ARTICLE Received 31 Oct 2013 | Accepted 16 Dec 2013 | Published 17 Jan 2014 DOI: 10.1038/ncomms4111 Stereospecific ring expansion from orthocyclophanes with central chirality to metacyclophanes with planar chirality Naoki Ishida1, Shota Sawano1 & Masahiro Murakami1 Carbon–carbon bonds constitute the major framework of organic molecules and carbon– hydrogen bonds are abundant in their peripheries. Such nonpolar s-bonds are thermo- dynamically stable and kinetically inert in general. Nonetheless, selective activation of those ubiquitous bonds may offer a straightforward method to construct and/or functionalize organic skeletons. Herein we describe ring expansion from orthocyclophanes to metacyclo- phanes occurring upon sequential action of light and a metal catalyst. Formally, specific non-strained carbon–hydrogen and carbon–carbon bonds are cleaved and exchanged without elimination of any leaving groups. Notably, the product is energetically uphill from the starting material, but the endergonic photocyclization step makes it possible to drive the trans- formation forward. The ring expansion is extended to the stereospecific synthesis of metacyclophanes possessing planar chirality, during which central chirality on a tertiary carbon is transferred to planar chirality. 1 Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan. Correspondence and requests for materials should be addressed to M.M. (email: [email protected]). NATURE COMMUNICATIONS | 5:3111 | DOI: 10.1038/ncomms4111 | www.nature.com/naturecommunications 1 & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4111 he number of functional groups that can be transformed by originally proposed by Wagner et al.41, the ketone 1a is transition metal catalysis has been considerably expanded. electronically excited and the excited carbonyl group acts as an TCarbon–carbon (C–C)1–15 and carbon–hydrogen (C–H) oxyl radical to site-specifically abstract the benzylic hydrogen46,47. bonds16–25, which are ubiquitous in organic compounds, are The resulting 1,4-biradical species Aa, having an o-phenylene intrinsically difficult to activate owing to their thermodynamic linker, spontaneously generates an isomeric mixture of the stability as well as their kinetic inertness. Selective transformation o-quinodimethanes (E)- and (Z)-Ba48. The (Z)-isomer having of such nonpolar s-bonds has provided a challenge that has an outward-oriented hydroxy group undergoes a 4p-electrocyclic motivated and inspired chemists to seek ways to activate these ring closure to form benzocyclobutenol (±)-5a. On the other bonds over the past two decades. hand, the (E)-isomer having an inward-oriented hydroxy group Metacyclophanes are cyclic compounds that have a central undergoes facile 1,5-proton shift to regenerate 1a rather than the arene unit with its 1,3-positions connected through an ansa ring closure. chain26. The arene unit can rapidly flip in many cases, but when The second step is a ring-opening reaction promoted by the the flipping is hindered, metacyclophanes can gain stable planar rhodium hydroxide complex (Fig. 2b, bottom). The hydroxy chirality. Such an intriguing chiral metacyclophane unit is found group of (±)-5a is exchanged onto the rhodium hydroxide to in various natural products like galeon and vancomycin27. Chiral generate rhodium benzocyclobutenolate Ca, in which the benzene metacyclophanes also constitute a key structural component of ring likely p-coordinates to rhodium49. Next follows b-carbon some pharmaceuticals28,29 and supramolecular host materials elimination, for which the p-coordination facilitates site-selective that accept small molecules30–32. Consequently, the development cleavage of the C(ipso)–C(sp3) bond to furnish arylrhodium Da. of methods to stereoselectively construct chiral metacyclophane Finally, protonation produces [9]metacyclophane 2a. skeletons has been of growing interest33–38. In order to assess the thermodynamics of this sequential We herein describe a sequential process to expand orthocy- process, DFT calculations were performed at the B3LYP/6-31 G(d) clophanes 1 into their more strained constitutional isomers, level (Gas phase at 1 atm, 298 K) (Supplementary Fig. 1). The metacyclophanes 2 (Fig. 1). Specific non-polar, unstrained C–H results suggest that (±)-5a and 2a are thermodynamically less and C–C bonds are cleaved and exchanged in a formal sense. Of stable than 1a by ca. 32.3 and 3.8 kcal mol À 1, respectively. The note is that the whole transformation is energetically uphill (vide irreversible formation of highly energetic intermediate (±)-5a by infra) and atom-economical. The overall driving force ultimately the first photocyclization process makes it possible to drive the derives from light. The process can also be extended to the energetically uphill transformation from the reactant 1a to its stereoselective synthesis of metacyclophanes 