Chase BruggemanCEM 852 Presentation

4/11/2020

1

OOH

HO

HOH

OHO

H

Luo et al. JACS 2019, 141, 20048

(–)-Oridonin

• Biological activity:• Anti-inflammatory• Leukemia treatment

• Produced by Rabdosia rubescens plant• Structural features:

• Three contiguous C-6 rings• Terminal alkene on C-7 ring• Cyclic hemiacetal

2

OOH

HO

HOH

OHO

H

Luo et al. JACS 2019, 141, 20048

Nazarov interrupted by nucleophilic alkene attack on 5-membered ring

3

BnO

H

OBn

H

O

BnO

H

OBn

H

O LA-

Si

Key Intermediate

OOH

HO

HOH

OHO

H

Luo et al. JACS 2019, 141, 20048

Synthesis involves joining & building upon two 6-membered rings

4

OOH

HO

HOH

OHO

H

SiO

OBnBnO

Br

OBnBnO

Si

O

+(+)-9 (+)-10

Luo et al. JACS 2019, 141, 20048

5

(+)-9 Synthesis begins with dimethyl cyclohexanone

O Br

O

1660%

DMF (8 eq)CHCl3, 0 °C, 50 min

PBr3 (4 eq)

CHCl3, 0 to 70 °C, 40 h15

88 mmol

Luo et al. JACS 2019, 141, 20048

6

Aldehyde converted to ester by Pinnickoxidation, then methylation

Br

O

O

1767%

2 steps

16124 mmol

NaH2PO4 (0.25 eq)

H2O2 (1 eq)

NaClO2 (1.4 eq)

H2O, MeCN, 0 to 30 °C, 3 h

K2CO3 (1 eq)

MeI (1.1 eq)DMF, rt, overnightBr

O

Luo et al. JACS 2019, 141, 20048

Ketone formed via chromate ester

7

Br

O

O

1845%

O

1788.4 mmol

AcOH (14 eq)Ac2O (4 eq)35 °C, 1 h

CrO3 (1.7 eq)

CH2Cl2, rt, 3 h

Br

O

O

Luo et al. JACS 2019, 141, 20048

Stereochemistry introduced with chiral boron compound

8Luo et al. JACS 2019, 141, 20048

Br

OHOH

(+)-1978%

98% ee

N BO

H

BH3·SMe2 (1.6 eq)

THF, 0 °C, 1.5 h(S)-oxazaborolidine (1.2 eq)18

19.2 mmolTHF, -40 °C, overnight

Br

O

O

O

Alcohols protected as benzyl ethers

9

Br

OBnBnO

(+)-967%

(+)-1949 mmol

NaH (5 eq)THF, 0 °C, 1 h

BnBr (4.8 eq)0 to 30 °C, 40 hBr

OHOH

Luo et al. JACS 2019, 141, 20048

(+)-10 synthesis begins with methyl cyclohexenone

10

O

Si (i-Bu)2AlH (2.4 eq)THF, 0 to 55 °C, 5 h Si

Al(i-Bu)2

2 eq

CuCl2·2H2O (0.004 eq)NHC-Ag (0.004 eq)

THF, 0 °C, overnight

O

Si

(+)-2052%

86% ee

S160 mmol

N+N

SO3- Ag

NHC-Ag2

Luo et al. JACS 2019, 141, 20048

Silyl group homologated in two steps:1) Removal by ICl

11

O

I

(+)-2173%

(+)-2011.9 mmol

diglyme (3 eq)ICl (2.5 eq)

hexafluoro-isopropanol40 °C, 5 minO

Si

Luo et al. JACS 2019, 141, 20048

Silyl group homologated in two steps:2) Pd-catalyzed addition

12

O

Si

(+)-2276%

(+)-218.63 mmol

ZnBr2 (4.2 eq)

Et2O, rt, overnightSi MgCl Si ZnBr

Pd(MeCN)2Cl2 (0.1 eq)

DMF, 45 °C, 4 h

4 eqO

I

Luo et al. JACS 2019, 141, 20048

Ketone converted to ester via tosyl ester:1) Tosylation

13

(+)-2216.5 mmol

NaN(SiMe3)2 (1.2 eq)

diglyme (2 eq)t-BuOMe, -78 °C, 2 h

Comins' Reagent (1.2 eq)2 h, -78 °C

NNCl

S

S

CF3

OO

OO CF3

Si

OO

Si

SCF3O

O

Luo et al. JACS 2019, 141, 20048

Ketone converted to ester via tosyl ester:2) Palladium catalyzed coupling

14

Si

OO

(+)-2363%

2 steps

Si

O

Pd(OAc)2 (0.12 eq)

PPh3 (0.24 eq)

