Boron Enolate Chemistry - ACS Symposium Series (ACS Publications)

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Chapter 4

Boron Enolate Chemistry

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Atsushi Abiko* Department of Biobased Materials Science, Graduate School of Science and Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan *E-mail: [email protected]; Telephone/Fax +81-(75)-724-7990

In 1976, Mukaiyama et al. published the first synthesis of di-n-butylboron trifluoromethanesulfonate (Bu2BOTf) and demonstrated that this Lewis acid is particularly suitable for the generation of boron enolates. In the presence of a sterically hindered amine base (typically i-Pr2EtN, Et3N or 2,6-lutidine) and Bu2BOTf, boron enolates are conveniently and regioselectively prepared from active methylene-carbonyl-containing compounds. The boron enolates were shown to be efficient intermediates for addition to carbonyls in cross-aldol reactions. The relative stereochemistry of the new chiral centers formed in the aldol product is a direct consequence of the enolate geometry, with Z-enolates affording the 2,3-syn aldol products and the E-enolates leading to the 2,3-anti isomers. The selectivity was extended to the development of the reagents for the enantioselective construction of two new chiral centers in an aldol addition, regardless of the chirality of the reaction components. The greatest contribution of the boron aldol methodologies to organic synthesis was most likely the realization of the concept of reagent control, using both auxiliary based internal and external chiral reagents. This modern methodology is now a powerful and practical tool for the highly enantioselective construction of complex organic molecules.

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Introduction: Historical Perspective In the early 1970s, Mukaiyama first described a boron enolate for the directed aldol reaction. The enolates were synthesized using various methods: by the addition reaction of thioborinate to ketene or methyl vinyl ketone (Scheme 1, Eqs 1, 2) (1), by the addition reaction of trialkylboranes to methyl vinyl ketone under a radical mechanism (Scheme 1, Eq 3), and by the reaction of trialkylboranes with α-diazoketones or α-diazoesters (Scheme 1, Eq 4) (2). The intermediate boron enolate was characterized by 1H NMR, and was shown to react with aldehydes to give β-hydroxy carbonyl compounds. With these procedures, studies on the reactivity of boron enolates were initiated. Then, a convenient and general method for boron enolate synthesis was developed by Mukaiyama (3–5). This important discovery led to the boron aldol reaction as a versatile tool in organic synthesis. Dialkylboron triflate, a new class of borylation reagents, was prepared from borane derivatives and trifluoromethanesulfonic acid. The triflates reacted smoothly with ketones in the presence of tertiary amines to give the corresponding boron enolates, which reacted with aldehydes to give aldol products (Scheme 1, Eq 5). Subsequently, extensive studies on the aldol reaction of boron enolates revealed its advantages of controlling the stereochemical course of the reactions in a diastereomerical and enantiomerical manner. The aldol reactions employing boron enolates have been exemplified as reliable, convenient tools in organic synthesis. In this chapter, the synthetic application of boron enolates focusing on the aldol reaction is overviewed. A number of review articles dealing with this subject are also available (6–12).

Stereochemistry of the Boron Aldol Reaction Following Mukaiyama’s publication, Masamune, Evans and Brown examined the possibility of using the boron aldol reaction to achieve the stereoselective formation of either the syn- or anti-aldol product from ethylketones (or propionates). For stereochemical control in the aldol reaction, boron enolates have distinct advantages over other metal enolates. 1. 2. 3.

In contrast to the complicated structure of the other metal enolate aggregates, boron enolates exist as a homogeneous species in solution. Compared to other metals, such as Li or Mg, the length of the B-O or B-C bond is shorter, thus forming a tight, well-organized transition state. The stereochemical properties of the enolate (E/Z) are more faithfully transferred to the products of the aldol reaction via a six-membered cyclic transition state.

Typically, the boron-mediated aldol reaction is considered to proceed through a Zimmermann-Traxler type cyclic transition state (Scheme 2). Thus, the shorter 124 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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bond length makes the transition state more compact. Furthermore, the two ligands (L) present on the boron atom facilitate chiral modification.

Scheme 1. Generation of boron enolates and the aldol reaction. 125 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 2. Stereochemical correlation of boron enolate and aldol products.

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Although the 6-membered chair conformation is usually adopted for the boron-mediated aldol reaction, a reversal of the sense of diastereofacial selectivity was generally observed for syn- and anti-selective asymmetric aldol reactions, irrespective of an internal or external reagent, such as Corey’s diazaborolidine reagents, Roush’s IPC reagent and chiral esters developed by Abiko and Masamune (vide infra). The density functional calculation suggested the contribution of boat structures to the reactions involving E- and unsubstituted boron enolates, while Z-boron enolates proceeded through the conventional chair conformation (13–17) (Figure 1).

