On the stereochemistry of the olefinic double bond in 13-membered heterocyclic rings accessible by ring-closing metathesis reaction

Article abstract of DOI:10.1016/j.tetlet.2012.09.065

13-Membered heterocyclic ring analogs of the core structure of manzamine alkaloids were synthesized by ring closing metathesis (RCM) reaction. The influence of a remote heteroatom (N, O, S) on E/Z stereochemistry of the olefinic double bond formed in RCM reaction using Grubbs 1st and 2nd generation ruthenium carbene complexes was evaluated. Studies show that RCM reaction is kinetically controlled and the hetero atoms influence the double bond stereochemistry.

Full text of DOI:10.1016/j.tetlet.2012.09.065

Tetrahedron Letters 53 (2012) 6877–6880
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
On the stereochemistry of the olefinic double bond in 13-membered
heterocyclic rings accessible by ring-closing metathesis reaction
⇑
H. Surya Prakash Rao , Shaik Rafi , P. Ratish Kumar, C. Guravaiah, Nandurka Muthanna
Department of Chemistry, Pondicherry University, Pondicherry 605 014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2012
Revised 13 September 2012
Accepted 15 September 2012
Available online 10 October 2012
13-Membered heterocyclic ring analogs of the core structure of manzamine alkaloids were synthesized
by ring closing metathesis (RCM) reaction. The influence of a remote heteroatom (N, O, S) on E/Z stereo-
chemistry of the olefinic double bond formed in RCM reaction using Grubbs 1st and 2nd generation
ruthenium carbene complexes was evaluated. Studies show that RCM reaction is kinetically controlled
and the hetero atoms influence the double bond stereochemistry.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ring-closing olefin metathesis
13-Membered rings
The 13-membered carbocyclic and heterocyclic ring structures
are expected to exhibit unique properties different from small
and medium ring structures both in terms of conformation and
reactivity.1 Nature selected some molecules with 13-membred
heterocyclic rings to impart unique properties for example, manz-
amine group of alkaloids represented by manzamine A 1 (Fig. 1).2
Biological studies on manzamines have shown that the 13-mem-
bered nitrogen containing heterocyclic ring is crucial for their bio-
logical activity.3
ero-atom substituted 13-membered rings by RCM reaction. In
this regard we set to investigate the influence of a remote hetero-
atom on the stereochemistry of the double bond when a 13-mem-
bered ring is constructed from the corresponding open-chain
dienes when RCM reaction is conducted with Grubbs 1st and 2nd
generation catalysts. For this purpose, we conceived of novel 13-
membered ring structures (11–17) with two oxygen atoms and a
strategically placed hetero-atom derivable from the corresponding
open chain bis-allyl ethers 4–10 (Scheme 1).
The ring-closing metathesis reaction (RCM) on dienes and ene
ynes with ruthenium carbene complexes like Grubbs 1st (2) and
2nd (3) generation catalysts (Fig. 1) has emerged in recent years
as the most potent tool for the synthesis of cyclic compounds, par-
ticularly those with medium and large rings.4 The RCM reaction on
dienes can provide cyclic olefins of E or Z stereochemistry. While
olefins with only Z stereochemistry are possible in the formation
of small rings (5–7), both E and Z double bonds can form in the case
of medium and large rings. Till date, there are no systematic exper-
imental studies on the RCM reaction to form macrocyclic rings vis a
vis stereochemistry of the newly generated double bond, even
though it is one of the most explored reactions from mechanistic
and synthetic points of view. It is to be noted that in the construc-
tion of the 13-membered heterocyclic rings as found in manz-
amine alkaloids mixtures of E and Z isomers of varying ratios
were realized.5
Claisen–Schmidt condensation between 2-hydroxyacetophe-
none 21 and 2-hydroxybenzaldehydes (salicylaldehydes) 18–20
provided corresponding chalcones 22–24 (Scheme 2).7 Hydrogena-
tive deoxygenation of chalcones 22–24 with Raney nickel
furnished corresponding reduced products8 which on reaction
N
N
H
H
Me Me
Me
OH
Me
N
N
N
PCy3
Ru
In continuation of our earlier studies on synthesis and stereo-
Me
N
H
Me
Ph
Cl
Cl
Cl
Cl
chemistry of nitrogen heterocycles,6 we wanted to prepare het-
Ru
Ph
PCy3
PCy3
⇑
Corresponding author. Tel.: +91 413 2654411; fax: +91 413 2655987.
1
2
3
E-mail addresses: hspr.che@pondiuni.edu.in, hspr@yahoo.com (H. Surya Prakash Rao).
Present address: Cosmic Discoveries, Institute of Life Sciences, University of
Hyderabad Campus, Hyderabad 500 042, India.
Figure 1. Structures of manzamine A 1, Grubbs 1st (2), and 2nd (3) generation
catalysts.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.065

