Stereochemistry ketene cycloaddition

Ketenes are especially reactive in [2 + 2] cycloadditions and an important reason is that they offer a low degree of steric interaction in the TS. Another reason is the electrophilic character of the ketene LUMO. As discussed in Section 10.4 of Part A, there is a large net charge transfer from the alkene to the ketene, with bond formation at the ketene sp carbon mnning ahead of that at the sp2 carbon. The stereoselectivity of ketene cycloadditions is the result of steric effects in the TS. Minimization of interaction between the substituents R and R leads to a cyclobutanone in which these substituents are cis, which is the stereochemistry usually observed in these reactions. 

The stereochemistry with respect to the ketene iminium salt in cases of monosubstituted or unsymmetrically disubstituted derivatives in cycloadditions to alkenes show differences from the ketene counterpart. In contrast to ketene cycloadditions of monosubstituted ketenes with alkenes where the substituent in the bicyclic derivative ends up in the endo position, the cycloaddition of two monosubstituted ketene iminium salts with cyclopentene and cyclohexenc gives the e.wp-substituted derivatives 4.6... 

The stereochemistry of ketene cycloadditions is remarkable,50 as exemplified in the following reaction ... 

Figure 3. Carbon-carbon bonds introduced from synthetic building blocks by Nicolaou et al. (A) and Danishefsky et al. (B, C2-C9 broken after ketene cycloaddition). In the putative biosynthesis of the diterpenoid 4,7-oxaeunicellanes from cembranoid precursors, only one additional carbon-carbon bond (Cl-CIO) would have to be formed (C). (1 R1 = (E)-N(6 )-methyluroca-nyl, R2 = beta-D-0(2)-acetylarabinopyranosyl stereochemistry has been omitted for clarity).

The stereochemistry of cycloaddition of chiral alkyl ketenes with imines has been explored in cycloadditions designed to prepare intermediates for carbapcncm synthesis. Reaction of kctcnc (S)-57, prepared by treatment of the acid chloride with diisopropylethylamine at —40 C. with imine 58 gives 90% of the cw-/3-lactam 59 with d.r. [(35,47 )/(3/f,45 )] 87.5 12.579. The ketene rat-60 reacts with imine 61 to give the ci x-/3-lactam 62, d.r. [(2R, 3R )I(2S, 3S )] 70 30 80. 

The stereochemistry of ketene cycloadditions has been a longstanding subject of interest, and the preferences for [2 - - 2] and [4 4- 2] cycloadditions of dihaloketenes with cyclopentadiene (Scheme 4.27) have been compared using various computational methods. ... 

An important point, however, is that although the configurations of the reactants are preserved in the products (i.e. the additions are stereoselective), some cycloadditions, including those of ketenes to imines, occur more rapidly in polar rather than in non-polar solvents (Scheme 8.9). For such examples it may well be that the addition proceeds in a stepwise manner (non-concerted), and the collapse of a dipolar intermediate is so quick that the stereochemistry of the reacting species is not compromised. 

The stereochemistry of ketene to alkcne cycloadditions is such that retention of the alkene configuration is observed. Furthermore, in cycloadditions with unsymmetrically substituted ketenes the larger of the two ketene substituents ends up as with respect to the adjacent alkene substituent (or eiulo in cycloalkene cycloadditions). This stereochemical outcome was originally attributed to the concerted [ff2a + n2a] nature of kctcnc to alkene cycloadditions,21 although more recent experimental and theoretical evidence indicate that these reactions are asynchronous and in some cases in which polarized double bonds are involved actual zwittcrions may be intermediates.9 1195 Also in certain cases the endo product in ketene to alkene cycloadditions may be the thermodynamic product from equilibration studies.22,23 Nevertheless, stereochemical control can be achieved in most such reactions as shown by the examples of 12,24 13,29 14,25 15,26 16,27 and 17.28... 

The 2 + 2-cycloaddition reaction of a-alkoxyketene-derived imines yields /l-lactams with quaternary stereogenic centres at C(4).33 The 2 + 2-cycloaddition of chiral aminoketenes with chiral imines yields cis-fi-lactams with the absolute stereochemistry of file C(3) and C(4) positions being controlled by the ketene partner only.34 The 2 + 2-cycloaddition of ketenes with (W)-2-/-butyldihydrooxazole (19) yields predominately the regioisomer (20) from steric control rather than the expected electronic control (Scheme 7).35 The double 2 + 2-cycloaddition reaction between ketenylidenetriphe-nylphosphorane (21) and carbon suboxide (22) produces the bis(ylidic) spirocyclobut-anedione (23) (Scheme 8).36 Semiempirical and ab initio calculations have been used to investigate the Lewis acid-promoted 2 + 2-cycloaddition leading to the formation of jS-lactones.37... 

Chiral imines derived from D-(+)-glucose have allowed an asymmetric synthesis of p-lactams by the [2+2] cycloaddition with ketenes [85]. c/A-p-Lac tarns were formed with very high diastereoselectivity and the stereochemistry at the C-3 and the C-4 was established as 3S and 4R from the known absolute configuration of the sugar moiety (Scheme 24). 

