1,2-Dioxines containing tethered hydroxyl functionality as convenient precursors for pyran syntheses

Article abstract of DOI:10.1021/jo050806n

A new method for the construction of tetrahydropyrans derived from readily available 1,2-dioxines containing a tethered hydroxyl moiety is described. The reaction proceeds via a base-catalyzed rearrangement of the 1,2-dioxines to either the isomeric cis or trans γ-hydroxy enones followed by intramolecular oxa-Michael addition of the tethered hydroxyl group.

Full text of DOI:10.1021/jo050806n

1,2-Dioxines Containing Tethered Hydroxyl Functionality as
Convenient Precursors for Pyran Syntheses
Thomas D. Avery,† Daniela Caiazza,† Julie A. Culbert,† Dennis K. Taylor,*,† and
Edward R. T. Tiekink‡
Department of Chemistry, The University of Adelaide, South Australia 5005, Australia, and
School of Science, Griffith University, Nathan, Queensland 4111, Australia
dennis.taylor@adelaide.edu.au
Received April 20, 2005
A new method for the construction of tetrahydropyrans derived from readily available 1,2-dioxines
containing a tethered hydroxyl moiety is described. The reaction proceeds via a base-catalyzed
rearrangement of the 1,2-dioxines to either the isomeric cis or trans γ-hydroxy enones followed by
intramolecular oxa-Michael addition of the tethered hydroxyl group.
Introduction
Pyrans represent an important structural motif in
many significant biologically active compounds with
many groups tackling their sytheses.1 Examples include
simple pyrans, represented by (+)-decarestrictine L, an
inhibitor of cholesterol biosynthesis,2 and the relatively
complex antimitotic macrolide spongistatin 1,3 Figure 1.
Primarily, our research group has focused on the
chemistry of monocyclic 1,2-dioxines 1 and the rear-
rangements that this class of compounds undergo. One
important base-catalyzed rearrangement, which is known
as the Kornblum-De La Mare reaction, converts 1,2-
dioxines 1 into cis γ-hydroxy enones 2 through removal
of the most acidic proton adjacent the O-O linkage,
Scheme 1.4 We have found that these enones are excep-
tional conjugate acceptors. They undergo facially selective
FIGURE 1. Examples of pyran-containing natural products.
1,4-addition with both carbon-centered nucleophiles such
as stabilized ylides,5 phosphonates,6 malonates7 and also
oxygen-centered nucleophiles when catalyzed by a suit-
able base.8 cis-γ-Hydroxy enones are, however, sus-
* To whom correspondence should be addressed. Phone: (+61) 8
8303 5494. Fax: (+61) 8 83034358.
† The University of Adelaide.
(4) Kimber, M. C.; Taylor, D. K. Trends Org. Chem. 2001, 9, 53.
(5) (a) Avery, T. D.; Haselgrove, T. D.; Rathbone, T. J.; Taylor, D.
K.; Tiekink, E. R. T., Chem. Commun. 1998, 333. (b) Palmer, F. N.;
Taylor, D. K., J. Chem. Soc., Perkin Trans. 1 2000, 1323. (c) Avery, T.
D.; Taylor, D. K.; Tiekink, E. R. T., J. Org. Chem. 2000, 65, 5531. (d)
Avery, T. D.; Greatrex, B. W.; Taylor, D. K.; Tiekink, E. R. T., J. Chem.
Soc., Perkin Trans. 1 2000, 1319. (e) Avery, T. D.; Fallon, G.; Greatrex,
B. W.; Pyke, S. M.; Taylor, D. K.; Tiekink, E. R. T., J. Org. Chem. 2001,
66, 7955. (f) Avery, T. D.; Jenkins, N. F.; Kimber, M. C.; Lupton, D.
W.; Taylor, D. K. Chem. Commun. 2002, 28.
(6) Kimber, M. C.; Taylor, D. K., J. Org. Chem. 2002, 67, 3142.
(7) Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Fallon, G.; Tiekink,
E. R. T. J. Org. Chem. 2002, 67, 5307.
(8) Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Tiekink, E. R. T.
J. Org. Chem. 2003, 68, 4239.
‡ Griffith University.
(1) Recent THP syntheses: (a) Clarke, P. A.; Martin, W. H. C.;
Hargreaves, J. M.; Wilson, C.; Blake, A. J. Chem. Commun. 2005, 1061.
(b) Alonso, D.; Perez, M.; Gomez, G.; Covelo, B.; Fall, Y. Tetrahedron
2005, 61, 2021 (c) Trost, B. M.; Rhee, Y. H. Org. Lett. 2004, 6, 4311.
(d) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 9536. Recent reviews: (e) Elliott, M.; Williams, E. J. Chem. Soc.,
Perkins Trans. 1 2001, 2303. (f) Elliott, M. J. Chem. Soc., Perkins
Trans. 1 2002, 2301.
(2) Grabley, S.; Hammann, P.; Hutter, K.; Kirsch, R.; Kluge, H.;
Thericke, R. J. Antibiot. 1992, 45, 1176.
(3) Paterson, I.; Chen, D.; Coster, M.; Acena, J.; Bach, J.; Gibson,
K.; Keown, L.; Oballa, R.; Trieselmann, T.; Wallace, D.; Hodgson, A.;
Norcross, R. Angew. Chem., Int. Ed. 2001, 40, 4055.
10.1021/jo050806n CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/21/2005
8344
J. Org. Chem. 2005, 70, 8344-8351

1,2-Dioxines as Convenient Precursors for Pyran Syntheses
SCHEME 1
gave the free alcohols 9 in excellent yield. The resultant
1,3-dienes 5 and 9 were subjected to photooxidation in
the presence of rose bengal bis(triethylammonium) salt
to yield the 1,2-dioxines 10a-g in yields ranging from
23 to 70%, Scheme 2.10
When 10a was allowed to react with an equimolar
amount of lithium hydroxide in THF, pyrans 12a and
13a were formed in 51% and 21% isolated yield, respec-
tively, Scheme 3, thus verifying the hypothesis. None of
the 1,4-diketone 14a was detectible under these condi-
tions, which is consistent with our previous observations
that mild amine bases effectively catalyze the rearrange-
ment of cis γ-hydroxy enones into 1,4-diketones5c while
hydroxide and alkoxide bases promote dimerization of cis
γ-hydroxy enones into THFs if no tethered hydroxyl
grouping is present.8
The structure and stereochemistry of 12a and 13a were
unambiguously elucidated through a combination of 1H,
13C, gCOSY, gHMBC, gHSQC, and ROESY NMR experi-
ments and further confirmed through the X-ray crystal
structure of 12a. Pyran 13a was acid sensitive and
underwent quantitative rearrangement to give furan 18a
when dissolved in CDCl3. Pyran 12a was also trans-
formed into furan 18a when allowed to react with
p-toluenesulfonic acid. Pyran 12a was found not to
interconvert to 13a or decompose over the reaction time
period when resubjected to the reaction conditions.
SCHEME 2
To avoid this furanization of the pyran products, the
hydroxyl groups within 12a and 13a were acetylated in
excellent yield, Scheme 3, and the resultant pyran
acetates 15a and 16a were found to be stable to acid,
which indicated the importance of the hydroxyl group in
the rearrangement to furan. Mechanistically, furaniza-
tion proceeds through isomeric hemiacetal formation,
which is prevented by acetylation. Elimination of water
followed by aromatization yields the 2,5-disubstituted
furan 18a. This mechanism also explains the greater
reactivity of the cis-substituted pyran (13a) toward
furanization.
