Discovery of a phosphine-mediated cycloisomerization of alkynyl hemiketals: Access to spiroketals and dihydropyrazoles via tandem reactions

Article abstract of DOI:10.1021/jo3001854

Reported here are details on the discovery of a phosphine-catalyzed isomerization of hemiketals and subsequent reactions of the cyclic keto enol ether products. The new cycloisomerization complements a previously reported amine-catalyzed process that gave oxepinones from the same hemiketal starting materials. In the absence of functionality (R²) on the cyclic keto enol ether, a rapid and facile dimerization occurs, giving spiroketal products. When the enone is substituted (i.e., R² = Ph), the cyclic keto enol ether is sufficiently stable so that it can be isolated; it can then be further reacted in the same pot to provide the corresponding dihydropyrazoles. Both the spiroketal and dihydropyrazole products arise by a tandem reaction that begins with the novel cycloisomerization. The method allows for the rapid introduction of complexity in the products from relatively simple starting materials. It should find application in the synthesis of natural product-like molecules.

Full text of DOI:10.1021/jo3001854

Article
pubs.acs.org/joc
Discovery of a Phosphine-Mediated Cycloisomerization of Alkynyl
Hemiketals: Access to Spiroketals and Dihydropyrazoles via Tandem
Reactions
Jaideep Saha, Chris Lorenc, Bikash Surana, and Mark W. Peczuh*
Department of Chemistry, University of Connecticut, 55 North Eagleville Road U3060, Storrs, Connecticut 06269, United States
S
* Supporting Information
ABSTRACT: Reported here are details on the discovery of a
phosphine-catalyzed isomerization of hemiketals and subse-
quent reactions of the cyclic keto enol ether products. The
new cycloisomerization complements a previously reported
amine-catalyzed process that gave oxepinones from the same
hemiketal starting materials. In the absence of functionality
(R2) on the cyclic keto enol ether, a rapid and facile dimeri-
zation occurs, giving spiroketal products. When the enone is substituted (i.e., R2 = Ph), the cyclic keto enol ether is sufficiently
stable so that it can be isolated; it can then be further reacted in the same pot to provide the corresponding dihydropyrazoles.
Both the spiroketal and dihydropyrazole products arise by a tandem reaction that begins with the novel cycloisomerization. The
method allows for the rapid introduction of complexity in the products from relatively simple starting materials. It should find
application in the synthesis of natural product-like molecules.
as MMP-3 and caspase-1, and antifungal activity. Following the
lead of these and related natural products, spiroketals have been
utilized as the core component of small molecule libraries.21−26
The synthetic methods themselves follow a few main strategies:
acid-mediated ketalization of keto-diols or hydroxy-hemiketals,
cyclization of glycal epoxides, and hetero-Diels−Alder reactions
of enones and enol ethers. Each of these approaches has been
effective at generating natural product and natural product-like
spiroketals. The new tandem sequence reported here involves a
[4 + 2] hetero-Diels−Alder reaction as the spiroketal forming
step; in fact, it is the facile access to and reactivity of the keto
enol ether via a phosphine-catalyzed cycloisomerization that
enable the cycloaddition reaction.
Phosphine-catalyzed annulation reactions are a powerful
means for the synthesis of a variety of carbocycles and hetero-
cycles.27,28 Previous syntheses commonly used formal cyclo-
addition approaches, tethered bifunctional nucleophilic additions
to activated ylides, or Morita−Baylis−Hillman (MBH)-
type reactions.27 There are only a few reports in the literature
on phosphine-catalyzed oxacycle synthesis from linear pre-
cursors.29−32 Pioneering work by Trost demonstrated a 1,3-
bis(diphenylphosphino)propane (dppp)-catalyzed cyclization
of hydroxy-2-alkynoates.29 The ordinarily nucleophilic γ posi-
tion of the internal alkynoate 4 (eq 1) was made electrophilic
(“umpoled”) through conjugate addition by the phosphine
followed by sequential isomerization and proton transfer steps.
Subsequent addition of the pendant hydroxyl group to the γ
position and release of the phosphine resulted in the formation
of the corresponding tetrahydrofuran 5. Fu and co-workers
INTRODUCTION
■
Tandem, or domino, reactions that serially organize multiple
bond forming events in a single operation have emerged as a
powerful tool for the construction of complex molecules
starting from simple starting materials.1−4 Tandem methods
typically circumvent conventional multistep processes and have
become a prevalent objective in organic reaction development.
When such reactions use a catalyst, the transformations serve as
candidates for the creation of diversity-oriented libraries
of small, highly functionalized molecules for the discovery of
medicinally important molecules in an economical and environ-
mentally acceptable way. Here we report on the discovery of a
reaction that isomerizes alkynyl hemiketals to their correspond-
ing cyclic keto enol ethers via phosphine catalysis. In the
absence of substitution on the enone moiety, the products un-
dergo a spontaneous hetero-Diels−Alder cycloaddition, yield-
ing novel dimeric spiroketals. When the enone is substituted, a
subsequent reaction with an azodicarboxylate yields the
corresponding dihydropyrazole.
A number of methods for the synthesis of spiroketals have
been developed.5−11 They were inspired by the challenge of
natural product total synthesis, physical investigations into the
fundamental principles governing spiroketal configuration, and
the biological activities associated with spiroketal-containing
natural products. Representative examples of natural product
spiroketals are oligomycin B (1),12−14 berkelic acid (2),15−17
and reveromycin A (3) (Figure 1).18−20 Among the structures
in Figure 1, oligomycin B is noteworthy because it contains a
ketone α to the spiroketal which parallels the organization of
functionality that develops in the new tandem reaction reported
here. Activities reported for 1−3 include cytotoxicity by inhi-
bition of ATP or protein synthesis, inhibition of proteases such
Received: January 30, 2012
Published: March 19, 2012
© 2012 American Chemical Society
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Figure 1. Representative natural products containing a spiroketal moiety.
have recently reported the asymmetric variant of this trans-
formation using a chiral phosphine catalyst which has expanded
the utility of the reaction.30 Similar annulation reactions have
been reported where an internal hydroxyl group attacks at the α
position of an ynone (6 in eq 2). Here the α carbon of the
ynone was rendered electrophilic through conjugate addition by
a phosphine and proton transfer. The cyclized products (i.e., 7)
are substituted keto enol ethers, a motif that occurs naturally in
aurones.33 In fact, several reports on the stepwise synthesis
of aurones have appeared in the literature.34,35 Keto enol
ethers can serve as important intermediates for further elab-
oration through either the ketone or the exocyclic enol ether
functionality.31,32
In the reaction, 14 was obtained by oxygen addition to the
β position of activated enone 13 and release of triethylamine.
Intermediate 13 was itself generated by the addition of
triethylamine to starting hemiketal (masked alkynone 12).
Mindful of the complementary reactivity of phosphines in
comparison to amines, we set about investigating the phoshine-
mediated cyclization of 11. Here we detail the discovery of a
new cycloisomerization of hemiketals such as 11, the scope and
reactivity of the subsequent isomerization product, and mecha-
nistic investigations for the transformation.
The keto enol ether unit also exhibits reactivity in inverse
electron demand Diels−Alder reactions, particularly when
substituents on the exocyclic olefin are absent; in the absence
of a partner for the cycloaddition, a dimerization occurs. Here 1
equiv of the enone acts as an electron-deficient diene and the
enol ether portion of another acts as the dienophile.36 An early
report by Ireland on the cycloaddition of unsubstituted keto
enol ethers mentioned that dimerization was a side reaction,37
while others simply noted the relative reactivity or instability of
related unsubstituted keto enol ethers.38−40 In the Ireland work,
dimerization of the keto enol ether 9 (eq 3) was prevented by
conducting the reaction in the presence of a large excess of
methacrolein. A crossed cycloaddition to form 10 (as the major
product isomer) by trapping the keto enol ether was affected in
situ. While such transformations demonstrated the potential to
be used for the synthesis of complex spiroketal scaffolded
libraries,37 a study on the precise reactivity of this class of
enones has remained largely unexplored.
RESULTS AND DISCUSSION
■
Discovery, Optimization, and Scope. The investigation
began by reacting hemiketal 11 with PMe3 as catalyst (Table 1
and Figure 2). Analysis of the reaction mixture by thin layer
chromatography (TLC) revealed a product that was less polar
than the starting material. It was isolated in 33% yield and
We recently developed a method to synthesize oxepinones
such as 14 by triethylamine-mediated isomerization of
hemiketals (11 in eq 4).41 The oxepinone products were to
serve as intermediates in the preparation of ring-expanded
glycals (oxepines) that have been synthetic targets in our group.42,43
1
analyzed by H and 13C NMR spectroscopy. The data clearly
indicated a product that was different from the previously
observed oxepinone 14. Duplicate signals in both H and 13C
1
NMR suggested a dimeric structure, which was further
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allenoates.44−48 We therefore next investigated how aryl
phosphines might fare in the reaction. Gratifyingly, the use of
catalytic PPh3 provided 15 in 96% yield (entry 4). Lowering the
catalyst loading (entry 5) or temperature (entry 6) provided
15, albeit in a slightly lower yield. In comparison to PPh3, alkyl/
aryl-substituted diphosphines showed a slight decrease in reac-
tion efficiency (entries 7−9). This came as a surprise because
we anticipated that the diphosphine catalysts would improve
the yield based on the cyclization mechanism originally put forth
by Trost.29 The electron-deficient P(pFPh)3 gave low conversion
(35%, entry 10). The use of solvents other than chloroform also
had a measurable effect on the reaction. Toluene resulted in a
similar product yield but required a longer reaction time (entry 11).
