Mechanistic studies in the radical induced DNA strand cleavage - Formation and reactivity of the radical cation intermediate

Article abstract of DOI:10.1016/S0040-4020(00)00335-5

In order to understand the heterolytic cleavage of 4'-DNA radical 1 and the regioselective attack of nucleophiles at the intermediate DNA radical cation 3, the chemistry of model radical 8 was studied. It turned out that the heterolytic cleavage in water is favored over homolysis because of the effective solvation of the ions 9 and 10. The regioselectivity of the nucleophilic attack at radical cation 10 can be explained with the valence bond configuration mixing (VBCM) model. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00335-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4117±4128
Mechanistic Studies in the Radical Induced
DNA Strand CleavageÐFormation and Reactivity
of the Radical Cation Intermediate
Ralf Glatthar,a Martin Spichty,a Andreas Gugger,a Rohit Batra,a Wolfgang Damm,a
a,
Matthias Mohr,b Hendrik Zipseb, and Bernd Giese
*
*
aDepartment of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
bDepartment Chemie, Ludwig-Maximilians-University of Munich, Butenandtstrasse 5-13, D-81377 Munich, Germany
Dedicated to Professor Rolf Huisgen on the occasion of his 80th birthday
Received 22 March 2000; accepted 14 April 2000
AbstractÐIn order to understand the heterolytic cleavage of 40-DNA radical 1 and the regioselective attack of nucleophiles at the
intermediate DNA radical cation 3, the chemistry of model radical 8 was studied. It turned out that the heterolytic cleavage in water is
favored over homolysis because of the effective solvation of the ions 9 and 10. The regioselectivity of the nucleophilic attack at radical cation
10 can be explained with the valence bond con®guration mixing (VBCM) model. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
time.1 Schulte-Frohlinde and von Sonntag suggested a
heterolytic scission of a 40-DNA radical 1 forming the
phosphorylated strand 2 and the DNA radical cation 3
(Scheme 1).2
The mechanism of the spontaneous cleavage of 40-DNA
radical 1 has been of interest in our laboratory for some
Scheme 1. General overview of the reaction pathways of C40-DNA radical and of its model system 8.
Keywords: 40-DNA radical; radical cation; regioselective addition; calculations; solvent effect; VBCM.
* Corresponding authors. aFax: 141-61-2671105; e-mail: bernd.giese@unibas.ch bFax: 149-89-2180-7738; e-mail: zipse@cup.uni-muenchen.de
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00335-5

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R. Glatthar et al. / Tetrahedron 56 (2000) 4117±4128
Scheme 2. Synthesis of the radical precursors 7 and 16.
We have shown that radical cation 3 can be reduced to the
corresponding enol ether 4 by electron transfer through
DNA3 or trapped by nucleophilic solvents (H2O or
MeOH) forming the regioisomeric adduct radicals 5 and
6, with 5 as the major trapping product.4,5 In this publica-
tion, we try to answer the following questions: Why is the
phosphate group cleaved heterolytically and not homolyti-
cally, and why is the formation of adduct radical 5 preferred
over that of adduct radical 6? We simulated the cleavage of
the 40-DNA radical with model system 8 which is suitable
also for theoretical investigations. Radical 8 was generated
by photolysis of ketone 7 and studied by electron spin reso-
nance (ESR). In order to answer the ®rst question (hetero-
lysis or homolysis) the thermodynamic aspects of the two
cleavage pathways of radical 8 were investigated with quan-
tum chemical calculations and Monte-Carlo solution simu-
lations. To ®nd an answer for the second question
(regioselectivity of the nucleophilic attack), trapping experi-
ments of radical cation 10 with different nucleophiles were
performed. The experimental observations were then
compared with the results of quantum chemical calcula-
tions.
The stereochemistry of the diastereomeric compounds can
be assigned by NOE or NOESY experiments and the cis-g-
effect.7
Generation of radical 8
Photoinduced Norrish Type I cleavage of pivaloyl ketone 7
and subsequent decarbonylation leads to the butyl radical
t
and radical 8. To study this Norrish Type I cleavage in more
detail, ESR measurements were performed with the two
precursors 7 and 16 which differ from each other by the
substituent at C3 (Scheme 3).
Both precursors were irradiated in benzene solution at
280 K in the cavity of an ESR spectrometer. The photolysis
of 16 (RˆOTBDMS) resulted in the formation of two radi-
cal species. Besides the well known hyper®ne coupling
t
pattern of butyl radical,8 we detected the ESR signal of
radical 17. The g-factor of radical 17 is 2.0031 which is a
typical value for C2-centered tetrahydofuran-2-yl radicals.9
The isotropic hyper®ne coupling constants and their assign-
ment to the hydrogen atoms of 17 are shown in Table 1. The
coupling constants of 17 are very similar to those published
by Grossi and coworkers for an analogous radical (SCH3
instead of OTBDMS, see Table 1).10 To further ensure the
identity of radical 17 and the correct assignment, we calcu-
lated the coupling constants of radical 17 (with TMS instead
of TBDMS) with the protocol UB3LYP/6-31Gp//UHF/3-
21Gp which produced reliable results for a wide range of
organic radicals.11 The calculated coupling constants are in
good agreement with the experimental values (Table 1) and
con®rm the formation of radical 17 by photolysis of precur-
sor 16.
Results and Discussion
Synthesis of the radical precursors 7 and 16
t
The butyl ketones 7 and 16 were synthesized via nitrile
oxide cycloaddition to furan starting from 2,2-dimethyl-
propionaldehyde oxime,6 subsequent hydrogenation,
methylation and separation of the diastereomers 15a and
15b by ¯ash chromatography. Silylation and phosphoryl-
ation yielded radical precursors 7 and 16 (Scheme 2).
When we repeated the experiment with precursor 7
Scheme 3. Norrish Type I cleavage of pivaloyl ketones 7 and 16.

R. Glatthar et al. / Tetrahedron 56 (2000) 4117±4128
4119
Table 1. Experimental and calculated isotropic hyper®ne coupling constants (in mT) of radicals 17 and 18
Exp.
Lit.a
Calc.b
Exp.
Lit.c
Calc.d
Me (3H)
1.96
1.09
±
±
0.13
0.31
1.95
1.50
±
±
0.06
0.32
1.68
1.15
0.03
0.04
0.17
0.28
Me (3H)
1.30
0.19
1.31
3.51
1.30
0.17
1.37
3.50
1.31
0.35
21.61
3.32
C3±H (1H)
C4±Ha (1H)
C4±Hb (1H)
C5±Ha (1H)
C5±Hb (1H)
C3±H (1H)
C4±H (1H)
C5±H (2H)
a SMe instead of OTBDMS (see Ref. 10).
b TMS instead of TBDMS.
c Ref. 10.
d Ref. 11.
(RˆOPO(OEt)2), we detected also two radical species: The
tbutyl radical and allyl radical 18 (g-factorˆ2.0029). Allyl
radical 18 could be identi®ed due to the results of earlier
ESR experiments of Grossi and coworkers in which 18 was
generated by an alternative route.10 In our experiment, allyl
radical 18 is formed by elimination of diethyl phosphoric
acid from radical 8 that can occur either by a two step
mechanism or a concerted mechanism.12,13 In Scheme 3
the two step mechanism is illustrated for radical 8. First,
heterolytic b-bond cleavage leads to phosphate anion 9
and radical cation 10.7 Subsequent deprotonation of radical
cation 10 yields allyl radical 18. Summing up the ESR
experiments, we have shown that with precursor 16
(unfavorable leaving group OTBDMS at C3) the direct
product of the Norrish Type I cleavage, radical 17, could
be detected. In contrast, with precursor 7 (leaving group
OPO(OEt)2 at C3) the elimination product 18 of the initially
generated radical 8 was observed.
Heterolytic versus homolytic b-bond cleavage of
radical 8
Various experimental studies have shown that the phosphate
group in b-(phosphatoxy)radicals is cleaved off heterolyti-
cally.1±5,7,14 The question arises why this b-bond cleavage
does not occur homolytically? Motivated by this question,
we investigated the thermodynamic aspects for these two
cleavage pathways of radical 8. We calculated the energy
differences between the products of the heterolysis
Scheme 4. Possible pathways for b-bond cleavage: homolysis versus heterolysis.
