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DOI: 10.1055/s-0029-1218664
Advances in 2-(Alkoxycarbonyl)allylboration of Carbonyl Compounds and Other Direct Methods for the Preparation of α-Exo-Alkylidene γ-Lactones
Publication History
Publication Date:
05 February 2010 (online)
Biographical Sketches
Abstract
Reagents and methodologies allowing for direct preparation of α-exo-alkylidene γ-lactones are of great interest because of the multiple biological properties demonstrated by these natural and unnatural compounds. Relatively few simple and direct methods are available for the preparation of these important compounds, and these methods along with their applications in target-oriented and diversity-oriented synthesis are covered in this review focusing on the most recent advances in the literature.
1 Introduction
1.1 Importance of α-Exo-Methylene and α-Exo-Alkylidene γ-Lactones
1.2 Overview of Indirect Preparative Methods
2 Direct Preparative Methods by Additions of 2-(Alkoxycarbonyl)allylmetal Reagents to Aldehydes and Ketones
2.1 Thermal Additions of 2-(Alkoxycarbonyl)allyl Boronates
2.2 Lewis Acid Catalyzed Additions of 2-(Alkoxycarbonyl)allyl Boronates
2.3 Brønsted Acid Catalyzed Additions of 2-(Alkoxycarbonyl)allyl Boronates
2.4 Preparation of Libraries of α-Exo-Methylene γ-Lactones and Their Functionalization into α-Exo-Alkylidene γ-Lactones
3 Additions of Other 2-(Alkoxycarbonyl)allylmetal Reagents
4 Barbier-Type Additions with 2-(Alkoxycarbonyl)allyl Halides
5 Other Direct Methods
6 Conclusion
Key words
allylations - boron - catalysis - lactones - natural products
1 Introduction
1.1 Importance of α-Exo-Methylene and α-Exo-Alkylidene γ-Lactones
The α-exo-methylene γ-butyrolactone ring is a key structural motif in many natural products, most notably the sesquiterpene lactones (Figure [¹] ). In 1985, it was estimated that approximately 10% of the known 30,000 natural products contained the α-exo-methylene γ-butyrolactone functionality. [¹] The number of natural products that contain an α-exo-methylene γ-butyrolactone keeps increasing, and more and more interest is being shown in these compounds due to their unique biological properties. In many cases, the high bioactivity of these heterocycles is due to the presence of the electrophilic α-exo-methylene γ-lactone moiety, which can trap nucleophilic sites on enzyme targets. These natural products have shown to be quite useful as DNA polymerase inhibitors, nuclear vitamin D receptor inhibitors, cellular steroidal inhibitors, blockers of tumor necrosis factor-α production, as well as many other uses. [²] The broad inhibitory actions of these natural products makes them potential drug candidates owing to their cytotoxic, allergenic, anti-inflammatory, phytotoxic, and antimicrobial properties. [³] In fact, the hydrochloride salt of one α-exo-methylene γ-lactone natural product, arglabin (Figure [¹] ), has been used successfully in Kazakhstan for the treatment of breast, colon, ovarian, and lung cancers. [4]
Figure 1 Selected natural products containing an α-exo-methylene γ-lactone ring
1.2 Overview of Indirect Preparative Methods
As a result of their biological importance, the synthesis of polysubstituted α-exo-methylene γ-lactones has been of interest to synthetic chemists for several years. A number of routes have been devised to access the α-exo-methylene and α-exo-alkylidene γ-lactone ring; however, they tend to be lengthy and cumbersome if the lactone contains any sort of substitution. [¹] For instance, a number of indirect approaches are based on the initial construction of a saturated γ-lactone, followed by an α-condensation to establish the exo-alkylidene unit. Examples of such strategies include the use of elimination reactions to establish the exo-methylene group (Scheme [¹] ). In this example, the condensation of an amine-chelated enolate (1) occurs with high anti/syn selectivity. [5] The dimethylamino substituent is then quaternized, and treated with base to give the α,β-unsaturated ester 2. The latter is then treated under acidic conditions, leading to cleavage of the benzyloxymethyl acetal and cyclization to give the β-hydroxy α-exo-methylene γ-lactone product 3. Although this approach requires additional steps to install the exo-methylene unit, it leads to the desired γ-lactone with excellent control of diastereoselectivity.
Scheme 1 A Claisen condensation-elimination approach to β-hydroxy α-exo-methylene γ-lactones
Wittig-Horner-Emmons-Wadsworth olefinations also require a late-stage installation of the exo-alkylidene unit. For example, Janecki and co-workers employed a nitro-Michael approach to construct cyclic phosphonate precursors 4 that can lead to both α-exo-methylene and α-exo-alkylidene γ-lactone products 5 and 6 (Scheme [²] ). [³a] Despite the rather long synthetic sequence, the ability to access several α-exo-alkylidene derivatives with a late-stage Horner-Emmons-Wadsworth (HEW) condensation with various aldehydes is a distinct advantage of this approach. However, the reaction provides mixtures of exo-alkylidene lactones with highly variable E/Z selectivity depending on the aldehyde used.
Scheme 2 General Horner-Emmons-Wadsworth olefination approach to α-exo-alkylidene γ-lactones 6
Using a similar approach to access bicyclic α-exo-alkylidene γ-lactones, Taylor and co-workers developed an interesting new one-pot process initiated by the conjugate addition of tethered phosphonate-stabilized anions (Scheme [³] ).6 The resulting enolate product 7 undergoes a proton transfer to provide a second phosphonate-substituted carbanion, 8, which can condense with various aldehydes. With aromatic aldehydes, the resulting α-exo-alkylidene γ-lactones 9 are obtained with high E/Z selectivity.
Scheme 3 General conjugate addition-HEW olefination approach to bicyclic α-exo-alkylidene γ-lactones 9
Another approach to bicyclic α-exo-alkylidene γ-lactones requires the preparation of iodinated alkynoate precursors 10 that can undergo a radical cyclization (Scheme [4] ). [7] The resulting alkenyl iodide 11 can be substituted to give the desired lactones 12.
Scheme 4 Radical cyclization approach to bicyclic α-exo-alkylidene γ-lactones 12
Many other indirect approaches are aimed at first accessing the key hydroxy ester intermediate containing the requisite α-exo-methylene unit. [8] As such, Giannis and co-workers prepared a set of inhibitors of the enzyme histone acetyltransferase via a Claisen condensation between ester 13 and various aldehydes. This process first led to the hydroxy ester intermediates 14, which were lactonized to give the racemic 3-carboxy α-exo-methylene γ-lactones 15 after removal of the PMB protecting group (Scheme [5] ). [8a]
Scheme 5 Claisen condensation approach to β-carboxy α-exo-methylene γ-lactones 15
Itoh and co-workers arrived at the required hydroxy aldehyde via an allylic silane, 16, which was transformed into a diol, 17 (Scheme [6] ). [9] Oxidation of the allylic alcohol using manganese dioxide provided the α-exo-methylene lactones 5 through the intermediacy of the corresponding lactol.
Scheme 6 Preparation of α-exo-methylene γ-lactones 5 from allylic silanes
A more recent approach by Ramachandran and co-workers elegantly exploits the cis-hydroalumination of acetylenic esters and subsequent electrophilic trapping of alkenyl alanes 18 with epoxides (Scheme [7] ). [¹0] Although it is an indirect approach that requires two distinct operations, it has the merit of permitting access to both isomers of α-alkylidene γ-lactones 6. Thus, a direct acid-catalyzed lactonization of hydroxy esters 19 affords the Z-isomer whereas treatment with lithium diisopropylamide and kinetic protonation of the chelated allylic carbanion 20 results in an inversion of configuration that leads to the E-isomer with very high selectivity.
