Total Synthesis with a Chirogenic Opening Move Demonstrated on Steroids with Estrane or 18a‐Homoestrane Skeleton

Quinkert, Gerhard; Grosso, M. Del; Döring, Astrid; Döring, Wolfgang; Schenkel, Ralf I.; Bauch, Markus; Dambacher, Gernot T.; Bats, Jan W.; Zimmermann, Gottfried; Dürner, Gerd

doi:10.1002/hlca.19950780524

Cited by 65 publications

(40 citation statements)

References 85 publications

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“…This type of acid-induced isomerization is well precedented in earlier Dane's-diene-based routes to steroids (39)(40)(41)(42)(43). It should be noted that when conducted thermally, DA reactions of cyclenones with 26 are not significantly regioselective (44,45). Thus, one would have expected, by precedent, that the thermally driven DA reaction of 7 with Dane's diene would have also produced 29 as a seriously competing primary product.…”

Section: Significancementioning

confidence: 70%

Stereospecific cis- and trans -ring fusions arising from common intermediates

Townsend

Ross

2014

Proc. Natl. Acad. Sci. U.S.A.

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Highly concise and stereospecific routes to cis and trans fusion, carrying various functionality at one of the bridgehead carbons, have been accomplished. Diels-Alder cycloaddition | cyclobutenone | angular methylation | mechanistic studies O ur group has been studying the synthetic utility of the DielsAlder (DA) reaction of the parent cyclobutenone, 2 (1). Recently reported results demonstrate that 2 is a highly reactive, endo-selective dienophile (Fig. 1, Eq. 1) (2). We have also developed a series of intramolecular Diels-Alder (IMDA) reactions, wherein the cyclobutenone component is tethered to various conjugated dienes (compare 4); cycloaddition of these substrates delivers adducts of the type 5, which can be readily converted to trans-fused systems bearing iso-DA patterns (Fig. 1, Eq. 2, 5→6) (3). Additionally, we have described the synthesis and DA cycloaddition of an even more powerful dienophile, 2-bromocyclobutenone (Fig. 1, Eq. 3, 7) (4). The direct adducts of this [4+2] reaction (compare 8) are readily converted to norcarane carboxylic acids (9) through exposure to hydroxide base. The research described herein was initially focused on efforts to add carbon-based nucleophiles to DA cycloadducts of the type 8. It might well have been expected that such reactions would give rise to products such as 10, wherein a ketone is appended to the junction of the norcarane system (Fig. 1, Eq. 4). Results and DiscussionWith a view toward accomplishing the transformation envisioned in Fig. 1, Eq. 4, compounds of the type 8 were exposed to methyllithium as described in Fig. 2. Interestingly, exposure of substrate 8a to the conditions shown led to an 81% yield of the angularly methylated product 11a, apparently unaccompanied by any part of the corresponding trans-fused diastereomer (Fig. 2, entry 1). Reactions conducted with related DA adducts 8b and 8c resulted in quite similar outcomes (Fig. 2, entries 2 and 3). Although we were confident that the products obtained were cisfused (Fig. 2, 11a-c), it was the synthesis of the rigorously assignable trans-fused product (vide infra) and its nonidentity with 11a that served to allow for sound assignment of the cisring fusion.An obvious mechanistic proposal to account for the formation of this structure envisions lithium-halogen exchange (5-8) leading to 12a and methyl bromide (Fig. 3). This step is followed by angular methylation (9-11) of 12a. It would not be surprising for such a reaction to have a very high preference for producing cis fusion. Clearly, a great deal of ring strain would be introduced in any transition state en route to trans-fused products.Whereas the enolate alkylation proposal is presumptive, several alternate formulations merited consideration. In principle, one can envision the possibility that lithium enolate 12a is not actually produced (perhaps due to ring strain). Rather, 11 (Fig. 3) arises from the merger of otherwise high-energy species en route to 12a and 12b. For instance, "radicaloid" (5) character could be generated at both the bridgehead ...

