The synthesis of 12-membered macrocycles containing a C1-C8 alkene unit via ring-closing metathesis

Article abstract of DOI:10.1016/j.tet.2012.04.043

Model cross and ring-closing metathesis strategies toward the C1-C8-linear carbon skeleton are presented. The introduction of a four-atom tether enables the formation of 12-membered rings in good-to-excellent yields and stereoselectivity. Furthermore, the study revealed that the cross-metathesis approach and the formation of medium ring sizes via ring-closing metathesis are much less favorable.

Full text of DOI:10.1016/j.tet.2012.04.043

Tetrahedron 68 (2012) 5081e5086
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The synthesis of 12-membered macrocycles containing a C1eC8 alkene unit via
ring-closing metathesis
a
,
b
a
,
b
,
c
c
ꢀc
ꢀ
*
ꢀ
Franc Pozgan , Bogdan Stefane
, Davor KiCemet , Janez Smodis , Rok Zupet
a
ꢀ
ꢀ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, SI-1000 Ljubljana, Slovenia
b EN-FIST Centre of Excellence, Dunajska 156, SI-1000 Ljubljana, Slovenia
c
ꢀ
ꢀ
Krka, d.d., Novo mesto, Smarjeska cesta 6, SI-8501 Novo mesto, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
Model cross and ring-closing metathesis strategies toward the C1eC8-linear carbon skeleton are pre-
sented. The introduction of a four-atom tether enables the formation of 12-membered rings in good-to-
excellent yields and stereoselectivity. Furthermore, the study revealed that the cross-metathesis
approach and the formation of medium ring sizes via ring-closing metathesis are much less favorable.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 23 January 2012
Received in revised form 23 March 2012
Accepted 10 April 2012
Available online 19 April 2012
This work is dedicated to Professor
Dr. Christian Bruneau on the occasion
of his 60th birthday
Keywords:
Renin inhibitors
Metathesis
Olefines
Lactones
Lactams
1. Introduction
administration properties. The first synthesis toward renin inhibitors
applied a convergent synthetic strategy via coupling of the enantio-
The renin-angiotensin system,1 known to regulate blood pressure,
has been the target of studies leading to the discovery of angiotensin-
converting enzyme inhibitors2 and angiotensin II receptor blockers.3
Due to its role in the enzymatic cascade, leading to the ultimate re-
lease of vasoconstricting peptides, renin was considered as an im-
portant target to prevent hypertension. Thorough, structure-based
design research revealed a number of potent inhibitors of renin.4
However, because none of the peptide-like renin inhibitors survived
all the stages of drug development, there was a need for new class-
es of nonpeptide renin inhibitors that fulfill all the criteria
for becoming a successful drug. Researchers designed a new class
of hydroxyethylene-based renin inhibitors that lack the peptide
backbone.5 From this research, the nonpeptide compound,
[2(S),4(S),5(S),7(S)-N-(carbamoyl-2-methylpropyl)-5-amino-4-hydr-
oxy-2,7-diisopropiyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]
octanamide] (aliskiren)6 emerged as a potent renin modulator,
exhibiting a sub-nanomolar binding affinity to human renin and oral
pure Grignard reagent and diastereomerically pure g
-lactone.7
Dondoni et al. described the synthesis of the renin inhibitor
SPP-100 involving the addition of the Grignard reagent to a nitrone
intermediate.8 Furthermore, Hanessian et al. developed a stereo-
controlled approach to CGP-60536B, a potent renin inhibitor, inwhich
the entire carbon skeleton of the target molecule was incorporated in
a partially functionalized bicyclic indolizidinone precursor.9 Later on
Skrydstrup et al. explored an alternative coupling strategy for the
preparation of the hydroxyethylene isostere-based class of protease
inhibitors.10 A similar methodology was applied for a SmI2-promoted
acyl-like radical addition reaction between an amino acid11a or N-acyl
oxazolidinones11b with substituted acrylates and acrylamides as a key
step to the synthesis of the potent renin inhibitor, aliskiren. An
asymmetric hydrogenationprocessfor the preparation of the aliskiren
intermediate has been developed using ligated rhodium and ruthe-
nium catalysts.12 Recently, Hanessian et al. described a total synthesis
of aliskiren, a strategy relying on the ring-closing metathesis reaction,
producing the nine-membered lactone as a key intermediate in an
excellent yield.13 Furthermore, novel nonpeptide small-molecule re-
nin inhibitors bearing an N-isopropyl P1 motif were discovered based
on an initial lead structure and aliskiren.14
* Corresponding author. Tel.: þ386 2419 264; fax: þ386 2419 220; e-mail
ꢀ
address: Bogdan.stefane@fkkt.uni-lj.si (B. Stefane).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.043

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F. Pozgan et al. / Tetrahedron 68 (2012) 5081e5086
5082
We now report a model study to generate 12-membered mac-
rocycles containing an unsaturated C1eC8 unit by ring-closing
metathesis.
2. Results and discussion
As a part of our efforts toward the synthesis of aliskiren ana-
logues, we envisioned that their C8-linear carbon skeleton A could
be assembled via the metathesis synthetic step due to the existing
symmetry in the chain structure (Scheme 1).
Scheme 1. Retrosynthetic pathway for the construction of the C8-linear carbon
framework A.
Scheme 3.
Initially, the cross-metathesis reaction (CM) of two differently
functionalized pentenes was undertaken. Thus, reacting the ketone
1 and alcohol 2 (in a 2-fold excess) in the presence of the HeG(II)
catalyst in refluxing dichloromethane resulted in the formation of
the asymmetric dimer 3 in a disappointing yield of 36%, mostly at
the expense of side products arising from isomerization and
homocoupling of the starting materials (Scheme 2).
isolated in a modest yield of 43%.16 It is worth mentioning that
applying the first-generation Grubbs catalyst did not result in the
formation of nonalactone 8. It has been noted that the site of the
ring closure in the formation of 12- to 21-membered macrocycles
by the RCM reaction may influence the reaction outcome.17 We
speculated that a low yield of the cyclization reaction affording the
nonalactone 8 might be due to the formation of a regioisomer
having a carbon-carbon double bond at position 4 instead of 5, if
compared to the successful formation of topsentolide B3. To in-
vestigate this hypothesis we evaluated the cyclization of compound
9 (Scheme 4), applying the same reaction conditions. The isomeric
nonanolactone 10 was isolated in a similar yield of 32%.