Notably, neither tetrahydrofuran (THF) nor methanol showed
significant product formation (entries 12 and 13).
To gather information about the scope of the reaction, a
number of different hemiketals (16−20) were prepared by
addition of TMS-acetylide to the corresponding lactones and sub-
sequent deprotection of the trimethylsilyl group (Figure 2).41
It is noteworthy that the cyclic hemiketal structure is maintained
for 16−18, whereas 19 and 20 proved to be acyclic ynones.
Under the optimized cyclization/dimerization conditions, aceto-
nide-protected hemiketals 16 and 17 underwent conversion to
tricyclic molecules 21 and 22 in 80 and 71% yields, respectively.
Substrate 18, lacking an acetonide on the C2−C3 diol, yielded 23
in moderate yield (55%), which suggested that rigidifying the
starting material played a role in the efficiency of the
transformation.49 Efficiency similar to the other rigid substrates
was achieved for cyclization of 19 and 20, giving spiroketals 24
and 25 in 90 and 79% yields, respectively.
Table 1. Investigation of Initial Reaction Conditions for the
Isomerization−Cycloaddition Dimerization
a
b
entry
phosphine
solvent
yield %
1
2
PMe3
PBu3
PtBu3
PPh3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
THF
33
30
10
96
85
77
72
84
88
35
3
4
c
5
PPh3
e
6
PPh3
7
dppe
8
dppp
9
PPh2Me
10
11
12
13
P(pFPh)3
PPh3
d
70
PPh3
0
PPh3
CH3OH
<2
a
b
All reactions conducted at rt for 6 h. Phosphine loading was 0.25
c
equiv except in entry 5. Phosphine loading was 0.05 equiv in this case.
Reaction took longer (∼1 day) to complete and significantly low
yielding for other substrates (e.g., with 13, only 18% product was
isolated). Reaction in toluene was run overnight (∼12 h). Reaction
performed at 0 °C.
d
e
The structure of each product in Figure 3 was assigned based
on comparison of its NMR spectra to that of 15. Specifically,
the appearance of a new signal (∼96−99 ppm) in the 13C NMR
indicated the presence of the spiroketal moiety. Designating the
configuration of the spiroketal for 21−25 was necessary
because we did not have X-ray crystallographic data as we
did in the case of 15. Products 21−23 gave only one of
two possible diastereomeric products; the spiroketal stereo-
chemistry was tentatively assigned as shown (Figure 3) based
on the structural (and reactive) similarity of the putative keto
enol ether to one that has been reported previously.36,50
Products 24 and 25 were isolated as a mixture of diastereomers.
We speculate that the spiroketal stereochemistry is constant for
24 and 25, and that the diastereomers are due to the
relationship of the two methyl groups in the tricyclic structures
(syn/anti).
Initial Mechanistic Considerations. Having established
that the new reaction was relatively general, we sought insight
into the pathway of the transformation. Ylide 28 (Scheme 1)
presented itself as a key intermediate to the transformation.
Attack at the carbon between the carbonyl and the phos-
phonium of 27 by the pendant oxygen gave rise to 28. A study
that reported on the intermolecular α addition of nitrogen
nucleophiles giving dehydroamino acids served as a model for
our thinking.51 That intermolecular reaction required buffered
conditions (for proton transfer) along with the phosphine
catalyst. The intramolecular reaction reported here does not
require buffered conditions; it does, however, favor the
formation of α-functionalized products. Phosphine addition at
the β position of the ynone likely facilitates attack at the α
carbon on both electronic and steric grounds. The central
question to us was the fate of ylide 28 in subsequent steps of
the transformation. We wanted to know if formation of dimeric
Figure 2. Structure of compound 15 from X-ray data.
supported by ESI-MS analysis. The connectivity of the dimeric
structure was identified by diagnostic NMR signals and 2D
NMR correlations (see Supporting Information for spectra).
For example, a 13C NMR signal at 198 ppm indicated a ketone,
and signals at 127 and 138 ppm suggested an olefin and a signal
at 98 ppm was diagnostic of a spiroketal. A crystal structure of
the product, shown in Figure 2, unambiguously proved the
connectivity of 15. The structure shows that a ring expansion of
the original hemiketal occurs along the course of the reaction.
Additionally, a third ring forms as a result of the dimerization.
Over the course of the tandem reaction, a bicyclic bis-enol ether
is formed to which is attached an additional ring via a spiroketal
linkage. Ascertaining the efficiency and scope of the reaction
then became our priority.
We proceeded to optimize the reaction conditions. Use of
PBu3 failed to improve the yield, and a bulkier alkyl phosphine
like P(tBu)3 resulted in lower efficiency (entries 2 and 3). The
difference in electronics between trialkyl and triaryl phosphines
favors different pathways with respect to reaction of
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species 29 occurred by a concerted [4 + 2] pathway by way of
cyclic keto enol ether 30 (path A) or by a phosphine-mediated
stepwise process (path B). In the stepwise sequence, ylide 28
could add onto either hemiketal 26 or enone 30 in a secondary
cycle.52 Conversely, cyclic keto enol ether 30 could undergo
a spontaneous homodimerization in a hetero-Diels−Alder
reaction.
Scheme 1
The sole precedent for dimerization of unsubstituted cyclic
keto enol ethers was of the glucose derivative 31 being con-
verted to 33 reported by Martin et al. (eq 5).36 Dimeriza-
tion was also mentioned in regard to 9 (eq 3),37 although a
dimeric product was not characterized. These observations
suggested that a concerted pathway was likely in our system
even though phosphine was present in the reaction. Because
a cyclic keto enol ether had been trapped with excess
methacrolein,37 trapping seemed to be a logical place to
begin our mechanistic investigations. Our strategy was to
evaluate both dienophiles and dienes as capture agents.
Reactions using 1 equiv of diphenyl acetylene and diethyl
acetylene dicarboxylate as dienophiles or 2 equiv of Danishefsky’s
diene with hemiketal 11 as starting material under the
established reaction conditions led to isolation of 15 as the
only product. Using 2 equiv of Rawal’s diene, however, led to
other products besides 15, which was isolated in 29% yield.
Phenolic hemiketal 34 was a minor product (5%) and came
about by Diels−Alder between the diene and the terminal alkyne
of 11.53 Mukaiyama aldol product 35 was also isolated from the
reaction in 61% yield; reactivity of this sort has been observed in
another system.54 We assigned the newly developed stereocenter
based on the product of reduction of 42 (vide infra).
Unfortunately, the trapping experiments did not provide solid
support for either mechanism.
In a different approach, we set out to synthesize compounds
that were precursors of the cyclic keto enol ether by a route that
did not utilize the phosphine-catalyzed isomerization (Scheme 2).
The objective was to access a general precursor that could allow
the generation of a series of cyclic keto enol ethers by a simple
operation. We thought such an experiment would create more value
in the current context of the phosphine-catalyzed cycloisomerization
process and give more insight into the mechanistic aspects.
An exo-glycal with a vinyl iodide unit was targeted as the
synthetic handle in our strategy.
Diol 36, prepared by known TMS-acetylide addition to the
corresponding lactol followed by silyl deprotection,55,56 was
Figure 3. Hemiketals and ynones 16−20 (top) and the corresponding dimeric spiroketals 21−25 (bottom) prepared by the tandem
cycloisomerization−cycloaddition reactions. Yields for the conversion are given in parentheses.
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Scheme 2
readily transformed to exo-glycal 37 using NIS with a high
preference for the Z isomer (Z/E 10:1). This cyclization could
serve as a complementary process to other existing methods to
obtain exo-glycals57−62 and is novel in its own right; exo-glycal
37 contained free C2 hydroxyl and vinyl iodide groups, both of
which were available for further functionalization. Upon Pd-
catalyzed dehalogenation, exo-glycal 37 was transformed to 38;
Swern oxidation of this material resulted in isolation of dimer
22 in 55% yield. Isolation of the dimeric material was a clear
indication that the hetero-Diels−Alder reaction was certainly
viable in our tandem reaction. Notably, Swern oxidation of 37
provided iodo-substituted keto enol ether 39, although decom-
position was observed upon prolonged storage.63 When 37 was
converted to 40 and subjected to Swern conditions, cyclic keto
enol ether 41 was the only isolated material. Compound 41 was
found to be unreactive in terms of the dimerization under a
number of reaction conditions. For example, when 41 was
refluxed in chloroform or toluene in either the presence or the
absence of PPh3, no further reaction was noted. Even in reac-
tions where 41 was subjected to higher temperature (180 °C)
under microwave conditions, no evidence for dimerization was
found. Considered collectively, the results suggested that the
cyclic keto enol ethers readily formed from hemiketals with
or without substitution on the alkyne; further, only when the
alkyne was unsubstituted did the subsequent dimerization
occur.
