Synthesis of gem-dideuterated tetradecanoic acids and their use in investigating the enzymatic transformation of (Z)-11-tetradecenoic acid into (E,E)-10,12-tetradecadienoic acid.

We report the preparation of the deuterated tetradecanoic acids [2,2,3,3-(2)H(4)]-, [2,2,3,3,10,10-(2)H(6)]-, and [2,2,3,3,13,13-(2)H(6)]-tetradecanoic acids (1, 2, and 3, respectively) and their use to investigate the mechanism of the enzymatic transformation of (Z)-11-tetradecenoic acid into (E,E)-10,12-tetradecadienoic acid. Probes 2 and 3 were prepared from intermediate ketones 7 and 10, which were transformed into the labeled bromides 17 and 18 by reduction with NaBD(4), tosylation of the resulting alcohol, replacement of the tosyloxy group by deuteride with LiAlD(4), hydrolysis, and reaction with N-bromosuccinimide. The resulting bromides were converted into the alpha-acetylenic esters 21 and 22, respectively, and the additional deuterium labels were introduced by reduction of the conjugated triple bond with Mg in deuterated methanol. The same sequence of reactions starting with 11-bromoundecane afforded 27. Saponification of the labeled esters 23, 24, and 27 gave the deuterated acids 2, 3, and 1, respectively. The results of the biochemical experiments showed that C10-H removal, but not elimination of C13-H, was sensitive to deuterium substitution in the transformation of (Z)-11-tetradecenoic acid into (E,E)-10,12-tetradecadienoic acid, which is consistent with the hypothesis that this desaturase reaction involves a first slow, C10-H bond cleavage, with probable formation of an unstable allylic intermediate, followed by a second fast C13-H bond removal and concomitant rearrangement.     

Selective photochemistry at stereogenic metal and ligand centers of cis-[Ru(diphosphine)2(H)2]: preparative, NMR, solid state, and laser flash studies

Three ruthenium complexes Λ-[cis-Ru((R,R)-Me-BPE)(2)(H)(2)] Λ-R,R-Ru1H(2), Δ-[cis-Ru((S,S)-Me-DuPHOS)(2)(H)(2)] Δ-S,S-Ru2H(2), and Λ-[cis-Ru((R,R)-Me-DuPHOS)(2)(H)(2)] Λ-R,R-Ru2H(2) (1 = (Me-BPE)(2), 2 = (Me-DuPHOS)(2)) were characterized by multinuclear NMR and CD spectroscopy in solution and by X-ray crystallography. The chiral ligands allow the full control of stereochemistry and enable mechanistic studies not otherwise available. Oxidative addition of E-H bonds (E = H, B, Si, C) was studied by steady state and laser flash photolysis in the presence of substrates. Steady state photolysis shows formation of single products with one stereoisomer. Solid state structures and circular dichroism spectra reveal a change in configuration at ruthenium for some Δ-S,S-Ru2H(2)/Λ-R,R-Ru2H(2) photoproducts from Λ to Δ (or vice versa) while the configuration for Λ-R,R-Ru1H(2) products remains unchanged as Λ. The X-ray structure of silyl hydride photoproducts suggests a residual H(1)···Si(1) interaction for Δ-[cis-Ru((R,R)-Me-DuPHOS)(2)(Et(2)SiH)(H)] and Δ-[cis-Ru((R,R)-Me-DuPHOS)(2)(PhSiH(2))(H)] but not for their Ru(R,R-BPE)(2) analogues. Molecular structures were also determined for Λ-[cis-Ru((R,R)-Me-BPE)(2)(Bpin)(H)], Λ-[Ru((S,S)-Me-DuPHOS)(2)(η(2)-C(2)H(4))], Δ-[Ru((R,R)-Me-DuPHOS)(2)(η(2)-C(2)H(4))], and trans-[Ru((R,R)-Me-DuPHOS)(2)(C(6)F(5))(H)]. In situ laser photolysis in the presence of p-H(2) generates hyperpolarized NMR spectra because of magnetically inequivalent hydrides; these experiments and low temperature photolysis with D(2) reveal that the loss of hydride ligands is concerted. The reaction intermediates [Ru(DuPHOS)(2)] and [Ru(BPE)(2)] were detected by laser flash photolysis and have spectra consistent with approximate square-planar Ru(0) structures. The rates of their reactions with H(2), D(2), HBpin, and PhSiH(3) were measured by transient kinetics. Rate constants are significantly faster for [Ru(BPE)(2)] than for [Ru(DuPHOS)(2)] and follow the substrate order H(2) > D(2) > PhSiH(3) > HBpin.     

