Stereoselective Total Synthesis of the Diastereomeric Tricyclic Alkaloids Tetraponerine-7 and Tetraponerine-8 Using O-Pivaloylated d -Arabinopyranosylamine as the Common Auxiliary

Article abstract of DOI:10.1055/s-0034-1380215

Based on a diastereoselective domino Mannich-Michael reaction cascade of 2-N-[(S)-3-{(benzyloxycarbonyl)[4-(tert-butyldiphenylsiloxy)butyl]amino}octylidene]-2,3,4-tri-O-pivaloyl-α-d-arabinopyranosylamine with the Danishefsky diene, the major component of

Full text of DOI:10.1055/s-0034-1380215

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, A–R
paper
A
I. Strassnig et al.
Paper
Synthesis
Stereoselective Total Synthesis of the Diastereomeric Tricyclic
Alkaloids Tetraponerine-7 and Tetraponerine-8 Using O-Pivalo-
ylated D-Arabinopyranosylamine as the Common Auxiliary
Irina Strassniga
OPiv
OPiv
O
O
C5H11
O
C5H11
O
Karsten Körberb
Udo Hüngerc
Horst Kunz*a
OPiv
NH2
N
O
Ph
N
Ph
O
O
a Institut für Organische Chemie, Johannes Gutenberg-Universität Mainz,
Duesbergweg 10–14, 55128 Mainz, Germany
hokunz@uni-mainz.de
b GBA/IO, Global Research Insecticide Chemistry, Crop Protection, BASF SE,
Carl-Bosch-Str. 38, 67056 Ludwigshafen, Germany
c E-EDK/K, Global Key Account Management, BASF SE, Carl-Bosch-Str. 38,
67056 Ludwigshafen, Germany
TBDPSO
OTBDPS
H
N
H
N
H
N
H
N
tetraponerine-8
tetraponerine-7
Dedicated to Professor Richard R. Schmidt on the occasion of his 80th birthday
Received: 23.03.2015
Accepted after revision: 21.04.2015
Published online: 11.06.2015
In the original article, the strong paralyzing effect of tet-
raponerine-8 on the European red ant (Myrmica rubra) was
described.1 In addition to this interesting insecticidal effect,
neurotoxic6 and cytotoxic activities7 of tetraponerines and
some of their derivatives have been reported. It was shown
that tetraponerines act as efficient inhibitors of nicotinic
acetylcholine receptors (nAChRs). Pharmacological studies
suggested that the different stereochemistry of T7 and T8
has an influence on the selective inhibition of the different
nicotinic acetylcholine receptors.6 The compounds with
longer alkyl chains at C5, such as T7 and T8, were generally
more potent than those with shorter alkyl groups, such as
T4. These results parallel the cytotoxic effects that tet-
raponerines and their analogues exhibit on HT29 (colorec-
tal) tumor cells.7
DOI: 10.1055/s-0034-1380215; Art ID: ss-2015-t0184-op
Abstract Based on a diastereoselective domino Mannich–Michael re-
action cascade of 2-N-[(S)-3-{(benzyloxycarbonyl)[4-(tert-butyldiphe-
nylsiloxy)butyl]amino}octylidene]-2,3,4-tri-O-pivaloyl-α-D-arabinopyra-
nosylamine with the Danishefsky diene, the major component of the
neurotoxic venom of the New Guinean ant Tetraponera punctulata, tet-
raponerine-8, and its diastereomer tetraponerine-7 were synthesized in
pure form. While the Mannich reaction of the arabinosyl imine of the
required (S)-configured β-aminoaldehyde gave the 2-substituted piper-
idinone precursor of tetraponerine-8 with excellent diastereoselectivity,
the analogous Mannich reaction of the (R)-configured β-aminoaldehyde
afforded the precursor of tetraponerine-7 with a selectivity of only 2:1
(mismatched case). The enantiomerically pure tetraponerine-8, de-
scribed as highly toxic for ants, exhibited only moderate toxicity to
sucking and stinging insects.
R
H
Key words piperidine alkaloids, tetraponerines, stereoselective
Mannich–Michael reaction, carbohydrate auxiliaries, nicotinic acetyl-
choline receptor inhibitor
H
R
N
N
N
N
T1 R = propyl
T5 R = pentyl
T2 R = propyl
T6 R = pentyl
In 1987, J. C. Braekman et al.1 discovered that the mid-
dle-sized tropical ant Tetraponera punctulata living in Pap-
ua New Guinea defends itself against larger sympatric ants
not by injection of a toxin through a sting, but by smearing
a segregated venom on the surface of the enemies. The par-
alyzing effect of this venom is caused by a group of struc-
turally related tricyclic alkaloids, the tetraponerines 1–8
T1–T8 (Figure 1).1,2 While the structure and the relative
configuration of the major component T8 was confirmed by
NMR and crystal structure analysis, the absolute configura-
tion was clarified through diastereoselective total synthesis
of enantiomerically pure natural tetraponerine-8.3 The
structures and configurations of other members of these
tricyclic alkaloids have also been elucidated by chemical
synthesis.3–5
R
H
6a
5
6
H
R
9
N
N
N
N
4
3
11a
1
T3 R =propyl
T7 (= 28) R = pentyl
T4 R = propyl
T8 (= 1) R = pentyl
Figure 1 Structure and configuration of the natural tetraponerines
The interesting biological properties of these alkaloids
have resulted in a number of stereoselective total syntheses
of racemic4,5,7–9 and enantiomerically enriched or pure tet-
raponerines.3,10 Recently, Gonzalez-Gomez, Guijarro, and
co-workers11 used an elegant indium-promoted aminoal-
lylation12 of ω-bromoalkanals for syntheses of enantiomeri-
cally pure tetraponerines-3 and -4; the enantiomers of tert-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

B
I. Strassnig et al.
Paper
Synthesis
butylsulfinamide served as the diastereodifferentiating
auxiliaries. These researchers successfully extended their
strategy to a general stereoselective synthesis of the natural
tetraponerines by combining this methodology with a
cross-metathesis reaction for elongating the C3 to a C5 alkyl
side chain at C5.13 Comparative studies of the cytotoxicity
of the different tetraponerines revealed that T7 exhibits
stronger growth inhibiting activity on MCF-7 (breast) tu-
mor cells than T8,13 both carrying the longer pentyl substit-
uent at C5. These results again suggest that the 6-6-5 struc-
ture isomers T7 and T8 with the longer C5 side chain, but
different configuration at C5 are of particular interest in
terms of biological activity.
H
N
H
N
O
OPiv
OPiv
OPiv
O
N
Cbz
1
OTBDPS
N
A
OPiv
OPiv
O
OPiv
N
C5H11
O
OSi(Me)3
N
Ph
OMe
B
+
We here describe the stereoselective synthesis of both
enantiomerically pure diastereomers T7 and T8 using O-
pivaloylated D-arabinopyranosylamine14 as the common
stereodifferentiating tool in a Mannich–Michael domino re-
action sequence.15
2
O
TBDPSO
The retrosynthetic analysis (Scheme 1) illustrates that
tetraponerine-8 (T8, 1), the major component of the ven-
om, is stereoselectively accessible from a (2S)-substituted
piperidine precursor A, which can be obtained through a
Mannich–Michael condensation reaction cascade of
Danishefsky diene 2 with the imine B formed from 2,3,4-
tri-O-pivaloyl-β-D-arabinopyranosylamine (3) and the (S)-
β-aminooctanal C. The aldehyde C should be available by
stereoselective hetero-Michael addition of a chiral amine to
tert-butyl (E)-oct-2-enoate (4) and subsequent reaction of
the adduct with silyl-protected 4-hydroxybutanal 5.
O
OPiv
OPiv
C5H11
O
+
OPiv
NH2
N
Ph
O
O
3
C
TBDPSO
O
C5H11
Ot-Bu
OTBDPS
O
4
NH2
O
5
While Danishefsky diene16 2 and arabinosylamine14
3
+
C5H11
Ot-Bu
are obtained according to described procedures, the prepa-
ration of β-aminoaldehyde C requires the stereoselective
addition of a chiral amine to an activated oct-2-enoic acid
Scheme 1 Retrosynthetic analysis for the stereoselective total synthe-
sis of (+)-tetraponerine-8
derivative. tert-Butyl oct-2-enoate
4 so far obtained
through Wittig olefination reactions17,18 was synthesized
from commercially available oct-2-enoic acid by treatment
with tert-butyl alcohol and di-tert-butyl dicarbonate in the
presence of 4-(dimethylamino)pyridine.19 The (S)-3-amino-
octanoic ester 6S, which is previously undescribed, was
prepared according to the strategy of Davies et al.20 by dias-
tereoselective addition of lithium benzyl[(S)-1-phenyleth-
yl]amide to 4. After single flash-chromatography, pure tert-
8R (Scheme 2). Hydrogenation of 6S and 6R as reported in
the literature21 in methanol under pressure of 6 atm using
palladium on charcoal required reaction times of several
days. Due to the long reaction time the methyl ester of the
3-aminooctanoate was formed as a byproduct. However hy-
drogenation of 6S and 6R using palladium hydroxide on
charcoal as the catalyst under atmospheric pressure gave
pure (S)-3-aminooctanoate 7S (98.7% ee) within three days
without formation of the methyl ester. Reductive N-alkyla-
tion of 7S with TBDPS-protected 4-hydroxybutanal 5 using
two equivalents of sodium triacetoxyborohydride smoothly
afforded the N-(4-TBDPS-oxybutyl)substituted (S)-3-amino
ester. In the corresponding reaction of the (3R)-enantiomer
a distinctly lower yield was recorded. It was revealed during
workup, that more N-dialkylated product was formed,
probably because of the more reactive fresh charge of the
sodium triacetoxyborohydride applied in this case. Both es-
ters 7 were reduced with lithium aluminum hydride in di-
ethyl ether to efficiently yield the 3-aminooctanol enantio-
mers 8S and 8R.
butyl
(S)-3-{benzyl[(S)-1-phenylethyl]amino}octanoate
(6S) was isolated in 80% yield (Scheme 2). Analogous addi-
tion of the (R)-enantiomer of the lithium amide afforded
the known18,21 (R)-3-aminooctanoic ester derivative 6R
useful for the total synthesis of tetraponerine-7 (vide infra).
After hydrogenolytic removal of the N-benzylic groups
both enantiomers of tert-butyl 3-aminooctanoate 7S and
7R were reacted with 4-(tert-butyldiphenylsiloxy)butanal22
(5) under reductive alkylation conditions to give the 3-{[4-
(tert-butyldiphenylsiloxy)butyl]amino} esters that were re-
duced to the enantiomers of the 3-aminooctanols 8S and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

C
I. Strassnig et al.
Paper
Synthesis
In contrast to these reduction reactions the oxidation of
alcohol 8S was found to be very difficult. Neither Swern ox-
idation, described as selective in the presence of secondary
amines,23 nor reaction with Dess–Martin periodinane24 af-
forded the desired aldehyde. To block the amino function of
enantiomers 8 from interfering with the oxidation process,
the benzyloxycarbonyl (Cbz) group was introduced under
Schotten–Baumann conditions (Scheme 2). Subsequent
Swern oxidation25 at –78 °C gave the aldehydes 9S and 9R in
high yields.
O
O
O
O
O
O
O
C5H11
OH
C5H11
O
t-BuOH, DMAP
4
81%
Ph
Ph
n-BuLi
Ph
N
n-BuLi
H
Ph
N
THF, – 78 °C
H
THF, – 78 °C
Ph
Ph
Ph
C5H11
6S
N
O
Ph
C5H11
6R
N
O
Ot-Bu
Ot-Bu
80%
81%
H2, Pd(OH)2/C
MeOH
NH2
O
NH2
O
C5H11
7S
Ot-Bu
C5H11
Ot-Bu
7R
81%
90%
O
45%
94%
TBDPSO
1.
5
Na(OAc)3BH, DCE
81%
2. LiAlH4, Et2O, 0 °C
95%
TBDPSO
OTBDPS
NH
HN
C5H11
C5H11
OH
OH
8R
8S
PhCH2OCOCl
1.
K2CO3 , EtOAc–H2O
92%
82%
TBDPSO
OTBDPS
2. (COCl)2; DMSO
Et3N, CH2Cl2, – 78 °C
91% 92%
Cbz
Cbz
N
N
C5H11
C5H11
O
O
9R
9S
Scheme 2 Synthesis of both enantiomers of 3-aminooctanal derivatives 9, see compound C in retrosynthetic Scheme 1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

D
I. Strassnig et al.
Paper
Synthesis
The condensation of 2,3,4-tri-O-pivaloyl-β-D-arabino-
pyranosylamine14c,26 (3) with the enantiomers of aldehydes
9S and 9R was carried out in n-pentane at room tempera-
ture in the presence of molecular sieves. After stirring for
22 hours, filtration through Hyflo®, and evaporation of the
solvent, the crude imines 10S and 10R were isolated as syr-
upy materials. Longer reaction times may result in the for-
mation of anomers of the imines that do not react in the fol-
lowing reaction. At –20 °C in dry tetrahydrofuran in the
presence of zinc chloride, imines 10S and 10R underwent
initial Mannich reaction with diene 2; it preferentially at-
tacks from the Re side.14,15 Subsequent Michael addition
and elimination of methanol afforded the 2-substituted
piperidinone derivatives 11 and 12 (Scheme 3). The diaste-
reoselectivity of the two conversions was dramatically dif-
ferent. While the Mannich reaction of 10S proceeded with
excellent stereoselectivity to yield 11 [Figure 2 (a)], that of
10R obviously constituted the mismatched case and gave
the diastereomers 12 and 13 in a ratio of only 2:1 in favor of
the desired precursor of tetraponerine-7 [Figure 2 (b)].
OTBDPS
OTBDPS
O
O
N
Ph
O
N
Ph
O
C5H11
O
C5H11
O
OPiv
OPiv
9R
9S
OPiv
NH2
O
3
molecular sieves 4 Å
pentane, 20 °C
OPiv
OPiv
OPiv
OPiv
OPiv
N
O
OPiv
N
O
N
O
Ph
OTBDPS
N
O
Ph
OTBDPS
O
O
OSi(Me)3
10S
10R
1)
H3CO
2
ZnCl2, THF, – 20 °C
2) 1 M HCl
OPiv
OPiv
OPiv
OPiv
O
O
OPiv
OPiv
N
O
N
O
Cbz
Cbz
12
N
N
OPiv
OPiv
O
11
OPiv
N
O
Cbz
59% from 9S
OTBDPS
OTBDPS
N
dr 98:1:1:0
13
58% from 9R
dr (12/13) = 2:1
OTBDPS
Scheme 3 Domino Mannich–Michael condensation cascade of N-arabinosyl imines 10S and 10R with diene 2 as matched and mismatched stereose-
lective processes
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

E
I. Strassnig et al.
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Synthesis
The low diastereoselectivity of the Mannich reaction in
case of the chiral aldimine 10R certainly is caused through
an interfering interaction of the urethane protecting group
with the promoting Lewis acid (Figure 4). The steering ef-
fect of the carbohydrate auxiliary in these processes is me-
diated by the coordination of the zinc chloride to the imine
nitrogen and to the carbonyl oxygen of the 2-O-pivaloyl
group (Figure 4, 10R, A).15 Because of the configuration of
this aldimine the carbonyl oxygen of the Cbz protecting
group is also in a favored position for cooperative coordina-
tion of the zinc ion. Thus, both diastereotopic sides of the
imine are shielded and the reaction with the nucleophile,
Danishefsky diene 2, logically is of lower selectivity.
Cl
Cl
Zn
O
OPiv
OPiv
O
O
N
C5H11
OTBDPS
N
Cbz
10R A
Cl
N
Cl
OPiv
OPiv
Zn
O
OPiv
C5H11
O
N
OTBDPS
Ph
O
Figure 2 Analytical HPLC of (a) piperidinone 11 obtained from 10S,
and (b) diastereomers 12/13 obtained from 10R
10R B
Figure 4 The role of the Cbz group in the mismatching coordination of
zinc chloride in nucleophilic attacks at 3-amino-substituted N-arabino-
syl aldimine 10R
The single diastereomer 11 formed from 9S in the
matched Mannich–Michael cascade and isolated after flash
chromatography surprisingly showed two sets of signals in
For further conversion of the pure N-arabinosyl-piper-
idinone derivative 11, reduction of the enone structure was
attempted with L-Selectride in tetrahydrofuran at –78 °C. In
contrast to closely related reactions the selective reduc-
tion15,27 of the C=C bond was not achievable in this way,
probably due to the urethane-functionalized side chain of
the compound. The reduction of the enone structure was
therefore carried out using sodium borohydride in ethanol
at room temperature to yield the piperidin-4-ol derivative
14 (Scheme 4) with high diastereoselectivity according to
TLC analysis. The reductive removal of the hydroxy group
was not possible by conversion into the xanthate and treat-
ment with tributyltin hydride28 or mesylation and reduc-
tion with lithium triethylborohydride (Super Hydride®)29 or
elimination using potassium tert-butoxide30 or DBU31 in
tetrahydrofuran. This problem was solved by treatment of
mesylate 15 with sodium iodide and zinc in boiling 1,2-di-
methoxyethane.32 A mixture of the desired piperidine de-
rivative 16 together with two elimination products 16a,b
1
its H NMR spectrum due to the rotamers of the urethane
protecting group. After hydrogenolysis of the Cbz group the
1
compound gave a clean H NMR spectrum, no signal dou-
bling remained (Figure 3).
Figure 3 1H NMR of piperidinone 11 in CDCl3 before (blue) and after
(red) hydrogenation
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

