Access to oxetane-containing psico-nucleosides from 2-methyleneoxetanes: A role for neighboring group participation?

Article abstract of DOI:10.1021/jo201565h

The first psico-oxetanocin analogue of the powerful antiviral natural product, oxetanocin A, has been readily synthesized from cis-2-butene-1,4-diol. Key 2-methyleneoxetane precursors were derived from β-lactones prepared by the carbonylation of epoxides. F⁺-mediated nucleobase incorporation provided the corresponding nucleosides in good yield but with low diastereoselectivity. Surprisingly, attempted exploitation of anchimeric assistance to increase the selectivity was not fruitful. A range of 2-methyleneoxetane and related 2-methylenetetrahydrofuran substrates was prepared to explore the basis for this. With one exception, these substrates also showed little stereoselectivity in nucleobase incorporation. Computational studies were undertaken to examine if neighboring group participation involving fused [4.2.0] or [4.3.0] intermediates is favorable (Figure presented).

Full text of DOI:10.1021/jo201565h

Article
pubs.acs.org/joc
Access to Oxetane-Containing psico-Nucleosides from
2-Methyleneoxetanes: A Role for Neighboring Group Participation?
Yanke Liang,† Nathan Hnatiuk,† John M. Rowley,‡ Bryan T. Whiting,‡ Geoffrey W. Coates,‡
Paul R. Rablen,§ Martha Morton,† and Amy R. Howell*,†
†Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060, United States
‡Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, New York 14853-1301, United States
§Department of Chemistry and Biochemistry, Swarthmore College, Swarthmore, Pennsylvania 19081-1397, United States
S
* Supporting Information
ABSTRACT: The first psico-oxetanocin analogue of the powerful
antiviral natural product, oxetanocin A, has been readily synthesized
from cis-2-butene-1,4-diol. Key 2-methyleneoxetane precursors were
derived from β-lactones prepared by the carbonylation of epoxides. F+-
mediated nucleobase incorporation provided the corresponding
nucleosides in good yield but with low diastereoselectivity.
Surprisingly, attempted exploitation of anchimeric assistance to
increase the selectivity was not fruitful. A range of 2-methyleneoxetane and related 2-methylenetetrahydrofuran substrates
was prepared to explore the basis for this. With one exception, these substrates also showed little stereoselectivity in nucleobase
incorporation. Computational studies were undertaken to examine if neighboring group participation involving fused [4.2.0] or
[4.3.0] intermediates is favorable.
Our interest in oxetane-containing psico-nucleosides grew out
of our discovery that 1,5-dioxaspiro[3.2]hexanes 4 provided
oxetane intact products 6 (Figure 2),8 presumably via oxonium
INTRODUCTION
■
Oxetanocin A (OXT-A; Figure 1), an unusual nucleoside with
an oxetanosyl sugar, was isolated in 1986 from the fermentation
broth of Baccilus megaterium.1 Because of its potent inhibition
of HSV-1, HSV-2, HCMV, and HIV-1,2 interest in the synthesis
and biological evaluation of OXT-A and related analogues was
intense over the next decade.3 For example, base-modified
OXTs, such as the thymine analogue, OXT-T, showed
promising activity against VZV, HSV-1, and HSV-2,4 while
the guanine congener, OXT-G, inhibited HBV5 and HCMV6
replication. With the exception of cyclopropyl-containing
carbocyclic nucleoside 1, all of the oxetanocin analogues
evaluated were derivatives of reducing sugars. We have become
interested in exploring the biological potential of nonreducing
(psico)-nucleosides containing an oxetanosyl sugar moiety.7
Herein we report a straightforward route to the first psico-
oxetanocin, 1′-fluoromethyl-OXT-A (2), and describe exper-
imental and theoretical studies on the potential of using
anchimeric assistance to enhance the diastereoselectivity in
nucleobase incorporation.
Figure 2. Pathways to oxetane-intact products from dioxaspirohexanes
4 or 2-methyleneoxetanes 3.
ions 5, in the presence of certain Lewis acids (including
protons). In particular, we reported that aromatic heterocycles
could be incorporated,9 and extension to the coupling with
nucleobases seemed logical. We have prepared hydroxymethyl-
branched psico-nucleosides by this pathway, and results will be
reported in due course. However, we also recognized that it
should be possible to directly access oxonium ions 7, related to 5,
Received: July 27, 2011
Published: October 26, 2011
Figure 1. Structures of oxetanocin A and related psico-nucleosides.
© 2011 American Chemical Society
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Scheme 1
from 2-methyleneoxetanes 3, the precursors of the dioxaspiro-
hexanes 4. We decided to explore this option using an electro-
philic fluorine source to prepare a direct analogue 2 of
OXT-A. A related incorporation of a nucleobase onto a 2-
methylenetetrahydrofuran using Selectfluor, a F+ source, had
been reported.10
chemical shifts are fairly characteristic and that they can be used
to differentiate the two sets of isomers. C4 chemical shifts are
less than 155 ppm, and C5 chemical shifts are greater than 120
ppm in N9-substituted isomers (the corresponding N7 isomer
shifts are generally over 160 ppm and under 120 ppm).15 On
1
the basis of the ratio deduced from H NMR and the quantity
of material isolated, the desired nucleoside 12-β was
determined to have been formed in 27% yield. Mixtures 12
and 13 were subjected to amine substitution,16 followed by
TBS cleavage. Separation of the β isomers from their α/β
mixtures was achieved either at the last stage or after amination,
affording the target molecule 2 and its regioisomer 14 in good
yields. The relative stereochemistry of both 2 and 14 was
confirmed by NOESY studies.17 This seven-step sequence
provided rapid, straightforward access to the target psico-
nucleoside 2 from the simple starting material, cis-2-butene-
1,4-diol. More importantly, the approach suggested that
nucleobase incorporation using F+ to generate an oxetane
oxonium ion was effective, with good conversion to nucleoside
product.
Although encouraged by the efficiency of nucleobase
incorporation, the diastereoselectivity of this step was not
satisfying. We anticipated that a benzoyl group on the C3
hydroxymethyl moiety would provide anchimeric assistance,
enhancing the desired stereoselectivity of the transformation.
Although low yields were obtained, Yamamura and co-
workers18 proposed transition states with neighboring group
participation for the key glycosyl bond formation step, in a
synthesis of OXT-A.
RESULTS AND DISCUSSION
■
Silyl-protected 2-methyleneoxetane 11 was chosen as the
substrate for exploring the feasibility of F+-mediated genera-
tion of oxonium ions 7 (E = F). 2-Methyleneoxetane 11 was
prepared in a straightforward, four-step procedure from cis-2-
butene-1,4-diol (Scheme 1). Standard silyl protection and
epoxidation by dimethyldioxirane (DMDO) of butenediol
provided epoxide 8. High-pressure carbonylation using catalyst
9 gave β-lactone 10 in good yield,11 illustrating the significant
practical utility of this approach to β-lactones. Methylenation12
of 10 provided methyleneoxetane 11 efficiently.
Fluorine-mediated nucleobase incorporation of 11 gave a
mixture of products. Initial purification provided a mixture of
four psico-nucleosides in a ratio of 3:3:2:1 and in a total yield of
76%, demonstrating that the formation and capture of the
oxonium ion from 11 was effective. The ratio of isomers was
1
calculated from the H NMR spectrum of the crude reaction
mixture. In addition to the alternative facial diastereomers of
12, the two other products were diastereomeric purine
regioisomers 13 (connected at N7, rather than N9). Alkylation
at N7 is known to take place in competition with
N9 alkylation.13 It is also possible that transglycosylation
could occur, which could result in isomerization at the
anomeric center.14 However, we believe this is unlikely based
on later results described in this paper. Further purification
provided 12 (N9) as a 37:63 mixture and 13 (N7) as a 23:77
mixture, both favoring the desired β isomers. The assignment of
regioisomers was determined based on purine 13C NMR
chemical shifts. It has been reported that the C4 and C5
To examine the potential of exploiting neighboring group
participation, β-lactone 15a (Table 1, entry 1) was prepared
from dibenzoylated cis-2-buten-1,4-diol by the same sequence
as had been used for TBS-protected β-lactone 10 (Scheme 1).
It is noteworthy that the high-pressure carbonylation proceeded
in lower yield (48%) and required higher catalyst loading (5%).
Methylenation gave a moderate yield of 2-methyleneoxetane
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than that of 16a and more efficient, the reaction of 16b (Table 1,
entry 2) provided multiple purine-containing products. Three
nucleosides were isolated, and a fourth was contaminated with
other byproducts. All four nucleosides clearly showed purine and
fluorine incorporation. 2-Methyleneoxetane 16c, which possesses
a benzoyl group on the C4 position, would be expected to induce
a bias to the opposite face through a bridged transition state (see
Figure 3, 19). However, nucleobase incorporation again
Table 1. Investigation of Anchimeric Assistance from C3
and/or C4 Benzoyl Groups of 2-Methyleneoxetanes
product
a
entry
R, R′
lactone 16 (% yield) 17 (% yield)
ratio
1
2
3
R, R′ = Bz
15a
16a (48)
16b (75)
16c (60)
17a (<20)
17b (53)
17c (45)
R = TBS, R′ = Bz 15b
R = Bz, R′ = TBS 15c
4:3:3:2
4:2:1:1
a
Product ratios were determined by a combination of the crude
1H NMR and the masses of the products isolated. Both N7 and N9
nucleosides were isolated.
Figure 3. Plausible oxonium ions from 16a.
proceeded in modest yield with multiple nucleoside products
(Table 1, entry 3). Although the outcomes with 16b and 16c were
somewhat better than that with 16a, neither showed the high
selectivity that is a hallmark of effective neighboring group
participation.
In light of the conclusion that anchimeric assistance did not
appear to play a role in the reactions of 2-methyleneoxetanes
16, we wondered if this was because of ring strain in the four-
membered ring in intermediates related to 18/19. To probe
whether releasing the ring strain from oxetanes by substituting
tetrahydrofurans might propel the transition states toward
closed forms (fused or bridged), 2-methylenetetrahydrofurans
(THFs) 22−25 (Table 2) were prepared as THF analogues to
access the types of oxonium ion intermediates we had
anticipated for 16 (see Figure 3).
16a. Fluorine-mediated nucleobase incorporation of this
provided a complex, low yielding mixture of products. Possible
side reactions may include hydrolysis of 16a or elimination of
one benzoyloxy substituent, followed by ring expansion.19
Complete separation of 17a proved impossible; however, the
purine-containing fractions were carried to the next stage, a
one-pot deprotection/amine incorporation. Nucleoside 14
was the only clean product isolated in 4% yield from 16a.
The poor efficiency of this route suggested that the anchimeric
assistance might not play a role in this substrate. Alternatively,
it was possible that opposing participation pathways were in
effect. Either fused oxonium ion 18 or bridged ion 19 could, in
theory, be involved in the conversion of 16a to nucleoside
products (Figure 3).
The γ-lactone precursors 26−29 of 2-methylene-THFs 22−
25 were prepared as shown in Scheme 3. γ-Lactone 26 was
synthesized from known γ-butyrolactone 30,21 while lactone 27
was prepared via benzoylation of known 4-hydroxy-γ-
butyrolactone (31).22 The synthesis of cis-γ-lactone 28 started
with the alkylation of diester 32,23 which predominantly gave
anti-product 33 in moderate yield. Chemoselective reduction
provided diol 34, which was cyclized to afford γ-lactone 35.
Deprotection followed by benzoylation of the resulting diol
gave 28 in moderate yield.24 The synthesis of trans-γ-lactone 29
involved direct alkylation of γ-butyrolactone 31, which favored
the desired diastereomer 36. Standard deprotection/protection
provided lactone 29.
In order to probe whether fused or bridged anchimeric
assistance might be involved, 2-methyleneoxetanes 16b and
16c, with different protecting groups on the C3 and C4
hydroxymethyl groups, were prepared from β-lactones 15b and
15c. The lactones were prepared from known, differentially
protected epoxide 2020 (Scheme 2). Carbonylation of 20
Scheme 2
2-Methylene-THFs 22−25, obtained from chemoselective
methylenation of the corresponding lactones 26−29, were
subjected to the Selectfluor-mediated nucleobase incorporation
conditions used for the 2-methyleneoxetanes, and the outcomes
are summarized in Table 2. 2-Methylenetetrahydrofuran 22
underwent F+-mediated purine incorporation in 43% yield, with
the isolation of four nucleoside products in a ratio of 5:3:3:1
1
(entry 1). The ratios were determined from H NMR of the
crude reaction mixture, where product purine protons can be
clearly distinguished. The identification of product purine peaks
in the crude NMR was based on the isolation of two sets of
product mixtures in an analogous fashion to the oxetanosyl
nucleosides. This result indicated that the six-membered
closed-ring transition state might again not be an important
contributor in the case of the 2-methylene-THFs.
