Stereoselective route towards 2,5-disubstituted piperidine alkaloids. Synthesis of (+)-pseudoconhydrine and (±)-epi-pseudoconhydrine

Article abstract of DOI:10.1016/S0040-4020(99)01105-9

This paper describes a new general approach towards functionalized piperidine alkaloids, based on the stereo- and regioselective palladium(0)- catalyzed nucleophilic ring-opening of vinyl epoxides by nitrogen nucleophiles. The latter reaction provides acc

Full text of DOI:10.1016/S0040-4020(99)01105-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2225±2230
Stereoselective Route towards 2,5-Disubstituted Piperidine
Alkaloids. Synthesis of (1)-Pseudoconhydrine and
(^)-epi-Pseudoconhydrine
a
Joakim Lofstedt, Helena Pettersson-Fasth and Jan-E. Backvall
b
a,
*
È
È
aDepartment of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
bDepartment of Organic Chemistry, Uppsala University, Box 531, SE-751 21 Uppsala, Sweden
Accepted 7 December 1999
AbstractÐThis paper describes a new general approach towards functionalized piperidine alkaloids, based on the stereo- and regioselective
palladium(0)-catalyzed nucleophilic ring-opening of vinyl epoxides by nitrogen nucleophiles. The latter reaction provides access to stereo-
de®ned anti and syn aminoalcohol derivatives, 1-benzyloxy-5-(p-toluenesulfonamido)-3-alken-2-ols (5), which were transformed to (1)-
pseudoconhydrine (3) and (^)-epi-pseudoconhydrine (9), respectively, via protection (silyl ether), hydrogenation, debenzylation and
cyclization. Detosylation±deprotection gave the ®nal products in good yields and high stereoisomeric purity. q 2000 Elsevier Science
Ltd. All rights reserved.
Introduction
that give access to all stereoisomers via a single common
route. The strategy outlined in the present work provides a
route to 2,5-disubstituted piperidine alkaloids of either cis
or trans stereochemistry using 1-benzyloxy-5-(p-toluene-
sulfonamido)-3-alken-2-ols (5) as key intermediates. The
absolute stereochemistry is introduced early in the sequence
via Sharpless epoxidation.
Piperidine alkaloids are widespread in nature and many
compounds of this family exhibit interesting biological
activity.1 Cassein (1)2 isolated from Cassia excelsa and
spectalin (2)3 from Cassia spectabilis are members of this
family that have been subject to synthetic studies. Pseudo-
conhydrine (3) has been isolated along with coniine (4) from
Poison Hemlock, Conium maculatum.4 Syntheses of
compound 3 in its racemic5 and enantiomerically pure6
form using different strategies have been reported
previously.
The use of amidoalkenols with the general structure 5 as
building blocks in the synthesis of 2,5-disubstituted pyrroli-
dine derivatives (6) and indolizidine alkaloids (7) has
previously been demonstrated in our laboratory7 (Scheme
1). Amidoalkenols of anti (5a) and syn (5b) stereochemistry
are readily available by a common route, starting from
either cis or trans-1-benzyloxy-2,3-epoxybutan-4-ol (8a or
8b), respectively. The versatility of intermediates 5 is
further demonstrated in this paper by the synthesis of
(1)-pseudoconhydrine (3) from 5a, and (^)-epi-pseudo-
conhydrine (9) from 5b (Scheme 1).
Results and Discussion
Amidoalkenol 5a with alkyl side chains of varying length is
readily available from trans epoxyalcohol 8a.7a The key
step in the synthesis of 5a is the Pd(0)-catalyzed regio-
and stereoselective ring-opening of vinylepoxide 10a
by NaNHTs.8 The reaction involves an external attack
by TsNH2 on an intermediate (p-allyl)palladium
complex.7a,8a,9 Protection of the hydroxy group of 5a as a
TBDMS ether using standard conditions10 gave the ether
11a in 91% yield, and subsequent hydrogenation employing
While there are several known routes towards piperidine
alkaloids, most of them suffer from lack of generality. It
was therefore of interest to develop new general approaches
Keywords: (1)-pseudoconhydrine; (^)-epi-pseudoconhydrine.
* Corresponding author. Tel.: 146-8-6747178; fax: 146-8-154908;
e-mail: jeb@organ.su.se
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01105-9

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J. Lofstedt et al. / Tetrahedron 56 (2000) 2225±2230
2226
Scheme 1.
Scheme 2. (a) TBDMSCl, imidazole, (b) PtO2, EtOH, H2 (c) Pd/C, MeOH, H2, (d) MsCl, Et3N, THF, (e) K2CO3, MeOH, (f) Na(Hg), Na2HPO4, MeOH, (g) HCl,
EtOH.
