Structural valve deterioration of bioprosthesis in the aortic position: A single-center experience.

BACKGROUND: Aortic valve replacement (AVR) is one of the most common open-heart surgical procedures. The durability of the tissue valve in the aortic position is crucial in AVR and transcatheter AVR. We reviewed structural valve deterioration using echocardiographic follow-up in three types of surgical aortic tissue valves. METHODS: A retrospective analysis was conducted where hemodynamic deterioration was evaluated and compared using transthoracic echocardiography, including pressure gradients and effective orifice area. Kaplan-Meier analyses were used to summarize the time to failure. RESULTS: The study included 133 Trifecta, 156 Epic, and 321 Magna Ease valves. Seventy-six percent (1941/2551) of patients had to be excluded due to insufficient echo data. Through univariate analysis, 34% (216/610) of valves met deterioration criteria after 24 months. Unadjusted survival curves showed a significant difference between valves (p ≤ .001), with a longer mean time to deterioration for the Magna Ease versus Trifecta and Epic of 68.9 versus 50.1 and 38.2 months, respectively. A Cox proportional hazard analysis found worse hazard ratios of 1.69 (p ≤ .04) and 2.4 (p ≤ .01) for Trifecta versus Magna and Epic versus Trifecta, respectively. CONCLUSION: All three valve types demonstrated structural valve deterioration on echocardiographic follow-up with significant differences in rate. The Magna Ease appeared to have the highest durability, and the Epic the lowest. Further investigation is warranted to confirm the results in a larger multicenter study.

Allylic alcohols and amines by carbenoid eliminative cross-coupling using epoxides or aziridines.

α-Lithiated terminal epoxides and N-(tert-butylsulfonyl)aziridines undergo eliminative cross-coupling with α-lithio ethers, to give convergent access to allylic alcohols and allylic amines, respectively. The process can be considered as proceeding by selective strain-relieving attack (ring-opening) of the lithiated three-membered heterocycle by the lithio ether and then selective ß-elimination of lithium alkoxide.

Electrophile dependent mechanisms in the asymmetric trapping of α-lithio-N-(tert-butoxythiocarbonyl)azetidine.

Sn-Li exchange and 'poor man's Hoffmann tests' establish asymmetric trapping of α-lithio-N-(tert-butoxythiocarbonyl) (Botc) azetidine to be controlled by dynamic thermodynamic resolution or dynamic kinetic resolution, depending on the electrophile. Unusually, different configurational stability is seen for the anion generated by lithiation compared to transmetallation. Configurational stability of α-lithio-N-Boc azetidine indicates instability with the N-Botc system is due to the C[double bond, length as m-dash]S group.

Synthesis and Homologation of an Azetidin-2-yl Boronic Ester with α-Lithioalkyl Triisopropylbenzoates.

An α-boryl azetidine, obtained by α-lithiation-borylation of N-Botc azetidine, undergoes reaction with α-triisopropylbenzoyloxy organolithiums to give homologated boronic esters that can be further oxidized, homologated, arylated, and deprotected to give a range of α-substituted azetidines. Scalemic α-boryl azetidine-α-triisopropylbenzoyloxy organolithium pairings show stereospecific reagent control, providing access to either diastereomeric series of homologated boronic esters with very high er's.

Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids.

(R,R)-Dimethyl tartrate acetonide 7 in THF/HMPA undergoes deprotonation with LDA and reaction at -78 °C during 12-72 h with a range of alkyl halides, including non-activated substrates, to give single diastereomers (at the acetonide) of monoalkylated tartrates 17, 24, 33a-f, 38a,b, 41 of R,R-configuration, i.e., a stereoretentive process (13-78% yields). Separable trans-dialkylated tartrates 34a-f can be co-produced in small amounts (9-14%) under these conditions, and likely arise from the achiral dienolate 36 of tartrate 7. Enolate oxidation and acetonide removal from γ-silyloxyalkyl iodide-derived alkylated tartrates 17 and 24 give ketones 21 and 26 and then Bamford-Stevens-derived diazoesters 23 and 27, respectively. Only triethylsilyl-protected diazoester 27 proved viable to deliver a diazoketone 28. The latter underwent stereoselective carbonyl ylide formation-cycloaddition with methyl glyoxylate and acid-catalysed rearrangement of the resulting cycloadduct 29, to give the 3,4,5-tricarboxylate-2,8-dioxabicyclo[3.2.1]octane core 31 of squalestatins/zaragozic acids. Furthermore, monoalkylated tartrates 33a,d,f, and 38a on reaction with NaOMe in MeOH at reflux favour (≈75:25) the cis-diester epimers epi- 33a,d,f and epi- 38a (54-67% isolated yields), possessing the R,S-configuration found in several monoalkylated tartaric acid motif-containing natural products.

Alkene protection against acid using a bromide substituent: application in a total synthesis of (-)-6,7-dideoxysqualestatin H5.

