epoxide opening reactions recent advances and synthetic ... · epoxide opening reactions thomas p....
TRANSCRIPT
Recent Advances and Synthetic Applications of Epoxide Opening Reactions
Thomas P. ZabawaScheidt Group Seminar
2-4-08
! Asymmetric Epoxidation Review
! General Epoxide Ring Opening Reactions
! Recent Methodological Advances
! Selected Synthetic Applications
! Polyepoxide Opening Cascades
O NuR R
OH
Nu
Selected Asymmetric Epoxide Forming Reactions
Katsuki-Sharpless Asymmetric Epoxidation (allylic alcohols)
HO
diethyl tartrate*, Ti(i-OPr)4 (cat)O
O
O
O
OH
OH
L-(+)-DET
ROOH, molecular sieves, CH2Cl2low temperature
HO
O
Shi Asymmetric Epoxidation (up to trisubstituted olefins)
R
CH3
O
O
O
O
O
O
H3C
H3C CH3
CH3
KHSO5 or H2O2, H2O/CH3CN
derived from D-fructose
R
CH3
O
General Epoxidation Reagents
-peroxyacids, peroxides, DMDO, O2, oxone etc...
General Ring Opening of Epoxides
O
R
R
Desymmetrization of meso-Epoxides
Nu-H, catalyst
R
R OH
Nu
Nu= N3, NHR, OR, O(CO)R, SR, X, CN, R
cat= Cr, Zr, Ti, Ac, Co
O
R
Kinetic Resolutions of Racemic Epoxides
Nu-H, catalyst R OH
Nu
Nu= N3, NHR, OR, O(CO)R, SR, OH, R
cat= Cr, Co, PdO
R
+
For current reviews see:Schneider, C. Synthesis 2006, 23, 3919-3944Yus, M.; Pastor, I. M. Curr. Org.Chem. 2005, 9, 1-29
O
R
Nucleophilic Attack of Chiral Epoxides
Nu-H, catalyst R OH
Nu
or
R Nu
OH
Nucleophilic Ring Openings of Epoxy Alcohols
OHO
RNu: R OH
OH
Nu
R OH
Nu
OH
+
R = n-alkyl
NucleophileR2NHROH
PhSH, PhSNaTMSN3
NH4OBnPhCO2H*LiBH4
Selectivity (3:2) 20-100 : 1
100 : 16-9 : 114 : 1100 : 1100 : 199 : 1
Sharpless, K. B.; Caron, M. J. Org. Chem. 1985, 50, 1557-1560*Dai, L.-X. et al. Tetrahedron Lett. 1986, 27, 4343-4346
O
(RO)3TiO
H
R
H
H
1
2
3
32
1
1
2
3
Ti(OiPr)4
chelate model for regioselectivity
Reductive Ring Opening of Epoxy Alcohols
BnO OH
O
[H]BnO OH
OH
+BnO OH
OH
Reagent/Conditions
Red-Al/THF/-20 °C
DIBAL/benzene/RT
LiAlH4/ether/RT
Product Ratio
150 : 1
1 : 13
1 : 1
O
OAl
H
RO OR
5-exo-tet
OOAli-Bu2
R
Red-Al: Intramolecular Hydride Delivery DIBAL: Complexation; Intermolecular Hydride Delivery
reversal in selectivity
Kishi, Y.; Finan, J. M. Tet. Lett. 1982, 23, 2719-2722Sharpless, K. B. et al. J. Org. Chem. 1982, 47, 1378-1380Viti, S. M. Tet. Lett. 1982, 23, 4541-4544Na
Red-Al =
Al
O O
HH
OCH3H3CO
i-Bu2Al H
Carbon-Carbon Bond Formation- Epoxy Alcohols
BnOOH
O Me2CuLi, Et2O, -20 °CBnO
OH
OH
CH3
+BnO
OH
CH3
OH
Me2CuLi:
Me3Al:
1
5
6
1::
orMe3Al, CH2Cl2, 0 °C
not seperable by chromatography
BnO
CH3
BnOOH
CH3
OH
+
Me2CuLi:
Me3Al:
10-12%
69-73%
74-79%
13-14%
NaIO4, THF-H2O
Selective cleavage of 1,2-diols
efficient method for the synthesis of chiral aldehydes
Roush, W. R. et al. Tet. Lett. 1983, 24, 1377-1380
Transfer of alkyl group from Cu occurs
intramolecularly
O
R
OM
H3C
product mixture
H
O
