Total synthesis of calystegine A7

Article abstract of DOI:10.1016/j.tet.2008.07.089

A straightforward chiral pool synthesis for the glycosidase inhibitor calystegine A₇ (isolated from Lycium chinense) from methyl α-d-glucopyranoside is described. Keysteps of this synthesis include a ultrasound assisted Zn-mediated tandem ring

Full text of DOI:10.1016/j.tet.2008.07.089

Tetrahedron 64 (2008) 9417–9422
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Total synthesis of calystegine A7
*
´
Rene Csuk , Erik Prell, Stefan Reißmann
Bereich Organische Chemie, Martin-Luther-Universita¨t Halle-Wittenberg, Kurt-Mothes-Strasse 2, D-06120 Halle (Saale), Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2008
Received in revised form 21 July 2008
Accepted 21 July 2008
Available online 26 July 2008
A straightforward chiral pool synthesis for the glycosidase inhibitor calystegine A7 (isolated from Lycium
chinense) from methyl a-D-glucopyranoside is described. Keysteps of this synthesis include a ultrasound
assisted Zn-mediated tandem ring opening reaction followed by a Grubbs’ catalyst mediated ring closure
metathesis.
Ó 2008 Elsevier Ltd. All rights reserved.
In memoriam Professor Dr. Martin Luckner
Keywords:
Calystegine A7
Total synthesis
Glycosidase inhibitor
1. Introduction
For the synthesis of calystegine A7 we planned a chiral pool
approach starting from well accessible methyl a-D-glucopyranoside
using a zinc mediated tandem ring opening reaction followed by
a ring closure metathesis using 2nd generation Grubb’s catalyst.
Calystegines1 are a family of polyhydroxylated nortropane alka-
loids that were first isolated from Calystegia sepium2,3 in 1988. They
are believed to function as nutritional mediators4 in the plant rhi-
zosphere. Since calystegines exhibit strong or specific glyosylhy-
drolase competitive inhibitory activity5–7 they were considered as
ideal probes for enzymatic mechanism8–10 as well as chemothera-
peutic drugs for the treatment of metabolic disorders11,12 (e.g., di-
abetes), cancer13 or for the treatment14,15 of viral diseases.
Calystegine A7 has previously been isolated from the root of
Lycium chinense and has been shown to act as a competitive in-
hibitor5 against trehalase. Unfortunately, the amount of isolated
calystegine A7 remained small since from the extraction and ex-
haustive chromatography of 5 kg roots of L. chinense only 8 mg of
the desired compound could be isolated. Thus, its structure has
been proposed from NMR spectroscopic data.
Thus, methyl
formed into well known methyl 2,3-anhydro-4,6-O-benzylidene-
-mannopyranoside (2)29,30 that was reduced with lithium
a-D-glucopyranoside (1) (Scheme 1) was trans-
a-D
tetrahydrido aluminate to afford the corresponding 3-deoxy
hexopyranoside 3 in 96% isolated yield. Deprotection of 3 with 0.1 M
sulfuric acid31 gave 4 whose regioselective tritylation afforded 5.
Compound 5 was benzylated (/6) followed by detritylation to
yield the corresponding 2,4-di-O-benzylated 3-deoxy mono-
saccharide 7 that was subsequently iodinated using triphenyl
phosphane/iodine32,33 to yield 96.5% of the 6-iodo-derivative 8.
An ultrasound assisted Zn-mediated tandem reaction19,27,34
furnished 1,8-nonadiene 9 as the main product (81.8% yield) to-
gether with minor amounts of its diastereomeric analogue 16 and
traces of 10. Carbobenzoxylation of 9 gave 64% of fully protected 11
that was subjected to a ring closure metathesis19,34 using Grubbs’
catalyst. The corresponding cycloheptene derivative 12 was hy-
In order to prove the structure as well as to obtain larger amounts
of this calystegine, a total synthesis seemed to be called for.
35
droxylated using BH3$THF/H2O2 to furnish the diastereomeric
2. Results and discussion
alcohols 13/14 that were smoothly oxidized with PCC to yield the
cycloheptanone 15. Hydrogenolysis of 15 in the presence of Pd/C
finally resulted in the formation of calystegine A7 being undis-
tinguishable from authentic material from L. chinense in each
aspect.
There has been considerable interest in the synthesis of calys-
tegines and more or less elaborate routes for the synthesis of
24–28
calystegines A3,16,17 B2,18–23 B3 and B4
have been described
so far.
The synthesis of analogues is presently under investigation in
our laboratories. In a preliminary test, calystegine A7 shows a Ki
value (
for calystegine B2 of 5.9
b
-glycosidase from almonds) of 2.1 mM as compared to a Ki
* Corresponding author. Tel.: þ49 345 5525660; fax: þ49 345 5527030.
E-mail address: rene.csuk@chemie.uni-halle.de (R. Csuk).
mM.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.089

9418
R. Csuk et al. / Tetrahedron 64 (2008) 9417–9422
O
O
O
O
O
O
HO
HO
O
O
steps
a
OH
Ph
O
Ph
O
OH
O
OH
1
2
3
b
O
O
O
O
O
O
TrO
BnO
TrO
HO
HO
HO
d
c
OBn
OH
OH
6
5
4
e
O
O
O
O
g
HO
BnO
f
I
BnO
OBn
BnO
OBn
NH-Bn
OBn
9
7
8
h
BnO
BnO
BnO
NH-Bn
OH
OBn
OBn
Bn
N
Cbz
OBn
16
10
11
i
OH
N
HO
BnO
BnO
BnO
BnO
j
+
Bn
Bn
Bn
N
N
OBn
13
OBn
OBn
12
Cbz
Cbz
Cbz
14
k
O
OH
HO
HN
OH
OH
l
HN
HO
Bn
N
HO
OBn
Cbz
17
calystegine A7
15
Scheme 1. (a) LiAlH4 (96%); (b) 0.1 M H2SO4 (quant.); (c) Ph3CCl (¼TrCl), pyridine, DMAP (87%); (d) BnBr, NaOH (quant.); (e) p-TsOH (quant.); (f) Ph3P, imidazole, iodine (97%); (g)
Zn , BnNH2, allylbromide, (82%); (h) CbzCl, NaHCO3 (64%); (i) Grubbs’ catalyst (80%); (j) BH3$THF, H2O2/NaOH (27% of 14 and 45% of 13); (k) PCC (86%); (l) Pd/C, H2 (92%).
*
3. Experimental
3.1. General
molybdate and cerium(IV) sulfate) followed by gentle heating. The
solvents were dried according to usual procedures.
