Cyclic oxonium ylides: Building blocks for iterative synthesis of polycyclic ethers

Article abstract of DOI:10.1016/S0040-4020(02)00051-0

A series of diazoketones bearing remote benzyl or allyl ethers was subjected to a variety of conditions for catalytic diazodecomposition and cyclic oxonium ylide formation as a possible method for polycyclic ether synthesis. Allyl ethers 19, 25 and 29 und

Full text of DOI:10.1016/S0040-4020(02)00051-0

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 2027±2040
Cyclic oxonium ylides: building blocks for iterative synthesis of
polycyclic ethers
p
È
Fredrik P. Marmsater, John A. Vanecko and F. G. West
Department of Chemistry, University of Utah, 315 S. 1400 East, Rm. 2020, Salt Lake City, UT84112-0850, USA
Received 1 December 2001;accepted 1 January 2002
AbstractÐA series of diazoketones bearing remote benzyl or allyl ethers was subjected to a variety of conditions for catalytic diazode-
composition and cyclic oxonium ylide formation as a possible method for polycyclic ether synthesis. Allyl ethers 19, 25 and 29 underwent
ef®cient conversion to the corresponding bis(pyran) and tris(pyran) products in the presence of Cu(tfacac)2, while benzyl ether 15 was
converted to bicyclic products 16 and 34 with Rh2(tpa)4. Treatment of homologous substrate 32 with Rh2(tpa)4 provided novel medium-ring
cyclopropanation products 35 in good yield. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
preliminary results of our efforts to apply metallocarbene/
oxonium ylide chemistry in an iterative approach to poly-
pyran domains such as those found in 1.7 Our general
strategy relied on the conversion of a 5-alkoxy-1-diazo-2-
pentanone such as 2 to a 2-substituted tetrahydropyran-3-
one such as 3 via catalytic decomposition of the diazo-
ketone, cyclization of the resulting carbenoid onto the
pendant ether oxygen, and migration of the exocyclic
group on the intermediate cyclic oxonium ylide to furnish
3 (Scheme 1). The migration was envisioned to occur by
either [1,2]-shift of a benzyl group or [2,3]-shift of an allyl
group. A particularly attractive feature of this approach is
the convenient placement of oxygenation and a carbon side-
chain at the appropriate points to permit their elaboration to
new ether and diazoketone groups for a subsequent
iteration. Here we detail the full scope of this study, includ-
ing some fascinating and unexpected catalyst effects.
Marine ladder toxins, exempli®ed by gambierol (1),1 have
attracted considerable attention in recent years. These
compounds are produced by dino¯agellate organisms asso-
ciated with `red tide' events and cases of food poisoning.2
Their apparent mechanism of action, binding to voltage-
gated sodium ion channels,3 has provoked interest in the
biomedical community regarding the possible development
of antagonists,4 and some have displayed promising anti-
fungal activity.5 However, most of these toxins are quite
scarce, suggesting that de novo synthesis may be the best
approach for probing structure-activity effects.
The ladder toxins contain a unique trans-fused polycyclic
ether skeleton made up repeating of 6-, 7-, 8- and
9-membered ether rings. This regular motif suggests that
iterative installation of successive ether rings may be an
especially suitable method of construction. Indeed, several
highly effective iterative strategies for polyether synthesis
have been described in recent years.6 We recently disclosed
Keywords: polycyclic ethers;oxonium ylides;sigmatropic rearrangement.
Corresponding author. Address: Department of Chemistry, University of
p
Alberta, Edmonton, Alta., Canada T6G 2G2. Tel.: 11-801-581-4954;
fax: 11-801-581-8433;e-mail: frederick.west@chem.ualberta.ca
Scheme 1.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00051-0

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F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2028
2. Results and discussion
2.1. An acyclic model system for [1,2]-shifts
Given our earlier studies with [1,2]-benzyl shifts,8 we
initially focused our attention on this approach, with the
expectation that the 2-benzyl substituent could be
oxidatively degraded to a two-carbon carboxylic acid side-
chain with RuO4.9 Competing carbenoid pathways were a
major concern with this approach: formation of cyclo-
pentanone 5 via C±H insertion into the benzyl ether methine
could be facile, and formation of the alternative oxonium
ylide 6 derived from addition to the neighboring pyran
oxygen was also possible (Scheme 2). Adams had
previously shown that C±H bonds next to ether oxygens
are particularly activated for insertion by rhodium
carbenoids.10 Generation of ylide 6 might be tolerated,
since it would have no low-energy rearrangement pathways
available. Several studies have provided indirect evidence
for interconversion between metallocarbenes and oxonium
ylides;11 if such an equilibrium were possible, ylide 6 might
be expected to revert to carbenoid 4 and eventually provide
the desired ylide 7 and/or C±H insertion product 5.
However, this argument also raised the possibility that
slow rearrangement of 7 could lead to reversion to 4 and
greater amounts of 5.
Scheme 3.
Section 2.3), but the overall yields were unacceptably low.
Minor dimerization pathways have been observed in other
carbenoid chemistry,14 and can predominate in certain intra-
molecular cases.15 However, we had not previously
observed this type of reactivity in systems in which viable
ylide rearrangement pathways were available. The close
structural similarity of 9 and 13 is especially striking,
suggesting that the methoxy group may play a signi®cant
role in the surprising reactivity differences observed for
these substrates.
Scheme 2.
Given these uncertainties, we chose to initially examine the
simple, acyclic model compound 9 (Scheme 3). Substrate 9
was prepared from known aldehyde 812 via Pinnick oxida-
tion followed by carboxyl activation and diazomethane
addition via the mixed anhydride. Treatment of 9 with
Rh2(OAc)4 gave both diastereomers of the desired [1,2]-
shift product 10 along with C±H insertion product 11.
Given the questionable synthetic utility of this result, we
then examined other catalysts for diazodecomposition.
Prior studies by Clark13 and by us8a,b had shown that use
of soluble copper(II) catalysts led to much more favorable
ratios of ylide-derived products to C±H insertion products,
as exempli®ed in the case of benzyl ether 13. Accordingly,
we next turned to copper(II) hexa¯uoroacetoacetonate in
re¯uxing CH2Cl2, conditions which had worked well with
13. None of the insertion product 11 was isolated, but to our
surprise, only traces of 10 were obtained. Instead, the major
product in a largely intractable and complex mixture was the
dimeric alkene 12. A somewhat more favorable 10/11/12
ratio could be obtained by using the optimal conditions
employed for [2,3]-shifts (Cu(tfacac)2/CH2Cl2/re¯ux;see
2.2. [1,2]-Shift of a cyclic substrate
The unexpected results with 9 prompted us to prepare a
more elaborate substrate, 15, whose greater rigidity could
favor the desired ylide pathway (Scheme 4). The known
trans-2-allyl-3-hydroxytetrahydropyran 1416 could be
converted to 15 via a 3-step sequence of O-benzylation,
ozonolysis with oxidative work-up and carboxyl activation/
diazomethane acylation. Treatment of 15 with Rh2(OAc)4
gave a combined 55% yield of oxonium ylide [1,2]-shift
products 16 and C±H insertion product 17 in a 2:3 ratio.
Although the [1,2]-shift product was formed exclusively as
the desired epimer (16a), the yield was unacceptably low.
As with acyclic model 9, use of Cu(hfacac)2 furnished
mainly the dimeric product (18). To our surprise, the opti-
mal conditions for [2,3]-shifts (Cu(tfacac)2/CH2Cl2/re¯ux;
see Section 2.3) gave C±H insertion product 17 in good
yield, with only a trace of the [1,2]-shift product.
Our prior experience with carbenoid-based methods of ylide
generation suggested that the conditions employed should

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F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2029
Scheme 4.
permit ef®cient formation of the desired oxonium ylides.
Why then were products of alternative carbenoid pathways
(C±H insertion and dimerization) predominating in these
systems? We wondered if the activation barrier for [1,2]-
shift, which is believed to occur via a 2-step homolysis/
recombination mechanism,8c,17 might be suf®ciently high
to permit competing reversion of the ylide to metallo-
carbene, with eventual drain-off via the undesired pathways.
If this were the case, we reasoned that rearrangement of
O-allyl oxonium ylides might have a greater likelihood for
success, as the concerted [2,3]-shifts would be expected to
experience lower activation barriers.8d
Scheme 5.
2.3. [2,3]-Shift with iteration
The necessary substrate 19 to examine an approach based on
oxonium ylide [2,3]-shifts could be prepared from 14 via a
route analogous to that used in the synthesis of 15 (Scheme
5). Treatment with Rh2(OAc)4 furnished roughly equal
amounts of ylide rearrangement products 20 (4:1 ratio of
inseparable epimers) and C±H insertion product 21 in a
combined 59% yield. Cu(hfacac)2 provided diminished
quantities of 21 and slightly greater amounts of 20. Notably,
the ratio of diastereomers in this case now favored axial
allyl isomer 20b (5:1 b/a). Further efforts to optimize for
the ylide pathway revealed that copper(II) tri¯uoroaceto-
acetonate in re¯uxing CH2Cl2 gave high yields of 20b,
along with traces of 20a and 21. Dropwise addition via
cannula over a 5 min period was found to be superior to
slow addition by syringe pump, likely due to slow thermal
diazoketone degradation. It is notable that no carbenoid
dimers were observed under any of the conditions surveyed.
The striking contrast in reactivity between 19 and the
closely related 15 is consistent with different rates of
rearrangement by their respective ylides. Ylide 22b, derived
from 19, undergoes ef®cient [2,3]-shift to give mainly 20,
with only small amounts of 21 formed via C±H insertion by
open carbenoid 22a. Ylide 23b, derived from 15 is slow to
rearrange, allowing a greater degree of reversion to
carbenoid 23a, which leads to insertion product 17 and
dimer 18. Similar arguments apply in the case of 9.
The high-yield conversion of 19 to 20b now raised the
possibility of a successful iterative strategy for polypyran
construction. However, this would require an adjustment of
the con®guration at the allyl-substituted carbon, selective
reduction of the adjacent ketone, and establishment of the
relative stereochemistry of the rearrangement products with
greater con®dence. To this end, the inseparable mixture was
reduced to give separable alcohols 24a and 24b (Scheme 6).
Prior treatment with base effected the epimerization of 20b
to the more stable equatorial isomer 20a needed for eventual
iteration, and reduction of the resulting mixture could be
carried out in situ. As expected, hydride delivery occurred
exclusively via axial attack for both 20a and 20b. Following
reduction, the relative stereochemistry of 24a and 24b was
determined by 2D NOESY experiments, which revealed
cross peaks between the 1,3-diaxial protons of 24a and
between one of the bridgehead axial protons and the
methylene protons of the axial allyl group of 24b. While
this procedure afforded synthetically useful quantities of
24a, additional material could be obtained by recycling
the undesired 24b to 20b by TPAP oxidation, followed by

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F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2030
Scheme 7.
Scheme 6.
another epimerization/reduction sequence. With 24a in
hand an additional iteration was investigated. The same
sequence of: (1) ozonolysis with oxidative work-up, (2)
allyl ether formation and (3) carboxyl activation/diazo-
methane acylation generated diazoketone 25. Application
of the optimum conditions from Scheme 5 effected the
conversion of 25 to 26b, isolated as the only detectable
isomer in 80% yield. Tris(tetrahydropyran) 26b was then
subjected to the epimerization conditions, providing a
10:1 mixture of 26a and b. A series of 2D NOESY experi-
ments analogous to those used with 24a, b once again
established the relative stereochemistry to be as shown.
This mixture could be reduced as before to give 27a and a
trace of an isomer.
troubling. An additional major product was isolated from
this reaction, whose structure proved to be enol ether 31.
This compound presumably also arises from the inter-
mediate oxonium ylide via a [1,4]-shift of the allyl group.
Thus, a total of 68% of the material was formed via the
oxonium ylide. [1,4]-Shift products from oxonium ylides
have been observed previously, though typically during
attempted [1,2]-shift of benzyl or simple alkyl sub-
stituents.8b,20 To our knowledge, this is the ®rst example
of a [1,4]-shift by an oxonium ylide occurring in
competition with a [2,3]-shift.21
To examine the applicability of this strategy to oxepane
construction, we also prepared diazoketone stubstrate 32
by Arndt±Eistert homologation of 19 (Scheme 8). Clearly,
ef®cient reaction via the ylide pathway would be dif®cult
when C±H insertion via 5- and 6-membered transition states
was possible. In fact, the Cu(tfacac)2 conditions successfully
applied to 19 converted 32 exclusively to 5-membered
spirocyclic C±H insertion product 33. This result was some-
what reminiscent of the unexpected conversion of 15 to 17
(Scheme 4). Earlier observations by Clark13a and by us8a,b
had led to the generalization that the C±H insertion pathway
was not favored with copper catalysts when viable ylide
rearrangements were available, but these results clearly
indicated that the situation was somewhat more compli-
cated. At this point, we chose to examine the behavior of
15 and 32 with the bulky rhodium complex Rh2(tpa)4
(tpaˆtriphenylacetate), as carbenoids derived from this
catalyst are reported to be quite sensitive to steric demand,22
which we thought might disfavor C±H insertion involving
the angular methine relative to the ylide pathway. In the
event, addition of 15 to Rh2(tpa)4 (3 mol% in re¯uxing
CH2Cl2;5 min addition via cannula) gave the desired
[1,2]-shift products 16a and 16b in a combined 58% yield
(2.1:1 ratio of epimers), along with another 12% of the
2.4. Other cases and catalyst effects
Given the frequent occurrence of angular methyl groups in
ladder toxin polypyran arrays, we sought to examine
whether the successful approach described earlier (Section
2.3) could be carried out using a tertiary allylic ether such as
29 (Scheme 7). This substrate could be prepared from 14
via a sequence involving oxidation,18 addition of methyl-
magnesium bromide, ozonolysis with oxidative work-up
and protection as the methyl ester to give hydroxyester
28. The tertiary alcohol was resistant to allylation under
standard conditions, but the palladium-catalyzed procedure
of Stoner cleanly provided a mixture of 28 and its allyl
ether.19 Saponi®cation and diazoketone acylation then
provided 29. When 29 was subjected to Cu(tfacac)2 in
re¯uxing dichloromethane, the expected [2,3]-shift products
30a and 30b were isolated, but in a disappointing 45%
combined yield, and with somewhat lower diastereo-
selectivity (1:3.5). Since the desired trans isomer was
readily available via base-catalyzed epimerization, the latter
issue was of little concern, but the low chemical yield was

