A stereoselective and short total synthesis of the polyhydroxylated gamma-amino acid (-)-detoxinine,based on stereoselective preparation of dihydropyrrole derivatives from lithiated alkoxyallenes

Based on our earlier results employing lithiated methoxyallene 2 as C(3) building block and imines 3 for the synthesis of dihydropyrrole derivatives 5, we have investigated chiral imines 6, 10, and 15 as electrophilic components. Combined with lithiated alkoxyallenes, these imines provide the corresponding primary adducts and finally the dihydropyrrole derivatives 8, 12, 17, 20, and 22 in good yields and with high to excellent syn selectivities. This stereochemical outcome is interpreted as a result of alpha-chelate control. Treatment with hydrochloric acid converted syn-8 and syn-12 into bicyclic compounds 9 and 13, whereas under more mildly acidic conditions adduct syn-17 was transformed into diol syn-18. The total synthesis of the uncommon gamma-amino acid (-)-detoxinine could be achieved by starting from (S)-malic acid, which was converted into imine 15 in four steps. Lithiated benzyloxyallene added to imine 15 and efficiently furnished the crucial dihydropyrrole derivative syn-22. The hydrogenolysis of this compound did not directly provide the protected triol 29 as anticipated, but a stepwise protocol made the triol available in a fairly satisfactory manner. A second crucial step of the synthesis was the selective oxidation of 29, which could be achieved by employing platinum dioxide and oxygen. The resulting bicyclic lactone 30 was smoothly transformed into enantiopure (-)-detoxinine. Thus, a fairly short synthesis of this natural product based on a lithiated alkoxyallene could be performed, demonstrating the potential of these intermediates for syntheses of interesting functionalized heterocyclic compounds.     

Reactions of Cycloaliphatic Thioketones and Their Oxo Analogues with Lithiated Methoxyallene: A New Approach to Vinylthiiranes

Admantanethione smoothly reacted with lithiated methoxyallene at low temperatures yielding the expected allenyl‐substituted thiolate, which upon aqueous work‐up underwent spontaneous 1,3‐cyclization to afford a hitherto unknown methoxy‐substituted vinylthiirane derivative. The analogous reaction with adamantanone led to the corresponding allenyl alcohol that can be isolated and—depending on the conditions applied—either be converted into the corresponding vinyloxirane or into the 2,5‐dihydrofuran derivative. Sterically more crowded thioketones were also combined with lithiated methoxyallene, but in these cases competitive 1,5‐cyclization leading to isomeric dihydrothiophene derivatives was observed. DFT calculations of model intermediates and products show distinct energy differences of the sulfur and the corresponding oxygen compounds. Desulfurization of the adamantanethione‐derived vinylthiirane yielded a methoxy‐substituted 1,3‐diene that was studied in cycloadditions with electron‐deficient dienophiles. Whereas in the case of tetracyanoethylene the corresponding cyclobutane derivative was formed, the reaction with nitrosobenzene provided the expected 1,2‐oxazine derivative. By reductive cleavage of the N? O bond this heterocycle was converted into an unsaturated amino alcohol bearing an adamantane moiety.     

First example of one-pot assembly of tetrasubstituted thiophene with amino- and ester functions from methoxyallene,methyl isothiocyanate,and methyl 2-bromoacetate

The previously unavailable methyl 4-methoxy-3-methyl-5-(methylamino)thiophene-2-carboxylate was obtained by the one-pot procedure from a lithiated methoxyallene, methyl isothiocyanate, and methyl 2-bromoacetate.     

Efficient approach to the Azaspirane core of FR 901483

[reaction: see text] An efficient approach to the azaspirane core of FR 901483 is described employing lithiated methoxyallene as a crucial C3 building block and a suitably protected enantiopure ketimine as the second component. The resulting dihydropyrrole derivative was smoothly converted into a spiro keto aldehyde which under acidic conditions provided a novel azanorbornane derivative 15. Under basic reaction conditions, the desired 5-azatricyclo[6.3.1.0(1,5)]dodecane skeleton 16 was generated. The ratio of diastereomers strongly depends on the reaction conditions employed with l-proline in DMSO providing the highest selectivity in favor of one azaspirane product.     

