Unusual strain-releasing nucleophilic rearrangement of a bicyclo[2.2.1]heptane system to a cyclohexenyl derivative

Article abstract of DOI:10.1021/jo301871d

We report an unusual strain-releasing reaction of 1-mesyloxy-8,7- dimethylbicyclo[2.2.1]heptane (3) by a base-promoted substitution at the chiral C3 followed by spontaneous concerted ring opening involving the most strained C2-C3-C4 bonds (with bond angle 94°) and the C2 bridgehead leading to anti-endo elimination of the C1-mesyloxy group by the conjugate base of adenine or thymine to give two diastereomeric C3′(S) and C3′(R) derivatives of 1-thyminyl and 9-adeninyl cyclohexene: 3 → T-4a + T-4b and 3 → A-5a + A-5b. These products have been unambiguously characterized by detailed 1D and 2D NMR (J-coupling constants and nOe analysis), mass, and UV spectroscopy. Evidence has been presented suggesting that the origin of these diastereomeric C3′(S) and C3′(R) derivatives of 1-thyminyl and 9-adeninyl cyclohexene from 3 is most probably a rearrangement mechanism of a trigonal bipyramidal intermediate formed in the S_N2 displacement-ring-opening reaction.

Full text of DOI:10.1021/jo301871d

Article
pubs.acs.org/joc
Unusual Strain-Releasing Nucleophilic Rearrangement of a
Bicyclo[2.2.1]heptane System to a Cyclohexenyl Derivative
Mansoureh Karimiahmadabadi, 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 an unusual strain-releasing reaction of 1-
mesyloxy-8,7-dimethylbicyclo[2.2.1]heptane (3) by a base-pro-
moted substitution at the chiral C3 followed by spontaneous
concerted ring opening involving the most strained C2−C3−C4
bonds (with bond angle 94°) and the C2 bridgehead leading to
anti−endo elimination of the C1-mesyloxy group by the conjugate
base of adenine or thymine to give two diastereomeric C3′(S) and
C3′(R) derivatives of 1-thyminyl and 9-adeninyl cyclohexene: 3 →
T-4a + T-4b and 3 → A-5a + A-5b. These products have been
unambiguously characterized by detailed 1D and 2D NMR (J-
coupling constants and nOe analysis), mass, and UV spectroscopy.
Evidence has been presented suggesting that the origin of these
diastereomeric C3′(S) and C3′(R) derivatives of 1-thyminyl and 9-
adeninyl cyclohexene from 3 is most probably a rearrangement
mechanism of a trigonal bipyramidal intermediate formed in the SN2 displacement-ring-opening reaction.
structure7 shows that there is considerable angular strain built in
the system, and all bond angles are less than the tetrahedral,
INTRODUCTION
■
Recently, we have completed the synthesis of the conformation-
particularly the C2−C3−C4 angle which is only 94° and most
strained. Despite this angular strain, the nucleophilic attack at C3
without a ″keto″ is unprecedented.6a,8 The base-induced
bimolecular nucleophilic displacements involving a C3 bridge-
carbon can occur only with inversion of configuration (SN2)
which has been known to be rare,6a,8 except in 7-
halonorbornane,9 7-halo-2-norbornanones,10 and 7-halo-2,3-
norbornadiones,11 simply because all groups involved in this
system cannot be planar in the trigonal bipyramidal transition
state8 owing to, first, angular constraints and, second, to the exo
C8-methyl and C1-hydrogen in compound 3 which sterically
hinder the approach of the incoming nucleophile.6a,8−11 In
contradistinction, the base-promoted 1,2-elimination from both
endo- and exo-2-bicyclo[2.2.1]heptyl halides and arenesulfonates
has been studied12a,b which gives competitive syn−endo and
anti−exo-H 1,2-elimination products along with a small amount
of solvolytic elimination product (nortricyclene).
We argued that since the approach of the nucleophile 1-
thyminyl (i.e., T−) or 9-adeninyl (i.e., A−) for any back-side
attack is sterically not likely in compound 3 the only possible way
for the T−/A− nucleophile to approach is the “in-line attack”
from the front-side to C3, i.e., 180° for the Nu−···C3···C2 bond
angle (i.e., opposite to C8-methyl and C1-hydrogen in
compound 3); hence, it is far from clear as to why two
ally locked dimethylbicyclo[2.2.1]heptane (1)1 to transform it to
the corresponding carbocyclic nucleosides for incorporating
them into oligo-DNA or -RNA to study their biochemical
properties as antisense agent2a−i and small interfering RNAs.2j−l
This led us to attempt coupling of thymine and adenine base to
the dimethylbicyclo[2.2.1]heptane system (2 or 3 in Scheme 1)
both through Mitsunobu coupling condition3a−h and by direct
displacement4a−c of a triflate or mesylate at C1 at various
temperatures and solvent conditions, but none of these worked.
We would like to report here an elusive strain-releasing
reaction5a−c of the bicyclo[2.2.1]heptane derivative [1-mesyloxy-
8,7-dimethylbicyclo[2.2.1]heptane (3)] under our coupling
conditions (DMF, NaH, reflux for 24 h under N2) by a
concerted base-promoted nucleophilic attack at the chiral C3 by
the conjugate base of adenine (A) or thymine (T), followed by
spontaneous ring opening of the most strained C2−C3−C4
(Scheme 1 for numbering) bonds leading to elimination of the
C1-mesylate group to give two diastereomeric products of
C3′(S) and C3′(R) derivatives of 1-thyminyl or 9-adeninyl
cyclohexene: 3 → T-4a + T-4b and 3 → A-5a + A-5b. It is
noteworthy that the first example of the cleavage of the C2−C3
bond releasing the angular strain of the C2−C3−C4 angle is
found in the solvolysis (AcOH/25 °C) of 2-tosyl-bicyclo[2.1.1]-
hexenes involving a nonclassical carbonium ion.6a,b
In contrast, we herein show the base-promoted cleavage of the
C2−C3 bond, releasing the angular strain of the C2−C3−C4
angle,5a−c which is devoid of a ″keto″ functionality.6a,8 The X-ray
Received: August 30, 2012
Published: October 12, 2012
© 2012 American Chemical Society
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Scheme 1. Syntheses of 1-((4R,7R,8S)-(S)-Benzyloxy(4-benzyloxymethyl-7,8-dimethylcyclohex-1-en-4-yl)methyl)thymine (T-
4a), 1-((4R,7R,8S)-(R)-Benzyloxy(4-benzyloxymethyl-7,8-dimethylcyclohex-1-en-4-yl)methyl)thymine (T-4b), 9-((4R,7R,8S)-
(S)-Benzyloxy(4-benzyloxymethyl-7,8-dimethylcyclohex-1-en-4-yl)methyl)adenine (A-5a), 9-((4R,7R,8S)-(R)-Benzyloxy(4-
a
benzyloxymethyl-7,8-dimethylcyclohex-1-en-4-yl)methyl)adenine (A-5b)
a
Intermediate (A1) shows the “in-line front-side attack” by the conjugate base of thymine, whereas Intermediate (A2) shows an identical SN2 attack
by the conjugate base of adenine, followed by the concerted cleavage of the C2−C3 bond and elimination of mesylate.
