Nature's Catalysts: A Search for Synthetic Equivalents … · R.A. RodriguezNature's Catalysts: A Search for Synthetic Equivalents IBaran GM 2010-08-21 OH HO OH OH HO OH OH ... H

Me H

Me

HO

H H

Me

H

OH

Me H

Me

HO

H H

Me

H

E.C. 1.14.15.4

!"#$%&'"()"*+",-./0"$1"2+")$"3.0"45")6(78")6(3"-+.,)($7"$7")6+"9:;<="!"#$%&!'(#9:;<="3%*3)-.)+"(3">$33(*&+?@"

!"=+,67$&$A(,.&".'B.7,+2+7)3"

!"C.D$-"(33%+3E"FGH")'"HGH@"

!!"I+A($3+&+,)(B()0J")6(3"(3"K6+-+")6+"2(7'").8+3"."3).7'"

Nature's Catalysts: A Search for Synthetic Equivalents I R.A. RodriguezBaran GM

2010-08-21

LM"FN"O"PN""

PM"<6+2$3+&+,)(B()0""

FM"I+A($3+&+,)(B()0""QM"R)+-(,3""

HM"R)+-+$3+&+,)(B()0""

C.D$-"(33%+3E"

OH OH OH OSLT"

=K$",$2>$7+7)3")$"6.B(7A"."A$$'"('+.E""

"";M"573>(-.)($7"1-$2"7.)%-+"U$-")6+".*(&()0")$")6(78"$%)3('+")6+"*$VW"

""XM"97/02+">$,8+)"$-"1%7'.2+7).&&0"1+.3(*&+@"

Y6(&$3$>60E"*+#!",-"#(!#.$/+#-01-2(/!+$%#("$/+/+.#3"!&#!+-#!3#

######################(4-#."-$(-'(#14-&/'(#!3#$%%#(/&-Z""

""LM"[)(&(/+"7.)%-+\3"K(3'$2")$"A.(7"5]RY5I;=5^]"

""PM"=.8+")(2+")$"'+,('+"(1"(1")6+",6.&&+7A+".)"6.7'"(3"

""""""_[]`;C9]=;aab">$33(*&+""

Co(OAc)3, O2

Cl3CO2H

1374

253

selectivity for chlorination (%) shown

Crabtree, R. Chem. Rev., 1985, 85, 245-269

5,,-+,6&#(!#24/%!'!247E"FM"U)6(3"(3"8+0W"`^"]^="a5C5="0$%-3+&1"

*0"K6.)",.7".7'",.77$)"*+"'$7+"K()6")$'.03")+,67$&$A(+3"

OHR

O

O

R

OH

O

O H

R

enediol

OH

OH

MeO2C

BzO

O

OH

MeO2C

BzO

78 %


2010-08-21

Y6(&$3$>60E"*+#!",-"#(!#.$/+#-01-2(/!+$%#("$/+/+.#3"!&#!+-#!3#(4-#."-$(-'(#14-&/'(#!3#$%%#(/&-Z""

""LM"[)(&(/+"7.)%-+\3"K(3'$2")$"A.(7"5]RY5I;=5^]"

""PM"=.8+")(2+")$"'+,('+"(1")6+",6.&&+7A+".)"6.7'"(3"_[]`;C9]=;aab">$33(*&+"

""FM"`^"]^="a5C5="0$%-3+&1"*0"K6.)",.7".7'",.77$)"*+"'$7+"K()6")$'.03")+,67$&$A(+3"

;7".))+2>)")$"A.(7"3$2+"1%7'.2+7).&"(73(A6)E"5#'-$"14#3!"#'7+(4-(/1#-86/)$%-+('####

N

NSO2Ar

CO2Et

Me O

OMe

OMe

H

N

NSO2Ar

CO2Et

Me OCO2Me

CO2Me

H

O3


2010-08-21

OH

HO

OH

OH

HO OH

OH

HO OH

O

HO OH

E.C.1.1.1.6

glyceroldehydrogenase

2. Acyclic polyol oxidation

[Part I] An initial attempt to gain fundamental insight

OH

HO

OH

OH

HO OH

E.C.1.1.1.18

OH

HO

O

OH

HO OH

OH

HO OH

O

HO OH

Pt/BiKimura, H. et al. Appl. Catal.A. General 1993, 96, 217

OH

HO OH

pH = 2-3

O

HO OH

OH

HO O

OH

O

HO

OH

HO O

O

HO O

OH

OH

DHA

GLYDHPYA

OXALA GLYA

pH GLYA (%) DHA (%) HPYA (%) OXALA (%)

6 4 20 36

1 25 20 40

8

5.5

Influence of pH on product distribution duringoptimization of Pt/Bi oxidation of glycerol

