New approach to the synthesis of macrocyclic tetralactones via ring-closing metathesis using Grubbs' first-generation catalyst

Article abstract of DOI:10.1021/jo062043p

(Chemical Equation Presented) A facile and efficient route to synthesize macrocyclic tetralactones with different ring sizes having a wide variety of spacers is described. The application of ring-closing metathesis for the synthesis of macrocyclic tetralactones is demonstrated with many examples in excellent yield. The representative structure of macrocyclic tetralactones is characterized by X-ray crystallography.

Full text of DOI:10.1021/jo062043p

SCHEME 1. Esterification of Dicarboxylic Acids Using
Alkenyl Bromide or Alcohol
New Approach to the Synthesis of Macrocyclic
Tetralactones via Ring-Closing Metathesis Using
Grubbs’ First-Generation Catalyst
Sengodagounder Muthusamy,*,†
Boopathy Gnanaprakasam,† and Eringathodi Suresh‡
School of Chemistry, Bharathidasan UniVersity, Tiruchirappalli,
Tamilnadu 620 024, India, and Central Salt & Marine
Chemicals Research Institute (CSIR), BhaVnagar,
Gujarat 364 002, India
as well as large rings from acyclic diene precursors. Many
macrolides have been ingeniously approached by RCM meth-
ods.3 Synthesis4 and studies5 of the macrocyclic dilactones are
impressive in organic chemistry due to their biological proper-
ties, complex formation, ion carriers, and application in the
perfume industry. Even though literature methods provide a
mixture of dilactones and tetralactones, the reactions give low
yields and require drastic conditions. Recently, we have
reported6 the synthesis of macrocyclic tetralactones via DCC/
DMAP cyclization of dicarboxylic acids. Since there has been
no other literature report toward the synthesis of macrocyclic
tetralactones, we herein report a successful method for macro-
cyclic tetralactones with different ring sizes via RCM reaction.
With the objective to develop a new alternative efficient
method for macrocyclic tetralactones, the required dicarboxylic
acids 1 were assembled by the recently reported6 method. The
dicarboxylic acids 1 having different spacers were alkylated via
two different methods. Method 1 involves the reaction of
dicarboxylic acid 1, alkenyl bromide, K2CO3, and a catalytic
amount of tetrabutylammonium iodide (TBAI) at room tem-
perature. The second method involves the reaction6 of dicar-
boxylic acid 1 and alkenol in the presence of DCC/DMAP.
The dialkylation reaction of dicarboxylic acid 1a and an
excess amount of allyl bromide was carried out on the basis of
muthu@bdu.ac.in
ReceiVed October 3, 2006
A facile and efficient route to synthesize macrocyclic
tetralactones with different ring sizes having a wide variety
of spacers is described. The application of ring-closing
metathesis for the synthesis of macrocyclic tetralactones is
demonstrated with many examples in excellent yield. The
representative structure of macrocyclic tetralactones is
characterized by X-ray crystallography.
Ring-closing metathesis (RCM) reactions have become one
of the most versatile and efficient methods for constructing many
carbo- and heterocyclic compounds.1 They have been exten-
sively used as a key step in a number of natural product
syntheses to install a cyclic structure.2 Olefin metathesis provides
an efficient methodology for CdC bond formation and has
received a great deal of attention for the synthesis of medium
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* To whom correspondence should be addressed. Fax: 91-431-2407053.
† Bharathidasan University.
‡ Central Salt & Marine Chemicals Research Institute (CSIR).
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10.1021/jo062043p CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/25/2007
J. Org. Chem. 2007, 72, 1495-1498
1495