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F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2031
cyclization pathway with Cu(tfacac)2 and cyclopropanation
to form a nine-membered ring with Rh2(tpa)4. Further
studies are underway to explore the generality of the last
process.
4. Experimental
4.1. General
Reactions were carried out in ¯ame-dried glassware under a
positive nitrogen atmosphere unless otherwise stated. Trans-
fer of anhydrous solvents and reagents was accomplished
with oven-dried syringes or cannula. Solvents were distilled
before use: methylene chloride from calcium hydride, tetra-
hydrofuran and diethyl ether from sodium/benzophenone
ketyl, toluene from sodium metal. Ethereal diazomethane
was prepared from Diazald according to literature
procedures.24 Thin layer chromatography was performed
on glass plates precoated with 0.25 mm Kieselgel 60 F254
(Merck). Flash chromatography columns were packed with
230±400 mesh silica gel (Merck). Radial chromatography
was carried out on a Chromatotron model 7924T (Harrison
Research) with plates prepared using silica gel 60 F254 with
gypsum binder (EM) on glass rotors. Proton nuclear
magnetic resonance spectra (1H NMR) were recorded at
300 or 500 MHz and coupling constants (J) are reported
in Hertz (Hz). Carbon nuclear magnetic resonance spectra
(13C NMR) were recorded at 75 or 125 MHz and are
reported (ppm) relative to the center line of the triplet
from chloroform-d (77.23 ppm). Yields reported in this
section are for speci®c runs;yields given in Section 2 are
average values taken from two or more runs.
Scheme 8.
[1,4]-shift product 34. Given the isolation of a combined
70% of oxonium ylide-derived products from a case (15)
that had previously given mainly C±H insertion or
dimerization products, we revisited substrate 32 with
considerable optimism. However, exposure of 32 to the
same conditions unexpectedly furnished a mixture of cyclo-
propanes 35a and 35b in 82% yield as the only isolated
products. The connectivity of the novel 2,11-dioxa-
tricyclo[8.4.0.04,6]tridecan-7-ones was veri®ed through a
combination of 2D COSY, HMQC and HMBC NMR
experiments, although the relative con®guration of the two
new cyclopropane stereocenters could not be established.
Cyclopropanation to close a new nine-membered ring in
preference to C±H insertion (5- and 6-membered ring-
closure available) or ylide formation (via a 7-membered
ring) is quite surprising. The applicability of this process
to medium-ring formation merits further study.23
4.1.1. 5-Benzyloxy-1-diazo-4-methoxypentan-2-one 9. To
a solution of aldehyde 8 (0.675 g, 3.24 mmol) in BuOH
t
(36 mL) and 2-methyl-2-butene (16 mL) at rt was added a
solution of NaClO2 (0.879 g, 9.72 mmol), NaH2PO4 (1.52 g,
9.72 mmol), and H2O (36 mL) in three portions over a
15 min period. The resulting mixture becomes increasingly
yellow before returning to clear. The solution was mixed at
rt for a further 4 h before being poured into sat. NH4Cl
(50 mL) and extracted with CH2Cl2 (4£50 mL). The
organics were dried (Na2SO4), ®ltered, and concentrated.
The crude acid was carried on without further puri®cation:
1
IR (neat);3440, 2934, 1733 cm 21; H NMR (300 MHz,
CDCl3) d 8.98 (br s, 1H), 7.38±7.25 (m, 5H), 4.57 (d,
JABˆ12.1 Hz, 1H), 4.56 (d, JABˆ12.1 Hz, 1H), 3.88±3.80
(m, 1H), 3.60±3.51 (m, 2H), 3.44 (s, 3H), 2.71±2.57 (m,
2H); 13C NMR (75 MHz, CDCl3) d 177.0, 138.0, 128.6,
128.0, 128.0, 76.6, 73.6, 70.8, 58.1, 37.2.
3. Conclusions
5-Benzyloxydiazoketones 9 and 15 undergo primarily C±H
insertion or carbenoid dimerization processes under the
standard oxonium ylide [1,2]-shift conditions that have
been successfully applied to simpler substrates. However,
the bulky catalyst Rh2(tpa)4 provided a combined 70% yield
of ylide-derived [1,2]- and [1,4]-shift products from 15. The
related allyloxydiazoketones 19, 25 and 29 all underwent
ef®cient conversion to bi- or tricyclic oxonium ylides, with
diastereoselective [2,3]-shift to the corresponding 2-allyl-
tetrahydropyran-3-ones. These examples demonstrate the
suitability of the oxonium ylide approach for the iterative
construction of polypyran arrays such as those found in
many marine ladder toxins. Finally, homologous substrate
32 reacted exclusively through a C±H insertion spiro-
To a solution of the acid (0.702 g, 3.13 mmol) in ether
(13 mL) at rt was added Et3N (0.50 mL, 4.07 mmol)
followed by isobutylchloroformate (0.53 mL, 4.07 mmol).
A white salt formed immediately and the solution became
very thick. Mixing was continued for 3 h at rt at which time
the salt was carefully ®ltered off and the ®ltrate concen-
trated. The crude mixed anhydride was then dissolved in
dry ether (10 mL) and added to an ethereal solution of
diazomethane at 2108C dropwise via cannula. The resulting
mixture was allowed to warm to rt over night. Concentration
and silica gel chromatography (3£8.5 cm column eluting

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F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2032
with 15% EtOAc/hexanes) provided the desired diazo-
ketone 9 (0.407 g, 51% from aldehyde) as a yellow oil: IR
(neat);3087, 3031, 2863, 2103, 1635 cm
(500 MHz, CDCl3) d 7.37±7.27 (m, 5H), 5.29 (br s, 1H),
4.57 (d, JABˆ12.1 Hz, 1H), 4.53 (d, JABˆ12.1 Hz, 1H),
3.89±3.85 (m, 1H), 3.58±3.49 (m, 2H), 3.41 (s, 3H),
2.61±2.50 (m, 2H); 13C NMR (125 MHz, CDCl3) d 193.0,
138.2, 128.6, 127.9, 127.9, 77.0, 73.6, 70.9, 58.0, 55.6, 43.4.
5 min before being cooled to rt. The reaction mixture was
washed with a 30% aqueous solution of NH4OH in sat.
NH4Cl (10 mL), the aqueous phase was washed with
EtOAc (3£10 mL) and the combined organics were dried
with MgSO4 and concentrated to leave a yellow oil. The oil
was eluted through a pipette with silica gel using EtOAc and
the eluent concentrated. The resulting oil was puri®ed using
radial chromatography on a 1 mm plate eluting with 50 mL
each of 40% and 60% EtOAc/hexanes to yield 0.004 g (5%)
of 1,2-shift product 10 and 0.016 g (18%) of dimer 12 as
colorless oils.
21
;
1H NMR
4.1.2. Decomposition of diazoketone 9 with Rh2(OAc)4. A
solution of 9 (0.158 g, 0.637 mmol) in CH2Cl2 (5 mL)) was
added via cannula to a re¯uxing solution of Rh2OAc4
(0.008 g, 0.03 equiv.) in CH2Cl2 (42 mL). The resulting
mixture was stirred for a further 5 min before being cooled
to rt, then washed with sat. NaHCO3 (10 mL). The aqueous
phase was further washed with EtOAc (3£10 mL) and the
combined organics were dried (MgSO4) and concentrated to
leave a yellow oil. The oil was eluted through a short silica
gel plug (pipette) using EtOAc and the eluant was concen-
trated. The resulting oil was puri®ed using radial chromato-
graphy on a 4 mm plate eluting with 50 mL each of 5, 10,
20, 40 and 60% EtOAc/hexanes to yield two main fractions
consisting of an inseparable mixture of C±H insertion
product 11 (0.026 g, 19%)1the minor diastereomer of
1,2-shift product 11 (0.0182 g, 13%) and the major dia-
stereomer of 11 (0.0316 g, 22%)1an uncharacterized
product, all as clear, colorless oils.
4.1.6. Carbene dimer 12. (3.2:1 mixture of E/Z isomers as
measured by alkene singlets in 1H NMR). Major isomer: Rf
0.11 (50 % EtOAc/hexanes);IR (neat);3475, 2923,
1
1684 cm21; H NMR (300 MHz, CDCl3) d 7.42±7.25 (m,
10H), 6.85 (s, 2H), 4.60±4.49 (m, 4H), 3.95±3.82 (m, 2H),
3.57±3.49 (m, 4H), 3.38 (s, 6H), 2.97±2.77 (m, 2H), 2.76±
2.55 (m, 2H); 13C NMR (75 MHz, CDCl3) d 198.9, 138.1,
137.1, 128.6, 128.0, 127.9, 76.3, 73.6, 70.7, 58.1, 43.8.
Minor isomer: 1H NMR (300 MHz, CDCl3) d 6.28 (s, 2H).
4.1.7. Decomposition of diazoketone 9 with Cu(tfacac)2.
A solution of diazoketone 9 (0.028 g, 0.11 mmol) in freshly
distilled CH2Cl2 (2 mL) was added via syringe pump over a
period of 1 h to a re¯uxing solution of Cu(tfacac)2 (0.004 g,
0.01 mmol) in CH2Cl2 (12 mL). The resulting mixture was
stirred a further 5 min before being cooled to rt. The
reaction mixture was washed with a sat. NaHCO3 (10 mL)
solution. The aqueous phase was washed with CH2Cl2
(3£10 mL) and the combined organics were dried with
MgSO4 and concentrated to leave a yellow oil. The oil
was eluted through a pipette with silica gel using EtOAc
and the eluent was concentrated. The resulting oil was
puri®ed using radial chromatography on a 1 mm plate
eluting with 50 mL each of 5, 10, 20, 40 and 60% EtOAc/
hexanes to yield 0.002 g (9%) of C±H insertion product 11,
0.005 g (22%) of 1,2-shift 10 product and 0.001 g (3%) of
dimer 12 as oils.
4.1.3. 2-Benzyl-5-methoxytetrahydropyran-3-one 10.
Major diastereomer: Rf 0.40 (50% EtOAc/hexanes);IR
21
(neat);3458, 2931, 1718 cm
;
1H NMR (300 MHz,
CDCl3) d 7.41±7.18 (m, 5H), 4.13 (ddd, Jˆ12.7, 2.1,
2.1 Hz, 1H), 4.01 (dd, Jˆ9.1, 3.5 Hz, 1H), 3.86±3.81 (m,
1H), 3.71 (dd, Jˆ12.7, 2.5 Hz, 1H), 3.36 (s, 3H), 3.22 (dd,
Jˆ14.7, 3.5 Hz, 1H), 2.89 (dd, Jˆ14.7, 9.0 Hz, 1H), 2.74
(ddd, Jˆ15.6, 4.1, 2.0 Hz, 1H), 2.68 (ddd, Jˆ15.6, 4.9,
4.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 206.9, 138.2,
129.6, 128.5, 126.7, 84.5, 68.0, 56.5, 43.2, 35.8;Anal. calcd
for C13H16O3: C, 70.89;H, 7.32;Found: C 71.35;H, 7.40.
Minor diastereomer: Rf 0.50 (50% EtOAc/hexanes); 1H
NMR (300 MHz, CDCl3) d 7.37±7.20 (m, 5H), 4.21 (ddd,
Jˆ12.0, 5.6, 0.8 Hz, 1H), 3.99 (dd, Jˆ8.7, 3.6 Hz, 1H), 3.85
(dddd, Jˆ10.3, 5.8, 5.8, 4.5 Hz, 1H), 3.54 (dd, Jˆ12.0,
5.8 Hz, 1H), 3.32 (s, 3H), 3.21 (dd, Jˆ14.6, 3.4 Hz, 1H),
2.81 (dd, Jˆ14.7, 8.8 Hz, 1H), 2.80±2.76 (m, 1H), 2.60
(ddd, Jˆ18.4, 5.9, 1.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 208.0, 137.9, 128.7, 128.1, 126.6, 83.1, 75.4,
69.3, 56.6, 42.5, 36.2.
4.1.8. trans-(2Rp,3Sp)-2-Allyl-3-hydroxytetrahydropyran
14. t-Butyllithium (100 mL, 170 mmol, 1.1 equiv.) was
added via cannula to a vigorously stirring solution of
dihydropyran (14.0 mL, 154 mmol) in THF (28.3 mL) at
2788C. The mixture was then carefully allowed to warm
to 2308C. When all of the yellow±orange precipitate had
dissolved the solution was allowed to warm to 08C and
stirred for 1 h. The solution was then cooled to 2788C,
added via cannula to CuI (14.9 g, 78.5 mmol, 0.51 equiv.)
in THF (60 mL), in a three neck ¯ask equipped with an
addition funnel charged with allyl bromide (5.07 mL,
58.5 mmol, 0.38 equiv.) in THF (39 mL), at 2788C. The
mixture was stirred for 1 h and the allyl bromide solution
was then added drop-wise over 15 min. After the addition
was complete, the solution was stirred at 2788C for 1 h and
then allowed to warm to room temperature and stirred for an
additional 3 h. The reaction was diluted with Et2O (100 mL)
and quenched with a 30% NH4OH saturated with NH4Cl
solution (100 mL). The resulting slurry was allowed to stir
for 1 h and then sit undisturbed until two layers formed. The
aqueous phase was extracted with Et2O (200 mL) and the
combined organic phase was washed with a 30% NH4OH
saturated with NH4Cl solution (300 mL), dried with
4.1.4. 3-Benzyloxy-4-methoxycyclopentanone 11. Rf 0.50
21
(50% EtOAc/hexanes);IR (neat);3462, 2931, 1746 cm
;
1H NMR (300 MHz, CDCl3) d 7.37±7.21 (m, 5H), 4.59 (d,
JABˆ12.0 Hz, 1H), 4.58 (d, JABˆ12.0 Hz, 1H), 4.23±4.17
(m, 1H), 4.05±4.02 (m, 1H), 3.36 (s, 3H), 2.63±2.52 (m,
2H), 2.36±2.26 (m, 2H); 13C NMR (75 MHz, CDCl3) d
214.8, 137.9, 129.6, 128.4, 127.8, 81.4, 79.0, 71.5, 57.1,
42.6, 42.2.
4.1.5. Decomposition of diazoketone 9 with Cu(hfacac)2.
A solution of diazoketone 9 (0.048 g, 0.19 mmol) in freshly
distilled toluene (5 mL) was added dropwise via cannula to
a re¯uxing solution of Cu(hfacac)2 (0.010 g, 0.02 mmol) in
toluene (13 mL). The resulting mixture was stirred a further