To extend and investigate the cyclization reaction
further, 1,2-dioxines 10b-f were also allowed to react
with LiOH and the products acetylated to furnish pyrans
15 and 16, Table 1, entries 2-6, Scheme 3. In nearly all
cases, lithium hydroxide favored the formation of the
trans pyrans 15. Of note was the lack of pronounced
influence that the substitution of the tethered hydroxyl
moiety had on the reaction outcome, compare entries 1
and 5. Moreover, switching to the use of NaOH had little
effect on product outcome, entries 1 and 7.
To further examine the influence of different bases on
reaction outcome, 1,2-dioxines 10a-f were allowed to
react with a catalytic amount of DABCO and the products
acetylated, Table 2. When catalyzed by DABCO, signifi-
cant amounts of 1,4-diketone 17 were observed in the
reaction mixtures and the major product was now found
to be the cis pyrans 16, which is in direct contrast to when
LiOH was employed above. Pyran formation was maxi-
mized and 1,4-diketone minimized when chloroform was
used as the reaction solvent. Pyran 12a was found not
ceptible to further rearrangement to furans under acidic
and neutral conditions and 1,4-diketones when amine
bases are employed. In the presence of hydroxide, self-
condensation occurs to form THFs with no competing 1,4-
diketone formation, Scheme 1.8
Thus, the ubiquity of pyrans in nature and these
previous discoveries moved us to examine whether, by
tethering a hydroxyl grouping to 1,2-dioxines, function-
alized oxygen containing heterocycles such as 3-hydroxy
pyrans could potentially be generated in a stereospecific
manner, Scheme 1. This report describes the synthesis
of the precursor hydroxyl containing 1,2-dioxines and a
domino Kornblum-De La Mare/intramolecular oxa-
Michael ring closure (OMIRC) reaction for the generation
of 3-hydroxypyrans.
Results and Discussion
To investigate this approach and to evaluate the effect
of substituents about the hydroxyl terminus a series of
1,2-dioxines 10a-g were synthesized, Scheme 2. Thus,
Wittig reaction of the phosphorane, generated from the
phosphonium salt 3 using potassium tert-butoxide with
hemiacetals 4, yielded the requisite 1,3-dienes 5 in
moderate yields, 52-64%. 1,3-Dienes 8 were synthesized
in good overall yields (70-86%) through Wittig reaction
of phosphorane, generated from phosphonium salt 79
using n-BuLi, with aldehydes 6. Deprotection with TBAF
(9) Merlic, C. A.; Aldrich, C. C.; Albanese-Walker, J.; Saghatelian,
A.; Mammen, J. J. Org. Chem. 2001, 66, 129
(10) Matsumoto, M.; Dobiasshi, S.; Kuroda, K.; Kondo, K. Tetrahe-
dron 1985, 41, 2147.
J. Org. Chem, Vol. 70, No. 21, 2005 8345

Avery et al.
SCHEME 3
TABLE 1. Formation of Pyrans 15 and 16 from
1,2-Dioxines 10 and LiOH
TABLE 3. Formation of Pyrans 15 and 16 from
trans-γ-Hydroxy Enones 11 and LiOH
entry
1,2-dioxine
product ratio 15:16a (% isolated yield)
product ratio 15:16a
entry
trans γ-hydroxy enone
(% isolated yield)b
1b
2b
3b
4b
5b
6b
7c
10a
10b
10c
10d
10e
10f
64 (46):36 (18)
71 (41):29 (11)
73 (55):27 (21)
36 (17):64 (40)
74 (38):26 (14)
40:60
1
2
3
4
5
6
11a
11b
11c
11d
11e
11f
82:18
86 (66):14 (10)
81 (54):19 (15)
80 (46):20 (7)
79:21
10a
75:25
80:20
a Ratio determined by 1H NMR spectra (300 MHz) of the crude
reaction mixtures. b Reactions performed in THF using 1 equiv of
LiOH with a concentration of 0.1 M with respect to 10. c Reactions
performed in THF using 1 equiv of NaOH with a concentration of
0.1 M with respect to 10.
a Ratio determined by 1H NMR spectra (300 MHz) of the crude
reaction mixtures. b Reactions performed in THF using 1 equiv of
LiOH with a concentration of 0.1 M with respect to 11.
SCHEME 4
TABLE 2. Formation of Pyrans 15 and 16 from
1,2-Dioxines 10 and DABCO
product ratio 15:16:17a
entry
1,2-dioxine
solvent
(% isolated yield)b
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
THF
6:56:38
2 (1):55 (22):43 (25)
4 (3): 67 (39):29 (17)
<1:63 (47):37 (24)
0:6:94
0:19:81
10a
10a
6:15:79
acetone
30:24:46
Examination of pyran formation from the base-
catalyzed cyclization of hydroxyl-tethered trans γ-sub-
stituted R,â-unsaturated esters by Gung et al.12 and
Mart´ın et al.13 (Scheme 4) has provided us with a basis
on which to build a rationalization of our results.
Gung et al. have found that the nature of the protecting
group on the γ-hydroxyl moiety influences which is the
most stable ground state (GS) conformer and, therefore,
dictates the preferred transition state for kinetically
controlled cyclization to cis and/or trans pyrans, Scheme
4 and Figure 2. Additionally, through variation of solvent
and the cation associated with the base, they found that
one can override the GS conformers contribution result-
ing in an altered cis/trans pyran ratio. Consequently, they
have proposed that the use of tighter binding (smaller)
cations and nonpolar solvents (in the presence of a cation)
increase the activation energy required for cyclization by
a Ratio determined by 1H NMR spectra (300 MHz) of the crude
reaction mixtures. b Reactions performed using 0.4 equiv of DAB-
CO with a concentration of 0.1 M with respect to 10.
to interconvert to 13a or decompose over the reaction
time when subjected to DABCO in chloroform. The use
of DABCO with the tertiary alcohols 10e and 10f led to
significant 1,4-diketone formation. This can be attributed
to the lesser nucleophilicity/basicity of the tertiary alcohol
relative to the primary alcohols.
cis-γ-Hydroxy enones may be catalytically isomerized
to the trans isomer by treatment with triphenylphos-
phine.11 Consequently, we also had the opportunity to
investigate pyran outcome when starting from the iso-
meric trans γ-hydroxy enones 11a-f. The use of trans-
γ-hydroxy enones 11a-f as alternative starting materials
generated pyrans 15 and 16 in virtually identical ratios
from each substrate (10a-f) using LiOH in THF, Table
3.
(12) (a) Gung, B. W.; Francis, M. B. J. Org. Chem. 1993, 58, 6177.
(b) Gung, B. W.; Wolf, M. A. J. Org. Chem. 1993, 58, 7038.
(13) (a) Betancort, J. M.; Mart´ın, V. S.; Padro´n, J. M.; Palazo´n, J.
M.; Ram´ırez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570. (b)
Ram´ırez, M. A.; Padro´n, J. M.; Palazo´n, J. M.; Mart´ın, V. S. J. Org.
Chem. 1997, 62, 4584.
(11) (a) Balci, M.; Sutbeyaz, Y. Tetrahedron Lett. 1983, 24, 4135.
(b) Sutbeyaz, Y.; Secen, H.; Balci, M. J. Org. Chem. 1988, 53, 2312. (c)
Sengul, M. E.; Simsek, N.; Balci, M. Eur. J. Org. Chem. 2000, 1359.
