Polypropionate synthesis 3+2 reactions

Scheme 24) [38]. Chemoselective enolization of the less substituted enone moiety under hydrogenation conditions accompanied by subsequent aldol reaction provided the corresponding hydroxyl-enones, such as 87-89, which could be converted to various building blocks for polypropionate synthesis. p-Me2N styryl vinyl enone also was employed successfully as an enolate precursor, as demonstrated by the formation of hydroxy enone 90. 

Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

SCHEME 10.3. Example of iterative sequences of aldol and crotylation reactions in planning of polypropionate synthesis. 

A different strategy that has also been well smdied for polypropionate synthesis is the hetero-Diels-Alder (HDA) reaction. The Danishefsky group has reported on one of the first attempts to obtain polypropionates via this method-ology. His group focused on the pyran subunit, a... 

Paterson I, Wallace DJ, Velazquez SM. Studies in polypropionate synthesis high -rr-face selectivity in syn and anti aldol reactions of chiral boron enolates of lactate-derived ketones. Tetrahedron Lett. 1994 35 9083-9086. 

Paterson I, Goodman JM, Isaka M. Aldol reactions in polypropionate synthesis high rr-face selectivity of enol hori-nates from a-chiral methyl and ethyl ketones under substrate control. Tetrahedron Lett. 1989 30 7121-7124. 

Paterson I, Tillyer RD. Studies in polypropionate synthesis high TT-face selectivity in syn aldol reactions of tin(II) enolates from (R)- and (S)-l-benzyloxy-2-methylpentan-3-one. Tetrahedron Lett. 1992 33 4233 236. 

Many examples of stereospecific allylation consistent with the above mechanism have been reported. As one example, the regioselective and highly diastereoselective allylation of the lactone 17 with the optically active allylic phosphate 16 proceeded with no appreciable racemization of the allylic part to give the lactones l8 and 19, and the reaction has been used for the synthesis of a polypropionate chain[26]. 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

Entry 10 was used in conjunction with dihydroxylation in the enantiospecific synthesis of polyols. Entry 11 illustrates the use of SnCl2 with a protected polypropionate. Entries 12 and 13 result in the formation of lactones, after MgBr2-catalyzed additions to heterocyclic aldehyde having ester substituents. The stereochemistry of both of these reactions is consistent with approach to a chelate involving the aldehyde oxygen and oxazoline oxygen. 

Scheme 20. Stereoselective synthesis of polypropionate fragments by a three-component pericyclic domino reaction...

The addition of an enolsilane to an aldehyde, commonly referred to as the Mukaiyama aldol reaction, is readily promoted by Lewis acids and has been the subject of intense interest in the field of chiral Lewis acid catalysis. Copper-based Lewis acids have been applied to this process in an attempt to generate polyacetate and polypropionate synthons for natural product synthesis. Although the considerable Lewis acidity of many of these complexes is more than sufficient to activate a broad range of aldehydes, high selectivities have been observed predominantly with substrates capable of two-point coordination to the metal. Of these, benzy-loxyacetaldehyde and pyruvate esters have been most successful. 

Scheme 2.6 provides an overall view of our strategy towards solving this problem. As depicted, our late generation synthesis embraces three key discoveries that were crucial to its success. We anticipated that the difficult Cl-Cll polypropionate domain could be assembled through a double stereodifferentiating aldol condensation of the C5-C6 Z-metalloenolate system B and chiral aldehyde C. Two potentially serious problems are apparent upon examination of this strategy. First was the condition that the aldol reaction must afford the requisite syn connectivity between the emerging stereocenters at C6-C7 (by uk addition) concomitant with the necessary anti relationship relative to the resident chirality at C8 (by Ik diastereoface addition). Secondly, it would be necessary to steer the required aldol condensation to C6 in preference to the more readily enolizable center at C2. 

To improve the levels of selectivity in additions to chiral aldehydes, it is possible to resort to the tactic of double diastereoselection with the use of chiral allylic boranes and boronates (see section Double Diastereoselection ). Bis(isopinocampheyl) allylic boranes and the tartrate allylic boronates (see following section), in particular, are very useful in the synthesis of polypropionate natmal products by reaction with a-methyl and a-alkoxy functionalized aldehydes. 

In 2007, Betzer, Ardisson and co-workers reported their synthesis of discodermo-lide [64] following the Marshall disconnection strategy of C7-C8 acetylide addition and Suzuki cross-coupling at C14-05 (Scheme 32) [53, 54], The synthesis of the key subunits 160 (C1-C7), 161 (C8-C14) and 162 (C15-C24) demonstrated the versatility of the Hoppe crotyltitanation reaction [166-169] in the synthesis of polypropionate motifs, using the incorporated (Z)-0-enecarbamate to configure the requisite alkene substitution patterns [170, 171],... 