94%

conversion: 75%; yield: 37%

Synthetic Equivalent: heterogeneous catalysis

OH

HO

OH

OH

HO O

OH

HO

O

OH

HO OH

strainrelease

HO

H

HO

OHOHH

HOOH HO

H

HOOHH

HOOH

O

Synthetic Equivalent: oxygen-platinum catalysis

Pt/C, O2

pH 8-9

Rules:1. Only axial are oxidized2. Selective in case of > 1 axial 3. Oxidation stops at monoketone

Synthetic Equivalent: chromate ester

OH

HO

OH

OH

HO OH

OH

HO

OH

OH

HO OCr VIHO

OH

O

O

HO

OH

50 °C

30 %

Cr

OH

OH

O

O

OH

OH

O

pH < 12 h, 33 °C

Santoro, M. et. al. Polyhedron,2007, 26, 1, 169-177

- Founded 1987 by former German National Research Center for Biotechnology now: Helmholtz Center for Infection Research - Comprehensive electronic enzyme information system: web-based user interface - Contain molecular and biochemical information on all classified enzymes: E.C. # - Characterized with respect to its catalyzed biochemical reaction - Currently maintained and further developed by Department of Bioinformatics and Biochemistry at TU Braunschweig - Updates performed twice a year (Including improvemens to the user interface)** - Latest update was performed July 2010

BRENDA (BRaunschweig ENzyme DAtabase):A powerful tool for the synthetic chemist

Oxidations of industrial importance: An underdeveloped market due to selectivity

myo-Inositoldehydrogenase

95%

Xanthomonas sp.

PCT Int. Appl.,2000075355

Heyns, K. et al. Methods Prep.Org. Chem., 1963, 2, 303

Cameron, R. E. et. al. JACS,1985, 107, 6116

1. Cyclic polyol oxidations

Corma, A. et al.Chem. Rev., 2007,

107, 2411-2502


2010-08-21

HO

OH

OH

OH

HO

OH

OH

OH1. Me2CO, H+

2. K2CO3, CH2O

3. TFA, H2O

D-Mannose

OH

OHOH

70 %, 3 stepsMoO3, H2O,

90 °CBilik RR

HO

OH

OH

OH

O

OH

HO

OH

OH

OH

OH

O

OHOHisomerization

enediol

OH

H

R

O

!O

HO

R

OR

OH

isomerization

epimerization

OO

O

O

HO

OHH

H

Mo

Mo

O

O

O

O

O

OH

H

HO

OH

OH

OHE.C.1.1.1.67

HO

OH

OH

OH

Carbohydrate isomerizations: enediol intermediates

O

O H

R

- Heyns- Amadori- Voight

R1

OH

O

R1

O

NHR

R2 R2

- Voight amination

RNH2

P2O5, "

O

O

N-glycoside(ring-opened form for simplicity)

HO

OH

OH

OH

OH

OHO

OH

OH

OH

OH

NR

HO

OH

OH

OH

O

NHR

Heyns

Amadori

56 %

Option 1 via isomerization after oxidation of the primary alcohol

- Bilik RR- Lorby-de Bryun-van Ekenstein (LdB-AvE)

Synthetic Equivalent: oxidation/isomerization

!

OH

NR

Amadori retron

OH

Landmarks in the history of carbohydrate chemistryor unrecognized synthetic opportunities?

Strategic oxidation of natural products: Boger's asymm. synthesis of vindoline

N

OH

O

CO2Me

OAc

Et

N

MeO

Me

N+

OH

OH

CO2Me

OAc

Et

N

MeO

Me

SiO2, Et3N

85 %

N

O

OH

CO2Me

OAc

Et

N

MeO

Me

N

OH

OH

CO2Me

OAc

Et

N

MeO

Me

H+

Application to simple #-hydroxy aldehydes/ketones

- Exploitation of additional driving forces??

- strain release (furanoid to pyranoid) - steric and/or electronic relief

Topics in current chemistry,2001, vol. 215/2001, 115-152SpringerLink

OH

OH

O

OHmannitol2-dehydrogenase

kineticdriving force

RNH2


2010-08-21

??

Option 2 via selective oxidation of secondary alcohol

Selective secondry aliphatic alcohol oxidations discussed a. Halogen-based oxidants b. Peroxides c. Dioxiranes d. Oppenauer variants

Arterburn, J.B. Tetrahedron2001, 57, 9765-9788

a. Halogen-based oxidants

- Bromide/chloride-based - N-halogenated reagents: N-bromoacetamide (NBA), N-bromosuccinimide NBS), N-chlorosuccinimide (NCS), trichloroisocyanuric acid (ICC)

viahypohalite

R

R

OX

H

Many commonly used oxidizing reagents oxidize 2° aliphatic alcohols at ratesslightly faster than 1° alcohols, but the difference in rates is not significant.

