Ring expansions of β-keto lactones with zinc carbenoids: Syntheses of (+)-patulolide A and (±)-patulolide B

Article abstract of DOI:10.1021/jo0264776

A one-pot ring expansion/oxidation/elimination method has been developed in which β-keto lactones are converted efficiently to α,β-unsaturated-γ-keto lactones. The reaction can be successfully applied to a variety of ring sizes. Alkene stereochemistry is dependent upon ring size and reaction conditions. The method was applied to the synthesis of (+)-patulolide A.

Full text of DOI:10.1021/jo0264776

Rin g Exp a n sion s of â-Keto La cton es w ith Zin c Ca r ben oid s:
Syn th eses of (+)-P a tu lolid e A a n d (()-P a tu lolid e B
Matthew D. Ronsheim and Charles K. Zercher*
Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824
ckz@christa.umh.edu
Received September 25, 2002
A one-pot ring expansion/oxidation/elimination method has been developed in which â-keto lactones
are converted efficiently to R,â-unsaturated-γ-keto lactones. The reaction can be successfully applied
to a variety of ring sizes. Alkene stereochemistry is dependent upon ring size and reaction conditions.
The method was applied to the synthesis of (+)-patulolide A.
As part of a research program directed toward the
development of zinc-mediated chain extension reactions,1
we recently developed a one-pot chain extension/oxida-
tion/elimination sequence for the generation of R,â-
unsaturated-γ-keto esters and amides (Scheme 1).2 The
successful application of this methodology to a formal
synthesis of the dilactone pyrenophorin 33 through the
interception of an acyclic precursor was described. Pyreno-
phorin is one of a large number of natural products that
possesses an R,â-unsaturated-γ-keto ester structural unit.
In most instances this functionality is found in macro-
cyclic compounds such as (+)-patulolide A (4) and (-)-
patulolide B (5),4 (+)-macrosphelide B (6),5 (-)-grahami-
mycin A (7),6 and others (Figure 1).7-9 In an effort to
advance the scope of this zinc-mediated methodology, we
undertook its application to macrocyclic ring expansion.
Patulolides A (4) and B (5) were selected as the
synthetic targets. A macrolide isolated from the culture
broth of Penicillium urticae mutant S11R59 by Yamada
F IGURE 1. Structures of macrocyclic natural products.
SCHEME 1. Ch a in Exten sion /Oxid a tion /
Elim in a tion Rea ction
and co-workers, patulolide A possesses antifungal, anti-
(1) (a) Brogan, J . B.; Zercher, C. K. J . Org. Chem. 1997, 62, 6444-
6446. (b) Hilgenkamp, R.; Zercher, C. K. Tetrahedron 2001, 57, 8793-
8800. (c) Verbicky, C. A.; Zercher, C. K. J . Org. Chem. 2000, 65, 5615-
5622. (d) Lai, S.; Zercher, C. K.; J asinski, J . P.; Reid, S. N.; Staples, R.
J . Org. Lett. 2001, 3, 4169-4171. (e) Hilgenkamp, R.; Zercher, C. K.
Org. Lett. 2001, 3, 3037-3040.
(2) Ronsheim, M. D.; Zercher, C. K. Submitted for publication.
(3) Nozoe, S.; Hirai, K.; Tsuda, K.; Ishibashi, K.; Shirasaka, M.;
Grove, J . F. Tetrahedron Lett. 1965, 4675-4677.
(4) Sekiguchi, J .; Kuroda, H.; Yamada, Y.; Okada, H., Tetrahedron
Lett. 1985, 26, 2341-2342.
bacterial, and antiinflammatory activities.10 Patulolide
B, isolated concurrently with patulolide A, is isomeric
with respect to the olefin and was reported to possess a
similar biological activity profile. A number of synthetic
approaches to patulolides A and B have been reported.11-13
Most strategies have relied upon lactonization as the
(5) (a) Hayashi, M.; Kim, Y.-P.; Hiraoka, H.; Natori, M.; Takamatsu,
S.; Kawakubo, T.; Masuma, R.; Komiyama, K.; Omurta, S. J . Antibiot.
1995, 48, 1435-1439. (b) Takamatsu, S.; Kim, Y.-P.; Hayashi, M.;
Hiraoka, H.; Natori, M.; Komiyama, K.; Omura, S. J . Antibiot. 1996,
49, 95-98.
(6) Gurusiddaiah, S.; Ronald, R. C. Antimicrob. Agents Chemother.
1981, 19, 153-165.
(7) Aldridge, D. C.; Armstrong, J . J .; Speake, R. N.; Turner, W. B.
J . Chem. Soc., Chem. Commun. 1967, 26-27.
(10) Rodphaya, D.; Sekiguchi, J .; Yamada, Y. J . Antibiot. 1986, 629-
635.
(8) Massias, M.; Molho, L.; Rebuffat, S.; Cesario, M.; Guilhen, J .
Phytochemistry 1989, 28, 1491-1494.
(11) Sharma, A.; Sankaranarayanan, S.; Chattopadhyay, S. J . Org.
Chem. 1996, 61, 1814-1816.
(12) (a) Kobayashi, Y.; Kishihara, K.; Watatani, K. Tetrahedron Lett.
1996, 37, 4383-4388. (b) Kobayashi, Y.; Nakano, M.; Kumar, G. B.;
Kishihara, K. J . Org. Chem. 1998, 63, 7505-7515.
(9) Zhang, H.; Tomoda, H.; Tabata, N.; Miura, H.; Namikoshi, M.;
Yamaguchi, Y.; Masuma, R.; Omura, S. J . Antibiot. 2001, 54, 635-
641.
10.1021/jo0264776 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/30/2003
1878
J . Org. Chem. 2003, 68, 1878-1885

Syntheses of (+)-Patulolide A and (()-Patulolide B
preferred method for macrocycle formation.14 Alterna-
tively, formation of the macrocycle with concomitant
incorporation of the R,â-unsaturated-γ-keto functionality
was used effectively by a number of research groups,15
including a recent report by Doyle in which macrocy-
clization of a bis-diazo precursor was induced.16
SCHEME 2. F or m a tion of Ma cr ocycles
We anticipated that olefin metathesis could be used
to generate a macrocyclic â-keto lactone. Following
reduction of the newly generated olefin, formation of the
R,â-unsaturated-γ-keto ester by application of the chain
extension/oxidation/elimination methodology would re-
sult in ring expansion and formation of the desired
macrocycle. Application of this reaction to macrocyclic
substrates would encounter issues unique to macrocyclic
skeletons. Most importantly, it was unknown how ring
size would influence the chain extension portion of the
reaction, since simple ring expansions of â-keto lactones
had not been studied. Furthermore, the role of the
macrocyclic substrate in affecting olefin generation and
selectivity was another unknown issue.