In a more complex scenario, the /J-substituents were also found to participate in partially matched or mismatched reactions577. Examples of double induction pave the route of polypropionate and polyketide synthesis and it was emphasized that the relative influence of the enolate or aldehyde component may be enhanced, depending on the coordinating metal employed in the double stereodifferentiating aldol reaction. Thus, it was found that, in spite of their modest synlanti selectivity, lithium enolates are effective in double stereodifferentiating aldol reaction578. In the matched and partially matched cases, lithium enolate face selectivity is opposite to that which is found for their boron or titanium counterparts. This is perfectly illustrated in a recent work by Roush and coworkers reporting a partial synthesis of Bafilomycin Aj (Scheme 122)579. 

Further developments have been made in the thiopyran approach to polypropionates based on the stereochemical control of the reaction of tetrahydrothiopyran-4-one with l,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde <07JOC1667>. The potential of this chemistry is illustrated by a nine-step enantioselective synthesis of membrenone B 63 <07JOC7805>. 

Hu, T., Takenaka, N., Panek, J. S. Asymmetric Crotylation Reactions in Synthesis of Polypropionate-Derived Macrolides Application to Total Synthesis of Oleandolide. J. Am. Chem. Soc. 2002,124,12806-12815. 

Aldol reactions using chiral auxiliaries are popular as the stereochemical outcome is usually highly predictable and, as such, they provide a reliable method for the incorporation of adjacent stereocenters. The oxazolidinone-based imides 36 and (ent)-36 are the most commonly employed, and these lead to syn aldol products with high levels of stereocontrol [20]. The reaction can be extended to include a variety of a-heteroatom functionality as in 37 (Scheme 9-13) [21]. Numerous examples of the use of these auxiliaries in the synthesis of polypropionate natural products have been reported. Many related auxiliaries are also available and the camphor-based sultam 38 is notable [22]. 

In the Evans synthesis of the polypropionate region (Scheme 9-45), the boron-mediated anti aldol reaction of -ketoimide ent-25 with a-chiral aldehyde 145 afforded 146 with 97% ds in what is expected to be a matched addition. Adduct 146 was then converted into aldehyde 147 in readiness for union with the C -Cs ketone. This coupling was achieved using the titanium-mediated syn aldol reaction of enolate 148 leading to the formation of 149 with 97% ds. 

A synthesis of both the polypropionate and spiroacetal fragments of rutamycin B have been described by Panek and Jain [65]. The majority of stereocenters were introduced via asymmetric allylation and crotylation reactions however, an aldol... 

The reaction of carbonyl compounds and allylmetal reagents is an important transformation in organic synthesis. Advances in stereoselective carbonyl allylation reactions have been spurred by interest in the synthesis of polypropionate-derived natural products, carbohydrates and other polyhydroxylated compounds. These reactions are ideally suited for the construction of stereochemically rich acyclic skeletons. Additionally, cyclic polyether-containing natural products, among others, have inspired chemists to investigate ring-closing allylation reactions. This review will focus on recent developments in the allylation reaction, with special emphasis on its application towards the synthesis of natural products. 

In their synthesis of (-i-)-damavaricin D (Fig. 11-24), Ronsh and co-workers used crotylboronate methodology three times in the assembly of the C(I)-C(13) polypropionate segment 250 [178, 204, 205]. The synthesis of 250 was designed so that chain growth occurs from C(13) to C(l) and such that the mismatched reaction necessary to install the C(10)-C(12) anp. anfl-dipropionate stereotriad could be dealt with early in the synthetic sequence, when the aldehyde substrate had a relatively modest diastereofacial bias (Scheme 11-9). 

Panek and co-workers have demonstrated that crotylsilanes 217 and 343 react with a variety of electrophiles including aldehydes, a, ff-unsaturated ketones, acetals and imines under appropriate activation conditions (usually Lewis acidic) to form homoallylic ethers [149, 261], homoallylic alcohols [58, 150, 151], tetrahy-drofurans [262, 263], cyclopentanes [264], pyrrolidines and homoallylic amines [265] with high levels of enantio- and diastereoselectivity [12]. This review will focus on the reactions of crotylsilanes 217 with Lewis acid-activated acetals and aldehydes, and the application of these reactions to the synthesis of polypropionate natural products [266-271]. 

Marshall s chiral allenylmetal reagents have been utilized in double asymmetric reactions with chiral aldehydes for the synthesis of polypropionate natural products. All four dipropionate diastereomers are accessible from the reactions of chiral allenylmetal reagents with a-chiraI-y5-alkoxy aldehydes 97 (153, 158, 276, 277]. The BF3-OEt2-catalyzed addition of allylstannane (l )-218a to aldehyde 97a occurs in high yield and diastereoselectivity to give the xyn.syn-dipropionate 395, presumably through either the synclinal or antiperiplanar Felkin transition states 396 and 397 (Eq. (11.31)). 

---