Hans Renata
Baran Group Meeting
09/01/2012
Non-Aldol Polyketide Syntheses
Examples of Bioactive Polyketides
Me Me
HO
MeO2C
O
Me
Me
O
O
HO
Me
HO
O
Me
O
HO
Me
Me
Me
O
Me
OH
Me
O
Me
Me
O
Me
OH
Me
Me
OH
Me
NH2
O
O
discodermolide
OH
O
O
OMe
Me
erythromycin
Me
HO
Me
OH
O
CO2Me
bryostatin 1
NMe2
Me
HO
O
Me
O
O
OH
O
OH
Et
H
O
HO
O
OAc
Me
Me
S
Me
N
Me
Me
Me
O
Me
epothilone A
O
OH
O
Approaches Not Discussed
1. Dithiane approach (Smith, Mori)
S
S
E+
5. Hetero Diels-Alder
For example:
- Mori's roxaticin, Tetrahedron, 1995, 51, 5299
- Smith's rapamycin
- Smith's altohyrtin C, ACIE, 2001, 40, 191
R1
2. Cyanohydrin approach (Rychnovsky)
Li
R
O
O
Me
Me
CN
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
OTBS
For example:
- Rychnovsky's roxaticin, JACS, 1994, 116, 1753
O
R2
6. Petasis-Ferrier
O
O
O
For example:
- Smith's phorboxazole A, JACS, 2001, 123, 10942
- Smith's dactylolide, JACS, 2002, 124, 11102
3. Allylation, crotylation, conjugate addition (Unless used in tandem reaction)
4. Methylketene dimerization approach (Calter)
O
O
Me
1.MeO
N
Li
Me
2. RCHO
Me
For example:
- Calter's siphonarienal, JOC, 2001, 66, 7500
R1
O
R2
R1
O
R2
Hans Renata
Baran Group Meeting
09/01/2012
Non-Aldol Polyketide Syntheses
Me
Transition Metal Catalysis
Me
Me
Me
OH
1. Carbometalation
Cp2Zr
Cl
Et Cl
AlEt2
Cp2Zr
Cl
nBu
AlEt2
Cp2Zr
Cl
Cl AlEt2
Et
AlEt2
AlEt2
nOct
ZrCl2
Me
Me
AlMe2
Ts
N
Et
40%
1. Zn(OTf)2
2. Pd vinylation
OH
Na/NH3
NH2
Me
OMgCl
Me
OH
OH
nOct
2
Generation of Reduced Polypropionates
(-)-ZACA
CO2H
borrelidin
Et
AlEt2
nOct
H
MgCl
nOct
O2
Et
O
Et
EtMgBr
5% Cp2ZrCl2
Et/Decyl
(major)
Et3Al
O
fluvirucin B1 agylcon
H
nOct
OH
Me
Peptide
Coupling HN
Al
Et
Me
NC
O
Et
nBu
Me
OH
nBu
nBu
nOct
Me
Me
OH
OH
Et3Al,
cat. Cp2ZrCl2
Me
OAc
Me
Magnesiation Cascade
(Hoveyda)
RCM
AlEt2
nBu
Cp2Zr
Me
3. BH3
(10% from styrene,
dr >80:1)
Early observation (cf. Dzhemilev ethylmagnesiation and Kulinkovich reaction)
- See ARKIVOC 2011, 34–53 for an extensive account
nBu
Me
HO
Zr-catalyzed Asymmetric Carboalumination (ZACA)
Cp2ZrCl2 + Et3Al
1. Ac2O
2. RuCl3,
NaIO4
NHTs
99%
Et
Me
Me
EtMgBr,
0.4% (S)-[EBTHI]-Zr-BINOL
O
Et
n-PrMgBr,
3% Cp2TiCl2
Et
Et
BrMg
("~70 turnovers")
BrMgO
OH
(Ph3P)2NiCl2,
72%
Br
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
Me
Me
Me
Et
Me
OH
OH
(19% from styrene,
dr >22/1.6/1)
O
Hoveyda et al. JACS, 1995, 117, 2943–2944
TPAP,
NMO
65%,
>99% ee
Et
OH
Hans Renata
Transition Metal Catalysis
Asymmetric hydroformylation of dienes is possible
Hydroformylation
Me
Catalyst-directing group on OH moiety (Breit)
1,2- Induction
Me
Me
OH
R CO
O
O
Me
Me
Et
O
L*:
PPh2
Me
Rh
H
O
H
R
R
Me
O
(iso:n = 91:9,
dr = 96:4)
Me
Proposed Stereochemistry
Model
O
O
Rh(CO)2acac,
L*,
20 atm H2/CO (1:1)
Et
O
Rh(CO)2acac,
P(OPh)3,
PPh2
20 bar H2/CO (1:1)
O
Baran Group Meeting
09/01/2012
Non-Aldol Polyketide Syntheses
O
OH
PPh2
PPh2
O
P O
Me
O
O
O
CO2H
syn:anti > 9:1
Me
Me
Et
Me
ambruticin
1,3- Induction
Jacobsen et al. JACS, 2001, 123, 10772–10773
Nozaki et al. Tetrahedron, 1997, 53, 7795–7804
Rh(CO)2acac,
P(OPh)3,
20 bar H2/CO (1:1)
Ph2P
O
Me
O
As part of tandem process...