Phosphine-Catalyzed Cycloisomerization of Alkynyl-
Substituted Hemiketals. On the basis of the control
experiments conducted, we hypothesized that the phosphine-
catalyzed reaction of substituted hemiketals such as 42 (Scheme 3)
would stop at the keto enol ether product unless a secondary
phosphine-catalyzed pathway to the dimer was operative.64−68
When 42 was treated with PPh3 under conditions used
previously for similar substrates such as 11, only unreacted
starting material was recovered after 12 h. The appearance of a
new product, however, was observed with higher catalyst
loading (50 mol %) in refluxing chloroform. The new product
was isolated in 96% yield as a single isomer and tentatively
assigned as 43. NMR analysis showed characteristic signals of
a cyclic keto enol ether, but at this stage, it was difficult to
determine the geometry of the exo-glycal as E or Z. A corro-
borative study was undertaken to determine if the Z geometry
shown for 43 was correct. Sodium borohydride reduction of
the hemiketal 42 provided a mixture of diols 44 in a 9:1
Scheme 3
diastereomeric ratio (92%, combined yield).69 The major
diastereomer of 44 was then subjected to known conditions
for cyclization61 that provided Z isomer 45 exclusively in 41%
isolated yield. Olefin geometry was determined by observation
of nOes (via NOESY spectra) between the olefin proton and
H2 and H2−H4 of exo-glycal 45. Swern oxidation on 45
provided a cyclic keto enol ether (70%) which after NMR
analysis was found to be compound 43. This result illumi-
nated two important features of the our tandem process. First,
formation of enone 43 provided additional evidence toward
the conclusion that isomerization of the hemiketal to an
intermediate cyclic keto enol ether followed by a hetero-
Diels−Alder reacton is the most likely pathway to the tricyclic
spiro compounds as described earlier. The inertness of 43 in
the presence of PPh3 even under conditions that included
refluxing chloroform reflects a greater electron density of the
double bond than in typical enone functionalities. We reasoned
that this class of compounds was a better fit as electron-deficient
diene and that substitution on the olefin (e.g., the terminal
phenyl group) most likely prevented the hetero-Diels−Alder
reaction under reflux or microwave heating due to sterics. Although
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Figure 4. Hemiketals and ynones 46−51 (top) and the corresponding cyclic keto enol ethers 52−57 (bottom) prepared by the cycloisomerization
reaction. Yields for the conversion are given in parentheses.
we have not investigated it here, we anticipate that alkyl groups at
this position would demonstrate similar behavior.
HSQC and found to be 52.5 and 21 Hz, which were in a close
agreement to those of reported compound 58.72 On the basis
of the comparison the reported data for 58 to the data we
collected for the isolated material, we proposed the structures
to be a 1,2-λ5 oxaphospholenes 62 (Scheme 4).
The second key feature of the transformation was the exclu-
sive formation of the Z isomer of 43. Interestingly, Gouverneur
et al.32 studied a phosphine-catalyzed cycloisomerization analo-
gous to ours and obtained five-membered keto enol ethers, but
predominantly with the E olefin configuration. On the basis of
the ease of preparation of the hemiketal starting materials and
the high efficiency for their transformation to the Z keto enol
ethers, we opted to examine the scope of our cyclo-
isomerization with substrates 46−51 (Figure 4). The substrates
were synthesized by addition of phenylacetylide onto the corre-
sponding lactones. Among them, 46−50 were converted to
substituted keto enol ethers 52−56 in 52−92% yield. Hemiketal
47 exhibited only moderate reactivity for the conversion to 53
(52%). Interestingly, the six-membered hemiketal 50 was
transformed to the seven-membered keto enol ether 56 with
good efficiency (75%), illustrating the versatility of the method.
To our surprise, however, hemiketal 51 provided only 14% of
expected product 57. The major product of the reaction, iso-
lated in 78% yield, was found to be a 1:1 mixture of diastereomers
of a previously unidentified material. After separation of the two
components by column chromatography, we began a structural
analysis on one of the isomers. ESI-MS analysis recorded a major
peak at m/z 903 that immediately indicated it as a PPh3 adduct
[M + PPh3] of the starting hemiketal 51. Therefore, a 31P NMR
analysis was performed to confirm the incorporation of phos-
phorus in the isolated material. An upfield signal at −44 ppm70
strongly suggested a pentacoordinated phosphorus species instead
of tetravalent phosphines.71 A 13C NMR spectrum confirmed the
presence of a spiro linkage with a signal at 98 ppm and a distinct
downfield signal for vinyl carbon at 154 ppm, which was further
confrmed with a DEPT-135 experiment. Further, this signal co-
rrelated to a downfield shifted vinyl proton at 7.5 ppm in 1H NMR.
Scheme 4
2
3JP,H and JP,C values for the vinyl proton were determined by
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Scheme 5
Intermediates along the pathway for the formation of 62 are
presented in Scheme 4; the rationale behind the proposed
mechanism was motivated by the reported molecules 58 and
59. Kwon et al.71 isolated a zwitterionic tetravalent phosphoium
enolate species (i.e., 59) which originated from a three-
component reaction of an alkyl or aryl phosphine, an alkynoate,
and an aldehyde. In that study, the addition of phosphine to the
alkynoate generated a zwitterion akin to 60, which then reacted
with the aldehyde to form the tetravalent zwitterion. Formation
of 62 from 51 follows a related pathway. Attack of PPh3 onto
the ynone results in the formation of 60. In Scheme 4, the
species on the left and right show how the diastereomers of 62
(α and β) arise by a bond rotation in the acyclic precursors 60
and 61. Upon proton transfer, carbanion 60 generated alkoxide
61. Instead of adding onto the carbon α to the carbonyl as in all
of the other examples, attack occurred on the carbonyl carbon
itself and resulted the formation of spirocycle 62. This alternate
pathway is probably due to a combination of two factors. First,
the formation of a six-membered ring (attack at carbonyl) is
kinetically favored relative to formation of the seven-membered
ring (attack at α carbon), and second, the lack of rigidifying
features on the substrate disfavors α attack. The consequence of
the attack by oxygen at the carbonyl carbon is that the reaction
course has been changed (trapped) to form oxaphospholene
62. Following the rationale of Kwon, the relatively poor ability
of the phenyl groups (compared to alkyl groups) to stabilize the
phosphonium species contributes to the formation of the
oxaphospholene instead of the corresponding zwitterionic
species. The formation of compound 62 therefore constitutes
another example of an isolable oxaphospholene.
Annulations with Substituted Cyclic Enol Ethers and a
Unified Mechanism. Because substituted cyclic enol ethers
52−57 were largely refractory to concerted cycloaddition reac-
tions, we sought to demonstrate their reactivity in a stepwise
annulation. Dihydropyrazoles are medicinally important com-
pounds73 that presented themselves as viable targets. The stra-
tegy was to utilize the phosphine catalyst present in the cyclo-
isomerization to react with diisopropylazodicarboxylate
(DIAD) to initiate a second transformation in one pot. The
reaction of azodicarboxylate compounds (DIAD in our case)
with phosphines forms a Huisgen zwitterion;74 these species
have found application in different transformations ranging from
Mitsunobu reactions75 to reactions involving carbonyl com-
pounds.76−79 Among these examples, the recent demonstration
of dihydropyrazole synthesis from the Huisgen zwitterion and
enones inspired our strategy.79 In the event, hemiketal 42 was
treated with 1.5 equiv of PPh3 in toluene and heated for 4 h to
isomerize it to the corresponding cyclic keto enol ether 43.
When conversion to 43 was deemed complete by TLC, 1.5 equiv
of DIAD was added to the mixture and then refluxed overnight.
Dihydropyrazole 63 was obtained in 71% yield in this tandem,
one-pot process (Scheme 5). The efficiency was only slightly less
than that obtained (80%) in a stepwise process between keto
enol ether and DIAD under similar conditions. Acyclic ynone 48,
treated in a similar manner, provided 64 in 58% yield as a
mixture of diastereomers. In the dihydropyrazole formation,
higher equivalents of PPh3 were utilized to affect the dehydrative
“second” transformation as it required stoichiometric PPh3. A
key point is that the cycloisomerization is, in fact, catalytic in
phosphine and therefore available for subsequent steps in the
same pot.
The cycloisomerization that converts alkynyl hemiketals such
as 65 to their corresponding cyclic keto enol ethers 72 is
common to both tandem processes described here. A
mechanism for the reaction, emphasizing the catalytic role of
the phosphine, is depicted in Scheme 6. Conjugate addition by
the phosphine to ynone 66 gives allenoate 67. Proton transfer80
then gives keto phosphonium species 68 which proceeds,
through intramolecular attack by oxygen on the carbon α to the
carbonyl, to ylide 69. The umpoled (electrophilic) behavior of
this carbon is courtesy of the adjacent phosphonium. Another
proton transfter gives zwitterionic phosphonium enolate 70,
which may be more accurately considered as its oxaphospho-
lene resonance form 71. Loss of the catalytic phosphine then
delivers 72. The identity of the alkynyl substituent R2 deter-
mines the subsequent fate of the cyclic keto enol ether 72.
When R2 is hydrogen (the unsubstituted series), a facile hetero-
Diels−Alder reaction then gives spiroketal 73; the phosphine-
catalyzed cycloisomerization followed by the [4 + 2] cyclo-
addition is the tandem process. When R2 is phenyl, 72 is a
stable, isolable product that is resistant to cycloadditions under
a variety of conditions. However, a stepwise annulation with
DIAD gives rise to dihydropyrazoles 74.
CONCLUSION
■
We have discovered a phosphine-catalyzed reaction that iso-
merizes hemiketals (masked ynones) to cyclic keto enol ethers.
