D ia ste re o se le c tiv e S yn th e sis o f F u se d L a c to n e-P yrro lid in o n e s. A p p licatio n to a F o rm al S yn th e sis o f ( − ) -S a lin o sp o ra m id e A .

A mild, diastereoselective synthesis of fused lactone-pyrrolidinones using an oxidative radical cyclization is reported. The methodology is demonstrated in a formal synthesis of (-)-salinosporamide A.


Supporting Information Placeholder
A mild, diastereoselective synthesis of fused lactonepyrrolidinones using an oxidative radical cyclization is reported. The methodology is demonstrated in a formal synthesis of (-)-salinosporamide A.
The development of new methodology for the rapid generation of molecular complexity from relatively simple starting materials is a continuing goal of modern target-oriented synthesis. Within this arena, oxidative radical reactions have emerged as powerful processes for the mild formation of carbon-carbon and carbonheteroatom bonds with control over multiple stereocenters. 1 In these reactions, substrate pre-functionalization is frequently not required and the product generally ends up at a higher oxidation level than the substrate thus providing a handle for subsequent synthetic manipulation. Manganese(III) acetate is a mild, economical, and relatively non-toxic reagent for the formation of electron deficient C-centered radicals from malonates and related CHacidic compounds, and has found wide use in organic synthesis in both method development and in the total synthesis of complex natural products. 2 Recently we reported an efficient synthesis of a number of [3.3.0]-bicyclic γ-lactones from variously substituted 4pentenyl malonates 3 along with application of this methodology to a diastereoselective synthesis of a cyclopentane-containing natural product. 4 Herein, we report the extension of this methodology to an efficient, diastereoselective synthesis of fused lactonepyrrolidinones from acyclic precursors. These bicyclic products contain multiple adjacent stereocenters, differentiated oxygen functionality and are formed in good yields under mild conditions. 5 Application of this methodology to the formal synthesis of the potent proteasome inhibitor (−)-salinosporamide A 6 is also reported.
Precedent for the proposed transformation comes from the groups of Miller 7 and Citterio. 8 The Miller group synthesized two tricyclic γ-lactones by the cyclization of α-amido malonates in the presence of manganese(III) acetate, and Citterio reported related reactions between α-amido malonates and alkenes for the formation of two γlactones and numerous other products. We aimed to extend these results to a mild and general diastereocontrolled synthesis of [3.3.0]-bicyclic γ-lactones bearing a variety of substituents (Scheme 1). Scheme 1. Cyclization precedent from Miller 7 and Citterio 8 with relation to current work.
The mechanism of the proposed reaction most likely involves single electron oxidation of the substrate 1 in the presence of manganese(III) acetate to deliver the corresponding α-amidomalonyl radical 2. 9 Cyclization of the α-amidomalonyl radical 2 may occur stereoselectively, via pre-transition state assembly 3, 10 to give the adduct radical 4 which, after further single electron oxidation and Salinosporamide A • up to four adjacent stereocenters • differentiated oxygen functionality • fused bicyclic ring system trapping by the adjacent oxygen atom would give oxocarbenium ion 5. Hydrolysis of 5 would give the desired fused lactonepyrrolidinones 6. We were mindful that the α-amidomalonyl radical 2 would likely exist as a mixture of s-cis and s-trans rotamers and that cyclization would only be geometrically possible from the strans conformer; hence, efficient interconversion of the two rotameric forms would be a prerequisite for efficient cyclization. 11 We have previously used copper(II) triflate as an additive in manganese(III) acetate-mediated cyclization reactions to promote γlactone formation 3 and we therefore elected to use the amide 7 as our test substrate with copper(II) triflate as additive. 12 Initial scoping reactions indicated that the lactone-pyrrolidinone 8 was formed in highest yield from the amidomalonate 7 using manganese(III) acetate and copper(II) triflate under relatively dilute reaction conditions contrary to what we had observed in the all carbon series (Table 1, entry 1). 3a,4,13 The diastereocontrol was improved by conducting the reactions at lower temperature with the highest diastereocontrol being observed at 25 °C, which gave the product in 72% yield as a 14:1 mixture of diastereomers at C-4 ( Table 1, entry 3). The structure of the major diastereomer of 8 was confirmed by single crystal X-ray diffraction studies. 14 Next we turned our attention to the cyclization of substituted substrates 9, with a view to the substituent acting as a control element for the formation of two further stereocenters in the product lactone-pyrrolidinone 10 ( Table 2). Gratifyingly, α-substituted amides 9 gave the highly substituted lactone-pyrrolidinones 10 with good yields and stereoselectivities (Table 2). 