Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2023 Jan 10;25(2):400–404. doi: 10.1021/acs.orglett.2c04095

Synthesis of Dihydropyridine Spirocycles by Semi-Pinacol-Driven Dearomatization of Pyridines

Joseph C Abell †, Christian P Bold †, Laia Vicens †, Tom Jentsch †, Noelia Velasco †, Jasper L Tyler †, Robert N Straker ‡, Adam Noble †, Varinder K Aggarwal †,*
PMCID: PMC9872164  PMID: 36626565

Abstract

graphic file with name ol2c04095_0007.jpg

The identification of the beneficial pharmacokinetic properties of aza-spirocycles has led to the routine incorporation of these highly rigid and three-dimensional structures in pharmaceuticals. Herein, we report an operationally simple synthesis of spirocyclic dihydropyridines via an electrophile-induced dearomative semi-pinacol rearrangement of 4-(1′-hydroxycyclobutyl)pyridines. The various points for diversification of the spirocyclization precursors, as well as the synthetic utility of the amine and ketone functionalities in the products, provide the potential to rapidly assemble medicinally relevant spirocycles.

Nitrogen heterocycles are highly prevalent in FDA-approved drug molecules, with the piperidine ring system representing the most common saturated N-heterocycle in marketed pharmaceuticals.1,2 Incorporating piperidine and dihydropyridine rings into spirocyclic systems provides the potential to generate inherently rigid three-dimensional structures that retain the beneficial pharmacokinetic properties of N-heterocycles.3,4 The high fraction of sp3-hybridized carbons (Fsp3), structural novelty, and limited conformational flexibility are predicted to give such structures a greater chance of achieving clinical success in drug discovery programs.5 Accordingly, such heterocyclic moieties have been incorporated into numerous approved drugs and promising clinical leads (Figure 1a).6−10

Figure 1.

Figure 1

Open in a new tab

(a) Piperidine-based spirocyclic pharmaceuticals. (b) Previous work: (i) dearomative 1,2-boronate rearrangement and (ii) alkylpyridinium-induced semi-pinacol rearrangement. (c) Electrophile-induced dearomative semi-pinacol ring expansion.

Despite their potential, synthetic methods for accessing piperidine spirocycles are significantly underdeveloped.11 Syntheses commonly employ relatively expensive N-protected piperidin-4-ones as precursors6 and require lengthy cyclization sequences to generate the spirocenter. Strategies that have been used to induce ring closure include acylation,12 alkylation,7,13 ring-closing metathesis,13 and cycloaddition reactions.14 One of the few available methods for accessing dihydropyridine spirocycles involves the condensation of amines with 1,5-dialdehydes (glutaraldehydes) bearing a carbocycle in the backbone.15 However, the lengthy multistep syntheses of the glutaraldehyde precursors somewhat limit the appeal of this approach.

Dearomatization reactions in which feedstock aromatic systems are converted to more complex sp3 rich structures represent a highly desirable strategy for accessing nonplanar scaffolds such as spirocycles.16 Previous publications from the group of Ready and our own have reported the generation of N-heterocycle boronate complexes and subsequent 1,2-migration reactions facilitated by N-acylation to provide dihydropyridyl boronic esters (Figure 1b, i).17,18 In 2011, Hayashi and co-workers demonstrated the dearomative spirocyclization of N-alkylpyridinium benzocyclobutenol derivatives (Figure 1b, ii).19 In this case, a semi-pinacol rearrangement is triggered by alcohol deacetylation, and the piperidine spirocycle is obtained following hydrogenation.

We envisaged a more general and straightforward approach in which easy-to-access hydroxycyclobutylpyridines (1) could undergo an electrophile-induced dearomatizing semi-pinacol ring expansion to deliver dihydropyridine spirocycles (Figure 1c, 2).20 We predicted that employing N-acylation activators should render these compounds isolable, giving the potential to either directly access these atypical structures or perform hydrogenation to the corresponding piperidine spirocycles.19 Herein, we report the successful synthesis of a broad range of dihydropyridine spirocycles through a dearomatizing semi-pinacol rearrangement, driven by the selective N-acylation of hydroxycyclobutylpyridines. The resulting products bearing a ketone and protected secondary amine provide the potential for bidirectional elaboration to assemble medicinally relevant spirocyclic scaffolds.

