Introduction

V. H. Rawal and S. A. Kozmin

Volume 46 of Science of Synthesis describes the assembly of a variety of cyclic and acyclic 1,3-diene-containing compounds, excluding those that contain direct heteroatom substitution of the diene moiety. The volume is organized by the classes of synthetic methods that are used for preparation of the 1,3-dienes and is intended to provide a comprehensive discussion of all classical and modern transformations that are employed for efficient assembly of this widely utilized class of organic compounds.

The volume begins with a discussion of alkenation methods (see ▶ Section 46.1), including the Wittig, the Horner–Wittig, the Horner–Wadsworth–Emmons, the Peterson, and the Julia reactions. (Note that, for consistency with the rest of Science of Synthesis, in this volume the term alkenation, rather than olefination, is used to describe reactions that involve formation of a C=C bond; the term alkenylation is used to describe coupling reactions involving a preformed C=C moiety.) Such methods rely on the general concepts outlined in ▶ Scheme 1, where heteroatom-stabilized reagents 2 or 6 are generated, typically by the action of a base on compounds 1 or 5, and then added to the carbonyl compounds 3 or 7, respectively. The addition step is followed by elimination (either in the same flask or in a separate step) to afford the desired 1,3-diene 4. Either the carbonyl compound 3 or the ylide 6 must contain an existing alkene moiety in order to yield the conjugated diene system present in 4.

▶ Scheme 1 Synthesis of 1,3-Dienes by Carbonyl Alkenation

▶ Schemes 2–5 depict several representative examples of applications of such methods in the context of complex molecule synthesis. The first case, shown in ▶ Scheme 2 (see also ▶ Section 46.1.1.2), represents the Wittig reaction of phosphonium salt 9 with aldehyde 8 to yield an advanced synthetic fragment 10 en route to the natural product callystatin A.[1] This example highlights the high efficiency of the assembly process, as well as the compatibility of the reaction with the lactone functionality.

▶ Scheme 2 Application of an Allylic Phosphorus Ylide to the Synthesis of (−)-Callystatin A[1]

The example in ▶ Scheme 3 (see also ▶ Section 46.1.3.1) illustrates the assembly of the 1,3-diene fragment of the natural product mniopetal E. In this case, the Horner–Wadsworth–Emmons reaction of aldehyde 11 with the anion generated upon treatment of ethyl (diethoxyphosphoryl)acetate with sodium hydride affords the desired 1,3-diene 12 with excellent efficiency and superb diastereoselectivity.[2]

▶ Scheme 3 Horner–Wadsworth–Emmons Reaction of an Enal in the Synthesis of Mniopetal E[2]

The Peterson reaction represents another efficient entry into 1,3-dienes. The most noteworthy feature of this method is reagent-based control of the diastereoselectivity of the final elimination step. ▶ Scheme 4 provides a representative example. Deprotonation of allyltriphenylsilane (13) with butyllithium, transmetalation with titanium(IV) isopropoxide, and finally addition of an aldehyde affords the desired β-hydroxy-α-vinylsilane 14, which undergoes stereospecific Peterson elimination reactions with acid or base to afford the corresponding E- or Z-diene, respectively (see also ▶ Section 46.1.4.2).[3]

▶ Scheme 4 Synthesis of a 1,3-Diene by Peterson Reaction[3]

The Julia reaction provides access to 1,3-dienes from α,β-unsaturated carbonyl compounds and alkyl sulfones under relatively mild conditions. A one-pot variant of this process is shown in ▶ Scheme 5. Deprotonation of sulfone 15 with sodium hexamethyldisilazanide, followed by addition of unsaturated aldehyde 16 affords the advanced synthetic fragment 17, which is used subsequently for the synthesis of marine natural product phorboxazole B (see also ▶ Section 46.1.5.1).[4]

▶ Scheme 5 Synthesis of the E,E-1,3-Diene Moiety of Phorboxazole B[4]

The alkylidenation of α,β-unsaturated carbonyl compounds (see ▶ Section 46.2) is a highly effective strategy for the synthesis of 1,3-dienes. Alkylidene complexes of transition metals can be employed to enable such transformations. One of the unique features of these methods is the ability to alkylidenate enolizable ketones or carboxylic acid derivatives, which can be quite challenging to conventional alkenation (olefination) methods. The general concept for assembly of 1,3-dienes using metal alkylidenes is shown in ▶ Scheme 6. The majority of such transformations entail methylenation or alkylidenation of unsaturated carbonyl compounds 19 with metal carbenes 18. Alternatively, the 1,3-dienes 20 can be assembled using unsaturated carbene complexes 21, especially those that are derived from titanium.

▶ Scheme 6 Synthesis of 1,3-Dienes by Metal-Based Alkylidenation Methods

The Tebbe reagent [(μ-chloro)bis(η5 -cyclopentadienyl)(dimethylaluminum)(μ-methylene)titanium(IV), (AlMe2){Ti(Cp)2}(μ-CH2)(μ-Cl)] is the classic reagent to enable efficient methylenation of a wide range of carbonyl compounds. The Tebbe reagent is prepared by the reaction of 2 equivalents of trimethylaluminum with dichlorobis(η5-cyclopentadienyl)titanium(IV). A representative example of the application of this reagent for the synthesis of 1,3-diene 22 is shown in ▶ Scheme 7 (see also ▶ Section 46.2.1.1.1).[5]

▶ Scheme 7 Transformation of an Unsaturated Aldehyde into a 1,3-Diene by Treatment with the Tebbe Reagent[5]

Diiodo(μ-methylene)dizinc(II) represents another useful reagent for the alkenation of aldehydes and ketones. Generally, Lewis acid activation is required for efficient use of this reagent. However, ketones that contain α-heteroatom substitution can be methylenated in the absence of a Lewis acid. A representative example is provided in ▶ Scheme 8 (see also ▶ Section 46.2.1.2), which illustrates the efficient transformation of enone 23 into diene 24.[6]

▶ Scheme 8 Transformation of an Enone into a 1,3-Diene by Methylenation with Diiodo- (μ-methylene)dizinc(II)[6]

Treatment of α-substituted γ-chloroallyl sulfide 25 with bis(η5-cyclopentadienyl)bis(triethyl phosphite)titanium(II) generates the intermediate alkenylcarbene complex 26 (▶ Scheme 9; see also ▶ Section 46.2.3.1). Subsequent addition of 1,5-diphenylpentan-3-one affords trisubstituted diene 27 in 64% yield.[7] The efficiency of this process, however, is generally dependent on the substitution of the starting γ-chloroallyl sulfide.

▶ Scheme 9 Synthesis of a 1,3-Diene by Bis(η5-cyclopentadienyl)titanium(II)-Promoted Reaction of a Ketone with a γ-Chloroallyl Sulfide[7]

▶ Section 46.3 covers two main alkene metathesis approaches to conjugated diene synthesis (▶ Scheme 10). The first process involves treatment of an alkene 28 with a stoichiometric amount of alkyne 29 in the presence of an appropriate metal alkylidene metathesis catalyst to give a 1,3-diene 30. This process is termed “ene–yne” or “enyne” metathesis. The second transformation entails the metathesis between a conjugated diene 32 and an alkene 31 to give increased substitution on the resulting conjugated diene 30. The latter approach has been employed less frequently due to the difficulty in differentiating between the two C=C bonds present in diene 32, with the less substituted alkene moiety typically being less...