Scheme 5. Reaction of radical cation 10 with the anionic nucleophiles CH3O2 (a) and CN2 (b) and the neutral nucleophile dimethylamine (c) in the presence of
Bu3SnH.

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R. Glatthar et al. / Tetrahedron 56 (2000) 4117±4128
Table 2. Photolysis of the radical precursor 7 in the presence of different nucleophiles (reaction conditions: conc. 7ˆ0.018 M21 in methanol, 0.18 M21
nucleophile, 0.18 M21 Bu3SnH, hn (.280 nm), 258C, 1 h)
Entry
Nucleophile
Regioselectivity 21:22
cis/trans ratio of 21
Yield (%)
a
b
c
CH3O2
CN2
Me2NH
3.5:1
.50:1
.50:1
5:1
2:1
100:1
55
56
56
(8!9110) and homolysis (8!19120) in the gas phase and
addition products 11c and 12c have to abstract a hydrogen
atom and to donate a proton in order to form the neutral
products 21c and 22c.
in water (Scheme 4).
In the gas phase, the formation of charged species is an
unfavorable process. Accordingly, ab initio PMP2/6-
311Gpp//UHF/6-311Gpp calculations for the cleavage
process of radical 8 predict that the products of the homo-
lysis (19120) are 77.6 kcal/mol more stable than those of
the heterolysis (9110). In solution, the energetic contribu-
tions of the solute±solvent interactions have to be taken into
account. Therefore, empirical Monte-Carlo simulations15
were performed to estimate the in¯uence of H2O as solvent.
The results of the simulations show that the ionic products
9110 are stronger solvated by 134 kcal/mol than the neutral
products 19120. By summing up the gas phase energies and
the solvation energies of the products, the heterolysis
(8!9110) becomes more favorable by 56.4 kcal/mol in
H2O than the homolytic cleavage (8!19120). Thus, with
radical 8 the heterolytic cleavage is favored over homolysis
because of the effective solvation of the ionic products
9110.
The experimental results are summarized in Table 2. Only
the C3 addition product 21 was detected in the reactions of
cyanide and dimethylamine, while both regioisomers were
formed in the reaction with methoxide in a ratio of
21:22ˆ3.5:1. This regioselectivity is similar to that
observed by Arnold16 and Roth20 for alkene radical cation
reactions with nucleophiles.
Regioisomer 21 can be formed as cis or trans diastereo-
isomer. With all three nucleophiles the cis isomer of product
21 was formed in excess because the substituent (Nu) in
radical 11 induces
a trans-attack of the H-donor
Bu3SnH.21 As expected, the cis±trans ratio of the diastereo-
isomers increased with increasing bulk of the substituent
from 2:1 (NuˆCN) via 5:1 (NuˆOCH3) to 100:1
(NuˆNMe2).
At ®rst glance one might expect the regioselectivity of the
nucleophilic attack at 10 to be determined through electro-
static effects as well as frontier orbital interactions. In the
former case, the center of positive charge in 10 will be
attacked preferentially while in the latter case the center
of largest LUMO coef®cient will be the most reactive. In
order to evaluate these possibilities, radical cation 10 was
optimized at the BHLYP/6-311G(d,p) level of theory.
Using this geometry the charge and spin density distribution
as well as the LUMO coef®cients was analyzed at the
BHLYP/6-31G(d,p) level of theory for the carbon atoms
C2 and C3 as well as the ring oxygen atom (Table 3).
Regioselectivity of the nucleophilic attack
Radical cations are known to undergo a variety of reactions,
such as addition of nucleophiles, reduction by electron
transfer, carbon±carbon bond cleavage and deprotonation
reactions.16±20 We focused our attention on the nucleophilic
trapping reaction. In order to elucidate the trapping regios-
electivity of radical cation 10 as a function of the nucleo-
phile, the precursor 7 was irradiated in the presence of
sodium methoxide, potassium cyanide, or dimethylamine.
The intermediate radicals 11 and 12, formed after addition
of the anionic nucleophiles, were quenched with Bu3SnH
yielding the products 21 (C3 addition) and 22 (C2 addition)
(Scheme 5). The reaction of radical cation 10 with dimethyl-
amine is slightly more complex because the initially formed
Most of the positive charge is located at carbon atom
C2 while the spin density is mainly located at C3 and O1.
This implies that electrostatic interactions will guide
Table 3. Spin densities, atomic charges, and LUMO coef®cients for radical cation 10, and spin densities for the corresponding neutral triplet (BHLYP/6-
31G(d,p)//BHLYP/6-311G(d,p) values)
Radical cation
Atomic charge
Neutral triplet
Spin density
Position
Spin density
LUMO coef®cient
O1
C2
C3
0.20
0.02
0.81
20.26
10.56
20.06
20.23
10.53
20.35
0.17
0.83
1.06

R. Glatthar et al. / Tetrahedron 56 (2000) 4117±4128
4121
Assuming Eq. (1) to be applicable for addition to the C2 as
well as the C3 position in 10, we can express the regioselec-
tivity for nucleophilic addition as a combination of three
reactivity factors DDE( f ), DDE(DERP), and DDE(B):
DDEpꢀC2±C3† ˆ DDEꢀ f† 1 DDEꢀDERP† 2 DDEꢀB†
ꢀ2†
ꢀ3†
ꢀ4†
ꢀ5†
DDEꢀ f† ˆ ꢀ f0C2 2 f0C3†G
DDꢀDERP† ˆ ‰ꢀ0:5 2 f0C2†DERCP2 2 ꢀ0:5 2 f0C3†DE Š
C3
RP
DDEꢀB† ˆ ꢀBC2 2 BC3†
All factors leading to negative values of DDEp(C2±C3)
re¯ect preferential formation of the C3 addition product
11. As outlined before22 the ®rst of these factors DDE( f )
can be correlated with the spin density at C2 and C3 after
one electron reduction and excitation to the triplet state. The
f0 factors will be smaller, hence the reaction barrier lower
for the position of higher spin density. According to the
triplet spin densities calculated at the BHLYP/6-
31G(d,p)//BHLYP/6-311G(d,p) level of theory (Table 3)
the C3 position is slightly more reactive than the C2 posi-
tion. The difference between these two centers appears to
derive from the fact that some of the spin density is also
Scheme 6. Valence bond con®guration mixing (VBCM) diagram for the
addition of nucleophiles to radical cation 10.
nucleophilic attack into the C2 position. Assuming
HOMO(nucelophile)±LUMO(radical cation) interactions
to be dominant, leads to a similar result: the LUMO coef®-
cient is signi®cantly larger at C2 (10.53) than at C3
(20.35). Taken together we have to recognize that neither
FMO nor electrostatic arguments give any indication for the
preferential formation of the C3 addition products.
Recently the regioselectivity observed in nucleophilic addi-
tion reactions to radical cations of heterocyclic aromatic
compounds has been studied using the valence bond con-
®guration mixing (VBCM) model.22,23 The VBCM model
assumes the reaction barrier to be the result of the crossing
of the reactant and product state curves (Scheme 6).
The reactant state refers to the separate reactants at in®nite
separation. The product state is described by a newly formed
polar covalent bond between the nucleophile and the alkene
radical cation. Formally this state derives from the reactant
state through: (i) one electron oxidation of the nucleophile;
(ii) one electron reduction of the radical cation to yield the
neutral alkene; and (iii) unpairing of the newly formed
alkene p-bond. This latter step can be approximated by
assuming conversion to the triplet state. The energetic
demand for all three steps are usually summed up in one
excitation energy factor G (Scheme 6). What fraction f0 of
the initial gap G enters into the barrier depends on the steep-
ness of the state curves, steeper curves leading to smaller
factors f0 and smaller barriers. As usual,22,23 the factor f0
integrates the steepness of the reactant and product curves
into an effective parameter. The transition state for the reac-
tion is located below the actual curve crossing point, the
energy difference being de®ned by the transition state reso-
nance energy B. Finally, the reaction barrier DEp is also
in¯uenced by the reaction exothermicity DERP. An approx-
imate equation22 integrating all four factors is thus:
Figure 1. Structures of the C3-addition products 11 and the C2-addition
products 12 formed through reaction of radical cation 10 with (a) methox-
ide, (b) cyanide and (c) dimethylamine. Only the most favorable conforma-
tions for each product are shown.
