The synthesis of deoxyfusapyrone. 1. An approach to the pyrone moiety

Article abstract of DOI:10.1021/jo0204707

An effective synthesis of the C1-C10 component of deoxyfusapyrone has been achieved that will allow for the synthesis of both the (R) and (S) form of the C-8 chiral center starting from optically pure (+)- and (-)-3,3-dimethyl-2-hydroxy-gammalactone (pantolactone).

Full text of DOI:10.1021/jo0204707

Th e Syn th esis of Deoxyfu sa p yr on e. 1.
An Ap p r oa ch to th e P yr on e Moiety
Michael G. Organ* and J unquan Wang
Department of Chemistry, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3
organ@yorku.ca
Received J uly 15, 2002
An effective synthesis of the C1-C10 component of deoxyfusapyrone has been achieved that will
allow for the synthesis of both the (R) and (S) form of the C-8 chiral center starting from optically
pure (+)- and (-)-3,3-dimethyl-2-hydroxy-gammalactone (pantolactone).
In tr od u ction
work at alkylating the methyl position via extended
enolate chemistry. However, this did not prove fruitful
in preliminary studies, especially when trying to alkylate
stereoselectively. We also considered an enantioselective
addition of an acetylene unit to an aldehyde (7) but were
concerned about the gem dimethyl next to the aldehyde
affecting both reactivity and selectivity at the carbonyl
site. With these issues in mind, it occurred to us that
starting off with C8 optically pure and already bearing
the alcohol would prove to be a productive approach to
make both enantiomers and to eliminate late-stage
enantioselective transformations. Conveniently, the en-
tire carbon framework of pantolactone (5), which is
available in both (R) and (S) forms, can be manipulated
into carbons 6-9 of 3 to provide both enantiomers of 3.
This approach is the opposite of those that begin with
the pyrone intact as the ring has to be constructed at
the end and this chemistry is discussed herein.
Deoxyfusapyrone (1), a secondary metabolite isolated
from rice cultures of Fusarium semitectum, has demon-
strated pronounced anti-fungal activity against plant
pathogenic and/or mycotoxigenic filamentous fungi.1
Compound 1 is a candidate for biotechnology applications
and has potential as a natural and safe herbicide to
suppress parasite seed germination.2
Structurally, 1 can be divided into three components:
a 4-deoxy glucose moiety, a pyrone component, and a
long-chain polyene fragment. Synthetically, there are a
number of challenges to consider when planning a route
for the preparation of 1. In particular, stereoselective
bond formation between the sp2 carbon of the pyrone (C3)
to the anomeric carbon of the sugar, the bis allylic chiral
center at C13, and the neopentyl/allylic chiral center at
C8 make the preparation of each subsection difficult.
Owing to the complexity of the structure, three of the
seven stereocenters of 1 remain undetermined, which
adds further intrigue to its synthesis. Thus, any proposed
synthetic route would have to be general enough to
facilitate the preparation of all possible diastereomers
of 1 to confirm the relative and absolute stereochemistry
of the compound.
The route that we have proposed for the preparation
of 1 is modular and allows for the parallel synthesis of
all eight diastereomers that arise from unassigned ste-
reocenters 8, 13, and 17 (i.e., the deoxy glucose stereo-
chemistry has been assigned unambiguously).1 The dis-
connections outlined in Figure 1 require the synthesis
of 2, 3, and 4 as the principal building blocks. The alkyne
in 3 will be hydrometalated in situ and connected to 4
by cross-coupling. Metalation of the resultant pyrone
followed by addition to epoxy glycal 2 will provide 1.
Central to this approach is the stereoselective synthesis
of both enantiomers of 3, which is the focus of this paper.
