Sequential nucleophilic addition/intramolecular cycloaddition to chiral nonracemic cyclic nitrones: A highly stereoselective approach to polyhydroxynortropane alkaloids

Article abstract of DOI:10.1021/jo200315k

Two new polyhydroxylated nortropane analogues closely related with Calystegines have been prepared in excellent chemical yields and complete selectivity. A synthetic strategy based on consecutive nucleophilic allylation, oxidation, and intramolecular dipolar cycloaddition was developed. The formation of key intermediate cycloadducts were observed to take place through the recently confirmed thermally induceded 2-aza-Cope rearrangement of nitrones.

Full text of DOI:10.1021/jo200315k

NOTE
pubs.acs.org/joc
Sequential Nucleophilic Addition/Intramolecular Cycloaddition to
Chiral Nonracemic Cyclic Nitrones: A Highly Stereoselective Approach
to Polyhydroxynortropane Alkaloids
Ignacio Delso,†,‡ Tomꢀas Tejero,‡ Andrea Goti,*,§ and Pedro Merino*,‡
†Servicio de Resonancia Magnetica Nuclear, CEQMA and ‡Departamento de Quimica Organica, Instituto de Sintesis Quimica y Catalisis
Homogenea (ISQCH), Universidad de Zaragoza, CSIC, 50009 Zaragoza, Aragoꢀn, Spain
§Dipartimento di Chimica Organica “Ugo Schiff”, Universitꢁa di Firenze, ICCOM-CNR, via della Lastruccia 13,
50019 Sesto Fiorentino (FI), Italy
S Supporting Information
b
ABSTRACT: Two new polyhydroxylated nortropane analogues closely related
with Calystegines have been prepared in excellent chemical yields and complete
selectivity. A synthetic strategy based on consecutive nucleophilic allylation,
oxidation, and intramolecular dipolar cycloaddition was developed. The forma-
tion of key intermediate cycloadducts were observed to take place through the
recently confirmed thermally induceded 2-aza-Cope rearrangement of nitrones.
alystegines are a class of polyhydroxylatednortropane alka-
loids that have been isolated from plants in the Convolvu-
C
laceae, Solanaceae, and Moraceae families, and they have been
shown to strongly inhibit glycosidases (Figure 1).1
It has been well-demonstrated for mono- and bicyclic poly-
hydroxylated alkaloids (e.g., pyrrolidines, indolizidines, and
pyrrolizidines) that stereochemical modifications to any of the
chiral centers of the molecule (including addition and/or elim-
ination of hydroxyl groups) can dramatically change the biolo-
gical activities toward the target glycosidases.2 As a consequence,
a considerable synthetic effort has been focused on the synthesis
of naturally occurring calystegines.3 However, much less effort
has been devoted to addressing calystegine-type nortropanes.4 A
few syntheses have been reported so far using nitrones as key
synthetic intermediates. Shing5 and Tamayo6 have used nitrones
as early intermediates in the synthesis of calystegines forming the
bicyclic system by intramolecular nucleophilic attack of nitrogen
to a keto group in the last step, and Kaliappan has reported
recently the synthesis of calystegine analogues based on addition
of organometallics to a cyclic nitrone.7 Syntheses of nortropane
alkaloids using nitrones as intermediates have been reported by
Black,8 Tufariello,9 and Davis,10
Here we report our own results in the field based on a com-
bination of organometallic addition and intramolecular cyclo-
addition to nitrones applied for the first time to the synthesis of
polyhydroxylated alkaloids. Additional experimental evidence for
the 2-aza-Cope rearrangement of alkenyl nitrones11 has been
collected during this study. In order to access heavily hydro-
xylated nortropanes, we selected nitrone 1 (Scheme 1), readily
prepared from D-arabinose in four steps,12 for this study. The
planned strategy involves allylation13 of nitrone 1 followed by
oxidation14 and further intramolecular 1,3-dipolar cycloaddition
of the resulting alkenyl nitrone.8,15
Figure 1. Calystegines isolated from natural sources (numbering is
indicated).
Allylation of 1 was carried out at 0 °C with an excess (3.0
equiv) of allylmagnesium bromide and furnished hydroxylamine
2 with complete diastereoselectivity and excellent chemical
yield.16 The relative stereochemistry of the newly generated
stereogenic center was confirmed by 2D NMR (NOESY and
COSY) experiments. Consistent with our previous reports
concerning nucleophilic additions to 1 and related nitrones,17
the observed high diastereofacial selectivity may be rationalized
by steric effects which concur to favor attack of the Grignard
reagent on the less hindered Re face of the nitrone, anti to the
vicinal benzyloxy substituent.18 Oxidation of 2 with manganese-
(IV) oxide19 gave nitrone 3 in 73% yield. In addition, the
regioisomeric nitrone 4 (24%) and isomerized nitrone 5 (3%)
were obtained (Scheme 1). When nitrone 3 was heated in a
sealed tube in toluene at 120 °C for 14 h, the cycloadduct 6 was
obtained in 97% yield, with complete regio- and stereocontrol, as
the only product of the reaction. The configurational assignment
of 6 was achieved by careful analyses of 1D and 2D NMR spectra.
Catalytic hydrogenolysis (10% Pd(OH)2ꢀC) in acidic methanol
furnished the hydrochloride 7 in quantitative yield (Scheme 1).
