[15186-48-8]  · C6H10O3  · (MW 130.14)

(a fully oxygenated three-carbon chiral electrophile employed for a variety of uses: as a stereochemical probe in nucleophilic additions; as a chiral starting material in total synthesis of sugars and nucleosides, b-lactams, and numerous complex natural products; as a starting material for other chiral building blocks)

Alternate Name: (R)-glyceraldehyde acetonide, D-glyceraldehyde acetonide, 2,3-O-isopropylidene-D-glyceraldehyde.

Physical Data: bp 72-74 °C/30 mmHg; [a]D + 80.1 (c 1.5, benzene)2

Solubility: freely soluble in organic solvents; forms a readily soluble hydrate in water, readily soluble in alcohols as the corresponding hemiacetal.

Analysis of Reagent Purity: analytical methods for determination of enantiomeric purity have been reported.6

Preparative Methods: prepared in two steps from D-mannitol via bis-ketalization to 1,2:5,6-bis-O-(1-methylethylidene)-D-mannitol, followed by oxidative cleavage with sodium periodate in dichloromethane.2 Classically obtained from D-mannitol by bis-ketalization and oxidative cleavage with lead tetraacetate.3 Bis-ketalization has been accomplished under a range of conditions;4 a comparative study of the most commonly employed methods has appeared.5

Purification: distilled under reduced pressure immediately prior to use. Partially polymerized material may be cracked by distillation under reduced pressure at 100 °C.2

Handling, Storage, and Precautions: to help prevent polymerization, anhydrous material is best stored dry at refrigerator or freezer temperatures and distilled immediately prior to use. Incompatible with acids, strong bases, and oxidizing and reducing agents.

As a Stereochemical Probe in Nucleophilic Additions

The reagent has been the compound of choice to probe stereochemistry in nucleophilic additions.1 It exhibits a moderate re enantiofacial preference for the addition of nucleophiles at the carbonyl, affording ‘anti’ products. This preference for addition is predicted by Felkin-Ahn transition-state analysis,7 and stands in contrast to that predicted by the Cram ‘chelate’ model.8 Thus on addition of alkyl-, allyl-, or phenylmagnesium, -lithium, or -zinc, anti/syn ratios ranging from 1:1 to 10:1 were observed (1).9 Curiously, PhTi(i-PrO)3 gave a reversal of the ordinary trend, affording 1:3 and 1:10 anti/syn ratios depending on conditions (2).9

Addition of 2-furyllithium to the reagent afforded a 2:3 anti/syn ratio; on addition of various zinc halides, this very modest si facial preference was overturned, resulting in an almost exclusive re-face addition. The resulting anti-addition product was parlayed into L-ribulose in four steps (3).10

Aldol reactions employing the (4R)-aldehyde also proceed with re enantiofacial preference. In the case of the lithium (Z)-enolate shown, the 3,4-anti-relationship derives from the re face preference for nucleophilic attack, while the 2,3-syn-relationship is predicted by a Zimmerman-Traxler-type11 chair transition state (4).12

The re facial preference displayed by the reagent is enhanced in reactions proceeding through Lewis acid-catalyzed ‘open’ transition states.13b Thus, when reacted with the ketene silyl acetal (5) under zinc iodide catalysis, a 96:4 ratio of products was obtained. The corresponding uncatalyzed reaction led to an 85:15 mixture of the same products in similar yield.13

The reagent's moderate facial preference makes it an ideal choice for illustrating the concept of double asymmetric induction.12 The chiral lithium (Z)-enolate, which also exhibits a moderate enantiofacial preference in reaction with achiral aldehydes, reacts with the reagent to afford a 61:28 ratio of products (6). This ‘mismatched’ case of asymmetric induction indicates that the facial preferences of the two compounds are working at cross-purposes. With the reagent's enantiomer, (4S)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde, a greater than 97:3 ratio of products is obtained, indicating ‘matched’ facial preferences.

An instance of the enantiofacial preference of the reacting partner overwhelming that of the reagent is shown in the case of the reagent's reaction with the tartrate-derived allyl boronates shown. Even in the ‘mismatched’ case, this example of ‘reagent-based’ stereocontrol affords a greater than 10:1 selectivity for the syn product (7).14

As a Chiral Starting Material in Sugar and Nucleoside Synthesis

Various D-sugars have been assembled using the reagent as the primary building block. Among the targets synthesized were 2-deoxyribose,15 2-deoxyribonolactone,13 and 2-methyleneribose,16 Erythrose, erythrulose, 2-deoxyribonolactone, ribonolactone, and lyxonolactone were prepared from addition of electrogenerated methyl dichloroacetate anion to the reagent, followed by subsequent divergent synthetic operations (8).17 In this instance, a greater than 95:5 anti/syn ratio of products was observed for the anion addition.

