PAPER
Formal Total Synthesis of Palmerolide A
Aldehyde 36
2891
time becomes too long (>24 h), some amount of decarbamated acid
will form; Rf = 0.48 (PE–EtOAc, 1:1); [a]D20 –35.6 (c 0.8, CH2Cl2).
To a stirred solution of alcohol 35 (32 mg, 0.038 mmol) and
NaHCO3 (10 mg, 0.119 mmol, 3 equiv) in CH2Cl2 (2 mL) at r.t. was
added DMP (33 mg, 0.078 mmol, 2 equiv) portionwise and stirring
was continued for 1 h. The reaction was quenched by the addition
of H2O (6 mL) and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (2 × 8 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated in vacuo. The resi-
due was purified by flash chromatography (PE–EtOAc, 6:1 – 3:1)
to give 30 mg (96%) of aldehyde 36 as a colorless oil; Rf = 0.68
(PE–EtOAc, 1:1); [a]D20 –46.2 (c 1.0, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 0.01, 0.03 [2 s, 3 H each,
OSi(CH3)2], 0.88 [s, 9 H, OSi(CH3)2C(CH3)3], 1.03 (d, J = 6.6 Hz,
3 H, 20-CH3), 1.08 [s, 9 H, OSi(Ph)2C(CH3)3], 1.19–1.57 (m, 8 H,
5-H, 6-H, 12-H, 13-H), 1.67 (s, 3 H, 17-CH3), 1.86 (s, 3 H, 22-CH3),
1.96–2.27 (m, 4 H, 4-H, 18-H), 2.65–2.85 (m, 1 H, 20-H), 3.97–
4.09 (m, 1 H, 7-H), 4.37–4.51 (m, 2 H, 10-H, 11-H), 4.62 (br s, 2 H,
NH2), 4.94–5.06 (m, 1 H, 19-H), 5.35–5.71 (m, 4 H, 8-H, 9-H, 14-
H, 16-H), 5.75 (d, J = 15.5, 1 H, 2-H), 6.04 (dd, J = 14.2, 11.2 Hz,
1 H, 15-H), 6.70 (d, J = 9.7 Hz, 1 H, 21-H), 6.75–6.88 (m, 1 H, 3-
H), 7.29–7.46 (m, 6 H, C6H5), 7.58–7.72 (m, 4 H, C6H5).
1H NMR (400 MHz, CDCl3): d = 0.01, 0.03 [2 s, 3 H each,
OSi(CH3)2], 0.88 [s, 9 H, OSi(CH3)2C(CH3)3], 1.06 (d, J = 4.8 Hz,
3 H, 20-CH3), 1.08 [s, 9 H, OSi(Ph)2C(CH3)3], 1.18–1.64 (m, 8 H,
5-H, 6-H, 12-H, 13-H), 1.68 (s, 3 H, 17-CH3), 1.76 (s, 3 H, 22-CH3),
1.83–2.54 (m, 4 H, 4-H, 18-H), 2.83–3.02 (m, 1 H, 20-H), 3.93–
4.11 (m, 1 H, 7-H), 4.35 (s, 1 H, NH2), 4.39–4.54 (m, 4 H, 10-H, 11-
H), 4.95–5.15 (m, 1 H, 19-H), 5.33–5.71 (m, 4 H, 8-H, 9-H, 14-H,
16-H), 5.76 (d, J = 15.7 Hz, 1 H, 2-H), 6.04 (dd, J = 14.9, 10.9 Hz,
1 H, 15-H), 6.29 (d, J = 8.8 Hz, 1 H, 21-H), 6.72–6.93 (m, 1 H, 3-
H), 7.29–7.49 (m, 6 H, C6H5), 7.56–7.75 (m, 4 H, C6H5), 9.42 (s, 1
H, 23-H).
13C NMR (100 MHz, CDCl3): d = –4.8 [OSi(CH3)2], –4.4
[OSi(CH3)2], 12.5 (C-22 CH3), 16.1 (C-20 CH3), 16.5 (C-17 CH3),
18.2 [OSi(CH3)2C(CH3)3], 19.4 [OSi(Ph)2C(CH3)3], 24.4 (C-5),
25.9 [OSi(CH3)2C(CH3)3], 27.1 [OSi(Ph)2C(CH3)3], 29.4 (C-13),
29.5 (C-12), 33.0 (C-4), 38.1 (C-20), 38.3 (C-6), 43.7 (C-18), 72.4
(C-11), 73.5 (C-19), 73.6 (C-7), 76.5 (C-10), 121.0 (C-2), 126.6 (C-
15), 127.5 (C6H5), 127.6 (C6H5), 127.9 (C-9), 128.4 (C-16), 129.7
(C6H5), 129.8 (C6H5), 131.2 (C-22), 132.5 (C-14), 133.3 (C-17),
134.1 (C6H5), 134.9 (C-8), 135.9 (C6H5), 135.9 (C6H5), 144.6 (C-
21), 149.5 (C-3), 156.5 (CONH2), 166.3 (C-1), 172.1 (C-23).
