Stereoselective total synthesis of (-)-batzellasides a, b, and c

Article abstract of DOI:10.1002/ejoc.201201567

Total synthesis of (-)-L-batzellasides A, B, and C has been achieved in 13 steps from known lactone 2 in 12.6, 13.2, and 13.8 % overall yields, respectively. The key steps in this synthesis were the stereoselective introduction of an allyl group at the C1

Full text of DOI:10.1002/ejoc.201201567

FULL PAPER
DOI: 10.1002/ejoc.201201567
Stereoselective Total Synthesis of (–)-Batzellasides A, B, and C
Toru Okaki,[a] Ryohei Fujimura,[b] Masataka Sekiguchi,[c] Dejun Zhou,[c] Kenji Sugimoto,[c]
Daishiro Minato,[c] Yuji Matsuya,[c] Atsushi Kato,[d] Isao Adachi,[d] Yasuhiro Tezuka,[e]
Ralph A. Saporito,[f] and Naoki Toyooka*[a,b]
Keywords: Natural products / Total synthesis / Asymmetric synthesis / Allylation / Nitrogen heterocycles
Total synthesis of (–)-
L
-batzellasides A, B, and C has been
at the C1 position by acyliminium chemistry and Brown’s
asymmetric allylation of the corresponding aldehydes to con-
struct a stereocenter on the side chain.
achieved in 13 steps from known lactone 2 in 12.6, 13.2, and
13.8% overall yields, respectively. The key steps in this syn-
thesis were the stereoselective introduction of an allyl group
ficient and stereoselective total synthesis of (–)-l-batzellas-
ides A, B, and C, which are the enantiomers of these natural
products, starting from commercially available tri-O-benzyl-
d-glucal (1).[4]
Introduction
Batzellasides A, B, and C were isolated from a Madagas-
can sponge Batzella sp., which was collected off the west
coast of Madagascar by Crews in 2005,[1] and showed anti-
bacterial activities against Staphylococcus epidermidis with
minimum inhibitory concentrations (MICs) of less than
6.3 μg/mL (Figure 1). In addition, these compounds were
the first example of an iminosugar from a marine organism,
which is an important structural framework for the inhibi-
tion of glycosidases.[2] For these reasons, batzellasides are
an attractive synthetic target. The first total synthesis of
natural (+)-d-batzellaside B was reported by Yoda’s group
in 2011,[3a] and the absolute configuration of natural (+)-d-
batzellaside B was determined to be 1S,3S,4S,5R,8S. How-
ever, the synthesis required 22 steps starting from a known
tribenzyl ether derived from l-arabinose, and only resulted
in a 3.9% overall yield, although a new formal synthetic
route has been reported.[3b] Herein, we report on the ef-
Figure 1. Structure of natural d-batzallasides A, B, and C and l-
enantiomers.
Results and Discussion
The synthesis began with pyridinium chlorochromate
(PCC) oxidation of tri-O-benzyl-d-glucal (1), following the
method of Squarcia et al.,[5] which resulted in a 55% yield
of lactone 2. The direct conversion of 2 into methyl ester 3
under Fischer’s esterification conditions has been re-
ported,[5] however we obtained a very low yield of 3 under
the same reaction conditions. As an alternative route to 3,
we performed hydrolysis of 2 with LiOH, followed by esteri-
fication with diazomethane at 0 °C, which resulted in a 94%
yield of 3 in two steps. Azide 4 was synthesized in one step
from 3 by a Mitsunobu reaction with HN3 and diethyl azo-
dicarboxylate (DEAD), resulting in an 82% yield. A pre-
vious synthesis of azide 4 required a two-step conversion,
involving mesylation and substitution with NaN3.[4] Cata-
lytic hydrogenation of 4 over Pd/C gave rise to lactam 5 in
an 98% yield (Scheme 1).
[a] Graduate School of Innovative Life Science, University of
Toyama,
3190 Gofuku, Toyama 930-8555, Japan
[b] Graduate School of Science and Technology for research,
University of Toyama,
3190 Gofuku, Toyama 930-8555, Japan
E-mail: toyooka@eng.u-toyama.ac.jp
Homepage: http://www.u-toyama.ac.jp/en/index.html
[c] Graduate School of Medicine and Pharmaceutical Sciences,
University of Toyama,
2630 Sugitani, Toyama 930-0194, Japan
[d] Department of Hospital Pharmacy, University of Toyama,
2630 Sugitani, Toyama 930-0194, Japan
[e] Institute of Natural Medicine, University of Toyama,
2630 Sugitani, Toyama 930-0194, Japan
[f] Department of Biology, John Carroll University,
University Heights, Ohio 44118, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201567.
Eur. J. Org. Chem. 2013, 2841–2848
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2841

N. Toyooka et al.
FULL PAPER
Figure 3. Stereoselectivity of allylation of iminium salt.
Once key and common intermediate 7 was obtained, we
next focused our attention on the construction of the
stereocenter on the side chain. For this purpose, we adopted
Brown’s asymmetric allylation reaction[8] of aldehyde 8,
which was easily derived from 7. The Lemieux–Johnson
oxidation of 7 afforded 8, which was treated with (+)-B-
allyldiisopinocampheylborane [(+)-(Ipc)2B(allyl)] solution
to provide adduct 9 as a single diastereomer in 70% yield.
The stereochemistry of the newly formed stereocenter on 9
was determined by a NOESY experiment of cyclic carb-
amate 10 derived from 9 (Scheme 3). From the observed
NOE between Ha and Hb in 10, the stereochemistry at C8
Scheme 1. Synthesis of 5. Reagents and conditions: (a) PCC,
CH2Cl2, reflux (55%); (b) LiOH, MeOH/H2O (3:1), reflux;
(c) CH2N2, EtOAc, 0 °C (94%, 2 steps); (d) HN3, Ph3P, DEAD,
THF, 0 °C to room temp. (82%); (e) H2, 10% Pd/C, EtOAc (98%). was determined to be R, unambiguously (Figure 4).
Lactam 5 was converted into carboxybenzyl (Cbz)-imide
6, which was subjected to allylation of the corresponding
acyliminium ion. Treatment of 6 with diisobutylaluminium
hydride (DIBAL) at –78 °C followed by allyltrimethylsilane
in the presence of BF3·Et2O gave an allylated product in a
1
ratio of 10:1 (estimated from H NMR spectroscopic data),
and major product 7 was isolated in 50% yield (Scheme 2).
The stereochemistry of 7 was determined to be as shown in
Figure 2 based upon correlation between protons Ha and
Hb from a NOESY experiment.
Scheme 3. Synthesis of key intermediate (10). Reagents and condi-
tions: (a) OsO4, NaIO4, 2,6-lutidine, 1,4-dioxane/H2O (3:1); (b) (+)-
(Ipc)2B(allyl), Et2O, –78 °C (70% 2 steps); (c) NaH, THF/DMF
(3:1) (90%).
Scheme 2. Synthesis of 7. Reagents and conditions: (a) Lithium
bis(trimethylsilyl)amide, CbzCl, THF, –78 °C to 0 °C (83%);
(b) DIBAL, CH2Cl2, –78 °C; (c) allyltrimethylsilane, BF3·Et2O,
CH2Cl2, –78 °C (50%, 2 steps).
Figure 4. Stereochemistry of 10.
Installation of a different side chain for batzellasides A,
B, and C was achieved by olefin cross metathesis reaction
with 1-nonene, 1-octene or 1-decene, which resulted in ole-
fins 11, 12, and 13 as a E, Z mixture in 85, 90, and 91%
yields, respectively (Scheme 4). The cross metathesis reac-
tion proceeded smoothly and was catalyzed by Hoveyda–
Figure 2. Stereochemistry of 7.
Grubbs’ 2nd generation catalyst,[9] rather than Grubbs’ cat-
alyst.[10] Finally, hydrogenation of olefins 11, 12, and 13 by
The stereoselectivity of the above allylation reaction was using Pearlman’s catalyst, followed by hydrolysis of the cy-
explained by A(1,3) strain[6] and stereoelectronic effects[7] as clic carbamate with KOH resulted in (–)-l-batzellasides A,
shown in Figure 3.