Asymmetric dihydroxylations of 1-substituted (E)- and (Z)-3-methylpent-2-en-4-ynes: full compliance with the Sharpless mnemonic re-established and embellished

Asymmetric dihydroxylations ("ADs") of the pentenynyl chlorides (E)- and (Z)-1 or the pentenyne-based ester (Z)-3 in the presence of (DHQ)(2)-containing ligands delivered diol stereoisomers (2R,3S)-2, (2R,3R)-2, and (3S,4R)-4, respectively. The ADs of pentenynyl ethers (E)-10 and (Z)-12, respectively, have the same stereochemical preference under analogous conditions; these reattributions correct previous reports of the contrary. The Sharpless mnemonic rationalizes all these results implying that each substrate prefers a Sharpless/Norrby instead of a Chapleur orientation in the transition state.     

Synthesis of deuterium-labeled derivatives of dimethylallyl diphosphate

Short practical syntheses for five deuterium-labeled derivatives of dimethylallyl diphosphate (DMAPP) useful for enzymological studies are reported. These include the preparation of the C1-labeled derivatives (R)-[1-2H]3-methylbut-2-enyl diphosphate ((R)-[1-2H]1-OPP) and (S)-[1-2H]3-methylbut-2-enyl diphosphate ((S)-[1-2H]1-OPP), the C2-labeled derivative [2-2H]3-methylbut-2-enyl diphosphate ([2-2H]1-OPP), and the methyl-labeled derivatives (E)-[4,4,4-2H3]3-methylbut-2-enyl diphosphate ((E)-[4,4,4-2H3]1-OPP) and (Z)-[4,4,4-2H3]3-methyl-but-2-enyl diphosphate ((Z)-[4,4,4-2H3]1-OPP).     

Stereochemistry of Delta4 dehydrogenation catalyzed by an ivy (Hedera helix) Delta9 desaturase homolog

The stereochemistry of palmitoyl-ACP Delta(4) desaturase-mediated dehydrogenation has been examined by tracking the fate of deuterium atoms located on stereospecifically monodeuterated substrates-(4S)- and (4R)-[4-(2)H(1)]-palmitoyl-ACP and (5S)- and (5R)-[5-(2)H(1)]-palmitoyl-ACP. It was found that the introduction of the (Z)-double bond between C-4 and C-5 of a palmitoyl substrate occurs with pro-R enantioselectivity-a result which matches that obtained for a closely related homolog-castor stearoyl-ACP Delta(9) desaturase. These data show that despite the difference in regioselectivity between the two enzymes, the stereochemistry of hydrogen removal is conserved.     

Synthesis of unsaturated polyazamacrolides from the ladybird beetle Subcoccinella vigintiquatuorpunctata

The pupal defensive secretion of the ladybird beetle Subcoccinella vigintiquatuorpunctata consists of a mixture of macrocyclic polyamines (polyazamacrolides, PAMLs) dominated by three dimeric, 30-membered bislactones (1, 2, and 3), which represent the three possible head-to-tail combinations of the two building blocks (S)-(Z)-11-(2-hydroxyethylamino)-5-tetradecenoic acid (4) and (S)-(5Z,8Z)-11-(2-hydroxyethylamino)-5,8-tetradecadienoic acid (5). We now report the synthesis of these three alkaloids via a route involving the nucleophilic opening of a chiral aziridine as a common step.     

Stereochemical analysis of isopentenyl diphosphate isomerase type II from Staphylococcus aureus using chemically synthesized (S)- and (R)-[2-2H]isopentenyl diphosphates

[chemical reaction: see text]. To study the catalysis of isopentenyl diphosphate (IPP) isomerase type II from Staphylococcus aureus, which is a flavoprotein catalyzing the interconversion of IPP and dimethylallyl diphosphate, we have chemically synthesized (S)- and (R)-[2-2H]IPP and carried out stereochemical analysis of the reaction. Our results show that the C-2 deprotonation of IPP by this enzyme is pro-R stereospecific, suggesting a similar stereochemical course as the type I enzyme.     

