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C. Taillefumier et al. / Tetrahedron 60 (2004) 2213–2224
H0-8), 3.38 (dd, 1H, Jgem¼14.3 Hz, JCH ,CHa¼4.5 Hz,
4.4.8. [2R,3R,4R,5R,8S]-2[(4R)-2,2-Dimethyl-1,3-dioxo-
lan-4-yl]-3,4-isopropylidenedioxy-8-methyl-1-oxa-6,9-
diazaspiro-[4,6]-undecane 7,10-dione, 38. Compound 38
was synthesised in 20% yield (3 steps) from 25b, following
the same procedure described above for the preparation of
33 from 24, in identical scale (see general procedure of
cyclisation); Glassy solid; Rf 0.3 (silica gel, EtOAc);
2
CHHPh), 2.99–3.16 (m, 3H, 2£H-2 and CHHPh), 1.50 (s,
3H, CH3), 1.41 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.31 (s, 3H,
CH3); 13C NMR (CDCl3, 100.6 MHz): d 171.7, 170.0
(2£CvO), 136.1 (Cipso), 127.3–130.2 (5C Ar), 113.9
(acetal), 109.8 (acetal), 91.1 (C-3), 86.5 (C-4), 81.8 (C-6),
80.7 (C-5), 75.4 (C-7), 65.9 (C-8), 57.5 (Ca ), 40.2 (C-2),
Phe
37.0 (CH2Ph), 26.6, 25.8, 25.4, 24.7 (4£CH3); m/z (EIþ)
447.3 [(MH)þ, 3%], 446.2 [Mþ, 7%], 431.2 [(M2CH3)þ,
7%], 355.2 (4), 297.1 (5), 239.0 (9), 166.7 (8), 141.0 (19),
119.9 (62), 100.9 (100).
[a]2D6¼267.3 (c 0.3 CHCl3); H NMR (CDCl3, 400 MHz):
1
d 7.33 (br s, 1H, NH), 5.89 (br s, 1H, NHAla), 4.87 (dd, 1H,
J4,5¼6.0 Hz, J5,6¼1.2 Hz, H-5), 4.54 (d, 1H, J4,5¼6.0 Hz,
H-4), 4.37 (m, 1H, H-7), 4.28 (m, 1H, H-6), 4.13–4.22 (m,
0
2H, CHa and H-8), 3.75 (dd, 1H, Jgem¼8.8 Hz, J7,8 ¼6.6 Hz,
4.4.6. [2R,3S,4S,5S,8S]-2[(4R)-2,2-Dimethyl-1,3-dioxo-
lan-4-yl]-3,4-isopropylidenedioxy-8-methyl-1-oxa-6,9-
diazaspiro-[4,6]-undecane 7,10-dione, 33. The synthesis
of 33 from 24 is described in the general procedure of
cyclisation. Glassy solid; Rf 0.3 (silica gel, EtOAc);
[a]2D2¼216.0 (c 0.8 CHCl3); nmax (KBr) 3435, 2987,
H0-8), 3.21 (d, 1H, Jgem¼14.3 Hz, H-2), 2.96 (br d, 1H,
Jgem¼14.5 Hz, H0-2), 1.56 (s, 3H, CH3), 1.55 (s, 3H, CH3),
1.46 (d, 3H, J¼6.7 Hz, CH3Ala), 1.40 (s, 3H, CH3), 1.35 (s,
3H, CH3); 13C NMR (CDCl3, 100.6 MHz): d 170.7, 169.5
(2£CvO), 113.9 (acetal), 110.6 (acetal), 93.8 (C-3), 88.5
(C-4), 85.1 (C-6), 80.5 (C-5), 75.9 (C-7), 65.6 (C-8), 50.1
1
1685, 1457, 1382, 1211; H NMR (CDCl3, 400 MHz): d
(Ca ), 40.1 (C-2), 26.09, 26.05, 24.7, 24.3 (4£CH3), 15.5
Ala
8.38 (br s, 1H, NH), 7.62 (d, 1H, JCH ,NHAla¼5.0 Hz,
(CH3Ala); m/z (EIþ) 371.2 [(MþH)þ, 14%], 370.2 [Mþ,
4%], 355.2 [(M-CH3)þ, 41%], 269.1 (64), 141.0 (53), 101.0
(100).
