Non-Racemic Chiral Macrocycles
FULL PAPER
Compound 4v(Bn)c: Purification of the crude product by flash column
chromatography (silica gel; hexane/ethyl acetate 100:0 ! 95:5) afforded
4v(Bn)c as a colourless oil (4.90 g, 60%). Rf =0.4 (silica gel; hexane/
ethyl acetate 95:5); [a]D20 =+4.9 (c = 0.003in CH 2Cl2); IR: n˜max =1732
(C=O), 1637 cmꢀ1(C=C); 1H NMR (360 MHz, CDCl3): d=0.88 (d, J=
7 Hz, 3H; CHCH3), 1.0 (d, J=7 Hz, 3H; CHCH3), 1.36–1.58 (m, 4H;
NCH2CH2 and ArCH2CH2), 1.83–1.88 (m, 1H; CH3CHCH3), 2.33–2.42
(m, 2H; NCH2), 2.47–2.56 (m, 2H; ArCH2), 3.38 (d, J=13.5 Hz, 1H;
NCHHAr), 3.55–3.56 (m, 2H; NCHCH2OCH2), 3.66 (s, 3H; COOCH3),
3.79 (d, J=13.5 Hz, 1H; NCHHAr), 4.05–4.07 (m, 2H; OCH2C=CH2),
5.87 (dd, J=1.5, 3.3 Hz, 1H; CHH=C, trans-C(=O)O-R), 6.28 (dd, J=
1.5, 2.8 Hz, 1H; CHH=C, cis-C(=O)O-R), 6.79–6.82 (m, 2H; ArH2,6),
7.16–7.32 (m, 5H; NCH2Ar), 7.51–7.54 ppm (m, 2H; ArH3,5); 13C NMR
(90 MHz, CDCl3): d=20.9 (CH3CHCH3), 21.8 (CH3CHCH3), 28.6
(ArCH2CH2), 28.9 (CH3CHCH3), 29.2 (NHCH2CH2), 35.6 (ArCH2), 51.0
(NCH2), 52.2 (COOCH3), 56.0 (NCH2Ar), 65.2 (NCHCH), 69.6 and 69.7
(CHCH2OCH2 and CHCH2OCH2), 90.9 (CArI), 125.0 (CH2=C), 127.10
(NCH2CArH), 128.5 (NCH2CArH), 128.9 (NCH2CArH), 130.9 (CAr2,6H),
137.6 (CAr3,5H), 137.9 (CH2=C), 141.9 and 142.7 (CArCH2 and CArCH2N),
166.7 ppm (COOCH3); MS (EI): m/z (%): 549 (3) [M +], 506 (100) [M +
ꢀ(CH3)2CH], 421 (97) [M +ꢀ(CH3)2CHꢀCH2=CCOOCH3], 294 (10)
[M +ꢀ(CH3)2CHꢀCH2=CCOOCH3ꢀI]; elemental analysis calcd (%) for
C27H36INO3 (549.48): C 59.02, H 6.60, N 2.55; found: C 59.09, H 6.76, N
2.79.
phate and then concentrated in vacuo to afford the crude product. All re-
actions were performed on 1.8–20 mmol scale.
Compound 4v(Bn)p: Purification of the crude product by flash column
chromatography (silica gel; hexane/thyl acetate 9:1 ! 7:1) afforded
4v(Bn)p as a colourless oil (5.71 g, 75%). Rf =0.5 (silica gel; hexane/
ethyl acetate 7:1); [a]D20 =ꢀ45.3( c=0.01 in CH2Cl2); IR: n˜max =1739 (C=
O), 1642 cmꢀ1 (C=C); 1H NMR (360 MHz, CDCl3): d=0.84 (d, J=
7.0 Hz, 3H; CHCH3), 0.95 (d, J=7.0 Hz, 3H; CHCH3), 1.30–1.48 (m,
4H; NCH2CH2 and ArCH2CH2), 1.80–1.82 (m, 1H; CH3CHCH3), 2.33–
2.52 (m, 5H; NCH2 and ArCH2 and NCHCH), 3.43 (d, J=14 Hz, 1H;
NCHHAr), 3.80 (d, J
= 14 Hz, 1H; NCHHAr), 4.22–4.33 (m, 2H;
NCHCH2O), 5.76 (dd, J = 1.5, 10.5 Hz, 1H; CH=CHH, cis), 6.05 (dd, J
= 10.5, 17.5 Hz, 1H; CH=CH2), 6.31 (dd, J = 1.5, 17.5 Hz, 1H; CHH=
CH, trans), 6.75–6.77 (m, 2H; ArH2,6), 7.12–7.26 (m, 5H; NCH2Ar), 7.46–
7.49 ppm (m, 2H; ArH3,5); 13C NMR (90 MHz, CDCl3): d=20.7
(CH3CHCH3), 21.7 (CH3CHCH3), 28.7 (ArCH2CH2), 28.9 (CH3CHCH3),
29.1 (NCH2CH2), 35.5 (ArCH2), 50.7 (NBnCH2), 55.7 (NCH2Ar), 63.0
(CHCH2O), 64.1 (NBnCHCH), 90.9 (CArI), 127.0 (CH=CH2), 128.6
(NCH2CArH), 128.7 (NCH2CArH), 128.9 (NCH2CArH), 130.9 (CAr2,6H),
131.1 (CH2=C), 137.6 (CAr3,5H), 141.2 (CArCH2N), 142.6 (CArCH2),
166.6 ppm (OC=OCH); MS (CI): m/z (%): 506 (83) [M ++H], 464 (50)
[M +ꢀ(CH3)2CH+2H], 355 (100) [M +ꢀIꢀCH2=CH+4H]; elemental
analysis calcd (%) for C25H32INO2 (505.43): C 59.41, H 6.38, N 2.77;
found: C 59.56, H 6.25, N 2.83.
