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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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 (±)-Communesin F via a Cycloaddition with Indol-2-one

Total Synthesis of (±)-Communesin F via a Cycloaddition with Indol-2-one

Johannes Belmar and Raymond L. Funk

 DOI: http:// dx.doi.org/10.1021/ja307277w

It has been some time since my last entry. I was very busy with moving to the US and starting my master’s thesis. But as you can see after about 12 weeks I am back. I chose a rather short synthesis but there is still some work to be covered within the next weeks which should result in much more detailed write-ups.

The communesins are known to the synthetic community for quite a while and were the targets of extensive research and synthetic studies. The current paper utilized some nice methodology developed by the group and published in an earlier synthesis of perophoramidine. [1]

The synthesis begins with the union of azide 1 and bromooxindole 2. Because their initially reported conditions did not give any product at all it was found that the reaction proceeded smoothly in the presence of substoichiometric amounts of silver carbonate yielding 3. After tosylation the mixture was exposed to methanolysis to produce the backbone structure 4 of communesin F. Methylation with Meerweins’s salt, hydrogenolysis of the azide with subsequent Boc-protection and detosylation furnished amide 5.

 Scheme 1

The bromine was then used as a handle to introduce the prenyl sidechain with a Heck reaction to give an intermediate allylic alcohol. In the presence of mercury salts a cyclization took place constructing the crucial seven-membered amine ring. Deprotection of the amine under mild conditions using TBSOTf was followed by amide formation with some help from trimethylaluminium. The second side-chain was introduced in the usual sequence of deprotonation and subsequent alkylation with iodoacetonitrile.

 Scheme 2

The last ring was closed in a straightforward manner. Reduction of the nitrile to the aldehyde and the amide to the hemiaminal gave tetrahydrofuran 9. Reductive amination and acetylation finally produced communesin F in an overall yield of 6.7 %.

Scheme 3

The mechanism of the key step is pretty straightforward but nevertheless a nice one. After tosylating the oxindole nitrogen the resulting amide can be cleaved by methoxide to give an anilide anion which undergoes intramolecular attack on the indolenine 2 position to close the ring.

Scheme 4

[1] J. Am. Chem. Soc. 2004, 126, 5068

Yeah… that is it for the moment. I found some new interesting stuff to write-up, so I promise I will be up to date from now on J

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

 

Total Synthesis of Akuammiline Alkaloid (−)-Vincorine via Intramolecular Oxidative Coupling

Total Synthesis of Akuammiline Alkaloid (−)-Vincorine via Intramolecular Oxidative Coupling

Weiwei Zi, Weiqing Xie, and Dawei Ma

 DOI: http://dx.doi.org/10.1021/ja303602f

Vincorine is a rather young target for the synthetic community of which only a racemic synthesis has been published by the Qin group (J. Am. Chem. Soc., 2009, 131, 6013). Besides vincorine the akuammiline alkaloid family contains several interesting members like strictamine, scholarisine and aspidophylline. Total syntheses of most of the family members have been published within the last 20 years.

The group planned to access the crucial C-C bond marked in orange via an oxidative coupling. From the earlier synthesis of communisine A and B the group gained some experience with this kind of coupling reaction. [1] The remaining disconnections are straightforward leading to the key building blocks O-methyl-serotonin, a selenoaldehyde and ethyl acrylate.

 Scheme 1

First serotonin derivative 1 was double protected with Boc2O and oxidatively coupled to ethyl acrylate via a formal C-H activation under Pd(II) catalysis. [2] Hydrogenation of the

double bond and reduction of the ester gave alcohol 3 which was oxidized to the aldehyde and reacted with dimethyl malonate to give Michael acceptor 4. This was used in a highly stereoselective prolinol ether catalyzed Michael addition with the selenoaldehyde shown. Oxidation and base induced elimination furnished an exo-methylene group which shifted under the reaction conditions into conjugation but with the wrong geometry. Under UV-light irradiation the cis-double bond was changed into trans-configuration yielding key intermediate 6 in almost quantitative yield.

 Scheme 2

 

Going on with the synthesis the aldehyde was reduced, silylated, and the resulting ether heated on silica gel to remove selectively the indole Boc protecting group. In the presence of 2 equivalents of LHMDS and 1 equivalent of iodine the group was able to perform an awesome coupling reaction giving them almost the whole framework in one single step. Finally the least hindered methyl ester was removed under Krapcho’s decarboxylation conditions.

