Synthesis of (+)-Obtusenyne
FULL PAPER
A
7.68–7.71 (m, 4H; Ar), 7.38–7.47 (m, 6H; Ar), 7.23–7.25 (m, 2H; Ar),
(4-methoxyphenyl)-4a,6,7,8,11,11a-hexahydro-4H-1,3,5-trioxabenzocyclo-
nonene: Freshly distilled p-anisaldehyde (24 mL, 0.197 mmol), anhydrous
MgSO4 (ca. 10 mg) and PPTS (4 mg, 0.016 mmol) were added to a mix-
ture of the diols (ꢀ)-2 and (ꢀ)-27 (58 mg, 0.132 mmol) in dry benzene
(3.5 mL). The mixture was heated at reflux for 2 h. The mixture was al-
lowed to cool and was concentrated in vacuo to give the crude product.
Purification by flash chromatography (hexane/ether 4:1) furnished the
trans-PMP acetal (Z,2S,4aS,6S,7R,11aR)-7-tert-butyldiphenylsilanyloxy-6-
ethyl-2-(4-methoxyphenyl)-4a,6,7,8,11,11a-hexahydro-4H-1,3,5-trioxaben-
zocyclononene (59.4 mg, 83%) and the cis-PMP acetal (Z,2S,4aR,6S,7-
R,11aR)-7-tert-butyldiphenylsilanyloxy-6-ethyl-2-(4-methoxyphenyl)-
4a,6,7,8,11,11a-hexahydro-4H-1,3,5-trioxabenzocyclononene (4.4 mg, 6%),
both as clear and colourless oils.
7.23–7.25 (m, 2H; Ar), 5.38–5.43 (m, 1H; CH=CH), 5.00–5.05 (m, 1H;
CH=CH), 4.59 (d, J
11.0 Hz, 1H; CHHAr), 3.81 (s, 3H; OCH3), 3.71–3.77 (m, 1H), 3.62–3.68
(m, 3H), 3.51 (dt, J(H,H)=2.7, 9.0 Hz; 1H), 3.26–3.28 (m, 1H), 2.52–
A
N
AHCTREUNG
2.64 (m, ring CHH, 2H; CH2OH), 2.31–2.38 (m, 1H; ring CHH), 2.01–
2.16 (m, 2H; ring CH2), 1.92–2.01 (m, 1H; CHHCH3), 1.46–1.56 (m, 1H;
CHHCH3), 1.06 (s, 9H; C
U
G
114.0, 83.8 (CH), 76.9 (CH), 74.0 (CH), 73.7 (CH), 71.0 (CH2), 63.5, 55.3
(OCH3), 33.2 (CH2), 27.0 (SiC
N
N
10.1 ppm (CH2CH3); IR (film): n˜ =3617 cmꢀ1; MS (CI, NH3): m/z (%):
575 (10) [M+H]+, 319 (100); HRMS (CI, NH3): m/z: calcd for
C35H47O5Si: 575.319; found: 575.319; elemental analysis calcd (%) for
C35H46O5Si: C 73.13, H 8.04; found: C 73.1, H 8.3.
Data for the trans-PMP acetal: Rf =0.34 (hexane/ether 4:1); [a]2D5 =ꢀ39.1
(c=0.34 in CHCl3); 1H NMR (500 MHz, CDCl3): d=7.69–7.72 (m, 4H;
Ar), 7.41–7.50 (m, 6H; Ar), 7.35–7.37 (m, 2H; Ar), 6.86–6.88 (m, 2H;
Ar), 5.36–5.46 (brm, 1H; CH=CH), 5.40 (s, 1H; ArCHO2), 4.86–4.97
(Z,2S,3R,8R,9S)-8-tert-Butyldiphenylsilanyloxy-9-ethyl-2-methansulfonyl-
A
nesulfonyl chloride (50 mL, 0.646 mmol) was slowly added to a solution
of the alcohol (ꢀ)-32 (44 mg, 0.073 mmol), DMAP (40 mg, 0.368 mmol)
and triethylamine (0.25 mL, 1.79 mmol) in CH2Cl2 (1 mL). The reaction
mixture was stirred for 1 h at room temperature and was then quenched
by the addition of a saturated solution of aqueous NaHCO3 (10 mL). The
aqueous layer was extracted with CH2Cl2 (320 mL). The combined or-
ganic extracts were dried (MgSO4), filtered and concentrated in vacuo to
give the crude product. Purification by flash chromatography (hexane/
ether 1:1) furnished the title compound as a colourless oil (49 mg,
100%). Rf =0.31 (hexane/ether 1:1); [a]2D5 =41.1 (c=0.51 in CHCl3);
1H NMR (500 MHz, CDCl3): d=7.67 (m, 4H; Ar), 7.38–7.47 (m, 6H;