TABLE 1. Synthesis of the Dialkylated Compounds 2 via Scheme 1
a Yield (unoptimized) refer to isolated and chromatographically pure compounds 2.
method 1 to furnish the respective symmetrical dialkylated
SCHEME 2. Ring-Closing Metathesis of Compounds 2
product 2a in 90% yield (Scheme 1, Table 1, entry a) as a
colorless thick oil. Other dialkylated products 2b-j (Table 1,
entries b-j) were synthesized from the appropriate dicar-
boxylic acids 1. The dialkylation reaction of dicarboxylic acids
1 was performed using 5-bromo-1-pentene to afford products
2k-m (Table 1, entries k-m) having longer linkers between
two olefin functional groups. The dialkylation reaction of
dicarboxylic acid 1n and an excess amount of 4-allyloxyphenol
was carried out on the basis of method 2 to afford the respective
dialkylated product 2n in 88% yield (Table 1, entry n) having
an aromatic spacer. Similar methodology was followed with
3-allyloxyphenol or 4-allyl-2-methoxyphenol to furnish the
respective symmetrical diolefinic compounds 2o,p (Table 1,
entries o,p).
1496 J. Org. Chem., Vol. 72, No. 4, 2007

TABLE 2. Synthesis of the Macrocyclic Tetralactones 3 via Scheme 2
a Yields (unoptimized) refer to isolated pure compounds 3. b Ratio of isomers is determined by proton NMR spectroscopy.
We next performed the RCM reactions of the compounds 2
having a symmetrical diolefinic end using Grubbs’ first-
generation catalyst. Thus, compound 2a was stirred with 5 mol
% of Grubbs’ catalyst and 2 equiv of CsCl under an inert
atmosphere to afford 21-membered macrocyclic tetralactone 3a
in 64% yield (Scheme 2, Table 2, entry a). This reaction was
performed in DCM under high dilution and monitored with the
help of TLC. From the reaction mixture, 20% of the unreacted
starting material was recovered, and the yield is almost 85%
based on the recovery of the starting material. 1H NMR showed
the absence of olefinic CH2 hydrogens. Mass spectrum clearly
indicated that the molecular ion with a reduction of 28 atomic
mass unit from the starting material. The product 3a was
obtained as a single isomer based on the spectral data, which is
characterized as an E-isomer by the X-ray crystallography.7
To exploit this interesting result, the diallylated compound
2b was also subjected to RCM reaction using 5 mol % of the
Grubbs’ catalyst to afford the tetralactone 3b as a single isomer
based on the proton NMR having 20 atoms in the cyclic core
(Table 2, entry b). The unreacted starting material (20%) was
also recovered from this reaction. Next, the diolefinic com-
pounds 2c-i having allyl units were subjected to the RCM
reactions to afford the respective macrocycles 3c-i as a mixture
(7) See the Supporting Information for the ORTEP view and crystal data
of compounds 3a and 3f.
J. Org. Chem, Vol. 72, No. 4, 2007 1497

