Synthesis of Estrone

The classical work of Butenandt and Doisy on the isolation of the estrognic hormone, estrone in 1929 from pregnancy urine was aided by much preliminary biological work, the introduction of important bioassay methods by Allen and Doisy in 1923 and Ascheim and Zondek and the involvement of the company Sobering AG. The structure was elucidated through the work of several different groups on the synthesis of numerous degradation products. Estrone and its derivatives from such natural sources were soon introduced into therapy. The first synthesis of a steroid, namely the naphthalenic relative equilenin (3) 

This synthetic work became of added interest not only through the useful 

---

R B Woodward was one of the leading organic chemists of the middle part of the twenti eth century Known pnmanly for his achievements in the synthesis of complex natural products he was awarded the Nobel Pnze in chemistry in 1965 He entered Massachusetts Institute of Tech nology as a 16 year old freshman in 1933 and four years later was awarded the Ph D While a student there he earned out a synthesis of estrone a female sex hormone The early stages of Woodward s estrone synthesis required the conversion of m methoxybenzaldehyde to m methoxy benzyl cyanide which was accomplished in three steps... 

Fig. 4. Synthesis of estrone (20) through elimination of unactivated 19-methyl group via intramolecular functionalization of C-19. -TsOH...

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone appHes a tandem Claisen rearrangement and intramolecular ene-reaction (Eig. 23). StereochemicaHy pure (185) is synthesized from (2R)-l,2-0-isopropyhdene-3-butanone in an overall yield of 86% in four chemical steps. Heating a toluene solution of (185), enol ether (187), and 2,6-dimethylphenol to 180°C in a sealed tube for 60 h produces (190) in 76% yield after purification. Ozonolysis of (190) followed by base-catalyzed epimerization of the C8a-hydrogen to a C8P-hydrogen (again similar to conversion of (175) to (176)) produces (184) in 46% yield from (190). Aldehyde (184) was converted to 9,11-dehydroestrone methyl ether (177) as discussed above. The overall yield of 9,11-dehydroestrone methyl ether (177) was 17% in five steps from 6-methoxy-l-tetralone (186) and (185) (201). 

Thus, the rutro group at the illylic posmou is replaced by aucleophiles in the following three ways (1) assistance by transmon met il, f2 assistance by Lewis acids, and Ci) assistance by proton Zard and coworkers have reported a short total synthesis of estrone derivanves, where acid catalyzed dlylic 1,3-shift of nitro group Is used as a key step as shown in Scheme 7 4 ... 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

The total synthesis of ( )-estrone [( )-1 ] by Vollhardt et al. is a novel extension of transition metal mediated alkyne cyclotrimeriza-tion technology. This remarkable total synthesis is achieved in only five steps from 2-methylcyclopentenone (19) in an overall yield of 22%. The most striking maneuver in this synthesis is, of course, the construction of tetracycle 13 from the comparatively simple diyne 16 by combining cobalt-mediated and ort/io-quinodimethane cycloaddition reactions. This achievement bodes well for future applications of this chemistry to the total synthesis of other natural products. 

In Entry 11 the dienophile is an a-methylene lactam. As noted for this class of dienophiles, the stereoselectivity results from preferred exo addition (see p. 471). The reaction in Entry 12 was used in an enantiospecific synthesis of estrone. The dienophile was used in enantiomerically pure form and the dioxolane ring imparts a high facial selectivity to the dienophile. The reaction occurs through an endo TS. 

Similarly, an enantioselective synthesis of estrone is based on catalyst D.97... 

Pattenden reported a tandem cyclization approach for the synthesis of estrone in 2004. Later, they further demonstrated that this strategy could be used to generate the veratramine skeleton [26]. 

A similar transformation occurs as a critical step in the total synthesis of (+)-estrone by a Diels-Alder cycloaddition-cycloreversion pathway (Eq. 80).227 It is worth noting that in this reaction the conjugated double bond is stereoselectively reduced while both an isolated double bond and a ketone carbonyl are preserved. 

An efficient method for the generation of oquinodimethanes via desilylation reaction involves treatment of a 2-[(trimethylsilylmethyl)benzyl]trimethylarmnonium iodide with fluoride ion (equation 31)64. This reaction was applied by Saegusa and coworkers for the synthesis of estrone in which an intramolecular Diels-Alder reaction of an o-quinodimethane, generated in situ, served as the key reaction (equation 32)65. 