Scheme 2. CM experiment.
As the above described metathesis reaction led to the low yield of
the cross-coupling product, an alternative approach to the construc-
tion of the C1eC8-carbon unit, being incorporated in a cyclic struc-
ture, by employing a ring-closing (RC) metathesis reaction was
attempted.We started ourmetathesis approachfrom readilyavailable
anhydrides 4 (Scheme 3) that were prepared from the corresponding
pent-4-enoic acids in good yields. Once formed, the cyclic anhydrides
5 would be suitable for further desymmetrization with different nu-
cleophiles, thus directly leading to the C1eC8 fragment. However,
attempted RCM reactions of 4, employing different reaction condi-
tions and ruthenium catalysts (Grubbs catalyst second generation,
HoveydaeGrubbs second generation, and tricyclohexylphosphine[3-
phenyl-1H-inden-1-ylidene][1,3-bis(2,4,6trimethylphenyl)-4-5dihy-
droimidazol-2-ylidene]ruthenium(II)dichloride), did notproducethe
desired cyclic anhydrides 5. The reaction led to dimeric, cyclic-
dimeric, and oligomeric species as indicated by the mass spectrom-
etry. Upon hydrolysis of the crude metathesis reaction mixture we
were able to isolate the dicarboxylic acids 6a and 6b in reasonable
yields and satisfactory stereoselectivity regarding the newly formed
carbonecarbon double bond.
Scheme 4. RCM of simple nonanolactone ring precursors.
ꢁ
ꢁ
According to the results of Rao et al., and Hernandez-Galan
et al.,18 and our own observations we can conclude that high-
yielding cyclization in the synthesis of topsentolide B3 most prob-
ably results from the conformational restraints, the ThorpeeIngold
effect,19 originating in the side chain of topsentolide B3 and is ap-
parently not related to the position of the carbonecarbon double
bond in the final lactone ring.
However, the concept of tethering in intermolecular olefin
metathesis (i.e., CM) has proved to be beneficial and is a well-
established synthetic strategy. This approach also addresses two
major drawbacks of the CM strategy, i.e., E/Z stereoselectivity and
an excess of one of the reaction partners in the process. A tempo-
rarily installed unit connecting two fragments enables the forma-
tion of different ring sizes and can be disposed of from the system
after the completion of the desired transformation. The selection of
a disposable unit is based on the nature of the substrates and the
applied reaction conditions in the specific transformation. The
tethering unit should be stable during the synthetic operations and
Rao et al.15 reported an elegant synthesis of topsentolide B3
involving an RCM synthetic step for the formation of the
substituted nine-membered lactone ring, having a carbonecarbon
double bond at position 5. Encouraged by these results we first
tested the cyclization of model diene 7 (Scheme 4) catalyzed by the
HoveydaeGrubbs second-generation catalyst (HeG(II), 2.5 mol % in
refluxing dichloromethane). The corresponding nonalactone 8 was

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F. Pozgan et al. / Tetrahedron 68 (2012) 5081e5086
5083
Table 1
should be a functional group that is compatible with the catalytic
system.
In due course we oriented toward the RCM for the preparation of
Synthesis of 12-membered rings 14 with a C8 unit Aa
larger ring systems and subsequently synthesized dihydrazide 11
(Scheme 5) in which two identical five-carbon units are tethered
via 1,2-dimethylhydrazine, which served as a model substrate for
the formation of the 10-membered ring.
Entry
1
Productb
Yieldc (%)
85
77
Scheme 5. RCM reaction forming 10-membered heterocycle 12.
14a
Three different ruthenium metathesis catalysts (Grubbs’ catalyst
second generation, HoveydaeGrubbs second generation, and tri-
cyclohexylphosphine[3-phenyl-1H-inden-1-ylidene][1,3-bis(2,4,6-
trimethylphenyl)-4-5dihydroimidazol-2-ylidene]ruthenium(II) di-
chloride) were examined in the cyclization of 11 to 12. Among
them, the HoveydaeGrubbs second generation catalyst (2.5 mol %)
proved to be the most efficient, but still the product 12 was isolated
in a low yield (Scheme 5). However, not every ring size is accessible
with the same efficiency because of enthalpic (increasing strain in
the transition state) and entropic influences (probability of the
chain ends meeting) on the cyclization process. Consequently,
medium-sized rings are generally difficult to prepare.20
Next we considered a complementary route to a subunit of type A
(Scheme 1), starting from acyclic diester or amido-ester precursors
13. The RCM reaction of dienes 13 containing a four-atom tether
would afford 12-membered rings for the control of the E-configu-
ration of the newly formed double bond. Disposal of a tethering unit
from the RCM generated rings would directly lead to framework A.
Using glycol as a tether made it possible to test whether the
approach to the C1eC8-linear carbon framework through 12-
membered rings is more feasible. Apart from the glycol and ami-
noethanol tether-based RCM we introduced a 1,2-dihydroxybenzene
(catechol) tether to assist the RCM strategy. Thus, the unsubstituted
dienes 13aec smoothly underwent the RCM in the presence of the
HeG(II) catalyst (2.5 mol %, CH2Cl2, 40 ꢀC) and the corresponding
unsaturated 12-membered heterocyclic rings were formed in good-
to-excellent yields (Table 1, entries 1e3). Additionally, o-amino-
phenol and o-phenylenediamine were introduced as a link to expand
the tethering options in the studied system. The substrates 13d and
13e were also successfully cyclized to the 12-membered rings in
a 90% isolated yield for 14d and 94% for 14e, respectively (Table 1,
entries 4 and 5). Similar results were obtained using the iso-propyl
substituted analogues 13f and 13g. In all cases the mixtures of
E/Z-isomers in a ratio of 10:1 were observed.