Abstract The main computational studies on the formation of (3-lactams through [2+2] cycloadditions published during 1992-2008 are reported with special emphasis on the mechanistic and selectivity aspects of these reactions. Disconnection of the N1-C2 and C3-C4 bonds of the azetidin-2-one ring leads to the reaction between ketenes and imines. Computational and experimental results point to a stepwise mechanism for this reaction. The first step consists of a nucleophilic attack of the iminic nitrogen on the sp-hybridized carbon atom of the ketene. The zwitterionic intermediate thus formed yields the corresponding (3-1 actant by means of a four-electron conrotatoty electrocyclization. The steroecontrol and the periselectivity of the reaction support this two-step mechanism. The [2+2] cycloaddition between isocyanates and alkenes takes place via a concerted (but asynchronous) mechanism that can be interpreted in terms of a [n2s + (n2s + n2s)] interaction between both reactants. Both the regio and the stereochemistry observed are compatible with this computational model. However, the combination of solvent and substituent effects can result in a stepwise mechanism. 

This synthesis requires the separation of the diastereoisomers of 92 (obtained from D-penicillamine). An attempt to control the stereochemistry was developed by the Merck group in 1974, in a total synthesis based on the [2+2] cycloaddition of the ketene derived from azidoacetyl chloride and the chiral thiazoline 94. The reaction only gives the /ra .r-pcnam derivative 95, which could be epimerized via the Schiff base 96 (cisltrans ratio = 2 1) (Scheme 51). The separated tyr-isomcr has been transformed into synthetic penicillin G <1974JOC437>. 

It has been long established that Lewis acid-catalysed [2+2] cycloaddition of ketenes and carbonyl compounds provides access to 2-oxetanones. In the development of this reaction prior to 1996, there has been a specific focus on controlling the stereochemistry of the /3-lactone product and cycloadditions have been achieved between trimethyl-silylketene and aldehydes with up to 90% stereoselectivity, as discussed in CHEC-II(1996) <1996CHEC-II(1)721>. CHEC(1984) and CHEC-II(1996) also discuss examples of the Lewis acid-catalyzed, nonphotolytic [2+2] cycloaddition of electron-rich alkenes with aldehydes or ketones <1984CHEC(7)363, 1996GHEC-II(1)721>. While this method can have some advantages over the photolytic reaction in terms of regioselectivity, no examples of this reaction have been reported in recent years. 

A diastereoselective Mukaiyama aldol lactonization between thiopyridylsilylketene acetals and aldehydes was used to form the /3-lactone ring in the total synthesis of (-)-panclicin D <1997T16471>. Noyori asymmetric hydrogenation was a key step in a total synthesis of panclicins A-E and was used to establish the stereocenter in aldehyde 140, which in turn directed the stereochemistry of subsequent reactions <1998J(P1)1373>. The /3-lactone ring was then formed by a [2+2] cycloaddition reaction of 140 with alkyl(trimethylsilyl)ketenes and a Lewis acid catalyst. 

The condensation of an imine with a Reformatsky-type reagent and tandem reactions can result in asymmetric induction.3-207-484 87 The reaction of a ketene with an electron-rich alkene results in a [2+2] cycloaddition, although other systems can also be used,488 90 The stereochemistry of the adduct is cis, and functionalized ketenes can also be used. The ketene can be generated in situ (Scheme 26.21).491... 

Cyclobutanones.1 The carbene 1 when irradiated undergoes [2 + 2]cycloaddition with electron-rich alkenes to give, after decomplexation (02), cyclobutanones in —60-85% yield. The regio- and stereochemistry of the products correspond to that observed with ethoxyketene, which suggests that a ketene intermediate is involved. An intramolecular version of this cycloaddition is also efficient. 

Cycloaddition to alkenes. This ketene adds regioselectively to alkenes, even tet-rasubstituted ones, with preservation of the stereochemistry of the alkene to afford 2-chloro-2-cyanocyclobutanones in good yield. 

Treatment of acid chlorides with tertiary amines produces ketenes. In this case an intramolecular 2 + 2] cycloaddition is possible. The stereochemistry is trivial the cis ring junction is the only... 

The stereochemistry at the remaining centre comes from the way in which the two molecules approach each other. The two components are orthogonal and the dotted lines in the middle diagram below show how the new bonds are formed. The carbonyl group of the ketene will prefer to e in the middle of the ring and the side chain on the ketene will bend down away from the top ring. These [2 + 2] thermal cycloadditions normally give the all-ds product. 

Therefore, some conclusions have been generally accepted and have been summarized as follows the cycloaddition reaction is a stepwise reaction rather than a concerted one the reaction is initiated by nucleophihc attack of an imine to a ketene, giving rise to a zwitterionic intermediate a conrotatory eleclrocyclic ring-closure of the zwitterionic intermediate produces the final 2-azetidone product [85], As the stereochemistry of the structure of the P-lactams strongly affects their biological activity, the stereoselectivity of the process must be carefully considered. Uncatalysed as well as catalysed processes have been reported organometallic and organic catalysts have been utilized in procedures oriented to the syntheses of enantiopure P-lactams [90-92],... 

The synthesis of lipstatin 122 is too complex to discuss here in detail but an early stage in one synthesis uses a clever piece of chemoselectivity.23 Kocienski planned to make the P-lactone by a cycloaddition with the ketene 124 and to add the amino acid side chain 123 by a Mitsunobu reaction involving inversion. They therefore needed Z,Z-125 to join these pieces together. This was to be made in turn by a Wittig reaction from 126. The problem now is that 126 is symmetrical and cannot carry stereochemistry and that aldehydes are needed at both ends. 

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