Scheme 7 Steoreodivergent approach to α-exo-alkylidene γ-lactones 6
The p-F-Vivol˙SnCl4-catalyzed allylboration and crotylboration of aldehydes is a remarkably efficient process to prepare enantioenriched homoallylic alcohols. Its application to additions with the unprecedented pinacol 2-bromoallyl boronate reagent 21 was examined by Rauniyar and Hall (Scheme [8] ). [¹¹] This method is attractive because it offers the possibility of functionalizing the alkenyl bromide unit of the resulting addition products 22 via a nickel-promoted carbonylative cyclization, [¹²] thereby providing the desired α-exo-methylene γ-lactones 5. Thus, the 2-bromoallyl boronate reagent 21 was found to add to a variety of aldehydes with excellent enantioselectivity under chiral Brønsted acid catalyzed conditions. The subsequent carbonylation provides an expedient preparation of monosubstituted α-exo-methylene γ-lactones 5 with preservation of stereochemistry.
Scheme 8 Preparation of α-exo-methylene γ-lactones 5 by the bromoallylboration of aldehydes followed by carbonylation
Many of the above-mentioned indirect methods are quite general. However, a potentially more attractive strategy consists of the use of direct methods where the α-alkylidene moiety is present from the start, or introduced in only one operation from simple reagents and substrates. Such methods are particularly amenable to the preparation of combinatorial libraries of the desired lactones. The remainder of this review article surveys direct methods to attain α-exo-methylene and α-exo-alkylidene γ-lactones with a focus on advances reported in the past decade.
2 Direct Preparative Methods by Additions of 2-(Alkoxycarbonyl)allylmetal Reagents to Aldehydes and Ketones
Aldehydes and ketones constitute a very broad class of easily accessible starting materials. It is therefore not surprising that the addition of 2-(alkoxycarbonyl)allylmetal reagents have become a mainstream methodology to access α-exo-methylene or α-exo-alkylidene γ-lactones (Scheme [9] ). Mechanistically, most 2-(alkoxycarbonyl)allylmetal reagents add nucleophilically to aldehydes using the remote carbon, first leading to an aldol-like adduct, a hydroxy ester, which often lactonizes spontaneously to give the desired lactone product. Alternatively, an acid-catalyzed cyclization may be required, and can often be carried out sequentially in one pot, or as a separate operation on the crude hydroxy ester product (Scheme [9] ). Reagents based on boron, tin, silicon, zinc, and others have been reported, and are described below. The presence of a carboxy ester on the reagent limits the type of metal compatible with these reagents, such that overly reactive organometallics from lithium and magnesium are not suitable. The ester substituent also tends to suppress the nucleophilicity of these reagents such that additions to ketones are rarely successful. The use of 2-(alkoxycarbonyl)allylboronates has been widely studied because of the stability and convenience of these reagents and the high and reliable diastereoselectivity of their additions to carbonyl compounds. These reagents are described in the following section.
Scheme 9 General approach to α-exo-methylene γ-lactones 5 from the addition of allylic metal reagents to carbonyl compounds
2.1 Thermal Additions of 2-(Alkoxycarbonyl)allyl Boronates
In the past two decades, carbonyl allylation chemistry has been an invaluable tool for the stereocontrolled formation of carbon-carbon bonds in the field of organic synthesis (Scheme [¹0] ). [¹³] The usefulness and popularity of aldehyde allylation methods in the context of natural product synthesis is matched only by asymmetric aldol methodologies. The formation of homoallylic alcohol products with a terminal alkene functionality renders allylation methods even more attractive. For instance, possibilities for post-allylation transformations have indeed been greatly embellished by the recent development of catalytic alkene metathesis reactions.
Scheme 10 General approaches to substituted homoallylic alcohols from the addition of allylboron reagents to carbonyl compounds
Several excellent methodologies have been described for carbonyl allylation using stoichiometric chiral directors based on reagents of boron, silicon, tin, and titanium. [¹³] A number of substoichiometric (catalytic) methods have been reported for allylic reagents of silicon, tin, boron, and chromium. [¹4] Of all possible allylic metal reagents, however, the use of allylic boron reagents has been highly dominant in the user community. [¹5] Allylic boron reagents belong to the type I class (Scheme [¹¹] , M = B), which involves closed cyclic, six-membered chair-like transition states characterized by internal activation of the carbonyl by the boron atom. [¹6]
Scheme 11 Mechanistic classification for allylic metal reagents of type I and II (type III not shown)
Moreover, as a result of the type I mechanism, diastereoselection with γ-substituted reagents is generally very high. This important observation was first noted by Hoffmann and Zeiss, [¹7] and constitutes a significant advantage of boron reagents over all type II reagents such as trialkylsilanes and trialkylstannanes.
The first report of a preparation of unsubstituted 2-(alkoxycarbonyl)allylboron reagent and subsequent addition to aldehydes was disclosed by Villiéras and co-workers in 1993. [¹8] The desired reagent 24a was prepared in a stereoselective fashion via a regioselective hydroalumination of methyl propiolate followed by trapping of the resulting alkenyl alane 23 with highly electrophilic halomethylboronic esters (Scheme [¹²] ). The resulting 2-(alkoxycarbonyl)allyl boronate reagent 24a was combined with various aldehydes to provide the expected alcohols 25 after a long reaction time of almost two weeks at room temperature. In refluxing toluene, a significant proportion of lactonized product 5 was isolated. The 3-methylated homologue 24b can be obtained, however, as a mixture of isomers. [¹9]
Scheme 12 Early approach to the preparation of 2-(alkoxycarbonyl)allyl boronates; pin = OC(Me)2C(Me)2O
Our group was initially interested in this class of reagents as a means to access lactones with an embedded quaternary carbon center. To this end, we successfully developed an efficient approach to prepare 3,3-disubstituted 2-(alkoxycarbonyl)allyl boronates (24) through a stereoselective carbocupration of acetylenic esters followed by electrophilic trapping of the resulting alkenylcopper intermediates 26 with halomethylboronates (Scheme [¹³] ). [²0] The stereoselectivity of this process was found to be optimal when using HMPA as an additive. [²¹] It was anticipated that these reagents could lead to quaternary carbon centers with high diastereocontrol. Indeed, tetrasubstituted allylic boronates 24 were found to add to aldehydes stereospecifically to afford, through the intermediacy of open intermediates 25, α-exo-methylene γ-lactones 5 embedding the desired quaternary carbon center. [²0] Using a double-auxiliary approach (with matched chiral carboxy ester and chiral boronic ester), high enantioselectivities were obtained in the formation of α-exo-methylene γ-lactones 5.
Scheme 13 Approach to α-exo-methylene γ-lactones using tetrasubstituted 2-(alkoxycarbonyl)allyl boronates 24
The nucleophilicity of reagents of type 24, however, is greatly attenuated by the 2-(alkoxycarbonyl) substituent, and by the steric effect from the two substituents R¹ and R² on carbon 3. Not surprisingly, reaction times were very long: as much as two full weeks at room temperature or several hours at elevated temperatures. As a result of the mitigated reactivity of these reagents, ketones are generally unreactive.
