DOI:10.1002/chem.201901304 Full Paper & Photochemistry Intramolecular[2+2] Photocycloaddition of Cyclic Enones: Selectivity Control by Lewis Acids and Mechanistic Implications SanerPoplata, Andreas Bauer,Golo Storch,and ThorstenBach*[a] Abstract: The intramolecular [2+2] photocycloaddition of 3- complexindicate that attractive dispersion forces may be re- alkenyl-2-cycloalkenones was performed in an enantioselec- sponsible for achange of the binding mode. The catalytic tive fashion (nine representative examples, 54–86 %yield, [2+2] photocycloaddition wasshown to proceed on the trip- 76–96% ee)upon irradiation at l=366 nm in the presence let hypersurface with aquantum yield of 0.05. The positive of an AlBr3-activated oxazaborolidine as the Lewis acid. An effect of Lewis acids on the outcomeofagiven intramolecu- extensive screening of proline-derived oxazaborolidines lar [2+2] photocycloaddition was illustrated by optimizing showed that the enantioface differentiation depends strong- the key step in aconcise total synthesis of the sesquiterpene ly on the nature of the aryl group at the 3-position of the ( )-italicene. Æ heterocycle. DFT calculations of the Lewisacid–substrate Introduction The intramolecular [2+2] photocycloaddition[1] of appropriately substituted 2-cycloalkenones is an enormously powerful trans- formation which has been extensively used in the total synthe- [2] Scheme1.The conversion of carvone(1)intocarvonecamphor (2)repre- sis of natural products. The reaction can be performed by senting the first intramolecular [2+2] photocycloadditionreaction of acyclic direct irradiation, typically at awavelength (l)of300–370 nm. enone.[6–9] 11 1 [3] Since intersystem crossing in enones is fast (k 10 sÀ ), the ISCffi reactionproceeds via the first excited triplet state (T1)which has p–p*character.Compared to intermolecularreactions, constitution and configuration.[8] Meinwald and Schneider opti- there is an improved regioselectivity as the internal olefin is mized the reactionemploying anartificial light source with an enforced to approachthe photoexcited enone via an initial emission maximum at l= 355 nm and couldisolate the desired cyclization to a1,4-diradical.[4] Five-memberedring formation is product with amaximum yield of 35 %.[9] preferred where possible and dictates the regioselectivity of Despite the fact, that the reactionissopowerful, enantiose- the reaction.[5] lectivevariants of the enone [2+2] photocycloaddition have Historically,the reaction belongs to one of the first photo- relied, until very recently,onthe covalentattachment of a chemicaltransformationsknown to organic chemists. In 1908, chiral auxiliary.[10] In 2013, our group presented the first enan- Ciamician and Silber reported on the formation of carvonecam- tioselective[11] enone [2+2] photocycloaddition reaction medi- phor (2)upon exposure of carvone (1)tosunlight ated by chiral Lewis acids.[12, 13] The substrates were 5,6-dihy- (Scheme 1).[6] The same observation was made by Sernagiotto dro-4-pyridones[14] to which an alkenyl chain was attached at afew years later.[7] In 1957, Büchi and Goldmanisolated prod- the nitrogen atom. The chiral Lewis acid acts by coordination uct 2—still prepared by sunlight irradiation—and proved its to the carbonyl carbonatom andlowers the energy difference betweenthe ground state (S0)and the first excited state (S1). The chromophore is activated[15] and the allowed p–p*absorp- [a] S. Poplata,Dr. A. Bauer,Dr. G. Storch,Prof. Dr.T.Bach tion is red-shifted to absorbatl 360 nm. Although there is a Department Chemie and Catalysis Research Center (CRC) weak n–p*absorption of uncomplexeddihydropyridone at a Technische UniversitätMünchen, 85747 Garching (Germany) E-mail:[email protected] similar wavelength,the Lewis acid complex has amuch higher Supporting information and the ORCID identification number(s) for the au- absorption coefficient and the reaction thus proceeds enantio- thor(s) of this article can be found under: selectively.Despite the fact that the reactioncould be extend- https://doi.org/10.1002/chem.201901304. ed to the intramolecular [2+2] photocycloaddition of 3-alkeny- 2019 The Authors. Published by Wiley-VCH Verlag GmbH&Co. KGaA. loxy-2-cycloalkenones,[16] the intermolecular reaction of simple This is an open access article under the terms of the Creative Commons At- 2-cycloalkenones,such as 2-cyclohexenone, remained elusive tributionNon-Commercial License,whichpermitsuse, distributionand re- [17] production in any medium, provided the original work is properly cited and until very recently. In the context of the latter topic, we had is not used for commercial purposes. performed optimization reactions with 3-alkenyl-2-cycloalke- Chem. Eur.J.2019, 25,8135 –8148 8135 2019 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Full Paper Table 1. Racemic [2+2] photocycloaddition reactions of enones 5:Substi- tution patterns, reaction times and yields. Figure 1. General structure of [2+2] photocycloaddition substrates A and of Substrate[a] XYRR1 t [h] Yield[%] putative chiral catalysts B;structure of chiral [2+2] photocycloaddition sub- strate rac-3. 