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4.4.41.8 β-Silyl Carbonyl Compounds (Update 2013)

DOI: 10.1055/sos-SD-104-00164

Nahra, F.; Riant, O.Science of Synthesis Knowledge Updates, (20132197.

General Introduction

β-Silyl carbonyl or carboxy compounds are attractive synthetic intermediates (Scheme 1).[‌1‌‌9‌] The position of the silyl group far from the carbonyl group allows for numerous transformations on the latter, and, with the well-known resistance of the silyl group to a wide range of conditions,[‌10‌] more complex molecules can be constructed from this type of intermediate. If the silyl group is installed enantioselectively on a saturated carbon, it can influence the adjacent addition of other groups.[‌11‌,‌12‌] The silyl group can be retained through several synthetic steps, only to be converted later into another functional group.

Scheme 1 β-Silyl Carbonyl Compounds as Useful Synthetic Intermediates in Total Synthesis[‌5‌‌9‌]

One of the most exploited advantages of the silyl group is its function as a masked hydroxy or acetoxy moiety.[‌13‌] This type of transformation, when applied to β-silyl carbonyl compounds, gives access to aldol-type products[‌14‌] (Scheme 2) and 1,3-diols[‌15‌] (Scheme 3). The main advantage of using a silyl group is that a wide range of transformations can be applied before unmasking to the desired function, thus avoiding any β-elimination that usually takes place with aldol products.[‌14‌] For example, β-silyl malonate 1 readily undergoes decarboxylation followed by α-alkylation of the subsequently formed monoester to furnish the desired product 2 in good yield and with excellent diastereoselectivity (dr 20:1) in favor of the 2,3-anti relationship between the benzyl group and the silyl group (Scheme 2).[‌12‌] This relationship is of significant interest since the dimethyl(phenyl)silyl group can be converted into a hydroxy group with complete retention of configuration, thus giving access to the anti aldol-type ester 3 with no risk of β-elimination or retro-aldol reaction.

Scheme 2 Decarboxylation, Enolate Alkylation, and Silyl-to-Hydroxy Conversion[‌12‌]

β-Silyl aldehyde 4 is reduced to alcohol 5 in high yield without any effect on the silyl moiety and its configuration. Oxidation and diacetylation of alcohol 5 gives the 1,3-diacetylated diol 6 in good yield (Scheme 3).[‌15‌] Again, retention of stereochemistry at the silyl position is observed.

Scheme 3 Conversion of a β-Silyl Carbonyl System into a Diacetylated Diol[‌15‌]

β-Silyl alkenyl carbonyl compounds are particularly interesting due to their ability to undergo insertion of an alkyl or aryl group in the position geminal to the silyl moiety.[‌16‌,‌17‌] In this case, the C—Si bond is the most susceptible to transfer, although the carbon substituent to be transferred from the silicon atom must be an activated carbon such as an aryl, benzyl, or allyl group. Thus, β-silyl enone 7 is activated by tetrabutylammonium fluoride to afford a silicate intermediate. Once this intermediate is formed, the benzyl group on the silicon atom is transferred to the geminal position and subsequent in situ oxidation of the tertiary silyl intermediate gives the β-keto tertiary alcohol 8 in good yield and with good diastereoselectivity (Scheme 4).[‌18‌] In some cases, the tertiary silyl intermediates can be isolated and then oxidized, but it has been found that in situ oxidation provides better yields.

Scheme 4 Geminal Alkylation–Oxidation of a β-Silyl Alkenyl Carbonyl System[‌18‌]

β-Silyl carbonyl species that are also allylsilanes are an important class of compounds due to their wide utility in organic synthesis.[‌9‌,‌19‌‌21‌] Enantioenriched allylic β-silyl carbonyl systems are effective allylating agents, rendering them useful building blocks for further transformations. The presence of the carbonyl group at the β-position offers a unique opportunity to perform asymmetric intramolecular allylation to give five-membered rings bearing a chiral homoallylic alcohol.[‌22‌] As shown in Scheme 5, in the presence of a Lewis acid, β-silyl ketones 9 and 10 are converted into the corresponding cyclic alcohols, bearing two stereogenic carbon centers, with excellent yields and very high levels of enantio- and diastereoselectivity.

Scheme 5 Asymmetric Intramolecular Allylation of Allylic β-Silyl Ketones[‌22‌]

Another advantage of β-silyl carbonyl compounds, more particularly β-silyl ketones, is their reactivity in the Baeyer–Villiger reaction.[‌23‌,‌24‌] In this case, oxidation only occurs on the side of the ketone where the silyl group is placed. This type of transformation is a very useful tool in synthetic procedures, as demonstrated in the synthesis of ester 13 (Scheme 6), a key intermediate in the total synthesis of (+)-sporochnol A (see Scheme 1).[‌5‌,‌25‌] Thus, cyclic β-silyl ketone 11 is readily oxidized to lactone 12 in high yield and with high selectivity. β-Elimination and subsequent alkylation gives ester 13 in moderate yields. In this case, the silyl group acts as a masked alkene.

Scheme 6 Baeyer–Villiger Oxidation and β-Silyl Elimination[‌5‌]

A more recent example of silicon-directed regio- and stereocontrol is the silicon-tethered Diels–Alder reaction (Scheme 7).[‌26‌] β-Silyl acrylate 14, carrying a diene on one of the substituents at the silicon atom, reacts by a [4 + 2] cycloaddition to form the bicyclic product 15 in a regio- and stereoselective manner. Although the Diels–Alder adduct 15 has been observed, attempts to isolate it result in decomposition. Therefore, the crude product 15 is directly subjected to either protodesilylation or oxidation conditions to provide the cyclohexene products 16 and 17, respectively, in good yields.[‌26‌‌28‌] It should be noted that such silicon-tethered Diels–Alder reactions convert α,β-unsaturated β-silyl carbonyl compounds into saturated β-silyl carbonyl compounds.

Scheme 7 Silicon-Tethered Diels–Alder Reaction Followed by Either Protodesilylation or Selective Oxidation[‌26‌]

In recent years, the formation of saturated β-silyl carbonyl compounds from their unsaturated counterparts has gained considerable attention. The latter are readily reduced[‌29‌] or alkylated[‌30‌,‌31‌] to form the saturated compounds, usually employing transition-metal catalysis. Both racemic and enantioselective versions of these reactions have become well established.[‌9‌]

Saturated and unsaturated β-silyl carbonyl compounds can be formed in many different ways. More recently, attention has focused in particular upon silylmetalation reactions catalyzed by transition metals, which have allowed the development of new methodologies. As such, silylmetalation has become one of the most powerful tools to introduce a silicon group β to a carbonyl or carboxy group in a stereo- and enantioselective manner. Along with hydrosilylation, 1,4-addition of nucleophiles to unsaturated β-silyl carbonyl compounds, and some rearrangement reactions, silylmetalation has been extensively studied since the beginning of the 21st century.

References