Ramachandran et al. subsequently prepared trisubstituted 2-(alkoxycarbonyl)allyl boronates using the Miyaura-Hosomi borylation of allylic acetates (Scheme [¹4] ), themselves obtained stereoselectively via carboalumination and aldehyde trapping. [²²] Using stoichiometric copper chloride, various SN2′ products 24 were obtained with high E/Z selectivity. The α-unsubstituted products (R² = H) were examined in aldehyde allylboration to give the expected α-exo-methylene γ-lactone product 5a. Kabalka and co-workers used similar chemistry, under palladium catalysis, to generate the same trisubstituted allylic boronic esters that were also transformed into useful trifluoborate salts. [²³]
Scheme 14 Hosomi-Miyaura borylation approach to trisubstituted 2-(alkoxycarbonyl)allyl boronates
2.2 Lewis Acid Catalyzed Additions of 2-(Alkoxycarbonyl)allyl Boronates
The idea that Lewis acids could accelerate carbonyl allylboration reactions was counter-intuitive on a mechanistic standpoint because the carbonyl is internally activated by the boron atom in the transition state for this reaction (cf. Scheme [¹¹] ). Moreover, by potentially inducing a changeover from a type I mechanism towards open transition structures, the use of Lewis acids could be detrimental to the reaction’s diastereoselectivity. As it turned out, Lewis acid catalyzed allylborations are possible and highly beneficial with reagents of low reactivity like 2-(alkoxycarbonyl)allyl boronates. We had successfully developed the above-described method (cf. Scheme [¹³] ) to access 3,3-disubstituted 2-(alkoxycarbonyl)allyl boronates (24) through a stereoselective carbocupration of acetylenic esters followed by electrophilic trapping with halomethylboronates. [²0] The nucleophilicity of reagents 24, however, is greatly attenuated by the 2-alkoxycarbonyl substituent, and by the steric effect from the two substituents on carbon 3 (i.e., R¹, R²). Reaction times were very long: as much as two full weeks at room temperature. To address this issue, we screened several dozen metal salts for catalysis, in particular metal triflates, using a qualitative NMR-based experiment at room temperature. To our surprise, both scandium(III) triflate and copper(II) triflate led to a dramatic rate acceleration. [²4] A side-by-side comparison of model allylborations, both uncatalyzed and catalyzed, was set up with reagent 24c. The outcome, highlighted in Scheme [¹5] , confirmed that allylborations could be catalyzed with a dramatic rate acceleration and with preservation of the stereospecificity of the traditional uncatalyzed variant. [²4]
Scheme 15 Comparison of thermal uncatalyzed and scandium(III)-catalyzed allylborations with reagent 24c and benzaldehyde as model substrates
Our original communication also reported control experiments, such as the reaction of an ester-less allylic boronate, which provided an indication that the 2-alkoxycarbonyl substituent of allylic boronates 24 was not necessary and that the catalytic manifold could be generalized to many other reagents. This observation was further confirmed in a subsequent report by Miyaura and co-workers who demonstrated that additions of the pinacol crotylboronates can be accelerated not only by scandium(III) triflate but also by classical hard Lewis acids like boron trifluoride, titanium(IV) chloride, and aluminum trichloride. [²5] In the context of 2-(alkoxycarbonyl)allyl boronates, this discovery provided a new set of reaction conditions to access α-exo-methylene γ-lactones.
Our own investigations of the scope and limitations of the scandium(III) triflate catalyzed additions of reagents 24 to aldehydes, leading to the formation of α-exo-methylene γ-lactones 5, demonstrated several advantages of the Lewis acid catalyzed allylboration manifold in addition to the shorter reaction times. [²6] For example, hindered aldehydes such as cyclohexanecarbaldehyde that used to give low yields under non-catalyzed conditions suddenly became suitable substrates under the catalytic manifold (Scheme [¹6] ).
Scheme 16 Example of hindered aliphatic aldehyde in the Lewis acid catalyzed additions of 2-(alkoxycarbonyl)allyl boronates
Scheme 17 Tandem borylation/boron trifluoride catalyzed allylboration by Kabalka and co-workers
Our results with the 2-(alkoxycarbonyl)allyl boronates and the interesting stereochemistry of their acid-catalyzed additions to aldehydes have inspired other investigators. Kabalka and co-workers have reported that boron trifluoride is also an excellent catalyst for the additions of 2-(alkoxycarbonyl)allyl boronates to aldehydes, [²7] and they have developed a convenient procedure using silica-supported boron trifluoride in the second stage of a one-pot tandem process initiated by a palladium-catalyzed allylic borylative cross-coupling of Baylis-Hillman adducts (Scheme [¹7] ). This methodology was subsequently exploited in the total syntheses of eupomatilones 2 and 5. [²8]
In the same line, Ramachandran and co-workers have further developed our findings on the stereochemistry of the additions of allyl boronates 24 by showing that the occurrence of isomerization observed between reagent 24d and certain aldehydes can be controlled by the actual strength of the Lewis acid employed (Scheme [¹8] ). [²9] Thus, whereas benzaldehyde and electron-rich aromatic aldehydes tend to provide the cis-configured lactone products (e.g., 5c) with moderately active Lewis acids, the trans lactone 5d is obtained with strong Lewis acids. Aromatic aldehydes with electron-withdrawing substituents produce predominantly the cis-substituted lactones regardless of the nature of the Lewis acid employed.
Scheme 18 Stereochemical control in lactone formation using the Lewis acid catalyzed allylboration, by Ramachandran and co-workers
In the reaction between 3-substituted 2-(alkoxycarbonyl)allyl boronates and aliphatic aldehydes, the use of indium(III) triflate promotes the oxonia-Cope rearrangement faster than the final lactonization step, leading to the corresponding E-alkylidene lactones (Scheme [¹9] ). [³0] Thus, for example, with ytterbium(III) triflate the hydroxy ester intermediate 25e cyclizes directly (or with an additional protic acid catalyzed step) to give the β-substituted α-exo-methylene γ-lactone 5e in high diastereoselectivity. With indium(III) triflate and excess aldehyde, the oxonia-Cope rearrangement takes precedent to give a modified hydroxy ester intermediate 27 that cyclizes to give the alternate, α-exo-alkylidene γ-lactone product 5f. These elegant studies by Ramachandran and co-workers on the effect of the nature of the Lewis acid catalysts provide more levels of divergent control of chemoselectivity in these allylboration/lactonization reactions.
Scheme 19 Promotion of oxonia-Cope pathway prior to lactone formation using the Lewis acid catalyzed allylboration
As described above, E-configured 3-substituted 2-(alkoxycarbonyl)allyl boronates add to aldehydes to give hydroxy esters that lead to the cis-3,4-disubstituted α-exo-methylene γ-lactone products 5 after an acid-promoted cyclization (Scheme [²0] ). In one more example of the versatility of the allylboration/lactonization approach to α-exo-methylene γ-lactones, Kabalka and co-workers developed Mitsunobu-like conditions with a mechanism thought to transform the secondary alcohol into a phosphonium salt that can lactonize by nucleophilic attack of the carboxy ester. [³¹] This useful complementary process occurs by inversion of configuration to give the trans-3,4-disubstituted lactones 5 as single diastereomers in most cases.
Scheme 20 Diastereochemical control on the hydroxy ester intermediate of the aldehyde allylboration/lactonization strategy
Mechanistic considerations of the new Lewis acid catalyzed allylboration conditions are worth discussing in this review. At the outset, the fact that the additions of crotylboronates are stereospecific provided us with a strong indication that the catalytic allylboration was probably still proceeding through the usual chair-like transition state characteristic of type I allylation reagents. Further confirmation of this mechanism was obtained by the measurement of rate orders, [³²] which confirmed the bimolecularity of the process with respect to the two substrates involved; that is, a rate equation proportional to K[allyl boronate] [¹] [aldehyde] [¹] . This important result left two possibilities for the site of coordination of the Lewis acid: aldehyde double coordination (A) or coordination to a boronate oxygen (B) (Figure [²] ).
Figure 2 Possible mechanisms of activation by the Lewis acid
This intriguing question was addressed by comparing the effect of scandium(III) triflate on the 3,3-dimethylallyl boronate 28 and its borabicyclononane analogue 29 (Scheme [²¹] ). Whereas the boronate 28 is accelerated over 100 fold, the Lewis acid had no effect on the dialkylborane 29: neither rate acceleration nor any decomposition. [³²] Other control experiments ruled out the possibility of transmetallation of the allyl boronate, as well as catalysis by adventitious triflic acid.