8346 J. Org. Chem., Vol. 70, No. 21, 2005

1,2-Dioxines as Convenient Precursors for Pyran Syntheses
FIGURE 2. Transition states contributing to pyran formation.
lowering the HOMO of the nucleophile through coordina-
tion, thus rendering the GS conformational preferences
insignificant due to the activation energy being higher
than that required for rotamer interconversion, Figure
2. Mart´ın et al. expanded on these findings with their
work on related systems depicted within Scheme 4, for
which they used computational techniques to justify their
findings. Instead of considering only the CH- and CX-
eclipsed rotamers as potential GS conformations as Gung
et al.,12a did Mart´ın et al.13 reasoned and subsequently
demonstrated that cation coordination could in fact favor
the noneclipsed rotamers, Figure 2.
It has been proposed that for trans γ-hydroxy R,â-
unsaturated esters the CO eclipsed rotamer is pre-
ferred.14 Consequently, we suggest that this finding may
be extrapolated to our cis/trans γ-hydroxy enone systems
due to similarity in electronics. Therefore, if the CO
eclipsed rotamer of our cis/trans γ-hydroxy enones pre-
domines, then we would expect the “cis” pyrans to
dominate in the absence of small tightly coordinating
cations, Figure 2. Indeed, we observe in all cases “cis”
pyran formation dominating when cyclization was carried
out in the presence of DABCO in chloroform, Table 2.
Exploration of more polar solvents resulted in a gradual
increase in the proportion of “trans” pyran with increased
solvent polarity.
When utilizing LiOH as the base, which has the tightly
coordinating lithium cation, we observe a shift to “trans”
pyran dominance, Table 1. This result is in agreement
with the findings of Mart´ın et al. and suggest that the
cis γ-hydroxy enone is formed primarily from the base
induced ring-opening of 1,2-dioxines 10.4 Predominance
of the “cis” pyran in entries 4 and 6, Table 1, may be a
result of the increased steric bulk or changes in the
electronics of the systems. It is unlikely to be a result of
increased trans γ-hydroxy enone formation as the trans
γ-hydroxy enones favor formation of the “trans” pyrans,
Table 3. The “trans” pyran dominance seen when starting
from the trans γ-hydroxy enones, where the ratio in all
cases was 4:1 (Table 3), is in contradiction to the Mart´ın
et al. model which was validated for a range of X
substituents, Scheme 4. Our findings are further com-
plicated by a number of currently unquantified factors.
First, it is difficult to quantify the amount of pyran
generated from cis γ-hydroxy enone when starting from
1,2-dioxines; it is clear that it has an effect on the pyran
ratio (compare Table 1 to 3). When using 1,2-dioxine 10
as a starting material, cis γ-hydroxy enone is generated
primarily with trans γ-hydroxy enone forming through
(14) Gung, B. W.; Wolf, M. A.; Zhu, Z. J. Org. Chem. 1993, 58, 3350.
J. Org. Chem, Vol. 70, No. 21, 2005 8347

Avery et al.
SCHEME 5
TABLE 4. Formation of Pyrans 19-22
isolated by column chromatography, rather were directly
acetylated in the crude reaction mixture still containing
LiOH, entry 4 Table 4. This alternative approach was
not found to effect the ratios of the resulting pyrans,
compare entries 1 and 4, Table 4. Thus, the stability of
the pyrans in the crude reaction mixture prior to acety-
lation and subsequently on silica during the purification
by column chromatography, was not likely to result in
the discrepancies in the overall pyran ratios observed.
The second explanation was found not to be plausible by
monitoring the DABCO-catalyzed decomposition of 1,2-
dioxine 10g to 1,4-diketone by 1H NMR with both
diastereomers showing equal rates of decomposition. The
third explanation is more plausible as greater variation
in pyran ratio is observed in the reactions where decom-
position to 1,4-diketone predominates, entry 2, Table 4.
In these cases, unequal amounts of the diastereomers of
1,2-dioxine/trans γ-hydroxy enone are being competitively
drawn off to 1,4-diketone as the rates of pyran formation
differ considerably with solvent and base. The discrep-
ancy in the ratio of pyrans observed in entry 3, Table 4,
could also be a function of the formation of trans
γ-hydroxy enone as its synthesis too involves the forma-
tion of 1,4-diketone and to a small extent pyran. The ratio
of cis:trans-substituted pyrans (with respect to acetate
and keto side chains) resulting from each diastereomer
of 10g or 11g give a clear pattern where the dominating
pyran arises from the transition state in which the
stereogenic methyl group is equatorial, overriding any
coordinating effects. This effect was also observed by
Mart´ın et al.13a
To expand the methodology and introduce another
stereogenic center to the pyran synthesis it was realized
that pyran formation would still occur if the 1,2-dioxine
was initially epoxidized.16 Pyran formation would lead
to the introduction of a hydroxyl moiety stereoselectively,
adjacent the aromatic ketone, Scheme 6. Using parent
1,2-dioxine 10a, epoxidation proceeded in excellent yield
using m-CPBA, with only a trace of cyclization product
26 observed.17 Cyclization proceeded in moderate yield
in the presence of PTSA (unoptimized conditions) to give
1,2-dioxine 26, followed by regioselective ring opening of
the peroxide bond in the presence of triethylamine and
protection of the diol afforded diacetate 27 in good yield.
starting
entry material
product ratio 19:20:21:22:23a
base/solvent
(% isolated yield)
1b
2c
3b
4d
10g
10g
11g
10g
LiOH/THF
DABCO/CHCl3
LiOH/THF
LiOH/THF
9 (8):52 (42):37 (29):2 (1):(0)
[23:68:8:1] (24):(34)
13:54:28:5:0
4:51:40:5:0
a Ratio determined by 1H NMR spectra (300 MHz) of the crude
reaction mixtures. b Reactions performed in THF using 1 equiv of
LiOH with a concentration of 0.1 M with respect to 10g or 11g.
c Reactions performed in chloroform using 0.4 equiv of DABCO
with a concentration of 0.1 M with respect to 10g or 11g. d Pyrans
not isolated prior to acetylation.
reversible Michael addition of hydroxide.8 Second, the cis
and trans γ-hydroxy enones have a free OH grouping in
the γ position, which is able to, in both its protonated
and deprotonated forms, coordinate cations. Finally, our
assumption that the similarities in electronic structure
when comparing our keto systems with the ester systems
of Gung et al. and Mart´ın et al. is insignificant may not
be entirely true. Importantly, while a full mechanistic
rationale is yet to be determined, the synthetic utility of
this new reaction has clearly been demonstrated.
1,2-Dioxine 10g was also synthesized in order to
investigate further the influence of substitution on pyran
formation and because this system is also of interest as
it generates pyrans closely resembling (+)-decarestrictine
L. 1,2-Dioxine 10g was generated as a diastereomeric
pair through a similar sequence described in Scheme 2
from phosphonium salt 3 and 5-methyltetrahydro-2-
furanol 4d derived from γ-valerolactone.15 Treatment of
10g and isomeric 11g with base followed by acetylation
generated pyrans 19-22 in a variety of yields, Scheme
5, Table 4. Pyrans 19 and 20 arise from one of the
diastereomers of 1,2-dioxine 10g or trans γ-hydroxy
enone 11g and pyrans 21 and 22 from the other diaste-
reomer. Therefore, one would expect their combined ratio
(19 + 20):(21 + 22) to be almost equal; however, this was
found not to be the case, Table 4. There are several
possible reasons for this: (i) the comparative stability of
each hydroxy pyran isomer (prior to acetylation) in the
reaction mixture and during purification by column
chromatography, (ii) the comparative decomposition rate
of 1,2-dioxine/trans γ-hydroxy enone diastereomers into
1,4-diketone, or (iii) the rate of pyran cyclization. To
address the first case, an experiment identical to that
shown in entry 1, Table 4, was conducted with the
exception that the resulting hydroxy pyrans were not
This latter variation may represent a novel alternative
for the preparation of exotic perhydrofuro[3,2-b]pyran
(16) Martin, D. D.; Marcos, I. S.; Basabe, P.; Romero, R. E.; Moro,
R. F.; Lumeras, W.; Rodriguez, L.; Urones, J. G. Synthesis 2001, 1013.
(17) Greatrex, B. W.; Jenkins, N. F.; Taylor, D. K.; Tiekink, E. R.
