Approaches Towards… 1985 to 2005 Yi Yang See Baran Lab Group Meeting 01/23/2016 O O O Me O H MeO O O O Me Me HO Me H OH O OMe O O O Me OH H O AcO MeO 2 C O O Me Me OH O CO 2 Me OH Me O O Me O OH H azadirachtin (see Classics III) Nicolaou: ACIE 2002, 2103 ACIE 2002, 2107 ACIE 2003, 3637 ACIE 2005, 3443 ACIE 2005, 3447 Murai: Synlett 1995, 895 Synlett 1997, 737 Tet. Lett.1999, 4387 Synthesis 2000, 1878 Org. Lett. 2002, 2877 Watanabe: Tet. Lett. 1997, 4429 ACIE 2007, 1512 Main Journals covered: Journal of the American Chemical Society Angewandte Chemie International Edition Journal of Natural Products Helvetica Chimica Acta Organic Letters The Journal of Organic Chemistry Tetrahedron Tetrahedron Letters O Me OMe Me H H O Me Me O O N NMe O OAc OH OH eleutherobin Highly sought after targets/natural product class with numerous approaches towards: O O O O O O O O O HO O Me HO 2 C Me Me OH H Me H H H Me H H H H H H HO Me H H H Me Me H H Me OH H H gambieric acid A and related polyether natural products N N N H N H OH H manzamine A (see Classics II) O N H NH Cl O HN H N O N Me Me N O Cl O HO Me Me diazonamide A (see Classics II) O Me O O O O OH N O Me Me N O O HO OH Me MeO Br MeO phorboxazole Criteria for selection: - published within the time period of 1985 to 2005 - limited papers from the original group who published the approach (or indicated in some form or another that the project was discontinued) - group that published approach have yet to disclose full synthetic route to natural product - approaches that led to formal synthesis are excluded Me O OH Me Me OR OR Me H HO H OH H tiglianes Me HO OH HO H HO Me Me O ingenanes see Baran Group Meeting Seiple, 2007 Me Me Me O OBz H O OAc O OH AcO HO taxol R O Examples: JACS 1996, 10803 JOC 2001, 2394 JOC 1987, 2346 Tetrahedron 1986, 3323 Tetrahedron 2004, 9179 Tet. Lett. 1993, 5999 Tet. Lett. 1986, 203 Disclaimer: The purpose of this group meeting is to highlight various synthetic approaches/methodologies to natural products which for one reason or another, did not lead to the completion of the target material. It is by no means exhaustive but designed to be comprehensive within the selected publications. More often than not, failed routes are not disclosed in chemical literature and this seminar only serves to cover material that this presenter finds unusual or interesting. Lastly, comments from the original papers are reproduced to provide appropiate context to each work. Highlights in these excerpts unless stated are absent from the original work. Organization of material: - material that were covered in previous Baran lab group meeting will be referenced accordingly - organized by natural product families - approaches published outside of the restricted time frame will not be discussed in detail, but references are provided - approaches to polyketide natural products have been delibrately left out in this group meeting
Transcript
Approaches Towards… 1985 to 2005Yi Yang See Baran Lab Group Meeting01/23/2016
Main Journals covered:Journal of the American Chemical SocietyAngewandte Chemie International EditionJournal of Natural ProductsHelvetica Chimica ActaOrganic LettersThe Journal of Organic ChemistryTetrahedronTetrahedron Letters
O
Me
OMe
MeH
HOMe Me
O
O
NNMe
O
OAcOH
OH
eleutherobin
Highly sought after targets/natural product class with numerous approaches towards:
O
OO
O
OO
OO
O
HO
OMe
HO2C
MeMe
OH
HMe
HH
H
Me
HHHHHH
HOMe
H
HH Me Me H H
Me OHH
H
gambieric acid Aand related polyether
natural products
N
N NH
N
H
OH
Hmanzamine A
(see Classics II)
O NH
NH
Cl
O
HNHN O
N
Me Me
N
O
Cl
OHO
MeMe
diazonamide A (see Classics II)
O Me
O
O
O
O
OH
N
O
MeMe
N
O
OHO
OH
Me
MeO Br
MeO
phorboxazole
Criteria for selection:- published within the time period of 1985 to 2005- limited papers from the original group who published the approach (or indicated in some form or another that the project was discontinued)- group that published approach have yet to disclose full synthetic route to natural product- approaches that led to formal synthesis are excluded
Disclaimer:The purpose of this group meeting is to highlight various synthetic approaches/methodologies to natural products which for one reason or another, did not lead to the completion of the target material. It is by no means exhaustive but designed to be comprehensive within the selected publications.
