Stereospecific Cis- and Trans-Ring Fusions Arising from Common Intermediates

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

Steven D. Townsenda, Audrey G. Rossb, Kai Liua, and Samuel J. Danishefskya,b,1

aLaboratory of Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, New York, NY 10065; and bDepartment of Chemistry, Columbia University, New York, NY 10027

Contributed by Samuel J. Danishefsky, April 25, 2014 (sent for review February 14, 2014) Highly concise and stereospecific routes to cis and trans fusion, disaggregation, would accomplish the observed overall angular carrying various functionality at one of the bridgehead carbons, methylation, culminating in 11. Exclusive formation of a cis-ring have been accomplished. fusion would again be expected, in terms of a solvent-cage− induced “memory effect,” as well as of the ring strain associated Diels–Alder cycloaddition | cyclobutenone | angular methylation | with the transition state leading to a trans junction (for reviews on mechanistic studies the concept of “chiral memory,” see refs. 12 and 13). Here, we present only the limiting possibility, i.e., coupling of “enolyl” and ur group has been studying the synthetic utility of the Diels– “methyl” free radicals. The important distinction between OAlder (DA) reaction of the parent cyclobutenone, 2 (1). pathways i and ii in Fig. 3 is that the former corresponds to Recently reported results demonstrate that 2 is a highly reactive, a classic enolate methylation. By contrast, in pathway ii the endo-selective dienophile (Fig. 1, Eq. 1) (2). We have also de- coupling event occurs somewhere en route to metal–halogen veloped a series of intramolecular Diels–Alder (IMDA) reac- exchange. tions, wherein the cyclobutenone component is tethered to Because the cis-specific outcome of the reaction did not serve various conjugated dienes (compare 4); cycloaddition of these to answer the mechanistic question, a more illuminating probe substrates delivers adducts of the type 5, which can be readily would be required. The thought was that, if the reaction were

converted to trans-fused systems bearing iso-DA patterns (Fig. 1, occurring through path i, with the alkylating agent corresponding CHEMISTRY Eq. 2, 5→6) (3). Additionally, we have described the synthesis to methyl bromide, then one could anticipate potential compe- and DA cycloaddition of an even more powerful dienophile, 2- tition between the MeBr generated through metal–halogen ex- bromocyclobutenone (Fig. 1, Eq. 3, 7) (4). The direct adducts of change and incident MeBr in solution. By contrast, path ii this [4+2] reaction (compare 8) are readily converted to nor- dictates that the angular methyl group in 11 must arise only from carane carboxylic acids (9) through exposure to hydroxide base. the original methyllithium. To probe this distinction in practice, The research described herein was initially focused on efforts to it would be necessary to fashion an experiment that would allow add carbon-based nucleophiles to DA cycloadducts of the type 8. us to discern between the methyl group of solution-based methyl It might well have been expected that such reactions would give bromide and other species capable of methyl transfer that arise rise to products such as 10, wherein a ketone is appended to the during progression of the metal–halogen exchange. 4 junction of the norcarane system (Fig. 1, Eq. ). As shown in Fig. 4, Eq. 5, reaction of 8a with CD3Li was – Results and Discussion conducted for 15 min at 78 °C. Following this, CH3Br was added to the reaction mixture. Deuterated compound 13 was obtained With a view toward accomplishing the transformation envisioned in 64% yield, along with 16% of 11a. For control purposes, the in Fig. 1, Eq. 4, compounds of the type 8 were exposed to experiment was also conducted in the opposite sequence, wherein methyllithium as described in Fig. 2. Interestingly, exposure of CH Li was used in the metal–halogen exchange, and CD Br was 8a 3 3 substrate to the conditions shown led to an 81% yield of the subsequently added to the reaction mixture (Fig. 4, Eq. 6). In this 11a angularly methylated product , apparently unaccompanied by mode, 11a was obtained in 59% yield, along with a 14% yield of trans any part of the corresponding -fused diastereomer (Fig. 2, 13. These observations suggest substantial angular methylation in entry 1). Reactions conducted with related DA adducts 8b and 8c 2 3 resulted in quite similar outcomes (Fig. 2, entries and ). Significance Although we were confident that the products obtained were cis- fused (Fig. 2, 11a–c), it was the synthesis of the rigorously as- signable trans-fused product (vide infra) and its nonidentity The development of strategies in organic synthesis is an im- with 11a that served to allow for sound assignment of the cis- portant challenge, from the perspective of creative design as ring fusion. well as application to the pharmaceutical industry. In this pa- An obvious mechanistic proposal to account for the formation per, we study a promising new solution to a classical problem of this structure envisions lithium–halogen exchange (5–8) in organic synthesis: namely, the control of ring junction ste- leading to 12a and methyl bromide (Fig. 3). This step is followed reochemistry in a particularly challenging setting, wherein one of the rings composing the junction is four membered. This by angular methylation (9–11) of 12a. It would not be surprising system was selected because it poses a particularly difficult for such a reaction to have a very high preference for producing challenge for the synthesis of trans-fused junctions. We believe cis fusion. Clearly, a great deal of ring strain would be introduced that the solution to the problem described herein will have in any transition state en route to trans-fused products. broad applications in organic synthesis. Whereas the enolate alkylation proposal is presumptive, sev-

