Umpolung Synthesis of 1,3-Amino Alcohols: Stereoselective Addition

Letter pubs.acs.org/OrgLett

Umpolung Synthesis of 1,3-Amino Alcohols: Stereoselective Addition of 2‑Azaallyl Anions to Epoxides Paige E. Daniel, Alexandria E. Weber, and Steven J. Malcolmson* Department of Chemistry, Duke University, Durham, North Carolina 27708, United States S Supporting Information *

ABSTRACT: We report the direct preparation of 1,3-amino alcohols that contain up to three contiguous stereogenic centers by the umpolung coupling of imines and epoxides. Nucleophilic 2-azaallyl anions, generated from imines, are stereoselectively added to epoxides to furnish 1,3-amino alcohols after hydrolysis of the product imine. Transformations afford amino alcohols with >98% site selectivity with respect to both reaction partners and in up to >98% yield and >20:1 dr.

A

Scheme 1. Stereoselective Methods to 1,3-Amino Alcohols

mino alcohols are common motifs in a large number of naturally occurring molecules and medicinal compounds.1 In contrast to the numerous methods for stereoselective preparation of 1,2-amino alcohols,2 there are fewer means of accessing the 1,3congeners,3 particularly those containing a stereotriad within the three-carbon unit. Commonly, the Mannich reaction,4 employing an electrophilic imine (Scheme 1), has been utilized to prepare 1,3amino alcohols. This strategy, like several others,5,6 does not generate the amino alcohol framework directly. Instead, a subsequent reduction event is required to produce the 1,3amino alcohol. Often in preparing a stereotriad by Mannich chemistry, one of the substituents, R1-R3, is a carbonyl or R1 and R2 are linked in a carbocycle. Contrastingly, intramolecular C−H amination has emerged as an efficient tactic for direct stereoselective preparation of this moiety. While several catalytic variants are known,7 this strategy necessitates preassembly of the hydrocarbon skeleton, including requisite stereochemistry.8 Rarely do these strategies generate tertiary alcohols. Our umpolung approach9 employs an intermolecular, stereoselective C−C bond-forming reaction that directly generates the 1,3-amino alcohol without further redox manipulation by the combination of 2-azaallyl anions10−12 with 1,2-disubstituted epoxides. Exclusive benzylic attack upon the epoxide with complete inversion of stereochemistry occurs from the Nsubstituted carbon nucleophiles at their least hindered α-tonitrogen position, delivering amino alcohols with three contiguous stereogenic centers in up to >98% yield and >20:1 dr. 1,3-Amino tertiary alcohol products are formed by stereoselective 2-azaallyl anion addition to the terminal position of 2,2-disubstituted epoxides. Benzophenone-derived imine 1a and trans-β-methylstyrene oxide 3a can be coupled to form amino alcohol 4a as a mixture of syn- and anti-isomers at the site of C−C bond formation (Table 1). A survey of bases of sufficient strength to deprotonate 1a (pKa = 24.3)13 and form the azaallyl anion revealed the critical role Li plays in promoting the desired reaction (entries 1−6), suggesting that Li © 2017 American Chemical Society

may also act as a Lewis acid to activate the epoxide for attack.14 Regardless of counterion or conditions, the azaallyl anion reacts through its least substituted nucleophilic position15 and adds to 3a exclusively at the benzylic carbon to afford amino alcohol 4a, favoring the syn-diastereomer.16 Lowering the reaction temperature to −45 °C increases the diastereoselectivity to 6:1 (entry 7), and increasing to 2 equiv of nucleophile (entry 9) leads to complete consumption of epoxide in 4 h with amino alcohol 4a isolated in 79% yield (5.5:1 dr). Both imine tautomers, 1a and 2a (Table 1), lead to the same resonance stabilized azaallyl anion, enabling whichever isomer is more easily accessed to be employed in forming 1,3-amino alcohols. Subjection of aldimine 2a to the standard deprotonation conditions (2.0 equiv LiHMDS), however, does not generate the Received: May 15, 2017 Published: June 28, 2017 3490