DEp ˆ f0G 1 ꢀ0:5 2 f0†DERP 2 B
ꢀ1†

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R. Glatthar et al. / Tetrahedron 56 (2000) 4117±4128
Table 4. Absolute and relative reaction energies (all energies are in kcal/mol) (in parenthesis) for the gas phase reaction of 10 with (a) methoxide, (b) cyanide,
and (c) dimethylamine [BHLYP/6-311G(d,p) level of theory]
Nucleophile
CH3O2
System
DEtot
DH298
DG298
DG(SP)298
11a (C3)
12a (C2)
2173.7 (10.5)
2174.2 (0.0)
2168.9 (11.5)
2170.4 (0.0)
2156.7 (11.0)
2157.7 (0.0)
2154.8 (10.7)
2155.5 (0.0)
CN2
11b (C3)
12b (C2)
2148.0 (0.0)
2140.5 (17.5)
2145.4 (0.0)
2139.0 (16.4)
2127.1 (0.0)
2133.6 (16.5)
2133.5 (0.0)
2126.8 (16.7)
HNMe2
11c (C3)
12c (C2)
219.8 (10.3)
220.1 (0.0)
215.8 (11.2)
217.0 (0.0)
21.9 (10.8)
22.7 (0.0)
22.8 (10.2)
23.0 (0.0)
located on the ring oxygen atom adjacent to C2 and that this
delocalization reduces the C2 spin density. The difference
( f0C22f0C3) is solely dependent on the characteristics of the
radical cation and thus independent of the nucleophile. We
may therefore conclude that the reactivity factor DDE( f )
points to preferred addition to C3 of radical cation 10 for
all nucleophiles. The difference in resonance energies
DDE(B) has been shown to be dependent on the LUMO
coef®cients of radical cation 10.22 Using the data given in
Table 3 we see that addition to the C2 position is preferred
in this case. Again, this argument is solely dependent on the
characteristics of radical cation 10 and thus independent of
the choice of nucleophile. Considering only the reactivity
factors DDE( f ) and DDE(B), we must conclude that no clear
preference exists for addition to either the C2 or the C3
position in radical cation 10. This conclusions also suggests
that the third reactivity factor DDE(DERP) might be mainly
responsible for the observed regioselectivities. Under the
condition that the f0 factors are smaller than 0.5, Eq. (4)
implies that formation of the more stable regioisomer will
be accompanied by a lower reaction barrier. The magnitude
of DDE(DERP) depends directly on the relative stability of
the C3 and C2 addition products 11 and 12, respectively. We
therefore studied the addition products obtained from reac-
tion of 10 with (a) methoxide, (b) cyanide, and (c) dimethyl-
amine at the BHLYP/6-311G(d,p) level of theory. The
structures of the C2 and C3 addition products for these
three nucleophiles are shown in Fig. 1 (only the ener-
getically most favorable conformations are shown), and
the absolute and relative reaction energies for the addition
reaction have been collected in Table 4.
addition of the BHLYP/6-31pG(d,p) thermochemical
corrections gives slightly different free enthalpies
DG(SP)298. These differ, however, only marginally from
the free enthalpy differences calculated at the BHLYP/
6-31pG(d,p) level (Table 4). Single point calculations
using the even larger aug-cc-pVTZ basis set were performed
for the dimethylamine adducts 11c and 12c, but the relative
energy changes not signi®cantly. It decreases by only
0.2 kcal/mol so that 11c and 12c become equal in
energy. This indicates that the BHLYP/aug-cc-pVDZ
single point energies are suf®ciently accurate for the present
purpose.
We can thus conclude that gas phase calculations predict the
C2 and C3 addition products of methoxide and dimethyl-
amine to be of similar stability while a clear preference for
C3 addition is predicted for cyanide. This result can be
understood on the basis of two electronic effects: (a) radical
stability and (b) anomeric effects. With focus on the local
environment of the radical center the C3 addition products
are tertiary alkyl radicals with additional stabilization
through the ring oxygen atom while the C2 addition
products are secondary alkyl radicals. Depending on the
nucleophile of choice, the C2 addition products might,
however, be stabilized through anomeric and exoanomeric
effects. The preferred conformer found for 12a does indeed
allow for both stereoelectronic effects to be present. We
might, however, also consider the much lower dipole
moments of the C2 addition products 12a and 12c to be
the source of stabilization relative to the corresponding C3
addition products. This type of stabilization appears to be
unavailable for cyanide addition product 12b. The different
dipole moments calculated in the gas phase (Table 5) also
suggest that solvent effects will lead to signi®cant changes
in the relative energies between C2/C3 regioisomers.
Formation of the C2 addition products is slightly preferred
for the nucleophiles methoxide and dimethylamine while
cyanide strongly prefers addition to the C3 position in the
gas phase. This conclusion does not depend on whether
energies, enthalpies or free enthalpies are considered.
Combination of single point energies calculated at the
BHLYP/aug-cc-pVDZ//BHLYP/6-311G(d,p) level and
The PCM continuum solvation method24 was used to
explore the different solvation free enthalpies for the gas
phase structures shown in Fig. 1 in methanol (eˆ32.6).
Table 5. Gas phase dipole moments and relative free enthalpies (all energies are in kcal/mol) in methanol solution for the addition products formed in the
reaction of 10 with (a) methoxide, (b) cyanide, and (c) dimethylamine [PCM/BHLYP/6-311G(d,p)//BHLYP/6-311G(d,p)]
Nucleophile
CH3O2
System
m [D]
DDG298 (SP) (in MeOH)
DDG298 (in MeOH)
11a (C3)
12a (C2)
2.6
0.6
10.3
0.0
10.3
0.0
CN2
11b (C3)
12b (C2)
3.7
4.4
0.0
17.0
0.0
16.9
HNMe2
11c (C3)
12c (C2)
5.8
3.5
0.0
15.4
0.0
15.3

R. Glatthar et al. / Tetrahedron 56 (2000) 4117±4128
4123
The resulting differences in free enthalpies of solvation
DGsolv were combined with the gas phase free enthalpy
differences DG(SP)298 from Table 4 to obtain an estimate
for the free enthalpy differences DDG298(SP) in methanol
solution at 298 K (Table 5). Addition of the two ionic
nucleophiles methoxide and cyanide appears to proceed
with similar regioselectivity in the gas phase and in metha-
nol solution. The situation is, however, considerably differ-
ent for addition of dimethylamine. In this latter case, the C3
addition product 11c is better solvated than 12c by more
than 5 kcal/mol, leading to a completely different relative
product stability in solution than in the gas phase. In how far
these large differences in free energy of solvation are due to
the use of gas phase structures was probed by reoptimization
of all structures shown in Fig. 1 in the presence of the PCM
solvent model. Only small structural relaxation can be noted
under these conditions and the calculated free energy differ-
ences DDG298 using relaxed structures are quite close to
those calculated for the gas phase structures (Table 5).
Considering the predicted differences in reaction energies
in Table 5, we can therefore conclude that the third reac-
tivity factor DDE(DERP) is favorable for C3 addition of
cyanide and dimethylamine, while no clear regiochemical
preference exists for addition of methoxide. Gratifyingly,
the experimentally observed regioselectivities are not too
far from what would be predicted from consideration of
the product stabilities alone. This implies that the in¯u-
ence of the other two reactivity factors DDE( f ) and
DDE(B) cannot be too large in addition reactions to radical
cation 10.
Scheme 7. Conformers for the calculation of the isotropic hyper®ne
coupling constants of radical 23.
four different ring conformers of radical 23 were calculated
with the method UB3LYP/6-31G(d)//UHF/3-21G(d).11
Scheme 7 shows these four conformers 23a±d in a Newman
projection along the C3±C2 bond. Additionally the relative
UB3LYP/6-31G(d)//UHF/3-21G(d) energies are listed
below. The lowest energy is found for the conformer 23a
which pro®ts from a stabilizing interaction of the single
occupied molecular orbital (SOMO) with the sp-orbital of
the C3±O bond. The least stable conformer is 23d with
eclipsed methyl and OTMS group. Finally, the isotropic
hyper®ne coupling constants given in Table 1 were calcu-
lated by averaging over all four conformers. The contribu-
tion of each conformer to the mean value was determined
with a Boltzmann distribution using the relative UB3LYP/
6-31G(d)//UHF/3-21G(d) energies.