3.2. Methyl (R)-4,6-O-benzylidene-3-deoxy-a-D-arabino-
Melting points are uncorrected (Leica hot stage microscope),
optical rotations were obtained using a Perkin–Elmer 341 polari-
meter (1 cm micro cell), NMR spectra were recorded using the
hexopyranoside (3)
To an ice-cold solution of 2 (15.63 g, 59 mmol) in dry dieth-
ylether (150 ml) LiAlH4 (8.98 g, 237 mmol) was added in small
portions. The reaction mixture was allowed to warm to room
temperature and then refluxed for another 16 h. After cooling,
a satd aq solution of magnesium sulfate (40 ml) was carefully
added, the mixture filtered, the residue washed with hot ethyl ac-
etate (3ꢀ100 ml) and the combined organic phases were evapo-
rated. The residue was subjected to chromatography (silica gel,
Varian spectrometers Gemini 200, Gemini 2000 or Unity 500 (
d
given in ppm, J in Hz, internal Me4Si or internal CCl3F), IR spectra
(film or KBr pellet) on a Perkin–Elmer FT-IR spectrometer Spectrum
1000, MS spectra were taken on a Intectra GmbH AMD 402 (elec-
tron impact, 70 eV) or on a Finnigan MAT TSQ 7000 (electrospray,
voltage 4.5 kV, sheath gas nitrogen) instrument; for elemental
analysis a Foss-Heraeus Vario EL instrument was used; TLC was
performed on silica gel (Merck 5554, detection by UV absorption or
by treatment with a solution of 10% sulfuric acid, ammonium
hexane/ethyl acetate 1:1) to afford 3 (15.2 g, 96.4%) as colourless
20
crystals. Mp 109 ꢁC (lit.30 108–110 ꢁC), [
a
]
88.35 (c 0.82, CHCl3)
D

R. Csuk et al. / Tetrahedron 64 (2008) 9417–9422
9419
20
(lit.36
[
a
]
95.5 (c 2, CHCl3)); Rf 0.42 (hexane/ethyl acetate 1:1);
1132 (s), 1055 (s), 983 (s), 958 (s), 901 (m), 877 (m), 845 (m), 819
(m), 764 (s), 748 (s), 708 (s), 654 (m), 643 (m), 633 (s), 536 (m), 503
(m) cmꢂ1; UV–vis (methanol): lmax¼275.89 nm, A¼0.46; 1H NMR
D
UV–vis (methanol): lmax1¼267.13 nm, A¼0.23, lmax2¼272.84 nm,
A¼0.28, lmax3¼278.50 nm, A¼0.24, lmax4¼282.89 nm, A¼0.14; IR
(KBr):
n
¼3406 (s), 3007 (m), 2962 (s), 2937 (s), 2859 (m), 1624 (w),
(500 MHz, CDCl3):
d
¼7.48–7.25 (ddd, 15H, phenyl-H), 4.51 (s, 1H, H-
1462 (m), 1452 (m), 1385 (s), 1368 (m), 1336 (m), 1320 (m), 1294
(m), 1242 (m), 1194 (m), 1133 (s), 1101 (s), 1060 (s), 1043 (s), 1016 (s),
1), 3.85 (m, 2H, H-2, H-4), 3.69 (ddd, 1H, J¼4.8, 6.4 Hz, H-5), 3.48
(dd, 1H, J¼9.8, 4.8 Hz, H-60), 3.40 (s, 3H, OCH3), 3.38 (dd, 1H, J¼9.8,
6.4 Hz, H-6), 2.60 (d, 1H, J¼2.9 Hz, OH), 2.06 (ddd, 1H, J¼13.3 Hz, H-
30), 1.83 (ddd, 1H, J¼13.3 Hz, H-3), 1.77 (d, 1H, J¼7.0 Hz, OH); 13C
1002 (s) cmꢂ1
;
1H NMR (500 MHz, CDCl3):
d
¼7.39–7.16 (m, 5H,
phenyl-H), 5.48 (s, 1H, H-8), 4.47 (s, 1H, H-1), 4.14 (dd, 1H, J¼9.4,
3.9 Hz, H-60), 3.90 (dd, 1H, J¼3.1, 4.2 Hz, H-2), 3.86 (ddd, 1H, J¼3.6,
4.3, 12.4 Hz, H-4), 3.74 (ddd, 1H, J¼3.9, 4.3, 10.2 Hz, H-5), 3.70 (dd,
1H, J¼9.4, 10.2 Hz, H-6), 3.32 (s, 3H, OCH3), 2.01 (ddd, 1H, J¼12.9,
3.6, 4.2 Hz, H-30), 1.97 (ddd, 1H, J¼12.9, 3.1, 12.4 Hz, H-3); 13C NMR
NMR (125 MHz, CDCl3):
d
¼143.51 (Ci of trityl), 128.58 (Car), 128.00
(Car), 127.25 (Car), 99.97 (C(1)), 87.59 (C(CPh3)), 70.99 (C(5)), 68.04
(C(4)), 65.73 (C(6)), 65.18 (C(2)), 54.85 (OCH3), 34.15 (C(3)); MS
(ESI): m/z (%)¼443.3 (MþNa, 100), 862.9 (M2þNa, 30), 427.5 (MþLi,
100), 847.1 (M2þLi, 7), 953.1 (M2þLi2ClO4, 5). Anal. Calcd for
(125 MHz, CDCl3):
d¼137.79 (Ci of benzylidene), 129.31 (Car), 128.57
(Car), 126.41 (Car), 102.40 (CH of benzylidene), 101.06 (C(1)), 74.15
(C(4)), 69.57 (C(6)), 68.10 (C(2)), 65.21 (C(5)), 55.16 (OCH3), 32.24
(C(3)); MS (EI, 70 eV): m/z (%)¼266 (9), 235 (2), 223 (6), 205 (7), 189
(2), 175 (1), 162 (16), 149 (3), 145 (12), 129 (5), 117 (100); MS (ESI):
m/z (%)¼266.9 (MþH, 100), 289.1 (MþNa, 55), 554.9 (M2þNa, 40),
275.4 (MþLi, 28), 292.2 (MþLiH2O, 70), 305.9 (MþLiMeOH, 100).
Anal. Calcd for C14H18O5 (266.30): C, 63.15; H, 6.81. Found: C, 62.92;
H, 6.96.
C26H28O5 (420.51): C, 74.27; H, 6.71. Found: 74.11; H, 6.91.
3.5. Methyl 2,4-di-O-benzyl-3-deoxy-6-O-triphenylmethyl-
-arabino-hexopyranoside (6) and methyl 2,4-di-O-benzyl-3-
deoxy- -arabino-hexopyranoside (7)
a-
D
a-D
To an ice-cold solution of 5 (6.97 g, 16.6 mmol) in dry DMF
(150 ml) sodium hydride (65–65% in mineral oil, 4.77 g, 99.4 mmol)
was slowly added in several portions. Stirring at 0 ꢁC followed by
stirring at room temperature was continued for another hour, then
at 0 ꢁC benzyl bromide (5.95 ml, 49.7 mmol) was slowly added.
