The Journal of Organic Chemistry
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gave 16 as a colorless oil (2.63 g, 66%, >99:1 dr); [α]2D5 +3.5 (c 1.0 in
CHCl3); νmax (film) 3512 (O−H), 1728 (CO); δH (400 MHz,
CDCl3) 0.06 (3H, s, MeSiMe), 0.09 (3H, s, MeSiMe), 0.90 (9H, s,
SiMe3), 1.29 (3H, s, MeCMe), 1.31 (3H, d, J 7.1, C(α)Me), 1.32 (3H,
s, MeCMe), 1.50 (9H, s, CMe3), 3.33 (1H, d, J 9.2, OH), 3.42 (1H, dd,
J 11.6, 3.4, C(6)HA), 3.44−3.47 (1H, m, C(3)H), 3.74 (1H, dd, J 11.6,
3.8, C(6)HB), 3.82−3.88 (1H, m, C(2)H) overlapping 3.85 (1H, d, J
15.2, NCHAHBPh), 3.99 (1H, q, J 7.1, C(α)H), 4.14 (1H, dd, J 8.2,
3.1, C(4)H), 4.44−4.49 (1H, m, C(5)H), 4.79 (1H, d, J 15.2,
NCHAHBPh), 7.22−7.39 (8H, m, Ph), 7.49−7.54 (2H, m, Ph); δC
(100 MHz, CHCl3) −5.6, −5.4 (SiMe2), 18.4 (SiCMe3), 20.1
(C(α)Me), 25.9 (SiCMe3), 26.5, 26.9 (CMe2), 27.9 (OCMe3), 53.8
(NCH2Ph), 56.3 (C(3)), 58.2 (C(α)), 62.4 (C(6)), 72.8 (C(2)), 77.8
(C(4)), 78.0 (C(5)), 81.8 (OCMe3), 108.7 (CMe2), 126.2, 127.0 (p-
Ph), 127.9, 128.0, 128.1 (o,m-Ph), 141.8, 142.0 (i-Ph), 172.9 (C(1));
m/z (ESI+) 600 ([M + H]+, 100%), 544 ([M − C4H7]+, 20%); HRMS
(ESI+) C34H54NO6Si+ ([M + H]+) requires 600.3720; found 600.3734.
tert-Butyl (2S,3R,4R,5S,αS)-2,4,5,6-Tetrahydroxy-3-[N-ben-
zyl-N-(α-methylbenzyl)amino]-4,5-O-isopropylidene-6-O-tert-
butyldimethylsilylhexanoate 18. BuLi (2.5 M in hexanes, 5.82 mL,
14.6 mmol) was added dropwise to a stirred solution of (S)-N-benzyl-
N-(α-methylbenzyl)amine (3.18 g, 15.0 mmol) in THF (140 mL) at
−78 °C, and stirring was continued for 30 min. A solution of 9 (3.50 g,
9.39 mmol) in THF (140 mL) was then added via cannula, and the
reaction mixture was stirred for 2 h. (−)-CSO 4 (4.31 g, 18.8 mmol)
was then added, and the reaction mixture was allowed to warm to rt
over 12 h. The mixture was quenched with satd aqueous NH4Cl (10
mL) and then concentrated in vacuo. The resultant residue was
dissolved in Et2O (200 mL) and then washed sequentially with 10%
aqueous citric acid (200 mL), satd aqueous NaHCO3 (200 mL), and
brine (200 mL), then dried and concentrated in vacuo. Purification via
flash column chromatography (eluent 30−40 °C petrol/Et2O, 10:1)
gave 18 as a pale yellow oil (3.39 g, 60%, >99:1 dr); [α]2D5 −4.1 (c 1.0
in CHCl3); νmax (film) 3491 (O−H), 3085, 3063, 3029, 2928, 2855
(C−H), 1736 (CO); δH (400 MHz, CDCl3) 0.15 (6H, s, SiMe2),
1.01 (9H, s, SiCMe3), 1.26 (3H, s, MeCMe), 1.38 (3H, s, MeCMe),
1.44 (3H, d, J 6.9, C(α)Me), 1.54 (9H, s, CMe3), 3.13 (1H, d, J 7.1,
OH), 3.52 (1H, dd, J 10.4, 8.9, C(6)HA), 3.73−3.78 (2H, m, C(3)H,
C(6)HB), 3.79 (1H, d, J 16.2, NCHAHBPh), 4.08 (1H, q, J 6.9,
C(α)H), 4.13 (1H, d, J 7.1, C(2)H), 4.23 (1H, ddd, J 8.9, 5.7, 2.8,
C(5)H), 4.42 (1H, dd, J 10.0, 5.7, C(4)H), 4.50 (1H, d, J 16.2,
NCHAHBPh), 7.23−7.44 (10H, m, Ph); δC (100 MHz, CDCl3) −5.1
(SiMe2), 18.4 (SiCMe3), 20.2 (C(α)Me), 25.4 (MeCMe), 25.9
(SiCMe3), 28.0 (CMe3), 28.1 (MeCMe), 50.8 (NCH2Ph), 57.7
(C(3)), 59.8 (C(α)), 62.8 (C(6)), 70.4 (C(2)), 73.9 (C(4)), 77.9
(C(5)), 81.7 (CMe3), 107.2 (CMe2), 126.4, 127.4 (p-Ph), 127.5, 128.0,
128.2, 128.4 (o,m-Ph), 141.8, 142.0 (i-Ph), 172.7 (C(1)); m/z (ESI+)
600 ([M + H]+, 100%); HRMS (ESI+) C34H53NNaO6Si+ ([M + Na]+)
requires 622.3534; found 622.3535.