Conclusion
Generation of the tetrahydrofuran-2-yl radical 8 through
photoinduced Norrish I cleavage is rapidly followed by
heterolytic elimination of phosphate (8!10). In benzene
as solvent, deprotonation of radical cation 10 yields the
corresponding allyl radical 18. Using the unfavorable
leaving group TBDMSO as b-substituent no elimination
can be observed. Calculations show that in the gas phase
the heterolytic elimination process is strongly disfavored in
comparison to the homolytic b-bond cleavage, whereas in
polar solution the heterolysis dominates over homolysis due
to the effective solvation of the charged products of the
heterolysis. The radical cation 10 formed in the heterolysis
was trapped by anionic as well as neutral nucleophiles. The
regioselectivities observed in the trapping step are not in
agreement with the charge distribution in radical cation
10, but mainly re¯ect the stabilities of the primary addition
products.
For the calculation of the gas phase energy difference
between the products of the heterolysis (9110) and homo-
lysis (19120), the ethyl groups in the phosphate moieties
were replaced by methyl groups to save computational time.
All products were fully optimized on the unrestricted
Hartree±Fock level with the basis set 6-311G(d,p). The
gas phase energies were determined by single point, spin
projected26 Mo¤ ller-Plesset second order perturbation
calculations27 using the basis set 6-311G(d,p). The
atomic charges were calculated with the CHELPG pro-
cedure.28
The reaction of radical cation 10 with methoxide, cyanide,
and dimethylamine has been studied using the hybrid
density functional BHandHLYP29 in combination with the
6-311G(d,p) basis set. This method has been used success-
fully before in studies of alkene radical cations with nucleo-
philes and will be designated `BHLYP/6-311G(d,p)'.30
Using these geometries single point energies have been
calculated with the same density functional but the slightly
larger aug-cc-pVDZ and, in part, aug-cc-pVTZ basis sets.31
Due to known problems with diffuse basis functions, the
spin and charge distribution as well as the LUMO
coef®cients have been calculated at the BHLYP/
6-31G(d,p)//BHLYP/6-311G(d,p) level of theory. Atomic
charges have been obtained by ®tting the molecular
Computational procedures
Quantum chemical calculations
All ab initio and DFT calculations were carried out with the
program Gaussian94 and Gaussian98.25 For the calcu-
lation of the isotropic hyper®ne coupling constants of
radical 17, we replaced the TBDMS group by a TMS (see
radical 23, Scheme 7). In order to take into account the
¯exibility of the ring system, the coupling constants of

4124
R. Glatthar et al. / Tetrahedron 56 (2000) 4117±4128
electrostatic potential using the CHELPG procedure. The
LUMO coef®cients refer to the 2PZ component of the
6-31G split valence basis set. Using the 3PZ coef®cients,
the same trends are observed.
sized or commercially available references and quanti®ed
using internal calibration.
General procedure for ESR measurements of precursors
7 and 16
Monte-Carlo solution simulations
In a typical experiment ,150 mg of the precursor were
dissolved in benzene (1 ml). The resulting solution was
deoxygenated by bubbling argon through the solution for
15 min. After sealing the quartz tube, the sample was cooled
down to 280 K in the ESR probe head and irradiated using
the Hg±Xe high-pressure lamp of Hanovia. The in situ
formed radicals were identi®ed directly by the resulting
The simulations were carried out with the program boss
3.4.32 The solvent was represented by a cubic box (side
Ê
lengthˆ25 A) containing 512 TIP4P water molecules at
298 K and 1 atm. Free energies of solvation changes were
calculated for the interconversions of 10 to 13 and 9 to 14
(with methyl instead of ethyl in the phosphate moieties).
The mutations took place within 20 steps by gradually
converting the UHF/6-311G(d,p) optimized geometries,
t
ESR spectra. The g-factor of the butyl radical (2.0028)8
was used as internal reference to determine the g-factors
of radicals 17 and 18.
the
UMP2/6-311G(d,p)//UHF/6-311G(d,p)
atomic
CHELPG charges (see above) and the standard Lennard±
Jones parameters into each other. Each step consisted of
2£106 con®gurations for equilibration followed by 4£106
con®gurations for averaging.
Synthesis of the radical precursor
2,2-Dimethyl-propionaldehyde oxime. To a solution of
pivalaldehyde (50.0 g, 580 mmol) in 1/1 EtOH/H2O
(240 ml) with ice (250 g) and NH2OH´HCl (44.3 g,
638 mmol) NaOH (58.0 g, 1.45 mol) as a 50% solution
and ice alternatively were added in order to keep the
temperature at 258C. After stirring for 2 h the reaction
mixture was extracted with Et2O (1£500 ml). The cooled
aqueous phase was neutralized with conc. HCl and extracted
with Et2O (2£500 ml). The combined organic layers were
dried over MgSO4 and evaporated in vacuo yielding the
oxime (38.6 g, 66%) as a colorless solid: 1H NMR
(300 MHz, CDCl3) d 9.04 (s, 1H), 7.36 (s, 1H), 1.11 (s,
9H); 13C NMR (75.5 MHz, CDCl3) d 159.1, 33.6, 27.3; IR
(KBr) 3329, 2964, 1872, 1702, 1648, 1463, 1391, 1366,
1305, 1206, 948 cm21; MS (EI) m/z 86, 85, 84, 73, 69, 68,
58, 57, 56, 55, 53, 52, 51, 50, 44, 43, 42, 41. Anal. Calcd for
C5H11NO [101.15]: C, 59.37; H, 10.96; N, 13.85; O, 15.82.
Found: C, 59.12; H, 11.21; N, 13.73; O, 15.75.
Experimental
General experimental information
All reagents are commercially available from Fluka Chemie
Co. and Aldrich Chemical Co. and used without further
puri®cation. Et2O and THF were distilled from NaH. All
temperatures and boiling points (bp) are uncorrected. The
reactions were carried out under argon (Ar) with the exclu-
sion of moisture. Flash-chromatography was conducted
with silica gel C 560 KV of Chemische Fabrik Uetikon
and silica gel 60 of Merck Co using the indicated and freshly
distilled solvents. NMR spectra: Varian Gemini 300 or
Bruker AMX 400 (1H, 13C and 31P with tetramethysilane,
chloroform-d3 as internal and triphenyl phosphate (-18) as
external standard; relative stereochemistry by NOEDIF or
NOESY experiments). ESR spectra: Bruker ESP-300. IR
spectra: Perkin±Elmer 1600 Series FT-IR. MS: VG
70-250 (for FAB with 3-nitrobenzyl alcohol as matrix),
Finnigan MAT 312 or Hewlett±Packard 5890 Series; GC/
MS using a Hewlett±Packard 5970A or 5971 mass selective
detector. UV/VIS-spectrometer: Perkin±Elmer Lamda II.
Photolysis: Oriel 68810 with Osram 500 W mercury arc
high-pressure lamp in combination with a 280 nm cut-off
®lter. For in situ generation of the radicals observed during
ESR measurements: Hanovia 977-B1 (1000 W) Hg±Xe
high pressure lamp with a water cooled IR-Filter UG-5 of
Schott.
1-Chloro-2,2-dimethyl-propan-1-one oxime. To a solution
of 2,2-dimethylpropionaldehyde oxime (32.7 g, 323 mmol)
in dry DMF (250 ml) was added 1/6 (,8 g) of the amount of
N-chlorosuccinimide (46.2 g, 339 mmol). HCl as gas
(,20 ml) was bubbled through the solution to initiate the
reaction indicated by the arising blue color of the solution.
The rest of the succinimide was added in portions with
intermediate cooling to keep the temperature below 358C.
