The synthesis of prostaglandins (PGs) is another good example of a preparation in which asymmetric organic reactions play an important role.
Prostaglandins are formed in human tissues, ¯uids, and organs and can in- ¯uence the reproductive process, gastric secretion, control of blood pressure, and hypertension and respiration, as well as mediate pain and in¯ammation from cardiovascular problems associated with platelet aggregation. These compounds were ®rst discovered in the 1930s but became prominent only in the 1960s. They were ®rst found in secretions of the prostate gland, hence the name prostaglandins. In vivo, such compounds are synthesized from arachidonic acid, an unsaturated acid with a 20 carbon chain and four unsaturated CbC bonds or from other polyunsaturated acids.10 Because prostaglandins are a speci®c type of compound showing signi®cant bioactivity but in only limited natural supply, an e½cient and ¯exible synthesis of PGs is essential to ensure an adequate supply of natural PGs and arti®cial analogs for biological, physiological, and medicinal investigations. Asymmetric synthesis has played an important role in synthesizing prostaglandin subunits.
Compound 78, or prostanoic acid, the simplest prostaglandin compound, contains an a-side chain and also an o-side chain. Asymmetric synthesis of prostaglandins must involve the assembly of these subunits, as well as the introduction of other functionalities.
As mentioned in Chapter 2, the introduction of the a- and o-side chains is controlled by the chirality at C-11 of 78 through 1,2-anti-induction. If the C-11 protected hydroxyl moiety of 78 is a-orientated (a and b are adopted from carbohydrate chemistry, indicating the relative position of substituents), the newly
TABLE 7±1. Comparison of Some Total Syntheses of Natural Products
Erythronolide A
Ansa Chain of
Target Molecule
6-Deoxyerythronolide B
Derivative
Rifamycin B
66
66
Approach (control)
Acyclic (reagent)
Cyclic (substrate)
Acyclic (substrate)
Acyclic (reagent)
Acyclic
Chiral centers created
8
10
7
7
8
Overall selectivity
85
46
50
75
78
Overall yield
5.7
0.3
0.2
2.1
13.8
Number of steps
23
49
49
46
24
Starting material
36
5
…G†-52
…ÿ†-52
71
Reprinted with permission by VCH, Ref. 1.
413
414 APPLICATIONS OF ASYMMETRIC REACTIONS
Scheme 7±20. Retro synthesis of PEG2.
linked o-side chain will be in b-induction (anti to the C-11 hydroxy moiety). Similarly, the a-side chain will be introduced in an a-position (anti to the o-side chain).
Taking the synthesis of PEG2 as an example, PGs can be assembled from an unsaturated 4-hydroxycyclopent-4-enone and some side chains (Scheme 7±20).
7.4.1Three-Component Coupling
Among many other excellent methods, convergent three-component coupling, the consecutive linking of the a- and o-side chains to an unsaturated 4-hydroxy- 2-cyclopentenone derivative, is the most direct and e¨ective synthesis.
To achieve the three-component coupling, O-protected 2-cyclopentanone undergoes organometallic-mediated conjugate addition of the o-side chain unit, followed by electrophilic trapping of the enolate intermediate by an a-chain organic halide.11 However, it is not easy to realize this simple goal because the low stereoselectivity associated with other side reactions is a major problem, and this problem remained unresolved until oranozinc chemistry was applied to this synthesis.
As shown in Scheme 7±21, an equimolar mixture of dimethylzinc and the o- side chain vinyl lithium is treated sequentially with siloxyl-2-cyclopentenone and the propargylic iodide in the presence of HMPA. The desired product 79 is formed with 71% yield.12 The acetylenic product is a common intermediate for the general synthesis of naturally occurring PGs.
Organocopper chemistry also provides a straightforward synthesis through a special alkylation procedure (Scheme 7±22). An organocopper reagent, generated in situ from equimolar amounts of o-side chain vinyl lithium, CuI, and
Scheme 7±21. One pot synthesis of the PG framework by an organozinc procedure.
7.4 THE SYNTHESIS OF PROSTAGLANDINS
415
Scheme 7±22. One pot synthesis of PGs via an organocuprate/organotin procedure.
2.3 equivalents of (n-C4H9)3P, undergoes conjugate addition to the chiral siloxy enone in the presence of organotin compounds. Sequential treatment of the organocopper reagent with the enone HMPA, triphenyltin chloride, and a-side chain propargylic iodide o¨ers the desired compound 81 with more than 80% yield.13
As shown in Schemes 7±21 and 7±22, the desired stereochemistry at C-8 and C-12 in the PG framework can be established via three-component coupling. The remaining issue is the question of how to stereoselectively build the chiral 2-cyclopentenone and the lower o-side chain. Sections 7.4.2 and 7.4.3 introduce some general procedures for asymmetric syntheses of these PG subunits.
7.4.2Synthesis of the o-Side Chain
Various catalytic or stoichiometric asymmetric syntheses and resolutions o¨er excellent approaches to the chiral o-side chain. Among these methods, kinetic resolution by Sharpless epoxidation,14 amino alcohol±catalyzed organozinc alkylation of a vinylic aldehyde,15 lithium acetylide addition to an alkanal,16 reduction of the corresponding prochiral ketones,17 and BINAL±H reduction18 are all worth mentioning.