We selected as our initial target a 14-membered-ring
unsaturated lactone, which required the generation of a
13-membered â-keto lactone precursor (Scheme 2). Treat-
ment of diketene 8 with 3-buten-1-ol provided unsatur-
ated â-keto ester 9a in 84% yield. Dianion formation and
alkylation with 6-bromohex-1-ene provided the meta-
thesis precursor 10a in 78% yield. Treatment with the
first generation Grubb’s metathesis catalyst resulted in
efficient formation of the â-keto lactone 11a in 73% as
an inseparable mixture of olefin isomers. Olefin selectiv-
ity was determined through NOESY analysis, with the
E-isomer dominating in a 4:1 ratio. Quantitative reduc-
tion of the alkenes provided access to the thirteen-
membered â-keto lactone 12a . Exposure of 12a to chain
extension/oxidation/elimination reaction conditions pro-
vided the R,â-unsaturated-γ-keto lactone 13a in 69% as
a single isomer, which was assigned the E-configuration
due to the 15.5 Hz coupling constant. Chain extension of
this macrocyclic substrate (as well as the other substrates
discussed herein) proceeded more slowly than that of
their acyclic analogues; however, the rate of chain
extension could be enhanced by exposure of the â-keto
lactone to diethyl zinc prior to the addition of the
methylene iodide. The use of diethyl zinc to facilitate
enolate formation has been applied with success in other
chain extension studies,1c but it is particularly advanta-
geous in systems where enolate formation is slow. A
protocol that involved treatment of the â-keto lactone
with excess diethyl zinc prior to addition of methylene
iodide (in situ carbenoid formation) was used throughout
this study, although similar results with longer reaction
times could be obtained by direct exposure of the â-keto
lactone to the preformed carbenoid.
The formation of 13- and 15-membered R,â-unsatur-
ated-γ-keto lactones was undertaken through application
of the identical strategy (Scheme 2). A mixture of
14-membered â-keto lactones 11b was produced through
metathesis in a combined 65% yield. The olefin selectivity
was once again assigned through NOESY analysis and
was quite different (1:1.5; E:Z) from that of the previous
system. Both olefins were reduced efficiently through
catalytic hydrogenation, and the resulting â-keto lactone
12b was exposed to the one-pot chain extension/oxidation/
elimination sequence. Formation of the 15-membered-
ring 13b was facilitated in 66% yield, once again as the
E-isomer exclusively.
(13) (a) Makita, A.; Yamada, Y.; Okada, H. J . Antibiot. 1986, 39,
1257-1262. (b) Ayyangar, N. R.; Chanda, B.; Wakharkar, R. D.; Kasar,
R. A. Synth. Commun. 1988, 18, 2103-2109. (c) Ichimoto, I.; Ohotomo,
Y.; Kirihata, M.; Tsuji, H.; Ueda, H. Chem. Express 1989, 4, 625-628.
(d) Yadav, J . S.; Krishna, P. R.; Gurjar, M. K. Tetrahedron 1989, 45,
6263-6270. (e) Solladie, G.; Gerber, C. Synlett 1992, 449-450. (f) Yang,
H.; Kuroda, H.; Miyashita, M.; Irie, H. Chem. Pharm. Bull. 1992, 40,
1616-1618. (g) Kalita, D.; Khan, A. T.; Barua, N. C.; Bez, G.
Tetrahedron 1999, 55, 5177-5184.
An approach to the 13-membered γ-keto lactone 13c
required formation of a 12-membered â-keto lactone 12c.
Metathesis provided an inseparable mixture of olefin
isomers 11c in which the E-isomer was favored (4:1).
Reduction of the olefin and exposure to chain extension/
oxidation/elimination reaction conditions provided, for the
first time, two isomeric products in an approximate 10:1
ratio. Structural assignment was made on the basis of
1H NMR coupling, and indicated that the major product
13c possessed the anticipated E-olefin configuration.
Olefinic protons in the minor product 14c possessed a
(14) Mori, K.; Sakai, T. Leibigs. Ann. Chem. 1988, 13-17.
(15) (a) Bestmann, H. J .; Kellermann, W.; Pecher, B. Synthesis 1993,
149-152. (b) Kamezawa, M.; Kitamura, M.; Nagaoka, H.; Tichibana,
H.; Ohtani, T.; Noashima, Y. Liebigs Ann. Chem. 1996, 167-170. (c)
Le Floc’h, Y.; Yvergnaux, F.; Toupet, G. R. Bull. Soc. Chim. Fr. 1991,
742-759.
(16) Doyle, M. P.; Hu, W.; Phillips, I. M.; Wee, A. G. Org. Lett. 2000,
2, 1777-1779.
J . Org. Chem, Vol. 68, No. 5, 2003 1879

Ronsheim and Zercher
SCHEME 3. F or m a tion of th e Kin etic a n d
Th er m od yn a m ic P r od u cts
SCHEME 4. P r ep a r a tion of th e P a tu lolid e Rin g
System
12.7 Hz coupling constant, which led to its assignment
as the Z-isomer. The unprecedented appearance of the
Z-isomer in the ring expansion of 12c raised questions
regarding the comparative thermodynamic stability of
the two isomers, 13c and 14c. In their investigation of
patulolides A and B (12-membered rings), Doyle and co-
workers utilized iodine-mediated isomerization to probe
the relative energies of macrocyclic R,â-unsaturated-γ-
keto lactones. In a similar fashion, exposure of 13c to
catalytic iodine for 3 days resulted in complete isomer-
ization to the thermodynamically more stable Z-isomer
(14c). Since the chain extension/oxidation/elimination
reaction of 12c resulted in a 10:1 mixture of E- and
Z-isomers, the reaction was either operating under
kinetic control or only partial isomerization had taken
place. During optimization studies of acyclic substrates,2
elimination of the iodide had been determined to proceed
most efficiently when the intermediate iodide was ex-
posed to excess DBU (10 equiv) for between 30 and 60 s.
We anticipated that stirring the reaction mixture for a
greater period of time in the presence of the iodide salts
and DBU would facilitate isomerization of the E-isomer
13c to the thermodynamically more stable Z-olefin isomer
14c. Repeating the chain extension/oxidation/ elimination
reaction and allowing the reaction mixture to stir for 10
min after addition of excess DBU resulted in (Scheme 3)
exclusive formation of the Z-olefin isomer 14c in 56%
yield. In contrast, exclusive formation of the E-olefin
isomer 13c was possible through a kinetically controlled
elimination reaction. Isolation of the intermediate iodide
15 and exposure of the iodide to DBU (1.2 equiv in ether)
facilitated formation of the 13c.
SCHEME 5. F or m a tion of P a tu lolid es A a n d B
potential problems in the isolation of a low molecular
weight alcohol, we captured the intermediate alkoxide
17 with diketene 8 to form the desired â-keto ester 18.
Dianion formation and alkylation with allyl bromide
provided the desired olefin 19 in an 80% yield. Exposure
of 19 to our standard olefin metathesis conditions did not
produce the 11-membered ring in an acceptable yield.
When the catalyst load was increased to 15%, added in
three portions over a 24-h period, formation of the desired
11-membered ring 20 was accomplished. Although sig-
nificant oligomerization was observed, the lactone was
isolated in 52% with exclusive formation of the Z-isomer.
Hydrogenation of the olefin provided the â-keto lactone
21.
Application of this strategy to the preparation of the
12-membered-ring macrolides patulolides A (4) and B (5)
mandated the use of a smaller ring system (Scheme 4).
The preparation of the 11-membered-ring precursor
through ring-closing metathesis and the selection of
appropriate elimination conditions for control of olefin
geometry were anticipated to be strongly influenced by
the smaller ring size. The R-stereocenter was incorpo-
rated through opening of R-propylene oxide with an
organocuprate derived from allyl bromide 16. To avoid
Exposure of 21 to chain extension/iodination/ elimina-
tion reaction conditions returned only starting material.
No reaction, including ring expansion, was observed
under these conditions. As mentioned earlier, chain
extension (ring expansion) of these macrocyclic systems
is more sluggish than that of the acyclic systems,
1880 J . Org. Chem., Vol. 68, No. 5, 2003

Syntheses of (+)-Patulolide A and (()-Patulolide B
and the solution was allowed to warm to room temperature.