After stirring for 2 h the reaction mixture was poured on ice
water (700 ml) and the aqueous phase was extracted with
Et2O (2£350 ml). After washing with H2O (1£600 ml) the
combined organic layers were dried over MgSO4 and
concentrated in vacuo yielding the hydroxy iminoylchloride
1
(41.8 g, 95%) as a pale yellow solid: H NMR (300 MHz,
General procedure for photolysis of precursors 7 and 16
CDCl3) d 9.23 (s, 1H), 1.27 (s, 9H); 13C NMR (75.5 MHz,
CDCl3) d 150.0, 39.8, 27.8; IR (KCl) 3329, 2976, 1622,
1480, 1461, 1427, 1396, 1366, 1254, 1045, 1009,
973 cm21; MS (EI) m/z 100, 99, 84, 69, 68, 67, 57, 56, 55,
54, 53, 52, 51, 50, 49, 43, 42, 41. Anal. Calcd for
C5H10ClNO [135.59]: C, 44.29; H, 7.43; N, 10.33; O,
11.80. Found: C, 45.30; H, 7.81; N, 10.07; O, 12.63.
A solution of 10±20 mg of the precursor 7 or 16 in 3 ml
MeOH was deoxygenated in a quartz-cuvette by bubbling
argon through it for 15 min. Undecane as internal standard,
a 10-fold excess of tributyltinhydride as H-donor and a
10-fold excess of the desired nucleophile was added.
Irradiations were carried out for 1 h at 258C using an
Osram high-pressure mercury arc lamp (500 W, 280 nm
cut-off ®lter). The irradiation mixtures were analyzed and
identi®ed without work-up directly by GC with the synthe-
3-tert-Butyl-3a,6a-dihydrofuro[2,3-]isoxazole (13). To a
solution of 1-chloro-2,2-dimethyl-propan-1-one oxime
(17.0 g, 125 mmol) in furan (1000 ml) was added over a

R. Glatthar et al. / Tetrahedron 56 (2000) 4117±4128
4125
period of 26 h by a syringe pump NEt3 (25.4 g, 251 mmol)
in furan (60 ml). After the completed addition and stirring
for additional three days by total enclosure of light the
reaction mixture was concentrated in vacuo. The residue
was dissolved in Et2O (750 ml) and washed with sat.
NaHCO3 solution (1£750 ml). After extracting the aqueous
phase with Et2O (2£750 ml) the organic layers were
combined, dried over MgSO4 and concentrated in vacuo.
The residue was puri®ed by chromatography (Uetikon,
pentane/tbutylmethyl ether 20/1!10/1) giving compound
layers were dried over MgSO4 and concentrated in vacuo.
The diastereomers were separated and puri®ed by chroma-
tography (Merck, toluene/acetone 40/1!20/1) giving
compound 15a (2.83 g, 43%) and 15b (1.34 g, 20%) as
1
colorless oils: 15a: H NMR (300 MHz, CDCl3) d 4.31
(ddd, Jˆ4.8, 3.3, 1.4 Hz, 1H), 4.17 (ddd, Jˆ10.8, 8.1,
5.9 Hz, 1H), 4.08 (td, Jˆ8.3, 2.2 Hz, 1H), 3.03 (dd, Jˆ
3.2, 1.7 Hz, 1H), 2.22±2.09 (m, 1H), 1.94 (dddd, Jˆ13.1,
6.0, 2.3, 1.2 Hz, 1H), 1.28 (s, 3H), 1.24 (s, 9H); 13C NMR
(75.5 MHz, CDCl3) d 220.3, 95.5, 78.6, 67.4, 45.4, 32.3,
26.1, 25.8; IR (NaCl) 3492, 2973, 2880, 1687, 1483,
1456, 1391, 1365, 1315, 1294, 1220, 1179, 1146, 1117,
1091, 1049, 1035, 985 cm21 MS (EI) m/z 186 (M1), 171,
129, 102, 101, 87, 85, 84, 83, 73, 71, 69, 59, 58, 57, 56, 55,
53, 45, 44, 43, 42, 41. Anal. Calcd for C10H18O3 [186.25]: C,
64.49; H, 9.74; O, 25.77. Found: C, 64.26; H, 9.73; O, 25.69.
15b: 1H NMR (300 MHz, CDCl3) d 4.30 (td, Jˆ7.0, 3.0 Hz,
1H), 4.02 (td, Jˆ8.3, 5.6 Hz, 1H), 3.89 (dt, Jˆ8.6, 7.4 Hz,
1H), 2.91 (d, Jˆ3.1 Hz, 1H), 2.15±2.04 (m, 1H), 1.95 (ddd,
Jˆ15.4, 12.5, 4 Hz, 1H), 1.31 (s, 3H), 1.24 (s, 9H); 13C
NMR (75.5 MHz, CDCl3) d 220.8, 90.7, 75.8, 64.6, 45.0,
31.7, 26.1, 20.5; IR (NaCl) 3456, 2956, 2875, 1691, 1483,
1
13 (8.90 g, 43%) as a colorless solid: H NMR (300 MHz,
CDCl3) d 6.55 (dt, Jˆ3.1, 0.7 Hz, 1H), 5.84 (d, Jˆ8.8 Hz,
1H), 5.76 (ddd, Jˆ8.8, 2.5, 1.1 Hz, 1H), 5.31 (t, Jˆ2.6 Hz,
1H); 1.29 (s, 9H); 13C NMR (75.5 MHz, CDCl3) d 162.3,
148.6, 101.2, 89.5, 86.8, 33.1, 29.0; IR (KBr) 3100, 2970,
2907, 2872, 1607, 1480, 1463, 1397, 1366, 1352, 1283,
1247, 1221, 1204, 1142, 1054, 1030, 1017, 980, 937, 918,
891, 864, 826, 802, 725 cm21; MS (EI) m/z 167 (M1), 152,
124, 111, 109, 107, 95, 91, 81, 79, 77, 69, 68, 67, 65, 57, 56,
55, 53, 52, 51, 41. Anal. Calcd for C9H13NO2 [167.21]: C,
64.65; H, 7.84; N, 8.38; O, 19.14. Found: C, 64.73; H, 7.65;
N, 8.36; O, 19.14.
1451, 1391, 1365, 1202, 1175, 1121, 1101, 1041, 992 cm21
;
(2Rp)-tert-Butylcarbonyl-(3Sp)-hydroxytetrahydrofuran
(14). To a stirred solution of compound 13 (4.50 g,
26.9 mmol) in 5/1 MeOH/H2O (90 ml) boric acid (5.02 g,
80.7 mmol) and ®ve spatula tips of W-2 RaNi, previously
activated by washing with H2O (10£) and MeOH (5£), were
added. After exchanging the Ar- by a H2 atmosphere and
stirring for 19 h the reaction mixture was ®ltered through
Celite. The Celite was washed extensively with MeOH and
the collected ®ltrate was concentrated in vacuo to the
volume of the H2O. After adding H2O (100 ml) with NaCl
(10 g) the aqueous phase was extracted with CH2Cl2
(3£250 ml). The combined organic layers were decolorized
by activated carbon, dried by MgSO4 and concentrated in
vacuo yielding compound 14 (4.19 g, 90%) as a pale yellow
MS (EI) m/z 171, 153, 129, 115, 102, 101, 85, 83, 73, 71, 69,
59, 58, 57, 56, 55, 53, 45, 44, 43, 42, 41. Anal. Calcd for
C10H18O3 [186.25]: C, 64.49; H, 9.74. Found: C, 64.66; H,
9.86. The relative stereochemistry of 15a and 15b was
determined by NOESY experiments.