An important role for the bridged transition state (analogous
to 19) was also discounted due to the low facial
provided an inseparable 3:2 mixture of β-lactones 21. Although
the lactones were again inseparable after hydrogenolysis,
benzoylation provided readily separated β-lactones 15b and
15c. Methylenation gave 2-methyleneoxetanes 16b and 16c,
which were reacted with Selectfluor and 6-chloropurine under
conditions identical to those used for 16a. Although cleaner
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Table 2. Investigation of Anchimeric Assistance in 2-Methylenetetrahydrofurans
a
b
c
1
See text for discussion. Yield calculated over three steps from 35 (see ref 24 for details). Crude H NMR showed multiple products.
Scheme 3
the reaction of 2-methylene-THF 24, having cis-substituents,
proceeded in good overall yield, there were multiple nucleoside
products, again suggesting that anchimeric assistance had
not played a major role (entry 3). Surprisingly, the trans-
isomer 25 produced predominantly 37 in 72% yield (entry 4).
Thus, with the exception of 2-methylenetetrahydrofuran 25,
which will be discussed further below, it appeared that neither
the 2-methyleneoxetanes nor the 2-methylene-THFs reacted
along pathways that had significant involvement of oxonium
ions stabilized by neighboring groups. We decided to examine
this further from a quantum mechanics standpoint.
With the possible exception of compound 25, anchimeric
assistance apparently does not govern the outcome of these
fluorine-mediated nucleobase incorporation reactions. One
potential explanation is that the invocation of anchimeric
assistance rests on the assumption that the oxonium ions shown
in Figure 3 are more stable than the corresponding open forms
of these cations. However, if that were not the case (i.e., if the
cations were only equally stable to the open carbocations, or
even less stable), then anchimeric assistance would not dictate
the stereochemical outcome. The fluorination reactions would
proceed partially or entirely through open carbocations that
would not be expected to show a strong stereochemical
preference in their reactivity. Since there is no convincing
literature evidence for remote neighboring group participation
(e.g., 19),25 we decided to focus on the more likely fused
intermediate 18.
diastereoselectivity (∼1:1 dr of N9 isomers only; no N7
isomers observed) of the reaction with 23 (entry 2). This lack
of observation of N7 isomers is a clear indication that the
formation of the psico-nucleosides was irreversible and suggests
that their presence in other reactions was not due to
transglycosylation under these reaction conditions. Although
Electronic structure calculations were used to evaluate the
relative stability of open and fused carbocations. In order to
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Figure 4. Rotatable bonds in oxetane precursor and in corresponding open and fused oxonium ions.
reduce computational time, the benzoyl group was replaced
with an acetyl group in the system shown in Figure 4. If the
fused structure were more stable than the open structure,
anchimeric assistance would be expected to yield a strong
stereochemical effect on the outcome of the reaction. On the
other hand, if the open form were more stable, no such
behavior would be expected.
Referring to “the open form” in fact oversimplifies the matter
since different conformations are possible about the four
dihedral angles marked a, b, c, and d in Figure 4. In order to
address the matter in a thorough fashion, calculations were
performed on all possible structures. The three dihedral angles
a, b, and d were given starting values of ±60 and 180° and the
dihedral angle c starting values of 0 (Z) and 180° (E), for a
total of 54 (3 × 3 × 3 × 2) starting structures. The starting
material was treated in like fashion (18 starting structures), as
was the fused cation (3 starting structures).
The calculations indicated that, indeed, as one would expect,
the fused cation is more stable than the open structure, and by a
large amount (∼10 kcal/mol), for both the four-membered ring
system shown above and also for the corresponding five-
membered ring system. The calculations thereby reject lack of
stability of the fused cations as an explanation for the lack of
stereospecificity. The involvement of trans-fused cations was
also considered. For the oxetane system, the most stable trans-
fused intermediate is some 21 kcal/mol higher in energy than
the most stable cis-fused intermediate (Figure 5a). Further-
seem likely that a competition between cis- and trans-fused
cations explains the lack of stereoselectivity in most of the THF
cases. A full tabulation of the calculated energies for the starting
compounds and for the cation intermediates appears in the
Supporting Information.
It is possible that solvent plays a major role in relative
stabilization of the oxonium ion intermediates or in the
efficiency of formation of the fused species. The calculations
were conducted without taking solvent into account. The
nucleobase incorporation reaction of 2-methyleneoxetane 15b
was repeated in acetonitrile, DMF, and 1,2-dichloroethane. The
outcomes were essentially unchanged in comparison to that in
nitromethane.
What else might explain the experimentally observed
behavior? Anchimeric assistance is a well-documented
phenomenon and is used extensively to guide stereochemistry
in the synthesis of carbohydrates and similar structures.
However, the commonly used cases differ from the structures
considered here in one important way: normally, the fused ions
are five-membered rings, not six- or seven-membered rings.
In the more usual case, illustrated in Figure 6, only two
dihedral angles, a and c, describe the conformational space
Figure 6. Rotatable bonds in oxetane precursor and in the
corresponding open and fused oxonium ions for five-membered
systems.
available to the starting material and to the “open” cation. In
the oxetanocin-type systems, however (Figure 4), three
dihedral anglesa, b, and cdescribe the space. This
difference might matter if the carbocationic intermediate is
very short-lived. Normally, one assumes that an intermediate
exists sufficiently long that it will adopt the most favorable
conformation before reacting. However, the intermediate
carbocation might in fact be so reactive that the time scale for
its reaction with a nucleophile is of the same order as the time
scale for conformational exploration of the dihedral angles a, b,
and c. The more traditional systems that form a five-membered
cycle have an advantage, essentially entropic in nature, in that
the cation needs only to explore rotation around two dihedral
angles, a and c, in order to find the most stable cyclic structure.
In fact, it is really only one dihedral angle because the angle
marked c has a very strong preference for a Z arrangement, such
that the E conformations can for most practical purposes be
neglected.
Figure 5. Plausible cis-fused, trans-fused, and open monocyclic
intermediates.
more, the most stable trans-fused intermediate is 2.5 kcal/mol
higher in energy than even the LEAST stable conformation of
the open (non-anchimerically assisted) cation. In the five-
membered ring (THF) system, the most stable trans-fused
intermediate is 11 kcal/mol higher in energy than the most
stable cis-fused structure (Figure 5b). In this case, it is more
stable than most of the conformations of the open cation and
only 0.5 kcal/mol higher in energy than the most stable
monocyclic conformation. Thus, it is not entirely unreasonable
to imagine that the trans-fused structure might participate if
there were some kinetic barrier that hindered formation of the
much more stable cis-fused structure. Nevertheless, it does not
The systems we examined, however, require exploration
around both the angles marked a and b (c can be neglected,
again, because of the strong preference for a Z conformation).
Crudely speaking, nine conformations (3 × 3) need to be
explored, instead of just three. It is worth noting that, in the
neutral starting materials, the most stable conformations are
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ones in which the acetoxy oxygen is far from the carbon to
which a bond must be formed in the fused carbocation
structure.
To examine experimentally if a five-membered oxonium-
fused cation is involved in fluorine-mediated nucleobase
incorporation of α-methylene cyclic ethers, methylene-THF
39, derived from readily prepared γ-lactone 38, was treated with
Selectfluor and 6-chloropurine. Diastereomer 40 was isolated in
very good yield (Scheme 4). This outcome supports an
psico-nucleoside products, with clear signs of fluorine and
nucleobase incorporation. Purification provided β-nucleosides
47 and 48 in good yields. The relative stereochemistry was
confirmed by NOESY studies.17 The reaction rate was slower in
this reaction than in the nucleobase incorporation of 2-
methylene-THF 39. Considering the bulkiness of the
neighboring isopropyl group, the rate of the nucleophilic
addition of the nucleobase to the fluorinated five-membered
oxonium intermediate is likely to be decreased, facilitating the
formation of both N9 and N7 products. Only β-face
nucleosides 47 and 48 were isolated, strongly indicating the
involvement of anchimeric assistance via a five-membered
oxonium intermediate for the methyleneoxetane system.
While logically possible that entropic effects related to
exploration of conformational space account for the general
lack of neighboring group participation for the six-membered
transition states, such an explanation does not seem likely. The
concentration of nucleophile in these experiments is not
particularly high, which further decreases the likelihood that the
intermolecular reaction could compete with conformational
exploration. Furthermore, a reaction run at a 10-fold dilution
on 2-methyleneoxetane 16b gave nucleosides 17b in essentially
the same ratio as the result in Table 1.
The major product of a reaction that involves multiple
pathways may not necessarily arise from the lowest energy
intermediate, based on the Curtin−Hammet principle. Indeed,
computational studies on related five-membered oxocarbenium
ions have shown inconsistency between calculations and
experimental results if the most stable conformation was the
only argument considered.28 The reaction outcome and the
corresponding DFT calculations of glycosylations involving
related bicyclic thioglycoside intermediates29 further support
the likelihood of reaction from a less stable intermediate. Unlike
most glycosylations,30 the transition states in our investigation
bear a substituent on the C1 position. Thus, in the cases of 4,6-
fused and 5,6-fused transition states (the ones with apparent
anchimeric assistance), the nucleobase would have to attack a
pseudotertiary carbon center (see Figure 7). In accordance with
Scheme 4
important role for anchimeric assistance in methylene-THF
systems.
In order to further investigate if a five-membered oxonium
bridge can be also formed in methyleneoxetane systems, the
preparation of a β-lactone related to γ-lactone 38 was
attempted. Several synthetic strategies were explored, including
[2 + 2] reaction of aldehydes and ketene precursors, direct
hydroxylation of β-lactones, the synthesis of α-silyl-β-lactones
for Fleming−Tamao oxidation, and the preparation of
α-benzoyloxy-β-hydroxy acids for lactonization. None of these
provided adequate materials for further transformations to
the desired α-benzoyloxy-β-lactones. Finally, a titanium enolate
aldol condensation using thioester 41 and isobutyraldehyde
provided anti-α-benzyloxy-β-hydroxy thioester 42 as a single
diastereomer (Scheme 5).26 Compound 42 was then lactonized
Scheme 5
Figure 7. SN2-like trajectory for nucleobase incorporation on fused
carbocation from 2-methyleneoxetane 16b.
the Curtin−Hammet principle, the transition barrier of this
nucleophilic addition may be large enough to hamper anchimeri-
cally assisted product formation, although both the 4,6-fused and
5,6-fused cations are at least 10 kcal/mol more stable than their
corresponding open oxocarbenium ions. It is entirely possible
(and even likely) that the fused carbocation is forming, but if the
reaction proceeds mostly by an SN1 pathway, this will not be
evident. On the other hand, when five-membered anchimeric
assistance was utilized (Schemes 4 and 5), the formation of the
open oxocarbenium ions is likely to be less favored because
of the adjacent strong electron-withdrawing benzoyloxy group
by mercury trifluoroacetate to afford α-benzyloxy-β-lactone 43
in moderate yield. Isobutyraldehyde was used in this sequence
due to unsuccessful lactonization of substrates derived from
other aldehydes (e.g., acetaldehyde). Upon hydrogenolysis27
and benzoylation, the desired α-benzoyloxy-β-lactone 45 was
obtained in good yields. Methylenation of 45 provided
methyleneoxetane 46, which underwent F+-mediated nucleo-
base incorporation. Crude NMR showed a 1:1 mixture of two
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on C2.31 Instead, products resulting from the 4,5-fused and 5,5-
fused cations would be more readily formed. The formation of a
single product for methylene-THF 39, while methyleneoxetane
46 resulted in both N7 and N9 isomers (but on a single face), is
interesting. As mentioned previously, the latter was the slowest
F+-mediated nucleobase incorporation conducted. This would
be consistent with the pathway involving the open oxocarbe-
nium ion being suitably high enough in energy that it does not
compete with the congested SN2-like reaction with the fused
cation. The presence of the regioisomeric products is likely a
reflection of migration of the TMS group between N7 and N9
over the course of the longer reaction period.
The high stereoselectivity in the nucleobase incorporation for
2-methylene-THF 25 is likely to be a result of conformational
influences that affect the relative energies of the intermediates
and the transition states. According to the proposal by Woerpel
and co-workers and calculations by Rhoad et al.,28 five-
membered oxocarbenium ions are likely to adopt low energy
conformations that place C3 substituents having oxygen
attached to the ring in a pseudoaxial position. As a result, it
would be likely that the trans-hydroxymethyl at C2 would be
pseudoaxial, as well. It would not be unexpected that this could
alter the relative energies of the intermediates or the barriers to
the reactions from them.