The reaction provides the key step in a stereoselective synthesis of estrone methyl ether (6) from 5.b... 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolare (29) to the scalemic sulfoxide (30). Direct treatment of the crude Michael adduct with mew-chloroperbeuzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (31) X — a and ftH R = H in over 90% yield. 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone applies a tandem Claisen rearrangement and intramolecular ene-reaction. Most 19-nonsteroid contraceptive agents are produced by total synthesis from nonsteroidal starting materials. 

Vollhardt et al. The total synthesis of estrone, which is one of the three naturally occurring estrogens and a primary estrogenic component of several pharmaceutical preparations, was achieved in a few chemical operations [48]. Precursor 52 was prepared via consecutive cobalt(I)-mediated... 

The synthesis of (+)-estrone methyl ether (36) illustrates the enantioselective construction of a polycyclic target by the use of chiral auxiliary control to establish the first cyclic stereogenic center [14], In this case, the specific design of the naphthyldiazoester 32 directed Rh-mediated intramolecular C-H insertion selectively toward one of the two diastereotopic C-H bonds on the target methylene. The new ternary center so created then biased the formation of the adjacent quaternary center in the course of the alkylation. The chiral skew in the product cyclo-pentanone (35) controlled the relative and absolute course of the intramolecular cycloaddition, to give the steroid (+)-estrone methyl ether (36). 

Compounds of this type are regarded as 4,5-disubstituted isoxazoles, and as such they react. Their formation from 2-acylcyclohexanones and hydroxylamine is a special case of the general method of isoxazole formation from /9-diketones. 2-Formyl (hydroxymethylene) cyclohexanones, obtained from the respective cyclohexanones and ethyl formate, give 3-unsubstituted derivatives [Eq. (7)].84-91 This reaction has been applied to a stereospecific synthesis of estrone.87,89... 

An impressive synthesis of estrone (51) was reported Vrdlhardt and cowoikers. G>bait-catalyzed cooligomerization of the diyne (49) with bis(trimethylsilyl)acelylene gave the estratrienone (50) in 71% yield. Introduction of the hydroxy substituent at C-3 was then cleverly achieved by selective proto-desilylation at C-2, followed by oxidation of the carbon-silicon bond using LTFA (Scheme 19). 

A well designed simple cyclopropyl ring opening is a key step of a new total synthesis of ( )-estrone by Pattenden (Scheme 22). An initial 2-endo-trig macrocyclization was followed by the ring opening. Two additional cy-clizations stereoselectively assembled the estrone skeleton 66, albeit in low yield [81]. 

It is instructive to follow the evolution of the strategic principles with an example of the total synthesis of estrone 128 (Scheme 3.33), as it can be regarded historically as one of the trial cases used to evaluate the effectiveness of various synthetic approaches.The first total synthesis of estrone, reported in 1948 by Anner and Mischner, involved 18 steps with an overall yield of 0.1 % (based on the starting material, m-bromoanisole). In 1958, Johnson s group accomplished the synthesis in 10 steps with a 4.2% yield based on 2-methoxytetralone 129. Finally, in 1965, Torgov and co-workers carried out a six-step synthesis, also based on 129, but in 25% yield. 

Finally, the search for a strategic bond is always simplified when even a first glance analysis leads to the identification of those bonds that clearly cannot be considered strategic. The latter include bonds in aromatic rings (see, however, an exception in Vollhardt s synthesis of estrone) or heteroaromatic rings, as well as bonds which are located in readily available fragments (such as monosaccharides, amino acids, natural fatty acids, etc.). 

The functionally and stereochemistry provided by aldehyde (100) have led to the use of the tandem Cope-Claisen rearrangement for the synthesis of estrone methyl ether (117) and steroid synthons. Thermolysis of triene (115 Scheme 8) provides aldehyde (116) as the major component of a 2/1 mixture ... 

Because halohydrins are easily converted to epoxides by intramolecular 5 2 reaction (Section 9.6), they have been used in the synthesis of many naturally occurring compounds. Key steps in the synthesis of estrone, a female sex hormone, are illustrated in Figure 10.14. 

---