DBU

BnO

HO

HBr

BnO

O

BzO

O

OBn OBn

TMS

Problem Session (5) 2020/06/13 Shimizu Shinsuke

Please provide following reaction mechanisms and stereoselectivities

Problem 2

Problem 1

OH

HOH

OH

O

H

OHH

2-22-1

1. EtAlCl2 (3 eq), toluene, 0 °C to rt, 57%2. LiAlH4 (5 eq), Et2O, 0 °C to rt3. NaIO4 (1.38 eq), THF/pH 7 buffer (2/1)

10 °C to rt, 69% (2 steps)

4. (MeO)2CMe2 (20 eq), PTSA (0.1 eq)acetone, rt; NaHCO3 (20 eq); evaporation; DMP (3.5 eq), CH2Cl2, 0 °C; DMP (2 eq), rt, 66%

5. iBu2AlH (2 eq), CH2Cl2/Et2O (3/1), -100 °C to rt; Red-Al (3 eq), THF, rt; aq.HCl, MeOH, rt, 56%(diastereomer at C6: 21%)

pH 7 buffer: 0.2 M aqueous solution of a 1:1 mixture of Na2HPO4:NaH2PO4

PTSA DMP

Red-Al

1. EtAlCl2 (1.5 eq), CH2Cl2/THF (20/1), 40 °C2. O2, TPP (0.0056 eq), Fluorescent lamps, CDCl3, rt

; Ac2O (0.9 eq), pyridine (0.3 eq)DMAP (0.024 eq), rt, 43% (2 steps)

3. RhCl(PPh3)3 (1.0 eq), toluene, reflux, 67%4. vinyl lithium, Et2O, -78 °C to 0 °C5. m-CPBA (2 eq), NaHCO3 (10 eq), CH2Cl2, 0 °C, 70% (2 steps)6. NBS (1.2 eq), silica gel (200 wt%), CH2Cl2, rt, 89%

DMAPTPP

1-1

NBS

NBr

O

O

OI

O

OAcOAc

AcO

N

NMe2

Me

SO3H

NaAl(OC2H4OMe)2H2 N

NH

N

HN

Ph

PhPh

Ph

N

N

Vinyl lithium was prepared by mixingvinyl bromide (4 eq) and t-butyl lithium (7.5 eq).

1-2

HO

HOH

BzO

O

OH

In these reactions, enantio excess (ee) were not mentioned.

6

TMS

OBn

ClEtAl

TMSH

O

OBn OBn

TMS

OBn

BnOClEtAlO

TMS

O O

OO

1-1 1-3

O

OBn OBn

EtAlCl2

ClEtAl

Nazarov cyclization

(4 , conrotatory)

1-4

O

OBn

Hosomi-Sakuraireaction

5-exo, beta-effect

1-5

work up

OBn

BnOClEtAlO

TMS

1-6

Cl

OBn

BnOO

1-7

OBn

BnOO

1-8

H+

ClEtAl

H

OBn

BnOO

1-10

H

step 1

light, TPP

OOH

O O

O O

MeO OH

pKa

11.5

5.2NH

N

O

NMe2

OBn

BnOO

1-11

H

O

H

2020/06/13 Shimizu ShinsukeProblem Session (5) Answer

topic: Total synthesis of oridonin by Luo group

(Kong, L.; Su, F.; Yu, H.; Jiang, Z.; Lu, Y.; Luo, T. J. Am. Chem. Soc. 2019, 141, 20048.)

Problem 1

Answer 1

O

O

AcOH

Discussion 1-1:

Torquoselectivity

-1-

1. EtAlCl2 (1.5 eq), CH2Cl2/THF (20/1), 40 °C2. O2, TPP (0.0056 eq), Fluorescent lamps, CDCl3, rt

; Ac2O (0.9 eq), pyridine (0.3 eq)DMAP (0.024 eq), rt, 43% (2 steps)

3. RhCl(PPh3)3 (1.0 eq), toluene, reflux, 67%4. vinyl lithium, Et2O, -78 °C to 0 °C5. m-CPBA (2 eq), NaHCO3 (10 eq), CH2Cl2, 0 °C, 70% (2 steps)6. NBS (1.2 eq), silica gel (200 wt%), CH2Cl2, rt, 89%

1-1Vinyl lithium was prepared by mixing

vinyl bromide (4 eq) and t-butyl lithium (7.5 eq).