eral alternate formulations merited consideration. In principle, Author contributions: S.D.T., A.G.R., and S.J.D. designed research; S.D.T. and K.L. per- one can envision the possibility that lithium enolate 12a is not formed research; S.D.T., K.L., and S.J.D. analyzed data; and S.D.T. and S.J.D. wrote actually produced (perhaps due to ring strain). Rather, 11 (Fig. the paper. 3) arises from the merger of otherwise high-energy species The authors declare no conflict of interest. en route to 12a and 12b. For instance, “radicaloid” (5) charac- 1To whom correspondence should be addressed. E-mail: [email protected]. 12b ter could be generated at both the bridgehead ( )and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. methyl carbon centers. Coupling of these species, before their 1073/pnas.1407613111/-/DCSupplemental.

www.pnas.org/cgi/doi/10.1073/pnas.1407613111 PNAS Early Edition | 1of5 Downloaded by guest on September 29, 2021 Fig. 3. Mechanistic proposals.

yield of angular methylation in this experiment presumably reflects some degree of competitive reaction between methyllithium and methyl bromide.) Thus, at least under these conditions, incident CH3Br is fully competitive with methylating agent generated in the metal–halogen exchange. This experiment also serves to rule out any “cage effect” between methyl bromide generated in the immediate sphere of the enolate and solution- based methyl bromide. We emphasize that the combined results of these studies rule out the intermediacy of species 12b, insofar as it implies a special affinity to join the bromine-bearing bridgehead carbon to the methyl group in the original methyllithium species. Also excluded are possibilities arising from initial “nucleophilic methylation” of the ketone followed by formation of a highly strained epoxide, culminating in suprafacial migration of the methyl group to provide overall stereochemical iii 8 Fig. 1. Expanding the scope of the Diels–Alder reaction. retention (Fig. 4, hypothetical path , Eq. ). The results shown in Fig. 4, Eqs. 5–7 clearly exclude path iii because, in the latter mode the methyl group of solution-based “methyl X” would not the initial 15-min interval. However, because the reaction was not appear in the product. Finally, one additional control experiment complete after 15 min, the remaining methyl bromide (CD3Br or was conducted, wherein cyclohexanone was subjected to reaction CH3Br) was forced to compete with the newly introduced alky- with CD3Li, in the presence of CH3I. We observed generation of lating agent (CH3Br or CD3Br) in a 1:1 ratio. ethane and addition of CD3 to the ketone. Importantly, no ex- Whereas these experiments are certainly consistent with eno- change event between CH3I and CD3Li and subsequent attack late formation followed by conventional alkylation, they did not with CH3Li were observed. fully document the source of the angular methyl group before It will be recognized that the chemistry disclosed thus introduction of the external methylating agent (CD3Br or far corresponds to what would be possible directly from in- CH Br). In a more discriminating experiment, CD Li was added termolecular DA cycloaddition to the unknown 2-methyl- 3 3 8 to a solution already containing an equivalent of both CH3Br and cyclobutenone. Next, we wondered whether could serve as 8a (Fig. 4, Eq. 7). This reaction gave rise to 25% of recovered 8a a precursor to a trans-fused bicyclic [4.2.0] system. Because 8 as well as ca. 20% each of 11a and 13. (The somewhat reduced a compound of the type can be viewed as a bifunctional elec- trophile, it was of interest to explore its chemistry upon reaction

Fig. 2. Reaction of DA adducts with methyllithium. Fig. 4. Mechanistic evaluation of methylation.

