2,2,3-Trisubstituted Tetrahydrofurans and 2H-Tetrahydropyrans by Tandem Demethoxycarbonylation-Michael Addition Reactions

Article abstract of DOI:10.1021/jo971600s

A tandem demethoxycarbonylation-Michael addition reaction has been developed as a synthetic route to highly functionalized five- and six-membered oxygen heterocycles. Methyl esters, activated toward decarboxylation by a C-2 ethoxycarbonyl group and tethered by a three- or four-atom chain to an acrylate Michael acceptor, have been prepared and used as the cyclization substrates. Treatment of these compounds with lithium chloride in DMEU (1,3-dimethyl-2-imidazolidinone) at 120 °C for 4-8 h results in chemoselective S_N2 dealkylation of the methyl esters, decarboxylation, and cyclization of the intermediate enolates by a Michael addition to the pendent acrylate moiety. This affords tetrahydrofuran and 2H-tetrahydropyran derivatives in 60-90% yields with diastereoselectivities up to 7.5:1 in favor of the product having the C-2 ethoxycarbonyl group trans to the C-3 acetic ester side chain. The reaction works best for the preparation of five- and six-membered rings, and cyclizations proceed most cleanly from substrates which cyclize through a tertiary enolate. Synthetic and mechanistic details are presented.

Full text of DOI:10.1021/jo971600s

144
J . Org. Chem. 1998, 63, 144-151
2,2,3-Tr isu bstitu ted Tetr a h yd r ofu r a n s a n d 2H-Tetr a h yd r op yr a n s
by Ta n d em Dem eth oxyca r bon yla tion -Mich a el Ad d ition Rea ction s
Richard A. Bunce,* Eric D. Dowdy,1 R. Shawn Childress, and Paul B. J ones1
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071
Received August 27, 1997X
A tandem demethoxycarbonylation-Michael addition reaction has been developed as a synthetic
route to highly functionalized five- and six-membered oxygen heterocycles. Methyl esters, activated
toward decarboxylation by a C-2 ethoxycarbonyl group and tethered by a three- or four-atom chain
to an acrylate Michael acceptor, have been prepared and used as the cyclization substrates.
Treatment of these compounds with lithium chloride in DMEU (1,3-dimethyl-2-imidazolidinone)
at 120 °C for 4-8 h results in chemoselective SN2 dealkylation of the methyl esters, decarboxylation,
and cyclization of the intermediate enolates by a Michael addition to the pendent acrylate moiety.
This affords tetrahydrofuran and 2H-tetrahydropyran derivatives in 60-90% yields with diaste-
reoselectivities up to 7.5:1 in favor of the product having the C-2 ethoxycarbonyl group trans to
the C-3 acetic ester side chain. The reaction works best for the preparation of five- and
six-membered rings, and cyclizations proceed most cleanly from substrates which cyclize through
a tertiary enolate. Synthetic and mechanistic details are presented.
In tr od u ction
antioxidants8 and in several drug compounds.9,10 We
present here our results on the use of the demethoxy-
carbonylation-Michael addition reaction for the prepara-
tion of highly substituted tetrahydrofuran and 2H-
tetrahydropyran derivatives.
Decarboxylation reactions initiated by SN2 dealkylation
of activated esters occupy an important place in organic
synthesis, providing a mild method for the removal of a
directing group after alkylation or acylation.2 Early work
by others3 has described several tandem reaction pro-
cesses which capture the intermediate enolate generated
in this reaction when run under aprotic conditions.
Reports from this laboratory have further demonstrated
the use of a tandem demethoxycarbonylation-Michael
addition sequence for the preparation of carbocycles,4
lactones, and lactams.5 Our recent efforts have focused
on extending this methodology to the synthesis of oxygen
heterocycles. Tetrahydrofurans and 2H-tetrahydropyr-
ans are widely distributed in nature and are key struc-
tural components of a variety of ionophores6 and poly-
ether antibiotics.7 Additionally, aryl-fused systems are
important substructures found in naturally occurring
Syn th esis of Cycliza tion Su bstr a tes
The synthesis of precursors to simple functionalized
tetrahydrofurans is outlined in Scheme 1. The starting
alkoxyacetic esters 1-3 were prepared by treatment of
3-buten-1-ol derivatives11 with chloroacetic acid in the
presence of 2 equiv of NaH12 followed by esterification
under basic conditions.13,14 Conversion to the mixed
malonate esters 4-6 was accomplished by treatment of
the alkoxyacetic esters with 2 equiv of LDA at -78 °C
followed by methyl chloroformate.15 Methylation,16,17
ozonolysis,4a and Wittig olefination4a then furnished the
cyclization substrates 10-12. A similar sequence was
X Abstract published in Advance ACS Abstracts, December 15, 1997.
(1) Undergraduate research participants: P.B.J. (1991-1993); E.D.D.
(1991-1995). This work was taken, in large part, from the senior
research thesis of E.D.D.
(2) For reviews of SN2 ester cleavage, see: (a) McMurry, J . Org.
React. 1976, 24, 187-224. (b) Krapcho, A. P. Synthesis 1982, 805-
822, 893-914.
(3) Related dealkoxycarbonylation-initiated processes: (a) Ring
contraction: Takei, S.; Kawano, Y. Tetrahedron Lett. 1975, 4389-4392.
(b) Alkylative spiroannulation: Eilerman, R. G.; Willis, B. J . J . Chem.
Soc., Chem. Commun. 1981, 30-32. (c) Heterocycle formation by
O-alkylation of geometrically constrained conjugated enols: Bo¨hrer,
G.; Bo¨hrer, P.; Knorr, R. Chem. Ber. 1990, 123, 2167-2172.
(4) (a) Bunce, R. A.; Dowdy, E. D.; J ones, P. B.; Holt, E. M. J . Org.
Chem. 1993, 58, 7143-7148. (b) Bunce, R. A.; Schilling, C. L., III. J .
Org. Chem. 1995, 60, 2748-2752. (c) Bunce, R. A.; Harris, C. R. Synth.
Commun. 1996, 26, 1969-1975. (d) Bunce, R. A.; Peeples, C. J .; Holt,
E. M. 203rd National ACS Meeting, San Francisco, CA, April 1992,
Abstract no. 6.
(9) See for example: (a) Lednicer, D.; Mitscher, L. A. The Organic
Chemistry of Drug Synthesis; Wiley: New York, 1977, 1, 286-292; 1980,
2, 314-322; 1984, 3, 109-115. (b) Lednicer, D.; Mitscher, L. A.; Georg,
G. I. The Organic Chemistry of Drug Synthesis; Wiley: New York, 1990;
Vol. 4, 209-211. (c) Wolff, M. E., Ed. Berger’s Medicinal Chemistry
and Drug Discovery, 5th ed.; Wiley: New York, 1995; Vol. 1, 986-989.
(10) Witiak, D. T.; Loh, W.; Feller, D. R.; Baldwin, J . R.; Newman,
H. A. I.; Sober, C. L.; Cavestri, R. C. J . Med. Chem. 1979, 22, 699-
705.
(11) Several of the 3-buten-1-ol and 4-penten-1-ol derivatives have
been described previously, see Bunce, R. A.; Bennett, M. J . Synth.
Commun. 1993, 23, 1009-1020.
(12) (a) Glover, S. A.; Golding, S. L.; Goosen, A.: McCleland, C. W.
J . Chem. Soc., Perkin Trans. 1 1983, 2479-2483. (b) See also, Gershon,
H.; Shanks, L.; DeAngelis, A. J . Pharm. Sci. 1979, 68, 82-84.
(13) Degenhardt, C. R. J . Org. Chem. 1980, 45, 2763-2766.
(14) Details of the preparation of 1-3 and 13-16 can be found in
the Supporting Information.
(5) Bunce, R. A.; Schilling, C. L., III. Tetrahedron 1997, 53, 9477-
9486.
(15) Rathke, M. W.; Deitch, J . Tetrahedron Lett. 1971, 2953-2956.
(16) Inomata, K.; Aoyama, S.; Kotake, H. Bull. Chem. Soc. J pn.
1978, 51, 930-932.
(17) Methylation in a separate step was found to be superior to direct
methylation of the crude malonate anion.
(18) J ameson, D. L.; Hilgen, S. E.; Hummel, C. E.; Pichla, S. L.
Tetrahedron Lett. 1989, 30, 1609-1612.
(6) Dobler, M. Ionophores and Their Structures; Wiley: New York,
1981.
(7) Westley, J . W., Ed. Polyether Antibiotics: Naturally Occurring
Acid Ionophores; Marcel Dekker: New York, 1982; Vol. 1-2.
(8) Ellis, G. P.; Lockhart, I. M., Eds. Chromans and Tocopherols;
Wiley: New York, 1981.
S0022-3263(97)01600-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/09/1998

Tandem Demethoxycarbonylation-Michael Addition Reactions
J . Org. Chem., Vol. 63, No. 1, 1998 145
Sch em e 1a
Sch em e 3a
a
Key: (a) 2 LDA, THF, -78 °C; ClCO2Me, 56-68%; (b) NaH,
DMF; CH3I, 88-98%; (c) O3, CH2Cl2, -78 °C; Me2S, -78 f 20 °C;
Ph3PdCHCO2Et, PhH, 80 °C, 50-56%.