BnO

HO

HBr

BnO

O

1-2

O

OBn OBn

TMS

H

1-A

Py-H

AcOPyridine

OBn

BnOO

H

1-9H O

O

RhIII

Cl

HL

L

R H

L

O

R

OBn

BnOO

1-12

H

O

H 1-13 (L = PPh3)

RhICl(PPh3)3RhIII

Cl

H

O

RL L

L

R

L

1-15 (L = PPh3)

RhIII

Cl

H

CO

L R

1-14 (L = PPh3)

OBn

BnOH

O

1-17

RhICl(PPh3)2(CO)

step 3

OBn

OBnHO

1-19

OBn

OBn

H

O

1-18

Li

Li step 4

Li

ClO

O

OH

1-21step 5

OBn

OBnO

1-20O O

OH

Ar

epoxidation atmore electron rich olefin

OBn

OBnHO

O

step 2

-2-

H

OBnO

BnO

H

OH

1-22

OBnO

BnO

H

O

H

1-23

N

Br O

O

NBS

1-2

BnO

HO

HBr

BnO

O

step 6

Discussion 1-2:

stereoselectivity of

rearrangement

1-16

m-CPBA

rearrangement of4° carbon

oxidative addition

reductive eliminationCO insertion

R-1:

; work up

Br

TMSH

Cl2FeOH

H

Me

H

Me

Me

Me

MeMe

Me

Me Me

Me

Me

Me

H

Me

Me

H Me

HMe

Me

Me

H Me

H

MeH Me

H

H

Me HMe

MeMe

MeMe

MeMe

Me

Me

H

Me

H

H

MeH

Me

H

Discussion 1-1: Torquoselectivity of Nazarov cyclization (clockwise or counterclockwise?)

Torquoselectivity: steric repulsion and stereoelectronic effect are the driving force for the selectivity.

175 °C

1-241-25

cis-trans-hexadiene

175 °C

1-261-27

trans-trans-hexadiene

(cis-cis isomer was not obtained)

175 °C

1-24

175 °C

clockwiserotation

counter-clockwiserotation

1-25

cis-trans-hexadiene

1-28 1-29

1-30 1-31

175 °C

1-26

175 °C

clockwiserotation

counter-clockwiserotation

1-27

trans-trans-hexadiene1-32 1-33

1-34 1-351-36

cis-cis-hexadiene

example of steric repulsion: Winter, R. E. K. Tetrahedron Lett. 1965, 17, 1207.

example of stereoelectronic effect: Denmark, S. E.; Wallace, M. A.; Walker, C. B. J. Org. Chem. 1990, 55, 5543.

O TMS

1-37 (88% ee)

O

1-38: 58% (88% ee)

FeCl3

CH2Cl2-50 °C

H

H HHH

TMS

Cl2FeO

H

H

1-40 (eq-TMS, chair)

low orbital interaction

1-41 (ax-TMS, chair)

high orbital interaction

Cl2FeOTMS

1-39

H

FeCl3

counter-clockwiserotation

clockwiserotation

OFeCl2

1-42

H H

Cl

protonation

H

-3-ent-1-42 ent 1-38

R

OAlEtCl

BnO HH

BnO

anti

BnOOBn

O

H

H

anti

O

OBnH

H

anti

HTMS

O

ClEtAlO

H

BnO

BnH

O

BnO OBnH

H

anti

O

O

AlEtClTMS

OBn

R

BnOOBn

O

H

H

BnO

H

R = -Me: 1-43a

R = -Me: 1-43b

(dr = 1:1, mixture)

OBn

R

OBn

TMS

1-45 (21%)1-44 (35%)

Model experiment for Nazarov cyclization and Hosomi-Sakurai reaction

1-43a 1-50

O

OBn OBn

EtAlCl2

ClEtAl

conrotatory

counterclockwiserotation

TMS

O

OBn OBn

TMS BnO

OBn

H

ClEtAlO

1-51

1-43a 1-46

O

OBn OBn

EtAlCl2

ClEtAl

clockwise rotation

conrotatory

TMS

O

OBn OBn

TMS

1-47

R

ClEtAlO

TS-1-48 (R = OBn)

