Total synthesis and absolute stereochemistry of (+)-batzellaside B and its C8-epimer, a new class of piperidine alkaloids from the sponge batzella sp.

Article abstract of DOI:10.1016/j.tetlet.2011.01.018

The first total synthesis of (+)-batzellaside B and its C8-epimer was completed from a known l-arabinose-derived tribenzyl ether in 22 steps with overall yields of 3.9% and 5.4%, respectively. The absolute configuration of (+)-batzellaside B was unambiguously determined to be 1S,3S,4S,5R,8S by the Mosher analysis of a synthetic intermediate prepared through a separate route.

Full text of DOI:10.1016/j.tetlet.2011.01.018

Tetrahedron Letters 52 (2011) 1173–1175
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis and absolute stereochemistry of (+)-batzellaside B and its
C8-epimer, a new class of piperidine alkaloids from the sponge Batzella sp.
Jolanta Wierzejska a, Manami Ohshima a, Toshiyasu Inuzuka b, Tetsuya Sengoku a, Masaki Takahashi a,
Hidemi Yoda a,
⇑
a Department of Materials Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Naka-ku, Hamamatsu 432-8561, Japan
b Division of Instrumental Analysis, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of (+)-batzellaside B and its C8-epimer was completed from a known L-arabinose-
Received 15 December 2010
Accepted 5 January 2011
Available online 13 January 2011
derived tribenzyl ether in 22 steps with overall yields of 3.9% and 5.4%, respectively. The absolute config-
uration of (+)-batzellaside B was unambiguously determined to be 1S,3S,4S,5R,8S by the Mosher analysis
of a synthetic intermediate prepared through a separate route.
Ó 2011 Elsevier Ltd. All rights reserved.
the first total synthesis and absolute stereochemical assignment
of (+)-batzellaside B as a representative example among constitu-
ent members of the batzellaside family.
OH
OH
OH
OH
*
Our strategy for the target-directed synthesis involves the use
N
H
R
of commercially available
L-arabinose as an appropriate chiral
source for the required stereocenters (Scheme 1). The synthesis
batzellaside A; R = C10H21
B; R = C9H19
began with the preparation of 2,3,5-tri-O-benzyl-L-arabinose 1 by
following the published procedure.2 Reaction of 1 with p-methoxy-
phenylmethyl amine (MPMNH2) in refluxing toluene led to com-
plete consumption of the substrate and clean formation of
aminal intermediate, which would exist in equilibrium with the
C; R = C11H23
The batzellasides are a novel class of C-alkylated iminosugars
originally isolated from Batzella sp., a sponge collected off the west
coast of Madagascar, on the basis of the first example of iminosug-
ars from marine organism.1 In addition to antibacterial potency
against Staphylococcus epidermidis with MIC values less than
corresponding
c-hydroxy imine. In agreement with our previous
HO
OH
a
BnO
BnO
OBn
OH
HO
OH
-arabinose
O
O
6.3 lg/mL, their unique structural properties provide an intriguing
L
1
extension of the iminosugar frameworks due to the fact that they
are biosynthetically related to a variety of plant-derived alkaloids
rather than marine-derived ones, thereby attracting attention to
the research field of contemporary drug discovery. Unfortunately,
the low natural abundance of batzellasides has limited their avail-
ability, further impeding complete understanding of the absolute
configurations and extensive studies on the development of biolog-
ically potent analogues. Although total synthesis would address
this supply problem, no reports, to our knowledge, have appeared
previously describing successful studies on the synthesis of these
compounds. In this publication, we report our initial efforts in
OBn OH
OBn
BnO
BnO
OBn
NHMPM
b
c
MPMHN
OBn
O
OBnOH
OBn
BnO
O
OBn
BnO
OBn
OBn
d
e
OBn
N
N
O
NH
MPM
MPM
MPM
2
3
4
Scheme 1. Reagents and conditions: (a) see Ref. 2; (b) MPMNH2, toluene, reflux,
5 h; (c) CH2@CHMgCl, THF, ꢀ78 to 0 °C, 2 h; 81% (two steps); (d) PCC, MS 4 Å,
CH2Cl2, 0 °C–rt, 1 h; 64%; (e) (i) OsO4, NMO, acetone, rt, 4 days; (ii) NaIO4, THF–H2O
(1:1), 0 °C to rt, 3 days; (iii) NaBH4, MeOH, 0 °C–rt, 24 h; (iv) BnBr, Ag2O, DMF, rt,
24 h; 90% (four steps).
⇑
Corresponding author. Tel./fax: +81 53 478 1150.