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F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2033
anhydrous MgSO4, concentrated to a small volume
(,20 mL) and immediately dissolved in MeOH (146 mL)
and cooled to 08C. After slow, careful addition of mCPBA
(18.8 g, 76.1 mmol) the reaction was stirred until comple-
tion as determined by TLC (1 h) and then diluted with Et2O
(130 mL). The reaction was then carefully quenched with
sat. NaHCO3/ice mixture (200 mL). The aqueous phase was
extracted with Et2O (2£100 mL). The combined organic
phase was washed with equal volumes of sat. NaHCO3,
brine, dried over anhydrous MgSO4, ®ltered, and concen-
trated. The residue was puri®ed by ¯ash chromatography to
yield 7.87 g of 2-methoxy-2-allyl-3-hydroxytetrahydro-
pyran as a mixture of diastereomers (78% over two steps).
Rf 0.22, 0.28 (30% EtOAc/hexanes) Major diastereomer: Rf
0.22, (30% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) d
5.94±5.08 (m, 1H), 5.19±5.09 (m, 2H), 3.58±3.44 (m, 3H),
3.28 (s, 3H), 2.57±2.46 (m, 2H), 1.85±1.78 (m, 2H), 1.73±
1.57 (m, 3H); 13C NMR (125 MHz, CDCl3) d 133.8, 118.3,
99.8, 69.9, 60.8, 47.8, 38.1, 28.3, 25.4.
1.71±1.59 (m, 2H), 1.41 (dddd, Jˆ12.6, 10.6, 10.6, 4.9 Hz,
1H); 13C NMR (125 MHz, CDCl3) d 138.7, 135.6, 128.6,
128.1, 127.9, 116.9, 80.7, 77.0, 70.9, 68.1, 36.9, 29.5, 25.6.
Anal. calcd for C15H20O2: C, 77.55, H, 8.68. Found, C,
77.37, H, 8.78.
4.1.10. General procedure for ozonolysis: trans-3-benzyl-
oxytetrahydropyran-2-yl)acetic acid. Ozone was bubbled
into
a solution of 2-allyl-3-benzyloxytetrahydropyran
(228 mg, 0.98 mmol) in CH2Cl2 (6.9 mL) and MeOH
(1.3 mL) at 2788C until the solution turned a persistent
blue color. The solution was then allowed to stir for
30 min. Argon was bubbled into the solution until it was
colorless, after which the cooling bath was removed and
argon was bubbled until the reaction mixture reached rt.
The reaction mixture was then concentrated and the residue
was dissolved in 88% formic acid (0.73 mL) and 30% H2O2
(0.36 mL) and heated to 608C for 6 h. The reaction mixture
was then concentrated and the residue was dissolved in Et2O
(50 mL) and extracted with 1 M KOH (3£10 mL). The
combined basic aqueous phase was washed with Et2O
(30 mL). The aqueous phase was then acidi®ed with 3N
HCl until pH,1±2, saturated with NaCl, then extracted
with EtOAc (4£50 mL). The combined organic phase was
dried over anhydrous MgSO4, ®ltered, concentrated and
placed under high vacuum overnight to afford 191 mg
(78%) of trans-3-benzyloxytetrahydropyran-2-yl)acetic
acid as a thick oil. IR (neat) 3035, 2949, 2868, 1706,
To a solution of Et3SiH (36.5 mL, 228 mmol, 5 equiv.)
and 2-methoxy-2-allyl-3-hydroxytetrahydropyran (7.86 g,
45.7 mmol) in CH2Cl2 (152 mL) and CH3CN (152 mL) at
08C was added BF3´OEt2 (11.6 mL, 91.5 mmol, 2 equiv.).
The reaction was stirred for 3 h and poured into a sat
NaHCO3/ice mixture (200 mL). The aqueous phase was
then extracted with CH2Cl2 (2£100 mL) and the combined
organic phase was washed with brine (300 mL), dried over
anhydrous MgSO4, ®ltered, concentrated and puri®ed by
¯ash chromatography to yield 5.16 g (80%) of 14 as a color-
less oil: Rf 0.14 (30% EtOAc/hexanes);IR (neat) 3405,
1
1098 cm21; H NMR (500 MHz, CDCl3) d 7.36±7.28 (m,
5H), 4.64 (d, JABˆ11.5 Hz, 1H), 4.45 (d, JABˆ11.5 Hz, 1H),
3.95±3.92 (m, 1H), 3.64 (ddd, Jˆ12.7, 8.8, 3.7 Hz, 1H),
3.42 (ddd, Jˆ11.7, 11.7, 2.8 Hz, 1H), 3.19 (ddd, Jˆ10.7,
9.0, 4.1 Hz, 1H), 2.94 (dd, Jˆ15.5, 3.5 Hz, 1H), 2.48 (dd,
Jˆ15.5, 8.4 Hz, 1H), 2.33±2.30 (m, 1H), 1.74±1.65 (m,
2H), 1.48±1.41, (m, 1H); 13C NMR (125 MHz, CDCl3) d
171.7, 133.9, 128.7, 128.1, 128.0, 77.7, 76.7, 70.8, 68.2,
38.1, 29.1, 25.3. HRMS (FAB, M11) for C14H19O4 calcd
251.1285, found: m/z 251.1287.
1
2936, 2852, 1096 cm21; H NMR (300 MHz, CDCl3) d
5.92 (dddd, Jˆ17.1, 10.1, 7.1, 7.1 Hz, 1H), 5.15±5.06 (m,
2H), 3.93±3.86 (m, 1H), 3.41±3.28 (m, 2H), 3.1 (ddd,
Jˆ8.8, 7.5, 3.9 Hz, 1H), 2.63±2.53 (m, 1H), 2.33±2.23
(m, 1H), 2.13±2.05 (m, 1H), 1.72±1.71 (m, 3H), 1.46±
1.33 (m, 1H); 13C NMR (75 MHz, CDCl3) d 135.4, 117.1,
81.9, 70.5, 67.9, 37.2, 33.0, 25.8.
4.1.9. 1-Diazo-3-((2Rp,3Sp)-3-benzyloxytetrahydropyran-
2-yl)propan-2-one 15. trans-2-Allyl-3-benzyloxytetra-
hydropyran: to a solution of NaH (193 mg, 4.84 mmol,
1.1 equiv.) in THF (8.8 mL, 0.5 M) at 08C was added
4.1.11. General procedure for diazoketone formation: 1-
diazo-3-((2Rp,3Sp)-3-benzyloxytetrahydropyran-2-yl)-
propan-2-one (15). Freshly distilled oxalyl chloride
(0.22 mL, 2.45 mmol, 1.2 equiv.) was added to a solution
of acid trans-3-benzyloxytetrahydropyran-2-yl)acetic acid
(996 mg, 3.97 mmol) in CH2Cl2 (15.9 mL, 0.25 M). One
drop of DMF was added (gas evolution) and the reaction
was stirred at rt for 4 h. The solvent was then evaporated
with a stream of nitrogen, and the residue was placed under
high vacuum for 30 min. The residue was then dissolved in
Et2O (15 mL) and added via cannula to a freshly prepared
solution of CH2N2 (,16 mmol) in Et2O (45 mL) at 2458C.
After stirring at 2458C for 60 min, the bath was removed
and the reaction stirred for an additional 60 min. A stream of
nitrogen was introduced, after the solvent was evaporated,
the yellow residue was dissolved in Et2O (12 mL) and the
solvent was again evaporated with a stream of nitrogen. The
crude reaction mixture was puri®ed by radial chromato-
graphy (4 mm plate, 200 mL of 25% followed by 200 mL
of 35% EtOAc/hexanes) to yield 628 mg (57%) of 15 as a
yellow oil: Rf 0.31 (50% EtOAc/hexanes);IR (neat) 3127,
2-allyl-3-hydroxytetrahydropyran
(14)
(625 mg,
4.40 mmol) in THF (1.0 mL) via cannula. The reaction
was stirred for 10 min and benzyl bromide (0.56 mL,
4.62 mmol, 1.05 equiv.) was added via syringe follwed by
tetrabutyl ammonium iodide (87 mg, 0.44 mmol, 10 mol%).
The reaction was allowed to warm to rt and stirred over-
night. The mixture was diluted with Et2O (40 mL) and was
then quenched by the addition of water (40 mL). The
aqueous phase was then extracted with Et2O (2£40 mL)
and the combined organic phase was washed with brine
(100 mL), dried over anhydrous MgSO4, ®ltered, concen-
trated and puri®ed by ¯ash chromatography to yield 791 mg
(77%) of trans-2-allyl-3-benzyloxytetrahydropyran as a
colorless oil. Rf 0.61 (50% Et2O/hexanes);IR (neat) 3072,
1
3010, 2939, 2849, 1453, 1099 cm21; H NMR (500 MHz,
CDCl3) d 7.36±7.29 (m, 5H), 5.93±5.85 (m, 1H), 5.13±5.05
(m, 2H), 4.63 (d, JABˆ11.4 Hz, 1H), 4.46 (d, JABˆ11.4 Hz,
1H), 3.93±3.89 (m, 1H), 3.34 (ddd, Jˆ11.5, 11.5, 2.9 Hz,
1H), 3.26 (ddd, Jˆ8.9, 7.9, 3.1 Hz, 1H), 3.16 (ddd, Jˆ10.6,
9.0, 4.2 Hz, 1H), 2.70±2.64 (m, 1H), 2.31±2.22 (m, 2H),
1
2960, 2944, 2863, 2104, 1620, 1335, 1066 cm21; H NMR
(500 MHz, CDCl3) d 7.36±7.27 (m, 5H), 5.31 (br s, 1H),
4.64 (d, JABˆ11.5 Hz, 1H), 4.43 (d, JABˆ11.5 Hz, 1H),

