Facile synthesis of saturated eight-membered ring lactones

Article abstract of DOI:10.1081/SCC-100104408

The synthesis of functionalized saturated eight-membered ring lactones from their corresponding seco acids is a very facile process using conventional macrolactonization protocols. This heretofore unrecognized and overlooked strategy is illustrated for se

Full text of DOI:10.1081/SCC-100104408

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FACILE SYNTHESIS OF
SATURATED EIGHT-MEMBERED
RING LACTONES
Keith R. Buszek a , Youngmee Jeong a , Nagaaki
Sato a , Peter C. Still a , Pedro L. Muiño a &
Indranath Ghosh a
a Department of Chemistry , Kansas State
University , Manhattan, KS, 66506-3701, U.S.A.
Published online: 09 Nov 2006.
To cite this article: Keith R. Buszek , Youngmee Jeong , Nagaaki Sato , Peter C.
Still , Pedro L. Muiño & Indranath Ghosh (2001) FACILE SYNTHESIS OF SATURATED
EIGHT-MEMBERED RING LACTONES, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 31:11, 1781-1791,
DOI: 10.1081/SCC-100104408
To link to this article: http://dx.doi.org/10.1081/SCC-100104408
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SYNTHETIC COMMUNICATIONS, 31(11), 1781–1791 (2001)
FACILE SYNTHESIS OF SATURATED
EIGHT-MEMBERED RING LACTONES
Keith R. Buszek,* Youngmee Jeong, Nagaaki Sato,
Peter C. Still, Pedro L. Muino, and Indranath Ghosh
Department of Chemistry, Kansas State University,
Manhattan, KS 66506-3701
ABSTRACT
The synthesis of functionalized saturated eight-membered
ring lactones from their corresponding seco acids is a very
facile process using conventional macrolactonization proto-
cols. This heretofore unrecognized and overlooked strategy
is illustrated for several examples. A possible explanation
for the success of this approach is also presented.
The synthesis of medium-sized rings is an important problem in
organic chemistry and represents a fantastic challenge. Such rings are con-
sidered among the most challenging and difficult systems to construct pre-
sumably due to a combination of unfavorable entropic and enthalpic
factors, and the lack of general methods for their preparation.1 A certain
lore has developed that saturated eight-membered ring lactones, in particu-
lar, are difficult or impossible to access via their corresponding seco acids.
Indeed, the literature is replete with admonitions regarding such attempts.
For example, Lee recently stated: ‘‘It is well-known that eight-membered-
ring lactones are the least accessible ones via traditional lactone-forming
* Corresponding author.
1781
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1782
BUSZEK ET AL.
reactions starting from o-halo and o-hydroxy-carboxylic acids.’’2 Cane also
noted that ‘‘the chemical synthesis of functionalized eight-membered ring
lactones (2-oxocanones) is extremely challenging, and virtually no func-
tionalized eight-membered ring lactones are known among natural prod-
ucts.’’3 Funk further observed that eight-membered lactones ‘‘are difficult,
if not impossible, to prepare from the corresponding hydroxy acids.’’4
Despite preliminary evidence published by us to the contrary,5–7 there per-
sists a nearly universal belief that saturated monocyclic eight-membered
lactones in particular cannot be prepared directly from their corresponding
seco acids. These views, however, are almost certainly based on the singular
observation that 7-hydroxyheptanoic acid 1 does not lactonize under the
Corey-Nicolaou,8 Keck-Boden,9 Yamaguchi,10 Mukaiyama,11 or other
macrolactonization protocols (Scheme 1). In fact, in virtually every descrip-
tion of these lactonization protocols, the eight-membered entry is conspicu-
ously absent. As a consequence, an enormous investment has been directed
toward developing alternative chemical and enzymatic3 strategies to circum-
vent this perceived obstacle, despite the fact that the most straightforward
retrosynthetic disconnection often involves the acyl-oxygen bond. App-
roaches to saturated lactones based on this strategy would yield enormous
synthetic simplification. This paper dispels the entrenched misconceptions
regarding the synthesis of eight-membered ring lactones in the manner
described and reports a simple and expeditious strategy using conventional
macrolactonization protocols for effecting this change with a range of
variously substituted seco acid precursors.