OR

R

XH

OR

H

XH

vs.

more electron rich

Reasoning and considerartions behind highly selective oxidizing reagents:

Mechanism of bromide oxidation(Venkatasubramanian N. et. al. Tet. Lett., 1968, 14, 1711-1714)

TEMPO & TEMPO-type oxidations

- Discovered by Lebedev and Kazarnowskii in 1960- Stability of radical attributed to steric protection of methyls- Highly selective for 1° alcohols- R = OH, NHAc reactivity steered - Chemoselectivie: inert towards 2° alcohols but converts aldehydes to carboxylic acids

NMe

Me

Me

Me

O

- Sterics- Electronics (electron rich or electron deficient carbon in the transition state?)

Proposed mechanisms: alkaline vs. acidic conditions

NMe

Me

Me

Me

O

N+Me

Me

Me

Me

N+Me

Me

Me

Me

O

-O O

H RH

O

OH

R

[O]

Angelin, M. et. al. Eur. J. Org,Chem., 2006, 4323-4326

R

R

Industry applications:

Pagliaro, M. et. al. OPRD, 2010, 14, 245-251

- H+

Basic

Acidic

(Anelli-Montanari process)

(cat.)

N+Me

Me

Me

Me

HO O

H RH

NMe

Me

Me

Me

OH

O

R

B:

Naik, N. et. al. Tetrahedron, 1998, 54, 667

R

R

OX

H

hydrideanion

protontransfer

B:

2° 1°

OR

R

[Cr]H

RDS

deprotonationcomplexation

OR

R

[Cr]OHR

RH

B:

OH OH OH OBr2, HMPT,NaHCO3,

H2O/CH2Cl2

91 %

Br BrR

R

O

H H

H2O

Br BrR

R

O

H R'

H2O

R

R

O

H Br

H2O

(C)

- Parallelism with chromic acid oxidation (alcohols > ethers)- However, while 2-propanol reacts 1500X faster than diisopropyl ether, the rate constants for the Br2 oxidation of both 2-propanol and diisopropyl ether (25 °C pH 4.6) are identical.

H

OH

BrBr

(B)Br Br

R

R

O

H H

H2O

R

O

R

+ 2Br + H+ + H3O+-

(A)

Selective oxidation of 1° alcohols using TEMPO: Breton, T. Eur. J. Org. Chem2007, 1567-1570

TEMPO+ BF4-

O

HO OMe

O

86%

DMF, 2,6 Lut.

OH

HOO

HO OMe

OHOH

HO


2010-08-21

OH

OH

O

OH

Et4NCl3, py.,DABCO,

CH3CN, rt

100%

O

OH

Me

OH

Et

Me

HO

Me

Me

O

O

Me

Me

OH

O

OHO

N+

Me

O

Me

-O Me

Me

OHMe

OMe

(Bu3Sn)2O,Br2

CH2Cl2, rt

O

O

Me

OH

Et

Me

HO

Me

Me

O

O

Me

Me

OH

O

OHO

N+

Me

O

Me

-O Me

Me

OHMe

OMe

58 %

HO

OH

O O HO

O

O O

Me

OH

H H

H

Me

MeHO

OH

HO Me

H

R

HH

HH

H

HO Me

H

R

HHO

HH

!: 62 %": 100 %

Cl2 (1.1 eq.),

(5 eq.) py,CHCl3

Me

OHOBnO

OH

OBnBnO

O

BnO

OH

OBnBnO

O

O

N

OH

N

OH

OHOH

Me

CO2Bn

Me

BnO2C

Me

O

N

OH

N

OH

OH

Me

CO2Bn

Me

BnO2C

Me

O

i. Bu2SnO, MeOH, #

ii. Br2, CH2Cl2, Bu3SnOMe

i. Bu2SnO, MeOH, #

ii. Br2, CH2Cl2, Bu3SnOMe

conclusion: It is evident that the influence of polar groups is very pronounced.

While several arguments can be advanced to explain the negative

$* value, the simplest explanation is a rate-determining loss of the

secondary hydrogen as an anion.

Rate mesurements on the bromine oxidation of alcohols with suitableelectronegative and electropositive substituents

Taft plot for the Br2 oxidation of:

Me

O

H HRElectronegativeand Electropositive groupscompared to R = H

-F

H -

standard

- Br

- OMe

- Et

Ph -

- MeC2H5 -

magnitude of $* = -2.6

(Bu3Sn)2O, Br2,

CH2Cl2, rt

64%

87%

92%

Linear free energy correlation: Taft plot (like Hammett but for aliphatics)

