Total Synthesis of Jiadifenolide

Total Synthesis of Jiadifenolide

Ian Paterson,* Mengyang Xuan, and Stephen M. Dalby*

DOI: http://dx.doi.org/10.1002/anie.201404224

As promised months ago here is the write-up of the second Jiadifenolide synthesis published this year. The main features of this synthesis from the Paterson group consist of a boron-aldol reaction and a neat SmI2 mediated radical cyclization. Though a racemic synthesis (like in the good old days) this route provides an efficient and highly selective access to Jiadifenolide.

The synthesis started with Luche reduction of cyclopentenone 1 which in turn was treated with mCPBA followed by TBS protection to give oxirane 2. In the presence of BF3 the epoxide rearranged to the corresponding ketone with excellent diastereocontrol. HWE reaction, LiAlH4 reduction and acylation then delivered allyl acetate 5. Silylketene acetal formation and subsequent heating in benzene resulted in Ireland-Claisen rearrangement to yield after another LiAlH4 reduction alcohol 6 in moderate yield. Hydrolysis of the TBS ether and global Swern oxidation finally furnished 7.

Scheme 1

 scheme_1_17102014

The remaining carbon skeleton was attached utilizing the boron enolate of lactone 8 followed by TES protection. Upon treatment with samarium diiodide the last quaternary center was formed giving tricycle 10 in good yield. A possible transition state is depicted below. Deprotection and PCC oxidation then delivered ketone 11. The hydroxyl group at the ring junction was then introduced by a Rubottom oxidation, the ketone subsequently reduced and protected. All that remained was dihydroxylation of the double bond, oxidation to the pyruvate and deprotection of the TES group to complete the synthesis.

 

Scheme 2

 scheme_2_17102014

An Enantiospecific Synthesis of Jiadifenolide

An Enantiospecific Synthesis of Jiadifenolide

David A. Siler, Jeffrey D. Mighion, and Erik J. Sorensen

DOI: http://dx.doi.org/10.1002/anie.201402335

jiadifenolide

In a recent communication the Sorensen group disclosed a short synthesis of Jiadifenolide isolated by the Fukuyama group in 2009. Only one synthesis has been reported to date from the Theodorakis group. The latest disclosure comprises just one major scheme proving the efficiency of this approach. As a last introductory remark it should be noted that Jiadifenolide exhibits some promising neurotrophic activity potentiating neurite outgrowth in rats.

 

As can be found in an older JOC paper pulegone 1 can be converted into ketone 2 in three steps consisting of bromination, Favorskii rearrangement and subsequent ozonolysis. A two-step Robinson annulation then provided Hajos-Parrish ketone 3 in good yield. One-pot double methylation of the a-position of the ketone furnished 4 with the olefin shifted into the five-membered ring. Protection of the ketone with ethylene glycol and DIBAL reduction to alcohol 5 set the stage for an interesting one-carbon homologation to nitrile 6. A mechanistic rationale will be discussed later.

Scheme 1

scheme_1_27042014

With this nitrile in hand an intramolecular Ritter reaction was utilized to produce tricyclic lactone 7. Condensation with hydroxylamine set the stage for a directed C-H oxidation developed by the Sanford group functionalizing selectively only one of the neighboring methyl groups. Although in low yield this transformation allowed a straightforward access to the core structure of Jiadifenolide. Reductive cleavage of the oxime to ketone 9 was followed by vinyl triflate formation and methoxycarbonylation to ester 10. Lactone formation and Scheffer-Weitz epoxidation then provided epoxide 11.

 Scheme 2

scheme_2_27042014

 

To conclude α-halogenation was directly followed by an interesting DMDO mediated oxidation and hydrolysis of the epoxide to finally yield Jiadifenolide in moderate yield over 3 steps.

Scheme 3

 scheme_3_27042014

A mechanistic proposal can be found in the JOC paper cited below. After oxidation to the aldehyde the carbonyl is attacked by TosMIC to form an oxazoline ring. This undergoes an inter- or intramolecular proton shift giving rise to the stabilized oxazoline with the negative charge located next to the tosylgroup. Ring opening then forms an intermediate vinyl formamide which presumably is attacked by methanol to furnish after elimination of methylformate and tolylsulfinic acid the desired nitrile in fairly good yield.

