Aminoalkylation of [1.1.1]Propellane Enables Direct Access to High

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

pubs.acs.org/OrgLett

Aminoalkylation of [1.1.1]Propellane Enables Direct Access to HighValue 3‑Alkylbicyclo[1.1.1]pentan-1-amines Jonathan M. E. Hughes,† David A. Scarlata,† Austin C.-Y. Chen,‡,⊥ Jason D. Burch,§ and James L. Gleason*,† †

Department of Chemistry, McGill University, 801 Sherbrooke West, Montreal, QC H3A 2K6, Canada Inception Sciences, 6175 Nancy Ridge Drive, San Diego, California 92121, United States § Inception Sciences, 7150 Frederick-Banting Street, Saint-Laurent, QC H4S 2A1, Canada Downloaded via NOTTINGHAM TRENT UNIV on August 13, 2019 at 13:12:10 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

‡

S Supporting Information *

ABSTRACT: Bicyclo[1.1.1]pentanes are effective bioisoteres for aromatic rings, tert-butyl groups, and alkynes. Here we report the first method to synthesize 3-alkylbicyclo[1.1.1]pentan-1-amines directly from [1.1.1]propellane via sequential addition of magnesium amides and alkyl electrophiles. The mild reaction conditions tolerate a variety of important functional groups and enable efficient incorporation of several pharmaceutically relevant amines onto the bicyclo[1.1.1]pentane scaffold. This method’s utility is highlighted by its ability to significantly streamline the syntheses of several important bicyclo[1.1.1]pentan-1-amine building blocks.

O

ularly useful but challenging subset of BCP building blocks to access is those which are nonsymmetrical and 1,3-disubstituted. Recent approaches to these include atom transfer radical additions,7 one-pot organometallic addition/electrophilic trappings,4,7d,8 and one-pot Grignard addition/metal-catalyzed cross-coupling reactions.4,7d,9,10 While these methods have largely expanded the synthetic accessibility of many types of BCP building blocks, the synthesis of BCP-amines (e.g., 8, Figure 1B) has remained challenging. For example, BCP amino esters 10 and 11 have been incorporated into various peptides and drug candidates, but each required a lengthy synthesis (7 and 4 steps from 6, respectively).2f,11−13 Considering the importance of nitrogen-containing compounds within the pharmaceutical industry, the development of methods to efficiently access BCP-amines is of paramount importance. Notably, Baran and co-workers reported an elegant strategy to access monosubstituted BCP-amines (7) via the addition of a wide variety of “turbo amide” nucleophiles to 6, solving one of the long-standing challenges in this area.14 However, while this method is highly applicable to the incorporation of the BCP unit as a terminal group, it does not address the challenge of incorporating BCP-amines as core units bearing functionalization on both sides of the BCP.15 To this end, Kanazawa et al. recently developed a radical multicomponent carboamination of 6 to access 1,3-disubstituted BCP hydrazine dicarboxylates 9, although this method required additional steps to reveal the amine functionality.16 Thus, while there has been noteworthy progress, there is still an unmet need for the direct synthesis of 1,3-disubstituted BCP-amines.

ver the past two decades, the bicyclo[1.1.1]pentane (BCP) motif has emerged as a unique bioisostere for phenyl rings, tert-butyl groups, and internal alkynes.1−4 Replacement of a 1,4-disubstituted phenyl ring with a 1,3disubstituted BCP moiety was first demonstrated by Pellicciari and co-workers in their synthesis of BCP-containing metabolic glutamate receptor (mGluR1) antagonist 1 (Figure 1A).2a Notably, they showed that the required 180° spatial separation of key pharmacophoric groups could be achieved using the BCP unit and that an aromatic spacer was not essential for mGluR1 antagonism. This seminal report spurred the exploration of this motif in a wide range of molecular frameworks, including replacement of a fluorophenyl ring in a γ-secretase inhibitor (BMS-708,163),2d replacement of phenyl rings in LpPLA2 inhibitors darapladib and rilapladib,2g and sirtuin activator resveratrol (Figure 1A).2h Importantly, these examples demonstrated improvements in physicochemical properties such as passive permeability, aqueous solubility, lipophilicity, and metabolic stability. BCP incorporation has also been shown to decrease nonspecific binding across a variety of molecular scaffolds, further highlighting the potential benefits of this isosteric replacement.2i Importantly, the installation of a BCP fragment serves to increase a molecule’s 3-dimensionality, which is a factor that has been shown to correlate to clinical trial success.5 While the benefits of BCP incorporation in medicinal chemistry are apparent, a substantial hurdle to employing this strategy has been a shortage of synthetic methods to access useful building blocks. As a result, this limitation has spurred significant efforts toward the synthesis of bridgeheadsubstituted BCPs in recent years, where the majority of methods take advantage of the inherent reactivity of the central bond in highly strained [1.1.1]propellane (6).6 One partic© XXXX American Chemical Society

