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Review
. 2017:78:205-352.
doi: 10.1016/bs.alkal.2017.07.001. Epub 2017 Aug 16.

Cephalotaxus Alkaloids

Joëlle Pérard-Viret  1 , Laith Quteishat  2 , Rana Alsalim  2 , Jacques Royer  1 , Françoise Dumas  2
Affiliations
Review

Cephalotaxus Alkaloids

Joëlle Pérard-Viret et al. Alkaloids Chem Biol. 2017.

Abstract

Cephalotaxus alkaloids represent a family of plant secondary metabolites known for 60 years. Significant activity against leukemia in mice was demonstrated for extracts of Cephalotaxus. Cephalotaxine (CET) (1), the major alkaloid of this series was isolated from Cephalotaxus drupacea species by Paudler in 1963. The subsequent discovery of promising antitumor activity among new Cephalotaxus derivatives reported by Chinese, Japanese, and American teams triggered extensive structure elucidation and biological studies in this family. The structural feature of this cephalotaxane family relies mainly on its tetracyclic alkaloid backbone, which comprises an azaspiranic 1-azaspiro[4.4]nonane unit (rings C and D) and a benzazepine ring system (rings A and B), which is linked by its C3 alcohol function to a chiral oxygenated side chain by a carboxylic function alpha to a tetrasubstituted carbon center. The botanical distribution of these alkaloids is limited to the Cephalotaxus genus (Cephalotaxaceae). The scope of biological activities of the Cephalotaxus alkaloids is mainly centered on the antileukemic activity of homoharringtonine (HHT) (2), which in particular demonstrated marked benefits in the treatment of orphan myeloid leukemia and was approved as soon as 2009 by European Medicine Agency and by US Food and Drug Administration in 2012. Its exact mechanism of action was partly elucidated and it was early recognized that HHT (2) inhibited protein synthesis at the level of the ribosome machinery. Interestingly, after a latency period of two decades, the topic of Cephalotaxus alkaloids reemerged as a prolific source of new natural structures. To date, more than 70 compounds have been identified and characterized. Synthetic studies also regained attention during the past two decades, and numerous methodologies were developed to access the first semisynthetic HHT (2) of high purity suitable for clinical studies, and then high grade enantiomerically pure CET (1), HHT (2), and analogs.

Keywords: Alkaloid; Antiparasitic agent; Antiviral; Cancer; Cephalotaxine; Cephalotaxus; Harringtonine; Homoharringtonine; Leukemia; Protein synthesis inhibitor.

