Aldingenin

 

Aldingenin

Organic Letters 2012, 14, 2168

M. T. Crimmings*, C. O. Hughes

The retrosynthesis of aldingenin begins with the deprotection of the benzyl ether and the bromoetherification of compound 13.  The bromoetherification step using 2,4,4,6-tetrabromocyclohexa-2,5-dienone (TBCO) also gave the 5-exo product (i.e. produced bromotetrahydrofuran ring) which reduced the overall yield.  The tertiary hydroxyl group in 13 was prepared by the addition of “Me^-” to ketone 12 by using MeLi along with CeCl₃.LiCl.  Here the attacking reagent is presumably the less nucleophilic “MeCeCl₂” with additional coordination with LiCl.   When isopropylidiene phosphorane was used on aldehyde 10, the prenyl product 12 could not be prepared. So, the prenyl group in 12 was prepared by a cross-metathesis reaction between alkene 11 and 2-methyl-2-butene (also served as the solvent!).  This is a really neat trick because alkene 11 was prepared from aldehyde 10 by using a variation of “Wittig-reaction” – Nysted conditions (Zn₃Br₂(CH₂)₂, BF₃.OEt₂, THF).  Again, this was necessitated by the failure of traditional Wittig and Tebbe reagents in this step, which I suspect might be due to the presence of a keto group in addition to the aldehyde.  Keto-aldehyde 10 was prepared by a double Swern oxidation step of alcohol 9, which, in turn was prepared from compound 8.  In this step, the cyclopentadienyl ketal got hydrolyzed to reveal the diol which immediately cyclized with the internal ketone group.  Compound 8 is an alpha-hydroxy ketone, and is formed by the nucleophilic attack of dithiane 7’ on aldehyde 7.  This is the classic “umpulong” chemistry and it required the presence of CeCl₃.LiCl along with the base (nBuLi).  The Crimmins group also came up with a method to dry CeCl₃ – which was crucial in this step.  The aldehyde group in 7 came by the Ley oxidation of alcohol 6, which was prepared from diol 5.  syn-Diol 5 was prepared by a hydroxyl-directed stereoselective dihydroxylation step employing OsO₄ along with TMEDA – which is quite noteworthy.  Alkene 4 is ripe for a RCM disconnection to reveal bis-alkene 3, which came from the removal of the chiral auxiliary from 2. Compound 2 was prepared by a “anti-selective-aldol” reaction between dibenzyl acetal 1’ and the chiral thiazolidinone 1.

Unfortunately, at the end of the synthesis the spectra of the natural and the synthetic material did not match! That’s not what you want to see at the end of the synthesis – but a great job by the synthetic chemist nevertheless – after all this was the structure they proposed!  So, the structure of the naturally isolated material needs to be elucidated correctly. 

Isonitramine

 

 

Isonitramine

Organic Letters 2012, 14, 852

Y. Park, Y. J. Lee, S. Hong, M. Lee, H. Park*

The retrosynthesis of isonitramine begins with the unmasking of the amine (from the amide) and the alcohol (from the ketone).  The diphenylmethyl protection on amine 11 was removed by hydrogenation and amide 10 was reduced by lithium aluminum hydride reduction.  Amide 10 was prepared by the stereoselective reduction of the ketone group in 9 by Dibal-H.  The Al coordinates on the side containing the amide oxygen while delivering the hydride ion, thus giving the R configuration on secondary alcohol in 10.  Ketone 9 was derived by decarboxylation of ketoester 8, which is the Robinson annulation product of diester 7.  At this stage, there is a protecting group interchange in 6.  Compound 6 is derived by xanthate group removal from 5, which in turn is coming from the radical addition of xanthate and “ethylacetate anion” across the carbon-carbon double bond in 4.  Compound 4 is prepared from bromide 3 (because the non-brominated version did not give high ee).  The synthesis of compound 3 is what drives this synthesis – the “phase transfer catalyst” driven asymmetric allylation of alpha-tertbutoxycarbonyllactam compound 2.  A chiral PTC is used which gives the product is highly stereoselective fashion, but it required the 2-bromoallyl bromide instead of allyl bromide.  This is an example of the utility of “Br” as a masked “H” to improve stereoselectivity.  Compound 2 is prepared by installing the butoxycarbonyl group on valerolactam.

