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En route to sugar–alkaloid conjugates
Carbohydrate Research 346 (2011) 1546–1550
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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
Article history: Available online 27 April 2011 Dedicated to Professor Dr. András Liptak on the occasion of his 75th birthday
a b s t r a c t After stereoselective addition of N-iodosuccinimide to glycals subsequent dehalogenation results in formation of N-glycopyranosyl succinimides. By UV irradiation both azepindiones and preferentially [5.3.1.02,6] tricyclic oxalactams could be obtained. Their transformation into a number of novel sugar conjugates resembling some prominent alkaloid N-pyrrol components by thiation and reduction is reported. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: N-2-Deoxyglycopyranosyl succinimides [5.3.1.02,6] Oxalactams Simplexin oxa-analogs Glycopyranosyl-N-pyrrol
1. Introduction 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 Irradiation of these imides resulted in abstraction of a c- or dhydrogen atoms in a Norrish-Type II reaction. By subsequent intramolecular alkylation (Yang cyclization) the azepindiones (9, 11) and the tricyclic aminals (10, 13) could be obtained (Scheme 1).
formational assignments of these novel bicyclic and tricyclic ring systems by 1H NMR and 13C NMR were in line with those discussed in previous contributions.1,2,6 OR RO RO
⇑ Corresponding author. Tel.: +49 40 42838 4241; fax: +49 40 42838 4325. E-mail address: [email protected] (J. Thiem). 0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2011.04.022
OR O
NIS RO
1 R = Me 2 R = Bn
2. Results and discussion Treatment of tri-O-methy-D-glucal (1)3 with N-iodosuccinimide (NIS) gave the corresponding 2-deoxy-2-iodo-a-D-mannopyranosyl derivative 3 in 80% yield. Further radical reduction with tri-nbutyl stannic hydride gave the reduced material 5 in 91% yield. Starting from tri-O-benzyl-D-glucal (2)4 the NIS reaction gave compound 4,5 further radical reduction led to 6,5 and palladium/charcoal 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%). 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 elimination product 1 and a transformation of 82% to the novel products 9 and 10 in 11% and 58% yield, respectively. The 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-
OR O
nBu3 SnH
H 2 /Pd-C Me 2t BuSiOTf
O
OR O
OR O
O N
O
I N
3 R = Me 4 R = Bn
OR RO RO
O
RO
O
5 6 7 8
R = Me R = Bn R=H R = SiMe 2t Bu
1
H N
N O
hν RO
O 10
RO
O
O
4
OR O R=H R = Me2 tBuSi Scheme 1.
1
N 6
7
9 11
O 3
10
OR OR OH OR 10 12
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C.-E. Sowa, J. Thiem / Carbohydrate Research 346 (2011) 1546–1550
Ar
N
OH O OH
S
S P
O OH
O
S P
OH
N
S
Simplexin
N
OR OR RO
1
N
6
R'
S
N
RO
OR
RO
RO
Fru p-1-N-pyrrol
Ar
O OR
O
S
Galp-6-N-pyrrol
N O
H
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 basic conditions, provided a leaving group would be present.7,8 In this case the amide group (even protonated) cannot function as a leaving 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 attempted to keep the unusual tricyclic system intact. Since a hydrolysis of neither the amide nor the aminal could be achieved, transformation of the amide into a thioamide and a further reductive step should lead to the required annelated tetrahydropyrrol ring system. 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 nicely and quantitatively gave the thioamide component 15 (13C: C@S 210.0). Further reduction with Raney nickel led to the oxaanalog alkaloid system 17 (13C: CH2-3 56.34). The corresponding transformation of 12 gave 14, further the thioamide 16 and the final system 18 in acceptable yields (Scheme 2). An unusual transformation was observed when the starting tricyclic 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 carbon shift in the 13C NMR for C-3 (111.85), C-4 (113.56), C-5 (99.32),
O N
OR
MeCON(SiMe 3 ) 2
OR OH OR 10 12
N
OR OR OR OSiMe 3
13 14 Lawesson
R = Me R = SiMe2 t Bu
Tol., 60° C O
O
S N
OR OR OR OSiMe3
15 16
O
O
Py
R = Me R = SiMe 2t Bu
N
Raney-Ni/H2
17 18 Scheme 2.
N
S
S S
P
-
R = Me R = SiMe2 tBu
O
3
1
N OMe OMe OMe
12
6
Ar S O
Ar P S
Δ
S
− H 2S
P S O N
Ar O
HS
1
3
OMe OMe OMe
N 6
6 12
b
3
P
OMe OMe OMe
S
S
1
1
Ar P a
10
19
c Ar =
1
OMe OMe OMe
OMe
Scheme 3.
and C-6 (134.19). It is N-a-glycosylated (J1,10 = 2.0 and J1,100 = 1.5 Hz) and displays a bond linking the pyrrol C2-position (numbered C-6) to the sugar C5-position (numbered C-7) representing 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 formation 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 temperatures promote an often reported radical induced reductive carbon-sulfur cleavage to give the final product 19 (Scheme 3).
OR OR OR OSiMe3
EtOH/H2 O
R = Me R = SiMe2 tBu
S
O 6
Ar
S P
12
MeO MeO MeO
Lawesson
6 12
Figure 1.