Epoxide-Opening with Isocyanates
Roush, W. R.; Adam, M. A. J. Org. Chem. 1985, 50, 3752-3757
R OH
O NaH
BnN C O
R O
O
N O
R O
OH
BnN
O
Na, NH3
R OH
OH
NH2
94% (2 steps)minor biproduct-acyl transfer can occur
RNH
O
OH
O
LiOH, EtOH-H2O
R O
OH
HN
O
R= alkyl55-88% yield
Payne Rearrangement- Nucleophilic Trapping
OH (cat)
R
HO
O
:Nu
opening
R
OH
OH
Nu! Although the most substituted epoxide is favored, the terminal epoxide is more reactive (toward Nu attack)
! Trans epoxides are more stable than cis-epoxides
! Directing group (heteroatom- oxygen) was essential for optimal reactivity
Sharpless, K. B. et al. Pure & Appl. Chem. 1983, 55, 589
R OH
O
R
HO
O
OH
OBnO
NH2Ts, NaOH,
H2O, dioxane, 60 oCNHTs
BnO
OH
OH 61%
OH
OBnO
NaBH4, NaOH,
H2O, t-BuOH, refluxH
BnO
OH
OH 70%
OH
OBnO
PhSH, NaOH,
H2O, dioxane, 65 oCSPh
BnO
OH
OH 81%
Meso-Epoxide Opening with Dithiols
O
RR
+HS SHDouble Asymmetric Ring
Opening (ARO) Strategy
R R
HOS SH
S, S R R
HOS SH
R, R
major minor
minorminormajor major
R R
HOS S
R R
OH
C2 symmetrical- S, S, S, S
R R
HOS S
R R
OH
meso
R R
HOS S
R R
OH
C2 symmetrical- R, R, R, R
Jacobsen, E. N.; Wu, M. H. J. Org. Chem. 1998, 63, 5252-5254
Meso-Epoxide Opening with Dithiols (continued)
SH
O
cat. 1 (2 mol %), TBME
Catalyst 1
O
Cr
N
O
N
t-Bu
t-Bu
t-Bu
t-BuCl
OH
S 89% yield59% ee
SH
SH
O
cat. 1 (10 mol %),TMBE/THF OH
S
S
HO
95% yield (all isomers)C2:meso = 1.8:185% ee (C2)
S
S
TIPSO
OTIPS54% overall yield99% ee
Na/NH3, THF
SH
OTIPS
90% yield99% ee
Jacobsen, E. N.; Wu, M. H. J. Org. Chem. 1998, 63, 5252-5254
Opening of Vinyl Epoxides with Alkyne Nucleophiles
Somfai, P.; Restorp, P. (Stockholm, Sweeden) Eur. J. Org. Chem. 2005, 70, 3946-3951
O
OTBDPSLiEtO
BF3 . OEt2, Et2O
OTBDPS
OH
OEt
- Yield= 52-65% for a variety of alkyne substrates (alkyl, substituted alkyl)
- >98:2 SN2/SN2'
xylenes,reflux
OTBDPS
OH
O
O
O
OTBDPS
98%
AlEt2EtO
- treatment of epoxides with alane can favor SN2' (moderate to excellent E/Z selectivity- substrate dependent
Epoxide Rearrangement- Alkynylation Sequence
Koide, K.; Albert, B. J. J. Org. Chem. 2008, 73, 1093-1098
R
O Cp2ZrCl2, AgOTf
R1AgR
OH
R1
R
O
Cp2Zr
R1
OTf
formal1,2-hydride shift
HR
O
Cp2Zr
R1
OTfalkynyl-migration
R
O
R1
Cp2(TfO)Zrworkup
R
OH
R1
epoxides: alkyl, aryl, spiro-alkynes: alkyl, aryl, hetero-yields: 33-88%
-Current efforts are aimed to develop an asymmetric variant of this process
facial selectivity bias?rearrangement
Synthesis of cis-Diols from !,"-Epoxy-#,$-unsaturated Esters
CO2Etn-Pr
O B(OH)3, Pd(PPh3)4
THFCO2Et
n-Pr
OH
OH
96% yield98:2 dr
CO2Etn-Pr
Pd(II)
B(OH)3
Pd(0)
O
B
OH
O
inversion
Pd(0)
CO2Et
inversion
workup
Miyashita, M. et al (Hokkaido University) Chem. Lett. 2004, 764-765
- High yields and selectivities for alkyl- (and alkyl- trisubstituted) epoxides
CO2Et
OH
OH
BnO
93%
CO2Et
HO
OH
92%
CH3