4 possessing planar more strained constitutional isomer 2a. chirality. Results Synthesis of planar-chiral cyclophanes 4. We next tried to utilize Ring expansion of orthocyclophane 1a to metacyclophane 2a. the arylrhodium intermediate D for the subsequent C–C bond Initially, a THF solution of orthocyclophane 1a (0.02 M) in a formation, aiming at the synthesis of metacyclophanes having stable Pyrex tube was irradiated with UV light (270–350 nm) for 13 h planar chirality. Thus, the racemic benzocyclobutenol (±)-5a (Fig. 2a). Photocyclization39–41 took place to afford benzo- was treated with a rhodium catalyst in the presence of methyl vinyl cyclobutenol (±)-5a in 92% isolated yield. Subsequently, the ketone (3, 10 equiv.) in toluene at room temperature for 10 h benzocyclobutenol (±)-5a was treated with a catalytic amount of (Fig. 3). The reaction furnished [9]metacyclophane 4a (69% isolated ° yield) that successfully incorporated 3 at the arene carbon [Rh(OH)(cod)]2 at 60 C in MeOH for 5 h. The benzocyclobutene 1 ring was opened with site-selective cleavage of the C(sp2)–C(sp3) between the 1,3-ansa chain. The HNMRof4a shows the two bond42–45 to afford [9]metacyclophane 2a in 72% isolated distinctly coupled doublets at d 3.44 (d, J ¼ 14.6 Hz, 1 H) and yield. The 1H NMR of 2a shows only one singlet peak for d 3.95 (d, J ¼ 14.6 Hz, 1 H), indicating the inequivalency of the the benzylic protons of the ansa chain (d 3.67 (s, 2H)), suggesting two benzylic protons of the ansa chain. The chiral HPLC analysis that the benzene ring flips up and down freely across the ansa of the 4a exhibited two peaks of equal intensities in consistence chain. with a racemic mixture of two enantiomers. We assume that A two-step mechanistic sequence for the ring expansion is the sterics of the middle substituent prohibit the flipping of the shown in Fig. 2b. The first step is a photo-induced ring benzene ring and give rise to stable planar chirality. closing reaction (Fig. 2b, top). According to the mechanism Next, our interest was directed to the stereochemical course of the ring opening/addition process, during which central chirality of benzocyclobutenol 5a disappeared and planar chirality was O generated with 4a. The racemic mixture of benzocyclobutenol R (±)-5a was successfully separated by preparative chiral HPLC to the two enantiomers ( þ )- and (–)-5a. The reaction of ( þ )-5a H (499:1 enantiomeric ratio (er)) with 3 in the presence of the R H achiral [Rh(OH)(cod)] catalyst afforded ( þ )-4a in 72% yield O 2 X n (Fig. 4). A chiral HPLC analysis showed that the enantiomeric 2 purity was retained (499:1 er). This result assured the O O stereochemical integrity during the transfer of central chirality n X R of 5a to planar chirality of 4a (ref. 50), letting us examine the Me O 1 3 stereospecificity of chiral transfer in more detail. Thus, the two- step ring expansion of orthocyclophane 1b to metacyclophane Me (±)-4b was carried out (Fig. 5a). n The first photocyclization of 1b afforded benzocyclobutenol X ± 4 ( )-5b as a single diastereomer (78% isolated yield). It was determined by NOE analysis that the hydroxy group was trans to Figure 1 | Ring expansion reactions. Conversion of orthocyclophanes 1 to the (trimethylsilyl)methyl substituent. Subsequent treatment of metacyclophanes 2 and 4. (±)-5b with the rhodium catalyst in the presence of 3 (10 equiv) 2 NATURE COMMUNICATIONS | 5:3111 | DOI: 10.1038/ncomms4111 | www.nature.com/naturecommunications & 2014 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4111 ARTICLE O OH CH3 O [Rh(OH)(cod)]2 hν (2.5 mol %) THF, rt, 13 h MeOH, 60 °C, 5 h O O 1a (±)-5a 92% O 2a 72% 1st step H * H CH O 3 H2C O H2C O hν O O O 1a 1a* Aa OH OH O O (Z )-Ba (±)-5a H O CH3 O O O 1a (E )-Ba 2nd step O OH O[Rh] [Rh] OH [Rh] −H O O 2 O (±)-5a Ca O Da O H2O − [Rh] OH [Rh] = Rh O 2a Figure 2 | Ring expansion of 1a to 2a. (a) Reaction scheme. (b) Plausible mechanism. O OH O [Rh(OH)(cod)]2 O (2.5 mol %) + Me Toluene, rt, 10 h Me O 3 (±)-5a (10 equiv) O (±)-4a 69% Figure 3 | Planar chiral derivatives. Rhodium-catalysed reaction of (±)-5a with 3. in toluene at room temperature for 24 h furnished [9]metacyclo- The plausible explanation for the diastereoselectivity observed phane (±)-4b in 62% isolated yield, again as a single in the first photocyclization step is shown in Fig. 5b (ref. 41). diastereomer. No other diastereomer was detected in the crude Although the 1,4-biradical species Ab generated from 1b reaction mixture. The (trimethylsilyl)methyl substituent and the potentially gives rise to four stereoisomers (E,Z)-Bb,(E,E)-Bb, C–C bond newly formed between the arene and 3 were assigned (Z,Z)-Bb and (Z,E)-Bb, the formation of (Z,Z)-Bb and (Z,E)-Bb as trans to each other by a series of NMR analyses (1H, 13C, is disfavoured because of steric repulsion arising between the DEPT, COSY, HMQC, HMBC and NOESY).