T. J. Org. Chem. 2003, 68, 5205.
(15) Paquette, L. A.; Lanter, J. C.; Wang, H.-L. J. Org. Chem. 1996,
61, 1119.
8348 J. Org. Chem., Vol. 70, No. 21, 2005

1,2-Dioxines as Convenient Precursors for Pyran Syntheses
MHz) δ 21.1, 25.2, 29.4, 41.5, 67.8, 72.0, 76.3, 128.3, 128.6,
133.1, 137.2, 170.3, 197.8; EIMS m/z 263 ([M + H]+, 27), 202
(12), 174 (1), 105 (100), 77 (27), 71 (11), 43 (46). Anal. Calcd
for C15H18O4: C, 68.68; H, 6.91. Found: C, 68.04; H, 6.71.
SCHEME 6
(()-(2S,3S)-2-(2-Oxo-2-phenylethyl)tetrahydro-2H-3-
pyranyl acetate (16a): colorless oil; Rf 0.38 (1:3 ethyl acetate/
hexanes); IR (neat) 1732, 1682, 1598, 1581, 1449, 1372, 1243,
1090, 1020 cm-1 1H NMR (600 MHz) δ 1.42-1.46 (m, 1H),
;
1.78-1.84 (m, 1H), 1.87-1.95 (m, 1H), 2.02-2.09 (m, 1H), 2.13
(s, 3H), 2.97 (dd, J ) 16.8, 5.4 Hz, 1H), 3.29 (dd, J ) 16.8, 7.2
Hz, 1H), 3.57 (ddd, J ) 12.6, 11.4, 2.4 Hz, 1H), 3.99-4.02 (m,
1H), 4.19 (ddd, J ) 7.2, 5.4, 1.8 Hz, 1H), 4.96-4.98 (m, 1H),
7.44-7.47 (m, 2H), 7.54-7.57 (m, 1H), 7.93-7.95 (m, 2H); 13
C
NMR (150 MHz) δ 20.5, 21.1, 27.8, 40.6, 68.2, 69.2, 74.4, 128.1,
128.5, 133.2, 137.0, 170.6, 197.3; EIMS m/z 263 ([M + H]+,
71), 202 (52), 174 (5), 105 (71), 77 (51), 71 (34), 43 (100). Anal.
Calcd for C15H18O4: C, 68.68; H, 6.91. Found: C, 68.43; H,
7.02.
skeletons such as those found within herbicidin B and G
and aureonuclemycin.18
(()-(2S,3R)-2-[2-(4-Methoxyphenyl)-2-oxoethyl]tetra-
hydro-2H-3-pyranyl acetate (15b): colorless oil; Rf 0.30 (1:3
ethyl acetate/hexanes); IR (neat) 1732, 1682, 1601, 1576, 1512,
1239, 1172, 1198, 1037 cm-1; 1H NMR (300 MHz) δ 1.45-1.58
(m, 1H), 1.65-1.85 (m, 2H), 1.96 (s, 3H), 2.16-2.25 (m, 1H),
2.97 (dd, J ) 15.6, 3.6 Hz, 1H), 3.15 (dd, J ) 15.6, 8.4 Hz,
1H), 3.42 (ddd, J ) 11.4, 11.4, 3.0 Hz, 1H), 3.85-3.91 (m, 1H),
3.87 (s, 3H), 3.98 (ddd, J ) 9.6, 8.4, 3.6 Hz, 1H), 4.64 (ddd, J
) 10.8, 9.6, 4.5 Hz, 1H), 6.90-6.96 (m, 2H), 7.92-7.97 (m, 2H);
13C NMR (75 MHz) δ 21.0, 25.1, 29.4, 41.1, 55.4, 67.7, 72.0,
76.4, 113.7, 130.4, 130.6, 163.5, 170.2, 196.3; EIMS m/z 292
(M+, 9), 256 (7), 232 (12), 135 (100), 92 (7), 77 (13), 55 (5), 43
(100); HRMS (EI) calcd for C16H20O5 292.1311, found 292.1307.
(()-(2S,3S)-2-[2-(4-Methoxyphenyl)-2-oxoethyl]tetra-
hydro-2H-3-pyranyl acetate (16b): colorless solid; mp 74-
75 °C; Rf 0.15 (1:3 ethyl acetate/hexanes); IR (Nujol) 1725,
1681, 1601, 1578, 1515, 1239, 1216, 1090, 1023 cm-1; 1H NMR
(300 MHz) δ 1.42-1.47 (m, 1H), 1.75-1.99 (m, 2H), 2.03-2.12
(m, 1H), 2.14 (s, 3H), 2.92 (dd, J ) 16.5, 5.4 Hz, 1H), 3.25 (dd,
J ) 16.5, 6.9 Hz, 1H), 3.58 (ddd, J ) 11.7, 11.7, 2.1 Hz, 1H),
3.87 (s, 3H), 3.98-4.04 (m, 1H), 4.18 (ddd, J ) 6.9, 5.4, 1.5
Hz, 1H), 4.96-4.98 (m, 1H), 6.90-6.95 (m, 2H), 7.91-7.96 (m,
2H); 13C NMR (75 MHz) δ 20.5, 21.1, 27.8, 40.2, 55.4, 68.3,
69.4, 74.7, 113.7, 130.2, 130.5, 163.6, 170.6, 195.8; EIMS m/z
292 (M+, 2), 279 (1), 256 (3), 232 (51), 204 (4), 179 (2), 163 (5),
135 (100), 121 (1), 92 (7), 77 (10), 55 (4), 43 (43). Anal. Calcd
for C16H20O5: C, 65.74; H, 6.89: Found: C, 65.69; H, 6.80.
(()-(2S,3R)-2-[2-(4-Bromophenyl)-2-oxoethyl]tetra-
hydro-2H-3-pyranyl acetate (15c): colorless oil; Rf 0.44 (1:3
ethyl acetate/hexanes); IR (neat) 1732, 1682, 1597, 1586, 1571,
1244, 1097, 1039, 1007 cm-1; 1H NMR (300 MHz) δ 1.45-1.58
(m, 1H), 1.67-1.83 (m, 2H), 1.99 (s, 3H), 2.17-2.26 (m, 1H),
2.96 (dd, J ) 15.9, 3.3 Hz, 1H), 3.17 (dd, J ) 15.9, 8.4 Hz,
1H), 3.40 (ddd, J ) 11.4, 11.4, 3.3 Hz, 1H), 3.84-3.90 (m, 1H),
3.95 (ddd, J ) 9.6, 8.4, 3.3 Hz, 1H), 4.63 (ddd, J ) 10.8, 9.6,
4.5 Hz, 1H), 7.58-7.62 (m, 2H), 7.80-7.84 (m, 2H); 13C NMR
(75 MHz) δ 21.1, 25.1, 29.4, 41.4, 67.8, 71.9, 76.3, 128.3, 129.9,
131.9, 136.0, 170.2, 197.0; EIMS m/z 342 ([M + H]+, 3), 340
(3), 282 (15), 280 (16), 185 (61), 183 (58), 157 (6), 142 (7), 97
(11), 71 (15), 50 (4), 43 (100); HRMS (EI) calcd for C15H17O4Br
341.0389, found 341.0389.
