Asymmetric total synthesis of (+)-2-epi-deoxoprosopinine

Article abstract of DOI:10.1055/s-2000-8733

The asymmetric synthesis of (+)-2-epi-deoxoprosopinine [(S,S,R)-5] in eleven steps and with excellent diastereomeric and enantiomeric purity (de, ee ≥96%) is described. As key steps, the 1,2-addition of a dodecyl nucleophile to an aldehyde-SAMP hydrazone and the α-alkylation of 2,2-dimethyl-1,3-dioxan-5-one SAMP hydrazone are employed to generate two of the three stereogenic centers. Creation of the third stereogenic center was achieved in a domino deprotection/cyclisation/reduction sequence.

Full text of DOI:10.1055/s-2000-8733

SPECIAL TOPIC
2099
Asymmetric Total Synthesis of (+)-2-epi-Deoxoprosopinine
Dieter Enders,* Jan H. Kirchhoff
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax +49(241)8888127; E-mail: Enders@RWTH-Aachen.de
Received 19 August 2000; revised 2 September 2000
wide variety of physiological properties, including anal-
Abstract: The asymmetric synthesis of (+)-2-epi-deoxoprosopinine
gesic, anaesthetic and antibiotic activity.4
[(S,S,R)-5] in eleven steps and with excellent diastereomeric and
enantiomeric purity (de, ee ≥96%) is described. As key steps, the
1,2-addition of a dodecyl nucleophile to an aldehyde-SAMP hydra-
zone and the a-alkylation of 2,2-dimethyl-1,3-dioxan-5-one SAMP
hydrazone are employed to generate two of the three stereogenic
centers. Creation of the third stereogenic center was achieved in a
domino deprotection/cyclisation/reduction sequence.
During the last few years these molecules have become
interesting targets in total synthesis. Some syntheses of
the racemates have been reported,5 however, in most ap-
proaches to this class of molecules an enantiopure sub-
stance was used as starting material (“ex chiral pool
synthesis”)6 and only a few examples employing asym-
metric synthesis have been published.7
Key words: asymmetric synthesis, deoxoprosopinine, SAMP/
RAMP hydrazone method, natural products, piperidine alkaloids
As part of our continuing studies towards the asymmetric
total synthesis of piperidine- and pyrrolidine alkaloids,8
we herein wish to disclose an efficient asymmetric synthe-
sis of (S,S,R)-(+)-2-epi-deoxoprosopinine [(S,S,R)-5] em-
ploying the SAMP/RAMP hydrazone method as key
steps.
Hydroxylated piperidine alkaloids are abundantly found
in living systems. The wide range of their potent physio-
logical effects stems from their ability to mimic carbohy-
drates in a variety of enzymatic processes.1 Prosopis
alkaloids form a small subgroup of alkaloid lipids contain-
ing a 2,6-disubstituted 3-piperidinol framework with a
long aliphatic appendage at the 6-position. At one end of
these molecules is the polar head group with a configura-
tion of the 1,3-diol unit similar to those in deoxynojirimy-
cin 1, a potent a-glucosidase I and II inhibitor,2 while the
lipophilic tail resembles the membrane lipid sphingosine
2. Seven piperidine alkaloids, among them (+)-prosopin-
ine 3 and (+)-prosophylline 4 have been isolated from the
leaves of the West African savanna tree Prosopis africana
Taub.3
As disclosed in the retrosynthetic analysis (Scheme 1), the
title alkaloid (S,S,R)-5 can be traced back to electrophilic
iodo amine A and the dihydroxyacetone enolate synthon
B of which the SAMP hydrazone C is an enantiopure syn-
thetic equivalent.9 Amine A in turn may be prepared by
nucleophilic 1,2-addition10 of a dodecyl nucleophile to the
CN double bond of SAMP hydrazone D. Accordingly, the
final synthetic transformation would be an intramolecular
reductive amination.
OH
OH
OH
OH
I
+
OH
n-C12H25
N
H
n-C12H25
NHZ
O
HO
OH
OH
H3C
OH
OH
(S,S,R)-5
A
B
11
(+)-2-epi-Deoxoprosopinine
N
H
H2N
1
2
CH3
CH3
O
OH
OH
OH
OH
OTBS
O
O
O
H3C
n-C12H25MLn
+
H3C
N
N
N
N
N
9
9
H
H
N
4
3
OCH3
H3CO
OH
OH
3
2
C
D
6
H3C
N
9
Retrosynthetic analysis
H
(R,S,R)-5
Scheme 1
As outlined in Scheme 2, the synthesis starts from 3-(tert-
butyldimethylsiloxy)propanenitrile 6, readily prepared
via TBS protection of commercially available 3-hydrox-
ypropanenitrile.11 Aldehyde 712 was obtained by reduction
Due to their structural features mentioned above these
polysubstituted piperidine alkaloids and their deoxygenat-
ed derivatives (e.g. (+)-deoxoprosopinine 5) exhibit a
Synthesis 2000, No. 14, 2099–2105 ISSN 0039-7881 © Thieme Stuttgart · New York

2100
D. Enders, J. H. Kirchhoff
SPECIAL TOPIC
of nitrile 6 with diisobutylaluminium hydride following For protection, amine (R)-10 was transformed to a benzyl-
an analogous literature procedure.13 The crude aldehyde carbamate. Introduction of the Z-protecting group with
was treated with (S)-1-amino-2-(methoxymethyl)pyrroli- excess benzyl chloroformate and triethylamine in dichlo-
dine (SAMP) affording hydrazone (S)-8 in 72% yield over romethane turned out to be unsatisfactory because of the
2 steps. As the first key step in the synthesis, the diastere- long reaction times and the unacceptable yields. It there-
oselective 1,2-addition of a dodecyl nucleophile to the CN fore proved advantageous to carry out the reaction in a
double bond of hydrazone (S)-8 (D) by several nucleo- two-phase solvent system of water and chloroform using
philes, such as organolithium, -cerium, -ytterbium and catalytic amounts of tetra-n-butylammonium iodide and
Grignard reagents was investigated. The best results were Na2CO3, as base, to yield carbamate (R)-11 in a yield of
achieved by treatment of hydrazone (S)-8 with three 79% over two steps from hydrazine (R,S)-9.