The solution was allowed to stir for 2 h and, washed with 20
mL of sat. aqueous NH4Cl (20 mL). The organic layer was
washed with sat. aqueous Na2HCO3 (20 mL) and the layers
were separated. The combined aqueous washings were ex-
tracted (3 × 20 mL) with Et2O and the combined organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was chromatographed on silica (10:1, hexanes/
ethyl acetate; Rf 0.23) to yield 1.31 g (84%) of 9a as a clear oil.
1H NMR (400 MHz, CDCl3) keto form δ 5.75 (tdd, 1H, J ) 6.8,
10.5, 17.2 Hz), 5.14-5.07 (m, 2H), 4.20 (t, 2H, J ) 6.6 Hz),
3.46 (s, 2H), 2.44-2.38 (m, 2H), 2.27 (s, 3H); visible resonances
corresponding to enol form include δ 12.1 (s), 4.99 (s), 1.96 (s);
13C NMR (100 MHz, CDCl3) keto and enol resonances δ 200.7,
175.8, 167.3, 133.8, 117.7, 117.5, 89.9, 64.5, 63.2, 50.2, 33.2,
33.1, 30.3, 21.4.
presumably due to the decreased acidity of the R-meth-
ylene protons. Attempts to deprotonate the â-keto lactone
by refluxing the methylene chloride solution of 21 with
diethyl zinc or carbenoid were unsuccessful.
In an effort to obtain higher reaction temperatures that
might facilitate deprotonation of 21, benzene was se-
lected. Surprisingly, deprotonation and subsequent ring
expansion was observed to occur at room temperature in
benzene. The precise role benzene plays in facilitating the
acid-base reaction is unclear, yet additional experiments
revealed the general phenomenon that benzene acceler-
ates the chain extension. The chain extension/oxidation/
iodination reaction of racemic 21 resulted in clean
formation of patulolide B 5 in 66% yield. Doyle16 reported
that patulolide B is the more stable isomer, and the
results obtained in our studies of 12c confirmed that the
elimination reaction was operating under thermodynamic
control. However, the conformational biasing inherent to
the smaller ring system raised the possibility that the
Z-isomer might, in fact, be the kinetically controlled
product. Isolation of the intermediate iodide 22 proceeded
efficiently. Application of optimized kinetically controlled
elimination conditions provided a 48% yield of (+)-
patulolide A 4 as a single isomer.
Bu t-3-en yl 3-Oxo-d ec-9-en oa te (10a ). A 100-mL round-
bottom flask containing a suspension of NaH (60% in hexanes,
134 mg, 3.3 mmol) in THF (10 mL) was cooled to 0 °C under
a blanket of N2. A solution of â-keto ester 9a (468 mg, 3.0
mmol) dissolved in THF (5 mL) was added slowly and the
solution was allowed to stir for 30 min until the suspension
became a clear yellow solution. The solution was cooled to -15
°C and n-BuLi (1.3 M in hexanes, 2.5 mL, 3.3 mmol) was added
slowly. The solution was allowed to stir for an additional 20
min, at which time 6-bromo-1-hexene (0.44 mL, 3.3 mmol) was
added. The solution was allowed to warm to room temperature
and stirred overnight. The resulting thick suspension was
quenched with sat. aqueous NH4Cl (20 mL) and washed
successively with D.I. H2O (20 mL) and brine (20 mL). The
organic layer was separated and the combined aqueous wash-
ings were extracted with Et2O (3 × 20 mL). The combined
organic extracts were dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was chromatographed on
silica (15:1, hexanes/ethyl acetate; Rf 0.21) to yield 510 mg
(78%) of 10a as a clear oil. 1H NMR (500 MHz, CDCl3) keto
form δ 5.83-5.73 (m, 2H), 5.14-4.92 (m, 4H), 4.19 (t, 2H, J )
6.5 Hz), 3.43 (s, 2H), 2.54 (t, 2H, J ) 7.5 Hz), 2.43-2.39 (m,
2H), 2.07-2.02 (m, 2H), 1.63-1.57 (m, 2H), 1.43-1.27 (m, 4H);
1H NMR (500 MHz, CDCl3) visible resonances corresponding
to enol form include δ 2.23-2.17 (m); 13C NMR (125 MHz,
CDCl3) keto and enol resonances δ 202.9, 167.4, 139.0, 139.0,
134.2, 133.9, 117.7, 117.5, 114.7, 114.6, 89.1, 64.5, 63.2, 49.4,
43.2, 35.2, 33.8, 33.7, 33.3, 33.1, 28.8, 28.8, 28.7, 28.6, 26.3,
23.5; HRMS (CI) [M + NH4]+ calcd for C14H26NO3 256.1907,
found 256.1909.
In conclusion, we have demonstrated that application
of a chain extension/oxidation/elimination reaction to
macrocyclic â-keto lactones provides access to analogous
R,â-unsaturated-γ-keto lactones. Olefin stereochemistry
is affected by the interplay of ring size and reaction
conditions, but can be influenced by selection of condi-
tions that operate under kinetic or thermodynamic
control.
Exp er im en ta l Section
Gen er a l Exp er im en ta l Deta ils. Unless otherwise noted,
all reactions were run under a nitrogen atmosphere in oven-
dried glassware and stirred with Teflon-coated magnetic stir
bars. The terms concentrated in vacuo or under reduced
pressure refer to the use of a rotary-evaporator or vacuum
pump. Tetrahydrofuran (THF) and diethyl ether were distilled
from purple benzophenone ketyl prior to use. Benzene was
distilled from calcium hydride prior to use. Methylene chloride
(CH2Cl2) was distilled from P2O5 prior to use. Ethyl acetate
(EtOAc) was distilled prior to use. Hexanes were distilled prior
to use. Diethylzinc was purchased and used as a solution (1.0
M in hexanes). Iodine was sublimed prior to use. Column
chromatography was performed with flash silica gel (32-
63µm), for which mobile phases were used as noted. Thin layer
chromatography (TLC) was visualized by UV and anisaldehyde
or KMnO4 stains. The Rf values were determined with the
same solvent used for column chromatography. Unless other-
wise noted, all NMR experiments were carried out in deute-
riochloroform (CDCl3) solvent. Low-resolution mass spectro-
scopy was performed by the University of New Hampshire
Instrumentation. High-resolution mass spectroscopy was per-
formed at Merck Pharmaceutical Co. Optical rotations were
conducted in the specified solution and concentrations are
given in g/mL. Melting points are uncorrected.
Oxa cyclotr id ec-10-en e-2,4-d ion e (11a ). To a solution of
â-keto ester 10a (102 mg, 0.43 mmol) in dry CH2Cl2 (250 mL)
was added bis(cyclohexylphosphine)benzylidine ruthenium(IV)
dichloride (35 mg, 0.043 mmol). This solution was heated to
reflux for 4 h. The solution was allowed to cool and concen-
trated in vacuo. The residue was chromatographed on silica
(10:1, hexanes/ethyl acetate; Rf 0.19) to yield 66 mg (73%) of
11a as an inseparable 4:1 mixture of E- and Z-isomers,
respectively. 1H NMR (500 MHz, CDCl3) major isomer δ 5.50-
5.43 (m, 1H), 5.32-5.28 (m, 1H), 4.23-4.21 (m, 2H), 3.39 (s,
2H), 2.51 (t, 2H, J ) 7.0 Hz), 2.38-2.35 (m, 2H), 2.02-1.99
(m, 2H), 1.66 (m, 2H, J ) 6.5 Hz), 1.47-1.31 (m, 4H); 1H NMR
(500 MHz, CDCl3) minor isomer δ 4.26-4.24 (m), 3.42 (s),
2.55-2.52 (m), 2.43-2.40 (m), 2.09-2.05 (m); 13C NMR (125
MHz, CDCl3) visible signals corresponding to both E- and
Z-isomers δ 203.3, 167.1, 134.6, 132.5, 127.2, 127.1, 65.4, 64.3,
50.2, 50.0, 43.5, 42.3, 32.4, 32.1, 27.8, 27.4, 27.2, 26.6, 26.4,
25.3, 23.1, 23.0; IR (film) 2929.6, 2856.0, 1743.0, 1713.4,
1254.5; HRMS (EI) [M + H]+ calcd for C12H19O3 211.1642,
found 211.1604.
