SYNTHESIS
Papers
610
13C NMR (67.8 MHz, CDCl3): δ = 162.4 (s), 139.7 (d), 135.2 (d),
134.4 (d), 130.9 (d), 125.0 (d), 123.6 (s), 68.9 (d), 55.5 (t), 35.8 (t),
23.5 (q).
washed with H2O (10 mL). The dried (MgSO4) solution was concen-
trated in vacuo and the residue was then purified using flash chroma-
tography (2% MeOH in CH2Cl2) to give
a mixture of
MS (CI): m/z (%) = 287 (11, M+), 270 (37, M+ – H2O), 208 (18,
M+ – Br), 190 (8, M+ – Br, – H2O), 175 (26, aldehyde from retro al-
dol), 113 (96, oxazole from retro aldol), 95 (100, aldehyde – HBr), 67
(20).
diastereoisomers of the amide 6 (165 mg, 61%) as an orange oil.
IR (neat): ν = 3293, 1742 , 1668, 1631, 1548, 985 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.14 (m, 1 H, oxazole =CH), 6.61
(ddd, 1 H, J = 7.6, 15.6, 15.6 Hz, COCH=CH), 6.35–6.50 (m, 2 H,
CHOHCH=CHCH=C), 6.13 (dd, 1 H, J = 4.2, 19.0 Hz, SnCH=),
5.95–6.05 (m, 1 H, SnCH=CH), 5.97 (d, 1 H, J = 15.6 Hz,
COCH=CH), 5.65–5.75 (m, 2 H, NH and CHOHCH=CH), 4.80 [m, 1
H, CHOR(Pr-i)], 4.66 (dd, 1 H, J = 3.8, 8.0 Hz, COCHN), 4.10 (m, 1
H, CONCHH), 3.96 (m, 2 H, CONHCH2), 3.92 (m, 1 H, CONCHH),
3.78 (m, 1 H, CH2CHOH), 2.85–3.05 (m, 2 H, CH2CHOH), 2.64
(sext, 1 H, J = 6.6 Hz, =CHCHCH3), 2.39 [d, 3 H, J = 4.3 Hz,
C(CH3)Br], 2.25–2.30 (m, 2 H, COCHCH2), 1.98–2.08 (m, 2 H,
COCHCH2CH2), 1.80 (br s, 1 H, OH), 1.46 (app quint, 6 H, J = 2.2,
8.0 Hz, SnCH2CH2), 1.28 (app d sext, 6 H, J = 2.2, 8.0 Hz,
SnCH2CH2CH2), 1.01 (app dd,3 H, J = 1.0, 6.6 Hz, =CHCHCH3),
0.93 [app dd, 6 H, J = 2.2, 6.6 Hz, CH(CH(CH3)2)], 0.89 (t, 15 H, J
= 8.0 Hz, SnCH2CH2CH2CH3).
Anal. calcd for C8H11NO2 (153.2): C, 45.85; H, 4.9; N, 4.9; found: C,
45.5; H, 4.9; N, 4.7.
(±)-2-[(3E,5E)-6-Bromo-2-hydroxyhepta-3,5-dienyl]-4-formylox-
azole (21):
Activated MnO2 (24.6 g, 260 mmol) was added carefully, in one por-
tion, to a stirred solution of the diol 20 (2.0 g, 13 mmol) in anhyd
CH2Cl2 (150 mL) and the mixture was stirred at r.t. overnight. The
mixture was filtered through Celite and the filtrate concentrated in
vacuo. The residue was purified by flash chromatography (CH2Cl2) to
give the aldehyde 21 (1.3 g, 70%) as an orange solid; mp 30–32°C.
IR (CHCl3): ν = 3382, 1694, 1651, 1587, 968 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.89 (s, 1 H, CHO), 8.22 (s, 1 H, H-
5), 6.44 (dd, 1 H, J = 1.2, 11.1 Hz, =CHCH=CBr), 6.37 (dd, 1 H, J =
11.1, 14.3 Hz, CHOHCH=CH), 5.74 (dd, 1 H, J = 5.8, 14.3 Hz,
CHOHCH=), 4.73 (app q, 1 H, J = 5.8 Hz, CH2CHOH), 3.32 (br s, 1
H, CHOH), 3.05 (m, 2 H, CH2CHOH), 2.3 (s, 3H, CH3).
13C NMR (100 MHz CDCl3): δ = 183.4 (d), 163.5 (s), 145.2 (d), 140.4
(s), 135.8 (d), 130.8 (d), 125.5 (d), 124.0 (s), 69.0 (d), 35.6 (t), 23.6 (q).