F
I. Strassnig et al.
Paper
Synthesis
was obtained. Only a sample of the major product 16 was
purified by chromatography, however the isolated mixture
was subjected to hydrogenolysis of the Cbz group concomi-
tantly resulting in saturation of the double bounds of 16a,b.
Removal of the TBDPS group from the obtained N-arabi-
nosyl piperidine 17 gave compound 18, which was subject-
ed to mild acidolytic removal of the auxiliary. Evaporation
of the solvent in vacuo and extraction with diethyl ether
quantitatively returned the arabinose auxiliary 19, which
after simple conversion can be re-introduced to the process.
Treatment of the remaining hydrochloride dissolved in wa-
ter with sodium carbonate and extraction with diethyl
ether allowed for the isolation of the pure piperidine deriv-
ative 20 with the (4-hydroxybutyl)amino side chain. The
now required oxidation of the alcohol to the aldehyde func-
tionality proved to be the most difficult problem due to the
presence of the secondary amine groups33 in 20. In a rare
example,34 Dess–Martin periodinane in dichloromethane
was used for the successful oxidation of an alcohol in the
presence of a secondary amine group within the molecule.
Application of these conditions to 20 resulted in an insepa-
rable mixture of products. Using Ley’s tetrapropylammoni-
um perruthenate (TPAP)35 and N-methylmorpholine N-ox-
ide, Kibayashi et al.36 successfully oxidized an alcohol in the
presence of a secondary amine and a phenol group. In this
case, the formed aldehyde was trapped in a semi-aminal
structure. This situation appeared similar to the oxidative
conversion of amino alcohol 20 into the tetraponerine ami-
nal structure. Treatment of 20 with catalytic tetrapro-
pylammonium perruthenate and two equivalents of N-
methylmorpholine N-oxide in dichloromethane in the pres-
ence of molecular sieves (4 Å) at room temperature actually
afforded the target compound 1. After the addition of 0.01
M sodium hydroxide in order to complete the aminal for-
mation and purification by flash chromatography, tet-
raponerine-8 (1) was isolated as a colorless oil that, accord-
O
OPiv
OPiv
OPiv
O
S
Me
OPiv
S
O
OH
OPiv
OPiv
Me
Cl
N
O
N
O
O
O
DMAP
Cbz
Cbz
NaBH4
N
N
11
14
pyridine, r.t.
98%
15
EtOH, r.t.
66%
DME, heat
> 72%
NaI, Zn
OTBDPS
OTBDPS
OPiv
OPiv
OPiv
OPiv
OPiv
OPiv
OPiv
OPiv
OPiv
OPiv
OPiv
OPiv
N
O
N
N
O
N
O
O
Cbz
Cbz
Cbz
N
H
N
N
+
H ,
2
N
Pd(OH)2/C
16b
+
16b
16
i-PrOH
17
56% rel. to 15
OTBDPS
OTBDPS
OTBDPS
OTBDPS
TBAF
THF
66%
OPiv
OPiv
1. TPAP, NMO, CH2Cl2
H
H
N
molecular sieves (4 Å)
powder, r.t.
HN
OPiv
OPiv
OPiv
1 M HCl
MeOH
N
O
OPiv
OH
N
H
H
O
+
H
2. 0.01 M NaOH
13%
N
N
1
18
20
19
quant.
93%
OH
OH
Scheme 4 Total synthesis of (+)-tetraponerine-8 from enantiomerically pure dehydropiperidinone 11
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

G
I. Strassnig et al.
Paper
Synthesis
ing to its NMR spectrum, was identical to the natural prod-
uct.1 The yield obtained after workup and purification was
rather low. This is due to a number of byproducts arising
from the interfering effect of the two amino functions in 20
during the oxidation reaction.
Swern oxidation of 21 using dimethyl sulfoxide/oxalyl
chloride resulted in the formation of the aldehyde with con-
comitant chlorination of the enaminone structure (Scheme
6). 5-Chloro-2,3-dihydropyridin-4(1H)-one 22, interesting
for further modification reactions of the piperidine portion,
was isolated after flash chromatography in 70% yield.
In order to prevent interferences caused by the amino
groups during the oxidation of the side chain alcohol, the
sequence of reactions was changed in the total synthesis of
Oxidation of the alcohol 21 with Dess–Martin perio-
dinane yielded the desired aldehyde 23 without side reac-
tion (Scheme 5). Its conversion into the protected 1,3-diox-
olane 24 using ethylene glycol in toluene under reflux was
not optimized; byproducts were formed due to the high
temperature used. Chromatographic purification gave 24 in
moderate yield. Reduction of the enaminone using sodium
borohydride in ethanol afforded the piperidin-4-ol 25,
which was subjected to mesylation to give mesylate 26 al-
most quantitatively. Its treatment with sodium iodide/zinc
in boiling 1,2-dimethoxymethane produced the reduced
compound together with the two dehydropiperidines as
was observed in the synthesis of tetraponerine-8 (Scheme
4). The mixture was subsequently subjected to hydrogeno-
lytic removal of the Cbz group with concomitant saturation
1
the diastereomer tetraponerine-7 (T7, 28). The H and 13C
NMR spectra of the mixture of diastereomers 12 and 13
(Scheme 2) showed a high degree of correspondence in the
signals of the piperidine part of compounds 12 and 11 thus
providing evidence that the major diastereomer 12 has 2S
configuration. The mixture 12/13 was treated with tetrabu-
tylammonium fluoride in tetrahydrofuran for removal of
the TBDPS group. After purification by flash chromatogra-
phy diastereomer 21 was isolated in highly enriched form
in 66% yield (Scheme 5). Regarding the difficulties in the fi-
nal oxidation reaction during the synthesis of tetraponer-
ine-8 (1), the conversion of the alcohol into the correspond-
ing aldehyde was performed at this stage.
OPiv
OPiv
OPiv
Dess–Martin
periodinane
HO
p-TsOH
OH
OPiv
O
O
OPiv
80%
TBAF
THF
OPiv
N
O
N
12/13
O
Cbz
toluene, heat
Cbz
CH2Cl2
N
N
21
23
66%
O
OH
O
OPiv
OPiv
OPiv
OPiv
OPiv
OPiv
Me
O
S
O
O
OH
Cbz
O
OPiv
N
OPiv
N
OPiv
O
S
N
O
O
O
Me
Cl
NaBH4
Cbz
Cbz
N
24
45%
pyridine, DMAP
r.t.
N
N
EtOH
r.t.
25
97%
54%
26
O
O
O
O
O
O
OPiv
OPiv
OPiv
56%
H
H
OPiv
OPiv
N
O
1. NaI, Zn
DME, heat
1. 1 M HCl
MeOH, r.t.
OPiv
OH
H
N
N
H
N
O
+
2. 2 M HCl, Et2O
r.t.
27
2. H2, Pd(OH)2/C
28
19
78%
3 steps
i-PrOH
O
O
Scheme 5 Total synthesis of (+)-tetraponerine-7 from dehydropiperidinones 12/13
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

H
I. Strassnig et al.
Paper
Synthesis
Cl
OPiv
OPiv
OPiv
OPiv
O
O
OPiv
OPiv
N
O
N
O
(COCl)2, DMSO
Et3N
Cbz
Cbz
N
N
CH2Cl2
22
21
70%
OH
O
Scheme 6 Chlorination of the enaminone during Swern oxidation of alcohol 21
of the carbon–carbon double bonds of the byproducts to
furnish the piperidine 27 in satisfying yield after the two
steps.
oxidation of this alcohol function was performed as the fi-
nal step immediately resulting in the aminal structure
(Scheme 4).
In the concluding part of the total synthesis of natural
tetraponerine-7 (28), cleavage from the arabinose auxiliary
and solvolysis of the acetal protection are achieved by aci-
dolysis. Treatment of 27 with dilute hydrochloric acid in
methanol at room temperature detached the precursor of
the alkaloid from the carbohydrate auxiliary, and also ef-
fected solvolysis of the acetal to some extent. To complete
the acetal hydrolysis the solvent was evaporated and the re-
maining substances were treated with aqueous 2 M hydro-
gen chloride and diethyl ether. The arabinose auxiliary 19
can be recovered from the ether solution, while the water
solution was brought to pH 8 with 10% aqueous sodium hy-
droxide; extraction with dichloromethane gave the pure
natural tetraponerine-7 (28) in 78% yield after three steps.
Both enantiomerically pure natural alkaloids are stereo-
selectively accessible using the same arabinopyranosyl-
amine auxiliary, which induces the (S)-configuration at the
α-position of the crucial piperidinone intermediates [which
becomes the (R)-configuration at C6a in the target com-
pounds 1 and 28]. After disconnection from the stereoselec-
tively synthesized tetraponerine precursors, the arabinosyl
auxiliary 19 can quantitatively be recovered. A series of ho-
mologues in the piperidine, as well as in the pyrrolidine
ring, of these alkaloids are accessible using this strategy by
modification of the alk-2-enoic acid and/or the N-(sil-
oxy)alkyl component. It also can be translated to the syn-
thesis of bis-pyrrolidino tetraponerines T1, T2, T5, and T6 if
glycosyl imines of type 10 are reacted with allylsilanes14c or
allylstannanes and the stereoselectively formed homoallyl-
amines are subjected to ring-closing iodoamination.37
Preliminary investigations of the insecticidal effects
showed that racemic tetraponerine-8 prepared according to
the procedure described by Barluenga et al.9b had a 100%
mortal effect on Plutella xylostella (diamond back moth) in a
concentration of 500 ppm. The racemate of 1 also killed
75% of Myzus persicae (green peach aphid) at a concentra-
tion of 300 ppm. Surprisingly, the synthesized natural (+)-
tetraponerine-8 (1) exhibited no toxic effects on both or-
ganisms in identical concentrations. Further studies are
needed to clarify this astonishing result.
1
According to its H NMR spectrum, the product 28 is
identical with natural tetraponerine-7. In NOESY NMR ex-
periments a cross-peak between H6a and H11a gives evi-
dence of the correct annulation of the six-membered rings
(Figure 5). The absence of any cross-peak between H6a and
the proton at C5 confirms the correct configuration at C5.
H
6a
H
5
H
6a
H
H
5
H
N 11a
N
N11a
N
1
28
Figure 5 1H NMR NOE experiments confirming the configuration of
(+)-tetraponerine-7 (28) and (+)-tetraponerine-8 (1)
Solvents for moisture-sensitive reactions (THF, MeOH, CH2Cl2) were
distilled and dried according to standard procedures.18 Reactions
were monitored by TLC with pre-coated silica gel 60 F254 aluminum
plates (Merck). Flash column chromatography was performed with
silica gel (35–70 μm) from Agros Chemicals. 1H, 13C, and 2D NMR
spectra were recorded with Bruker AC-300, AM-400, or AV-400 spec-
trometers. Assignment of proton and carbon signals was achieved by
additional COSY and HMQC experiments when noted. FD-MS were
recorded on a Finnigan MAT-95 instrument; ESI-MS were measured
on a Micromass-Q-TOF-Ultima-3 instrument, which when equipped
with a LockSpray interface also served for measuring HRMS-ESI. Opti-
cal rotations [α]D were measured with a Perkin Elmer polarimeter
In the 1H NMR spectrum of tetraponerine-8 (1), the NOE
contacts between H5, H6a, and H11a document the cis lo-
cation of H5, H-6a, and H11a.
The strategy pursued in the synthesis of (+)-tetraponer-
ine-7 (Scheme 5), involving the early oxidation of the pri-
mary side chain alcohol and protection of the formed alde-
hyde as an acetal prior to the removal of the N-protecting
group, was more efficient compared to the route used for
the synthesis of natural (+)-tetraponerine-8, in which the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

