A Photorearrangement To Construct the ABDE Tetracyclic Core of

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

A Photorearrangement To Construct the ABDE Tetracyclic Core of Palau’amine Samuel Aubert-Nicol, Jean Lessard, and Claude Spino* Département de Chimie, Université de Sherbrooke, 2500 Boul. Université, Sherbrooke, Québec, Canada, J1K 2R1 S Supporting Information *

ABSTRACT: A synthesis of the ABDE tetracyclic carbon core of palau’amine was achieved in 9 steps from commercial materials. The core’s most notable feature, a highly strained trans cyclopenta[c]pyrrolidine, was obtained in high yield using a ring contraction strategy starting from a much less strained trans bicyclic lactam derivative that is accessible in only 7 steps.

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analysis,5−7 computational methods,8,9 and chemical synthesis.10 This revision added a new challenge in approaching the core structure, since the revised trans-bicyclo[3.3.0]octane contains approximately 27 kJ/mol more strain energy than its cis counterpart.9,11,12 It also makes palau’amine stand out as one of the very few known natural products containing such a feature, structures 7−10 being examples (Figure 1).13−16 Furthermore, to our knowledge, the only natural products bearing a transazabicyclo[3.3.0]octane core are palau’amine and its closely related congeners, for example, styloguanidine (4) and their respective bromo (2, 5) and dibromo (3, 6) derivatives. Understandably, the reassignment of the junction’s geometry foiled many ongoing total syntheses in various research groups.17 On the other hand, synthetic strategies directed toward the biosynthetically related axinellamines (11−14) and massadines (15−16, Figure 2) became adaptable to generate a common precursor on the way to palau’amine. This allowed the

ince its isolation in 1993 from the marine sponge Stylotella Agminata by the group of Scheuer,1 palau’amine (1, Figure 1) has garnered much attention from the chemical community.

Figure 1. A few examples of strained natural products containing a 5,5trans ring junction.

From a medicinal standpoint, palau’amine exhibits potent biological activity, mainly as an immunosuppressant and cytotoxic agent.1−3 From a synthetic perspective, palau’amine’s unique and densely functionalized core is an interesting challenge and ground for the development of innovative synthetic methodologies and strategies.4 Among the difficulties included in this core, and one of its most unique features, is the junction of the two five-membered D and E rings: originally assigned as cis, the ring junction was later revised as trans by the efforts of independent groups using a combination of NMR © XXXX American Chemical Society

Figure 2. Natural products biosynthetically related to palau’amine. Received: March 13, 2018

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DOI: 10.1021/acs.orglett.8b00819 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Baran group to complete the first total synthesis of the racemic,18 and subsequently nonracemic,19 alkaloid. To address the challenge of the trans-cyclopenta[c]pyrrolidine, they first generated a “macro-palau’amine” 17 precursor and used a transannular cyclization to obtain the trans ring-junction (Scheme 1a). The macrocyclic template kept both

Scheme 2. Strategies toward the trans Azabicyclo[3.3.0]octane Core of Palau’amine by the Groups of (a) Romo and (b, c) Feldman

Scheme 1. Strategies toward the trans Azabicyclo[3.3.0]octane Core of Palau’amine by the Groups of (a) Baran and (b) Namba and Tanino

