Neighboring-group participation in nitrile-forming Beckmann fragmentation reactions: Synthesis of enantiopure (E)-2,3-Di-O-substituted-5-methoxypent-4- enenitriles and their conversion into pyranosylamines

Article abstract of DOI:10.1002/ejoc.200400498

The selective Beckmann fragmentations of multifunctionalised ketoximes have been proven to proceed effectively to give the corresponding nitriles. The chiral (E)-1,3,4-tri-O-substituted-6-methoxy-hex-5-en-2-one oxime derivatives, available from glycals and glycosyl glycals, gave enantiopure (E)-2,3-di-O-substituted-5-methoxypent-4-enenitriles by treatment with mesyl chloride and triethylamine. The C1-C2 heterolytic fragmentation was completely controlled and directed by the adjacent C1 ether oxygen, which generates a carbonium-oxonium ion as an active electrofugal group. Unexpectedly, the C3 heteroatom did not assist the cleavage reaction and products derived from C2-C3 fragmentation were never detected. The excellent regio- and stereospecificity of the fragmentation reaction, based on the stereochemical outcome, are discussed. A simple synthetic approach to some pyranosylamines is also described. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400498

FULL PAPER
Neighboring-Group Participation in Nitrile-Forming Beckmann Fragmentation
Reactions: Synthesis of Enantiopure (E)-2,3-Di-O-substituted-5-methoxy-
pent-4-enenitriles and Their Conversion into Pyranosylamines
Pietro Passacantilli,*[a] Clara Centore,[a] Elena Ciliberti,[a] Giovanni Piancatelli,*[a] and
Francesca Leonelli[a]
Keywords: Beckmann fragmentation / Acyclic multifunctional methyl enol ethers / Enantiopure (E)-2,3-di-O-substituted-
5-methoxypent-4-enenitriles / Pyranosylamines
The selective Beckmann fragmentations of multifunction-
carbonium-oxonium ion as an active electrofugal group. Un-
alised ketoximes have been proven to proceed effectively to expectedly, the C3 heteroatom did not assist the cleavage
give the corresponding nitriles. The chiral (E)-1,3,4-tri-O-
substituted-6-methoxy-hex-5-en-2-one oxime derivatives,
available from glycals and glycosyl glycals, gave enantiopure
reaction and products derived from C2−C3 fragmentation
were never detected. The excellent regio- and stereospecific-
ity of the fragmentation reaction, based on the stereochem-
ical outcome, are discussed. A simple synthetic approach to
some pyranosylamines is also described.
(E)-2,3-di-O-substituted-5-methoxypent-4-enenitriles
by
treatment with mesyl chloride and triethylamine. The C1−C2
heterolytic fragmentation was completely controlled and dir- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ected by the adjacent C1 ether oxygen, which generates a
Germany, 2004)
Introduction
trile products, which can then easily be converted into bio-
logically important 18-nor-17-ketosteroids.[6Ϫ11]
Heterolytic fragmentations are a widespread class of or-
ganic reactions that involve the regulated cleavage of mol-
ecules whose structures contain combinations of atoms,
such as carbon, oxygen, nitrogen, sulfur, silicon, and hal-
ogens.[1] The Beckmann fragmentation can be included in
this class of reaction when ketoximes are cleaved into ni-
triles and a second fragment. In particular, nitrile-forming
fragmentation reactions have been observed to occur in ke-
toximes with α-substituents, such as heteroatoms, which can
stabilize the intermediary carbocations. Since the formation
of nitriles is an important aspect of this fragmentation,
these reactions can be utilized both for degradation and
structure elucidation and for preparative purposes.[2Ϫ4]
During recent years, cyclic ketoximes have been widely
studied and utilized in organic synthesis. Thus, the
Beckmann fragmentation has proven to be particularly use-
ful for cyclic ketoximes with quaternary centers adjacent to
the oxime carbon.[2Ϫ4] Recently, Hu and co-workers devel-
oped a novel and practical procedure for heterolytic frag-
mentation of steroid 17-oximes.[5] This protocol represents
the best method with which to obtain 13,17-seco-alkeneni-
Furthermore, cyclic ketoximes that contain functional
groups that direct the fate of the cationic intermediates have
been utilized preparatively.[2Ϫ4] Nishiyama et al. found that
the Beckmann fragmentation of cyclic β-trimethylsilyl ke-
toximes is completely controlled and directed by a trimeth-
ylsilyl group to give regio- and stereospecific unsaturated
nitriles.[12] More recently, Fleming et al.[13] reported a sili-
con-directed Beckmann fragmentation of a suitable cyclic
ketoxime acetate with a dimethylphenylsilyl group as the
active electrofugal group in the β-position,[1] in which a
high level of stereocontrol in the open-chain unsaturated
nitrile, the key intermediate in the synthesis of phytol, was
achieved.
However, a significant drawback of this approach is that
the fragmentation produces two or more products when the
oxime is acyclic: a nitrile and the product or products de-
rived from the cation. Hence, the reaction is preparatively
useful only when the nitrile is the desired product.[2Ϫ4,14]
To the best of our knowledge, the synthetic utility of the
Beckmann fragmentation has never been studied with
differentially and densely functionalised ketoximes, particu-
larly acyclic and unsymmetrically substituted ketoximes.
Some years ago, we described the synthesis of acyclic
multifunctional compounds, such as (E)-1,3,4-tri-O-substi-
tuted-6-methoxyhex-5-en-2-ol derivatives 1, that are readily
available by a one-pot procedure from O-benzyl derivatives
of glycals and glycosyl glycals by reaction with the
[a]
Dipartimento di Chimica and Istituto di Chimica
`
Biomolecolare del CNR - Sezione di Roma- Universita ‘‘La
Sapienza’’,
Piazzale Aldo Moro 5, 00185-Roma, Italy
Fax: (internat.) ϩ39-06-490631
E-mail: pietro.passacantilli@uniroma1.it
giovanni.piancatelli@uniroma1.it
Eur. J. Org. Chem. 2004, 5083Ϫ5091
DOI: 10.1002/ejoc.200400498
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5083

P. Passacantilli, C. Centore, E. Ciliberti, G. Piancatelli, F. Leonelli
FULL PAPER
Tl(NO3)3/NaBH4 reagent combination.[15,16] These com- Surprisingly, we observed a very fast reaction (15 min) lead-
pounds have been utilized as precursors in the synthesis of ing directly to the regioselective formation of (E,2R,3R)-
some biologically active products, such as natural and un- 2,3-bis(benzyloxy)-5-methoxypent-4-enenitrile (4a) and
natural sphingosines.[17]
(E,2S,3R)-2,3-bis(benzyloxy)-5-methoxypent-4-enenitrile
Prompted by these findings, we became interested in ex- (4b) as the only reaction products and in acceptable yields
ploiting the reactivity of ketoximes derived from 1 in heter- (60Ϫ70%). The structures of 4a and 4b were determined by
olytic fragmentation reactions. These acyclic molecules, HRMS analysis and from the spectroscopic data: 4a, 13C
with two O-protected hydroxy groups, C1 and C3, both lo- NMR: δ ϭ 116.6 (CN), 72.5, 69.8 (CH2Ph) ppm; 4b, 13C
cated adjacent to the oxime C2 atom, contain a suitable NMR: δ ϭ 116.8 (CN), 72.3, 69.7 (CH2Ph) ppm. Neither
combination (scaffold or frame) of groups and heteroatoms compound showed a CN absorption in their IR spectra,
with which to study the regio- and stereocontrol of neighb- like other nitriles described in this work, and similarly to
oring-group participation in nitrile-forming Beckmann what has been previously observed for α-alkoxynitriles.[25,26]
fragmentation reactions.
The structures of compounds 4a,b were confirmed by
Here we describe some of our results in the development correlation with products obtained by known methods
of a method in which regio- and stereocontrolled bond frag- (Scheme 2). Starting from 5a, available from the O-benzyl
mentation of densely functionalised ketoximes occurs to derivative of -xylal[15,16] and in accordance with the reac-
give enantiopure functionalised pentanenitrile derivatives, tion sequence depicted in Scheme 2, a compound identical
which are valuable as precursors in the synthesis of biologi- to 4a, already prepared from 1a (see Scheme 1), was ob-
cally active compounds, such as glycosylamines,[18] 1-β-am- tained. Then 5b, available from the O-benzyl derivative of
ino-1-deoxynojirimycins[19,20] and -glucoamidines.[21Ϫ23]
-arabinal,[15,16] was converted by the same reaction se-
quence into (E,2R,3S)-2,3-bis(benzyloxy)-5-methoxypent-
4-enenitrile (8b), the enantiomer of 4b.
Results and Discussion
All the starting materials were prepared in one step from
O-benzyl derivatives of glycals and glycosyl glycals accord-
ing to our previously reported procedure by reaction with
Tl(NO3)3/NaBH4 reagent combination in methanol.[15,16,24]
The C2 free hydroxy groups of 1a,b (available from O-
benzyl derivatives of -glucal and -galactal, respectively)
were easily oxidized to the corresponding ketones 2a,b in
high yield (90Ϫ95%) by reaction with PDC in acetonitrile
(Scheme 1). The reaction of compounds 2a,b with three
equivalents of hydroxylamine, prepared from hydroxylam-
ine hydrochloride and triethylamine in a 1:1 EtOH/THF
solution, gave ketoximes 3a,b as E/Z stereoisomeric mix-
tures (75Ϫ80%). Since the mechanism of the Beckmann
fragmentation requires reagents with dehydrating proper-
ties,[5,6,11] the ketoximes 3a,b were treated with mesyl chlo-
ride and triethylamine in dichloromethane at room temp., a
reagent combination previously utilized for this purpose.[24]
˚
Scheme 2. Reagents and conditions: a) PDC, CH3CN, 4-A molecu-
lar sieves, room temp. (80%); b) NH2OH·HCl, NEt3, EtOH/THF
1:1, 40 °C, (90%); c) CH3SO2Cl, NEt3, CH2Cl2, room temp. (90%)
In general, the heterolytic fragmentation is stereospecific
and carbonϪcarbon cleavage occurs when an active electro-
fugal group is anti to a nucleofugal group on the nitrogen,
as shown in Scheme 3.[2Ϫ4,12,13]
Scheme 3
Both the mildness of the experimental conditions and the
fast reaction times can be explained by a stereocontrolled
donation of electrons by the oxygen atom of the C1 benzyl-
oxy group to the fragmenting carbon, which favours the
formation of a more accessible and less crowded transition
˚
Scheme 1. Reagents and conditions: a) PDC, CH3CN, 4-A molecu-
lar sieves, room temp. (90Ϫ95%); b) NH2OH·HCl, NEt3, EtOH/
THF 1:1, 40 °C, (75Ϫ80%); c) CH3SO2Cl, NEt3, CH2Cl2, room
temp. (60Ϫ70%)
5084
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5083Ϫ5091

Neighboring-Group Participation in Beckmann Fragmentation Reactions
FULL PAPER
state (Scheme 3). Unexpectedly, the C3 heteroatom did not 4a as the only detectable reaction product (Scheme 4). The
assist the cleavage reaction and products derived from yields were modest (30Ϫ40%), probably because the py-
C2ϪC3 fragmentation were never detected. Note that in a ranoside-oxonium ion is an inefficient cationic leaving
previous study of a series of (E)- and (Z)-ketoximes the group. We were unable to detect any other products from
same fragmentation products were observed, the reactions the fragmentation reaction or the starting compounds
varying only in their rate constants for fragmentation and 12d,e. In particular, C2ϪC3 fragmentation products were
in their yields.[27]
never observed.