Scheme 1.
During the course of the first total synthesis of the powerful antitumor
agent octalactin A,5 we observed an unusually efficient ring closure of the
saturated hydroxy acid 3 using the Corey-Nicolaou double-activation lactoni-
zation method (Scheme 2).8 It was subsequently found that this discovery
represents a general phenomenon for substituted saturated hydroxy carboxylic
acid precursors. Several representative examples were chosen to document gen-
erality and are shown in Table 1. Reaction yields range from good to excellent
and reaction times are usually 24 h or less. In the octalactin series (entries 1–3)
it was found that removing the substituent at C-7 resulted in even faster ring

SATURATED EIGHT-MEMBERED RING LACTONES
1783
Scheme 2.
closure with the anti-stereoisomer requiring much shorter reaction times
(entries 4 and 5). It was also found that the size of the protecting groups
had little effect on the reaction times or yields. It is significant to note that a
pair of vicinal stereocenters is not required for lactonization (entries 8 and 9).
In no case was diolide product formation observed, as evidenced by high
resolution mass spectral analysis, under the reaction conditions employed. A
kinetic study (Table 2) of three other members of the octalactin series (entries
1–3) revealed that there is a modest dependence of the first-order rate of
lactonization on the stereochemical configuration of the seco acid, i.e., at C-
3 and C-7. Not surprisingly, the calculated enthalpy of activation correlated
with the total steric energy of the lactone as determined by MM2 calcula-
tions.12 In the case of the C-3 epimer this strain was compensated for by a
less negative entropy of activation.
The basic idea that substitution in an acyclic chain can facilitate ring
closure is certainly known.13 The Thorpe-Ingold,14 gem-dialkyl15 and gem-
dialkoxy16 effects have been widely cited and investigated along with related
conformational effects on ring closure. It is surprising then that the current
idea has never been applied to the synthesis of medium rings. Substitution
limits rotational degrees of freedom and therefore makes the reaction entro-
pically less unfavorable. However, substitution in some cases may be enthal-
pically advantageous as well, based on changes in bond angle distortion
from the seco acid to the lactone. The conformational effect of quatenary
centers in controlling torsional angles, for example, has been reported.17 We
compared the minimized bond angles in the seco acid 1 and the correspond-
ing methyl ethers (OMe vs. OMPM) of compounds 19 and 21 to those in
their lactones using molecular mechanics computational methods (including
Monte Carlo sampling of all conformational space) with the AMBER force
field.18 It is interesting to note that in our study, there is a significantly
smaller cumulative bond angle change and smaller change for nearly
every individual angle in the substituted lactones compared to the unsub-
stituted case. Although a complete explanation for the facility of substituted
medium-ring lactonization is not yet available, these calculations neverthe-
less have some predictive value and suggest, for example, that a single
substituent at C-3 is more beneficial than one at C-7.19

1784
BUSZEK ET AL.
Table 1. Representative Examples of Eight-Membered Ring Lactonization
aIsolated yields; Corey-Nicolaou method (reference 8) was used for lactonization.

SATURATED EIGHT-MEMBERED RING LACTONES
1785
Table 2. Kinetic Data for Lactonization of Selected Epimers in the Octalactin
Series
Epimer ÁH6 (kcal/mol) ÁS (kcal/molÁK) k (secÀ1, 115ꢀC) MM2 (kcal/mol)
¼
6¼
C.7
C.3, C.7
C.3
21.4
20.4
28.2
À0.027
À0.030
À0.011
1.33Â10À5
1.48Â10À5
7.52Â10À6
2.5
0.0
9.5
In conclusion, we have identified a general strategy for the facile con-
struction of functionalized, saturated eight-membered lactones, and by
extension, their corresponding ethers.20 The elucidation of the differential
contributions of the various groups based on position and stereochemistry
and the correlation with the reactive conformations as calculated by mol-
ecular mechanics would be a valuable contribution and is under investiga-
tion. Application of this approach to the synthesis of other saturated
lactone- and ether-containing natural products is also in progress and will
be reported as developments merit.
