M.T. Allingham et al. / Tetrahedron 72 (2016) 496e503
501
aqueous formaldehyde (37% w/v, 28 mL) and dichloromethane
(30 mL)) was added and the reaction stirred for a further 24 h. After
washing with water (2ꢄ30 mL), the organic fraction was dried
(MgSO4) and the solvent removed by rotary evaporator. The solid
obtained was triturated with ether (5ꢄ30 mL), and the resulting oil
purified by column chromatography (5% diethyl ether/petrol) to
yield the desired product as an unstable clear oil (1.08 g, 72%). Rf
0.19 (5% diethyl ether in petrol); dH 6.35 (1H, dd, J 17.7, 10.1 Hz), 6.20
(1H, dd, J 17.7, 1.6 Hz), 5.83 (1H, dd, J 1.6, 10.1 Hz), 4.02e4.14 (2H, m,
2ꢄCH), 3.54 (1H, t, J 6.7 Hz), 2.65 (2H, t, J 7.0 Hz, CH2),1.85e1.52 (4H,
m, 2ꢄCH2), 1.40 (3H, s, Me), 1.35 (3H, s, Me); dC 200.3, 136.5, 128.1,
108.8, 75.8, 69.3, 32.9, 26.9, 25.7, 20.1; nmax (thin film) 2985 (CeH),
1701 (C¼O), 1681 (C¼C), 1369 (CeH).
cmꢂ1; HRMS(EI) found 567.3876, C29H57N3O4Si2 ([M]þ) requires
567.3888.
6.1.5.1. Guanidinium salt 7d. This was prepared in an identical
manner from enone 6 (2.97 g, 15.0 mmol), guanidine (400.0 mg,
6.8 mmol), TBDPSCl (5.61 g, 20.4 mmol) and imidazole (1.87 g,
27.2 mmol). Purification by column chromatography (gradient
elution in CHCl3 then 2%, 3%, 4%, 5%, 10%, 15% and 20% MeOH in
CHCl3) collecting the fractions eluted at 4e5 % MeOH in CHCl3 gave
7d (2.21 g, 36%) as an amorphous white solid. 7d Rf¼0.29 (4% MeOH
in CHCl3); [
a
]
25þ44 (c 0.5 in CHCl3); mp 200 ꢀC; dH 9.48 (2H, br s,
NH), 7.71e7.64 (8H, m, 8ꢄCH), 7.44e7.34 (12H, m, 12ꢄCH),
3.94e4.05 (2H, m, 2ꢄCH), 3.69e3.53 (6H, m, 2ꢄCH2, 2ꢄCH), 3.02
(2H, dd, J 5.3, 11.7 Hz, 2ꢄCH), 2.65e2.41 (2H, m), 1.97e1.50 (12H, m,
6ꢄCH2), 1.40e1.15 (2H, m), 1.02 (18H, s, 2ꢄtBu); dC 148.3, 135.4,
135.4, 133.5, 133.4, 129.6, 129.5, 127.5, 78.7, 71.6, 66.7, 42.7, 33.5,
32.8, 26.0, 26.0, 19.1, 17.0; nmax (in CHCl3) 3360 (NeH), 2947 (CeH),
1664 (NeH); HRMS(EI) found 816.4583, C49H66N3O4Si2 ([MþH]þ)
requires 816.4592.