Scheme 3. (a) TBDMSCl, imidazole, (b) PtO2, EtOH, H2 (c) Pd/C, MeOH, H2, (d) MsCl, Et3N, THF, (e) K2CO3, MeOH, (f) Na(Hg), Na2HPO4, MeOH, (g) HCl,
EtOH.
PtO2 and 1 atm. of H211 gave 12a in 97% yield. The benzyl
group of 12a was removed by hydrogenolysis10 over
palladium on carbon to give 13a in 93% yield. Mesylation
and subsequent cyclization employing K2CO3 in MeOH12
afforded the tosyl piperidine 15a in 81% yield. The
N-tosyl protective group was removed with Na/NH3 in
EtOH13 to give the free amine 16a in 85% yield. Stirring
of 16a in EtOH containing 1% HCl (10 equiv.) afforded
(1)-3 as its HCl salt in 98% yield.14 The free base was
released by treatment with 2 M NaOH (Scheme 2). (1)-
Pseudoconhydrine (3) was characterized and spectral data
were in accordance with those previously reported.6e
The same reaction sequence was employed to convert the
racemic syn aminoalcohol derivative 5b to (^)-9 (Scheme
3). The syn amidoalcohol 5b was obtained from palladium-
catalyzed ring opening of the (cis, Z)-epoxide 10b by
NaNHTs.7a The detosylation step in this sequence was

È
J. Lofstedt et al. / Tetrahedron 56 (2000) 2225±2230
2227
Scheme 4. (a) Ag2O, BnBr, CH2Cl2, (b) (2)-DET (7%), Ti(i-PrO)4 (6%), t-BuOOH, CH2Cl2.
carried out using Na(Hg).15 The (^)-epi-pseudoconhydrine
(9) was characterized as its hydrochloride salt which is
known in the literature.6b
using chloroform-d1 (7.26 ppm H, 77 ppm 13C) as internal
standard unless otherwise stated. Accurate mass measure-
ments were preformed with a JEOL SX 102 mass spectro-
meter with m-nitrobenzylalcohol as matrix. IR spectra were
obtained on a Perkin±Elmer FTIR spectrometer. Optical
rotations were measured using Perkin±Elmer 241 polari-
meter. GC±MS were measured with a Thermo Quest GCQ
plus. The (Z)-2-butene-1,4-diol and 2-butyne-1,4-diol are
commercially available. The enantiomeric purity of epoxide
8a was determined by HPLC analysis using a Chiragel
OD-H column, ¯ow rate 0.5 ml/min, 80/20, hexane/2-
propanol.
1
For an ef®cient synthesis of the target compounds it is
necessary to have easy access to 8a and 8b. The latter
compounds are prepared from (E)- and (Z)-2-butene-1,4-
diol, respectively. The (E)-2-butene-1,4-diol (18a) was
prepared by reduction of the alkyne moiety in 17 with
LiAlH4.16,17 Monobenzylation of the (Z)-2-butene-1,4-diol
under the previously employed standard conditions
(1 equiv. NaH, BnBr, THF) worked satisfactorily and
afforded the monoether in 70% yield. However, the corre-
sponding monobenzylation of (E)-2-butene-1,4-diol (18a)
in THF was sluggish and gave a poor yield of the monoether
(,20%). For an ef®cient synthesis of pseudoconhydrine
((1)-3) it was therefore necessary to improve the synthesis
of 8a and hence the monoalkylation of 18a to 18b. A change
of solvent to DMF led to some improvement of the yield
(50%). Recently, the use of Ag2O together with BnBr was
successfully used to monobenzylate diols.18 Reaction of 18a
with 1.1 equiv. BnBr in the presence of 1.0 equiv. Ag2O in
CH2Cl2 (RT)19 dramatically improved the yield (84%) as
well as the simplicity of the reaction.
Compound 18b. To a stirred solution of the diol 18a
(0.53 g, 6.0 mmol) in CH2Cl2 (11 ml) was added freshly
prepared Ag2O (1.39 g, 6.0 mmol) and BnBr (0.78 ml,
6.6 mmol). The reaction was stirred for 15 h and ®ltered
through a short silica gel pad, which was washed with
diethyl ether. Evaporation of the solvent followed by ¯ash
chromatography (SiO2, pentane:ether (75:25)) gave 0.90 g
(84%) of the monoalkylated product 18b. Spectral data were
in accordance with those previously reported.16
Compound 5a was prepared using the procedure previously
described.7a Pd(PPh3)4 (33 mg, 0.028 mmol), NaNHTs
(110 mg, 0.57 mmol), and NH2Ts (100 mg, 0.57 mmol)
were combined and an argon atmosphere was applied.
