1 Stereoselective Acetate Aldol Reactions Pedro Romea and Felix` Urp´I

Home , Aldol reaction, Silyl enol ether, Stereoselectivity

1 Stereoselective Acetate Aldol Reactions Pedro Romea and Felix` Urp´ı

1.1 Introduction

The stereochemical control of aldol reactions from unsubstituted enol- or enolate- like species, what are known as acetate aldol reactions, has been a matter of concern for nearly 30 years [1, 2]. Indeed, pioneering studies soon recognized that the asymmetric installation of a single stereocenter in such aldol reactions was much more demanding than the simultaneous construction of two new stereocenters in the related propionate counterparts (Scheme 1.1) [3]. This challenge, together with the ubiquitous presence of chiral β-hydroxy α-unsubstituted oxygenated structures in natural products, has motivated the development of new concepts and strategies and a large number of highly stereoselective methodologies. These involve Lewis-acid-mediated additions of enolsilane derivatives of carbonyl compounds to aldehydes (Mukaiyama aldol variant) [4, 5], a plethora of transformations that take advantage of the reactivity of boron, titanium(IV), and tin(II) enolates (metal enolates) [6], and some insightful organocatalytic approaches [7]. In spite of these accomplishments, the quest for more powerful and selective methodologies and a better understanding of their intricate mechanisms is an active area of research. Herein, we describe the most signiﬁcant achievements in the ﬁeld of stereoselective acetate aldol reactions based on the Lewis-acid-mediated addition of enolsilanes and metal enolates to aldehydes, with particular attention to their application to the asymmetric synthesis of natural products. Recent advances in parallel organocatalytic procedures are not discussed.

O OH O O OH RCHO RCHO R2 R1 R R1 R1 R R2: Me R2: H Me H

Propionate aldol reaction Acetate aldol reaction Two new stereocenters A single new stereocenter Four stereoisomers Two stereoisomers

Scheme 1.1 Aldol reactions.

Modern Methods in Stereoselective Aldol Reactions, First Edition. Edited by Mahrwald, R. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA. 2 1 Stereoselective Acetate Aldol Reactions

1.2 Mukaiyama Aldol Reaction

1.2.1 Concept and Mechanism

With some signiﬁcant exceptions, enolsilanes are unreactive toward aldehydes.1) This lack of reactivity can be overcome by increasing the electrophilic character of aldehydes or the nucleophilicity of enolsilanes. The former option is achieved by coordination of Lewis acids (MLn) to the carbonyl group, which enhances the electrophilicity of the C=O bond and facilitates the attack of enolsilanes. This represents the canonical Mukaiyama aldol variant ((1) in Scheme 1.2) [4, 5]. It also covers vinylogous aldol transformations, which involve the reactions of γ -unsubstituted β, γ -conjugated enolsilanes ((2) in Scheme 1.2) [8]. In turn, the latter option takes advantage of the activation of the nucleophilic character of = enolsilanes by binding of Lewis bases such as phosphoramides (O P(NR2)3)tothe silicon atom ((3) in Scheme 1.2) [9]. Early mechanistic analyses suggested that Lewis-acid-mediated aldol reactions represented in Scheme 1.2 proceeded through open transition states [4, 5, 10]. This model assumes a transoid geometry for the Lewis-acid-aldehyde complex, which the enolsilane attacks following antiperiplanar or synclinal approaches, as represented in Scheme 1.3. Antiperiplanar transition states I and II are usually more favorable because of the minimization of dipolar interactions, the steric interactions between 1 2 the enolsilane (R or R3SiO groups) and the aldehyde (R group) being the main source of instability. Similar steric interactions arise in synclinal transition states III and IV, whereas V and VI are characterized by a destabilizing interaction between the enolsilane and the Lewis acid coordinated to the carbonyl oxygen. Then, steric and stereoelectronic interactions determine the relative stability of

ML SiR O n O 3 OH O (1) + R2 H R1 R2 R1

MLn SiR3 O β O OH β O (2) + R2 H R1 R2 R1 γ α

R3 Si O O O=P(NR2)3 OH O (3) + R2 H R1 R2 R1

Scheme 1.2 Mukaiyama aldol variants.

1) As silyl enolates derived from amides and trihalosilyl enolates. 1.2 Mukaiyama Aldol Reaction 3

MLn MLn O O H H H H R2 H R2 H 1 1 R OSiR3 R3SiO R III Antiperiplanar approaches

MLn MLn 1 1 R3SiO MLn R MLn OSiR3 R O O O O H H H H 1 1 R R3SiO R OSiR3 R2 H R2 H R2 H R2 H H H H H III IV V VI Synclinal approaches

Scheme 1.3 Open transition states for Mukaiyama aldol reactions.

I–VI and the capacity to differentiate one from the other faces of the carbonyl bond. Despite the importance and utility of this paradigm, it is probably an oversim- plified model because it ignores the fate of the silyl group. In this respect, some models take into account the silicon moiety and suggest cyclic transition states VII–IX, as represented in Scheme 1.4. Importantly, the role of the silyl group is not limited to influencing the nature of the transition state, because the silicon transfer from the enolsilane to the β-alkoxy position may be a key step in the overall mechanism and becomes crucial to the turnover necessary for nonstoichiometric transformations [11]. Irrespective of the mechanistic pathway, the asymmetric induction achieved by these Lewis-acid-mediated aldol reactions depends on chiral elements on the enolsilane (the nucleophilic partner), the aldehyde (the electrophilic partner), or the Lewis acid (the activating element), so they must all cooperate to provide the appropriate face differentiation of the carbonyl bond in order to control the configuration of the new stereocenter. The influence of these elements is discussed in the following sections.

1 1 1 R R R R3 H SiR3 H H ML SiR Si X O n O 3 O M O O MLn O L R2 R2 R2 m VII VIII IX

Scheme 1.4 Cyclic transition states for Mukaiyama aldol reactions. 4 1 Stereoselective Acetate Aldol Reactions

1.2.2 Chiral Auxiliaries

In the context of emergence of chiral auxiliaries as powerful platforms to achieve asymmetric transformations, Helmchen reported highly diastereoselective aldol reactions of chiral auxiliary-based silyl ketene acetals (1)and(2) [12, 13]. As shown

in Scheme 1.5, TiCl4-mediated additions of 1 and 2 to isobutyraldehyde afforded aldol adducts 3 and 4 in good yields and excellent diastereomeric ratios, presumably through a chairlike transition state in which the titanium atom is simultaneously coordinated to the carbonyl and the OTBS group. In turn, these adducts can be converted into the corresponding β-hydroxy acids in quantitative yield by simple treatment with KOH in methanol. This approach was quickly surpassed by alternative methodologies based on chiral aldehydes or Lewis acids and bases (Sections 1.2.4–1.2.6). Nevertheless, new ﬁndings restored the interest in this sort of transformations a few years ago. Indeed, Kobayashi described highly stereoselective vinylogous Mukaiyama aldol reactions using silyl vinyl ketene N,O-acetals prepared from valine-derived

1,3-oxazolidin-2-ones [14]. As represented in Scheme 1.6, TiCl4-mediated additions of α-methyl acetal (5) to aliphatic, α, β-unsaturated, and aromatic aldehydes afforded δ-hydroxy-α-methyl-α, β-unsaturated imides (6) in excellent yields and diastereomeric ratios. Such outstanding remote asymmetric induction was be- lieved to arise from a conformation in which the chiral heterocycle is almost perpendicular to the dienol plane and the isopropyl group overhangs the upper face of the dienol moiety. Then, the aldehyde approaches from the less hindered face through an open transition state in which the α-methyl group appears to be essential to achieve the observed high stereocontrol. Finally, the chiral auxiliary can be removed by well-known methodologies used for Evans auxiliaries.

Ar Ar N SO Ph 1 equiv TiCl4 NSO2Ph O 2 + i-PrCHO O ° CH2Cl2, –80 C OTBS O OH 1 dr 95 : 5 62% 3 Ar: 3,5-Me2Ph

1 equiv TiCl4 + i-PrCHO NSO Ph ° Ar 2 NSO Ph Ar NSO2Ph CH2Cl2, –80 C O Ar 2 O O H i-Pr O dr 97 : 3 51% OTBS TBS O O OH 2 Cl4Ti 4 Ar: 3,5-Me2Ph

Scheme 1.5 Chiral auxiliary-based Mukaiyama aldol reactions. 1.2 Mukaiyama Aldol Reaction 5

O O OTBS O β OH 1 equiv TiCl4 O N α + RCHO O N R ° α δ CH2Cl2, –78 C

dr > 95 : 5 65–97% 56 ′ ′ R: i-Pr, CH2R , CH=CHR , Ph

Me Me α Me OTBS γ Me OTBS H Cl4Ti H H N H H O O Xc H R H Cl Ti H O 4 O R

Scheme 1.6 Chiral auxiliary-based vinylogous Mukaiyama aldol reactions.

This methodology was used for the construction of the AB ring of fomitellic acids (7) (Scheme 1.7) [15]. Initially, application of the standard conditions to ent-5 and enal (8) provided the desired aldol (9), but the reaction was slow and hard to reproduce. Then, a thorough study of this particular reaction uncovered signiﬁcant rate enhancements by adding catalytic amounts of water in toluene, which permitted to obtain aldol (9) in 76% yield as a single diastereomer in a straightforward and consistent way [16]. The origin of this catalytic effect remains unclear, but it has proved to be general and has been successfully applied to other aldehydes [17].

O OTBS O 1 equiv TiCl4,10 mol% H2O O N + H OTBDPS ° PhCH3, – 50 C

8 76% ent-5 HO O O OH

O N OTBDPS HO O H HO2C 7 9

Scheme 1.7 Synthesis of the central ring of fomitellic acids. 6 1 Stereoselective Acetate Aldol Reactions

TBSO OTBS TBSO O OH TBSO O OH 1.5 equiv BF3·OEt2 + RCHO + ° R R CH2Cl2, –78 C 10 11 12 R dr (11 : 12) Ph 60 : 40 i-Pr 50 : 50

PhCH2CH2 36 : 64 PhCH=CH 33 : 67

Scheme 1.8 Asymmetric induction imparted by a silyl enol ether from a chiral methyl ketone.

1.2.3 Chiral Methyl Ketones

There are no systematic studies on the asymmetric induction imparted by chiral methyl ketones. However, most of the examples reported so far suggest that substrate-controlled Mukaiyama aldol reactions based on chiral methyl ketones are poorly stereoselective. This lack of stereocontrol is well illustrated by the aldol reaction of chiral silyl enol ether (10), in which the major diastereomer, 11 or 12, depends on the achiral aldehyde (Scheme 1.8) [18]. In a more complex framework, De Brabander also reported that silyl enol ethers from enantiomeric methyl ketones (13)and(ent-13) underwent additions to chiral aldehyde (14) to afford the corresponding aldol adducts 15 and 16 in similar yields (Scheme 1.9) [19]. Considering that the new C11-stereocenters possess the same conﬁguration in both adducts and that the diastereoselectivity is

CO2Me CO2Me

O O O O OH dr 92 : 8 60%

11 O (1)TMSOTf, 2,6-lutidine O ° OMe 13 (2)1.3 equiv BF3·OEt2, CH2Cl2, –78 C 15 OPMB O

H O CO2Me O CO2Me OMe 14 O O OPMB O O OH

11 O dr 89 : 11 51% O ent-13 16 OMe OPMB

Scheme 1.9 Chiral methyl ketones in stereoselective Mukaiyama aldol reactions. 1.2 Mukaiyama Aldol Reaction 7

TMS OTMS O O OH 1 equiv TiCl4 Si + RCHO R O Cl (1) Ti R CH Cl , –78 °C Cl3 2 2 PivO Me dr > 89 : 11 PivO H H PivO 61–78% 17 R: n-C5H11, i-Pr, t-Bu 18

OTMS O OH 0.3 equiv BF3·OEt2 (2) + i-PrCHO CH Cl , –78 °C OPG 2 2 OPG PG: PMB, TES dr > 96 : 4 36% 20 19

Scheme 1.10 Asymmetric induction imparted by chiral α-hydroxy methyl ketones in Mukaiyama aldol reactions. comparable for both processes, it can be concluded that the asymmetric induction provided by the aldehyde is much more important than that provided by the ketone. Lactate-derived and other α-hydroxy methyl ketones are exceptions to this trend. Thus, Trost found that TiCl4-mediated aldol reactions of pivaloyl-protected silyl enol ether (17)affordedβ-hydroxy ketones (18) in high yields and diastereomeric ratios up to 98 : 2 [20]. This was assumed to be achieved through an eight-membered cyclic transition state in which the titanium is simultaneously bound to the aldehyde and the enolsilane ((1) in Scheme 1.10). Importantly, dipole–dipole interactions are understood to favor the antiperiplanar arrangement of the C–OPiv and the C–OSi bonds and impel the aldehyde toward the less hindered face of the enolsilane. Moreover, Kalesse reported that parallel BF3-catalyzed additions of silyl enol ethers (19) to isobutyraldehyde afforded the corresponding aldols (20) with excellent diastereoselectivity but in low yield ((2) in Scheme 1.10) [21]. The origin of such remarkable stereocontrol is unclear. At this point, it is worth mentioning that Yamamoto has also reported highly diastereoselective Mukaiyama aldol reactions based on chiral β-tris(trimethylsilyl) silyloxy methyl ketones containing a single stereocenter at the β-position [22]. This chemistry is discussed in connection with parallel methodologies (Sections 1.2.4 and 1.3.6). Finally, Ley reported that reactions of silyl enol ethers from chiral π-allyltricarbonyliron lactone or lactam complexes proceeded with a signiﬁcant remote stereocontrol [23]. This is illustrated by the BF3-mediated addition of complexes 21 to benzaldehyde furnishing β-hydroxy ketones (22) with excellent diastereomeric ratios (Scheme 1.11). The remarkable 1,7-induction provided by these substrates is due to the chiral environment created on the lower face of the silyl enol ether (the upper face is blocked by the tricarbonyliron moiety) by the endo-oriented methyl substituent at the sp3-stereocenter. Then, the incoming activated aldehyde approaches in a synclinal arrangement in which unfavorable steric interactions are minimized. 8 1 Stereoselective Acetate Aldol Reactions

O O Fe(CO)3 Fe(CO)3 X X OTMS ° O (1) BF3·OEt2, PhCHO, CH2Cl2, –78 C OH H Me (2) HF/pyridine H Me Ph 21 X: O, NBn dr > 93 : 7 66–81% 22

O Fe(CO)3 X OTMS

H Me Lower face F B 3 O H Ph

Scheme 1.11 Asymmetric induction imparted by chiral π-allyltricarbonyl iron complexes in Mukaiyama aldol reactions.

As the iron lactone and lactam (22) can be easily decomplexed to afford a rich array of stereodeﬁned derivatives, this reaction may represent a powerful tool to the rapid construction of highly functionalized systems under remote stereocontrol.For instance, total synthesis of (−)-gloeosporone (23) commenced with the addition of silyl enol ether from methyl ketone (24) to benzyloxypropanal, which afforded aldol (25) as a single diastereomer in a 63% yield (Scheme 1.12) [24].

1.2.4 Chiral Aldehydes

The asymmetric induction of chiral aldehydes in Mukaiyama aldol reactions is much more important and has stimulated the formulation of increasingly more reﬁned models to predict the π-facial selectivity in nucleophilic additions to the carbonyl bond [25]. Therefore, the inﬂuence of α-andβ-substituents has received particular attention and is described in detail in the following sections.

1.2.4.1 1,2-Asymmetric Induction Pioneering studies on acyclic stereoselection established that Mukaiyama acetate aldol additions of enolsilane derivatives (26)and(27) to chiral α-methyl aldehydes

O O O Fe(CO)3 Fe(CO)3 O O OH O (1) TMSOTf, Et N, CH Cl , 0 °C O 3 2 2 OH O H C H H C H 5 11 (2) BF3·OEt2, BnOCH2CH2CHO 5 11 O CH Cl , –78 °C 24 2 2 25 O (3) HF/pyridine OBn C5H11 63% 23 (−) Gloeosporone

Scheme 1.12 Synthesis of (−)-gloeosporone. 1.2 Mukaiyama Aldol Reaction 9

(28) proceeded with high diastereofacial selectivity to favor 3,4-syn aldol adducts (29) (Scheme 1.13) [26]. As expected, the 1,2-asymmetric induction of such aldehydes was eroded when R2 was sterically similar to the α-methyl. The challenge posed by these transformations can be met by using more bulky nucleophiles, as has been observed in the aldol additions of enolsilanes (26), (27), and (30) to 2-methyl-3-phenylpropanal (Scheme 1.14). The stereochemical outcome of these reactions shows that enhance- 1 ment of the steric hindrance of R and SiR3 groups gives the corresponding 3,4-syn aldols (31) in higher diastereomeric ratios [26, 27]. A parallel improvement can also be attained by employing more bulky Lewis acids, but steric inﬂuences must be analyzed carefully because some combinations of bulky nucleophiles and Lewis acids do not provide the expected results [27]. The Felkin–Anh model [25, 28] is usually invoked to account for the asymmetric induction observed in the Mukaiyama aldol additions to these chiral α-methyl aldehydes. Thus, once the methyl group has been identiﬁed as the medium size group, the major 3,4-syn diastereomer is obtained by bringing the enolsilane close to the face of the C=O bond in which the steric interactions between the nucleophile and the α-substituent (H vs Me) are weaker (X in Scheme 1.15). The total synthesis of borrelidin (32) reported by Theodorakis contains a good example of stereocontrol based on the asymmetric induction imparted by such chiral aldehydes [29]. As represented in Scheme 1.16, the Mukaiyama aldol addition of silyl ketene acetal (27c)toα-methyl aldehyde (33) produced the desired ester (34)

OTBS O O OH 1 equiv BF ·OEt R2 3 2 4 R2 1 + 1 3 R H ° R CH2Cl2, –78 C

1 2 26 R : Me, t-Bu, R : Ph, PhCH=CH, Cy dr 91 : 9 to 97 : 3 68–81% 3,4-syn 27 R1: OMe, Ot-Bu 28 29

Scheme 1.13 Asymmetric induction imparted by chiral α-methyl aldehydes in Mukaiyama aldol reactions.

OSiR3 O O OH 1 equiv BF3·OEt2 4 1 + 1 R H Ph ° R 3 Ph CH2Cl2, –78 C

26, 27, 30 28d 31 1 Enolsilane R SiR3 dr yield (%) 26a Me TBS 57 : 43 72 27a MeO TBS 62 : 38 78 27b t-BuO TBS 71 : 29 88 30a t-BuS TBS 85 : 15 43 30b t-BuS TIPS 93 : 7 78

Scheme 1.14 Mukaiyama aldol additions to (R) 2-methyl-3-phenylpropanal. 10 1 Stereoselective Acetate Aldol Reactions

MLn MLn O OH H O O Me O OH 2 2 4 R R2 R2 4 R R1 3 R1 3 Me H H H 3,4-anti Nu OSiR3 Nu 3,4-syn XI Nu : X R1

Scheme 1.15 The Felkin–Anh model for Mukaiyama aldol additions to chiral α-methyl aldehydes.

OTBS O O + TBSO OMEM PMBO H H 27c 33 CO2H H BF ·OEt , 4 Å MS, THF, –78 °C dr 80 : 20 95% CN 3 2 O

O HO O OH O TBSO OMEM HO PMBO H

34 32 Borrelidin

Scheme 1.16 Synthesis of borrelidin.

as a 80 : 20 mixture of diastereomers in a 95% combined yield, which demonstrates the π-facial selectivity provided by the α-stereocenter of aldehydes of this kind [30]. The substitution of the methyl group by a heteroatom affects these transformations dramatically. Indeed, a tenet in asymmetric synthesis states that nucleophilic additions to chiral aldehydes bearing an α-heteroatom attain outstanding levels of stereocontrol provided that the reaction is carried out under conditions in which chelate organization is favored. In this context, the Cram model [25, 31] accounts for the stereochemical outcome of chelate-controlled Mukaiyama aldol reactions. According to this model, the appropriate choice of the Lewis acid and the protecting group of α-hydroxy aldehydes permits the formation of stable ﬁve-membered chelated complexes and gives the corresponding 3,4-syn aldol adducts in a highly diastereoselective manner, presumably through an open transition state in which the nucleophile approaches the less hindered face of the chelated carbonyl group (Scheme 1.17). This highly reliable and powerful element of stereocontrol has been widely exploited in the synthesis of natural products. For instance, Sunazuka and Omura used a chelate-controlled Mukaiyama aldol reaction for the total synthesis of an epimer of guadinomine C2 (35). As shown in Scheme 1.18, addition of silyl ketene S,O-acetal (36a) to chiral α-OPMB aldehyde (37) in the presence of 1.1 equiv of TiCl3(i-PrO) gave 3,4-syn aldol (38) with exceptional diastereoselectivity in 64% yield [32]. 1.2 Mukaiyama Aldol Reaction 11

L MLn n OSiR3 M O O OOPG O OH ML R1 R2 n OPG 4 R2 H H 2 R1 3 R H OPG R2 H OPG Nu 3,4-syn

Scheme 1.17 Cram model for Mukaiyama aldol additions to chiral α-hydroxy aldehydes.

OTMS O O OH 1.1 equiv TiCl (i-PrO) + 3 EtS H OTBS ° EtS OTBS CH2Cl2, –78 C OPMB OPMB 36a 37 dr > 99 : 1 64% 38 O HN O NH OH HN N NH H N H 2 OH N CO H O N 2 ′ H 35 3 S Epimer of guadinomine C2 O

Scheme 1.18 Synthesis of (3 S) epimer of guadinomine C2.

· Moreover, Forsyth reported that the addition of mild Lewis acid MgBr2 OEt2 to a mixture of chiral silyl enol ether (39)andα-OPMB aldehyde (40) triggered a smooth aldol reaction that furnished 3,4-syn aldol (41) as a single diastereomer in 79% yield, which was further elaborated to a hapten for azaspiracids (Scheme 1.19) [33]. A very similar transformation was also reported by Evans [34, 35].