O
1
OMe 6 12 Tol., 90 ° C OMe OMe OH
10
R' O
O
Ar O
O Securin
3. Experimental 3.1. General For general methods cf. 18.
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C.-E. Sowa, J. Thiem / Carbohydrate Research 346 (2011) 1546–1550
3.2. N-(2-Deoxy-2-iodo-3,4,6-tri-O-methyl-a-Dmannopyranosyl)-succinimide (3) Compound 13 (4.56 g, 24.2 mmol) under argon cover in a brown glass flask was dissolved in anhydrous acetonitrile (100 mL), treated with N-iodosuccinimide (10.6 g, 48 mmol) and stirred for 12 h at room temperature. The solvent was evaporated, the raw material 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 syrup. Yield 8.9 g (89%); ½a20 D 52 (c 1.34, CHCl3). 1 H 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, H-3), 3.58 and 3.73 (each dd, each 1H, J5,6 = 10.0, J5,60 = 6.0, J6,60 = 12.0 Hz, H-6, H-60 ), 3.67 (dd, 1H, J3,4 = 2.5, J4,5 = 2.0 Hz, H-4), 4.33 (ddd, 1H, J4,5 = 2.0, J5,6 = 10.0, J5,60 = 6.0 Hz, H-5), 5.22 (d, 1H, J1,2 = 11.5 Hz, H-1). 13 C NMR (100 MHz, CDCl3): d = 27.55 (2C, CH2, imide), 28.19 (C2), 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. 3.3. N-(2-Deoxy-3,4,6-tri-O-methyl-a-D-arabinohexopyranosyl)-succinimide (5) 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 purified on silica gel with toluene/ethyl acetate 4:1 to 1:1 to give 5 as a colorless syrup. Yield 4.5 g (91%); ½a20 24 (c 1.56, D CHCl3). 1 H NMR (400 MHz, CDCl3): d = 1.71 (ddd, J1,2 = 5.0, J2,20 = 13.7 J2,3 = 5.5 Hz, H-2), 2.69 (s, 4H, imide), 2.74 (ddd, 1H, J1,20 = 7.0, J2,20 = 13.7, J2,30 = 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, J2,3 = 5.5, J20 ,3 = 4.5, J3,4 = 6.0 Hz, H-3), 3.74 (dd, 1H, J5,6 = 4.0, J6,60 = 10.5 Hz, H-6), 3.89 (dd, 1H, J5,60 = 5.0, J6,60 = 10.5 Hz, H-60 ), 4.27 (ddd, 1H, J4,5 = 6.5, J5,6 = 4.0, J5,60 = 5.0 Hz, H-5), 5.65 (d, 1H, J1,2 = 5.0, J1,20 = 7.0 Hz, H-1). 13 C 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). 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. 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 colorless crystalline material. Yield 122 mg (99%); mp 135 °C; ½a20 D 43 (c 1.02, CHCl3). 1 H NMR (400 MHz, CDCl3): d = 1.88 (dd, J1,2 = 7.0, J2,20 = 14.5, J2,3 = 5.5 Hz, H-2), 2.43 (ddd, 1H, J1,20 = 3.0, J2,20 = 14.5, J2,30 = 9.5 Hz, H-20 ), 2.65(s, 4H, imide), 3.31 (dd, 1H, J3,4 = 8.0, J4,5 = 9.0 Hz, H-4), 3.44 (ddd, 1H, J4,5 = 9.0, J5,6 = 3.5, J5,60 = 5.0 Hz, H-5), 3.61–3.64 (m, 2H, H-6, H-60 ), 4.24 (ddd, 1H, J2,3 = 5.5, J20 ,3 = 9.5, J3,4 = 8.0 Hz, H3), 5.58(d, 1H, J1,2 = 7.0, J1,20 = 3.0 Hz, H-1).
13
C 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). 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-Darabino-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 colorless syrup. Yield 5.31 g (99%); ½a20 D 5 (c 0.83, CHCl3). 1 H NMR (400 MHz, CDCl3): d = 0.03–0.08 (m, 18H, SiCH3), 0.86 0.93 (m, 27H, tert -Bu), 1.40 (ddd, 1H, J1,2 = 11.0, J2,20 = 11.5, J2,3 = 2.5 Hz, H-2), 2.65 (s, 4H, imide), 3.25 (ddd, 1H, J1,20 = 2.5, J2,20 = 11.5, J2,30 = 1.5 Hz, H-20 ), 3.69 (dd, 1H, J3,4 = 2.5, J4,5 = 2.0 Hz, H-4), 3.85 (dd, 1H, J5,6 = 6.5, J6,60 = 10.0 Hz, H-6), 3.92 (ddd, 1H, J4,5 = 2.0, J5,6 = 6.5, J5,60 = 6.0 Hz, H-5), 3.98–4.02 (m, 2H, H-3, H60 ), 5.73 (d, 1H, J1,2 = 11.0, J1,20 = 2.5 Hz, H-1). 13 C 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. 3.6. (1S,7R,8R,9R,10R)-8,9-Dimethoxy-10-methoxymethyl-11oxa-2-aza-bicyclo[5.4.0]undecan-3,6-dione (9) and (1S,6S,7R,8S,9R)-6-hydroxy-8,9-dimethoxy-7-methoxymethyl11-oxa-2-aza-tricyclo[5.3.1.02,6]undecan-3-one (10) 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-Omethyl-D-glucal (1, 476 mg, 12%) could be isolated. Compound 9: yield 0.55 g (11%); colorless syrup; ½a20 D 19 (c 0.51, CHCl3). 1 H 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 s, each 3H, OCH3), 3.66 (m, 1H, H-9), 3.79 (ddd, 1H, J4,50 = 3.5, J40 ,50 = 5.0, J5,50 = 15.5 Hz, H-50 ), 3.87–4.11 (m, 3H, H-10, H-12, H120 ), 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). 13 C 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). 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. Compound 10: yield 2.89 g (58%); colorless syrup; ½a20 D 87 (c 1.45, CHCl3). 1 H NMR (400 MHz, DMSO-d6): d = 2.54 (ddd, 1H, J1,10 = 3.0, J9,10 = 10.0, J10,100 = 13.0 Hz, H-10), 2.16, 2.23–2.37(each m, 3H, H4, H-5, H-50 ), 2.44 (ddd, 1H, J1,100 = 1.5, J9,100 = 6.5, J10,100 = 13.0 Hz, H-100 ), 3.00 (ddd, 1H, J4,40 = 13.5, J40 ,5 = 18.0, J40 ,50 = 3.0 Hz, H-40 ), 3.31 (ddd, 1H, J8,9 = 9.0, J9,10 = 10.0, J9,100 = 6.5 Hz, H-9), 3.54, 3.56, 3.68 (each s, each 3H, OCH3), 3.55 (d, 1H, J12,120 = 11.0 Hz, H-12),
C.-E. Sowa, J. Thiem / Carbohydrate Research 346 (2011) 1546–1550