I
I. Strassnig et al.
Paper
Synthesis
241. RP-HPLC was performed using a Knauer Maxi-Star K-1000 gradi-
ent pump, a Knauer four-channel degasser and a Knauer diode array
detector DAD K-2800 with application of Knauer Chromgate soft-
ware. A Luna C18 RP column (Phenomenex) was used for analytical
measurements (flow rate 1 mL/min). Semi-preparative RP-HPLC sep-
arations were performed on a Knauer HPLC system consisting of two
Knauer K-500 pumps and a Phenomenex Luna C18 column at a flow
rate of 10 mL/min.
13C NMR (75.4 MHz, CDCl3): δ = 172.41 (C=O), 143.29, 142.23 (C1Ar),
128.34, 128.27, 128.20, 128.08 (C2Ar, C3Ar, C5Ar, C6Ar), 127.00, 126.63
(C4Ar), 80.01 [C(CH3)3], 58.49 (NCHCH3), 54.05 (CHCH2CO2), 50.22
(NCH2Ph), 37.97 (CH2CO2), 33.58, 31.95, 26.73, 22.83 (C4, C5, C6, C7),
28.19 [C(CH3)3], 20.63 (NCHCH3), 14.24 (CH3CH2).
MS (FD): m/z = 409.0 [M+].
tert-Butyl (R)-3-{Benzyl[(S)-1-phenylethyl]amino}octanoate (6R)
Following the typical procedure for 6S using tert-butyl (E)-oct-2-
enoate (4; 5.9 g, 29.8 mmol), (R)-N-benzyl-1-phenylethylamine (10
mL), anhyd THF (150 mL), and 1.6 M BuLi in hexane (28 mL) gave 6R
as a yellowish oil; yield: 9.85 g (81%); Rf = 0.71 (cyclohexane–EtOAc,
19:1); [α]D23 +6.27 (c 1, CHCl3) [Lit.21 [α]D20 +7.60 (c 1.4, CHCl3)].
tert-Butyl (E)-Oct-2-enoate (4)
To a solution of Boc2O (21.7 g, 0.1 mol) in t-BuOH (150 mL) was added
DMAP (1.8 g, 0.15 mol). After dissolution, (E)-oct-2-enoic acid (7.5
mL, 7.07 g, 0.05 mol) was added dropwise. Evolution of CO2 started
immediately, and within 15 min the color of the solution changed
from yellow to orange and to reddish-brown. The mixture was stirred
at r.t. for 4 h and then the solvent was evaporated in vacuo. The resi-
due was dissolved in CH2Cl2 (200 mL), washed with 1 M HCl (150 mL),
sat. NaHCO3 solution (150 mL), and H2O (150 mL). The solution was
dried (MgSO4) and the solvent was evaporated in vacuo. The brown
crude product was purified either by distillation in vacuo to give the
product as a colorless oil; yield: 5.2 g (52%); bp 100 °C/22 mbar (Lit.18
bp 100–120 °C/1.33 mbar); or purification was carried out by flash
chromatography (cyclohexane–EtOAc, 30:1) to give the product as a
yellowish oil; yield: 8.01 g (81%); Rf = 0.58 (cyclohexane–EtOAc, 30:1).
1H NMR (400 MHz, CDCl3): δ = 6.84 (dt, J3,2 = 15.6 Hz, J3,4 = 6.9 Hz, 1 H,
CH=CHCO), 5.71 (dt, J2,3 = 15.6 Hz, J2,4 = 1.5 Hz, 1 H, CH=CHCO), 2.14
(qd, J4,5 = J4,3 = 7.3 Hz, J4,2 = 1.5 Hz, 2 H, CH2CH=CH), 1.46 [s, 9 H,
C(CH3)3], 1.44–1.40 (m, 2 H, CH2), 1.31–1.25 (m, 4 H, 2 CH2), 0.87 (t,
J = 7.0 Hz, 3 H, CH3).
13C NMR (100.6 MHz, CDCl3): δ = 166.32 (C=O), 148.32 (CH=CHCO),
122.99 (CH=CHCO), 80.04 [C(CH3)3], 32.13 (CH2CH=CH), 31.46 (CH2),
28.26 [C(CH3)3], 27.88 (CH2), 22.56 (7-CH2), 14.07 (CH3CH2).
1H NMR (300 MHz, CDCl3): δ = 7.61–7.08 (m, 10 H, HAr), 3.86–3.74 (m,
2
H, NCHCH3, NCHaCHbPh), 3.48 (d, JNCHb,NCHa = 15.0 Hz, 1 H,
NCHaCHbPh), 3.36–3.22 (m, 1 H, CHCH2CO2), 1.96 (dd, JH2a,H2b = 14.6
Hz, JH2a,H3 = 3.8 Hz, 1 H, CHaHbCO2), 1.87 (dd, JH2b,H2a = 14.6 Hz,
JH2b,H3 = 9.1 Hz, 1 H, CHaHbCO2), 1.63–1.13 (m, 8 H, 4-CH2, 5-CH2, 6-
CH2, 7-CH2), 1.40 [s, 9 H, C(CH3)3], 1.33 (d, JαCHCH3,αCH = 7.0 Hz, 3 H,
NCHCH3), 0.89 (t, J = 7.1 Hz, 3 H, CH3CH2).
13C NMR (75.4 MHz, CDCl3): δ = 172.41 (C=O), 143.30, 142.24 (C1Ar),
128.34, 128.27, 128.20, 128.08 (C2Ar, C3Ar, C5Ar, C6Ar), 127.00, 126.63
(C4Ar), 80.01 [C(CH3)3], 58.49 (NCHCH3), 54.07 (CHCH2CO2), 50.22
(NCH2Ph), 37.98 (CH2CO2), 33.58, 31.95, 26.73, 22.83 (C4, C5, C6, C7),
28.19 [C(CH3)3], 20.63 (NCHCH3), 14.24 (CH3CH2).
tert-Butyl (S)-3-Aminooctanoate (7S); Typical Procedure
To aminooctanoic ester 6S (8.0 g, 19.5 mmol) dissolved in MeOH (100
mL) was added 10% Pd(OH)2/C (2.0 g). The mixture was stirred under
H2 at r.t. for 3 d. After filtration through Hyflo® the solvent was evap-
orated in vacuo. The crude product was purified by flash chromatog-
raphy (EtOAc–MeOH, 9:1) to give a colorless oil; yield: 3.4 g (81%);
98.7% ee [chiral GC analysis (injector: 220 °C, column: 130 °C, detec-
tor: 150 °C, flow: 2.0 mL/min): tR = 5.31, 5.67 min, space ratio:
tert-Butyl (S)-3-{Benzyl[(S)-1-phenylethyl]amino}octanoate (6S);
Typical Procedure
23
0.66:99.34]; Rf = 0.15 (EtOAc–MeOH, 9:1); [α]D +13.8 (c 0.7, CHCl3)
(S)-N-Benzyl-1-phenylethylamine (8.5 mL, 8.59 g, 40.6 mmol) was
dissolved in anhyd THF (130 mL) and cooled to –78 °C; 1.6 M BuLi in
n-hexane (23.6 mL, 37.8 mmol) was slowly added dropwise and the
color changed from pale rose to pink. The mixture was stirred at
–78 °C for 30 min, and then a solution of tert-butyl (E)-oct-2-enoate
(4; 5 g, 25.5 mmol) in anhyd THF (20 mL) was added. The solution was
stirred at –78 °C under argon for 3 h. Subsequently sat. aq NH4Cl (50
mL) was added, and the solution was allowed to warm up to r.t. THF
was evaporated in vacuo. H2O (150 mL) was added to the residue, and
the solution was extracted with CH2Cl2 (3 × 100 mL). The combined
organic extracts were washed with brine (200 mL) and dried (MgSO4),
and the solvent was evaporated in vacuo to yield a yellow, slightly vis-
cous liquid (13.3 g), which was purified by flash chromatography (cy-
clohexane–EtOAc, 19:1) to give a colorless oil; yield: 8.35 g (80%);
[Lit.21 (R)-enantiomer: [α]D20 –14.3 (c 0.7, CHCl3)].
1H NMR (300 MHz, CDCl3): δ = 3.20–3.05 (m, 1 H, CHNH2), 2.37 (dd,
JH2a,H2b = 15.5 Hz, JH2a,H3 = 4.1 Hz,
1 H, CHaCHbCO2), 2.16 (dd,
JH2b,H2a = 15.6 Hz, JH2b,H3 = 8.8 Hz, 1 H, CHaCHbCO2), 1.76 (s, 2 H, NH2),
1.44 [s, 9 H, C(CH3)3)], 1.40–1.21 (m, 8 H, 4-CH2, 5-CH2, 6-CH2, 7-CH2),
0.87 (t, J8-CH3,7-CH2 = 6.6 Hz, 3 H, CH3CH2).
13C NMR (75.4 MHz, CDCl3): δ = 171.95 (C=O), 80.39 [C(CH3)3], 48.40
(CHNH2), 43.69 (CH2CO2), 37.33, 31.78, 25.68, 22.56 (C4, C5, C6, C7),
28.10 [C(CH3)3], 14.12 (CH3CH2).
MS (ESI): m/z = 216.2 [M + H]+, 238.2 [M + Na]+.
tert-Butyl (R)-3-Aminooctanoate (7R)
Following the typical procedure for 7S using 6R (9.82 g, 24.0 mmol),
10% Pd(OH)2/C (2.4 g), and i-PrOH (90 mL) gave a colorless oil; yield:
4.67 g (90%); Rf = 0.13 (EtOAc–MeOH, 9:1); [α]D23 –13.26 (c 0.7, CHCl3)
[Lit.21 [α]D20 –14.3 (c 0.7, CHCl3)].
1H NMR (300 MHz, CDCl3): δ = 3.26–3.11 (m, 1 H, CHNH2), 2.95 (s, 2
H, NH2), 2.41 (dd, JH2a,H2b = 15.9 Hz, JH2a,H3 = 4.0 Hz, 1 H, CHaCHbCO2),
2.24 (dd, JH2b,H2a = 15.8 Hz, JH2b,H3 = 8.6 Hz, 1 H, CHaCHbCO2), 1.44 [s,
9 H, C(CH3)3], 1.41–1.19 (m, 8 H, 4-CH2, 5-CH2, 6-CH2, 7-CH2), 0.87 (t,
J8-CH3,7-CH2 = 6.6 Hz, 3 H, CH3CH2).
23
Rf = 0.74 (cyclohexane–EtOAc, 19:1); [α]D –7.60 (c 1.4, CHCl3) [Lit.21
(R,R)-enantiomer: [α]D20 +7.60 (c 1.4, CHCl3)].
1H NMR (300 MHz, CDCl3): δ = 7.53–7.17 (m, 10 H, HAr), 3.82 (q,
JαCH,αCHCH3 = 7.1 Hz, 1 H, NCHCH3), 3.80 (d, JNCHa,NCHb = 15.1 Hz, 1 H,
NCHaCHbPh), 3.49 (d, JNCHb,NCHa = 15.0 Hz, 1 H, NCHaCHbPh), 3.38–3.23
(m, 1 H, CHCH2CO2), 1.96 (dd, JH2a,H2b = 14.5 Hz, JH2a,H3 = 3.8 Hz, 1 H,
CHaHbCO2), 1.87 (dd, JH2b,H2a = 14.5 Hz, JH2b,H3 = 9.2 Hz, 1 H, CHaHbCO2),
1.65–1.09 (m, 8 H, 4-CH2, 5-CH2, 6-CH2, 7-CH2), 1.41 [s, 9 H, C(CH3)3],
1.33 (d, JαCHCH3,αCH = 7.0 Hz, 3 H, NCHCH3), 0.89 (t, J8-CH3,7-CH2 = 7.1 Hz, 3
H, CH3CH2).
13C NMR (75.4 MHz, CDCl3): δ = 172.30 (C=O), 81.13 [C(CH3)3], 48.67
(CHNH2), 42.55 (CH2CO2), 36.83, 31.83, 25.68, 22.66 (C4, C5, C6, C7),
28.22 [C(CH3)3], 14.12 (CH3CH2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

J
I. Strassnig et al.
Paper
Synthesis
tert-Butyl (S)-3-{[4-(tert-Butyldiphenylsiloxy)butyl]amino}octan-
oate; Typical Procedure
was evaporated in vacuo. The product 8S was sufficiently pure for fur-
ther conversion. Colorless oil; yield: 4.94 g (95%); Rf = 0.22 (EtOAc–
MeOH, 3:1); [α]D23 +18.1 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3, COSY): δ = 7.72–7.60 (m, 4 H, HAr), 7.46–
7.34 (m, 6 H, HAr), 3.87 (ddd, JH1a,H1b = 10.8 Hz, JH1a,H2a = 6.1 Hz,
To a solution of 7S (3.3 g, 15.3 mmol) in DCE (70 mL) at 0 °C was add-
ed a solution of 4-(tert-butyldiphenylsiloxy)butanal22 (5; 5.3 g, 16.2
mmol) in DCE (90 mL). The mixture was stirred for 15 min and, sub-
sequently, NaB(OAc)3H (6.5 g, 30.6 mmol) was added. The solution
was stirred at r.t. for 14 h. The solvent was evaporated in vacuo. EtOAc
(150 mL) and sat. NaHCO3 solution (200 mL) were added to the resi-
due. The aqueous solution was extracted with EtOAc (2 × 50 mL) and
the combined organic layers were washed with brine (2 × 150 mL)
and dried (MgSO4), and the solvent was evaporated in vacuo. The
product was purified by flash chromatography (cyclohexane–EtOAc,
3:1) to give a pale yellow oil; yield: 6.5 g (81%); Rf = 0.27 (cyclohex-
ane–EtOAc, 2:1); [α]D23 +2.1 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3, COSY): δ = 7.71–7.62 (m, 4 H, HAr), 7.46–
7.33 (m, 6 H, HAr), 3.66 (t, J4′-CH2,3′-CH2 = 6.1 Hz, 2 H, CH2OSi), 2.93–2.85
(m, 1 H, CHCH2CO2), 2.57 (t, J1′-CH2,2′-CH2 = 7.0 Hz, 2 H, NHCH2), 2.31 (d,
J2-CH2,H3 = 6.3 Hz, 2 H, CH2CO2), 1.65–1.48 (m, 4 H, 2′-CH2, 3′-CH2), 1.45
[s, 9 H, CO2C(CH3)3], 1.40–1.23 (m, 8 H, 4-CH2, 5-CH2, 6-CH2, 7-CH2),
1.04 [s, 9 H, SiC(CH3)3], 0.89 (t, J8-CH3,7-CH2 = 6.9 Hz, 3 H, CH3CH2).
JH1a,H2b = 3.3 Hz,
JH1b,H2b = 8.4 Hz, JH1b,H2a = 3.0 Hz, 1 H, CHaHbOH), 3.66 (t, J4′-CH2,3′-CH2
6.0 Hz, 2 H, CH2OSi), 2.77–2.64 (m, 2 H, H3, NHCHaHb), 2.62–2.53 (m,
H, NHCHaHb), 1.73 (ddt, JH2a,H2b = 14.5 Hz, JH2a,H1a = 6.1 Hz,
1 H, CHaHbOH), 3.76 (ddd, JH1b,H1a = 10.9 Hz,
=
1
JH2a,H1b = JH2a,H3 = 3.0 Hz, 1 H, H2a), 1.64–1.50 and 1.40–1.21 (2 × m, 5
H, 7 H, 2′-CH2, 3′-CH2, 4-CH2, 5-CH2, 6-CH2, 7-CH2), 1.48–1.41 (m, 1 H,
H2b), 1.05 [s, 9 H, C(CH3)3], 0.90 (t, J8-CH3,7-CH2 = 6.9 Hz, 3 H, CH3CH2).
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 135.69, 127.74 (C2Ar, C3Ar,
C5Ar, C6Ar), 134.09 (C1Ar), 129.67 (C4Ar), 63.81 (CH2OSi), 62.90
(CH2OH), 59.43 (C3), 46.59 (NHCH2), 33.99 (C4), 33.58 (C2), 32.09,
30.42, 26.96, 25.77, 22.74 (C5, C6, C7, C2′, C3′), 26.99 [C(CH3)3], 19.34
[C(CH3)3], 14.17 (CH3CH2).
MS (ESI): m/z = 456.3 [M + H]+.
HRMS: m/z [M + H] calcd for C28H46NO2Si (455.75): 456.3298; found:
456.3311.
13C NMR (100.6 MHz, CDCl3, DEPT, HMQC): δ = 172.27 (C=O), 135.70,
127.72 (C2Ar, C3Ar, C5Ar, C6Ar), 134.17 (C1Ar), 129.64 (C4Ar), 80.42
[C(CH3)3], 63.96 (CH2OSi), 55.11 (C3), 46.93 (NHCH2), 40.61 (CH2CO2),
34.59, 32.15, 30.63, 27.02, 25.58, 22.75 (C4, C5, C6, C7, C2′, C3′), 28.26
[CO2C(CH3)3], 26.99 [SiC(CH3)3], 19.34 [SiC(CH3)3], 14.20 (CH3CH2).
Anal. Calcd for C28H45NO2Si: C, 73.79; H, 9.95; N, 3.07. Found: C,
73.58; H, 9.98; N, 5.02.
(R)-3-{[4-(tert-Butyldiphenylsiloxy)butyl]amino}octanol (8R)
MS (ESI): m/z = 470.3 [M – Ot-Bu + H2O]+, 526.3 [M + H]+, 548.3 [M +
Following the typical procedure for 8S using tert-butyl (R)-3-{[4-
(tert-butyldiphenylsiloxy)butyl]amino}octanoate (4.93 g, 9.38
mmol), 1 M LiAlH4 (9.9 mL, 9.9 mmol), and anhyd Et2O (45 mL) gave a
colorless oil; yield: 4.01 g (94%); Rf = 0.04 (cyclohexane–EtOAc, 3:1);
[α]D23 –17.1 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.71–7.61 (m, 4 H, HAr), 7.46–7.33 (m,
6 H, HAr), 3.87 (ddd, JH1a,H1b = 10.7 Hz, JH1a,H2a = 6.1 Hz, JH1a,H2b = 3.4 Hz,
1 H, CHaHbOH), 3.80–3.72 (m, 1 H, CHaHbOH), 3.67 (t, J4′-CH2,3′-CH2 = 5.8
Hz, 2 H, CH2OSi), 2.79–2.64 (m, 2 H, H3, NHCHaHb), 2.63–2.52 (m, 1 H,
NHCHaHb), 1.73 (ddt, JH2a,H2b = 14.4 Hz, JH2a,H1a = 6.1 Hz,
JH2a,H1b = JH2a,H3 = 3.0 Hz, 1 H, H2a), 1.64–1.14 (m, 13 H, 2′-CH2, 3′-CH2,
Na]+.
HRMS: m/z [M + H] calcd for C32H52NO3Si: 526.3716; found: 526.3709.
Anal. Calcd for C32H51NO3Si: C, 73.09; H, 9.78; N, 2.66. Found: C,
73.07; H, 9.86; N, 4.02.
tert-Butyl (R)-3-{[4-(tert-Butyldiphenylsiloxy)butyl]amino}octa-
noate
Following the typical procedure for the S-enantiomer using 7R (4.62
g, 21.5 mmol), 4-(tert-butyldiphenylsiloxy)butanal22 (5; 7.35 g, 22.5
mmol), DCE (200 mL), and NaB(OAc)3H (8.9 g, 42.0 mmol) gave a pale
yellow oil; yield: 4.93 g (9.38 mmol, 45%); Rf = 0.15 (cyclohexane–
EtOAc, 7:2); [α]D23 –2.6 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.73–7.59 (m, 4 H, HAr), 7.48–7.31
(m, 6 H, HAr), 3.67 (t, J4′-CH2,3′-CH2 = 5.9 Hz, 2 H, CH2OSi), 2.95–2.85 (m,
1 H, CHCH2CO2), 2.59 (t, J1′-CH2,2′-CH2 = 6.8 Hz, 2 H, NHCH2), 2.32 (d,
J2-CH2,H3 = 6.2 Hz, 2 H, CH2CO2), 1.67–1.48 (m, 4 H, 2′-CH2, 3′-CH2), 1.45
[s, 9 H, CO2C(CH3)3], 1.36–1.20 (m, 8 H, 4-CH2, 5-CH2, 6-CH2, 7-CH2),
1.05 [s, 9 H, SiC(CH3)3], 0.89 (t, J8-CH3,7-CH2 = 6.7 Hz, 3 H, CH3CH2).
H2b, 4-CH2, 5-CH2, 6-CH2, 7-CH2), 1.05 [s, 9 H, C(CH3)3], 0.90 (t, J8-CH3,7-CH2
6.7 Hz, 3 H, CH3CH2).
=
13C NMR (75.4 MHz, CDCl3): δ = 135.67, 127.73 (C2Ar, C3Ar, C5Ar, C6Ar),
134.07 (C1Ar), 129.67 (C4Ar), 63.79 (CH2OSi), 62.80 (CH2OH), 59.39
(C3), 46.52 (NHCH2), 33.89 (C4), 33.53 (C2), 32.07, 30.39, 26.87, 25.76,
22.72 (C5, C6, C7, C2′, C3′), 26.99 [C(CH3)3], 19.33 [C(CH3)3], 14.16
(CH3CH2).
MS (ESI): m/z = 456.3 [M + H]+.
HRMS: m/z [M + H] calcd for C28H46NO2Si (455.75): 456.3298; found:
456.3299.
13C NMR (75.4 MHz, CDCl3): δ = 172.26 (C=O), 135.69, 127.72 (C2Ar
,
C3Ar, C5Ar, C6Ar), 134.15 (C1Ar), 129.64 (C4Ar), 80.52 [C(CH3)3], 63.94
(CH2OSi), 55.13 (C3), 46.86 (NHCH2), 40.41 (CH2CO2), 34.42, 32.10,
30.59, 26.90, 25.57, 22.74 (C4, C5, C6, C7, C2′, C3′), 28.26 [CO2C(CH3)3],
26.99 [SiC(CH3)3], 19.33 [SiC(CH3)3], 14.19 (CH3CH2).
(S)-3-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsiloxy)but-
yl]amino}octanol; Typical Procedure
To a solution of 8S (4.9 g, 10.8 mmol) in EtOAc (70 mL) at 0 °C was
added H2O (70 mL), K2CO3 (3.0 g, 21.5 mmol), and finally benzyl chlo-
roformate (3.1 mL, 3.7 g, 21.5 mmol). The ice bath was removed and
the mixture stirred at r.t. for 90 min. After the addition of 1 M KH2PO4
solution (250 mL) the layers were separated and the aqueous layer
was extracted with EtOAc (3 × 80 mL). The combined organic layers
were washed with brine (200 mL), dried (MgSO4) and the solvent was
evaporated in vacuo. The crude product was purified by flash chro-
matography (cyclohexane–EtOAc, 6:1) to give a pale yellow oil; yield:
HRMS: m/z [M + H] calcd for C32H52NO3Si: 526.3716; found: 526.3717.
(S)-3-{[4-(tert-Butyldiphenylsiloxy)butyl]amino}octanol (8S);
Typical Procedure
To tert-butyl (S)-3-{[4-(tert-butyldiphenylsiloxy)butyl]amino}octa-
noate (6.0 g, 11.4 mmol) in anhyd Et2O (55 mL) at 0 °C was added
dropwise 4 M LiAlH4 in Et2O (3 mL, 12.0 mmol). The mixture was
stirred for 90 min at 0 °C and then cautiously and sequentially H2O
(0.5 mL), 15% aq NaOH solution (0.5 mL), and H2O (1.5 mL) were add-
ed. After filtration the solution was dried (MgSO4) and the solvent
23
5.86 g (92%); Rf = 0.24 (cyclohexane–EtOAc, 4:1); [α]D –2.0 (c 1,
CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