EXPERIMENTAL SECTION
■
General Carbonylation Procedure.11a A 100 mL Parr high-
pressure reactor with a mechanical stirrer was dried overnight under
vacuum. In a N2 drybox, the reactor was charged with [(ClTPP)Al-
(THF)2]+[Co(CO)4]− (9) (0.01 equiv) and oxiranes (1 equiv, 1 M in
THF), then closed and removed from the drybox. The reactor was
pressurized with 800 psi CO, stirred at 60 °C for 26 h, then cooled and
vented. The volatile materials were removed in vacuo. Purification by
flash chromatography on silica gel (petroleum ether/EtOAc 9:1)
afforded the β-lactones as white solids.
General Methylenation Procedure.12 A solution of dimethylti-
tanocene (0.5 M in toluene, 1.5 equiv) and β-lactone (1 equiv) was
stirred at 80 °C under N2 in the dark. The reaction was monitored
over a period of 2 h by TLC. A second portion of dimethyltitanocene
(0.5−1 equiv) was added if the starting material was still present, and
the reaction was stirred at 80 °C until the starting material
disappeared. The reaction mixture was allowed to cool to rt, and
petroleum ether (20 × PhCH3 volume) was added, followed by
overnight stirring. The mixture was filtered through Celite, and the
Celite cake was washed with petroleum ether until the filtrate was
colorless. The filtrate was concentrated and purified by flash
chromatography on silica gel to afford the corresponding 2-
methyleneoxetanes or THFs as pale yellow oils.
6-Chloro-9-(trimethylsilyl)-9H-purine.33 A mixture of 6-chloro-
9H-purine (0.17 g, 1.1 mmol) and chlorotrimethylsilane (2.3 mL) in
HMDS (12 mL) was refluxed at 120 °C for 1 h until a clear solution
resulted. After cooling to rt, the reaction was concentrated in vacuo to
provide 6-chloro-9-(trimethylsilyl)-9H-purine as a yellow solid (0.25 g,
1.1 mmol), which was used directly for the next reaction.
CONCLUSION
■
General Procedure for Fluorine-Mediated Nucleobase
Incorporation. A solution of 2-methyleneoxetanes or THFs
(1 equiv, 0.08 M in nitromethane) was added to a solution of 6-
chloro-9-(trimethylsilyl)-9H-purine (1.5 equiv, 0.12 M in nitro-
methane), followed by the addition of Selectfluor (1.2 equiv) in one
portion. The solution was stirred at rt for 2 h. The resulting solution
was concentrated, and the diastereomeric ratio of the psico-nucleosides
A fluorine-containing psico-oxetanocin A analogue has been
prepared in a straightforward manner. Key steps of the
protocol, including carbonylation of readily accessible epoxides
and fluorine-mediated nucleobase incorporation, will allow for
rapid construction and, thus, evaluation of other novel psico-
nucleosides containing an oxetane sugar. Although the protocol
suffers from relatively low stereoselectivity in nucleobase
incorporation, it should be noted at this stage, when we are
trying to evaluate the potential of psico-oxetanocin-type
frameworks, access to both facial diastereoisomers is a plus.
There are biologically interesting L- and D-nucleosides that have
the nucleobase and a C4 hydroxymethyl moiety in an anti-
relationship.32 In addition, neighboring group participation in
F+-mediated nucleobase incorporation with both 2-methyl-
eneoxetanes and 2-methylenetetrahydrofurans has been stud-
ied. Anchimeric assistance has been seen with five-membered
closed-ring transition states, but generally not with six- or
seven-membered ones. Electronic structural calculations have
been conducted, and they support the concept that
intermediates having neighboring group participation are
significantly lower in energy than the related open
oxocarbenium ions. Our experimental results demonstrate
that this greater stability may not be the only factor to
influence the reaction outcome. The 4,6- and 5,6-fused cationic
intermediates accessible from the 2-methyleneoxetanes and 2-
methylene-THFs investigated are sterically congested, and
reaction along this trajectory appears not to dominate. There
would be similar congestion in the 4,5- and 5,5-fused cationic
intermediates. However, the experimental outcomes suggest
that the corresponding open oxocarbenium ions experience
enough destabilization in comparison to the energy difference
between the neighboring group-stabilized intermediates and the
transition state leading to product that the predominant
pathway involves anchimeric assistance.
1
was determined by H NMR of the crude product.
cis-1,4-Bis(tert-butyldimethylsilyloxy)but-2-ene.34 cis-1,4-Bu-
tenediol (2.12 g, 24 mmol) was dissolved in CH2Cl2 (60 mL).
Imidazole (4.92 g, 72 mmol) and DMAP (59 mg, 0.48 mmol) were
added to the solution. tert-Butyldimethylsilylchloride (7.3 g, 48 mmol)
was added, and the solution was stirred for 12 h. The solvent was
removed in vacuo. The residue was dissolved in diethyl ether (60 mL)
and washed with 1 M HCl (60 mL) and brine (60 mL). The organic
layer was dried (MgSO4) and concentrated to afford cis-1,4-bis(tert-
1
butyldimethylsilyloxy)but-2-ene as a colorless oil (6.84 g, 90%): H
NMR (400 MHz, CDCl3) δ 5.56 (m, 2H), 4.25 (d, J = 3.2 Hz, 4H),
0.91 (s, 18H), 0.10 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 130.4,
59.8, 26.1, 18.6, −5.0.
cis-2,3-Bis(tert-butyldimethylsilyloxymethyl)oxirane (8).35
A
solution of dimethyldioxirane (10.5 mL, 0.23 M, 2.43 mmol) in
CH2Cl2 was added to a solution of cis-1,4-bis(tert-butyldimethylsilyloxy)-
but-2-ene (0.4 g, 1.21 mmol) in CH2Cl2 (2 mL), and the resulting
solution was stirred at rt for 4 h. The solution was concentrated in vacuo
and purified by flash chromatography on silica gel (petroleum ether/
1
EtOAc 95:5) to give 8 as a colorless oil (0.38 g, 94%): H NMR (400
MHz, CDCl3) δ 3.81 (dd, J = 11.8, 3.6 Hz, 2H), 3.73 (dd, J = 11.7, 5.6
Hz, 2H), 3.13 (m, 2H), 0.91 (s, 18H), 0.09 (s, 6H), 0.08 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 61.9, 57.1, 26.1, 18.5, −5.0, −5.0.
trans-3,4-Bis(tert-butyldimethylsilyloxymethyl)oxetan-2-
one (10). The general carbonylation procedure was applied to cis-2,3-
bis(tert-butyldimethylsilyloxymethyl)oxirane (8) (5.1 g, 15 mmol).
Purification afforded 10 as a white solid (3.5 g, 63%): mp 43−44 °C;
IR (KBr) 2959, 2929, 2858, 1818, 1466, 1255, 1130, 1014, 863, 838,
778 cm−1; 1H NMR (300 MHz, CDCl3) δ 4.63 (ddd, J = 3.2, 3.2, 3.2
Hz, 1H), 4.02 (m, 2H), 3.83 (m, 2H), 3.74 (ddd, J = 3.7, 3.7, 3.7 Hz,
1H), 0.90 (s, 9H), 0.89 (s, 9H), 0.08 (s, 6H), 0.08 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 169.4, 73.9, 62.4, 58.0, 54.7, 26.0, 25.9, 18.5,
18.4, −5.3, −5.3, −5.3, −5.4; MS (EI) m/z 345 (M+ − CH3), 303,
9968
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The Journal of Organic Chemistry
Article
273, 231, 189, 171, 147, 117 (100), 89, 73; HRMS (ESI) calcd for
C17H37O4Si2 (M+ + H) m/z 361.2225, found 361.2226.
i-PrOH saturated with ammonia (4 mL). The solution was sealed
in a reaction vessel and stirred at 100 °C overnight. The solution was
allowed to cool to rt, and the solvent was removed in vacuo.
Purification by flash chromatography on silica gel (CH2Cl2/MeOH
95:5) provided a mixture of bis-TBDMS protected adenine containing
trans-3,4-Bis(tert-butyldimethylsilyloxymethyl)-2-methyle-
neoxetane (11). The general methylenation procedure was applied
to trans-3,4-bis(tert-butyldimethylsilyloxymethyl)oxetan-2-one (10)
(0.20 g, 0.55 mmol). Purification by flash chromatography on silica
gel (petroleum ether/EtOAc/Et3N 97:2:1) afforded 11 as a pale
yellow oil (0.162 g, 81%): IR (KBr) 2955, 2930, 2896, 2858, 1694,
1472, 1256, 1141, 1059, 838, 778 cm−1; 1H NMR (300 MHz, CDCl3)
δ 4.63 (ddd, J = 4.2, 4.2, 4.2 Hz, 1H), 4.12 (m, 1H), 3.83 (m, 4H),
3.76 (m, 1H), 3.40 (m, 1H), 0.91 (s, 9H), 0.90 (s, 9H), 0.09 (s, 6H),
0.07 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 164.2, 83.2, 79.6, 64.8,
63.0, 45.5, 26.1, 26.1, 18.6, 18.5, −5.2, −5.2; MS (EI) m/z 301 (M+ −
C4H9), 271, 231, 211, 169, 147, 117, 89, 73 (100); HRMS (ESI) calcd
for C18H39O3Si2 (M+ + H) m/z 359.2432, found 359.2417.
1
nucleoside as a clear oil (7.6 mg, 93%): H NMR (300 MHz, CDCl3)
(peaks assigned for the β-product) δ 8.28 (s, 1H), 8.12 (s, 1H), 6.09
(s, 2H), 5.21 (dd, J = 47.2, 10.3 Hz, 1H), 4.94 (dd, J = 47.2, 10.4 Hz,
1H), 4.88 (m, 1H), 4.23 (dd, J = 10.9, 5.9 Hz, 1H), 4.05 (dd, J = 11.0,
5.0 Hz, 1H), 3.88 (dd, J = 12.4, 3.1 Hz, 1H), 3.66 (dd, J = 12.3, 3.0 Hz,
1H), 3.61 (m, 1H), 0.92 (s, 9H), 0.73 (s, 9H), 0.12 (s, 3H), 0.10 (s,
3H), −0.05 (s, 6H); (peaks assigned for the α-product) δ 8.27 (s, 1H),
8.22 (s, 1H), 6.14 (s, 2H), 5.23 (dd, J = 46.9, 10.1 Hz, 1H), 4.96 (m,
1H), 4.90 (dd, J = 46.8, 10.3 Hz, 1H), 3.97 (dd, J = 11.9, 3.2 Hz, 1H),
3.88 (m, 1H), 3.61 (m, 2H), 3.36 (ddd, J = 5.4, 5.4, 5.4 Hz, 1H), 0.95
(s, 9H), 0.69 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H), −0.21 (s, 3H), −0.32
(s, 3H); 13C NMR (75 MHz, CDCl3) (peaks assigned for β-product) δ
3α,4β-Bis(tert-butyldimethylsilyloxymethyl)-2-(6-chloro-9H-
purin-9-yl)-2-fluoromethyloxetane (12) and 3α,4β-Bis(tert-
butyldimethylsilyloxymethyl)-2-(6-chloro-7H-purin-7-yl)-2-flu-
oromethyloxetane (13). The general procedure for fluorine-mediated
nucleobase incorporation was applied to trans-3,4-bis(tert-butyldime-
thylsilyloxymethyl)-2-methyleneoxetane (11) (0.15 g, 0.42 mmol). A 1H
NMR of the crude product indicated the formation of four psico-
nucleosides in a ratio of 1:1:0.6:0.3. Purification by flash chromatography
on silica gel (petroleum ether/EtOAc 70:30) afforded a mixture of four
diastereomers as a clear wax (0.17 g, 76%). Further purification by flash
chromatography on silica gel (petroleum ether/EtOAc 70:30) provided
an 12 as inseparable 63:37 mixture, favoring the desired β-product as a
155.8, 153.0, 148.8, 138.9, 120.3, 92.4 (d, JCF = 19 Hz), 82.8 (d, JCF
=
178 Hz), 81.5, 64.3, 59.3 (d, JCF = 2.3 Hz), 46.5, 26.0, 25.9, 18.4, 18.4,
−5.3, −5.3, −5.4, −5.4; (peaks assigned for the α-product) δ 155.9,
152.7, 149.1, 139.3, 121.1, 94.3 (d, JCF = 19 Hz), 82.7 (d, JCF = 180
Hz), 80.6, 64.7, 59.3, 42.0, 26.1, 25.9, 18.7, 18.2, −5.1, −5.2, −5.8,
−5.8; MS (EI) m/z β-product 496 (M+ − CH3), 454, 338, 196, 136,
117, 89, 73 (100), 56; α-product 496 (M+ − CH3), 454, 338, 281, 196,
136, 117, 89, 73 (100), 56. This mixture of bis-TBDMS-protected
nucleosides (35 mg, 0.068 mmol) was dissolved in THF (2 mL), and a
solution of TBAF in THF (1 M, 0.17 mL, 0.17 mmol) was added
dropwise. The resulting solution was stirred at rt for 1 h. The solvent was
removed in vacuo, and the residue was purified by flash chromatography
on silica gel (EtOAc/i-PrOH/acetone/H2O 80:8:8:4) to afford 2 as a
clear wax (12 mg, 96%): IR (KBr) 3386 (br), 2925, 2852, 1655, 1603,
1385 cm−1; 1H NMR (500 MHz, CD3OD) δ 8.31 (s, 1H, H8), 8.20 (s,
1H, H2), 5.25 (dd, J = 46.9, 10.6 Hz, 1H), 5.05 (dd, J = 46.6, 10.6 Hz,
1H), 4.83 (m, 1H), 4.12 (dd, J = 11.6, 6.8 Hz, 1H), 4.05 (dd, J = 11.6,
6.2 Hz, 1H), 3.82 (dd, J = 13.3, 1.8 Hz, 1H), 3.63 (m, 2H); 13C NMR
(100 MHz, CD3OD) δ 157.5 (C6), 153.8 (C2), 149.3 (C4), 140.3 (C8),
120.8 (C5), 93.6 (d, JCF = 19 Hz), 83.8 (d, JCF = 177 Hz), 83.3, 64.1,
59.1 (d, JCF = 3 Hz), 47.8; HRMS (ESI) calcd for C11H15FN5O3 (M+ +
H) m/z 284.1153, found 284.1154.
