Distal two-bond versus three-bond electronegative oxo-substituent effect controls the kinetics and thermodynamics of the conversion of a C -nitroso function to the corresponding oxime in the conformationally locked pentofuranose (Bicyclo[2.2.1]heptane) system

Article abstract of DOI:10.1021/jo500266k

We report the high-yielding and scalable diastereospecific synthesis of isomeric bicyclo[2.2.1]heptane-7- and -8-oximes and their corresponding C-nitroso derivatives, which are the key intermediates for the synthesis of carbanucleosides. Neither the (C7-R)-nitroso- nor (C8-S)-nitrosobicycloheptane system requires any external base in DMSO-d₆ to afford the corresponding oxime, and no reverse isomerization from the oxime to the C-nitroso compound was observed. The conversion of the (C8-S)-nitroso compound to the E/Z-oximes was ～8 times faster (at 40 °C) than that of the (C7-R)-nitroso derivative. The mechanism involves first-order reaction kinetics for the conversion of either the (C7-R)- or (C8-S)-nitroso derivative to the corresponding E/Z-oximes. The lower rate of conversion of the (C7-R)-nitroso compound to the corresponding oximes compared with that of the (C8-S)-nitroso derivative is attributed to the fact that the acidic H8 ionizing center is two bonds away from the OPMB group on C1 in the latter whereas H7 is three bonds away from the C1 OMe group in the former, making the effect of the electron-withdrawing group on C1 stronger in the latter.

Full text of DOI:10.1021/jo500266k

Article
pubs.acs.org/joc
Distal Two-Bond versus Three-Bond Electronegative Oxo-Substituent
Effect Controls the Kinetics and Thermodynamics of the Conversion
of a C‑Nitroso Function to the Corresponding Oxime in the
Conformationally Locked Pentofuranose (Bicyclo[2.2.1]heptane)
System
Mansoureh Karimiahmadabadi,† Sayeh Erfan,† Andras Foldesi, and Jyoti Chattopadhyaya*
̈
Program of Chemical Biology, Department of Cell and Molecular Biology, Biomedical Centre, Uppsala University, SE-75123 Uppsala,
Sweden
S
* Supporting Information
ABSTRACT: We report the high-yielding and scalable di-
astereospecific synthesis of isomeric bicyclo[2.2.1]heptane-7-
and -8-oximes and their corresponding C-nitroso derivatives,
which are the key intermediates for the synthesis of carbanu-
cleosides. Neither the (C7-R)-nitroso- nor (C8-S)-nitroso-
bicycloheptane system requires any external base in DMSO-d6
to afford the corresponding oxime, and no reverse isomer-
ization from the oxime to the C-nitroso compound was
observed. The conversion of the (C8-S)-nitroso compound to
the E/Z-oximes was ∼8 times faster (at 40 °C) than that of the
(C7-R)-nitroso derivative. The mechanism involves first-order
reaction kinetics for the conversion of either the (C7-R)- or
(C8-S)-nitroso derivative to the corresponding E/Z-oximes.
The lower rate of conversion of the (C7-R)-nitroso compound to the corresponding oximes compared with that of the (C8-S)-
nitroso derivative is attributed to the fact that the acidic H8 ionizing center is two bonds away from the OPMB group on C1 in
the latter whereas H7 is three bonds away from the C1 OMe group in the former, making the effect of the electron-withdrawing
group on C1 stronger in the latter.
therefore could not be used for the synthesis of diastereomeri-
cally pure modified oligo-DNA and -RNA for further studies.
Another problem was that the coupling worked only with
adenine but not with thymine or any other nucleobase despite
several changes in the reaction conditions. We therefore
turned our interest to the synthesis of the 1-β-C8′-desmethyl
analogue 19, which is a known compound,3c using Grubbs’
catalyst in 19 steps with a low overall yield to construct the
carbasugar ring.3c
Although 5-exo free-radical cyclization to a tethered olefin
affords the fused carbacyclic sugars, an exocyclic C8-methyl
group remains a permanent structural element (as in 20 → 21,
21→ 23, and 24 → 25). On the other hand, the 5-exo free-radical
cyclization to a tethered oximino group can provide synthetic
access to the corresponding desmethyl sugars (as in 14 → 22 and
22 → 19), which is necessary for the coupling with the aglycones
to give a defined stereochemical outcome.
INTRODUCTION
■
We recently completed the synthesis of the conformationally
locked bicycloheptane derivatives1 21 and 25 (Figure 1) in
order to transform them into the corresponding β-D-carbocyclic
nucleosides for incorporation into oligo-DNA or -RNA to study
their biochemical properties as antisense agents2a−j and small
interfering RNAs in order to control RNA translation to proteins.
The availability of carbocyclic-modified nucleosides without
any substitution, such as3c 19 obtained using 8-desmethylheptane
system 22 (Figure 1), is also important to modify DNA and
RNA duplexes at different positions with hydrophobic groups.
This hydrophobic modification will enable us to understand if the
pentose O4′ actually acts as an important hydration site into the
major and minor grooves in DNA/DNA, DNA/RNA, and RNA/
RNA duplexes, thereby controlling the endo- and exo-nucleolytic
enzymatic reactions.2a−j
In our previous studies,1 we were able to perform a radical
ring closure to form bicyclo[2.2.1]heptane 21 (20 → 21;
Figure 1), which allowed us to perform a nucleobase coupling
without any difficulty to give compound 23. The main problem
of this coupling reaction was that the S and R diastereomers
arising from the methyl group at C8′ were inseparable and
We were convinced that a free-radical oximino cyclization
route3a to synthesize 1-β-C8′-desmethyl analogue 19 could be a
Received: February 6, 2014
Published: July 22, 2014
© 2014 American Chemical Society
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Figure 1. Scheme for 5-exo free-radical addition to olefins, as in 20 → 21 and 24 → 25, or to oximino groups, as in 14 → 22. PMB =
p-methoxybenzyl.
Figure 2. The conversion of C-nitroso intermediates 7 and 16 to the corresponding oximes constitutes a key step for the synthesis of the desmethyl
fused carbocylic nucleosides 19 and 10a and carbocylic sugar 10b.
worthwhile alternative to explore (Figure 2A) via incorporation
of an easily removable NHOBn group3a at C8 followed by
oxidation and deoxygenation steps (15 → 16 → 17 → 18 →
19; Figure 2A). We argued3a that this would involve fewer syn-
thetic steps than Jacobson’s3c and Nielsen’s3d fused carbacycle
syntheses via ring closure metathesis (RCM) using Grubbs’
catalyst.3c−f In the debenzylation reaction of compound 15,
the desired oxime 17 and C-nitroso side product 16 (Figure 2A)
were isolated and identified.3a,b Clearly, the formation of C-nitroso
compound 16 as a side product adversely affected the yield
of the target oxime 17, although the former could be easily
separated from the latter. However, we observed that under
neutral NMR conditions at ambient temperature in CDCl3
or DMSO-d6, C-nitroso compound 16 was irreversibly
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Scheme 1. Synthesis of C-Nitroso 16 and the Corresponding Oximes E/Z-17 and Mechanism of the Conversion from C-Nitroso
Compound 16 to Oximes E/Z-17 Showing an Intermolecular H Shuttle Involving a Water Molecule
converted to the isomeric E/Z-oximes 17, albeit over a period
of 7−10 days. If we could accelerate the rate of conversion
of C-nitroso derivative 16 to oximes 17, it would open a new
means to use the oximino radical cyclization path to construct
the carbocyclic ring.
Hence, we became interested in finding a convenient
procedure for the conversion of the former to the latter, which
required that we carefully determine the kinetics and
thermodynamics of the conversion of the C-nitroso derivative
16 to the isomeric E/Z-oximes 17 in order to make our synthetic
scheme effective (Figure 2A). Conversions of various C-nitroso
compounds to the corresponding oximes requiring various
reaction conditions (acidic/basic/neutral)4a−e suggested that we
needed to characterize the reaction conditions required for the
formation of 17 from 16.