Received: February 17, 2011
Published: April 15, 2011
r
2011 American Chemical Society
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Scheme 1. Synthesis of Polyhydroxylated Nortropane
Scheme 3. Synthesis of Phenyl-Substituted Nortropane
The formation of nitrone 11 is consistent with a thermally
promoted 2-aza-Cope rearrangement of nitrone 10 through the
cyclic transition state A (Scheme 3). The same rearrangement
has been detected rarely for both cyclic and acyclic nitrones.11
We have demonstrated both theoretically and experimentally
that the energy barrier of the rearrangement is comparable to that
required for the intramolecular cycloaddition.11 Isolation of
nitrone 11 constitutes another clear experimental evidence for
such rearrangement. In the case of nitrone 10 the driving force
responsible for the rapid formation of 11 is the enhanced stability
of the latter due to the conjugation between the nitrone
functionality and the phenyl group. The allyl group may migrate
only on one face of the nitrone due to its cyclic structure, thus
producing a unique stereoisomer. Therefore, this rearrangement
may be used in principle for synthesizing nitrones hardly
accessible by other means. Indeed, milder heating of 10 at
80 °C furnished the isomeric nitrone 11 as the only product.
From a synthetic point of view, the formation of nitrone 11 is
not problematic since intramolecular 1,3-dipolar cycloaddition of
11 would afford the same adduct 12 (Scheme 3). Isomeric
nitrones 10 and 11 are connected by chairlike six-membered
transition state A, corresponding to allylic fragment rearrange-
ment, as demonstrated through theoretical calculations.11 In-
deed, prolonged heating (36 h) of the reaction mixture led to
cycloadduct 12 in quantitative yield. Finally, catalytic hydrogena-
tion of 12 under acidic conditions afforded, in quantitative yield,
1-phenyl-nor-tropane derivative 13 which was isolated and
characterized as the corresponding hydrochloride salt. It is
worthy to note that a 5-phenylnortropane related to 13 under-
went reductive ring-opening to the corresponding aminocyclo-
heptane by catalytic hydrogenation with Pd/C under similar
pressure (40 psi).8c
Scheme 2. Synthesis of Phenyl-Substituted Nortropane
In order to study the generality of the process and exploit
molecular diversity by introducing an additional substituent at
the bridgehead C-5 (calystegine’s numbering), the above proto-
col was applied to the nitrone 8 which was prepared by addition
of phenylmagnesium bromide to 1 and subsequent oxidation as
described.20 Allylation of 8 in THF at 0 °C afforded the
hydroxylamine 9 in quantitative yield as the only diastereomer.
Again, the configurational assignment of 9, ascertained by NMR
techniques, was in agreement with attack to the less hindered Re
face. In this case, the oxidation of 9 with MnO2 afforded in
quantitative yield only the expected nitrone 10, as a consequence
of C-2 being a quaternary carbon atom (Scheme 2).
In summary, we have reported a versatile method for the
synthesis of polyhydroxylated nortropane analogues related to
calystegines, substituted at both bridgehead carbon atoms with
defined configuration. These patterns of substitution are other-
wise difficult to obtain, and the methodology described here is
expected to find further application in the synthesis of nortro-
pane alkaloids.
’ EXPERIMENTAL SECTION
Upon heating in toluene at 120 °C in a sealed tube for 14 h,
complete conversion of 10 was observed. In contrast to the
behavior of 3, formation of nitrone 11 was also observed in
addition to the expected adduct 12, the ratio 11:12 being 38:62.
General Methods. The reaction flasks and other glass equipment
were heated in an oven at 130 °C overnight and assembled in a stream of
Ar. All reactions were monitored by TLC on silica gel 60 F254; the
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position of the spots was detected with 254 nm UV light or by spraying
with one of the following staining systems: 50% methanolic sulfuric acid,
5% ethanolic phosphomolybdic acid, or iodine. Preparative centrifugally
accelerated radial thin-layer chromatography (radial chromatography)
was performed with solvents that were distilled prior to use; the rotors
(1 or 2 mm layer thickness) were coated with silica gel TLC grade with
binder and fluorescence indicator, and the eluting solvents were
delivered by the pump at a flow rate of 0.5ꢀ1.5 mL minꢀ1. Column
chromatography was carried out in a MPLC system using silica gel 60
μm. Melting points were uncorrected. 1H and 13C NMR spectra were
recorded on 400 or 500 instruments in the stated solvent. Chemical
shifts are reported in ppm (δ) relative to CHCl3 (δ = 7.26) in CDCl3.
Peak assignments were made on the basis of standard COSY and
NOESY experiments and according to numbering represented in
Figure 1 for compounds 7 and 13.
CH2Ph), 4.49 (s, 2H, CH2Ph), 4.50 (d, J = 11.7 Hz, 1H, CH2Ph), 4.57
(d, J = 11.7 Hz, 1H, CH2Ph), 4.60 (dt, J = 14.6, 0.9 Hz, 1H, CH2OBn),
4.62ꢀ4.64 (m, 1H, H4), 5.02ꢀ5.05 (m, 1H, CH2CHdCH2),
5.06ꢀ5.08 (m, 1H, CH2CHdCH2), 5.65 (dddd, J = 16.6, 10.8, 7.9,
6.2 Hz, 1H, CH2CHdCH2), 7.17ꢀ7.31 (m, 15H, Ar); 13C NMR (100
MHz, CDCl3) δ 35.4 (CH2CHdCH2), 62.7 (CH2OBn), 71.4
(CH2Ph), 72.5 (CH2Ph), 73.6 (CH2Ph), 78.5 (C2), 79.8 (C3), 82.8
(C4), 119.2 (CH2CHdCH2), 127.8 (Ar), 128.0 (Ar), 128.0 (Ar), 128.0
(Ar), 128.1 (Ar), 128.5 (Ar), 128.6 (Ar), 132.5 (CH2CHdCH2), 137.0
(Ar), 137.4 (Ar), 137.5 (Ar), 142.6 (C5). Anal. Calcd for C29H31NO4: C,
76.12; H, 6.83; N, 3.06. Found: C, 76.33; H, 6.66; N, 2.92.
