Expeditious Asymmetric Synthesis of Polypropionates Relying on Sulfur Dioxide-Induced C–C Bond Forming Reactions

: For a long time, the organic chemistry of sulfur dioxide (SO 2 ) consisted of sulﬁnates that react with carbon electrophiles to generate sulfones. With alkenes and other unsaturated compounds, SO 2 generates polymeric materials such as polysulfones. More recently, H-ene, sila-ene and hetero-Diels–Alder reactions of SO 2 have been realized under conditions that avoid polymer formation. Sultines resulting from the hetero-Diels–Alder reactions of conjugated dienes and SO 2 are formed more rapidly than the corresponding more stable sulfolenes resulting from the cheletropic additions. In the presence of a protic or Lewis acid catalyst, the sultines derived from 1-alkoxydienes are ionized into zwitterionic intermediates bearing 1-alkoxyallylic cation moieties which react with electro-rich alkenes such as enol silyl ethers and allylsilanes with high stereoselectivity. (C–C-bond formation through Umpolung induced by SO 2 ). This produces silyl sulﬁnates that react with carbon electrophiles to give sulfones (one-pot four component asymmetric synthesis of sulfones), or with Cl 2 , generating the corresponding sulfonamides that can be reacted in situ with primary and secondary amines (one-pot four component asymmetric synthesis of sulfonamides). Alternatively, Pd-catalyzed desulﬁnylation generates enantiomerically pure polypropionate stereotriads in one-pot operations. The chirons so obtained are ﬂanked by an ethyl ketone moiety on one side and by a prop-1-en-1-yl carboxylate group on the other. They are ready for two-directional chain elongations, realizing expeditious synthesis of long-chain polypropionates and polyketides. The stereotriads have also been converted into simpler polypropionates such as the cyclohexanone moiety of baconipyrone A and B, Kishi’s stereoheptad unit of rifamycin S, Nicolaou’s C 1 –C 11 -fragment and Koert’s C 16 –C I fragment of apoptolidin A. This has also permitted the ﬁrst total synthesis of (-)-dolabriferol. dienes and enoxysilanes than those presented in Scheme 1 can be used in our reaction cascade. Fragment 57 is adequately protected for the glycosidation steps necessary in the construction of apoptolidin A. Diene 49 (derived from inexpensive ( R )-1-phenylethanol) and silyl ethers 50 (1:1 E / Z mixture) were reacted with a catalytic amount of (CF 3 SO 2 ) 2 NH in SO 2 /CH 2 Cl 2 (5:1) cooled to − 78 °C. After neutralization of the acid catalyst with Et 3 N and solvent evaporation, alcoholysis with i a


One-Pot Synthesis of Polypropionate Stereotriads Ready for Bidirectional Chain Elongations
For the stereotriads 6 and their enantiomeric forms ( Figure 2) to become useful chirons (enantiomericallly pure synthetic intermediates) in the constructions of complicated polypropionates and analogues, their alcoholic moiety must be protected adequately and their R 3 et R 4 terminus should be functions that can enter directly in stereoselective C-C bond forming reactions, typically metal aldol reactions. Chirons of type 7 and 8 (and their enantiomers) have been obtained in one-pot operations (Scheme 1) [16]. Their group R 3 is an ethyl ketone which can be elongated into a system containing up to two further stereogenic centers via a direct aldol reaction, while the R 4 terminus is a protected ethyl ketone under the form of (Z)-prop-1-en-1-yl carboxylate (ethyl ketone enol carboxylate) that stays intact and can be used in the second chain elongation reaction, also producing up to two further stereogenic centers (see below Section 4). In the presence of SO 2 , alkenes, alkynes and polyenes produce polymeric materials, including polysulfones (copolymer with sulfur dioxide) [58][59][60]. Competing with these reactions, SO 2 -catalyzed alkene isomerization can be observed. We have demonstrated that the latter reaction may not imply a hetero-ene reaction of the alkene with SO 2 , followed by a fast [1,3]-sigmatropic shift of the intermediate β,γ-sulfinic acid and retro-ene reaction [61,62]. Instead, an allylic hydrogen atom is abstracted form the alkene by