A. Dondoni et al.
7.40–7.10, 6.70–6.30 (2m, 19H, Ph), 5.58, 4.44 (2d, J=12.0 Hz, 2H,
PhCH2), 4.47 (dd, J3,4 ~0.5, J4,5 =6.0 Hz, 1H, H-4), 4.45, 4.41 (2d, J=
11.8 Hz, 2H, PhCH2), 4.32, 4.22 (2d, J=11.5 Hz, 2H, PhCH2), 4.21 (ddd,
galacto-nonanoate ((R)-benzylated-21ba): 1H NMR ([D6]acetone): d=
7.75–7.20 (m, 25H, 5Ph), 7.60 (d, J3,NH =10.0 Hz, 1H, NH), 4.94, 4.91
(2d, J=11.0 Hz, 2H, PhCH2), 4.88, 4.83 (2d, J=10.0 Hz, 2H, PhCH2),
4.86, 4.69 (2d, J=10.5 Hz, 2H, PhCH2), 4.64, 4.59 (2d, J=12.0 Hz, 2H,
J
6,7 =4.0,
J7,8a =3.5, J7,8b =3.0 Hz, 1H, H-7), 4.20 (q, J=7.0 Hz, 2H,
OCH2CH3), 4.05 (ddd, JFa,3 =5.0, JFb,3 =21.0 Hz, 1H, H-3), 3.79 (dd, J5,6
=
PhCH2), 4.60 (dd, J3,4 ~0.5 Hz, 1H, H-3), 3.80 (dd, J8,9a =3.5, J9a,9b
11.0 Hz, 1H, H-9a), 3.75 (dd, J4,5 =9.0, J5,6 =9.5 Hz, 1H, H-5), 3.71 (dd,
8,9b =1.5 Hz, 1H, H-9b), 3.65 (dd, J3,4 ꢀ0.5, J4,5 = 9.0 Hz, 1H, H-4), 3.63
(dd, J6,7 =9.0, J7,8 =9.2 Hz, 1H, H-7), 3.53 (s, 3H, OCH3), 3.51 (ddd, J7,8
9.2, J8,9a 3.5, J8,9b 1.5 Hz, 1H, H-8), 3.48 (q, J=0.7 Hz, 3H,
=
5.0 Hz, 1H, H-6), 3.72 (s, 3H, OCH3), 3.66 (dd, J4,5 = 6.0, J5,6 = 5.0 Hz,
1H, H-5), 3.62 (dd, J8a,8b =10.5 Hz, 1H, H-8a), 3.46 (dd, J7,8b = 3.0, J8a,8b
= 10.5 Hz, 1H, H-8b), 1.22 (t, J = 7.0 Hz, 3H, OCH2CH3); 13C NMR:
d=163.8 (dd, 2JC,Fa =32.3, 2JC,Fb =32.2 Hz), 152.6, 140.9, 137.6, 137.5,
J
=
=
=
137.4, 128.5–127.8 (9C), 115.0 (dd, 1JC,Fa =260.0, 1JC,Fb =261.0 Hz), 114.8
OCH3), 3.27 (dd, J5,6 = 9.5, J6,7 = 9.0 Hz, 1H, H-6), 1.20 (s, 3H, CH3),
1.02 (s, 3H, CH3).
2
(4C), 82.3, 78.5, 77.9, 76.3, 73.5, 72.3, 72.1, 69.6, 62.9, 57.1 (dd, JC,Fa
=
25.1, JC,Fb =25.0 Hz), 55.7, 13.8; 19F NMR: d=À107.9 (dd, JFa,H =5.0,
(2’S)-Methyl 4,8-anhydro-5,6,7,9-tetra-O-benzyl-2,3-dideoxy-2,2-dimethyl-
3-(3’,3’,3’-trifluoro-2’-methoxy-2’-phenyl-propionylamino)-d-erythro-l-
galacto-nonanoate ((S)-benzylated-21ba): 1H NMR ([D6]acetone): d=
7.79–7.22 (m, 25H, 5Ph), 7.60 (d, J3,NH =10.5 Hz, 1H, NH), 4.88, 4.82
(2d, J=11.5 Hz, 2H, PhCH2), 4.76, 4.62 (2d, J=11.0 Hz, 2H, PhCH2),
4.70, 4.64 (2d, J=10.0 Hz, 2H, PhCH2), 4.59, 4.55 (2d, J=11.5 Hz, 2H,
J
Fa,Fb =256.3 Hz, 1F, Fa), À118.6 (dd, JFb,H =21.0 Hz, 1F, Fb); MALDI-
TOF MS: m/z: 662.0 [M ++H], 684.1 [M ++Na], 700.0 [M ++K]; elemen-
tal analysis calcd (%) for C38H41F2NO7 (661.73): C 68.97, H 6.25, F 5.74,
N 2.12; found: C 68.94, H 6.22, F 5.77, N 2.15.