K
I. Strassnig et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3, COSY): δ = 7.70–7.59 (m, 4 H, HAr, SiPh2),
7.46–7.28 (m, 11 H, HAr, SiPh2 and Bn), 5.22–5.08 (m, 2 H, PhCH2),
4.34–4.19R, 4.15–3.98 (m, 1 H, H3), 3.68, 3.63R (t, J4′-CH2,3′-CH2 = 6.0 Hz,
2 H, CH2OSi), 3.59–3.56, 3.56–3.50R (m, 1 H, CHaHbOH), 3.41R (dt, 1 H,
tracts were washed with brine (120 mL), 2 M HCl (100 mL), and sat.
NaHCO3 solution (120 mL) and dried (MgSO4). The solvent was evapo-
rated in vacuo and the residue was purified by flash chromatography
(cyclohexane–EtOAc, 8:1) to give a colorless oil; yield: 4.98 g (91%);
Rf = 0.26 (cyclohexane–EtOAc, 8:1); [α]D23 –6.5 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3, COSY): δ = 9.79–9.56 (m, 1 H, CHO), 7.73–
7.58 (m, 4 H, HAr, SiPh2), 7.47–7.27 (m, 11 H, HAr, SiPh2, Bn), 5.22–5.06
(m, 2 H, PhCH2), 4.43–4.27 (m, 1 H, H3), 3.68, 3.63R (t, J4′-CH2,3′-CH2 = 6.1
Hz, 2 H, CH2OSi), 3.22–3.06 (m, 2 H, NCH2), 2.80–2.51 (m, 2 H,
CH2CHO), 1.74–1.45 (m, 6 H, 4-CH2, 2′-CH2, 3′-CH2), 1.37–1.13 (m, 6
H, 5-CH2, 6-CH2, 7-CH2), 1.05 [s, 9 H, C(CH3)3], 0.92–0.80 (m, 3 H,
CH3CH2).
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 200.94R, 200.41 (CHO),
156.26R, 156.18 (C=O), 136.91R, 136.75 (C1′Ar, Bn), 135.67, 127.76
(C2Ar, C3Ar, C5Ar, C6Ar, SiPh2), 133.98 (C1Ar, SiPh2), 129.72 (C4Ar, SiPh2),
128.59, 128.22R, 128.00, 127.71 (C2′Ar, C3′Ar, C4′Ar, C5′Ar, C6′Ar, Bn),
67.31, 67.01R (PhCH2), 63.67, 63.60R (CH2OSi), 52.99R, 52.17 (C3),
48.57, 48.01R (CH2CHO), 45.48, 45.33R (NCH2), 33.80, 33.24R, 31.66,
30.27, 26.70R, 26.21, 26.31R, 25.85, 22.65 (C4, C5, C6, C7, C2′, C4′),
26.98 [C(CH3)3], 19.31 [C(CH3)3], 14.12 (CH3CH2).
JH1b,H1a = 11.4 Hz, JH1b,2-CH2 = 3.0 Hz, CHaHbOH), 3.08, 3.02R (t, J1′-CH2,2′-CH2
=
7.4 Hz, 2 H, NCH2), 1.81–1.70R (m, 1 H, H2a), 1.70–1.46 (m, 7 H, H2b,
4-CH2, 2′-CH2, 3′-CH2), 1.34–1.19 (m, 6 H, 5-CH2, 6-CH2, 7-CH2), 1.04
[s, 9 H, C(CH3)3], 0.92–0.82 (m, 3 H, CH3CH2).
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 158.28R, 156.53 (C=O),
136.83 (C1′Ar, Bn), 135.66, 127.76 (C2Ar, C3Ar, C5Ar, C6Ar, SiPh2), 133.95
(C1Ar, SiPh2), 129.74 (C4Ar, SiPh2), 129.69 (C4′Ar, Bn), 128.69, 128.62R,
128.24, 128.10R (C2′Ar, C3′Ar, C5′Ar, C6′Ar, Bn), 67.41R, 67.23 (PhCH2),
63.75, 63.60R (CH2OSi), 59.64, 58.84R (CH2OH), 52.78 (C3), 42.44
(NCH2), 36.39, 35.97R (C2), 33.75, 33.26R, 31.76, 30.46, 27.08, 26.48R,
26.33, 22.69, (C4, C5, C6, C7, C2′, C4′), 26.96 [C(CH3)3], 19.31 [C(CH3)3],
14.15 (CH3CH2).
MS (ESI): m/z = 590.4 [M + H]+, 612.3 [M + Na]+, 628.3 [M + K]+, 1201.7
[2 M + Na]+.
HRMS: m/z [M + Na] calcd for C36H51NO4SiNa: 612.3485; found:
612.3497.
MS (ESI): m/z = 588.4 [M + H]+, 610.4 [M + Na]+, 626.4 [M + K]+, 1197.7
Anal. Calcd for C36H51NO4Si: C, 73.30; H, 8.71; N: 2.37. Found: C,
73.01; H, 8.56; N, 2.43.
[2 M + Na]+.
HRMS: m/z [M + Na] calcd for C36H49NO4SiNa: 610.3329; found:
610.3318.
(R)-3-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsiloxy)but-
yl]amino}octanol
Anal. Calcd for C36H49NO4Si: C, 73.55; H, 8.40; N, 2.38. Found C: 72.25;
H, 8.11; N, 3.24.
Following the typical procedure for the S-enantiomer using 8R (3.92
g, 8.6 mmol), K2CO3 (2.37 g, 17.1 mmol), benzyl chloroformate (2.5
mL, 17.6 mmol), EtOAc (56 mL) and H2O (56 mL) gave a pale yellow
oil; yield: 4.18 g (82%); Rf = 0.23 (cyclohexane–EtOAc, 4:1); [α]D23 +1.8
(c 1, CHCl3).
(R)-3-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsiloxy)but-
yl]amino}octanal (9R)
Following the typical procedure for 9S using (R)-3-{(benzyloxycar-
bonyl)[4-(tert-butyldiphenylsiloxy)butyl]amino}octanol (4.13 g, 7.0
mmol), oxalyl chloride (0.68 mL, 7.9 mmol), DMSO (1.1 mL, 15.5
mmol), anhyd CH2Cl2 (35 mL), and Et3N (4.8 mL, 34.6 mmol) gave a
slightly yellow oil; yield: 3.77 g (92%); Rf = 0.26 (cyclohexane–EtOAc,
8:1); [α]D23 +5.4 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 9.79–9.56 (m, 1 H, CHO), 7.73–7.55 (m,
4 H, HAr, SiPh2), 7.48–7.22 (m, 11 H, HAr, SiPh2 and Bn), 5.19–4.99 (m, 2
H, PhCH2), 4.42–4.23 (m, 1 H, H3), 3.73–3.51 (m, 2 H, CH2OSi), 3.21–
3.02 (m, 2 H, NCH2), 2.81–2.46 (m, 2 H, CH2CHO), 1.71–1.44 (m, 6 H,
4-CH2, 2′-CH2, 3′-CH2), 1.32–1.12 (m, 6 H, 5-CH2, 6-CH2, 7-CH2), 1.02
[s, 9 H, C(CH3)3], 0.92–0.75 (m, 3 H, CH3CH2).
13C NMR (75.4 MHz, CDCl3): δ = 200.96R, 200.43 (CHO), 156.26 (C=O),
136.96 (C1′Ar, Bn), 135.69, 127.77 (C2Ar, C3Ar, C5Ar, C6Ar, SiPh2), 134.01
(C1Ar, SiPh2), 129.73 (C4Ar, SiPh2), 128.61, 128.21, 128.02 (C2′Ar, C3′Ar,
C4′, C5′Ar, C6′Ar, Bn), 67.33, 67.03R (PhCH2), 63.70, 63.63R (CH2OSi),
53.02R, 52.20 (C3), 48.56, 48.04R (CH2CHO), 45.35 (NCH2), 33.77,
33.25R, 31.68, 30.29, 26.71, 26.32, 22.66 (C4, C5, C6, C7, C2′, C4′),
26.99 [C(CH3)3], 19.33 [C(CH3)3], 14.13 (CH3CH2).
1H NMR (300 MHz, CDCl3): δ = 7.71–7.61 (m, 4 H, HAr, SiPh2), 7.49–
7.28 (m, 11 H, HAr, SiPh2, Bn), 5.24–5.09 (m, 2 H, PhCH2), 4.34–4.18R,
4.12–4.00 (m, 1 H, H3), 3.68, 3.64R (t, J4′-CH2,3′-CH2 = 6.0 Hz, 2 H, CH2OSi),
3.60–3.50 (m, 1 H, CHaHbOH), 3.41R (dt, 1 H, JH1b,H1a = 11.4 Hz, JH1b,2-CH2
=
2.7 Hz, CHaHbOH), 3.10, 3.03R (t, J1′-CH2,2′-CH2 = 7.9 Hz, 2 H, NCH2), 1.83–
1.40 (m, 8 H, H2a, H2b, 4-CH2, 2′-CH2, 3′-CH2), 1.35–1.15 (m, 6 H, 5-
CH2, 6-CH2, 7-CH2), 1.04 [s, 9 H, C(CH3)3], 0.91–0.80 (m, 3 H, CH3CH2).
13C NMR (75.4 MHz, CDCl3): δ = 158.28 (C=O), 136.82 (C1′Ar, Bn),
135.66, 127.76 (C2Ar, C3Ar, C5Ar, C6Ar, SiPh2), 133.96 (C1Ar, SiPh2),
129.74 (C4Ar, SiPh2), 128.67, 128.63R, 128.11R (C2′Ar, C3′Ar, C5′Ar, C6′Ar,
Bn), 127.09 (C4′Ar, Bn), 67.42R, 67.26 (PhCH2), 63.73, 63.60R (CH2OSi),
59.61, 58.84R (CH2OH), 52.82, 52.79R (C3), 42.43 (NCH2), 36.33, 35.96R
(C2), 33.26, 31.75, 30.46, 27.08R, 27.04, 26.48, 22.69, (C4, C5, C6, C7,
C2′, C4′), 26.97 [C(CH3)3], 19.31 [C(CH3)3], 14.15 (CH3CH2).
MS (ESI): m/z = 590.4 [M + H]+.
HRMS: m/z [M + Na] calcd for C36H51NO4SiNa: 612.3485; found:
612.3456.
MS (ESI): m/z = 588.4 [M + H]+.
(S)-3-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsiloxy)but-
yl]amino}octanal (9S); Typical Procedure
HRMS: m/z [M + Na] calcd for C36H49NO4SiNa: 610.3329; found:
610.3323.
To a stirred solution of oxalyl chloride (0.9 mL, 1.3 g, 10.5 mmol) in
anhyd CH2Cl2 (32 mL) at –78 °C was added DMSO (1.46 mL, 1.6 g, 20.6
mmol). After 5 min a solution of (S)-3-{(benzyloxycarbonyl)[4-(tert-
butyldiphenylsiloxy)butyl]amino}octanol (5.5 g, 9.3 mmol) in anhyd
CH2Cl2 (11 mL) was added dropwise, and the mixture was stirred at
–78 °C for 30 min. Then, Et3N (6.4 mL) was added and stirring was
continued for 5 min; the mixture was allowed to warm up to r.t., H2O
(50 mL) was added, and the layers were separated. The aqueous solu-
tion was extracted with CH2Cl2 (3 × 40 mL). The combined organic ex-
2-N-[(S)-3-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsiloxy)but-
yl]amino}octylidene]-2,3,4-tri-O-pivaloyl-α-D-arabinopyranosyl-
amine (10S); Typical Procedure
To a solution of 2,3,4-tri-O-pivaloyl-α-D-arabinopyranosylamine14c (3,
2.09 g, 5.2 mmol) in n-pentane (40 mL) was added dropwise aldehyde
9S (3.68 g, 6.26 mmol) dissolved in n-pentane (25 mL). The mixture
turned turbid, and freshly dried molecular sieves (4 Å, 4.2 g) were
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

