Lycoposerramine-S

 

Lycoposerramine-S

Angew. Chem. Int. Ed. 2012, 51, 11824

TN. Shimada, Y. Abe, S. Yokoshima, T. Fukuyama*

The retrosyntheses of Lycoposerramine S beings with the deprotection of the Boc group, N-methylation (para-formaldehyde and sodium cyanoborohydride) and deprotection of the nosyl (4-nitrobenzenesulfonamide) group from 13.  Compound 13 was prepared from 12 by bis-mesylating the bis-alcohol and then treating it with 4-nitrobenzulfonamide using Cs₂CO₃ as the base.  This is the first time I saw the use of 4-nitrobenzenesulfonamide to install the nosyl group.  Compound 12 was prepared from hydroxyalkene 11 by first activating the hydroxyl group as thionocarbonate and then cyclizing it under free-radical-conditions to the alkene group.  Alkene 11 was prepared by dehydrating the secondary alcohol in 10.  Compound 10 was prepared by the reduction of the ketone group and reductive removal of the chiral auxiliary in compound 9, which in turn, was prepared by reacting aldehyde 7 with amine 8.  The reaction between 7 and 8 is the key step of this synthesis.  Aldehyde group reacts with the amine to generate the amine which then gets polarized and undergoes a 1,3-dipolar addition with the alkene group thereby completing the bicyclic-ring formation as shown in the graphic below the main scheme.  Aldehyde 7 was prepared by oxidation of alcohol 6, which in turn was derived from vinyl-iodide 4 by going through an initial metal-halogen exchange followed by addition of lactone 5.  Vinyl-iodide 4 was prepared from symmetrical alkyne 3, which was easily obtained from alkyne 1.

Overall, this is a very interesting synthesis from the Fukuyama group in the sense that the product is formed from rather simple looking precursors and is made with the minimum of fuss.  The cycloaddition step is quite noteworthy.

 

 

Corallopyronin A and Myxopyronin B

 

Corallopyronin A and Myxopyronin B

Angew. Chem. Int. Ed. 2012, 51, 11381

A. Rentsch and M. Kalesse*

http://onlinelibrary.wiley.com/doi/10.1002/anie.201206560/abstract

 The retrosynthesis of corallopyronin begins with removal of protecting groups (OTBS, and OCH2OTBS) and oxidation of the alcohol in 19 to the corresponding ketone.  The OCH₂OTBS group is called tert-butyldimethylsiloxylmethyl group or SOM and was used for differentiating two hydroxyl groups earlier in the synthesis.  Secondary alcohol 19 is prepared by connecting fragments “A” and “B” by an alkylation reaction that used LiTMP as the base. 

Fragment “A” has a terminal conjugated aldehyde on the right-hand-side that is installed by reduction of the corresponding ester to the alcohol followed by oxidation to the aldehyde.  The left-hand-side of fragment “A” has a terminal propene that is formed by reacting acetaldehyde with the sulfone formed by the oxidation of intermediate 18.  Compound 18 is prepared by a Mitsunobu reaction between phenyltetrazole thiol 17 and terminal alcohol 16.  The TBS-protected secondary chiral alcohol of 16 is formed by using (-)-DIPCl as the chiral reduction agent upon ketone 15.  This reduction gave the product with 95% ee and the absolute stereochemistry was confirmed by making the corresponding Mosher’s esters.  Ketone 15 is formed by reacting zincate 12 with aldehyde 14 followed by Swern oxidation of the resulting alcohol.  Aldehyde 14 comes by a selective oxidative cleavage of the more electron-rich alkene in 13.  Finally, compound 13 is prepared from Gerinol by an oxidation and Wittig protocol.  The zincate intermediate 12 was prepared in an interesting fashion from bromo-boronate 11 by treatment with dimethylzinc.  In turn, compound 11 is prepared from bromo-alkyne 10, which I presume comes from butynol. 