Highly stereoselective iodolactonization of 4,5-allenoic acids--an efficient synthesis of 5-(1'-iodo-1'(Z)-alkenyl)-4,5-dihydro-2(3H)-furanones

In this paper, it is reported that the efficient iodolactonization of 4,5-allenoic acid with I2 in cyclohexane in the presence or absence of K2CO3 afforded 5-(1'-iodo-1'(Z)-alkenyl)-4,5-dihydro-2(3H)-furanones highly stereoselectively. However, the reaction of axially optically active 4,5-allenoic acids (R)-(-)-5 a and (R)-(-)-5 b with I2 afforded the corresponding products with a serious loss of chirality. This problem was solved by conducting the iodolactonization with N-iodosuccinimide in CH2Cl2 in the presence of Cs2CO3; however, the Z/E selectivity is somewhat lower. The pure optically active Z products were prepared by subsequent kinetic resolution with Sonogashira coupling. The reaction of the substrates with a substituent at the 3-position of the starting 4,5-allenoic acids afforded the trans-4,5-disubstituted gamma-butyrolactones as the only products. The reaction of the 4,5-allenoic acids (S)-(+)-1 l, (R)-(-)-1 l, and (S)-(+)-1 m with a center chirality at the 3-position afforded the trans products with very high enantiopurity and up to 98:2 Z/E selectivity regardless of the axial chirality of the allene moiety.     

Synthesis of dideuterated and enantiomers of monodeuterated tridecanoic acids at C-9 and C-10 positions

We report a route for the preparation of mono and dideuterated tridecanoic acids: (R)-[9-(2)H(1)]-, (S)-[9-(2)H(1)]-, (R)-[10-(2)H(1)]-, (S)-[10-(2)H(1)]-, [9,9-(2)H(2)]-, and [10, 10-(2)H(2)]-tridecanoic acids required as probes for biochemical studies on desaturases. The key intermediates in the synthesis of all these probes are ketones 9, which give rise to the corresponding alcohols 10 and 13 by reduction with LiAlD(4) and LiAlH(4), respectively. Derivatization of nondeuterated racemic alcohols 13 with (S)-(+)-9-anthranylmethoxyacetic acid ((S)-(+)-9-AMA) and chromatographic resolution of both diastereoisomers allowed us to determine the absolute configuration of the stereogenic centers by (1)H NMR using an adaptation of the model proposed by Riguera and co-workers which was validated with alcohols of known absolute configuration. Both enantiomeric alcohols (R)- and (S)-13 were recovered by reduction of each diastereomeric ester with LiAlH(4). Mesylation of alcohols 10 and 13 followed by nucleophilic substitution by LiAlD(4) generated the saturated methoxymethyl derivatives 12 and 16, respectively. Final deprotection and Jones oxidation of the resulting alcohols afforded the above deuterated tridecanoic acids.     

A stereocontrolled synthesis of (R,Z)- and (R,E)-14-methyl-8-hexadecenals (trogodermal), the sex pheromones of trogoderma species

A stereocontrolled synthesis of (R,Z)- and (R,E)-14-methyl-8-hexadecenals with high stereochemical purity in both absolute and geometrical configurations was achieved by the use of the S_N2 type ring-opening reaction of (S)-β-methyl-β-propiolactone for the construction of the (R)-configurations, adn the cis-addition of diorganocuprate to acetylene adn the S_N2′ type ring-opening reaction of δ-vinyl-δ-valerolactone for the introduction of (Z)- and (E)-double bonds, respectively.     

基于半刚性乳酸衍生物的单一手性配位聚合物的合成、 结构与性质

在溶剂热反应条件下, 用预先合成的乳酸衍生物(R)-H₂CBA和(S)-H₂CBA分别与含氮辅助配体(E)-1,2-二(4-吡啶基)乙烯(DPEE)和1,4-二(1H-咪唑-1-基)苯(1,4-DIB)组合, 制备出2对不同结构的单一手性配位聚合物[Cd₂((R)-CBA)₂(DPEE)(H₂O)₂]_n(1-D), [Cd₂((S)- CBA)₂(DPEE)(H₂O)₂]_n(1-L), [Cd((R)-CBA)(1,4-DIB)]·H₂O(2-D)和[Cd((S)-CBA)(1,4-DIB)]·H₂O(2-L). 其中1-D和1-L是由梯形Cd-CBA链和DPEE配体连接成的二维框架结构; 而2-D和2-L是三维超分子框架结构, 包含3种不同类型的对映手性螺旋链. 对上述化合物进行了粉末X射线衍射、 热重分析和圆二色谱分析, 并对其荧光性质进行了讨论.     