In order to study the role of the benzyl(methylene)-
Then, (E,2S,3S,4S)-3,4-bis(benzyloxy)-6-methoxyhex-5-
oxonium ion 9, the stabilized electrofugal group, in con- en-2-ol 14, available from the O-benzyl derivative of -
trolling and directing the regiochemistry of the fragmen- rhamnal, was converted into the ketoxime 16 as an E/Z
tation reaction, we examined the reactivity of stereoisomeric mixture (Scheme 5). Subsequent treatment
(E,2R,3R,4R)-1,3-di-O-substituted-4-benzyloxy-6-meth- with mesyl chloride, as described previously, led almost
oxyhex-5-en-2-ol derivatives, such as 10aϪe, with differently quantitatively to the formation of the corresponding mesyl
protected C1 and C3 hydroxy groups, such as a sugar moi- derivative as the only reaction product (E/Z mixture); that
ety either at C1 or C3. These compounds are readily avail- is, no by-products of either the Beckmann fragmentation or
able from O-benzyl derivatives of cellobial,[15,16] maltal (see the Beckmann rearrangement reactions were detected. Note
Expt. Sect.), lactal,[15,16] melibial[15,16] and gentiobial[24] (see also that C2ϪC3 heterolytic cleavage products were never
Expt. Sect.) respectively.
detected.
Compounds 12a,b,c, prepared from 10a,b,c by the reac-
tion sequence shown in Scheme 4, reacted similarly to 3a,b
as described above, undergoing regioselective C1ϪC2 frag-
mentation to give (E,2R,3R)-2-O-substituted-3-benzyloxy-
5-methoxypent-4-enenitriles 13 with a sugar moiety at C2,
such as 2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-β--glucopyranosyl (13a),
2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-α--glucopyranosyl (13b) and
2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-β--galactopyranosyl (13c), in the
same yields as reported before (60Ϫ70%) (Scheme 4). The
outcome of the reaction clearly indicates that the presence
of a sugar derivative adjacent to the ketoxime moiety in
12a,b,c does not influence the Beckmann fragmentation or
its regiochemistry.
˚
Scheme 5. Reagents and conditions: a) PDC, CH3CN, 4-A molecu-
lar sieves, room temp. (95%); b) NH2OH·HCl, NEt3, EtOH/THF
1:1, 40 °C (80%); c) CH3SO2Cl, NEt3, CH2Cl2, room temp. (90%)
Interestingly, the ketoximes 12d,e, prepared from 10d,e
and with a sugar derivative located at C1, underwent the
regioselective heterolytic cleavage reaction with the unusual
All the above results indicate that the benzyloxy group at
pyranoside-oxonium ion as the electrofugal group to give the C3-position did not assist the heterolytic cleavage de-
˚
Scheme 4. Reagents and conditions: a) PDC, CH3CN, 4-A molecular sieves, room temp. (90Ϫ95%); b) NH2OH·HCl, NEt3, EtOH/THF
1:1, 40 °C (75Ϫ80%); c) CH3SO2Cl, NEt3, CH2Cl2, room temp. (30Ϫ70%)
Eur. J. Org. Chem. 2004, 5083Ϫ5091
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5085

P. Passacantilli, C. Centore, E. Ciliberti, G. Piancatelli, F. Leonelli
FULL PAPER
spite being adjacent to the reaction center possibly due to the Beckmann fragmentation reaction to give enantiopure
some steric interaction involved in the formation of the (E)-2,3-O-disubstituted-5-methoxypent-4-enenitriles, pre-
transition state and the necessary stereochemistry of the re- cursors of biologically active compounds. Then the regio-
action pathway (Scheme 3). As has been described in the and stereocontrolled participation of an adjacent coplanar
literature, effective assistance requires a transition state in trans/anti ether oxygen, which generates a carbonium-ox-
which both of the carbon atoms involved in the fragmen- onium ion as the active electrofugal group, was unambigu-
tation, the leaving group on the nitrogen and the ‘‘assisting ously demonstrated. The results give a new insight into both
atom’’ lie in or near a common plane, as shown in the mechanism and the stereochemical requirements of the
Scheme 3.[2Ϫ4,12,13] To the best of our knowledge, there is neighboring groups in the electronically assisted carbon-
no evidence in the literature of such highly regio- and stere- cleavage reaction and provides scope to broaden the syn-
ocontrolled assistance in the Beckmann fragmentation reac- thetic utility of this reaction.
tion.
Synthetic Application
Experimental Section
The compounds obtained from the Beckmann fragmen-
General: 1H (200 MHz) and 13C NMR (50.3 MHz) spectra were
recorded with a Varian Gemini 200 spectrometer with CDCl3 as
the solvent and internal standard. IR spectra were recorded with
an IR Equinox 55 Bruker spectrometer. HRMS spectra were re-
corded with a Micromass Q-TOF micro Mass Spectrometer
(Waters). Optical rotations were measured by using the sodium D
line of a DIP 370 Jasco digital polarimeter. Yields are given for
isolated products after column chromatography showed a single
spot on TLC and when no impurities were detected in the 1H NMR
spectra. All reactions were performed under N2 in flame-dried
glassware. All solvents and commercially available reagents were
used without further purification unless otherwise noted. All reac-
tions were monitored by thin-layer chromatography (TLC) carried
out on Merck F-254 silica glass plates visualized with UV/light and
heat-gun treatment with 2  H2SO4 solution. Column chromatog-
raphy was performed using Merck silica gel 60 (230Ϫ400 mesh).
tation are precursors of δ-hydroxynitriles and they can be
utilized in strategies leading to the synthesis of protected
pyranosylamines by reductive cyclization.[18] The reductive
cyclization of hydroxynitriles to provide glycosylamines is a
known reaction.[28,29] However, owing to the biological ac-
tivity of this class of cyclic N,O-acetals, glycosylamines are
a
central motif in N-linked glycopeptides and
glycoproteins,[30Ϫ32] the development of new synthetic stra-
tegies remains an important goal.[33]
Some pyranosylamines, such as 19a,b (Scheme 6), were
synthesized starting with the preparation of (2R,3R)-2,3-di-
O-substituted-5-oxopentanenitriles 18a,b, which were easily
and almost quantitatively obtained from 4a and 13a,
respectively, by treatment with acid as catalyst in THF.
Upon exposure to sodium borohydride in ethanol, 18a,b
were first converted into the corresponding δ-hydroxyni-
triles and subsequent reductive cyclization afforded the new
pyranosylamines 19a,b in acceptable yields (55%) as the
only reaction products. In both cases, reductive cyclization
resulted in the preferential formation of the β anomer, as
previously reported for these reactions.[18] However, it is
worth noting that in the case of compounds 19, the β con-
figuration means an axial orientation, as shown by the 13C
NMR analysis of the C1 atom shielded at around
77 ppm.[18] This sequence thus allows a simple approach to
a library of stereodefined pyranosylamines.
Starting Materials: All the starting materials were prepared from
their corresponding glycals or glycosyl glycals.[15,16,24] Since com-
pounds 5a,b and 10b,e have not been described before, we report
the analytical data in the Expt. Sect..
Linear Methoxy Alcohol 5a: Compound 5a was prepared from per-
benzylated -xilal (200 mg, 0.67 mmol) by following our previously
described method,[15,16] and was obtained as a viscous oil (122 mg,
55%). [α]D ϭ ϩ48.7 (c ϭ 1.1, CHCl3). IR (CHCl3): ν˜ ϭ 3300, 3150,
3090, 1690, 1650, 1625, 1520, 1430, 1380, 1230, 1120, 1090 cmϪ1
.
1H NMR: δ ϭ 7.52Ϫ7.30 (m, 10 H, Ph), 6.55 (d, J ϭ 12.5 Hz, 1
H, 1-H), 4.90Ϫ4.52 (m, 6 H, 2-H, 4-H, 2 CH2Ph), 3.80 (dd, J ϭ
5.0, 7.0 Hz, 1 H, 3-H), 3.80 (m, 2 H, 5-HA, 5-HB), 3.58 (s, 3 H,
OCH3) ppm. 13C NMR: δ ϭ 152.7 (C-1), 138.2, 137.5 (Cquat, Ph),
128.2, 127.9, 127.5, 127.4 (Ph), 98.7 (C-2), 79.5, 78.1 (C-3, C-4),
72.5, 70.4 (CH2Ph), 63.8 (C-5), 55.5 (OCH3) ppm. HRMS: calcd.
for C20H24O4: 346.2018 [M ϩ NH4]ϩ; found: 346.2015.
Linear Methoxy Alcohol 5b: Compound 5b was prepared from per-
benzylated -arabinal (200 mg, 0.67 mmol) by following our pre-
viously described method,[15,16] and was obtained as a viscous oil
(122 mg, 55%). [α]D ϭ ϩ58.7 (c ϭ 1.3, CHCl3). IR (CHCl3): ν˜ ϭ
3300, 3150, 3090, 1690, 1650, 1625, 1520, 1430, 1380, 1230, 1120,
1
1090 cmϪ1. H NMR: δ ϭ 7.52Ϫ7.30 (m, 10 H, Ph), 6.58 (d, J ϭ
Scheme 6. Reagents and conditions: a) THF/4  HCl (5:1), room
temp.; b) NaBH4, THF/EtOH (1:1), reflux
12.3 Hz, 1 H, 1-H), 4.90Ϫ4.60 (m, 5 H, CH2Ph, HA of CH2Ph, 2-
H, 4-H), 4.42 (d, J ϭ 12.0 Hz, 1 H, HB of CH2Ph), 3.92 (dd, J ϭ
8.0, 6.0 Hz, 1 H, 3-H), 3.80 (m, 2 H, 5-HA, 5-HB), 3.65 (s, 3 H,
OCH3) ppm. 13C NMR: δ ϭ 151.7 (C-1), 138.2 (Cquat, Ph), 128.2,
127.8, 127.6, 127.4 (Ph), 99.7 (C-2), 81.5, 78.1 (C-3, C-4), 72.7,
69.3 (CH2Ph), 62.2 (C-5), 55.9 (OCH3) ppm. HRMS: calcd. for
Conclusions
In conclusion, we have found that acyclic, differentially
and densely functionalised ketoximes successfully undergo C20H24O4: 346.2018 [M ϩ NH4]ϩ; found: 346.2013.