Sch em e 2a
a
Key: (a) NaH, DMF, MeO2CCHClCO2Et; (b) NaH, DMF, MeI,
81-83%; (c) TsOH, acetone, 74%; (d) Ph3PdCHCO2Et, PhH, 80
°C, 74%; (e) O3, CH2Cl2, -78 °C; Me2S, -78
Ph3PdCHCO2Et, PhH, 80 °C, 55%.
f 20 °C;
Ta ble 1. Syn th esis of Mon ocyclic Oxygen Heter ocycles
substrate
n
R,R
H,H
5,5-diMe
4,4-diMe
H,H
product
R,R
H,H
5,5-diMe 60:40
4,4-diMe 84:16
a :ba
% yieldb
10
11
12
25
26
27
0
0
0
1
1
1
35
36
37
38
39
40
76:24
67
67
60
93
75
72
H,H
88:12
a
6,6-diMe
5,5-diMe
6,6-diMe 81:19
5,5-diMe 81:19
Key: (a) 2 LDA, THF, -78 °C; ClCO2Me, 59-65%; (b) NaH,
DMF; CH3I, 88-92%; (c) O3, CH2Cl2, -78 °C; Me2S, -78 f 20 °C;
Ph3PdCHCO2Et, PhH, 80 °C, 40-56%.
a
Ratios represent the percentage of the crude reaction mixture
b
containing the indicated isomer. Yields refer to isolated purified
products (a +b).
used to prepare 2H-tetrahydropyran precursors 25-28
from substituted 4-penten-1-ols (Scheme 2).11,14
Ta ble 2. Syn th esis of Ar yl-F u sed Oxygen Heter ocycles
The synthesis of starting materials for the aryl-fused
oxygen heterocycles is given in Scheme 3. The 2,2,3-
trisubstituted 2,3-dihydrobenzofuran precursor 31 was
generated by Wittig olefination of aldehyde 30, prepared
in three steps from 2-(2-hydroxyphenyl)-1,3-dioxolane
(29).18 Compound 34 for the synthesis of the 2,2,3-
trisubstituted 3,4-dihydro-2H-1-benzopyran system was
prepared using an ozonolysis-Wittig protocol on alkene
33 which is available in two steps from 2-(2-propenyl)-
phenol (32).
substrate
n
product
a :ba
% yieldb
31
34
0
1
42
43
84:16
84
76
80:20c
a
Ratios represent the percentage of the crude reaction mixture
b
containing the indicated isomer. Yields refer to isolated purified
products (a +b). c Minor isomer contained 5-7% of the noncyclized
product resulting from demethoxycarbonylation and double bond
migration.
Resu lts a n d Discu ssion
work,4a,b but the current procedure is less hazardous and
gives slightly better diastereoselectivity. The reaction
provides optimum yields of cyclized products using
substrate concentrations of ca. 0.1 M on scales up to 5
mmol; higher concentrations or larger reaction scales
The results of our tandem demethoxycarbonylation-
Michael synthesis of oxygen heterocycles are summarized
in Tables 1 and 2. The optimized reaction conditions
involve heating each substrate in dry DMEU (1,3-
dimethyl-2-imidazolidinone)19 containing 4-6 equiv of
lithium chloride at 120 ( 5 °C for 4-8 h. The reaction
also proceeds in HMPA, as reported in our earlier
(19) Barker, B. J .; Rosenfarb, J .; Caruso, J . A. Angew. Chem., Int.
Ed. Engl. 1979, 18, 503-507.

146 J . Org. Chem., Vol. 63, No. 1, 1998
Bunce et al.
Sch em e 4
Sch em e 5
result in reduced selectivity and lower yields of cyclized
material. Product purification can be effected by pre-
parative thin-layer chromatography or flash chromatog-
raphy, and generally isomers are easily separated.
Product structures were established by spectroscopic
correlation with compounds previously prepared and
characterized in the carbocycle series.4a IR spectroscopy
indicated the loss of the conjugated double bond. 1H
NMR spectra confirmed the absence of the methoxycar-
bonyl group and the acrylate double bond. As in our
earlier carbocycle work,4a the trans isomer showed the
C-2 methyl upfield by 0.08-0.18 ppm and the C-3
methine downfield by 0.32-0.75 ppm relative to the cis
isomer. These observations are in agreement with the
shielding-deshielding characteristics of the nearby car-
bonyl-containing functionality. Additionally, the trans
isomer exhibited two doublets of doublets for the side
chain methylene group; these signals were not always
distinguishable in the cis isomer. 13C NMR gave a correct
accounting of the different types of carbons and cor-
roborated the IR and 1H NMR assignments. Finally,
exact molecular mass measurements and elemental
analyses of the products were consistent with the struc-
tures proposed.
The reaction tandem is initiated by chemoselective
SN2-type dealkylation of the methyl ester2,20 to generate
gaseous methyl chloride and a carboxylate anion acti-
vated toward decarboxylation by the R-ethoxycarbonyl
group. At 120 °C, the carboxylate moiety is spontane-
ously lost to afford the enolate, which cyclizes by a
favorable 5- or 6-[enolexo]-exo-trig22 Michael addition on
the pendent acrylate ester (see Scheme 4). As noted
previously,4 the best yields of cyclized products are
obtained when the decarboxylation proceeds through a
tertiary enolate, and when closure occurs to give a five-
or six-membered ring.
where ester-activated substrates gave unimpressive re-
sults and often produced substantial quantities of decar-
boxylated, uncyclized material. Among the compounds
studied, only hindered substrate 28 gave a significant
amount of uncyclized product 41. The improved yields
and selectivities in the current study may derive in part
from a gem-dimethyl effect (if this moiety does not hinder
the Michael addition) or an oxygen atom effect, both of
which should facilitate ring formation.20 Aryl-fused
systems were also produced in good yield, benefiting from
the proximity of the rigidly held reacting partners;5
substrate 34, however, gave 5-7% of the noncyclized
product derived from demethoxycarbonylation and double
bond migration along with the desired heterocycle 43.
The trans selectivity observed in the ring closure is of
considerable interest and merits further discussion.
Since steric interactions alone would tend to disfavor the
trans product,4a electronic factors must control the reac-
tion. Calculations by others21 have suggested that sec-
ondary orbital interactions, similar to those used to
rationalize the endo rule in the Diels-Alder reaction,
may play an important role in ring closures of this type
(Scheme 5). In chair transition state trans-44, the
dominant interaction would involve the HOMO of the
enolate (Michael donor) and the LUMO of the s-cis R,â-
unsaturated ester carbonyl (Michael acceptor). This
overlap would stabilize the transition state leading to the
trans product, and thus, govern the outcome of the
reaction.22 The lower selectivity observed in the five- (vs
the six-) membered ring closures contrasts with observa-
tions in the carbocycle series and likely derives from the
greater strain required to align the interacting π systems
for optimum orbital overlap. This strain should increase
as the distance between the interacting π systems
decreases. In the current substrates, the two C-O single
bonds (each ca. 0.10-0.15 Å shorter than a comparable
C-C bond)23 would shorten the connecting chain suf-
ficiently to inhibit overlap of the interacting donor and
acceptor moieties, particularly in five-membered ring
closures. Finally, transition state cis-44 should be dis-
The preparation of simple oxygen heterocycles pro-
ceeded in 60-90% yields with diastereoselectivities up
to 7.5:1 in favor of the product isomer having the C-2
ethoxycarbonyl group trans to the C-3 acetic ester side
chain. This outcome differs from our carbocycle work4a
(20) (a) For
a general review of factors effecting ring closure
reactions: Illuminati, G.; Mandolini, L. Acc. Chem. Res 1981, 14, 95-
102. (b) gem-Dimethyl effect: Allinger, N. L.; Zalkow, V. J . Org. Chem.
1960, 25, 701-704. (c) Oxygen atom effect: Dale, J . Tetrahedron 1974,
30, 1683-1694. Presumably, both of these these factors also increased
the rate of cyclization.
(21) (a) Smith, M. B. Organic Synthesis; McGraw-Hill: New York,
1994; p 132. (b) Isaacs, N. S. Physical Organic Chemistry; Wiley: New
York, 1987; p 287.
(22) (a) Baldwin, J . E.; Luche, M. J . Tetrahedron 1982, 38, 2939-
2947.
(23) Sevin, A.; Tortajada, J .; Pfau, M. J . Org. Chem. 1986, 51, 2671-
2675.

Tandem Demethoxycarbonylation-Michael Addition Reactions
J . Org. Chem., Vol. 63, No. 1, 1998 147
or 400 MHz and at 75 or 100 MHz, respectively, and are
referenced to internal (CH3)4Si. High-resolution mass spectra
(HRMS, EI/DP) were obtained at 70 eV. Elemental analyses
are (0.3%.
favored relative to trans-44 due to additional strain
required to achieve chairlike overlap as well as unfavor-
able interactions between the enolate methyl and C-4 of
the developing rings.
R ep r esen t a t ive Met h oxyca r b on yla t ion P r oced u r e:
Eth yl Meth yl (()-(3-Bu ten oxy)p r op a n ed ioa te (4). The
general procedure of Rathke and Deitch15 was adapted and
carried out 4× on a 25 mmol scale. LDA (50 mmol) was
generated at -78 °C in 75 mL of THF from 5.25 g (7.27 mL,
52.0 mmol) of diisopropylamine and 31.3 mL of 1.6 M n-BuLi
in hexanes (50.0 mmol). To the stirred solution of LDA was
added a solution of 3.95 g (25.0 mmol) of 1 in 25 mL of THF
dropwise during 15 min. The mixture was stirred at -78 °C
for 15 min, and a solution of 2.36 g (1.93 mL, 25.0 mmol) of
methyl chloroformate in 10 mL of THF was added dropwise
over a period of 10 min. The reaction was stirred for 10 min
at -78 °C and quenched with 50 mL of 1 M HCl. The mixture
was warmed to 20 °C, the organic layer was separated, and
the aqueous phase was extracted with ether (2×). The
combined organic extracts were washed with H2O, 5% NaH-
CO3, and saturated NaCl, dried (MgSO4), and concentrated
under vacuum. The product from the four runs was purified
by vacuum distillation to afford 12.1 g (56.1 mmol, 56%) of 4
as a colorless oil: bp 74-76 °C (0.5 mmHg); IR (thin film) 3085,
The aryl ring in the benzofuran ring closure precludes
a chairlike transition state since the ether oxygen, the
aromatic ring, and the acrylate acceptor would remain
essentially coplanar during the reaction. In this ex-
tended π system, steric interaction between the enolate
methyl and the acrylate group should force the enolate
to rotate out of planarity. Once the enolate moiety tilts
out of plane, the trans product should become favored
since formation of the cis isomer would require the
methyl to rotate past the C-H at the acrylate terminus.
In the benzopyran case, overlap between the aromatic
ring and the acrylate is eliminated, a chair transition
state is again possible, and the trans product should
predominate. This structure, however, positions the
enolate R-carbon in close proximity to the benzylic
methylene, giving rise to competitive double bond migra-
tion by proton exchange.
In summary, we have developed and optimized a
procedure for the preparation of highly functionalized
tetrahydrofuran- and 2H-tetrahydropyran-3-acetic esters
using a tandem demethoxycarbonylation-Michael addi-
tion strategy. The cyclization substrates are readily
available, the procedure is simple, and the products are
furnished in good yields with useful selectivities. We are
continuing our exploration of this reaction for the syn-
thesis of other functionalized ring structures. Several
related procedures are also under development.
