Diastereoselective α-Hydroxylation of N-tert ... - ACS Publications

Letter Cite This: Org. Lett. 2018, 20, 1236−1239

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Diastereoselective α‑Hydroxylation of N-tert-Butanesulfinyl Imidates and N′-tert-Butanesulfinyl Amidines with Molecular Oxygen Peng-Ju Ma,†,‡ Hui Liu,† Yan-Jun Xu,† Haji Akber Aisa,† and Chong-Dao Lu*,† †

Key Laboratory of Plant Resources and Chemistry of Arid Zones, Xinjiang Technical Institute of Physics & Chemistry, Chinese Academy of Sciences, Urumqi 830011, China ‡ University of Chinese Academy of Sciences, Beijing 100049, China S Supporting Information *

ABSTRACT: Diastereoselective α-hydroxylation using molecular oxygen has been achieved with chiral α-alkyl N-tert-butanesulfinyl imidates and α-aryl N′-tertbutanesulfinyl amidines. The aza-enolates generated from deprotonation of imidates/amidines can be intercepted by O2 with excellent diastereocontrol and subsequently transformed into α-hydroxylation products in the presence of the reductant trimethyl phosphite.

ptically pure α-hydroxy acid derivatives are important structural motifs in organic synthesis.1 Oxidation of the enolates derived from carboxylic acid derivatives is one of the most straightforward methods for preparation of enantioenriched α-hydroxy acid derivatives.2 On the basis of this transformation, asymmetric catalysis has been developed but is limited mainly to substrates such as β-keto acid derivatives, which are prone to enolization.3 For acid derivatives such as amides that possess low α-CH acidity, asymmetric inductions involving chiral oxidants4 or enolates containing chiral auxiliaries are attractive. More than 30 years ago, Evans’ pioneering work proved the feasibility of asymmetric αhydroxylation using enolates derived from chiral carboximides.5 Since then, a few other chiral imidates and amides have been developed to enable this transformation in the presence of suitable oxidants.6 Molecular oxygen is an ideal oxidant because it is readily available, inexpensive, and environmentally benign.7 However, oxygen has only recently been used to α-hydroxylate enolates that are generated from acid derivatives bearing chiral auxiliaries. In 2010, Brigaud and co-workers reported an elegant diastereoselective α-hydroxylation of 2-(trifluoromethyl)oxazolidine (Fox)-based chiral amide enolates with molecular oxygen.8 In that study, the Fox chiral auxiliary performed much better than the Evans oxazolidinone in the presence of oxygen, which the authors attributed to the stability of the intermediate peroxide species in the Fox process. This work constitutes a rare example of successful hydroxylation of chiral enolates with molecular oxygen as oxidant.9,10 However, that report only considered α-alkyl-substituted chiral amides, which limits its potential applications in organic synthesis.8 As equivalents of chiral amides, N-tert-butanesulfinyl (N-tBS) imidates or N′-tert-butanesulfinyl (N′-tBS) amidines have been used for asymmetric construction of C−C or C−N bonds at the α-position via diastereoselective alkylation11 and addition to electrophiles containing polarized π-bonds such as aldehydes, imines, 1,4-addition acceptors, and nitrosoarenes (Scheme

O

© 2018 American Chemical Society

1a).12−15 To date, diastereoselective C−O bond formation using N-tBS imidates or N′-tBS amidines has not been disclosed. Scheme 1. Transformations Involving the α-Position of Ntert-Butanesulfinyl Imidates or N’-tert-Butanesulfinyl Amidines

Here, we report that molecular oxygen can be used as an effective trapping reagent to intercept the aza-enolates derived from N-tBS imidates or N′-tBS amidines, forming α-hydroxy imidates or amidines in the presence of trialkyl phosphite with excellent diastereocontrol (Scheme 1b). The starting material for the preparation of N-tBS imidates or N′-tBS amidines is tertbutanesulfinamide (tBSNH2),16 both enantiomers of which are stable and inexpensive17 and have low molecular weight. As a result, an α-hydroxy functional group can be economically and stereospecifically installed in either the R or S configurations by Received: January 17, 2018 Published: February 6, 2018 1236