Figure 1. Calculated transition state structures in the aldol reaction

The stereospecificity of the aldol reaction was demonstrated by Masamune with ethylketones and thiopropionates. E- or Z- enolate (18) was selectively prepared; E-ketone enolates were prepared by the reaction of diazoketones with trialkylborane, which were isomerized to the corresponding Z-enolates by the action of catalytic lithium phenoxide. The Z-enolates afforded the syn-aldol products with over 20:1 selectivity, whereas the E-isomers had a lower selectivity (anti:syn=3-4:1) (19) (Scheme 3, Eq 1). The complementary E- and Z-enolates of tert-butyl thiopropionate were prepared by the reaction of the ester with dicyclopentylboron triflate and diisopropylethylamine or by the addition reaction of thioborinate to methylketene, respectively (Scheme 3, Eqs 2, 3). The boron enolates derived from tert-butyl thiopropionate gave the corresponding aldol products with better selectivity (>20:1) for both Z- and E-enolates (20). The 9-BBN enolate of phenyl thiopropionate gave the syn-aldol product selectively (21) (Scheme 4).

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Scheme 3. Stereospecificiy of the aldol reaction: ethyl ketones, tert-butyl thiopropionate.

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Scheme 4. Aldol reaction of phenyl thiopropionate. To develop practical asymmetric reagents, a selective and convenient procedure for the synthesis of either Z- or E-enolate and the elucidation of the conditions of the isomerization of enolates (or the avoidance of isomerization) must be found. Although Mukaiyama’s protocol for the direct enolization seemed most convenient, the factors affecting the stereochemical outcome of the enolate formation were found to be complex. Intensive studies concluded that the stereoselective synthesis of E- and Z- enolates occurred from ketones, thioesters and carboxylic esters. For ketones, Z-enolates could be synthesized with high selectivity using a combination of small boron triflate (Bu2BOTf) and bulky tertiary amine (i-Pr2EtN) at a low temperature (16, 20, 22) (Scheme 5, Eq 1). E-enolate was synthesized using dialkylboron chloride with a sterically demanding ligand on boron (e.g., cHex) with a small amine base (Et3N) (23, 24) (Scheme 5, Eq 2). The reactivity of the parent carbonyl components and the selectivity of the enolate formation were rationalized as summarized in Scheme 6. The boron compounds (R2BOTf or R2BCl) are Lewis acids, and when the Lewis basicity of an amine is too strong, boron compounds form a tight amine-borane complex (Scheme 6, Eq 1). A tertiary amine is not sufficiently basic to deprotonate carbonyl compounds; enolization must proceed through the activation of carbonyl compounds by complexation with a Lewis acid (e.g., a boron compound) (Scheme 6, Eq 2, path b). The balance of Lewis acidity and Lewis basicity is critical for the success of enolate formation. Carboxylic esters, a carbonyl family with relatively less acidic α-protons, were claimed to be unreactive for enolization under the standard conditions (16, 24–26) (Scheme 6). Later, a reinvestigation by Abiko and Masamune corrected the misconception regarding the reactivity of the esters (27, 28). Treatment of benzyl propionate with certain pairs of dialkylboron triflates (1.3 equiv) and an amine (1.5 equiv) in dichloromethane at −78 °C for 2 h and then with isobutyraldehyde provided the corresponding aldol product in high yield. Both the size of the boron triflate and that of the amine were very important for successful aldol reactions, and the combination of a smaller boron triflate (Bu2BOTf) and a smaller amine (Et3N) led to failure of enolization of the ester (Scheme 7). 129 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 5. Selective generation of Z- or E-enolate from ethyl ketones.

Scheme 6. Enolate formation from ethyl ketone with a boron compound and an amine. 130 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 7. Enolate formation from carboxylic ester with a boron compound and an amine.

Scheme 8. Enolate formation with a boron compound and an amine showing the stereochemistry. Stereoselectivity of the enolate was explained based on the ground state conformation of the boron-carbonyl complex: Z-enolate formation from the extended conformation and E-enolate formation from the U-shaped conformation. Thus, the steric effect of the substituents R of the carbonyl compound and R1 of the boron reagent sensitively affect the stereochemistry of the resulting enolate (Scheme 8). 131 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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For carboxylic esters, the syn:anti selectivity was sensitively affected by the alcohol residue of the ester and the enolization reagents. A bulkier ester or a smaller amine produces more of the anti isomer (compare Table 1, entries 1, 2, 3; 4, 6, 9; 5, 7, 10, 12; 8, 11). The ratio was highly dependent on the enolization temperature. The lower the temperature, the more of the anti isomer produced (compare Table 1, entries 6, 7, 9; 10, 11, 12). The varying syn:anti ratios depending on the enolization temperature was shown due to the isomerization of the enolate. For benzyl propionate, enolization at 0, -78 and -90 °C gave the aldol products in the ratio of anti:syn = 10:90, 90:10 and >95:5, respectively (Table 2, entries 1, 2, 3). Enolization was conducted in two steps: first enolization at −90 °C for 1 h [providing the enolate with Z:E = 5:>95] and then standing at 0 °C for 2 h. The aldol reaction in the standard manner afforded the product with syn:anti = 90:10, which corresponds to the enolate with Z:E = 90:10 (Table 2, entry 4). Similar experiments using propiophenone did not show isomerization of the enolate (Table 2, entries 5-9). The difference in the isomerization is attributed to the contribution of the C-bound form in the enolate (vide infra).

