Recent Advances in THP Method Development and Its Applications in Totoal Synthesis of THP Containing
Natural Products
Eur. J. Org. Chem. 2006, 2045Tetrahedron 2008, 2683
Jingqi Wang
04/06/2010
Tetrahydropyran(THP) Natural Products
O
O
O
O
CH2
O
O
N
Me
O
NO
Me
Br
OMe
MeO
Me
R2
OHOH
Me
R1O O
Me
OAcMeO2C
MeHO
O
O
O
OHMe
Me
O
MeOHOH H
OMe CO2Me
O
O
N
O
NHMeO
O
Me
OMe OO
O
O
Me
Me
Bryostatin 1
Leucascandrolide A
OO
O
CO2Me
Me
MeO
Me
CO2Me
Exiguolide
O
Me
O
O
Me
RO
O
HOChrolactomycin (R=OMe)Okilactomycin (R=Me)
O
O
O
O
O
Me
N
O
NH
MeOO
OMe
H H
Me
Neopeltolide
1113
Phorboxazole A, R1=OH, R2=HPhorboxazole A, R1=H, R2=OH
Overview of Methods for THP Synthesis
O Type I Disconnections12
O
Type II Disconnections34
2
• Neuocleophilic Substitution Cyclization: SN1 and SN2• Metal or halide Promoted Cyclization• Oxy-Michael Addition
• Prins Cyclization• Petasis-Ferrier Rearrangement• Ring-Closing Metathesis Reaction
• Hetero-Diels-Alder Reaction• Ring Expansion: Baeyer-Villiger Oxidation of Cyclopentanones• Reduction of Hemiacetals
Tetrahedron 64 (2008) 2683-2723
SN2 Nucleophilic Cyclization
O
O
N
O
NHMeO
O
Me
OMe OO
O
O
Me
Me
Leucascandrolide A
OTBS
Me
OMe OO
OH OPMB
OTBS
Me
OMe OOTs
OPMBOTBS
TBSO
S
S O
OPMB
S
S
OPMB
OH OTsNaH
PhH, 90 °C75%
1. HF.Pyr
2. NaH, PhH, 60 °C
73%
Williams, D. R Angew. Chem., Int. Ed. 2003, 42, 3934-3938
SN2 Nucleophilic Cyclization
O
O
O
O
CH2
O
O
N
Me
O
NO
Me
Br
OMe
MeO
MeOH
OH
Me
Phorboxazole A
O
CH2
O
O
N
PivO
OTBS
PMBO
OH
O
O
N
OTBS
PMBO
PivO
HO
TsOO
O
NPMBO
OPiv
O
NPMBO
O
O
OPiv
OH
1. MsCl, Et3N2. TsOH, MeOH
3. NaH, PhMe, Δ72%
NaH
PhH, Δ89%
Williams, D. R Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12058-12063
SN2 Nucleophilic Cyclization
Phorboxazole A
O
OPMB
O
CH2
O
O
N
Me
O
NO
Me
Br
MeO
MeO
MeOH
OH
Me
OH
O
O
O
O
CH2
O
O
N
Me
O
NO
Me
Br
MeO
MeO
MeOH
OH
Me
OH
TBSO
O
OPMB
O
O
N
Me
O
NO
Me
Br
MeO
MeO
MeOH
OH
Me
OH
OH
OTES
OTBS
1. MsCl, Et3N2. PPTS, MeOH
83%
3. Et3N, MeCN, Δ
White, J. D Org. Lett. 8 (2006), 6043–6046
SN1 Nucleophilic Cyclization
O
O OH OHO
OHn-C12H25
O
(+)-Muconin
OBoc
OOH
TMS Co2(CO)6
BF3.OEt2
CH2Cl2
TMS
(OC)6Co2 O
OtBuO
OO OH
OHTMS Co2(CO)6
1. CAN, acetone
2. K2CO3, MeOH3. CH2(OMe)2, CSA
OO
O
MeMe
Martín, V. S J. Org. Chem. 71 (2006), 2339–2345.