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F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2034
3.89±3.86 (m, 1H), 3.62 (ddd, Jˆ8.7, 8.7, 3.0 Hz, 1H), 3.36
(ddd, Jˆ11.8, 11.8, 2.7 Hz, 1H), 3.16 (ddd, Jˆ10.6, 9.1,
4.4 Hz, 1H), 2.86 (dd, Jˆ14.7, 2.5 Hz, 1H), 2.42±2.38 (m,
1H), 2.31±2.28 (m, 1H), 1.72±1.58 (m, 2H), 1.42 (dddd,
Jˆ12.7, 12.7, 10.6, 4.7 Hz, 1H); 13C NMR (125 MHz,
CDCl3) d 193.3, 138.5, 128.6, 128.0, 127.9, 78.3, 76.9,
70.7, 68.1, 55.5, 44.3, 29.3, 25.5;Anal. calcd for
C15H18N2O3: C, 65.68, H, 6.61, N, 10.21. Found, C, 65.88,
H, 6.58, N, 9.68.
4.1.16. Carbene dimer 18. Rf 0.33 (50% EtOAc/hexanes);
1
IR (neat) 2936, 2873, 1680, 1098, 738 cm21; H NMR
(300 MHz, CDCl3) d 7.37±7.25 (m, 5H), 6.81 (d,
Jˆ1.8 Hz, 1H), 4.63 (d, JABˆ11.5 Hz, 1H), 4.39 (d,
JABˆ11.5 Hz, 1H), 3.86±3.81 (m, 1H), 3.70 (ddd, Jˆ8.8,
8.8, 3.7 Hz, 1H), 3.35 (ddd, Jˆ11.3, 11.3, 2.9 Hz, 1H), 3.15
(ddd, Jˆ10.4, 9.8, 4.5 Hz, 1H), 3.04 (ddd, Jˆ15.4, 3.6,
2.1 Hz, 1H), 2.68 (dd, Jˆ15.9, 8.6 Hz, 1H), 2.33±2.28 (m,
1H), 1.72±1.54 (m, 2H), 1.48±1.34 (m, 1H); 13C NMR
(75 Hz, CDCl3) d 199.1, 138.3, 136.9, 128.6, 128.0,
127.9, 77.5, 77.0, 70.6, 68.0, 45.0, 29.2, 25.4;HRMS (EI)
for C30H36O6 calcd 492.2511, found: m/z 492.2506.
4.1.12. General procedure for decomposition of diazo-
ketones using rhodium catalysts: decomposition of
diazoketone 15 with Rh2(OAc)4. To a solution of
Rh2(OAc)4 (6 mg, 0.014 mmol, 3 mol%) in CH2Cl2
(32 mL, 0.015 M) and heated to re¯ux was added via
syringe pump (addition time 1 h) a solution of diazoketone
15 (133 mg, 0.48 mmol) in CH2Cl2 (5.0 mL). When the
addition was complete the reaction mixture was
concentrated. Radial chromatography (2 mm plate,
200 mL 25% EtOAc/hexanes followed by 200 mL 30%
EtOAc/hexanes) yielded 25 mg (21%) of 16a and 41 mg
(34%) of 17.
4.1.17. Decomposition of diazoketone 15 with Cu-
(tfacac)2. Compound 15 (141 mg, 0.57 mmol) was treated
to the general procedure (Cu(tfacac)2 (21 mg, 0.056 mmol,
10 mol%), CH2Cl2 (57 mL, 0.01 M)) and puri®cation by
¯ash chromatography (silica gel, 2 cm£18 cm column,
solvent ramp: 100 mL each of 20, 30, 50, 60% Et2O/
hexanes) yielded 77 mg (55%) of 17 as a colorless oil.
4.1.18. 1-Diazo-3-((2Rp,3Sp)-3-allyloxytetrahydropyran-
2-yl)propan-2-one (19). Compound 14 (2.037 g,
14.35 mmol) was treated to the general ozonolysis pro-
cedure (CH2Cl2 (100 mL), MeOH (18 mL), 88% formic
acid (10.8 mL) 30% H2O2 (5.6 mL)) to afford 1.95 g
(85%) of trans-3-hydroxytetrahydropyran-2-yl)acetic acid
as a thick brown oil. Rf 0.22 (5% MeOH/CH2Cl2/2 drops
4.1.13. (1Sp,3Rp,6Rp)-3-Benzyl-2,7-dioxabicyclo[4.4.0]-
decan-4-one (16a). Rf 0.52 (50% EtOAc/hexanes);IR
(neat) 3029, 2944, 2849, 1723, 1099 cm21 1H NMR
;
(500 MHz, CDCl3) d 7.29±7.19 (m, 5H), 3.99 (dd, Jˆ8.1,
3.5 Hz, 1H), 3.93±3.89 (m, 1H), 3.42±3.35 (m, 1H), 3.32±
3.24 (m, 3H), 2.89±2.85 (m, 1H), 2.80 (dd, Jˆ14.7, 8.1 Hz,
1H), 2.47±2.40 (m, 1H), 2.16±2.13 (m, 1H), 1.76±1.68 (m,
2H), 1.55±1.47 (m, 1H); 13C NMR (125 Hz, CDCl3) d
205.4, 138.4, 129.9, 128.4, 126.5, 84.4, 77.4, 77.1, 67.8,
45.7, 35.7, 29.4, 25.3;HRMS (EI) for C 15H18O3 calcd
246.1256, found: m/z 246.1260.
21
1
HOAc in 10 mL);IR (neat) 3224, 2501, 1686 cm ; H
NMR (300 MHz, CDCl3) d 9.9 (br s, 1H), 3.96±3.89 (m,
1H), 3.49 (ddd, Jˆ9.0, 7.8, 3.9 Hz, 1H), 3.43±3.34 (m, 2H),
2.92 (dd, Jˆ15.4, 3.9 Hz, 1H), 2.54 (dd, Jˆ15.4, 7.8 Hz,
1H), 2.18±2.08 (m, 2H), 1.76±1.67 (m, 2H), 1.51±1.37
(m, 1H); 13C NMR (75 MHz, CDCl3) d 177.5, 79.2, 70.4,
68.1, 38.2, 33.2, 25.7.
4.1.14. (1Sp,6Rp)-6-Benzyloxy-2-oxabicyclo[4.3.0]nonan-
8-one (17). Rf 0.44 (50% EtOAc/hexanes);IR (neat) 3032,
The acid (2.28 g, 14.3 mmol) was dissolved in THF (20 mL)
and then added via cannula to a vigorously stirring mixture
of NaH (1.03 g, 42.8 mmol, 3 equiv.) in THF (5 mL) at 08C.
After 10 min, allyl bromide was added via syringe
(1.24 mL, 14.3 mmol, 1 equiv.) and the mixture was heated
to re¯ux. After 10 h, the reaction was cooled to rt, diluted
with Et2O (15 mL), quenched with water (10 mL) and the
aqueous phase was then washed with Et2O (30 mL),
acidi®ed with 3N HCl until the pH,1±2, and then extracted
with Et2O (8£50 mL). The combined organic phase was
dried over anhydrous MgSO4, ®ltered, and concentrated to
afford 2.67 g (95%) of trans-3-allyloxytetrahydropyran-2-
yl)acetic acid as a thick yellow oil. Rf 0.53 (5% MeOH/
CH2Cl2/2 drops HOAc in 10 mL);IR (neat) 3224, 2544,
1
2935, 2860, 1745, 1454, 1097 cm21; H NMR (300 MHz,
CDCl3) d 7.36±7.23 (m, 5H), 4.49 (d, JABˆ11.2 Hz, 1H),
4.41 (d, JABˆ11.2 Hz, 1H), 3.96±3.90 (m, 2H), 3.50±3.40
(m, 1H), 2.76 (ddd, Jˆ18.4, 5.1, 1.1 Hz, 1H), 2.64 (dd,
Jˆ18.2, 1.2 Hz, 1H), 2.42 (d, JABˆ18.1 Hz, 1H), 2.33±
2.29 (m, 1H), 2.22 (d, JABˆ18.2 Hz, 1H), 1.93±1.70 (m,
3H); 13C NMR (125 MHz, CDCl3) d 216.1, 138.4, 128.7,
127.8, 127.5, 80.1, 79.9, 67.1, 64.0, 44.8, 41.8, 28.9, 23.5;
HRMS (EI) for C15H18O3 calcd 246.1256, found: m/z
246.1258.
4.1.15. General procedure for decomposition of diazo-
ketones using copper catalysts: decomposition of diazo-
ketone 15 with Cu(hfacac)2. To a solution of Cu(hfacac)2
(14 mg, 0.028 mmol, 10 mol%) in CH2Cl2 (30 mL, 0.01 M)
heated to re¯ux was added via syringe pump (addition time
1 h) a solution of diazoketone 15 (76 mg, 0.28 mmol) in
CH2Cl2 (3.0 mL). When the addition was complete the reac-
tion mixture was cooled to rt and a solution of 30% NH4OH
saturated with NH4Cl (60 mL) was added. The aqueous
phase was extracted with CH2Cl2 (2£50 mL), the combined
organic phase was dried with anhydrous MgSO4, ®ltered
and concentrated. Puri®cation by radial chromatography
(2 mm plate, solvent ramp: 100 mL each of 20, 30, 50,
60% Et2O/hexanes) yielded 28 mg (20%) of 18 as a yellow-
ish crystalline solid.
1686 cm21 1H NMR (500 MHz, CDCl3) d 9.25 (br s,
;
1H), 5.88 (dddd, Jˆ17.1, 10.6, 5.8, 5.8 Hz, 1H), 5.25
(ddd, Jˆ17.1, 3.3, 1.6 Hz, 1H), 5.18±5.15 (m, 1H), 4.13±
4.09 (m, 1H), 3.94±3.89 (m, 2H), 3.59 (ddd, Jˆ9.0, 3.8,
3.8 Hz, 1H), 3.40 (ddd, Jˆ11.7, 11.7, 2.8 Hz, 1H), 3.10
(ddd, Jˆ10.6, 9.2, 4.4 Hz, 1H), 2.91 (dd, Jˆ15.5, 3.8 Hz,
1H), 2.49 (dd, Jˆ15.5, 8.3 Hz, 1H), 2.26±2.23 (m, 1H),
1.71±1.64 (m, 2H), 1.42±1.34 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 176.6, 134.9, 117.4, 77.7, 76.8, 69.9,
68.2, 38.2, 29.3, 25.4. HRMS (FAB, M21) for C10H15O4
calcd 199.0970, found: m/z 199.0974.
3-Allyloxytetrahydropyran-2-yl)acetic
acid
(409 mg,