COEt3N (1.63 eq)

MeOH, DMF, 45 °C, 2 hSCF3O

O

Luo et al. JACS 2019, 141, 20048

Ester converted to aldehyde via Weinrebamide

15

(+)-238.48 mmol

n-BuLi (7.8 eq)

THF, -78 °C to rt, 10 minrt, 1.5 h

CH3NHOCH3·HCl (4 eq)

THF, -78 °C, 1 h

Si

ONO

Si

OO

Si(+)-1070%

2 stepsO

(i-Bu)2AlH (2.25 eq)1.5 h, -78 °C

Luo et al. JACS 2019, 141, 20048

Blocks 9 and 10 connected via vinyl lithium

16

Br

OBnBnO

(+)-91.1 eq

t-BuLi (2.2 eq)Et2O, -78 °C, 30 min

Si(+)-10

5.85 mmol1 eq

O

Et2O, -78 °C, 110 minSi

OH

OBnBnO

Luo et al. JACS 2019, 141, 20048

Secondary alcohol oxidized by dichromate

17

SiOH

OBnBnO

Cornforth reagent (1.1 eq)DMF, 0 °C, 3 h

NH+Cr

O-O

O

OCr

O-

O

O

2

SiO

OBnBnO

(+)-8b61%

2 steps

Luo et al. JACS 2019, 141, 20048

Interrupted Nazarov commences with Lewis acid

18

SiO

OBnBnO

(+)-8b1.75 mmol

EtAlCl2 (1.5 eq)

CH2Cl2/THF 20:1 v/v40 °C, 22 h

BnO

H

OBn

H

O

Luo et al. JACS 2019, 141, 20048

Alkene converted to conjugated carbonyl with singlet oxygen

19

BnO

H

OBn

H

O

HN

N

NH

N

TPP (0.56 mol%)hv, O2

(1 atm)

CDCl3, rt, 36 h

DMAP (0.024 eq)

pyridine (0.3 eq)Ac2O (0.9 eq)

rt, 5 h

N

N

BnO

H

OBn

H

O

O

(-)-2543%

2 steps

Luo et al. JACS 2019, 141, 20048

Aldehyde cleaved with Wilkinson’s catalyst

20

BnO

H

OBn

H

O

O

(-)-253.38 mmol

RhCl(PPh3)3 (1 eq)

toluene, reflux, 4 h

BnO

H

OBn

H

O

(-)-2667%

Luo et al. JACS 2019, 141, 20048

Vinyl lithium adds to ketone

21

BnO

H

OBn

H

O

(-)-262.47 mmol

Br4 eq

t-BuLi (7.5 eq)Et2O, -78 °C, 30 min

Li

Et2O, -78 °C to 0 °C, 80 min

BnO

H

OBn

H

HO

Luo et al. JACS 2019, 141, 20048

mCPBA selectively oxidizes bisubstitutedalkene

22

BnO

H

OBn

H

HO

mCPBA (2 eq)NaHCO3

(10 eq)

CH2Cl2

Cl

O

OOH

BnO

H

OBn

H

O

H

HHO

(-)-2770%

2 steps

Luo et al. JACS 2019, 141, 20048

Ring expanded by radical bromine addition

23

BnO

H

OBn

H

O

H

HHO

(-)-272.08 mmol

NO

O BrNBS (1.2 eq)

silica gelCH2Cl2, rt, 30 min

BnO

HO

HOBn

O

H

H

Br

(-)-2889%

Luo et al. JACS 2019, 141, 20048

Primary halide converted to vicinal diol by RuO4, then OsO4

24

BzO

HO

OH

HOBz

OH

O

H

H

(-)-3070%

2 steps

BzO

HO

HOBz

O

H

H

BnO

HO

HOBn

O

H

H

Br(-)-28

1.86 mmol

NaIO4 (8 eq)

RuCl3·3H2O (2 eq)MeCN/CCl4

1:1 v/v

pH 7 bufferrt, 2.5 h

NMO (5 eq)OsO4

(0.05 eq)

acetone/H2O 8:1 v/v40 °C, 30 min

O

N+O

Luo et al. JACS 2019, 141, 20048

Lewis acid opens epoxide & rearranges rings

25

OHBzO

HO

OH

HOBz

OH

(-)-3157%

BzO

HO

OH

HOBz

OH

O

H

H

(-)-300.88 mmol

EtAlCl2 (3 eq)

toluene, 0 °C to rt, 2 h

Luo et al. JACS 2019, 141, 20048

Ether groups deprotected to form hemiacetal

26

OHBzO

HO

OH

HOBz

OH

(-)-310.47 mmol

LiAlH4 (5 eq)