EXPERIMENTAL
General
1H NMR spectra were recorded on a Varian Unity Plus 400-MHz
1
spectrometer operating at 399.886 MHz for H and 100.560 MHz for 13C,
in the indicated solvents. Infrared (IR) spectra were obtained using a
Perkin-Elmer Model 1310 infrared spectrophotometer or a Mattson Sirius
100 FT-IR with 25-mm KBr plates. Mass spectra were recorded at the Mass
Spectrometry Laboratory at the University of Kansas using the fast atom
bombardment (FAB) technique and employing a matrix of either glycerol or
m-nitrobenzyl alcohol. Optical rotations were performed on a Perkin-Elmer
241 polarimeter using a 1-cm3 capacity quartz cell (1-dm path length) in the
indicated solvent system at the recorded concentration. Thin layer
chromatography (TLC) was performed using E. Merck silica gel (60 F
254) plates of 0.25 mm thickness. Visualization was accomplished with
short wavelength ultraviolet light, and anisaldehyde dip reagent.
Hydrocarbon and chlorinated solvents were distilled from calcium hydride.
All other solvents were performed under a positive atmosphere of dry
nitrogen or argon.

1786
BUSZEK ET AL.
Representive Procedure
To a stirred solution of the hydroxy carboxylic acid 21 (125 mg,
0.422 mmol) in 15 mL of dry CH2Cl2 was added triphenylphosphine
(125 mg, 0.48 mmol) followed by 2,20-dipyridyl disulfide (105 mg,
0.48 mmol) and the mixture stirred until TLC (40% ethyl acetate in hexanes)
showed complete loss of starting material (usually 0.5 h–2 h). The mixture
was concentrated in vacuo and dissolved in 150 mL of dry toluene. To the
solution was added 1.2 mL of a 0.006 M solution of AgBF4 in dry toluene
and the mixture heated under reflux for 12 h. The mixture was cooled and
solvents removed in vacuo. The residue was purified by flash chromatogra-
phy (0.5% acetone in CH2Cl2) to afford 95 mg (81%) of the lactone 22. High
resolution FAB mass spectral analysis revealed the [MþH]þ ion for 22 and
thus confirmed the presence of the eight-membered lactone.21 The structure
was further and unequivocally established by oxidative hydrolysis of the
MPM ether (DDQ, CH2Cl2, H20) to furnish (þ)-cephalosporolide D
which exhibited the same physical and spectroscopic data as that reported
for the authentic sample, except for the optical rotation, which was opposite
in direction.22
[4R-[4a,5a,8a(R*)]]-8-[2-[[(1,1-Dimethylethyl)diphenylsily1]oxy]-1-meth-
1
ylethyl]-4-[(4-methoxyphenyl)methoxy]-5-methyl-2-oxocanone (4). H NMR
(CDCl3) ꢀ 7.61 (4 H, m), 7.39 (6 H, m), 7.29 (2 H, d, J ¼ 8.4 Hz), 6.85
(2 H, d, J ¼ 8.4 Hz), 4.84 (1 H, d, J ¼ 12.0 Hz), 4.56 (1 H, m), 4.36
(1 H, d, J ¼ 12.0 Hz), 3.85 (1 H, dd, J ¼ 10.0, 4.0 Hz), 3.78 (3 H, s), 3.58
(1 H, d, J ¼ 6.2 Hz), 3.51 (1 H, dd, J ¼ 10.0, 4.4 Hz), 2.98 (1 H, dd,
J ¼ 13.2, 6.2 Hz), 2.46 (1 H, d, J ¼ 13.2 Hz), 1.93 (2 H, m), 1.63 (3 H, m),
1.16 (1 H, m), 1.04 (12 H, s), 0.96 (3 H, d, J ¼ 6.8 Hz); 13C NMR (CDCl3) ꢀ
171.7, 159.1, 135.5, 135.4, 133.4, 133.3, 130.4, 129.7, 129.5, 127.7, 127.6,
113.6, 78.0, 77.8, 70.3, 65.0, 55.2, 40.3, 37.8, 34.8, 31.3, 29.6, 26.9, 23.9,
21.5, 19.3, 13.2; IR (neat) 2920, 2960, 2860, 1720, 1605, 1505, 1455,
1425, 1245, 1175, 1105, 1080, 1035, 820, 740, 700; FAB HRMS, m/z
575.3189, MþH calcd for C35H47O5Si 575.3194; Anal. Calcd for
C35H46O5Si: C, 73.13; H, 8.07. Found: C, 73.28; H, 7.99; [a]20D: À65.4
(c1.3, CHCl ).