After stirring at room temperature for another 3 h, methanol
(100 ml) was carefully added and the solvents were removed under
diminished pressure. The oily residue was dissolved in diethylether
(250 ml) and washed with water and brine (100 ml each) and dried
(MgSO4); the solvents were evaporated and 6 (15.59 g) was directly
used for the next step. To a solution of crude 6 (15.59 g) in methanol
(200 ml) and dichloromethane (100 ml) catalytic amounts of
p-TsOH were added and the mixture was stirred at room temper-
ature for 1 day. After neutralization (triethylamine), the solvents
were removed in vacuo, the residue was dissolved in ether (250 ml)
and washed with water and brine (150 ml each). After drying
(MgSO4) the solvent was removed and the residue was subjected to
chromatography (silica gel, hexane/ethyl acetate 85:15) to afford 7
(5.94 g, quant.) as a highly viscous, colourless oil. Rf 0.38 (hexane/
3.3. Methyl 3-deoxy-a-D-arabino-hexopyranoside (4)
A suspension of 3 (15.94 g, 60 mmol) in water (100 ml) was
heated at 60 ꢁC in the presence of sulfuric acid (10 ml, 0.1 M) for 4 h.
After cooling to room temperature barium oxide (0.16 g,
1.044 mmol) was added, the mixture was filtered and the filtrate
was extracted with ethyl acetate (50 ml). The aqueous layer was
concentrated under diminished pressure and the residue dried over
potassium hydroxide to afford 4 (10.7 g, quantitative) as colourless
20
crystals. Mp 122–123 ꢁC (lit.31 123.5–124 ꢁC); [
a
]
108.02 (c 0.54,
D
MeOH) (lit.36
[a]
20 126.5 (c 1, MeOH)); Rf 0.0 (hexane/ethyl acetate
D
1:1); IR (KBr):
n
¼3382 (s), 3002 (m), 2981 (s), 2966 (s), 2939 (s),
2903 (s), 2880 (s), 2842 (m), 2509 (s), 1560 (s), 1454 (s), 1414
(s), 1391 (s), 1366 (m), 1348 (s), 1292 (s), 1256 (m), 1195 (s), 1140 (s),
1124 (s), 1104 (s), 1046 (s), 1021 (s) cmꢂ1; 1H NMR (500 MHz, D2O):
d
¼4.51 (s,1H, H-1), 3.34 (s, 3H, OCH3), 3.84 (dd,1H, J¼3.0, 3.9 Hz, H-
2), 3.78 (dd, 1H, J¼12.1, 2.3 Hz, H-60), 3.70 (ddd, 1H, J¼4.8, 10.1,
11.1 Hz, H-4), 3.64 (dd, 1H, J¼12.1, 6.5 Hz, H-6), 3.52 (ddd, 1H, J¼2.3,
6.5, 10.1 Hz, H-5), 1.98 (ddd, 1H, J¼13.6, 3.0, 4.9 Hz, H-30), 1.71 (ddd,
ethyl acetate 5:3); [
a
]
20 70.08 (c 0.63, CHCl3); IR (film):
n
¼3474 (m),
D
3063 (m), 3030 (m), 2930 (s), 1605 (w), 1497 (m), 1455 (s), 1371 (s),
1317 (m), 1186 (s), 1145 (s), 1050 (s), 981 (s), 909 (w), 834 (w), 739
(s), 699 (s), 613 (m), 542 (m), 510 (m) cmꢂ1; UV–vis (methanol):
1H, J¼13.6, 3.1, 11.1 Hz, H-3); 13C NMR (100 MHz, CDCl3):
¼99.53
d
(C(1)), 73.58 (C(5)), 67.08 (C(2)), 61.46 (C(4)), 61.13 (C(6)), 54.58
(OCH3), 33.57 (C(3)); MS (EI, 70 eV): m/z (%)¼147 (1), 130 (6), 129
(13), 115 (7), 111 (1), 101 (3), 100 (6), 87 (3), 82 (3), 74 (100), 71 (13);
MS (ESI): m/z (%)¼201.5 (MþNa, 65), 185.5 (MþLi, 100), 217.5 (MþLi
(MeOH), 35). Anal. Calcd for C7H14O5 (178.19): C, 47.19; H, 7.92.
Found: C, 46.94; H, 7.97.
lmax1¼269.12 nm,
A¼0.33,
lmax2¼274.91 nm,
A¼0.39,
lmax3¼280.75 nm, A¼0.30; 1H NMR (500 MHz, CDCl3):
d
¼7.35–7.24
(m, 10H, phenyl-H), 4.61 (s, 1H, H-1), 4.52 (s, 2H, CH2 (C4-Bn)), 4.55
(d,1H, J¼11.5 Hz, CH2 (C2-Bn)), 4.46 (d,1H, J¼11.5 Hz, CH20 (C2-Bn)),
3.83 (dd, 1H, J¼7.4, 4.0 Hz, H-60), 3.76 (ddd, 1H, J¼3.7, 9.7, 10.6 Hz,
H-4), 3.69 (dd, 1H, J¼2.9, 3.7 Hz, H-2), 3.67 (dd, 1H, J¼7.4, 3.7 Hz, H-
6), 3.58 (ddd, 1H, J¼3.7, 4.0, 9.7 Hz, H-5), 3.35 (s, 3H, H-OCH3), 2.23
(ddd, 1H, J¼13.2, 3.8, 3.8 Hz, H-30), 1.74 (ddd, 1H, J¼13.2, 2.9,
3.4. Methyl 3-deoxy-6-O-triphenylmethyl-a-D-arabino-
hexopyranoside (5)
10.6 Hz, H-3); 13C NMR (125 MHz, CDCl3):
d¼138.20 (Ci (C4-Bn)),
138.07 (Ci (C2-Bn)), 128.40 (Car), 127.78 (Car), 127.73 (Car), 127.60
(Car), 98.26 (C(1)), 74.76 (C(5)), 71.80 (C(2)), 71.07 (CH2 (C2-Bn)),
71.03 (CH2 (C4-Bn)), 70.17 (C(4)), 62.92 (C(6)), 54.62 (OCH3), 29.03
(C(3)); MS (ESI): m/z (%)¼376.9 (MþNH4, 3), 381.4 (MþNa, 100),
739.0 (M2þNa, 5). Anal. Calcd for C21H26O5 (358.44): C, 70.37; H,
7.31. Found: C, 70.12; H, 7.49.
To a solution of 4 (11.1 g, 62.0 mmol) and dimethylaminopyr-
idine (DMAP) (1.28 g, 10.5 mmol) in dry pyridine (100 ml) trityl
chloride (21.92 g, 78.6 mmol) was added in several portions. Stir-
ring at room temperature was continued for another day, then
additional DMAP (1.28 g, 10.5 mmol) was added and the reaction
mixture stirred at 40 ꢁC for 2 h. The solvents were removed under
reduced pressure and the residue was dissolved in dichloro-
methane (200 ml). The organic phase was washed with water
(150 ml), dried (MgSO4), the solvent was removed and the residue
was subjected to chromatography (silica gel, hexane/ethyl acetate
1:1) to afford 5 (22.8 g, 87%) as colourless crystals. Mp 84–85 ꢁC;
3.6. Methyl 2,4-di-O-benzyl-3,6-dideoxy-6-iodo-a-D-arabino-
hexopyranoside (8)
To a solution of 7 (5.9 g, 16.5 mmol) in toluene (100 ml) con-
taining triphenylphosphane (9.83 g, 76.7 mmol) under argon iodine
(8.65 g, 34.1 mmol) was added in several portions. After stirring at
90 ꢁC for 2 h the reaction mixture was decanted and the remaining
oil washed with ether (3ꢀ100 ml). The combined organic phases
[
a]
20 23.47 (c 0.75, CHCl3); Rf 0.26 (methanol/ethyl acetate¼1:8); IR
D
(KBr):
n
¼3425 (s), 3058 (m), 3032 (m), 2932 (s), 1962 (w), 1718 (w),
1596 (m), 1490 (s), 1448 (s), 1374 (m), 1326 (m), 1222 (s), 1188 (s),

9420
R. Csuk et al. / Tetrahedron 64 (2008) 9417–9422
were evaporated and the remaining residue was subjected to
chromatography (silica gel, hexane/ethyl acetate 85:15) to afford 8
(7.52 g, 97.5%) as colourless crystals. Rf 0.40 (hexane/ethyl acetate
(N-Bn)), 36.68 (C(7)), 35.30 (C(4)); MS (ESI): m/z (%)¼442.4 (MþH,
100). Anal. Calcd for C30H35O2N (441.62): C, 81.59; H, 7.99. Found: C,
81.64; H, 8.15.