3.64 (d, 1H, J8,9 = 9.0 Hz, H-8), 4.05 (d, 1H, J12,120 = 11.0 Hz, H-120 ), 5.58 (dd, 1H, J1,10 = 3.0, J1,100 = 1.5 Hz, H-1), 6.10 (s, 1H, 6-OH). 13 C 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). 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. 3.7. (1S,7R,8R,9R,10R)-8,9-Bis-(tert-butyldimethylsiloxy)-10tert-butyldimethylsiloxymethyl-11-oxa-2-azabicyclo[5.4.0]undecan-3,6-dione (11) and (1S,6S,7R,8S,9R)-8,9bis-(tert-butyldimethylsiloxy)-7-tertbutyldimethylsiloxymethyl-6-hydroxy-11-oxa-2-azatricyclo[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 acetate 6:1 to 1:2. The transfer of 8 was 73%. Compound 11: yield 63 mg (21%); colorless crystals; mp 71 °C;½a20 D 45 (c 0.79, CHCl3). 1 H NMR (400 MHz, CDCl3): d = 0.0–0.15 (m, 18H, SiCH3), 0.80– 0.95 (m, 27H, tert-Bu), 2.37 (ddd, 1H, J4,40 = 13.0, J4,5 = 6.5, J4,50 = 3.5 Hz, H-4), 2.49 (ddd, 1H, J4,40 = 13.0, J40 ,5 = 4.0, J40 ,50 = 4.0 Hz, H-40 ), 2.54 (dd, 1H, J1,7 = 2.5, J7,8 = 2.5 Hz, H-7), 2.93 (ddd, 1H, J4,5 = 6.5, J40 ,5 = 4.0, J5,50 = 17.0 Hz, H-5), 3.66 (dd-d, 1H, J8,9 = 3.0, J9,10 = 0.5 Hz, H-9), 3.79 (ddd, 1H, J4,50 = 3.5, J40 ,50 = 4.0, J5,50 = 17.0 Hz, H-50 ), 3.90–4.05 (m, 3H, H-10, H-12, H-120 ), 4.40 (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). 13 C 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). 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 12: yield 186 mg (62%); colorless syrup; ½a20 D 11 (c 0.85, CHCl3). 1 H 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, J10,100 = 13.0 Hz, H-10), 1.93–2.01(m, 2H, H-5, H-50 ), 2.13 (ddd, 1H, J4,40 = 12.0, J4,5 = 7.5, J4,50 = 4.0 Hz, H-4), 2.23 (ddd, 1H, J1,100 = 2.0, J9,100 = 7.0, J10,100 = 13.0 Hz, H-100 ), 2.85 (ddd, 1H, J4,40 = 12.0, J40 ,5 = 7.0, J40 ,50 = 3.5 Hz, H-40 ), 3.62 (d, 1H, J12,120 = 11.5 Hz, H-12), 3.99 (d, 1H, J12,120 = 11.5 Hz, H-120 ), 4.04 (d, 1H, J8,9 = 7.5 Hz, H-8), 4.28 (ddd, 1H, J8,9 = 7.5, J9,10 = 10.0, J9,100 = 7.0 Hz, H-9), 5.35 (dd, 1H, J1,10 = 3.0, J1,100 = 2.0 Hz, H-1), 6.47 (s, 1H, 6-OH). 13 C 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). 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. 3.8. (1S,6S,7R,8S,9R)-8,9-Dimethoxy-7-methoxymethyl-6trimethylsiloxy-11-oxa-2-aza-tricyclo[5.3.1.02,6]undecan-3-one (13) Compound 10 (757 mg, 2.63 mmol) was dissolved under nitrogen 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-
1549
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%); ½a20 D 62 (c 1.11, CHCl3). 1 H NMR (400 MHz, CDCl3): d = 0.22 (s, 9H, SiCH3), 1.70 (ddd, 1H, J1,10 = 2.5, J9,10 = 9.0, J10,100 = 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, J1,100 = 1.5, J9,100 = 6.5, J10,100 = 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, J9,10 = 9.0, J9,100 = 6.5 Hz, H-9), 5.49 (dd, 1H, J1,10 = 2.5, J1,100 = 2.5 Hz, H-1). 13 C 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). 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-tertbutyldimethylsiloxymethyl-6-trimethylsiloxy-11-oxa-2-azatricyclo[5.3.1.02,6]undecan-3-one (14) 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 diisopropylamine (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 14 as a colorless syrup. Yield 307 mg (89%); ½a20 D 34 (c 0.70, CHCl3). 1 H 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, 1H, J1,10 = 2.5, J9,10 = 7.0, J10,100 = 13.0 Hz, H-10), 2.00 (m, 1H, H-40 ), 2.23–2.31 (m, 2H, H-5, H-100 ), 2.44 (ddd, 1H, J4,40 = 12.5, J4,5 = 16.0, J4,50 = 4.0 Hz, H-4), 3.80 (d, 1H, J12,120 = 11.5 Hz, H-12), 3.83 (d, 1H, J8,9 = 8.0 Hz, H-8), 4.09 (d, 1H, J12,120 = 11.5 Hz, H-120 ), 4.47 (ddd, 1H, J8,9 = 8.0, J9,10 = 7.0, J9,100 = 9.5 Hz, H-9), 5.41 (dd, 1H, J1,10 = 2.5, J1,100 = 2.5 Hz, H-1) 13 C 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). 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. 3.10. (1S,6S,7R,8S,9R)-8,9-Dimethoxy-7-methoxymethyl-6trimethylsiloxy-11-oxa-2-aza-tricyclo[5.3.1.02,6]undecan-3thione (15) 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 solvent 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 745 mg (99%); ½a20 D 32 (c 0.56, CHCl3). 1 H NMR (250 MHz, CDCl3): d = 0.22 (s, 9H, SiCH3), 1.78 (ddd, 1H, J1,10 = 2.5, J9,10 = 9.0, J10,100 = 13.5 Hz, H-10), 2.06 (ddd, 1H, J4,5 = 2.1, J40 ,5 = 7.0, J5,50 = 12.5 Hz, H-5), 2.23(ddd, 1H, J4,50 = 4.0, J40 ,50 = 12.5, J5,50 = 12.5 Hz, H-50 ), 2.43 (ddd, 1H, J1,100 = 2.5, J9,100 = 7.0, J10,100 = 13.5 Hz, H-100 ), 2.94 (ddd, 1H, J4,40 = 16.5, J4,5 = 2.1,
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J4,50 = 4.0 Hz, H-4), 3.22 (ddd, 1H, J4,40 = 16.5, J40 ,5 = 7.0, J40 ,50 = 12.5 Hz, H-4), 3.43, 3.44, 3.55 (each s, each 3H, OCH3), 3.44 (d, 1H, J12,120 = 10.0 Hz, H-12), 3.60 (d, 1H, J8,9 = 9.5 Hz, H-8), 3.84 (d, 1H, J12,120 = 10.0 Hz, H-120 ), 4.14 (ddd, 1H, J8,9 = 9.5, J9,10 = 9.0, J 9,100 = 7.0 Hz, H-9), 5.79 (dd, 1H, J1,10 = 2.5, J1,100 = 2.5 Hz, H-1). 13 C 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. 3.11. (1S,6S,7R,8S,9R)-8,9-Bis-(tert-butyldimethylsiloxy)-7-tertbutyldimethylsiloxymethyl-6-trimethylsiloxy-11-oxa-2-azatricyclo[5.3.1.02,6]undecan-3-thione (16) 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 syrup. Yield 1.21 g (99%); ½a20 D 45 (c 0.47, CHCl3). 