Paper
Organic & Biomolecular Chemistry
a stirred solution of 29 (200 mg, 0.45 mmol) in CH2Cl2 (EtOH- m, C(6)H), 5.80–5.86 (1H, m, C(5)H), 6.85 (2H, d, J 8.7, Ar), 7.19
stabilised, 20 mL). The reaction mixture was stirred at rt for (2H, d, J 8.7, Ar); δC (100 MHz, CDCl3) 22.5 (C(α)Me), 26.4, 27.0
12 h before Na2S2O3 (excess) was added. After stirring for 1 h (CMe2), 29.9 (C(7)), 46.3 (C(8)), 55.3 (OMe), 60.9 (C(α)), 63.0
the reaction mixture was filtered and concentrated in vacuo to (C(2)), 65.1 (C(2′)), 69.7 (C(1′)), 79.1, 79.2 (C(3), C(4)), 108.6
give a 68 : 32 mixture of 32 and 33. Purification via flash (CMe2), 113.9, 128.3 (Ar), 128.7 (C(6)), 129.9 (C(5)), 137.4, 158.6
column chromatography (eluent 30–40 °C petrol–EtOAc, 5 : 1) (Ar); m/z (ESI+) 400 ([M
gave 33 as a colourless oil (48 mg, 24%, >99 : 1 dr); [α]2D5 −26.0 C21H31NNaO5+ ([M + Na]+) requires 400.2094; found 400.2082.
(c 0.52 in CHCl3); νmax (ATR) 2980, 2932 (C–H), 1731 (CvO), (2S,3S,4S,αR,Z)-N(1)-(α-Methyl-p-methoxybenzyl)-2-(hydroxy-
+
Na]+, 100%); HRMS (ESI+)
1611 (CvC); δH (400 MHz, CDCl3) 1.32 (3H, s, MeCMe), 1.42 methyl)-3,4-dihydroxy-3,4-O-isopropylidine-1,2,3,4,7,8-hexa-
(3H, s, MeCMe), 1.43–1.45 (12H, m, CMe3, C(α)Me), 2.26–2.31 hydroazocine 36. NaIO4 (9.41 g, 44.0 mmol) was added to a
(1H, m, C(6)HA), 2.64–2.71 (1H, m, C(6)HB), 3.44 (1H, dd, J 8.6, solution of 35 (1.66 g, 4.40 mmol) in MeOH–H2O (v/v 5 : 1,
1.15, C(2)H), 3.69 (1H, dd, 6.3, 1.15, C(1)H), 3.81 (3H, s, OMe), 40 mL). The resultant mixture was left to stir at rt for 4 h then
3.95 (1H, q, J 6.6, C(α)H), 3.99 (1H, d, J 6.3, C(9)H), 4.81–4.85 filtered through Celite® (eluent MeOH). NaBH4 (1.66 g,
(1H, m, C(3)H), 5.10 (1H, d, J 4.3, C(7)H), 5.59–5.65 (1H, m, 44.0 mmol) was then added to the filtrate and the reaction
C(5)H), 5.77–5.82 (1H, m, C(4)H), 6.87 (2H, d, J 8.6, Ar), 7.28 mixture was allowed to stir at rt for 12 h before satd aq. NH4Cl
(2H, d, J 8.6, Ar); δC (100 MHz, CDCl3) 21.5 (C(α)Me), 27.0, 27.1 (2 mL) was added. The resultant mixture was filtered through
(CMe2), 28.0 (CMe3), 34.8 (C(6)), 55.2 (OMe), 61.3, 61.6 (C(1), Celite® (eluent CHCl3–MeOH, 3 : 1) and concentrated in vacuo.
