Total Synthesis of Borrelidin
3.80 (s, 3H), 3.86 (m, 1H), 4.06 (m, 1H), 4.41 (d, 1H, J ) 11.9
Hz), 4.44 (d, 1H, J ) 11.9 Hz), 4.57 (m, 1H), 4.96 (m, 1H), 6.11
(m, 1H), 6.37 (dd, 1H, J ) 15.2, 11.2 Hz), 6.87 (d, 2H, J ) 8.6
Hz), 7.07 (d, 1H, J ) 11.2 Hz), 7.24 (d, 2H, J ) 8.6 Hz, ArH);
13C NMR (67.5 MHz, CDCl3) δ -4.7, -4.4, 14.5, 16.4, 16.5, 18.0,
19.4, 19.5, 20.4, 20.6, 25.0, 25.5, 25.8, 26.9, 27.0, 27.2, 29.6, 30.1,
30.6, 30.8, 30.9, 35.4, 36.4, 39.6, 39.9, 40.8, 40.9, 41.4, 45.1, 45.7,
55.1, 61.9, 62.0, 71.5, 72.6, 73.7, 73.9, 74.0, 75.6, 85.0, 98.6, 98.9,
113.6, 114.4, 128.0, 128.9, 130.5, 141.5, 149.3, 159.0, 171.5; HRMS
(FAB, m-NBA) [M + Na]+ calcd for C47H76O7NBrSiNa 896.4472,
found 896.4473.
temperature. The mixture was filtered through a pad of silica gel
and concentrated in vacuo. The residue was purified by flash
chromatography (10:1 to 5:1 hexanes/EtOAc) to afford 35 (6.10
mg, 13%), 36 (10.5 mg, 22%), the desired 37 (10.2 mg, 21%), and
the C11 epimer 38 (9.20 mg, 19%) each as a yellow oil.
36 : [R]24D +16.2° (c 0.91, CHCl3); IR (KBr) 3471, 2954, 2856,
2213, 1738, 1644, 1613, 1587, 1514, 1464, 1362, 1301, 1250, 1174,
1
1080, 1039, 973, 939, 836, 775, 758 cm-1; H NMR (400 MHz,
CDCl3) δ 0.10 (s, 3H), 0.16 (s, 3H), 0.67 (m, 1H), 0.76 (d, 3H,
J ) 6.6 Hz), 0.77 (d, 3H, J ) 6.9 Hz), 0.72-1.66 (m, 26H), 1.67-
2.19 (m, 6H), 2.20-2.62 (m, 4H), 3.27 (dd, 1H, J ) 9.0, 7.5 Hz),
3.35 (dd, 1H, J ) 9.0, 6.3 Hz), 3.69 (d, 1H, J ) 9.0 Hz), 3.80 (s,
3H), 4.00 (dt, 1H, J ) 8.8, 2.2 Hz), 4.39 (d, 1H, J ) 11.7 Hz),
4.45 (d, 1H, J ) 11.7 Hz), 5.15 (ddd, 1H, J ) 11.2, 7.0, 3.8 Hz),
6.53 (ddd, 1H, J ) 14.5, 11.2, 1.6 Hz), 6.60 (d, 1H, J ) 11.2 Hz),
6.87 (d, 1H, J ) 8.7 Hz), 7.26 (d, 1H, J ) 8.7 Hz); 13C NMR (100
MHz, CDCl3) δ -5.0, -3.5, 15.4, 18.0, 18.1, 19.2, 20.1, 25.0, 25.6,
25.9, 26.1, 29.0, 29.7, 30.2, 35.3, 35.5, 36.4, 37.6, 41.7, 43.2, 46.8,
48.8, 55.2, 72.8, 73.0, 74.3, 74.9, 79.7, 113.8, 114.6, 116.0, 140.9,
144.5, 159.2, 171.5; HRMS (FAB, m-NBA) [M + Na]+ calcd for
C42H67O6NSiNa 732.4635, found 732.4640.