1758, 1648, 1005, 924 cm-1 1H NMR δ 5.83 (ddt, 1 H, J )
;
17.1, 10.3, 6.8 Hz), 5.11 (d, 1 H, J ) 17.1 Hz), 5.06 (d, 1 H, J
) 10.3 Hz), 4.52 (s, 1 H), 4.27 (q, 2 H, J ) 7.2 Hz), 3.81 (s, 3
H), 3.65 (t, 2 H, J ) 6.8 Hz), 2.43 (q, 2 H, J ) 6.8 Hz), 1.30 (t,
3 H, J ) 7.2 Hz); 13C NMR δ 166.9, 166.4, 134.0, 116.9, 79.0,
70.6, 61.9, 52.7, 33.7, 13.9; HRMS m/z Calcd for C10H16O5:
216.0997. Found: 216.0992.
The following compounds were prepared by the same
procedure. The yields are based on four runs using 25 mmol
(100 mmol total) of the ester.
Eth yl Meth yl (()-(1,1-Dim eth yl-3-bu ten oxy)pr opan edio-
a te (5): 15.3 g (62.5 mmol, 62.5%) from 2; bp 82-84 °C (0.5
mmHg); IR (thin film) 3080, 1775, 1750, 1644, 1390, 1372, 920
1
Exp er im en ta l Section
cm-1; H NMR δ 5.85 (ddt, 1 H, J ) 16.5, 10.7, 7.1 Hz), 5.06
(m, 2 H), 4.66 (s, 1 H), 4.24 (m, 2 H), 3.79 (s, 3 H), 2.30 (d, 2
H, J ) 7.1 Hz), 1.29 (t, 3 H, J ) 7.2 Hz), 1.21 (s, 6 H); 13C
NMR δ 168.4, 167.9, 133.8, 117.8, 78.6, 72.3, 61.8, 52.6, 45.3,
25.1, 25.0, 13.9; HRMS m/z Calcd for C12H20O5: 244.1311.
Found: 244.1305.
DMF (BaO, 20 mmHg), DMEU (CaH2, 0.5 mmHg), and
diisopropylamine (CaH2) were distilled from the indicated
desiccant and stored over 4-Å molecular sieves under N2; THF
was distilled from LiAlH4 under N2. Other reagents were used
as received. All reactions were run under dry N2 in oven-dried
glassware. Unless otherwise indicated, the NH4Cl (5%),
NaHCO3 (5%), Na2S2O3 (5%), NaCl (saturated), NaOH (0.02
M), and HCl (0.5-1 M) used in workup procedures refer to
aqueous solutions. Reactions were monitored by one of the
following methods: (1) TLC on hard layer silica gel GF plates
(Analtech) using UV or phosphomolybdic acid detection or (2)
capillary GC with FI detection (SE-30 column, 6 m × 0.25 mm
i.d., 0.25 µm film thickness) programmed between 50 and 300
°C. Preparative separations were performed using one of the
following methods: (1) PTLC on 20-cm × 20-cm silica gel GF
plates (Analtech), (2) flash vacuum chromatography26 on silica
gel (Grace, grade 62, 60-200 mesh), or (3) flash chromatog-
raphy27 on silica gel (60-200 mesh) mixed with Sylvania no.
2282 UV-active phosphor. Band elution, where appropriate,
was monitored using a hand-held UV lamp. Melting points
Eth yl Meth yl (()-(2,2-Dim eth yl-3-bu ten oxy)pr opan edio-
a te (6): 14.7 g (60.1 mmol, 60%) from 3; bp 65-67 °C (0.2
mmHg); IR (thin film) 3085, 1755, 1649, 1395, 1370, 983, 920
1
cm-1; H NMR δ 5.87 (dd, 1 H, J ) 17.5, 10.8 Hz), 5.04 (d, 1
H, J ) 17.5 Hz), 4.99 (d, 1 H, J ) 10.8 Hz), 4.47 (s, 1 H), 4.26
(m, 2 H), 3.80 (s, 3 H), 3.35 (s, 2 H), 1.30 (t, 3 H, J ) 7.1 Hz),
1.07 (s, 6 H); 13C NMR δ 167.0, 166.5, 144.9, 112.0, 79.8, 79.6,
61.8, 52.6, 38.0, 23.7 (2), 13.9; HRMS m/z Calcd for C12H20O5:
244.1311. Found: 244.1310.
Eth yl Meth yl (()-(4-P en ten oxy)p r op a n ed ioa te (17):
13.3 g (58 mmol, 58%) from 13; bp 84-86 °C (0.5 mmHg); IR
1
(thin film) 3085, 1758, 1648, 1003, 920 cm-1; H NMR δ 5.80
(ddt, 1 H, J ) 17.2, 10.3, 6.8 Hz), 5.03 (d, 1 H, J ) 17.2 Hz),
4.97 (d, 1 H, J ) 10.3 Hz), 4.49 (s, 1 H), 4.27 (q, 2 H, J ) 7.1
Hz), 3.81 (s, 3 H), 3.60 (t, 2 H, J ) 6.8 Hz), 2.16 (q, 2 H, J )
6.8 Hz), 1.77 (quintet, 2 H, J ) 6.8 Hz), 1.30 (t, 3 H, J ) 7.1
Hz); 13C NMR δ 167.0, 166.4, 137.7, 114.9, 79.1, 70.7, 61.9,
52.6, 29.8, 28.4, 13.9; HRMS m/z Calcd for C11H18O5: 230.1154.
Found: 230.1149.
1
are uncorrected. IR spectra are referenced to polystyrene. H
NMR and 13C NMR spectra were measured in CDCl3 at 300
Eth yl Meth yl (()-(1,1-Dim eth yl-4-p en ten oxy)p r op a n e-
d ioa te (18): 17.0 g (65.8 mmol, 66%) from 14; bp 92-94 °C
(0.5 mmHg); IR (thin film) 3082, 1776, 1750, 1648, 1390, 1375,
(24) (a) Stork, G.; Winkler, J . D.; Saccomano, N. Tetrahedron Lett.
1983, 24, 465-468. (b) Stork, G.; Saccomano, N. Nouv. J . Chem. 1986,
10, 677-679. (c) Bunce, R. A.; Wamsley, E. J .; Pierce, J . D.; Shell-
hammer, A. J ., J r.; Drumright, R. E. J . Org. Chem. 1987, 52, 464-
466. (d) d’Angelo, J .; Guingant, A.; Riche, C.; Chiaroni, A. Tetrahedron
Lett. 1988, 29, 2667-2670. (e) d’Angelo, J .; Ferroud, C.; Riche, C.;
Chiaroni, A. Tetrahedron Lett. 1989, 30, 6511-6514. (f) Dumas, F.;
d’Angelo, J . Tetrahedron Asymmetry 1990, 1, 167-170. (g) Barco, A.;
Benetti, S.; Spalluto, G.; Casolari, A.; Pollini, G. P.; Zanirato, V. J .
Org. Chem. 1992, 57, 6279-6286.
1
1000, 912 cm-1; H NMR δ 5.81 (ddt, 1 H, J ) 17.1, 10.3, 6.8
Hz), 5.02 (d, 1 H, J ) 17.1 Hz), 4.93 (d, 1 H, J ) 10.3 Hz), 4.62
(s, 1 H), 4.25 (m, 2 H), 3.79 (s, 3 H), 2.15 (m, 2 H), 1.61 (m, 2
H), 1.29 (t, 3 H, J ) 7.2 Hz), 1.22 (s, 6 H); 13C NMR δ 168.4,
167.9, 138.5, 114.2, 78.5, 72.2, 61.7, 52.6, 39.7, 28.0, 25.2, 25.1,
13.9; HRMS m/z Calcd for C13H22O5: 258.1467. Found:
258.1458.
Eth yl Meth yl (()-(2,2-Dim eth yl-4-p en ten oxy)p r op a n e-
d ioa te (19): 15.1 g (58.5 mmol, 58.5%) from 15; bp 88-89 °C
(0.5 mmHg); IR (thin film) 3078, 1774, 1750, 1642, 1380, 1368,
(25) March, J . Advanced Organic Chemistry, 4th ed.; Wiley: New
York, 1992; p 21.
(26) Leopold, E. J . J . Org. Chem. 1982, 47, 4592-4594.
(27) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

148 J . Org. Chem., Vol. 63, No. 1, 1998
Bunce et al.
1
1000, 918 cm-1; H NMR δ 5.81 (ddt, 1 H, J ) 17.0, 10.8, 7.5
4.22 (q, 2 H, J ) 7.1 Hz), 3.76 (s, 3 H), 2.21 (m, 2 H), 1.72 (s,
Hz), 5.02 (m, 2 H), 4.44 (s, 1 H), 4.27 (m, 2 H), 3.80 (s, 3 H),
3.27 (s, 2 H), 2.07 (d, 2 H, J ) 7.5 Hz), 1.30 (t, 3 H, J ) 7.1
Hz), 0.93 (s, 6 H); 13C NMR δ 167.1, 166.6, 134.9, 117.2, 79.6
(2), 61.8, 52.6, 43.2, 34.9, 24.1 (2), 14.0; HRMS m/z Calcd for
C13H22O5: 258.1467. Found: 258.1477.
3 H), 1.62 (m, 2 H), 1.28 (t, 3 H, J ) 7.1 Hz), 1.27 (s, 6 H); 13
C
NMR δ 171.5, 170.9, 139.1, 113.9, 80.2, 78.7, 61.6, 52.5, 43.2,
28.3, 27.0 (2), 22.9, 13.8; HRMS m/z Calcd for C14H24O5:
272.1464. Found: 272.1459.
Eth yl Meth yl (()-(2,2-Dim eth yl-4-p en ten oxy)m eth yl-
p r op a n ed ioa te (23): 10.9 g (40.0 mmol, 88%) from 19; bp
84-87 °C (0.5 mmHg); IR (thin film) 3078, 1750, 1642, 1398,
1370, 998, 915 cm-1; 1H NMR δ 5.82 (ddt, 1 H, J ) 17.3, 10.7,
7.5 Hz), 4.99 (m, 2 H), 4.23 (q, 2 H, J ) 7.1 Hz), 3.77 (s, 3 H),
3.19 (s, 2 H), 2.03 (d, 2 H, J ) 7.5 Hz), 1.61 (s, 3 H), 1.28 (t, 3
H, J ) 7.1 Hz), 0.89 (s, 6 H); 13C NMR δ 170.1, 169.4, 135.2,
116.4, 81.4, 73.6, 61.5, 52.4, 43.4, 34.5, 24.1 (2), 20.7, 14.0;
HRMS m/z Calcd for C14H24O5: 272.1464. Found: 272.1462.