NaBH4 (13 mg, 0.33 mmol) was added portionwise, and stirring was
continued at −20 °C for 2 h. The reaction mixture was then allowed to
warm to rt and concentrated in vacuo. The residue was partitioned
between H2O (10 mL) and Et2O (10 mL), and the aqueous layer was
extracted with Et2O (3 × 10 mL). The combined organic extracts were
dried and concentrated in vacuo to give a 15:85 mixture of 16 and 20.
Purification via flash column chromatography (eluent 30−40 °C
petrol/Et2O, 20:1) gave 20 as a pale yellow oil (132 mg, 66%, >99:1
dr); [α]2D5 −11.3 (c 1.0 in CHCl3); νmax (film) 3496 (O−H), 3085,
3062, 3028, 2981, 2955, 2932, 2885, 2857 (C−H), 1724 (CO); δH
(400 MHz, CDCl3) 0.08 (3H, s, MeSiMe), 0.09 (3H, s, MeSiMe), 0.92
(9H, s, SiCMe3), 1.36 (3H, s, MeCMe), 1.37 (3H, s, MeCMe), 1.42
(3H, d, J 7.0, C(α)Me), 1.47 (9H, s, CMe3), 2.72 (1H, d, J 6.8, OH),
3.36 (1H, t, J 5.2, C(3)H), 3.52 (1H, dd, J 11.4, 3.5, C(6)HA), 3.77
(1H, dd, J 11.4, 4.0, C(6)HB), 4.05 (1H, d, J 15.0, NCHAHBPh), 4.05−
4.09 (1H, m, C(2)H), 4.21−4.27 (1H, m, C(5)H), 4.30 (1H, q, J 7.0,
C(α)H), 4.32−4.38 (1H, m, C(4)H) overlapping 4.35 (1H, d, J 15.0,
NCHAHBPh), 7.18−7.40 (10H, m, Ph); δC (100 MHz, CDCl3) −5.5,
−5.3 (SiMe2), 18.5 (SiCMe3), 20.1 (C(α)Me), 26.0 (SiCMe3), 26.3,
27.1 (CMe2), 27.9 (CMe3), 53.1 (NCH2Ph), 59.9 (C(α)), 60.2 (C(3)),
63.2 (C(6)), 72.3 (C(2)), 77.2 (C(4)), 79.0 (C(5)), 82.4 (CMe3),
108.2 (CMe2), 126.3, 126.9 (p-Ph), 128.1, 128.6 (o,m-Ph), 142.0,
144.0 (i-Ph), 173.1 (C(1)); m/z (ESI+) 600 ([M + H]+, 100%);
HRMS (ESI+) C34H54NO6Si+ ([M + H]+) requires 600.3715; found
600.3716.
tert-Butyl (2S,3R,4R,5S,αS)-2,4,5,6-Tetrahydroxy-3-[N-ben-
zyl-N-(α-methylbenzyl)amino]-4,5-O-isopropylidenehexa-
noate 23. TBAF (1.0 M in THF, 9.75 mL, 9.75 mmol) was added
dropwise to a stirred solution of 18 (1.17 g, 1.95 mmol) in THF (15
mL) at rt, and the resultant mixture was stirred at rt for 16 h. The
reaction mixture was diluted with Et2O (30 mL) and washed with H2O
(20 mL). The aqueous layer was extracted with Et2O (3 × 20 mL),
and the combined organic extracts were dried and concentrated in
vacuo. Purification via flash column chromatography (eluent 30−40
°C petrol/EtOAc, 5:1) gave 23 as a white solid (807 mg, 85%, >99:1
dr); mp 83−89 °C; [α]D25 +5.6 (c 1.0 in CHCl3); νmax (film) 3490
(O−H), 3085, 3062, 3029, 2980, 2935 (C−H), 1730 (CO); δH
(400 MHz, CDCl3) 1.25 (3H, s, MeCMe), 1.35 (3H, s, MeCMe), 1.42
(3H, d, J 6.8, C(α)Me), 1.51 (9H, s, CMe3), 2.66 (1H, d, J 5.3,
C(6)OH), 3.21 (1H, d, J 6.1, C(2)OH), 3.37−3.44 (1H, m, C(6)HA),
3.46−3.54 (1H, m, C(6)HB), 3.73−3.76 (1H, m, C(3)H), 3.78 (1H, d,
J 13.1, NCHAHBPh), 4.02 (1H, q, J 6.8, C(α)H), 4.12 (1H, d, J 6.1,
C(2)H), 4.16−4.22 (1H, m, C(5)H), 4.46−4.52 (1H, m, C(4)H)
overlapping 4.48 (1H, d, J 13.1, NCHAHBPh), 7.22−7.43 (10H, m,
Ph); δC (100 MHz, CDCl3) 20.4 (C(α)Me), 25.2 (MeCMe), 27.9
(CMe3), 28.0 (MeCMe), 51.2 (NCH2Ph), 57.3 (C(3)), 60.0 (C(α)),
