Synthesis of the Tricyclic Core of Colchicine via a Dienyne Tandem Ring-Closing Metathesis Reaction

Link: Org Lett ASAP

François-Didier Boyer and Issam Hanna*

Unité de Chimie Biologique, AgroParisTech, INRA, F-78026 Versailles, and Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France

This paper presented a very neat use of RCM and quite clever strategy to construct the 7,7-fused core of colchicine. For the first time, the 7,7-fused bicyclic system could be accessed very quickly in a single step. This main strategy is summarized in the retrosynthetic analysis below.

Therefore, substrate 4 was needed for the RCM step and it was constructed according to the following scheme.

The key reactions were formylation of 6 mediated by SnCl4 to give 7 and the synthesis of propargylic alcohol 14 which was achieved in three steps from 5, using the Ohira-Bestman reagent in the last step.

Next, sequential RCM reactions were performed on 14 using Grubbs' second generation catalyst (15) after the protection of the OH group with TMS. The reaction proved to be very efficient, providing the desired 16 in 74% yield from 14.

This intermediate 16 was further elaborated as shown in Scheme 4 via oxidative rearrangement. Compound 18 could be obtained in high yield. However, going along a more well-known route of previous total syntheses of colchicine, intermediate 19 could be obtained in modest yield, along with 20, from 17. This latter route effectively constituted a formal synthesis of colchicine. The final completion of this molecule by a novel sequence is currently under investigation.

Overall, the double RCM (enyne RCM and RCM) in constructing the 7,7-core of colchicine presented in this paper is quite ingenius.

Isoxazole-Directed Pinacol Rearrangement: Stereocontrolled Approach to Angular Stereogenic Centers

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114201809/ABSTRACT

From Prof. Keisuke Suzuki's group at Tokyo Institute of Technology, Tokyo, Japan with collaboration with Prof. Jeffrey W. Bode at University of California, Santa Barbara, CA

The work in this ACIEE EarlyView article stemmed from synthetic studies toward some polyketide-derived natural products, such as seragakinone A (1) and the antibiotic BE-43472A (2). A general method for installing quaternary stereogenic centers at the angular position of these natural products was required.

A general approach to solve this problem involved a pinacol type alkyl shift as shown in Scheme 2.

However, this approach had some issues that needed addressing. First, I needed to be generated stereoselectively. Second, since both carbinol carbons are tertiary, the OH at the angular position had to be the only leaving group to facilitate migration of R group. A successful two-step process was reported in this article, employing a substrate of type 3, incorporating oxazole ring in the tricyclic core. (R)-3 can be readily prepared in enantio-pure form. General strategy is summarized in Scheme 3.

It was found that starting with (R)-3, addition of an alkyl group proceeded stereoselectively to give cis-diol without the loss of ee, as seen in Scheme 4 in the case of vinyl addition. Pleasingly, treatment of 4a afforded enantio-enriched (S)-5a in high yield and high ee (no loss of ee from chiral 3).

When reaction started with starting material trans-diol 6, it was surprising to find that enantiomeric (R)-5a was obtained in excellent yield and high ee.

This result illustrated the amazing carbocation-stabilizing ability of the oxazole ring. This concept was and illustrated again in separate racemization experiments as shown in equations 2 and 3.

As shown in Eq 2 and 3, when chiral (R)-3 was subjected to protic acid conditions, 3 was recovered with only 60% ee in 94% yield. And when (R)-3 was subjected to Lewis acid-promoted allylsilane addition, 5e was afforded in racemic form. These two experiments showed that racemization occurred in the generation of carbocation at the carbinol carbon, stabilized by oxazole. This is particularly impressive provided that this carbocation was situated alpha to a carbonyl.

The overall mechanism of the process was proposed and summarized in Scheme 5. Basically, exposure of cis-diol to Lewis acid could lead to intermediate A, which led to enantio-enriched product C, or racemization intermediate B, which ultimately led to ent-C.