CH3CN (5 ml) was added and a yellow color appeared. A
solution of 10a (110 mg, 0.47 mmol) in 0.5 ml CH3CN was
added and the reaction was stirred at 408C for 6 h. 170 mg
Sharpless epoxidation20 using standard conditions, 7% (2)-
diethyltartrate ((2)-DET) and 6% Ti(i-PrO)4, gave the
epoxide as an oil in 87% yield and 93% ee. To improve
the enantiomeric excess by recrystallization, the product
was converted to the 2,4-dichlorobenzoate. The ester was
successfully recrystallized and hydrolyzed (NaOH in
MeOH, RT, overnight) to give the epoxide 8a in more
than 99.5% ee (Scheme 4).
1
(90%) of 5a was isolated: H NMR (CDCl3) d 7.70 (d,
Jˆ8.4 Hz, 2H, Ts), 7.31 (m, 5H, Ph), 7.21 (d, Jˆ8.4 Hz,
2H, Ts), 5.40 (m, 2H, CHvCH), 5.08 (d, Jˆ8.1 Hz, 1H,
NH), 4.50 (s, 2H, PhCH2), 4.12 (m, 1H, CHOH), 3.72
(quintet, Jˆ7.3 Hz 1H, CHNHTs), 3.29 (dd, Jˆ3.3,
9.5 Hz, 2H, BnOCH2), 3.15 (dd, Jˆ7.7, 9.5 Hz, 2H,
BnOCH2), 2.52 (d, Jˆ3.3 Hz, 1H, OH), 2.36 (s, 3H, Ts),
1.20±1.50 (several m, 4H), 0.80 (t, Jˆ7.3 Hz, 3H, Me). 13C
NMR (CDCl3) d 142.7, 138.0, 137.5, 131.4, 129.7, 129.1
(2C), 128.1 (2C), 127.5, 127.4 (2C), 126.9 (2C), 73.7, 73.1,
70.2, 55.2, 37.7, 21.4, 18.5, 13.8. [a]2D3ˆ2128 (cˆ1.15,
CHCl3).
Conclusions
The piperidine alkaloids (1)-pseudoconhydrine (3) and
(^)-epi-pseudoconhydrine (9) were synthesized employing
5a and 5b, respectively, as stereode®ned key intermediates.
By using a slight modi®cation of this method 5-hydroxy-
2,6-dialkylpiperidines such as cassein (1) and spectaline (2)
should also be available.
Compound 11a. To a stirred solution of amidoalcohol 5a
(0.35 g, 0.87 mmol) in DMF (3.5 ml) at 08C was added
imidazole (0.19 g, 2.78 mmol) and TBDMSCl (0.20 g,
1.30 mmol). The mixture was stirred at 08C for 2 h and at
RT for an additional 2 h. The reaction mixture was then
partitioned between ether and brine, then dried (Na2SO4)
and concentrated. The crude product was puri®ed by ¯ash
chromatography (SiO2, pentane:ether (1:1)) to afford 0.41 g,
(91%) of the product. 1H NMR (CDCl3) d 7.72 (d,
Jˆ7.9 Hz, 2H, Ts), 7.34 (m, 5H, Ph), 7.31 (d, Jˆ7.9 Hz,
2H, Ts), 5.40 (m, 2H, CHˆCH), 4.97 (d, Jˆ7.8 Hz, 1H,
NH), 4.48 (d, Jˆ2.0, 2H, PhCH2), 4.15 (m, 1H,
The possibility of forming stereode®ned 5- and 6-membered
ring structures from the same precursor makes amido-
alkenols 5 powerful tools for the synthesis of these hetero-
cyclic compounds.
Experimental
General
1H (13C NMR)-spectra were recorded at 400 (100.6) MHz

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J. Lofstedt et al. / Tetrahedron 56 (2000) 2225±2230
2228
CHOTBDMS), 3.76 (quintet, Jˆ6.5 Hz 1H, CHNHTs),
3.19 (m, 2H, BnOCH2) 2.39 (s, 3H, Ts) 1.20±1.50 (several
m, 4H), 0.85 (m, 12H, t-BuSi1Me), 0.00 (s, 3H, MeSi),
20.03 (s, 3H, MeSi). 13C NMR (CDCl3) d(142.8, 138.2,
138.1, 131.7, 130.1, 129.4 (2C), 128.2 (2C), 127.4 (2C),
127.3 (2C), 127.0, 74.9, 73.3, 71.7, 55.1, 38.2, 25.9, 21.6,
18.6, 18.4, 13.8, 24.6. IR 3273, 2929, 2857, 1453, 1161,
1094, 698. HRMS Calcd for C28H43O4NSiS1Na: 540.2580,
found: 540.2597. [a]2D2ˆ2158 (cˆ1.2, CHCl3).