5086
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5083Ϫ5091

Neighboring-Group Participation in Beckmann Fragmentation Reactions
FULL PAPER
Linear Methoxy Alcohol 10b: Compound 10b was prepared from
perbenzylated maltal (200 mg, 0.23 mmol) by following our pre-
viously described method,[15,16] and was obtained as a viscous oil
(124 mg, 60%). [α]D ϭ ϩ72.3 (c ϭ 1.3, CHCl3). IR (CHCl3): ν˜ ϭ
3300, 3140, 3050, 1690, 1655, 1630, 1530, 1430, 1380, 1230, 1120,
85.4 (C-3), 78.4 (C-4), 74.0, 73.2, 73.0 (CH2Ph), 69.3 (C-1), 56.0
(OCH3) ppm. HRMS: calcd. for C28H30O5: 464.2437 [M ϩ NH4]ϩ;
found: 464.2439.
Aldehyde 6a: This compound was prepared by the general pro-
cedure from 5a (122 mg, 0.37 mmol) followed by column chroma-
tography (SiO2; n-hexane/EtOAc, 8:2) to give 6a as a viscous oil
(97 mg, 80%). [α]D ϭ ϩ11.3 (c ϭ 1.5, CHCl3). IR (CHCl3): ν˜ ϭ
3150, 3090, 2700, 1730, 1680, 1670, 1600, 1530, 1420, 1230, 1100,
1
1090 cmϪ1. H NMR: δ ϭ 7.42Ϫ7.20 (m, 30 H, Ph), 6.20 (d, J ϭ
12.7 Hz, 1 H, 1-H), 5.21Ϫ4.40 (m, 17 H, 6 CH2Ph, 1Ј-H, 2Ј-H, 3Ј-
H, 4Ј-H, 2-H), 4.35Ϫ4.10 (m, 2 H, 3-H, 4-H), 4.02Ϫ3.60 (m, 6 H,
5Ј-H, 6Ј-HA, 6Ј-HB, 5-H, 6-HA, 6-HB), 3.47 (s, 3 H, OCH3), 2.78
(br. s, OH) ppm. 13C NMR: δ ϭ 152.8 (C-1), 138.3, 137.8, 137.6,
137.4, 137.0 (Cquat, Ph), 128.0, 127.8, 127.7, 127.6, 127.5, 126.4
(Ph), 99.3 (C-1Ј), 97.2 (C-2), 81.5, 79.8, 79.4, 77.2, 76.7, 75.9 (C-
2Ј, C-3Ј, C-4Ј, C-5Ј, C-3, C-4), 75.1, 74.6, 74.4, 73.2, 72.9 (CH2Ph),
70.0 (C-5), 69.4, 68.0 (C-6Ј, C-6) ppm. HRMS: calcd. for
C55H60O10: 898.4530 [M ϩ NH4]ϩ; found: 898.4538.
1090 cmϪ1 1H NMR: δ ϭ 9.91 (d, J ϭ 1.8 Hz, 1 H, HϪCO),
.
7.52Ϫ7.25 (m, 10 H, Ph), 6.56 (d, J ϭ 12.8 Hz, 1 H, 5-H), 4.80
(dd, J ϭ 12.8, 9.2 Hz, 1 H, 4-H), 4.82 (d, J ϭ 9.0 Hz, 1 H, HA of
CH2Ph), 4.60 (s, 2 H, CH2Ph), 4.39 (d, J ϭ 9.0 Hz, 1 H, HB of
CH2Ph), 4.09 (dd, J ϭ 9.2, 4.8 Hz, 1 H, 3-H), 3.94 (dd, J ϭ 4.8,
1.8 Hz, 1 H, 2-H), 3.60 (s, 3 H, OCH3) ppm. 13C NMR: δ ϭ 201.8
(CO), 152.0 (C-5), 137.9, 137.3 (Cquat, Ph), 128.3, 127.9, 127.4 (Ph),
98.1 (C-4), 77.3, 76.1 (C-3, C-2), 72.8, 70.3 (CH2Ph), 54.7 (OCH3)
ppm. HRMS: calcd. for C20H22O4: 344.1862 [M ϩ NH4]ϩ; found:
344.1865.
Linear Methoxy Alcohol 10e: Compound 10e was prepared from
perbenzylated gentiobial[24] (200 mg, 0.23 mmol) by following our
previously described method,[15,16] and was obtained as a viscous
oil (124 mg, 60%). [α]D ϭ ϩ5.6 (c ϭ 1.3, CHCl3). IR (CHCl3): ν˜ ϭ
3300, 3140, 3050, 1690, 1655, 1630, 1530, 1430, 1380, 1230, 1120,
Aldehyde 6b: This compound was prepared by the general pro-
cedure from 5b (122 mg, 0.37 mmol) followed by column chroma-
tography (SiO2; n-hexane/EtOAc, 8:2) to give 6b as a viscous oil
(97 mg, 80%). [α]D ϭ ϩ32.7 (c ϭ 1.5, CHCl3). IR (CHCl3): ν˜ ϭ
3150, 3090, 2700, 1730, 1680, 1670, 1600, 1530, 1420, 1230, 1100,
1
1090 cmϪ1. H NMR: δ ϭ 7.45Ϫ7.25 (m, 30 H, Ph), 6.60 (d, J ϭ
12.5 Hz, 1 H, 1-H), 5.21Ϫ4.40 (m, 17 H, 6 CH2Ph, 1Ј-H, 2Ј-H, 3Ј-
H, 4Ј-H, 2-H), 4.35Ϫ4.0 (m, 2 H, 3-H, 4-H), 4.0Ϫ3.62 (m, 6 H, 5Ј-
H, 6Ј-HA, 6Ј-HB, 5-H, 6-HA, 6-HB), 3.62 (s, 3 H, OCH3), 2.78 (br.
s, OH) ppm. 13C NMR: δ ϭ 150.7 (C-1), 138.1, 138.0, 137.9, 137.6,
137.5 (Cquat, Ph), 127.9, 127.8, 127.7, 127.6, 127.4, 127.3, 127.1,
127.0 (Ph), 103.9 (C-1Ј), 99.1 (C-2), 84.2, 81.9, 81.5, 77.3, 76.8,
74.3 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-3, C-4), 75.2, 74.3, 73.9, 73.1, 72.1
(CH2Ph), 69.8 (C-5), 69.1, 68.4 (C-6Ј, C-6) ppm. HRMS: calcd. for
C55H60O10: 898.4530 [M ϩ NH4]ϩ; found: 898.4528.
1090 cmϪ1 1H NMR: δ ϭ 9.91 (d, J ϭ 1.8 Hz 1 H, HϪCO),
.
7.52Ϫ7.25 (m, 10 H, Ph), 6.56 (d, J ϭ 12.8 Hz, 1 H, 5-H), 4.80
(dd, J ϭ 12.8, 9.2 Hz, 1 H, 4-H), 4.82Ϫ4.60 (m, 3 H, CH2Ph, HA
of CH2Ph), 4.39 (d, J ϭ 2.0 Hz, 1 H, HB of CH2Ph), 4.09 (dd, J ϭ
9.2, 4.8 Hz, 1 H, 3-H) 3.94 (dd, J ϭ 4.8, 1.8 Hz, 1 H, 2-H), 3.60
(s, 3 H, OCH3) ppm. 13C NMR: δ ϭ 201.8 (CO), 152.0 (C-5), 137.9,
137.3 (Cquat, Ph), 128.3, 128.0, 127.4 (Ph), 98.1 (C-4), 85.3, 77.3
(C-3, C-2), 72.8, 69.1 (CH2Ph), 55.8 (OCH3) ppm. HRMS: calcd.
Synthesis of Ketones 2a,b, 11aϪe and 15 and Aldehydes 6a,b. Gen-
eral Procedure: The appropriate alcohol (0.23 mmol) was dissolved for C20H22O4: 344.1862 [M ϩ NH4]ϩ; found: 344.1859.
in dry CH3CN (7 mL) in the presence of powdered molecular sieves
Ketone 11a: This compound was prepared by the general procedure
from 10a (200 mg, 0.23 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 8:2) to give 11a as an amorphous powder
(184 mg, 92%). [α]D ϭ Ϫ14.0 (c ϭ 1.3, CHCl3). IR (CHCl3): ν˜ ϭ
3060, 3020, 3010, 1730, 1690, 1550, 1510, 1420, 1290, 1180, 1100,
(4 A, 2 g·mmolϪ1) and the mixture was treated with PDC (0.17 g,
˚
0.46 mmol). The reaction mixture was stirred at room temperature
overnight and then was filtered through Celite, washing with
CH3CN. After evaporation of the solvent under reduced pressure
the crude product was purified by column chromatography.
1
1090 cmϪ1. H NMR: δ ϭ 7.40Ϫ7.25 (m, 30 H, Ph), 6.56 (d, J ϭ
Ketone 2a: This compound was prepared by the general procedure
from 1a (200 mg, 0.44 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 8:2) to give 2a as a viscous oil (189 mg,
95%). [α]D ϭ Ϫ57.0 (c ϭ 1.3, CHCl3). IR (CHCl3): ν˜ ϭ 3150, 3090,
12.0 Hz, 1 H, 6-H), 5.10Ϫ4.80 (m, 6 H, 2 CH2Ph, 3-H, 5-H),
4.71Ϫ4.42 (m, 12 H, 4 CH2Ph, 1Ј-H, 2Ј-H, 4Ј-H, 4-H), 4.40Ϫ4.23
(m, 4 H, 3Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 3.82 (m, 2 H, 1-HA, 1-HB),
3.50 (s, 3 H, OCH3) ppm. 13C NMR: δ ϭ 206.6 (CO), 151.3 (C-6),
1H 138.1, 137.9, 137.7, 137.1 (Cquat, Ph), 127.9, 127.8, 127.7, 127.6,
127.4, 127.3, 127.1, 127.0 (Ph), 101.6 (C-1Ј), 97.9 (C-5), 84.2, 83.6,
1730, 1695, 1625, 1520, 1500, 1230, 1190, 1120, 1090 cmϪ1
.
NMR: δ ϭ 7.38Ϫ7.17 (m, 15 H, Ph), 6.44 (d, J ϭ 12.8 Hz, 1 H, 6-
H), 4.79 (dd, J ϭ 12.8, 9.4 Hz, 1 H, 5-H), 4.67Ϫ4.18 (m, 8 H, 3 81.4, 77.6, 77.3, 74.7 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-3, C-4), 74.5, 74.3,
CH2Ph, 1-HA, 1-HB), 4.16 (dd, J ϭ 9.4, 3.8 Hz, 1 H, 4-H), 3.94 (d,
J ϭ 3.8 Hz, 1 H, 3-H), 3.48 (s, 3 H, OCH3) ppm. 13C NMR: δ ϭ
207.3 (CO), 151.6 (C-6), 137.6, 137.2, 136.8 (Cquat, Ph), 128.2,
128.0, 127.9, 127.7, 127.3 (Ph), 97.8 (C-5), 86.6 (C-3), 77.6 (C-4),
74.2, 74.0, 72.9 (CH2Ph), 69.3 (C-1), 55.7 (OCH3) ppm. HRMS:
calcd. for C28H30O5: 464.2437 [M ϩ NH4]ϩ; found: 464.2433.
