synthesis of alkaloid ( )-205b via stereoselective
TRANSCRIPT
Synthesis of Alkaloid (−)-205B via Stereoselective Reductive Cross-Coupling and Intramolecular [3+2]
Cycloaddition
Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134, 15237-15240.
Kara George Rosenker Current Literature 6 October 2012
N
H
H
Me
HMe
Me
NH
MeMe
H H
H
Me
H
(!)-205B
Kara Rosenker @ Wipf Group Page 1 of 16 10/6/2012
(−)-205B Isolation, Structure, and Biological Activity
§ Isolated in 1987 by Daly and co-workers from the skin extracts of the Panamanian frog Dendrobates pumilio
§ The structure was first reported as 1 and revised in 1998 by Daly and co-workers based on extensive FTIR, NMR, and HRMS
§ The absolute sterochemistry was reported in 2003 by Toyooka and co-workers based on their total synthesis of (+)-205B
§ (−)-205B possesses an unusual and unique 8b-azaacenaphthylene ring system containing 5 asymmetric centers
§ Target of interest due to intriguing structure and the discovery that the unnatural enantiomer, (+)-205B, blocks the 7α nicotinic acetylcholine receptor in a selective fashion
Tokuyama, T.; Nishimori, N.; Shimada, A.; Edwards, M. W.; Daly, J. W. Tetrahedron 1987, 43, 643. Tokuyama, T.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. An. Asoc. Quim. Argent. 1998, 86, 291. Toyooka, N.; Fukutome, A.; Shinoda, H.; Nemoto, H. Angew. Chem. Int. Ed. 2003, 42, 3808. Tsuneki, H.; You, Y.; Toyooka, N.; Kagawa, S.; Kobayashi, S.; Sasaoka, T.; Nemoto, H.; Kimura, I.; Dani, J. A. Mol. Pharmacol. 2004, 66, 1061.
N
H
H
Me
HMe
Me
NH
MeMe
H H
H
Me
H
(!)-205B
N
H
H
Me
HMe
Me1
5a
8
2a
5a
8
2a
Kara Rosenker @ Wipf Group Page 2 of 16 10/6/2012
Toyooka and Co-Workers: (+)-205B
Toyooka, N.; Fukutome, A.; Shinoda, H.; Nemoto, H. Angew. Chem. Int. Ed. 2003, 42, 3808. Tsuneki, H.; You, Y.; Toyooka, N.; Kagawa, S.; Kobayashi, S.; Sasaoka, T.; Nemoto, H.; Kimura, I.; Dani, J. A. Mol. Pharmacol. 2004, 66, 1061.
N
H
H
Me
HMe
Me(!)-205B
Intramolecular MannichN
H
H
Me
HMe
Me(+)-205B
5a
8
2aBocN
HMe
HMe
OO
EtO2C
NO
O
CO2MeH
Me H
NO
O
CO2MeH
Me H MeH
Asymmetric Conjugate Addition
NMeO2CH
Me H
CO2Me
H OTBDPSNMeO2CCO2Me
H OTBDPS
Asymmetric Conjugate Addition
Absolute Stereochemistry
§ 30 steps (longest linear) § Determined the absolute stereochemistry of the natural product to
be (−)-205B § Key features:
§ Stereocontrolled Michael-type additions to enaminoesters
Kara Rosenker @ Wipf Group Page 3 of 16 10/6/2012
Smith and Co-Workers: (-)-205B
Smith, A. B; Kim, D.-S. Org. Lett. 2005, 7, 3247.
§ 19 steps (longest linear) § 5.6% overall yield § Key features:
§ Dithiane three-component linchpin coupling § One-pot sequential construction of the indolizidine ring
N
H
H
Me
HMe
Me(!)-205B
N
H
H HO
HMe
SS
Me
OTBDPS
OTBSTsHN
OO
SS
OO
TsNS S
TBS Me
OTBDPS
O
RCMOne-pot Sequential
Cyclization
Three-Component Linchpin Coupling
Kara Rosenker @ Wipf Group Page 4 of 16 10/6/2012
Comins and Co-Workers: (-)-205B
Tsukanov, S. V.; Comins, D. L. Angew. Chem. Int. Ed. 2011, 50, 8626.
§ 11 steps (longest linear) § 8% overall yield § Key features:
§ Asymmetric N-acylpyridinium reaction § Tsuji-Trost allylic amination of a vinylogous amide
N
H
H
Me
HMe
Me(!)-205B
NH
MeO
Me NH
MeO
HN
OOAc
N
O
CO2R*N
OMeTIPS
RCMConjugateAddition Tsuji-Trost
Cross-Metathesis
Kara Rosenker @ Wipf Group Page 5 of 16 10/6/2012
Title Paper: Retrosynthesis of (−)-205B
Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134, 15237-15240.
