Bordeaux I University Stéphane Quideau, Ph.D. Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales 1 Comparative Strategies in Natural Products Synthesis Université Bordeaux 1 Master de Chimie (CO-3) Stéphane Quideau, Ph.D. Institut Européen de Chimie et Biologie & Laboratoire de Chimie des Substances Végétales Centre de Recherche en Chimie Moléculaire Université Bordeaux 1 [email protected]Tel : 05-40-00-30-10 Cel : 06-62-91-65-51 The objective of this course is to provide graduate students majoring in chemistry with a strengthened knowledge of organic synthesis. The student will utilize his/her knowledge of organic reactions, mechanisms, and controls to critically and comparatively study the challenges of natural products synthesis. Toward this objective, total syntheses of various targets accomplished by different research groups over the years will be discussed. The different synthetic strategies will be compared via a retrosynthetic analysis approach (i.e., topological disconnection path to starting materials). The different tactics (i.e., choice of reactions and combinations thereof) will be discussed by highlighting the key steps of the actual syntheses. Targets: Camptothecin, Biotin, Denticulatins, Dynemycin A , Dysidiolide, Epothilones , FK-506, Quadrone, Strychnine, Zaragozic Acids, Taxol. Suggested Readings and Reference Sources: • E. J. Corey and Xue-Min Cheng, The Logic of Chemical Synthesis, Wiley. • K. C. Nicolaou and E. J. Sorensen, Classics in Total Synthesis, VCH. • Tse-Lok Ho, Tactics of Organic Synthesis, Wiley. • A. Koskinen, Asymmetric Synthesis of Natural Products, Wiley. • S. Warren, Designing Organic Synthesis, Wiley. • S. Warren, Organic Synthesis, The Disconnection Approach, Wiley
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Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
1
Comparative Strategies in Natural Products Synthesis
Université Bordeaux 1Master de Chimie (CO-3)
Stéphane Quideau, Ph.D.Institut Européen de Chimie et Biologie
&Laboratoire de Chimie des Substances Végétales
Centre de Recherche en Chimie MoléculaireUniversité Bordeaux 1
The objective of this course is to provide graduate students majoring in chemistry with a strengthenedknowledge of organic synthesis. The student will utilize his/her knowledge of organic reactions,mechanisms, and controls to critically and comparatively study the challenges of natural productssynthesis. Toward this objective, total syntheses of various targets accomplished by different researchgroups over the years will be discussed. The different synthetic strategies will be compared via aretrosynthetic analysis approach (i.e., topological disconnection path to starting materials). The differenttactics (i.e., choice of reactions and combinations thereof) will be discussed by highlighting the key steps ofthe actual syntheses.
Suggested Readings and Reference Sources:• E. J. Corey and Xue-Min Cheng, The Logic of Chemical Synthesis, Wiley.• K. C. Nicolaou and E. J. Sorensen, Classics in Total Synthesis, VCH.• Tse-Lok Ho, Tactics of Organic Synthesis, Wiley.• A. Koskinen, Asymmetric Synthesis of Natural Products, Wiley.• S. Warren, Designing Organic Synthesis, Wiley.• S. Warren, Organic Synthesis, The Disconnection Approach, Wiley
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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• Strategies and Tactics in Organic Synthesis (volume series).
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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General Guidelines
A. Convergent / linear synthesis
9
92 20vs.
better not so good
The overall yield is a function of the yield of every steps !
eg, 10 steps95% each 0.9510 = 60%90% each 0.9010 = 34%70% each 0.7010 = 3%
B. Timing of bad risky steps early middle late1 3 2
C. sp2 centers vs. sp3 centers available less available, but stereogenic centers ⇒ Diels-Alder
ClaisenCarbonyl addition
D. Intra/intermolecular reactions
Intramolecular bond forming reaction have entropic and stereochemical/conformational advantages!
