A novel oxy-oxonia(azonia)-cope reaction: serendipitous discovery and its application to the synthesis of macrocyclic musks.

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CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)

A Novel Oxy-Oxonia(Azonia)-Cope Reaction: Serendipitous Discovery and Its Application to the Synthesis of Macrocyclic Musks by Yue Zou* a ), Lijun Zhou a ) b ), Changming Ding a ), Quanrui Wang b ), Philip Kraft c ), and Andreas Goeke c ) a

) Givaudan Fragrances (Shanghai) Ltd., Li Shi Zhen Road 298, Shanghai 201203, P. R. China (e-mail: [email protected]) b ) Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. China c ) Givaudan Schweiz AG, Fragrance Research, berlandstrasse 138, CH-8600 Dbendorf Dans les champs de lobservation le hasard ne favorise que les esprits pre´pare´s Im Reich der Beobachtung begnstigt der Zufall den vorbereiteten Geist In the field of observation, chance favors the prepared mind

Louis Pasteur, 1854

This brief review, including new experimental results, is the summary of a talk at the GDCh conference flavors & fragrances 2013 in Leipzig, Germany, 11th – 13th September, 2013. Musk odorants are indispensable in perfumery to lend sensuality to fine fragrances, a nourishing effect to cosmetics, and a comforting feeling to laundry. We have recently found serendipitously a new oxy-oxonia-Cope rearrangement. In this account, we review the background of oxonia-sigmatropic rearrangements and the discovery of this novel reaction. Special attention is focused on the versatile lactone and lactam formation reactions via [n þ 4] ring enlargement and the macrocyclization in the synthesis of new macrocyclic musks. The synthesized structures provide new insights into the structureodor relationships of musks.

Introduction. – Rearrangement reactions of molecular C-atom skeletons represent one of the most attractive and dynamic areas in organic synthesis, and [3,3]-sigmatropic rearrangements are key features in such rearrangement reactions. The most wellknown [3,3]-sigmatropic rearrangements are the Claisen rearrangement, the Cope rearrangement, and their tandem variants (Scheme 1) [1 – 3]. The rearrangements were defined with Y ¼ C-atom for the Cope and Y ¼O-atom for the Claisen rearrangement by thermal isomerization. Since its discovery by Ludwig R. Claisen nearly 100 years ago, the Claisen rearrangement has become a powerful synthetic tool for organic chemists [4]. However, its mechanism was proposed only in the 1960s, ca. 25 years after the Cope rearrangement was reported. They are both prototypes of [3,3]-sigmatropic rearrangements, and they have been proven very useful in the synthesis of natural products and fine chemical compounds both in the laboratory and on an industrial scale [5]. In most cases, stereochemical and theoretical studies suggested that the rearranging substrate adopts a six-membered chair-like transition state with a delocalized electronic structure. 2014 Verlag Helvetica Chimica Acta AG, Zrich


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Scheme 1. [3,3]-Sigmatropic Rearrangement Reactions

Oxonia-sigmatropic rearrangements are efficient synthetic links between the Cope rearrangement and the pinacol-terminated Prins cyclizations. Initial observations date back to reports of Mousset and co-workers in 1969 [6]. Later, Overman and co-workers started to elaborate this route for syntheses of tetrahydrofurans [7] [8] and a variety of natural products [9 – 12]. Unexpectedly, mechanistic studies revealed that the formation of 3-acyltetrahydrofurans took place by the Prins cyclizationpinacol rearrangement reaction sequence (Path A, Scheme 2), and not by sequential 2-oxonia[3,3]-sigmatropic rearrangementaldol cyclization (Path B, Scheme 2) [7] [8]. The fact that chiral nonracemic tetrahydrofurans 4 can be prepared from optically active allylic acetals (5S)-1 without loss of enantiomeric purity also indicated a Prins cyclizationpinacol mechanism (Path A), since the 2-oxonia-[3,3]-sigmatropic rearrangement

Scheme 2. Prins-Pinacol Reaction (Path A) vs. Oxonia-Cope/Aldol Cyclization (Path B)

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intermediate 5 in Path B was achiral [8]. However, in recent years, it has been demonstrated that oxonia-Cope rearrangements are the prevailing mechanism in Prins reactions [13 – 20]. In comparison with Cope rearrangements, the substitution of one sp2-configured C-atom by an oxonium ion is the underlying feature of the oxonia rearrangement. Other important features are the stoichiometric amount of Lewis acids used, as well as the expected formation of the six-membered ring intermediate 3 which conserves the stereochemical outcome of the reaction by establishing equatorial substituents. Intermediate 2 can undergo a reversible oxonia rearrangement, which leads to the loss of steric information and to racemization of the otherwise identical compound 4 [18]. Recently, the Lewis acid-catalyzed allyl transfer of secondary and tertiary allyl alcohols to carbonyl compounds [11] [21] has been much studied and applied to natural-product synthesis [22]. This reaction also proceeds via an oxoniaCope transition state. Charge has been well-known for a long time to be a key component in the arena of [3,3]-sigmatropic rearrangements (Eqn. 1, Scheme 3). The rate acceleration of Cope

Scheme 3. Dramatic Rate Acceleration of [3,3]-Sigmatropic Reactions Relative to the Cope Rearrangement of Hexa-1,5-diene (LA, Lewis acid)