20
85:15); [
a
]
20 81.94 (c 1.01, CHCl3); IR (KBr):
n
¼3446 (m), 3028 (m),
Data for 16: colourless oil; [
a]
ꢂ34.39 (c 0.69, CHCl3); IR (film):
D
D
2928 (m), 2869 (m), 1498 (w), 1454 (m), 1389 (w), 1354 (w), 1340
(w), 1316 (w), 1245 (w), 1228 (w), 1201 (m), 1184 (m), 1174 (m), 1143
(m), 1105 (m), 1069 (m), 1035 (m), 972 (m), 924 (w), 890 (w), 867
(w), 768 (w), 751 (m), 739 (m), 696 (m), 622 (w), 609 (w), 538 (w),
489 (w) cmꢂ1; UV–vis (methanol): lmax1¼269.82 nm, A¼0.58,
n
¼3317 (w), 3064 (m), 3029 (m), 2927 (m),1640 (w), 1604 (w), 1496
(m), 1454 (m), 1360 (m), 1206 (m), 1065 (s), 1028 (m), 994 (m), 920
(m), 735 (m), 698 (s), 618 (w) cmꢂ1; UV–vis (methanol): lmax1
264.00 nm, A¼0.755; lmax2¼268.87 nm, A¼0.771; lmax3
¼
¼
274.91 nm, A¼0.764; lmax4¼335.85 nm, A¼0.206; 1H NMR
lmax2¼274.85 nm, A¼0.63; 1H NMR (500 MHz, CDCl3):
d
¼7.37–7.24
(400 MHz, CDCl3):
d
¼7.33–7.17 (m, 15H, phenyl), 5.75 (m, 2H,
(d, 10H, phenyl-H), 4.67 (s, 1H, H-1), 4.58 (d, 1H, J¼6.8 Hz, CH2 (C2-
J¼19.3, 17.0 Hz, H-8), 5.16 (dd, 2H, J¼11.2, 19.3 Hz, Hz, H-), 5.10 (dd,
2H, 0J¼10.5, 17.0 Hz, H-9), 3.93 (dd, 1H, H-3)0, 4.52 (d, 1H, J¼11.4 Hz,
CH2 (C3-Bn)), 4.40 (d, 1H, J¼10.9 Hz, CH2 (C5-Bn)), 4.17 (d, 1H,
J¼10.9 Hz, CH2 (C5-Bn)), 4.17 (d, 1H, J¼11.4 Hz, CH2 (C3-Bn)), 3.79
Bn)), 4.57 (d, 1H, J¼6.8 Hz, CH20 (C2-Bn)), 4.53 (d, 1H, J¼11.4 Hz, CH2
0
(C4-Bn)), 4.45 (d, 1H, J¼11.4 Hz, CH2 (C4-Bn)), 3.62 (dd, 1H,
J¼10.2 Hz, H-60), 3.59 (m, 3H, J2;H,H¼2.9, 3.4 Hz, 3J4;H,H¼3.4, 10.5 Hz,
3J5;H,H¼7.5 Hz, H-2, H-4, H-5), 3.44 (s, 3H, H-OCH3), 3.30 (dd, 1H,
J¼10.2, 7.5 Hz, H-6), 2.25 (ddd, 1H, J¼13.0, 3.4, 3.4 Hz, H-30), 1.75
(ddd, 1H, J¼13.0, 2.9, 10.5 Hz, H-3); 13C NMR (125 MHz, CDCl3):
0
(ddd, 1H, H-5), 3.81 (d, 1H, J¼13.4 Hz, CH2 (N-Bn)), 3.79 (d, 1H,
J¼13.4 Hz, CH2 (N-Bn)), 2.89 (ddd, 1H, J¼2.9, 6.5, 6.8 Hz, H-6), 2.27
(m, 1H, J¼6.8 Hz, H-70), 2.17 (m, 1H, J¼6.5 Hz, H-7), 1.80 (ddd, 2H, H-
d¼138.18 (Ci (C4-Bn)), 138.04 (Ci (C2-Bn)), 128.46 (Car), 128.40 (Car),
4); 13C NMR (100 MHz, CDCl3):
d
¼140.60 (Ci (C3-Bn)), 139.01 (C(2)),
127.86 (Car),127.83 (Car),127.69 (Car),127.57 (Car), 98.33 (C(1)), 74.90
(C(2)), 73.62 (C(4)), 71.62 (C(5)), 71.11 (CH2 (C2-Bn)), 71.00 (CH2
(C4-Bn)), 54.95 (OCH3), 29.34 (C(3)), 7.68 (C(6)); MS (ESI): m/z
(%)¼486.6 (MþNH4, 45), 491.5 (MþNa, 100), 769.0 (cluster
(Mþ278) Na, 13); 475.9 (MþLi, 85), 493.9 (MþLiþH2O, 40), 507.3
(MþLiMeOH, 100), 753.3 (cluster (Mþ278) Li, 75). Anal. Calcd for
139.80 (Ci (C5-Bn)), 138.72 (Ci of benzylamine), 135.80 (Car), 128.46
(Car), 128.33 (Car), 128.23 (Car), 128.17 (Car), 128.14 (Car), 128.08 (Car),
127.73 (Car), 127.57 (Car), 127.52 (Car), 127.37 (Car), 127.29 (Car),
126.94 (Car), 126.87 (Car), 126.72 (Car), 117.04 (C(9)), 116.45 (C(1)),
77.19 (C(6)), 77.06 (C(5)), 71.90 (CH2 (C5-Bn)), 70.13 (CH2 (C3-Bn)),
53.13 (C(3)), 51.99 (CH2 (N-Bn)), 36.82 (C(7)), 35.41 (C(4)). Anal.
Calcd for C30H35O2N (441.62): C, 81.59; H, 7.99. Found: C, 81.62; H,
8.11.
C
21H25O4I (468.34): C, 53.86; H, 5.38. Found: C, 53.61; H, 5.55.
