Stereospecific cis- and trans-ring fusions arisingfrom common intermediatesSteven 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, ColumbiaUniversity, 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,carrying various functionality at one of the bridgehead carbons,have been accomplished.

Diels–Alder cycloaddition | cyclobutenone | angular methylation |mechanistic studies

Our group has been studying the synthetic utility of the Diels–Alder (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 de-veloped a series of intramolecular Diels–Alder (IMDA) reac-tions, wherein the cyclobutenone component is tethered tovarious conjugated dienes (compare 4); cycloaddition of thesesubstrates delivers adducts of the type 5, which can be readilyconverted to trans-fused systems bearing iso-DA patterns (Fig. 1,Eq. 2, 5→6) (3). Additionally, we have described the synthesisand DA cycloaddition of an even more powerful dienophile, 2-bromocyclobutenone (Fig. 1, Eq. 3, 7) (4). The direct adducts ofthis [4+2] reaction (compare 8) are readily converted to nor-carane carboxylic acids (9) through exposure to hydroxide base.The research described herein was initially focused on efforts toadd carbon-based nucleophiles to DA cycloadducts of the type 8.It might well have been expected that such reactions would giverise to products such as 10, wherein a ketone is appended to thejunction of the norcarane system (Fig. 1, Eq. 4).

Results and DiscussionWith a view toward accomplishing the transformation envisionedin Fig. 1, Eq. 4, compounds of the type 8 were exposed tomethyllithium as described in Fig. 2. Interestingly, exposure ofsubstrate 8a to the conditions shown led to an 81% yield of theangularly methylated product 11a, apparently unaccompanied byany part of the corresponding trans-fused diastereomer (Fig. 2,entry 1). Reactions conducted with related DA adducts 8b and8c resulted in quite similar outcomes (Fig. 2, entries 2 and 3).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 nonidentitywith 11a that served to allow for sound assignment of the cis-ring 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 followedby angular methylation (9–11) of 12a. It would not be surprisingfor such a reaction to have a very high preference for producingcis fusion. Clearly, a great deal of ring strain would be introducedin any transition state en route to trans-fused products.Whereas the enolate alkylation proposal is presumptive, sev-

eral alternate formulations merited consideration. In principle,one can envision the possibility that lithium enolate 12a is notactually produced (perhaps due to ring strain). Rather, 11 (Fig.3) arises from the merger of otherwise high-energy speciesen route to 12a and 12b. For instance, “radicaloid” (5) charac-ter could be generated at both the bridgehead (12b) andmethyl carbon centers. Coupling of these species, before their

disaggregation, would accomplish the observed overall angularmethylation, culminating in 11. Exclusive formation of a cis-ringfusion would again be expected, in terms of a solvent-cage−induced “memory effect,” as well as of the ring strain associatedwith the transition state leading to a trans junction (for reviews onthe concept of “chiral memory,” see refs. 12 and 13). Here, wepresent only the limiting possibility, i.e., coupling of “enolyl” and“methyl” free radicals. The important distinction betweenpathways i and ii in Fig. 3 is that the former corresponds toa classic enolate methylation. By contrast, in pathway ii thecoupling event occurs somewhere en route to metal–halogenexchange.Because the cis-specific outcome of the reaction did not serve

to answer the mechanistic question, a more illuminating probewould be required. The thought was that, if the reaction wereoccurring through path i, with the alkylating agent correspondingto methyl bromide, then one could anticipate potential compe-tition between the MeBr generated through metal–halogen ex-change and incident MeBr in solution. By contrast, path iidictates that the angular methyl group in 11 must arise only fromthe original methyllithium. To probe this distinction in practice,it would be necessary to fashion an experiment that would allowus to discern between the methyl group of solution-based methylbromide and other species capable of methyl transfer that ariseduring progression of the metal–halogen exchange.As shown in Fig. 4, Eq. 5, reaction of 8a with CD3Li was

conducted for 15 min at –78 °C. Following this, CH3Br was addedto the reaction mixture. Deuterated compound 13 was obtainedin 64% yield, along with 16% of 11a. For control purposes, theexperiment was also conducted in the opposite sequence, whereinCH3Li was used in the metal–halogen exchange, and CD3Br wassubsequently added to the reaction mixture (Fig. 4, Eq. 6). In thismode, 11a was obtained in 59% yield, along with a 14% yield of13. These observations suggest substantial angular methylation in

Significance

The development of strategies in organic synthesis is an im-portant challenge, from the perspective of creative design aswell as application to the pharmaceutical industry. In this pa-per, we study a promising new solution to a classical problemin organic synthesis: namely, the control of ring junction ste-reochemistry in a particularly challenging setting, wherein oneof the rings composing the junction is four membered. Thissystem was selected because it poses a particularly difficultchallenge for the synthesis of trans-fused junctions. We believethat the solution to the problem described herein will havebroad applications in organic synthesis.

Author contributions: S.D.T., A.G.R., and S.J.D. designed research; S.D.T. and K.L. per-formed research; S.D.T., K.L., and S.J.D. analyzed data; and S.D.T. and S.J.D. wrotethe paper.

