Total Syntheses Completed by the Trauner Grouporggroup/supergroup_pdf/rmoreau_trauner.pdfSynthesis...
26
Total Syntheses Completed by the Trauner Group Robert Moreau Supergroup Meeting 15 September 2004
Transcript of Total Syntheses Completed by the Trauner Grouporggroup/supergroup_pdf/rmoreau_trauner.pdfSynthesis...
Total Syntheses Completed by the Trauner Group
Robert MoreauSupergroup Meeting15 September 2004
Completed Total Syntheses
NH
NMe
Br
BrMeO
OH
O
amathaspiramide F
Me
O
HO
frondosin B
O
O
Me CHOHO
O
MeH
H
pinnatal
Me
O
H
MeOMe
OMe
O
crispatene
O
O
Me CHOHO
O
sterekunthal A
Me
O
H
MeOMe
O
photodeoxytridachione
Frondosins
Me
O
HO
Me
O
Me
Me
OHHO
OH OO OH
frondosin A frondosin B
frondosin C frondosin D
• marine terpenoids from the sponge Dysidea frondosa• inhibit interleukin-8 binding in the low micromolar range and could,
therefore, be used to prevent rheumatoid arthritis and psoriasis• also have been shown to exhibit HIV-inhibitory properties
Frondosin B Retrosynthesis
[Pd]
MeO
O
MeO
TfO
MeO
OH
MeO
OTfMe
O
MeO
O
• desired a one-step bicyclization via the first intramolecularArcadi-Cacchi reaction
C.C. Hughes, D. Trauner. Angew. Chem. IE. 2002, 1569.
Synthesis of Benzofuran Alkyl Iodide
Pd(PPh3)4, CuI, Et3N
MeCN, reflux94%
MePMBOMePMBO
BrOAc
MeO
OAc
MeO
O
MeHO
MeO
1. TFA, CH2Cl2, 83%
2. K2CO3, MeOH, reflux92%
O
MeI
MeO
MsCl, Et3N, THF, 0oC
then NaI, acetone, reflux93%
R
Alkyne starting material prepation: A. Murai, T. Oka. Tetrahedron 1998, 54, 1.
Completion of the Synthesis
Me
O
HO
OMe
OMe
OMe
OMe
OMe
OMeLi
OMe
OMe
OTf
OMe
O
MeO
O
Me
O
MeO
O
MeI
MeO
HMPA
THF, -78oC to rt, 85%
1. ion-exchange resin acetone, H2O, reflux
2. NaHMDS, PhNTf2THF, Et2O
75%, 2 steps
Pd(PPh3)4, DIEA
DMA, 90oC70%
1. MeMgBr, THF, -78oC to rt
2. Me2Zn, TiCl4, CH2Cl2, 0oC to rt
82%, 2 steps
Me
O
MeO
NaSEt
DMF, reflux90%
frondosin B
Mechanistic Insights
OMe
OMe
OTf
O
Me
O
MeO
O
Me
O
MeO
O
OMe
OMe
[Pd]OTf
O
H [Pd]OTf
H
H
OMe
OMe
[Pd]
O
TfO
O
MeO
H
MeO
[Pd]O
MeO
MeO
[Pd]
OMe
OMe
[Pd]
O
TfOH
O
MeO
MeO
[Pd]H
O
MeO
MeO
[Pd]
A
B
C
-H[Pd]OTf
-H+
-H+
Danishefsky’s AlkyneHO
CO2MeO HO
CO2Me
OH
Me
HOCO2Me
OH
Me
OO
O
Al
OMe
HOOH
O
MeO Me
AlMe3
CO2MeMe
S
S.J. Danishefsky, M. Inoue, M.W. Carson, A.J. Frontier. JACS, 2001, 1878.
Amathaspiramides
N NMe
Br
BrMeO
OH
ON NMe
Br
BrMeO
OH
ONH
NMe
Br
BrMeO
OH
O
NH
NMe
Br
BrMeO
OH
ON NMe
Br
BrMeO
OH
ONH
NMe
Br
BrMeO
OH
O
MeO
Me
O
amathaspiramide A amathaspiramide B amathaspiramide C
amathaspiramide Famathaspiramide Eamathaspiramide D
• marine alkaloids isolated from a New Zealand collection of the bryozoan Amathia wilsoni
• novel spirobicyclic core of pyrrolidine and pyrrolidinone rings• several are moderately cytotoxic or show antiviral and antibiotic
properties
(-)-Amathaspiramide F Retrosynthesis
NH
NHMe
Br
BrMeO
O
O
N O
Br
BrMeO
NO2
NMe
NNMe
OH BrBr
MeO
NO2
NH
NMe
Br
BrMeO
OH
O
amathaspiramide F
+
C.C. Hughes, D. Trauner. Angew. Chem. IE. 2002, 4556.