diastereomeric C3′(S) and C3′(R) products in ca. 1:1 ratio were
obtained in our reaction unless the C3 center was racemized
before or after the ring-opening reaction. These are the reasons
why we considered it important to rigorously characterize the
reaction products and establish this unusual reaction course of
the bicyclo[2.2.1]heptane chemistry and discuss briefly a
plausible mechanistic outcome.
bicyclo[2.2.1]heptane (2). Accurate determination of the
stereochemistry of the chiral centers in the hydroxy precursor,
compound 2, is important in view of the rearrangement that takes
place on its mesylate 3 upon treatment with the 9-adenylate or 1-
thyminalate ion. This has been determined by nOe experiments
and coupling constant analysis: irradiation of H1 [Figure S6,
Panel A1, SI (Supporting Information)] showed strong nOe
enhancements for H3 (3.0%, dH1,H3(calc) ≈ 2.4 Å), 8-Me (2.7%,
dH1,8Me(calc) ≈ 2.6 Å), and H2 (2.4%, dH1,H2(calc) ≈ 2.5 Å), which
proved that 8Me is on the same face of the 2,4-fused carbocycle as
the H3-(S) and H2-(R), which indicated that the C8 center has
(R) configuration. On the other hand, the weak nOe enhance-
ment for H8 (0.6%, dH1,H8 ≈ 3 Å) upon H1 irradiation showed
that H1 and H8 are trans oriented.
In addition, irradiation of 8Me (Figure S6, Panel A2, SI)
showed 1.3% nOe enhancement for H5 (d8Me,H5 ≈ 2.4 Å) which
confirmed that 8Me and H5 are located on the same face. So,
these assignments confirmed the (R)-configuration at the C8
center and (S)-configuration at the C1 center, which means that
the C1-hydroxy group in 2 is in endo orientation. The assignment
of these configurations for 2 is also consistent with what has been
assigned for the precursor: 3-(benzyloxy)-4-[benzyloxymethyl]-
RESULTS AND DISCUSSION
■
1.0. Reaction of 1-Mesyloxy-8,7-dimethylbicyclo-
[2.2.1]heptane (3) with Thymine (T). 1.1. Preparation of
1-Mesyloxy-8,7-dimethylbicyclo[2.2.1]heptane (3). Appropri-
ately protected (1S,2R,3S,4R,7R,8R)-3-(benzyloxy)-4-[benzy-
loxymethyl]-1-mesyloxy-8,7-dimethylbicyclo[2.2.1]heptane (3)
was prepared from (1S,2R,3S,4R,7R,8R)-3-(benzyloxy)-4-[ben-
zyloxymethyl]-1-[(4-methyloxyphenyl)methoxy]-8,7-
dimethylbicyclo[2.2.1]heptane (1) (Scheme 1). Deprotection of
the p-methoxybenzyl (PMB) group at C1 from 1 using 2%
trifluoroacetic acid (TFA) in dichloromethane (DCM) at room
temperature afforded the intermediate 2 (71%, [α]D25 °C = 31°).
1.2. Stereochemical Assignment of (1S,2R,3S,4R,7R,8R)-3-
(Benzyloxy)-4-[benzyloxymethyl]-1-hydroxyl-8,7-dimethyl-
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1-[(4-methyloxyphenyl)methoxy]-8,7-dimethylbicyclo[2.2.1]-
heptane (1).1 Quiet expectedly, the nOe assignments confirmed
the preservation of the configuration at the C1 center during the
deprotection of the p-methoxybenzyl (PMB) group 1 (1 → 2).
These results have been further evidenced by the observed
3
coupling constants in that the JH2,H3 = 3.5
0.2 Hz for
compound 2 corresponded to the torsion angle ϕ H2−C2−C3−H3
=
60 2°, thereby confirming the H2 and H3 have cis orientation
with 1(S) configuration. On the other hand, the 3JH1,H8 = 4.8
0.2 Hz (Figure S7, SI), corresponding to a torsion for
ϕH1−C1−C8−H8 of 132
2°, thereby indicating a transoid
orientation between H1 and H8, which confirms the C1(S)
and C8(R) configurations
After esterification of the 1-hydroxyl group of
(1S,2R,3S,4R,7R,8R)-3-(benzyloxy)-4-(benzyloxymethyl)-1-hy-
droxy-8,7-dimethylbicyclo[2.2.1]heptane (2 → 3) with methyl-
sulfonyl chloride in dry pyridine at 0 °C, the key intermediate 3
(82%, [α]D25 °C = 28.5°) was obtained, which was also confirmed
by NMR (Figure S8−S13, SI) and mass spectroscopy.
1.3. Reaction of 1-Mesyloxy-8,7-dimethylbicyclo[2.2.1]-
heptane (3) with Thymine or Adenine. The key precursor 3
was subjected to the coupling reaction with thymine or adenine
in anhydrous DMF in the presence of NaH as a base at 150 °C for
∼24 h. The products formed in the reaction mixture were
separated by silica gel chromatography into pure components
with an isolated yield of 26% each for T-4a and T-4b in a yield of
25% each for A-5a and A-5b. The NMR assignments showed
unexpected thymine (T)−N1 or adenine (A)−N9 nucleophilic
attack at C3′ (Scheme 1) with cleavage of the most strained C2−
C3 bond and concomitant elimination of C1′-mesylate to give a
diastereomerically pure C1′−C2′ double bond containing T-4a
and T-4b or A-5a and A-5b, respectively.