an alkanesulfonyl radical intermediate equilibrating with the polysulfone [63][64][65]. Since 1914 [66] it has been well-known that 1,3-dienes (that can adopt a s-cis-conformation) and sulfur dioxide equilibrate with their sulfolenes (cheletropic additions). On heating (>100 • C) the sulfolenes undergo cheletropic eliminations giving back the 1,3-dienes and SO 2 . The first examples of hetero-Diels-Alder additions of SO 2 involved highly reactive dienes such as 1,4,5,6-tetramethyl-2,3-dimethylidenetriclo[2.1.1.0 5,6 ]hexane [67] and orthoquinodimethane [68]. Below −60 • C simple 1,3-dienes such as isoprene and piperylene react with SO 2 equilibrating with their sultines resulting from hetero-Diels-Alder reactions that are much faster than the corresponding cheletropic additions. Deguin and Vogel showed in 1992 that (E,E)-deuteriopiperylene (11) equilibrates with sultine 12 at −80 • C in the presence of an acid catalyst such as CF 3 COOH. At −60 • C 12 is isomerized into the more stable isomeric sultine 13, by cycloreversion into the initial cycloaddents and readdition in a second hetero-Diels-Alder reaction (Scheme 2). Both the [4+2]-cycloadditions 11 + SO 2 → 12 and 11 + SO 2 → 13 are highly regio-and stereoselective [69]. As for many Diels-Alder reactions, the acid-catalyzed hetero-Diels-Alder reactions of SO 2 adheres to the Alder-endo rule and to the Woodward-Hoffmann rule of suprafaciality for the diene [69]. Sulfur dioxide itself catalyzes its cycloadditions [70][71][72][73]. In the absence of acid, the secondary deuterium kinetic isotopic effects of the SO 2 reaction with the dideuterodiene 15-d 2 induced a regioselectivity opposite to the equilibrium isotopic regioselectivity. Sultine ortho-17 formed faster than regioisomer meta-17. On staying at −55 • C, ortho-17 was slowly isomerized into meta-17 (Scheme 2). This demonstrates that the hetero-Diels-Alder reaction of SO 2 follows a mechanism with asynchronous formation of the C-S and C-O bonds in the transition state: the C-S bond is formed to a greater extent than the C-O bond [74].
The sulfolenes arising from the cheletropic additions of SO 2 to alkyl substituted 1,3-dienes are about 10 kcal mol −1 more stable than their isomeric sultines. In contrast, fluorosultines that result from the hetero-Diels-Alder reactions of SO 2 with 1-fluoro-1,3dienes are more stable than their isomeric sulfolenes. This is assigned to an enthalpic anomeric effect of the F-C-O(S=O) moiety in the sultines [75].
With 1-alkoxy-3-acyloxy-1,3-dienes 10 (prepared in four steps from butan-3-one and (S)-1-phenylethanol [76], the corresponding sultines 19 are not seen at −100 • C (large excess of SO 2 , CH 2 Cl 2 or toluene as co-solvent) as these dienes generate the corresponding sulfolenes at this temperature already. Nevertheless, sultines 19 are believed to be formed as intermediates before the isomeric sulfolenes (Scheme 3). In the presence of an acid catalyst (protic acid or Lewis acid), they equilibrate with zwitterionic intermediates 20 that can be reacted with electron-rich alkenes such as enoxysilane (Z)-9. This generates the silyl sulfinates 24. The role of SO 2 is to convert the electron-rich dienes into 1-alkoxyallyl cation intermediates, realizing an inversion of polarity (Umpolung) that make possible the C-C coupling reaction between the two nucleophilic partners 10 and (Z)-9 [77]. deuterium kinetic isotopic effects of the SO2 reaction with the dideuterodiene 15-d2 induced a regioselectivity opposite to the equilibrium isotopic regioselectivity. Sultine ortho-17 formed faster than regioisomer meta-17. On staying at −55 °C, ortho-17 was slowly isomerized into meta-17 (Scheme 2). This demonstrates that the hetero-Diels-Alder reaction of SO2 follows a mechanism with asynchronous formation of the C-S and C-O bonds in the transition state: the C-S bond is formed to a greater extent than the C-O bond [74].

Scheme 2.
Simple dienes that can adopt a s-cis conformation undergo SO2 and acid-catalyzed hetero-Diels-Alder reactions with SO2 at low temperature, giving sultines that are about 10 kcal mol −1 less stable than the corresponding sulfolenes.