CO2Et
OH
OH
H3C
CH3
Ph
H3C
86%
n-Pr
O
O
BHO
Terminal Epoxides in the Synthesis of !-Lactones
Jacobsen, E. N.; Movassaghi, M. J. Am. Chem. Soc. 2002, 124, 2456-2457
R
O
N
O
TMS
BF3 . OEt2, CH2Cl2, 0oC
O
R
N
O
TMS
KHF2, H2O
CH3CN
O
R
O
cyclic ketenaminal
O
O
89%
O
O
BnO
84%
O
O
X
Cl = 84%Br = 95%OPh = 92%CN = 69%
O
O
H3CO65%
O
O
O
91%
O
O
significant drop in regioselectivity and efficiency
Synthesis of 2,5-Disubstituted Piperdine Alkaloids
BnOOH
O BnOO
Me1. TPAP, NMO, CH2Cl2
2.Me
PPh3Br
KOt-Bu, 40%
BnO Me
OH
NHTsPd(PPh3)4
NaNHTs 91%
MsO Me
OTBS
NHTs
1. TBSCl, imidazole2. PtO2, H2, MeOH3. Pd/C, H2, MeOH4. MsCl, Et3N, THF 66%
1. K2CO3, MeOH2. Na(Hg), Na2HPO4, MeOH
NH
HO
Me3. HCl, EtOH 67%
Backvall, J.-E. et al. Tetrahedron 2000, 2225-2230
NH
NH
HO
H3C (CH2)12COCH3
HO
H3C (CH2)12COCH3
synthesized with SAE
- Cytotoxic activity- Antifungal activity
HCl
TPAP:
N Ru
O
O
O
O anti- (syn- diasteromer synthesized from cis-epoxide diasteromer)
Synthesis of 1-oxaspiro[4.5]decan-2-ones
O
OO
O
OHNH
O
CH3CH3
H3C
Aranorosin:- Posesses antibiotic and antifungal activity- Synthesized in 1996 (J. Chem. Soc., Perkin Trans. 1, 1996, 1385)
O
CO2Et
DBU, DMF, 180 oC
76%
O
CO2Et
NaBH4, CeCl3MeOH, 83%
HO
CO2Et
m-CPBA
CHCl379%
HO
CO2Et
O
1. Ti(Oi-Pr)4, Br2, CH2Cl22. H2O 64%
O
O
HO Br
OO
HEtO2C
(OR)3Ti
Nu
1. protection2. elimination
3. epoxidation
O
O
RO
O
Maier, M. E. et al (Germany) Tetrahedron 2003, 59, 7949-7960
Selectivity model:
Luchereduction
Epoxide Opening with Ketone Enolate Anions- Synthesis of Norlignan Currculigine
H3CO
H3CO
OH AD-mix-!
MeSO2NH2, t-BuOH/H2O90%
H3CO
H3CO
OH
OH
OH
1. TsCl, pyr.
2. K2CO3
79%, 99%ee
H3CO
H3CO
OH
O
NaH, CH3I
95%
H3CO
H3CO
OCH3
O
OCH3
OCH3
OK
BF3.OEt2, THF
43%
H3CO
H3CO
OCH3 O
OH
OCH3
OCH3
Norlignan Currculigine:- in vivo anti-arrhythmic activity
Posner, G. H. et al. J. Org. Chem. 2003, 68, 3049-3054
Epoxide Opening for the Synthesis of NO Synthase Inhibitors
O O
OBnBnO
O
BnO OBn
N3OH
O
BnO OBn
H2N OH
CH3CN80%
LiAlH4, THF
84% DMF, Et3N76%
O O
OBnBnO
synthesized in 2 steps from D-mannitol
HOOH
OH
OHOH
OH
- NO plays a significant role in the regulation of processes such as inhibition of platelet aggregation, neruonal transmission, and vasodilation
RN
SMe
NRNaN3, SiO2,
C2 symmetry
Le Merrer, Y. et al. Synlett, 1996, 275-277
O
BnO OBn
HN OH
NR
RHN
R= PhCH2O(CO)
Ladder Polyether Natural Products
OO
O
O
O
O
O
O
O
O
O
O
O
O
Me
H
O H
H
HH H
HMe H
HH
HH H
H
Me
OH
HH
OH
HH
H HH
HH
Me
OH
HH
gymnocin A- isolated from "red tide" bacteria- has shown in vitro cytotoxicity toward leukemic cells
O
O
O
O
O
O
O
OO
O O
O
Me
O
H
HO
H H H Me
HH H Me
H
H
H
H Me HH
Me Me HH
H
Me
brevetoxin B- "Red tide" neurotoxin- these toxins act by binding to sodium channels of neurons, keeping them oen, thereby causing depolarization of the cell membrane.