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rearrangements by charge has been widely studied. One example is the anionic oxyCope rearrangement reported by Evans et al. (Eqn. 2, Scheme 3) [23]. The driving force for the neutral or anionic oxy-Cope rearrangement is that the product is an enol or enolate such as 10, which can tautomerize to the corresponding carbonyl compound 11. This product will generally not equilibrate back to the other rearrangement isomers. The oxy-Cope rearrangement proceeds at a much faster rate, when the starting alcohol 9 is deprotonated, e.g., with KH. The reaction is then up to 1017 times faster than the neutral Cope rearrangement of hexa-1,5-diene 6 to 8 (Eqn. 1, Scheme 3) [23]. Another example are the 2-azonia-[3,3]-sigmatropic rearrangements (cationic aza-Cope rearrangements of 12 to 15), which take place at temperatures 100 – 2008 lower than rearrangements of hydrocarbon counterparts (Eqn. 3, Scheme 3) [6 – 8]. 2-AzoniaCope rearrangements can be driven to completion by a tandem Mannich cyclization process, which was first introduced by Overman et al. [24]. This transformation has provided impressive possibilities for the rapid assembly of novel pyrrolidine-containing structures 18 (Eqn. 4, Scheme 3). In this review, we summarize the serendipitous discovery and further development of a novel oxy-oxonia(azonia)-Cope reaction and its application to the synthesis of macrocyclic musks (Eqn. 5, Scheme 3) [25 – 27]. For its natural, sweet, and sensual odors, musks are one of the most versatile odorant classes used in perfumery [28]. Structurally quite different molecules may have similar musk odors. Commercial musks can be classififed in four groups (Fig. 1): nitro musks such as musk ketone (23), macrocyclic musks such as ()-(R)-muscone (24), polycyclic musks such as Galaxolide (25), and linear aliphatic and alicyclic musks such as Serenolide (26). Due to a certain phototoxicity of nitro musks, and the lack of biodegradation of polycyclic musks [28] [29], the two most important musk families of today are macrocycles derived from the natural lead ()-(R)-muscone (24), and linear alicyclic musks [29]. Macrocyclic musks are the only family that occurs in nature, and they are much appreciated in perfumery for their natural and authentic odor quality; in addition, they generally biodegrade readily [30]. The relationship between molecular structure and odor is one of the most fascinating research topics for the fragrance chemist [31]. Despite a great deal of research on macrocyclic musks, the overall picture of the structureodor relationships of macrocyclic musks is still incomplete. While there are many synthetic tools for ring-closure or ring-enlargement reactions towards macrocyclic musks [32], positioning C¼C bonds in stereochemically well-defined positions in a macrocylic ring still constitutes a synthetic challenge, and therefore, the influence of differently configured C¼C bonds on the olfactory properties of macrocycles of different sizes is not well-studied and understood.

Fig. 1. Representative perfumery ingredients of the musk family

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Serendipitous Discovery of a Novel Oxy-Oxonia-Cope Reaction. – The oxyoxonia(azonia)-Cope rearrangement was serendipitously found during our investigation of the green-smelling natural lead compound perilla aldehyde which occurs, for example, in the essential oil of Perilla frutescens [33]. The leaves are frequently used as a condiment and became popular in the West due to the growing popularity of sushi. An organocatalytic multicomponent a-methylenation/DielsAlder reaction had been developed as a general synthetic route to substituted cyclohexene-carbaldehyde derivatives [34]. This versatile chemistry led to the discovery of the new proprietary fragrance ingredient Shisolia (31), which possesses a powerful green, fruity, apple, cinnamic, and anisic odor, and 32 with an odor recalling cassis, grapefruit, and woods (Scheme 4) [34] [35]. The oxy-oxonia-Cope reaction was discovered during attempts to synthesize novel oxaspiro analogs of odorant 32 (Scheme 4) [35]: in the presence of MeCHO and a catalytic amount of a Lewis acid, aldehyde 30 smoothly rearranged to 34 without any of the expected Prins cyclization product 33 being detectable. The starting aldehyde 30 was conveniently synthesized by a domino sequence similar to that of Shisolia (31): an organocatalytic multicomponent a-methylenation/DielsAlder reaction of prenal (27), formaldehyde, and diene 29. The in situ-generated unstable 2-formyl-3-methylbuta-1,3-diene (28) was trapped by another reactive diene 29 to give the cross-DielsAlder reaction product 30 [34]. This reaction can be considered as a novel tandem cross-dimerization/oxy-oxoniaCope rearrangement sequence (Scheme 5) [25]. Compared to the known oxonia-Cope reaction, four evidently different features can be attributed to this reaction: i) the Scheme 4. Serendipitous Discovery of a Novel Oxy-Oxonia-Cope Reaction while Studying the Chemistry of Shisolia (31) and the Cassis, Grapefruit-smelling Lead Compound 32


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Scheme 5. Tandem Cross-Dimerization/Oxy-Oxonia-Cope Sequence of Two Different Carbonyl Compounds

