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Synthesis of
Abyssomicin C
Marie-Caroline CordonnierLitterature Review23/01/2009
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.
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.
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.
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.
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
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
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.
� 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.
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.
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
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.
End of the synthesis
� Never completed because Sorensen published at the same time a full synthesis of Abyssomicin C…
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.
Synthesis of the Diels-Alder substrate
Lautens et al. Org. Lett. 2002, 4, 1879. Schick et al. Tetrahedron: Asymmetry. 1993, 4, 695.
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.
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.
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
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%...
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%
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.
Nicolaou’s Synthesis: Studies toward
the oxabicyclic core
Abae et al. Org. Lett. 2000, 2, 3937. Maier et al. Org. Lett. 2005, 7, 3089.
Nicolaou’s Synthesis: Studies toward
the oxabicyclic core
Kocienski, P. Phosphorus Sulfur 1985, 24, 97.
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
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.
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.
Nicolaou’s synthesis
Xu et al. Bioorg. Med. Chem. 1996, 4, 375.Maier et al. Org. Lett. 2006, 8, 1025.
Nicolaou’s synthesis: fragment
coupling
Several oxidants were used but after 1st oxidation hemiketalization took place
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
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
Abyssomicin C and
atrop-Abyssomicin C
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
Comparison in numbers
Sorensen’s synthesis
Nicolaou’s synthesis
Number of linear steps
15 16steps
15 16
Overall yield 2 % 4 %