Synthesis of a dimethylfuran-containing macrolide insect pheromone

Article abstract of DOI:10.1080/00397910802527748

The synthetic pathway to the furan-containing macrolide pheromone (1) of Galerucella beetles was shortened from 13 steps in the original synthesis to 10 steps, and the overall yield was increased greater than six-fold. A concise Reformatsky-based sequence of reactions was utilized to construct the key precursor, 2,3-dimethyl-2-butenolide. Reduction of the butenolide with diisobutylaluminum hydride afforded 3,4-dimethylfuran. A one-pot sequence of lithiation, alkylation by a tetrahydropyranyl (THP)-containing iodide, a second lithiation, and, finally, formylation gave the required tetrasubstituted furan intermediate, 3,4-dimethyl-5-[5-(tetrahydrofuran-2-yloxy)pentyl]-2-furaldehyde. To continue construction of the three-carbon acyl side chain, the aldehyde was converted to an unsaturated ester by a Horner-Wadsworth-Emmons (HWE) condensation with triethyl phosphonoacetate. After reduction of the double bond in the ester side chain and removal of protective groups, the lactone ring was closed using the Mitsunobu method, which is milder, is simpler, and could be accomplished with less solvent than the previous (Yamaguchi) method.

Full text of DOI:10.1080/00397910802527748

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Synthesis of a Dimethylfuran-
Containing Macrolide Insect
Pheromone
Richard J. Petroski a , Robert J. Bartelt a & Karl
Vermillion a
a U.S. Department of Agriculture, Agricultural
Research Service, National Center for Agricultural
Utilization Research, Peoria, Illinois, USA
Published online: 19 Mar 2009.
To cite this article: Richard J. Petroski , Robert J. Bartelt & Karl Vermillion (2009)
Synthesis of a Dimethylfuran-Containing Macrolide Insect Pheromone, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:8, 1389-1405, DOI: 10.1080/00397910802527748
To link to this article: http://dx.doi.org/10.1080/00397910802527748
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Synthetic Communications1, 39: 1389–1405, 2009
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802527748
Synthesis of a Dimethylfuran-Containing
Macrolide Insect Pheromone
Richard J. Petroski, Robert J. Bartelt, and Karl Vermillion
U.S. Department of Agriculture, Agricultural Research Service, National
Center for Agricultural Utilization Research, Peoria, Illinois, USA
Abstract: The synthetic pathway to the furan-containing macrolide pheromone
(1) of Galerucella beetles was shortened from 13 steps in the original synthesis
to 10 steps, and the overall yield was increased greater than six-fold. A concise
Reformatsky-based sequence of reactions was utilized to construct the key pre-
cursor, 2,3-dimethyl-2-butenolide. Reduction of the butenolide with diisobutyl-
aluminum hydride afforded 3,4-dimethylfuran. A one-pot sequence of lithiation,
alkylation by a tetrahydropyranyl (THP)-containing iodide, a second lithiation,
and, finally, formylation gave the required tetrasubstituted furan intermedi-
ate, 3,4-dimethyl-5-[5-(tetrahydrofuran-2-yloxy)pentyl]-2-furaldehyde. To con-
tinue construction of the three-carbon acyl side chain, the aldehyde was
converted to an unsaturated ester by a Horner–Wadsworth–Emmons (HWE)
condensation with triethyl phosphonoacetate. After reduction of the double bond
in the ester side chain and removal of protective groups, the lactone ring was
closed using the Mitsunobu method, which is milder, is simpler, and could be
accomplished with less solvent than the previous (Yamaguchi) method.
Keywords: 2,3-Dimethyl-2-butenolide, 12,13-dimethyl-5,14-dioxabicyclo[9.2.1]-
tetradeca-1(13),11-dien-4-one, 3,4-dimethylfuran, Galerucella, macrolide, phero-
mone, purple loosestrife, Reformatsky
Received July 15, 2008.
This article is not subject to U.S. copyright laws.
The mention of trade names or commercial products in this article is solely
for the purpose of providing specific information and does not imply
recommendation or endorsement by the U.S. Department of Agriculture.
Address correspondence to Richard J. Petroski, U.S. Department of Agricul-
ture, Agricultural Research Service, National Center for Agricultural Utilization
Research, Crop Bioprotection Research Unit, 1815 N. University Street, Peoria,
IL 61604. E-mail: Richard.Petroski@ars.usda.gov
1389