Conclusion
Herein, we have presented a novel synthesis of 3-hy-
droxypyrans utilizing 1,2-dioxines with tethered hydroxyl
functionality as masked cis/trans γ-hydroxy enones.
There is a clear preference for “trans” pyran formation
when utilizing LiOH as the base while amine bases such
as DABCO favor “cis” pyran formation. Importantly,
while a full mechanistic rationale is yet to be determined,
the synthetic utility of this new reaction has clearly been
demonstrated.
Experimental Section
General Procedure for LiOH-Mediated Pyran Syn-
thesis. To a 0.1 M solution of 1,2-dioxine or trans γ-hydroxy
enone in THF was added lithium hydroxide (1 equiv) and the
mixture stirred for 2-4 days. The volatiles were removed in
vacuo, and the crude pyrans were then purified by column
chromatography. Pyridine (15 equiv), acetic anhydride (9
equiv), and DMAP (0.2 equiv) were then added to the combined
pyrans, and the solution was stirred overnight. Dichlo-
romethane was then added, the solution was extracted with
water, the organic layer was dried (MgSO4) and filtered, and
the volatiles were removed in vacuo. The crude pyrans were
purified by column chromatography.
General Procedure for DABCO-Mediated Pyran Syn-
thesis. To a 0.1 M solution of 1,2-dioxine or trans γ-hydroxy
enone in chloroform was added DABCO (0.4 equiv) and the
mixture stirred overnight. The volatiles were removed in
vacuo, and the crude pyrans were then purified by column
chromatography. Pyridine (15 equiv), acetic anhydride (9
equiv), and DMAP (0.2 equiv) were then added to the combined
pyrans, and the solution was stirred overnight. Dichlo-
romethane was then added, the solution was extracted with
water, the organic layer was dried (MgSO4) and filtered, and
the volatiles were removed in vacuo. The crude pyrans were
purified by column chromatography.
(()-(2S,3R)-2-(2-Oxo-2-phenylethyl)tetrahydro-2H-3-
pyranyl acetate (15a): colorless oil; Rf 0.25 (1:3 ethyl acetate/
hexanes); IR (neat) 1732, 1683, 1598, 1581, 1449, 1374, 1239,
(()-(2S,3S)-2-[2-(4-Bromophenyl)-2-oxoethyl]tetra-
hydro-2H-3-pyranyl acetate (16c): colorless oil; Rf 0.32 (1:3
ethyl acetate/hexanes); IR (neat) 1732, 1688, 1586, 1568, 1373,
1
1097, 1039 cm-1; H NMR (600 MHz) δ 1.52 (dddd, J ) 12.6,
1243, 1090, 733 cm-1 1H NMR (300 MHz) δ 1.42-1.47 (m,
;
10.8, 10.8, 4.2 Hz, 1H), 1.67-1.71 (m, 1H), 1.73-1.81 (m, 1H),
1.96 (s, 3H), 2.17-2.24 (m, 1H), 3.03 (dd, J ) 16.2, 3.6 Hz,
1H), 3.19 (dd, J ) 16.2, 8.4 Hz, 1H), 3.42 (ddd, J ) 12.0, 12.0,
2.4 Hz, 1H), 3.86-3.90 (m, 1H), 3.99 (ddd, J ) 9.6, 8.4, 3.6
Hz, 1H), 4.64 (ddd, J ) 10.8, 9.6, 4.8 Hz, 1H), 7.44-7.48 (m,
2H), 7.54-7.57 (m, 1H), 7.95-7.97, (m, 2H); 13C NMR (150
1H), 1.75-1.95 (m, 2H), 2.03-2.10 (m, 1H), 2.14 (s, 3H), 2.90
(dd, J ) 16.8, 5.1 Hz, 1H), 3.26 (dd, J ) 16.8, 7.5 Hz, 1H),
3.56 (ddd, J ) 11.7, 11.7, 2.1 Hz, 1H), 3.97-4.02 (m, 1H), 4.16
(ddd, J ) 7.5, 5.1, 1.2 Hz, 1H), 4.94-4.98 (m, 1H), 7.57-7.62
(m, 2H), 7.78-7.82 (m, 2H); 13C NMR (75 MHz) δ 20.4, 21.1,
27.8, 40.6, 68.2, 69.1, 74.4, 128.3, 129.6, 131.8, 135. 7, 170.5,
196.3; EIMS m/z 341 (M+, 65), 283 (53), 282 (59), 281 (56),
280 (54), 185 (100), 183 (100), 169 (7), 143 (26), 104 (4), 97
(18) Newcombe, N. J.; Mahon, M. F.; Molloy, K. C.; Alker, D.;
Gallagher, T. J. Am. Chem. Soc. 1993, 115, 6430.
J. Org. Chem, Vol. 70, No. 21, 2005 8349

Avery et al.
(10), 71 (18), 43 (40); HRMS (EI) calcd for C15H17O4Br
341.0389, found 341.0393.
4.15 (ddd, J ) 9.6, 8.7, 3.6 Hz, 1H),a 4.26 (ddd, J ) 8.1, 5.1,
1.5 Hz, 1H),b 4.81 (ddd, J ) 10.5, 9.6, 4.8 Hz, 1H),a 4.83-4.86
(m, 1H),b 7.31-7.58 (m, 26H),a,b 8.00-8.05 (m, 4H);a,b 13C NMR
(75 MHz) δ 20.9,a 21.1,b 25.5,b 26.5,a 28.6,b 33.8,a 40.9,b 42.1,a
68.5,b 69.5,a 70.8,a 72.6,b 80.2,a 80.4,b 124.6, 124.7, 126.3, 127.1,
127.1, 127.2, 127.8, 128.2, 128.4, 128.5, 128.5, 128.6, 132.9,
133.0, 137.3, 137.5, 141.3, 147.5, 148.3, 170.1,a 170.5,b 197.8,b
198.1;a EIMS m/z 414 (M+, 17), 373 (40), 354 (6), 180 (44), 157
(19), 105 (84), 77 (39), 43 (100). Anal. Calcd for C27H26O4: C,
78.24; H, 6.32. Found: C, 77.96; H, 6.43.
(()-(2R,3S,6R)-6-Methyl-2-(2-oxo-2-phenylethyl)tetra-
hydro-2H-3-pyranyl acetate (19): yield 60 mg, 8%; colorless
oil; Rf ) 0.35 (1:4 ethyl acetate/hexane); IR (neat) 1738, 1687,
1597, 1581, 1449, 1374, 1240, 1042 cm-1; 1H NMR (600 MHz)
δ 1.23 (d, J ) 6.0 Hz, 3H), 1.34 (dddd, J ) 13.2, 6.0, 3.6, 3.6
Hz, 1H), 1.83 (dddd, J ) 13.2, 7.2, 3.6, 3.6 Hz, 1H), 1.92-2.01
(m, 2H), 2.02 (s, 3H), 3.15 (dd, J ) 16.2, 6.0 Hz, 1H), 3,24 (dd,
J ) 16.2, 6.6 Hz, 1H), 4.02 (ddq, J ) 7.2, 6.0, 6.0 Hz, 1H),
4.61 (ddd, J ) 6.6, 6.0, 3.6 Hz, 1H), 4.99 (ddd, J ) 7.2, 3.6, 3.6
Hz, 1H), 7.45-7.48 (m, 2H), 7.55-7.58 (m, 1H), 7.93-7.95 (m,
2H); 13C NMR (150 MHz) δ 18.3, 21.1, 23.5, 27.3, 38.7, 67.6,
67.9, 69.4, 128.1, 128.6, 133.1, 137.1, 170.3, 197.6; EIMS m/z:
277 ([M + H]+, 5), 216 (24), 105 (100), 77 (21), 43 (42); HRMS
(ESI) calcd for C16H20O4 + Na 299.1259, found 299.1263.
