Synthesis of stereopentad analogues of the C14-C22 segment of callystatin A through additions of chiral allenylzinc reagents to stereotriads.

The addition of (P)- and (M)-allenylzinc reagents, prepared in situ through Pd-catalyzed metalation of (R)- and (S)-3-butyn-2-ol mesylates, to diastereomeric stereotriad aldehydes 8, 13, 18, and 23 of syn,syn, syn,anti, anti,anti, and anti,syn stereochemistry was examined. Additions to the former two aldehydes afforded the four anti adducts with high diastereoselectivity and negligible mismatching. Significant mismatching was observed with the latter two aldehydes and the (M)-allenylzinc reagent. An evaluation of possible transition states is presented in consideration of steric and dipolar control elements.     

Methyl 2,3,4-Tri-O-benzyl-alpha-D-glucopyranosyl-Derived gamma-Silyloxy Allylic Stannanes as Reagents for S(E)2' Additions to Aldehydes

The methyl alpha-D-glucopyranoside allylic stannanes 3.1 and 3.2 were prepared from the 3-(5-pyranosyl)-2-propenal 2.1 and the cuprate Bu(3)Sn(Bu)CuCNLi(2), followed by trapping of the derived enolate with TBSCl. The major stannane, 3.1, underwent BF(3)-promoted addition to 2-nonynal to afford a single syn adduct 4.1 in 70-90% yield. The minor stannane, 3.2, gave rise to a 70:30 mixture of adduct 4.1 and the diastereomeric syn adduct 5.1 under these conditions. The stereochemistry of the adduct 4.1 was proven by degradation of the bis-TBS derivative 4.2 to aldehyde 4.3, prepared independently from the (R,Z)-gamma-OTBS crotyl stannane 4.4 and 2-nonynal along similar lines. Analogous degradation of the adducts 4.1 and 5.1 led to a ca. 65:35 mixture of aldehydes 4.3 and its enantiomer. Accordingly, it can be surmised that the addition of stannane 3.2 to 2-nonynal takes place mainly by a syn S(E)2' pathway. BF(3)-promoted additions to enal 6.1 proceeded as expected. Stannane 3.1 afforded the syn adduct 6.2 in 87-97% yield, and stannane 3.2 gave rise to a 9:1 mixture of syn and anti adducts 7.1 and 7.4 in 70-80% yield.     

Synthesis of a C20-C26 segment of superstolide A by addition of a chiral allenylzinc reagent to (R)-N-boc alaninal

[reaction: see text] Additions of chiral allenylzinc and indium reagents to N-Boc alaninal were examined as a possible route to a C20-C26 segment of superstolide A. Allenylzinc reagents, prepared in situ by palladiozincation of (R)- and (S)-5-pivalyloxy-3-butyn-2-ol mesylate, showed excellent reagent control to afford the anti,syn and anti,anti diastereomers as the nearly exclusive adducts.     

Highly enantioselective michael addition of silyl nitronates to alpha,beta-unsaturated aldehydes catalyzed by designer chiral ammonium bifluorides: efficient access to optically active gamma-nitro aldehydes and their enol silyl ethers

Highly enantioselective Michael addition of silyl nitronates to alpha,beta-unsaturated aldehydes has been accomplished by the utilization of designer N-spiro C2-symmetric chiral quaternary ammonium bifluoride 1 as an efficient catalyst, providing direct access to both optically active gamma-nitro aldehydes, a very useful precursor to various complex organic molecules including aminocarbonyls, and their enol silyl ethers, a Mukaiyama donor of potential synthetic utility for further selective transformations. For instance, the reaction of trimethylsilyl nitronate 2 (R1 = Me) with trans-cinnamaldehyde (R2 = Ph, R3 = H) in toluene in the presence of (R,R)-1 (2 mol %) proceeded smoothly at -78 degrees C to give the desired enol silyl ether 3 (R1 = Me, R2 = Ph, R3 = H) in 90% isolated yield (anti/syn = 83:17) with 97% ee (anti isomer), and simple treatment of 3 thus obtained with 1 N HCl in THF at 0 degrees C afforded the corresponding gamma-nitro aldehyde 4 quantitatively without loss of diastereo- and enantioselectivity.     