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F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2035
2.05 mmol) was subjected to the general procedure for
diazoketone formation (oxalyl chloride (0.22 mL,
2.45 mmol, 1.2 equiv.), CH2Cl2 (14 mL), one drop of
DMF at rt, CH2N2 (,8 mmol), Et2O (30 mL) at 2108C
for 60 min then rt for 60 min) and puri®ed by radial
chromatography (4 mm plate, solvent ramp: 100 mL each
of 20, 30, 40, 50, 60% Et2O/hexanes) to yield 307 mg (67%)
of 19 as a yellow oil. Rf 0.15 (50% Et2O/hexanes);IR (neat)
2.73 (ddd, Jˆ18.5, 4.9, 1.3 Hz, 1H), 2.56 (dd, Jˆ18.3,
1.3 Hz, 1H), 2.30 (dd, Jˆ17.9, 1.1 Hz, 1H), 2.20±2.17 (m,
1H), 2.19 (d, Jˆ17.8 Hz, 1H), 1.83±1.69 (m, 3H); 13C NMR
(75 MHz, CDCl3) d 216.2, 135.0, 116.6, 80.0, 77.5, 67.1,
62.9, 44.8, 41.8, 28.8, 23.5.
4.1.23. Decomposition of diazoketone 19 with Cu-
(tfacac)2. Compound 19 (230 mg, 1.02 mmol) was treated
to the general procedure (CH2Cl2 (102 mL, 0.01 M),
Cu(tfacac)2 (19 mg, 0.05 mmol, 5 mol%), 5 min addition
via cannula) and puri®cation by ¯ash chromatography
(silica gel, 3 cm£18 cm column, solvent ramp: 200 mL
each of 20, 30, 50, 60% Et2O/hexanes) yielded 10 mg
(5%) of 21 and 162 mg (80%) of an inseparable mixture
of 20a/20b (20a/20b, 1:30 determined by GC).
1
3082, 2939, 2856, 2102, 1736, 1640, 1097 cm21; H NMR
(500 MHz, CDCl3) d 5.87 (dddd, Jˆ17.2, 10.4, 5.6, 5.5 Hz,
1H), 5.35 (br s, 1H), 5.25 (dddd, Jˆ17.1, 1.7, 1.7, 1.7 Hz,
1H), 5.16 (dddd, Jˆ10.4, 1.2, 1.2, 1.2 Hz, 1H), 4.10 (dddd,
Jˆ12.6, 5.4, 1.4, 1.4 Hz, 1H), 3.9 (dddd, Jˆ12.6, 5.7, 1.3,
1.3 Hz, 1H), 3.87±3.82 (m, 1H), 3.57 (ddd, Jˆ9.1, 9.0,
3.1 Hz, 1H), 3.35 (ddd, Jˆ11.6, 8.8, 2.9 Hz, 1H), 3.07
(ddd, Jˆ10.7, 9.1, 4.5 Hz, 1H), 2.85 (dd, Jˆ14.5, 2.9 Hz,
1H), 2.41 (app br s, 1H), 2.27±2.17 (m, 1H), 1.71±1.59 (m,
2H), 1.36 (dddd, Jˆ12.7, 12.7, 10.7, 4.9 Hz, 1H); 13C NMR
(125 MHz, CD2Cl2) d 193.5, 135.7, 116.8, 78.5, 77.2, 69.9,
68.2, 55.3, 44.7, 29.7, 25.8;Anal. calcd for C 11H16N2O3: C,
58.91, H, 7.19. Found, C, 59.28, H, 7.20.
4.1.24. Epimerization and reduction of 20a/20b (one-pot
procedure). Catalytic DBU (1 drop) was added to mixture
of 20a/20b (142 mg, 0.72 mmol, 20a/20b, 1:30) in THF
(3.6 mL). The reaction was monitored by GC and stirred
until no further change in epimer ratio was observed
(16 h). The reaction was cooled to 08C and LiAlH4 was
added (14 mg, 0.36 mmol), and the reaction was stirred
until complete consumption of the ketone was evident by
TLC. The reaction was quenched with 1:1 Na2SO4´10H2O/
Celite and the resulting slurry was stirred for 30 min.
Anhydrous MgSO4 was added and the slurry stirred for
and additional 30 min. The slurry was then ®ltered, concen-
trated and the products separated by ¯ash chromatography
to afford 24a (95 mg, 67%) and 24b (14 mg, 10%).
4.1.19. Decomposition of diazoketone 19 with Rh2(OAc)4.
Compound 19 (50 mg, 0.22 mmol) was treated according to
the general procedure (CH2Cl2 (15 mL, 0.015 M),
Rh2(OAc)4 (3 mg, 0.007 mmol, 3 mol%), addition time
3 h via syringe pump) and ¯ash chromatography yielded
12 mg (25%) of ketone 21 and 14 mg (32%) of an
inseparable mixture of 20a/20b (5a/5b, 4:1 determined by
GC).
4.1.20. (1Sp,3Rp,6Rp)-3-Allyl-2,7-dioxabicyclo[4.4.0]decan-
4-one (20a). Rf 0.38 (30% EtOAc/hexanes);IR (neat) 2945,
2854, 1724, 1641, 1097 cm21; 1H NMR (500 MHz, CDCl3)
d 5.85 (dddd, Jˆ17.1, 10.3, 6.8, 6.8 Hz, 1H), 5.16±5.15 (m,
1H), 5.12±5.11 (m, 1H), 3.96±3.92 (m, 1H), 3.85 (dd,
Jˆ7.6, 4.3 Hz, 1H), 3.45±3.39 (m, 1H), 3.37±3.30 (m,
2H), 2.89 (dd, Jˆ15.8, 5.0 Hz, 1H), 2.64 (app br s, 1H),
2.50±2.41 (m, 1H), 2.39±2.32 (m, 1H), 2.22±2.05 (m,
1H), 1.80±1.75 (m, 2H), 1.57±1.49 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 205.4, 134.2, 117.6, 83.1, 77.5, 77.1,
67.7, 45.6, 33.8, 29.3, 25.3.
Two pot procedure: catalytic DBU (1 drop) was added to a
mixture of 20a/20b (307 mg, 1.57 mmol, 20a/20b, 1:30) in
toluene (15 mL, 0.1 M). The reaction was heated to re¯ux
and monitored by GC until no further no further change in
epimer ratio was observed (5 h). The mixture was then
condensed and passed through a short pad of silica gel
(3 cm in a disposable pipette) eluting with 50% Et2O/
hexanes. The solution was then concentrated to yield
301 mg (98%) of a mixture of 20a/20b enriched in 20a.
The mixture was dissolved in THF, cooled to 08C and
LiAlH4 (30 mg, 0.8 mmol) was added, the reaction was
then allowed to stir until complete consumption of the
ketone was evident by TLC. The reaction was quenched
with 1:1 Na2SO4´10H2O/Celite and the resulting slurry
was stirred for 30 min. Anhydrous MgSO4 was added and
the slurry stirred for and additional 30 min. The slurry was
then ®ltered, concentrated and the products separated
by ¯ash chromatography (silica gel, 2 cm£28 cm
column, solvent ramp: 100 mL each of 40, 50, 60, 70%
Et2O/hexanes) to afford 261 mg, (86%) of 24a (84% from
20a/20b) and 37 mg (12%) of 24b.
4.1.21. (1Sp,3Sp,6Rp)-3-Allyl-2,7-dioxabicyclo[4.4.0]decan-
4-one (20b). Rf 0.38 (30% EtOAc/hexanes);IR (neat) 3077,
1
2944, 2855, 1722, 1641, 1091 cm21; H NMR (500 MHz,
CDCl3) d 5.78 (dddd, Jˆ14.2, 9.6, 9.6, 7.1 Hz, 1H), 5.16±
5.15 (m, 1H), 5.13±5.12 (m, 1H), 4.09 (dd, Jˆ9.8, 5.4 Hz,
1H), 3.95±3.94 (m, 1H), 3.50 (ddd, Jˆ10.7, 9.2, 4.5 Hz,
1H), 3.44±3.38 (m, 1H), 3.34 (ddd, Jˆ11.7, 9.3, 5.5 Hz,
1H), 2.85 (ddd, Jˆ16.4, 5.5, 1.1 Hz, 1H), 2.61 (ddddd,
Jˆ14.4, 9.6, 7.1, 1.2, 1.2 Hz, 1H), 2.45 (dd, Jˆ16.4,
11.7 Hz, 1H), 2.39 (ddddd, Jˆ14.5, 6.7, 5.3, 1.2, 1.2 Hz,
1H), 2.13±2.08 (m, 1H), 1.81±1.76 (m, 2H), 1.53±1.45
(m 1H); 13C NMR (125 MHz, CDCl3) d 207.7, 132.9,
118.6, 81.8, 76.8, 70.1, 67.8, 43.7, 34.5, 29.4, 25.5.
4.1.25. (1Sp,3Rp,4Sp,6Rp)-3-Allyl-2,7-dioxabicyclo[4.4.0]-
decan-4-ol (24a). Rf 0.12 (30% EtOAc/hexanes);IR
(neat) 3435, 3075, 2943, 2868, 1103, 1066 cm21 1H
;
NMR (500 MHz, CDCl3) d 5.94 (dddd, Jˆ17.1, 10.1, 6.9,
6.9 Hz, 1H), 5.15 (dddd, Jˆ17.2, 1.5, 1.5, 1.5 Hz, 1H),
5.09±5.07 (m, 1H), 3.92±3.88 (m, 1H), 3.50 (ddd,
Jˆ10.7, 9.4, 4.5 Hz, 1H), 3.44±3.38 (m, 1H), 3.34 (ddd,
Jˆ11.7, 9.3, 5.5 Hz, 1H), 3.02±2.95 (m, 2H), 2.58±2.53
(m, 1H), 2.36±2.03 (m, 2H), 2.07± 2.03 (m, 1H), 1.76±
1.68 (m, 2H), 1.63 (br s, 1H), 1.51±1.37 (m 2H); 13C
4.1.22. (1Sp,6Rp)-6-Allyloxy-2-oxabicyclo[4.3.0]nonan-8-
one (21). Rf 0.34 (30% EtOAc/hexanes);IR (neat) 2934,
1
2860, 1750, 1095 cm21; H NMR (300 MHz, CDCl3) d
5.83 (dddd, Jˆ17.2, 10.4, 5.6, 5.6 Hz, 1H), 5.22 (dddd,
Jˆ17.2, 1.7, 1.7, 1.7 Hz, 1H), 5.13 (dddd, Jˆ10.4, 1.5,
1.5, 1.5 Hz, 1H), 3.99±3.83 (m, 4H), 3.46±3.38 (m, 1H),

È
F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2036
NMR (125 MHz, CDCl3) d 135.7, 117.7, 82.1, 78.4, 77.5,
70.5, 68.5, 39.6, 37.4, 29.9, 26.2;Anal. calcd for C 11H18O3:
C, 66.64, H, 9.15. Found, C, 66.37, H, 9.19.
24 mg (80%) of 2-((1Sp,3Rp,4Sp,6Rp)-4-allyloxy-2,7-dioxa-
bicyclo[4.4.0]decan-3-yl)acetic acid as a golden oil. If a
small amount of the bicyclic hydroxy-acid remained, the
two acids could be separated by ¯ash chromatography
(silica gel, solvent ramp: 100 mL each of 2.5, 5, 7.5, 10%
MeOH/CH2Cl2/20 drops glacial HOAc). Rf 0.55 (5%
MeOH/CH2Cl2/2 drops glacial HOAc in 10 mL);IR (neat)
4.1.26. (1Sp,3Sp,4Sp,6Rp)-3-Allyl-2,7-dioxabicyclo[4.4.0]-
decan-4-ol (24b). Rf 0.08 (30% EtOAc/hexanes); 1H
NMR (500 MHz, CDCl3) d 5.87 (dddd, Jˆ17.2, 10.1, 7.1,
7.1 Hz, 1H), 5.17±5.08 (m, 2H), 4.08 (ddd, Jˆ11.0, 5.5,
5.5 Hz, 1H), 3.99 (ddd, Jˆ15.7, 5.4, 5,4 Hz, 1H), 3.93±
3.89 (m, 1H), 3.59±3.50 (m, 1H), 3.17 (ddd, Jˆ10.9, 9.2,
4.3 Hz, 1H), 2.98 (ddd, Jˆ11.6, 9.3, 4.4 Hz, 1H), 2.59±2.53
(m, 1H), 2.43±2.38 (m, 1H), 2.14 (ddd, Jˆ11.5, 4.5, 4.5 Hz,
1H), 1.95±1.92 (m, 1H), 1.75±1.61 (m, 4H), 1.40±1.32 (m,
1H); 13C NMR (125 MHz, CDCl3) d 135.2, 117.2, 77.6,
76.2, 69.1, 68.2, 68.1, 34.4, 29.5, 28.8, 25.9.
1
3100, 2944, 2871, 1712, 1098 cm21; H NMR (500 MHz,
CDCl3) d 10.6 (br s, 1H) 5.87 (dddd, Jˆ16.3, 10.3, 5.9,
5.9 Hz, 1H), 5.26 (dddd, Jˆ17.3, 1.6, 1.6, 1.6 Hz, 1H),
5.18 (dddd, Jˆ10.3, 1.2, 1.2, 1.2 Hz, 1H), 4.12 (dddd,
Jˆ12.5, 5.4, 1.2, 1.2 Hz, 1H), 3.94±3.89 (m, 2H), 3.69
(ddd, Jˆ8.9, 8.9, 3.8 Hz, 1H), 3.39±3.34 (m, 1H), 3.22
(ddd, Jˆ10.9, 9.3, 4.5 Hz, 1H), 3.08 (ddd, Jˆ11.1, 8.9,
4.5 Hz, 1H), 2.95 (ddd, Jˆ11.5, 8.9, 4.2 Hz, 1H), 2.88
(dd, Jˆ15.6, 3.8 Hz, 1H), 2.50 (dd, Jˆ15.7, 8.2 Hz, 1H),
2.48±2.45 (m, 1H), 2.07±2.04 (m, 1H), 1.72±1.68 (m, 2H)
1.47±1.35 (m, 2H); 13C NMR (125 MHz, CDCl3) d 177.4,
134.6, 117.7, 77.9, 77.2, 76.7, 76.0, 69.9, 68.0, 37.9, 35.4,
29.3, 25.4;HRMS (FAB, M 21) for C13H19O5 calcd
255.1233, found: m/z 255.1234.
Oxidation of 24b: TPAP (30 mg, 0.086 mmol, 6 mol%) was
added to a mixture of NMO (388 mg, 3.31 mmol), 24b
Ê
(285 mg, 1.44 mmol), crushed and oven dried 4 A molecu-
lar sieves, and CH2Cl2 (9.56 mL, 0.15 M). After 10 min the
reaction was complete as ascertained by TLC, the mixture
was ®ltered and condensed. The resulting oil was passed
through a short pad of silica gel (2 cm in a disposable
pipette) eluting with 50% Et2O/hexanes and condensed to
yield 248 mg (88%) of pure 20b.
Isobutyl chloroformate (70 mL, 0.53 mmol, 1.0 equiv.) was
added to a mixture of triethylamine (74 mL, 0.53 mmol,
1.0 equiv.) and the allyl ether prepared above (137 mg,
0.53 mmol) in Et2O (2.12 mL). The reaction was heated to
re¯ux for 2.5 h then ®ltered and added via cannula to a
solution of CH2N2 (,4 mmol) in Et2O (,12 mL) at 08C.
The reaction was allowed to stand for 12 h and then diluted
with Et2O (12 mL) and carefully quenched with 0.1 M
HOAc (10 mL) until gas evolution ceased. The organic
phase was then washed with sat. NaHCO3 (20 mL). The
aqueous phase was extracted with Et2O (10 mL) and the
combined organic phase was washed with brine (30 mL),
dried over anhydrous MgSO4, ®ltered, concentrated and
puri®ed by ¯ash chromatography (silica gel, 2 cm£12 cm
column, 30% EtOAc/hexanes) to yield 58 mg (44%) of 25
as a yellow solid. Rf 0.13 (30% EtOAc/hexanes);IR (KBr)
4.1.27. 1-Diazo-3-((1Sp,3Rp,4Sp,6Rp)-4-allyloxy-2,7-dioxa-
bicyclo[4.4.0]decan-3-yl)propan-2-one (25). Compound
24a (489 mg, 2.47 mmol) was treated to the general ozo-
nolysis procedure (CH2Cl2 (17.3 mL), MeOH (3.3 mL),
88% formic acid (1.85 mL), 30% H2O2 (0.96 mL)) to afford
453 mg (85%) of 2-((1Sp,3Rp,4Sp,6Rp)-4-hydroxy-2,7-
dioxabicyclo[4.4.0]decan-3-yl)acetic acid as a white solid.
Alternatively, the crude reaction mixture can be puri®ed
directly after the oxidation by concentration followed by
¯ash chromatography (silica gel, solvent ramp: 100 mL
each of 2.5, 5, 7.5, 10% MeOH/CH2Cl2/20 drops glacial
HOAc). Rf 0.25 (5% MeOH/CH2Cl2/2 drops glacial
HOAc in 10 mL);mp 149±153 8C;IR (KBr) 3433, 2960,
3124, 2954, 2852, 2104, 1635, 1097 cm21 1H NMR
;
1
1724, 2858, 1690 cm21; H NMR (500 MHz, d6-acetone)
(500 MHz, CDCl3) d 5.86 (dddd, Jˆ16.3, 10.4, 5.0,
5.0 Hz, 1H), 5.34 (br s, 1H), 5.34±5.22 (m, 1H), 5.17±
5.15 (m, 1H), 4.12±4.08 (m, 1H), 3.92±3.87 (m, 2H), 3.65
(ddd, Jˆ8.9, 8.9, 2.8 Hz, 1H), 3.37±3.32 (m, 1H), 3.19 (ddd,
Jˆ10.6, 9.3, 4.4 Hz, 1H), 3.03 (ddd, Jˆ11.1, 8.9, 4.4 Hz,
1H), 2.92 (ddd, Jˆ11.6, 8.9, 4.3 Hz, 1H), 2.81 (app br d,
Jˆ14.8 Hz, 1H), 2.45 (ddd, Jˆ11.6, 4.4, 4.4 Hz, 1H), 2.47±
2.36 (s, br 1H), 2.04±2.01 (m, 1H) 1.72±1.66 (m, 2H),
1.44±1.32 (m, 2H); 13C NMR (125 MHz, CD2Cl2, 2258C)
d 193.2, 134.9, 117.1, 77.8, 77.4, 76.5, 75.8, 69.8, 67.9,
55.5, 43.8, 35.4, 29.3, 25.5;HRMS (FAB, M 11) for
C14H21N2O4 calcd 281.1501, found: m/z 281.1501.
d 10.6 (br s, 1H), 3.98±3.88 (br s, 1H), 3.81±3.78 (m,
1H), 3.55 (ddd, Jˆ9.1, 9.1, 2.7 Hz, 1H), 3.37 (ddd,
Jˆ10.8, 9.4, 4.5 Hz, 1H), 3.33±3.28 (m, 1H), 2.96±2.88
(m, 2H), 2.87 (dd, Jˆ15.7, 2.8 Hz, 1H), 2.26 (dd, Jˆ15.7,
9.3 Hz, 1H), 2.55±2.22 (m, 1H), 1.94±1.91 (m, 1H), 1.66,
1.59 (m, 2H), 1.44 (ddd, Jˆ11.2, 11.2, 11.2 Hz, 1H), 1.38±
1.30 (m, 1H); 13C NMR (125 MHz, d6-acetone) d 173.5,
80.7, 79.1, 78.2, 70.1, 68.5, 40.5, 38.5, 30.5, 26.7;HRMS
(FAB, M21) for C10H15O5 calcd 215.0920, found: m/z
215.0912.
The acid (25 mg, 0.12 mmol) was dissolved in DME
(0.3 mL) and then added via cannula to a mixture of KH
(40 mg of 35% dispersion in mineral oil, 0.35 mmol,
3 equiv., washed with hexanes prior to addition25) in DME
(0.3 mL) at 08C. After 10 min, allyl bromide was added
(11 mL, 0.13 mmol, 1.1 equiv.). The reaction was carefully
quenched after 4 h with water (0.3 mL). The organic phase
was extracted with 1N KOH (0.3 mL) and the combined
aqueous phase was then washed with Et2O (2 mL), acidi®ed
with 3N HCl until the pH,1±2, and then extracted with
Et2O (8£2 mL). The combined organic phase was dried
over anhydrous MgSO4, ®ltered, and concentrated to afford
4.1.28. Tris(pyran) 26b (a-isomer). Compound 25 (35 mg,
0.13 mmol) was treated under the general procedure
(CH2Cl2 (12.5 mL, 0.01 M), Cu(tfacac)2 (2 mg, 5 mol%))
and puri®ed by ¯ash chromatography (silica gel,
2 cm£12 cm column, solvent ramp: 100 mL each of 10,
20, 30, 40% Et2O/hexanes) to afford 25 mg (80%) of 26b
as a white solid. Rf 0.30 (50% Et2O/hexanes);mp 84±85 8C;
1
IR (KBr) 2955, 2874, 1722, 1107, 1021 cm21; H NMR
(500 MHz, CD2Cl2) d 5.78 (dddd, Jˆ17.0, 10.2, 6.9,
6.9 Hz, 1H), 5.16±5.10 (m, 2H), 4.04 (ddd, Jˆ9.8, 5.5,
0.6 Hz, 1H), 3.91±3.86 (m, 1H), 3.56 (ddd, Jˆ11.1, 9.3,

