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Non-Aldol Polyketide SynthesesHans Renata Baran Group Meeting09/01/2012
O O
O O
MeO2C
MeO
OMe
MeMe
MeMe
OHO
H
OAc
OH
HO
HO
CO2Me
bryostatin 1
O
O
O
OHMe
OH
Me
OMe
Et
MeHO
Me
Me
O
O
OMe
OMe
OHMe
NMe2HO Me
erythromycin
OMe
O
Me
Me
Me
OH
Me
MeOH
HOMe Me
OH O
O
NH2
discodermolide
O
O O
Me Me
Me
Me
OH
HO
OMe
N
SMe
epothilone A
Examples of Bioactive Polyketides
Approaches Not Discussed
1. Dithiane approach (Smith, Mori)
S S E+
For example: - Mori's roxaticin, Tetrahedron, 1995, 51, 5299- Smith's rapamycin- Smith's altohyrtin C, ACIE, 2001, 40, 191
2. Cyanohydrin approach (Rychnovsky)
O O
R
MeMe
CNLi For example:
- Rychnovsky's roxaticin, JACS, 1994, 116, 1753
3. Allylation, crotylation, conjugate addition (Unless used in tandem reaction)
5. Hetero Diels-Alder
O
OTBS
R1 R2
For example:- Jacobsen's ambruticin, JACS, 2001, 123, 10772- Snider's pseudomonic acid A, JACS, 1982, 104, 1113- Danishefsky's zincophorin, JACS, 1987, 109, 1572
6. Petasis-Ferrier
O
O
O
R1 R2 O
O
R1 R2
For example:- Smith's phorboxazole A, JACS, 2001, 123, 10942- Smith's dactylolide, JACS, 2002, 124, 11102
4. Methylketene dimerization approach (Calter)
OO
Me
Me
NMeMeO
Li
1.
2. RCHO
For example:- Calter's siphonarienal, JOC, 2001, 66, 7500
Non-Aldol Polyketide SynthesesHans Renata Baran Group Meeting09/01/2012
Transition Metal Catalysis1. CarbometalationZr-catalyzed Asymmetric Carboalumination (ZACA)Early observation (cf. Dzhemilev ethylmagnesiation and Kulinkovich reaction)- See ARKIVOC 2011, 34–53 for an extensive account
Cp2ZrCl2 + Et3AlCl
AlEt2Cl
Cp2ZrEt
Cp2ZrCl
AlEt2
Cp2ZrCl
AlEt2
nBunBu
Cp2ZrCl AlEt2
nBu
nBuAlEt
nBu
nBu
nOct
Et3Al,cat. Cp2ZrCl2
nOct
EtAlEt2 nOct
HAlEt2 nOct
Et/Decyl
ZrCl2
2
Et3Al
nOct
EtAlEt2
O2
nOct
EtOH
Generation of Reduced PolypropionatesMe
AlMe2(-)-ZACA
Me1. Zn(OTf)22. Pd vinylation
Me Me MeOH
Me
(19% from styrene,dr >22/1.6/1)
Me Me MeOH
MeMe Me Me
OAcMe
HO
1. Ac2O2. RuCl3, NaIO4
3. BH3
ONC
Me Me MeOH
OHMe
O
HCO2H
borrelidin
Me
OH
Me
OMgCl
EtMgCl
Me
OH
EtNHTs
Me
OH
EtNH2
O
HNEt Et
Me
O
OH
fluvirucin B1 agylcon
RCM
PeptideCoupling
OH
Et
BrMgO
Et
BrMg
OH
Et
O
EtOH
Hoveyda et al. JACS, 1995, 117, 2943–2944
EtMgBr5% Cp2ZrCl2 Ts
N
40%
Na/NH3
99%
EtMgBr,0.4% (S)-[EBTHI]-Zr-BINOL
n-PrMgBr,3% Cp2TiCl2
("~70 turnovers")
Br
(Ph3P)2NiCl2, 72%
TPAP,NMO
65%,>99% ee
Magnesiation Cascade(Hoveyda)
(10% from styrene,dr >80:1)
Selected references:- Negishi et al. JACS, 1995, 117, 10771–10772- Negishi et al. PNAS, 2004, 101, 5782–5787- Negishi et al. JACS, 2005, 127, 2838–2839
(major)
Non-Aldol Polyketide SynthesesHans Renata Baran Group Meeting09/01/2012
Transition Metal CatalysisHydroformylationCatalyst-directing group on OH moiety (Breit)
RMe
O O
PPh2
RMe
O O
PPh2
Osyn:anti > 9:1
1,2- Induction
Rh(CO)2acac,P(OPh)3,
20 bar H2/CO (1:1)
H
R
MeO
OPPh2Rh
H
CO
Proposed StereochemistryModel
1,3- Induction
R
OO Me
Ph2P
R
OO Me
Ph2P
O
anti:syn > 9:1
Rh(CO)2acac,P(OPh)3,
20 bar H2/CO (1:1)
OMe
PPh2
Rh R
O
1,2-Anti Induction
O O
Me Me
Ph
OOMe
MePh
facial approach
O O
Me Me
Ph
O
dr > 99:1
Asymmetric hydroformylation of dienes is possible
O Et
Me
MeO Et
Me
Me Me
O
PPh2
OPO
O
Rh(CO)2acac,L*,
20 atm H2/CO (1:1)
O Et
Me
Me Me
OCO2H
Me
OHOH
As part of tandem process...
