Synthesis of (-)-N-acetylslaframine by C-1, C-5 bis-hydroxyalkylation of (5)-2-(N,N-dibenzylamino)-1,5-pentanediol via highly diastereoselective lithiation of the dicarbamate

Article abstract of DOI:10.1055/s-2007-983724

(-)-N-Acetylslaframine, a stable form of the indolizidine alkaloid (-)-slaframine, has been synthesised by a new strategy. Applying highly stereoselective lithiation and substitution reactions, C-2, C-3 and C-8 of the bicyclic skeleton were introduced to

Full text of DOI:10.1055/s-2007-983724

1984
PAPER
Synthesis of (–)-N-Acetylslaframine by C-1, C-5 Bis-hydroxyalkylation of
(S)-2-(N,N-Dibenzylamino)-1,5-pentanediol via Highly Diastereoselective
Lithiation of the Dicarbamate
S
ynthesisof (–)-
N
-
i
Acetyl
e
Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Corrensstraße 40, 48149 Münster, Germany
Fax +49(251)8336531; E-mail: dhoppe@uni-muenster.de
Received 23 February 2007; revised 18 April 2007
Our synthetic plan was based on the electrophilic intro-
Abstract: (–)-N-Acetylslaframine, a stable form of the indolizidine
duction of a 2-hydroxyethyl residue at C-1 and a hy-
alkaloid (–)-slaframine, has been synthesised by a new strategy. Ap-
droxymethyl group at C-5 of an L-glutamic acid derived
plying highly stereoselective lithiation and substitution reactions,
C-2, C-3 and C-8 of the bicyclic skeleton were introduced to an L-
dicarbamate 5,5 to form the carbon skeleton of 1 and 2
glutamic acid derived diol dicarbamate.
(Scheme 1), followed by intramolecular double cy-
cloalkylations at the nitrogen atom, to the chiral indolizi-
dine 3. Finally, functional group manipulations were
envisaged to lead to the targets 1 or 2.
Key words: indolizidines, chiral 2-amino-1-w-alkanediols, lithiat-
ed dicarbamates, diastereoselectivity, (–)-sparteine
The starting material, (S)-N,N-dibenzylglutaminediol (6),
was prepared according to the method of Heymès et al.6
via dibenzyl (S)-N,N-dibenzylglutamic acid ester
(Scheme 2). Bis-acylation of 6 using the appropriate car-
bamoyl chlorides via standard methods, furnished the di-
carbamates 5a or 5b.5 For the synthesis of the mixed
dicarbamate 5c, a route via intermediate silyl protection of
the more reactive 5-OH group was required.
(–)-Slaframine (1) is produced by the mould Rhizoctonia
leguminicola, growing on rotting clover (Figure 1).3
When eaten by ruminants, such as cattle, it causes the so-
called ‘slobber syndrome’. Several asymmetric total syn-
theses of 1, the structure of which is usually characterised
as its more stable N-acetyl derivative 2, have been report-
ed.4
Previously, we investigated the regio- and diastereoselec-
tivity of the lithiation of dicarbamate 5a (Scheme 3).5,7 It
was found that the position of lithiation could be directed
by the conditions of deprotonation. Thus, the deprotona-
tion in diethyl ether, in the absence of any diamine, and
methylation led to the 1-substitution product 10 (presum-
ably via lithium compound 9a), whereas the same reaction
OAc
H
8
1
7
6
8a
1
2
R = H
R = Ac
2
4N
3
5
RHN
Figure 1
OCb1
OAc
H
H
N
N
Cb2O
H2N
1
3
HO
3
HO
HS
HR
HR
HS
L-glutamic acid
2
1
2
Cb2O
OCb1
Cb2O
OCb1
5
3
1
5
4
4
NBn2
NBn2
4
5
3–5 a Cb1 = Cb2 = Cby
Cby =
C
O
N
O
b Cb1 = Cb2 = Cb = C(=O)Ni-Pr2
c Cb1 = Cby, Cb2 = Cb
Scheme 1
SYNTHESIS 2007, No. 13, pp 1984–1994
x
x.
x
x
.
2
0
0
7
Advanced online publication: 18.06.2007
DOI: 10.1055/s-2007-983724; Art ID: T04107SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (–)-N-Acetylslaframine
1985
O
O
N
O
O
N
O
O
1
3
(a)
5
NBn2
2
4
5a, 78%
HO
OH
NBn2
(b)
6
= Cby
N
O
O
N
O
O
NBn2
TBSO
OH
5b, 74%
NBn2
7, 74%
= Cb
(c, d)
(e)
HO
OCby
CbO
OCby
NBn2
NBn2
8, 98%
5c, 99%
Scheme 2 Reagents and conditions: (a) NaH, THF, reflux, 1 h, CbCl or CbyCl, reflux, 16 h; (b) Et3N, DMAP, TBSCl, CH2Cl2, 0 °C→r.t.,
48 h; (c) NaH, THF, reflux, 1 h, CbyCl, reflux, 16 h; (d) TBAF, r.t., 72 h; (e) NaH, THF, reflux, 1 h, CbCl, reflux, 16 h.
sequence in the presence of (–)-sparteine (13) achieved The
2,2,4,4-tetramethyl-1,3-oxazolidine-3-carbonyl
the 5-substitution product 12 (via carbanionic intermedi- group (Cby) is easily removed under acidic conditions,
ate 11a). However, the selectivities appeared to be insuf- whereas the N,N-diisopropylcarbamoyl group (Cb) re-
ficient for the proposed synthesis. In addition, a quires the application of lithium aluminum hydride or ex-
differentiation between both O-carbamoyl groups was re- cess diisobutylaluminum hydride (DIBAL-H).8,9
quired during the course of the planned synthesis.
To find the best conditions for regio- and diastereoselec-
tive lithiation, a careful study was undertaken (Scheme 4).
HS
HR
HR
HS
2
1
5
3
CbyO
OCby
4
NBn2
5a
s-BuLi,
(–)-sparteine,
Et2O
s-BuLi,
Et2O
Li
Li
O
N
H
H
O
2
5
3
1
CbyO
O
O
4
N
O
OCby
O
NBn2
NBn2
11a
9a
ElX
ElX
El
El
CbyO
OCby
CbyO
OCby
NBn2
NBn2
10
12
N
N
Li = Li⋅13
(–)-sparteine (13)
Scheme 3
Synthesis 2007, No. 13, 1984–1994 © Thieme Stuttgart · New York

1986
D. Hoppe et al.
PAPER
As expected, after (–)-sparteine-mediated lithiation and The synthesis of the key intermediate 4c requires the dia-
methylation with iodomethane (MeI), dicarbamate 5a af- stereoselective introduction of a 2-hydroxyethyl group into
forded the 5S-substitution product 12a with good yield the 1-position and a hydroxymethyl group into the 5-posi-
and diastereoselectivity. From the bis(N,N-diisopropyl- tion of the dicarbamate. Consequently, mixed carbamate
carbamate) 5b, under identical conditions, the 1S-product 5c was deprotonated by sec-butyllithium/(–)-sparteine
10b was the major product, accompanied by 14% of 12b. (13) and allowed to react with 3.0 equivalents of ethylene
Fortunately, the mixed dicarbamate 5c yielded the pure oxide and boron trifluoride–diethyl ether complex
1S-substitution product 10c in high yield. Compound 10c, (BF3·OEt2) (Scheme 5). Under optimum conditions, the
albeit in lower yield (46%), was also produced when no diastereomerically pure alcohol 14 was isolated in 66%
additive was used.
yield.10 For the next step, double deprotonation of 14 with
3.5 equivalents of sec-butyllithium/(–)-sparteine (13) and
subsequent quenching of the O,C-dianion with excess
methyl chloroformate, gave the diastereomerically pure
diester 15 in 57% yield. All attempts at using O-silyl
ethers of 14 resulted in lower yields of 15 and more by-
products.11 Treatment of 15 with 6.0 equivalents of
DIBAL-H in THF, led to the reduction of the methyl ester
group and the reductive cleavage of the carbonic ester
function, to afford diol 4c in 98% yield.
HS
HR
HR
HS
(a, b)
80%
2
5
3
1
CbyO
OCby
CbyO
OCby
4
NBn2
NBn2
12a
5a
(a, b)
70%
CbO
OCb
CbO
CbO
OCb
OCb
NBn2
NBn2
12b
OH
5b
+
(a–c)
(d, e)
5c
CbO
OCby
NBn2
NBn2
14, 66%, dr >97:3
10b
(14:86)
O
O
C
OMe
(a, b)
87%
OH
MeO
O
CbO
OCby
CbO
OCby
HO
NBn2
NBn2
10c
(f)
CbO
OCby
5c
CbO
OCby
NBn2
Scheme 4 Reagents and conditions: (a) s-BuLi/13, Et2O, –78 °C,
7 h; (b) MeI, –78 °C→20 °C, 14 h.
NBn2
4c, 98%
15, 57%, dr >97:3
Scheme 5 Reagents and conditions: (a) s-BuLi/13, Et2O, –78 °C,
7 h; (b) ethylene oxide, –78 °C; (c) BF3·OEt2, –78 °C→20 °C, 14 h;
(d) s-BuLi/13, –78 °C, 7 h; (e) MeOC(=O)Cl, –78 °C→20 °C, 14 h;
(f) DIBAL-H, THF, 0 °C, 2 h.
These surprising results reflect a delicate competition be-
tween (–)-sparteine (13) and both of the carbamoyl groups
as complexing agents in the kinetically controlled depro-
tonation step. Obviously, the remote carbamoyl group at
the 5-position plays an important role by internal com-
plexation during deprotonation at the 1-position. The
smaller 5-OCb group is more efficient than the bulky 5-
OCby group in accomplishing internal complexation and
formation of 9c (Figure 2). As the control experiment
demonstrates (see above), (–)-sparteine (13) is not re-
quired for achieving high regio- and diastereoselectivity,
although it enhances the rate of lithiation.
For the construction of the indolizidine core from diol 4c,
N,N-di-debenzylation and activation of both hydroxy
groups for double cycloalkylation was required
(Scheme 6). Initially, 4c was converted into the dimesy-
late, however, a mixture of quaternary ammonium salts 18
and 19 was formed, which proved to be inseparable and
apparently consisted of mesylates and chlorides. When
this mixture was subjected to hydrogenolysis and base
treatment, the mixed indolizidine dicarbamate 20 could be
isolated in low yield (17%). Although many variations of
both steps were attempted, no improvement in yield could
be achieved. Compound 20, as a colourless solid, was sub-
jected to an X-ray crystal structure analysis (Figure 3),
which confirmed the assumed structure.12 A more effi-
cient route began with a palladium-catalysed N,N-di-
debenzylation of diol 4c, followed by tert-butoxycarbon-
ylation, leading to the tert-butoxycarbonyl (N-Boc) deriv-
ative 16. This was converted into the O,O¢-dimesylate and
L
NR2
O
O
Li
O
O
NR2
NBn2
9c
L = OEt2, or monodentate (–)-sparteine (13)
Figure 2
Synthesis 2007, No. 13, 1984–1994 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-N-Acetylslaframine
1987
the Boc group was removed by treatment with trifluoro- syntheses4i–k,n–p the problem was solved by preparing the
acetic acid, which, in addition, cleaved the OCby group, ketone, its oxime, followed by hydrogenation from the
yielding the indolizidine 6-monocarbamate 17. Since the exo-face combined with hydrogenolysis of the N–O bond.
dicarbamate 20 could also easily be partially deprotected Following this standard route, alcohol 17 was converted
to form 17 in 93% yield, the configurations of 20 and 17 into the 1O-trityl ether 21 and deprotected to the 6-alcohol
are identical.