(2Rp)-tert-Butylcarbonyl-(3Sp)-diethylphosphoryloxy-(2Rp)-
methyltetrahydrofuran (7). Furanol 15a (960 mg,
5.15 mmol) in dry CH2Cl2 (20 ml) was cooled to 08C
followed by addition of N-methyl imidazole (5.08 g,
61.9 mmol) and ClPO(OEt)2 (4.63 g, 25.8 mmol). After stir-
ring for 15 min at 08C and 15 h at 258C the reaction mixture
was diluted with CH2Cl2 (80 ml) and washed with 30%
tartaric acid solution (1£100 ml). The aqueous phase was
extracted with Et2O (3£150 ml) and the organic layers were
combined and washed successively with sat. NaHCO3
(1£400 ml) and H2O (1£400 ml). After drying over
MgSO4 and concentrating in vacuo the residue was puri®ed
by chromatography (Merck, pentane/acetone 10/1!5/1)
yielding the phosphate 7 (1.62 g, 98%) as a colorless oil:
1H NMR (300 MHz, CDCl3) d 4.87 (dd, Jˆ4.6, 4.5 Hz, 1H),
4.19±4.00 (m, 6H), 2.36±2.22 (m, 2H), 1.36±1.30 (m, 6H),
1.31 (s, 3H), 1.22 (s, 9H); 13C NMR (75.5 MHz, CDCl3) d
215.1, 94.0 (d, Jˆ9.5 Hz), 84.1 (d, Jˆ5.6 Hz), 66.8, 63.7 (d,
Jˆ6.0 Hz), 63.6 (d, Jˆ6.0 Hz), 45.1, 31.7, 26.1, 25.7, 16.0
(d, Jˆ7.2 Hz); 31P NMR (121 MHz, CDCl3) d 23.18 (sext,
Jˆ7.2 Hz); IR (NaCl) 2979, 2934, 1699, 1482, 1445, 1392,
1368, 1268, 1154, 1102, 1036, 930 cm21; MS (EI) m/z 323
(M1H1), 237, 156, 155, 138, 127, 109, 99, 84, 83, 82, 81,
69, 57, 55, 53, 43, 41. Anal. Calcd for C14H27O6P [322.34]:
C, 52.17; H, 8.44; O, 29.78. Found: C, 52.12; H, 8.53; O,
29.91.
1
solid: H NMR (300 MHz, CDCl3) d 4.68±4.61 (m, 2H),
4.17 (dt, Jˆ8.7, 6.7 Hz, 1H), 3.94 (td, Jˆ8.4, 3.9 Hz, 1H),
2.47 (d, Jˆ5.8 Hz, 1H), 2.16 (dtd, Jˆ13.6, 8.7, 5.0 Hz, 1H),
2.03 (dddd, Jˆ13.1, 6.7, 3.9, 1.6 Hz, 1H), 1.22 (s, 9H); 13C
NMR (75.5 MHz, CDCl3) d 214.4, 84.0, 73.5, 67.2, 44.0,
35.6, 25.7; IR (KBr) 3438, 2970, 2873, 1710, 1479, 1393,
1367, 1325, 1292, 1229, 1184, 1112, 1054, 1023, 1004, 921,
898, 872, 852, 816 cm21; MS (EI) m/z 157, 144, 116, 101,
88, 87, 86, 85, 71, 70, 69, 59, 58, 57, 56, 55, 45, 43, 42, 41.
Anal. Calcd for C9H16O3 [172.22]: C, 62.77; H, 9.36; O,
27.87. Found: C, 62.60; H, 9.28; O, 27.98.
(2Rp)-tert-Butylcarbonyl-(3Sp)-hydroxy-(2Rp)-methyl-
tetrahydrofuran (15a) and (2Sp)-tert-butylcarbonyl-
(3Sp)-hydroxy-(2Sp)-methyltetrahydrofuran (15b). To a
solution of 14 (6.13 g, 35.6 mmol) in dry THF (250 ml)
was added at 2788C a 1.5 M LDA solution (83.1 ml,
124.6 mmol). The resulting mixture was stirred for 15 min
at 2788C and for 2.5 h at 258C. After the deprotonation the
mixture was cooled again to 2788C and MeI (50.5 g,
356 mmol) was added. Stirring for 3 h at 2788C the mixture
was allowed to warm up to 258C slowly overnight using
intermediately an ice bath. After 17 h the suspension was
quenched with sat. NH4Cl solution (200 ml) and poured in a
10% Na2S2O3 solution (400 ml). The aqueous solution was
extracted with Et2O (3£750 ml) and the combined organic
(2Rp)-tert-Butylcarbonyl-(3Sp)-tert-butyldimethyl-silyloxy-
(2Rp)-methyltetrahydrofuran (16). To a solution of 15a
(500 mg, 2.69 mmol) in dry DMF (5 ml) were added imida-
zole (1.84 g, 26.8 mmol) and TBDMSCl (2.09 g, 13.4
mmol). After stirring for 19 h MeOH (5 ml) was added
and the reaction mixture was poured on H2O (100 ml).
The aqueous phase was extracted with Et2O (3£100 ml)

4126
R. Glatthar et al. / Tetrahedron 56 (2000) 4117±4128
and the combined organic layers were washed with H2O
(2£250 ml). After drying over MgSO4 and concentrating
in vacuo the residue was puri®ed by chromatography
(Merck, pentane/Et2O 1/0!40/1) yielding the silylether
C5H10O2 [102.13]: C, 58.80; H, 9.87; O, 31.33. Found: C,
58.57; H, 9.65; O, 31.32.
(2Sp)-Methyl-(3Sp)-phenylcarbonyloxytetrahydrofuran.
To a solution of DEAD (6.82 g, 39.2 mmol) and benzoic
acid (4.78 g, 39.2 mmol) in dry Et2O (20 ml) was added a
solution of P(Ph)3 (10.6 g, 39.2 mmol) and (3Sp)-hydroxy-
(2Rp)-methyltetrahydrofuran (2.00 g, 19.6 mmol) in dry
Et2O (30 ml) over a period of 5 min with intermediate cool-
ing to guarantee 258C. After stirring for 4 h the suspension
was ®ltered, the residue washed with Et2O and the ®ltrate
concentrated in vacuo. The crude product was puri®ed by
chromatography (Uetikon, pentane/acetone 20/1!5/1)
1
16 (704 mg, 87%) as a colorless oil: H NMR (300 MHz,
CDCl3) d 4.25 (d, Jˆ3.8 Hz, 1H), 4.14 (ddd, Jˆ11.3, 7.8,
5.6 Hz, 1H), 4.06 (tdd, Jˆ8.2, 1.7, 0.6 Hz, 1H), 2.16±2.04
(m, 1H), 1.81±1.75 (m, 1H), 1.25 (s, 3H), 1.20 (d, Jˆ
0.6 Hz, 9H), 0.84 (d, Jˆ0.6 Hz, 9H), 0.06 (s, 3H), 0.02 (s,
3H); 13C NMR (75.5 MHz, CDCl3) d 216.6, 95.4, 79.9,
67.3, 45.1, 34.2, 27.0, 25.9, 25.8, 18.0, 24.8,25.2; IR
(NaCl) 2954, 2931, 2882, 2858, 1699, 1483, 1472, 1462,
1390, 1364, 1272, 1188, 1117, 1098, 1054, 1030, 1002, 987,
922, 836, 777 cm21; MS (EI) m/z 301 (M1H1), 285, 243,
216, 215, 187, 171, 159, 157, 143, 131, 129, 115, 101, 83,
75, 74, 73, 59, 57, 45, 43, 41. Anal. Calcd for C16H32O3Si
[300.51]: C, 63.95; H, 10.73. Found: C, 63.83; H, 10.68.
1
yielding the ester (2.77 g, 69%) as a pale yellow oil: H
NMR (300 MHz, CDCl3) d 8.09±7.99 (m, 2H), 7.60±7.52
(m, 1H), 7.47±7.39 (m, 2H), 5.51 (ddd, Jˆ6.1, 3.9, 2.1 Hz,
1H), 4.11 (td, Jˆ8.3, 6.8 Hz, 1H), 4.03 (qd, Jˆ6.4, 2.9 Hz,
1H), 3.83 (td, Jˆ8.6, 5.6 Hz, 1H), 2.42 (dddd, Jˆ13.9, 8.7,
6.9, 6.1 Hz, 1H), 2.14 (dddd, Jˆ13.8, 7.9, 5.8, 2.1 Hz, 1H),
1.32 (d, Jˆ6.4 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d
166.0, 133.0, 130.1, 129.6, 128.4, 77.6, 75.8, 66.0, 33.6,
14.4; IR (NaCl) 3063, 2983, 2938, 2871, 1718, 1602,
1584, 1491, 1451, 1384, 1356, 1314, 1275, 1176, 1156,
1114, 1089, 1070, 1026, 993, 948, 900, 859, 806,
713 cm21; MS (FAB, NBA) m/z 207, 206 (M1), 205, 191,
149, 123, 106, 105, 101, 85, 84, 83, 77, 71, 69, 57, 55, 51,
50, 45, 43, 41, 39. Anal. Calcd for C12H14O3 [206.24]: C,
69.88; H, 6.84; O, 23.27. Found: C, 69.73; H, 6.68; O, 23.40.