More often than not, failed routes are not disclosed in chemical literature and this seminar only serves to cover material that this presenter finds unusual or interesting.
Lastly, comments from the original papers are reproduced to provide appropiate context to each work. Highlights in these excerpts unless stated are absent from the original work.
Organization of material:- material that were covered in previous Baran lab group meeting will be referenced accordingly- organized by natural product families- approaches published outside of the restricted time frame will not be discussed in detail, but references are provided- approaches to polyketide natural products have been delibrately left out in this group meeting
Approaches Towards… 1985 to 2005Yi Yang See Baran Lab Group Meeting01/23/2016
Approaches to steroid skeletons:
Ruveda:
MeO
OMe
OMeMeMeO2C
NaBH4, CeCl3
MeOH
OMe
OMeMeMeO2C
O
O
HO
Me O
O Me
Me
then KOtBu; pTSA
OO
O
Me
Me CO2Me
H
22%
O Me
Me
H
MeO2CMe
O
Me furan
HO
Onimbolide
Pure & Appl. Chem. 1996, 683
Aubert & Malacria:
O
Me
stepsOO
MePh
Me
OOMePh
Me
orOMe
H
MePhCpCo(CO)2;
SiO2
48%
Me
H
Ph OO
MeCpCo(CO)2, hv
66%Me
H
Ph OO
Me
CpCoOrgLett. 2004, 3937
Approaches towards natural products with medium rings
OMeMe
H
HO OMe
AcO
HOH
Me
pestalotiopsin A
OMeMe
HH
Me OH
OHH
OMe
taedolidol
9 member ringcleavage Ring Closing Metathesis fails
See Nathan's Group Meeting on Taxol for a more comprehensive coverage
MeMeMe
OAcH
OAc
OR
AcO
HOO
taxicin-I triacetate
Kishi's approach:
MeMeMe
OHH
OPG1
OPG2
HO
O
NiCl2/CrCl2H2O
X2
X1 MeMeMe
O OH
OPG1
OPG2
OHC+
O
HMe
HO OOH
rudmollin
O
HMe
HO OOH
Wender-Fisher intermediate
OO
OrgLett. 2000, 2531
OO
Little's Approach:
1. vinyllithium2. xylenes, reflux3. CSA, MeOH O
OMe1. O3 Ac2O, Et3N2. CpLi; AcOH O
OMe
MeO2C
1.
2. diimide
NNRO2C CO2R
R = CH2CCl3
thenelectrochem
NN
O OMeMeO2C
NaHMDS;oxaziridine
NN
O OMeMeO2C
OHPhMe,reflux
70%
OOMe
HO
MeO2C4 steps
OOMe
O
HO
1. ClSiMe2CH2Br2. Bu3SnH, AIBN3. KF, H2O2
44%O
OMe
O
HO OH
4 steps OO
HO OH
MeH
"While the chemistry described herein did not culminate in the total synthesis of rudmollin (1), it did provide a useful and interesting forum for the exploration of new chemistry."