H

OH

ClCl

O

H

HCl

Cl


2010-08-21

Me

Me

HO

O

O

OH

OH

Me

Me

O

O

O

OH

OH

2 eq. NBA,

tBuOH/H2O

10 °C, 5 h

C(CN)CH2OHMe

Me

HO

O4 eq. NBA,

CH3OH/H2Opy. rt, 5 h

C(CN)CH2OHMe

Me

O

O

71%

90-96%

OH

OH

MeO2C

BzO

O

OH

MeO2C

BzO1.5 eq. NBS,

DME/H2O

78 %

OH OH OH O

N

N

NN

N

N

O

O O

Cl

Cl ClOH

HO OH(ICC)

acetone,pyridine

O

O

O

AcHN

OH

HOMe

Me

O

O

O

AcHN

O

HOMe

Me

O

O

OMe

MeNAc

HO

HO

NCS,

SMe

Me

Me

Me

CH2Cl2, -78 °C

NCS,

SMe

Me

Me

Me

CH2Cl2, 0 °C

72 %

H H H H

H H

H H

H

H H

H

HH

H H

NCS/Diisopropylsulfide: temperature-controlled selectivity

Mechanism of NBS oxidationVenkatasubramanian N. et. al. Can. J. Chem., 1969, 47, 1969,

Venkatasubramanian N. et. al. Tet. Lett., 1967, 35, 3349-3354

Sb

Br

Cl ClCl

ClCl

Br

S+

Et Et

3.173 A°

2.170 A°

Me

Me

OH

H

N

Me

Br

Me

+ 2

Me

O

Me

NH

Me

Me

+ 2 + Br2 [1]

Me

Me

OH

H

+ Br2

Me

O

Me

+ 2HBr [2]

2HBr + 2 N

Me

Br

Me

NH

Me

Me

2 + 2Br2 [3]

- [3] is 104 faster than [2]

- NBS oxidation is composed of two stages, an initial slow reaction superceded

by a faster one involving the attack of Br2 on the alcohol moiety

2Br - Hg(OAc)2 HgBr2 + 2OAc-

R

R

O

H H

Proposed mechanism:Initial slow stage

Br N

O

O

slow R

O

R

+ HBr + HN

O

O

Proposed mechanism: [3]/[2]Second stage involving the fast attack by Br2

is completely supressed by addition of Hg(OAc)2 Kinetics & Mechanismof KBrO3 [Br(V)] see: Srinivasan N. S. et. al.

Tetrahedron, 1974, 30, 2785

Kinetics of NCS see: Srinivasan N. S. et. al. Tet.

Lett., 1970, 24, 2039-2042

Clarke. C. et. al. Tetrahedron,

1988, 44, 13, 3931-3944

65%

70%

Snyder and co workers?

Reagent dependent results: trichloroisocyanuric acid (ICC)

NBA in excess

Kim, K. S. et. al. J. Chem.

Soc., Chem. Commun.,

1984, 762-763


2010-08-21

b. Peroxides - Molybdenum-cat. with peroxides

c. Dioxiranes - DMDO proposed mechanism (Bovicelli, P. et. al. Tetrahedron, 1996, 52, 10969)

OHOH

OH

O

OH

OH

OH

O

OH

O

Tricetylpyridinium-12-tungstophosphate (CWP) = [PW12O40][C5H5N(CH2)15CH3]3

(NH4)6Mo7O24, K2CO3,H2O2, Bu4NCl, THF

rt, 24 h

88%

HO

OH

HO

O

[C5H5N+(CH2)15CH3]3[PMo12O40]3-,

tBuOOH, PhH, 75 °C

100%

- Neopentyl: quantitative yield

- Tungsten-cat. with peroxides: solvent dependent cleavage

CWP (1.6 %),

CWP (1.6%)

H2O2, H2O,tBuOH

H2O2, H2O,CHCl3,rt, 16 h

68%

93%

OH OH

- Linear 1,2 diol; 1,3 diol; 1,4 diol; 1,5 diol; 1,7 diol = no problem

Cr-PILC cat./TBHP,

CH2Cl2, rt, N2

H2O2, TS-1n

O OH

n

O OH

n

1, 2 diol (n = 0); 89%1, 4 diol (n = 2); 100%1, 7 diol (n = 5); 94%

1, 3 diol (n = 1); 84%1, 4 diol (n = 2); 100%1, 5 diol (n = 3); 93%

Titanium doped zeolites (TS-1)

Chromiapillared montmorillonite (Cr-PILC)

homogeneous

heterogeneous

rt, 2 days

Me

OH

OH

O

OMe Me

OH

O

OMe

OH

OH

O

OMeH

O

MeO

!+!-

1. hyperconjugation (oxygen lone pair donating into O-C bond making H hydridic)

DMDO (4 eq),acetone

77%

HO OH

Me

O

OH

O

OMe

Me

Me

most e- rich C-H:

2. 2° C-H more e- rich than 1° C-H due to inductive effects

DMDO superb regioselectivity for cyclic polyol systems:Not only 2° C-H > 1° C-H, but also selective for single 2° C-H

OH

OH

OH

OH

OH

O

DMDO (1.5 eq.),Acetone

> 90%

OH

OH

N3

O

OH

N3

MeMe

H

R

HH

OH

HO

MeMe

H

R

HH

HO

O

DMDO sensitivity to sterics(Buxton, P. C. et. al. Tet. Lett., 1999, 40, 4729-4732)

DMDO (2 eq.), Acetone

75%

0-5 °C, 16 h

rt, 42 h

rt, 12 h

DMDO (1.5 eq.),Acetone

> 95%

rt, 12 h

Bovicelli, P. et. al. Tetrahedron,

1998, 54, 14301-143134.


