En route to sugar-alkaloid conjugates

Article abstract of DOI:10.1016/j.carres.2011.04.022

After stereoselective addition of N-iodosuccinimide to glycals subsequent dehalogenation results in formation of N-glycopyranosyl succinimides. By UV irradiation both azepindiones and preferentially [5.3.1.0^2,6] tricyclic oxalactams could be ob

Full text of DOI:10.1016/j.carres.2011.04.022

Carbohydrate Research 346 (2011) 1546–1550
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
En route to sugar–alkaloid conjugates
⇑
Carsten-Endres Sowa, Joachim Thiem
University of Hamburg, Faculty of Science, Department of Chemistry, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 27 April 2011
After stereoselective addition of N-iodosuccinimide to glycals subsequent dehalogenation results in for-
mation of N-glycopyranosyl succinimides. By UV irradiation both azepindiones and preferentially
[5.3.1.02,6] tricyclic oxalactams could be obtained. Their transformation into a number of novel sugar con-
jugates resembling some prominent alkaloid N-pyrrol components by thiation and reduction is reported.
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor Dr. András Liptak on
the occasion of his 75th birthday
Keywords:
N-2-Deoxyglycopyranosyl succinimides
[5.3.1.02,6] Oxalactams
Simplexin oxa-analogs
Glycopyranosyl-N-pyrrol
1. Introduction
formational assignments of these novel bicyclic and tricyclic ring
systems by 1H NMR and 13C NMR were in line with those discussed
As reported earlier N-2-deoxyglycopyranosyl succinimides such
as 5 and 8 could be photochemically transformed into mixtures of
the bicyclic (9, 11) and tricyclic (10, 12) oxalactams, respectively.1,2
in previous contributions.1,2,6
OR
OR
O
Irradiation of these imides resulted in abstraction of a
c- or d-
OR
O
NIS
hydrogen atoms in a Norrish-Type II reaction. By subsequent intra-
molecular alkylation (Yang cyclization) the azepindiones (9, 11)
and the tricyclic aminals (10, 13) could be obtained (Scheme 1).
O
N
RO
I
RO
RO
RO
O
1
R = Me
3 R = Me
2 R = Bn
4
R = Bn
OR
OR
2. Results and discussion
nBu3SnH
OR
O
O
Treatment of tri-O-methy-
(NIS) gave the corresponding 2-deoxy-2-iodo-
syl derivative 3 in 80% yield. Further radical reduction with tri-n-
D
-glucal (1)3 with N-iodosuccinimide
-mannopyrano-
RO
RO
O
a
-D
N
N
O
O
O
butyl stannic hydride gave the reduced material 5 in 91% yield.
Starting from tri-O-benzyl-D
-glucal (2)4 the NIS reaction gave com-
pound 4,5 further radical reduction led to 6,5 and palladium/char-
coal hydrogenation under pressure gave the unblocked material
7 quantitatively. Its treatment with tert butyldimethylsilyl triflate
at ꢀ80 °C led to the desired compound 8 (98%).
5
6
R = Me
R = Bn
H
2 /Pd-C
7 R = H
Me2tBuSiOTf
8
R = SiMe2tBu
Irradiation of compound 5 in acetonitrile at room temperature
with UV light at k = 254 nm for 7 h gave after work-up 12% of elim-
ination product 1 and a transformation of 82% to the novel prod-
hν
H
N
O
O
O
1
O
1
7
10
3
RO
N
10
4
OR
ucts
9 and 10 in 11% and 58% yield, respectively. The
OR
6
RO
corresponding irradiation of the N-glycosylsuccinimide 8 gave a
transformation of 73% to lead to the azepindione 11 in 21% and
the tricyclic aminal 12 in 62% yield (Scheme 1). Structural and con-
OH OR
OR
O
9
11
R = H
R = Me2tBuSi
10
12
⇑
Corresponding author. Tel.: +49 40 42838 4241; fax: +49 40 42838 4325.
E-mail address: joachim.thiem@chemie.uni-hamburg.de (J. Thiem).
Scheme 1.
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.04.022

C.-E. Sowa, J. Thiem / Carbohydrate Research 346 (2011) 1546–1550
1547
Ar
S
S
P
P
N
OH
N
OH
S
O
O
12
6
O
1
MeO
OH
Ar
S
O
OH
O
10
Lawesson
Tol., 90
MeO
O
N
O
MeO
1
OMe
Securin
6
12
OMe
Simplexin
°
C
OMe
N
OH
R'
N
10
3
19
OR
1
OR
S
S
P
Ar
P
N
RO6
O
Ar
S
S
R'
O
OR
RO
RO
RO
OR
O
1
S
Frup-1-N-pyrrol
Galp-6-N-pyrrol
O
N
N
1
3
OMe
12
6
OMe
Figure 1.
OMe
S
OMe
12
O
H
6
OMe
Ar
P
OMe
P
Ar
Surprisingly, the N-acylated aminal bond could not be opened
even under drastic conditions neither with acid nor with base.
There are only two previous reports on structures displaying the
[5.3.1.02,6] system and they indicate a limited reactivity under ba-
sic conditions, provided a leaving group would be present.7,8 In this
case the amide group (even protonated) cannot function as a leav-
ing group. Attempts to activate the system via enolization did not
work, and apparently the strongly shielded amide cannot be
alkylated.
Driven by the idea to form oxa-analogs of the alkaloid systems
of simplexins9 and securins10 (norsecurins11) (Fig. 1) it was at-
tempted to keep the unusual tricyclic system intact. Since a hydro-
lysis of neither the amide nor the aminal could be achieved,
transformation of the amide into a thioamide and a further reduc-
tive step should lead to the required annelated tetrahydropyrrol
ring system.
S
S
S
a
O
Ar
P
P
-
S
Δ
− H2S
S
Ar
S
O
HS
1
O
1
S
3
N
N
OMe
OMe
OMe
OMe
6
12
6
OMe
OMe
c
b
Ar =
OMe
Scheme 3.