E-mail address: tchyoda@ipc.shizuoka.ac.jp (H. Yoda).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.018

1174
J. Wierzejska et al. / Tetrahedron Letters 52 (2011) 1173–1175
findings on similar reactions,3 this equilibrium was shifted toward
the ring-opened form through the treatment of this mixture with
vinylmagnesium chloride, facilitating the syn-selective reaction to
provide the diastereomerically pure adduct 2 in 81% yield from 1.
When the secondary hydroxyl group of 2 was converted into the
carbonyl group upon the treatment with pyridinium chlorochro-
OBn
OBn
a
OBn
OBn
OBn
OBn
9
+
N
R
N
R
10a
; R = Boc
10b
; R = Boc
10b'; R = H
mate (PCC), in situ cyclization took place to give
c-lactam 3 in
b
OBn
64% yield, whose stereochemistry at the C5 center was established
by comparison of its 13C NMR spectrum with that for the antipode
of 3.4 Oxidative cleavage of the vinyl group in 3 by a two step pro-
cedure of dihydroxylation with N-methylmorpholine-N-oxide
(NMO) and OsO4 followed by reaction with NaIO4 gave aldehyde,
which was subjected to successive NaBH4 reduction and benzyl
protection without purification, giving the corresponding benzyl
ether 4 in 90% over four steps.
At this point, we envisioned that replacement of the MPM moi-
ety of 4 with the Boc functionality would offer potential advanta-
ges making the lactam carbonyl more reactive in nucleophilic
processes due to reduced conjugation of the amide bonding associ-
ated with delocalization of the nitrogen electron pair in the second
carbonyl system.5 Accordingly, the treatment of 4 with ceric
ammonium nitrate (CAN) removed the MPM group to give unsub-
c
OBn
OBn
d
10b
OHC
OBn
N
Boc
11
OBn
OH
3
f
4
OH
OH
*
OH
8
2
5
OBn
OH
N
R
N
H
C9H19
C9H19
1
*
7
6
12α; less polar
β; more polar
HCOOH
(R = Boc)
12
14α; 8-epi-(+)-betzellaside B
14β; (+)-betzellaside B
(formate salts)
e
13
13β
α
(R = H)
Scheme 3. Reagents and conditions: (a) CH2@CHCH2SnBu3, TBSOTf, toluene,
ꢀ78 °C, 9 h; 30% (10a), 66% (10b); (b) MeOH–HCl, rt, 2 h, 81%; (c) (i) OsO4, NMO,
acetone–H2O (3:2), rt, 24 h; (ii) NaIO4, THF–H2O (1:1), 0 °C to rt, 4 h; 91% (two
steps); (d) C9H19MgBr, THF, ꢀ78 °C to 0 °C, 4.5 h; 45% (12
HCl, rt, 12 h; (13 ) 90%; (13b) 84%; (f) (i) H2, Pd/C (10% Pd), MeOH–HCl, rt, 11 days;
(ii) HCO2H, MeOH, rt; (14 ); 90% (14b); 70%.
situted c-lactam, which was then converted into the Boc-protected
5 with (Boc)2O in 77% for two steps (Scheme 2). As expected, the
reaction of 5 with vinylmagnesium chloride resulted in nucleo-
philic addition to the carbonyl group on the c-lactam ring to afford
a), 45% (12b); (e) MeOH–
a
a
the corresponding hemiaminal. This product could be reduced un-
der the Luche conditions due to spontaneous equilibrium with the
acyclic enone at ambient temperature, giving rise to acyclic allyl
alcohol 6 in 81% for two steps.6 This compound was then deoxy-
genated in two steps by quantitative transformation into ethyl car-
bonate 7 followed by catalytic transfer hydrogenolysis using
ammonium formate and triethylamine in the presence of tetra-
kis(triphenylphosphine)palladium to give acyclic olefin 8 in 86%
without isolation of the internal olefinic product of 8.7 Then, the
piperidine ring system was constructed by conversion of the ole-
finic endgroup of 8 into aldehyde through the dihydroxylation–
oxidation sequence, which underwent spontaneous in situ cycliza-
tion to form the heterocyclic hemiaminal 9 in excellent yield (98%
for two steps).