MS (EI): m/z (%) = 204 (100, M+ – HBr), 175 (25, aldehyde from ret-
ro-aldol), 163 (20), 145 (10), 135 (10), 110 (45, oxazole from retro-
aldol), 82 (25), 65 (60), 54 (40), 43 (35).
13C NMR (100 MHz, CDCl3): δ = 172.7 (s), 171.7 (s), 165.1 (s), 161.9
(s), 161.8 (s), 160.1 (s), 143.6 (d), 143.5 (d), 143.4 (d), 143.3 (d),
136.7 (s), 136.6 (s), 134.5 (d), 134.4 (d), 131.3 (d), 131.1 (d), 130.4
(d), 130.2 (d), 125.2 (d), 125.1 (d), 124.1 (d), 124.0 (d), 123.7 (d),
123.6 (d), 81.2 (d), 81.1 (d), 69.2 (d), 69.1 (d), 61.2 (d), 61.0 (d), 47.3
(t), 47.2 (t), 45.0 (t), 44.9 (t), 37.9 (d), 37.8 (d), 31.6 (t), 30.2 (d), 30.1
(d), 29.0 (t), 27.3 (t), 25.3 (t), 23.8 (q), 23.7 (q), 21.6 (t), 19.6 (q), 19.5
(q), 17.9 (q), 17.8 (q), 14.3 (q), 14.2 (q), 13.6 (q), 9.4 (t).
HRMS: m/z found: M+ – H2O, 266.9670; C11H11BrNO2 requires
M+ – H2O, 266.9695).
14,15-Anhydro-16,37-dihydrovirginiamycin M2 (22):
A solution of Ph3As (2.25 mg, 7.35 µmol) in anhyd DMF (1 mL) was
added dropwise, over 2 min, to a stirred solution of tris(benzylidene-
acetone)dipalladium(0) (0.84 mg, 0.919 µmol) in anhyd DMF (8 mL)
at r.t., under an atmosphere of N2, in a scrupulously dried flask. The
mixture was stirred for 30 min and a solution of the vinylstannane
substituted vinylbromide 6 (81 mg, 0.092 mmol), in anhyd DMF
(1 mL), was added dropwise over 2 min. The mixture was heated at
100°C for 18 h and was then allowed to cooled to r.t. The solvent was
removed in vacuo and the residue was purified by flash chromatogra-
phy (5% MeOH in CH2Cl2) to give the macrolide 22 (16 mg, 30%) as
a pale yellow oil as a mixture of diastereoisomers. The product was
found to decompose readily at r.t. or over long periods at –20°C.
IR (CHCl3): ν = 3385, 1741, 1678, 1618, 969 cm–1.
(±)-2-[(3E,5E)-6-Bromo-2-hydroxyhepta-3,5-dienyl]oxazole-4-
carboxylic Acid (8):
A solution of 80% NaClO2 (138 mg, 1.53 mmol) and KH2PO4
(243 mg, 1.79 mmol), in H2O (1 mL), was added dropwise, over 2
min, to a stirred solution of the aldehyde 21 (292 mg, 1.02 mmol) and
2-methylbut-2-ene (0.54 mL, 5.11 mmol) in t-BuOH (10 mL) at 0°C
and the mixture was stirred overnight while allowing to warm to r.t.
The t-BuOH was removed in vacuo and the residue was partitioned
between EtOH (10 mL) and 5 M HCl (5 mL). The mixture was sepa-
rated and the aqueous layer was then extracted with EtOAc (2 × 10
mL). The extracts were combined and the dried solution (MgSO4)
was concentrated in vacuo to give the acid 8 (270 mg, 80%) as a yel-
low hydroscopic solid.
UV (EtOH) = λmax (ε) = 210 (91 000), 278 nm (84 850).
1
H NMR (500 MHz CDCl3): δ = 8.12 (0.6 H, oxazole =CH), 8.10 (0.4
IR (CHCl3): ν = 3424, 1718, 1653, 1570 cm–1.
