Asymmetric Synthesis of Homoallylic Amines and Functionalized Pyrrolidines via Direct Amino-Crotylation of In Situ Generated Imines

Schaus, Jennifer V.; Jain, Neha; Panek, James S.

doi:10.1016/s0040-4020(00)00870-x

Cited by 48 publications

(17 citation statements)

References 38 publications

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“…The aza-analogue of the SMS condensation has been reported [35,[45][46][47]. Veenstra and Schmid in 1997 [46] were the first to perform the three-component condensation between an aldehyde 6, an amine 92 and an allylsilane 1.…”

Section: Deviancementioning

confidence: 99%

The Modified Sakurai and Related Reactions

Jacques

Markó

Pospíšil

2005

Multicomponent Reactions

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Section: Deviancementioning

confidence: 99%

The Modified Sakurai and Related Reactions

Jacques

Markó

Pospíšil

2005

Multicomponent Reactions

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“…In order to access macrocyclic bis -lactam substrates, we utilized cyclodimerization of stereochemically well-defined homoallylic amino esters7 using Zr(IV)-catalyzed ester-amide exchange 8. Alloc-protected amino esters 1a–d were prepared using asymmetric crotylation7 of the iminium species derived from condensation of allyl carbamate with aromatic aldehydes (Scheme 1).…”

mentioning

confidence: 99%

“…Alloc-protected amino esters 1a–d were prepared using asymmetric crotylation7 of the iminium species derived from condensation of allyl carbamate with aromatic aldehydes (Scheme 1). Subsequent alloc removal9 using a polymer-bound Pd (0) reagent (PS-PPh 3 -Pd) 10 simplified product purification and afforded amino ester monomers 2a–d .…”

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confidence: 99%

Reaction Discovery Employing Macrocycles: Transannular Cyclizations of Macrocyclic Bis-lactams

et al. 2008

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Macrocyclic bis-lactams have been synthesized by cyclodimerization of homoallylic amino esters employing a Zr(IV)-catalyzed ester-amide exchange protocol. Base-mediated transannular cyclizations have been identified to access both bicyclic [5][6][7][8][9][10][11] and tricyclic [5-8-5] frameworks in good yield and diastereoselectivity. Preliminary mechanistic studies support an olefin isomerizationintramolecular conjugate addition pathway.Macrocyclic natural products often exhibit important biological activities and have thus inspired a number of studies involving diversity-oriented synthesis of macrocyclic frameworks. 1 Recent studies have also highlighted elegant examples of transannular cyclizations enroute to complex natural products. 2 As part of our studies, we considered preparation of macrocycles as substrates for reaction discovery 3 and potential complexity-generating transannular cyclizations. 4,5 In this communication, we report the preparation of 14-membered ring bislactams 6 and their conversion to polycyclic frameworks by divergent, transannular reaction processes as well as preliminary computational studies to probe the reaction mechanism.In order to access macrocyclic bis-lactam substrates, we utilized cyclodimerization of stereochemically well-defined homoallylic amino esters 7 using Zr(IV)-catalyzed ester-amide exchange. 8 Alloc-protected amino esters 1a-d were prepared using asymmetric crotylation 7 of the iminium species derived from condensation of allyl carbamate with aromatic aldehydes (Scheme 1). Subsequent alloc removal 9 using a polymer-bound Pd (0) reagent (PS-PPh 3 -Pd) 10 simplified product purification and afforded amino ester monomers 2a-d. As cyclodimerization of 2 involves consecutive intermolecular and intramolecular amidations, we anticipated that concentration may play an important role in reaction efficiency. Therefore, a range of concentrations (0.10-0.80 M) were examined for cyclodimerization of 2a using Zr (Ot-Bu) 4 -2-hydroxypyridine (HYP) 8 as catalyst (Scheme 2). Based on these studies, an optimal concentration for production of 14-membered bis-macrolactam 3a was found to be 0.60 M.Macrocyclic bis-lactams 3b-d were also prepared in moderate to good yield using the optimized conditions. The structure and stereochemistry of bis-lactam 3b was confirmed by single x-ray crystal structure analysis (one conformer shown). 10With the target macrolactams in hand, we focused on reaction discovery to identify complexitygenerating transannular cyclizations. Initial attempted intramolecular hydroamidation 11 of bislactam 3b utilizing carbophilic late-transition metal catalysts including Pd(II), Ag(I), Pt(II), Au(I), and Au(III) 12 failed to afford any cyclized products. After reaction screening, use of NaH as base 13 in DMF at 60 °C was found to provide tricyclic [5-8-5] product 5 (dr= 5:1:1) (Scheme 3, entry 1). Reaction at room temperature using NaH gave no conversion indicating a high activation energy for transannular cyclization (Scheme 3, entry 2). Further optimization ...