Eth yl Meth yl (()-(3,3-Dim eth yl-4-p en ten oxy)m eth yl-
p r op a n ed ioa te (24): 9.98 g (36.7 mmol, 92%) from 20; used
without further purification; IR (thin film) 3083, 1750, 1643,
1385, 1375, 982, 914 cm-1; 1H NMR δ 5.76 (dd, 1 H, J ) 17.8,
10.4 Hz), 4.90 (m, 2 H), 4.25 (m, 2 H), 3.78 (s, 3 H), 3.49 (t, 2
H, J ) 7.7 Hz), 1.69 (t, 2 H, J ) 7.7 Hz), 1.63 (s, 3 H), 1.29 (t,
3 H, J ) 7.1 Hz), 1.01 (s, 6 H); 13C NMR δ 170.7, 169.3, 147.6,
110.6, 81.8, 63.3, 61.7, 52.5, 41.7, 35.5, 27.0 (2), 20.5, 14.0;
HRMS m/z Calcd for C14H24O5: 272.1464. Found: 272.1463.
Rep r esen ta tive Ozon olysis-Wittig P r oced u r e: Eth yl
(()-(E )-5-(1-(E t h oxyca r b on yl)-1-(m e t h oxyca r b on yl)-
eth oxy)-2-p en ten oa te (10). The procedure of Bunce and co-
workers4a was used. A solution of 9.20 g (40.0 mmol) of 7 in
300 mL of CH2Cl2 was cooled to -78 °C and treated with O3
until the solution turned a light blue color. The reaction was
quenched at -78 °C with 6.20 g (7.33 mL, 100 mmol) of Me2S,
warmed to 20 °C, stirred for 3 h, and concentrated under
vacuum. To the resulting light yellow oil was added 250 mL
of benzene and 20.9 g (60.0 mmol) of ethyl (triphenylphospho-
ranylidene)acetate.28 The solution was refluxed for 12 h and
then cooled and concentrated under vacuum to afford a tan
semisolid mass. The residue was layered on top of a 10 cm ×
10 cm plug of silica gel in a sintered glass frit, and 2 L of 15%
ether in hexanes was poured through under aspirator vacuum.
Concentration of the filtrate afforded the crude product as a
viscous yellow oil. This oil was flash chromatographed on a
50 cm × 2.5 cm silica gel column eluted with increasing
concentrations of ether in hexanes. The major band gave 7.19
g (20.8 mmol, 59.5%) of 10 as a colorless oil: IR (thin film)
Eth yl Meth yl (()-(3,3-Dim eth yl-4-p en ten oxy)p r op a n e-
d ioa te (20): 16.8 g (65.1 mmol, 65%) from 16; bp 83-84 °C
(0.5 mmHg); IR (thin film) 3084, 1760, 1644, 1385, 1370, 981,
1
915 cm-1; H NMR δ 5.76 (dd, 1 H, J ) 17.8, 10.4 Hz), 4.92
(m, 2 H), 4.46 (s, 1 H), 4.27 (m, 2 H), 3.81 (s, 3 H), 3.56 (t, 2 H,
J ) 7.5 Hz), 1.73 (t, 2 H, J ) 7.5 Hz), 1.30 (t, 3 H, J ) 7.1 Hz),
1.02 (s, 6 H); 13C NMR δ 167.0, 166.5, 147.4, 110.8, 79.2, 68.7,
61.9, 52.7, 41.0, 35.4, 26.9 (2), 13.9; HRMS m/z Calcd for
C13H22O5: 258.1467. Found: 258.1471.
Rep r esen ta tive Meth yla tion P r oced u r e: Eth yl Meth yl
(()-(3-Bu ten oxy)m eth ylp r op a n ed ioa te (7). The general
alkylation procedure of Inomata and co-workers was used.16,17
To a suspension of 1.22 g (51.0 mmol) of oil-free NaH in 75
mL of DMF was added a solution of 10.8 g (50.0 mmol) of 4 in
25 mL of DMF dropwise with stirring. The mixture was
stirred for 30 min, and a solution of 10.7 g (4.67 mL, 75.0
mmol) of methyl iodide in 10 mL of DMF was added dropwise.
The reaction was heated at 50 °C for 12 h, cooled, quenched
with 5% NH4Cl, and extracted with ether (3×). The combined
organic extracts were washed with H2O, 5% Na2S2O3, and
saturated NaCl, dried (MgSO4), and concentrated under
vacuum. Final purification by vacuum distillation afforded
10.2 g (44.5 mmol, 89%) of 7 as a colorless oil: bp 72-74 °C
(0.2 mmHg); IR (thin film) 3085, 1752, 1648, 1376, 998, 920
1
cm-1; H NMR δ 5.82 (ddt, 1 H, J ) 17.2, 10.3, 6.9 Hz), 5.08
(d, 1 H, J ) 17.2 Hz), 5.03 (d, 1 H, J ) 10.3 Hz), 4.25 (q, 2 H,
J ) 7.2 Hz), 3.79 (s, 3 H), 3.58 (t, 2 H, J ) 6.9 Hz), 2.38 (q, 2
H, J ) 6.9 Hz), 1.64 (s, 3 H), 1.29 (t, 3 H, J ) 7.2 Hz); 13C
NMR δ 169.8, 169.2, 134.5, 116.5, 81.7, 65.5, 61.7, 52.5, 34.3,
20.6, 13.9; HRMS m/z Calcd for C11H18O5: 230.1154. Found:
230.1150.
The following compounds were prepared on varying scales
using the same procedure. Purification was achieved by
vacuum distillation or silica gel flash chromatography eluted
with ether in hexanes.
Eth yl Meth yl (()-(1,1-Dim eth yl-3-bu ten oxy)m eth yl-
p r op a n ed ioa te (8): 11.2 g (43.4 mmol, 97%) from 5; bp 79-
81 °C (0.5 mmHg); IR (thin film) 3080, 1750, 1645, 1390, 1372,
1750, 1735, 1658, 1375 cm-1
;
1H NMR δ 6.96 (dt, 1 H, J )
1
1000, 920 cm-1; H NMR δ 5.95 (ddt, 1 H, J ) 17.1, 10.3, 7.2
15.7, 6.8 Hz), 5.90 (d, 1 H, J ) 15.7 Hz), 4.26 (q, 2 H, J ) 7.2
Hz), 4.18 (q, 2 H, J ) 7.2 Hz), 3.79 (s, 3 H), 3.67 (t, 2 H, J )
6.6 Hz), 2.53 (q, 2 H, J ) 6.7 Hz), 1.64 (s, 3 H), 1.29 (t, 6 H, J
) 7.2 Hz); 13C NMR δ 167.7, 169.1, 166.3, 144.9, 123.0, 81.8,
64.4, 61.8, 60.1, 52.6, 32.7, 20.8, 14.2, 14.0; HRMS m/z Calcd
for C14H22O7: 302.1364. Found: 302.1358. Anal. Calcd for
C14H22O7: C, 55.62; H, 7.28. Found: C, 55.64; H, 7.25.
The following compounds were prepared on varying scales
using the same procedure. Purification was achieved by silica
gel flash chromatography eluted with ether in hexanes.
E t h yl (()-(E)-5-(1-(E t h oxyca r b on yl)-1-(m et h oxyca r -
bon yl)eth oxy)-5-m eth yl-2-h exen oa te (11): 7.95 g (24.1
mmol, 56%) from 8; IR (thin film) 1750, 1730, 1660, 1392, 1374
cm-1; 1H NMR δ 7.11 (dt, 1 H, J ) 15.7, 7.5 Hz), 5.84 (d, 1 H,
J ) 15.7 Hz), 4.28-4.17 (complex, 4 H), 3.77 (s, 3 H), 2.46 (d,
2 H, J ) 7.5 Hz), 1.74 (s, 3 H), 1.29 (m, 12 H); 13C NMR δ
171.3, 170.6, 166.3, 145.2, 123.7, 80.4, 78.4, 61.7, 60.1, 52.6,
47.1, 26.9, 26.8, 23.1, 14.2, 13.8; HRMS m/z Calcd for
C16H26O7: 330.1678. Found: 330.1675. Anal. Calcd for
C16H26O7: C, 58.18; H, 7.88. Found: C, 58.12; H, 7.93.
E t h yl (()-(E)-5-(1-(E t h oxyca r b on yl)-1-(m et h oxyca r -
bon yl)eth oxy)-4,4-dim eth yl-2-pen ten oate (12): 4.74 g (14.4
mmol, 50%) from 9; IR (thin film) 1749, 1722, 1651, 1392, 1370,
Hz), 5.04 (m, 2 H), 4.22 (q, 2 H, J ) 7.1 Hz), 3.76 (s, 3 H), 2.32
(d, 2 H, J ) 7.2 Hz), 1.74 (s, 3 H), 1.28 (t, 3 H, J ) 7.1 Hz),
1.25 (s, 6 H); 13C NMR δ 171.4, 170.8, 134.8, 117.2, 80.3, 78.7,
61.6, 52.5, 48.6, 26.7, 26.6, 23.0, 13.8; HRMS m/z Calcd for
C13H22O5: 258.1467. Found: 258.1469.
Eth yl Meth yl (()-(2,2-Dim eth yl-3-bu ten oxy)m eth yl-
p r op a n ed ioa te (9): 9.78 g (37.9 mmol, 91%) from 6; used
without further purification; IR (thin film) 3085, 1750, 1648,
1393, 1373, 985, 919 cm-1; 1H NMR δ 5.87 (dd, 1 H, J ) 17.5,
10.7 Hz), 5.01 (d, 1 H, J ) 17.5 Hz), 4.97 (d, 1 H, J ) 10.7 Hz),
4.24 (q, 2 H, J ) 7.1 Hz), 3.77 (s, 3 H), 3.28 (s, 2 H), 1.61 (s, 3
H), 1.28 (t, 3 H, J ) 7.1 Hz), 1.04 (s, 6 H); 13C NMR δ 170.0,
169.3, 145.5, 111.5, 81.5, 74.0, 61.5, 52.4, 37.7, 23.8 (2), 20.7,
14.0; HRMS m/z Calcd for C13H22O5: 258.1464. Found:
258.1460.