4 (0.22 g, 24%): Rf (hexaneꢀEtOAc, 1:1) = 0.30; [R]25D = ꢀ35 (c
1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.03 (ddq, J = 15.8, 7.3,
1.3 Hz, 1H, CH2CHdCH2), 3.34ꢀ3.41 (m, 1H, CH2CHdCH2), 3.76
(dd, J = 10.1, 3.3 Hz, 1H, CH2OBn), 3.92 (dd, J = 10.1, 5.7 Hz, 1H,
CH2OBn), 3.59ꢀ4.03 (m, 1H, H2), 4.16 (dd, J = 3.0, 1.8 Hz, 1H, H3),
4.41 (d, J = 11.9 Hz, 1H, CH2Ph), 4.42 (d, J = 12.0 Hz, 1H, CH2Ph), 4.44
(d, J = 11.9 Hz, 1H, CH2Ph), 4.45 (d, J = 11.7 Hz, 1H, CH2Ph), 4.47 (d,
J = 11.8 Hz, 1H, CH2Ph), 4.52 (d, J = 12.0 Hz, 1H, CH2Ph), 4.53ꢀ4.55
(m, 1H, H4), 5.05 (ddd, J = 10.0, 2.8, 1.4 Hz, 1H, CH2CHdCH2), 5.09
(ddd, J = 17.3, 3.2, 1.6 Hz, 1H, CH2CHdCH2), 5.73 (dddd, J = 17.2,
(2R,3R,4R,5R)-2-Allyl-3,4-bis(benzyloxy)-5-(benzyloxy-
methyl)pyrrolidin-1-ol (2). To a cooled (0 °C) solution of nitrone 1
(1.0 g, 2.4 mmol) in anhydrous THF (30 mL) was added allylmagne-
sium bromide (7.2 mL of a 1 M solution in THF, 7.2 mmol) dropwise.
After the solution was stirred for 13 h at 0 °C, the reaction was quenched
with satd aq NH4Cl (20 mL). The reaction mixture was diluted with
diethyl ether (20 mL), the organic layer was separated, and the aqueous
layer was extracted with diethyl ether (2 ꢁ 20 mL). The combined
organic extracts were washed with brine (20 mL), dried over MgSO4,
and filtered, and the solvent was eliminated under reduced pressure to
afford the crude product which was purified by radial chromatography
(hexaneꢀEtOAc, 7:3) to give pure 2 (1.15 g, 98%) as an oil: Rf
10.0, 7.3, 6.3 Hz, 1H, CH2CHdCH2), 7.16 ꢀ 7.30 (m, 15H, Ar); 13
C
NMR (100 MHz, CDCl3) δ 29.6 (CH2CHdCH2), 67.0 (CH2OBn),
71.6 (CH2Ph), 71.8 (CH2Ph), 73.5 (CH2Ph), 77.7 (C3), 78.2 (C2), 84.5
(C4), 118.8 (CH2CHdCH2), 127.8 (Ar), 127.8 (Ar), 127.9 (Ar), 128.0
(Ar), 128.1 (Ar), 128.2 (Ar), 128.4 (Ar), 128.5 (Ar), 128.6 (Ar), 130.0
(CH2CHdCH2), 137.2 (Ar), 137.3 (Ar), 137.7 (Ar), 144.2 (C5). Anal.
Calcd for C29H31NO4: C, 76.12; H, 6.83; N, 3.06. Found: C, 76.35; H,
6.98; N, 2.96.
(hexaneꢀEtOAc, 7:3) = 0.55; [R]22 = ꢀ3 (c 0.815, CHCl3); 1H
D
NMR (400 MHz, CDCl3) δ 2.27ꢀ2.37 (m, 1H, CH2CHdCH2), 2.66ꢀ
2.75 (m, 1H, CH2CHdCH2), 3.37 (dt, J = 8.5, 5.1 Hz, 1H, H2),
3.52ꢀ3.57 (m, 1H, H5), 3.65 (dd, J = 9.6, 6.5 Hz, 1H, CH2OH), 3.80
(dd, J = 9.6, 5.2 Hz, 1H, CH2OH), 3.86 (dd, J = 4.8, 2.5 Hz, 1H, H3), 3.97
(dd, J = 4.2, 2.5 Hz, 1H, H4), 4.45 (d, J = 11.8 Hz, 1H, CH2Ph), 4.47 (d,
J = 11.9 Hz, 1H, CH2Ph), 4.51 (d, J = 11.8 Hz, 1H, CH2Ph), 4.54 (d, J =
12.0 Hz, 1H, CH2Ph), 4.54 (d, 1H, J = 12.0 Hz, 1H, CH2Ph), 4.59 (d, J =
12.0 Hz, 1H, CH2Ph), 5.07ꢀ5.15 (m, 2H, CH2CHdCH2), 5.86 (dddd,
J = 16.9, 10.2, 7.5, 6.7 Hz, 1H, CH2CHdCH2), 7.27ꢀ7.38 (m, 15H, Ar);
13C NMR (100 MHz, CDCl3) δ 32.6 (CH2CHdCH2), 68.4
(CH2OBn), 69.5 (C2), 69.9 (C5), 71.7 (CH2Ph), 71.7 (CH2Ph), 73.4
(CH2Ph), 84.2 (C4), 85.3 (C3), 117.1 (CH2CH=CH2), 127.6 (Ar),
127.7 (Ar), 127.7 (Ar), 127.9 (Ar), 127.9 (Ar), 128.3 (Ar), 128.3 (Ar),
128.4 (Ar), 135.5 (CH2CHdCH2), 138.1 (Ar), 138.2 (Ar), 138.5 (Ar).
Anal. Calcd for C26H27NO4: C, 74.80; H, 6.52; N, 3.35. Found: C, 74.73;
H, 6.41; N, 3.24.