Proline AlkylationBr Br
MeO NO2
NNMe
OH
NNMe
OTBS
N O
Br
BrMeO
NO2
NMeN O
Br
BrMeO
NO2
NMe
tBuLi, HMPATHF, -78oC to rt
then TBSCl, 0oCMgBr2-OEt2
-78oC to rt72%
+
10:1
S
Completion of the Synthesis
4M H2SO4
THF86%
1. TFAA, py, CH2Cl2, 0oC
2. MeOH, 0oC to rt98%
NH
O
Br
BrMeO
NO2
NHMe
N
Br
BrMeO
NO2
F3C ONHMe
ON
Br
BrMeO
N
F3C ONHMe
OOH
N O
Br
BrMeO
NO2
NMe
SnCl2, PhSH, Et3N
MeCN85%
1. IBX,THF, DMSO65%
2. LiBH4, THF, 0oC to rt80% N
HNMe
Br
BrMeO
OH
O
amathaspiramide F
Biomimetic Synthesis of Pinnatal and Sterekunthal
O
O
Me CHOHO
O
O
Me CHOHO
O
O
MeH
H
O
O
Me CHO
O
MeH
H
HO
O
O
Me CHO
O
MeH
H
OO
O
HO
H
H
O
O
HO OMe
O
O
HOO
pinnatal
isopinnatal
sterekunthal A
sterekunthal B
pyranokunthone A
pyranokunthone B
anthrakunthone
• Isolated from the Bignoniaceae plant family• Lead compounds for antimalarial drugs
Biosynthetic Hypothesis
OO
O
HO
H
H
O
O
HO OMe
O
O
HO OH
O
O
HO OHO
O
HO O
OH
pyranokunthone B
pyranokunthone A
[4 + 2]
(E)-isomer
6π(Z)-isomer
O
O
HO OH
lapacholNatural Yellow 16Aldrich 250mg $42
J.P. Malerich, D. Trauner. JACS, 2003, 9554.
Biosynthetic Hypothesis, cont.
O
O
Me CHOHO
O
O
Me CHOHO
O
O
MeH
HO
O
HOO
O
O
HO OMe
O
anthrakunthonesterekunthal Apinnatal
O
O
HO OMe
pyranokunthone B
allylic [O] [4 + 2]
retro-[4 + 2] [O]
-HCOOH
Differentiated Diol Synthesis
1. TBDPSCl
2. mCPBA3. HIO4
TBDPSOO
TBDPSO
OEtO
TBDPSO
OTHP
HO
KHMDS, 18-C-6
THF, -78oC76%
1. DIBAL, CH2Cl2, -78oC94%
2. DHP, PPTS, CH2Cl299%
PO
TFEOTFEO
OEt
O
Advancement of the Synthesis
O
OTHP
O
O
HO OH
O
O
HO O
OTHP
O
O
HO O
OTHP
Me
1. TBAF, THF, 90%
2. MnO2, CH2Cl2, 0oC81%
6π electrocyclization
β-alanine, AcOH
PhH, 90oC54%
TBDPSO
OTHP
Completion of Synthesis
O
O
HO O
O
Me [4 + 2]rt, neat
91%
retro-[4 + 2]160oC
PhH92%
O
O
Me CHOHO
O
MeH
H
pinnatal
O
O
Me CHOHO
O
sterekunthal A
1. pTsOH, MeOH, 97%
2. Swern, 87%
O
O
HO O
OTHP
Me
Molluscan Polypropionates
Me
O
H
MeOMe
OMe
O
H
MeOMe
OMe
O
Me
O
H
MeOMe
O
O
MeO
O
OMe
MeO
O
OMeO
MeO
O
OMeOMe
photodeoxytridachione
9,10-deoxytridachionetridachiapyrone Itridachiapyrone A
tridachiapyrone E crispatene
• feature an α-methoxy-γ-pyrone moiety and are proposed to act as a natural sunscreen due to their UV-light-absorbent properties
• two categories: those featuring a cyclohexadiene core and others with a bicyclo[3.1.0]hexene core
• (-)-crispatene isolated from the mollusc Elysia crispata in 1981 by Ireland
Interrelationship
RMe
O
H
MeOMe
O
R
O
O
OMe
R
MeO
O
OMe
R
O
MeOO
hν
thermaldisrotatory
6π electrocyclization
thermal[π 4a + π2a]
cycloaddition
• in 1979, Ireland and Scheuer found that the cyclohexadiene core can be photochemically converted to the bicyclo[3.1.0]hexene core in vivo and in vitro
• this suggests that both compounds are directly derived from a common acyclic precursor
Photodeoxytridachione Core Synthesis
OCO2Et
OH CO2EtCO2Et
MeH
Me
DIBAL
CH2Cl2, 0oC93%
1. TPAP, NMO, CH2Cl2
2.
