Kevin ByrneLiu Research GroupJanuary 21st, 2020

AC B

B AC

[6-5-5]ryanodane core

[5-6-5]isoryanodane core

HOHO

HMe Me

MeOH

O

Me

Me

OH

OH

OH

(+)-perseanol

• Isolated from Persea indica, an evergreen shrub found in Azores, Madeira, and the Canary Islands.

• Ryanodane and isoryanodane natural products display insecticidal properties by allosterically binding to ryanodine receptors (RyR), which modulate Ca2+ release.• Mammalian isoforms require pyrrole-2-carboxylate ester

• Central bridging 7-membered lactol core with six hydroxyl groups.• Two syn-diol motifs at the A-B and B-C ring fusions.

• This work: concise asymmetric total synthesis of (+)-perseanol from inexpensive (R)-pulegone (~$20/g).

for high-affinity binding.

HOHO

HMe Me

MeOH

O

Me

Me

OH3

(+)-Perseanol

OH

OH

5Anhydroperseanol

HOHO

HMe Me

Me

O

Me

Me

OH

OH

O

RORO

HMe Me

Me

O

Me

ORO

6

78

9A-ring

fragment

10C-ring

fragment

RORO

HMe Me

Me

OH

Me

OR[Pd]

RO

MeRO

H Me

RO

H

MeMe

H

Br

OHHRO

H

MeMe

H[M]

BrRO

MeRO

H

OH

Me

epoxidation/reductive cyclization [O]

CO insertion

Pd cyclizationcascade

fragmentcoupling

+

Me

O Me

Me

11(R)-pulegone

O

EtO19

Retrosynthetic Analysis:

2

Me

O Me

Me

11(R)-pulegone

1) Br2, NaHCO3 Et2O, -10 °C, 3 hr

2) NaOMeMeOH, 55 °C, 4 hr

1278% 1.3:1 d.r.

MeMe

Me

MeO O 1) KHMDS2) O2, P(OMe)3

THF-78 °C, 2 hr

1367% 9:1 d.r.

MeMe

Me

MeO2C OH

Me

O Me

MeBrBr

Na OMeH

Me

O Me

MeBrBr

Na

- NaBrMe

- MeOHMe

MeBr

ONa OMe- MeOH

12

MeMe

Me

MeO O

Me

O Me

Me

Me

O Me

Me Br Br

Me

O Me

MeBr

Br Me

O Me

MeBrBr

11

12

MeMe

Me

MeO O

K N(TMS)2H MeMe

Me

MeO O K

O OSET

MeMe

Me

MeO O O OK Me

Me

Me

MeO2C OOK

MeMe

Me

MeO2C OOK

13

MeMe

Me

MeO2C OHNH4Clworkup

- PO(OMe)3

P(OMe)3 MeMe

Me

MeO2C OK

Ring Contraction

⍺-Hydroxylation

3

13

MeMe

Me

MeO2C OH m-CPBA, NaHCO3DCM

0 °C, 2 hr

1492% single d.r.

MeMe

Me

MeO2C OH

O

Et2Al(TMP)toluene

0 °C, 3 hr

1568%

MeMeO2C OH

OH

Me

1,2-DCERT to 0 °C, 3 hr

1787%

Me OO

Me

OH Ph1) CSA, PhCH(OMe)22) DIBAL-H

OHHOH—CSA

OMe

OMe

OMe

OMe 15

CSA

H

- MeOH

CSA

H

HOOMe

OP.T.

OOMe

OCSA

- MeOHH

PhO

O

H

- H—CSA16

13

MeMe

Me

MeO2C OHm-CPBA

Me OHMe

MeO

O Me

OO

OH

Ar

H

14

MeMe

Me

MeO2C OH

O- m-CBA

14

MeMe

MeO2C OH

O

N

Et2Al

MeMe

MeMeH

- TMPMeMeO2C OH

O

Me

AlEt2 Rochelle’s Saltworkup

15

MeMeO2C OH

OH

Me

Epoxidation

Allylic Alcohol Formation

Diol Protection

Me Me

OSHO

OO

CSA =

4

OMeMeO

NN

OTfCuI

CuIIO

OTf

NN

OCuII

NNTfO

½

CuIIOH

OTf

NNCuII

O

OTf

NN

HR

CuIIO

OTf

NN

R

NHO

NO

O2

NO

NHO

R

O

H18

17

H2O ORH

NMeN+NMI

15

MeMeO2C OH

1,2-DCERT to 0 °C, 3 hr

1787%

Me OO

Me

OH Ph1) CSA, PhCH(OMe)22) DIBAL-HOHMe MeCN, air

RT, 2 hr

18; C-ringFragment

98%

Me OO

Me

O Ph

(5 mol%)Cu(MeObpy)OTf ABNO (1 mol%)NMI (10 mol%)

