recent syntheses published in nature
TRANSCRIPT
Organic Syntheses Published in Nature
and Why
(2005-2010)
MacMillan Group Meeting17 March 2011
Jeff Garber
NH
Me
NC
Me
MeMe
Me
H
H
Me
Cl
Cl
O
Cl
Cl
Cl
HO3S
Cl6O O
O
O
OPivMeO2C
MeMe O
CO2Me
MeMe
OHMe
OH
HO
Me
MeMe
Me
Me
O
H
HMe
MeOH
HOHO Me
OH
Nature
! First published November 4, 1869
! Published by Alexander Macmillan
! Started by Joseph Norman Lockyer
! 2009 Impact factor: 34.48
! Comparable to Science in all statistics
! Far fewer chemistry articles not related to chemical biology or biochemistry
Nature
! First published November 4, 1869
! Published by Alexander Macmillan
! Started by Joseph Norman Lockyer
! 2009 Impact factor: 34.48
! Comparable to Science in all statistics
! Far fewer chemistry articles not related to chemical biology or biochemistry
Nature
Report original scientific research
Are of outstanding scientific importance
Reach a conclusion of interest to an interdisciplinary readership
Criteria for publication (Articles and Letters)
About 10,000 articles submitted/year
Only about 800 are accepted (8%)
Decision about broad interest made solely by Nature editors, not referees
www.nature.com
Why Nature?
Biological Activity
Methodology
Concepts
Family
First Synthesis
BroadInterest
Nature
"Synthesis and structural analysis of 2-quinuclidonium tetrafluoroborate"
Papers not covered in this talk
Tani, K., Stoltz, B. M. Nature, 2006, 441, 731-734.
"Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions"Sutherland et al. Nature, 2009, 459, 239-242.
"Umpolung reactivity in amide and peptide synthesis"
Johnston et al. Nature, 2010, 465, 1027-1033.
"Highly efficient molybdenum-based catalysts for enantioselective alkene metathesis"Hoveyda et al. Nature, 2008, 456, 933-937.
"Scaleable catalytic asymmetric Strecker syntheses of unnatural a-amino acids"Jacobsen et al. Nature, 2009, 461, 968-971.
Total synthesis of marine natural products without using protecting groups
Baran, P.S., Maimone, T. J., Richter, J. M. Nature, 2007, 446, 404-408.
NH
Cl
NC O
Me
MeMeH
H
(+)-welwitindolinone
NH
Me
NC
Me
Me
H
H
NH
Me
NC
Me
MeMe
Me
H
H
(!)-hapalindole U
(+)-ambiguine H
MeCl
H H Me
Me NH
NC
(!)-fischerindole I
Protecting Group Free Syntheses:General Concept
NH
Me
NC
Me
MeMe
Me
H
H
NH
NC
Me
Me Me
Me
Me OP2O63-
N
OH
PG
OPG
Me
NR
PG
NH
Me
Me X
Me
OMe
! "Caged reactivity"
! Protecting groups needed
"Standard" Biological
Baran
! No protecting groups
! Enzymes necessary
! No protecting groups! No enzymes
Ambiguine H
(!)-Hapalindole U
Me
MeOH
Me
OMe
39%, 4 steps
NH
Br
50%
NH
Br O
MeMe
