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M. Belohradsky et al. / Tetrahedron 59 (2003) 7751–7760
7757
2,2-Bis(hydroxymethyl)-1-aza-4-oxaspirodecane13 (3) and
oligo(ethylene glycol) ditosylates14 4a-b were prepared
according to known procedures.
50 mmol). Benzyl chloroformate (1.2 mL, 8 mmol, in
15 mL of dioxane) was added during 2 h under a vigorous
stirring at 08C and the reaction mixture was stirred another
2 h at ambient temperature. Dioxane was evaporated, the
residue was dissolved in water and extracted with ethyl
acetate (5£70 mL). The organic layer was dried over
MgSO4, evaporated and the crude product was purified by
column chromatography (150 g of silica gel, 0.5–2% of
methanol in chloroform).
4.2. Synthetic procedures
Two alternative procedures, A and B, have been employed
for the cis–trans isomer separation in the course of the
synthesis. According to procedure A, which is applicable
only for the lower homologue, the isomer separation follows
immediately the macrocyclization step. In procedure B, on
the other hand, the crude reaction mixture which results
from the macrocyclization is subjected to hydrolysis,
N-Cbz-reprotection and oxidation prior to the isomer
separation.
1
cis-6a. Yield 1.8 g (75%); colorless crystals; mp 658C. H
NMR (500 MHz, CDCl3) d 3.56–3.63 (m, 16H, CH2CH2O),
3.73 (d, 4H, J¼9.6 Hz, CH2O), 3.82 (d, 4H, J¼9.6 Hz,
CH2O), 3.82 (bs, 4H, CH2OH), 4.03 (bs, 2H, OH), 5.05
(s, 4H, CH2Ph), 5.72 (bs, 2H, NH), 7.30–7.38 (m, 10H,
C6H5). 13C NMR (125.7 MHz, CDCl3) d 59.74 (.C,),
64.68 (CH2OH), 66.76 (CH2Ph), 70.65 (CH2O), 70.94
(CH2O), 71.17 (CH2O), 128.20(C6H5), 128.21(C6H5),
128.51(C6H5), 136.25(C6H5), 156.31 (OCONH). FAB(þ)
MS m/z (%): 651 ([MþH]þ, 45%). Anal. calcd for
C32H46N2O12: C, 59.06; H, 7.13; N, 4.31. Found: C,
59.34; H, 7.26; N, 4.11.
4.3. Procedure A
4.3.1. Isomerically uniform bis(oxazolidines) cis- and
trans-5a. Solutions of diol 3 (12 g, 60 mmol) in dry dioxane
(350 mL) and ditosylate 4a (27 g, 65 mmol) in dry dioxane
(350 mL) were added slowly (30 mL/h) by dual syringe
pump to a vigorously stirred suspension of freshly powdered
KOH (85%; 14 g, 200 mmol) in dry dioxane (300 mL) at
808C. After heating and stirring for another 10 h and
subsequent cooling the deposited salts were filtered off,
washed with dioxane (200 mL) and the solvent was
evaporated. The residue was subjected to column chroma-
tography (silica gel; 900 g; chloroform–methanol–triethyl-
amine 95:4:1) yielding a mixture of cis-5a and trans-5a
(7.1 g, 43%). The mixture was re-chromatographed
(silica gel; 900 g, chloroform–methanol 98:2) yielding the
individual isomers.
trans-6a. Yield 1.9 g (79%); oil. 1H NMR (500 MHz,
CDCl3) d 3.56–3.66 (m, 16H, CH2CH2O), 3.63 (d, 4H, J¼
9.6 Hz, CH2O), 3.75 (d, 4H, J¼9.6 Hz, CH2O), 3.82 (bs,
4H, CH2OH), 4.02 (bs, 2H, OH), 5.06 (s, 4H, CH2Ph),
5.84 (bs, 2H, NH), 7.28–7.37 (m, 10H, C6H5). 13C NMR
(125.7 MHz, CDCl3) d 59.55 (.C,), 64.89 (CH2OH),
66.66 (CH2Ph), 70.68 (CH2O), 71.00 (CH2O), 71.05
(CH2O), 128.11 (C6H5), 128.14 (C6H5), 128.51 (C6H5),
136.36 (C6H5), 156.33 (OCONH). FAB(þ) MS m/z (%): 651
([MþH]þ, 75%). Anal. calcd for C32H46N2O12: C, 59.06; H,
7.13; N, 4.31. Found: C, 59.08; H, 7.27; N, 4.09.
cis-5a. Yield 2.4 g (15%); colorless crystals; mp 76–788C.