Scheme 21 Control experiments to elucidate the mode of activation of the Lewis acid catalyzed allylboration
Altogether, these experiments are consistent with a mechanism of catalysis based on electrophilic activation of the boron atom through coordination of one of the boronate oxygens. This mechanism of activation is in accord with an experimental study by Brown and co-workers, who concluded that the ”reactivity of boron-based allylation reagents can be rationalized in terms of the relative availability of lone pairs of electrons on the oxygen atoms attached to the boron". [³³] Furthermore, this mechanism has recently been validated using density functional theory calculations, where coordination of the least hindered pseudo-equatorial boronate oxygen was found to be more favorable than coordination to the carbonyl of the aldehyde. [³4]
2.3 Brønsted Acid Catalyzed Additions of 2-(Alkoxycarbonyl)allyl Boronates
Shortly after initiating an investigation on the scope of substrates, we quickly found limits to the new Lewis acid catalyzed conditions. As shown with boronate 24e, one of the problems was in the form of electron-rich aromatic aldehydes such as anisaldehyde (Scheme [²²] ), and hindered aldehydes such as cyclohexane carboxaldehyde, which provided low yields with scandium(III) triflate at room temperature. [²6] To solve this new hurdle, strong protic acids were attempted as catalysts despite our huge apprehension that the allylic boronates would undergo protodeboronation or cationic oligomerization. In a model reaction between allyl boronate 24f and benzaldehyde catalyzed by triflic acid, however, we realized that a near-quantitative yield of the lactone product 5h could be obtained at 0 ˚C (Scheme [²³] ), a temperature at which scandium(III) triflate was essentially useless (<5% yield). [³5] Moreover, this result came with an added bonus: the open hydroxy ester intermediates lactonized spontaneously in the presence of triflic acid so that there was no longer a need to treat the crude reaction mixtures with toluenesulfonic acid to induce cyclization. This made the whole triflic acid catalyzed procedure even more convenient than anticipated at the outset.
Scheme 22 Example of a difficult substrate in the scandium(III)-catalyzed allylborations
Scheme 23 Comparison of triflic acid catalyzed and scandium(III)-catalyzed allylborations
The use of electron-rich aldehydes was motivated by our plan to synthesize the eupomatilones (e.g., 30, Figure [³] ), a new class of lignans isolated from the Australian shrub eupomati bennetii. [³6]
Figure 3 Eupomatilone-6 (30) and its three possible diastereomers
Due to the difficulty of interpreting coupling constants in five-membered-ring systems, the original assignment of the relative stereochemistry of the eupomatilones was ambiguous, and engendered confusion in subsequent synthetic efforts. [³7] To help address this issue, we first targeted the postulated structure of eupomatilone-6 using a triflic acid catalyzed allylboration with reagent 24d (Scheme [²4] ). [³5] Thus, when attempted with the hindered and electron-rich aldehyde 31, the addition worked very well but it provided the opposite diastereomer to that expected from the putative six-membered chair-like transition structure. The trans-configured lactone 5i was isolated instead of the expected cis diastereomer 5j. A thorough study of scope and mechanism confirmed our suspicions that this inversion of stereochemistry is due to the formation of a transient carbocation. When the aldehyde substituent is an electron-rich group with the ability to stabilize a positive charge in the aldol borate intermediate 25, bond rotation can occur to relieve the steric interaction between the aldehyde substituent and the substituent originally in the 3-position on the allyl boronate (Scheme [²5] ). Lactonization subsequently occurs and provides the trans lactone isomer. [³8]
Scheme 24 Unexpected stereochemical course in the triflic acid catalyzed allylboration between reagent 24d and aldehyde 31
Scheme 25 Rationale for observed stereochemistry when aldehyde contains an electron-withdrawing group (EWG) or electron-donating group (EDG)
Nonetheless, this serendipitous result of Scheme [²4] was most welcome because it complements the thermal reaction between 24d and 31, which does provide the expected syn diastereomer 5j. In the end, a single allyl boronate, 24d, led to a stereodivergent preparation of all four diastereomers of eupomatilone-6 (cf. Figure [³] ). A total of five X-ray crystallographic structures of the final diastereomers and intermediates unambiguously confirmed the relative stereochemistry of the natural eupomatilones. [³5]
2.4 Preparation of Libraries of α-Exo-Methylene γ-Lactones and Their Functionalization into α-Exo-Alkylidene Lactones
Due to the biological properties of many of these α-exo-methylene γ-lactones and the desire to understand their structure-activity relationship with various biological targets, convenient and efficient syntheses of libraries of these γ-lactones are essential. Libraries of γ-lactones 5 containing various substitutents at the β- and γ-positions have been made by (a) a two-step Baylis-Hillman and carbonyl allylation protocol, purified by fluorous-phase-extraction techniques [³9] (Scheme [²6] ) and (b) an allylboration and lactonization reaction, purified by HPLC. [40]
Scheme 26 Fluorous-phase synthesis of substituted α-exo-methylene γ-lactones
Since many of the natural products containing the γ-lactone moiety are further functionalized, various routes to further functionalize γ-lactones were investigated, and these results led to the formation of α-exo-alkylidene and α-alkylated γ-lactones. [40] When looking at the structure of the α-exo-methylene γ-lactones, it was obvious to us that the most suitable modification would be to further modify the exo-methylene group. Moreover, substrates containing a less electrophilic α-exo-methylene γ-lactone moiety might help to mitigate the promiscuous reactivity of these compounds in biological systems and allow for more selective targeting. Alkenes can be modified through many different types of reactions. Heck coupling reactions, conjugate additions, cross-metathesis, Morita-Baylis-Hillman reactions, cycloadditions and various other oxidation or reduction reactions are just a few of the possibilities that are available to functionalize this methylene group. [4¹] Reports have been published wherein cross-metathesis has been utilized to functionalize the exo-methylene unit of the unsubstituted γ-lactone. [4²] However, in the case of γ-lactones containing further functionality, cross-metathesis was too unreliable for efficient library synthesis. [40] As such, the method of choice to further functionalize this methylene unit turned out to be the Heck reaction. Indeed, there is a vast amount of literature available that makes use of Heck or Heck-type reactions to couple alkenes to aryl or alkyl halides or pseudo-halides. [4³] The coupling of α,β-unsaturated enoates (present in these γ-lactones) to aryl halides, however, is much less investigated. Moreover, alkenes that are gem-disubstituted are somewhat problematic in Heck reactions due to steric hindrance and competing β-hydrogen eliminations. [44] After screening of various conditions for the Heck reaction, suitable conditions were found that successfully converted the exo-methylene unit of the γ-lactones 5 into an α-alkylidene unit in analogues 6. [40] A library of 20 different α-alkylidene γ-lactones was created using four different starting γ-lactones and five different aryl iodides (Scheme [²7] ). Functionalization of these α-methylene units into α-alkylidene units might help to tune the reactivity of these compounds and, in such a way, provide more selective drug candidates for the treatment of various diseases.
Scheme 27 Library of α-exo-alkylidene γ-lactones 6
3 Additions of Other 2-(Alkoxycarbonyl)allylmetal Reagents
The two other traditional semi-metals used in carbonyl allylation chemistry are silicon and tin. [¹] Only a few examples of 2-(alkoxycarbonyl)allylic trialkyl tin and silicon reagents have been reported (Scheme [²8] ). These reagents are unsubstituted at the 3-position, which reflects the relatively difficult synthetic access to geometrically defined reagents of this sort. Tin-based reagent 32 adds to aldehydes at low temperatures (e.g., -78 ˚C) but requires a super-stoichiometric amount of strong Lewis acids (Scheme [²8] , equation 1). [45] Tanaka and co-workers made 2-carboxamido derivatives 33 that requires a separate step for lactonization (Scheme [²8] , equation 2). [46] Using chiral α-substituted amines as the amide precursor, enantioselectivities up to 80% ee can be obtained. Masuyama and co-workers developed an indirect, in situ method to prepare allylic tin reagents from the corresponding allylic carbonates 34 (Scheme [²8] , equation 3). [47] Under palladium catalysis in the presence of stoichiometric tin(II) chloride, the allylic palladium complex presumably transmetallates to the tin reagents, which add onto aldehydes to give the desired lactones in modest yields. Reactions with 3-substituted reagents, however, are highly diastereoselective using these conditions. Not suprisingly, the analogous silicon reagents such as 35 are much less reactive and require a higher reaction temperature (Scheme [²8] , equation 4). [48] Even under these conditions, reactions with aldehydes provide low yields.
Scheme 28 Additions of 2-(alkoxycarbonyl)allylic stannanes and silanes onto aldehydes
Sidduri and Knochel generated a mixed zinc-copper reagent 36 that also led to a one-pot preparation of α-exo-methylene γ-lactones 5 (Scheme [²9] ). [49] In this case, no additional step is necessary for the lactonization. The desired allylation reagents are formed with high selectivity in the cis-carbocupration, and the diastereoselectivity of aldehyde additions is high, which hints to a chair-like transition state (37) similar to allylboration reactions.