1 H 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, J1,10 = 2.5, J9,10 = 10.0, J10,100 = 11.5 Hz, H-10), 2.38 (ddd, 1H, J1,100 = 2.0, J9,100 = 1.0, J10,100 = 11.5 Hz, H-100 ), 2.05 (ddd, 1H, J4,5 = 3.5, J40 ,5 = 6.5, J5,50 = 11.5 Hz, H-5), 2.42 (m, 1H, H-50 ), 2.98(ddd, 1H, J4,40 = 12.0, J4,5 = 3.5, J4,50 = 6.5 Hz, H-4), 3.22 (ddd, 1H, J4,40 = 12.0, J40 ,5 = 6.5, J40 ,50 = 17.0 Hz, H-4), 3.81 (d, 1H, J12,120 = 11.5 Hz, H-12), 3.94 (d, 1H, J8,9 = 8.0 Hz, H-8), 4.12 (d, 1H, J12,120 = 11.5 Hz, H-120 ), 4.52 (ddd, 1H, J8,9 = 8.0, J9,10 = 10.0, J9,100 = 1.0 Hz, H-9), 5.78 (dd, 1H, J1,10 = 2.5, J1,100 = 2.0 Hz, H-1). 13 C 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). 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. 3.12. (1S,6S,7R,8S,9R)-8,9-Dimethoxy-7-methoxymethyl-6trimethylsiloxy-11-oxa-2-aza-tricyclo[5.3.1.02,6]undecane (17) 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 residue evaporated and the raw material purified on silica gel with toluene/ethyl acetate 3:1 containing triethylamine (2%) to give 17 as a colorless syrup. Yield 83 mg (51%); ½a20 87 (c 0.47, D CHCl3). 1 H NMR (400 MHz, CDCl3): d = 0.17 (s, 3H, SiCH3), 1.54 (ddd, 1H, J1,10 = 2.5, J9,10 = 10.0, J10,100 = 12.5 Hz, H-10), 1.67–1.94 (m, 4H, H-4, H-40 , H-5, H-50 ), 2.25 (ddd, 1H, J1,100 = 2.0, J9,100 = 6.5, J10,100 = 12.5 Hz, H-100 ), 2.57 (ddd, 1H, J3,30 = 11.5, J3,4 = 9.0, J3,40 = 6.0 Hz, H-3), 3.34 (d, 1H, J12,120 = 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, J12,120 = 10.0 Hz, H-120 ), 4.22 (ddd, 1H, J8,9 = 9.0, J9,10 = 10.0, J9,100 = 6.5 Hz, H-9), 4.49 (dd, 1H, J1,10 = 2.5, J1,100 = 2.0 Hz, H-1). 13 C 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.
3.13. (1S,6S,7R,8S,9R)-8,9-Bis-(tert-butyldimethylsiloxy)-7-tertbutyldimethylsiloxymethyl-6-trimethylsiloxy-11-oxa-2-azatricyclo[5.3.1.02,6]undecane (18) 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%); 1 H 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, J1,10 = 2.5, J9,10 = 9.5, J10,100 = 12.0 Hz, H-10), 1.60–2.00 (m, 4H, H-4, H-40 , H-5, H-50 ), 2.29 (ddd, 1H, J1,100 = 2.0, J9,100 = 5.5, J10,100 = 12.0 Hz, H-100 ), 2.63 (ddd, 1H, J3,30 = 12.0, J3,4 = 9.5, J3,40 = 5.0 Hz, H-3), 3.65 (d, 1H, J12,120 = 11.0 Hz, H-12), 3.67 (m, 1H, H-30 ), 3.73 (d, 1H, J8,9 = 9.0 Hz, H-8), 3.89 (d, 1H, J12,120 = 11.0 Hz, H-120 ), 4.36 (ddd, 1H, J8,9 = 9.0, J9,10 = 9.5, J9,100 = 5.5 Hz, H-9), 4.55 (dd, 1H, J1,10 = 2.5, J1,100 = 2.0 Hz, H-1). 13 C 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. 3.14. (1S,6S,7R,8S,9R)-8,9-Dimethoxy-7-methoxymethyl-11oxa-2-aza-tricyclo[5.3.1.02,6]undecan-3,5-diene (19) Compound 10 (357 mg, 1.24 mmol) dissolved in anhydrous toluene (4 mL) was treated with Lawesson0 s reagent (550 mg, 1.2 mmol) for 2 h at 90 °C. The solvent was evaporated and the residue purified on silica gel with toluene/ethyl acetate 3:1 to give 19 as a colorless syrup. Yield 170 mg (54%); ½a20 D 15 (c 0.93, CHCl3). 1 H NMR (400 MHz, DMSO-d6): d = 1.80 (ddd, 1H, J1,10 = 2.0, J9,10 = 9.0, J10,100 = 12.0 Hz, H-10), 2.21 (ddd, 1H, J8,9 = 7.5, J9,10 = 9.0, J9,100 = 6.5 Hz, H-9), 2.25 (ddd, 1H, J1,100 = 1.5, J9,100 = 6.5, J10,100 = 12.0 Hz, H-100 ), 3.26, 3.49, 3.58 (each s, each 3H, OCH3), 3.62(d, 1H, J12,120 = 11.0 Hz, H-12), 3.63 (d, 1H, J8,9 = 7.5 Hz, H-8), 4.07 (d, 1H, J12,120 = 11.0 Hz, H-120 ), 5.85 (m, 1H, H-1), 5.91 (dd, 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). 13 C 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). 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. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
Sowa, C.-E.; Thiem, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1879–1881. Sowa, C.-E.; Kopf, J.; Thiem, J. J. Chem. Soc., Chem. Commun. 1995, 211–212. Hirst, E. L.; Woolvin, C. S. J. Chem. Soc. 1931, 1131–1137. Boullanger, P.; Martin, J. C.; Descotes, G. J. Heterocycl. Chem. 1975, 12, 91–93. Laupichler, L.; Sowa, C.-E.; Thiem, J. Bioorg. Med. Chem. 1994, 2, 1281–1294. Thiering, S.; Sowa, C.-E.; Thiem, J. J. Chem. Soc., Perkin Trans. 1 2001, 801–806. Trost, B. M.; Fray, M. J. Tetrahedron Lett. 1984, 4605–4608. Trost, B. M.; Hiemstra, H. J. Am. Chem. Soc. 1982, 104, 886–887. Negi, R.; Fakhir, T. M. Phytochemistry 1988, 27, 3027–3028. Snieckus, V. In The Alkaloids; Academic Press: New York, 1973; Vol. 14, Heathcock, C. H.; von Geldern, T. W. Heterocycles 1987, 25, 75–78. Cava, M. P.; Levinson, M. J. Tetrahedron 1985, 41, 5061–5087. Cherkasov, R. A.; Kutyrev, G. A.; Pudovik, A. N. Tetrahedron 1985, 41, 2567– 2624. Huo, S.; Li, Y.; Liang, C.; Li, J.; Zhao, W. J. Carbohydr. Chem., 2011, 30, in press. Vàtele, J.-M.; Hanessian, S. Tetrahedron 1996, 52, 10557–10568. Maier, W. F.; von Ragué Schleyer, P. J. Am. Chem. Soc. 1986, 108, 1891–1900. McEwen, A. B.; von Ragué Schleyer, P. J. Am. Chem. Soc. 1986, 108, 3951–3960. Lazarevic, D.; Streicher, H.; Thiem, J. Carbohydr. Res. 2009, 344, 1449–1452.