Thus, the tertiary alcohol in compound 10 could be protected
with a trimethylsilyl group to give 13 (13C: C@O 181.9), which in
turn with Lawesson’s reagent12,13 in toluene for 0.5–1 h at 60 °C ni-
cely and quantitatively gave the thioamide component 15 (13C:
C@S 210.0). Further reduction with Raney nickel led to the oxa-
analog alkaloid system 17 (13C: CH2-3 56.34). The corresponding
transformation of 12 gave 14, further the thioamide 16 and the fi-
nal system 18 in acceptable yields (Scheme 2).
An unusual transformation was observed when the starting tri-
cyclic material 10 was treated with Lawesson’s reagent in toluene
for 2 h at 90 °C. In this case the pyrrol-bridged sugar derivative 19
resulted in good yield. The pyrrol ring is evident by the typical car-
bon shift in the 13C NMR for C-3 (111.85), C-4 (113.56), C-5 (99.32),
and C-6 (134.19). It is N-
a
-glycosylated (J1,10 = 2.0 and
0
J1,10 = 1.5 Hz) and displays a bond linking the pyrrol C2-position
(numbered C-6) to the sugar C5-position (numbered C-7) repre-
senting a structural feature hitherto not observed (Scheme 3).
Recently some sugar pyrrol conjugates were reported, which
carry the (substituted) pyrrol N-linked at C1 in a fructopyranose
or C6 in a galactopyranose system.14 Their straight forward forma-
tion was by treatment of the corresponding imidazolyl sulfonates15
with the pyrrol N-anion (Fig. 1).
Overall, the new reaction formally seems to correspond to the
reduction of an amide (10) to give an enamine (19), and at this
stage a tentative attempt is proposed to account for this rather
unusual transfer. Following a primary sulfation of 10 to give the
thioamide an attack of the 6-OH at the phosphorus reagent should
give the intermediate a resembling 15. The subsequent elimination
of the thiophosphorus reagent will lead to the bridge head olefin
intermediate b. Contrary to Bredt’s rule it is assumed to be stable
in accord with reports of von Ragué Schleyer et al.16,17 indicating
that such olefins can be considered as stabilizing elements within
and for tricyclic systems. Further, by enolization the equilibrium
would be expected to be shifted to give the heteroaromatic pyrrol
system c. Sulfur components present at these elevated tempera-
tures promote an often reported radical induced reductive car-
bon-sulfur cleavage to give the final product 19 (Scheme 3).
O
O
O
O
MeCON(SiMe3)2
Py
N
N
OR
OR
OR
OR
OR
OR
OH
OSiMe3
10
12
13
14
R = Me
R = SiMe2tBu
R = Me
R = SiMe2tBu
Lawesson
Tol., 60° C
O
O
S
N
N
OR
OR
Raney-Ni/H2
EtOH/H2O
OR
OR
OR
OR
3. Experimental
OSiMe3
OSiMe3
17
18
R = Me
R = SiMe2tBu
15
16
R = Me
R = SiMe2tBu
3.1. General
For general methods cf. 18.
Scheme 2.

1548
C.-E. Sowa, J. Thiem / Carbohydrate Research 346 (2011) 1546–1550
3.2. N-(2-Deoxy-2-iodo-3,4,6-tri-O-methyl-
mannopyranosyl)-succinimide (3)
a-
D-
13C NMR (100 MHz, CDCl3): d = 7.24 (2C, CH2, imide), 31.09
(CH2, C-2), 59.71 (CH2, C-6), 68.93, 69.29 (C-4, C-5), 74.29, 75.31
(C-1, C-3), 180.30 (2C, q, imide C@O).
Compound 13 (4.56 g, 24.2 mmol) under argon cover in a brown
glass flask was dissolved in anhydrous acetonitrile (100 mL), trea-
ted with N-iodosuccinimide (10.6 g, 48 mmol) and stirred for 12 h
at room temperature. The solvent was evaporated, the raw mate-
rial dissolved in ethyl acetate, the solution washed with aqueous
sodium sulfite solution, dried over sodium sulfate and purified
on silica gel with toluene/ethyl acetate 3:1 to give 3 as a colorless
Anal. Calcd for C10H15NO6 (245.2): C, 48.98; H, 6.17; N, 5.71.
Found: C, 48.92; H, 6.21; N, 5.65.
3.5. N-(3,4,6-Tri-O-tert-butyldimethylsilyl-2-deoxy-
a-D-
arabino-hexopyranosyl)-succinimide (8)
Under nitrogen compound 7 (2.25 g, 9.23 mmol) was dissolved
in anhydrous tetrahydrofuran (60 mL) and pyridine (20 mL) and
cooled to ꢀ80 °C. During vigorous stirring tert-butyldimethylsilyl
triflate (7.0 mL, 30.05 mmol) was added, after which the reaction
mixture was gradually warmed to room temperature within 5 h.
The clear solution was evaporated, the remainder dissolved in
ether, washed with water and aqueous sodium chloride, dried over
sodium sulfate and evaporated. Following purification on silica gel
with toluene/ethyl acetate 10:1 the product 8 resulted as a color-
syrup. Yield 8.9 g (89%); ½a D20
ꢁ
52 (c 1.34, CHCl3).
1H NMR (400 MHz,CDCl3): d = 2.64 (s, 4H, imide), 3.37, 3.40,
3.47 (each s, each 3H, OCH3), 3.36 (dd, 1H, J2,3 = 3.0, J3,4 = 2.5 Hz,
0
H-3), 3.58 and 3.73 (each dd, each 1H, J5,6 = 10.0, J5,6 = 6.0,
J6,6 = 12.0 Hz, H-6, H-60), 3.67 (dd, 1H, J3,4 = 2.5, J4,5 = 2.0 Hz, H-4),
0
0
4.33 (ddd, 1H, J4,5 = 2.0, J5,6 = 10.0, J5,6 = 6.0 Hz, H-5), 5.22 (d, 1H,
J1,2 = 11.5 Hz, H-1).
13C NMR (100 MHz, CDCl3): d = 27.55 (2C, CH2, imide), 28.19 (C-
2), 55.51, 55.79, 56.45 (3C, OCH3), 61.41 (CH2, C-6), 67.56, 73.81,
74.94 (C-3, C-4, C-5), 79.99 (C-1), 177.36 (2C, q, imide C@O).
