-
Total Synthesis of (–)-‐Crinipellin A
Taek Kang, Seog Boem Song,
Won-‐Yeob Kim, Byung Gyu Kim,
and Hee-‐Yoon Lee* Department of
Chemistry, Korea Advanced InsFtute of
Science and Technology, Daejeon,
305-‐701, Korea J. Am. Chem. Soc.
2014, 136, 10274–10276.
• Crinipellins (1 – 5) were first
isolated from the basidiomycete
Crinipellis s5pitaria in 1979.
• These compounds display anFbacterial
and anFcancer acFvity.
• Compounds 6 – 9 were isolated
late from a different fungal
strain, Crinipellis sp. 113 and
only show moderate anFcancer acFvity.
• These are the only known class
of tetraquinane natural products.
• Only previously reported total
synthesis of a crinipellin natural
product is Piers’ report of the
total synthesis of crinipellin B1.
1. Kang, T.; Song, S. B.;
Kim, W.-‐Y.; Kim, B. G.; Lee,
H.-‐Y. J. Am. Chem. Soc. 2014,
136, 10274–10276.
Ka5e Boknevitz 1 Liu Lab
I. IntroducCon
O O
O O
O O
O O O
O
O
O
O
O
HO
R2
OHOR
HO
HO
HO
OH
R1HO
H H
H
R1 OH
HH
R2
H
1 - crinipellin A, R = H2 - O-acetylcrinipellin A, R = Ac
3 - tetrahydrocrinipellin A
4 - crinipellin B, R1,R2 = O5 - dihydrocrinipellin B,
R1 = H, R2 = OH
6 - dihydrocrinipellin A, R1,R2 = O7 - tetrahydrocrinipellin
B,
R1 = H, R2 = OH
8 - crinipellin C 9 - crinipellin D
-
Total Synthesis of (–)-‐Crinipellin A
• Eight conFguous stereocenters •
Tetraquinane skeleton • UFlize their
recently reported syntheFc methodology
for triquinane synthesis from acyclic
substrates.
2 Liu Lab
II. SyntheCc ConsideraCons N2
C
NN
Extension of TMM strategy to tetraquinane
H
HOOO O
(–)-Crinipellin A
H
TBDPSO10
•OTBDPS
N2
12
HO
13
OOTBS
14
TBDPSO11
III. RetrosyntheCc Analysis
TBDPSO11'
-
Total Synthesis of (–)-‐Crinipellin A
3 Liu Lab
OOTBS a) Ph3PCH3Br, tBuOK
tBuOH, Et2O, RT, 99%
OTBS b) TBAF, THF
RT, 99%
OH c) (COCl)2, DMSO, THF,
Et3N, –78 °C to RT
O
d) Ph3PCCH3COOEtTHF, reflux
91% for 2 steps
e) LiAlH4, Et2O
0 °C to RT, 96%
f) D-DET, TBHP, Ti(OiPR)4
CH2Cl2, –30 °C, 87%
g) (COCl)2, DMSOCH2Cl2
Et3N, –78 °C to RT
HO EtOOCOHO
OO
h) K2CO3Bestmann-Ohira
reagent, MeOH, RT87% for 2 steps
O
i) Fe(acac)3, THF, toluene, –15 °C, 94%
BrMg OMe
OMe
•
MeO OMeOH
j) TBDPSCl, imidazoleDMAP
CH2Cl2, RT, 96%•
MeO OMeOTBDPS
k) p-TsOH•H2O, HCHOTHF, H2O, RT, 93%
•OTBDPS
Ol) NH2HNTs
MeOH, RT, 97%•
OTBDPSNNHTs
14
1616'
14'15'
17'
15''
1917
13
15
19'20
18
IV. Forward Synthesis
-
Total Synthesis of (–)-‐Crinipellin A
4 Liu Lab
•OTBDPS
NNHTs
NaHToluene
reflux87%
H
TBDPSO20 10
•OTBDPS
NNTs
20
HH
•OTBDPS
NN S
OONa
•
NN
TBDPSO
NN
TBDPSO
TBDPSOTBDPSOTBDPSO
H
TBDPSO10
-
Total Synthesis of (–)-‐Crinipellin A
5 Liu Lab
H
TBDPSO10
H
HO10'
H
O22
H
O22'
m) TBAF
THF, 60 °C
n) PCC,
CH2Cl2, RT79% for 2 steps
o) KHMDSDavis' oxaziridine
THF, –78 °C HO
p) DMP, pyr.CH2Cl2, RT
79% for 2 steps
H
O23
O
q) nBuLi(+)-(S)-N,S-dimethyl-S-phenyl-sulfoxime
–78 °C, 80%
H
OHO
SO PhN
s) 2,6-lutidine,TBSOTf
CH2Cl2, RT, 98%
24