Epoxide Mediated Cyclization
• Nakanishi Cascade Hypothesis: Transformation of polyepoxide into a ladder polyether via cascade of epoxide-opening events.
• THF-selective(5-exo) epoxide-opening cascades are supports for Cane-Celmer-Westley hypothesis for biosynthesis of Monensin
• THP-selective(6-endo) epoxide-opening cascades promoted by H2O are supports for Nakanishi hypothesis (Timothy F. Jamison)
O
OO
OO
OHCH
MeHH
OH
HMe
HMe
H MeH H
OH
Brevenal
Epoxide Mediated Cyclization
OHR
O
OHR
O
O
HO
R
O
HO
R
OHO
HR
OHO
HR
5-exo
favored6-endo
6-endo
favoredR=(CH=CH2)
5-exo
favoredR=CH2X
R
O
OHO
HO
HR
OHO
HR
R
O
OH
O
HO
R
H
H
O
HO
R
H
H
6-exo
favored
6-exo
favoredR=CH2X
7-endo
7-endo
favoredR=(CH=CH2)
cis-epoxide
trans-epoxide
cis-epoxide
trans-epoxide
Baldwin Rules:
Tetrahedron 64 (2008) 2683-2723
Epoxide Mediated Cyclization
OHR
O
O
HO
R
6-endo
favoredR=(CH=CH2)trans-epoxide
OHR
O
O
HO
R
6-endo
favoredtrans-epoxide
MeO OMe
La
OHTMS
O
O
HO
TMS
6-endo
favoredtrans-epoxide
Tetrahedron 64 (2008) 2683-2723
Alkene, Alkyne and Cyclopropane-Mediated Cyclization
• Mercury-mediated cyclization• Halo-mediated cyclization• Seleno-mediated cyclization (higher trans-selectivity-kinetic product)• Palladium-mediated cyclization• Other metal-mediated cyclization (Pt, Sn, Ag, Ce, Au)• Metal carbene-mediated cyclization (generated from diazo-compounds)• Acids-mediated cyclization
OH
+ E
OH
E
OE
O- E
OH
E
6-exo, - H
6-exo
- H
Onium intermediate
OHHOHgX2
OHOHgX X
O OH
HgX
O OH
HgX
Murcury-Mediated Cyclopropane Cyclization
OHO
OH
OH
O OH OH
Zincophorin
N2O
O
0.1% Rh2[5-R-MEPY]4CH2Cl2, Δ
91%, > 95% ee
O
O
OH
O OH
BzO
O OH
BzOO
1. Hg(OCOCF3)2, CH2Cl22. KBr aq.
3. Bu3SnH, PhMe-THF
85%, dr= 93:7
J. Cossy, J. Org. Chem. 69 (2004), 4626–4647
Pd-mediated Alkene Cyclization
O Me
O
O
O
Me
NH
O
Me
OH
H H
Zampanolide
OBn
HO
OBn
OCO2Et
5% Pd(PPh3)4THF, rt
OBn
O
OBn
OBn
HO
OBn
OCO2Et
5% Pd(PPh3)4THF, rt
OBn
O
OBn
71%
68%
D. Lee, Tetrahedron Lett. 45 (2004), 7151–7155
Metal Carbene Mediated Cyclization
O O
N2
H
OH
5 mol% Cu(tfacac)2CH2Cl2, reflux
80%, dr= 30:1O O
H
OH
1. DBU
2. LAH
86%O OH
H
OH
O OH
OH
O
N2
5 mol% Cu(tfacac)2CH2Cl2, reflux
80%O O
H
OH
O
H
H1. DBU
2. LAH86%
O OH
OH
OH
H
H
F.G. West, J. Am. Chem. Soc. 123 (2001), 5144–5145
Oxy-Michael Addition (6-exo-trig)
O
O
N
O
NHMeO
O
