Asymmetric lithiation-substitution sequences of substituted allylamines

[reaction: see text] (-)-Sparteine-mediated asymmetric lithiation-substitution sequences of 2- and 3-substituted N-(Boc)-N-(p-methoxyphenyl) allylic amines with electrophiles have been investigated. Asymmetric lithiation-substitutions of N-(Boc)-N-(p-methoxyphenyl) allylic amines 11, 12, 13, 14, and 15 provide highly enantioenriched enecarbamates in good yields. Further transformations to give aldehydes, acids, ketones, and a Diels-Alder adduct are reported. The 1,4-addition products from reactions of the lithiated allylic amines from 14 and 15 with conjugated activated alkenes gives enecarbamates with two and three stereogenic centers in good yields with high diastereomeric and enantiomeric ratios. Synthetic transformation of these products by acid hydrolysis and subsequent cyclization provide stereoselective access to bicyclic compounds containing four and five stereogenic centers with high diastereoselectivity and enantioselectivity. It is suggested that allyllithium complexes generated by asymmetric deprotonation react with most electrophiles with inversion of configuration.     

Synthetic Applications of the beta-Lithiation of beta-Aryl Secondary Amides: Diastereoselective and Enantioselective Substitutions

The sequence of beta-lithiation and electrophilic substitution of beta-aryl secondary amides is reported. The lithiations occur regioselectively at the beta-position, and the resulting lithiated intermediates can be reacted with a wide range of electrophiles to give substituted products. Reactions of beta-lithiated amides bearing an alpha-substituent provide substituted products with high diastereoselectivity. Electrophilic substitutions of beta-lithiated N-methylamides in the presence of the chiral diamine (-)-sparteine provide highly enantioenriched products. The methodology is used to synthesize enantioenriched beta-aryl beta-substituted amides, acids, and lactones.     

Enantioselective synthesis of 2-substituted 2-phenylethylamines by lithiation-substitution sequences: synthetic development and mechanistic pathway

The lithiation and asymmetric substitution of N-(2-phenylethyl)isobutyramide (2) with selected electrophiles, under the influence of (-)-sparteine, provides benzylically substituted products in 58-90% yields with enantiomeric ratios (ers) from 72:28 to 91:9. Syntheses of enantioenriched dihydroisoquinolines (S)-18 and (S)-19 and a tetrahydroisoquinoline (4S)-20 provide examples of synthetic applications. Mechanistic investigations suggest the enantiodetermining step at -78 degrees C is a dynamic thermodynamic resolution.     

Highly enantioselective electrophilic α-bromination of enecarbamates: chiral phosphoric acid and calcium phosphate salt catalysts

Metal-free chiral phosphoric acids and chiral calcium phosphates both catalyze highly enantio- and diastereoselective electrophilic α-bromination of enecarbamates to provide an atom-economical synthesis of enantioenriched vicinal haloamines. Either enantiomer can be formed in good yield with excellent diastereo- and enantioselectivity simply by switching the catalyst from a phosphoric acid to its calcium salt.     

Highly enantioselective syntheses of anti homoaldol products by (-)-sparteine-mediated lithiation/transmetalation/substitution of N-Boc allylic amines

[reaction: see text](-)-Sparteine-mediated lithiation/transmetalation/substitution of N-Boc allylic amines provides anti-configured homoaldol precursors in yields of 38-85% and enantiomeric ratios of 83:17-99:1. Subsequent O-protection and hydrolysis allows access to O-protected homoaldol adducts in good yields. The absolute configurations of the homoaldol products have been assigned by calculation of optical rotations and by X-ray crystallography of derivatives. A stereochemical course of reaction for the lithiation/transmetalation/substitution sequence is proposed.     

