MeO MeO N O OH OMe O X X = Cl, (-)

Total Synthesis of (-­‐)-­‐Acutumine and (-­‐)-­‐Dechloroacutumine S. M. King, N. A. Calandra, S. B. Herzon, Angew. Chem. Int. Ed. 2013, 52, 3642-­‐3645. O
O
OMe
MeO
MeO
N
X
OH
X = Cl, (-)-acutumine (1)
X = H, (-)-dechloroacutumine (2)
1 O
O
OMe
MeO
MeO
•  (-­‐)-­‐acutumine isolated from the roots of Sinomenium acutum (tree in Asia) •  inhibiGon of human T-­‐cell proliferaGon N
X
OH
X = Cl, (-)-acutumine (1)
X = H, (-)-dechloroacutumine (2)
•  (-­‐)-­‐dechloroacutumine was isolated from a chlorinedificient culture of Menispermum dauricum (shrub in Asia and America) •  stereogenic, heavily oxidized spirocyclopentenone rings •  dense array of heteroatom-­‐containing funcGonal groups •  secondary alkyl chloride funcGonal group in 1 S. M. King, N. A. Calandra, S. B. Herzon, Angew. Chem. Int. Ed. 2013, 52, 3642. 2 Simple and general strategy to synthesize hasubanan alkaloids: S. B. Herzon, N. A. Calandra, S. M. King, Angew. Chem. Int. Ed. 2011, 50, 8863. 3 TMS-­‐cyclopentadiene: •  stabilizing the azaquinone 9 •  stereochemistry control S. B. Herzon, N. A. Calandra, S. M. King, Angew. Chem. Int. Ed. 2011, 50, 8863. 4 S. B. Herzon, N. A. Calandra, S. M. King, Angew. Chem. Int. Ed. 2011, 50, 8863. 5 ExplanGon: faster retro-­‐cycloaddiGon reacGons aRributed to donaGon of electron density from the C-­‐Si bonding orbital to the anGbonding orbitals of the C-­‐C σ bonds that are breaking in the reacGon transiGon state S. B. Herzon, N. A. Calandra, S. M. King, Angew. Chem. Int. Ed. 2011, 50, 8863. 6 Difference: •  stereoselecGve construcGon of C8-­‐C9 bonds •  other suitable precursor to the stereogenic, highly oxidized spirocylopentenone ring S. M. King, N. A. Calandra, S. B. Herzon, Angew. Chem. Int. Ed. 2013, 52, 3642. 7 Synthesis of enyne 10: O
O
O
TMSOTf, Pd(OAc)2
TMS-TMS, PhCH3, 0 ºC
then NaOAc, AcOH
91 %
TMS
O
O
O
LHMDS
Comins reagent
THF, -78 ºC to 0 ºC
91 %
8
7
five steps
from D-ribose
TMS
TMS
O
O
TfO
9
SnBu3
[Pd(PPh3)2Cl2], LiCl
O
O
THF, 24 ºC
77 %
10
S. M. King, N. A. Calandra, S. B. Herzon, Angew. Chem. Int. Ed. 2013, 52, 3642. 8 Ph
Ph
O
N B
H
Synthesis of diol 17: Me
O
N3
MeO
MeO
H2O2
HCO3H
48%
MeO
OMe
(S)-o-tol-CBS
TMS
+
MeO
78%, 93% ee
N3
O
11
TMS
TMS
O
PMe3
MeO
MeO
MeO
99%
N3
MeOTf, THF
-78 ºC to -30 ºC to -90 ºC
O
N
MeO
O
then 10.Li
-90 ºC to 24 ºC
85%
12
TMS
TMS
TMS
TMS
O
O
O
+
MeO
O
N+
Me
MeO
O
MeO
MeO
O
N
Me
10.Li
4
S. M. King, N. A. Calandra, S. B. Herzon, Angew. Chem. Int. Ed. 2013, 52, 3642. 13
9 TMS
TMS
TMS
O
O
MeO
O
N
Me
O
MeO
PhCH3, 135 ºC
O
MeO
MeO
98%
O
N
Me
Bu3SnH
[Pd(PPh3)4]
THF, 24 ºC
67%
14
13
SnBu3
O
O
TBAF
MeO
MeO
O
TMS
O
N
Me
O
O
MeO
DMF, -10 ºC
37%
(gram scale)
SnBu3
MeO
N
16
15
OH
1) CuCl2, THF, 24 ºC
83%
2) PTSA, H2O, MeOH, 60 ºC
95%
O
OH
MeO
MeO
Cl
N
17
S. M. King, N. A. Calandra, S. B. Herzon, Angew. Chem. Int. Ed. 2013, 52, 3642. 10 CompleGGon of the syntheses: OH
O
OH
MeO
Cl
MeO
O
O
1) TFAA, DMSO
DCM, -60 ºC
MeO
then DIPEA
N
then NaSCH3
-60 ºC to 0 ºC
O
Cl
MeO
CH2N2 in ether
THF, 24 ºC
97% (two steps)
N
18
17
H
O
S
O
MeO
MeO
O
OMe
Me
Cl
NIS, HCO2H
O
OMe
DIPEA
O
DCM, 0 ºC to 24 ºC
3:1 d.r.