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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
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Article history: Available online 27 April 2011 Dedicated to Professor Dr. András Liptak on the occasion of his 75th birthday
a b s t r a c t After stereoselective addition of N-iodosuccinimide to glycals subsequent dehalogenation results in formation of N-glycopyranosyl succinimides. By UV irradiation both azepindiones and preferentially [5.3.1.02,6] tricyclic oxalactams could be obtained. Their transformation into a number of novel sugar conjugates resembling some prominent alkaloid N-pyrrol components by thiation and reduction is reported. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: N-2-Deoxyglycopyranosyl succinimides [5.3.1.02,6] Oxalactams Simplexin oxa-analogs Glycopyranosyl-N-pyrrol
1. Introduction 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 Irradiation of these imides resulted in abstraction of a c- or dhydrogen atoms in a Norrish-Type II reaction. By subsequent intramolecular alkylation (Yang cyclization) the azepindiones (9, 11) and the tricyclic aminals (10, 13) could be obtained (Scheme 1).
formational assignments of these novel bicyclic and tricyclic ring systems by 1H NMR and 13C NMR were in line with those discussed in previous contributions.1,2,6 OR RO RO
⇑ Corresponding author. Tel.: +49 40 42838 4241; fax: +49 40 42838 4325. E-mail address: [email protected] (J. Thiem). 0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2011.04.022
OR O
NIS RO
1 R = Me 2 R = Bn
2. Results and discussion Treatment of tri-O-methy-D-glucal (1)3 with N-iodosuccinimide (NIS) gave the corresponding 2-deoxy-2-iodo-a-D-mannopyranosyl derivative 3 in 80% yield. Further radical reduction with tri-nbutyl stannic hydride gave the reduced material 5 in 91% yield. Starting from tri-O-benzyl-D-glucal (2)4 the NIS reaction gave compound 4,5 further radical reduction led to 6,5 and palladium/charcoal 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%). 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 elimination product 1 and a transformation of 82% to the novel products 9 and 10 in 11% and 58% yield, respectively. The 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-
OR O
nBu3 SnH
H 2 /Pd-C Me 2t BuSiOTf
O
OR O
OR O
O N
O
I N
3 R = Me 4 R = Bn
OR RO RO
O
RO
O
5 6 7 8
R = Me R = Bn R=H R = SiMe 2t Bu
1
H N
N O
hν RO
O 10
RO
O
O
4
OR O R=H R = Me2 tBuSi Scheme 1.
1
N 6
7
9 11
O 3
10
OR OR OH OR 10 12
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C.-E. Sowa, J. Thiem / Carbohydrate Research 346 (2011) 1546–1550
Ar
N
OH O OH
S
S P
O OH
O
S P
OH
N
S
Simplexin
N
OR OR RO
1
N
6
R'
S
N
RO
OR
RO
RO
Fru p-1-N-pyrrol
Ar
O OR
O
S
Galp-6-N-pyrrol
N O
H
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 basic conditions, provided a leaving group would be present.7,8 In this case the amide group (even protonated) cannot function as a leaving 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 attempted to keep the unusual tricyclic system intact. Since a hydrolysis of neither the amide nor the aminal could be achieved, transformation of the amide into a thioamide and a further reductive step should lead to the required annelated tetrahydropyrrol ring system. 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 nicely and quantitatively gave the thioamide component 15 (13C: C@S 210.0). Further reduction with Raney nickel led to the oxaanalog alkaloid system 17 (13C: CH2-3 56.34). The corresponding transformation of 12 gave 14, further the thioamide 16 and the final system 18 in acceptable yields (Scheme 2). An unusual transformation was observed when the starting tricyclic 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 carbon shift in the 13C NMR for C-3 (111.85), C-4 (113.56), C-5 (99.32),
O N
OR
MeCON(SiMe 3 ) 2
OR OH OR 10 12
N
OR OR OR OSiMe 3
13 14 Lawesson
R = Me R = SiMe2 t Bu
Tol., 60° C O
O
S N
OR OR OR OSiMe3
15 16
O
O
Py
R = Me R = SiMe 2t Bu
N
Raney-Ni/H2
17 18 Scheme 2.
N
S
S S
P
-
R = Me R = SiMe2 tBu
O
3
1
N OMe OMe OMe
12
6
Ar S O
Ar P S
Δ
S
− H 2S
P S O N
Ar O
HS
1
3
OMe OMe OMe
N 6
6 12
b
3
P
OMe OMe OMe
S
S
1
1
Ar P a
10
19
c Ar =
1
OMe OMe OMe
OMe
Scheme 3.
and C-6 (134.19). It is N-a-glycosylated (J1,10 = 2.0 and J1,100 = 1.5 Hz) and displays a bond linking the pyrrol C2-position (numbered C-6) to the sugar C5-position (numbered C-7) representing 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 formation 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 temperatures promote an often reported radical induced reductive carbon-sulfur cleavage to give the final product 19 (Scheme 3).
OR OR OR OSiMe3
EtOH/H2 O
R = Me R = SiMe2 tBu
S
O 6
Ar
S P
12
MeO MeO MeO
Lawesson
6 12
Figure 1.