This study also prompted us to reinvestigate the relatively poor
yield of the oximes 8a (Figure 2B) obtained by the removal of
the C7′-benzyloxyamino group in the 2-oxabicyclo[2.2.1]heptane
system 6a from our previously published work.3a Upon re-
examination of this oxidative removal (mCPBA/K2CO3 in
EtOAC) of the benzyl protecting group from (C7′-R)-NHOBn
compound 6a,3a we found that the poor yield reported for
the oxime in the above deprotection was due to formation of
C-nitroso compound 7 as a side product (Figure 2B) in addition
to oximes 8b. Both C-nitroso derivative 7 and oximes 8b were
isolated in pure form.
Herein we report the kinetics of the conversion of C-nitroso
compounds 7 and 16 to the corresponding isomeric E/Z-
oximes 8b and 17, respectively, which helped to expedite the
synthesis of the target desmethyl fused carbocylic sugar 10b
and carbanucleosides 10a and 19 (Figure 2).
RESULTS AND DISCUSSION
■
1. Synthesis of the Bicyclic Nucleoside Precursors
C-Nitroso 16 and Oximes E/Z-17. 1.1. Synthesis of
Bicyclo[2.2.1]heptane Derivative 15. The synthesis of oxime
17 started from the known tetrahydrofuran derivative 11
(Scheme 1).1 Compound 11 was treated with OsO4 in H2O,
N-methylmorpholine-N-oxide (NMO), and NaIO4 in a one-
pot reaction5 to obtain aldehyde 12 without purification.
Aldehyde 12 was then directly used for the oximation3a with
O-benzylhydroxylamine hydrochloride to give benzoximes E-13
and Z-13 as a mixture that was separated (44% overall yield,
1
3:1 E/Z by H and 13C NMR analysis; see the Experimental
Section and the Supporting Information).6a Compounds E-13
and Z-13 were separately subjected to esterification of the
4-OH with methyloxalyl chloride in dry pyridine at 50 °C. The
products obtained from these two individual reactions were
the same inseparable mixtures (∼3:1 E/Z by 1H NMR analysis)
of the isomers E-14 and Z-14 regardless of the starting isomer
employed (E-13 or Z-13). This result indicates that the thermo-
dynamically more stable product, the E isomer, is formed as the
major isomer in both cases. The inseparable 3:1 mixture of E-14
and Z-14 was obtained in 68% yield. This mixture was subjected
to free-radical cyclization,1 which was carried out under N2 in
anhydrous toluene with Bu3SnH under reflux, adding azobis-
(isobutyronitrile) (AIBN) as an initiator in a dropwise manner;
this resulted in the formation of compound 15 in 65% yield.
The hexenyl radical cyclization of compounds E-14 and Z-14 at
C4 proceeded in the 5-exo cyclization mode1 to give only one
[2.2.1]-fused product, H1,H8-trans-fused product 15 with the
(8S) configuration. Detailed NMR analysis of 15 confirmed that
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Table 1. NOE Enhancement Data, Computational Simulations (in Hyperchem Pro 6.0),8 and the Newman Projection(s) across
C8/C1, Showing the Configurational Orientation in Compounds 15 and 16; Irradiations at H1 and H8 for Both Compounds,
Suggesting the S Configuration at C8 and the R Configuration at C1, and Vicinal Coupling Constant Data Are Also Shown
the diastereotopically pure product 15 exclusively has α-8-
NHOBn (C8-S) and β-1-OPMB (C1-R) configurations. This
result was verified by NOE experiments and coupling constant
analysis (Table 1; also see the Supporting Information).
α1-carbon atom (i.e., Z), this carbon experiences significant
upfield shift, whereas the chemical shift of the second α2-carbon is
either unaffected or shows a downfield shift.6b On the other hand,
in the 1H NMR spectra, protons on the same side of the double
bond as the OH (i.e., E) show significant downfield shifts.6b
On this basis, the oxime isomers were assigned as illustrated in
Figure 3A. The E-17:Z-17 isomeric ratio observed when 16 was
converted to the oximes in CDCl3 and DMSO-d6, was ∼4:1.
2. Synthesis of C-Nitroso 7 and Oximes E-8b and Z-8b.
We previously synthesized carbacyclic thymidine nucleoside
8a with C7′-NHOBn compound 6a (Scheme 2).3a The same
route (1 → 2a → 3a → 4a → 5a → 6a) was not general for
the construction of fused carbabicycles lacking C7′ and C8′
substituents by replacing O4′ with an 8′-CH2. Hence, we
became interested in exploring the free-radical cyclization1 of
a vicinal C4′-alkyloximino group in a C1-methyl glycoside, as in
compound 2b (1 → 2b → 3b → 4b → 5b → 6b; Scheme 2). If
successful, this strategy would permit the construction of [2.2.1]
carba systems on both the α and β faces of the sugar ring.
The synthesis of oximes E-8b and Z-8b started from the
known α-D-ribofuranose 13a (Scheme 2). Compound 1 was
treated with p-toluenesulfonic acid·H2O in MeOH to obtain
methyl glycoside 2b1 as an inseparable mixture of β and α
1.2. Synthesis of C-Nitroso 16 and the Corresponding
Isomeric Oximes E-17 and Z-17. Oxidation of benzyloxyamine
15 with mCPBA in EtOAc in the presence of K2CO3 as a base
at room temperature for ∼1 h removed the benzyl group to
give a mixture of three compounds, C-nitroso 16, oxime E-17,
and oxime Z-17, all of which have close Rf values by TLC in
several solvent systems and very closely overlapping chemical
shifts, posing a considerable challenge for purification and
structural identification (part II of the Supporting Information).
However, we obtained pure C-nitroso compound 16 (20%) and
the oximes E-17 and Z-17 (28%) as a 4:1 mixture of isomers.
The chemical identities were confirmed by detailed 1D and 2D
1H and 13C NMR spectroscopy as well as mass spectrometry.
Indication of the presence of the C-nitroso compound in the
mixture of the mCPBA oxidation reaction was based on the
observation of an unexpected H8 resonance4a−e at 5.8 ppm
that showed a correlation peak to a carbon resonating at 71 ppm.
The presence of this extra CH indicated that the new peak most
probably originates from the C-nitroso4a−e compound 16, since
the literature shows that a typical oxime can be formed from a
C-nitroso intermediate having Hα chemical shifts of 5−6 ppm.4a−e
The configurations of C-nitroso 16 and oximes E-17 and
Z-17 were confirmed by 1D NOEs and coupling constant
analysis (Table 1). No NOE enhancements could confirm the
configurations in the E-17 and Z-17 isomers (part II of the
Supporting Information), but they were confirmed by 1H and/
or 13C shifts. The 13C resonances of oximes have been widely
studied. For example, for a range of cyclic ketoximes (Figure 3)
it was found that when the N−OH points toward a specific
1
anomers in 81% yield. The H NMR assignment showed an
anomeric ratio of ∼10:1. Reduction of the nitrile group of 2b
with DIBALH afforded aldehyde 3b, which was directly used for
the oximation3a with O-benzylhydroxylamine to obtain oxime
4b as a mixture of E and Z isomers (1.6:1 by 1H NMR) in 83%
yield in two steps. As discussed above,6a the findings that E-4b
1
has a pairwise downfield H shift (δH6 = 2.82 ppm) and
corresponding upfield 13C shift (δC6 = 30.1 ppm) proved the E
1
configuration, whereas the opposite for Z-4b (δ H = 2.68 ppm
and δ C = 34.1 ppm) proved the Z configuration of the oxime.6a
13
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1
Figure 3. H and 13C chemical shifts supporting the assignments of the E and Z configurations for (A) oxime 17 and (b) oxime 8b.
