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Prof. Ang Li
Kosuke Minagawa (D2)
Literature Seminar 2017. 10. 28
1
2
3
NH
N NH
O
O
H
H
H
i-Bu
Me
MeH
MeH
N
Me
Me
CHO
delavatine A8)
O OO
O
Me
O
Me
H
H
Me
O
H
H
rubriflordilactone A4)
aspidodasycarpine1)
HN
N
Me
H
H
O OMe
OH
O
H
N
Me
Me H
H
daphenylline5)
HO O OH
Me
HO
Me
HO
O Meclostrubin6) drimentine A7)
MeN
O
MeH
H
Me
O
HMe
OH
O
OH
H
fusarisetin A2)
H
Me
H
Me
HOHO2C
NHO
sespenine3)
N
O
Me
Me
H
Me
OH
MeMeileabethoxazole9)
1. J. Am. Chem. Soc. 2016, 138, 3982.; 2. J. Am. Chem.Soc. 2012, 134, 920.; 3. Angew. Chem. Int. Ed. 2014, 53, 9012.;
4. J. Am. Chem. Soc. 2014, 136, 16477.; 5. Nature Chem. 2013, 5, 679.; 6. Nature commun. 2015, 6, 6445.;
7. J. Am. Chem. Soc. 2016, 138, 3982.; 8. J. Am. Chem. Soc. 2017, 139, 5558.; 9. Angew. Chem. Int. Ed. 2016, 55, 2851.
Natural Products
Synthesized by Ang Li group
4
PhHO
MeMe
O
CHO
Me
NTs
Lu, Z.; Li, Y.; Deng, J.; Li, A. Nature Chem. 2013, 5, 679.
Yang, M.; Yang, X.; Sun, H.; Li, A. Angew. Chem. Int. Ed. 2016, 55, 2851.
Li, H.; Chen, Q.; Lu, Z.; Li, A. J. Am. Chem. Soc. 2016, 138, 15555.
55%
86%
N
Me
CO2Me
O
O
OTBS
~ 6 -Electrocyclization / Aromatization ~
h (Hg lamp)0 °C
N
Me
CO2Me
O
O
H
H
OTBS
71%
DBU, air, 60 °C
67%N
Me
CO2Me
O
O OTBS
N
O
Me
Me
TIPS
O
Sii-Pr2
H
Me
mesitylene140 °C, air
68%
N
O
Me
Me
TIPS
O
Sii-Pr2
H
Me
Me
H
N
O
TIPS
Bu3Sn
O
OTf
Me Si
i-Pr i-Pr
Me Pd(PPh3)4
HOMe
Me
O
Me
N
Me
Ts
toluene, 90 °C;DDQ
82%
HOMe
Me
O
Me
N
Me
Ts
LiN(TMS)2
N
N N
N
SO2Et
5
O
Br
NTs
N
CO2Me
H
Zhou, S.; Zhang, D.; Sun, Y.; Li, R.; Zhang, W.; Li, A. Adv. Synth. Catal. 2014, 356, 2867.
NTs
N
CO2Me
HO+
Entry Conditions Yield
AIBN, n-Bu3SnH, toluene, 80 °C
Et3B, O2, n-Bu3SnH, THF, 22 °C
[Ru(bpy)3]Cl2·6H2O, Et3N, blue LED, DMF, 22 °C
[Ir(bpy)2(dtbbpy)]PF6, Et3N, blue LED, DMF, 22 °C
1
2
3
4
8%
13%
11%
90%
NTs
O
HO
87% (d.r. = 2.2:1)
NTs
N
CO2Me
OMe
OH
H
O
HMe
H
MeMe
81%
NTs
N
CO2Me
OMe
OH
H
O
O
H Me
Me
H
MeMe
73% (d.r. = 5.8:1)
Conditions
6
3
O
+NH
R1
R2
NH
R1 O
R2
Eu(fod)3 (10 mol%)1,2-dichloroethane
80 °C, 24 h
H
NH
Me Me
CO2Me
H
Me
Me
H
MeH
Me Me
O
HNO
H
Me
H
H
81% (d.r. = 1.6:1)
HNO
H
Me
H
H
X
X = Br (82%)X = OMe (87%)
Me
OTBSOMe
HNO
91% (d.r. = 1:1)
90%
Xiong, X.; Zhang, D.; Li, J.; Sun, Y.; Zhou, S.; Yang, M.; Shao, H.; Li, A. Chem. Asian J. 2015, 10, 869.
HH
7
8
9
aspidodasycarpine
HN
N
Me
H
H
O OMe
OH
O
H
N
N
Me
H
H
R1
OR2
O
OH
7 16HN
N
Me
H
H
R1
OR2
O
16HN
N
Me
H
H
R1
O
3
HN
O
NR1
Me
HN
O
Me
H2N
Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982.
