Stereoselective azidation

Oppolzer s camphor sultam, a well known chiral auxiliary, has been applied to the asymmetric synthesis of chial fluorine-containing amino acids <07OL2513>. Photoinduced addition of perfluoroalkyl iodides 189 to /V-acyloylcamphorsultam 188 in the presence of an aqueous solution of sodium sulfite provides alkyl iodides 190 with moderate to good stereoselectivities. Azide displacement with the major diastereomer of 190 proceeds with inversion of configuration. Subsequent removal of the sultam auxiliary and hydrogenation of the azide afford the chiral fluorine-containing amino acid 192. 

A mechanistic rationale for the observations is presented, although it is not really known why it is the potassium enolate, the trisyl azide and the acetic acid quench that lead to the high yield in the stereoselective azide transfer reactions2. The diastereomeric //-configurated carbox-imides were prepared via a bromination/azide substitution sequence, not detailed here2. 

The application of these observations to a stereoselective azide transfer is shown in the following example. Reaction of the dilithiuni compound 6, prepared from the racemic 3-hy-droxybutyrate 5 with trisyl azide and acetic acid quench, leads to the (3-hydroxy-a-azido ester 7 in 77% yield and a diastereoselection d.r. [(2R, >R )/(2R, 3S )] of 82 18 (determined by H NMR). 

This multi-step scheme illustrates the synthetic efforts that have been invested in the construction of homochiral biaryl 15 without loss of enantiomeric purity. It covers many significant modem synthetic reactions diastereoselective cyanation, of the carbonyl group in (-i-)-9 in step i, promoted by a fi-orientation of the carbonyl oxygen to the orffio-substituent as the result of a stereoelectronic effect [52] oxidative removal of the Cr(CO)3 group in 13 (step vi) and stereoselective azidation with inversion of the configuration (step vii). For more details, the interested reader should consult the cited literature. 

The use of Af,Af-dimethylethylenediamine (DMEDA) as a base catalyst in an aqueous solution of ethanol/toluene for the stereoselective azidation under click reaction conditions (copper (II) salts and L-ascorbate) is the very efficient way to accomplish this [3+2] cycloaddition. The intermediate addition product formed under the reaction conditions is an unstable triazoline, which immediately decomposes (with the loss of nitrogen) with the exclusive formation of aziridines-ffised ffirobenzoxazocine or benzodiazocine as depicted in Scheme 6.7. 

The properties of chlorine azide resemble those of bromine azide. Pon-sold has taken advantage of the stronger carbon-chlorine bond, i.e., the resistance to elimination, in the chloro azide adducts and thus synthesized several steroidal aziridines. 5a-Chloro-6 -azidocholestan-3 -ol (101) can be converted into 5, 6 -iminocholestan-3l -ol (102) in almost quantitative yield with lithium aluminum hydride. It is noteworthy that this aziridine cannot be synthesized by the more general mesyloxyazide route. Addition of chlorine azide to testosterone followed by acetylation gives both a cis- and a trans-2iddMct from which 4/S-chloro-17/S-hydroxy-5a-azidoandrostan-3-one acetate (104) is obtained by fractional crystallization. In this case, sodium borohydride is used for the stereoselective reduction of the 3-ketone... 

An in depth account of intramolecular 1,3-dipoIar cycloadditions involving dipoles such as nitrUe oxides, sUyl nitronates, H-nitrones, azides, and nitrUimines is presented with particular emphasis on the stereochemistry during the cycloaddition. Various methods employed for the generation of the dipoles and their applications to stereoselective synthesis are also discussed. 

Keywords Intramolecular 1,3-dipolar cycloadditions. Stereoselectivity, Nitrile oxides, SUyl nitronates. Oximes, H-Nitrones, Azides, NitrUimines... 

Similarly, diethylaluminum azide gives (3-azido alcohols. The epoxide of 1-methylcyclohexene gives the tertiary azide, indicating that the regiochemistry is controlled by bond cleavage, but with diaxial stereoselectivity. 

The indium-mediated allylation of trifluoroacetaldehyde hydrate (R = H) or trifluoroacetaldehyde ethyl hemiacetal (R = Et) with an allyl bromide in water yielded a-trifluoromethylated alcohols (Eq. 8.56).135 Lanthanide triflate-promoted indium-mediated allylation of aminoaldehyde in aqueous media generated (i-airiinoalcohols stereoselectively.136 Indium-mediated intramolecular carbocyclization in aqueous media generated fused a-methylene-y-butyrolactones (Eq. 8.57).137 Forsythe and co-workers applied the indium-mediated allylation in the synthesis of an advanced intermediate for azaspiracids (Eq. 8.58).138 Other potentially reactive functionalities such as azide, enone, and ketone did not compete with aldehyde for the reaction with the in situ-generated organo-indium intermediate. 

The stereoselective total synthesis of (+)-epiquinamide 301 has been achieved starting from the amino acid L-allysine ethylene acetal, which was converted into piperidine 298 by standard protocols. Allylation of 297 via an. V-acyliminium ion gave 298, which underwent RCM to provide 299 and the quinolizidine 300, with the wrong stereochemistry at the C-l stereocenter. This was corrected by mesylation of the alcohol, followed by Sn2 reaction with sodium azide to give 301, which, upon saponification of the methyl ester and decarboxylation through the Barton procedure followed by reduction and N-acylation, gave the desired natural product (Scheme 66) <20050L4005>. 