Scheme 2. Synthesis of Oxabicyclo[2.2.1]heptan-7-oxime (8b); The Mechanism of the Conversion from C-Nitroso 7 to Oxime
8b Involves an Intermolecular Hydrogen Shift
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Table 2. NOE Enhancement Data and Modeling (in Hyperchem Pro. 6.0)8 of Compounds 6b and 7; Irradiations at H1 and H7
for Compound 6b Suggesting the R Configuration at C7 and the R Configuration at C1, Irradiations at H2 and H7 for
Compound 7 Suggesting the R Configuration at C7 and the R Configuration at C2, and Vicinal Coupling Constant Data Are
Also Shown
After 2-OH esterification of the isomers E-4b and Z-4b
with phenyl chlorothionoformate in dry pyridine at room
temperature, the key intermediate for the radical cyclization,
2-O-phenoxythiocarbonyl 5b, was obtained in 72% yield.
The mixture of E- and Z-5b was subjected to radical ring
closure in degassed anhydrous toluene at reflux temperature in
the presence of Bu3SnH, adding AIBN dropwise as a radical
initiator.1,2b Since the radical transition state3a is exactly the
same for both E-5b and Z-5b, only one C2−C7 cis-fused 5-exo
product 6b, with the (7R) configuration, was obtained in
54% yield. The stereochemistry of the new stereocenters was
assigned by 1D NOE enhancement and coupling constant
analysis for compound 6b (Table 2).
The presence of H7 indicated that 7 was not an oxime but
rather an intermediate (i.e., a C-nitroso compound).6a,b The
configurations of the C-nitroso derivative 7 were confirmed by
1D NOE and coupling constant analysis (Table 2). In addition,
irradiation of H2 led to a 3% NOE enhancement for H7
(dH2,H7 ≈ 2.5 Å), which confirmed that H2 and H7 are located
on the same face in C-nitroso 7. Therefore, these assignments
confirmed the R configuration at the C7 center and the R
configuration at the C2 center, which indicates a cis orientation
of H7 and H2 in 7. The assignment of these configurations
for 7 is also consistent with what was assigned for the precursor
2-oxabicyclo[2.2.1]heptane 6b. Moreover, we confirmed the
1
configurations in isomers E-8b and Z-8b by H and/or 13C
Oxidation of benzyloxyamine 6b with mCPBA in EtOAc
in the presence of K2CO3 as a base at ambient temperature for
∼1 h removed the benzyl group to give C-nitroso compound 7
shifts as shown in Figure 3B.6b
3. Mechanism of Conversion of C-Nitroso Compounds
16 and 7 to the Corresponding Oximes E/Z-17 and
E/Z-8b: Kinetic and Thermodynamic Studies of Oxime
Formation. 3.1. Kinetics and Thermodynamics of the
Conversion of C-Nitroso Derivative 16 to Oximes E-17 and
Z-17 in the Oxabicyclo[2.2.1]heptane System. As evidenced
above, C-nitroso 16 and oximes E-17 and Z-17 were isolated in
pure forms and fully characterized by NMR spectroscopy and
mass spectrometry, suggesting that these compounds are fairly
stable in CDCl3 at room temperature. Therefore, DMSO-d6
was used for higher-temperature studies. C-Nitroso compound
16 was found to be converted almost completely (>99%) to
oximes E-17 and Z-17 in DMSO-d6 in 58 h at 298 K, and no
reverse isomerization toward C-nitroso compound 16 was
observed under our experimental conditions. We subsequently
plotted ln([16]) as a function of time for the conversion of 16
to E-17 + Z-17 to obtain the first-order rate constant k at
different temperatures7a,b (Table 3). The populations of 16,
1
(30%) and oximes E- and Z-8b (40%, 10:2, H NMR) as a
mixture of isomers. We observed that the conversion of
C-nitroso compound 7 in DMSO-d6 or in CDCl3 was very slow
at room temperature. However, the reaction at >40 °C for
conversion of C-nitroso compound 7 in DMSO-d6 to oximes
was faster and quite suitable for our synthetic purposes, even
though it was 8 times slower than the conversion of C-nitroso
derivative 16 (see below). The low boiling point of CDCl3 did
not allow the temperature to be raised in order to perform the
reaction under neutral conditions, and it was not pursued for
our preparative purposes.
The C-nitroso derivative 7 and oximes E-8b and Z-8b were
characterized by detailed 1D and 2D NMR spectroscopy and
mass spectrometry. H7 for the C-nitroso compound shows a
resonance at 5.4 ppm (part I of the Supporting Information),
which is connected to a carbon resonating at 66.8 ppm.
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Table 3. Kinetic and Thermodynamic Data (k, ΔH⧧, −TΔS⧧, and ΔG⧧) for the Conversions of Compound 7 to E/Z-8b and
Compound 16 to E/Z-17
a
The E isomer is the major product for 7 → E/Z-8b (10:2 E/Z by 1H NMR analysis) and for 16 → E/Z-17b (4:1 E/Z by 1H NMR analysis). E/Z
isomerization of oximes under various conditions has been reported.10a−e The present studies were performed under neutral conditions, and we did
not observe any E/Z isomerization. The activation energy (Ea) was calculated from the Arrhenius equation (see Figures 4A and 5A).7c For 7 →
b
E-8b + Z-8b, Ea = 112.6 0.2 kJ/mol, and for 16 → E-17b + Z-17b, Ea = 104.1 3 kJ/mol. The Eyring equation7c gave the activation parameters
ΔH⧧, ΔS⧧, and ΔG⧧ (see Figures 4B and 5B).
Figure 4. (A) Plot of ln(k) vs 1/T (Arrhenius plot) for the conversion of nitroso compound 16 to E/Z-17. The plot shows a linear correlation (95%
confidence level); the slope (−Ea/R) gave the activation energy Ea. (B) Plot of ln(k/T) vs 1/T [Eyring plot, based on the equation ln(k/T) =
−ΔH⧧/RT + ln(kB/h) + ΔS⧧/R) for the conversion of compound 16 to E/Z-17. This plot also shows a linear correlation; the slope (−ΔH⧧/R) gave
the enthalpy of activation ΔH⧧, whereas the intercept gave the entropy of activation ΔS⧧.
E-17, and Z-17 at different time intervals were obtained from
the peak integrals of H8 for the C-nitroso compound and H1
for the oximes. The Arrhenius plot7c of ln(k) versus 1/T shows
a linear correlation (Figure 4A), from which the slope gave Ea.
Moreover, a plot of ln(k/T) versus 1/T [based on the Eyring
equation,7c ln(k/T) = −ΔH⧧/RT + ln(kB/h) + ΔS⧧/R, where
kB is the Boltzmann constant and h is the Planck constant]
shows a linear correlation (Figure 4B). The slope (which
should be equal to −ΔH⧧/R) gave the enthalpy of activa-
tion ΔH⧧, whereas the intercept [which should be equal to
ΔS⧧/R + ln(kB/h)] gave the entropy of activation ΔS⧧. The
free energy of activation, ΔG⧧, was also calculated (Table 3).
In CDCl3 and DMSO-d6 the conversion of C-nitroso
compound 16 at ambient temperature is very slow (i.e., in a
week), but when 16 was converted to oxime 17, it gave the two
isomers E-17 and Z-17 in a 4:1 ratio.
