Concise Syntheses of bis‐Strychnos Alkaloids (−)‐Sungucine, (−)‐Isosungucine,and (−)‐Strychnogucine B from (−)‐Strychnine

The first chemical syntheses of complex, bis‐Strychnos alkaloids (?)‐sungucine ( 1 ), (?)‐isosungucine ( 2 ), and (?)‐strychnogucine B ( 3 ) from (?)‐strychnine ( 4 ) is reported. Key steps included (1) the Polonovski–Potier activation of strychnine N‐oxide; (2) a biomimetic Mannich coupling to forge the signature C23?C5′ bond that joins two monoterpene indole monomers; and (3) a sequential HBr/NaBH₃CN‐mediated reduction to fashion the ethylidene moieties in 1 – 3 . DFT calculations were employed to rationalize the regiochemical course of reactions involving strychnine congeners.     

Divergent Total Syntheses of (−)‐Daphnilongeranin B and (−)‐Daphenylline

(?)‐Daphnilongeranin B and (?)‐daphenylline are two hexacyclic Daphniphyllum alkaloids, each containing a complex cagelike backbone. Described herein are the first asymmetric total synthesis of (?)‐daphnilongeranin B and a bioinspired synthesis of (?)‐daphenylline with an unusual E ring embedded in a cagelike framework. The key features include an intermolecular [3+2] cycloaddition, a late‐stage aldol cyclization to install the F ring of daphnilongeranin B, and a bioinspired cationic rearrangement leading to the tetrasubstituted benzene ring of daphenylline.     

An Efficient Synthesis of a Potential (−)‐Reserpine Intermediate from (−)‐Shikimic Acid of the Chiral Pool

A highly stereoselective route to the polysubstituted chiral octahydrobenzofuran 12 , a potential synthon for the E‐ring core in the (?)‐reserpine synthesis, is described. The α‐bromo acetal 11 was obtained from inexpensive (?)‐shikimic acid ( 3 ) through a series of highly stereoselective chemical reactions (Scheme). Et₃B/Bu₃SnH‐Mediated intramolecular radical cyclization of 11 led to compound 12 with the required configuration.     

On the Solution Behaviour of Benzyllithium⋅(−)‐Sparteine Adducts and Related Lithium Organyls – A Case Study on Applying 7Li,15N{1H} HMQC and Further NMR Methods,Including Some Investigation into Asymmetric Synthesis

2D ⁷Li,¹⁵N heteronuclear shift correlation through scalar coupling has successfully been applied to several lithium organyls consisting of polydentate N ligands such as N,N,N′,N′‐tetramethylethylenediamine (tmeda), N,N,N′,N′,N′′‐pentamethyldiethylentriamine (pmdta) and (?)‐sparteine. Structural insights on the conformation of benzyllithium ? pmdta ( 5 ) in a toluene solution and the strength of ion pairing in combination with PGSE NMR measurements, ¹H,¹H‐NOESY and ¹H,⁷Li‐HOESY experiments are presented. By studying in detail the formation of 5 in solution, a transient species has been observed for the first time and assigned to a pre‐complex of nBuLi and pmdta. In addition, the solution behaviour of the complex formed between benzyllithium and (?)‐sparteine ( 8 ) has been studied by PGSE and multinuclear NMR spectroscopy. The straightforward synthesis and first applications in asymmetric lithiations are also reported, which show that the new system benzyllithium ? (?)‐sparteine ( 8 ) provide poorer enantioselective induction than the classical nBuLi ? (?)‐sparteine ( 6 ). The results were supported by deprotonation experiments confirming that the formation of 8 relies on two relevant factors, namely temperature and lithiating reagent. The existence of 8 may thus interfere with the asymmetric induction when the system nBuLi ? (?)‐sparteine is used in the enantioselective deprotonations of N‐Boc‐N‐(p‐methoxyphenyl)‐benzylamine conducted in toluene.     

Catalytic Asymmetric Total Synthesis of (−)‐Galanthamine and (−)‐Lycoramine

The catalytic asymmetric total syntheses of (?)‐galanthamine ( 1 ) and (?)‐lycoramine ( 2 ) have been achieved by using a conceptually new strategy featuring two metal‐catalyzed reactions as the key steps. A new method for the construction of 3,4‐fused benzofurans has been developed through a palladium‐catalyzed intramolecular Larock annulation reaction, which was successfully applied to the construction of the ABD tricyclic skeleton of 1 and 2 . To achieve the asymmetric synthesis of 1 and 2 , a Sc^III/N,N′‐dioxide complex was used to catalyze the enantioselective conjugate addition of 3‐alkyl‐substituted benzofuranone to methyl vinyl ketone for the construction of a chiral quaternary carbon center.     