2of5 | www.pnas.org/cgi/doi/10.1073/pnas.1407613111 Townsend et al. Downloaded by guest on September 29, 2021 Fig. 5. Dianion addition to DA adduct 8a.

with a dianion (14). In our inaugural experiment, we studied the reaction of 8a with the previously established geminal dianion 14 , derived from bis-deprotonation of phenyl methyl sulfone (for Fig. 7. Dianion addition to DA adducts 8b and 8c. the chemistry of α,α-dilithiosulfones, see refs. 15–22). Re- markably, reaction of 8a with 14 afforded an angular phenyl- sulfonylmethyl product in 84% yield, as a single stereoisomer could be viewed from the perspective of a 1,2 migration of the σ (Fig. 5). At this stage, the stereochemistry of the junction could bond (Fig. 8, path i). Alternatively, one could also envision not be assigned with confidence. Reductive cleavage of the formation of a high-energy cyclopropane by intramolecular al- phenylsulfonyl moiety was accomplished through reaction with kylation, (compare 23b) followed by ring opening of the edge Raney Ni in ethanol. Interestingly, the resultant angular methyl cyclopropane bond to 16 (Fig. 8, path ii)(30–32). Although compound, although broadly similar to 8a, was different in de- pathways i and ii are distinct, discerning between them would be tail. Given our confidence in the assignment of 11a as bearing a complex matter and we presently have no distinguishing ex- a cis junction, it was surmised that both the initial angular phe- nylsulfonylmethyl compound generated from the dianion chem- perimental evidence that speaks to these lines of conjecture. We istry and its reductively derived angular methyl product should note that by either mechanism, the immediate preworkup spe- 24 be formulated as trans-fused systems 15a and 16a, respectively. cies should correspond to anion . Indeed, when the reaction 8 14 To verify the junction configuration, the known hydrindenone conducted between and was worked up with D2O, the 17 (23, 24) was converted to diazoketone 19, through a seldom- deuterated sulfone 25 (as a mixture of H,D stereoisomers) was used Forster reaction (25, 26) of intermediate α-oximinoketone obtained. We note, parenthetically, that this latent anion was 18 (Fig. 6). Ring contraction of 19 via Wolff rearrangement (27) also successfully reacted with methyl iodide, although, in that CHEMISTRY provided ester 20 and, thence, acid 21. The latter, upon Barton– case, the desired compound was not separable from 15a, which McCombie-inspired homolytically induced decarboxylation (28), was generated during the workup. afforded 22. This compound was also obtained, albeit in only We note that these previous mechanistic proposals centered 27% yield, by subjecting our compound 16a to microwave Wolff– on pathways involving nucleophilic addition to the sterically Kischner conditions (29). hindered concave face of the molecule. We acknowledge that an Similarly, adducts 8b and 8c were converted to their trans- alternative mechanistic pathway could also explain the observed 15b 15c fused angularly functionalized counterparts, and (Fig. 7). stereoselectivity. In this case, lithium–halogen exchange by the This overall transformation formally corresponds to what could sulfone dianion could, in theory, generate enolate 12a and trans be accomplished from suprafacial DA cycloaddition to -2- a bromosulfone anion. After α elimination, generation of a car- methylcyclobutenone or by an antarafacial DA cycloaddition to bene and addition of this species across the double bond of 12a cis-2-methylcyclobutenone (vide supra). We note that it is our would give rise to intermediate 23b. The delineation of the experience that in DA cycloadditions, α-halocyclenones are far precise pathway to the trans junction is the subject of current more effective dienophiles than are their α-H or α-Me coun- computational analysis. terparts. This improvement in dienophilicity is still another ad- 7 vantage of this chemistry. By combining the high-quality dienophilicity of (4) with the The mechanism by which 8 is converted to 15 cannot be capacity to generate bicyclo[4.2.0]octane ring junctions from cis asserted in detail. At first glance, this reaction could be viewed as angularly brominated -DA products, we have entered into the elusive structural space of trans-fused cyclobutanones. We won- adirectSN2 displacement of the angular bromide, although this is mechanistically unlikely (8). Another more precedent- dered whether these findings could be extended to generate supported possibility envisions 1,2-addition of 14 to the keto 16-norsteroids bearing four-membered D rings. Although such group of 8. The path from phenylsulfonyl-stabilized anion 23a to 16, systems are known, they were previously obtained by ring con- which corresponds overall to a 1,2 migration of a carbanion, traction of standard steroids (33–37).