We began by synthesizing the requisite 4-hydroxycyclobutylpyridine starting materials (Scheme 1). This was achieved in a single step via the 1,2-addition of metalated pyridines, generated by deprotonation or halogen–metal exchange, to a variety of cyclic ketones.21

Scheme 1. Synthesis of Hydroxycycloalkylpyridines (1).

Scheme 1

Open in a new tab

With hydroxycyclobutylpyridine substrates in hand, we set about investigating the dearomative semi-pinacol spirocyclization reaction. Fluorine-labeled 1h was selected as the model substrate allowing the use of 19F NMR to monitor reaction progress (Table 1). An initial screen of acylating agents showed that the combination of 2,2,2-trichloroethyl chloroformate (TrocCl) in chloroform allowed access to desired product 2 in 52% isolated yield (Table 1, entry 1). The presence of diisopropylethylamine (DIPEA) was required to sequester the HCl generated, preventing yield-limiting precipitation of the pyridine starting material hydrochloride salt. It must also be noted that under these conditions, the direct acylation of the hydroxy group was observed, resulting in minor product 3. Although the use of the more sterically hindered acylating agent 1,1-dimethyl-2,2,2-trichloroethyl chloroformate (TCBocCl) successfully suppressed acylation of the tertiary alcohol (Table 1, entry 2), we were keen to explore other more common activators. We therefore turned to tert-butyloxycarbonyl as a hindered, commonly used, yet easily cleaved protecting group. Unfortunately, the application of di-tert-butyl dicarbonate (Boc2O) in chloroform resulted in a very slow reaction, requiring 6–7 days to achieve full conversion at reflux (Table 1, entries 3 and 4). Surprisingly, the inclusion of a substoichiometric amount of 4-(dimethylamino)pyridine (DMAP) was found to completely reverse the selectivity of the acylation, exclusively generating O-acylation product 3 (Table 1, entry 5). Finally, a screen of high-boiling point solvents showed that employing acetonitrile with 5 equiv of Boc2O gave an NMR yield of 85% after 24 h (Table 1, entries 6 and 7).22 While degradation of the dihydropyridine spirocycles was not directly observed, the discrepancy between the NMR yield and isolated yield may hint at minor levels of instability toward chromatographic purification.

Table 1. Optimization Studies.

graphic file with name ol2c04095_0006.jpg

entry acylating agent (equiv) solvent, time yield of 2 (%)a yield of 3 (%)a
1b TrocCl (1.5) CHCl3, 18 h 60 (52) 10 (9)
2b TCBocCl (1.5) CHCl3, 18 h 85 0
3 Boc2O (1.5) CHCl3, 7 days 81 0
4 Boc2O (5.0) CHCl3, 6 days 88 0
5c Boc2O (1.5) CHCl3, 18 h 0 96
6 Boc2O (1.5) MeCN, 48 h 44 0
7 Boc2O (5.0) MeCN, 24 h 85 (68) 0
Open in a new tab
a

Yield determined by 19F NMR. Isolated yields in parentheses.

b

Reaction performed at room temperature with DIPEA (1.5 equiv).

c

With DMAP (0.3 equiv).

Having established the optimal conditions, we then investigated the scope of the reaction (Scheme 2). Cyclopentanone spirocycle 2a was obtained in an excellent yield of 96% from 4-(1-hydroxycyclobutyl)pyridine and isolated in comparable yield when prepared on a gram scale. The spirocyclization reaction also worked for the expansion of three- and five-membered cyclic alcohols to form products 2b and 2c in good yields. However, identical conditions were unsuccessful in generating the corresponding cycloheptanone product 2d. In addition, starting materials bearing heteroatoms in the cyclobutane ring were amenable to this transformation, providing 2e and 2f in 78% and 64% yields, respectively. Employing an unsymmetrical 4-hydroxycyclobutylpyridine gives two possible products depending on the carbon–carbon bond that undergoes migration. Pleasingly, in the case of tricyclic product 2g, a single regioisomer was obtained, demonstrating the greater migratory aptitude of a tertiary carbon over a secondary carbon.23 We then explored the effect of substituents and functional handles on the pyridine ring. It was observed that 3-substituted pyridines were well tolerated in this transformation, allowing the generation of dihydropyridine spirocycles bearing halogen (2h and 2i), diisopropylamide (2j), and aromatic groups (2k). Due to the increase in steric hindrance around the pyridine nitrogen, the formation of 2-methyl substrate 2l required the addition of an additional 5 equiv of Boc2O to achieve full conversion. It was noted that the addition of the acylating agent in installments over the course of the reaction was superior to increasing the initial reaction stoichiometry, which was attributed to the Boc2O gradually decomposing under the reaction conditions. Employing the analogous 2-phenylpyridine starting material was found to show no conversion under the reaction conditions. To overcome this, the more reactive acylating agent 2,2,2-trichloro-1,1-dimethylethyl chloroformate (TCBocCl) was utilized and enabled spirocycle 2m to be produced in 77% yield. This effect was also observed upon extending the protocol to the dearomatization of quinolines. With Boc2O, competing O-acylation was found to dominate at increased temperatures and increasing the number of equivalents of the electrophile had a negligible impact on product formation. However, the use of TCBocCl enabled spirocyclization products 2n–2s containing chloro, bromo, fluoro, and methoxy functionalities to be accessed in synthetically useful yields. The limit of reactivity was found upon employing 2-fluoropyridine starting materials, for which the deactivating effect of the fluorine atom prevented any observable 2t formation with either Boc2O or TCBocCl.

