divergenttotal)synthesis) of...
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Divergent Total Synthesis of indoxamycins A, C and F
Julien Pomarole
He, C.; Zhu, C.; Dai, Z.; Tseng, C.-‐C.; Ding, H. Angew. Chem. Int. Ed. 2013, ASAP DOI : 10.1002/anie.201307426
November, 14th 2013
IntroducPon
• Isolated from saline culture of marine-‐derived acPnomycetes (Sato, 2009)
• Biologic acPviPes : – HT-‐29 tumor cell :
• IC50 = 0.59 (indoxamycin A) • IC50 = 0.31 (indoxamycin F)
– Mitomycin : IC50 = 0.66 µm (both)
• [5,5,6] tricyclic 2
indoxamycin A
O
O OH
indoxamycin C
O
OH
OHO
O
HO
CO2Hindoxamycin F
Retrosynthesis
3
O
MeO2C
H
5
O
indoxamycin A
O
O OH
indoxamycin C
O
OH
OHO
O
HO
CO2Hindoxamycin F
or or
late-stagedivergent
transformation
O
6
CO2MeH
O
reductive1,6-enyne
cyclization
Ireland-Claisenrearrangement O
MeO2C
7
O
O
TMS8
Synthesis of the common intermediate
4
OH
HO
O
TMS
109
EDC•HClDMAP
DCM0 °C → 25°C
90%
O
O
TMS8
OMeO2C
12
TMS
MeO2C
TMS
11
1/ CrO3, 3,5-DMP, DMC–20 °C → 25 °C, 86%
2/ DDQ, dioxan100 °C, 83%
1/KHMDS, TMSCl, Et3Ntoluene, –78 °C → 70 °C
2/ TMSCHN2toluene/MeOH, 25 °C85% (over 2 steps)
Synthesis of the common intermediate
5
OMeO2C
12
TMS
K2CO3
MeOH, 25 °C85%
OMeO2C
7
Pd2(dba)3, P(o-tol)3Et3SiH, AcOH
benzene, 25 °C87%
HO
MeO2C
13
1/ LiHMDSMander's reagentTHF, –78 °C
2/ NaH, MeIDME, 25 °C78% (over 2 steps)
O
MeO2C
16
CO2MeH H
OMe
MeO2C15
CO2Me
+
O
OMeNMander'sreangent
Synthesis of the common intermediate
6
O
MeO2C
16
CO2MeH
DIBAL-H
DCM/toluene–78 °C
OH
18
CO2MeH
HO
Dess-Martin PeriodinateNaHCO3
DCM0 °C → 25 °C
76%(over 2 steps)
MgBr
THF, –78 °C
then
N Cl
–78 °C → 25 °C80 %
O
MeO2C
H
23
Op-TsOH•H2O
toluene, 60 °C82%
O
MeO2C
H
5
O
O
OMeO2C
H
6
Synthesis of the indoamycin A
7
O
MeO2C
H
5
O
PhNTf2L-selectride
THF–78 °C → 25 °C
79%
TfO
MeO2C
24
O
Pd(OAc)2, PPh3Et3N, HCO2H
THF, 65 °C85%
MeO2C
25
ODIBAL-H
pentane, –105 °C81%
26
O
O
27n-BuLi
THF, 25 °C95%
indoxamycin A
O
O OH
PEtOEtO
O
OTMS
O
27
Synthesis of the indoxamycin C
8
O
MeO2C
H
5
O1/ NABH4, CeCl3•7 H2O–20 °C
2/ DIBAL-H, DCM–50 °C84% (over 2 steps) 29
O
O
HO SOCl2pyridine
Et2O, 0 °C97%
30
O
O
Cl1/ 27, n-BuLiTHF, 25 °C
2/ AgNO3acetone/H2O (4:1), 25 °C78 % (over 2 steps)
indoxamycin C
O
OH
OHO
PEtOEtO
O
OTMS
O
27
Synthesis of the indoxamycin F
9
29
O
O
HO
PhSCl, Et3N
Et2O, 0 °C92%
32
O
O
SO
Ph
(EtO)2P(O)CH2CO2MeNaH
THF, 25 °C95%
33
O
HO
CO2Me
LiOH
MeOH/THF (3:1)25 °C92%
O
HO
CO2Hindoxamycin F
Asymmetric synthesis
10
OMeO2C
7
[Pd(MeCN)4](BF4)2(R)-Segphos
Et3SiH, HCO2H
benzene, 25 °C, 30 min46%
HO
MeO2C(+)-13
ee = 93%
O
MeO2C
H
5ee = 96%
after recrystallization
O
(–)-indoxamycin A
O
O OH
(–)-indoxamycin C
O
OH
OHO
O
HO
CO2H
(–)-indoxamycin F
or or
Conclusion • 3 totals synthesis with 1 commun intermediated :
– Indoxamycin A : 16 steps • Racemic :Yield = 8% • EnanPoselecPve : Yield = 4%
– Indoxamycin C : 17 steps • Racemic : Yield = 10% • EnanPoselecPve : Yield = 5%
– Indoxamycin F : 17 steps • Racemic : Yield = 11% • EnanPoselecPve : Yield = 5%
• 3 keys steps : – Ireland-‐Claisen rearrangement, – Stereodivergent reducPve 1,6-‐enyne cyclizaPon, – Tandem 1,2-‐addiciton/oxa-‐Michael/methylenaPon reacPon
11
Allylic oxidaPon
12 Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem. 1978, 43, 2057–2059.
ReducPve 1,6-‐enyne cyclizaPon
13 Trost, B. M.; Rise, F. J. Am. Chem. Soc. 1987, 109, 3161–3163.
Mechanism
14 He, C.; Zhu, C.; Dai, Z.; Tseng, C.-‐C.; Ding, H. Angew. Chem. Int. Ed. 2013, ASAP
O
OMeO2C
H
6
MgBrO
MeO2C
19
OH
O
MeO2C
5
O
N
O
MeO2CO
N
O
MeO2CO
N N
HO
MeO2C
H
23
Ort
Mislow rearrangement
15 Bickart, P.; Carson, F. W.; Jacobus, J.; Miller, E. G.; Mislow, K. J. Am. Chem. Soc. 1968, 90, 4869.
Asymmetric synthesis
16
Entry [Pd] acid t (h)
(+)-‐13, 2a-‐epi-‐13
Yield (%) ee (%)
1 Pd2dba3 AcOH 24 15, n.d. 65, —
2 Pd(ja)2 AcOH 10 40, 32 72, 64
3 [Pd(MeCN)4](BF4)2 AcOH 0.5 42, 33 84, 71
4 [Pd(MeCN)4](BF4)2 HCO2H 0.5 46, 43 93, 80
OMeO2C
7
[Pd], (R)-SegphosEt3SiH, acid
benzene, 25 °C
HO
MeO2C(+)-13
HO
MeO2C
2a-epi-13