Ph2P
Proposed Stereochemistry
Model
O
O
Rh
P
Ph2
O
H
Me
anti:syn > 9:1
Me
Me
Si
Me
O
O
Me
Me
Me
Me
OH
OH
Me
Me
Me
Me
59%, dr = 92:8
insertion/
RE
Me
CO
O
Si
O
Me
Me
Me
Other accessible triads:
OH
Me
O
O
OH
[O]
O
O
80%
Me
H
RhLn
Ph
O
Si
via:
O
Rh(CO)2acac,
P(OPh)3,
20 bar H2/CO (1:1)
O
Me
1,2-Anti Induction
Ph
Rh cat.,
CO
R
R
O
Me
Si
Me
Me
R
O
O
Ph
facial approach
Me
dr > 99:1
O
Selected references:
- Liebigs Ann. Chem. 1997,
1841–1851
- Eur JOC, 1998, 1123–1134
- JOC, 2001, 66, 4870–4877
OH
R
(Start with alkyne, without oxidation step)
OH
O
OH
R
(Start with alkyne, with oxidation step)
Leighton et al. JACS, 1997, 119, 12416
Leighton et al. JACS, 2000, 122, 8587
Leighton et al. ACIE, 2001, 40, 2915
Hans Renata
Baran Group Meeting
09/01/2012
Non-Aldol Polyketide Syntheses
Reductive Coupling Approach
(See Reductive Coupling GM, IY, 2009)
Use of silicon tether in reductive coupling (Phillips)
Some Highlights
iPr
Construction of ene-1,5-diol motif (Micalizio)
O
"
R1
Me
O
"
Me
OH
R2
Me
PMBO
OH
R1
Me
iPr
O
R2
Me
Me
Me
iPr
ClTi(OiPr)3,
iPrMgCl
Si
Me
PMBO
Me
Me
OH
ClTi(OiPr)3
R'MgCl
O
R
OiPr
OiPr Me
Ti
O
R'CHO
Ti
via:
iPr
O
R
R
PMBO
R'
OH
iPr
O Si
Me
H
Ti(OiPr)2
Me
Me
JACS, 2005, 127, 3694
HO
iPrO
OiPr
OH
R1
Ti
OiPr
Ti
R4
R4
R3
OH
R2
Applications in total synthesis:
Me
CoCl2,
ligand, Me3Al,
ethylene
For example: JACS, 2010, 132, 3295
JACS, 2012, 134, 6556
Me
OR
Me
NH
Me
R
Me
Me O
O
dictyostatin
R
MeO
OMe
O
1. Hydrovinylation
R2
R3
JACS, 2006, 128, 2764
Me
OH
O
Cobalt chemistry - untapped potential?