4-Hydroxy-6-methyl-2-pyrone (6) is available inexpen-
sively, thus we were drawn strongly toward trying to
Resu lts a n d Discu ssion
Pantolactone was reductively opened efficiently to triol
8,3 which was then selectively protected under thermo-
dynamic conditions with acid and p-methoxybenzalde-
hyde dimethyl acetal.4 After oxidation,5 the Corey-Fuchs
procedure provided acetylene 11 (Scheme 1).6 At this
stage we attempted selective deprotection of the primary
alcohol to produce the PMB-protected secondary alcohol
using DIBAL-H.7 Despite repeated attempts, we could
not get this reaction to proceed selectively, always
obtaining a mixture of the free primary and secondary
alcohol in a ratio of approximately 1.2:1, respectively.
Ultimately, the free primary alcohol 15 was obtained by
a short series of selective protection/deprotection steps
(Scheme 2).8 We are continuing our efforts in the mean-
(3) Shiina, I.; Shibata, J .; Ibuka, R.; Imai, Y.; Mukaiyama, T. Bull.
Chem. Soc. J pn. 2001, 74, 133-122.
(4) Lokot, I. P.; Pashkovsky, F. S.; Lakhvich, F. A. Tetrehedron 1999,
55, 4783-4792
(1) Evidente, A.; Conti, L.; Altomare, C. Nat. Toxins 1994, 2, 4-13.
(2) (a) Altomare, C.; Perrone, G.; Zonno, M. C. J . Nat. Prod. 2000,
63, 1131-1135. (b) Altomare, C.; Perrone, G.; Zonno, M. C. Cereal Res.
Commun. 1997, 25, 349-351. (c) Zonno, M. C.; Vurro, M. Weed Res.
1999, 39, 15-20.
(5) Mancuso, A. J .; Huang, S. L.; Swern, D. J . Org. Chem. 1978, 43,
2480-2482.
(6) Corey, E. J .; Fuchs, P. L. Tetrehedron Lett. 1972, 36, 3769-3772.
(7) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett.
1983, 1593-1596.
10.1021/jo0204707 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/11/2002
J . Org. Chem. 2002, 67, 7847-7851
7847

Organ and Wang
F IGURE 1. Retrosynthetic analysis of deoxyfusapyrone.
SCHEME 1a
SCHEME 2a
a
Reagents and conditions: (a) 80% HOAc, rt, 2 h;(b) TBDMSCl,
TEA, 4-(dimethylamino)pyridine (DMAP), CH2Cl2, rt; (c) NaH,
THF, then BnBr, rt; (d) TBAF, THF, rt.
a
Reagents and conditions: (a) LAH, THF, 0 °C; (b) PMPCH-
(OMe)2, camphor sulfonic acid, CH2Cl2, rt; (c) DMSO, (COCl)2,
TEA, CH2Cl2, -78 °C to rt; (d) CBr4, PPh3, CH2Cl2, rt; (e) n-BuLi,
THF, -78 °C to rt, then NH4Cl (aq).
â-keto ester 18 was followed by saponification to provide
19 and condensation with 2,2-dimethyl-1,3-dioxane-4,6-
dione (Meldrum’s acid) to yield the critical tetracarbonyl
penultimate compound 20.4
time to selectively open the dioxane ring using other
procedures.9
Oxidation followed by aldol condensation10 provided 17
Thermal rearrangement of 20 in refluxing toluene for
a short period of time selectively yielded carboxylic acid
2111 quantitatively, which upon re-submission to these
reaction conditions decarboxylated providing the desired
protected alcohol 22 in excellent yield (Scheme 4).4
Conveniently, the two steps can be compressed into one
by simply heating for a prolonged period of time. Depro-
tection of 22 would yield 3, although the alcohol would
be kept protected until after the bond connections to 2
and 4 have been established to complete the synthesis
of the various diastereoisomers of 1.
as a mixture of diastereomers (Scheme 3). Formation of
(8) (a) Panek, J . S.; Liu, P. J . Am. Chem. Soc. 2000, 122, 11090-
11097. (b) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979,
20, 99-102.