OTMS O OTBS TMS + N3 H OPMB O CO2H 39 40 O 12 equiv MgBr2·OEt2 H O ° 79% CH2Cl2, –78 to –25 C H H N O O OH OTBS TMS

N3 OPMB Hapten of azaspiracids 41

Scheme 1.19 Synthesis of a hapten for azaspiracids. 12 1 Stereoselective Acetate Aldol Reactions

In the absence of chelated intermediates, nucleophilic additions to chiral aldehydes possessing an α-heteroatom are currently explained by the polar Felkin–Anh [36] and Cornforth models [37], which apply to conformations XII–XV arising from rotation about the C1–C2 bond of the aldehyde (Scheme 1.20) [25]. The polar Felkin–Anh model is based on the premise that staggered transition states positioning the C–X bond perpendicularly to the carbonyl bond are preferred ((1) in Scheme 1.20). In turn, the Cornforth model embraces the assumption that electrostatic effects are instrumental in dictating a nearly antiparallel relationship between the carbonyl and the C–X bond ((2) in Scheme 1.20). Then, the stereochemical outcome of these additions depends on the steric interactions between the nucleophile and the remaining α-substituents in alternative transition states. Application of both models to Mukaiyama aldol reactions predicts the preferential formation of 3,4-anti aldol adducts. Most of the aldol reactions involving such aldehydes proceed in accordance with these expectations, but systematic studies on the addition of enolsilanes (42)to α-chloro, α-hydroxy, and α-amino aldehydes (43–45) revealed that their diastereoselectivity is dependent signiﬁcantly on the α-heteroatom and the steric bulk of nucleophiles (Scheme 1.21) [38–40]. Thus, additions of acetone-derived enolsilane (42a) to aldehydes (43)and(44) possessing an electronegative α-heteroatom such as chlorine or oxygen afforded the corresponding 3,4-anti aldols (46a) and (47a) (dr 60 : 40 and 82 : 18, respectively), whereas more sterically hindered pinacolone-derived enolsilane (42c) gave under the same conditions 3,4-syn aldol (46c) or equimolar mixtures of 3,4-anti and syn diastereomers (47c). In turn, N-benzyl-N-tosyl protected valinal (45) always furnished 3,4-anti aldols (48)in modest to excellent diastereomeric ratios (Scheme 1.21). In view of these and a few related studies on the inﬂuence of bulky Lewis acids, Somfai proposed that N-protected valinal (45) prefers the polar Felkin–Anh

MLn MLn O OH H O OR2 O OH 2 2 (1) 4 R X X 4 R R1 3 R1 3 2 X R H H H X 3,4-syn Nu OSiR3 Nu 3,4-anti XIII Nu : XII R1

MLn MLn O OH R2 O O H O OH 2 2 (2) 4 R H R2 4 R R1 3 R1 3 X X H H X X 3,4-syn Nu OSiR3 Nu 3,4-anti XV Nu : XIV R1

Scheme 1.20 Models for Mukaiyama aldol additions to chiral aldehydes possessing an α-heteroatom. 1.2 Mukaiyama Aldol Reaction 13

OTMS O O OH O OH BF ·OEt 3 2 4 4 1 + 1 + 1 R H ° R 3 R 3 CH2Cl2, –60 or –78 C X X X 42 43–45 3,4-anti 3,4-syn 46–48

EnolsilaneR1 Aldehyde X Aldols dr (anti/syn) Yield (%)

42a Me 43 Cl 46a 60 : 40 94 42b i-Pr Cl 46b 65 : 35 92 42c t-Bu Cl 46c 16 : 84 99

42a Me 44 OTBS 47a 82 : 18 66 42b i-Pr OTBS 47b 75 : 25 69 42c t-Bu OTBS 47c 50 : 50 66

42a Me 45 NTsBn 48a 78 : 22 60 42b i-Pr NTsBn 48b 93 : 7 94 42c t-Bu NTsBn 48c 98 : 2 85

Scheme 1.21 Mukaiyama aldol additions to chiral aldehydes possessing an α-heteroatom. manifold, which is not seriously affected by the size of the nucleophile ((1) in Scheme 1.20) [39]. In turn, Mukaiyama aldol additions to α-chloro aldehyde (43) would proceed essentially through antiperiplanar Cornforth transition state XVI provided that R1 is small enough to avoid serious steric interactions with chlorine (Scheme 1.22). Facing such deleterious interactions, sterically hindered silyl enol ethers would react through antiperiplanar anti-Cornforth transition state XVII.A similar rationale could be applied to α-silyloxy aldehyde (44).

1.2.4.2 1,3-Asymmetric Induction Mukaiyama aldol additions to chiral α-unsubstituted aldehydes bearing a β-heteroatom usually proceed with signiﬁcant levels of 1,3-anti asymmetric induction [41]. As illustrated in Scheme 1.23, most of the aldol reactions of silyl enol ethers (42)withβ-hydroxy, β-chloro, and β-azido aldehydes (49) produce the

i-Pr i-Pr H Cl H Cl Steric interactions O OH O OH 1 1 4 1 4 R R R 3 H O O H R1 3 H H Cl TMSO LA LA OTMS Cl 3,4-syn H H 3,4-anti XVII XVI Antiperiplanar Antiperiplanar anti-Cornforth approach Cornforth approach Note: positions of R1 and OTMS can be interchanged

Scheme 1.22 Cornforth model for Mukaiyama aldol additions to (S) 2-chloro- 3-methylbutanal. 14 1 Stereoselective Acetate Aldol Reactions

OTMS O X O OH X LA 1 + 2 1 2 R H R ° R 35R CH2Cl2, –78 C 1 2 R : i-Pr, t-Bu R : i-Pr, CH2CH2R dr 75 : 25 to 98 : 2 60–99% X: OBn, OTBS, Cl, N3 LA: BF3·OEt2, TiCl4, MeAlCl2 42 49 3,5-anti 50

Scheme 1.23 Asymmetric induction imparted by chiral α-unsubstituted aldehydes bearing a β-heteroatom in Mukaiyama aldol reactions.

corresponding 3,5-anti aldols (50) in high diastereomeric ratios regardless of the chelating ability of the Lewis acid and the hydroxyl protecting group [42–44]. The stereochemical outcome of these reactions may not be readily interpreted because both open-chain and chelation control lead to the same 3,5-anti diastereomer (50). Thus, Evans proposed, after a systematic and insightful study, a revised induction polar model and a chelate-controlled model to account for the high 1,3-asymmetric induction provided by such chiral aldehydes [43]. The former is an open-chain model ((1) in Scheme 1.24) derived from several assumptions common to the Felkin–Anh analysis for 1,2-asymmetric induction. First, it is assumed that torsional effects dictate that aldehyde transition state conformations adopt a staggered relationship between the forming bond and the aldehyde α-substituents. Second, it is also assumed that the principal diastereomer arises from the reactant-like transition state wherein the β-stereocenter is oriented anti, rather than gauche, to the forming bond because this geometry reduces nonbonded interactions between the aldehyde α-substituents and the incoming nucleophile. In turn, the chelate-controlled model applies to suitable β-hydroxy-protected aldehydes able to form stable six-membered chelates, which can subsequently react through transition states involving either boat or half-chair conformations ((2) in Scheme 1.24).

Nu R2 ML SiR H H X O n O 3 H H X OH O HOMLn 2 + X H (1) R H R1 R2 5 3 R1 X H 2 H O R 3,5-anti diastereomer MLn

Ln Half-chair Boat M SiR3 2 PGO O O PG O H R PGO OH O or PG (2) + Ln M OC O R2 H R1 2 R2 5 3 R1 R M C H L O H n 3,5-anti diastereomer

Nu Nu

Scheme 1.24 Evans models for Mukaiyama aldol additions to chiral α-unsubstituted aldehydes bearing a β-heteroatom. 1.2 Mukaiyama Aldol Reaction 15

Regardless of mechanistic considerations, the predictable and high stereocontrol provided by these aldehydes has been used in many total syntheses. Evans reported in the total synthesis of bryostatin 2 (51) that aldol coupling of bis(trimethylsilyl)dienol ether (52a)withβ-OPMB aldehyde (53) ((1) in Scheme 1.25) was only modestly stereoselective when it was carried out in the presence of · · MgBr2 OEt2 or BF3 OEt2, whereas strong Lewis acid (TiCl4,SnCl4) did not effect ◦ a clean transformation. Alternatively, mild TiCl2(i-PrO)2 in CH2Cl2 at −78 Cde- livered aldol (54) in a high-yielding and stereoselective manner (dr 86 : 14, 93%). Importantly, the diastereoselectivity was improved by using toluene (dr 94 : 6, 83%), a result that is consistent with the operation of electrostatic effects as the stereochemical control element [45]. In turn, Panek took advantage of the 1,3-asymmetric induction of β-alkoxy aldehydes in a challenging Mukaiyama aldol reaction to assemble an advanced intermediate in the total synthesis of leucascandrolide A (55) [46]. Indeed, the coupling of chiral silyl enol ether (56) and aldehyde (57) ((2) in Scheme 1.25) afforded the desired anti aldol (58) in 81% yield and excellent diastereomeric ratio (dr > 94 : 6). This, presumably occurred through an open transition state in which the β-stereocenter of the aldehyde determines the approach of the nucleophile to the carbonyl in accordance with the revised polar model described in (1) of Scheme 1.24. Finally, Nelson also used this reactivity in the total synthesis of the apoptolidine C aglycone (59) [47]. In this case, silyl enol ether (60) participated in a highly stereoselective addition to chiral aldehyde (61) ((3) in Scheme 1.25), affording aldol (62) as a single diastereomer in 71% yield. A matched pairing of aldehyde and enolsilane facial biases acting in the transition state shown in Scheme 1.25 was invoked to explain such outstanding stereoselectivity [48]. The aforementioned transformations show that the 1,3-anti asymmetric induction of protected β-hydroxy aldehydes can be very successful, but this control element should be used with caution because the diastereoselectivity drops when the steric bulk of the protecting group increases [49, 50]. Taking advantage of this trend, Yamamoto reported that the extremely bulky tris(trimethylsilyl)silyl group (TTMSS, (Me3Si)3Si), also known in the literature as the hypersilyl or super silyl group, confers to β-OTTMSS aldehydes an outstanding 1,3-syn asymmetric induction [51]. This silicon-protecting group is also remarkable because it permits acetaldehyde derived TTMSS enol ether to participate in highly diastereoselective Mukaiyama aldol additions to a large variety of aldehydes.2) Moreover, these additions can incorporate other TTMSS enol ethers in cascade aldol reactions with excellent levels of 1,2-Felkin and 1,3-syn-asymmetric induction. This is shown in the sequential addition of acetaldehyde- and acetophenone-derived TTMSS enol ethers to 2-phenylpropanal (Scheme 1.26) [51, 52]. On the basis of the open-chain model proposed by Evans ((1) in Scheme 1.24), the rationale for the observed 1,3-syn induction of β-OTTMSS aldehydes considers that the size of this silicon-protecting

2) Mukaiyama aldol reactions involving silyl enol ethers from aldehydes are particularly troublesome, and a few examples have been reported. 16 1 Stereoselective Acetate Aldol Reactions

TMSO OTMS O OPMB O O OH OPMB TiCl (i-PrO) Ph 2 2 Ph (1) MeO + H MeO PhCH , –78 °C Ph 3 Ph 52a 53dr 94 : 6 83% 54

CO2t-Bu BnO R O OTMS O O BF3·OEt2 (2) + O O H ° CH2Cl2, –78 C F3B O H H H 56 57 CO2t-Bu Nu BnO dr > 94 : 6 81% O O OH O

58 PMBO TESO OTMS H BF3 BF ·OEt R H TBSO 3 2 TMSO O (3) ° MeO CH2Cl2, –78 C Single diastereomer OTES RL 71% H OPMB H 60 O TESO O 61 TBSO OPMB MeO O HO TES 62

OH HO H OMe OH MeO2C N OH O O O MeO O OMe H OH O O O O N OH OH O O O O O O OMe O O OH O OH Pr O CO2Me

51 55 59 Bryostatin 2 Leucascandrolide A Apoptolidine C Aglycone

Scheme 1.25 Use of 1,3-asymmetric induction imparted by chiral β-hydroxy aldehydes in Mukaiyama aldol reactions in the synthesis of natural products.

group now dictates that the carbonyl group is antiperiplanar to the OTTMSS substituent and far from the R1 group, which avoids unfavorable steric interactions. Therefore, conformation XVIII is responsible to the predominant formation of the 3,5-syn aldol diastereomer. As discussed in Section 1.3.6, this chemistry combined with lithium-mediated aldol reactions from β-OTTMSS methyl ketones provides new entries to efﬁcient synthesis of natural products. 1.2 Mukaiyama Aldol Reaction 17

OSi OSi O O OSi O OSi OSi 0.05 mol% HNTf2 Ph + Ph Ph Ph H ° H ° Ph CH2Cl2, –78 C CH2Cl2, –78 C Si : TTMSS dr 94 : 6 78% 1,2-Felkin asymmetric induction 1,3-syn asymmetric induction

OSi OSi O OSi OSi H H Steric interactions H H O OSi OSi 1 H R1 H R R 35R1 R 35R1 H O O H 3,5-anti aldol Si OSi Si 3,5-syn aldol Nu Nu : Nu XIX R XVIII

Scheme 1.26 Mukaiyama aldol reactions of tris(trimethylsilyl)silyl enolsilanes.

1.2.4.3 Merged 1,2- and 1,3-Asymmetric Induction The high asymmetric induction imparted by α-andβ-substituted aldehydes documented in previous sections raises the prospect that there might exist intrinsic stereochemical relationships between both substituents that are either mutually reinforcing or opposing. This is particularly true for α-methyl β-alkoxy aldehydes. Indeed, the stereochemical outcome of Mukaiyama aldol additions to these chiral aldehydes under nonchelation conditions can be easily interpreted by in- voking the 1,2-Felkin and 1,3-anti asymmetric induction provided by the α-methyl and the β-oxygenated substituent, respectively. Hence, it is not surprising that the BF3-mediated additions of silyl enol ethers (42)toα-methyl-β-OPMB aldehydes (63) and (64) largely depend on the relative conﬁguration of the aldehyde (Scheme 1.27). Astheinﬂuencesoftheα-methyl and the β-OPMB substituents match in anti-substituted aldehyde (63), Felkin aldols (65) were virtually obtained as a single diastereomer, whereas syn-substituted aldehyde (64), in which those factors are opposing, gave mixtures of aldols (67)and(68) in variable diastereomeric ratios [53]. Interestingly, additions to 64 showed a turnover in carbonyl face selectivity (from Felkin to anti-Felkin) on decreasing the size of the enolsilane group R. This implies that the β-stereocenter becomes the dominant control element in the reactions with sterically nondemanding enolsilanes. Moreover, a decrease in the solvent polarity produced an increase of anti-Felkin diastereomer (68), which means that 1,3-induction is enhanced relative to 1,2-induction in nonpolar media. After a seminal analysis of these stereochemical data, Evans concluded that 1,2-stereoinduction is found in those reactions proceeding through an antiperiplanar open transition state such as XX, while dominant 1,3-stereoinduction is manifest from a synclinal open transition state such as XXII. Then, a subtle balance of stereoelectronic effects and steric interactions between the Lewis acid and the R group of the nucleophile on transition states XX–XXIII represented in Scheme 1.28 determines the stereochemical outcome of these reactions [53]. The consistently high stereocontrol provided by Mukaiyama aldol reactions of anti α-methyl β-oxygenated aldehydes has been successfully used in the synthesis of many natural products [54]. Evans reported that BF3-mediated vinylogous 18 1 Stereoselective Acetate Aldol Reactions

O OPMB O OH OPMB O OH OPMB

H R + R OTMS 63 Felkin 65 antiFelkin 66 42 R O OPMB O OH OPMB O OH OPMB CH Cl or PhCH , –78 °C 2 2 3 + H R R

64 Felkin 67 antiFelkin 68

EnolsilaneR Aldehyde Solvent 65 : 66 67 : 68 Yield (%)

42a Me 63 CH2Cl2 97 : 3 86 42b i-Pr 98 : 2 98 42c t-Bu 99 : 1 94

42a Me 64 CH2Cl2 17 : 83 82 42b i-Pr 56 : 44 98 42c t-Bu 96 : 4 89

42a Me 64 PhCH3 6 : 94 92 42b i-Pr 32 : 68 86 42c t-Bu 88 : 12 75

Scheme 1.27 Mukaiyama aldol additions to α-methyl β-alkoxy aldehydes.

OPG OPG i-Pr H i-Pr H H Me H Me O OH OPG H O R : t-Bu (R)TMSO H O H H R H BF3 (TMSO)R BF3 H TMSO R XXI Felkin/1,3-syn XX Synclinal transition states Antiperiplanar transition states

i-Pr i-Pr H OPG H OPG H Me H Me O OH OPG R : Me O H O H OTMS(R) H H R H BF3 BF3 R(OTMS) H XXII R OTMS anti-Felkin/1,3-anti XXIII

Scheme 1.28 Evans models for Mukaiyama aldol additions to syn α-methyl β-alkoxy aldehydes.

◦ aldol addition of Chan’s diene (52a) to chiral aldehyde (69)intolueneat−90 C gave β-hydroxy ketone (70), an advanced intermediate in the total synthesis of callipeltoside A (71), with excellent stereocontrol (dr > 95 : 5) in 88% yield ((1) in Scheme 1.29) [55]. In turn, Paterson developed a highly efﬁcient coupling of chiral silyl enol ether (72) and elaborate α-methyl β-oxygenated aldehyde (73)to 1.2 Mukaiyama Aldol Reaction 19

TMSO OTMS O O O O O OH O O

BF3·OEt2 (1) MeO + H MeO ° PhCH3, –90 C 52a 69 dr > 95 : 5 88% 70 TBSO TBSO OPMB OPMB

MeO2C MeO2C TBSO O TBSO O 72 MeO MeO t-Bu t-Bu O H O (2) t-Bu Si + t-Bu Si O O OTMS O OH O

O BF ·OEt O 3 2 74 CH Cl , –78 °C 73 2 2 dr > 98 : 2 91% OMe OMe

OMe OMe O OTES O OTES TBS TBS O O O (1) LiHMDS, TMSCl TBSO OH O O O (3) ° Et3N, THF, –78 C TBSO O OMe (2) OMe 76H 77 78 ° BF3·OEt2, 4 Å MS, CH2Cl2, –78 C dr > 95 : 5 72%

O O MeO2C MeO NH HO O MeO O O OMe H HO O OH

HO OH O O OH O O H HO O HO MeO O O HO OMe

OMe 71 75 79 Callipeltoside A Pre-Swinholide A Bafilomycin A Cl 1

Scheme 1.29 Use of asymmetric induction imparted by anti α-methyl β-oxygenated aldehydes in Mukaiyama aldol reactions in the synthesis of natural products. obtain aldol (74) as a single diastereomer in 91% yield, which was easily converted into preswinholide A (75) ((2) in Scheme 1.29) [56], the monomeric seco acid of swinholide A [57, 58]. Finally, the conversion of methyl ketone (76)intothe corresponding silyl enol ether and subsequent BF3-mediated addition to aldehyde (77) in the presence of 4 A˚ molecular sieves allowed Roush to generate aldol (78), the penultimate precursor of baﬁlomycin A1 (79), with a high diastereoselectivity (dr > 95 : 5) in 72% yield ((3) in Scheme 1.29) [59]. 20 1 Stereoselective Acetate Aldol Reactions

TESO OTMS O OTBS TESO O OH OTBS BF3·OEt2 (1) + Ar Ar H ° CH2Cl2, –78 C 80 81 dr 86 : 14 95% 82 PMP PMP

OTMS O O O O OH O O BF ·OEt (2) + 3 2 H ° PhCH3, –78 C 42a 83 dr 97 : 3 86% 84

Scheme 1.30 Asymmetric induction imparted by syn α-methyl β-oxygenated aldehydes in Mukaiyama aldol reactions.

Parallel Mukaiyama aldol additions to syn-α-methyl β-oxygenated aldehydes have also been applied to the synthesis of natural products, but the uncertainty of their stereochemical outcome and the poorer diastereoselectivities often provided by these aldehydes have restricted their use compared to their anti counterparts. Re- markably, most of the examples found in the literature about these transformations involve Felkin-like reactions leading to all syn aldols. For instance, Floreancig reported the preparation of Felkin aldol (82) in excellent yield as an inseparable 86 : 14 mixture of diastereomers by addition of sterically hindered silyl enol ether (80)to chiral syn-α-methyl β-silyloxy aldehyde (81) ((1) in Scheme 1.30) [60, 61]. Further- more, Kalesse described one of the few examples of substrate-controlled Mukaiyama aldol reaction in which the 1,3-induction of the β-oxygenated stereocenter prevailed over the Felkin induction imparted by the α-stereocenter [62]. This engaged the silyl enol ether (42a) addition to syn-aldehyde (83), which afforded aldol (84)with excellent diastereoselectivity (dr 97 : 3) in 86% yield ((2) in Scheme 1.30) [63]. Following these analyses, π-facial selectivity of chiral aldehydes possessing α- and β-heteroatoms could be expected to arise from the summation of the inductions imparted by both substituents. Unfortunately, α,β-bisalkoxy aldehydes do not fulﬁll such expectations. Mukaiyama aldol additions to syn-α,β-bisalkoxy aldehydes under nonchelating conditions are too reliant on the hydroxyl protecting groups and the steric encumbrance of the enolsilane and usually proceed with poor stereocontrol. Thesameoccurstoanti diastereomers, but anti-conﬁgured α-OBn β-OTBS aldehyde (85) exhibited uniformly high selectivities toward 3,4-anti aldols (86) irrespective of the steric hindrance of silyl enol ethers (42) ((1) in Scheme 1.31) [38]. A similar trend was observed for α-amino β-alkoxy aldehydes [64]. In this case, addition of silylenolether(42c)toanti α-N-BnTs β-OTBS aldehyde (87) afforded 3,4-anti aldol (88) as a single diastereomer in 92% yield ((2) in Scheme 1.31). The highly diastereoselective aldol reaction of silyl enol ether (ent-38)and anti-aldehyde (89) affording anti aldol (90) is consistent with these features ((1) in Scheme 1.32). Moreover, alternative patterns occasionally proceed with excellent levels of diastereoselectivity. For instance, Paterson reported that silyl enol ether (42a)andsyn-aldehyde (91) participated in a highly diastereoselective reaction (dr 93 : 7) toward all syn-aldol (92), thus indicating that the steric effect of the large 1.2 Mukaiyama Aldol Reaction 21

OTMS O OTBS O OH OTBS BF3·OEt2 (1) + 4 R H ° R 3 CH2Cl2, –78 C OBn OBn R : Me, i-Pr, t-Bu dr > 97 : 3 77–86% 42 85 86

OTMS O OTBS O OH OTBS BF3·OEt2 (2) + 4 t-Bu H Ph ° t-Bu 3 Ph CH2Cl2, –60 C NBnTs NBnTs dr > 98 : 2 92% 42 87 88

Scheme 1.31 Asymmetric induction imparted by chiral aldehydes possessing α-andβ-heteroatoms in Mukaiyama aldol reactions.