Scheme 2. Substrate Scope for the Dearomative Spirocyclization Reaction.

Scheme 2

Open in a new tab

Reaction performed with 6.7 mmol of 1a.

An additional 5.0 equiv of Boc2O was added after 12 h of reaction time.

All reactions were performed on a 0.25 mmol scale. Isolated yields are given.

Next, the scope of activating agents for enacting the spirocyclization was investigated (Scheme 3). Chloroformates were generally successful in achieving the desired reactivity without the need for increased temperatures or a large excess of an activating agent. The ratio of the spirocycle to the O-acylation product varied from reagent to reagent, broadly correlating with the relative steric bulk of the electrophile. Methyl chloroformate and TrocCl gave the corresponding spirocycle (2aa and 2ab) and O-acylation (3aa and 3ab) products in an approximate 2:1 ratio. Minor competing O-acylation was also observed for allyl chloroformate and benzyl chloroformate, which provided the desired dihydropyridine spirocycles (2ac and 2ad) in 68% and 71% yields, respectively. However, no O-acylation was observed using the more hindered TCBocCl or 9H-fluorenylmethyl chloroformate (FmocCl), which provided spirocycles 2ae and 2af(24) in high yields. Beyond chloroformates, pivaloyl chloride was demonstrated to be a suitable acylating agent for the reaction, giving spirocyclic amide 2ag in a modest yield. In addition, triflic anhydride and tosyl chloride were found to promote spirocyclization under the same reaction conditions, providing sulfonamides 2ah and 2ai. The yield of product formation was noticeably lower with nosyl chloride (2aj) due to a lack of solubility of this reagent in chloroform. It must also be noted that the ability to install a broad range of protecting groups in the spirocyclic products provides the opportunity to deprotect the amine functionality orthogonal to any sensitive groups present in the molecule.25

Scheme 3. Activator Scope for Dearomative Spirocyclization Reaction.

Scheme 3

Open in a new tab

NMR yield calculated using using dibromomethane as an internal standard.

All reactions were performed on a 0.25 mmol scale. Isolated yields are given.

Finally, dihydropyridine spirocycles 2a and 2k were efficiently converted to highly valuable piperidine spirocycles (4a and 4b) by reduction with hydrogen gas over palladium on carbon (Scheme 4). In the case of 2k, hydrogenation proceeded with excellent diastereoselectivity, highlighting the synthetic utility of this approach. This transformation demonstrates the utility of this dearomatization procedure, allowing access to both dihydropyridine and piperidine spirocyclic scaffolds.

Scheme 4. Hydrogenation of Spirocyclic Dihydropyridines.

Scheme 4

Open in a new tab

Identity of the major diastereomer unknown.

Isolated yields are given.

In conclusion, we have developed a highly efficient protocol for the dearomatizing spirocyclization of 4-(1′-hydroxycycloalkyl)pyridines. The starting materials, accessed in a single step from commercially available pyridine precursors, were observed to undergo semi-pinacol ring expansion reactions upon N-acylation. The applicability of this strategy was demonstrated through the synthesis of a diverse family of dihydropyridine spirocycles in which both the scope of the pyridine precursors and the activating agent were explored. Finally, the hydrogenation of the dihydropyridine spirocyclic products to their corresponding piperidine analogues was demonstrated. The various points for diversification of the spirocyclization precursors (ring size and pyridine substitution pattern), as well as the synthetic utility of the secondary amine and ketone functionalities in the products, provide the potential to rapidly assemble medicinally relevant spirocyclic scaffolds.

