Cuantificaci´on de los coeficientes LSP

The use of the Diels-Alder reaction in total synthesis grew substantially after Stork’s synthesis of cantharidin and many classic targets were accessed this way including Gates’ morphine synthesis,13 _{and Woodward’s steroid syntheses.}14 _{Several variations of the}

Diels-Alder reaction have been extensively studied and widely used in the synthesis of natural products and pharmaceuticals, and due to vast amount of information on the topic, only a few recent examples that showcase the transformation of simple starting material to complex natural products will be discussed below.

In memory of Aaron C. Kinsman, the total synthesis of (+)-haplindole Q will be discussed. In 2003, Kinsman and Kerr were able to access the four contiguous stereocenters required for (+)-hapalindole Q through a Diels-Alder reaction between achiral indole 2-25 and cyclohexadiene 2-26 (Scheme 2-6).15 Stereoselective control in the reaction was brought about with MacMillan’s chiral organocatalyst (2-27). MacMillian’s chiral amine catalyst reacts with α,β-unsaturated aldehydes to form an iminium ion which effectively lowers the LUMO of the dienophile, due to the amplified electron withdrawing effect of the iminium ion.16 Since the catalyst is chiral, it allows for a highly enantioselective Diel-Alder reaction to occur. As shown in the transition state 2- 28, the top face of the molecule is blocked, thus favouring only one enantiomer. Although the Diels-Alder cycloadduct was formed in a low 35% yield, they were able to obtain the product with high endo selectivity (70%) and a high ee of 93%. Further manipulations were done to complete the total synthesis of (+)-haplindole Q in a total 12 steps from indole 2-25 in a 1.7% overall yield.

Scheme 2-6 Kinsman and Kerr’s synthesis of (+)-hapalindole Q

In 2007 the Jullian group isolated the sesterterpenoid bolivianine (2-37) from Hedyosmum angustifolium (Chloranthaceae).17 Jullian hypothesized that bolivianine is synthesized within the organism from: 1) allylic oxidation of onoseriolide (2-31, Scheme 2-7), 2) nucleophilic attack to geranylpyrophosphate (2-32, GPP), and lastly 3) an annulation and hetero-Diels-Alder to form the remaining rings.

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Scheme 2-7 Jullian’s proposed biosynthesis of bolivianine

Inspired by the proposed biogenesis of bolivianine by Jullian, the Liu group thought they could synthesize onoseriolide, and then access bolivianine from a Diels- Alder/intramolecular hetero-Diels-Alder cascade between oxidized onoseriolide and GPP related terpene, β-E-ocimene (2-38).18 As seen in Scheme 2-8, entry 1, oxidized onoseriolide and terpene 2-38 were heated to 150 °C in toluene (sealed tube), and remarkably they were able to access bolivianine in a 52% yield. Through their Diels- Alder/intramolecular hetero-Diels-Alder cascade they were able to generate three new rings, four C-C bonds, and five sterogenic centers with excellent selectivity. To determine if the hetero-Diels-Alder reaction initiates the cascade, the Liu group attempted a Diels-Alder between 2-33 and dienophile 2-39 (Scheme 2-8, entry 2). Despite many attempts, the reaction did not work suggesting that the hetero-Diels-Alder reaction only occurs once the proper orientation is set from the initial Diels-Alder reaction. They were able to show that this was indeed the case as a hetero-Diels-Alder occurred at room temperature for compound 2-40 (Scheme 2-8, entry 3), which was already in the proper orientation. Based on their findings they can explain the high selectivity of their Diels- Alder cascade due to: 1) diene 2-38 will react with dienophile 2-33 from the least

hindered face to form endo product 2-36, and as a result 2) the orientation of the dienophile for the hetero-Diels-Alder is aligned to react at the a-face of the diene, yielding bolivianine.

Scheme 2-8 Liu group’s total synthesis of bolivianine (1), and mechanism investigations (2 and 3)

One of the most famous natural product targets known is the anti-cancer drug paclitaxel (Taxol, 2-42, Figure 2-2).19 Taxol comes from a family of terpenes called taxanes, which contain at least 350 members with varying oxidation states, including decinnamoyltaxinine E (2-43), taxabaccatin III (2-44), taxusin (2-45), taxadienone (2-46). A parent molecule of the taxanes is taxadiene (2-47); this minimally oxidized natural product has functional group handles for further oxidation.

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Figure 2-2 Examples of taxanes

Taxadiene is produced in extremely small quantities in nature (less than 1 mg from 750 kg of tree bark from T. brevifolia),20 thus developing a method to access it would allow the synthesis of various taxanes and derivatives for further pharmaceutical testing. In 2012, the Baran group completed a gram-scale synthesis of the taxadiene, with a Diels- Alder reaction detrimental to their synthetic route (Scheme 2-9).21 Starting from known diene 2-48 and ketone 2-49, they were able to access intermediate 2-50 in three steps. An intramolecular Diels-Alder reaction formed compound 2-51 with a 47% yield of the desired diastereomer. Compound 2-51 was then converted to taxadienone (2-46) in two steps, which could then be converted to taxadiene (2-47) in three more steps. More recently, the Baran group was able to highlight the utility of their taxadienone synthesis in the first total synthesis of decinnamoyltaxinine E (18 steps from 2-46) and taxabaccatin III (19 steps from 2-46).22 Although the key Diels-Alder step in Baran’s synthesis looks fairly simple, Williams23 had accessed (±)-taxadiene with a Diels-Alder reaction; however, his synthesis had 26 steps, while Baran’s synthesis had 10 steps. The difference in the amount of synthetic steps goes to show how powerful the Diels-Alder can be given the right substrates.

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