Bu t-3-en yl 3-Oxo-bu ta n oa te (9a ).17A 100-mL round-bot-
tom flask was equipped with a stir bar and charged with 15
mL of benzene (20 mL), diketene (1.0 mL, 13.0 mmol), and
3-buten-1-ol (0.86 mL, 10 mmol) under an atmosphere of N2
at 0 °C. Triethylamine was added (2.1 mL, 15 mmol) slowly
Oxa cyclotr id eca n e-2,4-d ion e (12a ). To a 100-mL round-
bottom flask containing â-keto lactone 11a (53 mg, 0.25 mmol)
in MeOH (5 mL) under a blanket of N2 was added 10% Pd on
carbon (25 mg). The vessel was purged with hydrogen via a
balloon and the nitrogen inlet was removed. The suspension
(17) Broggini, G.; Garanti, L.; Molteni, G.; Zechi, G. Tetrahedron
1998, 54, 2843-2852.
J . Org. Chem, Vol. 68, No. 5, 2003 1881

Ronsheim and Zercher
was allowed to stir at room temperature with the balloon
attached for 4 h. The suspension was filtered and concentrated
in vacuo to yield 50 mg (95%) of 12a as a white solid; mp 39.0-
40.5 °C. 1H NMR (500 MHz, CDCl3) δ 4.21-4.19 (m, 2H), 3.44
(s, 2H), 2.63-2.61 (m, 2H), 1.71-1.62 (m, 4H), 1.44-1.36 (m,
2H), 1.34-1.28 (m, 8H); 13C NMR (125 MHz, CDCl3) δ 202.6,
166.8, 65.5, 50.5, 42.0, 26.5, 25.9, 25.2, 25.1, 24.9, 23.2, 21.8.
solution was allowed to warm to room temperature and stirred
overnight. The resulting thick suspension was quenched with
sat. aqueous NH4Cl (20 mL) and washed successively with D.I.
H2O (20 mL) and brine (20 mL). The organic layer was
separated and the combined aqueous washings were extracted
with Et2O (3 × 20 mL). The combined organic extracts were
dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was chromatographed on silica (15:1, hexanes/ethyl
acetate; Rf 0.21) to yield 721 mg (71%) of 10b as a clear oil. 1H
NMR (500 MHz, CDCl3) keto form δ 5.81-5.76 (m, 2H), 5.06-
4.93 (m, 4H), 4.15 (t, 2H, J ) 6.0 Hz), 3.43 (s, 2H), 2.54 (t, 2H
J ) 7.5 Hz), 2.15-2.10 (m, 2H), 2.07-2.02 (m, 2H), 1.78-1.72
(m, 2H), 1.65-1.58 (m, 2H), 1.41-1.29 (m, 4H); 1H NMR (500
MHz, CDCl3) visible resonances corresponding to enol form
include δ 2.22-2.17 (m); 13C NMR (125 MHz, CDCl3) keto and
enol resonances δ 202.9, 167.4, 138.9, 137.4, 115.6, 114.6, 89.1,
64.9, 63.2, 49.5, 43.2, 35.2, 33.7, 30.1, 28.8, 28.7, 28.1, 27.9,
26.3, 23.5; IR (film) 2977.6, 2936.8, 2360.2, 2342.5, 1734.1,
1717.4; HRMS (CI, NH3) [M + NH4]+ calcd for C15H28NO3
270.2063, found 270.2066.
E-Oxacyclotetr adec-10-en e-2,4-dion e (E-11b) an d Z-Oxa-
cyclotetr a d ec-10-en e-2,4-d ion e (Z-11b). To a solution of
â-keto ester 10b (200 mg, 0.79 mmol) in dry CH2Cl2 (250 mL)
was added bis(cyclohexylphosphine)benzylidine ruthenium(IV)
dichloride (33 mg, 0.040 mmol). This solution was heated to
reflux for 3 h. The solution was allowed to cool and concen-
trated in vacuo. The residue was chromatographed on silica
(13:1, hexanes/ethyl acetate) to yield 77 mg (44%) of the less
polar isomer (Rf 0.19) (Z-11b) as a clear oil. 1H NMR (500 MHz,
CDCl3) δ 5.49-5.44 (m, 1H), 5.31-5.26 (m, 1H), 4.18-4.16 (m,
2H), 3.42 (s, 2H), 2.56-2.53 (m, 2H), 2.23-2.19 (m, 2H), 2.03-
1.99 (m, 2H), 1.77-1.64 (m, 4H), 1.37-1.32 (m, 4H); 13C NMR
(125 MHz, CDCl3) δ 203.2, 167.5, 131.1, 128.9, 64.3, 50.6, 41.2,
28.5, 27.6, 26.9, 25.9, 23.5, 22.3. The more polar isomer (Rf
0.17) (E-11b) was isolated (38 mg, 21%) as a clear oil. 1H NMR
(400 MHz, CDCl3) δ 5.45-5.28 (m, 2H), 4.21-4.18 (m, 2H),
3.44 (s, 2H), 2.50-2.46 (m, 2H), 2.22-2.17 (m, 2H), 2.06-2.01
(m, 2H), 1.81-1.64 (m, 4H), 1.44-1.30 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 204.2, 167.4, 131.2, 130.3, 66.7, 49.2, 43.0, 31.9,
30.7, 28.3, 27.3, 26.3, 24.1; IR (film) 2928.4, 2855.6, 1743.5,
1714.0; HRMS (CI, NH3) [M + NH4]+ calcd for C13H24NO3
242.1750, found 242.1759.
E-Oxa cyclotetr a d ec-3-en e-2,5-d ion e (13a ).18 A 100-mL
round-bottom flask was equipped with a stir bar and charged
with 15 mL of methylene chloride and â-keto lactone 12a (39
mg, 0.19 mmol). To this solution was added diethyl zinc (1.0
M in hexanes, 1.14 mL, 1.14 mmol) under an atmosphere of
N2 at 0 °C. This solution was allowed to stir for 5 min and
CH2I2 (0.95 mL, 1.18 mmol) was added. The solution was
monitored by TLC until starting material was no longer visible
(approximately 45 min). Iodine (300 mg, 1.18 mmol) was added
to the reaction mixture in a single portion. The reaction
mixture turned pink and was allowed to stir for an additional
30 s. A saturated solution of sodium thiosulfate (10 mL) was
added and the mixture was stirred until the pink color had
disappeared. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (0.28
mL, 1.9 mmol) was added and the mixture was stirred for 1
min and washed with saturated aqueous ammonium chloride
(20 mL) and the layers were separated. The aqueous layer was
extracted with diethyl ether (3 × 25 mL). The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated in vacuo. The residue was chromatographed on
silica (15:1, hexanes/ethyl acetate; Rf 0.19) to yield 30 mg (69%)
1
of 13a as a yellow oil. H NMR (500 MHz, CDCl3) δ 7.39 (d,
1H, J ) 15.6 Hz), 6.60 (d, 1H, J ) 15.6 Hz), 4.33-4.31 (m,
2H), 2.55-2.52 (m, 2H), 1.77-1.70 (m, 4H), 1.56-1.52 (m, 2H),
1.46-1.35 (m, 8H); 13C NMR (125 MHz, CDCl3) δ 201.1, 165.3,
138.0, 130.5, 66.8, 42.3, 28.6, 27.5, 27.5, 26.8, 26.7, 26.5, 23.6;
HRMS (CI) [M + Na]+ calcd for C13H20O3Na 247.1304, found
247.1317.