C(α)), 77.5, 77.8 (C(9), C(3)), 81.5 (C(2)), 82.0 (CMe3), 94.5 Purification via flash column chromatography (eluent
(C(7)), 108.1 (CMe2), 113.9 (Ar), 125.4 (C(5)), 128.8 (Ar), 129.6 30–40 °C petrol–EtOAc, 5 : 1) gave 36 as a yellow oil (877 mg,
(C(4)), 134.9, 159.0 (Ar), 168.0 (CO2 Bu); m/z (ESI+) 913 ([2M + 57%, >99 : 1 dr); [α]2D5 +38.7 (c 0.38 in CHCl3); νmax (ATR) 3469
t
Na]+, 100%), 446 ([M + H]+, 80%); HRMS (ESI+) C25H36NO6
(O–H), 2980, 2933 (C–H), 1610 (CvC); δH (400 MHz, CDCl3)
+
([M + H]+) requires 446.2573; found 446.2542. Further elution 1.29 (3H, s, MeCMe), 1.33 (3H, d, J 6.8, C(α)Me), 1.39 (3H, s,
gave 32 as a colourless oil (57 mg, 40%, >99 : 1 dr); [α]D25 −1.65 MeCMe), 2.05–2.24 (3H, m, C(7)H2, OH), 2.88–3.01 (3H, m,
(c 1.03 in CHCl3); νmax (ATR) 3493 (O–H), 2982, 2933, 2867 C(2)H, C(8)H2), 3.65 (1H, dd, J 11.1, 6.3, C(1′)HA), 3.72 (1H, dd,
(C–H), 1727 (CvO), 1611 (CvC); δH (400 MHz, CDCl3) 1.40 J 11.1, 6.6, C(1′)HB), 3.77 (3H, s, OMe), 3.84 (1H, app t, J 8.6,
(6H, s, CMe2), 1.48 (CMe3), 2.03–2.09 (1H, m, C(7′)HA), 2.29–2.40 C(3)H), 4.06 (1H, q, J 6.8, C(α)H), 4.61–4.66 (1H, m, C(4)H),
(1H, m, C(7′)HB), 2.79 (1H, ddd, J 14.4, 12.6, 4.6, C(8′)HA), 2.85 5.64–5.71 (1H, m, C(6)H), 5.84 (1H, dd, J 11.6, 3.8, C(5)H), 6.84
(1H, dd, J 9.8, 3.5, C(2′)H), 2.93–2.98 (1H, m, C(8′)HB), 3.38 (1H, (2H, d, J 8.6, Ar), 7.22 (2H, d, J 8.6, Ar); δC (100 MHz, CDCl3)
app t, J 9.8, C(3′)H), 4.19 (1H, app d, J 3.5, C(2)H), 4.49 (1H, br t, 22.4 (C(α)Me), 26.6, 27.0 (CMe2), 29.9 (C(7)), 46.0 (C(8)), 55.2
J 7.3, C(4′)H), 5.55–5.62 (1H, m, C(6′)H), 5.86–5.90 (1H, m, (OMe), 58.9 (C(α)), 61.8, 62.0 (C(2), C(1′)), 79.1 (C(4)), 82.3
C(5′)H); δC (100 MHz, CDCl3) 26.9, 27.0 (CMe2), 28.1 (CMe3), (C(3)), 108.8 (CMe2), 113.9, 127.8 (Ar), 128.5 (C(6)), 130.3 (C(5)),
28.7 (C(7′)), 46.8 (C(8′)), 59.9 (C(2′)), 72.8 (C(2)), 78.5 (C(4′)), 81.2 138.2, 158.4 (Ar); m/z (ESI+) 717 ([2M + Na]+, 100%); HRMS
(C(3′)), 81.9 (CMe3), 109.1 (CMe2), 127.4 (C(6′)), 130.4 (C(5′)), (ESI+) C20H29NNaO4 ([M + Na]+) requires 370.1989; found
+
171.7 (C(1)); m/z (ESI+) 649 ([2M + Na]+, 100%), 336 ([M + Na]+, 370.1983.
85%), 314 ([M + H]+, 90%); HRMS (ESI+) C16H27NNaO5
([M + Na]+) requires 336.1781; found 336.1787.