The NMR evidence that proves the proposed structure of the
two isolated diastereomeric olefinic products T-4a ([α]D25 °C =
14.5°) and T-4b ([α]D25 °C = 19.3°), on one hand, and A-5a
([α]D25 °C = 16°) and A-5b ([α]D25 °C = 23.3°), on the other
hand, is based on J-coupling, HMBC, and nOe data as well as on
UV and high-resolution mass spectrometry. Comparison of
[α]D25 °C values shows that T-4a and A-5a have a lower value
compared to those of T-4b and A-5b. Immediate inspection of
the chemical shifts (δ) and coupling constants (Table 1) gave a
clear hint that T-4a, T-4b and A-5a, A-5b (for atom numbering,
see Scheme 1 and legend) are likely to be similar because of the
fact that in all four compounds their H1′, H2′ double triplet
(olefinic system) and H3′ singlets appear with very similar
chemical shifts (Table 1). The fact that the δ H3′ of all four
compounds, T-4a (δ 5.90), T-4b (δ 5.86) and A-5a (δ 5.98), A-
5b (δ 5.97), appear as a sharp singlet which has moved downfield
by ∼2.51 ppm in comparison with the parent 1-mesyloxy-8,7-
3
dimethylbicyclo[2.2.1]heptane (3) JH2,H3 ≈ 3 Hz suggested
quite early that the C2′−C3′ covalent bond is broken as a result
of a new C3′−N bond formation owing to the nucleophilic attack
by the conjugate base of the 1-thyminyl and 9-adeninyl moiety
(see below). Further detailed comparison of 500 and 600 MHz
NMR properties (Table 1) for thyminylcyclohexenyl derivatives
T-4a and T-4b and adeninylcyclohexenyl derivatives A-5a and A-
5b shows that the dispersion of the chemical shifts of H5′, H5″ in
T-4a [Δδ(H5′−H5″) = 0.16 ppm] and A-5a [Δδ(H5′−H5″) = ∼0
ppm] is very small, whereas the corresponding chemical shifts in
the case of T-4b [Δδ(H5′−H5″) = 0.87 ppm] and A-5b [Δδ(H5′−H5″)
= 1.0 ppm] are more dispersed, thereby showing that the
anisotropic effects of the nucleobase on H5′/5″ in T-4a/A-5a are
very similar because they experience very similar diamagnetic
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Table 2. Determination of Various Interproton Distances as Well as of Glycosyl Conformation Based on 1D nOe Experiments of
Compounds T-4a/T-4b/A-5a and A-5b (Actual 1D nOe Experiments Have Been Summarized in SD1)
effect owing to the fact that they are spatially just under the
nucleobase (see the nOe effect), which tentatively settles the
configuration at C3′ to be (S). In addition, δ H7′ and δ H8′ have
isochronous chemical shifts in T-4a (δ 2.33) and A-5a (δ 2.51),
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Figure 1. Panel A: Newman projections across the C1′−C2′ (A2) and C4′−C6′ (A1) bonds in T-4a are shown (for all other compounds, see Table S1
(SI) for coupling constants and corresponding dihedral angles). Projection A2 through the C1′−C2′ bond shows an experimental 3JH1′,H2′ = 10 0.2 Hz,
giving torsion, ϕH1′−C1′−C2′−H2′ = 15.5 2°, and allylic, 4JH2′, H8′ = 1.83 0.2 Hz, which in turn shows in projection A1 that ϕC3′−C4′−C6″−H6″ = 57.9 2°
and ϕC5′−C4′−C6′−H6′ = 57.3 2°. Panel B: Newman projections across the C7′−C2′ (A2) and C4′−C8′ (A1) bonds in T-4a are shown. Projection A2
through the C2′−C7′ bond shows an experimental 3JH2′,H7′ = 2.4 0.2 Hz, giving torsion, ϕH2′−C2′−C7′−H7′ = 118.8 2°, and allylic, 4JH1′, H7′ = 2 0.2
Hz, which in turn shows in projection A1 that the ϕC3′−C4′−C8′−8′Me = 49.5 2°, ϕ8′Me−C8′−C4′−C5′ = 68.8 2°, and ϕC5′−C4′−C8′−H8′ = 49.9 2°.
whereas the corresponding chemical shifts are relatively more
dispersed in T-4b (δ 1.91 for H7′ and δ 2.14 for H8′) and A-5b
(δ 1.46 for H7′ and δ 2.24 for H8′).
Since the NMR and nOe assignments are very closely similar
for T-4a and A-5a and T-4b and A-5b, we restrict the discussion
of our NMR observations and resulting arguments for
unambiguous characterization only for pure T-4a, as an example,
which also apply for the other compounds. Full NMR
assignments for all of the other products (T-4b, A-5a, and A-
5b in comparison with T-4a) are given in Table 1 based on actual
spectra for all diastereomers of A and T which can be found in the
SI.
Our detailed NMR studies on all of these four compounds
have allowed us to assign the chemical shift of each proton
resonance and their J-coupled multiplicities (Table 1), which in
turn have allowed us to ascertain steric proximities of each proton
by detailed nOe studies. This information showed that the only
difference between T-4a and T-4b isomers on one hand and A-
5a and A-5b, on the other, arises from the configuration
differences at the C3′ center. The detailed nOe studies have led
us to assign 3′(S) configuration for T-4a and A-5a and 3′(R)
configuration for T-4b and A-5b.
NMR of Compound Thyminylcyclohexen Derivative T-4a.
(a) An important observation is the disappearance of a broad
3JH2,H3 ≈ 3 Hz coupling constant between H2 and H3,
found in the starting 1-mesyloxy-8,7-dimethylbicyclo-
[2.2.1]heptane (3) and the appearance of a sharp singlet
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at δ 5.90 in the 1H NMR spectrum (500 MHz) for H3′ in
the product T-4a (Figure S14, SI): It should be noted that
a cisoid orientation of H2 and H3 with ϕ[H2−C2−C3−H3] of
60 5° corresponds to a 3JH2,H3 ≈ 3 Hz, whereas a transoid
H2 and H3 corresponds to ϕ[H2−C2−C3−H3] = 180 5°,
which corresponds to a 3JH2,H3 = 11.16 0.2 Hz. Since a
clean singlet for H3′ is only observed (see SI), it clearly
suggests that the vicinal H2′ is absent, which in turn leads
us to conclude that there is no covalent carbon−carbon
bond between C2′−C3′, thereby explaining the absence of
vicinal 3JH2′,H3′ coupling.
nor T-4b showed the bathochromic shift of the absorption
maxima expected for N3-alkylated pyrimidinones upon
increase of the pH16 (Figure S27, SI).