Enhancement of diastereoselectivity in photodimerization of alkyl 2-naphthoates with chiral auxiliaries via inclusion within γ-cyclodextrin cavities

Irradiations of alkyl 2-naphthoates are known to result in four isomeric "cubane-like" photodimers: anti(HH)-2, syn(HH)-2, anti(HT)-2, and syn(HT)-2 where the anti(HH)-2, anti(HT)-2, and syn(HT)-2 consist of pairs of diastereomers. Here, chiral auxiliary and chiral microreactor strategies have been combined to achieve high diastereoselectivity in photodimerizations of an enantiomeric pair of 2-naphthoates with (R)- and (S)-1-methoxycarbonylethyl esters as chiral auxiliaries (1R and 1S). Thus, irradiations of their γ-cyclodextrin (γ-CD) complexes have been conducted. Fluorescence, IR, and NMR spectra of both enantiomers of 1 demonstrate that their γ-CD complexes are mainly 2:2 with the molecules of 1 in head-to-head orientations. Irradiation of the complexes in the solid state mainly resulted in anti(HH)-2. The absolute configuration of each diastereomer of anti(HH)-2 has been established for the first time here. The diastereomeric excesses (de's) of anti(HH)-2 from 1R and 1S were 94% and 86%, respectively. These de's are much higher than those found from irradiations in solution (55% for 1R and 1S), where the opposite diastereomeric form is in excess! Calculations of the energies of various conformations of the head-to-head 2:2 inclusion complexes were performed using the PM3 approach. The predicted major diastereomers based on the calculation are consistent with those found experimentally.     

Diastereoselective additions of chiral vinylzinc reagents to alpha-chiral aldehydes

[reaction: see text] Additions of vinylic zinc bromide reagents to alpha-chiral aldehydes (R(1) = CH(2)OTBS, R(2) = Me; R(1) = Me, R(2) = OTBS) in the presence of lithiated (+)- or (-)-N-methylephedrine proceed with predominant reagent control to afford anti or syn adducts stereoselectively, except when the aldehydes possess an alkoxy substituent at the alpha- or beta-positions (R(1) = Me, R(2) = OBn; R(1) = CH(2)OBn, R(2) = Me), in which case chelation-controlled adducts predominate.     

Synthesis of a C1-C21 subunit of the protein phosphatase inhibitor tautomycin: a formal total synthesis

The synthesis of a C1-C21 subunit of tautomycin is described. The convergent route employs enantioenriched allenylstannane and zinc reagents derived from (S)-3-butyn-2-ol methanesulfonate. These reagents react with appropriate aldehyde segments to yield syn and anti adducts with high diastereoselectivity. The derived lithioalkynes are joined stepwise to a CO equivalent, (MeONMe)2C=O, to afford an intermediate ketone which is converted to the core spiroketal moiety of tautomycin upon acid treatment. Chain elongation by another addition of the aforementioned allenylzinc reagent to a spiroketal aldehyde proceeds with high diastereoselectivity to install the remaining stereocenters. The resulting homopropargylic alcohol adduct is converted to a methyl ketone through intramolecular hydrosilylation of the alkyne and Tamao oxidation of the derived five-membered siloxane. This ketone proved identical to an intermediate employed by Chamberlin in a prior total synthesis of tautomycin.     

