1504 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8
Bookser et al.
added. After this mixture stirred for 30 min, H2 evolution had
ceased. The reagent 2-(trimethylsilyl)ethoxymethyl chloride
(5.30 mL, 29.9 mmol) was added and the mixture allowed to
stir at room temperature for 16 h. Then the mixture was
diluted with 250 mL of ether, washed with water (2 × 200
mL) and brine, dried (MgSO4) and evaporated to provide an
oil which was subjected to chromatography eluting with a
hexane/EtOAc gradient of 20:1, 15:1, and 10:1 to provide 1.3
g (23%) of the less polar regioisomer assigned as 2-(2-
(trimethylsilyl)ethoxymethyl)tetrazole, 19a : 1H NMR (CDCl3)
0.04 (s, 9), 0.96 (t, 2, J ) 7 Hz), 3.72 (t, 2, J ) 7 Hz), 5.95 (s,
2), 8.60 (s, 1).
Step 2. To a solution of 19a (500 mg, 2.5 mmol) in 10 mL
of THF and 10 mL of DMPU at -78 °C was added t-BuLi (3.67
mL of a 1.7 M solution in hexanes, 6.24 mmol) which produced
an orange suspension. This was allowed to stir at -78 °C for
5 min and then 1,5-dibromopentane (1.71 mL, 12.5 mmol) was
added; this mixture stirred at -23 °C for 7 h to produce a
yellow solution. Aqueous NH4Cl was added and the mixture
extracted with ether (2 × 100 mL). The combined ether
extracts were washed with water (2 × 200 mL) and brine, dried
(MgSO4) and evaporated to provide an oil which was sub-
jected to chromatography eluting with a hexane/EtOAc gradi-
ent of 20:0, 20:1, 10:1 and 5:1 which provided 468 mg of 75%
pure 19b with the 25% impurity being 19a . This material
was used to alkylate compound 4 without further purifi-
cation. Compound 19b: 1H NMR (CDCl3) 0.02 (s, 9), 0.97 (t,
2, J ) 7 Hz), 1.57 (quintet, 2, J ) 7 Hz), 1.8-2.1 (m, 4), 2.98
(t, 2, J ) 7 Hz), 3.45 (t, 2, J ) 7 Hz), 3.71 (t, 2, J ) 7 Hz), 5.86
(s, 2).
Diben zyl 5-Br om op en tylp h osp h on a te (21b). A 60%
suspension of NaH in mineral oil (2.00 g, 50 mmol) was
slurried with 5 mL of dry hexane, the hexane decanted by
syringe under N2 (2×) and the solid dried under a high
vacuum. To the solid was added 250 mL of DMF and while
this suspension stirred at 5 °C, dibenzyl phosphite (21a ) (10.0
mL, 45.5 mmol) was added slowly. After this mixture stirred
for 1 h, 1,5-dibromopentane (7.5 mL, 55 mmol) was added at
5 °C and the resulting mixture allowed to stir at room
temperature for 16 h, then it was diluted with ether, washed
with water (2×) and brine, dried (MgSO4) and evaporated to
provide an oil which was subjected to chromatography eluting
first with CH2Cl2 and then with 18:1 CH2Cl2/MeOH to provide
9.03 g (49%) of the title compound as an oil: 1H NMR (CDCl3)
1.3-2.0 (m, 8), 3.46 (t, 2, J ) 7 Hz), 4.9-5.1 (m, 4), 7.25-7.45
(m, 10).
This method was used to prepare all compounds 7 or the
ester precursors of compounds 7 and compound 6f′ (the
reduced product of 6f in Figure 2).
1
Compound 7f: mp 115-118 °C; H NMR (DMSO-d6) 1.17
(t, 3, J ) 7 Hz), 1.2-1.8 (m, 6), 2.26 (t, 2, J ) 7 Hz), 3.15 (br
s, 2), 3.84 (t, 2, J ) 7 Hz), 4.03 (q, 2, J ) 7 Hz), 4.80 (br s, 1),
4.91 (d, 1, J ) 6 Hz), 6.95 (d, 1, J ) 4 Hz), 7.28 (s, 1), 7.45 (d,
1, J ) 4 Hz); UV (methanol) λmax 283 nm (ꢀ 6545). Anal.
(C14H22N4O3) C, H, N.
