Total Synthesis of Rapamycin
FULL PAPER
J=8.3 Hz, 2H, ArH), 7.21 (d, J=8.3 Hz, 2H, ArH), 6.85 (d, J=8.4 Hz,
2H, ArH), 6.83 (d, J=8.4 Hz, 2H, ArH), 5.65 (d, J=9.5 Hz, 1H, H30),
4.80 (d, J=11.0 Hz, 1H, Ar-CH2), 4.58 (d, J=11.1 Hz, 1H, Ar-CH2),
4.42–4.34 (m, 3H, 2ꢅAr-CH2, H28), 3.85 (app dd, J=9.0, 3.7 Hz, 1H,
H34), 3.80 (s, 3H, Ar-OCH3), 3.79 (s, 3H, Ar-OCH3), 3.59 (d, J=6.5 Hz,
1H, H26), 3.53 (s, 3H, C27-OCH3), 3.43–3.37 [4H, m, including; 3.41 (s,
3H, C39-OCH3), H40], 3.34 (dd, J=7.5, 2.9 Hz, 1H, H27), 3.30 (dd, J=8.7,
5.3 Hz, 1H, H22), 3.18–3.10 (m, 2H, H22, H31), 3.00–2.87 (m, 3H, H39, di-
thiane), 2.75–2.64 (m, 2H, dithiane), 2.34 (dd, J=15.1, 9.5 Hz, 1H, H33),
2.12–2.02 (m, 3H, H38, H33, H25), 1.99–1.89 (m, 2H, H23, dithiane), 1.87–
1.81 (m, 1H, H41), 1.79–1.56 [m, 7H, including; 1.76 (s, 3H, C29-CH3), di-
thiane, H35, H42, H24), 1.45–1.24 (m, 3H, H37, H41, H36), 1.17–1.01 [m, 5H,
including; 1.09 (d, J=6.8 Hz, 3H, C31-CH3), H36, H24), 1.00–0.85 [m, 28H,
including; 0.95 (d, J=6.8 Hz, 3H, C25-CH3), H42, C35-CH3, C23-CH3, TBS,
TES], 0.74 (q, J=12.0 Hz, 1H, H38), 0.54 (q, J=7.9 Hz, 6H, TES), 0.08
(s, 3H, TBS), 0.07 ppm (s, 3H, TBS); 13C NMR (CDCl3, 150 MHz): d=
158.9 (Ar), 158.8 (Ar), 137.6 (C29), 132.0 (Ar), 131.0 (Ar), 129.0 (C30),
128.9 (Ar), 128.7 (Ar), 113.6 (Ar), 113.5 (Ar), 86.4 (C27), 84.6 (C39), 80.4
(C26), 79.7 (C28), 76.0 (C22), 75.8 (C40), 72.9 (Ar-CH2), 72.7 (Ar-CH2), 71.8
(C34), 60.6 (C27-OCH3), 57.9 (C39-OCH3), 57.2 (C32), 55.2 (Ar-OCH3), 55.2
(Ar-OCH3), 39.1 (C24), 38.9 (C36), 38.5 (C31), 38.4 (C33), 36.7 (C35), 36.0
(C38), 34.1 (C41), 33.4 (C37), 32.0 (C42), 31.2 (C25), 31.0 (C23), 26.3 (di-
thiane), 25.9 (TBS), 25.6 (dithiane), 24.9 (dithiane), 18.2 (TBS), 18.1
(C23-CH3), 15.2 (C25-CH3), 15.2 (C31-CH3), 14.8 (C35-CH3), 13.0 (C29-CH3),
6.9 (TES), 4.9 (TES), ꢀ4.5 (TBS), ꢀ4.7 ppm (TBS); IR (thin film): n˜ =
3725, 3528, 2955, 2927, 2874, 2347, 2157, 2025, 1613, 1587, 1514, 1458,
1370, 1301, 1248, 1172, 1111, 1037, 975, 876, 835, 774, 746 cmꢀ1; HMRS
(ESI): m/z: calcd for C59H102O9S2Si2Na: 1097.6396; found: 1097.6351
[M+Na]+.