73.0, 72.4 (CH2Ph), 69.0, 68.2 (C-6Ј, C-1), 55.4 (OCH3) ppm.
HRMS: calcd. for C55H58O10: 896.4374 [M ϩ NH4]ϩ; found:
896.4377.
Ketone 11b: This compound was prepared by the general procedure
from 10b (200 mg, 0.23 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 8:2) to give 11b as a viscous oil (184 mg,
92%). [α]D ϭ ϩ68.9 (c ϭ 1.1, CHCl3). IR (CHCl3): ν˜ ϭ 3050, 3025,
Ketone 2b: This compound was prepared by the general procedure
from 1b (200 mg, 0.44 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 8:2) to give 2b as a viscous oil (183 mg,
92%). [α]D ϭ Ϫ21.0 (c ϭ 1.2, CHCl3). IR (CHCl3): ν˜ ϭ 3145, 3090,
3010, 1728, 1690, 1555, 1515, 1420, 1280, 1160, 1100, 1090 cmϪ1
.
1H NMR: δ ϭ 7.50Ϫ7.30 (m, 30 H, Ph), 6.52 (d, J ϭ 13 Hz, 1 H,
6-H), 5.10 (d, J ϭ 3.2 Hz, 1 H, 1Ј-H), 5.02Ϫ4.60 (m, 5 H, 2 CH2Ph,
H-5), 4.58Ϫ4.42 (m, 12 H, 4 CH2Ph, 2Ј-H, 4Ј-H, 3-H, 4-H),
1720, 1695, 1625, 1525, 1510, 1500, 1230, 1190, 1130, 1080 cmϪ1
.
1H NMR: δ ϭ 7.40Ϫ7.20, (m, 15 H, Ph), 6.55 (d, J ϭ 12.7 Hz, 1 4.30Ϫ3.52 (m, 6 H, 3Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB, 1-HA, 1-HB), 3.48
H, 6-H), 4.72 (dd, J ϭ 2.7, 9.8 Hz, 1 H, 5-H), 4.62Ϫ4.32 (m, 8 H, (s, 3 H, OCH3) ppm. 13C NMR: δ ϭ 205.3 (CO), 152.1 (C-6), 138.7,
3 CH2Ph, 1-HA, 1-HB), 4.10Ϫ3.94 (m, 2 H, 3-H, 4-H), 3.52 (s, 3
H, OCH3) ppm. 13C NMR: δ ϭ 207.0 (CO), 152.1 (C-6), 138.0,
137.3 (Cquat, Ph), 128.3, 128.0, 127.8, 127.5, 127.4 (Ph), 98.1 (C-5),
138.3, 138.1, 137.8, 137.3 (Cquat, Ph), 128.3, 128.2, 128.1, 128.0,
127.8, 127.6, 127.5, 127.4 (Ph), 99.2 (C-1Ј), 97.7 (C-5), 84.5, 81.5,
79.6, 77.8, 77.4 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-4), 75.4, 74.8, 74.3, 73.3,
Eur. J. Org. Chem. 2004, 5083Ϫ5091
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5087

P. Passacantilli, C. Centore, E. Ciliberti, G. Piancatelli, F. Leonelli
FULL PAPER
73.1, 72.6 (CH2Ph), 71.1 (C-3), 69.3, 68.2 (C-6Ј, C-1), 55.8 (OCH3) H, HB of CH2Ph), 3.98 (dd, J ϭ 9.1, 4.1 Hz, 1 H, 4-H), 3.74 (d,
ppm. HRMS: calcd. for C55H58O10: 896.4374 [M ϩ NH4]ϩ; J ϭ 4.1 Hz, 1 H, 3-H), 3.48 (s, 3 H, OCH3), 2.24 (s, 3 H, CH3)
found: 896.4380.
ppm. 13C NMR: δ ϭ 209.8 (CO), 151.5 (C-6), 137.8, 137.1 (Cquat
,
Ph), 128.2, 128.0, 127.7, 127.5, 127.3 (Ph), 98.2 (C-5), 88.1, 77.8
(C-4, C-3), 76.3, 69.3 (CH2Ph), 55.7 (OCH3), 27.4 (C-1) ppm.
HRMS: calcd. for C21H24O4: 358.2018 [M ϩ NH4]ϩ; found:
358.2015.
Ketone 11c: This compound was prepared by the general procedure
from 10c (200 mg, 0.23 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 8:2) to give 11c as an amorphous powder
(187 mg, 94%). [α]D ϭ Ϫ5.1 (c ϭ 1.1, CHCl3). IR (CHCl3): ν˜ ϭ
3060, 3020, 3010, 1730, 1696, 1545, 1510, 1416, 1290, 1180, 1100,
Synthesis of Ketoximes 3a,b, 12aϪe and 16 and Aldoximes 7a,b.
General Procedure: NEt3 (0.19 g, 1.86 mmol) and NH2OH·HCl
(44·mg, 0.62 mmol) were added to a solution of the appropriate
carbonilic compound (0.21 mmol) in freshly distilled THF (3 mL)
and abs. EtOH (3 mL). The solution was stirred at 40 °C overnight.
After evaporation of the solvent under reduced pressure the crude
product was taken up with Et2O and washed in a separating funnel
with H2O (till neutral), brine, dried with anhydrous Na2SO4 and
the solvent removed. The residue was then purified by column
chromatography.
1
1048 cmϪ1. H NMR: δ ϭ 7.41Ϫ7.26 (m, 30 H, Ph), 6.52 (d, J ϭ
12.9 Hz, 1 H, 6-H), 5.00 (d, J ϭ 12.9 Hz, 1 H, HA of CH2Ph), 4.89
(dd, J ϭ 12.9, 3.0 Hz, 1 H, 5-H), 4.71Ϫ4.22 (m, 16 H, HB of
CH2Ph, 5 CH2Ph, 1Ј-H, 2Ј-H, 3Ј-H, 4Ј-H, 4-H), 4.13 (dd, J ϭ 9.2,
3.3 Hz, 1 H, 3-H), 3.92 (d, J ϭ 7.5 Hz, 1 H, 1-HA), 3.88 (d, J ϭ
7.5 Hz, 1 H, 1-HB), 3.60Ϫ3.48 (m, 3 H, 5Ј-H, 6Ј-HA, 6Ј-HB), 3.47
(s, 3 H, OCH3) ppm. 13C NMR: δ ϭ 207.1 (CO), 151.3 (C-6), 138.6,
138.5, 138.1, 137.9, 137.6, 137.5 (Cquat, Ph), 128.3, 128.2, 128.1,
128.0, 127.9, 127.8, 127.6, 127.5, 127.3 (Ph), 102.3 (C-1Ј), 98.4 (C-
5), 84.1, 82.2, 79.0, 78.0, 75.0, 72.8 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-3, C-
4), 69.3, 68.5 (C-6Ј, C-1), 55.7 (OCH3) ppm. HRMS: calcd. for
C55H58O10: 896.4374 [M ϩ NH4]ϩ; found: 896.4376.
Ketoxime 3a (E/Z): This compound was prepared by the general
procedure from 2a (189 mg, 0.42 mmol) followed by column chro-
matography (SiO2; n-hexane/EtOAc, 75:25) to give 3a as a viscous
oil (156 mg, 80%). IR (CHCl3): ν˜ ϭ 3577, 3355, 3090, 3080, 1610,
Ketone 11d: This compound was prepared by the general procedure
from 10d (200 mg, 0.23 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 8:2) to give 11d as a viscous oil (179 mg,
90%). [α]D ϭ ϩ19.5 (c ϭ 1.1, CHCl3). IR (CHCl3): ν˜ ϭ 3050, 3015,
1
1460, 1095, 1075, 1040 cmϪ1. H NMR: δ ϭ 7.45Ϫ7.22 (m, 15 H,
Ph), 6.65 (d, J ϭ 14 Hz, 1 H, 6-H), 5.22Ϫ5.02 (m, 1 H, 5-H),
5.00Ϫ4.60 (m, 8 H, 3 CH2Ph, 1-HA, 1-HB), 4.58Ϫ4.43 (m, 1 H, 3-
H), 4.40Ϫ4.30 (m, 1 H, 4-H), 3.70 (s, 3 H, OCH3), 3.30 (br. s, OH)
ppm. 13C NMR: δ ϭ 156.8, 156.6 (C-2), 151.6, 151.5 (C-6), 138.6,
138.3, 138.0, 137.5, 137.6 (Cquat, Ph), 128.5, 128.4, 128.3, 128.2,
128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3 (Ph), 99.1, 98.6
(C-5), 81.9, 78.8, 78.0, 77.1 (C-3, C-4), 73.5, 73.2, 72.9, 72.1
(CH2Ph), 69.7, 67.9 (C-1), 55.8 (OCH3) ppm. HRMS: calcd. for
C28H31NO5: 479.2546 [M ϩ NH4]ϩ; found: 479.2543.
3010, 1730, 1690, 1555, 1520, 1430, 1280, 1160, 1110, 1090 cmϪ1
.
1H NMR: δ ϭ 7.45Ϫ7.30 (m, 30 H, Ph), 6.32 (d, J ϭ 13.1 Hz, 1
H, 6-H), 5.05 (d, J ϭ 4.2 Hz, 1 H, 1Ј-H), 5.03Ϫ4.65 (m, 5 H, 2
CH2Ph, 5-H), 4.58Ϫ4.42 (m, 12 H, 4 CH2Ph, 2Ј-H, 4Ј-H, 3-H, 4-
H), 4.35Ϫ3.52 (m, 6 H, 3Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB, 1-HA, 1-HB),
3.42 (s, 3 H, OCH3) ppm. 13C NMR: δ ϭ 206.7 (CO), 151.4 (C-6),
138.5, 138.3, 138.0, 137.5, 136.5 (Cquat, Ph), 128.0, 127.9, 127.8,
127.7, 127.6, 127.4, 127.3, 127.1, 126.9 (Ph), 97.6 (C-1Ј), 96.7 (C-
5), 86.5, 78.2, 77.8, 77.4 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-4), 75.4, 74.8,
74.3, 73.3, 73.1, 72.6 (CH2Ph), 70.1 (C-3), 69.2, 67.9 (C-6Ј, C-1),
55.5 (OCH3) ppm. HRMS: calcd. for C55H58O10: 896.4374 [M ϩ
NH4]ϩ; found: 896.4370.
Ketoxime 3b (E/Z): This compound was prepared by the general
procedure from 2b (183 mg, 0.41 mmol) followed by column chro-
matography (SiO2; n-hexane/EtOAc, 75:25) to give 3b as a viscous
oil (151 mg, 80%). IR (CHCl3): ν˜ ϭ 3578, 3350, 3090, 3080, 1615,
1520, 1510, 1500, 1460, 1100, 1075, 1040 cmϪ1 1H NMR: δ
.