一种含阻转异构体的二羧酸铀(Ⅵ)有机-金属配合物

Uranium(Ⅵ) complex [UO₂((R，S)-1，1′-binaphthylene-2，2′-dicarboxylate)(H₂O)] was obtained by the hydrothermal treatment of UO₂(NO₃)₂·6H₂O with (R，S)-1，1′-binaphthylene-2，2′-dicarboxylic acid(BCA) (L) in water at 180 ℃ in Pyrex tube. The crystal belongs to monoclinic system， space group C2/c， with a=1.640 3(3) nm， b=1.196 7(2) nm， c=1.066 3(17) nm， β=104.412(4)°， V=2.027 2(6) nm³， Z=4. CCDC: 659617.     

Substrate-dependent stereochemical course of the (Z)-13-desaturation catalyzed by the processionary moth multifunctional desaturase

The stereochemical course of the Delta13 desaturation involved in the biosynthesis of Thaumetopoea pityocampa sex pheromone was studied using stereotopically labeled and tagged palmitic acids as metabolic probes. In the synthetic pathway, a functionalized acetylene common synthon was used for introducing the four deuterium tags. Further coupling of the tetradeuterated synthon to the appropriated alkynol and a double chemoenzymatic strategy to resolve the alcohol functionality allowed one to obtain the enantiomerically enriched probes used in the mechanistic studies. Mass spectrometric analyses of extracts from tissues cultured with each probe revealed that removal of the C13 and C14 hydrogens in 11-hexadecynoate and (Z)-11-hexadecenoate are pro-(R)- and pro-(S)-specific syn-dehydrogenation processes, respectively. This finding constitutes the first example in the literature of an enzymatic (Z)-desaturation exhibiting a substrate-dependent stereochemical course.     

Assay for the enantiomeric analysis of [2H1]-fluoroacetic acid: insight into the stereochemical course of fluorination during fluorometabolite biosynthesis in streptomyces cattleya

A sensitive method for the configurational analysis of (R)- and (S)-[2H1]-fluoroacetate has been developed using 2H[1H]-NMR in a chiral liquid crystalline solvent. This has enabled biosynthetic experiments to be conducted which reveal stereochemical details on biological fluorination occurring during the biosynthesis of fluoroacetate and 4-fluorothreonine in the bacterium Streptomyces cattleya. In particular, feeding experiments to S. cattleya with isotopically labeled (1R, 2R)- and (1S, 2R)-[1-2H1]-glycerol 3d and 3e and [2,3-2H(4)]-succinate 4a gave rise to samples of enantiomerically enriched [2-2H1]-fluoroacetates 1a. The predominant enantiomer resulting from each experiment suggests that the stereochemical course of biological fluorination takes place with an overall retention of configuration between a glycolytic intermediate and fluoroacetate 1. Consequently, this outcome suggests that the stereochemical course of the recently identified fluorinase enzyme which mediates a reaction between fluoride ion and S-adenosyl-l-methionine (SAM), occurs with an inversion of configuration.     

Synthesis of (2S,3S)-[3-(2)H1]-4-methyleneglutamic acid and (2S,3R)-[2,3-(2)H2]-4-methyleneglutamic acid

(2S,3S)-[3-(2)H1]-4-Methyleneglutamic acid 1a and (2S,3R)-[2,3-(2)H2]-4-methyleneglutamic acid 1b have been synthesised for use in biosynthetic and metabolic studies.     

Novel oximato-bridged platinum(II) di- and trimer(s): synthetic, structural, and in vitro anticancer activity studies

