P-Lactams, 3-hydroxy

Hydroxyazetidin-2-ones can be oxidised efficiently to azetidine-2,3-diones by P205 in DMSO <00JPR585>, and then the 3-carbonyl group can be alkylated stereoselectively by application of the Baylis-Hillman reaction <99TL7537> or by use of substituted propargyl bromides to provide densely functionalized 3-hydroxy-P-lactams . 

Indium mediated allylation of 4-acetoxy-2-azetidinones gave the products 57 in high yield <99SL447> and similar reactions with azetidin-2,3-diones gave 3-substituted 3-hydroxy-P-lactams 58 <98H97>. 

In 2002, the asymmetric synthesis of 3-substituted 3-hydroxy-p-lactams has been reported to be realized by metal-mediated l,3-butadien-2-ylation reactions between 1,4-dibromo-2-butyne and optically pure azetidine-2,3-diones [64]. This latter starting material was prepared via Staudinger reaction followed by sequential transesterification and Swem oxidation (Scheme 15), [65]. 

In 2001, Sierra and coworkers have reported that ethyl 3-ferrocenylpropanoate reacting with an excess of lithium diisopropylamide (LDA) afforded an enolate that condensed with imine the resulting reaction mixture contained the expected 2-azetidinone as a cisltrans mixture (3 1), and the unexpected 3-hydroxy p-lactam [136]. The ferrocene moiety was linked to the p-lactam ring at the C-3 position, (Scheme 51). 

Work from this laboratory has demonstrated the synthetic potential of the ring opening at C2-C3 bond of a-hydroxy p-lactams to produce a-amino acid derivatives, Fig. 7. 

Ring opening of p-lactams at C2-C3 with application in peptide synthesis was first reported on a-keto p-lactams 126 ([116] for applications of a-keto p-lactams, see [117]), Scheme 42. These p-lactams, readily available via oxidation of 3-hydroxy p-lactams 125, undergoes a Baeyer-Villiger reaction upon exposure to m-CPBA and affords /V-carboxy a-amino acid anhydrides (NCAs) 127 [118]. Shortly after, it was discovered that a more direct, one pot route to these NCAs is feasible by treatment of 3-hydroxy p-lactams with a solution of commercial bleach... 

Scheme 44 Ring expansion of 3-hydroxy P-lactams leading to NCA s formally derived from serine analogues...

The NCA 138 represents the amino-protected and carboxy-activated form of poly-oxamic acid 140, the hydroxylic amino acid portion of the antifungal family of polyoxins 139, Fig. 8. Other polyolic NCAs such as 141,142, and 143, Fig. 9, have also been prepared from the corresponding a-hydroxy p-lactams with equal success [123, 124]. 

A combination of the Sharpless AD technique and the ring expansion of 3-hydroxy p-lactams to NCAs has also been applied on compounds 153, Scheme 48, to provide a route to NCAs 155. The requisite [5-lactams 154, which exhibit a relative unlike configuration between stereocenters C4 and Cct<, are not directly accessible via [2+2] cycloaddition reaction [130]. 

In this chapter, we describe an account of our research on the chemistry and biology of paclitaxel and taxoid anticancer agents (taxoid = taxol-like compound). The topics covered in this chapter include (i) the development of a practical and efficient method for the semisynthesis of paclitaxel and docetaxel using chiral 3-hydroxy-P-lactams as synthetic intermediates, (ii) structure-activity relationship (SAR) studies of various taxoids that led to the discovery of the extremely potent second-generation taxoids, and (iii) biological and conformational studies with the use of fluorine-containing taxoids as probes. ... 

The stereochemistry of the cyclopropyl as well as oxirane moiety in these P-lactams was determined based on the single crystal X-ray analysis of P-lactam 34 and the 4-nitrobenzoyl derivative (37) of 3-hydroxy-P-lactam 32.71 The extremely high diastereoselectivity observed in these cyclopropanation and epoxidation reactions can be explained by taking into account the highly organized transition state structures illustrated in Figure 1. The directing effect of the C-3... 

Ojima, 1., Process for the Production of Chiral Hydroxy-P-Lactams and Hydroxyamino Acids Derived Therefrom, U.S. Patent, 1994, 5,294,737. 

A comparison of the reactivity of C-N or C-P fission in P-lactams and four-membered cyclic phosphonamidates, respectively, shows the latter to be much more reactive (95PAC711). The absolute configuration of some 1,3,4-trisubstituted P-Iactams is determined by CD spectra (95TL4217). A ring expansion of 3-amido-l-hydroxy-p-lactams to 4-imidazolin-2-ones by the action of tosyl chloride and organic base is reported (95TL1617). 

Metal-mediated carbonyl allylation, allenylation, and propargylation of optically pure azetidine-2,3-diones were investigated in aqueous environments. Different metal promoters showed varied regioselec-tivities on the product formation during allenylation/propargylation reactions of the keto-P-lactams. The stereochemistry of the new C3-substituted C3-hydroxy quaternary center was controlled by placing a chiral substituent at C4. The process led to a convenient entry to densely functionahzed hydroxy-P-lactams (Eq. 8.82). 

Scheme 15 Asymmetric synthesis of 3 substituted 3 hydroxy P lactams...

In 2000, the metal-mediated carbonyl propargylation or allenylation of enantio-merically pure azetidine-2,3-diones [211] has been reported to afford stereoselec-tively functionalized 3-substituted 3-hydroxy-p-lactams (Scheme 95), [212]. 

In this development, both amino moieties are differentially protected and thus, incorporation of these amino acids into peptide chains either at the a- or p-position is possible. This procedure has also been applied to the synthesis of piperazine-2-carboxylic acids and derived peptides [135], Scheme 51. For example, the bicyclic ot-hydroxy p-lactam 161, upon ring expansion and subsequent coupling of the resulting NCA 162 with a-amino esters, affords 163 in good yield. 

The transformation of a-hydroxy p-lactams 173a-c, Scheme 53, readily available from the 4-formyl 2-azetidinone 172, into their corresponding NCAs illustrates the scope of the present approach. NCAs 174a and 174b, upon treatment with (S )-PheOMe and (5)-ValOMe in the presence of KCN as promoter, render... 

Ketones have been also used as electrophiles for the synthesis of natural products. Thus, the partial synthesis of oxybutynin (ditropan) has been accomplished by the aldol reaction between cyclohexanone (3b) and ethyl phenylglyoxylate (23, R = Ph, R =EtO, Scheme 4.9) [69]. Also using a diastereoselective approach the synthesis of 3-functionalized 3-hydroxy-P-lactams has been achieved with good yields and total diastereoselectivity [70]. 

The selective acid-induced removal of sulfinyl protecting group from the N-sulfinyl-l -amino-dioxolan-4-ones 91 provided the corresponding 1 -aminodioxolan-4-ones 92 (Scheme 3.34) [69]. The base-induced cychzation in the unprotected dioxolan-4-one 92 has been reported to afford the corresponding chiral tetrasubstituted 3-hydroxy-p-lactams 93 in good yields and excellent diastereoselectivity. 

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