Stereoselective Synthesis of β-Hydroxy Enamines, Aminocyclopropanes, and 1,3-Amino Alcohols via Asymmetric Catalysis

Abstract

Tandem methods for the catalytic asymmetric preparation of enantioenriched β-hydroxy (E)-enamines and cyclopropylamines are presented. The diastereoselective hydrogenation of enantioenriched (E)-trisubstituted hydroxy enamines to generate 1,2-disubstituted 1,3-amino alcohols is also outlined. These methods are initiated by highly regioselective hydroboration of N-tosyl substituted ynamides with diethylborane to generate β-amino alkenyl boranes. In situ boron to zinc transmetalation generates β-amino alkenyl zinc reagents. These functionalized vinylzinc intermediates were subsequently added to aldehydes in the presence of catalyst derived from an enantioenriched amino alcohol (morpholino isoborneol, MIB). The catalyst promotes highly enantioselective C–C bond-formation to provide β-hydroxy enamines in good isolated yields (68–86%) with 54–98% enantioselectivity. The intermediate zinc β-alkoxy enamines can be subjected to a tandem cyclopropanation to afford amino cyclopropyl carbinols with three continuous stereocenters in a one-pot procedure with good yields (72–82%), enantioselectivities of 76–94% and diastereomeric ratios >20:1. Diastereoselective hydrogenation of isolated enantioenriched β-hydroxy enamines over Pd/C furnished syn-1,2-disubstituted-1,3-amino alcohols with high yields (82–90%) and moderate to excellent diastereoselectivities. These methods were used in an efficient preparation of the enantioenriched precursor to PRC200-SS derivatives, which are potent serotonin-norepinephrine-dopamine reuptake inhibitors.

Alkylative Carboxylation of Ynamides and Allenamides with Functionalized Alkylzinc Halides and Carbon Dioxide by a Copper Catalyst

“…[5b,d,e,i, 6c, 10] In this context, we have achieved the alkylativec arboxylation of ynamides with dialkylzinc reagents (R 2 Zn) and CO 2 which affords a,b-dehydro-a-amino acid esters bearing ab ranched alkyl group introduced by the addition of dialkylzinc reagents. Herein, we report our studies on the alkylativec arboxylationso fy namides and allenamides [13][14][15][16][17][18] with alkylzinch alides and CO 2 ,w hich afford various a,b-dehydro-a-a nd b-amino acid esters with well-controlled configuration. [5i] Although these methods can afford av ariety of a,b-dehydroamino acid esters with well-controlled configurations, the introducible alkyl groups are limitedt omethyl, ethyl, or butyl due to the accessibility of dialkylzincr eagents.…”

Synthesis of 1,2‐Amino Alcohols by Sigmatropic Rearrangements of 3‐(N‐Tosylamino)allylic Alcohol Derivatives

“…[11] Chirality transfer with a-allyloxy acetamides derived from secondary 3-(N-tosylamino)allylic alcohols: The [2,3]-Wittig rearrangement of secondary 3-(N-tosylamino)allylic alcohol derivatives should afford functionalized 1,2-amino alcohols and create, at the same time, a disubstituted alkene. The presence of a stereocenter in the starting substrates may alter the 1,2-diastereoselectivity and this had to be checked prior to investigating chirality transfer in the absolute sense (Scheme 19).…”

“…Acyclic 3-aminoallylic alcohols A, which are stable vinylogous hemiaminals, [8] appeared as an interesting subclass of functionalized enA C H T U N G T R E N N U N G amides that could be engaged in reactions carried out with regular allylic alcohol or derivatives. [9][10][11] We reasoned that the [3,3]-Ireland-Claisen rearrangement [12] of silyl ketene acetals C generated from glycolates B [13] or the [2,3]-Wittig rearrangement of ethers D, [14] triggered by deprotonation with a base, should constitute interesting entries to g,dunsaturated a-hydroxy-b-amino acid derivatives E. In com-pounds E, the carbonyl group and the olefin could undergo subsequent transformations and provide access to a variety of highly functionalized 1,2-amino alcohols, which are found in many natural and/or biologically active compounds (Scheme 1). [15] This route to 1,2-amino alcohols would be complementary to other strategies involving the formation of a s bond between the two heterosubstituted asymmetric carbon atoms, with control of their configuration, such as the addition of a-amino carbon nucleophiles to aldehydes [16] or conversely, a-alkoxy carbon nucleophiles to imines, [17] as well as crossreductive couplings between C=N and C=O bonds.…”

Regio‐ and Stereoselective Hydrophosphorylation of Ynamides: A Facile Approach to (Z)‐β‐Phosphor‐Enamides

“…[3] The inherent polarization of the ynamide triple bond attributed to the electron-donating ability of nitrogen affords a keteni-minium form, which undergoes regioselective nucleophilic addition to the α-carbon of activated and polarized alkynes ( Figure 1, eq 1). [5] Because of the intrinsic difference in the reaction mechanism, β-addition of ynamides afford functionalized enamides with a complete switch in regioselectivity. [5] Because of the intrinsic difference in the reaction mechanism, β-addition of ynamides afford functionalized enamides with a complete switch in regioselectivity.…”