(33 mg) was added. A hydrogen pressure of 1 atm. was
applied, and the reaction was stirred at RT for 1 h. After
®ltration and concentration 60 mg (93%) of compound 13a
was recovered. 1H NMR (CDCl3) d 7.74 (d, Jˆ8.4 Hz, 2H,
Ts), 7.28 (d, Jˆ8.4 Hz, 2H, Ts), 4.55 (d, Jˆ8.4, 1H), 3.60
(m, 1H), 3.39 (m, 2H), 3.20 (m, 2H, BnOCH2), 2.41 (s, 3H,
Ts), 1.90 (br s, 1H) 1.20±1.60 (several m, 8H), 0.86 (m, 9H,
t-BuSi), 0.76 (t, 3H, Me), 0.04 (s, 3H, MeSi), 0.01 (s, 3H,
MeSi). 13C NMR (CDCl3) d(143.0, 138.2, 129.4 (2C), 126.9
(2C), 72.5, 66.0, 54.1, 37.3, 30.7, 29.6, 25.9, 21.6, 18.6,
18.1, 13.9, 24.3, 24.4. IR 3510, 3285, 2956, 2929,
2857, 1599, 1462, 1322, 1254, 1159, 1094, 836. HRMS
Calcd for C21H39O4NSiS1Na: 452.2267, found: 452.2265.
[a]2D2ˆ268 (cˆ1.3, CHCl3). The product was of .99.5% ee
as determined by HPLC analysis using a Chiragel OD-H
column (¯ow rate 0.5 ml/min, 90/10, hexane/2-propanol).
Compound 11b. To a stirred solution of amidoalcohol 5b
(0.30 g, 0.75 mmol) in DMF (2.5 ml) at 08C was added
imidazole (0.16 g, 2.4 mmol) and TBDMSCl (0.16 g,
1.1 mmol). The procedure outlined for 11a afforded
1
0.34 g, (87%) of 11b. H NMR (CDCl3) d 7.71 (d, 2H,
Ts), 7.32 (m, 5H, Ph), 7.22 (d, 2H, Ts), 5.45 (m, 2H,
CHvCH), 4.49 (d, Jˆ2.0, 2H, PhCH2), 4.34 (d,
Jˆ8.0 Hz, 1H, NH), 4.19 (m, 1H), 3.79 (m, 1H), 3.23 (dd,
Jˆ9.0, 6.5, 1H), 3.19 (dd, Jˆ9.0, 5.0, 1H), 2.39 (s, 3H, Ts),
1.20±1.50 (several m, 4H), 0.92 (m, 12H, t-BuSi1Me), 0.02
(s, 3H, MeSi), 20.03 (s, 3H, MeSi). 13C NMR (CDCl3) d
143.7, 138.2 (2C), 132.0, 130.3, 129.5 (2C), 128.4, 128.3,
127.7 (2C), 127.5 (2C), 127.1, 74.9 (2C), 71.5, 55.0, 38.3,
36.4, 31.4, 25.8, 25.7, 18.5, 18.2, 13.6, 24.6. IR 3269, 2956,
2928, 2856, 1669, 1455, 1387, 1160, 1094, 814, 697.
Compound 13b. Compound 12b (147 mg, 0.28 mmol) was
dissolved in MeOH (5 ml), and 5% palladium on carbon
(101 mg) was added. A hydrogen pressure of 1 atm. was
applied, and the reaction was stirred at RT for 3.5 h. After
®ltration and concentration 110 mg (90%) of compound 13b
was recovered. 1H NMR (CDCl3) d 7.75 (d, 2H, Ts), 7.29 (d,
2H, Ts), 4.21 (d, Jˆ8.0, 1H), 3.45 (m, 1H), 3.36 (m, 1H),
3.24 (m, 1H), 3.14 (m, 1H), 2.42 (s, 3H, Ts), 1.69 (m, 1H)
1.20±1.50 (several m, 7H), 0.9 (m, 9H, t-BuSi), 0.79 (t,
Jˆ7.0, 3H, Me), 0.05 (s, 3H, MeSi), 0.02 (s, 3H, MeSi).
13C NMR (CDCl3) d 143.2, 138.6, 129.6 (2C), 127.1 (2C),
72.5, 66.2, 53.9, 37.4, 30.6, 29.4, 25.8, 21.4, 18.5, 18.1,
13.8, 24.2, 24.9. IR 3510, 3282, 2956, 2929, 2857, 1599,
1460, 1322, 1254, 1159, 1094, 835.