(CDCl3): 7.45Ϫ7.12 (m, 15 H, Ph), 6.48 (d, J ϭ 13.3 Hz, 1 H, 6-
H), 5.01Ϫ4.62 (m, 10 H, 3 CH2Ph, 1-HA, 1-HB, 3-H, 5-H), 4.18
(dd, J ϭ 9.3, 7.0 Hz, 1 H, 4-H), 3.53 (s, 3 H, OCH3), 3.30 (br. s,
OH) ppm. 13C NMR: δ ϭ 155.8 (C-2), 151.3 (C-6), 138.1, 138.0,
137.9, 137.8, 137.4 (Cquat, Ph), 128.0, 127.9, 127.8, 127.7, 127.6,
127.5, 127.4, 127.2, 127.0, 126.8 (Ph), 99.4, 98.9 (C-5), 80.0, 77.8,
77.1, 76.8 (C-3, C-4), 75.9, 75.2, 72.9, 72.3, 72.2, 71.1 (CH2Ph),
68.8, 67.0 (C-1), 55.3 (OCH3) ppm. HRMS: calcd. for C28H31NO5:
479.2546 [M ϩ NH4]ϩ; found: 479.2541.
Ketone 11e: This compound was prepared by the general procedure
from 10e (200 mg, 0.23 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 8:2) to give 11e as an amorphous powder
(179 mg, 90%). [α]D ϭ ϩ2.6 (c ϭ 1.2, CHCl3). IR (CHCl3): ν˜ ϭ
3060, 3020, 3010, 1730, 1696, 1545, 1510, 1416, 1290, 1180, 1100,
1
1048 cmϪ1. H NMR: δ ϭ 7.41Ϫ7.26 (m, 30 H, Ph), 6.58 (d, J ϭ
12.5 Hz, 1 H, 6-H), 5.00Ϫ4.22 (m, 17 H, 6 CH2Ph, 1Ј-H, 2Ј-H, 3Ј-
H, 4Ј-H, 5-H), 4.13Ϫ3.88 (m, 1 H, 3-H), 3.92 (d, J ϭ 7.5 Hz, 1 H,
1-HA), 3.88 (d, J ϭ 7.5 Hz, 1 H, 1-HB), 3.60Ϫ3.48 (m, 4 H, 5Ј-H,
6Ј-HA, 6Ј-HB, 4-H), 3.51 (s, 3 H, OCH3) ppm. 13C NMR: δ ϭ 205.4
(CO), 151.4 (C-6), 138.1, 137.9, 137.6, 137.5 (Cquat, Ph), 127.8,
127.7, 127.6, 127.5, 127.3, 127.2, 127.0 (Ph), 102.9 (C-1Ј), 97.6 (C-
5), 86.1, 83.9, 81.5, 76.7, 75.1, 74.4 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-3, C-
4), 74.5, 74.1, 73.7, 73.1, 72.9 (CH2Ph), 70.2, 68.9 (C-6Ј, C-1), 55.4
(OCH3) ppm. HRMS: calcd. for C55H58O10: 896.4374 [M ϩ
NH4]ϩ; found: 896.4376.
Aldoxime 7a (E/Z): This compound was prepared by the general
procedure from 6a (97 mg, 0.30 mmol) followed by column chro-
matography (SiO2; n-hexane/EtOAc, 75:25) to give 7a as a viscous
oil (91 mg, 90%). IR (CHCl3): ν˜ ϭ 3568, 3340, 3078, 3070, 1625,
1560, 1520, 1510, 1470, 1100, 1085, 1030 cmϪ1. 1H NMR: δ ϭ 8.68
(br. s, OH), 7.38 (d, J ϭ 7.9 Hz, 1 H, 1-H), 7.40Ϫ7.20 (m, 10 H,
Ph), 6.40 (d, J ϭ 12.3 Hz, 1 H, 5-H), 4.72Ϫ4.62 (m, 3 H, CH2Ph,
H-4), 4.42 (t, J ϭ 12.3 Hz, 2 H, CH2Ph), 3.98 (dd, J ϭ 7.9, 5.7 Hz,
1 H, 2-H), 3.85 (dd, J ϭ 5.7, 3.3 Hz, 1 H, 3-H), 3.53 (s, 3 H, OCH3)
Ketone 15: This compound was prepared by the general procedure
from 14 (200 mg, 0.58 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 8:2) to give 15 as a viscous oil (189 mg,
95%). [α]D ϭ ϩ95.2 (c ϭ 1.1, CHCl3). IR (CHCl3): ν˜ ϭ 3100, 3050,
ppm. 13C NMR: δ ϭ 152.3 (C-1), 149.6 (C-5), 138.2, 137.7 (Cquat
,
Ph), 128.2, 128.1, 128.0, 127.9, 127.6, 127.4, 127.3 (Ph), 98.8 (C-4),
77.7, 76.8 (C-2, C-3), 71.0, 69.2 (CH2Ph), 55.9 (OCH3) ppm.
HRMS: calcd. for C20H23NO4: 359.1971 [M ϩ NH4]ϩ; found:
359.1975.
1730, 1695, 1625, 1525, 1510, 1500, 1380, 1230, 1190, 1130 cmϪ1
.
1H NMR: δ ϭ 7.35Ϫ7.15 (m, 10 H, Ph), 6.44 (d, J ϭ 12.5 Hz, 1
H, 6-H), 4.80 (dd, J ϭ 12.5, 9.1 Hz, 1 H, 5-H), 4.72 (d, J ϭ 13.7 Hz,
1 H, HA of CH2Ph), 4.57 (d, J ϭ 12.5 Hz, 1 H, HA of CH2Ph),
Aldoxime 7b (E/Z): This compound was prepared by the general
4.45 (d, J ϭ 12.5 Hz, 1 H, HB of CH2Ph), 4.24 (d, J ϭ 13.7 Hz, 1 procedure from 6b (97 mg, 0.30 mmol) followed by column chro-
5088  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 5083Ϫ5091

Neighboring-Group Participation in Beckmann Fragmentation Reactions
FULL PAPER
matography (SiO2; n-hexane/EtOAc, 75:25) to give 7b as a viscous
(OCH3) ppm. HRMS: calcd. for C55H59NO10: 911.4483 [M ϩ
oil (91 mg, 90%). IR (CHCl3): ν˜ ϭ 3578, 3350, 3090, 3070, 1620, NH4]ϩ; found: 911.4485.
1530, 1510, 1500, 1470, 1100, 1085, 1030 cmϪ1. 1H NMR: δ ϭ 8.68
Ketoxime 12d (E/Z): This compound was prepared by the general
(br. s, OH), 7.38 (d, J ϭ 7.9 Hz, 1 H, 1-H), 7.40Ϫ7.20 (m, 10 H,
Ph), 6.48 (d, J ϭ 12.9 Hz, 1 H, 5-H), 4.72Ϫ4.62 (m, 3 H, CH2Ph,
H-4), 4.42 (t, J ϭ 12.3 Hz, 2 H, CH2Ph), 3.98 (dd, J ϭ 7.9, 6.1 Hz,
1 H, 2-H), 3.85 (dd, J ϭ 6.1, 3.7 Hz, 1 H, 3-H), 3.53 (s, 3 H, OCH3)
procedure from 11d (179 mg, 0.20 mmol) followed by column chro-
matography (SiO2; n-hexane/EtOAc, 75:25) to give 12d as a viscous
oil (137 mg, 75%). IR (CHCl3): ν˜ ϭ 3570, 3358, 3078, 3080, 1620,
1457, 1120, 1100, 1090, 1065, 1040, 1028 cmϪ1 1H NMR: δ ϭ
.
ppm. 13C NMR: δ ϭ 151.9 (C-1), 149.6 (C-5), 138.2, 137.7 (Cquat
,
7.40Ϫ7.15 (m, 30 H, Ph), 6.50 (m, 1 H, 6-H), 5.15Ϫ4.38 (m, 14 H,
6 CH2Ph, 1Ј-H, 5-H), 4.36Ϫ4.20 (m, 7 H, 2Ј-H, 3Ј-H, 4Ј-H, 6Ј-HA,
6Ј-HB, 3-H, 4-H), 3.72Ϫ3.45 (m, 3 H, 5Ј-H, 1-HA, 1-HB), 3.45 (s,
1.7 of 3 H, OCH3), 3.43 (s, 1.3 of 3 H, OCH3) ppm. 13C NMR:
δ ϭ 156.1, 155.4 (C-2), 152.3, 151.4 (C-6), 138.5, 138.4, 138.3,
138.1, 138.0, 137.8, 137.7, 137.6 (Cquat, Ph), 127.9, 127.8, 127.6,
127.5, 127.4, 127.1, 127.0, 126.9, 126.8, 126.7 (Ph), 98.1, 97.9, 97.6
(C-1Ј, C-5), 82.9, 82.1, 79.9, 79.6, 77.4, 76.7, 75.8, 75.2, 74.7, 74.0,
71.9, 71.2 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-3, C-4), 75.4, 75.1, 74.9, 73.8,
73.5, 73.2, 73.1, 72.7, 70.0, 69.9, 69.0, 68.2, 67.6 (CH2Ph, C-6Ј, C-
1), 55.3 (OCH3) ppm. HRMS: calcd. for C55H59NO10: 911.4483 [M
ϩ NH4]ϩ; found: 911.4488.
Ph), 128.2, 128.0, 127.9, 127.8, 127.6, 127.5, 127.3 (Ph), 98.8 (C-4),
78.7, 77.9 (C-2, C-3), 71.0, 69.2 (CH2Ph), 55.9 (OCH3) ppm.
HRMS: calcd. for C20H23NO4: 359.1971 [M ϩ NH4]ϩ; found:
359.1969.
Ketoxime 12a (E/Z): This compound was prepared by the general
procedure from 11a (184 mg, 0.21 mmol) followed by column chro-
matography (SiO2; n-hexane/EtOAc, 75:25) to give 12a as a viscous
oil (150 mg, 80%). IR (CHCl3): ν˜ ϭ 3570, 3358, 3078, 3080, 1620,
1457, 1120, 1100, 1090, 1065, 1040, 1028 cmϪ1 1H NMR: δ ϭ
.
7.48Ϫ7.15 (m, 30 H, Ph), 6.45 (m, 1 H, 6-H), 5.05Ϫ4.38 (m, 14 H,
6 CH2Ph, 1Ј-H, 5-H), 4.36Ϫ4.20 (m, 7 H, 2Ј-H, 3Ј-H, 4Ј-H, 6Ј-HA,
6Ј-HB, 3-H, 4-H), 3.72Ϫ3.45 (m, 3 H, 5Ј-H, 1-HA, 1-HB), 3.45 (s,
1.7 of 3 H, OCH3), 3.43 (s, 1.3 of 3 H, OCH3) ppm. 13C NMR:
δ ϭ 155.5, 155.0 (C-2), 151.3, 151.1 (C-6), 138.4, 138.2, 138.1,
138.0, 137.8, 137.6, 137.5, 137.3 (Cquat, Ph), 127.9, 127.8, 127.7,
127.6, 127.5, 127.3, 127.2, 126.9, 126.7 (Ph), 100.6, 100.2 (C-1Ј),
98.6 (C-5), 84.3, 81.7, 81.5, 78.6, 77.4, 76.8, 75.9, 75.2, 74.8, 74.1,
73.9, 73.0 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-3, C-4), 75.4, 75.1, 74.9, 73.8,
73.5, 73.2, 73.1, 72.7, 70.0, 69.9, 69.0, 68.2, 67.6 (CH2Ph, C-6Ј, C-
1), 55.3 (OCH3) ppm. HRMS: calcd. for C55H59NO10: 911.4483 [M
ϩ NH4]ϩ; found: 911.4489.