DOI: 10.1021/acs.orglett.7b01471 Org. Lett. 2017, 19, 3490−3493

Letter

Organic Letters Table 1. Evaluation of Reaction Conditionsa

Table 2. Azaallyl Anion Addition to trans-1,2-Disubstituted Epoxidesa

entry

imine

base

temp (°C); time (h)

conv (%)b

drc syn:anti 4a

1 2 3 4 5 6 7 8 9d 10d

1a 1a 1a 1a 1a 1a 1a 1a 1a 2a

LiHMDS NaHMDS KHMDS LiHMDS NaHMDS KHMDS LiHMDS LiHMDS LiHMDS LDA

0; 4 0; 4 0; 4 −20; 3.5 −20; 3.5 −20; 3.5 −45; 4 −60; 24 −45; 4 −45; 4

>98 66 13 87 19 98 (79)e >98 (74)e

3.5:1 3.0:1 2.5:1 4.0:1 3.5:1 − 6.0:1 6.5:1 5.5:1 5.5:1

entry

product Ar; R

temp (°C); time (h)

yield(%)b

drc syn:anti

1 2 3 4 5 6 7 8 9 10 11 12

4-OMeC6H4; Me (4b) 4-CF3C6H4; Me (4c) 4-CNC6H4; Me (4d) 4-BrC6H4; Me (4e) 3-MeC6H4; Me (4f) 3-BrC6H4; Me (4g) 2-MeC6H4; Me (4h) 2-BrC6H4; Me (4i) Ph; n-Bu (4j) Ph; CH2OTBS (4k) Ph; i-Pr (4l) Ph; Ph (4m)

−45; 4 −78; 24 −78; 24 −78; 48 −60; 24 −60; 27 −45; 48 −45; 24 −60; 24 −45; 24 −45; 48 −60; 24

94 73d >98 77d 67 81 78 73d 57 92 43 67d

9.0:1 16.0:1 >20:1 14.5:1 11.0:1 8.0:1 9.5:1 7.0:1 7.0:1 13.5:1 >20:1 16.5:1

a

Reactions run with 0.1 mmol of imine; see the Supporting Information (SI) for experimental details. bBased on consumption of 3a as determined by 500 MHz 1H NMR spectroscopy of the unpurified mixture in comparison with an internal standard. c Determined by 500 MHz 1H NMR spectroscopy of the unpurified mixture. dReaction with 2.0 equiv of imine and 4.0 equiv of base. e Isolated yield of the diastereomeric mixture after purification.

a

See the SI for experimental details. bIsolated yields of diastereomeric mixtures after purification unless otherwise noted. cDiastereomeric ratio determined by 500 MHz 1H NMR spectroscopy of the unpurified mixture. dIsolated yield of the major diastereomer.

Scheme 2. Nucleophile Variation in Azaallyl Anion Couplings with Epoxide 3da,b,c

azaallyl anion even with extended reaction times; instead, the stronger LDA is needed (2:1 LDA:2a, 10 min at 22 °C, entry 10). Azaallyl anion addition under the established conditions then delivers 4a in 74% yield and 5.5:1 dr. A number of trans-1,2-disubstituted epoxides, several of which are easily prepared in enantioenriched form,17 readily react with the azaallyl anion formed from imine 1a (Table 2), providing a convenient two-step protocol for accessing enantioenriched 1,3amino alcohols. Reaction of electron-rich p-methoxyphenyl/ methyl epoxide 3b furnishes amino alcohol 4b in 94% yield and 9:1 dr (entry 1), and electron-withdrawing groups in the para-position permit higher diastereoselectivity to be achieved at lower reaction temperature (4c−e formed in 14.5 to >20:1 dr, entries 2−4). Metaand ortho-substitution of aromatic rings within the electrophile are also tolerated; amino alcohols 4f−i are generated in 67−80% yield and 7−11:1 dr (entries 5−8). Variation of the epoxide’s alkyl substituent reveals that heteroatoms and branching within the alkyl chain are amenable to azaallyl anion addition (entries 9−11). For example, silyl ether 4k, bearing differentiated hydroxyl groups, is formed in 92% yield and 13.5:1 dr. Although slower to react, i-Prsubstituted epoxide 3l delivers amino alcohol 4l in >20:1 dr. In addition to aryl/alkyl-substituted epoxides, trans-stilbene oxide can be coupled to form amino alcohol 4m in 67% yield with high diastereoselectivity (16.5:1 dr). In all cases, the product is generated with >98% site selectivity with respect to both the nucleophile and epoxide. Several azaallyl anions, including those with aryl, heteroaryl, vinyl, and alkynyl substituents, are excellent partners for transformations with trans-disubstituted epoxide 3d (Scheme 2).18 As with the parent nucleophile, the presence of parasubstituents on the aromatic ring of the azaallyl anion leads to high diastereoselectivity in forming amino alcohols 4n−o (16.5:1 and >20:1 dr, respectively). Aryl-substituted nucleophiles with groups at the meta- or ortho-positions add efficiently to generate 4p−q in 86−91% yield. A pyridyl-containing azaallyl anion furnishes amino

a

See the SI for experimental details. bIsolated yields of diastereomeric mixtures after purification unless otherwise noted. cDiastereomeric ratio determined by 500 MHz 1H NMR spectroscopy of the unpurified mixture. dFrom ketimine isomer 1. eReaction at −78 °C. fReaction at −60 °C. gFrom aldimine isomer 2b. hReaction for 48 h. iLiHMDS added to a −45 °C solution of ketimine 1f or 1g and epoxide 3d. Ar = 4-CNC6H4.