Scheme 3. Unexpected trans-Azabicyclo[3.3.0]octane Core atoms involved in the cyclization in close proximity, which was a key factor in overcoming the increase in strain during the ring-closing event. This strategy might be biosynthetically inspired, as a similar ring closing event was suggested for the biosynthesis of a related alkaloid.20 The second of the only two completed syntheses of palau’amine reported so far was published by the groups of Namba and Tanino, and also used a transannular cyclization strategy to access the trans-azabicyclo[3.3.0]octane moiety. The authors report calculations and experimental studies which indicate that the macrocyclic template 18 was held together by the coordination of a lithium cation by an amide anion and an ester carbonyl group (Scheme 1b).3 Three other approaches to palau’amine were successful in yielding the azabicyclo[3.3.0]octane core. Opening a cis-fused lactam to the sulfonamide-alcohol 20 in 5 steps, the group of Romo used an SN2 displacement of an activated alcohol by a sulfonamide under Mitsunobu conditions to give a high yield of the desired trans-cyclopenta[c]pyrrolidine structure 21 (Scheme 2a).21 The other two approaches were reported by the Feldman group and gave low to modest yields of the transcyclopenta[c]pyrrolidines 23 and 25 (Scheme 2b and c).22 We have developed a strategy employing a photochemical rearrangement of a N-mesyloxylactam to generate the strained trans-cyclopenta[c]pyrrolidine in high yield. The rearrangement is related to the more familiar Lossen rearrangement, but is unique in its mechanism and scope.23 We had previously demonstrated our rearrangement’s potential to generate a transcyclopenta[b]pyrrolidine (Scheme 3).24 The yield of 29 was only 16%, but this product was totally unexpected, and we knew that it could be improved. Herein, we report an efficient

synthesis of the ABDE tetracyclic carbon framework of palau’amine using this strategy. To obtain the requisite trans-fused bicyclic hydroxamic acid precursor for our key rearrangement, we devised the synthesis described in Scheme 4, starting by the conversion of cyclohexene to adipaldehyde by ozonolysis. Reacting adipaldehyde with methyl cyanoacetate under secondary amine catalysis allowed us to obtain aldehyde 33 as a mixture of two equilibrating epimers at the acidic α-cyanoester center. The substituents on the five-membered ring were in a trans relationship. Due to the initially very low yields obtained for this reaction, many different conditions were tested with varying factors, including the amine catalysts, solvents, and reaction temperature. The most impactful factor was the nature of the secondary amine catalyst. Proline showed an almost 3fold increase in yield over any other amine tested. Although the yield remained modest, we decided against optimizing further B


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Organic Letters Scheme 4. Synthesis of the Precursor for the Key Photochemical Rearrangement

at this stage, since synthesis of the actual palau’amine would certainly need a different starting material. The rest of the synthesis proceeded smoothly. First, the condensation of benzylhydroxylamine afforded oxime 34 as a mixture of four isomers. Flash chromatography of the mixture allowed separation of the two geometric isomers about the oxime double bond, and each fraction consisted of a mixture of the two epimers at the α-cyanoester position. Upon standing, both fractions converted back to a mixture of the four initial isomers. The equilibrating fractions were combined and used together in a one-pot reduction/cyclization sequence to afford the protected hydroxamic acid 35 as a mixture of two stereoisomers. Cobalt-catalyzed chemoselective reduction of the nitrile and treatment with Boc2O afforded the protected primary amines 36a and 36b, which were at this point separable by flash chromatography. They were obtained in a 3:1 ratio in favor of the desired diastereomer. The assignment of the diastereomers was established by NMR analysis and later confirmed by the XRD spectrum of the minor diastereomer (see Supporting Information (SI)). Again, optimization of this ratio was unnecessary for the model study. Finally, deprotection and activation of the cyclic hydroxamic acid allowed us to obtain the desired precursor 37a to test our key rearrangement step. To our delight, treatment of precursor 37a in the photolysis conditions previously developed in our laboratory gave two compounds, 38a and 39a, both containing the desired substituted trans-azabicyclo[3.3.0]octane core. They were obtained in high yield with no optimization required (Scheme 5). The yield of 83% is remarkable, given the introduction of such severe strain in the structure: the difference in strain energy between trans-bicyclo[4.3.0]nonane and trans bicyclo[3.3.0]octane amounts to 44 kJ/mol.11,12 The developing strain actually does not seem to influence the yield of the product at all, as it is comparable or even superior to other rearrangements performed on unstrained substrates. It even compares favorably to some substrates with fully substituted (quaternary) migrating centers, which usually rearrange in higher yields than their lesser substituted analogs.23,24 N-Mesyloxylactam 37b, obtained from the minor diastereomer 36b, rearranged with equal ease