22. This was oxidised to ketone 23, transformed to oxime
24 (E/Z = 23:72) and then subjected to hydrogenation/
hydrogenolysis under the influence of PtO2 to afford the
amino alcohol 25. Bis-acetylation of 25 led to (–)-N-ace-
tylslaframine (2).
OCby
OCby
OH
H
H
(a, b)
92%
N
NH
CbO
Bn2
CbO
Boc
OH
OH
OTr
OTr
OH
H
H
4c
(f)
16
(a)
(b)
1
17
6
N
N
CbO
HO
(c, d, e)
59%
21, 73%
22, 93%
OCby
X
OCby
H
N
+
OTr
OTr
Bn2N
X
H
N
H
CbO
Bn2
CbO
OH
(d)
X
19
(c)
H
N
X
18
HO
N
(g)
O
N
23, 83%
CbO
17
24, 95%, E/Z = 23:72
OCby
H
(h, i)
93%
OH
OAc
H
H
N
N
CbO
(e)
(f)
8
20, 29% (from 4c)
1
3
7
6
8a
4N
H
2
X = MeSO3 or Cl
5
H2N
AcHN
25
2, 86%
Scheme 6 Reagents and conditions: (a) Pd/C, H2, MeOH, 14 h at
20 °C, 5 h at 65 °C; (b) Boc2O, Et3N, MeOH, 3 h at 40 °C, 14 h at
20 °C; (c) MsCl, Et3N, CH2Cl2, –20 °C, 14 h; (d) TFA, CH2Cl2,
20 °C, 14 h; (e) K2CO3, MeOH, 65 °C, 14 h; (f) MsCl, DMAP, pyri-
dine, 0 °C, 2 h; (g) Pd(OH)2/C, Et3N, H2, MeOH, 14 h at 20 °C, 5 h at
60 °C; (h) 5 N HCl, THF, MeOH, 65 °C, 14 h; (i) 5 N NaOH, 65 °C,
14 h.
Scheme 7 Reagents and conditions: (a) Ph3CCl, DBU, CH2Cl2,
20 °C, 48 h; (b) DIBAL-H, THF, 2 h at –78 °C, 14 h at 20 °C; (c)
(COCl)2, CH2Cl2, –78 °C, DMSO, 5 h at –78 °C, Et3N, 1 h at –78 °C,
1 h at 20 °C; (d) HONH2·HCl, pyridine, EtOH, 4 h at 80 °C, 16 h at
20 °C; (e) PtO2, H2, EtOH, HCl, 20 °C, 14 h; (f) Ac2O, pyridine,
20 °C, 2 h.
1
The melting point of 2 and the H and 13C NMR data of
our sample match14 well with those reported by Pearson.4a
The optical rotation in chloroform (–18.0, c 0.40) is higher
than reported by Pearson (–11.2, c 1.45).4a,15
In summary, a new strategy for the synthesis of (–)-
slaframine (1) has been developed. Crucial steps are the
highly diastereoselective introductions of C-2, C-3 and
C-5 moieties for the construction of the indolizidine core
by two electrophilic substitution reactions at C-1 and C-5
of a lithiated 2-amino-alkanediyl dicarbamate, which was
derived from L-glutamic acid.
Reactions with air- and moisture-sensitive compounds were per-
formed under an argon atmosphere. All solvents were refluxed over
a suitable drying agent and distilled immediately before use. (–)-
Sparteine (13) was purchased from Aldrich and used without further
purification. Et3N and DMSO were refluxed over CaH2 and distilled
under an argon atmosphere. s-BuLi was received as a 1.3 M solu-
tion in cyclohexane–hexane (92:8) and was filtered and titrated be-
fore use.16 N,N-Diisopropylcarbamoyl chloride17 and 2,2,4,4-
tetramethyl-1,3-oxazolidine-3-carbonyl chloride18 were prepared
following a procedure developed in the research group. Preparative
liquid chromatography was performed with flash column chroma-
tography (FCC) under 1.5 bar argon pressure using silica gel grade
40–60 mm from Merck, Darmstadt. TLC was performed using alu-
Figure 3
The synthesis of 2 was completed via the 1-O-protected
diol 22. The central issue of this synthetic sequence con-
sisted of the substitution of the 6-OH group by an amino
group with inversion of configuration (Scheme 7). The
most obvious route – activation of the 6-OH group and
SN2-substitution by azide – is, according to results ob-
tained by Wasserman13 and Gmeiner,4i hampered by the
formation of a tricyclic aziridinium ion. In a number of
Synthesis 2007, No. 13, 1984–1994 © Thieme Stuttgart · New York

1988
D. Hoppe et al.
PAPER
minum silica gel plates 60 F254 from Merck, Darmstadt. The detec-
tion of the products was performed under UV light at 254 nm as
well as with staining agents followed by heating. Gas chromatogra-
phy was performed on Agilent 6890 from Agilent, USA, using an
achiral HP5-quarz column (program: 50 °C start temperature for
0 min, 10 °C/min heating rate, 300 °C final temperature for 15 min)
from Hewlett–Packard, USA. The optical rotation was measured in
a 10 cm cuvette on a polarimeter of the types Perkin–Elmer 241 or
341 from Perkin–Elmer & Co GmbH, Überlingen. Elemental anal-
yses were performed on a Vario EL III from Elementar Analysen-
systeme GmbH, Hanau, or on a CHN-O-Rapid from Heraeus, Hanau.
Melting points were measured on a MFB595 from Gallenkamp,
UK, or on a Stuart Melting Point Apparatus SMP3 from Bibby Ster-
lin Ltd, UK, and are uncorrected. IR-measurements were performed
on an IFS 28 from Bruker Optik GmbH, Karlsruhe, or 5 DXC from
Nicolet, Offenbach. Mass spectrometry was carried out by electron
spray ionization (ESI) or as exact mass determination on a
MicroTof from Bruker Datronics, Bremen, or on Quattro LCZ,
Micromass, UK, with a nanospray inlet. The 1H and 13C NMR spectra
were measured on ARX300, AMX400 spectrometers from Bruker,
Analytische Messtechnik, Karlsruhe, and Varian Inova 500, Varian
Unity Plus 600 from Varian Associated, USA. TMS (d = 0.0 ppm)
or CDCl3 (d = 7.26 ppm for remaining CHCl3) were used as internal
standards in 1H NMR and CDCl3 (d = 77.0 ppm) for 13C NMR spec-
tra. H-XA and H-XB indicate unassigned diastereotopic methylene
protons. Chemical shifts in brackets give the values of the minor
amide torsion isomers.
(S)-2-(N,N-Dibenzylamino)-5-pentane-1,5-diyl Bis(N,N-diiso-
propylcarbamate) (5b)
According to general procedure A, the product was formed by the
reaction of NaH (60% in mineral oil, 0.84 g, 21.0 mmol, 3.0 equiv),
diol 6 (2.1 g, 7.0 mmol) and CbCl (3.44 g, 21.0 mmol, 3.0 equiv) in
THF (40 mL). After aqueous workup, purification by FCC (Et2O–
PE, 1:2) yielded 5b.
20
Yield: 2.86 g, 5.2 mmol (74%); highly viscous oil; [a]D –15.2 (c
1.02, CHCl3); Rf = 0.37 (Et2O–PE, 1:1).
IR (film): 3085, 3062, 3032, 2970, 2939, 2874, 1694, 1456, 1439,
749, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.18, 1.19 (2 × d, 3JCbCH–CbCH3
=
6.5 Hz, 2 × 6 H, Cb-CH3), 1.22 (m, 12 H, Cb-CH3), 1.47 (m, 1 H,
H-4A), 1.56 (m, 1 H, H-4B), 1.73 (m, 1 H, H-3A), 1.87 (m, 1 H, H-
3B), 2.89 (m, 1 H, H-2), 3.62, 3.78 [2 × d, 2Jgem = 13.8 Hz, 2 × 2 H,
(PhCH2)2N], 3.92 (m, 3JCbCH–CbCH3 = 6.5 Hz, 4 H, Cb-CH), 4.00 (m,
1 H, H-5), 4.19 (dd, 2J1A–1B = 11.3 Hz, 3J1A–2 = 5.9 Hz, 1 H, H-1A),
4.26 (dd, 2J1A–1B = 11.3 Hz, 3J1B–2 = 5.3 Hz, 1 H, H-1B), 7.19–7.35
(m, 10 H, Hphenyl).
13C NMR (100 MHz, CDCl3): d = 21.1 (Cb-CH3), 25.8 (C-4), 26.6
(C-3), 45.9 (Cb-CH), 53.9 [(PhCH2)2N], 56.3 (C-2), 63.9 (C-1),
64.7 (C-5), 126.8, 128.1, 128.8 (Cphenyl), 140.1 (Cq, Cphenyl), 155.1,
155.8 (Cb-NC=O).
MS (ESI): m/z = 554.5 [M + H]+, 576.5 [M + Na]+.
Anal. Calcd for C33H51N3O4: C, 71.57; H, 9.28; N, 7.59. Found: C,
71.29; H, 9.45; N, 7.41.
Synthesis of Dicarbamates 5a and 5b; General Procedure A
NaH (60% in mineral oil, 2.0–3.0 equiv) was suspended in THF
(0.5 mL/mmol). A solution of the alcohol (1.0 equiv) in THF
(0.5 mL/mmol) was added and the suspension was heated at reflux
for 1 h. CbCl (2.0–3.0 equiv) or CbyCl (2.0–3.0 equiv) dissolved in
THF (0.5 mL/mmol) was added dropwise and the mixture was heat-
ed at reflux overnight. After cooling to r.t., H2O (1.0 mL/mmol) and
Et2O (1.0 mL/mmol) were added, the aqueous layer was washed
with Et2O (2 × 1.0 mL/mmol) and the combined organic layers
were dried over Na2SO4. After filtration, the solvent was removed
under vacuum and the crude product was purified by FCC (Et2O–
PE).
(S)-2-(N,N-Dibenzylamino)-5-(tert-butyldimethylsilyloxy)pen-
tan-1-ol (7)
To (S)-2-(N,N-dibenzylamino)-1,5-pentanediol (6; 11.91 g,
39.8 mmol), dissolved in CH2Cl2 (50 mL), a mixture of Et3N
(4.02 g, 39.8 mmol, 1.0 equiv), DMAP (2.38 g, 19.5 mmol,
0.5 equiv) and tert-butylchlorodimethylsilane (7.05 g, 48.2 mmol,
1.2 equiv) in CH2Cl2 (20 mL) was added at 0 °C. After stirring for
48 h at r.t., the mixture was treated with H2O (25 mL) and Et2O
(25 mL). The aqueous layer was washed with Et2O (3 × 25 mL) and
the combined organic layers were dried over Na2SO4, filtered and
the solvent was removed under vacuum. Purification by FCC
(Et2O–PE, 1:3→1:2) yielded mainly 7 along with a few milligrams
of the double O-silyl substituted product.