Compound 4v(Bn)a: Compound 4v(Bn) (0.90 g, 2.0 mmol) in tetrahydro-
furan (4 mL) was added at 08C to a solution of sodium hydride (60%
dispersion in mineral oil) (0.096 g, 2.2 mmol), previously washed with
hexane, in tetrahydrofuran (6 mL). The reaction mixture was heated to
reflux under nitrogen for 5 h. The flask was then allowed to cool to 08C
in an ice bath. Tetrabutylammonium iodide (0.015 g, 0.039 mmol) and
allyl bromide (0.26 mL, 3.0 mmol) were added in succession and the reac-
tion mixture was left stirring for 14 h allowing the ice to melt. The reac-
tion was then quenched with water (5 mL) and extracted with dichloro-
methane (220 mL). The combined extracts were washed with brine (2
10 mL) dried over magnesium sulphate and then concentrated in vacuo
to afford the crude product as pale oil. Purification of the crude product
by flash column chromatography (silica gel; hexane/diethyl ether 10:0 !
4:1) afforded 4v(Bn)a as a colourless oil (0.95 g, 97%). Rf =0.5 (silica
Typical procedure for the Heck coupling reactions: A flask containing a
stirrer bar and fitted with a condenser was placed under an inert atmos-
phere of nitrogen and charged with the appropriate Heck acceptor
alkene 4v(Bn)c, 4v(Bn)a, 4v(Bn)p, 1v(Bn)c, 1v(Bn)p, 1pc, 1pp or
1vMe (Bn)p (1.0 mmol), palladium(ii) acetate (0.1 mmol), sodium hydro-
2
gencarbonate (2.5 mmol) and tetra-n-butyl ammonium chloride
(1.0 mmol). Dry DMF (0.05m) was then added and the mixture was satu-
rated with nitrogen. The flask was lowered into a preheated oil bath held
at 1108C and stirred for 16 h. After cooling, the product mixture was di-
luted with diethyl ether (40 mL) and the precipitate filtered. The filtrate
was concentrated in vacuo to afford the crude products. Reactions were
performed on 0.7–12.0 mmol scale.
Compound m2-4v(Bn)c: Purification of the crude product by careful
flash column chromatography (silica gel; hexane/diethyl ether 10:0!4:1)
afforded m2-4v(Bn)c as a white feathery solid (0.464 g, 40%). Rf =0.32
(silica gel; hexane/diethyl ether 1:1); m.p. 96–988C; [a]2D0 =ꢀ21.7 (c=
0.011 in CH2Cl2); IR: n˜max =1708 (C=O), 1644 cmꢀ1 (C=C); 1H NMR
(360 MHz, CDCl3): d=0.79 (d, J=6.5 Hz, 3H; CHCH3), 0.92 (d, J=
6.5 Hz, 3H; CHCH3), 1.30–1.43 (m, 4H; NCH2CH2 and ArCH2CH2),
1.77–1.80 (m, 1H; CH3CHCH3), 2.29–2.45 (m, 4H; NCH2CH2 and
ArCH2CH2), 2.56–2.60 (m, 1H; NCHCH), 3.39–3.52 (m, 2H;
CHCH2OCH2), 3.44 (d, J=14.0 Hz, 1H; NCHHAr), 3.60 (s, 3H; OCH3),
3.78 (d, J=14.0 Hz, 1H; NCHHAr), 4.02 (dd, J=6.5, 10.5 Hz, 1H;
CHCHHOCH2), 4.19 (dd, J=2.0, 10.5 Hz, 1H; CHCHHOCH2), 6.83–
6.85 (m, 2H; ArH2,6), 7.04–7.06 (m, 2H; ArH3,5), 7.11–7.27 (m, 5H;
NCH2Ar), 7.39 ppm (s, 1H; ArCH=C); 13C NMR (90 MHz, CDCl3): d=
20.7 (CH3CHCH3), 21.7 (CH3CHCH3), 28.4 (CH3CHCH3), 29.74, 29.78
and 29.95 (NCH2CH2, ArCH2CH2 and CHCH2OCH2), 35.9 (ArCH2CH2),
51.5 (NCH2CH2), 51.6 (COOCH3), 55.6 (NCH2Ar), 64.7 (NCH), 73.4
(NCHCH2), 110.6 (C=CHCAr), 127.1, 128.4, 128.5, 128.7, 129.0
(CH2CH2CAr3,5, CH2CH2CAr2,6H and NCH2Ar), 138.0 (ArCH2=C), 140.5
and 141.1 (NCH2CAr and CArCH2CH2), 158.7 (ArCH=C), 169.1 ppm (C=
O); MS (FAB, positive): m/z (%): 844 (100) [M ++H], 800 (32) [M +
ꢀ(CH3)2CH]; elemental analysis calcd (%) for C54H70N2O6 (843.14): C
76.92, H 8.37, N 3.32; found: C 76.93, H 8.40, N 3.40.
