Synthesis of Chiral 1,2-Oxazinanes and Isoxazolidines via Nitroso

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

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Synthesis of Chiral 1,2-Oxazinanes and Isoxazolidines via Nitroso Aldol Reaction of Distal Dialdehydes Isai Ramakrishna, Panduga Ramaraju, and Mahiuddin Baidya* Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India S Supporting Information *

ABSTRACT: The first catalytic enantioselective nitroso aldol reaction of distal dialdehydes is reported. The reaction is catalyzed by simple L-proline at room temperature and subsequent reduction delivered biologically potent and synthetically versatile N−O bond containing five- and six-membered heterocycles, 1,2-oxazinanes, and isoxazolidines in high yields and excellent enantioselectivities (up to >99% ee). The method was further exploited to prepare chiral 3-hydroxypiperidines and -pyrrolidines that are otherwise difficult to access.

D

Scheme 1. Catalytic Enantioselective Synthesis of N−O BondContaining Heterocycles

evising catalytic and enantioselective strategies, where multiple bond-forming events occur in one operation using an inexpensive catalytic system with simple experimental protocol, is a continuous enterprise in contemporary organic synthesis. In this context, construction of optically active heterocycles possessing an N−O bond, for instance, derivatives of isoxazolidines and 1,2-oxazinanes, is highly demanding owing to their prevalence in diverse biologically active compounds (Figure 1).1 They also serve as versatile synthetic intermediates

Figure 1. Selective examples of bioactive N−O bond-containing heterocycles.

as the facile cleavage of N−O bond offers chiral 1,3- and 1,4amino alcohols, which can be found in number of natural products and are also important building blocks for asymmetric transformations.2,3 Among the various catalytic methods developed for accessing enantioenriched 1,2-oxazinane and isoxazolidine frameworks, [3 + 2] and homo [3 + 2] dipolar cycloadditions of nitrones and nitrosoarenes with activated olefins and cyclopropanes have been predominant (Scheme 1a).4,5 However, these processes are primarily effective with transition-metal catalysts in combination with expensive and bulky ligands under inert conditions. Currently, asymmetric organocatalytic processes toward the synthesis of these pivotal saturated N,O-heterocycles are very limited. Asymmetric nitroso aldol/Michael addition cascade pioneered by Yamamoto et al. and later advanced by Guofu and others, are applicable only for 1,2-oxazinane system and strategically incongruous for isoxazoline framework (Scheme 1b).6,7 Although high enantioselectivities were accomplished in these cases, the preparation of starting materials generally © XXXX American Chemical Society

required several steps, posing restriction to its rapid adoption. At present, a straightforward catalytic asymmetric method, particularly an enantioselective organocatalytic process suitable for both isoxazolidines and 1,2-oxazinanes systems, remains elusive. Distal dialdehydes such as succinaldehyde and gluteraldehyde are high-value synthons.8 They are readily available and display unique reactivity profile arising from the presence of innate donor−acceptor reactivity center in the carbon chain. We envisioned that the asymmetric reactions of distal dialdehydes with nitroso compounds in the presence of chiral organocatalyst would be a convenient route to access chiral N−O bond Received: December 21, 2017

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DOI: 10.1021/acs.orglett.7b03968 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters containing heterocycles with desired ring size (Scheme 1c).9 The chiral organocatalyst would facilitate the enantioselective nitroso aldol reaction of the dialdehyde to give reactive species A, which may experience intramolecular nucleophilic addition to produce hemiaminal B. The in situ reduction of the hemiaminal B under acidic conditions shall provide desired heterocycles with high asymmetric induction. Although the proposed strategy is very attractive, there are two challenges to substantiate this idea. First, nitroso compound is a prototype of ambident electrophile, and thus, controlling the regioselectivity, i.e., the reaction via oxygen center (O-nitroso aldol) or nitrogen center (N-nitroso aldol), is a prime issue.10 Second, these distal dialdehydes undergo homoaldol reactions to produce various oligomers under acidic and basic conditions.8a Therefore, a very mild reaction condition is crucial to overcome the pitfalls of oligomerization. Guided by these considerations, herein, we report the first organocatalyzed nitrosoaldol reaction of distal dialdehydes en route to the synthesis of both isoxazolidine and 1,2-oxazinane derivatives in high yields and excellent enantioslectivities (Scheme 1c). The synthetic utility of this protocol was further highlighted through the rapid production of optically active 3hydroxypiperidines and -pyrrolidines, a demanding class of molecules in the drug development arena.11 We commenced our investigation by evaluating the reaction of glutaraldehyde 1a with nitrosobenzene 2a in the presence of various organocatalysts (Table 1). While proline-derived