Me
OMe OO
O
O
Me
Me
Leucascandrolide A
OTBS
Me
OH OO
CO2Et
Me
Me
OTBS
OTBS
Me
OH OHO
CO2Et
Me
Me
OTBS
10 mol% t-BuOK
THF, 0 °C
81%, dr=9:1
E.M. Carreira, J. Org. Chem. 68 (2003), 9274–9283
Oxy-Michael Addition (6-exo-dig cascade 6-exo-trig)
TBSO
O
OO 1. 10 mol % CSACH2Cl2-MeOH 5:1
2. 10 mol% TsOHPhMe
TBSO
O
OHOH
O
OOTBS
HO
O
O
OTBS
O
6-exo-dig 6-exo-trig
BocN
O
O
OTBS
OTBS
TBAF
THF, rt
N
O
O
O
Boc
O
H
H
90%
85%
Oxy-Michael Addition (6-endo-dig)
O
O H
HO
OMe
Amberlyst-15
CDCl3, reflux, 18h
90%, dr>10:1
O
O H
HO
OMe
Amberlyst-15
CDCl3, reflux, 23h
78%, dr>10:1
O
O H
O
OMe
O
O H
O
OH
NH
O
(-)-Apicularen A
M.A. Rizzacasa, Org. Lett. 6 (2004), 1289–1292
Prins Cyclization
Main drawback: racemization of stereocenters by competing oxonia-Cope rearrangement
O Me
O
O
O
Me
OHC
H H
(+)-Dactylolide
TMS
OBPSOH
PMBO
H
O
MeOTBS
TMSOTf, Et2O
85%, one diastereomer
OTBS
OBPS
O
Me
H H
OPMB
Tetrahedron 2010, 413
Petasis-Ferrier Rearrangement
O Me
O
O
O
Me
OHC
H H
(+)-Dactylolide
O Me
O
O
O
Me
NH
O
Me
OH
H H
Zampanolide
O
O
O
O
CH2
O
O
N
Me
O
NO
Me
Br
OMe
MeO
Me
R2
OHOH
Me
R1
Phorboxazole A, R1=OH, R2=HPhorboxazole A, R1=H, R2=OH
O
Me
O
O
Me
MeO
O
HO
Okilactomycin (R=Me)
Smith, A. B. Acc Chem Res. 2008 May;41(5):675-87
Petasis-Ferrier Rearrangement
O
Me
O
O
Me
MeO
O
HO
Okilactomycin (R=Me)
ONap
PhSe
BnO
O
O
OH
O
OH1. TMSOTf2. Cp2TiMe2
3. Me2AlCl
45%, 3 steps
ONap
PhSe
BnO
O
O
Smith, A. B.; Basu, K.; Bosanac, T. J. Am. Chem. Soc. 2007, 129, 14872.
Hetero-Diels-Alder Reaction
Me
Me
OR
R1CHO+O
O
Me
R1Me
N
O
Me
OCr
X1)
2) TBAF, AcOH, THF(X=Cl or SbF6)
O O
NH
Me
Me
OAcO Me
Me
O
Me
OH
HO
FR901464
A B
Jacobsen, E. N Angew. Chem. Int. Ed. 2002, 41, 3059–3061
Hetero-Diels-Alder Reaction
O
O
O
O
CH2
O
O
N
Me
O
NO
Me
Br
OMe
MeO
Me
R2
OHOH
Me
R1
Phorboxazole A, R1=OH, R2=HPhorboxazole B, R1=H, R2=OH
O
OTBS
O
N
Me
O
N Me
Me
O
H
O
O
CH2
MeOSETO
Jacobson's Catalyst O
OTBS
O
CH2
O
O
N
Me
O
N Me
Me
OTES
CO2Me
I. Paterson Org. Biomol. Chem. 2004 , 2 , 3026I. Paterson Tetrahedron Lett. 2003 , 44 , 3749
Reduction of Cyclic Hemiacetal
O Me
O
O
O
Me
OHC
H H
(+)-Dactylolide
O Me
O
O
O
Me
NH
O
Me
OH
H H
Zampanolide
OMeOTBS
TBSOOTES
O
1. allylMgBr
2. Et3SiH, TFA, THF78%
OMeOTBS
TBSOOTES
Pseudo-axial delivery of hydride provides 2,6-cis-THP
F. Ding , M. P. Jennings , Org. Lett. 2005 , 7 , 2321
