Aldehydes stereoselective synthesis

HIYAMA - HEATHCOCK Stereoselectiveailylation Stereoselective synthesis o( anti homoaitylic alcohols by Cr promoted atlylation o( aldehydes. 

An expedient and stereoselective synthesis of bicyclic ketone 30 exemplifies the utility and elegance of Corey s new catalytic system (see Scheme 8). Reaction of the (R)-tryptophan-derived oxazaboro-lidine 42 (5 mol %), 5-(benzyloxymethyl)-l,3-cyclopentadiene 26, and 2-bromoacrolein (43) at -78 °C in methylene chloride gives, after eight hours, diastereomeric adducts 44 in a yield of 83 % (95 5 exo.endo diastereoselectivity 96 4 enantioselectivity for the exo isomer). After reaction, the /V-tosyltryptophan can be recovered for reuse. The basic premise is that oxazaborolidine 42 induces the Diels-Alder reaction between intermediates 26 and 43 to proceed through a transition state geometry that maximizes attractive donor-acceptor interactions. Coordination of the dienophile at the face of boron that is cis to the 3-indolylmethyl substituent is thus favored.19d f Treatment of the 95 5 mixture of exo/endo diastereo-mers with 5 mol % aqueous AgNC>3 selectively converts the minor, but more reactive, endo aldehyde diastereomer into water-soluble... 

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

Allylboron compounds have proven to be an exceedingly useful class of allylmetal reagents for the stereoselective synthesis of homoallylic alcohols via reactions with carbonyl compounds, especially aldehydes1. The reactions of allylboron compounds and aldehydes proceed by way of cyclic transition states with predictable transmission of olefinic stereochemistry to anti (from L-alkene precursors) or syn (from Z-alkene precursors) relationships about the newly formed carbon-carbon bond. This stereochemical feature, classified as simple diastereoselection, is general for Type I allylorganometallicslb. 

An interesting and stereoselective synthesis of 1,3-diols has been developed which is based on Lewis acid promoted reactions of /f-(2-propenylsilyloxy (aldehydes. Using titanium(IV) chloride intramolecular allyl transfer takes place to give predominantly Ag/r-l,3-diols, whereas anti-1,3-diols, formed via an / / /-molecular process, are obtained using tin(IV) chloride or boron trifluoride diethyl ether complex71. 

The stereoselectivity of Lewis acid promoted reactions between 2-butenylstannanes and aldehydes has been widely studied, and several very useful procedures for stereoselective synthesis have been developed. In particular syn-products are formed stereoselectively in reactions between trialkyl- and triaryl(2-butenyl)stannanes, and aldehydes induced by boron trifluoride-diethyl ether complex, irrespective of the stannane geometry66. 

Figure 10.28 Complementary routes for the stereoselective synthesis of hydrolytically stable sugar phosphonates, either from the bioisosteric phosphonate analog of DHAP or from phosphonylated aldehydes.

An extension of this method can be used to prepare allylic alcohols. Instead of being protonated, the (3-oxido ylide is allowed to react with formaldehyde. The (J-oxido ylide and formaldehyde react to give, on warming, an allylic alcohol. Entry 12 is an example of this reaction. The reaction is valuable for the stereoselective synthesis of Z-allylic alcohols from aldehydes.245... 

The overall transformation of this sequence corresponds to the aldol addition of an aldehyde with a cyclic ketone. The actual aldol addition frequently proceeds with low stereocontrol, so this sequence constitutes a method for stereoselective synthesis of the aldol adducts. The reaction has been done with several Lewis acids, including SnCl4, BF3, and Ti(0-/-Pr)3Cl. 

Treatment of 122 with (R,R)-tartrate crotyl-boronate (E.R.R)-W 1 provides the alcohol corresponding to 123 with 96% stereoselectivity. Benzylation of this alcohol yields 123 with 64% overall yield. The crude aldehyde intermediate obtained by ozonolysis of 123 is again treated with (Z,R,R)-111 (the second Roush reaction), and a 94 5 1 mixture of three diastereoisomers is produced, from which 124 can be isolated with 73% yield. A routine procedure completes the synthesis of compound 120, as shown in Scheme 3-44. Heating a toluene solution of 120 in a sealed tube at 145°C under argon for 7 hours provides the cyclization product 127. Subsequent debromination, deacylation, and Barton deoxygenation accomplishes the stereoselective synthesis of 121 (Scheme 3-44). 