(9) For a review on the selective deprotection of p-methoxyben-
zylidene acetals, see: Greene, T. W.; Wuts, P. G. M. Protecting Groups
in Organic Synthesis, 2nd ed.; J ohn Wiley and Sons: New York, 1991;
pp 132-134.
(10) Huerta, F. F.; Ba¨ckvall, J .-E. Org. Lett. 2001, 3, 1209-1212.
7848 J . Org. Chem., Vol. 67, No. 22, 2002

The Synthesis of Deoxyfusapyrone. 1
SCHEME 3a
a
Reagents and conditions: (a) DMSO, (COCl)2, TEA, CH2Cl2, -78 °C to rt; (b) LiCH2COOtBu, THF, -78 °C to rt, then NH4Cl (aq); (c)
PCC, NaOAc, CH2Cl2, rt; (d) TFA, CH2Cl2, 0 °C; (e) Meldrum’s acid, TEA, DMAP, DCC, CH2Cl2, rt.
SCHEME 4a
a
Reagents and conditions: (a) reflux, toluene, 1.5 h; (b) reflux, toluene, 30 h; (c) reflux, toluene, 72 h.
Mech a n ist ic Con sid er a t ion s. This last result has
shed new evidence on the mechanism of similar cycliza-
tion/decarboxylation reactions reported in the literature.
Tetracarbonyl compounds resembling 23 (see Figure 2)
were reported to undergo decarboxylation first leading
to dioxinones 244 which are known to be in equilibrium
between the corresponding ketene (25) and acetone.12
Cyclization of the enol onto the ketene moiety would then
provide the pyrone (26) directly. Indeed, when compounds
resembling 24 were prepared by an alternate means,
heating them provided the pyrone, which in this case
proceeds via the corresponding ketene with little doubt.12
The results from the present study suggest that 20 (or
23) is thermally stable toward decarboxylation and it
undergoes concurrent rearrangement and liberation of
acetone with no decarboxylation (via a structure like 27).
However, on prolonged heating, decarboxylation does
take place providing 22 (or 26). This finding has provided
a new and very efficient synthesis of 3-carboxypyrones
and we are presently working to determine the scope of
this synthetic sequence.
In summary, a concise and efficient synthetic route has
been devised to prepare pyrone 22, which has a chiral
alcohol-bearing center on it adjacent to the gem dimethyl
group. This route will allow the synthesis of both the (R)
and (S) isomers of 22 beginning with both isomers of
optically pure pantolactone. The careful isolation of the
3-carboxypyrone 28 has cast doubt on the currently
accepted mechanism for the decarboxylative cyclizations
of tetracarbonyl compounds resembling 23 while provid-
ing an effective entry into the synthesis of 3-carboxypy-
rones.
Exp er im en ta l Section
Gen er a l P r oced u r es. All reactions were carried out under
dry argon unless otherwise indicated. Solvents were distilled
prior to use: Et2O was distilled from sodium benzophenone;
CH2Cl2 was distilled from CaH2. Melting points are uncor-
rected. Proton and carbon NMR spectra were recorded at 400
and 100 MHz, respectively. NMR chemical shifts are listed
relative to CHCl3 (δ 7.24) for 1H NMR and (δ 77.00) for 13C
NMR. All carbon NMR spectra were obtained using the
(11) Kang, J .; Kim, Y. H.; Park, M.; Lee, C. H.; Kim, W.-J . Synth.
Commun. 1984, 14, 265-269.
(12) Bach, T.; Kirsch, S. Synlett 2001, 1974-1976.
J . Org. Chem, Vol. 67, No. 22, 2002 7849

Organ and Wang
F IGURE 2. Mechanism of the cyclization/decarboxylation sequence.
attached proton test (APT) pulse sequence where carbons
attached to an odd number of protons are down (-) and all
other signals are up (+).
