Total Synthesis of Dolabriferol†C by a Highly Stereoselective One-Pot Coupling of a meso-3,7-Diketone with Two Chiral Aldehydes.

Total synthesis of the noncontiguous polypropionate dolabriferol C was achieved by retro-Claisen fragmentation of its putative contiguous precursor under mild conditions, thus establishing the former as a plausible isolation artifact. The precursor was prepared by a novel one-pot three-component bisaldol coupling of a meso (Z,Z)-bisenolate (generated in situ from a 3,7-diketone) with two enantioenriched aldehydes to set the absolute configuration of seven stereocenters in one step. The first aldol reaction proceeded with enantioselective desymmetrization of the bisenolate to produce an enantiomerically pure enolate-aldolate. Quenching at this stage enabled a streamlined synthesis of dolabriferol. Addition of a racemic aldehyde to the enolate-aldolate resulted in aldol coupling with kinetic resolution of the "matched" aldehyde; overall, a sequential enantiotopic-group-selective (SEGS) bisaldol reaction. Because the desired adduct results from the "mismatched" aldol reaction, use of enantioenriched aldehyde was required.

On the Origin of Dolabriferol: Total Synthesis via Its Putative Contiguous Precursor.

The putative contiguous polypropionate precursor of dolabriferol was synthesized using as the key step a rationally designed enantiomer-selective aldol coupling (i.e., with kinetic resolution) of a racemic C1-C8 ketone fragment with an enantiopure C9-C15 aldehyde fragment. When exposed to alumina, the precursor was cleanly transformed into dolabriferol via a regioselective retro-Claisen fragmentation, providing the first experimental evidence for the proposed origin of dolabriferol and demonstrating that it is a plausible isolation artifact.

A systematic study of the effects of relative configuration, protecting group, and enolate type on the diastereoselectivities of aldol reactions of a chiral ethyl ketone with 2-methylpropanal.

The diastereoselectivities of aldol reactions of 2-methylpropanal with various enolates of 5-O-methoxymethyl and 5-O-triethylsilyl derivatives of the four racemic diastereomers of 6-(2-ethyl-1,3-dioxolan-2-yl)-5-hydroxy-4-methylheptan-3-one are reported. Reactions of the (E)-enol dicyclohexylborinates, (Z)-enol 9-BBN borinates (i.e., 9-((Z)-enoxy)-9-borabicyclo[3.3.1]nonanes), Li (E)-enolates, Li (Z)-enolates, and Ti(IV) (Z)-enolates were examined. Boron and Li enolates were prepared by standard methods, but Ti(IV) enolates were obtained via transmetalation of the Li (Z)-enolates by reaction with TiCln(Oi-Pr)(4-n) (n = 0-2). Aldol relative topicity (simple diastereoselectivity) was strongly correlated to the enolate geometry: anti aldols from (E)-enolates and syn aldols from (Z)-enolates. However, for each enolate type, the diastereoface selectivities varied widely (by factors of 5-400) with the relative configuration and nature of the C5 protecting group in the 8 starting ketones. Plausible transition state models are postulated to rationalize some of these observations. The relative configurations for the complete set of 16 diastereomeric 2-(2-ethyl-1,3-dioxolan-2-yl)-7-hydroxy-3-(methoxymethoxy)-4,6,8-trimethylnonan-5-one aldol adducts were confirmed by NMR analysis of 12 acetonide derivatives prepared from the corresponding 5,7-syn diols. Examination of the NMR data for the above set of aldol adducts revealed consistent trends that were exploited to assign the relative configurations of 13 diastereomeric 2-(2-ethyl-1,3-dioxolan-2-yl)-7-hydroxy-3-(triethylsilyloxy)-4,6,8-trimethylnonan-5-one aldol adducts.

Total synthesis of muamvatin.