The presence of a bromide substituent, instead of a hydrogen or methyl group, on a carbon-carbon double bond, protects the alkene from addition reactions when exposed to trifluoroacetic acid. This concept is used to circumvent concomitant loss of unsaturation in a late-stage acid-catalysed 6,8- to 2,8-dioxabicyclo[3.2.1]octane rearrangement towards (-)-6,7-dideoxysqualestatin H5. The inertness of the alkenyl bromide functionality is demonstrated through several synthetic transformations in the assembly of the rearrangement substrate. Completion of the natural product synthesis is facilitated by post-rearrangement removal of the bromide substituent through stereoselective C-C cross-coupling in the presence of ester and hydroxyl functionalities.

On the ozonolysis of unsaturated tosylhydrazones as a direct approach to diazocarbonyl compounds.

The scope and limitations are described of reacting unsaturated tosylhydrazones with O3 followed by Et3N for the generation of 1,4- and 1,5-diazocarbonyl systems. Tosylhydrazones, from tosylhydrazide condensation with readily available δ- and ε-unsaturated α-ketoesters, led in the former case to a 2-pyrazoline whereas the latter cases led to α-diazo-ε-ketoesters, although a terminal alkene produced a tetrahydropyridazinol. Using the ozonolysis-Et3N strategy, tosylhydrazones from cyclic enones give 2,5- and 2,6-diazoketones with aldehyde or ester functionality at the 1-position; the α-diazoaldehydes prefer the s-trans conformation, with a rotation barrier of 74 kJ mol-1 at 25 °C determined by NMR. This one-pot ozonolysis/Bamford-Stevens chemistry demonstrates both the tolerance of tosylhydrazones to ozone, and the subsequently added amine playing a dual role to directly transform the intermediate tosylhydrazone ozonides into products containing reactive diazo and ketone functionalities; such adducts are of particular value as precursors to cyclic carbonyl ylides for 1,3-dipolar cycloadditions.

Asymmetric Induction in C-Alkylation of Tropane-Derived Enamines: Congruence Between Computation and Experiment.

Quantum chemical studies of C-ethylation of 1-methyl- and 1,4,4-trimethyl-tropane-derived enamines predict good (89:11 er, B3LYP) and high (98:2 er, B3LYP) levels, respectively, of asymmetric induction in the resulting α-alkylated aldehydes. The nonracemic tropanes were synthesized using Mannich cyclization strategies (Robinson-Schöpf and by way of a Davis-type N-sulfinyl amino bisketal, respectively), and ethylation of the derived enamines was found to support the predicted sense and magnitude of asymmetric induction (81:19 er and 95:5 er, respectively). A comparison of several computational methods highlights the robustness of predicted trends in enantioselectivity, enabling theory to guide synthesis.

Aruncin B: Synthetic Studies, Structural Reassignment and Biological Evaluation.

A ring-closing alkene metathesis (RCM)/ oxyselenation-selenoxide elimination sequence was established to the sodium salts E- and Z-25 of the originally proposed structure for the recently isolated cytotoxin aruncin B (1), as well as to the sodium salt Z-34 of a related ethyl ether regioisomer; however, none of their corresponding free acids could be obtained. Their acid sensitivity, together with detailed analysis of the spectroscopic data indicated that profound structural revision was necessary. This led to reassignment of aruncin B as a Z-γ-alkylidenebutenolide Z-36. Although a related RCM/ oxyselenation-selenoxide elimination sequence was used to confirm the γ-alkylidenebutenolide motif, a ß-iodo Morita-Baylis-Hillman reaction/ Sonogashira cross-coupling-5-exo-dig lactonisation sequence was subsequently developed, due to its brevity and flexibility for diversification. Aruncin B (36), together with 14 γ-alkylidenebutenolide analogues, were generated for biological evaluation.

Synthesis of (-)-6,7-Dideoxysqualestatin H5 by Carbonyl Ylide Cycloaddition-Rearrangement and Cross-electrophile Coupling.

An asymmetric synthesis of (-)-6,7-dideoxysqualestatin H5 is reported. Key features of the synthesis include the following: (1) highly diastereoselective n-alkylation of a tartrate acetonide enolate and subsequent oxidation-hydrolysis to provide an asymmetric entry to a ß-hydroxy-α-ketoester motif; (2) facilitation of Rh(II)-catalyzed cyclic carbonyl ylide formation-cycloaddition by co-generation of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and (3) stereoretentive Ni-catalyzed Csp3-Csp2 cross-electrophile coupling between tricarboxylate core and unsaturated side chain to complete the natural product.

Total Synthesis and Structural Revision of the Cytotoxin Aruncin B.

The sodium salts E-15 and Z-15 of the originally proposed dihydropyran acid structure of aruncin B (1) were prepared through ring-closing alkene metathesis (RCM) and ethoxyselenation-selenoxide elimination, but acid sensitivity of these salts, together with inconsistencies in the spectral data, suggested a significant structural misassignment. A ß-iodo Morita-Baylis-Hillman reaction to give Z-iodo ester 24, followed by Sonogashira cross-coupling-5-exo-dig lactonization, provided concise access to a Z-γ-alkylidenebutenolide 18, which possessed data corresponding to those originally reported for aruncin B.

Recent applications in natural product synthesis of dihydrofuran and -pyran formation by ring-closing alkene metathesis.

