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S. Chandrasekhar et al. / Tetrahedron 64 (2008) 5174–5183
was quenched with water (2 mL) and then concentrated under
reduced pressure. The residue was diluted with water (15 mL),
washed twice with Et2O (15 mL), and the ethereal solution was
washed with 15 mL of 10% NaHCO3. The aqueous layer was acidified
with HCl (0.1 N) until pH¼1–2 and extracted with EtOAc
(4ꢂ50 mL). The organic layer was then washed with brine (50 mL),
dried over Na2SO4, filtered, and concentrated under reduced
pressure to give (S)-N-Boc-N-methylphenylalanine III as a light
yellow viscous oil (6.4 g, quantitative). Rf 0.35 (hexanes–ethyl
acetate, 4:1, v/v).
concentrated in vacuo to give the crude amine as colorless oil
(0.38 g, 90%), which was subjected to the next reaction without
purification. Rf 0.15 (hexanes–ethyl acetate, 2:1, v/v).
1H NMR (400 MHz, CDCl3): d 7.40–7.10 (m, 7H), 6.86 (dd, J¼8.5,
14.3 Hz, 2H), 5.80–5.55 (m, 1H), 5.0–4.88 (m, 3H), 4.42 (s, 2H), 3.80
(s, 3H), 3.50–3.30 (m, 3H), 3.00–2.89 (m, 2H), 2.36 (s, 3H), 2.25–1.96
(m, 1H), 1.70–1.10 (m, 8H), 0.94 (dd, J¼14.3, 6.2 Hz, 3H); EIMS (m/z):
454.2 (MþH)þ.
To a solution of the above-obtained crude amine, carboxylic acid
fragment II (110 mg, 0.8 mmol) in CH2Cl2 (12 mL), was added HOBt
(15 mg, 0.1 mmol) followed by EDCI (477 mg, 2.5 mmol). The re-
action was stirred for 6 h at room temperature, quenched with HCl
(1 N, 15 mL), and diluted with Et2O (20 mL). The aqueous layer was
extracted with Et2O (20 mL) and the resulting solution washed with
brine (10 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel chro-
matography (10% Et2O in petroleum ether) to afford diene 2
as colorless oil (141 mg, 76%). Rf 0.65 (hexanes–ethyl acetate,
2:1, v/v).
1H NMR (400 MHz, CDCl3): (2 rotamers in a 1:1 ratio) d 9.95 (br
s, 1H), 7.33–7.16 (m, 2H), 7.21–7.00 (m, 3H), 4.85 (dd, J¼11.0, 5.0 Hz,
0.5H), 4.63 (dd, J¼11.0, 4.5 Hz, 0.5H), 3.40–3.20 (m, 1H), 3.15–2.98
(m, 1H), 2.76 (s, 1.5H), 2.69 (s, 1.5H), 1.39 (s, 4.5H), 1.33 (s, 4.5H); 13
C
NMR (100 MHz, CDCl3): d 76.3, 156.4, 137.5, 129.1, 128.7, 126.8, 80.8,
61.5, 35.3, 32.9, 28.3; [a]2D3 ꢀ67.5 (c 2.1, CHCl3); IR (neat): n 2976 (br),
1740, 1695, 1480, 1454, 1392, 1367, 1322, 1253, 1155, 1080, 961, 862,
700, and 666 cmꢀ1
.