Ketoxime 12e (E/Z): This compound was prepared by the general
procedure from 11e (179 mg, 0.20 mmol) followed by column chro-
matography (SiO2; n-hexane/EtOAc, 75:25) to give 12e as a viscous
oil (140 mg, 77%). IR (CHCl3): ν˜ ϭ 3570, 3357, 3088, 3080, 1618,
1
1457, 1110, 1065, 1040 cmϪ1. H NMR: δ ϭ 7.48Ϫ7.15 (m, 30 H,
Ph), 6.46 (m, 1 H, 6-H), 5.03Ϫ4.38 (m, 14 H, 6 CH2Ph, 1Ј-H, 5-
H), 4.30Ϫ4.15 (m, 7 H, 2Ј-H, 3Ј-H, 4Ј-H, 6Ј-HA, 6Ј-HB, 3-H, 4-H),
3.92 (m, 1 H, 5Ј-H), 3.70Ϫ3.43 (m, 2 H, 1-HA, 1-HB), 3.45 (s, 1.5
of 3 H, OCH3), 3.41 (s, 1.5 of 3 H, OCH3) ppm. 13C NMR: δ ϭ
155.3, 154.7 (C-2), 151.4, 151.0 (C-6), 139.2, 139.0, 138.9, 138.7,
138.6, 138.3, 137.9, 137.0 (Cquat, Ph), 128.8, 128.6, 128.4, 128.3,
128.2, 128.1, 127.9, 127.6 127.4, 127.2, 127.0 (Ph), 102.8, 102.4 (C-
1Ј), 97.4 (C-5), 85.7, 83.9, 81.5, 79.5, 79.2, 78.6, 77.8, 74.8, 74.1,
73.7 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-3, C-4), 75.4, 75.1, 74.9, 73.8, 73.5,
73.2, 73.1, 72.7, 70.0, 69.9, 68.8, 68.7, 68.3 (CH2Ph, C-6Ј, C-1),
55.2, 55.0 (OCH3) ppm. HRMS: calcd. for C55H59NO10: 911.4483
[M ϩ NH4]ϩ; found: 911.4487.
Ketoxime 12b (E/Z): This compound was prepared by the general
procedure from 11b (184 mg, 0.21 mmol) followed by column chro-
matography (SiO2; n-hexane/EtOAc, 75:25) to give 12b as a viscous
oil (146 mg, 78%). IR (CHCl3): ν˜ ϭ 3570, 3358, 3078, 3080, 1620,
1457, 1120, 1100, 1090, 1065, 1040, 1028 cmϪ1 1H NMR: δ ϭ
.
7.40Ϫ7.15 (m, 30 H, Ph), 6.50 (m, 1 H, 6-H), 5.15Ϫ4.38 (m, 14 H,
6 CH2Ph, 1Ј-H, 5-H), 4.36Ϫ4.20 (m, 7 H, 2Ј-H, 3Ј-H, 4Ј-H, 6Ј-HA,
6Ј-HB, 3-H, 4-H), 3.72Ϫ3.45 (m, 3 H, 5Ј-H, 1-HA, 1-HB), 3.45 (s,
1.7 of 3 H, OCH3), 3.43 (s, 1.3 of 3 H, OCH3) ppm. 13C NMR:
δ ϭ 155.1, 149.1 (C-2), 152.3, 151.1 (C-6), 138.4, 138.3, 138.1,
137.9, 137.7, 137.6, 137.4, 137.3 (Cquat, Ph), 127.9, 127.8, 127.7,
127.6, 127.3, 127.2, 126.9, 126.7, 126.6 (Ph), 99.0, 98.6, 97.6 (C-1Ј,
C-5), 84.3, 81.7, 81.5, 79.6, 77.4, 76.7, 75.8, 75.2, 74.7, 74.0, 71.9,
71.2 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-3, C-4), 75.4, 75.1, 74.9, 73.8, 73.5,
73.2, 73.1, 72.7, 70.0, 69.9, 69.0, 68.2, 67.6 (CH2Ph, C-6Ј, C-1),
55.3 (OCH3) ppm. HRMS: calcd. for C55H59NO10: 911.4483 [M ϩ
NH4]ϩ; found: 911.4480.
Ketoxime 16 (E/Z): This compound was prepared by the general
procedure from 15 (189 mg, 0.55 mmol) followed by column chro-
matography (SiO2; n-hexane/EtOAc, 75:25) to give 16 as a viscous
oil (158 mg, 80%). IR (CHCl3): ν˜ ϭ 3578, 3350, 3090, 3080, 1615,
1520, 1510, 1500, 1460, 1100, 1075, 1040 cmϪ1 1H NMR: δ ϭ
.
7.60Ϫ7.25 (m, 10 H, Ph), 6.40 (d, 0.6 of J ϭ 6.3 Hz, 1 H, 6-H),
6.36 (d, 0.4 of J ϭ 6.3 Hz, 1 H, 6-H), 5.05Ϫ4.42 (m, 5 H, 2 CH2Ph,
5-H), 4.15Ϫ3.97 (m, 2 H, 3-H, 4-H), 3.56 (s, 3 H, OCH3), 2.05 (s,
1.2 of 3 H, CH3), 1.98 (s, 1.8 of 3 H, CH3) ppm. 13C NMR: δ ϭ
157.9, 156.7 (C-2), 150.8 (C-6), 138.1, 137.5, 137.3 (Cquat, Ph),
127.7, 127.5, 127.3, 127.1, 127.0, 126.8 (Ph), 98.5, 98.3 (C-5), 83.5,
78.4, 77.4, 76.4 (C-3, C-4), 72.3, 71.0, 69.3, 69.1 (CH2Ph), 55.4
(OCH3), 15.9, 9.8 (C-1) ppm. HRMS: calcd. for C21H25NO4:
373.2127 [M ϩ NH4]ϩ; found: 373.2130.
Ketoxime 12c (E/Z): This compound was prepared by the general
procedure from 11c (187 mg, 0.21 mmol) followed by column chro-
matography (SiO2; n-hexane/EtOAc, 75:25) to give 12c as a viscous
oil (150 mg, 80%). IR (CHCl3): ν˜ ϭ 3570, 3357, 3088, 3080, 1618,
Synthesis of Nitriles 4a,b, 8b, 13a؊c and 17. General Procedure:
CH3SO2Cl (55 mg, 0.48 mmol) was added to a stirred solution of
the appropriate oxime (0.16 mmol) in dry CH2Cl2 (4 mL) and NEt3
(140 mg, 1.44 mmol). After stirring for 30 min at room tempera-
ture, the solvent was evaporated at reduced pressure and the residue
was taken up with Et2O, washed in a separating funnel with H2O
(till neutral), brine, dried with anhydrous Na2SO4 and the solvent
removed. The crude product was then purified by column chroma-
tography.
1
1457, 1110, 1065, 1040 cmϪ1. H NMR: δ ϭ 7.48Ϫ7.15 (m, 30 H,
Ph), 6.48 (m, 1 H, 6-H), 5.05Ϫ4.38 (m, 14 H, 6 CH2Ph, 1Ј-H, 5-
H), 4.35Ϫ4.15 (m, 7 H, 2Ј-H, 3Ј-H, 4Ј-H, 6Ј-HA, 6Ј-HB, 3-H, 4-H),
3.92 (m, 1 H, 5Ј-H), 3.72Ϫ3.45 (m, 2 H, 1-HA, 1-HB), 3.45 (s, 1.7
of 3 H, OCH3), 3.43 (s, 1.3 of 3 H, OCH3) ppm. 13C NMR: δ ϭ
156.3, 155.7 (C-2), 151.7, 151.5 (C-6), 139.2, 139.1, 139.0, 138.8,
138.6, 138.5, 138.2, 138.0 (Cquat, Ph), 128.6, 128.4, 128.3, 128.1,
127.9, 127.8, 127.6, 127.5, 127.4 (Ph), 101.8, 101.2 (C-1Ј), 99.4 (C-
5), 82.7, 82.5, 79.6, 79.5, 79.4, 78.6, 77.8, 74.8, 74.1, 73.7 (C-2Ј, C-
3Ј, C-4Ј, C-5Ј, C-3, C-4), 75.4, 75.1, 74.9, 73.8, 73.5, 73.2, 73.1, Nitrile 4a: This compound was prepared by the general procedure
72.7, 70.0, 69.9, 68.8, 68.7, 68.3 (CH2Ph, C-6Ј, C-1), 56.2, 56.0 from 3a (156 mg, 0.34 mmol) followed by column chromatography
Eur. J. Org. Chem. 2004, 5083Ϫ5091
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5089

P. Passacantilli, C. Centore, E. Ciliberti, G. Piancatelli, F. Leonelli
FULL PAPER
(SiO2; n-hexane/EtOAc, 85:15) to give 4a as a viscous oil (66 mg,
60%). [α]D ϭ Ϫ45.2 (c ϭ 1.4, CHCl3). IR (CHCl3): ν˜ ϭ 3100, 2900,
1H NMR: δ ϭ 7.40Ϫ7.10 (m, 25 H, Ph), 6.78 (d, J ϭ 12.6 Hz, 1
H, 5-H), 5.00 (d, J ϭ 6.3 Hz, 1 H, 1Ј-H), 4.96 (d, J ϭ 13.5 Hz, 1
1600, 1480, 1360, 1190, 1110, 1040, 1018 cmϪ1 1H NMR: δ ϭ H, HA of CH2Ph), 4.84 (dd, J ϭ 12.6, 7.5 Hz, 1 H, 4-H), 4.81 (d,
.
7.50Ϫ7.20 (m, 10 H, Ph), 6.59 (d, J ϭ 12.9 Hz, 1 H, 5-H), 4.88 (d,
J ϭ 13.5 Hz, 1 H, HB of CH2Ph), 4.74Ϫ4.38 (m, 11 H, 4 CH2Ph,
J ϭ 11.7 Hz, 1 H, HA of CH2Ph), 4.79 (dd, J ϭ 12.9, 8.7 Hz, 1 H, 2Ј-H, 3Ј-H, 4Ј-H), 4.32 (d, J ϭ 6.9 Hz, 1 H, 2-H), 4.02 (dd, J ϭ
4-H), 4.67 (s, 2 H, CH2Ph), 4.58 (d, J ϭ 11.7 Hz, 1 H, HB of 7.5, 6.9 Hz, 1 H, 3-H), 3.80Ϫ3.50 (m, 3 H, 5Ј-H, 6Ј-HA, 6Ј-HB),
CH2Ph), 4.28 (d, J ϭ 5.4 Hz, 1 H, 2-H), 3.95 (dd, J ϭ 8.7, 5.4 Hz,
3.56 (s, 3 H, OCH3) ppm. 13C NMR: δ ϭ 153.5 (C-5), 138.5, 138.0,
1 H, 3-H), 3.62 (s, 3 H, OCH3) ppm. 13C NMR: δ ϭ 153.3 (C-5), 137.8, 137.6 (Cquat, Ph), 128.2, 127.9, 127.5 (Ph), 116.6 (CN), 99.6
137.6, 135.8 (Cquat, Ph), 128.7, 128.5, 128.3, 127.7 (Ph), 116.6 (CN), (C-1Ј), 96.5 (C-4), 81.5, 79.3, 77.2, 71.5 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-
97.0 (C-4), 76.6 (C-3), 72.5 (CH2Ph), 71.6 (C-2), 69.8 (CH2Ph), 3), 70.9 (C-2), 75.6, 75.0, 73.5, 72.8, 69.7, 67.6 (CH2Ph, C-6Ј), 56.2
56.1 (OCH3) ppm. HRMS: calcd. for C20H21NO3: 341.1865 [M ϩ (OCH3) ppm. HRMS: calcd. for C48H51NO8: 787.3802 [M ϩ
NH4]ϩ; found: 341.1870.