E. Double diastereodifferentiation
RO
HMe
OMR'
OH+
Si/Re5/1 (inherent preference)
Si/Re1/5
R
Me
OHR'
Me OH
O
R
Me
R'
OH
O
reflects both inherent preferences
+ 25/1
OH
Me
NB: This estimate does not take into account kinetic resolution
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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F. Enantiomeric excess
definition = (d% - l% / d% + l%) x 100
Coupling chiral, scalemic (not racemic) fragments
A + B → C ee?
90% ee
90% ee
95/5 d/l
dd 0.95 x 0.95 = 0.90dl 0.95 x 0.05 = 0.05 (separable diast.)ld 0.05 x 0.95 = 0.05 (separable diast.)ll 0.05 x 0.05 = 0.0025
⇒ ee = 90/025 ⇒ 360/1 ⇒ 99.4%
NB: This estimate does not take into accountkinetic resolution
G. Natural and unnatural polarization of functional groups
Synthetic target may be viewed in terms of their ionic components
R
O
α
β
γ
Nu
R
Oα α carbon is negative!
R
O β
E
β carbon is positive!
Nu
R
O
γ
δ
δ
δ
δ
δδ
δ
Michael 1,4-addition
γ carbon is negative!
BaseR
O
γ
E
Arrays of alternate negative/positive centers are easier to construct!
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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R
O
acyl anion(not accessible!)
S S
R
S S
R HR
O
HE
H. Topological disconnections to simplify structures ⇒ Retrosynthetic analysis
• E. J. Corey, JACS 1975, 97, 6116 (strategic bond disconnections).• E. J. Corey and Xue-Min Cheng, The Logic of Chemical Synthesis, Wiley.
Perception of strategic bondsThe most desirable bond disconnections in the antithetic manipulation of structure are those in which thefollowing structural features are minimized:
(i) appendages(ii) appendages carrying chiral centers(iii) rings of medium or large size(iv) bridged ringsStrategic bonds (to break in the retrosynthetic manipulation) vs. core bonds (not to break!)
Analysis of Bridged Polycyclic Molecular Networks
Me OH
a b
c d
a b
cd
Me OH Me OH
Me OH Me OH
*
**
*
*
*
**
Rule #1A strategic bond must be in a four-, five-, six- or seven-membered “primary” ring (relatively easy to form)
a secondary six-membered ringenvelope of two fused four membered-ring
A primary ring is one which cannot be expressed as the envelope of two or more smaller rings bridged orfused to one another.
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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Rule #2
A strategic bond must be directly attached to another ring (exo to another ring, except three-membered rings)because a ring disconnection which produces two functionalized appendages leads to a more complex systemthan a ring disconnection that lead to one or no functionalized appendages.
⇒ mimimize appendages on rings!
A1
2
Out of six bonds in ring A, only bonds 1 and 2 can be strategic
Rule #3
To achieve maximal simplification of the cyclic system, strategic bonds should be in the ring (or rings) whichexhibits the greatest degree of bridging.
central four-membered ringof maximum bridging
Disconnection of any bond in that central four-membered ring produces a major network simplification to adecalin system.
The maximum bridging ring is selected from the set of “synthetically significant rings” (all primary rings— Rule #1— plus all secondary rings less than eight membered, ie, those that can be formed from a pair ofsmaller primary rings)
Maximum bridging rings of a molecule are those rings which are bridged at the greatest number of sites.
** *
*How many sitesbridged at?
Rule #4
To avoid the formation of rings having greater than seven members, any bond common to a pair of bridged orfused rings whose envelop is > eight-membered cannot be considered strategic.
The bonds that are eliminated from further consideration by this rule are termed core bonds
a core bondDO NOT BREAK!
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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Exception : when the two fused or bridged rings being examined are directly joined elsewhere by anotherbond.
core bond?No, breaking does not lead to a ten-membered ring, butto two fused six-membered rings!
Rule #5
Bonds within aromatic rings are not considered to have potential strategic character.
Rule #6
If a cyclic arc linking a pair of common atoms (fusion atoms, bridgeheads, or spiro ring junction atoms)contains a chiral carbon atom, then none of the bonds in the cyclic arc may be considered strategic.
⇒ mimimize appendages with chiral centers!
Don’t!
This situation is undesirable because it is difficult to control stereochemistry efficiently at centers onappendages as opposed to centers in rings.