60.9 (C(6)), 69.7 (C(2)), 73.8 (C(4)), 77.1 (C(5)), 82.0 (CMe3),
107.4 (CMe2), 126.5, 127.4 (p-Ph), 127.5, 128.0, 128.2, 128.4 (o,m-
Ph), 141.3, 141.7 (i-Ph), 172.7 (C(1)); m/z (ESI+) 486 ([M + H]+,
+
100%); HRMS (ESI+) C28H40NO6 ([M + H]+) requires 486.2850;
tert-Butyl (2R,3R,4S,5S,αS)-2,4,5,6-Tetrahydroxy-3-[N-ben-
zyl-N-(α-methylbenzyl)amino]-4,5-O-isopropylidene-6-O-tert-
butyldimethylsilylhexanoate 20. DMSO (0.47 mL, 6.67 mmol)
was added dropwise to a stirred solution of (COCl)2 (56 μL, 0.67
mmol) in CH2Cl2 (2.5 mL) at −78 °C, and the resultant mixture was
stirred for 5 min. A solution of 16 (200 mg, 0.33 mmol) in CH2Cl2
(2.5 mL) was then added via cannula, and the reaction mixture was
stirred at −78 °C for 30 min. Et3N (0.19 mL, 1.33 mmol) was added,
and stirring was continued for a further 10 min. The reaction mixture
was then allowed to warm to rt over 20 min. H2O (20 mL) was added,
and the resultant mixture was extracted with CH2Cl2 (3 × 20 mL).
The combined organic extracts were dried and concentrated in vacuo
to give 19 as a yellow oil (192 mg); δH (400 MHz, CDCl3) 0.14 (6H,
s, SiMe2), 0.97 (9H, s, SiCMe3), 1.14 (3H, s, MeCMe), 1.36 (3H, s,
MeCMe), 1.42 (3H, d, J 6.8, C(α)Me), 1.50 (9H, s, OCMe3), 3.79
(1H, dd, J 11.4, 8.2, C(6)HA), 3.94−4.04 (2H, m, C(5)H, C(6)HB)
overlapping 3.97 (1H, q, J 6.8, C(α)H), 4.19 (1H, d, J 16.5,
NCHAHBPh), 4.28 (1H, dd, J 9.0, 6.1, C(4)H), 4.46 (1H, d, J 16.5,
NCHAHBPh), 4.92 (1H, d, J 9.0, C(3)H), 7.24−7.34 (10H, m, Ph);
m/z (ESI+) 598 ([M + H]+, 100%). Crude 19 (192 mg) was dissolved
in MeOH (4 mL), and the resultant solution was cooled to −20 °C.
found 486.2839.
tert-Butyl (4R,5S,αS)-2-Keto-4,5-dihydroxy-4,5-O-isopropyli-
dene-6-[N-benzyl-N-(α-methylbenzyl)amino]hexanoate 27.
MsCl (40 μL, 0.52 mmol) was added dropwise to a stirred solution
of 23 (50 mg, 0.10 mmol), Et3N (0.14 mL, 1.0 mmol), and DMAP (5
mg, cat.) in CH2Cl2 (2 mL) at −10 °C, and the resultant mixture was
stirred at −10 °C for 6 h. H2O (1 mL) was added, and the reaction
mixture was extracted with CH2Cl2 (2 × 10 mL). The combined
organic extracts were washed sequentially with 10% aq CuSO4 (10
mL), H2O (10 mL), and satd aq NaHCO3 (10 mL). The organic layer
was then dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30−40 °C petrol/Et2O, 10:1) gave
27 as a pale yellow oil (16 mg, 34%, >99:1 dr); [α]2D5 +13.2 (c 1.0 in
CHCl3); νmax (film) 3085, 3062, 3029, 2982, 2934, 2837 (C−H), 1721
(CO); δH (400 MHz, CDCl3) 1.27 (3H, s, MeCMe), 1.37 (3H, s,
MeCMe), 1.41 (3H, d, J 6.9, C(α)Me), 1.55 (9H, s, CMe3), 1.97 (1H,
dd, J 16.1, 3.5, C(3)HA), 2.55 (1H, dd, J 13.4, 6.9, C(6)HA), 2.74 (1H,
dd, J 16.1, 10.1, C(3)HB), 2.75 (1H, dd, J 13.4, 5.5, C(6)HB), 3.56
(1H, d, J 13.7, NCHAHBPh), 3.74 (1H, d, J 13.7, NCHAHBPh), 4.03
(1H, q, J 6.9, C(α)H), 4.27 (1H, app dt, J 6.9, 5.5, C(5)H), 4.49 (1H,
9693
dx.doi.org/10.1021/jo5018298 | J. Org. Chem. 2014, 79, 9686−9698