Eth yl Meth yl (()-Meth yl(4-p en ten oxy)p r op a n ed ioa te
(21): 11.3 g (46.3 mmol, 89%) from 17; bp 88-89 °C (0.5
mmHg); IR (thin film) 3085, 1750, 1648, 1377, 1000, 919 cm-1
;
1H NMR δ 5.81 (ddt, 1 H, J ) 17.2, 10.3, 7.0 Hz), 5.03 (d, 1 H,
J ) 17.2 Hz), 4.95 (d, 1 H, J ) 10.3 Hz), 4.25 (q, 2 H, J ) 7.1
Hz), 3.79 (s, 3 H), 3.52 (t, 2 H, J ) 6.6 Hz), 2.14 (q, 2 H, J )
7.0 Hz), 1.72 (quintet, 2 H, J ) 7.0 Hz), 1.63 (s, 3 H), 1.29 (t,
3 H, J ) 7.1 Hz); 13C NMR δ 169.9, 169.2, 138.0, 114.6, 81.6,
65.3, 61.6, 52.5, 29.9, 29.0, 20.5, 13.9; HRMS m/z Calcd for
C12H20O5: 244.1310. Found: 244.1309.
1
985 cm-1; H NMR δ 6.98 (d, 1 H, J ) 16.0 Hz), 5.82 (d, 1 H,
J ) 16.0 Hz), 4.24 (q, 2 H, J ) 7.1 Hz), 4.19 (q, 2 H, J ) 7.1
Hz), 3.77 (s, 3 H), 3.38 (s, 2 H), 1.61 (s, 3 H), 1.29 (t, 3 H, J )
7.1 Hz), 1.28 (t, 3 H, J ) 7.1 Hz), 1.10 (s, 6 H); 13C NMR δ
Eth yl Meth yl (()-(1,1-Dim eth yl-4-p en ten oxy)m eth yl-
p r op a n ed ioa te (22): 10.8 g (39.7 mmol, 88%) from 18; bp
70-72 °C (0.3 mmHg); IR (thin film) 3085, 1752, 1650, 1390,
1375, 1000, 913 cm-1; 1H NMR δ 5.84 (ddt, 1 H, J ) 17.1, 10.2,
6.8 Hz), 5.02 (d, 1 H, J ) 17.1 Hz), 4.92 (d, 1 H, J ) 10.2 Hz),
(28) (a) Maercker, A. Org. React. 1965, 14, 270-490. (b) Fieser, L.
F.; Fieser, M. Reagents for Organic Synthesis; Wiley: New York; 1967;
Vol. 1, pp 112-114.

Tandem Demethoxycarbonylation-Michael Addition Reactions
J . Org. Chem., Vol. 63, No. 1, 1998 149
169.8, 169.2 167.1, 155.2, 118.9, 81.6, 73.3, 61.7, 60.2, 52.5,
37.9, 23.7 (2), 21.0, 14.3, 14.0; HRMS m/z Calcd for C16H26O7:
330.1678. Found: 330.1676. Anal. Calcd for C16H26O7: C,
58.18; H, 7.88. Found: C, 58.39; H, 7.96.
6.30 (s, 1 H), 5.23 (s, 1 H), 4.29 (q, 2 H, J ) 7.1 Hz), 4.13 (m,
2 H), 4.03 (m, 2 H), 3.83 (s, 3 H), 1.29 (t, 3 H, J ) 7.1 Hz); 13
C
NMR δ 166.1, 165.4, 155.5, 130.3, 128.3, 127.6, 122.9, 114.0,
99.0, 77.8, 65.1, 62.3, 53.0, 13.7; HRMS m/z Calcd for
C15H18O7: 310.1052. Found: 310.1049.
E t h yl (()-(E)-6-(1-(E t h oxyca r b on yl)-1-(m et h oxyca r -
bon yl)eth oxy)-2-h exen oa te (25): 7.96 g (25.2 mmol, 56%)
from 21; IR (thin film) 1750, 1735, 1660, 1375 cm-1; 1H NMR
δ 6.97 (dt, 1 H, J ) 15.6, 6.8 Hz), 5.84 (d, 1 H, J ) 15.6 Hz),
4.25 (q, 2 H, J ) 7.1 Hz), 4.18 (q, 2 H, J ) 7.1 Hz), 3.79 (s, 3
H), 3.56 (t, 2 H, J ) 6.5 Hz), 2.33 (q, 2 H, J ) 7.2 Hz), 1.79
(quintet, 2 H, J ) 6.8 Hz), 1.63 (s, 3 H), 1.29 (2 t, 6 H, J ) 7.1
Hz); 13C NMR δ 169.7, 169.1, 166.4, 148.3, 121.5, 81.5, 64.8,
61.6, 59.9, 52.5, 28.4, 28.1, 20.6, 14.1, 13.9; HRMS m/z Calcd
for C15H24O7: 316.1521. Found: 316.1517. Anal. Calcd for
C15H24O7: C, 56.96; H, 7.59. Found: C, 57.19; H, 7.63.
E t h yl (()-(E)-6-(1-(E t h oxyca r b on yl)-1-(m et h oxyca r -
bon yl)eth oxy)-6-m eth yl-2-h ep ten oa te (26): 6.74 g (19.6
mmol, 52%) from 22; IR (thin film) 1750, 1728, 1660, 1395,
1376 cm-1; 1H NMR δ 7.02 (dt, 1 H, J ) 15.6, 6.8 Hz), 5.83 (d,
1 H, J ) 15.6 Hz), 4.22 (q, 2 H, J ) 7.1 Hz), 4.18 (q, 2 H, J )
7.1 Hz), 3.76 (s, 3 H), 2.42 (m, 2 H), 1.72 (s, 3 H), 1.67 (m, 2
H), 1.28 (s, 6 H), 1.28 (2 t, 6 H, J ) 7.1 Hz); 13C NMR δ 171.3,
170.7, 166.6, 149.5, 120.9, 80.2, 78.2, 61.6, 60.0, 52.5, 42.4, 27.0,
26.9, 26.7, 23.0, 14.2, 13.8; HRMS m/z Calcd for C17H28O7:
344.1835. Found: 344.1843. Anal. Calcd for C17H28O7: C,
59.30; H, 8.14. Found: C, 59.55; H, 8.20.
E t h yl (()-(E)-6-(1-(E t h oxyca r b on yl)-1-(m et h oxyca r -
bon yl)eth oxy)-5,5-d im eth yl-2-h exen oa te (27): 5.57 g (16.2
mmol, 51%) from 23; IR (thin film) 1750, 1728, 1658, 1396,
1372 cm-1; 1H NMR δ 6.99 (dt, 1 H, J ) 15.6, 7.7 Hz), 5.83 (d,
1 H, J ) 15.6 Hz), 4.24 (q, 2 H, J ) 7.1 Hz), 4.18 (q, 2 H, J )
7.1 Hz), 3.78 (s, 3 H), 3.23 (s, 2 H), 2.21 (d, 2 H, J ) 7.7 Hz),
1.62 (s, 3 H), 1.30 (t, 3 H, J ) 7.1 Hz), 1.29 (t, 3 H, J ) 7.1
Hz), 0.93 (s, 6 H); 13C NMR δ 169.9, 169.3, 166.4, 146.6, 123.5,
81.4, 73.4, 61.6, 60.0, 52.4, 41.5, 35.2, 24.4 (2), 20.7, 14.2, 14.0;
HRMS m/z Calcd for C17H28O7: 344.1835. Found: 344.1839.
Anal. Calcd for C17H28O7: C, 59.30; H, 8.14. Found: C, 59.59;
H, 8.17.
The crude ethyl methyl (()-(2-formylphenoxy)propanedioate
ethylene ketal was alkylated with methyl iodide on a 22.5
mmol scale using the same procedure given for the preparation
of 7. The crude ethyl methyl (()-(2-formylphenoxy)methyl-
propanedioate ethylene ketal (6.42 g) was isolated as a light
yellow oil and used without further purification. IR (thin film)
1745, 1602, 1494, 1373, 752 cm-1; 1H NMR δ 7.56 (d, 1 H, J )
8.0 Hz), 7.24 (t, 1 H, J ) 7.5 Hz), 7.09 (t, 1 H, J ) 7.5 Hz),
6.88 (d, 1 H, J ) 8.2 Hz), 6.25 (s, 1 H), 4.28 (q, 2 H, J ) 7.1
Hz), 4.12 (m, 2 H), 4.02 (m, 2 H), 3.82 (s, 3 H), 1.73 (s, 3 H),
1.25 (t, 3 H, J ) 7.1 Hz); 13C NMR δ 169.6, 168.8, 153.0, 130.1,
129.8, 127.4, 123.4, 118.4, 99.0, 83.0, 65.1, 62.2, 53.0, 19.9, 13.7;
HRMS m/z Calcd for C16H20O7: 324.1208. Found: 324.1202.
A solution of 6.42 g (19.8 mmol) of ethyl methyl (()-(2-
formylphenoxy)methylpropanedioate ethylene ketal in 100 mL
of acetone was treated with 100 mg of p-TsOH and stirred at
rt for 4 h. The reaction was concentrated, diluted with ether,
washed with 5% NaHCO3 and saturated NaCl, dried (MgSO4),
and concentrated under vacuum. The crude aldehyde was
flash chromatographed on a 50 cm × 2.5 cm silica gel column
eluted with increasing concentrations of ether in hexanes.
Concentration of the major band gave 4.08 g (14.6 mmol, 60%
from 29) of aldehyde 30 as a light yellow oil. IR (thin film)
2875, 2761, 1741, 1688, 1595, 1488, 1373, 759 cm-1; 1H NMR
δ 10.59 (s, 1 H), 7.88 (d, 1 H, J ) 7.7 Hz), 7.48 (t, 1 H, J ) 7.5
Hz), 7.15 (t, 1 H, J ) 7.5 Hz), 6.93 (d, 1 H, J ) 8.2 Hz), 4.29
(q, 2 H, J ) 7.1 Hz), 3.84 (s, 3 H), 1.87 (s, 3 H), 1.25 (t, 3 H, J
) 7.1 Hz); 13C NMR δ 190.1, 168.9, 168.1, 157.4, 135.1, 128.4,
127.8, 123.1, 117.8, 83.1, 62.5, 53.2, 20.7, 13.6; HRMS m/z
Calcd for C14H16O6: 280.0946. Found: 280.0941.