Scheme 3

 

The last ring was closed after direct conversion of the TBS ether into allyl chloride 10, Boc-removal with TMSOTf, and intramolecular alkylation to give 11. After reductive amination with formalin the group isolated (-)-Vincorine with an overall yield of 5 % over 18 steps in the longest linear sequence.

 Scheme 4

 

But how does the oxidative coupling work? The authors state that it might work through a radical mechanism as proposed in their communesin A and B syntheses. In the present publication no mechanism is given only some sort of transition state structure as is reproduced below. According to their postulation the doubly deprotonated starting material reacts through a Zimmermann-Traxler-like transition state stitching both ends together via intermediate radicals formed by two SET to iodine. In the last step the pyrrolidine ring is closed as usual.

 Scheme 5

 

During a group meeting we discussed the mechanistic rationale behind this reaction and came up with a mechanism like that shown below which is better harmonized with the usual reactivity observed in halogenation reactions with indoles. So after double deprotonation with LHMDS the indole 3-position is iodinated to form an indoline system which undergoes pyrrolo-indoline formation. The former indole nitrogen can then kicks out the iodide through a SN2’-type reaction. Now the malonate anion attacks the former 3-position of the indole and closes stereospecifically to give the expected product. The obvious problem is the source of stereocontrol.

 Scheme 6

 

If you perform a minimization of the starting material then you will recognize that the unsaturated side chain with the bulky TBS group shields the upper face of the indole. I would think that this bulkiness is responsible for the observed facial selectivity of the iodine addition. The remaining steps are now stereospecific and can only lead to the product.

 Scheme 7

Or can someone offer me a better explanation with respect to the stereoselectivity observed?

_____________________________________________________________________________________________

Addendum:

As Dave suggested a lithium aggregate might be respsonsible for the oberserved stereoselectivity of the iodine attack. So I created the following 3D model and minimized it with ChemDraw. Given that lithium couples the enolate and the deprotonated indole nitrogen and is additionally coordinated by two THF molecules then you get this prediction. Maybe this offers another explanation for the observed stereoselectivity though I am still not satisfied with both models. Nevertheless big thanks for this suggestion.

Scheme 8

 Big THX to Bobby for proofreading and questions.

[1] http://dx.doi.org/10.1002/anie.201106205

[2] http://dx.doi.org/10.1002/anie.200500468

Scalable Total Synthesis of (-)-Berkelic Acid Using a Protecting-Group-Free Strategy

Scalable Total Synthesis of (-)-Berkelic Acid Using a Protecting-Group-Free Strategy[1]

Francisco J. Fananás, Abraham Mendoza, Tamara Arto, Baris Temelli, and Felix Rodriguez

 DOI: dx.doi.org/10.1002/anie.201109076

Berkelic acid is a rather old target to the synthetic community and three total syntheses have been published to date. Interestingly the material provided by synthesis produced contradictory biological results compared to earlier studies. So besides showing the power of their methodology the group planned to provide enough material for refined studies.

 Scheme 1

As can be seen from scheme 1 the group planned to construct almost the whole framework in one single step after disconnection of the side. It should be noted that the group has some experience with this kind of cascade transformations of which they can rely on. Nevertheless instead of employing palladium catalysts the group turned their attention to silver catalysis. With this cascade reaction in mind they hoped that the stereogenic methyl group would control the stereoselectivity of the whole transformation.

The three key building blocks were prepared in a straightforward manner. Starting from commercially available butynol 1 the hydroxy functionality was mesylated and replaced by diethylmalonate to give after complete reduction diol 2. Starting from ester 3 the second fragment was prepared by triflation of the least hindered hydroxy group followed by Suzuki cross coupling with the trifluoroborate of heptyne. Hydroxy-directed reaction with formaldehyde and subsequent oxidation produced ester 4. The last building block stems from dimethyl malate which was doubly alkylated in the first place. Then the a-hydroxy ester was used for a periodate cleavage followed by cyanohydrin formation which was catalyzed by PNPCl.[2]

 Scheme 2

 

Combination of the red fragment 2 and orange fragment 4 was accomplished in the presence of 5 mol% silver(II). Subsequent hydrogenation of the resulting double bond yielded 7 in good yield and diastereoselectivity favoring the desired one. Appel reaction under standard conditions was followed by cyanohydrin alkylation and unmasking of the ketone to give protected Berkelic acid 9. Small amounts of Berkelic acid can be produced in good yield by selective saponification of the more active ester. This was only done when material was needed for testing or analysis as the natural product is a short-lived compound.

