Synthesis of podophyllum lignans via an isolable o-quinonoid pyrone

Jones, David W.; Thompson, Adrian M.

doi:10.1039/c39870001797

Cited by 21 publications

(5 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…and 145-148 "C; 6,(400 MHz; CDC1,) 2.11 (1 H, dd, J4. 5 Compound 33 (4a-OH) (64 mg, 70%) remained in the mother liquors. It could be crystallised with difficulty from benzeneether, m.p.…”

Section: Preparation Of the Epoxidementioning

confidence: 99%

See 1 more Smart Citation

Synthesis of (±)-4-deoxypodophyllotoxin, (±)-podophyllotoxin and (±)-epipodophyllotoxin

Jones¹,

Thompson²

1993

J. Chem. Soc., Perkin Trans. 1

Self Cite

View full text Add to dashboard Cite

Leeds LS2 9JT, UK 6,7-Methylenedioxy-l -(3',4',5'-trimethoxyphenyl)-2-benzopyran-3-one 1 and dimethyl fumarate in acetonitrile give mostly the C-2 exo-C0,Me adduct 4 which is transformed in four steps into epipodophyllotoxin 1 Oa. Attempted addition of dimethyl maleate to 1 proceeds with decarboxylation of the putative endo-adduct 11 to a transient o-quinodirnethane which undergoes a highly regioselective 1,5-hydrogen shift to the dihydronaphthalene 14. The alternative 1.5-shifts are shown for the model o-quinodimethane 22 [22 and 22a (arrows)] it being suggested that the shift in 22a is disfavoured by the steric clash shown therein. The product 14 is converted into 4-deoxypodophyllotoxin in an efficient sequence of reactions having as a key step a high-yield epimerisation of the aldehyde 26 to 27. The dihydronaphthalene 14 is also converted into podophyllotoxin 1 Ob (seven steps, 24% overall yield); novel steps include the epimerisation of 35 to 36 and selective oxidation of 34 to 35 using (Bu,Sn),O-I,.In the foregoing paper we described how ( k )-podophyllotoxin could be synthesised by Diels-Alder addition of the isolable pyrone 1 and methyl 4-benzoyloxycrotonote 2. The resulting adduct 3 with a trans C(l)-C(2) stereochemistry is the result of preferred exo-addition of the dienophile C0,Me group. We argued' that improved exo-selectivity at C-2, and endo-selectivity at C-3, would be expected upon addition of dimethyl fumarate to 1. There was every prospect that the resulting adduct 4 (Scheme 1) could be converted into (&)-epipodophyllotoxin using reactions already developed in the preceding paper. The main potential problem with this proposal appeared to be the necessity for selective reduction of the 3-C02Me group in the conversion of 8 into 9. 1 2 3 Unless otherwise specified Ar = 3,4,54rimethoxphenyIReaction of 1 with dimethyl fumarate in boiling benzene gave the adducts 4 and 6 in a ratio of cu. 3.5 :.1. As in the addition of 2 to 1' the ratio of the 2-em-adduct 4 to 2-endo-adduct 6 increased (to cu. 5 : 1) when adduct formation was carried out in acetonitrile at 50°C; pure 4 was then isolated (76%) by crystallisation of the adduct mixture from ethanol. Hydrogenolysis of 4 over palladium (HOAc, 50 "C) proceeded with predominant inversion at C-1 to give 7 in 50% recrystallised yield. Oxidative decarboxylation of 7 Pb(OAc), in THFHOAc (5 : l), 20 "C] gave 8 in 61% yield by crystallisation of the crude product from ether. After some experimentation, 8 and lithium triethylborohydride in dry THF at -20 "C, was induced to give methyl epipodophyllate 9a in 65% yield. Using our ZnC1,4 A molecular sieves/THF procedure this was lactonised in 8 1% yield to ( f )-epipodophyllotoxin 10a. Methyl epipodophyllate !la was readily epimerised at C-4 by HCl-H,O-THF to give methyl podophyllate 9b (63%)' This was lactonised to podophyllotoxin lob using ZnC1, and molecular sieves (75% yield). Thus, both epipodophyllotoxin 10a and podophyllotoxin lob are available from the fumarate adduct 4 of the pyrone 1. C02Me 1 + Me02C Ar 4 X,X...

show abstract

“…and 145-148 "C; 6,(400 MHz; CDC1,) 2.11 (1 H, dd, J4. 5 Compound 33 (4a-OH) (64 mg, 70%) remained in the mother liquors. It could be crystallised with difficulty from benzeneether, m.p.…”

Section: Preparation Of the Epoxidementioning

confidence: 99%

“…143-144 "C; SH(400 MHz; CDCl,) 2.50 (1 H, vbr t, J 7, OH), 3.07 (1 H, td, J 3 , 5 and 13, 3-H), 3.62 (1 H, dd, J5. 5 (5 cm3) was added a 1 mol dmP3 solution of LiEt,BH in THF (0.45 cm3; 4 equiv.) and the solution stirred for 3 h at -76 "C (bath temp.).…”

Section: Preparation Of the Diol 34 (4a-ohmentioning

confidence: 99%

Synthesis of (±)-4-deoxypodophyllotoxin, (±)-podophyllotoxin and (±)-epipodophyllotoxin

Jones¹,

Thompson²

1993

J. Chem. Soc., Perkin Trans. 1

Self Cite

View full text Add to dashboard Cite

show abstract

“…Importantly, the reductive cleavage of the oxa bridge with Raney nickel occurs chemo-and stereospecifically, with retention of the C1 stereochemistry, establishing the 1,2-cis-2,3-trans relationship. When combined with the efficient lactonisation procedure developed by Jones, [53] this provides rapid access to epipodophyllotoxin (6) and, after C4 epimerisation, podophyllotoxin (5) in 19 and 11 % yields from piperonal, respectively (Scheme 14). Scheme 14. Alternatively, acid-catalysed elimination of the oxa bridge leads to the dihydronaphthol 77 and catalytic reduction of this leads to the desired 1,2-cis stereochemistry.…”

Section: C-ring Formation By Cycloaddition Reactionsmentioning

confidence: 99%

Advances in the Synthesis of Aryltetralin Lignan Lactones

Sellars

Steel

2007

Eur J Org Chem

View full text Add to dashboard Cite

Etoposide and tenoposide, derivatives of the aryltetralin lignan lactone podophyllotoxin (5), are clinically important anticancer agents. The structure of podophyllotoxin includes four contiguous chiral centres contained within a stereochemically unstable trans‐fused tetrahydronaphthalene lactone skeleton. Reflecting this challenging structure and important biological role there has been long‐standing interest in developing efficient stereocontrolled syntheses of this class of natural product. This microreview summarises the key developments towards this end focussing on more recent developments both from within the authors group and elsewhere.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

show abstract

“…Catalytic reduction (H2/Pd-C) then gave (15a) which was readily lactonised to 4-deoxypodophyllotoxin (35 min , 66"C, 80%) using our ZnClTTHF-4 %, molecular sieves procedure. 1 Received, 18th March 1988; Corn. 8/01091I…”

Section: O]non-5-enementioning

confidence: 99%