3.7. (3S,5S,6R) 6-(N-Benzylamino)-3,5-bis(benzyloxy)-1,8-
nonadiene (9), (3S,5S,6S)- 6-(N-benzylamino)-3,5-
bis(benzyloxy)-1,8-nonadiene (16) and (3S,5S) 3,5-
bis(benzyloxy)-6-hydroxy-1,8-nonadiene (10)
Data for 10: viscous oil; Rf 0.26 (hexane/ethyl acetate 85:15);
20
[a
]
ꢂ19.85 (c 0.67, CHCl3); IR (film): ¼3418 (m), 3064 (m), 3029
n
D
(m), 2926 (m), 2863 (m), 1678 (m), 1640 (m), 1604 (m), 1496 (m),
1455 (s), 1353 (m), 1206 (m), 1069 (s), 1028 (s), 994 (m), 923 (m),
735 (s), 698 (s), 618 (m) cmꢂ1; UV–vis (methanol): lmax1
268.92 nm, A¼0.748; lmax2¼274.90 nm, A¼0.749; lmax3
¼
To a solution of 8 (2.32 g, 4.95 mmol) in dry THF (100 ml) acid
activated Zn powder (4.5 g, 68.8 mmol) was added and put in an
ultrasound cleaning bath for 20 min. At a temperature of 38 ꢁC
benzylamine (2.71 ml, 24.8 mmol) was slowly added and the
treatment with microwaves was continued for another 6 h. Then
allylbromide (1.28 ml, 14.9 mmol) was added, microwaves were
applied for another 45 min, the mixture was cooled to room tem-
perature and filtered over a small pad of silica gel. The solvents
were removed and the residue partioned between dichloro-
methane and water (50 ml each), the aq phase was extracted with
dichloromethane (3ꢀ50 ml), the combined organic layers were
dried and the solvents evaporated. The residue was subjected to
chromatography (silica gel, hexane/ethyl acetate 75:25) to afford 9
(1.79 g, 81.8%) and 16 (0.21 g, 9.6%); the formation of traces of 10
was observed on several occasions.
¼
332.04 nm, A¼0.276; 1H NMR (500 MHz, CDCl3):
d
¼7.35–7.19 (m,
10H, phenyl-H), 5.73 (m, 2H, H-2, H-8), 5.01 (m, 2H, H-1, H-9), 4.44
(d, 1H, J¼11.5 Hz, CH2 (C5-Bn)), 04.44 (d, 1H, J¼11.8 Hz, CH2 (C3-
Bn)), 4.29 (d, 1H, J¼11.5 Hz, CH2 (C5-Bn)), 4.19 (d, 1H, J¼11.8 Hz,
0
CH2 (C3-Bn)), 3.89 (ddd, 1H, H-7), 3.76 (ddd, 1H, H-5), 2.74
(ddd, 1H, H-4), 2.06 (ddd, 1H, H-30), 1.96 (ddd, 1H, H-3), 1.65
(ddd, 1H, H-6); 13C NMR (100 MHz, CDCl3):
d
¼140.64 (C(2)), 139.09
(Ci (C7-Bn)), 138.79 (Ci (C5-Bn)), 136.43 (C(8)), 128.31 (Car), 128.19
(Car), 128.18 (Car), 128.16 (Car), 128.09 (Car), 127.73 (Car), 127.63
(Car), 127.44 (Car), 127.29 (Car), 127.29 (Car), 126.86 (Car), 126.72 (Car),
116.88 (C(1)), 116.59 (C(9)), 77.51 (C(7)), 76.68 (C(5)), 76.42 (C(4)),
72.35 (CH2 (C7-Bn)),70.64 (CH2 (C5-Bn)), 36.87 (C(3)), 34.61 (C(6)).
Anal. Calcd for C23H28O3 (352.47): C, 78.38; H, 8.01. Found: C, 78.11;
H, 8.24.
Data for 9: colourless oil; Rf 0.2 (hexane/ethyl acetate 85:15);
20
[
a]
ꢂ33.70 (c 0.98, CHCl3); IR (film):
n
¼3321 (m), 3064 (m), 3029
3.8. (3S,5S,6R) 6-[N-Benzyl-N-(benzyloxy-carbonyl)amino]-
3,5-bis(benzyloxy)-1,8-nonadiene (11)
D
(m), 2929 (m), 1949 (w), 1640 (m), 1605 (m), 1496 (m), 1454 (m),
1360 (m), 1206 (m), 1068 (m), 1028 (m), 995 (m), 919 (m), 735 (m),
697 (m), 608 (w), 462 (w) cmꢂ1; UV–vis (methanol): lmax
¼
To a solution of 9 (2.16 g, 4.88 mmol) in dichloromethane
(100 ml) water (20 ml) and NaHCO3 (4.10 g, 48.8 mmol) were
added, then benzyl chloroformate (2.04 ml, 12.2 mmol) was added
dropwise and stirring at room temperature continued for another
18 h. The layers were separated, the organic layer was washed with
water (100 ml), the aq layer with dichloromethane (3ꢀ100 ml) and
the combined organic layers were dried (MgSO4) and the solvents
were evaporated. The residue was subjected to chromatography
275.26 nm, A¼0.80; 1H NMR (500 MHz, CDCl3):
¼7.32–7.18 (m,
d
3
3
15H, phenyl-H), 5.76 (m, 2H, J2;H,H¼18.7 Hz, J8;H,H¼14.3 Hz, H-2,
H-8), 5.20 (dd, 2H, J¼10.3, 18.7 Hz, H-1), 5.06 (dd, 2H, J¼10.2,
14.3 Hz, H-9), 4.53 (d, 1H, J¼11.8 Hz, CH2 (C3-Bn)), 4.42 (d, 1H,
0
J¼11.4 Hz, CH2 (C5-Bn)), 4.21 (d, 1H, J¼11.4 Hz, CH2 (C5-Bn)), 4.18
0
(d, 1H, J¼11.8 Hz, CH2 (C3-Bn)), 3.95 (dd, 1H, H-3), 3.82 (d, 1H,
J¼13.4 Hz, CH2 (N-Bn)), 3.79 (ddd, 1H, J¼4.0 Hz, H-5), 3.79 (d, 1H,
0
J¼13.4 Hz, CH2 (N-Bn)), 2.90 (ddd, 1H, J¼4.0, 6.5, 6.7 Hz, H-6), 2.28