Sharpless epoxidation reactions are thoroughly discussed in Chapter 4. This section shows how this reaction is used in the asymmetric synthesis of PG side chains. Kinetic resolution of the allylic secondary alcohol …G†-82 allows the preparation of (R)-82 at about 50% yield with over 99% ee (Scheme 7±23).19
Scheme 7±23. Kinetic resolution of the chiral o-side chain via Sharpless epoxidation reactions.
416 APPLICATIONS OF ASYMMETRIC REACTIONS
Alkylzinc addition to an aldehyde was introduced in Chapter 2. In this case, 2 mol% of DAIB catalyzes the addition of dialkylzinc to a tin containing a,b- unsaturated aldehyde 84, giving the o-side chain 85 with 84% yield and 85% ee (Scheme 7±24).
In the presence of chiral diamine 86, addition of lithium acetylenide to an aldehyde 87 gives product 88 with 87% yield and 76% ee (Scheme 7±25).
Methods such as borane reduction and BINAL±H reduction are discussed in Chapter 6, and indeed ketone 89 can be reduced by chiral borane, providing the o-side chain 90 at 65% yield and 97% ee (Scheme 7±26).
Another method for ketone reduction, BINAL±H asymmetric reduction, can also be used in o-side chain synthesis. An example of applying BINAL±H asymmetric reduction in PG synthesis is illustrated in Scheme 7±27. This has been a general method for generating the alcohol with (15S)-con®guration. The binaphthol chiral auxiliary can easily be recovered and reused. As shown in Scheme 7±27, when the chiral halo enone 91 is reduced by (S)-BINAL±H at ÿ100 C, product (15S)-92 can be obtained with high enantioselectivity.
Scheme 7±24. Asymmetric synthesis of the chiral o-side chain via dialkylzinc addition.
Scheme 7±25. Asymmetric synthesis of the chiral o-side chain through chiral ligandinduced nucleophilic addition.
Scheme 7±26. Asymmetric synthesis of the chiral o-side chain via chiral borane reduction.
7.4 THE SYNTHESIS OF PROSTAGLANDINS
417
Scheme 7±27. Asymmetric synthesis of the chiral o-side chain via catalytic hydrogenation.
7.4.3 The Enantioselective Synthesis of (R)-4-Hydroxy-2-
Cyclopentenone
Many methods have been reported for the enantioselective synthesis of the remaining PG building block, the (R)-4-hydroxy-cyclopent-2-enone. For example, the racemate can be kinetically resolved as shown in Scheme 7±28. (S)-BINAP±Ru(II) dicarboxylate complex 93 is an excellent catalyst for the enantioselective kinetic resolution of the racemic hydroxy enone (an allylic alcohol). By controlling the reaction conditions, the CbC double bond in one enantiomer, the (S)-isomer, will be prone to hydrogenation, leaving the slow reacting enantiomer intact and thus accomplishing the kinetic resolution.20
Asymmetric ring opening of 3,4-epoxy cyclopentanone (desymmetrization) catalyzed by 2 mol% of an (R)-BINOL±modi®ed aluminum complex a¨ords the (4R)-hydroxy enone in 95% ee at 98% yield (Scheme 7±29).2
Scheme 7±30 shows how the diketone 94 can be reduced by (S)-BINAL±H to give the desired (3R)-hydroxy-propenone 95 with 65% yield and 94% ee.
Scheme 7±28. Ru(II)±BINAP-mediated kinetic resolution of 4-hydroxy-2-cyclopen- tenone.
Scheme 7±30. Asymmetric synthesis of a PG building block via catalytic hydrogenation.
7.5 THE TOTAL SYNTHESIS OF TAXOLÐA CHALLENGE AND OPPORTUNITY FOR CHEMISTS WORKING IN THE AREA OF ASYMMETRIC SYNTHESIS
Since the discovery of the high anticancer activity of taxol, much attention has been drawn to its asymmetric synthesis. The total synthesis stood for more than 20 years as a challenge for organic chemists. The compound taxoids are diterpenoids isolated from Taxus species and have a highly oxidized tricyclic carbon framework consisting of a central eight-membered and two peripheral six-membered rings (see Fig. 7±2).21
Over the past few years, several groups have accomplished the total synthesis of taxol by way of independent and original pathways. The successful synthesis of taxol can be considered one of the landmarks of organic synthesis.22 The total synthesis generally involves two stages: the synthesis of the side chain and the synthesis of the polycyclic ring system. Approaches to synthesizing the polycyclic skeleton of taxol can be divided into two types. One elaborates natural terpenes to generate the AB ring system of taxol by epoxy alcohol fragmenta-
Figure 7±2. Structure and numbering of taxol and baccatin III.
7.5 THE TOTAL SYNTHESIS OF TAXOL
419
tion; the other involves a convergent strategy, including a B ring-closure reaction applied to a connected AC ring system.