Enantioselective total synthesis of muamvatin was achieved by ring-chain tautomerization of an acyclic derivative assembled by sequential substrate-controlled stereoselective aldol reactions of a chiral ketone with two achiral aldehydes. Although the trioxaadamantane tautomer was shown to be thermodynamically more stable than alternative forms, the kinetic barrier to cyclization was significant. This observation raises doubts about the proposed formation of muamvatin as an artifact of isolation.

Aldol reactions with kinetic resolution: scope and limitations of ketal- and dithioketal-protected ß-ketoaldehydes.

The multiplicativity rule suggests that aldol coupling of chiral reactants will proceed with substantial mutual kinetic enantioselection (MKE) (racemic reactants) or via a highly enantioselective kinetic resolution (KR) (one enantiopure reactant) if the relative topicity is highly selective and the ketone enolate and aldehyde each have high diastereoface selectivity. The scope and limitations of that paradigm were explored by determining the stereoselectivities of aldol reactions of ketone 1a (known to give 3,5-trans aldol adducts with high selectivity) with a series of ketal- and dithioketal-protected ß-ketoaldehydes (±)-5 (predicted to have high Felkin diastereoface selectivity). Using racemic reactants, all reactions of the (c-Hex)(2)B enolates (highly anti-selective relative topicity) were remarkably selective and gave the 3,5-trans-3,1"-anti-1",2"-syn adduct, one of eight possible diastereomers, via a diastereoselective (dr > 20) preferential reaction (MKE > 17) of like reactant enantiomers [i.e., (3R)-1a + (R)-5 and (3S)-1a + (S)-5]. Reactions of the corresponding Ti(IV) "ate" enolates (anticipated syn-selective relative topicity) were much less selective, and only those of MOM-protected 1a with dithiolane-protected (±)-5 (i.e., X = S, n = 1) gave high selectivity in favor of the 3,5-trans-3,1"-syn-1",2"-syn adduct via a diastereoselective (dr > 20) preferential reaction (MKE ≥ 6) of unlike reactant enantiomers [i.e., (3R)-1a + (S)-5 and (3S)-1a + (R)-5]. Analogous reactions of the (c-Hex)(2)B and Ti(IV) "ate" enolates of enantiopure (+)-1a (R = MOM) with (±)-5c (R(2) = Me, X = S, n = 1) occurred with KR to give the corresponding enantiopure adducts with the expected stereoselectivity. The adducts have applications in polyproionate synthesis.

On the origin of siphonariid polypropionates: total synthesis of caloundrin B and its isomerization to siphonarin B.

Enantioselective synthesis of the enantiomer of caloundrin B was achieved by strategic aldol coupling of an enantiopure trioxaadamantane-containing ketone with a racemic pyrone-containing aldehyde via kinetic resolution. In the presence of imidazole, ent-caloundrin B is cleanly isomerized to ent-siphonarin B confirming the proposed structure and absolute configuration for caloundrin B and establishing that it is a plausible biosynthetic product from which siphonarin B and baconipyrones A and C can originate.

The thiopyran route to polypropionates.

The strategic use of thiopyran templates to facilitate polypropionate synthesis was first demonstrated in Woodward's landmark total synthesis of erythromycin A in 1981 where the topology of a fused bicyclic system was exploited. In the ensuing three decades, various alternative strategic applications of thiopyran motifs to achieve key stereoselective transformations have emerged including, inter alia, unique substrates for chemoenzymatic syntheses, surrogates for 3-pentanone in enantioselective aldol reactions, and templates for enantiotopic group selective reactions. This review summarizes these developments.

Total synthesis of depsilairdin.