NH
MeMe
Me
H
O
Pd(II), NaO2CH
65%TBAB, Et4N
60%, two steps
then HCO2H, CDMT
2) COCl2, Et3N
1) NaBH3CN, NH4OAc, µ";
NH
Me
NC
Me
Me
H
H
! 8 steps, 7.61% yield (from commercially available materials)
LiHMDS, Cu(II)
! Previous: 20 steps, racemic (Natsume, 1990)
Nature starting material
(+)-Ambiguine H
h!, Et3N
! 10 steps, 2.88% yield by RSM (from commercially available materials)
! No previous syntheses
NH
Me
NC
Me
Me
H
H
N
MeMe
Me
H
HN
Cl
BMe
Me
N
MeMe
Me
H
HN
Cl
B
R
Hprenyl-9-BBN
t-BuOCl 60%
R = t-prenyl
N
MeMe
Me
H
H
N
B
R
H ClN
MeMe
Me
H
HN
B
RCl HN
H
Me
NC
Me
MeMe
Me
H
H
43%63% by RSM
(")-Hapalindole U
H2N
(!)-Fischerindole I
(R)-carvone oxide
O
O
Me
Me
O
MeMe
Cl
H H
then vinyl-MgBr
2) NCS, PPh3
1) LHMDS
16.5%, two stepsNature starting material
LHMDS, indole
Cu(II)62 %
OMe
Cl
H H
Me57% by RSM
2) NaBH3CN, NH4OAc
1) H+, µ"
42%
MeCl
H H Me
Me NH
H
NH
H2N
(!)-Fischerindole I
! 7 steps, 2.14% yield by RSM! Previous: Baran, JACS 2005, 1.14%, 7 steps
DDQ, H2O
MeCl
H H Me
Me NH
HHCO2H, CDMT;
then COCl2, Et3N95%
NMe
Cl
H H Me
Me NH
H
C
NMe
Cl
H H Me
Me NH
C
HMe
Cl
H H Me
Me NH
NC
92%
! 13% without first two steps
(+)-Welwitindolinone
! 8 steps, 0.94% yield by RSM
! Baran, JACS 2005: 0.28% overall
(!)-fischerindole I
44%! 5.7% without first two steps (listed in Nature)
MeCl
H H Me
Me NH
NC
MeCl
H H Me
Me N
NC
F
MeCl
H H Me
Me
NC
H
NH
FOH
MeCl
H H Me
Me
NC
NH
OH
NH
Cl
NC O
Me
MeMeH
H
XeF2, H2O
H2O
!F-[1,5]
sigmatropic
Marine natural products overview
First Synthesis
Family
Concepts
MethodologyBroadInterest
! (!)-hapalindole U
! Shorter route = faster optimization
! ambiguine H
! Members of four families
! Protecting group free syntheses ! Rules for effective synthesis
! "Gram-scale"
! welwitindolinone A, (!)-fischerindole I
! Direct indole coupling
! XeF2 initiated cyclization
Biological Activity
! Anti-fungal, -bacterial -mycotic, -cancer
! Norrish-like fragmentation cascade
! Stigonemataceae family of cyanobacteria
! Activities of some comparable to streptomycin, puramycin, amphotericin
Total synthesis of bryostatin 16 usingatom-economical and chemoselective approaches
O O
O
O
OPivMeO2C
MeMe O
CO2Me
MeMe
OHMe
OH
HO
Trost, B. M., Dong, G. Nature, 2008, 456, 485-488.
bryostatin 16
Bryostatin 16:Retrosynthetic Analysis
O O
O
O
OPivMeO2C
MeMe O
CO2Me
MeMe
OHMe
OH
HO
O O
O
O
OPivMeO2C
MeMe
MeMe
OTBS
OH
MeO
HO
MeO2C
Cationic Au
Pd-catalyzedalkyne macrocylization
O O
CO2H
OHOPMB
MeO2C
MeMe
MeMe
OTBSMe
MeOPMBO
MeO2C
OTES
O OTMS
MeMe
MeMe
OTBS
OPMB O
OTBDPS
O
Carbonylation
Bryostatin 16:Retrosynthetic Analysis
O OTMS
MeMe
MeMe
OTBS