Syntheses of the independently synthesized reference
compounds
(2Rp)-Methoxy-(2Rp)-methyltetrahydrofuran (22a). To a
solution of 4,5-dihydro-2-methylfuran (7.00 g, 83.2 mmol)
in dry MeOH (7 ml) were added 10 drops of acetic acid.
After stirring for 15 min at 258C and re¯uxing for 15 min
the reaction mixture was cooled to 258C and neutralized
with ®ve spatula tips of NaOMe. The suspension was
®ltered and the ®ltrate was distilled (113±1158C, 60 mm)
giving the volatile acetal 22a (3.84 g, 40%) as a colorless
(3Sp)-Hydroxy-(2Sp)-methyltetrahydrofuran. A solution
of (2Sp)-Methyl-(3Sp)-phenylcarbonyloxytetrahydrofuran
(6.60 g, 32.0 mmol) and NaOMe (,1 g) in dry MeOH
(70 ml) was stirred for 16 h. The reaction mixture was
poured on sat. NaCl solution (150 ml) and the aqueous
phase was extracted successively with Et2O (5£150 ml),
CH2Cl2 (3£150 ml) and ethyl acetate (3£150 ml). The
organic layers were combined, dried over MgSO4 and
concentrated in vacuo. The residue was puri®ed by chroma-
tography (Uetikon, pentane/acetone 5/1) giving the furanol
(2.20 g, 67%) as a colorless oil: 1H NMR (300 MHz,
CDCl3) d 4.17 (s, 1H), 4.04 (q, Jˆ7.9 Hz, 1H), 3.80±3.71
(m, 2H), 2.52 (s, 1H), 2.28±2.16 (m, 1H), 1.99±1.90 (m,
1H), 1.27 (d, Jˆ6.4 Hz, 3H); 13C NMR (75.5 MHz, CDCl3)
d 78.5, 73.0, 65.5, 35.6, 13.8; IR (NaCl) 3416, 2976, 2935,
2876, 1440, 1382, 1354, 1331, 1291, 1196, 1155, 1128,
1082, 1021, 991, 972, 907, 868, 836, 734 cm21; MS (EI)
m/z 102 (M1), 87, 83, 71, 69, 59, 58, 57, 56, 55, 53, 45, 44,
43, 42, 41. Anal. Calcd for C5H10O2 [102.13]: C, 58.80; H,
9.87; O, 31.33. Found: C, 58.33; H, 9.60; O, 31.79.
1
liquid: H NMR (300 MHz, CDCl3) d 3.93±3.80 (m, 2H),
3.20 (s, 3H), 2.09±1.96 (m, 2H), 1.94±1.83 (m, 1H), 1.79±
1.68 (m, 1H), 1.42 (s, 3H); 13C NMR (75.5 MHz, CDCl3) d
107.1, 67.1, 48.1, 37.6, 24.2, 20.8; IR (NaCl) 2987, 2948,
2884, 2827, 1460, 1378, 1323, 1243, 1201, 1156, 1119,
1069, 1028, 900, 845 cm21; MS (EI) m/z 117 (M1H1)
101, 86, 85, 83, 75, 74, 73, 72, 71, 59, 57, 55, 53, 45, 44,
43, 42, 41. Anal. Calcd for C6H12O2 [116.16]: C, 62.04; H,
10.41; O, 27.55. Found: C, 61.80; H, 10.31; O, 27.73.
(3Sp)-Hydroxy-(2Rp)-methyltetrahydrofuran. To a solu-
tion of 4,5-dihydro-2-methylfuran (10.0 g, 119 mmol) in
dry THF (100 ml) was added at 08C carefully borane±
dimethyl sul®de complex (9.04 g, 119 mmol). After stirring
for 1 h at 258C the reaction mixture was cooled again to 08C
followed by a slow addition of 3 N NaOH solution (42 ml)
and 30% H2O2 solution (20 ml). After completion of the
addition the suspension was stirred for 6 h at 258C followed
by an addition of K2CO3 (65.0 g). Transferring the suspen-
sion in a separatory funnel the organic layer was separated.
The aqueous phase was extracted with Et2O (3£250 ml) and
the organic layers were combined, dried over MgSO4 and
concentrated in vacuo. The residue was puri®ed by chroma-
tography (Uetikon, pentane/acetone 5/1!2/1) yielding the
(3Sp)-Methoxy-(2Rp)-methyltetrahydrofuran (21a1). To
a solution of KOH (5.17 g, 78.3 mmol) in dry DMSO
(20 ml) was added slowly (3Sp)-hydroxy-(2Rp)-methyltetra-
hydrofuran (2.00 g, 19.6 mmol) followed by MeI (5.56 g,
39.2 mmol) using intermediately a cooling bath. After stir-
ring for 30 min at 258C the reaction mixture was poured on
H2O (150 ml) and the aqueous phase was extracted with
CH2Cl2 (4£100 ml). The organic extracts were combined,
washed with H2O (5£200 ml), dried over MgSO4 and
concentrated carefully in vacuo. After distillation (116±
1188C, 760 mm) the volatile 21a1 (1.05 g, 46%) was
obtained as a colorless liquid: 1H NMR (300 MHz,
CDCl3) d 3.94 (td, Jˆ8.4, 3.5 Hz, 1H), 3.89 (qd, Jˆ6.2,
1
desired furanol (4.62 g, 38%) as a colorless oil: H NMR
(300 MHz, CDCl3) d 3.99±3.89 (m, 3H), 3.82 (qd, Jˆ6.4,
3.4 Hz, 1H), 3.59 (d, Jˆ4.1 Hz, 1H), 2.15 (dtd, Jˆ13.0, 8.6,
6.4 Hz, 1H), 1.85 (dddd, Jˆ13.0, 6.7, 4.3, 3.2 Hz, 1H), 1.19
(d, Jˆ6.4 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d 81.8,
76.8, 66.0, 34.3, 18.8; IR (NaCl) 3418, 2972, 2932, 2877,
1707, 1446, 1377, 1314, 1252, 1188, 1089, 1008, 984, 942,
870, 833 cm21; MS (EI) m/z 102 (M1), 87, 83, 71, 69, 59,
58, 57, 56, 55, 53, 45, 44, 43, 42, 41. Anal. Calcd for

R. Glatthar et al. / Tetrahedron 56 (2000) 4117±4128
4127
3.5 Hz, 1H), 3.83 (td, Jˆ8.8, 6.8 Hz, 1H), 3.53 (dt, Jˆ6.3,
3.1 Hz, 1H), 3.33 (s, 3H), 2.05 (dddd, Jˆ13.1, 9.2, 8.2,
6.5 Hz, 1H), 1.91 (ddt, Jˆ13.1, 6.6, 3.3 Hz, 1H), 1.23 (d,
Jˆ6.4 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d 86.7, 79.4,
66.4, 56.8, 31.5, 19.5; IR (NaCl) 2973, 2932, 2876, 2825,
1708, 1641, 1456, 1373, 1207, 1118, 1067, 1020, 952,
854 cm21; MS (EI) m/z 116 (M1), 115, 101, 85, 83, 73,
72, 71, 59, 58, 57, 55, 45, 43, 42, 41. Anal. Calcd for
C6H12O2 [116.16]: C, 62.04; H, 10.41; O, 27.55. Found:
C, 61.80; H, 10.50; O, 27.26.
64.84; H, 8.16; N, 12.60. Found: C, 64.75; H, 8.22; N, 12.60.
The relative stereochemistry of 21b1 and 21b2 was deter-
mined by NOEDIF experiments.