reaction represents an intermolecular disproportionation of the different C¼O groups to form a homoallylic ester 38. ii) Unlike in the crossed-Tishchenko reaction [36], this disproportionation of two different aldehydes is not the result of a hydride transfer: it is brought about by a sigmatropic oxonia-Cope rearrangement involving the b,g-C¼C bond of substrate 35. iii) The transformation was clean, and the formation of homo- or cross-aldol products was not observed. iv) The transformation is truly catalytic, and the use of 10 mol-% of Lewis acid is sufficient to complete the conversion. A thermal conversion of 30 with MeCHO to product 34 was not observed under thermal conditions at temperatures of < 3508 (Scheme 4) [25]. Thus, in analogy to the above considerations on [3,3]-sigmatropic rearrangements, this reaction of b,g-unsaturated carbonyl compound 35 to homoallylic ester 38 was described as an oxy-oxonia-Cope rearrangement [25]. Oxy-Oxonia-Cope ([n þ 4]) Ring-Enlargement Macrolactonization. – After the serendipitous discovery of this versatile intermolecular rearrangement, a novel and general macrolactonization method has been elaborated by simply linking R1 together with R2 or R3 by a C-atom chain of a given length (Scheme 5) [25]. This rearrangement can be regarded as a new [n þ 4] ring-enlargement lactone formation method from simple cyclic ketone derivatives. Naturally occurring medium-sized lactones, especially those containing eight and nine C-atoms in the ring, are rare in nature, but a few natural products such as 39 – 41 have nevertheless been isolated to date (Fig. 2). The construction of medium-sized rings by intramolecular cyclization is frequently found more difficult than that of macrocyclic compounds, and thus represents a cumbersome step not only in natural biosyntheses, but also in modern synthetic technology [37] [38]. Compared with macrocyclic lactones, which constitute important musk odorants, structureodor correlations of medium-sized lactones have been less studied. In one article, i.e., [39], ()-phoracantholide I (41) was reported to possess a camphoraceous, coniferous, and woody odor [39]. The high reactivity of the oxyoxonia-Cope rearrangement, which constitutes an [n þ 4] ring-enlargement reaction,

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Fig. 2. Naturally occurring medium-sized lactones

enabled us to apply it also in the synthesis of medium-sized lactones (Scheme 6) [25]. The precursors of these lactones, a-vinyl-cycloalkanones 42 were prepared by slight modifications to known methodology [25]. The resulting lactone target structures were fully characterized by 2D-NMR recordings, and unequivocally determined by X-ray crystallographic analysis of (E)-44h. Yields and selectivities of the lactone formation depend primarily on the ring size of the product and the reaction temperature. High (Z)-selectivities were observed in lactones with nine-membered rings (i.e., 44a and 44b; Scheme 6). In addition, the Me group in bicyclic 44b was found to be exclusively in the anti-position. This excellent diastereoselectivity was also observed for the higher homolog 44i, irrespective of the C¼C bond configuration of the product. The C¼C bonds in lactones with ten- and eleven-membered rings preferentially have (E)configuration, although the (E)-selectivities of eleven-membered rings (i.e., 44j – 44l; Scheme 6) were quite poor. The odor characteristics of these lactones were evaluated. Both nine-memered rings, 44a and 44b, possess earthy, camphor, and borneol-like odors without any musk character. Their ten-membered ring derivatives, such as 44c, had a sweet woody facet, but camphoraceous impressions dominated. Compound 44d with a bulky tBu substituent has a very weak musky note with green and agrestic nuances. The phenyl-substituted lactones 44e – 44h were all odorless. The bicyclic lactone 44i possessed a herbal, carvone-like, camphoraceous, and woody odor. The eleven-membered lactones 44j – 44l had weaker fruity, woody, and earthy notes. Lactones with larger rings were also synthesized as outlined in Fig. 3 [25]. While the twelve-membered lactone 44m was synthesized from a-isopropenyl-cyclooctanone in moderate yield with a poor (E)-selectivity, the 16-membered lactones 44n – 44p were prepared with excellent yield and selectivity from a-isopropenyl-cyclododecanone. Compound 44m possesses a fatty, dusty, and woody odor, while 44n – 44p have generally very weak odor, and are almost odorless. This indicated that the substitution pattern is not complimentary to the musk receptor(s), which was already expected from the established musk olfactophore models [27] [28]. It is important to note that, unlike the syn/anti-selectivity, the C¼C bond configuration of the lactones significantly depends on the reaction temperature. This


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Scheme 6. New Medium-Sized Lactones Obtained from Oxy-Oxonia-Cope ([n þ 4]) Ring-Enlargement Reactions and Their Olfactory Properties (LA, Lewis acid)

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Fig. 3. New macrocyclic lactones obtained by oxy-oxonia-Cope ([n þ 4]) ring-enlargement reactions and their olfactory properties

influence has been thoroughly investigated in the reaction of substrate 42q with PhCHO in the presence of 20 mol-% BF3 · Et2O (Scheme 7): product (E)-44q was formed predominantly at low temperature ( 208), while (Z)-44q was isolated as the major isomer at elevated temperatures. However, both (E)-44q and (Z)-44q were generated with exclusive anti-diastereoselectivity (dr > 99 : 1) as confirmed by X-ray crystallography [25]. Furthermore, the chirality transfer in oxonia-Cope rearrangements was investigated (Scheme 8). The optically active substrate (R)-46 was prepared by enzymatic kinetic resolution of rac-trans-45 as a key step (Scheme 8). The oxonia-Cope Scheme 7. Influence of Reaction Temperature on the C¼C Bond Configuration of Oxonia-Cope Rearrangement Products


