First Total Synthesis of Cryptotrione (X.S. Peng, 2020)

Cryptotrione (1) is a complex terpenoid isolated in 2010. Now Xiao-Shui Peng (彭小水) and coworkers from the Chinese University of Hong Kong reported the racemic total synthesis in the journal Angewandte Chemie. For the synthesis of this unique spiro-terpenoid, they opted for a late-stage polyene cyclization to install the western part of the molecule (see Figure 1) from precursor 2. The bicyclo[3.1.0]hexane unit should be available through a platinum-catalyzed enyne cycloisomerization. Finally, fragment 3 should be available from homoveratric acid (4).

cryptotrione-1.pngFigure 1: Retrosynthetic analysis for the total synthesis cryptotrione (1).

Synthesis of Fragment 3 and Cyclosiomerization

Compound 5 is a literature-known compound synthesized in three steps from homoveratric acid (4, see Scheme 1). The acid was transformed into the dicarbonyl  followed by functionalization to the diazo fragment with pABSA. Then the [Rh] catalyzed dediazotization led to the carbene in situ which cyclized to 5 in 90% yield. Then α functionalization was followed by diastereoselective ketone reduction and TIPS protection. The formal reduction of the ester to the aldehyde 6 was realized in a two-step procedure. For the synthesis of fragment 3 aldehyde was prolonged under HWE conditions and reduction followed by Piv protection delivered 3 in nine steps from homoveratric acid (4).

cryptotrione-2.pngScheme 1: Synthesis of fragment 3 from homoveratric acid (4).

After an intensive screening of catalyst (Pt, Au), conditions, and protecting group strategy 3 could successfully undergo cycloisomerization to bicyclo[3.1.0]hexane 7 good yield and excellent stereoselectivity (see Scheme 2). The authors noted that the usage of steric demanding TIPS group was necessary for good selectivity. The protecting group was immediately cleaved and the resulting cyclopentene was reduced. Then the free alcohol was oxidized to the ketone 8 using Dess-Martin Periodinane. Functionalization with geranyl bromide introduced the desired polyene moiety. However, the transformation only gave a 1:1 diastereomeric mixture. This mixture was selectively reduced by L-selectride and the desired isomer was carried on by protection to cyclization precursor 2. The undesired isomer could be oxidized and epimerized to the starting material. Lewis acidic polyene cyclization then gave the trans decalin product in 58% yield using Bi(OTf)3. Finally, the functionalization of the benzene ring was accomplished using NBS for bromination.

cryptotrione-3.pngScheme 2: Polyene cyclization for the synthesis of the trans decalin system.

Completion of the total synthesis

With 9 in hand, Suzuki–Miyaura coupling was followed by reductive deprotection and reduction of the alkene yielding in 10 as shown in Scheme 3. The authors noted that direct isopropylation failed and alkene reduction was only possible after the cleavage of the protection groups due to steric hindrance. Diol 10 was selectively oxidized to the aldehyde followed by Knoevenagel reaction and 1,4-addition with homoallylmagnesium bromide delivered 11 in good yields and diastereoselectivity (which can be completely reversed by changing the reaction conditions; not shown). Then 11 was transformed into 12 using a three-step protocol (reduction, tosylation, and hydride replacement). Finally, deprotection and oxidation gave in situ quinone 13 which was directly transformed into cryptotrione (1) by Wacker oxidation.

cryptotrione-4.pngScheme 3: Completion of the total synthesis of cryptotrione (1).

In summary, Prof. Peng and coworkers were able to synthesize cryptotrione (1) in 29 steps from homoveratric acid (4) using a challenging platinum-catalyzed cycloisomerization and a late-stage trans decalin formation by Lewis acidic polyene cyclization. They were also able to confirm the relative confirmation of the terpenoide.

Published in: M. Y. Lyu, Z. Zhong, V. K. Y. Lo, H. N. C. Wong, X.-S. Peng Angewandte Chemie Int. Ed. 2020 doi: 10.1002/anie.202009255