DOI: 10.1021/acs.orglett.8b00178 Org. Lett. 2018, 20, 1236−1239

Letter

Organic Letters

Table 1. Substrate Scope of the α-Hydroxylation of N-tertButanesulfinyl Imidates and N′-tert-Butanesulfinyl Amidinesa

using the suitable enantiomer of the N-tBS amide chiral auxiliary. Initially, we examined the α-hydroxylation of (RS)-N-tertbutanesulfinyl imidate 1a by exposing the enolized 1a to a bubbling stream of dry oxygen at −78 °C in the presence of P(OMe)3 as reductant. Screening of bases18 led us to select sodium bis(trimethylsilyl)amide (1.2 equiv) as the best choice for this reaction: complete conversion of starting material was observed when the reaction mixture was maintained at −78 °C for 2 h, yielding the α-hydroxy imidate 2a in 84% yield with excellent diastereocontrol (>20:1 dr, Scheme 2). We then Scheme 2. Initial Results of α-Hydroxylation of N-tertButanesulfinyl Imidates and N′-tert-Butanesulfinyl Amidines

carried out the reaction with α-phenyl imidates 1b, but conversion was low even after prolonging the reaction time to 8 h at −78 °C. Product 2b was obtained in 56% yield (>20:1 dr) with recovery of 37% of 1b. Attempts to improve the yield by raising the reaction temperature were unsuccessful, indicating the relatively low reactivity of α-aryl-substituted N-tBS imidates. To our delight, swapping the methoxy group in the imidate 1b with a 4-morpholinyl group dramatically improved the efficiency of the reaction. Performing the reaction with 3b at −78 °C provided the desired α-phenyl α-hydroxy amidine 4b in excellent yield with excellent diastereoselectivity (93% yield, >20:1 dr). In the case of α-methyl N′-tBS amidine 3a, hydroxylation was also possible but 2.0 equiv of base and warming the reaction mixture to −50 °C were required to achieve satisfactory results (81% yield, 25:1 dr). The absolute configuration of the newly formed chiral center was S based on X-ray crystal structures of 4a and 2b.19 The hydroxylated imidates 2a and 2b were easily converted to the corresponding amidines 4a and 4b in high yields via cyanide-promoted aminolysis, leaving the chiral structure intact (Scheme 2).11c With the optimal reaction conditions in hand, the substrate scope for the diastereoselective α-hydroxylation was examined (Table 1). A range of imidates 1 bearing various α-alkyl substitutions including nonfunctionalized aliphatic groups (entries 1−5) and ether-, vinyl-, or alkynyl-containing alkyl groups (entries 6−11) were smoothly hydroxylated to give the corresponding products 2c−k in good yields (75−97%). Moreover, α-branched alkyl-substituted imidate 1l was a good substrate in this oxygen-dependent hydroxylation protocol (entry 12).20 Next, α-aryl-substituted amidines were investigated under the hydroxylation conditions. In the cases of amidines with ortho-, meta-, or para-substituted aryl groups at the α position, α-hydroxylated products 4c−h were obtained in

entry

imidate/amidine (R)

product

yieldb (%)

1 2c 3 4 5 6 7 8 9 10 11 12 13 14c 15 16d 17d 18 19 20e 21e

1a (Me) ent-1a (Me) 1c (Et) 1d (nPr) 1e (Bn) 1f (tBuMe2SiO(CH2)3) 1g (PMBO(CH2)3) 1h (CH2CH(CH2)3) 1i (allyl) 1j (MeCCCH2) 1k (PhCCCH2) 1l (iPr) 3b (Ph) ent-3b (Ph) 3c (4-MeC6H4) 3d (3-MeC6H4) 3e (2-MeC6H4) 3f (4-MeOC6H4) 3g (4-FC6H4) 3h (4-ClC6H4) 3i (3,4-diClC6H3)

2a ent-2a 2c 2d 2e 2f 2g 2h 2i 2j 2k 2l 4b ent-4b 4c 4d 4e 4f 4g 4h 4i

84 76 87 75 85 97 85 96 88 84 85 92 93 90 99 89 92 92 (89)f 87 78 47

a

Reaction conditions: 1 or 3 (0.30 mmol), NaHMDS (0.36 mmol), and trimethyl phosphite (0.60 mmol) in anhydrous THF (2.0 mL) at −78 °C with a bubbling stream of oxygen. Reactions were complete within 2 h unless otherwise noted. Diastereoselective ratios were determined by 1H NMR spectroscopy of the crude reaction mixture. b Isolated yield after silica gel chromatography. cThe (S)-enantiomer of N-tert-butanesulfinyl imidate was used. dThe reaction mixture was stirred for 4 h at −78 °C before quenching. eThe reaction mixture was stirred for 1 h at −78 °C and then gradually warmed to −50 °C and stirred for 3 h before quenching. fThe reaction on a 1 g scale.

good to excellent yields (entries 15−20). The hydroxylation reaction was easily scaled up to the 1 g scale without obvious loss of yield (entry 18). Aryl amidine with 3,4-dichloro substitutions on the phenyl group resisted hydroxylation: the hydroxylated amidine 4i was obtained in only 47% yield, and nearly half the starting material was recovered (entry 21). Using enantiomers of 1a and 3b led to facile synthesis of the corresponding functionalized secondary alcohols ent-2a and ent-4b with an R configuration at the α-position (entries 2 and 14). For all cases in Table 1, α-hydroxylation proceeded with excellent diastereocontrol (>20:1 dr). We were interested in applying our hydroxylation protocol to α,α-disubstituted imidates.21 Preliminary results revealed that hydroxylation of chiral α,α-disubstituted imidates such as 5 and 7 was feasible, yielding products in good yields but with low diastereoselectivities as expected (Scheme 3). High conversion required warming the reaction from −78 to −10 °C. Manipulations of the imidate/amidine group on the αhydroxylated products are presented in Scheme 4. Treatment of silyloxy imidate 9 with DIBAL-H in THF provided the 1237

