Hans Renata Baran Group Meeting Non-Aldol Polyketide Syntheses · Hans Renata Non-Aldol Polyketide...

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


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)


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


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


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


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


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


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


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


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


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!"

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