New building block for polyhydroxylated piperidine: total synthesis of 1,6-dideoxynojirimycin

(3R,4S)-3-Hydroxy-4-N-allyl-N-Boc-amino-1-pentene 10, an important precursor for the synthesis of polyhydroxylated piperidines, has been achieved as a single diastereomer without racemization via vinyl Grignard addition to N-Boc-N-allyl aminoaldehyde 9, which was derived from an enantiopure natural amino acid. Having forged a tetrahydropyridine ring scaffold 13 from 10 in 85% yield via RCM using Grubbs II catalyst, we were able to effect its stereodivergent dihydroxylation, via a common epoxide intermediate to yield a range of interesting hydroxylated piperidines, including ent-1,6-dideoxynojirimycin (ent-1,6-dDNJ) 1 (28% overall yield) and 5-amino-1,5,6-trideoxyaltrose 2 (29% over all yield) in excellent dr. To the best of our knowledge, our synthesis of ent-1,6-dDNJ 1 is the most expeditious to date.     

A catalytic, asymmetric formal synthesis of (+)-hamigeran B

A concise asymmetric, formal synthesis of (+)-hamigeran B is reported. A Pd-catalyzed, decarboxylative allylic alkylation, employing a trifluoromethylated derivative of t-BuPHOX, is utilized as the enantioselective step to form the critical quaternary carbon center in excellent yield and enantioselectivity. The product is converted in three steps to a late-stage intermediate previously used in the synthesis of hamigeran B.     

Highly enantioselective mukaiyama aldol reaction of alpha,alpha-dichloro ketene silyl acetal: an efficient synthesis of a key intermediate for diltiazem

An efficient synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), has been developed on the basis of the highly enantioselective Mukaiyama aldol reaction of p-anisaldehyde (4a) with alpha,alpha-dichloro ketene silyl acetal 5. Thus, the reaction using a stoichiometric amount of chiral oxazaborolidinone catalyst 12a proceeded to excellent yield (83%) and high enantioselectivity (96% ee), together with the chiral ligand 13a in nearly quantitative recovery. The reaction using a substoichiometric amount of 12e (20 mol %) also proceeded to excellent yield (88%), with somewhat lower enantioselectivity (77% ee). The aldol product 3a thus obtained was easily converted to (-)-2 in excellent yield (80%) and high optical purity (>99% ee). The highly enantioselective Mukaiyama aldol reaction with 5 catalyzed by 12a proved to be applicable to various aldehydes. An efficient preparation of 5 from inexpensive starting materials was also described.     

Synthesis of bisbenzannulated spiroketals-model studies for a modular approach to rubromycins

[reaction: see text] A highly flexible synthesis of bisbenzannulated spiroketals is described with additions of lithiated methoxyallene to aryl aldehydes and Heck reactions as key steps. Subsequent hydrogenations and ketalizations afforded the desired spiroketals in good yields and with predominating trans-configuration. With model compound 30, already bearing the fully substituted naphthyl core of rubromycins, the ketalization proceeded efficiently providing the expected product 31 and the isopropoxy compound 32. Both products are advanced model compounds of heliquinomycin.     

Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinonide

The first enantioselective total synthesis of (-)-triptolide (1), (-)-triptonide (2), (+)-triptophenolide (3), and (+)-triptoquinonide (4) was completed. The key step involves lanthanide triflate-catalyzed oxidative radical cyclization of (+)-8-phenylmenthyl ester 30 mediated by Mn(OAc)3, providing intermediate 31 with good chemical yield (77%) and excellent diastereoselectivity (dr 38:1). (+)-Triptophenolide methyl ether (5) was then prepared in > 99% enantiomeric excess (> 99% ee), and readily converted to natural products 1-4. In addition, transition state models were proposed to explain the opposite chiral induction observed in the oxidative radical cyclization reactions of chiral beta-keto esters 17 (without an alpha-substituent) and 17a (with an alpha-chloro substituent).     

Reactions of heterocumulenes with organometallic reagents: XIX. Quantum-chemical study on S-alkylation and intramolecular cyclization of lithiated methoxyallene adducts with methyl, phenyl, and 3-(methylsulfanyl)phenyl isothiocyanates. Concurrent formation of pyrrole and/or thiophene rings

Concurrent reaction paths leading to the formation of thiophene and/or pyrrole rings from adducts of lithiated methoxyallene with methyl, phenyl, and 3-(methylsulfanyl)phenyl isothiocyanates were simulated by quantum-chemical methods. According to the calculations, pyrrole ring closure is kinetically more favorable for the adduct of 1-lithio-1-methoxyallene with methyl isothiocyanate, both reaction channels are equally probable for the adduct with phenyl isothiocyanate, and thiophene ring closure is the main reaction path for the adduct with 3-(methylsulfanyl)phenyl isothiocyanate.     