equivalents of a dodecylytterbium reagent, obtained from
dodecyllithium and dry ytterbium(III) chloride, at
To obtain a suitable electrophile for the a-alkylation of
hydrazone (S)-14 (C), carbamate (R)-11 was transformed
-100 °C, furnishing hydrazine (R,S)-9 in 84% yield and
into iodide (R)-13 (A). First, the silyl ether in (R)-11 was
cleaved with excess tetra-n-butylammonium fluoride
(TBAF) in THF in the presence of ammonium fluoride,
which buffered the solution to a neutral pH value. The re-
excellent diastereomeric excess of 95% (determined by
13C NMR). N-N bond cleavage affording a-branched
amine (R)-10 was accomplished by heating with borane-
tetrahydrofuran complex (10 equivalents) in THF under
sulting alcohol (R)-12, obtained in 90% yield, was then
reflux for 4 hours, followed by methanolysis according to
converted into its corresponding iodide.16 Treatment of al-
a standard procedure developed by our group.14 To ensure
cohol (R)-12 with imidazole, triphenylphosphine and ele-
mental iodine in a mixture of ether and acetonitrile
that the N-N bond cleavage proceeded without racemisa-
tion, a sample of amine (R)-10 was converted to the
furnished iodide (R)-13 in 91% yield. With this key com-
Mosher amide with (S)-a-methoxy-a-(trifluorometh-
pound in hand, the a-alkylation of SAMP hydrazone
(S)-14 to establish the second stereogenic center was next
yl)phenylacetyl chloride (MTPA-Cl).15 As expected, the
diastereomeric excess of the amide was determined to be
examined (Scheme 3).
95% by 13C NMR, revealing that no racemisation during
Thus, SAMP hydrazone (S)-14 was metalated at -78 °C
with tert-butyllithium in THF and the resulting aza-eno-
late was alkylated with the iodide (R)-13 affording the
N-N bond cleavage had occurred.
O
a-alkylated hydrazone (R,S,S)-15 with a diastereomeric
a
NC
excess of 95% (determined by 13C NMR analysis). Due to
OTBS
H
OTBS
the acidity of the carbamate proton in (R)-13, it was nec-
essary to employ two equivalents of the metalated SAMP-
hydrazone (S)-14. Hexamethylphosphoramide (HMPA)
was needed as an additive to keep the lithiated carbamate
(R)-13 in solution. The reaction was complete after 18 h.
This extraordinarily long reaction time can be rationalised
by considering the negative charge of the electrophile.
Separation of the product (R,S,S)-15 and excess hydra-
zone (S)-14 by column chromatography could not be
achieved on a preparative scale, so that the hydrolytic
cleavage of the auxiliary was carried out on a mixture of
both. Therefore, a solution of hydrazones (R,S,S)-15 and
(S)-14 in ether was treated with aqueous oxalic acid.17 Be-
cause of the high volatility of the ketone derived from
(S)-14, pure ketone (R,S)-16 was obtained without chro-
matographic purification in 80% yield (2 steps) and a di-
astereomeric excess of 95% (1H, 13C NMR). It should be
noted that under these mild conditions even acid sensitive
protecting groups like acetals and carbamates are tolerat-
ed. Furthermore the method allows recycling of the chiral
auxiliary.
6
7
72%
(2 steps)
b
H3CO
N
N
N
HN
c
H3CO
84%
H
OTBS
n-C12H25
(R,S)-9
OTBS
(S)-8
de = 95%
d
NH2
HNZ
e
n-C12H25
(R)-10
OTBS
n-C12H25
OTBS
79%
(2 steps)
ee = 95%
(R)-11
f
90%
HNZ
HNZ
g
91%
OH
n-C12H25
n-C12H25
I
(R)-13
(R)-12
The next steps in the synthesis were the deprotection of
the amine functionality, with subsequent formation of pi-
Reagents and conditions: a) DIBAL-H, THF, 0 °C to r.t., 2 h, then 1
M tartaric acid; b) SAMP, 0 °C to r.t., 16 h; c) YbCl36 H2O, n-
C12H25Li, -100 °C, then (S)-8/THF, 2 h, -100 °C to r.t.; d) BH3∑THF peridine 18 via the cyclic imine intermediate (S,R)-17. In
(excess), THF, reflux, 4 h; e) BnOC(O)Cl (ZCl), n-Bu4NI, Na2CO3,
CHCl3/H2O, reflux, 3 days; f) TBAF, NH4F, THF, r.t., 5 h; g) imida-
zole, PPh3, I2, Et2O/CH3CN 3:2, 0 °C, 5 h
a domino reaction, the amine protecting group was re-
moved by catalytic hydrogenolysis over palladium on
charcoal, and the released amine cyclised under reductive
amination conditions to furnish piperidines (S,S,R)-18 and
Scheme 2
(S,S,S)-18 in a ratio of 98:2 and an overall yield of 88%.
Synthesis 2000, No. 14, 2099–2105 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Total Synthesis of (+)-2-epi-Deoxoprosopinine
2101
For the major diastereomer (S,S,R)-18, strong nuclear
Overhauser effects are observed between the protons at
C-2, C-4ax. and C-6, indicating a 2,4,6 cis-substitution pat-
tern with the protons in the axial position, and between the
proton at C-3 and the axial methyl group of the acetonide,
revealing an equatorial cis position of the proton at C-3
with respect to that at C-2. In contrast, the axial protons at
C-2 and C-4 of the minor diastereomer (S,S,S)-18 exhibit
no interaction with the proton at C-6 due to its equatorial
position, but instead with the methylene protons of the
carbon chain. Again a strong resonance between the equa-
torial proton at C-3 and the methyl group of the acetonide
is observed, indicating a 2,3-cis-substitution pattern at the
piperidine ring.
OCH3
N
N
N
O
HNZ
N
a
OCH3
n-C12H25
O
O
O
H3C CH3
H3C CH3
(R,S,S)-15
(S)-14
de = 95 %
80%
(2 steps)
b
"H"
H
H
HNZ
O
H
c
H
n-C12H25
N
C
n-C12H25
H
O
O
O
H
O
CH3
These results clearly indicate that the reductive amination
leads exclusively to the 2,3-cis-substituted epimers of ac-
etonide-protected (+)-2-epi-deoxoprosopinine [(S,S,R)-
18] and (+)-2-epi-deoxoprosophylline [(S,S,S)-18]. The
observed configuration can be explained by sterical
shielding of the re face of imine (S,R)-18 by the acetonide
group, leading to an attack of hydrogen from the si face,
resulting in a 2,3-cis-substitution pattern (Scheme 3).
H3C CH3
"H"
de = 95%
(R,S)-16
H3C
(S,R)-17
88%
CH3
CH3
O
O
CH3
O
CH3
+
O
n-C12H25
N
H
n-C12H25
N
H
At this stage of the synthesis, the enantiomeric excess of
diastereomerically pure acetonide (S,S,R)-18 was deter-
mined by treatment with (S)-MTPA-chloride yielding a
diastereomerically pure amide with a diastereomeric ex-
cess greater than 96% (NMR, HPLC), revealing that ace-
tonide (S,S,R)-18 is enantiomerically pure and during the
synthesis no racemisation occurred.