 Scheme 4

scheme_4_27042014

The problem set will be provided within this week and will also discuss the recent total synthesis from Paterson et al.

A Concise Synthesis of (−)-Lasonolide A

A Concise Synthesis of (−)-Lasonolide A

Barry M. Trost, Craig E. Stivala, Kami L. Hull, Audris Huang, and Daniel R. Fandrick

DOI: http//dx.doi.org/10.1021/ja411270d

Not so many total syntheses have been published these days but this one caught my attention (some might say for obvious reasons…). Though lasanolide A has been made a couple of times but never in such a neat fashion utilizing some pretty efficient metal catalyzed processes. Trost’s retrosynthesis is shown below. The two major fragments were assembled by an intermolecular ruthenium mediated enyne coupling and a Yamaguchi macrocyclization. The western fragment in turn derives from an alkyne precursor to which the side chain is attached by consecutive HWE and Wittig olefinations. The stereochemistry is set by a highly efficient ProPhenol aldol reaction. The eastern fragment also makes use of a HWE olefination and a Hiyama coupling, respectively. A ruthenium catalyzed hydrosilylation and cross metathesis then give retrosynthetically the diol shown whose stereochemical information derives from an enzymatic reduction and an old-school CBS reduction.

 Scheme 1

  scheme_1_19012014

Starting in the forward sense the side chain of the western fragment was prepared in just four steps. Neopentyl cuprate addition to propargyl alcohol was followed by acetonide cleavage / esterification. TBS protection and formation of the Wittig salt furnished fragment 3 in a pretty efficient manner.

 Scheme 2

 scheme_2_23012014

The other part of the western fragment originates from a ProPhenol mediated aldol reaction to give 6 in nearly enatiomerically pure form. DIBAL reduction and subsequent TBDPS protection was followed by stereoselective acetal formation and Ley oxidation yielding 8. Only one diastereomer is obtained in the acetalization step under thermodynamic conditions. Deprotection of the alcohol directly provided the hemiacetal 9 as an inconsequential mixture of diastereomers. HWE olefination and DIBAL reduction produced aldehyde 10 which could be coupled with 3 in the presence of KHMDS. After a survey of methods the acetal cleavage was preferably accomplished with LiBF4 completing the synthesis of the western fragment.

 Scheme 3
 scheme_3_23012014

Ok, now let us have look at the synthesis of the eastern fragment. It kicks off with an old school Blaise reaction (Reformatsky with a nitrile) to give dicarbonyl 12 which eventually was reduced to hydroxyester 13 by an enzyme called CDX-024. TIPS-protection and two-step conversion of the ester to ketone 15 was followed by a these-days-rather-rare CBS reduction to propargyl alcohol 16. Ensuing trans-selective hydrosilylation developed in the Trost labs and cross-metathesis with crotonaldehyde furnished directly pyran 18.

 Scheme 4

scheme_4_23012014

The remaining acid side chain was introduced by HWE olefination using lithium hydroxide in the presence of mole sieves. Allylation utilizing a Hiyama-coupling of the vinyl silane, saponification and TBS protection then furnished eastern fragment 22.

 Scheme 5

 scheme_5_23012014

Completion of the synthesis was brought about by a powerful intermolecular ruthenium mediated enyne coupling giving mainly the linear isomer 23 in a 3 : 1 ratio. This result is rather unprecedented because this reaction usually favors the formation of branched products. As acetone proved to be the most effective solvent in this reaction under the conditions employed the formation of an acetonide was observed which was cleaved off with CSA in an ensuing step. After selective TBS-protection of the three least hindered alcohols the seco acid was closed under Yamaguchi macrolactionization conditions to give after global deprotection lasonolide A in an overall yield of 1.6 % (16 steps LLS with respect to allyl cyanide).