1
5 (27.5 mg, 3%): Rf (hexaneꢀEtOAc, 1:1) = 0.15; H NMR (400
MHz, CDCl3) δ 1.81 (dd, J = 7.5, 1.7 Hz, 3H, CHdCHCH3), 3.83 (dd,
J = 9.9, 3.7 Hz, 1H, CH2OBn), 3.89 (dd, J = 9.9, 6.3 Hz, 1H, CH2OBn),
4.03ꢀ4.08 (m, 1H, H2), 4.23 (dd, J = 2.5, 1.4 Hz, 1H, H3), 4.35 (d, J =
11.3 Hz, 1H, CH2Ph), 4.41 (d, J = 11.3 Hz, 1H, CH2Ph), 4.44 (d, J = 11.8
Hz, 1H, CH2Ph), 4.49 (d, J = 11.8 Hz, 1H, CH2Ph), 4.49 (d, J = 11.8 Hz,
1H, CH2Ph), 4.55 (d, J = 11.8 Hz, 1H, CH2Ph), 4.94 (s, 1H, H4), 5.97
(dc, J = 12.0, 7.5 Hz, 1H, CHdCHCH3), 6.41ꢀ6.47 (m, 1H,
CHdCHCH3), 7.06ꢀ7.31 (m, 15H, Ar).
6,7-Bis(benzyloxy)-1-benzyloxymethyl-3,8-epoxy-9-nortro-
pane (6). A solution of nitrone 3 (0.457 g, 1 mmol) was dissolved in
anhydrous toluene (25 mL), placed in a sealed tube, and heated at
120 °C under an argon atmosphere for 14 h, at which time the solvent
was partially evaporated and the resulting solution was filtered through a
pad of silica gel. After the silica was washed with diethyl ether, the
resulting solution was evaporated under reduced pressure to afford 6
(0.443 g, 97%) as an oil that did not need any additional purification:
[R]25D = ꢀ24 (c 0.39, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.33
(dd, J = 11.7, 2.9 Hz, 1H, H4a), 1.34 (ddd, J = 12.3, 5.0, 3.2 Hz, 1H, H2a),
1.89 (d, J = 12.3 Hz, 1H, H2b), 2.12 (dddd, J = 11.7, 10.4, 4.6, 3.0 Hz, 1H,
H4b), 3.26 (d, J = 10.3 Hz, 1H, CH2OBn), 3.42 (d, J = 10.3 Hz, 1H,
CH2OBn), 3.54 (ddd, J = 10.5, 2.0, 0.8 Hz, 1H, H5), 3.83 (d, J = 2.6 Hz,
1H, H7), 4.27 (dd, J = 2.6, 1.1 Hz, 1H, H6), 4.39 (d, J = 11.9 Hz, 1H,
CH2Ph), 4.43 (d, J = 11.8 Hz, 1H, CH2Ph), 4.44 (d, J = 12.2 Hz, 1H,
CH2Ph), 4.47 (d, J = 11.8 Hz, 1H, CH2Ph), 4.51 (d, J = 11.9 Hz, 1H,
(2R,3R,4R)-2-Allyl-3,4-bis(benzyloxy)-5-(benzyloxymethyl)-
3,4-dihydro-2H-pyrrole 1-Oxide (3), (2R,3R,4R)-5-Allyl-3,4-
bis(benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-2H-pyrrole
1-oxide (4), and (2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzylo-
xymethyl)-5-((E)-prop-1-enyl)-3,4-dihydro-2H-pyrrole 1-Oxide
(5). To a cooled (0 °C) solution of 2 (0.919 g, 2 mmol) in CH2Cl2
(30 mL) was added activated manganese(IV) oxide (2.09 g, 2.4 mmol).
portionwise After 15 min of stirring at 0 °C, the reaction mixture was
warmed to room temperature, and stirring was continued until complete
disappearance of the starting material (TLC, ca. 2 h). The reaction
mixture was filtered through a pad of Celite and anhydrous MgSO4, and
the resulting filtrate was evaporated under reduced pressure to give the
crude product which was purified by radial chromatography (hexaneꢀ
EtOAc, 1:1) to give nitrones 3, 4 and 5.
CH2Ph), 4.64ꢀ4.68 (m, 2H, H3, CH2Ph), 7.15ꢀ7.28 (m, 15H, Ar); 13
C
NMR (100 MHz, CDCl3) δ 37.1 (C2), 39.7 (C4), 67.3 (C5), 71.4
(CH2Ph), 72.2 (CH2Ph), 72.7 (CH2OBn), 73.5 (CH2Ph), 76.8 (C1),
79.0 (C3), 83.0 (C6), 86.9 (C7), 127.5 (Ar), 127.7 (Ar), 127.7 (Ar), 127.8
(Ar), 127.9 (Ar), 127.9 (Ar), 128.2 (Ar), 128.3 (Ar), 128.4 (Ar), 137.8
(Ar), 138.2 (Ar), 138.4 (Ar). Anal. Calcd for C29H31NO4: C, 76.12; H,
6.83; N, 3.06. Found: C, 76.38; H, 6.87; N, 2.96.
