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A novel catalytic asymmetric route towards skipped dienes with a methyl-substituted centralstereogenic carbonHuang, Yange; Fañanás-Mastral, Martín; Minnaard, Adriaan J.; Feringa, Bernard

Published in:Chemical Communications

DOI:10.1039/c3cc41021h

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Citation for published version (APA):Huang, Y., Fañanás-Mastral, M., Minnaard, A. J., & Feringa, B. (2013). A novel catalytic asymmetric routetowards skipped dienes with a methyl-substituted central stereogenic carbon. Chemical Communications,49(32), 3309-3311. https://doi.org/10.1039/c3cc41021h

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A novel catalytic asymmetric route towards skippeddienes with a methyl-substituted centralstereogenic carbon†

Yange Huang, Martın Fananas-Mastral, Adriaan J. Minnaard and Ben L. Feringa*

A highly efficient method for the enantioselective synthesis of

1,4-dienes (skipped dienes) with a methyl-substituted central

stereogenic carbon using copper-catalysed asymmetric allylic

alkylation of diene bromides was developed. Excellent regio- and

enantioselectivity (up to 97 : 3 SN20/SN2 ratio and 99% ee) were

achieved with broad substrate scope.

Natural products containing 1,4-dienes (skipped dienes) suchas polyunsaturated fatty acids have important biologicalfunctions.1 Particularly interesting molecules with a 1,4-dienebearing a methyl-substituted central stereogenic carbon includehennoxazole A,2 ansalactam A,3 ambruticin S,4 iejimalide5 andphorbasins,6 shown in Scheme 1, which are potent antibiotic,antifungal and cytotoxic agents. These ubiquitous moleculesshare this common structural motif which imparts uniqueproperties to them.

The efficient preparation of these structural motifs remainsa major challenge in organic chemistry, although multi-stepsynthesis methods7 have been reported. An elegant synthesis ofthe above motif was reported by the group of Micalizio8 usingtitanium-promoted reductive cross-coupling reaction betweenvinylcyclopropanes and alkynes (or vinylsilanes). To the best ofour knowledge, the only catalytic asymmetric synthesis of the3-methyl substituted 1,4-diene unit with broad substrate scopewas reported by the group of RajanBabu achieved by hydro-vinylation of 1,3-dienes with excellent regio- and enantio-selectivity.9 Some examples have been reported in the literaturefor the synthesis of related structures using copper-catalysedasymmetric allylic alkylation (AAA)10 mainly with longer alkylchains at the central position. The group of Hoveyda describedcopper-catalysed AAA of allylic phosphates with a diethylzincreagent including one example of a skipped diene.11 Li andAlexakis reported an asymmetric allylic substitution of enyne

chlorides with Grignard reagents which was also extended totwo diene chlorides for the synthesis of 3-ethyl and 3-phenethylsubstituted skipped dienes.12 Since the introduction of amethyl branch remains a highly desired goal in view of itsimportance in natural product synthesis,13 we report here ahighly efficient catalytic methodology to prepare this structuralmotif with broad substrate scope and excellent enantio-selectivity using copper-catalysed AAA of diene bromides withmethylmagnesium bromide.

Our investigation started with the asymmetric allylic alkyla-tion of ((1E,3E)-5-bromopenta-1,3-dienyl)benzene 1a14 withMeMgBr in dichloromethane at �80 1C employing a copperbromide dimethylsulfide complex (CuBr�SMe2) and L1 asligand (Table 1, entry 1). Product 2a was isolated in 65% yieldwith 85% ee and the ratio of 2a : 3a (SN20/SN2) was 79 : 21. Toincrease both the regio- and enantioselectivity of the reaction, aseries of catalysts based on the chiral ligands depicted inTable 1 were tested. Both Tol-BINAP (L2) and JosiPhos type

Scheme 1 Skipped polyenes found in diverse natural products.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4,