Acknowledgments

J.C.A. and J.L.T. thank the Bristol Chemical Synthesis Centre for Doctoral Training and the EPSRC (EP/G036764/1) for funding. C.P.B. thanks the Swiss National Science Foundation for a Postdoc Mobility Fellowship (P500PN_202691). L.V. thanks the Spanish Ministry of Science, Innovation and Universities for a Ph.D. grant (FPU16/04231) and a mobility fellowship (EST19/00778). The authors thank N. E. Pridmore (University of Bristol) for X-ray analysis.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.2c04095.

  • Experimental procedures, characterization data, and 1H and 13C NMR spectra for all novel compounds (PDF)

The authors declare no competing financial interest.

Author name changed from Noelia Velasco Perez to Noelia Velasco on January 10, 2023.

Supplementary Material

ol2c04095_si_001.pdf (9.3MB, pdf)

References

  1. Bhutani P.; Joshi G.; Raja N.; Bachhav N.; Rajanna P. K.; Bhutani H.; Paul A. T.; Kumar R. U.S. FDA Approved Drugs from 2015–June 2020: A Perspective. J. Med. Chem. 2021, 64, 2339. 10.1021/acs.jmedchem.0c01786. [DOI] [PubMed] [Google Scholar]
  2. Vitaku E.; Smith D. T.; Njardarson J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257. 10.1021/jm501100b. [DOI] [PubMed] [Google Scholar]
  3. a Zheng Y.; Tice C. M.; Singh S. B. The use of spirocyclic scaffolds in drug discovery. Bioorg. Med. Chem. Lett. 2014, 24, 3673. 10.1016/j.bmcl.2014.06.081. [DOI] [PubMed] [Google Scholar]; b Hiesinger K.; Dar’in D.; Proschak E.; Krasavin M. Spirocyclic Scaffolds in Medicinal Chemistry. J. Med. Chem. 2021, 64, 150. 10.1021/acs.jmedchem.0c01473. [DOI] [PubMed] [Google Scholar]
  4. Marson C. M. New and unusual scaffolds in medicinal chemistry. Chem. Soc. Rev. 2011, 40, 5514. 10.1039/c1cs15119c. [DOI] [PubMed] [Google Scholar]
  5. a Lovering F.; Bikker J.; Humblet C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752. 10.1021/jm901241e. [DOI] [PubMed] [Google Scholar]; b Lovering F. Escape from Flatland 2: complexity and promiscuity. MedChemComm 2013, 4, 515. 10.1039/c2md20347b. [DOI] [Google Scholar]
  6. Vardanyan R.Heterocyclic Drug Discovery; Elsevier, 2017; pp 287–297. [Google Scholar]
  7. a Sarver P.; Acker M.; Bagdanoff J. T.; Chen Z.; Chen Y. N.; Chan H.; Firestone B.; Fodor M.; Fortanet J.; Hao H.; et al. 6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors. J. Med. Chem. 2019, 62, 1793. 10.1021/acs.jmedchem.8b01726. [DOI] [PubMed] [Google Scholar]; b Bagdanoff J. T.; Chen Z.; Acker M.; Chen Y. N.; Chan H.; Dore M.; Firestone B.; Fodor M.; Fortanet J.; Hentemann M.; et al. Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors. J. Med. Chem. 2019, 62, 1781. 10.1021/acs.jmedchem.8b01725. [DOI] [PubMed] [Google Scholar]
  8. Gammans R. E.; Mayol R. F.; Labudde J. A. Metabolism and disposition of buspirone. Am. J. Med. 1986, 80, 41. 10.1016/0002-9343(86)90331-1. [DOI] [PubMed] [Google Scholar]
  9. Romanet P.; Stewart A. G. Value of Fenspiride in the Treatment of Inflammation Diseases in Otorhinolaryngology. European Respiration Review 1991, 1, 105. [Google Scholar]
  10. Patil S. P.; Pacitti M. F.; Gilroy K. S.; Ruggiero J. C.; Griffin J. D.; Butera J. J.; Notarfrancesco J. M.; Tran S.; Stoddart J. W. Identification of antipsychotic drug fluspirilene as a potential p53-MDM2 inhibitor: a combined computational and experimental study. J. Comput. Aided Mol. Des. 2015, 29, 155. 10.1007/s10822-014-9811-6. [DOI] [PubMed] [Google Scholar]
