The Journal of Organic Chemistry
Article
171.8, 171.4, 170.9, 155.8, 137.9, 137.6, 135.9, 128.9, 128.5, 128.4,
127.8, 127.7, 116.0, 80.2, 79.9, 75.0, 74.7, 73.2, 71.7, 60.8, 59.8, 50.9,
36.2, 36.1, 35.9, 35.1, 34.9, 33.4, 33.2, 32.1, 28.3, 28.2, 25.0, 21.3, 18.5,
13.9. IR: ν 3304, 2960, 2933, 2870, 2361, 2336, 1732, 1652, 1454,
1365, 1141 cm−1. HRMS (ESI) calcd for [C34H48N2O6 + Na+]
603.3405, found 603.3394.
0.64 (m, 6H). HRMS (ESI) calcd for [C33H44N2O5 + H+] 549.3323,
found 549.3316.
A solution of the above material (30 mg, 0.055 mmol) in 6 mL
MeOH was hydrogenated over Pd−C (15 mg, 0.014 mmol) at 3 bar
for 21 h. Additional Pd−C (7.8 mg, 0.007 mmol) was added and
hydrogenation was continued for 40 h. The suspension was filtered,
the filtrate was evaporated, and the residue was purified by FC (DCM/
acetone 7:3 + 3% MeOH) on silica gel 60 (20−45 μm) to yield 4 mg
(16%) of 1-SR as an amorphous white solid and 18 mg (72%) of a 2:1
mixture of 1-SR and 14S-1-SR. 1-SR: [α]D24 = +49.9° (c 0.16, CHCl3).
1H NMR (500 MHz, CDCl3): δ 7.24−7.10 (m, 5H), 6.00 (d, J = 6.8
Hz, 1H), 5.66 (dd, J = 11.7, 5.7 Hz, 1H), 4.95−4.89 (m, 1H), 3.72−
3.55 (m, 3H), 3.55−3.46 (m, 1H), 3.29 (dd, J = 15.1, 5.6 Hz, 1H),
2.95 (dd, J= 15.3, 11.7 Hz, 1H), 2.94 (s, 3H), 2.73−2.63 (m, 1H), 2.33
(td, J = 12.7, 3.8 Hz, 1H), 2.09−1.99 (m, 1H), 1.77−1.11 (m, 14H),
0.85−0.78 (m, 6H). 13C NMR (125 MHz, CDCl3): 177.7, 174.8,
173.5, 136.1, 128.6, 128.3, 126.9, 73.7, 66.8, 55.7, 52.4, 36.8, 36.4, 35.1,
34.7, 34.2, 32.8, 31.0, 29.6, 23.1, 22.8, 18.8, 18.1, 13.8. (Single isomer).
IR: ν 3308, 2929, 1730, 1649, 1541, 1458, 670 cm−1. HRMS (ESI)
calcd for [C26H40N2O5 + H+] 461.3010, found 461.3015.
(S)-(R)-8-(((R)-1-(Benzyloxy)but-3-en-2-yl)amino)-8-oxooc-
tan-4-yl-2-(methylamino)-3-phenyl-propanoate. To a solution
of (S)-(R)-8-(((R)-1-(benzyloxy)but-3-en-2-yl)amino)-8-oxooctan-4-
yl 2-((tert-butoxycarbonyl)-(methyl)-amino)-3-phenyl-propanoate
(735 mg, 1.23 mmol) in 40 mL DCM were added TIPS (290 μL,
1.42 mmol) and 10 mL TFA and the mixture was stirred at rt for 30
min. After cooling to 0 °C it was poured into 150 mL sat. NaHCO3,
150 mL DCM were added and the phases were separated. The aq.
phase was extracted twice with 150 mL DCM, the combined organic
phases were dried over MgSO4, and the solvent was evaporated. FC
(hexane/EtOAc 1:1 + 2% Et3N) gave 602 mg (99%) of (S)-(R)-8-
(((R)-1-(benzyloxy)but-3-en-2-yl)amino)-8-oxooctan-4-yl-2-(methyla-
24
mino)-3-phenyl-propanoate as clear viscous oil. [α]D = +23.4° (c
1
0.48, CHCl3). H NMR (400 MHz, CDCl3): δ 7.39−7.18 (m, 10H),
5.92−5.80 (m, 2H), 5.32−5.14 (m, 3H), 4.93−4.83 (m, 1H), 4.71−
4.63 (m, 1H), 4.55 (d, J = 12.1 Hz, 1H), 4.51 (d, J = 12.1 Hz, 1H),
3.55 (d, J = 4.2 Hz, 2H), 3.42 (t, J = 7.1 Hz, 1H), 2.92 (d, J = 7.0 Hz,
2H), 2.36 (s, 3H), 2.23−2.10 (m, 2H), 1.71−1.29 (m, 6H), 1.18−1.02
(m, 2H), 0.82 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
174.4, 171.89, 171.84, 137.8, 137.3, 135.91, 129.3, 129.2, 128.5, 128.4,
127.9, 127.7, 126.7, 116.0, 74.2, 73.3, 71.8, 64.9, 64.8, 50.9, 39.6, 39.5,
36.2, 35.9, 34.7, 33.3, 33.2, 21.4, 21.0, 18.6, 18.3, 13.94, 13.91. IR: ν
3312, 2935, 2870, 2358, 1725, 1642, 1540, 1455, 1362, 1254, 1179,
1114 cm−1. HRMS (ESI) calcd for [C29H40N2O4+Na+] 503.2880,
found 503.2874.