Me
MeO
Me
SiH
Me
MeO
Me
Si O
Me
MeOH
Me
OH OH
Me
MeO
Me
SiRhLnCO
H
Me
MeO
Me
Si O
via:insertion/
RE
ambruticin
Rh cat.,CO [O]
Other accessible triads:
R
OH OH
R
OH OHO
(Start with alkyne, without oxidation step) (Start with alkyne, with oxidation step)
Proposed StereochemistryModel
Rh(CO)2acac,P(OPh)3,
20 bar H2/CO (1:1)
80%
Selected references:- Liebigs Ann. Chem. 1997, 1841–1851- Eur JOC, 1998, 1123–1134- JOC, 2001, 66, 4870–4877
L*:
(iso:n = 91:9,dr = 96:4)
Jacobsen et al. JACS, 2001, 123, 10772–10773Nozaki et al. Tetrahedron, 1997, 53, 7795–7804
59%, dr = 92:8
Leighton et al. JACS, 1997, 119, 12416Leighton et al. JACS, 2000, 122, 8587Leighton et al. ACIE, 2001, 40, 2915
Non-Aldol Polyketide SynthesesHans Renata Baran Group Meeting09/01/2012
Reductive Coupling Approach(See Reductive Coupling GM, IY, 2009)
Some Highlights
Construction of ene-1,5-diol motif (Micalizio)
O
Me
R1
Me Me
R2O
Me
" "
Me MeMe
OHR1
Me
R2OH
via:
TiOMe
R
TiO O
Me
OiPr OiPr
R'R
R'CHO
If the third coupling partner is another alkyne:
TiO
R2
R4
R3
TiOiPr
OiPriPrO
R3 R4OH R2R1
OH
R2
R3
R4
R1
R1
Me
OH O
Me
Me
OMe
HO
Me Me Mecallystatin A(ACIE, 2008, 47, 7837)
NH
OMe
Me
OR
MeMeO
Me
MeO
O
Me
O
O
Me
macbecin 1(ACIE, 2008, 47, 4005)
Applications in total synthesis:
Use of silicon tether in reductive coupling (Phillips)
PMBO
Me
OSi
Me
iPriPrClTi(OiPr)3,
iPrMgCl PMBO
Me
O Si MeiPriPr
Me
via:
PMBO
Me
O SiiPriPr
Ti(OiPr)2
Me
H
MeO
OH
Me
MeOH
OH
Me
MeHO
OMe
dictyostatin
Cobalt chemistry - untapped potential?