Ar), 7.26–7.28 (m, 2H; Ar), 6.87–6.88 (m, 2H; Ar), 5.37–5.45 (m, 1H;
(brm, 1H; CH=CH), 4.27 (dd, J
ACHTREUNG
(s, 3H; OCH3), 3.66–3.74 (m, 3H; 3OCH), 3.48 (td, J
AHCTREUNG
2.5 Hz, 1H; OCH), 3.30–3.37 (m, 1H; OCH), 2.69–2.88 (m, 2H; ring
CH2), 1.97–2.22 (m, 3H; ring CH2, CHHCH3), 1.32–1.43 (m, 1H;
CHHCH3), 1.06 (s, 9H; C
N
N
CH2CH3); 13C NMR (125 MHz, CDCl3): d=160.1, 136.0, 135.9, 134.2,
133.4, 130.3, 129.9, 129.7, 129.6, 127.8, 127.6, 127.4, 125.2, 113.6, 101.3,
84.8, 79.7, 74.6, 71.8 (CH2), 66.1, 55.3 (OCH3), 33.4 (CH2), 28.2, 27.0
(SiC
N
N
13C NMR (100 MHz, CDCl3): d=160.1, 136.0, 135.9, 134.2, 133.4, 130.3,
129.9, 129.7, 129.6, 127.8, 127.6, 127.4, 125.2, 113.6, 101.3, 84.8 (OCH),
79.7 (OCH), 74.6, 71.8 (CH2), 66.1 (OCH), 55.3 (OCH3), 33.4 (CH2),
CH=CH), 5.03–5.13 (m, 1H; CH=CH), 4.56 (d, J
CHHAr), 4.50 (dd, (H,H)=10.5, 2.8 Hz, 1H; CHHOMs), 4.37 (d,
(H,H)=10.5 Hz, 1H; CHHAr), 4.26 (dd, J(H,H)=10.5, 1.3 Hz, 1H;
CHHOMs), 3.81 (s, 3H; OCH3), 3.61–3.66 (m, 2H), 3.57 (dt, J(H,H)=
A
J
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28.1, 27.0 (SiC
N
N
J
A
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(CCl4): n˜ =3072 cmꢀ1; MS (CI, NH3): m/z (%): 573 (10) [M+H]+, 137
(100); HRMS (CI, NH3): m/z: calcd for C35H45O5Si: 573.3036; found:
573.3040; elemental analysis calcd (%) for C35H44O5Si: C 73.39, H 7.74;
found: C 73.2, H 7.8.
ACHTREUNG
8.6, 3.0 Hz, 1H), 3.46–3.51 (m, 1H), 3.00 (s, 3H; SO2CH3), 2.53–2.58 (m,
2H; ring CH2), 2.39–2.42 (m, 1H; ring CHH), 2.15–2.20 (m, 1H; ring
CHH), 1.95–2.00 (m, 1H; CHHCH3), 1.42–1.47 (m, 1H; CHHCH3), 1.05
Data for the cis-PMP acetal: Rf =0.26 (hexane/ether 4:1); [a]2D5 =87.0 (c=
(s, 9H; C
(CH3)3), 0.97–0.98 ppm (m, 3H; CH2CH3); 13C NMR (100 MHz,
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0.22 in CHCl3); 1H NMR (500 MHz, CDCl3): d=7.65–7.69 (m, 4H; Ar),
CDCl3): d=159.3, 135.99, 135.95, 134.1, 133.3, 129.9, 129.8, 129.75,
128.85, 127.78, 127.6, 125.6, 114.0, 84.0 (CH), 75.1 (CH), 73.3, 72.7 (CH),
7.38–7.47 (m, 8H; Ar), 6.86–6.88 (m, 2H; Ar), 5.87 (dt, J
5.8 Hz, 1H; CH=CH), 5.57 (dt, J(H,H)=10.8, 5.8 Hz, 1H; CH=CH), 5.46
(s, 1H; ArCHO2), 4.26 (d, J(H,H)=12.4 Hz, 1H; CHHO), 3.99–4.20 (m,
2H), 3.95 (dd, J(H,H)=12.4, 1.7 Hz, 1H; CHHO), 3.80 (s, 3H; OCH3),
3.43–3.44 (m, 1H; OCHCH2O), 3.21 (dd, J(H,H)=10.0, 5.2 Hz, 1H), 2.94
(q, J(H,H)=11.3 Hz, 1H; ring CH2), 2.76–2.81 (m, 1H; ring CH2), 2.24
(dt, J(H,H)=12.0, 5.8 Hz, 1H; ring CH2), 2.07 (dt, J(H,H)=12.0, 5.8 Hz,
1H; ring CH2), 1.45–1.54 (m, 1H; CHHCH3), 1.26–1.33 (m, 1H;
A
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71.1 (CH2), 68.8, 55.3 (OCH3), 37.5, 33.1, 27.0 (SiC
23.9 (CH2), 19.4 (SiC
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3095 cmꢀ1; MS (CI, NH3): m/z (%): 670, 80 [M+NH4]+, 121 (100);
HRMS (CI, NH3): m/z: calcd for C36H52NO7SSi: 670.3234; found:
670.3230; elemental analysis calcd (%) for C36H48O7SSi: C 66.23, H 7.41;
found: C 66.3, H 7.4.
