Letter pubs.acs.org/OrgLett
Double-Diels−Alder Approach to Maoecrystal V. Unexpected C−C Bond-Forming Fragmentations of the [2.2.2]-Bicyclic Core Brandon R. Smith and Jon T. Njardarson* Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States S Supporting Information *
ABSTRACT: Synthetic studies toward maoecrystal V are reported. An oxidative dearomatization/Diels−Alder cascade to assemble the natural product carbocyclic core in one step is proposed. A facile electrocyclization is shown to suppress the intramolecular allene Diels−Alder pathway. This obstacle is alleviated via a stepwise approach with an allene equivalent to access the key cyclopentadiene-fused [2.2.2]-bicyclic core. Upon treatment with Lewis acid, the proposed intramolecular heteroDiels−Alder reaction is cleanly and unexpectedly diverted either via C−C bond-forming fragmentation to the spiro-indene product (when R = OMe) or via elimination (when R = H).
M
aoecrystal V’s1 unique rigid diterpenoid architecture and originally reported anticancer activity has attracted great attention from the synthetic community. Thirteen years since its isolation, five research groups have masterfully managed a complete total synthesis of maoecrystal V (Figure 1).2 Not
Scheme 1. Dearomatization/Diels−Alder Cascade
cyclization would be expected to yield a bicyclooctane core (3) containing a reactive cyclopentadiene moiety that could then engage an aldehyde in an intramolecular hetero-Diels−Alder reaction. This proposed one-pot dearomatization/Diels−Alder cascade would very efficiently assemble the molecule’s four contiguous stereogenic centers with minimal unwanted redox chemistry or protection/deprotection steps. Dearomatization precursor 5 would be built in a few steps from readily available building blocks 6−8. To probe the feasibility of the oxidative dearomatization/ intramolecular allene Diels−Alder reaction, a model system was investigated (Scheme 2). Stille coupling5 of vinyl iodide 10 and stannane 9, which was synthesized from guaiacol (8) in two steps, delivered 11 in good yield. Following oxidation, several methods were explored for transforming aldehyde 12 into allene 14. Petasis titanium carbene method6 resulted in low allene yields and competing olefin isomerization, which is why ultimately a two-step instillation was implemented. Toward that end, 12 was first converted to a mixture of propargyl alcohols7 which was treated with Schwartz reagent8 to deliver the desired allene 13. The allene was promptly desilylated with TBAF to
Figure 1. Maoecrystal V total synthesis summary.
surprisingly, the use of Diels−Alder chemistry to construct the [2.2.2]-bicyclic core of the molecule has been a common theme, with four of the five successful total syntheses featuring this as a key step. Numerous other research groups have communicated their creative efforts toward maoecrystal V over the years.3 While the originally reported anticancer prowess has since been demonstrated to be incorrect,2g the molecules’ majesty remains for many who have pursued it. Our maoecrystal V retrosynthesis (Scheme 1) was inspired by our group’s theme of leveraging oxidative dearomatization to rapidly assemble complex structures from simple, achiral phenolic precursors.4 We envisioned a cascade whereby the entire carbon skeleton of maoecrystal V (2) could be constructed in a single reaction. Oxidative dearomatization of an appropriately decorated allene (5) followed by Diels−Alder © 2017 American Chemical Society
Received: August 22, 2017 Published: September 14, 2017 5316
DOI: 10.1021/acs.orglett.7b02606 Org. Lett. 2017, 19, 5316−5319
Letter
Organic Letters
cyclopentadiene 22, which is a model of the desired oxidation state for this position toward maoecrystal V.9,10 Enone 20b was also subjected to hydrogenation in the presence of palladium on barium sulfate, which demonstrated that the strained olefin could be selectively reduced (21). With syntheses of model systems 19 and 22 established, we set out to synthesize constructs suitable for advancement to 1 (Scheme 4). Toward that end, alkyne 7 was converted to allylic
Scheme 2. Intramolecular Allene Diels−Alder Model Studies: Unexpected Electrocyclization
Scheme 4. First Approach toward the All-Carbon Cyclopentadiene-Fused Hetero-Diels−Alder Substrate