Exception : A bond directly attached to a chiral center can be broken if that center is the only chiral one onthe arc linking the two common atoms
OK!(but again don’t if center 3 is chiral!
Rule #7 : The C-Heterobond Procedure
To the set of strategic bonds determined by rules 1-6, C-X bonds (X = O, N, S) are added!
OHH
1 23
4OHH
* *
12
34
O2NHO
12
34
O2NO
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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“One-Group Transforms”
“Two-Group Transforms”
NB: This analysis is limited to one-bond disconnections. Keep in mind the possibility of bond-pairdisconnecting transforms ⇒ applications of powerful ring transforms [4+2], [2+2], [2+1]
Ref: EJ Corey, JACS, 1974, 96, 7724
O
OH
O
OH
eliminated by rule 2 (not exocyclic)kept by the C-Heterobond procedure
O
FGA 1-GRP
OLG
alkylation
FGA
O
FGI
O OH
2-GRP
aldolO CHO
FGI
O
FGI
O
O
2-GRP
Michael
O
O
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0Quadrone - “The Taxol of its time”
A. General
• Sesquiterpene (i.e., 15 carbon skeleton) isolated from Aspergillus terreus in 1978• This quadicyclic ketone was viewed as “a popular test of design and execution” for synthetic organic chemists • Four rings, 5 contiguous steregenic centers:
one cis-fused bicyclo[3.3.0]octane subunitone bicyclo[3.2.1]octane subunit4 neopentyl and 1 quaternary (C-1) asymmetric carbonC-1 is common to each four rings!
• Shows cell-growth inhibitory activity:somewhat surprising, since quadrone is devoid of the electrophilicfunctionality common in sesquiterpene antitumor agents
quadrone is actually the progenitor of the α-methyleneketone, terrecyclic acid A
1) Identify rings with maximum bridging:look for bridgehead carbons to identify the ring of maximum bridging
2) Identify strategic bonds vs. core bonds:• A strategic bond (i.e., most desirable to break in retrosynthetic analysis) must be within a ring of
maximum bridging• A core bond (i.e., not to be broken in retrosynthetic analysis)
O
O
core bondDo Not Break !
O
• Breaking this core bond would lead to a nine-membered ring ⇒ need for a medium-size ringformation synthetic step (difficult!)
• Any non-core bonds in maximally-bridged ring can be a strategic bond!
O
O
Burke
O
O
CHO
O
O
Kende
O
O
Magnus
CO2Et
TMSO
R
acyclic!
O O O
core bond broken!
O
O
bridging
bridge head bridge head
O
O
O
H
O
O
ring with maximum bridging!
O O
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The Burke routeJACS 1984, 106, 4558
All new carbon-carbon bonds are formed via intramolecular deliveryRetrosynthetic analysis
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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This is actually (ent)-quadrone
O
O
CHO
O
OO
OO
1
O
CHO
O
key starting materialwith correct stereo. at spiro center!
spiro[4,5]decadienoneBurke, JOC 1981, 46, 2400
Aldol
CHO
O
O
O
O
CHO
O
OH
O
OHC
H
axial! ⇒ contrathermodynamic ⇒ kinetic control
E Nu
retro-Aldol
thermoneutral+ 5 Kcal/mol
E Nu
1
core bond
convexe
concave
retro-Michael
downhill- 20 Kcal/mol
i.e.,
This plan involves a bond formation through the convexe face ⇒ difficult!This was in the first Burke's grant proposal; a referee claimed that such a bond was impossible to make!Burkeet al. found a way (more than 50 sets of conditions were tried...
O
O
CHOMichael
Nu centers = -E centers = +
+
+
+ + We shall see how Burke et al. controlled this reaction!
exo-orientation of CHO, as exo-face slightlyless hindered (not obvious! Burke was concerned about the possibility of having formed the endo-product, for Aldol was difficult to achieve
convexe/exo-face is less hindered!
Synthesis
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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O O
O
CHO
O
O
O
CHO
O
CHO
O
OO
O
electron-rich alkenecould use electrophilic ozone,but degradation problems!