The sulfolenes arising from the cheletropic additions of SO2 to alkyl substituted 1,3dienes are about 10 kcal mol −1 more stable than their isomeric sultines. In contrast, fluorosultines that result from the hetero-Diels-Alder reactions of SO2 with 1-fluoro-1,3dienes are more stable than their isomeric sulfolenes. This is assigned to an enthalpic anomeric effect of the F-C-O(S=O) moiety in the sultines [75].
With 1-alkoxy-3-acyloxy-1,3-dienes 10 (prepared in four steps from butan-3-one and (S)-1-phenylethanol [76], the corresponding sultines 19 are not seen at −100 °C (large excess of SO2, CH2Cl2 or toluene as co-solvent) as these dienes generate the corresponding sulfolenes at this temperature already. Nevertheless, sultines 19 are believed to be formed as intermediates before the isomeric sulfolenes (Scheme 3). In the presence of an acid catalyst (protic acid or Lewis acid), they equilibrate with zwitterionic intermediates 20 that can be reacted with electron-rich alkenes such as enoxysilane (Z)-9. This generates the silyl sulfinates 24. The role of SO2 is to convert the electron-rich dienes into 1-alkoxyallyl cation intermediates, realizing an inversion of polarity (Umpolung) that make possible the C-C coupling reaction between the two nucleophilic partners 10 and (Z)-9 [77].
After removal of SO2 in excess and solvent under vacuum, enough K2CO3 in CH3CN was added to neutralize the acid catalyst. Then a 1:1 mixture of Pd(AcO)2/Ph3P and iso-Scheme 2. Simple dienes that can adopt a s-cis conformation undergo SO 2 and acid-catalyzed hetero-Diels-Alder reactions with SO 2 at low temperature, giving sultines that are about 10 kcal mol −1 less stable than the corresponding sulfolenes. The silyl sulfinates 23 can be isolated, or converted in situ into sulfinate salts that are quenched by all kinds of electrophiles to give sulfones (four-component synthesis of polyfunctional sulfones [80]), or converted in situ (with Cl2 or N-chlorosuccinimide) into sulfonyl chlorides that react with amines to produce sulfonamides (four-component synthesis of polyfunctional sulfonamides [81,82]). Acidic treatment of 23 also leads to desulfinylation producing the stereotriads in a lower yield, due to elimination of 1-phenylethanolgenerating dienes 26 and aldols 27, the latter undergoing retro-aldol decomposition into penta-3-one and aldehydes 28 (Scheme 4). This is avoided when the silyl sulfinates are treated under neutral or slightly basic conditions (K2CO3) in isopropanol in the presence of a catalytic amount of Pd(AcO)2 and Ph3P. Without Ph3P the reaction does not occur Scheme 3. Proposed mechanism for the reaction cascade producing the syn,anti-stereotriad 7 as major product: (1) face-selective acid-catalyzed hetero-Diels-Alder reaction of SO 2 , (2) immediate ionization of the sultine so-obtained into a zwitterion, (3) face-selective quenching of the alkoxyallyl cation intermediate by the enoxysilane, (4) intramolecular or intermolecular silyl transfer forming a silyl sulfinate (can be isolated), (5) its Pd-catalyzed alcoholysis with isopropanol forming the corresponding, β,γ-unsaturated sulfinic acid which (6) undergoes a face-selective H-retro-ene reaction.