Regio- and stereoselectivity in the reactions of organometallic reagents with an electron-deficient and an electron-rich vinyloxirane: applications for sequential bis-allylic substitution reactions in the generation of vicinal stereogenic centers

Vinyloxiranes provide opportunities for bis-allylic substitution reactions and the generation of new vicinal stereogenic centers if regio- and stereocontrol can be achieved. Ethyl (E)-4,5-epoxy-2-hexenoate affords excellent S(N)2':S(N)2 regioselectivity and anti:syn product diastereoselectivity with dialkyzinc reagents in the presence of CuCN, and conversion of the resultant allylic alcohol to the acetate affords good syn:anti product diastereoselectivity in S(N)2'-selective allylic substitutions with alkylcyanocuprates in THF. (E)-1-(tert-Butyldimethylsilyloxy)-2,3-epoxy-4-hexenonate gives excellent S(N)2':S(N)2 regioselectivity and anti:syn product diastereoselectivity with dialkyzinc reagents in THF or DMF or Grignard reagents in Et(2)O/THF (10/1) in the presence of CuCN. Conversion of the product allylic alcohol into the allylic phosphate affords excellent S(N)2' regioselectivity and syn:anti product diastereoselectivity with lithium alkylcyanocuprates for primary and secondary alkyl transferable ligands, while S(N)2 regioselectivity is observed for the tert-butyl ligand. Reaction conditions have been developed for regio- and stereocontrolled bis-allylic substitution reactions on both electron-rich and electron-deficient alkenyloxiranes, providing a methodology for the generation of vicinal alkane stereogenic centers.     

Unexpected syn hydride migration in the non-aldol aldol reaction

[structure: see text] Non-aldol aldol rearrangement of the epoxy silyl ether 13b afforded the expected anti methyl ketone 14, while the diastereomeric epoxy silyl ether 13a afforded the syn methyl ketone 8b via an unprecedented syn hydride migration. Calculations suggest that this unusual reaction proceeds via the carbocation, which cannot easily rotate due to steric hindrance.     

Highly efficient aldol additions of DHA and DHAP to N-Cbz-amino aldehydes catalyzed by L-rhamnulose-1-phosphate and L-fuculose-1-phosphate aldolases in aqueous borate buffer

Aldol addition reactions of dihydroxyacetone (DHA) to N-Cbz-amino aldehydes catalyzed by L-rhamnulose-1-phosphate aldolase (RhuA) in the presence of borate buffer are reported. High yields of aldol adduct (e.g. 70-90%) were achieved with excellent (>98?:?2 syn/anti) stereoselectivity for most S or R configured acceptors, which compares favorably to the reactions performed with DHAP. The stereochemical outcome was different and depended on the N-Cbz-amino aldehyde enantiomer: the S acceptors gave the syn (3R,4S) aldol adduct whereas the R ones gave the anti (3R,4R) diastereomer. Moreover, the tactical use of Cbz protecting group allows simple and efficient elimination of borate and excess of DHA by reverse phase column chromatography or even by simple extraction. This, in addition to the use of unphosphorylated donor nucleophile, makes a useful and expedient methodology for the synthesis of structurally diverse iminocyclitols. The performance of aldol additions of dihydroxyacetone phosphate (DHAP) to N-Cbz-amino aldehydes using RhuA and L-fuculose-1-phosphate aldolase (FucA) catalyst in borate buffer was also evaluated. For FucA catalysts, including FucA F131A, the initial velocity of the aldol addition reactions using DHAP were between 2 and 10 times faster and the yields between 1.5 and 4 times higher than those in triethanolamine buffer. In this case, the retroaldol velocities measured for some aldol adducts were lower than those without borate buffer indicating some trapping effect that could explain the improvement of yields.     

Asymmetric aldol reaction organocatalyzed by (S)-proline-containing dipeptides: improved stereoinduction under solvent-free conditions

The organocatalytic activity of the methyl ester of (S)-proline-(S)-phenylalanine, (S,S)-2, in the asymmetric aldol reaction between cyclohexanone and acetone with various aromatic aldehydes under solvent-free conditions in a ball mill has been evaluated. α,α-Dipeptide (S,S)-2 catalyzed the stereoselective formation of the expected aldol products, with higher diastereo- and enantioselectivity relative to similar reactions in solution, up to 91:9 anti:syn diastereomeric ratio and up to 95% enantiomeric excess.     