HO
1. OsO4 cat., N-methyl morpholine N-oxide2. NaIO4
TsOH, PhH
O
TiCl4, R4N OCOCF3
H
A
CO2MeH
A
B
B
C
KOH, PhH, refluxdibenzo-18-crown-6
95%
92%
96%remains to build lactone!
not so trivial due to difficulties in forming C-5 enolate regioselectively
HO
TsOH, morpholinePhH, reflux
OO
50 trials withdifferent condition sets
JACS 1984, 106, 4558
O
Danishefsky's intermediateJACS 1981, 103, 4136
axial ⇒ contrathermodynamic: this is not so easy, but Burke provided a solution to complete his formal total synthesis
add 1C
Wharton fragmentationJOC 1961, 26, 3615
H
OO
1. HOCH2CH2OH, TsOH2. t-BuOOH, NaOH, aq. MeOH (epoxidation at α-face because β-face is blocked by the ethano bridge)
H2NNH2.xH2OMeOH–AcOH
OH
5
92%
O
i.e. allylic transposition from enone
Hg(OAc)2, i-Pr2NEt, xylene, Δ
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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O
12
3
1 2
3
allyl vinyl ether ⇒ [3,3] Claisen with sterecontrol!
α-face
[3,3]
CHO
α-faceH2, Pd/C
CHO
axialO
O OO O
O
Danishefsky'sintermediate
56
contains all the target carbons!
formal total Σ total Σ
need to:1. form C5–C6 bond
2. reduce C-6, oxidize C-73. disconnect C-6 and C-7,
then reattach through oxygen togive lactone
7
total synthesis completion
1. aq. HCl2. HOAc–H2SO4 (Aldol)
CHOOO O
AcO 79% (4:1)
400 °Csealed tube
O
O
+
61%
33%
TBSO OHOH
Ag2CO3 – CeliteFetizon's reagent
O
XO
YA: X = O, Y = H, HB: X = H, H, Y = O
92% (1:1)
Jones
(+)-quadrone
19 steps and 6.2% overall yield from spiro [4,5]decadienone
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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CO2HO
H
O
H
O O
3:1O
CO2H
H
terrecyclic acid A
H melting point!!! quadrone
isoquadrone
O
CO2H
H
HO
mp was for isoquadrone, not quadrone!!!mp changed on second measure ⇒ quadrone!!! (ouf!!!)
14 steps, 2.4% overall
Danishefsky
LDA (3 equiv.), CH2O gas62%
H2, Pd-C
O
CO2H
H
HO
100%
190 -195°C5 min
The Sclessinger routeJOC1983, 48, 1147
Intramolecular Diels-AlderRetrosynthetic analysis
O
CO2HH
O
OO
OH
O
OH
O
O
(+)-quadrone Danishefsky'sintermediate
1 23
4
5
23
45
1 remove 1C
cyclohexene⇒ D.A.
core bond
core bond
Synthesis
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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O
MeO2CI
O
MeO2C
O
OH
NHN
O
OHOO
CO2HO
O
CO2H
H
OH
NN
Cr
OO
OH
O
N
HN
Cr
OOH
ON
NCr
OHOH
O
regioselectivity of allylic oxidation?more stable trisubstituted olefin product !? (thermo control !)Also complex attacks less hinderedface (hydrogen) of molecule!
cannot collapse to ketone, since no hydrogen to remove!
or "Cr(V)" O
O
[3,3]
nice 1,3-diaxial dispostion for [3,3]i.e., 6-membered TS
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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The Wender routesJOC 1985, 50, 4418
Intramolecular Diels-Alder / Ring Expansion SequenceRetrosynthetic analysis
terrecyclic acidi A
CO2t-BuOCO2H
H
Oring
expansion
CO2t-Bu
OMeCl
LG
cycloaddition
OMe
MeO2C
t-BuO2C
core bond broken!
form core bond!