2
14b
3
4
81
90
14c
14d
14e
5
6
94
85
14f
7
81
In order to establish the configuration of the major isomer in
products 14 we prepared a single crystal of compound 14b suitable
for X-ray analysis,21 which together with 1H, 13C, and NOESY NMR
spectroscopy confirmed the E-isomer to be the major one in all
cases. Different shieldings of the allylic carbons in the olefin
structures could be significant for trans and cis isomers, as is evi-
dent in linear structures.22 Namely, we have observed a systematic
upfield shift for the allylic carbons in cis isomers 14 compared to
trans-14.
14g
a
Reaction conditions: HoveydaeGrubbs second-generation catalyst (2.5 mol %),
DCM, reflux, 5e25 h.
b
The ratio of E/Z was determined by 1H NMR spectroscopy and was found to be
10:1 in all cases.
c
Yields of pure isolated products are given.
Finally, we validated the ring opening reaction of the macro-
cycles 14. Thus, the ester functionality of 14d was selectively hy-
drolyzed by using LiOH in ethanol/water mixture leading to the
bifunctional C1eC8-linear alkene 15 in an excellent yield of 96%
(Scheme 6).
In conclusion, model ring-closing metathesis strategies toward
the C1eC8-carbon skeleton have been presented. The introduction
of a four-atom tether enables the formation of 12-membered rings
in good yields and stereoselectivity with E-isomer being the major

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F. Pozgan et al. / Tetrahedron 68 (2012) 5081e5086
5084
3H, CH2CH] in CHCH2OH), 2.65e2.88 (m, 2H, CH2CH]CH),
3.58e3.70 (m, 2H, H2COH), 4.34 (t, J¼7.3 Hz, 1H, CHCOPh),
5.26e5.30 (m, 2H, CH]CH), 7.09e7.48 (m, 13H, Ar), 7.88e7.91 (m,
2H, Ar); 1H NMR (300 MHz, CDCl3) major isomer:
d 1.54 (rs,1H, OH),
2.19e2.48 (m, 3H, CH2CH] and CHCH2OH), 2.65e2.88 (m, 2H,
CH2CH]CH), 3.58e3.70 (m, 2H, H2COH), 4.47 (t, J¼7.3 Hz, 1H,
CHCOPh), 5.34e5.38 (m, 2H, CH]CH), 7.09e7.48 (m, 13H, Ar),
7.88e7.91 (m, 2H, Ar); 13C NMR (75.5 MHz, CDCl3) major isomer:
Scheme 6. Opening of macrocycle 14d.
d
35.3, 37.0, 48.3, 54.0, 66.6, 126.6, 127.0, 127.9, 128.1, 128.42, 128.44,
128.6, 128.8, 129.4, 130.0, 132.8, 136.7, 139.1, 142.0, 199.3; m/z (EIꢂ)
371 (MHþ); HRMS (EIꢂ): MHþ, found 371.2014. C26H27O2 requires
371.2011.
one. Furthermore, the presented study revealed that the CM ap-
proach and the formation of medium ring sizes via RCM are much
less favorable, compared to the formation of 12-membered systems
14. The selective base hydrolysis of the macrocycle 14 led to the
asymmetric C1eC8-linear alkene skeleton.
3.2.2. (2S)-2-Isopropylpent-4-enoic anhydride (4b). To the solution
of (S)-2-isopropylpent-4-enoic acid23 (4a) (1.0 g, 7.04 mmol) in dry
dichloromethane (17 mL) the solution of N,N0-dicyclohex-
ylcarbodiimide (0.747 g, 3.62 mmol) in dry dichloromethane (8 mL)
was added over a period of 6 h. The reaction mixture was allowed
to stir for an additional hour at room temperature. After the re-
action was completed the reaction mixture was filtered and the
solvent evaporated at 40 ꢀC under reduced pressure. The residue
was suspended in petroleum ether (30 mL) and cooled to ꢂ20 ꢀC
for 8 h. The precipitated material was filtered off and washed with
petroleum ether (10 mL). The solvent was removed by evaporation
3. Experimental section
3.1. General information
All non-aqueous reactions were run in flame-dried glassware
under a positive pressure of argon with exclusion of the moisture
from reagents and glassware using standard techniques for ma-
nipulating air-sensitive compounds. Anhydrous solvents were
obtained using standard drying techniques. Unless stated other-
wise, commercial-grade reagents were used without further puri-
fication. Reactions were monitored by analytical thin-layer
chromatography (TLC) or reverse-phase HPLC. Visualization of the
developed TLC chromatogram was performed by UV absorbance or
aqueous potassium permanganate. Flash chromatography was
performed on 230e400-mesh silica gel with the indicated solvent
system. Yields refer to chromatographically and spectroscopically
(1H and 13C NMR) homogenous materials. Reverse-phase HPLC
under a reduced pressure at 40 ꢀC and a colorless oily residue was
25
distilled under vacuum. Yield 824 mg (88%). [
a
]
Hg
þ12.6 (c 5.0,
CH2Cl2); IR (NaCl, cmꢂ1) 2965, 1811, 1744, 1643, 1466, 1371, 1032; 1H
NMR (300 MHz, CDCl3)
d
1.00 (d, 6H, J¼7.0 Hz, eCH(Me)2), 1.01 (d,
6H, J¼7.0, eCH(Me)2), 1.97 (sym 7-line m, 2H, J¼7.0 Hz, eCH(Me)2),
2.25e2.41 (m, 6H, H2C]CHeCH2CH), 5.03e5.14 (m, 4H, H2C]
CHe), 5.71e5.85 (m, 2H, H2C]CHe); 13C NMR (126 MHz, DMSO-
d6)
d
19.3, 28.1, 30.4, 54.9, 115.6, 138.1, 170.9; m/z (EIþ) 267 (MHþ);
HRMS (EIþ): MHþ, found 267.1963. C16H27O3 requires 267.1960.