Table 1. Enolate formation from carboxylic ester

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Table 2. Isomerization of boron enolate

Enol Borate Concerning the stereospecificity of the stereochemistry of the enolates and the resulting aldol products, enol borates were shown to behave differently (29). Z- and E-enol borates were synthesized by the specific reactions: Z-enolate was synthesized by the Grignard reaction of Z-butenyl magnesium bromide and a borate followed by oxidation using trimethylamine oxide (Scheme 9, Eq 1), and E-enolate was synthesized by hydroboration of 2-butyne followed by oxidation (Scheme 9, Eq 2). Both of the enol borates, irrespective of the stereochemistry, gave syn-aldol products preferentially (30) ( Scheme 9). Enol borates derived from phenyl thiopropionate behaved similarly. The Eor Z- enriched mixture of enol borates, which were prepared by the reaction of phenyl thiopropionate and chlorodioxaborolane at specific temperatures, produced the aldol products with aldehydes having similar syn:anti ratios favoring the synisomer (31–34) (Scheme 10).

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Scheme 9. Stereoselective synthesis and aldol reaction of Z-and E-enol borates.

Scheme 10. Aldol reaction of phenyl thiopropionate. 134 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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The results were rationally explained by the involvement of different transition states for the enolates: boat-TS for E-enolate and chair-TS for Z-enolate (35) (Scheme 11).

Scheme 11. Transition state model for the aldol reaction of phenyl thiopropionate.

Asymmetric Aldol Reaction The most important reaction in the enolate chemistry is the aldol reaction. From a synthesis perspective, asymmetric aldol reactions could be categorized into four types, depending on the chirality of the reaction components (Scheme 12).

Scheme 12. Asymmetric aldol reaction categories. 135 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Substrate Control When a chiral aldehyde is reacted with achiral enolates, the selectivity of the reaction is explained by the Felkin-Anh model or the Cram’s chelate model, depending on the substituents of the aldehyde (Scheme 13). In the Felkin-Anh model, the largest (L) or polar (X) α-substituent occupies the conformation perpendicular to the plane of the carbonyl group, and the nucleophile approaches from the least hindered trajectory (Scheme 13, Eq 1). Typically, substrate-controlled reactions do not show significant selectivity, except for some special cases. Alpha substituents with lone pairs can coordinate metal ions together with carbonyl lone pairs (Scheme 13, Eq 2). The chelation ring becomes the dominant factor in determining the conformation and gives very high selectivity for nucleophilic attack.

Scheme 13. Models for carbonyl conformations and diastereoselective nucleophilic attack.

Double Stereodifferentiation When both reaction components are chiral, the net selectivity is affected by the stereoselectivity of each component. When the diastereofacial selectivity of the enolate of a chiral carbonyl compound is sufficiently high (e.g. >20:1), the stereochemistry of the product aldols can be determined by the stereochemistry (sense of chirality) of the enolate chiral reagent. Thus, the stereochemistry of the aldol product can be controlled by the selection of the sense of chirality of these enantiomeric chiral reagents. This strategy of reagent-oriented stereocontrol is defined as double asymmetric synthesis (36). Reagent-controlled reactions are categorized into internal chiral reagent control and external chiral reagent control. 136 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Internal Chiral Reagent Control

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When the chiral moiety is covalently connected to the enolate as an auxiliary, the reagent is called an internal chiral reagent. The auxiliary group is readily introduced and removed after the reaction. Chiral imides, α-oxyketones and esters have been developed as asymmetric aldol reagents (Scheme 14, Eq 1).

Scheme 14. Chiral reagent control

External Chiral Reagent Control When a chiral controller unit is not covalently connected, the reagent is called an external chiral reagent and can be used for unit-elongation type reactions and for fragment-coupling-type reactions (Scheme 14, Eq 2). As an external chiral reagent, the chiral controller unit could be stoichiometric as a ligand of metal or catalytic as an asymmetric catalyst. Chiral reagent control asymmetric aldol reactions involving boron enolate are discussed below in detail.

Internal Chiral Reagent Control In the reaction of a chiral substrate with a chiral reagent, the use of an S or R reagent with a large diastereofacial selectivity enhances the apparent facial selectivity of the substrate in the matched pair reaction and overrides it in the mismatched pair reaction. In this manner, the stereochemical course of the reaction is controlled by the reagent.