Anal. Calcd for C13H20 INO6 (413.2): C, 37.79; H, 4.88; N, 3.39.
Found: C, 37.65; H, 4.81; N, 3.28.
less syrup. Yield 5.31 g (99%); ½a D20
ꢀ5 (c 0.83, CHCl3).
ꢁ
1H NMR (400 MHz, CDCl3): d = 0.03–0.08 (m, 18H, SiCH3), 0.86
0
ꢀ0.93 (m, 27H, tert -Bu), 1.40 (ddd, 1H, J1,2 = 11.0, J2,2 = 11.5,
0
J2,3 = 2.5 Hz, H-2), 2.65 (s, 4H, imide), 3.25 (ddd, 1H, J1,2 = 2.5,
J2,2 = 11.5, J2,3 = 1.5 Hz, H-20), 3.69 (dd, 1H, J3,4 = 2.5, J4,5 = 2.0 Hz,
0
0
0
3.3. N-(2-Deoxy-3,4,6-tri-O-methyl-
hexopyranosyl)-succinimide (5)
a
-D
-arabino-
H-4), 3.85 (dd, 1H, J5,6 = 6.5, J6,6 = 10.0 Hz, H-6), 3.92 (ddd, 1H,
0
J4,5 = 2.0, J5,6 = 6.5, J5,6 = 6.0 Hz, H-5), 3.98–4.02 (m, 2H, H-3, H-
60), 5.73 (d, 1H, J1,2 = 11.0, J1,2 = 2.5 Hz, H-1).
0
Compound 3 (7.12 g, 17.2 mmol) was dissolved in anhydrous
toluene (130 mL) and tri-butyl stannic hydride (33.6 mL, 26 mmol)
and a catalytic amount of azobisisobutyronitrile (AIBN) added.
After 12 h at 70 °C the solvent was removed, taken up in
acetonitrile and washed with light petroleum ether. Following
evaporation of the acetonitrile phase the raw material was puri-
fied on silica gel with toluene/ethyl acetate 4:1 to 1:1 to give 5
13C NMR (100 MHz, CDCl3): d = ꢀ5.35 to ꢀ4.72 (6C, SiCH3),
25.14, 25.17, 25.29, (9C, tert-Bu), 17.90, 17.97, 18.21 (3C, q, Si–C),
28.05 (2C, CH2, imide), 29.25 (CH2, C-2), 61.45 (CH2, C-6), 67.58,
70.95, 71.45 (C-3, C-4, C-5), 81.36 (C-1), 176.34 (2C, q, imide C@O).
Anal. Calcd for C28H57NO6Si3 (558.0): C, 57.19; H, 9.77; N, 2.38.
Found: C, 57.24; H, 9.76; N, 2.36.
as
CHCl3).
a
colorless syrup. Yield 4.5 g (91%);
½
a 2D0
ꢁ
24 (c 1.56,
3.6. (1S,7R,8R,9R,10R)-8,9-Dimethoxy-10-methoxymethyl-11-
oxa-2-aza-bicyclo[5.4.0]undecan-3,6-dione (9) and
1H NMR (400 MHz, CDCl3): d = 1.71 (ddd, J1,2 = 5.0, J2,2 = 13.7
(1S,6S,7R,8S,9R)-6-hydroxy-8,9-dimethoxy-7-methoxymethyl-
0
J2,3 = 5.5 Hz, H-2), 2.69 (s, 4H, imide), 2.74 (ddd, 1H, J1,2 = 7.0,
11-oxa-2-aza-tricyclo[5.3.1.02,6]undecan-3-one (10)
0
J2,2 = 13.7, J2,3 = 4.5 Hz, H-20), 3.32, 3.37, 3.45 (each s, each 3H,
OCH3), 3.67 (dd, 1H, J3,4 = 6.0, J4,5 = 6.5 Hz, H-4), 3.69 (ddd, 1H,
0
0
Compound 5 (6.07 g, 21.1 mmol) was dissolved in degassed
anhydrous acetonitrile (4 L) and irradiated at 18 °C for 7 h with
UV light (k = 254 nm). The solvent was evaporated and the raw
material purified on silica gel with toluene/acetone 6:1 to 2:1.
The transfer of 5 was 82%, and as side product 3, 4, 6-tri-O-
0
J2,3 = 5.5, J2 ,3 = 4.5, J3,4 = 6.0 Hz, H-3), 3.74 (dd, 1H, J5,6 = 4.0,
J6,6 = 10.5 Hz, H-6), 3.89 (dd, 1H, J5,6 = 5.0, J6,6 = 10.5 Hz, H-60),
0
0
0
0
4.27 (ddd, 1H, J4,5 = 6.5, J5,6 = 4.0, J5,6 = 5.0 Hz, H-5), 5.65 (d, 1H,
0
J1,2 = 5.0, J1,2 = 7.0 Hz, H-1).
13C NMR (100 MHz, CDCl3): d = 24.74(2C, CH2, imide), 25.79
(CH2, C-2), 55.78, 56.67, 57.81 (3C, OCH3), 59.76 (CH2, C-6),
63.10, 65.32, 66.36 (C-3, C-4, C-5), 71.81 (C-1), 175.42 (2C, q, imide
C@O).
methyl-D-glucal (1, 476 mg, 12%) could be isolated.
Compound 9: yield 0.55 g (11%); colorless syrup; ½a D20
ꢁ
19 (c
0.51, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.40 (m, 1H, H-4), 2.54 (dd, 1H,
J1,7 = 3.0, J7,8 = 2.5 Hz, H-7), 2.39 (m, 1H, H-5), 3.49, 3.51, 3.73 (each
Anal. Calcd for C13H21NO6 (287.3): C, 54.35; H, 7.37; N, 4.88.
Found: C, 54.22; H, 7.31; N, 4.65.
0
s, each 3H, OCH3), 3.66 (m, 1H, H-9), 3.79 (ddd, 1H, J4,5 = 3.5,
J4 ,5 = 5.0, J5,5 = 15.5 Hz, H-50), 3.87–4.11 (m, 3H, H-10, H-12, H-
120), 4.34 (dd, 1H, J7,8 = 2.5, J8,9 = 3.0 Hz, H-8), 5.08(dd, 1H,
J1,7 = 3.0, J1,NH = 7.5 Hz, H-1), 7.08 (d, 1H, J1,NH = 7.5 Hz, NH).