O
1
OMe 6 12 Tol., 90 ° C OMe OMe OH
10
R' O
O
Ar O
O Securin
3. Experimental 3.1. General For general methods cf. 18.
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C.-E. Sowa, J. Thiem / Carbohydrate Research 346 (2011) 1546–1550
3.2. N-(2-Deoxy-2-iodo-3,4,6-tri-O-methyl-a-Dmannopyranosyl)-succinimide (3) Compound 13 (4.56 g, 24.2 mmol) under argon cover in a brown glass flask was dissolved in anhydrous acetonitrile (100 mL), treated with N-iodosuccinimide (10.6 g, 48 mmol) and stirred for 12 h at room temperature. The solvent was evaporated, the raw material 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 syrup. Yield 8.9 g (89%); ½a20 D 52 (c 1.34, CHCl3). 1 H 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, H-3), 3.58 and 3.73 (each dd, each 1H, J5,6 = 10.0, J5,60 = 6.0, J6,60 = 12.0 Hz, H-6, H-60 ), 3.67 (dd, 1H, J3,4 = 2.5, J4,5 = 2.0 Hz, H-4), 4.33 (ddd, 1H, J4,5 = 2.0, J5,6 = 10.0, J5,60 = 6.0 Hz, H-5), 5.22 (d, 1H, J1,2 = 11.5 Hz, H-1). 13 C NMR (100 MHz, CDCl3): d = 27.55 (2C, CH2, imide), 28.19 (C2), 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. 3.3. N-(2-Deoxy-3,4,6-tri-O-methyl-a-D-arabinohexopyranosyl)-succinimide (5) 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 purified on silica gel with toluene/ethyl acetate 4:1 to 1:1 to give 5 as a colorless syrup. Yield 4.5 g (91%); ½a20 24 (c 1.56, D CHCl3). 1 H NMR (400 MHz, CDCl3): d = 1.71 (ddd, J1,2 = 5.0, J2,20 = 13.7 J2,3 = 5.5 Hz, H-2), 2.69 (s, 4H, imide), 2.74 (ddd, 1H, J1,20 = 7.0, J2,20 = 13.7, J2,30 = 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, J2,3 = 5.5, J20 ,3 = 4.5, J3,4 = 6.0 Hz, H-3), 3.74 (dd, 1H, J5,6 = 4.0, J6,60 = 10.5 Hz, H-6), 3.89 (dd, 1H, J5,60 = 5.0, J6,60 = 10.5 Hz, H-60 ), 4.27 (ddd, 1H, J4,5 = 6.5, J5,6 = 4.0, J5,60 = 5.0 Hz, H-5), 5.65 (d, 1H, J1,2 = 5.0, J1,20 = 7.0 Hz, H-1). 13 C 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). 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. 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 colorless crystalline material. Yield 122 mg (99%); mp 135 °C; ½a20 D 43 (c 1.02, CHCl3). 1 H NMR (400 MHz, CDCl3): d = 1.88 (dd, J1,2 = 7.0, J2,20 = 14.5, J2,3 = 5.5 Hz, H-2), 2.43 (ddd, 1H, J1,20 = 3.0, J2,20 = 14.5, J2,30 = 9.5 Hz, H-20 ), 2.65(s, 4H, imide), 3.31 (dd, 1H, J3,4 = 8.0, J4,5 = 9.0 Hz, H-4), 3.44 (ddd, 1H, J4,5 = 9.0, J5,6 = 3.5, J5,60 = 5.0 Hz, H-5), 3.61–3.64 (m, 2H, H-6, H-60 ), 4.24 (ddd, 1H, J2,3 = 5.5, J20 ,3 = 9.5, J3,4 = 8.0 Hz, H3), 5.58(d, 1H, J1,2 = 7.0, J1,20 = 3.0 Hz, H-1).
13
C 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). 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-Darabino-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 colorless syrup. Yield 5.31 g (99%); ½a20 D 5 (c 0.83, CHCl3). 1 H NMR (400 MHz, CDCl3): d = 0.03–0.08 (m, 18H, SiCH3), 0.86 0.93 (m, 27H, tert -Bu), 1.40 (ddd, 1H, J1,2 = 11.0, J2,20 = 11.5, J2,3 = 2.5 Hz, H-2), 2.65 (s, 4H, imide), 3.25 (ddd, 1H, J1,20 = 2.5, J2,20 = 11.5, J2,30 = 1.5 Hz, H-20 ), 3.69 (dd, 1H, J3,4 = 2.5, J4,5 = 2.0 Hz, H-4), 3.85 (dd, 1H, J5,6 = 6.5, J6,60 = 10.0 Hz, H-6), 3.92 (ddd, 1H, J4,5 = 2.0, J5,6 = 6.5, J5,60 = 6.0 Hz, H-5), 3.98–4.02 (m, 2H, H-3, H60 ), 5.73 (d, 1H, J1,2 = 11.0, J1,20 = 2.5 Hz, H-1). 13 C 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. 3.6. (1S,7R,8R,9R,10R)-8,9-Dimethoxy-10-methoxymethyl-11oxa-2-aza-bicyclo[5.4.0]undecan-3,6-dione (9) and (1S,6S,7R,8S,9R)-6-hydroxy-8,9-dimethoxy-7-methoxymethyl11-oxa-2-aza-tricyclo[5.3.1.02,6]undecan-3-one (10) 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-Omethyl-D-glucal (1, 476 mg, 12%) could be isolated. Compound 9: yield 0.55 g (11%); colorless syrup; ½a20 D 19 (c 0.51, CHCl3). 1 H 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 s, each 3H, OCH3), 3.66 (m, 1H, H-9), 3.79 (ddd, 1H, J4,50 = 3.5, J40 ,50 = 5.0, J5,50 = 15.5 Hz, H-50 ), 3.87–4.11 (m, 3H, H-10, H-12, H120 ), 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). 13 C 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). 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. Compound 10: yield 2.89 g (58%); colorless syrup; ½a20 D 87 (c 1.45, CHCl3). 1 H NMR (400 MHz, DMSO-d6): d = 2.54 (ddd, 1H, J1,10 = 3.0, J9,10 = 10.0, J10,100 = 13.0 Hz, H-10), 2.16, 2.23–2.37(each m, 3H, H4, H-5, H-50 ), 2.44 (ddd, 1H, J1,100 = 1.5, J9,100 = 6.5, J10,100 = 13.0 Hz, H-100 ), 3.00 (ddd, 1H, J4,40 = 13.5, J40 ,5 = 18.0, J40 ,50 = 3.0 Hz, H-40 ), 3.31 (ddd, 1H, J8,9 = 9.0, J9,10 = 10.0, J9,100 = 6.5 Hz, H-9), 3.54, 3.56, 3.68 (each s, each 3H, OCH3), 3.55 (d, 1H, J12,120 = 11.0 Hz, H-12),