(()-(2S,3S,6R)-6-Methyl-2-(2-oxo-2-phenylethyl)tetra-
hydro-2H-3-pyranyl acetate (20): yield 326 mg, 42%; color-
less oil; Rf ) 0.40 (1:4 ethyl acetate/hexane); IR (neat) 1732,
1688, 1597, 1580, 1449, 1244, 1082 cm-1; 1H NMR (600 MHz)
δ 1.20 (d, J ) 6.6 Hz, 3H) 1.48 (dddd, J ) 13.8, 5.4, 3.0, 3.0
Hz, 1H), 1.54 (dddd, J ) 13.8, 13.8, 10.8, 3.0 Hz, 1H), 1.82
(dddd, J ) 14.4, 13.8, 5.4, 3.0 Hz, 1H), 2.05 (dddd, J ) 14.4,
3.0, 3.0, 3.0 Hz, 1H), 2.11 (s, 3H), 3.05 (dd, J ) 16.8, 6.0 Hz,
1H), 3.28 (dd, J ) 16.8, 6.0 Hz, 1H), 3.60 (ddq, J ) 10.8, 6.6,
3.0 Hz, 1H), 4.22 (ddd, J ) 6.0, 6.0, 1.2 Hz, 1H), 4.94 (ddd, J
) 3.0, 3.0, 1.2 Hz, 1H), 7.44-7.47 (m, 2H), 7.54-7.57 (m, 1H),
7.93-7.95 (m, 2H); 13C NMR (150 MHz) δ 21.2, 21.8, 27.7, 28.1,
40.7, 68.5, 74.2, 74.4, 128.1, 128.5, 133.1, 137.1, 170.7, 197.4;
EIMS m/z 277 ([M + H]+, 27), 216 (25), 105 (100), 77 (22), 43
(55). Anal. Calcd for C16H20O4: C, 69.54; H, 7.29. Found: C,
69.23; H, 7.41.
(()-(2R,3S,6S)-6-Methyl-2-(2-oxo-2-phenylethyl)tetra-
hydro-2H-3-pyranyl acetate (21): yield 232 mg, 29%; color-
less oil; Rf ) 0.60 (1:4 ethyl acetate/hexane); IR (neat) 1738,
1690, 1597, 1580, 1449, 1239, 1088, 1039 cm-1; 1H NMR (600
MHz) δ 1.12 (d, J ) 6.6 Hz, 3H), 1.44 (dddd, J ) 13.8, 13.2,
10.8, 4.8 Hz, 1H), 1.55 (dddd, J ) 13.2, 12.0, 10.2, 2.4 Hz, 1H),
1.73 (dddd, J ) 13.8, 4.8, 2.4, 2.4 Hz, 1H), 1.92 (s, 3H), 2.17
(dddd, J ) 12.0, 4.8, 4.8, 4.8 Hz, 1H), 3.02 (dd, J ) 15.6, 4.2
Hz, 1H), 3.18 (dd, J ) 15.6, 7.8 Hz, 1H), 3.54 (ddq, J ) 10.8,
6.6, 2.4 Hz, 1H), 4.05 (ddd, J ) 9.6, 7.8, 4.2 Hz, 1H), 4.60 (ddd,
J ) 10.2, 9.6, 4.8 Hz, 1H), 7.44-7.47 (m, 2H), 7.54-7.57 (m,
1H), 7.95-7.97 (m, 2H); 13C NMR (150 MHz) δ 21.0, 21.2, 29.5,
32.4, 41.8, 72.2, 73.8, 75.8, 128.3, 128.5, 133.0, 137.3, 170.4,
197.9; EIMS m/z 277 ([M + H]+, 33), 216 (65), 105 (100), 77
(25), 43 (68). Anal. Calcd for C16H20O4: C, 69.54; H, 7.29.
Found: C, 69.35; H, 7.39.
(()-(2S,3R)-2-[2-(2-Naphthyl)-2-oxoethyl]tetrahydro-
2H-3-pyranyl acetate (15d): pale yellow oil; Rf 0.28 (1:4 ethyl
acetate/hexanes); IR (neat) 1732, 1682, 1628, 1596, 1578, 1507,
1
1469, 1375, 1238, 1038, 867, 817 cm-1; H NMR (600 MHz) δ
1.54 (dddd, J ) 12.6, 10.8, 10.8, 4.2 Hz, 1H), 1.67-1.72 (m,
1H), 1.74-1.82 (m, 1H), 1.98 (s, 3H), 2.21-2.25 (m, 1H), 3.13
(dd, J ) 15.6, 3.6 Hz, 1H), 3.35 (dd, J ) 15.6, 8.4 Hz, 1H),
3.43 (ddd, J ) 11.4, 11.4, 2.4 Hz, 1H), 3.86-3.91 (m, 1H), 4.05
(ddd, J ) 9.6, 8.4, 3.6 Hz, 1H), 4.70 (ddd, J ) 10.8, 9.6, 4.2
Hz, 1H), 7.53-7.56 (m, 1H), 7.57-7.60 (m, 1H), 7.86 (dd, J )
7.8, 0.6 Hz, 1H), 7.88 (d, J ) 9.0 Hz, 1H), 7.97 (dd, J ) 7.8,
0.6 Hz, 1H), 8.04 (dd, J ) 9.0, 1.8 Hz, 1H), 8.46 (d, J ) 1.2 Hz,
1H); 13C NMR (75 MHz) δ 21.1, 25.1, 29.4, 41.4, 67.8, 72.0,
76.3, 123.9, 126.7, 127.7, 128.4, 128.4, 129.6, 130.1, 132.4,
134.5, 135.5, 170.2, 197.7; EIMS m/z 313 ([M + H]+, 74), 253
(40), 155 (100), 127 (11), 43 (12). Anal. Calcd for C19H20O4: C,
73.06; H, 6.45. Found: C, 72.54; H, 6.60.
(()-(2S,3S)-2-[2-(2-Naphthyl)-2-oxoethyl]tetrahydro-
2H-3-pyranyl acetate (16d): colorless solid; mp 75-76.5 °C;
Rf 0.35 (1:3 ethyl acetate/hexanes); IR (Nujol) 1726, 1677, 1628,
1597, 1578, 1242, 1090 cm-1;1H NMR (600 MHz) δ 1.44-1.47
(m, 1H), 1.80-1.86 (m, 1H), 1.89-1.97 (m, 1H), 2.07-2.11 (m,
1H), 2.15 (s, 3H), 3.09 (dd, J ) 16.8, 5.4 Hz, 1H), 3.43 (dd, J
) 16.8, 7.2 Hz, 1H), 3.59 (ddd, J ) 12.6, 12.0, 3.0 Hz, 1H),
4.00-4.04 (m, 1H), 4.24 (ddd, J ) 7.2, 5.4, 1.8 Hz, 1H), 5.01-
5.03 (m, 1H), 7.53-7.56 (m, 1H), 7.58-7.61 (m, 1H), 7.87 (dd,
J ) 7.8, 0.6 Hz, 1H), 7.88 (d, J ) 9.0 Hz, 1H), 7.96 (dd, J )
7.8, 0.6 Hz, 1H), 8.01 (dd, J ) 9.0, 1.8 Hz, 1H), 8.45 (d, J )
