total synthesis of (+)-cytosporolide a via a … · total synthesis of (+)-cytosporolide a via a...
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Literature report
Total Synthesis of (+)-Cytosporolide A via a Biomimetic Hetero-Diels−Alder ReactionHetero-Diels Alder Reaction
Reporter: Zhang-Pei Chen
Checker: Shu-Bo Hu
Date: 29/12/2015
Takao, K. et al.Takao, K. et al.J. Am. Chem. Soc. 2015, 137, 15971.
Revised structure of (+)-cytosporolide A and related natural products
Proposed biosynthesis of (+)-cytosporolide A
OHHO2C OHHO2C
HO
Me
Me Me
OH
O
H
hetero-Diels-Alderreaction
HO
Me
Me Me
OH
O
H
OH
HOMe
2: (+) cytosporolide A
O
C7H15
H
OH
HOMe
O
C7H15
5: ( ) fuscoatrol A 62: (+)-cytosporolide A 5: (-)-fuscoatrol A 6
Me MHOHO
OHHO
CO2H
Me
Me
HO
MeOOH
Me
Me
HO
OHMe
HO
MeO5: ( ) fuscoatrol A
OHHO
O
HO
Meconformer conformer
5: (-)-fuscoatrol A( : = 3:1, CDCl3)
C7H157 (+)-CJ-12,373
Synthesis of (-)-fuscoatrol A
Tadano, K. et al. Angew. Chem. Int. Ed. 2008, 47, 3426.
Synthesis of (-)-fuscoatrol A
Synthesis of (-)-fuscoatrol A
Synthesis of (-)-fuscoatrol A
Nozaki–Hiyama–Kishi reaction
The Nozaki–Hiyama–Kishi reaction is a nickel/chromium coupling reaction formingan alcohol from the reaction of an aldehyde with an allyl or vinyl halide.Compared to Grignard reactions, this reaction is very selective towards aldehydeswith large tolerance towards a range of functional groups such as ketones, esters,amides and nitriles. Enals give exclusively 1,2-addition. Solvents of choice are DMF
d DMSO l t i t i l bilit f th h i lt N kiand DMSO, one solvent requirement is solubility of the chromium salts. Nozaki-Hiyama-Kishi reaction is a useful method for preparing medium-size rings.
From Wikipedia
Synthesis of (-)-fuscoatrol A
Synthesis of the precursor of o-quinone methide intermediate
Hetero-Diels-Alder reaction
CO Me HO C
a) toluene, 100 oC, 70 hMe
Me Me
H
OHHO
CO2Me
EtO+b) 6M N OH M OH
Me
Me Me
H
O
OHHO2C
HH O
C7H15
b) 6M aq. NaOH, MeOH
H O
C7H15
HH
42 40 43a
44%, 43a:43b:43c = 3:1:1
Me Me O
OHHO2C
Me Me O
OHHO2C
Me H
H OH
HMe H
H OH
H++
C7H15C7H1543b 43c
Hetero-Diels-Alder reaction
Entry Conditions Yield (43a/43b/43c)
1 Toluene, 100 oC, 7 h 44% (7:1:1)
2 Toluene, 150 oC, 3 h 14% (4:1:0)
3 Silica gel (500 wt%) Toluene 100 oC 15 h 32% (5:3:0)3 Silica gel (500 wt%), Toluene, 100 C, 15 h 32% (5:3:0)
4 Silica gel (500 wt%), Toluene, 150 oC, 2 h 21% (17:6:1)
Plausible transition states for the hetero-Diels−Alder reaction
Unsuccessful trials
Unsuccessful trials
Me MeAcO
OHHO
CO2MeAcO
Me Me O
OHHO2C
toluene, 22%Me
OH
H OMe O
EtO+Me OH
HOMe
OH
H
46OAc C7H15 OAcC7H1540 47
OHHO2C
HO
Me
Me Me
OH
O
HH
OH
HOMe
O
C7H152 (+)-cytosporolide A
Completion of the total synthesis of (+)-cytosporolide A
The application of o-quinone methide intermediates in total synthesis
Young, R. N. et al. J. Am. Chem. Soc. 1994, 116, 759.