In the past two decades, alkene metathesis has risen in prominence to become a significant synthetic strategy for alkene formation. Many total syntheses of natural products have used this transformation. We review the use, from 2003 to 2015, of ring-closing alkene metathesis (RCM) for the generation of dihydrofurans or -pyrans in natural product synthesis. The strategies used to assemble the RCM precursors and the subsequent use of the newly formed unsaturation will also be highlighted and placed in context.

α- and α'-Lithiation-Electrophile Trapping of N-Thiopivaloyl and N-tert-Butoxythiocarbonyl α-Substituted Azetidines: Rationalization of the Regiodivergence Using NMR and Computation.

(1)H NMR and computational analyses provide insight into the regiodivergent (α- and α'-) lithiation-electrophile trapping of N-thiopivaloyl- and N-(tert-butoxythiocarbonyl)-α-alkylazetidines. The magnitudes of the rotation barriers in these azetidines indicate that rotamer interconversions do not occur at the temperature and on the time scale of the lithiations. The NMR and computational studies support the origin of regioselectivity as being thiocarbonyl-directed lithiation from the lowest energy amide-like rotameric forms (cis for N-thiopivaloyl and trans for N-tert-butoxythiocarbonyl).

Anomalous nuclear Overhauser effects in carbon-substituted aziridines: scalar cross-relaxation of the first kind.

Anomalous NOESY cross-peaks that cannot be explained by dipolar cross-relaxation or chemical exchange are described for carbon-substituted aziridines. The origin of these is identified as scalar cross-relaxation of the first kind, as demonstrated by a complete theoretical description of this relaxation process and by computational simulation of the NOESY spectra. It is shown that this process relies on the stochastic modulation of J-coupling by conformational transitions, which in the case of aziridines arise from inversion at the nitrogen center. The observation of scalar cross-relaxation between protons does not appear to have been previously reported for NOESY spectra. Conventional analysis would have assigned the cross-peaks as being indicative of a chemical exchange process occurring between correlated spins, were it not for the fact that the pairs of nuclei displaying them cannot undergo such exchange.

Amine protection/α-activation with the tert-butoxythiocarbonyl group: application to azetidine lithiation-electrophilic substitution.

tert-Butoxythiocarbonyl (Botc), the long-neglected thiocarbonyl analogue of Boc, facilitates (unlike its alkoxycarbonyl cousin) α-lithiation and electrophile incorporation on N-Botc-azetidine. N,N,N',N'-endo,endo-Tetramethyl-2,5-diaminonorbornane proved optimal as a chiral ligand, generating adducts with er up to 92:8. Facile deprotection, under conditions that left the corresponding N-Boc systems intact, was achieved using either TFA or via thermolysis in ethanol.

Intramolecular oxonium ylide formation-[2,3] sigmatropic rearrangement of diazocarbonyl-substituted cyclic unsaturated acetals: a formal synthesis of hyperolactone C.

Rh(II)-catalyzed oxonium ylide formation-[2,3] sigmatropic rearrangement of α-diazo-ß-ketoesters possessing γ-cyclic unsaturated acetal substitution, followed by acid-catalyzed elimination-lactonization, provides a concise approach to 1,7-dioxaspiro[4.4]non-2-ene-4,6-diones. The process creates adjacent quaternary stereocenters with full control of the relative stereochemistry. An unsymmetrical monomethylated cyclic unsaturated acetal leads to hyperolactone C, where ylide formation-rearrangement proceeds with high selectivity between subtly nonequivalent acetal oxygen atoms.

Generation and electrophile trapping of N-Boc-2-lithio-2-azetine: synthesis of 2-substituted 2-azetines.

s-BuLi-induced α-lithiation-elimination of LiOMe from N-Boc-3-methoxyazetidine and further in situ α-lithiation generates N-Boc-2-lithio-2-azetine which can be trapped with electrophiles, either directly (carbonyl or heteroatom electrophiles) or after transmetalation to copper (allowing allylations and propargylations), providing a concise access to 2-substituted 2-azetines.

An approach to hyperolactone C and analogues using late stage conjugate addition on an oxonium ylide-derived spirofuranone.

A stereocontrolled synthesis of norphenyl hyperolactone C together with its utility as a direct precursor to the anti-HIV agent hyperolactone C and analogues by addition of organolithiums, are described. Preliminary studies to access this key building block in a catalytic enantioselective manner are also reported.

α-Lithiation-electrophile trapping of N-thiopivaloylazetidin-3-ol: stereoselective synthesis of 2-substituted 3-hydroxyazetidines.

α-Lithiation of N-thiopivaloylazetidin-3-ol and subsequent electrophile trapping provides access to a range of 2-substituted 3-hydroxyazetidines with generally good trans-diastereoselectivity, aside from deuteration, which gives the cis-diastereoisomer. Deuterium labeling studies indicate that the initial α-deprotonation occurs preferentially, but not exclusively, in a trans-selective manner. These studies also suggest that the stereochemical outcome of the electrophile trapping depends on the electrophile used but is independent of which α-proton (cis or trans to the hydroxyl group) is initially removed.