afford 14 and set the stage for investigating the key dearomatization/Diels−Alder. To our surprise, treatment of 14 with PIDA in methanol yielded two cyclized products (15 and 16) which likely originate from 6π-electrocyclization of the highly reactive ortho-quinone ketal intermediate. To navigate around the competing allene electrocyclization pathway, we chose to move forward with an allene equivalent. This was accomplished by converting aldehyde 12 into an allylic alcohol (17, Scheme 3). We were pleased to discover that Scheme 3. Synthesis of Cyclopentadiene Fused [2.2.2]Bicycle
alcohol 23,11 then nosylated and subjected to SN2 displacement12 by alkyne 24. Vinyl iodide 25 was obtained following reductive acetate removal. Stille coupling with 9 afforded alcohol 26, which was converted in two steps to dearomatization precursor 27. Dearomatization successfully delivered 28 as a mixture of alcohols, which after oxidation yielded enones 29a−b. Crystal structure allowed unambiguous structure confirmation of enone 29b. Although we were able to reduce the [2.2.2]-bicyclo olefin we were unable to convert the alkyne of 28, 29a,b, or resulting derivatives into the desired Z-olefin. Furthermore, attempts at synthesizing fused cyclopentadienes such as 31 were complicated by undesired enolization pathways (30) being preferred. Our struggles in reducing the alkyne to the desired Z-olefin led us to explore alternative approaches to this transformation. Eventually, we were led to work by Isobe13 whereby a biscobalt−alkyne complex is reductively cleaved in the presence of a hydride source to yield a Z-olefin. After evaluating the reduction of alkynes 25−29 it was determined that reduction of 26 to afford 32 gave the best yield with no unwanted doublebond isomerization (Scheme 5). The Isobe reduction protocol
dearomatization of 17 afforded a mixture of Diels−Alder cycloaddition products 18 in excellent yield. This mixture was readily dehydrated to desired cyclopentadiene 19 using Burgess’ reagent. Based on this reactivity and the yield, we could confidently conclude that two of the three alcohol diastereomers, including the major, had a syn-relationship with the adjacent methine hydrogen atom. We next set out to synthesize cyclopentadiene 22. Oxidation of 18 afforded a separable mixture of enones 20a and 20b. Gratifyingly, the structure of 20a could be elucidated by X-ray crystallography. The crystal structure revealed that the methine hydrogen next to the ketone was positioned exo, which meant that the same hydrogen atom in major isomer 20b was endo. Treatment of enone 20b with TBSOTf and 2,6-lutidine transformed it to 5317
DOI: 10.1021/acs.orglett.7b02606 Org. Lett. 2017, 19, 5316−5319
Letter
Organic Letters Scheme 5. Successful Synthesis of the All-Carbon Cyclopentadiene Fused Hetero-Diels−Alder Substrate
Scheme 6. Unexpected Fragmentations
can also be performed as a one-pot procedure, affording 32 in 54% yield. With the Z-olefin safely in hand we oxidized allylic alcohol 32 with Dess−Martin periodinane, treated the resulting aldehyde with vinylmagensium bromide, and selectively removed the aryl silyl ether. Dearomatization/Diels−Alder of phenol 33 proceeded in good yield, affording two alcohol diastereomers (34) in a 10:3 ratio. To our delight, 34 underwent Burgess dehydration in excellent yield to afford cyclopentadiene 35, thus bringing us tantalizingly close to investigating the proposed hetero-Diels−Alder reaction toward installation of maoecrystal V’s strained tetrahydrofuran ring. Removal of the alkyl silyl ether was accomplished with tetrabutylammonium fluoride, which was immediately followed by oxidation to yield target cyclopentadiene aldehyde 3 in 74% yield over two steps. With 3 in hand, we began to investigate reaction conditions needed to engage the aldehyde and cyclopentadiene groups in an intramolecular hetero-Diels−Alder reaction (Scheme 6). Gentle heating of 3 in toluene revealed a clean reaction taking place at 95 °C. Characterization revealed that instead of desired cycloadduct 2 being formed an unexpected [3.2.1]-bicyclic product 38 was afforded in high yield. We postulate that, upon heating, one of the bicyclic bonds breaks to reveal either a cyclopentadiene anion (36) or