(S,S,S)-18
(S,S,R)-18 dr = 98 : 2
d
87%
OH
OH
n-C12H25
N
H
The final step in the synthesis towards (S,S,R)-(+)-2-epi-
deoxoprosopinine [(S,S,R)-5] was the hydrolytic cleavage
of the acetal group. In contrast to a literature procedure,6a
involving hydrochloric acid in methanol, an improved
yield of 87% could be achieved by using an acidic ion ex-
change resin. In this way, the target molecule (S,S,R)-5
was isolated as a colourless amorphous solid with a dias-
tereo- and enantiomeric excess greater than 96%.
(S,S,R)-5
ee,de≥96 %
Reagents and conditions: a) t-BuLi, THF, -78 °C, 2 h, then HMPA,
(R)-13/THF, -78 °C, 16 h; b) sat. oxalic acid, Et2O, r.t., 5 h; c) H2,
Pd/C (10%), EtOH, r.t., 2 h; d) Lewatit S 100‰, MeOH, reflux 2 h,
then sat. NH4OH
Scheme 3
In conclusion, an efficient asymmetric synthesis of
(+)-2-epi-deoxoprosopinine [(S,S,R)-5] was successfully
carried out in 11 steps to afford the target molecule in 23%
overall yield and with excellent diastereomeric and enan-
tiomeric excess. The applicability of the SAMP/RAMP
hydrazone method with respect to a-alkylation and
1,2-addition for the synthesis of polyhydroxylated piperi-
dine alkaloids has been demonstrated. Biological tests to-
wards the physiological activity of (S,S,R)-(+)-2-epi-
deoxoprosopinine are now in progress.
After chromatographic separation of both epimers, stere-
ochemical assignments were established through NOE-
NMR techniques on each isomer leading to the structures
sketched in the Figure.
n-H25C12
H
H
H
4
4
H
H
6
6
5
5
H
H
All chemicals were of reagent grade and used from freshly opened
containers. Ytterbium(III) chloride hexahydrate was purchased
from Aldrich, t-BuLi (1.6 M in hexane) from Merck, Darmstadt,
1-Iodododecane and Florisil‰ from Acros, ion exchange resin Le-
watit S 100‰ from Fluka. tert-Butyldimethylsilyl chloride was used
as a 50% solution in toluene obtained from Wacker Silan, München.
Solvents were dried and purified by conventional methods prior to
use. Et2O and THF were freshly distilled from benzophenone and
Na/lead alloy under Ar; DMF and MeCN from CaH2. Preparative
column chromatography: Merck silica gel 60, particle size 0.040-
n-C12H25
Heq
2
2
3
3
Heq
Heq
HN
HN
O
O
O
CH3 ax
O
CH3 ax
H3C
minor diastereomer (S,S,S)-18
H3C
major diastereomer (S,S,R)-18
Figure
Synthesis 2000, No. 14, 2099–2105 ISSN 0039-7881 © Thieme Stuttgart · New York

2102
D. Enders, J. H. Kirchhoff
SPECIAL TOPIC
0.063 mm (230-400 mesh, flash). Analytical TLC: Silica gel 60
F254 plates, Merck, Darmstadt. Optical rotation values were mea-
sured on a Perkin-Elmer P241 (589 nm), solvents used were of
Merck UVASOL-quality. Microanalyses were obtained from a Her-
aeus CHN-O-RAPID element analyser. Mp: Büchi 510. HRMS:
Finnigan MAT 95. Mass spectra: Finnigan MAT 212 (EI 70 eV). IR
16 h. A solution of 1-iodododecane (21.32 g, 72 mmol, 9 equiv) in
anhyd Et2O (60 mL) was cooled to -20 °C and treated dropwise
with t-BuLi (1.6 M in hexane, 77 mL, 122 mmol), whilst the reac-
tion mixture was slowly cooled to -40 °C. After stirring for 0.5 h at
that temperature, the mixture was warmed to r.t. and stirred for an
additional 2 h. The ytterbium(III) chloride/THF suspension was
cooled to -78 °C and the organolithium solution was added drop-
wise via a canula. The suspension was stirred for 2 h at this temper-
ature, turning to an orange colour. After cooling to -100 °C, a
solution of hydrazone (S)-8 (2.40 g, 8 mmol, 1 equiv) in anhyd THF
(12 mL) was added dropwise. The mixture was stirred at this tem-
perature for an additional 2 h, then warmed to r.t. overnight and
quenched with sat. NaHCO3 (40 mL). The resulting slurry was ex-
tracted with Et2O (4 ¥ 100 mL) and dried (MgSO4). After removal
of the solvent, the yellow residue was purified by flash chromatog-
raphy (silica gel, pentane/Et2O, 10:1 to 4:1, 1% Et3N) to yield hy-
drazine (R,S)-9 as a pale yellow oil; yield: 3.16 g (84%).
1
spectra: Perkin-Elmer FT/IR 1750. H NMR spectra (300 MHz,
400 MHz and 500 MHz), 13C NMR (75 MHz, 100 MHz and 125
MHz): Gemini 300, Varian VXR 300, Varian Inova 400 and Varian
Unity 500 (TMS as internal standard). HPLC: Gilson Abimed, col-
umn: Lichrosorb‘ Si 60 (7µm), UV detector. (S)-1-Amino-2-
(methoxymethyl)pyrrolidine (SAMP),18 2,2-dimethyl-1,3-dioxan-
5-one19 and 2,2-dimethyl-1,3-dioxan-5-one SAMP hydrazone9a
were prepared according to published procedures.
(2S)-(E)-(-)-3-[(1-tert-Butyldimethylsilyloxy)propylidene)-2-
(methoxymethyl)-1-pyrrolidinamine [(S)-8]
[a]D25 -56.5° (c 1.01, CHCl3).
3-(tert-Butyldimethylsiloxy)propanal (7) was prepared following
an analogous literature procedure:13 A solution of diisobutylalumin-
ium hydride (1 M in hexane, 200 mL, 200 mmol, 1.33 equiv) was
added dropwise at 0 °C to a stirred solution of 3-(tert-butyldimeth-
ylsiloxy)propanenitrile 611 (24.2 g, 150 mmol) in anhyd THF
(350 mL) under Ar. The reaction was allowed to warm to r.t. and
stirred for an additional 2 h. The reaction mixture was quenched by
dropwise addition to a rapidly stirred mixture of 1 M tartaric acid
(700 mL) and Et2O (300 mL) at 0 °C. After separation, the aqueous
phase was extracted with Et2O (3 ¥ 150 mL) and the combined or-
ganic phases were washed with brine, and dried (MgSO4). After
concentration in vacuo, the crude product was obtained as a reddish-
brown oil; yield: 20.4 g, which was used without further purifica-
tion in the next step. The crude aldehyde 7 was cooled to 0 °C and
SAMP (19.5 g, 150 mmol, 1.0 equiv) was added dropwise. The re-
action mixture was allowed to warm to r.t. overnight, poured into
Et2O (400 mL) and dried (MgSO4). After removal of the solvent un-
der reduced pressure and purification of the brown residue by flash
chromatography (silica gel; pentane/Et2O, 4:1, 1% Et3N), hydra-
zone (S)-8 was obtained as a colourless oil; yield: 32.3 g (72% over
2 steps).