Most of the previously available methods utilized stepwise
functionalization either by elimination from a keto substrate or
by oxidation of allylic alcohols; a ring expansion of lactones has
also been reported.81 Substituted keto enol ethers can also be
transformed to important building blocks upon manipulating
either the enol ether or the keto group. For example, one
served as a key intermediate in the synthesis of the natural
product Herbicidin B.82 The products of our phosphine-
catalyzed cycloisomerization were complementary to those
from an earlier amine-catalyzed isomerization. That is, the
amine-catalyzed isomerization provided oxepinone products,
and the phosphine reaction gave cyclic keto enol ethers. The
divergence in reaction pathways and the umpoled reactivity
under phosphine catalysis are consistent with reports of ynone
and ynoate reactivity in other systems. Moreover, our observa-
tions indicate a dependence on the nature of the alkynyl
substituent for the ultimate identity of the product. When the β
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Scheme 6
1.43−1.36 (m, 15H), 1.34 (s, 3H), 1.31 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 199.0, 136.2, 130.7, 111.1, 110.6, 109.7, 109.6, 96.6, 78.4,
77.4, 75.7, 74.3, 74.0, 73.8, 69.7, 69.1, 66.8 (2), 27.9, 27.3, 27.1, 27.0,
26.4, 26.1, 25.4, 25.3, 24.3, 19.4; HRMS m/z (M)+ calcd for
C28O12H40 568.2520, found 568.2516.
carbon of the enone was unsubstituted, rapid dimerization gave
spiroketal products. Data collected in this study suggest that
the dimerization occurs via a concerted hetero-Diels−Alder
process. In the cases where a phenyl group was on the β carbon,
the cyclic keto enol product was stable and isolable. On the
basis of the reaction conditions, this substituted cyclic keto enol
ether could be further derivatized in the same pot to afford
dihydropyrazoles. The one-pot transformation certainly offers
more avenues for new reaction discovery to prepare diverse
heterocyclic scaffolds. In total, the tandem method allows for
the rapid introduction of complexity in the products from
relatively simple starting materials.
Compound 22. Compound 22 was obtained in 71% yield (0.023 g)
using hemiketal 17 as starting material (0.037 g, 0.071 mmol) under
the general reaction conditions: Rf 0.68 (7:3 Hex/EtOAc); [α]D +13.2
1
(c 1.1, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.72−7.63 (m, 8H),
7.43−7.34 (m, 12 H), 4.74−4.69 (m, 2H), 4.38 (d, J = 5.8 Hz, 1H),
4.18−4.11 (m, 1H), 4.08−4.02 (m, 1H), 4.00−3.80 (m, 4H), 3.31
(ddd, J = 1.9, 4.8, 9.8 Hz, 1H), 2.40−2.28 (m, 1H), 2.13−1.93 (m,
3H), 1.55 (s, 3H), 1.48 (s, 3H), 1.37 (s, 3H), 1.27 (s, 3H), 1.08−1.03
(m, 18H); 13C NMR (100 MHz, CDCl3) δ 199.5, 137.9, 136.0, 135.8,
133.9, 133.7, 133.5, 130.0, 129.9, 129.8, 127.9, 127.8, 127.7 (2), 126.7,
110.6, 109.7, 97.1, 77.4, 75.7, 74.9, 70.7, 69.6, 64.6, 63.0, 28.4, 27.2,
27.1, 25.9, 25.8, 19.6, 19.4, 19.2; HRMS m/z (M)+ calcd for
C52O10H64Si2 904.4038, found 904.4009.
EXPERIMENTAL SECTION
■
General Procedure for Cycloisomerization of 11 and 16−20.
PPh3 (0.25 equiv, 0.004−0.0125 mmol) was added to a solution of the
hemiketals (11, 16−18) or ynones (19 and 20) (0.15−0.5 mmol) in
CHCl3 (1.5−5.0 mL) and stirred at room temperature for 6−12 h.
The progress of the reaction was monitored by thin layer chromato-
graphy (TLC). Upon completion of the reaction as deteremined
by the disappearance of the starting material in TLC, the reaction
solvent was removed in vacuo and the residue was purified by flash
column chromatography to obtain dimeric spiroketals 15 and 21−25
in 55−96% yields.
Compound 23. Following the general procedure, compound 23
was obtained in 55% yield (0.027 g) from cycloisomerization and
dimerization of 18 (0.047 g, 0.11 mmol): Rf 0.59 (7:3 Hex/EtOAc);
1
[α]D +51.1 (c 1.2, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.69−
7.14 (m, 30H), 4.87−4.77 (m, 3H), 4.72−4.64 (m, 3H), 4.61−4.48
(m, 5H), 4.35 (dd, J = 2.7 Hz, 1H), 4.26−4.11 (m, 3H), 4.08−405 (m,
2H), 3.94−3.84 (m, 3H), 3.73−3.67 (m, 2H), 2.41−2.30 (m, 1H),
2.23−1.96 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 199.9, 139.0,
138.4, 138.3, 138.0, 137.9, 137.6, 136.5, 128.7, 128.6, 128.5, 128.4 (2),
128.3, 128.2, 128.1 (2), 128.0 (2), 127.8, 127.7, 127.6, 127.4, 127.2,
98.6, 79.7, 77.4, 76.0, 75.3, 73.9, 73.8, 73.5, 72.8, 72.6, 72.5, 72.3, 70.8,
70.3, 68.8, 25.1, 19.4; HRMS m/z (M + H)+ calcd for C56O10H56
888.3874, found 888.3858.
Compound 15. Following the general procedure, 15 was obtained
from cycloisomerization and dimerization of 11 (0.050 g, 0.27 mmol)
in 96% yield as a white solid (0.048 g): mp 116−118 °C; Rf 0.47 (7:3
Hex/EtOAc); [α]D −79.3 (c 1.4, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ 4.87 (d, J = 5.6 Hz, 1H), 4.62 (ddd, J = 0.9, 2.3, 5.6 Hz, 1H),
4.52 (d, J = 6.0 Hz, 1H), 4.49 (dd, J = 2.3, 13.4 Hz, 1H), 4.31 (ddd, J =
3.5, 6.5 Hz, 1H), 4.00 (d, J = 13.4, 1H), 3.87 (dd, J = 3.4, 11.5 Hz,
1H), 3.75 (dd, J = 6.5, 11.5 Hz, 1H), 2.32 (ddd, J = 10, 15.2 Hz 1H),
2.05 (d, J = 16.0 Hz, 1H), 2.0 (m, 2H), 1.47 (s, 3H), 1.45, (s, 3H),
1.38 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 198.9, 138.4, 127.7,
110.4, 110.3, 97.0, 78.8, 75.9, 72.4, 69.3, 65.9, 59.5, 28.3, 27.4, 26.4,
26.3, 24.3, 19.5; HRMS m/z (M + H)+ calcd for C18O8H25 369.1549,
found 369.1549.
Compound 24. Following the general procedure, compound 19
(0.049 g, 0.39 mmol) was converted to 24 as a mixture of
diastereomers in 90% overall yield (0.044 g): Rf 0.62 (17:3 Hex/
EtOAc); 1H NMR (400 MHz, CDCl3) δ 4.21 (m, 1H), 3.89 (m, 2H),
3.71 (m, 1H), 3.13 (ddd, J = 6.3 Hz, 1H), 2.41 (m, 1H), 2.26 (m, 1H),
2.07 (m, 4H), 1.88 (m, 2H), 1.62 (m, 1H), 1.12−1.07 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 205.1, 205.0, 133.6, 133.4, 132.0, 131.8,
96.5, 96.4, 64.1, 63.0, 60.6, 39.5, 39.3, 38.2, 38.1, 31.9, 31.2, 28.2, 27.7,
25.7, 25.6, 20.2, 20.0, 19.8, 18.8, 14.2, 14.1; HRMS m/z (M + H)+
calcd for C14H21O4 253.1440, found 253.1408.
Compound 25. Following general procedure, compound 25
(0.019 g, 0.15 mol) was obtained from 20 as mixture of diastereomers
in overall 79% yield (0.015 g): Rf 0.53 (85:15 Hex/EtOAc); 1H NMR
(400 MHz, CDCl3) δ 4.36 (m, 1H), 3.87 (m, 1H), 2.97 (tdd, J = 13.9,
7.6, 6.4, 2.1 Hz, 1H), 2.38 (m, 1H), 2.32−2.22 (m, 2H), 2.15−1.99
Compound 21. Following the general procedure, compound 21
was obtained from 16 (0.07 g, 0.25 mmol) in 80% yield (0.055 g): Rf
1
0.41 (7:3 Hex/EtOAc); [α]D +69.4 (c 2.3, CH2Cl2); H NMR (400
MHz, CDCl3) δ 4.87 (d, J = 5.4 Hz, 1H), 4.68−4.59 (m, 2H), 4.58−
4.52 (m, 1H), 4.40−4.27 (m, 3H), 4.08 (d, J = 5.2 Hz, 2H), 3.99 (dd,
J = 8.7, 6.2 Hz, 1H), 3.88 (dd, J = 8.7, 4.8 Hz, 1H), 3.60 (dd, J = 1.3,
8.0 Hz, 1H), 3.37−2.21 (m, 1H), 2.01−1.19 (m, 3H), 1.49 (s, 3H),
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(m, 4H), 1.93−1.64 (m, 4H), 1.29−1.20 (m, 6H); 13C NMR (100
MHz, CDCl3) δ 203.9, 203.7, 133.6, 133.4, 127.6, 96.3, 71.5, 71.3,
66.1, 66.0, 36.1, 35.4, 30.1, 29.6, 25.8, 25.6, 23.4, 23.0, 21.0, 20.9, 20.6,
20.2, 19.8; HRMS m/z (M + H)+ calcd for C14H21O4 253.1440, found
253.1408.