B, and C in 75, 67, and 69% yield as formic acid salts,
2842
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2841–2848

Stereoselective Total Synthesis of (–)-Batzellasides A, B, and C
Table 1. NMR spectroscopic data for batzellaside A, B, and C, and C8 epimers in [D4]MeOH.
(–)-l-Batzellaside B
formic acid salt
(+)-d-Batzellaside B
(–)-l-Batzellaside A
formic acid salt
(–)-l-Batzellaside C
formic acid salt
19
20
21
formic acid salt[3a]
δH (J in Hz) δC
δH (J in Hz)
δC
δC
δC
δC
δC
δC
3.91 br. m
72.1
3.91 ddd (3.0. 3.0. 3.0)
3.86–3.75 m
3.65–3.49 m
2.01 ddd (14.7. 13.5. 2.4)
1.83 dt (14.4. 3.0. 3.0)
1.76–1.64 m
1.46 br. s
1.30 br. s
0.90 t (6.8)
72.0
67.3
67.2
60.8
58.5
53.4
39.4
39.4
33.0
32.5
30.7
30.7
30.6
30.4
26.2
23.7
14.4
72.0
67.3
67.2
60.9
58.5
53.4
39.5
39.4
33.1
33.0
32.6
30.80
30.75
30.70
30.5
26.3
23.7
14.4
72.1
67.3
67.2
60.8
58.5
53.4
39.5
33.1
33.0
32.6
30.8
30.7
30.5
30.4
26.3
23.7
14.4
69.7
67.2
67.1
61.0
58.1
51.3
39.2
38.4
33.1
32.0
30.7
30.5
30.4
26.3
23.7
14.4
69.7
67.2
67.1
61.0
58.1
51.3
39.2
38.4
33.1
32.0
30.80
30.75
30.70
30.4
26.7
23.7
14.4
69.7
67.2
67.1
61
3.83–3.75 m 67.3
3.59–3.50 m 67.2
2.01 t (14.9) 60.8
1.84 d (14.3) 58.5
1.73–1.69 m 53.5
1.48 br. s
1.32 br. s
0.90 t (6.8)
58.1
51.3
39.2
38.4
33.1
32.0
30.74
30.70
30.5
26.7
23.7
14.4
39.5
39.4
33.0
32.6
30.8
30.7
30.5
30.4
26.3
23.7
14.4
respectively. The spectroscopic data for synthetic (–)-l-
batzellaside B were in good agreement with those reported
values as shown in Table 1.[3]
Scheme 4. Synthesis of (–)-batzellasides A, B, and C. Reagents and
conditions: (a) 2nd generation Hoveyda–Grubbs catalyst (10 mol-
%), 1-nonene or 1-octene or 1-decene, CH2Cl2, reflux (11: 85%, 12:
90%, 13: 91%); (b) H2, Pd(OH)2 (20%), EtOH; (c) KOH (aq.), 2-
propanol, reflux, then HCO2H [(–)-batzellaside A: 75%, (–)-batzel-
laside B: 67%, (–)-batzellaside C: 69%].
Scheme 5. Synthesis of 19, 20, and 21. Reagents and conditions:
(a) (–)-(Ipc)2B(allyl), Et2O, –78 °C (71% 2steps); (b) NaH, THF/
DMF (3:1; 87%); (c) 2nd generation Hoveyda–Grubbs catalyst
(10 mol-%), 1-nonene, 1-octene or 1-decene, CH2Cl2, reflux (16:
90%, 17: 90%, 18: 88%); (b) H2, Pd(OH)2 (20%), EtOH; (c) KOH
(aq.), 2-propanol, reflux, then CO2H (19: 72%, 20: 67%, 21: 55%).
C8 epimers 19, 20, and 21 were also synthesized in the
same manner as for Schemes 3 and 4 by using (–)-
(Ipc)2B(allyl) instead of (+)-(Ipc)2B(allyl) through alcohol
14, cyclic carbamate 15, and olefins 16, 17, and 18 as shown exhibited the most potent inhibition against this enzyme
in Scheme 5. with IC50 values of 6.7 μm. Epimer 21 was also a good in-
A previous study demonstrated that (+)-d-batzellas- hibitor for β-galactosidase. Epimer 19 had a lower inhibi-
ides A, B, and C inhibited the growth of Staphylococcus tion toward β-galactosidase relative to (–)-l-batzellaside A,
epidermidis with MICs of Ͻ 6.3 μg/mL.[1] However, there and it was the only compound that inhibited β-glucuronid-
was no report about glycosidase inhibition. Thus, we first ase. Among (–)-l-batzellasides A, B, and C and their epi-
analyzed the inhibitory activities of (–)-l-batzellasides A, B, mers 19, 20, and 21, both the length of the side chain and
and C and newly synthesized C8 epimers 19, 20, and 21 the stereochemistry at the C8 position are important for the
towards various glycosidases. The IC50 values towards spe- inhibitory activities against β-galactosidase and β-glucuron-
cific glycosidases are summarized in Table 2. All of the syn- idase. Among them, inhibitors of β-glucuronidase have the
thesized compounds showed inhibitory activity against bo- potential to become drugs that suppress the side effects of
vine liver β-galactosidase. It is not easy to find the struc- camptotecin derivative CPT-11, an anti-tumor drug used
tural requirements against this inhibition but it seems that for the treatment of small-cell lung carcinoma and other
the deoxy l-xylo configuration of the piperidine ring is im- solid tumors. CPT-11 is changed to an active form SN-38
portant for inhibition. Among them, (–)-l-batzellaside A by the action of carboxyesterase in the liver. SN-38 is fur-
Eur. J. Org. Chem. 2013, 2841–2848
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2843

N. Toyooka et al.
FULL PAPER
Table 2. Concentration of batzellaside giving 50% inhibition of various glycosidases.
IC50 (µm)
19 (–)-Batzellaside B
Enzyme
(–)-Batzellaside A
20
(–)-Batzellaside C
21
α-Glucosidase (from yeast)
n.i.[a]
43
n.i.
50
n.i.
18
n.i.
n.i.
n.i.
n.i.
85
n.i.
n.i.
897
83
n.i.
26
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
45
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
35
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
43
β-Glucosidase (from bovine liver)
α-Galactosidase (from coffee beans)
β-Galactosidase (from bovine liver)
α-Mannosidase (from Jack beans)
β-Mannosidase (from snail)
α-l-Fucosidase (from bovine kidney)
α-l-Rhamnosidase (from Penicillium decumbens)
β-Glucronidase (from E. coli)
n.i.
6.7
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
7.5
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
Trehalase (from porcine kidney)
Amyloglucosidase (from Aspergillus niger)
[a] n.i.: no inhibition (less than 50% inhibition at 1000 mm).
ing, the reaction mixture was filtered through a Celite pad. The
Celite pad was washed several times with AcOEt, and the filtrates
were combined and concentrated resulting in a black oil, which was
purified by chromatography on silica gel (160 g, n-hexane/acetone,
10:1) to give 2 (23.9 g, 55.5 mmol, 55%) as a pale yellow solid. The
spectroscopic data were identical with those of reported values.[4]
ther changed to inactive SN-38 glucuronate conjugate,
which is excreted into bile.[11] By the action of β-glucuronid-
ase from intestinal bacteria, deconjugation of SN-38 glucur-
onide gives rise to SN-38, which causes the severe diarrhea
in patients treated with CPT-11. Therefore, the inhibitory
activity of compound 19 against β-glucuronidase is note-
worthy.
Methyl (3R,4R,5R)-3,4,6-Tris(benzyloxy)-5-hydroxyhexanoate (3):
The procedure in ref.[4] was modified as described. Aqueous LiOH
(1 n, 1.4 mL) was added to a solution of 2 (0.62 g, 1.44 mmol) in
MeOH (4.2 mL). The reaction mixture was heated to reflux for 2 h.