6878
H. S. P. Rao et al. / Tetrahedron Letters 53 (2012) 6877–6880
NaBH4
E/Z
CHO
O
MeOH
OH
SOCl2
Cl
O
O
O
O
0 oC-rt
2 h, 90%
reflux
O
O
0.5 h, 86%
RCM
X
X
R2
R2
R1
R1
29
30
31
4-10
11-17
Scheme 1. Synthesis of 13-membered ring structures via RCM reaction.
NaH, DMF
oC-rt
O
O
30
31
+
0
O
12 h, 90%
OH
O
OH
R1
O
OH
8
CHO
60% aq. KOH
oC- rt
+
Scheme 4. Synthesis of bis-allyl ether precursor 8.
R2
0
HO
R2
R1
18-20
48 h, 45-48%
21
22-24
The synthesis of sulfur incorporated bis-allyl thio ether 9 was
achieved by the reaction of benzyl chloride 31 with Na2S under ba-
sic conditions (Scheme 5). Further oxidation of 9 with oxone re-
sulted in sulfone 10.
i) Raney Ni
isopropanol
reflux, 16 h
23-27%
O
O
18, 22, 4: R1 = R2 = H;
19, 23, 5: R1 = Cl, R2 = H;
: R1 = Cl, R2 = Me
20 24 6
,
Besides characteristic peaks, the 1H and 13C NMR spectra of allyl
ethers/allyl thioethers 4, 7–10 revealed C2-symmetric nature of the
molecules.
ii) Allyl bromide
NaH, DMF
,
R2
0
oC-rt, 75-93%
R1
The reaction of bis-allyl ether 4 (X = CH2) with 10 mol % of
Grubbs 1st generation ruthenium carbene complex in dry dichloro-
methane reflux for 14 h yielded (E)-11 as a single geometrical iso-
mer in 63% yield (Scheme 6, Table 1, entry 1).
4-6
Scheme 2. Synthesis of bis-allyl ether precursors 4–6 for RCM reaction.
The cyclic olefin (E)-11 was characterized on the basis of spec-
tral (1H, 13C, DEPT NMR, and MS spectra) and analytical data. C2-
symmetric nature of (E)-11 was evident from its 1H NMR spectrum,
which displayed characteristic singlets at d 4.54 for C10 and C13
methylenes and at 6.05 ppm for C11 and C12 olefinic hydrogen
atoms. The 13C NMR spectrum showed 10 signals with diagnostic
peaks located at d 67.8 for C10 and C13 carbons and 111.7 ppm
for the C11 and C12 olefinic carbons. Stereochemistry of the double
bond was assigned E (trans) on the basis of 1H and 13C NMR spec-
tral data. The data reported by Ibrahim and coworkers for crown
formazans 32 (Fig. 2) were used to assign stereochemistry to the
double bond in 11.13 In the 1H NMR spectrum of 32 the OCH2
hydrogens of the E-isomer appeared upfield at d 4.60 ppm as sin-
glet whereas for the Z isomer of 32 it appeared downfield at d
4.77 ppm as doublet (J = 3.7 Hz). Similarly in the 13C NMR spec-
trum, corresponding OCH2 carbon in E-isomer appeared downfield
with allyl bromide and sodium hydride furnished bis-allyl ethers
4–6.
The oxime9 25 derived from 2-hydroxybenzaldehyde 18 was
treated with HCOONH4/Pd–C to provide the secondary amine 26
(Scheme 3).10 Attempted bis-allylation of 27 furnished undesired
N-allylated product 27. Therefore, the secondary amine was con-
verted into N-formyl derivative 28 with ethyl formate.11 Further
reaction of phenolic hydroxy groups with allyl bromide furnished
bis-allyl ether 7.
The allyl protected 2-hydroxybenzaldehyde 29 was reduced
with NaBH4 in methanol to provide benzyl alcohol 30 (Scheme
4). This product was treated with thionyl chloride to furnish benzyl
chloride 31. The Williamson reaction between the benzylic alcohol
30 and benzylic chloride 31 in the presence of sodium hydride in
DMF furnished 8.12
OH
OH
10% Pd/C
HCO2NH4
NH2OH.HCl
NH4OAc
EtOH, 2 h
87%
CHO
OH
OH
N
N
H
MeOH, rt
16 h
OH
18
25
26
Ally lbromide
NaH, DMF
0
HCO2Et, HCO2H
DMF, 1,4-dioxane
10 h, 52%
oC-rt, 12 h
79%
OH
OH
O
OH
Allyl bromide
NaH, DMF
O
O
N
CHO
N
N
0 oC-rt
12 h, 82%
CHO
7
28
27
Scheme 3. Synthesis of bis-allyl ether precursor 7 for RCM reaction.