A really impressive synthesis relying mainly on powerful transition metal catalyzed transformation. I hope you also liked the quiz… If you have any suggestions please let me know.

 Scheme 6

 scheme_6_23012014

Total Synthesis of Amphidinolide F

Total Synthesis of Amphidinolide F

Gaelle Valot, Christopher S. Regens, Daniel P. O’Malley, Edouard Godineau, Hiroshi Takikawa, and Alois Fürstner

DOI: http://dx.doi.org/10.1002/anie.201301700

 

Finally I found the time finish this nice paper form the Fürstner group. I was super busy the last weeks finishing some reports but I really wanted to feature this cool piece of work. This is the second total synthesis of amphidinolide F published so far, the first one dating back to 2012.[1]

Due to a promising biological profile i.e. exhibition of high cyctotoxicity against lymphoma and epidermoid carcinoma cells quite some endeavors towards syntheses of the amphidinolides have been undertaken. It should be noted that only amphidinolide C proved to be highly bioactive.

The general synthetic plan is outlined in scheme 1. The key steps being first the disconnection of the uncommon 1,4-diketone into a homopropargyl alcohol to give 2 which could be assembled by a RCAM to give acyclic precursor 3: This was broken down into three fragments of similar complexity which were stitched together by a Stille coupling and an esterification.

Scheme 1

 scheme_1_17052013

The synthesis of red fragment 4 began with monosilylation of propanediol and TEMPO oxidation to give aldehyde 7. Palladium mediated Marshall reaction furnished alcohol 8 which was pushed forward to aldehyde 9 through a four-step sequence consisting of deprotection/bis-protection/mono-deprotection/oxidation. A second indium mediated Marshall reaction yielded bisalkyne 10 in good yield. After TBS protection of the free alcohol a nice sila-cupration with subsequent methylation gave enyne 11. Next the TMS group was removed, the resulting alkyne methylated and the vinyl silane transformed into the corresponding vinyl iodide producing red fragment 4 in good overall yield.

 Scheme 2

scheme_2_17052013

Blue fragment 5 was synthesized in a straightforward manner starting from readily available epoxide 12 which was alkynylated with propyne to give alcohol 13. The next step made use of a facile cobalt mediated Mukaiyama oxidative aerobic cyclization yielding tetrahydrofuran 14.[2] Parikh-Doering oxidation and subsequent N-methylephedrine mediated alkenylation furnished diene 5.

 Scheme 3

scheme_3_17052013

The synthesis of green fragment 6 began with elaboration of readily available lactone 16 which was protected and methylated to give 17. Monoreduction and Wittig olefination provided alcohol 18 and after TBAF mediated cyclization followed by trityl cleavage tetrahydrofuran 19. Swern oxidation and subsequent proline catalyzed aldol reaction delivered ketone 20 which was protected and transformed into silyl enol ether 21. Palladium mediated stannylation and saponification of the ethyl ester then generated green fragment 6.

 Scheme 4

 scheme_4_17052013

With all three fragments in hand the group could finally stitch everything together. Blue and green fragment 5 and 6, respectively were combined under Yamaguchi esterification conditions. After some optimization fragments 22 and 4 could be joined together in a facile Stille coupling to give RCAM precursor 23 in moderate yield.

Two strategies were probed for the next step which turned out to give very similar yields. In a first shot the RCAM was run first with catalyst A followed by PPTS mediated TES deprotection. In a second round the TES group was removed first and the RCAM run in the presence of catalyst B.

 Scheme 5

 scheme_5_17052013

The resulting homopropargyl alcohol was then cyclized with catalytic PtII to give an intermediate dihydrofuran which was opened up to provide ketone 23. Ley oxidation and final global desilylation of three TBS groups under earlier reported deprotection conditions yielded amphidinolide F in good overall yield.