1.2 Hz, 1H); 13C NMR (75 MHz) δ 20.5, 21.2, 27.8, 40.7, 68.3,
69.3, 74.6, 123.8, 126.7, 127.7, 128.4, 128.5, 129.6, 129.9, 132.5,
134.4, 135.6, 170.6, 197.3; EIMS m/z 312 (M+, 4), 252 (6), 155
(100), 127 (26), 43 (23). Anal. Calcd for C19H20O4: C, 73.06; H,
6.45. Found: C, 73.11; H, 6.50.
(()-(2S,3R)-6,6-Dimethyl-2-(2-oxo-2-phenylethyl)tet-
rahydro-2H-3-pyranyl acetate (15e): colorless oil; Rf 0.33
(3:17 ethyl acetate/hexanes); IR (neat) 1740, 1690, 1598, 1581,
1
1449, 1368, 1232, 1093 cm-1; H NMR (600 MHz) δ 1.16 (s,
3H), 1.26 (s, 3H), 1.57-1.74 (m, 3H), 1.94 (s, 3H), 2.00-2.04
(m, 1H), 2.98 (dd, J ) 15.6, 3.6 Hz, 1H), 3.12 (dd, J ) 15.6,
7.8 Hz, 1H), 4.26 (ddd, J ) 10.2, 7.8, 3.6 Hz, 1H), 4.57 (ddd, J
) 10.2, 10.2, 4.8 Hz, 1H), 7.43-7.47 (m, 2H), 7.53-7.56 (m,
1H), 7.94-7.96 (m, 2H); 13C NMR (150 MHz) δ 21.1, 21.5, 26.0,
30.7, 35.4, 42.2, 69.2, 72.2, 72.9, 128.3, 128.5, 132.9, 137.5,
170.4, 198.1; EIMS m/z 291 (M+, 23), 230 (60), 175 (15), 157
(20), 149 (16), 120 (11), 105 (100). Anal. Calcd for C17H22O4:
C, 70.32; H, 7.64. Found: C, 70.40; H, 7.44.
(()-(2S,3S)-6,6-Dimethyl-2-(2-oxo-2-phenylethyl)tet-
rahydro-2H-3-pyranyl acetate (16e): colorless oil; Rf 0.21
(3:17 ethyl acetate/hexanes); IR (neat) 1736, 1687, 1598, 1581,
1
1449, 1366, 1243, 1042 cm-1; H NMR (600 MHz) δ 1.23 (s,
3H), 1.26 (s, 3H), 1.34 (ddd, J ) 13.2, 7.2, 1.2 Hz, 1H), 1.73
(ddd, J ) 13.2, 13.2, 5.4 Hz, 1H), 1.90-1.99 (m, 2H), 2.09 (s,
3H), 3.04 (dd, J ) 16.8, 6.0 Hz, 1H), 3.21 (dd, J ) 16.8, 6.0
Hz, 1H), 4.41 (ddd, J ) 6.0, 6.0, 1.2 Hz, 1H), 4.90-4.92 (m,
1H), 7.43-7.46 (m, 2H), 7.53-7.56 (m, 1H), 7.93-7.96 (m, 2H);
13C NMR (150 MHz) δ 21.2, 21.3, 24.7, 30.6, 31.2, 40.9, 67.7,
68.5, 72.4, 128.1, 128.5, 133.1, 137.1, 170.8, 197.7; EIMS m/z
291 (M+, 84), 273 (4), 231 (84), 213 (75), 175 (18), 157 (56),
147 (13), 110 (27), 105 (100), 77(67), 43 (96). Anal. Calcd for
C17H22O4: C, 70.32; H, 7.64. Found: C, 70.06; H, 7.87.
(()-(2S,3S,6S)-6-Methyl-2-(2-oxo-2-phenylethyl)tetra-
hydro-2H-3-pyranyl acetate (22): yield 11 mg, 1%; colorless
oil; Rf ) 0.37 (1:4 ethyl acetate/hexane); IR (neat) 1731, 1681,
1
1597, 1580, 1449, 1243, 754 cm-1; H NMR (600 MHz) δ 1.22
(d, J ) 6.6 Hz, 3H), 1.57 (dddd, J ) 13.8, 7.2, 6.6, 4.2 Hz, 1H),
1.73 (dddd, J ) 13.8, 4.2, 4.2, 4.2 Hz, 1H), 1.83 (dddd, J )
13.8, 7.2, 6.6, 4.2 Hz, 1H), 1.97 (dddd, J ) 13.8, 4.2, 4.2, 4.2
Hz, 1H), 2.03 (s, 3H), 3.10 (dd, J ) 15.6, 5.4 Hz, 1H), 3.23 (dd,
J ) 15.6, 7.8 Hz, 1H), 3.96 (ddq, J ) 6.6, 6.6, 4.2 Hz, 1H),
4.43 (ddd, J ) 7.8, 5.4, 5.4 Hz, 1H), 4.70 (ddd, J ) 6.6, 5.4, 4.2
Hz, 1H), 7.44-7.48 (m, 2H), 7.54-7.57 (m, 1H), 7.93-7.95 (m,
2H); 13C NMR (150 MHz) δ 18.9, 21.2, 24.0, 28.1, 40.4, 67.3,
70.1, 70.8, 128.2, 128.6, 133.1, 136.9, 170.4, 197.5; EIMS m/z
277 ([M + H]+, 27), 258 (26), 233 (26), 216 (45), 105 (100), 77
(24), 43 (39); HRMS (ESI) calcd for C16H20O4 + Na 299.1259,
found 299.1263.
2-(2-Oxo-2-phenylethyl)-6,6-diphenyltetrahydro-2H-3-
pyranyl Acetate (15f and 16f). Cis (16f)a and trans (15f)b
isomers were inseparable by column chromatography and were
obtained as a 3:2 mixture, respectively: pale yellow solid; mp
45-50 °C; Rf 0.55 (3:7 ethyl acetate/hexanes); IR (Nujol) 1734,
1683, 1597, 1580 cm-1 1H NMR (300 MHz) δ 1.92 (s, 3H),a
;
2.12 (s, 3H),b 1.66-2.21 (m, 6H),a,b 2.57 (ddd, J ) 14.1, 3.3,
3.3 Hz, 1H),b 2.84 (ddd, J ) 14.1, 3.6, 3.6 Hz, 1H),a 3.01 (dd,
J ) 16.2, 5.1 Hz, 1H),b 3.08 (dd, J ) 14.7, 3.6 Hz, 1H),a 3.41
(dd, J ) 14.7, 8.7 Hz, 1H),a 3.52 (dd, J ) 16.2, 8.1 Hz, 1H),b
8350 J. Org. Chem., Vol. 70, No. 21, 2005

1,2-Dioxines as Convenient Precursors for Pyran Syntheses
(()-3-[(1aR,2S,5R,5aS)-5-Phenylperhydrooxireno[2,3-
d][1,2]dioxin-2-yl]-1-propanol (24).10 To a solution of 1,2-
dioxine 10a (366 mg, 1.66 mmol) in dichloromethane (15 mL)
was added 70% 3-chloroperbenzoic acid (1.229 g, 4.98 mol) and
the solution stirred for 3 days at ambient temperature.