O
O
O
O
O
O
O
O
HO
OH
H H H HMe
Me
H
Me
OH
Me Me H H
H
H
HH
gambierolisolated neurotoxin
H
Epoxide Opening Cascade
O
O
O
O
O
O
O
OO
O O
O
Me
O
H
HO
H H H Me
HH H Me
H
H
H
H Me HH
Me Me HH
H
Me
LGO
Me
O
H
HO
Me
Me
Me H
Me Me
Me
OH
O OO O
O OO
O
O
O
Brevetoxin B
- Structure determined in 1981 (Koji Nakanishi)- Nakanishi theorized that this class of polyethers might be biosynthesized from acyclic polyepoxy compounds in a dramatic cascade event- This hypothesis has not yet been confirmed or discounted experimentally- K. C. Nicolaou completed the synthesis of brevetoxin B in 1995 (Clasics in Total Synthesis Cover) with some epoxide opening chemistry (formation of THP rings), but did not utilize a cascade event
epoxide opening cascade
Murai's Proposed Polyether Synthesis
Proposed Biomimetic Cascade:
OOO
X R O
O
O
H H HNu
H H HR
OO
RO
O
RO
O
RO
O
O
Nu
Murai, A. et al. Tetrahedron 1997, 53, 12425-12468
termination step (intra- or intermolecular)
briged oxonium species
cascade
Initial Screening- Single Ring
O
Br R
AgOTf (4.5 equiv)
Solvent / H2O (5:1), 25 oC O R
OTf
H2Oendo
exo
O
O
R
RH
OH
H
HOH
R = (CH2)3OTBDPS
Solvent Yield % (endo + exo) Ratio (endo : exo)
CH2Cl2benzene
Et2OTHF
dioxane
(CH3)2COCH3NCDMSO
0
359161702148
-
3.8 : 117 : 13.8 : 14.0 : 13.6 : 11.5 : 12.4 :1
O
H
H H
H ROAc
nOeobserved
Murai Tetrahedron 1997, 53, 12425-12468
*majority of mass balance was recovered s.m.
Optimization and Cyclization of syn- and anti-Diepoxides
O
O
O O
R
Br
R= CH2OTBDPS
HR
H
OTfHH
AgOTf (1.2 equiv)
CH2Cl2, 25 oC
O O
R
Br
R= CH2OTBDPS
AgOTf (1.2 equiv)
CH2Cl2, 25 oC
39%
O
O
H
HR
OTf
H
29%
Murai Tetrahedron 1997, 53, 12425-12468
O
Br R
AgOTf (1.2 equiv)
CH2Cl2, 25 oC
R = (CH2)3OTBDPS
O RH
HOTf
83% (9.8:1 selectivity)
Jamison Synthetic Targets
O
O
O
O O
O
O
O
O
O
O
O
O
O
O
HOCH3
H
O
H3C
HO
H
H3C
H
H
H3C
H
H
H
H
H
HO
H HH
H H H H HH3C
H H
HH H H H H
H
H
HO
gymnocin B
O
O
O
O
O
O
O O
O O
O
H3C
HO
H
H
H
H
H
H
HHHHHCH3
NaO3SO
NaO3SOH H H H H
CH3
CH3
CH3
CH3
H
CH3
H
OH
yessotoxin
O
H3C
H3C
Br
OH
CH3
O
O
H3C OH
OCH3
CH3
H3CH
H
armatol AO
O
O
Br
H3C
H3C
H
HH
CH3
O
H
OH
H3C OH
CH3
CH3
H
16-epi-dioxepande hydrothyrsiferol
Jamison's Homologation-Epoxidation-Cyclization Strategy
Me3Si
OH
O
O
O
H H H
HO
H H H
Me
Me3Si
OH
SiMe3
OH
Me3Si
1. DIBAL, I2
2. MeMe3Si 2. Shi epoxidation3. LiOH, H2O, THF, MeOH 65%
n-BuLi, TMEDA, CuI, DMAP 76%
SiMe3
OH
H
O1. Ac2O, DMAP, NEt3
Et2O . BF3,
CH2Cl2 80%
OSiMe3
HHO
>95% (Z) >95% ee
>95% dr (inversion)
1. TBAF, THF
2. n-BuLi, Me3SiCl72%