3,3-Dim eth ylbu ta n e-1,2,4-tr iol (8), [2-(4-Meth oxyp h e-
n yl)-5,5-d im eth yl-1,3-d ioxa n -4-yl]m eth a n ol (9a ), a n d 2-(4-
Met h oxyp h en yl)-5,5-d im et h yl-1,3-d ioxa n e-4-ca r b a ld e-
h yd e (9b). These compounds were prepared following the
procedure outlined by Lokot and co-workers.4 Spectral data
generated for these compounds compared well with those
reported.
hexane/ethyl acetate) providing 4.19 g of 12 (87% from 10) as
a white solid. Mp 54-56 °C (EtOAc/hexanes); 1H NMR (CDCl3)
δ 4.31 (s, 1H), 3.76 (d, J ) 10.8 Hz, 1H), 3.51 (d, J ) 10.8 Hz,
1H), 2.81 (br s, 2H), 2.51 (d, J ) 1.8 Hz, 1H), 1.06 (s, 3H), 1.02
(s, 3H); 13C NMR (CDCl3) δ 83.1 (+), 74.2 (+), 70.4 (+), 70.1
(-), 39.2 (+), 21.5 (-), 19.7 (-); IR (neat) 3307, 2114 cm-1
.
5-(ter t-Bu t yld im et h ylsila n yloxy)-4,4-d im et h ylp en t -1-
yn -3-ol (13). To a solution of diol 12 (2.05 g, 16 mmol),
TBDMSCl (2.65 g, 17.6 mmol), and DMAP (0.08 g, 0.64 mmol)
in CH2Cl2 (30 mL) was added triethylamine (2.5 mL, 1.78 g,
17.6 mmol) at rt. After being stirred for 16 h, the mixture was
washed successively with water, saturated NH4Cl, and brine.
The organic layer was dried over anhydrous MgSO4 and
filtered, and the solvent was removed in vacuo. Purification
by flash chromatography (hexane:ethyl acetate, 15:1) provided
4-(2,2-Dibr om ovin yl)-2-(4-m eth oxyph en yl)-5,5-dim eth yl-
[1,3]d ioxa n e (10). To a stirred brown suspension of Ph3P
(71.34 g, 272 mmol) and CBr4 (45.1 g, 136 mmol) in CH2Cl2
(150 mL) was added a solution of aldehyde 9b (17.0 g, 68
mmol) in CH2Cl2 (50 mL) at 0 °C. The mixture was stirred for
2 h at rt, diluted with ether, and filtered. The brown solid was
washed with ether. Hexane was added to the filtrate resulting
in additional precipitation. The product was filtered off, the
volume of the mother liquor was reduced, and the flask was
placed in the refrigerator for 16 h resulting in additional
precipitation. This process was repeated twice more providing
27.5 g of 10 in total (96%) as white needles. Mp 77-78 °C
(EtOAc/hexanes); 1H NMR (CDCl3) δ 7.46 (d, J ) 8.1 Hz, 2H),
6.93 (d, J ) 8.1 Hz, 2H), 6.53 (d, J ) 8.5 Hz, 1H), 5.52 (s, 1H),
4.35 (d, J ) 8.6 Hz, 1H), 3.83 (s, 3H), 3.80 (d, J ) 11.6 Hz,
1H), 3.71 (d, J ) 11.6 Hz, 1H), 1.25 (s, 3H), 0.89 (s, 3H); 13C
NMR (CDCl3) δ 160.2 (+), 134.9 (-), 130.6 (+), 127.6 (-), 113.8
(-), 101.9 (-), 93.5 (+), 85.0 (-), 78.5 (+), 55.3 (-), 34.1 (+),
21.4 (-), 19.4 (-). Anal. Calcd for C15H18Br2O3: C, 44.36; H,
4.47. Found: C, 44.67; H, 4.58.
4-E t h yn yl-2-(4-m e t h o xy p h e n y l)-5,5-d im e t h y l[1,3]-
d ioxa n e (11). To a stirred solution of 10 (15.28 g, 37.64 mmol)
in THF (120 mL) was added n-BuLi (82.8 mmol, 2.2 equiv,
1.5 M solution in hexanes) at -78 °C. The mixture was allowed
to reach rt over a period of 2 h where it was stirred for 0.5 h.