Compound 19. Alkynone 19 was prepared following similar
procedure as used to prepare 20 as described below and was isolated in
60% (2 steps) as a yellow oil (0.226 g) from 0.300 g of the lactone
(3.0 mmol): Rf 0.24 (70:30 Hex/EtOAc); 1H NMR (400 MHz,
CDCl3) δ 3.67−3.57 (m, 2H), 3.32 (s, 1H), 2.79−2.70 (m, 1H),
2.08−2.0 (m, 1H), 1.67−1.60 (m, 1H), 1.18 (d, J = 7.2 Hz, 3H), 1.14
(t, J = 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 191.5, 80.6, 80.1,
71.1, 59.9, 45.4, 34.9; HRMS m/z (M + H)+ calcd for C7H11O2
127.0759, found 127.0753.
as eluent to give 37 (Z/E 10:1) as a white solid (0.116 g, 93%):
Rf 0.56 (70:30 Hex/EtOAc); [α]D +103.2 (c 0.45, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ 5.47 (s, 1H), 4.90 (t, J = 5.0 Hz, 1H), 4.48−4.43
(m, 2H), 4.26 (m, 1H), 4.21 (dd, J = 8.1, 1.2 Hz, 1H), 4.08 (dd, J =
8.8, 6.0 Hz, 1H), 4.02 (dd, J = 8.6, 4.3 Hz, 1H), 1.96 (d, J = 2.8 Hz,
1H), 1.39 (s, 3H), 1.37 (s, 3H), 1.34 (s, 3H), 1.32 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 155.0, 110.3, 109.7, 74.5, 74.3, 73.9, 71.7, 67.6,
67.0, 55.2, 27.1, 26.4, 25.5, 24.8; HRMS m/z (M + H)+ calcd for
C14H22IO6 413.0461, found 413.0454.
Compound 38. Compound 37 (0.024 g, 0.058 mmol) was dis-
solved in EtOH (2 mL); solid Pd(PPh3)4 (3.3 mg, 0.0029 mmol) was
added, and the resulting solution was refluxed for 4 h. After removal of
solvent under reduced pressure, the crude residue was purified by
column chromatography to afford compound 38 (0.011 g, 70%) as
white solid: Rf 0.40 (70:30 Hex/EtOAc); [α]D +59.4 (c 0.7, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 4.55 (d, J = 8.0 Hz, 1H), 4.46−4.42
(m, 2H), 4.35−4.26 (m, 2H), 4.22−4.21 (m, 2H), 4.14−4.09 (m, 2H),
1.95 (s, 1H), 1.46 (s, 6H), 1.40 (s, 3H), 1.38 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 156.2, 110.2, 109.6, 92.0, 74.1, 74.0, 72.8, 71.9,
69.6, 67.1, 27.1, 26.5, 25.5, 24.8; HRMS m/z (M + H)+ calcd for
C14H23O6 287.1495, found 287.1483.
Compound 20. TMS-acetylene (0.47 mL, 3.29 mmol) was
dissolved in dry THF (2 mL) and cooled to −78 °C. To this solution
was added nBuLi (2.0 mL, 1.6 M) dropwise into the resulting solution
for 30 min while maintaining the temperature at −78 °C. To this
homogeneous solution was added valerolactone (0.3 g, 3.0 mmol) as a
solution in THF (2 mL) dropwise and stirred at −78 °C for 3 h.
Progress of the reaction was monitored by TLC. Upon complete
disappearance of the lactone, the mixture was diluted with additional
5 mL of THF and quenched with addition of saturated NH4Cl (5 mL).
The organic layer was extracted in EtOAc (2 × 15 mL) and washed
with H2O (20 mL) and brine (10 mL). The organic layers were dried
over Na2SO4, and the solvent was removed under reduced pressure.
This material was subjected to the next step without further
purification. It was taken in a mixture of CH3CN/H2O (10:1), and
CsF (0.65 g, 4.5 mmol) was added at 0 °C. The mixture was allowed
to warmed to rt over 2 h. EtOAc(10 mL) was added to the mixture,
and it was then washed with H2O (10 mL). The organic layer was
dried with Na2SO4 and concentrated under reduced pressure. The
residue was purified by column chromatography using 4:1 Hex/EtOAc
as eluent to give 20 as yellow oil (0.26 g, 68% over 2 steps): Rf 0.23
Compound 39. Following the same procedure as for 43 below,43
compound 37 (0.016 g, 0.039 mmol) was converted compound 39
(0.007 g, 41%): 1H NMR (400 MHz, CDCl3) δ 6.82 (s, 1H), 4.79 (dd,
J = 7.2, 1.6 Hz, 1H), 4.49−4.46 (m, 2H), 4.29−4.23 (m, 2H), 3.73
(dd, J = 8.4, 1.7 Hz, 1H), 1.51 (s, 3H), 1.47−1.40 (m, 9H); 13C NMR
(125 MHz, CDCl3) δ 186.7, 155.4, 112.9, 112.6, 110.0, 74.7, 74.3,
73.1, 72.7, 66.8, 27.2, 26.3, 25.1, 25.0; HRMS m/z (M + H)+ calcd for
C14H20IO6 411.0305, found 411.0315.
Swern Oxidation of 38. Following the general procedure for
Swern oxidation,43 compound 38 (0.05 g, 0.17 mmol) yielded dimer
21 (0.027 g, 55%).
Compound 40.58 Compound 37 (0.011 g, 0.03 mmol) was
dissolved in diethylamine (0.5 mL), and the solution was thoroughly
degassed by bubbling N2 through the mixture. To this solution were
added Pd(PPh3)4 (2.0 mg, 0.0013 mmol), CuI (1.0 mg, 0.0052 mmol),
and phenyl acetylene (6 μL, 0.030 mmol) successively. The reaction
was stirred at rt, and TLC was monitored until disappearance of the
starting materials. The reaction was then diluted with EtOAc (2 ×
5 mL) and washed with H2O (5 mL). Solvents were removed under
reduced pressure, and the residue was purified by column chromato-
graphy to afford compound 40 (0.011 g, 97%): Rf 0.48 (70:30 Hex/
1
(70:30 Hex/EtOAc); H NMR (500 MHz, CDCl3) δ 3.69−3.62 (m,
2H), 2.78−2.71 (m, 1H), 2.10−2.0 (m, 2H), 1.67−1.60 (m, 1H), 1.21
(d, J = 7.1 Hz, 3H), 0.23 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
191.7, 101.2, 99.4, 60.3, 45.3, 35.2, 16.2, 0.62; HRMS m/z (M + H)+
calcd for C7H11O2 127.0759, found 127.0715.
Reaction of 11 with Rawal’s Diene. PPh3 (0.014 g, 0.05 mmol)
was added to a solution of Rawal’s diene (0.118 g, 0.52 mmol) and
hemiketal 11 (0.048 g, 0.26 mmol) in CHCl3 (12 mL) and stirred 5 h
at rt. The reaction was monitored by TLC. Upon completion, the
solvent was removed under reduced pressure and the crude product
was purified by flash chromatography which afforded 15 (0.014 g,
29%), compound 34 (0.005 g, 5%), and the aldol product 35 (0.065 g,
61%) in a 3:1:12 ratio.
1
EtOAc); H NMR (400 MHz, CDCl3) δ 7.42−740 (m, 2H), 7.33−
7.28 (m, 3H), 5.33 (s, 1H), 5.08 (t, J = 2.0, 1H), 4.60−4.54 (m, 2H),
4.37−4.30 (m, 2H), 4.17−4.09 (m, 2H), 2.21 (br s, 1H), 1.46 (s, 3H),
1.45 (s, 3H), 1.40 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 161.9, 131.3, 128.4, 127.9, 124.0, 110.3, 109.7, 92.8, 89.7, 84.9, 73.9,
73.8, 71.9, 67.0, 65.2, 27.1, 26.5, 25.5, 24.8; HRMS m/z (M + H)+
calcd for C22H27O6 387.1808, found 387.1779.
1
Compound 34: Rf 0.9 (1:1 Hex/EtOAc); H NMR (400 MHz,
CDCl3) δ 7.45 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 4.96 (dd,
J = 4.0, 5.8 Hz, 1H), 4.59 (d, J = 5.7 Hz, 1H), 4.22−4.17 (m, 1H),
4.13−4.09 (m, 1H), 1.37 (s, 3H), 1.25 (s, 3H), 0.98 (s, 9H), 0.20 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 128.3, 127.9, 120.2, 119.5,
112.7, 107.2, 86.0, 81.0, 71.1, 26.4, 25.9, 24.9, −4.2; HRMS m/z (M +
H)+ calcd for C19H31O5Si 367.1941, found 367.1945.
Compound 41. Following the general procedure Swern oxidation,
compound 40 (0.010 g, 0.026 mmol) afforded cyclic keto enol ether
41 (0.0062 g, 62%): Rf 0.56 (12:0.5 DCM/Et2O); [α]D 161.6 (c 0.5,
1
CH2Cl2); H NMR (300 MHz, CDCl3) δ 7.56−7.45 (m, 2H), 7.38−
7.30 (m, 3H), 5.80 (s, 1H), 4.77 (d, J = 7.6 Hz, 1H), 4.52 (d, J =
7.2 Hz, 1H), 4.56−4.39 (m, 1H), 4.21−4.07 (m, 2H), 3.69 (d, J = 7.8
Hz, 1H), 1.54 (s, 3H), 1.47−1.43 (m, 6H), 1.40 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 188.4, 156.1, 132.1, 128.8, 128.4, 112.7, 110.0,
99.9, 98.8, 85.5, 77.4, 75.6, 75.1, 73.5, 66.8, 27.1, 26.4, 25.3, 25.2;
HRMS m/z (M + H)+ calcd for C22H25O6 385.1651, found 385.1625.
