“…The structures of the products were assigned from their 13 C NMR spectra through the reduction of the intensities of the signals for the substituted carbon atoms relative to those of the corresponding signals for the starting materials (for details, see Supporting Information). Similarly, the OMe DMG, which originated with the discovery of the DoM reaction by Wittig and Gilman [39][40][41] and has been used widely and dependably, [1,[42][43][44] does not interfere with clean deprotonation ortho to the O-carbamate, as shown by the conversion of 2-and 4-methoxy derivatives 4d and 4f into the corresponding products 5h-5j ( [11][12][13][14] albeit with less selectivity than that for the 3-chloro analogue 4b ( Table 2, Entries 5-6). Thus, 2-and 4-chloro O-carbamates 4a and 4c afford products 5a-5c and 5g, respectively, and the 3-chloro derivative 4b leads to 2-substituted products 5d-5f with selected electrophiles ( Table 2, Entries 1-7).…”
Section: Resultsmentioning
confidence: 99%
“…Thus, 2-and 4-chloro O-carbamates 4a and 4c afford products 5a-5c and 5g, respectively, and the 3-chloro derivative 4b leads to 2-substituted products 5d-5f with selected electrophiles ( Table 2, Entries 1-7). Similarly, the OMe DMG, which originated with the discovery of the DoM reaction by Wittig and Gilman [39][40][41] and has been used widely and dependably, [1,[42][43][44] does not interfere with clean deprotonation ortho to the O-carbamate, as shown by the conversion of 2-and 4-methoxy derivatives 4d and 4f into the corresponding products 5h-5j ( [11][12][13][14] albeit with less selectivity than that for the 3-chloro analogue 4b ( Table 2, Entries 5-6). The 2-, 3-, and 4-OMOM derivatives, 4g, 4h, and 4i showed less desirable regioselectivity.…”
A systematic study on the competitive metalation of derivatives containing four directed metalation groups (DMGs), namely, Cl, OMe, methoxymethoxy (OMOM), and CONEt2, in comparison with the OCONEt2 DMG is described. In addition, the anionic ortho‐Fries (AoF) rearrangement, the double metalation–electrophile quench of 1,2‐ and 1,4‐O‐carbamates, and iterative metalation procedures are presented. The results provide new methodologies for the synthesis of contiguously functionalized 1,2,3‐ and 1,2,3,4‐substituted aromatic derivatives of difficult accessibility and potential broad utility. A comparison of the present methodology with previously developed routes is provided for selected examples with emphasis on such substituted compounds.
“…The structures of the products were assigned from their 13 C NMR spectra through the reduction of the intensities of the signals for the substituted carbon atoms relative to those of the corresponding signals for the starting materials (for details, see Supporting Information). Similarly, the OMe DMG, which originated with the discovery of the DoM reaction by Wittig and Gilman [39][40][41] and has been used widely and dependably, [1,[42][43][44] does not interfere with clean deprotonation ortho to the O-carbamate, as shown by the conversion of 2-and 4-methoxy derivatives 4d and 4f into the corresponding products 5h-5j ( [11][12][13][14] albeit with less selectivity than that for the 3-chloro analogue 4b ( Table 2, Entries 5-6). Thus, 2-and 4-chloro O-carbamates 4a and 4c afford products 5a-5c and 5g, respectively, and the 3-chloro derivative 4b leads to 2-substituted products 5d-5f with selected electrophiles ( Table 2, Entries 1-7).…”
Section: Resultsmentioning
confidence: 99%
“…Thus, 2-and 4-chloro O-carbamates 4a and 4c afford products 5a-5c and 5g, respectively, and the 3-chloro derivative 4b leads to 2-substituted products 5d-5f with selected electrophiles ( Table 2, Entries 1-7). Similarly, the OMe DMG, which originated with the discovery of the DoM reaction by Wittig and Gilman [39][40][41] and has been used widely and dependably, [1,[42][43][44] does not interfere with clean deprotonation ortho to the O-carbamate, as shown by the conversion of 2-and 4-methoxy derivatives 4d and 4f into the corresponding products 5h-5j ( [11][12][13][14] albeit with less selectivity than that for the 3-chloro analogue 4b ( Table 2, Entries 5-6). The 2-, 3-, and 4-OMOM derivatives, 4g, 4h, and 4i showed less desirable regioselectivity.…”
A systematic study on the competitive metalation of derivatives containing four directed metalation groups (DMGs), namely, Cl, OMe, methoxymethoxy (OMOM), and CONEt2, in comparison with the OCONEt2 DMG is described. In addition, the anionic ortho‐Fries (AoF) rearrangement, the double metalation–electrophile quench of 1,2‐ and 1,4‐O‐carbamates, and iterative metalation procedures are presented. The results provide new methodologies for the synthesis of contiguously functionalized 1,2,3‐ and 1,2,3,4‐substituted aromatic derivatives of difficult accessibility and potential broad utility. A comparison of the present methodology with previously developed routes is provided for selected examples with emphasis on such substituted compounds.