cation (37), which is then immediately captured intramolecularly with either an oxocarbenium ion or enolate, respectively. This new fragmentation pathway provides novel synthetic entry into gibberellin-type natural product architectures. Interestingly, when aldehyde 3 was subjected to a Lewis acid (Sc(OTf)3 or BF3·OEt2), neither 2 or 38 was formed, but instead spiro-indene 41 was formed in high yield as a single diastereomer. This surprising result strongly suggests that one key part of the proposed heterDiels−Alder reaction did indeed take place via a Prins cyclization to form the cyclohexene ring, albeit as the undesired quaternary spiro-stereocenter (40). The intermediate allylic cation was unfortunately not trapped intramolecularly in a 5endo fashion by the newly formed alcohol to form 2, but instead a fragmentation of the [2.2.2]-bicyclic ring system took place. We postulate that this facile intramolecular termination of the Prins reaction is driven by the dimethyl acetal resulting in an oxocarbenium ion, which ends up as an α-keto ester group. Seeking to probe the mechanism of these unexpected [2.2.2]bicyclic fragmentations and to also access the all quaternary spiro-stereocenter while maintaining the [2.2.2]-bicyclic ring system, we set out to remove the dimethyl acetal moiety (Scheme 7). Alcohol 34 was deketalized using samarium diiodide, and then the alcohol mixture subjected to Burgess’s
Scheme 7. Synthesis of Quaternary Spirocenter
reagent to yield cyclopentadiene 42. Attempts to directly deketalize 35 resulted in skeletal fragmentation to the [3.2.1] system along with removal of the dimethyl acetal. The silyl ether of 42 was cleaved with TBAF followed by Dess−Martin oxidation to deliver aldehyde 43. Thermal studies on 43 revealed no reaction after heating at 110 °C for 72 h, supporting our theory for skeletal fragmentation enabled by electron donation from the dimethyl acetal. We were pleased to find that treatment of 43 with Lewis acid resulted in clean consumption of the aldehyde but again found that the stepwise hetero-Diels−Alder reaction was intercepted, this time resulting in elimination (44) rather than tetrahydrofuran formation. However, we were successful in forming the cyclohexene ring while maintaining the [2.2.2]-bicycle, albeit in the wrong stereochemistry for advancement to (1). We are confident that manipulation of Lewis acid and reaction conditions could deliver the desired sterochemical arrangement. In summary, we have implemented a double Diels−Alder approach to maoecrystal V (1). Dearomatization/Diels−Alder of appropriately substituted allylic alcohols allows for construction of the [2.2.2]-bicyclic core of 1. Our proposed hetero-Diels−Alder reaction was unexpectedly intercepted by either fragmentation (38 and 41) or elimination (44) pathways. Despite this, our success in forming spirocycle 44 provides valuable clues into the hetero-Diels−Alder and offers hope that 5318
DOI: 10.1021/acs.orglett.7b02606 Org. Lett. 2017, 19, 5316−5319
Letter
Organic Letters
(6) Petasis, N. A.; Hu, Y.-H. J. Org. Chem. 1997, 62, 782. (7) A 3:1 mixture of constitutional isomers was formed, with the minor component resulting from silyl hopping to the alcohol position. This mixture was inseparable but inconsequential as only the free alcohol reacted with Schwartz reagent. (8) Pu, X.; Ready, J. M. J. Am. Chem. Soc. 2008, 130, 10874. (9) Chisholm and co-workers (ref 3l) tested a hetero-Diels−Alder approach to maoecrystal V on a system lacking functionality on the bicycle and with a dithiane-containing carbon tether and failed to observe the desired reactivity. (10) Subjecting 20a to identical enolization conditions delivered a 1:1 mixture of 22 and exocyclic silyl enol ether. See the Supporting Information for more details. (11) Taber, D. F.; Sikkander, M. I.; Berry, J. F.; Frankowski, K. J. J. Org. Chem. 2008, 73, 1605. (12) Taber, D. F.; Gu, P.; Li, R. J. Org. Chem. 2009, 74, 5516. (13) (a) Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609. (b) Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2004, 43, 2020. (c) Goto, T.; Urabe, D.; Masuda, K.; Isobe, Y.; Arita, M.; Inoue, M. J. Org. Chem. 2015, 80, 7713.
further exploration of reaction conditions may allow access to maoecrystal V (1).