(silica gel, hexane/ethyl acetate 85:15) to afford 11 (1.8 g, 64%) as
a colourless, viscous oil. Rf 0.48 (hexane/ethyl acetate 85:15); [a]
D
20
(m, 1H, J¼6.5 Hz, H-70), 2.18 (m, 1H, J¼6.5 Hz, H-7), 1.77 (m, 2H, H-
4); 13C NMR (125 MHz, CDCl3):
d
¼139.06 (C(2)), 138.78 (Ci (C3-Bn)),
ꢂ16.72 (c 0.62, CHCl3); IR (film): ¼3065 (m), 3031 (s), 2929 (m),
n
138.78 (Ci (C5-Bn)), 138.78 (Ci of benzylamine), 135.85 (C(8)),
128.48 (Car), 128.33 (Car), 128.27 (Car), 128.28 (Car), 128.18 (Car),
127.84 (Car), 127.82 (Car), 127.73 (Car), 127.58 (Car), 127.48 (Car),
126.83 (Car), 117.19 (C(9)), 116.58 (C(1)), 77.27 (C(6)), 77.13 (C(5)),
71.87 (CH2 (C5-Bn)), 70.10 (CH2 (C3-Bn)), 57.75 (C(3)), 51.90 (CH2
1951 (w), 1702 (s), 1643 (m), 1606 (m), 1586 (m), 1496 (s), 1454 (s),
1415 (s), 1366 (s), 1236 (s), 1178 (m), 1097 (s), 1028 (s), 994 (s), 920
(s), 821 (m), 769 (s), 735 (s), 697 (s), 598 (m), 458 (m) cmꢂ1; UV–vis
(methanol): lmax1¼267.19 nm, A¼0.20, lmax2¼272.86 nm, A¼0.25,
lmax3¼228.25 nm, A¼0.23, lmax4¼282.96 nm, A¼0.16; 1H NMR

R. Csuk et al. / Tetrahedron 64 (2008) 9417–9422
9421
(500 MHz, CDCl3):
d
¼7.46–7.07 (m, 20H, phenyl), 5.56 (m, 2H, H-2,
1030 (s), 1110 (m), 990 (m), 980 (m), 920 (w), 805 (w), 760 (s), 745
H-8), 5.03–4.77 (m, 6H, H-1, H-10, H-9, H-90, CH2-Cbz), 4.42 (m, 2H,
CH20 (N-Bn), CH2 (CBz-Bn)), 4.24 (m, 1H, H-6), 4.16 (m, 4H, CH2-Bn),
3.75 (m, 2H, H-3, H-5), 2.44 (m, 1H, H-70), 2.30 (ddd, 1H, H-7), 1.77
(m, 1H, H-40), 1.68 (m, 1H, H-4); 13C NMR (125 MHz, CDCl3):
(s), 690 (s), 630 (w), 610 (w) cmꢂ1
; UV–vis (methanol):
lmax1¼268.50 nm, A¼0.635; lmax2¼274.65 nm, A¼0.582; 1H NMR
(500 MHz, CDCl3):
d¼7.36–7.08 (m, 20H, phenyl-H), 5.07 (d, 1H,
J¼12.4 Hz, CH2 (CBz-Bn)), 5.05 (d, 1H, J¼12.4 Hz, CH2 (CBz-Bn)),
4.54 (d, 1H, JH¼10.9 Hz, CH20 (N-B0n)), 4.50 (d,1H, J¼10.9 Hz, CH2 (N-
Bn)), 4.46 (d, 1H, J¼11.6 Hz, CH2 (C2-Bn)), 4.44 (d, 1H, J¼11.6 Hz,
CH2 (C2-Bn)), 4.27 (m, 1H, H-1), 4.22 (d, 2H, J¼11.3 Hz, CH2 (C4-
Bn)), 4.00 (m, 1H, H-4), 3.82 (m, 1H, H-5), 3.66 (m, 1H, H-2), 2.93 (s,
1H, OH (C5-OH)), 2.01 (m, 1H, H-60), 2.01 (m, 1H, H-6), 1.83 (m, 2H,
H-3), 1.61 (m, 1H, H-70), 1.53 (m, 1H, H-7); 13C NMR (125 MHz,
d¼156.46 (CO (CBz)), 138.83 (C(2)), 138.62 (Ci (C3-Bn)), 138.46 (Ci
(C5-Bn)), 137.57 (Ci, CBn), 136.70 (Ci of benzylamine), 135.55 (C(8)),
128.51 (Car), 128.42 (Car), 128.26 (Car), 127.92 (Car), 127.81 (Car),
127.73 (Car),127.67 (Car),127.57 (Car),127.44 (Car), 126.81 (Car),117.11
(C(9)), 116.97 (C(1)), 77.99 (C(3)), 77.84 (C(5)), 73.10 (CH2 (C3-Bn)),
72.44 (CH2 (C5-Bn)), 69.87 (CH2 (CBz-Bn)), 60.48 (C(6)), 49.10 (CH2
(N-Bn)), 38.76 (C(4)), 32.86 (C(7)); MS (ESI): m/z (%)¼598.9 (MþNa,
100), 1173.1 (M2þNa, 5), 582.7 (MþLi, 100), 1157.1 (M2þLi, 3). Anal.
Calcd for C38H41O4N (575.75): C, 79.27; H, 7.18. Found: C, 79.14; H,
7.44.
CDCl3):
d¼156.51 (CO (CBz)),140.01 (Ci (C2-Bn)),138.17 (Ci (C4-Bn)),
137.77 (Ci of benzylamine), 136.50 (Ci (CBz)), 128.49 (Car), 128.43
(Car), 128.23 (Car), 127.85 (Car), 127.79 (Car), 127.75 (Car), 126.37 (Car),
125.89 (Car), 79.81 (C(2)), 77.99 (C(4)), 73.05 (C(5)), 71.67 (CH2 (C2-
Bn)), 71.50 (CH2 (C4-Bn)), 67.13 (CH2 (CBz-Bn)), 60.49 (C(1)), 47.57
(CH2 (N-Bn)), 32.15 (C(6)), 29.44 (C(3)), 21.68 (C(7)); MS (ESI): m/z
(%)¼567.4 (MþH, 10), 589.6 (MþNa, 100), 1153.5 (M2þNa, 55). Anal.
Calcd for C36H39O5N (565.72): C, 76.43; H, 6.95. Found: C, 76.31; H,
3.9. (3S,5S,6R) 6-[N-Benzyl-N-(benzyloxy-carbonyl)amino]-
3,5-bis(benzyloxy)-cycloheptene (12)
To a solution of 11 (1.77 g, 3.07 mmol) in dry dichloromethane
(100 ml) under argon Grubbs’ catalyst (20 mg) was added and
stirring at room temperature was continued for 24 h. The mixture
was filtered through a short pad of silica gel, the filtrate evaporated
and the remaining residue subjected to chromatography (silica gel,
hexane/ethyl acetate (9:1)) to afford 12 (1.35 g, 80.4%) as a highly
viscous oil and unreacted 11 (0.22 g). Rf 0.26 (hexane/ethyl acetate
7.06.
