Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

Abstract

The pool of abundant chiral terpene building blocks (i.e., "chiral pool terpenes") has long served as a starting point for the chemical synthesis of complex natural products, including many terpenes themselves. As inexpensive and versatile starting materials, such compounds continue to influence modern synthetic chemistry. This review highlights 21st century terpene total syntheses which themselves use small, terpene-derived materials as building blocks. An outlook to the future of research in this area is highlighted as well.

Figure 1

Chiral pool terpenes of both historical and modern use in natural product synthesis.

Figure 2

Selected terpene syntheses of the 20^th century. Terpene syntheses can be roughly grouped according to the structural similarity of the starting terpene with that of the final product.

Figure 3

Various diterpenes containing 5,8,5-fused ring systems.

Figure 4

Complex diterpenes from Euphorbiaceae.

Figure 5

Cha’s pinacol-type rearrangement to access the ingenane ring system.

Scheme 1

Bermejo’s Synthesis of (+)-Paeonisuffrone from (+)-Carvone (2008)

Scheme 2

Maimone’s Synthesis of (+)-Cardamom Peroxide from (−)-Myrtenal (2014)

Scheme 3

Bachi’s Synthesis of (+)-Yingzhaosu A from (−)-Limonene (2005)

Scheme 4

Vosburg’s 4-step Synthesis of (+)-Artemone from (−)-Linalool (2015)

Scheme 5

Romo’s 10-step Synthesis of (+)-Omphadiol from (−)-Carvone (2011)

Scheme 6

Liu’s Synthesis of (+)-Onoseriolide and (−)-Bolivianine from (+)-Verbenone (2013)

Scheme 7

Sorensen’s Synthesis of (−)-Jiadifenolide Employing (+)-Pulegone (2014)

Scheme 8

Zhang’s Synthesis of (−)-Jiadifenolide from Pulegone-derived Building Block 84 (2015)

Scheme 9

Shenvi’s 8-step Synthesis of (−)-Jiadifenolide from (+)-Citronellal (2015)

Scheme 10

Chain’s 8-step Total Synthesis of (−)-Englerin A (2011)

Scheme 11

Metz’s Total Synthesis of (−)-Englerin A from (−)-isopulegol (2013)

Scheme 12

Overman’s Chiral Pool-based Synthesis of (−)-Aplyviolene from (+)-Fenchone (2012)

Scheme 13

Vanderwal and Alexanian’s Synthesis of (+)-Chlorolissoclimide from (+)-Sclareolide (2015).

Scheme 14

Lindel’s Total Synthesis of (+)-Cubitene from (+)-Carvone (2012)

Scheme 15

Hoppe’s Total Synthesis of (+)-Vigulariol from Cryptone (2008)

Scheme 16

Reisman’s Synthesis of (+)-Ryanodol from (−)-Pulegone (2016)

Scheme 17

Williams’ Chiral Pool-based Synthesis of (+)-Fusicoauritone (2007)

Scheme 18

Conversion of (+)-3-Carene into Funk’s Keto Ester (209).

Scheme 19

Wood’s Total Synthesis of Ingenol (2004)

Scheme 20

Baran’s Synthesis of Ingenol from (+)-3-Carene (2013)

Scheme 21

Baran’s Chiral Pool-based Synthesis of (+)-Phorbol (2016)

Scheme 22

Inoue’s Synthesis of (+)-Crotophorbolone (214) from (−)-Carvone (2015)

Scheme 23

Corey’s (−)-Limonene-derived Synthesis of (+)-Pseudopteroxazole (2003)

Scheme 24

Li’s Isopulegol-based Synthesis of (+)-Ileabethoxazole (2016)

Scheme 25

Li’s Syntheses of (+)-Pseudopteroxazole and (+)-seco-Pseudopteroxazole from Intermediate 278 (2016)

Scheme 26

Nicolaou and Chen’s Chiral Pool-based Synthesis of (−)-Platensimycin (2008)

Scheme 27

Lee’s Formal Synthesis of Platensimycin from (+)-Carvone (2009)

Scheme 28

Ma’s Syntheses of (+)-leucosceptroids A and B from (−)-Citronellol (2015)

Scheme 29

Trauner’s Total Synthesis of (−)-Nitidasin Employing (−)-Citronellene (2014)

Scheme 30

Maimone’s (−)-Linalool-based Synthesis of (−)-6-epi-ophiobolin N (2016)

Scheme 31

Shing’s (+)-Carvone-based Synthesis of (−)-Samaderine Y (2005)

Scheme 32

Li’s Total Synthesis of the Reported Structure of Rubriflordilactone B (2016)

Scheme 33

Tang’s Synthesis of Schilancitrilactones B and C from (−)-Carvone (2015)