Having established the method, several substrates were investigated for scope of the reaction. All pinacol rearrangement substrates were synthesized in excellent yields and stereoselectivities to provide only cis-diol (4b-f). On treatment of 4b-e with BF3-OEt2, pinacol products 5b-e were obtained in excellent yields and ees.

The only exception was 4f where the alkynyl group could not migrate fast enough, and this led to racemization intermediate B (Scheme 5, vide supra), which ultimately led to loss in ee in 5f. This problem could be gotten around by complexing the alkynyl group of 4f with Co2(CO)6 before subjecting to Lewis acid conditions. Using this solution, after decomplexation, 5f was afforded in high yield over three steps, and in high ee.

After the method was well-established, it was tested in natural product synthetic studies. Isoprenoid-containing natural product, such as 1 was looked at.

Prenyl group installation was performed on (R)-3 using prenylbarium reagent, followed by treatment with BF3-OEt2. The reaction sequence proceeded smoothly, and stereo- and regioselectively to provide 8 in both excellent yield and ee (Scheme 6).

Fischer Carbene Catalysis of Alkynol Cycloisomerization: Application to the Synthesis of the Altromycin B Disaccharide

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070435s.html

From Prof. Frank E. McDonald's group at Emory University, Atlanta, GA.

This article appeared in Org Lett ASAP demonstrates the utility of Fischer carbene and its novel non-photochemical method of activation for use in catalytic alkynyl alcohol cycloisomerization.

The general concept of this catalyst is shown in the following figure.

As seen in the figure, in the presence of catalytic amount of tungsten complex, alkynyl alcohol 1 is expected to cycloisomerize to give dihydropyran derivative 2. As for the tungsten complex, the conventional method of generating this catalyst involves photolysis of W(CO)6 in presence of Et3N. However, the tungsten Fischer carbene 3 could also be activated by Et3N to generating the reactive catalyst. Thus a stable and easily-prepared tungsten Fischer carbene 3 served a the pre-catalyst for the reaction.

Upon obtaining the optimal conditions for generating the catalyst, a number of substrates were screen in cycloisomerization and the results are summarized in the table below.

As seen in the table, a variety of cyclic enol ether products could be prepared using this method in good to excellent yields. However, further optimizations were needed for substrates possessing C3- and C4-oxygen substituents (such as 20, vide infra) as this substrate, under the current conditions, cycloisomerized to give a mixture of endo and exo cyclic products, 21 and 22, respectively. This is in contrast to using DABCO under photochemical conditions which gave better results with this substrate. The optimizations are shown in the table below.

The selectivity between endo and exo cyclization was found to depend on the steric bulk of C3-OSiR3 group. According to the proposed mechanism below, by having small SiR3 group on C3, coordination of tungsten to alkyne functioned as Lewis acid activation for the substrate to cyclize in the endo fashion. However, by increasing steric bulk of OSiR3, this pathway became less favored (see steric interaction in 25) while the eta-2 cooridnation of tungsten became more prominent. This action led to formation of the desired tungsten vinylidene, intermediate which further led to the desired endo cyclization product (ie. 23 -> 24 -> 26 -> 21). (Compare entries 3 and 6 in Table 2).

Finally, the utility of this method was shown in the successful synthesis of altromycin disaccharide as shown in the scheme below.

Synthesis of the Tricyclic Core of Vinigrol via an Intramolecular Diels-Alder Reaction

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol0702977.html

From Prof. Louis Barriault's group at the University of Ottawa, Ottawa, Canada

A recent article in Org Lett ASAP detailing a partial total synthesis of vinigrol (1), particularly the tricyclic core structure of the natural product. The natural product shows antihypertensive and platelet aggregation-inhibiting properties.

The authros planned to use intramolecualr Diels-Alder reaction to construct this core. The planned cycloaddition looked quite funky as the orientation of the dienophile seemed quite strained in order to have a good interaction with the diene, not to mention that the orientation of diene had to cooperate. Nonetheless, the strategy seemed ambitious. In their retrosyn, they were led back to aldehyde 10 as the simpler building block.