1H NMR (300 MHz, CDCl3): d = -0.01 (s, 6H, SiCH3), 0.88 (m,
12H, C(CH3)3, CH2CH3), 1.16-1.39 [m, 22H, H3C(CH2)11], 1.42-
1.79 (m, 5H, NCH2CHHCH2, CH2CH2OSi), 1.82-1.95 (m, 1H,
NCHH), 2.11 (m, 1H, NCH2CHH), 2.55 (m, 1H, NCH2), 2.82 (m,
1H, HNCH), 3.28-3.33 (m, 1H, H3COCH2CH), 3.30 (s, 3H,
OCH3), 3.37 (m, 1H, H3COCHH), 3.54 (dd, 1H, J = 9.06, 3.69 Hz,
H3COCHH), 3.69 (m, 2H, CH2OSi).
13C NMR (75 MHz, CDCl3): d = -4.82 (SiCH3), 14.65 (CH2CH3),
18.77 [C(CH3)3], 21.57 (CH2CH3), 23.23 (NCH2CH2), 25.89 (CH2
chain), 26.51 [C(CH3)3], 26.77 (NCH2CH2CH2), 29.91-30.35 (6 C-
atoms, CH2 chain), 30.67 (CH2 chain), 32.47 (HNCHCH2 chain), 34.52
(CH2 chain), 36.04 (CH2CH2OSi), 57.67 (NCH2), 57.81 (HNCH),
59.54 (OCH3), 62.44 (CH2OSi), 66.45 (NCHCH2CH3), 75.59
(CH2CH3).
IR (film):n = 2954-2850 (C-H), 1464, 1387, 1361, 1255, 1187,
1097 (Si-O), 1006, 939, 919, 836 (Si-O-C), 776 (Si-C), 723, 663
cm-1.
MS (EI): m/z (%) = 470 (29, M+), 425 (100, M+-CH2OCH3), 395
(10), 365 (23), 311 (5, M+-CH2CH2OTBS), 285 (7), 169 (5,
C12H25+), 129 (15), 96 (11), 73 (17), 70 (22, c-C4H8N+), 57 (22, t-
[a]D28 -133° (c 1.20, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.01 (s, 6H, SiCH3), 0.84 [s, 9H,
C(CH3)3], 1.69-1.95 (m, 4H, NCH2CH2CH2), 2.38 (dt, 2H, J = 5.5,
6.59 Hz, N=CHCH2), 2.67 (m, 1H, NCHH), 3.26-3.40 (m, 3H,
H3COCHHCH, NCHH), 3.32 (s, 3H, OCH3), 3.51 (m, 1H,
H3COCHH), 3.70 (t, 2H, J = 6.59 Hz, CH2OSi), 6.60 (t, 1H, J = 5.5
Hz, HC=N).
+
C4H9 ).
Anal. Calcd. for C27H58N2O2Si (470.861): C, 68.87; H, 12.42; N,
5.95. Found: C, 68.51; H, 12.63; N, 6.51.
HRMS: m/z calcd for C27H58N2O2Si+: 470.4268. Found: 470.4267.
(1R)-(-)-Benzyl-N-[1-(2-{[1-(tert-butyl)-1,1-dimethylsi-
13C NMR (75 MHz, CDCl3): d = -4.73 (SiCH3), 18.83 [C(CH3)3],
22.70 (NCH2CH2), 26.46 [C(CH3)3], 27.16 (NCH2CH2CH2), 37.08
(N=CHCH2), 50.73 (NCH2), 59.71 (OCH3), 62.37 (CH2OSi), 63.88
(NCHCH2CH3), 75.36 (CH2CH3), 136.18 (N=C).
lyl]oxy}ethyl)tridecyl]carbamate [(1R)-11]
Hydrazine (R)-9 (2.56 g, 5.45 mmol) was dissolved in anhyd THF
(20 mL) under Ar. After addition of borane-tetrahydrofuran-com-
plex (1 M THF, 55 mL, 55 mmol, 10 equiv), the mixture was heated
under reflux for 4 h. After cooling to r.t., MeOH (30 mL) was cau-
tiously added and the solvent was removed under reduced pressure.
MeOH (80 mL) was added and the mixture was heated under reflux
for an additional hour. After cooling to r.t., the solvent was evapo-
rated and the residue was dried in vacuo to yield a turbid oil; 2.68 g.
The crude amine (R)-10 was dissolved in CHCl3 (100 mL), and tet-
ra-n-butylammonium iodide (61 mg, 0.15 mmol, 3 mol%), a solu-
tion of Na2CO3 (6.90 g) in H2O (30 mL) and benzyl chloroformate
(2.32 g, 13.6 mmol, 2.5 equiv) were added and the mixture was
heated under reflux for 3 days. After cooling to r.t., the phases were
separated and the aqueous phase was extracted with CH2Cl2 (2 ¥ 30
mL). The combined organic layers were washed with sat. Na2CO3
(2 ¥ 10 mL), H2O (10 mL), and brine (10 mL), and dried (MgSO4).
The residue obtained after removal of the solvent was purified by
column chromatography (pentane/Et2O, 7:1 to 4:1, 1% Et3N) to
IR (film): n = 2954-2826 (C-H), 1604 (C=N), 1472, 1462, 1386,
1361, 1340, 1255, 1197, 1097 (Si-O), 1006, 940, 837 (Si-O-C), 776
(Si-C), 728 cm-1.
MS (EI): m/z (%) = 300 (2, M+), 255 (100, M+-CH2OCH3), 186 (1,
M+-SMP), 123 (7), 99 (7), 73 (29), 70 (14, c-C4H8N+), 45 (5,
+
H2C = OCH3 ).