R4
R1
R1
Me
JACS, 2006, 128, 5340–5341
O
R2 R3
Me
Me Me
Me
If the third coupling partner is another alkyne:
MeO
Me
Me
via:
OH
Me
65%
Me
Me
iPr
O Si
OH
Me
O
H
O
O
Me
Me
macbecin 1
O (ACIE, 2008, 47, 4005)
Me
O 2. Alder-ene reaction
Me
Me
callystatin A
(ACIE, 2008, 47, 7837)
TMS
EtO
CoBr2,
ligand,
Zn, ZnI2
Me
For example: OL, 2011, 13, 304–307
OL, 2011, 13, 5700–5703
Me
MeO2C
TMS
Hans Renata
Main Group Chemistry
Silirane reactivity profile
Acylsilane in Johnson's synthesis of zaragozic acid C
O
TBS
MgBr
O
TBS
O
TBS
tBuO2C
tBuO2C
OtBu
TBSO
BrMg O
O
OH
H
CO2tBu
COtBu
H
tBuO2C
tBuO2C
OTBS
OtBu
O
MgBr
O
MgBr
O
OtBu
O
TBSO
tBuO
O
tBu
tBu
Si
tBu
tBu
Bn
tBu
N
OTMS
tBu Si O
CuI (20%)
Si
Me
CO2H
CO2H
O
Me
95%
Et
1. Ph3PCH2Br
74%
2. PhMe2C(OOH), over 2 steps
KH, CsF
O
OH
Et
O
OH
Et
Me
Me
OH
Me
Me
Me
Me
O
tBu Si O
SnBr4
Me
OH H
O
HO2C
tBu
Et
OAc
Me
then
CuSO4,
Ac2O
Me
Me
tBu
Me
Me
Me
epi-stegobinone
zaragozic acid C
JOC, 2007, 72, 1027–1030
Variations on a theme
tBu
Si
tBu
R
tBu
tBu
Si
1,2,4-triols from allenes
tBu
R
Si
tBu
tBu Si AgLn
R
OTf
electrophilic
Ln = alkene, or phosphine ligand if present
For mechanistic studies: JACS, 2003, 125, 10659–10663 (thermal)
JACS, 2004, 126, 9993–10002 (Ag catalyzed)
tBu
Si
R
•
tBu
H
Me
Cy
AgTFA;
CuI, iPrCHO
70%, 96:3:1 dr
1. mCPBA
2. KOtBu
TBAF
tBu
tBu
AgX
Acc. Chem. Res., 2000, 33, 813–820
O
O
electrophilic
Metal-catalyzed
R2
CHO
Me
Silirane ring opening (Woerpel)
Thermal
Si
X
R1
R2
O
Johnson et al. JACS, 2008, 130, 17281–17283
Δ
H
74% from butene
AcO
Me
nucleophilic attack possible
if X = leaving group
tBu Si O
[O]
Bn
Bn
tBu
R1
tBu
X
Si
TBS
Me
3 contiguous stereogenic centers in the correct
oxidation state
strategic protecting group scheme that masked
every functional group except the 2º alcohol
tBu
Application in synthesis
H
OTBS
45–50% yield (15 g scale)
diastereoselection >10:1
tBu
O
OtBu
MgBr
CO2tBu
O
TBSO
tBuO2C
Baran Group Meeting
09/01/2012
Non-Aldol Polyketide Syntheses
tBu Si O
OH
Me
iPr
iPr
Me
Cy
60%
over 2 steps
OH
OH
Cy
OL, 2009, 11, 2173–2175
Hans Renata
Lithiation-Borylation-Allylation Cascade (Aggarwal)
Variations on a theme (contd.)
Insertion into vinyl epoxides
General idea:
Si
O
tBu
R2
tBu
H
O Si tBu
R2
2% AgOTs
R1
BR'2 Me Si
3
Li
Highly diastereoselective
O
Me3Si
functionalization
possible
R
NiPr2
O
2
tBu
O
Baran Group Meeting
09/01/2012
Non-Aldol Polyketide Syntheses
R3
O
tBu Si
R1
tBu
R
H
R
O
R
Me
OEt
37–80%
Me3Si
Proposed Zimmerman-Traxler-like TS
tBu
Si
Me
O
R"
SiMe3
Anti-diol
RCHO
OEt
Me
Me
R
Achieving stereocontrol
tBu
tBu Si O
Me
Me
OH
OH
AgTFA
R
O
R"
tBu
tBu
H
R"
Si
O
Me3Si
OCb
OH
H
JACS, 2009, 131, 14182–14183
Reaction with dienoates
H
R3
H
R1
BR'2
BR'2
OH
B O
B
Si
OH
O
O
Me
O
tBu
H
Me
R
H
C5H11
R
R
[O]
O
OH
O
R
H
OH
R"
SiMe3
R
tBu O
tBu
OEt
R"
SiMe3
R"
OH
solandelactone E
JACS, 2011, 133, 406–408
Reaction with dienes
tBu
Si
tBu
R1
tBu
H
1% AgTFA
R2
tBu H R1
Si