NH4]ϩ; found: 787.3807.
Nitrile 4a: This compound was prepared by the general procedure
from 7a (91 mg, 0.27 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 85:15) to give 4a (77 mg, 90%).
Nitrile 13c: This compound was prepared by the general procedure
from 12c (150 mg, 0.17 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 85:15) to give 13c as a viscous oil (76 mg,
60%). [α]D ϭ Ϫ37.0 (c ϭ 1.4, CHCl3). IR (CHCl3): ν˜ ϭ 3058, 3022,
Nitrile 4a: This compound was prepared by the general procedure
from 12d (137 mg, 0.15 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 85:15) to give 4a (15 mg, 30%).
3018, 1760, 1698, 1540, 1500, 1418, 1300, 1180, 1100, 1048 cmϪ1
.
1H NMR: δ ϭ 7.40Ϫ7.26 (m, 25 H, Ph), 6.58 (d, J ϭ 12.6 Hz, 1
H, 5-H), 4.95Ϫ4.59 (m, 10 H, 4 CH2Ph, HA of CH2Ph, 4-H), 4.43
(m, 4 H, HB of CH2Ph, 1Ј-H, 2Ј-H, 2-H), 4.05 (dd, J ϭ 9.3, 9.3 Hz,
1 H, 3-H), 3.91 (d, J ϭ 2.7 Hz, 1 H, 4Ј-H), 3.81 (dd, J ϭ 9.9,
9.0 Hz, 1 H, 5Ј-H), 3.62Ϫ3.51 (m, 3 H, 3Ј-H, 6Ј-HA, 6Ј-HB), 3.47
(s, 3 H, OCH3) ppm. 13C NMR: δ ϭ 153.3 (C-5), 138.2, 138.0,
137.9, 137.7, 137.4 (Cquat, Ph), 128.3, 128.0, 127.8, 127.7, 127.4
(Ph), 116.1 (CN), 101.2 (C-1Ј), 96.9 (C-4), 81.6, 78.6, 75.8, 73.7,
73.4 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-3), 74.9, 74.6, 73.5, 73.3, 69.49
(CH2Ph), 68.7 (C-2), 68.3 (C-6Ј), 55.9 (OCH3) ppm. HRMS: calcd.
for C48H51NO8: 787.3802 [M ϩ NH4]ϩ; found: 787.3803.
Nitrile 4a: This compound was prepared by the general procedure
from 12e (140 mg, 0.16 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 85:15) to give 4a (20 mg, 40%).
Nitrile 4b: This compound was prepared by the general procedure
from 3b (151 mg, 0.33 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 85:15) to give 4b as a viscous oil (64 mg,
60%). [α]D ϭ ϩ18.0 (c ϭ 1.4, CHCl3). IR (CHCl3): ν˜ ϭ 3100, 3090,
3070, 1680, 1618, 1587, 1540, 1500, 1420, 1400, 1390, 1020 cmϪ1
.
1H NMR: δ ϭ 7.50Ϫ7.20 (m, 10 H, Ph), 6.62 (d, J ϭ 13.3 Hz, 1
H, 5-H), 4.98 (d, J ϭ 11.6 Hz, 1 H, HA of CH2Ph), 4.75Ϫ4.60 (m,
3 H, CH2Ph, 4-H), 4.58 (d, J ϭ 11.6 Hz, 1 H, HB of CH2Ph), 4.20
(d, J ϭ 6.0 Hz, 1 H, 2-H), 4.05 (dd, J ϭ 6.6, 6.0 Hz, 1 H, 3-H),
3.55 (s, 3 H, OCH3) ppm. 13C NMR: δ ϭ 152.9 (C-5), 137.4, 135.7
(Cquat, Ph), 128.7, 128.5, 128.4, 128.3, 127.5 (Ph), 116.8 (CN), 97.4
(C-4), 76.6 (C-3), 72.3 (CH2Ph), 71.3 (C-2), 69.7 (CH2Ph), 56.0
(OCH3) ppm. HRMS: calcd. for C20H21NO3: 341.1865 [M ϩ
NH4]ϩ; found: 341.1862.
Mesylate 17 (E/Z): This compound was prepared by the general
procedure from 16 (158 mg, 0.44 mmol) followed by column chro-
matography (SiO2; n-hexane/EtOAc, 85:15) to give 17 as a viscous
oil (172 mg, 90%). IR (CHCl3): ν˜ ϭ 3578, 3350, 3090, 3071, 1630,
1520, 1510, 1480, 1460, 1100, 1075, 1040 cmϪ1 1H NMR: δ ϭ
.
7.40Ϫ7.20 (m, 10 H, Ph), 6.58 (d, 0.1 of J ϭ 13.3 Hz, 1 H, 6-H),
6.47 (d, 0.9 of J ϭ 13.3 Hz, 1 H, 6-H), 4.80Ϫ4.32 (m, 6 H, 2
CH2Ph, 3-H, 5-H), 3.84 (dd, J ϭ 9.9, 4.7 Hz, 1 H, 4-H), 3.53 (s,
0.1 of 3 H, OCH3), 3.48 (s, 0.9 of 3 H, OCH3), 2.94 (s, 3 H,
CH3SO2), 2.04 (s, 3 H, CH3) ppm. 13C NMR: δ ϭ 168.5 (C-2),
153.6, 152.0 (C-6), 137.9, 136.8 (Cquat, Ph), 128.4, 128.1, 127.8,
127.6, 127.5 126.8 (Ph), 97.7, 95.3 (C-5), 81.7, 77.9, 77.6 (C-3, C-
4), 73.2, 70.1, 69.4 (CH2Ph), 56.1, 55.9 (OCH3), 36.2 (CH3SO2),
16.6 (C-1) ppm. HRMS: calcd. for C22H27NO6S: 451.1903 [M ϩ
NH4]ϩ; found: 451.1907.
Nitrile 8b: This compound was prepared by the general procedure
from 7b (91 mg, 0.27 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 85:15) to give 8b (the enantiomer of 4b) as
a viscous oil (77 mg, 90%). [α]D ϭ Ϫ18.2 (c ϭ 1.3, CHCl3).
Nitrile 13a: This compound was prepared by the general procedure
from 12a (150 mg, 0.17 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 85:15) to give 13a as a viscous oil (76 mg,
60%). [α]D ϭ Ϫ25.6 (c ϭ 1.4, CHCl3). IR (CHCl3): ν˜ ϭ 3048, 3046,
Preparation of Aldehydes 18a,b. General Procedure: 4  HCl (1 mL)
was added to a solution of the appropriate enol ether (0.60 mmol)
in THF (5 mL) and then stirred at room temperature for 4 h. The
3022, 3018, 1696, 1540, 1500, 1415, 1220, 1182, 1098, 1022 cmϪ1
.
1H NMR: δ ϭ 7.40Ϫ7.26 (m, 25 H, Ph), 6.60 (d, J ϭ 13.2 Hz, 1 reaction mixture was diluted with Et2O and washed in a separating
H, 5-H), 4.90Ϫ4.40 (m, 16 H, 5 CH2Ph, 1Ј-H, 2Ј-H, 3Ј-H, 4Ј-H, 2-
funnel with NaHCO3, H2O, brine and dried with anhydrous
H, 4-H), 4.05 (dd, J ϭ 9.8, 5.0 Hz, 1 H, 3-H), 3.65Ϫ3.45 (m, 3 H, Na2SO4. After evaporation of the solvent under reduced pressure
5Ј-H, 6Ј-HA, 6Ј-HB), 3.40 (s, 3 H, OCH3) ppm. 13C NMR: δ ϭ the crude product was purified by column chromatography.
153.0 (C-5), 138.0, 137.6, 137.4, 137.1 (Cquat, Ph), 127.9, 127.8,
Aldehyde 18a: This compound was prepared by the general pro-
127.6, 127.3, 127.1 (Ph), 115.6 (CN), 100.6 (C-1Ј), 96.4 (C-4), 83.7,
cedure from 4a (150 mg, 0.46 mmol) followed by column chroma-
80.9, 76.7, 75.6, 74.5, (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-3), 75.1, 74.4, 74.1,
tography (SiO2; n-hexane/EtOAc, 7:3) to give 18a as a viscous oil
72.9, 69.1 (CH2Ph), 68.6 (C-2), 67.9 (C-6Ј), 55.5 (OCH3) ppm.
(122 mg, 85%). [α]D ϭ Ϫ22.5 (c ϭ 1.4, CHCl3). IR (CHCl3): ν˜ ϭ
HRMS: calcd. for C48H51NO8: 787.3802 [M ϩ NH4]ϩ; found:
3100, 2900, 2700, 1700, 1500, 1480, 1360, 1190, 1110, 1040, 1018
787.3805.
cmϪ1. 1H NMR: δ ϭ 9.72 (t, J ϭ 1.5 Hz, 1 H, HϪCO), 7.45Ϫ7.27,
Nitrile 13b: This compound was prepared by the general procedure
from 12b (146 mg, 0.16 mmol) followed by column chromatography
(SiO2; n-hexane/EtOAc, 85:15) to give 13b as a viscous oil (68 mg,
55%). [α]D ϭ ϩ44.0 (c ϭ 1.1, CHCl3). IR (CHCl3): ν˜ ϭ 3033, 3030,
(m, 10 H, Ph), 4.82 (d, J ϭ 12.0 Hz, 1 H, HA of CH2Ph), 4.64 (s,
2 H, CH2Ph), 4.49 (d, J ϭ 12.0 Hz, 1 H, HB of CH2Ph), 4.22 (m,
2 H, 2-H, 3-H), 2.88 (dd, J ϭ 5.7, 1.5 Hz, 2 H, 4-H) ppm. 13C
NMR: δ ϭ 198.0 (CO), 136.8, 135.0 (Cquat, Ph), 128.6, 128.4, 128.0,
127.9 (Ph), 116.1 (CN), 73.5, 72.74 (CH2Ph), 73.0, 69.1 (C-2, C-3),
3020, 3010, 1696, 1540, 1510, 1410, 1222, 1182, 1098, 1020 cmϪ1
.