OTMS O OTBS O OH OTBS BF3·OEt2 (1) + CN CN N H ° N 3 CH2Cl2, –78 C 3 OPMB OPMB dr 95 : 5 91% ent-38 89 90

PMP PMP

OTMS O O O O OH O O BF3·OEt2 (2) + H ° CH2Cl2, –78 C TBSO TBSO dr 93 : 7 53% 42a 91 92

Scheme 1.32 Mukaiyama aldol reactions involving α,β-bisalkoxy aldehydes. alkyl group overrode any electronic stereocontrol from the oxygenated substituents ((2) in Scheme 1.32) [65, 66]. In spite of these successful examples, most of the stereocontrolled aldol reactions of α, β-bisalkoxy aldehydes rely on the use of lithium enolates (Section 1.3.5). The stereochemical outcome of all these Mukaiyama aldol reactions involving α, β-disubstituted aldehydes can be dramatically affected if they are carried out under chelating conditions. Particularly, Evans established that the choice of the Lewis acid was crucial to the control of the additions to syn α-methyl β-OPG (PG: 3) Bn, TBS) aldehydes (93) (Scheme 1.33) [67]. Thus, BF3-mediated additions of silylenolether(42c) to these aldehydes provided Felkin aldols (94) in excellent diastereomeric ratios (dr > 96 : 4), whereas opposite anti-Felkin aldols (95) were 4) obtained with the same level of diastereoselectivity by using Me2AlCl. Further theoretical and spectroscopic studies revealed that these transformations proceed through a cationic dimethylaluminum chelate that preferentially adopts a boat conformation and directs the attack of the nucleophile to the Si face of the C=O bond (Scheme 1.33). From a general point of view, these results demonstrate

3) Related anti α-methyl β-oxygenated aldehydes do not display any remarkable stereocontrol in chelating-controlled reactions. 4) Similar results were obtained with MeAlCl2. 22 1 Stereoselective Acetate Aldol Reactions

OTMS O OH OPG t-Bu 42c t-Bu 1 equiv BF ·OEt , CH Cl , –78 °C 3 2 2 2 dr > 96 : 4 78–91% O OPG Felkin 94

H Me OTMS H Me O OH OPG PG: Bn, TBS PG Al 42c 2.5 equiv Me2AlCl O O t-Bu 93 H t-Bu CH Cl , –78 °C 2 2 Me H i-Pr dr > 97 : 3 51–73% anti-Felkin 95

Scheme 1.33 Inﬂuence of Lewis acids on the stereochemical outcome of Mukaiyama aldol reactions of α-methyl β-alkoxy aldehydes.

the exceptional chelating ability of this aluminum Lewis acid and expand the stereochemical control provided by these aldehydes [68, 69].

1.2.5 Chiral Lewis Acids

Not surprisingly, the crucial role played by Lewis acids in Mukaiyama aldol reactions has stimulated the search for chiral ligands to dictate the stereochemical outcome of these transformations. The resultant chiral Lewis acids must increase the electrophilicity of aldehydes, create a suitable asymmetric environment around the carbonyl bond, and, as far as possible, facilitate catalytic turnover at the same time [5]. The following section describes how the intense efforts directed to this challenging objective have already provided highly enantioselective approaches, paying particular attention to those chiral Lewis acids used in the synthesis of natural products. Mukaiyama and Kobayashi reported the ﬁrst chiral complexes to provide stereocontrolled acetate Mukaiyama aldol reactions. These initially consisted of three pieces: Sn(OTf)2, an optically active diamine, and a tin(IV) additive. Thus, stoichiometric amounts of Sn(OTf)2, proline-derived diamines (96), and tributyltin

OTMS O 1.2 equiv 96 O OH 1 equiv Sn(OTf)2, 1.1 equiv Bu3SnF + EtS H R ° EtS R CH2Cl2, –78 C 36a R: Ph, CH CH Ph, i-Pr, t-Bu 97 2 2 er 89 : 11 to 99 : 1 50–90%

N N 96a 96b N N H Me Me

Scheme 1.34 Asymmetric Mukaiyama aldol reactions promoted by stoichiometric amounts of Sn(OTf)2 and proline-derived diamines. 1.2 Mukaiyama Aldol Reaction 23

fluoride promoted highly enantioselective additions of silyl ketene S,O-acetal (36a) to representative aldehydes, leading to the corresponding β-hydroxy thioesters (97) (Scheme 1.34) [70]. Application of these conditions to the TBS ketene acetal from benzyl acetate furnished similar results [71]. Remarkably, these additions were also successful when using catalytic amounts of Sn(OTf)2 and diamine (96b) without tributyltin fluoride provided that the reaction was carried out in propionitrile, and the enolsilane and the aldehyde were both added slowly to the reaction mixture [72]. The power of this methodology was demonstrated on the addition of 36a to chiral α-OTBS aldehydes (98)and(ent-98), in which the C3 stereocenter of aldols (99)and(100) was controlled by the diamine (96) regardless of the inherent diastereofacial preference of the chiral aldehydes (Scheme 1.35) [73, 74]. Mechanistic analyses of this reaction suggested that such excellent stereocontrol might arise from the approach of the enolsilane to the less hindered face of the aldehyde in the highly ordered complex shown in Scheme 1.36 [75]. Regarding the catalytic turnover, the metal exchange reaction with TMSOTf to regenerate the catalyst was identified as a crucial step, because TMSOTf can promote an alternative achiral route (Scheme 1.36) that erodes the enantioselectivity if the silyl transfer is slow (kturnover ≈ kachiral). Thus, the need to minimize this side reaction led to the use of a more polar solvent such as propionitrile, which increases kturnover,andto the slow addition of both the enolsilane and the aldehyde to the reaction mixture. This methodology showed that catalytic asymmetric Mukaiyama aldol reactions were possible and could be used successfully in organic synthesis, but it suffered from the difficulty of handling Sn(OTf)2 [76] and the need for the reagents to be added to the reaction mixture slowly. In the early 1990s, some chiral catalysts derived from the easily available BINOL ligand emerged as candidates to overcome such limitations. Mukaiyama was the first to use a BINOL-derived titanium–oxo complex to catalyze the addition of silyl ketene S,O-acetals to a limited number of aldehydes with modest stereocontrol [77]. This was followed by Mikami’s findings on highly enantioselective ene and aldol reactions catalyzed by BINOL–titanium complex (101). Remarkably, addition of silyl enol ether (26a) to methyl glyoxylate afforded α-hydroxy ester (102)asa

O OH 0.2 equiv ent-96b OTMS O 0.2 equiv 96b O OH 0.2 equiv Sn(OTf) 0.2 equiv Sn(OTf) R 2 + R 2 R EtS 3 EtCN, –78 °C EtS H EtCN, –78 °C EtS 3 OTBS OTBS OTBS 100 36a 99 dr > 95 : 5 85% 98a R: Me dr 94 : 6 85% 98b R: Ph

O OH 0.2 equiv ent-96b OTMS O 0.2 equiv 96b O OH 0.2 equiv Sn(OTf) 0.2 equiv Sn(OTf) R 2 + R 2 R EtS 3 EtCN, –78 °C EtS H EtCN, –78 °C EtS 3 OTBS OTBS OTBS ent-99 36a ent-100 dr > 95 : 5 85% ent-98a R: Me dr 96 : 4 85% ent-98b R: Ph

Scheme 1.35 Asymmetric Mukaiyama aldol reactions promoted by catalytic amounts of Sn(OTf)2 and proline-derived diamines. 24 1 Stereoselective Acetate Aldol Reactions

H Sn(OTf) RCHO N N 2 Naphthyl Sn SO CF N N N Me O O 2 3 H H O H N Me Sn CF SO Me TfO OTf 3 2 96b R O OTMS OTMS kturnover kchiral EtS R EtS

TfO L2 TMS H Sn NN O O O OTf Sn SO CF RCHO O O 2 3 TMSOTf + Me O H H R EtS R CF3SO2 R OTMS SEt O OTMS EtS TMSOTf + OTMS EtS R kachiral

Scheme 1.36 Mechanism for the Mulaiyama aldol reaction catalyzed by Sn(OTf)2 and a proline-derived diamine.

single enantiomer ((1) in Scheme 1.37) [78], whereas aldol reactions of silyl ketene S,O-acetals (36) and a wide array of aldehydes furnished thioesters (103) in good to high yields and enantiomeric ratios up to 98 : 2 ((2) in Scheme 1.37) [79]. Crossover experiments and analyses of the stereochemical outcome of related reactions led to the suggestion of a cyclic six-membered transition state for these transformations, wherein the oxygen of the activated carbonyl bond interacts

with the transferring group, H or SiR3 for ene or aldol reactions, respectively (Scheme 1.38). Furthermore, the enantioselectivity was further improved by the addition of achiral ligands or by more bulky silicon groups, which suggests a more complex mechanism [80]. Irrespective of the mechanism, the synthetic potential of both transformations was demonstrated in two-directional ene processes [81] and aldol reactions involving chiral aldehydes by using a catalyst derived from BINOL

and TiCl2(i-PrO)2 [82].

OTBS O TBSO OH ° CH2Cl2, 0 C (1) + H CO2Me CO2Me 26a 102 5 mol % O Cl (R) BINOL-TiCl2 Ti O Cl 101 OTMS O O OTMS

(2) R1S + H R2 R1S R2 ° PhCH3, 0 C 36 103 er 90 : 10 to 98 : 2 60–84%

Scheme 1.37 Asymmetric Mukaiyama aldol reactions catalyzed by BINOL-TiCl2. 1.2 Mukaiyama Aldol Reaction 25

SR1 OTBS TBSO OH O OTMS H Me3Si O 1 2 LnTi CO Me R S R LnTi O O 2 R2 CO2Me

Scheme 1.38 Cyclic transition states for ene and aldol reactions.

Preparation of 4 Å MS the titanium catalyst (S) BINOL + Ti(i-PrO)4 Catalyst A Et O, reflux, 1 h 1:1 2 4 Å MS, 3 mol% TFA (S) BINOL + Ti(i-PrO)4 Catalyst B Et O, reflux, 1 h 2:1 2 4 Å MS (S) BINOL + Ti(i-PrO)4 Catalyst C 2:1 Et2O, reflux, 1 h

(1) 20 mol% Catalyst A OTMS O ° O OH 4 Å MS, Et2O, –20 C, 12 h (1) + 1 1 t-BuS H R (2) HCl, MeOH t-BuS R 1 36b R : CH2R, Cy, CH=CHR 106 Ar, CH2OBn er > 95 : 5 70–90% OTMS O O O 10 mol%Catalyst B TFA (2) + 1 H R 4 Å MS, Et O, –20 °C 1 CH Cl , 0 °C 1 MeO 1 2 MeO O R 2 2 O R R : CH R, Cy 2–3 d 2 TMS 104 CH=CHR, Ar er 89 : 11 to 99 : 1 50–88% 107 10 mol% Catalyst C OTMS O O OH 0.5 equiv B(OMe)3 (3) + 1 t-BuS R1 t-BuS H R 4 Å MS, Et O, rt, 4 d 1 2 R : CH2R, Ar 105 er 91 : 9 to 96 : 4 90–100% 108

Scheme 1.39 Asymmetric Mukaiyama aldol reactions catalyzed by BINOL/Ti(i-PrO)4.

Keck reported a similar methodology in which the titanium catalyst was prepared by mixing BINOL ligand and Ti(i-PrO)4 [83]. The stereocontrol was again excellent, but Keck warned about the unknown structure of the catalytic species and empha- sized the pronounced sensitivity of these reactions to BINOL–metal stoichiometry and the presence of other additives. Indeed, the catalytic species can be prepared according to several protocols adapted to different nucleophiles. Therefore, these have been applied to reactions from silyl ketene S,O-acetal (36b) [83], diene (104) [84, 85], and vinyl ketene S,O-acetal (105) [86] leading to β-hydroxy thioesters (106), dihydropyrones (107), and β-hydroxy α, β-unsaturated thioesters (108)inahighly enantioselective manner ((1–3) in Scheme 1.39). A thorough analysis and optimization of these transformations revealed the nonlinear effects and the dramatic influence of some additives [87, 88], which confirmed Keck’s comments about the sensitivity of these reactions to structural and experimental modifications [89]. In spite of these limitations, these catalysts 26 1 Stereoselective Acetate Aldol Reactions

TMSO OTMS O (1) 10 mol% 1:1 (R) BINOL/Ti(i-PrO)4 O O OH THF, –78 °C to rt EtO + H Ph EtO Ph (2) TFA, –78 °C to rt 52b 109 er > 98 : 2 85% O O OH OH 110 (+)-Cryptofolione Ph

Scheme 1.40 Synthesis of (+)-cryptofolione.

are an important tool for the stereocontrolled synthesis of natural products [90]. This is illustrated by the catalytic addition of Chan’s diene (52b) to cinnamaldehyde affording aldol (109), an intermediate in the total synthesis of (+)-cryptofolione (110) described by Meshram (Scheme 1.40) [91]. At the same time that Mikami and Keck developed their BINOL-derived titanium catalysts, Carreira reported that mononuclear Ti(IV) complex (111a), generated from a chiral tridentate Schiff base, Ti(i-PrO)4, and 3,5-di-tert-butylsalicylic acid, triggered extremely efficient reactions of silyl ketene acetals (112) and a wide range of aldehydes [92] including α, β-ynals [93] to yield β-hydroxy esters (113)with enantiomeric ratios up to 99 : 1 ((1) in Scheme 1.41). The stereocontrolled synthesis of ester (115) by addition of silyl ketene acetal (112a) to chiral aldehyde (114)inthe total synthesis of roflamycoin (116), reported by Rychnovsky ((2) in Scheme 1.41) [94], is a convincing demonstration of the potential of this methodology [95]. This method was also applied to O-silyl dienolate (117), which yielded carbonyl adducts (118) in a stereocontrolled manner ((3) in Scheme 1.41) [96]. Furthermore, a parent chiral Ti(IV) complex (111b) prepared by mixing the chiral tridentate Schiff base and Ti(i-PrO)4 (the structure of the active catalyst has not been determined yet) promoted the enantioselective addition of 2-methylpropene to aldehydes leading to β-hydroxy methyl ketones (119) ((4) in Scheme 1.41) [97]. The success of all these transformations is largely due to the effective transfer of the silyl group. As represented in Scheme 1.42, this transfer is understood to occur intramolecularly through an intermediate XXIV, wherein the ligand associated with the metal complex serves as a shuttle, transiently undergoing silylation. In this context, the replacement of isopropoxide groups by salicylic acid in catalyst (111) became crucial, as it facilitated the silyl transfer, which finally produced a strong increase of yields, enantioselectivities, and catalytic turnover. The prominence of boron Lewis acids in metal-enolate-mediated aldol reactions (Section 1.3) often overshadows their contribution to the development of asymmetric Mukaiyama aldol counterparts. Nevertheless, oxazaborolidinone complexes readily prepared from α-amino acids are among the most successful chiral Lewis acids for highly stereocontrolled transformations [98]. Introduced by Kiyooka, valine-derived N-tosyl oxazaborolidinone (120)wassuc- cessfully engaged in stoichiometric Mukaiyama aldol reactions [99, 100]. Its ability as a chiral promoter was demonstrated in synthetic studies involving a wide array of 1.2 Mukaiyama Aldol Reaction 27

t-Bu (1) 0.5 – 2mol %

Br N O Ti O O O O

t-Bu 111a OTMS O O OH ° t-Bu Et2O, –20 or 0 C (1) R1O + H R2 R1O R2 (2) TBAF or TFA, THF a R1: Me, b R1: Et, 1 113 c R : Bn er > 96 : 4 72–98% 112 TMS OTMS O OTBS OBn O O OTBS OBn 5 mol% 111a (2) + MeO H ° MeO Et2O, –10 C 112a 114 115 84%

OH OH OH OH OH OH OH

OH 116 O O Roflamycoin HO O

O O O O O OH ° (1) 1–3 mol% 111a, Et2O, 0 C (3) TMSO + H R O R (2) TFA, THF 117 118 er 90 : 10 to 97 : 3 70–95%

t-Bu (1) 2–10 mol%

Br N O Ti O OR OR 111b OMe O O OH 0–23 °C (4) + H R R (2) 2 M HCl, Et2O er 83 : 17 to 99 : 1 79–99% 119

Scheme 1.41 Asymmetric Mukaiyama aldol reactions catalyzed by Carreira’s titanium complex. enolsilanes derived from phenyl acetate, methyl acetoacetate, and methyl ketones (Scheme 1.43) [101, 102]. Remarkably, 120 facilitated the addition of silyl enol ether (121) to chiral aldehyde (122) and the subsequent syn reduction of the resulting aldol adduct to give diol (123) with excellent diastereoselectivity in 64% yield. In turn, Corey reported that Mukaiyama aldol additions of silyl enol ethers (42)to representative aldehydes in the presence of catalytic amounts of tryptophan-derived chiral borane complex (124) furnished β-hydroxy ketones (125) enantioselectively 28 1 Stereoselective Acetate Aldol Reactions

t-Bu Me3Si O O t-Bu t-Bu MeO O O O Me3Si Ti t-Bu O O L3 O O O Ti MeO R H R L3

t-Bu t-Bu

Me SiO O SiMe 3 t-Bu t-Bu O O 3 O O O O Ti Me3Si MeO R O O L3 Ti O O L3 MeO R MeO R XXIV

Scheme 1.42 Mechanism for the asymmetric Mukaiyama aldol reaction catalyzed by Car- reira’s titanium complex.

Ts N O OTMS O O B O OH O H 120 + PhO H ° PhO CH2Cl2, –78 C O dr 87 : 13 72% O

TBS TBS MeO OTMS O O O O O OH O O 120 TMSO + H MeO ° CH2Cl2, –78 C O O dr 96 : 4 65% TBS O O OTMS O O O O O

BnO H

121 120, EtCN, –78 °C dr 99 : 1 64% O 122 (+ ca 10% aldol adduct)

TBS O O OH OH O O O O

BnO

123 O

Scheme 1.43 Asymmetric Mukaiyama aldol reactions catalyzed by a valine-derived N-tosyl oxazaborolidinone. 1.2 Mukaiyama Aldol Reaction 29

O N H N O Ts B OTMS O O OH Bu 124 (1) 1 + 2 1 2 R H R EtCN, –78 °C R R 1 1 2 d R : Ph e R :Bu R : CH2R, Cy, Ar 125 er 93 : 7 to 97 : 3 56–100% 42

Br O OH ° (2) (1) Furan, 5 mol% 124, CH2Cl2, –78 C CHO CO2Et OTMS 126 (2) ,THF, –78 °C Br OEt dr 83 : 17 er 86 : 14, 67% 112b

Scheme 1.44 Asymmetric Mukaiyama aldol reactions catalyzed by a tryptophan-derived chiral borane complex.

H N O O OH O H 2 O OH H R B Nu O 1 2 N H O O 1 2 R R O O Nu R R S O N B R2 OBu Ts O S Ts XXV XXVI

Scheme 1.45 Transition states for asymmetric Mukaiyama aldol reactions catalyzed by oxazaborolidinones.

((1) in Scheme 1.44) [103].5) In a ﬁne example of tandem catalysis, Carreira used this complex to construct the azabicyclononane core common to a family of biomolecules [104]. Thus, it catalyzed the Diels–Alder reaction of furan and bromoacrolein followed, on consumption of the educts, by aldol addition of silyl ketene acetal (112b), which led to the stereoselective formation of β-hydroxy ester (126) ((2) in Scheme 1.44) [105]. Mechanistic studies on these and other reactions and X-ray crystallographic evidence led to the suggestion that the stereocontrol achieved by these transformations arose from the assemblies shown in Scheme 1.45, wherein a hydrogen bond between formyl and oxygen came up as a crucial stereocontrol element [106]. Thus, pyramidalization of the sulfonamide due to a gearing interaction with the isopropyl substituent in Kiyooka’s complex XXV orients the sulfonamide residue to shield the Re face of the aldehyde, which impels the nucleophile to approach the opposite

5) Oxazaborolidinone (124) also participated in stereocontrolled additions of diene (104)to aldehydes affording dihydropyrones, but the enantioselectivity was modest in this case. 30 1 Stereoselective Acetate Aldol Reactions

O N B N OTBS O Ts Ph O OH 127 H i-PrOH (1) + 1 MeO R1 MeO H R BuCN, –78 °C 129 R1: CH R, Cy, t-Bu 131 2 er 88 : 12 to 99 : 1 60–80% CH=CHR, Ar O

O N B N Ts Ar OTMS O 128 H O OH Ar: 3,5-CF3Ph (2) + 1 1 H H R BuCN, –78 °C H R R1: alkyl, Ar 130 er 75 : 25 to 97 : 3 52–89% 132

O O (1) ent-127 HN O OTMS HN OH O EtCN, –78 °C (3) + O O O O O O H (2) HF·pyr THF/pyr, 0 °C 134 133 135 Lactimidomycin Single enantiomer 60%

Scheme 1.46 Asymmetric Mukaiyama aldol reactions catalyzed by tryptophan-derived B-aryl oxazaborolidinones.

face. Conversely, attractive π − π interaction in Corey’s complex XXVI blocks the Si face of the aldehyde and favors the attack of the nucleophile on the less hindered Re face. On the basis of these and other precedents [107], Kalesse reported that tryptophan-derived B-aryl oxazaborolidinones (127)and(128) underwent enantioselective vinylogous Mukaiyama aldol reactions from dienes (129)and(130), furnishing δ-hydroxy esters (131) or aldehydes (132) in high yields under stoichiometric conditions ((1) and (2) in Scheme 1.46). Importantly, the latter is the ﬁrst asymmetric vinylogous Mukaiyama aldol reaction with aldehyde-derived silyl dienol ethers. Moreover, B-phenyl oxazaborolidinone (127) was successfully used by Furstner¨ to assemble silyl enol ether (133) and aldehyde (134) in the penultimate step of the total synthesis of lactimidomycin (135) ((3) in Scheme 1.46) [108]. In turn, Harada also found that an allo-threonine-derived B-phenyl oxazaborolidinone catalyzed the enantioselective addition of dimethylsilyl ketene S,O-acetals to acetophenone [109]. In addition to these Lewis acids, Evans disclosed that Cu(II), Sn(II), and Sc(III) complexes of chiral pyridine-bisoxazoline (pybox) and bisoxazoline (box) ligands catalyze the asymmetric Mukaiyama aldol reactions of chelating electrophiles. For instance, low catalyst loadings of Cu(II) pybox–complex (136) were enough to trigger the addition of several nucleophiles to benzyloxyacetaldehyde, affording the 1.2 Mukaiyama Aldol Reaction 31

(1) 36a, 36b, 112b OTMS O OH 0.5 mol% CH Cl , –78°C 2 2 OBn 2 R R (2) 1 M HCl, THF O 137–139 O N O er > 99 : 1 95–99% OBn NCuN + H Ph Ph O O OH 2 SbF6 TMSO OTMS (1) 52a, CH Cl , –78 °C 2 2 OBn 136 MeO MeO (2) 1 M HCl, THF 140 er 98 : 2 96%

Scheme 1.47 Asymmetric Mukaiyama aldol reactions catalyzed by a pybox copper complex. corresponding aldol adducts (137–140) in high yields and excellent stereocontrol (Scheme 1.47) [110]. The proposed catalytic cycle for these aldol reactions is outlined in Scheme 1.48. Coordination of the aldehyde to the Cu(II) center produces complex XXVII, which undergoes the nucleophilic addition to produce a copper aldolate XXVIII. Importantly, both intra- and intermolecular fast silyl transfers form XXIX and subsequent decomplexation affords the aldol adduct and regenerates catalyst (136). In turn, a stereochemical model XXX containing a chelated α-OBn aldehyde at the metal center, which forms a square pyramidal copper intermediate, accounts for the direction of the induction observed. Unfortunately, only benzyloxy-like acetaldehydes participated in this highly enantioselective reaction. Other aldehydes capable of engaging in ﬁve-membered chelated complexes such as glyoxalate esters required Sn(II)-box or Sc(III)-pybox complexes (141a and 142a, respectively) to react with silyl ketene S,O-acetals with similar levels of enantioselectivity ((1) and (2) in Scheme 1.49) [111, 112].