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Section: Significancementioning

confidence: 70%

Stereospecific cis- and trans -ring fusions arising from common intermediates

Townsend

Ross

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Since the trifluoromethanesulfonyl group is highly electron-withdrawing in nature, the electrophilic reactivity of the ketone is significantly high in converting to a dioxilane, and the electronwithdrawing character of the amide retards Baeyer-Villiger oxidative rearrangement. These strongly indicated that electrophilic activation of ketone is possible by attaching electron-withdrawing sulfonylamide groups on both a-methylene carbons of the ketone, but not by bulky sulfonylamide (2, 3, 7) and ether group (8).…”

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confidence: 97%

“…According to the reported procedure, 9 was arylsulfonated with the corresponding chlorides in methylene chloride giving 10a, b. 8) Cyclization of 10 was carried out with to afford olefins 11a, b, which were then ozonolyzed to the ketones 2 and 3 (Chart 1).…”

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confidence: 99%

An Approach to a Chiral Cycloalkanone-Mediated Asymmetric Epoxidation of Stilbene with Oxone.

Matsumoto

Tomioka

2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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In these years we have been involved in the development of external chiral ligands effective for a variety type of catalytic asymmetric reactions. 1,2) As an approach toward asymmetric epoxidation of an olefin with oxone ® , 3) we designed a chiral ketone 1 for a precursor to a dioxilane ( Fig. 1).4) The chiral ketone 1 is characteristic by a 1,2-diphenylethane-1,2-diamine backbone 5) and benzenesulfonamide moiety as an electron-withdrawing group for electrophilic activation of a ketone carbonyl group as well as prevention of BaeyerVilliger oxidative rearrangement of a dioxilane. 6) However, enantioselectivity was relatively low, 30% ee for epoxidation of stilbene, even though the sense of enantiofacial differentiation was exactly the same as we predicted.7) The corresponding dioxilane A, generated from 1 and oxone ® , is anticipated to take a rigid conformation B due to steric reason, of which chiral environment is expected to be good for enantiofacial selection (Fig. 2). Since modification of the benzene ring of arylsulfonamide is one possibility to tune up the structure 1, new chiral ketones 2 and 3 bearing bulky 2,4,6-trimethyl and 2,4,6-triisopropylbenzenesulfonamides were synthesized and examined their efficiency. Three cyclohexyl versions 4-6 were also prepared and evaluated in an epoxidation of stilbene. Other than seven-membered cycloalkanones, the 11-memberd cycloalkanones 7 and 8 bearing a binaphthyl backbone were prepared and also examined their attitudes toward an asymmetric epoxidation of stilbene. It is noteworthy that epoxidation of stilbene with 4 gave stilbene oxide in reasonably high yield and almost the same enantioselectivity, regardless of whether stoichiometric (1.0 eq) or substoichiometric (0.3 eq) amount of 4 was used.Synthesis of the 7-Membered Chiral and C2 Symmetric Cycloalkanones 2-6 The ketones 2 and 3 were readily prepared in three steps starting from commercially available (S,S)-diamine 9 (Chart 1). According to the reported procedure, 9 was arylsulfonated with the corresponding chlorides in methylene chloride giving 10a, b.8) Cyclization of 10 was carried out with 3-iodo-2-iodomethylpropene in N,N-dimethylformamide (DMF) to afford olefins 11a, b, which were then ozonolyzed to the ketones 2 and 3 (Chart 1).The chiral ketones 4-6 bearing a cyclohexanediamine backbone were prepared by the same reaction sequence from (R,R)-diamine 12 9) (Chart 2). The phosphonamide 6 was designed expecting more bulkiness than 4 and 5 around the nitrogen.Synthesis of the 11-Membered Chiral Cycloalkanones 7 and 8 The ketone 7 was readily prepared from a binaph- Sakyo-ku, Kyoto 606-8501, Japan. Received July 30, 2001; accepted September 27, 2001 Chiral and C2-symmetric seven-membered cycloalkanones 2-6 bearing 1,2-diphenylethane-1,2-diamine and cyclohexane-1,2-diamine backbones were synthesized and evaluated their asymmetry inductive behaviours in an asymmetric epoxidation of stilbene with oxone ® . Although the reaction of the ketones 2 and 3 of a 1,2-diphenylethane-1,2-diamine backbone gave stilb...