9747 AG Groningen, The Netherlands. E-mail: b.l.feringa@rug.nl;

Fax: +31 50 363 4278; Tel: +31 50 363 4296

† Electronic supplementary information (ESI) available: General procedures forthe synthesis of substrates and products; 1H and 13C NMR spectral data of allproducts. See DOI: 10.1039/c3cc41021h

Received 6th February 2013,Accepted 5th March 2013

DOI: 10.1039/c3cc41021h

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3310 Chem. Commun., 2013, 49, 3309--3311 This journal is c The Royal Society of Chemistry 2013

ligands (L4 and L5) afforded lower ee than L1. We then used thecombination of CuBr�SMe2 with TaniaPhos (L3), which hasemerged as an excellent catalyst for the introduction of themethyl unit via copper-catalysed AAA.15 We were pleased to seethat the use of this catalytic system led to product 2a in 66%yield with >99% ee and with excellent regioselectivity (2a : 3a =95 : 5). It is important to note that only 1,3-substitution hap-pened and no 1,5-substitution adduct was detected.

With this highly selective catalyst in hand, we studied thesolvent effects on the reaction. We found that dichloromethanewas still the most effective solvent. When we used toluene,product 2a was obtained with 95% ee but with lower regio-selectivity (Table 1, entry 6). The use of THF gave comparableregioselectivity as DCM but the ee decreased to 87% (entry 7).The situation in diethyl ether was even worse; the enantio-selectivity decreased and the regioselectivity was totallyswitched, with the linear product 3a being the main productof the reaction (entry 8).

To study the scope of this new enantioselective transformation,a series of substrates were tested under the optimized condi-tions (Table 1, entry 3). Excellent regio- and enantioselectivitywere obtained in all cases (Scheme 2).

This new methodology proved to be also very efficient for analkyl substituted substrate such as 1b (R1 = iso-Bu) whichafforded 1,4-diene 2b with excellent selectivity. It should benoted that product 2b represents the side chain of phorbasins(Scheme 1). Notably, both the regio- and enantioselectivity ofthe reaction dropped considerably when we used a (2E,4E)/(2Z,4E) isomeric mixture of substrate 1b. The E-geometry of thedouble bond next to the bromide seems crucial for achievinghigh ee and regioselectivity (Scheme 3). A remarkable result wasobtained with ester-substituted diene bromide 1c which ledexclusively to product 2c, without any traces of the 1,2-, 1,4- or1,6-addition to the carbonyl moiety or of the 1,5-substitutionproduct. Moreover, product 2c is a core unit of iejimalides(Scheme 1). The versatile substituent TBSOCH2, as present indiene 1d, had no influence on the enantioselectivity and diene2d could be obtained with 99% ee although a slightly lowerregioselectivity was observed. The more substituted substrates1e and 1f, with methyl groups at R2 or R3, could also be used inthis transformation. Again, 2e and 2f were obtained exclusivelywith excellent selectivity. We also tested the effect of the remotedouble bond geometry as the presence of a Z-double bond iscommon in some natural products like hennoxazole A. We were

Table 1 Optimization of the copper-catalysed AAA of 1a

Entrya Ligand Solvent Yieldb [%] SN20/SN2c eed [%]

1 L1 DCM 65 79 : 21 852 L2 DCM 68 36 : 64 �50 f

3 L3 DCM 66 95 : 5 >994 L4 DCM 75 50 : 50 �62 f

5 L5 DCM 51 23 : 77 326 L3 Toluene 25e 80 : 20 957 L3 THF 34e 91 : 9 878 L3 Et2O 46e 8 : 92 71

a Reaction conditions: MeMgBr (0.3 mmol) was added to a stirredsolution of CuBr�SMe2 and a ligand in dry solvent at �80 1C; 1a(0.25 mmol) in 1 mL of dry solvent was added dropwise over 1 h.b Isolated combined yield. c Determined by 1H NMR or GC. d Deter-mined by chiral GC. e Mixture of products. f The negative ee valueindicates that the opposite enantiomer was formed.