Fragment “B” has a terminal vinyl carbamate group on the right-hand-side.  Since vinyl-amines are unstable, a Curtius-rearragement is used to prepare this functionality.  This gives us acid 9 as the precursor, which is prepared from aldehyde 8 by a Horner-Wadsworth-Emmons reaction of phosphonate ester 8 with aldehyde 7.  Aldehyde 7 is prepared from TBS protected alcohol 6, which came from protected alcohol 5.  Here, we see the installation of the SOM group to differentiate the terminal (TBS protected) alcohol from the hydroxyl group on the enol-form of the diketoester.  Pyrone 5 comes from the rearrangement of ketone formed by the oxidation of 4.  Compound 4 is prepared by the signature reaction of the Kalesse group – “the Vinylogous Mukaiyama Aldol Reaction” (VMAR).  Thus, the reaction of aldehyde 3 with the vinylogous-silyl-ketene-acetal 3 generates the desired product 4.  Compound 2 is prepared from beta-(-)-citronellene by (a) selective oxidative-cleavage of (R)-3,7-dimethylocta-1,6-diene; (b) reduction of the aldehyde to the alcohol; and (c) protection of the alcohol as TBS ether.

In this paper, the authors have also described the completion of the synthesis of a related natural product – Myxopyronin B.  Retrosynthetically, it involves the combination of Fragment “B” with aldehyde 22 (followed by oxidation and the removal of SOM protecting group).  Aldehyde 22 is derived from ester 21, which in turn, comes by an oxidation-Wittig sequence on alcohol 20.  Alcohol 20 is prepared by the attack of nBu-cupurate (prepared by reacting nBuLi with BrCu(SMe₂)) on ethyl butynoate – an example of nBuLi being used as the reagent with the “nBu” portion getting installed on the molecule.

Overall, an excellent piece of work from the Kalesse group which includes the signature “VMAR” (i.e. Vinylogous Mukaiyama Aldol Reaction).  Other interesting features include the Curtius reaction which installs the sensitive vinylcarbamate group, SOM groups that allows for the differentiation of hydroxyl groups, selective oxidative cleavage of electron-rich alkenes in presence of electron-deficient alkenes, liberal use of easy-to-perform oxidations and reductions, use of (-)-DIPCl to establish the desired “R” configuration, using easily available chiral starting materials "geraniol" and "beta-(-)-citronellene", and finally, the use of buffered HF.pyridine in THF/pyridine to remove the silyl protecting groups.  The fact that all this was done by a single chemist makes it even more commendable!

Helioporin C

Helioporin C

Organic Letters 2012, 14, 5996

W. Lorsberg, S. Werle, J.-M. Neudorlf, H.-G. Schmalz*

http://pubs.acs.org/doi/abs/10.1021/ol302898h

The retrosynthesis of helioporin C begins with oxidation of the allylic hydroxyl group in 15 thus generating the sensitive a,b-unsaturated ketone in the last step.  These conjugated unsaturated species are very reactive and can sometime lead to unnecessary side reactions and it is wise to leave their formation towards the end.  The hydroxyl group of 15 was formed by the addition of the vinylic Grignard reagent 14 on aldehyde 13.  The aldehyde functionality was formed by a TBS deprotection followed by oxidative cleavage of the diol by using periodic acid from 12.  The chiral methyl group on 12 was installed by a stereoselective reduction of alkene 11 by a hydrogenation procedure that used an Iridium-based chiral catalyst developed by Pfaltz.  Alkene 11 came by an ene-reaction between alkene 9 and TBS-protected glycolaldehyde using dimethylaluminum chloride.  Compound 9 was prepared by a Friedel-Crafts-type cyclization procedure on 8, again using dimethylaluminum chloride as the catalyst.  These two steps are really interesting as they use the same reagent!  But, more importantly, the relative geometry (syn) is established in this step with moderate selectivity (4:1).  Compound 9 was not separable from its diastereoisomer and was therefore carried on into the next step where the undesired isomer was separable.  Compound 8 was prepared by an alkyl-Suzuki-reaction (not often seen!) between 9-BBN-derivative of alkene 6 and vinyl iodide 7.  The hydroboration protocol is well established and so this is a reliable disconnection strategy.  Alkene 6 was prepared in extremely high yields and selectivity by a stereoselective methylation/elimination procedure that used a chiral catalyst derived from (S,S-TADDOL) and used the cuparate as the attacking species.  Chloride 5 was installed by a unique oxidative chlorination step, which I had never seen before, from allylic alcohol 4.  Alcohol 4 was prepared by a nucleophilic attack by aryl-lithium derived from bromide 3, which in turn was prepared from dimethoxy compound 2.  The bromo-group on 2 was installed by brominating commercially available 1,2-dimethoxy-3-methylbenzene.

