Notes
J . Org. Chem., Vol. 67, No. 8, 2002 2733
mixture was kept in a freezer overnight (18 h). It was then
stirred in air and allowed to warm to room temperature in 1 h.
EtOAc (150 mL), brine (50 mL) and 5% H3PO4 (50 mL) were
added. The separated organic solution was washed with 5% H3-
PO4 (100 mL), saturated aqueous sodium bicarbonate solution
(2 × 100 mL), water (100 mL), and brine (100 mL), dried with
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (10 to 20% EtOAc-CH2Cl2) afforded 12 (1.25
g, 61%). 1H NMR (300 MHz, CDCl3) δ 5.18-5.14 (m, 1 H), 4.62-
4.57 (m, 1 H), 4.41-4.34 (m, 1 H), 4.27-4.21 (m, 1H), 3.82-
3.68 (m, 6 H), 2.63 (br s, 1H), 2.23-2.05 (m, 2H), 1.83-1.62 (m,
10 H), 1.43 (s, 9 H), 1.29-1.01 (m, 11 H); 13C NMR (75.5 MHz,
CDCl3) δ 172.4, 171.3, 155.8, 85.7, 79.6, 69.6, 59.0, 57.5, 56.3,
54.1, 52.3, 43.2, 41.1, 37.0, 29.4, 28.3, 28.1, 26.2, 26.1, 25.9;
HRMS m/z (M+) Calcd for C24H42N2O7: 471.3070. Found:
471.3061.
Meth yl N-Ben zyloxyca r bon yl-L-cycloh exylglycin e-4(R)-
(1-h ydr oxy-3,3-dim eth ylpr opoxyl)-L-pr olin ecar boxylate (17).
Amino ester 16 was prepared from 9 following the procedures
described for the preparation of compound 11, except that after
the hydrogenation was complete, 1 N HCl (1.2 equiv) in dioxane
was added. The solution was then concentrated in vacuo to give
an oil. The coupling of 16 and N-Cbz-cyclohexylglycine followed
the procedure described for 12 to give product 17 as a white solid
(3.5 g, 89%, two steps) after flash chromatography (1% MeOH/
CH2Cl2). 1H NMR (500 MHz, CDCl3) δ 7.37-7.28 (m, 10 H), 5.44
(br d, J ) 9.08 Hz, 1H), 5.08 (AB q, J ) 12.2 Hz, 2 H), 4.58 (dd,
J ) 8.5, 6.3 Hz, 1 H), 4.49 (AB q, J ) 11.7 Hz, 2 H), 4.36-4.30
(m, 2H), 3.79 (dd, J ) 10.1, 5.7 Hz, 1 H), 3.73 (s, 3 H), 3.60-
3.52 (m, 3 H), 2.15-2.02 (m, 1 H), 2.07-2.02 (m, 1 H), 1.83-
1.65 (m, 7 H), 1.28-1.00 (m, 11 H); 13C NMR (125 MHz, CDCl3)
δ 172.6, 171.1, 156.5, 136.6, 128.7, 128.6, 128.3, 128.2, 127.9,
127.8, 75.7, 73.3, 69.5, 66.9, 66.8, 57.9, 57.1, 54.4, 52.5, 41.4,
41.0, 37.2, 29.7, 28.1, 26.8, 26.6, 26.4, 26.3, 26.2; HRMS m/z (M+)
Calcd for C34H46N2O7: 595.3383. Found: 595.3375.
2.28 (m, 1 H), 2.03-1.93 (m, 2 H), 1.87-1.66 (m, 7 H), 1.31-
1.02 (m, 11 H); 13C NMR (100 MHz, d6-DMSO) δ 170.6, 168.8,
157.3, 134.7, 127.7, 119.6, 114.5, 109.0, 107.5, 74.0, 67.1, 56.8,
55.4, 54.4, 51.2, 42.1, 40.4, 37.7, 36.8, 29.3, 28.0, 25.5, 25.3, 24.8,
24.1, 22.7, 22.0; HRMS m/z (M+) Calcd for C27H38N2O6: 487.2808.
Found: 487.2799.
Meth yl N-(3-Hyd r oxyp h en yl)a cetyl-L-cycloh exylglycin e-
4(R)-(1-h yd r oxy-4,4-d im eth ylbu toxyl)-L-p r olin eca r boxy-
la te (24). (i) Preparation of 5-Benzyloxy-2-methyl-1-pentene
(21): To the solution of ethyl 4-methylpent-4-enoate (20) (10.0
g, 70.3 mmol) in anhydrous tetrahydrofuran (200 mL) at 0 °C
under a nitrogen atmosphere was added cautiously a lithium
aluminum hydride solution in THF (91.0 mL, 1.0 M, 91.0 mmol).