H. S. P. Rao et al. / Tetrahedron Letters 53 (2012) 6877–6880
6879
Cl
Na2S
Oxone
O
O
O
O
O
O
S
O
50% NaOH
EtOH, 100 o
71%
MeOH, H2O (1:1)
0 oC to rt, 74%
S
C
31
9
10
Scheme 5. Synthesis of bis-allyl thioether 9 and sulfone 10.
(X = NCHO) provided inseparable E/Z mixture of 14 in 70% yield
in the ratio of 29:71 (Table 1, entry 4). Both 1H and 13C NMR spec-
tra of 14 displayed two sets of signals for each isomer due to re-
stricted rotation in the formamide moiety. RCM reaction of bis-
allyl ether 8 (X = O) provided (E)-15 exclusively (Table 1, entry
5). Next, the sulfur containing allyl ether 8 (X = S) was subjected
to RCM reaction to realize the inseparable mixture of E and Z iso-
mers of 16 in 72% yield in the ratio of 57:43 (Table 1, entry 6).
Although there are a few reports that the sulfur atom present in
dienes can poison the Grubbs 1st generation catalyst,14 we did
not encounter any difficulty. To establish the stereochemistry of
the newly formed double bond in 16 we have independently
synthesized the Z-isomer (Z)-16 from (Z)-1,4-bis(2-(chloro-
methyl)phenoxy)but-2-ene 3315 by treating with Na2S (Scheme
7). The 1H and 13C NMR spectral values of (Z)-16 were used to iden-
tify this isomer in the mixture obtained from RCM reaction. Finally
we subjected sulfone 10 (X = SO2) to RCM reaction and it provided
an inseparable E and Z isomer mixture of 17 in the ratio of 52:48 in
81% yield (Table 1, entry 7). Diagnostic 13C NMR chemical shift
values (d) of allylic OCH2 carbons for 11–17 are given in Table 1.
Even though the present work is preliminary to predict the pre-
cise influence of a remote heteroatom on the transition states in-
volved in the RCM reaction, it is clear that remote heteroatoms
do interact with ruthenium and influence transition state geome-
tries. To evaluate kinetic versus thermodynamic control on the
reaction, we repeated the RCM on 4 (X = CH2), 8 (X = O), and 9
(X = S) with Grubbs 2nd generation catalyst, both at 40 °C (dichlo-
romethane reflux) and at elevated temperature (65 °C in dry ben-
zene). In all the cases there was no change in the ratio of E/Z
isomers as compared to when we employed the Grubbs 1st gener-
ation catalyst (Table 1), which indicates the kinetic control in the
reaction.16 Finally we found that at dichloromethane reflux
(40 °C) the RCM was at least two times slower with Grubbs 2nd
generation catalyst compared to that of the Grubbs 1st generation
catalyst.
Grubbs 1st & 2nd
generation catalyst
(10 mol%)
O
O
X
DCM, reflux
14-24 h, 63-73%
R2
R1
O
4-10
11
10
1
10
9
O
11
9
1
O
O
X
5
X
5
R2
R2
R1
R1
E
Z
11-17
: R1 = R2 = H, X = CH2;
: R1 = Cl, R2 = H, X =
CH2; 6, 13: R1 = Cl, R2 = Me, X = CH2; 7, 14: R1 = R2
H, X = NCHO; 8, 15: R1 = R2 = H, X = O; 9, 16: R1 = R2
10, 17
4, 11
5, 12
=
= H, X = S;
: R1 = R2 = H, X = SO2
Scheme 6. The RCM reaction on bis-allyl ethers 4–10 leading to 13-membered ring
formation.