The authors declare no conflict of interest.1To whom correspondence should be addressed. E-mail: s-danishefsky@ski.mskcc.org.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1407613111/-/DCSupplemental.

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the initial 15-min interval. However, because the reaction was notcomplete after 15 min, the remaining methyl bromide (CD3Br orCH3Br) was forced to compete with the newly introduced alky-lating agent (CH3Br or CD3Br) in a 1:1 ratio.Whereas these experiments are certainly consistent with eno-

late formation followed by conventional alkylation, they did notfully document the source of the angular methyl group beforeintroduction of the external methylating agent (CD3Br orCH3Br). In a more discriminating experiment, CD3Li was addedto a solution already containing an equivalent of both CH3Br and8a (Fig. 4, Eq. 7). This reaction gave rise to 25% of recovered 8aas well as ca. 20% each of 11a and 13. (The somewhat reduced

yield of angular methylation in this experiment presumablyreflects some degree of competitive reaction between methyl-lithium and methyl bromide.) Thus, at least under these con-ditions, incident CH3Br is fully competitive with methylatingagent generated in the metal–halogen exchange. This experimentalso serves to rule out any “cage effect” between methyl bromidegenerated in the immediate sphere of the enolate and solution-based methyl bromide. We emphasize that the combined resultsof these studies rule out the intermediacy of species 12b, insofaras it implies a special affinity to join the bromine-bearingbridgehead carbon to the methyl group in the original methyl-lithium species. Also excluded are possibilities arising from ini-tial “nucleophilic methylation” of the ketone followed byformation of a highly strained epoxide, culminating in suprafacialmigration of the methyl group to provide overall stereochemicalretention (Fig. 4, hypothetical path iii, Eq. 8). The results shownin Fig. 4, Eqs. 5–7 clearly exclude path iii because, in the lattermode the methyl group of solution-based “methyl X” would notappear in the product. Finally, one additional control experimentwas conducted, wherein cyclohexanone was subjected to reactionwith CD3Li, in the presence of CH3I. We observed generation ofethane and addition of CD3 to the ketone. Importantly, no ex-change event between CH3I and CD3Li and subsequent attackwith CH3Li were observed.It will be recognized that the chemistry disclosed thus

far corresponds to what would be possible directly from in-termolecular DA cycloaddition to the unknown 2-methyl-cyclobutenone. Next, we wondered whether 8 could serve asa precursor to a trans-fused bicyclic [4.2.0] system. Becausea compound of the type 8 can be viewed as a bifunctional elec-trophile, it was of interest to explore its chemistry upon reaction

Fig. 1. Expanding the scope of the Diels–Alder reaction.

Fig. 2. Reaction of DA adducts with methyllithium.

Fig. 3. Mechanistic proposals.

Fig. 4. Mechanistic evaluation of methylation.

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with a dianion (14). In our inaugural experiment, we studied thereaction of 8a with the previously established geminal dianion14, derived from bis-deprotonation of phenyl methyl sulfone (forthe 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(Fig. 5). At this stage, the stereochemistry of the junction couldnot be assigned with confidence. Reductive cleavage of thephenylsulfonyl moiety was accomplished through reaction withRaney Ni in ethanol. Interestingly, the resultant angular methylcompound, although broadly similar to 8a, was different in de-tail. Given our confidence in the assignment of 11a as bearinga cis junction, it was surmised that both the initial angular phe-nylsulfonylmethyl compound generated from the dianion chem-istry and its reductively derived angular methyl product shouldbe formulated as trans-fused systems 15a and 16a, respectively.To verify the junction configuration, the known hydrindenone

17 (23, 24) was converted to diazoketone 19, through a seldom-used Forster reaction (25, 26) of intermediate α-oximinoketone18 (Fig. 6). Ring contraction of 19 via Wolff rearrangement (27)provided ester 20 and, thence, acid 21. The latter, upon Barton–McCombie-inspired homolytically induced decarboxylation (28),afforded 22. This compound was also obtained, albeit in only27% yield, by subjecting our compound 16a to microwave Wolff–Kischner conditions (29).Similarly, adducts 8b and 8c were converted to their trans-

fused angularly functionalized counterparts, 15b and 15c (Fig. 7).This overall transformation formally corresponds to what couldbe accomplished from suprafacial DA cycloaddition to trans-2-methylcyclobutenone or by an antarafacial DA cycloaddition tocis-2-methylcyclobutenone (vide supra). We note that it is ourexperience that in DA cycloadditions, α-halocyclenones are farmore effective dienophiles than are their α-H or α-Me coun-terparts. This improvement in dienophilicity is still another ad-vantage of this chemistry.The mechanism by which 8 is converted to 15 cannot be

asserted in detail. At first glance, this reaction could be viewed asa direct SN2 displacement of the angular bromide, althoughthis is mechanistically unlikely (8). Another more precedent-supported possibility envisions 1,2-addition of 14 to the ketogroup of 8. The path from phenylsulfonyl-stabilized anion 23a to 16,which corresponds overall to a 1,2 migration of a carbanion,