OPMB
OTBDPS
O
TMS
MeMe
MeMe
OTBS
OPMB O
OTBDPS
O
Me MeTBSO
OH
Me MeHO
! Convergent and "atom economical"
! Incorporates new methodologies
! Adaptable to analogue syntheses
Tandem alkene-alkyne coupling/ Michael addition
commercially available
O
H
OH
Bryostatin 16
! Previous route 16 steps from
67%, 94% ee
2) NaH, PMB-Br
1) (Ipc)2B(allyl)
90%
H2O, dioxane
87 %
OsO4, NaIO4
O
Me MeTBSO
OPMB
Me MeTBSO
TMS
MeMe
OTBS
8 steps
OO
Me Me
HO
O
Me
Me
PMBO
O
OTBDPS
O
Br OEtt-BuLi, ZnMe2
97%
Me MeTBSO O
H
H
2) Dess-Martin
1) In, InF3 (10 mol %)Br
TMS
OH
3) (S)-CBS (5%)61%, 90 % ee, three steps
Bryostatin 16
34%, 80% by RSM1) CpRu(MeCN)3PF6, 13%
TMS
MeMe
OTBS
O
MeMe
OPMB O
OTBDPS
O
OH
2) NBS98%
O OBr
MeMe
MeMe
OTBS
OPMB O
OTBDPS
93%
2) PdCl2(MeCN)2, dppf
1) CSA, MeOH
CO (1 atm), MeOH
O O
CO2Me
OPMBMeO2C
MeMe
MeMeMeO
OTBDPS
OH83%, 93% by RSM
O
Bryostatin 16
49%, 55% by RSM5 steps, PG/FG switching
O O
CO2Me
OPMBMeO2C
MeMe
MeMeMeO
OTBDPS
OH
POMe
O
OMeMe
O
N2
O O
CO2H
OPMBMeO2C
MeMe
MeMeMeO
OTES
OH
OTBSMe
PMBO
MeO2C
O
OMe
HO
MeO2C
MeMe53%
7 stepsO OOH
OHOHOH
67%3 steps
D-glactonic acid 1,4-lactone
Naturestarting material
Bryostatin 16
O O
CO2H
OPMBMeO2C
MeMe
MeMeMeO
OTES
OH
OTBSMe
PMBO
MeO2C
then acid, DMAP
O O
O
O
OPMBMeO2C
MeMe
MeMe
OTBS
OTES
MeO
PMBO
MeO2C
92%
46% diol, 58% mono-PMB
Resubject mono-PMB
DDQ, pH 7.0 buffer
75% overall
O O
O
O
OHMeO2C
MeMe
MeMe
OTBS
OTES
MeO
HO
MeO2C
(2,4,6-Cl3Ph)CH2Cl, Et3N;
Bryostatin 16
O O
O
O
OHMeO2C
MeMe
MeMe
OTBS
OTES
MeO
HO
MeO2C
O O
OHMeO2C
MeMe
CO2Me
MeMe
OTES
MeO
HO
O
O
OTBS
(2,6-(OMe)2Ph)3P (15 mol%)
56%
Pd(OAc)2 (12 mol%)
O O
O
O
OPivMeO2C
MeMe O
CO2Me
MeMe
OHMe
OH
HO
73%
2) Piv2O, DMAP
AgSbF6 (20 mol%)1) AuCl(PPh3) (20 mol%)
3) TBAF32%, last two steps
! Longest linear: 26 steps, 0.09%
! By RSM: 0.27%
! 35 total steps
! From commercial: 45 steps
Bryostatin 16 overview
First Synthesis
Family
Concepts
MethodologyBroadInterest
! First bryostatin 16 synthesis
! Failed metathesis attempts
! Only one synthesized
! Chemoselectivity ! Adaptability to analogues
! Fourth bryostatin synthesis
! Pd-catalyzed alkyne-alkyne macrocylization
! Au-catalyzed dihydropyran formation Biological Activity
! Significant anticancer potential during in vivo trials
! Analogues and other bryostatins accessible
! Suggested potential for cognitive impairments
! Atom economy ! Testing of methodologies
! Tandem Ru coupling/Michael
The total synthesis of (!)-cyanthiwigin F bymeans of catalytic enantioselective alkylation
Me
MeMe
Me
Me
O
H
H
(!)-Cyanthiwigin F
Enquist, J. A., Stoltz, B. M. Nature, 2008, 453, 1228-1231.