Compound 43. Swern Oxidation Method. To a solution of
oxalyl chloride (6 μL, 0.07 mmol) in dry DCM (1 mL) was
added DMSO (9 μL, 0.12 mmol), and the mixture was stirred
for 30 min at −78 °C. A separate solution of compound 45
(0.015 g, 0.06 mmol) in DCM was prepared and added drop-
wise to the former solution and stirred for an additional
1 h while maintaining the temperature at −78 °C. TEA (80 μL,
0.6 mmol) was next added to the reaction mixture as a solution
in DCM and slowly warmed to room temperature over a period
of 4 h. Solvents were removed under reduced pressure, and the
crude was subjected to flash column chromatography, which
1
Compound 35: Rf 0.17 (1:1 Hex/EtOAc); H NMR (400 MHz,
CDCl3) δ 7.53 (d, J = 12.5 Hz, 1H), 5.14 (d, J = 12.5 Hz, 1H), 4.55 (d,
J = 6.2 Hz, 1H), 4.40−4.33 (m, 1H), 4.03−3.91 (m, 2H), 3.14−2.99
(m, 4H), 2.83 (br s, 3H), 2.75 (d, J = 13.9 Hz, 1H), 2.63 (s, 1H), 1.52
(s, 3H), 1.37 (s, 3H), 0.88 (s, 9H), 0.29 (s, 3H), 0.27 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 192.2, 153.1, 108.2, 97.6, 85.8, 80.5, 78.6,
75.8, 71.4, 61.7, 52.2, 45.0, 37.2, 27.7, 26.2, 25.6, −2.6, −2.2; HRMS
m/z (M + H)+ calcd for C21H37NO5Si calcd 412.2519, found
412.2528.
Compound 37. Diol 36 (0.087 g, 0.30 mmol) was taken in dry
THF (6 mL), and NIS (0.1 g, 0.39 mmol) was added at rt. After
stirring overnight, the mixture was diluted with an additional 10 mL of
THF and to it was added a 10% (v/v) Na2S2O3 solution(10 mL) and
extracted with EtOAc (2 × 5 mL). The combined organic layers were
dried over Na2SO4 and the solvent removed under reduced pressure.
The residue was purified by column chromatography using 4:1 Hex/EtOAc
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afforded cyclic keto enol ether 43 (0.01 g, 70%) as a colorless
oil: [α]D −63.4 (c 0.5, CH2Cl2); Rf 0.79 (12:0.5 CH2Cl2/Et2O);
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.40−
7.28 (m, 3H), 6.71 (s, 1H), 4.76 (m, 1H), 4.57 (d, J = 7.8 Hz,
1H), 4.24−4.14 (m, 2H), 1.54 (s, 3H), 1.45 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 191.4, 149.0, 133.5, 131.2, 129.2, 128.7,
115.8, 112.0, 75.2, 73.6, 67.6, 26.9, 25.2; HRMS m/z (M + H)+
calcd for C15H17O4 261.1127, found 261.1125.
130.0, 129.6, 123.6, 114.4, 110.3, 101.2, 88.7, 86.5, 81.7, 80.8, 74.5,
67.9, 27.2, 26.7, 25.7, 25.6; HRMS calcld for C20H23O5 (M + H −
H2O)+ 343.1545, found 343.1523.
Compound 47. Hemiketal 47 was prepared following the
procedure used for 42. From the lactone (0.100 g, 0.271 mmol), 47
was isolated in 51% yield (0.065 g) as a mixture of diastereomers: Rf
0.45 (70:30 Hex/EtOAc); 1H NMR (400 MHz, CD3OD) δ 7.86−7.82
(m, 2H), 7.78−7.69 (m, 6H), 7.47−7.29 (m, 22H), 4.38 (s, 1H), 4.05
(s, 1H), 3.92 (s, 0.4 H), 3.74 (d, J = 8.4 Hz, 0.5H), 3.60−3.54 (m,
2H), 3.51−3.39 (m, 3H), 1.15−1.13 (m, 24H), 1.06 (s, 3H), 0.99 (s,
3H); 13C NMR (100 MHz, CD3OD) δ 190.7, 137.9, 137.8, 137.6,
137.5, 135.6, 134.8, 134.6, 134.3, 134.0, 132.7, 132.1, 131.3, 131.1,
131.0, 130.9, 129.9, 129.8, 129.6, 129.3, 128.8, 128.6, 128.5, 124.2,
121.3, 103.2, 98.4, 95.4, 89.8, 89.5, 87.1, 84.8, 78.5, 78.0, 69.1, 43.8,
42.2, 41.9, 27.9, 27.8, 23.7, 22.2, 21.6, 20.8, 20.7, 20.6; ; HRMS m/z
(M + H)+ calcd for C30H35O3Si 471.2355, found 471.2327.
Compound 44. Hemiketal 42 (0.04 g, 0.15 mmol) was taken in
absolute EtOH (3 mL) and cooled to 0 °C in an ice bath. NaBH4
(0.009 g, 0.225 mmol) was then added to the solution. The solution
was allowed to warm to rt and stirred overnight. The reaction mixture
was then quenched with dropwise addition of AcOH, and pH was
adjusted to neutral. The solution was then diluted with EtOAc
(10 mL), and the organic layer was washed with H2O (10 mL) and
dried over Na2SO4. The crude residue was purified by column
chromatography using 7:3 Hex/EtOAc as eluent, which gave diol 44
(0.037 g, 92%) in a 9:1 mixture of diastereomers. Data for the major
isomer are as follows: white solid, mp 69−70 °C; Rf 0.21 (70:30 Hex/
EtOAc); 1H NMR (500 MHz, CD3OD) δ 7.46−7.44 (m, 2H), 7.37−
7.34 (m, 3H), 4.67 (d, J = 6.8 Hz, 1H), 4.39−4.34 (m, 1H), 4.32 (t, J =
6.7 Hz, 1H), 4.01 (dd, J = 11.7, 3.7 Hz, 1H), 3.87 (m, 1H), 1.54 (s,
3H), 1.41 (s, 3H); 13C NMR (125 MHz, CD3OD) δ 132.7, 129.8,
129.6, 129.5, 110.3, 88.8, 86.8, 81.1, 79.6, 62.5, 61.9, 27.9, 25.6; HRMS
m/z (M + H)+ calcd for C15H19O4 263.1283, found 263.1257.
Compound 45. Compound 44 (0.023 g, 0.088 mmol) was taken
in CH3OH (4 mL) and treated with NaOMe (0.02 g, 0.35 mmol). The
solution was then heated under reflux conditions at 100 °C for 4 h.
After, the reaction was cooled to rt, CH3OH was removed in vacuo,
and the crude material was taken in EtOAc (10 mL), washed with
0.1 N HCl (0.5 mL), and washed with H2O (10 mL). The organic
layer was concentrated and purified by flash chromatography, which
afforded compound 45 in 41% yield (0.0094 g): Rf 0.62 (1:1 Hex/
Compound 48. 48 was prepared following the procedure used on
42. Starting with 1.5 g of the lactone (14.5 mmol), 48 was isolated in
1
61% as acyclic ynone (1.8 g): Rf 0.52 (80:20 DCM/Et2O); H NMR
(400 MHz, CDCl3) δ 7.54−7.51 (m, 2H), 7.42−7.38 (m, 1H), 7.34−
7.36 (m, 2H), 3.73−3.63 (m, 2H), 2.88−2.79 (m, 2H), 2.15−2.07
(m, 1H), 1.72−1.64 (m, 1H), 1.24 (d, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 192.0, 133.0, 130.7, 128.6, 119.9, 92.1, 86.9,
60.0, 45.4, 35.3, 16.2; HRMS m/z (M + H)+ calcd for C13H15O2
203.1072, found 203.1076.
Compound 49. 49 was prepared from γ-valerolactone following a
similar procedure as was used to prepare 42. Starting from 0.5 g of
valerolactone (4.99 mmol), 49 was isolated in 57% yield (0.575 g) as
1
the acyclic ynone: Rf 0.57 (80:20 DCM/Et2O); H NMR (500 MHz,
CDCl3) δ 7.54 (d, J = 7.8, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.35 (t, J =
7.6 Hz, 2H), 3.85 (m, 1H), 2.87−2.75 (m, 2H), 2.38 (d, J = 4.4 Hz,
1H), 1.92−1.78 (m, 2H), 1.22 (d, J = 6.3 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 188.2, 133.1, 130.8, 128.7, 119.9, 91.1, 87.9, 67.0,
42.0, 33.0, 23.6; HRMS m/z (M + H)+ calcd for C13H15O2 203.1072,
found 203.1076.