Compound 6f′: 1H NMR (DMSO-d6) 1.17 (t, 3, J ) 7 Hz),
1.2-1.8 (m, 6), 2.27 (t, 2, J ) 7 Hz), 3.36 (br s, 2), 3.79 (t, 2, J
) 7 Hz), 4.04 (q, 2, J ) 7 Hz), 4.62 (br s, 1), 5.30 (br s, 1), 7.12
(s, 1), 8.00 (s, 1); UV (methanol) λmax 278 nm (ꢀ 4680); APCI
MS (positive mode) M + 1 calcd 295, found m/z 295.
Isola tion of Rep r esen ta tive N1- a n d N3-Alk yla tion
P r od u cts. 3-(5-Ca r beth oxyp en tyl)-6,7-d ih yd r oim id a zo-
[4,5-d ][1,3]d ia zep in -8(3H)-on e (5f) a n d 1-(5-Ca r beth oxy-
p en t yl)-6,7-d ih yd r oim id a zo[4,5-d ][1,3]d ia zep in -8(1H )-
on e (6f). Reaction of the base 4 (37.8 mmol) with ethyl
6-bromohexanoate (37.8 mmol) as previously described1 pro-
vided an N3/N1-alkylation mixture which was subjected to
chromatography on SiO2 eluting with a CH2Cl2/methanol
gradient of 20:1, 17.5:1 and 15:1 to provide a fraction which
was reduced to a minimal volume and diluted with ether. The
resulting solid was collected to provide 1.30 g of the N3-isomer
5f as a tan solid. The 1H and 13C NMR assignments were made
1
1
based in part on H-1H coupling (COSY) and H-13C coupling
(HETCOR) two-dimensional NMR experiments. Compound
5f: mp 128-131 °C; 1H NMR (DMSO-d6) 1.17 (t, 3, J ) 7 Hz,
ester CH3), 1.25 (quin, 2, J ) 7 Hz, C3′ Hs), 1.55 (quin, 2, J )
7 Hz, C4′ Hs), 1.71 (quin, 2, J ) 7 Hz, C2′ Hs), 2.28 (t, 2, J )
7 Hz, C5′ Hs), 3.78 (d, 2, J ) 4 Hz, C7 Hs), 3.96 (t, 2, J ) 7
Hz, C1′ Hs), 4.04 (q, 2, J ) 7 Hz, ester CH2), 7.45 (d, 1, J ) 4
Hz, H5), 7.67 (s, 1, H2), 8.4-8.5 (m, 1, H6); 13C NMR (DMSO-
d6) 14.1 (ester CH3), 24.0 (C4′), 25.4 (C3′), 29.4 (C2′), 33.3 (C5′),
42.4 (C1′), 51.5 (C7), 59.7 (ester CH2), 128.7 (C8a), 136.3 (C2),
146.4 (C3a), 151.1 (C5), 172.8 (C6′), 181.1 (C8); UV (methanol)
λmax 231 nm (ꢀ 14300), 235 (14300), 302 (4,700). Anal.
(C14H20N4O3) C, H, N.
Further elution with 15:1 CH2Cl2/methanol provided 2.04
g of a mixture of N3- and N1-isomers (5f and 6f). This was
subjected to MPLC eluting with a CH2Cl2/methanol gradient
of 17.5:1 and 15:1 which provided 875 mg of additional 5f. The
total yield of 5f was 2.17 g (20%). Further elution with 12.5:1
provided a fraction which was reduced to a minimal volume
and diluted with ether. The resulting solid was collected to
provide 676 mg (6%) of the N1-isomer 6f as orange crystals.
The 1H and 13C NMR assignments were made based in part
on 1H-1H coupling (COSY) and 1H-13C coupling (HETCOR)
two-dimensional NMR experiments. Compound 6f: mp 113-
This method was also used to prepare the phosphonate
electrophiles 20b and 21c.