5a CH2CH2 CH2 HH891 5b CH2CH2 CMe2 HH387 5c CH2CH2 OHH587 5d CMe2CH2 CH2 HH579 nones of general structure A (Figure 1) for which there has not 5e CH2 CH2 HH47 56 5f CH2CH2 CH2 Me H568 yet been areport on an enantioselective variant. [b] 5g CH2CH2 CH2 HMe5.5 51 The reactionwas studied with abroad variety of chiral oxa- 5h CH CH OMeH 880 [18] 2 2 zaborolidine Lewis acids B (variation of X’ and Y’)and the re- 5i CMe2CH2 CH2 Me H588 [c] sults of this study are disclosed in this Full Paper.Inaddition, 5j CH2 CH2 Me H863 we couldshow with chiral substrate rac-3 that Lewis acid coor- [a] Unless notedotherwise, the reactionswere performed under anhy- dination lends asignificantly improvedselectivity to the reac- drous and oxygen-free conditionsat an irradiation wavelengthofl = tion. This reaction was used in the total synthesis of italicene 366 nm (emission maximum of the light source)and at asubstrate con- and isoitalicene. Mechanistic studies confirm the fact that the centration of20mm in CH2Cl2 as the solvent at ambienttemperature. [b] Olefinic by-products wereremoved by ozonolysis. [c] An irradiation reactionproceeds on the triplet surfaceand computational wavelength of l= 350 nm (emission maximum of the light source) was studies offer an explanation for an unexpected reversal in the used. enantioselectivity of the process. maximum at l=366 nm.[22] Typically,full conversion of 2-cyclo- Results and Discussion hexenones (5a–5d, 5f–5i)was achieved after amaximum irra- diationtime of 8h.The blue-shifted absorption of cyclopente- Synthesis of starting materials and racemic[2+2] photocy- nones 5e and 5j required for substrate 5e alonger irradiation cloaddition time of 47 hwhile in the case of enone 5j ashort-wavelength Our experiments focussed on 2-cyclopentenones and 2-cyclo- emitter (l=350 nm) was used to complete the reactionina hexenones, which carry an alkenyl chain at position C-3. To the reasonable period of time. best of our knowledge,the first intramolecular [2+2] photocy- Oxazaborolidine Lewis acids of general formula B (Figure 1) [23] cloaddition of a3-alkenyl-substituted 2-cycloalkenone was were prepared from the respective aminoalcohols by oxaza- mentioned in acommunication by Corey and Sestanj.[19] Since borolidine formation and subsequent complexation with AlBr3 then, this compound class has been extensively used and as the activating Lewis acid. Other activators did not match there are aplethora of examples for their intramolecular [2+2] the enantioselectivity achievedwith this Lewis acid neither did photocycloaddition.[1] other amino alcohol skeletons. In the optimization experi- The precursors are typicallyprepared from 3-ethoxy-2-cyclo- ments, we thus focussed on amino alcohols derivedfrom pro- alkenones by addition of the respective alkenyl metal reagent line. Accordingly,the synthesis commencedwith known l-pro- [23] and subsequenthydrolysis.[20] The previously unknowncom- line methyl ester 7 which was converted to amino alcohols pounds 5c and 5h were synthesized from the chloromethyl- 8 by treatment with an excess (2.5 equiv) of the respective substituted olefinic acetal 4 whichwas obtained by aknown Grignardreagent (Scheme 3). The latter in turn was formed procedure[21] and which underwent nucleophilic substitution from aryl (Ar) bromide by direct magnesiation in the presence by an allylic alcohol (Scheme 2). of catalytic amountsofiodine. Yields were high (>80 %) both Table 1lists the substrates 5 and racemic products rac-6 for the formation of the alcohols and for the subsequent hy- which were investigated in the presentstudy.Irradiation was drogenolysis of the N-benzyl group to the target compounds performed with fluorescent lamps which exhibit an emission (see the Supporting Information for more details). There was some concern regarding apossible racemization at the stereogeniccenterofproline during the Grignardaddi- tion which is the reason we attempted to determine the enan- tiomericexcess (ee)ofthe amino alcohols after deprotection. However, asatisfactory separation of the enantiomersbychiral HPLC could not be achieved and an unambiguous ee determi- nation was impossible. Tworepresentative amino alcohols Scheme2.Preparation of photocycloaddition substrates 5c and 5h from al- were hence converted into the respective oxazolidinones 10a lylic chloride 4. and 10b which were amenable to HPLC separation (Figure 2). Chem. Eur.J.2019,