Imide Auxiliary Chiral imide reagents derived from valinol or phenylalaninol, and norephedrine are particularly important (16, 37–40) (Scheme 15). 137 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 15. Internal chiral reagent: imide-type reagents

The derived (Z)-dibutylboron enolates react with a broad range of aldehydes, including chiral α-substituted aldehydes, in near perfect stereoselectivities for both newly formed asymmetric centers. Furthermore, a wide range of enolate substituents, R1, such as n-alkyl, -CH2COOMe, -CH=CH2, -OMe, OBn, and -SMe, are tolerated without loss of reaction stereoselectivity. Scheme 16 represents an application to the double asymmetric synthesis. The diastereomer ratio 36:64 is the diastereoselectivity of the substrate aldehyde (substrate-controlled reaction). When chiral imide XV was used for the aldol reaction, 2R, 3R isomer predominated over 400:1. The “enantiomeric” chiral imide XN overrode the selectivity to 1: >500 favoring the 2S, 3S-isomer (Scheme 16). The chiral auxiliary group can be removed from the aldol products or the derived compounds to produce carboxylic acids (37, 41, 42), alcohols (43–46), esters (47, 48), aldehydes or ketones via thioesters (49–51) or Weinreb amides (46, 52–54), without loss of the stereochemical integrity (Scheme 17). The power of this methodology has been exhibited in many natural product syntheses. Lewis acid catalysis makes the aldol reaction of the boron enolate and related systems derived from propionylimides anti-selective via the acyclic transition state. The selectivity was sensitively affected by the choice of Lewis acid. With a small Lewis acid, such as TiCl4, the major product of the reaction became the non-Evans syn isomer, and with a large Lewis acid, such as Et2AlCl, the reaction was anti-selective (55–58) (Scheme 18). The chiral bornanesultam reagent shows similar selectivity with higher crystallinity (59, 60) (Scheme 19).

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Scheme 16. Reagent-controlled aldol reaction of chiral imide reagents

Scheme 17. Transformation of the aldol product.

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Scheme 18. Lewis acid-catalyzed aldol reaction of a boron enolate of an imide reagent.

Scheme 19. Bornanesultam reagent for an asymmetric aldol reaction. 140 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Chiral α-Oxyketone Reagents Chiral α-oxyketone reagents were developed as asymmetric aldol reagents. The chiral ethyl ketone reagent was easily prepared from R- or S-mandelic acid in 3 steps (Scheme 20). The Z-boron enolate, generated with dialkylboron triflate and diisopropylethylamine, selectively reacted with aldehydes including α-chiral ones, to give syn-aldol products with high diastereofacial control. The facial selectivity was affected by the bulkiness of the boron reagent, and the use of 9-BBNOTf for aldehydes with an α-substituent and that of c-Pen2BOTf for aldehydes carrying no α-substituent were recommended. The chiral controller moiety could be oxidatively cleaved to β-hydroxy-α-methyl carboxylic acids (Scheme 20). The selection of the appropriate enantiomeric reagent led to the creation of the syn-3-hydroxy-2-methylcarbonyl system with a selected absolute configuration, as depicted in Scheme 21 (61, 62).

Scheme 20. Preparation and aldol reaction of a chiral ethyl ketone reagent derived from mandelic acid.

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Scheme 21. Reagent-controlled aldol reaction of a chiral ethyl ketone reagent.

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Complementary syn- and anti- selective asymmetric aldol reactions of lactic acid-derived chiral ketones were developed by Paterson et al. (63). The enolization conditions used for these reactions were originally designed for the synthesis of E-enolate. The benzoyloxy-substituted ethyl ketone afforded anti-β-hydroxy-α-methyl ketones with high selectivity (Scheme 22, Eq 1). In contrast, the benzyloxy substituent caused the formation of the chelate complex of boron to facilitate the Z-enolate formation (Scheme 22, Eq 2). The aldol products were transformed to ethyl ketones or aldehydes, after protection of the β-hydroxyl group by SmI2 reduction or oxidative cleavage, respectively (Scheme 22, Eq 3).

Scheme 22. Asymmetric aldol reaction of lactate-derived ethyl ketones.

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The absolute stereochemistry of the products shown in Scheme 22, Eqs 1 and 2 shows the opposite sense of facial selectivity of Z- and E-enolate. This was rationalized by the cyclic transition state model described in Scheme 23.

Scheme 23. Transition state model for E- and Z-enolates.

Chiral Carboxylic Ester Reagent It is possible to control the stereochemical course of the aldol reaction of propionate esters by the judicious choice of enolization conditions. Thus, the combination of Bu2BOTf-i-Pr2EtN leads to the predominant formation of the synaldol products (Scheme 24, Eq 4), while the enolization of a bulkier ester with c-Hex2BOTf-Et3N at a lower temperature affords the corresponding anti-aldol products selectively (64) (Scheme 24, Eq 2). Two complementary esters were developed for the asymmetric aldol reaction (65–67). Both reagents were prepared from readily available nor-ephedrine (68) (Scheme 24, Eq 1) or ephedrine (Scheme 24, Eq 3) in easily scalable operations, and upon aldol reaction, they exhibited excellent diastereo- (>98:2) and diastereofacial (>95:5) selectivities with a wide range of aldehydes (Scheme 24).