3-(6-(3-Br om op h en yl)-5-ca r beth oxy-5-m eth ylh exyl)co-
for m ycin Aglycon (7u ). Step 1, Alk yla tion . According to
the method previously described1 ketone 4 (1.09 g, 7.3 mmol)
was alkylated with 11d (3.07 g, 7.3 mmol). Chromatography
on SiO2 with a CH2Cl2/methanol gradient of 20:1, 18:1 and 16:1
provided 1.08 g (31%) of 3-(6-(3-bromophenyl)-5-carbethoxy-
5-methylhexyl)-6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-
one (5u ) as a light yellow gum: 1H NMR (DMSO-d6) 0.96 (s,
3), 1.0-1.6 (m, 4), 1.13 (t, 3H, J ) 7 Hz), 1.70 (quin, 2, J ) 7
Hz), 2.65 (d, 1, J ) 13 Hz), 2.92 (d, 1, J ) 13 Hz), 3.73 (d, 2,
J ) 4 Hz), 3.94 (t, 2, J ) 7 Hz), 4.02 (q, 2, J ) 7 Hz), 7.08 (d,
1, J ) 8 Hz), 7.23 (t, 1, J ) 8 Hz), 7.27 (s, 1), 7.42 (d, 1, J ) 8
Hz), 7.43 (d, 1, J ) 4 Hz), 7.62 (s, 1), 8.34 (br m, 1).
1
116 °C; H NMR (DMSO-d6) 1.17 (t, 3, J ) 7 Hz, ester CH3),
1.25 (quin, 2, J ) 7 Hz, C3′ Hs), 1.53 (quin, 2, J ) 7 Hz, C4′
Hs), 1.67 (quin, 2, J ) 7 Hz, C2′ Hs), 2.27 (t, 2, J ) 7 Hz, C5′
Hs), 3.8 (br s, 2, C7 Hs), 4.04 (q, 2, J ) 7 Hz, ester CH2), 4.18
(t, 2, J ) 7 Hz, C1′ Hs), 7.37 (br s, 1, H5), 7.84 (s, 1, H2), 8.2
(br s, 1/2, H6), 10.6 (br s, 1/2, H4); 13C NMR (DMSO-d6) 14.1
(ester CH3), 23.9 (C4′), 25.1 (C3′), 30.1 (C2′), 33.3 (C5′), 46.3
(C1′), 55.5 (br s, C7), 59.6 (ester CH2), 117.7 (C8a), 141.5 (C2),
153.5 (br s, C3a), 148.5 (C5), 172.7 (C6′), 181.2 (C8); UV
(methanol) λmax 231 nm (ꢀ 17100), 235 (16900), 301 (5020).
Anal. (C14H20N4O3) C, H, N.
St ep 2, R ed u ct ion . According to the method previously
described1 5u (1.08 g, 2.27 mmol)was reduced with NaBH4 (106
mg, 2.72 mmol). Chromatography on SiO2 with a CH2Cl2/
methanol/triethylamine gradient of 25:1:0.25 and 20:1:0.2
provided a fraction which was reduced to a minimal volume
and diluted with ether. The resulting solid was collected to
provide 802 mg (74%) of 7u as a white solid: mp 133-136 °C;
1H NMR (DMSO-d6) 0.97 (s, 3), 1.15 (t, 3H, J ) 7 Hz), 1.2-
1.8 (m, 6), 2.65 (d, 1, J ) 13 Hz), 2.93 (d, 1, J ) 13 Hz), 3.15
(br s, 2), 3.84 (t, 2, J ) 7 Hz), 4.03 (q, 2, J ) 7 Hz), 4.80 (br s,
1), 4.90 (br s, 1), 6.96 (d, 1, J ) 4 Hz), 7.08 (d, 1, J ) 8 Hz),
7.24 (t, 1, J ) 8 Hz), 7.28 (s, 1), 7.42 (d, 1, J ) 8 Hz), 7.45 (br
s, 1). Anal. (C22H29BrN4O3) C, H, N.
Alter n a te Meth od for th e P r ep a r a tion of 3-Alk yl-6,7-
d ih yd r oim id a zo[4,5-d ][1,3]d ia zep in -8(3H)-on es. 3-Ben -
zyl-6,7-dih ydr oim idazo[4,5-d][1,3]diazepin -8(3H)-on e (5f ′).
To a suspension of 2-amino-1-(1-benzyl-5-amino-1H-imidazol-
4-yl)ethanone dihydrochloride (8)16a (1.00 g, 3.3 mmol) in
16.5 mL of DMSO at 70 °C was added triethyl orthoformate
(2.74 mL, 16.5 mmol). After 15 min the resulting solution was
cooled to room temperature and stirred with Darco G-60
charcoal and filtered. The filtrate was concentrated under high
vacuum distillation to a 5 mL volume and then poured onto
ether. The solvent was decanted off of the resulting red oil
and it was mixed with methanol. The resulting white precipi-
tate was filtered and the filtrate concentrated and then diluted