13C NMR (100 MHz, CDCl3): d = 30.1, 38.2(2C, CH2, C-4, C-5),
53.6 (C-7), 56.6, 57.9, 60.1 (3C, OCH3), 61.2 (CH2, C-12), 67.2,
72.0, 76.8 (C-8, C-9, C-10), 84.1 (C-1), 178.0 (q, C-3, N–C@O),
207.1 (q, C-6, C@O).
0
0
0
3.4. N-(2-Deoxy-a-D-arabino-hexopyranosyl)-succinimide (7)
Compound 65 (258 mg, 0.5 mmol) was dissolved in a mixture of
ethyl acetate (5 mL), methanol (5 mL) and acetic acid (2 mL),
Hydrogenation (H2, 80 bar) was done with palladium/charcoal
(10%, 101 mg) for 24 h at room temperature. After filtration over
Celite the residue was codistilled with toluene three times and
the raw material crystallized from isopropanol to give 7 as a color-
Anal. Calcd for C13H21NO6 (287.3): C, 54.35; H, 7.37; N, 4.88.
Found: C, 54.28; H, 7.21; N, 4.76.
less crystalline material. Yield 122 mg (99%); mp 135 °C; ½a D20
ꢁ
43 (c
Compound 10: yield 2.89 g (58%); colorless syrup; ½a D20
ꢁ
87 (c
1.02, CHCl3).
1.45, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.88 (dd, J1,2 = 7.0, J2,2 = 14.5,
1H NMR (400 MHz, DMSO-d6): d = 2.54 (ddd, 1H, J1,10 = 3.0,
0
0
0
0
0
J2,3 = 5.5 Hz, H-2), 2.43 (ddd, 1H, J1,2 = 3.0, J2,2 = 14.5, J2,3 = 9.5 Hz,
J9,10 = 10.0, J10,10 = 13.0 Hz, H-10), 2.16, 2.23–2.37(each m, 3H, H-
H-20), 2.65(s, 4H, imide), 3.31 (dd, 1H, J3,4 = 8.0, J4,5 = 9.0 Hz, H-4),
4, H-5, H-50), 2.44 (ddd, 1H, J1,10 = 1.5, J9,10 = 6.5, J10,10 = 13.0 Hz,
0
0
0
H-100), 3.00 (ddd, 1H, J4,4 = 13.5, J4 ,5 = 18.0, J4 ,5 = 3.0 Hz, H-40),
0
0
0
0
0
3.44 (ddd, 1H, J4,5 = 9.0, J5,6 = 3.5, J5,6 = 5.0 Hz, H-5), 3.61–3.64 (m,
2H, H-6, H-60), 4.24 (ddd, 1H, J2,3 = 5.5, J2 ,3 = 9.5, J3,4 = 8.0 Hz, H-
3.31 (ddd, 1H, J8,9 = 9.0, J9,10 = 10.0, J9,10 = 6.5 Hz, H-9), 3.54, 3.56,
0
0
0
0
3), 5.58(d, 1H, J1,2 = 7.0, J1,2 = 3.0 Hz, H-1).
3.68 (each s, each 3H, OCH3), 3.55 (d, 1H, J12,12 = 11.0 Hz, H-12),

C.-E. Sowa, J. Thiem / Carbohydrate Research 346 (2011) 1546–1550
1549
3.64 (d, 1H, J8,9 = 9.0 Hz, H-8), 4.05 (d, 1H, J12,12 = 11.0 Hz, H-120),
tiously, then gradually warmed to room temperature and finally
heated to 70 °C for 1 h. After evaporation the residue was dissolved
in ethyl acetate, washed with water, dried and again evaporated.
The raw material was purified on silica gel with toluene/acetone
8:1 to 2:1 to give 13 as a colorless syrup. Yield 824 mg (87%);
0
0
5.58 (dd, 1H, J1,10 = 3.0, J1,10 = 1.5 Hz, H-1), 6.10 (s, 1H, 6-OH).
13C NMR (100 MHz, CDCl3): d = 30.6 (CH2, C-4), 34.5 (CH2, C-10),
34.6 (CH2, C-5), 56.4, 58.9, 60.7 (3C, OCH3), 69.3 (CH2, C-12), 78.4
(C-9), 80.8 (C-8), 82.7(q, C-7), 89.0 (C-1), 98.7 (q, C-6), 181.6 (q,
C-3, amide).
½
a 2D0
62 (c 1.11, CHCl3).
ꢁ
Anal. Calcd for C13H21NO6 (287.3): C, 54.35; H, 7.37; N, 4.88.
Found: C, 54.22; H, 7.29; N, 4.71.
1H NMR (400 MHz, CDCl3): d = 0.22 (s, 9H, SiCH3), 1.70 (ddd, 1H,
0
J1,10 = 2.5, J9,10 = 9.0, J10,10 = 11.5 Hz, H-10), 2.04(m, 1H, H-4), 2.16–
2.31 (m, 3H, H-40, H-5, H-50), 2.76 (ddd, 1H, J1,10 = 1.5, J9,10 = 6.5,
0
0
0
3.7. (1S,7R,8R,9R,10R)-8,9-Bis-(tert-butyldimethylsiloxy)-10-
tert-butyldimethylsiloxymethyl-11-oxa-2-aza-
bicyclo[5.4.0]undecan-3,6-dione (11) and (1S,6S,7R,8S,9R)-8,9-
bis-(tert-butyldimethylsiloxy)-7-tert-
J10,10 = 11.5 Hz, H-100), 3.42–3.54 (m, 3H, H-8, H-12, H-120), 3.42,
3.43, 3.54 (each s, each 3H, OCH3), 3.85 (ddd, 1H, J8,9 = 9.5,
0
J9,10 = 9.0, J9,10 = 6.5 Hz, H-9), 5.49 (dd, 1H, J1,10 = 2.5,
0
J1,10 = 2.5 Hz, H-1).
butyldimethylsiloxymethyl-6-hydroxy-11-oxa-2-aza-
13C NMR (100 MHz, CDCl3): d = 1.67 (3H, SiCH3), 31.48, 33.74,
35.85 (CH2, C-4, C-5, C-10), 57.96, 59.44, 60.55 (3C, OCH3), 70.24
(CH2, C-12), 78.68, 82.57, 84.79 (C-1, C-8, C-9), 86.06 (q, C-7),
99.99 (q, C-6), 180.57 (q, C-3).
tricyclo[5.3.1.02,6]undecan-3-one (12)
Compound 8 (412 mg, 0.7 mmol) was dissolved in degassed
anhydrous acetonitrile (400 mL) and irradiated at 18 °C for 5 h
with UV light (k = 254 nm). The solvent was evaporated and the
raw material purified on silica gel with light petrol ether/ethyl ace-
tate 6:1 to 1:2. The transfer of 8 was 73%.