Scheme 2 Copper-catalysed AAA of diene bromides 1. Reaction conditions: MeMgBr (0.3 mmol) was added to a stirred solution of CuBr�SMe2 and TaniaPhos (L3) indry DCM at �80 1C; substrate 1 (0.25 mmol) in 1 mL of dry DCM was added dropwise over 1 h. Yield represents combined isolated yield. Regioselectivity wasdetermined by 1H NMR or GC analysis. ee was determined by chiral GC or HPLC. a1 g scale, 1 mol% of catalyst; 58% yield, SN20/SN2 95 : 5, 99% ee. b Volatile products.

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pleased to find that the reaction also proceeded successfullywith (Z,E)-1g affording similar regio- and enantioselectivity tothat with (E,E)-1f, while no double bond isomerization wasdetected in 2g. These remarkable results show that the geometryof the double bond remote from the bromide seems to have noeffect on both the regio- and enantioselectivity (Scheme 3). Animportant feature is the scalability of this reaction. Synthesis of2a was executed on a larger scale (1 gram) using only 1 mol% ofcatalyst and still excellent ee and regioselectivity were obtained,with a similar yield.

Finally we tried further functionalization of the 1,4-diene 2dvia cross metathesis16 (Scheme 4) for future synthetic applica-tions. The initially attempted cross metathesis with ethylacrylate 4 using Grubbs’ first and second-generation catalystsand Hoveyda–Grubbs first-generation catalyst under differentconditions led to complicated products. However, the Hoveyda–Grubbs second-generation catalyst significantly improved theoutcome and afforded the product 5 as a single E,E-isomer. Thepresence of a protected alcohol and ester group facilitates theuse of optically active 5 as a versatile multifunctional buildingblock in natural product synthesis allowing for chain elonga-tion at each end of the molecule.

In summary, a copper-catalysed asymmetric allylic alkylationwith methylmagnesium bromide as a nucleophile employingprochiral diene bromides as substrates was developed. Thereaction leads to important chiral 1,4-diene building blocks withexcellent regio- and enantioselectivity (ee values up to 99%;SN20/SN2 ratio up to 97 : 3) in nearly all cases. Application of thismethodology to the total synthesis of phorbasins is ongoing.

T. D. Tiemersma-Wegman (Stratingh Institute for Chemistry)is acknowledged for high resolution mass spectrometry support,

M. J. Smith is acknowledged for chromatography support.Financial support from NRSC-Catalysis grant 200910018B isgratefully acknowledged.

Notes and references1 M. S. F. L. K. Jie, M. K. Pasha and M. S. K. Syed-Rahmatulla, Nat.

Prod. Rep., 1997, 14, 163–189.2 (a) T. Ichiba, W. Y. Yoshida, P. J. Scheuer and T. Higa, J. Am. Chem.

Soc., 1991, 113, 3173–3174; (b) T. Higa, J. Tanaka, A. Kitamura,T. Koyama, M. Takahashi and T. Uchida, Pure Appl. Chem., 1994, 66,2227–2230.

3 M. C. Wilson, S.-J. Nam, T. A. M. Gulder, C. A. Kauffman,P. R. Jensen, W. Fenical and B. S. Moore, J. Am. Chem. Soc., 2011,133, 1971–1977.

4 (a) D. T. Connor, R. C. Greenough and M. von Strandtmann, J. Org.Chem., 1977, 42, 3664–3669; (b) S. M. Ringel, R. C. Greenough,S. Roemer, D. Connor, A. L. Gutt, B. Blair, G. Kanter and M. vonStrandtmann, J. Antibiot., 1977, 371–375.

5 (a) J. Kobayashi, J. Cheng, T. Ohta, H. Nakamura, S. Nozoe,Y. Hirata, Y. Ohizumi and T. Sasaki, J. Org. Chem., 1988, 53, 6147;(b) Y. Kikuchi, M. Ishibashi, T. Sasaki and J. Kobayashi, TetrahedronLett., 1991, 32, 797.