Compound 50. Hemiketal 50 was prepared following a similar
procedure used to prepare 42; from the lactone (0.059 g, 0.24 mmol),
50 was isolated in 57% yield (0.049 g): Rf 0.18 (7:3 Hex/EtOAc); 1H
NMR (400 MHz, MeOD) δ 7.64−7.58 (m, 2H), 7.54−7.44 (m, 3H),
4.91 (dd, J = 1.5, 8.5 Hz, 1H), 4.72 (d, J = 8.6 Hz, 1H), 3.84−3.79 (m,
2H), 3.77−3.72 (m, 1H), 3.64−3.54 (m, 1H), 1.67 (s, 3H), 1.45 (s,
3H), 1.36 (s, 3H), 1.27 (s, 3H); 13C NMR (400 MHz, MeOD) δ
134.0, 132.2, 130.2, 121.6, 112.5, 100.2, 94.8, 88.7, 82.4, 79.6, 78.5,
72.3, 65.9, 63.5, 28.9, 27.1, 25.9, 18.6; HRMS m/z (M + H)+ calcd for
C20H24O6 361.1651, found 361.1666.
1
EtOAc); H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 8.0 Hz, 2H),
7.24 (t, J = 7.6 Hz, 2H), 7.09 (t, J = 7.6 Hz, 1H), 5.41 (s, 1H), 4.53−
4.49 (m, 2H), 4.40 (dd, J = 7.9, 2.8 Hz, 1H), 4.21 (dd, J = 12.1, 1.8 Hz,
1H), 4.16 (d, J = 2.9 Hz, 1H), 1.35 (s, 3H), 1.34 (s, 3H); 13C NMR
(100 MHz, CD3OD) δ 151.9, 137.7, 129.5, 129.1, 126.6, 111.0, 107.6,
75.8, 73.8, 71.7, 26.9, 24.9; HRMS m/z (M + H)+ calcd for C15H19O4
263.1283, found 263.1312.
Compound 42. Phenyl acetylene (0.46 mL, 4.16 mmol) was taken
in dry THF (1 mL), and the solution was cooled to −78 °C in a dry
ice/acetone bath. To this solution was added nBuLi (2.8 mL, 1.6 M),
and the temperature was allowed to rise slowly to −65 °C until
formation of a homogeneous solution was noted. D-Erythronolactone
(0.33 g, 2.08 mmol) was dissolved in 4 mL of dry THF and slowly
added to the mixture over a period of 10 min, and it was allowed to
warm to −50 °C over a period of 4 h. Upon completion (as monitored
by TLC), the reaction was quenched with saturated NH4Cl solution
(5 mL) and diluted with EtOAc (15 mL). The organic layer was
washed with H2O (20 mL) and brine (10 mL), dried over Na2SO4,
and filtered. The filtrate was concentrated in vacuo, and the crude
residue was purified by flash column chromatography using 4:1 Hex/
EtOAc as eluent, which gave hemiketal 42 (0.45 g, 83%) as a
diastereomeric mixture of hemiketals (10:1) (white solid): mp 62−64 °C;
Rf 0.42 (70:30 Hex/EtOAc); 1H NMR (400 MHz, CD3OD) δ
7.49−7.47 (m, 2H), 7.39−7.33 (m, 3H), 4.92 (dd, J = 5.6, 3.7 Hz,
1H), 4.82 (s, 1H), 4.55 (d, J = 5.6 Hz, 1H), 4.04 (dd, J = 10.3, 3.7 Hz,
1H), 3.95 (d, J = 10.2 Hz, 1H), 1.52 (s, 3H), 1.36 (s, 3H); 13C NMR
(100 MHz, CD3OD) δ 132.8, 130.0, 129.6, 114.1, 101.6, 88.2, 86.6,
86.3, 82.0, 72.1, 26.9, 25.6; HRMS m/z (M + H)+ calcd for C15H17O4
261.1127, found 261.1121.
Compound 51. Six-membered hemiketal 51 was prepared
following the procedure used for 42. Starting with 0.094 g of the lac-
tone (0.175 mmol), 51 was isolated in 92% yield (0.103 g) as a mix-
1
ture of anomers: Rf 0.58 (70:30 Hex/EtOAc); H NMR (400 MHz,
CDCl3) δ 7.56−7.20 (m, 25H), 5.18 (d, J = 11.1 Hz, 1H), 5.06−4.97
(m, 2H), 4.93−4.89 (m, 2H), 4.72 (dd, J = 12.2, 5.1 Hz, 1H), 4.66−
4.58 (m, 2H), 4.23−4.11 (m, 1H), 4.07 (t, J = 9.3 Hz, 1H), 3.99−3.90
(m, 2H), 3.87−3.70 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 138.9,
138.8, 138.7, 138.3, 138.2, 138.0(2), 132.3, 132.0, 129.2, 129.1, 128.5,
128.4(2), 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 121.8, 121.6,
96.3, 92.3, 88.4, 88.2, 85.0, 84.6, 84.3, 84.0, 83.8, 82.7, 77.9, 77.6, 76.0,
75.9, 75.3, 75.1, 74.6, 74.3, 73.6, 73.5, 72.0, 68.7, 68.5; ; HRMS m/z
(M + H)+ calcd for C42H41O6 641.2903, found 641.2913.
General Procedure for Cycloisomerization of 42 and 46−51.
To a solution of hemiketals/ynones (42 and 46−51) (0.15 mmol) in
CHCl3 (6 mL) was added PPh3 (0.075 mmol). The mixture was
heated to reflux at 70 °C overnight (progress of the reaction was
monitored by TLC). The solvent was removed under reduced
pressure, and the residue was purified by flash column chromatog-
raphy, which afforded corresponding cyclic keto enol ethers 43 and
52−57 in 52−92% yields.
Compound 46. Hemiketal 46 was prepared following a similar
procedure as used to prepare 42. From the corresponding lactone
(0.243 g, 0.940 mmol), 46 was isolated in 84% (0.284 g) as an
anomeric mixture as white solid: Rf 0.6 (70:30 Hex/EtOAc); 1H NMR
(400 MHz, CD3OD) δ 7.48−7.46 (m, 2H), 7.38−7.33 (m, 3H), 4.87
(dd, J = 5.5, 3.5 Hz, 1H), 4.79 (s, 1H), 4.61 (d, J = 5.6 Hz, 1H), 4.41
(m, 1H), 4.14−4.08 (m, 2H), 4.02 (m, 1H), 1.53 (s, 3H), 1.42 (s, 3H),
1.36 (s, 3H), 1.35 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 132.8,
Compound 43. Following the general procedure, hemiketal 42
was transformed to compound 43 in 96% yield. Spectra for 43 were
identical to those from its preparation via Swern oxidation as described
above.
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Article
Compound 52. Hemiketal 46 (0.035 g, 0.098 mmol) was
transformed to compound 52 (0.025 g, 0.069 mmol) in 71% yield
following the general procedure: [α]D +145.4 (c 2.6, CH2Cl2); Rf 0.58
6.93 (m, 40H), 6.73 (d, J = 7.0 Hz, 1H), 4.88 (d, J = 12.4 Hz, 1H),
4.82−4.76 (m, 2H), 4.68 (d, J = 12.1 Hz, 1H), 4.63 (d, J = 12.4 Hz,
1H), 4.44 (d, J = 10.7 Hz, 1H), 4.10−3.99 (m, 2H), 3.92−3.81 (m,
4H), 3.53 (d, J = 8.4 Hz, 1H), 3.19 (br s, 1H); 13C NMR (100 MHz,
CDCl3) δ 154.4 (d, J = 21.3), 144.4, 143.1, 139.0, 138.8, 138.6, 131.7,
129.0, 128.5, 128.4, 128.2, 128.1, 127.9, 127.7, 127.6, 127.2, 127.1,
98.1, 83.0, 75.5, 75.4, 75.1, 73.5, 73.3, 72.9, 71.6, 70.1; 31P NMR (300
MHz, CDCl3) δ −44.3. Mixed fractions containing both diastereomers
were obtained (0.065 g, 46%). The second diastereomer (Rf 0.17) was
isolated using 1:1 Hex/EtOAc as eluent (0.0.25 g, 18%): [α]D +44.3
(c 0.4, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.47−6.91 (m, 40H),
6.75 (d, J = 7.4 Hz, 1H), 4.88 (d, J = 11.6 Hz, 1H), 4.84−4.78 (m,
2H), 4.76−4.71 (m, 2H), 4.59 (d, J = 12.3 Hz, 1H), 4.45−4.41 (m,
1H), 3.93−3.86 (m, 1H), 3.74 (dd, J = 9.5 Hz, 1H), 3.67 (d, J = 9.5
Hz, 1H), 3.43 (dd, J = 10.6, 2.7 Hz, 1H), 3.21 (d, J = 10.2 Hz, 1H),
3.08 (d, J = 10.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 153.2 (d,
J = 23.1 Hz), 144.1, 139.3, 139.2, 139.1, 139.0, 138.8, 138.6, 132.5,
129.4, 128.8, 128.5, 128.4, 128.2, 128.1, 127.9, 127.8, 127.7, 127.6,
127.2, 126.9, 126.8, 126.2, 98.2, 84.8, 83.9, 78.8, 75.7, 75.5, 74.9, 73.5,
71.7, 68.5; 31P NMR (300 MHz, CDCl3) δ −48.7; HRMS m/z (M + H)+
calcd for C60H56O6P 903.3736, found 903.3771.