(1.4). Determination of C3′ Configuration in Diastereo-
meric 1-(Benzyloxy(4-benzyloxymethyl-7,8-dimethylcyclo-
hex-1-en-4-yl)methyl)thymine (T-4a and T-4b), 9-(Benzyloxy-
(4-benzyloxymethyl-7,8-dimethylcyclohex-1-en-4-yl)methyl)-
adenine (A-5a and A-5b), and Glycosyl Conformation
Assignment Through nOe Analysis. The stereochemistries of
all chiral centers in compounds T-4a, T-4b and A-5a, A-5b have
been determined by 1D nOe experiments which have been
summarized in Table 2. The detailed procedure, results, and
discussions of 1D nOe experiments can be however found in the
SI (see discussions for the nOe assignments under SD1 based on
Figures S26, S38, S47, and S58).
(b) On the other hand, the absorption of H2′ was evident
3
from its J-coupling with H1′, JH1′,H2′ = 10
0.2 Hz
corresponding to a torsion [ϕH1′−C1′−C2′−H2′ = 15.5 2°],
suggesting a cis orientation between H1′ and H2′. These
were further corroborated by the COSY spectrum (Figure
S21, Panel A1, SI) which showed a clear correlation
between H1′ and H2′, but no correlation was found
between H2′ and H3′.
1.5. Determination of Dihedral Angles through Analysis of
3
Three-Bond JHH by the Karplus Equation and the Newman
Projection for Rearranged Products. Since there are no vicinal
protons in the proximity of H3′, and it resonates as a singlet,
thereby proving the cleavage of the C2′−C3′ bond. On the basis
of the key observable J-coupling network, we describe here a
general proton−proton torsional framework, which is very
closely similar to all diastereomers (T-4a/T-4b/A-5a and A-5b)
using the Newman projection, taking compound T-4a as an
example, whereas the individual J-coupling network and the
corresponding dihedral angles for each of the isomers (T-4b, A-
5a and A-5b) are shown in Table S1 (SI) (for comparison),
including the Newman projections (Figure S22−S24, S33−S35,
and S45−S46, SI). In rearranged compound T-4a, the Newman
projections across the C1′−C2′ (projection A2) and C4′−C6′
(projection A1) are shown (Figure 1, Panel A). The
experimentally derived 3JH1′,H2′ = 10 0.2 Hz gives the dihedral
angle for the corresponding torsion, ϕH1′−C1′−C2′−H2′ = 15.5 2°,
and the allylic H2′ and H8′ coupling 4JH2′,H8′ of [4JH2′,H8′ = 1.83
0.2 Hz]. With these torsion angles fixed, we could calculate the
other significant torsions through modeling in HyperChem
(MM/Amber and semiempirical/AM1) which in turn shows
through projection A1 that the ϕC3′−C4′−C6′−H6′ = 57.9 2° and
(c) The presence of allylic H1′ and H7′ coupling [4JH1′,H7′ = 2
0.2 Hz] and also of the allylic H2′ and H8′ coupling
[4JH2′,H8′ of 1.83
0.2 Hz], as evidenced by detailed
decoupling experiments (Figure S23, SI), also shows the
covalent connectivity in the backbone C8′(H)−
C1′(H)C2′(H)−C7′(H).
(d) The presence of a three-bond J-coupling between H6′ and
H7′, 3JH6′,H7′ of 5.5 0.2 Hz, [ϕH6′−C6′−C7′−H7′ = 46 2°],
furthermore extends the backbone connectivity to
C6′(H2′)−C7′(H)−C2′(H)C1′(H)−C8′(H).
(e) Furthermore, we have observed two four-bond ″W″-
couplings,13 one between H2′ and H6′ (4JH2′,H6′ = 1.53
Hz) (Figure S24, SI), as well as a ″U″-type coupling14,15
between H6″ and H8′ (4JH6″,H8′ ≈ 1 Hz) (Figure S25, SI),
thereby showing that H2′ and H6′ are oriented on the β-
face, whereas H6″ and H8′ are on the α-face because the
H6′−C6′−C7′ and C7′−C2′−H2′ fragments in the
former and the H6″−C6′−C4′ and C4′−C8′−H8′
fragments in the latter are close to coplanar in an anti-
and cis-arrangement in ″W″ and ″U″ orientation,
respectively, which are prerequisites for proper orbital
alignment for the HCCCH fragments. The latter ″U″-type
coupling between H6″ and H8′ is particularly noteworthy
because it simply shows that the C4′ center is part of the
cyclohexene ring. Furthermore, the large allylic H2′−
C2′C1′−C8′−H8′ coupling of 1.83 0.2 Hz as well as
the allylic H1′−C1′C2′−C7′−H7′ coupling of 2 0.2
Hz show that both allylic C−H bonds are perpendicular to
the plane of the vinyl C−H group in the C1′C2′ double
bond, which altogether suggests that C6′−C4′−C8′−
C1′−C2′−C7′ constitutes a closed conformationally
constrained cyclohexene ring in T-4a.
ϕ
C5′−C4′−C6′−H6″ = 57.3 2°. In addition, projection B shows the
Newman projection across the C7′−C2′ (projection B2 in Figure
1) and C4′−C8′ (projection B1 in Figure 1) bonds. The
experimentally derived 3JH2′,H7′ = 2.4 0.2 Hz, which gives the
dihedral angle for the corresponding torsion, ϕH2′−C2′−C7′−H7′
=
118.8 2°, and the allylic H2′ and H8′ coupling [4JH2′, H8′ = 1.83
0.2 Hz ]. So, with these torsion angles fixed, we could
successfully calculate the other torsions through projection B1
that the ϕC3′−C4′−C8′−8′Me = 49.5 2°, ϕ8′Me−C8′−C4′−C5′ = 68.8
2°, and ϕC5′−C4′−C8′−H8′ = 49.9 2°.
Mechanism. Since the above NMR, UV, and mass
characterizations show that in each of the reactions two
diastereomers at the C3′ position are formed, we have performed
two sets of blank experiments to examine the origin of
intramolecular isomerization:
(f) The long-range 13C−1H connectivities (HMBC) of H3′
with C6-T and C2O(T) (Figure S21, Panel A3, SI)
confirm that the 1-thyminyl has formed a covalent bond
from its N1 to C3′ of the cyclohexene ring, as shown in T-
1
4a. On the other hand, the H−13C correlation in the
1. Treatment of pure T-4a or A-5a in an identical basic
condition (i.e., NaH in dry DMF, reflux for 24 h under
N2), followed by usual workup, as used for 3 → T-4a + T-
4b or 3 → A-5a + A-5b, gave us a full recovery of starting
material T-4a or A-5a without any contamination by other
isomers T-4b or A-5b. This suggests that no racemization
took place at C3′ after the nucleophilic ring-opening
reaction.