1H NMR (500 MHz, CDCl3) d 1.25–1.69 (m, 20H, C6H10),
2.39 (bs, 2H, NH), 3.51 (d, 4H, J¼9.0 Hz, CH2O), 3.52 (d,
4H, J¼9.0 Hz, CH2–O), 3.58–3.67 (m, 16H, CH2CH2O),
3.73 (s, 4H, CH2O). 13C NMR (125.7 MHz, CDCl3) d 23.72
(CH2), 25.12 (CH2), 37.55 (CH2), 64.81 (.C,), 69.73
(CH2O), 70.60 (CH2O), 71.09 (CH2O), 73.78 (CH2O),
95.65 (.C,). FAB(þ) MS m/z (%): 543 ([MþH]þ, 100%).
Anal. calcd for C28H50N2O8: C, 61.97; H, 9.29; N, 5.16.
Found: C, 61.71; H, 9.50; N, 4.93.
4.3.3. Isomerically uniform N-Cbz-protected bis(amino
acids) cis- and trans-7a. N-Cbz-protected bis(amino
alcohol) cis- or trans-6a (1.7 g, 2.6 mmol) was dissolved
in 1:1 mixture of H2O and CH3CN (130 mL) and treated
with NaHCO3 (0.5 g, 7.7 mmol) and TEMPO (0.4 g,
2.6 mmol). NaClO (15 mL of 0.7 M aqueous solution) was
added in several portions under stirring at room temperature
and the reaction was monitored by TLC. After 1–2 h, the
reaction mixture was evaporated to dryness and the solid
residue was treated with chloroform. Deposited salts
were filtered off and the crude product was purified by
column chromatography (200 g of silica gel, chloroform–
methanol–aq. ammonia: 100:20:3) followed by ion
exchange (Dowex 50, Hþ form).
trans-5a. Yield 2.5 g (15%); colorless crystals; mp 89–
1
918C. H NMR (500 MHz, CDCl3) d 1.25–1.70 (m, 20H,
C6H10), 2.12 (bs, 2H, NH), 3.50 (d, 4H, J¼9.0 Hz, CH2–O),
3.52 (d, 4H, J¼9.0 Hz, CH2–O), 3.60–3.66 (m, 16H,
CH2CH2–O), 3.72 (s, 4H, CH2–O). 13C NMR (125.7 MHz,
CDCl3) d 23.71 (CH2), 25.20 (CH2), 37.56 (CH2), 64.79
(.C,), 69.69 (CH2O), 70.57 (CH2O), 71.08 (CH2O), 73.74
(CH2O), 95.63 (.C,). FAB(þ) MS m/z (%): 543 ([MþH]þ,
100%). Anal. calcd for C28H50N2O8. 0.5H2O: C, 60.92; H,
9.31; N, 5.08. Found: C, 60.77; H, 9.19; N, 5.05.
cis-7a. 1.19 g (68%); glassy solid. 1H NMR (500 MHz,
CDCl3) d 3.53 (m, 8H, CH2CH2O), 3.66 (m, 4H,
CH2CH2O), 3.78 (m, 4H, CH2CH2O), 3.90 (d, 4H, J¼
9.4 Hz, CH2O), 4.10 (d, 4H, J¼9.4 Hz, CH2O), 5.03 (s, 4H,
CH2Ph), 6.58 (bs, 2H, NH), 7.26–7.37 (m, 10H, C6H5). 13
C
NMR (125.7 MHz, CDCl3) d 63.26 (.C,), 65.92 (CH2
Ph), 68.69 (CH2O), 69.27 (CH2O), 70.63 (CH2O), 127.70
(C6H5), 127.79 (C6H5), 128.35 (C6H5), 136.87 (C6H5),
154.98 (OCONH), 174.97 (COOH). FAB(2) MS m/z (%):
677 ([M2H]2, 100%), 699 ([MþNa–H]2, 80%). FAB(þ)
MS m/z (%): 739 ([MþKþNa]þ, 100%), 723 ([Mþ2Na]þ,
75%). Anal. calcd for C32H40N2O14·2H2O: C, 53.78; H,
6.48; N, 3.92. Found: C, 53.96; H, 6.17; N, 3.93.
4.3.2. Isomerically uniform N-Cbz protected bis(amino
alcohols) cis- and trans-6a. 3 M HCl (50 mL) was added to
an appropriate isomer of 5a (2 g, 3.7 mmol) and the mixture
was stirred and heated at 558C for 5 h. Hydrochloric acid
was evaporated, the resulting bis(amino alcohol hydro-
chloride) was dissolved in 1:1 mixture of dioxane and water
(70 mL) and treated with sodium hydrogen carbonate (4.2 g,