OAc
O
tBu Si H
tBu
R3CHO
H
R2
R3
OAc
Syn-diol
R1
TBAF;
Ac2O
R1
H
tBu Si O
Δ
R2
R3
R2
R3
Me3Si
O
B
O
O R
B
OH
R
O
SiMe3
R"
tBu
[O]
OH
SiO2
H
HO
O
tBu Si H
tBu
R"
SiMe3
O
R1
C5H11
R2
R3
JACS, 2012, 134, 12482–12484
OH
H
solandelactone F
H
O
O
OH
R
R"
OH
ACIE, 2010, 49, 4264–4268
ACIE, 2010, 49, 6673–6675
Org. Biomol. Chem. 2012, 10, 1795–1801
Hans Renata
Baran Group Meeting
09/01/2012
Non-Aldol Polyketide Syntheses
Cyclic Stereocontrol - Pericyclic Reactions
Use of Paterno-Buchi reaction (Asteltoxin, Schreiber)
OBn
Me
O
Me
63%
O
Me
Me
Me
hν
OBn
O
O
Me
mCPBA
80%
OHMe
ArCO2
OBn
O
O
H
HCl;
Me2NNH2
72%
OHMe
EtMgBr
O
HO
O
O
H
O
Me
OH Me
Et
OBn
O
Me
H
OMe
O
O
88%
OH
Me2CO,
CuSO4, CSA
O
Ph
BuLi
Me
O
asteltoxin
H
O
S
Ph
S
OH
Et
O
Et
OBn
OH Me
Me
NNMe2
HO
H
OHMe OH
O
Me
Me
OH Me
Et
H
O
OBn
OH Me
O
Et
Me
O
Me
Me
O
55%
over 2 steps
Me
O
H
Me
O
Me
JACS, 1984, 106, 4186–4188
Directed nitrile oxide cycloaddition (Epothilone, Carreira)
N
O
EtO P
EtO
3 equiv EtMgBr
OH
OTIPS 3.3 equiv iPrOH
+
Cl
Me
OH
Me
54%, 94% brsm
O
2. LiCl, DBU
EtO P
EtO
OTIPS
N O
OTIPS 1. TBSOTf
N O
N
Me
70%
(6:1 E:Z)
Me
OH
Me
S
Me
1. SmI2, B(OH)3
2. BEt3, NaBH4
S
OH
Me
68%
(9:1 E:Z)
O
Me
N
S
Me
Me
Me
Me
O
OH
Me
O
OH
epothilone A
O
O
Me
Me
Me
OH
1. SOCl2
2. TBAF
N
OH
77%
OH
OTIPS
N
Me
S
Me
OH
Me
OH
ACIE, 2001, 40, 2082
JACS, 2001, 123, 3611
JOC, 2001, 66, 6410
Hans Renata
Baran Group Meeting
09/01/2012
Non-Aldol Polyketide Syntheses
Cyclic Stereocontrol - Pericyclic Reactions
Cycloaddition-oxabicyclic ring opening (ionomycin, Lautens)
O
Me
O
Me
X
O
base
Me
[H];
Protection
O
Me
O
Me
Me OTIPS
Ni(COD)2,
(S)-BINAP,
DIBAL-H
OTIPS
Me
Me
95%,
93–95% ee
"Redoxmassage"
(D. Sarlah)
Me
82%
HO
OTIPS
Me
1. O3; NaBH4
2. DDQ
PMBO
79%
OH
Me
OH
23
OH
O
O
10
1
PMP
17
O
O
Me H Me H
OH
Me
Me
Me
Me
Me
Me
OH
O
Me
O
OTIPS
OH
ionomycin
Note: C1–C10 fragment was synthesized
via methylative oxabicyclic ring
opening
JACS, 1995, 117, 532
JACS, 1997, 119, 11090
OL, 2002, 4, 1879
Me
Me
C17–C23 fragment
Pericyclic reaction with sulfur (methynolide, Vedejs)
EtO2C
Me
Me
S
O
Ac2O, AcOH;
BF3.Et2O
EtO2C
81%
1. K2CO3;
then protect
Me
2. DIBAL; MsCl, BuLi
OAc
Me 3. LiBEt H
3
Me
S
Me
Me
HO
Me
OH
O
Et
Me
O
methynolide
Me
S
Et
H
O
Me
OR
Me
Et
OTf
76%
dr= 16:1
CO2Et
59%
S
O
O
Me
Me
35%
tBu
TfO
OR
H
Me
S
H
H
H
EtO2C
S
H
Me
OR
Me
Me
Me
OR
Me
Me
H
EtO2C
6 steps
S
OR
Me
Me
H
JACS, 1987, 109, 5878
JACS, 1989, 111, 8421, 8430
Hans Renata
Baran Group Meeting
09/01/2012
Non-Aldol Polyketide Syntheses
Conclusion
POLY
KETIDES
"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."
O
Me
Me
Me
Me
Et
Me
O
S
H
Me
S
Me
NH
O
Me
O
MOMO
O
Me
O
Me
MOMO
OBn
O
Me
CHO
Me
O
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?
Me
Me
halichomycin
(TL, 1994, 35, 5013)
H
O
Me
H
Me
Me
OH
H
O
O
O HO Me OMe
O
O
OMe
O
Me
O
OMe
Me
Me
OH
OH
neaumycin
(OL, 2012, 14, 1254)
O
O
O
OH
OH
HN
Me
OH
Me
Me
tripartilactam
(OL, 2012, 14, 1258)