Dichloromethane (10 mL) was then added and the solution
extracted with satd Na2S2O3 (20 mL) followed by NaHCO3 (20
mL). The organic layer was dried over MgSO4 and filtered,
and the volatiles were removed in vacuo. The crude epoxides
were purified by column chromatography to yield major
epoxide 24 (347 mg, 84%) as a colorless oil: Rf ) 0.50 (3:2 ethyl
acetate/hexane); IR (neat) 3392, 1597, 1580, 1493, 1455, 1049
cm-1; 1H NMR (300 MHz) δ 1.66-1.87 (m, 3H), 1.93-2.06 (m,
2H), 3.35 (d, J ) 4.5 Hz, 1H), 3.55 (d, J ) 4.5 Hz, 1H), 3.68
(dd, J ) 6.3, 6.3 Hz, 2H), 4.37 (dd, J ) 9.6, 3.9 Hz, 1H), 5.31
(bs, 1H), 7.38-7.41 (m, 5H); 13C NMR (75 MHz) δ 26.5, 28.4,
52.1, 52.8, 62.0, 77.9, 80.4, 128.0, 128.7, 129.1, 135.8; EIMS
m/z 236 (M+, 3), 204 (11), 131 (27), 120 (100), 105 (78), 77 (94),
71 (74). Anal. Calcd for C13H16O4: C, 66.09; H, 6.83. Found:
C, 65.90; H, 6.75.
(()-3-[(1aS,2S,5R,5aR)-5-Phenylperhydrooxireno[2,3-
d][1,2]dioxin-2-yl]-1-propanol (25): (17 mg, 4%) as a color-
less oil; Rf ) 0.47 (3:2 ethyl acetate/hexane); IR (neat) 3368,
1661, 1495, 1455, 1050 cm-1; 1H NMR (300 MHz) δ 1.64-2.13
(m, 6H), 3.57 (dd, J ) 4.2, 1.2 Hz, 1H), 3.62 (dd, J ) 4.2, 4.2
Hz, 1H), 3.73 (dd, J ) 6.3, 6.3 Hz, 2H), 4.36 (ddd, J ) 9.0, 5.1,
4.2 Hz, 1H), 5.32 (d, J ) 1.2 Hz, 1H), 7.36-7.43 (m, 3H), 7.51-
7.54 (m, 2H); 13C NMR (75 MHz) δ 25.6, 28.6, 51.8, 53.2, 62.7,
79.5 (masked carbon), 128.5, 128.6, 129.2, 135.1; EIMS m/z
236 (M+, 1), 131 (40), 120 (81), 105 (100), 91 (71), 77 (75), 71
(56); HRMS (ESI) calcd for C13H16O4 + Na 259.0946, found
259.0942.
(()-(3R,4S,4aS,8aS)-3-Phenylperhydrpyrano[3,2-c][1,2]-
dioxin-4-ol (26). To a solution of epoxide 24 (340 mg, 1.44
mmol) in dry dichoromethane (10 mL) was added p-toluene-
sulfonic acid (137 mg, 0.72 mmol) and the solution stirred
overnight. After this time, the volatiles were removed in vacuo
and the crude pyran purified by column chromatography to
yield pyran 26 (160 mg, 47%) as a colorless oil: Rf ) 0.25 (2:3
ethyl acetate/hexane); IR (neat) 3401, 1602, 1585, 1496, 1455,
1096 cm-1; 1H NMR (600 MHz) δ 1.69 (ddddd, J ) 13.8, 11.4,
10.2, 4.2, 1.2 Hz, 1H), 1.81 (ddddd, J ) 13.8, 4.2, 4.2, 4.2, 4.2
Hz, 1H), 2.01 (dddd, J ) 13.8, 4.2, 4.2, 4.2 Hz, 1H) 2.23 (dddd,
J ) 13.8, 10.8, 10.2, 4.2 Hz, 1H), 2.29 (bs, 1H), 3.63 (ddd, J )
11.4, 4.2, 1.2 Hz, 1H), 3.68 (ddd, J ) 11.4, 11.4, 4.2 Hz, 1H),
3.99 (dd, J ) 8.4, 5.4 Hz, 1H), 4.38 (ddd, J ) 10.8, 5.4, 4.2 Hz,
1H), 4.44 (dd, J ) 8.4, 8.4 Hz, 1H), 4.91 (d, J ) 8.4 Hz, 1H),
7.34-7.40 (m, 3H), 7.41-7.44 (m, 2H); 13C NMR (150 MHz) δ
24.2, 24.6, 61.6, 65.6, 75.1, 77.7, 86.5, 127.6, 128.5, 128.9, 135.4;
EIMS m/z 236 (M+, 13), 105 (26), 71 (100), 60 (35), 43 (71);
HRMS (ESI) calcd for C13H16O4 + Na requires 259.0946, found
259.0942.
(()-(2R,3S)-2-[(1S)-1-(Acetyloxy)-2-oxo-2-phenylethyl]-
tetrahydro-2H-3-pyranyl Acetate (27). To a solution of
pyran 26 (160 mg, 0.68 mmol) in dry dichloromethane (10 mL)
was added triethylamine (10 drops) and the solution stirred
overnight. The volatiles were then removed in vacuo, pyridine
(0.82 mL, 10.16 mmol), acetic anhydride (0.68 mL, 6.78 mmol),
and DMAP (33 mg, 0.27 mmol) were added, and the solution
was stirred overnight. Dichloromethane (10 mL) was then
added, the solution was extracted with water (10 mL), the
organic layer was dried (MgSO4) and filtered, and the volatiles
were removed in vacuo. The crude pyran was purified by
column chromatography to yield pyran 27 (150 mg, 69%) as a
colorless solid: mp ) 70-71 °C; Rf ) 0.36 (2:3 ethyl acetate/
hexane); IR (Nujol) 1739, 1729, 1687, 1597, 1580, 1234, 1092,
720 cm-1; 1H NMR (300 MHz) δ 1.39-1.42 (m, 1H), 1.63-1.68
(m, 1H), 1.81 (s, 3H), 1.83-1.91 (m, 1H), 1.99-2.04 (m, 1H),
2.12 (s, 3H), 3.53 (ddd, J ) 12.6, 12.6, 2.4 Hz, 1H), 3.91 (dd, J
) 7.2, 1.2 Hz, 1H), 4.09 (ddd, J ) 12.6, 4.8, 2.4 Hz, 1H), 4.67
(bs, 1H), 6.02 (d, J ) 7.2 Hz, 1H), 7.45-7.48 (m, 2H), 7.57-
7.60 (m, 1H), 8.00-8.01 (m, 2H); 13C NMR (75 MHz) δ 20.3,
20.6, 20.8, 27.3, 66.9, 68.5, 74.1, 77.8, 128.7, 128.9, 133.7, 135.8,
169.8, 170.4, 196.0; EIMS m/z 321 ([M + H]+,18), 277 (35),
261 (39), 218 (45), 105 (100), 77 (14), 43 (30); HRMS (ESI) calcd
for C17H20O6 + Na 343.1157, found 343.1157.
Acknowledgment. We thank the Australian Re-
search Council for financial support. E.R.T.T. thanks
the Queensland Government for the award of a Smart
Returns Fellowship. J.A.C. thanks the Faculty of Sci-
ence, University of Adelaide, for support in the form of
a scholarship.
Supporting Information Available: Experimental de-
tails for compounds 5a-d, 6a-c, 7, 8a-c, 9a-c, 10a-g, 12a,
13a, 14a, 17a-d, 23, 11a-g, 30a-c, and 31a-c. 13C NMR
spectra for compounds 10a-g, 12a, 13a, 14a, 15a-e, 16a-e,
17a,c-d, 18a, and 19-27 and 1H NMR spectra for compound
17b. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO050806N
J. Org. Chem, Vol. 70, No. 21, 2005 8351