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 %