Another aspect of the cycloaddition that required attention was the different approach of the dienophile to give a regioisomeric product 13 as shown in Scheme 3. Although the transition state leading to cycloadduct 13 seemed unlikely, this partial synthesis would also serve as a confirmation of this hypothesis.

In the forward direction, the synthesis started with aldehyde 10 as shown below.

Takai elefination of aldehyde 10 gave vinyl iodide 15. Buchwald's coupling protocol of 15 with 16 gave the ether 17. The care with temperature had to be taken as slightly higher temperature than 90 C would increase the amount of aldehyde 18 with epimerization at the alpha carbon. After ether 17 was obtained, it was subjected to i-Bu3Al as the Lewis acid to promote stereocontrol [3,3] sigmatropic rearrangement followed by immediate reduction to alcohol 19. Silylation then afforded 20.

Alkene 20 was subjected to conditions in scheme below. A more direct synthesis of the nitrile 22 would be to use of Grubbs' catalyst to perform cross metathesis with acrylonitrile followed by hydrogenation. But this did not work; only SM was returned. So it was resorted to KCN displacement of OTs group obtained from hydroboration-oxidation and then tosylation of alkene 20.

Then alkyne 24 was synthesis from the corresponding aldehyde of 23 using modified Ohira's protocol ((a) Roth, G. J.; Muller, S.; Bestmann, H. J. Synthesis 2004, 59. (b) Ohira, S. Synth. Commun. 1989, 19, 561.) as the aldehyde is sensitive to epimerization. The Wittig olefination of aldehyde 25 to alkene 26 was performed using Conia conditions (Conia, J.-M.; Limasset, J.-C. Bull. Soc. Chim. Fr. 1967, 114, 1936.)

An always-cool enyne ring-closing metathesis using Grubbs' second generation catalyst then afforded diene 27. Attempts to directly convert nitrile to corresponding enone 11 using Grignard reagents and various additives failed. Therefore, it was resorted to step-wise operations as shown.

BF3-OEt2-catalyzed Diels-Alder reaction then afforded the desired cycloadduct 12 in almost quantitative yield (as the only regioisomer). This result was not surprising as DFT calculations using Khon-Sham DFT at the B3LYP19 level of theory with a 6-31G** basis set also confirmed that the transition state leading to regioisomer 13 was 10.7 kcal/mol higher than the one leading to 12 (Scheme 7).

An ok partial synthesis overall with the exception of some noteworthy steps. The synthesis was also a little too linear.

Highly Stereoselective [4+3] Cycloadditions of Nitrogen-Stabilized Oxyallyl Cations with Pyrroles. An Approach to Parvineostemonine

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070103n.html

From Prof. Richard P. Hsung’s group at University of Wisconsin, Madison

This is some cool cycloaddition chemistry, specifically, the [4+3] cycloaddition of oxyallyl cation attaching to a chiral auxiliary to induce stereoselectivity. The 4-pi diene partner being studied is a pyrrole derivative, which is generally more difficult to undergo cycloaddition as the resulting cycloadduct tends to undergo retro-cycloaddition to restore its aromaticity.

The cycloaddition is performed in a one-pot fashion by a regioselective epoxidation of a chiral allenamide using DMDO (syringe pump addition), followed by addition of pyrrole. The reaction is conducted at -45 degrees C as this is believed to be optimal for epoxidation.

One of the synthetic cycloadduct (13), which was obtained as a single diastereomer in excellent yield (93%; d.r. = 95:5) using chiral allenamide derived from Seebach’s auxiliary was further used in subsequent transformations and has been shown susceptible as an approach in the synthesis of the natural product parvineostemonine (see scheme below, taken from their paper).

The key steps include their ability to selectively allylate an alpha carbon of the cyclic ketone using LHMDS in THF and HMPA, followed by RCM using Grubbs’ first generation catalyst. Another synthetic tactic worth mentioning is that when the deprotection of the Boc group was performed on compound 13 under acidic conditions, retro-Mannich type reaction resulted (see below, taken from their paper). But when either the ketone was reduced or in the case of the above scheme the C=C double bond was hydrogenated before the deprotection, the Boc removal proceeded uneventfully.