(S)-2-(N,N-Dibenzylamino)-5-pentane-1,5-diyl Bis(2,2,4,4-tet-
ramethyl-1,3-oxazolidine-3-carboxylate) (5a)
According to general procedure A, the product was formed by the
reaction of NaH (60% in mineral oil, 1.20 g, 30.0 mmol, 2.0 equiv),
diol 6 (4.0 g, 13.4 mmol) and CbyCl (5.73 g, 30.0 mmol, 2.0 equiv)
in THF (50 mL). After aqueous workup, purification by FCC
(Et2O–PE, 1:3) gave 5a.
Yield: 6.37 g, 10.5 mmol (78%); highly viscous oil; [a]D20 –11.6 (c
1.02, CHCl3); Rf = 0.45 (Et2O–PE, 1:1).
IR (film): 1740, 1690 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.21–1.59 (m, 24 H, Cby-CH3),
1.69 (m, 2 H, H-3), 1.83 (m, 2 H, H-4), 2.82 (m, 1 H, H-2), 3.53,
3.72 [2 × d, 2Jgem = 13.6 Hz, 2 × 2 H, (PhCH2)2N], 3.65 (s, 4 H, Cby-
CH2), 3.93 (m, 2 H, H-5), 4.15 (m, 2Jgem = 11.2 Hz, 3J1–5 = 5.1 Hz,
1 H, H-1), 4.26 (dd, 2Jgem = 11.2 Hz, 3J1–5 = 5.1 Hz, 1 H, H-1), 7.11–
7.38 (m, 10 H, Hphenyl).
20
Yield: 12.18 g, 29.4 mmol (74%); colourless oil; [a]D +63.4 (c
1.17, CHCl3); Rf = 0.61 (Et2O–PE, 1:1).
IR (film): 3420, 1680, 680 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.00 [s, 6 H, Si(CH3)2C(CH3)3],
0.85 [s, 9 H, Si(CH3)2C(CH3)3], 1.16 (m, 1 H, H-3B), 1.40 (m,
3J4–5 = 6.3 Hz, 2 H, H-3A, H-4B), 1.76 (m, 1 H, H-4A), 2.72 (dddd,
3
3J2–3 = 4.4 Hz, J1–2 = 5.0, 9.8 Hz, 1 H, H-2), 3.04 (m, 1 H, OH),
2
3
3.36 [d, Jgem = 13.4 Hz, 2 H, (PhCH2)2N], 3.39 (m, J1–2 = 5.0,
9.8 Hz, 2 H, H-1), 3.53 (m, 2 H, H-5), 3.75 [d, 2Jgem = 13.4 Hz, 2 H,
(PhCH2)2N], 7.23–7.45 (m, 10 H, Hphenyl).
13C NMR (75 MHz, CDCl3): d = –6.6 [Si(CH3)2C(CH3)3], 17.0
[Si(CH3)2C(CH3)3], 19.9 (C-3), 24.6 [Si(CH3)2C(CH3)3], 29.1 (C-
4), 52.0 [(PhCH2)2N], 57.6 (C-2), 59.7 (C-5), 61.6 (C-1), 125.9,
127.1, 127.7, 138.1 (Cphenyl).
13C NMR (100 MHz, CDCl3): d = 24.5, 25.8, 26.0, 26.5, 27.1 (Cby-
CH3), 26.9 (C-3), 27.0 (C-4), 54.2 [(PhCH2)2N], 56.8 (C-2), 60.0
(60.7), 60.9 (61.2) [NC(CH3)2CH2], 64.0 (C-1), 65.0 (C-5), 76.5,
76.7 (Cby-CH2), 95.1, 96.2 (96.4) [NC(CH3)2O], 127.4, 128.6,
129.3, 140.2 (Cphenyl),152.5, 153.2 (Cby-NC=O).
Anal. Calcd for C25H39NO2Si: C, 72.59; H, 9.50; N, 3.39. Found: C,
72.81; H, 9.73; N, 3.12.
2,2,4,4-Tetramethyl-1,3-oxazolidine-3-carboxylic Acid (S)-2-
(N,N-Dibenzylamino)-5-hydroxypent-1-yl Ester (8)
According to general procedure A, NaH (60% in mineral oil, 1.88 g,
47.0 mmol, 2.0 equiv), alcohol 7 (9.72 g, 23.5 mmol) and CbyCl
(9.01 g, 47.0 mmol, 2.0 equiv) in THF (60 mL) were reacted. After
aqueous workup, the crude product was treated with TBAF (1 M so-
Anal. Calcd for C35H51N3O6: C, 68.94; H, 8.43; N, 6.89. Found: C,
68.78; H, 8.37; N, 6.97.
Synthesis 2007, No. 13, 1984–1994 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-N-Acetylslaframine
1989
lution in THF, 70.5 mL, 70.5 mmol, 3.0 equiv) for 72 h at r.t., with-
out further solvent. H2O (50 mL) and Et2O (50 mL) were added, the
aqueous layer was washed with Et2O (2 × 30 mL) and the combined
organic layers were dried over MgSO4. After filtration, the solvent
was removed under vacuum and the crude product was purified by
FCC (Et2O–PE, 1:1→Et2O) to yield 8.
(2S,5S)-2-(N,N-Dibenzylamino)-5-methylpentane-1,5-diyl
Bis(2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate) (12a)
According to general procedure B, the product was formed by the
reaction of 5a (710 mg, 1.16 mmol), (–)-sparteine (13; 436 mg,
1.86 mmol, 1.6 equiv), s-BuLi (1.60 mL, 1.86 mmol, 1.6 equiv)
and MeI (0.12 mL, 1.86 mmol, 1.6 equiv) in Et2O (10 mL). Aque-
ous workup and purification by FCC (Et2O–PE, 1:4) yielded 12a.
20
Yield: 10.45 g, 23.0 mmol (98%); colourless oil; [a]D –33.3 (c
0.93, CHCl3); Rf = 0.16 (Et2O–PE, 1:1).
IR (film): 3420, 1680, 740, 690 cm–1.
20
Yield: 577 mg, 0.92 mmol (80%); colourless oil; dr = 97:3; [a]D
–6.7 (c 1.00, CHCl3); Rf = 0.42 (Et2O–PE, 1:1).
IR (film): 1685, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.21–1.60 (m, 14 H, Cby-CH3, H-
4), 1.70 (m, 2 H, H-3), 2.01 (m, 1 H, OH), 2.89 (m, 1 H, H-2), 3.47
1H NMR (300 MHz, CDCl3): d = 1.21 (d, 3J5–5-CH3 = 6.3 Hz, 3 H, 5-
CH3), 1.24–1.65 (m, 24 H, Cby-CH3), 1.68 (m, 2 H, H-3), 1.83 (m,
3J4–5 = 6.0 Hz, 2 H, H-4), 2.88 (m, 1 H, H-2), 3.59, 3.76 [2 × d,
2
(m, 2 H, H-5), 3.59, 3.80 [2 × d, Jgem = 13.4 Hz, 2 × 2 H,
2
(PhCH2)2N], 3.72 (s, 2 H, Cby-CH2), 4.18 (m, Jgem = 11.1 Hz,
3J1–2 = 5.0 Hz, 1 H, H-1), 4.33 (dd, 2Jgem = 11.1 Hz, 3J1–2 = 5.0 Hz,
2Jgem = 13.5 Hz, 2 × 2 H, (PhCH2)2N], 4.18 (m, Jgem = 11.2 Hz,
2
1 H, H-1), 7.15–7.35 (m, 10 H, Hphenyl).
3J1–2 = 5.3 Hz, 1 H, H-1), 4.30 (dd, 2Jgem = 11.2 Hz, 3J1–2 = 5.3 Hz,
3
3
1 H, H-1), 4.86 (tq, J5–5-CH3 = 6.3 Hz, J4–5 = 6.0 Hz, 1 H, H-5),
13C NMR (75 MHz, CDCl3): d = 25.9, 27.3 (C-4, Cby-CH3), 30.3
(C-3), 54.3 (C-2), 56.8 [(PhCH2)2N], 60.1 (61.2) [NC(CH3)2CH2],
63.0 (C-1), 64.1 (C-5), 76.2 (Cby-CH2), 96.4 (95.3) [NC(CH3)2O],
127.4, 128.6, 129.4, 140.1 (Cphenyl), 153.2 (Cby-NC=O).
7.15–7.40 (m, 10 H, Hphenyl).
13C NMR (75 MHz, CDCl3): d = 20.3 (5-CH3), 24.6, 25.8, 26.0,
27.1 (Cby-CH3), 25.1 (C-4), 33.9 (C-3), 54.3 [(PhCH2)2N], 57.3 (C-
2), 59.9, 61.2 [NC(CH3)2CH2], 64.1 (C-1), 71.5 (C-5), 76.5, 77.0
(Cby-CH2), 96.2, 96.5 [NC(CH3)2O], 127.3, 128.6, 129.3, 140.2
(Cphenyl), 152.7, 153.1 (Cby-NC=O).
Anal. Calcd for C27H38N2O4: C, 71.34; H, 8.43; N, 6.16. Found: C,
71.25; H, 8.76; N, 6.40.
2,2,4,4-Tetramethyl-1,3-oxazolidine-3-carboxylic Acid (S)-2-
(N,N-Dibenzylamino)-5-(N,N-diisopropylcarbamoyloxy)pent-
1-yl Ester (5c)
According to general procedure A, the product was formed by the
reaction of NaH (60% in mineral oil, 1.90 g, 47.4 mmol, 2.0 equiv),
alcohol 8 (10.78 g, 23.7 mmol) and CbCl (7.76 g, 47.4 mmol,
2.0 equiv) in THF (80 mL). After aqueous workup, purification by
FCC (Et2O–PE, 1:3→1:2) yielded 5c.
Anal. Calcd for C36H53N3O6: C, 69.31; H, 8.56; N, 6.74. Found: C,
69.27; H, 8.65; N, 6.46.
(2S,5S)-2-(N,N-Dibenzylamino)-5-methylpentane-1,5-diyl
Bis(N,N-diisopropylcarbamate) (12b) and (1S,2S)-2-(N,N-Di-
benzylamino)-1-methylpentane-1,5-diyl Bis(N,N-diisopropyl-
carbamate) (10b)
According to general procedure B, the product was formed by the
reaction of 5b (250 mg, 0.45 mmol), (–)-sparteine (13; 148 mg,
0.63 mmol, 1.4 equiv), s-BuLi (0.50 mL, 0.63 mmol, 1.4 equiv)
and MeI (0.08 mL, 1.35 mmol, 3.0 equiv) in Et2O (10 mL). Aque-
ous workup and purification by FCC (Et2O–PE, 1:4) gave a colour-
less oil (164 mg, 0.29 mmol, 70%), which was an inseparable
mixture of the isomers 12b and 10b (14:86).
Yield: 13.76 g, 23.7 mmol (99%); light-yellow, highly viscous oil;
[a]D20 –11.5 (c 1.36, CHCl3); Rf = 0.36 (Et2O–PE, 1:1).
IR (film): 3086, 3062, 3030, 2970, 2938, 2878, 1697, 1455, 1437,
746, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.18, 1.23 (2 × d, 3JCbCH–CbCH3
=
[a]D20 –0.6 (c 0.86, CHCl3); Rf = 0.39 (Et2O–PE, 1:1).