gel; hexane/diethyl ether 4:1); [a]2D0 =ꢀ48.8 (c=0.06 in CH2Cl2); IR:
ꢀ1
n˜max =1646 cm
(C=C); 1H NMR (360 MHz, CDCl3): d=0.81 (d, J=
7.0 Hz, 3H; CHCH3), 0.92 (d, J=7.0 Hz, 3H; CHCH3), 1.29–1.38 (m,
4H; NCH2CH2 and ArCH2CH2), 1.73–1.76 (m, 1H; CH3CHCH3), 2.26–
2.47 (m, 5H; NCH2, ArCH2 and NCHCH), 3.41 (d, J=14 Hz, 1H;
NCHHAr), 3.49 (d, J=4.5 Hz, 2H; OCH2CH=CH2), 3.79 (d, J=14 Hz,
1H; NCHHAr), 3.84–3.87 (m, 2H; NCHCH2OCH2), 5.08 (ddd, J=1.5,
4.5, 12.0 Hz, 1H; CH=CHH, cis), 5.84 (dd, J=1.5, 17.0 Hz, 1H; CH=
CHH, trans), 5.80–5.87 (m, 1H; CH=CH2), 6.73–6.75 (m, 2H; ArH2,6),
7.11–7.25 (m, 5H; NCH2Ar), 7.44–7.46 ppm (m, 2H; ArH3,5); 13C NMR
(90 MHz, CDCl3): d=19.4 (CH3CHCH3), 20.3(CH 3CHCH3), 27.1
(ArCH2CH2), 27.6 (CH3CHCH3), 27.8 (NHCH2CH2), 34.2 (ArCH2), 49.7
(NCH2), 54.5 (NCH2Ar), 63.8 (NCHCH), 67.6 (NCHCH2O), 70.9
(CHCH2O), 89.4 (CArI), 115.3(CH =CH2), 125.3(NCH 2CArH), 127.0
(NCH2CArH), 127.8 (NCH2CArH), 129.4 (CAr2,6H), 134.1 (CH2=CH), 136.1
(CAr3,5H), 140.6 (CArCH2N), 141.3ppm ( CArCH2); MS (CI): m/z (%): 492
(100) [M ++H], 448 (7) [M +ꢀ(CH3)2CH]; elemental analysis calcd (%)
for C25H34INO (491.45): C 61.10, H 6.97, N 2.85; found: C 61.25, H 6.96,
N 2.84.
General procedure for the formation of propenoyl alkenes 4v(Bn)p,
1v(Bn)p, 1pp and 1vMe (Bn)p: Aminoalcohol 4v(Bn), 1v(Bn), 1p or
2
Compounds m2-4v(Bn)p and m3-4v(Bn)p: Purification of the crude prod-
ucts by careful flash column chromatography (silica gel; hexane/diethyl
ether 10:1 ! 3:1) afforded m2-4v(Bn)p as a fluffy white solid (0.475 g,
25%) and m3-4v(Bn)p as a bright yellow fluffy solid (0.284 g, 15%).
Data for m2-4v(Bn)p: Rf =0.45 (silica gel; hexane/diethyl ether 3:1); m.p.
88–908C; [a]2D0 =ꢀ43.5 (c=0.08 in CH2Cl2); IR: n˜max =1709 (C=O),
1635 cmꢀ1 (C=C); 1H NMR (360 MHz, CDCl3): d=0.87 (d, J=6.5 Hz,
3H; CHCH3), 0.97 (d, J=6.5 Hz, 3H; CHCH3), 1.28–1.38 (m, 1H;
NCH2CHH), 1.39–1.52 (m, 3H; ArCH2CH2 and NCH2CHH), 1.89–1.95
1vMe (Bn) (1.0 mmol) was dissolved in dry dichloromethane (4 mL) and
2
cooled to 08C under an inert atmosphere of nitrogen. Triethylamine
(1.1 mmol) was slowly added followed by hydroquinone (0.01 mmol).
Keeping the reaction mixture at 08C, acryloyl chloride (1.1 mmol) was
added drop-wise over 15 minutes. The reaction was left stirring at the
same temperature for 2 h and was then poured into a separating funnel
containing 1.50 mL of cold water. The aqueous phase was extracted with
dichloromethane (28 mL) and the combined extracts, to which more
hydroquinone (0.01 mmol) was added, were dried over magnesium sul-
Chem. Eur. J. 2005, 11, 69 – 80
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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