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Scheme 8. Chirality Transfer in the Formation of Ten-Membered Ring Lactones (PCC, pyridinium chlorochromate)

rearrangement of (R)-46 and PhCHO resulted in a mixture (E)-47/(Z)-47 in a ratio of only 4 : 1, but in both products the stereochemical information was completely retained. The absolute configurations of compounds (R)-46, (E,S)-47 and (Z,R)-47 were determined by electronic circular dichroism (ECD) spectrocospy [25]. This complete chirality transfer was suggested to proceed via the trans-decalin-type species 48 to the major (E,S)-47 (99% ee) isomer. Isomer (Z,R)-47 was generated by the cis-decalinlike conformer 50, as this geometry leads to the observed (R)-configured isomer (Z)-47 with opposite absolute configuration. Both isomers descend from the intermediate (E)oxocarbenium species 48 and 50. Jasti and Rychnovsky had previously found that the occurrence of related (Z)-oxocarbenium species can be excluded [18] [40], since their involvement would lead to partial racemization. This experiment confirmed that the population of different chair-like conformers at a given temperature determines the configuration of the C¼C bonds in the oxonia-Cope products, while the configuration of intermediate oxocarbenium ions is responsible for the observed high anti-diastereoselectivity. Oxy-2-Azonia-Cope ([n þ 4]) Ring Enlargement to Macrocyclic Lactams. In contrast to the extensive use of esters in the fragrance industry, amides and their derivatives rarely occur in fragrances, presumably due to their high polarity and poor volatility. Compounds 52 – 54 (Fig. 4) are related amides of anilines of grapefruit and cassis odors, while Pepperwood (55) is a new proprietary fragrance material with a unique peppery, floral, and woody odor.

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Fig. 4. Representative amides in perfumery

With the aim to extend this odorant family, an analogous 2-azonia-Cope rearrangement via conversion of b,g-unsaturated aldehydes was elaborated, with imines replacing the aldehyde component of the 2-oxonia-Cope rearrangement (Scheme 9) [26]. For the azonia-Cope rearrangement, stoichiometric amounts of Lewis acids as catalysts led to very slow, though in most cases complete, conversions. Medium-sized lactams 58a – 58h and the macrocyclic lactam 58i were efficiently synthesized by using a similar [n þ 4] ring-expansion strategy. Nine-membered lactam 58a was obtained with exclusive (Z)-configuration, while the ten- and elevenmembered lactams, 58b – 58h, were formed with prevailing (E)-configurations, and the C¼C bond in the 16-membered ring 58i was formed with low stereoselectivity. Notably, cyclic imines were also applicable and resulted in bicyclic and tricyclic lactams, such as 58d, 58f, and indole 58g. The structures and geometries of these lactams, and their C¼C bond configurations were determined by NMR spectroscopy and X-ray crystallography. Compound 58b possessed a citrus, grapefruit, herbal, and bergamotlike odor, but had only a very slight musk aspect. The other lactams were very weakly odorous to odorless. To gain a deeper insight into the stereochemistry-defining step of this aza version, the preparation of ten-membered ring lactam 58b was investigated in more detail (Scheme 10). Treatment of the optically enriched cyclohexanone (S)-46 (98% ee) with acetaldehyde O-methyl oxime and 1.5 equiv. SnCl4 led to the rearrangement product (E,S)-58b with 90% ee in 89% yield after 60 min. Partial racemization is probably caused by concomitant racemization of (S)-46 under the strongly acidic conditions; the optical purity of the residual 3% of (S)-46, recovered after the reaction, was only 86% ee. The exclusive (E)-selectivity and high degree of absolute configuration (90% ee of (E,S)-58b), indicates that the reaction proceeds mainly via chair-like intermediate 59, assuming that the Me group adopts an equatorial position in the azonium ion. An analogous transition-state geometry was also suggested for the oxy-oxonia-Cope reaction [25]. Intramolecular Oxy-Oxonia-Cope Macrocyclization: Synthesis of Macrocyclic Musks [27]. In addition to the intermolecular [n þ 4] ring-enlargement approach to macrocyclic lactones and lactams, we were interested in applying the oxy-2-oxoniaCope rearrangement in an intramolecular fashion to construct alicyclic or macrocyclic ketones. As depicted in Scheme 11, the required macrocyclic precursors 62 from the


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Scheme 9. New Medium-Sized and Macrocyclic Lactams Obtained from Oxy-Azonia-Cope ([n þ 4]) Ring Enlargement and Their Olfactory Properties

intramolecular rearrangement intermediate 61 can be constructed by connecting substituents R2 and R6 of the starting materials in Scheme 5 by a linker of corresponding length to give substrates 60.

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Scheme 10. Partial Chirality Transfer in the Formation of Ten-Membered Ring Lactams

Scheme 11. Concept of the Intramolecular Oxy-Oxonia-Cope Macrocyclization

2-(Prop-1-en-2-yl)tridecanedial (60a) was chosen as the test substrate for the projected macrocyclization [27]. However, treatment of 60a with BF3 · Et2O (0.3 equiv.) in ClCH2CH2Cl afforded 62a in only trace amounts. The dimerized and cyclized 28membered ring 63 was isolated as the major product. Therefore, high-dilution conditions were employed to suppress the dimerization and intermolecular oligomerization. As a consequence, the yield of 62a increased considerably under these highdilution conditions. A yield of 52% was achieved, when a solution of compound 60a was slowly added to the Lewis acid solution by means of a syringe pump under optimized