Anal. Calcd. for C15H32N2O2Si (300.521): C, 59.95; H, 10.73; N,
9.32. Found: C, 59.81; H 10.73; N, 9.62.
(1R,2S)-(-)-N-{1-[2-(1-tert-Butyldimethysiloxy)ethyl]tridecyl}-
N-2-(methoxymethyl)-1-pyrrolidinamine [(R,S)-9]
In a 500 mL Schlenk flask, equipped with an oval stirring bar, ytter-
bium(III) chloride hexahydrate (9.26 g, 24 mmol, 3 equiv) was
dried at 140 °C and 0.1 Torr under stirring for 2 h. After cooling to
r.t., the dry colourless powder suspended in anhyd THF (140 mL)
was placed under an Ar atm, and stirred under ultrasonication for
Synthesis 2000, No. 14, 2099–2105 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Total Synthesis of (+)-2-epi-Deoxoprosopinine
2103
yield carbamate (R)-11 as a colourless oil; yield: 2.11 g (79% over
lour remained. After stirring for 5 h at this temperature, the reaction
2 steps).
[a]D25 -3.5° (c 1.0, CHCl3).
was complete (TLC control) and the mixture was poured into Et2O
(70 mL), washed with sat. Na2S2O3 (10 mL), brine (10 mL), and
dried (MgSO4). After evaporation of the solvent under reduced
pressure, the obtained residue was purified by flash chromatogra-
phy (pentane/Et2O, 10:1 to 1:1, 1% Et3N) affording iodide (R)-13 as
a colourless amorphous solid; yield: 585 mg (91%); mp: 67 °C.
1H NMR (400 MHz, CDCl3): d = 0.04 (s, 3H, SiCH3), 0.05 (s, 3H,
SiCH3), 0.88 [m, 12H, C(CH3)3, CH2CH3], 1.22-1.33 [m, 18H,
H3C(CH2)9], 1.48 (m, 2H, CH2 chain), 1.58 (m, 1H, NCH), 1.69-1.88
(m, 2H, NCHCH2 chain), 3.64-3.79 (m, 4H, CH2CH2OSi, CH2OSi),
5.08 (s, 2H, OCH2Ph), 5.17 (d, 1H, J = 7.5 Hz, NH), 7.28-7.36 (m,
5H, Harom).
13C NMR (100 MHz, CDCl3): d = -5.49 (SiCH3), 14.14 (CH2CH3),
18.15 [C(CH3)3], 22.71 (CH2CH3), 25.89 [C(CH3)3], 29.38-29.79
(8 C-atoms, CH2 chain), 31.94 (CH2 chain), 34.88 (NCHCH2 chain), 36.64
(CH2CH2OSi), 49.56 (NCH), 60.31 (CH2OSi), 66.27 (OCH2Ph),
127.88 (4 C-atoms), 128.41 (Carom), 136.9 (Cipso), 156.0 (CO).
[a]D28 -4.75° (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.88 (t, 3H, J = 6.9 Hz, CH3),
1.17-1.34 [m, 20H, H3C(CH2)10], 1.42 (m, 2H, NCHCH2 chain), 1.96
(m, 1H, CHHCH2I), 2.07 (m, 1H, CHHCH2I), 3.17 (m, 2H, CH2I)
3.68 (dquintet, 1H, J = 9.34, 4.40 Hz, NCH), 4.55 (d, 1H, J = 9.34
Hz, NH), 5.09 (s, 2H, OCH2Ph), 7.29-7.38 (m, 5H, Harom).
13C NMR (75 MHz, CDCl3): d = 1.44 (CH2I), 14.14 (CH3), 22.70
(CH2CH3), 25.73 (CH2 chain), 29.36-29.65 (7 C-atoms, CH2 chain),
31.92 (CH2 chain), 35.01 (NCHCH2 chain), 40.04 (CH2CH2I), 52.46
(NCH), 66.74 (OCH2Ph), 128.10, 128.17, 128.55 (Carom), 136.23
(Cipso), 156.11 (C=O).
IR (film): n = 3750-3120 (N-H), 3100-2855 (C-H), 1701 (C=O),
1532, 1511, 1464, 1254, 1094 (Si-O), 837 (Si-O-C), 777 (Si-C),
735, 697, 664 (C-Hoop) cm-1.
MS (EI): m/z (%) = 434 (42, M+-C4H9), 390 (8, M+-C4H9,-CO2),
208 (11), 130 (8), 100 (6), 91 (100, C7H7 ), 73 (6), 57 (5, C4H9 ).
IR (KBr): n = 3315 (N-H), 3059, 3032 (Car-H), 2917, 2849 (C-H),
1686 (C=O), 1541, 1473, 1469 (C=Car), 1444, 1351, 1297, 1285,
1270, 1257, 1196, 1171, 1156, 1139, 1126, 1089, 1053, 1042, 1024,
1009, 735, 697 (C-Hoop) cm-1.
+
+
Anal. alcd. for C29H53NO3Si (491.350): C, 70.82; H, 10.86; N, 2.85.
Found: C, 70.68; H, 11.29; N, 3.25.
MS (EI): m/z (%) = 487 (2, M+), 360 (6), 332 (25, M+-C2H4I), 318
(1R)-(-)-Benzyl-N-[1-(2-hydroxyethyl)tridecyl]carbamate [(R)-
12]
+
(5, M+-C12H25), 288 (52), 274 (10), 108 (17), 91 (100, C7H7 ).
Anal. Calcd. for C23H38INO2 (487.464): C, 56.67; H, 7.86; N, 2.87.
Found: C, 56.29; H, 7.61; N, 2.69.
Carbamate (R)-11 (4.59 g, 9.34 mmol) was dissolved in THF
(70 mL), ammonium fluoride (6.90 g, 187 mmol, 20 equiv) was
added and the suspension was treated with a solution of tetra-n-bu-
tylammonium fluoride (1 M in THF, 47 mL, 47 mmol, 5 equiv) and
stirred for 5 h. After complete conversion (TLC control), the mix-
ture was poured into H2O (200 mL) and extracted with CH2Cl2 (3 ¥
200 mL). The combined organic phases were washed with brine
(30 mL), dried (MgSO4). After removal of the solvent, the resulting
residue was purified by flash chromatography (pentane/Et2O, 2:1,
1% Et3N) to yield alcohol (R)-12 as a colourless amorphous solid;
yield: 3.17 g (90%); mp: 76 °C.