(R)- and (S)-4-TIPS-3-butyn-2-ol. Useful precursors of chiral allenylzinc and indium reagents

A convenient route to the enantiomers of 4-TIPS-3-butyn-2-ol of >95% enantiomeric purity by reduction of the ynone precursor 4 with the Noyori N-tosyl-1,2-diphenylethylenediamineruthenium cymene catalyst is described. The mesylate derivative of the (S) enantiomer (1c) is converted in situ to an allenylzinc or indium reagent in the presence of a catalyst derived from Pd(OAc)2 and Ph3P and either Et2Zn or InI. A second in situ addition of these reagents to aldehydes leads to anti homopropargylic alcohol adducts. The additions proceed in generally high (60-90%) yield with modest to excellent diastereoselectivity and high enantioselectivity. Only slight mismatching (<5%) is observed with chiral alpha-methyl and alpha-silyloxy aldehydes. Additions to alpha-substituted enals are highly diastereoselective, while beta,beta-disubstituted enals afford ca. 2:1 mixtures of anti and syn adducts.     

Catalysis of 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives in enantioselective anti-Mannich-type reactions: importance of the 3-acid group on pyrrolidine for stereocontrol

The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with alpha-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with alpha-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at the beta-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carbon-carbon bond formation and in directing anti-selectivity and enantioselectivity.     

Rearrangement of the (6S,8R,11S) and (6R,8S,11R) exocyclic 1,N2-deoxyguanosine adducts of trans-4-hydroxynonenal to N2-deoxyguanosine cyclic hemiacetal adducts when placed complementary to cytosine in duplex DNA

trans-4-Hydroxynonenal (HNE) is a peroxidation product of omega-6 polyunsaturated fatty acids. The Michael addition of deoxyguanosine to HNE yields four diastereomeric exocyclic 1,N(2)-dG adducts. The corresponding acrolein- and crotonaldehyde-derived exocyclic 1,N(2)-dG adducts undergo ring-opening to N(2)-dG aldehydes, placing the aldehyde functionalities into the minor groove of DNA. The acrolein- and the 6R-crotonaldehyde-derived exocyclic 1,N(2)-dG adducts form interstrand N(2)-dG:N(2)-dG cross-links in the 5'-CpG-3' sequence context. Only the HNE-derived exocyclic 1,N(2)-dG adduct of (6S,8R,11S) stereochemistry forms interstrand N(2)-dG:N(2)-dG cross-links in the 5'-CpG-3' sequence context. Moreover, as compared to the exocyclic 1,N(2)-dG adducts of acrolein and crotonaldehyde, the cross-linking reaction is slow (Wang, H.; Kozekov, I. D.; Harris, T. M.; Rizzo, C. J. J. Am. Chem. Soc. 2003, 125, 5687-5700). Accordingly, the chemistry of the HNE-derived exocyclic 1,N(2)-dG adduct of (6S,8R,11S) stereochemistry has been compared with that of the (6R,8S,11R) adduct, when incorporated into 5'-d(GCTAGCXAGTCC)-3'.5'-d(GGACTCGCTAGC)-3', containing the 5'-CpG-3' sequence (X = HNE-dG). When placed complementary to dC in this duplex, both adducts open to the corresponding N(2)-dG aldehydic rearrangement products, suggesting that the formation of the interstrand cross-link by the exocyclic 1,N(2)-dG adduct of (6S,8R,11S) stereochemistry, and the lack of cross-link formation by the exocyclic 1,N(2)-dG adduct of (6R,8S,11R) stereochemistry, is not attributable to inability to undergo ring-opening to the aldehydes in duplex DNA. Instead, these aldehydic rearrangement products exist in equilibrium with stereoisomeric cyclic hemiacetals. The latter are the predominant species present at equilibrium. The trans configuration of the HNE H6 and H8 protons is preferred. The presence of these cyclic hemiacetals in duplex DNA is significant as they mask the aldehyde species necessary for interstrand cross-link formation.     