1390
R. J. Petroski, R. J. Bartelt, and K. Vermillion
INTRODUCTION
Insect pheromones can have unusual chemical structures. Previously,
a furan-containing macrolide, 12,13-dimethyl-5,14-dioxabicyclo[9.2.1]-
tetradeca-1(13),11-dien-4-one, structure 1 in Fig. 1, was identified from
the beetle species Galerucella calmariensis and G. pusilla.[1] These species
were introduced into North America from Europe as biological control
agents for the invasive wetland weed purple loosestrife (Lythrum
salicaria) and have had significant success in suppressing this noxious
plant. A practical need is for scientists and land managers to be able to
monitor beetle populations, and the pheromone is useful for this
purpose.[1,2] An improved synthetic method for lactone 1 was developed
to help meet that need.
The original approach was to prepare 3,4-dimthylfuran (7 in Fig. 1)
by a Diels–Alder route, attach or elaborate appropriate functionalized
side chains at the 2-and 5-positions, and finally to join the ends of the side
chains to form the lactone ring.[1] This strategy was generally preserved in
the present work, but a simpler and less expensive (Reformatsky-based)
approach to 3,4-dimethylfuran was developed, a milder and simpler lac-
tonization reaction was employed, and the conditions for running several
other reactions were improved.
RESULTS AND DISCUSSION
To prepare dimethylbutenolide (6), hydroxyacetone (2) was acetylated to
acetyloxyacetone (3) with acetyl chloride in pyridine[3,4] in 77% yield
(Fig. 1). Reformatsky reaction[5] of 3 with ethyl 2-bromopropionate
and granulated zinc in ether afforded a mixture of ethyl 4-acetyloxy-
3-hydroxy-2,3-dimethylbutyrate (4) and 4-hydroxy-3,4-dimethyl-dihydro-
furan-2-one (5). When this mixture was refluxed in toluene with
p-toluenesulfonic acid and anhydrous MgSO4 as a drying agent,[6] 4 quickly
cyclized to 5, and 5 slowly dehydrated to 2,3-dimethyl-2-butenolide (6). The
yield of 6 from 3 was 72%.
Reduction of 6 to make 3,4-dimethylfuran (7) was done with diisobu-
tylaluminum hydride (DiBAL) and proceeded in 40% yield.[7] The entire
[1]
synthetic pathway to 7 was shortened from six steps
to just four by
changing from the previously used Diels–Alder route[1] to that based
on Reformatsky chemistry via intermediate 6. The new method was
efficient, used cheaper reagents, and was simpler to perform.
A minor difficulty was removal of toluene from 6, and residual
toluene was the major impurity after distillation (23%, by gas chromato-
graphy, GC). The small amount of this solvent did not interfere with

Dimethylfuran-Containing Macrolide Pheromone
1391
Figure 1. Synthesis of Galerucella macrolide pheromone (1) and various side
products of reaction steps (see text). Reaction conditions: (a) pyridine, 0ꢀC, acetyl
chloride addition over 45 min then reflux 3 h; 77% from 2; (b) granular zinc, ether,
iodine catalyst, reflux 4 h; (c) p-toluenesulfonic acid, powdered MgSO4, toluene,
reflux 6 h; 70% from 3; (d) diisobutylaluminum hydride, ether, ꢁ20ꢀC, 1 h;
40%; (e, in one pot) (1) addition of BuLi to 7, THF,ꢁ15ꢀC, 2 h, (2) addition of
2-[(5-iodopentyl)oxy]tetrahydropyran, ꢁ15ꢀC, 1 h, then rt, 1 h, (3) addition of
BuLi, 0ꢀC, 2 h, (4) addition of dimethylformamide, 0ꢀC, 15 min, then rt, 1 h;
56% overall; (f) triethyl 2-phosphonoacetate, LiOtBu, hexane, 25ꢀC 30 min, then
addition of 8, 2 h; 87%; (g) 10% pd on carbon, hexane, h2 (1 atm), rt, 4 h; 95%; (h)
pyridinium p-toluenesulfonate, EtOH, 55ꢀC, 3.5 h; quant.; (i) KOH, 1:1
MeOH=H2O, 45ꢀC, 4 h, quant.; (j) diethyl azodicarboxylate, triphenylphosphine,
toluene, rt, 15 min, then addition of 12 over 3.25 h; 60%.

1392
R. J. Petroski, R. J. Bartelt, and K. Vermillion
subsequent reactions and was readily removed later, from higher
molecular-weight products, but it made yield measurement for 6 (and
7) more difficult. An additional washing=extraction step is described in
the experimental section for removal of toluene, if this is desired.
As shown previously,[1] furan 7 could be lithiated at the 2-position[8] and
then alkylated with 2-[(5-iodopentyl)oxy]tetrahydropyran to give the trisub-
stituted furan 13 (62% yield of 13 from 7). In the subsequent reaction,
13 could be formylated[1,9] to 8 by lithiation of the 5-position, followed by
reaction with dry N,N-dimethylformamide (DMF). Furan-containing
compounds are often labile,[9] and in initial attempts to synthesize 1, there
was substantial loss of many furan intermediates during chromatographic
purification on silica gel (for example, up to 50% for trisubstituted furan
13). Here we found it was possible and convenient to do both addition
reactions sequentially in one pot, allowing tetrasubstituted furan 8 to be pre-
pared directly without having to isolate the rather labile 13. Incomplete reac-
tions in the one-pot approach gave 13 and aldehyde 15 as by-products.
These were carried along in the reaction scheme until their derivatives
(14 and 17) were removed during later steps, without chromatography.
To continue construction of the three-carbon acyl side chain, the
aldehyde 8 was converted to unsaturated ester 9 by a Horner–
Wadsworth–Emmons (HWE) condensation with triethylphosphonoace-
tate in hexane, using lithium tert-butoxide as the base.[10] This method
is milder and consistently gives higher yields than the commonly used
n-butyllithium base.[11] The yield of this reaction was improved from
40%[1] to 87%. Dry tetrahydrofuran (THF) is also an acceptable solvent
for this reaction. The side-chain double bond of 9 was selectively reduced
by hydrogenation over 10% Pd on carbon in hexane to give 10.[1,12]
Impurity 17 (Fig. 1), was removed from this relatively stable and nonvo-
latile product by Kugelrohr distillation, which was done to avoid possible
interference with the final lactonization reaction. Deprotection of the tet-
rahydropyranyl (THP) ether of 10 with pyridinium p-toluenesulfonate in
EtOH[13] afforded hydroxy ester 11. Saponification of 11 with potassium
hydroxide (KOH) in aqueous MeOH[1] yielded the hydroxy acid 12.
Intermediates 8–12 were not purified by chromatography, but the
nonacidic impurities were easily removed when an aqueous solution of
the potassium salt of hydroxy acid 12 was extracted with hexane.
The final reaction was to close the lactone ring. Previously,[1] lactone
formation was accomplished by converting hydroxy acid 12 to a mixed
anhydride with 2,4,6-trichlorobenzoyl chloride, followed by cyclization
under high-dilution conditions in refluxing toluene using 4-(N,N-dimethyla-
mino)pyridine as the catalyst.[14] Here we employed an alternative method
that utilizes triphenylphosphine and diethyl azodicarboxylate to activate
the hydroxyl function.[15] Some previously reported lactonizations were