The mixture was allowed to warm to room temperature and
stirred for 2 h. It was cooled to 0 °C, and aqueous saturated
potassium hydrogen sulfate solution was added cautiously until
no further gas evolution. Diethyl ether (400 mL), water (100 mL),
and brine (150 mL) were added, and the layers were separated.
The aqueous solution was extracted with ether (2 × 200 mL).
The organic solutions were combined, dried (MgSO4), filtered,
and concentrated in vacuo to give a clear and colorless oil. The
benzylation of this alcohol product followed the procedure
described for 7 to afford the benzyl ether 21 (8.25 g, 67% two
steps). (ii) Preparation of N-(3-Hydroxyphenyl)acetylcyclohexyl-
glycine (23): The corresponding methyl ester of 23 (4.9 g, 60%)
was prepared from 3-hydroxyphenylacetic acid (6.15 g, 40.4
mmol) and methyl cyclohexylglycine carboxylate hydrochloride
(5.6 g, 27.0 mmol) following the procedure described for 12. The
solution of this methyl ester (4.9 g, 16.2 mmol) and lithium
hydroxide (0.78 g, 32.4 mmol) in THF/MeOH/water (40 mL, 1:1:
1) was stirred at -10 °C for 4 h before it was concentrated in
vacuo to one-third of its original volume. Ethyl acetate (100 mL)
and brine (50 mL) were added, and layers were separated. The
aqueous solution was extracted with EtOAc (2 × 80 mL). The
organic solutions were combined, dried (MgSO4), filtered, and
concentrated in vacuo to give a brown solid, which was used
without further purification. 1H NMR (500 MHz, d6-DMSO) δ
12.5 (br s, 1 H), 9.27 (br s, 1 H), 8.16 (d, J ) 8.6 Hz, 1 H), 7.07-
7.03 (m, 1H), 6.68-6.58 (m, 3 H), 4.13-4.11 (m, 1 H), 3.45-
3.35 (m, 2 H), 1.72-1.55 (m, 6 H), 1.23-0.95 (m, 5 H); 13C NMR
(125 MHz, d6-DMSO) δ 172.0, 169.3, 156.1, 136.7, 128.0, 118.1,
115.0, 112.2, 85.0, 68.4, 55.8, 40.8, 28.2, 27.0, 24.7, 24.6; LRMS
m/z (M+) Calcd for C16H21NO4: 292.3. Found: 292.1. (iii)
Compound 24 was prepared as a white solid from the coupling
between 22 (2.97 g, 10.5 mmol) and 23 (3.70 g, 12.7 mmol)
following the procedure described for 12 (3.56 g, 65% two steps)
after flash chromatography (3-5% MeOH/CH2Cl2). 1H NMR (300
MHz, d6-DMSO) δ 9.25 (br s, 1 H), 8.12 (d, J ) 8.4 Hz, 1 H),
7.05-7.00 (m, 1H), 6.65-6.55 (m, 3 H), 5.16 (br s, 1 H), 4.37-
4.23 (m, 3 H), 3.71-3.44 (m, 5 H), 3.39-3.14 (m, 8 H), 2.11-
2.03 (m, 1 H), 1.91-1.82 (m, 1 H), 1.72-0.87 (m, 14 H); 13C NMR
(75.5 MHz, d6-DMSO) δ 172.2, 170.3, 169.9, 157.7, 137.7, 129.0,
119.7, 119.6, 116.1, 113.2, 68.8, 57.5, 55.2, 54.9, 54.6, 51.7, 41.8,
37.1, 28.6, 28.1, 27.9, 26.6, 25.8, 25.5; HRMS m/z (M+) Calcd for
Meth yl N-(3-Hyd r oxyp h en yl)a cetyl-L-cycloh exylglycin e-
4(R)-(1-h yd r oxy-3,3-d im eth ylp r op oxyl)-L-p r olin eca r boxy-
la te (18). To the mixture of 17 (3.5 g, 5.89 mmol) and 10%
palladium on carbon (1.1 g) in absolute ethanol (110 mL) at 0
°C was added a 4 N HCl solution in 1,4-dioxane (3.0 mL, 12
mmol). The reaction flask was opened to vacuum and refilled
three times with hydrogen gas through a balloon. After being
stirred at 0 °C for 1 h, the reaction was complete as indicated
by TLC. The solution was filtered through a Celite pad, and the
Celite pad was washed with EtOAc (3 × 50 mL). The solution
was concentrated in vacuo to give 13 as a yellow solid. This
product was coupled to 3-hydroxyphenylacetic acid following the
procedure described for 12 to give phenol alcohol 18 as an off-
white solid (1.6 g, 61% from 17) after flash chromatography (2.5-
1
5% MeOH/CH2Cl2). H NMR (500 MHz, CDCl3) δ 714-7.11 (m,
1 H), 6.72-6.63 (m, 3 H), 6.29 (br d, 1 H), 4.56-4.53 (m, 1 H),
4.50-4.46 (m, 1 H), 4.35-4.34 (m, 1 H), 3.92 (d, J ) 11.1 Hz, 1
H), 3.78-3.65 (m, 3 H), 3.68 (s, 3 H), 3.50 (AB q, J ) 15.4 Hz,
2 H), 2.23-2.19 (m, 1 H), 2.04-1.99 (m, 1 H), 1.79-1.60 (m, 7
H), 1.50-0.93 (m, 11 H); 13C NMR (125 MHz, CDCl3) δ 172.5,
171.3, 157.5, 136.1, 130.3, 121.6, 121.1, 115.4, 115.1, 78.8, 70.3,
59.6, 58.0, 55.5, 55.4, 52.5, 44.0, 43.4, 40.9, 37.7, 29.4, 28.9,
26.5, 26.4, 26.2, 26.1, 26.0, 25.7; HRMS m/z (M+) Calcd for
C27H40N2O7: 505.2914 Found: 505.2910.