Scheme 29 Preparation of mixed zinc-copper 2-(alkoxycarbonyl)allylmetal reagents 36 and their addition to aldehydes
4 Barbier-Type Additions with 2-(Alkoxycarbonyl)allyl Halides
Barbier-type additions are attractive methods because the required allylic halide precursors are often commercially available, and more stable than a pre-formed organometallic reagent (Scheme [³0] ). Zinc reagents can be prepared in this way from allylic bromides, [50] using zinc powder (Scheme [³0] , equations 1 and 2). [5¹] [5²] The cyclization occurs under the reaction conditions but mixtures of diastereomeric lactone products 5 tend to be isolated with 3-substituted reagents such as 38. More recently, a sonochemical procedure was reported (Scheme [³0] , equation 3), [5³] giving the desired lactone directly when tetrahydrofuran is employed as solvent. With N,N-dimethylformamide, the reaction affords the alcohol intermediate as product. Zinc-promoted Barbier-type allylations are mild enough for use on functionalized substrates. For example, Yang and co-workers have made use of a zinc-mediated Barbier reaction with either aldehydes or methyl ketones to form α-exo-methylene γ-lactones 39 containing novel indole substituents that were tested as inhibitors of kinase enzymes (Scheme [³0] , equation 4). [54]
Scheme 30 Barbier-type additions with zinc metal
Indium is an attractive metal in Barbier-type additions because it is compatible under aqueous conditions and the reactions occur at room temperature. Unlike zinc, however, the lactonization step is not spontaneous and requires an additional acid-catalyzed operation (Schemes [³¹] and [³²] ). The application of indium-promoted allylations with a simple 2-(alkoxycarbonyl)allyl reagent was first reported by Yus and co-workers (Scheme [³¹] ). [55] The group of Paquette and co-workers applied the same process with 3-substituted allylic bromide reagents 40 to access bicyclic α-exo-methylene γ-lactone products 42 via ring-closing metathesis on dienes 41 (Scheme [³²] ). [56] To this end, both the allylic bromide reagent and the aldehyde contain pendent alkenes. Unfortunately, the diastereoselectivity of the aldehyde additions is low.
Scheme 31 Barbier-type additions with indium metal
Scheme 32 Barbier-type additions with indium metal and 40 followed by ring-closing metathesis to give bicyclic lactones 42
A variety of other Barbier-type processes have been applied to the preparation of α-exo-methylene γ-lactones (Schemes [³³] - [³5] ). [57] [58] One example using metallic tin provided a trans-configured lactone product 5k showing antiproliferative properties (Scheme [³³] ). [59] Fürstner and Shi employed catalytic chromium and manganese as co-reductant in one example of a Nozaki-Hiyama-Kishi reaction providing a α-exo-methylene γ-lactone product 5l with methyl 2-(bromomethyl)acrylate (Scheme [³4] ). [60] The silane additive is required to help cleave the chromium-oxygen bond in the intermediate, and the resulting hydroxy ester product was lactonized in a separate acid-catalyzed step. Recently, Roy and co-workers developed a titanocene-promoted radical-induced process that produces the desired lactones 5 after acid-promoted cyclization (Scheme [³5] ). [6¹] Most examples described in this report employ aromatic aldehydes.
Scheme 33 Barbier-type addition with tin
Scheme 34 Barbier-type addition with chromium
Scheme 35 Barbier-type addition with titanium
5 Other Direct Methods
Cyclic phosphonates 4 can be employed in Horner-Emmons-Wadsworth olefinations with aldehydes to provide α-exo-alkylidene γ-lactones, usually with good E/Z selectivity (Scheme [³6] ). [6²] This method is very useful for the preparation of natural and unnatural γ-lactones that are unsubstituted in the ring (i.e., β- and γ-carbons). [6³] Because preparation of the reagent requires several steps (e.g., Scheme [²] ), more complex lactones are less readily accessible using this approach.
Scheme 36 Horner-Emmons-Wadsworth olefination approach to the preparation of α-exo-alkylidene γ-lactones
Gagnier and Larock described an efficient and direct heteroannulation method utilizing α-halo alkenoic acids 43 and substituted butadienes (Scheme [³7] ). [64] Under palladium catalysis in the presence of a bulky phosphine, (di-tert-butylphosphino)ferrocene, a cascade process leads to α-exo-alkylidene γ-lactones 6 in moderate to high yields.
Scheme 37 Transition-metal-catalyzed direct approach to α-exo-alkylidene γ-lactones
In a similar fashion, Zhang and co-workers have made use of a rhodium-catalyzed cycloisomerization protocol utilizing tethered 1,6-enynes 44 as an efficient route to γ-lactones 45 containing a β-vinyl group and various substituents on the exo-alkene as shown in Scheme [³8] . [65] In the presence of a rhodium catalyst, oxidative cyclization of the 1,6-enyne occurs to form a metallocyclopentane intermediate. Subsequent β-halide elimination forms the vinyl substituent of the final product and this is followed by reductive elimination to generate the vinyl chloride. Various alkyl and aryl substituents are tolerated on the end of the alkyne; however, bulky groups on the alkyne, or substrates with another carbonyl group in conjugation with the alkyne, are not tolerated.
Scheme 38 Cycloisomerization reaction of 1,6-enynes to form α-exo-halomethylene γ-lactones
Zhang and co-workers have also made use of similar substrates with allylic alcohols instead of allylic chlorides and subjected them to an intramolecular rhodium-catalyzed Alder-ene reaction and thereby accessed γ-lactones containing an aldehyde substituent in the β-position. [66]
6 Conclusion
Most direct methods to access α-exo-methylene and α-exo-alkylidene γ-lactones employ 2-(alkoxycarbonyl)allylic metal reagents, either as pre-formed reagents or generated in situ via Barbier-type processes. The aldehyde addition products of these various reagents produce hydroxy ester intermediates, which, in several cases, cyclize under the reaction conditions to afford the desired lactone products. Of all the classes of reagents described in this review, 2-(alkoxycarbonyl)allyl boronates stand out for their generality and their versatility. Indeed, additions with these stable reagents can be performed under thermal, Lewis acid catalyzed, or protic acid catalyzed conditions. Also, the mildness of these reaction conditions cannot be overlooked as they allow for sensitive aldehyde substrates to be used. Libraries of γ-lactones have been synthesized and are of interest for biological screening against various targets. Further modification of the α-exo-methylene γ-lactone unit is important for biological reasons and has been investigated, as exemplified by the conversion of α-exo-methylene γ-lactones into α-exo-alkylidene γ-lactones. Direct methods involving metal-catalyzed annulations or cycloisomerizations are also efficient at accessing substituted α-exo-methylene γ-lactones. These methods allow for differing substitution patterns in the final lactone products and provide convenient handles upon which further functionalizations can be carried out. Although direct approaches to the preparation of the desired γ-lactones are convenient, one current issue is the lack of methods to promote enantioselectivity. In this regard, indirect methods tend to be more amenable to the preparation of enantioenriched γ-lactones. Therefore, future applications of 2-(alkoxycarbonyl)allyl boronates and other allylmetal reagents should focus on the development of catalytic enantioselective methodologies.
Acknowledgment
We are grateful to the Natural Science and Engineering Research Council of Canada, for continuous financial support that has allowed us to contribute to this research area.