with the NMR and mass spectra, which also exhibited single
sets of peaks due to the symmetry-related to protons and carbon
atoms.
In conclusion, this work described the preparation of sym-
metrical bis-olefinic compounds by tethering several spacers
and their RCM reactions providing an expedient strategy for
the synthesis of symmetrical macrocyclic tetralactones. This
methodology brings another application of Grubbs’ catalyst for
the synthesis of macrocyclic tetralactones having different ring
sizes and spacers. These macrocyclic compounds are expected
to be potentially important to the biologically significant
materials and supramolecular chemistry.
FIGURE 1. Macrocyclic tetralactones with C2 symmetry.
Experimental Section
of E/Z isomers (Table 2, entries c-i) comprising 21, 24, and
27 atoms in the cyclic core with different spacers in very good
yield. The mixture of isomers 3f was subjected for crystallization
to furnish the single crystal, which was characterized7 as an
E-isomer on the basis of the X-ray crystallographic analysis.
The RCM reaction of the compound 2j having oxanorbornene
ring system furnished a mixture of products 3j. This may be
due to the ring-opening metathesis reaction1e of the oxanor-
bornene ring system under these experimental conditions. The
compound 2k having the pentenyl ester was subjected under
RCM conditions to afford the respective 31-membered macro-
cyclic tetralactone 3k as a single isomer (entry j). During this
reaction, 8% of the unreacted 2k was isolated. The diolefinic
esters 2l,m were subjected under similar conditions to furnish
the respective macrocyclic tetralactones 3l,m as a single isomers
(entries k,l) having 31 and 25 atoms in the cyclic core. The
ratio of the isomer of 3m could not be determined due to the
General Procedure for the Ring-Closing Metathesis of 2. To
an oven dried flask, bis-olefin 2 (1 equiv) and cesium chloride
(2 equiv) were charged in dry DCM (100 mL) under inert
atmosphere and refluxed. To the above refluxed solution was added
5 mol % of Grubbs’ first-generation catalyst in dry DCM (10 mL)
slowly for 2 h and stirred for the appropriate time. The reaction
was monitored by TLC. Finally, the reaction mixture was filtered
and the solvent evaporated under reduced pressure. The residue
was subjected to silica column (100-200 mesh) chromatography
using EtOAc/hexane to furnish the respective macrocyclic tetralac-
tone 3.
Macrocyclic Tetralactone 3a. To the stirred solution of
compound 2a (0.200 g, 0.483 mmol) and cesium chloride (0.162
g, 0.966 mmol) in dry DCM (100 mL) under nitrogen atmosphere
was slowly added 5 mol % of Grubbs’ catalyst (19 mg) in dry
DCM (10 mL) for 2 h and the mixture refluxed for 18 h. Purification
of the reaction mixture using a silica gel column (30:70 EtOAc/
hexane) afforded the tetralactone 3a (0.119 g, 64%) as a single
isomer. The unreacted compound 2a (0.04 g, 20%) was recovered:
white solid; mp 85-88 °C; νmax(KBr)/cm-1 3064, 2957, 2882, 1727,
1
complex nature of the H NMR. The synthesis of a larger
tethered compound 2n leading to the formation of a single
stereoisomer of the 37-membered oxa-heterocycle 3n (entry m).
Similarly, the diallylated compounds 2o,p afforded the respec-
tive 35-membered tetralactones 3o,p as a mixture of E/Z-
isomers. The control reaction without CsCl reduces the yield
in the range of 20-30% for the synthesis of 3 having
oxyethylene spacers. This may be due to the close proximity8
of the olefins resulting from the Cs complex formation with 2.
The crystal structure7 of 3f obtained from the mixture of isomers
indicates that the structure of the major isomer present in 3
tentatively assigned as the E-isomer.
1
1641, 1452, 1399, 1277, 1208, 1165, 988. H NMR (CDCl3, 200
MHz) δ 7.38 (m, 4H), 6.31-6.24 (m, 4H), 5.55 (d, 2H, J ) 8 Hz),
5.18 (s, 4H), 4.40 (d, 4H, J ) 8 Hz); 13C NMR (CDCl3, 50.3 MHz)
δ 172.1, 164.9, 164.8, 135.7, 135.6, 135.3, 130.1, 129.3, 129.1,
129.0, 128.7, 127.6, 127.3, 67.1, 67.0, 64.5, 60.9; HRMS (ESI+)
calcd for C20H18O8Na (M + Na)+ 409.0899, found 409.0865.
Acknowledgment. This research was supported by DST,
New Delhi. B.G. thanks CSIR, New Delhi, for a fellowship.
Subsequently, the representative isomerically pure tetralactone
3l and E/Z-isomers of 3o having olefin moiety were reduced in
the presence of Pd-C/H2 to furnish the respective macrocyclic
compounds 4a,b in an excellent yield with the complete
C2-symmetry (Figure 1). The structures of 4a,b were consistent
Supporting Information Available: Experimental procedures,
spectral data for the compounds 2a-p and 3b-i,k-p, ORTEP view
with CIF files for 3a and 3f, and copies of spectra for the
representative compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(8) Marsella, M. J.; Maynard, H. D.; Grubbs, R. H. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1101.
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