The Wittig reaction was employed to fuse diene 49 and aldehyde 50, in the final stages of the stereoselective synthesis of epothilone B, a macrocyclic compound with potential antifungal properties (equation 31)49. 

Scheme 3.7. Diastereoselective formation of /S-silyl ( )- or (Z)-ester enolates by silylcuprate conjugate addition followed by alkylation with aldehydes [49]. Stereoselective synthesis of ( )-and (Z)-allyl silanes [50].

Metallic tin, Sn(0), is even more effectively employed. For example, in the presence of Sn(0), allyl bromide and a-halocarbonyl compounds afford nucleophilic organometallic species, which add to aldehydes in good yields to give homoallylic alcohols (12) and g-hydroxycarbonyl compounds (13,14) respectively. a-Diketones could be reduced by activated Sn(0), to give tin(II) enediolates which in turn undergo aldol reaction to form a,g-dihydroxyketones (15,16). This reaction was successfully applied to a stereoselective synthesis of methyl D-glucosaminate (17). 

Huang, X.-T. Chen, Q.-Y. Ethyl a-Fluoro Silyl Enol Ether Stereoselective Synthesis and Its Aldol Reaction with Aldehydes and Ketones. J. Org. Chem. 2002, 67, 3231-3234. 

Another stereoselective synthesis (Scheme 11) is based on sugar aldehyde 35 and intermediate 36 subsequent 1,2-O-isopropylidine deprotection, N,0-debenzylation/olefin reduction/reductive cyclization in a single pot, and O-acetylation result in the formation of bicyclic aza sugar 37 (09TA1217). 

Murakami and Taguchi utilized a diastereoselective Grignard addition to a substituted-chiral oxazoline aldehyde 524 (Scheme 8.170) in an improved stereoselective synthesis of D-n7 o-phytosphingosine. The good stereoselectivity observed for 525 can be rationalized by a Felkin-Ahn transition state model although a chelation control mechanism could not be mled out. 

The other stereoselective synthesis/281 shown in Scheme 8, foresees conversion of Boc-L-Asp-OtBu 20 into the related (3-aldehyde 22 via the Weinreb amide 21 and its reduction with diisobutylaluminum hydride (DIBAL-H). Wittig condensation of 22 with the ylide derived from (3-carboxypropyl)triphenylphosphonium bromide using lithium hexamethyldisilaza-nide at —78 to 0°C, produces the unsaturated compound 23 which is catalytically hydrogenated to the protected L-a-aminosuberic acid derivative 24. Conversion of the co-carboxy group into the 9-fluorenylmethyl ester, followed by TFA treatment and reprotection of the M -amino group affords Boc-L-Asu(OFm)-OH (25). 

A range of electrophiles has been applied successfully, including I2, NCS, TMSC1, acid chlorides and aldehydes. The use of the latter allows the stereoselective synthesis of homopropargylic alcohols 34 (equation 14). 

A stereoselective synthesis of all E retinal, via a condensation of a Cio chloroacetal with (3-eyelogerany 1 sulfone was described by Julia et al. [29]. The chloroacetal was reacted with the silylenol ether, using TiCl4/Ti(OMe)4, to give in 63% yield, the chloromethoxyacetal derivative as a mixture of E Z isomers (80/20). The aldehyde was converted in 97% yield into the corresponding acetal with HC(OMe)3 and camphorsulfonic acid in methanol, Fig. (6). 

Babler and Schlidt [86] described a route to a versatile C15 phosphonate, used for a stereoselective synthesis of all E retinoic acid and p-carotene. Base-catalyzed isomerization of the vinyl-phosphonate afforded the corresponding allyl-phosphonate as the sole product. Homer-Emmons olefination with ethyl 3-methyl-4-oxo-2-butenoate concluded the facile synthesis of all E ethyl retinoate. The C15 phosphonate was synthesized starting from the epoxide of P-ionone. Subsequent isomerization with MgBr2, afforded the C14 aldehyde in 93%... 

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