4.1.26. (S)-((3S,5R)-9-(4-Methoxybenzyloxy)-3-methylnon-1-
en-5-yl)-2-(tert-butoxycarbonyl(methyl)amino)-3-phenyl-
propanoate (27)
1H NMR (300 MHz, CDCl3): d 7.32–7.11 (m, 7H), 6.82 (dd, J¼8.6,
3.0 Hz, 2H), 5.78–5.28 (m, 3H), 5.04–4.76 (m, 4H), 4.42 (s, 2H), 3.80
(s, 3H), 3.49–3.35 (m, 3H), 3.12–2.86 (m, 2H), 2.80 (s, 3H), 2.65–2.44
(m, 1H), 2.25–1.94 (m, 1H), 1.88–1.50 (m, 6H), 1.49–1.18 (m, 5H),
1.10–0.90 (m, 6H), 0.83 (d, J¼6.8 Hz, 1.5H), 0.65 (d, J¼6.8 Hz, 1.5H);
13C NMR (75 MHz, CDCl3): d 177.0, 170.4, 158.7, 144.6, 143.7, 137.0,
130.6, 129.3, 129.2, 128.9, 128.8, 128.3, 113.7, 112.6, 73.7, 72.4,
69.8, 65.2, 55.4, 41.0, 40.7, 36.7, 35.1, 34.2, 33.8, 33.5, 29.8, 21.8, 21.2,
20.1, 17.8; [a]2D3 ꢀ18.0 (c 2.0, CHCl3); EIMS (m/z): 600.3 (MþNa)þ;
To
a stirred solution of N-Boc-N-methyl-phenylalanine III
(524 mg, 1.88 mmol) in dry toluene (10 mL) were added 2,4,6-tri-
chlorobenzoyl chloride (500 mg, 2.0 mmol) and diisopropylethyl
amine (0.7 mL, 5.1 mmol). The mixture was stirred at room tem-
perature for 20 min, diluted with toluene (2 mL), and added
dropwise over a period of 3 min to a solution of DMAP (208 mg,
1.7 mmol) in toluene (6 mL) followed by the addition of compound
I (568 mg, 1.88 mmol) in 5 mL of toluene. After complete addition,
the mixture was stirred for an additional 1 h and concentrated in
vacuo. Purification of the residue by silica gel flash chromatography
(EtOAc–hexanes, 1:10) gave the ester 27 (831 mg, 88%). Rf 0.46
(hexanes–ethyl acetate, 4:1, v/v).
IR (neat): n 2975, 2932, 1736, 1695, 1512, 1245, 1174, and 1036 cmꢀ1
.
4.1.28. (3S,6R,8R,11R,13R)-3-Benzyl-13-(4-hydroxy-butyl)-4,6,8,11-
tetramethyl-1-oxa-4-azacyclotridecane-2,5-dione (28)
To a solution of diene 2 (14 mg, 0.002 mmol) in dry CH2Cl2
(80 mL) under nitrogen atmosphere was added Grubbs second
generationcatalyst A(4 mg, 0.02 mmol), and thesolutionwasstirred
at reflux for 12 h, a second portion of the catalyst (4 mg, 0.002 mmol)
was added, the reflux was continued for another 6 h, then filtered,
and the solvent was evaporated to yield the macrolide (E/Z >10:1).
This crude compound was subjected to hydrogenation without
further purification. Rf 0.56 (hexanes–ethyl acetate, 2:1, v/v).
1H NMR (300 MHz, CDCl3): d 7.32–7.28 (m, 5H), 7.22–7.15 (m,
2H), 6.90–6.84 (m, 2H), 5.28–5.04 (m, 2H), 5.01–4.76 (m, 1H), 4.41
(dd, J¼8.1, 10.1 Hz, 2H), 3.78 (s, 3H), 3.50–3.35 (m, 4H), 3.06–2.95
(m, 1H), 2.93–2.80 (m, 1H), 2.78 (s, 3H), 2.60–2.42 (m, 1H), 2.38–
2.30 (m,1H), 2.05–2.18 (m,1H),1.70–1.45 (m, 6H),1.42–1.31 (m,1H),
1.31–1.00 (m, 2H), 0.99–0.85 (m, 7H), 0.68 (d, J¼7.1 Hz, 2H); EIMS
(m/z): 572.3 (MþNa)þ; IR (neat): n 2960, 1737, 1638, 1513, 1247,
1H NMR (300 MHz, CDCl3): (2 rotamers) d 7.38–7.16 (m, 7H),
6.82 (dd, J¼8.6, 3.0 Hz, 2H), 5.76–5.55 (m, 1H), 5.03–4.65 (m, 3H),
4.39 (s, 2H), 3.77 (s, 3H), 3.45–3.33 (m, 2H), 3.31–3.14 (m, 1H), 3.10–
2.82 (m, 1H), 2.80–2.62 (m, 4H), 2.24–1.96 (m, 1H), 1.79–1.45 (m,
4H), 1.42–1.17 (m, 13H), 0.98 (q, J¼13.2, 6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 171.1,170.8,159.2,155.7, 155.2,144.0, 143.7, 137.7,
137.6, 130.7, 129.3, 128.2, 126.7, 126.5, 113.1, 112.8, 80.1, 79.8, 73.8,
72.6, 69.8, 60.8, 59.8, 40.6, 35.2, 35.1, 34.7, 34.6, 34.1, 33.9, 32.2, 29.7,
29.6, 21.9, 21.8, 20.3; [a]D23 þ4.6 (c 2.0, CHCl3); EIMS (m/z): 576.4
(MþNa)þ; HRMS-ESI: calcd for C33H47O6Na 576.3301, found
576.3320; IR (neat): n 2828, 2858, 1735, 1697, 1512, 1455, 1391, 1366,
1324, 1248, 1172, 1142, 1096, 750, and 699 cmꢀ1
.