86.5 mg, 377 mmol), DCC (78 mg, 377 mmol), and DMAP (4.5 mg,
37 mmol). After stirring for 24 h, saturated aqueous NH4Cl was added
and the reaction contents diluted with Et2O. The layers were separated,
the organic phase washed with saturated aqueous NaHCO3 (ꢅ2), and the
separate aqueous layers back-extracted individually with Et2O. The com-
bined organic extracts were dried over MgSO4 and concentrated in
vacuo, and the crude residue purified by flash chromatography (10–15%
EtOAc/hexanes) to afford the desired C34-ester as a colourless oil and as
a 1:1 mixture of rotamers (63.5 mg, 84%). Rf =0.58 (30% EtOAc/hex-
anes); [a]2D5 =ꢀ73.3 (c=1.00, CHCl3); 1H NMR (CDCl3, 600 MHz): d=
7.26–7.22 (m, 4H, ArH), 6.86–6.83 (m, 4H, ArH), 5.27 (brs, 0.5H, 0.5 of
H34), 5.25 (d, J=9.7 Hz, 1H, H30), 5.19 (brs, 0.5H, 0.5 of H34), 4.84 (brs,
0.5H, 0.5 of H2), 4.69 (brs, 0.5H, 0.5 of H2), 4.59 (d, J=11.0 Hz, 1H, Ar-
CH2), 4.44 (d, J=11.1 Hz, 1H, Ar-CH2), 4.41 (d, J=2.5 Hz, 2H, 2ꢅAr-
CH2), 4.15 (d, J=7.0 Hz, 1H, H28), 4.01 (brd, 0.5H, 0.5 of H6), 3.84 (brd,
0.5H, H6), 3.79 (s, 6H, 2ꢅAr-OCH3), 3.42–3.32 [m, 10H, including 3.60
(s, 6H, C27-OCH3, C39-OCH3), H31, H27, H40, H26], 3.26 (dd, J=4.0, 6.9 Hz,
1H, H22), 3.15 (brt, 1H, H22), 2.90–2.80 (m, 1.5H, H39, 0.5 of H6), 2.73–
2.61 [m, 1.5H, including; 2.69 (dd, J=16.8, 9.1 Hz, 1H, H33), 0.5 of H6],
2.44 (dd, J=16.8, 3.0 Hz, 1H, H33), 2.19 (brm, 1H, H3), 1.99–0.84 [m,
60H, including; 1.78 (brs, 3H, C29-CH3), 1.44 (s, 9H, Boc), 1.10 (brd, J=
6.1 Hz, 3H, C31-CH3), 0.96 (d, J=6.7 Hz, 3H, C25-CH3), 0.89 (s, 9H,
TBS), 0.84 (brd, J=6.6 Hz, 3H, C35-CH3), H38, H25, H35, H23, 2ꢅH42, H3,
2ꢅH24, H37, 2ꢅH41, 2ꢅH4, 2ꢅH5, 2ꢅH36)], 0.72 (m, 1H, H38), 0.49 (q, J=
8.0 Hz, 6H, TES), 0.07 (s, 3H, TBS), 0.05 ppm (s, 3H, TBS); 13C NMR
(CDCl3, 150 MHz): d=(208.4, 208.1) (C32), (171.4, 171.3) (C1), 159.2
(Ar), 159.2 (Ar), (155.9, 155.4) (C8), (139.7, 139.7) (C29), 131.7 (Ar), 131.1
(Ar), 129.3 (Ar), 129.2 (Ar), (127.2, 127.1) (C30), 113.9 (Ar), 113.8 (Ar),
84.6 (C27), 84.6 (C39), 83.0 (C26), (80.2, 80.1) (Boc), 78.2 (C28), 75.9 (C40),
75.4 (C22), (74.7, 74.5) (C34), 73.6 (Ar-CH2), 72.8 (Ar-CH2), 60.0 (C27-
OCH3), 58.2 (C39-OCH3), 55.5 (Ar-OCH3), 55.5 (Ar-OCH3), (55.1, 53.9)
(C2), 47.4 (C31), (42.2, 41.4) (C6), (41.1, 40.6) (C33), 39.3 (C24), 39.0 (C36),
(36.4, 36.3) (C38), 34.1 (C41), 33.3 (C35), 32.7 (C25), (31.7, 31.6) (C5), 31.2
(C23), 29.9 (C37), (28.6, 28.6) (Boc), 27.0 (C3), 26.1 (TBS), (25.0, 24.8)
(C4), (20.9, 20.8) (C42), 19.2 (C23-CH3), 18.4 (TBS), 17.2 (C25-CH3), 15.6
(C35-CH3), (15.3, 15.2) (C31-CH3), 13.2 (C29-CH3), 7.2 (TES), 5.2 (TES),
ꢀ4.3 (TBS), ꢀ4.5 ppm (TBS); IR (thin film): n˜ =2931, 1736, 1699, 1614,
1514, 1460, 1366, 1248, 1159, 1111 cmꢀ1; HMRS (ESI): m/z: calcd for
C67H113NO13Si2Na: 1218.7643; found: 1218.7646 [M+Na]+.