changed to DMSO, the reaction was very clean, furnishing 3a in 68% yield with 80% ee (Table 1, entry 4). Screening of other solvents resulted in only trace amount of product (entries 5−6). To improve the enantioselectivity further, the influence of various Brønsted acids as additives (10 mol %) were examined. Interestingly, the presence of aliphatic alcohol such as ethylene glycol (entry 7) and phenolic derivatives (entries 8−10) gave improved enantioselectivities up to 90% ee. The best result was obtained in the presence of 3,5-di-tert-butylcatechol, delivering 1,2-oxazinane 3a in 72% isolated yield and 93% enantiomeric excess (entry 11). With the optimum catalyst and reaction conditions in hand, we turned our attention to explore the scope of this asymmetric protocol (Scheme 2). Gratifyingly, a series of aryl nitroso Scheme 2. Catalytic Enantioselective Synthesis of 1,2Oxazinanesa

Table 1. Optimization of Nitroso Aldol Reaction of Distal Dialdehydea

a

entry

cat.

solvent

1 2 3 4 5 6 7 8 9 10 11

I II III I I I I I I I I

CH3CN CH3CN CH3CN DMSO dioxane DCE DMSO DMSO DMSO DMSO DMSO

additive (10 mol %)

ethylene glycol phenol catechol 8-hydroxyquinoline 3,5-di-tert-butylcatechol

yieldb (%)

eec (%)

15

nd

68 trace trace 64 54 65 55 72

80 nd nd 90 90 90 88 93

Reaction conditions: 1a (1.5 mmol), 2 (0.50 mmol), L-proline (20 mol %), DMSO (5 mL), 10 h. Yields of isolated products are given. Enantiomeric excess (ee) was determined by HPLC on a chiral stationary phase.

compounds having electron-donating and -withdrawing substituents at the para- and meta-positions smoothly reacted with glutaraldehyde 1a to afford 1,2-oxazinane derivatives (3b−h) in uniformly high yields (66−74%) and excellent enantioselectivities (95−99% ee). Halogen functionalities such as chloro (3d,f), bromo (3e,g), and fluoro (3h), which are important synthetic handles, were tolerated. Interestingly, the unnatural amino acid D-proline is also equally active to catalyze the O-selective nitroso aldol cascade, offering opposite enantiomers ent-3a,b and ent-3d with 93−96% ee. Accessing both enantiomers of 1,2-oxazinane heterocycle in high optical purity highlights the synthetic versatility of our protocol. We next examined the nitroso aldol reaction of lower homologue succinaldehyde (1b), and thus, nitrosoarene 2a was exposed to 1b under optimized reaction conditions (Scheme 3). To our satisfaction, O-selectivity was also preserved in this nitroso aldol process, and the desired isoxazolidine 4a was isolated in 99% ee. Remarkably, when the reaction was repeated in the absence of 3,5-di-tert-butylcatechol additive, the enantioselectivity was unaffected, suggesting an involvement of a more rigid transition state in the nitroso aldol process of

a

Reaction conditions: 1a (1.5 mmol), 2a (0.50 mmol), catalyst (20 mol %), solvent (5 mL), 10 h. bYield of isolated product. c Enantiomeric excess (ee) was determined by HPLC on a chiral stationary phase. nd: not determined.

organocatalysts II and III were unproductive, simple and naturally available organocatalyst L-proline (I) could promote the nitroso aldol reaction in acetonitrile solvent, and the desired 1,2-oxazinane 3a was isolated in 15% yield after reduction using NaBH4/AcOH conditions (entries 1−3). Despite a low yield, this outcome intriguingly validated our hypothesis. This nitroso aldol reaction proceeded with complete O-selectivity as Nnitroso aldol product was not detected. When the solvent was B