Compound 12a. Compound 11a (0.41 g, 0.79 mmol) was
dissolved in 21 ml of EtOH. PtO2 (13 mg, 0.056 mmol) was
added and a hydrogen pressure of 1 atm. was applied. The
reaction mixture was stirred at RT for 3 h, then ®ltered
through celite and concentrated to give 0.40 mg (97%) of
1
12a. H NMR (CDCl3) d 7.74 (d, Jˆ8.0 Hz, 2H, Ts), 7.32
(m, 5H, Ph), 7.25 (d, Jˆ8.0 Hz, 2H, Ts), 4.44 (s, 2H,
PhCH2), 3.69 (m, 1H, CHOTBDMS), 3.26 (m, 3H,
CHNHTs1BnOCH2), 2.40 (s, 3H, Ts) 1.20±1.60 (several
m, 8H), 0.84 (s, 9H, t-BuSi), 0.78 (t, 3H, Me), 0.00 (s, 3H,
MeSi), 20.02 (s, 3H, MeSi). 13C NMR (CDCl3) d 142.8,
138.3, 138.2, 129.4 (2C), 128.2 (2C), 127.5 (2C), 127.4
(2C), 126.9, 74.3, 73.2, 71.2, 54.2, 37.3, 30.54, 30.46,
25.9, 21.5, 18.4, 18.2, 13.9, 24.3, 24.7. IR 3278, 3030,
2955, 2828, 2856, 1496, 1454, 1252, 1161, 1094, 698,
664. HRMS Calcd for C28H45O4NSiS1H: 520.2939,
found: 520.2928. [a]2D2ˆ2128 (cˆ0.8, CHCl3).
Compound 15a. To a stirred solution of alcohol 13a
(0.162 g, 0.38 mmol) in THF (4.5 ml) at 08C, were added
Et3N (109 ml, 0.76 mmol) and MsCl (47 ml, 0.60 mmol).
The resulting solution was stirred at 08C for 1 h and at RT
for 2 h. The reaction mixture was partitioned between ether
and water, and the organic phase was dried (Na2SO4).
Concentration afforded the crude mesylate 14a, which was
dissolved in MeOH (7 ml). K2CO3 (0.46 g, 3.3 mmol) was
added and the mixture was stirred at RT for 23 h. The
solvent was evaporated and H2O (10 ml) was added, this
water phase was extracted EtOAc (3£15 ml). Drying
and concentration afforded an oil, which was puri®ed by
¯ash chromatography (SiO2, pentane:ether (75:25)) to
Compound 12b. Compound 11b (0.16 g, 0.3 mmol) was
dissolved in 8 ml EtOH. PtO2 (5 mg, 0.02 mmol) was
added and a hydrogen pressure of 1 atm. was applied. The
reaction was stirred at RT for 20 min, then ®ltered through
1
afford 0.13 g, (81%) of the product 15a. H NMR (CDCl3)
d 7.79 (d, Jˆ8.0 Hz, 2H, Ts), 7.21 (d, Jˆ8.0 Hz, 2H,
Ts), 3.85 (m, 1H, CHN), 3.72±3.69 (m, 3H, CH2N1
CHOTBDMS), 3.14 (dd, 1H, Jˆ1.8, 13.9), 2.38 (s, 3H,
Ts), 1.95 (m, 1H), 1.10±1.70 (several m, 7H), 0.85 (m,
12H, t-BuSi1Me), 0.01 (s, 3H, MeSi), 0.00 (s, 3H, MeSi).
13C NMR (CDCl3) d 142.2, 138.4, 129.0 (2C), 127.4 (2C),
64.6, 52.5, 46.6, 31.1, 26.1, 25.9, 21.5, 20.9, 19.9, 18.4,
14.1, 24.8 (2C). IR 3428, 2956, 2857, 1463, 1327, 1148,
1094, 835. HRMS Calcd for C21H37O3NSiS1H: 412.2342,
found: 412.2232. [a]2D2ˆ288 (cˆ1.1, CHCl3).