H

sterically disfavoured

1-49

EtAlCl2 (1.5 eq)

CH2Cl2/THF (20/1)40 °C

1-52 (R = OBn) 1-44 (35%)

TMS

ClEtAlO H

BnO

Cl

1-53 (R = OBn)

work upR

1-43b

EtAlCl2

O

OBn OBn

TMS

1-45 (21%)

-4-

Torquoselectivity

Hosomi-Sakurai reaction

TMS

TMSTMS

TMS

ClEtAlO

OBn

BnO

H H

TMS

ClEtAlO

OBn

BnO

H

ClEtAlO

OBn

BnO

H

14

Clwork up

1-43b 1-43b

O

OBn

O

BnO OBn

HTMS

ClEtAlOOAlEtCl

OBnHH

BnO

TMS

OBn

ClEtAl

TMS

1-1 1-55

EtAlCl2

O

OBn OBn

TMS

BnOOBn

O

H

1-57 (not obtained)

1-56 1-58

OBn

BnOO

1-8

H

H

conrotatory

conrotatory

clockwiserotation

counter-clockwiserotation

-5-

syn

OBn

BnOClEtAlO

TMS

1-5

H

BnOOBn

H

1-59

anti

H anti

H

OBn

NBSN OO

Br

OH

OBn

OBnO

H

H

OH

OBnHO

H

1-61 (favored) 1-62 (disfavored)

Discussion 1-2: stereoselectivity of rearrangement

OBnO

BnO

H

OH

1-22 1-60 (not obtained)

BnO

HO

HBr

BnO

O

NBS

N OO

Br

1-2 (89%)

BnO

HO

HBr

BnO

O

OBnO

BnO

H

OH

1-22

H

NBSN OO

Br

O

OH

H

BzO

1-60 (not obtained)

OBz

H

Br

O

OH

H

BzO

OBz

H

Br O

O

H

H

Br

1-63 (some substituents

were omitted)

1-2 (89%)

-6-

OH

OBn

OBnOH

1-66 (disfavored) 1-66 (disfavored)

H

OH

OBn

OBnOH

H H

OBnO

BnO

HO

1-64

Br

H

1-65 (not obtained)

BnO

H

H

BnO

O

O

Br

Stereoselectivity

Regioselectivity

rearrangement of3° carbonOBnO

BnO

H

OH

1-22

NBS

H

RL

RM

HO

H

RL

RM

HO

H

Br

1-71 1-72

OBnO

BnO

H

OH

1-22

O

OH

H

BzO

OBz

H

Br

1-2 (89%)

NBS

Other explanation

-7-

ClEtAlOBzO

OBz

OH

OH

OAl

OH

HO O

OH

OH OH

OH

HOH

OH

O

H

OHH

HO

OH

H

Me

OAlLiAlH4

H3Al H

Li

AlEtCl2

LiAlH4

Problem 2

Answer 2

OAlEtCl

O

O

Me

BzO

2-4

OBz

AlEtCl22-3

step 1

OAl

OBzO

OBz

AlO

H

2-5

OAlEtCl

OBzO

OBz

AlO

2-6

OAlEtCl

OAl

OBzO

OBz

OAl

2-7

OAl

AlOO

OBz

OAl

2-9

OAlBz

H

2-10

OHH

H

reduction of Bz group

; work up

step 2

HO OH

OH

2-11

HNaIO4

IO

O

O OO

Na

Discussion 2-1:

regioselectivity of rearrangement

-8-

Discussion 2-2:

regioselectivity of diol cleavage

2-22-1

1. EtAlCl2 (3 eq), toluene, 0 °C to rt, 57%2. LiAlH4 (5 eq), Et2O, 0 °C to rt3. NaIO4 (1.38 eq), THF/pH 7 buffer (2/1)

10 °C to rt, 69% (2 steps)

4. (MeO)2CMe2 (20 eq), PTSA (0.1 eq)acetone, rt; NaHCO3 (20 eq); evaporation; DMP (3.5 eq), CH2Cl2, 0 °C; DMP (2 eq), rt, 66%