After removal of SO 2 in excess and solvent under vacuum, enough K 2 CO 3 in CH 3 CN was added to neutralize the acid catalyst. Then a 1:1 mixture of Pd(AcO) 2 /Ph 3 P and isopropanol was added, and heating to 80 • C produced the final stereotriads. The stereoselectivity of the reaction cascade is explained in the following way (Scheme 3). The hetero-Diels-Alder reaction of SO 2 is face selective because the chiral auxiliary (1-alkoxy substituent of the diene) favors transition structure 18, the least encumbered face of the diene reacting preferentially. The acid catalyzed ionization of the resulting sultines 19 generate ion-pairs 20 in which the sulfinate anion remains closed to the 1-alkoxyallyl cation moieties. This forces the nucleophile (e.g., enoxysilane (Z)-12) to attack 20 on the face opposite to that occupied by the sulfinate anion (transition structure 21). The resulting adducts 22 undergo intramolecular silyl group transfers via conformations 22 . Alternatively, two molecules of 22 could undergo a double intramolecular silyl group transfer giving the silyl sulfinates 23. Alcoholysis of 23 gives sulfinic acids 24 which undergo H-retro-ene reactions generating 7, the stereoselectivity of which is controlled by steric factors making transition structures 24 preferred to 24 . For the reaction cascade using enoxysilane (Z)-9 and diene 10 with R = i-Pr, R* = (S)-1-phenylethyl) (1:1 SO 2 /toluene, catalyst AH = (CF 3 SO 2 ) 2 NH) the corresponding stereotriads 7 and 8 were isolated in 67 and 13 % yield, respectively, after column chromatography. Using Greene's chiral auxiliaries ((S)-1-[2,4,6-tris(isopropyl)phenyl]ethanol) [78]) instead of inexpensive (S)-1-phenylethanol the diastereoselectivity syn,anti vs. anti,anti-stereotriad was better than 95:5 [79].
The silyl sulfinates 23 can be isolated, or converted in situ into sulfinate salts that are quenched by all kinds of electrophiles to give sulfones (four-component synthesis of polyfunctional sulfones [80]), or converted in situ (with Cl 2 or N-chlorosuccinimide) into sulfonyl chlorides that react with amines to produce sulfonamides (four-component synthesis of polyfunctional sulfonamides [81,82]). Acidic treatment of 23 also leads to desulfinylation producing the stereotriads in a lower yield, due to elimination of 1-phenylethanolgenerating dienes 26 and aldols 27, the latter undergoing retro-aldol decomposition into penta-3-one and aldehydes 28 (Scheme 4). This is avoided when the silyl sulfinates are treated under neutral or slightly basic conditions (K 2 CO 3 ) in isopropanol in the presence of a catalytic amount of Pd(AcO) 2 and Ph 3 P. Without Ph 3 P the reaction does not occur (formation of Pd (0) species as catalyst). One can envisage a Pd (0) complex intermediate which adds oxidatively (retention of configuration) into the allylic C-SO 2 SiMe 3 bond of 23. Subsequent desulfinylation and protolysis of the Pd-SiMe 3 bond gives i-PrOSiMe 3 (driving force) and an (allyl)palladium hydride that undergoes regioselective and stereoselective β-insertion of hydride into another (allyl)Pd intermediate. An alternative mechanism (Scheme 3) is to invoke that the Pd (0) role is just to promote the Si-sulfinate bond cleavage under non-acidic conditions generating the corresponding β,γ-unsaturated sulfinic acids that, in turn, undergo H-retro-ene elimination of SO 2 [83].

Long-Chain Polypropionates through Bidirectional Chain Elongation
The polypropionate 31 (a stereodecad) containing 10 contiguous stereogenic centers has been obtained by two successive metal-aldol reactions of stereotriad 7 (Scheme 5) [84]. Applying Paterson's method for direct formation of enoxyboranes [85][86][87] the dicyclohexyl(enoxy)borane derived from 7 reacted with acetaldehyde giving an boron anti-2methylaldolate that was reduced directly with NaBH 4 generating a anti,anti-2-methyl-1,3-diol moiety, which was protected as the acetonide 29 (a stereohexad in one pot operation) in 61% overall yield. The (Z)-enol isobutyrate group of 29 was converted with retention into the (Z) lithium enolate 30 by reaction with MeLi . LiBr in ether. The latter added to the acetonide of D-glyceraldehyde giving a major lithium aldolate. Its phenylethyl ether was hydrogenolyzed under standard conditions and the aldol was reduced with Me 4 NB(AcO) 3 H [88,89] selectively into the corresponding anti-1,3-diol 31 (67% overall yield).
Catalysts 2021, 11, x FOR PEER REVIEW 9 of 23 Scheme 5. An example of bidirectional chain elongation of stereotriad 7 by two successive metal-aldol reactions; synthesis of a stereodecad from a stereotriad requiring the isolation of one synthetic intermediate.