Experimental and theoretical study of the intramolecular C–H···N and C–H···S hydrogen bonding effects in the 1H and 13C NMR spectra of the 2‐(alkylsulfanyl)‐5‐amino‐1‐vinylpyrroles: a particular state of amine nitrogen

In the ¹H NMR spectra of the 1‐vinylpyrroles with amino‐ and alkylsulfanyl groups in 5 and 2 positions, an extraordinarily large difference between resonance positions of the H_A and H_B terminal methylene protons of the vinyl group is discovered. Also, the one‐bond ¹J(C_β,H_B) coupling constant is surprisingly greater than the ¹J(C_β,H_A) coupling constant in pyrroles under investigation, while in all known cases, there was a reverse relationship between these coupling constants. These spectral anomalies are substantiated by quantum chemical calculations. The calculations show that the amine nitrogen lone pair is removed from the conjugation with the π‐system of the pyrrole ring so that it is directed toward the H_B hydrogen. These factors are favorable to the emergence of the intramolecular C–H_B???N hydrogen bonding in the s‐cis(N) conformation. On the other hand, the spatial proximity of the sulfur to the H_B hydrogen provides an opportunity of the intramolecular C–H_B???S hydrogen bonding in the s‐cis(S) conformation. Presence of the hydrogen bond critical points as well as ring critical point for corresponding chelate ring revealed by a quantum theory of atoms in molecules (QTAIM) approach confirms the existence of the weak intramolecular C–H???N and C–H???S hydrogen bonding. Therefore, an unusual high‐frequency shift of the H_B signal and the increase in the ¹J(C_β,H_B) coupling constant can be explained by the effects of hydrogen bonding. Copyright © 2013 John Wiley & Sons, Ltd.     

Total Synthesis of (−)‐Cleistenolide

An efficient and short total synthesis of (?)‐cleistenolide ( 1 ) from D ‐mannitol with an overall yield of 23.6% is described. The chiron approach for the synthesis of (?)‐cleistenolide involves a one‐C‐atom Wittig olefination, a selective allylic triethylsilyl protection, and a Grubbs‐catalyzed ring‐closure‐metathesis (RCM) reaction as the key steps.     

Synthesis of the Macrocyclic Spermidine Alkaloid (±)‐(2R*,3R*)‐3‐Hydroxycelacinnine

The macrocyclic lactam alkaloid (±)‐(2R*,3R*)‐3‐hydroxycelacinnine ( 1 ) derived from spermidine was synthesized via stereoselective epoxide‐ring opening with magnesium azide and cesium carbonate promoted macrocyclization of the ditosylated diamino precursor 12 with 1,4‐dibromobutane in the two key steps (Scheme 2). ¹H‐ and ¹³C‐NMR Signal assignments from COSY, HSQC, and HMBC 2D NMR data of the synthesized 1 were compared with the earlier‐described data of the natural 3‐hydroxycelacinnine. The similarity of their ¹³C‐NMR spectra point to the correctness of the proposed constitutional formula for natural 3‐hydroxycelacinnine; however, different ¹H‐NMR chemical shifts and coupling constants (J(2,3)=9.0 vs. 1.2 Hz, resp.) in the α‐hydroxy‐β‐amino lactam moiety suggest that natural 3‐hydroxycelacinnine is the 2,3‐cis‐epimer of one synthetic (±)‐ 1 .     

Vibrational Circular Dichroism and Theoretical Study of the Conformational Equilibrium in (−)‐S‐Nicotine

We report an extensive study of the molecular and electronic structure of (?)‐S‐nicotine, to deduce the phenomenon that controls its conformational equilibrium and to solve its solution‐state conformer population. Density functional theory, ab initio, and molecular mechanics calculations were used together with vibrational circular dichroism (VCD) and Fourier transform infrared spectroscopies. Calculations and experiments in solution show that the structure and the conformational energy profile of (?)‐S‐nicotine are not strongly dependent on the medium, thus suggesting that the conformational equilibrium is dominated by hyperconjugative interactions rather than repulsive electronic effects. The analysis of the first recorded VCD spectra of (?)‐S‐nicotine confirmed the presence of two main conformers at room temperature. Our results provide further evidence of the hypersensitivity of vibrational optical activity spectroscopies to the three‐dimensional structure of chiral samples and prove their suitability for the elucidation of solution‐state conformer distribution.     