(S,S,S,Z)-2-(Hydroxymethyl)-3,4-dihydroxy-1,2,3,4,7,8-hexa-
hydroazocine 37. 3.0 M aq. HCl (2 mL) was added to a stirred
+
(2S,3S,4S,1′R,αR,Z)-N(1)-(α-Methyl-p-methoxybenzyl)-2- solution of 36 (656 mg, 1.89 mmol) in MeOH (6 mL). The reac-
(dihydroxyethyl)-3,4-dihydroxy-3,4-O-isopropylidine-1,2,3,4,7,8- tion mixture was heated at reflux for 2 h then concentrated
hexahydroazocine 35. LiAlH4 (1.0
M in THF, 11.4 mL, in vacuo. The residue was dissolved in H2O (2 mL) and purified
11.4 mmol) was added to a stirred solution of 29 (2.56 g, on DOWEX 1X8–200 (OH− form) ion exchange resin to give 37
5.72 mmol) in THF (100 mL) at −78 °C. The reaction mixture as a colourless oil (229 mg, 70%, >99 : 1 dr); [α]2D5 −1.23 (c 1.06
was allowed to warm to rt over 12 h before 2.0 M aq. NaOH in MeOH); νmax (ATR) 3340 (O–H), 2939 (C–H), 1648 (CvC);
(10 mL) was added. The resultant mixture was stirred for 1 h δH (500 MHz, MeOH-d4) 2.13–2.18 (1H, m, C(7)HA), 2.26–2.35
then filtered through Celite® (eluent EtOAc), dried and con- (1H, m, C(7)HB), 2.42–2.47 (1H, m, C(2)H), 2.64 (1H, ddd,
centrated in vacuo. Purification via flash column chromato- J 13.6, 12.3, 4.7, C(8)HA), 2.82 (1H, ddd, J 13.6, 6.0, 1.9, C(8)HB),
graphy (eluent 30–40 °C petrol–EtOAc, 10 : 1 increased to 2 : 1) 3.13 (1H, app t, J 9.5, C(3)H), 3.41 (1H, dd, J 10.6, 7.3, C(1′)HA),
gave 35 as a pale brown oil (1.65 g, 77%, >99 : 1 dr); [α]2D5 +53.3 3.81 (1H, dd, J 10.6, 4.7, C(1′)HB), 4.16–4.19 (1H, m, C(4)H),
(c 0.29 in CHCl3); νmax (ATR) 3425 (O–H), 2982, 2934, 2836 5.51–5.57 (1H, m, C(6)H), 5.74–5.77 (1H, m, C(5)H);
(C–H), 1610 (CvC); δH (400 MHz, CDCl3) 1.21 (3H, s, MeCMe), δC (125 MHz, MeOH-d4) 28.8 (C(7)), 46.1 (C(8)), 61.4 (C(2)), 65.5
1.37 (3H, d, J 6.8, C(α)Me), 1.31 (3H, s, MeCMe), 2.08–2.18 (1H, (C(1′)), 74.0 (C(4)), 76.2 (C(3)), 127.0 (C(6)), 136.0 (C(5)); m/z
m, C(7)HA), 2.32–2.42 (1H, m, C(7)HB), 2.71 (1H, dd, J 8.6, 3.0, (ESI+) 196 ([M + Na]+, 30%), 174 ([M + H]+, 55%); HRMS (ESI+)
C(2)H), 2.81–3.05 (2H, m, 2 × OH) overlapping 2.87–2.91 (1H, C8H15NNaO3+ ([M + Na]+) requires 196.0944; found 196.0945.
m, C(8)HA), 3.05–3.13 (1H, m, C(8)HB), 3.39 (1H, dd, J 11.6, 3.5,
(1S,2S,3S,4R,7R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-7-iodo-
C(2′)HA), 3.51 (1H, dd, J 11.6, 4.3, C(2′)HB), 3.80 (3H, s, OMe), hexahydropyrrolizidinium iodide 39·HI. I2 (74 mg, 0.29 mmol)
3.92 (1H, q, J 6.8, C(α)H), 3.94–3.98 (1H, m, C(1′)H), 4.28 (1H, was added to a stirred solution of 37 (50 mg, 0.29 mmol) in
app t, J 8.6, C(3)H), 4.68–4.72 (1H, m, C(4)H), 5.69–5.76 (1H, MeOH (5 mL). The resultant mixture was stirred at rt for 12 h
3198 | Org. Biomol. Chem., 2013, 11, 3187–3202
This journal is © The Royal Society of Chemistry 2013