Fig. 6. Verification of trans fusion.

Townsend et al. PNAS Early Edition | 3of5 Downloaded by guest on September 29, 2021 Fig. 8. Mechanistic proposals.

Fig. 9. Synthesis of rac-D16-norestrone methyl ether.

We first selected a target whose structure, were it to be syn- Reaction of 28 with dianion 14 provided the angular phenyl- thesized, could be assigned with great confidence. As seen in sufonylmethyl compound 30 in 80% yield. Reduction of the 8,9- Fig. 9, DA cycloaddition between 7 and Dane’sdiene(26)(38–40) double bond led to the dihydro product 31. Next, reductive gave rise to 28. Clearly, 28 resulted from double-bond isomeri- clevage of the sulfone was accomplished to provide the angular zation of the primary DA product 27. This type of acid-induced methyl product 32. This assignment can be offered with complete isomerization is well precedented in earlier Dane’s-diene–based confidence because the chromatographic and spectral properties routes to steroids (39–43). It should be noted that when con- of rac-32 are identical to those of the enantiomerically homo- ducted thermally, DA reactions of cyclenones with 26 are not geneous adduct produced from the known ring contraction of significantly regioselective (44, 45). Thus, one would have estrone methyl ether 33 (22). expected, by precedent, that the thermally driven DA reaction of Ordinarily, binding of steroids to estrogen receptors requires 7 with Dane’s diene would have also produced 29 as a seriously a free phenolic hydroxyl in the A ring (47). However, attempts competing primary product. The absence of detected 29 again to cleave the methyl ether function of rac-32 to produce the points to the special character of the dienophile. Thus, 7 under- 16-norestrone were not successful, no doubt reflecting the goes DA cycloaddition with a level of regioselection that has only lability of the trans-fused cyclobutanone substructure to the con- previously been observed under Lewis acid catalysis (46). ditions used. In the end, it proved more straightforward to

Fig. 10. Synthesis of rac-D16-norestrone.

4of5 | www.pnas.org/cgi/doi/10.1073/pnas.1407613111 Townsend et al. Downloaded by guest on September 29, 2021 synthesize the triisopropyl silyl-protected version of Dane’s experimental sequence of lithium–halogen exchange and angular diene, i.e., 34 (Fig. 10) (synthesis details in SI Appendix). The methylation, access to the cis-fused series is gained. By contrast, latter was moved through the same sequence as was 26, leading reaction of the cis-fused bromocycloadducts with the presumed eventually to 37. Deprotection of the A-ring phenol and re- dilithiomethylphenyl sulfone leads to the trans-fused angularly – ductive cleavage of the carbon sulfur bond led to rac-D16-nor- substituted bicyclo[4.2.0]octane systems. estrone (39) (48). Conclusion ACKNOWLEDGMENTS. The authors thank Dr. George Sukenick, Hui Fang, and Sylvi Rusli of Sloan-Kettering Institute’s NMR core facility for spectro- It has been shown that a variety of sequences, initiated by DA scopic assistance and Dr. Suwei Dong and Adam Levinson for helpful discus- sions. This work was supported by National Institutes of Health Grant reactions of various conjugated dienes with 2-bromocyclobute- HL25848 (to S.J.D.). S.D.T. is grateful to Weill Cornell Medical College for none, set the stage for stereospecific angular functionalization of a National Cancer Institute postdoctoral fellowship (CA062948). A.G.R. the resultant cycloadducts. Through a remarkably straightforward acknowledges the National Science Foundation for a predoctoral fellowship.

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