After cooling, the reaction mixture was acidified with 10% HCl to
pH 4 and then the aqueous mixture was extracted with AcOEt
(3ϫ10 mL). The organic layers were combined, washed with brine,
and dried with anhydrous MgSO4. After removal of the solvent,
the residue was dissolved in Et2O (5 mL) and treated with ethereal
CH2N2, prepared from N-nitroso-N-methylurea (371 mg,
3.6 mmol) and a solution of KOH (0.57 g, 10.2 mmol) in a mixture
of H2O (2 mL) and Et2O (3 mL), at 0 °C for 30 min. The reaction
mixture was concentrated resulting in a pale yellow oil, which was
purified by chromatography on silica gel (30 g, AcOEt/n-hexane,
Conclusions
We have achieved the efficient and stereoselective total
synthesis of (–)-l-batzellasides A, B, and C, and the
enantiomers of these natural products, in 13 steps beginning
with known lactone 2. The total synthesis of (–)-l-batzella-
sides A, B, and C resulted in 12.6, 13.2, and 13.8% overall
yields, respectively, whereas C8 epimers 19, 20, and 21 re-
sulted in 13.0, 12.1, and 9.7% overall yields, respectively.
(–)-l-Batzellasides A and epimer 21 showed potent inhibi-
tion against bovine liver β-galactosidase, with IC50 values 1:4) to give 3 (0.63 g, 1.35 mmol, 94%) as a pale yellow oil. The
spectroscopic data were identical with those of reported values.[4]
of 6.7 and 7.5 μm, respectively. Epimer 19 was a moderate
inhibitor for β-glucuronidase. The flexible and synthetic
route developed here is currently being used to synthesize
additional congeners possessing shorter side chains, and
studies of the inhibitory activities of these congeners
towards various glycosidases are in progress.
Methyl (3R,4R,5S)-5-Azido-3,4,6-tris(benzyloxy)hexanoate (4): The
procedure in ref.[4] was modified as shown below. Ph3P (6.51 g,
24.8 mmol) was added to a solution of 3 (8.87 g, 19.1 mmol) in
tetrahydrofuran (THF; 25 mL). A solution of HN3 (0.8 n,
38.2 mmol) in benzene (48 mL), prepared from NaN3 (3.26 g,
50.2 mmol) and concentrated H2SO4 (1.26 mL, 23.7 mmol) in a
mixture of H2O (36 mL) and benzene (60 mL) at 0 °C, was added
to the stirred mixture. Diethyl azodicarboxylate (≈ 2.2 mol/L,
11.2 mL, 24.9 mmol) at 0 °C was added slowly to the stirred mix-
ture. The reaction mixture was stirred for 12 h at room temperature.
The solvent was removed to give a pale yellow oil, which was puri-
fied by chromatography on silica gel (80 g, AcOEt/n-hexane, 1:10)
to give 4 (7.67 g, 15.7 mmol, 82%) as a colorless oil. The spectro-
scopic data were identical with those for the reported values.[4]
Experimental Section
General Information: Flash chromatography was performed with
Kanto Kagaku silica gel 60N (63-210 mm). NMR spectra were re-
corded with a JEOL a-GX 400 or ECP-NMR 600 spectrometer in
the solvent indicated. Chemical shifts (δ) are reported downfield
from tetramethylsilane and referenced with CHCl3 (δ = 7.26 ppm)
as an internal standard. Peak multiplicities are designated by the
following abbreviations: s singlet, d doublet, t triplet, q quartet, m
multiplet, br. broad. High-resolution mass spectroscopic data was
obtained with a JEOL MStation JMS-700. All commercial reagents
were used as received unless otherwise noted.
(4R,5R,6S)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)piperidin-2-one
(5): Pd/C (10 %, 491 mg) was added to a solution of 4 (6.15 g,
12.6 mmol) in AcOEt (13 mL), and the resulting suspension was
hydrogenated at 1 atm under a hydrogen atmosphere for 48 h. The
catalyst was filtered off through a Celite pad and the filtrate was
(4R,5S,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)tetrahydro- evaporated to give 5 (5.34 g, 12.4 mmol, 98%) as a colorless oil.
pyran-2-one (2): PCC (43.6 g, 0.20 mol) and silica gel (60 g) were
added to a solution of 1 (42.1 g, 0.10 mol) in CH2Cl2 (100 mL).
The resulting suspension was heated to reflux for 12 h. After cool-
This compound was used directly in the next step without further
purification. The spectroscopic data were identical with those for
the reported values.[4]
2844
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2841–2848

Stereoselective Total Synthesis of (–)-Batzellasides A, B, and C
Benzyl (4R,5R,6S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-oxo-
piperidine-1-carboxylate (6): A solution of lithium bis(trimethyl-
were added. The resulting mixture was stirred at room temperature
for 17 h. The reaction solvent was removed to give a pale yellow oil,
silyl)amide (10.4 mL, 16.6 mmol, 1.6 mol/L, in THF) at –78 °C was which was purified by chromatography on silica gel (60 g, AcOEt/n-
added to a stirred solution of 5 (5.55 g, 12.9 mmol) in THF hexane, 1:15) to give 9 (1.44 g, 2.27 mmol, 70%) as a pale yellow
(26 mL). The resulting mixture was stirred at –78 °C for 0.5 h. oil. 1H NMR (300 MHz, CDCl3): δ = 7.32–7.26 (m, 20 H), 5.74 (1
Benzyl chloroformate (2.75 mL, 19.3 mmol) was added dropwise to
the mixture, and the reaction mixture was stirred at –78 °C for 1 h.
The reaction was quenched with saturated NaHCO3 (aq.) and then
the aqueous mixture was extracted with CH2Cl2 (3ϫ30 mL). The
organic layers were combined, washed with brine, dried with anhy-
drous MgSO4, and evaporated to give a pale yellow oil, which was
purified by chromatography on silica gel (80 g, AcOEt/n-hexane,
1:10) to give 6 (6.1 g, 10.8 mmol, 83%) as a colorless oil. 1H NMR
H, br.), 5.10–5.00 (m, 5 H), 4.76–4.57 (m, 6 H), 4.45 (dd, J = 6.3,
6.3 Hz, 1 H), 3.90–3.86 (m, 2 H), 3.64–3.58 (m, 2 H), 2.18–2.12 (m,
3 H), 1.94 (ddd, J = 13.1, 6.5, 6.3 Hz, 1 H), 1.67 (ddd, J = 13.1,
6.5, 6.3 Hz, 1 H), 1.66–1.65 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 156.3, 138.5, 138.1, 137.9, 136.3, 134.6, 128.3, 128.24,
128.21, 128.0, 127.6, 127.53, 127.46, 117.5, 80.6, 77.4, 76.6, 73.2,
73.07, 72.97, 72.6, 69.0, 68.7, 67.6, 53.3, 48.7, 42.3, 33.9 ppm. IR
(neat): ν = 3447, 1692 cm–1. MS (ESI): m/z = 635 [M+]. HRMS
˜
(300 MHz, CDCl3): δ = 7.43–7.17 (m, 20 H), 4.76–4.58 (m, 6 H), (ESI): calcd. for C40H45NO6 635.3247; found 635.3261. [α]2D2
=
4.74–4.39 (m, 3 H), 4.25 (ddd, J = 9.0, 7.6, 7.6 Hz, 1 H), 3.92 (dd,
J = 9.9, 1.2 Hz, 1 H), 3.85 (dd, J = 9.0, 5.4 Hz, 1 H), 3.64 (dd, J
= 9.9, 3.6 Hz, 1 H), 3.01 (dd, J = 17.1, 7.6 Hz, 1 H), 2.52 (dd, J =
17.1, 7.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.1,
153.5, 138.0, 137.5, 137.3, 135.0, 128.3, 128.2, 128.1, 128.0, 127.9,
127.7, 127.6, 127.4, 127.3, 127.1, 78.4, 74.4, 73.2, 72.9, 72.2, 68.5,
–15.3 (c = 1.60, CHCl3).