C.-E. Sowa, J. Thiem / Carbohydrate Research 346 (2011) 1546–1550
3.64 (d, 1H, J8,9 = 9.0 Hz, H-8), 4.05 (d, 1H, J12,120 = 11.0 Hz, H-120 ), 5.58 (dd, 1H, J1,10 = 3.0, J1,100 = 1.5 Hz, H-1), 6.10 (s, 1H, 6-OH). 13 C 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). 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. 3.7. (1S,7R,8R,9R,10R)-8,9-Bis-(tert-butyldimethylsiloxy)-10tert-butyldimethylsiloxymethyl-11-oxa-2-azabicyclo[5.4.0]undecan-3,6-dione (11) and (1S,6S,7R,8S,9R)-8,9bis-(tert-butyldimethylsiloxy)-7-tertbutyldimethylsiloxymethyl-6-hydroxy-11-oxa-2-azatricyclo[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 acetate 6:1 to 1:2. The transfer of 8 was 73%. Compound 11: yield 63 mg (21%); colorless crystals; mp 71 °C;½a20 D 45 (c 0.79, CHCl3). 1 H NMR (400 MHz, CDCl3): d = 0.0–0.15 (m, 18H, SiCH3), 0.80– 0.95 (m, 27H, tert-Bu), 2.37 (ddd, 1H, J4,40 = 13.0, J4,5 = 6.5, J4,50 = 3.5 Hz, H-4), 2.49 (ddd, 1H, J4,40 = 13.0, J40 ,5 = 4.0, J40 ,50 = 4.0 Hz, H-40 ), 2.54 (dd, 1H, J1,7 = 2.5, J7,8 = 2.5 Hz, H-7), 2.93 (ddd, 1H, J4,5 = 6.5, J40 ,5 = 4.0, J5,50 = 17.0 Hz, H-5), 3.66 (dd-d, 1H, J8,9 = 3.0, J9,10 = 0.5 Hz, H-9), 3.79 (ddd, 1H, J4,50 = 3.5, J40 ,50 = 4.0, J5,50 = 17.0 Hz, H-50 ), 3.90–4.05 (m, 3H, H-10, H-12, H-120 ), 4.40 (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). 13 C 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). 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 12: yield 186 mg (62%); colorless syrup; ½a20 D 11 (c 0.85, CHCl3). 1 H 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, J10,100 = 13.0 Hz, H-10), 1.93–2.01(m, 2H, H-5, H-50 ), 2.13 (ddd, 1H, J4,40 = 12.0, J4,5 = 7.5, J4,50 = 4.0 Hz, H-4), 2.23 (ddd, 1H, J1,100 = 2.0, J9,100 = 7.0, J10,100 = 13.0 Hz, H-100 ), 2.85 (ddd, 1H, J4,40 = 12.0, J40 ,5 = 7.0, J40 ,50 = 3.5 Hz, H-40 ), 3.62 (d, 1H, J12,120 = 11.5 Hz, H-12), 3.99 (d, 1H, J12,120 = 11.5 Hz, H-120 ), 4.04 (d, 1H, J8,9 = 7.5 Hz, H-8), 4.28 (ddd, 1H, J8,9 = 7.5, J9,10 = 10.0, J9,100 = 7.0 Hz, H-9), 5.35 (dd, 1H, J1,10 = 3.0, J1,100 = 2.0 Hz, H-1), 6.47 (s, 1H, 6-OH). 13 C 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). 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. 3.8. (1S,6S,7R,8S,9R)-8,9-Dimethoxy-7-methoxymethyl-6trimethylsiloxy-11-oxa-2-aza-tricyclo[5.3.1.02,6]undecan-3-one (13) Compound 10 (757 mg, 2.63 mmol) was dissolved under nitrogen 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-
1549
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%); ½a20 D 62 (c 1.11, CHCl3). 1 H NMR (400 MHz, CDCl3): d = 0.22 (s, 9H, SiCH3), 1.70 (ddd, 1H, J1,10 = 2.5, J9,10 = 9.0, J10,100 = 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, J1,100 = 1.5, J9,100 = 6.5, J10,100 = 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, J9,10 = 9.0, J9,100 = 6.5 Hz, H-9), 5.49 (dd, 1H, J1,10 = 2.5, J1,100 = 2.5 Hz, H-1). 13 C 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). 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-tertbutyldimethylsiloxymethyl-6-trimethylsiloxy-11-oxa-2-azatricyclo[5.3.1.02,6]undecan-3-one (14) 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 diisopropylamine (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 14 as a colorless syrup. Yield 307 mg (89%); ½a20 D 34 (c 0.70, CHCl3). 1 H 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, 1H, J1,10 = 2.5, J9,10 = 7.0, J10,100 = 13.0 Hz, H-10), 2.00 (m, 1H, H-40 ), 2.23–2.31 (m, 2H, H-5, H-100 ), 2.44 (ddd, 1H, J4,40 = 12.5, J4,5 = 16.0, J4,50 = 4.0 Hz, H-4), 3.80 (d, 1H, J12,120 = 11.5 Hz, H-12), 3.83 (d, 1H, J8,9 = 8.0 Hz, H-8), 4.09 (d, 1H, J12,120 = 11.5 Hz, H-120 ), 4.47 (ddd, 1H, J8,9 = 8.0, J9,10 = 7.0, J9,100 = 9.5 Hz, H-9), 5.41 (dd, 1H, J1,10 = 2.5, J1,100 = 2.5 Hz, H-1) 13 C 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). 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. 3.10. (1S,6S,7R,8S,9R)-8,9-Dimethoxy-7-methoxymethyl-6trimethylsiloxy-11-oxa-2-aza-tricyclo[5.3.1.02,6]undecan-3thione (15) 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 solvent 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 745 mg (99%); ½a20 D 32 (c 0.56, CHCl3). 1 H NMR (250 MHz, CDCl3): d = 0.22 (s, 9H, SiCH3), 1.78 (ddd, 1H, J1,10 = 2.5, J9,10 = 9.0, J10,100 = 13.5 Hz, H-10), 2.06 (ddd, 1H, J4,5 = 2.1, J40 ,5 = 7.0, J5,50 = 12.5 Hz, H-5), 2.23(ddd, 1H, J4,50 = 4.0, J40 ,50 = 12.5, J5,50 = 12.5 Hz, H-50 ), 2.43 (ddd, 1H, J1,100 = 2.5, J9,100 = 7.0, J10,100 = 13.5 Hz, H-100 ), 2.94 (ddd, 1H, J4,40 = 16.5, J4,5 = 2.1,