6.8 Hz, 2 × 6 H, Cb-CH3), 1.32, 1.44, 1.49, 1.58 (4 × s, 12 H, Cby-
CH3), 1.40–1.60 (m, 2 H, H-3A, H-4A), 1.75 (m, 1 H, H-3B), 1.90
(m, 1 H, H-4B), 2.88 (m, 1 H, H-2), 3.60, 3.78 [2 × d,
2Jgem = 13.7 Hz, 2 × 2 H, (PhCH2)2N], 3.72 (s, 2 H, Cby-CH2), 3.90
(sept, 3JCbCH–CbCH3 = 6.8 Hz, 2 H, Cb-CH), 4.00 (m, 2 H, H-5), 4.21
IR (film): 3086, 3065, 3033, 2969, 2934, 2871, 1697, 1681, 1456,
1436, 747, 699 cm–1.
MS (ESI): m/z = 568.5 [M + H]+, 590.4 [M + Na]+, 606.5 [M + K]+.
2
3
(dd, J1A–1B = 11.7 Hz, J1A–2 = 4.4 Hz, 1 H, H-1A), 4.32 (dd,
2J1A–1B = 11.7 Hz, 3J1B–2 = 5.7 Hz, 1 H, H-1B), 7.19–7.34 (m, 10 H,
Hphenyl).
Anal. Calcd for C34H53N3O4: C, 71.92; H, 9.41; N, 7.40. Found: C,
71.94; H, 9.43; N, 7.38.
Main isomer (10b):
13C NMR (100 MHz, CDCl3): d = 20.1, 20.9, 21.2 (Cb-CH3), 24.0,
25.1, 25.2, 25.3, 25.4 (Cby-CH3), 25.8 (C-4), 26.5 (C-3), 45.8 (Cb-
CH), 53.7 [(PhCH2)2N], 56.3 (C-2), 59.5 (60.7) [NC(CH3)2CH2],
63.6 (C-1), 64.5 (C-5), 75.9 (76.3) (Cby-CH2), 94.5 (95.9)
[NC(CH3)2O], 126.8, 128.0, 128.7 (Cphenyl), 139.7 (Cq, Cphenyl),
151.9 (152.6) (Cby-NC=O), 155.6 (Cb-NC=O).
1H NMR (300 MHz, CDCl3): d = 1.21 (2 × d, 3JCbCH–CbCH3 = 6.8 Hz,
2 × 12 H, Cb-CH3), 1.24 (d, 3 H, 1-CH3), 1.51 (m, 3J4–5B = 3J4–5A
=
6.4 Hz, 1 H, H-4A), 1.60 (m, 1 H, H-3A), 1.74 (m, 2 H, H-3B, H-4B),
2.65 (dt, 3J2–3 = 6.0 Hz, 3J1–2 = 4.8 Hz, 1 H, H-2), 3.61, 3.83 [2 × d,
3
2Jgem = 13.7 Hz, 2 × 2 H, (PhCH2)2N], 3.90 (m, JCbCH–CbCH3
=
3
6.8 Hz, 4 H, Cb-CH), 4.00 (t, J4–5A = 6.4 Hz, 1 H, H-5A), 4.01 (t,
MS (ESI): m/z = 582.4 [M + H]+, 604.4 [M + Na]+.
3
3
3J4–5B = 6.4 Hz, 1 H, H-5B), 5.18 (dq, J1–1-CH3 = 6.4 Hz, J1–2
=
Anal. Calcd for C34H51N3O5: C, 70.19; H, 8.84; N, 7.22. Found: C,
69.78; H, 8.81; N, 7.13.
4.8 Hz, 1 H, H-1), 7.17–7.35 (m, 10 H, Hphenyl).
13C NMR (75 MHz, CDCl3): d = 18.6 (1-CH3), 21.0 (Cb-CH3), 22.9
(C-4), 26.9 (C-3), 45.8 (Cb-CH), 54.8 [(PhCH2)2N], 60.7 (C-2),
64.7 (C-5), 71.0 (C-1), 126.8, 128.0, 128.9 (Cphenyl), 140.3 (Cq,
Methylation of Dicarbamates 5; General Procedure B
The carbamate (1.0 equiv) was dissolved in Et2O (20 mL/mmol)
and treated with (–)-sparteine (13; 1.4–3.5 equiv). After cooling to
–78 °C, s-BuLi (1.0–1.3 M in hexane–cyclohexane, 92:8, 1.4–
3.5 equiv) was added dropwise. After stirring at –78 °C for 5–7 h,
the electrophile (1.6–7.0 equiv) was added. The mixture was
warmed over night to r.t., then H2O (20 mL/mmol) and Et2O
(20 mL/mmol) were added. The aqueous layer was washed with
Et2O (2 × 20 mL/mmol) and the combined organic layers were dried
over MgSO4. After filtration, the solvent was removed under vacu-
um and the crude product was purified by FCC (Et2O–PE).
C
phenyl), 154.4, 155.8 (Cb-NC=O).
Minor isomer (12b):
1H NMR (300 MHz, CDCl3): d = 2.86 (m, 1 H, H-2), 4.17 (dd,
2J1A–1B = 11.3 Hz, J1A–2 = 5.4 Hz, 1 H, H-1A), 4.31 (dd, J1B–2
6.3 Hz, 2J1A–1B = 11.3 Hz, 1 H, H-1B), 4.86 (sext, 3J4–5 = 3J5–5-CH3
6.1 Hz, 1 H, H-5).
=
=
3
3
13C NMR (75 MHz, CDCl3): d = 24.4 (C-4), 28.3 (C-3), 53.9
[(PhCH2)2N], 56.8 (C-2), 63.9 (C-1), 71.4 (C-5).
Synthesis 2007, No. 13, 1984–1994 © Thieme Stuttgart · New York

1990
D. Hoppe et al.
PAPER
2,2,4,4-Tetramethyl-1,3-oxazolidine-3-carboxylic Acid (1S,2S)-
2-(N,N-Dibenzylamino)-5-(N,N-diisopropylcarbamoyloxy)-1-
methylpent-1-yl Ester (10c)
According to general procedure B, the product was formed by the
reaction of 5c (240 mg, 0.41 mmol), (–)-sparteine (13; 193 mg,
0.83 mmol, 2.0 equiv), s-BuLi (0.64 mL, 0.83 mmol, 2.0 equiv)
and MeI (0.20 mL, 2.48 mmol, 6.0 equiv) in Et2O (10 mL). Aque-
ous workup and purification by FCC (Et2O–PE, 1:4) yielded 10c.
No other isomers were detected in the 1H NMR spectrum.
13C NMR (75 MHz, CDCl3): d = 21.0 (Cb-CH3), 21.8 (C-4), 23.9,
24.1, 24.7, 24.9, 25.3, 25.4, 26.3, 26.6 (Cby-CH3), 26.6 (C-3), 35.5
(C-1¢), 45.8 (Cb-CH), 54.6 [(PhCH2)2N], 58.3 (C-1¢¢), 59.5 (61.2)
[NC(CH3)2CH2], 59.8 (C-2), 64.6 (C-5), 70.6 (C-1), 75.9 (76.5)
(Cby-CH2), 94.6 (96.3) [NC(CH3)2O], 127.0, 128.2, 128.9 (Cphenyl),
139.6 (Cq, Cphenyl), 152.9 (153.6) (Cby-NC=O), 155.7 (Cb-NC=O).
MS (ESI): m/z = 626.4 [M + H]+, 648.4 [M + Na]+.
Anal. Calcd for C36H55N3O6: C, 69.09; H, 8.86; N, 6.71. Found: C,
68.86; H, 9.04; N, 6.59.
20
Yield: 209 mg, 0.35 mmol (87%); colourless oil; [a]D +0.2 (c
1.40, CHCl3); Rf = 0.39 (Et2O–PE, 1:1).
Methyl (2R,5S,6S)-5-(N,N-Dibenzylamino)-2-(N,N-diisopropyl-
carbamoyloxy)-8-(methoxycarbonyloxy)-6-(2,2,4,4-tetrameth-
yl-1,3-oxazolidine-3-carbonyloxy)octanoate (15)
IR (film): 3086, 3063, 3029, 2972, 2939, 2871, 1695, 1682, 1456,
750, 700 cm–1.
According to general procedure B, the product was formed by the
reaction of 14 (152 mg, 0.24 mmol), (–)-sparteine (13; 0.20 mL,
0.85 mmol, 3.5 equiv), s-BuLi (0.77 mL, 0.85 mmol, 3.5 equiv)
and methyl chloroformate (0.13 mL, 1.70 mmol, 7.0 equiv) in Et2O
(10 mL). Aqueous workup and purification by FCC (Et2O–PE,
1:3→1:1) gave 15 as a regio- and diastereomerically pure colourless
resin.
1H NMR (300 MHz, CDCl3): d = 1.19, 1.22 (2 × d, 3JCbCH–CbCH3
=
6.8 Hz, 12 H, Cb-CH3), 1.28, 1.30, 1.44, 1.54 (4 × s, 12 H, Cby-
3
CH3), 1.29 (d, J1–1-CH3 = 6.4 Hz, 3 H, 1-CH3), 1.40–1.59 (m,
3J4–5 = 6.7 Hz, 2 H, H-3A, H-4B), 1.70–1.80 (m, 2 H, H-3B, H-4B),
2
2.69 (m, 1 H, H-2), 3.65, 3.78 [2 × d, Jgem = 13.4 Hz, 2 × 2 H,
3
(PhCH2)2N], 3.69 (s, 2 H, Cby-CH2), 3.90 (m, JCbCH–CbCH3
=
6.8 Hz, 2 H, Cb-CH), 4.01 (t, 3J4–5 = 6.7 Hz, 2 H, H-5), 5.32 (dq,
3
20
3J1–1-CH3 = 6.4 Hz, J1–2 = 3.9 Hz, 1 H, H-1), 7.17–7.35 (m, 10 H,
Yield: 102 mg, 0.14 mmol (57%); [a]D –18.5 (c 1.02, CHCl3);
Hphenyl).
Rf = 0.56 (Et2O).
13C NMR (75 MHz, CDCl3): d = 17.7 (1-CH3), 20.8 (Cb-CH3),
23.1, 24.8, 24.9, 25.2, 25.3, 26.2 (Cby-CH3), 23.4 (C-4), 26.5 (C-3),
45.5 (Cb-CH), 54.2 [(PhCH2)2N], 59.1 (60.6) [NC(CH3)2CH2], 60.2
(C-2), 64.5 (C-5), 69.9 (C-1), 75.8 (76.2) (Cby-CH2), 94.2 (95.8)
[NC(CH3)2O], 126.6, 127.8, 128.7 (Cphenyl), 139.7 (Cq, Cphenyl),
151.2 (151.9) (Cby-NC=O), 155.5 (Cb-NC=O).
IR (film): 3088, 3064, 3029, 2969, 2934, 2872, 1760, 1747, 1691,
1681, 752, 700 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.22 (m, 12 H, Cb-CH3), 1.27,
1.34, 1.39, 1.42, 1.52, 1.56, 1.57, 1.70 (8 × s, 12 H, Cby-CH3), 1.48–
1.60 (m, 1 H, H-4A), 1.75 (m, 3J3A–2 = 4.8 Hz, 1 H, H-3A), 1.87 (m,
1 H, H-4B), 1.91 (m, 3J3B–2 = 6.3 Hz, 1 H, H-3B), 1.95 (m, 1 H, H-
7A), 2.11 (m, 1 H, H-7B), 2.64 (m, 1 H, H-5), 3.56, 3.87 [2 × d,
2Jgem = 13.4, 14.2 Hz, 2 × 2 H, (PhCH2)2N], 3.64–3.76 (m, 2 H,
Cby-CH2), 3.71 [s, 3 H, O(CO)OCH3], 3.75 [s, 3 H,
CH2(CO)OCH3], 4.04 (m, 2 H, Cb-CH), 4.04 (m, 2 H, H-8), 5.03
(dd, 3J3A–2 = 4.8 Hz, 3J3B–2 = 6.3 Hz, 1 H, H-2), 5.33 (m, 1 H, H-6),
7.19–7.31 (m, 10 H, Hphenyl).