LiCl, DBU, MeCN 43%, 2 steps
20 mol% Me2AlCl
CH2Cl273%
KHMDS, 18-C-6
THF, -78oC79%
PO
TFEOTFEO
OEt
O
PO
EtOEtO
OEt
O
• A.K. Miller, D. Trauner. Angew. Chem. IE. 2003, 549.
Completion of the Synthesis
CO2Et
MeH
Me
MeH
Me
N
O
OMe
MeH
MeO
MeH
MeO
CO2Me
O
Me
O
H
MeO
OH
MeHNOMe-HCl,iPrMgCl
THF63%
EtMgBr
THF87%
LiHMDS
THF, hexanes, -78oC59%
CO2MeO
Cl
DBU
PhH, reflux78%
FSO2OMe
CH2Cl277% Me
O
H
MeOMe
O
photodeoxytridachione
(-)-Crispatene Core Synthesis
1. Ph3P=C(Me)CO2EtTHF, reflux, 94%
2. DIBAL, CH2Cl2, -78oC98%
3. Dess-Martin, CH2Cl2, 88%
MeO
Me
CO2Et
MeH
Me
OTBS OTBS
OMe
OTBS
I
CO2Et
Me
OTBS
Me
OTBS
Ph3P=CHCH3, I2,NaHMDS
THF, -78oC86%
Pd2(dba)3-CHCl3,
(2-furyl)3P, CuINMP57%
20 mol% Me2AlCl
CH2Cl2, 0oC to rt83%
CO2EtMe3Sn
• A.K. Miller, D.H. Byun, C.M. Beaudry, D. Trauner. PNAS. 2004, 12019.
Completion of the Synthesis
MeH
Me
N
O
OMeMeH
MeO
MeH
MeO
CO2Me
O
Me
O
H
MeO
OH
OTBS
Me Me
Me
OTBS
OTBS
Me
OTBS
MeHNOMe-HCl,iPrMgCl
THF76%
EtMgBr
THF 0oC87%
LiHMDS
THF, hexanes, -78oC74%
DBU
PhH, 60oC87%
FSO2OMe
CH2Cl2, -5oC
CO2MeO
Cl
Me
O
H
MeOMe
OMe
OTBS
Me
O
H
MeOMe
OMe
OH Dess-Martin
CH2Cl286%
CO2Et
MeH
Me
Me
OTBS
+
HF-py
py, THF91%
Me
O
H
MeOMe
OMe
O
crispatene32% 17%
Problem 1
N
Br
BrMeO
N
F3C ONHMe
OOH
IBX,THF, DMSO65%
N NMe
Br
BrMeO
OH
O
During the total synthesis of amathspiramide F, the Trauner group oxidatively cleaved an oxime with IBXto close the pyrrolidinone ring. Please provide a mechanism for this transformation.
F3CO
IO
OHO
O
IBX
Method: D.S. Bose, P. Srinivas. Synlett, 1998, 977.
Problem 2
CO2Et
MeH
Me
CO2EtO2N
O2N
CO2EtO2N
MeCO2Et
NO2
20 mol% Me2AlCl
CH2Cl2, 0oC to rt84%
toluene, 60oC
98%
Please explain why, under Lewis acid catalysis, 6π electrocyclization is effectively outcompeted bythe [π4a + π2a] cycloaddition to give the bicyclo[3.1.0]hexene moiety seen below.
![Absolute Asymmetric Synthesis [AAS] by Photochemistry on Solid-Stateorggroup/supergroup_pdf/qjin... · 2005-10-13 · Absolute Asymmetric Synthesis [AAS] by Photochemistry on Solid-State](https://static.fdocuments.us/doc/165x107/5ed92b286714ca7f4769461b/absolute-asymmetric-synthesis-aas-by-photochemistry-on-solid-state-orggroupsupergrouppdfqjin.jpg)
