Asymmetric total synthesis of an A-ring precursor to hormonally active 1.alpha.,25-dihydroxyvitamin D3

Abstract

A new sulfinyl orthoester has been designed and used effectively in one-flask syntheses of dienoate esters from allylic alcohols; this new method as well as a highly stereocontrolled [2 + 4]-cycloaddition are applied to synthesis of la,25-dihydroxyvitamin D3.The Diels-Alder reaction certainly is one of the very best methods for controlling stereochemistry while forming two carbon-carbon bonds in one operation.1 23Attempts to use 2-pyrones and to isolate the initial Diels-Alder cycloadducts have regularly been thwarted because of facile cycloreversion involving spontaneous loss of C02 from the bicyclic lactone adducts.2,3 We have discovered, however, that 3-sulfinyl-4 and 3-sulfonyl-2-pyrones5 react with en-(1) (a) Helmchen, G.;

The [4 + 2] Cycloaddition of 2‐Pyrone in Total Synthesis

“…A complementary approach as shown in Scheme was also reported later by Posner [32b]. Diels‐Alder reaction of enantiomerically pure 2‐pyrone ( S )‐lactate 112 and benzyl vinyl 113 ether promoted by Lewis acidic NMR shift reagent (–)‐Pr(hfc) 3 provided bicyclic lactone 114 in 98% yield in 98: 2 dr. Methanolysis of lactone 114 followed by the decarboxylation and double bond migration by N ‐methylmorpholine under high pressure produced cyclohexenol benzyl ether 116 .…”

“…These findings encouraged Posner and his coworkers to apply the Diels‐Alder reaction of 2‐pyrone in the efficient preparations of calcitirol and its analogs …”

“…As illustrated in Scheme ,[32a] the Diels‐Alder reaction of pyrone sulfone 23 and chiral alkyl vinyl ether 72a was promoted by Lewis acid MAD, generating bicyclic lactone 73a in excellent yield and stereoselectivity (93% yield, endo / exo = 98/2). Methanolysis of 73a , then removal of the sulfone group, followed by the isomerization of the olefin by DBU afforded the conjugated enoate ester 75b in 90% yield.…”

“…After further considerable investigation by Posner laboratory, it was found that equivalent amount of BINOL/titanium complex could promote the Diels‐Alder reaction of methyl 2‐pyrone 3‐carboxylate 25 and vinyl ether 117 , affording the cycloadduct 118 in excellent yield and high ee (Scheme ) [32c]. From cycloadduct 118 , the key intermediate 108 for the synthesis of 1α‐hydroxyvitamine D 3 compounds could be prepared in 3—4 steps.…”

Methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide) (MAD)

“…As a key step in the total synthesis of an A-ring precursor 45 to 1α,25-dihydroxyvitamin D 3 , an inverse-electron-demand Diels-Alder reaction was catalysed by MAD 1 to promote cycloaddition between pyrone sulfone 42 and the vinyl ether (S)-43 (Scheme 11) [18].…”