First Total Asymmetric Synthesis of the Cyclohexanol Subunit of Baconipyrones A and B
Baconipyrones A-D were isolated in 1989 by Faulkner and co-workers from Siphonaria baconi [90]. The stereotriad 7 (R = i-Pr, R* = (S)-1-phenylethyl) has been converted in two steps into cyclohexanone 34 (overall yield: 86%), subunit of baconipyrones A and B (Figure 1) [91]. Transesterification of enol isobutyrate 7 (Scheme 6) with Bu3SnOMe [92,93] induced the desired stereoselective intramolecular aldol reaction, giving 33. Transition structure 32 was proposed to explain the stereoselectivity hydrogenolysis of 33 and provided 34 quantitatively. Scheme 5. An example of bidirectional chain elongation of stereotriad 7 by two successive metal-aldol reactions; synthesis of a stereodecad from a stereotriad requiring the isolation of one synthetic intermediate.

Generalization of the SO2-Induced Umpolung. Short Synthesis of the C16-C28 Fragment of Apoptolidinone: Formal Total Synthesis of Apoptolidin A
Apoptolidin A (isolated from Nocardiopsis sp.) [143,144] and the natural analogues B, C, D, E and F [145][146][147] are leads for the chemotherapy of cancers [148][149][150][151]. They selectively induce apoptosis in cancer cells. The groups of Nicolaou [152,153] and Koert [154,155] have presented the first syntheses of apoptolidin A. The groups of Sulikowsky [156,157] and Crimmins [158] have reported syntheses of the aglycon apoptolidinone A. Fragments of this aglycon has been prepared by other groups [159].
Applying our SO2-induced Umpolung reaction, rapid access (nine steps) to Koert's C16-C28 polyketide fragment 57 (Scheme 9) of apoptolidinones A has been realized [160]. This work illustrates that other dienes and enoxysilanes than those presented in Scheme 1 can be used in our reaction cascade. Fragment 57 is adequately protected for the glycosidation steps necessary in the construction of apoptolidin A.

Generalization of the SO 2 -Induced Umpolung. Short Synthesis of the C 16 -C 28 Fragment of Apoptolidinone: Formal Total Synthesis of Apoptolidin A
Apoptolidin A (isolated from Nocardiopsis sp.) [143,144] and the natural analogues B, C, D, E and F [145][146][147] are leads for the chemotherapy of cancers [148][149][150][151]. They selectively induce apoptosis in cancer cells. The groups of Nicolaou [152,153] and Koert [154,155] have presented the first syntheses of apoptolidin A. The groups of Sulikowsky [156,157] and Crimmins [158] have reported syntheses of the aglycon apoptolidinone A. Fragments of this aglycon has been prepared by other groups [159].
Applying our SO 2 -induced Umpolung reaction, rapid access (nine steps) to Koert's C 16 -C 28 polyketide fragment 57 (Scheme 9) of apoptolidinones A has been realized [160]. This work illustrates that other dienes and enoxysilanes than those presented in Scheme 1 can be used in our reaction cascade. Fragment 57 is adequately protected for the glycosidation steps necessary in the construction of apoptolidin A. [164]. The resulting homoallylic alcohol was equilibrated with the hemiacetal 55 that underwent desilylation, debenzylation and Fischer glycosidation on treatment with HCl/MeOH at 50 °C. The resulting triol was then acetylated selectively into a diacetate (at C19 and C20); the most sterically hindered alcohol at C23 was then silylated giving 56. Sharpless asymmetric dihydroxylation [165] of 56 furnished a 4.5:1 mixture of the corresponding diol that was selectively monomethylated with MeI/Ag2O giving Koert's intermediate 57.