The total synthesis of depsilairdin, a host-selective phytotoxin isolated from Leptosphaeria maculans (the causal agent of blackleg disease of oilseed Brassicas), has been achieved by N-terminal extension of a suitably protected derivative of the hitherto unknown amino acid (2S,3S,4R)-3,4-dihydroxy-3-methyl-proline (Dhmp) followed by esterification with lairdinol A. The latter esterification, complicated by the sterically hindered nature of the carboxyl group, was accomplished by a novel method involving reaction of the 1-hydroxybenzotriazole (HOBt) derived active ester with the bromomagnesium alkoxide of lairdinol A. Three depsilairdin analogues were also prepared by replacing the Dhmp residue with L-proline and cis- and trans-4-hydroxy-L-proline. Phytotoxicity assays showed that the analogues were nontoxic to both blackleg-susceptible (brown mustard) and -resistant (canola) plants, suggesting that the presence of the Dhmp residue in depsilairdin is important for its host-selective toxicity toward brown mustard.

On the origin of siphonariid polypropionates: total synthesis of baconipyrone A, baconipyrone C, and siphonarin B via their putative common precursor.

The hypothesis that siphonariid polypropionates originate from nonenzymatic processes on acyclic biosynthetic precursors was tested by examining the properties of the putative common precursor for the S. zelandica decapropionates siphonarin B, caloundrin B, baconipyrone A, and baconipyrone C, i.e., (4S,5S,6S,8RS,10S,11S,12R,14R)-14-(6-ethyl-3,5-dimethyl-4-oxo-4H-pyran-2-yl)-5,11-dihydroxy-4,6,8,10,12-pentamethylpentadecane-3,7,9,13-tetraone. The first synthesis of such a precursor was achieved in an efficient and fully enantioselective manner using a thiopyran-based strategy for polypropionate synthesis. This putative precursor, a complex mixture of ring-chain and keto-enol tautomers, was kinetically stable and isomerized exceedingly slowly to the thermodynamically more stable siphonarin B. In the presence of imidazole, the mixture reached apparent equilibrium within several hours giving siphonarin B as the predominant component (ca. 70%), thereby constituting its enantioselective total synthesis. In the presence of alumina, both siphonarin B and the dihydroxytetraone precursor underwent retro-Claisen rearrangements (via a hemiacetal tautomer) to give baconipyrones A and C among other products. This is the first total synthesis of baconipyrone A and "biomimetic" synthesis of baconipyrone C. Control experiments suggested that baconipyrone A was produced in an unprecedented cascade process where the intermediate enol(ate) of the retro-Claisen rearrangement was directly engaged in aldol cyclization while baconipyrone C resulted from simple ketonization of the enol(ate). These experiments provide the first unambiguous demonstration that the baconipyrones are plausible isolation artifacts and suggest they are most likely derived from siphonarins rather than an "acyclic" precursor. Caloundrin B was not detected among the products from any of the isomerization experiments, suggesting the possibility that it is an unstable biosynthetic product.

Rational design of aldol reactions that proceed via kinetic resolution with switchable enantioselectivity.

The stereoselectivity of aldol reactions of chiral reactants can be factorized into to three stereocontrol elements: the diastereoface selectivities of the ketone enol(ate) and aldehyde and the relative topicity of the coupling. Application of the multiplicativity rule to these elements leads to the prediction that kinetic resolution (KR) should be possible if all three stereocontrol elements are strongly biased. As a corollary, the enantioselectivity of the kinetic resolution should be switchable by a change in the sense of selectivity of any of the stereocontrol elements. This hypothesis was tested using aldehyde and ketone reactants with high diastereoface selectivities and developing reaction conditions that strongly favor either syn or anti relative topicity. The aldehyde 2 undergoes aldol reactions with near-exclusive Felkin diastereoface selectivity, and hydroxy-protected derivatives of ketone 1 (R = MOM, Et(3)Si, or Ac) undergo aldol reactions with high diastereoface selectivity to give 3,5-trans adducts. High levels of anti and syn relative topicity were obtained with dicyclohexylboron enolates and Ti(O(i)Pr)(4)Li "ate" enolates, respectively. Using these enolates, aldol reactions of (+/-)-2 with (+/-)-1 gave two of the eight possible diastereomeric adducts (3 from a diastereoselective like combination of reactant enantiomers and 4 from a diastereoselective unlike combination) predominantly (>95% of the adducts) in ratios of 0.05-20:1; boron enolates favored the like reaction (3:4, 15-20:1) and Ti "ate" enolates favored the unlike reaction (3:4, 1:10-20). Under these conditions, the ratio of like and unlike products is a measure of the mutual kinetic enantioselection (MKE) and reflects the ratio of the rate constants for the competing like and unlike reactions. For each of the four diastereomers of 1, the reactions with the highest MKEs in favor of the like (3) or unlike products (4) were repeated using highly enantioenriched ketone. These reactions occurred with the expected KR (s = 10-20) allowing selective access to enantioenriched diastereomers of 3 or 4 from (+/-)-2. These adducts are useful for polypropionate synthesis, and this design strategy for KR should be applicable to related processes.