P en t-4-en yl 3-oxo-bu ta n oa te (9b).19 A 100-mL round-
bottom flask was equipped with a stir bar and charged with
15 mL of benzene (20 mL). Diketene (1.0 mL, 13.0 mmol) and
4-penten-1-ol (1.03 mL, 10 mmol) were added under an
atmosphere of N2 at 0 °C. Triethylamine was added (2.1 mL,
15 mmol) slowly and allowed to warm to room temperature.
The solution was allowed to stir for 2 h and washed with 20
mL of sat. aqueous NH4Cl (20 mL). The organic layer was
washed with sat. aqueous Na2HCO3 (20 mL) and the layers
were separated. The combined aqueous washings were ex-
tracted (3 × 20 mL) with Et2O and the combined organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was chromatographed on silica (10:1, hexanes/
ethyl acetate; Rf 0.23) to yield 1.38 g (81%) of 9b as a clear oil.
1H NMR (400 MHz, CDCl3) keto form δ 5.85 (tdd, 1H, J ) 6.8,
10.0, 17.2 Hz), 5.07-4.98 (m, 2H), 4.16 (t, 2H, J ) 6.8 Hz),
3.46 (s, 2H), 2.27 (s, 3H), 2.15 (q, 2H, J ) 6.8 Hz), 1.78 (p, 2H,
J ) 6.8 Hz); 1H NMR (400 MHz, CDCl3) visible resonances
corresponding to enol form include δ 1.96 (s); 13C NMR (100
MHz, CDCl3) keto and enol resonances δ 200.8, 167.3, 137.4,
115.6, 64.9, 63.8, 50.3, 30.3, 30.1, 27.8, 21.7; HRMS (CI, NH3)
[M + NH4]+ calcd for C9H18NO3 188.1284, found 188.1281.
P en t-4-en yl 3-Oxo-d ec-9-en oa te (10b). A 100-mL round-
bottom flask containing a suspension of NaH (60% in hexanes,
193 mg, 4.8 mmol) in THF (15 mL) was cooled to 0 °C under
a blanket of N2. A solution of â-keto ester 9b (680 mg, 4.0
mmol) dissolved in THF (5 mL) was added slowly and the
solution was allowed to stir for 30 min until the suspension
became a clear yellow solution. The solution was cooled to -15
°C and n-BuLi (1.3 M in hexanes, 4.0 mL, 5.2 mmol) was added
slowly and allowed to stir for an additional 20 min, at which
time 6-bromo-1-hexene (0.59 mL, 4.4 mmol) was added. The
The residue described in the previous reaction (preparation
of E-11b) was chromatographed on silica (13:1, hexanes/ethyl
acetate; Rf 0.19) to yield 77 mg (44%) of the less polar
1
component (Z-11b) as a clear oil. H NMR (500 MHz, CDCl3)
δ 5.49-5.44 (m, 1H), 5.31-5.26 (m, 1H), 4.18-4.16 (m, 2H),
3.42 (s, 2H), 2.56-2.53 (m, 2H), 2.23-2.19 (m, 2H), 2.03-1.99
(m, 2H), 1.77-1.64 (m, 4H), 1.37-1.32 (m, 4H); 13C NMR (125
MHz, CDCl3) δ 203.2, 167.5, 131.1, 128.9, 64.3, 50.6, 41.2, 28.5,
27.6, 26.9, 25.9, 23.5, 22.3.
Oxa cyclotetr a d eca n e-2,4-d ion e (12b).20 To a 100-mL
round-bottom flask containing â-keto lactone E-11b and Z-11b
(99 mg, 0.44 mmol) in EtOH (10 mL) under a blanket of N2
was added 10% Pd on carbon (40 mg). The vessel was purged
with hydrogen via a balloon and the nitrogen inlet was
removed. The suspension was allowed to stir at room temper-
ature with the balloon attached for 4 h. The suspension was
filtered and concentrated in vacuo to yield 94 mg (94%) of 12b
as a white solid; mp 34.0-35.2 °C. 1H NMR (500 MHz, CDCl3)
δ 4.21-4.19 (m, 2H), 3.43 (s, 2H), 2.59 (t, 2H, J ) 7.0 Hz),
1.72-1.66 (m, 4H), 1.42-1.20 (m, 12H); 13C NMR (125 MHz,
CDCl3) δ 202.6, 167.3, 65.2, 50.2, 41.1, 27.5, 26.3, 25.9, 25.5,
25.2, 24.7, 23.9, 21.2; HRMS (CI, NH3) [M + NH4]+ calcd for
C
13H26NO3 244.1907, found 244.1913.
E-Oxa cyclop en t a d ec-3-en e-2,5-d ion e (13b). A 100-mL
round-bottom flask was equipped with a stir bar and charged
with 15 mL of methylene chloride and â-keto ester 12b (87
mg, 0.39 mmol). To this solution was added diethyl zinc (1.0
(18) Baldwin, J . E.; Adlington, R. M.; Ramcharitar, S. H. Tetrahe-
dron 1992, 48, 2957-2976.
(19) Lermer, L.; Neeland, E. G.; Ounsworth, J . P.; Sims, R. J .;
Tischler, S. A.; Weiler, L. Can. J . Chem. 1992, 70, 1427-1445.
(20) Boger, D. L.; Mathvink, R. J . J . Am. Chem. Soc. 1990, 112,
4008-4011.
1882 J . Org. Chem., Vol. 68, No. 5, 2003

Syntheses of (+)-Patulolide A and (()-Patulolide B
M in hexanes, 2.3 mL, 2.3 mmol) under an atmosphere of N2
at 0 °C. This solution was allowed to stir for 5 min and CH2I2
(0.20 mL, 2.4 mmol) was added. The solution was monitored
by TLC until starting material was no longer visible (ap-
proximately 45 min). Iodine (616 mg, 2.4 mmol) was added to
the reaction mixture in a single portion and allowed to stir
until a pink color persisted for 30 s. A saturated solution of
sodium thiosulfate (10 mL) was added and the mixture was
stirred until the pink color had disappeared. 1,8-Diazabicyclo-
[5.4.0]undec-7-ene (DBU) (0.58 mL, 3.9 mmol) was added, the
mixture was stirred for 1 min and washed with saturated
aqueous ammonium chloride (20 mL), and the layers were
separated. The aqueous layer was extracted with diethyl ether
(3 × 25 mL). The combined organic layers were dried over
anhydrous sodium sulfate and concentrated in vacuo. The
residue was chromatographed on silica (15:1, hexanes/ethyl
acetate; Rf 0.19) to yield 62 mg (66%) of 13b as a yellow solid,
Oxa cyclod od eca n e-2,4-d ion e (12c).21 To
a
100-mL
round-bottom flask containing â-keto lactone 11c (91 mg, 0.46
mmol) in EtOH (10 mL) under a blanket of N2 was added
10% Pd on carbon (20 mg). The vessel was purged with
hydrogen via a balloon and the nitrogen inlet was removed.