3 (0.668 g, 73%): oil; Rf (hexaneꢀEtOAc, 1:1) = 0.42; [R]25D = ꢀ62
(c 1.57, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.38 (dddt, J = 14.2,
9.9, 7.9, 1.0 Hz, 1H, CH2CHdCH2), 2.85 (dddt, J = 14.2, 6.2, 3.7, 1.5
Hz, 1H, CH2CHdCH2), 3.79 (dd, J = 2.0, 1.1 Hz, 1H, H3), 3.89 (ddd,
J = 9.6, 3.3, 1.5 Hz, 1H, H2), 4.29 (ddd, J = 14.6, 1.5, 1.2 Hz, 1H,
CH2OBn), 4.30 (d, J = 11.8 Hz, 1H, CH2Ph), 4.35 (d, J = 11.8 Hz, 1H,
(3S,5R,6R)-1-(Hydroxymethyl)-8-azabicyclo[3.2.1]octane-
3,6,7-triol Hydrochloride (7). A solution of cycloadduct 6 (0.2 g,
0.44 mmol) in methanol (10 mL) was treated with Pd(OH)2ꢀC (350 mg)
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and hydrochloric acid (0.5 mL). The resulting mixture was stirred under
3 bar of hydrogen for 6 h. The catalyst was eliminated by filtration
through a pad of Celite, the filtrate was treated with 3 M HCl in
methanol, and the resulting solution was stirred at room temperature for
additional 10 min. The solvent was eliminated under reduced pressure to
afford pure 7 (0.1 g, quant) as a white solid: mp >150 °C dec; [R]26D =
þ10 (c 0.15, H2O); 1H NMR (400 MHz, D2O, 60 °C) δ 1.58 (dd, J =
14.0, 10.7 Hz, 1H, H2a), 1.68 (ddd, J = 14.3, 11.3, 3.2 Hz, 1H, H4a), 2.08
(ddd, J = 13.8, 6.0, 1.0 Hz, 1H, H2b), 2.27 (dddd, J = 5.7, 4.9, 3.0, 1.4 Hz,
1H, H4b), 3.60 (d, J = 12.9 Hz, 1H, CH2OH), 3.63 (d, J = 13.0 Hz, 1H,
CH2OH), 3.74 (t, J = 3.0 Hz, 1H, H5), 4.03ꢀ4.05 (m, 1H, H6),
4.05ꢀ4.11 (m, 2H, H3, H7); 13C NMR (100 MHz, D2O) δ 33.2 (C2),
34.0 (C4), 61.0 (C3), 61.4 (CH2OH), 61.7 (C5), 69.2 (C1), 78.1 (C7),
78.4 (C6). Anal. Calcd for C8H16ClNO4: C, 42.58; H, 7.15; N, 6.21.
Found: C, 42.76; H, 7.35; N, 6.10.
4.12 (s, 1H, H6), 4.19 (d, J = 11.8 Hz, 1H, CH2Ph), 4.35 (s, 1H, H7), 4.56
(d, J = 11.8 Hz, 1H, CH2Ph), 4.66 (d, J = 11.8 Hz, 1H, CH2Ph), 4.67 (d,
J = 12.0 Hz, 1H, CH2Ph), 4.84ꢀ4.89 (m, 2H, H5, CH2Ph),6.81 ꢀ 6.87
(m, 2H, Ar), 7.20ꢀ7.45 (m, 16H, Ar), 7.55 (d, J = 7.5 Hz, 2H, Ar); 13
C
NMR (125 MHz, CDCl3) δ 37.8 (C2), 47.3 (C4), 71.7 (CH2Ph), 72.1
(CH2Ph), 73.8 (CH2Ph), 74.7 (CH2OBn), 75.7 (C1), 79.0 (C5), 80.5
(C3), 84.4 (C7), 88.2 (C6), 126.5 (Ar), 127.4 (Ar), 127.5 (Ar), 127.6
(Ar), 127.7 (Ar), 127.8 (Ar), 127.9 (Ar), 128.0 (Ar), 128.1 (Ar), 128.4
(Ar), 128.4 (Ar), 137.7 (Ar), 138.2 (Ar), 138.5 (Ar), 143.2 (Ar). Anal.
Calcd for C35H35NO4: C, 78.77; H, 6.61; N, 2.62. Found: C, 78.83; H,
6.460; N, 2.78.
(2R,3R,4R)-2-Allyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-
5-phenyl-3,4-dihydro-2H-pyrrole 1-Oxide (11) and (1R,3S,
5S,6S,7R)-6,7-Bis(benzyloxy)-1-benzyloxymethyl-3,8-epoxy-
5-phenyl-9-nortropane (12). A solution of nitrone 10 (0.533 g, 1
mmol) was dissolved in anhydrous toluene (25 mL), placed in a sealed
tube, and heated at 120 °C under an argon atmosphere for 14 h, at which
time the solvent was partially evaporated and the resulting solution was
filtered through a pad of silica gel. After the silica was washed with diethyl
ether, the resulting solution was evaporated under reduced pressure, and
the residue was purified by radial chromatography using hexaneꢀEtOAc
4:1 as an eluant to afford a 38:62 mixture of compounds 11 and 12,
respectively, in quantitative yield.
(2S,3R,4R,5R)-2-Allyl-3,4-bis(benzyloxy)-5-(benzyloxymethyl)-
2-phenylpyrrolidin-1-ol (9). The reaction of 8 (0.987 g, 2 mmol)
with allylmagnesium bromide (6 mL of a solution 1.0 M in hexanes, 6
mmol), as described above for nitrone 1 to give 2, afforded pure 9 (1.07
1
g, quant): oil; [R]23 = ꢀ68 (c 0.60, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 2.84 (ddt, J = 15.0, 7.5, 1.3 Hz, 1H, CH2CHCH2), 3.17 (ddt,
J = 15.0, 1.3 Hz, 1H, CH2CHdCH2), 3.64 (c, J = 5.4 Hz, 1H, H5), 3.74
(dd, J = 9.7, 5.2 Hz, 1H, CH2OBn), 3.81 (d, J = 5.6 Hz, 1H, H4), 3.82
(dd, J = 11.2, 5.6 Hz, 1H, CH2OBn), 3.98 (d, J = 2.0 Hz, 1H, H3), 4.02
(d, J = 11.5 Hz, 1H, CH2Ph), 4.11 (d, J = 11.5 Hz, 1H, CH2Ph), 4.55 (s,
1H, NOH), 4.61 (s, 2H, CH2Ph), 4.81 (s, 2H, CH2Ph), 5.00ꢀ5.14 (m,
2H, CH2CHdCH2), 5.95 (dddd, J = 16,9, 10.2, 7.4, 6.6 Hz, 1H,
CH2CHdCH2), 6.86 ꢀ 9.91 (m, 2H, Ar), 7.18ꢀ7.39 (m, 16H, Ar),
7.54ꢀ7.59 (m, 2H, Ar); 13C NMR (75 MHz, CDCl3) δ 36.7 (CH2CHd
CH2), 61.5 (C2), 69.1 (C5), 71.1 (CH2OBn), 71.8 (CH2Ph), 72.0
(CH2Ph), 73.4 (CH2Ph), 82.7 (C4), 86.4 (C3), 117.5 (CH2CHd
CH2), 126.5 (Ar), 127.6 (Ar), 127.6 (Ar), 127.6 (Ar), 127.7 (Ar),
127.8 (Ar), 128.1 (Ar), 128.1 (Ar), 128.4 (Ar), 128.6 (Ar), 136.2
(CH2CHdCH2), 137.5 (Ar), 138.1 (Ar), 138.3 (Ar), 140.9 (Ar). Anal.