Scheme 5. Result of the Key Photochemical Rearrangement

to give a similar mixture of 38b and 39b in comparable yield (81%). Both isolated products 38a and 39a arise from the desired photochemical rearrangement. The first is the carbamate 38a, which is formed by the trapping of the intermediate acylium ion by methanol used as solvent: this is the trapping product that is usually observed. The second product is the urea 39a, which is generated from the intramolecular trapping of the intermediate by the Boc protected amine. The rearrangement was run in triplicate, and each time, the yield and the ratio of carbamate to urea differed only slightly, ranging from 81% to 84%, and from 48:52 to 57:43, respectively. We were also able to isolate urea 39a as the sole reaction product when the reaction was run in dichloromethane instead of methanol. In this case, however, the overall yield of the reaction was slightly lower (76%). Importantly, the ratio of these two products is inconsequential to the rest of the synthesis: both rearrangement products could be combined and used to complete the ABDE core of palau’amine. From the mixture of compounds 38a and 39a, the target molecule was obtained by a one-pot sequence of four reactions, as described in Scheme 6. First, treatment of the combined rearrangement products with aqueous acid allowed the rapid cleavage of the Boc protecting group. Then, hydrolysis of both C


Organic Letters

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Scheme 6. Completion of the ABDE Core of Palau’amine

Letter

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00819. Experimental procedures and copies of proton and carbon NMRs for all compounds (PDF) Accession Codes

CCDC 1829434−1829435 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Claude Spino: 0000-0001-6249-5908

the carbamate and urea moieties was performed by heating the mixture in a sealed tube, converting both substrates to the same diammonium intermediate 41. We next cooled down the reaction mixture to 75 °C, neutralized it with aqueous sodium hydroxide, and added compound 40, which allowed us to perform a Paal−Knorr synthesis of the requisite pyrrole. Finally, basification of the reaction medium and stirring at room temperature overnight yielded the desired ABDE core of palau’amine 43. The whole operation proceeded in 37% yield for the four chemical transformations in a single pot, averaging a yield of 78% per transformation. The single crystal XRD data from 43 confirmed its relative stereochemistry (Figure 3).

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the Natural Sciences and Engineering Council of Canada, through a Discovery Grant to C.S. and a postgraduate scholarship to S.A.N., as well as by the Université de Sherbrooke.

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REFERENCES

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Figure 3. XRD structure of 43.

In conclusion, we have demonstrated the power of the photochemical rearrangement of N-mesyloxylactams by preparing a highly strained trans-azabicyclo[3.3.0]octane in high yield. We also used the product from this rearrangement to complete the synthesis of the ABDE core of palau’amine in 9 steps. We believe that the C-ring guanidine of palau’amine could eventually be installed using a strategy similar to the one used by the Romo group in the total synthesis of phakellin with only a slight diversion from the pathway described herein.25 We are presently constructing a nonracemic and suitably functionalized E ring to reach palau’amine. Although the synthesis of such an intermediate is not trivial, we are hopeful that the key rearrangement will function as expected and believe that this strategy could realistically be amenable to an efficient total synthesis of the palau’amines and styloguanidines alkaloids. D


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(23) Drouin, A.; Winter, D. K.; Pichette, S.; Aubert-Nicol, S.; Lessard, J.; Spino, C. Photochemical Rearrangement of N-Mesyloxylactams: Stereospecific Formation of N-Heterocycles. J. Org. Chem. 2011, 76, 164−169. (24) Pichette, S.; Aubert-Nicol, S.; Lessard, J.; Spino, C. Regioselective Photochemical Rearrangement of N-Mesyloxylactams. Eur. J. Org. Chem. 2012, 2012, 1328−1335. (25) Wang, S.; Romo, D. Enantioselective Synthesis of (+)-Monobromophakellin and (+)-Phakellin: A Concise Phakellin Annulation Strategy Applicable to Palau’amine. Angew. Chem., Int. Ed. 2008, 47, 1284−1286.

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A Photorearrangement To Construct the ABDE Tetracyclic Core of

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