Dimethylfuran-Containing Macrolide Pheromone
1393
done under high-dilution reaction conditions to prevent dimerization,[15,16]
but this was less of a problem with 1, and lactonization ran successfully
at concentrations of up to 10 g per liter. This method proceeds at room
temperature and proved very satisfactory.
In the original synthesis of 1, formation of lactone dimer was noted
[R. J. B. unpublished data] and was 10.5–13.5% the amount of 1 in three
runs, verified by MS [m=z (%) 472 (Mþ, 100), 235 (17), 177 (48), 135 (75)]
and proton NMR (much like that of 1). Dimer formation results when the
concentration of reactants during lactonization is too high. In the present
study, the dimer was barely detectable (<1% the amount of 1). Having to
use the high-dilution technique is a substantial inconvenience when large
batches of lactone are to be prepared because of the great volumes of
solvents involved. Because of the low degree of dimerization observed
here, the present lactonization reaction can be run with far less solvent.
An analog of 1, with two additional carbons in the lactone ring, was also
found in the final crude product. This artifact of synthesis was identified as
14,15-dimethyl-7,16-dioxabicyclo[11.2.1]hexadeca-1(15),13-dien-6-one (21
in Fig. 1) by gas chromatographic=mass spectrometric (GC=MS) analysis
(at 264, molecular weight was 28 mass units higher than 1) and by NMR
(two additional methylene carbons in ester portion of lactone ring). This
same impurity 21 was found in the original synthesis[1] of 1 [R. J. B. unpub-
lished data]. Formation of precursor18 to this macrolide impurity occurred
when 9 was converted to 10, if triethyl phosphonoacetate (TEPA) was
present in the hydrogenation reaction mixture. Homologation of esters to
a,b-unsaturated esters with TEPA has been reported.[17] Formation of this
macrolide impurity can be easily prevented by washing the HWE reaction
mixture with 0.1 N NaOH during the workup and verifying removal of
TEPA by GC.
In summary, improvements to the synthetic pathway include a
concise Refomatsky-based route from commercially available 2 to 6 and
subsequently 7, an expeditious, one-pot route to aldehyde 8, a more effi-
cient HWE olefination, and the use of Mitsunobu lactonization chemistry.
Overall yield, from starting materials, was increased from 1%[1] to 6%, and
the total number of steps was reduced from 13 to 10. These improvements
should aid the practical availability of this pheromone.
EXPERIMENTAL
Chemicals and General Methods
Dry THF was prepared by distillation from sodium benzophenone ketyl.
Commercially available organic reagents were obtained from Aldrich and

1394
R. J. Petroski, R. J. Bartelt, and K. Vermillion
were used without further purification. Reactions were generally
performed under an atmosphere of dry argon in oven-dried glassware.
Removal of solvent during workups was accomplished by rotary
evaporation at water aspirator vacuum.
Analysis of Reaction Products
Progress of synthetic reactions was monitored by GC or GC=MS. All
1
structures were additionally verified by NMR. The H and 13C chemical
shifts for compounds 8–13 and 1 are given in Tables 1 and 2, respectively;
numbered structures are given in Fig. 2.
The Hewlett-Packard (HP) 5890 Series II gas chromatograph was
equipped with flame ionization detector and split=splitless inlet and
was interfaced to an HP ChemStation data system. The column was
a DB-5 capillary (30 m ꢂ 0.25 mm, 0.25-mm thick film, J&W Scientific,
Folsom, CA). Carrier gas was He. The oven temperature was
Table 1. Proton shifts (CDCL3)
Compound
Position
13
8
9
10
11
12
1
1
2
3
4
5
3.74, 3.39 3.73, 3.38 3.74, 3.40 3.74, 3.39 3.64 3.67 4.21
1.62, 1.62 1.61, 1.61 1.64, 1.64 1.62, 1.62 1.58 1.57 1.72
1.40, 1.40 1.40, 1.40 1.41, 1.41 1.37, 1.37 1.37 1.37 1.21
1.62, 1.62 1.69, 1.69 1.66, 1.66 1.59, 1.59 1.59 1.59 1.62
2.55, 2.55 2.64, 2.64 2.58, 2.58 2.51, 2.51 2.51 2.53 2.60
6
7
—
—
—
—
—
—
—
—
—
—
—
—
—
—
7A
8
8A
9
1.87
—
1.92
7.04
1.91
—
2.26
—
1.88
—
2.05
—
1.83
—
1.85
—
1.83 1.83 1.83
—
1.85 1.86 1.86
—
—
—
—
—
10
11
12
10
20
30
40
50
100
200
9.64
7.43
6.18
—
2.84
2.58
—
2.85 2.87 2.90
2.58 2.62 2.42
—
—
—
4.58
4.56
4.59
4.58
1.71, 1.58 1.70, 1.56 1.72, 1.58 1.71, 1.58
1.83, 1.52 1.81, 1.52 1.84, 1.54 1.83, 1.53
1.58, 1.53 1.55, 1.52 1.56, 1.53 1.57, 1.53
3.87, 3.50 3.85, 3.49 3.86, 3.51 3.87, 3.50
4.23
1.32
4.13
1.26
4.14
1.26