(1R,2S,4S)-(5Z)-(+)-Benzyl-N-{1-[2-(5-{[2-methoxymethyl]pyr-
rolidin-1-yl]imino}-2,2-dimethyl-1,3-dioxan-4-yl)ethyltride-
cyl]carbamate [(R,S,S)-15]
A solution of hydrazone (S)-149a (1.05 g, 4.32 mmol, 2.3 equiv) in
anhyd THF (45 mL) under Ar was treated at -78 °C with t-BuLi
(1.6 M in hexane, 2.60 mL, 4.14 mmol, 2.2 equiv) and stirred for
2 h. Hexamethylphosphoramide (HMPA) (7.6 mL) was added fol-
lowed by dropwise addition of a solution of iodide (R)-13 (915 mg,
1.88 mmol, 1 equiv) in anhyd THF (20 mL). The mixture was
stirred for an additional 16 h at -78 °C and quenched with pH 7
buffer (10 mL) at this temperature. Et2O (100 mL) was added and
the organic layer washed with brine (4 ¥ 10 mL). After drying
(MgSO4) and removal of the solvent under reduced pressure, the re-
maining pale yellow residue was purified by flash chromatography
(pentane/Et2O, 4:1 to 1:2, 3% Et3N). The product was obtained as a
colourless, oily mixture of hydrazone (R,S,S)-15 and unreacted hy-
drazone (S)-14, which was used in the next step without further sep-
aration; yield: 1.50 g (89% by NMR). An analytical sample was
obtained by HPLC chromatography (pentane/Et2O, 1:1, 0.3% Et3N)
as a colourless oil.
[a]D24 -4.8° (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.88 (t, 3H, J = 6.9 Hz, CH3),
1.20-1.56 [m, 22H, H3C(CH2)11], 1.81 (m, 1 H, NCH), 2.70 (br s,
2H, CH2CH2OH), 3.63 (dd, 2H, J = 7.7, 3.30 Hz, CH2OH), 3.80 (br
s, 1H, OH), 4.70 (br s, 1H, NH), 5.08 (d, 1H, J = 12.09 Hz, OCHH-
Ph), 5.12 (d, 1H, J = 12.09 Hz, OCHHPh), 7.29-7.39 (m, 5H,
Harom).
13C NMR (100 MHz, CDCl3): d = 14.11 (CH3), 22.67 (CH2CH3),
26.07 (CH2 chain), 29.32-29.63 (7 C-atoms, CH2 chain), 31.89 (CH2
chain), 35.54 (NCHCH2 chain), 38.65 (CH2CH2OH), 48.06 (NCH),
58.75 (CH2OH), 66.87 (OCH2Ph), 127.88, 128.03, 128.38 (Carom),
136.18 (Cipso), 157.16 (C=O).
(Z)-Isomer
IR (KBr): n = 3800-3120 (O-H, N-H), 3066, 3035 (Car-H), 2919,
2851 (C-H), 1690 (C=O), 1542, 1469 (C=Car), 1455, 1430, 1353,
1250, 1093, 1063, 869, 740, 694 (C-Hoop) cm-1.
[a]D28 +77.9° (c 0.77, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.88 (t, 3H, J = 6.7 Hz, CH3),
1.22-1.55 [m, 24H, CH2CHO, H3C(CH2)11], 1.37 (s, 3H,
[(H3C)2Ceq.], 1.39 [s, 3H, (H3C)2Cax.], 1.58-1.86 (m, 4H, NCH2CH2
CH2 pyrrolidine ring), 1.94 (m, 2H, CH2CH2CHO), 2.39 (m, 1H, NCH-
Heq.), 3.01 (dt, 1H, J = 8.8, 6.04 Hz, NCHHax.), 3.19 (m, 1H, NCH-
pyrrolidine ring), 3.29-3.42 (m, 2H, H3COCH2), 3.32 (s, 3H, H3CO),
3.61 (m, 1H, HNCH), 4.11 [dd, 1H, J = 15.66, 1.8 Hz,
(H3C)2COCHHax.], 4.34 [m, 1H, (H3C)2COCH], 4.49 [d, 1H,
J = 15.66 Hz, (H3C)2COCHHeq.], 4.76 (d, 1H, J = 8.79 Hz, NH),
5.06 (d, 1H, J = 12.2 Hz, OCHHPh), 5.11 (d, 1H, J = 12.2 Hz,
OCHHPh), 7.25-7.43 (m, 5H, Harom).
MS (EI): m/z (%) = 377 (15, M+), 332 (11, M+-C2H5O), 288 (40),
242 (13, H25C12CNH2CH2CH2OH+), 208 (69, M+-C12H25), 164 (61,
+
+
CbzNHCH2 ), 108 (15), 91 (100, C7H7 ).
Anal. Calcd. for C23H39NO3 (377.572): C, 73.17; H, 10.41; N, 3.71.
Found: C, 73.02; H, 10.61; N 3.54.
(1R)-(-)-Benzyl-N-[1-(2-iodoethyl)tridecyl]carbamate [(R)-13]
Alcohol (R)-12 (500 mg, 1.32 mmol) was dissolved in a mixture of
anhyd Et2O and anhyd MeCN (3:2, 33 mL) under Ar and cooled to
0 °C. Imidazole (167 mg, 2.45 mmol, 1.85 equiv) and triphe-
nylphosphine (607 mg, 2.32 mmol, 1.75 equiv) were added and the
mixture was treated portion-wise with iodine, until a pale yellow co-
13C NMR (75 MHz, CDCl3): d = 14.14 (CH2CH3), 22.70 (CH2CH3),
22.79 (NCH2CH2 pyrrolidine ring), 24.03 [(H3C)2C], 24.16 [(H3C)2C],
25.83 (CH2 chain), 26.70 (CH2CHO), 27.74 (NCHCH2 pyrrolidine ring),
Synthesis 2000, No. 14, 2099–2105 ISSN 0039-7881 © Thieme Stuttgart · New York

2104
D. Enders, J. H. Kirchhoff
SPECIAL TOPIC
29.37-30.12 (9 C-atoms, CH2 chain), 31.93 (CH2CH2CHO), 35.52
(NCHCH2 chain), 51.15 (HNCH), 55.65 (NCH2 pyrrolidine ring), 59.18
(OCH3), 59.83 [(H3C)2COCH2], 66.42 (OCH2Ph), 66.66 (NCHpyrro-
lidine ring), 70.29 [(H3C)2COCH], 75.55 (CH2CH3), 100.23 [(H3C)2C],
127.99, 128.03, 128.48 (Carom), 136.81 (Cipso), 156.14 (C=O),
162.63 (C=N).
1H NMR (500 MHz, CDCl3): d = 0.88 (t, 3H, J = 7.0 Hz, CH3),
1.24-1.32 [m, 22H, H3C(CH2)11], 1.37 (m, 1H, NCHCHHax.), 1.42
[s, 3H, (H3C)2Ceq.], 1.47 [s, 3H, (H3C)2Cax.], 1.47-1.51 (m, 1H,
NCHCHHeq.), 1.63 (tdd, 1H, J = 14.04, 4.58, 3.05 Hz, NCHCHCH-
Hax.), 1.89 (tdd, 1H, J = 14.04, 3.35, 3.05 Hz, NCHCHCHHeq.), 2.50
(m, 1H, NCHCH2O), 2.56 (m, 1H, NCHCchain), 3.78 [dd, 1H,
J = 12.2, 1.1 Hz, (H3C)2COCHHeq.], 3.91 (m, 1H, NCHCH), 4.11
[dd, 1H, J = 12.2, 1.1 Hz, (H3C)2COCHHax.].