13C NMR (100 MHz, CDCl3): d = 20.5 (Cb-CH3), 20.5 (C-3), 23.3,
23.9, 24.1, 24.4, 25.3, 25.5, 26.4, 27.6 (Cby-CH3), 29.0 (C-4), 31.6
(C-7), 45.7, 46.7 (Cb-CH), 51.9 (OCH3), 54.4 [(PhCH2)2N], 54.6
(OCH3), 59.4 (61.0) [NC(CH3)2CH2], 60.1 (C-5), 64.2 (C-8), 70.3
(C-6), 72.4 (C-2), 75.9 (76.4) (Cby-CH2), 94.4 (96.2) [NC(CH3)2O],
127.0, 128.2, 129.0 (Cphenyl), 139.5 (Cq, Cphenyl), 151.1 (152.0)
(Cby-NC=O), 154.7 (Cb-NC=O), 155.5 [O(CO)OCH3], 171.2
[CH2(CO)OCH3].
MS (ESI): m/z = 596.5 [M + H]+, 618.5 [M + Na]+.
Anal. Calcd for C35H53N3O5: C, 70.55; H, 8.97; N, 7.05. Found: C,
70.60; H, 8.98; N, 6.93.
2,2,4,4-Tetramethyl-1,3-oxazolidine-3-carboxylic Acid (1S,2S)-
2-(N,N-Dibenzylamino)-5-(N,N-diisopropylcarbamoyloxy)-1-
(2-hydroxyethyl)pent-1-yl Ester (14)
5c (1.004 g, 1.73 mmol) and (–)-sparteine (13; 0.56 mL,
2.42 mmol, 1.4 equiv) were dissolved in Et2O (50 mL). The mixture
was cooled to –78 °C, s-BuLi (1.93 mL, 2.42 mmol, 1.4 equiv) was
added dropwise and, after stirring for 7 h, the mixture became dark
red-brown. A precooled solution (–78 °C) of ethylene oxide [pre-
pared by condensing ethylene oxide (228 mg, 5.18 mmol,
3.0 equiv) in a flask at –78 °C and dissolving the condensate in Et2O
(5 mL)] was added. After a few minutes BF3·OEt2 (0.33 mL,
2.59 mmol, 1.5 equiv) was added rapidly and the mixture became
colourless. The mixture was warmed over night to r.t., then H2O
(10 mL) was added, the aqueous layer was washed with Et2O (2 ×
10 mL), and the combined organic layers were dried over Na2SO4.
After filtration, the solvent was removed under vacuum and purified
by FCC (n-pentane–Et2O, 1:1→Et2O) to give 14.
MS (ESI): m/z = 742.5 [M + H]+, 764.6 [M + Na]+, 780.5 [M + K]+.
Anal. Calcd for C40H59N3O10: C, 64.76; H, 8.02; N, 5.66. Found: C,
64.71; H, 8.27; N, 5.51.
2,2,4,4-Tetramethyl-1,3-oxazolidine-3-carboxylic Acid
(1S,2S,5R)-2-(N,N-Dibenzylamino)-5-(N,N-diisopropylcarbam-
oyloxy)-6-hydroxy-1-(2-hydroxyethyl)hex-1-yl Ester (4c)
To a solution of 15 (399 mg, 0.54 mmol), dissolved in THF (10 mL)
and cooled to –78 °C, was added a solution of DIBAL-H (1.0 M in
hexane, 3.23 mL, 3.23 mmol, 6.0 equiv). After stirring for 1 h at
–78 °C, the mixture was warmed to 0 °C and stirred for 2 h. MeOH
(5 mL) and H2O (3 mL) were added and the mixture was stirred for
1 h at 0 °C, then warmed to r.t. MgSO4 was added and, after filtra-
tion, the solvent was removed under vacuum. Purification by FCC
(Et2O–PE, 1:1→Et2O) gave 4c.
20
Yield: 713 mg, 1.14 mmol (66%); colourless resin; [a]D +7.7 (c
1.44, CHCl3); Rf = 0.43 (Et2O).
IR (film): 3339, 3086, 3063, 3028, 2974, 2937, 2875, 1690, 1667,
1493, 1453, 750, 701 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.21, 1.22 (2 × d, 3JCbCH–CbCH3
=
6.7 Hz, 12 H, Cb-CH3), 1.24, 1.25, 1.39, 1.42, 1.44, 1.55, 1.59, 1.62
(8 × s, 12 H, Cby-CH3), 1.45–1.65 (m, 3J4–5 = 5.7 Hz, 2 H, H-3A, H-
3
4A), 1.74 (m, J1¢–1¢¢ = 5.8 Hz, 2 H, H-4B, H-1¢A), 1.87 (m, 1 H, H-
20
3B), 1.97 (m, 1 H, H-1¢B), 2.76 (m, 1 H, H-2), 3.25 (m, 1 H, OH),
Yield: 347 mg, 0.53 mmol (98%); colourless resin; dr = 97:3; [a]D
+16.9 (c 0.97, CHCl3); Rf = 0.12 (Et2O).
3
3.43 (t, J1¢–1¢¢ = 5.8 Hz, 1 H, H-1¢¢A), 3.60, 3.85 [2 × d,
2Jgem = 13.5 Hz, 2 × 2 H, Ph(CH2)2N], 3.65 (m, 1 H, H-1¢¢B), 3.70
IR (film): 3422, 3090, 3066, 3032, 2974, 2940, 2878, 1685, 1670,
1654, 1456, 1438, 750, 700 cm–1.
3
(m, 2 H, Cby-CH2), 3.90 (m, JCbCH–CbCH3 = 6.7 Hz, 2 H, Cb-CH),
4.04 (t, 3J4–5 = 5.7 Hz, 2 H, H-5), 5.00 (m, 1 H, minor diastereomer,
dr >97:3), 5.39 (dt, 3J1–2 = 11.3 Hz, 3J1–1¢ = 3.0 Hz, 1 H, H-1), 7.19–
7.35 (m, 10 H, Hphenyl).
1H NMR (400 MHz, CDCl3): d = 1.23, 1.24 (2 × d, 3JCbCH–CbCH3
6.8 Hz, 12 H, Cb-CH3), 1.38, 1.41, 1.43, 1.54, 1.59 (5 × s, 12 H,
=
Synthesis 2007, No. 13, 1984–1994 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-N-Acetylslaframine
1991
Cby-CH3), 1.36–1.66 (m, 3J4–5 = 3J5–6 = 5.3 Hz, 2 H, H-4), 1.67 (m,
1 H, H-1¢A), 1.70 (m, 1 H, H-3A), 1.83 (m, 1 H, H-3B), 1.99 (m, 1 H,
H-1¢B), 2.70 (m, 1 H, H-2), 3.29 (br s, 2 H, OH), 3.40 (m, 1 H, H-
1¢¢A), 3.56, 3.85 [2 × m, 4 H, (PhCH2)2N], 3.61 (m, 1 H, H-1¢¢B),
3.67 (m, 2 H, H-6), 3.69 (3.71) (s, 2 H, Cby-CH2), 4.04 (m, 3JCbCH–
CbCH3 = 6.8 Hz, 2 H, Cb-CH), 4.83 (quin, 3J4–5 = 3J5–6 = 5.3 Hz, 1 H,
H-5), 5.36 (dt, 3J1–2 = 11.1 Hz, 3J1–1¢ = 3.2 Hz, 1 H, H-1), 7.21–7.34
(m, 10 H, Hphenyl).
13C NMR (100 MHz, CDCl3): d = 20.2 (C-4), 20.3 (Cb-CH3), 23.8,
24.0, 24.6, 24.9, 25.3, 25.5, 26.2, 26.5 (Cby-CH3), 28.6 (C-3), 35.5
(C-1¢), 46.4 (Cb-CH), 54.7 [(PhCH2)2N], 58.3 (C-1¢¢), 59.5 (61.2)
[NC(CH3)2CH2], 60.1 (C-2), 65.6 (C-6), 70.7 (C-1), 75.8 (76.4)
(Cby-CH2), 76.8 (C-5), 94.5 (96.3) [NC(CH3)2O], 127.0, 128.3,
128.8 (Cphenyl), 139.5 (Cq, Cphenyl), 152.9 (153.6) (Cby-NC=O),
156.3 (Cb-NC=O).
(104 mg, 0.77 mmol, 3.0 equiv) was added slowly and the mixture
was stirred for 2 h at 0 °C. CH2Cl2 (10 mL) and H2O (10 mL) were
added and the organic layer was washed with aq sat. CuSO4 (2 ×
10 mL) and H2O (10 mL). The organic layer was dried over MgSO4,
filtered and the solvent was removed under vacuum. The crude
product was dissolved in MeOH (10 mL) and added to a suspension
of Pd(OH)2/C (20% Pd, 100 mg) in MeOH (15 mL). Et3N (0.20 mL,
1.30 mmol, 5.0 equiv) was added and the flask was cycled between
vacuum and H2 6 times. After stirring for 14 h at r.t., the flask was
evacuated and filled with H2 again and the mixture was kept for 5 h
at 60 °C. After cooling to r.t., the mixture was filtered through a sil-
ica gel packed column, which was washed with MeOH (40 mL).
The solvent was removed under vacuum and the product was puri-
fied by FCC (Et2O–PE, 1:1→Et2O) to give 20.
Yield: 33 mg, 0.08 mmol (29%); colourless solid; mp 93.4 °C;
20
tR = 20.82 min (HP-5); [a]D +10.4 (c 0.24, CHCl3); Rf = 0.14
MS (ESI): m/z = 656.6 [M + H]+, 678.6 [M + Na]+, 694.6 [M + K]+.
(Et2O–PE, 1:1).
Anal. Calcd for C37H57N3O7: C, 67.76; H, 8.76; N, 6.41. Found: C,
67.73; H, 8.77; N, 6.26.
IR (film): 2978, 2935, 2864, 1699, 1680, 1474, 1439 cm–1.