HMQC spectrum shows the connection between H1′ and
C1′ at δ 130.6 as well as between H2′ and C2′ at δ 131.6
(Figure S21, Panel A4, SI), thereby confirming the
presence of the olefinic bond, C1′C2′, as in compound
T-4a.
(g) pH-dependent UV studies corroborated the presence of
an N1 attached base since the UV spectra of neither T-4a
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Figure 2. Mechanistic rationale for the SN2 transition state, in which, upon nucleophilic attack at C3′ in compound 3 a putative trigonal bipyramidal
intermediate (A) is formed. The C2′−C3′ bond breaking is slower than the pseudorotation of the resulting pentavalent carbon in the transition state (A)
because of distorted geometry across C2−C3−C4 bonds, leading to scrambling at the chiral C3′ center (B). When the Nu−···C3···C2 bond forms ″in-
line attack” geometry, i.e., 180° bond angle, the scission of the departing C2′−C3′ bond takes place with the scrambled chirality at C3′ to give racemic
mixtures, T-4a + T-4b or A-5a + A-5b.
2. Treatment of 1-mesyloxy-8,7-dimethylbicyclo[2.2.1]-
heptane (3) in an identical basic condition (i.e., NaH in
dry DMF, reflux for 24 h under N2), but in the absence of
adenine or thymine, followed by usual workup, as used for
3 → T-4a + T-4b or 3 → A-5a + A-5b, did not give the
expected anti−endo 1,2-elimination product at C1−C8,
since no syn−exo product is possible in our system, as in 3.
Noteworthy is also the fact that no other product was
formed in the above reaction, thereby ruling out any
carbocation intermediate after fragmentation. The ab-
sence of any 1,2-elimination product is not perhaps
surprising in view of the fact that there is only one
report12a of base-promoted 1,2-elimination for endo-2-
bicyclo[2.2.1]heptyl halides and sulfonates, in which: (i)
no methyl substituent was present on either of the carbons
involved in the elimination reaction!; (ii) a strong soluble
base t-BuOK in DMSO or triglyme was used at a high
temperature;12a (iii) since the 8-Me substituent in our
system in compound 3 is exo, as evident from the nOe
contacts as well as from the 3JH1,H8 = 4.8 0.2 Hz (Figure
S7, SI) corresponding to a transoid torsion for
ϕH1−C1−C8−H8 of 132 2°, the H8 on the C8 center is
sterically hindered for a potential 1,2-elimination reaction
in our chemical framework, as in 3. This means, first, the
conjugate base of 1-thyminyl (i.e., T‑) or 9-adeninyl (i.e.,
A‑) formed under our reaction condition, which attacks at
C3′ as a nucleophile to give the trigonal−bipyramidal
intermediate, and, second, the cleavage of the most
strained C2−C3 bond takes place. It is clear that the
trigonal bipyramidal intermediate for carbon is well-
known for its stereochemical rigidity and high inversion
barrier and that the bond breaking has always been
assumed to take place before any inversion.17a,b We may
have however a unique case here in that we have observed
full recovery of starting material in all of our starting
molecules with their chiral centers intact, i.e., either from 3
or T-4a or T-4b or A-5a or A-5b, which means that in the
absence of T− or A− in the reaction mixture no racemization
event takes place under the present alkaline reaction
conditions.
intramolecular exchange (rearrangement)17d with “sufficient
lifetime” relative to dissociation of the C2−C3 bond to give the
pair of diastereomers at C3.17a The nucleophilic attack takes
place from the apical position to form the trigonal bipyramidal
intermediate (A) in which the departing C2−C3 bond takes up
only a distorted apical geometry which prevents an actual bond
breaking process from taking place because of the angular strain
through the C2−C3−C4 bonds (Figure 2). This in turn initiates
shape changes to take place just as in the trigonal bipyramidal
shaped pentavalent phosphorus compounds, in which two
equatorial groups become apical and two apical groups become
equatorial because of the low energy barrier, through a concerted
shortening of apical bonds and lengthening of equatorial bonds
until the leaving group takes up an apical position. This means
that the bond-breaking process involving the departing C2−C3
bond is slower than the inversion, and the relatively lower
inversion barriers of substituents make the interconversions
possible. So far, unlike other second and higher row elements
which show higher coordination number, carbon has been
assumed17c to have the stereochemical rigidity and high inversion
barrier for substituent rearrangement in the transition state of a
trigonal bipyramidal geometry resisting any displacement.17a−c
The present scrambling of chirality during the base-induced
rearrangement provides further evidence supporting some recent
work on the hypervalent carbon atom in the context of the rigid,
ball-in-a-box model in the SN2 transition state,17e penta- and
hexacoordinated carbon by experimental electron density
distribution analysis,17f as well as some other theoretical and
experimental evidence that points to the transient formation of
pentavalent carbon.17g
CONCLUSIONS
■
An unusual nucleophilic substitution at the chiral C3 leads to the
release of angular strain of C2−C3−C4 bonds (with bond angle
94°) of conformationally locked 1-mesyloxy-8,7-
dimethylbicyclo[2.2.1]heptane (3). The nucleophilic attack at
the C3 leads to anti−endo 1,2-elimination of the C1-mesyloxy
group by the conjugate base of adenine or thymine to give two
diastereomeric C3′(S) and C3′(R) derivatives of 1-thyminyl and
9-adeninyl cyclohexene: 3 → T-4a + T-4b and 3 → A-5a + A-5b.