(!)-Cyanthiwigin F:Retrosynthetic Analysis
Radical acylationMe
MeMe
Me
Me
O
H
H
Me
O
Me
Me
O
H
H
Pd-cuprateenol triflate
coupling
Me
Me
Me
O
O
H
Me
Me
O
Vinyl borate CM,[O] RCM
Me
Me
O
O Negishi enoltriflate coupling
Me
Me
O
O O
O
O
O
Enantioselectivedouble allylation
Methylation
O
O O
O
O
OClaisen-Dieckmann
OO
O
O
(!)-Cyanthiwigin F
Pd(dmdba)2 (5 mol%)
! Sets all key stereochemistry in one step
OO
O
OO
O O
O
O
Oallyl alcohol, NaH
toluene, reflux
K2CO3, MeI
51%, two steps
O
O O
O
O
OMe
Me
1:1 racemic:mesoPPh2 N
O
t-Bu
Me
Me
O
O
64% yield, 99% ee
Me
Me
O
O
14% yield
(R,R)
meso
! Guides selective formation of other stereocenters
5.5 mol%
(!)-Cyanthiwigin F
O
O O
O
O
OMe
Me (R, R)
O
O O
O
O
OMe
Me
O
O O
O
O
OMe
Me
O
O O
OMe
Me
O
O O
OMe
Me
O
O O
O
Me
Me
O
O O
O
Me
Me
O
O O
O
Me
Me
O
O O
O
Me
Me
(S, R)
(R, S)
(S, S)(S, S)
meso (R, S)
(R, R)(R)
(S)
50%
25%
25%
50%
50%
R R
S R
R S
S S
(!)-Cyanthiwigin F
(R)
(S)O
O
Me
Me
O
O
Me
Me
(R, R)
O
O O
O
Me
Me
O
O O
O
Me
Me
O
O O
O
Me
Me
O
O O
O
Me
Me
(S, R)
(R, S)
(S, S)
R R
S R
S R
S S
O
O
Me
Me
O
O
Me
Me
O
O
Me
Me
(S, S)
meso (R, S)
(R, R)
18%
<1%
81%
(!)-Cyanthiwigin F
(R, R)
(S, R)
(R, S)
(S, S)
(S, S)
meso (R, S)
(R, R)
(R)
(S)
(S, S)
meso (R, S)
(R, R)
(R)
(S)
18%
<1%
81%
(!)-Cyanthiwigin F
(R, R)
(R, S)
(S, S)
meso (R, S)
(R, R)
(R)
(S)
(S, S)
meso (R, S)
(R, R)
(R)
18%
<1%
81%
(!)-Cyanthiwigin F
Me
Me
O
O
(R,R)
Me
Me
O
2) Zn, TMS-Cl, Pd(PPh3)41) KHMDS, PhN(Tf)2
57%, two steps
I
B(pin)
10% Hoveyda-Grubbs II
51%then NaBO3, THF/H2O
Me
Me
Me
O
O
H
t-BuSH, AIBN
57%
Me
O
Me
Me
O
H
H
Me
MeMe
Me
Me
O
H
H2) i-PrMgCl, CuCN;1) KHMDS, PhN(Tf)2
24%, two steps
! 9 steps from diallyl succinate
! 2.06% yield, 99% ee, single diastereomerPd(dppf)Cl2 (15 mol%)
Cyanthiwigin overview
First Synthesis
Family
Concepts
MethodologyBroadInterest
! First synthesis of F
! Third cyanthiwigin synthesis
! Only one synthesized
! Double enantioselective alkylation ! Key step guides stereochemistry
! Enantioselective Tsuji allylation
! Tandem RCM/CM
Biological Activity
! Cytotoxic against human tumor cells (3.1 µM)
! Suggests applicability to other cyanthiwigins
! Other cyanthins have variety of activities
Total synthesis of a chlorosulpholipid cytotoxin associated with seafood poisoning
Nilewski, C., Geisser, R. W., Carriera, E. M. Nature, 2007, 446, 404-408.