(3R,4aR,6R,7R,8S)-3-Allyl-6,7-bis(benzyloxy)-8-[(benzyloxy)-
methyl]hexahydropyrido[1,2-c][1,3]oxazin-1(3H)-one (10): THF/di-
methylformamide (DMF; 3:1, 4 mL) in a solution of 9 (0.20 g,
0.314 mmol) was added to NaH (17.6 mg, 0.441 mmol, 60% sus-
pension in mineral oil). The stirred reaction mixture was heated to
reflux for 20 h. After cooling, H2O (10 mL) was added, and then
the aqueous mixture was extracted with AcOEt (3ϫ10 mL). The
organic layers were combined, washed with brine, dried with
MgSO4, and evaporated to give a brown oil, which was purified by
chromatography on silica gel (5 g, n-hexane/AcOEt, 10:1) to give
10 (0.149 g, 0.283 mmol, 90 %) as a pale brown oil. 1H NMR
(300 MHz, CDCl3): δ = 7.35–7.26 (m, 15 H), 5.79 (ddt, J = 16.9,
10.3, 6.7 Hz, 1 H), 5.14 (d, J = 16.9 Hz, 1 H), 5.13 (d, J = 10.3 Hz,
1 H), 4.73–4.44 (m, 6 H), 4.29–4.28 (m, 1 H), 4.23 (dtd, J = 11.1,
6.7, 2.8 Hz, 1 H), 3.97 (dd, J = 10.3, 4.3 Hz, 1 H), 3.96–3.93 (m, 1
H), 3.73 (dd, J = 10.3, 2.6 Hz, 1 H), 3.68 (dddd, J = 11.1, 10.5,
2.8, 2.2 Hz, 1 H), 2.49 (dt, J = 14.2, 6.7 Hz, 1 H), 2.32 (dt, J =
14.2, 6.7 Hz, 1 H), 2.18 (dd, J = 14.0, 5.5 Hz, 1 H), 1.93 (dt, J =
13.5, 2.8 Hz, 1 H), 1.76 (dd, J = 14.0, 2.2 Hz, 1 H), 1.42 (dt, J =
13.5, 11.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.9,
138.3, 138.2, 137.9, 132.2, 128.3, 128.2, 127.6, 127.58, 127.53,
127.4, 127.3, 118.6, 78.1, 77.4, 75.8, 75.5, 73.3, 72.3, 71.5, 66.8,
65.9, 54.8, 40.5 ppm. IR (neat): ν = 1774, 1721 cm–1. MS (ESI):
˜
m/z = 565 [M+]. HRMS (ESI): calcd. for C35H35NO6 565.2464;
found 565.2454. [α]2D4 = +11.8 (c = 0.98, CHCl3).
Benzyl (2S,3R,4R,6R)-6-Allyl-3,4-bis(benzyloxy)-2-(benzyloxy-
methyl)piperidine-1-carboxylate (7): A solution of DIBAL (1 m,
11.2 mL, 1.16 mmol, in n-hexane) at –78 °C was added to a solu-
tion of 6 (5.07 g, 8.98 mmol) in CH2Cl2 (20 mL), and the reaction
mixture was stirred at the same temperature for 0.5 h. The reaction
was quenched with MeOH (6 mL) and Rochella salt (30%, aq.)
and then the aqueous mixture was extracted with CH2Cl2
(3ϫ30 mL). The organic layers were combined, washed with brine,
dried with anhydrous MgSO4 and evaporated to give a pale yellow
oil, which was purified by chromatography on silica gel (80 g, Ac-
OEt/n-hexane, 1:15) to give 7 (2.66 g, 4.49 mmol, 50%) as a pale
1
yellow oil. H NMR (300 MHz, CDCl3): δ = 7.34–7.22 (m, 20 H),
5.70 (br., 1 H), 5.20–5.09 (m, 2 H), 5.02–4.86 (m, 2 H), 4.78–4.44
(m, 7 H), 4.32 (dd, J = 6.4, 6.4 Hz, 1 H), 3.95–3.87 (m, 1 H), 3.82
(dd, J = 10.2, 5.7 Hz, 1 H), 3.65 (br., 1 H), 3.66 (dd, J = 10.2,
5.1 Hz, 1 H), 2.46–2.41 (m, 1 H), 2.26–2.15 (m, 1 H), 2.04 (ddd, J
= 12.0, 6.6, 6.4 Hz, 1 H), 1.57 (ddd, J = 12.0, 6.6, 6.4 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 155.8, 138.6, 138.2, 138.1, 136.5,
135.6, 128.3, 128.2, 128.1, 127.77, 127.67, 127.59, 127.53, 127.45,
127.41, 127.38, 127.25, 117.1, 100.5, 80.6, 73.0, 72.94, 72.86, 72.5,
54.0, 48.0, 39.5, 35.3, 34.3, 29.8 ppm. IR (neat): ν = 1682 cm–1. MS
˜
(ESI): m/z = 527 [M+]. HRMS (ESI): calcd. for C33H37NO5
527.2672; found 527.2661. [α]2D3 = –20.5 (c = 0.46, CHCl3).
(3R,4aR,6R,7R,8S)-6,7-Bis(benzyloxy)-8-(benzyloxymethyl)-3-
(dec-2-en-1-yl)hexahydropyrido[1,2-c][1,3]oxazin-1(3H)-one (11): 1-
Nonene (0.099 mL, 0.569 mmol) was added to a solution of 10
(30 mg, 56.9 μmol) in CH2Cl2 (2 mL) at room temperature. Second-
generation Hoveyda–Grubbs catalyst (3.7 mg, 5.69 μmol) was
added to the stirred mixture. The stirred reaction mixture was
heated to reflux for 24 h. After cooling, the reaction solvent was
removed in vacuo to give a black oil, which was purified by
chromatography on silica gel (5 g, AcOEt/n-hexane, 1:10) to give
11 (30.2 mg, 48.3 μmol, 85 %) as a pale brown oil. 1H NMR
(300 MHz, CDCl3): δ = 7.26–7.17 (m, 15 H), 5.44 (dt, J = 16.5,
5.3 Hz, 1 H), 5.31 (ddd, J = 16.5, 10.5, 5.1 Hz, 1 H), 4.64–4.40 (m,
6 H), 4.21 (br., 1 H), 4.10 (dtd, J = 11.1, 6.7, 2.8 Hz, 1 H), 3.89
(dd, J = 7.5, 3.0 Hz, 1 H), 3.85–3.84 (m, 1 H), 3.73 (dd, J = 7.5,
1.8 Hz, 1 H), 3.62–3.56 (m, 1 H), 2.38–2.33 (m, 1 H), 2.20–2.12 (m,
1 H), 1.93–1.82 (m, 2 H), 1.69 (d, J = 10.8 Hz, 1 H), 1.36–1.19 (m,
14 H), 0.82–0.79 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
153.1, 138.4, 138.3, 138.0, 135.0, 134.9, 133.8, 131.7, 128.3, 128.2,
127.7, 127.62, 127.57, 127.5, 127.3, 127.2, 78.1, 76.1, 75.8, 73.3,
72.2, 71.4, 66.8, 54.0, 47.9, 38.4, 35.6, 35.3, 34.3, 31.8, 31.6, 29.5,
69.5, 67.4, 53.2, 50.8, 39.1 ppm. IR (neat): ν = 1679 cm–1. MS
˜
(ESI): m/z = 591 [M+]. HRMS (ESI): calcd. for C38H41NO5
591.2985; found 591.2980. [α]2D3 = –8.2 (c = 1.10, CHCl3).