Synthesis of trifluoromethyl-substituted cyclopropanes via sequential Kharasch-dehalogenation reactions

A two-step process for the synthesis of trifluoromethyl-substituted cyclopropanes is described. Halothane, an anesthetic agent, is added to olefins in a ruthenium-catalyzed Kharasch reaction. The resulting 1,3-dihalides are converted into cyclopropanes by dehalogenation with magnesium. This procedure represents an alternative to metal-catalyzed cyclopropanations involving trifluoromethyl diazomethane.     

Stereospecific synthesis of the (3aα,11α,12aα)-decahydrobenzo[a]pyrrolo[3,2-g]quinolizine ring system

A stereospecific synthesis of racemic (3aα,11bα,12aβ)-1,2,3,3a,4,6,7,11b,12,12a-decahydro-9-methoxy-1-(methylsulfonyl)benzo[α]pyrrolo[3,2-g]quinolizine (2) is reported. Cyclocondensation of lithiated pyrrolecarboxamide 5 and dihydroisoquinoline 6 afforded the key tetracyclic intermediate 7 . Hydrogenation of 7 gave the 3aα,11bα,12aα-isomer 9 which was subsequently converted to 2 .     

Formal total synthesis of salicylihalamides A and B

An efficient synthesis of the macrolactone 3 of the salicylihalamides in 10 linear steps from alkene 6 is described. The key steps involved a Stille coupling between the chiral stannane 5 and benzyl bromide 4, which produced alkene 15 in good yield, and subsequent base-induced macrolactonization then gave compound 3. Macrolactone 3 was then converted into the known salicylihalamide A intermediate 18 in a three-step sequence. Compound 3 was also converted into another known salicylihalamide A and B intermediate 23 in a five-step sequence.     

Toward the synthesis of norzoanthamine: complete fragment assembly

The complex marine alkaloid norzoanthamine (2) was envisioned to be assembled from three key building blocks: the C1-C5 fragment A, the C6-C10 fragment B, and the C11-C24 fragment C. The synthesis of fragment A was achieved in 14 steps and 33% overall yield from (R)-gamma-hydroxymethyl-gamma-butyrolactone. Fragment B was made in two steps from PMB-protected 4-pentynol in 76% yield. The C11-C24 fragment C was made from (S)-carvone via (R)-isocarvone in 18 steps (6% overall yield). The convergent stereoselective synthesis of the entire carbon framework (C1-C24) of the target molecule was achieved via the following assemblage. Alkenyl iodide 20 derived from the C11-C24 fragment C was coupled to fragment B (C6-C10) through a high-yielding Stille coupling reaction of these two sterically very demanding coupling partners, affording the key Diels-Alder precursor 24. The intramolecular Diels-Alder reaction proceeded smoothly in excellent yield and diastereoselectivity, generating the tricyclic trans-anti-trans perhydrophenanthrene motif of norzoanthamine (C6-C24). The final fragment coupling between lithiated fragment A (C1-C5) and aldehyde 40 (C6-C24) has also been successfully accomplished affording the entire carbon framework of the natural product.     

A practical synthesis of pyoluteorin

A convenient, large-scale synthesis of the antibiotic pyoluteorin, 2,3-dichloro-5-(2′,6′-dihydroxybenzoyl)-pyrrole ( 1 ), is described. A key step in the synthesis involved a Friedel-Crafts aroylation of pyrrole with 2,6-dimethoxybenzoyl chloride ( 3 ) in methylene chloride. The desired intermediate, 2-(2′,6′-dimethoxybenzoyl)pyrrole ( 4 ), was obtained as the major product, along with a product of beta substitution ( 6 ). Compound 4 was converted to pyoluteroin ( 1 ) in four steps in an overall yield of 51%.     

Selective Catalytic Hydrogenations and Hydrogenolyses VIII [1]: Stereoselective Synthesis of the Stereomeric Pilopyl Alcohols

Summary.  The stereoselective synthesis of pilopyl- and isopilopyl alcohol is reported. The reaction of dimethyldioxanone and diethoxyphosphoryl-butyric acid ethyl ester afforded the corresponding dioxanylidenbutyric acid ester as the key intermediate. Upon treatment with mineral acid it cyclized giving 3-ethyl-4-hydroxymethylfuran-2-one which in turn could be converted either to 3-ethyl-4-methylfuranone or pilopyl alcohol with excellent stereoselectivity and quantitative chemical yield. On the other hand, hydrogenation and subsequent cyclization of the same key compound furnished isopilopyl alcohol with good stereomeric purity and yield. Corresponding author. E-mail: ebrei@cup.uni-muenchen.de Received April 3, 2002; accepted April 9, 2002     

Practical stereoselective synthesis of an alpha-trifluoromethyl-alpha-alkyl epoxide via a diastereoselective trifluoromethylation reaction

A practical stereoselective synthesis is reported for an alpha-trifluoromethyl-alpha-alkyl epoxide (1), which is an important pharmaceutical intermediate. The key step involves a chiral auxiliary-controlled asymmetric trifluoromethylation reaction for the introduction of the unique trifluoromethyl-substituted tertiary alcohol stereogenic center in the target molecule. The fluoride-initiated CF3 addition to chiral keto ester 6a proceeded with a diastereoselectivity up to 86:14. The major diastereomer was readily obtained with a >99.5:0.5 dr through a simple crystallization of the crude product mixture.     