SiMe O O 3 O [CuL ] (SbF ) R Bn 3 6 2 O O H Bn 2 O Me3Si L3 L3 O O Cu O Cu Ph N N O O O N Cu R Bn H Bn O Ph XXIX XXVII H O OSiMe 3 Bn L XXX Me Si 3 Nu 3 O O Cu R O R Bn XXVIII

Scheme 1.48 Mechanism for asymmetric Mukaiyama aldol reactions catalyzed by a pybox copper complex. 32 1 Stereoselective Acetate Aldol Reactions

O O (1) 10 mol% N N 141a Sn OTMS O Bn TfO OTf Bn O OH ° CH2Cl2, –78 C + OEt OEt (1) PhS H PhS (2) 1 M HCl, THF O O er 99 : 1 90%

SbF6 O O N (1) 10 mol% NScN 142a Cl Cl OTMS O Ph Ph O OH CH Cl , –78 °C OEt 2 2 OEt (2) t-BuS + H (2) 1 M HCl, THF t-BuS O O er 95 : 5 92%

SbF6 O O N (1) 10 mol% NScN 142b Cl Cl OTMS O t-Bu t-Bu O OH ° 2 equiv TMSCl, CH2Cl2, –78 C + OEt OEt (3) Ar H Ar (2) 1 M HCl, THF O O Ar: 2,6-Cl2Ph, 2-BrPh er 96 : 4 to 98 : 2 91–96% 144 143 O O (1) 10 mol% N N 141b Sn t-Bu t-Bu OTMS O TfO OTf O OH THF, –78 °C + OR OR (4) t-BuS t-BuS (2) 1 M HCl, THF O O er > 99 : 1 91–96% 145 R: Me, Bn, t-Bu

Scheme 1.49 Asymmetric Mukaiyama aldol reactions catalyzed by box and pybox complexes.

Therefore, other enolsilanes were surveyed in an effort to expand the scope of this glyoxalate aldol process. It was found that the addition of silyl enol ethers (143) catalyzed by Sc(III)-pybox (142b) furnished α-hydroxy-γ -keto esters (144)inhigh yields and excellent enantioselectivity, provided that TMSCl was added to facilitate catalyst turnover ((3) in Scheme 1.49). Importantly, t-Bu-catalyst (142b)affordedthe opposite direction of induction to that of 142a. Steric factors within the chiral pocket affecting the location of the aldehyde carbonyl in the complex have been proposed to explain this different behavior. Furthermore, Evans reported in a brilliant study that Sn(II)-box (141b) catalyst promoted highly enantioselective additions of silyl ketene S,O-acetals to pyruvate esters affording functionalized hydroxysuccinate 1.2 Mukaiyama Aldol Reaction 33 derivatives (145) with an absolute stereocontrol ((4) in Scheme 1.49) [113]. The scope of this reaction was further extended to include nucleophiles such as silyl enol ethers from methyl ketones and other electrophiles capable of providing five-membered chelated complexes such as 1,2-diketones. In spite of such advances, these transformations lack generality and can only be applied to a selected set of electrophiles, although their outstanding levels of enantioselectivity have allowed them to be widely used in the synthesis of natural products [114]. Beyond the results themselves, these studies had a profound impact on asymmetric reactions, because they introduced new concepts and chiral ligands suitable for Lewis-acid-mediated transformations based on aldehydes or ketones with chelating functional groups. Therefore, it is not surprising that a large amount of work has been devoted to surveying alternative box- and pybox-like ligands or to identifying other metals to catalyze such reactions [115–117]. Furthermore, they also inspired the development of new catalysts, such as C1-symmetric aminosulfoximines reported by Bolm, which undergo Cu(II)-catalyzed reactions with pyruvate esters [118], or a peptide bearing a Schiff base disclosed by Hoveyda, which promotes highly successful and experimental friendly AgF2-mediated stereocontrolled additions to a wide array of α-keto esters [119]. Regarding the use of copper-derived Lewis acids, Carreira devised a different way of taking advantage of the resultant chiral catalysts [120]. This involved the addition of O-silyl dienolate (117)toα, β-unsaturated and aromatic aldehydes catalyzed by a chiral copper complex generated in situ by mixing (S)-Tol-BINAP (146), Cu(OTf)2, and (Bu4N)Ph3SiF2 (TBAT), which afforded aldol adducts (147) with enantiomeric ratios up to 98 : 2 ((1) in Scheme 1.50). In turn, Campagne expanded the scope of this methodology to methyl ketones and diene (148), obtaining lactones (149) in modest to high yields in stereocontrolled way ((2) in Scheme 1.50) [121]. This reliable methodology has been often used in the synthesis of natural products. For instance, Scheidt used the diastereoselective reaction of 117 and chiral aldehyde (150) to prepare aldol (151), an important fragment of the total synthesis of (−)-okilactomycin (152) ((3) in Scheme 1.50) [122, 123]. Importantly, other Cu(I) sources served equally well as Cu(OTf)2. This result, along with the known reduction of Cu(II) to Cu(I) by enolsilanes, suggested that a Cu(I) complex was the catalytic species. Further spectroscopic studies confirmed this hypothesis and also supported a mechanism in which a copper enolate acted as the reactive species ((1) in Scheme 1.51). Nevertheless, studies on related additions from dienes such as 148 led Campagne to point out that this model did not account for the origin of the enantioselectivity because the chiral copper center is far away from the aldehyde. Instead, the reaction might proceed through an initial nonselective α-aldol, followed by a retroaldol step, producing a C-enolate that would evolve toward an allyl-copper intermediate, which would finally undergo an asymmetric allylation ((2) in Scheme 1.51) [124]. Finally, some studies have recently focused on the use of chiral Brønsted acids and other protic catalysts to control the stereochemical outcome of these reactions. Rawal described the first examples of hydrogen-bond-mediated enantioselective Mukaiyama acetate aldol reactions, which involved additions of O-silyl dienolates 34 1 Stereoselective Acetate Aldol Reactions

(1) 2 mol% P(p–MePh) 2.2 mol% Cu(OTf)2 2 4 mol% TBAT P(p–MePh)2 ° O O O THF, –78 C O O OH 146 (1) TMSO + H R1 O R1 (2) TFA, –78 °C to rt 1 117 R : CH=CHR, Ar er 92 : 8 to 98 : 2 48–98% 147 O TMSO O 11 mol % 146 10 mol% Cu(OTf)2, 20 mol % TBAT O (2) EtO + R1 149 THF, rt 1 1 R 148 R : alkyl, Ar R1: alkyl er > 94 : 6 39–81% R1:Ar er 80 : 20 to 91:9 39–71%

O O O OTBDPS (3) TMSO + H O O 117 150 25 mol% 146 H 20 mol% Cu(OTf)2, 30 mol% TBAT O THF, –50 °C CO2H O O OH OTBDPS O (–) Okilactomycin 152 151 dr 91 : 9 70%

Scheme 1.50 Asymmetric Mukaiyama aldol reactions catalyzed by a Tol-BINAP copper complex.

Cu(OTf)2 + Bu4N Ph3SiF2

(S) Tol–BINAP R1CHO ∗ O O ∗ O O O O OCuL CuFL (1) ∗ 1 TMSO ∗ L CuO O R L : (S) Tol–BINAP

O O OTMS O O

O R1 TMSO

O ∗ TMSO O OCuL O O R1CHO R1CHO O 1 (2) RO ∗ RO R RO RO CuFL ∗ ∗ 1 CuL CuL R C-enolate allyl–copper

Scheme 1.51 Proposed mechanisms for Mukaiyama aldol reactions catalyzed by Tol-BINAP copper complexes. 1.2 Mukaiyama Aldol Reaction 35

O S (1) 1mol % P NHTf 153 O

Ar Ar: 2,6-(i-Pr) -4-(9-anthryl)-C H OTMS O 2 6 2 O OH ° 1 : 1 PhCH3/hexane, –86 C,12–24 h Ar + H R1 Ar R1 (2) 1 M HCl 154 R1: CH=CHR, Ar 155 er 81 : 19 to 95 : 5 87–96%

Scheme 1.52 Asymmetric Mukaiyama aldol reactions catalyzed by a chiral N-triflylthiophosphoramide. to reactive aldehydes in the presence of diols as catalysts [125, 126]. Furthermore, Yamamoto found that catalytic amounts of N-triflylthiophosphoramide (153) promoted stereocontrolled additions of silyl enol ethers (154) from aryl methyl ketones to α, β-unsaturated and aromatic aldehydes, affording the corresponding β-hydroxy ketones (155) in high yields (Scheme 1.52) [127]. Importantly, mechanistic studies revealed that the actual catalyst was 153 itself rather than the silylated Brønsted acid. In turn, List reported that chiral disulfonimide (156) was an efficient catalyst for different Mukaiyama aldol reactions. Indeed, tiny amounts of this chiral Brønsted acid triggered additions of silyl ketene acetal (27c) to nonenolizable aldehydes, producing β-OTBS isopropyl esters (157) in high yields and enantioselectivities ((1) in Scheme 1.53) [128]. This chemistry was further extended to vinylogous and bisvinylogous additions of (158a)and(159)toα, β-unsaturated and aromatic aldehydes, which afforded the corresponding methyl esters (160)and(161)in a regio and stereocontrolled manner ((2) and (3) in Scheme 1.53) [129]. The mechanism of these transformations is unknown, but it was proposed that 156 might be first silylated by the ketene acetal, providing an N-silyl disulfonimide that could activate the aldehyde through O-silylation. Thus, the asymmetric induction would occur by stereochemical communication within an ion pair consisting of the disulfonimide anion and the silylated oxonium cation. Irrespective of such mechanistic considerations, these findings have paved the way for the development of a new sort of transformations based on the appropriate choice of chiral hydrogen-bond donors [130].

1.2.6 Chiral Lewis Bases

In addition to the above-mentioned methodologies based on the increase of the electrophilicity of aldehydes by binding Lewis or Brønsted acids to the carbonyl group, Denmark developed a variant of the Mukaiyama aldol reaction that takes advantage of the Lewis acidic silicon atom of trichlorosilyl enolates. Thereby, association of these enolates with Lewis bases gives rise to a hypervalent silicon 36 1 Stereoselective Acetate Aldol Reactions

SO2 0.5–2 mol% NH SO2 OTBS O Ar O OTBS 156 Ar: 3,5-(CF3)2Ph (1) + 1 1 i-PrO H R ° i-PrO R Et2O, –78 C, 12–24 h 1 27c R : CH=CHR, Ar er > 92 : 8 86–95% 157

OTBS O O OTBS 5 mol % 156 (2) + 1 1 MeO H R ° MeO R Et2O, –78 C, 72 h 1 158a R : CH=CHR, Ar er 78 : 22 to 98 : 2 65–80% 160

OTBS O O OTBS 5 mol % 156 (3) + 1 1 MeO αγε H R ° MeO R Et2O, –78 C, 72 h 1 159 R : CH=CHR, Ar er 76 : 24 to 95 : 5 161 ε/α up to 89 : 11 37–75%

Scheme 1.53 Asymmetric Mukaiyama aldol reactions catalyzed by a chiral disulfonimide.

moiety characterized by enhanced Lewis acidity. Thus, such a reacting species is poised for activation of the carbonyl component, which allows it to participate in highly efﬁcient aldol reactions (Scheme 1.2) [9]. Systematic investigation on aldol reactions of trichlorosilyl enolates revealed that chiral phosphoramide (162) triggered highly enantioselective additions of methyl ketone-derived enolates (163) to branched aliphatic, α, β-unsaturated, and aromatic aldehydes, affording β-hydroxy ketones (164) in high yields ((1) in Scheme 1.54).

Importantly, the Hg(II)-catalyzed transilylation of TMS enol ethers (42) with SiCl4 provided an entry to a one-pot method for the generation and reaction of these enolates with similar yields and enantioselectivities ((2) in Scheme 1.54) [131]. Echavar- ren used this method to prepare β-hydroxy ketone (165), an intermediate in the enantioselective synthesis of (−)-englerins A and B (166) ((3) in Scheme 1.54) [132]. This method was further tested on chiral substrates with different results. For instance, the additions of trichlorosilyl enolate from lactate-derived silyl enol ether (167) to benzaldehyde catalyzed by 162 or ent-162 produced the same 1,4-syn aldol (168) in both cases ((1) in Scheme 1.55). Conversely, parallel aldol additions of trichlorosilyl enolates from β-silyloxy silyl enol ethers (169)and(170)producedthe corresponding aldol adducts (171–174) depending on the phosphoramide ((2) and (3) in Scheme 1.55) [133]. The mechanism of all these reactions is rather complex. Indeed, exhaustive studies established that the process takes place via the simultaneous operation of two mechanistic pathways involving one or two phosphoramides bound to 1.2 Mukaiyama Aldol Reaction 37

Me Ph N O (1) 5–10 mol% P ° N N CH2Cl2, –78 C Ph OSiCl3 O Me O OH 162 (1) R1 + H R2 R1 R2 (2) NaHCO3 1 2 R : Me, CH2R, i-Pr R : CHR2, CH=CHR, Ar er 91 : 9 to 96 : 4 81–98% 164 163

OTMS O (1) Hg(OAc)2, SiCl4, CH2Cl2 O OH ° (2) 5–10 mol % 162, CH2Cl2, –78 C (2) R1 + H R2 R1 R2 (3) NaHCO3 2 42 R : CHR2, CH=CHR, Ar 164

OSiCl3 O (3) + H OTES

° 5 mol% ent-162, CH2Cl2, –78 C Ph O

O O OH H (–) Englerins A and B O A (R:H) B (R:COCH2OH) OTES H OR 166 dr > 93 : 7 91% 165

Scheme 1.54 Asymmetric Mukaiyama aldol reactions catalyzed by chiral phosphoramides. the silicon atom in cationic complexes XXXI and XXXII (Scheme 1.56). Their subsequent association with the aldehyde leads to a reversible albeit unfavorable formation of an activated complex, which evolves through cyclic transition states XXXIII or XXXIV. The rate of this cycle determines the turnover as well as the stereochemical outcome of the aldol reaction [134]. Thus, the achievement of highly stereocontrolled transformations requires that the aldol reaction mainly proceeds through one of these competitive pathways. A second type of Lewis base catalysis involves activation of weakly acidic SiCl4 by binding of strong Lewis basic chiral phosphoramide (175),whichleadstothe formation of a chiral Lewis acid in situ. This species has been shown to be a competent catalyst for Mukaiyama aldol additions of achiral and chiral silyl enol ethers to α, β-unsaturated and aromatic aldehydes (Scheme 1.57) [133, 135]. Furthermore, these procedures were also successful for the additions of silyl ketene acetal (27a) and vinylogous systems (158b)and(176)toabroadscope of aldehydes, affording β-andδ-hydroxy esters (177–179) in high yields and exceptional levels of regio- and enantioselectivity, which expanded the synthetic potential of this methodology (Scheme 1.58) [136–138]. Although the origin of the observed enantioselectivity is still unclear, spectroscopic and mechanistic studies of these reactions suggested that the catalytic 38 1 Stereoselective Acetate Aldol Reactions

O OH (1) SiCl4, 1 mol% Hg(OAc)2, CH2Cl2, rt ° Ph (2) PhCHO, 5 mol% 162, CH2Cl2, –78 C OTMS TBSO dr 60 : 40 85% (1) 168 TBSO O OH 167 (1) SiCl4, 1 mol% Hg(OAc)2, CH2Cl2, rt ° Ph (2) PhCHO, 5 mol% ent-162, CH2Cl2, –78 C TBSO dr > 98 : 2 85% 168

O OH (1) SiCl4, 1 mol% Hg(OAc)2, CH2Cl2, rt ° TBSO Ph (2) PhCHO, 10 mol% 162, CH2Cl2, –78 C OTMS dr 88 : 12 75% 171 (2) TBSO O OH 169 (1) SiCl4, 1 mol% Hg(OAc)2, CH2Cl2, rt ° TBSO Ph (2) PhCHO, 10 mol% ent-162, CH2Cl2, –78 C dr 95 : 5 80% 172

TBSO O OH (1) SiCl4, 1 mol% Hg(OAc)2, CH2Cl2, rt ° Ph (2) PhCHO, 10 mol% 162, CH2Cl2, –78 C 173 TBSO OTMS dr 81 : 19 58% (3) TBSO O OH 170 (1) SiCl4,1 mol% Hg(OAc)2, CH2Cl2, rt ° Ph (2) PhCHO, 10 mol% ent-162, CH2Cl2, –78 C 174 dr 85 : 15 61%

Scheme 1.55 Mukaiyama aldol reactions of chiral trichlorosilyl enolates catalyzed by chiral phosphoramides.

L Cl L R Cl SiCl3 Si Cl L O O OSi Ph N Cl R Cl O Cl P + R R N N XXXI Ph XXXII R PhCHO PhCHO

L L O Cl O OSiCl3 O OSiCl3 Cl Ph Si OSi O L Ph Cl Cl R Ph R Ph R O R XXXIII XXXIV Cationic octahedron chair Cationic trigonal bipyramide boat L: phosphoramide L: phosphoramide

Scheme 1.56 Mechanistic proﬁle adapted from the original proposed for the trichlorosilyl enolate from cyclohexanone. 1.2 Mukaiyama Aldol Reaction 39

SiCl4, 10 mol% i-Pr2NEt, 5 mol%

Me N O P N N (CH2)5 Me Me OTMS O O OH 2 175 (1) 2 + 1 2 1 R H R ° R R CH2Cl2, –78 C 2 1 R : n-Bu, i-Bu, i-Pr, Ph R : alkenyl, Ar er > 78 : 22 54–99% 42 O OH SiCl4, 5 mol% 175, 20 mol% i-Pr2NEt TBSO Ph CH Cl , –78 °C OTMS 2 2 dr 96 : 4 91% 172 (2) TBSO O OH 169 SiCl4, 5 mol% ent-175, 20 mol% i-Pr2NEt ° TBSO Ph CH2Cl2, –78 C dr 98 : 2 94% 171

TBSO O OH SiCl4, 5 mol% 175, 20 mol% i-Pr2NEt ° Ph CH2Cl2, –78 C 174 TBSO OTMS dr > 97 : 3 92% (3) TBSO O OH 170 SiCl4, 5 mol% ent-175, 20 mol% i-Pr2NEt ° Ph CH2Cl2, –78 C 173 dr > 97 : 3 94%

Scheme 1.57 SiCl4-mediated Mukaiyama aldol reactions of silyl enol ethers catalyzed by chiral phosphoramides.

OTBS O O OH SiCl , 5 mol% 175 (1) + 4 1 ° 1 MeO H R CH2Cl2, –78 C MeO R 1 27a R : alkyl, alkenyl, Ar er > 90 : 10 72–98% 177

OTBS O O OH SiCl4, 10 mol% 175 (2) + 1 1 EtO H R ° EtO R CH2Cl2, –78 C 1 158b R : alkyl, alkenyl, Ar er > 95 : 5 68–89% 178

O O O O O OH SiCl4, 10 mol% 175 (3) + 1 1 TBSO H R ° O R CH2Cl2, –78 C 1 176 R : alkyl, alkenyl, Ar er > 87 : 13 83–92% 179

Scheme 1.58 SiCl4-mediated Mukaiyama aldol reactions catalyzed by chiral phosphoramides. 40 1 Stereoselective Acetate Aldol Reactions

cycle involved a highly electrophilic, phosphoramide-bound silyl cation XXXV (Scheme 1.59). This species could then bind the aldehyde to form complex XXXVI, which would undergo the addition of the enolsilane through an open transition state. After cleavage of the silyl group and dissociation of the catalyst, the resultant aldolate XXXVII would give a trichlorosilyl ether (Scheme 1.59) [136, 139]. Finally, Denmark also reported that bis N-oxide (180), a Lewis base, catalyzed the aldol addition of methyl trichlorosilyl ketene acetal to a wide range of nonactivated ketones (Scheme 1.60). The resultant β-tert-hydroxy esters were obtained in excellent yields with enantioselectivities highly dependent on the structure of the ketone [140]. From a mechanistic point of view, this reaction is understood to proceed through a six-membered boatlike transition state organized around a cationic silicon center, in a way similar to the aldol additions to aldehydes described in Scheme 1.56.

O O OSiCl3 P 1 NR2 SiCl RO R R2N 4 NR2 TBSCl L

Cl TBS Cl Cl O OSiCl L 3 2 L Si L Cl RO R1 Cl XXXV XXXVII Cl R1CHO Cl L L OTBS Si Cl O R1 RO Cl H XXXVI

Scheme 1.59 Mechanism for the SiCl4-asymmetric Mukaiyama aldol reactions catalyzed by chiral phosphoramides.

° (1) 10 mol% 180, CH2Cl2, –20 C

N N t-Bu O O t-Bu O O OSiCl O O OH 3 n-Bu 180 n-Bu + 2 MeO R1 R2 MeO R (2) NaHCO3 R1 R1: alkyl, alkenyl, alkynil, Ar er 55 : 45 to 94 : 6 2 R : Me, Et, CH2R, alkynil 84–96%

Scheme 1.60 Asymmetric Mukaiyama aldol reactions catalyzed by a chiral bis N-oxide. 1.3 Metal Enolates 41

1.3 Metal Enolates

1.3.1 Concept and Mechanism

The enolization of a parent carbonyl compound with a strong base, a suitable com- bination of a Lewis acid and a tertiary amine, or by simple transmetallation affords metal enolates from nearly every element of the periodic table [141], which suggests that any element could participate in asymmetric aldol reactions. Nevertheless, only a narrow group of elements including lithium, boron, titanium, or tin fulﬁll the required conditions to undergo stereocontrolled aldol transformations. In essence, the conﬁgurationally stable O-enolates of these elements allow the aldol reactions to proceed through cyclic and highly organized transition states. Such transition states provide the appropriate environment to control the new stereocenters provided that the appropriate chiral elements are placed on the substrate, the aldehyde, or the ligands bound to the metal. Unfortunately, acetate aldol reactions mediated by such intermediates can evolve through different six-membered cyclic transition states XXXVIII–XLI (Scheme 1.61), which hampers the proper differentiation of the two faces of the carbonyl bond by the unsubstituted enolate. Indeed, pioneering studies soon recognized that the stereochemical control on the metal-enolate-mediated acetate aldol reaction (R2 = H in Scheme 1.1) was much more demanding than control on the similar propionate counterpart (R2 = Me in Scheme 1.1). Hence, this challenging transformation has attracted much attention in recent decades. At present, a wide range of highly stereoselective acetate aldol

O O OH

R1 R1 R2 New carbon-carbon bond A new stereocenter

Ln H Ln ML M M O m O O R2 R2CHO OO R1 R1 R1 R2 Metal enolate M: Li, B, Ti, Sn,... R1 1 R2 O R OR2 L M 2 2 ML n R MLn Transition state geometries R O n O O L M O O O n R1 R1 Chair Boat A Boat B Twist boat XXXVIII XXXIX XL XLI

Scheme 1.61 Metal-enolate-mediated acetate aldol reactions. 42 1 Stereoselective Acetate Aldol Reactions

reactions based on metal enolates from chiral auxiliaries, chiral Lewis acids, and chiral ketones complement the accomplishments described in the previous section.