a
NHAla), 4.87 (dd, 1H, J4,5¼5.7 Hz, J5,6¼4.0 Hz, H-5),
4.60 (m, 1H, CHa), 4.52 (d, 1H, J4,5¼5.7 Hz, H-4), 4.35
(m, 1H, H-7), 4.20 (dd, 1H, Jgem¼8.5 Hz, J7,8¼6.6 Hz,
H-8), 3.91 (dd, 1H, J5,6¼4.0 Hz, J6,7¼8.2 Hz, H-6), 3.73
4.4.9. [2R,3R,4R,5R,8S]-2[(Methoxymethoxy)methyl]-
3,4-isopropylidenedioxy-8-methyl-1-oxa-6,9-diazaspiro-
[4,6]-decane 7,10-dione, 39. Compound 39 was synthesised
in 29% yield (3 steps) from 26, following the same
procedure described above for the preparation of 33 from
24, in identical scale (see general procedure of cyclisation);
Rf 0.4 (silica gel, 10% MeOH in CH2Cl2); [a]2D2¼240.0 (c
1.1 CHCl3); 1H NMR (CDCl3, 400 MHz): d 7.35 (br s, 1H,
NH), 6.29 (br s, 1H, NHAla), 4.90 (dd, 1H, J4,5¼6.0 Hz,
J5,6¼1.4 Hz, H-5), 4.73 (m, 2H, OCH2OCH3), 4.55 (d, 1H,
J4,5¼6.0 Hz, H-4), 4.46 (m, 1H, H-6), 4.16 (m, 1H, CHa),
0
0
(dd, 1H, Jgem¼8.5 Hz, J7,8 ¼6.8 Hz, H -8), 3.28 (d, 1H,
Jgem¼16.6 Hz, H-2), 3.19 (d, 1H, Jgem¼16.6 Hz, H0-2),
1.48 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.39 (s, 3H, CH3),
1.36 (d, 3H, J¼6.7 Hz, CH3Ala), 1.32 (s, 3H, CH3); 13C
NMR (CDCl3, 100.6 MHz): d 175.0, 172.2 (2£CvO),
114.0 (acetal), 110.3 (acetal), 91.3 (C-3), 86.0 (C-4), 81.4
(C-6), 81.0 (C-5), 75.7 (C-7), 66.4 (C-8), 49.3 (Ca ),
Ala
40.5 (C-2), 27.2, 26.3, 25.7, 25.3 (4£CH3), 14.5 (CH3Ala);
m/z (EIþ) 371.1 [(MH)þ, 6%], 370.1 [Mþ, 5%], 356.1
[(MH2CH3)þ, 2%], 355.1 [(M2CH3)þ, 10%], 312.1
[(M2CH3COCH3)þ, 5%), 183.0 (11), 140.9 (22), 100.9
(100).
3.76 (dd, 1H, Jgem¼10.9 Hz, J6,7¼1.9 Hz, H-7), 3.64
0
0
(dd, 1H, Jgem¼10.9 Hz, J6,7 ¼2.1 Hz, H -7), 3.41 (s, 3H,
OCH2OCH3), 3.21 (d, 1H, Jgem¼14.0 Hz, H-2), 2.93 (br d,
1H, Jgem¼14.0 Hz, H0-2), 1.56 (s, 3H, CH3), 1.43 (d, 3H,
J¼6.8 Hz, CH3Ala), 1.34 (s, 3H, CH3); 13C NMR (CDCl3,
100.6 MHz): d 171.4, 169.8 (2£CvO), 111.4 (acetal), 97.2
(OCH2OCH3), 94.3 (C-3), 89.1 (C-4), 84.3 (C-6), 82.6
4.4.7. Compound 34. Compound 34 was synthesised from
32 in 15% yield and was obtained in addition of 33 (31%),
following the general procedure described for the cyclisa-
tion of linear dipeptides into diazepinediones. All the
reaction conditions were strictly identical to that described
above except that a higher concentration of the reaction
mixture was applied, 30 mM instead of 2.5 mM.