R1
O
HN TMS
Li
TMS
R2
R3
OHR1
NHHO
R2
R3
1. three-component coupling2. N-oxidation
direct [3+2]
sequential [3,3]/[3+2]
H
O
R4
(-H2O)
N
R2
R1O
R3
N
R2
R1O
R3
R4
R4
Control of reaction pathway dictates stereochemistry of the heterocyclic product
NH
MeMe
H H
H
Me
HNH
HMe
Me
H HH
TMS
MeOOMe
HO NO
CO2BuH
HMeH
MeO
MeO
MeH
HO
OBuO
MeMeO
OMe
NHHO
MeHMeO
OMe
O Me
Me OH
aza-Sakurai,alkene isomerization,
deoxygenation
N!O bond cleavage,conversion of ester
to allylsilane
condensation,intramolecular [3+2]
cycloaddtionreductive cross-coupling,
N-oxidation
(!)-205B
Kara Rosenker @ Wipf Group Page 6 of 16 10/6/2012
(E)-anti-Homoallylic Primary Amines
Schaus, J.V.; Jain, B.; Panek, J. S. Tetrahedron 2000, 56, 10263.
§ Chela&on-‐controlled addi&on reac&ons of chiral crotylsilanes for the synthesis of (E)-‐an&-‐homoallylic carbamates
§ Asymmetric crotyla&on and allyla&on reac&ons of imines and oximes
§ Iminine propargyla&on
Ramachandran, P. V.; Burghardt, T. E. Chem. – Eur. J. 2005, 11, 4387.
Song, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett. 2002, 43, 8653.
White, J. D.; Hansen, J. D. J. Org. Chem. 2005, 70, 1963.
Ph H
N SiMe3
Ph
NH2
Me92% ee, 96% de
BIcpMeO
Icp
MeH
K
78%
H
O
Me CO2MeSiMe2Ph H2NCO2Me
TiCl4CO2Me
HN
Me
MeBnO
MeBnO
50%, 30:1 dr
CO2Me
R
N
H
Bn
R
NHBn
Me87% (9:1 dr)
TMSTi(Oi-Pr)4i-PrMgCl TiL3
•TMS
HMe
TMSO
Me H
P(O)(OEt)2
NH
Me
BocHNBocHNN
H
OH BIcpIcp
HO
Kara Rosenker @ Wipf Group Page 7 of 16 10/6/2012
Methodology: Stereodefined Homoallylic Hydroxylamines
§ Reaction proceeds with aromatic and aliphatic aldehydes
§ Delivers stereodefined (E)-anti-homoallylic amines as single diastereomers
Angew. Chem. Int. Ed. 2009, 48, 3648; Org. Lett. 2009, 11, 5402; J. Am. Chem. Soc. 2009, 131, 17548.; J. Org. Chem. 2010, 75, 8048; . J. Am. Chem. Soc. 2011, 133, 9216.
R1 H
O R2
R3
OHR1
NH2
R2
R3
dr ≥ 20:1; E:Z ≥ 20:1rs ≥ 20:1
LiHMDS; Ti(Oi-Pr)4,RLi or RMgCl
Et2O
R1 H
N R2R3
R4
OHTi(Oi-Pr)4c-C5H9MgCl
Et2O R1
NHR2
R3
R4
(E)
anti≥ 95% ee
≥95% eeR1 H
N OH R3
R4
OH
R1
NHHO
R3
R4
not observed
reductive cross-coupling
R1 H
OR2
R3
O
R1 H
NTMS
R1H
NTMS
TiOi-Pr
Oi-Pr
TiOi-Pr
Oi-Pr R1H
NTMSTi
Oi-Pr
Oi-Pr
LiHMDS
Et2O
Ti(Oi-Pr)4s-BuLi
TiOi-Pr
Oi-Pr
OTiOi-Pr
H
R3
R2
NTMS
R1
H
N TiO
R2H
R3i-PrO
TMS
R1R1
NH2
R2
R3
Kara Rosenker @ Wipf Group Page 8 of 16 10/6/2012
Methodology: 1-Aza-7-oxabicyclo[2.2.1]heptanes
Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2011, 133, 9216.
Me
PhNO
Ph
A
N
Me
PhO
PhDds ≥ 20:1
toluene, 120 °C
74%
NO
PhH
MeRH N
O
HH
MeRPh
DB (C, minor)
vs[3+2]
[3,3]
NO
PhH
MeRH
NRH
MePh
H
ONR MePhO N
O
HH
MeRPh
[3+2]
A
R = (CH2)2Ph
Ph
NH
Me
PhH H
O
Me
PhNO
Ph
N
Me
PhO
Ph
N
Me
PhO
Ph
toluene, 50 °C
84% A67%
B C
B + C = 17% (B:C = 2.5:1)
HO
Kara Rosenker @ Wipf Group Page 9 of 16 10/6/2012
Methodology: 1-Aza-7-oxabicyclo[2.2.1]heptanes
Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2011, 133, 9216.