Synthesis of (+)-desdimethylquadroneOrg. Photochem. 1989, 10, 439
Alkene-Arene Photochemical Coupling - “The Home Run Approach”NB: Only novel development of carbon-carbon bond forming reaction (with Stille coupling)
in the past 25-30 years!Background Analysis
Possibilities of photocycloadditions
ortho para
weird, but so clever!meta
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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mechanism?
hν*
exciplexSynthesis
MeO2C MeO2C MeO2C MeO2CH
H
HMeO2C
H
H
H
HMeO2C
MeO2C
H
H
H
MeO2C HHH
intramolecular meta photocycloaddition
HH
21
H
CO2Me
hν via exciplex3
45
2,66
slightly favored!gives rise to CO2Me in less sterically
favored axial orientation in cycloadduct
1,3
1,5
+ epimer
poor regio- and diastereoselectivity,but highly expeditous synthesis!
versus
exciplex 1
MeO2C
NB: regio- and diastereoselectivity improves when ester group is replaced by more bulky alcohol group (via reduction)
H
H
exciplex 2
2
H3
[1,5]
CO2H
H
5
O
4
OO1
Δ
(+)-desdimethylquadrone
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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Strychnine
A. General
Strychnos alkaloid (poison / rain forest)first isolated from Strychnos ignatii by Pelletier and Caventou (1818)
complex heptacyclic structure (24 skeletal atoms):6 contiguous assymetric carbon centers5 of those are included within one saturated six-membered ring1 is quaternary!7-membered oxygen heterocyclic motif
“For its molecular size it is the most complex substance known”(Sir Robert Robinson, 1952)
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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The Martin RouteJACS 1996, 118, 9804
“biomimetic base-mediated rearrangement of corynantheoid skeletoninto strychnoid skeleton”
N
O
N
HO
HNH
N
MeO2C OR
NNH
OBnMeO2CH
H
NNH
OHMeO2CH
H
Cl
NN
OBnH
H
MeO2C
NNH
OH
HO
OBn
NNH H
O
OOBn
H
NNH
R = H (Overman's intermediate)R = Bn (Martin's intermediate, cannot deprotect!!!)
corinantheoidskeleton
OTMS
Hetero DA
+OBn
COCl+
vinilogous Mannich
6-membered ring from acyclic prec.with regio and stereocontrol!
H
SynthesisJACS 1996, 118, 9804
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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Epothilones
A. General
• Macrolides isolated from myxobacteria of the genus sorangium 16-membered macrocyclic polyketides featuring: methyl/hydroxyl triads (polyketide trademark) an aromatic thiazole ring (⇒ cysteine) an oxirane ring a gem-dimethyl group 7 stereogenic centers Multigram-scale supply from single batch fermentation! • Antitumor agents with antimitotic activity via stabilization of microtubules (Taxol-like activity!): broad activity against eukaryotic cells; epothilone B is twice as active as epothilone A epothilone B ⇒ apoptosis of mouse fibroblasts (L929) within three days at an IC50 dose of 2 ng/ml in vitro activity against breast and colon tumor cell epothilones and taxol probably occupy different but possibly overlapping binding sites on microtubules 1000 to 5000 times more active against multiple drug-resistant tumor cell lines 30 times more soluble in water
NB: the microtubule-stabilizing activity of the epothilones and taxol is shared by only one other naturalproduct ⇒ discodermolide
B. References
Höfle et al., Angew. Chem. IEE 1996, 35, 1567 (isolation, manuscript received on March 26)Danishefsky et al., Angew. Chem. IEE 1996, 35, 2801 (epothilone A, manuscript received on October 17)Danishefsky et al., Angew. Chem. IEE 1997, 36, 757 (epothilone B)Danishefsky et al., JACS 1997, 119, 10073 (the full story!)Nicolaou et al., Angew. Chem. IEE 1997, 36, 166 (epothilone A, manuscript received on November 25, 1996)Nicolaou et al., JACS 1997, 119, 7960 and 7974 (epothilones A and B, the full story!)Schinzer et al., Angew. Chem. IEE 1997, 36, 523 (epothilone A)Schinzer et al., Chem. Eur. J 1996, 2, 1477Wessjohann, Angew. Chem. IEE 1997, 36, 715 (highlights)
O
S
N
O
O
OH
R
OH O
epothilone A ⇒ R = Hepothilone B ⇒ R = Me
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
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C. Analysis
O
S
N
O
O
OH
R
OH O
O
S
N
O
OH
OH O
R
Aldol
esterification
Wittig
Three major fragments:one thiazole unittwo aldol components
disconnectionorder vary
Epoxidation is the last step in all syntheses
Variations ⇒ disconnection strategies and tactics to synthesis each fragment, especially in the northern half!