1
clear oil (93 mg, 42%; β-product, 27%): H NMR (400 MHz, CDCl3)
(peaks assigned for the β-product) δ 8.69 (s, 1H), 8.44 (s, 1H), 5.21
(dd, J = 47.3, 10.3 Hz, 1H), 5.01 (dd, J = 47.3, 10.4 Hz, 1H), 4.93 (m,
1H), 4.23 (dd, J = 11.2, 5.2 Hz, 1H), 4.01 (dd, J = 11.0, 5.1 Hz, 1H),
3.90 (dd, J = 12.2, 1.8 Hz, 1H), 3.63 (m, 2H), 0.93 (s, 9H), 0.67 (s, 9H),
0.12 (s, 3H), 0.11 (s, 3H), −0.08 (s, 3H), −0.09 (s, 3H); (peaks
assigned for the α-product) δ 8.67 (s, 1H), 8.52 (s, 1H), 5.23 (dd, J =
46.7, 10.0 Hz, 1H), 5.03 (dd, J = 46.7, 9.8 Hz, 1H), 5.00 (m, 1H), 3.99
(dd, J = 11.8, 3.4 Hz, 1H), 3.86 (dd, J = 12.1, 3.7 Hz, 1H), 3.63 (m, 1H),
3.54 (dd, J = 11.5, 4.6 Hz, 1H), 3.39 (m, 1H), 0.95 (s, 9H), 0.63 (s,
9H), 0.14 (s, 3H), 0.13 (s, 3H), −0.25 (s, 3H), −0.39 (s, 3H); 13C
NMR (100 MHz, CDCl3) (peaks assigned for the β-product) δ 151.9,
151.2, 150.3, 143.9, 132.5, 93.0 (d, JCF = 18 Hz), 82.6 (d, JCF = 179 Hz),
81.4, 63.8, 59.0, 46.0, 26.0, 25.8, 18.4, −5.3, −5.3, −5.4, −5.5; (peaks
assigned for the α-product) δ 151.6, 151.4, 150.9, 144.3, 133.2, 94.8 (d,
JCF = 20 Hz), 82.4 (d, JCF = 181 Hz), 80.0, 64.2, 59.0, 42.1, 26.1, 25.8,
18.7, 18.1, −5.1, −5.2, −5.8, −5.9; MS (EI) m/z β-product 515 (M+ −
CH3), 473, 357, 187, 147, 117, 89, 73 (100), 56; α-product 515 (M+ −
CH3), 473, 357, 299, 187, 147, 117, 89, 73 (100), 56. Compound 13 was
isolated as an inseparable 77:23 mixture, favoring the β-product as a clear
oil (80 mg, 34%; β-product, 27%): 1H NMR (300 MHz, CDCl3) (peaks
assigned for the β-product) δ 8.88 (s, 1H), 8.70 (s, 1H), 5.02 (dd, J =
46.7, 10.5 Hz, 1H), 4.92 (dd, J = 46.5, 10.5 Hz, 1H), 4.84 (m, 1H), 4.23
(dd, J = 10.7, 5.6 Hz, 1H), 4.11 (dd, J = 10.9, 5.8 Hz, 1H), 3.88 (dd, J =
12.5, 2.4 Hz, 1H), 3.69 (m, 1H), 3.63 (dd, J = 12.6, 2.7 Hz, 1H), 0.93 (s,
9H), 0.63 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H), −0.16 (s, 3H), −0.18 (s,
3H); (peaks assigned for the α-product) δ 8.90 (s, 1H), 8.80 (s, 1H),
5.27 (dd, J = 46.4, 10.4 Hz, 1H), 4.96 (m, 1H), 4.88 (dd, J = 46.4, 10.4
Hz, 1H), 4.02 (dd, J = 12.0, 3.5 Hz, 1H), 3.91 (dd, J = 12.0, 4.1 Hz, 1H),
3.79 (m, 2H), 3.38 (ddd, J = 5.0, 5.0, 5.0 Hz, 1H), 0.95 (s, 9H), 0.66 (s,
9H), 0.14 (s, 6H), −0.21 (s, 3H), −0.39 (s, 3H); 13C NMR (75 MHz,
CDCl3) (peaks assigned for β-product) δ 163.7, 152.6, 148.5, 142.2,
121.8, 94.1 (d, JCF = 19.6 Hz), 83.5 (d, JCF = 181.1 Hz), 81.6, 63.8, 59.6
(d, JCF = 2.9 Hz), 46.6, 26.0, 25.7, 18.3, −5.4, −5.4, −5.5, −5.6; (peaks
assigned for the α-product) δ 164.2, 152.5, 148.1, 141.5, 121.8, 95.0 (d, JCF
= 19.7 Hz), 85.2 (d, JCF = 181.8 Hz), 80.5, 64.4, 59.8, 42.1, 26.1, 25.8, 18.6,
18.1, −5.2, −5.2, −5.8, −5.9; MS (EI) m/z β-product 473
(M+ − C4H9), 443, 379, 357, 341, 269, 229, 187, 117, 89, 73 (100); α-
product 473 (M+ − C4H9), 443, 357, 299, 245, 187, 117, 89, 73 (100).
2β-(6-Amino-9H-purin-9-yl)-2α-fluoromethyl-trans-3α,4β-
bis(hydroxymethyl)oxetane (2). The 63:37 mixture of 3α,4β-
bis(tert-butyldimethylsilyloxy)methyl)-2-(6-chloro-9H-purin-9-yl)-2-
fluoromethyloxetane (12) (8.5 mg, 0.016 mmol) was dissolved in
2β-(6-Amino-7H-purin-7-yl)-2α-fluoromethyl-trans-3α,4α-
bis(hydroxymethyl)oxetane (14). The 3:1 mixture of 3α,4β-
bis(tert-butyldimethylsilyloxy)methyl)-2-(6-chloro-7H-purin-7-yl)-2-
fluoromethyloxetane (13) (70 mg, 0.098 mmol) was dissolved in
MeOH saturated with ammonia (10 mL). The solution was sealed in a
tube and stirred at 80 °C overnight. The solution was allowed to cool
to rt, and the solvent was removed in vacuo. Purification by flash
chromatography on silica gel (CH2Cl2/MeOH 96:4) provided bis-
TBDMS-protected analogue of 14 as a yellow solid (35 mg, 70%): mp
169−171 °C; IR (KBr) 3422, 2930, 2857, 1637, 1474, 1255, 1140,
1
1086, 838, 779 cm−1; H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H),
8.18 (s, 1H), 6.06 (br, 2H), 4.79 (m, 1H), 4.75 (dd, J = 46.9, 10.2 Hz,
1H), 4.58 (dd, J = 46.0, 10.3 Hz, 1H), 4.27 (m, 1H), 3.93 (m, 2H),
3.84 (dd, J = 12.5, 2.8 Hz, 1H), 3.69 (dd, J = 12.4, 2.9 Hz, 1H), 0.94
(s, 9H), 0.67 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H), −0.06 (s, 3H), −0.20
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.6, 153.9, 151.1, 142.5,
111.0, 91.9 (d, JCF = 22.1 Hz), 83.0 (d, JCF = 183.3 Hz), 81.4, 63.7,
59.4 (d, JCF = 4.7 Hz), 46.7, 26.1, 25.6, 18.4, 18.2, −5.4, −5.5, −5.6;
MS (EI) m/z 379 (M+ − H − OTBDMS), 357, 341, 229, 211, 187,
154, 117, 89, 73 (100); HRMS (ESI) calcd for C23H43FN5O3Si2
(M+ + H) m/z 512.2883, found 512.2873. This bis-TBDMS-protected
nucleoside (23 mg, 0.045 mmol) was dissolved in THF (2 mL), and a
solution of TBAF in THF (1 M, 0.11 mL, 0.11 mmol) was added
dropwise. The resulting solution was stirred at rt for 1 h. The solvent
was removed in vacuo, and the residue was purified by flash
chromatography on silica gel (EtOAc/EtOH/acetone/H2O
6:1:1:0.5) to afford 14 as a clear wax (12 mg, 94%): IR (KBr)
3422, 2925, 2855, 1637, 1597, 1560, 1475, 1398, 1037 cm−1; 1H NMR
(500 MHz, CD3OD) δ 8.44 (s, 1H, H8), 8.28 (s, 1H, H2), 4.95 (dd,
J = 46.7, 10.6 Hz, 1H), 4.84 (m, 1H), 4.76 (dd, J = 46.1, 10.6 Hz, 1H),
4.18 (dd, J = 9.9, 9.9 Hz, 1H), 3.99 (dd, J = 11.4, 5.4 Hz, 1H), 3.84 (m,
9969
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Article
1H), 3.80 (dd, J = 13.3, 2.6 Hz, 1H), 3.65 (dd, J = 13.3, 3.9 Hz, 1H);
13C NMR (125 MHz, CD3OD) δ 161.2 (C4), 154.1 (C2), 153.5 (C6),
144.7 (C8), 112.0 (C5), 93.6 (d, JCF = 25 Hz), 84.2 (d, JCF = 180 Hz),
83.8, 63.8, 58.8, 47.6; HRMS (ESI) calcd for C11H15FN5O3 (M+ + H)
m/z 284.1153, found 284.1148.
Pd(OH)2/C (0.44 g) was added. The mixture was stirred at rt
overnight under H2. It was then filtered through Celite and
concentrated to give a mixture of the corresponding alcohols as a
pale yellow oil (2.1 g, 89%). Benzoyl chloride (1.3 g, 1.1 mL, 9.5
mmol) was added dropwise into a solution of the alcohols (1.2 g, 4.8
mmol) and pyridine (0.75 g, 0.78 mL, 9.5 mmol) in CH2Cl2 (20 mL).
The solution was stirred at rt overnight. It was then diluted with Et2O
(100 mL), washed with 2 M HCl (50 mL), saturated NaHCO3
(50 mL), and brine (50 mL). The organic layer was dried (MgSO4)
and concentrated. Purification by flash chromatography on silica gel
(petroleum ether/EtOAc 92:8) provided 15b as a white solid (0.54 g,
33%): mp 44−46 °C; IR (KBr) 2952, 2929, 2885, 1826, 1724, 1279,
cis-1,4-Bis(benzoyloxy)but-2-ene.36 cis-1,4-Butenediol (10.0 g,
114 mmol) was dissolved in CH2Cl2 (150 mL). Pyridine (27.9 mL,
341 mmol) was added to the solution, which was cooled to 0 °C.