2010-08-21

d. Oppenauer (OPP) variants (aka Meerwein-Ponndorf-Verley-Reduction: MPV)

R3

O

R4R1

OH

R2

+

Al(OR)3

- Mechanism: internal hydride transfer to accepting surrogate

hydride

R3

OH

R4R1

O

R2

+

(OPP) (MPV)

HOi-Pr transferH O

Al-O+

R3

R4

R1

R2

Oi-Pr

Oi-Pr

- Oppenauer variant: 1,10 diol selective oxidation

OH OH

8

Al2O3 (2 eq.), PhCHO

rt, 24 h

65%

O OH

8

Potent analogues from natural products: Semi-synthesis real world example

[Part II] A big lesson from nature: Achieving true biomimicry

The Cell: The most basic and fundamental unit of life

A paradigm: Cell regulation and Biomimetic synthesis

CELL CYCLE:HOMEOSTASIS

Increasedcomplexity

Reusablestarting

materials

2° Metabolites

Macromolecules- Proteins- Lipids- Carbohydrates

Advancedintermediatesfor other cellularprocesses

Macromolecules- Proteins- Lipids- Carbohydrates

2° Metabolites

Advancedintermediates

from other cellularprocesses

[Nature's catalyst build complexity as well as degrade complexity]Total selective degradation: Some current tools for synthetic analysis

- provide the need for training of synthetic chemist in natural product synthesis

N

S

N

N

SS

N

O

HN

NHO

CO2H

N

O

NH

OO

NH2

N

S

O

NH

S

NO

N

OHN

HOHO

Me

Thiazolylpeptide (GE37468A)

Antimicrobial agent:

Bergman degredation:

The discovery of CB-184,375 andother semi-synthetic Thiopeptide Antibiotics.

Cubist Pharmaceuticals, 50th ICAAC National Meeting

Degradation name reactions: Edman degradation, Emde degradation,Gallagher-Hollander degradation, Hooker degradation,Marker degradation (Parke-Davis and Syntex), Strecker degradation,Von Braun amide degradation.

Fragmentations and RR's: Grob fragmentation, Hofmann RR, etc.

HN

O R3

O

OH

R2

R1HN

1. curtius RR

BnOH, !

HN

O R3

HN

R2

R1HNO

O

2. [H]

-CO2

NH2

O

R2

R1HN+

R3 H

O

O

R2

NH2R1

O

H2N R1

O

Interesting point...

+

Me

NH3+


2010-08-21

- Another company that values marine natural product drugs: PharmaMar (Zeltia) partnership with Johnson & Johnson

Market drug: Yondelis!;

Pipeline compounds: Aplidin!, Irvalec!, Zalypsis!, and PM01183

NH

SO

O

HO

MeO

N

O

N Me

OMe

HO Me

Me

O

O

Ac

OH

H

HH

H

Ecteinascidin 743

Yondelis!

N

OAc

N Me

OMe

HO Me

Me

O

O OH

H

HH

NH

O

CF3

Zalypsis!

N

O

N

Me O

O

Me

O

NH

NH

O

N

Me

Me

Me

O

N

OMe

O

O

Me Me

NHO

MeO

O

Me

Me

O OH

MeMe

OMe

Aplidin!

O

O

O

O

O

O

O

O

O

Me

O

H

H

H

H

Me

Me

H

H

H

H

MeH

HO

H

O

H

H

H

O

H

H

H

OO

H HO

HO

HO

HO H

Halichondrinb BNewman and Cragg. Curr. Med.

Chem, 2004, 11, 1693-1713

For more examples of advancedpreclinical and clinical trials ofmarine natural products:

(anticancer-tubulin interactive agent)(anticancer-apoptosis inducing agent)

Ecteinascidia turbinata

Aquaculture initial resultspromising but not ideal

Another class of privileged marine natural products: The Halichondrinbs

molluscs and sponges


2010-08-21

3. Oxidative aromatic ring fission: Synthetic strategy and selective degradation

Application to natural products: Woodward fission (Strychnine)

N

NSO2Ar

CO2Et

Me O

OMe

OMe

HO3, AcOH, H2O

29% N

NSO2Ar

CO2Et

Me OCO2Me

CO2Me

H

MeOH, HCl, ! 75%

NH

NSO2Ar

CO2Et

CO2Me

H

MeO2C

N

NSO2Ar

CO2Et

CO2Me

H

isomerization

O

N

NSO2Ar

CO2Et

CO2Me

O

Woodward R. B. et. al.