3.2. Kinetics and Thermodynamics of the Conversion of
(C7-R)-Nitroso 7 to Oximes E-8b and Z-8b in the
Bicyclo[2.2.1]heptane System. C-Nitroso compound 7 and
the isomeric oximes E-8b and Z-8b were isolated in pure
forms with an isolated yield of 30% for 7 and 40% for E-8b and
Z-8b. It was found that C-nitroso compound 7 is fairly stable in
both CDCl3 and DMSO-d6 under neutral conditions at room
temperature. Elevation of the temperature is not feasible in
CDCl3 because of its lower boiling point. Hence, an external
base was used in our initial study, which was unnecessary when
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Figure 5. (A): Plot of ln(k) vs 1/T (Arrhenius plot) for the conversion of nitroso compound 7 to a mixture of E/Z-8b. The plot shows a linear
correlation (95% confidence level); the slope (−Ea/R) gave the activation energy Ea. (B) Plot of ln(k/T) versus 1/T (Eyring plot) for the conversion
of compound 7 to E/Z-8b. This plot also shows a linear correlation; the slope (−ΔH⧧/R) gave ΔH⧧, whereas the intercept gave ΔS⧧.
we employed DMSO as a solvent under neutral conditions,
allowing us to study directly the transformation at a higher
temperature: The C-nitroso compound 7 in DMSO-d6 was found
to be converted almost completely (>99%) to the oxime (E-8b
and Z-8b) in ∼53 h at 313 K (40 °C) (see the Supporting
Information), and no reverse conversion was observed under
our experimental conditions. As for the conversion of C-nitroso
compound 16 to 17, we monitored the reaction kinetics in
neutral DMSO-d6 at five different temperatures by plotting
ln([7]) as a function of time for the conversion of C-nitroso 7
to the oximes E-8b + Z-8b, which gave the first-order rate
constant k (Table 3).7a,b The populations of 7, E-8b, and Z-8b
at different time intervals were obtained from the peak
integrals of H7 for the C-nitroso compound and H1 for the
oximes. The Arrhenius and Eyring plots (Figure 5) show
linear correlations, allowing Ea, ΔH⧧, ΔS⧧, and ΔG⧧ to be
determined (Table 3).
4. What Is the Difference in the Conversions of
C-Nitroso Compounds 7 and 16? The conversion of
C-nitroso compound 7 to the mixture of oximes E-8b and
Z-8b could only be conveniently induced in DMSO-d6 from
40 to 57 °C. On the other hand, the conversion of C-nitroso 16
to the oximes E-17 + Z-17 took place in DMSO-d6 from
25 to 45 °C. This finding suggests that an intermolecular six-
membered TS involving a water molecule and a proton shuttle
(Schemes 1 and 2)4f,g is most likely in both cases because the con-
version of the oxime to the nitroso is ∼3 times faster in DMSO-d6
(∼30% DOH) at 20 °C compared with that in CDCl3 (0.8%
water).
The conversion of 16 to E-17 + Z-17 was ∼8 times faster at
313 K than that of compound 7 to E-8b + Z-8b under identical
condition at 40 °C in DMSO-d6. The relative reactivity of the two
compounds 7 versus 16 arises from the positions of electron-
withdrawing groups. In C-nitroso 16, the acidic H8 (the ionizing
center) is situated two bonds away from the OPMB on C1,
whereas H7 in C-nitroso 7 is situated three bonds away from the
C1 OMe group. We have determined and compared the ΔG⧧
and Ea values for the two conversions and found that the values
for the conversion of 16 to pure oximes E-17 and Z-17 are lower
than those for the conversion of 7 to E-8b and Z-8b (Table 3).
Clearly, the conversion of C-nitroso compounds 16 and 7 to the
respective pure oximes E/Z-17 and E/Z-8b are spontaneous
because the product oximes 17 and 8b are thermodynamically
more stable than the C-nitroso compounds 16 and 7. Further
work on the mechanisms of these reactions is in progress.
CONCLUSIONS
■
In this study we synthesized bicyclo[2.2.1]heptane-8-oximes
E-17 and Z-17 and bicyclo[2.2.1]heptane-7-oximes E-8b and
Z-8b and their corresponding C-nitroso compounds 16 and 7
via a free-radical ring-closure reaction3 that gives an NHOBn
group at C8/C7 (15 and 6b). NMR spectroscopy experiments
were employed to characterize the synthesized compounds
unambiguously.
The C-nitroso derivative 7 is very sluggishly converted to
the corresponding oximes E-8b and Z-8b both in CDCl3 and
DMSO-d6 at room temperature (almost 10 days to reach
completion). C-Nitroso compound 7 in DMSO-d6 under
neutral conditions took 24 h at 45 °C to be transformed into
the oxime as the sole product. In contrast, C-nitroso derivative
16 gave a mixture of oximes E-17 and Z-17 with t99% = 58 h at
25 °C. In the conversion of 16 to E-17 + Z-17 we observed a
rate that is ∼8 times higher (at 40 °C) than that for 7 → E-8b +
Z-8b.7a,b Ea was obtained from the Arrhenius plots, and the
Eyring plots gave ΔG⧧ = 99.1 0.2 kJ/mol for 16 → E-17 +
Z-17 at 313 K in DMSO-d6 and ΔG⧧ = 105.2 0.1 kJ/mol for
7 → E-8b + Z-8b at 313 K. Thus, 16 → E-17 + Z-17 needs less
energy for conversion compared with 7 → E-8b + Z-8b.
The mechanism of the conversions 16 → E-17 + Z-17 and
7 → E-8b + Z-8b (Scheme 1) involves a faster intermolecular
proton shuttle for the former compared with the latter. This is
due to the different acidity of H8 in C-nitroso compound 16.
This ionizing center is situated two bonds away from the C1
OPMB group, compared with H7 in C-nitroso derivative 7, which
is situated three bonds away from the C1 OMe group. As a con-
sequence, the electron-withdrawing effect of the p-methoxybenzyl
(PMB) group in the former is felt more strongly.
Work is in progress to exploit this new chemistry and the
products for the synthesis of carba-LNA-modified oligonucleo-
tides in order to explore their biological properties.2a,11
The free-radical cyclization to a CNOBn moiety at C7/C8
followed by oxidation and deoxygenation steps opens new possibi-
lities for the synthesis of novel chiral carba- or oxabicyclo[2.2.1]-
heptane LNAs.3c This route involves fewer synthetic steps than the
earlier routes described by Jacobson3c and Nielsen3d for fused
carbacycles containing an extra carbon to give carba-ENAs. Our
novel synthesis allows the free-radical cyclization to be performed
with a tethered oximino function without an extra methyl group in
the cyclization to a double bond. It constitutes a high-yielding,
scalable route that does not require the use of expensive reagents
to the desired carba- or double carbanucleoside analogues.2a,11
7273
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Article
81.4 (C3E,Z), 75.6 (C5E,Z), 74.7 (C2E,Z), 73.1, 74.7 (CH2PhE,Z), 54.9
(OCH3E,Z), 30.2 (C6Z), 33.8 (C6E). MALDI-TOF m/z calcd for
C29H33NO6Na [M + Na]+ 514.221; found 514.222.
EXPERIMENTAL SECTION
■
General Procedures. All reagents were of the highest commercial
quality and were used without further purification. All non-aqueous
reactions were carried out under anhydrous conditions in dry, freshly
distilled solvents under N2(g). Reactions were monitored by TLC
carried out using UV light and/or cerium ammonium molybdate as
the visualizing agent. Flash chromatography was performed using silica
4-C-(Benzyloxyimino)ethyl-3,5-di-O-benzyl-1-O-methyl-2-O-
phenoxythiocarbonyl-β-D-ribofuranoside (5b). Compound 4b
(17 g, 34.6 mmol) was dissolved in 400 mL of anhydrous pyridine.