Dimethylfuran-Containing Macrolide Pheromone
1395
Table 2. Carbon shifts (CDCL3)
Compound
10
Position
13
8
9
11
12
1
1
2
3
4
5
6
7
7A
8
8A
9
10
11
12
10
20
30
40
50
100
200
67.5
29.5
25.6
28.3
26.0
151.2
114.4
7.9
67.3
29.4
25.9
27.7
26.5
158.7
118.8
7.6
135.5
8.8
147.0
176.7
67.4
29.4
25.9
28.0
26.3
154.3
117.6
8.0
67.5
29.5
25.8
28.5
26.0
148.8
114.6
8.3
62.9
32.6
25.2
28.4
25.9
148.7
114.7
8.3
115.4
8.3
146.0
21.7
33.3
173.0
62.9
32.4
25.2
28.3
25.7
148.8
115.0
8.3
115.5
8.3
145.7
21.6
32.9
177.0
63.0
25.3
22.3
25.0
23.2
148.3
115.2
8.0
115.2
8.3
146.2
22.8
34.9
173.8
120.9
8.3
136.2
127.5
8.9
115.4
8.3
144.6
129.3
111.6
167.9
98.8
30.7
19.6
25.4
62.3
60.1
14.4
145.9
21.7
33.3
172.9
98.8
30.8
19.7
25.5
62.3
60.3
14.1
98.8
30.8
19.6
25.5
62.2
98.9
30.8
19.7
25.5
62.4
60.4
14.2
programmed from 50 to 280ꢀC at 10ꢀC=min, and the detector tempera-
ture was 280ꢀC. The inlet temperature was 220ꢀC, and 1.0-mL sample
injections were made in splitless mode.
Electron impact mass spectra (70 eV) were obtained with an HP 5973
MSD instrument, interfaced to an HP 6890 GC, equipped with a splitless
inlet. Several columns were used but gave comparable results to that used
for GC. The oven temperature was typically programmed from 50 to
250ꢀC at 10ꢀC=min, the inlet temperature was 220ꢀC, and the transfer
line temperature was 250ꢀC. A thin-film column (DB-1, 15 m ꢂ 0.25 mm,
mm, 0.10-mm-thick film) was used to analyze for the dimer of 1 (oven
temperature programmed from 50 to 300ꢀC at 10ꢀC=min, inlet tempera-
ture 280ꢀC, and transfer line temperature 300ꢀC).
1H NMR, 13CNMR, and 2D NMR spectra were acquired on a Bruker
(Bellerica, MA) Avance 500 spectrometer using a 5-mm inverse broadband
probe. Samples were dissolved in CDCl3, and all spectra were acquired
at 300 K. 1H and 2-D homonuclear one-bond J coupling correlation
spectroscopy (COSY) spectra were acquired at 500 MHz, whereas 13C and

1396
R. J. Petroski, R. J. Bartelt, and K. Vermillion
1
Figure 2. Structures for the H and 13C chemical shifts for compounds 8–13 and
1, given in Tables 1 and 2.
distortionless enhancement by polarization transfer (DEPT) spectra were
acquired at 125 MHz. Heteronuclear single quantum coherence (HSQC)
and heteronuclear multiple bond correlation (HMBC) experiments were

Dimethylfuran-Containing Macrolide Pheromone
1397
conducted to aid in the assignment of chemical shifts. 1H- and 13C-Predictive
software[18] and analogy to known compounds also aided shift assignment.
Chemical shifts are reported as parts per million (PPM) relative to
tetramethylsilane (TMS).
Synthetic Details
The synthetic precursor, 2-[(5-iodoopentyl)oxy]tetrahydropyran, was
prepared from 1,5-pentanediol by monohalogenation with aqueous HI
(supplementary materials for Ref. 1), followed by protection of the free
hydroxyl group as a THP ether.[13] 5-Iodoopentan-1-ol MS (EI) m=z (%)
214 (Mþ, 0.3), 155 (5), 141 (2), 127 (3), 87 (35), 69 (100), 55 (8), 41 (73);
2-[(5-iodoopentyl)oxy]tetrahydropyran MS (EI) m=z (%) 298 (Mþ, 0.6),
297 (5), 197 (17), 183 (3), 171 (12), 155 (7), 85 (100), 69 (50), 56 (12), 41 (34).
Acetoxyacetone (3)
Hydroxyacetone (2, 50 g, 0.68 mol) and pyridine (58.2 mL, 57 g, 0.72 mol)
were added to a 250-mL three-neck flask equipped with a mechanical
stirrer, thermometer, and dropping funnel. The mixture was stirred at
0ꢀC (ice bath) while acetyl chloride (53.2 mL, 59 g, 0.75 mol) was added
dropwise (reaction exothermic) over the course of 45 min, keeping the
temperature less than 30ꢀC. Upon completion of the addition, the drop-
ping funnel was replaced with a reflux condenser. When the reaction
approached completion, as evidenced by a steady or dropping tempera-
ture, the mixture was heated to 60ꢀC for 3 h. After cooling, ether
(100 mL) was added to precipitate by-product pyridinium hydrochloride,
which was removed by filtration. The precipitate was rinsed with addi-
tional ether (3 ꢂ 100 mL). The ether filtrates were combined and washed
successively with brine (2 ꢂ 40 mL), saturated aqueous Na2CO3 (20 mL),
and water (20 mL). The resulting pale yellow solution was dried
(MgSO4). After filtration and removal of solvent, oil remained (67.8 g).
Kugelrohr distillation (oven temperature 40ꢀC, 0.04 torr) afforded
64.5 g of a colorless oil, which was 94% 3 (yield of 3 from 2 was 77%).
MS (EI) m=z (%) 116 (Mþ, 12), 86 (14), 73 (5), 43 (100).
Ethyl 4-Acetyloxy-3-hydroxy-2,3-dimethylbutyrate (4) and 4-Hydroxy-
3,4-dimethyl-dihydro-furan-2-one (5)
Granular zinc (30 g, 0.46 mol) was added to a 500-mL, round-bottomed
flask, and the metal was covered with ether (120 mL). Ethyl 2-bromo-
propionate (31 mL, 43.2 g, 0.23 mol), ester 3 (25 g, 0.22 mol), and a