5090
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5083Ϫ5091

Neighboring-Group Participation in Beckmann Fragmentation Reactions
FULL PAPER
[1]
45.0 (C-4) ppm. HRMS: calcd. for C19H19NO3: 327.1709 [M ϩ
C. A. Grob, P. W. Schiess, Angew. Chem. Int. Ed. Engl. 1967,
6, 1Ϫ15.
R. E. Gawley, Organic Reactions (Ed.: A. S. Kende), John
Wiley & Sons, New York, 1988, pp. 1Ϫ420.
M. S. Laxmisha, G. S. R. Subba Rao, Tetrahedron Lett. 2000,
41, 3759Ϫ3761.
A. Garzia Martinez, E. Teso Vilar, A. Garzia Fraile, S. de la
Moya Cerero, B. Lora Maroto, Eur. J. Org. Chem. 2002,
781Ϫ783.
C. Wang, X. Jiang, H. Shi, J. Lu, Y. Hu, H. Hu, J. Org. Chem.
2003, 68, 4579Ϫ4581.
A. H. Fenselau, E. H. Hamamura, J. G. Moffatt, J. Org. Chem.
1970, 35, 3546Ϫ3552.
D. C. Mammato, G. A. Eadon, J. Org. Chem. 1975, 40,
1784Ϫ1792.
M. Han, D. F. Covey, J. Org. Chem. 1996, 61, 7614Ϫ7616.
X. Jiang, C. Wang, Y. Hu, H. Hu, J. Org. Chem. 2000, 65,
3555Ϫ3557.
R. E. Dolle, H. S. Allaudeen, L. I. Kruse, J. Med. Chem. 1990,
33, 877Ϫ880.
A. Kuhl, H. Karels, W. Kreiser, Helv. Chim. Acta 1999, 82,
30Ϫ34.
H. Nishiyama, K. Sakuta, N. Osaka, H. Arai, M. Matsumoto,
K. Itoh, Tetrahedron 1988, 44, 2413Ϫ2426 and references ther-
ein.
NH4]ϩ; found: 327.1703.
[2]
Aldehyde 18b: This compound was prepared by the general pro-
cedure from 13c (152 mg, 0.20 mmol) followed by column chroma-
tography (SiO2; n-hexane/EtOAc, 7:3) to give 18b as a viscous oil
(117 mg, 80%). [α]D ϭ Ϫ42.5 (c ϭ 1.6, CHCl3). IR (CHCl3): ν˜ ϭ
[3]
[4]
3090, 3050, 2910, 2700, 1705, 1510, 1480, 1360, 1188, 1110, 1050,
1018 cmϪ1 1H NMR: δ ϭ 9.72 (t, J ϭ 1.6 Hz, 1 H, H-CO),
.
[5]
[6]
[7]
7.45Ϫ7.27 (m, 25 H, Ph), 4.92Ϫ4.58 (m, 11 H, 5 CH2Ph, 1Ј-H),
4.42Ϫ4.30 (m, 2 H, 2Ј-H, 3-H), 4.05 (d, J ϭ 2.7 Hz, 1 H, 4Ј-H),
3.81 (dd, J ϭ 9.3, 9.3 Hz, 1 H, 5Ј-H), 3.62Ϫ3.51 (m, 4 H, 3Ј-H, 6Ј-
HA, 6Ј-HB, 2-H), 2.90Ϫ2.82 (m, 2 H, 4-HA, 4-HB) ppm. 13C NMR:
δ ϭ 197.8 (CO), 138.4, 138.2, 138.1, 137.9, 137.5 (Cquat, Ph), 128.6,
128.5, 128.3, 128.1, 127.4 (Ph), 116.1 (CN), 101.6 (C-1Ј), 81.6, 78.6,
75.8, 73.7, 73.4 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-3), 74.9, 74.6, 73.5, 73.3,
69.49 (CH2Ph), 68.7 (C-2), 68.3 (C-6Ј), 41.8 (C-4) ppm. HRMS:
calcd. for C46H47NO8: 759.3645 [M ϩ NH4]ϩ; found: 759.3648.
[8]
[9]
[10]
[11]
[12]
Synthesis of Pyranosylamine 19a: NaBH4 (59 mg, 1.5 mmol) was
added to a solution of 18a (120 mg, 0.39 mmol) in dry THF (2 mL)
and abs. EtOH (2 mL). The mixture was refluxed for 1.5 h and the
solvent was removed under reduced pressure. The residue was taken
up with Et2O/EtOAc, 1:1, washed in a separating funnel with H2O
(till neutral), brine, dried with anhydrous Na2SO4 and the solvent
removed. The crude product was then purified by column chroma-
tography (SiO2; n-hexane/EtOAc, 6:4) to give 19a as a viscous oil
(67 mg, 55% yield). [α]D ϭ ϩ12.8 (c ϭ 1.1, CHCl3). IR (CHCl3):
ν˜ ϭ 3390, 3350, 3010, 2990, 1690, 1510, 1480, 1360, 1188, 1110,
[13]
I. Fleming, P. Maiti, R. Ramarao, Org. Biomol. Chem. 2003,
1, 3989Ϫ4004.
[14]
[15]
[16]
R. K. Hill, J. Org. Chem. 1962, 27, 29Ϫ35.
P. Passacantilli, Tetrahedron Lett. 1989, 30, 5349Ϫ5352.
E. Bettelli, P. D’Andrea, S. Mascanzoni, P. Passacantilli, G.
Piancatelli, Carbohydr. Res. 1998, 306, 221Ϫ230.
E. Bettelli, P. Chinzari, P. D’Andrea, P. Passacantilli, G. Pian-
catelli, A. Topai, Korean J. Med. Chem. 1996, 6, 339Ϫ343;
[Chem. Abstr. 1997, 126, 157 730].
A. D. Dorsey, J. E. Barbarow, D. Trauner, Org. Lett. 2003, 5,
3237Ϫ3239 and references therein.
H. Yoon, S. B. King, B. Ganem, Tetrahedron Lett. 1991, 32,
7199Ϫ7202.
G. Papandreou, M. K. Tong, B. Ganem, J. Am. Chem. Soc.
1050, 1018 cmϪ1
.
1H NMR: δ ϭ 7.36Ϫ7.20 (m, 10 H, Ph),
[17]
4.72Ϫ4.43 (m, 5 H, 2 CH2Ph, 1-H), 3.82Ϫ3.62 (m, 4 H, 2-H, 3-H,
5-HA, 5-HB), 2.63 (br. s, 2 H, NH2), 1.98Ϫ1.80 (m, 2 H, 4-HA, 4-
HB) ppm. 13C NMR: δ ϭ 137.9, 137.7 (Cquat, Ph), 128.3, 127.5,
127.2, 127.0 (Ph), 77.7, 77.1, 63.9 (C-1, C-2, C-3), 71.6 (CH2Ph),
59.6 (C-5), 33.9 (C-4) ppm. HRMS: calcd. for C19H23NO3:
331.2022 [M ϩ NH4]ϩ; found: 331.2028.
[18]
[19]
[20]
[21]
Synthesis of Pyranosylamine 19b: This compound was prepared
from 18b (117 mg, 0.16 mmol) in accord with the procedure de-
scribed for 19a, refluxing the reaction mixture for 4 h. The crude
product was purified by column chromatography (SiO2; n-hexane/
1993, 115, 11682Ϫ11690.
B. Ganem, M. K. Tong, G. Papandreou, PCT Int. Appl., WO
93 02091 A1, 1993; [Chem. Abstr. 1993, 119, 139697b].
B. Ganem, Acc. Chem. Res. 1996, 29, 340Ϫ347.
W. Canfield, U. S. Pat. Appl., US 2003/0133924 A1, 2003
[Chem. Abstr. 2003, 139, 112730h].
P. Passacantilli, S. Pepe, G. Piancatelli, D. Pigini, A. Squarcia,
Tetrahedron 2004, 60, 6453Ϫ6459.
[22]
[23]
EtOAc, 7:3) to give 19b as a viscous oil (65 mg, 55% yield). [α]D
Ϫ17.5 (c ϭ 1.2, CHCl3). IR (CHCl3): ν˜ ϭ 3389, 3350, 3012, 2990,
1692, 1516, 1478, 1360, 1188, 1110, 1048, 1013 cmϪ1 1H NMR:
ϭ
[24]
.
δ ϭ 7.42Ϫ7.20 (m, 25 H, Ph), 5.12Ϫ4.52 (m, 12 H, 4 CH2Ph, 1Ј-
H, 2Ј-H, 3Ј-H, 1-H), 4.43 (s, 2 H, CH2Ph), 3.95Ϫ3.83 (m, 3 H, 4Ј-
H, 2-H, 3-H), 3.80Ϫ3.68 (m, 3 H, 5Ј-H, 6Ј-HA, 6Ј-HB), 3.62Ϫ3.52
(m, 2 H, 5-HA, 5-HB), 2.05Ϫ1.85 (m, 2 H, 4-HA, 4-HB), 1.72 (br.
[25]
[26]
P. Ermert, A. Vasella, Helv. Chim. Acta 1991, 74, 2043Ϫ2053.
T. D. Heightman, P. Ermert, D. Klein, A. Vasella, Helv. Chim.
Acta 1995, 78, 514Ϫ532.
[27]
[28]
See ref.[2] and references therein, especially refs.[56,95]
.
s, 2 H, NH2) ppm. 13C NMR: δ ϭ 137.9, 137.7, 137.2, 137.0 (Cquat
,
L. E. Overman, D. J. Ricca, V. D. Tran, J. Am. Chem. Soc.
1993, 115, 2042Ϫ2044.
P. Deprez, J. Royer, H. P. Husson, Tetrahedron 1993, 49,
3781Ϫ3792.
K. Dwek, Chem. Rev. 1996, 96, 683Ϫ720.
G. Arsequell, G. Valencia, Tetrahedron: Asymmetry 1999, 10,
3045Ϫ3094.
M. J. Grogan, M. R. Pratt, L. A. Marcaurelle, C. R. Bertozzi,
Annu. Rev. Biochem. 2002, 71, 593Ϫ634.
K. C. Nicolaou, S. A. Snyder, A. Z. Nalbandian, D. A. Long-
bottom, J. Am. Chem. Soc. 2004, 126, 6234Ϫ6235.
Received July 16, 2004
Ph), 128.0, 127.8, 127.6, 127.3, 127.0 (Ph), 101.3 (C-1Ј), 81.4, 78.3,
76.6, 75.4, 74.7, 73.3, 67.9, (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-1, C-2, C-3),
74.5, 74.4, 73.5, 73.0 (CH2Ph), 67.6 (C-6Ј), 58.7 (C-5), 32.7 (C-
4) ppm. HRMS: calcd. for C46H51NO8: 763.3958 [M ϩ NH4]ϩ;
found: 763.3960.
[29]
[30]
[31]
[32]
[33]
Acknowledgments
We thank the University ‘‘La Sapienza’’ of Rome for financial sup-
port.
Eur. J. Org. Chem. 2004, 5083Ϫ5091
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5091