alcohol 4r (94% yield, 3.5:1 dr), which yielded crystals of the major diastereomer, illustrating the product’s stereochemical composition.16 This latter azaallyl anion was generated efficiently from aldimine 2b by deprotonation with LiHMDS although these conditions (10 min at 22 °C) have been unsuccessful with all other aldimines tested, indicating that pyridine coordination to the Li may facilitate deprotonation. 3491

DOI: 10.1021/acs.orglett.7b01471 Org. Lett. 2017, 19, 3490−3493

Letter

Organic Letters Scheme 3. Coupling with cis-Disubstituted Epoxidesa,b,c

Scheme 4. 1,3-Amino Tertiary Alcohol Synthesis via Azaallyl Anion/2,2-Disubstituted Epoxide Couplinga,b,c,d

a

See the SI for experimental details. bIsolated yields of diastereomeric mixtures after purification unless otherwise noted. cDiastereomeric ratio determined by 500 MHz 1H NMR spectroscopy of the unpurified mixture. dIsolated yield of the major diastereomer. a

See the SI for experimental details. bIsolated yields of diastereomeric mixtures after purification unless otherwise noted. cDiastereomeric ratio determined by 500 MHz 1H NMR spectroscopy of the unpurified mixture. dIsolated yield of the major diastereomer. eReaction for 19 h. f Calculated yield of product from a mixture that contains ca. 30 mol % 1a. gReaction at −20 °C.

In comparison to the trans-epoxides examined, cis-disubstituted epoxides are considerably less reactive, requiring 24 h at room temperature to furnish amino alcohols (Scheme 3). The higher temperature likely contributes to lower stereoselectivity.16 Benzylic attack by azaallyl anions upon terminal aryl-substituted epoxides deliver primary alcohols with good diastereocontrol (e.g., 8 formed in 5:1 dr, eq 1). In contrast, terminal alkylsubstituted epoxides unsurprisingly react at their less hindered position, furnishing secondary alcohols (e.g., 9 formed in 71% yield, eq 2).

Scheme 5. Representative Functionalization of 1,3-Amino Alcohol Products

2-Azaallyl anion additions to chiral epoxides provide operationally simple, expedient, and redox-economic means to prepare complex and difficult-to-access 1,3-amino alcohols efficiently and stereoselectively from readily accessible starting materials. The wealth of existing methods that afford epoxides enantioselectively17 further enhances the impact of these transformations. The development of other stereoselective methods with azaallyl reagents is underway.

The efficiency by which terminal alkyl-substituted epoxides undergo azaallyl anion addition inspired us to examine stereoselective reactions with 2,2-disubstituted epoxides for the direct formation of 1,3-amino tertiary alcohols (Scheme 4).19 The combination of 1a with α-methylstyrene oxide affords tertiary alcohol 11a in 4:1 dr with the major diastereomer isolated in 61% yield. The alkyl chain of the epoxide may be extended (11b16, in >98% yield) or may contain a silyl ether as a further synthetic handle (11c, in 89% yield). Cyclohexyl/methyl-substituted epoxide 10d furnishes amino alcohol 11d in 95% yield. Azaallyl anion additions to epoxides may be performed on gramscale (1.0 g 4d prepared in 91% yield, Scheme 5), and the product’s imine hydrolyzed under mildly acidic conditions to generate the free amine 12 (90% yield).20 The amino alcohols that are formed may serve as platforms for accessing complex and desirable molecular scaffolds, including N-heterocycles. N-tosylation of amine 12 followed by subjection to Mitsunobu conditions furnishes azetidine 13 in 81% yield over two steps. The stereocontrolled synthesis of such highly substituted azetidines has rarely been accomplished.21

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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.7b01471. Crystal structure data (CIF, CIF, CIF) Experimental procedures, analytical data for new compounds, spectral data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. 3492

DOI: 10.1021/acs.orglett.7b01471 Org. Lett. 2017, 19, 3490−3493

Letter

Organic Letters ORCID

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Steven J. Malcolmson: 0000-0003-3229-0949 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge Kangnan Li, Hope Knochenhauer, and Jason Luo for experimental assistance and helpful discussions and Dr. Roger Sommer (NC State) for X-ray crystallographic analysis. We thank the ACS Petroleum Research Fund (56575-DNI1) and Duke University for generous financial support. P.E.D. is grateful to the Department of Education for a GAANN fellowship (P200A150114).

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DOI: 10.1021/acs.orglett.7b01471 Org. Lett. 2017, 19, 3490−3493