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Figures

Figure 1
Figure 1
Scientific classification of Cephalotaxus genus and picture (from F. Dumas) of the fruits and leaves of Cephalotaxus fortunei at Parc Montsouris, Paris (France).
Figure 2
Figure 2
Cephalotaxine (1) and its natural esters (2–5) early characterized in Cephalotaxus harringtonia var. drupacea.
Figure 3
Figure 3
Cephalotaxanes (6), the skeleton (7) of minor homoerythrinane alkaloids, and the structurally unique Cephalotaxus alkaloid hainanensine (8).
Figure 4
Figure 4
Oxidized cephalotaxines.
Figure 5
Figure 5
Natural esters of cephalotaxine and cephalotaxinamide.
Figure 6
Figure 6
Natural esters of oxygenated cephalotaxines.
Figure 7
Figure 7
New N-oxides and ring D analogs of cephalotaxine.
Figure 8
Figure 8
Desmethylcephalotaxinone stereoisomer and cephalancetines A–D.
Figure 9
Figure 9
Cephalotines A–D.
Figure 10
Figure 10
Cephalozemines A–F and K–L and their yield from the natural sources in brackets.
Figure 11
Figure 11
Oxygenated Cephalotaxus esters and Cephalozemine J.
Figure 12
Figure 12
Dimeric Cephalotaxus esters.
Scheme 1
Scheme 1
Proposed biosynthetic pathway to cephalocyclidine A.
Scheme 2
Scheme 2
Main strategies to access cephalotaxine (1).
Figure 13
Figure 13
Main disconnections used for the construction of cephalotaxine ring B.
Figure 14
Figure 14
C4–C13 bond disconnection a for elaboration of cephalotaxine (1) B ring.
Scheme 3
Scheme 3
Formal synthesis of rac-Cephalotaxine (±)-(1) by Tietze (1997).
Scheme 4
Scheme 4
Formal synthesis of rac-Cephalotaxine (±)-(1) by Suga and Yoshida (2002).
Scheme 5
Scheme 5
Formal synthesis of rac-Cephalotaxine (±)-(1) by Stoltz (2007).
Scheme 40
Scheme 40
Asymmetric syntheses of (−)-drupacine (16) and formal asymmetric syntheses of cephalotaxine (−)-(1) and ent-cephalotaxine (+)-(1) by Stoltz (2007).
Scheme 6
Scheme 6
Formal synthesis of rac-Cephalotaxine (±)-(1) by Huang (2013).
Scheme 7
Scheme 7
Formal synthesis of rac-Cephalotaxine (±)-(1) by Huang and Wang (2015).
Scheme 8
Scheme 8
Formal synthesis of rac-Cephalotaxine (±)-(1) by Nagasaka (2002).
Scheme 9
Scheme 9
Formal synthesis of rac-Cephalotaxine (±)-(1) by Li (2007).
Scheme 10
Scheme 10
Formal synthesis of rac-Cephalotaxine (±)-(1) by Yang and Liu (2009).
Scheme 11
Scheme 11
Formal synthesis of rac-Cephalotaxine (±)-(1) by Zhang and Liu, the “dimethoxy” route (2013).
Scheme 12
Scheme 12
Formal synthesis of rac-Cephalotaxine (±)-(1) by Zhang and Liu, the “methylenedioxy” route (2013).
Scheme 13
Scheme 13
Formal synthesis of rac-Cephalotaxine (±)-(1) by Bubnov (2008).
Scheme 14
Scheme 14
Formal synthesis of rac-Cephalotaxine (±)-(1) by Li (2003).
Figure 15
Figure 15
C5–N9 bond disconnection c for construction of ring B of cephalotaxine (1).
Scheme 15
Scheme 15
Formal synthesis of rac-Cephalotaxine (±)-(1) by Li (2003): alternative synthesis of ketone (±)-197.
Scheme 16
Scheme 16
Formal synthesis of rac-Cephalotaxine (±)-(1) via Dolby–Weinreb enamine 203 by Li (2005).
Scheme 17
Scheme 17
Formal synthesis of rac-Cephalotaxine (±)-(1) via amino enone 194 by Li (2005).
Scheme 18
Scheme 18
Formal synthesis of rac-Cephalotaxine (±)-(1) by Tu and Zhang (2009).
Scheme 19
Scheme 19
Formal synthesis of rac-Cephalotaxine (±)-(1) by Li (2011).
Scheme 20
Scheme 20
Formal synthesis of rac-Cephalotaxine (±)-(1) by Jiang (2013).
Figure 16
Figure 16
C4–C5 bond disconnection b for elaboration of ring B of rac-cephalotaxine (±)-(1).
Scheme 21
Scheme 21
Formal synthesis of rac-Cephalotaxine (±)-(1) by Hong via Kuehne's intermediate (±)-123 (2015).
Scheme 22
Scheme 22
Formal synthesis of rac-Cephalotaxine (±)-(1) by Hong via Weinreb's intermediate (±)-12 (2015).
Scheme 23
Scheme 23
Total synthesis of rac-cephalotaxine (±)-(1) by Chandrasekhar (2016).
Figure 17
Figure 17
N9–C10 bond disconnection e for construction of cephalotaxine (1) B ring.
Scheme 24
Scheme 24
Stereoselective reduction of cephalotaxinone (10).
Scheme 25
Scheme 25
Formal asymmetric synthesis of cephalotaxine (−)-(1) by Tietze (1999).
Scheme 26
Scheme 26
Formal asymmetric synthesis of cephalotaxine (−)-(1) by Tu (2012).
Scheme 43
Scheme 43
Formal asymmetric synthesis of cephalotaxine (−)-(1) via Nagasaka's intermediate by Renaud (2012).
Scheme 27
Scheme 27
Alternative formal asymmetric synthesis of cephalotaxine (−)-(1) by Renaud (2012).
Scheme 42
Scheme 42
Formal asymmetric synthesis of cephalotaxine (−)-(1) by Mariano via Suga and Yoshida's intermediate (−)-102 (2006).
Scheme 28
Scheme 28
Formal asymmetric synthesis of ent-cephalotaxine (+)-(1) by Trost (2012).
Scheme 29
Scheme 29
Asymmetric synthesis of cephalotaxine (−)-(1) by Royer (2004).