The direct, stereoselective conversion of alkynes to A-sulfonylazetidin-2-imines 16 by the initial reaction of copper(l) acetylides with sulfonyl azides, followed, in situ, by the formal [2+2] cycloaddition of a postulated A-sulfonylketenimine intermediate with a range of imines has been described <06AG(E)3157>. The synthesis of A-alkylated 2-substituted azetidin-3-ones 17 based on a tandem nucleophilic substitution followed by intramolecular Michael reaction of primary amines with alkyl 5-bromo-4-oxopent-2-enoates has been... 

Enantiomerically pure 4,5,6-trihydroxy-norleucins (for instance 325) were obtained (197) from the hex-2-enono-1,4-lactone-2-mesylates (such as 152). These butenolides were stereoselectively hydrogenated to afford, upon treatment with sodium azide, the C-2-inverted derivatives, such as 324. Reduction of the azide function and hydrolysis of the acetal group gave the amino acids (namely 325), which were converted into lactones in acid media. 

In a similar way glycosyl diphenyl phosphates have been used in the stereoselective preparation of glycosyl azides on SN2-typc displacement of the phosphate group by sodium azide.27... 

A study of the kinetics and products of the thermolysis of a series of diaryl-phosphinic azides has been reported.119 Diethyl 1-diazomethylphosphonates undergo an aldol-type reaction with aldehydes to give l-diazo-2-hydroxyalkylphosphonates (152).120 Acidification of the diazophosphonates (153) possessing a chiral phosphorus centre yields mixtures of diastereoisomers (154) and epimers at C. For given R1 and R2, the reaction becomes increasingly stereoselective for X= OAc < Cl < OTs. It may be argued that protonation of (153) will yield a mixture of diastereoisomeric di-... 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

Jacobsen and coworkers discovered that chiral salicylimidato transition metal complexes activate epoxides in a stereoselective manner. The published mechanism indicates that one Cr° (salen)-N3 with (/ ,/ )-cyclohexyl backbone acts as Lewis acid and coordinates to the oxygen of PO, while a second catalyst molecule transfers the azide to the activated epoxide and thus opens the ring. The coplanar arrangement of the two chromium complexes prefers one enantiomer of PO and so induces stereochemical information [99,100, 121-129]. (cf. also Sect. 8.3) (Fig. 42). 

The Glaxo synthesis of zanamivir (2) started with the esterification of commercially available A-acetyl-neuraminic acid (88) with methanolic HCl to give the methyl ester as shown in Scheme 7.14 (Chandler and Weir, 1993 Chandler et ah, 1995 Patel, 1994 Weir et al., 1994). Global acetylation of all the hydroxyl groups with acetic anhydride in pyridine with catalysis by 4-(dimethylamino)pyridine (DMAP) led to the penta-acetoxy compound 89. Treatment of 89 with trimethylsilyl triflate in ethyl acetate at 52°C introduced the oxazoline as well as the 2,3-double bond to provide 86. Addition of trimethysilyl azide to the activated allylic oxazoline group led to the stereoselective introduction of azide at the C-4 position to afford 83 as in Scheme 7.13. 

Alternatively, the amino group was introduced subsequent to the reductive formation of the fluoroalkene [72]. The regio- and stereoselective conversion of the C5-hydroxyl group of the fluoroolefin to an amino group could be achieved through one-pot mesylation and azidation reaction (Scheme 25). 

The stereoselective intermolecular cycloaddition of azides to chiral cyclopenta-none enamines was reported, but both product yields and enantiomeric excesses (ee) were low (24) (Scheme 9.24). Ethyl azidoformate (115) and A-mesyl azido-formamimidate (116) underwent 1,3-dipolar cycloaddition with the monosubsti-tuted chiral enamine 114 to give products 117 and 118 in low yields with ee of 24 and 18%, respectively. Intermolecular cycloaddition of the A-mesyl azidoforma-mhnidate 116 with the disubstituted C2-symmetric chiral enamine 119 proceeded with good diastereoselectivity to give compound 120 in 18% yield. On cleavage of the enamine unit, compound 120 afforded 118 with low ee. 

An efficient stereoselective synthesis of the (pyrrolidin-2-ylidene)glycinate intermediate 325 was reported in a total synthesis of carzinophilin (326), employing an intramolecular cycloaddition of an azide with an alkene (63) (Scheme 9.63). The arabinose derivative 319 was converted into the required azide 321 via the triflate 320. Thermolysis of the azide 321 at 50 °C in THF produced the unstable triazoline 322, which on rearrangement gave the (pyrrolidin-2-ylidene)glycinate 325 in 60-72% overall yield from the triflate 320. 

Hudlicky et al. (65) reported a formal stereoselective total synthesis of the oxygenated pyrrolizidine alkaloids platynecine (336), dihydroxyheliotridane (337), hastanecine (341), and tumeforcidine (342), involving an intramolecular azide-diene cycloadditions (Scheme 9.65). Intramolecular 1,3-dipolar cycloaddition of... 

Pearson et al. (68) reported a versatile approach to pyrrolizidine and indolizidine alkaloids such as 355, 247, and 362 using intramolecular cycloadditions of azides with electron-rich dienes (Scheme 9.68). Azido dienes 353, 357, and 360 that possess a electron-donating group on the diene were prepared from the respective compounds 352, 356, and 359. On heating at 100 °C, the azido diene 353 underwent smooth intramolecular 1,3-dipolar cycloaddition in a stereoselective... 

---