analyses were performed using C18 column (60ꢁ4.6 mm, 2
mM)
3.2.3. Oct-4-enedioic acid (6a). To the solution of pent-4-enoic an-
hydride (4b) (547 mg, 3.0 mmol) in dichloromethane (150 mL) the
HoveydaeGrubbs second generation catalyst (47 mg, 0.075 mmol,
2.5 mol %) was added. The reaction mixture was refluxed for 12 h and
then evaporated at 25 ꢀC. The residue was dissolved in tetrahydro-
furan (15 mL) and NaOH (2 M, 3 mL) was added. The reaction mixture
was stirred at room temperature for 24 h. After the reaction was
completed the reaction mixture was evaporated under reduced
pressure and the residue dissolved in dichloromethane (20 mL) and
washed with NaOH solution (2 M, 30 mL). The water layer was
acidified with HCl (1:1, v/v) to pH¼1 and the product was extracted
with ethyl acetate (3ꢁ30 mL). The combined organic phases were
dried over anhydrous Na2SO4, filtered, and evaporated, yielding
280 mg (54%) of product. White crystals. Mp¼151e154 ꢀC; IR (NaCl,
cmꢂ1) 3477,1689,1432,1430,1328,1276,1208, 984, 935, 685; 1H NMR
and water/acetonitrile gradient; UV detection at 254 nm. Melting
points are uncorrected. Infrared spectra were recorded on an FTIR
spectrometer and are reported in reciprocal centimeters (cmꢂ1
)
Routine nuclear magnetic resonance spectra were recorded either
on a Bruker Avance DPX 300 or Avance III 500 MHz spectrometer.
Chemical shifts for 1H NMR spectra are recorded in parts per mil-
lion (ppm) from tetramethylsilane as an internal standard. Data
are reported as follows: chemical shift, number of equivalent nuclei
(by integration), multiplicity, (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, qn¼quintet, sext¼sextet, sept¼septet, m¼multiplet,
and br¼broad), coupling constants (J) quoted in hertz to the nearest
0.25 Hz. Chemical shifts for the 13C NMR spectra are recorded in
parts per million from tetramethylsilane using the central peak of
the solvent resonance as an internal standard. All spectra were
obtained with complete proton decoupling. High-resolution mass
spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/
MS instrument by electrospray ionization operating at a resolution
of 15,000 full widths at half height.
(300 MHz, DMSO-d6)
d 2.28e2.35 (m, 4H, eCHCH2CH2e), 2.39e2.45
(m, 4H, eCH2CH2CO2H), 5.40e5.554 (m, 2H, eCH]CHe); 13C NMR
(126 MHz, DMSO-d6) d
173.9, 129.3, 33.6, 27.4; m/z (EIꢂ) 171 (MHꢂ);
HRMS (EIꢂ): MHꢂ, found 171.0657. C8H11O4 requires 171.0657. Found:
C, 55.88; H, 7.06%. C8H12O4 requires C, 55.81; H, 7.02%.
3.2. Experimental procedures
3.2.4. (2S,7S)-2,7-Diisopropyloct-4-enedioic acid (6b). To the solu-
tion of (2S)-2-isopropylpent-4-enoic anhydride (1.0 g, 3.76 mmol)
in dichloromethane (150 mL) the HoveydaeGrubbs second gener-
ation catalyst (59 mg, 0.095 mmol, 2.5 mol %) was added. The re-
action mixture was refluxed for 12 h and then evaporated at 25 ꢀC.
The residue was dissolved in tetrahydrofuran (15 mL) and NaOH
(2 M, 6 mL) was added. The reaction mixture was stirred at room
temperature for 24 h. After the reaction was completed the reaction
mixture was evaporated under reduced pressure and the residue
dissolved in dichloromethane (20 mL) and washed with NaOH
solution (2 M, 30 mL). The water layer was acidified with HCl (1:1,
3.2.1. 8-Hydroxy-1,2,7-triphenyloct-4-en-1-one (3). To the solution
of ketone 1 (169 mg, 0.72 mmol) and alcohol 2 (233 mg,1.44 mmol)
in dichloromethane (10 mL) the HoveydaeGrubbs second-
generation catalyst (11 mg, 2.5 mol %) was added. The reaction
mixture was refluxed for 24 h and then evaporated under reduced
pressure. The residue, yellow oil, was purified by column chroma-
tography (SiO2, petroleum ether/ethyl acetate¼20:1) yielding
96 mg (36%) of 3; colorless oil, mixture of isomers¼1:4; IR (NaCl,
cmꢂ1) 3425, 3061, 3027, 2920, 1681, 1598, 1494, 1449, 699; 1H NMR
(300 MHz, CDCl3) minor isomer: d 1.54 (br s, 1H, OH), 2.19e2.48 (m,

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F. Pozgan et al. / Tetrahedron 68 (2012) 5081e5086
5085
v/v) to pH¼1 and the product was extracted with ethyl acetate
(3ꢁ30 mL). The combined organic phases were dried over anhy-
drous Na2SO4, filtered, and evaporated, yielding 900 mg of the
crude product. The purification by column chromatography (SiO2,
petroleum ether/ethyl acetate¼10:1þ2% CH3CO2H) yielded 703 mg
(73%) of pure product as colorless oil; IR (NaCl, cmꢂ1) 2965 (br),
(16 mg, 0.025 mmol, 2.5 mol %) was added. The reaction mixture
was heated at 40 ꢀC for 5e24 h. After the reaction was
completed (monitored by TLC or HPLC) the reaction mixture was
evaporated under reduced pressure and the residue chromato-
graphed on SiO2.