3
1H NMR (400 MHz, CDCl3): d = 1.19 (d, JCbCH–CbCH3 = 6.7 Hz,
2,2,4,4-Tetramethyl-1,3-oxazolidine-3-carboxylic Acid
(1S,2S,5R)-2-(tert-Butoxycarbonylamino)-5-(N,N-diisopropyl-
carbamoyloxy)-6-hydroxy-1-(2-hydroxyethyl)hex-1-yl Ester
(16)
12 H, Cb-CH3), 1.37, 1.39, 1.41, 1.54, 1.56 (5 × s, 12 H, Cby-CH3),
1.35 (m, 1 H, H-7A), 1.52 (m, 1 H, H-8A), 1.77 (m, 1 H, H-8B), 1.81
3
(m, J2A–3A = 3J2A–3B = 3J2B–3A = 8.7 Hz, 1 H, H-2A), 1.92 (m,
2J5A–5B = 9.7 Hz, 1 H, H-5A), 1.93 (m, 1 H, H-8a), 2.06 (q, 2J3A–3B
=
Palladium on activated carbon (10% Pd, 883 mg, 0.83 mmol,
0.4 equiv) was suspended in MeOH (20 mL). A solution of 4c
(1.363 g, 2.08 mmol) in MeOH (10 mL) was added and the flask
was cycled between vacuum and H2 6 times. After stirring for 14 h
at r.t. under H2, the flask was evacuated and filled with H2 again and
the mixture was stirred for a further 5 h at 60 °C. After cooling to
r.t., the mixture was filtered through a silica gel packed column and
washed with MeOH (40 mL). The solvent was removed under vac-
uum and the residue was dissolved in MeOH (20 mL). Et3N
(2.04 mL, 14.55 mmol, 7.0 equiv) and a solution of di-tert-butyl di-
carbonate (1.120 g, 5.20 mmol, 2.5 equiv) in MeOH (10 mL) were
added and the mixture was stirred for 3 h at 40 °C, then for 14 h at
r.t. Without further workup, the solvent was removed under vacuum
and the crude product was purified by FCC (EtOAc) to give 16.
8.7 Hz, 1 H, H-3A), 2.20 (m, 1 H, H-7B), 2.25 (m, 3J2B–3B = 2.4 Hz,
2
3
1 H, H-2B), 3.08 (dt, J3A–3B = 3J2A–3B = 8.7 Hz, J2B–3B = 2.4 Hz,
1 H, H-3B), 3.38 (dd, 2J5A–5B = 9.7 Hz, 3J5B–6 = 4.7 Hz, 1 H, H-5B),
3
3.72 (s, 2 H, Cby-CH2), 4.06 (m, JCbCH–CbCH3 = 6.7 Hz, Cb-CH),
4.78 (m, 1 H, H-6), 5.18 (m, 1 H, H-1).
13C NMR (100 MHz, CDCl3): d = 21.0 (Cb-CH3), 23.2 (C-8), 24.0,
24.3, 25.1, 25.4, 25.5, 25.5, 26.4, 27.0 (Cby-CH3), 30.4 (C-7), 31.4
(C-2), 45.7 (Cb-CH), 52.4 (C-3), 57.2 (C-5), 59.9 (60.5)
[NC(CH3)2CH2], 67.1 (C-8a), 70.2 (C-6), 74.6 (C-1), 76.0 (76.5)
(Cby-CH2), 95.1 (95.8) [NC(CH3)2O], 151.9 (152.6) (Cby-NC=O),
155.1 (Cb-NC=O).
MS (ESI): m/z = 440.5 [M + H]+, 462.4 [M + Na]+, 478.4 [M + K]+.
HRMS (ESI): m/z calcd for C23H41N3O5: 440.3124 [M + H]+,
462.2944 [M + Na]+; found: 440.3161 [M + H]+, 462.2945 [M +
Na]+.
20
Yield: 1.101 g, 1.91 mmol (92%); colourless solidified resin; [a]D
–3.0 (c 0.20, CHCl3); Rf = 0.22 (EtOAc).
IR (film): 3429, 2974, 2935, 2874, 1695, 1681, 1478, 1444 cm–1.
6-(1S,6R,8aS)-1-Hydroxy-1,2,3,5,6,7,8,8a-octahydroindolizin-
6-yl N,N-Diisopropylcarbamate (17)
Variant 1
3
1H NMR (400 MHz, CDCl3): d = 1.17 (d, JCbCH–CbCH3 = 6.8 Hz,
12 H, Cb-CH3), 1.34, 1.46, 1.49, 1.52 (4 × s, 12 H, Cby-CH3), 1.39
[s, 9 H, C(CH3)3], 1.38–1.43 (m, 1 H, H-3A), 1.68 (m, 3 H, H-4, H-
1¢A), 1.83 (m, 1 H, H-3B), 1.87 (m, 1 H, H-1¢B), 3.06 (br s, 2 H, OH),
3.48 (m, 1 H, H-1¢¢A), 3.62 (m, 3 H, H-1¢¢B, H-6), 3.71 (s, 2 H, Cby-
CH2), 3.76 (m, 1 H, H-2), 4.00 (m, 3JCbCH–CbCH3 = 6.8 Hz, 2 H, Cb-
CH), 4.53 (m, 1 H, NH), 4.78 (m, 1 H, H-5), 4.99 (m, 1 H, H-1).
16 (415 mg, 0.72 mmol) was dissolved in CH2Cl2 (20 mL), cooled
to –20 °C and Et3N (0.48 mL, 3.17 mmol, 4.4 equiv) followed by
MsCl (0.22 mL, 2.88 mmol, 4.0 equiv) were added slowly. After
14 h at –20 °C, the solution was treated with CH2Cl2 (10 mL) and
aq HCl (1 N, 10 mL). The organic layer was washed with H2O
(10 mL), sat. aq brine (10 mL) and dried with MgSO4. After filtra-
tion, the solvent was removed under vacuum and the residue was
dissolved in CH2Cl2 (20 mL). TFA (3.33 mL, 43.0 mmol,
60.0 equiv) was added and the solution was stirred for 14 h at r.t.
The solvent was removed under vacuum and the residue was dis-
solved in MeOH (20 mL) and treated with K2CO3 (2.97 g,
21.5 mmol, 30.0 equiv, pH >10). The mixture was heated for 14 h
at reflux, then the mixture was allowed to come to r.t., filtered and
the solvent was removed under vacuum. Purification by FCC
(CH2Cl2–MeOH, 20:1→10:1) gave 17.
13C NMR (100 MHz, CDCl3): d = 20.7, 21.3 (Cb-CH3), 23.9, 24.1,
25.3, 25.4, 25.7, 26.7, 26.8, 27.6 (Cby-CH3), 27.6 (C-4), 28.3
[C(CH3)3], 29.0 (C-3), 35.1 (C-1¢), 45.8 (46.4) (Cb-CH), 53.9 (C-2),
58.3 (C-1¢¢), 59.8 (61.1) [NC(CH3)2CH2], 65.7 (C-5¢), 72.7 (C-1),
76.0 (76.2) (Cby-CH2), 76.4 (C-5), 79.6 [C(CH3)3], 94.7 (96.2)
[NC(CH3)2O], 152.4 (153.1) (Cby-NC=O), 155.8 (Cb-NC=O),
156.2 (Boc-NHC=O).
MS (ESI): m/z = 576.4 [M + H]+, 598.4 [M + Na]+, 1173.7 [2 ×
M + Na]+.
Anal. Calcd for C28H53N3O9: C, 58.41; H, 9.28; N, 7.30. Found: C,
58.17; H, 9.37; N, 7.02.
Yield: 121 mg, 0.43 mmol (59%); colourless solid.
Variant 2
(1S,6R,8aS)-6-(N,N-Diisopropylcarbamoyloxy)-1,2,3,5,6,7,8,8a-
octahydroindolizin-1-yl 2,2,4,4-Tetramethyl-1,3-oxazolidine-3-
carboxylate (20)
4c (170 mg, 0.26 mmol) and DMAP (48 mg, 0.39 mmol, 1.5 equiv)
were dissolved in pyridine (5 mL) and cooled to 0 °C. MsCl
20 (142 mg, 0.32 mmol) was dissolved in a mixture of THF (5 mL),
MeOH (3 mL) and aq HCl (5 N, 5 mL). After 14 h reflux, the mix-
ture was cooled to r.t. and aq NaOH (5 N) was added until pH >10.
Additional aq NaOH (5 N, 1 mL) was added and the mixture was
Synthesis 2007, No. 13, 1984–1994 © Thieme Stuttgart · New York

1992
D. Hoppe et al.
PAPER
heated again for 14 h at reflux. The solvent was removed under vac-
uum and the residue was treated with Et2O (10 mL) and H2O
(10 mL). The aqueous layer was washed with Et2O (2 × 5 mL) and
the combined organic layers were dried over Na2SO4. After filtra-
tion, the solvent was removed under vacuum and purified by FCC
(CH2Cl2–MeOH, 20:1→10:1) to give 17.
(1S,6R,8aS)-1-Trityloxy-1,2,3,5,6,7,8,8a-octahydroindolizin-6-
ol (22)
21 (142 mg, 0.27 mmol) was dissolved in THF (10 mL) and cooled
to –78 °C. DIBAL-H (1.0 M in hexane, 5.39 mL, 5.39 mmol,
20.0 equiv) was slowly added and the solution was stirred for 2 h at
–78 °C, then allowed to come to r.t. and stirred for 14 h. THF
(10 mL) and MeOH (2 mL) were added, stirring was continued for
1 h, then H2O (1 mL) was added and the mixture was stirred for a
further 1 h. The mixture was dried over Na2SO4 and, after filtration,
the solvent was removed under vacuum. Purification by FCC
(CH2Cl2–MeOH, 20:1→10:1) gave 22.
Yield: 85 mg, 0.30 mmol (93%); colourless solid; mp 104.4 °C;
[a]D20 +39.8 (c 1.04, CHCl3); Rf = 0.35 (CH2Cl2–MeOH, 10:1).
IR (film): 3419, 3187, 2972, 2956, 2938, 2804, 1690, 1478, 1443
cm–1.
3
1H NMR (500 MHz, CDCl3): d = 1.19 (d, JCbCH–CbCH3 = 6.8 Hz,
20
Yield: 100 mg, 0.25 mmol (93%); colourless resin; [a]D +3.3 (c
12 H, Cb-CH3), 1.38 (m, 1 H, H-7ax), 1.70 (m, 1 H, H-8A), 1.76 (m,
0.69, CHCl3); Rf = 0.18 (CH2Cl2–MeOH, 10:1).
3J2A–3A = 3J2A–3B = 3J2B–3A = 9.1 Hz, 1 H, H-2A), 1.79 (m, 1 H, H-
IR (KBr): 3430, 3150, 3057, 3019, 2943, 2849, 2784, 1490, 1449,
746, 699 cm–1.
2
3
8B), 1.84 (m, 1 H, H-8a), 1.97 (t, J5ax–5eq = 9.7 Hz, J5ax–6ax
=
3J6ax–7ax = 10.4 Hz, 1 H, H-5ax), 2.11 (q, J3A–3B = 9.1 Hz, 1 H, H-
2
3A), 2.21 (m, 3J2B–3B = 2.5 Hz, 1 H, H-2B), 2.23 (m, 1 H, H-7eq), 2.41
1H NMR (400 MHz, CDCl3): d = 1.16–1.25 (m, J2A–3B = 8.8 Hz,
3
(br s, 1 H, OH), 3.13 (dt, 3J2A–3B = 9.1 Hz, J2B–3B = 2.5 Hz, 1 H, H-
2 H, H-2A, H-7A), 1.38 (m, 1 H, H-8A), 1.64 (m, 1 H, H-8a), 1.80–
3
3B), 3.41 (ddd, J5eq–6ax = 3J6ax–7eq = 4.6 Hz, J5eq–7eq = 1.4 Hz, 1 H,
H-5eq), 3.67, 4.06 (2 × m, 3JCbCH–CbCH3 = 6.8 Hz, 2 H, Cb-CH), 4.07
(m, 1 H, H-1), 4.80 (tt, 3J6ax–7A = 10.3 Hz, 3J5ax–6ax = 3J6ax–7ax = 10.4
Hz, 3J5eq–6ax = 3J6ax–7eq = 4.6 Hz, 1 H, H-6ax).