È
F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2037
4.5 Hz, 1H), 3.43 (ddd, Jˆ11.7, 9.4, 5.6 Hz, 1H), 3.39±3.34
(m, 1H), 3.10±3.05 (m, 2H), 2.82 (ddd, Jˆ16.3, 5.5, 1.1 Hz,
1H), 2.60 (ddddd, Jˆ14.5, 9.7, 7.2, 1.2, 1.2 Hz, 1H), 2.45
(ddd, Jˆ16.4, 11.7, 0.6 Hz, 1H), 2.36 (ddddd, Jˆ14.9, 6.9,
5.5, 1.4, 1.4 Hz, 1H), 2.28 (ddd, Jˆ11.4, 3.9, 3.9 Hz, 1H),
2.06±2.00 (m, 1H) 1.77±1.67 (m, 2H) 1.55±1.38 (m, 2H);
13C NMR (125 MHz, CD2Cl2) d 207.4, 133.6, 118.4, 81.7,
78.5, 77.6, 76.7, 69.6, 68.5, 43.9, 36.1, 34.8, 29.8, 26.1;
HRMS (EI) for C14H20O4 calcd 252.1362, found; m/z
252.1369.
for 2 min after which 14 (1.857 g, 13.1 mmol) in CH2Cl2
(13 mL) was added via cannula. After 15 min triethylamine
(9.12 mL, 65.4 mmol, 5 equiv.) was added via syringe. The
solution was stirred for 5 min after which the cooling bath
was removed and the solution warmed to rt. The reaction
was quenched by the addition of water (30 mL), the aqueous
phase was back extracted with CH2Cl2 (30 mL) and the
combined organic phase wash washed with 2% HCl, sat.
NaHCO3, and brine (50 mL each), dried with anhydrous
MgSO4, ®ltered and carefully concentrated. The crude
yellow oil was dissolved in toluene (120 mL) and cooled
to 2788C and MeMgBr (4.0 mL, 12.0 mmol) was added via
syringe. The reaction was stirred until the starting material
was consumed as ascertained by TLC plus an additional
30 min. The reaction was quenched by the addition of sat.
NH4Cl solution (100 mL) and the aqueous phase was back-
extracted with Et2O (100 mL). The combined organic phase
was dried with anhydrous MgSO4, ®ltered, concentrated and
puri®ed by ¯ash chromatography (silica gel, 5 cm£13 cm
column, 50% Et2O/hexanes) to yield 1.581 g (77%) of
(2Rp,3Sp)-2-allyl-3-methyl-3-hydroxytetrahydropyran as a
faintly yellow oil (5:1 inseparable mixture of dia-
stereomers). Rf 0.23 (50% Et2O/hexanes);IR (neat) 3466,
4.1.29. Tris(pyran) 26a (b-isomer). Catalytic DBU (1
drop) was added to 26b (22 mg, 0.087 mmol) in toluene
(0.9 mL, 0.1 M). The reaction was heated to re¯ux and
monitored by GC until no further change in epimer ratio
was observed (6 h). The mixture was then cooled to rt,
condensed and passed through a short pad of silica gel
(2 cm in a disposable pipette) eluting with 50% Et2O/
hexanes. The solution was then concentrated to yield
20 mg (91%) of a mixture of 26a/26b enriched in 26a as a
white solid (26a/26b, 10:1 determined by GC). Rf 0.36 (30%
EtOAc/hexanes);mp 88±94 8C;IR (KBr) 2955, 2861, 1723,
1098, 1023 cm21 1H NMR (500 MHz, CDCl3) d 5.84
;
1
(dddd, Jˆ17.0, 10.2, 6.7, 6.7 Hz, 1H), 5.13 (dddd,
Jˆ17.6, 2.4, 2.4, 2.4 Hz, 1H) 5.08±5.05 (m, 1H), 3.96±
3.92 (m, 1H), 3.83 (dd, Jˆ7.4, 4.3 Hz, 1H), 3.46±3.37 (m,
3H), 3.13±3.06 (m, 2H), 2.92 (dd, Jˆ15.5, 4.9 Hz, 1H),
2.68±2.61 (m, 1H), 2.49±2.32 (m, 3H), 2.09±2.04 (m,
1H), 1.78±1.72 (m, 2H), 1.63±1.56 (m, 1H), 1.49±1.40
(m, 1H); 13C NMR (75 MHz, CD2Cl2) d 205.2, 134.8,
117.5, 83.1, 78.4, 77.5, 77.2, 76.4, 68.4, 45.6, 36.0, 34.2,
29.7, 26.1.
3073, 2939, 2852, 1636, 1098 cm21; H NMR, major dia-
stereomer, (500 MHz, CDCl3) d 5.94±5.85 (m, 1H), 5.15±
5.04 (m, 2H), 4.02±3.98 (m, 1H), 3.41±3.35 (m, 1H), 3.18
(dd, Jˆ9.5, 3.3 Hz, 1H), 2.39±2.33 (m, 1H), 2.30±2.25 (m,
1H), 1.93±1.82 (m, 1H), 1.77±1.67 (m, 1H), 1.64±1.46 (m,
3H), 1.13 (s, 3H); 13C NMR, mixture of diastereomers,
(125 MHz, CDCl3) d 136.5, 136.3, 116.6, 116.5, 84.3,
84.1, 70.2, 69.1, 68.9, 68.0, 39.6, 37.6, 33.9, 33.7, 24.9,
22.6, 20.8 (one overlapping signal);HRMS (EI) for
C9H16O2 calcd 156.1151, found: m/z 156.1152.
4.1.30. Tris(pyran) 27a. LiAlH4 (2 mg, 0.04 mmol) was
added to a solution of 26a/26b (19 mg, 0.075 mmol) in
THF (0.75 mL, 0.1 M) cooled to 08C. The reaction was
then allowed to stir until complete consumption of the start-
ing material was evident by TLC. The reaction was
quenched with 1:1 Na2SO4´10H2O/Celite and the resulting
slurry was stirred for 30 min. Anhydrous MgSO4 was added
and the slurry stirred for and additional 30 min. The slurry
was then ®ltered, concentrated and the products separated
by ¯ash chromatography (silica gel, 2 cm£10 cm column,
solvent ramp: 100 mL each of 50, 60, 70, 80, 90% Et2O/
hexanes) to afford 18 mg (94%) of 27a as a white solid and
1 mg (5%) of an isomer. Rf 0.32 (100% Et2O);IR (KBr)
The tertiary alcohol prepared above (256 mg, 1.64 mmol)
was treated to the standard ozonolysis procedure (CH2Cl2
(11.5 mL), MeOH (2.2 mL), 88% formic acid (1.2 mL),
30% H2O2 (0.65 mL)). Directly following the oxidation,
the reaction mixture was concentrated and the residue was
placed under high vacuum for 6 h. The residue was then
dissolved in Et2O (10 mL) and cooled to 08C. Freshly
prepared diazomethane was then added by pouring through
a glass funnel (behind a blast shield, in a fume hood) and the
reaction was complete after 10 min as ascertained by TLC.
The solvent was evaporated with a stream of nitrogen (in a
fume hood) and the yellow residue was puri®ed by ¯ash
chromatography (silica gel, 2 cm£3 cm column, 50%
EtOAc/hexanes) to yield 147 mg (48%) of 28 as a white
1
3391, 2939, 2852, 1113, 1088 cm21; H NMR (500 MHz,
CDCl3) d 5.95 (dddd, Jˆ17.2, 10.1, 6.9, 6.9 Hz, 1H), 5.17±
5.13 (m, 1H), 5.10±5.08 (m, 1H), 3.93±3.90 (m, 1H), 3.54±
3.48 (m, 1H), 3.38 (ddd, Jˆ11.4, 11.4, 4.0 Hz, 1H), 3.18
(ddd, Jˆ9.2, 6.9, 4.2 Hz, 1H), 3.12±2.99 (m, 4H), 2.58±
2.53 (m, 1H), 2.40±2.28 (m, 3H), 2.08±2.05 (m, 1H),
1.76±1.69 (m, 2H), 1.61 (app br d, 1H), 1.54±1.39 (m,
3H); 13C NMR (75 MHz, CD2Cl2) d 135.7, 117.1, 82.0,
78.7, 77.8, 77.2, 77.0, 69.9, 68.4, 39.2, 36.9, 36.1, 29.8,
26.1;HRMS (EI) for C 14H22O4 calcd 254.1518, found; m/z
254.1508.
1
solid. Rf 0.25 (50% EtOAc/hexanes); H NMR (500 MHz,
CDCl3) d 3.92 (dddd, Jˆ11.4, 4.8, 1.7, 1.7 Hz, 1H), 3.70 (s,
3H), 3.61 (dd, Jˆ9.5, 3.5 Hz, 1H), 3.41 (ddd, Jˆ11.6, 11.6,
2.8 Hz, 1H), 2.72 (dd, Jˆ15.3, 3.4 Hz, 1H), 2.38 (dd,
Jˆ15.4, 9.5 Hz, 1H), 1.90±1.86 (m, 1H), 1.78±1.68 (m,
1H), 1.63±1.53 (m, 3H), 1.20 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 173.1, 81.5, 69.7, 68.4, 52.1, 40.2,
35.3, 25.1, 20.2;Anal. calcd for C H16O4: C, 57.43, H,
9
8.56. Found, C, 57.58, H, 8.75.
4.1.31. 2-((2Rp,3Sp)-3-Hydroxy-3-methyltetrahydropyran-
2-yl)aceticacidmethyl ester (28). To a solution of oxalyl
chloride (1.26 mL, 14.4 mmol, 1.1 equiv.) in CH2Cl2
(20 mL) cooled to 2788C was added DMSO (2.0 mL,
28.8 mmol, 2.2 equiv.) dropwise. The solution was stirred
4.1.32.
hydropyran-2-yl)propane-2-one 29. To
solution of 28 (50 mg, 0.27 mmol) and allylmethylcarbo-
nate (124 mL, 1.08 mmol, 4 equiv.) in THF (2.65 mL,
0.1 M) was added Pd(OAc)2 (1.2 mg, 0.0054 mmol,
1-Diazo-3-((2Rp,3Sp)-3-allyloxy-3-methyltetra-
degassed
a