r) NaBH(OAc)3
CH2Cl2, RT, 80%
H
HO
SO PhN 25
HO
H
HO
SO PhN 25'
TBSO
t) PDC, TBHPPhH, RT, 40%
H
HO
SO PhN 26
TBSOO
u) toluene
125 °C, 69%
H
27
TBSOOO
v) H2O2, NaHCO3,
THF, H2O, RT, 90%
H
TBSOOO O
27'
w) LiHMDS,Eschenmoser's salt
THF, –78 °C to –70 °C58%
H
TBSOOO O
28
x) TASF, DMF, RT40% with 35%
conversionH
HOOO O
(–)-1
-
Total Synthesis of (–)-‐Crinipellin A
6 Liu Lab
OOTBS
CH2
PPh3
OTBS
Ph3PO
OTBS
14 14'
Mechanism a: Wittig olefination
Cl
O
O
ClSO
Cl OO
OS
ClSCl
+ Cl + CO + CO2
OH
15
-HCl
O S
H
Et3NO SH
O
15'
Mechanism c: Swern oxidation
-SMe2
O
14'
Si
F N(nBu)4
OH
15
+H-TBSF
Mechanism b: TBS deprotection
V. Mechanisms
-
Total Synthesis of (–)-‐Crinipellin A
7 Liu Lab
Mechanism d: Horner-Wadsworth-Emmons olefinationSee mechanism
a
15''
O
OEt H
AlH3
OEt
O AlH3 O
HO
13
Mechanism e: LAH reduction
O O
O
O
OH
OHD-DET = L* + Ti(OiPr)4
Ti*LOiPr
OiPr + HO-O-tBu
13
OTiL*
OOtBu HOO
16
Mechanism f: Sharpless Asymmetric Epoxidation
Mechanism g: Swern oxidationSee mechanism c
-
Total Synthesis of (–)-‐Crinipellin A
8 Liu Lab
OO
16'
N2
(MeO)2PO O
Bestmann-OhiraReagent
MeOHN2
(MeO)2PO O
OMe-H N2
(MeO)2PO
OO
P(OMe)2O
N2O • N N
O
NN
OH
O
17
Mechanism h: Seyferth-Gilbert Homologation
-
Total Synthesis of (–)-‐Crinipellin A
9 Liu Lab
BrMg OMe
OMe
Fe(acac)3
-acac
18
LnFe OMe
OMe
O17LnFe
OMeMeOMechanism i:
•
MeO OMeOH
17'
N
HN
Cl SiPhPh
HN N SiPh
Ph
•
MeO OMeOH
17'
•
MeO OMeOTBDPS
19
Mechanism j: TBDPS protection
-
Total Synthesis of (–)-‐Crinipellin A
10 Liu Lab
•
MeO OMeOTBDPS
19
H•
MeOMeO
OTBDPS H
•
MeOOTBDPS
H2O
•
MeO OH2OTBDPS
•
MeO OHOTBDPS
H
PT•
OTBDPSO
19'
Mechanism k: Acetal hydrolysis
•OTBDPS
O
19'
H2NNHTs PT
•OTBDPS
HO HNNH
Ts
-H2O•
OTBDPSNNHTs
20
Mechanism l
-
Total Synthesis of (–)-‐Crinipellin A
11 Liu Lab
Mechanism m:See mechanism b
H
HO10' Cl Cr O
O
O
NH
PCC
PTH
OCrOHO Cl
O
H
OCr OO OH
H
H
O22
Mechanism n: PCC oxidation
H
O22
H
N SiMe3Me3Si
K
N SO O
O
Davis'oxaziridine
H
O
H
O
O
SN
OO
R
+HH
O22'
HO
Mechanism o:
-
Total Synthesis of (–)-‐Crinipellin A
12 Liu Lab
OI
O
OAcOAc
AcOH
O22'
HO
H
O
OIO
O
OAcO
OH H
O23
O
Mechanism p: Dess-Martin Periodinane Oxidation
H
O23
OSO
NPh
H
Li
SO
NPh +H
H
OHO
SO PhN 24
Mechanism q:
H
OHO
SO PhN 24
NaBH(OAc)3H
OO
SO PhN
BAcO
H
OAc
+HH
HO
SO PhN 25
HO
Mechanism r: Hydroxyl-directedRreduction
-
Total Synthesis of (–)-‐Crinipellin A
13 Liu Lab
H
HO
SO PhN 25'
TBSO
O Cr O Cr OO O O O
N H
H
H
HO
SO PhN
TBSO
CrO OH
OO Cr
O
OO
H
HO
SO PhN
TBSOOCr
O OOH
H
HO
SO PhN 26
TBSOO
Mechanism t: Allylic oxidation
H
O
SO PhN 26
TBSOO
H
H
27
TBSOOO
Mechanism u:
Mechanism s: TBS protectionSee mechanism j
H
27
TBSOOO
HO O
H
TBSOOO O
OH
H
TBSOOO O
27'
Mechanism v: Nucleophilic epoxidation
-
Total Synthesis of (–)-‐Crinipellin A
14 Liu Lab
H
TBSOOO O
27'
H
N SiSi
H
TBSO
O O O
NLi
H
TBSOOO O
NMe2H
N SiSi
LiH
TBSOOO O
28
Mechanism w:
Mechanism x: TBAF deprotectionSee mechanism b
H
HOOO O
(–)-Crinipellin A