13C NMR (125 MHz, CDCl3): d = 14.13 (CH2CH3), 18.63
[(H3C)2Ceq.] 22.70 (CH2CH3), 25.98 (NCHCH2 ring), 26.03
(NCHCH2 chain), 29.37 (CH2 chain), 29.62-29.70 (5 C-atoms, CH2
chain), 29.82 [(H3C)2Cax.], 29.87 (NCHCHCH2), 30.02 (CH2 chain),
31.93 (CH2 chain), 37.27 (CH2 chain), 51.75 (NCHCH), 55.66
(NCHCH2), 64.35 (NCHCH), 65.03 (NCHCH2O), 98.41 ((H3C)2C).
IR (film): n = 3334 (N-H), 3065 (Car-H), 2926, 2854 (C-H), 1713
(C=O), 1587, 1514, 1455, 1380 (C=Car), 1336, 1226, 1162, 1104,
1063, 1028, 909, 865, 757 (C-Hoop), 698, 667 (Hoop) cm-1.
MS (EI): m/z (%) = 601 (4, M+), 556 (80, M+-CH2OCH3), 543 [13,
M+-(H3C)2CO], 498 (100), 480 (12), 412 (12), 328 (21), 321 (48),
+
91 (41, C7H7 ).
+
HRMS: m/z calcd for C35H59N3O5 : 601.4455. Found: 601.4453.
IR (CHCl3): n = 3800-3100 (NH), 2988, 2952, 2919, 2870, 2850,
2814 (C-H), 2749, 2712, 2682, 2632, 2572, 2534 (C-H), 2370,
1578, 1509, 1498, 1463, 1421, 1401, 1381, 1343, 1295, 1276, 1257,
1222, 1205, 1099, 1077 cm-1.
MS (EI): m/z (%) = 339 (7, M+), 324 (22, M+-CH3), 264 (6), 224
(13), 170 (100, M+-C12H25), 112 [26, M+-C12H25-(H3C)2CO], 82
(11).
(1R,4S)-(-)-Benzyl-N-{1-[2-(2,2-dimethyl-5-oxo-1,3-dioxan-4-
yl)ethyltridecyl]carbamate [(R,S)-16]
The crude mixture of hydrazones (R,S,S)-15 and (S)-14 (1.50 g) in
Et2O (35 mL) was stirred vigorously at r.t. with sat. oxalic acid (8
mL) for 5 h. After complete conversion (TLC control), the phases
were separated and the aqueous phase was extracted with Et2O
(10 mL). The combined organic layers were washed with pH 7 buff-
er (5 mL) and brine (5 mL), dried (MgSO4), and the solvent was re-
moved under reduced pressure. Et2O (5 mL) was added and the
solution passed through a plug of cottonwool and Florisil‰. After
drying in vacuo, pure ketone (R,S)-16 was obtained as a yellow oil;
yield: 737 mg (80% over 2 steps).
+
HRMS: m/z calcd for C21H41NO2 : 339.3137. Found: 339.3133.
Further elution with Et2O afforded piperdine (S,S,S)-18 as a colour-
less oil; yield: 11 mg (3.1%).
[a]D28 +2.0° (c 1.0, CHCl3).
[a]D28 -89.3° (c 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): d = 0.88 (t, 3H, J = 6.9 Hz, CH3),
1.24-1.33 [m, 21H, H3C(CH2)10, NCHCHHeq.], 1.44 [s, 3H,
(H3C)2Ceq.], 1.45 [s, 3H, (H3C)2Cax.], 1.49 (m, 1H, NCHCHHchain),
1.61 (m, 1H, NCHCHHchain), 1.65 (dq, 1H, J = 14.04, 3.05 Hz,
NCHCHCHHeq.), 1.80 (dddd, 1H, J = 14.04, 13.74, 3.66, 3.05 Hz,
NCHCHCHHax.), 1.90 (dddd, 1H, J = 13.74, 13.43, 4.58, 4.27 Hz,
NCHCHHax.), 2.58 (m, 1H, NCHCH2O), 3.04 (m, 1H, NCHCchain),
3.70 [d, 1H, J = 12.0 Hz, (H3C)2COCHHeq.], 3.91 (m, 1H,
NCHCH), 4.08 [dd, 1H, J = 12.0, 2.5 Hz, (H3C)2COCHHax.].
13C NMR (125 MHz, CDCl3): d = 14.13 (CH2CH3), 18.68
[(H3C)2Ceq.] 22.19 (CH2CH3), 22.70 (NCHCH2 ring), 24.71 (NCH
CHCH2), 27.27 (CH2 chain), 29.36 (CH2 chain), 29.66-30.10 [8 C-at-
oms, CH2 chain, (H3C)2Cax.], 31.93 (CH2 chain), 45.34 (NCHCH), 51.45
(NCHCH2), 64.64 (NCHCH), 64.87 (NCHCH2O), 98.35 [(H3C)2C].
1H NMR (300 MHz, CDCl3): d = 0.88 (t, 3H, J = 6.7 Hz, CH3),
1.22-1.52 [m, 22H, CH2CHO, H3C(CH2)10], 1.42 (s, 3H,
[(H3C)2Ceq.], 1.47 [s, 3H, (H3C)2Cax.], 1.60 (m, 2H, NCHCH2 chain),
1.87 (m, 2H, CH2CH2CHO), 3.65 (m, 1H, NCH), 4.00 [d, 1H,
J = 16.76 Hz, (H3C)2COCHHeq.], 4.27 [dd, 1H, J = 16.76, 1.37 Hz,
(H3C)2CO CHHax.], 4.27 [m, 1H, (H3C)2COCH], 4.55 (d, 1H,
J = 9.06 Hz, NH), 5.06 (d, 1H, J = 12.36 Hz, OCH2Ph), 5.11 (d, 1H,
J = 12.36 Hz, OCH2Ph), 7.25-7.43 (m, 5H, Harom).