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(Z,2S,3R,8R,9S)-8-tert-Butyldiphenylsilanyloxy-2-cyanomethyl-9-ethyl-3-
(4-methoxybenzyloxy)-2,3,4,7,8,9-hexahydrooxonine: The mesylate, pre-
pared above, (49 mg, 0.075 mmol) was mixed with sodium cyanide
(13 mg, 0.265 mmol) and then dry DMF (0.3 mL) was added. The mix-
ture was heated at 608C for 6 h. The solution was then diluted with water
(10 mL) and extracted with CH2Cl2 (515 mL) and ether (515 mL).
The combined organic extracts were dried (MgSO4), filtered and concen-
trated in vacuo to give the crude product. Purification by flash chroma-
tography (hexane/ether 2:1) furnished the title compound as a colourless
oil (43 mg, 99%). Rf =0.60 (hexane/ether 1:1); [a]2D5 =ꢀ27.1 (c=0.43 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=7.67–7.70 (m, 4H; Ar), 7.39–
7.47 (m, 6H; Ar), 7.22–7.25 (m, 2H; Ar), 6.87–6.90 (m, 2H; Ar), 5.33–
CHHCH3), 1.09 (s, 9H; C
C
G
(OCH3), 29.3 (CH2), 27.0 (SiC(CH3)3), 26.9 (CH2), 25.5 (CH2), 19.3 (SiC-
G
(CH3)3), 8.8 ppm (CH2CH3); IR (film): n˜ =2961 cmꢀ1; MS (CI, NH3): m/z
(%): 590 (10) [M+NH4]+, 573 [M+H]+ (100); HRMS (ES): m/z: calcd
for C35H45O5Si: 573.3036; found: 573.3033.
(Z,2S,3R,8R,9S)-8-tert-Butyldiphenylsilanyloxy-9-ethyl-2-hydroxymethyl-
3-(4-methoxybenzyloxy)-2,3,4,7,8,9-hexahydro-oxonine ((ꢀ)-32): DIBAL-
H (0.28 mL of a 1.5m solution in toluene, 0.420 mmol) was added to a so-
lution of the trans-PMP acetal described above (50 mg, 0.087 mmol) in
CH2Cl2 (1 mL) at ꢀ788C. The reaction mixture was stirred at this tem-
perature for 10 min and was then warmed to ꢀ158C and stirred for an-
other 45 min. The reaction was quenched with MeOH (1 mL) at ꢀ788C.
A saturated solution of aqueous NH4Cl (1 mL) was then added and the
reaction mixture was warmed to room temperature. Water (5 mL) was
added to the resultant suspension and the aqueous layer was extracted
with ether (515 mL). The combined organic extracts were dried
(MgSO4), filtered and concentrated in vacuo to give the crude product.
Purification by column chromatography (hexane/ether 1:1) furnished the
alcohol (ꢀ)-32 as a colourless oil (44 mg, 88%). Rf =0.31 (hexane/ether
1:1); [a]2D5 =ꢀ55.4 (c=0.34 in CHCl3); 1H NMR (500 MHz, CDCl3): d=
5.39 (m, 1H; CH=CH), 4.96–5.04 (m, 1H; CH=CH), 4.60 (d, J
10.7 Hz, 1H; CHHAr), 4.37 (d, J(H,H)=10.7 Hz, 1H; CHHAr), 3.81 (s,
3H; OCH3), 3.57–3.62 (m, 3H), 3.36–3.41 (m, 1H), 2.78 (dd, J(H,H)=
17.0, 3.2 Hz, 1H; CHHCN), 2.62–2.66 (m, 2H; ring CH2), 2.57 (dd,
(H,H)=17.0, 3.9 Hz, 1H; CHHCN), 2.33–2.36 (m, 1H; ring CHH),
2.04–2.10 (m, 2H; ring CHH, CHHCH3), 1.34–1.43 (m, 1H; CHHCH3),
1.05 ppm (m, 12H; CH2CH3, C
(CH3)3); 13C NMR (100 MHz, CDCl3): d=
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J
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159.5, 135.9, 134.1, 133.2, 129.9, 129.7, 129.2, 127.8, 127.6, 125.1, 117.9,
114.0, 108.8, 84.5 (CH), 78.4 (CH), 73.7 (CH), 71.4 (CH2), 69.7 (CH),
55.3 (OCH3), 33.3 (CH2), 27.0 (SiC
(CH3)3), 10.2 ppm (CH2CH3); IR (film): n˜ =2260 cmꢀ1; MS (CI, NH3):
m/z (%): 601 (95) [M+NH4]+, 584 (70) [M+H]+, 121 (100); HRMS (CI,
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Chem. Eur. J. 2008, 14, 2867 – 2885
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2881