20
Data for 14: Rf 0.22 (hexane/ethyl acetate 85:15); [
0.67, CHCl3); IR (film):
2935 (s), 1953 (m), 1694 (s), 1606 (m), 1586 (m), 1496 (s), 1455
(s), 1415 (s), 1254 (s), 1207 (s), 1111 (s), 914 (m), 845 (m), 772 (s),
735 (s), 967 (s), 596 (m), 459 (m) cmꢂ1; UV–vis (methanol):
a
]
D
32.77 (c
n
¼3446 (s), 3088 (m), 3063 (s), 3030 (s),
lmax1¼234.96 nm, A¼2.895; lmax2¼269.18 nm, A¼0.489; lmax3
¼
85:15); [
a
]
20 60.34 (c 0.86, CHCl3); IR (film):
n
¼3366 (m), 3031 (m),
274.95 nm, A¼0.5404; 1H NMR (500 MHz, CDCl3):
¼7.34–7.08 (m,
d
D
2934 (m), 1694 (s), 1606 (m), 1496 (m), 1455 (s), 1411 (m), 1358 (m),
1254 (s), 1206 (m), 1175 (m), 1101 (s), 1028 (m), 772 (m), 735
20H, phenyl), 5.05 (d, 2H, J¼7.2 Hz, CH2 (CBz-Bn)), 4.55 (d, 1H,
J¼12.4 Hz, CH2 (N-Bn)), 4.39 (d, 1H, J¼12.4 Hz, CH2 (N-Bn)), 4.52 (d,
1H, J¼10.8 Hz, CH2 (C2-Bn)), 4.38 (d, 1H, J¼10.8 Hz, CH2 (C2-Bn)),
4.46 (m, 1H, H-1), 4.22 (d, 2H, J¼12.0 Hz, CH2 (C4-Bn)), 4.09 (m, 1H,
H-4), 3.93 (m, 1H, H-6), 3.80 (m, 1H, H-2), 2.45 (m, 1H, H-50), 2.09
(m, 1H, H-5), 1.94 (m, 2H, H-3), 1.74 (m, 1H, H-70), 1.65 (m, 1H, H-7);
(m), 697 (s), 600 (w), 458 (m) cmꢂ1; UV–vis (methanol): lmax1
¼
268.96 nm, A¼0.46, lmax2¼274.79 nm, A¼0.46; 1H NMR (500 MHz,
CDCl3):
d
¼7.70–7.06 (m, 20H, phenyl-H), 5.91 (m, 1H, H-1), 5.64 (m,
1H, H-2), 5.060 (dd, 1H, H-3), 4.63 (d, 1H, CH2 (Bn)), 4.52 (d, 1H,
J¼12.0 Hz, CH2 (Bn)), 4.47 (m, 3H, CH2 (Bn)), 4.41 (d, 1H, J¼12.0 Hz,
CH2 (Bn)), 4.26 (d, 1H, CH2 (Bn)), 4.19 (d, 1H, CH2 (Bn)), 4.06 (m, 1H,
H-5), 2.82 (dd, 1H, H-6), 2.33 (m, 2H, H-4), 1.83 (m, 2H, H-7); 13C
13C NMR (125 MHz, CDCl3):
d
¼155.92 (CO (CBz)), 141.21 (Ci (C2-
Bn)), 138.78 (Ci (C4-Bn)), 137.49 (Ci of benzylamine), 136.94 (Ci
(CBz)), 128.48 (Car), 128.39 (Car), 128.30 (Car), 127.85 (Car), 127.64
(Car), 127.57 (Car), 126.40 (Car), 125.83 (Car), 78.65 (C(2)), 77.69
(C(4)), 71.15 (C(5)), 70.54 (CH2 (C2-Bn)), 70.32 (CH2 (C4-Bn)), 67.25
(CH2 (CBz-Bn)), 65.79 (C(1)), 41.22 (CH2 (N-Bn)), 36.51 (C(6)), 29.12
(C(3)), 21.94 (C(7)); MS (ESI): m/z (%)¼566.7 (MþH, 10), 589.4
(MþNa, 15), 1153.6 (M2þNa, 100), 573.5 (MþLi, 100), 1137.5 (M2þLi,
95), 1243.3 (M2þLi2ClO4, 10). Anal. Calcd for C36H39O5N (565.72): C,
76.43; H, 6.95. Found: 76.37; H, 7.09.
NMR (125 MHz, CDCl3):
d
¼156.46 (CO (CBz)), 140.19 (Ci (C3-Bn)),
140.02 (Ci (C5-Bn)), 138.38 (Ci of benzylamine), 138.19 (Ci (CBz)),
128.37 (C(2)), 128.28 (C(1)), 128.23 (Car), 127.83 (Car), 127.71 (Car),
127.63 (Car), 127.54 (Car), 126.31 (Car), 126.06 (Car), 125.81 (Car),
79.08 (C(5)), 72.07 (C(3)), 70.82 (CH2 (C5-Bn)), 70.68 (CH2 (C3-Bn)),
67.09 (CH2 (CBz-Bn)), 57.19 (C(6)), 47.70 (CH2 (N-Bn)), 35.88 (C(4)),
25.95 (C(7)); MS (ESI): m/z (%)¼548.5 (MþH, 30), 570.5 (MþNa,
100), 1117.0 (M2þNa, 50). Anal. Calcd for C36H37O4N (547.68): C,
78.95; H, 6.81. Found: C, 78.72; H, 7.05.
3.11. (2S,4S,5R) 5-[N-benzyl-N-(benzyloxy-
carbonyl)amino]2,4-bis(benzyloxy)-cycloheptanone (15)
3.10. (2S,4S,5R)-5-[N-benzyl-(benzyloxy-carbonyl) amino]2,4-
bis(benzyloxy)cycloheptanol (13) and (3R,5S,6R)-6-[N-benzyl-
N-(benzyloxy-carbonyl)amino]3,5-bis(benzyloxy)-
cycloheptanol (14)
To a solution of 13 (0.33 g, 0.59 mmol) in dry dichloromethane
(50 ml) PCC (0.19 g, 0.59 mmol) was added and stirring at room
temperature was continued for another 24 h; more PCC (0.2 g,
0.93 mmol) was added and after 24 h of stirring the mixture was
decanted and the residue extracted with dichloromethane
(3ꢀ50 ml). The combined organic layers were washed with water
(50 ml), dried (MgSO4), filtered through a pad of silica gel, the fil-
trate was evaporated and the residue subjected to chromatography
To a ꢂ78 ꢁC cold solution of 12 (0.80 g, 1.47 mmol) in dry THF
(80 ml) BH3$THF (1 M, 5.87 ml, 5.87 mmol) was slowly added and
stirring at room temperature was continued for another 12 h. After
completion of the reaction aq sodium hydroxide (2 N, 10.5 ml) and
aq hydrogenperoxide (30%, 1.5 ml) was slowly added. After stirring
for 5 h at room temperature the phases were separated, the aq
phase was extracted with ether (3ꢀ50 ml), the combined organic
phases were dried (MgSO4) and the solvent was evaporated. The
residue was subjected to chromatography (silica gel, hexane/ethyl
acetate 9:1) to afford 13 (0.37 g, 44.75%) and 14 (0.22 g, 26.5%) as
(silica gel, hexane/ethyl acetate 85:15) to afford 15 (0.28 g, 86%) as
20
a colourless viscous oil. Rf 0.58 (hexane/ethyl acetate 85:15); [a]
D
1.691 (c 0.28, CHCl3); IR (film):
n
¼3418 (m), 2926 (m), 1694 (m),
1496 (m),1456 (m),1260 (m),1111 (m), 736 (m), 699 (m) cmꢂ1; UV–
vis (methanol): lmax1¼231.79 nm, A¼2.857; lmax2¼260.81 nm,
A¼0.673; 1H NMR (500 MHz, CDCl3):
d
¼7.39–6.98 (m, 20H, phenyl-
0
colourless oils.