2650, 1702, 1466; 1H NMR (300 MHz, CDCl3)
d
major isomer: 0.94
3.2.8.1. 1,4-Dioxacyclododec-8-ene-5,12-dione (14a). After the
chromatography (using dichloromethane as an eluent), the title
compound 14a was isolated, colorless oil, 180 mg (87%); IR (NaCl,
cmꢂ1): 2946, 1736, 1443, 1346, 1240, 1176, 1131, 1053, 974, 857; 1H
(d, J¼6.0 Hz, 12H, 2ꢁMe), 1.86 (sym 6-line m, J¼6.0 Hz, 2H),
2.10e2.26 (m, 6H), 5.45 (m, 2H); minor isomer: 0.98 (d, J¼6.0 Hz,
12H, 2ꢁMe), 1.89 (sym 6-line m, J¼6.0 Hz, 2H), 2.2e2.40 (m, 6H),
5.44 (m, 2H), 10.80 (br s, 2H); 13C NMR (75 MHz, CDCl3) major
NMR (300 MHz, CDCl3):
d
¼2.29e2.31 (m, 8H, eCH2CH2e), 4.35 (s,
isomer:
d
20.0, 20.5, 30.3, 32.4, 52.4, 129.5, 180.9; minor isomer:
4H, eOCH2CH2Oe), 5.39e5.41 (m, 2H, eCH]CHe); 13C NMR
19.9, 20.4, 27.0, 30.1, 52.9, 128.4, 181.6. MS-ESI m/z (%): 279 (100,
MþNaþ); HRMS calculated for C14H24O4Na: 279.1572; found:
279.1570.
(75 MHz, CDCl3):
d
¼172.9, 129.9, 60.8, 34.7, 29.2; m/z (EIþ) 199
(MHþ); HRMS (EIþ): MHþ, found 199.0976. C10H15O4 requires
199.0970.
3.2.5. Oxacyclonon-5-en-2-one (8). To a solution of pent-4-en-1-yl
pent-4-enoate (7) (168 mg, 1.0 mmol) in dichloromethane (50 mL),
the HoveydaeGrubbs second generation catalyst (16 mg,
0.025 mmol, 2.5 mol %) was added. The reaction mixture was
heated at 40 ꢀC for 5 h. After the reaction was completed the re-
action mixture was evaporated under reduced pressure and the
residue chromatographed (SiO2, dichloromethane) to give 61 mg
(43%) colorless oil; IR (NaCl, cmꢂ1) 2953, 2926, 1734, 1436, 1347,
3.2.8.2. 1-Oxa-4-azacyclododec-8-ene-5,12-dione
(14b). After
the chromatography (using dichloromethane/methanol¼20:1 as an
eluent), the title compound 14b was isolated as a mixture of iso-
mers E/Z¼10:1, white solid, 145 mg (74%). Mp¼144e145 ꢀC; IR (KBr,
cmꢂ1): 3281, 3098, 2936, 2849, 1719, 1641, 1566, 1439, 1346, 1263,
1181, 1040, 980, 955, 713; 1H NMR (300 MHz, CDCl3):
d
¼2.17e2.46
(m, 8H, eCH2CH2e), 3.55 (dt, J¼5.5, 5.5 Hz, 2H, eCH2CH2NHe), 4.29
(t, J¼5.0 Hz, 2H, eOCH2CH2e), 5.37e5.47 (m, 2H, eCH]CHe), 7.26
1254, 1159, 972; 1H NMR (300 MHz, CDCl3):
d
¼1.59e1.74 (m, 2H,
(s, 1H, eNHCOe); 13C NMR (75 MHz, DMSO):
d
¼173.8, 172.4, 130.6,
eCH2CH2CH2e), 2.00e2.20 (m, 2H, eCH2CH2CH]CH2), 2.29e2.44
(m, 4H, eCH2CH2COOe), 4.04e4.15 (m, 2H, eCH2Oe), 5.34e5.51
130.2, 60.6, 38.4, 37.1, 34.5, 29.1, 29.0; m/z (EIþ) 198 (MHþ); HRMS
(EIþ): MHþ, found 198.1125. C10H16NO3 requires 198.1130. Found: C,
60.61; H, 7.68; N, 7.08%. C10H15N2O2 requires C, 60.90; H, 7.67;
N, 7.10%.
(m, 2H, eCH]CHe); 13C NMR (75 MHz, CDCl3):
d¼173.4, 131.2,
128.9, 63.7, 34.7, 29.0, 28.9, 28.7; m/z (EIþ) 141 (MHþ); HRMS (EIþ):
MHþ, found 141.0912. C8H13O2 requires 141.0916.
3.2.8.3. 3,4,7,8-Tetrahydrobenzo[b][1,4]dioxacyclododecine-2,9-
dione (14c). After the chromatography (using petroleum ether/
ethyl acetate¼7:1 as an eluent), the title compound 14c was iso-
lated as a mixture of isomers E/Z¼10:1, white solid, 200 mg (81%).
Mp¼143e145 ꢀC; IR (KBr, cmꢂ1): 3065, 2951, 1755, 1493, 1345,
1238, 1151, 1119, 1097, 945, 840, 762; 1H NMR (300 MHz, CDCl3):
3.2.6. Oxacyclonon-6-en-2-one (10). To a solution of but-3-en-1-yl
hex-5-enoate (9) (178 mg, 1.06 mmol) in dichloromethane
(50 mL), the Hoveyda-Grubbs second generation catalyst
(17 mg, 0.027 mmol, 2.5 mol %) was added. The reaction mixture
was heated at 40 ꢀC for 12 h. After the reaction was completed
the reaction mixture was evaporated under reduced pressure
and the residue chromatographed (SiO2, petroleum ether/ethyl
d
¼2.42e2.48 (m, 4H, eCH2CH2e), 2.63e2.67 (m, 4H, eCH2CH2e),
5.61e5.65 (m, 2H, eCH]CHe), 7.08e7.14 (m, 2H, Ar), 7.22e7.26 (m,
acetate¼10:1) to give 48 mg (32%), colorless oil; IR (NaCl, cmꢂ1
)
2H, Ar); 13C NMR (75 MHz, CDCl3):
d¼170.8, 142.4, 130.0, 126.9,
2951, 2934, 1726, 1311,1224,1159, 1020, 962, 926; 1H NMR (500 MHz,
123.8, 43.7, 28.9; m/z (EIþ) 247 (MHþ); HRMS (EIþ): MHþ, found
247.0977. C14H15O4 requires 247.0970. Found: C, 68.36; H, 5.83.
C14H14O4 requires C, 68.36; H, 5.83%.