Received: July 12, 2019

A

DOI: 10.1021/acs.orglett.9b02426 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Table 1. Optimization of Amination Conditions to Provide a Long-Lived Metalated Intermediate 13a

entry

12 (equiv)

T (°C)

yield (%)b

% Dc

1 2 3 4 5 6 7 8

5.0 5.0 2.5 2.5 2.5 2.5 2.5 2.0

90 50 70 60 50 40 22 22

68 87 56 57 70 78 83 83

28 98 90 89 95 >99 >99 >99

a

Reactions were run in Et2O/THF for 16 h. bCombined isolated yields of 7 (R1 = R2 = Bn) + 14. cDetermined by 1H NMR integration of purified products.

in terms of both yield and Grignard intermediate stability (entries 3−7). Finally, we saw no change in yield or level of D incorporation when the amount of nucleophile was further reduced to 2.0 equiv, affording 14 in 83% yield and >99% D (entry 8). Having identified conditions under which metalated intermediate 13 was produced in high yield and was stable, we examined its in situ alkylation with simple alkyl halides (Table 2). We quickly found that addition of 5.0 equiv of 1-

Figure 1. (A) Examples of BCP-containing biologically active compounds. (B) Previous methods to synthesize bicyclo[1.1.1]pentan-1-amines and BCP amino esters 10 and 11.

Table 2. Optimization of the in Situ Alkylation of Intermediate 13 to Give N,N-Dibenzyl-3propylbicyclo[1.1.1]pentan-1-amine (15)a

In conjunction with a project within Inception Sciences, we sought a method to efficiently access 1,3-disubstituted BCPamines directly from [1.1.1]propellane (6). This goal was prompted by a need to develop an efficient route for the synthesis of amino ester 10, a structural component of an active pharmaceutical ingredient (API) in consideration for clinical development for immuno-oncology.13 Herein, we report the development of a convenient method to synthesize 3-alkylbicyclo[1.1.1]pentan-1-amines 8 directly from 6. Furthermore, we highlight the utility of this new method by significantly streamlining the synthesis of building blocks 10 and 11. The direct addition of “turbo amides” to 6 presumably generates a metalated intermediate (e.g., 13, Table 1) that should be capable of in situ trapping with an electrophile. To assess the feasibility of this approach and to probe the stability of 13 under the reported amination reaction conditions,14 we conducted a series of deuterium quenching experiments (Table 1). Accordingly, when 6 was allowed to react with 5.0 equiv of “turbo amide” 12 at 90 °C for 16 h and then was quenched with D2O, BCP-amine 14 was isolated in 68% yield but only with low deuterium incorporation (28%) at C3 (entry 1). Given this result, we hypothesized that the 3° Grignard 13 might have limited stability at elevated temperatures over extended periods of time.17 Indeed, when the reaction was instead conducted at 50 °C, 14 was isolated in an improved 87% yield and with 98% D incorporation (entry 2). We sought to reduce the number of equivalents of nucleophile to minimize byproduct formation from reaction of excess 12 and eventual electrophiles. With 2.5 equiv of 12, the reaction was still efficient, and an inverse correlation between reaction temperature and yield was again noted. Furthermore, these experiments revealed 22 °C as the ideal amination temperature

entry

n-PrI (equiv)

CuI (mol %)

T (°C)

yield (%)b

1 2 3 4 5d

5.0 5.0 5.0 2.2 2.2

− 10 10 10 10

22 22 50 50 50

19c 76 82 86 83

a

Alkylation reaction time = 24 h. bIsolated yields of 15. c52% of 7 (R1 = R2 = Bn) isolated. d1-Bromopropane employed as the electrophile.

iodopropane to 13 at 22 °C produced N,N-dibenzyl-3propylbicyclo[1.1.1]pentan-1-amine (15) but only in a modest 19% yield (entry 1). Given the poor reactivity in the alkylation step, we hypothesized that the addition of a copper salt, which is well-known to catalyze the coupling of alkyl Grignards and alkyl halides, would prove beneficial.18 Indeed, when CuI was employed as a catalytic additive in the reaction, the yield of 15 increased substantially (entry 2). Increasing the alkylation reaction temperature to 50 °C further improved the yield (entry 3), and we found that only 2.2 equiv of 1-iodopropane was required, providing 15 in 86% isolated yield (entry 4). Moreover, the reaction proceeded equally well when 1bromopropane was employed as the electrophile (entry 5). This is the first example of a 3-alkylbicyclo[1.1.1]pentan-1amine substrate being prepared from 6 in a single pot. B


Letter

Organic Letters Scheme 1. Scope of the Aminoalkylation Reaction of 6 to Give 1,3-Disubstituted BCP-amines

a

Alkyl iodide. bAlkyl bromide. cAlkyl tosylate.

