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
