Asymmetric Construction of All-Carbon Quaternary Stereocenters by Chiral-Auxiliary-Mediated Claisen Rearrangement and Total Synthesis of (+)-Bakuchiol

An asymmetric Claisen rearrangement using Oppolzer’s camphorsultam was developed. Under thermal conditions, a geraniol-derived substrate underwent the rearrangement with good stereoselectivity. The absolute configuration of the newly formed all-carbon quaternary stereocenter was confirmed by the total synthesis of (+)-bakuchiol from the rearrangement product.


Results and Discussion
Oppolzer's camphorsultam was used as a chiral auxiliary for the asymmetric Claisen rearrangement. We designed a novel substrate, a β-(allyloxy)acrylate derivative bearing the camphorsultam. Accordingly, N-propioloyl camphorsultam 5 was prepared by our previously reported procedure (Scheme 1) [16][17][18]. The oxy-Michael addition of geraniol to 5 in the presence of a catalytic amount of tributylphosphine gave adduct 6 with complete E-stereoselectivity [19]. A toluene solution of 6 in the presence of butylated hydroxytoluene (BHT) used as a polymerization inhibitor was heated in a sealed tube at 140 °C to provide mainly the (2R,3S)-isomer 7a as the rearrangement product in 72% yield, securing the two contiguous stereocenters including the quaternary carbon. The minor (2S,3R)-isomer 7b (8%) was easily separated from 7a by column chromatography on silica gel [20]. Scheme 1. Claisen rearrangement of geraniol-derived substrate 6.
By using a similar procedure, nerol-derived substrate 8 was prepared from 5 and nerol (Scheme 2). The Claisen rearrangement of 8 afforded (2R,3R)-isomer 7c and (2S,3S)-isomer 7d, accompanied by a small amount of 7a and 7b, respectively. Compared with the case of 6, however, lower stereoselectivity was observed. Brief exposure of 7a to base caused epimerization at C-2 to produce isomer 7d, indicating that the quaternary stereocenter in nerol-derived rearrangement product 7c has stereochemistry opposite to that in 7a. Scheme 2. Claisen rearrangement of nerol-derived substrate 8.
The stereochemistry of the newly formed quaternary stereocenter (C-3) in 7a was determined by the total synthesis of (+)-bakuchiol (4), a major component of the Indian medicinal plant Psoralea corylifolia Linn [8]. Base hydrolysis of 7a followed by decarboxylation provided enantiomerically pure aldehyde 9, and the chiral auxiliary was recovered (Scheme 3). Treatment of 9 with p-MeOC 6 H 4 MgBr afforded alcohol 10, which was subjected to dehydration using phosphoryl chloride to afford bakuchiol methyl ether 11 [21]. By comparing the optical rotation of synthetic  [9], the absolute configuration of the quaternary stereocenter in 7a was assigned as (S). According to a known procedure [22], demethylation of 11 finally provided (+)-bakuchiol (4), which was identical to the natural product in all respects.
Scheme 3. Determination of the stereochemistry at C-3 in 7a and total synthesis of (+)-bakuchiol.
To determine the configuration at C-2, rearrangement product 7a was heated at 160 °C (Scheme 4). The intramolecular carbonyl-ene reaction proceeded to provide cyclized 12a as a mixture of four diastereomers (dr = 3:2:2:1). Similarly, 7c was converted into 12c (dr = 9:8:2:1). Through NOE experiments on the isolated major diastereomers 12aa and 12ca, the stereochemistry at the C-2 in 7a and 7c was assigned as (R). Therefore, the configurations of all stereocenters in the rearrangement products 7a-d were unambiguously assigned. Scheme 4. Determination of the stereochemistry at C-2 in 7a and 7c.
The vicinal stereocenters in 15a and 18a were assigned by chemical transformation (Scheme 6). Chemoselective reduction of 7a, followed by acetylation of the resulting alcohol, provided acetate 19a. The spectroscopic data ( 1 H-and 13 C-NMR) of 19a were distinguishable from those of 19b derived from 7b. On the other hand, 15a was converted into acetate 20a. Desilylation of 20a, oxidation of the resulting alcohol to aldehyde, and subsequent Wittig olefination afforded 19a whose NMR spectra matched those of 19a derived from 7a. Compound 18a was also converted into 19a via acetate 21a. Therefore, the configuration of the vicinal stereocenters at the C-2 and C-3 in 15a and 18a coincides with that of 7a. Scheme 6. Determination of the stereochemistry at C-2 and C-3 in 15a and 18a.
The stereochemical outcomes observed in the reactions of 6, 14, 17, and 8 can be explained by the transition states depicted in Scheme 7.

R R
In the more favorable conformation of 6, 14, and 17, the carbonyl group is directed anti to the sulfonyl group and adopts an s-cis conformation with respect to the α,β-unsaturated bond [24]. The rearrangement proceeds predominantly from the Cα-Re-face through a six-membered chair-like transition state to avoid the steric repulsion that would be encountered along the Cα-Si-face path. As a result, 7a, 15a, and 18a were obtained as the major isomers. Also nerol-derived substrate 8 rearranges through the same Cα-Re-face path to produce 7c. In this case, the bulky homoprenyl group takes an axial orientation, which causes a decrease of the stereoselectivity.

Conclusions
In conclusion, we have developed an asymmetric Claisen rearrangement using Oppolzer's camphorsultam as a chiral auxiliary. Notably, rearrangement products 7a, 15a, and 18a possess a chiral quaternary carbon with high enantiomeric purity. In addition, this method has been applied to the total synthesis of (+)-bakuchiol (4). Further studies and applications of this work to natural product synthesis are in progress and will be reported in due course.