13C NMR (100 MHz, CDCl3): d = –4.8 [OSi(CH3)2], –4.4
[OSi(CH3)2], 9.7 (C-22 CH3), 15.8 (C-20 CH3), 16.5 (C-17 CH3),
18.2 [OSi(CH3)2C(CH3)3], 19.4 [OSi(Ph)2C(CH3)3], 24.4 (C-5),
25.9 [OSi(CH3)2C(CH3)3], 27.1 [OSi(Ph)2C(CH3)3], 29.4 (C-13),
29.6 (C-12), 33.1 (C-4), 38.1 (C-20), 38.3 (C-6), 43.6 (C-18), 72.5
(C-11), 73.0 (C-19), 73.6 (C-7), 76.4 (C-10), 120.8 (C-2), 126.4 (C-
15), 127.5 (C6H5), 127.6 (C6H5), 128.0 (C-9), 128.7 (C-16), 129.7
(C6H5), 129.8 (C6H5), 132.8 (C-14), 133.3 (C-17), 134.1 (C6H5),
134.9 (C-8), 135.9 (C6H5), 135.9 (C6H5), 139.7 (C-22), 149.7 (C-3),
154.1 (C-21), 156.0 (CONH2), 166.2 (C-1), 195.1 (C-23).
HRMS (ESI): m/z calcd for C49H71NO8Si2 + Na [M + Na]+:
880.46104; found: 880.45955.
Reduction of Acid 34 to Primary Alcohol 35
To a stirred solution of acid 34 (30 mg, 0.035 mmol) in THF (4 mL)
was added Et3N (5.3 mL, 0.039 mmol, 1.1 equiv). At 0 °C, methyl
chloroformate (4 mL, 0.039 mmol, 1.1 equiv) was added. After 10
min, the white solid was filtered off and the residue was concentrat-
ed to approximately 1 mL. At 0 °C, a solution of NaBH4 (5 mg, 0.13
mmol, 3–4 equiv) in MeOH (0.1 mL) was added. The mixture was
allowed to warm to r.t. and after 1 h, the reaction was quenched by
the addition of H2O (5 mL) and EtOAc (8 mL) followed by separa-
tion of the layers. The aqueous layer was extracted with EtOAc (2
× 8 mL). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated in vacuo. The residue was purified by flash
chromatography (PE–EtOAc, 3:1 → 2:1) to give 23 mg (80%) of al-
cohol 35 as a white foam; Rf = 0.57 (PE–EtOAc, 1:1); [a]D20 –46.3
(c 1.0, CH2Cl2).
HRMS (ESI): m/z calcd for C49H71NO7Si2 + Na [M + Na]+:
864.46613; found: 864.46615.
Vinyl Iodide 37
To a stirred suspension of CrCl2 (20 mg, 0.16 mmol, 8 equiv) in
THF (0.2 mL) at 0 °C was added a solution of aldehyde 36 (18 mg,
0.02 mmol) and CHI3 (40 mg, 0.10 mmol, 5 equiv) in THF (0.1 mL)
dropwise. The reaction mixture was allowed to warm to r.t. and stir-
ring was continued for 2 h. The reaction mixture was quenched by
the addition of H2O (2 mL) and diluted with EtOAc (6 mL). The lay-
ers were separated. The aqueous layer was extracted with EtOAc (2
× 6 mL) and the combined organic layers were dried (MgSO4), fil-
tered, and concentrated in vacuo. The residue was purified by flash
chromatography (PE–EtOAc, 10:1 → 7:1, + 0.05% Et3N) to give 19
mg (92%) of vinyl iodide 37 as a colorless oil; Rf = 0.65 (PE–
EtOAc, 2:1); [a]D20 –7.5 (c 1.0, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 0.01, 0.03 [2 s, 3 H each,
OSi(CH3)2], 0.88 [s, 9 H, OSi(CH3)2C(CH3)3], 0.96 (d, J = 6.6 Hz,
3 H, 20-CH3), 1.08 [s, 9 H, OSi(Ph)2C(CH3)3], 1.17–1.60 (m, 8 H,
5-H, 6-H, 12-H, 13-H), 1.67 (s, 6 H, 17-CH3, 22-CH3), 1.78–2.26
(m, 4 H, 4-H, 18-H), 2.52–2.68 (m, 1 H, 20-H), 3.97–4.06 (m, 3 H,
7-H, 23-H), 4.29–4.54 (m, 4 H, 10-H, 11-H, NH2), 4.84–4.96 (m, 1
H, 19-H), 5.24 (d, J = 9.7 Hz, 1 H, 21-H), 5.35–5.71 (m, 4 H, 8-H,
9-H, 14-H, 16-H), 5.75 (d, J = 15.5 Hz, 1 H, 2-H), 6.04 (dd,
J = 14.8, 10.9 Hz, 1 H, 15-H), 6.71–6.86 (m, 1 H, 3-H), 7.30–7.45
(m, 6 H, C6H5), 7.58–7.70 (m, 4 H, C6H5).