R

O

HH

Al(iBu)2

R

O Al(iBu)2 Rochelle’s Saltworkup

R

OH

17

R

O

OMeH

Al(iBu)2

- Al(iBu)2OMe R

O

H16

DIBAL Reduction AlcoholOxidation

5

Alkylation

Iodination

O

EtO

LDA, Et2Zn, HMPAI Me

Me

THF-78 °C to RT, 18 hr

O

EtO

Me

Me

19 (rac)-2170%

O

EtO

Me

Me

(rac)-2273%

I

MeCN0 °C to RT, 30 min

I2, CAN

O

EtO19

N(iPr)2LiH

- HN(iPr)2

O

EtO

Li O

EtO

EtZn

EtZn—Et- EtLi

HMPAMe

Me

I

- EtZnI

O

EtO

Me

Me

21

O

EtO

Me

Me

21

O

EtO

Me

MeCeIV

SET

O

EtO

Me

Me O

EtO

Me

MeI I

HI

O

EtO

Me

Me

22

I

I CeIII+SET

I CeIV+

- CeIV- HI

6

H NMe2

OBr

OBr

OO

OBr

O

NMe2

BrO

OBr

O

NMe2

Br - CO2- CO

H Br

NMe2Br

O

O

iPrI O

O

iPrIMe2N

Br Br

23

O

O

iPrIMe2N

Br Br

OiPrI

BrOBr

Me2N

OiPr

BrOMe2N

HIBr

- DMF:HBr

O

Br

Me

Me

24

I

Bromination

O

EtO

Me

Me

22

I

O

EtO

Me

MeI Na OH

O

Me

MeI

EtOHO

Na O

Me

MeI

- NaOEtHO

taut.

O

O

Me

Me

23

I

Hydrolysis

O

EtO

Me

Me

(rac)-2273%

I

1:1 MeOH:p-dioxaneRT, 3 hr

NaOH (aq)

O

O

Me

Me

(rac)-23

I

DCM0 °C to RT, 1 hr

DMF, (COBr)2

O

Br

Me

Me

(rac)-2468% (2 steps)

I

5:1 r.r.

7

O BN

BMePh

Ph

O

IBr

H

HH

HO B

NBH2Me

Ph

Ph

O

IBr

HH

MeOHquench

OH

Br

Me

Me

(1S,5R)-2744% 96:4 e.r.

I

BH2OMe+

(R)-24NB

O

PhPhH

Me

BH3 NEt2Ph

NBO

PhPhH

Me

Reductive Kinetic Resolution

O

Br

Me

Me

(rac)-2468% (2 steps) 5:1 r.r.

IDCM

RT, 5 hr

O

Br

Me

Me

(5S)-2443% 97:3 e.r.

I

OH

Br

Me

Me

(1S,5R)-2744% 96:4 e.r.

I+

DCMRT, 36 hr

CSA (20 mol%)

OPMB

BrMe

Me

29; A-ring Fragment

81%

IBH3 NEt2Ph

NBO

PhPhH

Me

(40 mol%)

N

Me

PMBO

HN

Me

O

CSA

PMB O R

HN

Me

OH

CSAR OPMB

H

+ H—CSA

N

Me

OH

+

29

Me Me

OSHO

OO

CSA =Alcohol Protection

N

Me

OPMBH—CSA

HN

Me

OPMBHN

Me

O

CSA

PMB 27HO R

HN

Me

O

CSA

PMB O R

H

CSA

8

Pd0MeBr

HO

H

MePdII

OH

H

Br

OH

Me

HPdII

Br

CO

Me

O

PdIIOH

H

Br

Me

OPdII

OH

30

NEt3

NEt3:HBr

O

Me

O

31CO +

SHN

O

O OKF

N-formylsaccharin

n-BuLi

NH4Cl workup

PMBO

H

MeMe

HLi

Br

PMBO

H

MeMe

HI

Br

OMeO

Ph

H

OH

Me

OMeO

Ph

H Me

PMBO

H

MeMe

H

Br

OHH

30

29

18

Fragment Coupling

Carbopalladation-Carbonylation Cascade

18 C-ring Fragment

Me OO

Me

O Ph

OPMB

BrMe

Me

29A-ring Fragment

IPMBO

H

MeMe

HI

Br

+

THF-78 to -50 °C, 1.5 hrO

MeOPh

H

OH

Me

OMeO

Ph

H Me

PMBO

H

MeMe

H

Br

OHH

n-BuLi

3075% 3.2:1 d.r.

OO

Ph

HMe

OPMB

H MeMe

H

O

Me

O

3157%

1,4-dioxane100 °C, 26 hr

(50 mol%)Pd(PPh3)4

N-formylsaccharinNEt3, KF

18 C-ring Fragment

Me OO

Me

O Ph

OPMB

BrMe

Me

29A-ring Fragment

IPMBO

H

MeMe

HI

Br

+

THF-78 to -50 °C, 1.5 hrO

MeOPh

H

OH

Me

OMeO

Ph

H Me

PMBO

H

MeMe

H

Br

OHH

n-BuLi

3075% 3.2:1 d.r.