15 The methylsubstituted substrate 9a was found to cyclize in excellent yield to give the lactone-pyrrolidinone 10a as a 6.6:1 mixture of C-3 epimers ( Table 2, entry 1). 13 Three further substrates 9b-d with saturated alkyl side-chains were found to cyclize similarly ( Table 2, entries 2-4). 13 A range of unsaturated side chains were also found to direct the stereochemical outcome of the cyclization with high levels of stereocontrol, affording lactone pyrrolidinones functionalized with propargyl, allyl, benzyl and benzyloxyethyl groups ( Table  2, entries [5][6][7][8]. 13 In all cases, the major diastereomer formed is in accord with cyclization via the chair-like Beckwith-Houk transition state (see pre-transition state assembly 3) 10 with the α-amido substituent occupying a pseudo-equatorial position. 16 The success of these cyclization reactions is likely in part due to the adduct radical (4) being benzylic. Indeed, cyclization of the terminal alkene substrate 1 (R, R', R'' = H) was initially found to be highly capricious with the corresponding lactone pyrrolidinone 6 (R, R', R'' = H) being isolated in highly variable yield (~20-70%). However, we found that the N-PMB-protected substrates 11 gave the corresponding lactone-pyrrolidinones 12 that were isolated with synthetically useful yields and with high diastereoselectivities ( Table 3). The success of these cyclizations may be related to the increased proportion of the s-trans radical corresponding to s-trans 2 with tertiary amide substrates compared with secondary amide substrates. R rial was used. e (-)-16 was also isolated in 26% yield. f Two equivalents of copper(II) triflate were used and (-)-16 was also isolated in 19% yield. g 0.1 equivalents of copper(II) triflate were used (-)-16 was also isolated in 79% yield.
A range of dialkyl malonates were tolerated 17 and substrates bearing unsaturated side chains gave the corresponding lactonepyrrolidinones with high levels of diastereocontrol (Table 3, entries 3-5). Cyclization of the allyl-substituted amide (-)-11e with two equivalents of manganese(III) acetate and one equivalent of copper(II) triflate, gave the desired lactone-pyrrolidinone (+)-12e in 43% yield along with the trans-fused [4.3.0]-bicyclic alkene (-)-16 in 26% yield, the structure of which was confirmed by single crystal X-ray diffraction studies (Scheme 2). 14 The lactone-pyrrolidinone (+)-12e could be isolated in 65% yield by increasing the copper loading to two equivalents with the cyclohexene being formed in 19% yield (Table 3, entry 6). Conversely reducing the copper loading to 0.1 equivalents gave the cyclohexene in 79% yield along with 9% of the lactone (+)-12e (Table 3, entry 7). The trans-fused [4.3.0]-bicyclic alkene (-)-16 is most likely formed from the initial adduct radical 14 which may arise from pre-transition state assembly 13 (Scheme 2). 10 Further 6-endo-trig cyclisation can occur, followed by oxidation of the second adduct radical 15 by copper(II) to give the trans-fused bicyclic cyclohexene (-)-16. Alternatively, the initially formed adduct radical 14 can be directly oxidized by copper(II) to give the lactone-pyrrolidinone (+)-12e; this is the major pathway at higher concentrations of copper(II). Scheme 2. Proposed mechanism of formation of (+)-12e and (-)-16 with the structure of 16 from single crystal X-ray diffraction studies. 14 The synthetic utility of the developed methodology was demonstrated by the enantioselective synthesis of the lactonepyrrolidinone 24, an intermediate in Danishefsky's synthesis of the proteasome inhibitor (-)-salinosporamide A (Scheme 4). 6d The known carboxylic acid 18 18 was readily prepared and converted into the allyl-substituted oxazolidinone 21 using an Evans asymmetric alkylation. 19 Hydrolysis of the chiral auxiliary in 21 required initial conversion into the corresponding benzyl ester followed by in situ hydrolysis to the carboxylic acid so as to avoid endo cleavage of the oxazolidinone. 19 The carboxylic acid was coupled with the amino malonate 22 under Schotten-Baumann conditions to give the amide 23. 6f Oxidative elimination of the selenide in amide 23 gave the enantioenriched cyclization substrate (-)-11e. Cyclization of malonate (-)-11e gave the required bicyclic γ-lactone (+)-12e in 65% yield, which was subjected to ozonolysis with a reductive work-up to afford alcohol 24. 6d, 20 The advanced intermediate 24 en route to salinosporamide A was prepared in 8 steps and 19% overall yield from γ-butyrolactone 17. 21 Scheme 3. Formal synthesis of (−)-salinosporamide A.
In summary, we have successfully developed a mild methodology for the synthesis of a range of fused bicyclic lactonepyrrolidinones with good diastereocontrol in the key cyclization step. The methodology has been applied to the enantioselective formal synthesis of (−)-salinosporamide A.