4.1.27. (S)-((3S,5R)-9-(4-Methoxybenzyloxy)-3-methylnon-1-
en-5-yl)-3-phenyl-2-((2R,4S)-N-2,4-trimethylhex-5-
enamido)propanoate (2)
1100, 910, and 726 cmꢀ1
.
To a solution of the above-obtained MPM protected macrocyclic
olefin (10.5 mg, 0.02 mmol) and 5% Pd–C (10 mg) in EtOAc (3 mL)
was bubbled H2 for 12 h. The solution was then filtered over Celite
and the filter cake was washed with EtOAc (2ꢂ5 mL). Evaporation
of the solvent afforded the hydrogenated macrolactam 28 as
colorless oil (6 mg, 80%). Rf 0.24 (hexanes–ethyl acetate, 2:1, v/v).
The spectral data of this macrolactam matched in all respects
with the reported data.3,4
To a stirred solution of compound 27 (0.54 g, 1.0 mmol) and 2,6-
lutidine (0.217 g, 2.0 mmol) in dry dichloromethane (15 mL) at
room temperature was added dropwise tert-butyldimethylsilyltri-
fluoromethane sulfonate (tert-BuMe2SiOTf; 0.38 g, 1.5 mmol). The
reaction mixture was stirred for 15 min, quenched with saturated
aq NH4Cl solution, and extracted with dichloromethane (3ꢂ30 mL).
The combined organic layers were washed with water (2ꢂ20 mL),
brine (20 mL), dried over Na2SO4, filtered, and concentrated in
vacuo to give OTBS ester, which was further subjected to silyl
deprotection without purification. To a stirred solution of OTBS
ester obtained by above procedure, in dry THF (10 mL), at room
temperature was added TBAF (1 M in THF, 0.52 g, 2.0 mmol). The
reaction mixture was stirred for 1 h, quenched with 10 mL of
saturated aq NH4Cl solution, and extracted with ethyl acetate
(3ꢂ10 mL). The combined organic phase was washed with water
(2ꢂ20 mL), brine (20 mL), dried over Na2SO4, filtered, and
1H NMR (600 MHz, CDCl3): d 7.32–7.22 (m, 3H), 7.21–7.15 (m,
2H), 5.28–5.22 (m, 1H), 3.67 (t, J¼6.4 Hz, 2H), 3.58–3.48 (m, 2H),
3.32–3.25 (m,1H), 3.00–2.90 (m,1H), 2.86 (s, 3H),1.95–1.78 (m,1H),
1.66–1.18 (m, 13H), 1.16–0.99 (m, 3H), 0.94 (d, J¼7.1 Hz, 3H), 0.91–
0.78 (m, 6H); 13C NMR (300 MHz, CDCl3): 178.6, 170.2, 138.8, 129.5,
128.4, 126.5, 74.2, 65.2, 62.1, 41.3, 40.8, 37.4, 35.5, 34.3, 33,4, 32.6,
32.2, 32.4, 29.6, 28.3, 23.6, 23,4, 22.5, 21.7, 21.4, 18.8; [a]2D3 ꢀ186 (c
0.4, CHCl3); HRMS-ESI: calcd for C26H41NO4Na 454.2933, found
454.2941; IR (neat): n 3434, 3027, 2925, 2854, 1735, 1632, 1452,
1275, 1213, and 1076 cmꢀ1
.