H), 5.00 (d, 1H, J¼12.0 Hz, CH2 (CBz-Bn)), 04.97 (d, 1H, J¼12.0 Hz,
20
Data for 13: Rf 0.44 (hexane/ethyl acetate 85:15); [
a
]
45.76 (c
D
CH2 (CBz-Bn)),0 4.59 (d, 1H, J¼11.8 Hz, CH2 (C4-Bn)), 4.49 (d, 1H,
0
0.49, CHCl3); IR (film):
2980 (m), 2860 (m), 1570 (s), 1610 (m), 1570 (m), 1500 (m), 1455 (s),
1410 (m), 1245 (m), 1200 (s), 1140 (m), 1100 (s), 1080 (s), 1070 (s),
n
¼3440 (m), 3100 (m), 3060 (m), 3030 (m),
J¼10.6 Hz, CH2 (N-Bn)), 4.43 (d, 1H, J¼11.2 Hz, CH2 (C2-Bn)), 4.33
(d, 1H, J¼10.6 Hz, CH2 (N-Bn)), 4.33 (m, 1H, CH2, H-2), 4.27 (d, 1H,
J¼11.8 Hz, CH2 (C4-Bn)), 4.17 (m, 1H, H-1), 4.13 (d, 1H, J¼11.2 Hz,

9422
R. Csuk et al. / Tetrahedron 64 (2008) 9417–9422
CH2 (C2-Bn)), 3.97 (m, 1H, H-4), 2.48 (m, 1H, H-60), 2.38 (m, 1H, H-
6), 2.25 (ddd, 1H, H-70), 1.83 (m, 1H, H-7), 1.49 (ddd, 2H, H-3); 13C
References and notes
1. Dra¨ger, B. Nat. Prod. Rep. 2004, 21, 211–223.
NMR (125 MHz, CDCl3):
d
¼209.33 (CO (C(5))), 171.09 (CO (CBz)),
2. Tepfer, A.; Goldmann, A.; Pamboukdjian, N.; Maille, M.; Lepingle, A.; Chevalier,
D.; Denarie, J.; Rosenberg, C. J. Bacteriol. 1988, 170, 1153–1161.
3. Goldmann, A.; Milat, M. L.; Ducrot, P. H.; Lallemand, J. Y.; Maille, M.; Lepingle,
A.; Charpin, I.; Tepfer, D. Phytochemistry 1990, 29, 2125–2127.
4. Goldmann, A.; Message, B.; Tepfer, D.; Molyneux, R. J.; Duclos, O.; Boyer, F.-D.;
Pan, Y. T.; Elbein, A. D. J. Nat. Prod. 1996, 59, 1137–1142.
5. Asano, N.; Kato, A.; Miyauchi, M.; Kizu, H.; Tomimori, T.; Matsui, K.; Nash, R. J.;
Molyneux, R. J. Eur. J. Biochem. 1997, 248, 296–303.
139.85 (Ci (C4-Bn)), 138.01 (Ci (C2-Bn)), 137.71 (Ci of benzylamine),
136.38 (Ci (CBz)), 128.44 (Car), 128.36 (Car), 127.91 (Car), 127.86 (Car),
126.53 (Car), 125.75 (Car), 79.38 (C(2)), 77.56 (C(4)), 71.93 (CH2 (C4-
Bn)), 71.24 (CH2 (C2-Bn)), 67.30 (CH2 (CBz-Bn)), 60.50 (C(1)), 47.80
(CH2 (N-Bn)), 39.04 (C(7)), 33.70 (C(6)), 21.16 (C(3)); MS (ESI): m/z
(%)¼587.0 (MþNa, 10), 1149.1 (M2þNa, 10). Anal. Calcd for
6. Asano, N.; Kato, A.; Kizu, H.; Matsui, K.; Griffiths, R. C.; Jones, M. G.; Watson, A.
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C
36H37O5N (563.70): C, 76.71; H, 6.62. Found: 76.51; H, 6.92.
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(calystegine A7) (17)
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A solution of 15 (0.18 g, 0.32 mmol) in ethyl acetate (20 ml) and
acetic acid (80 ml) was hydrogenated in the presence of Pd/C (0.2 g,
10% Pd) at a pressure of 2.38 atm for 24 h. The solvents were re-
moved under reduced pressure and the residue subjected to
chromatography (silica gel, methanol/water/concd ammonium
hydroxide 95:5:1) to afford 17 (0.047 g, 92.1%) as a viscous oil. Rf 0.2
20
16. Boyer, F. D.; Ducrot, P. H.; Henryon, V.; Soulie, J.; Lallemand, J. Y. Synlett 1992,
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(methanol/water/ammonium hydroxide 95:5:1); [
a
]
ꢂ1.87 (c
D
20
20
0.97, MeOH); [
a
]
D
ꢂ10.83 (c 0.3, H2O) (lit.5
[a
]
ꢂ10.8 (c 0.27,
D
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H2O)); IR (film):
n
¼3355 (s), 2926 (s), 2498 (m), 1652 (m), 1456 (m),
1085 (m) cmꢂ1
;
1H NMR (400 MHz, D2O):
d
¼3.85 (ddd, 1H,
3J2,3ax¼9.5 Hz, J2,3eq¼5.5 Hz, J2,7exo¼1.8 Hz, H2), 3.81 (m, 1H, H4),
3.35 (m, 1H, H5), 2.09 (m, 1H, H6endo), 2.06 (m, 1H, H7endo), 2.00
(dddd, 1H, 3J2,3eq¼5.5 Hz, 3J3eq,4¼2.2 Hz, 2J3ax,3eq¼14.7 Hz,
3
4
4J3eq,5¼1.8 Hz, H3eq), 1.61 (ddd, 1H, J2,3ax¼9.5 Hz, J3ax,4¼4.0 Hz,
3
3
2J3ax,4¼4.0 Hz, 2J3ax,3eq¼14.7 Hz, H3ax), 1.55 (m, 1H, H7exo), 1.42 (m,
1H, H6endo); 13C NMR (125 MHz, CD3OD):
d
¼92.04 (C(5)), 72.51
(C(4)), 71.60 (C(2)), 60.00 (C(1)), 35.84 (C(3)), 27.60 (C(6)), 24.96
(C(7)); MS (ESI): m/z (%)¼160.4 (MþH, 100), 182.3 (MþNa, 8). Anal.
Calcd for C7H14O3N (160.19): C, 52.49; H, 8.81. Found: C, 52.31; H,
8.95.
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Acknowledgements
32. Garegg, P. J.; Johansson, R.; Ortega, C.; Samuelson, B. J. Chem. Soc., Perkin Trans. 1
1982, 681–683.
We like to thank the Fond der Chemischen Industrie and
Biosolutions GmbH (Halle/Saale) for financial support, Dr. D. Stro¨hl
for taking numerous NMR spectra, Dr. R. Kluge for the ESI-MS
measurements, and Dr. R. Scha¨fer for helpful discussions. We are
indebted to Dr. C. Korb for performing the enzymatic assays.
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