1398
R. J. Petroski, R. J. Bartelt, and K. Vermillion
crystal of iodine were added. The reaction mixture was heated at
gentle reflux until 3 was fully consumed (4 h, reaction monitored by
GC=MS). Onset of reaction was characterized by disappearance of
iodine color, followed by development of cloudiness and yellow color
in solution.
The reaction mixture was cooled to 0ꢀC, and 2 N HCl (120 mL) was
added. The phases were separated, and the aqueous phase was extracted
with ether (3 ꢂ 50 mL). The organic phases were combined, washed with
brine (50 mL) and saturated aqueous NaHCO3 (20 mL), and then dried
(Na2SO4). Filtration and removal of solvent afforded 29.2 g of a mix-
ture containing 4 and 5 (two GC-separable diastereomers of each).
Mass spectrum of major diastereomer for 4: MS (EI) m=z (%) 203
(M-15, 0.05), 173 (M-45, 1), 145 (40), 131 (23), 117 (9), 102 (23), 99
(42), 74 (26), 57 (17), 43 (100); and for 5: MS (EI) m=z (%) 130 (Mþ,
14), 112 (28), 99 (7), 84 (9), 72 (13), 56 (20), 43 (100). Mass spectra
of diastereomers were nearly identical.
2,3-Dimethyl-2-butenolide (6)
Toluene (200 mL), powdered anhydrous MgSO4 (10 g), p-toluenesulfo-
nic acid (10 g), 4 þ 5 (30.6 g), and several boiling stones were added to
a 500-mL, three-neck flask equipped with a mechanical stirrer and
reflux condenser. The vigorously stirred mixture was heated to reflux.
The solution darkened rapidly. Reaction progress was monitored peri-
odically by GC-MS. Cyclization of 4 to 5 occurred quickly, but after
3 h, dehydration of 5 to 6 was still incomplete. Additional MgSO4
(5 g) and p-toluenesulfonic acid (2 g) were added, and the reaction
was complete after refluxing for another 4 h. The mixture was cooled
and filtered. The filtrate was washed successively with brine (100 mL),
5% NaHCO3 solution (100 mL), and brine (100 mL) again. The com-
bined aqueous layers were neutralized with solid NaHCO3 and
extracted with ether (3 ꢂ 100 ML). The orange-colored organic phases
were combined and dried (MgSO4). Solvent was removed by rotary eva-
poration. Kugelrohr distillation (oven temperature 60–100ꢀC, 0.10 torr)
afforded 17.9 g of a very pale yellow oil, which was 59% 6 (yield from
compound 3 was 72%). The major impurities were toluene (23%), and 5
(9%) by GC analysis; other impurities were not greater than 3%.
Removal of toluene from 6 by rotary evaporation without losing
product was difficult. MS (EI) m=z (%) 112 (Mþ, 73), 83 (70), 55
1
(100), 41 (8). H NMR d 1.82 (3H, s, CH3), 2.02 (3H, s, CH3), 4.62
(2H, s, -CH2-O). 13C NMR d 8.3 and 12.2 (-CH3), 72.5 (-CH2-O),
123.2 and 156.2 (olefinic C), and 175.4 (carbonyl C).

Dimethylfuran-Containing Macrolide Pheromone
1399
3,4-Dimethylfuran (7)
Dry ether (200 mL, distilled from benzophenone ketyl) and 6 (8.0 g, 71 mmol)
were added to a 500-mL, three-neck flask equipped with a mechanical stirrer,
thermometer, and dropping funnel. The mixture was stirred and cooled to
ꢁ20ꢀC. Diisobutylaluminum hydride (1 M solution in hexane, 80 mmol)
was added slowly, avoiding temperature increase. After addition was com-
plete, the mixture was allowed to stir at ꢁ20ꢀC for 1 h before quenching
the reaction with 10% aqueous H2SO4 (50 mL). After warming to ambient
temperature, the organic and aqueous phases were separated. The aqueous
phase was extracted with ether (3 ꢂ 40 mL), and the ether extracts were com-
bined with the organic phase, then washed with brine (50 mL) and 5%
NaHCO3 solution (50 mL), and dried (MgSO4). Filtration and removal of
solvent by distillation through a Vigreux column at atmospheric pressure,
followed by Kugelrohr distillation (oven temperature 40ꢀC, 16–20 mm Hg)
afforded 11.2 g of a clear colorless oil. The distillate contained primarily 7
and residual solvents (hexane, methylcyclopentane, and toluene). By NMR
(calculations based on integrals of methyl signals), the product was 25% 7
by weight; yield corrected for purity was 40%. Product 7 is relatively volatile,
and some was lost in the workup, reducing the yield. Removal of residual sol-
vents from 7 was difficult, but these did not interfere with the next reaction.
MS (EI) m=z (%) 96 (Mþ, 100), 95 (43), 81 (12), 67 (69), 65 (18), 53 (24), 41,
(28), 39 (26). 1H NMR d 1.97 (6H, s, CH3), 7.17 (2H, s, HC¼).
The following procedure can be used to remove toluene from com-
pound 6 (and therefore, from 7): Distilled 6 (3.38 g) was dissolved in water
(60 mL), and nonpolar organic impurities, such as toluene, were washed
away with hexane (60 mL). The hexane phase was extracted with water
(2 ꢂ 15 mL). The aqueous phases, now containing 6, were combined,
and NaCl (30 g) was added. The brine-containing solution turned cloudy
(salting out of 6) and was extracted with ether (4 ꢂ 50 mL). After drying
(Na2SO4) and removing the solvent, oil remained (2.76 g, purity of 98%
by GC analysis). Reduction of 6 (2.73 g of purified product, 24 mmol)
to 7 with diisobutylaluminum hydride (1 M solution in hexane, 28 mmol),
conducted as before with removal of solvent at atmospheric pressure
followed by Kugelrohr distillation, afforded a colorless oil (1.24 g). By
NMR, this product contained 90% 7 by weight, and yield from 6 was 49%.
3,4-Dimethyl-5-[5-(tetrahydrofuran-2-yloxy)pentyl]-2-furaldehyde (8)
A stirred solution of furan 7(1.18 g, 12.3 mmol) in dry THF (40 mL) was
cooled to ꢁ20ꢀC. Butyllithium (2.5 M solution in hexane, 13 mmol, slight
excess) was added dropwise, and the solution was stirred at ꢁ20ꢀC for 2h.