R1
NH2
R2
R3H
O N
R2
R1
OR3
O
OEt
toluene 4Å mol. sieves
rt to 120 °C2-12 h
CO2Me
2,3-anti; 3,4-syn; 4,5-anti; 5,6-anti
5 34
26
NO
R2H
R1HH N
O
HH
R2R3R1
major product
vs[3+2]
[3,3]
NR2
H
R1H
NR3H
R2R1
H
O
NR3 R2R1O N
O
HH
R2R3R1
[3+2]
EtO2C
R3O
R3
EtO2C
EtO2C
not observed
EtO2C EtO2C
EtO2C
Kara Rosenker @ Wipf Group Page 10 of 16 10/6/2012
Ti-Mediated Reductive Cross-Coupling
H
O
Me OH
O
OTMS
NH2O
O MeTMS
A
A, LiHMDS, Et2O; then Ti(Oi-Pr)4, s-BuLi;
then B
57%B
(91% ee) (91% ee)
Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134, 15237-15240.
NH2O
O MeTMSOTi
Oi-Pr
HTMS
Me
NTMSO
OH
N TiO
MeH
TMSi-PrO
TMS
O
O(91% ee)
HMeO
OMe
O Me
Me OH
low conversion poor steroselection
MeMeO
OMe
NHHO
Me
reductive coupling
Kara Rosenker @ Wipf Group Page 11 of 16 10/6/2012
Stereochemical Analysis of Reductive Cross-Coupling
NH2O
O Me TMS
NH2O
OMeTMSO Tii-PrO
H
TMS Me
N
H
TMS
O
O
NH2O
O Me TMS
NH2O
OMeTMS
O Tii-PrO
H
TMS Me
NTMSH
O
O
Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134, 15237-15240.
NH2O
O MeTMSOTi
Oi-Pr
HTMS
Me
NTMSO
OH
N TiO
MeH
TMSi-PrO
TMS
O
O(91% ee)
NH2O
O MeTMS
OTiOi-Pr
HTMS
Me
NTMS
HO
O
Kara Rosenker @ Wipf Group Page 12 of 16 10/6/2012
Asymmetric Synthesis of (−)-205B
N
CO2BuH
MeH
OTMS N
O
CO2BuHH
MeH
O
O TMS
O
O
dr ! 20:1
1. LAH, THF2. DMP, CH2Cl23. NaH, C, DME
51%
MeO
OP
TMS
OMeO
OMe
C
NO
HH
MeH
O
O TMS
OMe
O
TMS(E:Z = 2:1)
NO
HH
MeH
O
O TMS
TMS
NH
MeR
H H
TMS
HOH
R = CH2TMS
NH
MeR
H H
HH
R = CH2TMS
HO
1. DIBAL, CH2Cl22. NBSH, PPh3, DIAD NMM, -15 °C to rt
55%
Zn, HOAc; THF, 3 N HCl
82%
Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134, 15237-15240.
NH
MeTMS
HO
toluene, 4Å mol. sieves120 °C
67%
NH2O
O MeTMS
(BzO)2, K2HPO4, DMF;then N2H4, MeOH
50%
(91% ee)
O
O
H CO2Bu
O
Kara Rosenker @ Wipf Group Page 13 of 16 10/6/2012
Cationic Annulation: Aza-Sakakurai vs Aza-Cope
NH
MeR
H H
HH
R = CH2TMS
HO
NH
MeR
H H
TMS
HOH
aza-Sakurai
NH
MeR H
H
Me
HHO
N
R
H
HHO
MeH
TMS
N
R
H
HHO
MeH
TMS
H
-H+
N H
HHO
MeH
TMS
R
[3,3] N H
HOMe
H
TMS
retro aldol
aldolR
N H
HHOMe
H
TMSR
retro aldol aldol
NO
HH
MeH
O
O TMS
TMSZn, HOAc;
THF, 3 N HCl
Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134, 15237-15240.
Kara Rosenker @ Wipf Group Page 14 of 16 10/6/2012
Completion of (−)-205B
NH
MeMe
H H
H
Me
H
(!)-205B
NH
MeH H
HHO
NS
N
1. KOt-Bu, 18-crown-62. TCDI ,4-DMAP
59%
1. AIBN, Bu3SnH2. p-TsOH, benzene
61%
NH
MeH H
HHHO
TMS
Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134, 15237-15240.
Kara Rosenker @ Wipf Group Page 15 of 16 10/6/2012
Conclusion § Completed the asymmetric total synthesis of (−)-205B in 17 steps § Successfully employed two stereoselective synthetic methods developed in
their laboratories § Ti-mediated reductive cross-coupling of allylic alcohols with aldehydes
§ Path-selective intramolecular [3+2] cycloaddition of glyoxylate-based
homoallylic nitrones
R1
O
HN TMS
Li
TMS
R2
R3
OHR1
NHHO
R2
R3
1. three-component coupling2. N-oxidation
R1
NHHO
R2
R3
direct [3+2]
sequential [3,3]/[3+2]
H
O
R4
(-H2O)
N
R2
R1O
R3
N
R2
R1O
R3
R4
R4
Kara Rosenker @ Wipf Group Page 16 of 16 10/6/2012