Scheme 30
Scheme 30
Formal asymmetric synthesis of cephalotaxine (−)-(1) by Dumas and d’Angelo (2005).
Scheme 31
Scheme 31
Formal asymmetric synthesis of cephalotaxine (−)-(1) by Ikeda (1999).
Scheme 32
Scheme 32
Asymmetric formal synthesis of cephalotaxine (−)-(1) by El Bialy (2002).
Scheme 33
Scheme 33
Formal synthesis of cephalotaxine (−)-(1) by Hayes via Mori's intermediate (−)-88 (2008).
Scheme 34
Scheme 34
Second formal asymmetric synthesis of cephalotaxine (−)-(1) by Hayes (2008).
Scheme 36
Scheme 36
Total asymmetric synthesis of cephalotaxine (−)-(1) by Djaballah and Gin (2008).
Scheme 35
Scheme 35
Asymmetric synthesis of cephalotaxine (−)-(1) by Djaballah and Gin: formation of ring D (2008).
Scheme 37
Scheme 37
Total asymmetric synthesis of cephalotaxine (−)-(1) by Ishibashi (2008).
Scheme 38
Scheme 38
Formal asymmetric synthesis of cephalotaxine (−)-(1) by Nagasaka (1997).
Scheme 39
Scheme 39
Formal asymmetric synthesis of cephalotaxine (−)-(1) by El Bialy (2002).
Scheme 41
Scheme 41
Formal asymmetric synthesis of cephalotaxine (−)-(1) by Mariano via Mori's intermediate 430 (2006).
Figure 18
Figure 18
Target intermediates in the formal syntheses of (±)-cephalotaxine (1). Names in boxes refer to a formal synthesis.
Figure 19
Figure 19
Target intermediates in the formal asymmetric syntheses of cephalotaxine (1). Names in boxes refer to a formal synthesis.
Scheme 44
Scheme 44
Coupling of the side chain onto cephalotaxine (−)-(1).
Scheme 45
Scheme 45
Hemisynthesis of semisynthetic homoharringtonine (2) by Robin (1999).
Scheme 46
Scheme 46
Synthesis of [14C]-labeled homoharringtonine (−)-(2) by Marguerit (2015).
Scheme 47
Scheme 47
Synthesis of deoxyharringtonine (−)-(5) by Gin (2006).
Scheme 51
Scheme 51
Synthesis of side chain acids of harringtonines by Tietze (2005).
Scheme 48
Scheme 48
Synthesis of anhydroHT (−)-(20) by Djaballah and Gin (2008).
Scheme 49
Scheme 49
Synthesis of homoharringtonine (−)-(2) and homodeoxyharringtonine (−)-(22) by Djaballah and Gin (2008).
Scheme 50
Scheme 50
Synthesis of homoharringtonine side chain (R)-473 by Dumas and d’Angelo (2001).
Scheme 52
Scheme 52
Synthesis of harringtonines' side chains by Russel (2006).
Scheme 53
Scheme 53
Synthesis of harringtonines' side chains by Royer (2009).
Scheme 54
Scheme 54
Synthesis of harringtonines' side chains by Yang (2013).
Scheme 55
Scheme 55
Synthesis of homoharringtonine and homodeoxyharringtonine side chains by Hung (2014).
Scheme 56
Scheme 56
Synthesis of homoharringtonine side chain's analogs by Mac (2016).
Scheme 57
Scheme 57
Synthesis of cephalotaxine analogs by Tietze (2000).
Scheme 58
Scheme 58
Synthesis of deoxyharringtonine analogs by Tietze (2007).
Scheme 59
Scheme 59
Cephalotaxine's analog synthesized by Bubnov (2005–2010).
Scheme 60
Scheme 60
Synthesis of Cephalotaxine alkylated analogs by Royer (2004).
Scheme 61
Scheme 61
Synthesis of cephalotaxine “A” analogs by Royer (2010).
Scheme 62
Scheme 62
Formal synthesis of cephalotaxine “A analogs” by Chandrasekhar (2016).
Scheme 63
Scheme 63
Robin's synthesis of homoharringtonine analogs at the side chain.
Figure 20
Figure 20
Harringtonines analogs at the side chain (homoharringtonine (top) and drupangtonine (bottom) analogs) synthesized by Robin (2002–04).
Figure 21
Figure 21
Djaballah and Gin's cephalotaxine-ester analogs (2009).
Figure 22
Figure 22
Lai's homoharringtonine (2) aza analogs (2013).
Figure 23
Figure 23
Lai's homoharringtonine (2) acylated analogs (2013).
Figure 24
Figure 24
Simplified diagram of protein synthesis showing the A site where homoharringtonine (HHT) binds to inhibit protein synthesis. In the cytoplasm of the cells, ribosomes (green) bind to the mRNA containing the code translated from the switched on genes into the DNA. The 20 different amino acids carried by transfer RNA (tRNA) are recruited according to a three nuclear base code into the ribosome A site. The protein chain elongation includes the aminoacyl tRNA entry, its proofreading, the peptidyl transfer, and the ribosomal translocation along the tRNA chain. The cartoon on the right explains how HHT (2) inhibits protein synthesis through inhibition of initiation elongation step.
Figure 25
Figure 25
Interaction of homoharringtonine (2) with the ribosome of Haloarcula marismortui and the conformational changes associated with this binding.
Figure 26
Figure 26
Main pathways involved in apoptosis mechanism induced by homoharringtonine (2). Yellow: apoptosis factor; Blue: apoptosis intermediator; Turquoise: dual role as intermediator and factor; Green: apoptosis inhibitor.
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