These products have been unambiguously characterized by
detailed 1D and 2D NMR (J-resolved coupling constants and
nOe analysis), mass, and UV spectroscopy. The origin of these
diastereomeric C3′(S) and C3′(R) derivatives of 1-thyminyl and
9-adeninyl cyclohexene from 3 has been traced to a plausible
Clearly, given the above facts, it is likely that after the attack of
T− or A− at the C3 carbon center we have a trigonal−bipyramidal
intermediate, in which the racemization at C3 is likely to have
taken place through the formation of a species,17a,b which does
not have a chiral center any longer with a low energy barrier of
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clohex-1-en-4-yl)methyl)-thymine (T-4b). The compound 3 (20
mg, 45 μmol) was dissolved in anhydrous N,N-dimethylformamide (2
mL) and thymine (34.0 mg, 0.27 mmol), and NaH (9.6 mg, 0.4 mmol)
was added at room temperature. The reaction was stirred at 150 °C for
24 h. The mixture was dissolved in EtOAc and H2O and washed with
brine twice. The organic layer was separated, dried over MgSO4, and
concentrated. The crude product was chromatographed over silica gel
(0−40% EtOAc in petroleum ether, v/v) to give compound 4 as a
colorless oil (11.1 mg, 52%) as a separable mixture of T-4a (5.5 mg,
26%) and T-4b (5.5 mg, 26%).
rearrangement mechanism of the trigonal bipyramidal inter-
mediate formed in the SN2 displacement−ring-opening reaction.
EXPERIMENTAL SECTION
■
General Procedures. All reagents were the highest commercial
quality and were used without further purification. All nonaqueous
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 as visualizing agent and/or cerium−
ammonium−molybdate. Flash chromatography was performed using
T-4a: 1H NMR (500 MHz, CDCl3): δ 7.93 (1H, bs, NH), 7.12−7.21
(14H, m, aromatic), 7.12 (1H, d, J = 1 Hz, H6-T), 5.90 (1H, s, H3′), 5.47
(1H, dt, J1′,2′ = 10 Hz, JH2′, H7′ = 2.4, 4JH2′, H8′ = 1.83, H2′), 5.32 (1H, dt,
1
silica gel 60 (230−400 mesh). H and 13C NMR were obtained using
500 and 600 MHz instruments for 1H and 125 and 150 MHz for 13C.
The same spectrometers were used for the acquisition of the H−1H
1
J
1′,2′ = 10 Hz, JH1′, H8′ = 2.5, J1′,7′ = 2 Hz, H1′), 4.40 (1H, d, Jgem = 12 Hz,
homonuclear (COSY and nOe) and H−13C heteronuclear (HMQC
1
CH2Ph), 4.34 (1H, d, Jgem = 12 Hz, CH2Ph), 4.28 (2H, d, Jgem = 12 Hz,
CH2Ph), 3.39 (1H, d, Jgem = 9.5, H5′), 3.23 (1H, d, Jgem = 9.5, H5″), 2.33
(2H, m, H7′ & H8′), 2.03 (1H, dd, Jgem = 14.5, J6′,7′ = 5.5, H6′), 1.78
(3H, s, T-CH3), 1.21 (1H, dd, Jgem = 14.5, J6″,7′ = 10.7, H6″), 0.94 (3H, d,
J8′,Me = 7.5, 8′-CH3), 0.91 (3H, d, J 7′,Me = 6.6, 7′-CH3). 13C NMR (125
MHz): δ 163.2 (C4-T), 151.4 (C2-T), 138.0 (C6-T), 137.3, 136.6
(aromatic), 131.6 (C2′), 130.6 (C1′), 128.4, 128.3, 127.9, 127.6, 127.4,
127.2 (aromatic), 109.7 (C5-T), 87.6 (C3′), 74.9 (C5′), 73.3 (CH2Ph),
71.4 (CH2Ph), 45.2 (C4′), 35.6 (C8′), 35.1 (C6′), 28.4 (C7′), 22.2 (8′-
CH3), 15.4 (7′-CH3), 12.7 (T-CH3). MALDI-TOF m/z [M + Na]+
calcd for C29H34N2O4 Na 497.242, found 497.242.
and HMBC) correlations. Optical rotations were recorded on a
T
polarimeter, and values are reported as follows: [α]λ (c (g/100 mL),
solvent). The molecular modelings have been performed using
HyperChem Pro 6.018 using MM (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 have been obtained using the Karplus equation19
through the coupling constants (NMR data) input, whereas Hyper-
Chem was used where no coupling constant could be obtained. High-
resolution mass spectra (HRMS) with correct masses have been
obtained by MALDI-TOF mass spectroscopy.
T-4b: 1H NMR (600 MHz, CDCl3): δ 8.08 (1H, bs, NH), 7.76 (1H,
d, J = 1.2 Hz, H6-T), 7.17−7.27 (14H, m, aromatic), 5.86 (1H, s, H3′),
(1S,2R,3S,4R,7R,8R)-3-(Benzyloxy)-4-[benzyloxymethyl]-1-
hydroxyl-8,7-dimethylbicyclo[2.2.1]heptane (2). Compound 1
(100 mg, 0.20 mmol) was dissolved in 6 mL of dichloromethane and 2%
of trifluoroacetic acid. The solution was stirred at rt for 2 h, and then it
was neutralized with 0.05 mL of Et3N. Solvent was evaporated, and the
concentrate was purified by silica gel column chromatography (0−15%
EtOAc in petroleum ether, v/v) to give compound 2 as a colorless oil
(50.2 mg, 71%).
4
5.51 (1H, dt, J1′,2′ = 10.2 Hz, JH2′, H7′ = 2.4, JH2′, H8′ = 2.4, H2′), 5.33
(1H, dt, J1′,2′ = 10.2 Hz, 3JH1′, H8′ = 2.4, J1′,7′ = 1.8 Hz, H1′), 4.47 (1H, d,
Jgem = 12 Hz, CH2Ph), 4.37 (2H, ABq, Jgem = 12 Hz, CH2Ph), 4.25 (2H,
d, Jgem = 12 Hz, CH2Ph), 4.06 (1H, d, Jgem = 9 Hz, H5′), 3.18 (1H, d, Jgem
= 9 Hz, H5″), 2.14 (1H, m, H8′), 1.9 (1H, m, H7′), 1.88 (1H, dd, Jgem
=
13.8, J6′,7′ = 6.6, H6′), 1.36 (3H, s, T-CH3), 1.13 (1H, dd, Jgem = 13.8,
1H NMR (500 MHz, CDCl3): δ 7.18−7.23 (10H, m, aromatic), 4.38
(3H, ABq, Jgem = 12 Hz, CH2Ph), 4.27 (1H, d, Jgem = 12 Hz, CH2Ph),
3.61 (1H, m, H1), 3.49 (1H, d, Jgem = 9 Hz, H5), 3.41 (1H, d, Jgem = 9 Hz,
J
6″,7′ = 7.8, H6″), 0.97 (3H, d, JH8′,Me = 7.8 Hz, 8′-CH3), 0.91 (3H, d, J
H7′,Me = 6.5 Hz, 7′-CH3). 13C NMR (150 MHz): δ 163.2 (C4-T), 152.4
(C2-T), 139.4 (C6-T), 132.2 (C2′), 129.5 (C1′), 132.2, 129.5, 128.4,
127.9, 127.8, 127.6, 127.5 (aromatic), 109.5 (C5-T), 86.5 (C3′), 73.5
(CH2Ph), 73.3 (C5′), 70.7 (CH2Ph), 45.7 (C4′), 36.2 (C8′), 34.3
(C6′), 27.1 (C7′), 22.2 (7′-CH3), 16.4 (8′-CH3), 11.9 (T-CH3).