“…A simplified pathway towards triptolide has previously been proposed, also involving 3 as an intermediate [ 22 ]. A semi-synthetic conversion from 3 to triptolide was demonstrated earlier [ 24 ], practically mimicking the proposed biosynthetic route. Finally, detection of numerous putative intermediates of triptolide [ 25 ] lends further support for our hypothesis.…”
Section: Introductionmentioning
confidence: 58%
“…The yeast strain producing 3 in this study could potentially serve as a source for chemical synthesis of triptolide or triptolide derivatives [ 24 , 25 ]. However, 3 might even find direct applications as both 3 and its derivatives have been suggested to possess, among others, gastroprotective [ 36 ], anti-inflammatory [ 37 ] and anti-cancer properties [ 38 ].…”
The development of medical applications exploiting the broad bioactivities of the diterpene therapeutic triptolide from Tripterygium wilfordii is limited by low extraction yields from the native plant. Furthermore, the extraordinarily high structural complexity prevents an economically attractive enantioselective total synthesis. An alternative production route of triptolide through engineered Saccharomyces cerevisiae (yeast) could provide a sustainable source of triptolide. A potential intermediate in the unknown biosynthetic route to triptolide is the diterpene dehydroabietic acid. Here, we report a biosynthetic route to dehydroabietic acid by transient expression of enzymes from T. wilfordii and Sitka spruce (Picea sitchensis) in Nicotiana benthamiana. The combination of diterpene synthases TwTPS9, TwTPS27, and cytochromes P450 PsCYP720B4 yielded dehydroabietic acid and a novel analog, tentatively identified as ‘miltiradienic acid’. This biosynthetic pathway was reassembled in a yeast strain engineered for increased yields of the pathway intermediates, the diterpene olefins miltiradiene and dehydroabietadiene. Introduction in that strain of PsCYP720B4 in combination with two alternative NADPH-dependent cytochrome P450 reductases resulted in scalable in vivo production of dehydroabietic acid and its analog from glucose. Approaching future elucidation of the remaining biosynthetic steps to triptolide, our findings may provide an independent platform for testing of additional recombinant candidate genes, and ultimately pave the way to biotechnological production of the high value diterpenoid therapeutic.
“…Unlike precedent methods including biogenetic cascade radical [21, 27] or cationic [28–30] cyclization and alkylation of benzocyclohexanone derivatives, [18, 24] or Diels–Alder reaction [25] to construct the quaternary center, we envisioned that it could be formed enantioselectively via arylboronic acid addition to cyclic enone, a methodology pioneered by Prof. Lu [31] and developed by Prof. Stoltz [32–34]. Scheme 1Retrosynthetic analysis of 1 and 2
…”
Catalytic asymmetric formal synthesis of (−)-Triptophenolide and (+)-Triptolide have been achieved. Key reaction involves Palladium catalyzed asymmetric conjugate addition of aryl boronic acid to 3-methyl cyclohexe-1-none to form quaternary carbon. Claisen rearrangement and subsequent aldol reaction furnished trans-decaline key intermediate, which assured a formal total synthesis of (−)-Triptophenolide and (+)-Triptolide.Graphical Abstract
Electronic supplementary materialThe online version of this article (doi:10.1007/s13659-016-0100-z) contains supplementary material, which is available to authorized users.
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