Compound 63. Hemiketal 42 (0.049 g, 0.19 mmol) was taken in
dry toluene (3 mL) and treated with PPh3 (0.075 g, 0.28 mmol). The
resulting mixture was heated to 80 °C for 4 h. To that mixture was
then added 60 μL of diisopropylazodicarboxylate (DIAD), and the
mixture was refluxed at 110 °C for an additional 6 h. The solvent was
removed under reduced pressure, and the crude residue was purified
by flash column chromatography using 70:30 Hex/EtOAc as eluent,
which afforded compound 63 as a single diastereomer (0.063 g) in
73% yield as a white solid: mp 86−88 °C; Rf 0.47 (70:30 Hex/
EtOAc); [α]D −99.2 (c 0.6, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
7.40−7.28 (m, 5H), 5.72 (s, 1H), 5.34 (d, J = 5.8 Hz, 1H), 5.09−5.02
(m, 2H), 4.43−4.35 (m, 2H), 4.01 (dd, J = 12.6, 1.3 Hz, 1H), 1.45
(s, 3H), 1.43 (s, 3H), 1.31 (d, J = 2.3 Hz, 3H), 1.30 (d, J = 2.3 Hz,
3H), 1.27 (d, J = 4.3 Hz, 3H), 1.25 (d, J = 4.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 157.6, 157.2, 143.8, 137.4, 128.9, 128.3, 126.1,
114.8, 111.1, 72.2, 70.9, 70.7, 69.1, 67.5, 64.8, 28.4, 27.1, 22.2, 22.1
(3); HRMS m/z (M + H)+ calcd for C23H31N2O7 447.2131, found
447.2117.
1
(12:0.5 CH2Cl2/Et2O); H NMR (400 MHz, CDCl3) δ 7.75 (d, J =
7.4 Hz, 2H), 7.39−7.33 (m, 3H), 6.70 (s, 1H), 4.80 (d, J = 7.3 Hz,
1H), 4.57−4.53 (m, 2H), 4.28 (dd, J = 8.8, 6.3 Hz, 1H), 4.21 (dd, J =
8.8, 4.8 Hz, 1H), 3.87 (d, J = 7.3 Hz, 1H), 1.52 (s, 3H), 1.48 (s, 3H),
1.45 (s, 3H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.9,
148.4, 133.5, 131.1, 129.2, 128.4, 116.0, 112.6, 109.9, 77.0, 74.8, 74.7,
73.9, 67.0, 27.1, 26.6, 25.3; HRMS m/z (M + H)+ calcd for C20H25O6
361.1651, found 361.1626.
Compound 53. Following the general procedure, hemiketal 47
(0.020 g, 0.041 mmol) was transformed to 53 in 52% yield (0.010 g,
1
0.021 mmol): H NMR (400 MHz, CDCl3) δ 7.79−7.76 (m, 2H),
7.72−7.68 (m, 4H), 7.44−7.31 (m, 9H), 6.52 (s, 1H), 4.10 (d, J = 11.2
Hz, 1H), 4.01 (s, 1H), 3.87 (d, J = 11.2 Hz, 1H), 1.18 (s, 3H), 1.13 (s,
12H); 13C NMR (100 MHz, CDCl3) δ 192.8, 148.6, 136.3, 136.2,
130.6, 129.9, 129.7, 128.5, 128.3, 127.7, 127.4, 112.9, 80.8, 74.4, 38.5,
27.4, 27.3, 23.0, 20.3, 19.0; HRMS m/z (M + H)+ calcd for C30H35-
O3Si 471.2355, found 471.2315.
Compound 54. Under the general reaction conditions, hemiketal
48 (0.068 g, 0.34 mmol) was converted to compound 54 (0.060 g,
0.30 mmol) in 88% yield: Rf 0.70 (70:30 Hex/EtOAc); 1H NMR (400
MHz, CDCl3) δ 7.78 (d, J = 7.9 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.28
(m, 1H), 6.69 (s, 1H), 4.40 (dt, J = 11.0, 4.2 Hz, 1H), 4.24 (dt, J =
10.9, 3.0 Hz, 1H), 2.62 (m, 1H), 2.25 (m, 1H), 2.01 (m, 1H), 1.30 (d,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.2, 149.1, 134.5,
130.6, 128.5, 128.3, 113.0, 65.8, 40.5, 30.9, 16.2; HRMS m/z (M + H)+
calcd for C13H15O2 203.1068, found 203.1047.
Compound 55. Hemiketal 49 (0.0780 g, 0.38 mmol) was
converted to compound 55 in 92% yield using the general procedure
1
(0.072 g, 0.35 mmol): Rf 0.57 (70:30 Hex/EtOAc); H NMR (400
MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.28
(m, 1H), 6.67 (s, 1H), 4.33 (m, 1H), 2.69 (ddd, J = 18.3, 3.3, 2.6 Hz,
1H), 2.58 (m, 1H), 2.16−1.99 (m, 2H), 1.51 (d, J = 6.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 194.2, 149.3, 134.4, 130.7, 128.5, 128.3,
112.6, 73.2, 35.4, 29.6, 21.5; HRMS m/z (M + H)+ calcd for C13H15O2
203.1072, found 203.1068.
Compound 56. Following the general procedure, hemiketal 50
(0.033 g, 0.085 mmol) was converted to compound 56 in 75% yield
Compound 64. 64 was obtained from ynone 48 (0.039 g, 0.19
mmol) following the same procedure as was used to prepare 63. The
product was isolated as mixture of diastereomers in 58% yield (0.043 g):
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.9 Hz, 1H), 7.37−
7.25 (m, 2H), 7.14 (m, 1H), 6.70−6.71 (m, 1H), 5.40 (s, 1H), 5.12−
4.90 (m, 3H), 4.24−4.08 (m, 1H), 2.61−2.35 (m, 1H), 2.06 (s, 2H),
1.47−1.43 (m, 3H), 1.36−1.19 (m, 12H); 13C NMR (100 MHz,
CDCl3) δ 160.5, 155.8, 150.6, 150.3, 147.5, 136.2, 130.9, 129.0, 128.9,
128.5, 128.4, 128.3, 126.1, 102.9, 72.4, 71.0, 70.4, 70.1, 64.5, 64.0, 31.0,
22.3, 22.2(3), 22.1, 22.0, 21.9(2), 19.9, 19.6; HRMS m/z (M + H)+
calcd for C21H29N2O5 389.2076, found 389.2051.
1
(0.023 g, 0.064 mmol): [α]D +20.7 (c 1.0 CHCl3); H NMR (400
MHz, CDCl3) δ 7.73−7.70 (m, 2H), 7.40−7.35 (m, 3H), 7.05 (s, 1H),
4.97 (d, J = 9.7 Hz, 1H), 4.24 (dd, J = 8.0 Hz, 1H), 4.13−4.08
(m, 2H), 3.93 (dd, J = 9.2 Hz, 1H), 3.48 (m, 1H), 1.63 (s, 3H), 1.56
(s, 3H), 1.53 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
191.8, 150.3, 132.4, 131.1, 130.3, 128.9, 122.6, 112.2, 99.7, 81.7, 78.7,
76.2, 74.3, 62.7, 28.9, 27.3, 26.7, 19.2; HRMS m/z (M + H)+ calcd for
C20H25O6 361.1651, found 361.1667.
Compound 57. Following the general procedure, hemiketal 51
(0.100 g, 0.16 mmol) gave the corresponding cyclic keto enol ether 57
in 14% yield (0.014 g, 0.022 mmol): [α]D +65.6 (c 1.98, CH2Cl2); Rf
0.59 (70:30 Hex/EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J =
7.6 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.39−7.26 (m, 19H), 7.15−7.14
(m, 2H), 6.99 (s, 1H), 5.06 (d, J = 5.4 Hz, 1H), 4.89 (d, J = 11.6 Hz,
1H), 4.76 (d, J = 11.6 Hz, 1H), 4.64−4.60 (m, 2H), 4.56 (d, J = 5.3
Hz, 1H), 4.54 (d, J = 5.8 Hz, 1H), 4.48−4.39 (m, 3H), 4.11 (dd, J =
10.2, 7.5 Hz, 1H), 4.02 (t, J = 4.7 Hz, 1H), 3.90 (dd, J = 4.3, 1.8 Hz,
1H), 3.78 (dd, J = 10.2, 4.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
193.9, 150.0, 138.2, 138.1, 138.0, 137.3, 133.2, 131.1, 129.4, 128.9,
128.6, 128.4, 128.0, 127.9, 127.8, 119.8, 86.3, 82.5, 81.7, 73.6(2), 72.7,
72.2, 70.7; HRMS m/z (M + H)+ calcd for C42H41O6 641.2903, found
641.2878.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data for 15 are in the Cambridge Crystallo-
graphic Data Centre (CCDC), No. 864322. Copies of this
information may be obtained free of charge from CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44−1223−
336033; web: www.ccdc.cam.ac.uk/conts/retrieving/html;
email: deposit@ccdc.cam.ac.uk). Experimental details and
1
characterization data including H and 13C NMR spectra of
Compound 62. Oxaphospholene 62 was obtained in 78% yield as
a mixture of diastereomers during the reaction of hemiketal 51 with
PPh3. To a solution of 51 (0.100 g, 0.16 mmol) in CHCl3 (4 mL) was
added PPh3 (0.082 g, 0.03 mmol), and the mixture was heated to
reflux overnight. Formation of polar diastereomers was observed by
TLC. These were partially separated by flash column chromatography
using 7:3 Hex/EtOAc as eluent, which separated the first diastereomer
(Rf 0.30) of 62 (0.020 g, 14%): 1H NMR (400 MHz, CDCl3) δ 7.59−
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mark.peczuh@uconn.edu.
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Article
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors thank NSF for support of this work through a
CAREER grant to M.W.P. (CHE-0546311). Chris Incarvito in
the Chemistry Instrumentation Center at Yale University is
acknowledged for collection of X-ray data on 15.
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