hexachlorosulpholipid
Me
Cl
Cl
O
Cl
Cl
Cl
HO3S
Cl6
Hexachlorosulpholipid:Retrosynthetic Analysis
Me
Cl
Cl
O
Cl
Cl
Cl
HO3S Takai-Utimoto, [O]
Cl6 Me
Cl
Cl
OH
Cl
Cl
Cl6
OTBS
Me
Cl
Cl
OH
Cl6
OTBS
Me
Cl
Cl OTBS
O
6
chlorination
Anti-epoxide openingWittig, [O]
Me
Cl
Cl
O
OH
Me
Cl
ClOTBS
bis-hydroxylation,epoxidation
chlorination
reduction
MeCO2Et
Hexachlorosulpholipid: First Route
Et4NCl3Me
CO2Et68% Me
Cl
Cl
CO2Et DIBAL72% Me
Cl
Cl
87%Me
Cl
Cl
TBS-Climidazole
5.6:1, 68% major
OsO4, NMOAcetone/H2OMe
Cl
Cl
OH
OH
OH
OTBSOTBS
2) n-BuLiMe
Cl
Cl OTBS
O
6
Me
Cl
Cl
O
OH
75 %, (96% by RSM)1) Tf2O, DABCO
98%2) CSA, MeOH OTBS
6BrPh3P
1) Swern
62%, two steps4.2:1 Z:E
! Diastereoselective installation of chlorides ! Forms cis epoxide for chloride opening
! Wittig sets olefin geometry for chlorination
Hexachlorosulpholipid: First Route
1) Et4NCl3
41%, two steps2) CSA, MeOH
Me
Cl
Cl
OH
Cl6
OTBS
Me
Cl
Cl
OH
Cl
Cl
Cl6
1) DAIB, TEMPO
49%, two steps2) CrCl2, CHCl3
Me
Cl
Cl
OH
Cl
Cl
Cl6
OH
SO3•Pyr
27% (66% RSM) Me
Cl
Cl
O
Cl
Cl
Cl6 Cl
HO3S
Me
Cl
Cl OTBS
O
6 4% minor, 31% RSM39% major
TMS-Cl *
* * *
* * * * * *Cl
Hexachlorosulpholipid: First Route
Me
Cl
Cl
O
Cl
Cl
Cl6 Cl
HO3S
(±)-single diastereomer natural product
Me
Cl
Cl
O
Cl
Cl
Cl6 Cl
HO3S
* * *
! 2D 1H NMR and 1H-heteronuclear coupling experiments determine relative configuration
Me
Cl
Cl
O
Cl
Cl
6 Cl
HO3S
Cl
564
Me
Cl
Cl
OH
Cl6
OTBS
! Similar analysis of synthesized allylic chloride revealed 4,5-anti configuration
54
Hexachlorosulpholipid: Initial Route
Me
Cl
Cl OTBS
O
6
Me
Cl
Cl Cl
OHR
Me
Cl
Cl R
OCl-
TMS
Cl
OTMS
R
Me
Cl
ClR
OTMS
Me
Cl
Cl-
Cl-
or Me
Cl
Cl Cl
OHR
TMS-Cl
4%
39%
Hexachlorosulpholipid: Revised Route
Et4NCl3Me
CO2Et68% Me
Cl
Cl
CO2Et DIBAL72% Me
Cl
Cl
95%
Me
Cl
Cl
MCPBA1:1 dr
Ley oxidation; then n-BuLi
OH
OHO
OTBS6
BrPh3P
7:1 Z:E
Me
Cl
Cl
O
34% (56% by RSM)
OTBS6
ClR
OTMS
Me
ClCl-
TMS-Cl 43%73% by RSM
Me
Cl
Cl OTBS6
OH
Cl
! Shortens previous route by 3 steps
! Sets trans epoxide and utilizes anchimeric assistance to from chlorohydrin
! Improved Z-selectivity in Wittig
Hexachlorosulpholipid: Revised Route
Me
Cl
Cl
OH
Cl
Cl
Cl6
OH
1) DAIB, TEMPO
47%, two steps2) CrCl2, CHCl3Me
Cl
Cl
OH
Cl
Cl
Cl6 Cl
SO3•Pyr
99%
Me
Cl
Cl
O
Cl
Cl
Cl6 Cl
HO3S
2) CSA, MeOH1) Et4NCl3 (10:1 dr)
83% desired diastereomer91%, two steps
Me
Cl
Cl OTBS6
OH
Cl
! Identical NMR to natural product
! 10 steps from ethyl scorbate
! 1.15% of desired diastereomer (3.21% based on RSM)
Hexachlorosulpholipid overview
First Synthesis
Family
Concepts
MethodologyBroadInterest
! First chlorosulpholipid
! Only one synthesized
! Contributes to NMR database ! Use of anchimeric assistance
! J-based configurational analysis
Biological Activity
! Suggests framework for other syntheses
! Shown to inhibit cell growth
! Scaleable synthesis ! Facilitates biological studies
! Selective chlorination via cyclic chloronium
! Related compounds show anti-microbial activity
Total synthesis of eudesmane terpenes by site-selecitve C-H oxidations
Chen, K., Baran, P. S. Nature, 2009, 459, 824-828.