1400
R. J. Petroski, R. J. Bartelt, and K. Vermillion
Aliquots were periodically taken by syringe, quenched with D2O, and ana-
lyzed by GC=MS to follow the progress of lithiation. (Molecular weight of
7 increased from 96 to 97 if lithiation had occurred before D2O was added;
D2O had no effect on the mass spectrum when added to 7 before butyl-
lithium.) Upon warming again to room temperature, GC=MS analysis
revealed lithiation was >80% complete. (Observed percent lithiation is typi-
cally less than actual percent lithiation because of traces of water picked up
during the handling of samples). Then 2-[(5-iodopentyl)oxy]tetrahydropyran
(3.91 g, 13 mmol) was added dropwise. Stirring was continued for 1 h at
ꢁ20ꢀC and then for 1 h at room temperature. After alkylation of 7 to 13
was verified by GC=MS analysis, the solution was cooled to ꢁ5ꢀC. Butyl-
lithium solution (2.5 M in hexane, 13 mmol) was added. Stirring was contin-
ued for 1.5 h at room temperature. Aliquots were periodically taken by
syringe, quenched with D2O, and analyzed by GC=MS to follow the progress
of lithiation. (Molecular weight of 13 increased from 266 to 267 if lithiation
had occurred before D2O was added; D2O had no effect on the mass spectrum
when added to 13 before butyllithium.) GC=MS analysis revealed lithiation
was >80% complete. After cooling once more in an ice bath, dry dimethylfor-
mamide (DMF, distilled from CaH2, 1.5 mL, 19.4 mmol) was added to the
solution via syringe. The mixture was stirred at 0ꢀC for 30min and then 3h
at room temperature. After quenching with water (10 ml), the phases were
separated, the organic phase became bright orange, and the aqueous phase
became ruby red in color. The aqueous phase was extracted with 1:1 ether=
hexane (4 ꢂ 40 ml). The combined organic layers were successively washed
with 1 N HCl (10 mL), water (10 mL), 5% sodium bicarbonate (10 mL),
and brine (10 mL). A minor amount of additional product was recovered
from these aqueous washes by neutralizing with solid NaHCO3 and extract-
ing with 1:1 ether=hexane (3 ꢂ 40 ml), then washing with brine (5 mL). All
organic extracts were combined and dried (MgSO4). Filtration and removal
of solvent resulted in 3.46 g of product, which contained (GC analysis) 56%
product 8 (yield from 7 was 56%), 13% 3,4-dimethyl-furanaldehyde (15),
and 10% intermediate 13. MS (EI) m=z (%) 294 (Mþ, 0.5), 210 (100), 194
(5), 180 (7), 163 (8), 151 (59), 137 (41), 125 (34), 109 (10), 85 (78), 67 (15).
The NMR spectral data are given in Table 1. This compound was used in
the subsequent reaction without further purification. Mass spectrum of
impurity 15: MS (EI) m=z (%) 124 (Mþ, 100), 95 (14), 81 (5), 67 (21).
Ethyl 3-{3,4-Dimethyl-5-[5-(tetrahydrofuran-2-yloxy)pentyl]-
2-furyl}acrylate (9)
Triethyl 2-phosphonoacetate (TEPA, 2.84 g, 12.6 mmol) was added to dry
hexane (5 ml, dried over Na metal), and the mixture was stirred at 25ꢀC.