CDCl3):
d
¼1.66e1.73 (m, 2H, eCH2CH2CH2e), 2.03e2.09 (m, 2H,
eCH2CH2CH]CHe), 2.24e2.29 (m, 2H, eCH2COOe), 2.30e2.35 (m,
2H, ]CHeCH2eCH2Oe), 4.11e4.15 (m, 2H, eCH2CH2Oe), 5.29e5.50
(m, 2H, eCH]CHe); 13C NMR (126 MHz, CDCl3):
d¼173.7, 132.0,
3.2.8.4. 3,4,7,8-Tetrahydro-2H-benzo[b][1,4]oxaazacyclododecine-
2,9(10H)-dione (14d). After the chromatography (using petroleum
ether/ethyl acetate¼7:1 as an eluent), the title compound 14d was
isolated as a mixture of isomers E/Z¼10:1, white solid, 220 mg (90%).
Mp¼143e146 ꢀC; IR (KBr, cmꢂ1): 3676, 3287, 2963, 1763, 1657, 1526,
1452, 1186, 1096, 990, 915, 752; 1H NMR (500 MHz, CDCl3):
127.5, 62.9, 33.4, 32.0, 31.7, 24.5; m/z (EIþ) 141 (MHþ); HRMS (EIþ):
MHþ, found 141.0908. C8H13O2 requires 141.0916.
3.2.7. N,N0-Dimethyl-1,2-diazacyclodec-5-en-3,10-dione
(12). To
a solution of N,N0-dimethyl-N0-(pent-4-enoyl)pent-4-enehydrazide
(11) (224 mg, 1.0 mmol) in dichloromethane (50 mL), the
HoveydaeGrubbs second generation catalyst (16 mg, 0.025 mmol,
2.5 mol %) was added. The reaction mixture was heated at 40 ꢀC for
20 h. After the reaction was completed the reaction mixture was
evaporated under reduced pressure and the residue chromato-
graphed (SiO2, dichloromethane/methanol¼20:1)togive50 mg(26%)
white solid. Mp¼207e209 ꢀC; IR (NaCl, cmꢂ1) 2918, 1658, 1432, 1379,
d
¼2.47e2.51 (m, 2H, eCH2CH]CH2), 2.55e2.59 (m, 4H,
eCH2CH2COe), 2.74 (t, J¼6.0 Hz, 2H, eCH2CH2COe), 5.65e5.71 (m,
1H, eCH]CHe), 5.84e5.90 (m, 1H, eCH]CHe), 7.05 (dd, J¼1.5,
8.0 Hz, 1H, Ar), 7.12 (ddd, J¼1.5, 8.0, 8.0 Hz, 1H, Ar), 7.24 (ddd, J¼1.5,
8.0, 8.0 Hz,1H, Ar), 7.88 (rs,1H, AreNHeCOe), 8.23 (dd, J¼1.5, 8.0 Hz,
1H, Ar); 13C NMR (126 MHz, CDCl3):
d¼171.1,170.7,140.4,132.37 (2C),
130.1, 126.8, 124.5, 122.6, 122.2, 36.6, 34.6, 29.6, 28.5; m/z (EIþ) 246
(MHþ); HRMS (EIþ): MHþ, found 246.1125. C14H16NO3 requires
246.1130. Found: C, 68.44; H, 6.06; N, 5.70. C14H15NO3 requires C,
68.56; H, 6.16; N, 5.77%.
1277, 1149, 978; 1H NMR (300 MHz, CDCl3):
d
¼2.20e2.45 (m, 8H,
eCH2CH2e), 3.09 (s, 3H, eCH3), 3.12 (s, 3H, eCH3), 5.46e5.50 (m, 2H,
eCH]CHe); 13C NMR (75 MHz, CDCl3):
d
¼174.0, 173.9, 129.7, 129.4,
33.5, 33.2,31.8, 31.1, 27.0,26.7;m/z(EIþ)197(MHþ); HRMS(EIþ): MHþ,
found 197.1295. C10H17N2O2 requires 197.1290. Found: C, 60.89; H,
8.58; N, 13.90%. C10H16N2O2 requires C, 61.20; H, 8.22; N, 14.27%.
3.2.8.5. 3,4,7,8-Tetrahydrobenzo[b][1,4]diazacyclododecine-
2,9(1H,10H)-dione (14e). After the reaction was completed the re-
action mixture was cooled down to 0 ꢀC and the precipitated ma-
terial filtered off. White solid, 229 mg (94%). Mp¼266e268 ꢀC; IR
(KBr, cmꢂ1): 3242, 3028, 1646, 1599, 1531, 1499, 768; 1H NMR
3.2.8. General procedure for the synthesis of 12-membered hetero-
cycles (14aeg). To a solution of olefin 13 (1.0 mmol) in dichloro-
methane (50 mL), the HoveydaeGrubbs second generation catalyst
(300 MHz, DMSO):
d
¼2.27e2.39 (m, 8H, eCH2CH2e), 5.50e5.53 (m,

ꢀ
F. Pozgan et al. / Tetrahedron 68 (2012) 5081e5086
5086
2H, eCH]CHe), 7.18e7.23 (m, 2H, Ar), 7.28e7.34 (m, 2H, Ar),
8.95 ppm (rs, 2H, AreNHeCOe); 13C NMR (75 MHz, DMSO):
264.1228. Found: C, 63.54; H, 6.47; N, 5.23%. C14H17NO4 requires C,
63.87; H, 6.51; N, 5.32%.
d
¼171.9, 133.5, 132.1, 127.4, 127.1, 37.3, 30.1; m/z (EIþ) 245 (MHþ);
HRMS (EIþ): MHþ, found 245.1290. C14H17N2O2 requires 245.1290.
