& Aminocatalysis

Novel Organocatalytic Activation of Unmodified Morita–Baylis–Hillman Alcohols for the Synthesis of Bicyclic a-Alkylidene-Ketones

Julian Stiller,[b] Dorota Kowalczyk,[a] Hao Jiang,[b] Karl Anker Jørgensen,*[b] andŁukasz Albrecht*[a]

Abstract: The organocatalytic activation of Morita–Baylis–Hillman alcohols via H-bonding-iminium-ion formation isdemonstrated for the first time. This activation strategyenables the Morita-Baylis–Hillman alcohols to undergoa formal SN2’ reaction. In combination with the well-estab-lished enamine reactivity, this creates a new reactivity pat-tern. The application of this new activation mode for thesynthesis of bicyclic a-alkylidene-ketones is demonstrated.The developed reaction sequence proceeds efficiently af-fording nature-inspired target products with four contigu-ous stereogenic centers in a highly stereoselectivemanner.

Asymmetric transformations of carbonyl compounds aiming atthe introduction of specific structural motives to target mole-cules have gained increasing attention of the chemical com-munity.[1] A key to success of such a target-oriented strategy isthe ability of chiral catalysts to ensure high levels of stereoin-duction while providing a reactive intermediate with the de-sired reactivity profile defined by the structure of the targetproducts. In this respect, aminocatalytic strategies, utilizingchiral primary or secondary amines as the catalyst, are highlyreliable tools in modern asymmetric synthesis equippingchemists with a broad range of possibilities to access new re-action profiles in order to introduce specific structural motifs ina stereoselective fashion.[1c–e] Morita–Baylis–Hillman (MBH) alco-hols and their derivatives constitute highly useful type ofbuilding blocks that have been rarely employed in the field ofaminocatalysis.[2, 3] However, a direct application of unmodifiedMBH alcohols in asymmetric synthesis is still challenging andthe development of methods enabling their catalytic activationis of high interest in modern organic chemistry. Furthermore,

the introduction of alkylidene moiety through a formal SN2’ re-activity of MBH alcohols seems to be particularly interesting,which has not been explored in aminocatalysis before.

We envisioned that a novel activation mode of MBH alcoholsmight rely on the corresponding iminium-ion formation capa-ble of H-bonding interactions (Scheme 1). Such an iminium-ionshould possess enhanced reactivity towards formal SN2’ reac-tion leading to the introduction of a new stereogenic center inthe b-position and a-alkylidene moiety in the a-position to thecarbonyl functionality (Scheme 1, top). It was anticipated thatmerging of such an activation strategy with the well-recog-nized enamine activation should enable the formation ofa unique aminocatalytic intermediate and result in the devel-opment of a novel cascade reactivity—addition followed bya formal SN2’ reaction (Scheme 1, middle). An important chal-lenge of such a synthetic strategy relates to the presence ofa stereogenic center in the MBH alcohol substrate. For thisreason mismatching interactions between the chirality of themolecule and the catalyst might take place resulting in overallenantioselectivity deterioration.

Scheme 1. A novel aminocatalytic activation mode.

[a] D. Kowalczyk, Dr. Ł. AlbrechtInstitute of Organic Chemistry, Chemistry DepartmentLodz University of Technology, Zeromskiego 116, 90-924 Ł�dz (Poland)E-mail : lukasz.albrecht@wp.pl

[b] Dr. J. Stiller, Dr. H. Jiang, Prof. Dr. K. A. JørgensenCenter for Catalysis, Chemistry Department, Aarhus UniversityLangelandsgade 140, 8000 Aarhus C (Denmark)E-mail : kaj@chem.au.dk

Supporting information for this article is available on the WWW underhttp ://dx.doi.org/10.1002/chem.201404468.

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Importantly, the devised cascade reactivity should enablea facile construction of the a-alkylidene-ketone framework.This is a privileged scaffold that is found in natural productsand pharmacologically relevant molecules, such as chiloscy-phone, a naturally occurring sesquiterpene[4a] methylenomy-cin A and sarkomycin belonging to the family of cyclopenta-noid antibiotics[4b–d] with sarkomycin possessing interesting an-ticancer activity (Scheme 2, bottom).[5] The synthetic relevanceof a-alkylidene-ketones has been confirmed recently.[6] In par-ticular their ability to act as effective Michael acceptors hasbeen utilized in organic synthesis, including asymmetricorganocatalysis.[6a,b]

Herein, we report a novel aminocatalytic activation of un-modified MBH alcohols and its application for the synthesis ofbicyclic a-alkylidene-ketones. The developed approach utilizesa combination of a simple enamine activation with the uniqueability of an aminocatalyst to activate MBH alcohols fora formal SN2’ reaction via iminium-ion activation. As a proof-of-concept, the reaction between 2-(hydroxyalkyl)cyclopent-2-en-1-one 1 and olefinic oxindoles 2 in the presence of a primaryamine organocatalyst 3 was studied (Scheme 2).