JACS, 1954, 76, 4749

NH

NH

OH

OH

2. ClCO2iPr,

Na2CO3,

CHCl3/EtOH

NH

N

OH

OH

EtO

1. CH2O, 3d, rt, 95%

75%

O

OiPr

NN

CO2HCO2H

Me

EtO

1. LAH,2. HCl 39%3. h" / O2, 34%

HO

NH

OEt

N Me

HO

OH

N

N

H

H

H

O

Me

H

koumine

1. [H]

Liu, C.-T. et. al. JOC,

1983, 48, 44-47

2. -H2O

Application to natural products: Liu progress towards koumine

reasonablemechanism for 3?

Biomimetic Synthesis of (±)-8-Oxoerymelanthine: BF3-Et2O as an additive

N

OMe

MeO

MeO

O

O

CO2MeOMs

O3, BF3-Et2OCH2Cl2

-78 °C !

47%

MeO2C

NMeO

O

O

CO2MeOMs

MeO2C

(Yoshida, Y. et. al. JOC, 2009, 74, 6010-6015)

HO

O

OH

OH

E.C.1.13.11.22

caffeate3,4-dioxygenase CO2H

CO2HHO

O

OH

OH

ROOH

O

OCO2H

CO2H

hv

O

O

OH

OR

H2O

CO2H

CO2H

e- transfertype

B A

R = H; O2

R = substrate

O2


2010-08-21

Oxidation with ozone: BF3-Et2O as an additive, a proposed explanation

O

MeO

MeO

NMe

MeO2C

OHC

O

MeO

NMe

O

HO

RO

NMe

R = Me, Et

O

HO

NMe

O

RO2C

Oxidative aromatic ring fission: Oxidation with ozone

OO+

O-O

O+

-O

Unstable at high concentrations, decaying to O2

(half life of 30 min. at atmospheric conditions)Combustion of ozone at > 10 wt%Explosive nature attributed to reduced ozonide

- Generally accepted mechanism of ozonolysis of alkene (Rudolf Criegee-1953)

(Mander, L. N. and Williams, C. M. Tetrahedron, 2003, 59, 1105-1136)

75%

40%

Speyer (1926)

Rapoport & Payne (1950)

Oxidative aromatic ring fission: Ozonolysis on the morphine related alkaloids

A

B

C

A

B

C

Pschorr (1907)Wieland (1928)

0 °C, 1 mol O3/5 h0.5 M AcOH (4.5 N)

- O3 xs.

- HCO2H (aq.)

standardozonolysis??60% (Na salt)

Proposed mechanism for ozonolysis of phenols (vide infra)- for kinetic study on !,!,!-trifluorotoluene and 1,3,5- trifluorobenzene see: Karpel Vel Leitner, N. et. al. New. J. Chem., 1997, 21, 187-194

General selectivities for alkenes:- electron rich > neutral > electron poorSchreiber work-up conditions:- reductive or oxidative work-up yields different products

OO+

-O

dipolar

[1,3] O OO

R1 R2R1 R2

retro

[1,3]

O+ OO-

R1 R2

Criegeeintermediate

carbonyl

flip

O+O-

R1O

R2

[1,3]

O

O

O

R1

R2

ozonide

Bailey, P. S.,Ozonation in organicchemistry: Nonolefinic Compounds,

Academic, New York, 1982.

O

O

O

H2O

-H2O

OH

OH

OH

Path A Path B

O3 O3

O

O

OH

O

O

O O-

-O2

-H2O

O3

O

O-

O

O O

O

O

O

-O2

OH

OH

O

O

OH

OOH

O

O

OH

OOH

O

OHO

Additional increase in electrophilicity:

BF3O

O+

O

Why these conclusions?Studies of dry ozonations on silica gel (examples on next slide)

OH

H

-H2O2

H2O

BF3O

O+

-O


2010-08-21

CO2Me

MeMe

Me

Me

O

MeO2C

MeO2C

O

MeO2C CO2Me

MeMe

O

CO2Me

OH

CO2Me

MeO2C

MeMe

O

MeMe

Application to synthetic strategy: Yates synthesis of sesquiterpene skeleton

mechanism ?

O

EtH

HO

H

O

EtH

HHO

MeO2C

Expansion of the benzenoid synthon: An alternative to the bis acid

Expansion of the benzenoid synthon with ozone: Possible selectivity?

