General Approach for the Synthesis of 12-Methoxy-Substituted Sarpagine Indole Alkaloids Including (−)-12-Methoxy-<i>N</i>_b-methylvoachalotine, (+)-12-Methoxy-<i>N</i>_a-methylvellosimine, (+)-12-Methoxyaffinisine, and (−)-Fuchsiaefoline

The enantiospecific synthesis of 7-methoxy-d-tryptophan ethyl ester was completed by combination of the Larock heteroannulation process with a Schöllkopf-based chiral auxiliary in good yield. This ester was then employed in the first regiospecific, stereospecific total synthesis of (+)-12-methoxy-Na-methylvellosimine, (+)-12-methoxyaffinisine, (−)-fuchsiaefoline, and 12-methoxy-Nb-methylvoachalotine in excellent overall yield. The asymmetric Pictet−Spengler reaction and enolate-driven palladium-catalyzed cross-coupling processes served as key steps. The quaternary center at C(16) of 12-methoxy-Nb-methylvoachalotine was established via the Tollens reaction between (+)-12-methoxy-Na-methylvellosimine and formaldehyde to form diol 17. The two prochiral primary alcohols in diol 17 were differentiated by the oxidative cyclization(DDQ) of the hydroxyl group at the axial position of 17 with the benzylic postion at [C(6)] to form a cyclic ether [C(6)−O(17)]. After oxidative formation of the α-ester at C(16), the ether bond was reductively cleaved with TFA/Et3SiH in high yield. The DDQ-mediated oxidative cyclization and TFA/Et3SiH reductive cleavage served as protection/deprotection steps in order to provide a versatile entry into the voachalotine alkaloids

General Approach to the Total Synthesis of 9-Methoxy-Substituted Indole Alkaloids: Synthesis of Mitragynine, as well as 9-Methoxygeissoschizol and 9-Methoxy-<i>N</i>_b-methylgeissoschizol

Herein, the full details of the synthesis of the 9-methoxy-substituted Corynanthe indole alkaloids mitragynine (1), 9-methoxygeissoschizol (3), and 9-methoxy-Nb-methylgeissoschizol (4) are described. Initially, an efficient synthetic route to the optically active 4-methoxytryptophan ethyl ester 20 on a multigram scale was developed via a Mori−Ban−Hegedus indole synthesis. The ethyl ester of d-4-methoxytryptophan 20 was obtained with a radical-mediated regioselective bromination of indoline 12 serving as a key step. Alternatively, the key 4-methoxytryptophan intermediate 22 could be synthesized by the Larock heteroannulation of aryl iodide 10b with the internal alkyne 21a. The use of the Boc-protected aniline 10b was crucial to the success of this heteroannulation. The α,β-unsaturated ester 6 was synthesized via the Pictet−Spengler reaction as the pivotal step. This was followed by a Ni(COD)2-mediated cyclization to set up the stereocenter at C-15. The benzyloxy group in 31 was removed to provide the intermediate ester 5. This chiral tetracyclic ester 5 was employed to accomplish the first total synthesis of 9-methoxygeissoschizol (3) and 9-methoxy-Nb-methylgeissoschizol (4) as well as the opioid agonistic indole alkaloid mitragynine (1)

Enantiospecific Total Synthesis of the Important Biogenetic Intermediates along the Ajmaline Pathway, (+)-Polyneuridine and (+)-Polyneuridine Aldehyde, as well as 16-Epivellosimine and Macusine A

The first stereospecific synthesis of polyneuridine aldehyde (6), 16-epivellosimine (7), (+)-polyneuridine (8), and (+)-macusine A (9) has been accomplished from commercially available d-(+)-tryptophan methyl ester. d-(+)-Tryptophan has served here both as the chiral auxiliary and the starting material for the synthesis of the common intermediate, (+)-vellosimine (13). This alkaloid was available in enantiospecific fashion in seven reaction vessels in 27% overall yield from d-(+)-trytophan methyl ester (14) via a combination of the asymmetric Pictet−Spengler reaction, Dieckmann cyclization, and a stereocontrolled intramolecular enolate-driven palladium-mediated cross-coupling reaction. A new process for this stereocontrolled intramolecular cross-coupling has been developed via a copper-mediated process. The initial results of this investigation indicated that an enolate-driven palladium-mediated cross-coupling reaction can be accomplished by a copper-mediated process which is less expensive and much easier to work up. An enantiospecific total synthesis of (+)-polyneuridine aldehyde (6), which has been proposed as an important biogenetic intermediate in the biosynthesis of quebrachidine (2), was then accomplished in an overall yield of 14.1% in 13 reaction vessels from d-(+)-tryptophan methyl ester (14). Aldehyde 13 was protected as the Na-Boc aldehyde 32 and then converted into the prochiral C(16)-quaternary diol 12 via the practical Tollens’ reaction and deprotection. The DDQ-mediated oxidative cyclization and TFA/Et3SiH reductive cleavage served as protection/deprotection steps to provide a versatile entry into the three alkaloids polyneuridine aldehyde (6), polyneuridine (8), and macusine A (9) from the quarternary diol 12. The oxidation of the 16-hydroxymethyl group present in the axial position was achieved with the Corey−Kim reagent to provide the desired β-axial aldehydes, polyneuridine aldehyde (6), and 16-epivellosimine (7) with 100% diastereoselectivity

