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.

 

 

 

 

Alotaketal A

 

Alotaketal A

Organic Letters 2012, 14, 5492-5494

M. Xuan, I. Paterson, S. M. Dalby *

The retrosyntheses of Alotaketal A begins with a sequence of double oxidation of two alcohols (a primary and the other secondary) and then selective reduction of the aldehyde in presence of the ketone by using sodium triacetoxyborohydride.  This is a bold final step!  Compound 16 has the sensitive ketal group which is formed by internal cyclization and protection of compound 15.  The allylic alcohol in 15 is formed by the nucleophilic attack of lithiated 6 on lactone 14.  Lactone 14 is formed by an intermolecular HWE reaction of phosphonate 13, which comes by the coupling of acid chloride of 12 with alcohol 11.  Here, the Yamaguchi reagent (trichlorobenzoyl chloride) was used to activate the acid.  Compound 11 was prepared by the selective Johnson-Lemieux oxidation of the less-hindered alkene bond of compound 10.  Compound 10 was derived by an interesting allylic oxidation and then selective reduction procedure.  The allylic alcohol 9 gets oxidized to the ketone (at the unsaturated carbon) with simultaneous dehydration to give an a,b-unsaturated ketone (not drawn).  This is then stereoselectively reduced to the allylic alcohol 10 by using the bulky L-selectride.  The protected TBS ether in 9 came from by the reduction (and then protection) of ketone 8.  This a-hydroxyketone was prepared by Rubbotom oxidation of ketone 7 (7 was first converted to its TMS enol ether and then oxidized by using mCPBA).  Compound 7 was prepared from (R)-carvone by first chlorinating the allylic carbon (Ca(OCl)₂), then hydrolyzing it to the alcohol and then protecting it as TIPS-ether.

The intermediate 6 has the allylic iodide group, which came from the corresponding ester 5.  Ester 5 was treated with TMSCH₂MgCl which gave the double addition of the “CH₂-“ group on the ester.  It also produced a tertiary alcohol which eliminated.  Ester 5 came from a Nagao aldol reaction of chiral auxially 3 with aldehyde 2.  Aldehyde 2 is simply the oxidized form of geraniol – but it was produced in a rather round-about way.  Geraniol was first chlorinated and then reduced by LAH.  The allyl group was then oxidized to the aldehyde by MnO₂.

 

Aspercyclides A & B

Aspercyclides A  & B

Organic Letters 2012, 14, 4290-4292

T. Yoshino, I. Sato*, M. Hirama

The retrosyntheses of Aspercyclides A and B begin with a common advanced intermediate 8.  For aspercyclide A (which has an aldehyde group), the hydromethyl in 8 is first oxidized using manganese oxide and the benzylether is deprotected using boron trichloride.  For aspercyclide B (which has the hydroxymethyl group), the benzylether group is deprotected using boron trichloride.  Thus, with one advanced intermediate, they are able to get two natural products.  Intermediate 8 is prepared by a very interesting selective oxidative phenol-aryl bonding.  There are two phenolic groups present in 7 (the precursor to 8) and only one of them is oxidized and undergoes a ring-closure reaction with the other aryl ring.  The authors explain this chemo-selectivity on the relative electron richness of the two phenols.  One has alkyl substituents, while the other has a carbonyl group on it – the more electron rich phenol (with alkyl substituents) gets oxidized and reacts with the other.  They even did a side experiment where they took two phenols – one with alkyl groups and the other with carbonyl.  Only the one with the alkyl groups reacts with phenyl iodoacetate!  Very nice!! Moving along backwards, intermediate 7 comes by a slightly convoluted protection/deprotection series of steps, but it again has some interesting selectivity.  Intermediate 7 has the hydroxymethyl group protected as the TBS ether and with two open phenol groups.  All three were initially protected as TBS ether, but the two phenol hydroxyl groups were deprotected selectively by TBAF (i.e. TBAF left the hydroxymethyl TBS ether intact!)  Their precursor was formed by the acetonide deprotection of 6.  Intermediate 6 comes by esterification reaction between alcohol 4 and methyl ester 5.  Compound 4 was derived from a Heck reaction between alkene 3 and aryl iodide 2.  Alkene 3 was prepared by attack of butyl anion (from nBuLi) on epoxide formed by the Sharpless epoxidation (and the benzyl ether protection) on penta-1,4-dien-3-ol.  Also interesting are the preparation of intermediates 5 and 2 from a common precursor – 1.  Thus compound 5 is prepared by palladium catalyzed methyl zinc  substitution on iodide 1, whereas compound 2 is prepared by deprotection of the acetonide in 1, followed by reduction of the acid to the alcohol and the re-formation of the acetonide ring. 

