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Asymmetric Synthesis of α-Substituted Allyl Boranes and TheirApplication in the Synthesis of Iso-agatharesinol
Yuang Yu Fang and Varinder K. Aggarwal
University of Bristol, UK
Angew. Chem. Int. Ed. 2007, 46, 359-362
Stephan ElznerJanuary 06, 2007
Stephan Elzner @ Wipf Group 1 1/14/2007
Allyl boron reagents
• Important tool in the synthesis of natural products• Allyl addition of organoboron reagents to carbonyl compounds are highly
diastereoselective
• A number of reagents for enatioselective allylation were developed with chiral ligands atthe boron center
• Few protocols were developed in which the chiral center is a structural component of theallylic unit
Introduction
R1
R2
BLn*
R H
O
O
BL2*H
R1
R2
R
R
OH
R1
R2
R2L2B
R1
V. Aggarwal, G. Y. Feng, A. T. Schmidt, J. Am. Chem. Soc. 2005, 127, 1642-1643Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207-2293
B
2
(lIpc)2B
BO
O CO2iPr
CO2iPr
Stephan Elzner @ Wipf Group 2 1/14/2007
Allylboration of Imines
T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2006, 128, 9646-9647
Proposed transition state
O
OB
CF3
CF3
CF3
CF3
NR2
R1
toluene
-78°C to rt
NHR2
R1
- Enantioselective allylation of cyclic imines
Stephan Elzner @ Wipf Group 3 1/14/2007
Application: Synthesis of Alkaloids
• Crispine A Alkaloid with antitumor activity
• Coniine Neurotoxin found in poison hemlock
• ent-Corynantheidol
T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2006, 128, 9646-9647
Stephan Elzner @ Wipf Group 4 1/14/2007
Examples for Enantioselective Allylboration in total synthesis
- (+)-13-Deoxytedanolide
A. B. Smith, C. M. Adams, S. A. Lodise, A. P. Degnan, A. B. Smith, J. Am. Chem. Soc. 2003, 125, 350-351
- (+)-Brasilenyne
S. E. Denmark, S.-M. Yang, J. Am. Chem. Soc. 2004, 126, 12432-12440
Stephan Elzner @ Wipf Group 5 1/14/2007
1,3-Disubstituted Allylboronate
J. Pietruska, N. Schöne, Chem. Eur. J. 2004, 5011-5019
Aldol addition to chiral α-substituted allyl boronate compounds
R
OH
BO
OR
CO2Et
B*
MeC(OEt)3cat. EtCO2H
135°C
Johnson rearrangement R=Me : 95% Ph : 65%
R=Me : 78% Ph : 82%
PhCHO
CH2Cl2, rt
OMe
OMe
PhPh
PhPh
single diastereomer
R
O
B*
OEtCO2Et
Ph
Ph
OH
> 98% ee
R
OH
BO
OPh
Ph
Ph
Ph MeC(OEt)3cat. EtCO2H
135°C, 48%
RCO2Et
BO O
PhPhPh
Ph
PhCHO
CH2Cl2, rtCO2Et
Ph
Ph
OH
84%, 91%ee
Stephan Elzner @ Wipf Group 6 1/14/2007
E. M. Flamme, W. R. Roush, J. Am. Chem. Soc. 2002, 124, 13644-13645J. D. Hicks, E. M. Flamme, W. R. Roush, Roush, Org. Lett. 2005, 7, 5509-5512
- One-pot double allylboration with a 1,3-bifunctionalized boron reagent for the diastereo- andenantioselective synthesis of anti-1,5-diols
- Application: Synthesis of C(43)-C(67) fragment of Amphidinol 3
α-substituted allylboronate
α-Substituted Allylboronates
O
O
CHOTBDPSO
B
O
O
Ph
Ph
PhPh
B(lIpc)2
CH2Cl2, -78°C
O
O
TBDPSO
OB(lIpc)2
BO O
PhPhPh
Ph
O
O
TBDPSO
OH
OH
OO
CH2Cl2, rt
70 - 80%, dr 9:1
OO
O
H 43
50
B
O
O
Ph
Ph
PhPh
B(dIpc)2CH2Cl2, -78°C
R1
OB(dIpc)2
BO O
PhPhPh
Ph
R1CHO
(0.82 equiv.) OH R2
OH
R1
R1, R2 = Ph, Ph(CH2)2, (CH3)2CH, C6H11
72 - 95%, 91 - 95%ee
R2CHO
(1.7 eqiv.)