Aldehyde 12 prepared from alcohol 110: To a cooled (08C) solution of
110 (90.0 mg, 83.7 mmol) in THF/MeOH/H2O 10:9:1 (10 mL), was added
PhIACHTUNGTRENNUNG(O2CCF3)2 (178 mg, 465 mmol). The reaction was stirred for 30 min,
then quenched by the addition of saturated aqueous NaHCO3, and dilut-
ed with Et2O. The layers were separated, and the organic phase washed
with saturated aqueous Na2S2O3 and H2O. The separate aqueous layers
were back-extracted individually with ether (ꢅ2), and the combined or-
ganic extracts dried over MgSO4 and concentrated in vacuo. The crude
residue was purified by flash chromatography (10–20% EtOAc/hexanes)
to afford the desired C32-ketone as a colourless oil (69.2 mg, 84%). Rf =
0.46 (30% EtOAc/hexanes); [a]2D5 =ꢀ49.9 (c=1.00, CHCl3); 1H NMR
(CDCl3, 600 MHz): d=7.25 (d, J=7.2 Hz, 2H, ArH), 7.24 (d, J=9.0 Hz,
2H, ArH), 6.85 (t, J=8.1 Hz, 4H, ArH), 5.29 (d, J=9.6 Hz, 1H, H30),
4.59 (d, J 10.8 Hz, 1H, Ar-CH2), 4.44 (d, J=10.8 Hz, 1H, Ar-CH2), 4.41
(s, 2H, 2ꢅAr-CH2), 4.14 (d, J=6.6 Hz, 1H, H28), 3.85–3.81 (m, 1H, H34),
3.79 (s, 6H, 2ꢅAr-OCH3), 3.47–3.41 (m, 1H, H31), 3.40–3.35 (m, 8H, H26,
H40, 2ꢅ-OCH3), 3.33 (dd, J=9.0, 4.8 Hz, 1H, H22), 3.24 (dd, J=6.6,
4.2 Hz, 1H, H27), 3.16 (dd, J=9.0, 7.2 Hz, 1H, H22), 2.90–2.85 (m, 1H,
H39), 2.56 (dd, J=17.4, 1.8 Hz, 1H, H33), 2.48 (dd, J=18.0, 10.2 Hz, 1H,
H33), 2.07–2.01 (m, 1H, H38), 1.92–1.79 (m, 3H, H23, H25, H41), 1.75 (s,
3H, C29-CH3), 1.66–1.49 (m, 3H, H24, H35, H42), 1.37–1.24 (m, 3H, H36,
H37, H41), 1.14 (d, J=6.6 Hz, 3H, C31-CH3), 1.12–1.03 (m, 2H, H24, H36),
0.98–0.85 [m, 25H, including; 0.96 (d, J=7.2 Hz, 3H, C25-CH3), 0.92 (t,
J=7.2 Hz, 9H, TES), 0.89 (s, 9H, TBS), 0.87 (d, J=7.2 Hz, 3H, C23-
CH3), H42], 0.70 (q, J=12.0 Hz, 1H, H38), 0.54 (q, J=7.4 Hz, 6H, TES),
0.07 (s, 3H, TBS), 0.06 ppm (TBS); 13C NMR (CDCl3, 150 MHz): d=
213.3 (C32), 159.2 (Ar), 159.16 (Ar), 139.7 (C29), 131.8 (Ar), 131.1 (Ar),
129.4 (Ar), 129.2 (Ar), 127.1 (C30), 113.9 (Ar), 113.8 (Ar), 84.7 (C39), 83.1
(C27), 82.7 (C26 or C40), 78.0 (C28), 75.9 (C26 or C40), 75.4 (C22), 73.5 (Ar-
CH2), 72.8 (Ar-CH2), 72.0 (C34), 60.0 (C27-OCH3 or C39-OCH3), 58.1 (C27-
OCH3 or C39-OCH3), 55.5 (2ꢅAr-OCH3), 47.1 (C31), 44.0 (C33), 39.2
(C36), 36.6 (C24), 36.1 (C38), 35.6 (C35), 34.2 (C41), 33.6 (C37), 32.7 (C23 or
C25), 32.2 (C42), 31.2 (C23 or C25), 26.1 (TBS), 19.1 (C23-CH3 or C25-CH3),
18.4 (TBS), 17.1 (TES), 16.0 (C31-CH3), 15.6 (C23-CH3 or C25-CH3), 13.3
(C29-CH3), 7.1 (TES), 5.2 (TES), ꢀ4.3 (TBS), ꢀ4.5 ppm (TBS); IR (thin
film): n˜ =3508, 2930, 1707, 1611, 1514, 1460, 1248, 1110, 835 cmꢀ1; HMRS
(ESI): m/z: calcd for C56H96O10Si2Na: 1007.6434; found: 1007.6403
[M+Na]+.