H, oxazole =CH), 6.51 (dd, 0.6 H, J = 5.3, 16.1 Hz, COCH=CH), 6.47
(dd, 0.4 H, J = 5.3, 16.1 Hz, COCH=CH), 6.41 (ddd, 0.6 H, J = 1.9,
11.1, 15.1 Hz, CHOHCH=), 6.32 (ddd, 0.6 H, J = 1.9, 11.1, 15.1 Hz,
CHOHCH=), 6.24 (d, 1 H, J = 15.1 Hz, CH=CHCCH3), 5.98 [app t,
1 H, J = 11.1 Hz, C(CH3)=CHCH=], 5.77 (dd, 0.6 H, J = 1.9, 16.1
Hz, COCH=), 5.75 (dd, 0.4 H, J = 1.9, 16.1 Hz, COCH=), 5.66–5.75
(m, 1 H, NHCH2CH=), 5.65 (dd, 1 H, J = 7.1, 15.1 Hz,
CHOHCH=CH), 5.61 (m,1 H, NH), 4.74 [dd, 1 H, J = 1.9, 10.3 Hz,
0.6 H, CH(Pr-i)OR], 4.71 [dd, 0.4 H, J = 1.9, 10.3 Hz, CH(Pr-i)OR],
4.67 (dd, 0.6 H, J = 1.9, 8.7 Hz, COCH=), 4.63 (dd, 0.4 H, J = 1.9,
8.7 Hz, COCH=), 4.03 (app quint, 1 H, J = 7.1 Hz, CONCHH), 3.91
(m, 2 H, NHCH2CH=), 3.76 (m, 1 H, CONCHH), 3.76 (ddd, 0.6 H, J
= 1.9, 7.1, 11.1 Hz, CH2CHOH), 3.56 (ddd, 0.4 H, J = 1.9, 7.1, 11.1
Hz, 0.4 H, CH2CHOH), 3.04–3.26 (m, 2 H, CH2CHOH), 2.72 (m,1 H,
=CHCHCH3), 2.06 (m, 2 H, COCHCH2), 1.80–1.98 [m, 3 H,
COCHCH2CH2 and CHOR(CH(CH3)2)], 1.79 [s, 2 H, C(CH3)=CH)]
1.75 [s, 1 H, C(CH3)=CH], 1.08 (d, 2 H, J = 5.3 Hz, =CHCHCH3),
1.07 (d, 1 H, J = 5.3 Hz, =CHCHCH3), 0.94 [app t, 4 H, J = 7.0 Hz,
CHOR(CH(CH3)2)], 0.91 [app t, 2 H, J = 7.0 Hz, CHOR(CH(CH3)2)].
13C NMR (125 MHz CDCl3): δ = 171.5 (s), 166.6 (s), 160.5 (s), 160.2
(s), 145.4 (d), 145.3 (d), 143.2 (d), 138.8 (d), 138.5 (d), 136.8 (s),
135.5 (s), 135.2 (d), 134.9 (d), 130.3 (d), 129.9 (d), 127.5 (d), 127.0
1H NMR (400 MHz CD3OD): δ = 8.40 (s, 1 H, H-5), 6.42 (m, 2 H,
CHOHCH=CHCH=), 5.78 (dd, 1 H, J = 6.1, 14.4 Hz, CHOHCH=),
4.61 (q, 1 H, J = 6.1 Hz, CH2CHOH), 3.01 (d, 2 H, J = 6.1 Hz,
CH2CHOH), 2.55 (d,1 H, J = 1 Hz, OH), 2.33 (d, 3 H, J = 1 Hz, CH3).
13C NMR (100 MHz CD3OD): δ = 164.6 (s), 163.8 (s), 145.8 (d),
136.2 (d), 134.4 (s), 132.4 (d), 126.4 (d), 124.4 (s), 70.5 (d), 37.0 (t),
23.9 (q).
MS (EI): m/z (%) = 301 (5, M+), 282 (10, M+ – H2O), 204 (20), 177
(35), 164 (95), 127 (100), 189 (75), 96 (50), 91 (35), 80 (40).
HRMS: m/z found: M+ 300.9949; M+, C11H12BrNO4 requires
300.9950.
(4R,5R)-5-{(3E,5E)-N′-[2-(6-Bromo-2-hydroxypent-3,5-di-
enyl)oxazol-4-ylcarbonyl)-(R)-prolinoyloxy]}-[(2E)-N-(3-tribu-
tylstannylprop-2-enyl]-4,6-dimethylhept-2-enamide (6):
EDC (48 mg, 0.25 mmol) was added, in one portion, to a stirred solu-
tion of the acid 8 (56 mg, 0.18 mmol) in anhyd CH2Cl2 (5 mL), at
0°C, under an atmosphere of N2. The mixture was stirred for 30 min
and then HOBT (29 mg, 0.21 mmol) and Et3N (0.035 mL, 0.25 mmol)
were added, in one portion, followed by the addition of the amine 7
(100 mg, 0.167 mmol). The mixture was stirred overnight and then