MeMe
Me
Me
HOHO
4-epiajanol
MeMe
Me
Me
HO
dihydrojunenol
MeMe
Me
Me
HO HO
dihydroxyeudesmane
MeMe
Me
Me
HOHO HO
pygmol
MeMe
OH
HOHO
eudesmantetraol
Me
OHMe
MeMe
HOHO
11-epieudesmantetraol
HO
OH
eudesmane terpenes
Terpene Syntheses:General Concept
! Terpene biosynthesis
! Two phase total synthesis approach
oxidationphase
taxadiene
MeMe
Me
Me Me
H
MeMe
Me Me
HO BzOAcO O
OHOR1O
R2O
cyclasephase
paclitaxel
OP2O63-
MeH
4
geranylgeranyl pyrophosphate
R1 = Ac, R2 = Ph
NHBz O
OH
10-deactyl-baccatin III
R1,R2 = H
oxidationphase
cyclasephasesimple commercial
starting materialsMe
Me
Me
Me
HO
MeMe
Me
Me
HO
MeMe
HO
HO
HO Me
OH OH
4-epiajanol
eudesmantetraol
Dihydrojunenol
! 9 steps, 21%, single diastereomer
2) LiOH, i-PrOH
1)
63%, 89% ee
O
Me
O
MeMe
NH
Ph
OMePh
H
O
Me Me
5 mol%
99%
I2, pyridine
O
Me Me
IMgBr
2) PCC, MS
1)
74%, two steps
Me Me
I
OMe
MeO
Me
Me
P(Ph)3 (30 mol%)
Pd(OAc)2 (10 mol%)Me
MeO99%
LiMe2Cu
95%
2) Na, EtOH
1) Pd/C, H2
87%, two stepsMe
MeOH
Me
MeH
! Previous route: 9 steps, 8%, 3 isomers
! "Gram quantities" for oxidation studies
Eudesmane terpenes
! 12 steps each, 17 and 9% from commercial
82%
TFDO
100 W sunlamp
CH3CO2Br
! Reassigned dihydroxyeudesmane
! Structures verified by X-ray
Me
MeOH
Me
MeH
MeMe
MeMe
OO
NHF3CH2C
H3
H1 H2 H4H599%
CF3CH2NCO
O O
F3C Me MeMe
Me
Me
OO
NHF3CH2C
HO
MeMe
Me
Me
HOHO
MeMe
MeMe
OO
NHF3CH2C
Br
MeMe
Me
Me
HO HOthen LiOH
Ag2CO3, AcOH;
43%, 39% SM
82%
NaOMe
4-epiajanol
dihydojunenol
dihydroxyeudesmane
Eudesmane terpenes
MeMe
Me
Me
HOHO 52%, 30% RSM
LiOH
pygmolHO
AgCO3
MeMe
MeMe
OO
NHF3CH2C
H3
HO H2 H4H5
100 W sunlamp
CH3CO2BrMe
Me
MeMe
OO
NHF3CH2C
H3
HO H2 H4Br
MeMe
Me
OO
NHF3CH2C
HOAcOH
! 13 steps, 9% from commercial
! Previously unsynthesized
Eudesmane terpenes
TMP
MeMe
MeMe
OO
NHF3CH2C
H3
HO H2 H4H5
NBS
100 W sunlamp
CH3CO2BrMe
Me
MeMe
OO
NHF3CH2C
H3
HO H2 H4Br
MeMe
Me
OO
NHF3CH2C
HO
MeMe
Me
OHO
O
O Br
MeMe
HOHO
O
Me 52%, 30% RSM
LiOH
MeMe
OH
HOHO
eudesmantetraolMe
OHMe
MeMe
HOHO
11-epieudesmantetraolHO
OH
NaOH90%H2SO487%
! 15 steps, 4% from commercial
! Previously unsynthesized
Linear Oxidation Concept
! "...linear C-H activation strategy featuring multiple site selective oxidations in total synthesis"
Eudesmane terpenes overview
First Synthesis
Family
Concepts
MethodologyBroad
Interest
! Four unsynthesized
! Adaptable to new syntheses
! One improved intermediate
! Six Eudesmane terpenes
! References the terpene family (taxol)
! Two-phase synthesis approach ! "Retrosynthesis pyramid"
! "Gram-scale"
! One new analogue
! Trifluoroethyl carbamate directing group
! TFDO selective oxidation predicted by 13C NMR
Biological Activity
! Related to taxol
Why Nature?
Biological Activity
Methodology
Concepts
Family
First Synthesis
BroadInterest