- 1
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Janecki T.Blaszczyk E.Studzian K.Janecka A.Krajewska U.Rózalski M. J. Med. Chem. 2005, 48: 3216 - 3b
Rózalski M.Krajewska U.Panczyk M.Mirowski M.Rózalska B.Wasek T.Janecki T. Eur. J. Med. Chem. 2007, 42: 248 - 3c
Albrecht A.Koszuk JF.Modranka J.Rózalski M.Krajewska U.Janecka A.Studzian K.Janecki T. Bioorg. Med. Chem. 2008, 16: 4872 - 4
Zhangabylov NS.Dederer LY.Gorbacheva LB.Vasil’eva SV.Terekhov AS.Adekenov SM. Pharm. Chem. J. 2004, 38: 651 - 5
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Biel M.Kretsovali A.Karatzali E.Papamatheakis J.Giannis A. Angew. Chem. Int. Ed. 2004, 43: 3974 - 8b
Hughes MA.McFadden JM.Townsend CA. Bioorg. Med. Chem. Lett. 2005, 15: 3857 - 9
Nishiyama H.Yokoyama H.Narimatsu S.Itoh K. Tetrahedron Lett. 1982, 23: 1267 - 10
Ramachandran PV.Garner G.Pratihar D. Org. Lett. 2007, 9: 4753 - 11
Rauniyar V.Hall DG. J. Org. Chem. 2009, 74: 4236 - 12
Semmelhack MF.Brickner SJ. J. Org. Chem. 1981, 46: 1723 - 13a
Denmark SE.Almstead NG. In Modern Carbonyl ChemistryOtera J. Wiley-VCH; Weinheim: 2000. Chap 10. p.299-402 - 13b
Chemler SR.Roush WR. In Modern Carbonyl ChemistryOtera J. Wiley-VCH; Weinheim: 2000. Chap 11. p.403-490 - 14
Denmark SE.Fu J. Chem. Rev. 2003, 103: 2763 - 15a
Kennedy JWJ.Hall DG. In Boronic AcidsHall DG. Wiley-VCH; Weinheim: 2005. Chap 6. p.241-277 - 15b
Lachance H.Hall DG. Org. React. (New York) 2008, 73: 1-573 - 16
Denmark SE.Weber EJ. Helv. Chim. Acta 1983, 66: 1655 - 17a
Hoffmann RW.Zeiss H.-J. Angew. Chem., Int. Ed. Engl. 1979, 18: 306 - 17b
Hoffmann RW.Zeiss H.-J. J. Org. Chem. 1981, 46: 1309 - 18
Nyzam V.Belaud C.Villiéras J. Tetrahedron Lett. 1993, 34: 6899 - 19
Chataigner I.Zammattio F.Lebreton J.Villiéras J. Tetrahedron 2008, 64: 2441 - 20
Kennedy JWJ.Hall DG. J. Am. Chem. Soc. 2002, 124: 898 - 21
Zhu N.Hall DG. J. Org. Chem. 2003, 68: 6066 - 22
Ramachandran PV.Pratihar D.Biswas D.Srivastava A.Reddy MVR. Org. Lett. 2004, 6: 481 - 23
Kabalka GW.Venkataiah B.Dong G. J. Org. Chem. 2004, 69: 5807 - 24
Kennedy JWJ.Hall DG. J. Am. Chem. Soc. 2002, 124: 11586 - 25
Ishiyama T.Ahiko T.-a.Miyaura N. J. Am. Chem. Soc. 2002, 124: 12414 - 26
Kennedy JWJ.Hall DG. J. Org. Chem. 2004, 69: 4412 - 27
Kabalka GW.Venkataiah B.Dong G. Tetrahedron Lett. 2005, 46: 4209 - 28
Kabalka GW.Venkataiah B. Tetrahedron Lett. 2005, 46: 7325 - 29
Ramachandran PV.Pratihar D.Biswas D. Org. Lett. 2006, 8: 3877 - 30
Ramachandran PV.Pratihar D. Org. Lett. 2007, 9: 2087 - 31
Kabalka GW.Venkataiah B.Chen C. Tetrahedron Lett. 2006, 47: 4187 - 32
Rauniyar V.Hall DG. J. Am. Chem. Soc. 2004, 126: 4518 - 33
Brown HC.Racherla US.Pellechia PJ. J. Org. Chem. 1990, 55: 1868 - 34
Sakata K.Fujimoto H. J. Am. Chem. Soc. 2008, 130: 12519 - 35
Yu S.-H.Ferguson MJ.McDonald R.Hall DG. J. Am. Chem. Soc. 2005, 127: 12808 - 36a
Carroll AR.Taylor WC. Aust. J. Chem. 1991, 44: 1615 - 36b
Carroll AR.Taylor WC. Aust. J. Chem. 1991, 44: 1705 - 37a
Hong S.-p.McIntosh MC. Org. Lett. 2002, 4: 19 - 37b
Hutchison JM.Hong S.-p.McIntosh MC. J. Org. Chem. 2004, 69: 4185 - 37c
Gurjar MK.Cherian J.Ramana CV. Org. Lett. 2004, 6: 317 - 37d
Coleman RS.Gurrala SR. Org. Lett. 2004, 6: 4025 - 38
Elford TG.Yu SH.Arimura Y.Hall DG. J. Org. Chem. 2007, 72: 1276 - 39
Le Lamer A.-C.Gouault N.David M.Boustie J.Uriac P. J. Comb. Chem. 2006, 8: 643 - 40
Elford TG.Ulaczyk-Lesanko A.De Pascale G.Wright GD.Hall DG. J. Comb. Chem. 2009, 11: 155 - For example, see:
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Heck RF.Nolley JP. J. Org. Chem. 1972, 37: 2320 - 41b
Perlmutter P. Conjugate Addition Reactions in Organic Synthesis, Tetrahedron Organic Chemistry Series 9 Pergamon; Oxford: 1992. - 41c
Gibson SE.Keen SP. In Alkene Metathesis in Organic SynthesisFurstner A. Springer; Berlin/Heidelberg: 1999. - 41d
Mortia K.Suzuki Z.Hirose H. Bull. Chem. Soc. Jpn. 1968, 41: 2815 - 42a
Raju R.Allen LJ.Le T.Taylor CD.Howell AR. Org. Lett. 2007, 9: 1699 - 42b
Moise J.Arseniyadis S.Cossy J. Org. Lett. 2007, 9: 1695 - For reviews see:
- 43a
Heck RF. Acc. Chem. Res. 1979, 12: 146 - 43b
Crisp GT. Chem. Soc. Rev. 1998, 27: 427 - 43c
Beletskaya IP.Cheprakov AV. Chem. Rev. 2000, 100: 3009 - 43d
Whitcombe NJ.Hii KK.Gibson SE. Tetrahedron 2001, 57: 7449 - 43e
van der Boom ME.Milstein D. Chem. Rev. 2003, 103: 1759 - 43f
Dounay AB.Overman LE. Chem. Rev. 2003, 103: 2945 - 44
Du X.Suguro M.Hirabayashi K.Mori A. Org. Lett. 2001, 3: 3313 - 45
Baldwin JE.Adlington RM.Sweeney JB. Tetrahedron Lett. 1986, 27: 5423 - 46
Tanaka K.Yoda H.Isobe Y.Kaji A. J. Org. Chem. 1986, 51: 1856 - 47
Masuyama Y.Nimura Y.Kurusu Y. Tetrahedron Lett. 1991, 32: 225 - 48
Hosomi A.Hashimoto H.Sakurai H. Tetrahedron Lett. 1980, 21: 951 - 49
Sidduri AR.Knochel P. J. Am. Chem. Soc. 1992, 114: 7579 - 50
Öhler E.Reininger K.Schmidt U. Angew. Chem. Int. Ed. 1970, 6: 457 - 51
Lambert F.Kirschleger B.Villiéras J. J. Organomet. Chem. 1991, 406: 71 - 52
Mattes H.Benezra C. Tetrahedron Lett. 1985, 26: 5697 - 53
Lee AS.-Y.Chang Y.-T.Wang S.-H.Chu S.-F. Tetrahedron Lett. 2002, 43: 8489 - 54
Ding H.Zhang C.Wu X.Yang C.Zhang X.Ding J.Xie Y. Bioorg. Med. Chem. Lett. 2005, 15: 4799 - 55
Choudhury PK.Foubelo F.Yus M. Tetrahedron Lett. 1998, 39: 3581 - 56
Paquette LA.Méndez-Andino J. Tetrahedron Lett. 1999, 40: 4301 - 57
Nokami J.Tamaoka T.Ogawa H.Wakabayashi S. Chem. Lett. 1986, 541 - 58
Okuda Y.Nakatsukasa S.Oshima K.Nozaki H. Chem. Lett. 1985, 481 - 59