Hetero-Diels-Alder reactions have been employed with the reagent to afford pyrones that have been elaborated into D-sugars. Thus, 1-methoxy-3-(trimethylsilyloxy)buta-1,3-diene reacted with the reagent under Lewis acid catalysis to afford the pyrone in 72% yield (9). The pyrone was converted to 2-deoxy-D-ribonolactone to establish conclusively the stereochemistry of the newly formed center.18

Various sugars have been constructed in a one-carbon iterative fashion starting from the reagent via condensation with thiazole anion functioning as a carbonyl anion synthon. Following protection, methylation, reduction, and hydrolysis, the resulting a-benzyloxy aldehyde erythrose was obtained (10).19 Products can be resubjected to the sequence, affording protected pentoses through octoses.20 Using this methodology, a synthesis of the octulosonic acid KDO has been reported.21

A strategy for the assembly of various carbasugars and aminocarbasugars employed condensation of the reagent with 2-silyloxyfurans and 2-silyloxy-N-protected pyrroles. The additions proceed in high yield and stereoselectivity to afford a,b-unsaturated lactones and lactams, respectively, which were parlayed into pseudo-D-gulopyranose, pseudo-D-xylofuranose, pseudo-D-gulopyranosylamine, and psuedo-D-xylofuranosylamine (11).22

The HIV reverse-transcriptase inhibitor AZT was prepared via the (Z)-enone resulting from condensation of the reagent with (ethoxycarbonylmethyl)triphenylphosphonium bromide. Cyclization followed by Michael addition of hydrazoic acid afforded the azido lactone shown. Subsequent manipulations provided the target compound (12).23

Access to 2-difluoro-2-deoxy-D-sugars and their derived nucleosides was realized by Reformatsky condensation of the reagent with ethyl bromodifluoroacetate. The resulting difluoro ester was obtained as a 2.5:1 anti/syn mixture. Following separation, the major isomer was transformed into 2-deoxy-2-difluoro-D-ribose. The sugar was then elaborated into various difluorodeoxynucleosides, including the oncolytic Gemzar(tm) (13).24

As a Chiral Starting Material in b-Lactam Synthesis

Various b-lactams have been prepared via [2 + 2] cyclization of ketenes with aryl or benzyl imines derived from the reagent. Thus the para-methoxyphenyl imine derived from condensation of the corresponding aniline and the reagent underwent [2 + 2] cycloadditions with various ketenes to afford b-lactams in moderate yields but with very high stereoselectivity (14).25

A model study for the direct synthesis of peptidyl nucleosides used the benzyl imine of the reagent and the requisite ketene in a [2 + 2] cycloaddition to prepare b-lactams, which were further elaborated through deprotection and oxidation. Again, the stereoselectivity of the [2 + 2] cyclization was very high (15).26

As a Chiral Starting Material in Total Synthesis

Three examples illustrate the widespread use of the reagent as a chiral starting material in total synthesis. In the total synthesis of (+)-CP-263,114, the reagent was treated with the organomagnesium shown and the resulting adduct oxidized to afford the ketone. This was then parlayed into a key vinyl bromide coupling partner in the synthesis via the epoxide (16).27

In the enantioselective synthesis of neocarzinostatin aglycone, the reagent served as the starting point for assembly of the crucial chiral epoxydiyne fragment shown, proceeding via sequential addition of lithium trimethylsilylacetylide, oxidation, and Wittig coupling. Following separation of olefin isomers, the acetonide was unmasked and then monoprotected to reveal the allylic alcohol, which underwent Sharpless asymmetric epoxidation. Reketalization delivered the chiral epoxydiyne (17).28

In a total synthesis of (+)-brefeldin A, the reagent was elaborated into the a,b-enone shown, which participated in a palladium-mediated cyclopentene-forming reaction to afford the exo-olefin. Stereoselectivity in the ring-forming reaction was 3.5:1 in favor of the desired isomer over the alternative trans-cyclopentene. Ozonolysis and reduction of the resulting ketone, followed by protection afforded the MEM ether shown, where all the relevant stereocenters of the final target were established (18).29

The (4R)-aldehyde has also been employed as a chiral starting material in total syntheses of numerous complex targets including prostaglandin PGE1,30 PGF2a,31 PGB1 methyl ester,32 11-(R)-HETE,33 molybdenum cofactor,34 calcimycin class polyether ionophores,35 erythronolide B,36 (+)-9,11-dehydroestrone methyl ester,37 and 11,O(3)-dihydropseudopterolide.38 Total synthesis studies on the nargenicins,39 phorboxazole A,40 macrolactin A,41 neoliacinic acid,42 tetronasin,43 chlorothricolide,44 and the annonacious acetogenins45 have been undertaken using the reagent as a chiral building block or in key stereochemical studies.

As a Source of Other Chiral Building Blocks

The reagent is readily elaborated into several other key chiral building blocks, most notably the corresponding protected glycerol, (4S)-2,2-dimethyl-1,3-dioxolane-4-methanol (1), obtained by sodium borohydride reduction on aqueous solutions of the reagent.2 The 3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-propenoic acid esters 2, mentioned previously, have also found significant use in synthesis.46

Alternative Reagents -Variation of the Ketal Protecting Group

Analogous reagents have been prepared that employ different ketal protecting groups and which offer preparative and handling advantages over the isopropylidene ketal-derived reagent. Notable amongst them are (4R)-2,2-diethyl-1,3-dioxolane-4-carboxaldehyde (3),47 and (2R)-dioxaspiro[4,5]decane-2-carboxaldehyde (4).48 Both have found use in comparable synthetic situations since their introduction, though to a lesser extent than the reagent itself.

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Christopher R. Schmid

Eli Lilly and Company, Indianapolis, Indiana, USA

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