OO

Ph

HMe

OPMB

H MeMe

H

O

Me

O

3157%

1,4-dioxane100 °C, 26 hr

(50 mol%)Pd(PPh3)4

N-formylsaccharinNEt3, KF

OMeO

Ph

H Me

PMBO

H

MeMe

H

Br

OHH

3075% 3.2:1 d.r.

OMeO

Ph

H Me

PMBO

H

MeMe

H

Br

OHH

3075% 3.2:1 d.r.

9

OO

Ph

HMe

OPMB

HMe

MeH

O

Me

O

3157%

OO

Ph

HMe OH

HMe

MeH

O

Me

O

3780%

5:1 DCM:pH 7 buffer0 °C, 2.5 hr

DDQ

OHO

HMe Me

MeH

O

Me

O

3880% (combined) 3:1 r.r.

ODMDONa2SO4acetoneRT, 3 hr

O

Ph

O O

OMe

Cl Cl

NC CN

OR

HH OHR OPMB

DDQ

31 ClCl

HO

OH

CNCN

-

R O

OMe

OHH2O H2O R O

OMe

O

OHH

H

- H2O

OMe

H

O

R OH 37

+

H OHO O

MeMeH O O

O

MeMe

H

P.T.H O O

O

MeMe

HO

+HO OH

MeMe+

acetone

H2O37 38

Ph O

O

O O

MeMe

37 Ph O

OOO

Me Me

- acetonePh O

OO

H

O

HO

PhO

38

PMB Deprotection

Alcohol Oxidation

Acetal Semi-Deprotection10

BzOHO

HMe Me

MeH

O

Me

O

38

O MeMgClCeCl3 2LiCl

THF 0 °C, 30 min

BzOHO

HMe HO Me Me

MeH

O

Me

O

3968%

OO

HMe Me

MeH

O

Me

OMe

O

Ph

TFA

4190%

DCM 0 °C, 5 min

Me MgCl2Li- CeCl3 LiCl

CeCl3 2LiClMe MgCl

O

- MgCl2

HO MeO MeLi38

39

pH 7 bufferquench

OHO

H2O Me

MeO

Ph

OHO

HOMe

MeO

Ph

OHO Me

Me

O

Ph

OO Me

Me

O

Ph

H OO Me

Me

O

Ph

H TFA

39

TFA TFA TFA

- H—TFA

40 41

Turbo Grignard Addition

Orthobenzoate Formation

11

OO

HMe Me

MeH

O

Me

OMe

O

Ph 4190%

OO

HMe Me

MeOH

O

Me

OMe

O

Ph 4278%

OO

HMe Me

MeOH

O

Me

OMe

O

Ph 4368%

OSeO2

1,4-dioxane100 °C, 1 hr

(50 mol %)VO(OnPr)3

TBHP

toluene60 °C, 28 hr

OSe

OH SeHO

O[2,3]-sigmatropic shift O

SeOH silica gelworkup OH

41 42

O

VVOnPr

nPrOnPrO

43

tBOOH

tBuOH

VIIIOnPr

nPrOnPrO

OH42

OH

O

OHVV

nPrO

OnPrO OnPr

OHVV

nPrO

OnPrO OnPr

Allylic Oxidation

Epoxidation

12

OO

HMe Me

MeOH

O

Me

OMe

O

Ph43

O benzene10 °C, 5 min

OO

HMe Me

MeOH

O

Me

Me

O

Ph46

25% 43% BRSM

OH

OH

HOHO

HMe Me

MeOH

O

Me

Me

OH3

(+)-Perseanol90%

OH

OHPh

Li

MeOHRT, 1.5 hr

H2 (1 atm)Pd(OH)2/C(20 wt.%)

O

Me

OMe

O

Ph

Li

- PhNap

SET O

Me

OMe

O

LiO

Me

OMe

O

LiO

Me

Me

O

O

Li43 45

Ph

Li

- PhNap

SETO

Me

Me

O

O

Li

O

Me

Me

O

O

Li

O

Me

Me

OH

OHNaHCO3workup

Li

46

O

Me

Me

OH

OH

NaHCO3workup

46

OO

O

MeO

PhHO

HO

O

MeOH

3(+)-Perseanol

H2Pd(OH)2/C

OO

O

MeO

MagicPd

- toluene46

Reductive Cyclization

Alcohol Deprotection

13

OO

O

MeO

PhHO

HO

O

MeOH

3(+)-Perseanol

H2Pd(OH)2/C

OO

O

MeO

MagicPd

- toluene