There are three chiral centers in this molecule and two of these were installed by using chiral-catalysts.  Both of these steps gave the product in very high selectivities and that is a take-home message from this synthesis. Finally, they have also prepared Helioporin E, from intermediate 15 by using methanesulfonic acid at very low temperatures (not drawn).

(-)-Aurafuron A

(-)-Aurafuron A

Organic Letters 2012, 14, 3064

O. Hartmann & M. Kalesse*

The retrosynthesis of (-)-aurafuron A begins with the disconnection of the furanone ring into mono-dithane-β-diketone moiety followed by deprotections of the TBS ethers.  The formation of the furanone ring proved to be troublesome as several reagents failed to give the desired product.  The goal is to enolize the carbonyl group in 14 and then make it attack at the dithiane carbon (after hydrolysis or with simultaneous hydrolysis).  Synthetically, methyl iodide with CaCO3 in acetone gave the desired product, which was then followed by the removal of the TBS ethers by using HF.pyridine in THF/pyridine*.  Compound 14 was prepared by an aldol reaction between diethiane ketone 13 and the aldehyde 12 with lithium bistrimethylsilylamide employed as the base.  Compound 12 was prepared by a Suzuki reaction between vinly iodide 5 and boronate ester 11.  Boronate ester 11 was formed by a cross-metathesis reaction between vinyl boronate ester 10 and alkene 9.  The original strategy of the authors was to perform a Heck reaction between alkene 9 and vinyl iodide 5 to prepare 12.  When it failed, the present route was used instead.  This sort of thing happens quite frequently and it is really crucial to be able to make adjustments to the original plan.  In this regard, the terminal alkene is quite versatile intermediate as it can be easily transformed into a vinyl iodide or a boronate ester.  Moving further back, compound 9 was formed by the reaction of “butane anion” on aldehyde 7 by using a chiral borate.  This reaction gave the trans product exclusively.  Aldehyde 7 was prepared by another aldol condensation between propanal and 3-methylbutanal.  Vinyl iodide 5 was prepared by the selective deprotection of the primary TBS ether in 4 while keeping the secondary TBS ether intact.  This was achieved by using PPTS in methanol and was then followed by the syn reduction of the alkyne.  Compound 4 was prepared by TBS protection of the secondary alcohol in 3 followed by changing TMS group to the iodide.  Alcohol 3 came by (a) attack of TMS-acetylene on aldehyde; (b) oxidation of the racemic alcohol to the ketone; (c) stereoselective reduction of the ketone by using Noyori’s catalyst.  Aldehyde 2 was derived from butenol by protection and ozonolysis.

Overall, a neat synthesis from the Kalesse group with several noteworthy steps including tricky aldol condensations, an interesting cross-metathesis step (which incidentally has been used before in their labs), and a stereoselective establishment of the butene group.

*: Back in the year 2000, I was a postdoc with Prof. Kalesse and used HF.pyridine in THF/pyridine to deprotect two TBS ether in the final step of making ratjadone.  Ratjadone was very sensitive to even trace amounts of acids and we used extra pyridine during the TBS deprotection step.  It works really well!

