Enantiodivergent Syntheses of Pantolactone and Pantothenic Acid from d-Mannitol

Abstract

Efficient synthetic routes to both the enantiomers of pantolactone and pantothenic acid have been developed starting from D-mannitol-based D-glyceraldehyde acetonide through its conversion into a protected pantoic acid intermediate followed by either cyclization or amide bond formation with a β-amino ester, and subsequent appropriate deprotection. A significant amount of research interest has been focused on the synthesis of pantolactone (1), 1 pantothenic acid (2) ( Figure 1) and analogues 2 due to their biological activity and utility as chiral building blocks and/or chiral auxiliaries for a number of natural products syntheses. 3-5 The biologically active dextrorotatory enantiomer of pantothenic acid (2b), known as vitamin B5, a member of vitamin B complex, plays a key role in the biosynthesis of coenzyme A, releasing energy from carbohydrates, 6 synthesizing steroids, hormones, and the neurotransmitter acetylcholine, 6 and affecting cell division and DNA replication. 7 Pantothenic acid and its supplements have a wide therapeutic role. They are effective in the treatment of acne vulgaris by decreasing sebum secretion 8 and help to lower total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels in blood. 9 Pantothenic acid deficiency results in many abnormalities in health and can be supplied as dietary supplement through natural food sources, benefiting patients suffering from diabetes. The cosmetic industry also routinely use pantothenic acid as an additive in many cosmetic products because of its ability to optimize hydration and wound healing. 10Considering the importance of these compounds, many reports of the chiral synthesis of pantolactone have been documented that involve, among others, (i) chemical 11 and enzymatic 12 resolution of its racemates, (ii) asymmetric hydrogenation of ketopantolactone with rhodium complexes, 13 (iii) Sharpless asymmetric epoxidation of an allylic alcohol 14a and Sharpless asymmetric dihydroxylation of a cyclic silyl enol ether, 14b (iv) α,α-dialkylation of an ephedrine-derived chiral morpholin-3-one ester, 15 (v) enantioselective aldol reaction between a thiosilyl ketene acetal and ethyl glyoxylate, 16 and (vi) asymmetric hydrocyanation with oxynitrilase. 17 On the other hand, pantothenic acid (mostly isolated as its calcium salt) has been chemically synthesized by condensation of pantolactone and the calcium salt of β-alanine. 18 Figure 1 Structure of pantolactone and pantothenic acidA recent report describes the synthesis of pantothenic acid starting from pantolactone through an N-formyl imide intermediate. 19 In spite of these methods available in the literature, the development of expedient and flexible synthetic routes to these molecules in both the enantiomerically pure forms still continues due to the fact that the desired biological activity of a molecule often resides in one enantiomer; the other enantiomer may either be inactive or shows different activity. It is, therefore, conceivable that the biological profiles of both the enantiomers nee...

Asymmetric Synthesis of Pantolactone: Recent Advances

“…In 2012, Banerjee et al designed a synthetic route to chiral PL from (R)-glyceraldehyde acetonide (Scheme 19). [71] This process involved an initial aldol condensation reaction between Dglyceraldehyde acetonide 40 and ethyl isobutyrate 41 in the presence of lithium diisopropylamide at À 78 °C to give hydroxy esters 42 a and 42 b. Subsequently, the hydroxy groups of 42 a and 42 b were benzylated with benzyl bromide in the presence of sodium hydride to produce 43, and reduction of the ester groups with lithium aluminum hydride provided the corresponding alcohol 44 in a quantitative yield.…”