1
celite and concentrated to give 0.15 g, (92%) of 12b. H
NMR (CDCl3) d 7.79 (d, Jˆ8.0 Hz, 2H, Ts), 7.40±7.25
(m, 7H, Ts and Ph), 4.39 (s, 2H, PhCH2), 4.32 (d,
Jˆ8.2 Hz, 1H, NH), 3.73 (m, 1H, CHOTBDMS), 3.33
(dd, Jˆ9.5, 5.5 Hz, 1H), 3.26 (m, 1H), 3.25 (dd, Jˆ9.5,
5.5 Hz, 1H), 2.42 (s, 3H, Ts) 1.20±1.60 (several m, 8H),
0.89 (s, 9H, t-BuSi), 0.79 (t, 3H, Me), 0.03 (s, 3H, MeSi),
0.02 (s, 3H, MeSi). 13C NMR (CDCl3) d 143.0, 138.5,
132.0, 130.3 (2C), 129.5 (2C), 128.3 (2C), 127.5 (2C),
127.1, 75.0, 73.3, 71.5, 55.1, 38.3, 36.4, 31.4, 25.8, 21.5,
18.5, 18.2, 13.6, 24.7, 24.9. IR 3276, 3030, 2955, 2928,
2856, 1496, 1454, 1252, 1160, 1094, 819, 698.
Compound 15b. The procedure outlined for 15a was
employed. To 13b (0.141 g, 0.33 mmol) in THF (4 ml) at
08C, was added Et3N (90 ml, 0.65 mmol) and MsCl (40 ml,
0.52 mmol) and the resulting crude product was dissolved in
MeOH (6 ml) and K2CO3 (400 mg, 2.9 mmol) was added,
this afforded 0.107 g (79%) of product 15b. 1H NMR
Compound 13a. Compound 12a (80 mg, 0.15 mmol) was
dissolved in MeOH (3 ml), and 5% palladium on carbon

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J. Lofstedt et al. / Tetrahedron 56 (2000) 2225±2230
2229
(CDCl3) d 7.72 (d, 2H, Ts), 7.30 (d, 2H, Ts), 3.97 (m, 1H),
3.69 (dd, Jˆ13.5, 5.0 Hz, 1H), 3.33 (m, 1H), 2.71 (dd,
Jˆ13.5, 10.7 Hz, 1H), 2.45 (m, 1H), 2.42 (s, 3H, Ts),
1.20±1.70 (several m, 8H), 0.91 (m, 12H, t-BuSi1Me),
0.04 (s, 3H, MeSi), 0.01 (s, 3H, MeSi). 13C NMR (CDCl3)
d 142.9, 138.9, 129.5 (2C), 127.6 (2C), 66.8, 51.8, 46.6,
31.6, 29.0, 26.7, 25.7, 21.4, 19.6, 18.0, 13.8, 24.7, 24.9
(2C). IR 3286, 2956, 2857, 1355, 1175, 1160, 959, 914, 837,
665.
of HCl in EtOH (95%) (10 equiv. of HCl). After concentra-
tion the hydrochloride salt of 9 was isolated in 94% yield
(3.3 mg). Spectral data of the hydrochloride salt were in
accordance with those reported in Ref. 6b. Treatment with
2 M NaOH (1 ml) and extraction with ether (3£1.5 ml) gave
the free amine 9.
Acknowledgements
Compound 16a. A solution of 15a (93 mg, 0.23 mmol) in
EtOH (2 ml) was added to liquid ammonia (6 ml) with stir-
ring at 2788C. To this mixture was added sodium (0.3 g,
13 mmol) in small portions. The reaction was allowed to
reach RT. After 24 h the mixture was diluted with ether
(15 ml) and quenched with aqueous NH4Cl (sat) (1 ml).
The aqueous phase was separated, backextracted with
ether (2£15 ml) and dried over Na2SO4. Concentration in
vacuo afforded 50 mg (85%) of 16a as the only product.
Financial support from the Swedish Natural Science
Research Council is gratefully acknowledged. We also
thank Ms. Mikaela Recknagel for valuable help in the lab.
References
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T. H.; Blum, M. S.; Robertsson, H. G. J. Nat. Prod. 1990, 53, 429.
2. (a) Christo®dis, I.; Welter, A.; Jadot, J. Tetrahedron 1977, 33,
977. (b) Hasseberg, H.-A.; Gerlach, H. Liebigs. Ann. Chem. 1989,
255.
1
This colorless oil was used directly in the next step. H
NMR (CDCl3) d 3.55 (m, 1H), 3.10 (m, 1H), 2.5 (m, 2H)
1.90 (m, 1H), 1.70 (m, 2H) 1.20±1.00 (several m, 6H), 0.90
(m, 12H, t-BuSi1Me), 0.00 (s, 6H, MeSi). 13C NMR
(CDCl3) d 69.4, 55.6, 54.5, 38.9, 34.7, 31.6, 25.9, 19.5,
18.2, 14.3, 24.5. GCMS (CI, CH4) 258 (M11, 100%),
242 (M2CH3, 89%), 214 (M2C3H7, 16%), 200 (M2t-Bu,
31%), 126 (M2OTBDMS, 55%). IR 3339, 2956, 2928,
2857, 1463, 1257, 1098. HRMS Calcd for C14H31ONSi1H:
258.2254, found: 258.2255. [a]2D2ˆ138 (cˆ0.9, CHCl3).