(-)-Teuvcidin

(-)-Teuvcidin

Organic Letters 2012, 14, 2886

X. Liu, C.-S. Lee*

http://pubs.acs.org/doi/abs/10.1021/ol301098s

The retrosynthesis of (-)-teuvcidin beings with the addition of the furan-3-yllithium on the aldehyde group produced by oxonolysis of 14.  The addition of furan-3-yllithum to the aldehyde produces the corresponding hydroxyl anion that closes on the adjacent methyl ester to form the lactone.  Ester 14 was prepared by the oxidation of the aldehyde 13 to the corresponding acid and then esterification under neutral conditions by using diazomethane.  Diazomethane mediated esterfications are the norm in late-stage, acid- or base-sensitive molecules.  Compound 13 was derived from furan 12 by an oxidation protocol utilizing sodium salt of N-chlorobenzenesulfonamide in methanol.  This generates the dimethoxytetrahydrofuran ring initially, which get aromatized under acidic conditions to give the corresponding furan 12.  Compound 12 has an allyl substitution a to the aldehyde – which strongly points to a Claisen rearrangement as the next disconnection.  Thus, compound 12 is derived from 11 by using diisopropylethylamine in 1,2-dichlorobenzene at reflux.  Compound 11 was obtained by the O-alkylation of the enolate of aldehyde 10.  The authors tried direct  a-allylation of aldehyde 10 but failed and had to resort to an initial O-allylation followed by Claisen rearrangement.  Neat trick indeed!  Moving backwards, compound 10 was obtained from ester-epoxide 9 by using TBAF.  In the text, the authors state “Under the reaction conditions, dealkoxycarbonylation of (-)-9 generated an enolate, which underwent epoxide ring opening, acetal formation, and elimination of water to afford the fused furan moiety of (-)-10”. So, first TBAF removes the TMS-ethoxycarbonyl group first, then opens the epoxide, which attacks the carbonyl-carbon to get a hydroxyl group which gets eliminated as water.  Instead, I feel that after removal of the TMS-ethoxycarbonyl group, an enolate gets formed (from the ketone side) and it attacks the epoxide (via the O^‑).  The hydroxyl group that is formed is then eliminated as water.  In any case, whatever the mechanism, this is indeed a nice way to make the furan ring.  The epoxide group in 9 is derived from alkene 8.  The synthesis of compound 8 is the key methodology of this paper – It is formed by a tandem Michael-Coria-Ene-cascade-cyclization reaction.  So, what’s happening here?  The aldehyde enolate formed on 7 by Lewis acid activation attacks in a Michael fashion on the carbon-carbon double bond; this then attack the alkyne in a 6-endo-trig fashion to form the carbocyclic ring in 8.  Compound 7, not surprisingly, was prepared by a Knoevenagle reaction of b-keto-ester 5 on aldehyde 6.  The b-keto-ester 5 was prepared by an insertion of the diazo compound 4 on acid formed from 3 by (a) removal of TIPS group; (b) oxidation of the resulting alcohol to the acid.  Here, it is quite interesting to note the selective deprotection of the TIPS ether in presence of the TES-ether by using 1-chloro-ethylchloroformate (as the source of hydrogen chloride).  This is quite neat as it was quite clean reaction.  Compound 3 was prepared from ester 2 by reduction of the ester group followed by protection as TIPS.  Finally, compound 2 was prepared by the TES protection of the primary alcohol in 1.

Overall, some interesting transformations – (a) selective deprotections of the TIPS ether in presence of TES-ether; (b) unique cyclization protocol to form the carbocyclic ring (methodology which was published earlier by their group); (c) nice way to prepare a furan ring; and (d ) a stepwise Claisen rearrangement.