Scheme 12. Effect of Dilution on the Oxy-Oxonia-Cope Macrocyclization


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conditions (Scheme 12). Attempts to use Amerlyst 15 or other Lewis acids instead of BF3 · Et2O were unsuccessful. Employing this high-dilution methodology, the corresponding 14- to 18-membered macrocyclic derivatives 62a – 62e, respectively, were successfully synthesized via intramolecular oxonia-Cope rearrangement as key step. The yields of this cyclization reaction strongly depend on the ring sizes of the products (Scheme 13). In general, the following trend was observed: when the ring size was larger than twelve, formation of even-membered rings (such as 62c and 62e) was preferred over the formation of oddmembered rings (such as 62b and 62d). Shorter-chain substrates which would have resulted in 12- and 13-membered ring products gave only rise to the formation of 24and 26-membered dimerization/cyclization products in low yields. In contrast, the yields of 16- and 18-membered rings were both higher than 90%, while the yields of 14-, 15- and 17-membered rings were in the range of 35 – 45%. Doubly unsaturated macrocyclic musk odorants are rarely described in the literature, and, in addition to the olfactory properties, we were also curious to learn whether the oxy-oxonia-Cope rearrangement would tolerate unsaturated substrates. Therefore, the macrocyclization reaction was applied to construct a doubly-unsaturated macrocycle. The synthesis of the 14-membered derivative 74 of Cosmone (75; Scheme 14) commenced with the reaction of 5-bromopentan-1-ol (65) to the phosphonium bromide 66. The Wittig reaction with 6-chlorohexanal proceeded smoothly, and was followed by protection of the free OH group employing tBuPh2SiCl (TBDPSCl). Compound 67 (Z)/(E) (4 : 1) was then submitted to a Finkelstein transhalogenation to 68, followed by alkylation with the Weinreb amide 69 under Scheme 13. Influence of Ring-Sizes on the Oxy-Oxonia-Cope Macrocyclization (KHMDS, potassium bis(trimethylsilyl)amide; HMPT, tris(dimethylamino)phosphine; TBAF, tetrabutylammonium fluoride; PCC, pyridinium chlorochromate)

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Scheme 14. Synthesis of the Di-unsaturated Structural Isomer 74 of (5Z)-Cosmone (75; TBDPSCl, (tertbutyl)(chloro)(diphenyl)silane (tBuPh2SiCl); KHMDS, potassium bis(trimethylsilyl)amide; HMPA, hexamethylphosphoramide; PCC, pyridinium chlorochromate)

concomitant deconjugation of the C¼C bond into the terminal position. Deprotection of the distal OH group of 70, hydride reduction and pyridinium chlorochromate (PCC) oxidation of 71 concluded the preparation of dialdehyde 72 for the intramolecular [n þ 4] ring-enlargement sequence. This was performed by slow addition to a solution of BF3 · Et2O (vide supra) to afford 73 in 33% yield (Scheme 14). Both C¼C bonds were exclusively (Z)-configured, and there was no indication of isomerization of the (Z)-C¼C bond derived in the Wittig step under the acidic reaction conditions. Interestingly, the odor of ketone 74, obtained from formate 73 by two consecutive standard transformations, was not at all musk-like but rather woody, fruity, and green (see Fig. 5).


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Fig. 5. Olfactory properties and thresholds (th) of macrocyclic ketones 74 – 83

In a similar sequence, musc-3-enone (77) was also successfully synthesized from substrate 62b. A catalytic hydrogenation of 77 completed the new synthesis of ( )muscone (78; Scheme 15) [41] [42]. In analogy to the above route (Scheme 15), the cycloalk-3-en-1-yl formates 62a – 62e (Scheme 13) were transformed to the corresponding macrocyclic ketones 76 – 83, respectively. The odor thresholds (th) of these compounds, determined by GColfactometry, as well as their olfactory properties are compiled in Fig. 5. Four interesting conclusions can be drawn from the GC-threshold analyses: i) Although a C(5)¼C(6) bond generally improves the musk-like properties (e.g., muscone (78) vs. Muscenone [42]), a C(3)¼C(4) bond seems to rather decrease the intensity of the musk odor (77 vs. muscone (78)). This trend is also apparent in all other 14- to 16membered muscone derivatives collected in Fig. 5. ii) Only the 16-membered ring derivatives possess low odor thresholds, with unsaturated 79 being weaker than homoScheme 15. Synthesis of Musc-3-enone (77) and ( )-Muscone (78; PCC, pyridinium chlorochromate)

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muscone (80). iii) The C¼C bonds at C(3) and C(10) of 74 constrains the conformational freedom of the 14-membered ring ketone in such a way as to make the musk odor disappear (74 vs. 76) and weakens in addition the odor strength. iv) Finally, macrocycles containing more than 17 members such as products 81 – 83 have very weak musky odors. Conclusions. – The serendipitous discovery of the novel and atom-economical oxyoxonia(azonia)-Cope rearrangement enables a nucleophilic cross-dimerization of b,gunsaturated carbonyl compounds with saturated and aromatic aldehydes or imines. The irreversible reaction proceeds via sigmatropic rearrangements of intermediate oxonium or azonium species with disproportionation of the C¼O groups to result in homoallylic esters or amides. The transition states are highly ordered and allow high levels of diastereoselectivity. Stereochemical information encoded in the substrates can be efficiently transferred to a broad range of products. This review focused on the use of oxonia- and azonia-Cope transformations in the context of fragrance chemistry. Syntheses of medium-sized to macrocyclic lactones and lactams by inter- and intramolecular variants of the key reaction were described. These transformations led to a novel synthesis of ( )-muscone and offered additional insight into structureodor relationships of macrocyclic musk odorants. We thank Katarina Grman for GC-threshold determinations, Dr. Gerhard Brunner for NMR experiments, Dr. Joachim Schmid for the MS data, Dr. Zhiming Li (Fudan University) for ECD calculations, Dr. Zhenxia Chen (Fudan University) for X-ray structure determinations, and Gangfeng Tang (Fudan University) for HR-MS data.