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Scheme 24. Anti- and syn-selective asymmetric aldol reaction of chiral esters. It should be added that the stereochemistry of the major product of the antiand syn-aldol reaction is a result of the opposite diastereofacial selection of the intermediate enolates. This implies that the conformation of the transition states leading to anti-aldol from E-enolate and syn-aldol from Z-enolate are different.

Double Aldol Reaction: Doubly Borylated Enolate A natural extension of the syn- and anti-selective aldol reaction of propionate or ethyl ketone is an acetate aldol reaction. The aldol reaction of the boron enolate of acetate was shown to be a complex process (69). When the chiral acetate was treated with c-Hex2BOTf (2.0 equiv) and trimethylamine (2.4 equiv) in CH2Cl2 at -78 °C for 15 min, followed by isobutyraldehyde (3.0 equiv), three stereoisomeric bis-aldols were obtained in over 95% yield with a diastereomer ratio of 90:8:2. 145 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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The major bis-aldol product, obtained as a pure crystalline compound, was fully characterized by NMR and X-ray crystallography. Under the optimized reaction conditions, the double aldol reaction proceeded with high yield (>90 %) and selectivity (ds >84 %) (Scheme 25).

Scheme 25. Asymmetric double aldol reaction of chiral acetate ester.

The bis-aldol products were transformed to chiral triols of C3-symmetry in 5 steps (Scheme 26). After protection of the diol as acetonide, chiral auxiliary was removed by LiAlH4 reduction in 80-95% yield. PDC oxidation followed by the Grignard reaction in THF afforded the secondary alcohol in high stereoselectivity. (dr >10:1) With i-PrMgBr, however, reduction of the aldehyde was an accompanying reaction (35 %). Chiral triols of C3-symmetry were obtained after removal of the acetonide group.

Scheme 26. Synthesis of chiral triols of C3-symmetry. 146 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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The unique and unprecedented double aldol reaction was characterized as two aldol reactions occurring in one operation. The mechanism of this reaction was thoroughly investigated by a spectroscopic method; the novel doubly borylated enolate was identified as an intermediate, and more significantly, for the first time, the C-bound enolate was characterized to be responsible for this reaction. The proposed mechanism is summarized in Scheme 27 (70, 71).

Scheme 27. Mechanism of the double aldol reaction.

A boron triflate forms a complex with both a carbonyl compound and an amine reversibly. When the boron triflate-carbonyl compound complex is more favorable than the boron triflate-amine complex and the acidity of the α-proton of the boron-carbonyl complex is sufficiently high to be deprotonated with the amine, enolization proceeds (step 1). The initial product, an oxygen-bound mono-enolate, rapidly equilibrates with the carbon-bound enolate, and the latter is again enolized with the aid of boron triflate and an amine (step 2). This second enolization proceeds with an acetate ester (along with a thioacetate, acetyl-2-oxazolidinone and certain ketones), irrespective of the amount of the carbon-bound enolates. For acetates with a smaller alcohol residue, “step 2” is faster than “step 1”; thus, only the doubly borylated enolate is produced, even with 1 equivalent of boron triflate. For larger esters, “step 2” becomes slower because of steric hindrance. For acetophenone or 2-butanone, the concentration of the carbon-bound enolate 147 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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is too small to form the boron-carbonyl complex for further enolization to the doubly borylated enolate. In the enolization of acetate esters with a sufficiently large R, the configuration of the initially formed doubly borylated enolate is E occurs at a low temperature, and this enolate may isomerize to the Z-isomer upon warming. This facile isomerization implies that it also proceeds through a carbonbound boron enolate. The aldol reaction naturally proceeds in a stepwise manner to afford an α-boryl-β-boryloxy carbonyl intermediate, which isomerizes to the second (oxygen-bound) enolate with an E configuration. Then, the bis-aldol is produced after reaction with the second equivalent of the aldehyde. Naturally, the double aldol reaction is not limited to acetate esters. Under the standard reaction conditions (carbonyl compound (1.0 equiv), c-Hex2BOTf (2.5 equiv) and Et3N (3.0 equiv) in CDCl3 at 0 °C 5 min), the corresponding doubly borylated enolates were spectroscopically identified from methoxyacetone, acetic acid (with c-Hex2BOTf (4.0 equiv) and Et3N (5.0 equiv)), N,N-dimethylacetamide, and 2-acetylpyridine. Only an oxygen-bound mono-enolate, however, was detected from PhSCOCH3, acetophenone, 2-butanone, 4-methoxyacetophenone, or 2-methoxyacetophenone. With 1 equiv of the boron triflate, methoxyacetone and 3-acetyl-2-oxazolidinone afforded the oxygen-bound mono-enolate in >98% and 72% yields, respectively (condition [B]). The monoenolate of PhSCOCH3 and 2-methoxyacetophenone was slowly converted to the doubly borylated enolate after prolonged reaction at 0 °C with excess boron triflate (condition [C]) (Table 3). From these results, it is conceivable that the formation of the doubly borylated enolate, as well as the success of the double aldol reaction, should be attributed to the stability of the carbon-bound boron enolate species. Resonance stabilization of the carbon-bound enolates of carboxylic ester, thioester, and ketone diminished in this order, and the nearby chelating functional group stabilized the carbon-bound enolate intermediate of methoxyacetone, 2-acetylpyridine and 2-methoxyacetophenone. It is particularly interesting that, acetyl-2-oxazolidinone was converted to the corresponding doubly borylated enolate under the “standard reaction conditions”. In addition to the well-established asymmetric aldol reaction of the propionate derivative of chiral oxazolidinones, a few examples of asymmetric aldol reaction of acetyl oxazolidinones have been reported to afford the corresponding mono aldol products (72–74). With 2.5 equiv of n-Bu2BOTf and 3 equiv of triethylamine, (R)-acetylimide exhibited excellent stereocontrol of the aromatic aldehydes, even at room temperature, to afford (S,S)-diol as a major product (>95% ds) (75) (Scheme 28).