5
indolecyclization
Tostecyclization
Au(I)H
10
11
Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982.
2) NsCl, Et3NDMAP, CH2Cl273%
(p-CF3Ph)3PAuCl,AgSbF6,TTBP4A MS, 86%
HN
N
Me
Ts
N
N
Me
Ts
O
N
N
Me
Ts
OTIPS
Ns
NsTIPSOTf, Et3NCH2Cl2, 95%
N
N
Me
H
H
Ts
Ns
O
1) DDQ,THF/H2O = 10/188%
N N
t-Bu
t-But-BuTTBP
(2,4,6-tributylpyrimidine)
H H
H
12
13
N
N
Me
H
H
Ts
Ns
O
N
N
Me
H
H
Ts
Ns
OH
NaBH4
MeOH/CH2Cl20 oC, 90%
TMSCNBF·OEt2, 76%
N
N
Me
H
H
Ts
Ns
CN
DIBAL
CH2Cl2, -78oC
N
N
Me
H
H
Ts
Ns
O
H
aq. HCHONa2CO3
MeOH/CH2Cl254% (2 steps)
N
N
Me
H
H
Ts
Ns
OH
HO
Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982.
16 16
14
Synthesis of the lactol
Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982.
N
N
Me
H
H
Ts
Ns
OH
HO
N
N
Me
H
H
Ts
Ns
OBn
HO
HN
N
Me
H
H
Ts
OBn
OH
HN
N
Me
H
H
Ts
OBn
O
OI
N
N
Me
H
H
Ts
O
OBn
O
N
N
Me
H
H
Ts
O
OBn
OH
F3C OBn
NPh
1,4-dioxane4Å MS, TfOH
Basic condition: retro-aldol
Cl3C OBn
NH
(Yamada-Yu rgt.)
selfinstability againstacid promoters.
15
16
Divergent Synthesis from Common lactol
N
N
Me
H
H
Ts
O
OBn
OH
Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982.
aspidodasycarpine
HN
N
Me
H
H
O OMe
OH
O
H
lonicerine
HN
N
Me
H
H
OH
CO2Me
O
H
lanciferine (proposed)
HN
N
MeH
O OMe
O
O
MeO O
Ph
O
17
N
N
Me
H
H
Ts
O
OBn
OH
Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982.
aspidodasycarpine
HN
N
Me
H
H
O OMe
OH
O
H
HN
N
Me
H
H
OH
OBn
O
Ts
HN
N
Me
H
H
OMe
OBn
O
Ts
1) AZADONaClO2
2) TMSCHN2
MeOH, 0 oC,
80% (2 steps)O
1) BBr3, -78oC, 78%
2) Na naphthalenide
-78 oC, 76%
NaBH4, MeOH
0 oC
N
N
Me
H
H
Ts
OH
OBn
ONa
90%
18
19
N
N
Me
H
H
Ts
O
OBn
OH
TPAP, NMO
CH2Cl2,
0 oC, 86%N
N
Me
H
H
Ts
O
OBn
O
aq. LiOHTHF, 94%
HN
N
MeH
OH
O
TsO
OBn
1) AZADONaClO2
HN
N
MeH
OH
O
TsO
OBn
O
HN
N
MeO
TsO
2) I2, NaHCO3
MeCN, 0 oC
I
O
O
OBn
HN
N
MeO
TsO O
Na2CO3MeOH, 79%
H
OMeO
OBn
(X-ray crystallographic analysis)
Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982.
H
H
H
HH
91% (2 steps)
20
HN
N
MeH
O OMe
O
O
MeO O
Ph
O
cinnamic anhydrideDMAP, pyridine
79%
HN
N
MeO
TsO O
H
OMeO
OBn
Completion of the Synthesis of lanciferine
1) Na naphthalenide2) CH2O, H2, Pd/C,
50% (2 steps)
HN
N
MeO
MeO O
H
OMeO
OH
lanciferine (proposed)
Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982.
H
H
H
Ang Li et al. synthesized lanciferine (proposed), but1H NMR chemical shift of C18 methyl drastically differed from reported ( = 0.2).
(Lewin, G.; Kunesch, N.; Posson, J. J. Indian Chem. Soc. 1978, 55, 1096.)