(3S,4S,6S,8R,10S)-((S,3E,5E)-6-Bromo-6-cyano-1-{(1R,2R)-
2-[(4-methoxybenzyloxy)methyl]cyclopentyl}hexa-3,5-dienyl)
3-(tert-Butyldimethylsilyloxy)-4,6,8,10-tetramethyl-11-oxounde-
canoate (2). To a solution of 32 (195 mg, 0.223 mmol) in EtOH
(5 mL) was added PPTS (28.0 mg, 0.112 mmol), and the resulting
solution was stirred at 50 °C. After 10 h, the reaction mixture was
diluted with water, and the aqueous phase was extracted with
EtOAc. The combined organic extracts were dried over anhydrous
Na2SO4 and concentrated in vacuo. Flash chromatography (7:1
hexanes/EtOAc) afforded the corresponding alcohol59 (164 mg,
93%) as a colorless oil. [R]25 -10.2° (c 0.31, CHCl3); IR (KBr)
37: [R]24D -19.0° (c 0.54, CHCl3); IR (KBr) 3470, 2956, 2926,
D
1
3500, 2956, 2927, 1733, 1250, 1172, 1084, 1036 cm-1; H NMR
1
2853, 1737, 1513, 1463, 1249, 1079, 1036 cm-1; H NMR (270
(270 MHz, CDCl3) δ 0.03 (s, 3H), 0.07 (s, 3H), 0.80-0.91 (m,
24H), 0.94-1.41 (m, 4H), 1.45-1.81 (m, 9H), 1.88 (m, 1H), 2.06
(m, 1H), 2.31-2.60 (m, 4H), 3.24-3.47 (m, 4H), 3.80 (s, 3H),
4.06 (m, 1H), 4.37 (d, 1H, J ) 11.9 Hz), 4.41 (d, 1H, J ) 11.9
Hz), 4.93 (m, 1H), 6.10 (m, 1H), 6.36 (dd, 1H, J ) 14.8, 11.2 Hz),
6.87 (d, 2H, J ) 8.6 Hz), 7.06 (d, 1H, J ) 11.2 Hz), 7.24 (d, 2H,
J ) 8.6 Hz); 13C NMR (67.5 MHz, CDCl3) δ -4.7, -4.4, 14.4,
15.9, 18.0, 20.5, 20.6, 25.0, 25.8, 27.0, 27.2, 29.6, 30.1, 33.1, 35.4,
36.5, 39.5, 39.6, 41.0, 41.5, 45.1, 45.7, 55.1, 69.1, 71.7, 72.7, 73.9,
75.7, 85.0, 113.7, 114.4, 128.0, 129.0, 130.5, 141.5, 149.3, 159.0,
171.6; HRMS (FAB, m-NBA) [M + Na]+ calcd for C42H68O6-
NBrSiNa 812.3897, found 812.3936.
MHz, CDCl3) δ 0.10 (s, 3H), 0.11 (s, 3H), 0.79 (d, 3H, J ) 6.9
Hz), 0.81 (d, 3H, J ) 5.9 Hz), 0.86 (m, 3H), 0.89 (s, 9H), 1.03 (d,
3H, J ) 6.6 Hz), 0.76-1.41 (m, 9H), 1.52-2.20 (m, 7H), 2.26-
2.25 (m, 6H), 3.17 (dd, 1H, J ) 8.9, 7.6 Hz), 3,34 (dd, 1H, J )
8.9, 4.9 Hz), 3.80 (s, 3H), 4.04 (m, 1H), 4.08 (d, 1H, J ) 9.9 Hz),
4.38 (d, 1H, J ) 11.9 Hz), 4.43 (d, 1H, J ) 11.9 Hz), 5.02 (m,
1H), 6.17 (m, 1H), 6.30 (dd, 1H, J ) 14.8, 10.9 Hz), 6.82 (d, 1H,
J ) 10.9 Hz), 6.87 (d, 2H, J ) 8.6 Hz), 7.24 (d, 2H, J ) 8.6 Hz);
13C NMR (67.5 MHz, CDCl3) δ -5.4, -4.4, 14.9, 17.9, 18.6, 19.8,
20.7, 25.0, 25.9, 26.1, 26.2, 30.0, 30.3, 35.3, 35.6, 36.2, 36.4, 37.6,
42.7, 43.4, 43.6, 48.1, 55.3, 72.6, 72.9, 73.8, 74.0, 75.2, 77.2, 113.8,
115.5, 126.9, 128.9, 130.7, 139.7, 144.2, 159.1, 171.5; HRMS
(FAB, m-NBA) [M + Na]+ calcd for C42H67O6NSiNa 732.4635,
found 732.4639.
To a solution of the alcohol (153 mg, 0.194 mmol) in CH2Cl2
(4 mL) were added dried MS4 Å (1 g), TPAP (3.40 mg, 9.70 µmol),
and NMO (45.6 mg, 0.388 mmol) at room temperature. The
resulting solution was stirred for 30 min and filtered through a silica
pad. After evaporation of the filtrate, the residue was purified by
flash chromatography (15:1 hexanes/EtOAc) to afford 2 (120 mg,
38: [R]24D -17.6° (c 1.05, CHCl3); IR (KBr) 3454, 2955, 2926,
1
2854, 1737, 1513, 1463, 1248, 1175, 1078 cm-1; H NMR (270
MHz, CDCl3) δ 0.99 (s, 3H), 0.11 (s, 3H), 0.77 (d, 3H, J ) 6.9
Hz), 0.78 (d, 3H, J ) 5.9 Hz), 0.86 (s, 9H), 0.88 (m, 3H), 1.05 (d,
3H, J ) 6.9 Hz), 0.72-1.17 (m, 5H), 1.21-2.12 (m, 13H), 2.18-
2.40 (m, 4H), 3.27 (dd, 1H, J ) 8.9, 7.3 Hz), 3.36 (dd, 1H, J )
8.9, 5.9 Hz), 3.80 (s, 3H), 4.00 (m, 1H), 4.40 (d, 1H, J ) 11.9
Hz), 4.44 (d, 1H, J ) 11.9 Hz), 4.54 (d, 1H, J ) 3.3 Hz), 5.04 (m,
1H), 5.90 (m, 1H), 6.38 (dd, 1H, J ) 14.2, 11.5 Hz), 6.74 (d, 1H,
J ) 11.5 Hz), 6.87 (d, 2H, J ) 8.6 Hz), 7.25 (d, 2H, J ) 8.6 Hz);
13C NMR (67.5 MHz, CDCl3) δ -5.2, -4.3, 12.4, 17.9, 18.5, 19.9,
20.7, 25.0, 25.7, 25.9, 26.0, 29.4, 30.2, 35.7, 35.9, 37.0, 37.4, 37.5,
41.6, 43.8, 46.4, 48.4, 55.2, 72.0, 72.8, 73.2, 74.3, 74.7, 77.2, 112.4,
113.8, 126.7, 129.0, 130.7, 142.2, 145.8, 159.1, 171.3; HRMS
(FAB, m-NBA) [M + Na]+ calcd for C42H67O6NSiNa 732.4635,
found 732.4642.