Experimental Part General. All reactions were performed under Ar with solvents and reagents from commercial suppliers without further purification. Solvents for extraction and chromatography were of technical grade and used without further purification. Flash column chromatography (FC): Qingdao Haiyang Chemical silica gel (SiO2 ; 200 – 300 mesh) and SiO2 Merck grade (60 ); unless otherwise noted, a mixture of hexane/tBuOMe 50 : 1 was used as eluent. IR Spectra: Bruker Tensor 27 and Jasco FT/IR-4100; ñ in cm 1. 1H- and 13C-NMR spectra: AW 300 and AV2 400 MHz Bruker spectrometer instruments; in CDCl3 ; d in ppm rel. to Me4Si as internal standard, CHCl3 as internal reference unless otherwise stated; J in Hz. In the 13C-NMR spectra, the nature of the C-atoms (Cq , CH, CH2 , or Me) was determined by conducting DEPT 90 and DEPT-135 experiments. GC/MS: Agilent 6890 N and MSD 5975, with a column HP-5 MS (30 m 0.25 mm, 0.25 mm); in m/z (rel. %). HR-MS: Finnigan MAT 95 (San Jose, CA, USA) double-focusing magnetic sector mass spectrometer (geometry BE); in m/z. Synthetic Procedures. Syntheses of 44a – 44q, (R)-46, and 47 have been reported in [25], of 58a – 58i in [26]; and of 60, 62 – 74, and 76 – 83 in [27]. (2S)-2-(Prop-1-en-2-yl)cyclohexanone ((S)-46). To a soln. of rac-trans-2-(prop-1-en-2-yl)cyclohexanol (rac-trans-45; 8.5 g, 60.6 mmol) in dry THF (25 ml) were added vinyl acetate (230 g, 2.67 mol) and an enzyme (1.7 g; lipase from Pseudomonas fluorescens, Lot#: 2007-09-22; Shanghai Hanhong Chemical Co., Ltd.). The suspension was stirred at r.t. for 12 d, and the conversion was 45%. The soln. was treated with sat. aq. NaHCO3 (25 ml) and then H2O (100 ml). The solvent was evaporated and the crude products were separated by FC (SiO2 ) to give (1R,2S)-2-(prop-1-en-2-yl)cyclohexyl acetate (4.2 g) with 98% ee. To a 250-ml round-bottomed flask were added NaOH (1.32 g, 32.9 mmol), MeOH (3.52 g, 110 mmol), and H2O (2.0 ml). Then, (1R,2S)-2-(prop-1-en-2-yl)cyclohexyl acetate (2.0 g, 11.0 mmol,


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98% ee) in THF (10 ml) was added. The soln. was stirred at r.t. for 4 h. H2O (15 ml) and tBuOMe (15 ml) were added. The org. layer was dried (MgSO4 ), and the solvent was removed in a rotary evaporator to afford the crude (1R,2S)-2-(prop-1-en-2-yl)cyclohexanol which was pure enough to be used in the next step. The obtained crude alcohol was dissolved in CH2Cl2 (50 ml), and then PCC (4.73 g, 21.95 mmol) was added. The resulting soln. was stirred at r.t. for 4.5 h, prior to the addition of hexane (100 ml). The precipitate was filtered off over a short SiO2 column. The filtrate was concentrated and purified by FC (SiO2 ) to provide (S)-46 (1.4 g, 92%; 98% ee) as colorless liquid. [a] 20 D ¼ 64.7 (c ¼ 1.0, CHCl3 ). The NMR data were in accordance with those for the racemic mixture reported in [43]. (7E,10S)-3,4,5,6,9,10-Hexahydroazecin-1-methoxy-8,10-dimethyl-2(1H)-one ((E,S)-58b). Into a 50ml round-bottomed flask were added (S)-46 (0.25 g, 1.8 mmol) and acetaldehyde O-methyl oxime (0.79 g; 20% in CH2Cl2 , 2.2 mmol) in ClCH2CH2Cl (9.0 ml) to give a colorless soln. SnCl4 (0.70 g, 2.7 mmol) was added dropwise, and the resulting soln. was stirred at r.t. for 60 min. Sat. aq. NaHCO3 (10 ml) was added to destroy the catalyst, and the aq. layer was extracted with tBuOMe (2 10 ml). The combined org. layers were dried (MgSO4 ), and (E,S)-58b (0.34 g, 90% ee, yield 89%) was obtained after FC as colorless liquid. [a] 20 D ¼ þ 33.1 (c ¼ 1.0, CHCl3 ). IR (neat): 1769m (C¼ON), 1144s (CO). 1H-NMR: 1.33 (d, J ¼ 17.7, MeC(10)); 1.56 (s, MeC(8)); 1.86 – 1.76 (m, CH2(5), CH2(4)); 2.92 – 2.04 (m, CH2(6), CH2(9), CH2(3)); 3.66 (s, MeO); 4.76 – 4.69 (m, HC(10)); 5.08 (t, J ¼ 6.9, HC(7)). 13 C-NMR: 17.3 (q, MeC(8)); 18.1 (q, MeC(10)); 23.7 (t, C(4)); 28.5 (t, C(6)); 29.5 (t, C(5)); 31.4 (t, C(3)); 44.2 (t, C(9)); 56.6 (d, C(10)); 64.3 (q, MeO); 128.1 (d, C(7)); 134.4 (s, C(8)); 179.8 (s, C(2)). GC/EI-MS: 211 (8, M þ ), 180 (4), 130 (2), 165 (40), 138 (23), 123 (15), 109 (100), 94 (11), 74 (37), 55 (11), 41 (15). Determination of Absolute Configurations of (S)-46 and (E,S)-58b. Computational Chemistry for ECD Studies. All calculations were performed using the GAUSSIAN09 program package. Conformational analysis identified 3,3-conformations, resp. for (S)-46 and (E,S)-58b, with B3LYP/631G* energies within a range of 2.0 kcal mol 1 in the gas phase. Then, these conformations were relocated by full optimization at the B3LYP/6-31G* level in MeOH with the polarizable continuum model (PCM). The geometries of the ground states were then used to calculate the ECD spectra by using TDDFT at the B3LYP/6-31G* level in MeOH with the PCM model. The calc. excitation energies DEi (in nm) and rotatory strength (Ri ) were used to compute simulated ECD curves by using the Gaussian function:

DeðEÞ ¼

2 1 1 X 2 pffiffiffi DEi Ri eðEDEi Þ =s 2:297 1039 ps

where s is the width of the band at height 1/e, and i represents an index over all transitions. In the current work, a s value of 0.25 eV and rotatory strength in the dipole length form (R len ) were used. Finally, the B3LYP/6-31G* conformationally averaged ECD spectra of (S)-46 and (E,S)-58b were compared with the experimental ECD spectra, respectively, to obtain the absolute conformations. ECD of (S)-46. The calc. spectrum (a constant width of 0.25 eV for all transitions) of (S)-46 reproduced well the experimentally recorded spectrum. Since specifically, calc. signs as well as positions of the bands (S-type) matched well with those of ()-46, we deduced the absolute configuration of ()-46 as (S) (Fig. 6). ECD of (E,S)-58b. The calc. spectrum (a constant width of 0.25 eV for all transitions) of (E,S)-58b reproduced well the experimentally recorded spectrum. Since specifically, calc. signs as well as positions of the bands matched well with (þ)-58b, we deduced the absolute configuration of 58b as (S) as well (Fig. 7).

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Fig. 6. Recorded and calculated ECD spectra of 46. Recorded spectra for ()-46 (98% ee; c ¼ 6.9 mm, MeOH) is shown in blue full line; calculated spectra of (S)-46 in red dashed line.

Fig. 7. Recorded and calculated ECD spectra of (E,S)-58b. Recorded spectra for (þ)-58b (90% ee; c ¼ 0.10 mm, MeOH) is shown in red full line; calculated spectra of (S)-58b in blue dashed line. Calculated spectra were shifted to lower energy by 0.379 eV.

REFERENCES [1] [2] [3] [4] [5]

R. B. Woodward, R. Hoffmann, Angew. Chem., Int. Ed. 1969, 8, 781. G. B. Bennett, Synthesis 1977, 9, 589. R. P. Lutz, Chem. Rev. 1984, 84, 205. L. Claisen, Chem. Ber. 1912, 45, 3157. F. E. Ziegler, Acc. Chem. Res. 1977, 10, 227; J. Nowicki, Molecules 2000, 5, 1033.