After establishing optimized conditions for the one-pot aminoalkylation of 6, we examined the scope of this transformation to access an assortment of valuable BCPamine building blocks. A variety of unactivated primary (15− 21) and even secondary (22−23) alkyl halides afforded alkylation products in good yields (Scheme 1). Alkylation with activated allyl (24) and benzylic halides (25−32) also performed well in this reaction, and we found that benzylic tosylates were also capable electrophiles (25).19 We observed that various functional groups are tolerated, including acetals (19, 34−36), silyl ethers (20−21), electron-rich hetereocycles (32−33), olefins (24), and aryl bromides (26−27, 29). In addition, this method offers the potential to directly incorporate carbocyclic units, such as cyclopropyl (18) and cyclopentyl (23) moieties, onto a BCP scaffold. We also examined a series of different amine nucleophiles and found that cyclic and acylic benzylic amines afforded difunctionalized BCPs in synthetically useful yields (33−38). Thus, addition of benzyl n-butyl-, i-butyl-, t-butyl-, and cyclohexylamines, followed by trapping with 2-(2-iodoethyl)1,3-dioxolane, afforded alkylation products 33−36 in good yields. Moreover, addition of tetrahydroisoquinonline- or tryptamine-based amides, followed by electrophilic trapping, afforded 37 and 38 in 47% and 36% yield, respectively. In contrast, the addition of simple cyclic and acyclic dialkylamines, such as dibutylamine, N-benzyl piperazine, or pyrrolidine, did not afford high yields of the corresponding products. Specifically, the addition of the “turbo amides” derived from these amines required higher temperatures (90 °C) to achieve high conversions and were thus incompatible with the stability requirements of the metalated intermediate (vide supra).20

The difunctionalization reaction could be extended beyond the use of alkyl (pseudo)halide electrophiles. For example, quenching metalated intermediate 13 with ethyl cyanoformate generated amino ester 39. Notably, subsequent hydrogenolysis provides a two-step route to valuable amino ester 11, which was previously only accessible in 4 steps from 6.2f,11,12 Moreover, oxidation of 13 with Davis oxaziridine generated amino alcohol 40 in 54% yield. Finally, in situ conjugate addition of 13 onto 2-cyclohexen-1-one led to the formation of the cyclohexanone-substituted BCP-amine 41. These examples highlight the ability of this method to incorporate a diverse array of useful functional handles at both C1 and C3 of the BCP scaffold, enabling rapid access to high-value BCP building blocks. The utility of this method was further highlighted by its ability to significantly streamline the synthesis of key building block 10 (Scheme 2). The first-generation synthesis of 10 was achieved by an initial addition of phenylmagnesium bromide to 6, followed by trapping with methyl chloroformate to afford 42 (Scheme 2A).13 The phenyl group in 42 was transformed into the amine via ruthenium-catalyzed oxidative degradation followed by Curtius rearrangement, while chain extension was required to install the acetic acid unit. Overall, this synthesis of 10 proceeded in 7 steps and 8% overall yield from 6, but more importantly, its scale-up was cost prohibitive. In contrast, allylated BCP-amine 24, generated in 73% yield from 6 under our developed conditions (vide supra), served as a convenient precursor to amino ester 10 (Scheme 2B).21 Borhan oxidative cleavage of the alkene (OsO4, Oxone, TFA, DMF, rt)22 in 24 easily furnished the desired acid 46 in good yield. Subsequent Fischer esterification followed by benzyl deprotection smoothly delivered 10 in 84% yield. Thus, this newly developed aminoalkylation reaction enabled the synC


Organic Letters

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Scheme 2. (A) First- and (B) Second-Generation Syntheses of BCP Building Block 10

Overall yield starting from [1.1.1]propellane (6).

thesis of 10 in only 5 steps (4 pots) from 6 and in 38% overall yield, which is considerably more efficient than the previous route. In conclusion, we have reported the first method to access 3alkylbicyclo[1.1.1]pentan-1-amines directly from [1.1.1]propellane (6) via a one-pot aminoalkylation protocol. This reaction enabled the synthesis of a wide variety of difunctionalized bicyclo[1.1.1]pentane building blocks that contain high-value functional groups and also greatly simplified the synthesis of an important pharmaceutical building block. Given the ease with which highly functionalized bicyclo[1.1.1]pentanes can be prepared, we expect this method to be of great interest to chemists within the drug discovery community.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02426. Experimental procedures and characterization data for new compounds (PDF)

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REFERENCES

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Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

James L. Gleason: 0000-0003-1687-3343 Present Address ⊥

Pipeline Therapeutics, 10578 Science Center Drive, Suite 200, San Diego, CA, USA, 92121.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by an Engage grant provided by the Natural Sciences and Engineering Research Council of Canada (NSERC). J.M.E.H. thanks the NSERC and the Walter C. Sumner Foundation for postgraduate fellowships. D


Letter

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(22) Travis, B. R.; Narayan, R. S.; Borhan, B. Osmium TetroxidePromoted Catalytic Oxidative Cleavage of Olefins: An Organometallic Ozonolysis. J. Am. Chem. Soc. 2002, 124, 3824−3825.

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Aminoalkylation of [1.1.1]Propellane Enables Direct Access to High

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