 Scheme 3

 

The mechanism of the cool key step is presented below. On one hand the red fragment underwent a 5-exo-dig cyclization thus desymmetrizing the propanediol moiety to give after protodemetallation a tetrahydrofuran ring. On the other hand the carbonyl of the orange fragment underwent a 6-endo-dig cyclization. Supported by keto-enol tautomerism of the hydroxy functionality an ortho-quinone methide is formed. Michael addition of the enol ether from the red fragment onto the quinone methide was followed by acetal formation by the phenol. Hydrogenation of the newly formed double bond then gave intermediate 7.[3]

 Scheme 4

 

[1] I was pointed to the title which says “[…] protecting-group-FREE strategy”… I am not particularly sure how they got the title but I see almost two protecting groups: the TES-cyanohydrin and one of the methyl esters. Maybe the title refers to the neat cascade reaction in which no protecting groups are necessary…

[2] It is the first time I ever saw this reagent in action. It is usually used for halogenation reactions. The cited paper in this step found that in the presence of PNPCl the cyanohydrin formation is much faster which was ascribed to an activation of the carbonyl oxygen by the high oxophilicity of phosphorous.

[3] At first sight one might think of a Diels-Alder reaction. But brief examination of the stereochemistry on the newly formed pyran ring shows that only a stepwise mechanism can form this particular anti-substitution pattern.

Addendum: If you are interested in earlier studies of the group you should have a look into these two papers

Big THX to Bobby for proofreading.

Synthesis of Dragmacidin D via Direct C-H Couplings

Synthesis of Dragmacidin D via Direct C-H Couplings

Debashis Mandal, Atsushi D. Yamaguchi, Junichiro Yamaguchi, and Kenichiro Itami

DOI: http://dx.doi.org/10.1021/ja209945x

I thought about writing this review a few months ago but never found the time to get it done. But here it is and I hope you enjoy this cool paper as I did. I am a big fan of “flat” chemistry and C-H activation so naturally this piece had to be reviewed. Dragmacidin D itself shows some promising activity in the treatment of neurodegenerative diseases like Alzheimer’s or Parkinson’s disease. Only one total synthesis has been published by the Stoltz group in 2002 so there is still room for improvement. Retrosynthetically the group planned to stick all parts together via C-H activation/C-C coupling reactions.

 Scheme 1

The “sticky” –positions are marked in blue. As can be seen from this picture almost all crucial bonds can be formed through C-H activation (except the iodide).

Indole 1 was carboxylated to block the 3 position of the indole which would normally undergo iodination in the presence of NIS. Removal of the carboxyl group after halogenation gave indole 3. Tosylation was accomplished under standard conditions yielding the first coupling partner 4. Thiophene boronic acid 5 was oxidized to the corresponding alcohol to furnish after TIPS protection coupling partner 6. In the presence of PdII and silver(I) as the re-oxidant thiophene 7 formed in good yield on a gram scale. Desilylation and reductive desulfuration with Raney-Ni was followed by global deprotection and double MOM-protection to produce ketone 8. [1]

 Scheme 2

Next the 3 position of the indole moiety was again functionalized. This time pyrazine N-oxide was used in the presence of PdII to give 9. A TFAA mediated Polonovski-Potier rearrangement gave pyrazinone 10 which was used in a Friedel-Crafts-like acylation with 6-bromoindole to furnish 11 in good yield. Bromination of the ketone was accomplished via the TMS-enolate and NBS mediated bromination yielding 12. In the presence of Boc-guanidine Dragmacidin D was formed after deprotection.

 Scheme 3

 

Short and very efficient I would say. The only drawback might be that Dragmacidin D is formed in both enantiomeric forms. I was wondering how much silver the group stores in their laboratories J.

[1] Really a nice method to introduce the side chain on the indole. The net result is the reaction of an umpoled ketone with the aromatic ring.