Synthetic Routes to Methylerythritol Phosphate Pathway Intermediates and Downstream Isoprenoids

Abstract

Isoprenoids constitute the largest class of natural products with greater than 55,000 identified members. They play essential roles in maintaining proper cellular function leading to maintenance of human health, plant defense mechanisms against predators, and are often exploited for their beneficial properties in the pharmaceutical and nutraceutical industries. Most impressively, all known isoprenoids are derived from one of two C₅-precursors, isopentenyl diphosphate (IPP) or dimethylallyl diphosphate (DMAPP). In order to study the enzyme transformations leading to the extensive structural diversity found within this class of compounds there must be access to the substrates. Sometimes, intermediates within a biological pathway can be isolated and used directly to study enzyme/pathway function. However, the primary route to most of the isoprenoid intermediates is through chemical catalysis. As such, this review provides the first exhaustive examination of synthetic routes to isoprenoid and isoprenoid precursors with particular emphasis on the syntheses of intermediates found as part of the 2C-methylerythritol 4-phosphate (MEP) pathway. In addition, representative syntheses are presented for the monoterpenes (C₁₀), sesquiterpenes (C₁₅), diterpenes (C₂₀), triterpenes (C₃₀) and tetraterpenes (C₄₀). Finally, in some instances, the synthetic routes to substrate analogs found both within the MEP pathway and downstream isoprenoids are examined.

Keywords: Enzyme mechanism; MEP pathway.; isoprenoids; terpenes.

Fig. (1)

Examples of naturally occurring acyclic, monocylic and bicyclic monoterpenes.

Fig. (2)

Common chemical transformations from (+)-limonene and (+)-camphor.

Scheme. (1)

The MEP pathway to isoprenoids.

Scheme. (2)

Estramareix synthetic route to DX.

Scheme. (3)

Generalized synthetic routes to enantiomerically pure DX.

Scheme. (4)

Giner’s syntheses of C-1 isotopically labeled DX.

Scheme. (5)

Blagg and Poulter’s synthetic routes to both DX and DXP from D-threitol.

Scheme. (6)

Cox’s synthetic routes to DXP from the propargyl alcohol.

Scheme. (7)

O’Hagan’s synthetic route to CF-DX.

Scheme. (8)

Fox and Poulter’s synthesis to CF-DXP from a D-threitol derivative.

Scheme. (9)

Fox and Poulter’s synthesis of CF2-DXP from the D-tartrate derivative.

Scheme. (10)

Rohmer’s synthesis of ME from 3-methylfuran-2(5H)-one or citraconic anhydride.

Scheme. (11)

Fontana’s synthesis of ME from dimethylfumarate.

Scheme. (12)

Taylor’s synthesis of ME from 4-methyl 1,2-dioxine.

Scheme. (13)

Hoeffler’s synthesis of ME from 1,2-O-isopropylidene-α-D-xylofuranose.

Scheme. (14)

Coates’ synthesis of ME from D-arabitol.

Scheme. (15)

Koppisch and Poulter’s synthesis of MEP from 1, 2-propane diol.

Scheme. (16)

Coates’synthesis of MEP from D-arabitol.

Scheme. (17)

Koumbis’ synthesis of MEP from D-arabinose acetonide.

Scheme. (18)

Koppisch and Poulter’s synthesis of CDPME from MEP and CMP.

Scheme. (19)

Coates’synthesis of CDP-ME2P.

Scheme. (20)

Giner and Ferris synthesis of cMEPP.

Scheme. (21)

Coates’ synthesis of cMEPP from the protected D-threitol.

Scheme. (22)

Hecht’s synthesis of HDMAPP and isotopomers from the vinyloxirane.

Scheme. (23)

Fox and Poulter’s synthesis of HDMAPP via the chloroaldehyde intermediate.

Scheme. (24)

Davisson’s synthesis of both IPP and DMAPP.

Scheme. (25)

Fallis’ synthesis of both β-pinene (121) and α-pinene (122).

Scheme. (26)

Snider’s synthesis of both β-pinene and chrysanthenone.

Scheme. (27)

Johnson’s synthesis of a stereoisomeric mixture of 3-carene.

Scheme. (28)

Gibbs’ synthesis of 3-VFPP.

Scheme. (29)

Gibbs’ alternate synthetic route to 7-VFPP.

Scheme. (30)

Schull’s synthesis of digeranyl-substituted bisphosphonate.

Scheme. (31)

Coates’synthesis of aza-GGPP.

Scheme. (32)

Mu’s synthesis of 3-PhGGPP.

Scheme. (33)

Cornforth’s synthesis of squalene.

Scheme. (34)

Petersen’s synthesis of squalene using a Claisen rearrangement.

Scheme. (35)

White’s synthesis of C₃₄ botrycoccene.

Scheme. (36)

Shen’s synthesis of lycopene.

Scheme. (37)

Khachik and Chang’s synthesis of lutein.