The One-Pot Four-Component Synthesis of Polyfunctional Sulfones: Application to a Short Synthesis of the C1-C11 Fragment of Apoptolidin A
Another key intermediate in the total synthesis of apoptolidin A is the Nicolaou's C1-C11-fragment (+)-65 the preparation of which requires 11 steps [152]. Applying our SO2induced Umpolung reaction, an expeditious synthesis of this intermediate was realized with an overall yield of 29% starting with simple diene 58, enoxysilane 59 and the known enantiomerically pure (S)-3-methoxymethoxy-2-methylprop-1-yl iodide. The method required the isolation of only three synthetic intermediates (Scheme 10) [166]. In the presence of 0.4 equivalent of a strong acid such as (CF3SO2)2NH sulfur dioxide adds to the strans form of diene 58 equilibrating with a zwitterionic intermediate 60 that was quenched Scheme 9. Synthesis of Koert's C 16 -C 28 polyketide fragment of apoptolidin A. Diene 49 (derived from inexpensive (R)-1-phenylethanol) and silyl ethers 50 (1:1 E/Z mixture) were reacted with a catalytic amount of (CF 3 SO 2 ) 2 NH in SO 2 /CH 2 Cl 2 (5:1) cooled to −78 • C. After neutralization of the acid catalyst with Et 3 N and solvent evaporation, alcoholysis with i-PrOH (80 • C) gave a 4:1 mixture of stereotriad 51 and its α,β,γ-anti,anti stereomer. This mixture was converted into their kinetic silyl enol ethers and oxidized with mCPBA (Rubottom oxidation [161]) giving 52 that underwent Mukaiyama aldol coupling with aldehyde 53 [162,163], producing alkene 54. Ozonolysis of 54 followed by treatment with Me 2 S gave an aldehyde that was allylated under Brown's conditions [164]. The resulting homoallylic alcohol was equilibrated with the hemiacetal 55 that underwent desilylation, debenzylation and Fischer glycosidation on treatment with HCl/MeOH at 50 • C. The resulting triol was then acetylated selectively into a diacetate (at C 19 and C 20 ); the most sterically hindered alcohol at C 23 was then silylated giving 56. Sharpless asymmetric dihydroxylation [165] of 56 furnished a 4.5:1 mixture of the corresponding diol that was selectively monomethylated with MeI/Ag 2 O giving Koert's intermediate 57.

The One-Pot Four-Component Synthesis of Polyfunctional Sulfones: Application to a Short Synthesis of the C 1 -C 11 Fragment of Apoptolidin A
Another key intermediate in the total synthesis of apoptolidin A is the Nicolaou's C 1 -C 11 -fragment (+)-65 the preparation of which requires 11 steps [152]. Applying our SO 2induced Umpolung reaction, an expeditious synthesis of this intermediate was realized with an overall yield of 29% starting with simple diene 58, enoxysilane 59 and the known enantiomerically pure (S)-3-methoxymethoxy-2-methylprop-1-yl iodide. The method required the isolation of only three synthetic intermediates (Scheme 10) [166]. In the presence of 0.4 equivalent of a strong acid such as (CF 3 SO 2 ) 2 NH sulfur dioxide adds to the s-trans form of diene 58 equilibrating with a zwitterionic intermediate 60 that was quenched by the enoxysilane 59. One assumes that another zwitterionic intermediate 61 was formed, which after treatment with tetrabutylammonium fluoride generated the dihydroxyketone 62, an aldol that loses one equivalent of water under acidic conditions (p-TsOH, MeOH, 70 • C) to give the (E,E)-dienone 63 (one pot: 87% yield). Silyl ether and enol silyl ether formation was followed by oxidation with mCPBA. This generated an αhydroxyketone which was not isolated but directly submitted to the Malaprade oxidation, giving a carboxylic acid that was esterified in situ with diazomethane-producing ester 64. Dess-Martin oxidation of the primary alcohol of 64 gave an aldehyde that was reacted, without purification, with Et 3 SiCC-Li to give a 5:1 mixture of diastereomeric propargylic alcohols. They were silylated and the sulfone moiety underwent a Ramberg-Bäcklund rearrangement [167][168][169] providing a 12:1 mixture of (E,E,E)-/(E,E,Z)-triene-ester (+)-65. by the enoxysilane 59. One assumes that another zwitterionic intermediate 61 was formed, which after treatment with tetrabutylammonium fluoride generated the dihydroxyketone 62, an aldol that loses one equivalent of water under acidic conditions (p-TsOH, MeOH, 70 °C) to give the (E,E)-dienone 63 (one pot: 87% yield). Silyl ether and enol silyl ether formation was followed by oxidation with mCPBA. This generated an α-hydroxyketone which was not isolated but directly submitted to the Malaprade oxidation, giving a carboxylic acid that was esterified in situ with diazomethane-producing ester 64. Dess-Martin oxidation of the primary alcohol of 64 gave an aldehyde that was reacted, without purification, with Et3SiCC-Li to give a 5:1 mixture of diastereomeric propargylic alcohols. They were silylated and the sulfone moiety underwent a Ramberg-Bäcklund rearrangement [167][168][169] providing a 12:1 mixture of (E,E,E)-/(E,E,Z)-triene-ester (+)-65.