Clavosolide A

Clavosolide A

Organic Letters 2012, 14, 5614

G. Peh and P. E. Floreancig*

The retrosynthesis of clavosolide A beings with the dimerization of the hydroxyl-acid unit 11 by using the classical Yamaguchi cyclization (trichlorobenzoyl chloride, DMAP, toluene, 65 °C).  Advanced intermediate 11 was produced from 10 in three steps – first stereoselective reduction of the ketone in the presence of Corey’s boraxazoline chiral catalyst established the “S” configuration on the hydroxyl; then the TIPS group was removed under acidic conditions, which was followed by oxidation of the free primary alcohol selectively (over the secondary alcohol) to the corresponding acid by using bleach.  Intermediate 10 was prepared by a glycosidation reaction of sugar 9 with the secondary alcohol obtained by the reduction of the ketone group of 8.  It is interesting to note that reduction of ketone 8 was stereoselective in favoring the formation of the equatorial hydroxyl group only.  Compound 8 was prepared from enol-ether 7 by using DDQ and lithium perchlorate.  This oxidative cyclization is an offshoot of methodology that has been developed in the author’s laboratories during the past few years.  Compound 7 was prepared by alkylation of alcohol 5 with mesylate 6, followed by ruthenium catalyzed O-acetylation of the acetylinic bond.  Alcohol 5 was prepared from a zinc-mediated coupling between mesylate 4 and aldehyde 3 using conditions developed by the Marshall group.  Acetylene-mesylated 6 was prepared by Negeshi propargylation procedure on ketone 2, which in turn was prepared cyclopropanation of chloro-alkene 1.  This cyclopropanation procedure gives trans products selectively and proceeds via a conjugate addition step followed by enolate trapping.  (See JACS, 2010, 132, 14349). EXTRA: compound 1 was prepared by reacting allyl chloride with acetyl chloride!

Thus, in this synthesis, the cyclopropanation step was performed right in the beginning and all subsequent transformations kept the ring intact.  Also interesting was the oxidative cyclization step to prepare the pyran ring (7 to 8). 

Voacangalactone

Voacangalactone

Organic Letters 2012, 14, 5800

M. Harada, K. N. Asaba, M. Iwai, N. Kogure, M. Kitajima, and H. Takayama*

The retrosynthesis of Voacangalactone A begins with the reduction of keto-amide group in 17 to reveal the amine functionality.  Compound 17 was prepared by cyclization of the keto-ester on the deprotected amine, which in turn came by acylation of oxalyl chloride on indole 16.  The indole ring was closed by using Utimoto’s protocol employing NaAuCl₄.2H₂O as the oxidant on alkyne 15, which was prepared by a Sonogashira reaction between 2-iodo-4-methoxyaniline and alkyne 14.  Here, CuSO₄ was used as the copper source – no doubt reduced to Cu(I) by Na-ascorbate.  I had never seen being used in Sonogashira reaction, but this is referenced from the work of Bag, S. S. et al. Org. Chem. 2011, 76, 2332–2337.  Going further back, the alkyne 14 was prepared from alcohol 13 using standard transformations.  Compound 13’s precursor was iodo-alcohol 12, which came from acid 11.  Acid 11 was prepared by an iodo-lactonization-hydrolysis sequence on diester 10.  This is a really nice step as it establishes the lactone-ring elegantly and also allows differentiation of the oxidation states of the pendant carbon.  The bicyclic-amine 10 was closed by alkylating Cbz-amine 9.  Compound 9 is a penta-substituted cyclohexene and thus it is not surprising that an asymmetric Diels-Alder reaction was used to prepare it.  Its immediate precursor is the chiral auxiallary containing intermediate 8, which comes by a Diels-Alder reaction between dimethyl 2-methylenemalonate and diene 7.  This Diels-Alder reaction is between an electron-rich diene and an electron-deficient dienophile.  No wonder, it even goes at room temperature.  It is also completely regioselective – again due to the relative electronics of the reactants.  The absolute stereochemistry is driven by the chiral auxiallary.  This is the key step of this synthesis.  The diene was prepared by a Cu-mediated amination of vinyl-iodide 5.  Adjustment of the carbon oxidation states meant that 5 came from conjugated ester 4, which came from aldehyde 3 by a Wittig reaction.  Aldehyde 3 was prepared by reduction-oxidation sequence on acid 2, which was prepared by decarboxylation/hydrolysis of diester 1.  Diester 1 was prepared by alkylation of diethyl ethylmalonate.

 

Overall, a really nice synthesis.