Benzoyl chloride (39.6 mL, 341 mmol) was added dropwise to the
solution, and it was warmed to rt after 15 min and stirred for 4 h. The
solution was diluted with Et2O (125 mL) and washed with 2 M HCl
(125 mL), H2O (125 mL), saturated NaHCO3 (125 mL), and brine
(125 mL). The organic layer was dried (MgSO4) and concentrated in
vacuo. The resulting oil was purified by flash chromatography on silica
gel (petroleum ether/EtOAc 95:5−85:15) to give 1,4-cis- bis-
(benzoyloxy)but-2-ene as a white solid (33.3 g, 99%): 1H NMR
(300 MHz, CDCl3) δ 8.19 (m, 4H), 7.43 (m, 6H), 5.93 (m, 2H), 5.03
(m, 4H).
1
1120, 839, 706 cm−1; H NMR (400 MHz, CDCl3) δ 8.03 (m, 2H),
7.59 (tt, J = 7.4, 1.2 Hz, 1H), 7.45 (m, 2H), 4.67 (m, 1H), 4.65 (d, J =
4.4 Hz, 2H), 4.09 (ddd, J = 4.3, 4.3, 4.3 Hz, 1H), 4.06 (dd, J = 12.5, 2.5
Hz, 1H), 3.89 (dd, J = 12.5, 2.8 Hz, 1H), 0.90 (s, 9H), 0.09 (s, 3H),
0.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.9, 166.2, 133.7,
129.9, 129.4, 128.7, 74.9, 61.9, 59.6, 51.5, 25.9, 18.5, −5.3, −5.4; MS
(EI) m/z 293 (M+ − C(CH3)3), 179, 171, 135, 117, 105 (100), 77;
HRMS (ESI) calcd for C18H26NaO5Si (M+ + Na) m/z 373.1442,
found 373.1419. 15c (white solid, 0.62 g, 37%): mp 60−62 °C; IR
cis-2,3-Bis(benzoyloxymethyl)oxirane.37 cis-1,4-Bis-
(benzoyloxy)but-2-ene (20.0 g, 67.5 mmol) was dissolved in CH2Cl2
(50 mL). The solution was cooled to 0 °C. m-CPBA (25.0 g (70% in
m-CPBA), 101 mmol of m-CPBA) in CH2Cl2 (125 mL) was added
dropwise to the solution, which was stirred for 48 h at rt. The solution
was cooled to 0 °C, and the white solid (m-chlorobenzoic acid) was
removed by rapid filtration. The solution was then washed with
saturated NaHCO3, saturated Na2SO3, and brine. The organic layer
was dried (MgSO4), concentrated in vacuo, and purified by flash
chromatography on silica gel (petroleum ether/EtOAc 80:20) to give
cis-2,3-bis(benzoyloxymethyl)oxirane as a white solid (12.3 g, 58%):
1H NMR (300 MHz, CDCl3) δ 8.15 (m, 4H), 7.55 (m, 6H), 4.66 (m,
2H), 4.52 (m, 2H), 3.53 (t, J = 3.0 Hz, 2H).
1
(KBr) 2956, 2929, 2858, 1832, 1724, 1273, 1120, 839, 714 cm−1; H
NMR (300 MHz, CDCl3) δ 8.06 (m, 2H), 7.61 (m, 1H), 7.47 (m,
2H), 4.93 (m, 1H), 4.75 (dd, J = 12.9, 2.9 Hz, 1H), 4.59 (dd, J = 12.8,
4.5 Hz, 1H), 4.06 (dd, J = 11.0, 3.5 Hz, 1H), 3.87 (dd, J = 11.1, 2.9
Hz, 1H), 3.75 (m, 1H), 0.91 (s, 9H), 0.10 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 168.5, 166.3, 133.8, 130.0, 129.4, 128.8, 71.0, 63.8,
57.8, 56.4, 25.9, 18.4, −5.3, −5.4; MS (EI) m/z 293 (M+ − C(CH3)3),
213, 171 (100), 127, 105, 77; HRMS (ESI) calcd for C18H26NaO5Si
(M+ + Na) m/z 373.1442, found 373.1429.
trans-3-Benzoyloxymethyl-4-tert-butyldimethylsilyloxy-
methyl-2-methyleneoxetane (16b). The general methylenation
procedure was applied to trans-3-benzoyloxymethyl-4-(tert-
butyldimethylsilyloxymethyl)oxetan-2-one (15b) (0.35 g, 1 mmol).
Purification by flash chromatography on silica gel (petroleum ether/
EtOAc/Et3N 95:4:1) afforded 16b as a pale yellow oil (0.26 g, 75%):
trans-3,4-Bis(benzoyloxymethyl)oxetan-2-one (15a). The
general carbonylation procedure (modified to 600 psi CO, 30 °C)
was applied to cis-2,3-bis(benzoyloxymethyl)oxirane (810 mg, 2.6
mmol). Purification afforded 15a as a white solid (429 mg, 48%): mp
102−103 °C; IR (KBr) 3071, 2966, 1826, 1721, 1602, 1451, 1275,
1
1
IR (KBr) 2954, 2929, 2858, 1720, 1275, 1120, 839, 714 cm−1; H
1123, 827, 710 cm−1; H NMR (400 MHz, CDCl3) δ 8.00 (m, 4H),
NMR (300 MHz, CDCl3) δ 8.05 (m, 2H), 7.58 (m, 1H), 7.45
(m, 2H), 4.75 (m, 1H), 4.60 (dd, J = 11.4, 7.3 Hz, 1H), 4.50 (dd, J =
11.4, 5.5 Hz, 1H), 4.23 (m, 1H), 3.91 (m, 2H), 3.84 (dd, J = 11.9, 4.1
Hz, 1H), 3.74 (m, 1H), 0.91 (s, 9H), 0.09 (s, 3H), 0.09 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 166.5, 162.8, 133.4, 130.0, 129.9, 128.6,
82.7, 80.6, 64.3, 63.9, 42.6, 26.0, 18.5, −5.2; HRMS (ESI) calcd for
C19H28NaO4Si (M+ + Na) m/z 371.1649, found 371.1631.
7.58 (m, 2H), 7.41 (m, 4H), 4.94 (dd, J = 7.8, 3.9 Hz, 1H), 4.74 (dd,
J = 13.1, 3.9 Hz, 1H), 4.68 (m, 2H), 4.61 (dd, J = 13.0, 4.4 Hz, 1H),
4.06 (dd, J = 8.8, 4.4 Hz, 1H). 13C NMR (100 MHz, CDCl3), δ 166.9,
166.2, 166.1, 133.9, 133.8, 130.0, 130.0, 129.1, 129.1, 128.7, 128.7,
72.3, 63.4, 59.5, 55.7; MS (ESI) m/z 341 (M+ + H), 295, 219, 105
(100), 73. Anal. Calcd for C19H16O6: C, 67.05; H, 4.74. Found: C,
67.45; H, 4.47.
trans-4-Benzoyloxymethyl-3-tert-butyldimethylsilyloxy-
methyl-2-methyleneoxetane (16c). The general methylenation
procedure was applied to trans-4-benzoyloxymethyl-3-
(tert-butyldimethylsilyloxymethyl)oxetan-2-one (15c) (90 mg, 0.26
mmol). Purification by flash chromatography on silica gel (petroleum
ether/EtOAc/Et3N 96:3:1) afforded 16c as a pale yellow oil (54 mg,
60%): IR (KBr) 2954, 2929, 2858, 1726, 1695, 1273, 1124, 837, 712
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.09 (m, 2H), 7.58 (tt, J = 7.4,
1.3 Hz, 1H), 7.45 (m, 2H), 4.93 (m, 1H), 4.62 (dd, J = 12.5, 3.2
Hz, 1H), 4.51 (dd, J = 12.5, 5.5 Hz, 1H), 4.23 (dd, J = 3.7, 2.2 Hz,
1H), 3.85 (m, 3H), 3.49 (m, 1H), 0.90 (s, 9H), 0.08 (s, 3H), 0.08
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 163.3, 133.4, 130.0,
129.9, 128.6, 80.7, 80.0, 65.7, 62.8, 46.5, 26.0, 18.5, −5.2, −5.2; MS
(EI) m/z 291 (M+ − C(CH3)3), 179, 169, 105 (100), 95, 77; HRMS
(ESI) calcd for C19H28NaO4Si (M+ + Na) m/z 371.1649, found
371.1640.
3-(Benzoyloxymethyl)dihydrofuran-2(3H)-one (26). Pd-
(OH)2/C (180 mg) was added to a solution of 3-(benzyloxymethyl)-
dihydrofuran-2(3H)-one (30)21 (0.72 g, 3.5 mmol) in EtOH (18 mL).
The mixture was stirred at rt overnight under H2. It was then filtered
through Celite and concentrated to give the corresponding alcohol as a
pale yellow oil (0.46 g, 99%). The resulting alcohol was mixed with
CH2Cl2 (20 mL) and pyridine (0.55 g, 0.57 mL, 7.0 mmol). Benzoyl
chloride (0.98 g, 0.81 mL, 7.0 mmol) was added dropwise, and the
resulting mixture was stirred at rt overnight. It was then diluted with
CH2Cl2 (100 mL), washed with 2 M HCl (50 mL), saturated
trans-3,4-Bis(benzoyloxymethyl)-2-methyleneoxetane
(16a). The general methylenation procedure was applied to trans-3,4-
bis(benzoyloxymethyl)oxetan-2-one (15a) (0.66 g, 2.0 mmol). Purification
by flash chromatography on silica gel (petroleum ether/EtOAc/Et3N
92.5:7:0.5) afforded 16a as a yellow oil (0.32 g, 48%): IR (KBr) 3063,
1
2951, 1722, 1696, 1452, 1270, 1114, 709 cm−1; H NMR (400 MHz,
CDCl3) δ 8.01 (m, 4H), 7.53 (m, 2H), 7.39 (m, 4H), 5.04 (dd, J = 8.6, 4.6
Hz, 1H), 4.63 (m, 2H), 4.53 (m, 2H), 4.27 (s, 1H), 4.08 (s, 1H), 3.78 (dd,
J = 4.7, 2.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 166.5, 166.4, 161.7,
133.5, 133.5, 130.0, 129.9, 129.7, 129.7, 128.7, 128.6, 81.8, 80.0, 65.3, 63.7,
43.8; MS (ESI) m/z 361 (M+ + Na), 217, 118, 95 (100). Anal. Calcd for
C20H18O5: C, 70.99; H, 5.36. Found: C, 71.38; H, 4.96.
trans-3-Benzyloxymethyl-4-(tert-butyldimethylsilyloxymethyl)-
oxetan-2-one and trans-4-Benzyloxymethyl-3-(tert-
butyldimethylsilyloxymethyl)oxetan-2-one (21). The general
carbonylation procedure was applied to cis-2-benzoyloxymethyl-3-
tert-butyldimethylsilyloxymethyloxirane (20)20 (5 g, 16 mmol). Puri-
fication afforded 21a and 21b as an inseparable 3:2 mixture (4.34 g,
1
80%): H NMR (300 MHz, CDCl3) δ 7.35 (m, 10H), 4.75 (m, 1H),
4.62 (m, 5H), 4.03 (m, 2H), 3.86 (m, 6H), 3.72 (m, 2H), 0.91 (s, 9H),
0.91 (s, 9H), −0.05 (s, 12H).
trans-3-Benzoyloxymethyl-4-(tert-butyldimethylsilyloxymethyl)-
oxetan-2-one (15b) and trans-4-Benzoyloxymethyl-3-(tert-
butyldimethylsilyloxymethyl)oxetan-2-one (15c). trans-Benzyloxy-
methyl-(tert-butyldimethylsilyloxymethyl)oxetan-2-ones (21) (3.3 g,
9.7 mmol) were dissolved in EtOH/CH2Cl2 (v/v 4:1, 80 mL) and
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NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried
(MgSO4) and concentrated. Purification by flash chromatography on
silica gel (petroleum ether/EtOAc 70:30) provided 26 as a white solid
(0.60 g, 78%): mp 72−73 °C; IR (KBr) 2922, 1765, 1712, 1283, 1178,
1116, 1017, 716 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.98 (m, 2H),
7.54 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 4.65 (dd, J = 11.3, 4.0
Hz, 1H), 4.51 (dd, J = 11.3, 5.5 Hz, 1H), 4.39 (ddd, J = 8.9, 8.9, 3.3
Hz, 1H), 4.25 (m, 1H), 3.02 (m, 1H), 2.47 (m, 1H), 2.26 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 176.5, 166.2, 133.4, 129.6, 129.6, 128.5,
173.2, 137.8, 128.7, 128.1, 127.9, 73.7, 70.9, 68.3, 64.8, 61.4, 48.6, 14.4;
HRMS (ESI) calcd for C14H21O5 (M+ + H) m/z 269.1384, found
269.1384.
cis-3-Benzyloxymethyl-4-hydroxydihydrofuran-2(3H)-one
(35). CSA (11 mg, 0.047 mmol) was added to a solution of ethyl
erythro-2-benzyloxymethyl-3,4-dihydroxybutanoate (34) (0.11 g, 0.4
mmol) in CHCl3 (40 mL). The solution was refluxed for 24 h.
