synthesisof abyssomicin c - university of oxford
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Synthesis of
Abyssomicin C
Marie-Caroline CordonnierLitterature Review23/01/2009
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Isolation
� Isolated in 2004 from the actinomycete Verrucosispora strain collected from a sediment at a depth of 289m in the Japanese sea. (name: abyss)
Discovered as a whole family but only abyssomicin � Discovered as a whole family but only abyssomicin C shows antibiotic activity.
Süssmuth et al. Angew. Chem. Int. Ed. 2004, 43, 2574.
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Biological activity
� Antibiotic activity against Gram-positive bacteria including methicilin - resistant (MRSA, MIC = 4 µg/mL) and vancomycin - resistant (VRSA, MIC = 13 µg/mL) Staphylococcus aureus strains.
� Inhibitor of the enzyme responsible for the conversion of chorismate to para-aminobenzoic acid as such it is a potential antibacterial drug.
Süssmuth et al. Angew. Chem. Int. Ed. 2004, 43, 2574.
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Biological activity
� Could be explained by the Michael system missing in the inactive compounds
H3CCH3
O
H3CCH3
OHO
H3CCH3
OH
CH3
OH
O
O
O
OO
CH3
OH
O
O
O
OHO
CH3
OH
O
O
O
OHO
N
O
Abyssomicin CAbyssomicin B Abyssomicin D
Snider et al. Org. Lett. 2005, 7, 4939.
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Total Syntheses
� Because of this intringuing system and of the biological activity several groups attempted the total synthesis of Abyssomicin C.
� B. B. Snider � B. B. Snider Org. Lett. 2005, 7, 4939.
� E. J. Sorensen Angew. Chem. Int. Ed. 2005, 44, 6533.
� K. C. NicolaouAngew. Chem. Int. Ed. 2006, 45, 3256, and J. Am. Chem. Soc. 2007, 129,
429.
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Challenging structural elements
� Strained 11-membered macrocyclic ring
� 7 stereogenic centers
� Potentially reactive α, β unsaturated ketone
� Novel fused tetronate oxabicyclo[2,2,2]octane core
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Snider’s Approach: Retrosynthesis
� Biomimetic route
CH3
O
O
O
H3CCH3
OO
H3CCH3
OO HO
O
O
H3CCH3
OO MeO
O
O
Cyclisation 1 EpoxidationDeprotection
Synthesis of the Epoxidation of the more nucleophilic
OH
Abyssomicin C
O
H3CCH3
OO MeO
O
O
H3CCH3
OCHO
O
O
O
Intramolecular
Diels-Alder2
1. Maier et al. Synlett 2005, 314 and Maier et al. Org. Lett. 2005, 7, 3089.2. Yoshii et al. J. Org. Chem. 1987, 52, 4135.
Synthesis of the oxabicyclo[2.2.2]octane more nucleophilic
C=C from the less hindered face
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Snider’s Approach: Retrosynthesis
� Diels-Alder very risky� Creation of three stereocenters ⇒ 4 possible products
� Endo and Exo products are possible
The Key Step
� Facial selectivity is also an issue
� Reactivity of the methylene butenolide as dienophile? � Yoskii reported that reaction of a ten-atom tether proceeded
under forcing conditions (180°C in o-dichlorobenzene) with a low yield and as a mixture of 4 cycloadducts.
Yoshii et al. J. Org. Chem. 1987, 52, 4135.
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� Two encouraging factors� Presence of an acyl group in the tether ⇒ dienophile more
electron deficient
� Biosynthesis probably involves a similar Diels-Alder
The Key Step
Snider’s Approach: Retrosynthesis
� Biosynthesis probably involves a similar Diels-Alder reaction under physiological conditions in which the stereochemistry of the product is controlled by the substrate rather than an enzyme.
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Snider’s Approach: Synthesis of the
Diels-Alder Substrate
Hoffmann et al. Tet. Lett. 1985, 26, 6325. Yoshii et al. E. J. Chem. Soc. 1989, 712.Paintner et al. Tet. Lett. 2000, 41, 9977.
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Diels-Alder reaction
� One single cycloadduct isolated
� Desired cycloadduct formed showed by NOE in which C-16 is in endo position
� Novel and mild stereospecific Diels-Alder ⇒ facile access to the carboxylic skeleton of Abyssomicin C
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End of the synthesis
� Hydrolysis of the vinylogous carbonate with LiCl in DMSO: 88% yield1
� Epoxidation of the cyclohexene double bond afforded complex mixture in which enone double afforded complex mixture in which enone double bond had reacted� m-CPBA� DMDO
� Not surprising considering that this is probably the reason for Abyssomicin C’s biological activity
Yoshii et al. E. J. Chem. Soc. 1989, 712.
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End of the synthesis
� Never completed because Sorensen published at the same time a full synthesis of Abyssomicin C…
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Sorensen’s Approach: Retrosynthesis
� Convergent assymetric synthesis
CH3
OH
O
O
O
OO
Abyssomicin C
OO
OMeO
O1. Stereoselectiveepoxidation
2. Demethylation3. Intramolecular
epoxide opening
Abyssomicin C
OO MeO
O
O
O
O
O
Li
H
O
O O Intermolecularcarbonyl additions
IntramolecularDiels-Alder
Yoshii et al. Tet. Lett. 1986, 27, 3903.Yoshii et al. J. Org. Chem. 1990, 55, 3431.