Eth yl Meth yl (()-(E)-(2-(2-(Eth oxyca r bon yl)eth en yl)-
p h en oxy)m eth ylp r op a n ed ioa te (31). A solution of 4.05 g
(14.5 mmol) of 30 in 150 mL of benzene was treated with 5.08
g (14.6 mmol) of ethyl (triphenylphosphoranylidene)acetate,28
and the mixture was refluxed for 12 h. The solution was cooled
and concentrated under vacuum to afford a tan semisolid mass.
The residue was layered on top of a 10 cm × 10 cm plug of
silica gel in a sintered glass frit and 2 L of 15% ether in
hexanes was poured through under aspirator vacuum. Con-
centration of the filtrate afforded the crude product as a
viscous yellow oil. This oil was flash chromatographed on a
50 cm × 2.5 cm silica gel column eluted with increasing
concentrations of ether in hexanes. Concentration of the major
band gave 3.75 g (10.7 mmol, 74%) of 31 as a light yellow oil.
IR (thin film) 1749, 1711, 1626, 1595, 1488, 1373, 982, 759
E t h yl (()-(E)-6-(1-(E t h oxyca r b on yl)-1-(m et h oxyca r -
bon yl)eth oxy)-4,4-d im eth yl-2-h exen oa te (28): 2.48 g (7.21
mmol, 40%) from 24; IR (thin film) 1750, 1729, 1659, 1394,
1372, 985 cm-1; 1H NMR δ 5.95 (d, 1 H, J ) 13.1 Hz), 5.69 (d,
1 H, J ) 13.1 Hz), 4.25 (q, 2 H, J ) 7.1 Hz), 4.15 (q, 2 H, J )
7.1 Hz), 3.78 (s, 3 H), 3.56 (t, 2 H, J ) 7.3 Hz), 1.89 (t, 2 H, J
) 7.3 Hz), 1.63 (s, 3 H), 1.29 (t, 3 H, J ) 7.1 Hz), 1.28 (t, 3 H,
J ) 7.1 Hz), 1.20 (s, 6 H); 13C NMR δ 169.9, 169.4, 166.6, 152.9,
119.5, 81.8, 63.4, 61.8, 60.2, 52.3, 42.4, 36.0, 27.6 (2), 20.6, 14.1,
14.0; HRMS m/z Calcd for C17H28O7: 344.1835. Found:
344.1841. Anal. Calcd for C17H28O7: C, 59.30; H, 8.14.
Found: C, 59.47; H, 8.16.
1
cm-1; H NMR δ 8.08 (d, 1 H, J ) 16.2 Hz), 7.56 (d, 1 H, J )
Eth yl Meth yl (()-(2-F or m ylp h en oxy)m eth ylp r op a n e-
d ioa te (30). The general alkylation procedure of Inomata and
co-workers was used.16 To a suspension of 0.60 g (25.0 mmol)
of oil-free NaH in 10 mL of DMF was added a solution of 4.08
g (24.6 mmol) of 2918 in 15 mL of DMF. To the clear solution
was added 4.51 g (25.0 mmol) of ethyl methyl (()-chloropro-
panedioate29 in 15 mL of DMF. The reaction was stirred for
1 h at rt and for 8 h at 50 °C and then cooled, quenched with
5% NH4Cl, and extracted with ether (3×). The combined
organic extracts were washed with H2O, 0.02 M NaOH (until
the washes were colorless), H2O, and saturated NaCl, dried
(Na2SO4), and concentrated under vacuum. The crude ethyl
methyl (()-(2-formylphenoxy)propanedioate ethylene ketal
(7.00 g) was isolated as a light yellow oil and used without
further purification. IR (thin film) 1749, 1665, 1603, 1495,
7.7 Hz), 7.25 (t, 1 H, J ) 7.5 Hz), 7.06 (t, 1 H, J ) 7.5 Hz),
6.85 (d, 1 H, J ) 8.2 Hz), 6.64 (d, 1 H, J ) 16.2 Hz), 4.31 (q,
2 H, J ) 7.1 Hz), 4.27 (q, 2 H, J ) 7.1 Hz), 3.85 (s, 3 H), 1.78
(s, 3 H), 1.34 (t, 3 H, J ) 7.1 Hz), 1.28 (t, 3 H, J ) 7.1 Hz); 13
C
NMR δ 169.4, 168.6, 167.4, 153.5, 139.7, 130.7, 129.0, 126.9,
123.2, 119.8, 117.9, 83.1, 62.5, 60.2, 53.1, 20.2, 14.1, 13.7;
HRMS m/z Calcd for C18H22O7: 350.1365. Found: 350.1367.
Anal. Calcd for C18H22O7: C, 61.71; H, 6.29. Found: C, 61.94;
H, 6.34.
Eth yl Meth yl (()-Meth yl(2-(2-p r op en yl)p h en oxy)p r o-
p a n ed ioa te (33). Compound 32 was alkylated with ethyl
methyl (()-chloropropanedioate29 on a 22.5 mmol scale using
the same procedure given to alkylate 29 in the preparation of
30. Flash chromatography on a 100 cm × 2.5 cm silica gel
column eluted with increasing concentrations of ether in
hexanes gave 5.50 g (19.8 mmol, 88%) of ethyl methyl (()-(2-
(2-propenyl)phenoxy)propanedioate as a light yellow oil. IR
(thin film) 1773, 1751, 1648, 1370, 996, 916, 755 cm-1; 1H NMR
δ 7.15 (m, 2 H), 6.98 (t, 1 H, J ) 7.4 Hz), 6.74 (d, 1 H, J ) 8.1
Hz), 6.03 (ddt, 1 H, J ) 17.0, 10.1, 6.8 Hz), 5.20 (s, 1 H), 5.09
(d, 1 H, J ) 17.0 Hz), 5.05 (d, 1 H, J ) 10.1 Hz), 4.30 (q, 2 H,
J ) 7.1 Hz), 3.84 (s, 3 H), 3.51 (d, 2 H, J ) 6.8 Hz), 1.29 (t, 3
H, J ) 7.1 Hz); 13C NMR δ 166.2, 165.6, 154.7, 136.6, 130.3,
1
759 cm-1; H NMR δ 7.57 (d, 1 H, J ) 8.0 Hz), 7.29 (t, 1 H, J
) 7.5 Hz), 7.08 (t, 1 H, J ) 7.5 Hz), 6.86 (d, 1 H, J ) 8.2 Hz),
(29) The general chlorination procedure of Budesinsky and co-
workers was used; see Budesinsky, Z.; Budesinsky, M.; Svab, A. Collect.
Czech. Chem. Commun. 1981, 46, 2254-2262. The yield was 86%, bp
88-89 °C (2 mmHg). IR (thin film) 1762, 1367 cm-1 1H NMR δ 4.88
;
(s, 1 H), 4.30 (q, 2 H, J ) 7.1 Hz), 3.85 (s, 3 H), 1.32 (t, 3 H, J ) 7.1
Hz); 13C NMR δ 165.0, 164.4, 63.2, 55.1, 53.7, 13.8; HRMS m/z Calcd
for C6H935ClO4: 180.0190. Found: 180.0184.

150 J . Org. Chem., Vol. 63, No. 1, 1998
Bunce et al.
129.9, 127.2, 122.6, 115.6, 112.3, 77.0, 62.3, 53.0, 34.2, 13.9;
HRMS m/z Calcd for C15H18O5: 278.1154. Found: 278.1144.
The crude ethyl methyl (()-(2-(2-propenyl)phenoxy)pro-
panedioate was alkylated with methyl iodide on a 19.8 mmole
scale using the procedure described for the preparation of 7.
Flash chromatography on an 80 cm × 2.5 cm silica gel column
eluted with increasing concentrations of ether in hexanes gave
4.76 g (16.3 mmol, 94%) of 33 as a light yellow oil. IR (thin
film) 1746, 1635, 1367, 988, 909, 751 cm-1; 1H NMR δ 7.17 (d,
1 H, J ) 7.4 Hz), 7.08 (m, 1 H), 6.98 (t, 1 H, J ) 7.4 Hz), 6.78
(d, 1 H, J ) 8.1 Hz), 5.99 (ddt, 1 H, J ) 17.0, 10.1, 6.8 Hz),
5.06 (d, 1 H, J ) 17.0 Hz), 5.04 (d, 1 H, J ) 10.1 Hz), 4.27 (q,
2 H, J ) 7.1 Hz), 3.82 (s, 3 H), 3.46 (d, 2 H, J ) 6.8 Hz), 1.72
(s, 3 H), 1.25 (t, 3 H, J ) 7.1 Hz); 13C NMR δ 169.7, 168.9,
152.3, 136.8, 132.1, 130.3, 126.8, 123.0, 117.3, 115.6, 82.6, 62.3,
53.1, 34.4, 20.2, 13.9; HRMS m/z Calcd for C16H20O5: 292.1311.
Found: 292.1304.
Eth yl Meth yl (()-(E)-(2-(3-(Eth oxyca r bon yl)-2-p r op en -
yl)p h en oxy)m eth ylp r op a n ed ioa te (34). This compound
was prepared from 33 by the ozonolysis-Wittig procedure
given for the preparation of 10. Flash chromatography on an
80 cm × 2.5 cm silica gel column eluted with increasing
concentrations of ether in hexanes gave 3.18 g (8.93 mmol,
55%) of 34 as a light yellow oil. IR (thin film) 1746, 1714,
1651, 1367, 980, 751 cm-1; 1H NMR δ 7.12 (m, 3 H), 6.98 (t, 1
H, J ) 7.4 Hz), 6.77 (d, 1 H, J ) 8.2 Hz), 5.82 (dt, 1 H, J )
15.5, 1.6 Hz), 4.27 (q, 2 H, J ) 7.1 Hz), 4.16 (q, 2 H, J ) 7.1
Hz), 3.82 (s, 3 H), 3.60 (dd, 2 H, J ) 6.8, 1.6 Hz), 1.75 (s, 3 H),
1.26 (t, 3 H, J ) 7.1 Hz), 1.24 (t, 3 H, J ) 7.1 Hz); 13C NMR δ
169.5, 168.5, 166.6, 152.6, 147.0, 130.7, 129.5, 127.5, 123.0,
122.1, 116.8, 82.6, 62.3, 60.6, 53.1, 33.0, 20.5, 14.2 13.8; HRMS
m/z Calcd for C19H24O7: 356.1522. Found: 356.1509. Anal.