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“…The addition of crotylsilanes to in situ generated iminium ions for the formation of homoallylic amines and pyrrolidines has been well developed, and generally proceeds with high yield and selectivity. 6 Racemic allenes have been used in a variety of additions to imines, resulting in [3 + 2] and [4 + 2] annulation products, many with high diastereoselectivity and enantiomeric excess due to the use of chiral catalysts. 7 In addition, a few reports containing examples of allenylsilanes being used in [3 + 2] annulations with iminium ions are available, but they show a limited substrate scope and selectivity.…”

mentioning

confidence: 99%

Annulations of Enantioenriched Allenylsilanes with in Situ Generated Iminium Ions: Stereoselective Synthesis of Diverse Heterocycles

Brawn

Panek

2008

Org. Lett.

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Highly enantioenriched allenylsilanes participate in Lewis acid mediated annulations with in situ generated iminium ions derived from tert-butyl carbamate and methyl carbamate to selectively form functionalized 4,5-dihydropyrroles and 4,5-dihyrooxazines respectively. The dihydropyrrole products were further elaborated in a stereocontrolled vinylsilane terminated cyclization with in situ generated oxonium ions, resulting in pyranopyrroles.Recently allenes have emerged as an important functional group for a variety of organic transformations. 1 In particular, allenylsilanes have proven useful as carbon nucleophiles in addition to carbon-oxygen π-bonds producing homopropargylic alcohols, 2 homopropargylic ethers, 3 furans, 4 and dihydrofurans. 5 Many of these reactions occur with excellent diasetereo-and enantioselectivity.While the additions of allenylsilanes to carbonyl groups have been well developed, there are fewer examples of similar reactivity with activated carbon-nitrogen π-bonds. The addition of crotylsilanes to in situ generated iminium ions for the formation of homoallylic amines and pyrrolidines has been well developed, and generally proceeds with high yield and selectivity. 6 Racemic allenes have been used in a variety of additions to imines, resulting in [3 + 2] and [4 + 2] annulation products, many with high diastereoselectivity and enantiomeric excess due to the use of chiral catalysts. 7 In addition, a few reports containing examples of allenylsilanes being used in [3 + 2] annulations with iminium ions are available, but they show a limited substrate scope and selectivity. In interest of complete transparency, Danheiser was the first to demonstrate a [3 + 2] annulation of racemic allenylsilanes with β-alkoxylactams, affording pyrrolizinones as the major products. 5 More recently, Akiyama reported a Cu(I)-catalyzed cycloaddition to afford dihydroproline derivatives. 8 The purpose panek@bu.edu. Supporting Information Available Experimental data and selected spectral data for all new compounds. This material is available free of charge via the internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2011 September 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of this communication is to report our initial studies on the use of chiral allenylsilanes in annulations with N-acyl iminuim ions generated in situ from carbamates and aldehydes.We have recently reported an efficient synthesis of highly enantioenriched allenylsilane (S a ) −1 and its enantiomer. That sequence, from the corresponding propargylic alcohol, utilized a lipase resolution followed by a Johnson orthoester Claisen rearrangement. These reagents can be accessed on a multi-gram scale (>15g) with >95% ee. 3Several conditions were explored for the addition of these allenylsilanes to iminium ions, which were formed in situ by activating an aldehyde in the presence of an amine with a Lewis acid. After screening a number of amines, benzyl amines,...

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Asymmetric Synthesis of Homoallylic Amines and Functionalized Pyrrolidines via Direct Amino-Crotylation of In Situ Generated Imines

Cited by 48 publications

References 38 publications

The Modified Sakurai and Related Reactions

The Modified Sakurai and Related Reactions

Reaction Discovery Employing Macrocycles: Transannular Cyclizations of Macrocyclic Bis-lactams

Annulations of Enantioenriched Allenylsilanes with in Situ Generated Iminium Ions: Stereoselective Synthesis of Diverse Heterocycles

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