N-de(alpha-methyl)benzylation in presence of carbon-carbon double bonds in the synthesis of (+)-Pseudodistomin D

Amine as alpha methyl benzyl: Stephen Davies' group at Oxford used the (S)-N-alpha-methylbenzyl group to attach the (S)-N-allyl-N-alpha-methyl-benzylamide on a conjugated ester stereoselectively (>99% ee).  After subsequent Grubb's metathesis to create a 6-membered ring, they removed the chiral auxiliary (i.e alpha-methylbenzyl group) by hydrogenation using Pd(OH)2/C as the catalyst in methanol at 50 C.  Along similar lines, they attached the (S)-N-allyl-N-alpha-methyl-paramethoxybenzylamine group on the same conjugated ester stereoselectively (>90% ee).  This time, the chiral auxilliary (i.e alpha-methyl-paramethoxybenzyl group) was removed by using formic acid and triethylsilane, which also kept the isolated carbon-carbon double bonds intact.

Installation: (S)-alpha-methyl-paramethoxybenzylamine (>99% ee) is commercially available.

Survived: Grubbs

Removal: H2, Pd(OH)2/C;  also used HCOOH/Et3SiH

Reference: Organic Letters, 2012, 14, 1672-1675

The attack of lithium (S)-alpha-methyl-paramethoxybenzylamine on a conjugated ester creates the first stereocenter, which is then used to direct the next two sterocenters via a iodolactonization reaction.  However, there is a ~ 10% drop in stereoselectivity between using  (S)-alpha-methyl-paramethoxybenzylamine (ee = 90%) and (S)-alpha-methyl-benzylamine (ee =99%) - this difference is not explained and is carried throughout the synthesis.  After the iodolactonization step, a epoxide is formed which is then regioselectively (3:1 ratio) opened by NaN3 (in presence of NH4Cl in DMSO at 80 C).  The azide is reduced to the corresponding amine using Staudinger conditions - abeit with polymer supported PPh3 to ease the purification.

Selective TBS-ether deprotection in presence of TBDPS-ether in the synthesis of protectin-D1

Alcohols as TBS and TBDPS  ethers: Y. Kobayashi’s group had 2 alcohol groups in protectin-D1. One (primary) was protected as TBS (tert butyldimethylsilyl) ether and the other one (secondary)  was protected as TBDPS (tert butyldiphenyl) ether.  The TBS ether was deprotected selectively keeping the TBDPS ether intact.

Installation: not shown – but fairly simple substrates.  Standard methods would have sufficed.

Survived: H₂/Pd(Lindlar), Py.SO₃/NaClO₂/CH₂N₂

Removal: PPTS, CH₂Cl₂/EtOH, 94% yield

Reference: Tetrahedron Letters, 2011, 13, 3001-3004

There is one very interesting selective hydrogentation step towards the end of the synthesis.  In Scheme 5, intermediate 27 has two acetylinic bonds – one has two alkyl chains attached to it, while the other has a TMS group and an alkene attached to it.  Hydrogenation using Pd/BaSO₄ in ethyl acetate selectively reduced the alkyne with the two alkyl chains to the cis alkene, keeping the other acetylenic bond intact to give intermediate 28. 

Selective TES-ether deprotection followed by selective ester hydrolysis in the synthesis of (-)-CP2-Disarazole C1

Alcohols as TES and TBS  ethers: P. Wipf’s group had protected 3 alcohol groups in (-)-CP₂-Disarazole C_1.  Two were protected as TBS (tert butyldimethylsilyl) ethers and one was protected as TES (triethylsilyl) ether.  The TES ether was deprotected selectively keeping the two TBS ethers intact.

Installation: TESOTf, 2,6-lutidine, CH₂Cl₂, 0 °C, 93% yield

Survived: OsO₄/NMO, NaIO₄, NaBH₄, KHMDS

Removal: PPTS, MeOH, 0 °C, 63% yield

Reference: Organic Letters, 2011, 13, 4088-4091

Lactone as methyl ester:  A lactone was masked as a methyl ester. Another ester linkage was present in the molecule as it was dimer.  The simpler methyl ester was deprotected selectively in the presence of a substituted isopropyl ester.  Activation of the resulting acid with MNBA (2-methy-6-nitrobenzoic acid), DMAP, and triethylamine in toluene resulted in lactonization. 

Installation: commercially available starting material (serine methyl ester hydrochloride)

Survived: DDQ, Dess-Martin, KHMDS, PPTS

Removal: Ba(OH)₂, THF/H₂O followed by activation/lactonization: overall 55% yield in 2 steps.

Reference: Organic Letters, 2011, 13, 4088-4091

Interestingly, the preparation of one intermediate started with an ethyl ester, but it got transformed into a methyl ester during the deprotection of a TMS protecting acetylinic group (K₂CO₃, MeOH). 

Methyl Carbamate and tert butyl ester in the synthesis of (-) kainic acid

Amine as methyl carbamate:  T. Fukuyama's group converted an acid into a methyl carbamate protected amine by using a Curtius rearramgement. 
Installation: DPPA, NEt3, toluene, reflux then MeOH, reflux, 78% yield

Survived: Base (LiHMDS at -78 C), Zn/AcOH, LiAlH(Ot-Bu)3, TMSCN with BF3.OEt2
Removal: aq. NaOH, reflux , 70% yield
Reference: Organic Letters, 2011, 13, 2068.

Acid as tert-butyl ester: T. Fukuyama's group used a tert-butyl ester which came from commercially available tert-butyl bromoacetate.
Installation: Commercially available tert-butyl bromoacetate
Survived: Zn/AcOH, LiAlH(Ot-Bu)3, TMSCN with BF3.OEt2
Removal: aq. NaOH, reflux , 70% yield
Reference: Organic Letters, 2011, 13, 2068.

April 25, 2011

I will post examples of protecting groups in organic synthesis.  In my experience in organic and medicinal chemistry the proper choice, instllation, and removal of protecting groups is of paramount importance to the success of a synthetic scheme.  Anybody who embarks on a synthesis of a complex organic molecule encounters difficulties with protecting groups - on most occassions installation is relatively easy but removal difficult.  In my own case, my PhD got delayed by almost 6 months, because of an error in removing a trityl group from the imidazole ring of Histidine.  The choice of the reagent wasn't at fault - rather the work-up was wrong.  On the other hand, the success of my post-doc rested largely on an extremely efficient protocol for deprotecting a TBS ether using HF.pyridine in pyridine to stablize the acid-sensitive final product.

My aim is to highlight the (often overlooked) protection and deprotection strategies as they continue to evolve in organic synthesis.