A saturated NH4Cl solution was added and the mixture was
extracted into ether (2×). The combined organic layer was
washed with brine, dried over anhydrous MgSO4, and filtered.
The solvent was removed in vacuo to give the crude 11 as a
light yellow solid that underwent ketal hydrolysis without
further purification.
1
3.15 g of 13 (81%) as a colorless oil. H NMR (CDCl3) δ 4.20
(d, J ) 5.8 Hz, 1H), 3.76 (d, J ) 9.7 Hz, 1H), 3.75 (s, 1H), 3.39
(d, J ) 9.8 Hz, 1H), 2.42 (s, 1H), 1.02 (s, 3H), 0.93 (s, 3H),
0.89 (s, 9H), 0.06 (s, 6H); 13C NMR (CDCl3) δ 83.5 (+), 73.4
(+), 71.0 (+), 70.4 (-), 39.0 (+), 25.8 (-), 21.6 (-), 20.2 (-),
18.1 (+), -5.7 (-); IR (neat) 3464, 3312, 2114 cm-1
.
(3-Ben zyloxy-2,2-d im et h ylp en t -4-yn e)-1-ter t-b u t yld i-
m eth ylsila n e (14). To a suspension of NaH (0.20 g, 5.0 mmol,
60% suspension in mineral oil) in THF (5 mL) was added a
solution of 13 (1.10 g, 4.52 mmol) in THF (8 mL) at 0 °C. After
the solution was stirred for 0.5 h, benzyl bromide (0.70 mL,
1.01 g, 5.89 mmol) and DMF (3 mL) were added and the
mixture was stirred for 16 h at rt. Saturated NH4Cl solution
(30 mL) was added and the mixture was extracted with ether
(3×). The combined organic solutions were washed with brine,
dried over anhydrous MgSO4, and filtered. Following solvent
removal in vacuo, the crude material was directly desilylated.
3-Ben zyloxy-2,2-d im eth ylp en t-4-yn -1-ol (15). To a solu-
tion of crude 14 in THF (10 mL) was added TBAF (1.0 M in
THF, 6.8 mL) at rt. After the mixture was stirred for 16 h,
saturated NH4Cl was added and the solution was extracted
with ether (2×). The combined ether extracts were washed
with brine, dried over anhydrous MgSO4, and filtered. The
solvent was removed in vacuo and the product was purified
by flash chromatography (hexane:ethyl acetate, 8:1) to provide
1
901 mg of 15 (91% from 13) as a clear, colorless oil. H NMR
2,2-Dim eth ylp en t-4-yn e-1,3-d iol (12). Crude alkyne 11
(9.28 g, 37.64 mmol) was dissolved in 80% acetic acid and
stirred for 2 h at rt. The acetic acid was removed in vacuo
and the product was purified by flash chromatography (4:1
(CDCl3) δ 7.39-7.32 (m, 5H), 4.89 (d, J ) 11.8 Hz, 1H), 4.52
(d, J ) 11.8 Hz, 1H), 4.01 (d, J ) 1.4 Hz, 1H), 3.66 (dd, J )
10.9 Hz, 6.0 Hz, 1H), 3.44 (dd, J ) 10.9 Hz, 6.0 Hz, 1H), 2.55
(d, J ) 1.4 Hz, 1H), 2.45 (t, J ) 6.0 Hz, 1H), 1.06 (s, 3H), 1.05
7850 J . Org. Chem., Vol. 67, No. 22, 2002

The Synthesis of Deoxyfusapyrone. 1
(s, 3H); 13C NMR (CDCl3) δ 137.5 (+), 128.5 (-), 128.0 (-),
127.9 (-), 80.7 (+), 76.0 (-), 75.6 (+), 71.1 (+), 70.0 (+), 39.6
(+), 21.8 (-), 20.1 (-); IR (neat) 3424, 3297, 2110 cm-1; HRMS
(EI) calcd for C14H18O2 [M]+ 218.1307, found 218.1297.
