
O
OBn
N
-CH3
-CH3
-CH3
15%b
(after 6 steps)
12.
NH
H
O
O
OBn
N
-CH3
-H
13%b
13.
14.
15.
H
(after 6 steps)
d.r. = 4.3:1
N
Ph
Ph
H
H
O
O
10%b
(after 6 steps)
d.r. = 20:1
OBn
N
(CH2)4CH3
(CH2)4CH3
N
H
O
OH
-H
O
14%a
(after 5 steps)
OH
OMe
N
H
-(CH2)5-
-(CH2)5-
10%b
16.
COOH
(after 6 steps)
d.r. = 6:1
COOH
H
b
aIsolated yield after column chromatography, Isolated yield after preparative thin layer
chromatography (PTLC), d.r. = diastereomeric ratio
28

Synthesis of diacids
Further diversification on the oxepane scaffold was achieved after the Diels-Alder
reaction with maleic anhydride (20c) and hydrolysis of the formed anhydride to diacids
34 (Scheme 6). The dienes 33 were treated with maleic anhydride (20c) in toluene at
o
70 C for 3h. As soon as the dienes 33 were totally consumed (monitored by TLC), the
solvent was evaporated and the crude products were dissolved in a solution of 20% water
in THF and stirred at room temperature for 10h.
O
O
O
COOH
H
R3
X
1.
HOOC
H
20c
toluene, 70 oC, 3h
R3
X
O
H
O
R2
R1
O
O
R2
2. 20% H2O in THF, rt, 10h
20%-25% after 6 steps
O
O
33
R1
34
X = -NH, -NR4, -CH2
Scheme 6: Synthesis of diacid.
The solvent was evaporated by coevaporation with excess ethanol and purified by silica
gel chromatography to obtain the diacids 34 in 20% to 25% yield after 6 steps.22 The
diacids were formed as inseparable mixtures of two isomers determined by means of 1H
NMR spectroscopy. The structures, yields and diastereomeric ratios of the diacids are
shown in Table 1 and in the Supporting Information.
Summary and Conclusion
A collection of 77 fully functionalized oxepanes (library 1) has been synthesized by
means of the synthetic strategy shown in Scheme 2. The ring-closing enyne metathesis
reaction was used as the key step to synthesize the oxepane scaffold 1. Diversity on the
oxepane scaffold was generated by reacting isocyanates 18 and acid chlorides 19 with
alcohols to generate carbamates and esters respectively. In addition, carbamates were
synthesized by a two step procedure using carbonyl diimidazole and different primary
and secondary amines 17. The diene moiety was functionalized by Diels-Alder
cycloaddition to yield fused seven-six membered bicyclic systems. A collection of 22
29