1627

[6] P. Martinet, G. Mousset, M. Michel, Acad. Sci. Paris, Ser. C 1969, 268, 1303; J. A. Marshall, J. H. Babler, J. Org. Chem. 1969, 34, 4186. [7] M. H. Hopkins, L. E. Overman, J. Am. Chem. Soc. 1987, 109, 4748. [8] L. E. Overman, Acc. Chem. Res. 1992, 25, 352. [9] L. E. Overman, L. D. Pennington, J. Org. Chem. 2003, 68, 7143. [10] D. W. C. MacMillan, L. E. Overman, L. D. Pennington, J. Am. Chem. Soc. 2001, 123, 9033. [11] Y.-H. Chen, F. E. McDonald, J. Am. Chem. Soc. 2006, 128, 4568. [12] C. L. Pereira, Y.-H. Chen, F. E. McDonald, J. Am. Chem. Soc. 2009, 131, 6066. [13] J. J. Jaber, K. S. Mitsui, D. Rychnovsky, J. Org. Chem. 2001, 66, 4679. [14] S. R. Crosby, J. R. Harding, C. D. King, G. D. Parker, C. L. Willis, Org. Lett. 2002, 4, 577. [15] J. E. Dalgard, S. D. Rychnovsky, J. Am. Chem. Soc. 2004, 126, 15662. [16] R. Jasti, C. D. Anderson, S. D. Rychnovsky, J. Am. Chem. Soc. 2005, 127, 9939. [17] C. S. Barry, N. Bushby, J. R. Harding, R. A. Hughes, G. D. Parker, R. Roe, C. L. Willis, Chem. Commun. 2005, 3727. [18] R. Jasti, S. D. Rychnovsky, J. Am. Chem. Soc. 2006, 128, 13640. [19] P. O. Miranda, M. A. Ram rez, V. S. Mart n, J. I. Padroń, Chem. – Eur. J. 2008, 14, 6260. [20] J. D. Elsworth, C. L. Willis, Chem. Commun. 2008, 1587. [21] J. Nokami, K. Yoshizane, H. Matsuura, S. I. Sumida, J. Am. Chem. Soc. 1998, 120, 6609; A. V. Malkov, M. A. Kabeshov, M. Barlog, P. Kocovsky, Chem. – Eur. J. 2009, 15, 1570. [22] F. E. McDonald, C. L. Pereira, Y. H. Chen, Pure Appl. Chem. 2011, 83, 445. [23] D. A. Evans, A. M. J. Golob, J. Am. Chem. Soc. 1975, 97, 4765; M. D. Rozeboom, J. P. Kiplinger, J. E. Bartmess, J. Am. Chem. Soc. 1984, 106, 1025. [24] L. E. Overman, M. Kahimoto, J. Am. Chem. Soc. 1979, 101, 1310; L. E. Overman, L. T. Mendelson, J. Am. Chem. Soc. 1981, 103, 5579; L. E. Overman, J. Shim, J. Org. Chem. 1993, 58, 4662; S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem. Soc. 1993, 115, 9293; K. M. Brummond, J. Lu, Org. Lett. 2001, 3, 1347; S. Hanessian, M. Tremblay, J. F. W. Petersen, J. Am. Chem. Soc. 2004, 126, 6064; R. M. Carballo, M. Purino, M. A. Ramirez, V. S. Martin, J. I. Padron, Org. Lett. 2010, 12, 5334. [25] Y. Zou, C. Ding, L. Zhou, Z. Li, Q. Wang, F. Schoenebeck, A. Goeke, Angew. Chem., Int. Ed. 2012, 51, 5647; Y. Zou, L. Zhou, C. Ding, A. Goeke, Givaudan, PCT Int. Appl. WO 2013060011 A1, 2013. [26] L. Zhou, Z. Li, Y. Zou, Q. Wang, I. A. Sanhueza, F. Schoenebeck, A. Goeke, J. Am. Chem. Soc. 2012, 134, 20009. [27] Y. Zou, H. Mouhib, W. Stahl, A. Goeke, Q. Wang, P. Kraft, Chem. – Eur. J. 2012, 18, 7010. [28] G. Ohloff, W. Pickenhagen, P. Kraft, Scent and Chemistry – The Molecular World of Odors, Verlag Helvetica Chimica Acta, Zrich, and Wiley-VCH, Weinheim, 2011, pp. 339 – 364; P. Kraft, in Chemistry and Technology of Flavors and Fragrances, Ed. D. J. Rowe, Blackwell Publishing Ltd., Oxford, 2005, pp. 143 – 168; G. Fra´ter, J. Bajgrowicz, P. Kraft, Tetrahedron 1998, 54, 7633; P. Kraft, C. Denis, J. Bajgrowicz, G. Fra´ter, Angew. Chem. 2000, 112, 3106; P. Kraft, C. Denis, J. Bajgrowicz, G. Fra´ter, Angew. Chem., Int. Ed. 2000, 39, 2980. [29] P. Kraft, in Perspectives in Flavor and Fragrance Research, Eds. P. Kraft, K. A. D. Swift, Verlag Helvetica Chimica Acta, Zrich, and Wiley-VCH, Weinheim, 2005, pp. 127 – 144. [30] C. Fehr, J. Galindo, O. Etter, Eur. J. Org. Chem. 2004, 1953. [31] C. S. Sell, Angew. Chem. 2006, 118, 6402; C. S. Sell, Angew. Chem., Int. Ed. 2006, 45, 6254. [32] A. S. Williams, Synthesis 1999, 10, 1707. [33] A. Goeke, Y. Zou, Givaudan, WO2009021342, 2007. [34] Y. Zou, Q. Wang, A. Goeke, Chem. – Eur. J. 2008, 14, 5335. [35] A. Goeke, Y. Zou, Givaudan, PCT Int. Appl. WO 2010125100 A1 20101104, 2010. [36] Y. Hoshimoto, M. Ohashi, S. Ogoshi, J. Am. Chem. Soc. 2011, 133, 4668; W. I. Dzik, L. J. Goossen, Angew. Chem. 2011, 123, 11241; W. I. Dzik, L. J. Goossen, Angew. Chem., Int. Ed. 2011, 50, 11047. [37] H. M. C. Ferraz, F. I. Bombonato Jr., L. S. Longo, Synthesis 2007, 3261. [38] I. Shiina, Chem. Rev. 2007, 107, 239. [39] B. Bollbuck, P. Kraft, W. Tochtermann, Tetrahedron 1996, 52, 4581. [40] D. Cremer, J. Gauss, R. F. Childs, C. Blackburn, J. Am. Chem. Soc. 1985, 107, 2435.

1628


[41] K. H. Schulter-Elte, A. Hauser, G. Ohloff, Helv. Chim. Acta 1979, 62, 2673; J. Tsuji, T. Yamada, M. Kaito, T. Mandai, Tetrahedron Lett. 1979, 20, 2257; V. Rautenstrauch, R. L. Snowden, S. M. Linder, Helv. Chim. Acta 1990, 73, 896; V. P. Kamat, H. Hagiwara, T. Suzuki, M. Ando, J. Chem. Soc., Perkin Trans. 1 1998, 2253; Y. Tanabe, N. Matsumoto, T. Higashi, T. Misaki, T. Itoh, M. Yamamoto, K. Mitarai, Y. Nishii, Tetrahedron 2002, 58, 8269; H. Tsuji, K. Yamagata, Y. Itoh, K. Endo, M. Nakamura, E. Nakamura, Angew. Chem. 2007, 119, 8206; H. Tsuji, K. Yamagata, Y. Itoh, K. Endo, M. Nakamura, E. Nakamura, Angew. Chem., Int. Ed. 2007, 46, 8060. [42] O. Knopff, J. Kuhne, C. Fehr, Angew. Chem. 2007, 119, 1329; O. Knopff, J. Kuhne, C. Fehr, Angew. Chem., Int. Ed. 2007, 46, 1307. [43] J. M. Warrington, L. Barriault, Org. Lett. 2005, 7, 4589. Received February 3, 2014

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