NH

H

Me

MeMe

Me

Me

O

O

H

Me

MeMe

Me

Me

O

H

Me

MeMe

Me

Me

H

Me

MeMe

CO2H

CO2H

Oxidative degradation of benzene rings: carboxylic acid equvalents

- The carboxylic acid group is one of the most common functional groups - It's not always an easy task to carry this functionality through a sequence

Dry ozonation on silica gel (see: Cohen, E. K. et. al. JOC., 1975, 40, 2141)Reactivity vs Selectivity: A unique reactivity of ozone(Klein, H. et. al. Tet. Lett., 1975, 4249-4250)

Schmidt

BV

[O]

HN3

O

CO2Me

1. hydrolysis2. O3

1. O3, rt, 3.5 h

Schaffner et. al. Helv. Chim. Acta,

1956, 39, 174-183

Wenkert, E, et. al.

JOC, 1964, 86, 2044-2050

h! 1. Ph2CuLi

2. NaCl DMSO/H2O 125-127 °C

76%

Yates et. al. J.C.S.

Chem.Comm. 1980, 990

i. O3, HOAcii. H2O2

iii. CH2N2

65%(2 steps)

46%

1. O3, HOAc 0 °C, 1 h2. H2O2 (aq.)

3. NaOH (aq)4. CH2N2

40%

MeO OMe

-O

O

Na+

H

HO

H

OMe

OMeO

88%

", 1h,THF

NO2

Jung, M. E. et. al. JACS,

1980, 102, 2463-2464

steps

steps

A: 10 mmol O3/100g SiO2, -75 °CB: 10 mmol O3/200g-300g SiO2, -75 °CC: 10 mmol O3/200g-300g SiO2, 25% H2O, -75 °CD: RuO4 [O] (previously reported result)

CO2H

Conditions (A-D)

NO2

CO2H

CO2H

OH

A: 85-90% conversion; 60-80% yield

D: 25% yield

B: 95% conversion; 90% yield

A, B, D

B

B, C

B: 20-25% conversion; 20% yield

B: 95% conversion; 50% yield

C: 95% conversion; 75% yield


2010-08-21

Oxidative degradation of benzene rings: carboxylic acid equivalents - Caputo: first to apply RuO4 to cyclobutanols (30% vs 78%) and aromatic rings

Me

!

NBoc

O

OH

H

Me

!

NBoc

O

O

CO2Me

H

H

Oxidative degradation of benzene rings: Oxidation with RuO4

ORu

O

O

O

Readily decompose explosively at elevated temperatures

Safer anionic salt of TPAP (Pr4N+ RuO4-) is commonly used

Mechanism for its use in benzene degradation is unknown

Catalytic from RuCl3 or RuO2 in presence strong re-oxidant:

NaIO4, NaOCl, NaBrO3, oxone, O3, Ce(SO4)2, and K2S2O8.

OMe

H

H H

Me O

HO

OMe

H

H H

O

N

OAc

F3C O

N

OAc

CO2H

F3C O

NH

OAc

CO2H

ii. K2CO3

RuO4, NaIO4O

OH

RuO4: Chemoselectivity can be achieved(Haddad, M. et. al. JOC, 2010, 75, 6, 2077-2080)

No [O]

RuO4: Stereochemical information adjacent to reactive site is conserved

Expansion of the benzenoid synthon: One carbon dehomologation technique

HO2C

HO2C

OMe

H

H H

MeOH

i. RuCl3-H2O

NaIO4

1. RuCl3, NaIO4, EtOAc/MeCN/H2O

2. CH2N2

rt, 90 h 72%

Me

OtBu

O

Me

RuCl3, NaIO4,CCl4, MeCN, H2O

rt, 24 h

Org. Lett., 2009,11, 20, 4668-4670

NH

O

O

CCl3

Me

MeO

DRuCl3, HIO4,

CCl4, MeCN, H2Ort, 2 h

Chem. Comm., 2009, 29, 4396-4398

> 54% (4 step)

71%

N

O

OEt

RuCl3, HIO4,CCl4, MeCN, H2O,

50 °C, 2 h

PCT Int. Appl.# 2009037719

40%

RuCl3, NaIO4,CH2Cl2, CH3CN, H2O,

rt, 2h

Catalysis Comm., 2007, 9, 3, 416-420

82%

O

O

Me

Me

Tet. Asymm., 2007,18, 12, 1434-1442

70%

RuCl3, NaIO4,CCl4, MeCN, H2O,

70 °C, 3 h

Caputo, J. A. et. al.Tet. Lett, 1967, 4729-4731

Reactivity vs Selectivity: An attempt to realize relative rate

Me

NBoc

O

OH

H

O

HO2C

OHRuO4, NaIO4

OH

O

60 °C 10 d25%

rt, several days, 12%

57%

Clayden, J. et. al. Tetrahedron, 2002, 58, 4727-4739

Clayden, et. al. Tetrahedron,2002, 58, 4727-4739

1. RuCl3, NaIO4,EtOAc, MeCN, H2O,

rt, 4 h2. CH2N2, Et2O

R = H; > 57% (2 steps)R = OMe; > 67% (2 steps)

25 °C

2X

35 °C

45 °C

55 °C " 4 h

2X

2X

CO2H

R

?