3-Ben zyloxy-2,2-d im eth ylp en t-4-yn a l (16). To a stirred
solution of oxalyl chloride (0.20 mL, 0.290 g, 2.29 mmol) in
CH2Cl2 (15 mL) at -78 °C was added DMSO (0.36 mL, 0.390
g, 5.0 mmol) dropwise. The mixture was stirred for 0.5 h after
which 15 (0.453 g, 2.08 mmol) in CH2Cl2 (15 mL) was added
via cannula. After the solution was stirred for 40 min,
triethylamine (0.87 mL, 0.632 g, 6.24 mmol) was added and
the mixture was allowed to warm to rt over 2 h. Water (30
mL) was added and the phases were separated. The organic
layer was washed with brine (2×), dried over anhydrous
MgSO4, and filtered. The solvent was removed in vacuo and
the crude product was purified by flash chromatography
(hexane:ethyl acetate, 5:1) to provide 415 mg of 16 (92%) as a
5-(1,3-D io x o -4,4-d im e t h y l-5-b e n zy lo x y -6-y n e )-2,2-
d im eth yl[1,3]d ioxa n e-4,6-d ion e (20). To a solution of Mel-
drum’s acid (157 mg, 1.092 mmol), DMAP (38 mg, 0.312 mmol),
and DCC (225 mg, 1.092 mmol) in CH2Cl2 (1 mL) was added
a solution of 19 (285 mg, 1.04 mmol) in CH2Cl2 (4 mL). The
mixture was stirred for 16 h at rt, diluted with ether (10 mL),
and filtered. The white solid was washed with ether and the
combined organic solution was washed successively with 5%
HCl, water, and brine and then dried over anhydrous MgSO4.
Following filtration, the solvent was removed in vacuo provid-
ing essentially pure 20 (359 mg, 86% yield). The product was
re-crystallized from ether/pentane (298 mg, 71% yield) as a
yellow solid. 1H NMR (CDCl3) δ 15.0 (br s, 1H), 7.37-7.31 (m,
5H), 4.83 (d, J ) 11.6 Hz, 1H), 4.50 (d, J ) 11.4 Hz, 1H), 4.44
(d, J ) 16.2 Hz, 1H), 4.29 (s, 1H), 4.19 (d, J ) 16.4 Hz, 1H),
2.58 (d, J ) 1.3 Hz, 1H), 1.76 (s, 6H), 1.42 (s, 3H), 1.30 (s,
3H); 13C NMR (CDCl3) APT, δ 205.6 (+), 190.3 (+), 170.0 (+),
160.6 (+), 137.1 (+), 128.4 (-), 128.2 (-), 127.9 (-), 105.4 (+),
93.7 (+), 79.6 (+), 76.3 (+), 74.5 (-), 71.3 (+), 52.3 (+), 47.3
(+), 26.9 (-), 22.0 (-), 19.3 (-); IR (neat) 3286, 2113, 1739,
1
clear oil. H NMR (CDCl3) δ 9.63 (s, 1H), 7.40-7.32 (m, 5H),
4.87 (d, J ) 11.9 Hz, 1H), 4.53 (d, J ) 11.9 Hz, 1H), 4.22 (s,
1H), 2.60 (s, 1H), 1.27 (s, 3H), 1.15 (s, 3H); 13C NMR (CDCl3)
δ 203.9 (-), 137.3 (+), 128.4 (-), 128.0 (-), 127.9 (-), 79.3 (+),
76.5 (+), 72.8 (-), 71.0 (+), 50.0 (+), 19.3 (-), 17.3 (-); IR (neat)
3287, 2873, 2720, 2113, 1729 cm-1; HRMS (EI) calcd for
1717 cm-1
.