could be viewed from the perspective of a 1,2 migration of the σbond (Fig. 8, path i). Alternatively, one could also envisionformation of a high-energy cyclopropane by intramolecular al-kylation, (compare 23b) followed by ring opening of the edgecyclopropane bond to 16 (Fig. 8, path ii) (30–32). Althoughpathways i and ii are distinct, discerning between them would bea complex matter and we presently have no distinguishing ex-perimental evidence that speaks to these lines of conjecture. Wenote that by either mechanism, the immediate preworkup spe-cies should correspond to anion 24. Indeed, when the reactionconducted between 8 and 14 was worked up with D2O, thedeuterated sulfone 25 (as a mixture of H,D stereoisomers) wasobtained. We note, parenthetically, that this latent anion wasalso successfully reacted with methyl iodide, although, in thatcase, the desired compound was not separable from 15a, whichwas generated during the workup.We note that these previous mechanistic proposals centered

on pathways involving nucleophilic addition to the stericallyhindered concave face of the molecule. We acknowledge that analternative mechanistic pathway could also explain the observedstereoselectivity. In this case, lithium–halogen exchange by thesulfone dianion could, in theory, generate enolate 12a anda bromosulfone anion. After α elimination, generation of a car-bene and addition of this species across the double bond of 12awould give rise to intermediate 23b. The delineation of theprecise pathway to the trans junction is the subject of currentcomputational analysis.By combining the high-quality dienophilicity of 7 (4) with the

capacity to generate bicyclo[4.2.0]octane ring junctions fromangularly brominated cis-DA products, we have entered into theelusive structural space of trans-fused cyclobutanones. We won-dered whether these findings could be extended to generate16-norsteroids bearing four-membered D rings. Although suchsystems are known, they were previously obtained by ring con-traction of standard steroids (33–37).

Fig. 5. Dianion addition to DA adduct 8a.

Fig. 6. Verification of trans fusion.

Fig. 7. Dianion addition to DA adducts 8b and 8c.

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We first selected a target whose structure, were it to be syn-thesized, could be assigned with great confidence. As seen inFig. 9, DA cycloaddition between 7 and Dane’s diene (26) (38–40)gave rise to 28. Clearly, 28 resulted from double-bond isomeri-zation of the primary DA product 27. This type of acid-inducedisomerization is well precedented in earlier Dane’s-diene–basedroutes to steroids (39–43). It should be noted that when con-ducted thermally, DA reactions of cyclenones with 26 are notsignificantly regioselective (44, 45). Thus, one would haveexpected, by precedent, that the thermally driven DA reaction of7 with Dane’s diene would have also produced 29 as a seriouslycompeting primary product. The absence of detected 29 againpoints to the special character of the dienophile. Thus, 7 under-goes DA cycloaddition with a level of regioselection that has onlypreviously been observed under Lewis acid catalysis (46).

Reaction of 28 with dianion 14 provided the angular phenyl-sufonylmethyl compound 30 in 80% yield. Reduction of the 8,9-double bond led to the dihydro product 31. Next, reductiveclevage of the sulfone was accomplished to provide the angularmethyl product 32. This assignment can be offered with completeconfidence because the chromatographic and spectral propertiesof rac-32 are identical to those of the enantiomerically homo-geneous adduct produced from the known ring contraction ofestrone methyl ether 33 (22).Ordinarily, binding of steroids to estrogen receptors requires

a free phenolic hydroxyl in the A ring (47). However, attemptsto cleave the methyl ether function of rac-32 to produce the16-norestrone were not successful, no doubt reflecting thelability of the trans-fused cyclobutanone substructure to the con-ditions used. In the end, it proved more straightforward to

Fig. 8. Mechanistic proposals.

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

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

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synthesize the triisopropyl silyl-protected version of Dane’sdiene, i.e., 34 (Fig. 10) (synthesis details in SI Appendix). Thelatter was moved through the same sequence as was 26, leadingeventually to 37. Deprotection of the A-ring phenol and re-ductive cleavage of the carbon–sulfur bond led to rac-D16-nor-estrone (39) (48).

ConclusionIt has been shown that a variety of sequences, initiated by DAreactions of various conjugated dienes with 2-bromocyclobute-none, set the stage for stereospecific angular functionalization ofthe resultant cycloadducts. Through a remarkably straightforward

experimental sequence of lithium–halogen exchange and angularmethylation, access to the cis-fused series is gained. By contrast,reaction of the cis-fused bromocycloadducts with the presumeddilithiomethylphenyl sulfone leads to the trans-fused angularlysubstituted bicyclo[4.2.0]octane systems.

ACKNOWLEDGMENTS. The authors thank Dr. George Sukenick, Hui Fang,and Sylvi Rusli of Sloan-Kettering Institute’s NMR core facility for spectro-scopic assistance and Dr. Suwei Dong and Adam Levinson for helpful discus-sions. This work was supported by National Institutes of Health GrantHL25848 (to S.J.D.). S.D.T. is grateful to Weill Cornell Medical College fora National Cancer Institute postdoctoral fellowship (CA062948). A.G.R.acknowledges the National Science Foundation for a predoctoral fellowship.

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