DFT‐GIAO 1H and 13C NMR prediction of chemical shifts for the configurational assignment of 6β‐hydroxyhyoscyamine diastereoisomers

¹H and ¹³C NMR chemical shift calculations using the density functional theory–gauge including/invariant atomic orbitals (DFT–GIAO) approximation at the B3LYP/6‐311G++(d,p) level of theory have been used to assign both natural diastereoisomers of 6β‐hydroxyhyoscyamine. The theoretical chemical shifts of the ¹H and ¹³C atoms in both isomers were calculated using a previously determined conformational distribution, and the theoretical and experimental values were cross‐compared. For protons, the obtained average absolute differences and root mean square (rms) errors for each comparison showed that the experimental chemical shifts of dextrorotatory and levorotatory 6β‐hydroxyhyoscyamines correlated well with the theoretical values calculated for the (3R,6R,2′S) and (3S,6S,2′S) configurations, respectively, whereas for ¹³C atoms the calculations were unable to differentiate between isomers. The nature of the relatively large chemical shift differences observed in nuclei that share similar chemical environments between isomers was asserted from the same calculations. It is shown that the anisotropic effect of the phenyl group in the tropic ester moiety, positioned under the tropane ring, has a larger shielding effect over one ring side than over the other one. Copyright © 2009 John Wiley & Sons, Ltd.     

A series of 1‐[2‐aryl‐1‐diazenyl]‐3‐({3‐[2‐aryl‐1‐diazenyl]perhydrobenzo[d]imidazol‐1‐yl}methyl)perhydrobenzo[d]imidazoles. Synthesis and characterization

Reaction of diazonium salts with solutions of 1,2‐diaminocyclohexane mixed with formaldehyde affords the 1‐[2‐aryl‐1‐diazenyl]‐3‐({3‐[2‐aryl‐1‐diazenyl]perhydrobenzo[d]imidazol‐1‐yl}methyl)perhydrobenzo‐[d]imidazoles ( 6 ), a new series of bis‐triazenes with different connectivity than any previous type of bis‐triazene reported. The products have been characterized principally by NMR and IR spectroscopy, elemental analysis and unequivocally by X‐ray crystallography. The methylene protons of the perhydroimidazole rings are diastereotopic giving rise to a doublet of doublets pattern in the ¹H NMR spectra. However, detailed analysis of the NMR spectra shows that there is more than one set of doublet‐of‐doublet signals, suggesting the presence of different rotameric forms of the products. The ¹³C NMR spectral assignments were assisted by COSY and DEPT experiments with selected compounds.     

NMR Conformational Analysis and Theoretical Calculations for 2‐Aryl‐ 1,3‐dihydroxy‐4,4,5,5‐tetramethylimidazolidines

Conformational studies of 1,3‐dihydroxy‐4,4,5,5‐tetramethyl‐2‐(pyridin‐1‐yl)imidazolidine ( 1a ) and 1,3‐dihydroxy‐4,4,5,5‐tetramethyl‐2‐(pyridin‐3‐yl)imidazolidine ( 1b ), carried out by using 1D ¹H‐ and ¹³C‐NMR and 2D HMQC, HMBC, and NOESY experiments and with the aid of theoretical calculations, indicate that the OH groups are trans to the pyridinyl substituent. Because the two ¹H‐NMR signals of the Me groups are distinguishable and do not change between 290 and 380 K, it is proposed that 1a and 1b have each only one conformation in this temperature range. This behavior was not found with 1,3‐dihydroxy‐4,4,5,5‐tetramethyl‐2‐(pyridin‐2‐yl)imidazolidine ( 1c ) because its Me ¹H‐NMR signals cross over at 300 K. Hence, more than one conformation must be present, beyond those produced by simple inversions. Theoretical calculations including temperature and solvent effects were performed to provide further information on the conformational analysis and to help to assign the NMR data. The combination of NMR measurements and quantum‐chemical calculations is shown to be a very promising strategy for conformational analysis studies in solution.     

Total Synthesis of (−)‐Daphenylline

Total synthesis of (?)‐daphenylline, a hexacyclic Daphniphyllum alkaloid, was achieved. Construction of the tricyclic DEF ring system was initiated by asymmetric Negishi coupling followed by an intramolecular Friedel–Crafts reaction. Installation of a side chain onto the tricyclic core was carried out through Sonogashira coupling, stereocontrolled Claisen rearrangement by taking advantage of the characteristic conformation of the tricyclic DEF core, and the stereoselective alkylation of a lactone. After the introduction of a glycine unit, the ABC ring system was stereoselectively constructed through intramolecular cycloaddition of the cyclic azomethine ylide.     

Enantioselective Synthesis of (−)‐(R)‐Cordiachromene and (−)‐(R)‐Dictyochromenol Utilizing Intramolecular SNAr Reaction

A simple and efficient enantioselective synthesis of chromene, (?)‐(R)‐cordiachromene ( 1 ), and (?)‐(R)‐dictyochromenol ( 2 ) has been accomplished. This convergent synthesis utilizes intramolecular S_NAr reaction for the formation of chroman ring, and Seebach's method of ‘self‐reproduction of chirality’ should establish the (R)‐configuration of the C(2) side chain as key steps.     