General procedure for the synthesis of Mosherꢀs amides 21aa–ea and
21ab: CAN (1.10 g, 2.00 mmol) was added in one portion to a cooled
(08C) stirred solution of N-PMB-derivative (0.50 mmol) in CH3CN
(20 mL) and H2O (5 mL). The resulting mixture was vigorously stirred at
room temperature for 6 h, and quenched with saturated aqueous Na2SO3
solution (15 mL). The aqueous layer was extracted with AcOEt (3
30 mL), and the combined organic layer was washed with saturated aque-
ous NaHCO3 solution (310 mL), dried (Na2SO4), and concentrated to
give the corresponding unprotected b-amino ester.
PhCH2), 4.46 (dd, J3,4 ~0.5 Hz, 1H, H-3), 3.68 (dd, J8,9a =3.5, J9a,9b
=
11.0 Hz, 1H, H-9a), 3.63 (dd, J8,9b =2.0 Hz, 1H, H-9b), 3.62 (s, 3H,
OCH3), 3.57 (dd, J5,6 =9.5, J6,7 =9.0 Hz, 1H, H-6), 3.55 (q, J=0.7 Hz, 3H,
OCH3), 3.53 (dd, J4,5 =9.0 Hz, 1H, H-4), 3.40 (ddd, J7,8 =9.0 Hz, 1H, H-
8), 3.17 (dd, J6,7 = 9.0, J7,8 = 9.0 Hz, 1H, H-7), 2.75 (dd, J4,5 = 9.0, J5,6
=
9.5 Hz, 1H, H-5), 1.25 (s, 3H, CH3), 1.22 (s, 3H, CH3).
(2’R)-Methyl 4,8-anhydro-2,3-dideoxy-2,2-dimethyl-3-(3’,3’,3’-trifluoro-2’-
methoxy-2’-phenylpropionylamino)-d-erythro-l-gluco-nonanoate
((R)-
To a stirred solution of the above crude b-amino ester (~0.25 mmol) in
anhydrous CH2Cl2 (2 mL) were added either (R)- or (S)-a-methoxy-a-
(trifluoromethyl)phenylacetic acid (73 mg, 0.30 mmol), 1,3-dicyclohexyl-
carbodiimide (63 mg, 0.30 mmol), and a catalytic amount of 4-N,N-(dime-
thylamino)pyridine. The mixture was stirred for an additional 12 h at
room temperature then concentrated. The residue was taken into
AcOEt, washed with saturated aqueous NaHCO3 and brine, dried over
Na2SO4, and concentrated. The residue was purified by column chroma-
tography with the suitable elution system affording the corresponding
benzylated Mosherꢁs amide in almost quantitative yield.
21ca): 1H NMR (CDCl3 + D2O): d=7.92 (d, J3,NH =9.5 Hz, 1H, NH),
7.65–7.40 (m, 5H, Ph), 4.11 (dd, J3,4 =2.5 Hz, 1H, H-3), 3.85 (dd, J4,5 ~0.5,
J
5,6 =3.5 Hz, 1H, H-5), 3.79–3.62 (m, 2H, H-9a, H-9b), 3.72 (dd, J6,7 =8.5,
J
7,8 =9.0 Hz, 1H, H-7), 3.71 (s, 3H, OCH3), 3.54 (dd, J3,4 2.5, J4,5
=
ꢀ0.5 Hz, 1H, H-4), 3.48 (dd, J5,6 = 3.5, J6,7 = 8.5 Hz, 1H, H-6), 3.30 (q,
J=0.7 Hz, 3H, OCH3), 3.19 (ddd, J7,8 = 9.0, J8,9a = 3.5, J8,9b = 2.0 Hz,
1H, H-8), 1.24 (s, 6H, 2CH3).