Noncovalent bifunctional organocatalysts: powerful tools for contiguous quaternary-tertiary stereogenic carbon formation, scope, and origin of enantioselectivity

Relying on the assembly of commercially available catalyst building blocks, highly stereocontrolled quaternary carbon (all carbon substituted) formation has been achieved with unmatched substrate diversity. For example, the in situ assembly of a tricomponent catalyst system allows α-branched aldehyde addition to nitroalkene or maleimide electrophiles (Michael products), while addition to an α-iminoester affords Mannich reaction products. Very good yields are observed and for fifteen of the eighteen examples 96-99?% ee is observed. Using racemic α-branched aldehydes, two contiguous (quaternary-tertiary) stereogenic centers can be formed in high diastereo- and enantiomeric excess (eight examples) via an efficient in situ dynamic kinetic resolution, solving a known shortcoming for maleimide electrophiles in particular. The method is of practical value, requiring only 1.2?equiv of the aldehyde, a 5.0?mol?% loading of each catalyst component, for example, O-tBu-L-threonine (O-tBu-L-Thr), sulfamide, DMAP or O-tBu-L-Thr, KOH, and room temperature reactions. As a highlight, the first demonstration of ethylisovaleraldehyde (7) addition is disclosed, providing the most congested quaternary stereogenic carbon containing succinimide product (8) known to date. Finally, mechanistic insight, via DFT calculations, support a noncovalent assembly of the catalyst components into a bifunctional catalyst, correctly predict two levels of product stereoselectivity, and suggest the origin of the tricomponent catalyst system's exceptionality: an alternative hydrogen bond motif for the donor-acceptor pair than currently suggested for non-assembled catalysts.     

Asymmetric carbon-carbon bond formations by conjugate additions of lithiated N-boc allylic amines to nitroalkenes: enantioselective synthesis of functionalized cyclopentanoids

[reaction: see text] Allylic organolithiums generated by enantioselective deprotonation of N-Boc-N-(p-methoxyphenyl) allylic amines undergo conjugate additions with nitroalkenes to provide enecarbamates containing two contiguous stereogenic centers in good yields with high diastereoselectivities and enantioselectivities. Further elaboration of these adducts to enantioenriched substituted cyclopentanones and aminocyclopentanes is reported.     

Addition/oxidative rearrangement of 3-furfurals and 3-furyl imines: new approaches to substituted furans and pyrroles

Furans and pyrroles are important synthons in chemical synthesis and are commonly found in natural products, pharmaceutical agents, and materials. Introduced herein are three methods to prepare 2-substituted 3-furfurals starting from 3-furfural, 3-bromofuran, and 3-vinylfurans. Addition of a variety of organolithium, Grignard, and organozinc reagents (M-R) to 3-furfural provides 3-furyl alcohols in high yields. Treatment of these intermediates with NBS initiates a novel oxidative rearrangement that results in the installation of the R group in the 2 position of the 2-substituted 3-furfurals. Likewise, metalation of 3-bromofuran with n-BuLi and addition to benzaldehyde provides a furyl alcohol that is converted to 2-phenyl 3-furfural upon oxidative rearrangement. Enantioenriched disubstituted furans can be prepared starting with the Sharpless asymmetric dihydroxylation of 3-vinylfurans. The resulting enantioenriched diols undergo the oxidative rearrangement to furnish enantioenriched 2-substituted 3-furfurals with excellent transfer of asymmetry. This later method has been applied to the enantioselective preparation of an intermediate in Honda's synthesis of the natural product (-)-canadensolide. Mechanistic studies involving deuterium-labeled furyl alcohol suggest that the oxidative rearrangement proceeds through an unsaturated 1,4-dialdehyde intermediate. The alcohol then cyclizes onto an aldehyde, resulting in the elimination of water and rearomatization. On the basis of this proposed mechanism, we found that 3-furyl imines undergo the addition of organometallic reagents to provide furyl sulfonamides. Under the oxidative rearrangement conditions, 2-substituted 3-formyl pyrroles are formed, providing a novel route to these heterocycles. In contrast to the metalation of heterocycles, which often lead to mixtures of regioisomeric products, these new oxidative rearrangements of furyl alcohols and furyl sulfonamides generate only one regioisomer in each case.     