Calcd for C35H37NO4: C, 78.48; H, 6.96; N, 2.61. Found: C, 78.52; H,
6.81; N, 2.87.
11 (0.202 g, 38%): oil; Rf (hexaneꢀEtOAc, 4:1) = 0.36; [R]23D = þ8
(c 0.35, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.54 (d, J = 7.1 Hz, 2H,
CH2CHdCH2), 3.53 (d, J = 10.2 Hz, 1H, CH2OBn), 4.22 (d, J = 10.2
Hz, 1H, CH2OBn), 4.33 (d, J = 11.5 Hz, 1H, CH2Ph), 4.50 (d, J = 11.7
Hz, 1H, CH2Ph), 4.51 (d, J = 11.5 Hz, 1H, CH2Ph), 4.67 (d, J = 11.2 Hz,
1H, CH2Ph), 4.69 (d, J = 11.5 Hz, 1H, CH2Ph), 4.74 (d, J = 11.8 Hz, 1H,
CH2Ph), 4.80 (d, J = 4.3 Hz, 1H, H3), 5.01 (dd, J = 10.2, 2.0 Hz, 1H,
CH2CHdCH2), 5.15 (ddt, J = 17.1, 2.1, 1.2 Hz, 1H, CH2CHdCH2),
5.33 (d, J = 4.3 Hz, 1H, H4), 5.82 (ddt, J = 17.4, 10.1, 7.3 Hz, 1H,
CH2CHdCH2), 7.10ꢀ7.13 (m, 2H, Ar), 7.26 ꢀ7.32 (m, 8H, Ar),
7.34ꢀ7.41 (m, 5H, Ar), 7.43ꢀ7.47 (m, 3H, Ar), 8.41ꢀ8.45 (m, 2H, Ar);
13C NMR (125 MHz, CDCl3) δ 34.9 (CH2CHdCH2), 68.5 (CH2Ph),
71.2 (CH2OBn), 72.8 (CH2Ph), 73.6 (CH2Ph), 78.5 (C3), 82.1 (C2),
83.7 (C4), 120.1 (CH2CH=CH2), 127.7 (Ar), 127.7 (Ar), 127.8 (Ar),
127.8 (Ar), 128.0 (Ar), 128.0 (Ar), 128.2 (Ar), 128.3 (Ar), 128.4 (Ar),
128.5 (Ar), 130.2 (Ar), 131.7 (CH2CHdCH2), 137.6 (Ar), 137.7 (Ar),
137.8 (Ar), 139.1 (C5). Anal. Calcd for C35H35NO4: C, 78.77; H, 6.61;
N, 2.62. Found: C, 78.54; H, 6.40; N, 2.45.
(2S,3R,4R)-2-Allyl-3,4-bis(benzyloxy)-5-(benzyloxymethyl)-
2-phenyl-3,4-dihydro-2H-pyrrole 1-Oxide (10). The oxidation
of 9 (1.07 g, 2 mmol), as described above for hydroxylamine 2 to give 3,
afforded pure 10 (1.07 g, quant) as an oil: [R]21 = ꢀ91 (c 0.16,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.85 (dd, J = 14.3, 8.8 Hz, 1H,
CH2CHdCH2), 3.34 (ddt, J = 14.3, 5.1, 1.4 Hz, 1H, CH2CHdCH2),
4.31 (d, J = 4.5 Hz, 1H, H3), 4.37 (d, J = 0.9 Hz, 2H, CH2Ph), 4.41 (dd,
J = 13.4, 1.4 Hz, 1H, CH2OBn), 4.63 (d, J = 11.2 Hz, 1H, CH2Ph), 4.65
(d, J = 11.2 Hz, 1H, CH2Ph), 4.72 (d, J = 11.7 Hz, 1H, CH2Ph), 4.74 (d,
J = 11.5 Hz, 1H, CH2Ph), 4.81 (dd, J = 15.3, 4.5 Hz, 1H, H4), 4.87 (d, J =
13.8 Hz, 1H, CH2OBn), 5.14 (d, J = 17.0 Hz, 1H, CH2CHdCH2), 5.23
(d, J = 10.1 Hz, 1H, CH2CHdCH2), 5.78 (dddd, J = 17.1, 10.2, 8.8, 5.2
Hz, 1H, CH2CHdCH2), 7.01ꢀ7.06 (m, 2H, Ar), 7.26ꢀ7.46 (m, 18H,
Ar); 13C NMR (125 MHz, CDCl3) δ 39.7 (CH2CHdCH2), 61.5
(CH2OBn), 72.4 (CH2Ph), 73.2 (CH2Ph), 73.8 (CH2Ph), 82.7 (C3),
83.1 (C4), 83.7 (C2), 120.8 (CH2CHdCH2), 127.9 (Ar), 127.9 (Ar),
128.0 (Ar), 128.0 (Ar), 128.0 (Ar), 128.2 (Ar), 128.3 (Ar), 128.4 (Ar),
128.5 (Ar), 128.5 (Ar), 131.9 (CH2CHdCH2), 135.8 (Ar), 137.2, (Ar)
137.5 (Ar), 137.6 (Ar), 144.0 (C5). Anal. Calcd for C35H35NO4: C,
78.77; H, 6.61; N, 2.62. Found: C, 78.90; H, 6.70; N, 2.85.