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02606. Experimental procedures as well as spectral and X-ray crystallography data (PDF) Crystallographic data for 20a (CCDC 1552225) (CIF) Crystallographic data for 29b (CCDC 1552226) (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Brandon R. Smith: 0000-0001-7051-5059 Jon T. Njardarson: 0000-0003-2268-1479 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support was provided by The University of Arizona. REFERENCES
(1) Li, S.-H.; Wang, J.; Niu, X.-M.; Shen, Y.-H.; Zhang, H.-J.; Sun, H.D.; Li, M. L.; Tian, Q.-E.; Lu, Y.; Cao, P.; Zheng, Q.-T. Org. Lett. 2004, 6, 4327. (2) (a) Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J. Am. Chem. Soc. 2010, 132, 16745. (b) Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860. (c) Lu, P.; Gu, Z.; Zakarian, A. J. Am. Chem. Soc. 2013, 135, 14552. (d) Lu, P.; Mailyan, A.; Gu, Z.; Guptill, D. M.; Wang, H.; Davies, H. M. L.; Zakarian, A. J. Am. Chem. Soc. 2014, 136, 17738. (e) Zheng, C.; Dubovyk, I.; Lazarski, K. E.; Thomson, R. J. J. Am. Chem. Soc. 2014, 136, 17750. (f) Zhang, W.-B.; Shao, W.-B.; Li, F.-Z.; Gong, J.-X.; Yang, Z. Chem. - Asian J. 2015, 10, 1874. (g) Cernijenko, A.; Risgaard, R.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 9425. (3) (a) Gong, J.; Lin, G.; Li, C.; Yang, Z. Org. Lett. 2009, 11, 4770. (b) Krawczuk, P. J.; Schone, N.; Baran, P. S. Org. Lett. 2009, 11, 4774. (c) Nicolaou, K. C.; Dong, L.; Deng, L.; Talbot, A. C.; Chen, D. Y.-K. Chem. Commun. 2010, 46, 70. (d) Peng, F.; Yu, M.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 6586. (e) Singh, V.; Bhalerao, P.; Mobin, S. M. Tetrahedron Lett. 2010, 51, 3337. (f) Lazarski, K. E.; Hu, D. X.; Stern, C. L.; Thomson, R. J. Org. Lett. 2010, 12, 3010. (g) Baitinger, I.; Mayer, P.; Trauner, D. Org. Lett. 2010, 12, 5656. (h) Peng, F.; Danishefsky, S. J. Tetrahedron Lett. 2011, 52, 2104. (i) Gu, Z.; Zakarian, A. Org. Lett. 2011, 13, 1080. (j) Dong, L.; Deng, L.; Lim, Y.H.; Leung, G. Y. C.; Chen, D. Y.-K. Chem. - Eur. J. 2011, 17, 5778. (k) Lazarski, K. E.; Akpinar, B.; Thomson, R. J. Tetrahedron Lett. 2013, 54, 635. (l) Carberry, P.; Viernes, D. R.; Choi, L. B.; Fegley, M. W.; Chisholm, J. D. Tetrahedron Lett. 2013, 54, 1734. (m) Jansone-Popova, S.; May, J. A. Tetrahedron 2016, 72, 3734. (4) (a) McGrath, N. A.; Bartlett, E. S.; Sittihan, S.; Njardarson, J. T. Angew. Chem., Int. Ed. 2009, 48, 8543. (b) Morton, J. G. M.; Draghici, C.; Kwon, L. D.; Njardarson, J. T. Org. Lett. 2009, 11, 4492. (c) McGrath, N. A.; Binner, J. R.; Markopoulos, G.; Brichacek, M.; Njardarson, J. T. Chem. Commun. 2011, 47, 209. (d) Yang, Q.; Njardarson, J. T.; Draghici, C.; Li, F. Angew. Chem., Int. Ed. 2013, 52, 8648. (e) Yang, Q.; Draghici, C.; Njardarson, J. T.; Li, F.; Smith, B. R.; Das, P. Org. Biomol. Chem. 2014, 12, 330. (5) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600. 5319
DOI: 10.1021/acs.orglett.7b02606 Org. Lett. 2017, 19, 5316−5319