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F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2038
2 mol%). The solution was degassed again and triphenyl-
phosphine was added (5.6 mg, 0.022 mmol, 0.08 equiv.)
and the solution was heated to re¯ux for 20 h. The reaction
was then allowed to cool to rt, then condensed and passed
through a short pad of silica gel (3 cm in a disposable
pipette) eluting with 50% EtOAc/hexanes. The solvent
was removed under reduced pressure and the crude material
was puri®ed by ¯ash chromatography to obtain 33 mg
(55%) of 2-((2Rp,3Sp)-3-allyloxy-3-methyltetrahydro-
pyran-2-yl)aceticacid methyl ester and 20 mg (40%
4.1.33. Decomposition of diazoketone 29 with Cu-
(tfacac)2. The compound 29 (21 mg, 0.082 mmol) was
treated according to the general procedure (Cu(tfacac)2
(3.3 mg, 0.009 mmol, 10 mol%), CH2Cl2 (8.8 mL,
0.01 M)) and puri®cation by radial chromatography (2 mm
plate, solvent ramp: 100 mL each of 10, 15, 20% EtOAc/
hexanes) yielded 4 mg (23%) of 31, 2 mg (10%) of 30a and
6 mg (35%) of 30b.
4.1.34. (1Sp,3Rp,6Rp)-1-Methyl-3-allyl-2,7-dioxabicyclo-
[4.4.0]decan-4-one (30a). Rf 0.60 (50% EtOAc/hexanes);
recovery) of the starting material. Rf 0.54 (50% EtOAc/
1H
21
1
hexanes);IR (neat) 2950, 2863, 1744, 1125 cm
;
IR (neat) 3078, 2946, 2856, 1721, 1134, 1089 cm21; H
NMR (500 MHz, CDCl3) d 5.90±5.82 (m, 1H), 5.25±5.20
(m, 1H), 5.11±5.07 (m, 1H), 3.97±3.90 (m, 3H), 3.75±3.72
(m, 1H), 3.68±3.67 (app br t, 3H), 3.44±3.39 (m, 1H), 2.74
(ddd, Jˆ15.3, 2.8, 1.1 Hz, 1H), 2.30 (ddd, Jˆ15.3, 10.0,
1.2 Hz, 1H), 2.02±1.99 (m, 1H), 1.70±1.58 (m, 3H), 1.20
(s, 3H); 13C NMR (125 MHz, CDCl3) d 172.9, 136.0, 115.7,
80.1, 73.6, 68.7, 62.1, 51.9, 35.3, 35.2, 24.6, 16.9;HRMS
(CI, M11) for C12H21O4 calcd 229.1440, found: m/z
229.1445.
NMR (500 MHz, CDCl3) d 5.83 (dddd, Jˆ17.1, 10.1, 6.9,
6.9 Hz 1H), 5.11 (ddd, Jˆ17.2, 3.4, 1.5 Hz, 1H), 5.07±5.05
(m, 1H), 4.10±4.08 (m, 1H), 4.00±3.96 (m, 1H), 3.47 (ddd,
Jˆ12.6, 11.6, 2.8 Hz, 1H), 3.40 (dd, Jˆ12.6, 5.9 Hz, 1H),
2.73±2.68 (m, 1H), 2.60±2.54 (m, 1H), 2.45±2.39 (m, 2H),
1.95±1.84 (m, 2H), 1.70±1.59 (m, 2H), 1.31 (d, Jˆ0.7 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 208.0, 134.1, 117.8,
77.9, 77.8, 72.1, 68.7, 41.8, 37.1, 35.4, 24.3, 14.2;HRMS
(CI) for C12H18O3 calcd 210.1256, found: m/z 210.1237.
To a solution of the allylated product from above (151 mg,
0.66 mmol) in MeOH (1.32 mL, 0.5 M) was added 2N
LiOH (0.66 mL). The reaction was stirred until completion
as ascertained by TLC (12 h). The solution was transferred
to a separatory funnel and diluted with 2 M NaOH (1 mL)
and water (5 mL) and washed with Et2O (2x10 mL). The
aqueous phase was acidi®ed with 3N HCl until the pH,1±2
and extracted with EtOAc (5£10 mL). The combined
organic phase was dried with anhydrous MgSO4, ®ltered
and concentrated to afford 138 mg (98%) of 2-((2Rp,3Sp)-
3-allyloxy-3-methyltetrahydropyran-2-yl)acetic acid as a
brownish oil. IR (neat) 3048, 2944, 2863, 1722,
4.1.35. (1Sp,3Sp,6Rp)-1-Methyl-3-allyl-2,7-dioxabicyclo-
[4.4.0]decan-4-one (30b). Rf 0.55 (50% EtOAc/hexanes);
1H NMR (500 MHz, CDCl3) d 5.86 (dddd, Jˆ17.2, 10.3,
7.1, 7.1 Hz, 1H), 5.15±5.08 (m, 2H), 4.15 (dd, Jˆ8.4,
4.4 Hz, 1H), 3.99±3.96 (m, 1H), 3.66 (dd, Jˆ11.7, 6.7 Hz,
1H), 3.49±3.44 (m, 1H), 2.80 (dd, Jˆ18.8, 6.7 Hz, 1H),
2.66±2.60 (m, 1H), 2.41 (ddd, Jˆ18.8, 11.7, 0.6 Hz, 1H),
2.38±2.31 (m, 1H), 1.96±1.93 (m, 1H), 1.87±1.77 (m, 1H),
1.67±1.61 (m, 2H), 1.19 (d, Jˆ0.9 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 208.7, 134.5, 117.8, 79.8, 76.5, 72.3,
68.6, 40.5, 38.3, 37.6, 24.3, 18.0.
1136 cm21; H NMR (500 MHz, CDCl3) d 10.93 (br s,
4.1.36. (1Sp,6Rp)-1-Methyl-4-allyloxy-2,7-dioxabicyclo-
[4.4.0]dec-3-ene (31). Rf 0.69 (50% EtOAc/hexanes);IR
1
1H), 5.86 (dddd, Jˆ17.1, 10.5, 5.3, 5.3 Hz, 1H), 5.25±
5.22 (m, 1H), 5.11±5.09 (m, 1H), 3.97±3.91 (m, 3H), 3.71
(dd, Jˆ10.0, 2.7 Hz, 1H), 3.46±3.41 (m, 1H), 2.81 (dd,
Jˆ15.6, 2.8, Hz, 1H), 2.35 (ddd, Jˆ15.6, 10.1, 1.7 Hz,
1H), 2.09±2.02 (m, 1H), 1.72±1.58 (m, 3H), 1.21 (s, 3H);
13C NMR (125 MHz, CDCl3) d 177.3, 135.8, 115.9, 79.8,
73.6, 68.8, 62.2, 35.2, 35.1, 24.5, 16.9;HRMS (FAB, M 11)
for C11H19O4 calcd 215.1283, found: m/z 215.1289.
1
(neat) 2942, 2852, 1157, 1091 cm21; H NMR (500 MHz,
CDCl3) d 6.01 (dd, Jˆ2.2, 0.7 Hz, 1H), 5.95 (dddd, Jˆ17.2,
10.4, 5.6, 5.6 Hz, 1H), 5.32 (dddd, Jˆ17.2, 1.6, 1.6, 1.6 Hz,
1H), 5.24±5.21 (m, 1H), 4.15 (dddd, Jˆ12.2, 5.5, 1.5,
1.5 Hz, 1H), 4.11 (dddd, Jˆ12.3, 5.7, 1.5, 1.5 Hz, 1H),
3.97 (dddd, Jˆ11.4, 5.0, 1.3, 1.3 Hz, 1H), 3.44 (ddd,
Jˆ12.6, 11.5, 2.4 Hz, 1H), 3.35 (dd, Jˆ10.6, 6.1 Hz, 1H),
2.35 (dd, Jˆ15.8, 6.3 Hz, 1H), 2.14 (ddd, Jˆ15.8, 10.7,
2.2 Hz, 1H), 1.94±1.78 (m, 2H), 1.65±1.55 (m, 2H), 1.18
(d, Jˆ0.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 137.0,
133.9, 124.0, 117.8, 76.3, 73.2, 69.5, 68.7, 36.7, 28.4, 24.6,
15.2;HRMS (CI) for C 12H18O3 calcd 210.1256, found: m/z
210.1253.
The acid prepared above (63 mg, 0.29 mmol) was treated
according to the general procedure for diazoketone forma-
tion (oxalyl chloride (31 mL, 0.35 mmol, 1.2 equiv.),
CH2Cl2 (2 mL), one drop of DMF, CH2N2 (,4 mmol),
Et2O (12 mL)) and puri®ed by radial chromatography
(2 mm plate, 100 mL of 20% followed by 100 mL of 35%
EtOAc/hexanes) to yield 46 mg (67%) of 29 as a yellow
solid. Rf 0.36 (50% EtOAc/hexanes);IR (neat) 3084,
4.1.37. Epimerization of 30a/30b. Catalytic DBU (1 drop)
was added to mixture of 30a/30b (7 mg, 0.03 mmol, 30a/
30b, 1:5 as determined by GC) in toluene (0.33 mL). The
reaction was heated to 808C and monitored by TLC and
stirred until only 30a was observed (4 h). The reaction
was cooled to rt and loaded onto a short pad of silica
(1 cm in a disposable pipette) eluting with 10% EtOAc/
hexanes (10 mL). The solvent was evaporated under
reduced pressure to afford 6 mg of 30a (86%, 30a/30b,
32:1 as determined by GC).
2943, 2860, 2102, 1636, 1352, 1130 cm21 1H NMR
;
(500 MHz, CDCl3) d 5.86 (dddd, Jˆ17.2, 10.4, 5.1,
5.1 Hz, 1H), 5.33 (br s, 1H), 5.23 (dddd, Jˆ17.2, 1.8, 1.8,
1.8 Hz, 1H), 5.09 (dddd, Jˆ10.4, 1.4, 1.4, 1.4 Hz, 1H),
3.97±3.89 (m, 3H), 3.70 (dd, Jˆ10.1, 2.1 Hz, 1H), 3.42±
3.37 (m, 1H), 2.72 (dd, Jˆ14.9, 1.8 Hz, 1H), 2.28 (app br t,
1H), 2.01±1.97 (m, 1H), 1.73±1.58 (m, 3H), 1.19 (s, 3H);
13C NMR (125 MHz, CDCl3) d 193.9, 136.0, 115.7, 80.1,
73.6, 68.7, 62.1, 55.3, 41.5, 35.2, 24.6, 17.1;HRMS (CI,
M11) for C12H19N2O4 calcd 239.1396, found: m/z
239.1403.
4.1.38. 1-Diazo-4-((2Rp,3Sp)-3-allyloxytetrahydropyran-
2-yl)butane-2-one 32. To a solution of diazoketone 19