(R)-2-Methylpent-4-enoic acid (ent-6). To a solution of (S)-4-
benzyl-3-((R)-2-methylpent-4-enoyl)-oxazolidin-2-one (6.24 g, 22.8
mmol) in 60 mL THF/water 4:1 was added LiOH (2.18 g, 91.2
mmol) and 50% H2O2 (2.90 mL, 50.2 mmol) and the mixture was
stirred at rt overnight. The pH was then adjusted to 1−2 with 90 mL 1
M HCl and the mixture was extracted thrice with 300 mL Et2O. The
combined organic extracts were dried over MgSO4 and the solvent was
removed. The product was distilled under reduced pressure to yield
20
ent-6 (1.91 g, 73%) as a colorless liquid. [α]D = −10.3° (c 1.92,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 11.17 (s br, 1H), 5.77−5.63
(m, 1H), 5.07−4.94 (m, 2H), 2.56−2.43 (m, 1H), 2.43−2.31 (m, 1H),
2.20−2.09 (m, 1H), 1.12 (d, J = 7.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 182.6, 135.1, 117.2, 39.1, 37.4, 16.3. IR: ν 2979, 2666, 1703,
1643, 1417, 1244, 916 cm−1. HRMS (ESI) calcd for [C6H9O2 − H+]
113.0608, found 113.0608.
(S)-(R)-8-(((R)-1-(Benzyloxy)but-3-en-2-yl)amino)-8-oxooc-
tan-4-yl-2-((S)-N,2-dimethylpent-4-enamido)-3-phenylpropa-
noate. To a solution of 6 (72 mg, 0.63 mmol) and HATU (239 mg,
0.63 mmol) in 3.7 mL dry DMF was added DIEA (0.2 mL, 1.15
mmol) and the mixture was stirred for 5 min at rt. Then (S)-(R)-8-
(((R)-1-(benzyloxy)but-3-en-2-yl)amino)-8-oxooctan-4-yl-2-(methyla-
mino)-3-phenyl-propanoate (196 mg, 0.41 mmol) was added and the
resulting solution was stirred at rt for 4 h. After removal of DMF 7.5
mL DCM and 7.5 mL 10% MeCN in water were added and the phases
were separated. The aq. phase was extracted twice with 7.5 mL DCM,
the combined organic extracts were dried over MgSO4, and the solvent
was evaporated. FC (hexane/EtOAc 1:1 + 2% Et3N) yielded 180 mg
(77%) of (S)-(R)-8-(((R)-1-(benzyloxy)but-3-en-2-yl)amino)-8-ox-
ooctan-4-yl 2-((S)-N,2-dimethylpent-4-enamido)-3-phenylpropanoate
(S)-(S)-8-(((R)-1-(Benzyloxy)But-3-en-2-yl)amino)-8-oxooc-
tan-4-yl-2-((R)-N,2-dimethylpent-4-enamido)-3-phenylpropa-
noate. To a solution of ent-6 (191 mg, 1.67 mmol) and HATU (635
mg, 1.67 mmol) in 10 mL dry DMF was added DIEA (0.6 mL, 3.34
mmol) and the mixture stirred for 5 min at rt. Then 13 (535 mg, 1.11
mmol) was added and the resulting solution was stirred at rt for 5 h.
After removal of DMF 20 mL DCM and 20 mL 10% MeCN in water
were added. The phases were separated and the aq. solution was
extracted twice with 20 mL DCM. The combined organic extracts
were dried over MgSO4 and the solvent was evaporated. FC (hexane/
EtOAc 1:1 + 2% Et3N) gave 630 mg (98%) of (S)-(S)-8-(((R)-1-
24
1
as yellowish resin. [α]D = −9.6° (c 0.48, CHCl3). H NMR (400
MHz, CDCl3): δ 7.41−7.10 (m, 10H), 6.20−5.65 (m, 3H), 5.35−5.15
(m, 3H), 5.05−4.60 (m, 4H), 4.59−4.49 (m, 2H), 3.62−3.52 (m, 2H),
3.44−3.25 (m, 1H), 3.09−2.94 (m, 1H), 2.93−2.81 (m, 3H), 2.70−
2.55 (m, 1H), 2.45−2.34 (m, 1H), 2.32−2.13 (m, 2H), 2.09−1.80 (m,
2H), 1.75−1.40 (m, 6H), 1.39−1.11 (m, 2H), 1.08−0.74 (m, 6H). 13C
NMR (100 MHz, CDCl3): δ 176.4, 172.1, 171.0, 137.9, 137.1, 136.2,
135.97, 135.92, 128.9, 128.44, 128.37, 127.7, 116.4, 116.0, 74.7, 73.20,
73.16, 71.8, 58.4, 51.0, 50.93, 50.88, 37.8, 36.2, 35.8, 35.7, 34.9, 33.3,
33.1, 21.4, 18.5, 16.8, 14.0, 13.9. IR: ν 3311, 3069, 3029, 2954, 2868,
2330, 1732, 1637, 1090 cm−1. HRMS (ESI) calcd for [C35H48N2O5 +
Na+] 599.3455, found 599.3454.