Dimethylfuran-Containing Macrolide Pheromone
1401
Lithium tert-butoxide (1.0 M solution in hexane, 13 mmol) was added in one
portion via syringe. The solution became turbid and only slight heating of
the mixture was observed. After stirring for one h, a solution of the aldehyde
8 (3.43 g of previous product, containing 6.53 mmol 8, in 2mL of ether) was
added dropwise. The solution clarified as aldehyde was added but an oily
paste appeared. Ether (20 mL) was added, and the oil slowly dissolved.
The mixture was allowed to stir for a total of 5.5 h before water (10 mL)
was added to quench the reaction. The hexane phase, containing the pro-
duct, was washed with 0.1 N NaOH (10 mL) and water (10 mL). (The NaOH
wash removes excess TEPA, which, if present, would lead to formation of
homolog 18 during the subsequent hydrogenation reaction of 9 to 10.)
The aqueous phase was back-extracted with hexane (30 mL), and the hexane
phases were combined, washed with a saturated brine solution (10 mL), and
dried (Na2SO4). Removal of TEPA was verified by GC analysis. Filtration
and removal of solvent resulted in 4.21g of product, which contained 49%
product 9 (yield from 8 was 87%), 23% ethyl 3-{3,4-dimethyl-2-furyl}-
acrylate (16) from residual 15, and 10% compound 13. MS (EI) m=z (%)
364 (Mþ, 9), 280 (56), 234 (52), 207 (37), 179 (16), 133 (17), 85 (100), 67
(15). The NMR spectral data are given in Table 1. This compound was
used in the next reaction without further purification. Mass spectrum of
impurity 16: MS (EI) m=z (%) 194 (Mþ, 80), 149 (100), 122 (60), 107 (30),
91 (47), 77 (37), 67 (15).
Ethyl 3-{3,4-Dimethyl-5-[5-(tetrahydrofuran-2-yloxy)pentyl]-
2-furyl}propanoate (10)
Hexane (125 ml), ester 9 (4.19 g of previous product, 5.63 mmol), and the
10% palladium on carbon catalyst (ca. 100mg) were added to a 500-mL
round-bottomed flask that was capped with a septum and equipped with
a magnetic stirrer and a two syringe needles. Either hydrogen or argon could
be delivered through one needle, and the second needle served as a vent. The
mixture was stirred and hydrogen was bubbled in, vigorously at first, to satu-
rate the system, and then more slowly, reducing to several bubbles per sec-
ond. To monitor progress by GC, the solution was purged with argon, an
aliquot was taken, and, if the reaction was incomplete, hydrogen was again
introduced. After 7 h, additional solvent (125 mL) and 10% palladium on
carbon catalyst (ca. 100 mg) were added. The reaction was complete after
24 h, and the mixture was purged with argon and filtered through a plug
of powdered MgSO4 to remove the catalyst. The amount of the crude pro-
duct after solvent removal was 3.86 g, which contained 36% saturated ester
10, 19% ethyl 3-{3,4-dimethyl-2-furyl}propanoate (17) from residual 16,
and 13% compound 13. The ester impurity 17 was removed by Kugelrohr

1402
R. J. Petroski, R. J. Bartelt, and K. Vermillion
distillation of this lower-boiling point compound (0.1 torr, 80ꢀC) to afford
an oily residue (2.82 g), which contained 12% compound 13 and 70% pro-
duct 10. The yield of the conversion of 9 to 10 was 96%. There was less than
3% overreduction (i.e., of the furan ring). MS (EI) m=z (%) 366 (Mþ, 25), 321
(10), 281 (100), 263 (13), 235 (10), 209 (26), 193 (83), 177 (22), 149 (12), 135
(80), 85 (75), 67 (10). The NMR spectral data are given in Table 1. The
compound was used directly in the next reaction. Mass spectrum of ester
impurity 17 (removed by Kugelrohr distillation): MS (EI) m=z (%) 196
(Mþ, 19), 167 (4), 122 (57), 109 (100), 79 (11). The mixture also contained
a small amount (<2%) of ethyl 3-{3,4-dimethyl-5-[5-(tetrahydrofuran-2-
yloxy)pentyl]-2-furyl}pentanoate (18): MS (EI) m=z (%) 394 (Mþ, 7), 349
(5), 309 (63), 263 (14), 237 (11), 177 (20), 149 (39), 135 (36), 85 (100). This
ester could be as much as 19% of the hydrogenation product if the excess
TEPA was not removed.
Ethyl 3-[5-(5-Hydroxypentyl)-3,4-dimethyl-2-furyl]propanoate (11)
The THP protecting group was removed from 10 (2.80 g of previous
product, 5.36 mmol), using absolute ethanol (80 mL) and pyridinium
p-toluenesulfonate (PPTS, 250 mg, 1.02 mmol) catalyst. The mixture was
stirred and heated to 55ꢀC for 4.5 h, when analysis by GC-MS indicated that
the reaction was complete. The ethanol was removed by rotary evaporation.
The product was taken up in ether (10 mL) and passed through a
1.0 cm ꢂ 5 cm column of silica gel to remove the catalyst. The silica was
rinsed with 20 mL of ether to ensure complete recovery of the hydroxy ester
12. Removal of solvent afforded 2.32 g of oil, which contained 67% 11 (yield
from 10 was >99%) and 8% 3,4-dimethyl-2-(5-hydroxypentyl)-furan (14)
from residual 13. There was evidence for other impurities, but none of these
exceeded 2% by GC. MS (EI) m=z (%) 282 (Mþ, 26), 237 (8), 209 (54), 195
(25), 149 (8), 135 (100), 123 (11), 91 (8), 55 (11). The NMR spectral data are
given in Table 1. This compound was used directly in the next reaction. Mass
spectrum of impurity, 14: MS (EI) m=z (%) 182 (Mþ, 19), 149 (3), 135 (8),
123 (15), 109 (100), 79 (12). The mixture also contained a small amount
(<2%) of ethyl 3-{3,4-dimethyl-5-[5-hydroxyoxy)pentyl]-2-furyl}pentanoate
(19): MS (EI) m=z (%) 310 (Mþ, 33), 265 (19), 237 (58), 209 (9), 195 (89), 149
(100), 135 (68), 123 (25), 109 (15).
3-[5-(5-Hydroxypentyl)-3,4-dimethyl-2-furyl]propanoic Acid (12)
A 1:1 mixture of water and MeOH (80 mL) was placed in a flask with
solid KOH (2.25 g). Ester 11 (2.30 g of previous product, 5.36 mmol)