We initiated our studies with the goal of finding appropriatereaction conditions for the devised synthetic strategy. The ini-tial catalyst screening identified a quinine-derived primaryamine catalyst in combination with (S)-mandelic acid[7] as themost suitable catalytic system for the transformation andchloroform as the best solvent (see the Supporting Informationfor details). Further screening revealed that lowering reactiontemperature resulted in longer reaction times and led to im-proved enantio- and diastereoselectivity (Table 1, compare en-tries 1–3). It was found that the reaction rate at ambient tem-peratures could easily be improved by employing an excess ofalcohol 1 a maintaining the stereoselectivity of the transforma-tion at the comparable level (Table 1, compare entries 3–7). In-terestingly, isolated unreacted alcohol 1 a was enantiomericallyenriched, indicating that the reaction also occurs in a kineticresolution manner (Table 1, entries 6 and 7). Hence matching–mismatching interactions between the catalyst-bound enaminepart of the substrate and its chiral MBH alcohol moiety havean influence on the stereoselectivity of the reaction. The use ofolefinic counterpart in excess resulted in a decrease in reactivi-ty (Table 1, entry 8). Notably, all reactions afforded a-alkyli-dene-ketone 4 a as single E-isomer.

With the optimized reaction conditions in hand, the scopeand limitations of the methodology were investigated. Gratify-

ingly, various olefinic oxindoles 2 were successfully employedin the developed reaction sequence (Scheme 3). Importantly,both electron-donating and electron-withdrawing substituentscould be present on the aromatic moiety of olefinic oxindoleframework of 2 affording target products in good yields and inhigh stereoselectivities. Furthermore, the position of the sub-stituent had no significant influence on the reaction outcomeand disubstituted derivatives were well-tolerated. Interestingly,N-unprotected oxindoles could also be employed in the reac-tion sequence with similar results as demonstrated in the syn-thesis of 4 h. In all cases the formation of E-configured a-alkyli-dene-ketone 4 a–h was observed.

In the course of further studies various MBH alcohols 1 wereutilized in the developed reaction sequence (Scheme 4). It wasfound that MBH alcohols 1 i and 1 j derived from both elec-tron-poor and electron-rich benzaldehydes, respectively, easilyreacted under optimized reaction conditions. Furthermore,a heteroaromatic framework and alkyl side-chain could be in-troduced on the alkylidene moiety of the target ketones 4 asdemonstrated in the synthesis of 4 k and 4 l. Although a slightlylower enantioselectivity was observed in those cases, the dia-stereoselectivity was still perfect. Notably, products 4 i–l wereformed as single E-isomers. Finally, synthesis of terminal meth-ylene-derivative 4 m proved possible employing 2-(hydroxyme-thyl)cyclopentenone (1 m) as starting alcohol, albeit resultingin lower diastereoselectivity in this single case. Disappointingly,

Scheme 2. Enantioselective approach to bicyclic a-alkylidene-ketones.

Table 1. Enantioselective approach to bicyclic a-alkylidene-ketones 4 : op-timization studies.[a]

Entry 1 a[equiv]

2 a[equiv]

T[oC]

t[h]

Conv.(yield [%])[b]

d.r.[c] ee[%][d]

1 1.1 1 50 20 84 (71) >95:5 722 1.1 1 40 20 80 (72) >95:5 863 1.1 1 RT 8 d >95 (83) >95:5 874 2 1 RT 67 >95 (83) >95:5 915[e] 2 1 RT 40 >95 (83) >95:5 906[f] 2.5 1 RT 40 >95 (79) >95:5 907[g] 3 1 RT 40 >95 (84) >95:5 908 1 2 RT 9 d 85 >95:5 89

[a] Reactions performed on 0.1 mmol scale (for details see the SupportingInformation). [b] Conversion as determined by 1H NMR spectroscopy ofa crude reaction mixture. Isolated yields are given in parenthesis. [c] De-termined by 1H NMR spectroscopy of a crude reaction mixture. [d] Deter-mined by a chiral stationary phase UPC2. [e] Concentration 0.5 m. [f] Un-reacted alcohol 1 a isolated with 29 % ee. [g] Unreacted alcohol 1 a isolat-ed with 25 % ee.

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MBH alcohol derived from 2-cyclohexen-1-one failed to reactunder optimized reaction conditions.