Et2O, 0 °C to rt, 4.5 hOH

HO

HOH

OH

HOH

OH

OHHO

HOH

OHO

HNaIO4

(1.38 eq)

pH 7 bufferTHF, 10 °C to rt, 3.5 h

(-)-3369%

2 steps

Luo et al. JACS 2019, 141, 20048

Inverting alcohol stereochemistry:1) Acetal protection allows selective oxidation

27

OO

HO

OO

HOH

HO

HOH

OHO

H

(-)-330.214 mmol

2,2-dimethoxy propane (20 eq)p-TsOH (0.1 eq)

acetone, rt, 10 min

OI

O

OOO

O O

O

DMP (3.5 eq)DCM, 0 °C, 4 h

DMP (2 eq)DCM, rt, overnight

(-)-3466%

Luo et al. JACS 2019, 141, 20048

Inverting alcohol stereochemistry:2) Ketones reduced to new alcohols

28

OHHO

HOH

OHO

H

(-)-356%

OHHO

HOH

OHO

H

(-)-3521%

Recycled to (-)-34 byprevious reaction

OO

HO

OO

H

(-)-340.0414 mmol

(i-Bu)2AlH (2 eq)CH2Cl2/Et2O 1:3 v/v

-100 °C, 5 min, then rt

ONa+O

O OAl

-H

H

Red-Al ® (3 eq)THF, rt, 1 h

+HCl (5% aq,

2 mL)

Luo et al. JACS 2019, 141, 20048

Alkene converted to conjugated carbonyl with singlet oxygen (again)

29

OOH

HO

HOH

OHO

HOH

HO

HOH

OHO

H

(-)-315.6 μmol

HN

N

NH

N

TPP (3 mol%)hv, O2

CDCl3, rt, 15 h

DMAP (2 eq)

pyridine (1 eq)Boc2O (3 eq)

CH2Cl2, 0 °C, 20 min

N

N

HCl (6M, 3.8 eq)

2

(-)-Oridonin47%

Luo et al. JACS 2019, 141, 20048

Thank you!

30

OOH

HO

HOH

OHO

H

NHC-Ag synthesis begins with chiral glycinol

31

NH OHO

O

imidazole (3.9 eq)Et3N (2.7 eq)

SOCl2 (1.3 eq)

CH2Cl2, -50 °C to 4 °C, 13.5 hN OO

OSO

B78.4%

A16.8 mmol

May et al. Angew. Chem. Int. Ed. 2008, 47, 7358

Sulfur oxidized to leaving group by RuO4

32

N OO

OSO

B13.1 mmol

RuCl3•2H2O (7 mol%)NaIO4

(1.6 eq)

pH 7 bufferCH2Cl2/MeCN 1:1 v/v

0 to 22 °C, 25 min

N OO

OS

OC

74.2%

O

May et al. Angew. Chem. Int. Ed. 2008, 47, 7358

Diethyl aniline protected with Boc group

33

NH2

61 mmol

(Boc)2O (1.1 eq)H2O, 48 h

NH

OO

D89.9%

May et al. Angew. Chem. Int. Ed. 2008, 47, 7358

Fragments joined, then protecting groups removed

34

N OO

OS

OC

3.17 mmol

O

NH

OOD

1.5 eqNaH (1.7 eq)

DMF, 22 °C, 15 min

DMF, 22 °C, 12 h

H2SO4 (18 M, 13.5 eq)

dioxane, 22 °C, 48.5 hH2N HN

E77.3%

May et al. Angew. Chem. Int. Ed. 2008, 47, 7358

Aryl group added with palladium catalyst

35

H2N HN

E3.75 mmol

Br

SO

OO

(1 eq)Pd2(dba)3

(5.8 mol%)

NaOt-Bu (1.75 eq)rac-BINAP (0.175 eq)

THF, 66 °C, 15 h

NH HN

F~80%

SO

O O

O

Pd

Pd

3

Pd2(dba)3

PP

PhPh

PhPh

rac-BINAP

May et al. Angew. Chem. Int. Ed. 2008, 47, 7358

Methylene group bridges nitrogen atoms

36

NH HN

SO

O O

F9.71 mmol

N+ I-

(5 eq)AcOH (15 eq)

110 °C, 1h

N N

SO

O O-

G50%

May et al. Angew. Chem. Int. Ed. 2008, 47, 7358

Catalyst dimer formed with silver oxide

37

AgNO3

(10 mmol)

NaOH (40 mmol)H2O, immediate

Ag2O

(2 eq used below)N N

SO

O O-

G0.201 mmol

4Å MSTHF/benzene 1:1 v/v

80 °C, 2 h

N+N

SO3- Ag

NHC-Ag98%

2

May et al. Angew. Chem. Int. Ed. 2008, 47, 7358