3. (a) Rice, W. Y.; Coke, J. L. J. Org. Chem. 1966, 31, 1010. (b)
Highet, R. J. J. Org. Chem. 1964, 29, 471. (c) Highet, R. J.;
Highet, P. F. J. Org. Chem. 1966, 31, 1275. (d) Hill, R. K.
Chemistry of the Alkaloids; Pelletier, S. W., New York, 1970,
pp 385. (e) Toyooka, N.; Yoshida, Y.; Yotsui, Y.; Momose, T.
J. Org. Chem. 1999, 64, 4914.
4. Ladenburg, A.; Adam, G. Chem. Ber. 1891, 24, 1671.
5. (a) Marion, L.; Cockburn, W. F. J. Am. Chem. Soc. 1949, 49,
3402. (b) Harding, K. E.; Burks, S. R. J. Org. Chem. 1984, 49, 40.
Compound 16b. To a solution of 15b (100 mg, 0.24 mmol)
and Na2HPO4 (287 mg, 2.0 mmol) in dry MeOH (2 ml) at
RT was added Na(Hg) (6%, 796 mg). The mixture was
heated to 508C and stirred for 18 h. The reaction was
allowed to reach RT, ®ltered through celite and the ®lter
cake rinsed with EtOAc. Brine was added and the organic
layer was separated. The aqueous phase was backextracted
three times with EtOAc, and the combined organic layers
were dried (Na2SO4). Concentration afforded 50 mg (81%)
of 16b. 1H NMR (CDCl3) d 3.71 (m, 1H), 2.85 (dd, Jˆ13.0,
2.5 Hz, 1H), 2.70 (dd, Jˆ13.0, 1.7 Hz, 1H) 2.41 (m, 1H),
1.72±1.15 (several m, 11H), 0.85 (m, 12H, t-BuSi1Me),
0.03 (s, 3H, MeSi) 0.01 (s, 3H, MeSi). 13C NMR (CDCl3)
d 65.2, 55.5, 52.7, 39.3, 31.7, 27.2, 25.8, 19.1, 18.0, 14.2,
24.8, 24.9.
È
(c) Spath, E.; Kuffner, F.; Ensfeller, L. Chem. Ber. 1933, 66, 591.
(d) Brown, E.; Lavoue, J.; Dhal, R. Tetrahedron 1973, 29, 455.
6. (a) Tadano, K. I.; Iimura, Y.; Suami, T. J. Carbohydrate Chem.
1985, 4, 129. (b) Takahata, H.; Inose, K.; Momose, T. Heterocycles
1994, 38, 269. (c) Sakagami, H.; Kamikubo, T.; Ogasawara, K.
J. Chem. Soc., Chem. Commun. 1996, 1433. (d) Cossy, J.; Dumas,
C.; Pardo, D. G. Synlett, 1997, 905. (e) Moody, C. J.; Lightfoot,
A. P.; Gallagher, P. T. J. Org. Chem. 1997, 62, 746. (f) Oppolzer,
W.; Bochet, C. G. Tetrahedron Lett. 1995, 36, 2959. (g) Hirai, Y.;
Shibuya, K.; Fukuda, Y.; Yokoyama, H.; Yamaguchi, S. Chem.
Lett. 1997, 3, 221. (h) Dockner, M.; Sasaki, N. A.; Riche, C.;
Potier, P. Liebigs Ann., Recl. 1998, 6, 1267. (i) Herdeis, C.;
Schiffer, T. Synthesis 1997, 1405. (j) Agami, C.; Couty, F.; Lam,
H.; Mathieu, H. Tetrahedron 1998, 54, 8783.
(1)-Pseudoconhydrine 3. The silyl ether 16a (25 mg,
0.10 mmol) was stirred for 2 h in 3.5 ml of a 1% solution
of HCl in EtOH (95%) (10 equiv. of HCl). After concentra-
tion, the hydrochloride salt of 3 was isolated and washed
with CH2Cl2 to give 17 mg (98%). [a]2D1ˆ13.678 (cˆ0.52,
È
7. (a) Pettersson-Fasth, H.; Riesinger, S. W.; Backvall, J.-E.
J. Org. Chem. 1995, 60, 6091. (b) Riesinger, S. W.; Lofstedt, J.;
È
È
Pettersson-Fasth, H.; Backvall, J.-E. Eur. J. Org. Chem. 1999, 3277.
È
È
8. (a) Bystrom, S. E.; Aslanian, R.; Backvall J. E. Tetrahedron
Lett. 1985, 26, 1749. (b) Kohrt, J. T.; Gu, J.-X.; Johnson, C. R.