Allylsilanes as Nucleophiles: Development of Two-Directional Polypropionate-Polyketide Synthesis
Like enol silyl ethers, allylsilanes are nucleophiles that can be used in our SO2-induced CC bond-forming reaction. Using allyldisilane 67 and two different dienes, 66 and 69, the stereotetrads 70 can be prepared in one-pot operations (Scheme 11). Diene 66 possesses a 1-(1-phenyl)ethoxy group whereas diene bears a 1-[1-(4-fluorophenyl]ethoxy substituent. The SN1 and E1 cleavage of the benzylic C-O ether bond of the 1-phenylethoxy group are faster than the SN1 and E1 C-O benzylic bond cleavage of the 1-(4-fluorophenyl)ethoxy group; the pseudo-symmetrical stereotetrad is suitable for two successive aldol reactions on both their chain terminus. This permits the expeditious syntheses of long-chain polyketides and polypropionates.
Reaction of diene 66 with 67 and SO2 promoted by Me3SiOTf generated the product of mono-alkoxyallylation 68. The reaction 66 + 67 → 68 is faster than the reaction of monoallysilane 68 with diene 67 + SO2 because bisallylsilane 66 enjoys twice the β-silicon effect.
In the presence of one equivalent of diene 66 the product of double oxyallytion is not Scheme 10. An expeditious synthesis of the Nicolaou's C 1 -C 11 fragment of apoptolidin A.

Allylsilanes as Nucleophiles: Development of Two-Directional Polypropionate-Polyketide Synthesis
Like enol silyl ethers, allylsilanes are nucleophiles that can be used in our SO 2 -induced CC bond-forming reaction. Using allyldisilane 67 and two different dienes, 66 and 69, the stereotetrads 70 can be prepared in one-pot operations (Scheme 11). Diene 66 possesses a 1-(1-phenyl)ethoxy group whereas diene bears a 1-[1-(4-fluorophenyl]ethoxy substituent. The S N 1 and E 1 cleavage of the benzylic C-O ether bond of the 1-phenylethoxy group are faster than the S N 1 and E 1 C-O benzylic bond cleavage of the 1-(4-fluorophenyl)ethoxy group; the pseudo-symmetrical stereotetrad is suitable for two successive aldol reactions on both their chain terminus. This permits the expeditious syntheses of long-chain polyketides and polypropionates. Scheme 11. Convergent synthesis of complicated polypropionate-polyketide fragments through dissymmetrical two-directional chain elongation.

Conclusions
At low temperature, and in the presence of a protic or Lewis acid, catalyst 1-alkoxy-1,3-dienes undergo fast hetero-Diels-Alder reactions with SO2, forming unstable sultines that are converted rapidly into zwitterionic intermediates containing 1-oxyallyl cation moieties. The latter are quenched in situ by electron-rich alkenes such as silyl enol ethers generating β,γ-unsaturated silyl sulfinates. Sufur dioxide induces a stereoselective C-C bond forming reactions between electron-rich dienes and alkenes (Umpolung through SO2). The silyl sulfinates so obtained can be converted in situ into stereotriads that are flanked by an ethyl ketone group at one side and by an enol ester of an ethyl ketone on the other side. In a few synthetic steps the synthesis of the cyclohexanone unit of baconipyrones and of the two fragments of (-)-dolabriferol have been realized. With the first total synthesis of (-)-dolabriferol we could establish its absolute configuration. Aldol condensation of the ethyl ketone group of one of our stereotriads has opened a very short route to Kishi's stereoheptad, which he used to construct rifamycin-S. A similar strategy has permitted us to obtain the Koert's C16-C28 polyketide fragment of apoptolidin A. Under Scheme 11. Convergent synthesis of complicated polypropionate-polyketide fragments through dissymmetrical twodirectional chain elongation.