2010-08-21

OMe

H

H H

HO

OHMe

H

H H

OH

Me

RuO4 degradation of steroids: An opportunity to gain mechanistic insight(Piatak, D. M. et. al. JOC., 1969, 34, 116-120)Conditions: RuO2, NaIO4, Acetone/H2O

OHMe

H

H H

Me

OAcMe

H

H H

AcO

OAcMe

H

OH H

AcO

O

+

OAcMe

H

H H

AcO

Me

71%

RuO2, NaIO4,Acetone/H2O

rt, 4.5 h

51%


rt, 4 h

HO2C

HO2C

OAcMe

H

H H

minor

HO2C

HO2C

OAcMe

H

H H

major (77%)

OAcMe

H

OH H

AcO

O

minor (5%)

+

Me

Destabilizing effect

2X benzylic [O]: major (40%)

RuO2,NaIO4,

Me2CO/H2O

rt, 4.5 hOAcMe

H

OH H

HO

1. RuO2, NaIO4, Acetone/H2O rt, 4.5 h

O

MeO

OAcMe

H

H

O

MeO2C

OAcMe

H

HO

R

O

OH

MeO

OAcMe

H

H

O

O

MeOH

2. CH2N2

3. MeOH

MeOHExpected:

R = CO2Me; 30%R = OMe; NOT observed (decarboxylation)

RuO2,NaIO4,

Me2CO/H2O

rt, 4.5 h

Destabilizing effect

HO2C

HO2C

OMe

H

H H

99%


rt, 4 h

HO2C

HO2C

OMe

H

H H

HO2C

HO2C

OMe

H

H H

Conclusions: At least two competing pathways at play involving benzylic [O]

O

OMe

H

H H

O

O

Anhydride intermediates via decarboxylation?Decarboxylation process is sensitive to sterics?

A: Slow when e- density is taken from oxygen; C-H [O] at 3° benzylic carbon

B: Additional e- donating groups may overcome the slower benzylic C-H [O]

C: Presence of tertiary hydroxyl retards further decarboxylation

H2O

O

OMe

H

H H

O

HO

OMe

H

H H

O

O

HO2C

O

OO

Ru

-CO2

HO2C

HO2C

OMe

H

H H


2010-08-21

OMe

H

H H

Me O

NH

H

Me

MeMe

Me

Me

O

Expansion of the benzenoid synthon: Reactivity vs Selectivity

RuO4O3

H

Me

MeMe

CO2H

Me

H

H HHO2C

HO2C

CO2H

vsRuO2, NaIO4,rt, 4 h

Conclusions: Both ozone and RuO4 have their advantages. Ozone seems to bea more selective reagent. The use in catechol-type substrates shows promise forits use in complex systems. RuO4 on the other hand, is one of a kind in its abilityto degrade much less electron rich substrates and is a somewhatunderappreciated reagent but may prove to be selective, especially in cases ofm-methoxybenzene or p-methoxybenzene substrate types.

O

O3, rt,3.5 h

Achieving true biomimicry: RuO4, a privileged reagnt

Achieving truebiomimecry

Increasedcomplexity

Degredationchemistry

R

R

R

R

O

R

OH

RR

OH

R

H H

RR

RR

O OH

C-O bondformation

C-C bondcleavage

RR

HO OH

H

O

R

OMe

H

H H

Me O

HO2C

HO2C

OMe

H

H H

RuO4: Reactivity

RuO4 catalyzed oxidative polyenecyclization:The next generation of the cyclase/oxidase phase approach

O

OH OHHH

oxidative polycyclization of squalene with cat. RuO4:

RuO2-2H2O (20 mol5)NaIO4 (8 eq.)EtOAc/MeCN/H2O (3:3:1), 0 °C, 30 min

(Caserta, T. et. al. Tetrahedron, 2005, 61, 927-939)

OHO

Me

Me O O O OOH

Me

Me

H Me H Me MeH Me H H H

(All threo)

50%

headtail

e.g. tail to head

e.g. tail to tail

(1,5 diene)

O

OH

MeMeMe

H

H

O

Me

HO

Me

Me

HO

O

HOH

H

Me Me

Me

OHO

RR

O

?

neodolabelline*only one synthesis of reported of 4,5 deoxy: longest linear 16 steps, 4.5% overall Williams and Heidebrecht, W. JACS, 2003, 125, 1843.

45

Roth and Stark. Angew. Chem. Int. Ed., 2006, 45, 6218-6221.

Efficient oxidative cyclization of 1,6-Dienes:

yields: 40-85%

48%, dr >95:5

RuCl3 5 mol%,NaIO4/wet silica (4 eq.)

EtOAc/MeCN (1:1)

0 °C, 10 min

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