Calcd for C19H24O7: C, 64.04; H, 6.74. Found: C, 63.85; H,
6.75.
21.8, 14.0 (2); HRMS m/z Calcd for C12H20O5: 244.1311.
Found: 244.1306. Anal. Calcd for C12H20O5: C, 59.02; H, 8.20.
Found: C, 58.94; H, 8.23.
The following compounds were prepared on varying scales
using the same procedure. Purification was achieved by
PTLC30 eluted with increasing concentrations of ethyl acetate
in hexanes.
Eth yl (()-(2R*,3S*)-2-(Eth oxyca r bon yl)-2,5,5-tr im eth -
yltetr a h yd r ofu r a n -3-a ceta te (36a ): 130 mg (0.48 mmol,
1
48%) from 11; IR (thin film) 1740, 1388, 1375 cm-1; H NMR
δ 4.25-4.11 (complex, 4 H), 3.06 (m, 1 H), 2.66 (dd, 1 H, J )
15.6, 4.8 Hz), 2.29 (dd, 1 H, J ) 15.6, 10.3 Hz), 2.13 (dd, 1 H,
J ) 12.1, 6.8 Hz), 1.60 (t, 1 H, J ) 12.1 Hz), 1.35 (s, 3 H), 1.28
(m, 12 H); 13C NMR δ 174.7, 172.1, 84.0, 81.2, 61.0, 60.5, 44.0,
41.9, 34.9, 30.0, 28.2, 20.9, 14.1, 14.0; HRMS m/z Calcd for
C14H24O5: 272.1624. Found: 272.1623. Anal. Calcd for
C14H24O5: C, 61.76; H, 8.82. Found: C, 61.91; H, 8.85.
Eth yl (()-(2R*,3R*)-2-(Eth oxyca r bon yl)-2,5,5-tr im eth -
yltetr a h yd r ofu r a n -3-a ceta te (36b): 53 mg (0.19 mmol,
1
19%) from 11; IR (thin film) 1740, 1385, 1370 cm-1; H NMR
δ 4.24-4.09 (complex, 4 H), 2.72 (m, 1 H), 2.52 (dd, 1 H, J )
15.9, 4.3 Hz), 2.11 (dd, 1 H, J ) 15.9, 10.5 Hz). 2.06 (m, 1 H),
1.76 (t, 1 H, J ) 12.4 Hz), 1.49 (s, 3 H), 1.44 (s, 3 H), 1.30 (t,
3 H, J ) 7.1 Hz), 1.28 (t, 3 H, J ) 7.1 Hz), 1.27 (s, 3 H); 13C
NMR δ 173.8, 172.0, 85.5, 81.8, 60.9, 60.6, 45.8, 44.2, 35.0,
29.8, 28.5, 24.9, 14.2 (2); HRMS m/z Calcd for C14H24O5:
272.1624. Found: 272.1619. Anal. Calcd for C14H24O5: C,
61.76; H, 8.82. Found: C, 61.95; H, 8.84.
Eth yl (()-(2R*,3R*)-2-(Eth oxyca r bon yl)-2,4,4-tr im eth -
yltetr a h yd r ofu r a n -3-a ceta te (37a ): 132 mg (0.49 mmol,
1
49%) from 12; IR (thin film) 1734, 1389, 1373 cm-1; H NMR
δ 4.24-4.11 (complex, 4 H), 3.65 (m, 2 H), 2.63 (dd, 1 H, J )
8.3, 6.9 Hz), 2.48-2.33 (complex, 2 H), 1.37 (s, 3 H), 1.29 (t, 3
H, J ) 7.2 Hz), 1.27 (t, 3 H, J ) 7.2 Hz), 1.02 (s, 3 H), 1.01 (s,
3 H); 13C NMR δ 176.0, 172.2, 84.6, 79.9, 61.0, 60.6, 50.5, 42.0,
31.3, 24.4, 21.5, 20.9, 14.2, 14.1; HRMS m/z Calcd for
C14H24O5: 272.1624. Found: 272.1627. Anal. Calcd for
C14H24O5: C, 61.76; H, 8.82. Found: C, 61.88; H, 8.87.
The minor 2R*,3S* isomer 37b could not be isolated free of
contamination.
Eth yl (()-(2R*,3S*)-2-(Eth oxyca r bon yl)-2-m eth yl-2H-
tetr a h yd r op yr a n -3-a ceta te (38a ): 220 mg (0.82 mmol, 82%)
from 25; IR (thin film) 1738, 1378 cm-1; 1H NMR δ 4.25 (m, 2
H), 4.14 (q, 2 H, J ) 7.1 Hz), 3.78 (m, 2 H), 2.69 (m, 1 H), 2.59
(dd, 1 H, J ) 15.3, 5.3 Hz), 2.30 (dd, 1 H, J ) 15.3, 9.1 Hz),
1.80-1.50 (complex, 3 H), 1.44 (m, 1 H), 1.31 (t, 3 H, J ) 7.1
Hz), 1.30 (s, 3 H), 1.26 (t, 3 H, J ) 7.1 Hz); 13C NMR δ 173.8,
172.8, 79.0, 63.7, 61.1, 60.4, 34.9, 34.0, 25.2, 21.4, 21.0, 14.2,
14.1; HRMS m/z Calcd for C13H22O5: 258.1467. Found
258.1466. Anal. Calcd for C13H22O5: C, 60.47; H, 8.53.
Found: C, 60.73; H, 8.59.
Repr esen tative P r ocedu r e for th e Tan dem Dem eth oxy-
ca r bon yla tion -Mich a el Ad d ition Rea ction : Eth yl (()-
(2R*,3S*)-2-(Eth oxyca r bon yl)-2-m eth yltetr a h yd r ofu r a n -
3-a ceta te (35a ) a n d Eth yl (()-(2R*,3R*)-2-(Eth oxyca r -
b on yl)-2-m et h ylt et r a h yd r ofu r a n -3-a cet a t e (35b ). The
general procedure of Bunce and co-workers4a was used. To a
25-mL three-necked round-bottomed flask, equipped with a
magnetic stirrer, a reflux condenser, a rubber septum, and a
drying tube were added 92 mg (2.2 mmol) of dry LiCl and 151
mg (0.50 mmol) of 10. DMEU (5 mL) was added via syringe,
and the reaction mixture was stirred at rt to dissolve the LiCl.
Once homogeneous, the reaction was heated in an oil bath
(preheated to 120 ( 5 °C) until GC indicated complete
consumption of starting material (4-8 h). The reaction was
cooled, quenched with 5% NH4Cl, and extracted with ether
(3×). The combined ether layers were washed with 5% NH4-
Cl, H2O, and saturated NaCl, dried (MgSO4), and concentrated
under vacuum. The crude product was purified by PTLC,30
eluted with increasing concentrations of ethyl acetate in
hexanes, to afford 62 mg (0.25 mmol, 51%) of 35a and 18 mg
(0.07 mmol, 16%) of 35b. The spectral data for 35a were: IR
Eth yl (()-(2R*,3R*)-2-(Eth oxyca r bon yl)-2-m eth yl-2H-
tetr a h yd r op yr a n -3-a ceta te (38b): 30 mg (0.11 mmol, 11%)
1
from 25; IR (thin film) 1740, 1381 cm-1; H NMR δ 4.23 (q, 2
H, J ) 7.1 Hz), 4.14 (q, 2 H, J ) 7.1 Hz), 3.82 (m, 1 H), 3.72
(m, 1 H), 2.54 (m, 2 H), 2.14 (m, 1 H), 1.79 (m, 1 H), 1.62 (m,
2 H), 1.49 (m, 1 H), 1.46 (s, 3 H), 1.31 (t, 3 H, J ) 7.1 Hz), 1.26
(t, 3 H, J ) 7.1 Hz); 13C NMR δ 174.0, 173.0, 79.2, 64.3, 60.8,
60.4, 41.0, 36.5, 25.7, 24.9, 24.5, 14.3, 14.2; HRMS m/z Calcd
for C13H22O5: 258.1467. Found 258.1463. Anal. Calcd for
C13H22O5: C, 60.47; H, 8.53. Found: C, 60.71; H, 8.61.
Eth yl (()-(2R*,3S*)-2-(Eth oxycar bon yl)-2,6,6-tr im eth yl-
2H-tetr a h yd r op yr a n -3-a ceta te (39a ): 172 mg (0.60 mmol,
(thin film) 1740 cm-1 1H NMR δ 4.25-4.12 (complex, 4 H),
;
4.01 (m, 1 H), 3.92 (m, 1 H), 2.81 (m, 1 H), 2.64 (dd, 1 H, J )
15.6, 4.8 Hz), 2.28 (dd, 1 H, J ) 15.6, 10.5 Hz), 2.21 (m, 1 H),
1.70 (dq, 1 H, J ) 12.3, 8.1 Hz), 1.31 (s, 3 H), 1.30 (t, 3 H, J )
7.1 Hz), 1.27 (t, 3 H, J ) 7.1 Hz); 13C NMR δ 174.6, 172.1,
83.9, 66.9, 61.1, 60.5, 41.8, 34.9, 31.5, 19.6, 14.1 (2); HRMS
m/z Calcd for C12H20O5: 244.1311. Found: 244.1309. Anal.
Calcd for C12H20O5: C, 59.02; H, 8.20. Found: C, 59.27; H,
8.22.
1
60%) from 26; IR (thin film) 1738, 1382, 1369 cm-1; H NMR
δ 4.27-4.10 (complex, 4 H), 2.73 (m, 1 H), 2.54 (dd, 1 H, J )
15.3, 5.8 Hz), 2.27 (dd, 1 H, J ) 15.3, 9.0 Hz), 1.96 (m, 1 H),
1.59 (m, 1 H), 1.51 (m, 1 H), 1.36 (m, 1 H), 1.30 (t, 3 H, J ) 7.1
Hz), 1.29 (s, 3 H), 1.28 (t, 3 H, J ) 7.1 Hz), 1.25 (s, 3 H), 1.14
(s, 3 H); 13C NMR δ 175.3, 173.0, 73.4, 61.0, 60.4, 45.0, 34.4,
33.3, 31.8, 31.3, 26.6, 24.4, 22.0, 14.2, 14.0; HRMS m/z Calcd
for C15H26O5: 286.1780. Found: 286.1782. Anal. Calcd for
C15H26O5: C, 62.94; H, 9.09. Found: C, 63.11; H, 9.12.