1.3.2 Chiral Auxiliaries

The poor stereocontrol observed in preliminary studies on aldol reactions from unsubstituted enolates triggered an intense search for an efﬁcient covalently bound chiral auxiliary. Among the large number of reported auxiliaries, chiral 1,1,2-triphenylethanediol arising from mandelic esters quickly achieved a promi- nent position [142]. Indeed, the lithium enolate from acetate (181) (Scheme 1.62) provides high yields and diastereoselectivities and has been successfully used in the synthesis of β-hydroxy carbonyl structures present in natural products [142b, 143]. However, the extremely low temperatures essential to attain high diastereoselectivities thwarted further applications and the quest for a more general approach remained active [144, 145]. Thus, considering that boron enolates from N-acetyl oxazolidinone (182) (Scheme 1.63) afforded nearly equimolar mixture of diastereomers [3a, 146, 147], Nagao and Fujita ﬁndings on unprecedented stereocontrolled

O Ph OH O Ph ° OH (1) LDA, THF, 0 C OH O O (2) i-PrCHO, T < –106 °C Ph Ph Ph Ph 181 dr 95 : 5 ~100%

Scheme 1.62 Chiral auxiliary-based lithium-mediated stereoselective aldol reaction.

O O O O OH ° (1) Bu2BOTf, i-Pr2NEt, CH2Cl2, –78 C O N O N (2) i-PrCHO, –78 °C

i-Pr dr 52 : 48 86% i-Pr 182

S O S O OH ° (1) Sn(OTf)2, (C5H10)NEt, CH2Cl2, –40 C O N O N (2) i-PrCHO, –78 °C

Et dr 91 : 9 60% Et 183

S O S O OH ° (1) Sn(OTf)2, (C5H10)NEt, CH2Cl2, –40 C S N S N Ph (2) PhCH=CHCHO, –78 °C

i-Pr dr 97 : 3 81% i-Pr 184

Scheme 1.63 Chiral auxiliary-based tin(II)-mediated stereoselective aldol reactions. 1.3 Metal Enolates 43

OTf OTf S O Sn S O Sn S O OH S O Sn(OTf)2 RCHO O X N X N X N R R (C H )NEt X N 1 5 10 R R1 R1 R1

Scheme 1.64 Mechanism for tin(II)-mediated aldol reactions.

Sn(II)-mediated aldol reactions from N-acetyl oxazolidinethione (183) [148] and thiazolidinethione (184) [149]6) were particularly outstanding (Scheme 1.63). The rationale for these highly stereoselective transformations placed four ligands on the Sn(II) atom in the transition state. Hence, the exocyclic sulfur atom was responsible for the lasting chelated tin enolate and the coordination of the incoming aldehyde far from the R1 group of the chiral auxiliary (Scheme 1.64). Eventually, a chairlike cyclic six-membered transition state accounted for the conﬁguration of the new stereocenter in the major diastereomer. This methodology has been largely used in the synthesis of natural products [150]. Its synthetic potential can be illustrated by the syntheses of (+)-phorboxazole A (185), reported by Smith et al. [151], in which the highly diastereoselective addition of the Sn(II)–enolate from ent-184 to chiral aldehyde (186) followed by the easy removal of the chiral auxiliary of the resultant aldol (187) furnished the desired β-hydroxy acid (188) in excellent overall yield (Scheme 1.65). Despite these successes, the attention was focused on the development of similar procedures using other Lewis acids. In this context, Yan took advantage of Ti(IV)-mediated aldol reactions from camphor-derived thioimide (189)with representative aldehydes to obtain adducts 190 in excellent yields and diastereoselectivities ((1) in Scheme 1.66) [152]7) whereas Urp´ı and Vilarrasa used N-acetyl thiazolidinethione (184) in parallel aldol additions to α, β-unsaturated aldehydes to yield aldols (191) in high diastereomeric ratios ((2) in Scheme 1.66) [153]. Last approach was particularly inspiring because both enantiomers of the chiral auxiliary can be prepared from natural and unnatural α-amino acids [154], TiCl4 is an easily available Lewis acid, and permitted the isolation of pure diastereomers 191 in higher yields than the Sn(II)-based methodology. Then, the stage was set for further developments in this area. The crucial role of the exocyclic C=S bond was well established through careful analyses of aldol reactions involving N-acetyl oxazolidinones. As for boron enolates, titanium-mediated aldol reaction from N-acetyl-4-isopropyl-1,3-oxazolidin-2-one (182) (Scheme 1.63) gave good yields but poor diastereoselectivities [155], whereas the stereochemical outcome from a close 5,5-disubstituted oxazolidinone turned out to be dramatically dependent on the metal of the enolate [156]. Thus, the most striking advances came up from sulfur-containing chiral auxiliaries. Indeed, Phillips [157] and Crimmins

6) Oxazolidinethiones turned out to be slightly less stereoselective than the corresponding thiazolidinethiones for α, β-unsaturated aldehydes. 7) Boron enolates afforded lower diastereomeric ratios. 44 1 Stereoselective Acetate Aldol Reactions

OTf O Sn S O H O OTBDPS S O OH 186 S N ° S N O OTBDPS CH2Cl2, –78 C dr 91 : 9 91% 187

MeO Br OH ° LiOH, H2O2, THF, 0 C 99% O

N O MeO OH O O O O O OH HO N O HO O OTBDPS O 188 185 (+)-Phorboxazole A

Scheme 1.65 Synthesis of (+)-phorboxazole A.

S O S O OH ° (1) TiCl4, i-Pr2NEt, CH2Cl2, –78 C (1) O N O N R (2) RCHO, –78 °C

dr > 91 : 9 85–91% 189 190

S O S O OH ° (1) TiCl4, i-Pr2NEt, CH2Cl2, –40 C (2) S N S N R (2) RCH=CHCHO, –78 °C i-Pr dr 90 : 10 64–82% i-Pr 184 191

Scheme 1.66 Chiral auxiliary-based titanium(IV)-mediated stereoselective aldol reactions.

[158] reported that N-acetyl oxazolidinethiones (192)and(193) underwent highly diastereoselective additions to aliphatic, α, β-unsaturated, and aromatic aldehydes, affording aldols (194)and(195) in high yields and diastereoselectivities ((1) and (2) in Scheme 1.67), whereas Sammakia [159], Crimmins [158, 160], and Olivo [161] described that boron and titanium enolates from N-acetyl thiazolidinethiones (196–198) provided high levels of stereocontrol with a wide range of aldehydes, affording aldols (199–201) in high yields ((3–5) in Scheme 1.67) [162]. This chemistry has been widely applied to the synthesis of natural products [163], as can be illustrated by two concurrent reports on the total synthesis of cyanolideA(202). Thereby, Pabbaraja took advantage of a highly diastereoselective 1.3 Metal Enolates 45

S O S O OH (1) 1 equiv TiCl4, 1 equiv (–)-sparteine, 1 equiv NMP ° CH2Cl2, 0 C (1) O N O N R (2) RCHO, –78 °C Ph Ph 194 Ph dr > 85 : 15 55–90% Ph 192 S O S O OH ° (1) 2 equiv TiCl4, 2 equiv i-Pr2NEt, CH2Cl2, –40 C (2) O N O N R (2) RCHO, –78 °C

dr > 93 : 7 72–89% 195

193

S O S O OH (1) 1.3 equiv PhBCl2, 2.6 equiv (–)-sparteine CH2Cl2, rt (3) S N S N R (2) RCHO, –78 °C to rt 199 dr > 90 : 10 65–92% 196 S O S O OH ° (1) 1 equiv TiCl4, 1 equiv i-Pr2NEt, CH2Cl2, –78 C (4) S N S N R (2) RCHO, –78 °C dr > 94 : 6 79–95% 200

197

S O (1) 1 equiv TiCl4, 1 equiv (–)-sparteine S O OH ° CH2Cl2, –78 C (5) S N S N R (2) RCHO, –78 °C dr > 91 : 9 91–98% 201

198

Scheme 1.67 Oxazolidinethione- and thiazoldinethione-based stereoselective aldol reactions. titanium-mediated aldol reaction of N-acetyl thiazolidinethione (203) and aldehyde (204) to prepare aldol (205), which was subsequently treated with MeNHOMe·HCl to remove the chiral auxiliary and produce Weinreb amide (206) in an excellent yield ((1) in Scheme 1.68) [164]. In turn, Rychnovsky claimed that similar titanium- and tin-based methodologies on aldehyde (207) led exclusively to the pro- todesilylated product, but the reaction proceeded smoothly using boron-mediated Sammakia’s conditions to provide aldol adduct 208 as a single diastereomer, which was easily converted into carboxylic acid (209) ((2) in Scheme 1.68) [165]. The mechanism of these transformations is poorly understood, and alternative models are often proposed. This is the case of thiazolidinethione (196). As 46 1 Stereoselective Acetate Aldol Reactions

(1) TiCl , i-Pr NEt MeNHOMe·HCl S O 4 2 S O OH OBn O OH OBn CH Cl , 0 °C imidazole 2 2 Me (1) S N O OBn S N N CH2Cl2, rt (2)H , –78 °C 97% OMe Bn Bn 203 204 205 206 dr 90 : 10 85%

S O (1) PhBCl2, (–)-sparteine S O OH O OH CH Cl , rt LiOH 2 2 TMS TMS (2) S N O S N ° HO THF, H2O, 0 C (2) TMS, 0 °C 91% H 196 207 208 209 Single diastereomer 70% Et OMe MeO OMe O O O O O O O MeO O MeO O O 202 Cyanolide A OMe Et

Scheme 1.68 Synthesis of cyanolide A.

Ph Cl S B S O S O OH R N S H H S N or S N R H O LnB O R H O H H

XLII XLIII

2 R H Cl R2 4 X H Ti S O OH R O 1 O R N S H X N R H or N 1 S R 2 TiCl R 1 R O 3 R2 R H X O R2 R2 H Phillips X: O R1: i-Pr R2: Ph 1 2 XLIV XLV Crimmins X: S R : 2,4,6-Me3Ph R : H

Scheme 1.69 Transition states for oxazolidinethione- and thiazolidinethione-based aldol reactions. Evans oxazolidinone auxiliary fails to give high selectivities in acetate aldol reactions, Sammakia speculated that the boron-mediated reaction from 196 ((3) in Scheme 1.67) proceeded through an open transition state, but a more common cyclic chairlike transition state was not ruled out (XLII and XLIII, respectively, in Scheme 1.69) [159a]. On the other hand, the opposite stereochemistry obtained in the titanium-mediated reactions led Phillips [157a] and Crimmins [158] to propose a chelated chairlike or a non-chelated boatlike transition states (XLIV and XLV, respectively, in Scheme 1.69) to account for the observed stereocontrol. 1.3 Metal Enolates 47

1.3.3 Stoichiometric Lewis Acids

Simultaneously to the search for a covalently bound chiral auxiliary, many efforts were invested in the development of chiral Lewis acids. Thereby, the coordination of a Lewis acid to a carbonyl should enhance its acidity and allow the formation of the corresponding enolate by simple addition of a tertiary amine. Alternatively, it could also be introduced by transmetallation of a preformed enolate. In any case, chiral ligands on these Lewis acids should provide the source for a proper discrimination of the two faces of the C=Obondofthealdehydeinsuchaway that the stereoselective carbon–carbon bond formation would render the desired aldol adduct without the need of further synthetic steps. Therefore, this approach would avoid the introduction and the removal of the chiral auxiliary, increasing the efﬁciency of the process. The Lewis acids (210–215) represented in Scheme 1.70 fulﬁlled such requirements and afforded the corresponding aldol products in excellent enantioselectivities [166–170].

B O O O OH i-Pr NEt RCHO (1) + B 2 Et CS TfO Et CS Et CS R 3 Pentane, 0 °C 3 –78 °C 3 166 Ph Masamune 210 Ts er > 95 : 5 71–95% Ph N Ts B Ph O N O N O OH Et N RCHO B Ph 3 (2) + Ts PhS Br N PhS PhS R CH Cl , rt –90 °C Ts 2 2 Corey167 211 er 92 : 8 to 96 : 4 82–84% B(Ipc) O O 2 O OH i-Pr2NEt or Et3N RCHO (3) 1 + 1 1 R XB ° R –78 °C R R CH2Cl2, –78 C Paterson168 2 er 77 : 23 to 89 : 11 48–78% 212 X: Cl 213 X: OTf BL O O 2 O OH Et N RCHO (4) + 3 R1S BrB R1S R1S R 1 : 1 CH Cl /Et O –78 °C 1 2 2 2 R :t -Bu, CEt3 15 °C 214 er > 92 : 8 60–90% Gennari169 2 Ti OLi O L2 O OH RCHO (5) + Ti t-BuO L L Et O, –30 °C t-BuO –78 °C t-BuO R Cl 2 170 215 Duthaler H O er > 95 : 5 51–80% O H O L: O H O H

Scheme 1.70 Chiral Lewis acids in asymmetric aldol reactions. 48 1 Stereoselective Acetate Aldol Reactions

Unfortunately, most of them have been scarcely used in the synthesis of natural products and a short number of applications can be found in the literature [171]. Commercially available isopinocampheylborane chloride (212) (Ipc2BCl) is the exception, because it participates in many double asymmetric aldol reactions from chiral ketones (Section 1.3.6) [1b, 168]. This failure is occasionally due to the troublesome preparation of some of these Lewis acids, but the Achilles heel of the overall strategy lies on the purification of the resulting products. Indeed, these Lewis acids must provide high stereoselective transformations, because mixtures of enantiomers cannot be easily purified and they come across the whole synthetic sequence. Thus, this strategy becomes synthetically useful when the aldol reaction proceeds in a highly stereoselective manner or is applied to chiral substrates, as occurs in the synthesis of Sch38516 aglycon (216) (Scheme 1.71). While lithium, sodium, or titanium enolates of chiral ketone (217) and aldehyde (218) delivered almost equimolar mixtures of both diastereomers, boryl bromide (214) provided a highly stereoselective aldol coupling (dr 95 : 5) and furnished pure aldol (219) in 40–45% yield after a simple chromatographic purification (Scheme 1.71) [171d].

1.3.4 Catalytic Lewis Acids

Inspired by Nature, the attention was also focused on class II aldolases that use zinc cations to activate the enolate partner (a metal enolate) as well as other centers on the enzyme assist to the activation of the incoming aldehyde. Considering such a mechanism, Shibasaki and Trost described the ﬁrst direct aldol reactions from unmodiﬁed methyl ketones in the presence of multifunctional catalysts.

TBDPSO

217

° (1) Lewis acid, R3N, Et2O, 4 C O OH (2) O H N3 218 HN O OH

TBDPSO N3 216 Sch38516 aglycon

219 dr 87 : 13 61% conversion with 212, i-Pr2NEt dr 95 : 5 79% conversion with 214, Et3N

Scheme 1.71 Synthesis of Sch38516 aglycon. 1.3 Metal Enolates 49

O O + R1 H R2 R1: Me, Et, Ph R2: Cy, i-Pr, t-Bu Li O O Li 20 mol% 220 THF, –20 °C O Ln O O O Li O OH

R1 R2 er 72 : 28 to 97 : 3 53–90% 220 (R)-LLB

H R1 O O Li O O R1 H R2 H 1 OLn R OLi O Li O

R1 H OLn H O OLnO O Li R2 O O OH R2 OLn R1 R2

Scheme 1.72 Asymmetric aldol reactions of methyl ketones catalyzed by LnLi3 tris(binaphthoxide).

Shibasaki reported that LnLi3 tris(binaphthoxide) (220) triggered direct catalytic asymmetric aldol reactions of methyl ketones and α-branched aldehydes under mild conditions in good to high yields (Scheme 1.72) [172, 173]. Heralding a new mechanistic paradigm, Shibasaki speculated that the central lanthanum(III) atom of 220 functions as a Lewis acid activating the aldehyde, whereas the lithium binaphthoxide moiety acts as a Brønsted base. Thus, this catalyst mimicked the enzymatic activity and permitted the efﬁcient stereoselective aldol reactions represented in Scheme 1.72 [174]. In turn, Trost described that one of the zinc atoms of bimetallic catalyst (221) could form the metal enolate while the second one bound to the aldehyde acting as a Lewis acid center. Then, aldol additions of aryl methyl ketones to α-branched aldehydes proceeded in good yields and outstanding enantioselectivities (Scheme 1.73) [175]. Furthermore, studies have expanded the scope of this procedure to other functionalizable ketones, such as methyl vinyl ketone, and the simple acetone [176]. Both methodologies were applied to the synthesis of fostriecin (222), using methyl ynones (223) as the active methylene partners (Scheme 1.74). Thereby, aldol addition of 223a to chiral aldehyde (224) in the presence of catalyst ent-220 gave aldol (225) in 65% yield and 78 : 22 diastereomeric ratio [177]. In turn, 221 catalyzed the reaction of 223b and α-ketal aldehyde (226) to produce aldol (227)asasingle enantiomer in 58% yield [178, 179]. 50 1 Stereoselective Acetate Aldol Reactions

Ph OH Ph HO Ph Ph O O N OH N Ar + H R1 Ar: Ph, naphthyl, 2-furyl R2: Cy, i-Pr, t-Bu 221 5 mol% 221 THF, 5 °C 15 mol% Ph3P=S, 4 Å MS

2 ZnEt2 –3 C2H6 O OH Et O O R Zn Zn R Ar R1 O er > 96 : 4 40–62% R ArCOMe –C2H6 O OH Ar 1 Ar R O O O O Zn R R Zn H R1 R1 O O Ar R R Ar O O Ar O O H O O O O R Zn Zn R1 O R Zn Zn O O O O Ar R O O R R Zn Zn R Ar O R

Scheme 1.73 Asymmetric aldol reactions of methyl ketones catalyzed by a zinc bimetallic complex.

More recently, Shibasaki has reported a new direct catalytic asymmetric aldol process inspired in the biosynthesis of 1,3-diols. This procedure takes advantage of a soft Lewis acid/hard Brønsted base cooperative catalyst comprising biphosphine (228) and [Cu(CH3CN)]PF6/LiOAr to promote enantioselective aldol additions of thioamides (229) to aliphatic aldehydes, affording aldols (230) in high yields (Scheme 1.75) [180]. These examples have stimulated the development of new metal catalysts, which proves the interest on this kind of reactions. Regrettably, most of them can be used on a reduced range of substrates or show a low reactivity, which restrict their synthetic scope [181].

1.3.5 Chiral Aldehydes

The asymmetric induction imparted by chiral aldehydes in aldol reactions involving achiral unsubstituted metal enolates is usually low. This is the case of chiral aldehydes bearing a Cα stereocenter. Indeed, pioneering studies revealed that 1.3 Metal Enolates 51

O O

O O H H 224 OMOM O EtO OEt 226 10 mol% ent-220 3 mol% 221, 4 Å MS

THF, –20 °C THF, rt SiR3

223a SiR3: SiMe3 223b SiR3: SiBnMe2 OH O OH O

O O

OMOM SiMe3 EtO OEt SiBnMe2 225 227 dr 78 : 22 65% 58% OH NaHO3PO OH O O OH 222 Fostriecin

Scheme 1.74 Synthesis of fostriecin.