Reaction of diene 66 with 67 and SO 2 promoted by Me 3 SiOTf generated the product of mono-alkoxyallylation 68. The reaction 66 + 67 → 68 is faster than the reaction of monoallysilane 68 with diene 67 + SO 2 because bisallylsilane 66 enjoys twice the β-silicon effect. In the presence of one equivalent of diene 66 the product of double oxyallytion is not formed; only sulfinate 68 is formed. It can be reacted without purification with SO 2 and diene 69, providing a bis(silyl sulfinate) which is not isolated but submitted directly to the double Pd (0) -catalyzed desilylation and desulfitation reactions, furnishing the stereotetrad 70, isolated in 54% yield (one-pot). Selective debenzylation of 70 with BCl 3 /pentamethylbenzene eliminated the phenylethyl group, giving a homoallylic alcohol that was not isolated but treated directly with (Me 3 Si) 2 NLi to engender the corresponding lithium alcoholate 71 (one pot). The latter underwent rapid acyl group migration from the neighboring enol benzoate forming lithium enolate 72. Without isolation, the latter enolate reacted with Me 3 SiCl giving a (Z)-enoxysilane that was reacted in situ with isobutyraldehyde and BF 3 etherate, providing aldol 73 which was a single stereomer isolated in 72% yield. Reduction of aldol 72 under Narasaka's conditions [170] gave the corresponding syn-1,3-diol that was converted in situ into its acetonide 74 (83%, overall). The treatment of enol benzoate 74 with MeLi . LiBr furnished the corresponding lithium (Z)-enolate. It was quenched by the chiral aldehyde 75 producing a major aldol that was not isolated but directly reduced under Evans' conditions [88,89]. This furnished 76, a polyketides containing 11 stereogenic centers. As the configuration of the 1-oxydienes 66 and 69 can be either (R) or (S) and since the two successive aldol reactions on the intermediate stereotetrad can used a wide variety of aldehydes under well-chosen conditions, a very large library of polyketides can be prepared applying our method illustrated in Scheme 11 [171,172].

Conclusions
At low temperature, and in the presence of a protic or Lewis acid catalyst, 1-alkoxy-1,3-dienes undergo fast hetero-Diels-Alder reactions with SO 2 , forming unstable sultines that are converted rapidly into zwitterionic intermediates containing 1-oxyallyl cation moieties. The latter are quenched in situ by electron-rich alkenes such as silyl enol ethers generating β,γ-unsaturated silyl sulfinates. Sufur dioxide induces a stereoselective C-C bond forming reactions between electron-rich dienes and alkenes (Umpolung through SO 2 ). The silyl sulfinates so obtained can be converted in situ into stereotriads that are flanked by an ethyl ketone group at one side and by an enol ester of an ethyl ketone on the other side. In a few synthetic steps the synthesis of the cyclohexanone unit of baconipyrones and of the two fragments of (-)-dolabriferol have been realized. With the first total synthesis of (-)-dolabriferol we could establish its absolute configuration. Aldol condensation of the ethyl ketone group of one of our stereotriads has opened a very short route to Kishi's stereoheptad, which he used to construct rifamycin-S. A similar strategy has permitted us to obtain the Koert's C 16 -C 28 polyketide fragment of apoptolidin A. Under strongly acidic conditions, s-trans-1-alkoxydienes and enoxysilanes react with SO 2 forming sulfinates that are quenched in situ with electrophiles to generate polyfunctional sulfones with a conjugated (E,E)-dienone moiety. The method has permitted an efficient synthesis of Nicolaou's C 1 -C 11 fragment of apoptolidin A. The stereotriads undergo two successive metal aldol reactions that produce complicated polyketides and polypropionates in a few steps. Allylsilanes can be used instead of enoxysilanes in our SO 2 -induced Umpolung reaction. With 2-[(methyldiphenyl)methyl]allylmethyl(diphenyl)silane), two successive alkoxyallylations with two different 1-alkoxydienes can be run in the same pot, thus generating stereotetrads ready for two successive aldol reactions (two-directional chain elongations). The strategy permits us to construct, in a few steps, complicated polyketides and polypropionates in a combinatorial fashion.
Funding: The research was financed by the University of Lausanne, the Ecole Polytechnique Fédérale de Lausanne (EPFL), the Swiss National Science Foundation and the University of Oviedo.