Benzyl (2S,3R,4R,6R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-
[(2R)-2-hydroxypent-4-enyl]piperidine-1-carboxylate (9): A 1,4-diox-
ane/H2O mixture (3:1, 40 mL) in a solution of 7 (1.92 g, 3.24 mmol)
was added to 2,6-lutidine (0.75 mL, 6.48 mmol) and OsO4 (4.0 mL,
0.648 mmol, 4% in H2O) at 0 °C. NaIO4 (2.77 g, 13.0 mmol) was
added to the resulting mixture. The reaction mixture was stirred at
room temperature for 2 h. After the reaction was complete, HCl
(10%, aq., 20 mL) was added, and the aqueous mixture was ex-
tracted with CH2Cl2 (3ϫ10 mL). The organic layers were com-
bined, washed with brine, dried with anhydrous MgSO4 and evapo-
rated to give aldehyde 8 as a colorless oil, which was used directly
in the next step.
(+)-(Ipc)2B(allyl) solution (1.0 m, 2.7 mL, 2.67 mmol, in n-pentane)
was added to a solution of aldehyde 8 in Et2O (5 mL) at –78 °C.
The reaction mixture was stirred at –78 °C for 2 h. After the reac-
tion was complete, MeOH (2.0 mL) and 2-aminoethanol (4.0 mL)
29.3, 29.1, 22.6, 14.1 ppm. IR (neat): ν = 1691 cm–1. MS (ESI): m/z
˜
= 625 [M+]. HRMS (ESI): calcd. for C40H51NO5 625.3767; found
625.3778.
Eur. J. Org. Chem. 2013, 2841–2848
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2845

N. Toyooka et al.
FULL PAPER
(3R,4aR,6R,7R,8S)-6,7-Bis(benzyloxy)-8-(benzyloxymethyl)-3-(non-
2-en-1-yl)hexahydropyrido[1,2-c][1,3]oxazin-1(3H)-one (12): 1-Oc-
tene (0.146 mL, 0.93 mmol) was added to a solution of 10 (49 mg,
93.0 μmol) in CH2Cl2 (4 mL) at room temperature. Second-genera-
tion Hoveyda–Grubbs catalyst (5.0 mg, 9.3 μmol) was added to the
stirred mixture. The stirred reaction mixture was heated to reflux
for 15 h. After cooling, the reaction solvent was removed in vacuo
to give a black oil, which was purified by chromatography on silica
gel (10 g, n-hexane/acetone, 20:1) to give 12 (51 mg, 83.7 μmol,
the resulting suspension was hydrogenated at 1 atm under a hydro-
gen atmosphere for 7 d. The catalyst was filtered off through a
Celite pad and the filtrate was evaporated to give a hydrogenated
product. A solution of KOH (4 m aq., 1 mL) was added to a solu-
tion of this product in 2-propanol (1 mL), which was heated to
reflux for 2 h. After cooling, the solvent was evaporated, and the
residue was purified by DOWEX 50W resin (X-8, H+ form, eluent:
0.7 n aqueous NH3), subjected to counterion exchange with formic
acid/methanol (1% v/v) at room temperature, and concentrated in
1
90%) as a pale brown oil. H NMR (500 MHz CDCl3): δ = 7.33–
7.27 (m, 15 H), 5.34 (dt, J = 14.3, 7.2 Hz, 1 H), 5.50–5.31 (m, 1 89.8 μmol, 67%). H NMR (500 MHz, CD3OD): δ = 3.91 (br. m,
vacuo to yield (–)-batzellaside B as the formic acid salt (33 mg,
1
H), 4.75–4.41 (m, 6 H), 4.28 (1 H, br.), 4.22–4.15 (m, 1 H), 3.96
(dd, J = 10.1, 4.4 Hz, 1 H), 3.94–3.87 (m, 2 H), 3.80 (dd, J = 10.1,
1 H), 3.83–3.75 (m, 3 H), 3.59–3.50 (m, 2 H), 2.01 (tt, J = 14.9,
2.3 Hz, 1 H), 1.84 (d, J = 14.3 Hz, 1 H), 1.73–1.69 (m, 2 H), 1.48
2.6 Hz, 1 H), 3.72–3.65 (m, 1 H), 2.53–2.11 (m, 2 H), 2.04–1.55 (m, (br. s,2 H), 1.32 (br. s,16 H), 0.90 (t, J = 6.8 Hz, 3 H) ppm. 13C
6 H), 1.37–1.26 (m, 8 H), 0.88 (t, J = 6.5 Hz, 3 H) ppm. 13C NMR NMR (125 MHz, CD3OD): δ = 72.1, 67.3, 67.2, 60.8, 58.5, 53.5,
(125 MHz, CDCl3): δ = 153.2, 138.5, 138.4, 138.0, 135.0, 134.97, 39.5, 39.4, 33.0, 32.6, 30.8, 30.7, 30.5, 30.4, 26.3, 23.7, 14.4 ppm.
134.8, 133.8, 128.4, 128.36, 128.26, 127.7, 127.67, 127.66, 127.61,
127.5, 127.4, 78.1, 76.1, 75.9, 73.3, 72.3, 71.4, 66.8, 54.0, 47.9, 38.4, (c = 0.5, MeOH).
[α]2D5[3] = –13.5 (c = 0.1, MeOH), for enantiomer, ref.[3a] [α]2D3 = +9.3
35.3, 35.2, 34.3, 32.6, 31.7, 29.3, 28.8, 22.7, 14.1 ppm. IR (neat): ν
˜
(–)-L-Batzellaside C, Formic Acid Salt: Pd(OH)2/C (20%, 3 mg) was
= 1690 cm–1. MS (ESI): m/z = 611 [M+]. HRMS (ESI): calcd. for
added to a solution of 13 (21 mg, 32.8 μmol) in EtOH (3 mL), and
the resulting suspension was hydrogenated at 1 atm under a hydro-
gen atmosphere for 7 d. The catalyst was filtered off through a
Celite pad and the filtrate was evaporated to give a hydrogenated
product. A solution of KOH (4 m aq., 0.5 mL) was added to a
solution of this product in 2-propanol (0.5 mL), which was heated
to reflux for 2 h. After cooling, the solvent was evaporated, and
the residue was purified by DOWEX 50W resin (X-8, H+ form,
eluent: 0.7 n aqueous NH3), subjected to counterion exchange with
formic acid/methanol (1% v/v) at room temperature, and concen-
trated in vacuo to yield (–)-batzellaside C as the formic acid salt
C39H49NO5 611.3611; found 611.3616.
(3R,4aR,6R,7R,8S)-6,7-Bis(benzyloxy)-8-(benzyloxymethyl)-3-
(undec-2-en-1-yl)hexahydropyrido[1,2-c][1,3]oxazin-1(3H)-one (13):
1-Decene (0.40 mL, 2.12 mmol) was added to a solution of 10
(112 mg, 0.21 mol) in CH2Cl2 (6 mL) at room temperature. Second-
generation Hoveyda–Grubbs catalyst (13.0 mg, 21.2 μmol) was
added to the stirred mixture. The stirred reaction mixture was
heated to reflux for 15 h. After cooling, the reaction solvent was
removed in vacuo to give a black oil, which was purified by
chromatography on silica gel (10 g, n-hexane/acetone, 20:1) to give
13 (123 mg, 0.19 mmol, 91 %) as a pale brown oil. 1H NMR
(500 MHz CDCl3): δ = 7.34–7.27 (m, 15 H), 5.33 (dt, J = 14.4,
7.2 Hz, 1 H), 5.43–5.33 (m, 1 H), 4.75–4.41 (m, 6 H), 4.29 (br., 1
H), 4.20–4.16 (m, 1 H), 3.98–3.90 (m, 3 H), 3.81 (dd, J = 10.3,
2.9 Hz, 1 H), 3.69–3.65 (m, 1 H), 2.51–2.18 (m, 2 H), 2.05–1.59 (m,
6 H), 1.35–1.26 (m, 12 H), 0.88 (t, J = 6.6 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 153.2, 138.43, 138.37, 138.0, 135.0, 134.96,
133.8, 131.8, 128.4, 128.35, 128.25, 127.7, 127.65, 127.60, 127.5,
127.4, 127.2, 78.1, 76.9, 76.1, 75.8, 73.3, 72.2, 71.4, 66.8, 54.0, 47.9,
38.4, 35.3, 34.2, 32.6, 31.9, 31.8, 29.3, 29.25, 29.1, 22.7, 14.1 ppm.