MALDI-TOF m/z [M+Na]+ calcd for C29H34N2O4 Na 497.242, found
497.243.
9-((4R,7R,8S)-(S)-Benzyloxy-(4-benzyloxymethyl-7,8-dime-
thylcyclohex-1-en-4-yl)methyl)-adenine (A-5a) and 9-
((4R,7R,8S)-(R)-Benzyloxy-(4-benzyloxymethyl-7,8-dimethylcy-
clohex-1-en-4-yl)methyl)-adenine. Compound 3 (20 mg, 45 μmol)
was dissolved in anhydrous N,N-dimethylformamide (2 mL) and
adenine (36.0 mg, 0.27 mmol), and NaH (9.6 mg, 0.4 mmol) was added
at room temperature. The reaction was stirred at 150 °C for 24 h. The
mixture was dissolved in EtOAc and H2O and washed with brine twice.
The organic layer was separated, dried over MgSO4, and concentrated.
The crude product was chromatographed over silica gel (0−70% EtOAc
in petroleum ether, v/v) to give compound 5 as a colorless oil (10.9 mg,
50%) as a separable mixture of A-5a (5.45 mg, 25%) and A-5b (5.45 mg,
25%).
H5′), 3.40 (1H, d, J3,2 = 3.5 Hz, H3), 2.46 (1H, m, H7), 2.20 (1H, t, J1,2
3 Hz, J2,3 = 3.5 Hz, H2), 2.11 (1H, t, Jgem = 11.5 Hz, H6), 1.48 (1H, m,
H8), 1.23 (3H, d, J = 7.5 Hz, 7-CH3), 1.13 (1H, dd, Jgem = 12 Hz, J6,7
=
=
5.5 Hz, H6′), 0.94 (3H, d, J = 7.0 Hz, 8-CH3). 13C NMR (125 MHz): δ
138.8, 128.3, 128.2, 127.5, 127.4, 127.1 (aromatic), 84.0 (C3), 81.1
(C1), 73.4 (CH2Ph), 71.2 (CH2Ph), 70.8 (C5), 53.5 (C4), 48.7 (C2),
47.3 (C8), 42.1 (C6), 31.2 (C7), 18.4 (7-CH3), 13.6 (8-CH3). MALDI-
TOF m/z [M + Na]+ calcd for C24H30O3 Na 389.209, found 389.208.
(1S,2R,3S,4R,7R,8R)-3-(Benzyloxy)-4-[benzyloxymethyl]-1-
mesyloxy-8,7-dimethylbicyclo[2.2.1]heptane (3). Compound 2
(50 mg, 0.14 mmol) was dissolved in dry pyridine (2 mL).
Methanosulfonyl chloride (16.2 μL, 0.21 mmol) was added at 0 °C.
The reaction was stirred at room temperature for 1 h. The reaction
mixture was partitioned between EtOAc and H2O. The organic layer was
washed with brine twice and dried over MgSO4, filtered, and
concentrated.
The concentrate was purified by silica gel column chromatography
(0−10% EtOAc/petroleum ether, v/v) to give 3 as a colorless oil (53
mg, 82%).
A-5a: 1H NMR (500 MHz, CDCl3): δ 8.29 (1H, s, H2-A), 7.96 (1H,
s, H8-A), 7.01−7.20 (15H, m, aromatic), 5.98 (1H, s, H3′), 5.69 (2H, bs,
NH2), 5.51 (1H, dt, J1′,2′ = 10.38, Hz, J2′,8′ = 1.58 Hz, J2′,7′ = 1.89 Hz,
H2′), 5.37 (1H, dt, J1′,2′ = 10.38 Hz, J1′,7′ = 1.89 Hz, J1′,8′ = 2.21 Hz, H1′),
4.30 (1H, d, Jgem = 11.5 Hz, CH2Ph), 4.26 (1H, d, Jgem = 11.5 Hz,
CH2Ph), 4.16 (1H, d, Jgem = 12 Hz, CH2Ph), 4.03 (1H, d, Jgem = 12 Hz,
CH2Ph), 3.23 (2H, s, H5′, H5″), 2.51 (2H, m, H7′ & H8′), 2.03 (1H,
dd, Jgem = 14.5, J6′,7′ = 4.5, 4J2′,6′ = 1.5, H6′), 1.25 (1H, H6″), 0.91 (6H, t,
J8′,Me = 8, J7′,Me = 6.6, 8′-CH3, 7′-CH3). 13C NMR (125 MHz): δ 155.2
(C6-A), 152.6 (C2-A), 140.9 (C8-A), 138.3, 136.9 (aromatic), 132.2
(C2′), 131.3 (C1′), 128.6, 127.9, 127.7, 127.1, 127.6, 127.2 (aromatic),
87.6 (C3′), 75.2 (C5′), 73.7 (CH2Ph), 71.5 (CH2Ph), 45.5 (C4′), 36.0
(C6′), 35.6 (C8′), 30.0 (C7′), 28.6 (7′-CH3), 15.9 (8′-CH3). MALDI-
TOF m/z [M + H]+ calcd for C29H34N5O2 484.271, found 484.271.