MOESM3 of Tumor specific liposomes improve detection of pancreatic adenocarcinoma in vivo using optoacoustic tomography

Additional file 3: Figure S3.   Representative locations of organs on MSOT at both 46 and 49 mm. Organs are noted PT = Pancreas tumor, S = Spleen, L = Liver, BV = Blood vessel, K = Kidney

MOESM1 of Tumor specific liposomes improve detection of pancreatic adenocarcinoma in vivo using optoacoustic tomography

Additional file 1: Figure S1.   Structures of the lipids used for control and Sdc1-tagged liposome synthesis

MOESM2 of Tumor specific liposomes improve detection of pancreatic adenocarcinoma in vivo using optoacoustic tomography

Additional file 2: Figure S2. Absorption spectrum for CF-750 encapsulated Sdc1 liposomes. The liposomes demonstrated fluorescence activity with peak absorbance at 750 nm. Encapsulating the CF-750 dye within the Sdc1 liposomes did not change the optical activity of the dye

Conformational Analysis of the <i>cis</i>- and <i>trans</i>-Adducts of the Pictet−Spengler Reaction. Evidence for the Structural Basis for the C(1)−N(2) Scission Process in the <i>c</i><i>is</i>- to <i>trans</i>-Isomerization

The stable conformations of both the trans- and cis-1,3-disubstituted Nb-benzyl stereoisomers of the Pictet−Spengler reaction have been determined by NMR spectroscopy and X-ray crystallography in order to better understand the C(1)−N(2) cis- to trans-isomerization process. In the Na-H series, the chair conformation was preferred for the trans-isomer 3a, while the cis-isomer 3b existed predominantly in the boat form. However, in the Na-methyl series (1a, 1b, 2a, 2b), both the cis (1b, 2b) and trans (1a, 2a) diastereomers existed in the chair conformation to relieve the A(1,2)-strain between the Na-methyl function and the substituent at C(1). The difference in the preferred conformations of the cis-isomers in the Na-H and Na-methyl series (as compared to the preferred conformations in the trans-isomers) can be employed to understand the reduced rate of epimerization of cis-2b into trans-2a as compared to 3b into 3a. This provides the structural basis for the carbocation-mediated intermediate in the C(1)−N(2) scission process

Comparisons of mortality rate by demographic and drug use history on enrollment and MMT treatment characteristics of clients.

<p>*Average methadone dose is calculated as the sum of all methadone doses divided by the number of days methadone was received.</p><p>**Only HIV-positive clients are included in the category “Antiretroviral therapy (ART).”</p><p>^†Urine tests positive for opiates during treatment is calculated by the total number of routine urine drug tests that yielded positive results as a percentage of the total number of tests taken during the six years of follow-up.</p

The overall picture of clients' treatment dynamics.

<p>The study participants were enrolled between March 23, 2004 and October 31, 2004, and followed until June 30, 2010. Treatment break means clients missed more than 30 consecutive days during the follow-up period. The first line (solid line) means a client was treated continuously before he/she dropped out of MMT. The second line means a clients dropped out of MMT for a period of time (broken line), reenrolled in MMT (solid line), and then dropped out of MMT again. Even if a client dropped out of MMT, he/she was followed so he/her (live or dead) was assessed during the follow-up period.</p

Results from multivariate Cox PH models indicating factors associated with mortality over the six-year follow-up period.

<p>*Observed time in the study was calculated as the time from the start of methadone treatment to either death or study completion (30 June 2010), whichever occurred first.</p>§<p>PY: person-years, HR: hazard ratio, CI: 95% confidence interval.</p>†<p>Average methadone dose is calculated as the sum of all methadone doses divided by the number of days methadone was received.</p>#<p>Length of treatment is calculated as the total number of days that clients took methadone in the MMT clinics, than transfer to the number of years by dividing 365.</p>‡<p>Urine tests positive for opiates during treatment is calculated by the total number of routine urine drug tests that yielded positive results as a percentage of the total number of tests taken during the six years of follow-up.</p>#<p>Adjusting for confounding variables including living situation, injection in the past month, having relatives who were MMT patients.</p>&<p>Results of univariate Cox regression.</p