1
(9 mg, 22.6 μmol, 69%). H NMR (500 MHz, CD3OD): δ = 3.91
(br. m, 1 H), 3.83–3.77 (m, 3 H), 3.65–3.50 (m, 2 H), 2.01 (dt, J =
14.9, 2.3 Hz, 1 H), 1.83 (d, J = 14.3 Hz, 1 H), 1.73–1.66 (m, 2 H),
1.47 (br. s,2 H), 1.32 (br. s,18 H), 0.89 (t, J = 6.8 Hz, 3 H) ppm.
13C NMR (125 MHz, CD3OD): δ = 72.1, 67.3, 67.2, 60.8, 58.5,
53.4, 39.5, 33.1, 33.0, 32.6, 30.8, 30.7, 30.5, 30.4, 26.3, 23.7,
14.4 ppm. [α]2D2 = –7.4 (c = 0.1, MeOH).
Benzyl (2S,3R,4R,6R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-6-
[(2S)-2-hydroxypent-4-enyl]piperidine-1-carboxylate (14): In a 1,4-
dioxane/H2O mixture (3:1, 20 mL), a solution of 7 (0.49 g,
0.84 mmol) was added to 2,6-lutidine (0.19 mL, 1.68 mmol) and
OsO4 (1.0 mL, 0.17 mmol, 4% in H2O) at 0 °C. To the resulting
mixture was added NaIO4 (0.718 g, 3.36 mmol). The reaction mix-
ture was stirred at room temperature for 2 h. After the reaction was
complete, HCl (10% aq., 10 mL) was added, and then the aqueous
mixture was extracted with CH2Cl2 (3ϫ10 mL). The organic layers
were combined, washed with brine, dried with anhydrous MgSO4,
and evaporated to give aldehyde 8 as a colorless oil, which was
used directly in the next step.
IR (neat): ν = 1693 cm–1. MS (ESI): m/z = 639 [M+]. HRMS (ESI):
˜
calcd. for C41H53NO5 639.3924; found 639.3927.
(–)-L-Batzellaside A, Formic Acid Salt: Pd(OH)2/C (20%, 3 mg) was
added to a solution of 11 (20 mg, 31.9 μmol) in EtOH (3 mL), and
the resulting suspension was hydrogenated at 1 atm under a hydro-
gen atmosphere for 5 d. The catalyst was filtered off through a
Celite pad and the filtrate was evaporated to give a hydrogenated
product. A solution of KOH (4 m aq., 0.5 mL) was added to a
solution of this product in 2-propanol (0.5 mL), and the resulting
mixture was heated to reflux for 2 h. After cooling, the solvent was
evaporated, and the residue was purified by DOWEX 50W resin
(X-8, H+ form, eluent: 0.7 n aqueous NH3), subjected to counter-
ion exchange with formic acid/methanol (1% v/v) at room tempera-
ture, and concentrated in vacuo to yield (–)-batzellaside A as the
formic acid salt (9 mg, 23.9 μmol, 75 %). 1H NMR (500 MHz,
CD3OD): δ = 3.91 (br. m, 1 H), 3.83–3.75 (m, 3 H), 3.65–3.51 (m,
2 H), 2.00 (tt, J = 14.4, 2.4 Hz, 1 H), 1.83 (d, J = 14.3 Hz, 1 H),
1.73–1.68 (m, 2 H), 1.47 (br. s,2 H), 1.31 (br. s,16 H), 0.90 (t, J =
6.8 Hz, 3 H) ppm. 13C NMR (125 MHz, CD3OD): δ = 72.0, 67.3,
67.2, 60.9, 58.5, 53.4, 39.5, 39.4, 33.1, 33.0, 32.6, 30.8, 30.75, 30.70,
30.5, 26.3, 23.7, 14.4 ppm. [α]2D5 = –5.9 (c = 0.2, MeOH).
(–)-(Ipc)2B(allyl) solution (1.0 m, 0.81 mL, 0.81 mmol, in n-pent-
ane) was added to a solution of aldehyde 8 in Et2O (3 mL) at
–78 °C. The reaction mixture was stirred at –78 °C for 2 h. After
the reaction was complete, MeOH (1.0 mL) and 2-aminoethanol
(2.0 mL) were added. The resulting mixture was stirred at room
temperature for 17 h. The reaction solvent was removed to give a
pale yellow oil, which was purified by chromatography on silica gel
(15 g, AcOEt/n-hexane, 1:15) to give 14 (0.38 g, 0.60 mmol, 71%)
as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ = 7.36–7.29
(m, 20 H), 5.78 (br., 1 H), 5.18–5.02 (m, 4 H), 4.86 (br., 1 H), 4.78–
4.64 (m, 6 H), 4.44 (dd, J = 5.1, 5.1 Hz, 1 H), 3.92–3.85 (m, 1 H)
3.79–3.69 (m, 1 H), 3.64–3.56 (m, 2 H), 2.24–2.10 (m, 4 H), 1.98
(ddd, J = 13.5, 5.1, 4.2 Hz, 1 H) 1.86–1.73 (m, 2 H), 1.38 (ddd, J
(–)-L-Batzellaside B, Formic Acid Salt: Pd(OH)2/C (20%, 5 mg) was
added to a solution of 12 (82 mg, 134 μmol) in EtOH (5 mL), and
2846
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2841–2848

Stereoselective Total Synthesis of (–)-Batzellasides A, B, and C
= 13.5, 5.2, 4.2 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
4.9 Hz, 1 H), 3.74–3.72 (m, 1 H), 2.53–2.12 (m, 2 H), 2.09–1.56 (m,
156.3, 138.5, 138.1, 138.0, 136.1, 128.4, 128.26, 128.22, 128.0, 6 H), 1.33–1.26 (m, 8 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
127.6, 127.5, 127.4, 127.2, 116.6, 80.3, 77.4, 73.6, 73.4, 72.9, 72.5,
(125 MHz, CDCl3): δ = 152.7, 138.5, 138.2, 138.1, 134.8, 128.3,
69.1, 66.8, 53.4, 48.1, 42.9, 41.4, 35.0, 32.6, 31.0, 21.5 ppm. IR 128.25, 128.2, 127.7, 127.6, 127.55, 127.48, 127.4, 127.3, 75.5, 74.5,
(neat): ν = 3448, 1667 cm–1. MS (ESI): m/z = 635 [M+]. HRMS
74.3, 73.2, 72.9, 72.4, 71.3, 67.3, 56.6, 56.3, 47.2, 47.0, 37.8, 34.5,
34.2, 32.4, 32.1, 31.6, 31.3, 29.2, 29.0, 28.7, 22.7, 14.1 ppm. IR
˜
(ESI): calcd. for C40H45NO6 635.3247; found 635.3242. [α]2D2
–10.3 (c = 1.00, CHCl3).
=
(neat): ν = 1699 cm–1. MS (ESI): m/z = 611 [M+]. HRMS (ESI):
˜
calcd. for C39H49NO5 611.3611; found 611.3590.