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Table 3. Doubly borylated enolate formation from acetyl derivatives.

Scheme 28. Asymmetric double aldol reaction of chiral acetylimide.

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External Chiral Reagent Control

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Using an external chiral reagent, it is possible to skip the step of removing the chiral controller moiety from the product. In the process, which involves the assembly of the two prefixed chiral fragments with the concomitant creation of a stereogenic center or centers, the crucial role of the external chiral reagent control becomes even more evident. Chiral boron reagents, such as 2,5-disubstituted borolane reagents, diazaborolidine reagents and diisopinocampheylborane (IPC) regents, have been used for simple acetate-type and anti-selective asymmetric aldol reactions and for fragment coupling aldol reactions.

Borolane Reagents 2,5-Dimethylborolane was developed and its utility was evaluated for asymmetric hydroboration, carbonyl reduction, crotylboration and the aldol reaction (76–79). An asymmetric aldol reaction of propionate ester of bulky thiol (3-ethyl-3pentanethiol) produced anti-aldol product with high diastereo- (30-33: 1) and enantioselectivity (>97.9% ee) (Scheme 29). The corresponding acetate reactions proceeded to give the aldol product enantioselectively (89.4-98.4% ee).

Scheme 29. R*2BOTf=2,5-Dimethylborolane-mediated asymmetric aldol reaction.

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In the aldol reaction with a chiral aldehyde, the newly formed stereo-center(s) were controlled by the chirality of the boron reagent. (double asymmetric synthesis) (Scheme 30).

Scheme 30. 2,5-Dimethylborolane-mediated asymmetric aldol reaction: Double asymmetric synthesis.

Although the ability to control the asymmetric reactions is excellent, the preparation of the reagent is tedious. The borolane structure as a mixture of diastereomers was prepared by the Grignard reaction followed by methanolysis. The cis-isomer was removed from the mixture by complexation with dimethylaminoethanol. Then, trans-borolane was resolved by selective complex formation with prolinol and valinol to afford the stable aminoalcohol complex of each enantiomer. The triflate reagent used for the aldol reaction was liberated via trifluoromethanesulfonic acid treatment of the dihydridoborate (Scheme 31). Reetz et al. reported the related chiral 2,5-diphenylborolane with comparable selectivity. The boron enolate was generated via transmetallation of the ketene silyl acetal with the chloro borane (80, 81) (Scheme 32).

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Scheme 31. Preparation of chiral 2,5-dimethylborolane.

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Scheme 32. 2,5-Diphenylborolane-mediated asymmetric aldol reaction.

Diazaborolidine Reagents Corey et al. developed chiral diazaborolidine reagents, which could be prepared in situ from C2-chiral bis-sulfonamide and boron tribromide (82, 83) (Scheme 33, Eq 1). Enolization of diethyl ketone with the toluenesulfonamide reagent and diisopropylethylamine gave the syn-isomer of the aldol product predominantly with high enantioselectivity (Scheme 33, Eq 2). In addition, phenyl thioacetate was enolized with the toluenesulfonamide reagent and triethylamine to give the aldol product with high enantioselectivity (Scheme 33, Eq 3). For phenyl thiopropionate, the related 4-nitrobenzenesulfonamide reagent was used to realize the syn-selective aldol reaction (Scheme 33, Eq 4). Carboxylic esters were used as substrates for the anti-selective aldol reaction using the 3,5-bistrifluoromethylbenzenesulfonamide reagent. Under the specified conditions, the propionate of sterically demanding alcohols (tert-butyl or (+)-menthyl) were reacted with aldehydes to give anti-aldol products with high diastereo- and enantioselectivity (Scheme 34).