of the C1-allylated products 10a,b in 96%, which could be separated
in part by column chromatography on silica gel. Unfortunately, our
initial attempts to determine the absolute configuration of the new-
ly formed stereocenter based on the 1H NMR analysis of the major
isomer 10b failed due to overlapping resonances for the C1 methine
proton and protons of the Boc groups. Alternatively, N-unsubstitut-
ed piperidine analogue 10b0 prepared by the treatment of 10b with
HCl in methanol was assumed to provide well-separated resonances
in the 1H NMR spectrum. Indeed, 10b0 showed clearly distinguish-
able multiplicities in the 1H NMR spectrum, giving J coupling con-
3
3
3
stants of JH2eq–H3 = 2.8 Hz, JH2ax–H3 = 11.7 Hz, JH1–H2eq = 2.8 Hz,
3
and JH1–H2ax = 2.7 Hz. Analysis of the given J values allowed us to
Having the hemiaminal intermediate in hand, our next objec-
tive was the introduction of a carbon side chain at the C1 position
of the six-membered piperidine ring system (Scheme 3). Thus, a
Lewis acid mediated allylation of 9 was carried out by using allyl-
tributylstannane and tert-butyldimethylsilyl triflate (TBSOTf) in
toluene at ꢀ78 °C.8 Under these conditions, the reaction took place
in a stereoselective manner to form a 1:2 diastereomeric mixture
visualize the three-dimensional structure of the substituted piperi-
dine ring system, demonstrating the desired 1,5-syn relative orien-
tation of the substituents with (S)-configuration at the C1 position
of 10b (see Supplementary data).
In the next step, we subjected 10b to dihydroxylation–oxida-
tion sequence under the above reaction conditions. These reactions
took place very efficiently to give the corresponding aldehyde 11 in
91% yield for two steps. Introduction of the alkyl side chain by
Grignard addition furnished a 1:1 mixture of diastereomeric alco-
hols 12 in 90% yield, being separated by chromatography on silica
BnO
O
OBn
OBn
BnO
HO
OBn
OBn
OBn NHBoc
OBn
b
to provide less and more polar fractions 12
After acid-catalyzed independent removal of the Boc groups of the
diastereomers 12 ,b (90% and 84% yield, respectively), the result-
ing N-unsubstituted piperidine analogues 13 ,b were then hydro-
a and 12b, respectively.
N
R
N
O
OBn
Boc
a
4
; R = MPM
5; R = Boc
a
a
genated in the presence of 10% Pd/C and HCl under H2 atmosphere
to give HCl salts of the fully deprotected products,9 which were
subjected to counteranion exchange through the treatment with
formic acid in methanol to afford the corresponding formate salts
OBn
NHBoc
NHBoc
OBn
OBn
3
4
OBn
c
e
f
2
OBn
OBn
5
OBn
N
1
HO
OR' OBn
OBn
6
Boc
9
14a
,b in 90% and 70% yield, respectively.
6
7
; R' = H
; R' = CO2Et
d
Figure 1 depicts the 1H NMR spectra of these final products.
8
Remarkably, the spectral shape observed for 14b closely matches
that for formate salt of (+)-batzellaside B, which has been given
in the literature.1 On the other hand, inspection of the 1H NMR
Scheme 2. Reagents and conditions: (a) (i) CAN, MeCN–H2O (9:1), 0 °C to rt, 2.5 h;
(ii) Boc2O, Et3N, DMAP, CH2Cl2, 0 °C, 2 h; 77% (two steps); (b) CH2@CHMgCl, THF,
ꢀ78 °C, 1.5 h; (c) NaBH4, CeCl3ꢁ7H2O, MeOH, 0 °C, 2 h; 81% (two steps); (d) ClCO2Et,
py, 0 °C to rt, 12 h; quant.; (e) Pd(PPh3)4, HCO2NH4, Et3N, toluene, reflux, 30 min;
86%; (f) (i) OsO4, NMO, acetone, rt, 24 h; (ii) NaIO4, THF–H2O (1:1), 0 °C to rt, 3.5 h;
98% (two steps).
spectrum of 14
a revealed that resonances assignable to the pro-
tons at the C2 position (H2 and H20) were significantly shifted
downfield relative to those of 14b, accompanied by noticeable

J. Wierzejska et al. / Tetrahedron Letters 52 (2011) 1173–1175
1175
OBn
-0.04
MTPA
OBn
O
-0.03
+0.14
OBn
N
+0.04
+0.12
+0.10
+0.13
+0.09
-0.11
-0.04
-0.01
-0.05
Boc
(S)- or (R)-16α
Figure 2. Model projection for the
DdSR value distributions in ppm (600 MHz,
CDCl3).