The solution was cooled to 0 °C, and then phenyl chlorothionoformate
was added dropwise (9.5 mL, 69.2 mmol) while the temperature was
maintained at 0 °C. After overnight stirring at room temperature,
pyridine was removed under reduced pressure. The residue was dissolved
in CH2Cl2 and washed with a saturated solution of NaHCO3 twice. The
organic layer was separated, dried over MgSO4, and concentrated. The
concentrate was purified by silica gel column chromatography (0−10%
v/v EtOAc in petroleum ether) to give compound 5b as a yellowish oil
(15.6 g, 72%, mixture of E and Z isomers).
1
gel 60G (230−400 mesh). H and 13C NMR spectra were obtained
1
using 500 and 600 MHz instruments for H and 125 and 150 MHz
instruments for 13C. The same spectrometers were used for the
1
1
acquisition of H−1H homonuclear (COSY and NOE) and H−13C
heteronuclear (HMQC and HMBC) correlations. Molecular modeling
was performed using HyperChem Pro 6.08 using molecular mechanics
(AMBER) followed by the semiempirical AM1 method (as
implemented in HyperChem Pro 6.0) to analyze the structures of all
products reported in the schemes. The dihedral angles were obtained
using the Karplus equation9 through the input of coupling constants
(NMR data), whereas HyperChem8 was used where no coupling
constants could be obtained. High-resolution mass spectra (HRMS)
with correct masses were obtained by MALDI-TOF mass spectroscopy.
4-C-Cyanomethyl-3,5-di-O-benzyl-1-O-methyl-α,β-D-ribofu-
ranoside (2b). Compound 1b (20 g, 48.84 mmol) was stirred with
6% p-toluenesulfonic acid·H2O in MeOH (400 mL) at rt for 24 h, and
the mixture was neutralized with saturated solution of Na2CO3, con-
centrated, diluted with H2O, and extracted with CH2Cl2. After drying
over MgSO4, it was purified by silica gel column chromatography
(25−30% EtOAc/petroleum ether) to give compound 2b as a colorless
oil (15 g, 80.1%) as an inseparable mixture of α and β anomers.
Major isomer (β): 1H NMR (500 MHz, CDCl3): δ 7.28−7.40
(13H, m, aromatic), 4.90 (1H, s, H1), 4.69 (1H, d, Jgem = 12 Hz,
CH2Ph), 4.58 (1H, d, Jgem = 12 Hz, CH2Ph), 4.57 (1H, bs, H3), 4.12
(2H, q, CH2Ph), 4.06 (1H, t, H2), 3.68 (1H, d, Jgem = 9.5 Hz, H5),
3.46 (1H, d, Jgem = 9.5 Hz, H5′), 3.30 (3H, s, OCH3), 2.92 (2H, s, H6,
H6′), 2.62 (1H, bs, OH). 13C NMR (125 MHz, CDCl3): δ 138.7,
138.5 (aromatic), 134.4 (C7), 128.9, 128.4, 128.2, 127.9 (aromatic),
118.3 (C8), 107.6 (C1), 86.8 (C4), 82.1 (C2), 75.2 (C5), 75.1 (C3),
73.3 (CH2Ph), 72.8 (CH2Ph), 55.3 (OCH3), 38.1 (C6). MALDI-TOF
m/z calcd for C22H25NO5Na [M + Na]+ 406.163; found 406.163.
4-C-(Benzyloxyimino)ethyl-3,5-di-O-benzyl-1-O-methyl-β-D-
ribofuranoside (4b). To a solution of 2b (16 g, 41.72 mmol) in dry
dichloromethane (DCM, 300 mL) was added DIBALH (166.9 mL,
1.0 M solution in toluene) dropwise at −78 °C. After 4 h of stirring at
the same temperature, the mixture was allowed to warm to 0 °C, and
then 1 N HCl solution was added to quench the reaction. The mixture
was stirred for 30 min at 0 °C, and the resulting suspension was
diluted with DCM. The organic layer was separated and washed with
brine, dried over MgSO4, and coevaporated with dry pyridine twice to
give crude compound 3b, which was dissolved in dry DCM (600 mL)
and dry pyridine (15 mL). To this solution, O-benzylhydroxylamine
hydrochloride (16.6 g, 104.3 mmol) was added. The mixture was
heated at reflux for 2 h, cooled to rt, and neutralized by the addition
of a saturated aqueous solution of NaHCO3. The organic layer was
separated, dried over MgSO4, evaporated, and chromatographed over
silica gel (15−20% EtOAc/petroleum ether) to give 4b (17 g, 83%) as
a mixture of Z and E isomers.
1H NMR (500 MHz, CDCl3): δ 7.62 (1H, app t, J = 6.5 Hz, H7E),
7.24−7.41 (40H, m, aromaticE,Z), 7.02 (1H, app t, J = 6.5 Hz, H7Z),
6.98 (4H, d, J = 8.5 Hz, aromaticE,Z), 5.73 (2H, m, H2E,Z), 5.15 (2H, s,
CH2NOBnE), 5.10 (3H, s, CH2NOBnZ, H1E), 5.08 (1H, s, H1Z), 4.59
(4H, d, Jgem = 7.5 Hz, CH2Ph), 4.51 (2H, d, Jgem = 8.5 Hz, CH2Ph),
4.47 (2H, d, Jgem = 7.5 Hz, CH2Ph), 4.44 (1H, d, J2,3 = 3 Hz, H3E),
4.42 (1H, d, J2,3 = 5 Hz, H3Z), 3.68 (4H, m, H5, H5′E,Z), 3.37 (3H, s,
OCH3E), 3.35 (3H, s, OCH3Z), 3.01 (1H, dd, Jgem = 16.5 Hz, J6′,7
=
6 Hz, H6′E), 2.79 (1H, dd, Jgem = 17 Hz, J6′,7 = 4.5 Hz, H6E), 2.92 (2H,
d, J = 6.5 Hz, H6, H6′). 13C NMR (125 MHz, CDCl3): δ 194.4, 194.3
(CSE,Z), 149.1 (C7E), 148.6 (C7Z), 138.1, 138.0, 137.6, 137.5, 138.5
(aromaticE,Z), 129.6, 129.5, 128.3, 128.1, 127.9, 127.8, 127.6, 127.5,
126.8, 126.6 (aromaticE,Z), 121.7, 121.8 (aromaticE,Z), 104.7, 104.5
(C1E,Z), 84.8, 84.6 (C2E,Z), 83.8, 83.7 (C4E,Z), 80.15, 79.8 (C3E,Z),
75.5, 75.4 (CH2PhE,Z) 74.8, 74.4 (C5E,Z), 73.5, 73.4 (CH2PhE,Z), 55.1
(OCH3E,Z), 33.1 (C6Z), 30.0 (C6Z). MALDI-TOF m/z calcd for
+
C36H37NO7SNa [M + Na] 650.219; found 650.219.
(1R,3R,4R,5R,7S)-7-(Benzyloxy)-1-[(benzyloxy)methyl]-3-
methoxy-5-benzyloxyamino-2-oxabicyclo[2.2.1]heptane (6b).
Compound 5b (14 g, 22.32 mmol) was dissolved in 500 mL of
anhydrous toluene, which was purged with N2 for half an hour. The
mixture was heated to reflux, and Bn3SnH (12 mL in 60 mL of
anhydrous toluene) and AIBN (1.8 g in 60 mL of anhydrous toluene)
were added dropwise over 3 h; reflux was continued for 2 h. The
solvent was evaporated, and the concentrate was purified by silica gel
column chromatography (20−25% v/v EtOAc in petroleum ether) to
give compound 6b as a colorless oil (5.7 g, 54%).