Iridium-Catalyzed Chemo-, Diastereo-, and Enantioselective Allyl-Allyl Coupling: Accessing All Four Stereoisomers of (E)-1-Boryl-Substituted 1,5-Dienes by Chirality Pairing

Here, we report a highly chemo-, diastereo-, and enantioselective allyl-allyl coupling between branched allyl alcohols and α-silyl-substituted allylboronate esters, catalyzed by a chiral iridium complex. The α-silyl-substituted allylboronate esters can be chemoselectively coupled with allyl electrophiles, affording a diverse set of enantioenriched (E)-1-boryl-substituted 1,5-dienes in good yields, with excellent stereoselectivity. By permuting the chiral iridium catalysts and the substrates, we efficiently and selectively obtained all four stereoisomers bearing two consecutive chiral centers. Mechanistic studies via density functional theory calculations revealed the origins of the diastereo- and chemoselectivities, indicating the pivotal roles of the steric interaction, the β-silicon effect, and a rapid desilylation process. Additional synthetic modifications for preparing a variety of enantioenriched compounds containing contiguous chiral centers are also included.     

Direct α‐Vinylidenation of Aldehydes and Subsequent Cascade: Gold and Amine Catalysts Work Synergistically

Carbonyl‐substituted allenes are highly important synthetic intermediates for a number of heterocycles and strained‐ring systems. However, chemistry of allenyl aldehydes has not been explored as extensively as their ketone, ester, or amide analogues because of a lack of general synthetic methods. Described herein is the first direct α‐vinylidenation of aldehydes and an α‐vinylidenation/γ‐functionalization cascade to access tri‐ and tetrasubstituted allenyl aldehydes using a combination of a gold catalyst and an secondary amine. The reactive enamine intermediate of an aldehyde reacts with the gold‐activated hypervalent silylethynyl benziodoxolone to selectively generate the corresponding trisubstituted allenyl aldehyde. The allenyl aldehyde can further react with another equivalent of the alkynylation reagent or other electrophiles to afford tetrasubstituted allenes bearing an aldehyde group, an acetylene, and a halogen functionality. This method enables rapid access to polysubstituted furans from aldehydes.     

Concise syntheses of 13-methylprotoberberine and 13-methyltetrahydroprotoberberine alkaloids

The concise syntheses of eight 13-methylprotoberberine (13-MePB) and eight enantioenriched 13-methyltetrahydroprotoberberine (13-MeTHPB) alkaloids have been achieved in a tactically modular fashion. This synthetic work features a one-pot metal-free Pictet-Spengler/Friedel-Crafts hydroxyalkylation/dehydration/oxidation sequence and a following highly enantioselective Ir-catalyzed hydrogenation. Given such brevity and modularity, our developed synthetic route would be greatly beneficial to the efficient syntheses of existing natural products and new fully synthetic variants of 13-MePB and 13-MeTHPB family.     

Asymmetric gamma-deprotonation and homoaldol reaction of 1,3-dien-2-yl carbamates: stereo- and regiochemistry

[reaction: see text] Lithium compounds 7 are configurationally stable intermediates obtained by deprotonation of 1,3-dien-2-yl carbamates 6 with n-butyllithium/(-)-sparteine with a high degree of enantiotopic differentiation at the gamma-position. They react with electrophiles regioselectively giving highly enantioenriched products. Starting with different isomers or changing the double-bond geometries in 6 leads to either of the enantiomers.     

Stereocontrolled asymmetric synthesis of syn-E-1,4-diol-2-enes using allyl boronates and its application in the total synthesis of solandelactone F