Interestingly, when compound 7, which was prepared ac-cording to a literature procedure,[8] was employed in the devel-oped annulation strategy the efficient and highly stereoselec-tive formation of an unexpected reaction product (4 o) was ob-served (Scheme 5, bottom). Single crystal X-ray analysis re-vealed its structure as 4 o in contrast to anticipated 4 n. Thisfinding prompted us to re-elucidate the structure of 7. It wasunambiguously assigned as 8 by a single crystal X-ray analysis.This indicates that when benzo[b]thiophene-2,3-dione 5 wastreated with stabilized phosphorus ylide 6 the Wittig reactionoccurred at the carbonyl group adjacent to the sulfur atom af-fording 8. This result is in marked contrast with previous litera-ture reports involving 5 as a substrate in a Wittig reactionyielding 7 as a product.[8] Moreover, it demonstrates that 5shows a completely different and so far unexpected reactivitycompared to the isatines and coumarandione which react atthe b-carbonyl functionality.[8, 9]

The single crystal X-ray analysis of 4 o and 4 h allowed us tounambiguously assign the relative and absolute configura-tion.[10] The absolute configuration of other products 4 a–g and4 i–m is assigned by analogy. Based on the configurational as-signments of the products 4 a plausible reaction mechanism is

proposed (Scheme 6). The reaction is initiated by condensationof the catalyst 3 a with the starting MBH alcohol 1 to give imi-

Scheme 3. Enantioselective approach to bicyclic a-alkylidene-ketones 4 : re-action scope.

Scheme 4. Enantioselective approach to bicyclic a-alkylidene-ketones 4 - re-action scope.

Scheme 5. Revised reactivity of benzo[b]thiophene-2,3-dione: application inthe synthesis of a-alkylidene-ketone 4 o.

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nium ion 9. Subsequent tautomerization affords diene inter-mediate 10 which can undergo a formal [4+2]-cycloadditionwith the olefinic oxindole 2. A stepwise mechanism for thisprocess is postulated,[11] in which the first step is an enamine-mediated conjugate addition to the Michael acceptor 2 afford-ing 11, followed by cyclization via SN2’-type reaction proceed-ing with the elimination of a water molecule. However, a mech-anism of the cyclization step involving a simple addition andsubsequent E1cb-elimination might also be possible. Notably,in both of the cases elimination step is assisted via the H-bonding-interactions with iminium-ion moiety of the molecule.The stereochemical outcome of the reaction is postulated tobe based on p-stacking interactions between the quinolinering in the catalyst and the diene moiety, facilitating a transitionstate of the reaction which provide an effective shielding ofone of the faces of the diene. Thereby, olefin 2 approaches 10from the side opposite to the functionalities providing the p-stacking interactions giving 4 in a highly enantio- and diaste-reoselective fashion. Interestingly, when an O-protected MBHalcohol was employed in the developed reaction sequence, noconversion was observed, supporting the importance of postu-lated activation of MBH alcohol 1 via intramolecular H-bondinginteractions present in the developed iminium-ion-mediatedactivation strategy.

In conclusion, we have developed a novel enantioselectiveapproach to bicyclic a-alkylidene-ketones. It combines a well-established enamine reactivity of carbonyl compounds witha unique activation of Morita–Baylis–Hillman alcohols via imini-

um-ion formation making it more prone to undergo formalSN2’ reaction. The developed synthetic strategy benefits fromoperational simplicity, high efficiency and excellent enantio-and diastereoselectivities. Importantly, it enables a direct appli-cation of unmodified MBH alcohols. Furthermore, the a-alkyli-dene moiety was introduced with complete selectivity yieldingtarget products as single E-isomers.

Acknowledgements

Thanks are expressed to Aarhus University, FNU and CarlsbergFoundation for support. This project was realized within theHoming Plus Programme (co-financed from European Union,Regional Development Fund) and Kolumb Supporting Grant,both from the Foundation for Polish Science. Thanks are ex-pressed to Jacob Overgaard for performing X-ray analysis.

Keywords: activation strategies · alpha-alkylidene-ketones ·asymmetric synthesis · Morita–Baylis–Hillman adducts ·organocatalysis

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[7] For the influence of the acid on the reaction outcome, see the Support-ing Information.

[8] For selected examples, see: a) F. M. Soliman, M. M. Said, Sulfur Lett.1991, 13, 213; b) Y. Cao, X. Jiang, L. Liu, F. Shen, F. Zhang, R. Wang,Angew. Chem. 2011, 123, 9290; Angew. Chem. Int. Ed. 2011, 50, 9124;c) Y.-M. Cao, F.-F. Shen, F.-T. Zhang, R. Wang, Chem. Eur. J. 2013, 19, 1184.

[9] For a recent review, see: L. Hong, R. Wang, Adv. Synth. Catal. 2013, 355,1023.

[10] See the Supporting Information for details. CCDC 999371 (8), 999372(4 o) and 999373 (4 h) contain the supplementary crystallographic datafor this paper. These data can be obtained free of charge from The

Scheme 6. Enantioselective approach to bicyclic a-alkylidene-ketones 4 : re-action mechanism.

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Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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2012, 134, 2543; c) J. Stiller, P. H. Poulsen, D. C. Cruz, J. Dourado, R. L.Davis, K. A. Jørgensen, Chem. Sci. 2014, 5, 2052.

Received: July 18, 2014Published online on August 25, 2014

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