In conclusion, we have completed the total synthesis of
(+)-batzellaside B and its C8-epimer from a known -arabinose-
L
Figure 1. Comparison of 1H NMR spectra of 14
a and 14b.
derived tribenzyl ether in 22 steps with overall yields of 3.9%
and 5.4%, respectively. In the course of our synthetic studies the
absolute configuration of (+)-batzellaside B also has been unambig-
uously determined to be 1S,3S,4S,5R,8S by the modified Mosher
analysis of the synthetic intermediate prepared through the sepa-
rate route. The present study represents the first total synthesis of
this class of natural products as well as the first report revealing
the unspecified absolute stereochemistry. Efforts to provide a more
facile and efficient route to this class of natural products and to ex-
plore synthetic access to homologous batzellaside derivatives are
in progress.
changes in spectral shapes of the H20 and H7 with even less re-
solved multiplets. In addition, the 13C NMR chemical shifts for
14b are completely consistent with literature data of structurally
related batzellaside A,1 whereas significant differences in the cor-
responding spectral data are evident in the case of 14
observations, it is evident that 14b can be assigned as the formate
salt of (+)-batzellaside B and 14
should be its C8-epimer.10
a. From these
a
After the completion of the total synthesis, we turned next to
spectroscopic determination of the absolute stereochemistry of
the final products. Unfortunately, an attempt to determine the
Acknowledgment
absolute configurations at the C8 chiral centers of 14
a and 14b
by employing the Mosher’s method11 failed due to indistinguish-
able proton resonances. Therefore, we explored a separate route
involving the intermediacy of a structurally simpler system so as
to validate the Mosher analysis (Scheme 4). Based on these consid-
erations, 11 was allylated by following the Barbier-type protocol12
to give a mixture of low and more polar diastereomeric isomers
This research was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supplementary data
15
by silica-gel column chromatography, we subjected 15
tization with (R)- and (S)- -methoxy- -(trifluoromethyl)phenyl-
acetyl chloride (MTPA-Cl) to convert into the corresponding (S)-
and (R)-16 , respectively. Model projection performed according
to the empirical method with the
dSR (=dS ꢀ dR, ppm) value distri-
butions11b for (S)- and (R)-16
allowed precise determination of
the absolute stereochemistry, indicating the absolute configura-
tions at C8 for 15 and 15b to be R and S, respectively (Fig. 2).
Meanwhile, 15b was shown to undergo the cross metathesis with
1-heptene and subsequent hydrogenation to result in exclusive
production of 12b as evidenced by identity of the 1H NMR reso-
nances (see Supplementarydata). Consequently, the definitive con-
clusion drawn from the correlation of the above structure/absolute
a
and 15b, respectively. After the separation of each component
Supplementary data (spectroscopic data for all intermediates,
structural analysis of 10b0, details of the transformation of 15b into
12b) associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2011.01.018.
a
to deriva-
a
a
a
D
References and notes
a
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2. Tejima, S.; Fletcher, H. G., Jr. J. Org. Chem. 1963, 28, 2999–3004.
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a
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3 would have the (R)-configuration at the newly formed
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configuration relationship is that the C8 stereochemistries of 14
a
and 14b should be R and S, respectively.
6. On the basis of simple 1H NMR spectral data, it is reasonable to assume that 6
was formed as a single diastereomer.
OBn
O
O
7. (a) Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 91–95; (b) Radinov, R.; Hutchings,
S. D. Tetrahedron Lett. 1999, 40, 8955–8960.
3
4
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Ph
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a
OR
8
2
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L.; Colombo, L.; Colombo, M.; Di Giacomo, M.; Manzoni, L.; Vodopivec, B.;
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L.; Colombo, L.; Colombo, M.; Manzoni, L.; Scolastico, C. Tetrahedron 2003, 59,
6241–6250.
11
5
OBn
MeO CF3
F3C OMe
N
Boc
1
*
7
6
(R)-MTPA
(S)-MTPA
15α; less polar
15
β; more polar
9. The crude HCl salts were purified on DOWEX 50W-X8 (H+ form resin) column
with aqueous NH3 at 0.7 M prior to use.
c
(R = H)
12
β
b
10. The observed optical rotation of 14b (½a D25
ꢂ
+9.3 (c 0.5, MeOH)) close to that for
+10 (c 0.5, MeOH), see Ref. 1) indicated their
(
)
(
) 16
(R = (S)-MTPA or (R)-MTPA)
α
S - or R -
the natural product (lit. ½a D25
ꢂ
structural and stereochemical identity.
Scheme 4. Reagents and conditions: (a) CH2@CHCH2Br, Mg, THF, ꢀ40 °C, 1 h then
ꢀ30 °C, 2 h; 58% (15 ), 27% (15b); (b) (R)- or (S)-MTPA-Cl, py, rt, 24 h (for (S)-16 ),
5 days (for (R)-16 ); 46% ((S)-16 ), 81% ((R)-16 ); (c) (i) 1-octene, Grubbs II
complex, toluene, rt, 4.5 h; (ii) H2, Pd/C(en), MeOH, rt, 12 h; 61% (for two steps).
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a
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