5. iBu2AlH (2 eq), CH2Cl2/Et2O (3/1), -100 °C to rt; Red-Al (3 eq), THF, rt; aq.HCl, MeOH, rt, 56%(diastereomer at C6: 21%)

pH 7 buffer: 0.2 M aqueous solution of a 1:1 mixture of Na2HPO4:NaH2PO4

BzO

HO

HOH

BzO

O

OH

6

work up

2-1

BzO

HO

HOH

BzO

O

OH

OH

OBzO

OBz

HO

2-6

OH

OAl

Li

O

OBzO

BzO

OAl

2-8

H2Al

H

or

1. steric repulsion2. dipole moment

3. low Cieplak effect

OHHOH

O

OH

HCO3-

OH

O

O

OHO

; DMP

HO

H

O

OI

O

OAcOAc

AcO

OHH

O

OH

OHH

2-17

O

2-13

OHHOH

O

OH

OH

OMeMeO OHMeMeO OMe

OMe

MeHO

H+

H+

OHOH

O

OH

O

2-18

OHHOH

O

OH

O

; DMP

OI

O

OAcOAc

AcO

-H+

2-21

OHOH

O

O

O

2-20

2-22

OH

O

O

OO

OH

OH

OH

H

O

2-12

step 3

2-19

step 4

i-Bu2AlH

2-23

OOH

O

OAl

O OH

O

OAl

H; aq. HCl

Ali-Bu2H

H

; Red-Al

NaAl(OC2H4OMe)2H2

Al(OC2H4OMe)2H

H

O

Al

2-2 step 5 -9-

Discussion 2-3:

reduction of diketone

O

H

2-14 2-15 2-16

2-16

2-24

OH

O

OH

OHH

O

H

2-26

OH

O

OH

OHH

O

H

2-25

OH2

OH

O

OH

OHH

O

H

2-27

OH

H

OI

O

OAcAcO

H

1

6

H+

OAl

OBzO

OBz

AlOO

H

HClEtAl

OAl

OBzO

OBz

AlO

OAl

OBzO

OBz

AlO OAlEtCl OHOAlEtCl

H

OAlEtCl

OAl

OBzO

OBz

AlO

Discussion 2-1: regioselectivity of rearrangement

OAl

O

O

Me

BzO

2-30

OBz

AlEtCl2

O

OH

H

Me

BzO

2-3

OBz

OH

OH AlO

AlEtCl2

2-32 (disfavored)

O

H

O

O

Bz

AlO

OAlOAlEtCl

2-31 (favored)

path b:1. large conformational change

for rearrangement2. destabilization of cation by

electron withdrawing group (OAl)

2-33 (disfavored)

less substituted olefin

2-5 (favored)

more substituted olefin

path bpath a

2-34 (unfavored)

anti-Bredt's rule

path d path epath f

OH

OBzO

OBz

HO

2-6 (57%)

work up

Bz

-10-

3° cation 3° cation

H

OAl

OMe

BzO

2-36

OBz

AlO OAlEtCl

path c

2° cation H

df

e

c a

b

OOH

OH

H OHIOO

R

Na

R

R OHHOH

OH

H OH

O

O

H

OH

O

RR

R

-11-

HO OH

OH

OH

HIO

O

O OO

Na

Discussion 2-2: regioselectivity of diol cleavage

OH

HO O

OH

OH

2-41 (favored)

OHH

H

2-42

(1°-OH, 3°-OH)

OHHOH

O

OH

H OH

2-13

2-44 (R = CH2OH

2°-OH, 3°-OH)

2-43 (R = CH2OH

disfavored)

OO

H

OH

H OH

2-45 (R = CH2OH)

not obtained

Discussion 2-3: reduction of diketone

O

HO

O

O

H

OH

6

OH

HO

O

O

H

OH

6

OH

H

O6

conditions

2-22 2-51 (desired) 2-52 (undesired)

entry conditions results

1 2-51:2-52=2.5:1

2 2-51:2-52=8:1

LiAlH4 (3 eq), THF, -78 °C

i-Bu2AlH (3 eq), CH2Cl2/THF (3/1), -100 °C

111

The order of reduction:

-> Reduction at C1-ketone proceeded first.

2-53

OH

O

O

OO

Ali-Bu2HTable 2-1

H

i-Bu2AlH

i-Bu2AlH

1

6