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“…Prominent among the methods that have been developed are those based on Diels-Alder reactions (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), transition metal-catalyzed cyclizations of enynes and triynes (13)(14)(15)(16), and biogenetic-type electrophilic cyclizations of polyene precursors (17)(18)(19)(20)(21).…”

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confidence: 99%

A total synthesis of estrone based on a novel cascade of radical cyclizations

Pattenden

González

McCulloch

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Two conceptually different and novel radical-mediated cascade reactions leading to a total synthesis of the steroid (؎)-estrone 1 and to a synthesis of 14-epiestrone 40 are described. Treatment of the iododienynone 23 with Bu3SnH͞2,2-azobis(isobutyronitrile) (AIBN) triggers a 13-endo-dig radical macrocyclization followed by two sequential radical transannulation reactions leading to the crystalline estrane 24 in 50% yield. The x-ray crystal structure of 24 established its trans, syn, stereochemistry. Transposition of the enone functionality in 24 next led to 38, which was then converted into 39 by reductive methylation. Deprotection of the methyl ether 39 finally gave 14-epiestone 40. When the substituted iodovinylcyclopropane 55 was treated similarly with Bu3SnH͞AIBN, the resulting radical center underwent a different sequence of cascade macrocyclization-transannulation reactions producing the trans, anti, trans estrane 56 in 12% overall yield. Oxidation of 56, using CrO 3-H2SO4 next led to the cyclopentanone 57, which, on deprotection using BBr3 gave (؎)-estrone 1. A number of alternative substituted iodopolyenynones and iodovinylcyclopropanes, i.e., 8a, 8b, 33, 49a, and 49b, underwent similar radical-mediated cascade cyclizations leading to other estranes, i.e., 21a, 21b, 35, and 50, and, in one case, to the 6,6,5,6-tetracycle 51, in variable overall yields. The structures and stereochemistries of several estranes were established by using x-ray crystal structure measurements in combination with analysis of their NMR spectroscopic data and correlation with literature precedent. Since the synthesis of the female sex hormone estrone 1 by Anner and Miescher in 1948 (1), and the syntheses of nonaromatic steroids, such as cortisone 2 and aldosterone 3 during the 1950s, a plethora of ingenious designs have been explored to synthesize members of the steroid family of natural products. Prominent among the methods that have been developed are those based on Diels-Alder reactions (2-12), transition metal-catalyzed cyclizations of enynes and triynes (13-16), and biogenetic-type electrophilic cyclizations of polyene precursors (17-21).Over the past 10 years, we (22-26) and others (27-38) have examined the scope of a variety of cascade radical-mediated processes to elaborate steroids and other polycyclic ring systems. Thus, we have already described an approach to steroids based on consecutive 6-endo-trig (ref. 39 and references therein) and sequential transannular (40) radical cyclizations from appropriate polyene selenyl ester precursors, illustrated in the conversions 4 3 5 and 6 3 7, respectively.We have now extended our studies and examined a different approach to estrone 1 and estranes, whereby the nonaromatic tricyclic B,C,D ring system is produced in a single step by radical-mediated macrocyclizations in tandem with consecutive transannulations from an appropriate ortho-disubstituted arylpolyene precursor.These approaches to estranes are captured in a retrosynthetic manner in Scheme 1. Thus, in one approach, we ha...

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Total Synthesis with a Chirogenic Opening Move Demonstrated on Steroids with Estrane or 18a‐Homoestrane Skeleton

Cited by 65 publications

References 85 publications

Stereospecific cis- and trans -ring fusions arising from common intermediates

Stereospecific cis- and trans -ring fusions arising from common intermediates

An Approach to a Chiral Cycloalkanone-Mediated Asymmetric Epoxidation of Stilbene with Oxone.

A total synthesis of estrone based on a novel cascade of radical cyclizations

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