Concentration and purification by flash chromatography on silica gel
(petroleum ether/EtOAc 60:40) afforded 35 as a clear oil (71 mg,
81%): IR (KBr) 3435 (br), 2922, 1772, 1456, 1369, 1213, 1167, 1093,
66.8, 63.1, 39.4, 25.9; MS (EI) m/z 220 (M+), 122, 105 (100), 99, 77;
HRMS (ESI) calcd for C12H12NaO4 (M+ + Na) m/z 243.0628, found
243.0624.
1
1032, 972, 742, 700 cm−1; H NMR (400 MHz, CDCl3) δ 7.33 (m,
5H), 4.69 (m, 1H), 4.57 (s, 2H), 4.31 (dd, J = 10.2, 4.0 Hz, 1H), 4.27
(dd, J = 10.2, 1.4 Hz, 1H), 3.96 (d, J = 5.7 Hz, 2H), 3.33 (d, J = 4.2
Hz, 1H), 2.86 (ddd, J = 5.7, 5.7, 5.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 175.6, 137.2, 128.8, 128.4, 128.0, 74.9, 74.0, 69.4, 65.3, 45.2;
MS (EI) m/z 121 (BnOCH2), 116 (M+ − BnOH), 107, 91 (100), 79,
73; HRMS (ESI) calcd for C12H14NaO4 (M+ + Na) m/z 245.0784,
found 245.0776.
4-Benzoyloxydihydrofuran-2(3H)-one (27). 4-Hydroxydihy-
drofuran-2(3H)-one (31)22 (0.21 g, 2.1 mmol) was mixed with
CH2Cl2 (8 mL) and pyridine (0.33 g, 0.34 mL, 4.2 mmol). Benzoyl
chloride (0.58 g, 0.48 mL, 4.2 mmol) was added dropwise, and the
resulting mixture was stirred at rt overnight. It was then diluted with
Et2O (20 mL), washed with 2 M HCl (20 mL), H2O (20 mL),
saturated NaHCO3 (20 mL), and brine (20 mL). The organic layer
was dried (MgSO4) and concentrated. Purification by flash
chromatography on silica gel (petroleum ether/EtOAc 80:20)
provided 27 as a white solid (0.32 g, 74%): mp 98−99 °C; IR
(KBr) 2925, 1774, 1718, 1281, 1176, 715 cm−1; 1H NMR (300 MHz,
CDCl3) δ 8.01 (d, J = 7.3 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.44 (t, J =
7.8 Hz, 2H), 5.67 (m, 1H), 4.61 (dd, J = 11.1, 4.7 Hz, 1H), 4.50 (d, J =
11.0 Hz, 1H), 2.97 (dd, J = 18.5, 6.7 Hz, 1H), 2.75 (d, J = 18.5 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 174.7, 165.9, 133.8, 129.8, 129.0,
128.7, 73.2, 70.5, 34.7; MS (EI) m/z 206 (M+), 123, 105 (100), 77,
51; HRMS (ESI) calcd for C11H10NaO4 (M+ + Na) m/z 229.0471,
found 229.0495.
cis-4-Benzoyloxy-3-(benzoyloxymethyl)dihydrofuran-2(3H)-
one (28). Pd(OH)2/C (80 mg) was added to a mixture of cis-3-
benzyloxymethyl-4-hydroxydihydrofuran-2(3H)-one (35) (0.28 g,
1.3 mmol) and EtOH (15 mL). The mixture was stirred at rt under
H2 for 2 h. It was then filtered through Celite and concentrated to
give the corresponding diol as a clear oil (0.17 g, 99%): IR (KBr)
1
3421 (br), 2925, 1763, 1211, 1165, 1041, 912 cm−1; H NMR (300
MHz, CD3OD) δ 4.65 (m, 1H), 4.39 (dd, J = 10.0, 3.5 Hz, 1H),
4.22 (d, J = 10.0 Hz, 1H), 3.93 (d, J = 6.3 Hz, 2H), 2.88 (ddd, J =
6.0, 6.0, 6.0 Hz, 1H); 13C NMR (75 MHz, CD3OD) δ 177.2, 75.1,
68.2, 56.4, 47.4; HRMS (ESI) calcd for C5H8NaO4 (M+ + Na) m/z
155.0315, found 155.0315. This diol was then mixed with CH2Cl2
(15 mL) and pyridine (0.99 g, 1.03 mL, 12.6 mmol). Benzoyl
chloride (1.77 g, 1.46 mL, 12.6 mmol) was added dropwise, and the
resulting mixture was stirred at rt overnight. The reaction mixture
was then diluted with Et2O (50 mL), washed with 2 M HCl
(20 mL), H2O (20 mL), saturated aqueous NaHCO3 (20 mL), and
brine (20 mL). The organic layer was dried (MgSO4) and
concentrated. Purification by flash chromatography on silica gel
(petroleum ether/EtOAc 70:30) provided 28 as a white solid,
which was contaminated with a single, unidentified byproduct (∼15
mol %). Prior attempts at repeated purification had led to
decomposition; consequently, this material was used directly in
the preparation of cis-4-benzoyloxy-3-benzoyloxymethyl-2-methyl-
enetetrahydrofuran (24). Characterization of 28: IR (KBr) 3063,
Diethyl erythro-2-benzyloxymethyl-3-hydroxysuccinate
(33).38 n-BuLi (2.5 M in hexane, 9.5 mL, 23.8 mmol) was added
dropwise to a solution of diisopropylamine (4.3 mL, 26.2 mmol) in
THF (40 mL) at 0 °C. The resulting pale yellow solution was stirred at
0 °C for 10 min and cooled to −78 °C. A solution of diethyl 2-
hydroxysuccinate (32)23 (2.06 g, 10.8 mmol) in THF (2 mL) was
added dropwise. The solution was stirred at −78 °C for 30 min and
at −20 °C for 1 h. After cooling to −78 °C, a solution of
benzyloxymethyl chloride (1.86 g, 1.65 mL, 11.9 mmol) in HMPA
(8 mL) was added dropwise. The reaction was stirred at −78 °C for
5 h. After the addition of glacial acetic acid (3 mL) and Et2O
(4 mL), the mixture was poured into H2O (50 mL) and extracted
with Et2O (2 × 50 mL). The combined organic extracts were
washed with 1 M HCl (2 × 25 mL), saturated NaHCO3 (50 mL),
and brine (50 mL). The organic layer was dried (MgSO4) and
concentrated. Purification by flash chromatography on silica gel
(petroleum ether/EtOAc 80:20) afforded 33 as a pale yellow oil
(1.34 g, 40%): IR (KBr) 3348 (br), 2981, 2927, 1736, 1228, 1097,
2966, 1784, 1722, 1277, 1115, 710 cm−1 1H NMR (300 MHz,
;
CDCl3) δ 7.98 (t, J = 8.1 Hz, 4H), 7.58 (m, 2H), 7.42 (m, 4H), 5.94
(m, 1H), 4.92 (dd, J = 11.5, 4.3 Hz, 1H), 4.69 (dd, J = 11.4, 8.7 Hz,
1H), 4.61 (dd, J = 11.1, 3.7 Hz, 1H), 4.53 (d, J = 11.2 Hz, 1H), 3.43
(m, 1H); MS (EI) m/z 218 (M+ − BzOH), 122, 105 (100), 77, 51;
HRMS (ESI) calcd for C19H16NaO6 (M+ + Na) m/z 363.0839,
found 363.0825.
1
1028 cm−1; H NMR (400 MHz, CDCl3) δ 7.34 (m, 5H), 4.58 (m,
3H), 4.26 (m, 2H), 4.15 (m, 2H), 3.92 (dd, J = 9.5, 5.6 Hz, 1H),
3.83 (dd, J = 9.2, 9.2 Hz, 1H), 3.29 (m, 1H), 3.26 (m, 1H), 1.30 (t,
J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 173.8, 170.4, 138.1, 128.6, 128.0, 127.9, 73.7, 69.0, 67.1,
62.1, 61.2, 49.1, 14.3, 14.3; HRMS (ESI) calcd for C16H23O6 (M+ +
H) m/z 311.1489, found 311.1488.
trans-3-Benzyloxymethyl-4-hydroxydihydrofuran-2(3H)-one
(36). n-BuLi (2.5 M in hexane, 10.8 mL, 27 mmol) was added
dropwise to a solution of diisopropylamine (4.46 mL, 27 mmol) in
THF (20 mL) at 0 °C. The resulting pale yellow solution was stirred at
0 °C for 10 min and cooled to −78 °C. A solution of β-hydroxy-γ-
butyrolactone (31)22 (1.1 g, 10.8 mmol) in THF (5 mL) was added
dropwise. After stirring at −78 °C for 10 min, a solution of
benzyloxymethyl chloride (1.86 g, 1.65 mL, 11.9 mmol) in HMPA
(7 mL) was added dropwise. The reaction was stirred at −78 °C for 2
h. After the addition of 1 M HCl (50 mL), the mixture was extracted
with Et2O (2 × 50 mL). The combined organic extracts were washed
with H2O (50 mL), saturated aqueous NaHCO3 (50 mL), and brine
(50 mL). The organic layer was dried (MgSO4) and concentrated.
Purification by flash chromatography on silica gel (petroleum ether/
EtOAc 1:1) afforded 35 (0.12 g, 5%) and 36 as clear oils (0.24 g,
10%). Characterization of 36: IR (KBr) 3433 (br), 2868, 1772, 1458,
1363, 1178, 1109, 1026, 739, 698 cm−1; 1H NMR (300 MHz, CDCl3)
δ 7.32 (m, 5H), 4.59 (m, 1H), 4.52 (m, 2H), 4.44 (m, 1H), 4.08 (dd,
J = 9.4, 4.3 Hz, 1H), 3.79 (m, 2H), 3.01 (s, 1H), 2.72 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 176.5, 137.6, 128.7, 128.1, 127.8, 74.1, 73.7,
Ethyl erythro-2-benzyloxymethyl-3,4-dihydroxybutanoate
(34). BH3·SMe2 (2 M in THF, 0.39 mL, 0.78 mmol) was added
dropwise to a solution of diethyl erythro-2-benzyloxymethyl-3-
hydroxysuccinate (33) (0.24 g, 0.78 mmol) in THF (1.5 mL) as gas
released. The solution was stirred at rt for 30 min, and NaBH4 (3 mg,
0.078 mmol) was added. The resulting mixture was stirred at rt
overnight. CH3OH (1 mL) was added, and the solution was
concentrated in vacuo to give a yellow oil. Purification by flash
chromatography on silica gel (CH2Cl2/CH3OH 96:4) afforded 34 as a
colorless oil (0.11 g, 51%; 64% based on recovered starting material):
1
IR (KBr) 3423 (br), 2924, 2854, 1720, 1458, 1186, 1099 cm−1; H
NMR (400 MHz, CDCl3) δ 7.32 (m, 5H), 4.53 (s, 2H), 4.21 (q, J =
7.1 Hz, 2H), 4.08 (m, 1H), 3.78 (m, 2H), 3.73 (m, 1H), 3.66 (m, 1H),
3.18 (d, J = 6.6 Hz, 1H), 2.89 (dt, J = 5.8, 5.8 Hz, 1H), 2.17 (t, J = 6.3
Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
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71.0, 67.6, 49.9; MS (EI) m/z 121 (BnOCH2), 116 (M+ − BnOH),
107, 91 (100), 79, 73; HRMS (ESI) calcd for C12H14NaO4 (M+ + Na)
m/z 245.0784, found 245.0777.
trans-4-Benzoyloxy-3-benzoyloxymethyl-2-methylenetetra-
hydrofuran (25). The general methylenation procedure was applied
to trans-4-benzoyloxy-3-(benzoyloxymethyl)dihydrofuran-2(3H)-one
(29) (193 mg, 0.57 mmol). Purification by flash chromatography on
silica gel (petroleum ether/EtOAc/Et3N 89:10:1) afforded 25 as a pale
yellow oil (111 mg, 58%): IR (KBr) 2924, 1718, 1275, 1111, 712
trans-4-Benzoyloxy-3-(benzoyloxymethyl)dihydrofuran-
2(3H)-one (29). Pd(OH)2/C (50 mg) was added to a solution of
trans-3-benzyloxymethyl-4-hydroxydihydrofuran-2(3H)-one (36)
(0.19 g, 0.86 mmol) and EtOH (10 mL). The mixture was stirred
at rt under H2 for 2 h. It was then filtered through Celite and
concentrated to give the corresponding diol as a clear oil (0.11 g,
1
cm−1; H NMR (400 MHz, CDCl3) δ 8.05 (m, 4H), 7.56 (m, 2H),
7.43 (m, 4H), 5.59 (m, 1H), 4.59 (dd, J = 11.4, 5.2 Hz, 1H), 4.52 (m,
2H), 4.42 (dd, J = 11.3, 8.1 Hz, 1H), 4.31 (dd, J = 10.5, 2.2 Hz, 1H),
4.12 (m, 1H), 3.45 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 166.5,
166.2, 160.6, 133.6, 133.4, 129.9, 129.9, 129.8, 129.5, 128.7, 128.6,
83.4, 76.1, 73.7, 64.6, 47.3; MS (EI) m/z 216 (M+ − BzOH), 122,
105, 94 (100), 77, 51; HRMS (ESI) calcd for C20H18NaO5 (M+ + Na)
m/z 361.1046, found 361.1038.