Overall, this is a very neat synthesis and has some very interesting selective transformations (selective TBS ether deprotection & selective phenolic oxidative cyclization).  

 

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).

 

(+)-Sch 725680

(+)-Sch 725680

Organic Letters, 2012, 14, 4303-4305

Toshifumi Takeuchi et al.

The retrosynthesis of (+)-Sch725680, begins with disconnecting the ester bond, thus giving acid chloride 13 and alcohol 10 as the main components.  Alcohol 10 comes from an hydroxyl addition on to a carbon-carbon triple bond in alkyne 9.  (Synthetically this is accomplished by just acidic treatment of the in-situ generated alcohol on the conjugated triple bond).  Compound 9 comes from an Aldol-condensation of ketone 8, which is generated by (a) alkyne lithium addition on aldehyde 6,; (b) methyl lithium attack on Weinreb amide portion of the molecule and finally,; (c) oxidation of the alcohol formed to the ketone functionality by using PCC.  Compound 6 comes by ring-opening of lactone 5 by N, O-dimethylhydroxylamine hydrochloride and oxidation of the primary alcohol.  The protected alcohol 5 comes from diol 4, which is formed by a cyclization of terminal alcohol on the chiral auxiliary 3.  Compound 3 is generated by a titanium mediated aldol reaction of imide 1 with aldehyde 2.

 

 

 

 

(-)-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.

Organic Letters, 2012, 14, 2078

J. P. Lajiness, W. Jiang, D. L. Boger

This paper describes the synthesis of (+)-spegazzinine, isolated from Aspidosperma chakensis in 1956.  From a synthetic point of view, there are 4 attached rings – two of which are spiro bound, 5 contiguous chiral centers – 3 of which are quaternary.  Boger’s group had developed a powerful methodology to construct the core of this molecule back in 2002, where 1,3,4-oxadiazoles undergo a intramolecular Diels-Alder reaction with a dienophile.  The resulting adduct loses nitrogen and undergoes a 1,3-dipolar cycloaddition reaction with an indole ring to furnish 3 atteched rings with upto 6 chiral centers formed stereoselectively around the central ring in a single step.  (See: JACS, 2002, 124, 11292).  The synthesis of (+)-spegazzinine is thus an extension of that methodology.

 



In the case of (+)-spegazzinine, the vinyl ether in not present, instead of the ester – there is an alcohol group, the aryl ring in indole is substituted with a hydroxyl group, and lastly, instead of the amide – there is an amine.

Retrosynthetically, (+)-spegazzinine is prepared by the reduction of the corresponding amide 9, since the amide is essential for the [4+2]/[3+2] cascade.  The hydroxyl group in 9 comes from a cyano hydrin in 8, which is produced by ring-opening (“reduction”) of 7.  Compound 7 is derived from the ester 6 – which is the key intermediate produced by the [4+2]/[3+2] cascade.  Its precursor, 5 has the 1,3,4-oxadiazole ring and the alkene group, which is in turn made by coupling the appropriate acid chloride with amine 4.  The oxadiazole ring is made by the hydrazide 3, which comes from activated amine 1.

The next retrosynthesis is of (-)-okilacomycin D, whose synthesis was recently completed by Thomas Hoye's group in Univ. of Minnesota.  The most interesting feature of the synthesis is the intra molecular Diels Alder reaction in the penultimate step to create the spiro tetranoate portion of the molecule.

 

(+)-Amabiline

(rac)-Trigonoliimine B

Reference: T. Buyck, Q. Wang, J. Zhu Org. Lett. 2012, 14, 1338