 

Scheme 6

 scheme_6_17052013

[1] It just happened to be that I am currently working next to the guy who completed the first total synthesis of amphidinolide F… which is pretty cool J

[2] The cited Pagenkopf paper states that the advantage of this second generation catalyst is the separation of the product from the catalyst which was a main drawback of earlier published systems. DOI: http://dx.doi.org/10.1021/ol9023375

Total Syntheses of (-)-Acutumine and (-)-Dechloroacutumine

Total Syntheses of ()-Acutumine and (-)-Dechloroacutumine

Sandra M. King, Nicholas A. Calandra, and Seth B. Herzon

DOI: http://dx.doi.org/10.1002/anie.201210076

Recently the Herzon group disclosed the neat syntheses of (-)-acutumine and (-)-dechloroacutumine. Driven by the interesting biological features (e.g. inhibition of human T-cell proliferation) and the densely functionalized structure the group devised a versatile approach towards both natural products. The common tetrahydroindolone core of the acutumines and the hasubanane alkaloids offered the opportunity to rely to some extent on earlier work on hasubanonine and related congeners.[1] The main steps of the synthesis include the earlier employed lithium acetylide addition to an iminium ion, an intramolecular Hosomi-Sakurai reaction and a nice introduction of an unsaturated ketone.

Scheme 1

scheme_0_10032013

The first two fragments are not featured in full detail in the paper so I present them separately. Fragment 5 can easily be accessed in five steps from glucose ribose 1. Acetonide and acetal formation was followed by an Appel reaction and concomitant reductive ring opening to give aldehyde 3. Addition of vinyl Grignard, RCM in the presence of Grubbs-I and oxidation of the alcohol yielded known ketone 5 in good overall yield.

 Scheme 2

scheme_1_10032013

The second fragment was synthesized from trimethoxy acetophenone ketal 6 which underwent an interesting reductive ketal cleavage / hydroboration / oxidation procedure to give alcohol 7. Mesylation and SN2 replacement with sodium azide then furnished 8.

 Scheme 3

 scheme_2_10032013

The following sequence of steps has been used in the synthesis of the hasubanane alkaloids. Oxidative dearomatization of 8 was followed by stereoselective Diels Alder reaction of the less hindered double bond. Finally trimethylphosphine mediated Aza-Wittig reaction produced key intermediate 11.

 Scheme 4

 scheme_3_10032013

Elaboration of ketone 5 began with stereoselective Michael addition of (TMS)2 in the presence of catalytic Pd(OAc)2 and subsequent cleavage of the resultant TMS enol ether. Enol triflate formation and Stille coupling produced acetylide 14.

 Scheme 5

scheme_4_10032013

Next methylation of the imine and addition of the lithium acetylide of 14 furnished a single diastereomer of 15. The diastereoselectivity in this step is not straightforward to explain. Building a model does not help much because addition seems to occur from the concave site which should be less favored. The group offers an explanation in the paper: “The contrasteric diastereoselectivity in the addition step may be due to unfavorable torsional strain within the pyrrolidine ring in the alternate diastereomer”. For related addition products the group had access to X-ray structures which proved the relative stereochemistry.

Extrusion of TMS-pentadiene under thermal conditions was followed by regioselective hydrostannylation to give 17. TBAF mediated Hosomi-Sakurai reaction proceeded in moderate yield to close the remaining five-membered ring. Metal-halogen exchange with CuCl2 and deprotection of the diol then yielded 19.

 Scheme 6

 scheme_5_10032013

Introduction of the remaining oxygen functionality proved to be fairly difficult. To the end the group had to rely on a rather steppy but successful approach. Oxidation of the diol to the vicinal diketone was followed by methyl sulfide addition and methylation to give 21. SN2’ replacement by formic acid and thermally induced Claisen rearrangement and subsequent aminolysis furnished hemiketal 24.

 Scheme 7

scheme_6_10032013

With fragment 24 only a few steps were left to complete the endeavor. Oxidation of the hemiketal and succeeding reduction with sodium borohydride gave 25 in good overall yield in excellent diastereoselectivity. In the presence of rhodium and high pressure hydrogen 25 was transformed into acutumine in low yield. In the presence of palladium on charcoal beside the double bond the chlorine could be removed to give dechloroacutumine in good yield.

 Scheme 8

 scheme_7_10032013

Overall a really nice paper which is definitely worth a read.