I noticed that all but 2 steps had >90% yield (and those two were also >85%)!!  Although most steps are fairly standard, but I still find it very impressive – especially when considering the messy “tin chemistry” and the final two reduction steps.  

 

Ripostatin B

 

 

Ripostatin B

Angew. Chem. Int. Ed. 2012, 51, 3396

P. Winter, W. Hiller, & M. Christmann*

The retrosynthesis of Ripostatin B begins with a deprotection of the protected secondary hydroxyl groups and the oxidation of the primary alcohol group to the acid.  It is interesting to note that the two secondary hydroxyl groups were differently protected – one as a TBS group and the other as an ester group.  It is rather unusual to see the final stage deprotection using LiBEt₃, but worked in this case quite selectively, without harming the conjugated lactone functionality.  The isolated double bond in 14 was installed by a RCM reaction using Grela’s catalyst on substrate 13.  The allyl group was installed by a Stille coupling on vinyl iodide 12, which in turn was derived from a Yamaguchi esterification of acid 11 with alcohol 10.  The alcohol group in 10 was derived by an Evans-Tischchenko reduction of the ketone, which was present as it dithiane derivative in 9.  The preparation of compound 9 was the showcase event in this total synthesis – the coupling of a silylated dithane with two different epoxides – and this required some optimization with regards to the order of addition (i.e. after anion formation, epoxide 4 was added followed by epoxide 7).  It is also important to note that this step gave mono-protected TBS ether.  The other elegant strategy was the preparation of both epoxides 4 and 7 from geranyl acetate.  Epoxide 7 was derived from aldehyde 6 (stereselective epoxide formation with the increase of one carbon atom via a Corey-Chaykovsky procedure followed by Jacobsen resolution), which came from epoxide 5 by sodium periodate mediated oxidative cleavage.  Epoxide 5 was derived a lithium cupurate addition on geranyl acetate.  In contrast epoxide 4 (which has the same carbon count at geranyl acetate), came by an internal attack of the hydroxide on a chiral “Cl” atom – which was installed in stereospecific manner by using the Jorgensen/MacMillan protocol.  The terminal hydroxyl group came from the reduction of aldehyde 3 which was prepared as before from epoxide 2 (sodium periodate oxidation).  Epoxide 2 was prepared by vinyl Grignard substitution on geranyl acetate. 

So, overall a very nice semi-convergent synthesis with some interesting transformations by the group of my former colleague, Mathias Christmann.

Ripostatin A

 

Ripostatin A

Org. Letters 2012, 14, 4690

W. Tang & E. V. Prusov*

The retrosynthesis of Ripostatin A begins with a deprotection of the protected methyl acetal which quite sensitive.  This was achieved by a mild neutral aqueous hydrolysis.  The terminal acid functionality was derived from oxidation of the primary alcohol by Dess-Martin periodinane oxidation followed by Pinnick Oxidation (sodium perchlorate).  The alcohol was originally in its TBS-protected form in 8.  Predictably, the central alkene group in 8 was formed by a ring-closing-metathesis reaction using Grubb’s second generation catalyst. The double allyl groups required for the RCM reaction were neatly installed by a double Stille reaction between allyl stannane 5 and double-vinyl-iodide compound 6.  Conceptually, this is really interesting as it reduces the need to install the two carbon-carbon-double-bond groups separately.  The ester group of compound 6 is the next disconnection giving rise to acid 5 and alcohol 4.  The ketal group of 4 comes from the open ketone 3, which is prepared by an Patterson Aldol reaction between methyl ketone 2 and aldehyde 1.  The syntheses of both 1 and 2 have been described by the authors in their previous publication Angew. Chem. Int. Ed. 2012, 51, 3401–3404.