Novel platinum complexes of trans geometry [PtCl(2){(Z)-R(H)C═NOH}(2)] [R = Me (1), Et (3)] and [PtCl(2){(E)-R(H)C═NOH}{(Z)-R(H)C═NOH}] [R = Me (2), Et (4)] as well as the classic trans-[PtCl(2)(R(2)C═NOH)(2)] [R = Me, Et] were reacted with an equivalent amount of silver acetate in acetone solution at ambient temperature, resulting in formation of unprecedented head-to-tail-oriented oximato-bridged dimers [PtCl{μ-(Z)-R(H)C═NO}{(Z)-R(H)C═NOH}](2) [R = Me (5), Et (7)], [PtCl{μ-(Z)-R(H)C═NO}{(E)-R(H)C═NOH}](2) [R = Me (6), Et (8)], and [PtCl(μ-R(2)C═NO)(R(2)C═NOH)](2) [R = Me (9), Et (10)], correspondingly. The dimeric species feature a unique six-membered diplatinacycle and represent the first example of oxime ligands coordinated to platinum via the oxygen atom. All complexes were characterized by elemental analyses, electrospray ionization mass spectrometry, IR and multinuclear ((1)H, (13)C, and (195)Pt) NMR spectroscopy, as well as X-ray diffraction in the cases of dimers 6 and 9. Furthermore, the crystal and molecular structures of a trimeric oximato-bridged complex 11 comprising three platinum units connected in a chain way were established. The cytotoxicity of both dimers and the respective monomers was comparatively evaluated in three human cancer cell lines: cisplatin-sensitive CH1 cells as well as cisplatin-resistant SW480 and A549 cells, whereupon structure-activity relationships were drawn. Thus, it was found that dimerization results in a substantial (up to 7-fold) improvement of IC(50) values of (aldoxime)Pt(II) compounds, whereas for the analogous complexes featuring ketoxime ligands the reverse trend was observed. Remarkably, the novel dimers yielded no cross-resistance with cisplatin in SW480 cells, exhibiting up to 2-fold enhanced cytotoxicity in comparison with the CH1 cell line and thereby possessing a promising potential to overcome resistance toward platinum anticancer drugs. The latter point was also confirmed by investigating the potency of apoptosis induction in the case of one monomer as well as one dimer; the investigated complexes proved to be strong apoptotic agents which could induce cell death even in the cisplatin-resistant SW480 cell line.     

Chiral phosphane alkenes (PALs): simple synthesis, applications in catalysis, and functional hemilability

A simple synthesis of a chiral phosphane alkene (PAL) involves: 1) palladium-catalyzed Suzuki coupling of 10-bromo-5H-dibenzo[a,d]cyclohepten-5-ol (1) with phenylboronic acid to give quantitatively 10-phenyl-5H-dibenzo[a,d]cyclohepten-5-ol (2); 2) reaction of 2 with Ph(2)PCl under acidic conditions to give a racemic mixture of the phosphane oxide (10-phenyl-5H-dibenzo[a,d]cyclohepten-5-yl)diphenylphosphane oxide ((Ph)troppo(Ph), 3), which is separated into enantiomers by using high-pressure liquid chromatography (HPLC) on a chiral column; 3) reduction with trichlorosilane to give the enantiomerically pure phosphanes (R)- and (S)-(10-phenyl-5H-dibenzo[a,d]cyclohepten-5-yl)diphenylphosphane ((Ph)tropp(Ph), 4). This highly rigid, concave-shaped ligand serves as a bidentate ligand in Rh(I) and Ir(I) complexes. Catalysts prepared from [Rh(2)(mu(2)-Cl)(2)(C(2)H(4))(4)] and (S)-4 have allowed the efficient enantioselective 1,4-addition of arylboronic acids to alpha,beta-unsaturated carbonyls (Hayashi-Miyaura reaction) (5-0.1 mol % catalyst, up to 95% ee). The iridium complex (S,S)-[Ir((Ph)tropp(Ph))(2)]OTf ((S,S)-6; OTf=SO(3)CF(3)) has been used as a catalyst in the hydrogenation of various nonfunctionalized and functionalized olefins (turnover frequencies (TOFs) of up to 4000 h(-1)) and moderate enantiomeric excesses have been achieved (up to 67% ee). [Ir((Ph)tropp(Ph))(2)]OTf reversibly takes up three equivalents of H(2). The highly reactive octahedral [Ir(H)(2)(OTf)(CH(2)Cl(2))(H(2)-(Ph)tropp(Ph))(2)] could be isolated and contains two hydrogenated monodentate H(2)-(Ph)tropp(Ph) phosphanes, one CH(2)Cl(2) molecule, one triflate anion, and two hydrides. Based on this structure and extensive NMR spectroscopic studies, a mechanism for the hydrogenation reactions is proposed.     