Total Synthesis of Marine Eicosanoid (−)‐Hybridalactone

(?)‐Hybridalactone ( 1 ) is a marine eicosanoid isolated from the red alga Laurencia hybrida. This natural product contains cyclopropane, cyclopentane, 13‐membered macrolactone and epoxide ring systems incorporating seven stereogenic centers. Moreover, this compound has an acid‐labile skipped Z,Z‐diene motif. In this paper, we report on the total synthesis of (?)‐hybridalactone ( 1 ). The unique eicosanoid (?)‐hybridalactone ( 1 ) was synthesized starting from optically active γ‐butyrolactone 2 in a linear sequence comprising 21 steps with an overall yield of 21.9 %. A key step in the synthesis of (?)‐hybridalactone ( 1 ) is the methyl phenylsulfonylacetate‐mediated one‐pot synthesis of the cis‐cyclopropane‐γ‐lactone derivative. This reaction provided an efficient and stereoselective access to cis‐cyclopropane‐γ‐lactone 12 . Further elaboration of the latter compounds through desulfonylation, epoxidation, oxidation, Wittig olefination and Shiina macrolactonization afforded (?)‐hybridalactone.     

Structural determination of ε‐lactams by 1H and 13C NMR

The thermodynamic products (ε‐lactams) of the degradation of ten different spirocyclic oxaziridines were analyzed by ¹H and ¹³C NMR spectroscopy. The preferred conformations were determined by examining the homonuclear spin–spin coupling constant and the chemical shift effects of the N‐substituent and the alkyl group of the aliphatic ring on ¹H and ¹³C NMR spectra. Copyright © 2009 John Wiley & Sons, Ltd.     

Powder X‐ray study of racemic (2RS,3RS)‐5‐amino‐3‐[4‐(3‐methoxyphenyl)piperazin‐1‐yl]‐1,2,3,4‐tetrahydronaphthalen‐2‐ol

The structure of the title benzovesamicol analogue, C₂₁H₂₇N₃O₂, an important compound for the diagnosis of Alzheimer's disease, has been determined by X‐ray powder diffraction. The title compound was firstly synthesized and characterized by spectroscopic methods (FT–IR, and ¹³C and ¹H NMR). The compound is a racemic mixture of enantiomers which crystallizes in the monoclinic system in a centrosymmetric space group (P2₁/c). Crystallography, in particular powder X‐ray diffraction, was pivotal in revealing that the enantio‐resolution did not succeed. The piperazine ring is in a chair conformation, while the cyclohexene ring assumes a half‐chair conformation. The crystal packing is dominated by intermolecular O—H...N hydrogen bonding which links molecules along the c direction.     

Convergent Total Syntheses of (−)‐Rubriflordilactone B and (−)‐pseudo‐Rubriflordilactone B

A highly convergent strategy for the synthesis of the natural product (?)‐rubriflordilactone B, and the proposed structure of (?)‐pseudo‐rubriflordilactone B, is described. Late stage coupling of diynes containing the respective natural product FG rings with a common AB ring aldehyde precedes rhodium‐catalyzed [2+2+2] alkyne cyclotrimerization to form the natural product skeleton, with the syntheses completed in just one further operation. This work resolves the uncertainty surrounding the identity of pseudo‐rubriflordilactone B and provides a robust platform for further synthetic and biological investigations.     

C?H···N and C?H···O intramolecular hydrogen bonding effects in the 1H, 13C and 15 N NMR spectra of the configurational isomers of 1‐vinylpyrrole‐2‐carbaldehyde oxime substantiated by DFT calculations

According to the ¹H, ¹³C and ¹⁵N NMR spectroscopic data and DFT calculations, the E‐isomer of 1‐vinylpyrrole‐2‐carbaldehyde adopts preferable conformation with the anti‐orientation of the vinyl group relative to the carbaldehyde oxime group and with the syn‐arrangement of the carbaldehyde oxime group with reference to the pyrrole ring. This conformation is stabilized by the C? H···N intramolecular hydrogen bond between the α‐hydrogen of the vinyl group and the oxime group nitrogen, which causes a pronounced high‐frequency shift of the α‐hydrogen signal in ¹H NMR (～0.5 ppm) and an increase in the corresponding one‐bond ¹³C–¹H coupling constant (ca 4 Hz). In the Z‐isomer, the carbaldehyde oxime group turns to the anti‐position with respect to the pyrrole ring. The C? H···O intramolecular hydrogen bond between the H‐3 hydrogen of the pyrrole ring and the oxime group oxygen is realized in this case. Due to such hydrogen bonding, the H‐3 hydrogen resonance is shifted to a higher frequency by about 1 ppm and the one‐bond ¹³C–¹H coupling constant for this proton increases by ～5 Hz. Copyright © 2008 John Wiley & Sons, Ltd.     

Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (?)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO₄)₂‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (?)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.