(C-5), 69.0 (C-7), 56.4 (OCH2OCH3), 50.4 (Ca ), 40,7
Ala
(C-2), 26.5, 25.1 (2£CH3), 15.8 (CH3Ala); m/z (EIþ) 345.1
[(MþH)þ, 2%], 329.0 [(M2CH3)þ, 2%], 313.0 (3), 269 (3),
257.0 (3), 241 (3), 215 (6), 157 (25), 67.9 (100).
Data for 34. Rf 0.1 (silica gel, EtOAc); [a]2D5¼225.0 (c 1.6
CHCl3); nmax (neat) 3535, 3305, 2987, 2936, 1662, 1533,
4.4.10. Deprotection of 30. Compound 30 (45 mg,
0.12 mmol) was treated with a 90 vol% TFA/H2O solution
cooled at 0 8C, for 4 h. The mixture was concentrated in
vacuo and coevaporated with toluene (3£) and MeOH (3£)
to give quantitatively a mixture of the two pyranoid anomers
40 and the two furanoid anomers 41 in a 5:1 ratio.
Purification using reversed-phase high performance liquid
chromatography by gradient elution (2% CH3CN/H2O to
8% CH3CN/H2O) allowed us to isolate pure, one isomer of
the pyranose derivatives 40.
1
1455, 1373; H NMR (CDCl3, 400 MHz): d 8.11 (br s,
1H, NH), 7.13 (br d, 1H, J¼6.8 Hz, NHAla), 5.12 (d, 1H,
J4,5¼6.0 Hz, H-4), 5.08 (dd, 1H, J4,5¼6.0 Hz,
J5,6¼3.9 Hz, H-5), 4.48 (m, 1H, CHa), 4.36 (dd, 1H,
J5,6¼3.9 Hz, J6,7¼7.9 Hz, H-6), 4.29–4.15 (m, 2H, H-7
and H-8), 3.69 (m, 1H, H0-8), 3.19 (d, 1H, Jgem¼13.6 Hz,
H-2), 2.78 (d, 1H, Jgem¼13.6 Hz, H0-2), 1.52 (s, 3H,
CH3), 1.44 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.36 (s, 3H,
CH3), 1.23 (d, 3H, J¼6.9 Hz, CH3Ala); 13C NMR (CDCl3,
100.6 MHz): d 173.3, 169.9 (2£CvO), 113.8 (acetal),
110.3 (acetal), 94.1 (C-3), 85.6 (C-6), 85.3 (C-4), 83.5
Data for the pure 40 derivative: 1H NMR (D2O, 400 MHz):
d 4.21 (m, 1H, CHa), 4.11(m, 1H, H-7), 3.93 (pseudo t, 1H,
J¼3.7 Hz, H-5), 3.80 (br d, 1H, J5,6¼4.0 Hz, J6,7,1.0 Hz,
H-6), 3.71 (d, 1H, J4,5¼3.4 Hz, H-4), 3.63 (m, 2H, 2£H-8),
2.50–2.75 (m, 2£H-2 partially exchanged), 1.29 (d, 3H,
J¼7.3 Hz, CH3Ala); 13C NMR (D20, 100.6 MHz): d 178.4,
(C-5), 76.9 (C-7), 66.8 (C-8), 48.5 (Ca ), 43.5 (C-2),
Ala
27.0, 26.3, 25.8, 24.9 (4£CH3), 15.0 (CH3Ala); m/z (EIþ)
741.8 [(MH)þ, 26%], 741.0 [Mþ, 9%], 725.6
[(M2CH3)þ, 27%], 581.1 (14), 527.1 (10), 371.1 (12),
354.1 (42), 283.0 (22), 140 (20), 100.9 (100).