1H NMR (500 MHz, CDCl3): δ 7.15−7.31 (15H, m, aromatic),
4.87 (1H, s, H1), 4.63 (2H, s, CH2Ph), 4.53 (2H, ABq, Jgem = 12 Hz,
CH2Ph), 4.41 (2H, ABq, Jgem = 12.5 Hz, CH2Ph), 4.18 (1H, s, H3),
3.82 (1H, m, H7), 3.54 (2H, ABq, Jgem = 11.5 Hz, H5, H5′), 3.26 (3H,
s, OCH3), 2.62 (1H, q, J2,3 = 1.5 Hz, J2,7 = 4 Hz, H2), 1.97 (2H, m, H6,
H6′). 13C NMR (125 MHz, CDCl3): δ 138.4, 138.0 (aromatic), 129.6,
128.5, 128.3, 127.3 (aromatic), 101.2 (C1), 86.0 (C4), 82.5 (C3),
73.4 (CH2Ph), 71.8 (CH2Ph), 68.8 (C5), 56.7 (C7), 54.9 (OCH3),
46.2 (C2), 32.2 (C6). MALDI-TOF m/z calcd for C29H33NO5Na
[M + Na]+ 498.226; found 498.226.
(1R,3R,4R,5R,7S)-7-(Benzyloxy)-1-[(benzyloxy)methyl]-3-
methoxy-5-nitroso-2-oxabicyclo[2.2.1]heptane (7) and N-
[(1R,3R,4R,5Z/E,7S)-7-(Benzyloxy)-1-[(benzyloxy)methyl]-3-
methoxy-2-oxabicyclo[2.2.1]heptan-5-ylidene]hydroxylamine
(8b). To compound 6b (950 mg, 1.99 mmol) were added mCPBA
(837 mg, 3.4 mmol) and K2CO3 (550 mg, 3.98 mmol). The reaction
mixture was stirred at rt for 1 h, after which it was diluted with EtOAc
and extracted with saturated aqueous NaHCO3. The organic phase
was dried over anhydrous sodium sulfate, filtered, and evaporated.
The residue was chromatographed on silica gel (25−35% EtOAc
in petroleum ether) to give 7 (230 mg, 30%) and a 10:2 mixture of
E- and Z-8b (300 mg, 40%).
1H NMR (500 MHz, CDCl3): δ 7.62 (1H, app t, J = 6.3 Hz, H7E),
7.22−7.51 (30H, m, aromatic), 7.04 (1H, app t, J = 5.3 Hz, H7Z), 5.14
(2H, s, CH2NOBnE), 5.10 (2H, s, CH2NOBn ), 4.87 (1H, s, H1E),
Z
4.85 (1H, s, H1Z), 4.68 (2H, d, Jgem = 8.2 Hz, CH2Ph), 4.66 (2H, d,
Jgem = 8.5 Hz, CH2Ph), 4.57 (2H, d, Jgem = 8.5 Hz, CH2Ph), 4.55 (2H,
d, Jgem = 8.2 Hz, CH2Ph), 4.52 (1H, s, CH2Ph), 4.47 (1H, s, CH2Ph),
4.14 (2H, t, 6 Hz, H3E,Z), 4.05 (2H, m, H2E,Z), 3.46 (1H, d, Jgem = 8.14
Hz, H5E), 3.43 (1H, d, Jgem = 8.14 Hz, H5Z), 3.34 (1H, d, Jgem = 8.14
Hz, H5′E), 3.29 (1H, d, Jgem = 8.14 Hz, H5′Z), 3.31 (3H, s, OCH3E),
3.28 (3H, s, OCH3Z), 2.93 (1H, dd, Jgem = 17 Hz, J6′,7 = 5.3 Hz, H6′Z),
2.83 (1H, dd, Jgem = 16.7 Hz, J6′,7 = 5.1 Hz, H6Z), (2H, s, H6, H6′E).
13C NMR (125 MHz, CDCl3): δ 149.3 (C7E), 148.9 (C7Z), 138.0,
137.9, 137.2 (aromatic), 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9,
127.7, 127.6 (aromatic), 107.3 (C1E,Z), 84.6 (C4E), 84.6 (C4Z),
Nitroso 7: 1H NMR (500 MHz, CDCl3): 7.16−7.29 (11H, m,
aromatic), 5.41 (1H, dt, H7), 4.57 (1H, s, H1), 4.58 (1H, d, Jgem = 12
Hz, CH2Ph), 4.52 (2H, ABq, Jgem = 6.6 Hz, CH2Ph), 4.44 (1H, d, Jgem
=
11.4 Hz, CH2Ph), 4.32 (1H, bs, H3), 3.61 (2H, ABq, Jgem = 11.4 Hz,
H5, H5′), 3.25 (3H, s, OCH3), 3.20 (1H, dd, J2,3 = 1.2 Hz, J2,7
=
4.2 Hz, H2), 2.49 (1H, dd, Jgem = 13.2 Hz, J6,7 = 4.2 Hz, H6′),
7274
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The Journal of Organic Chemistry
Article
2.08 (1H, dd, Jgem = 13.8 Hz, J6′,7 = 10.8 Hz, H6′). 13C NMR (150
MHz, CDCl3): δ 138.7, 137.8 (aromatic), 128.9, 128.7, 128.6, 128.3,
127.8 (aromatic), 100.7 (C1), 86.9 (C4), 82.5 (C3), 73.9 (CH2Ph),
72.6 (CH2Ph), 68.2 (C5), 66.8 (C8), 55.4 (OCH3), 46.1 (C2), 32.0
(C6). MALDI-TOF m/z calcd for C22H25NO5Na [M + Na]+ 406.163;
found 406.163.
chromatography (5−25% EtOAc/petroleum ether) to yield a mixture
of E-14 and Z-14 (3.1 g, 4.53 mmol, 3:1 E:Z, 68%).
E-14: 1H NMR (500 MHz, CDCl3): δ 7.47 (1H, d, J8,1 = 8 Hz, H8),
7.40−7.14 (17H, m, aromatic), 6.87 (2H, d, J = 8.8 Hz, PMB), 5.14
(2H, s, NOCH2Ph), 4.63 (1H, d, Jgem = 11 Hz, CH2Ph), 4.55 (1H, d,
J = 12 Hz, CH2Ph), 4.51 (1H, d, J = 11.7 Hz, CH2PMB), 4.50 (1H, d,
J = 12 Hz, CH2Ph), 4.43 (1H, d, J6,6′ = 11 Hz, H6), 4.27 (2H, 2 × d,
Jgem = 11 Hz, CH2Ph, J3,2 = 6.3 Hz, H3), 4.21 (1H, d, J5,5′ = 10.7 Hz,
H5), 4.20 (1H, d, CH2PMB), 4.01 (1H, dd, J1,2 = 4.7 Hz, H1), 3.94
(1H, d, H5′), 3.91 (1H, d, H6′), 3.87 (3H, s, oxalyl-CH3), 3.86 (1H,
m, H2), 3.79 (3H, s, OCH3-PMB). 13C NMR (125 MHz, CDCl3): δ
159.4 (C4-PMB), 157.9 (C(O)OMe), 156.6 (C(O)), 148.3 (C8),
137.6, 137.5, 137.4, 130.1, 128.42, 128.4, 128.36, 128.0, 127.9,
127.8, 127.7 (aromatic), 113.8 (C3-PMB), 92.3 (C4), 85.1 (C2), 83.5
(C3), 76.2 (NOCH2), 74.3 (C1), 74.2 (C6), 73.6 (CH2Ph), 73.5
(CH2Ph), 70.5 (CH2PMB), 66.5 (C5), 55.2 (OCH3), 53.5 (CH3-
oxalyl). MALDI-TOF m/z calcd for C39H41NO10K [M + K]+ 722.237;
found 722.235.