(2S,4E,6Z,8R,9S,11R,13S,15S,16S)-16-(tert-Butyldimethylsi-
lyloxy)-8-hydroxy-2-{(1R,2R)-2-[(4-methoxybenzyloxy)methyl]-
cyclopentyl}-9,11,13,15-tetramethyl-18-oxooxacyclooctadeca-4,6-
diene-7-carbonitrile (37) (Oxidation/Reduction of 38). To a
solution of 38 (13.2 mg, 18.6 µmol) in CH2Cl2 (1 mL) was added
Dess-Martin periodinane (22.6 mg, 55.9 µmol). After stirring for
30 min, the reaction was quenched by saturated aqueous Na2S2O3
solution and saturated aqueous NaHCO3 solution, and the aqueous
phase was extracted with CH2Cl2. The combined organic extracts
were dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue (39) was subjected to the next reaction without further
purification.
79%) as a colorless oil. [R]25 -3.7° (c 0.19, CHCl3); IR (KBr)
D
1
2955, 2929, 2856, 1731, 1513, 1462, 1249, 1084 cm-1; H NMR
(270 MHz, CDCl3) δ 0.03 (s, 3H), 0.07 (s, 3H), 0.80-0.91 (m,
21H), 0.93-1.10 (m, 2H), 1.07 (d, 3H, J ) 6.9 Hz), 1.18-1.43
(m, 2H), 1.47-1.76 (m, 9H), 1.86 (m, 1H), 2.05 (m, 1H), 2.30-
2.59 (m, 4H), 3.23-3.38 (m, 2H), 3.80 (s, 3H), 4.05 (m, 1H), 4.40
(d, 1H, J ) 11.9 Hz), 4.44 (d, 1H, J ) 11.9 Hz), 4.96 (m, 1H),
6.10 (m, 1H), 6.36 (dd, 1H, J ) 15.2, 11.2 Hz), 6.87 (d, 2H, J )
8.6 Hz), 7.07 (d, 1H, J ) 11.2 Hz), 7.24 (d, 2H, J ) 8.6 Hz), 9.61
(d, 1H, J ) 1.6 Hz); 13C NMR (67.5 MHz, CDCl3) δ -4.7, -4.4,
13.0, 14.6, 18.0, 20.4, 20.5, 25.0, 25.8, 27.3, 27.4, 29.7, 30.2, 35.4,
36.3, 36.5, 39.5, 40.7, 41.5, 44.1, 45.1,45.2, 55.2, 71.5, 72.7, 74.0,
75.6, 85.1, 113.6, 114.4, 128.1, 129.0, 130.5, 141.5, 149.3, 159.0,
171.6, 205.1; HRMS (FAB, m-NBA) [M + Na]+ calcd for
C42H66O6NBrSiNa 810.3740, found 810.3770.
(2S,4E,6Z,8R,9S,11R,13S,15S,16S)-16-(tert-Butyldimethylsi-
lyloxy)-8-hydroxy-2-{(1R,2R)-2-[(4-methoxybenzyloxy)methyl]-
cyclopentyl}-9,11,13,15-tetramethyl-18-oxooxacyclooctadeca-4,6-
diene-7-carbonitrile (37) (Intramolecular Reformatsky-Type
Reaction of 2). To a solution of SmI2 (0.1 M solution in THF, 20
mL, 2.00 mmol) was added HMPA (240 µL, 1.37 mmol) at room
temperature. The resulting solution was cooled to -78 °C, and 2
(54.2 mg, 68.9 µmol) was added dropwise over 30 min. After
exposure to oxygen gas, the reaction mixture was treated with silica
gel (20.0 g) and hexane (20 mL) and stirred for 20 min at room
To a solution of the crude 39 in MeOH (1 mL) at 0 °C was
added cerium(III) chloride (14.0 mg, 37.2 µmol) followed by
sodium borohydride (1.40 mg, 37.2 µmol). The reaction was stirred
for 10 min and then poured into water. The aqueous phase was
(59) The chemical number of the alcohol in the Supporting Information
is 32a.
J. Org. Chem, Vol. 72, No. 8, 2007 2755