L
I. Strassnig et al.
Paper
Synthesis
added. The mixture was stirred under argon at r.t. for 22 h, and then
the suspension was filtered through Hyflo® and the solvent was
evaporated in vacuo. The syrupy crude product 10S was directly used
for the subsequent reaction.
(2S)-2-[(R)-2-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsil-
oxy)butyl]amino}heptyl]-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyra-
nosyl)-2,3-dihydropyridine-4(1H)-one (12) and (2R)-2-[(R)-2-
{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsiloxy)butyl]ami-
no}heptyl]-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyranosyl)-2,3-di-
hydropyridine-4(1H)-one (13)
(2S)-2-[(S)-2-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsil-
oxy)butyl]amino}heptyl]-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyra-
nosyl)-2,3-dihydropyridine-4(1H)-one (11); Typical Procedure
Following the typical procedure for 11 using imine 10R (5.3 mmol),
Danishefsky diene 2 (1.14 g, 6.4 mmol), 1 M ZnCl2 in THF (11.6 mL,
11.6 mmol), and anhyd THF (27 mL) gave a pale yellow, viscous oil;
yield: 3.23 g (58%, 2 steps); dr 67:33:0:0 [HPLC (gradient: 95% MeCN,
5% H2O to 100% MeCN, 15 min, then 30 min 100% MeCN): tR = 31.37
(minor diastereomer), 33.22 min (major diastereomer)]; Rf = 0.37 (cy-
clohexane–EtOAc, 2:1).
To the crude imine 10S (5.2 mmol) dissolved in anhyd THF (26 mL)
was added, under stirring at –78 °C, 1 M ZnCl2 in THF (11.4 mL, 11.4
mmol) and the mixture was stirred for 10 min. Danishefsky diene16
2
(1.1 g, 6.4 mmol) was added dropwise and the mixture was stirred for
a further 30 min at –78 °C and then 48 h at –20 °C. The reaction was
stopped by addition of 1 M aq HCl (5.2 mL). The mixture was concen-
trated in vacuo and the remainder taken up in Et2O (100 mL). The or-
ganic layer was separated and then washed with sat. NaHCO3 solution
(3 × 30 mL) and 10% Titriplex® solution (2 × 30 mL) to eliminate zinc
compounds. After additional washing with brine (50 mL), the solu-
tion was dried (MgSO4) and the solvent was evaporated in vacuo to
give an orange syrupy crude product (6.4 g) that was purified by flash
chromatography (cyclohexane–EtOAc, 4:1) to give a yellow amor-
phous solid; yield: 3.18 g (3.06 mmol, 59%, 2 steps); dr 98:1:1:0
[HPLC (gradient: 95% MeCN, 5% H2O to 100% MeCN (15 min), then 30
min 100% MeCN): tR = 30.52 (major diastereomer), 34.48 and 37.67
min (minor diastereomers)]; Rf = 0.35 cyclohexane–EtOAc, (2:1);
[α]D23 +80.6 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3, COSY): δ = 7.68–7.59 (m, 4 H, HAr, SiPh2),
7.46–7.26 (m, 11 H, HAr, SiPh2 and Bn), 6.89R, 6.78 (d, JH6,H5 = 7.9 Hz, 1
H, H6), 5.44R, 5.39 (t, JH2′,H1′ = JH2′,H3′ = 9.6 Hz, 1 H, H2′), 5.31–5.24 (m, 1
H, H4′), 5.21–5.02 (m, 3 H, PhCH2, H3′), 4.97R, 4.93 (d, JH5,H6 = 7.5 Hz, 1
H, H5), 4.40R, 4.28 (d, JH1′,H2′ = 9.0 Hz, 1 H, H1′), 4.16–4.03, 4.03–3.92R
(m, 1 H, H2′′), 3.85 (dd, JH5′a,H5′b = 13.3 Hz, 1 H, H5′a), 3.71–3.50 (m, 4
H, H5′b, H2, CH2OSi), 3.26–3.08 (m, 1 H, N′CHaCHb), 3.06–2.89 (m, 1 H,
N′CHaCHb), 2.69R, 2.58 (dd, JH3a,H3b = 16.8 Hz, JH3a,H2 = 5.9 Hz, 1 H, H3a),
2.46R, 2.30 (d, JH3b,H3a = 16.4 Hz, 1 H, H3b), 2.17–2.02, 2.01–1.87R (m, 2
H, H1′′a, H1′′b), 1.85–1.17 (m, 10 H, 2′′′-CH2, 3′′′-CH2, 3′′-CH2, 4′′-CH2,
5′′-CH2), 1.28–1.10 (m, 2 H, CH3CH2), 1.26R, 1.19, 1.13, 1.11 [s, each 9
H, Piv-C(CH3)3], 1.03 [s, 9 H, SiC(CH3)3], 0.90–0.76 (m, 3 H, CH3CH2).
13C NMR (100.6 MHz, CDCl3, DEPT, HMQC): δ = 192.00 (C4), 177.39,
177.28, 177.00 (Piv-C=O), 156.35, 156.25R (Cbz-C=O), 148.60, 148.38R
(C6), 137.06, 136.85R (C1′Ar, Bn), 135.65, 127.78 (C2Ar, C3Ar, C5Ar, C6Ar,
SiPh2), 134.01, 133.95R (C1Ar, SiPh2), 129.75 (C4Ar, SiPh2), 128.69,
128.60R, 128.31R, 128.22 (C2′Αρ, C3′Ar, C5′Ar, C6′Ar, Bn), 128.00 (C4′Ar,
Bn), 100.01R, 99.73 (C5), 91.40, 90.86R (C1′), 71.41R, 71.22 (C3′),
67.88R, 67.67 (C4′), 67.21, 67.01R (PhCH2), 66.98, 66.84R (C5′), 66.73,
66.47R (C2′), 63.74, 63.63R (CH2OSi), 54.53, 54.41R (C2′′), 51.30R, 50.34
(C2), 42.31 (C1′′′), 39.58 (C3), 39.04, 38.99, 38.93 [Piv-C(CH3)3], 33.96R,
33.87 (C1′′), 34.40, 31.92R, 31.81, 30.69, 30.53R, 26.38, 25.82 (C3′′, C4′′,
C5′′, C2′′′, C3′′′), 27.32, 27.22 [Piv-C(CH3)3], 26.97 [SiC(CH3)3], 22.68
(CH3CH2), 19.31 [SiC(CH3)3], 14.15 (CH3CH2).
Major Diastereomer 12
1H NMR (400 MHz, CDCl3, COSY): δ = 7.69–7.59 (m, 4 H, HAr, SiPh2),
7.46–7.27 (m, 11 H, HAr, SiPh2 and Bn), 6.92R, 6.85 (d, JH6,H5 = 7.6 Hz, 1
H, H6), 5.53R, 5.49 (t, JH2′,H1′ = JH2′,H3′ = 9.6 Hz, 1 H, H2′), 5.28–5.06 (m, 3
H, H4′, PhCH2), 5.13 (dd, JH3′,H2′ = 9.9 Hz, JH3′,H4′ = 2.9 Hz, 1 H, H3′),
5.04R, 4.99 (d, JH5,H6 = 7.7 Hz, 1 H, H5), 4.69R, 4.39 (d, JH1′,H2′ = 9.2 Hz, 1
H, H1′), 3.83, 3.72R (d, JH5′a,H5′b = 13.1 Hz, 1 H, H5′a), 3.67–3.47 (m, 3 H,
H2, CH2OSi), 3.37–3.26 (m, 1 H, H2′′), 3.52, 3.16R (d, JH5′b,H5′a = 13.1 Hz,
1 H, H5′b), 3.10–2.91 (m, 2 H, N′CH2), 2.76R, 2.66 (dd, JH3a,H3b = 16.3 Hz,
JH3a,H2 = 6.4 Hz, 1 H, H3a), 2.34–1.84 (m, 3 H, H3b, 1′′-CH2), 1.76–1.39,
1.25–1.17 (m, 12 H, 2′′′-CH2, 3′′′-CH2, 3′′-CH2, 4′′-CH2, 5′′-CH2, 6′′-CH2),
1.27, 1.14, 1.12 [s, each 9 H, Piv-C(CH3)3], 1.03 [s, 9 H, SiC(CH3)3], 0.85
(t, J7′′-CH3,6′′-CH2 = 6.6 Hz, 3 H, CH3CH2).
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 191.76R, 191.40 (C4), 177.42,
177.29, 177.19 (Piv-C=O), 157.01R, 156.35 (Cbz-C=O), 149.11, 147.27R
(C6), 137.26R, 137.07 (C1′Ar, Bn), 135.67, 127.78 (C2Ar, C3Ar, C5Ar, C6Ar,
SiPh2), 134.04, 133.95R (C1Ar, SiPh2), 129.76 (C4Ar, SiPh2), 128.76,
128.67R, 128.41, 128.06R (C2′Ar, C3′Ar, C5′Ar, C6′Ar, Bn), 127.96 (C4′Ar,
Bn), 100.48R, 100.29 (C5), 92.17, 90.84R (C1′), 71.74R, 71.19 (C3′),
68.30R, 67.85 (C4′), 67.35, 67.18R (PhCH2), 66.34R, 66.18 (C5′), 65.61
(C2′), 63.80, 63.72R (CH2OSi), 54.07 (C2′′), 52.72R, 51.63 (C2), 42.80
(C1′′′), 40.66 (C3), 39.09, 39.02, 38.93 [Piv-C(CH3)3], 35.08, 34.88R
(C1′′), 33.92, 33.84R, 32.80, 31.93R, 31.85, 30.52, 26.11 (C3′′, C4′′, C5′′,
C2′′′, C3′′′), 27.35, 27.23 [Piv-C(CH3)3], 26.99 [SiC(CH3)3], 22.72R, 22.64
(CH3CH2), 19.32 [SiC(CH3)3], 14.16 (CH3CH2).
Minor Diastereomer 13
1H NMR (400 MHz, CDCl3, COSY): δ = 7.71–7.58 (m, 4 H, HAr, SiPh2),
7.47–7.28 (m, 11 H, HAr, SiPh2 and Bn), 7.16R, 7.12 (d, JH6,H5 = 7.9 Hz, 1
H, H6), 5.33 (t, JH2′,H1′ = JH2′,H3′ = 9.7 Hz, 1 H, H2′), 5.24–5.07 (m, 4 H, H5,
H4′, PhCH2), 5.06–4.97 (m, 1 H, H3′), 4.00 (d, JH1′,H2′ = 9.2 Hz, 1 H, H1′),
3.86 (d, JH5′a,H5′b = 13.4 Hz, 1 H, H5′a), 3.70–3.59 (m, 2 H, CH2OSi), 3.59–
3.50 (m, 1 H, H2′′), 3.42 (d, JH5′b,H5′a = 13.3 Hz, 1 H, H5′b), 3.38–3.24 (m,
1 H, H2), 3.21–3.09 (m, 1 H, N′CHaCHb), 3.09–2.95 (m, 1 H, N′CHaCHb),
2.64R, 2.56 (dd, JH3a,H3b = 16.3 Hz, JH3a,H2 = 5.7 Hz, 1 H, H3a), 2.48–2.34
(m, 1 H, H3b), 2.10–1.98 (m, 2 H, 1′′-CH2), 1.76–1.36, 1.24–1.16 (m, 12
H, 2′′′-CH2, 3′′′-CH2, 3′′-CH2, 4′′-CH2, 5′′-CH2, 6′′-CH2), 1.27, 1.13, 1.12
[s, each 9 H, Piv-C(CH3)3], 1.04 [s, 9 H, SiC(CH3)3], 0.89–0.77 (m, 3 H,
CH3CH2).
MS (ESI): m/z = 1039.6 [M + H]+, 1061.6 [M + Na]+, 2079.3 [2 M + H]+,
2101.2 [2 M + Na]+.
HRMS: m/z [M + Na] calcd for C60H86N2O11SiNa: 1061.5899; found:
1061.5897.
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 191.32 (C4), 177.31, 177.25,
176.60 (Piv-C=O), 156.20R, 156.13 (Cbz-C=O), 147.54R, 147.47 (C6),
137.22R, 137.17 (C1′Ar, Bn), 135.66, 127.82 (C2Ar, C3Ar, C5Ar, C6Ar,
SiPh2), 133.97, 133.87R (C1Ar, SiPh2), 129.81 (C4Ar, SiPh2), 128.77R,
128.66, 128.58, 128.49R (C2′Ar, C3′Ar, C5′Ar, C6′Ar, Bn), 128.41, 128.35R
(C4′Ar, Bn), 101.29, 101.20R (C5), 91.13, 90.87R (C1′), 71.28, 71.15R
(C3′), 67.97R, 67.92 (C4′), 67.41R, 67.33 (C2′), 67.04, 66.96R (PhCH2),
66.46R, 66.39 (C5′), 63.71, 63.62R (CH2OSi), 58.99R, 58.92 (C2), 55.77
2-N-[(R)-3-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsiloxy)but-
yl]amino}octylidene]-2,3,4-tri-O-pivaloyl-α-D-arabinopyranosyl-
amine (10R)
Following the typical procedure for 10S using 3 (2.13 g, 5.3 mmol), 9R
(3.74 g, 6.36 mmol), n-pentane (65 mL), and molecular sieves (4.5 g).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

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I. Strassnig et al.
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Synthesis
(C2′′), 46.48 (C1′′′), 39.34 (C3), 39.12, 38.92 [Piv-C(CH3)3], 31.92R,
31.86 (C1′′), 34.53, 33.93, 31.82R, 31.75, 30.51, 30.40R, 26.45 (C3′′, C4′′,
C5′′, C2′′′, C3′′′), 27.35, 27.20, 27.18 [Piv-C(CH3)3], 26.99 [SiC(CH3)3],
22.65 (CH3CH2), 19.32 [SiC(CH3)3], 14.15 (CH3CH2).
tion (40 mL). The solution was dried (Na2SO4) and the solvents were
evaporated in vacuo to give product that was dried under high vacu-
um to give a yellow viscous oil; yield: 1.85 g (98%); Rf = 0.56 (cyclo-
hexane–EtOAc, 3:1); [α]D23 –12.2 (c 1, CHCl3).
MS (ESI): m/z = 1039.6 [M + H]+, 1061.6 [M + Na]+, 1077.6 [M + K]+.
Major Diastereomer
1H NMR (400 MHz, CDCl3, COSY): δ = 7.70–7.57 (m, 4 H, HAr, SiPh2),
7.47–7.27 (m, 11 H, HAr, SiPh2 and Bn), 5.42 (t, JH2′,H1′ = JH2′,H3′ = 9.4 Hz,
1 H, H2′), 5.22–4.89 (m, 4 H, H4′, PhCH2, H3′), 4.48–4.37 (m, 1 H, H4),
4.34R, 4.17 (d, JH1′,H2′ = 9.1 Hz, 1 H, H1′), 4.23–4.00 (m, 1 H, H2′′), 3.72
(dd, JH5′a,H5′b = 13.0 Hz, JH5′a,H4′ = 1.6 Hz, 1 H, H5′a), 3.68–3.52 (m, 3 H,
H5′b, CH2OSi), 3.34–3.21 (m, 1 H, H6a), 3.08–2.95 (m, 2 H, N′CH2),
2.96 (s, 3 H, SO2CH3), 2.61–2.51 (m, 1 H, H2), 2.49–2.33 (m, 1 H, H6b),
2.11–2.00 (m, 1 H, H5a), 1.99–1.78 (m, 1 H, H3a), 1.74–1.38 (m, 7 H,
H5b, 1′′-CH2, 2′′′-CH2, 3′′′-CH2), 1.32–1.15 (m, 9 H, H3b, 3′′-CH2, 4′′-
CH2, 5′′-CH2, 6′′-CH2), 1.25, 1.14, 1.13 [s, each 9 H, Piv-C(CH3)3], 1.04
[s, 9 H, SiC(CH3)3], 0.86 (t, J7′′-CH3,6′′-CH2 = 6.7 Hz, 3 H, CH3CH2).
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 177.38, 177.33, 177.06 (Piv-
C=O), 156.86R, 156.33 (Cbz-C=O), 137.14R, 136.90 (C1′Ar, Bn), 135.65,
127.79 (C2Ar, C3Ar, C5Ar, C6Ar, SiPh2), 133.97, 133.87R (C1Ar, SiPh2),
129.79 (C4Ar, SiPh2), 128.63R, 128.35, 127.70, 127.56R (C2′Ar, C3′Ar,
C5′Ar, C6′Ar, Bn), 128.24, 128.03R (C4′Ar, Bn), 87.36, 86.76R (C1′), 79.95
(C4), 71.76, 71.67R (C3′), 68.85R, 68.62 (C4′), 67.34, 66.05R (PhCH2),
65.37R, 65.29 (C2′), 64.98 (C5′), 63.81, 63.66R (CH2OSi), 53.60 (C2),
53.44 (C2′′), 42.60 (C6), 42.17 (C1′′′), 39.07, 38.86, 38.74 [Piv-C(CH3)3],
38.71 (SO2CH3), 37.13 (C3), 33.80 (C1′′), 32.76 (C5), 31.72, 30.70,
30.60R, 27.06, 26.21, 25.97 (C3′′, C4′′, C5′′, C2′′′, C3′′′), 27.38, 27.29,
27.18 [Piv-C(CH3)3], 26.98 [SiC(CH3)3], 22.69 (CH3CH2), 19.30
[SiC(CH3)3], 14.14 (CH3CH2).
(2S)-2-[(S)-2-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsil-
oxy)butyl]amino}heptyl]-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyra-
nosyl)piperidin-4-ol (14); Typical Procedure
To solution of 11 (2.94 g, 2.83 mmol) in EtOH (60 mL) was added
NaBH4 (0.42 g, 11.1 mmol) and the solution stirred at r.t. for 48 h. Af-
ter the addition of H2O (1.5 mL), the solution was concentrated in vac-
uo. The residue was dissolved in CH2Cl2 (150 mL) and this was
washed with sat. NaHCO3 solution (3 × 100 mL) and brine (2 × 100
mL). The solution was dried ((Na2SO4) and the solvent was evaporated
in vacuo. MeOH (2 × 50 mL) was distilled from the residue to give
crude product (2.8 g), which was purified by flash chromatography
(cyclohexane–EtOAc, 3:1) to give a colorless oil; yield: 1.96 g (66%);
23
Rf = 0.53 (cyclohexane–EtOAc, 2:1); major diastereomer: [α]D –12.7
(c 1, CHCl3); mixture of diastereomers: [α]D23 –15. 6 (c 1, CHCl3).
Major Diastereomer
1H NMR (400 MHz, CDCl3, COSY): δ = 7.71–7.59 (m, 4 H, HAr, SiPh2),
7.47–7.23 (m, 11 H, HAr, SiPh2 and Bn), 5.45R, 5.41 (t,
JH2′,H1′ = JH2′,H3′ = 9.4 Hz, 1 H, H2′), 5.27–4.96 (m, 4 H, H4′, PhCH2, H3′),
4.38R, 4.20 (d, JH1′,H2′ = 9.1 Hz, 1 H, H1′), 4.15–4.03 (m, 1 H, H2′′), 3.73
(dd, JH5′a,H5′b = 13.0 Hz, JH5′a,H4′ = 1.6 Hz, 1 H, H5′a), 3.67–3.55 (m, 3 H,
H5′b, CH2OSi), 3.51–3.39 (m, 1 H, CHOH), 3.30–3.11 (m, 1 H, H6a),
3.10–2.94 (m, 2 H, N′CH2), 2.59–2.44 (m, 1 H, H2), 2.43–2.26 (m, 1 H,
H6b), 2.17–2.08R, 2.00–1.92 (m, 1 H, H3a), 1.90–1.74 (m, 1 H, H5a),
1.72–1.40 (m, 6 H, 1′′-CH2, 2′′′-CH2, 3′′′-CH2), 1.36–1.06 (m, 8 H, 3′′-
CH2, 4′′-CH2, 5′′-CH2, 6′′-CH2), 1.28–1.08 (m, 1 H, H5b), 1.25R, 1.24,
1.14, 1.13 [s, each 9 H, Piv-C(CH3)3], 1.05, 1.04R [s, 9 H, SiC(CH3)3],
1.03–0.91 (m, 1 H, H3b), 0.86 (t, J7′′-CH3,6′′-CH2 = 6.8 Hz, 3 H, CH3CH2).
MS (ESI): m/z = 1121.7 [M + H]+, 1143.6 [M + Na]+.
HRMS: m/z [M + H] calcd for C61H93N2O13SSi: 1121.6168; found:
1121.6184; m/z [M + Na] calcd for C61H92N2O13SSiNa: 1143.5987;
found: 1143.6022.
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 177.42, 177.35, 176.99R,
175.92 (Piv-C=O), 156.70R, 156.25 (Cbz-C=O), 137.19R, 136.92 (C1′Ar,
Bn), 135.65, 127.78 (C2Ar, C3Ar, C5Ar, C6Ar, SiPh2), 133.95, 133.89R (C1Ar,
SiPh2), 129.78 (C4Ar, SiPh2), 128.74R, 128.52R, 128.45, 127.92 (C2′Ar,
C3′Ar, C5′Ar, C6′Ar, Bn), 127.72 (C4′Ar, Bn), 86.90, 86.85R (C1′), 71.85R,
71.78 (C3′), 69.12 (CHOH), 68.95R, 68.68 (C4′), 67.23, 66.94R (PhCH2),
65.39R, 65.29 (C2′), 65.03R, 64.96 (C5′), 63.82, 63.66R (CH2OSi), 53.20
(C2), 52.93 (C2′′), 42.84 (C6), 42.49 (C3), 41.73 (C1′′′), 39.05, 38.84,
38.70 [Piv-C(CH3)3], 34.76R, 34.65 (C5), 33.99 (C1′′), 31.75R, 31.68,
30.73, 30.59R, 27.02, 26.25, 25.90 (C3′′, C4′′, C5′′, C2′′′, C3′′′), 27.37,
27.29, 27.17 [Piv-C(CH3)3], 26.97 [SiC(CH3)3], 22.70 (CH3CH2), 19.29
[SiC(CH3)3], 14.17 (CH3CH2).
(2R)-2-[(S)-2-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsil-
oxy)butyl]amino}heptyl]-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyra-
nosyl)piperidine (16)
To a solution of mesylate 15 (1.85 g, 1.65 mmol) in DME (30 mL) were
added dry NaI (1.24 g, 8.25 mmol) and zinc (1.08 g, 16.50 mmol). The
mixture was stirred under reflux for 18 h and then filtered. The solu-
tion was washed with H2O (20 mL) and the aqueous layer extracted
with Et2O (2 × 15 mL). The combined organic solutions were washed
with brine (30 mL) and dried (Na2SO4). The solvent was evaporated in
vacuo and the product purified by flash chromatography (cyclohex-
ane–EtOAc, 12:1) to give a colorless viscous oil; yield: 1.21 g mixture
of 16 and elimination products 16a/b; Rf = 0.49 (16), Rf = 0.41 (16a/b)
23
MS (ESI): m/z = 1043.6 [M + H]+, 1065.6 [M + Na]+.
(cyclohexane–EtOAc, 12:1); major product 16: [α]D –19.5 (c 1,
CHCl3).
HRMS: m/z [M + H] calcd for C60H91N2O11Si: 1043.6392; found:
1043.6417.
Pure Major Product 16
1H NMR (400 MHz, CDCl3, COSY): δ = 7.71–7.60 (m, 4 H, HAr, SiPh2),
7.48–7.23 (m, 11 H, HAr, SiPh2 and Bn), 5.47R, 5.43 (t,
JH2′,H1′ = JH2′,H3′ = 9.5 Hz, 1 H, H2′), 5.22–4.94 (m, 4 H, PhCH2, H4′, H3′),
4.38R, 4.20 (d, JH1′,H2′ = 9.1 Hz, 1 H, H1′), 4.22–3.98 (m, 1 H, H2′′), 3.76
(dd, JH5′a,H5′b = 13.0 Hz, JH5′a,H4′ = 1.7 Hz, 1 H, H5′a), 3.71–3.54 (m, 3 H,
H5′b, CH2OSi), 3.24–2.94 (m, 3 H, H6a, N′CH2), 2.57–2.45 (m, 1 H, H2),
2.45–2.32 (m, 1 H, H6b), 1.91–1.39 (m, 10 H, H3a, 4-CH2, H5a, 1′′-CH2,
2′′′-CH2, 3′′′-CH2), 1.32–1.16 (m, 10 H, H3b, H5b, 3′′-CH2, 4′′-CH2, 5′′-
CH2, 6′′-CH2), 1.26R, 1.24, 1.14, 1.13 [s, each 9 H, Piv-C(CH3)3], 1.05,
1.04R [s, 9 H, SiC(CH3)3], 0.86 (t, J7′′-CH3,6′′-CH2 = 6.5 Hz, 3 H, CH3CH2).
(2S)-2-[(S)-2-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsil-
oxy)butyl]amino}heptyl]-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyra-
nosyl)piperidin-4-yl Methanesulfonate (15)
To piperidinol 14 (1.75 g, 1.68 mmol) dissolved in pyridine (20 mL)
was added DMAP (14 mg, 0.11 mmol). The mixture was cooled an ice
bath and MsCl (0.16 mL, 0.23 g, 2.02 mmol) was added dropwise, and
the mixture was stirred at r.t. for 5 h. After the addition of brine (20
mL) to the mixture, the layers were separated and the aqueous layer
was extracted with CH2Cl2 (2 × 15 mL). The combined organic layers
were washed with sat. NaHCO3 solution (40 mL) and sat. NaCl solu-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