Influence of carrier ligand NH hydrogen bonding to the O6 and phosphate group of guanine nucleotides in platinum complexes with a single guanine ligand

Coordinated N,N',N"-trimethyldiethylenetriamine (Me3dien) has several possible configurations: two have mirror symmetry (R,S configurations at the terminal nitrogens) and the terminal N-Me's anti or syn with respect to the central N-Me (anti-(R,S) and syn-(R,S) isomers, respectively), and two are nonsymmetrical (R,R and S,S configurations at terminal nitrogens, rac denotes a 1:1 mixture of the two isomers). For each configuration, two Me3dienPtG atropisomers can be formed (anti or syn orientation of central N-Me and G 06, G = guanine derivative), and these can be observed since the terminal N-Me's decrease the rate of G rotation about the Pt-N7 bond. In symmetrical syn-(R,S)-Me3dienPtG derivatives with G = 9-EtG and 3'-GMP, the anti rotamer, which can form O6-NH H-bonds, was slightly favored over the syn rotamer but never more than 2:1. This anti rotamer is also favored by lower steric repulsion between the terminal N-Me's and G O6; thus, the contribution of O6-NH H-bonding to the stability of the anti rotamer could be rather small. With G = 5'-GMP, an O6-NH H-bond in the anti rotamer and a phosphate-NH H-bond in the syn rotamer can form. Only the syn rotamer was detected in solution, indicating that NH H-bonds to 5'-phosphate are far more important than to O6, particularly since steric factors favor the anti rotamer. Interconversion between rotamers was faster for syn-(R,S)- than for rac-Me3dien derivatives. This appears to be determined by a smaller steric impediment to G rotation of two "quasi equatorial" N-Me's, both on one side of the platinum coordination plane (syn-(R,S) isomer), than one "quasi equatorial" and one "quasi axial" N-Me on either side of the coordination plane (rac isomer).     

Unraveling the mechanism of epoxide formation from sulfur ylides and aldehydes

Sulfur ylides R(2)S(+)-C(-)HR' react with aldehydes R' '-CHO to form epoxides, predominantly as the trans isomers, in a synthetically useful reaction which is increasingly used in its asymmetric variant with chiral sulfides. The mechanisms of the "model" reaction (R = Me, R' = R' ' = H) and the reaction forming stilbene oxide (R = Me, R' = R' ' = Ph) have been studied in detail using density functional theory, the B3LYP density functional, and flexible basis sets. It has been shown that for this reaction involving highly polar intermediates, continuum solvation models need to be used throughout to obtain reasonable results. For the reaction of benzaldehyde with dimethylsulfonium benzylide, the key steps are shown to be quasi [2 + 2] addition of the ylide to the aldehyde to form a betaine R'-CH(S(+)Me(2))-CH(O(-))-R' ' in which the charged groups are gauche to one another, and torsional rotation around the C-C single bond of the betaine to form its rotamer with the two charged groups anti. The final step, elimination of sulfide from this second rotamer of the betaine, is found to be facile. In the case of the anti pathway, leading to trans-stilbene epoxide, the initial addition is found to be rate-determining, whereas for the diastereomeric syn pathway, leading to the cis-epoxide, it is instead the torsional rotation which is slowest. These results are in excellent agreement with experiment, unlike previous computational work. The unexpected and apparently unprecedented (for C-C bond-forming reactions) importance of the torsional rotation step, especially in the syn case, is due to the fact that all the barriers involved are low-lying. This novel picture of the mechanism provides a sound basis for the future development of chiral sulfides for enantioselective epoxide synthesis.     