Supporting Information
Experimental details and characterization data. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION
Corresponding Author * jonathan.burton@chem.ox.ac.uk Notes § Authors to whom correspondence regarding X-ray crystallography should be addressed.

ACKNOWLEDGMENT
We thank GlaxoSmithKline and AstraZeneca for CASE awards and the EPSRC for funding. We are grateful to Prof. Danishefsky (Sloan Kettering Institute for Cancer Research and Columbia University), for providing spectroscopic data. We thank the Diamond Light Source for an award of beamtime on I19 (MT7768), and the instrument scientists for their generous help and support.  (9) For a review of the mechanisms of manganese(III) acetatemediated reactions see: Snider, B. B. Tetrahedron 2009, 65, 10738-10744. (10) The pre-transition state assembly is in keeping with the Beckwith-Houk model for the cyclization of 5-hexenyl radicals: (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett. 1985, 26, 373-376;(b) Houk, K. N.;Paddonrow, M. N.;Spellmeyer, D. C.;Rondan, N. G.;Nagase, S. J. Org. Chem. 1986, 51, 2874-2879 As well as restricted rotation around the C-N acyl (peptide) bond, rotation may also expected be restricted around the C-N alkyl bond owing to overlap of the SOMO and the N-lone pair. For calculation of some barriers to rotation in related systems, see: MacInnes, I.; Walton, J. C.; Nonhebeal, D. C. J. Chem. Soc., Perkin Trans. 2 1987, 1789-1794 Citterio found that the diethyl analogue of 7 underwent oxidative radical cyclisation with manganese(III) acetate in acetic acid to give a cyclised benzylic acetate and not a [3.3.0]-bicyclic γ-lactone.

REFERENCES
The relative configuration of the products was assigned on the basis of 1 H NMR nOe experiments or by analogy (see Supporting Information). The diastereoselectivities are measured from the crude reaction mixture. In some cases other components were present in the crude reaction mixture which may be other diastereomers but these components could not be characterized.
For N-protecting group-dependent diastereoselective cyclizations of α-amido radicals see: Nagashima, H.; Ozaki, N.; Ishii, M.; Seki, K.; Washiyama, M.; Itoh, K. J. Org. Chem. 1993, 58, 464-470. (17) The ethyl ester 11b routinely gave inferior yields of lactone 12b when compared with the corresponding methyl or tbutyl ester substrates 11a and 11c. This may be related to the ease of formation/hydrolysis of the presumed oxocarbenium ion related to 5; however, both Citterio (ref. 8) and Our synthetic material matched the literature data very well except that there was a small discrepancy in the 13 C NMR resonance of the carbon adjacent to the hydroxyl group most likely the result of a solvation effect. We therefore converted 24 into the corresponding benzyl ether which was an excellent match with the literature data (ref. 6d). The optical purity our synthetic 24 was shown to be >95% e.e. by chiral HPLC. See Supporting Information for details.