Ph Ph P P 3 mol% Ph Ph 228 S O S OH 3 mol% [Cu(CH CN) ]PF R + 3 4 6 R N H R1 N R1 R R LiO R: Me, allyl 230 3 mol% 229 O er 94 : 6 to 97 : 3 76–89%

DMF, –60 °C, 40 h

Scheme 1.75 Asymmetric aldol reactions of thioamides catalyzed by a copper biphosphine complex. aldol additions of lithium, boron, and titanium enolates to these aldehydes led to the Felkin product with a simple 1,2-diastereoselection often insufﬁcient to be synthetically useful. For instance, the addition of lithium enolate from tert-butyl acetate to chiral aldehyde (28c)affordedFelkin 3,4-syn adduct (29c) in good yield but low diastereoselectivity ((1) in Scheme 1.76), much lower than that attained under Mukaiyama conditions [26, 182] (Schemes 1.13 and 1.14). This trend was also observed in chiral aldehydes possessing alkoxy groups at the Cβ position. Thereby, aldol additions of metal enolates from isopropyl methyl ketone to aldehyde (231) bearing a Cβ–OPMB group (or Cβ–OTBS) mainly gave 3,5-anti aldols (232)in excellent yields but low stereocontrol ((2) in Scheme 1.76) [43, 183], much poorer 52 1 Stereoselective Acetate Aldol Reactions

M O O O OH t-BuO (1) 4 H ° t-BuO 3 THF or CH2Cl2, –78 C 28c 3,4-syn 29c M: Li dr 60 : 40 78% M: TBS/BF3·OEt2 dr 94 : 6 77%

M O O OPMB O OH OPMB i-Pr (2) H ° i-Pr 3 5 THF or CH2Cl2, –78 C 231 3,5-anti 232 M: Li dr 71 : 29 99% M: 9-BBN dr 42 : 58 81% M: TiCln dr 60 : 40 98% M: TBS/BF3·OEt2 dr 92 : 8 91%

Scheme 1.76 Asymmetric induction imparted by chiral aldehydes in aldol reactions involving metal enolates.

than that provided by the Mukaiyama variant (Scheme 1.23). Interestingly, the best results were achieved with lithium enolates under conditions in which chelate organization was unlikely. Unfortunately, these studies did not permit a clear identiﬁcation of the dominant element governing the aldol reactions of chiral β-alkoxy α-methyl aldehydes. Thus, any prediction of the stereochemical outcome of such reactions must take into account the complete architecture of the substrates. A good example of these difﬁculties was described by Roush in the synthesis of (+)-tedanolide and (+)-13-deoxytedanolide (233 and 234, respectively, in Scheme 1.77). Indeed, lithium enolate derived from structurally complex methyl ketone (235) reacted with anti β-silyloxy α-methyl aldehyde (236) to give 3,4-syn aldol (237) in good yield and excellent diastereoselectivity (Scheme 1.77), whereas the parallel addition to syn β-silyloxy α-methyl aldehyde (238) provided a 78 : 22 mixture of diasteromers (239)in 40% yield (Scheme 1.77). Roush suggested that the diminished diastereoselectivity observed for the latter was due to a mismatched induction imparted by the syn-aldehyde (238), because the transition state XLVII for this aldol reaction was destabilized relative to the transition state XLVI from anti-aldehyde (236) because of the stereoelectronic repulsion of interacting dipole of the aldehyde carbonyl and the C15 OTES group [184, 185]. Chiral aldehydes bearing a Cα heteroatom are the exception to this rule, and some of them give access to highly stereocontrolled transformations. A systematic study of aldol additions to chiral α-alkoxy aldehydes carried out by Evans demonstrated that the stereocontrol provided by lithium enolates was superior to that obtained from the corresponding enolsilane nucleophiles. The levels of asymmetric induction are relatively insensitive to both the α-oxygen protecting group and the steric 1.3 Metal Enolates 53

TES TBS O OH O O O (1) LiHMDS, 4 Å MS, THF, –78 °C TES TBS O O OMe O OAlloc O O O ° (2) O , –78 C H TBSO OAllyl OTBS O OMe O OAlloc 236 dr > 95 : 5 59% 237 TBSO OAllyl OTBS TES TBS 235 O OH O O O (1) LiHMDS, 4 Å MS, THF, –78 °C OPMB TES TBS O OMe O OTBDPS O O O ° (2) O , –78 C H TBSO OAllyl OPMB OTBS OTBDPS 238 dr 78 : 22 40% 239 O R O HO O

O OMeO 233 R: OH (+)-Tedanolide 234 R: H (+)-13-Deoxytedanolide HO O OH O OTES OTBS PGO O OH OTES OTBS H TESO H R H 1 15 1 H 15 R R1 R 15 R H Li O Li TBSOH O O 236 OPG OPG XLVI R O OTES OTBS PGO O OH OTES OTBS H H H R H H R2 15 R2 15 R2 R 15 TBSO O O Li O 238 OPG H OPG TES XLVII

Scheme 1.77 Syntheses of (+)-tedanolide and(+)-13-deoxytedanolide. hindrance of the enolate, but they depend to some extent on the nature of the β-alkyl substituent. Thereby, aldol additions of lithium enolates from alkyl methyl ketones to α-OBn aldehyde (240) furnished 3,4-anti aldols (241) in high yields and excellent diastereoselectivities (Scheme 1.78) [38, 186]. Remarkable levels of stereocontrol can also be attained with chiral aldehydes possessing two alkoxy groups at Cα and Cβ positions, wherein the π-facial selectivity depends on their relative conﬁguration and the metal enolate. Thus, anti-α, β-bisalkoxy aldehydes (242) reacted with methyl ketone-derived lithium enolates to give consistently 3,4-anti aldols (243) in excellent yields irrespective of both protecting groups ((1) in Scheme 1.79), whereas syn-α, β-bisalkoxy aldehydes resulted more sensitive and only the additions of related enolborinates to syn-α, β-OTBS aldehyde (244) provided the corresponding 3,4-syn aldols (245)in high yields and diastereoselectivities ((2) in Scheme 1.79) [38]. Satake and Tachibana described that a related transformation involving a chiral bisalkoxy aldehyde played a crucial role in the total synthesis of (−)-brevisin (246). Thereby, aldol addition of 54 1 Stereoselective Acetate Aldol Reactions

M O O OH O 4 + H ° R 3 R CH2Cl2 or THF, –78 C OBn OBn R: Me, i-Pr, t-Bu 240 3,4-anti 241 M: TMS/BF3·OEt2 M: Li R: Me dr 80 : 20 67% dr 94 : 6 88% R: i-Pr dr 53 : 47 60% dr 91 : 9 84% R: t-Bu dr 64 : 36 65% dr 89 : 11 76%

Scheme 1.78 Asymmetric induction imparted by (R)-2-benzyloxy-3-methylbutanal.

Li O O OPG2 O OH OPG2 + 4 (1) R H R 3 THF, –78 °C OPG1 OPG1 R: Me, i-Pr, t-Bu PG1,PG2: Bn, dr > 98 : 2 83–99% 3,4-anti 243 TBS, CMe2 242 9-BBN O O OTBS O OH OTBS + 4 (2) R H R 3 CH Cl , –78 °C OTBS 2 2 OTBS R: Me, i-Pr, t-Bu 244 dr > 93 : 7 87–91% 3,4-syn 245 Bn Bn O O O O OH OTES BnO H O BnO H O (1) LDA, THF, 0 °C (3) O O (2) O OTES H H O O H , –78 °C O H H 249 H 247 H O O BnO BnO dr 74 : 26 80% 248 O BnO HO H BnO O OH OH O H O O H H H H O OH H H O 246 (–)-Brevisin H O

Scheme 1.79 Asymmetric induction imparted by α, β-bisalkoxy aldehydes in aldol reactions involving metal enolates.

lithium enolate from structurally complex methyl ketone (247)toanti-α, β-bisalkoxy aldehyde (248) led to the construction (dr 74 : 26) of polycyclic core 249 in 80% yield ((3) in Scheme 1.79), which suggests that the stereochemical outcome might be due to the above-mentioned trend [187, 188]. Aldol additions of lithium enolates to other chiral α-heterosubstituted aldehydes also show a similar trend favoring the 3,4-anti diastereomer. Thus, Britton observed that lithium enolates of methyl ketones reacted with α-chloro aldehydes (250)to provide the corresponding anti aldols (251) in good to high yields and diastereoselectivities up to 95 : 5 ((1) in Scheme 1.80) [189]. In turn, Carrillo and Badia reported 1.3 Metal Enolates 55

Li O O O OH R2 R2 (1) 1 + H 1 R THF, –78 °C R Cl Cl R1: alkyl, Ph R2: alkyl dr 80 : 20 to 95 : 5 63–90% 251 250 O O Ph Ph N N OH O OH O OH OH O Ph LDA ent-253 LDA 253 Ph (2) N H N O THF, –78 °C O THF, –78 °C O NBoc OH NBoc NBoc OH 255 dr 56 : 44 61% 252 dr 98 : 2 79% 254

Scheme 1.80 Asymmetric induction imparted by α-heterosubstituted aldehydes in aldol reactions involving metal enolates. that Garner’s aldehyde (252) underwent double asymmetric lithium-mediated aldol reactions with pseudoephedrine chiral auxiliaries (253), affording anti diastereomers 254 and 255 both for the matched and mismatched case ((2) in Scheme 1.80) [190].

1.3.6 Chiral Methyl Ketones

Unlike what happens with aldehydes, metal enolates from chiral methyl ketones are an important source of substrate-controlled aldol reactions, which are especially useful in advanced steps of the synthesis of natural products. Unfortunately, the clear understanding of these reactions is frequently challenged by the broad scope of substrates that can support them and the different sort of elements controlling their stereochemical outcome. Facing this problem and aiming to shed light to such intricate structural diversity, examples reported in the literature

O O OH OTIPS (1) LDA, THF, –78 °C R (1) N N 3 O OTIPS 3 OTMS (2) R 256 H Single diastereomer 94% OTMS 258 257 PMB OTBS O OTBS O OH O OTBS ° R1 (1) KHMDS, THF, –78 C R1 (2) R2 PMB O O OTBS OMMTr 259 dr 88 : 12 65% (2) H R2 261 260 OMMTr

Scheme 1.81 Stereoselective aldol reactions of metal enolates from chiral ketones. 56 1 Stereoselective Acetate Aldol Reactions

have been organized according to the structure of the ketone, namely, the sort of substituents (alkyl or hydroxy groups) on chiral centers at the α-orβ-position to the carbonyl.

1.3.6.1 α-Methyl Ketones There are no systematic studies on acetate aldol reactions based on chiral α-methyl ketones and most of the reported examples involve chiral aldehydes, so it is usually difﬁcult to recognize the contribution of each partner to the control of the new stereocenter. Lithium and potassium enolates have been reported to furnish 1,4-anti adducts in double stereodifferentiating processes. For instance, Carter described that the reaction of lithium enolate of methyl ketone (256) and chiral anti α,β-bisalkoxy aldehydes (257) afforded a single diastereomer of 1,4-anti aldols (258) in 94% yield ((1) in Scheme 1.81) [191], likely as a result of the asymmetric induction provided by the aldehyde (Scheme 1.79). In turn, Kalesse reported that coupling of methyl ketone (259) and aldehyde (260) produced diastereoselectively aldol (261)when KHMDS was used as the base ((2) in Scheme 1.81) [192]. Otherwise, chiral α-methyl ketones derived from Roche ester have proved to be an excellent platform to provide highly stereoselective aldol reactions. Particularly, Paterson reported that dicyclohexyl borinates from benzyl-protected ketones (262) furnished 1,4-syn aldols (263) with a remarkable stereocontrol ((1) in Scheme 1.82) [1b, 35a, 193]. Theoretical calculations have suggested that these additions proceed through a highly ordered transition state in which a hydrogen bond between = the benzyl ether and the incoming aldehyde (ArCH2O ···H–C O) determines the diastereoselective formation of 263 [194]. This procedure turned out to be

O O OH (1) Cy BCl, Et N (1) 2 3 1 ArCH O 4 R ArCH2O (2) RCHO 2 262 1,4-syn 263

BCy Cy BCl, Et N O 2 ArCH Me 2 3 2 O H RCHO H ArCH O Cy O 2 B CyO R

O Cy B OH O OSugar 2 O

H ODMB ODMB OTES OTES O (2) ° ° H OH Et2O, –78 C to 0 C MeO O O MeO OTBS 89% dr > 95 : 5 MeO OTBS Br Br Br 264 265 266 Dolastatin 19

Scheme 1.82 Stereoselective aldol reactions of boron enolates from chiral Roche ester-derived methyl ketones. 1.3 Metal Enolates 57

Cl4 Ti O BnO O O OH TiCl , i-Pr NEt TiCl , RCHO (1) 4 2 4 BnO ° BnO R CH2Cl2, –78 C 262 dr > 90 : 10 77–93% 263 O O Cl4 Ti H O OH H BnO O O OH ent-267 OTBDPS 267 OTBDPS (2) BnO BnO TiCl4 TiCl4 OTBDPS OTBDPS 270 dr 92 : 8 85% dr 94 : 6 88% 269

O OTBDPS Cl4 O OTBDPS Ti O OH OTBDPS H BnO O H O OH OTBDPS ent-268 268 (3) BnO BnO TiCl4 TiCl4 272 dr 94 : 6 77% dr 93 : 7 90% 271

Scheme 1.83 Stereoselective aldol reactions of titanium enolates from (S) 4-benzyloxy-3-methyl-2-butanone. particularly valuable in the addition to chiral aldehydes leading to the 1,4-syn Felkin adducts [195], as for the conversion of chiral aldehyde (264)intoaldol (265) in the total synthesis of dolastatin 19 (266) ((2) in Scheme 1.82) [195b]. Higher diastereoselectivities were further achieved by using chiral boron Lewis acid as Ipc2BCl (212, see Scheme 1.70) in matched pairs of double asymmetric aldol reactions, which expanded the scope of this methodology to silicon-protected Roche-derived methyl ketones with great success [196]. In turn, Romea and Urp´ı took advantage of the chelating capability of benzyloxy group of these Roche-derived methyl ketones to disclose highly sterecontrolled titanium-mediated reactions with a wide array of aliphatic, α, β-unsaturated, and aromatic aldehydes, affording syn aldols (263) in high yields and diastereoselectivity without needing other sources of chirality ((1) in Scheme 1.83) [197]. Furthermore, double asymmetric aldol additions to protected lactaldehydes ((2) in Scheme 1.83) and Roche ester-derived chiral aldehydes ((3) in Scheme 1.83) provided the corresponding 1,4-syn aldols (269–272) in high yields and excellent diastereomeric ratios (dr ≥ 92:8).

1.3.6.2 α-Hydroxy Ketones The lack of stereocontrol imparted by borinates from mandelic-acid-derived α-OTBS methyl ketone observed in early studies on asymmetric aldol reactions suggested that such systems might be unsuitable for these transformations [3c]. However, Trost proved that the appropriate choice of the Lewis acid and the hydroxy protecting group on lactate-derived methyl ketones allowed highly stereoselective processes ((1) in Scheme 1.10) [20]. Thereby, a remarkable 1,4-anti induction could be expected from α-alkoxy methyl ketones provided that the proper boron Lewis acid was used. Evans reported that 58 1 Stereoselective Acetate Aldol Reactions

O O OH (1) L BCl, Et N, CH Cl , –78 °C 2 3 2 2 1 (1) 4 (2) EtCHO PMBO PMBO 273 1,4-anti 274 L2BCl dr (anti/syn) Yield (%)

Cy2BCl 66 : 34 25 (+)–Ipc2BCl, (+)-212 18 : 82 44 (–)–Ipc2BCl, (–)-212 95 : 5 66

(2) TBDPSO HO OH OPMB 6 276 7 9 O O (1) (+)-212, i-Pr NEt (2) 2 SiMe Ph CH Cl , –78 °C 2 2 2 H O O 277 O O OH

6 SiMe2Ph TBDPSO 7 9 OPMB dr 81 : 19 41% 275 Amphidinolide Y (keto form) 278

Scheme 1.84 Stereoselective aldol reactions of boron enolates from chiral α-hydroxy methyl ketones.

the addition of the dicyclohexyl borinate from lactate-derived methyl ketone (273)to propanal furnished 1,4-anti aldol (274) in a low diastereomeric ratio, whereas it was considerably improved by using (−)-212 ((1) in Scheme 1.84) [45]. Furstner¨ also employed this method in one of the key steps of the synthesis of amphidinolide Y (275) (Scheme 1.84) [198]. Thus, boron-mediated aldol addition of α-OPMB methyl ketone (276) to chiral aldehyde (277) furnished anti aldol (278) in moderate yield and good diastereoselectivity ((2) in Scheme 1.84). Parallel trends have been observed in other transformations from α-OBn methyl ketones. For instance, TiCl3(i-PrO)-mediated aldol additions of methyl ketones (279) to isobutyraldehyde afforded the corresponding 1,4-anti adducts (280)inyieldsup to 93% and 85 : 15 diastereomeric ratio ((1) in Scheme 1.85) [199].8) In turn, lithium counterpart from ketone (281) gave aldol (282) in similar diastereoselectivity ((2) in Scheme 1.85) [21, 200]. Foreseeing the inﬂuence of the protecting group of these ketones on the stereochemical outcome of this sort of reactions, the reactivity of α-silyloxy ketones was also assessed. As for benzyl-protected ketones, addition of the dicyclohexyl borinate of α-OTES methyl ketone (283) to isobutyraldehyde gave 1,4-anti aldol (284) in good yield and high diastereomeric ratio ((3) in Scheme 1.85) [21]. However, the diastereoselectivity was dramatically eroded for

8) Similar results are obtained with other aliphatic, α, β-unsaturated, and aromatic aldehydes. 1.3 Metal Enolates 59

O O OH ° (1) TiCl3(i-PrO), i-Pr2NEt, CH2Cl2, –78 C (1) R R 1 4 (2) i-PrCHO ArCH2O ArCH2O dr 85 : 15 77–93% R: Me, Bn, i-Bu 1,4-anti 280 279 O O OH (1) LiHMDS, THF, –78 °C (2) (2) i-PrCHO OPMB OPMB 281dr 87 : 13 46% 282 O O OH ° (1) Cy2BCl, Et3N, Et2O, –78 C (3) (2) i-PrCHO OTES OTES 283dr 84 : 16 63% 284

(1) TiCl4, i-Pr2NEt O ° TBSO H O OH CH2Cl2, –94 C R (4) R R 1 TiCl4 4 (2) i-PrCHO i-Pr O TBSO O TBSO dr 77 : 23 to 96 : 4 R: Me, Bn, i-Pr 71–95% 1,4-syn 286 285

Scheme 1.85 Stereoselective aldol reactions of metal enolates from chiral α-hydroxy methyl ketones. alkaline enolates [21], whereas the enolization of α-OTBS ketones (285)with TiCl4/i-Pr2NEt and subsequent addition to isobutyraldehyde provided 1,4-syn aldols (286) ((4) in Scheme 1.85) [201]. The rationale for this result was based on a six-membered chairlike transition state in which the antiperiplanar distribution of both TBSO–C and C–OTi bonds acted as the key element to determine the syn conﬁguration.9) The synthesis of the spiroketal core of spirangien A (287) (Scheme 1.86) is a good example of the intricacy of these aldol reactions. Paterson reported that the stereochemical outcome of the aldol addition of boron and lithium enolates from α-OTES methyl ketone (288) to chiral aldehyde (289) was very sensitive to the enolization procedure. Preliminary studies using LDA or Cy2BCl/Et3N furnished 1,4-anti aldol (290), but this inherent diastereoselectivity in the undesired direction was eventually overturned by using (−)-Ipc2BCl to afford 1,4-syn aldol (291) (Scheme 1.86) [202]. Therefore, boron Lewis acid determined the stereochemical outcome of this transformation and prevailed over the induction imparted by ketone enolates (288) and aldehyde (289). Surprisingly, Kalesse [203] and Cossy [204]10)

9) In support for this theoretical model, it has been observed that the more sterically bulky the R group (Me to i-Pr) the better the diastereoselectivity is for aliphatic as well as α,β-unsaturated and aromatic aldehydes. 10) Importantly, no reaction was observed when the starting TBS-protected ketone was treated with (−)-Ipc2BCl/Et3N. 60 1 Stereoselective Acetate Aldol Reactions

M Li OO O O OO OPG OPG O O OPG OPG 1 2 + R R + R H H OTES OPG 288 289 292 293

M: Li, Cy2B, (–)-Ipc2B PG: TES or TBS

OO O OH OO OPG OPG O OH OPG OPG 1 2 1 R R 1 R 4 4 OTES OPG 1,4-anti 290 1,4-syn 294 + PG: TES dr 75 : 25 overall yield 60% OO O OH OO PG: TBS dr 75 : 25 isolated yield 45% 1 R 4 COOH OTES MeO 1,4-syn 291

M dr (290 : 291) Overall yield HO Li 74 : 26 79% O Cy2B 84 : 16 79% O (–)-Ipc2B 28 : 72 65% MeO OH HO 287 Spirangien A

Scheme 1.86 Synthesis of spirangien A.

established that lithium-mediated aldol reactions from fully silylated enolates (292) (PG: TES or TBS) and aldehydes (293) (PG: TES or TBS) afforded the desired 1,4-syn aldols (294) in 75 : 25 diastereomeric ratio (Scheme 1.86), which proved that subtle changes on the metal and the structure of the reactant partners can dramatically affect the stereochemical outcome of these aldol reactions. Finally, it is worth mentioning that the lithium enolate of the camphor-based α-OTMS methyl ketone (295) afforded the corresponding aldol adducts (296)with a remarkable high diastereoselectivity [205]. As shown in Scheme 1.87, the aldol addition proceeded through a chelated six-membered chairlike transition state in which the bulky camphor backbone determined the approach of the aldehyde. From a conceptual point of view, the camphor acted as a chiral auxiliary in such a way that the removal of the silicon-protecting group of 293 and the appropriate manipulation of the resultant hydroxy ketones yielded enantiopure β-hydroxy acids or ketones and camphor (Scheme 1.87).

1.3.6.3 β-Hydroxy Ketones Aldol reactions of β-hydroxy methyl ketones are very sensitive to the metal of the enolate and the hydroxy protecting group. Indeed, enolization of β-alkoxy ketones 1.3 Metal Enolates 61

OTMS OTMS (1) LDA, THF, –78 °C TMS O (2) RCHO O O R O Li dr > 92 : 8 O 295 67–80% HO R 296 O OH O OH and or HO R R2 R1 O

Scheme 1.87 Stereoselective aldol reactions of lithium enolates from a camphor-based α-OTMS methyl ketone.

(297) with boron Lewis acids and tertiary amines yielded the less substituted enolborinate that participated in highly stereocontrolled reactions, affording 1,5-anti aldols (298) with excellent diastereoselectivity (Scheme 1.88). Instead, other metals and protecting groups provided poorer results [206, 207]. As previously pointed for related transformations (Scheme 1.82), a theoretical model that accounts for such a high stereocontrol is based on a boat-shaped transition structure in which a stabilizing formyl hydrogen bond exists between the alkoxy oxygen and the aldehyde proton [194]. Evans and Sammakia applied this powerful transformation in crucial steps of the total syntheses of oxopolyene macrolides roxaticin and dermostatin A (299 and 300, respectively, in Scheme 1.89). Thereby, Evans described that treatment of β-alkoxy methyl ketone (301)withBu2BOTf/Et3N produced a boron enolate that reacted with β-OTBS aldehyde (302), affording anti aldol (303)asasingle diastereomer (dr > 95 : 5) in 79% yield ((1) in Scheme 1.89) [114c]. In turn, Sammakia reported that coupling of dicyclohexylborinate from β-alkoxy methyl ketone (304)andβ-benzyloxy aldehyde (305) provided anti aldol product (306)in excellent yield and diastereoselectivity ((2) in Scheme 1.89) [159d, 208]. The dominant 1,5-anti trend observed for these transformations has been occasionally overridden by the inﬂuence of remote stereocenters, functional groups, or chiral boron Lewis acids [209]. In this context, Dias established that good levels of substrate-controlled 1,5-syn stereoinduction were obtained in boron-mediated aldol reactions of β-trihalomethyl- as well as β-tert-butyl-β-hydroxy methyl ketones (307) possessing different hydroxy protecting groups ((1) in Scheme 1.90) [210, 211].

R1 R2O O R2O O OH 2 H (1) L2BX, R3N R O 1 1 1 5 3 R 3 H R R (2) R CHO O B L 2 R : alkyl O 3 L 1,5-anti 298 297 X: Cl, OTf R

Scheme 1.88 Stereoselective aldol reactions of boron enolates from chiral β-hydroxy methyl ketones. 62 1 Stereoselective Acetate Aldol Reactions

O O O O O O OH OTBSO O (1) Bu BOTf, Et N, Et O, –78 °C (1) 2 3 2 (2) –110 °C OBn OBn PMBO 301 O OTBSO O dr > 95 : 5 79% 303 H

302 PMBO PMP PMB O O O O O O OH O O O (1) Cy BCl, Et N, Et O, –10 °C (2) 2 3 2 (2) PMP OH PMB OH O 304 O O O O dr 94 : 6 93% H 306 O

O 305 O –78 to –26 °C OH OH OH OH OH OH OH OH OH OH OH OH

OH O O OH HO O O OH

299 (+)-Roxaticin 300 Dermostatin A

Scheme 1.89 Examples of 1,5-anti asymmetric induction imparted by boron enolates from chiral β-hydroxy methyl ketones in the synthesis of natural products.