Synthetic studies on siphonariid polypropionates: synthesis and isomerization of the caloundrin B trioxaadamantane ring system.

(1R,3R,5R,7R,8S,9R,10S)-3,5-Diethyl-8,9,10-trimethyl-2,4,6-trioxatricyclo[3.3.1.1(3,7)]decan-1-ol (II), a model of the trioxaadamantane ring system embedded in caloundrin B, was prepared by isomerization of the thermodynamically unstable (9S)-diastereomer (I) in the presence of imidazole. Alternatively, isomerization of I with HF.py or DBU gave the hemiacetal III or its retro-Claisen ester IV, respectively, which represent structural motifs present in the closely related siphonariid polypropionates siphonarin B and baconipyrone C.

Enantiospecific total synthesis of lairdinol A.

The synthesis of lairdinol A, a component of the host-selective phytotoxin depsilairdin, was achieved in 12 steps (18% overall yield) without the use of protecting groups starting with the Diels-Alder reaction of (R)-carvone with 3-trimethylsilyloxy-1,3-pentadiene. The key step established the trans ring fusion by preferential epoxidation of a trans-fused enone in an equilibrating mixture of the cis-fused and trans-fused diastereomers (i.e., equivalent to a dynamic kinetic resolution of these isomers). The synthesis confirms the absolute configurations of lairdinol A and its enantiomer, cyperusol C.

The thiopyran route to polypropionates: enantioselective synthesis of membrenone B from racemic fragments.

(6S,7S,8S,9R,10S)-(--)-Membrenone B was synthesized in nine steps (9.4% overall yield) beginning with two-directional aldol coupling of tetrahydro-4H-thiopyran-4-one with racemic 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde. The first aldol reaction occurs with dynamic kinetic resolution to give a single adduct (>98% ee). The second aldol reaction is highly diastereoselective (three of eight possible adducts), and both major products are converted to membrenone B. The route also constitutes a formal synthesis of membrenone A.

Enantioselective total synthesis of cyathin A3.

The total synthesis of (-)-cyathin A3 is described. The key step involves an unusual enantioselective Diels-Alder reaction of 2,5-dimethyl-1,4-benzoquinone with 2,4-bis(trimethylsilyloxy)-1,3-pentadiene, using Mikami's catalyst [(R)-BINOL + Cl2Ti(OiPr)2 + 4 A mol sieves] modified by addition of Mg and SiO2. Because cyathin A3 is easily transformed into allocyathin B3, cyathin B3, cyathin C3, and neoallocyathin A4, this route also constitutes formal syntheses of these natural products.

Thiopyran route to polypropionates: exploiting and overcoming double stereodifferentiation and mutual kinetic enantioselection in aldol couplings of chiral fragments.

The aldol reaction of tetrahydro-4H-thiopyranone with 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde (I) gives four possible diastereomeric adducts (II). Aldol reactions of I with each of the diastereomers of II and their corresponding methoxymethyl ethers III via the Ti enolates were investigated. Using racemic reactants, reactions with II proceeded with high levels of mutual kinetic enantioselection (MKE) and double stereodifferentiation (DS) to give one of the eight possible bisaldol adducts. Similar reactions of III proceeded with low levels of MKE and DS and gave two bisaldol adducts, one from each of the possible combinations of enantiomeric reactants. By extension, 11 of the 20 possible diastereomers of the bisaldol adduct could be obtained selectively. These adducts are useful for polypropionate synthesis.