1. Hydrovinylation
RR
MeCoCl2,
ligand, Me3Al,ethylene
EtO
O
Me
TMSMe
MeO2CTMS
CoBr2,ligand,
Zn, ZnI2
2. Alder-ene reaction
R
OH MeClTi(OiPr)3
R'MgCl
JACS, 2005, 127, 3694
JACS, 2006, 128, 2764
65%
JACS, 2006, 128, 5340–5341
For example: JACS, 2010, 132, 3295 JACS, 2012, 134, 6556
For example: OL, 2011, 13, 304–307 OL, 2011, 13, 5700–5703
tBuO
tBuO2C
Non-Aldol Polyketide SynthesesHans Renata Baran Group Meeting09/01/2012
Main Group ChemistryAcylsilane in Johnson's synthesis of zaragozic acid C
tBuO2C TBS
O MgBr
BrMg OO
TBSOtBu
TBSOO MgBr
O
TBS
OtBu
TBSOO
TBS
O
OtBuMgBrOH
tBuO2C
O MgBrO
OtBu
tBuO2COTBS
HTBSOtBuO2C OTBS
COtBu
OHCO2tBu
OO
HO2C OHCO2HCO2H
OOH
Bn
Me
AcO
BnMe
O
H
zaragozic acid C
Silirane ring opening (Woerpel)
Si
MeMe
tButBu Si O
Me
Me
OAc
tButBu
Et
OTMSMe
Si O
Me
Me
tButBu O
MeEt
BnN
Me
CHO
Me
OH
Me
OH
MeEtO
Me
Me
OMe
O
EtMe
epi-stegobinone
SitBu
tBu
RSi
tBu tBuΔ Si
R
tButBuThermal
Metal-catalyzedelectrophilic
SitBu
tBu
AgX
electrophilic
SitBu
OTf
tBuAgLn R Si
R
tButBu
Ln = alkene, or phosphine ligand if present
Si
R1
tButBu
Silirane reactivity profile
O
X H Si O
R1
tButBu
XR2
R2
nucleophilic attack possibleif X = leaving group
[O]Application in synthesis
Variations on a theme
1,2,4-triols from allenes
Cy•
MeH
SitBu
tBuSi O
Cy
iPr
tButBu
Me
MeiPr
OH
CyOH
OH
45–50% yield (15 g scale)diastereoselection >10:1
3 contiguous stereogenic centers in the correctoxidation statestrategic protecting group scheme that maskedevery functional group except the 2º alcohol
Johnson et al. JACS, 2008, 130, 17281–17283
For mechanistic studies: JACS, 2003, 125, 10659–10663 (thermal) JACS, 2004, 126, 9993–10002 (Ag catalyzed)
Acc. Chem. Res., 2000, 33, 813–820
AgTFA;
CuI, iPrCHO
1. mCPBA2. KOtBu TBAF
70%, 96:3:1 dr60%
over 2 steps
OL, 2009, 11, 2173–2175
CuI (20%)
74% from butene
SnBr4
95%
1. Ph3PCH2Br2. PhMe2C(OOH), KH, CsF
74%over 2 steps
thenCuSO4,Ac2O
JOC, 2007, 72, 1027–1030
CO2tBu
H
O
O
H
R1 H
Non-Aldol Polyketide SynthesesHans Renata Baran Group Meeting09/01/2012
Variations on a theme (contd.)
SitBu
tBu
Insertion into vinyl epoxides
OO Si
tButBu
O
H R3
OO
R2
R3SiR1
R2
R1R2
H
tBu
tBu
Highly diastereoselectivefunctionalization
possible
Me
O
OEtMe
Reaction with dienoates
Si O
MeMe
tButBu
OEt
SitBu
tBu
O OSi
O
HR
Me
Me
tButBu
SiO
O
Me
Me
R
OEt
tBu
tBu
Proposed Zimmerman-Traxler-like TS
Reaction with dienes
R2
R1
SitBu
tBu
OSi
H R1
R2R3
tButBu
HOSi
H R1
R2R3
tButBu
HO
OSi
R1
R2HtBu
tBu
R3
SiH
H
R3
OAc
R2R1tBu
OActBu
Lithiation-Borylation-Allylation Cascade (Aggarwal)
O
Li
HR NiPr2
O
Me3SiB
Me3SiBR'2
OCb
BR'2
HR
Me3Si
Me3Si
BR'2R
H
R"
O
R R"
OH
SiMe3
R"R
OH
OH
Anti-diol
BSiMe3
R R"
OH
SiMe3
R"R
OH
OH
Me3SiB O
OSyn-diol
BO
O
O SiMe3R"
OH
SiMe3
R"R
OH
OH
2% AgOTs
JACS, 2009, 131, 14182–14183
AgTFA RCHO
37–80%
JACS, 2011, 133, 406–408
1% AgTFAΔ
SiO2TBAF;Ac2O
JACS, 2012, 134, 12482–12484
General idea:
R
R"
R"
R
OO
C5H11
HOH
OH H
solandelactone E
Achieving stereocontrol
OO
C5H11
HOH
OH H
solandelactone F
R
[O]
[O]
ACIE, 2010, 49, 4264–4268ACIE, 2010, 49, 6673–6675Org. Biomol. Chem. 2012, 10, 1795–1801
R3CHO