R1 (1) Cy BCl, Et N H H PGO O 2 3 PGO O OH ° Et2O or CH2Cl2, –30 C or rt H OPG (1) 1 1 2 R L O R 15R (2) R2CHO, –78 °C B R1: CCl , CF , t-Bu O 3 3 L R2 1,5-syn 308 PG: TBS, Bn, PMB dr > 65 : 35 79–98% 307 OPG H H (TES) SiO O (TES) SiO O OH 3 1 3 (1) LiHMDS, DMF, –60 °C DMF R H (2) 1 Li 1 152 R 2 O R R (2) R CHO DMF 1 O R : n-Hept, i-Pr, t-Bu 2 dr ≥ 85 : 15 70–84% R 1,5-syn 310 309

Scheme 1.90 1,5-syn Asymmetric induction of metal enolates from chiral β-hydroxy methyl ketones.

Theoretical calculations on the competing pathways involved in these reactions suggested that a boatlike transition state lacking the formyl hydrogen bond is the most stable one and led to 1,5-syn aldol adducts (308) (Scheme 1.90). Moreover, Yamamoto reported that lithium enolates of β-super silyloxy methyl ketones (309) added to aliphatic, α, β-unsaturated, and aromatic aldehydes in DMF to provide 1,5-syn aldols (310) in outstanding diastereoselectivities ((2) in Scheme 1.90) [22]. 1.3 Metal Enolates 63

In this case, a chairlike transition state that minimizes the unfavorable steric interactions was invoked to rationalize the observed syn induction.

1.3.6.4 β-Hydroxy α-Methyl Ketones Most of the examples reported in the literature on substrate-controlled acetate aldol additions of β-hydroxy-α-methyl ketones involve boron enolates. Thus, the stereochemical outcome of these reactions depends on the 1,5-anti and 1,4-syn inductions imparted by the β-hydroxy and the α-methyl groups, respectively (Schemes 1.82 and 1.88). In this scenario, an anti-β-hydroxy-α-methyl array corresponds to a matched case and the resultant aldol reactions usually proceed in excellent diastereoselectivities. An exceptional example of this sort of reactions involved the aldol addition of the dicyclohexyl borinate of methyl ketone (311) to chiral aldehyde (312) that furnished aldol (313), an advanced intermediate in the total synthesis of reidispongiolide A (314), as a single diastereomer in 70% yield (Scheme 1.91) [61d, 212]. Otherwise, the diastereoselectivity of syn β-hydroxy-α-methyl mismatched pairs is very sensitive to the structure of the methyl ketone, although the conﬁguration of the new stereocenter is used to be ruled by the β-hydroxy group. For instance, a systematic study carried out by Dias on the boron-mediated aldol reactions of methyl ketones (315) established that the prevailing 1,5-anti induction imparted by the β-alkoxy led to the adducts 316 (Scheme 1.92) [213]. These studies also

OMe OMe MeO BCy OMe MeO O 2 O OMe H N + H O OMe

O O O 311 312 ° O Et2O,–78 to 0 C

1,5-anti OMe OMe MeO MeO O OH OMe OMe H N O OMe O O O 1,4-syn Single diastereomer 70% O 313 OMe OMe MeO

MeO O OMe OMe H N O OMe O O O 314 Reidispongiolide A O

Scheme 1.91 Synthesis of reidispongiolide A. 64 1 Stereoselective Acetate Aldol Reactions

PMP PMP

O O O O O O OH ° (1) Cy2BCl, Et3N, Et2O, –30 C (2) i-PrCHO, –78 °C R1 R2 R1 R2 315 316 KetoneR1 R2 Aldol dr Yield (%) 315a H H 316a 86 : 14 83 315b H Me 316b 86 : 14 97 315c Me H 316c > 95 : 5 77

Scheme 1.92 Stereoselective acetate aldol reactions of boron enolates from β-hydroxy α-methyl ketones.

O OPMB M TBSO O TBSO O H TBSO O OH OPMB R Enolization R 318 R ° THF or CH2Cl2, –78 C

317 319 KetoneR Enolization conditions Aldol dr Yield (%) ° 317a BzOCH2 LiHMDS, THF, –78 C 319a 91 : 9 90 NaHMDS, THF, –78 °C 50 : 50 51 ° Bu2BOTf, Et3N, CH2Cl2, –40 C 55 : 45 65 ° 317b TBDPSOCH2 LiHMDS, THF, –78 C 319b 75 : 25 59 ° 317c H2C=CH LiHMDS, THF, –78 C 319c 67 : 33 85

Scheme 1.93 Stereoselective acetate aldol reactions of metal enolates from β-hydroxy α-methyl ketones.

proved that even the configuration of the γ -stereocenter plays a significant role on the stereochemical outcome of these reactions, as occurs for ketone (315c) [214]. However, it is worth keeping in mind that these transformations are not completely well understood and unexpected effects can play a crucial role. Other metal enolates have also been used in these reactions, but it is difficult to predict their stereochemical induction. For instance, Roush found that the diastereoselectivity of the reaction of syn β-OTBS-α-methyl ketone (317a)andthe chiral aldehyde (318) producing aldol (319a) was strongly dependent on the metal enolate (Scheme 1.93). Furthermore, the moderate and low diastereoselectivity observed for related ketones (317b)and(317c) suggests that the presence of a chelating group at δ-position was crucial to attain a high stereocontrol and proves that these aldol reactions are governed by subtle structural details [215].

1.3.6.5 α,β-Dihydroxy Ketones The diastereoselectivity of substrate-controlled aldol reactions from α,β-dihydroxy methyl ketones depends on the metal enolate, the conﬁguration of α-and β-stereocenters, and the hydroxy protecting groups. In this context, the remarkable 1.3 Metal Enolates 65

1,5-anti induction of boron-mediated aldol reactions of β-alkoxy methyl ketones (Scheme 1.88) also operates in these systems and may be assisted by the parallel 1,4-anti bias observed in related α-hydroxy methyl ketones (Scheme 1.84). Therefore, it is not surprising that the addition of the dicyclohexyl borinate of the α, β-dialkoxy methyl ketone (320) to aldehyde (321) led to the isolation of a single diastereomeric aldol adduct 322 in 93% yield (Scheme 1.94) [216]. In spite of these accomplishments, most of the substrate-controlled aldol reactions from α, β-dihydroxy methyl ketones reported in the literature take advantage of the high nucleophilicity of alkaline enolates. Particularly, lithium-mediated aldol reactions from chiral syn-α, β-dihydroxy methyl ketones have been thoroughly assessed along the syntheses of amphidinolides. These studies have proved that the protecting groups play a crucial role in the stereochemical outcome of such additions. Unfortunately, they are very sensitive to the structure of the reactive partners and the whole reaction conditions, which makes difﬁcult to foresee the stereochemical outcome of a particular transformation. For instance, it was well documented that silicon-protecting groups provided poor stereocontrolled reactions [217], so it was usual that the lithium-mediated addition of α, β-disilyloxy methyl ketone (323) to chiral aldehyde (324) gave anti-aldol (325) in a very poor diastereomeric ratio ((1) in Scheme 1.95). Nevertheless, Carter found that TMEDA increased the reactivity of the lithium enolate of methyl ketone (323), produced a stereochemical reversal on the aldol addition to aldehyde (324), and the bias favoring 1,4-syn (326)was ◦ even improved by cooling to −100 C ((1) in Scheme 1.95) [218]. Furthermore, the protection of the Cα hydroxyl with a chelating group modiﬁes the stereoselectivity of these reactions dramatically. Indeed, α-OPMB ketone (327), structurally close to 323, reacted with aldehyde (328) to afford aldol (329) in 69% yield as a single diastereomer through a chelated transition state ((2) in Scheme 1.95) [219], which obviously makes the most of the chelating ability of the benzyl-like protecting group placed at the α-position. As anticipated by these results, α-alkoxy-β-silyloxy methyl ketones have been involved in much more stereoselective transformations. In a thorough analysis on the reactivity of alkaline enolates from syn α, β-dihydroxy methyl ketones, Furstner¨ described that the addition of the lithium enolate from α-OPMB-β-OTBS methyl ketone (330) to aldehyde (331) afforded aldol (332) as a single diastereomer in 52% yield ((1) in Scheme 1.96) [217d, 220]. The excellent diastereoselectivity was ascribed to the 1,4-anti directing effect imparted by the α-alkoxy group (Scheme 1.84). This hypothesis was corroborated by the fact that the related disilyloxy ketone furnished

O O O O OH OTES (1) Cy BCl, Et N, pentane 2 3 R TESO TESO (2) O OTES OBn R OBn 320 H 321 322

dr > 98 : 2 93%

Scheme 1.94 Stereoselective aldol reactions of boron enolates from α,β-dihydroxy methyl ketones. 66 1 Stereoselective Acetate Aldol Reactions

1,4-anti

TESO O OH OTES (1) LDA, Et O-THF, –40 °C 2 R1 (2) O OTES OTES R2 TESO O H 325 1 324 R2 dr 55 : 45 66% (1) R 1,4-syn OTES TESO O OH OTES 323 (1) LDA, TMEDA, Et O-THF, T 2 R1 (2) O OTES OTES H R2 ° 326 324 R2 T: –78 C dr 67 : 33 T: –100 °C dr 89 : 11 65% yield

TESO O O TESO O OH O (1) LDA, Et2O Li OTES –78 °C R'' (2) O O OTES H H TESO OPMB (2) TESO OPMB H PMB R' 327 dr > 95 : 5 69% 328 329 CN CN 1,4-anti 1,4-syn O OH OH O OH OH HO HO

OH OH

O O O O

O O Amphidinolide B1 Amphidinolide B2

Scheme 1.95 Syntheses of amphidinolide B1 and B2.

a poor 67 : 33 mixture of the two possible diastereomers. However, minor changes on the aldehyde and the ketone were responsible for significant differences on the diastereoselectivity. For instance, a less elaborate aldehyde as 333 delivered the anti aldol (334) in 70% yield and a slightly lower diastereomeric ratio (compare (1) and (2) in Scheme 1.96). Moreover, the diastereoselectivity was seriously eroded when the reaction was carried out on ketone (335) lacking remote OTBDPS group, which afforded aldol (336) in a modest diastereomeric ratio (compare (2) and (3) in Scheme 1.96) [217d]. The reason why this particular reaction shows a significantly lower selectivity is unclear, and it is also instructive to realize the dramatic influence of the ketone partner. Other protecting groups have also been used in these transformations [221]. For instance, Zhao reported that the diastereoselective addition of the potassium enolate from α, β-diMOM protected methyl ketone (337) to aldehyde (331)inan advanced step of the total synthesis of amphidinolide H1 (Scheme 1.97) produced diastereoselectively 1,4-anti-aldol (338) in 67% yield (Scheme 1.97) [221b]. 1.3 Metal Enolates 67

1,4-anti

TBSO O TBSO O OH ° (1) LDA, Et2O, –78 C (1) TBDPSO TBDPSO O RCOO OPMB (2) RCOO OPMB 330 H Single diastereomer 52% 331 332 O O TBSO O TBSO O OH ° (1) LDA, Et2O, –78 C (2) TBDPSO TBDPSO O RCOO OPMB (2) RCOO OPMB H I 330 333 dr > 91 : 9 70% I 334 TESO O TESO O OH (1) LDA, Et O, –78 °C (3) 2 O RCOO OPMB (2) RCOO OPMB H I 335 333 dr 76 : 24 58% I 336

1,4-anti O OH HO

OH R: Me Amphidinolide B4 R O R: CH2OH Amphidinolide H1 O

Scheme 1.96 Syntheses of amphidinolide B4 and H1.

MOMO O MOMO O OH (1) KHMDS, –78 °C TBDPSO TBDPSO O RCOO OMOM (2) RCOO OMOM H 337 dr 88 : 12 67% 331 338

O O

Scheme 1.97 Synthesis of amphidinolide H1.

1.3.6.6 Remote Stereocontrol Rarely, other unusual arrangements can come into action and provide insightful synthetic approaches. This is the case of 1,6-asymmetric induction disclosed by Paterson for the synthesis of (+)-discodermolide (339) (Scheme 1.98) [222]. The second-generation approach on the total synthesis of (+)-discodermolide was based on the assembly of methyl Z-enone (340) (C6–C24 fragment) and aldehyde 68 1 Stereoselective Acetate Aldol Reactions

24 trans conformation A(1,3) minimization 7

O 10 OTBS O O O R H L Cy2B Me OTBS NH2 340 RCHO (1) Cy BCl, Et N 2 3 R L Me 1 5 H dr > 95 : 5 64% Cy (2) MeO C H 2 O B Cy TBSO O 341 O R

5S MeO2C TBSO OH O OTBS O O OTBS NH 342 2 24 HO 7 10 O O 6 OH O O 1 5 OH NH2 339 Discodermolide OH

Scheme 1.98 Synthesis of discodermolide.

(341) (C1–C5 fragment) [223]. As shown in Scheme 1.98, a boron-mediated aldol reaction of both fragments afforded the required 5S product 342 in 64% yield and an outstanding diastereomeric ratio (dr > 95 : 5). The rationale for this unparalleled remote stereocontrol invoked a chairlike transition state in which the dienolate was constrained in the lower energy trans conformation, allylic strain A(1,3) was minimized, and other steric clashes were avoided. Thus, all these elements were combined in such a way that the remote C10 γ -stereocenter of 340 provided an unprecedented 1,6-asymmetric induction. Irrespective of the mechanistic pathway followed by this transformation, it is a proof of the power of substrate-controlled aldol reactions provided that the appropriate structural elements are identiﬁed and placed at the right position.

1.4 Conclusions

In spite of early reports, enolsilanes and metal enolates have emerged as highly valuable intermediates for stereoselective acetate aldol reactions. Recent advances in this area have delivered highly stereoselective methodologies based on Mukaiyama and metal enolate-mediated aldol reactions from chiral auxiliaries, stoichiometric and catalytic Lewis acids and bases, or acting in substrate-controlled reactions, References 69 which facilitate the synthesis of structurally complex natural products. Unfortu- nately, the structural and reactive elements that determine the conﬁguration of the resultant aldol adducts are sometimes unclear and a proper understanding of the transition states involved in many of these transformations is still lacking. Thus, more insightful, simple, and reliable methodologies, as well as a better knowledge of their mechanisms, would be truly welcome.

References

1. (a) Braun, M. (1995) in Houben-Weyl, Oxford, pp. 629–660; (b) Nelson, S.G. Vol. E21b (eds G. Helmchen, (1998) Tetrahedron: Asymmetry, 9, 357; R.W. Hoffmann, J. Mulzer, and E. (c) Mahrwald, R. (1999) Chem. Rev., Schaumann), Thieme, Stuttgart, p. 99, 1095; (d) Carreira, E.M. (1999) in 1603; (b) Cowden, C.J. and Paterson, Comprehensive Asymmetric Catalysis, I. (1997) Org. React., 51, 1; (c) Palomo, Vol. 3 (eds E.N. Jacobsen, A. Pfaltz, C., Oiarbide, M., and Garc´ıa, J.M. and H. Yamamoto), Springer-Verlag, (2002) Chem. Eur. J., 8, 36; (d) Berlin, pp. 996–1065; (e) Carreira, Palomo, C., Oiarbide, M., and Garc´ıa, E.M., Fettes, A., and Marti, C. (2006) J.M. (2004) Chem. Soc. Rev., 33, 65; (e) Org. React., 67,1. Mahrwald, R. (ed.) (2004) Modern Aldol 6. (a) Braun, M. (1987) Angew. Chem. Int. Reactions, Wiley-VCH Verlag GmbH, Ed. Engl., 26, 24; (b) Ariza, X., Garc´ıa, Weinheim; (f) Geary, L.M. and Hultin, J., Romea, P., and Urp´ı, F. (2011) P.G. (2009) Tetrahedron: Asymmetry, 20, Synthesis, 2175. 131. 7. (a) Pellissier, H. (2007) Tetrahedron, 2. For the application of aldol reactions to 63, 9267; (b) Guillena, C., Najera,´ C., the total synthesis of natural products, and Ramon,´ D.J. (2007) Tetrahedron: see: (a) Yeung, K.-S. and Paterson, I. Asymmetry, 18, 2249; (c) Mukherjee, (2002) Angew. Chem. Int. Ed., 41, 4632; S., Yang, J.W., Hoffmann, S., and List, (b) Yeung, K.-S. and Paterson, I. (2005) B. (2007) Chem. Rev., 107, 5471; (d) Chem. Rev., 105, 4237; (c) Schetter, B. Trost, B.M. and Brindle, C.S. (2010) and Mahrwald, R. (2006) Angew. Chem. Chem. Soc. Rev., 39, 1600. Int. Ed., 45, 7506; (d) Brodmann, T., 8. Casiraghi, G., Battistini, L., Curti, Lorenz, M., Schackel,¨ R., Simsek, S., C., Rassu, G., and Zanardi, F. (2011) and Kalesse, M. (2009) Synlett, 174; (e) Chem. Rev., 111, 3076. Li, J. and Menche, D. (2009) Synthesis, 2293. 9. For a comprehensive review on the use 3. (a) Evans, D.A., Bartroli, J., and Shih, of chiral Lewis bases on stereoselec- T.L. (1981) J. Am. Chem. Soc., 103, tive reactions, see: Denmark, S.E. and 2127; (b) Heathcock, C.H., Pirrung, Beutner, G.L. (2008) Angew. Chem. Int. M.C., Lampe, J., Buse, C.T., and Ed., 47, 1560. Young, S.D. (1981) J. Org. Chem., 46, 10. Denmark, S.E. and Lee, W. (2008) 2290; (c) Masamune, S., Lu, L.D.-L., Chem. Asian J., 3, 327. Jackson, W.P., Kaiho, T., and Toyoda, 11. For an insightful discussion see: (a) T. (1982) J. Am. Chem. Soc., 104, 5523. Carreira, E.M. (1999) in Comprehensive 4. (a) Mukaiyama, T., Narasaka, K., and Asymmetric Catalysis,Vol.3 (eds E.N. Banno, K. (1973) Chem. Lett., 1011; Jacobsen, A. Pfaltz, and H. Yamamoto), (b) Mukaiyama, T., Banno, K., and Springer-Verlag, Berlin, pp. 996–1065; Narasaka, K. (1974) J. Am. Chem. Soc., (b) Carreira, E.M., Fettes, A., and 96, 7503. Marti, C. (2006) Org. React., 67,1. 5. (a) Gennari, C. (1992) in Comprehensive 12. Helmchen, G., Leikauf, U., and Organic Synthesis Series,Vol.2 (eds Taufer-Knopfel,¨ I. (1985) Angew. Chem. B.M. Trost and I. Fleming), Pergamon, Int. Ed. Engl., 24, 874. 70 1 Stereoselective Acetate Aldol Reactions

13. For related transformations, see: (a) 30. For other examples, see: (a) Bohm,¨ C., Oppolzer, W. and Marco-Contelles, Schinner, M., Bubert, C., Zabel, M., J. (1986) Helv. Chim. Acta, 69, 1699; Labahn, T., Parisini, E., and Reiser, (b) Taber, D.F. and Hoerrner, R.S. O. (2000) Eur. J. Org. Chem., 2955; (1992) J. Org. Chem., 57, 441; (c) (b) Stevens, B.D., Bungard, C.J., and Oppolzer, W. and Starkemann, C. Nelson, S.G. (2006) J. Org. Chem., 71, (1992) Tetrahedron Lett., 33, 2439. 6397. 14. Shirokawa, S,-i., Kamiyama, M., 31. Cram, D.J. and Kopecky, K.R. (1959) J. Nakamura, T., Okada, M., Nakazaki, Am. Chem. Soc., 81, 2748. A., Hosokawa, S., and Kobayashi, S. 32. Hirose, T., Sunazuka, T., Tsuchiya, (2004) J. Am. Chem. Soc., 126, 13604. S., Tanaka, T., Kojima, Y., Mori, R., 15. Yamaoka, M., Fukatsu, Y., Nakazaki, Iwatsuki, M., and Omura, S. (2008) A., and Kobayashi, S. (2009) Tetrahe- Chem. Eur. J., 14, 8220. dron Lett., 50, 3849. 33. (a) Nguyen, S., Xu, J., and Forsyth, 16. Yamaoka, M., Nakazaki, A., and C.J. (2006) Tetrahedron, 62, 5338; (b) Kobayashi, S. (2010) Tetrahedron Lett., Forsyth, C.J., Xu, J., Nguyen, S.T., 51, 287. Samdal, I.A., Briggs, L.R., Rundberget, 17. Nakamura, T., Shirokawa, S.-i., T., Sandvik, M., and Mile, C.O. (2006) Hosokawa, S., Nakazaki, A., and J. Am. Chem. Soc., 128, 15114. Kobayashi, S. (2006) Org. Lett., 8, 34. Evans, D.A., Kværnø, L., Dunn, T.B., 677. Beauchemin, A., Raymer, B., Mulder, 18. Jung, M.E., and van den Heuvel, A. J.A., Olhava, E.J., Juhl, M., Kagechika, (2003) Org. Lett., 5, 4705. K., and Favor, D.A. (2008) J. Am. 19. Pan, Y. and De Brabander, J.K. (2006) Chem. Soc., 130, 16295. Synlett, 853. 35. For other synthetic applications, see: (a) 20. Trost, B.M. and Urabe, H. (1990) J. Evans, D.A., Ripin, D.H.B., Halstead, Org. Chem., 55, 3982. D.P., and Campos, K.R. (1999) J. Am. 21. Lorenz, M., Bluhm, N., and Kalesse, M. Chem. Soc., 121, 6816; (b) Voight, (2009) Synthesis, 3061. E.A., Roethle, P.A., and Burke, S.D. 22. Yamaoka, Y. and Yamamoto, H. (2010) (2004) J. Org. Chem., 69, 4534; (c) J. Am. Chem. Soc., 132, 5354. Nicolaou, K.C., Pihko, P.M., Bernal, F., 23. Ley, S.V., Cox, L.R., Middleton, B., and Frederick, M.O., Qian, W., Uesaka, N., Worrall, J.M. (1999) Tetrahedron, 55, 3515. Diedrichs, N., Hinrichs, J., Koftis, T.V., 24. Ley, S.V., Cleator, E., Harter, J., and Loizidou, E., Petrovic, G., Rodriguez, Hollowood, C.J. (2003) Org. Biomol. M., Sarlah, D., and Zou, N. (2006) J. Chem., 1, 3263. Am. Chem. Soc., 128, 2244; (d) Wang, 25. Mengel, A. and Reiser, O. (1999) Chem. C. and Forsyth, C.J. (2006) Org. Lett., Rev., 99, 1191. 8, 2997; (e) Zeitouni, J., Norsikian, S., 26. Heathcock, C.H. and Flippin, L.A. Merlet, D., and Lubineau, A. (2006) (1983) J. Am. Chem. Soc., 105, 1667. Adv.Synth.Catal., 348, 1662; (f) Hon, 27. (a) Davis, A.P. and Plunkett, S.J. (1995) Y.-S. and Hsieh, C.-H. (2006) Tetra- J. Chem. Soc., Chem. Commun., 2173; hedron, 62, 9713; (g) Prantz, K. and (b) Davis, A.P., Plunkett, S.J., and Mulzer, J. (2010) Chem. Eur. J., 16, 485; Muir, J.E. (1998) Chem. Commun., 179. (h) Brimble, M.A., Finch, O.C., Heapy, 28. (a) Cherest,´ M. Felkin, H., and A.M., Fraser, J.D., Furkert, D.P., and Prudent, N. (1968) Tetrahedron Lett., O’Connor, P.D. (2011) Tetrahedron, 18, 2199; (b) Anh, N.T. and Eisenstein, 67, 995; (i) Nakagawa-Goto, K. and O. (1977) Nouv. J. Chem., 1, 61; (c) Crimmins, M.T. (2011) Synlett, 1555. Wu, Y.-D. and Houk, K.N. (1987) J. 36. For studies on Felkin-Anh model of Am. Chem. Soc., 109, 908. aldehydes bearing an α-heteroatom, 29. Vong, B.G., Kim, S.H., Abraham, S., see: (a) Lodge, E.P. and Heathcock, and Theodorakis, E.A. (2004) Angew. C.H. (1987) J. Am. Chem. Soc., 109, Chem.Int.Ed., 43, 3947. 3353; (b) Wong, S.S. and Paddon-Row, References 71