12 (0.331 g, 62%). The physical and spectroscopic properties were
identical to those of the same compound obtained by heating at 120 °C
for 36 h as described above.
(3S,5S,6R)-1-(Hydroxymethyl)-5-phenyl-8-azabicyclo[3.2.1]-
octane-3,6,7-triol (13). The hydrogenation of 12 (0.533 g, 1 mmol),
as described above for cycloadduct 6 to give 8, afforded pure 13 (0.3 g,
quant) as a white solid: mp >150 °C dec; [R]27D = þ21 (c 0.34, H2O);
1H NMR (500 MHz, D2O) δ 1.77ꢀ1.86 (m, 2H, H2a, H4a), 2.24 (dd, J =
13.9, 5.9 Hz, 1H, H4b), 2.63 (dd, J = 14.1, 5.9 Hz, 1H, H2b), 3.81 (d, J =
12.9 Hz, 1H, CH2OH), 3.84 (d, J = 12.9 Hz, 1H, CH2OH), 4.15 (s, 1H,
H7), 4.41 (tt, J = 11.4, 6.0 Hz, 1H, H3), 4.50 (s, 1H, H6), 7.26 (d, 1H, J =
7.5 Hz, Ar), 7.39 (t, 1H, J = 7.4 Hz, Ar), 7.47 (t, 1H, J = 7.6 Hz, Ar); 13C
NMR (100 MHz, D2O) δ 32.6 (C4), 44.6 (C2), 61.2 (C3), 62.8
(CH2OH), 68.3, 71.8 (C5), 79.7 (C7), 80.4 (C6), 125.1 (Ar), 128.3
(Ar), 128.9 (Ar), 136.3 (Ar). Anal. Calcd for C14H20ClNO4: C, 55.72;
H, 6.68; N, 4.64. Found: C, 55.83; H, 6.45; N, 4.86.
(1R,3S,5S,6S,7R)-6,7-Bis(benzyloxy)-1-benzyloxymethyl-3,8-
epoxy-5-phenyl-9-nortropane (12). Heating of 10 (0.2 g, 0.36
mmol), as described above for nitrone 3 to give 6, but for 36 h, afforded
pure 12 (0.2 g, quant) as an oil: Rf (EtOAc) = 0.54; [R]26 = þ2
’ ASSOCIATED CONTENT
D
(c 0.416, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.61ꢀ1.66 (m, 1H,
H2a), 2.13 (d, J = 11.8 Hz, 1H, H4a), 2.30 (d, J = 11.9 Hz, 1H, H2b), 2.53
(ddd, J = 11.7, 4.7, 3.0 Hz, 1H, H1),3.59 (d, J = 10.2 Hz, 1H, CH2OBn),
3.77 (d, J = 10.2 Hz, 1H, CH2OBn), 4.07 (d, J = 11.8 Hz, 1H, CH2Ph),
Supporting Information. 1H and 13C NMR spectra of
S
b
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
4142
dx.doi.org/10.1021/jo200315k |J. Org. Chem. 2011, 76, 4139–4143

The Journal of Organic Chemistry
NOTE
’ AUTHOR INFORMATION
(9) (a) Tufariello, J. J.; Trybulski, E. J. J. Chem. Soc., Chem. Commun.
1973, 720. (b) Tufariello, J. J.; Mullen, G. B.; Tegeler, J. J.; Trybulski,
E. J.; Wong, S. C.; Ali, S. A. J. Am. Chem. Soc. 1979, 101, 2435–2442.
(c) Tufariello, J. J. Acc. Chem. Res. 1979, 12, 396–403.
Corresponding Author
*E-mail: pmerino@unizar.es, andrea.goti@unifi.it.
(10) Davis, F. A.; Theddu, N.; Edupuganti, R. Org. Lett. 2010,
12, 4118–4121.
’ ACKNOWLEDGMENT
(11) Merino, P.; Tejero, T.; Mannucci, V. Tetrahedron Lett. 2007,
48, 3385–3388See also ref 8a.
(12) Cardona, F.; Faggi, E.; Liguori, M.; Cacciarini, A.; Goti, A.
Tetrahedron Lett. 2003, 44, 2315–2318.
(13) For previous work on allylation of acyclic nitrones, see:
(a) Merino, P.; Delso, I.; Mannucci, V.; Tejero, T. Tetrahedron Lett.
2006, 47, 3311–3314. (b) Merino, P.; Mannucci, V.; Tejero, T.
Tetrahedron 2005, 61, 3335–3347. For a review on allylation of CdN
systems, see: (c) Merino, P.; Tejero, T.; Delso, I.; Mannucci, V. Compr.
Org. Synth. 2005, 2, 479–498.
We thank the Spanish Ministry of Science and Innovation
(MICINN, Madrid, Spain, Project CTQ2010-19606), the FEDER
Program and the Government of Aragon (Zaragoza, Spain),
Ente Cassa di Risparmio di Firenze (CRF, Italy), and MIUR
(PRIN 2008, Italy) for support of our programs.
’ REFERENCES
(14) For oxidation of cyclic hydroxylamines to nitrones, see:
(a) Revuelta, J.; Cicchi, S.; Goti, A.; Brandi, A. Synthesis 2007, 485–504.
(b) Merino, P. In Science of Synthesis; Padwa, A., Bellus, D., Eds.; George
Thieme:: Stuttgart, 2004; Vol. 27, pp 511ꢀ584.
(1) (a) Biastoff, S.; Draeger, B. In The Alkaloids: Chemistry and
Biology; Cordell, G. A., Ed.; Academic Press: Oxford, 2007; Vol. 64, pp
49ꢀ102. (b) Draeger, B. Nat. Prod. Rep. 2004, 21, 211–223.
(c) Molyneux, R. J.; Nash, R. J.; Asano, N. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Pergamon Press: Oxford,
1996; Vol. 11, pp 303ꢀ343.