Northern half
Southern half
Possible macrocyclization strategies:macrolactonizationmacroaldolizationring-closing olefin metathesis
NB: Danishefsky implemented them all!
The Danishefsky’s routeJACS 1997, 119, 10073
First Syntheses of Epothilones A and Bvia Suzuki Coupling and Macroaldolization
Retrosynthetic analysis
O
S
N
O
OH
OH O
R
OH
S
N
R
X
X
O
OP
OP
B-alkyl Suzuki
Xmacroaldolization
+
esterificationA
B
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
NB: Danishefsky and his co-workers also developped a route to epothilones based on ring-closing olefinmetathesis to achive macrocyclization (JACS 1997, 119, 10073).
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
2. HF, MeCN, a few splinters of glass(catalysis by H2SiF6)
O O O OO O O OH
TBSO O OTBSHO2C
O
NO
OO
HO
+B
Anti–Cram Aldol
LDA, THF, -78°C
oxazolidinone-based Evans' chiral auxiliary
How would you make this chiral aldehyde?
This a case of double diasteredifferentitionoverruling Cram selectivity (mismatched chiral pair)
+ NaHMDS, MeI
hept-6-enoic acid
asymmetric alkylation
70%
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
39
TBSO O OTBSHO2C
OH
S
N
A
+DCC, DMAP
O
S
N
O
OTBS
OP O
P = TBS
80% via ring-closing metathesisepothilone A
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Dynemicin A
A. General
• Enediyne isolated from fermentation broth ofMicromonospora chersina(Konishi, 1989)
• Antitumor antibiotichigh levels of invitro antitumor activity comparable to those of two other enediyne natural products, calicheamicin andesperamicin (show overhead!)
• Only members of the natural enediynes to possess an anthraquinone, astructural feature also common to the anthracycline antibiotics.
No carbohydrate moiety (affect DNA binding properties)Strained epoxy (Z)-enediyne bridge across bicyclic ring system
• Bergman cycloaromatization of enediynes:H
H
H
H
ΔBergman cyclization
H
H
H
H
highly unstable1,4-dehydrobenzene
a biradical species!
Natural enediynes are thought to display their antitumor activity via Bergman cycloaromatization of theirenediyne unit; the resulting biradical species being capable of inducing double-stranded DNA cleavage! Thiswas a novel biomechanism of action for antitumor agents!
• Biomechanism of action of dynemicin A:1) the anthraquinone unit functions as a DNA intercalating agent (i.e., delivery system), and as the initial site of reduction in the activation of dynemicin A.2) base-mediated epoxide opening to a quinone methide followed by trapping with a bionucleophile (i.e., triggering device: sp2 → sp3) causes the two triple bonds of the otherwise inactive enediyne unit (i.e., warhead) to come close enough together to undergo Bergman cyclization.3) Bergman cyclization: biradical product abstracts DNA hydrogen ⇒ DNA cleavage!
HNOH
OH
O
O OH
OOMe
CO2H bioreduction
3.54 Å
HNOH
OH
O
OH OH
OOMe
CO2HHB
HNOH
OH
O
OH OH
HOOMe
CO2H
a quinone methide!
BioNu
HNOH
OH
OH
OH OH
HOOMe
CO2H
Nu
3.17 Å
Bergman!