Dimethylfuran-Containing Macrolide Pheromone
1403
was added, and the mixture was heated to 45ꢀC and stirred for 4 h. A
small amount of fine precipitate became visible upon cooling. The solu-
tion was concentrated to about 40 mL (most of the MeOH was removed),
water (20 mL) was added, and the resulting solution was extracted with
hexane (3 ꢂ 40 mL) to remove nonacidic organic impurities, such as com-
pound 14. The combined hexane washes were back-extracted with water
(10 mL), which had been made alkaline with a few mg of KOH. The com-
bined aqueous solution was acidified (pH < 2) with 25% HCl, and the
solution was extracted with ether (5 ꢂ 40 mL) to recover free acid 12.
The combined extracts were washed with water (10 mL) and brine
(10 mL) and dried (MgSO4). Filtration and concentration of solvent at
water aspirator pressure to about 5 mL, followed by removal of the
remaining solvent under a stream of argon, afforded 2.17 g of product
which contained 78% compound 12 (>99% yield from 11), about 1%
3-[5-(5-hydroxypentyl)-3,4-dimethyl-2-furyl]pentanoic acid (20), and
minor unidentified impurities. MS (EI) m=z (%) 254 (Mþ, 25), 195 (18),
181 (100), 149 (5), 135 (49), 91 (6), 55 (8). The NMR spectral data are
given in Table 1. This compound was stored as a solution in ether at
ꢁ70ꢀC and used directly in the final reaction. The solvent was removed
under a stream of argon just before use.
12,13-Dimethyl-5,14-dioxabicyclo[9.2.1]tetradeca-1(13),11-dien-4-one (1)
Anhydrous deoxygenated toluene (24 mL, dried by distillation from
the sodium ketyl of benzophenone) was added to triphenylphosphine
(2.11 g, 8.05 mmol). Diethyl azodicarboxylate (DEAD, 3.7 mL of a 40%
solution in toluene, 8.22 mmol) was added at 25ꢀC, and the mixture
was stirred for 15 min. Hydroxy acid 12 (409 mg of previous product,
1.61 mmol, in 16 mL dry toluene) was added at a rate of 5 mL=h via
syringe pump. The mixture was stirred for a further 2.5 h and stored
overnight at ꢁ20ꢀC. After warming to ambient temperature, the solvent
was removed.
A large portion of the impurities (related to DEAD and by-product
triphenylphosphine oxide) were removed from the product oil by adding
20% ether in hexane (120 mL), followed by silica gel (10 g), and stirring
the mixture for 15 min. After filtration through a sintered glass funnel,
the filtrate containing 1 was saved. The dried filter cake was transferred
to a column, and additional 1 was eluted with 20% ether in hexane
(80 mL). The solutions, containing 1, were stored at ꢁ20ꢀC overnight,
decanted from precipitated triphenylphosphine oxide, then combined,
reduced in volume from 320 mL to 75 mL, and again cooled to ꢁ20ꢀC
overnight to remove additional precipitated triphenylphosphine oxide.

1404
R. J. Petroski, R. J. Bartelt, and K. Vermillion
After solvent removal, the oil contained partially purified 1. Alterna-
tively, the product oil (dissolved in toluene) can be purified by direct
application to a larger silica column as described later for the partially
purified material.
The product was purified on an open column of silica gel (20 g,
column dimensions 2.8 cm ꢂ 9.5 cm), eluting with hexane (25 mL, 1
fraction), 5% ether in hexane (40 mL, 1 fraction), and 10% ether in
hexane (10 mL, 15 fractions). Compound 1 was present, in high purity,
in the sixth through tenth fractions, eluted with 10% ether in hexane.
The fifth fraction eluted with 10% ether also contained 1 but with a sig-
nificant amount of a side product (21, 13% of total by GC analysis).
When chromatography was complete, 220 mg of 1 had a final purity of
95%, and 22 mg had a purity of 79%; overall yield of 1 from 12 was
60%. MS (EI) m=z (%) 236 (Mþ, 82), 208 (19), 193 (33), 180 (8), 149
(22), 135 (100), 123 (28), 91 (18), 77 (20). The NMR spectral data are
given in Table 1. The MS and NMR spectral data were consistent with
previous work.[1]
A different synthetic batch, from which TEPA had not been removed
during the earlier synthetic step, contained a higher (19%) amount of side
product 21. This was chromatographed to afford 20 mg of the compound
for analysis by GC=MS and NMR. MS (EI) m=z (%) 264 (Mþ, 100), 249
(8), 235 (8), 221 (16), 208 (26), 195 (15), 193 (12), 191 (15), 177 (79), 149
1
(37), 135 (97), 123 (22), 109 (8), 91 (12), 77 (11). H NMR d1.24 (2H, m,
H-3), 1.44 (2H, m, H-12), 1.64 (2H, m, H-2), 1.69 (2H, m, H-11), 1.84
(6H, s, H-7a and H-8a), 2.32 (2H, t, J12-13 ¼ 6.2, H-13), 2.54 (2H, t,
J10-11 ¼ 5.8, H-10), 2.58 (2H, t, J4-5 ¼ 6.1, H-5), 4.09 (2H, t, J1-2 ¼ 5.4,
H-1). 13C NMR d 8.20 and 8.2.2 (7a and 7b, -CH3), 23.19 (C-3), 24.05
(C-12), 24.75 (C-5), 25.12 (C-10), 26.22 (C-4), 26.73 (C-11), 27.62 (C-2),
35.24 (C-13), 62.62 (C-1, -CH2-O), 115.15 (C-7), 115.77 (C-8), 146.69
(C-9), 147.74 (C-6), 173.35 (C-14, carbonyl C).
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