rt, 24h
Stephan Elzner @ Wipf Group 7 1/14/2007
Aggarwal: Preliminary work
- Enantioselective synthesis of secondary alcohols and amines using chiral organoboranes generated from sulfonium ylides
V. Aggarwal, G. Y. Feng, A. T. Schmidt, J. Am. Chem. Soc. 2005, 127, 1642-1643
Mechanism
S+
O
BF4-
R1
BR31.2 eq. LiHMDS
dioxane, THF, 5°CR
R1
BR2R
R1
OH
H2O2, NaOH
R
R1
NH2
70 -87%, 95- 96%ee
NH2OSO3H
68-72%, 96-97%ee
R1 = Et, nBu, Ph
R = H, Me, Cl
S+
OR1
-
Stephan Elzner @ Wipf Group 8 1/14/2007
Main article: Synthesis and application of α-substituted allyl boranes
V. Aggarwal et al, Angew. Chem. Int. Ed. 2001, 40, 1430-1433
V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007, 46, 359-362
- Aldol addition to α-substituted allyl boranes
OH
Ph
HO
• Excellent enantio- and diastereoselectivity• High Z selectivity• Chiral sulfide recovered (>90%)• Side reaction (< 20%):
- Synthesis of the sulfonium salt
SO2ClO
SO
1) PPh3 dioxane/H2O reflux, 92%
2) PhCOCH2Cl K2CO3, 82%
SO
h!
Ph
O
S
O76%
S
O
endo/exo 20:1
1) PdS/C, H2
2) recryst. 84%
S+
O
Ph1) LiHMDS, -78°C THF/CH2Cl2 30 min
2)
B
R-100°C
BF4-
B
Ph R
PhCHO
-100°CPh R
Ph
OH
9
BnBrNaBF4 (aq.)
CH2Cl2
S+
O
Ph
BF4-
48% overall
Stephan Elzner @ Wipf Group 9 1/14/2007
Mechanism
Aggarwal, Angew. Chem. Int. Ed. 2007, 119, 363-366
Stephan Elzner @ Wipf Group 10 1/14/2007
Expansion of Methodology
V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007, 46, 359-362
1,3 borotropic rearrangement:
- Other enatiomer acessible via borane-isomerisation/aldol sequence
S+
O
Ph1) LiHMDS, -78°C THF/CH2Cl2 30 min
2)
B
R-100°C
BF4-
B
RPhCHO
-78°CPhR
Ph
OH
15
Ph
B
RPh
-100°C to 0°C
Stephan Elzner @ Wipf Group 11 1/14/2007
Application: Total synthesis and structural confirmation of(+)-iso-agatharesinol
V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007, 46, 359-362 C.-X. Yang, S.-S.-Huang, X.-P. Jang, Z.-J. jia, Planta Med. 2004, 70, 446-451
Confirmation of relative stereochemistry (racemic)
1) LiHMDS, -78°C THF/CH2Cl2 30 min
2)
B
-100°C
OTBS
3) TBSOCH2CHO
OTBS
OH
OTBSOPiv
72%, > 99%ee
1) LiBH4
2) TBAF
OH
OH
OHOH
S+
O
BF4-
OPiv
81%
→ matched NMR data
S+
OPiv
BF4- 1) LiHMDS, -78°C
THF/CH2Cl2 30 min
2)
B
-100°C
OTBS
3) TBSOCH2CHO
OTBS
OH
OTBSOPiv
78%
1) LiBH4
2) TBAF
OH
OH
OHOH
OH
OH
OHOH
1) DEAD, PPh3 p-NO2C6H4CO2H
2) LiBH43) TBAF
Asymmetric total synthesis
(+)-Iso-agatharesinol: Nor-lignane, isolated from asparagus gobicus (2004)
Stephan Elzner @ Wipf Group 12 1/14/2007
Conclusion
• A stereocontrolled synthesis of α-substituted allyl boranes wasdeveloped
• Subsequent aldol reaction yielded Z-configured homoallylicalcohols in excellent enantio- and stereoselectivity
• The methodology was expanded via 1,3-borotropicrearrangement and subsequent aldol reaction
• Applied to the first total synthesis of (+)-iso-agatharesinol
Stephan Elzner @ Wipf Group 13 1/14/2007