6-(2-Ben zyloxy-1,1-d im et h ylb u t -3-yn yl)-4-h yd r oxy-2-
oxo-2H-p yr a n -3-ca r boxylic Acid (21). A solution of 20 (78
mg, 0.195 mmol) in dry toluene (4 mL) was heated under reflux
for 1.5 h and then cooled to rt. The solvent was removed in
vacuo to provide essentially pure product that was purified
by re-crystallization from ether/pentane to provide 66 mg of
21 (99%) as a white powder. Mp 90-92 °C dec; 1H NMR
(CDCl3) δ 13.92 (s, 1H), 12.58 (br s, 1H), 7.33-7.21 (m, 5H),
6.30 (s, 1H), 4.81 (d, J ) 12.0 Hz, 1H), 4.46 (d, J ) 12.1 Hz,
1H), 4.35 (d, J ) 1.3 Hz, 1H), 2.58 (d, J ) 1.6 Hz, 1H), 1.45 (s,
3H), 1.37 (s, 3H); 13C NMR (CDCl3) δ 178.0 (+), 174.1 (+), 171.2
(+), 165.8 (+), 136.8 (+), 128.5 (-), 128.1 (-), 128.0 (-), 101.5
(-), 90.7 (+), 79.1 (+), 76.6 (+), 72.9 (-), 71.1 (+), 45.1 (+),
22.8 (-), 20.0 (-); IR (neat) 3288, 3200-2400 (br), 2114, 1713,
1669 cm-1; HRMS (EI) calcd for C19H18O6 [M]+ 342.108, found
342.108.
C
14H16O2 [M]+ 215.1072, found 215.1097.
ter t-Bu tyl 5-Ben zyloxy-3-h yd r oxy-4,4-d im eth ylh ep t-6-
yn oa te (17). To a solution of diisopropylamine (0.54 mL, 0.39
g, 3.85 mmol) in THF (5 mL) was added n-BuLi (1.5 M in
hexane, 2.6 mL, 3.85 mmol) dropwise at -78 °C. After 10 min,
tert-butyl acetate was added and the mixture was stirred for
40 min after which a solution of 16 (0.756 g, 3.50 mmol) in
THF (5 mL) was added via cannula. The mixture was allowed
to warm to rt slowly at which time a solution of saturated NH4-
Cl was added. The mixture was extracted with ether and the
combined organic layers were washed with brine and dried
over anhydrous MgSO4. Following filtration, the solvent was
removed in vacuo and the crude material was purified by flash
chromatography (hexane:ethyl acetate, 10:1) to give 1.14 g of
17 (98%) as a colorless oil. This material was used directly in
1
the next step with no further purification. H NMR (CDCl3) δ
6-(2-Ben zyloxy-1,1-d im eth ylbu t-3-yn yl)-4-h yd r oxyp y-
r a n -2-on e (22). A solution of 20 (69 mg, 0.173 mmol) in dry
toluene (5 mL) was heated under reflux for 72 h and then
cooled to rt. The solvent was removed in vacuo to provide
essentially pure product that was purified by re-crystallization
from ether/pentane to provide 47 mg of 22 (92%).