3
[4R-[4a,5a,8b(R*)]]-8-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1-methyl-
ethyl]-4-[(4-methoxyphenyl)methoxy]-5-methyl-2-oxocanone (6). 1H NMR
(CDCl3) ꢀ 7.61 (4 H, m), 7.40 (6 H, m), 7.30 (2 H, d, J ¼ 8.4 Hz), 6.86 (2 H,
d, J ¼ 8.4 Hz), 4.80 (1 H, d, J ¼ 11.5 Hz), 4.67 (1 H, m), 4.38 (1 H, d,
J ¼ 11.5 Hz), 3.85 (1 H, dd, J ¼ 10.1, 4.0 Hz), 3.78 (3 H, s), 3.62 (1 H, m),
3.51 (1 H, dd, J ¼ 10.1, 3.8 Hz), 2.95 (1 H, dd, J ¼ 13.0, 6.2 Hz), 2.56 (1 H, d,
J ¼ 13.0 Hz), 1.88 (2 H, m), 1.65 (3 H, m), 1.18 (1 H, m), 1.04 (9 H, s), 1.02 (3
H, d, J ¼ 6.8 Hz), 0.94 (3 H, d, J ¼ 7.0 Hz); 13C NMR (CDCl3) ꢀ 172.3, 159.1,

SATURATED EIGHT-MEMBERED RING LACTONES
1787
135.5, 135.4, 133.3, 130.1, 129.7, 129.5, 127.9, 127.6, 127.5, 113.7, 78.4, 77.9,
70.6, 65.0, 55.2, 40.2, 37.9, 35.6, 31.4, 29.5, 26.9, 21.3, 19.3, 13.2; IR (neat)
3065, 2920, 1715, 1505, 1460, 1240, 1100, 1090, 1035; FAB HRMS, m/z
575.3195, MþH calcd for C35H47O5Si 575.3194; Anal. Calcd for
C35H46O5Si: C, 73.13; H, 8.07. Found: C, 73.35; H, 8.20. [a]20D: À37.0
(c1.4, CHCl ).
