A wide range of aldehydes was efficiently protected as pyrrole carbinol derivatives by direct addition of lithium pyrrolate in THF at -78 °C. The protection is chemoselective towards aldehydes over ketones and the O-lithiated, O-protonated or O-silylated carbinols may be used to block the aldehyde from nucleophilic and basic reagents at low temperatures. Mild, basic deprotection using DBU, NaOMe or TBAF allows for in situ trapping-reactions (such as Wadsworth-Horner-Emmons olefination) of the released aldehyde.Protection of the aldehyde group is often required in synthesis programs. However, owing to the limited number of efficient and selective methods, the unmasking of the aldehyde (via oxidative cleavage of alkenes, or oxidation of alcohols, for example) is often the chosen strategy. 1 Additionally, a chemoselective base-mediated aldehyde protection/deprotection sequence is absent from the literature despite the complementary nature of this approach to others and its potential use in synthesis. 2,3 Having identified the pyrrole carbinol 4 as a suitably protected form of the aldehyde, we embarked upon a systematic study to: identify a general, straightforward method of generating these intermediates directly from aldehydes, probe their utility as protected aldehydes in subsequent reactions and ascertain mild deprotection methods to deblock the intermediates. Herein, we wish to report our findings in this area. Scheme 1 a) Pyrrole (1.05 equiv), base (1.0 equiv), -78 °C, THF then 1 for 15 min. b) NH 4 Cl (aq).Initially, a range of metal pyrrolates 5 in THF 6 at low temperature was screened against iso-butyraldehyde (1) to ascertain their efficiency in the formation of pyrrole carbinol 2 (Table 1). Alkali metal pyrrolates were superior to their alkaline earth counterparts and lithium was the metal of choice (Scheme 1). Having identified the optimal conditions for the additions, the scope of the reaction was probed using a range of commercial aldehydes. Treatment of aliphatic, unsaturated, aromatic, and heteroaromatic aldehydes with one equivalent of lithium pyrrolate in THF at -78 °C for 30 minutes followed by a saturated aqueous NH 4 Cl work-up, led in all cases to high crude yields of the desired pyrrole carbinol products (Scheme 2). 7,8 Scheme 2 a) Pyrrole (1.05 equiv), BuLi (1.0 equiv), -78 °C, THF then RCHO. b) NH 4 Cl (aq). c) DBU (5 mol%), THF, r.t. d) NaOMe (5 mol%), THF, r.t.The crude materials were purified by flash column chromatography on silica gel to give pure pyrrole carbinols in high yields in all cases. The crude NMR yields and the purified yields were the same within error and confirmed the stability of the pyrrole carbinols to silica gel. Deprotection to the aldehyde was possible using catalytic DBU 9 or NaOMe in THF at room temperature. In most cases, barring aliphatic aldehydes, DBU facilitated a smooth deprotection. NaOMe was effective for abranched or a-trisubstituted aliphatic aldehydes, but caused degradation to certain conjugated aldehydes.For the pyrrole carbinols of aliphatic aldehyd...

a-Alkylidene-g-butyrolactones are widespread in nature and have diverse and potentially useful biological properties. [1] Representative examples range from the relatively simple paeonilactone B, [2] to more complex compounds such as helenalin isobutyrate [3a] and the recently isolated montahibisciolide. [3b] Numerous procedures are available to prepare a-alkylidene-g-butyrolactones; in particular, the initial construction of the lactone with subsequent methylenation is popular, but the majority of the routes are lengthy and low yielding. [1][2][3] As part of our growing interest in tandem or telescoped processes, [4] we designed a one-pot approach to a-alkylidene-g-butyrolactones (Scheme 1). The key was the use of diethyl phosphonoacetate 1, which, after deprotonation, was expected to undergo an intramolecular Michael addition [5,6] to give enolate 2. We anticipated subsequent proton transfer to generate the more stable phosphonate anion 3 and then addition of an aldehyde to initiate an intermolecular HornerWadsworth-Emmons (HWE) olefination [7] to yield cyclic dicarbonyl compound 4. In addition, we anticipated that the sequence would be cis selective in the formation of tetrahydrobenzofuran-2,5-dione 4 (n = 1).Ketophosphonate 5 was used to assess the viability of the approach shown in Scheme 1. Compound 5 was prepared from readily available 4-hydroxy-2-cyclohexenone [8] and commercially available diethyl phosphonoacetic acid by using 2-propanephosphonic acid anhydride (T3P) as the coupling agent. When ketophosphonate 5 was treated with KOtBu in THF, the expected Michael adduct 6 was obtained in 50 % yield (Scheme 2). Phosphonate 6 was used to optimize the key HWE methylenation in terms of base, solvent, stoichiometry, and formaldehyde source. KOtBu in THF proved to be the best base/solvent combination and paraformaldehyde was the optimal formaldehyde source. The amethylene lactone product 7 a was highly base-sensitive, and the use of a substoichiometric quantity of base (0.95 equiv) gave product 7 a in 83 % yield.A more efficient transformation was achieved by performing a sequential one-pot process. Thus, treatment of ketophosphonate 5 with KOtBu (0.95 equiv) in THF, and the addition of paraformaldehyde after 60 minutes, produced the expected a-methylene lactone 7 a in 77 % overall yield. This result emphasizes the advantages of a sequential one-pot process-it avoids a complicated intermediate workup process and the overall yield is improved (77 %, compared to 43 % over two steps). This variant was termed a telescoped intramolecular Michael addition/HWE olefination (TIMO) process. Lactone 7 a is novel although the corresponding trans isomer is known.[9] The cis arrangement of 7 a was confirmed by obtaining an X-ray crystallographic structure.[10] Scheme 1. Proposed TIMO approach to a-alkylidene-g-butyrolactones.

[reaction: see text] A short stereoselective total synthesis of the polyketide natural product, tarchonanthuslactone, has been achieved. The key sequence involves the first reported catalytic enantioselective reduction of an N-acyl pyrrole and subsequent use of this stereocenter in a diastereoselective reductive cascade. This proceeded with unprecedentedly high stereocontrol and offered an elegant method of generating the desired syn stereochemistry present in the final target in one step.