(3Sp)-N,N-Dimethylamino-(2Rp)-methyltetrahydrofuran
(21c1) and (3Sp)-N,N-dimethylamino-(2Sp)-methyltetra-
hydrofuran (21c2). To a stirred solution of (2Rp)-methyl-
tetrahydrofuran-3-one (3.00 g, 30.0 mmol) in dry MeOH
Ê
(200 ml) were added molecular sieve 4 A (4.00 g) and
Me2NH´HCl (14.9 g, 180 mmol). This suspension was
treated with a solution of NaBH3CN (1.32 g, 21.0 mmol)
in MeOH (20 ml) over a period of 15 min and stirred for
30 h. After passing through Celite and concentration of the
®ltrate to a volume of ,100 ml in vacuo the remaining
solution was poured on H2O (100 ml) and the aqueous
phase was extracted with Et2O (5£150 ml). The organic
extracts were combined, dried over MgSO4 and concen-
trated carefully in vacuo. The diastereomers were separated
and puri®ed by chromatography (Merck, MeOH) giving,
after each fraction was de novum dissolved in Et2O
(10 ml), ®ltered and concentrated in vacuo, compound
21c1 (388 mg, 10%), compound 21c2 (1.13 g, 29%) and a
3/1 mixture of 21c1/21c2 (527 mg, 14%) as colorless oils:
21c1: 1H NMR (300 MHz, CDCl3) d 3.91 (quint, Jˆ5.9 Hz,
1H), 3.88±3.77 (m, 2H), 2.54 (dt, Jˆ8.0, 5.7 Hz, 1H), 2.26
(s, 6H), 2.03±1.88 (m, 2H), 1.27 (d, Jˆ6.3 Hz, 3H); 13C
NMR (75.5 MHz, CDCl3) d 77.1, 72.6, 66.4, 43.2, 29.0,
20.4; IR (NaCl) 2971, 2868, 2824, 2778, 2242, 1658,
1460, 1376, 1263, 1159, 1100, 1071, 1042, 901, 857,
733 cm21; MS (EI) m/z 130, 129 (M1), 100, 86, 85, 84,
71, 70, 68, 58, 57, 56, 44, 43, 42, 41. Anal. Calcd for
C7H15NO [129.20]: C, 65.07; H, 11.70; N, 10.84; O,
12.38. Found: C, 64.78; H, 11.46; N, 10.85; O, 12.75.
21c1: 1H NMR (300 MHz, CDCl3) d 4.07 (quint, Jˆ
6.3 Hz, 1H), 3.99 (td, Jˆ8.7, 3.9 Hz, 1H), 3.81 (q,
Jˆ8.4 Hz, 1H), 2.67 (ddd, Jˆ9.3, 7.4, 6.1 Hz, 1H), 2.24
(s, 6H), 2.03±1.85 (m, 2H), 1.14 (d, Jˆ6.4 Hz, 3H); 13C
NMR (75.5 MHz, CDCl3) d 76.2, 68.9, 65.6, 45.0, 28.1,
15.0; IR (neat) 2976, 2871, 2819, 2775, 2598, 1657, 1458,
1379, 1347, 1278, 1208, 1160, 1120, 1084, 1066, 1033, 942,
894, 859 cm21; MS (EI) m/z 130, 129 (M1), 100, 86, 85, 84,
71, 70, 68, 58, 57, 56, 44, 43, 42, 41. Anal. Calcd for
C7H15NO [129.20]: C, 65.07; H, 11.70; N, 10.84. Found:
C, 64.74; H, 11.53; N, 10.81. The relative stereochemistry
of 21c1 and 21c2 was determined by cis-g-effects.
(3Sp)-Methoxy-(2Sp)-methyltetrahydrofuran (21a2). As
in the preparation of 21a1, KOH (5.17 g, 78.3 mmol) in
dry DMSO (20 ml), adding (3Sp)-hydroxy-(2Sp)-methyl-
tetrahydrofuran (2.00 g, 19.6 mmol) at 258C, MeI (5.56 g,
39.2 mmol) at 08C and stirring for 3 h at 258C yielded the
volatile 21a2 (596 mg, 26%) after work-up and distillation
(110±1128C, 760 mm) as a colorless liquid: 1H NMR
(300 MHz, CDCl3) d 3.98 (dt, Jˆ8.0, 7.6 Hz, 1H), 3.85
(qd, Jˆ6.4, 4.2 Hz, 1H), 3.76±3.69 (m, 2H), 3.34 (s, 3H),
2.07±2.01 (m, 2H), 1.25 (d, Jˆ6.4 Hz, 3H); 13C NMR
(75.5 MHz, CDCl3) d 81.9, 77.8, 65.6, 57.0, 31.5, 14.1;
IR (NaCl) 2976, 2934, 2880, 2829, 2696, 1641, 1452,
1381, 1353, 1293, 1209, 1154, 1090, 1047, 1019, 989,
942, 879, 850, 694 cm21; MS (EI) m/z 101, 85, 83, 73, 72,
71, 59, 58, 57, 55, 45, 43, 42, 41. Anal. Calcd for C6H12O2
[116.16]: C, 62.04; H, 10.41; O, 27.55. Found: C, 61.84; H,
10.28; O, 27.63.
(3Sp)-Cyano-(2Rp)-methyltetrahydrofuran (21b1) and
(3Sp)-cyano-(2Sp)-methyltetrahydrofuran (21b2). To a
solution of (2Rp)-methyltetrahydrofuran-3-one (2.50 g,
25.0 mmol) and TosMIC (4.88 g, 25.0 mmol) in dimethoxy-
ethane (20 ml) was added at 08C a solution of KOtBu
(5.78 g, 50.0 mmol) in tBuOH (50 ml) and dimethoxyethane
(30 ml). After stirring for 45 min at 08C and 1 h at 258C
the reaction mixture was poured on H2O (300 ml) and the
aqueous phase was extracted with Et2O (4£200 ml). The
combined organic layers were dried over MgSO4 and
concentrated carefully in vacuo. The diastereomers were
separated and puri®ed by chromatography (Uetikon, pen-
tane/Et2O 1/1) giving compound 21b1 (457 mg, 17%) and
21b2 (453 mg, 16%) as colorless oils: 21b1: 1H NMR
(300 MHz, CDCl3) d 4.06±3.97 (m, 2H), 3.87 (td, Jˆ8.5,
6.9 Hz, 1H), 2.56 (dt, Jˆ9.4, 7.9 Hz, 1H), 2.37 (dddd,
Jˆ12.5, 9.5, 7.8, 6.8 Hz, 1H), 2.23 (dtd, Jˆ12.8, 7.8,
5.2 Hz, 1H), 1.39 (d, Jˆ6.1 Hz, 3H); 13C NMR
(75.5 MHz, CDCl3) d 119.9, 78.5, 67.0, 34.9, 30.8, 19.0;
IR (NaCl) 2978, 2935, 2876, 2242, 1457, 1387, 1360, 1306,
1242, 1126, 1098, 1052, 1024, 940, 869 cm21; MS (EI) m/z
111 (M1), 96, 82, 80, 70, 69, 68, 67, 66, 64, 58, 55, 54, 53,
52, 51, 45, 43, 42, 41. Anal. Calcd for C6H9NO [111.14]: C,
64.84; H, 8.16; N, 12.60; O, 14.40. Found: C, 64.78; H,
8.10; N, 12.52; O, 14.40. 21b2: 1H NMR (300 MHz,
CDCl3) d 4.08 (td, Jˆ8.3, 5.6 Hz, 1H), 4.02 (quint,
Jˆ6.2 Hz, 1H), 3.75 (ddd, Jˆ8.9, 6.8, 6.8 Hz, 1H), 3.13
(ddd, Jˆ8.4, 6.1, 4.8 Hz, 1H), 2.42±2.23 (m, 2H); 1.45 (d,
Jˆ6.3 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d 119.3, 75.2,
66.4, 34.0, 31.0, 17.4; IR (NaCl) 2982, 2938, 2881, 2241,
1455, 1388, 1357, 1293, 1241, 1183, 1149, 1122, 1081,
1056, 1024, 996, 938, 865, 691 cm21; MS (EI) m/z 111
(M1), 96, 82, 80, 70, 69, 68, 67, 66, 64, 58, 55, 54, 53,
52, 45, 43, 42, 41. Anal. Calcd for C6H9NO [111.14]: C,
Acknowledgements
We would like to thank Prof. William. L. Jorgensen and his
coworkers Dr Daniel L. Severance and Dr Nora McDonald
from the Yale University, New Haven, and Prof. Sason
Shaik from the Hebrew University, Jerusalem, for their
scienti®c support. We are grateful to the Swiss National
Science Foundation for ®nancial support. Hendrik Zipse
and Matthias Mohr thank the Volkswagen Stiftung and the
Fonds der Chemischen Industrie for ®nancial support.
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