13C NMR (75 MHz, CDCl3): d = 14.14 (CH2CH3), 22.70 (CH2CH3),
23.64 [(H3C)2Ceq.], 23.88 [(H3C)2Cax.], 24.50 (CH2 chain), 25.85
(CH2CHO), 29.30-30.33 (9 C-atoms, CH2 chain), 31.92
(CH2CH2CHO), 35.57 (NCHCH2 chain), 50.64 (NCH), 66.59 (2 C-at-
oms, (H3C)2COCH2, (OCH2Ph), 73.96 [(H3C)2COCH], 100.83
[(H3C)2C], 128.03, 128.06, 128.51 (Carom), 136.64 (Cipso), 156.17
(C=O amide), 209.63 (C=O ketone).
(2S,3S,5R)-(+)-6-Dodecyl-2-(hydroxymethyl)piperdin-3-ol
[(S,S,R)-5]
IR (CHCl3): n = 3323 (N-H), 3035, 3020 (Car-H), 2923, 2853 (C-H),
1751 (C=O amide), 1682 (C=O ketone), 1541, 1468, 1456, 1382,
1351, 1313, 1293 (C=Car), 1253, 1223, 1163, 1124, 1087, 1062,
1011, 907, 858, 776, 753, 725, 696 (C-Hoop) cm-1.
Acetonide (S,S,R)-18 (110 mg, 0.324 mmol) was dissolved in
MeOH (10 mL), ion exchange resin Lewatit S 100‰ (621 mg) was
added and the mixture was heated for 2 h under reflux. After cooling
to r.t., sat. NH4OH (1 mL) was added and the mixture was passed
through silica gel followed by a mixture of CH2Cl2/MeOH (5:1,
20 mL). After evaporation of the solvent under reduced pressure
and repetition of this procedure, the resulting solid was crystallised
from acetone/pentane to yield the deprotected product as a colour-
less solid; yield: 84 mg (87%); mp: 59 °C.
MS (EI): m/z (%) = 431 [16, M+- (H3C)2CO], 332 (5, M+-
C12H25CHNHZ), 296 (11), 288 (20), 278 (15), 238 (8), 91 (100,
+
C7H7 ), 72 (14).
Anal. Calcd. for C29H47NO5 (489.702): C, 71.07; H, 9.67; N, 2.86.
Found: C, 71.07; H, 9.42; N, 2.73.
[a]D26 +2.7° (c 1.0, CH3OH).
1H NMR (400 MHz, CD3OD): d = 0.88 (t, 3H, J = 6.9 Hz, CH3),
1.25-1.31 [m, 22H, H3C(CH2)11], 1.33-1.61 (m, 3H, NCHCH2,.
NCHCHCHHax.), 1.85 (dddd, 1H, J = 13.74, 3.57, 3.05, 2.74 Hz,
NCHCHCHHeq.), 2.52 (m, 1H, NCHCchain), 2.67 (td, 1H, J = 5.77,
1.65 Hz, NCHCH2OH), 3.60 (dd, 2H, J = 6.87, 5.77 Hz, CH2OH),
3.79 (m, 1H, NCHCH).
13C NMR (100 MHz, CD3OD): d = 13.47 (CH3), 22.72 (CH2CH3),
25.89 (NCHCH2 chain), 26.09 (NCHCH2), 29.45-29.89 (7 C-atoms,
CH2 chain), 31.67 (NCHCHCH2), 32.04 (CH2 chain), 36.58 (CH2 chain),
56.71 (NCHCH2), 61.31 (NCHCH), 63.22 (CH2OH), 64.60
(NCHCH).
(1S,5S,8R)-(-)-8-Dodecyl-3,3-dimethyl-2,4-dioxa-7-azabicyclo-
[4.4.0]decane [(S,S,R)-18]
Through a suspension of ketone (R,S)-16 (517 mg, 1.06 mmol) and
Pd/C (10% on charcoal, 500 mg) in EtOH (30 mL), a stream of hy-
drogen was passed for 2 h. After complete conversion (TLC con-
trol) the mixture was flushed with Ar and filtered through Celite‰
and the solvent removed under reduced pressure. After flash col-
umn chromatography (Et2O, 1% Et3N), piperidine (S,S,R)-18 was
obtained as colourless oil; yield: 306 mg (85%).
[a]D28 -0.5° (c 1.0, CHCl3).
Synthesis 2000, No. 14, 2099–2105 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Total Synthesis of (+)-2-epi-Deoxoprosopinine
2105
IR (KBr): n = 3800-3170 (NH, OH), 2953, 2916, 2850, 2800,
1995, 6, 1525.
f) Yuasa, Y.; Ando, J.; Shibuya, S. J. Chem. Soc., Perkin
Trans. 1 1996, 793.
g) Kadota, I.; Kawada, M.; Muramatsu, Y.; Yamamoto, Y.
Tetrahedron Lett. 1997, 38, 7469.
h) Ojima, I.; Vidal, E. S. J. Org. Chem. 1998, 63, 7999.
i) Herdeis, C.; Telser, J. Eur. J. Org. Chem. 1999, 1407.
j) Koulocheri, S. D.; Haroutouinian, S. A. Tetrahedron Lett.
1999, 40, 6869.
2506, 2413, 1724, 1584, 1472, 1079, 886, 719 cm-1.
MS (EI): m/z (%) = 299 (2.0, M+), 268 (100, M+-OCH3), 130 (78.7,
M+-C12H25).
+
HRMS: m/z calcd for C18H37NO2 : 299.2824. Found: 299.2825.
Acknowledgement
k) Datta, A.; Kumar, J. S. R. Presented at the American
Chemical Society Meeting San Francisco, 2000; Abstr. Nr.
ORGN 762.
This work was generously supported by the Deutsche Forschungs-
gemeinschaft (Leibniz Prize, Sonderforschungsbereich 380) and
the Fonds der Chemischen Industrie. We thank Degussa AG, BASF
AG, Bayer AG and Wacker Chemie for the donation of chemicals.
We are indebted to Daniel Steinbusch for his excellent contributions
as an undergraduate student.
(7) Ciufolini, M. A.; Hermann, C. W.; Whitmire, K. H.; Byrne, N.
E. J. Am. Chem. Soc. 1989, 111, 3473.
Toyooka, N.; Yoshida, Y.; Momose, T. Tetrahedron Lett.
1995, 36, 3715.
Hirai, Y.; Watanabe, J.; Nozaki, T.; Yokoyama, H.;
Yamaguchi, S. J. Org. Chem. 1997, 62, 776.
Agami, C.; Couty, F.; Mathieu, H. Tetrahedron Lett. 1998, 39,
3505.
Yang, C.; Liao, L.; Xu, Y.; Zhang, H.; Xia, P.; Zhou, W.
Tetrahedron: Asymmetry 1999, 10, 2311.
References
(1) For further informations concerning hydroxylated piperidines,
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Synthesis 2000, No. 14, 2099–2105 ISSN 0039-7881 © Thieme Stuttgart · New York