DOI: 10.1021/acs.orglett.8b00178 Org. Lett. 2018, 20, 1236−1239

Letter

Organic Letters Scheme 3. Attempts toward α-Hydroxylation of α,αDisubstituted N-tert-Butanesulfinyl Imidates

Scheme 5. Rationalization of Stereochemistry

Scheme 4. Downstream Manipulations of α-Hydroxy Imidate/Amidines

sulfinyl amidines using molecular oxygen as the oxidizer. This protocol allows efficient access to chiral α-alkyl- and α-arylsubstituted glycolate analogues. The ability to manipulate the imidate and amidine groups can generate a range of chiral hydroxyl group-containing products that are suitable for further transformations.

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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.8b00178. Experimental details; characterization data of all new compounds (PDF) Accession Codes

CCDC 1818028−1818030 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

Haji Akber Aisa: 0000-0003-4652-6879 Chong-Dao Lu: 0000-0001-8968-0134

protected 1,2-amino alcohol 10 in 88% yield. Addition of MeMgBr to 9 yielded ketimine 11, a useful precursor for chelation-controlled ketimine addition reactions.22 Desulfinylation of the benzoylated imidate derivative 12 using anhydrous HCl in MeOH led to ester 13 in 86% yield, while exposing 12 to hydrolysis conditions (4 M H2SO4) led to amide 14 in 78% yield. The α-hydroxy amidine 4f was directly reduced to aldimine23 with LiAlH4 or underwent direct nucleophilic addition with MeMgBr, without the need to protect the free hydroxyl group. Both α-hydroxy N-tBS aldimine 15 and ketimine 16 are relatively stable and can be stored in a freezer (−18 °C) for 2 weeks without obvious loss of purity.24 To rationalize the observed stereochemistry of the hydroxylation products, we propose a well-documented Ellman’s chelated chairlike 6/4-membered transition state TS1.25 Molecular oxygen approaches from the Si-face of (E)-(RS)aza-enolate to minimize nonbonding interactions between the oxygen and the tBu group in the imidate/amidine. Subsequent reduction of the hydroperoxide intermediate with trimethyl phosphite gives α-hydroxylation product with an (RS,2S) configuration (Scheme 5). In summary, we have described a highly diastereoselective αhydroxylation of N-tert-butanesulfinyl imidates/N′-tert-butane-

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (U1403301 and 21572262), the Recruitment Program of Global Experts (Xinjiang Program), and the Director Foundation of XTIPC (2015RC014).

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REFERENCES

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DOI: 10.1021/acs.orglett.8b00178 Org. Lett. 2018, 20, 1236−1239

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Organic Letters

Chem. Rev. 2010, 110, 3600−3740. (d) Dong, H.-Q.; Xu, M.-H.; Feng, C.-G.; Sun, X.-W.; Lin, G.-Q. Org. Chem. Front. 2015, 2, 73−89. (17) Both enantiomers of tert-butanesulfonamide (ee ∼ 99.3−99.5%) used in this work were purchased from AllyChem (Dalian, China) at a cost of 2500 RMB per kg (approximately 400 USD per kg). (18) The reaction using LiHMDS gave product 2a in 35% yield with 2.5:1 dr, and the reaction using KHMDS gave 2a in 36% yield with > 20:1 dr. (19) For single-crystal X-ray structures of compounds 2b, 4a, and 4f, see the Supporting Information. (20) We could not examine α-tert-butyl substituted N-tBS imidate because our attempts to synthesize this compound have been unsuccessful so far. (21) For m-CPBA oxidation of stereodefined polysubstituted silyl ketene aminals, see: Huang, J. Q.; Nairoukh, Z.; Marek, I. Eur. J. Org. Chem. 2017, DOI: 10.1002/ejoc.201701516. (22) (a) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001, 66, 8772−8778. (b) Evans, J. W.; Ellman, J. A. J. Org. Chem. 2003, 68, 9948−9957. (23) Douat, C.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron Lett. 2000, 41, 37−40. (24) Substantial degradation of the α-hydroxy imines 15 and 16 was observed when these samples sat on the bench for 2 days at room temperature. For a report on auto-oxidation of α-hydroxy imines, see: Murakami, M.; Komoto, I.; Ito, H.; Ito, Y. Synlett 1993, 1993, 511− 512. (25) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003, 125, 11276−11282.

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DOI: 10.1021/acs.orglett.8b00178 Org. Lett. 2018, 20, 1236−1239