 

(-)-Huperzine A

 

 

(-)-Huperzine A

Organic Letters, 2012, 14, 4446-4449

R. Ding, B.-F. Sun, G.-Q. Lin

The retrosynthesis of (-)-Huperzine begins with an acid-mediated rearrangement along with dehydration to install the two double bonds.  The conditions for these two transformations took a while to develop as there were other side-reactions occurring as well.  The rearrangement is especially noteworthy since it allows the use of (R)-pugelone as the starting material.  The tertiary alcohol in 10 is formed by ethyl Grignard addition to the ketone 9, which in turn comes by oxidation of diastereomeric alcohols 8.  An elegant Heck-reaction forms the bicyclic structure from 7.  This shows the two parts of the molecule – the “cyclohexene” and the “pyridine” parts – linked through a methylene group.  Thus, alcohol 7 comes by reduction of ketone 6, which is setup to be derived by an enolate addition of ketone 4 on bromide 5.  Compound 4 is derived by a Buchwald-type coupling of Boc amine on enol triflate 3.  The enol triflate 3 is derived from 2, which is easily accessible from (R)-pulegone.

(-)-KAITOCEPHALIN

 

 

(-)-KAITOCEPHALIN

Organic Letters, 2012, 14, 1644-1647

K. Takahashi, D. Yamaguchi, J. Ishihara, S. Hatakeyama*

The retrosythesis of (-)-Kaitocephalin begins with unmasking all the acid groups by oxidizing phenyl and carbon-carbon double bonds while the amino and alcohol groups are also simultaneously generated by deprotecting the oxazolidone ring of 14.  This is very rarely seen in total syntheses as people generally shy away from such strong oxidations towards the end of the synthesis.  So, keeping a benzene ring and carbon-carbon double bonds are “masked acids” is a useful disconnection.  Compound 14 predictably comes from acid chloride 13 and deprotected form of amine 12.  Compound 12 is formed by a stereoselective intramolecular C-H amination in 11 mediated by a Rh catalyst.   This is a neat way of establishing a crucial stereocenter.  Compound 11 comes from protected alcohol 10.  Compound 10 is generated by an intramolecular addition of a carbamate on cyclic sulfamate 9, which comes from another stereoselective intramolecular C-H amination of sulfonamide 8.  This step is very similar to the preparation of 12 from 11 – sulfonyl versus and carbonyl and also a different ligand is used in the Rh catalyst.  Compound 8 comes from protected alcohol 7, which in turn is prepared by a Overman rearrangement reaction of alcohol 6.  This step establishes the quaternary spiro stereocenter.  Compound 6 is formed by a Suzuki reaction between alkyl boronate ester and vinyl iodide 5.  This comes from protection-deprotection of alcohol 4 whose precursor is ketone 3.  Ketone 3 comes from the iodination of 2, which is derived from alcohol 1, by an enzyme-mediated stereoselective oxidation.

 

(-)-205B

 

 

(-)-205B

J. Am.  Chem. Soc., 2012, 134, 15237

D. Yang & G. C. Micalizio*

 

The retrosynthesis of (-)-205B, an azatricyclododecene isolated from Dendrobates pumilio, begins with deoxygenation and rearrangement of the double bond of compound 10, which in turn is derived from alcohol 9.  Alcohol 9 is formed by an aza-Sakurai reaction/ring-opening sequence from bicyclic compound 8.  Alkene 8 is derived from ester 7 by a reduction and deoxygenation procedure  Compound 7 comes by a reduction and Horner-Wadsworth-Emmons reaction of reagent 6 with ester 5.  Bicyclic compound 5 is derived from a intra-molecular [2+3] cycloaddition reaction involving the iminium ion formed by the addition of butylglyoxolate with amine-oxide 4.  Compound 4 is formed by oxidation of amine 3, which in turn is derived from a reductive cross-coupling between silane 2 and aldehyde 1.  Overall, the retrosynthesis is derived from two methodologies developed in the Micalizio lab – (a) Ti-mediated reductive cross-coupling between an aldehyde and an allylic alcohol (compound 3 from 1); and (b) intramolecular [3+2] cyclization of a glyoxalate-based homoallylic nitrone (compound 5 from 4).