6 . 1 . 4 . ( 2 R , 6 S , 6 00S , 8 0R ) - 6 , 6 00- b i s ( h y d r o x y m e t h y l ) -
3,300,4,40,400,5,500,6,60,600,70,9’-dodecahydro-10H,30H-dispiro[pyran-2,20-
pyrimido[1,2-a]pyrimidine-80,200-pyran]-50-ium chloride 7b. A solu-
tion of guanidine (68.0 mg, 1.2 mmol) in dry DMF (5 mL) was added
to a cooled (0 ꢀC) solution of enone 6 (0.5 g, 2.5 mmol) in dry DMF
(2 mL) and the reaction warmed to rt over 24 h. The reaction was
cooled (0 ꢀC) and methanolic HCl (7 mL, prepared from acetyl
chloride (1 mL) and dry methanol (6 mL)) was then added and the
reaction stirred for a further 3 h. After evaporation, column chro-
matography (graduated solvent system 0%,1%, 3%, 5%,10%,15%, 20%,
40% MeOH in CHCl3) followed by collecting of the fractions eluting
at 15e20 % gave 7b (0.23 g, 45%) as a highly hygroscopic solid. Rf
6.1.6. (6R, 600R, 2R, 200R)-6,600-Dimethyldispiro [tetrahydropyran-2,20-
(2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a] pyrimidine)-80,200-tetra-
hydropyran]-90-ium tetraphenylborate 7e. The reaction for the
preparation of 7a was repeated with the omission of the final wash
with NaBF4 solution. Purification of the residue obtained by column
chromatography gave the corresponding guanidinium chloride
(199.7 mg, 0.581 mmols) which was dissolved in dry THF (5 mL)
and NaBPh4 (0.6 g, 1.75 mmols) was added. After stirring this
mixture for 6 h, the solvent was removed in vacuo and the white
solid obtained dissolved in dichloromethane (20 mL) and washed
with H2O (2ꢄ50 mL) to remove NaCl and excess NaBPh4. The so-
lution was dried (MgSO4), filtered and the solvent removed in vacuo
to give 7e as a white solid (321.8 mg, 0.513 mmols) in 88% yield.
0.17 (15% MeOH/CHCl3); [
a
]
25 þ28 (c 0.5, MeOH). dH 3.74e3.92 (4H,
D
m, 2ꢄCH2), 3.52e3.63 (4H, m, 2ꢄCH2), 3.35e3.50 (2H, m, 2ꢄCH),
1.70e2.20 (14H, m), 1.35e1.55 (4H, m, 2ꢄCH2); dC 151.2, 81.2, 74.0,
67.3, 44.6, 35.9, 34.7, 28.6, 20.1; m/z (CI) 340.2 (100% [MþH]þ);
HRMS(EI) found 340.2236, C17H30N3O4 ([M]þ) requires 340.2236.
6.1.5. (2R,6S,600S,80R)-6,600-bis(((isopropyldimethylsilyl)oxy)methyl)-
3,300,4,40,400,5,500,6,60,600,70,90-dodecahydro-10H,30H-dispiro[pyran-2,20-
pyrimido[1,2-a]pyrimidine-80,200-pyran]-50-ium tetrafluoroborate 7c
[
a
]
27þ67 (c 0.5 in CHCl3); mp 63e65 ꢀC (dec); dH 7.48e7.54 (8H, m,
8ꢄArH), 7.07 (8H, app t, J 7.4 Hz, 8ꢄArH), 6.93 (4H, t, J 7.2 Hz,
4ꢄArH), 6.31 (2H, br s, 2ꢄNH), 3.41e3.52 (4H, m, 4ꢄCH), 2.92 (2H,
dd, J 12.4, 5.5 Hz, 2ꢄCH), 1.78 (2H, dd, J 13.5, 4.3 Hz, 2ꢄCH),
1.26e1.58 (14H, m), 1.11 (6H, d, J 6.1 Hz, 2ꢄCH3); dC 164.7, 164.4,
164.0, 163.6, 148.0, 136.0, 125.8, 121.9, 79.0, 67.0, 42.7, 33.3, 32.8,
32.0, 21.7, 18.0; dB ꢂ6.46. HRMS (CI) found 308.2332. ([MþH]þ)
and
3,300,4,40,400,5,500,6,60,600,70,90-dodecahydro-10H,30H-dispiro[pyran-2,20-
pyrimido[1,2-a]pyrimidine-80,200-pyran]-50-ium
fluoroborate 7d
(2R,6S,600S,80R)-6,600-bis(((tert-butyldiphenylsilyl)oxy)methyl)-
Guanidinium salt 7d. Guanidine (403.0 mg, 6.8 mmol) as a solution