1
Oxime E-8b: H NMR (600 MHz, DMSO-d6): δ 10.66 (1H, s,
NOH), 7.24−7.36 (13H, m, aromatic), 4.67 (1H, s, H1), 4.48 (1H, d,
Jgem = 12 Hz, CH2Ph), 4.53 (2H, d, Jgem = 12.5 Hz, CH2Ph), 4.58 (1H,
d, Jgem = 12 Hz, CH2Ph), 4.28 (1H, s, H3), 3.66 (2H, ABq, Jgem = 11.4
Hz, H5, H5′), 3.25 (3H, s, OCH3), 3.13 (1H, bs, H2), 2.37 (1H, d,
Jgem = 16.8 Hz, H6), 2.37 (1H, d, Jgem = 15 Hz, H6′). 13C NMR (150
MHz, DMSO): δ 157.4 (C7), 138.7, 138.2 (aromatic), 128.6, 127.9,
127.8, 127.7 (aromatic), 102.9 (C1), 86.2 (C4), 80.5 (C3), 72.7
(CH2Ph), 71.4 (CH2Ph), 54.6 (OCH3), 50.5 (C2), 34.8 (C6).
MALDI-TOF m/z calcd for C22H25NO5Na [M + Na]+ 406.163; found
406.163.
(3S,5S)-4-(Benzyloxy)-5-[(1R,2E/Z)-2-(benzyloxy)imino-1-[(4-
methoxyphenyl)methoxy]ethyl]-3-[(benzyloxy)methyl]oxolan-
3-ol (E/Z-13). Compound 11 (7.42 g, 15.1 mmol) was dissolved
in acetone (110 mL). OsO4 (4.93 mL, 0.76 mmol), NMO (2.65 g,
19.66 mmol), and H2O (16.7 mL) were added at room temperature.
The reaction mixture was stirred at rt overnight and then partitioned
between EtOH and H2O. The organic phase was dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo to give the
crude aldehyde. The crude aldehyde (1.16 g, 2.36 mmol) was dis-
solved in dry dichloromethane (55 mL), and pyridine (1.2 mL) and
O-benzylhydroxylamine hydrochloride (960 mg, 4.72 mmol) were
added at room temperature. The reaction mixture was stirred at
reflux for 2 h and then cooled to room temperature, and saturated
aqueous NaHCO3 was added. The organic layer was separated, dried
over MgSO4, and evaporated. The residue was subjected to short
column chromatography over silica gel (10%−30% EtOAc/petroleum
ether) to give a mixture of E-13 and Z-13 (621 mg, 1.04 mmol, ∼3:1
E:Z, 44%).
1
Z-14: H NMR (500 MHz, CDCl3): δ 4.59 (m, 1H, H1), 4.18 (m,
1H, H3), 3.81 (m, 1H, H2).
(1R,4R,5S,6R,7R)-N,7-Bis(benzyloxy)-4-[(benzyloxy)methyl]-
6-[(4-methoxyphenyl)methoxy]-2-oxabicyclo[2.2.1]heptan-5-
amine (15). The mixture of E-14 and Z-14 (910 mg, 1.24 mmol) was
dissolved in anhydrous toluene (130 mL), and then the solution was
purged with N2 for 40 min. The mixture was refluxed, and Bn3SnH
(0.8 mL in 20 mL in dry toluene) and AIBN (40 mg in 10 mL in dry
toluene) were added dropwise over 5 h; then the mixture continued to
reflux for 1 h. The mixture was cooled to room temperature, and the
solvent was evaporated. The residue was chromatographed on silica
gel (5−30% EtOAc in petroleum ether) to give 15 (433 mg, 60%).
1H NMR (600 MHz, CDCl3): δ 7.29−7.08 (17H, m, aromatic), 6.84
(2H, d, J = 8.4 Hz, PMB), 6.0 (1H, d, J = 4.8 Hz, NH), 4.69 (2H, ABq,
Jgem = 11.4 Hz, CH2Ph), 4.61 (1H, d, J = 12 Hz, CH2Ph), 4.54−4.44
(4H, m, CH2Ph × 2, CH2PMB), 4.36 (1H, d, J = 11.4 Hz, CH2Ph),
4.08 (1H, s, H2), 3.95 (1H, d, J = 7.5 Hz, H6), 3.93 (1H, s, H3), 3.80
Z-13: 1H NMR (500 MHz, CDCl3): δ 7.40−7.17 (17H, m,
aromatic), 6.9 (1H, d, J8,1= 6 Hz, H8), 6.82 (2H, d, Jgem = 8.5 Hz, PMB),
5.15 (2H, ABq, Jgem = 12 Hz, NOCH2Ph), 4.67 (1H, dd, J1,2 = 3.5 Hz,
H1), 4.63 (2H, q, CH2Bn), 4.53 (1H, d, J = 11.5 Hz, CH2PMB), 4.37
(2H, q, Jgem = 12 Hz, 3OCH2Ph), 4.31 (1H, d, CH2PMB), 4.14 (1H, t,
J2,3 = 2.8 Hz, H2), 3.86 (1H, d, J = 9.5 Hz, H6), 3.81−3.76 (6H, m,
OCH3, H3, H6′, H5), 3.67 (1H, d, J = 9.5 Hz, H5′), 2.72 (1H, d, OH).
13C NMR (125 MHz, CDCl3): δ 159.6 (C4-PMB), 150.8 (C8), 138.1,
(3H, s, OCH3), 3.69− 3.63 (3H, m, H6′, H5, H5′), 3.46 (1H, d, J8,1
=
3.6 Hz, H8), 3.38 (1H, s, H1). 13C NMR (125 MHz, CDCl3): δ 159.6
(C-PMB), 138.6, 138.2, 130.8, 129.6, 128.8, 128.1, 127.9, 127.8
(aromatic), 114.2 (C-PMB), 82.0 (C1), 81.9 (C3), 78.1 (C2), 76.9
(NOCH2), 73.9 (CH2Ph), 72.3 (CH2Ph), 71.0 (CH2Ph), 68.2 (C5),
67.1 (C6), 55.69 (OCH3), 52.9 (C4). MALDI-TOF m/z calcd for
C36H40NO6 [M + H]+ 582.286; found 582.286.
(1R,4R,5S,6R,7R)-7-(Benzyloxy)-4-[(benzyloxy)methyl]-6-[(4-
methoxyphenyl)methoxy]-5-nitroso-2-oxabicyclo[2.2.1]-
heptane (16) and N-[(1R,4R,5Z/E,6R,7R)-7-(Benzyloxy)-4-
(benzyloxy)methyl-6-[(4-methoxyphenyl)methoxy]-2-
oxabicyclo[2.2.1]heptan-5-ylidene]hydroxylamine (E/Z-17). To
compound 15 (1.74 g, 2.99 mmol) were added mCPBA (840 mg,
3.65 mmol) and K2CO3 (994 mg, 7.2 mmol). The reaction mixture was
stirred at rt for 1 h, after which it was diluted with EtOAc and extracted
with saturated aqueous NaHCO3. The organic phase was dried over
anhydrous sodium sulfate, filtered, and evaporated. The residue was
chromatographed on silica gel (5−35% in ethyl acetate in petroleum
ether) to give 16 (290 mg, 20%) and E/Z-17 (415 mg, 28%).
E-17: 1H NMR (600 MHz, CDCl3): δ 7.78 (1H, s, OH), 7.38−7.26
(12H, m, aromatic), 6.89 (2H, d, J = 8.5 Hz, PMB), 4.76 (2H, ABq,
Jgem = 12 Hz, CH2Ph), 4.66−4.57 (5H, m, CH2Ph, CH2PMB), 4.28
(1H, d, J3,2 = 1.5 Hz, H3), 4.22 (1H, s, H1), 4.09 (1H, d, J2,3 = 1.5 Hz,
H2), 4.05 (1H, d, Jgem = 6.5 Hz, H6), 3.83 (3H, s, OCH3), 3.81 (2H, s,
H5, H5′), 3.67 (1H, d, Jgem = 6.5 Hz, H6′). 13C NMR (125 MHz,
CDCl3): δ 160.5 (C8), 159.5 (C-PMB), 138.2, 137.9, 129.7, 129.6,
127.8, 127.6, 127.6, 127.5 (aromatic), 113.8 (C-PMB), 81.4 (C1), 78.0
(C2), 75.2 (C3), 73.7 (CH2Ph), 73.6 (CH2PMB), 72.3 (CH2Ph), 71.9
(CH2Ph), 70.9 (C6), 65.1 (C5), 55.3 (OCH3), 54.2 (C4). MALDI-
TOF m/z calcd for C29H32NO6 [M + H]+ 490.223; found 490.223.