1
99%): IR (KBr) 3406 (br), 2935, 1765, 1178, 1093, 1024 cm−1; H
NMR (300 MHz, CD3OD) δ 4.57 (m, 1H), 4.47 (dd, J = 9.4, 5.8 Hz,
1H), 4.10 (dd, J = 9.4, 3.5 Hz, 1H), 3.88 (m, 2H), 2.57 (m, 1H); 13C
NMR (75 MHz, CD3OD) δ 178.0, 74.4, 69.3, 58.6, 51.8; HRMS (ESI)
calcd for C5H8NaO4 (M+ + Na) m/z 155.0315, found 155.0315. This
diol was then mixed with CH2Cl2 (10 mL) and pyridine (0.67 g, 0.7
mL, 8.5 mmol). Benzoyl chloride (1.19 g, 1.0 mL, 8.5 mmol) was
added dropwise, and the resulting mixture was stirred at rt overnight. It
was then diluted with Et2O (50 mL), washed with 2 M HCl (30 mL),
H2O (30 mL), saturated aqueous NaHCO3 (30 mL), and brine
(30 mL). The organic layer was dried (MgSO4) and concentrated.
Purification by flash chromatography on silica gel (petroleum ether/
EtOAc 70:30) provided 29 as a white solid (0.22 g, 75%): mp 111−
4β-Benzoyloxy-3α-benzoyloxymethyl-β-2β-(6-chloro-9H-
purin-9-yl)-2α-fluoromethyltetrahydrofuran (37). The general
procedure for fluorine mediated nucleobase incorporation was applied
to trans-4-benzoyloxy-3-benzoyloxymethyl-2-methylenetetrahydrofur-
1
an (25) (41 mg, 0.12 mmol). An H NMR of the crude nucleosides
showed >20:1 dr. Purification by flash chromatography on silica gel
(petroleum ether/EtOAc 65:35) afforded 37 as a white solid (44 mg,
72%): mp 141−143 °C; IR (KBr) 2922, 1720, 1589, 1560, 1271, 1115,
712 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.53 (s, 1H),
8.11 (d, J = 7.5 Hz, 2H), 7.63 (m, 1H), 7.50 (m, 3H), 7.23 (m, 4H),
5.72 (m, 1H), 5.04 (dd, J = 46.1, 10.2 Hz, 1H), 4.97 (dd, J = 46.4, 9.9
Hz, 1H), 4.83 (m, 2H), 4.68 (m, 2H), 4.40 (d, J = 11.0 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 166.1, 165.2, 151.9, 151.5, 151.0, 143.9,
133.9, 133.8, 133.0, 129.9, 129.3, 129.0, 128.9, 128.5, 128.2, 97.7
(d, JCF = 19 Hz), 82.5 (d, JCF = 182 Hz), 76.3, 74.6, 60.9, 50.7; HRMS
(ESI) calcd for C25H20ClFN4NaO5 (M+ + Na) m/z 533.0998, found
533.0987.
1
113 °C; IR (KBr) 3060, 2935, 1774, 1714, 1273, 1113, 710 cm−1; H
NMR (300 MHz, CDCl3) δ 8.00 (t, J = 8.4 Hz, 4H), 7.60 (m, 2H), 7.46
(m, 4H), 5.70 (m, 1H), 4.88 (dd, J = 11.4, 3.6 Hz, 1H), 4.80 (dd, J =
10.7, 6.2 Hz, 1H), 4.71 (dd, J = 11.4, 5.0 Hz, 1H), 4.45 (dd, J = 10.7,
3.4 Hz, 1H), 3.29 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.0,
166.1, 134.1, 133.7, 130.0, 129.9, 128.8, 128.8, 73.1, 71.9, 62.2, 46.2; MS
(EI) m/z 218 (M+ − BzOH), 122, 105 (100), 77, 51; HRMS (ESI)
calcd for C19H16NaO6 (M+ + Na) m/z 363.0839, found 363.0833.
3-Benzoyloxymethyl-2-methylenetetrahydrofuran (22). The
general methylenation procedure was applied to 3-(benzoyloxymethyl)-
dihydrofuran-2(3H)-one (26) (147 mg, 0.67 mmol). Purification by
flash chromatography on silica gel (petroleum ether/EtOAc/Et3N
95:4:1) afforded 22 as a pale yellow oil (76 mg, 54%): IR (KBr) 2957,
3-Benzoyloxydihydrofuran-2(3H)-one (38). 3-Hydroxydihy-
drofuran-2(3H)-one39 (0.20 g, 2.0 mmol) was mixed with CH2Cl2
(8 mL) and pyridine (0.23 g, 0.24 mL, 2.94 mmol). Benzoyl chloride
(0.41 g, 0.34 mL, 2.94 mmol) was added dropwise, and the resulting
mixture was stirred at rt for 8 h. It was then diluted with Et2O (20
mL), washed with 2 M HCl (10 mL), saturated NaHCO3 (10 mL),
and brine (10 mL). The organic layer was dried (MgSO4) and
concentrated. Purification by flash chromatography on silica gel
(petroleum ether/EtOAc 70:30) provided 38 as a pale yellow oil (0.14
g, 35%): IR (KBr) 3064, 3003, 2924, 1788, 1726, 1269, 1176, 1111,
1
2893, 1720, 1276, 1113, 713 cm−1; H NMR (300 MHz, CDCl3) δ
8.05 (m, 2H), 7.58 (m, 1H), 7.45 (t, J = 7.7 Hz, 2H), 4.47 (dd, J = 11.0,
5.8 Hz, 1H), 4.36 (m, 1H), 4.33 (dd, J = 11.0, 7.8 Hz, 1H), 4.20 (m,
1H), 4.09 (m, 1H), 3.97 (m, 1H), 3.21 (m, 1H), 2.28 (m, 1H), 1.97
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 166.6, 162.8, 133.3, 130.2,
129.8, 128.6, 80.8, 69.2, 66.2, 40.6, 29.2; MS (EI) m/z 218 (M+), 122,
105, 96 (100), 77; HRMS (ESI) calcd for C13H15O3 (M+ + H) m/z
219.1016, found 219.1003.
4-Benzoyloxy-2-methylenetetrahydrofuran (23). The general
methylenation procedure was applied to 4-benzoyloxydihydrofuran-
2(3H)-one (27) (148 mg, 0.72 mmol). Purification by flash
chromatography on silica gel (petroleum ether/EtOAc/Et3N 97:2:1)
afforded 23 as a pale yellow oil (71 mg, 48%): IR (KBr) 2918, 1718,
1277, 1113, 712 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.05 (m, 2H),
7.58 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 5.57 (m, 1H), 4.37
(s, 1H), 4.33 (m, 2H), 3.97 (s, 1H), 2.98 (m, 1H), 2.83 (d, J = 17.0
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.4, 160.5, 133.5, 129.9,
129.9, 128.6, 81.4, 75.2, 73.7, 35.7; MS (EI) m/z 204 (M+), 105 (100),
77, 51; HRMS (ESI) calcd for C12H13O3 (M+ + H) m/z 205.0859,
found 205.0852.
1
1016, 710 cm−1; H NMR (400 MHz, CDCl3) δ 8.05 (m, 2H), 7.57
(m, 1H), 7.43 (m, 2H), 5.65 (dd, J = 9.5, 8.7 Hz, 1H), 4.50 (ddd, J =
9.1, 9.1, 2.5 Hz, 1H), 4.34 (ddd, J = 9.6, 9.6, 6.5 Hz, 1H), 2.79 (dddd,
J = 12.9, 9.0, 6.5, 2.5 Hz, 1H), 4.41 (dddd, J = 12.9, 9.6, 9.6, 9.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 172.9, 165.5, 133.8, 130.0,
128.8, 128.6, 68.3, 65.3, 29.0; MS (EI) m/z 206 (M+), 122, 105 (100),
77, 51; HRMS (ESI) calcd for C11H10NaO4 (M+ + Na) m/z 229.0471,
found 229.0461.
3-Benzoyloxy-2-methylenetetrahydrofuran (39). The general
methylenation procedure was applied to 3-benzoyloxydihydrofuran-
2(3H)-one (38) (0.127 g, 0.62 mmol). Purification by flash chromatog-
raphy on silica gel (petroleum ether/EtOAc/Et3N 89:10:1) afforded 39 as
a pale yellow oil (88 mg, 70%): IR (KBr) 2924, 1718, 1655, 1275, 1176,
1115, 714 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 7.7 Hz, 2H),
7.57 (m, 1H), 7.45 (m, 2H), 5.86 (m, 1H), 4.48 (s, 1H), 4.30 (m, 3H),
2.40 (m, 1H), 2.23 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 166.0, 160.8,
133.4, 130.1, 129.9, 128.6, 84.8, 73.3, 68.9, 32.3; MS (EI) m/z 204 (M+),
122, 105 (100), 77, 51; HRMS (ESI) calcd for C12H13O3 (M+ + H) m/z
205.0859, found 205.0839.
cis-4-Benzoyloxy-3-benzoyloxymethyl-2-methylenetetrahy-
drofuran (24). The general methylenation procedure was applied to
cis-4-benzoyloxy-3-(benzoyloxymethyl)dihydrofuran-2(3H)-one (28)
(90 mg, 0.26 mmol). Purification by flash chromatography on silica
gel (petroleum ether/EtOAc/Et3N 89:10:1) afforded 24 as a pale
yellow oil (33 mg, 22% from 35 over 3 steps): IR (KBr) 2924, 1720,
3α-Benzoyloxymethyl-2β-(6-chloro-9H-purin-9-yl)-2α-fluo-
romethyltetrahydrofuran (40). The general procedure for fluo-
rine-mediated nucleobase incorporation was applied to 3-benzoyloxy-
2-methylenetetrahydrofuran (39) (74 mg, 0.36 mmol). Purification by
flash chromatography on silica gel (petroleum ether/EtOAc 60:40)
afforded 40 as a white solid (99 mg, 73%, >16:1 dr). Characterization
for the major isomer: mp 167−169 °C; IR (KBr) 3128, 3062, 2912,
1
1277, 1111, 1065, 710 cm−1; H NMR (300 MHz, CDCl3) δ 8.00 (t,
J = 8.4 Hz, 4H), 7.56 (m, 2H), 7.42 (m, 4H), 5.82 (m, 1H), 4.73 (dd,
J = 11.1, 5.8 Hz, 1H), 4.59 (m, 1H), 4.51 (s, 1H), 4.34 (m, 2H), 4.10
(s, 1H), 3.51 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 166.4, 166.0,
160.6, 133.7, 133.4, 129.9, 129.8, 129.6, 128.7, 128.6, 82.0, 74.2, 73.4,
61.6, 44.0; MS (EI) m/z 216 (M+ − BzOH), 122, 105, 94 (100), 77,
51; HRMS (ESI) calcd for C20H18NaO5 (M+ + Na) m/z 361.1046,
found 361.1040.