1H NMR (400 MHz, CDCl3): d = 0.01, 0.03 [2 s, 3 H each,
OSi(CH3)2], 0.88 [s, 9 H, OSi(CH3)2C(CH3)3], 0.97 (d, J = 4.8 Hz,
3 H, 20-CH3), 1.08 [s, 9 H, OSi(Ph)2C(CH3)3], 1.38–1.62 (m, 6 H,
5-H, 6-H, 12-H), 1.66 (s, 3 H, 17-CH3), 1.73 (s, 3 H, 22-CH3), 1.80–
2.27 (m, 6 H, 4-H, 13-H, 18-H), 2.60–2.74 (m, 1 H, 20-H), 3.98–
4.08 (m, 1 H, 7-H), 4.36 (br s, 1 H, NH2), 4.40–4.50 (m, 4 H, 10-H,
11-H), 4.84–4.97 (m, 1 H, 19-H), 5.28 (d, J = 10.6 Hz, 1 H, 21-H),
5.34–5.71 (m, 4 H, 8-H, 9-H, 14-H, 16-H), 5.74 (d, J = 15.4 Hz, 1
H, 2-H), 6.03 (dd, J = 15.2, 10.9 Hz, 1 H, 15-H), 6.21 (d, J = 14.7
Hz, 1 H, 24-H), 6.72–6.88 (m, 1 H, 3-H), 7.04 (d, J = 14.7 Hz, 1 H,
23-H), 7.29–7.45 (m, 6 H, C6H5), 7.58–7.71 (m, 4 H, C6H5).
13C NMR (100 MHz, CDCl3): d = –4.8 [OSi(CH3)2], –4.4
[OSi(CH3)2], 14.1 (C-22 CH3), 16.5 (C-20 CH3), 17.0 (C-17 CH3),
18.2 [OSi(CH3)2C(CH3)3], 19.4 [OSi(Ph)2C(CH3)3], 24.4 (C-5),
25.9 [OSi(CH3)2C(CH3)3], 27.1 [OSi(Ph)2C(CH3)3], 29.5 (C-13),
29.5 (C-12), 33.0 (C-4), 36.9 (C-20), 38.3 (C-6), 43.8 (C-18), 68.6
(C-23), 72.4 (C-11), 73.6 (C-7), 74.4 (C-19), 76.4 (C-10), 121.2 (C-
2), 126.6 (C-15), 127.3 (C-21), 127.5 (C6H5), 127.6 (C6H5), 127.9
(C-9), 128.1 (C-16), 129.7 (C6H5), 129.8 (C6H5), 131.8 (C-22),
132.2 (C-14), 133.3 (C-17), 134.1 (C6H5), 134.9 (C-8), 135.9
(C6H5), 135.9 (C6H5), 149.0 (C-3), 156.0 (CONH2), 166.5 (C-1).
13C NMR (100 MHz, CDCl3): d = –4.8 [OSi(CH3)2], –4.4
[OSi(CH3)2], 12.4 (C-22 CH3), 16.5 (C-17 CH3), 16.9 (C-20 CH3),
18.2 [OSi(CH3)2C(CH3)3], 19.4 [OSi(Ph)2C(CH3)3], 24.4 (C-5),
25.9 [OSi(CH3)2C(CH3)3], 27.1 [OSi(Ph)2C(CH3)3], 29.4 (C-13),
29.7 (C-12), 33.0 (C-4), 37.3 (C-20), 38.3 (C-6), 43.8 (C-18), 72.4
(C-10), 73.7 (C-7), 74.0 (C-19), 74.4 (C-24), 76.4 (C-11), 121.1 (C-
HRMS (ESI): m/z calcd for C49H73NO7Si2 + Na [M + Na]+:
866.48178; found: 866.48250.
Synthesis 2009, No. 17, 2881–2892 © Thieme Stuttgart · New York