González AG.Hernández Silva M.Padrón JI.León F.Reyes E.Álvarez-Mon M.Pivel JP.Quintana J.Estévez F.Bermejo J. J. Med. Chem. 2002, 45: 2358 - 60
Fürstner A.Shi N. J. Am. Chem. Soc. 1996, 118: 2533 - 61
Paira M.Banerjee B.Jana S.Mandal SK.Roy SC. Tetrahedron Lett. 2007, 48: 3205 - 62
Lee K.Jackson JJ.Wiemer DF. J. Org. Chem. 1993, 58: 5967 - 63
Trost BM.Corte JR.Gudiksen MS. Angew. Chem. Int. Ed. 1999, 38: 3662 - 64
Gagnier SV.Larock RC. J. Org. Chem. 2000, 65: 1525 - 65
Yong X.Li D.Zhang Z.Zhang X. J. Am. Chem. Soc. 2004, 126: 7601 - 66
Lei A.He M.Zhang X. J. Am. Chem. Soc. 2002, 124: 8198
References
- 1
Hoffmann HMR.Rabe J. Angew. Chem., Int. Ed. Engl. 1985, 24: 94 - 2
Konaklieva MI.Plotkin BJ. Mini Rev. Med. Chem. 2005, 5: 73 - 3a
Janecki T.Blaszczyk E.Studzian K.Janecka A.Krajewska U.Rózalski M. J. Med. Chem. 2005, 48: 3216 - 3b
Rózalski M.Krajewska U.Panczyk M.Mirowski M.Rózalska B.Wasek T.Janecki T. Eur. J. Med. Chem. 2007, 42: 248 - 3c
Albrecht A.Koszuk JF.Modranka J.Rózalski M.Krajewska U.Janecka A.Studzian K.Janecki T. Bioorg. Med. Chem. 2008, 16: 4872 - 4
Zhangabylov NS.Dederer LY.Gorbacheva LB.Vasil’eva SV.Terekhov AS.Adekenov SM. Pharm. Chem. J. 2004, 38: 651 - 5
Bernardi A.Beretta MG.Colombo L.Gennari C.Poli G.Scolastico C. J. Org. Chem. 1985, 50: 4442 - 6
Edwards MG.Kenworthy MN.Kitson RRA.Scott MS.Taylor RJK. Angew. Chem. Int. Ed. 2008, 47: 1935 - 7a
Haaima G.Weavers RT. Tetrahedron Lett. 1988, 29: 1085 - 7b
Haaima G.Lynch M.-J.Routledge A.Weavers RT. Tetrahedron 1991, 47: 5203 - 8a
Biel M.Kretsovali A.Karatzali E.Papamatheakis J.Giannis A. Angew. Chem. Int. Ed. 2004, 43: 3974 - 8b
Hughes MA.McFadden JM.Townsend CA. Bioorg. Med. Chem. Lett. 2005, 15: 3857 - 9
Nishiyama H.Yokoyama H.Narimatsu S.Itoh K. Tetrahedron Lett. 1982, 23: 1267 - 10
Ramachandran PV.Garner G.Pratihar D. Org. Lett. 2007, 9: 4753 - 11
Rauniyar V.Hall DG. J. Org. Chem. 2009, 74: 4236 - 12
Semmelhack MF.Brickner SJ. J. Org. Chem. 1981, 46: 1723 - 13a
Denmark SE.Almstead NG. In Modern Carbonyl ChemistryOtera J. Wiley-VCH; Weinheim: 2000. Chap 10. p.299-402 - 13b
Chemler SR.Roush WR. In Modern Carbonyl ChemistryOtera J. Wiley-VCH; Weinheim: 2000. Chap 11. p.403-490 - 14
Denmark SE.Fu J. Chem. Rev. 2003, 103: 2763 - 15a
Kennedy JWJ.Hall DG. In Boronic AcidsHall DG. Wiley-VCH; Weinheim: 2005. Chap 6. p.241-277 - 15b
Lachance H.Hall DG. Org. React. (New York) 2008, 73: 1-573 - 16
Denmark SE.Weber EJ. Helv. Chim. Acta 1983, 66: 1655 - 17a
Hoffmann RW.Zeiss H.-J. Angew. Chem., Int. Ed. Engl. 1979, 18: 306 - 17b
Hoffmann RW.Zeiss H.-J. J. Org. Chem. 1981, 46: 1309 - 18
Nyzam V.Belaud C.Villiéras J. Tetrahedron Lett. 1993, 34: 6899 - 19
Chataigner I.Zammattio F.Lebreton J.Villiéras J. Tetrahedron 2008, 64: 2441 - 20
Kennedy JWJ.Hall DG. J. Am. Chem. Soc. 2002, 124: 898 - 21
Zhu N.Hall DG. J. Org. Chem. 2003, 68: 6066 - 22
Ramachandran PV.Pratihar D.Biswas D.Srivastava A.Reddy MVR. Org. Lett. 2004, 6: 481 - 23
Kabalka GW.Venkataiah B.Dong G. J. Org. Chem. 2004, 69: 5807 - 24
Kennedy JWJ.Hall DG. J. Am. Chem. Soc. 2002, 124: 11586 - 25
Ishiyama T.Ahiko T.-a.Miyaura N. J. Am. Chem. Soc. 2002, 124: 12414 - 26
Kennedy JWJ.Hall DG. J. Org. Chem. 2004, 69: 4412 - 27
Kabalka GW.Venkataiah B.Dong G. Tetrahedron Lett. 2005, 46: 4209 - 28
Kabalka GW.Venkataiah B. Tetrahedron Lett. 2005, 46: 7325 - 29
Ramachandran PV.Pratihar D.Biswas D. Org. Lett. 2006, 8: 3877 - 30
Ramachandran PV.Pratihar D. Org. Lett. 2007, 9: 2087 - 31
Kabalka GW.Venkataiah B.Chen C. Tetrahedron Lett. 2006, 47: 4187 - 32
Rauniyar V.Hall DG. J. Am. Chem. Soc. 2004, 126: 4518 - 33
Brown HC.Racherla US.Pellechia PJ. J. Org. Chem. 1990, 55: 1868 - 34
Sakata K.Fujimoto H. J. Am. Chem. Soc. 2008, 130: 12519 - 35
Yu S.-H.Ferguson MJ.McDonald R.Hall DG. J. Am. Chem. Soc. 2005, 127: 12808 - 36a
Carroll AR.Taylor WC. Aust. J. Chem. 1991, 44: 1615 - 36b
Carroll AR.Taylor WC. Aust. J. Chem. 1991, 44: 1705 - 37a
Hong S.-p.McIntosh MC. Org. Lett. 2002, 4: 19 - 37b
Hutchison JM.Hong S.-p.McIntosh MC. J. Org. Chem. 2004, 69: 4185 - 37c
Gurjar MK.Cherian J.Ramana CV. Org. Lett. 2004, 6: 317 - 37d
Coleman RS.Gurrala SR. Org. Lett. 2004, 6: 4025 - 38
Elford TG.Yu SH.Arimura Y.Hall DG. J. Org. Chem. 2007, 72: 1276 - 39
Le Lamer A.-C.Gouault N.David M.Boustie J.Uriac P. J. Comb. Chem. 2006, 8: 643 - 40
Elford TG.Ulaczyk-Lesanko A.De Pascale G.Wright GD.Hall DG. J. Comb. Chem. 2009, 11: 155 - For example, see:
- 41a
Heck RF.Nolley JP. J. Org. Chem. 1972, 37: 2320 - 41b
Perlmutter P. Conjugate Addition Reactions in Organic Synthesis, Tetrahedron Organic Chemistry Series 9 Pergamon; Oxford: 1992. - 41c
Gibson SE.Keen SP. In Alkene Metathesis in Organic SynthesisFurstner A. Springer; Berlin/Heidelberg: 1999. - 41d
Mortia K.Suzuki Z.Hirose H. Bull. Chem. Soc. Jpn. 1968, 41: 2815 - 42a
Raju R.Allen LJ.Le T.Taylor CD.Howell AR. Org. Lett. 2007, 9: 1699 - 42b
Moise J.Arseniyadis S.Cossy J. Org. Lett. 2007, 9: 1695 - For reviews see:
- 43a
Heck RF. Acc. Chem. Res. 1979, 12: 146 - 43b
Crisp GT. Chem. Soc. Rev. 1998, 27: 427 - 43c
Beletskaya IP.Cheprakov AV. Chem. Rev. 2000, 100: 3009 - 43d
Whitcombe NJ.Hii KK.Gibson SE. Tetrahedron 2001, 57: 7449 - 43e
van der Boom ME.Milstein D. Chem. Rev. 2003, 103: 1759 - 43f
Dounay AB.Overman LE. Chem. Rev. 2003, 103: 2945 - 44
Du X.Suguro M.Hirabayashi K.Mori A. Org. Lett. 2001, 3: 3313 - 45
Baldwin JE.Adlington RM.Sweeney JB. Tetrahedron Lett. 1986, 27: 5423 - 46