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I. Strassnig et al.
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Synthesis
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 177.48R, 177.42, 177.39,
176.92R, 176.87 (Piv-C=O), 156.69, 156.39R (Cbz-C=O), 137.30R,
136.83 (C1′Ar, Bn), 135.67, 127.77 (C2Ar, C3Ar, C5Ar, C6Ar, SiPh2), 134.00,
133.94R (C1Ar, SiPh2), 129.75 (C4Ar, SiPh2), 128.64, 128.52R, 127.85,
127.73R (C2′Ar, C3′Ar, C5′Ar, C6′Ar, Bn), 128.44R, 128.23 (C4′Ar, Bn), 88.45,
88.08R (C1′), 72.06R, 72.01 (C3′), 69.09R, 68.85 (C4′), 67.25, 66.85R
(PhCH2), 65.36R, 65.25 (C2′), 64.97R, 64.86 (C5′), 63.84, 63.69R
(CH2OSi), 55.48R, 55.36 (C2), 53.79 (C2′′), 45.14R, 45.00 (C6), 42.61
(C1′′′), 39.06, 38.85, 38.69 [Piv-C(CH3)3], 37.64 (C3), 34.57, 34.09R
(C1′′), 37.16, 33.19R, 32.52, 31.83R, 31.75, 30.74, 30.62R, 26.30R, 26.07,
26.15R, 25.91, 24.56R, 24.27 (C4, C5, C3′′, C4′′, C5′′, C2′′′, C3′′′), 27.40,
27.31, 27.19 [Piv-C(CH3)3], 26.98 [SiC(CH3)3], 22.73 (CH3CH2), 19.29
[SiC(CH3)3], 14.18 (CH3CH2).
flash chromatography (EtOAc containing 2% Et3N) to give yellow vis-
cous oil; yield: 195 mg (66%); Rf = 0.21 (EtOAc containing 2% Et3N);
[α]D23 –18.2 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 5.46 (t, JH2′,H1′ = JH2′,H3′ = 9.5 Hz, 1 H,
H2′), 5.21–5.13 (m, 1 H, H4′), 5.08 (dd, JH3′,H2′ = 9.9 Hz, JH3′,H4′ = 3.3 Hz,
1 H, H3′), 4.28 (d, JH1′,H2′ = 9.2 Hz, 1 H, H1′), 3.88 (dd, JH5′a,H5′b = 13.1 Hz,
JH5′a,H4′ = 2.2 Hz, 1 H, H5′a), 3.66–3.44 (m, 3 H, CH2OH, H5′b), 3.22–3.09
(m, 1 H, H6a), 2.76–2.63 (m, 1 H, H2), 2.63–2.54 (m, 2 H, N′CH2), 2.51–
2.36 (m, 2 H, H2′′, H6b), 1.86–1.38 (m, 10 H, H3a, 4-CH2, H5a, 1′′-CH2,
2′′′-CH2, 3′′′-CH2), 1.38–1.18 (m, 10 H, H3b, H5b, 3′′-CH2, 4′′-CH2, 5′′-
CH2, 6′′-CH2), 1.23, 1.14, 1.10 [s, each 9 H, Piv-C(CH3)3], 0.86 (t,
J7′′-CH3,6′′-CH2 = 6.7 Hz, 3 H, CH3CH2).
13C NMR (75.4 MHz, CDCl3): δ = 177.48, 177.46, 176.94 (Piv-C=O),
89.27 (C1′), 72.10 (C3′), 68.95 (C4′), 65.29 (C2′), 65.19 (C5′), 62.65
(CH2OH), 55.86 (C2), 55.46 (C2′′), 46.93 (C6), 45.22 (C1′′′), 39.04,
38.83, 38.72 [Piv-C(CH3)3], 38.02 (C1′′), 34.57, 33.32, 32.48, 32.09,
29.28, 26.12, 25.48, 24.08 (C3, C4, C5, C3′′, C4′′, C5′′, C2′′′, C3′′′), 27.38,
27.27, 27.14 [Piv-C(CH3)3], 22.73 (CH3CH2), 14.15 (CH3CH2).
MS (ESI): m/z (16) = 1027.7 [M + H]+, 1049.7 [M + Na]+; m/z
(16a/b) = 1025.7 [M + H]+.
HRMS: m/z [M + H] calcd for C60H91N2O10Si: 1027.6443; found:
1027.6445.
MS (ESI): m/z = 553.4 [M – OPiv]+, 655.5 [M + H]+, 1373.0 [2 M + Na +
(2R)-2-[(S)-2-{[4-(tert-Butyldiphenylsiloxy)butyl]amino}heptyl]-
1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyranosyl)piperidine (17)
CH3CN]+.
To a solution of the mixture 16 + 16a/b (1.21 g) in i-PrOH (35 mL) was
added 10% Pd(OH)2/C (400 mg) under an argon atmosphere. The mix-
ture was stirred under H2 at r.t. for 48 h. After filtration through
Hyflo®, the solvent was evaporated in vacuo and the product was pu-
rified by flash chromatography (cyclohexane–EtOAc, (2:1) to give a
pale yellow oil; yield: 825 mg (56%, 2 steps); Rf = 0.16 (cyclohexane–
EtOAc, 2:1); [α]D23 –10.4 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3, COSY): δ = 7.69–7.60 (m, 4 H, HAr), 7.46–
7.32 (m, 6 H, HAr), 5.48 (t, JH2′,H1′ = JH2′,H3′ = 9.5 Hz, 1 H, H2′), 5.21–5.13
(m, 1 H, H4′), 5.08 (dd, JH3′,H2′ = 9.9 Hz, JH3′,H4′ = 3.3 Hz, 1 H, H3′), 4.31
(d, JH1′,H2′ = 9.2 Hz, 1 H, H1′), 3.84 (dd, JH5′a,H5′b = 13.1 Hz, JH5′a,H4′ = 2.1
Hz, 1 H, H5′a), 3.66 (t, J4′′′-CH2,3′′′-CH2 = 5.9 Hz, 2 H, CH2OSi), 3.53 (d,
JH5′b,H5′a = 12.9 Hz, 1 H, H5′b), 3.23–3.12 (m, 1 H, H6a), 2.83–2.55 (m, 4
H, H2, H2′′, N′CH2), 2.54–2.38 (m, 1 H, H6b), 2.00–1.38 (m, 10 H, H3a,
4-CH2, H5a, 1′′-CH2, 2′′′-CH2, 3′′′-CH2), 1.35–1.19 (m, 10 H, H3b, H5b,
3′′-CH2, 4′′-CH2, 5′′-CH2, 6′′-CH2), 1.25, 1.16, 1.12 [s, each 9 H, Piv-
C(CH3)3], 1.04 [s, 9 H, SiC(CH3)3], 0.88 (t, J7′′-CH3,6′′-CH2 = 6.6 Hz, 3 H,
CH3CH2).
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 177.43, 176.97 (Piv-C=O),
135.67, 127.78 (C2Ar, C3Ar, C5Ar, C6Ar), 134.00 (C1Ar), 129.73 (C4Ar),
89.69 (C1′), 72.19 (C3′), 68.89 (C4′), 65.44 (C2′), 65.22 (C5′), 63.78
(CH2OSi), 56.22 (C2′′), 55.16 (C2), 46.41 (C1′′′), 45.30 (C6), 39.07,
38.86, 38.77 [Piv-C(CH3)3], 34.11, 32.72, 32.07, 30.42, 29.83, 27.54,
26.06, 25.47, 23.63 (C3, C4, C5, C1′′, C3′′, C4′′, C5′′, C2′′′, C3′′′), 27.42,
27.33, 27.20 [Piv-C(CH3)3], 27.00 [SiC(CH3)3], 22.75 (CH3CH2), 19.34
[SiC(CH3)3], 14.18 (CH3CH2).
HRMS: m/z [M + H] calcd for C36H67N2O8: 655.4897; found: 655.4916.
(2R)-2-{(S)-2-[(4-Hydroxybutyl)amino]heptyl}piperidine (20)
To a solution of N-arabinosyl piperidine 18 (184 mg, 0.28 mmol) in
MeOH (6 mL), 1 M HCl (0.47 mL) was added and the mixture stirred at
r.t. for 18 h. The solvent was evaporated in vacuo. Et2O (35 mL) was
added to the residue and the mixture extracted with H2O (3 × 15 mL).
The ether solution quantitatively contains 2,3,4-tri-O-pivaloyl-D-
arabinopyranose (19). To the combined aqueous solutions, Na2CO3
was added until pH 11 was reached. The aqueous solution was ex-
tracted with Et2O (3 × 20 mL). The combined ether solutions were
dried (MgSO4). Evaporation of the solvent afforded compound 20 suf-
ficiently pure for further conversion as a colorless viscous oil; yield:
71 mg (93%); Rf = 0.12 (EtOAc containing 2% of Et3N); [α]D23 +10.9 (c 1,
CHCl3).
1H NMR (400 MHz, CDCl3, COSY): δ = 3.62–3.46 (m, 2 H, CH2OH),
3.07–2.94 (m, 1 H, H6a), 2.71–2.41 (m, 5 H, H2, H6b, H2′, 1′′-CH2),
1.83–1.70 (m, 1 H, H4a), 1.68–1.49 (m, 6 H, H3a, H5a, 2′′-CH2, 3′′-
CH2), 1.46–1.18 (m, 12 H, H4b, H5b, 1′-CH2, 3′-CH2, 4′-CH2, 5′-CH2, 6′-
CH2), 1.12–0.98 (m, 1 H, H3b), 0.86 (t, J7′-CH3,6′-CH2 = 6.9 Hz, 3 H,
CH3CH2).
13C NMR (100.6 MHz, CDCl3, DEPT, HMQC): δ = 62.57 (CH2OH), 56.16
(C2), 55.65 (C2′), 47.02 (C6), 46.69 (C1′′), 41.82 (C1′), 34.09 (C3),
33.94, 32.43, 32.19, 29.23, 26.80, 25.19 (C5, 3′-CH2, 4′-CH2, 5′-CH2, 2′′-
CH2, 3′′-CH2), 24.96 (C4), 22.72 (CH3CH2), 14.17 (CH3CH2).
MS (ESI): m/z = 271.2 [M + H]+.
MS (ESI): m/z = 791.6 [M – OPiv]+, 893.7 [M + H]+, 915.7 [M + Na]+,
931.7 [M + K]+, 1823.4 [2 M + K]+.
HRMS: m/z [M + H] calcd for C16H35N2O: 271.2749; found: 271.2760.
HRMS: m/z [M
893.6079.
+ H] calcd for C52H85N2O8Si: 893.6075; found:
(+)-Tetraponerine-8 (1)
To a solution of piperidine derivative 20 (43.4 mg, 0.16 mmol) in an-
hyd CH2Cl2 (3 mL) were added freshly dried powdered molecular
sieves (4 Å, 25 mg) and NMO (37.6 mg, 0.32 mmol). The mixture was
stirred and to this was added TPAP (4 mg, 0.01 mmol). The color of
the mixture changed to dark green then to black. The mixture was
stirred at r.t. for 3 h and then the solvent was evaporated in vacuo.
The residue was stirred with 0.01 M NaOH solution (6 mL) for 10 min.
The aqueous suspension was extracted with Et2O (2 × 10 mL). The
combined ether solutions were washed with brine (15 mL) and dried
(MgSO4). After evaporation of the solvent, the product (35 mg) was
(2R)-2-{(S)-2-[(4-Hydroxybutyl)amino]heptyl}-1-(2,3,4-tri-O-piv-
aloyl-α-D-arabinopyranosyl)piperidine (18)
To a solution of 17 (402 mg, 0.45 mmol) in anhyd THF (15 mL) was
added 1 M TBAF in THF (0.9 mL, 0.9 mmol) dropwise; the color
changed to yellow and orange. The mixture was stirred at r.t. for 20 h
and then sat. NH4Cl solution (15 mL) was added. The aqueous layer
was extracted with Et2O (2 × 10 mL). The combined organic solutions
were washed with brine (20 mL) and dried (MgSO4). The solvent was
evaporated in vacuo and the remaining viscous brown oil purified by
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I. Strassnig et al.
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Synthesis
obtained as a brown oil that was purified by flash chromatography
(CHCl3–EtOH, 9:1) to give a colorless oil; yield: 5 mg (13%); Rf = 0.20
(CHCl3–EtOH, 9:1); [α]D23 +66.9 (c 0.2, CHCl3) [Lit.3 [α]D20 +99.0 (c 0.6,
CHCl3)].
1H NMR (400 MHz, C6D6, COSY): δ = 3.15 (ddd, JH3b,H3a = 8.1 Hz,
JH3b,H2a = 8.1 Hz, JH3b,H2b = 2.2 Hz, 1 H, H3b), 2.83 (ddd, JH10eq,H10ax = 10.2
(2S)-2-{(R)-2-[(Benzyloxycarbonyl)(4-oxobutyl)amino]heptyl}-1-
(2,3,4-tri-O-pivaloyl-α-D-arabinopyranosyl)-2,3-dihydropyridin-
4(1H)-one (23)
To a solution of 23 (923 mg, 1.15 mmol) in anhyd CH2Cl2 (12 mL) at
0 °C was slowly added dropwise 15% Dess–Martin periodinane solu-
tion in CH2Cl2 (4.96 g, 1.75 mmol) and the mixture was stirred at °C
for 2 h. Subsequently, 1 M NaOH (20 mL) was added. After separation,
the aqueous layer was extracted with Et2O (2 × 15 mL). The combined
organic solutions were washed with brine (30 mL) and dried (MgSO4).
The solvent was evaporated in vacuo and the crude product purified
by flash chromatography (EtOAc–cyclohexane, 5:1) to give a colorless
oil; yield: 735 mg (80%); Rf = 0.56 (EtOAc–cyclohexane, 5:1).
1H NMR (400 MHz, CDCl3, COSY): δ = 9.73, 9.65R (s, 1 H, CHO), 7.40–
7.21 (m, 5 H, HAr), 6.88R, 6.87 (d, JH6,H5 = 7.6 Hz, 1 H, H6), 5.51R, 5.48 (t,
JH2′,H1′ = JH2′,H3′ = 9.6 Hz, 1 H, H2′), 5.28–5.20 (m, 1 H, H4′), 5.20–5.04
(m, 3 H, PhCH2, H3′), 4.96 (d, JH5,H6 = 7.3 Hz, 1 H, H5), 4.61R, 4.42 (d,
JH1′,H2′ = 9.1 Hz, 1 H, H1′), 4.13–3.97 (m, 1 H, H2′′), 3.92, 3.83R (d,
JH5′a,H5′b = 12.9 Hz, 1 H, H5′a), 3.79–3.65 (m, 1 H, H2), 3.61, 3.36R (d,
JH5′b,H5′a = 13.1 Hz, 1 H, H5′b), 3.13–2.89 (m, 2 H, N′CH2), 2.71R, 2.64
(dd, JH3a,H3b = 16.4 Hz, JH3a,H2 = 6.0 Hz, 1 H, H3a), 2.47–2.34 (m, 2 H,
H1′′a, H1′′b), 2.27 (d, JH3b,H3a = 16.5 Hz, 1 H, H3b), 2.12–1.66 (m, 4 H,
2′′′-CH2, 3′′′-CH2), 1.61–1.14 (m, 8 H, 3′′-CH2, 4′′-CH2, 5′′-CH2, 6′′-CH2),
1.26R, 1.23, 1.11, 1.10 [s, each 9 H, Piv-C(CH3)3], 0.87–0.78 (m, 3 H,
CH3CH2).
Hz, JH10eq,H9ax = 4.9 Hz, JH10eq,H9eq = 2.9 Hz,
JH11a,H1a = 8.0 Hz, JH11a,H1b = 5.7 Hz, 1 H, H11a), 2.16–2.08 (m, 1 H, H5),
2.07–2.00 (m, 1 H, H3a), 1.82–1.12 (m, 22 H, 1-CH2, 2-CH2, H10ax
1 H, H10eq), 2.31 (dd,
,
H6a, 7-CH2, 8-CH2, 9-CH2, 6-CH2, pentyl 12-CH2, 13-CH2, 14-CH2, 15-
CH2), 0.90 (t, J16-CH3,15-CH2 = 7.0 Hz, 3 H, 16-CH3).
13C NMR (100.6 MHz, C6D6, HMQC): δ = 85.60 (C11a), 62.71 (C6a),
61.37 (C5), 51.56 (C10), 49.03 (C3), 37.98 (C6), 34.61 (C7), 32.99
(C12), 32.81 (C14), 29.73 (C1), 26.24 (C9), 25.23 (C13), 25.13 (C8),
23.16 (C15), 20.23 (C2), 14.39 (C16).
MS (ESI): m/z = 154.2 [C10H20N]+, 249.2 [M – H]+, 250.2 [M]+, 251.3 [M
+ H]+.
Anal. Calcd for C16H30N2: C, 76.74; H, 12.07; N, 11.19. Found: C, 76.25;
H, 11.54; N, 11.56.
(2S)-2-{(R)-2-[(Benzyloxycarbonyl)(4-hydroxybutyl)amino]hep-
tyl}-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyranosyl)-2,3-dihydropy-
ridin-4(1H)-one (21)
13C NMR (100.6 MHz, CDCl3, DEPT, HMQC): δ = 201.76, 201.21R (CHO),
192.15R, 191.39 (C4), 177.28, 177.23, 177.10 (Piv-C=O), 156.63R,
156.41 (Cbz-C=O), 149.36, 147.94R (C6), 136.88R, 136.79 (C1Ar),
128.62, 128.11 (C2Ar, C3Ar, C5Ar, C6Ar), 128.30 (C4Ar), 100.29R, 100.10
(C5), 92.18, 91.23R (C1′), 71.50R, 71.03 (C3′), 68.12R, 67.84 (C4′), 67.35
(PhCH2), 66.64, 66.42R (C5′), 66.21, 65.81R (C2′), 54.47 (C2′′), 52.40R,
51.55 (C2), 42.48 (C1′′′), 41.43, 41.34R (C1′′), 40.06 (C3), 39.02, 38.96,
38.86 [Piv-C(CH3)3], 34.78, 34.52R, 33.29R, 32.54, 31.81R, 31.75, 29.75,
26.03 (C3′′, C4′′, C5′′, C2′′′, C3′′′), 27.30, 27.19, 27.15 [Piv-C(CH3)3],
22.64R, 21.73 (CH3CH2), 14.08 (CH3CH2).
To the diastereomeric piperidinones 12/13 (2.36 g, 2.27 mmol) in an-
hyd THF (50 mL) was added 1 M TBAF in THF (4.5 mL, 4.5 mmol); the
color changed to deep red. The mixture was stirred at r.t. for 24 h and
then sat. NH4Cl solution (40 mL) was added. The aqueous solution
was extracted with Et2O (2 × 30 mL). The combined organic layers
were washed with brine (80 mL) and dried (MgSO4). After evapora-
tion of the solvent the remaining brown oil was purified by flash
chromatography (EtOAc–cyclohexane, 10:1) to give highly enriched
21, which contained only small amounts of the (2R)-diastereomer, as
a pale yellow oil; yield: 1.2 g (66%); Rf = 0.34 (EtOAc–cyclohexane,
10:1).
1H NMR (400 MHz, CDCl3, COSY): δ = 7.38–7.21 (m, 5 H, HAr), 6.94 (d,
JH6,H5 = 7.4 Hz, 1 H, H6), 5.48R, 5.42 (t, JH2′,H1′ = JH2′,H3′ = 9.5 Hz, 1 H, H2′),
5.25–5.18 (m, 1 H, H4′), 5.17–5.04 (m, 3 H, PhCH2, H3′), 5.01, 4.95R (d,
JH5,H6 = 7.4 Hz, 1 H, H5), 4.71R, 4.44 (d, JH1′,H2′ = 8.1 Hz, 1 H, H1′), 3.90–
3.50 (m, 5 H, H5′a, H2, CHaHbOH, CHaHbOH, H2′′), 3.43–3.20R (m, 1 H,
H5′b), 3.13–2.86 (m, 2 H, N′CH2), 2.72R, 2.62 (dd, JH3a,H3b = 16.2 Hz,
JH3a,H2 = 6.6 Hz, 1 H, H3a), 2.32R, 2.24 (d, JH3b,H3a = 16.4 Hz, 1 H, H3b),
2.16–2.05R, 2.03–1.92 (m, 1 H, H1′′a), 1.87–1.70 (m, 1 H, H1′′b), 1.69–
1.53 (m, 2 H, 2′′′-CH2), 1.51–1.37 (m, 2 H, 3′′′-CH2), 1.28–1.12 (m, 8 H,
3′′-CH2, 4′′-CH2, 5′′-CH2, 6′′-CH2), 1.24R, 1.16, 1.10, 1.08R, 1.06 [s, each
9 H, Piv-C(CH3)3], 0.87–0.75 (m, 3 H, CH3CH2).
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 193.48R, 192.88 (C4), 177.23,
177.16, 177.00 (Piv-C=O), 156.75, 156.38R (Cbz-C=O), 151.35R, 149.20
(C6), 137.06R, 136.28 (C1Ar), 128.57R, 128.17, 127.96, 127.85R (C2Ar,
C3Ar, C4Ar, C5Ar, C6Ar), 99.74 (C5), 92.20R, 90.96 (C1′), 71.56R, 70.93
(C3′), 68.16R, 67.85 (C4′), 67.13 (PhCH2), 66.58, 66.40R (C5′), 66.06R,
65.68 (C2′), 62.31, 62.18R (CH2OH), 54.41 (C2′′), 52.35 (C2), 43.17
(C1′′′), 39.59, 38.50R (C3), 38.98, 38.91, 38.81 [Piv-C(CH3)3], 34.52R,
34.16 (C1′′), 32.92, 31.82R, 31.69, 29.92R, 29.71, 26.45R, 25.36, 25.96
(C3′′, C4′′, C5′′, C2′′′, C3′′′), 27.27, 27.20, 27.13 [Piv-C(CH3)3], 22.61
(CH3CH2), 14.07 (CH3CH2).
MS (ESI): m/z [M = C44H66N2O11 (799.00)] = 799.4 [M + H]+, 821.5 [M +
Na]+, 837.5 [M + K]+, 1597.9 [2 M + H]+, 1619.9 [2 M + Na]+, 1635.9 [2
M + K]+.
(2S)-2-[(R)-2-{(Benzyloxycarbonyl)[3-(1,3-dioxolan-2-yl)pro-
pyl]amino}heptyl]-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyranosyl)-
2,3-dihydropyridin-4(1H)-one (24)
Aldehyde 23 (735 mg, 0.92 mmol) was dissolved in anhyd toluene (8
mL). Sequentially ethylene glycol (0.1 mL, 115 mg, 1.86 mmol) and
TsOH·H2O (5 mg, 0.03 mmol) were added. The mixture was stirred
and heated under reflux until no more H2O is separated (ca. 16 h,
temp. of oil bath 120–130 °C). The mixture was cooled to r.t. and sat.
NaHCO3 solution (10 mL) was added. The aqueous layer was extracted
with Et2O (2 × 8 mL) and the combined organic solutions were
washed with brine (10 mL) and dried (MgSO4). The solvent was evap-
orated in vacuo to give a brown oil (736 mg) that was purified by flash
chromatography (cyclohexane–EtOAc, (1:1) to give a colorless oil;
yield: 353 mg (45%); Rf = 0.19 (cyclohexane–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3, COSY): δ = 7.41–7.27 (m, 5 H, HAr), 6.89R,
6.86 (d, JH6,H5 = 7.7 Hz, 1 H, H6), 5.53R, 5.48 (t, JH2′,H1′ = JH2′,H3′ = 9.5 Hz, 1
H, H2′), 5.26–5.04 (m, 4 H, H4′, PhCH2, H3′), 4.98R, 4.96 (d, JH5,H6 = 7.6
Hz, 1 H, H5), 4.84, 4.81R (t, JH4′′′,3′′′-CH2 = 4.3 Hz, 1 H, H4′′′), 4.72R, 4.40 (d,
JH1′,H2′ = 9.2 Hz, 1 H, H1′), 4.21–4.02 (m, 1 H, H2′′), 3.97–3.77 (m, 4 H,
OCH2CH2O), 3.71 (d, JH5′a,H5′b = 12.8 Hz, 1 H, H5′a), 3.66–3.58 (m, 1 H,
MS (ESI): m/z [M = C44H68N2O11 (801.02)]= 801.5 [M + H]+, 823.5 [M +
Na]+, 839.5 [M + K]+, 1602.0 [2 M + H]+, 1624.0 [2 M + Na]+, 1640.0 [2
M + K]+.
H2), 3.24–3.05 (m,
2 H, H5′b, N′CHaCHb), 3.05–2.92 (m, 1 H,
N′CHaCHb), 2.76R, 2.66 (dd, JH3a,H3b = 16.3 Hz, JH3a,H2 = 6.4 Hz, 1 H, H3a),
2.27, 2.16R (d, JH3b,H3a = 16.1 Hz, 1 H, H3b), 2.08–1.87 (m, 1 H, H1′′a),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