1.90 (m, J3A–3B = 8.8 Hz, J5A–5B = 10.4 Hz, J5A–6 = 3J6–7A
=
3
4
2
2
3
10.4 Hz, 4 H, H-2B, H-3A, H-5A, OH), 1.97 (m, 1 H, H-8B), 2.15 (m,
1 H, H-7B), 2.82 (t, 2J3A–3B = 3J2A–3B = 8.8 Hz, 1 H, H-3B), 3.26 (dd,
3
3J5B–6 = 3J6–7B = 4.6 Hz, 1 H, H-5B), 3.90 (tt, J5A–6 = 3J6–7A = 10.4
3
Hz, J5B–6 = 3J6–7B = 4.6 Hz, 1 H, H-6), 4.23 (m, 1 H, H-1), 7.21–
13C NMR (125 MHz, CDCl3): d = 21.1 (Cb-CH3), 22.5 (C-8), 30.0
(C-7), 33.9 (C-2), 45.7 (Cb-CH), 51.9 (C-3), 56.9 (C-5), 67.8 (C-
8a), 70.0 (C-6), 72.2 (C-1), 155.1 (Cb-NC=O).
MS (ESI): m/z = 285.5 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H28N2O3: 285.2178; found:
7.48 (m, 15 H, Hphenyl).
13C NMR (75 MHz, CDCl3): d = 23.7 (C-8), 32.8 (C-7), 33.7 (C-2),
52.2 (C-3), 59.8 (C-5), 66.7 (C-6), 67.2 (C-8a), 73.9 (C-1), 87.0
(CPh3), 127.0, 127.7, 129.2 (Cphenyl), 144.9 (Cq, Cphenyl).
MS (ESI): m/z = 243.1 [CPh3]+, 400.2 [M + H]+, 422.2 [M + Na]+.
285.2200.
HRMS (ESI): m/z calcd for C27H29NO2: 400.2271 [M + H]+,
422.2079 [M + Na]+; found: 400.2254 [M + H]+, 422.2091 [M +
Na]+.
(1S,6R,8aS)-1-Trityloxy-1,2,3,5,6,7,8,8a-octahydroindolizin-6-
yl N,N-Diisopropylcarbamate (21)
17 (130 mg, 0.46 mmol) and triphenylmethyl chloride (3.80 g,
13.7 mmol, 30.0 equiv) were dissolved in CH2Cl2 (10 mL), treated
with DBU (2.73 mL, 18.3 mmol, 40.0 equiv) and stirred at r.t. for
48 h. CH2Cl2 (20 mL) and H2O (10 mL) were added, the aqueous
layer was washed with CH2Cl2 (2 × 10 mL) and the combined or-
ganic layers were dried over Na2SO4. After filtration, the solvent
was removed under vacuum and the residue was purified by FCC
(Et2O–PE, 1:2→1:1) to give 21.
(1S,8aS)-1-Trityloxy-1,2,3,5,6,7,8,8a-octahydroindolizin-6-one
(23)
Oxalyl chloride (0.13 mL, 1.57 mmol, 7.2 equiv) was dissolved in
CH2Cl2 (10 mL) and cooled to –78 °C. DMSO (0.23 mL,
3.14 mmol, 14.4 equiv) was added slowly and the mixture was
stirred for 30 min. A solution of 22 (87 mg, 0.22 mmol) in CH2Cl2
(5 mL) was added slowly (generation of gas was observed). After
5 h at –78 °C, Et3N (0.89 mL, 6.53 mmol, 30.0 equiv) was added
and stirring was continued for 1 h at –78 °C, then at r.t. for 1 h. H2O
(10 mL) and CH2Cl2 (10 mL) were added, the aqueous layer was
washed with CH2Cl2 (2 × 10 mL) and the combined organic layers
were dried over Na2SO4. After filtration, the solvent was removed
under vacuum and the product was purified by FCC (n-pentane–
Et2O, 1:1→Et2O) to give 23.
Yield: 173 mg, 0.33 mmol (73%); colourless resin; tR = 30.59 min
20
(HP-5); [a]D –3.8 (c 0.49, CHCl3); Rf = 0.18 (n-pentane–Et2O,
1:1).
IR (film): 3087, 3059, 3032, 2967, 2936, 2867, 1684, 1490, 1477,
1444, 755, 704 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.17, 1.18 (2 × d, 3JCbCH–CbCH3
=
6.6 Hz, 12 H, Cb-CH3), 1.25–1.33 (m, 3J2A–3B = 9.0 Hz, 2 H, H-2A,
20
Yield: 72 mg, 0.18 mmol (83%); colourless resin; [a]D –40.6 (c
H-7A), 1.39 (m, 1 H, H-8A), 1.59 (m, 1 H, H-8a), 1.85–2.00 (m,
0.69, CHCl3); Rf = 0.38 (Et2O).
2
3
2J3A–3B = 9.0 Hz, J5A–5B = 10.4 Hz, J5A–6 = 3J6–7A = 10.7 Hz, 4 H,
IR (KBr): 3150, 3057, 3033, 2979, 2935, 2777, 1715, 1490, 1447,
2
H-2B, H-3A, H-5A, H-8B), 2.23 (m, 1 H, H-7B), 2.86 (dt, J3A–3B
=
=
750, 707 cm–1.
4
2
3J2A–3B = 9.0 Hz, J3B–5B = 0.9 Hz, 1 H, H-3B), 3.30 (ddd, J5A–5B
10.4 Hz, 3J5B–6 = 3J6–7B = 4.6 Hz, 4J3B–5B = 0.9 Hz, 1 H, H-5B), 3.62,
4.12 (2 × m, 3JCbCH–CbCH3 = 6.6 Hz, 2 H, Cb-CH), 4.21 (m, 1 H, H-
1), 4.89 (tt, 3J5A–6 = 3J6–7A = 10.7 Hz, 3J5B–6 = 3J6–7B = 4.6 Hz, 1 H,
H-6), 7.20–7.48 (m, 15 H, Hphenyl).
1H NMR (500 MHz, CDCl3): d = 1.46 (m, J2A–3A = 3J2B–3A
=
3
8.6 Hz, 3J2A–3B = 3J2B–3B = 2.9 Hz, 1 H, H-2A), 1.56 (m, 1 H, H-2B),
1.77 (m, 1 H, H-8A), 2.06 (q, 2J3A–3B = 8.6 Hz, 1 H, H-3A), 2.24 (m,
1 H, H-8B), 2.25 (m, 1 H, H-7A), 2.33 (m, 1 H, H-8a), 2.53 (m, 1 H,
H-7B), 2.83 (dt, 2J3A–3B = 8.6 Hz, 3J2A–3B = 3J2B–3B = 2.9 Hz, 1 H, H-
3B), 2.85 (d, 2J5A–5B = 15.1 Hz, 1 H, H-5A), 3.35 (dd, 2J5A–5B = 15.1
13C NMR (75 MHz, CDCl3): d = 20.8 (Cb-CH3), 23.4 (C-8), 30.6
(C-7), 32.4 (C-2), 45.0 (46.4) (Cb-CH), 51.5 (C-3), 56.2 (C-5), 66.4
(C-8a), 68.9 (C-6), 74.2 (C-1), 86.9 (CPh3), 126.9, 127.7, 129.1
(Cphenyl), 145.0 (Cq, Cphenyl), 155.2 (Cb-NC=O).
Hz, J5B–7B = 1.7 Hz, 1 H, H-5B), 4.33 (dt, J1–2A = 3J1–8a = 5.6 Hz,
4
3
3J1–2B = 8.0 Hz, 1 H, H-1), 7.22–7.48 (m, 15 H, Hphenyl).
13C NMR (125 MHz, CDCl3): d = 23.9 (C-8), 32.4 (C-2), 38.4 (C-
7), 51.7 (C-3), 62.6 (C-5), 64.1 (C-8a), 74.0 (C-1), 87.2 (CPh3),
127.1, 127.8, 129.0 (Cphenyl), 144.7 (Cq, Cphenyl), 208.1 (C-6).
MS (ESI): m/z = 243.1 [CPh3]+, 527.3 [M + H]+, 549.3 [M + Na]+,
1053.6 [2 × M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C34H42N2O3: 527.3268; found:
527.3231.
MS (ESI): m/z = 243.1 [CPh3]+, 398.2 [M + H]+, 420.2 [M + Na]+,
430.2 [M + MeOH + H]+, 452.2 [M + MeOH + Na]+.
Synthesis 2007, No. 13, 1984–1994 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-N-Acetylslaframine
1993
2
HRMS (ESI): m/z calcd for C27H27NO2: 398.2099 [M + H]+,
420.1916 [M + Na]+, 430.2353 [M + MeOH + H]+, 452.2172 [M +
MeOH + Na]+; found: 398.2115 [M + H]+, 420.1916 [M + Na]+,
430.2377 [M + MeOH + H]+, 452.2196 [M + MeOH + Na]+.
1.98 [s, 3 H, NH(CO)CH3], 2.00 (q, J3A–3B = 9.1 Hz, 1 H, H-3A),
2.07 [s, 3 H, O(CO)CH3], 2.15 (dd, 2J5ax–5eq = 11.4 Hz, 3J5eq–6 = 2.6
Hz, 1 H, H-5eq), 2.28 (dddd, 2J2A–2B = 14.4 Hz, J2B–3A = 9.1 Hz,
3
3J1–2B = 8.5 Hz, J2B–3B = 1.8 Hz, 1 H, H-2B), 3.00 (ddd, 2J5ax–5eq
=
3
11.4 Hz, 3J5ax–6 = 3J5eq–6 = 3J6–7ax = 3J6–7eq = 2.6 Hz, 4J5ax–7 = 1.7 Hz,
2
3
3
(1S,8aS)-6-Hydroxyimino-1-trityloxy-1,2,3,5,6,7,8,8a-octa-
hydroindolizin (24)
1 H, H-5ax), 3.06 (td, J3A–3B = J2A–3B = 9.1 Hz, J2B–3B = 1.8 Hz,
1 H, H-3B), 4.16 (dq, 3J5ax–6 = J5eq–6 = 3J6–7ax = 3J6–7eq = 2.6 Hz, 1 H,
3
3
3
3
23 (58 mg, 0.15 mmol) and hydroxylamine hydrochloride (42 mg,
0.60 mmol, 4 equiv) were dissolved in EtOH (6 mL) and pyridine
(2 mL). The mixture was kept for 4 h at 80 °C and then at r.t. for
16 h. The solvent was removed under vacuum and the residue was
dissolved in CH2Cl2 (20 mL) and treated with sat. aq NaHCO3
(10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL),
the combined organic layers were dried over MgSO4 and, after fil-
tration, the solvent was removed under vacuum. Purification by
FCC (n-pentane–Et2O, 1:1→Et2O) gave (E)-24 and (Z)-24.
H-6), 5.22 (ddd, J1–2A = 2.5 Hz, J1–2B = 8.5 Hz, J1–8a = 4.9 Hz,
1 H, H-1), 6.27 (br d, 3J6–NH = 8.2 Hz, 1 H, NH).
13C NMR (125 MHz, CDCl3):14 d = 20.6 (C-8), 21.1 [O(CO)CH3],
23.5 [NH(CO)CH3], 28.2 (C-7), 30.6 (C-2), 43.9 (C-6), 53.0 (C-3),
57.5 (C-5), 67.3 (C-8a), 74.8 (C-1), 169.1 [NH(CO)CH3], 170.7
[O(CO)CH3].