(3S,4aR,6R,7R,8S)-3-Allyl-6,7-bis(benzyloxy)-8-(benzyloxymeth-
yl)hexahydropyrido[1,2-c][1,3]oxazin-1(3H)-one (15): NaH (42 mg,
1.0 mmol, 60% suspension in mineral oil) was added to a solution
of 14 (0.442 g, 0.70 mmol) in THF/DMF (4:1, 10 mL). The stirred
reaction mixture was heated to reflux for 15 h. After cooling, H2O
(10 mL) was added and the aqueous mixture was extracted with
(3S,4aR,6R,7R,8S)-6,7-Bis(benzyloxy)-8-(benzyloxymethyl)-3-
(undec-2-en-1-yl)hexahydropyrido[1,2-c][1,3]oxazin-1(3H)-one (18):
1-Decene (0.17 mL, 0.91 mmol) was added to a solution of 15
(48 mg, 0.091 mol) in CH2Cl2 (5 mL) at room temperature. Second-
generation Hoveyda–Grubbs catalyst (5 mg, 9.1 μmol) was added
AcOEt (3 ϫ 10 mL). The organic layers were combined, washed to the stirred mixture. The stirred reaction mixture was heated to
with brine, dried with MgSO4, and evaporated to give a brown oil,
which was purified by chromatography on silica gel (15 g, n-hexane/
reflux for 15 h. After cooling, the reaction solvent was removed in
vacuo to give a black oil, which was purified by chromatography
acetone, 10:1) to give 15 (0.320 g, 0.61 mmol, 87%) as a pale brown on silica gel (10 g, n-hexane/acetone, 20:1) to give 18 (51 mg,
oil. 1H NMR (400 MHz, CDCl3): δ = 7.27–7.21 (m, 15 H), 5.74 0.08 mmol, 88 %) as a pale brown oil. 1H NMR (500 MHz,
(ddt, J = 17.3, 10.3, 6.6 Hz, 1 H), 5.08 (d, J = 17.1 Hz, 1 H), 5.07 CDCl3): δ = 7.33–7.27 (m, 15 H), 5.52–5.30 (m, 2 H), 4.64–4.47
(d, J = 10.3 Hz, 1 H), 4.59–4.38 (m, 6 H), 4.34 (m, 1 H), 4.09–3.95 (m, 6 H), 4.29 (br., 1 H), 4.13–4.02 (m, 3 H), 3.98–3.89 (m, 1 H),
(m, 3 H), 3.86–3.83 (m, 1 H), 3.79–3.77 (m, 1 H), 3.70–3.68 (m, 1
3.84 (dd, J = 10.1, 4.9 Hz, 1 H), 3.73–3.71 (m, 1 H), 2.48–2.13 (m,
2 H), 2.04–1.54 (m, 6 H), 1.33–1.26 (m, 12 H), 0.88 (t, J = 6.6 Hz,
H), 2.48 (dt, J = 13.2, 6.6 Hz, 1 H), 2.25 (dt, J = 13.2, 6.6 Hz, 1
H), 2.15–2.07 (m, 1 H), 1.88–1.81 (m, 1 H), 1.65–1.56 (m, 2 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 152.8, 138.6, 138.3,
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 152.6, 138.5, 138.2,
135.0, 134.6, 132.7, 131.8, 128.4, 128.35, 128.25, 127.8, 127.7,
138.1, 132.6, 128.4, 128.2, 127.7, 127.66, 127.63, 127.55, 127.54, 127.6, 127.5, 127.4, 127.2, 75.3, 74.5, 73.2, 73.0, 72.5, 71.4, 70.5,
127.4, 118.6, 75.1, 74.3, 73.0, 72.6, 71.3, 67.4, 56.8, 47.4, 39.1, 34.2, 67.4, 67.1, 56.7, 55.4, 47.2, 45.9, 37.9, 34.6, 34.28, 32.6, 32.2, 31.9,
31.4 ppm. IR (neat): ν = 1699 cm–1. MS (ESI): m/z = 527 [M+].
31.4, 29.7, 29.3, 29.1, 22.7, 14.1 ppm. IR (neat): ν = 1699 cm–1. MS
˜
˜
HRMS (ESI): calcd. for C33H37NO5 527.2672; found 527.2671.
(ESI): m/z = 639 [M+]. HRMS (ESI): calcd. for C41H53NO5
[α]2D9 = –59.5 (c = 1.1, CHCl3).
639.3924; found 639.3909.
(3S,4aR,6R,7R,8S)-6,7-Bis(benzyloxy)-8-(benzyloxymethyl)-3-
(dec-2-en-1-yl)hexahydropyrido[1,2-c][1,3]oxazin-1(3H)-one (16): 1-
Nonene (0.14 mL, 0.834 mmol) was added to a solution of 15
(44 mg, 83.4 μmol) in CH2Cl2 (5 mL) at room temperature. Second-
generation Hoveyda–Grubbs catalyst (5.0 mg, 8.34 μmol) was
added to the stirred mixture. The stirred reaction mixture was
heated to reflux for 24 h. After cooling, the reaction solvent was
removed in vacuo to give a black oil, which was purified by
chromatography on silica gel (5 g, n-hexane/acetone, 20:1) to give
16 (47 mg, 75.1 μmol, 90 %) as a pale brown oil. 1H NMR
(2S,3R,4R,6R)-6-[(S)-2-Hydroxydodecyl]-2-(hydroxymethyl)-
piperidine-3,4-diol, Formic Acid Salt (19): Pd(OH)2/C (20%, 5 mg)
was added to a solution of 16 (110 mg, 178 μmol) in EtOH (5 mL),
and the resulting suspension was hydrogenated at 1 atm under a
hydrogen atmosphere for 7 d. The catalyst was filtered off through
a Celite pad and the filtrate was evaporated to give a hydrogenated
product. A solution of KOH (4 m aq., 1.5 mL) was added to a
solution of this product in 2-propanol (1.5 mL), which was heated
to reflux for 2 h. After cooling, the solvent was evaporated, and
the residue was purified by DOWEX 50W resin (X-8, H+ form,
(500 MHz, CDCl3): δ = 7.32–7.25 (m, 15 H), 5.55–5.33 (m, 2 H), eluent: 0.7 n aqueous NH3), subjected to counterion exchange with
4.68–4.44 (m, 6 H), 4.30 (br., 1 H), 4.13–4.02 (m, 3 H), 3.91–3.89 formic acid/methanol (1% v/v) at room temperature, and concen-
(m, 1 H), 3.84 (dd, J = 10.1, 4.9 Hz, 1 H), 3.74–3.72 (m, 1 H), trated in vacuo to yield 19 (48 mg, 128.2 μmol, 71%). 1H NMR
2.53–2.11 (m, 2 H), 2.09–1.51 (m, 6 H), 1.31–1.26 (m, 10 H), 0.88
(t, J = 6.9 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 152.8,
138.6, 138.5, 138.2, 134.9, 134.6, 128.4, 128.3, 128.2, 127.8, 127.7,
127.65, 127.6, 127.4, 127.2, 75.2, 74.5, 73.0, 72.6, 71.4, 69.5, 67.4,
56.6, 53.8, 47.2, 37.9, 34.6, 34.3, 33.2, 32.6, 32.2, 31.7, 31.4, 29.7,
(500 MHz, CD3OD): δ = 3.93–3.76 (m, 5 H), 3.64 (br., s, 1 H), 3.49
(t, J = 6.3 Hz, 1 H), 2.12 (tt, J = 13.7, 1.8 Hz, 1 H), 1.98–1.84 (m,
2 H), 1.69–1.66 (m, 1 H), 1.47 (br. s,2 H), 1.31 (br. s,16 H), 0.89 (t,
J = 6.9 Hz, 3 H) ppm. 13C NMR (125 MHz, CD3OD): δ = 69.7,
67.2, 67.1, 61.0, 58.1, 51.3, 39.2, 38.4, 33.1, 32.0, 30.7, 30.5, 30.4,
26.3, 23.7, 14.4 ppm. MS (FAB): m/z = 378 [M+ + 1]. HRMS
28.8, 22.6, 14.1 ppm. IR (neat): ν = 1699 cm–1. MS (ESI): m/z =
˜
625 [M+]. HRMS (ESI): calcd. for C40H51NO5 625.3767; found
625.3785.
(FAB): calcd. for C19H40NO6 378.2855: found 378.2843. [α]2D8
–16.0 (c = 0.1, MeOH).