Tanaka K.Yoda H.Isobe Y.Kaji A. J. Org. Chem. 1986, 51: 1856 - 47
Masuyama Y.Nimura Y.Kurusu Y. Tetrahedron Lett. 1991, 32: 225 - 48
Hosomi A.Hashimoto H.Sakurai H. Tetrahedron Lett. 1980, 21: 951 - 49
Sidduri AR.Knochel P. J. Am. Chem. Soc. 1992, 114: 7579 - 50
Öhler E.Reininger K.Schmidt U. Angew. Chem. Int. Ed. 1970, 6: 457 - 51
Lambert F.Kirschleger B.Villiéras J. J. Organomet. Chem. 1991, 406: 71 - 52
Mattes H.Benezra C. Tetrahedron Lett. 1985, 26: 5697 - 53
Lee AS.-Y.Chang Y.-T.Wang S.-H.Chu S.-F. Tetrahedron Lett. 2002, 43: 8489 - 54
Ding H.Zhang C.Wu X.Yang C.Zhang X.Ding J.Xie Y. Bioorg. Med. Chem. Lett. 2005, 15: 4799 - 55
Choudhury PK.Foubelo F.Yus M. Tetrahedron Lett. 1998, 39: 3581 - 56
Paquette LA.Méndez-Andino J. Tetrahedron Lett. 1999, 40: 4301 - 57
Nokami J.Tamaoka T.Ogawa H.Wakabayashi S. Chem. Lett. 1986, 541 - 58
Okuda Y.Nakatsukasa S.Oshima K.Nozaki H. Chem. Lett. 1985, 481 - 59
González AG.Hernández Silva M.Padrón JI.León F.Reyes E.Álvarez-Mon M.Pivel JP.Quintana J.Estévez F.Bermejo J. J. Med. Chem. 2002, 45: 2358 - 60
Fürstner A.Shi N. J. Am. Chem. Soc. 1996, 118: 2533 - 61
Paira M.Banerjee B.Jana S.Mandal SK.Roy SC. Tetrahedron Lett. 2007, 48: 3205 - 62
Lee K.Jackson JJ.Wiemer DF. J. Org. Chem. 1993, 58: 5967 - 63
Trost BM.Corte JR.Gudiksen MS. Angew. Chem. Int. Ed. 1999, 38: 3662 - 64
Gagnier SV.Larock RC. J. Org. Chem. 2000, 65: 1525 - 65
Yong X.Li D.Zhang Z.Zhang X. J. Am. Chem. Soc. 2004, 126: 7601 - 66
Lei A.He M.Zhang X. J. Am. Chem. Soc. 2002, 124: 8198
References
Figure 1 Selected natural products containing an α-exo-methylene γ-lactone ring
Scheme 1 A Claisen condensation-elimination approach to β-hydroxy α-exo-methylene γ-lactones
Scheme 2 General Horner-Emmons-Wadsworth olefination approach to α-exo-alkylidene γ-lactones 6
Scheme 3 General conjugate addition-HEW olefination approach to bicyclic α-exo-alkylidene γ-lactones 9
Scheme 4 Radical cyclization approach to bicyclic α-exo-alkylidene γ-lactones 12
Scheme 5 Claisen condensation approach to β-carboxy α-exo-methylene γ-lactones 15
Scheme 6 Preparation of α-exo-methylene γ-lactones 5 from allylic silanes
Scheme 7 Steoreodivergent approach to α-exo-alkylidene γ-lactones 6
Scheme 8 Preparation of α-exo-methylene γ-lactones 5 by the bromoallylboration of aldehydes followed by carbonylation
Scheme 9 General approach to α-exo-methylene γ-lactones 5 from the addition of allylic metal reagents to carbonyl compounds
Scheme 10 General approaches to substituted homoallylic alcohols from the addition of allylboron reagents to carbonyl compounds
Scheme 11 Mechanistic classification for allylic metal reagents of type I and II (type III not shown)
Scheme 12 Early approach to the preparation of 2-(alkoxycarbonyl)allyl boronates; pin = OC(Me)2C(Me)2O
Scheme 13 Approach to α-exo-methylene γ-lactones using tetrasubstituted 2-(alkoxycarbonyl)allyl boronates 24
Scheme 14 Hosomi-Miyaura borylation approach to trisubstituted 2-(alkoxycarbonyl)allyl boronates
Scheme 15 Comparison of thermal uncatalyzed and scandium(III)-catalyzed allylborations with reagent 24c and benzaldehyde as model substrates
Scheme 16 Example of hindered aliphatic aldehyde in the Lewis acid catalyzed additions of 2-(alkoxycarbonyl)allyl boronates
Scheme 17 Tandem borylation/boron trifluoride catalyzed allylboration by Kabalka and co-workers
Scheme 18 Stereochemical control in lactone formation using the Lewis acid catalyzed allylboration, by Ramachandran and co-workers
Scheme 19 Promotion of oxonia-Cope pathway prior to lactone formation using the Lewis acid catalyzed allylboration
Scheme 20 Diastereochemical control on the hydroxy ester intermediate of the aldehyde allylboration/lactonization strategy
Figure 2 Possible mechanisms of activation by the Lewis acid
Scheme 21 Control experiments to elucidate the mode of activation of the Lewis acid catalyzed allylboration
Scheme 22 Example of a difficult substrate in the scandium(III)-catalyzed allylborations
Scheme 23 Comparison of triflic acid catalyzed and scandium(III)-catalyzed allylborations
Figure 3 Eupomatilone-6 (30) and its three possible diastereomers
Scheme 24 Unexpected stereochemical course in the triflic acid catalyzed allylboration between reagent 24d and aldehyde 31
Scheme 25 Rationale for observed stereochemistry when aldehyde contains an electron-withdrawing group (EWG) or electron-donating group (EDG)
Scheme 26 Fluorous-phase synthesis of substituted α-exo-methylene γ-lactones
Scheme 27 Library of α-exo-alkylidene γ-lactones 6
Scheme 28 Additions of 2-(alkoxycarbonyl)allylic stannanes and silanes onto aldehydes
Scheme 29 Preparation of mixed zinc-copper 2-(alkoxycarbonyl)allylmetal reagents 36 and their addition to aldehydes
Scheme 30 Barbier-type additions with zinc metal
Scheme 31 Barbier-type additions with indium metal
Scheme 32 Barbier-type additions with indium metal and 40 followed by ring-closing metathesis to give bicyclic lactones 42
Scheme 33 Barbier-type addition with tin
Scheme 34 Barbier-type addition with chromium
Scheme 35 Barbier-type addition with titanium
Scheme 36 Horner-Emmons-Wadsworth olefination approach to the preparation of α-exo-alkylidene γ-lactones
Scheme 37 Transition-metal-catalyzed direct approach to α-exo-alkylidene γ-lactones
Scheme 38 Cycloisomerization reaction of 1,6-enynes to form α-exo-halomethylene γ-lactones