1.3.4 Stereochemical Analysis
Prior to exploration of the reaction scope we endeavored to analyze the high level of 1,4-stereoinduction observed in the three component coupling reaction. To this end, the TBS derivative of coupling product 1.23 (1.24) was subjected to two diastereoselective directed reductions (Figure 1-8). The Evan’s anti reduction19 proceeded with excellent diastereoselection, affording 1,3-anti-diol 1.25. The Prasad syn reduction20 cleanly gave 1,3-
syn-diol 1.26. Both diols were subjected to acid-catalyzed lactonizations in order to obtain rotation-restricted compounds for 2D NMR analysis. Cyclization of diol 1.25 gave the corresponding mono(lactone) 1.27, while the syn-diol 1.26 gave a bis(lactone) (1.28). This divergence in reactivity can be rationalized by the relatively-high energy barrier for formation of a trans-fused bicycle in the anti diol case. We used nOesy analysis of each lactone to provide conclusive evidence for the assignment of the relative configuration of the fully-substituted center, which is depicted in Figure 1-8.
Figure 1-8. Subsequent Ketone Reduction/StereochemicalAnalysis
1.3.5 Reaction Scope
With a highly-diastereoselective method in hand for a quaternary Claisen/β- hydroxyketone synthesis, we set out to investigate the reaction scope (Table 1-2). First, three silyl glyoxylates were tested with β-lactone 1.19a. While the TBS/Bn and TES/Bn showed similar efficiencies (61%/67% yield; 1.22, 1.29a), the TBS/tBu case showed a highly diminished yield (35%; 1.29b). This may be attributed to the added steric bulk proximal to the reactive centers, hindering both the initial nucleophilic attack by the Reformatsky reagent and second C–C bond formation with the β-lactone. Next, a series of β-substituted-β-lactones (1.19b – 1.19e) were screened. The reaction proved tolerant of alkyl, aryl, and protected hydroxyl functionalities with yields ranging from 33-64% and complete diastereoselection in all cases. Disubstituted β-lactones also performed well, with the cis and trans hydrocinnamyl derivatives showing good yields, but reduced, identical diastereoselection (1.29h, 1.29i; 5.1
dr). A disubstituted alkynyl β-lactone, however, maintained complete diastereoselection (1.29j).
Protecting group identity on the β-lactam substrates proved important. While the electron deficient Boc and Tosyl groups showed analogous reactivity to the β-lactones, albeit with no diastereocontrol, the TBS-protected lactam failed to react. Presumably this is an electronic effect, although steric encumbrance cannot be ruled out. Additional five-membered ring electrophiles were tested with varying results. -Butyrolactone reacted smoothly under the reaction conditions (1.29g), but gave an unstable product that required immediate silyl protection due to a dominant retro-Claisen pathway. A furanone (1.29n) and oxazolinone (1.29o) were tested; each would provide useful functional handles. Unfortunately, neither reaction provided desired product.
Table 1-2. Substrate Scopea,b
Product Yield dr Product Yield dr
1.22 61% >20:1 1.29hd 49% 5:1 1.29a 67% >20:1 1.29id 72% 5:1 1.29b 35% >20:1 1.29jd 63% >20:1 1.29c 64% >20:1 1.29k 65% 1:1 1.29d 33% >20:1 1.29l 55% 1:1 1.29e 48% >20:1 1.29m 0% N/D 1.29f 59% >20:1 1.29n 0% N/D 1.29g 28%c N/A 1.29od 0% N/D
a. All reactions: 2.3 equiv 1.12, 1.0 equiv silyl glyoxylate, 1.6 equiv lactone/lactam, [silyl
glyoxylate]0 = 0.5M. b. See section 1.5 Experimental Details for more information. c. Yield reported over two steps. d.Si = TES.
The effect of lithium chloride was tested during the course of this investigation. Reported by Knochel, Reformatsky reagents can often exhibit enhanced reactivity due to the formation of a zincate complex.21 This additive had a minor effect on yield for some substrates, but no pattern or predictability was observed in terms of structures that would benefit from the
addition of this salt (See section 1.5 Experimental Details). A final perturbation of the title reaction tested was the initiation via allylzinc bromide. In this experiment, the zinc nucleophile reacted without discrimination, yielding a complex mixture.
1.3.6 Origin of Diastereoselectivity
The impressive stereochemical outcome of this reaction may be explained by the borrowing of some key features from the initial Greszler double Reformatsky reaction (1.8, Figure 1-5). After Reformatsky attack on silyl glyoxylate and subsequent Brook rearrangement, isomerization to the seven-membered (E)-glycolate enolate chelate structure occurs to give the second, active nucleophilic species. In this event, diastereofacial approach of the β-lactone will dictate the stereochemical outcome of the emerging fully-substituted center. Here, we deviate from the previous model wherein the -methyl substituent of the Reformatsky reagent dictated approach of the ketone electrophiles. In the present case, it seems plausible that the β-lactone will approach with its β-substituent pointing away from the enolate, but a second controlling element must be at play to distinguish between transition structures
Figure 1-9. Competing Transition State Models
We propose a subtle, electrostatic effect governs the complete diastereoselection of the title reaction. As depicted in Figure 1-9, a lone pair repulsion between the β-lactone ring oxygen, and the benzyloxy substituent on the glycolate enolate might provide enough of a barrier to encourage reactivity through 1.30, providing the observed diastereomer. More experimentation would be necessary to confirm this or alternative models of diastereoselectivity. With the lack of diasterocontrol observed for the β-lactam substrates, it is apparent they are poorly differentiated in our working model or react through an orthogonal transition state.
1.3.7 Subsequent Transformations of β-Hydroxyketone Products
The β-hydroxyketone product scaffold obtained from the title reaction provides unique opportunities for subsequent manipulation. Functionality present includes: two differentiated esters, a highly-substituted ketone, β-hydroxyl group, and the moiety provided by the β-lactone substrate selection. In addition to the derivations described in Figure 1-8 (directed ketone reductions/cyclizations to form mono or bis(lactones)), we have shown selective manipulation of the ester functionality (Scheme 1-6). A two-step sequence beginning with Prasad reduction followed by acetonide protection provides diester 1.32. At this stage, selective reduction of the
ethyl ester was achieved upon treatment with DIBAL-H to provide monoalcohol 1.33. Alternatively, subjection of the diester to lithium triethylborohydride (Super-Hydride) afforded diol 1.34 for further transformation.