  11. Kotha S.; Panguluri N. R.; Ali A. Design and Synthesis of Spirocycles. Eur. J. Org. Chem. 2017, 2017, 5316. 10.1002/ejoc.201700439. [DOI] [Google Scholar]
  12. Habashita H.; Kokubo M.; Hamano S. I.; Hamanaka N.; Toda M.; Shibayama S.; Tada H.; Sagawa K.; Fukushima D.; Maeda K.; et al. Design, Synthesis, and Biological Evaluation of the Combinatorial Library with a New Spirodiketopiperazine Scaffold. Discovery of Novel Potent and Selective Low-Molecular-Weight CCR5 Antagonists. J. Med. Chem. 2006, 49, 4140. 10.1021/jm060051s. [DOI] [PubMed] [Google Scholar]
  13. Jenkins I. D.; Lacrampe F.; Ripper J.; Alcaraz L.; Van Le P.; Nikolakopoulos G.; De Almeida Leone P.; White R. H.; Quinn R. J. Synthesis of Four Novel Natural Product Inspired Scaffolds for Drug Discovery. J. Org. Chem. 2009, 74, 1304. 10.1021/jo802456w. [DOI] [PubMed] [Google Scholar]
  14. a Brown D. G.; Bernstein P. R.; Griffin A.; Wesolowski S.; Labrecque D.; Tremblay M. C.; Sylvester M.; Mauger R.; Edwards P. D.; Throner S. R.; et al. Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine-3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition. J. Med. Chem. 2014, 57, 733. 10.1021/jm4014828. [DOI] [PubMed] [Google Scholar]; b King T. A.; Stewart H. L.; Mortensen K. T.; North A. J. P.; Sore H. F.; Spring D. R. Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment-Based Drug Discovery. Eur. J. Org. Chem. 2019, 2019, 5219. 10.1002/ejoc.201900847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Foos J.; Steel F.; Rizvi S. Q. A.; Fraenkel G. Synthesis and nuclear magnetic resonance spectra of N-carboethoxy-4-spiro-1,4-dihydropyridines. J. Org. Chem. 1979, 44, 2522. 10.1021/jo01328a042. [DOI] [Google Scholar]
  16. Wertjes W. C.; Southgate E. H.; Sarlah D. Recent advances in chemical dearomatization of nonactivated arenes. Chem. Soc. Rev. 2018, 47, 7996. 10.1039/C8CS00389K. [DOI] [PubMed] [Google Scholar]
  17. a Llaveria J.; Leonori D.; Aggarwal V. K. Stereospecific Coupling of Boronic Esters with N-Heteroaromatic Compounds. J. Am. Chem. Soc. 2015, 137, 10958. 10.1021/jacs.5b07842. [DOI] [PubMed] [Google Scholar]; b Panda S.; Coffin A.; Nguyen Q. N.; Tantillo D. J.; Ready J. M. Synthesis and Utility of Dihydropyridine Boronic Esters. Angew. Chem., Int. Ed. 2016, 55, 2205. 10.1002/anie.201510027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. For examples of dihydropyridine synthesis from activated pyridines, see:; a Kratena N.; Marinic B.; Donohoe T. Recent advances in the dearomative functionalisation of heteroarenes. Chem. Sci. 2022, 13, 14213. 10.1039/D2SC04638E. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Bull J. A.; Mousseau J. J.; Pelletier G.; Charette A. B. Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition to N-Activated Pyridines. Chem. Rev. 2012, 112, 2642. 10.1021/cr200251d. [DOI] [PubMed] [Google Scholar]; c Andersson H.; Olsson R.; Almqvist F. Reactions between Grignard reagents and heterocyclic N-oxides: Stereoselective synthesis of substituted pyridines, piperidines, and piperazines. Org. Biomol. Chem. 2011, 9, 337. 10.1039/C0OB00336K. [DOI] [PubMed] [Google Scholar]; d Stout D. M.; Meyers A. I. Recent Advances in the Chemistry of Dihydropyridines. Chem. Rev. 1982, 82, 223. 10.1021/cr00048a004. [DOI] [Google Scholar]; e Heusler A.; Fliege J.; Wagener T.; Glorius F. Substituted Dihydropyridine Synthesis by Dearomatization of Pyridines. Angew. Chem., Int. Ed. 2021, 60, 13793. 10.1002/anie.202104115. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Harawa V.; Thorpe T. W.; Marshall J. R.; Sangster J. J.; Gilio A. K.; Pirvu L.; Heath R. S.; Angelastro A.; Finnigan J. D.; Charnock S. J.; Nafie J. W.; Grogan G.; Whitehead R. C.; Turner N. J. Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines. J. Am. Chem. Soc. 2022, 144, 21088. 10.1021/jacs.2c07143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hayashi T.; Ohmori K.; Suzuki K. Ring Expansion Approach to Azaspiro[4.5]decane Skeletons via Electrophilic Activation of Benzocyclobutenols Bearing Pyridyl Group. Chem. Lett. 2011, 40, 612. 10.1246/cl.2011.612. [DOI] [Google Scholar]
  20. For examples of semi-pinacol reactions in the synthesis of spirocycles, see:; a Song Z. L.; Fan C. A.; Tu Y. Q. Semipinacol Rearrangement in Natural Product Synthesis. Chem. Rev. 2011, 111, 7523. 10.1021/cr200055g. [DOI] [PubMed] [Google Scholar]; b Meyer A. M.; Katz C. E.; Li S. W.; Vander Velde D.; Aubé J. A Tandem Prins/Schmidt Reaction Approach to Marine Alkaloids: Formal and Total Syntheses of Lepadiformines A and C. Org. Lett. 2010, 12, 1244. 10.1021/ol100113r. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Gregson C. H. U.; Noble A.; Aggarwal V. K. Divergent, Strain-Release Reactions of Azabicyclo[1.1.0]butyl Carbinols: Semipinacol or Spiroepoxy Azetidine Formation. Angew. Chem., Int. Ed. 2021, 60, 7360. 10.1002/anie.202100583. [DOI] [PMC free article] [PubMed] [Google Scholar]; d López M. M.; Jamey N.; Pinet A.; Figadère B.; Ferriè L. Oxidative Ring Expansion of Cyclobutanols: Access to Functionalized 1,2-Dioxanes. Org. Lett. 2021, 23, 1626. 10.1021/acs.orglett.1c00070. [DOI] [PubMed] [Google Scholar]; e Kerner M. J.; Wipf P. Semipinacol-Type Rearrangements of [3-(Arylsulfonyl)bicyclo[1.1.0]butan-1-yl]alkanols. Org. Lett. 2021, 23, 3615. 10.1021/acs.orglett.1c01004. [DOI] [PubMed] [Google Scholar]
  21. See the Supporting Information for specific conditions.
  22. See the Supporting Information for full optimization results.
  23. Marson C. M.; Walker A. J.; Pickering J.; Hobson A. D.; Wrigglesworth R.; Edge S. J. Stereoselective construction of quaternary centers at ambient temperature by the highly stereocontrolled migration of groups containing sp-, sp2-, and sp3-hybridized carbon atoms. J. Org. Chem. 1993, 58, 5944. 10.1021/jo00074a019. [DOI] [Google Scholar]
  24. The structure of spirocycle 2af was confirmed by single-crystal X-ray crystallography. See the Supporting Information for details. Deposition Number 2216520.
  25. a Jarowicki K.; Kocienski P. Protecting groups. J. Chem. Soc., Perkin Trans. 1 2001, 2109. 10.1039/b103282h. [DOI] [Google Scholar]; b Javorskis T.; Orentas E. Chemoselective Deprotection of Sulfonamides under Acidic Conditions: Scope, Sulfonyl Group Migration, and Synthetic Applications. J. Org. Chem. 2017, 82, 13423. 10.1021/acs.joc.7b02507. [DOI] [PubMed] [Google Scholar]; c Bezençon O.; Bur D.; Weller T.; Richard-Bildstein S.; Remen L.; Sifferlen T.; Corminboeuf O.; Grisostomi C.; Boss C.; Prade L.; Delahaye S.; Treiber A.; Strickner P.; Binkert C.; Hess P.; Steiner B.; Fischli W. Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors. J. Med. Chem. 2009, 52, 3689. 10.1021/jm900022f. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ol2c04095_si_001.pdf (9.3MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Articles from Organic Letters are provided here courtesy of American Chemical Society

RESOURCES