HNOH
OH
O
O OH
OOMe
CO2H
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41
B. References
Hoffmann, American Scientist 1993, 81, 324 (of what use enediynes)Bergman, Acc. Chem. Res. 1973, 6, 25 (Bergman cyclization)Konishi et al., J. Antibiot. 1989, 42, 1449 (isolation)Schreiber et al., JACS 1993, 115, 10378Myers, A. G.et al., JACS 1997, 119, 6072, and Chem. & Biol. 1995, 2, 33Danishefsky, JACS 1996, 118, 9509
NB: For a non radical but polar cycloaromatization alternative pathway to biological activity, see:Magnus et al., JACS 1993, 115, 12627.
C. Retrosynthetic Analysis and Synthesis
The Myers’s routeJACS 1997, 119, 6072
Chem. & Biol. 1995, 2, 33
Highly Convergent Route Allowing for the Synthesis of Dynemicin Analogs
Retrosynthetic Analysis
isobenzofuran 4π component
F
F
+
+
" "
a stable quinone imineas 2π component
HNOH
OH
O
O OH
OOMe
CO2HN
O
OOMe
CO2ROH
OH
O
OH
OH
HNA
D
O
O OH
O
N
O
OA
D
O
X
Y
B
C
analogs
loci of chirality!
B
CE
[4π + 2π]
angucycline chemistry
E
NB: reactive anthraquinone unit is introduced at the later stage of the synthesis! Synthetic problem is reducedto the preparation of the quinone imine Diels-Alder component ⇒ easy access to various analogs!
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N
O
OOMe
CO2RN
OTBS
H
O
O
OH
OMeOMe
oxidation to quinone imineFGI within A ring
A
HN
OMe
O
OMe
a quinolone
down to one stereogenic center !need syn addition of (Z)-enediyne unit!
B(OH)2NH
OMe
O
O
+
Suzuki
TfO
O
OMe
O
Synthesis
O
O OO
OEtO
O
O O500 g scale (94 %)2. recrystallization
(benzene)
1.
O
O
O OMeMeO
NHBOC
B(OH)2
36 %
KO-t-Bu, t-BuOH, reflux
Enantioselective Synthesis of Quinone Imine
Michael-Dieckman
A. G. Myers, M. E. Fraley, N. J. TomJACS, 1994, 116, 11556-11557
1. NaH, (TfO)2O, - 78 °C, Et2O2. Pd(PPh3)4, Na2CO3dioxane, reflux
magnesium chelation with methoxyl oxygenscauses the alkoxide to adopt a half-chair conformation in which the methyl group is placedin a pseudoequatorial position!
axial mode of entry for the acetylide!
cis
TBS
H
EtMgBr, -78°C → 0°C, THFO
O Cl
Yamaguchi reaction
TL 1983, 24, 1801
N
OTBS
O
OHOMeOMe
O
O
94 %
1. p-TsOH.H2O, acetone (hydrolyse ketal in 83 %)2. 1,1'-thiocarbonyl-diimidazole, DMAP (85 %) N
OTBS
O
O
O
OO
S
a thionocarbonate
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46
1.
N
OMe
O
MeO
H
O
Yamaguchi reaction
early!
H
H O
N
OMe
OTBS SiMe2thexyl
MgBrCl
O
OMe
N
OMe
OH
O
MeO
H
Br
O
OH
2. TBAF
first stereogenic
center(axial)
60%
!?
JACS 1990, 112, 7410
50%
DBUepimerization
N
OMe
OH
O
MeO
Johnson, Chem. Rev. 1968, 375Allylic A1,3 strain!
CO2H
Pd(PPh3)4, CuI
Cl Cl
Cl O
Cl
ideal for subsequentcyclization!
1.
2. LiOH DMAP, toluene, rt
Yamaguchi macrolactonization conditions
N
OMe
O
O
MeO
O
N
OMe
O
MeO
H
O
H
H O
or PyBroP, Et3N
involve benzylic oxidation with CAN to oxygenate at C-11
N
OMe
O
O
OH
O
H
H O
OBzbase-labile
via β-elimination
113
4
need to reposition C3–C4 olefin,while controlling stereo at C4
JACS 1992, 114, 5898
direct hydride introdution at C4 withconcommitant deoxygenation at C11 of the allylic alcohol moiety to repositionthe olefin with desired stereochemistry at C4did not work ⇒ allylic diazene rearrangement!