Anal. Calcd for C16H29NO6 (359.5): C, 53.46; H, 8.13; N, 3.90.
Found: C, 52.90; H, 8.01; N, 3.72.
3.9. (1S,6S,7R,8S,9R)-8,9-Bis-(tert-butyldimethylsiloxy)-7-tert-
butyldimethylsiloxymethyl-6-trimethylsiloxy-11-oxa-2-aza-
tricyclo[5.3.1.02,6]undecan-3-one (14)
Compound 11: yield 63 mg (21%); colorless crystals; mp
71 °C;½a 2D0
ꢁ
45 (c 0.79, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.0–0.15 (m, 18H, SiCH3), 0.80–
0
0.95 (m, 27H, tert-Bu), 2.37 (ddd, 1H, J4,4 = 13.0, J4,5 = 6.5,
Compound 12 (311 mg, 0.53 mmol) was dissolved in degassed
anhydrous THF (10 mL) and pyridine (0.5 mL) under nitrogen and
cooled to -80 °C. Under vigorous stirring trimethylsilyl triflate
(0.16 mL, 0.85 mmol) was added cautiously. Following gradually
warming to room temperature the mixture was kept at 50 °C for
3 h. Excess of triflate was decomposed by addition of diisopropyl-
amine (0.2 mL), and the mixture was evaporated to dryness.
Following solution in ether, washing with water and aqueous
sodium chloride and drying over sodium sulfate purification
was on silica gel with light petrol ether/diethyl ether 4:1 to give
0
0
0
0
0
J4,5 = 3.5 Hz, H-4), 2.49 (ddd, 1H, J4,4 = 13.0, J4 ,5 = 4.0, J4 ,5 = 4.0 Hz,
H-40), 2.54 (dd, 1H, J1,7 = 2.5, J7,8 = 2.5 Hz, H-7), 2.93 (ddd, 1H,
0
0
J4,5 = 6.5, J4 ,5 = 4.0, J5,5 = 17.0 Hz, H-5), 3.66 (dd-d, 1H, J8,9 = 3.0,
0
0
0
J9,10 = ꢀ0.5 Hz, H-9), 3.79 (ddd, 1H, J4,5 = 3.5, J4 ,5 = 4.0,
J5,5 = 17.0 Hz, H-50), 3.90–4.05 (m, 3H, H-10, H-12, H-120), 4.40
0
(dd, 1H, J7,8 = 2.5, J8,9 = 3.0 Hz, H-8), 4.91 (dd, 1H, J1,7 = 2.5,
J1,NH = 7.5 Hz, H-1), 6.62 (d, 1H, J1,NH = 7.5 Hz, NH).
13C NMR (100 MHz, CDCl3): d = ꢀ5.31 to ꢀ4.62 (6C, SiCH3),
17.90–18.53 (3C, SiC), 25.77–26.62 (9C, tert-Bu), 31.24, 37.71 (2C,
CH2, C-4, C-5), 55.66 (C-7), 60.71 (CH2, C-12), 67.17, 71.93, 75.17
(C-8, C-9, C-10), 82.83 (C-1), 175.39 (q, C-3, N–C@O), 206.39 (C-6,
C@O).
14 as a colorless syrup. Yield 307 mg (89%); ½a D20
ꢁ
34 (c 0.70,
CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.05–0.18 (m, 18H, SiCH3), 0.21,
0.22, 0.23 (3s, 9H, SiCH3), 0.88–0.97 (m, 27H, tert-Bu), 1.73 (ddd,
Anal. Calcd for C28H57NO6Si3 (588.0): C, 57.19; H, 9.77; N, 2.38.
Found: C, 56.85; H, 9.91; N, 2.21.
1H, J1,10 = 2.5, J9,10 = 7.0, J10,10 = 13.0 Hz, H-10), 2.00 (m, 1H, H-40),
0
Compound 12: yield 186 mg (62%); colorless syrup; ½a D20
ꢁ
11 (c
2.23–2.31 (m, 2H, H-5, H-100), 2.44 (ddd, 1H, J4,4 = 12.5,
0
0
0
0.85, CHCl3).
J4,5 = 16.0, J4,5 = 4.0 Hz, H-4), 3.80 (d, 1H, J12,12 = 11.5 Hz, H-12),
1H NMR (400 MHz, CDCl3): d = 0.0–0.15 (m, 18H, SiCH3), 0.82–
0.83 (m, 27H, tert-Bu), 1.66 (ddd, 1H, J1,10 = 3.0, J9,10 = 10.0,
3.83 (d, 1H, J8,9 = 8.0 Hz, H-8), 4.09 (d, 1H, J12,12 = 11.5 Hz, H-120),
0
0
4.47 (ddd, 1H, J8,9 = 8.0, J9,10 = 7.0, J9,10 = 9.5 Hz, H-9), 5.41 (dd,
J10,10 = 13.0 Hz, H-10), 1.93–2.01(m, 2H, H-5, H-50), 2.13 (ddd, 1H,
1H, J1,10 = 2.5, J1,10 = 2.5 Hz, H-1)
0
0
J4,4 = 12.0, J4,5 = 7.5, J4,5 = 4.0 Hz, H-4), 2.23 (ddd, 1H, J1,10 = 2.0,
13C NMR (100 MHz, CDCl3): d = ꢀ6.0 to ꢀ2.3 (6C, SiCH3), 1.8 (3C,
SiCH3), 18.3–18.6 (3C, SiC), 25.7–26.5 (9C, tert-Bu), 31.4, 33.4,
39.8(CH2, C-4, C-5, C-10), 61.8 (CH2, C-12), 70.8, 77.3, 84.5 (C-1,
C-8, C-9), 86.3 (q, C-7), 100.1 (q, C-6), 181.9 (q, C-3).