6 (a) D. Vuong and R. J. Capon, J. Nat. Prod., 2000, 63, 1684;M. McNally and R. J. Capon, J. Nat. Prod., 2001, 64, 645;(b) H.-S. Lee, S. Y. Park, C. J. Sim and J.-R. Rho, Chem. Pharm. Bull.,2008, 56, 1198.

7 (a) T. K. Macklin and G. C. Micalizio, J. Am. Chem. Soc., 2009, 131,1392–1393; (b) S. Hanessian, T. Focken, X. Mi, R. Oza, B. Chen,D. Ritson and R. Beaudegnies, J. Org. Chem., 2010, 75, 5601–5618.

8 T. K. Macklin and G. C. Micalizio, Nat. Chem., 2010, 2, 638–643.9 (a) R. K. Sharma and T. V. RajanBabu, J. Am. Chem. Soc., 2010, 132,

3295–3297; (b) A. Zhang and T. V. RajanBabu, J. Am. Chem. Soc.,2006, 128, 54–55; (c) C. R. Smith and T. V. RajanBabu, Org. Lett.,2008, 10, 1657–1659.

10 For reviews on Cu-catalysed AAA, see: (a) S. Harutyunyan, T. denHartog, K. Geurts, A. J. Minnaard and B. L. Feringa, Chem. Rev.,2008, 108, 2824; (b) A. Alexakis, J. E. Backvall, N. Krause, O. Pamiesand M. Dieguez, Chem. Rev., 2008, 108, 2796; (c) J.-B. Langlois andA. Alexakis, in Transition Metal Catalyzed Allylic Substitution inOrganic Synthesis, ed. U. Kazmaier, Springer-Verlag, Berlin, 2012,pp. 235–268.

11 M. A. Kacprzynski and A. H. Hoveyda, J. Am. Chem. Soc., 2004, 126,10676–10681.

12 H. Li and A. Alexakis, Angew. Chem., Int. Ed., 2012, 51, 1055–1058.13 During the preparation of this manuscript Mauduit et.al. reported a

single example of a 3-methyl substituted skipped diene usingcopper-catalyzed AAA with dimethylzinc. M. Magrez, Y. L. Guen,O. Basle, C. Crevisy and M. Mauduit, Chem.–Eur. J., 2013, 19,1199–1203.

14 D. D. Kim, S. J. Lee and P. Beak, J. Org. Chem., 2005, 70, 5376–5386.15 For selected examples, see: (a) F. Lopez, A. W. van Zijl,

A. J. Minnaard and B. L. Feringa, Chem. Commun., 2006, 409–411;(b) K. Geurts, S. P. Fletcher and B. L. Feringa, J. Am. Chem. Soc., 2006,128, 15572–15573; (c) M. Fananas-Mastral, B. ter Horst,A. J. Minnaard and B. L. Feringa, Chem. Commun., 2011, 47,5843–5845; (d) M. Perez, M. Fananas-Mastral, P. H. Bos,A. Rudolph, S. R. Harutyunyan and B. L. Feringa, Nat. Chem.,2011, 3, 377–381.

16 (a) S. J. Connon and S. Blechert, Angew. Chem., Int. Ed., 2003, 42,1900–1923; (b) A. H. Hoveyda and A. R. Zhugralin, Nature, 2007, 450,243–251; (c) C. Samojlowicz, M. Bieniek and K. Grela, Chem. Rev.,2009, 109, 3708–3742; (d) G. C. Vougioukalakis and R. H. Grubbs,Chem. Rev., 2010, 110, 1746–1787.

Scheme 3 Effect of double bond geometry on ee and regioselectivity.

Scheme 4 Cross metathesis between 1,4-diene 2d and ethyl acrylate 4.

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