The application of o-quinone methide intermediates in total synthesis
Snider, B. B. et al. J. Org. Chem. 1996, 61, 2839.
The application of o-quinone methide intermediates in total synthesis
Wilson, P. D. et al. Heterocycles, 2004, 62, 445.
Pettus, T. R. R. et al. Org. Lett. 2008, 10, 1477.
The application of o-quinone methide intermediates in total synthesis
Herzon, S. B. et al. J. Am. Chem. Soc. 2010, 132, 2540.
(+)-Cytosporolides A−C were isolated by Che and co-workers in 2010 fromthe fungus Cytospora sp., which was found in a soil sample collected onthe fungus Cytospora sp., which was found in a soil sample collected onthe Qinghai-Tibetan plateau at high altitude. These compounds showedantimicrobial activity against the Gram-positive bacteria Staphylococcusaureus and Streptococcus pneumoniae. Based on NMR experiments, thep p p ,structure of (+)-cytosporolide A was originally assigned as 1, which featuresan unusual peroxylactone skeleton. The absolute stereochemistry wasdetermined by a combination of NOESY data and CD spectra. Later, aystructural revision of this natural product was suggested by Spence andGeorge after they re-evaluated the NMR data. Revised structure 2 consistsof a complicated pentacyclic ring system containing an oxygenatedcaryophyllene skeleton connected to a substituted isochroman ring. Abiogenetic study indicated that (+)-cytosporolide A (2) is derived from ahetero-Diels−Alder reaction between (−)-fuscoatrol A (3) and o-quinone
thid i t di t 5 t d f ( ) CJ 12 373 (4) P t timethide intermediate 5 generated from (+)-CJ-12,373 (4). Putativeprecursor 3 is a known caryophyllene sesquiterpenoid isolated from themarine fungus Humicola fuscoatra, and was also isolated along with
t lid f C t It t t h b t bli h d b Xcytosporolides from Cytospora sp. Its structure has been established by X-ray diffraction data and NMR spectroscopy. The other precursor,isochroman carboxylic acid 4, has been previously isolated from Penicilliumsp as a topoisomerase II inhibitor These known compounds could besp. as a topoisomerase II inhibitor. These known compounds could becoupled to create the intricate structure of cytosporolides in nature.
In summary, we have completed the first total synthesis of (+)-t lid A (2) b i th t ti bi th ti h t Di l Aldcytosporolide A (2) by using the putative biosynthetic hetero-Diels−Alder
reaction between (−)-fuscoatrol A (3) and the o-quinone methidegenerated from (+)-CJ-12,373 (4). To achieve this goal, we synthesized( ) fuscoatrol A (3) from synthetic intermediate 10 in our previous total(−)-fuscoatrol A (3) from synthetic intermediate 10 in our previous totalsynthesis of (+)-pestalotiopsin A (12). Furthermore, (+)-CJ-12,373 (4) wassynthesized through a Kolbe−Schmitt reaction and an oxa-Pictet−Spenglerreaction starting with aryl derivative 18 and chiral epoxide 19 The hetero-reaction starting with aryl derivative 18 and chiral epoxide 19. The hetero-Diels−Alder reaction of diprotected 32 and o-quinone methide precursor 4or 22 showed complete chemo-, regio-, and stereoselectivity to producecycloadduct 33 as a single isomer In this reaction protection of the twocycloadduct 33 as a single isomer. In this reaction, protection of the twohydroxy groups in fuscoatrol A was required. Instead of this, enzymes orother substances may contribute to the assembly of the cytosporolideskeleton in nature. Our total synthesis has validated the biogeneticy ghypothesis and established the structure of cytosporolide A.