=
(3S,4aR,6R,7R,8S)-6,7-Bis(benzyloxy)-8-(benzyloxymethyl)-3-
(non-2-en-1-yl)hexahydropyrido[1,2-c][1,3]oxazin-1(3H)-one (17): 1-
Octene (0.25 mL, 1.57 mmol) was added to a solution of 15 (83 mg,
157 μmol) in CH2Cl2 (8 mL) at room temperature. Second-genera-
tion Hoveyda–Grubbs catalyst (10 mg, 17.7 μmol) was added to the
stirred mixture. The stirred reaction mixture was heated to reflux
for 15 h. After cooling, the reaction solvent was removed in vacuo
to give a black oil, which was purified by chromatography on silica
gel (10 g, n-hexane/acetone, 10:1) to give 17 (86 mg, 141.3 μmol,
(2S,3R,4R,6R)-2-(Hydroxymethyl)-6-[(S)-2-hydroxyundecyl]-
piperidine-3,4-diol, Formic Acid Salt (20): Pd(OH)2/C (20%, 5 mg)
was added to a solution of 17 (82 mg, 134 μmol) in EtOH (5 mL),
and the resulting suspension was hydrogenated at 1 atm under a
hydrogen atmosphere for 6 d. The catalyst was filtered off through
a Celite pad and the filtrate was evaporated to give a hydrogenated
product. A solution of KOH (4 m aq., 1 mL) was added to a solu-
tion of this product in 2-propanol (1 mL), which was heated to
reflux for 2 h. After cooling, the solvent was evaporated, and the
residue was purified by DOWEX 50W resin (X-8, H+ form, eluent:
0.7 n aqueous NH3), subjected to counterion exchange with formic
1
90%) as a pale brown oil. H NMR (500 MHz, CDCl3): δ = 7.33–
7.27 (m, 15 H), 5.55–5.33 (m, 2 H), 4.72–4.44 (m, 6 H), 4.29 (br.,
1 H), 4.14–4.02 (m, 3 H), 3.93–3.90 (m, 1 H), 3.84 (dd, J = 10.1, acid/methanol (1% v/v) at room temperature, and concentrated in
Eur. J. Org. Chem. 2013, 2841–2848
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2847

N. Toyooka et al.
FULL PAPER
vacuo to yield 20 (33 mg, 89.8 μmol, 67%). H NMR (500 MHz,
1
(grant to N. T.). The authors gratefully thank Dr. Ryuta Miyatake
CD3OD): δ = 3.92–3.78 (m, 5 H), 3.64 (br. s,1 H), 3.50 (m, 1 H), and Ms. Kazuko Sawaya for measurements of HRMS and HRMS
2.01 (dt, J = 14.9, 2.3 Hz, 1 H), 1.83 (d, J = 14.3 Hz, 1 H), 1.95–
1.82 (m, 2 H), 1.70 (m, 1 H), 1.47 (br. s,2 H), 1.31 (br. s,14 H), 0.90
(t, J = 6.3 Hz, 3 H) ppm. 13C NMR (125 MHz, CD3OD): δ = 69.7,
67.2, 67.1, 61.0, 58.1, 51.3, 39.2, 38.4, 33.1, 32.0, 30.8, 30.75, 30.70,
30.4, 26.7, 23.7, 14.4 ppm. MS (FAB): m/z = 364 [M+ + 1]. HRMS
(FAB) spectra.
[1]
[2]
N. L. Segraves, P. Crews, J. Nat. Prod. 2005, 68, 118–121.
a) R. J. Nash, A. Kato, C.-Y. Yu, G. W. J. Fleet, Future Med.
Chem. 2011, 3, 1513–1521; b) N. Asano, Cell. Mol. Life Sci.
2009, 66, 1479–1492; c) K. Afarinkia, A. Bahar, Tetrahedron:
Asymmetry 2005, 16, 2139–2187; d) M. S. M. Pearson, M.
Mathé-Allainmat, V. Fargeas, J. Lebreton, Eur. J. Org. Chem.
2005, 2159–2191; e) N. Asano, R. J. Nash, R. J. Molyneux,
G. W. J. Fleet, Tetrahedron: Asymmetry 2000, 11, 1645–1680,
and references therein.
(FAB): calcd. for C18H38NO6 364.2699; found 364.2688. [α]2D3
=
–7.0 (c 0.1, MeOH), for enantiomer, ref.[3a] [α]2D3 = +4.7 (c = 0.2,
MeOH).
(2S,3R,4R,6R)-2-(Hydroxymethyl)-6-[(S)-2-hydroxytridecyl]-
piperidine-3,4-diol, Formic Acid Salt (21): Pd(OH)2/C (20%, 3 mg)
was added to a solution of 18 (51 mg, 79.7 μmol) in EtOH (3 mL),
and the resulting suspension was hydrogenated at 1 atm under a
hydrogen atmosphere for 6 d. The catalyst was filtered off through
a Celite pad and the filtrate was evaporated to give a hydrogenated
product. A solution of KOH (4 m aq., 1 mL) was added to a solu-
tion of this product in 2-propanol (1 mL), which was heated to
reflux for 2 h. After cooling, the solvent was evaporated, and the
residue was purified by DOWEX 50W resin (X-8, H+ form, eluent:
0.7 n aqueous NH3), subjected to counterion exchange with formic
acid/methanol (1% v/v) at room temperature, and concentrated in
[3]
[4]
a) J. Wierzejska, M. Ohshima, T. Inuzuka, T. Sengoku, M. Tak-
ahashi, H. Yoda, Tetrahedron Lett. 2011, 52, 1173–1175; b) J.
Wierzejska, S. Motogoe, Y. Makino, T. Sengoku, M. Takah-
ashi, H. Yoda, Beilstein J. Org. Chem. 2012, 8, 1831–1838.
When we began the total synthesis of batzellasides A, B, and
C, the absolute configuration of these natural products had not
yet been determined. Therefore, we planned an effective and
short total synthesis of these compounds starting from com-
mercially available tri-O-benzyl-d-glucal (1). As a result, we
achieved the total synthesis of (–)-l-batzellasides A, B, and C.
A. Squarcia, F. Vivolo, H.-G. Weinig, P. Passacantilli, G. Pian-
catelli, Tetrahedron Lett. 2002, 43, 4653–4655.
1
vacuo to yield 21 (17 mg, 43.8 μmol, 55%). H NMR (500 MHz,
[5]
[6]
CD3OD): δ = 3.91–3.76 (m, 5 H), 3.63 (br. s,1 H), 3.49 (t, J =
6.6 Hz, 1 H), 2.12 (tt, J = 13.2, 2.3 Hz, 1 H), 1.96–1.82 (m, 2 H),
1.70–1.66 (m, 1 H), 1.47 (m, 2 H), 1.31 (br. s,18 H), 0.89 (t, J =
6.9 Hz, 3 H) ppm. 13C NMR (125 MHz, CD3OD): δ = 69.7, 67.2,
67.1, 61.0, 58.1, 51.3, 39.2, 38.4, 33.1, 32.0, 30.74, 30.70, 30.5, 26.7,
23.7, 14.4 ppm. MS (FAB): m/z = 392 [M+ + 1]. HRMS (FAB):
calcd. for C20H42NO6 392.3012; found 392.3023. [α]2D4 = –4.4 (c
0.15, MeOH).
R. W. Hoffmann, Chem. Rev. 1989, 89, 1841–1873.
[7] P. Deslongchamps, Stereoelectronic Effects in Organic Chemis-
try, Pergamon, New York, 1983, pp. 209–290.
[8] P. K. Jadhav, K. S. Bhat, P. T. Perumal, H. C. Brown, J. Org.
Chem. 1986, 51, 432–439.
[9] S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J.
Am. Chem. Soc. 2000, 122, 8168–8179.
[10] a) P. Schwab, M. B. France, J. W. Ziller, R. H. Grubbs, Angew.
Chem. 1995, 107, 2179–2181; Angew. Chem. Int. Ed. Engl. 1995,
34, 2039–2041; b) M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs,
Org. Lett. 1999, 1, 953–956. For 12: Grubbs’ 1st generation
catalyst resulted in no reaction, the 2nd generation catalyst
gave 74% yield.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of all new compounds as well as
NOESY and COSY spectra of 7 and 10.
Acknowledgments
[11] N. Aneda, H. Nagata, H. Furuta, T. Yokokura, Cancer Res.
1990, 50, 1715–1720.
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science
Received: November 21, 2012
Published Online: March 19, 2013
2848
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2841–2848