7.38-7.31 (m), 4.87 (d), 4.51 (d), 4.52-4.13 (m), 3.36 (d), 3.18
(d), 2.53 (s), 2.39-2.29 (m), 1.49 (s), 1.09 (s), 1.02 (s), 0.99 (s),
0.98 (s); HRMS (EI) calcd for C20H28O4 [M + H]+ 333.2066,
found 333.2069.
ter t-Bu tyl 5-Ben zyloxy-4,4-dim eth yl-3-oxoh ept-6-yn oate
(18). A mixture of 17 (0.446 g, 1.343 mmol), sodium acetate
(0.1 g), and PCC (1.74 g, 8.06 mmol, 6 equiv) in CH2Cl2 (20
mL) was stirred for 16 h at rt and then diluted with ether (20
mL). The solution was decanted out of the flask and passed
through a short column of Florisil. The column was flushed
with ether and the eluent pooled. Following solvent removal
in vacuo, the product was purified by flash chromatography
(hexane:ethyl acetate, 15:1) to afford 264 mg of 18 (60%) as a
colorless oil. The reaction was very clean and unreacted
â-hydroxyester 17 (0.135 g, 30% recovered) was readily
recovered. 1H NMR (CDCl3) δ 12.51 (s, 1H), 7.34 (br s, 5H),
4.81 (d, J ) 11.6 Hz, 1H), 4.48 (d, J ) 11.2 Hz, 1H), 3.48 (s,
2H), 2.55 (s, 1H), 1.48 (s, 9H), 1.35 (s, 3H), 1.22 (s, 3H).
5-Ben zyloxy-4,4-d im eth yl-3-oxoh ep t-6-yn oic Acid (19).
Trifluoroacetic acid (1.5 mL) was added to a stirred solution
of 18 (0.450 g, 1.364 mmol) in CH2Cl2 (3 mL) at 0 °C. After
the mixture was stirred for 2.5 h, a solution of saturated
sodium bicarbonate was added dropwise until the bubbling
subsided. A saturated NH4Cl solution (10 mL) was added to
keep the mixture mildly acidic and the mixture was extracted
with ether (3×). The combined organic layers were washed
with brine (2×), dried over anhydrous MgSO4, and filtered.
Following solvent removal in vacuo, the crude product (285
mg, 76%) was collected and used in the next step with no
Pyrone 22 was also obtained from compound 21 by decar-
boxylation. A solution of 21 (25 mg, 0.073 mmol) in dry toluene
(3 mL) was heated under reflux for 24 h and then cooled to rt.
The solvent was removed to provide essentially pure product
that was purified by re-crystallization from ether/pentane to
provide 21 mg of 22 (95%) as light yellow prisms. Mp 123-
1
125 °C (CHCl3/hexanes); H NMR (CDCl3) δ 11.08 (br s, 1H),
7.32-7.21 (m, 5H), 6.16 (s, 1H), 5.63 (s, 1H), 4.80 (d, J ) 11.9
Hz, 1H), 4.47 (d, J ) 11.8 Hz, 1H), 4.36 (d, J ) 0.5 Hz, 1H),
2.52 (s, 1H), 1.40 (s, 3H), 1.33 (s, 3H); 13C NMR (CDCl3) δ 172.4
(+), 169.9 (+), 167.6 (+), 137.2 (+), 128.4 (-), 127.9 (-), 127.8
(-), 101.3 (-), 90.1 (-), 79.7 (+), 76.1 (+), 73.4 (-), 71.2 (+),
44.2 (+), 22.7 (-), 20.3 (-); IR (neat) 3293, 3032, 2113, 1690.
Anal. Calcd for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.15;
H, 6.37.
Ack n ow led gm en t. This work was supported by
funding from NSERC Canada and the Ontario Research
and Development and Challenge Fund.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
10, 12, 13, 15-22 and 13C NMR spectra for 10, 12, 13, 15, 16,
20-22. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
further purification. H NMR (CDCl3) δ 12.12 (s, 1H), 7.39-
7.33 (m, 5H), 4.83 (d, J ) 11.6 Hz, 1H), 4.51 (d, J ) 11.6 Hz,
1H), 4.38 (s, 1H), 3.63 (d, J ) 3.2 Hz, 2H), 2.60 (s, 1H), 1.38
(s, 3H), 1.25 (s, 3H).
J O0204707
J . Org. Chem, Vol. 67, No. 22, 2002 7851