in DMF (5 mL) was added to a stirred and cooled (0 ꢀC) solution of
enone 6 (2.84 g, 14.3 mmol) in dry DMF (64 mL) and the mixture
slowly warmed to rt over 24 h. Methanolic HCl (25 mL, prepared
from the addition of acetyl chloride (5 mL) to cooled dry methanol
(20 mL)) was added and the mixture stirred for a further 4 h. The
solvent was removed under reduced pressure and the resulting oil
purified by column chromatography (gradient elution in CHCl3 then
3%, 5%, 10%, 15%, 20% and 50% MeOH in CHCl3) with the fraction
eluted at 10% being collected. These fractions were then dissolved
in dry DMF (20 mL), cooled (0 ꢀC) and TBDMSCl (3.1 g, 20.6 mmol)
and imidazole (1.87 g, 27.5 mmol) added. After stirring to rt over
24 h the reaction was diluted with dichloromethane (100 mL) and
washed with water (5ꢄ30 mL), LiBr solution (aq satd, 30 mL) and
water (30 mL) then dried (MgSO4). The organic phase was evapo-
rated to ca. 30 mL and a solution of NaBF4 (satd, 30 mL) added and
the mixture stirred for 16 h. The organic phase was separated,
washed with water (3ꢄ30 mL), dried (MgSO4) and the solvent re-
moved by rotary evaporation. Purification by column chromatog-
raphy (gradient elution in CHCl3 then 0.5%, 1%, 2%, 5%, 10% and 20%
MeOH in CHCl3) collecting the fractions eluting in 1e5% MeOH in
CHCl3 gave 7c (1.31 g, 29%) as an amorphous white solid. 7c Rf¼0.35
C
17H30N3O2 requires 308.2333; found 319.1660 ([M]ꢂ) C24H20B re-
quires 319.1664.
6.2. General method for glycinate Schiff’s base reactions
The guanidinium salt 7aee (0.04 mmol) and the glycinate
Schiff’s base 8 (120 mg, 0.407 mmol) were dissolved in dichloro-
methane (2 mL) and aqueous NaOH solution (2 mL, 2M), was added.
This mixture was cooled (0 ꢀC), vigorously stirred and BnBr
(139 mg, 0.814 mmol, 120 mL) was then added in one portion. After
stirring to rt over 16 h, dichloromethane (15 mL) was added and the
organic layer separated, dried (MgSO4) and evaporated, then pu-
rified by column chromatography (diethyl ether/petrol). Conver-
sion rates were determined by 1H NMR and ee’s (þ/ꢂ 3%) were
determined on
hexane:dioxane).
a
Bakerbond DNPG column (98.5:1.5
6.3. General method for phase transfer epoxidation of chal-
cones 10aee
(4% MeOH in CHCl3); [
a
]
25 þ47 (c 0.5 in CHCl3); mp 207e209 ꢀC; dH
6.3.1. Using sodium hypochlorite solution. The guanidinium salt
7aee (0.025e0.10 equiv) and the chalcone 10aee (1.04e1.60 mmol)
were dissolved in toluene (2e3 mL per mmol 10) and the mixture
cooled (0 ꢀC) and stirred vigorously. Sodium hypochlorite solution
(8% aqueous solution, 1.2 mL per mmol 10, 3 equiv) was then added
and the reaction stirred to rt over 16 h. Dichloromethane (15 mL)
D
7.45 (2H, br s, NH), 3.85e3.66 (4H, m, 2ꢄCH2), 3.51 (4H, d, J 5.0 Hz,
2ꢄCH2), 3.18 (2H, dd, J 12.3, 5.2 Hz, 2ꢄCH), 1.54e2.00 (14H, m)
1.19e1.34 (2H, m, 2ꢄCHH), 0.85 (18H, s, 6ꢄCH3), ꢂ0.03 (12H, s,
4ꢄCH3); dC 148.5, 80.6, 78.9, 71.8, 66.3, 44.9, 33.8, 33.0, 26.2, 25.8,
18.2, 17.1, ꢂ5.3; nmax (CHCl3) 3370 (NeH), 2953 (CeH), 1660 (NeH)