The suspension was allowed to stir at room temperature with
the balloon attached for 3 h. The suspension was then filtered
and concentrated in vacuo to yield 86 mg (95%) of 12c as a
clear oil. 1H NMR (500 MHz, CDCl3) δ 4.19-4.17 (m, 2H), 3.43
(s, 2H), 2.65-2.63 (m, 2H), 1.73-1.65 (m, 4H), 1.49-1.44 (m,
2H), 1.37-1.27 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 202.9,
167.0, 66.5, 50.9, 40.5, 26.5, 26.1, 24.6, 23.5, 23.0, 21.7; HRMS
(CI, Na) [M + Na]+ calcd for C11H18O3Na 221.1148, found
221.1170.
(3E)-Oxa cyclotr id ec-3-en e-2,5-d ion e (13c) a n d (3Z)-
oxa cyclotr id ec-3-en e-2,5-d ion e (14c). A 100-mL round-
bottom flask was equipped with a stir bar and charged with
15 mL of methylene chloride and â-keto lactone 12c (96 mg,
0.48 mmol). To this solution was added diethyl zinc (1.0 M in
hexanes, 2.9 mL, 2.9 mmol) under an atmosphere of N2 at 0
°C. This solution was allowed to stir for 5 min and CH2I2 (0.24
mL, 2.9 mmol) was added. The solution was monitored by TLC
until starting material was no longer visible (approximately
45 min). Iodine (756 mg, 2.9 mmol) was added to the reaction
mixture in a single portion and allowed to stir until a pink
color persisted for 30 s. A saturated solution of sodium
thiosulfate (10 mL) was added and the mixture was stirred
until the pink color had disappeared. 1,8-Diazabicyclo[5.4.0]-
undec-7-ene (DBU) (0.72 mL, 4.8 mmol) was added and the
mixture was stirred for 1 min. The mixture was washed with
saturated aqueous ammonium chloride (20 mL) and the layers
were separated. The aqueous layer was extracted with diethyl
ether (3 × 25 mL). The combined organic layers were dried
over anhydrous sodium sulfate and concentrated in vacuo. The
residue was chromatographed on silica (15:1, hexanes/ethyl
acetate; Rf 0.21) to yield 63 mg (62%) of 13c as a yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.52 (d, 1H, J ) 15.6 Hz), 6.49
(d, 1H, J ) 15.6 Hz), 4.30-4.28 (m, 2H), 2.50-2.48 (m, 2H),
1.75-1.73 (m, 4H), 1.46-1.40 (m, 8H); 13C NMR (125 MHz,
CDCl3) δ 201.5, 165.9, 139.8, 129.4, 65.9, 42.4, 27.7, 27.5, 27.1,
27.1, 23.9, 23.5. The more polar component (15:1, hexanes/
ethyl acetate; Rf 0.19) was isolated (6.3 mg, 6%) to yield 14c
1
mp 41.7-43.2 °C. H NMR (500 MHz, CDCl3) δ 7.21 (d, 1H, J
) 15.6 Hz), 6.64 (d, 1H, J ) 16.1 Hz), 4.27-4.25 (m, 2H), 2.57-
2.55 (m, 2H), 1.76-1.71 (m, 4H), 1.49-1.32 (m, 12H); 13C NMR
(125 MHz, CDCl3) δ 201.4, 165.4, 138.5, 130.9, 66.5, 41.3, 28.9,
27.9, 27.6, 27.5, 27.1, 27.0, 26.5, 25.0; HRMS (CI, NH3) [M +
NH4]+ calcd for C14H26NO3 256.1907, found 256.1912.
Bu t-3-en yl 3-oxo-n on -8-en oa te (10c). A 100-mL round-
bottom flask containing a suspension of NaH (60% in hexanes,
480 mg, 12 mmol) in THF (30 mL) was cooled to 0 °C under a
blanket of N2. A solution of â-keto ester 9a (1.56 g, 10 mmol)
dissolved in THF (5 mL) was added slowly and the solution
was allowed to stir for 30 min until the suspension became a
clear yellow solution. The solution was cooled to -15 °C and
n-BuLi (1.3 M in hexanes, 9.2 mL, 12 mmol) was added slowly
and allowed to stir for an additional 20 min after which time
5-bromo-1-pentene (1.3 mL, 11 mmol) was added. The solution
was allowed to warm to room temperature and stirred over-
night. The resulting thick suspension was quenched with sat.
aqueous NH4Cl (30 mL) and washed successively with D.I. H2O
(30 mL) and brine (30 mL). The organic layer was separated
and the combined aqueous washings were extracted with Et2O
(3 × 20 mL). The combined organic extracts were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was
chromatographed on silica (15:1, hexanes/ethyl acetate; Rf
1
as a yellow oil. H NMR (500 MHz, CDCl3) δ 6.45 (d, 1H, J )
1
0.23) to yield 1.53 g (68%) of 10c as a clear oil. H NMR (500
12.7 Hz), 6.02 (d, 1H, J ) 12.7 Hz), 4.21-4.19 (m, 2H), 2.62-
2.60 (m, 2H), 1.76-1.71 (m, 2H), 1.69-1.64 (m, 2H), 1.52-
1.44 (m, 4H), 1.37-1.33 (m, 4H); 13C NMR (125 MHz, CDCl3)
δ 202.7, 165.8, 139.3, 126.5, 66.5, 40.8, 26.3, 26.1, 26.0, 25.1,
24.5, 21.0; HRMS (CI, NH3) [M + NH4]+ calcd for C12H22NO3
228.1594, found 228.1601.
MHz, CDCl3) keto form δ 5.83-5.73 (m, 2H), 5.10-4.94 (m,
4H), 4.19 (t, 2H, J ) 6.8 Hz), 3.43 (s, 2H), 2.56-2.53 (m, 2H),
2.43-2.39 (m, 2H), 2.08-2.04 (m, 2H), 1.64-1.61 (m, 2H),
1
1.45-1.37 (m, 2H); H NMR (500 MHz, CDCl3) visible reso-
nances corresponding to enol form include δ 2.22-2.19 (m);
13C NMR (125 MHz, CDCl3) keto and enol resonances δ 202.7,
167.4, 138.5, 134.1, 133.9, 117.6, 114.9, 89.2, 64.5, 63.2, 49.4,
43.0, 35.1, 33.6, 33.3, 33.1, 28.4, 25.9, 23.1; HRMS (CI, NH3)
[M + NH4]+ calcd for C13H24NO3 242.1750, found 242.1753.
Z-Oxa cyclod od ec-3-en e-2,5-d ion e (14c). When the above
reaction of 12c was allowed to stir for 10 min after addition of
the DBU, compound 14c was the sole product and was isolated
in 56%.