Non-Aldol Polyketide SynthesesHans Renata Baran Group Meeting09/01/2012
Cyclic Stereocontrol - Pericyclic Reactions
O
MeMe O
OBn
O O
Me Me
H
OBn
O O
Me
H
OBnArCO2
OHMemCPBA
O
OHMe
HO
Me
NNMe2
OBn
EtMgBr
OEt
OHMe
HO
O
OBn
Me
Me
MeOO
Et
H
MeOHMe
OH
O
OMeMe
O
asteltoxin
Use of Paterno-Buchi reaction (Asteltoxin, Schreiber)
OEt
OHMe
HO
O
O
Me
Me
Me
OEt
OHMe
HO
OMe
Me
MeSO
Ph
H
HO SO
Ph
O
O
Me
S
NMe
O OHMe
MeOH
Me Me
O
Me
PO
EtOEtO
N
Cl
OH
Directed nitrile oxide cycloaddition (Epothilone, Carreira)
OTIPS
OH Me
OTIPS
OH Me
ONPO
Me
EtOEtO
OTIPS
OH Me
ON
Me
N
SMe
1. TBSOTf2. LiCl, DBU
1. SmI2, B(OH)32. BEt3, NaBH4
OTIPS
OH MeMe
N
SMe
OHOHO
Me
S
NMe
MeOH
OH
hν
63% 80%
HCl;Me2NNH2
72%O
Et
OHMe
OH
OH
OBnMe
Me2CO,CuSO4, CSA
55%over 2 steps
BuLi
88%
JACS, 1984, 106, 4186–4188
3 equiv EtMgBr3.3 equiv iPrOH
54%, 94% brsm 70%(6:1 E:Z)
68%(9:1 E:Z)
1. SOCl22. TBAF
77%
+
epothilone A ACIE, 2001, 40, 2082JACS, 2001, 123, 3611JOC, 2001, 66, 6410
Me
Me
Non-Aldol Polyketide SynthesesHans Renata Baran Group Meeting09/01/2012
Cyclic Stereocontrol - Pericyclic ReactionsCycloaddition-oxabicyclic ring opening (ionomycin, Lautens)
O
MeO
Me
X O
Me
Me
O
O Me
OTIPSMe
Ni(COD)2,(S)-BINAP,DIBAL-H
OTIPSMe Me
HO
O OMe
OH O
H
OH OH
MeMeH MeMe
OH Me Me Me Me
O
OHMe
OTIPSMe Me
PMBO
MeMe
OTIPSOO
PMP
OH
O
O
OMe
MeHO
MeEt
Me
OH
methynolide
EtO2C
Me
Me
StBu
O
EtO2C
SMe
OAc
Me
Me
SMe
OR
MeS
Me
EtO2COR
H
Me
S
HMeEtO2C
H
ORMe
HMeS
HMe H
ORMe
HS
O
Et
Me
Me
Me
OR
H
Pericyclic reaction with sulfur (methynolide, Vedejs)
95%,93–95% ee
"Redox-massage"(D. Sarlah)
1. O3; NaBH42. DDQ
base[H];
Protection
79%
82%
ionomycin
23 1710 1
C17–C23 fragmentNote: C1–C10 fragment was synthesized via methylative oxabicyclic ring opening
JACS, 1995, 117, 532JACS, 1997, 119, 11090OL, 2002, 4, 1879
Ac2O, AcOH;BF3.Et2O
81%
1. K2CO3; then protect2. DIBAL; MsCl, BuLi
3. LiBEt3H
35%
TfO CO2Et
6 steps
OTfO
Et
76%dr= 16:1
59%
JACS, 1987, 109, 5878JACS, 1989, 111, 8421, 8430
Non-Aldol Polyketide SynthesesHans Renata Baran Group Meeting09/01/2012
Conclusion
NHOO
Me MeO
Me
Me
Me
Me
O
Me
Et
Me
halichomycin(TL, 1994, 35, 5013)
O OMe
OMeMe
Me
O
O
OH
Me
OH
Me
OO Me
O
O OMeHO
Me MeOH
OMe
H
HH
neaumycin(OL, 2012, 14, 1254)
HN
Me Me
O O O OH
OH
OHMe
tripartilactam(OL, 2012, 14, 1258)
POLYKETIDES"The armory of the synthetic chemist is richly endowed with weapons of great effectiveness in
the stereoselective, or often stereospecific, generation of newly created asymmetric centers within rigid systems, as best exemplified by cyclic–and especially fused polycyclic–systems. By contrast, the construction of asymmetric arrays in a desired stereochemical sense in flexible, open chain systems is rare, or little understood when observed, and generalizations are dangerous."
S S
OO
H
MOMOMe Me
OBn
Me Me Me
OO
CHOMOMO
Me Me
"the use of sulfur atoms to create rings by bridging carbon atoms that are destined to become methyl groups; indeed, a glamorization of the lowly, usually modest methyl group, which at first sight would hardly be expected to play a prominent role in the direction of stereoselective synthetic operations!"
Where are we today?