3
[4S-[4b,5a,8b(R*)]]-8-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1-meth-
1
ylethyl]-4-[(4-methoxyphenyl)methoxy]-5-methyl-2-oxocanone (8). H NMR
(CDCl3) ꢀ 7.64 (4 H, m), 7.41 (6 H, m), 7.31 (2 H, d, J ¼ 8.6 Hz), 6.89 (2
H, d, J ¼ 8.6 Hz), 4.83 (1 H, br d, J ¼ 12.3 Hz), 4.77 (1 H, d, J ¼ 11.3 Hz),
4.39 (1 H, d, J ¼ 11.3 Hz), 3.80 (3 H, s), 3.63 (1 H, dd, J ¼ 10.1, 8.7 Hz), 3.52
(1 H, dd, J ¼ 10.1, 5.2 Hz), 3.36 (1 H, m), 2.93 (1 H, dd, J ¼ 12.8, 6.5 Hz),
2.75, (1 H, dd, J ¼ 12.8, 5.2 Hz), 1.82 (3 H, m), 1.65 (2 H, m), 1.43 (1 H, m),
1.04 (9 H, s), 1.03 (3 H, d, J ¼ 6.0 Hz), 0.89 (3 H, d, J ¼ 7.0 Hz); 13C NMR
(CDCl3) ꢀ 172.0, 159.2, 135.5, 135.4, 133.4, 133.1, 129.8, 129.5, 129.4, 127.9,
127.5, 113.6, 80.1, 77.8, 70.1, 65.1, 55.2, 40.2, 38.5, 35.4, 31.7, 29.4, 26.8,
21.4, 19.3, 13.3; IR (neat) 3070, 2960, 2920, 1715, 1505, 1450, 1250, 1110,
1090, 1035, 820, 740, 705 cmÀ1; FAB HRMS, m/z 575.3189, M þ H calcd
for C35H47O5Si 575.3194; Anal, Calcd for C35H46O5Si: C, 73.13; H, 8.07.
Found: C, 72.92; H, 7.98. [a]20D: À15.6 (c0.85, CHCl ).
3
[4S-[4b,5a,8a(R*)]]-8-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1-meth-
ylethyl]-4-[(4-methoxyphenyl)methoxy]-5-methyl-2-oxocanone (10). 1H NMR
(CDCl3) ꢀ 7.61 (4 H, m), 7.40 (6 H, m), 7.25 (2 H, d, J ¼ 8.6 Hz), 6.88 (2 H,
d, J ¼ 8.6 Hz), 4.63 (1 H, m), 4.58 (1 H, d, J ¼ 10.9 Hz), 4.39 (1 H, d,
J ¼ 10.9 Hz), 3.84 (1 H, dd, J ¼ 10.1, 4.2 Hz), 3.80 (3 H, s), 3.53 (1 H, dd,
J ¼ 10.1, 3.8 Hz), 3.22 (1 H, td, J ¼ 10.4, 3.7 Hz), 2.89 (1 H, dd, J ¼ 11.6,
3.8 Hz), 2.72 (1 H, t, J ¼ 11.6), 1.91, (1 H, m), 1.67 (3 H, m), 1.45 (1 H, br d,
J ¼ 12.9 Hz), 1.20 (1 H, m), 1.08 (1 H, d, J ¼ 6.7 Hz), 1.04 (9 H, s), 0.99 (3 H,
d, J ¼ 6.9 Hz); 13C NMR (CDCl3) ꢀ 172.7, 159.3, 135.6, 135.4, 133.4, 133.3,
130.0, 129.7, 129.5, 128.6, 127.7, 127.6, 113.8, 82.6, 78.1, 71.5, 64.9, 55.2,
40.2, 39.0, 36.6, 32.3, 28.0, 26.9, 21.2, 19.3, 13.3; IR (neat) 3070, 2960, 2920,
1715, 1505, 1450, 1250, 1110, 1090, 1035, 820, 740, 705 cmÀ1; FAB HRMS,
m/z 575.3190, MþH calcd for C35H47O5Si 575.3194; Anal. Calcd for: C,
73.13; H, 8.07. Found: C, 73.39; H, 8.01; [a]20D: À9.0 (c0.77, CHCl ).