(benzyloxy)but-3-en-2-yl)amino)-8-oxooctan-4-yl-2-((R)-N,2-dime-
20
thylpent-4-enamido)-3-phenylpropanoate as dark yellow oil. [α]D
=
1
−41.6° (c 1.01, CHCl3). H NMR (400 MHz, CDCl3): δ 7.38−7.12
(m, 10H), 6.30−6.19 (m, 1H), 5.93−5.81 (m, 1H), 5.45−5.33 (m,
1H), 5.32−5.14 (m, 3H), 5.02−4.80 (m, 3H), 4.74−4.62 (m, 1H),
4.58−4.48 (m, 2H), 3.56 (d, J = 5.0 Hz, 2H), 3.38 (dd, J = 14.7, 5.7
Hz, 1H), 3.09−3.00 (m, 1H), 2.88−2.76 (m, 3H), 2.63−2.53 (m, 1H),
2.27−2.11 (m, 3H), 1.94−1.77 (m, 1H), 1.74−1.16 (m, 8H), 1.05 (d, J
= 7.0 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 176.4, 172.3, 172.2, 170.7, 137.9, 137.2, 136.96, 136.92, 128.9, 128.4,
127.70, 127.67, 116.2, 116.0, 115.9, 74.79, 74.75, 73.2, 71.8, 71.7, 61.8,
58.7, 50.9, 38.6, 37.8, 36.10, 35.8, 34.6, 33.1, 29.7, 21.4, 21.3, 18.6,
18.5, 16.9, 16.6, 14.0. IR: ν 3310, 3064, 2974, 2933, 2871, 2360, 2341,
1732, 1636, 1541, 1456, 1129, 1089, 917, 738, 698 cm−1. HRMS (ESI)
calcd for [C35H48N2O5+Na+] 599.3455, found 599.3445.
(3S,6S,10R,16R)-3-Benzyl-10-(hydroxymethyl)-4,6-dimethyl-
16-propyl-1-oxa-4,11-diazacyclo-hexadecane-2,5,12-trione (1-
SR). A solution of (S)-(R)-8-(((R)-1-(benzyloxy)but-3-en-2-yl)-
amino)-8-oxooctan-4-yl 2-((S)-N,2-dimethylpent-4-enamido)-3-phe-
nylpropanoate (132 mg, 0.23 mmol) in 66 mL toluene was refluxed
with Grubbs II catalyst (28.6 mg, 0.03 mmol) for 16 h. After solvent
removal the residue was submitted to FC in hexane/EtOAc 1:2 to
yield 30 mg (24%) of (3S,6S,10R,16R)-3-benzyl-10-((benzyloxy)-
methyl)-4,6-dimethyl-16-propyl-1-oxa-4,11-diazacyclohexadec-8-ene-
2,5,12-trione as a brown resin. 1H NMR (400 MHz, CDCl3): δ 7.34−
7.02 (m, 10H), 5.77−5.54 (m, 1H), 5.37−5.20 (m, 1H), 5.00−4.77
(m, 1H), 4.51−4.34 (m, 2H), 4.28−3.74 (m, 2H), 3.63−3.14 (m, 2H),
3.06−2.55 (m, 5H), 2.34−2.03 (m, 3H), 1.99−0.96 (m, 11H), 0.90−
(3S,6R,10R,16S)-3-Benzyl-10-(hydroxymethyl)-4,6-dimethyl-
16-propyl-1-oxa-4,11-diazacyclohexa-decane-2,5,12-trione (1-
RS). To a solution of (S)-(S)-8-(((R)-1-(benzyloxy)but-3-en-2-yl)-
amino)-8-oxooctan-4-yl 2-((R)-N,2-dimethylpent-4-enamido)-3-phe-
nylpropanoate (300 mg, 0.52 mmol) in 150 mL toluene was added
Grubbs II catalyst (66 mg, 0.08 mmol) and the reaction mixture was
refluxed for 20 h. The solvent was evaporated and the residue was
filtered through silica gel (hexane/EtOAc 2:3) to yield 180 mg (63%)
of crude (3S,6R,10R,16S)-3-benzyl-10-((benzyloxy)methyl)-4,6-di-
I
dx.doi.org/10.1021/jo3027643 | J. Org. Chem. XXXX, XXX, XXX−XXX