The solandelactones A-H comprise a novel class of oxygenated fatty acids bearing an eight-membered lactone, trans cyclopropane, and a 2-ene-1,4-diol subunit. The relative stereochemistry of the 1,4-diol subunit is anti in solandelactones A, C, E & G, and syn in solandelactones B, D, F & H. Having prepared one member of the solandelactones bearing anti stereochemistry (solandelactone E), we have targeted the syn series and developed methodology for the synthesis of enantioenriched syn-2-ene-1,4-diols. The methodology comprises asymmetric deprotonation of an alkyl 2,4,6-triisopropylbenzoate using sBuLi/sparteine, followed by addition of the α-lithiobenzoate to β-silyl vinyl boronic acid ethylene glycol ester. The boron-ate complex generated undergoes a 1,2-metallate rearrangement furnishing an intermediate allyl boronic ester which is trapped by an aldehyde in the presence of MgBr(2) to furnish anti-β-hydroxy E-allylsilanes in good yields, high diastereoselectivity and high enantioselectivity. These sensitive products were oxidized using mCPBA to the corresponding epoxides and subsequently treated with acid to furnish syn-E-2-ene-1,4-diols (~4:1 d.r.). Application of the methodology to appropriately functionalized aldehyde and ω-alkenyl 2,4,6-triisopropylbenzoate coupling partners, led to a short, highly selective route to solandelactone F (bearing a syn-E-2-ene-1,4-diol).     

Highly stereoselective synthesis of anti,anti-dipropionate stereotriads: a solution to the long-standing problem of challenging mismatched double asymmetric crotylboration reactions

The stereocontrolled synthesis of the β-branched anti,anti-dipropionate stereotriad 4 via aldol or crotylmetal chemistry represents a historical challenge to the organic synthesis community. Here we describe a general solution to the long-standing problem associated with the synthesis of 4 by utilizing mismatched double asymmetric crotylboration reactions of enantioenriched α-methyl substituted aldehydes with the chiral, nonracemic crotylborane reagent (S)-(E)-22 (or its enantiomer). This method not only provides direct access to anti,anti-dipropionate stereotriads 24 [a synthetic equivalent of 4] with very good (5-8:1) if not excellent (≥15:1) diastereoselectivity from β-branched chiral aldehydes with ≤50:1 intrinsic diastereofacial selectivity preferences but also provides a vinylstannane unit in the products that is properly functionalized for use in subsequent C-C bond-forming events. We anticipate that this method will be widely applicable and will lead to substantial simplification of strategies for synthesis of polyketide natural products.     

Noncovalent Bifunctional Organocatalysts: Powerful Tools for Contiguous Quaternary‐Tertiary Stereogenic Carbon Formation,Scope, and Origin of Enantioselectivity

Relying on the assembly of commercially available catalyst building blocks, highly stereocontrolled quaternary carbon (all carbon substituted) formation has been achieved with unmatched substrate diversity. For example, the in situ assembly of a tricomponent catalyst system allows α‐branched aldehyde addition to nitroalkene or maleimide electrophiles (Michael products), while addition to an α‐iminoester affords Mannich reaction products. Very good yields are observed and for fifteen of the eighteen examples 96–99 % ee is observed. Using racemic α‐branched aldehydes, two contiguous (quaternary–tertiary) stereogenic centers can be formed in high diastereo‐ and enantiomeric excess (eight examples) via an efficient in situ dynamic kinetic resolution, solving a known shortcoming for maleimide electrophiles in particular. The method is of practical value, requiring only 1.2 equiv of the aldehyde, a 5.0 mol % loading of each catalyst component, for example, O‐tBu‐L ‐threonine (O‐tBu‐L ‐Thr), sulfamide, DMAP or O‐tBu‐L ‐Thr, KOH, and room temperature reactions. As a highlight, the first demonstration of ethylisovaleraldehyde ( 7 ) addition is disclosed, providing the most congested quaternary stereogenic carbon containing succinimide product ( 8 ) known to date. Finally, mechanistic insight, via DFT calculations, support a noncovalent assembly of the catalyst components into a bifunctional catalyst, correctly predict two levels of product stereoselectivity, and suggest the origin of the tricomponent catalyst system’s exceptionality: an alternative hydrogen bond motif for the donor‐acceptor pair than currently suggested for non‐assembled catalysts.     