Z-17: 1H NMR (500 MHz, CDCl3): δ 4.38 (1H, s, H1), 4.22 (1H,
d, J2,3 = 2 Hz, H3), 4.05 (1H, m, H2). 13C NMR (125 MHz, CDCl3):
δ 81.13 (C1), 77.8 (C3), 78.1 (C2).
137.6, 137.2, 130.2, 128.5, 128.46, 128.4, 128.4, 128.38, 128.3, 127.8,
127.76, 127.7, 113.9 (aromatic), 85.2 (C3), 84.9 (C2), 81.2 (C4), 76.6
(NOCH2Ph), 75.8 (C6), 73.9 (5OCH2Bn), 72.2 (3OCH2Bn), 72.0
(CH2PMB), 71.1 (C1), 69.8 (C5), 55.3 (CH3). MALDI-TOF m/z calcd
for C36H39NO7Na [M + Na]+ 620.262; found 620.262.
E-13: 1H NMR (500 MHz, CDCl3): δ 7.5 (1H, d, J8,1 = 6 Hz, H8),
7.41−7.29 (13H, m, aromatic), 7.19−7.16 (4H, m), 6.85 (2H, d, Jgem
=
8.8 Hz, PMB), 5.15 (2H, s, CH2Ph), 4.63 (2H, q, J = 12 Hz,
5OCH2Ph), 4.56 (1H, d, Jgem = 11.4 Hz, CH2PMB), 4.45 (1H, d, J =
11.7 Hz, 3OCH2Ph), 4.36 (H, d, 3OCH2Ph), 4.29 (1H, d, CH2PMB),
3.99−3.95 (2H, m, H3, H1), 3.88 (1H, d, J = 9.1 Hz, H6), 3.85−3.78
(6H, m, OCH3, H2, H6′, H5), 3.73 (1H, bs, OH), 3.67 (1H, d, J =
9.5 Hz, H5′). 13C NMR (125 MHz, CDCl3): δ 159.5 (C4-PMB),
148.6 (C8), 138.0, 137.6, 137.5, 130.2, 128.8, 128.4, 128.3, 128.0,
127.8, 127.79, 127.8, 113.8 (aromatic), 85.8 (C2), 85.4 (C3), 81.2
(C4), 76.1 (NOCH2Ph), 75.7 (C6), 75.1 (C1), 73.9 (5OCH2Bn), 72.6
(3OCH2Bn), 70.5 (CH2PMB), 70.0 (C5), 55.3 (CH3). MALDI-TOF
m/z calcd for C36H39NO7Na [M + Na]+ 620.262; found 620.262.
(1R,2E/Z,3S,5S)-4-(Benzyloxy)-5-[2-[(benzyloxy)imino]-1-[(4-
methoxyphenyl)methoxy]ethyl]-3-[(benzyloxy)methyl]oxolan-
3-yl methyl oxalate (E/Z-14). The mixture of E-13 and Z-13 (3.99 g,
6.68 mmol) was dissolved in dry pyridine (190 mL), and methyloxalyl
chloride (2.8 mL, 30 mmol) was added at room temperature. The
reaction mixture was stirred at 50 °C overnight, after which it was
quenched with saturated NaHCO3 solution and extracted with DCM.
The organic phase was dried over anhydrous sodium sulfate, filtered,
and evaporated. The crude product was purified by silica gel column
1
16: H NMR (500 MHz, CDCl3): δ 7.8 (1H, s, OH), 7.32−7.07
(12H, m, aromatic), 6.81 (2H, d, J = 8.5 Hz, PMB), 5.81 (1H, d,
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The Journal of Organic Chemistry
Article
J8,1 = 2 Hz, H8), 4.66 (2H, ABq, Jgem = 12 Hz, CH2Ph), 4.49 (1H, d,
J = 12 Hz, CH2Ph), 4.44 (2H, ABq, J = 11.5 Hz, CH2PMB), 4.36 (1H,
m, J1,2 = 3 Hz, H1), 4.25 (1H, d, J = 11.5 Hz, CH2Ph), 4.15 (1H, s,
H2), 4.11 (1H, d, J = 7.5 Hz, H6), 4.05 (1H, s, H3), 3.76 (3H, s,
OCH3), 3.54 (2H, m, H6′, H5), 3.35 (1H, d, J = 9.5 Hz, H5′).
13C NMR (125 MHz, CDCl3): δ 159.9 (C-PMB), 138.3, 138.2,
130.0, 129.4, 128.9, 128.7, 128.2, 127.9 (aromatic), 114.3 (C-PMB),
81.5 (C3), 78.6 (C1), 77.8 (C2), 74.1 (CH2Ph), 72.5 (CH2PMB), 72.5
(CH2Ph), 71.5 (CH2Ph), 71.1 (C8), 66.6 (C5), 66.5 (C6), 56.1 (C4),
55.6 (OCH3). MALDI-TOF m/z calcd for C29H32NO6 [M + H]+
490.223, found 490.224.
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ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR, COSY, HMQC, and HMBC spectra for
compounds 2b, 4b, 5b, 6b, 7, E-8b, and Z-8b (in part I) and
E-13, Z-13, E-14, Z-14, 15, 16, E-17, Z-17, and 23 (in part II);
1D NOE spectra for compounds 6b and 7 (in part I) and 15
and 16 (in part II); and molecular structures based on
molecular mechanics and semiempirical calculations for
compounds 6b and 7 (in part I) and 15 and 16 (in part II).
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: jyoti@boc.uu.se
■
Author Contributions
†M.K. and S.E. contributed equally.
(8) HyperChem Pro, version 6.0; Hypercube Inc.: Gainesville, FL,
2000.
Notes
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J.; Diez, E. J. Chem. Inf. Comput. Sci. 2004, 44, 1680−1685.
(b) Chimiche, R. R.; Ricerche, M. J. Chem. Inf. Comput. Sci. 1996,
36, 885−887.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Generous financial support from the Swedish Natural Science
■
́
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THEOCHEM 2006, 764, 161−166. (b) Cocivera, M.; Fyfe, C. A.;
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(c) Alexander, M. V.; Zhang, K.; Ivanov, A. V.; Ushakov, I. A.; Afonin,
A. V.; Petrushenko, K. B.; Li, S.; Ma, J. S.; Mikhaleva, A. I.; Trofimov,
B. A.; Yang, G. Monatsh. Chem. 2009, 140, 1475−1480. (d) Karabatsos,
G. J.; Taller, R. A. Tetrahedron 1968, 24, 3347−3360. (e) Jordan, E.;
Hauser, C. R. J. Am. Chem. Soc. 1936, 58, 1304−1305.
Research Council (Vetenskapsradet), the Swedish Foundation
̊
for Strategic Research (Stiftelsen for Strategisk Forskning), the
̈
EU-FP6-funded RIGHT Project (Project LSHB-CT-2004-
005276), and Uppsala University is gratefully acknowledged.
We also thank one of the referees of JOC for a kind discussion
and comment on the six-membered TS involving water.
(11) Zhou, C.; Chattopadhyaya, J. Curr. Opin. Drug Discovery Dev.
2009, 12, 876−898.
DEDICATION
■
This work is dedicated to Professor C. B. Reese (FRS) on the
occasion of his 84th birthday.
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