J. Org. Chem. 1998, 63, 5088.
1
MeOH). lit.6f [a]D21ˆ13.568 (cˆ0.40, MeOH). H NMR
(CD3OD) d 3.82 (m, 1H), 3.33 (m, 1H), 3.07 (m, 1H)
2.73 (t, Jˆ11 Hz, 1H), 2.10 (m, 2H), 1.68±1.36 (m, 6H),
0.98 (t, Jˆ7.3 Hz 3H). Treatment of the salt with 2 M NaOH
(1 ml) and extraction with ether (3£1.5 ml) released the free
amine 3, which after removing of the solvent was obtained
as a crystalline compound. [a]2D2ˆ111.28(cˆ0.23, EtOH).
(lit.6e [a]2D9ˆ111.18(cˆ1.0, EtOH). Spectral data were in
accordance with those previously reported.6e
9. For Pd(0)-catalyzed reactions of vinylepoxides with nucleo-
philes see: (a) Tsuji, J.; Kataoka, H.; Kobayashi, Y. Tetrahedron
Lett. 1981, 22, 2575. (b) Trost, B. M.; Molander, G. A. J. Am.
Chem. Soc. 1981, 103, 5969. (c) Trost, B. M.; Sudhakar, A. R.
J. Am. Chem. Soc. 1987, 109, 3792. (d) Bernet, B.; Vasella, A.
Tetrahedron Lett. 1983, 24, 5491. (e) Tenaglia, A.; Waegell, B.
Tetrahedron Lett. 1988, 29, 4851. (f) Trost, B. M.; Romero, A. G.
J. Org. Chem. 1986, 51, 2332. (g) Tsuji, J. Pure & Appl. Chem.
1982, 54, 197. (h) Trost, B. M.; Kou, G.-H.; Benneche, T. J. Am.
Chem. Soc. 1988, 110, 621. (i) Trost, B. M.; Shi, Y. J. Am. Chem.
Soc. 1993, 115, 9421. (j) Trost, B. M.; Bunt, R. C. Angew. Chem.
(^)-epi-Pseudoconhydrine 9. The silyl ether 16b (5 mg,
0.02 mmol) was stirred for 2 h in 0.7 ml of a 1% solution

È
J. Lofstedt et al. / Tetrahedron 56 (2000) 2225±2230
2230
1996, 108, 70. Trost, B. M.; Krueger, A. C.; Bunt, R. C.;
Zambrano, J. J. Am. Chem. Soc. 1996, 118, 6520.
È
10. Schink, H. E.; Pettersson, H.; Backvall, J. E. J. Org. Chem.
1991, 56, 2769.
method for the LiAlH4 reduction of 17 to 18a, which in our
hands gave a lower yield than the method of Schloss and
Hartman.16 (b) McDonald, W. S.; Verbicky, C. A.; Zercher, C. K.
J. Org. Chem. 1997, 62, 1215.
È
11. Backvall, J. E.; Andersson, P. G.; Stone, G. B.; Gogoll, A.
J. Org. Chem. 1991, 56, 2988.
È
12. Backvall, J. E.; Schink, H. E.; Renko, Z. D. J. Org. Chem.
1990, 55, 826.
Â
18. Bouzide, A.; Sauve, G. Tetrahedron Lett. 1997, 34, 5945.
19. In the procedure described for monobenzylation of diols
1.5 equiv. of Ag2O was employed. With our substrate 18a this
led to substantial dibenzylation. However, the use of only
1 equiv. of Ag2O signi®cantly improved the yield of 18b.
20. (a) Katsuki, T.; Lee, A. W. M.; Ma, P.; Martin, V. S.;
Masamune, S.; Sharpless, K. B.; Tuddenham, D.; Walker, F. J.
J. Org. Chem. 1982, 47, 1373. (b) Gao, Y.; Hanson, R. M.;
Klunder, J. M.; Ko, S. Y.; Masamune, S.; Sharpless, K. B. J. Am.
Chem. Soc. 1987, 109, 5765.
13. Yamazaki, N.; Kibayashi, C. J. Am. Chem. Soc. 1989, 111,
1396.
14. Cunico, R. F.; Bedell, L. J. Org. Chem. 1980, 45, 4797.
15. Trost, B. M.; Weber, L.; Strege, P.; Fullerton, T. J.; Dietsche,
T. J. J. Am. Chem. Soc. 1978, 100, 3426.
16. Schloss, J. E.; Hartman, F. C. Bioorganic Chem. 1980, 9, 217.
17. (a) McDonald et al.17b recently published a high yielding