Direct catalytic asymmetric Mannich-type reaction of hydroxyketone using a Et2Zn/linked-BINOL complex: synthesis of either anti- or syn-beta-amino alcohols

Full details of a direct catalytic asymmetric Mannich-type reaction of a hydroxyketone using a Et2Zn/(S,S)-linked-BINOL complex are described. By choosing the proper protective groups on imine nitrogen, either anti- or syn-beta-amino alcohol was obtained in good diastereomeric ratio, yield, and excellent enantiomeric excess using the same zinc catalysis. N-Diphenylphosphinoyl (Dpp) imine 3 gave anti-beta-amino alcohols in anti/syn = up to >98/2, up to >99% yield, and up to >99.5% ee, while Boc-imine 4 gave syn-beta-amino alcohols in anti/syn = up to 5/95, up to >99% yield, and up to >99.5% ee. The high catalyst turnover number (TON) is also noteworthy. Catalyst loading was successfully reduced to 0.02 mol % (TON = up to 4920) for the anti-selective reaction and 0.05 mol % (TON = up to 1760) for the syn-selective reaction. The Et2Zn/(S,S)-linked-BINOL complex exhibited far better TON than in previous reports of catalytic asymmetric Mannich-type reactions. Mechanistic studies to clarify the reason for the high catalyst efficiency as well as transformations of Mannich adducts are also described.     

A new, non-iterative asymmetric synthesis of long-chain 1,3-polyols

A new approach to the asymmetric synthesis of pentadeca-1,3,5,7,9,11,13,15-octols and their derivatives is presented. It is based on the Sharpless asymmetric dihydroxylation (AD) of 4,4'-methylene[(1R,1'S,6R,6'S)-6-acetoxycyclohept-3-en-1-yl]bis(4-methoxybenzoate) (9), derived from a double [3+4] cycloaddition of the 1,1,3-trichloro-2-oxyallyl cation with 2,2'-methylenedifuran (1). The diol (-)-10, obtained in 98.4% ee from 9 with "AD-mix-beta(5x), was oxidised into (2R and 2S,4S,6R)-tetrahydro-2-hydroxy-6-((4S,6S)-(6-hydroxy-4-[(4-methoxybenzoyl)oxy]cyclohept-1-en-1-yl)-2-oxopropyl)-2H-pyran-4-yl 4-methoxybenzoates ((-)-18). By the combinations of Evans' anti and Nasaraka's syn reductions of aldol (-)-18 with the double Mitsunobu reaction, 16 diastereomeric pentadeca-1,3,5,7,9,11,13,15-octols and analogues can be obtained, in principle, with high enantio- and diastereoselectivities.     

Intramolecular photocycloadditions of 6,6′-dimethyl-4,4′-polymethylenedioxy-di-2-pyrones

Photosensitized reactions of 4,4′-polymethylene-di-2-pyrones 2b-e afforded [2+2]-cycloadducts 3-5 , site-selectively. The selectivity depended upon the methylene chain length. Namely, the three carbon chain gave a syn head-to-head adduct 3b at the 3,4-position of the 2-pyrone ring, the four to six carbon chains gave syn head-to-head adducts 4c-e at the 5,6-position and/or anti head-to-head adducts 5d,e at the 5,6-position, respectively. The intramolecular cycloaddition mechanism was also explained from results calculated by means of PM3-CI method.     

Gamma-radiolysis DNA products: synthesis of 6-(alpha-thyminyl)-5,6-dihydro-4-thiothymine derivatives

Far-UV photolysis of 4-thiothymidylyl(3'-5')thymidine led to the formation of three stable derivatives: one resulting from a combination between a 3'-end methylene radical and a 5'-end C(4) radical [4-(alpha-thyminyl) derivative] and two formed after a combination between a 3'-end methylene radical and a 5'-end C(6) radical [6-(alpha-thyminyl) derivative]. In the latter series, two stereochemical pathways took place during the reaction between the methylene and C(6) radicals. The major pathway occurred when the 5'-base glycosidic bond had an anti conformation leading to an S configuration of the C(6) Tp-end. The minor pathway, which had never been reported before in this series, involved a 5'-base in a syn conformation leading consequently to the R configuration at the C(6) Tp-end. The 5,6-dihydrothymine moiety of these two adducts presented a 5,6-trans diaxial substitution that resulted from the epimerization, at the 5,6-dihydropyrimidine 5-position, of a less stable cis-disubstituted intermediate.