(2’S)-Methyl 4,8-anhydro-2,3-dideoxy-2,2-dimethyl-3-(3’,3’,3’-trifluoro-2’-
methoxy-2’-phenylpropionylamino)-d-erythro-l-gluco-nonanoate
((S)-
21ca): 1H NMR (CDCl3 + D2O): d=8.06 (d, J3,NH =10.0 Hz, 1H, NH),
7.60–7.38 (m, 5H, Ph), 4.28 (dd, J3,4 =2.0 Hz, 1H, H-3), 3.83 (dd, J4,5 ~0.5,
A
vigorously stirred mixture of the above crude Mosherꢁs amide
(~0.25 mmol), 20% palladium hydroxide on carbon (50% w/w of sub-
strate), AcOEt (2 mL), and EtOH (2 mL) was degassed under vacuum
and saturated with hydrogen (by a H2-filled balloon) three times. After
stirring under a slightly positive pressure of hydrogen (balloon) at room
temperature for 3–5 h, palladium hydroxide on carbon was filtered off
through a plug of cotton and washed thoroughly with MeOH (2 mL),
H2O (0.5 mL), and DMF (2 mL). The combined filtrates were concentrat-
ed to give the corresponding deprotected Mosherꢁs amide in almost
quantitative yield. This debenzylation step was unnecessary starting from
7ba (gluco series) since a homogeneous distribution of DdRS signs was al-
ready observed in the 1H NMR spectra of the corresponding benzylated
Mosherꢁs amides (see ref. [42]).
J5,6 =3.0 Hz, 1H, H-5), 3.78–3.60 (m, 2H, H-9a, H-9b), 3.72 (s, 3H,
OCH3), 3.68 (dd, J6,7 =9.0, J7,8 =9.5 Hz, 1H, H-7), 3.52 (dd, J3,4 = 2.0, J4,5
ꢀ0.5 Hz, 1H, H-4), 3.45 (dd, J5,6 = 3.0, J6,7 = 9.0 Hz, 1H, H-6), 3.32 (q,
J=0.7 Hz, 3H, OCH3), 3.17 (ddd, J8,9a =3.0, J8,9b =3.5 Hz, 1H, H-8), 1.26
(s, 6H, 2CH3).
(2’R)-Methyl 4,7-anhydro-2,3-dideoxy-2,2-dimethyl-3-(3’,3’,3’-trifluoro-2’-
methoxy-2’-phenylpropionylamino)-d-glycero-d-altro-octanoate
((R)-
21da): 1H NMR (CDCl3 + D2O): d=8.63 (d, J3,NH =9.0 Hz, 1H, NH),
7.60–7.40 (m, 5H, Ph), 4.18 (dd, J3,4 =2.5, J4,5 =7.5 Hz, 1H, H-4), 4.11
(dd, J3,NH = 9.0, J3,4 = 2.5 Hz, 1H, H-3), 4.08 (dd, J5,6 =6.0, J6,7 =8.5 Hz,
1H, H-6), 3.92 (ddd, J7,8a =3.5, J7,8b =5.0 Hz, 1H, H-7), 3.81 (dd, J4,5
=
7.5, J5,6 = 6.0 Hz, 1H, H-5), 3.74 (dd, J8a,8b =12.5 Hz, 1H, H-8a), 3.68 (s,
3H, OCH3), 3.58 (dd, J7,8b = 5.0, J8a,8b = 12.5 Hz, 1H, H-8b), 3.42 (q, J=
0.7 Hz, 3H, OCH3), 1.35 (s, 3H, CH3), 1.23 (s, 3H, CH3).
(2’R)-Methyl 4,8-anhydro-2,3-dideoxy-2,2-dimethyl-3-(3’,3’,3’-trifluoro-2’-
methoxy-2’-phenyl-propionylamino)-d-threo-l-galacto-nonanoate ((R)-
21aa): 1H NMR (CDCl3 + D2O): d=8.70 (d, J3,NH =9.0 Hz, 1H, NH),
7.63–7.43 (m, 5H, Ph), 4.06 (dd, J3,4 ~0.5 Hz, 1H, H-3), 4.02 (dd, J6,7 =3.0,
J7,8 ~0.5 Hz, 1H, H-7), 3.86 (dd, J8,9a =7.0, J9a,9b =12.0 Hz, 1H, H-9a), 3.76
(s, 3H, OCH3), 3.70 (dd, J8,9b =3.0 Hz, 1H, H-9b), 3.66 (dd, J5,6 =9.0 Hz,
1H, H-6), 3.55 (q, J=0.7 Hz, 3H, OCH3), 3.51 (dd, J4,5 =8.5 Hz, 1H, H-
4), 3.50 (dd, J4,5 = 8.5, J5,6 = 9.0 Hz, 1H, H-5), 3.49 (ddd, J7,8 ꢀ0.5, J8,9a
= 7.0, J8,9b = 3.0 Hz, 1H, H-8), 1.34 (s, 3H, CH3), 1.16 (s, 3H, CH3).