0
0
0
J9,10 = 7.0, J10,10 = 13.0 Hz, H-100), 2.85 (ddd, 1H, J4,4 = 12.0,
0
0
0
J4 ,5 = 7.0, J4 ,5 = 3.5 Hz, H-40), 3.62 (d, 1H, J12,12 = 11.5 Hz, H-12),
0
0
0
0
3.99 (d, 1H, J12,12 = 11.5 Hz, H-120), 4.04 (d, 1H, J8,9 = 7.5 Hz, H-8),
0
0
4.28 (ddd, 1H, J8,9 = 7.5, J9,10 = 10.0, J9,10 = 7.0 Hz, H-9), 5.35 (dd,
Anal. Calcd for C31H65NO6Si4 (660.2): C, 56.40; H, 9.92; N, 2.12.
Found: C, 56.98; H, 10.14; N, 2.01.
0
1H, J1,10 = 3.0, J1,10 = 2.0 Hz, H-1), 6.47 (s, 1H, 6-OH).
13C NMR (100 MHz, CDCl3): d = ꢀ4.52, ꢀ3.38 (6C, SiCH3), 17.55,
17.88, 17.90 (3C, q, SiC), 25.28, 25.44, 25.93 (9C, tert-Bu), 30.84
(CH2, C-5), 39.03 (CH2, C-4), 60.26 (CH2, C-12), 71.53 (C-9), 75.30
(C-8), 82.60 (q, C-7), 84.31 (C-1), 99.03 (q, C-6), 181.89 (q, C-3,
amide).
3.10. (1S,6S,7R,8S,9R)-8,9-Dimethoxy-7-methoxymethyl-6-
trimethylsiloxy-11-oxa-2-aza-tricyclo[5.3.1.02,6]undecan-3-
thione (15)
Anal. Calcd for C28H57NO6Si3 (588.0): C, 57.19; H, 9.77; N, 2.38.
Found: C, 56.85; H, 9.91; N, 2.21.
Compound 13 (720 mg, 2.00 mmol) was dissolved in degassed
anhydrous toluene (10 mL) under nitrogen and treated with
Lawesson’s reagent (492 mg, 1.2 mmol) for 1 h at 60 °C. The sol-
vent evaporated and the raw material purified on silica gel with
toluene/ethyl acetate 10:1 to 2:1 to give 15 as a yellow syrup. Yield
3.8. (1S,6S,7R,8S,9R)-8,9-Dimethoxy-7-methoxymethyl-6-
trimethylsiloxy-11-oxa-2-aza-tricyclo[5.3.1.02,6]undecan-3-one
(13)
745 mg (99%); ½a 2D0
ꢀ32 (c 0.56, CHCl3).
ꢁ
1H NMR (250 MHz, CDCl3): d = 0.22 (s, 9H, SiCH3), 1.78 (ddd, 1H,
0
Compound 10 (757 mg, 2.63 mmol) was dissolved under nitro-
gen in degassed anhydrous DMF (5 mL) and pyridine (0.4 mL), and
a catalytic amount of dimethylaminopyridine was added. At 0 °C
bistrimethylsilyl acetamide (1.0 mL, 3.9 mmol) were added cau-
J1,10 = 2.5, J9,10 = 9.0, J10,10 = 13.5 Hz, H-10), 2.06 (ddd, 1H, J4,5 = 2.1,
0
0
0
0
0
J4 ,5 = 7.0, J5,5 = 12.5 Hz, H-5), 2.23(ddd, 1H, J4,5 = 4.0, J4 ,5 = 12.5,
J5,5 = 12.5 Hz, H-50), 2.43 (ddd, 1H, J1,10 = 2.5, J9,10 = 7.0,
0
0
0
J10,10 = 13.5 Hz, H-100), 2.94 (ddd, 1H, J4,4 = 16.5, J4,5 = 2.1,
0
0

1550
C.-E. Sowa, J. Thiem / Carbohydrate Research 346 (2011) 1546–1550
0
0
0
J4,5 = 4.0 Hz, H-4), 3.22 (ddd, 1H, J4,4 = 16.5, J4 ,5 = 7.0,
3.13. (1S,6S,7R,8S,9R)-8,9-Bis-(tert-butyldimethylsiloxy)-7-tert-
butyldimethylsiloxymethyl-6-trimethylsiloxy-11-oxa-2-aza-
tricyclo[5.3.1.02,6]undecane (18)
0
0
J4 ,5 = 12.5 Hz, H-4), 3.43, 3.44, 3.55 (each s, each 3H, OCH3), 3.44
0
(d, 1H, J12,12 = 10.0 Hz, H-12), 3.60 (d, 1H, J8,9 = 9.5 Hz, H-8), 3.84
(d, 1H, J12,12 = 10.0 Hz, H-120), 4.14 (ddd, 1H, J8,9 = 9.5, J9,10 = 9.0, J
0
0
9,100 = 7.0 Hz, H-9), 5.79 (dd, 1H,
J1,10 = 2.5, J1,10 = 2.5 Hz, H-1).
Compound 16 (105 mg, 0.16 mmol) dissolved in ethanol (8 mL)
was treated with aqueous Raney nickel (2.0 g) for 3 min at room
temperature. The catalyst was filtered off, the residue evaporated
and the raw material purified on silica gel with light petrol
ether/diethyl ether 5:1 to 1:1 containing triethylamine (2%) to give
18 as a colorless syrup. Yield 45 mg (45%);
13C NMR (100 MHz, CDCl3): d = 1.58 (3H, SiCH3), 35.00, 36.02
(CH2, C-5, C-10), 45.16 (C-4), 57.88, 59.49, 60.52 (3C, OCH3),
70.18 (CH2, C-12), 78.62, 82.23 (C-8, C-9), 86.52 (q, C-7), 88.20
(C-1), 103.81 (q, C-6), 210.03 (q, C-3).