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Synthesis of the Diels-Alder substrate
Lautens et al. Org. Lett. 2002, 4, 1879. Schick et al. Tetrahedron: Asymmetry. 1993, 4, 695.
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Snider’s Approach: Synthesis of the
Starting Material
O
O
OH O OTHP
O
1.DHP2. DIBAL
94%
Snider’s preparation of the starting material is 63% yield
Sorensen’s preparation is OEt
H+
O
O
O
O
70%
Rh/Al2O3H2
96%
Sorensen’s preparation is 50% yield
prepared on 100g scale from
Andrus et al. J. Org. Chem. 1997, 62, 5542.
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Synthesis of the Diels-Alder adduct
� Contains all carbons of Abyssomicin C� Contains all carbons of Abyssomicin C� But yields modest and variable� Mixture of diastereomers
Yoshii et al. J. Org. Chem. 1987, 52, 4135.
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Cyclisation Step
OTBSO O
O
OMe
O
O O
O
OMe
O
OO
O
Unstable trienone
Sc(OTf)3, DCM, 0°C(65%)
Toluene, 100°C(79%)
� OTBS used as precursor of the trienone� Trienone is an unstable compound ⇒ one pot
synthesis required
OMeO
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Optimised cyclisation step
� Is it really interesting? As the overall yield of the 2 � Is it really interesting? As the overall yield of the 2 steps is 51%...
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Completion of the synthesis
OO
OMeO
OO
O
OMeO
O
O
DMDO, Acetone67%
LiCl, DMSOquant
OO
OHO
O
O
CH3
OH
O
O
O
OO
quant.
p-TsOH, LiCl,MeCN50%
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Nicolaou’s Approach: Retrosynthesis
Maier et al. Synlett 2005, 314 and Maier et al. Org. Lett. 2005, 7, 3089.Xu et al. Bioorg. Med. Chem. 1996, 4, 375.
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Nicolaou’s Synthesis: Studies toward
the oxabicyclic core
Abae et al. Org. Lett. 2000, 2, 3937. Maier et al. Org. Lett. 2005, 7, 3089.
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Nicolaou’s Synthesis: Studies toward
the oxabicyclic core
Kocienski, P. Phosphorus Sulfur 1985, 24, 97.
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Nicolaou’s synthesis: improved
approach
MeO2CHO
O
O
H
OH
PhS
Reductive elimination/methylation
� More efficient approach
O
O
H
H
PhS
O
OMe
PhS
OH
Oxidation
Lewis-Acid templatedDiels-Alder
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Nicolaou’s synthesis: Improved
synthesis
Corey et al. J. Org. Chem. 1966, 31, 4097. Corey et al. Angew. Chem. Int. Ed. 1998, 37, 1986.Cohen et al. Acc. Chem. Res. 1989, 22, 152.
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Nicolaou’s synthesis: Synthesis of the
oxabicyclic[2,2,2]octane core
CO2MeHO
CO2MeAcO
O
t-BuOOHVO(OEt)3
93%
Ac2O95%
LHMDSaq. NH4Clth TESCl
O
OOH
O
CH3
OTES
O
O
O
then TESCl97% over 2 stepsDieckmann condensation
Sharpless et al. J. Am. Chem. Soc. 1974, 96, 5254. Evans et al. Synlett 1992, 269.
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Nicolaou’s synthesis
Xu et al. Bioorg. Med. Chem. 1996, 4, 375.Maier et al. Org. Lett. 2006, 8, 1025.
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Nicolaou’s synthesis: fragment
coupling
Several oxidants were used but after 1st oxidation hemiketalization took place
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Nicolaou’s synthesis: synthesis of
Abyssomicin C framework
CH3
O
O
O
+O O 1. t-BuLi
2. (CH2SH)2TMSOTf
76% over 2 steps
CH3
OH
O
O
O
HOS
S
OTES
OH
1. IBX2. vinyl MgBr65% over 2 steps
CH3
OH
O
O
O
SS
OHGrubb's II
85%
CH3
OH
O
O
O
HO
SS
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Nicolaou’s synthesis: completion of
the synthesis
CH3
OH
O
O
O
HO
SS
CH3
OH
O
O
O
O
SS
IBX
50%
PhI(OTFA)2
CH3
OH
O
O
O
O
CH3
OH
O
O
O
O
CDCl3O O
71%
67%
Abyssomicin C atrop-Abyssomicin C
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Abyssomicin C and
atrop-Abyssomicin C
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Comparison of Sorensen’s and
Nicolaou’s total syntheses
� Highlight the power of the Diels-Alder reaction� Either intramolecular to form a strained macrocyclic system� Or intermolecular via a Lewis mediated templated transition
statestate
� Both well-suited to synthesize new analogues to enable further studies of the structure-activity relationship
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Comparison in numbers
Sorensen’s synthesis
Nicolaou’s synthesis
Number of linear steps
15 16steps
15 16
Overall yield 2 % 4 %