Oxa cyclod od ec-9-en e-2,4-d ion e (11c). To a solution of
â-keto ester 10c (236 mg, 1.05 mmol) in dry CH2Cl2 (250 mL)
was added bis(cyclohexylphosphine)benzylidine ruthenium(IV)
dichloride (42 mg, 0.050 mmol). This solution was heated to
reflux for 4 h. The solution was allowed to cool and concen-
trated in vacuo. The residue was chromatographed on silica
(10:1, hexanes/ethyl acetate; Rf 0.20) to yield 143 mg (69%) of
11c as an inseparable 6:1 mixture of E- and Z-isomers,
respectively. 1H NMR (500 MHz, CDCl3) major isomer δ 5.46-
4.42 (m, 1H), 5.35-5.29 (m, 1H), 4.32-4.28 (m, 2H), 3.35 (s,
2H), 2.65-2.62 (m, 2H), 2.44-2.39 (m, 2H), 2.14-2.08 (m, 2H),
1.70-1.64 (m, 2H), 1.55-1.50 (m, 2H); 1H NMR (500 MHz,
CDCl3) visible signals corresponding to minor isomer δ 3.93
(s), 2.53-2.50 (m); 13C NMR (120 MHz, CDCl3) visible signals
corresponding to both E- and Z-isomers δ 202.8, 167.1, 135.3,
132.8, 127.0, 126.5, 64.7, 63.3, 50.7, 50.3, 40.7, 40.5, 33.3, 32.0,
27.6, 26.5, 25.3, 24.4, 23.1, 22.2; IR (film) 2929.6, 2856.0,
E-Oxa cyclod od ec-3-en e-2,5-d ion e (13c). The reaction of
12c is initiated as described above. After treatment with the
saturated sodium thiosulfate solution, the reaction mixture
was diluted with diethyl ether and washed with an aqueous
solution of ammonium chloride. The layers were separated and
the aqueous phase was extracted with diethyl ether. The
combined organic layers were dried over anhydrous sodium
sulfate and concentrated in vacuo. The residue, which con-
tained 15, was dissolved in diethyl ether and brought to -15
°C. To this solution was added DBU (1.2 equiv) and the
mixture was allowed to stir for approximate 1 min. The
mixture was filtered through a plug of silica. The silica plug
was washed with diethyl ether and the filtrate was concen-
trated under reduced pressure at room temperature. Chro-
matography provided 13c as the sole product in 61%
yield.
1743.0, 1713.4; HRMS (CI, NH3) [M + NH4]+ calcd for C11H20
-
(21) Ireland, R. E.; Brown, F. R. J . Org. Chem. 1980, 45, 1868-
1880.
NO3 214.1440, found 214.1437.
J . Org. Chem, Vol. 68, No. 5, 2003 1883

Ronsheim and Zercher
(R)-1-Meth ylp en t-4-en yl 3-Oxo-bu ta n oa te (18). A 250-
mL round-bottom flask was fitted with a 100-mL addition
funnel and purged with N2 for 30 min. The round-bottom flask
was charged with Mg° (1.8 g, 75 mmol), THF (50 mL), and a
crystal of iodine. The addition funnel was charged with allyl
bromide 16 (3.2 mL, 37.5 mmol) and THF (50 mL). A 5-mL
portion of the allyl bromide solution was added and the
magnesium-containing solution was allowed to stir until the
brown color disappeared. After waiting an additional 10 min,
the remaining allyl bromide/THF solution was added dropwise
over a 1-h period. Following completion of the addition, the
mixture was allowed to stir for an additional 1 h. The mixture
was brought to -40 °C and CuI (215 mg, 1.13 mmol) was
added. The resulting light green mixture was allowed to stir
for an additional 10 min, at which time R-propylene oxide (1.05
mL, 15 mmol) in THF (10 mL) was added in a single portion.
The mixture was allowed to warm to -15 °C and allowed to
stir for an additional 2 h. A solution of diketene (2.9 mL, 37.5
mmol) in THF (10 mL) was added dropwise over 15 min. The
solution was allowed to stir for an additional 15 min, then
allowed to stir at 0 °C for an additional 30 min. The solution
was quenched with saturated aqueous ammonium chloride (50
mL). The layers were separated and the organic layer was
washed with H2O (50 mL) and brine (50 mL). The layers were
separated, the combined aqueous layers were extracted with
Et2O (3 × 50 mL), and the combined organic layers were dried
over anhydrous sodium sulfate. The solution was filtered and
concentrated in vacuo. The residue was chromatographed on
silica (15:1, hexanes/ethyl acetate; Rf 0.18) to yield 1.27 g (46%)
of 18 as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 5.80 (tdd,
1H, J ) 6.5, 10.0, 17.0 Hz), 5.05-4.95 (m, 3H), 3.43 (s, 2H),
2.27 (s, 3H), 2.26-2.05 (m, 2H), 1.73 (m, 1H), 1.60 (m, 1H),
mg, 0.047 mmol). Following an additional 8 h at reflux, the
solution was allowed to cool and concentrated in vacuo. The
residue was chromatographed on silica (10:1, hexanes/ethyl
acetate; Rf 0.20) to yield 90 mg (52%) of 20 as a single isomer.
1H NMR (500 MHz, CDCl3) δ 5.37-5.25 (m, 2H), 5.04-4.98
(m, 1H), 3.39 (d, 1H, J ) 11.2 Hz), 3.31 (d, 1H, J ) 11.2 Hz),
2.80 (m, 1H), 2.36-2.24 (m, 3H), 2.11 (m, 1H), 1.96 (m, 1H),
1.73-1.60 (m, 2H), 1.20 (d, 3H, J ) 6.3 Hz); 13C NMR (125
MHz, CDCl3) δ 203.2, 164.7, 133.2, 127.5, 73.8, 54.9, 41.3, 34.9,
32.1, 28.1, 21.7; [R]D -239 (c 0.0155 g/mL, EtOH).
(11R)-11-Meth yloxa cyclou n d eca n e-2,4-d ion e (21). To a
100-mL round-bottom flask containing â-keto lactone 20 (180
mg, 0.92 mmol) in EtOH (10 mL) under a blanket of N2 was
added 10% Pd on carbon (30 mg). The vessel was purged with
hydrogen via a balloon and the nitrogen inlet was removed.
The suspension was allowed to stir at room temperature with
the balloon attached for 4 h. The suspension was then filtered
and concentrated in vacuo to yield 173 mg (95%) of 21 as a
1
clear oil. H NMR (500 MHz, CDCl3) δ 4.99 (m, 1H), 3.41 (d,
1H, J ) 13.7 Hz), 3.37 (d, 1H, J ) 13.7 Hz), 2.69 (ddd, 1H, J
) 3.4, 11.2, 15.6 Hz), 2.40 (ddd, 1H, J ) 3.4, 10.3, 15.6 Hz),
1.92 (m, 1H), 1.78-1.15 (m, 12H); 13C NMR (125 MHz, CDCl3)
δ 203.5, 166.1, 74.2, 52.5, 39.3, 31.1, 24.8, 24.0, 23.2, 22.9, 20.7;
[R]D -100.0 (c 0.0114 g/mL).
(()-(3E)-12-Meth yloxa cyclod od ec-3-en e-2,5-d ion e (5).
A 100-mL round-bottom flask was equipped with a stir bar
and charged with 10 mL of benzene and diethyl zinc (1.0 M in
hexanes, 1.70 mL, 1.70 mmol) under an atmosphere of N2 at
room temperature. Methylene iodide (0.14 mL, 1.73 mmol) was
added and the resulting white suspension was stirred for 10
min. A solution of racemic â-keto lactone 21 (34 mg, 0.17 mmol)
in benzene (5 mL) was added rapidly by syringe and allowed
to stir until the starting material was no longer visible by TLC
(approximately 1.5-2.0 h). Iodine (440, 1.73 mmol) was added
to the reaction mixture in a single portion and allowed to stir
until a pink color persisted for 30 s. A saturated solution of
sodium thiosulfate (20 mL) was added and the mixture was
stirred until the pink color had disappeared. To this solution
was added DBU (0.25 mL, 1.70 mmol) and the mixture was
stirred for 1 min, washed with saturated aqueous ammonium
chloride (25 mL), and extracted with diethyl ether (3 × 25 mL).