Approaches Towards… 1985 to 2005Yi Yang See Baran Lab Group Meeting01/23/2016
2nd Generation:O
TBSO
1. RMgBr, [Cu]2. MeLi; PhNTf23. [Pd], CO, MeOH
MeO2C
TBSO
OO
Me3
1. TsOH2. KtBuO
H
HOTBS
CO2MeMeO
H
HTBSO
CO2Me
MeO
+ +
25%15%
H
HOTBS
CO2Me
MeO60%
H
H O
CO2MeMe
MeO
MeO
1. LDA (3eq)*; TMSCl2. NBS
H
H O
CO2MeMe
MeO
MeO
1. NaOH, H2O22. Ph3P=CH23. [Pd], NH4HCO2, R3P
H
H
CO2MeMe
MeO
MeO
OH
PPh3 used
ORH
H
CO2MeMe
MeO
MeO
OH
Me
PBu3 used equiv. important to prevent side pdt
OH
H
HHO
H
OHMeMe HO
OH
HO
Me
H Me
kalmanolrelated NP: grayanotoxins
H
H
OHMeMe
HO
H
Me
O
Me
H
HROMe
O O Me
MeMe
OR
H
HRO
MeO2C
Me
MeO+
Br
ROMeMe
"It is hoped that the lessons learned in this series of experiments can be successfully applied to the acquisition of kalmanol and bioactive analogs thereof."
O
MeMe
O Me
Me OHOHO
pleuromutilin
Zard's attempt 1:
Me
CO2EtCOCl
N-hydroxythiopyridone,phenylvinylsulfone, hv
20%80% if no acceptor
Me
CO2Et
SN
Zard's attempt 2:
Me
CO2Et
OSePh
allylSnBu3,ACCN
55%
Me
CO2Et
H O4 steps Me
OO
MeMe
O
SEtO
SMeHO
OMe
Me
O S OEt
S
DLP60%
OrgLett. 2003, 325
HO 1. nBuLi (2eq.); TMSCl2. nBuLi
HOTMS
TMS
TiCl4 or ZnCl2 TMS H
O
TMSH
1. Br22. Et3N Br H
O
TMSH
Br H
O
HTMS
+
I2
steps
H
H
CO2MeMe
Bn
vinyl bromide, tBuLi, then steps
O
HH O
O
MeMeMe
OTBS
H
OBn
1. Tebbe2. heat H
H
Me MeTBSO
H
OMe OBn
9steps H
H
Me MeTBSO
HO
MeOH
MeOH
H
HHO
JACS, 1996, 727JOC, 1995, 6912
Mechanistic Question: TMS
CHOBrBr
H TMS
TMS H
O
TMSH
Br2
cis
trans
CHO
Br TMSBr
TMSH
Br H
O
TMSH
anti
syn
HO
TMS
1. Red-Al2. PDC3. Br2; Et3N Br H
O
HTMS
DIBAL Br OH
HTMS
Me
Me OMe
OMeBr O
HTMS
OMeMe
Me
1. Et2AlCl2. H+; TBAF
Br
HOMeMe
resolutionJOC, 1993, 2714
Approaches Towards… 1985 to 2005Yi Yang See Baran Lab Group Meeting01/23/2016
O
Me
Me OH
OAc
MeMe
H
H
eunicellins
O
MeMeO
1. LDA, allylBr2. HBr, hv3. NaI4. SmI2
O
Me
Me
OH
CAN O
O
Me ONO2
Me
27%
+ 7% exo-olefin
Tetrahedron, 1997, 4331
Hoffmann's approach:
O
Me
OMe
MeH
HOHMe Me
OH
eleutherobin core
Winkler's approach:
Me
Br
SO2
Me
CHO
+ SnCl2, NaI
86%SO2
Me
HOMe
1. DMP2. AgNO33. PhMe, Δ
MeO
Me
CO2MeBr
Me
Me CHO
+SnCl2, NaI
72% Me
MeOH
CO2Me1. DIBAL2. BaMnO4
Me
MeO OH
Me Me
O
H
H
O
MeMe OTBS
heat;TBSOTf
1. DIBAL2. VO(acac)2 TBHP3. NaOH4. NaIO4
Me Me
OOH
H
H
O