Eth yl (()-(2R*,3R*)-2-(Eth oxycar bon yl)-2,6,6-tr im eth yl-
2H-tetr a h yd r op yr a n -3-a ceta te (39b): 43 mg (0.15 mmol,
The spectral data for the 2R*,3R* isomer 35b: IR (thin film)
1740 cm-1 1H NMR δ 4.20-4.05 (complex, 5 H), 3.90 (m, 1
;
H), 2.46 (dd, 1 H, J ) 15.4, 4.1 Hz), 2.39 (m, 1 H), 2.20 (m, 1
H), 2.07 (dd, 1 H, J ) 15.4, 10.2 Hz), 1.73 (m, 1 H), 1.42 (s, 3
H), 1.23 (t, 3 H, J ) 7.1 Hz), 1.20 (t, 3 H, J ) 7.1 Hz); 13C
NMR δ 173.8, 172.0, 85.1, 67.7, 60.4, 60.3, 45.9, 35.6, 31.9,
(30) For non-UV active compounds, PTLC plates were visualized
with I2 vapor and bands were separated, cut from the plates, and
extracted with ether. The ether extracts were washed with 5% Na2S2O3,
saturated NaCl, dried (MgSO4), and concentrated under vacuum.
1
15%) from 26; IR (thin film) 1739, 1388, 1374 cm-1; H NMR

Tandem Demethoxycarbonylation-Michael Addition Reactions
J . Org. Chem., Vol. 63, No. 1, 1998 151
δ 4.23-4.06 (complex, 4 H), 2.73 (dd, 1 H, J ) 16.5, 9.9 Hz),
2.51 (dd, 1 H, J ) 16.5, 2.9 Hz), 1.98 (m, 1 H), 1.84 (m, 1 H),
1.67 (m, 1 H), 1.57 (m, 2 H), 1.41 (s, 3 H), 1.30 (t, 3 H, J ) 7.1
Hz), 1.26 (t, 3 H, J ) 7.1 Hz), 1.24 (s, 3 H), 1.13 (s, 3 H); 13C
NMR δ 174.7, 173.4, 73.7, 60.5, 60.3, 45.0, 41.6, 37.0, 36.7,
32.2, 27.0, 24.3, 23.0, 14.2, 14.0; HRMS m/z Calcd for
C15H26O5: 286.1780. Found: 286.1777. Anal. Calcd for
C15H26O5: C, 62.94; H, 9.09. Found: C, 63.02; H, 9.05.
Eth yl (()-(2R*,3S*)-2-(Eth oxycar bon yl)-2,5,5-tr im eth yl-
2H-tetr a h yd r op yr a n -3-a ceta te (40a ): 152 mg (0.55 mmol,
6.88 (m, 2 H), 4.31-4.15 (complex, 4 H), 3.85 (t, 1 H, J ) 7.4
Hz), 2.61 (dd, 1 H, J ) 16.6, 7.1 Hz), 2.59 (dd, 1 H, J ) 16.6,
8.1 Hz), 1.71 (s, 3 H), 1.29 (t, 3 H, J ) 7.1 Hz), 1.28 (t, 3 H, J
) 7.1 Hz); 13C NMR δ 171.4, 171.3, 158.2, 129.1, 128.3, 124.5,
121.1, 110.1, 89.9, 61.6, 60.8, 47.8, 36.6, 24.6, 14.0 (2); HRMS
m/z Calcd for C16H20O5: 292.1310. Found: 292.1307. Anal.
Calcd for C16H20O5: C, 65.75; H, 6.85. Found: C, 65.84; H,
6.88.
Eth yl (()-(2R*,3S*)-2-(Eth oxyca r bon yl)-3,4-d ih yd r o-2-
m eth yl-2H-1-ben zop yr a n -3-a ceta te (43a ): 176 mg (0.58
mmol, 58%) from 34; IR (thin film) 1735, 1594, 1490, 1375,
1
55%) from 27; IR (thin film) 1738, 1390, 1372 cm-1; H NMR
1
δ 4.30-4.06 (complex, 4 H), 3.35 (s, 2 H), 2.68 (m, 1 H), 2.51
(dd, 1 H, J ) 15.5, 3.6 Hz), 1.94 (dd, 1 H, J ) 15.5, 10.3 Hz),
1.50 (m, 2 H), 1.35 (s, 3 H), 1.31 (t, 3 H, J ) 7.1 Hz), 1.25 (t,
3 H, J ) 7.1 Hz), 1.10 (s, 3 H), 0.86 (s, 3 H); 13C NMR δ 173.2,
172.0, 78.5, 71.3, 61.4, 60.4, 38.9, 36.7, 33.5, 30.4, 27.1, 24.1,
14.3, 14.1 (2); HRMS m/z Calcd for C15H26O5: 286.1780. Found
286.1774. Anal. Calcd for C15H26O5: C, 62.94; H, 9.09.
Found: C, 63.19; H, 9.13.
751 cm-1; H NMR δ 7.12 (t, 1 H, J ) 6.9 Hz), 6.98 (d, 1 H, J
) 7.1 Hz), 6.88 (m, 2 H), 4.16 (m, 4 H), 2.91 (m, 2 H), 2.59 (d,
2 H, J ) 17.5 Hz), 2.15 (dd, 1 H, J ) 16.3, 9.5 Hz), 1.55 (s, 3
H), 1.25 (t, 3 H, J ) 7.1 Hz), 1.20 (t, 3 H, J ) 7.1 Hz); 13C
NMR δ 173.0, 172.5, 153.2, 129.9, 127.6, 120.9, 118.7, 116.5,
79.9, 61.5, 60.7, 33.3, 33.1, 28.5, 21.9, 14.2, 14.0; HRMS m/z
Calcd for C17H22O5: 306.1468. Found: 306.1463. Anal. Calcd
for C17H22O5: C, 66.67; H, 7.19. Found: C, 66.47; H, 7.17.
The minor 2R*,3R* isomer 43b could not be isolated free of
contamination.
The minor 2R*,3R* isomer 40b could not be isolated free of
contamination.
Eth yl (()-(E)-6-(1-(Eth oxycar bon yl)eth oxy)-4,4-dim eth -
yl-2-h exen oa te (41): 172 mg (0.60 mmol, 60%) from 28; IR
(thin film) 1748, 1730, 1641, 1385, 1372 cm-1; 1H NMR δ 5.96
(d, 1 H, J ) 13.1 Hz), 5.69 (d, 1 H, J ) 13.1 Hz), 4.23-4.13
(complex, 4 H), 3.92 (q, 1 H, J ) 6.9 Hz), 3.63 (m, 1 H), 3.40
(m, 1 H), 1.87 (m, 2 H), 1.38 (d, 3 H, J ) 6.9 Hz), 1.29 (2 t, 6
H, J ) 7.2 Hz), 1.20 (s, 6 H); 13C NMR δ 173.5, 166.7, 153.0,
119.4, 75.0, 67.4, 60.7, 60.2, 42.0, 36.0, 27.6, 27.5, 18.7, 14.2,
14.1; HRMS m/z Calcd for C15H26O5: 286.1780. Found:
286.1774. Anal. Calcd for C15H26O5: C, 62.94; H, 9.09.
Found: C, 63.16; H, 9.14.
Ack n ow led gm en t. The authors acknowledge the
Oklahoma Center for the Advancement of Science and
Technology (OCAST, HR1-035) and the NIH (GM 54256)
for support of this research. E.D.D. and P.B.J . wish to
thank the College of Arts and Sciences at OSU for
support in the form of Lew Wentz Scholarships. Funds
for the 300 and 400 MHz NMR spectrometers of the
Oklahoma Statewide Shared NMR Facility were pro-
vided by the NSF (BIR-9512269), the Oklahoma State
Regents for Higher Education, the W. M. Keck Founda-
tion, and Conoco Inc. Partial support of our mass
spectrometer facility by the NIH and the OCAST is also
appreciated.
Eth yl (()-(2R*,3R*)-2-(Eth oxyca r bon yl)-2,3-d ih yd r o-2-
m eth ylben zofu r a n -3-a ceta te (42a ): 205 mg (0.70 mmol,
70%) from 31; IR (thin film) 1734, 1595, 1488, 1373, 752 cm-1
;
1H NMR δ 7.19-7.11 (complex, 2 H), 6.88 (m, 2 H), 4.27-4.17
(complex, 5 H), 2.77 (dd, 1 H, J ) 16.2, 6.6 Hz), 2.59 (dd, 1 H,
J ) 16.2, 8.5 Hz), 1.56 (s, 3 H), 1.29 (t, 3 H, J ) 7.1 Hz), 1.27
(t, 3 H, J ) 7.1 Hz); 13C NMR δ 173.1, 171.6, 157.9, 128.9,
128.6, 124.5, 121.3, 110.0, 89.0, 61.7, 60.8, 44.3, 35.6, 18.6, 14.0,
13.9; HRMS m/z Calcd for C16H20O5: 292.1310. Found:
292.1311. Anal. Calcd for C16H20O5: C, 65.75; H, 6.85.
Found: C, 65.91; H, 6.87.
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
preparation of the starting (ω-alkenyloxy)acetic acids and
1
compounds 1-3 and 13-16. High resolution H and 13C NMR
spectra for the (ω-alkenyloxy)acetic acids and compounds 1-9,
13-24, 30, and 33 (64 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
Eth yl (()-(2R*,3S*)-2-(Eth oxyca r bon yl)-2,3-d ih yd r o-2-
m eth ylben zofu r a n -3-a ceta te (42b): 40 mg (0.14 mmol,
14%) from 31; IR (thin film) 1740, 1602, 1488, 1381, 755 cm-1
;
1H NMR δ 7.18 (t, 1 H, J ) 8.0 Hz), 7.10 (d, 1 H, J ) 7.6 Hz),
J O971600S