(2’S)-Methyl 4,7-anhydro-2,3-dideoxy-2,2-dimethyl-3-(3’,3’,3’-trifluoro-2’-
methoxy-2’-phenylpropionylamino)-d-glycero-d-altro-octanoate
21da): 1H NMR (CDCl3 + D2O): d=8.36 (d, J3,NH =9.0 Hz, 1H, NH),
7.62–7.40 (m, 5H, Ph), 4.10 (dd, J3,4 =4.5 Hz, 1H, H-3), 4.09 (dd, J4,5
6.0 Hz, 1H, H-4), 3.76 (ddd, J6,7 =5.5, J7,8a =3.0, J7,8b =3.5 Hz, 1H, H-7),
3.68 (s, 3H, OCH3), 3.61 (dd, J5,6 =4.5 Hz, 1H, H-6), 3.59 (dd, J8a,8b
((S)-
=
=
12.5 Hz, 1H, H-8a), 3.54 (q, J=0.7 Hz, 3H, OCH3), 3.52 (dd, J4,5 = 6.0,
J5,6 = 4.5 Hz, 1H, H-5), 3.35 (dd, J7,8b = 3.5, J8a,8b = 12.5 Hz, 1H, H-8b),
1.34 (s, 3H, CH3), 1.29 (s, 3H, CH3).
(2’S)-Methyl 4,8-anhydro-2,3-dideoxy-2,2-dimethyl-3-(3’,3’,3’-trifluoro-2’-
methoxy-2’-phenyl-propionylamino)-d-threo-l-galacto-nonanoate
((S)-
21aa): 1H NMR (CDCl3 + D2O): d=8.93 (d, J3,NH =9.0 Hz, 1H, NH),
7.64–7.43 (m, 5H, Ph), 4.06 (dd, J3,4 ~0.5 Hz, 1H, H-3), 3.97 (dd, J6,7 =2.5,
J7,8 ~0.5 Hz, 1H, H-7), 3.86 (dd, J8,9a =7.0, J9a,9b =12.0 Hz, 1H, H-9a), 3.79
(s, 3H, OCH3), 3.69 (dd, J8,9b =3.0 Hz, 1H, H-9b), 3.57 (dd, J5,6 =9.0 Hz,
1H, H-6), 3.47 (dd, J4,5 =9.0 Hz, 1H, H-4), 3.45 (ddd, 1H, H-8), 3.42 (q,
J=0.7 Hz, 3H, OCH3), 3.28 (dd, J4,5 = 9.0, J5,6 = 9.0 Hz, 1H, H-5), 1.36
(s, 6H, CH3).
(2’R)-Methyl 4,7-anhydro-2,3-dideoxy-2,2-dimethyl-3-(3’,3’,3’-trifluoro-2’-
methoxy-2’-phenylpropionylamino)-d-glycero-d-ido-octanoate
21ea): 1H NMR (CDCl3 + D2O): d=8.17 (d, J3,NH =10.5 Hz, 1H, NH),
7.62–7.40 (m, 5H, Ph), 4.48 (dd, J3,4 =8.0 Hz, 1H, H-3), 4.25 (dd, J5,6
((R)-
=
1.5, J6,7 =5.0 Hz, 1H, H-6), 4.08 (dd, J4,5 =4.5 Hz, 1H, H-4), 3.98 (dd, J4,5
= 4.5, J5,6 = 1.5 Hz, 1H, H-5), 3.90 (ddd, J7,8a =3.5, J7,8b =2.0 Hz, 1H, H-
7), 3.73 (dd, J8a,8b =13.5 Hz, 1H, H-8a), 3.68 (s, 3H, OCH3), 3.64 (dd, J7,8b
= 2.0, J8a,8b = 13.5 Hz, 1H, H-8b), 3.57 (q, J=0.7 Hz, 3H, OCH3), 1.28
(s, 3H, CH3), 1.14 (s, 3H, CH3).
(2’R)-Methyl 4,8-anhydro-5,6,7,9-tetra-O-benzyl-2,3-dideoxy-2,2-dimeth-
yl-3-(3’,3’,3’-trifluoro-2’-methoxy-2’-phenylpropionylamino)-d-erythro-l-
7122
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 7110 – 7125