at d 70.8 ppm, whereas in Z-isomer it appeared upfield at d
62.6 ppm. For the cyclic olefin (E)-11 the OCH2 hydrogens ap-
peared at d 4.54 ppm as singlet in the 1H NMR spectrum and at d
67.8 ppm for the corresponding carbon in the 13C NMR spectrum
indicating E-stereochemistry of the double bond.
Generality of the exclusive formation of E-isomeric cyclic olefin
in the RCM reaction on 4 (X = CH2) was ascertained by exposing
dienes 5 (X = CH2) and 6 (X = CH2) to Grubbs 1st generation
catalyst and in both the instances only E-isomeric cyclic olefins
(E)-12 and (E)-13 were obtained (Scheme 6, Table 1, entries 2
and 3). There was no trace of Z-isomer. Exclusive arrival of E-iso-
mer (E)-11 in RCM reaction prompted us to study the influence
of heteroatom on the stereochemistry of the alkene. Accordingly,
the bis-allyl ethers 7–10 were subjected to RCM reaction and the
results are gathered in Table 1. Cyclization of the bis-allyl ether 7
In conclusion, we have prepared heteroatom (oxygen, nitrogen,
and sulfur) substituted 13-membered rings with E/Z-olefinic dou-
ble bonds from corresponding bis-allyl ethers by RCM reaction
and delineated their stereochemistry on the basis of NMR chemical
shifts. Stereochemistry of the olefinic double bond appears to be
influenced by the presence of remote hetero-atom.
Table 1
Diagnostic 13C NMR spectral values of allylic OCH2 carbons in olefins 14–20 and E/Z ratio
Entry
Substrate
Product
X
R1
R2
13C NMR spectral values (in d ppm)
Yield (%)
Ratio of E/Z isomersa
for allylic OCH2 (C10 and C13) carbons of E/Z-isomers
1
2
3
4
5
6
7
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CH2
CH2
CH2
NCHO
O
H
Cl
Cl
H
H
H
H
H
H
Me
H
H
69.0/—
68.2/—
68.3/—
70.8/61.9
67.7/—
63
73
71
70
69
72
81
100:0
100:0
100:0
29:71
100:0
57:43
52:48
S
SO2
H
H
71.4/64.6
71.2/65.1
a
Average of integration of at least two relevant signals in the 13C NMR spectra of the crude products was used to elicit the ratio of E/Z isomeric olefins.

6880
H. S. P. Rao et al. / Tetrahedron Letters 53 (2012) 6877–6880
1Η: δ 4.60 (s)
References and notes
13C: δ 70.8 ppm
13 1Η: δ 4.77 (d, J = 4 Hz)
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1
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1Η: δ 4.67
11
12
(d, J = 4 Hz)
13C: 64.5 ppm
Na2S
O
O
10 13
δ
O
O
9
1
50% NaOH
EtOH, H2O (1:1)
reflux, 6h, 57%
S
5
Cl
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33
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Scheme 7. Independent synthesis of 13-membered dioxa-thia macrocycle (Z)-16
and diagnostic NMR spectral values.
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H.S.P.R. thanks UGC, UGC-SAP, CSIR, and DST-FIST for financial
assistance. S.R., C.G., and N.M. thank CSIR/UGC for providing fel-
lowship. We thank IACS, Kolkata and SAIC, IIT, Chennai for record-
ing HRMS spectra.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.065.