Diarylprolinol in an asymmetric aldol reaction of an α-alkyl-α-oxo aldehyde as an electrophile

The direct aldol reaction of an α-alkyl-α-oxo aldehyde was catalyzed by trifluoromethyl-substituted diarylprolinol 1 to afford a γ-oxo-β-hydroxy-α-substituted aldehyde in good yield with excellent anti-selectivity and excellent enantioselectivity.     

New convergent synthesis of 1alpha,25-dihydroxyvitamin D3 and its analogues by Suzuki-Miyaura coupling between A-ring and C,D-ring parts

A new convergent method for the synthesis of 1alpha,25-dihydroxyvitamin D(3) and its analogues has been developed that involves efficient preparation of the A-ring part 1a, (Z)-(3S,5R)-1-bromomethylene-3,5-bis(tert-butyldimethylsilyloxy)-2-methylenecyclohexane, starting from epichlorohydrin (4) and its Suzuki-Miyaura coupling reaction with the C,D-ring part 12. Thus, (R)-4 was converted to (3S,5R)-5-(tert-butyldimethylsilyloxy)-8-(trimethylsilyl)-oct-1-en-7-yn-3-ol (3a) through a ten-step reaction sequence in 49% overall yield. Compound 3a thus obtained was treated with a Ti(O-i-Pr)(4)/2 i-PrMgCl reagent and then with NBS to afford (Z)-(1S,2S,5R)-2-bromomethyl-3-[bromo(trimethylsilyl)methylene]-5-(tert-butyldimethylsilyloxy)cyclohexanol (10a) in 51% yield, from which 1a was obtained in 87% yield by sequential treatment with TBSCl/imidazole, DBU, and Cs(2)CO(3). The resulting A-ring intermediate 1a was reacted with alkenylboronate 12 in the presence of a PdCl(2)(dppf) catalyst to furnish 1alpha,25-dihydroxyvitamin D(3) in 82% yield after protodesilylation. Similarly, all of the other three possible stereoisomers of A-ring parts 1b, 1c, and 1d were prepared, from which 1-epi-, 3-epi-, and 1,3-di-epi-1alpha,25-dihydroxyvitamin D(3) were synthesized by coupling with 12 in excellent yield, respectively. Starting from 1a and 1c, des-C,D-1alpha,25-dihydroxyvitamin D(3) analogues, retiferol 13 and its 3-epi derivative, were also prepared, respectively.     

Ring-closure reactions of 1,2-diaza-4,5-benzoheptatrienyl metal compounds: experiment and theory

2-Alkenylbenzylidene hydrazones 5a-m, which are accessible in good to excellent yields in a four-step synthesis, are converted into 1,2-diaza-4,5-benzoheptatrienyl metal compounds 1a-m by treatment with KO-t-Bu as base. These metal compounds undergo the various types of reactions in good yields and exclusively depending on the nature of substituents R(1) and R(3). Thus, metal compounds 1a-c carrying alkyl substituents R(1) and R(3) form 3H-benzodiazepines 6a-c after electrophilic quench of the intermediate cyclic anion 7 in a 7-endo-trig electrocyclic reaction with a mo?bius aromatic transition structure 1(-)-TS. Similarly, a benzothienyl derivative 5n is converted into diazepine 6d. Potassium compounds 1d-h, which are N-methyl and aryl substituted at R(3), form 1,2-dihydrophthalazines 8a-e in a predominantly charge-controlled 6-exo-trig cyclization reaction. In contrast, aryl-aryl-substituted systems 5i-m did not lead to cyclic products upon deprotonation, but the intermediate open-chain metal compounds 1i-m were trapped by acid chlorides at N1 to yield the hydrazides 10a-e. We interpret thermodynamics and kinetics of these reactions in the context of the Baldwin rules on the basis of quantum chemical calculations and discuss the transition structures considering the results of NICS and NBO-charge calculations. Examples of the products 6, 8, and 10 could be characterized by X-ray diffraction.