[1] http://dx.doi.org/10.1002/anie.201102226

Total Synthesis of (±)-Maoecrystal V

Total Synthesis of (±)-Maoecrystal V

Feng Peng and Samuel J. Danishefsky

DOI: http://dx.doi.org/10.1021/ja309905j

Yet another interesting synthesis of Maoecrystal V was just reported from Danishefsky and Peng. Besides the completed total synthesis a first attempt is also featured in this article which might have been successful when the crucial Diels Alder reaction would have given them the correct stereoisomer. After straightforward preparation of precursor A Diels Alder reaction furnished B instead of C. This outcome puts paid to the whole strategy because there is no handle on the C2-bridge with which the required functionalities could be introduced.

Scheme 1

scheme_1_17022013

With this result in hand the group started a study which then turned out be the starting point of their revised synthesis. In the first step readily accessible precursors 1 and 2 where joined together in moderate yield. Global reduction with DIBAL-H and selective oxidation of the allylic alcohol gave 4 which was acylated with D and converted to TBS enol ether 5. Under almost identical conditions as for the synthesis of B this time Diels Alder product 6 was obtained after TBAF mediated desilylation and base induced desulfinylation. Epoxidation of the unsaturated lactone double bond was followed by MgI2 facilitated opening of the epoxide with formation of the corresponding a-iodo alcohol. Dehalogenation was accomplished with Bu3SnH to give 7.

 Scheme 2

scheme_2_17022013

Next the cyclohexadiene ring was functionalized. Stereoselective epoxidation with mCPBA and subsequent opening under acid catalysis furnished tetrahydrofurane 9. Acetylation of the alcohol and reduction of the ketone yielded an inseparable mixture of diastereomers which proved to be inconsequential because the alcohol will be transformed into a sp2 center during the synthesis.[1] MOM-protection and deacetylation gave homoallylic alcohol which could be epoxidated again to epoxide 12. Oxidation and acetic anhydride assisted opening of the epoxide was followed by conjugate addition of phenyl thiol and reduction of the ketone to give thioether 14. Desulfination with Raney-Ni and elimination of the alcohol furnished at last enol ether 15. Though the functionalization of the cyclohexadiene ring seems to be pretty steppy the transformations could be executed in overall acceptable yield.

Scheme 3

scheme_3_17022013

To the end of the synthesis mainly the remaining methyl groups have to be introduced. Therefore again an epoxidation was used to functionalize the enol ether double bond. Note the overall inversion of the stereogenic center comparing 14 and 16. Under Lewis acidic conditions the epoxide was opened to ketone 16 in a Rubottom-type oxidation. Then a rather cool approach for the introduction of a gem-dimethyl group was utilized. First the ketone was transformed to an exomethylene group in the presence of Lombardo’s reagent. A Simmons-Smith cyclopropanation converts the double bond into the spiro-cyclopropane 17 which was opened under hydrogenolytic conditions after deprotection and adjustment of the oxidation states of the appendant alcohols. Chemoselective methylenation of the less hindered ketone was accomplished again in the presence of Lombardo’s reagent and followed by acid catalyzed migration of the double bond. Saegusa oxidation, epoxidation with TFDO and Lewis acid assisted opening of the ketone produced Maoecrystal V.[2]

Scheme 4

scheme_4_17022013

[1] Though the following purification steps were of course be affected.

[2] I know that this piece of work is not a pretty recent one anymore but I really wanted to cover this nice synthesis. I am really busy these days. Hopefully this changes within the next weeks because there are a lot of nice papers out. I hope you guys are still enjoying my posts and thanks for still visiting my blog…

Total Synthesis of Branimycin: An Evolutionary Approach

Total Synthesis of Branimycin: An Evolutionary Approach

Valentin S. Enev, Wolfgang Felzmann, Alexey Gromov, Stefan Marchart, and Johann Mulzer

DOI: http://dx.doi.org/10.1002/chem.201200257

As the title suggests this full account features a collection of approaches towards the central core of branimycin. All those who are interested in a great story of evolutionary chemical design really should have a look at the full paper. I will focus in this short write-up only on the longest linear sequence.