MeMe OH
48%
51%
1. SmI2, cat. NiI2 72%2. COCl2, pyr
Me Me
OO
H
HMeMe O
O
OH
1. VO(acac)2, TBHP; Et3N, SiO22. K2CO3 O
MeH
HMeMe
OH
63% O
Me
OH
"Studies directed toward the isomerization of the C-3 exo-methylene to the ∆ 2,3 alkene present in eleutherobin are currently underway, and our results will be reported in due course"
OrgLett, 2003, 1805
NO
MeO
selaginoidine
MeO2C
Padwa's Model System:
OEtN3
OCO2Et+
Bu3P, heatEtSCH2COCl
NCO2Et
OSEt
OEt
1. NaIO42. TFA
NO
Et O
CO2EtSEt
40%
OrgLett, 2005, 1339
Approaches towards alkaloids
O
HO
Me
O
O Me
OHO
Me
Me Me
Me
HH
H
HO
trans: pycnidionecis: eupenifeldin
O
HO
Me
OMe
Me Me
H
Me
HOH
epolone B
Model Studies:
CO2H
CO2H
OO
O OMe
OrgLett. 1999, 1933OrgLett. 2002, 3009
1. ClCH2OCH2CCH2. iBuOCOCl; CH2N23. Rh2(OAc)4
4. 6 NHCl5. NaH, MeI
humulene150°C, 24h
O
OMe
MeMe
H
Me
OMe
60%
heat
20%
dimer with pycnidione
stereochemistry
Me Me
MeMe
humulene:
O Me
CO2Me
stepsOOAc
O
MeTBSO
1.
2. CeCl3, NaBH4
O
OTBS
Me
OH
HO
CN
OAc
PhS
Me
HO
O
steps humuleneheat22%
deoxy-epolone B
Real tropolone system:
Approaches Towards… 1985 to 2005Yi Yang See
NN
H madangamine A
N
CHO
HN
H
OH
Hircinal B
N
CHO
HN
H
H
[H]NN
Biogenetic relations:
N
CO2Me1. BnBr2. NaBH43. LDA, BuBr
NBn
Bu5 steps
NBn
Bu NHCOCF31. mcpba2. TFAA
NBn
Bu NHCOCF3CO2Me
EtO OEt
ONaO O
NBn
CO2EtOH
EtO2C
Bu
F3COCHN
+
BnN
EtO2C
Bu
OHCO2Et
NHCOCF3
K2CO3BnN
N
Bu
HOO
HN
N
Bu
BnOO
+
50% from N-oxide65:35
OrgLett. 2005, 2437
NO
H
N
HO OHsarain Asee GM on synthesis
above 40 steps
Weinreb's approach
O
SESHN
1. mCPBA2. Et3SiH, BF3.Et2O
68% N
O
SES
1. butadiene, 12kbar2. TosMIC, KOtBu3. DIBAL
46% NSES
CHO1. diallylamine, [Pd]2. 5% HCl3. NH2OBn
66%mechanism? NSES
NBnO
NSES
NBnO
OH
hydroboration
PMBCl, TBAINaH, reflux
NSES
CN
PMBO
73%
1. LiAlH42. Hg(TFA)2, O2, NaBH4, HFIP
N 33SES
PMBO NH
OH
"product has the N/C-2 bond of 1 and
possesses suitable functionality at C-3
for constructionof the “eastern”
macrocyclic ring."
JOC 1997, 1920For other approaches:Tet. Lett. 2004, 6509JOC 2007, 768OrgLett. 2015, 568OrgLett. 2015, 1946
N
N NH
N
H
OH
Hmanzamine A
(see Classics II)
O
HNO
NMe
gelsemine
Approach 1:
OHNMe
Oseveralsteps NMe
OH
TBDPSO
NMeO
TBS1. Fe(CO)52. Me3NOthen steps?
JACS 2003, 13326steps??
steps??