To a solution of the C34-ester prepared above (62.0 mg, 52.0 mmol) in
CH2Cl2/pH 7 phosphate buffer 8:1 (4.5 mL) was added DDQ (29.4 mg,
130 mmol) as a solid. The reaction was stirred rapidly for 2 h, then diluted
with aqueous pH 7 phosphate buffer and CH2Cl2. The organic layer was
separated and the aqueous phase back-extracted with CH2Cl2 (ꢅ2). The
combined organic extracts were washed with saturated aqueous NaHCO3
(ꢅ2), dried over NaSO4 and concentrated in vacuo. Purification of the
crude residue by flash chromatography (20–30% EtOAc/hexanes) gave
the desired diol as a colourless oil and as a 1:1 mixture of rotamers
(46.0 mg, 93%). Rf =0.23 (30% EtOAc/hexanes); [a]2D5 =ꢀ93.4 (c=1.00,
CHCl3); 1H NMR (CDCl3, 600 MHz): d=5.36 (d, J=9.5 Hz, 1H, H30),
5.29 (brs, 0.5H, 0.5 of H34), 5.19 (brs, 0.5H, 0.5 of H34), 4.83 (brs, 0.5H,
0.5 of H2), 4.68 (brs, 0.5H, 0.5 of H2), 4.21 (d, J=5.5 Hz, 1H, H28), 3.99
(brm, 0.5H, 0.5 of H6), 3.87 (brm, 0.5H, 0.5 of H6), 3.53–3.45 (m, 2H,
H26, H31), 3.42–3.33 [m, 9H, including; 3.40 (s, 3H, C39-OCH3), 3.39 (s,
3H, C27-OCH3), H40, 2ꢅH22], 3.15 (brd, J=5.5 Hz, 1H, H27), 2.97–2.82
(m, 1.5H, H39, 0.5 of H6), 2.72–2.59 (m, 1.5H, including 2.68 (dd, J=8.8,
16.9 Hz, H33), 0.5 of H6], 2.51–2.44 (m, 1H, H33), 2.17 (m, 1H, H3), 1.99–
1.55 [m, 16H, including 1.75 (s, 3H, C29-CH3), H38, H25, H35, H41, H23, H24,
2ꢅH5, H3], 1.46–0.82 [m, 44H, including 1.44 (brs, 9H, Boc), 1.13 (brd,
J=6.4 Hz, 3H, C31-CH3), 0.88 (s, 9H, TBS), 0.84 (d, J=6.7 Hz, 3H, C23-
CH3), C25-CH3, C35-CH3, TES], 0.76 (m, 1H, H38), 0.57 (q, J=7.9 Hz, 6H,
TES), 0.07 (s, 3H, TBS), 0.05 ppm (s, 3H, TBS); 13C NMR (CDCl3,
150 MHz): d=(208.3, 208.0) (C32), (171.4, 171.3) (C1), (155.9, 155.4) (C8),
(138.5, 138.4) (C29), (126.9, 126.7) (C30), 84.6 (C39), 81.0 (C28), 80.2 (C27),
(80.1, 80.0) (Boc), 75.9 (C40), 74.9 (C26), 74.5 (C34), 67.6 (C22), 59.5 (C27-
OCH3), 58.3 (C39-OCH3), (55.1, 54.0) (C2), (47.1, 47.0) (C31), 42.2 (C6),
(41.4, 40.6) (C33), (39.2, 38.8) (C36), 37.5 (C24), (36.4, 36.3) (C38), 34.4
(C41), 33.8 (C23), 33.4 (C35), 33.3 (C25), (31.9, 31.7) (C5), 29.9 (C37), (28.6,
28.6) (Boc), 27.0 (C3), 26.1 (TBS), 25.1 (C4), 20.8 (C42), (18.8, 18.4)
To a cooled (ꢀ58C) solution of the C32-ketone prepared above (62.0 mg,
63.1 mmol) in CH2Cl2 (4 mL) was added N-Boc-l-pipecolinic acid (9;
Chem. Eur. J. 2009, 15, 2874 – 2914
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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