OH
Me3SiHO
1. DIBAL, I2
2. MeMe3Si
n-BuLi, TMEDA, CuI, DMAP 71%
OH
HO
SiMe3Me3Si
O
O
O
H H H
HO
H H H
Me
Jamison, T. F.; Heffron, T. P. Org. Lett. 2003, 5, 2339-2342
- Electron donting silyl directing group (axial in 6-mem t.s.) enhances rate of endo cyclization
OOO
HSiR3
R
H
HH
Jamison's Disappearing Directing Group Strategy
HO
OO
Me SiMe3
Jamison, T. F. et al. J. Am. Chem. Soc. 2006, 128, 1056-1057
Me3Si
BF3.OEt2
CH2Cl2, 0oC
Cs2CO3
MeOH, reflux
O
OHO
MeSiMe3 H
H H
14%
OO
HO
Me3Si
Me
Me3Si
H
50%
Optimization (formation of 1st ring, then cyclization):
O
O
SiMe3Me
HOH
SiMe3
Cs2CO3, CsF
MeOH, reflux
O
OHO
MeH H
H H
55%
Application to the Synthesis of a Tetracyclic Polyether:
O
HHO
SiMe3
O
SiMe3
O
MeO
SiMe3
SiMe3
1. Cs2CO3, CsF, MeOH, reflux
2. Ac2O, DMAP, pyridine, CH2Cl2 O
O
O
OMe
AcO
H H H H
H H H H
15%
proto-desilyation
synthesized in 9 steps LLS, 14 total operations
Water Promoted Epoxide-Opening Cascade
Jamison, T. F.; Vilotijevic, I. Science 2007, 317, 1189-1192
O
O
O
Me
HOH
H
H2O
70 oC, 24 hO
O
O
HO
Me
H H H
H H H60%
O
O
O
HOH
H
H2O
70 oC, 24 hO
O
O
Me
HO
H H H
H H H
53%
MeO
OH
H
OO
H H
HH
O
H
O
H O
H
H
OO
H H
HH
O
OH H
HO
H
OHH
Possible Hydrogen Bonding Interactions:
no directing groups needed
THP vs. THF Selectivity- a Transition State Analysis
Me
HO
O
epoxy alcohol
OO
H
Me
H
HHH -H
OMe
HOH
H
fused transition state THP
O
O
H
H
Me
H
HH-H
OHO
Me
H
spirotransition stateTHF
"template" THP ring pre-formed
Me
HO
O
O
H
H
OO
H
Me
H
HH
Otrans-6,6
transition state
less strained
HO
O
H
H
Me
H
Htrans-6,5
transition state O
H
H
H
Hmore strained
H
O
O
Me
HOH
H
HO
O
HO
MeH H
H H
Jamison, T. F.; Vilotijevic, I. Science 2007, 317, 1189-1192
generaly favored (thus the use of
directing groups)
McDonald's Synthesis of Fused Polyoxepanes
McDonald, F. E. et al. J. Am. Chem. Soc. 2005, 127, 4586-4587
O
O
O
OOMe2N
MeMe
Me3Si
MeO
O
O
O H SiMe3
H
OAc
MeMe
MeH
O
1. BF3.OEt2, CH2Cl2
2. Ac2O, pyridine
O
O
O
OOMe2N
MeMe
Me3Si
MeBF3
O
O
OOMe2N
MeMe
Me3Si
Me
O
BF3
O
O
OMe2N
O
Me3Si
Me
O
BF3
MeMeH
O
O
O
O H SiMe3
H
O
MeMe
MeH
Me2N
BF3
45%
workup / acylation
Conclusions
! Recent advances in epoxide opening reactions include many novel carbon-hetero atom and carbon-carbon bond forming sequences
! Epoxide opening reactions are synthetically useful due to advances in epoxidation reactions
! The possiblity of epoxide opening cascades in the biosynthesis of ladder polyethers is gaining respectability as recent advances provide more examples of efficient cascade reactions