Anal. Calcd for C16H29NO5SSi (375.6): C, 51.17; H, 7.78. Found:
C, 50.80; H, 7.51.
1H NMR (400 MHz, CDCl3): d = ꢀ0.09 to 0.14 (6s, 18H, SiCH3),
0.16 (s, 9H, SiCH3), 0.83–0.87 (3s, 27H, tert-Bu), 1.57 (ddd, 1H,
0
3.11. (1S,6S,7R,8S,9R)-8,9-Bis-(tert-butyldimethylsiloxy)-7-tert-
butyldimethylsiloxymethyl-6-trimethylsiloxy-11-oxa-2-aza-
tricyclo[5.3.1.02,6]undecan-3-thione (16)
J1,10 = 2.5, J9,10 = 9.5, J10,10 = 12.0 Hz, H-10), 1.60–2.00 (m, 4H, H-4,
H-40, H-5, H-50), 2.29 (ddd, 1H, J1,10 = 2.0, J9,10 = 5.5,
0
0
J10,10 = 12.0 Hz, H-100), 2.63 (ddd, 1H, J3,3 = 12.0, J3,4 = 9.5,
0
0
0
0
J3,4 = 5.0 Hz, H-3), 3.65 (d, 1H, J12,12 = 11.0 Hz, H-12), 3.67 (m,
Compound 14 (1.2 g, 1.81 mmol) was dissolved in degassed
anhydrous toluene (10 mL) under nitrogen and treated with
Lawesson’s reagent (450 mg, 1.1 mmol) for 30 min at 60 °C. The
solvent evaporated and the remainder purified on silica gel with
light petrol ether/diethyl ether 10:1 to 3:1 to give 16 as a yellow
1H, H-30), 3.73 (d, 1H, J8,9 = 9.0 Hz, H-8), 3.89 (d, 1H,
J12,12 = 11.0 Hz, H-120), 4.36 (ddd, 1H, J8,9 = 9.0, J9,10 = 9.5,
0
0
0
J9,10 = 5.5 Hz, H-9), 4.55 (dd, 1H, J1,10 = 2.5, J1,10 = 2.0 Hz, H-1).
13C NMR (100 MHz, CDCl3): d = ꢀ4.8 to ꢀ3.2 (6C, SiCH3), 1.9 (3C,
SiCH3), 17.5, 17.8, 17.9 (3C, SiC), 25.2–25.9 (9C, tert-Bu), 25.1, 35.7
(CH2, C-4, C-5), 38.6 (CH2, C-10), 54.6(CH2, C-3), 71.4 (C-12), 78.0
(C-9), 82.1 (C-8), 83.7 (q, C-7), 93.1 (C-1), 104.8 (q, C-6).
Anal. Calcd for C31H65NO5SSi4(676.3): C, 55.06; H, 9.69; N, 2.07.
Found: C, 55.01; H, 9.87; N, 2.05.
syrup. Yield 1.21 g (99%); ½a D20
ꢀ45 (c 0.47, CHCl3).
ꢁ
1H NMR (400 MHz, CDCl3): d = 0.05–0.19 (6s, 18H, SiCH3), 0.22
(s, 9H, SiCH3), 0.89–0.93 (3s, 27H, tert-Bu), 1.85 (ddd, 1H,
0
J1,10 = 2.5, J9,10 = 10.0, J10,10 = 11.5 Hz, H-10), 2.38 (ddd, 1H,
J1,10 = 2.0, J9,10 = 1.0, J10,10 = 11.5 Hz, H-100), 2.05 (ddd, 1H,
0
0
0
J4,5 = 3.5, J4 ,5 = 6.5, J5,5 = 11.5 Hz, H-5), 2.42 (m, 1H, H-50),
3.14. (1S,6S,7R,8S,9R)-8,9-Dimethoxy-7-methoxymethyl-11-
0
0
2.98(ddd, 1H, J4,4 = 12.0, J4,5 = 3.5, J4,5 = 6.5 Hz, H-4), 3.22 (ddd,
oxa-2-aza-tricyclo[5.3.1.02,6]undecan-3,5-diene (19)
0
0
0
0
0
0
1H, J4,4 = 12.0, J4 ,5 = 6.5, J4 ,5 = 17.0 Hz, H-4), 3.81 (d, 1H,
0
J12,12 = 11.5 Hz, H-12), 3.94 (d, 1H, J8,9 = 8.0 Hz, H-8), 4.12 (d, 1H,
Compound 10 (357 mg, 1.24 mmol) dissolved in anhydrous tol-
uene (4 mL) was treated with Lawesson0s reagent (550 mg,
1.2 mmol) for 2 h at 90 °C. The solvent was evaporated and the res-
idue purified on silica gel with toluene/ethyl acetate 3:1 to give 19
J12,12 = 11.5 Hz, H-120), 4.52 (ddd, 1H, J8,9 = 8.0, J9,10 = 10.0,
0
0
0
J9,10 = 1.0 Hz, H-9), 5.78 (dd, 1H, J1,10 = 2.5, J1,10 = 2.0 Hz, H-1).
13C NMR (100 MHz, CDCl3): d = ꢀ5.00 to ꢀ2.20 (6C, SiCH3), 1.95
(3C, SiCH3), 18.63–18.82 (3C, SiC), 26.03–26.73 (9C, tert-Bu), 35.81,
39.27, 45.32 (CH2, C-4, C-5, C-10), 61.99 (CH2, C-12), 71.12, 77.20
(C-8, C-9), 87.14 (q, C-7), 88.24 (C-1), 104.25 (q, C-6), 211.51 (q,
C-3, C@S).
as a colorless syrup. Yield 170 mg (54%); ½a D20
ꢁ
15 (c 0.93, CHCl3).
1H NMR (400 MHz, DMSO-d6): d = 1.80 (ddd, 1H, J1,10 = 2.0,
0
J9,10 = 9.0, J10,10 = 12.0 Hz, H-10), 2.21 (ddd, 1H, J8,9 = 7.5,
0
0
0
J9,10 = 9.0, J9,10 = 6.5 Hz, H-9), 2.25 (ddd, 1H, J1,10 = 1.5, J9,10 = 6.5,
J10,10 = 12.0 Hz, H-100), 3.26, 3.49, 3.58 (each s, each 3H, OCH3),
0
Anal. Calcd for C31H65NO5SSi4 (676.3): C, 55.06; H, 9.69; N, 2.07.