The combined organic layers were dried with anhydrous
sodium sulfate and concentrated in vacuo. The residue was
chromatographed on silica (2:1, hexanes/Et2O; Rf 0.22) to yield
1
1.26 (d, 3H, J ) 6.5 Hz); H NMR (500 MHz, CDCl3) visible
resonance corresponding to enol form δ 1.95 (s); 13C NMR (125
MHz, CDCl3) resonances corresponding to keto and enol forms
δ 200.8, 166.9, 137.9, 137.7, 115.3, 115.2, 90.3, 72.0, 70.2, 50.6,
35.3, 35.1, 30.3, 29.8, 21.4, 20.2, 20.0. [R]D -17.1, (c 0.0226
g/mL, EtOH).
(R)-1-Meth ylp en t-4-en yl 3-Oxo-h ep t-6-en oa te (19). A
100-mL round-bottom flask containing a suspension of NaH
(60% in hexanes, 525 mg, 13.1 mmol) in THF (30 mL) was
cooled to 0 °C under a blanket of N2. A solution of â-keto ester
18 (2.19 mg, 11.9 mmol) dissolved in THF (5 mL) was added
slowly and the solution was allowed to stir for 30 min until
the suspension became a clear yellow solution. The solution
was cooled to -15 °C and n-BuLi (2.5 M in hexanes, 5.2 mL,
13.1 mmol) was added slowly. The solution was stirred for an
additional 20 min, at which time allyl bromide (1.13 mL, 13.1
mmol) was added. The solution was allowed to warm to room
temperature and stirred overnight. The resulting thick sus-
pension was quenched with sat. aqueous NH4Cl (30 mL) and
washed successively with D.I. H2O (30 mL) and brine (30 mL).
The organic layer was separated and the combined aqueous
washings were extracted with Et2O (3 × 20 mL). The combined
organic extracts were dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was chromatographed on
silica (20:1, hexanes/ethyl acetate; Rf 0.20) to yield 2.12 g (80%)
of 19 as a clear oil. 1H NMR (500 MHz, CDCl3) δ 5.85-5.75
(m, 2H), 5.07-4.96 (m, 5H), 3.42 (s, 2H), 2.65 (t, 2H, J ) 7.3
Hz), 2.38-2.33 (m, 2H), 2.12-2.06 (m, 2H), 1.73 (m, 1H), 1.59
(m, 1H), 1.25 (d, 3H, J ) 6.3 Hz); 13C NMR (125 MHz, CDCl3)
δ 202.2, 167.0, 137.8, 136.8, 115.8, 115.3, 72.0, 49.9, 42.3, 35.1,
29.8, 27.6, 20.1; IR (film) 2978.8, 2935.5, 1734.8, 1717.4; HRMS
(CI, NH3) [M + NH4]+ calcd for C13H24 NO3 242.1750, found
242.1755; [R]D -13.3 (c 0.011 g/mL, EtOH).
1
24 mg (66%) of 5 as a yellow oil. H NMR (500 MHz, CDCl3)
δ 6.44 (d, 1H, J ) 13.2 Hz), 6.02 (d, 1H, J ) 13.2 Hz), 4.97 (m,
1H), 2.69 (ddd, 1H, J ) 3.4, 7.8, 18.1 Hz), 2.54 (ddd, 1H, J )
3.9, 8.3, 18.1 Hz), 1.82-1.29 (m, 10H), 1.27 (d, 3H, J ) 5.9
Hz); 13C NMR (125 MHz, CDCl3) δ 203.1, 165.5, 139.8, 126.1,
74.8, 40.4, 32.0, 25.0, 24.4, 23.6, 20.6, 19.9.
(+)-(12R)-12-Meth yloxacyclododec-3E-en e-2,5-dion e (4).
A 100-mL round-bottom flask was equipped with a stir bar
and charged with 10 mL of benzene and diethyl zinc (1.0 M in
hexanes, 1.90 mL, 1.90 mmol) under an atmosphere of N2 at
room temperature. Methylene iodide (0.16 mL, 1.94 mmol) was
added and the resulting white suspension was stirred for 10
min. A solution of â-keto lactone 21 (38.6 mg, 0.19 mmol) in
benzene (2.5 mL) was added rapidly by syringe and allowed
to stir until the starting material was no longer visible by TLC
(approximately 1.5 h). Iodine (495 mg, 1.94 mmol) was added
to the reaction mixture in a single portion and allowed to stir
until a pink color persisted for 30 s. A saturated solution of
sodium thiosulfate (20 mL) was added and the mixture was
stirred until the pink color had disappeared. The mixture was
diluted with diethyl ether (20 mL) and washed with an
aqueous solution of ammonium chloride (25 mL). The layers
were separated and the aqueous phase was extracted with
diethyl ether (3 × 25 mL). The combined organic layers were
dried over anhydrous sodium sulfate and concentrated in
vacuo. The residue, which contained 24, was dissolved in
(11R)-11-Meth yloxa cyclou n d ec-7-en e-2,4-d ion e (20). To
a solution of â-keto ester 19 (202 mg, 0.90 mmol) in dry CH2-
Cl2 (250 mL) was added bis(cyclohexylphosphine)benzylidine
ruthenium(IV) dichloride (38 mg, 0.047 mmol). This solution
was heated to reflux for 8 h and additional catalyst was added
(38 mg, 0.047 mmol). Reflux was continued for an additional
8 h, at which time another portion of catalyst was added (38
1884 J . Org. Chem., Vol. 68, No. 5, 2003

Syntheses of (+)-Patulolide A and (()-Patulolide B
diethyl ether (1 mL) and brought to -15 °C. To this solution
was added DBU (0.04 mL, 0.25 mmol) and the mixture was
allowed to stir for approximately 2 min. The mixture was
filtered through a plug of silica. The silica plug was washed
with diethyl ether (3 × 2 mL) and the filtrate was concentrat-
edunder reduced pressure in a water bath that was maintained
at room temperature. Chromatography on silica (2:1, hexanes/
Et2O, Rf 0.19) yielded 3 (19 mg, 48%) as a white solid (mp
80.2-81.4 °C (lit.22 mp 83-84 °C)), [R]D 26.5 (c 0.00204 g/mL,
EtOH); 1H NMR (500 MHz, CDCl3) δ 7.23 (d, 1H, J ) 16.1
Hz), 6.78 (d, 1H, J ) 16.1 Hz), 4.89 (m, 1H), 2.73 (ddd, 1H, J
) 3.4, 10.7, 14.2 Hz), 2.47 (ddd, 1H, J ) 3.4, 10.3, 14.2 Hz),
1.85 (m, 1H), 1.70-1.30 (m, 9H), 1.39 (d, 3H, J ) 6.4 Hz).
Ack n ow led gm en t. We thank the University of New
Hampshire and the National Institutes of Health (R15
GM060967-01) for supporting this work.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for compounds 9a -13a , 9b-13b, 10c-14c, 18-21, 4, and 5.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Sekiguchi, J .; Kuroda, H.; Yamada, Y.; Okada, H. Tetrahedron
Lett. 1985, 26, 2341-2342.
J O0264776
J . Org. Chem, Vol. 68, No. 5, 2003 1885