Scheme 1

As can be seen from scheme 1 the synthesis focusses mainly on three fragments where green fragment 1 and blue fragment 2 constitute the main part of the molecule. The synthesis of fragment 1 is described in a previous paper but also featured in the following. The evolutionary design is limited to the synthesis of 2 and fragment 3 is commercially available dimethyl malonate.

The first route to allylalcohol 7 started from (R,R)-dimethyltartrate which was protected and reduced to diol 5. Methylation, tosylation, Finkelstein reaction, and reductive acetonide cleavage then furnished 7 in low yield. A more direct access from glycidol 6 is also presented. After methylation of the hydroxy function the epoxide was opened under Corey-Chaykovsky conditions to give 7. TIPS protection and ozonolysis of the olefin produced aldehyde 8.

Scheme 2

Next aldehyde 8 underwent a Marshall reaction with a chiral silylallene to give in high yield and stereoselectivity alkyne 9. Aqueous ammonium chloride was necessary for in situ deprotection of the resulting TMS ether. MOM protection of the alcohol and Schwartz reaction with subsequent iodine quench was used to arrive at vinyl iodide 10. Protection group switch from TIPS to the more convergent cleavage TBS group is straightforward giving green fragment 1.

 Scheme 3

The synthesis of the blue fragment began with Diels Alder reaction between two equivalents of furan and methyl propiolate. With ester 11 in hand the surplus ester group was removed following Barton’s protocol. Saponification and esterification with HPT produced thiohydroxamate ester 12 which loses CO2 under reductive radical reaction conditions yielding 13. Opening of one of the dihydrofurans gives a racemic mixture of alcohols 14 which were in turn protected. The silyl group was used as a handle in a Tamao-Fleming oxidation to introduce the terminal alcohol to give after methylation rac15.

Scheme 4

The next step in the synthesis is an interesting chiral resolution strategy by a “chiral hydride”. This is transferred from a Ni-(R)-BINAP complex with DiBAl-H as the hydride source. Never saw this kind of strategy in a total synthesis before but it is really a pretty neat solution. Although half of the material got lost in this step it provides rapid access to the blue fragment 2. If you are interested in this step you should have a look into this one [1]. So with enantiomerically pure 16 in hand the alcohol was oxidized and the PMB group replaced with a TBS group. After chemo- and stereoselective epoxidation (maybe guided by the methoxy group?) the blue fragment 2 was ready for the crucial coupling step.

 Scheme 5

Metal/halogen exchange of 1 with tBuLi and quench with 2 generated an alcoholate which immediately opens the epoxide in a 5-exo-tet reaction to give 19. This advanced intermediate was protected as a TBS ether and exposed to Cr(VI) which is known to promote allylic oxidation/rearrangement/oxidation to give in the end an unsaturated ketone. An attempted Claisen rearrangement to introduce the side chain did not give any positive results so the group had to pursue a different route. Michael addition of dimethylmalonate, triflation of the ketone, and reduction saved the day giving 21 in good overall yield.

 Scheme 6

Global reduction with LiBEt3H, selective monomethylation and MOM-deprotection produced diol 22. Chemoselective TEMPO oxidation (primary vs. secondary alcohol) to the aldehyde and Pinnick oxidation gave seco-acid 23. Some macrolactonization conditions were screened but the rather old school Corey-Nicolaou reaction proved to be successful to furnish after desilylation branimycin. As can be seen from scheme 7 it was not possible to control the stereochemistry a to the ester functionality. The preceding methylation to differentiate the hydroxy functionalities did not result in any chiral resolution so this stereocenter remains racemic giving at last two diastereomers of branimycin. Nevertheless the absolute of this stereocenter could be unambiguously resolved which remained unclear at the beginning of the story.

 Scheme 7

Sorry for the long delay of posting but I am really busy with finishing my exams and planning my move to the US.

 

[1] http://dx.doi.org/10.1016/S0040-4020(97)10211-3