1. MeAlCl2, CH2Cl22. MesNHNH2
N
OMe
O
RO
N
O
H
H ON H
stereoselectivesigmatropic [1,5] shift
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N
OMe
O
RO O
H
H O
11 steps N
OMe
O
O
butyrolactone vinylogous carbonate
CO2Me
OH
OMe
OMe
O
O
Br
Friedel–Crafts
1. anhydrous AgOTf, 1 min 2. Me2SO4, K2CO3
N
OMe
OMe
CO2Me
MeO OMe
OO
O
OMeO2C
MeO2C
H 57% (1:1)
CO2HNOMe
OMe OMe
OMe
CO2Me
MeAlCl2, Et3SiHO
OR
NOMe
OMe OMe
OMe
CO2MeO
OR
1. SOCl22. TMSOTf3. DDQ
51%OH
O1. m-CPBA (epoxidation)2. DBU (removal of carbamate via β-elimination)3. CAN (oxidation to target)
HNOMe
OMe
O
O OMe
OOMe
CO2Me
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The Danishefsky’s routeJACS 1996, 118, 9509
Stille-mediated Ethylene Interpolation
Retrosynthetic Analysis
HNOH
OH
O
O OH
OOMe
CO2H
ZZHN
OP
X
Y
W W
V
U
TT
ZZN
OP
X
Y
V
U
ZZN
OP
V
U WintramolecularReissert coupling
intermolecularethylene interpolation
2 4
7
stereochemically more demandingsince need to control cis relationships between C2, C4 and C7!
need to control cis stereochemistryat C4 and C7, cis stereochemistry at C2 would be fixed by cyclization
unsuccessful?
successful!
Popp, Chem. Heterocycl. Comp. 1982, 32, 353
Yamaguchi reaction-like
Synthesis
OCHO
OMe
ZnCl2, CH2Cl2, rt
endo-selectiveDiels–Alder O
OMe
H
H CHO60%
hemiacetal formationpossible since reactive centersare both on the α-face ⇒ would not be possible with exo-cycloadduct!
racemate!
CAN
O
O
H
O
HO
47
control of C4–C7 cis relatioship!
4
7
1. NH4OAc, AcOH, 100 °C2. TBSCl, imidazole
90%
N
OTBSOTBS
desired quinoline!
87%
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N
OTBSOTBS
N
OTBSOTBS
OH
OH
N
TBSO
OTBSH
HO
O
W
W
N
OTBSOTBS
O
O
PhPh BrMg TIPS
O
O
Cl
N
OTBSOTBS
O
O
PhPh
O
O
TIPS
N
OTBS
O
O
PhPh
O
O
TIPS
Danishefsky's solution fi render the α-face even more hindered than the β-face:
TMS O
O
N
2
OTBS
undesired attack sterically prevented
OH
OH
80% (9:1)
TEOC
I
1. Ph2C(OMe)2, H2SO4, CH2Cl22. TBSCl, imidazole
83%
I
THF, -20°C
difficult task of the ethylene interpolation route: an ethynyl group must be introduced at C2 cis to both C4 and C7, that is onto the already sterically hindered β-face
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N
O
OCO2MOM
OMe
OMOM
MOMO
O
O
O
LHMDSN
O
OCO2MOM
OMe
OMOM
MOMO O
3 steps
(rac)-dynemicin A
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Dysidiolide
A. General
• sesterterpene (i.e., C25) γ-hydroxybutenolide isolated from the marine sponge Dysidea etheria de Laubenfels • Antimitotic activity; it is the only known natural inhibitor of cdc25A, a signaling
protein phosphatase known to activate the G2/M transition of the cell cycle:
inhibition of cdc25A ⇒ cell cycle arrestation ⇒ cell division prevention⇒ applications for cancer treatment
micromolar activity against A-549 human lung carcinoma and P388murine leukemia cancer cells
Is this cancer cell growth inhibition due to the inhibition of cdc25A by dysidiolide?
• Unusual rearranged carbon skeleton with two fused six-membered rings possessing four stereogeniccenters, plus two functionalized appendages.