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).