(15) For previous reports on intramolecular dipolar cycloadditions
of alkenyl cyclic nitrones toward tropanes, see: Shing, T. K. M.; Wong,
W. F.; Ikeno, T.; Yamada, T. Org. Lett. 2007, 9, 207–209.
(16) No better results were obtained and longer reaction times were
needed on carrying out the reaction at lower temperatures (ꢀ15 and
ꢀ80 °C) or in the presence of Lewis acids such as ZnCl2, Zn(OTf)2,
(2) For recent examples and reviews, see: (a) Pandey, G.;
Grahacharya, D.; Shashidhara, K. S.; Khan, M. I.; Puranik, V. C. Org.
Biomol. Chem. 2009, 7, 3300–3307. (b) Li, R.; Bols, M.; Rousseau, C.;
Zhang, X.-G.; Wang, R. W.; Qing, F. L. Tetrahedron 2009, 65, 3717–
3727. (c) D’Alonzo, D.; Guaragna, A.; Palumbo, G. Curr. Med. Chem.
2009, 16, 473–505. (d) Baumann, D.; Bennis, K.; Ripoche, I.; Thery, V.;
Troin, Y. Eur. J. Org. Chem. 2008, 5289–5300. (e) Alam, M. A.; Kumar,
A.; Vankar, Y. D. Eur. J. Org. Chem. 2008, 4972–4980.
Et2AlCl, and BF3 Et2O.
3
(17) Merino, P.; Delso, I.; Tejero, T.; Cardona, F.; Marradi, M.;
Faggi, E.; Parmeggiani, C.; Goti, A. Eur. J. Org. Chem. 2008, 2929–2947.
(18) Merino, P.; Tejero, T.; Revuelta, J.; Cicchi, S.; Goti, A. Eur. J.
Org. Chem. 2004, 776–782.
(3) (a) Boyer, F.-D.; Lallemand, J.-Y. Tetrahedron 1994,
50, 10443–10458. (b) Asano, N.; Kato, A.; Kizu, H.; Matsui, K.; Griffiths,
R. C.; Jones, M. G.; Watson, A. A.; Nash, R. J. Carbohydr. Res. 1997,
304, 173–178. (c) Boyer, F. D.; Hanna, I. Tetrahedron Lett. 2001,
42, 1275–1277. (d) Skaanderup, P. R.; Madsen, R. Chem. Commun.
2001, 1106–1107. (e) Marco-Contelles, J.; de Opazo, E. J. Org.
Chem. 2002, 67, 3705–3717. (f) Koulocheri, S. D.; Pitsinos, E. N.;
Haroutounian, S. A. Synthesis 2002, 1707–1710. (g) Skaanderup, P. R.;
Madsen, R. J. Org. Chem. 2003, 68, 2115–2122. (h) Garcia-Moreno,
M. I.; Mellet, C. O.; Fernandez, J. M. G. Eur. J. Org. Chem. 2004,
1803–1819. (i) Csuk, R.; Prell, E.; Reissmann, S. Tetrahedron 2008,
64, 9417–9422. (j) Chen, Y.-L.; Redlich, H.; Bergander, K.; Froelich, R.
Org. Biomol. Chem. 2007, 20, 3330–3339. (k) Monrad, R. N.; Pipper,
C. B.; Madsen, R. Eur. J. Org. Chem. 2009, 3387–3395. (l) Chagnault, V.;
Compain, P.; Lewinski, K.; Ikeda, K.; Asano, N.; Martin, O. R. J. Org.
Chem. 2009, 74, 3179–3182. (m) Moosophon, P.; Baird, M. C.;
Kanokmedhakul, S.; Pyne, S. G. Eur. J. Org. Chem. 2010, 3337–3344.
(n) Moosophon, P.; Baird, M. C.; Kanokmedhakul, S.; Pyne, S. G. Eur. J.
Org. Chem. 2010, 3337–3344.
(19) Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetrahedron Lett.
2001, 42, 6503–6505.
(20) Merino, P.; Delso, I.; Tejero, T.; Cardona, F.; Goti, A. Synlett
2007, 2651–2654.
(4) (a) Garcia-Moreno, M. I.; Benito, J. M.; Ortiz Mellet, C.; Garcia
Fernandez, J. M. J. Org. Chem. 2001, 66, 7604–7614. (b) Garcia-Moreno,
M. I.; Mellet, C. O.; Garcia Fernandez, J. M. Tetrahedron 2007,
63, 7879–7884. (c) Aguilar, M.; Gloster, T. M.; Garcia-Moreno, M. I.;
Mellet, C. O.; Davies, G. J.; Llebaria, A.; Casas, J.; Egido-Gabas, M.;
Fernandez, J. M. G. ChemBioChem 2008, 9, 2612–2618. (d) Chagnault,
V.; Compain, P.; Lewinski, K.; Ikeda, K.; Asano, N.; Martin, O. R. J. Org.
Chem. 2009, 74, 3179–3182.
(5) Shing, T. K. M.; Wong, W. F.; Ikeno, T.; Yamada, T. Org. Lett.
2007, 9, 207–209.
(6) Lo, Re, D.; Franco, F.; Sanchez-Cantalejo, F.; Tamayo, J. A. Eur.
J. Org. Chem. 2009, 1984–1993.
(7) Kaliappan, K. P.; Das, P.; Chavan, S. T.; Sabharwal, S. G. J. Org.
Chem. 2009, 74, 6266–6274.
(8) (a) Bapat, J. B.; Black, D. St.C.; Brown, R. F. C.; Ichlov, C. Aust. J.
Chem. 1972, 25, 2445–2450. (b) Black, D. St. C.; Craig, D. C.; Edwards,
G. L.; Laaman, S. L. Tetrahedron Lett. 1998, 39, 5849–5852. (c) Black, D.
St.C.; Craig, D. C.; Edwards, G. L.; Laaman, S. L. Bioorg. Chem. 1999,
27, 91–99.
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