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1.79–1.43 (m, 6 H, H1′′b, 2′′′-CH2, 3′′′-CH2, H3′′a), 1.31–1.15 (m, 7 H,
H3′′b, 4′′-CH2, 5′′-CH2, 6′′-CH2), 1.25, 1.24, 1.12 [s, each 9 H, Piv-
C(CH3)3], 0.84 (t, J7′′-CH3,6′′-CH2 = 6.5 Hz, 3 H, CH3CH2).
31.6 mg, 0.28 mmol). The mixture was stirred at r.t. for 4.5 h, then
quenched by the addition of brine (5 mL). The aqueous layer was ex-
tracted with CH2Cl2 (2 × 5 mL). The combined organic solutions were
washed with sat. NaHCO3 solution (10 mL) and brine (10 mL) and
dried (MgSO4). The solvent was evaporated in vacuo and the product
dried under high vacuum to give a yellow oil that was sufficiently
pure for further conversion; yield: 205 mg (97%); Rf = 0.71 (cyclohex-
ane–EtOAc, 1:1).
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 191.92R, 191.46 (C4), 177.39,
177.25, 177.16 (Piv-C=O), 156.97R, 156.39 (Cbz-C=O), 148.74, 146.62R
(C6), 137.20R, 136.98 (C1Ar), 128.64, 128.04 (C2Ar, C3Ar, C5Ar, C6Ar),
128.39 (C4Ar), 104.26, 103.99R (C4′′′), 100.65R, 100.46 (C5), 92.03,
90.66R (C1′), 71.80R, 71.13 (C3′), 68.32R, 67.89 (C4′), 67.19 (PhCH2),
66.57, 66.26R (C5′), 66.12, 65.54R (C2′), 64.98 (OCH2CH2O), 54.06
(C2′′), 52.73R, 51.66 (C2), 42.70 (C1′′′), 40.89R, 39.35 (C3), 39.05, 38.98,
38.89 [Piv-C(CH3)3], 34.89 (C1′′), 33.67R, 32.72, 31.89R, 31.85, 31.39,
31.29R, 26.01, 24.71R, 23.75 (C3′′, C4′′, C5′′, C2′′′, C3′′′), 27.31, 27.18
[Piv-C(CH3)3], 22.66 (CH3CH2), 14.13 (CH3CH2).
(2S)-2-[(R)-2-{(Benzyloxycarbonyl)[3-(1,3-dioxolan-2-yl)pro-
pyl]amino}heptyl]-N-(2,3,4-tri-O-pivaloyl-α-D-arabinopyrano-
syl)piperidine
To the crude mesylate 26 (205 mg, 0.22 mmol) dissolved in DME (5
mL) were sequentially added freshly dried NaI (165 mg, 1.1 mmol)
and zinc (144 mg, 2.2 mmol). The mixture was stirred and heated un-
der reflux for 16 h. After filtration, the filtrate was washed with H2O
(8 mL) and the aqueous layer extracted with Et2O (2 × 5 mL). The
combined organic solutions were washed with brine (15 mL) and
dried (MgSO4). The solvent was evaporated in vacuo and the remain-
ing residue purified by flash chromatography (cyclohexane–EtOAc,
3:1) to give a colorless oil; yield (27 which contains some amounts of
elimination products): 105 mg of product; Rf = 0.51 (cyclohexane–
EtOAc, 3:1).
1H NMR (300 MHz, CDCl3): δ = 7.50–7.18 (m, 5 H, HAr), 5.55–5.38 (m,
1 H, H2′), 5.28–4.92 (m, 4 H, H4′, PhCH2, H3′), 4.86, 4.79R (t, JH4′′′,3′′′-
CH2 = 4.2 Hz, 1 H, H4′′′), 4.19R, 4.03 (d, JH1′,H2′ = 9.1 Hz, 1 H, H1′), 4.15–
3.99 (m, 1 H, H2′′), 3.99–3.62 (m, 5 H, OCH2CH2O, H5′a), 3.57–2.88 (m,
4 H, H5′b, H6a, N′CH2), 2.74–2.57 (m, 1 H, H2), 2.56–2.41 (m, 1 H,
H6b), 1.84–1.32 (m, 10 H, H3a, 4-CH2, H5a, 1′′-CH2, 2′′′-CH2, 3′′′-CH2),
1.32–1.10 (m, 10 H, H3b, H5b, 3′′-CH2, 4′′-CH2, 5′′-CH2, 6′′-CH2), 1.23,
1.14, 1.10 [s, each 9 H, Piv-C(CH3)3], 0.89–0.79 (m, 3 H, CH3CH2).
MS (ESI): m/z [M = C46H70N2O12 (843.05)] = 843.5 [M + H]+, 865.5 [M +
Na]+, 881.5 [M + K]+, 1686.1 [2 M + H]+, 1708.1 [2 M + Na]+, 1724.0 [2
M + K]+.
(2S)-2-[(R)-2-{(Benzyloxycarbonyl)[3-(1,3-dioxolan-2-yl)pro-
pyl]amino}heptyl]-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyrano-
syl)piperidin-4-ol (25)
To piperidinone 24 (353 mg, 0.42 mmol) dissolved in EtOH (10 mL)
was added NaBH4 (63 mg, 1.66 mmol). The mixture was stirred at r.t.
for 44 h. Then a few drops of H2O were added, and the solvent was
evaporated in vacuo. The residue was dissolved in CH2Cl2 (25 mL),
washed with NaHCO3 solution (15 mL) and then brine (2 × 15 mL).
The solution was dried (MgSO4) and the solvent was evaporated in
vacuo to give a yellow oil (347 mg) that was purified by flash chroma-
tography (cyclohexane–EtOAc, 3:2) to give a colorless oil; yield: 191
mg (54%); Rf = 0.47 (major diastereomer) and 0.38 (minor diastereo-
mer) (cyclohexane–EtOAc, 1:1).
MS (ESI): m/z [M = C46H74N2O11 (831.09)] = 831.5 [M + H]+, 853.5 [M +
Major Diastereomer
Na]+, 869.5 [M + K]+, 1684.0 [2 M + Na]+.
1H NMR (400 MHz, CDCl3, COSY): δ = 7.42–7.20 (m, 5 H, HAr), 5.47R,
5.43 (t, JH2′,H1′ = JH2′,H3′ = 9.4 Hz, 1 H, H2′), 5.24–4.94 (m, 4 H, H4′,
PhCH2, H3′), 4.88, 4.81R (t, JH4′′′,3′′′-CH2 = 4.3 Hz, 1 H, H4′′′), 4.22R, 4.06 (d,
JH1′,H2′ = 9.4 Hz, 1 H, H1′), 4.15–3.97 (m, 1 H, H2′′), 3.97–3.71 (m, 5 H,
OCH2CH2O, H5′a), 3.66–3.48 (m, 2 H, CHOH, H5′b), 3.29–2.99 (m, 3 H,
H6a, N′CH2), 2.75–2.64R, 2.64–2.55 (m, 1 H, H2), 2.52–2.35 (m, 1 H,
H6b), 1.97–1.43 (m, 9 H, H3a, H5a, 1′′-CH2, 2′′′-CH2, 3′′′-CH2, H3′′a),
1.33–0.99 (m, 9 H, H3b, H5b, H3′′b, 4′′-CH2, 5′′-CH2, 6′′-CH2), 1.25,
1.16R, 1.14, 1.12 [s, each 9 H, Piv-C(CH3)3], 0.87 (t, J7′′-CH3,6′′-CH2 = 6.7 Hz,
3 H, CH3CH2).
(2S)-2-[(R)-2-{[3-(1,3-Dioxolan-2-yl)propyl]amino}heptyl]-1-
(2,3,4-tri-O-pivaloyl-α-D-arabinopyranosyl)piperidine (27)
To a solution of the product mixture described above (105 mg) in i-PrOH
(4 mL) was added 10% Pd(OH)2/C (25 mg). The mixture was stirred
under H2 atmosphere for 42 h. After filtration through Hyflo®, the
solvent was evaporated from the filtrate and the remaining residue
purified by flash chromatography (CHCl3–EtOH, 9:1) to give a pale
yellow oil; yield: 85 mg (56%, 2 steps); Rf = 0.50 (CHCl3–EtOH, 9:1).
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 177.46, 177.06, 177.00 (Piv-
C=O), 156.64R, 156.52 (Cbz-C=O), 137.18R, 136.95 (C1Ar), 128.66,
128.55R, 127.93, 127.82R (C2Ar, C3Ar, C5Ar, C6Ar), 128.45R, 128.29 (C4Ar),
104.25, 104.10R (C4′′′), 88.45R, 88.01 (C1′), 72.02R, 71.89 (C3′), 68.93
(CHOH), 68.86R, 68.75 (C4′), 67.22, 66.95R (PhCH2), 65.49 (C5′), 65.35R,
65.29 (C2′), 65.04 (OCH2CH2O), 53.68R, 53.53 (C2), 52.54 (C2′′), 42.37
(C6), 42.32 (C3), 41.98 (C1′′′), 39.07, 38.87, 38.76 [Piv-C(CH3)3], 38.32R,
37.75, 34.87R, 34.78, 33.49, 33.09R, 31.91, 31.46, 26.47, 24.59R, 23.72
(C5, C1′′, C3′′, C4′′, C5′′, C2′′′, C3′′′), 27.40, 27.30, 27.18 [Piv-C(CH3)3],
22.73 (CH3CH2), 14.18 (CH3CH2).
1H NMR (300 MHz, CDCl3): δ = 5.45 (t, JH2′,H1′ = JH2′,H3′ = 9.6 Hz, 1 H,
H2′), 5.21–5.14 (m, 1 H, H4′), 5.06 (dd, JH3′,H2′ = 9.9 Hz, JH3′,H4′ = 2.9 Hz,
1 H, H3′), 4.84 (t, JH4′′′,3′′′-CH2 = 4.0 Hz, 1 H, H4′′′), 4.21 (d, JH1′,H2′ = 9.2 Hz,
1
H, H1′), 4.01–3.75 (m, 5 H, OCH2CH2O, H5′a), 3.57 (d,
JH5′b,H5′a = 13.2 Hz, 1 H, H5′b), 3.19–2.71 (m, 5 H, H6a, H2′′, N′CH2, H2),
2.61–2.48 (m, 1 H, H6b), 2.01–1.47 (m, 10 H, H3a, 4-CH2, H5a, 1′′-CH2,
2′′′-CH2, 3′′′-CH2), 1.46–1.13 (m, 10 H, H3b, H5b, 3′′-CH2, 4′′-CH2, 5′′-
CH2, 6′′-CH2), 1.22, 1.13, 1.08 [s, each 9 H, Piv-C(CH3)3], 0.85 (t,
J7′′-CH3,6′′-CH2 = 6.9 Hz, 3 H, CH3CH2).
MS (ESI): m/z [M = C38H68N2O9 (696.95)] = 595.4 [M – OPiv]+, 697.5 [M
MS (ESI): m/z [M = C46H74N2O12 (847.09)] = 847.6 [M + H]+, 869.6 [M +
+ H]+, 1456.9 [2 M + CH3CN + Na]+.
Na]+, 885.6 [M + K]+, 1716.1 [2 M + Na]+.
(+)-Tetraponerine-7 (28)
(2S)-2-[(R)-2-{(Benzyloxycarbonyl)[3-(1,3-dioxolan-2-yl)pro-
pyl]amino}heptyl]-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyrano-
syl)piperidin-4-yl Methanesulfonate (26)
To arabinosyl piperidine 27 (85 mg, 0.12 mmol) dissolved in MeOH (3
mL) was added 1 M HCl (0.4 mL), the solution was stirred at r.t. for 18
h, and MeOH was evaporated in vacuo. The remaining residue was ex-
tracted with Et2O (3 mL). The ether solution contains the 2,3,4-tri-O-
pivaloyl-arabinose 19. It was extracted with H2O (2 × 3 mL). The H2O
To a solution of piperidinol 25 (191 mg, 0.23 mmol) in anhyd pyridine
(4 mL) at 0 °C were added DMAP (2 mg, 0.02 mmol) and MsCl (21 μL,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R