Enantioselectivity in Ni(II) Schiff-base complexes derived from amino-acids and (S)-o-N-(N-benzylprolyl)aminobenzophenone: molecular structure of several chiral Ni(II) Schiff-base complexes, circular dichroism and molecular mechanics studies

Several Ni(II) complexes derived from (S)-o-N-(N-benzylprolyl)aminobenzophenone ((S)-BBP) and amino acids of general formula [Ni((S)-BBP-L-(or D-)-aa)] were prepared. The crystal and molecular structures of [Ni((S)-BBP-Gly)], [Ni((S)-BBP-L-Ser)] and [Ni((S)-BBP-L-aaIm)](aaIm =L-2-amino-3-(imidazol-1-yl)propanoate were determined by X-ray diffraction analysis. In the three complexes the nickel atoms display a square-planar coordination and the overall structure around the metal indicates that the entire Schiff-base ligands form quite rigid frameworks. Molecular mechanics calculations were carried out for complexes [Ni((S)-BBP-Gly)], [Ni((S)-BBP-Ser)] and [Ni((S)-BBP-aaIm)] containing either the L- or D-amino acid forms, and the factors controlling the stereoselectivity are discussed. Several other [Ni((S)-BBP-L-aa)] complexes are also prepared and their circular dichroism spectra in solution and of the solids dispersed in KBr disks are measured and discussed. In agreement with other studies in solution with similar [Ni((S)-BBP-aa)] complexes, the Cotton effects for the bands with lambda(max) at 520--530 nm are positive when the amino acids have the L-configuration at the alpha-carbon. The same is observed in this work for the solid-state CD spectra of all compounds.     

Rotation of the exo-methylene group of (R)-3-methylitaconate catalyzed by coenzyme B(12)-dependent 2-methyleneglutarate mutase from Eubacterium barkeri

2-Methyleneglutarate mutase from the anaerobe Eubacterium (Clostridium) barkeri is an adenosylcobalamin (coenzyme B(12))-dependent enzyme that catalyzes the equilibration of 2-methyleneglutarate with (R)-3-methylitaconate. Two possibilities for the mechanism of the carbon skeleton rearrangement of the substrate-derived radical to the product-related radical are considered. In both mechanisms an acrylate group migrates from C-3 of 2-methyleneglutarate to C-4. In the "addition-elimination" mechanism this 1,2-shift occurs via an intermediate, a 1-methylenecyclopropane-1,2-dicarboxylate radical, in which the migrating acrylate is simultaneously attached to both C-3 and C-4. In the "fragmentation-recombination" mechanism the migrating group, a 2-acrylyl radical, becomes detached from C-3 before it starts bonding to C-4. In an attempt to distinguish between these two possibilities we have investigated the action of 2-methyleneglutarate mutase on the stereospecifically deuterated substrates (Z)-3-methyl[2'-(2)H(1)]itaconate and (Z)-3-[2'-(2)H(1),methyl-(2)H(3)]methylitaconate. The enzyme catalyzes the equilibration of both compounds with their corresponding E-isomers and with a 1:1 mixture of the corresponding (E)- and (Z)-2-methylene[2'-(2)H(1)]glutarates, as shown by monitoring of the reactions with (1)H and (2)H NMR. In the initial phase of the enzyme-catalyzed equilibration a significant excess (8-11%) of (E)-3-methyl[2'-(2)H(1)]itaconate over its equilibrium value was observed ("E-overshoot"). The E-overshoot was only 3-4% with (Z)-3-[2'-(2)H(1),methyl-(2)H(3)]methylitaconate because the presence of the deuterated methyl group raises the energy barrier from 3-methylitaconate to the corresponding radical. The overshoot is explained by postulating that the migrating acrylate group has to overcome an additional energy barrier from the state leading back to the substrate-derived radical to the state leading forward to the product-related radical. It is concluded that the fragmentation-recombination mechanism can provide an explanation for the results in terms of an additional energy barrier, despite the higher calculated activation energy for this pathway.     

Synthesis of (E)-4-hydroxydimethylallyl diphosphate. An intermediate in the methyl erythritol phosphate branch of the isoprenoid pathway

The syntheses of (E)-1-hydroxy-2-methyl-2-buten-4-yl diphosphate ((E)-4-hydroxydimethylallyl diphosphate, HDMAPP), an intermediate in the methyl erythritol phosphate pathway, and (E)-[4-(2)H]HDMAPP were accomplished in two steps from (E)-4-chloro-2-methyl-2-butenal. The synthetic route is easily adaptable for the facile incorporation of tritium at C-4 of the diphosphate.