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Scheme 33. Diazaborolidine-mediated asymmetric aldol reactions.

It should be noted that regarding the diastereofacial selection of these aldol reactions, the anti- and acetate reactions exhibited the opposite sense to the synaldol reaction. Naturally, it is conceivable that the syn- and anti-aldol products were products of Z- and E- boron enolates, respectively. The stereochemistry of the enolate formation was rationalized as a result of the change in the ground state conformation of the borane-carbonyl complex (Scheme 35).

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Scheme 34. Diazaborolidine-mediated anti-selective asymmetric aldol reactions.

Scheme 35. Stereochemistry of the enolate formation.

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IPC and Related Reagents Diisopinocampheylborane was synthesized by hydroboration of α-pinene followed by crystallization, which was transformed to the triflate or chloride (Scheme 36, Eq 1). Boron enolates, derived from achiral ethyl and methyl ketones by enolization with diisopinocamphenylboron triflate or diisopinocamphenylchloroborane in the presence of tertiary amine bases (i-Pr2NEt or Et3N), underwent enantio- and diastereoselective aldol reactions with aldehydes (84–86). The aldol reaction between ethyl ketones and aldehydes using (+)- or (-)-(IPC)2BOTf/i-Pr2Net in dichloromethane via the derived chiral Z-boron enolates gave syn-α-methyl-β-hydroxy ketones in good enantiomeric excess (66 ~ 90% ee) and with high diastereoselectivity (>90%) (Scheme 36, Eq 2). In contrast, the anti-selective aldol reaction of diethylketone via the isomeric E-enolate by enolization with (-)-(IPC)2BCl) with methacrolein proceeded with negligible enantioselectivity (Scheme 36, Eq 3). Use of both the triflate and chloride reagents in the aldol reaction of methyl ketones with aldehydes gave β-hydroxy ketones in moderate enantiomeric excess (57 ~ 78% ee) (Scheme 36, Eq 4). A reversal in the enantioface selectivity of the aldehyde compared to the corresponding ethyl ketone syn aldol was observed. This variable selectivity is interpreted as evidence for the participation of competing chair and boat transition states. Specifically for the development of an anti-selective asymmetric aldol reaction, the new chiral ligand was designed based on computer-aided transition state modeling. The chloroborane derived from (-)-menthone in two steps followed by crystallization (Scheme 37) gave high diastereoselectivity (86:14 to 100:0 anti:syn) and in good enantiomeric excess (56 ~ 88% ee) for the aldol reactions of a range of cyclic and acyclic ketones with an aldehyde (87–89) (Scheme 38). Unsubstituted and anti-aldol products with excellent diastereo- and enantioselectivity were formed when enolates, generated from the corresponding thioacetates and thiopropionates using bromoborane and triethylamine, were treated with aldehydes (Scheme 38).

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Scheme 36. Preparation and aldol reaction of IPC reagent.

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Scheme 37. Synthesis of the [(Menth)CH2]2BCl-OEt2 reagent.

Scheme 38. Asymmetric aldol reaction mediated by the [(Menth)CH2]2BCl-OEt2 reagent.

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The syn-selective asymmetric aldol reaction of methyl propionate using (-)-IPC2BOTf-Et3N at 0 °C exhibited excellent selectivity for achiral or chiral aldehydes. Z-enolate was produced at a higher enolization temperature (0 °C) with a small ester (methyl propionate) (90, 91) (Scheme 39, Eq 1). The anti-selective reaction, using tert-butyl propionate as a substrate and enolization at a low temperature (-78 °C), however, showed high diastereoselectivity and moderate to good enantioselectivity (Scheme 39, Eq 2) (92).

Scheme 39. Asymmetric aldol reaction of propionate esters mediated by the IPC-boron reagent.

The reaction was extended to the phenylacetate system. For the syn-selective reaction, a higher temperature was applied for enolization in CH2Cl2 to facilitate isomerization. The anti-isomer was obtained by enolization at a low temperature in pentane to prevent isomerization (Scheme 40).

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Scheme 40. Asymmetric aldol reaction of phenylacetate esters mediated by the IPC-boron reagent.