A-5b :1H NMR (500 MHz, CDCl3): δ 8.58 (1H, s, H8-A), 8.30 (1H,
s, H2-A), 7.15−7.22 (15H, m, aromatic), 6.16 (2H, bs, NH2), 5.97 (1H,
1H NMR (600 MHz, CDCl3): δ 7.18−7.24 (15H, m, aromatic), 4.37
(3H, m, Jgem = 12 Hz, CH2Ph, H1), 4.27 (1H, d, Jgem = 12 Hz, CH2Ph),
3.47 (1H, bs, J2,3 ≈ 3 Hz, H3), 3.48 (1H, d, Jgem = 9 Hz, H5), 3.41 (1H, d,
Jgem = 9 Hz, H5′), 2.93 (3H, s, Me), 2.53 (1H, m, H7), 2.50 (1H, t, H2),
2.12 (1H, t, Jgem = 11.4 Hz, H6), 1.80 (1H, t, J1,8 = 5.4 Hz, H8), 1.18 (3H,
d, J = 7.2 Hz, 7-CH3), 1.14 (1H, dd, Jgem = 12 Hz, J6′,7 = 6.6 Hz, H6′),
0.99 (3H, d, J = 7.2 Hz, 8-CH3). 13C NMR (150 MHz): δ 138.9, 138.6,
128.8, 128.7, 128.0, 127.9, 127.6 (aromatic), 87.9 (C1), 83.3 (C3), 73.8
(CH2Ph), 71.8 (CH2Ph), 70.6 (C5), 53.5 (C4), 48.1 (C2), 44.9 (C8),
42.0 (C6), 38.6 (CH3-Ms), 31.4 (C7), 18.3 (7-CH3), 16.7 (8-CH3).
MALDI-TOF m/z [M + Na]+ calcd for C25H32O5 SNa 467.187, found
467.188.
1-((4R,7R,8S)-(S)-Benzyloxy-(4-benzyloxymethyl-7,8-dime-
thylcyclohex-1-en-4-yl)methyl)-thymine (T-4a) and 1-
((4R,7R,8S)-(R)-Benzyloxy-(4-benzyloxymethyl-7,8-dimethylcy-
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s, H3′), 5.50 (1H, dt, J1′,2′ = 9.5 Hz, 4J2′,8′ = 2.44 Hz, H2′), 5.37 (1H, dt,
Maddileti, S.; Wihlborg, A. K.; Erlinge, M.; Malmsjo, T. K.; Harden
Boyer, J. L.; Jacobson, K. A. J. Med. Chem. 2002, 45, 208−218. (c) Ludek,
O. R.; Marquez, E. Synthesis 2007, 22, 3451−3460. (d) Ludek, O. R.;
Meier, C. Eur. J. Org. Chem. 2006, 941−946. (e) Lee, K.; Cass, C.;
Jacobson, K. A. Org. Lett. 2002, 4, 597−599. (f) Lee, K.; Ravi, G.; Ji, X.
D.; Marquez, V. E.; Jacobson, K. A. Bioorg. Med. Chem. Lett. 2001, 11,
1333−1337. (g) Elhalem, E.; Pujol, C. A; Damonte, E. B.; Rodriguez, J.
B. Tetrahedron 2010, 66, 3332−3340. (h) Kumamoto, H.; Deguchi, K.;
Wagata, t.; Furuya, Y.; Odanaka, Y. Tetrahedron 2009, 65, 8007−8013.
(4) (a) Kim, H. S.; Jacobson, K. A. Org. Lett. 2003, 5 (10), 1665−1668.
(b) Bremond, P.; Audran, G.; Monti, H.; Clercq, E. D. Synthesis 2008,
20, 3253−3260. (c) Hartung, R. E.; Paquette, L. A. Synthesis 2005, 19,
3209−3218.
J
1′,2′ = 9.5 Hz, J1′,7′ = 2.14 Hz, J1′,8′ = 2.44 Hz, H1′), 4.53 (2H, s, CH2′Ph),
4.42 (1H, d, Jgem = 11.5 Hz, CH2Ph), 4.23 (1H, d, Jgem = 9.5, H5′), 3.92
(1H, d, Jgem = 11.5 Hz, CH2Ph), 3.23 (1H, d, Jgem = 9.5, H5″), 2.24 (1H,
m, H8′), 1.78 (1H, dd, Jgem = 14.5, J6′,7′ = 5.5, 4J2′,6′ = 0.9, H6′), 1.46 (1H,
m, H7′), 1.08 (1H, dd, Jgem = 14.5, J6′,7′ = 7.5, H6″), 1.04 (3H, d, J8′,Me
=
7.5, 8′-CH3), 0.65 (3H, d, J8′,Me = 7, 7′-CH3). 13C NMR (125 MHz): δ
151.1 (C2-A), 144.0 (C8-A), 132.6 (C2′), 129.8 (C1′), 128.5, 128.2,
127.8, 127.7, 127.3 (aromatic), 85.3 (C3′), 73.6 (C5′), 70.7 (CH2Ph),
45.4 (C4′), 37.1 (C8′), 36.2 (C6′), 26.8 (C7′), 21.9 (7′-CH3), 16.9 (8′-
CH3). MALDI-TOF m/z [M + H]+ calcd for C29H34N5O2 484.271,
found 484.270.
ASSOCIATED CONTENT
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3512. (b) Mehta, G.; Mohal, N.; Lakshminath, S. Tetrahedron Lett. 2002,
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■
S
* Supporting Information
1H, 13C NMR, COSY, HMQC, and HMBC spectra for
compounds 2, 3, T-4a, T-4b, A-5a, and A-5b (SI); 1H-
homodecoupling for compounds T-4a, T-4b, A-5a, and A-5b;
3
1D nOe spectra for compounds 2 and JHH vicinal coupling
constant of compounds T-4a, T-4b, A-5a, and A-5b along with
Newman projections of these compounds; molecular structures
based on MM and semiempirical calculations for compounds T-
4a, T-4b, A-5a, and A-5b. UV spectra of compound T-4a, T-4b,
A-5a, and A-5b in various pH. This material is available free of
charge via the Internet at http://pubs.acs.org.
(7) Newton, M. G.; Pantaleo, N. S.; Kirbawy, S.; Allinger, N. L. J. Am.
Chem. Soc. 1978, 100, 2176−2180.
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(9) Lumb, J. T.; Whitham, G. H. Chem. Commun. 1966, 400.
(10) Nash, J. J.; Waugh, T; Morrison, H. Tetrahedron Lett. 1998, 39,
6449−6452.
(11) Jenkins, M. N.; Nash, J. J.; Morrison, H. Tetrahedron Lett. 2002,
43, 3773−3775.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jyoti@boc.uu.se
■
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
Generous financial support from the Swedish Natural Science
Research Council (Vetenskapsradet), the Swedish Foundation
for Strategic Research (Stiftelsen for Strategisk Forskning), and
the EU-FP6 funded RIGHT and NATT projects are acknowl-
edged.
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