1
1726, 1589, 1560, 1271, 1136, 1111, 933, 712 cm−1; H NMR (500
MHz, CDCl3) δ 8.72 (s, 1H), 8.40 (s, 1H), 8.07 (d, J = 7.6 Hz, 2H),
7.64 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 6.69 (s, 1H), 5.18
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The Journal of Organic Chemistry
Article
(dd, J = 46.1, 10.1 Hz, 1H), 5.00 (dd, J = 47.0, 10.1 Hz, 1H), 4.52
(ddd, J = 8.2, 8.2, 8.2 Hz, 1H), 4.41 (m, 1H), 2.36 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 165.0, 152.1, 151.5, 150.5, 143.8, 134.0, 129.9,
129.0, 128.9, 97.8 (d, JCF = 17 Hz), 82.0 (d, JCF = 179 Hz), 77.3, 69.2,
31.5; HRMS (ESI) calcd for C17H14ClFN4NaO3 (M+ + Na) m/z
399.0631, found 399.0650.
chromatography on silica gel (petroleum ether/EtOAc/Et3N 96:3:1)
afforded 46 as a pale yellow oil (31 mg, 65%): IR (KBr) 2962, 2925,
1
2853, 1729, 1700, 1274, 1119, 711 cm−1; H NMR (400 MHz, CDCl3)
δ 8.10 (d, J = 7.5 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (d, J = 7.8 Hz,
2H), 5.80 (m, 1H), 4.56 (dd, J = 7.7, 3.9 Hz, 1H), 4.36 (dd, J = 3.7,
2.0 Hz, 1H), 4.21 (dd, J = 3.7, 1.2 Hz, 1H), 2.21 (m, 1H), 1.06 (d, J = 6.7
Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 165.8, 161.7, 133.7, 130.1, 129.5, 128.7, 91.1, 83.4, 71.9, 31.5, 17.3, 16.7;
HRMS (ESI) calcd for C14H16NaO3 (M+ + Na) m/z 255.0992, found
255.0988.
S-tert-Butyl erythro-2-benzyloxy-3-hydroxy-4-methylpen-
tanethioate (42).26 TiCl4 (1 M in CH2Cl2, 13.4 mL, 13.4
mmol) was added dropwise to a solution of S-tert-butyl 2-
(benzyloxy)ethanethioate (41)40 (2.13 g, 8.94 mmol) in CH2Cl2
(100 mL) at −78 °C. After 2 min, triethyl amine (1.9 mL, 13.4
mmol) was added dropwise. After 30 min stirring at −78 °C,
isobutyraldehyde (1.22 mL, 13.4 mmol) was added, and the resulting
solution was left at −78 °C for 3 h. The reaction was quenched with
saturated NaHCO3 (50 mL), and the resulting slurry was filtered
through Celite. The organic layer was separated and washed with
saturated NaHCO3 (50 mL) and H2O (50 mL), dried (MgSO4), and
concentrated. Purification by flash chromatography on silica gel
(petroleum ether/EtOAc 92:8) afforded 42 as a pale yellow oil (2.5
g, 90%): 1H NMR (300 MHz, CDCl3) δ 7.38 (m, 5H), 4.83 (d, J = 11.3
Hz, 1H), 4.46 (d, J = 11.3 Hz, 1H), 3.83 (d, J = 6.4 Hz, 1H), 3.64 (ddd,
J = 5.5, 5.2, 5.1 Hz, 1H), 2.24 (d, J = 4.6 Hz, 1H), 1.97 (m, 1H), 1.51 (s,
9H), 0.97 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 203.4, 137.2, 128.7, 128.4, 128.3, 86.3, 77.2, 73.7, 47.9,
30.0, 29.5, 19.9, 16.5.
3α-Benzoyloxy-2β-(6-chloro-9H-purin-9-yl)-2α-fluorometh-
yl-4β-isopropyloxetane (47) and 3α-Benzoyloxy-2β-(6-chloro-
7H-purin-7-yl)-2α-fluoromethyl-4-isopropyloxetane (48).
The general procedure for fluorine-mediated nucleobase incorpora-
tion was applied to trans-3-benzoyloxy-4-isopropyl-2-methyleneox-
etane (46) (45 mg, 0.19 mmol). 1H NMR of the crude mixture
showed a 1:1 ratio of two fluorinated nucleosides. Purification by flash
chromatography on silica gel (petroleum ether/EtOAc 70:30−60:40)
afforded 47 as a clear wax (27 mg, 34%) and 48 as a clear wax (26 mg,
34%). Characterization of 47: IR (KBr) 2963, 2924, 2852, 1737, 1732,
1
1590, 1562, 1266, 1123, 711 cm−1; H NMR (500 MHz, CDCl3) δ
8.71 (s, 1H, H2), 8.59 (s, 1H, H8), 8.12 (d, J = 7.4 Hz, 2H), 7.68 (t, J
= 7.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 6.10 (d, J = 5.6 Hz, 1H), 5.32
(dd, J = 46.4, 10.6 Hz, 1H), 5.19 (dd, J = 46.3, 10.6 Hz, 1H), 4.65 (dd,
J = 7.9, 5.6 Hz, 1H), 2.15 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H), 0.97 (d, J
= 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 164.8, 152.5 (C2),
151.9 (C4), 150.8 (C6), 143.0 (C8), 134.3, 132.7, 130.2, 129.0, 128.6
(C5), 92.7 (d, JCF = 19 Hz), 90.1, 80.8 (d, JCF = 182 Hz), 73.1, 32.6,
17.3, 16.4; HRMS (ESI) calcd for C19H19ClFN4O3 (M+ + H) m/z
405.1124, found 405.1128. Characterization of 48: IR (KBr) 2964,
trans-3-Benzyloxy-4-isopropyloxetan-2-one (43). S-tert-
Butyl erythro-2-benzyloxy-3-hydroxy-4-methylpentanethioate (42)
(2.5 g, 8.1 mmol) was dissolved in CH3CN (250 mL), and
Hg(OCOCF3)2 (5.2 g, 12 mmol) was added. The resulting solution
was immediately immersed in a preheated 50 °C oil bath and heated
for 5 min. A white precipitate was formed, and the slurry was filtered
through Celite and washed with CH2Cl2 and concentrated.
Purification by flash chromatography on silica gel (petroleum ether/
EtOAc 92:8) afforded 43 as a pale yellow oil (0.80 g, 45%): IR (KBr)
1
2924, 1734, 1268, 1119, 711 cm−1; H NMR (500 MHz, CDCl3) δ
8.95 (s, 1H), 8.94 (s, 1H), 8.12 (dd, J = 7.2, 1.3 Hz, 2H), 7.69 (tt, J =
7.5, 1.2 Hz, 1H), 7.55 (tt, J = 7.9, 1.6 Hz, 2H), 5.96 (d, J = 4.7 Hz,
1H), 5.22 (dd, J = 46.4, 10.5 Hz, 1H), 5.13 (dd, J = 46.4, 10.6 Hz, 1H),
4.62 (dd, J = 8.0, 4.8 Hz, 1H), 2.03 (m, 1H), 1.03 (d, J = 6.7 Hz, 3H),
0.97 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 164.8, 163.7
(C4), 153.2 (C2), 147.8 (C8), 142.7 (C6), 134.6, 130.2, 129.2, 128.4,
121.8 (C5), 93.8 (d, JCF = 19 Hz), 90.6, 82.6 (d, JCF = 183 Hz), 74.0,
32.6, 17.2, 16.5; HRMS (ESI) calcd for C19H19ClFN4O3 (M+ + H) m/
z 405.1124, found 405.1124.
Calculational Details. Calculations were carried out on the three
model structures shown in Figure 4 (starting material, open
carbocation, and cyclic oxonium ion) and on the corresponding
system with a five-membered ring. Trial conformations were generated
by setting the three dihedral angles a, b, and d to initial values of ±60
and 180°, and the dihedral angle c to initial values of 0 (Z) and 180° (E).
This approach yielded 54 (3 × 3 × 3 × 2) starting structures for each of
the two starting materials, 18 (3 × 3 × 2) starting structures for each of
the two open carbocations and three starting structures for each of the
two cyclic oxonium ion.
1
3033, 2964, 2877, 1834, 1142, 876, 744, 700 cm−1; H NMR (400
MHz, CDCl3) δ 7.38 (m, 5H), 4.85 (d, J = 11.7 Hz, 1H), 4.69 (d, J =
11.7 Hz, 1H), 4.61 (d, J = 3.6 Hz, 1H), 4.22 (dd, J = 8.4, 3.6 Hz, 1H),
1.89 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 168.4, 136.4, 128.8, 128.6, 128.3, 84.5,
83.7, 72.7, 31.1, 18.1, 17.1; HRMS (ESI) calcd for C13H16NaO3 (M+ +
Na) m/z 243.0992, found 243.0983.
trans-3-Hydroxy-4-isopropyloxetan-2-one (44). Pd(OH)2/C
(7 mg, 0.05 mmol) was added to a solution of trans-3-benzyloxy-4-
isopropyloxetan-2-one (43) (56 mg, 0.25 mmol) in THF (5 mL). The
mixture was stirred at rt under H2 for 2 h. It was then filtered through
Celite and concentrated to give 44 as a clear oil (33 mg, 100%): IR
1
(KBr) 3437 (br), 2966, 2879, 1832, 1146, 874, 849 cm−1; H NMR
(300 MHz, CDCl3) δ 4.83 (m, 1H), 4.19 (dd, J = 8.2, 3.2 Hz, 1H),
3.29 (br, 1H), 1.96 (m, 1H), 1.08 (d, J = 6.6 Hz, 3H), 1.04 (d, J = 6.8
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.4, 86.7, 78.5, 31.2, 18.2,
17.0; HRMS (ESI) calcd for C6H10NaO3 (M+ + Na) m/z 153.0522,
found 153.0492.
For each trial structure, initial geometry optimization was carried
out at HF/6-31G*. In some cases, more than one starting structure
yielded a single optimized structure; that is, the total number of unique
conformations was less than the number of starting conformations.
Subsequent CBS-QB3 calculations were carried out each unique
structure.41 All structures were of C1 symmetry and were verified as
minima via calculation of analytical second derivatives.
trans-3-Benzoyloxy-4-isopropyloxetan-2-one (45). trans-3-
Hydroxy-4-isopropyloxetan-2-one (44) (30 mg, 0.23 mmol) was
dissolved in CH2Cl2 (2 mL), and pyridine (27 mg, 0.03 mL,
0.35 mmol) was added. Benzoyl chloride (49 mg, 0.04 mL, 0.35 mmol)
was added dropwise, and the resulting mixture was stirred at rt for
2 h. The reaction mixture was then concentrated and purified by flash
chromatography on silica gel (petroleum ether/EtOAc 90:10) to
provide 45 as a clear oil (48 mg, 88%): IR (KBr) 2968, 2879, 1842,
All calculations were performed using the Gaussian 09 package.42
Energies as well as key dihedral angles and distances are provided with
the Supporting Information.
1
1735, 1271, 1130, 710 cm−1; H NMR (400 MHz, CDCl3) δ 8.08 (d,
J = 7.5 Hz, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 5.88
(d, J = 3.7 Hz, 1H), 4.41 (dd, J = 7.9, 3.7 Hz, 1H), 2.13 (m, 1H), 1.12
(d, J = 6.7 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.0, 164.7, 134.3, 130.3, 128.8, 128.2, 84.4, 77.0, 31.0,
17.8, 17.1; HRMS (ESI) calcd for C13H15O4 (M+ + H) m/z 235.0965,
found 235.0956.
trans-3-Benzoyloxy-4-isopropyl-2-methyleneoxetane (46).
The general methylenation procedure was applied to trans-3-benzoyloxy-4-
isopropyloxetan-2-one (45) (48 mg, 0.21 mmol). Purification by flash
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data, as well as
1
copies of high-resolution H and 13C NMR spectra for new
compounds. A file of energies of intermediates, as well as key
dihedral angles and distances. This material is available free of
charge via the Internet at http://pubs.acs.org.
9973
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Article
(23) Motozaki, T.; Sawamura, K.; Suzuki, A.; Yoshida, K.; Ueki, T.;
Ohara, A.; Munakata, R.; Takao, K.-i.; Tadano, K.-i. Org. Lett. 2005, 7,
2261.
(24) cis-γ-Lactone 28 was contaminated with a minor byproduct due
to partial decomposition on silica gel during column chromatography.
The mixture, however, was carried forward to the methylenation step
to give 24 as a pure compound. The yield of 24 was calculated from 35
over three steps.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: amy.howell@uconn.edu.
ACKNOWLEDGMENTS
■
Support from the National Science Foundation (CHE-
0944213-ARH) and the Department of Energy (DE-FG02-
05ER15687-GWC) is gratefully acknowledged. This research
was also supported in part by the National Science Foundation
through TeraGrid resources provided by NCSA under Grant
No. TRA100004.
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step reacted with alcoholic solvents to give ring-opened products
under these conditions. Consequently, THF was used as the solvent.
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when a system related to 39 was used. Our argument for the reason 24
gives multiple products is provided in this paragraph: Tseng, C. K.-H.;
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