In Holton's and Wender's work, the total synthesis was achieved by sequentially forming the AB ring through the fragmentation of epoxy alcohols derived from …ÿ†-camphor and a-pinene. Nicolau's, Danishefsky's, and Kuwajima's total syntheses involved B ring closure connecting the A and C rings, whereas in Mukaiyama's synthesis, the aldol reaction was extensively applied to construct the polycyclic system.
7.5.1Synthesis of Baccatin III, the Polycyclic Part of Taxol
The structures of taxol and its polycyclic part baccatin III are shown in Figure 7±2, and the numbering of these two compounds is extensively used throughout the rest of this chapter. Because connecting the side chain to baccatin III is just routine chemistry, we introduce only the synthesis of baccatin III and the taxol side chain.
7.5.1.1 Holton's Construction of the Polycyclic Ring. In Holton's synthesis,23 compound 97, which can be prepared from camphor derivatives, is the starting material. Hydroxy-directed epoxidation of compound 97 gives unstable compound 98, which fragments in situ to provide compound 99, thus furnishing the AB skeleton of taxol (Scheme 7±31).24
A magnesium enolate of 99 is susceptible to aldol condensation with 4- pentenal, and the crude product can be directly protected to give its ethyl carbonate 100. a-Hydroxylation of the carbonyl group yields the hydroxyl carbonate 101. Reduction of the carbonyl group generates a triol, and this compound can be simultaneously converted to carbonate 102. Swern oxidation of 102 gives ketone 103, which can be rearranged25 to produce lactone product 104 (Scheme 7±32).
Lactone product 104 is now susceptible to reductive C-3 hydroxyl removal, providing an enol product 105 that can be converted to the ketone 106 upon silica gel treatment. C-1 a-hydroxylation of compound 106 provides compound 107. Compound 108 is then produced via Red-Al reduction of 107 and subsequent formation of the cyclic carbonate upon phosgene treatment (Scheme 7±33).
Ozonolysis and subsequent diazomethane treatment convert compound 108
Scheme 7±31
420 APPLICATIONS OF ASYMMETRIC REACTIONS
Scheme 7±32. Reagents and conditions: a: (1) Mg[N(Pri)2]2 (prepared by reaction of HN(Pri)2 with MeMgBr in THF); (2) 4-pentenal, THF, ÿ23 C, 1.5 hour; (3) Cl2CO, CH2Cl2, ÿ10 C, 0.5 hour, then ethanol 0.5 hour. b: LDA, THF, ÿ35 C, 0.5 hour, then …‡†-camphorsulphonyl oxaziridine, 0.5 hour, ÿ78 C. c: (1) 20 eq. of Red-Al, toluene, ÿ78 C, 6 hours, then warm to 25 C for 6 hours; (2) Cl2CO, pyridine, CH2Cl2, ÿ78 to 25 C, 1 hour. d: Swern oxidation. e: 1.05 eq. of LTMP, ÿ25 to ÿ10 C.
Scheme 7±33. Reagents and conditions: a: SmI2 reduction. b: Silica gel treatment. c:
(1) 4 eq. of LTMP, 10 C; (2) 5 eq. of …G†-camphorsulfonyl oxaziridine, ÿ40 C. d:
to methyl ester 109. Dickmann cyclization of 109 gives enol ester 110, which can be further converted to 111 via decarbomethoxylation. Compound 111 already possesses the ABC ring skeleton of a taxol compound (Scheme 7±34).
Next is the construction of the D ring. The TMS enol ether of compound 111 undergoes oxidation with m-CPBA, providing the C-5a trimethylsilyloxy ketone 112. Addition of methyl Grignard reagent to the ketone group and subsequent dehydration provides compound 113. Osmylation of the CbC double
bond then gives the triol 114, which can be converted to compound 115 via the mesylate or tosylate, thus furnishing the D ring of taxol. Addition of phenyllithium to the carbonate carbonyl group followed by TPAP oxidation provides compound 116. Oxidation of C-9 by benzeneseleninic anhydride followed by a t-BuOK±mediated rearrangement provides the baccatin III compound 117, which possesses all the functional groups of the polycyclic part of taxol (Scheme 7±35).
7.5.1.2 Wender's Approach. Wender's synthesis27 of baccatin III starts from the compound verbenone, a compound that can easily be prepared from pinene, which in turn is an abundant component of pine trees and a major constituent of the industrial solvent turpentine. The retro synthesis is outlined in Scheme 7±36.
In the synthetic procedure, verbenone 118, the air oxidation product of pinene, is ®rst treated with t-BuOK, followed by the addition of prenyl bromide to give a C-11 alkylated product. Selective ozonolysis of the more electron-rich double bond provides the aldehyde 119 with 85% yield. The A ring of taxane is then created through photorearrangement of the aldehyde 119, yielding the chrysanthenone derivative 120 (85% yield, over 94% ee).
Completion of the B ring starts by introducing a two-carbon connector between the C-2 and C-9 carbonyls of 120. This is achieved in two steps. First, the lithium salt of ethyl propiolate is selectively added to the C-9 carbonyl, and the resulting alkoxide is trapped in situ with TMSCl, producing the TMS-protected product 121. The C-9 methyl group is then introduced through conjugate ad-