Thiopyran route to polypropionates: an efficient synthesis of serricornin.

The synthesis of serricornin [(4S,6S,7S)-7-hydroxy-4,6-dimethylnonan-3-one], a sex pheromone produced by the female cigarette beetle (Lasioderma serricorne F.), in seven steps from readily available racemic 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde (6) is described. The key steps include enantioselective aldol reaction of 6 with tetrahydrothiopyran-4-one catalyzed by 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole to fabricate the tetrapropionate skeleton, stereoselective Li(s)Bu(3)BH reduction of the resulting aldol adduct, Barton-McCombie deoxygenation, and Raney nickel desulfurization.

Asymmetric synthesis of hexapropionate synthons by sequential enantiotopic group selective enolization of meso diketones.

Meso 1,9-diketones (six to seven stereocenters) are readily obtained by stepwise or simultaneous two-directional aldol reactions of tetrahydro-4H-thiopyran-4-one with a thiopyran-derived aldehyde or dialdehyde. Enantioselective enolizations of these diketones with the lithium amide from (R,R)-bis(1-phenylethyl)amine occur with simultaneous kinetic resolution to give the mono-TMS enol ethers in >90% yields (BORSM) and >95% ee. The products are applicable to polypropionate synthesis. [reaction: see text]

Catalytic enantioselective Diels-Alder reaction by self-assembly of the components on a Lewis acid template.

Thermal Diels-Alder reaction of 2,4-hexadienol with methyl acrylate is unselective. By simultaneous coordination of diene and dienophile to a chiral bimetallic Lewis acid catalyst, a LACASA-DA reaction occurs with complete control of regio-, diastereo-, and enantioselectivity to give a single adduct. [reaction: see text]

Enantioselective direct intermolecular aldol reactions with enantiotopic group selectivity and dynamic kinetic resolution.

[reaction: see text] Proline-catalyzed aldol reactions of tetrahydro-4H-thipyranone with racemic 1,4-dioxa-8-thia-spiro[4.5]decane-6-carboxaldehyde and with meso/dl 1,4-dioxa-8-thiaspiro[4.5]decane-6,10-dicarboxaldehyde proceed with dynamic kinetic resolution and give single adducts in good yields with excellent ee's. The high enantiotopic group selectivity results from the high intrinsic diastereoface selectivity of the aldehydes. These reactions significantly extend the scope of the enantioselective direct aldol reaction and constitute simple and efficient syntheses of useful tetrapropionate synthons.

Syn-anti isomerization of aldols by enolization.

A variety of aldol adducts are shown to undergo efficient syn-anti isomerization in the presence of imidazole by an enolization mechanism. Isomerizations are high yielding and occur with little or none of the usual byproducts arising from competing elimination or retroaldol reactions. Most substrates reach equilibrium within 0.3-3 days at ambient temperature in chloroform, benzene, or dichloromethane containing 0.3-1 M imidazole. The process is particularly facile for aldols derived from tetrahydro-4H-thiopyran-4-one with rate constants for equilibration varying over ca. 1 order of magnitude for the adducts studied; structurally related aldols derived from cyclohexanone isomerized ca. 3-4 times slower. Isomerization of the acyclic aldol 5-hydroxy-4-methyl-5-phenyl-3-pentanone required heating to 60 degrees C but was achieved with minimal (<5%) retroaldol or elimination. A methoxymethyl ether derivative isomerized 30-40 times slower than the parent aldol. Isomerization of alpha,alpha'-disubstituted aldols and alpha,alpha'-bisaldols indicated low regioselectivity in the enolization. The synthetic utility of the process was demonstrated with the effective preparation of aldol stereoisomers unobtainable by direct methods.