Stereochemical Control in Fragment-Assembly Aldol Reactions Stereochemical control in the formation of a stereogenic center or centers is crucial in fragment assembly for a convergent synthesis of a complex natural product. Consider an aldol reaction that involves a chiral or achiral aldehyde and an enolate derived from a chiral ketone. For this purpose, the use of an enantiomerically pure reagent to mediate the ketone enolization and the subsequent aldol reaction predictably modifies the selectivity intrinsic to the corresponding enolate prepared from an achiral reagent. Selection of an R- or S- external chiral reagent provides a method of control (93–95). In example 1, the diastereofacial selectivity of a chiral methyl ketone was evaluated as 2:1 favoring the C9 S isomer by the reaction with diethylboron triflate as a borylating reagent. With R,R-dimethylborolane triflate, the diastereoselectivity was increased to 6:1, and with the S,S-dimethylborolane reagent, the major product changed to the C9 R isomer in 1:2 (Scheme 41). Examples 2 and 3, represent the assembly of a chiral aldehyde and a chiral methyl ketone. In both cases, inherent diastereofacial selectivity was enhanced using the chiral borolane reagent (Schemes 42 and 43).

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Scheme 41. Example of external reagent control in fragment assembly reaction 1.

Scheme 42. Example of external reagent control in fragment assembly reaction 2.

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Scheme 43. Example of external reagent control in fragment assembly reaction 3.

The IPC reagent is also useful for the fragment-coupling type aldol reaction. Inherent diastereofacial selectivity was reversed or enhanced using a chiral boron reagent (96–98) (Schemes 44 and 45).

Scheme 44. Example of external reagent control in fragment assembly reaction 4. 162 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 45. Example of external reagent control in fragment assembly reaction 5.

Generation of Boron Enolate via the 1,4-Addition of an Organoboron Compound to α,β-Unsaturated Compounds Alkylative Reaction The 1,4-addition of alkylboranes to α,β-unsaturated carbonyl compounds was reported by Suzuki et al in 1967 (99) (Scheme 46). The mechanism of the reaction was proved to involve a radical mechanism (100), and the structure of the intermediate boron enolate was determined by Köster (101).

Scheme 46. Generation of boron enolate via the 1,4-addition of an organoboron compound. Based on these findings, further investigation expanded the scope of the reaction to the addition of an alkyl radical to methyl vinyl ketone (Scheme 47, Eq 1), the reductive generation of boron enolate from α-haloketone (Scheme 47, Eq 2), and the intramolecular cyclization of ω-haloenone (Scheme 47, Eq 3) (102–104). 163 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Scheme 47. Generation of boron enolates via 1,4-addition with a radical mechanism.

The sources of alkylboranes were expanded to the hydroboration products of catecholborane (105) (Scheme 48).

Scheme 48. One-pot reaction involving hydroboration, radical generation and 1,4-addition. 164 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Reductive Generation of the Boron Enolate

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Although 1,2-reduction is a major pathway for the hydroboration of cyclohexenone, and acyclic α,β-unsaturated carbonyl compounds can proceed in a 1,4-fashion to produce boron enolate as an intermediate. α,β-Unsaturated ketones, which can readily adopt an s-cis conformation, undergo conjugate reduction by catecholborane at room temperature. α,β-Unsaturated imides, esters, and amides are unreactive under the same conditions. The Rh(PPh3)Cl catalyst greatly accelerates the 1,4-addition process, resulting in the conjugate reduction of these substrates by catecholborane at -20 °C. A concerted pericyclic [4p + 2σ] mechanism was proposed for this reaction (106) (Scheme 49).

Scheme 49. Conjugate reduction of α,β-unsaturated carbonyl compounds by catecholeborane. Especially, β-substituted (E)-α,β-uneaturated ketones reacted with dialkylboranes to selectively form Z-boron enolate. Using chiral IPC2BH, an asymmetric reductive aldol reaction was reported (107–110) (Scheme 50). An intramolecular reaction was also reported (111) ( Scheme 51).

Scheme 50. Reductive aldol reaction.

Scheme 51. Intramolecular reductive aldol reaction. 165 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Roush et al. reported that morpholine acrylamide is a particularly good substrate for the syn-selective reductive asymmetric aldol reaction using IPC2BH hydroboration, with dr, syn:anti = 13~20:1 and 96~98% ee (112, 113) (Scheme 52, Eq 1). A high ee for the anti-selective variant was achieved using 3-ethylpentyl acrylate as a substrate, dr anti:syn = 10~20:1, 83~87% ee (114) (Scheme 52, Eq 2).

Scheme 52. Diisopinocampheylborane-mediated reductive aldol reactions.

Conclusion In this chapter, advances in boron enolate chemistry were overviewed with a focus on the aldol reaction. Currently, boron aldol chemistry appears to have matured with the development of many convenient and reliable methodologies, which enable the synthesis of complex molecules in a stereo-defined manner. Eventually, some of the reagents were used, even in a practical synthesis. Moreover, the identification of a carbon-bound form of boron enolates as an important species in the boron enolate synthesis introduced a new direction in boron enolate chemistry. Boron enolate chemistry and the boron aldol reaction will continue to be an important research area in the future. 166 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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