DOI: 10.1021/acs.orglett.7b03968 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Catalytic Enantioselective Synthesis of Isoxazolidinesa

Scheme 5. Cleavage of N−O Bond and Synthesis of Chiral Piperidine and Pyrrolidine Derivatives

a Reaction conditions: 1a (1.5 mmol), 2 (0.50 mmol), L-proline (20 mol %), DMSO (5 mL), 10 h. Yields of isolated products are given. Enantiomeric excess (ee) was determined by HPLC on a chiral stationary phase. bReaction was performed in the presence of 3,5-ditert-butylcatechol (10 mol %).

and 99% ee (Scheme 5a). Syntheses of chiral piperidines were conveniently accomplished in two steps. The free hydroxyl group of 3 was first protected with p-TsCl and then exposed to Mo(CO)6, allowing N−O bond cleavage and subsequent SN2 displacement to provide 9 and 10 in high yields and excellent enantioselectivities (Scheme 5b). Adaptation of the same strategy for isoxazolidine products 4b,e resulted in fivemembered 3-hydroxypyrrolidines 13 and 14 with 99% enantiopurities. It is worth noting that 3-hydroxypyrrolidine and -piperidine motifs represent the core structure of numerous biologically relevant natural products and pharmaceutical agents, for which typical syntheses involve multistep process.11 The amino alcohol 15 was also prepared via N−O bond cleavage of isoxazolidine 4b in 70% yield (Scheme 5d). Further, compounds 8 and 12 were crystallized, and X-ray analysis unambiguously confirmed the product structure which arises from the O-selective nitroso aldol process and also established the R configuration of products 3d and 4e (Scheme 5). The stereochemistry of 1,2-oxazinane and isoxazolidine derivatives in Schemes 2 and 3 were tentatively assigned by analogy. The X-ray structure of N-heterocycles 10 and 14 also validate this analysis. In conclusion, we have presented the first asymmetric nitroso aldol reaction of distal dialdehydes to access N−O bondcontaining chiral heterocycles. The protocol is very simple, uses small organic molecule proline as a catalyst, and delivered demanding 1,2-oxazinanes and isoxazolidines in high yields and excellent enantioselectivites. The synthetic utility of this protocol has been showcased through the production of biologically relevant chiral 3-hydroxypiperidine and pyrrolidine derivatives.

succinaldehyde. Similar to glutaraldehyde, nitroso aldol/ cyclization reaction of succinaldehyde is also quite general and various substituted isoxazolidine (4a−k) were obtained in high yields (62−73%) and excellent enantioselectivities (90−99%). However, the reactions were unproductive with strongly electron-withdrawing substituted arylnitroso compounds (4l,m). The opposite enantiomers ent-4b and ent-4h were also prepared by employing D-proline as a catalyst in 95% and 99% optical purity, respectively. When the higher homologue adepaldehyde (1c) was employed, instead of N−O heterocycle formation, the Oselective nitroso aldol/homoaldol cascade product 5 was formed in 40% yield and 41% ee (Scheme 4). The unfavorable formation of seven membered hemiaminal is possibly responsible for this deviation. The synthetic utility of enantioenriched N−O bondcontaining products (3,4) has been highlighted through the synthesis of chiral amino alcohol and nitrogen heterocycles (Scheme 5). Treatment of 1,2-oxazinane 3d with Mo(CO)6 cleanly cleaved the N−O bond to offer aminodiol 6 in 77% yield Scheme 4. Nitroso Aldol Reaction of Adepaldehyde

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DOI: 10.1021/acs.orglett.7b03968 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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Further applications in total syntheses of natural products are currently underway.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03968. Complete experimental details, characterization data for the prepared compounds (PDF) Accession Codes

CCDC 1585723−1585726 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

Mahiuddin Baidya: 0000-0001-9415-7137 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge DST (EMR/2014/000225) for financial support. I.R. thanks IIT Madras for HTRA. REFERENCES

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DOI: 10.1021/acs.orglett.7b03968 Org. Lett. XXXX, XXX, XXX−XXX