OOHHOMe2Si
OSiMe2
mcpbaMe2Si
OApproach 2:O
HH
SiMe2OH
H
HOMe2Si
O
2
hv+ +
38% 4% 12% OrgLett 1999, 2073"model for the skeleton of the alkaloid gelsemine"
"Synthetic approaches to gelsemine using thismethodology are under consideration"
Baran Lab Group Meeting01/23/2016
N
Hhetisine skeleton
Winkler's Approach:
NBoc
OMe
hv
86%NBoc
H
O
Me PPTS,heat
84%N Boc
O
HJACS, 2001, 7429
NNH
NHN
O
O
MeH
N
Ospiroquinazoline NP
Hart's Approach
NH
N
O
Ac1. H2NCH2CH2SH2. BrCH2COBr3. NR4Br
N
N
O
N
O
SMe
LDA (2.2 eq);Li2CuCl4;gramine methosulfate
N
N
O
N
O
SMe
indole
N
N
O
N
O
SMe
N
O
CbzHN
1. mCPBA2. TFA/CHCl3
80%N
N
O
N
O
N
O
CbzHN
S
JOC, 1999, 2990
Approaches Towards… 1985 to 2005Yi Yang See
OTMSMeO2C CO2Me
1st Generation
HO
CO2MeMeO2C36%
HO
CO2Me
Br2, ZnBr2
Br
O
O
AgNO3, MeOH
65% 98%CO2Me
OHO
MeO2C
OO
MeO2C OH
Ph
O 1. PhCOCl2. NaBH43. NBS
44%
"ketone group in 9 was at the wrong end of the three-carbon bridge, and this route had to be abandoned when we were unable to transpose the carbonyl group to the other side of the ring."
OTHP MeO2C NO2
2nd Generation
CO2MeO2N
OTHP
MeO2C
OTHP
+ NO2
43% 39%
+ other isomers
18%crystalline
- chirality transfer from THP ring indicated the possibility of using chiral sugar auxillary for asymmetric approach
single isomer at THP
1. Al/Hg2. EtO2CCl, Et3N3. HCl4. mcpba
47% CO2MeEtO2CHN
OH
O
AlCl3
MgBr2
OH
ONHCO2Et
CO2Me35%
39%CO2Me
HOEtO2CHN
Odesired shift
undesired shift
CO2MeO2N
OTHP8 steps
HOEtO2CHN
O
OAc53%
1. PhNMe3Br22. DHP, acid3. K2CO34. PPTS, EtOH HO
EtO2CHN O62%15 steps from phenol, 11.7%7 crystalline intermediates'2 serious chromatographies'
after optimization:
OEtOEt
1. PCC2. vinylMgBr3. SOCl2
EtO2CHN O
OEtOEt
Cl
80%
TMS2CuLi
EtO2CHN O
OEtOEt
TMS(CH2O)3HCO2H
ONEtO2C
O
noroxindolylgelsemine ketone
20 steps from phenol 6.6% yield
Tetrahedron, 1988, 3931
"we chose the route involving spiroannulation onto a ketone precisely because there were no established methods for doing that. It forced us to invent and we did."
"but in the end it was not completed, because no one would fund us to put the two pieces of work together"
O
HNO
NMe
gelsemine
Stork's Approach
O
O OH
CO2Me
OOEt
Br
1. AIBN2. LDA, (PhSe)2; mcpba3. DIBAL
O
OH
OEt1. PhCH2CO2H2. acid3. PivCl
O
O
OPiv
OPh
O
O
OPh
H
LDA, TMSCl96%"a target which was chosen not only to test the
validity of the synthetic scheme, but also because it might be possible to introduce into it the amine functionality which is required to construct the pyrrolidine and oxindole rings of 1 [gelsemine] itself."
6:1 alkene isomers
Tet. Lett. 1987, 1035Fleming's Approach"We reported earlier our plan to synthesize gelsemine (1) by way, successively, of a diketone of the general structure (3), with the ketone group differentiated is some way, and a ketone of general structure (2). In each of the synthetic steps (3 -> 2) and (2 -> 1), a ketone group is to serve as the precusor of a quaternary centre, and it is the challenge of these steps that most excited our interest in the synthesis of gelsemine. "