Enantio- and Diastereoselective NiH-Catalyzed Hydroalkylation of Enamides or Enecarbamates with Racemic α-Bromoamides**

Catalytic methods which control multiple stereogenic centers simultaneously are highly desirable in modern organic synthesis and chemical manufacturing. Herein, we report a regio-, enantio-, and diastereoselective NiH-catalyzed hydroalkylation process which proceeds with simultaneous control of vicinal stereocenters originating from two readily accessible partners, prochiral internal alkenes (enamides or enecarbamates) and racemic alkyl electrophiles (α-bromoamides or Katritzky salts). This reaction produces high-value β-aminoamides and their derivatives under mild conditions and with precise selectivity. Preliminary studies of the mechanism indicate that the reaction involves an enantioselective syn-hydronickelation to generate an enantiomerically enriched alkylnickel(II) species. Subsequent enantioconvergent alkylation with a racemic alkyl electrophile generates the desired product as a single stereoisomer.     

Highly Stereocontrolled Cyclopropanation by the 1,3-Elimination of a Bis(tributylstannyl)propanol Derivative

The highly stereoselective ring closure of gamma-hydroxystannyl derivative was realized. The aldol reaction of methyl bis(tributylstannyl)propionate (2) with aldehyde 5 proceeds stereoselectively to give (gamma-hydroxypropyl)stannane 6, and the cyclopropanation reaction of aldol product 6 proceeds smoothly in a highly stereoselective manner presumably via a W-shape transition state. The stannyl group on the cyclopropane ring can be converted into various electrophiles with a retention of configuration. As a result, various stereocontrolled 1,2,3-trisubstituted cyclopropanes can be obtained in high yields.     

Synthesis of propionate motifs: diastereoselective tandem reactions involving anionic and free radical based processes

Reported herein is a strategy employing a Mukaiyama reaction in tandem with a hydrogen transfer reaction for the elaboration of propionate motifs. The nature of the protecting groups on the chiral beta-alkoxy aldehyde and the type of Lewis acid used are varied to modulate the stereochemical outcome of the tandem reactions. The mode of complexation is thus controlled (monodentate or chelate) for the Mukaiyama reaction to give access to either syn or anti aldol products, precursors of the free radical reduction reaction. The endocyclic effect is subsequently capitalized upon to control the hydrogen transfer step so that the syn-reduced product may be achieved. Proceeding with excellent yield and diastereoselectivity, the synthetic sequence proposed gives access to syn-syn and syn-anti propionate motifs. Also considered is a complementary approach using a chelation-controlled Mukaiyama reaction in tandem with a free radical allylation reaction under the control of the endocyclic effect that leads to the anti-anti product.     

FeCl3-catalyzed tandem Prins and Friedel–Crafts cyclization: a highly diastereoselective route to polycyclic ring structures

Catalytic FeCl₃ in the presence of 4 Å molecular sieves has been shown to effect highly diastereoselective tandem Prins and Friedel–Crafts cyclization of substituted (E/Z)-6-phenylhex-3-en-1-ol and a variety of aldehydes to provide a range of polycyclic compounds in good to excellent yields. The reaction of an enantioenriched alcohol with an aldehyde provided the cyclization product without loss of optical activity. Furthermore, a Lewis acid catalyzed ring opening resulted in functionalized tetralin derivatives with multiple chiral centers.     

Asymmetric Dearomatization of Indole Derivatives with N‐Hydroxycarbamates Enabled by Photoredox Catalysis

Dearomatization of indoles provides efficient synthetic routes for substituted indolines. In most cases, indoles serve as nucleophiles. Reported here is an asymmetric dearomatization reaction of indole derivatives that function as electrophiles. The combination of a photocatalyst and chiral phosphoric acid open to air unlocks the umpolung reactivity of indoles, enabling their dearomatization with N‐hydroxycarbamates as nucleophiles. A variety of fused indolines bearing intriguing oxy‐amines were constructed in excellent yields with moderate to high enantioselectivities. Mechanistic studies show that the realization of two sequential single‐electron transfer oxidations of the indole derivatives is key, generating the configurationally biased carbocation species while providing the source of stereochemical induction. These results not only provide an efficient synthesis of enantioenriched indoline derivatives, but also offer a novel strategy for further designing asymmetric dearomatization reactions.