O
MeO
N
Cl
MeO
19
CH2CN, 100 ºC
N
20
O
H
O
O
MeO
MeO
N
21
OMe
O
NH3
Cl
MeOH, 0 ºC
HO
H
O
MeO
MeO
OMe
O
Cl
N
22
S. M. King, N. A. Calandra, S. B. Herzon, Angew. Chem. Int. Ed. 2013, 52, 3642. 11 HO
H
O
MeO
MeO
OMe
O
1) DMP, DCM, 24 ºC
Cl
2) NaBH4, EtOH, 0 ºC
28% (five steps)
N
22
OMe
O
O
MeO
MeO
OH
Cl
N
23 dehydroacutumine
1) [Rh(nbd)(dppb)]BF4
H2 (300 psi), DCE, 24 ºC
17% (for 1)
2) H2, Pd/C
60% (for 2)
O
O
OMe
MeO
MeO
N
X
OH
X = Cl, (-)-acutumine (1)
X = H, (-)-dechloroacutumine (2)
S. M. King, N. A. Calandra, S. B. Herzon, Angew. Chem. Int. Ed. 2013, 52, 3642. 12 Conclusion: •  strategic applicaGon of TMS-­‐cyclopentadiene as stabilizaGon and stereocontrolled element •  stereo-­‐ and regioselecGve hydrostannylaGon •  Hosomi-­‐Sakurai cyclizaGon to form two conGguous quaternary centers •  allylic formate rearrangement to establish the oxygenaGon paRern of the spirocyclopentenone rings •  selecGve hydroganGon S. M. King, N. A. Calandra, S. B. Herzon, Angew. Chem. Int. Ed. 2013, 52, 3642. 13 END 14 Synthesis of starGng compound 7: OH
O
HO
OH
acetone
H2SO4
OH
rt, 1h (93%)
1) CH3PPh3Br
t-BuOK, THF
O
O
HO
OH
2) NaIO4, DCM/H2O
(65% for 2 steps)
O
D-Ribose
HO
O
O
O
MgBr , THF, -78 ºC
O
(84%)
i) Grubbs 1st gen. cat.
DCM, rt, 4h
ii) PCC, 12h
(87%, one-flask)
O
O
O
O
A. B. Smith III, Q. Han, P. A. S. Breslin, G. K. Beauchamp, Org. Le>. 2005, 7, 5075. 15 Synthesis of starGng compound 11: O
MeO
HO
OH , PTSA
benzene (71%)
MeO
OMe
MeO
O
O
i) 9-BBN-H
toluene, reflux
ii) H2O2, reflux
(76%)
MeO
OMe
MeO
OH
MeO
OMe
1) MsCl, TEA, DCM
2) NaN3, DMF, 90 ºC
(92%)
N3
MeO
MeO
OMe
J. A. Soderquist, I. Kock, M. E. Estrella, Org. Process Res. Dev. 2006, 10, 1076. 16