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F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2039
(108 mg, 0.48 mmol) in THF (20 mL) and water (10 mL)
was added silver nitrate (86 mg, 0.51 mmol, 1.05 equiv.).
The reaction was stirred for 16 h and then diluted with
water (30 mL) and extracted with CH2Cl2 (5£30 mL). The
combined organic phase was dried with anhydrous MgSO4,
®ltered and concentrated to yield 100 mg (98%) of
3-((2Rp,3Sp)-3-allyloxytetrahydropyran-2-yl)propanoic acid
as a yellow oil. IR (neat) 3080, 2940, 2860, 1710,
the general procedure (Rh2(tpa)4 (10 mg, 0.007 mmol,
3 mol%), CH2Cl2 (24 mL, 0.01 M)) and puri®cation by
radial chromatography (2 mm plate, 200 mL 25% EtOAc/
hexanes followed by 200 mL 30% EtOAc/hexanes) yielded
22 mg (41%) of 16a, 9 mg (17%) of 16b, and 6 mg (12%) of
34.
4.1.41. (1Sp,3Sp,6Rp)-3-Benzyl-2,7-dioxabicyclo[4.4.0]-
decan-4-one (16b). Rf 0.48 (50% EtOAc/hexanes); 1H
NMR (500 MHz, CDCl3) d 7.33±7.19 (m, 5H), 4.28±4.25
(m, 1H), 3.96±3.91 (m, 1H), 3.55 (ddd, Jˆ10.6, 9.4, 4.5 Hz,
1H), 3.43±3.34 (m, 2H), 3.16 (dd, Jˆ14.2, 9.9 Hz, 1H),
2.93±2.86 (m, 2H), 2.50 (dd, Jˆ16.5, 11.5 Hz, 1H), 2.09±
2.06 (m, 1H), 1.81±1.76 (m, 2H), 1.52±1.45 (m, 1H); 13C
NMR (125 MHz, CDCl3) d 207.9, 137.0, 129.5, 128.8,
127.1, 83.3, 76.6, 70.4, 67.8, 44.1, 36.2, 29.3, 25.5.
1100 cm21 1H NMR (300 MHz, CDCl3) d 9.50 (br s,
;
1H), 5.89 (dddd, Jˆ17.1, 10.3, 6.0, 6.0 Hz, 1H), 5.25
(ddd, Jˆ17.2, 1.6, 1.6 Hz, 1H), 5.16 (ddd, Jˆ10.3, 1.2,
1.2 Hz, 1H), 4.10 (dddd, Jˆ12.6, 5.6, 1.5, 1.5 Hz, 1H),
3.95±3.85 (m, 2H), 3.35±3.26 (m, 1H), 3.12 (ddd, Jˆ8.8,
8.8, 2.8 Hz, 1H), 3.02 (ddd, Jˆ10.3, 8.9, 4.2 Hz, 1H), 2.60±
2.38 (m, 2H), 2.29±2.19 (m, 2H), 1.76±1.55 (m, 3H), 1.40±
1.24 (m, 1H); 13C NMR (75 MHz, CDCl3) d 179.5, 135.1,
117.3, 80.3, 77.3, 70.0, 67.9, 30.7, 29.4, 27.5, 25.5. HRMS
(FAB, M11) for C11H19O4 calcd 215.1283, found: m/z
215.1283.
4.1.42.
(1Sp,6Rp)-4-Benzyloxy-2,7-dioxabicyclo[4.4.0]-
dec-3-ene (34). Rf 0.60 (50% EtOAc/hexanes);IR (neat)
1
3031, 2033, 2849, 1145, 1069 cm21; H NMR (500 MHz,
The acid prepared above (128 mg, 0.59 mmol) was treated
according to the general procedure for diazoketone forma-
tion (oxalyl chloride (63 mL, 0.72 mmol, 1.2 equiv.),
CH2Cl2 (4 mL), one drop of DMF) and puri®ed by radial
chromatography (2 mm plate, 200 mL of 50% EtOAc/
hexanes) to yield 129 mg (91%) of 32 as a yellow oil. Rf
0.33 (50% EtOAc/hexanes);IR (neat) 3089, 2933, 2853,
CDCl3) d 7.27±7.17 (m, 5H), 6.16±6.15 (m, 1H), 4.59 (d,
JABˆ11.4 Hz, 1H), 4.53 (d, JABˆ11.4 Hz, 1H), 3.87±3.83
(m, 1H), 3.36±3.27 (m, 2H), 3.18 (ddd, Jˆ10.9, 9.4, 4.5 Hz,
1H), 2.42 (dd, Jˆ15.9, 6.5 Hz, 1H), 2.24 (ddd, Jˆ15.9, 9.6,
2.2 Hz, 1H), 2.08±2.05 (m, 1H), 1.72±1.62 (m, 2H), 1.45±
1.38 (m, 1H); 13C NMR (125 MHz, CDCl3) d 138.6, 137.4,
128.7, 128.2, 127.9, 126.3, 74.6, 74.5, 70.6, 67.9, 31.5, 29.1,
25.5;HRMS (EI) for C 15H18O3 calcd 246.1256, found: m/z
246.1262.
1
2099, 1642, 1372, 1345, 1098 cm21; H NMR (500 MHz,
CDCl3) d 5.89 (dddd, Jˆ17.2, 10.4, 5.7, 5.7 Hz, 1H), 5.26
(dddd, Jˆ17.2, 1.6, 1.6, 1.6 Hz, 1H), 5.25 (br s, 1H), 5.16
(dddd, Jˆ10.3, 1.3, 1.3, 1.3 Hz, 1H), 4.10 (dddd, Jˆ12.5,
5.6, 1.3, 1.3 Hz, 1H), 3.92 (dddd, Jˆ12.5, 5.8, 1.4, 1.4 Hz,
1H), 3.89±3.83 (m, 1H), 3.3 (ddd, Jˆ11.3, 11.3, 3.0 Hz,
1H), 3.11±2.96 (m, 2H), 2.54±2.39 (m, 2H), 2.30±2.17
(m, 2H), 1.73±1.54 (m, 3H), 1.39±1.26 (m, 1H); 13C
NMR (125 MHz, CDCl3) d 195.4, 135.2, 117.2, 80.3,
77.0, 70.1, 67.9, 54.4, 37.3, 29.5, 27.9, 25.6;Anal.
calcd for C12H18N2O3: C, 60.49, H, 7.61. Found, C, 60.62,
H, 7.58.
4.1.43. Decomposition of diazoketone 25 with Rh2(tpa)4.
The compound 32 (44 mg, 0.18 mmol) was treated accord-
ing to the general procedure (Rh2(tpa)4 (7 mg, 0.005 mmol,
3 mol%), CH2Cl2 (17 mL, 0.01 M)) and puri®cation by ¯ash
chromatography (silica gel, 2 cm£15 cm, 100 mL 20%
EtOAc/hexanes, 200 mL 25% EtOAc/hexanes, 100 mL
35% EtOAc/hexanes) yielded 16 mg (42%) of 35a and
13 mg (35%) of 35b.
4.1.44. Cyclopropane diastereomer 35a. Rf 0.39 (50%
EtOAc/hexanes);IR (neat) 3005, 2931, 2849, 1695, 1378,
1209, 1091 cm21; 1H NMR (500 MHz, CDCl3) d 4.26 (dd,
Jˆ11.7, 5.1 Hz, 1H), 3.84±3.81 (m, 1H), 3.28±3.23 (m,
1H), 3.09 (ddd, Jˆ9.5, 6.7, 3.5 Hz, 1H), 2.79 (dd, Jˆ14.6,
10.1 Hz, 1H), 2.72 (ddd, Jˆ10.6, 9.4, 4.9 Hz, 1H), 2.58 (dd,
Jˆ11.0, 11.0 Hz, 1H), 2.54 (dd, Jˆ14.9, 10.5 Hz, 1H),
2.37±2.32 (m, 1H), 2.20±2.13 (m, 2H), 2.02±1.96 (m,
1H), 1.79±1.71 (m, 1H), 1.58±1.40 (m, 3H), 1.28±1.20
(m, 1H), 0.88 (ddd, Jˆ8.2, 6.8, 5.1 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 209.9, 80.7, 79.7, 71.0, 67.8, 39.6,
31.6, 28.8, 26.2, 25.6, 24.4, 9.9;HRMS (CI, M 11) for
C12H19O3 calcd 211.1334, found: m/z 211.1327.
4.1.39. Decomposition of diazoketone 32 with
Cu(tfacac)2. The compound 32 (40 mg, 0.17 mmol) was
treated according to the general procedure (Cu(tfacac)2
(6 mg, 0.017 mmol, 10 mol%), CH2Cl2 (17 mL, 0.01 M))
and puri®cation by ¯ash chromatography (silica gel,
2 cm£15 cm, 100 mL 20% EtOAc/hexanes, 200 mL 25%
EtOAc/hexanes, 100 mL 35% EtOAc/hexanes) yielded
19 mg (55%) of ketone 33 as a colorless oil. Rf 0.37 (50%
Et2O/hexanes);IR (neat) 3080, 2941, 2863, 1743, 1091,
1
1073 cm21; H NMR (500 MHz, CDCl3) d 5.94±5.81 (m,
1H), 5.23 (dddd, Jˆ17.2, 1.5, 1.5, 1.5 Hz, 1H), 5.15 (dddd,
Jˆ10.3, 1.4, 1.4, 1.4 Hz, 1H), 4.14 (dddd, Jˆ12.8, 2.8, 1.5,
1.5 Hz, 1H), 3.92 (dddd, Jˆ12.7, 5.8, 1.4, 1.4 Hz, 1H),
3.71±3.65 (m, 1H), 3.42 (ddd, Jˆ11.4, 11.4, 3.2 Hz, 1H),
3.28 (dd, Jˆ10.5, 4.2 Hz, 1H), 2.51 (d, JABˆ18.0 Hz, 1H),
2.47 (d, JABˆ18.0 Hz, 1H), 2.45±2.22 (m, 2H), 2.08±1.94
(m, 2H), 1.74±1.59 (m, 3H), 1.42±1.29 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 217.7, 135.0, 117.1, 83.1, 78.2, 70.1,
62.4, 42.1, 36.6, 33.2, 25.9, 24.8;HRMS (EI) for C 12H18O3
calcd 210.1256, found: m/z 210.1241.
4.1.45. Cyclopropane diastereomer 35b. Rf 0.24 (50%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3, 458C) d
3.87±3.84 (m, 1H), 3.73 (dd, Jˆ11.8, 4.8 Hz, 1H), 3.34
(dd, Jˆ11.1, 6.8 Hz, 1H), 3.29 (ddd, Jˆ11.5, 11.5, 3.2 Hz,
1H), 3.20 (ddd, Jˆ10.0, 10.0, 4.9 Hz, 1H), 2.98 (ddd, Jˆ9.9,
9.9, 2.9 Hz, 1H), 2.68 (ddd, Jˆ15.9, 13.1, 1.6 Hz, 1H), 2.47
(dd, Jˆ15.9, 7.9 Hz, 1H), 2.31 (dddd, Jˆ14.4, 12.4, 10.1,
1.8 Hz, 1H), 2.10±1.98 (m, 3H), 1.84±1.77 (m, 1H), 1.66±
1.54 (m, 3H), 1.28 (dddd, Jˆ12.6, 12.6, 11.0, 5.3 Hz, 1H),
0.93 (ddd, Jˆ7.9, 7.9, 4.9 Hz, 1H); 13C NMR (125 MHz,
4.1.40. Decomposition of diazoketone 15 with Rh2(tpa)4.
Compound 15 (60 mg, 0.22 mmol) was treated according to

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F. P. Marmsater et al. / Tetrahedron 58 (2002) 2027±2040
2040
10. (a) Wang, P.;Adams, J. J. Am. Chem. Soc. 1994, 116, 3296.
(b) Spero, D. M.;Adams, J. Tetrahedron Lett. 1992, 33, 1143.
11. (a) Mori, T.;Taniguchi, M.;Suzuki, F.;Doi, H.;Oku, A.
J. Chem. Soc., Perkin Trans. 1 1998, 3623. (b) Oku, A.;
Murai, N.;Baird, J. J. Org. Chem. 1997, 62, 2123. (c) Pirrung,
M. C.;Brown, W. L.;Rege, S.;Laughton, P. J. Am. Chem.
Soc. 1991, 113, 8561. (d) Sueda, T.;Nagaoka, T.;Goto, S.;
Ochiai, M. J. Am. Chem. Soc. 1996, 118, 10141.
CDCl3, 458C) d 207.7, 80.3, 77.1, 67.8, 65.3, 40.8, 31.5,
29.4, 25.4, 24.3, 22.5, 11.7.
Acknowledgements
Acknowledgement is made to the Donors of the Petroleum
Research Fund, administered by the American Chemical
Society, for support of this work. We also thank Dr Charles
L. Mayne for assistance with high-®eld NMR experiments,
and Professor J. S. Clark and Dr Eric J. Stoner for helpful
discussions.
12. Sulikowski, G. A.;Lee, W.-M.;Jin, B. Org. Lett. 2000, 2,
1439.
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È
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