3
[4S-(4b,5a)]-4-[(4-methoxyphenyl)methoxy]-5-methyl-2-oxocanone (12)
1H NMR (CDCl3) ꢀ 7.25 (2 H, d, J ¼ 8.6 Hz), 6.88 (2 H, d, J ¼ 8.6 Hz),
4.54 (1 H, d, J ¼ 10.6 Hz), 4.51 (2 H, m), 4.36 (1 H, d, J ¼ 10.6 Hz), 3.77
(3 H, s), 3.72 (1 H, m), 2.92 (1 H, dd, J ¼ 12.4, 4.0 Hz), 2.72 (1 H, apparent t,
J ¼ 12.4 Hz), 1.61–1.88 (5 H, m), 1.05 (3 H, d, J ¼ 6.8 Hz); 13C NMR
(CDCl3) ꢀ 172.1, 159.3, 130.1, 129.5, 113.8, 79.6, 78.1, 68.9, 55.2, 40.2,
38.1, 31.4, 29.5, 21.4; IR (neat) 3055, 2990, 1705, 1421, 1265, 1090 cmÀ1
FAB HRMS, m/z 279.1593, MþH calcd for C16H23O4 279.1597; Anal.
;

1788
BUSZEK ET AL.
Calcd for C16H22O4; C, 69.04; H, 7.97. Found: C, 68.94; H, 8.16; [a]20D:
À48.1 (c2.2, CHCl ).
3
[4R-(4a,5a)]]-4-[(4-methoxyphenyl)methoxy]-5-methyl-2-oxocanone (14)
1H NMR (CDCl3) ꢀ 7.27 (2 H, d, J ¼ 8.8 Hz), 6.83 (2 H, d, J ¼ 8.8 Hz), 4.71
(1 H, d, J ¼ 11.6 Hz), 4.60 (2 H, m), 4.38 (1 H, d, J ¼ 11.6 Hz), 3.81 (3 H, s),
3.75 (1 H, m), 2.94 (1 H, dd, J ¼ 12.6, 6.8 Hz), 2.71 (1 H, dd, J ¼ 12.6,
2.6 Hz), 1.66–1.75 (3 H, m), 1.81–1.90 (2 H, m), 1.04 (3 H, d, J ¼ 6.8 Hz);
13C NMR (CDCl3) ꢀ 172.6, 159.3, 130.3, 129.5, 113.8, 79.0 77.7, 70.6, 55.2,
38.3, 37.6, 31.9, 20.6, 19.3; IR (neat) 3045, 2990, 1700, 1422, 1240,
1090 cmÀ1; FAB HRMS, m/z 279.1595, MþH calcd for C16H23O4
279.1597; Anal. Calcd for C16H22O4: C, 69.04; H, 7.97. Found: C, 68.87;
H, 7.99; [a]20D: À21.4 (c2.5, CHCl ).
3
[6R-(6a,7a)]-6-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-methyl-2-oxo-
1
canone (16). H NMR (CDCl3) ꢀ 4.69–4.72 (2 H, m), 3.48 (1 H, m), 2.71–
2.93 (2 H, m), 1.59–1.87 (5 H, m), 1.01 (3 H, d, J ¼ 6.4 Hz), 0.91 (9 H, s),
0.17 (3 H, s), 0.12 (3 H, s); 13C NMR (CDCl3) ꢀ 171.6, 74.4, 70.2, 38.3, 37.7,
32.2, 25.6, 21.9, 19.3, 19.0, À4.2, À5.2; IR (neat) 2955, 1710, 1265, 1095;
FAB HRMS, m/z 273.1893, MþH calcd for C14H29O3Si 273.1887; Anal.
Calcd for C14H28O3Si: C, 61.72; H, 10.36. Found: C, 61.56; H, 10.18;
[a]20D:þ16.7 (c1.7, CHCl ).
3
[6R-(6a,7b)]-7-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-methyl-2-oxoca-
none (18) 1H NMR (CDCl3) ꢀ 4.71–4.76 (2 H, m), 3.54 (1 H, m), 2.63–2.85 (2 H,
m), 1.64–1.94 (5 H, m), 0.98 (3 H, d, J ¼ 6.4 Hz), 0.89 (9 H, s), 0.15 (3 H, s) 0.08
(3 H, s); 13C NMR (CDCl3) ꢀ 172.5, 75.1, 69.6, 39.0, 37.5, 31.0, 25.6, 22.1. 19.7,
19.2,À4.2, À4.8; IR (neat) 2955, 1705, 1250, 1090; FAB HRMS, m/z 273.1883,
MþH calcd for C14H29O3Si 273.1887; Anal. Calcd for C14H28O3Si: C, 61.72;
H, 10.36. Found: C, 61.37; H, 10.04; [a]20D:þ12.4 (c1.5, CHCl 3).