C
28H43N2O7: 519.3070. Found: 519.3080.
Met h yl 8(R)-13(S)-Cycloh exyl-6,6-d im et h yl-12,15-d i-
oxo-2,7-d ioxa -11,14-d ia za t r icyclo[15.3.1.1(8,11)]d ocosa -
1(21),17,19-tr ien e-10(S)-ca r boxyla te (25). Compound 25 was
prepared from the phenol 24 (3.55 g, 6.84 mmol) following the
procedure described for 19 to give 25 as a white solid (0.35 g,
Met h yl
7(R)-12(S)-Cycloh exyl-5,5-d im et h yl-11,14-d i-
1
oxo-2,6-d ioxa -10,13-d ia za tr icyclo[14.3.1.1(7,10)]h en eicosa -
1(20),16,18-tr ien e-9(S)-ca r boxyla te (19). A solution of the
phenol alcohol 18 (1.60 g, 3.16 mmol) and 1,1′-(azodicarbonyl)-
dipiperidine (ADDP) (2.40 g, 9.51 mmol) in anhydrous CH2Cl2
(400 mL) was bubbled with argon gas through a frit glass
bubbler for 20 min. To this solution at 0 °C was added
triphenylphosphine (2.50 g, 9.53 mmol). After 20 min at 0 °C,
the solution was allowed to warm to room temperature and
stirred overnight (24 h) under a nitrogen atmosphere. TLC
indicated the complete consumption of the starting material.
After removal of solvent in vacuo, the residue was purified by
flash chromatography (1-3% MeOH/CH2Cl2) to afford the mac-
rocycle 19 (0.62 g, 40%). 1H NMR (400 MHz, d6-DMSO) δ 7.16-
7.14 (m, 1H), 6.74-6.69 (m, 3 H), 6.24 (br d, J ) 9.2 Hz, 1 H),
4.74-4.70 (m, 1 H), 4.57 (dd, J ) 10.6, 7.5 Hz, 1 H), 4.33-4.32
(m, 1 H), 4.25-4.18 (m, 1 H), 4.12-4.07 (m, 1 H), 4.00-3.97 (m,
1 H), 3.75 (s, 3 H), 3.70-3.66 (m, 2 H), 3.49-3.47 (m, 1 H), 2.32-
10%) after flash chromatography (1% MeOH/CH2Cl2). H NMR
(500 MHz, CDCl3) δ 7.17-7.14 (m, 1 H), 6.77-6.70 (m, 3 H),
6.16 (br d, J ) 8.5 Hz, 1 H), 4.61-4.57 (m, 1 H), 4.42-4.39 (m,
1 H), 4.27-4.25 (m, 1 H), 4.02-3.99 (m, 2 H), 3.77-3.75 (m, 1
H), 3.69 (s, 3 H), 3.68-3.65 (m, 1 H), 3.58 (d, J ) 14.6 Hz, 1 H),
3.47 (d, J ) 14.6 Hz, 1 H), 2.24-2.19 (m, 1 H), 1.93-1.59 (m, 10
H), 1.52-1.42 (m, 1 H), 1.29-0.96 (m, 11 H); 13C NMR (125 MHz,
CDCl3) δ 172.4, 171.1, 171.0, 158.6, 136.4, 129.8, 121.5, 116.8,
112.0, 75.7, 69.7, 68.3, 57.9, 56.0, 55.3, 52.1, 43.6, 41.3, 39.7,
37.8, 29.0, 28.8, 26.9, 26.3, 25.8, 25.7, 24.1, 23.0; HRMS m/z (M+)
Calcd for C28H41N2O6: 501.2965. Found: 501.2959.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for key compounds, and NMR conformational analysis
of 19. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O020075G