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J4,50 = 4.0 Hz, H-4), 3.22 (ddd, 1H, J4,40 = 16.5, J40 ,5 = 7.0, J40 ,50 = 12.5 Hz, H-4), 3.43, 3.44, 3.55 (each s, each 3H, OCH3), 3.44 (d, 1H, J12,120 = 10.0 Hz, H-12), 3.60 (d, 1H, J8,9 = 9.5 Hz, H-8), 3.84 (d, 1H, J12,120 = 10.0 Hz, H-120 ), 4.14 (ddd, 1H, J8,9 = 9.5, J9,10 = 9.0, J 9,100 = 7.0 Hz, H-9), 5.79 (dd, 1H, J1,10 = 2.5, J1,100 = 2.5 Hz, H-1). 13 C 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. 3.11. (1S,6S,7R,8S,9R)-8,9-Bis-(tert-butyldimethylsiloxy)-7-tertbutyldimethylsiloxymethyl-6-trimethylsiloxy-11-oxa-2-azatricyclo[5.3.1.02,6]undecan-3-thione (16) 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 syrup. Yield 1.21 g (99%); ½a20 D 45 (c 0.47, CHCl3). 1 H 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, J1,10 = 2.5, J9,10 = 10.0, J10,100 = 11.5 Hz, H-10), 2.38 (ddd, 1H, J1,100 = 2.0, J9,100 = 1.0, J10,100 = 11.5 Hz, H-100 ), 2.05 (ddd, 1H, J4,5 = 3.5, J40 ,5 = 6.5, J5,50 = 11.5 Hz, H-5), 2.42 (m, 1H, H-50 ), 2.98(ddd, 1H, J4,40 = 12.0, J4,5 = 3.5, J4,50 = 6.5 Hz, H-4), 3.22 (ddd, 1H, J4,40 = 12.0, J40 ,5 = 6.5, J40 ,50 = 17.0 Hz, H-4), 3.81 (d, 1H, J12,120 = 11.5 Hz, H-12), 3.94 (d, 1H, J8,9 = 8.0 Hz, H-8), 4.12 (d, 1H, J12,120 = 11.5 Hz, H-120 ), 4.52 (ddd, 1H, J8,9 = 8.0, J9,10 = 10.0, J9,100 = 1.0 Hz, H-9), 5.78 (dd, 1H, J1,10 = 2.5, J1,100 = 2.0 Hz, H-1). 13 C 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). 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. 3.12. (1S,6S,7R,8S,9R)-8,9-Dimethoxy-7-methoxymethyl-6trimethylsiloxy-11-oxa-2-aza-tricyclo[5.3.1.02,6]undecane (17) 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 residue evaporated and the raw material purified on silica gel with toluene/ethyl acetate 3:1 containing triethylamine (2%) to give 17 as a colorless syrup. Yield 83 mg (51%); ½a20 87 (c 0.47, D CHCl3). 1 H NMR (400 MHz, CDCl3): d = 0.17 (s, 3H, SiCH3), 1.54 (ddd, 1H, J1,10 = 2.5, J9,10 = 10.0, J10,100 = 12.5 Hz, H-10), 1.67–1.94 (m, 4H, H-4, H-40 , H-5, H-50 ), 2.25 (ddd, 1H, J1,100 = 2.0, J9,100 = 6.5, J10,100 = 12.5 Hz, H-100 ), 2.57 (ddd, 1H, J3,30 = 11.5, J3,4 = 9.0, J3,40 = 6.0 Hz, H-3), 3.34 (d, 1H, J12,120 = 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, J12,120 = 10.0 Hz, H-120 ), 4.22 (ddd, 1H, J8,9 = 9.0, J9,10 = 10.0, J9,100 = 6.5 Hz, H-9), 4.49 (dd, 1H, J1,10 = 2.5, J1,100 = 2.0 Hz, H-1). 13 C 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.
3.13. (1S,6S,7R,8S,9R)-8,9-Bis-(tert-butyldimethylsiloxy)-7-tertbutyldimethylsiloxymethyl-6-trimethylsiloxy-11-oxa-2-azatricyclo[5.3.1.02,6]undecane (18) 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%); 1 H 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, J1,10 = 2.5, J9,10 = 9.5, J10,100 = 12.0 Hz, H-10), 1.60–2.00 (m, 4H, H-4, H-40 , H-5, H-50 ), 2.29 (ddd, 1H, J1,100 = 2.0, J9,100 = 5.5, J10,100 = 12.0 Hz, H-100 ), 2.63 (ddd, 1H, J3,30 = 12.0, J3,4 = 9.5, J3,40 = 5.0 Hz, H-3), 3.65 (d, 1H, J12,120 = 11.0 Hz, H-12), 3.67 (m, 1H, H-30 ), 3.73 (d, 1H, J8,9 = 9.0 Hz, H-8), 3.89 (d, 1H, J12,120 = 11.0 Hz, H-120 ), 4.36 (ddd, 1H, J8,9 = 9.0, J9,10 = 9.5, J9,100 = 5.5 Hz, H-9), 4.55 (dd, 1H, J1,10 = 2.5, J1,100 = 2.0 Hz, H-1). 13 C 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. 3.14. (1S,6S,7R,8S,9R)-8,9-Dimethoxy-7-methoxymethyl-11oxa-2-aza-tricyclo[5.3.1.02,6]undecan-3,5-diene (19) Compound 10 (357 mg, 1.24 mmol) dissolved in anhydrous toluene (4 mL) was treated with Lawesson0 s reagent (550 mg, 1.2 mmol) for 2 h at 90 °C. The solvent was evaporated and the residue purified on silica gel with toluene/ethyl acetate 3:1 to give 19 as a colorless syrup. Yield 170 mg (54%); ½a20 D 15 (c 0.93, CHCl3). 1 H NMR (400 MHz, DMSO-d6): d = 1.80 (ddd, 1H, J1,10 = 2.0, J9,10 = 9.0, J10,100 = 12.0 Hz, H-10), 2.21 (ddd, 1H, J8,9 = 7.5, J9,10 = 9.0, J9,100 = 6.5 Hz, H-9), 2.25 (ddd, 1H, J1,100 = 1.5, J9,100 = 6.5, J10,100 = 12.0 Hz, H-100 ), 3.26, 3.49, 3.58 (each s, each 3H, OCH3), 3.62(d, 1H, J12,120 = 11.0 Hz, H-12), 3.63 (d, 1H, J8,9 = 7.5 Hz, H-8), 4.07 (d, 1H, J12,120 = 11.0 Hz, H-120 ), 5.85 (m, 1H, H-1), 5.91 (dd, 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). 13 C 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). 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. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
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