[4R-(4a,8b)]-4-[(4-methoxyphenyl)methoxy]-8-methyl-2-oxocanone (20).
1H NMR (CDCl3) ꢀ 7.24 (2 H, d, J ¼ 8.8 Hz), 6.87 (2 H, d, J ¼ 8.8 Hz), 4.71
(1 H, m), 4.50 (1 H, d, J ¼ 11.6 Hz), 4.46 (1 H, d, J ¼ 11.6 Hz), 3.88 (3 H, s),
3.75 (1 H, m), 2.89 (1 H, dd, J ¼ 12.9, 6.2 Hz), 2.71 (1 H, dd, J ¼ 12.9,
3.8 Hz), 1.64–1.96 (6 H, m), 1.35 (3 H, d, J ¼ 6.0 Hz); 13C NMR (CDCl3)
ꢀ 184.2, 159.5, 130.3, 129.4, 114.1, 77.5, 75.6, 70.7, 55.5, 38.3, 37.7, 32.2,
21.9, 19.0; IR (neat) 3054, 2987, 1702, 1422, 1266, 1092 cmÀ1; FAB HRMS,
m/z 279.1602, MþH calcd for C16H23O4 279.1597; Anal. Calcd for
C16H22O4: C, 69.04; H, 7.97. Found: C, 69.15; H, 8.21; [a]20D ¼ À26.0 (c
1.2, CHCl3).
[4S-(4b,8b)]-4-[(4-methoxyphenyl)methoxy]-8-methyl-2-oxocanone (22).
1H NMR (CDCl3) ꢀ 7.27 (2 H, d, J ¼ 8.8 Hz), 6.86 (2 H, d, J ¼ 8.8 Hz), 4.77
(1 H, m), 4.61 (1 H, d, J ¼ 11.2 Hz), 4.45 (1 H, d, J ¼ 11.2 Hz), 3.79 (3 H, s),
3.75 (1 H, m), 2.68–2.76 (2 H, m), 1.81–1.87 (3 H, m), 1.60–1.67 (3 H, m),
1.33 (3 H, d, J ¼ 6.4 Hz); 13C NMR (CDCl3) ꢀ 172.8, 159.4, 130.5, 129.5,

SATURATED EIGHT-MEMBERED RING LACTONES
1789
114.0, 94.6, 75.7, 70.1, 55.5, 38.7, 38.2, 33.3, 21.6, 19.4; IR (neat) 3054, 2990,
1698, 1436, 1258, 1092 cmÀ1; FAB HRMS, m/z 279.1596, MþH calcd for
C16H23O4 279.1597; Anal. Calcd for C16H22O4: C, 69.04; H, 7.97. Found: C,
69.31; H, 7.80; [a]20D ¼ þ18.6 (c1.4, CHCl ).
3
ACKNOWLEDGMENT
This work was generously supported by the American Cancer Society
and the NSF-EPSCoR program. Acknowledgment is also made to the
Donors of the Petroleum research Fund, administered by the American
Chemical Society, for additional support of this research.
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1790
BUSZEK ET AL.
Garratt, D.G.; Hayakawa, K.; Heggie, W.; Hesson, D.P.; Hoppe, D.;
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Geminal dimethyl substitution at C-7 failed to induce lactonization.
The complete results from these calculations will be described
elsewhere.
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opposite than that reported for the natural compound: Ackland, J.J.;

SATURATED EIGHT-MEMBERED RING LACTONES
1791
Hanson, J.R.; Hitchcock, P.B.; Ratcliffe, A.H. J. Chem. Soc., Perkin
Trans. 1 1985, 843.
Received in the USA May 26, 2000