Acknowledgements
3.2.8.6. 6,11-Diisopropyl-1-oxa-4-azacyclododec-8-ene-5,12-
dione (14f). After the chromatography (using dichloromethane/
methanol¼100:1 as an eluent), the title compound 14f was isolated
as a mixture of isomers E/Z¼10:1, white solid, 238 mg (85%).
Mp¼180e185 ꢀC; IR (KBr, cmꢂ1): 3675, 3298, 2987, 2970, 2901,
1712, 1646, 1560, 1405, 1383, 1393, 1241, 1075, 1066, 1056, 959, 892,
The Ministry of Higher Education, Science and Technology of the
Republic of Slovenia and the Slovenian Research Agency (P1-0230-
0103) are gratefully acknowledged for their financial support. The
study was performed and financed as a part of the EN/FIST Centre
of Excellence.
764; 1H NMR (500 MHz, CDCl3):
d¼0.89 (d, J¼6.5 Hz, 3H, eCH3),
0.90 (d, J¼6.5 Hz, 3H, eCH3), 0.93 (d, J¼7.0 Hz, 3H, eCH3), 0.94 (d,
J¼7.0 Hz, 3H, eCH3), 1.59 (ddd, J¼3.0, 9.0, 12.0 Hz, 1H,
eCH(CH(CH3)2)CH2eCH]CHe), 1.74e1.81 (m, 1H, eCHCH(CH3)2),
1.82e1.90 (m, 1H, eCHCH(CH3)2), 2.08e2.15 (m, 2H, eCH(CH3)2),
2.19e2.26 (m, 3H, eCH2eCH]CHeCH2e), 2.91e2.94 (m, 1H,
eOCH2CH2NHe), 3.61e3.65 (m, 1H, eOCH2CH2NHe), 4.19e4.27 (m,
1H, eOCH2CH2NHe), 4.92e4.97 (m, 1H, eOCH2CH2NHe),
5.27e5.38 (m, 3H, eCH]CHe, eCH2eNHeCOe); 13C NMR
Supplementary data
Characterization and synthetic procedures for the starting ma-
terials 7, 9 and 13ae13g, as well as ORTEP diagrams of compounds
14b and 14d. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2012.04.043.
References and notes
(126 MHz, CDCl3):
d
¼176.1, 174.8, 130.7, 129.4, 60.0, 56.7, 53.4, 38.3,
33.8, 33.5, 30.9, 30.1, 21.3, 20.7, 20.3, 20.2; m/z (EIþ) 282 (MHþ);
HRMS (EIþ): MHþ, found 282.2056. C16H28NO3 requires 282.2050.
Found: C, 68.20; H, 9.51; N, 4.82%. C16H27NO3 requires C, 68.29; H,
9.67; N, 4.98%.
1. (a) Brewster, U. C.; Parazella, M. A. Am. J. Med. 2004, 116, 263; (b) MacGregor, G.
A.; Markandu, N. D.; Roulston, J. E.; Jones, J. C.; Morton, J. J. Nature 1981, 291,
329.
2. Patchett, A. A.; Cordes, E. H. Adv. Enzymol. Relat. Areas Mol. Biol. 1985, 57, 1.
3. (a) Ruilope, L. M.; Rosei, E. A.; Bakris, G. L.; Mancia, G.; Poulter, N. R.; Taddei, S.;
Unger, T.; Volpe, M.; Waeber, B.; Zanna, F. Blood Pressure 2005, 14, 196; (b)
Oparil, S.; Yarrows, S. A.; Patel, S.; Fang, H.; Zhang, J.; Satlin, A. Lancet 2007, 370,
221.
3.2.8.7. 3,8-Diisopropyl-3,4,7,8-tetrahydro-2H-benzo[b][1,4]-oxa-
azacyclododecine-2,9(10H)-dione (14g). After the chromatography
(using dichloromethane/methanol¼100:1 as an eluent), the title
compound 14f was isolated as a mixture of isomers E/Z¼10:1, white
solid, 266 mg (81%). Mp¼167e170 ꢀC; 1H NMR (500 MHz, CDCl3):
4. Kasani, N.; Subedi, R.; Stier, M.; Holsworth, D. D.; Maiti, S. N. Heterocycles 2007,
73, 47.
5. Wood, J. M.; Maibaum, J.; Rahuel, J.; Grutter, M. G.; cohen, N.-C.; Rasetti, V.;
Ruger, H.; Goschke, R.; Stutz, S.; Fuhrer, W.; Schilling, W.; Rigollier, P.; yama-
guchi, Y.; Cumin, F.; Baum, H.-P.; Schnell, C. R.; Herold, P.; Mah, R.; Jensen, C.;
O’Brien, E.; Stanton, A.; Bedigien, M. P. Biochem. Biophys. Res. Commun. 2003,
308, 698.
d¼0.97 (d, J¼6.5 Hz, 3H, eCH3), 1.02 (d, J¼6.5 Hz, 3H, eCH3), 1.04 (d,
J¼7.0 Hz, 3H, eCH3), 1.06 (d, J¼7.0 Hz, 3H, eCH3), 1.92e1.99 (m, 1H,
eCH(CH3)2), 2.06e2.10 (m, 1H, eCH2eCH]CHe), 2.18e2.25 (m, 3H,
eCH2eCH]CHeCH2e), 2.40e2.43 (m, 1H, eCH(CH3)2), 2.48e2.56
(m, 2H, eCHCH(CH3)2), 5.54e5.59 (m, 1H, eCH]CHe), 5.65e5.71
(m, 1H, eCH]CHe), 7.01 (dd, J¼1.5, 8.0 Hz, 1H, Ar), 7.19 (ddd, J¼1.5,
8.0, 8.0 Hz, 1H, Ar), 7.22 (rs, 1H, AreNHeCOe), 7.24 (ddd, J¼1.5, 8.0,
8.0 Hz, 1H, Ar), 7.72 (dd, J¼1.5, 8.0 Hz, 1H, Ar); 13C NMR (126 MHz,
6. For the identification numbers of this compound and its hemifumarate ana-
logue see Refs. 7 and 8.