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extracts and 2 M HCl (3 mL) were added to the remainder and it was
stirred for 2 h. To the aqueous solution, 10% NaOH solution was added
until pH 8 was reached. The basic solution was extracted with CH2Cl2
(3 × 5 mL). The combined organic solutions were dried (MgSO4) and
the solvent was evaporated in vacuo. The product was purified by
flash chromatography (CHCl3–EtOH, 9:1) to give a colorless oil; yield:
(2) Merlin, P.; Braekman, J. C.; Daloze, D.; Pasteels, J. M. J. Chem.
Ecol. 1988, 14, 517.
(3) Yue, C.; Royer, J.; Husson, H. P. J. Org. Chem. 1990, 55, 1140.
(4) Macours, P.; Braekman, J. C.; Daloze, D. Tetrahedron 1995, 51,
1415.
(5) Devijver, C.; Macours, P.; Braekman, J. C.; Daloze, D.; Pasteels, J.
M. Tetrahedron 1995, 51, 10913.
23
23 mg (78%, 3 steps); Rf = 0.13 (CHCl3–EtOH, 9:1); [α]D +22.5 (c 2.2,
CHCl3) [Lit.4 [α]D20 +30.0 (c 0.22, CHCl3)].
(6) Kem, W. R.; Wildeboer, K.; LeFrancois, S.; Raja, M.; Marszalec,
W.; Braekman, J. C. Cell. Mol. Neurobiol. 2004, 24, 535.
(7) Rouchaud, A.; Braekman, J. C. Eur. J. Org. Chem. 2009, 2666.
(8) (a) Merlin, P.; Braekman, J. C.; Daloze, D. Tetrahedron Lett. 1988,
29, 1691. (b) Merlin, P.; Braekman, J. C.; Daloze, D. Tetrahedron
1991, 47, 3805. (c) Pleheiers, M.; Heilporn, S.; Ekelmans, D.;
Leclercq, S.; Sangermano, M.; Breakman, J. C.; Daloze, D. Can. J.
Chem. 2000, 78, 1030.
1H NMR (400 MHz, C6D6, COSY): δ = 3.32 (dd, JH11a,H1a = 4.7 Hz,
JH11a,H1b = 2.9 Hz, 1 H, H11a), 3.18 (ddd, JH3a,H3b = 11.5 Hz, JH3a,H2a = 7.0
Hz, JH3a,H2b = 5.2 Hz, 1 H, H3a), 2.85–2.74 (m, 3 H, H5, H3b, H10eq),
2.09–2.01 (m, 1 H, H6a), 1.94 (ddd, JH6ax,H6eq = 13.1 Hz, JH6ax,H6a = 11.6
Hz, JH6ax,H5 = 5.5 Hz, 1 H, H6ax), 1.85–1.17 (m, 19 H, 6-CH2, 2-CH2,
H10ax, 1-CH2, 8-CH2, 9-CH2, pentyl 12-CH2, 13-CH2, 14-CH2, 15-CH2),
1.16–1.09 (m, 1 H, H6eq), 0.93 (t, J16-CH3,15-CH2 = 6.9 Hz, 3 H, 16-CH3).
(9) (a) Jones, T. H. Tetrahedron Lett. 1990, 31, 4543. (b) Barluenga, J.;
Tomas, M.; Kouznetsov, V.; Rubio, E. J. Org. Chem. 1994, 59,
3699. (c) Kim, J. T.; Gevorgyan, V. Org. Lett. 2002, 4, 4697.
(d) Charette, A. B.; Mathieu, S.; Martel, J. Org. Lett. 2005, 7, 5401.
(10) (a) Yue, C.; Gauthier, I.; Royer, J.; Husson, H.-P. J. Org. Chem.
1996, 61, 4949. (b) Takahata, H.; Kubota, M.; Ikota, N. J. Org.
Chem. 1999, 64, 8594. (c) Stragies, R.; Blechert, S. J. Am. Chem.
Soc. 2000, 122, 9584. (d) Airian, E.; Girard, N.; Pizetti, M.;
Salvadori, J.; Taddei, M.; Mann, A. J. Org. Chem. 2010, 75, 8670.
(11) Bosque, I.; Gonzalez-Gomez, J. C.; Guijarro, A.; Foubelo, F.; Yus,
M. J. Org. Chem. 2012, 77, 10340.
13C NMR (100.6 MHz, C6D6, HMQC, HMBC): δ = 75.52 (C11a), 56.74
(C6a), 53.32 (C5), 50.99 (C10), 50.63 (C3), 34.22 (C7), 32.51 (C14),
32.23 (C6), 31.05 (C12), 30.52 (C1), 27.40 (C13), 26.52 (C9), 25.23
(C8), 23.24 (C15), 22.20 (C2), 14.43 (C16).
MS (ESI): m/z = 249.2 [M – H]+, 250.2 [M]+, 251.2 [M + H].+
HRMS: m/z [M + H] calcd for C16H31N2: 251.2487; found: 251.2476.
(2S)-2-{(R)-2-[(Benzyloxycarbonyl)(4-oxobutyl)amino]heptyl}-5-
chloro-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyranosyl)-2,3-dihydro-
pyridin-4(1H)-one (22)
(12) Gonzalez-Gomez, J. C.; Medjahdi, M.; Foubelo, F.; Yus, M. J. Org.
Chem. 2010, 75, 6308.
(13) Bosque, I.; Gonzalez-Gomez, J. C.; Loza, M. I.; Brea, M. J. Org.
Chem. 2014, 79, 3982.
Following the typical procedure for 9S using piperidinone 21 (404
mg, 0.5 mmol), oxalyl chloride (0.05 mL, 0.55 mmol), DMSO (0.08 mL,
1.1 mmol), Et3N (0.35 mL, 2.5 mmol), and CH2Cl2 (6 mL) with a reac-
tion time of 35 min and purification by flash chromatography (cyclo-
hexane–EtOAc, 1:1) gave a colorless oil; yield: 292 mg (70%); Rf = 0.53
(cyclohexane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): δ = 9.73, 9.66R (br s, 1 H, CHO), 7.41–7.21
(m, 5 H, HAr), 7.12 (s, 1 H, H6), 5.54–5.35 (m, 1 H, H2′), 5.29–5.21 (m, 1
H, H4′), 5.19–5.01 (m, 3 H, PhCH2, H3′), 4.65R, 4.44 (d, JH1′,H2′ = 8.9 Hz, 1
H, H1′), 4.12–3.69 (m, 3 H, H2′′, H2, H5′a), 3.63, 3.37R (d, JH5′b,H5′a = 13.4
Hz, 1 H, H5′b), 3.12–2.90 (m, 2 H, N′CH2), 2.88–2.68 (m, 1 H, H3a),
2.52–2.28 (m, 3 H, 1′′-CH2, H3b), 2.11–1.65 (m, 4 H, 2′′′-CH2, 3′′′-CH2),
1.60–1.15 (m, 8 H, 3′′-CH2, 4′′-CH2, 5′′-CH2, 6′′-CH2), 1.26, 1.23, 1.11 [s,
each 9 H, Piv-C(CH3)3], 0.88–0.73 (m, 3 H, CH3CH2).
(14) (a) Kunz, H.; Pfrengle, W.; Sager, W. Tetrahedron Lett. 1989, 30,
4109. (b) Laschat, S.; Kunz, H. Synlett 1990, 629. (c) Kunz, H.;
Pfrengle, W.; Rück, K.; Sager, W. Synthesis 1991, 1039.
(15) (a) Kunz, H.; Pfrengle, W. Angew. Chem. 1989, 101, 1041; Angew.
Chem., Int. Ed. Engl. 1989, 28, 1067. (b) Kranke, B.; Hebrault, D.;
Schultz-Kukula, M.; Kunz, H. Synlett 2004, 671. (c) Kranke, B.;
Kunz, H. Org. Biomol. Chem. 2007, 5, 349.
(16) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807.
(17) Bollbuck, B.; Kraft, P.; Tochtermann, W. Tetrahedron 1996, 52,
4581.
(18) Michael, J. P.; Gravestock, D. J. Chem. Soc., Perkin Trans. 1 2000,
1919.
(19) Steglich, W.; Höfle, G. Angew. Chem. 1969, 81, 1001; Angew.
Chem., Int. Ed. Engl. 1969, 8, 981.
MS (ESI): m/z [M = C44H65ClN2O11 (833.45)] = 833.5 [M(35Cl) + H]+,
835.5 [M(37Cl) + H]+, 855.4 [M(35Cl) + Na]+, 857.4 [M(37Cl) + Na]+.
(20) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183.
(21) Davies, S. G.; Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie,
L. J.; Price, P. D.; Mortimer, A. J. P.; Russell, A. J.; Smith, A. D. Tet-
rahedron: Asymmetry 2006, 17, 1793.
(22) Freeman, F.; Kim, D. S. H. L.; Rodriguez, E. J. Org. Chem. 1992, 57,
1722.
Acknowledgment
This work was supported by the Naturstoffsynthese-Zentrum der
Universität Mainz and by the Fonds der Chemischen Industrie.
(23) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron 1997,
53, 10229.
(24) Kikuchi, H.; Yamamoto, K.; Horoiwa, S.; Hirai, S.; Kasahara, R.;
Hariguchi, N.; Matsumoto, M.; Oshima, Y. J. Med. Chem. 2006,
49, 4698.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380215.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(25) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
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Asymmetry 2005, 16, 529.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R