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.

New section

To all of you who like to work yourself through a total synthesis rather then just reading the write-up I created a new section which contains a problem of the total synthesis as well as the solution. I will add bit by bit all the older syntheses as well so you can learn even more from this page. I hope you enjoy it and leave me a comment about your thoughts. Stay tuned…

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

Part 2: Enantioselective Total Synthesis of (−)-Citrinadin A and Revision of Its Stereochemical Structure

Part 2: Enantioselective Total Synthesis of (−)-Citrinadin A and Revision of Its Stereochemical Structure

 Zhiguo Bian, Christopher C. Marvin, and Stephen F. Martin

 DOI: http://dx.doi.org/10.1021/ja405547f

So folks, here it is. Took me a few days longer as promised but finally I made it. Though citrinadin A is closey related to citrinadin B the synthetic approach of the Martin group is much different from that of Wood et al.. Their retrosynthetic considerations are summarized in scheme 1. Interestingly the introduction of the epoxyketone utilizes almost the same chemistry under similar reaction conditions. Contrary to the Wood approach the spiro-oxindole is build up by an epoxidation / semipinacol rearrangement in a diastereoselective manner. This disconnection leads back to the bromoindole shown which in turn is introduced by a Fischer indole synthesis. The tertiary alcohol and amine are derived from selective epoxidation / epoxide opening to give a lactam which tracks back to a vinylogous Mannich reaction between 2 and A.

Scheme 1

scheme_1_06012014

 Dimethylcyclohexadione 1 is monoprotected and methoxycarbonylated with dimethylcarbonate. Subsequent triflation and copper-mediated introduction of another methylgroup then leads to ester 2. In the presence of LDA and in situ transmetallation with zinc chloride a vinylogous enolate is formed which reacts with in situ formed pyridinium ion A. After acidic hydrolysis ester 4 is formed which undergoes base mediated lactam formation to give 5.

 Scheme 2

  scheme_2_06012014

Next TIPS cleavage sets the stage for the stereoselective introduction of a methyl group which had to be accomplished in a two-step sequence. After cuprate addition derived from PhMe2SiCH2MgCl and reduction of the ketone the silylgroup was removed under harsh conditions to provide alcohol 8. Epoxidation of the unsaturated lactam with peracid and ensuing opening with dimethylamine then leads to 10.

 Scheme 3

 scheme_3_06012014

The dioxolane is then directly used in a Fischer indole synthesis with bromophenylhydrazine in aqueous sulfuric acid to give indole 11 in pretty good yield. Successive reduction of the lactam carbonyl was accomplished by combined alane / borohydride reduction which proved to give the best yields of 12. In situ protection of the sensitive amine moieties with PPTS and epoxidation with Davis oxaziridine yields an intermediate indoline which undergoes semipinacol rearrangement in the presence of acetic acid to give the core structure of the citrinadins with complete control of the quaternary carbon centre. Sonogashira coupling then provides alkyne 15.

 Scheme 4

 scheme_4_06012014

All that remains was to transform the triple bond into the epoxyketone which was accomplished after amide formation with dimethylvaline utilizing again the Gold mediated oxygenation and subsequent Enders epoxidation protocol (cf. Wood et al.).

 Scheme 5

 scheme_5_06012014

Pretty cool synthesis. It was very intriguing to me to see two almost completely different approaches of the Wood and Martin group which were also published back to back and ultimately corrected the proposed structure of the citrinadins.

Part I: An Enantioselective Total Synthesis and Stereochemical Revision of (+)-Citrinadin B

Part I: An Enantioselective Total Synthesis and Stereochemical Revision of (+)-Citrinadin B

Ke Kong, John A. Enquist, Jr., Monica E. McCallum, Genessa M. Smith, Takanori Matsumaru, Elnaz Menhaji-Klotz, and John L. Wood

 DOI: http://dx.doi.org/10.1021/ja405548b

I decided to have a closer look at this and a second paper from the Martin group quite a while ago but I could not find the time to finish the write-up. I recently moved to a new place and had to get everything managed in time… Well I am not done yet but somehow I found the time to get this first piece done. The second paper on this topic will follow within the next few days.

 Scheme 1

scheme_1_27102013

At the outset of Wood’s work the group decided to target the different stereocenters independently. This would enable them to diversify the strategy later towards the synthesis of different members of this class of natural products. It should be noted at this point that their initial strategy made use of L-alanine which was expected to yield ent-citrinadin B. Instead it turned out this strategy actually furnished citrinadin B.

The retrosynthetic analysis is shown in scheme 2. Gold mediated oxygenation of an alkyne would introduce the side-chain ketone while the epoxide derives from Enders’ epoxidation. Sonogashira cross coupling and regioselective epoxide opening would then lead to the bromo-oxindole shown. Extrusion of one carbon via Corey-Chaykovsky epoxidation and [3+2] nitrone cycloaddition leads to the unsaturated ketone depicted. Reductive Trost enyne coupling and Heck coupling ultimately tracks back to dibromoaniline and L-alanine derived nitrone.

 Scheme 2

scheme_2_27102013

In the first step dibromoaniline 1 undergoes trimethylaluminum mediated amidation and TBS protection to give enamide 2 which cleanly underwent Heck reaction to give 3 as the expected racemic mixture. Benzylation of the amide nitrogen, TBS cleavage and Swern oxidation of the resulting alcohol then furnished aldehyde 4. Alkynylation and another TBS protection set the stage for a neat reductive Trost enyne coupling. Desilylation and Swern oxidation produced unsaturated spiro ketone 6. As mentioned above the group needed a racemic mixture to explore the synthesis of other members of this group of natural products containing the enantiomeric spirocyclic center.

Scheme 3

scheme_3_27102013

With ketone 6 in hand the crucial nitrone cycloaddition was examined. Fortunately the group found that in the presence of L-proline only two of the four possible diastereomers were formed in moderate and good yield, respectively. Though diastereomer 7b displayed the minor stereoisomer the group was able to produce enough material by this strategy.

Corey-Chaykovsky epoxidation was used to introduce the missing methylene group. This was opened by in situ generated TMSI to give ammonium salt 9 which was reduced under Clemmensen conditions yielding diol 10.

Scheme 4

 scheme_4_27102013

Moving on with the synthesis the group transformed the diol into the corresponding epoxide 11 by chemoselective mesylation and cyclization. Sonogashira coupling and concomitant oxidative debenzylation with t-BuLi in the presence oxygen set the stage for regioselective epoxide opening with sodium azide yielding alkyne 13. Gold catalyzed oxygenation was followed by Enders’ diethylzinc mediated epoxidation and Boc protection to give a 1 : 1 mixture of epoxides 15a and 15b. Interestingly the Martin group also utilized the same strategy to introduce the unsaturated ketone and Enders’ epoxidation.

 Scheme 5

scheme_5_27102013

These could be elaborated by a three step sequence into ent-citrinadin B and citrinadin B. At this point the group surprisingly found that the published spectra of citrinadin B matched with the spectra of what was believed to be ent-citrinadin B.

Stay tuned for the Martin synthesis of citrinadin A.

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

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