MS (ESI): m/z = 241.15 [M + H]+, 263.15 [M + Na]+.
HRMS (ESI): m/z calcd for C12H30N2O3: 241.1574 [M + H]+,
263.1366 [M + Na]+; found: 241.1515 [M + H]+, 263.1333 [M +
Na]+.
(E)-24
20
Yield: 14 mg, 0.03 mmol (23%); colourless resin; [a]D –30.1 (c
0.41, CHCl3); Rf = 0.30 (Et2O).
Acknowledgment
IR (film): 3169, 3088, 3055, 3030, 2955, 2920, 2840, 1490, 1448,
758, 706 cm–1.
MS (ESI): m/z = 243 [CPh3]+, 413 [M + H]+.
The authors would like to thank the Deutsche Forschungsgemein-
schaft (SFB 424) and the Fonds der Chemischen Industrie for ge-
nerous support.
HRMS (ESI): m/z [M + H]+ calcd for C27H28N2O2: 413.2224; found:
413.2197.
References
(Z)-24
20
(1) In part from: Padeken, L. Dissertation; Universität Münster:
Germany, 2005.
(2) X-ray analysis.
(3) (a) Aust, S. D.; Broquist, H. P.; Rinehart, K. L. Jr. J. Am.
Chem. Soc. 1966, 88, 2879. (b) Gardiner, R. A.; Rinehart,
K. L. Jr.; Snyder, J. J.; Broquist, H. P. J. Am. Chem. Soc.
1968, 90, 5639.
(4) For previous enantioselective syntheses, see: (a) Pearson,
W. H.; Bergmeier, S. C. J. Org. Chem. 1991, 56, 1976.
(b) Choi, J. R.; Han, S.; Cha, J. K. Tetrahedron Lett. 1991,
32, 6469. (c) Sibi, M. P.; Christensen, J. W.; Li, B.;
Renhowe, P. A. J. Org. Chem. 1992, 57, 4329. (d) Sibi, M.
P.; Christensen, J. W. J. Org. Chem. 1999, 64, 6434.
(e) Knapp, S.; Gibson, F. S. J. Org. Chem. 1992, 57, 4802.
(f) Hua, D. H.; Park, J. G.; Katsuhira, T.; Bharathi, S. N. J.
Org. Chem. 1993, 58, 2144. (g) Knight, D. W.; Sibley, A.
W. Tetrahedron Lett. 1993, 34, 6607. (h) Knight, D. W.;
Sibley, A. W. J. Chem. Soc., Perkin Trans. 1 1997, 2179.
(i) Gmeiner, P.; Junge, D.; Kärtner, A. J. Org. Chem. 1994,
59, 6766. (j) Szeto, P.; Lathbury, D. C.; Gallagher, T.
Tetrahedron Lett. 1995, 36, 6957. (k) Stockmann, R. A.;
Szeto, P.; Thompson, S. H. J.; Hadley, M. S.; Lathbury, D.
C.; Gallagher, T. Synlett 1996, 853. (l) Kang, S. H.; Kim, J.
S.; Youn, J. Tetrahedron Lett. 1998, 39, 9047.
Yield: 43 mg, 0.10 mmol (72%); colourless resin; [a]D –7.2 (c
1.13, CHCl3); Rf = 0.11 (Et2O).
IR (film): 3170, 3087, 3056, 3031, 2952, 2921, 2841, 1490, 1448,
752, 706 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.48 (m, 3J2A–3B = 9.1 Hz, 1 H, H-
3
2A), 1.59 (m, J2B–3B = 3.7 Hz, 1 H, H-2B), 1.68 (m, 2 H, H-7A, H-
8A), 1.92 (m, 1 H, H-8B), 2.17 (m, 2J3A–3B = 9.1 Hz, 1 H, H-3A), 2.24
(m, 1 H, H-8a), 2.86 (dt, 2J3A–3B = 3J2A–3B = 9.1 Hz, 3J2B–3B = 3.7 Hz,
1 H, H-3B), 2.93 (m, 2J5A–5B = 11.3 Hz, 1 H, H-5A), 3.40 (d, 2J5A–5B
=
11.3 Hz, 1 H, H-5B), 3.41 (m, 1 H, H-7B), 4.32 (m, 1 H, H-1), 7.24–
7.48 (m, 15 H, Hphenyl).
13C NMR (125 MHz, CDCl3): d = 21.8 (C-8), 22.7 (C-7), 31.5 (C-
2), 49.9 (C-3), 54.3 (C-5), 64.5 (C-8a), 74.3 (C-1), 87.1 (CPh3),
127.0, 127.8, 129.0, 144.8 (Cphenyl), 155.4 (C-6).
MS (ESI): m/z = 413.4 [M + H]+, 435.3 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C27H28N2O2: 413.2224; found:
413.2240.
(1S,6S,8aS)-1-Acetoxy-6-(N-acetylamino)-1,2,3,5,6,7,8,8a-oc-
tahydroindolizin (2)
24 (E/Z-mixture, 16 mg, 0.039 mmol) and platinum(IV) oxide
(10 mg, 0.04 mmol, 1.0 equiv) were added to a mixture of EtOH
(4 mL) and concd HCl (0.3 mL). The flask was cycled between vac-
uum and H2 6 times and, after stirring for 14 h under H2, the mixture
was filtered, the solvent was removed under vacuum and the residue
was dissolved in pyridine (5 mL). Ac2O (2 mL) was added and the
mixture was stirred at r.t. for 2 h. The solvent was removed under
vacuum and the residue was purified by FCC (CH2Cl2–MeOH,
20:1→10:1) to give 2.
(m) Carretero, J. C.; Gómez Arrayás, R. Synlett 1999, 49.
(n) Dong, H. Q.; Lin, G. Q. Chin. Chem. Lett. 1998, 9, 999;
Chem. Abstr. 1999, 131, 337217. (o) Comins, D. L.; Fulp,
A. B. Org. Lett. 1999, 1, 1941. (p) Pourashraf, M.; Delair,
P.; Rasmussen, M.; Greene, A. E. J. Org. Chem. 2000, 65,
6966. (q) Cossy, J.; Willis, C.; Bellosta, V.; Saint-Jalmes, L.
Synthesis 2002, 951.
(5) Guarnieri, W.; Grehl, M.; Hoppe, D. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1734; Angew. Chem. 1994, 106, 1815.
(6) According to: Velluz, L.; Amiard, G.; Heymès, R. Bull. Soc.
Chim. Fr. 1954, 1012.
(7) For reviews, see: (a) Hoppe, D.; Hense, T. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2282; Angew. Chem. 1997, 109,
2376. (b) Hoppe, D.; Marr, F.; Brüggemann, M.
Organolithiums in Enantioselective Synthesis, In Topics in
Yield: 8 mg, 0.033 mmol (86%); colourless solid; mp 140 °C;
[a]D20 –18.0 (c 0.40, CH2Cl2); Rf = 0.38 (CH2Cl2–MeOH, 10:1).
1H NMR (500 MHz, CDCl3):14 d = 1.39–1.46 (m, 1 H, H-7ax), 1.47–
3
3
1.56 (m, J8ax–8a = 11.1 Hz, 1 H, H-8ax), 1.56–1.61 (m, J8eq–8a
=
=
=
2.8 Hz, 1 H, H-8eq), 1.75 (dtd, 2J2A–2B = 14.4 Hz, 3J2A–3A = 3J2A–3B
3J2B–3A = 9.1 Hz, 1 H, H-2A), 1.86 (ddd, J1–8a = 4.9 Hz, J8ax–8a
3
3
3
11.1 Hz, J8eq–8a = 2.8 Hz, 1 H, H-8a), 1.89–1.94 (m, 1 H, H-7eq),
Synthesis 2007, No. 13, 1984–1994 © Thieme Stuttgart · New York

1994
D. Hoppe et al.
PAPER
W. Methods Enzymol. 1997, 276, 307. (c) Absorption
Organometallic Chemistry, Vol. 5; Hodgson, D. M., Ed.;
Springer-Verlag: Weinheim, 2003, 61.
correction, Denzo: Otwinowski, Z.; Borek, D.; Majewski,
W.; Minor, W. Acta Crystallogr. A 2003, 59, 228.
(d) Structure solution, SHELXS-97: Sheldrick, G. M. Acta
Crystallogr. A 1990, 46, 467. (e) Structure refinement,
SHELXL-97: Sheldrick, G. M., Universität Göttingen,
Germany, 1997. (f) Graphics, SCHAKAL: Keller, E.,
Universität Freiburg, Germany, 1997. CCDC 637855
contains the supplementary crystallographic data for this
paper. This data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK; fax: +44(1223)336033, E-mail:
deposit@ccdc.cam.ac.uk.
(8) Schwerdtfeger, J.; Kolczewski, S.; Weber, B.; Fröhlich, R.;
Hoppe, D. Synthesis 1994, 1573.
(9) (a) Tomooka, K.; Komine, N.; Sasaki, T.; Shimizu, H.;
Nakai, T. Tetrahedron Lett. 1998, 39, 9715. (b) Shimizu,
H.; Saito, T.; Kumobayashi, H. Adv. Synth. Catal. 2003, 345,
185.
(10) Since polymerisation of ethylene oxide competes with
substitution, the yields vary strongly when changing the
reaction conditions.
(11) Even lithiation in one methyl group of a O-dimethylphenyl-
silyl residue was observed.
(12) X-ray crystal data for 20; empirical formula C23H41N3O5;
formula weight 439.59; colourless crystal; crystal size
0.30 × 0.15 × 0.15 mm; crystal system = monoclinic; Z = 2;
space group P21 (no. 4); unit cell dimensions a = 5.831 (1)
Å, b = 31.008 (1) Å, c = 7.542 (1) Å, b = 112.66 (1)°;
V = 1258.4 (3) Å3; D(calculated) = 1.160 g/cm3; absorption
coefficient 0.657 mm–1; empirical absorption correction
(0.827 £T £0.908); l = 1.54178 Å; T = 223 K; w and f
scans; 3453 reflections collected ( h, k, l); [(sinq)/l] =
0.58 Å–1; 2029 independent (Rint = 0.037) and 1616
observed reflections [I 2 sigma (I)]; 288 refined
parameters; R = 0.047, wR2 = 0.128; Flack parameter 0.2
(4), max. residual electron density 0.20 (–0.13) e/Å3;
Hydrogen atoms calculated and refined as riding atoms. Data
set was collected with a Nonius KappaCCD diffractometer.
(a) Data collection, COLLECT: Nonius B. V. 1998.
(b) Data reduction, Denzo-SMN: Otwinowski, Z.; Minor,
(13) Wasserman, H. H.; Vu, C. B. Tetrahedron Lett. 1994, 35,
9779.
(14) Using CDCl3, fresh de-acidification by filtration over basic
Al2O3 was necessary. Otherwise, signal broadening or the
signal set of a second compound (presumably the slowly
exchanging ammonium salt of 2) appears.
(15) Eight different values between –10.0 and –18.8 have been
reported for [a]D of 2.4
(16) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41,
1879.
(17) Hoppe, D.; Hanko, R.; Brönneke, A.; Lichtenberg, F.; van
Hülsen, E. Chem. Ber. 1985, 118, 2822.
(18) Hintze, F.; Hoppe, D. Synthesis 1992, 1216.
Synthesis 2007, No. 13, 1984–1994 © Thieme Stuttgart · New York