18
21
22
N
Me
Me O
H
O
H
H
longeracinphyllin A
Li, 2017e
N
Me
Me H
H
daphenylline
Li, 2013d
Yokoshima & Fukuyama, 2016e
NMe
Me
Me
codaphniphylline
Heathcock, 1995c
OO
OMe
Me
N
O
O
Me
Me
Me
daphnilactone A
Heathcock, 1989a
NMe
HO
CO2Me
OAcdaphmanidin E
Carreira, 2011b
Daphniphyllum alkaloids
aHethcock, C. H. et al. J. Am. Chem. Soc. 1989, 111, 1530.bCarreira, E. M. et al. Angew. Chem. Int. Ed. 2011, 50, 11501.cHethcock, C. H. et al. J. Org. Chem. 1995, 60, 1120. dLi, A. et al. Nat. Chem. 2013, 5, 679.eYokoshima, S.; Fukuyama, T. et al. Angew. Chem. Int. Ed. 2016, 55, 6067.eLi, A. et al. DOI: 10.1021/jacs.7b09186
23
Li, J.; Zhang, W.; Zhangm F.; Li, A. DOI: 10.1021/jacs.7b09186
N
Me
Me O
H
O
H
H
longeracinphyllin A
N
Me
Me OCO2Me
H
O
O
N
Me
Me O
H
O
O
•
CO2Me
N
Me
Me O
HO
H
N
Me O
O
CO2Me
I
O
OH
Me
HN
Ns
O
H
H
HO2C
CO2Me
OTBS
[3+2]H
1017
24
N
Ns
O
Me
Li, J.; Zhang, W.; Zhangm F.; Li, A. DOI: 10.1021/jacs.7b09186
O
OH
Me
HN
Ns
OTBDPS
N
Me
Ns
N
Ns
O
Me+
conditions
Entry ConditionsYield
AgNTf2, Ph3P
AgNTf2, Ph3P, TTBP, 4Å MS
1a
2b
3b,c
4b,c,d
66%
15%
20%
74%
AgNTf2, CyJohnPhos, TTBP, 4Å MS5b,c,d 84%
6-exo 7-endo
0%
8%
7%
25%
5%
a 5 mol% [Au], MeOH/toluene (1/10), 22 oC, 30 min.b 6 mol% [Ag], i-PrOH/CH2Cl2 (1/20), 22
oC, 24 h.c 5 mol% [Phosphine ligand].d 10 mol% TTBP, 10 wt% 4Å MS.
Au(PPh3)NTf2
AgNTf2
DIAD, PPh3, THF
1)
2) TBDPSOTf85% (2 steps)
99%eePCy2
CyJohnPhos
N N
t-Bu
t-But-BuTTBP
25
Li, J.; Zhang, W.; Zhangm F.; Li, A. DOI: 10.1021/jacs.7b09186
N
Ns
O
MeN O
O
HO2C
CO2Me
OTBS
N
Me O
O
CO2Me
OTBS
Me
MeO2C
OTBS
O
H
H
N
Me O
O
CO2Me
OTBS
N
Me O
O
CO2Me
I
N
Me O
CO2MeO
H
1) p-thiocresolDMF, K2CO3
2)
EDCI, HOBT,Et3N, CH2Cl2
3) DBU, MeCN
95 oC
rt to 95 oC
69% (3 steps)
1) HF·py, THF
0 oC to rt
2) I2, imidazole
PPh3, CH2Cl20 oC, 85% (2 steps)
Zn, CuI
sonication
35 oC, 90%
H
26
27
28
29
Li, J.; Zhang, W.; Zhangm F.; Li, A. DOI: 10.1021/jacs.7b09186
N
Me
Me O
H
O
H
H
O
N
Me
Me O
H
O
H
H
S
N
Me
Me O
H
S
H
H
S
N
Me
Me O
H
O
H
H
longeracinphyllin A
Lawesson's reagent
1,2-dichlorobenzene
170 oC
Silica gelair, 67%
Raney NiEtOH, 90%
30
31
Appendix
32
33
34
35
N
Me
Me O
CO2MeO
O
N
Me
Me OCO2Me
CO2Me
O
O
H
OMe
OPAr3
N
Me
Me OCO2Me
CO2Me
O
O
H
PAr3 PAr3
N
Me
Me OCO2Me
CO2Me
O
O
H
PAr3
N
Me
Me OCO2Me
CO2Me
O
O
H
phosphine-catalized [3+2] reaction is generally known stepwise mechanism.- In the first step, necleophile attacks to less hindered carbon from convex face.
36
-the dienophile reacts from concave face, because of the steric repulsion betweenphosphine legand and highlighted H and/or Me?
N
Me
Me O
CO2MeO
O
Ar3P
O
OMe
N
Me
Me O
CO2MeO
O
Ar3P
O
OMe
H
H
N
Me
Me O
CO2MeO
OH
OMe
O
Ar3P
N
Me
Me O
CO2MeO
O
CO2Me
H
37
38
Mechanism of the photocatalyzedrafical conjugate addition
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