€
€
7. (a) Rueger, H.; Stutz, S.; Goschke, R.; Spindler, F.; Mailbaum, J. Tetrahedron Lett.
€
2000, 41, 10085; (b) Sandham, D. A.; Taylor, R. J.; Carey, J. S.; Fassler, A. Tetra-
hedron Lett. 2000, 41, 10091.
8. Dondoni, A.; De Lathauwer, G.; Perrone, D. Tetrahedron Lett. 2001, 42, 4819.
9. Hanessian, S.; Claridge, S.; Johnstone, S. J. Org. Chem. 2002, 67, 4261.
10. (a) Blakskjaer, P.; Hoj, B.; Riber, D.; Skrydstrup, T. J. Am. Chem. Soc. 2003, 125,
4030; (b) Jensen, C. M.; Lindsay, K. B.; Taaning, R. H.; Karaffa, J.; Hansen, A. M.;
Skrydstrup, T. J. Am. Chem. Soc. 2005, 127, 6544.
CDCl3):
d
¼173.9, 173.0, 143.6, 131.3, 130.8, 130.0, 126.7, 126.5, 126.2,
122.4, 54.4, 53.5, 34.3, 31.6, 30.9, 29.7, 21.1, 21.0, 20.1, 19.2; m/z (EIþ)
328 (MꢂHꢂ); HRMS (EIþ): (MꢂH)ꢂ, found 328.1920. C20H26NO3
requires 328.1918. Found: C, 73.11; H, 8.40; N, 4.23%. C20H27NO3
requires C, 72.92; H, 8.26; N, 4.25%.
11. (a) Lindsay, K. B.; Skrydstrup, T. J. Org. Chem. 2006, 71, 4766; (b) Karaffa, J.;
Lindsay, K. B.; Skrydstrup, T. J. Org. Chem. 2006, 71, 8219.
12. (a) Boogers, J. A. F.; Felfer, U.; Kotthaus, M.; Lefort, L.; Steinbauer, G.; de Vries, A.
H. M.; de Vries, J. G. Org. Process Res. Dev. 2007, 11, 585; (b) Andeushko, N.;
€
€
Andrushko, V.; Thyrann, T.; Konig, G.; Borner, A. Tetrahedron Lett. 2008, 49,
5980.
ꢁ
ꢁ
3.2.8.8. 8-((2-Hydroxyphenyl)amino)-8-oxooct-4-enoic acid (15).
To the solution of 14d (193 mg, 0.79 mmol) in ethanol (2 mL)
LiOH$H2O (100 mg, 2.37 mmol) in water (1 mL) was added. The re-
action mixture was stirred at 25 ꢀC for 48 h. The reaction was
quenched with HCl (1 M, 10 mL) and the product was extracted with
ethyl acetate (3ꢁ10 mL). The combined organic layers were dried
over anhydrous NaSO4, and evaporated under reduced pressure to
give 200 mg (96%) of analytically pure product 15. Mp¼84e86 ꢀC; 1H
13. Hanessian, S.; Guesne, S.; Chenard, E. Org. Lett. 2010, 12, 1816.
14. Yamaguchi, Y.; Menear, K.; Cohen, N.-C.; mah, R.; Cumin, F.; Schnell, C.; Wood,
J. W.; Maibaum, J. Bioorg. Med. Chem. Lett. 2009, 19, 4863.
15. Sreedhar, E.; Venkanna, A.; Chandramouli, N.; Babu, K. S.; Rao, J. M. Eur. J. Org.
Chem. 2011, 1078.
16. As indicated by MS analysis of crude reaction mixture, dimeric, cyclic-dimeric,
and oligomeric species were formed as side products.
€
17. (a) Furstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942; (b) Goldring, W. P.
D.; Hodder, A. S.; Weiler, L. Tetrahedron Lett. 1998, 39, 4955.
ꢁ
ꢁ
ꢁ
18. Ramirez-Farnandez, J.; Collado, I. G.; Hernandez-Galan, R. Synlett 2008, 339.
19. Forbes, M. D. E.; Patton, J. T.; Myers, T. L.; Maynard, H. D.; Smith, D. W., Jr.;
Schulz, G. R.; Wagener, K. B. J. Am. Chem. Soc. 1992, 10978.
20. (a) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073; (b) Yet, L. Chem. Rev. 2000,
100, 2963; (c) Michaut, A.; Rodriguez, J. Angew. Chem., Int. Ed. 2006, 45, 4740.
21. See Supplementary data.
22. De Haan, J. W.; Van de Ven, L. J. M. Org. Magn. Reson. 1973, 3, 147.
23. (a) Hodgson, D. M.; Foley, A. M.; Lovell, P. J. Synlett 1999, 744; (b) Chakraborty,
T. K.; Chosh, A. Synlett 2002, 2039.
NMR (500 MHz, CDCl3):
d
¼2.15e2.29 (m, 6H), 2.44 (t, J¼8.0 Hz, 2H),
5.38e5.55 (m, 2H), 6.73e6.78 (m, 1H), 6.85 (dd, J¼1.5, 8.0 Hz, 1H),
6.91e6.97 (m, 1H), 7.64e7.68 (m, 1H), 9.23 (br s, 1H), 9.68 (m, 1H),
12.01 (m, 1H); 13C NMR (126 MHz, CDCl3):
d
¼173.8, 171.2, 147.9, 129.4,
129.2, 126.3, 124.6, 122.4, 118.9, 115.9, 35.7, 33.6, 28.1, 27.4; m/z (EIþ)
264 (MHþ); HRMS (EIþ): MHþ, found 264.1230. C14H18NO4 requires