Found: C, 55.01; H, 9.87; N, 2.05.
0
3.62(d, 1H, J12,12 = 11.0 Hz, H-12), 3.63 (d, 1H, J8,9 = 7.5 Hz, H-8),
4.07 (d, 1H, J12,12 = 11.0 Hz, H-120), 5.85 (m, 1H, H-1), 5.91 (dd,
0
3.12. (1S,6S,7R,8S,9R)-8,9-Dimethoxy-7-methoxymethyl-6-
1H, J3,5 = 1.0, J4,5 = 3.0 Hz, H-5), 6.23(dd, 1H, J3,4 = 2.0, J4,5 = 3.0 Hz,
H-4), 6.62 (dd, 1H, J3,4 = 2.0, J3,5 = 3.0 Hz, H-3).
trimethylsiloxy-11-oxa-2-aza-tricyclo[5.3.1.02,6]undecane (17)
13C NMR (100 MHz, CDCl3): d = 36.65 (CH2, C-10), 57.74, 59.39,
60.61 (3C, OCH3), 70.96 (CH2, C-12), 79.51 (C-9), 81.41 (C-8), 84.44
(q, C-7), 86.27 (C-1), 99.32 (C-5), 111.85 (C-3), 113.56 (C-4), 134.19
(q, C-6).
Compound 15 (178 mg, 0.47 mmol) dissolved in ethanol
(10 mL) was treated with aqueous Raney nickel (2.0 g) for
3 min at room temperature. The catalyst was filtered off, the res-
idue evaporated and the raw material purified on silica gel with
toluene/ethyl acetate 3:1 containing triethylamine (2%) to give
Anal. Calcd for C13H19NO4 (253.3): C, 61.64; H, 7.56; N, 5.53.
Found: C, 60.99; H, 7.44; N, 5.41.
17 as a colorless syrup. Yield 83 mg (51%); ½a D20
ꢁ
87 (c 0.47,
CHCl3).
References
1H NMR (400 MHz, CDCl3): d = 0.17 (s, 3H, SiCH3), 1.54 (ddd, 1H,
1. Sowa, C.-E.; Thiem, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1879–1881.
2. Sowa, C.-E.; Kopf, J.; Thiem, J. J. Chem. Soc., Chem. Commun. 1995, 211–212.
3. Hirst, E. L.; Woolvin, C. S. J. Chem. Soc. 1931, 1131–1137.
4. Boullanger, P.; Martin, J. C.; Descotes, G. J. Heterocycl. Chem. 1975, 12, 91–93.
5. Laupichler, L.; Sowa, C.-E.; Thiem, J. Bioorg. Med. Chem. 1994, 2, 1281–1294.
6. Thiering, S.; Sowa, C.-E.; Thiem, J. J. Chem. Soc., Perkin Trans. 1 2001, 801–806.
7. Trost, B. M.; Fray, M. J. Tetrahedron Lett. 1984, 4605–4608.
0
J1,10 = 2.5, J9,10 = 10.0, J10,10 = 12.5 Hz, H-10), 1.67–1.94 (m, 4H, H-4,
H-40, H-5, H-50), 2.25 (ddd, 1H, J1,10 = 2.0, J9,10 = 6.5,
0
0
J10,10 = 12.5 Hz, H-100), 2.57 (ddd, 1H, J3,3 = 11.5, J3,4 = 9.0,
0
0
0
0
J3,4 = 6.0 Hz, H-3), 3.34 (d, 1H, J12,12 = 10.0 Hz, H-12), 3.40, 3.45,
3.51 (each s, each 3H, OCH3), 3.42 (m, 1H, H-30), 3.48 (d, 1H,
J8,9 = 9.0 Hz, H-8), 3.85 (d, 1H, J12,12 = 10.0 Hz, H-120), 4.22 (ddd,
0
8. Trost, B. M.; Hiemstra, H. J. Am. Chem. Soc. 1982, 104, 886–887.
9. Negi, R.; Fakhir, T. M. Phytochemistry 1988, 27, 3027–3028.
0
1H, J8,9 = 9.0, J9,10 = 10.0, J9,10 = 6.5 Hz, H-9), 4.49 (dd, 1H,
10. Snieckus, V. In The Alkaloids; Academic Press: New York, 1973; Vol. 14,
11. Heathcock, C. H.; von Geldern, T. W. Heterocycles 1987, 25, 75–78.
12. Cava, M. P.; Levinson, M. J. Tetrahedron 1985, 41, 5061–5087.
13. Cherkasov, R. A.; Kutyrev, G. A.; Pudovik, A. N. Tetrahedron 1985, 41, 2567–
2624.
14. Huo, S.; Li, Y.; Liang, C.; Li, J.; Zhao, W. J. Carbohydr. Chem., 2011, 30, in press.
15. Vàtele, J.-M.; Hanessian, S. Tetrahedron 1996, 52, 10557–10568.
16. Maier, W. F.; von Ragué Schleyer, P. J. Am. Chem. Soc. 1986, 108, 1891–1900.
17. McEwen, A. B.; von Ragué Schleyer, P. J. Am. Chem. Soc. 1986, 108, 3951–3960.
18. Lazarevic, D.; Streicher, H.; Thiem, J. Carbohydr. Res. 2009, 344, 1449–1452.
0
J1,10 = 2.5, J1,10 = 2.0 Hz, H-1).
13C NMR (100 MHz, CDCl3): d = 1.96 (3H, SiCH3), 25.19, 35.44
(CH2, C-4, C-5), 37.70 (CH2, C-10), 56.34 (CH2, C-3), 57.87, 59.15,
60.27 (3C, OCH3), 70.35(C-12), 79.12 (C-9), 82.88 (C-8), 84.72 (q,
C-7), 93.82 (C-1), 105.52 (q, C-6).
Anal. Calcd for C16H31NO5Si(345.5): C, 55.62; H, 9.04; N, 4.05.
Found: C, 55.95; H, 9.35; N, 3.89.