M.N. (1990) J. Chem. Soc., Chem. and Prunet, J. (2006) Synlett, 2269; Commun., 456. (g) Li, D.-R., Zhang, D.-H., Sun, 37. (a) Cornforth, J.W., Cornforth, R.H., C.-Y., Zhang, J.-W., Yang, L., Chen, and Mathew, K.K. (1959) J. Chem. Soc., J., Liu, B., Su, C., Zhou, W.-S., and 112; (b) Evans, D.A., Siska, S.J., and Lin, G.-Q. (2006) Chem. Eur. J., 12, Cee, V.J. (2003) Angew. Chem. Int. Ed., 1185; (h) Keck, G.E., Welch, D.S., 42, 1761; (c) Cee, V.J., Cramer, C.J., and Vivian, P.K. (2006) Org. Lett., 8, and Evans, D.A. (2006) J. Am. Chem. 3667; (i) Keck, G.E., Welch, D.S., and Soc., 128, 2920. Poudel, Y.B. (2006) Tetrahedron Lett., 38. For an outstanding analysis of the 47, 8267; (j) Jung, H.H., Seiders, J.R., asymmetric induction in methyl ke- and Floreancig, P.E. (2007) Angew. tone aldol additions to α-alkoxy and Chem. Int. Ed., 46, 8464; (k) Keaton, α, β-bisalkoxy aldehydes, see Evans, K.A. and Phillips, A.J. (2008) Org. D.A., Cee, V.J., and Siska, S.J. (2006) J. Lett., 10, 1083; (l) Yang, J.-H., Liu, J., Am. Chem. Soc., 128, 9433. and Hsung, R.P. (2008) Org. Lett., 10, 39. Borg, T., Danielsson, J., and Somfai, P. 2525; (m) Smith, A.B. III, Cox, J.M., (2010) Chem. Commun., 46, 1281. Furuichi, N., Kenesky, C.S., Zheng, J., 40. For studies on Mukaiyama aldol addi- Atasoylu, O., and Wuest, W.M. (2008) tions to α-epoxy aldehydes, see: Ruland, Org. Lett., 10, 5501; (n) Sabitha, G., Y., Noereuil, P., and Baltas, M. (2005) Gopal, P., Reddy, C.N., and Yadav, J.S. Tetrahedron, 61, 8895. (2009) Synthesis, 3301; (o) Hajare, 41. For an early report, see Reetz, M.T. A.K., Ravikumar, V., Khaleel, S., and Jung, A. (1983) J. Am. Chem. Soc., Bhuniya, D., and Reddy, D.S. (2011) J. 105, 4833. Org. Chem., 76, 963; (p) Pan, Y. and 42. Evans, D.A., Duffy, J.L., and Dart, M.J. De Brabander, J.K. (2006) Synlett, 853. (1994) Tetrahedron Lett., 35, 8537. 49. Peuchmaur, M. and Wong, Y.-S. (2007) 43. Evans, D.A., Dart, M.J., Duffy, J.L., and J. Org. Chem., 72, 5374. Yang, M.G. (1996) J. Am. Chem. Soc., 50. For a highly 1,3-syn diastereoselective 118, 4322. Mukaiyama aldol addition to a chiral 44. Huh, C.W., Schroeder, C., Singh, G., α, α-dimethyl-β-OTBS aldehyde, see: and Aube,´ J. (2011) J. Org. Chem., 76, Zhu, B. and Panek, J.S. (2001) Eur. J. 3160. Org. Chem., 1701. 45. Evans, D.A., Carter, P.H., Carreira, 51. (a) Boxer, M.B. and Yamamoto, H. E.M., Charette, A.B., Prunet, J.A., and (2006) J. Am. Chem. Soc., 128, 48; Lautens, M. (1999) J. Am. Chem. Soc., (b) Boxer, M.B. and Yamamoto, H. 121, 7540. (2007) J. Am. Chem. Soc., 129, 2762; 46. Su, Q., Dakin, L.A., and Panek, J.S. (c) Boxer, M.B., Albert, B.J., and (2007) J. Org. Chem., 72,2. Yamamoto, H. (2009) Aldrichimica 47. Vargo, T.R., Hale, J.S., and Nelson, Acta, 42, 3, and references therein. S.G. (2010) Angew. Chem. Int. Ed., 49, 52. For triple cascade aldol reactions, see: 8678. (a) Albert, B.J. and Yamamoto, H. 48. For other successful applications to (2010) Angew. Chem. Int. Ed., 49, 2747; the synthesis of natural products, (b) Albert, B.J., Yamaoka, Y., and see: (a) Paterson, I., Smith, J.D., and Yamamoto, H. (2011) Angew. Chem. Ward, R.A. (1995) Tetrahedron, 51, Int. Ed., 50, 2610. 9413; (b) Yokokawa, F., Asano, T., 53. For an insightful analysis of 1,2- and and Shioiri, T. (2001) Tetrahedron, 57, 1,3-asymmetric induction in diastere- 6311; (c) Sinz, C.J. and Rychnovsky, oselective Mukaiyama aldol additions, S.D. (2002) Tetrahedron, 58, 6561; see: Evans, D.A., Dart, M.J., Duffy, J.L., (d) Li, D.R., Tu, Y.Q., Lin, G.-Q., and Yang, M.G. (1996) J. Am. Chem. and Zhou, W.-S. (2003) Tetrahedron Soc., 118, 4322. Lett., 44, 8729; (e) Williams, D.R., 54. (a) Evans, D.A., Trotter, B.W., Patnaik, S., and Plummer, S.V. (2003) Coleman, P.J., Cotˆ e,´ B., Dias, L.C., Org. Lett., 5, 5035; (f) Vincent, A. Rajapakse, H.A., and Tyler, A.N. (1999) 72 1 Stereoselective Acetate Aldol Reactions

Tetrahedron, 55, 8671; (b) Keck, G.E., X., Shao, N., Palani, A., Aslanian, Knutson, C.E., and Wiles, S.A. (2001) R., and Buevich, A. (2007) Org. Lett., Org. Lett., 3, 707; (c) Henryon, V., 9, 2597; (c) Chakraborty, T.K. and Liu, L.W., Lopez, R., Prunet, J., and Chattopadhyay, A.K. (2008) J. Org. Fer´ ezou,´ J.-P. (2001) Synthesis, 2401; Chem., 73, 3578; (d) Paterson, I., (d) Toshima, K., Jyojima, T., Miyamoto, Ashton, K., Britton, R., Cecere, G., N., Katohno, M., Nakata, M., and Chouraqui, G., Florence, G.J., Knust, Matsumura, S. (2001) J. Org. Chem., H., and Stafford, J. (2008) Chem. Asian 66, 1708; (e) Savall, B.M., Blanchard, J., 3, 367; (e) Shao, N., Huang, X., N., and Roush, W.R. (2003) Org. Lett., Shao, N., Palani, A., Aslanian, R., 5, 377; (f) Paterson, I., Davies, R.D.M., Buevich, A., Piwinski, J., Huryk, R., Heimann, A.C., Marquez, R., and and Seidel-Dugan, C. (2009) Synthesis, Meyer, A. (2003) Org. Lett., 5, 4477; 2855; (f) Evans, D.A., Trotter, B.W., (g) Pihko, P.M. and Erkkila,¨ A. (2003) Coleman, P.J., Cotˆ e,B.,Dias,L.C.,´ Tetrahedron Lett., 44, 7607; (h) Dias, Rajapakse, H.A., and Tyler, A.N. (1999) L.C.,Steil,L.J.,andVasconcelos, Tetrahedron, 55, 8671. V.deA. (2004) Tetrahedron: Asymmetry, 62. Janssen, D., Albert, D., Jansen, R., 15, 147; (i) Lopez, R., Poupon, J.-C., Muller,¨ R., and Kalesse, M. (2007) Prunet, J., Fer´ ezou,´ J.-P., and Ricard, L. Angew. Chem. Int. Ed., 46, 4898. (2005) Synthesis, 644; (j) Nakamura, R., 63. For other anti-Felkin additions to Tanino, K., and Miyashita, M. (2005) syn α-methyl β-oxygenated aldehy- Org. Lett., 7, 2929; (k) Kleinbeck, F. des, see: (a) Mitchell, I.S., Pattenden, and Carreira, E.M. (2009) Angew. Chem. G., and Stonehouse, J. (2005) Org. Int. Ed., 48, 578. Biomol. Chem., 3, 4412; (b) Trost, 55. Evans, D.A., Hu, E., Burch, J.D., and B.M., O’Boyle, B.M., and Hund, D. Jaeschke, G. (2002) J. Am. Chem. Soc., (2009) J. Am. Chem. Soc., 131, 15061; 124, 5654. (c) Henryon, V., Liu, L.W., Lopez, R., 56. Paterson, I., Ward, R.A., Smith, J.D., Prunet, J., and Fer´ ezou,´ J.-P. (2001) Cumming, J.G., and Yeung, K.-S. Synthesis, 2401. (1995) Tetrahedron, 51, 9437. 64. Restorp, P. and Somfai, P. (2005) Org. 57. For the synthesis of swinholide A, Lett., 7, 893. see: Paterson, I., Yeung, K.S., Ward, 65. Paterson, I., Di Francesco, M.E., and R.A., Smith, J.D., Cumming, J.G., and Kuhn,¨ T. (2003) Org. Lett., 5, 599. Lamboley, S. (1995) Tetrahedron, 51, 66. Kobayashi, S., Wakabayashi, T., and 9467. Yasuda, M. (1998) J. Org. Chem., 63, 58. For similar transformations, see: (a) 4868. Paterson, I., Yeung, K.S., Watson, C., 67. Evans, D.A., Allison, B.D., Yang, M.G., Ward, R.A., and Wallace, P.A. (1998) and Masse, C.E. (2001) J. Am. Chem. Tetrahedron, 54, 11935; (b) Nakamura, Soc., 123, 10840. R., Tanino, K., and Miyashita, M. 68. (a) Zanato, C., Pignataro, L., Hao, Z., (2003) Org. Lett., 5, 3583. and Gennari, C. (2008) Synthesis, 2158; 59. Scheidt, K.A., Bannister, T.D., Tasaka, (b) Mitchell, I.S., Pattenden, G., and A., Wendt, M.D., Savall, B.M., Fegley, Stonehouse, J. (2005) Org. Biomol. G.J., and Roush, W.R. (2002) J. Am. Chem., 3, 4412. Chem. Soc., 124, 6981. 69. For an enlightening example of the 60. Wan, S., Wu, F., Rech, J.C., Green, dramatic inﬂuence of chelation based M.E., Balachandran, R., Horne, W.S., on remote functional groups, see Day, B.W., and Floreancig, P.E. (2011) Smith, A.B. III, Beauchamp, T.J., J. Am. Chem. Soc., 133, 16668. LaMarche, M.J., Kaufman, M.D., Qiu, 61. For other Felkin additions to syn Y., Arimoto, H., Jones, D.R., and α-methyl β-oxygenated aldehydes, Kobayashi, K. (2000) J. Am. Chem. Soc., see: (a) Samadi, M., Munoz-Letelier, 122, 8654. C., Poigny, S., and Guyot, M. (2000) 70. (a) Kobayashi, S. and Mukaiyama, T. Tetrahedron Lett., 41, 3349; (b) Huang, (1989) Chem. Lett., 297; (b) Kobayashi, References 73

S., Uchiro, H., Fujishita, Y., Shiina, Y., Du, Y., and Feng, X. (2005) J. Org. I., and Mukaiyama, T. (1991) J. Am. Chem., 70, 8533. Chem. Soc., 113, 4247. 86. Heumann, L.V. and Keck, G.E. (2007) 71. Mukaiyama, T., Kobayashi, S., and Org. Lett., 9, 4275. Sano, T. (1990) Tetrahedron, 46, 4653. 87. For studies on the reactivity of 72. Kobayashi, S., Furuya, M., Ohtsubo, A., O-silyldienolates, see: (a) Keck, G.E. and Mukaiyama, T. (1991) Tetrahedron: and Yu, T. (1999) Org. Lett., 1, 289; Asymmetry, 2, 635. (b) Soriente, A., De Rosa, M., Villano, 73. Kobayashi, S., Ohtsubo, A., and R., and Scettri, A. (2004) Curr. Org. Mukaiyama, T. (1991) Chem. Lett., Chem., 8, 993, and references therein; 831. (c) Villano, R., Acocella, M.R., De Rosa, 74. For applications to the synthesis of M., Soriente, A., and Scettri, A. (2004) natural products, see: (a) Shiina, I., Tetrahedron: Asymmetry, 15, 2421; (d) Hashizume, M., Yamai, Y.-s., Oshiumi, Xu,Q.,Yu,J.,Han,F.,Hu,J.,Chen, H., Shimazaki, T., Takasuna, Y.-j., W., and Yang, L. (2010) Tetrahedron: and Ibuka, R. (2005) Chem. Eur. J., 11, Asymmetry, 21, 156; (e) Wang, G., 6601; (b) Shiina, I., Takasuna, Y.-j., Zhao, J., Zhou, Y., Wang, B., and Qu, Suzuki, R.-s., Oshiumi, H., Komiyama, J. (2010) J. Org. Chem., 75, 5326. Y., Hitomi, S., and Fukui, H. (2006) 88. (a) Zimmer, R., Peritz, A., Czerwonka, Org. Lett., 8, 5279; (c) Fukui, H. and R., Schefzig, L., and Reiβig, H.-U. Shiina, I. (2008) Org. Lett., 10, 3153. (2002) Eur. J. Org. Chem., 3419; (b) 75. Such a transition state has been pro- Zimmer, R., Schefzig, L., Peritz, posed in a more broad context, which A., Dekaris, V., and Reissig, H.-U. involves the reaction of propionate-like (2004) Synthesis, 1439; (c) Zimmer, ketene S, O-acetals. See: Kobayashi, S., R., Dekaris, V., Knauer, M., Schefzig, Uchiro, H., Shiina, I., and Mukaiyama, L., and Reissig, H.-U. (2009) Synth. T. (1993) Tetrahedron, 49, 1761. Commun., 39, 1012. 76. Mukaiyama, T. and Kobayashi, S. 89. Kobayashi also reported the enantios- (1994) Org. React., 46,1. elective aldol reaction of 36a catalyzed 77. Mukaiyama, T., Inubushi, A., Suda, by a zirconium complex prepared from S., Hara, R., and Kobayashi, S. (1990) 3,3’-diiodo BINOL, see: (a) Yamashita, Chem. Lett., 1015. Y., Ishitani, H., Shimizu, H., and 78. Mikami, K. and Matsukawa, S. (1993) Kobayashi, S. (2002) J. Am. Chem. Soc., J. Am. Chem. Soc., 115, 7039. 124, 3292; (b) Kobayashi, S., Ueno, M., 79. Mikami, K. and Matsukawa, S. (1994) Saito, S., Mizuki, Y., Ishitani, H., and J. Am. Chem. Soc., 116, 4077. Yamashita, Y. (2004) Proc. Nat. Acad. 80. Matsukawa, S. and Mikami, K. (1995) Sci., 101, 5476; (c) Seki, K., Ueno, M., Tetrahedron: Asymmetry, 6, 2571. and Kobayashi, S. (2007) Org. Biomol. 81. (a) Mikami, K., Matsukawa, S., Chem., 5, 1347. Nagashima, M., Funabashi, H., and 90. (a) Soriente, A., De Rosa, M., Dovinola, Morishima, H. (1997) Tetrahedron Lett., P., Sodano, G., and Scettri, A. (1998) 38, 579; (b) Mikami, K., Kawakami, Y., Tetrahedron: Asymmetry, 9, 2197; (b) Akiyama, K., and Aikawa, K. (2007) J. Dalgard, J.E. and Rychnovsky, S.D. Am. Chem. Soc., 129, 12950. (2004) Org. Lett., 6, 2713; (c) Keck, 82. Mikami, K., Matsukawa, S., Sawa, G.E. and Truong, A.P. (2005) Org. Lett., E., Harada, A., and Koga, N. (1997) 7, 2153; (d) Yajima, A., van Brussel, Tetrahedron Lett., 38, 1951. A.A.N., Schripsema, J., Nukada, T., and 83. Keck, G.E. and Krishnamurthy, D. Yabuta, G. (2008) Org. Lett., 10, 2047; (1995) J. Am. Chem. Soc., 117, 2363. (e) Iqbal, M., Mistry, N., and Clarke, 84. Keck, G.E., Li, X.-Y., and P.A. (2011) Tetrahedron, 67, 4960. Krishnamurthy, D. (1995) J. Org. 91. Kumar, R.N. and Meshram, H.M. Chem., 60, 5998. (2011) Tetrahedron Lett., 52, 1003. 85. For a related transformation using Cat- 92. (a) Carreira, E.M., Singer, R.A., and alyst A, see: Yang, W., Shang, D., Liu, Lee, W. (1994) J. Am. Chem. Soc., 116, 74 1 Stereoselective Acetate Aldol Reactions

8837; (b) Singer, R.A. and Carreira, Kiyooka, S.-i. (2009) Bull. Chem. Soc. E.M. (1997) Tetrahedron Lett., 38, 927. Jpn., 82, 1528; (e) Hurski, A.L. and 93. Singer, R.A., Shepard, M.S., and Kulinkovich, O.G. (2010) Tetrahedron Carreira, E.M. (1998) Tetrahedron, Lett., 51, 3497. 54, 7025. 103. Corey, E.J., Cywin, C.L., and Roper, 94. Rychnovsky, S.D., Khire, U.R., and T.D. (1992) Tetrahedron Lett., 33, 6907. Yang, G. (1997) J. Am. Chem. Soc., 119, 104. Schindler, C.S., Stephenson, C.R.J., 2058. and Carreira, E.M. (2008) Angew. Chem. 95. For other applications to the synthe- Int. Ed., 47, 8852. sis of natural products, see: (a) Li, 105. For other synthetic applications, see: K.W., Wu, J., Xing, W., and Simon, (a) Itsuno, S. and Komura, K. (2002) J.A. (1996) J. Am. Chem. Soc., 118, Tetrahedron, 58, 8237; (b) Itsuno, S., 7237; (b) Smith, A.B. III, Minbiole, Arima, S., and Haraguchi, N. (2005) K.P., Verhoest, P.R., and Schelhaas, M. Tetrahedron Lett., 65, 12074. (2001) J. Am. Chem. Soc., 123, 10942; 106. Corey, E.J., Barnes-Seeman, D., and (c) Myers, A.G., Hogan, P.C., Hurd, Lee, T.W. (1997) Tetrahedron Lett., 38, A.R., and Goldberg, S.D. (2002) Angew. 1699, and references therein. Chem.Int.Ed., 41, 1062. 107. Ishihara, K., Kondo, S., and Yamamoto, 96. (a) Singer, R.A. and Carreira, E.M. H. (2000) J. Org. Chem., 65, 9125. (1995) J. Am. Chem. Soc., 117, 12360; 108. Micoine, K. and Furstner,¨ A. (2010) J. (b) Kim, Y., Singer, R.A., and Carreira, Am. Chem. Soc., 132, 14064. E.M. (1998) Angew. Chem. Int. Ed. 109. Adachi, S., and Harada, T. (2008) Org. Engl., 37, 1261. Lett., 10, 4999. 97. Carreira, E.M., Lee, W., and Singer, 110. Evans, D.A., Kozlowski, M.C., Murry, R.A. (1995) J. Am. Chem. Soc., 117, J.A., Burgey, C.S., Campos, K.R., 3649. Connell, B.T., and Staples, R.J. (1999) 98. For pioneering studies, see: Parmee, J. Am. Chem. Soc., 121, 669. E.R., Hong, Y., Tempkin, O., and 111. Evans, D.A., MacMillan, D.W.C., and Masamune, S. (1992) Tetrahedron Lett., Campos, K.R. (1997) J. Am. Chem. Soc., 33, 1729, and references therein. 119, 10859. 99. (a) Kiyooka, S.-i. and Hena, M.A. 112. Evans, D.A., Masse, C.E., and Wu, J. (1999) J. Org. Chem., 64, 5511; (b) (2002) Org. Lett., 4, 3375. Kiyooka, S.-i., Shahid, K.A., Goto, F., 113. Evans, D.A., Burgey, C.S., Kozlowski, Okazaki, M., and Shuto, Y. (2003) J. M.C., and Tregay, S.W. (1999) J. Am. Org. Chem., 68, 7967. Chem. Soc., 121, 686. 100. For preliminary reports, see: (a) 114. (a) Evans, D.A., Fitch, D.M., Smith, Kiyooka, S.-i., Kaneko, Y., Komura, T.E., and Cee, V.J. (2000) J. Am. Chem. M., Matsuo, H., and Nakano, M. (1991) Soc., 122, 10033; (b) Evans, D.A., J. Org. Chem., 56, 2276; (b) Kiyooka, Rajapakse, H.A., and Stenkamp, D. S.-i., Kaneko, Y., and Kume, K.-i. (2002) Angew. Chem. Int. Ed., 41, 4569; (1992) Tetrahedron Lett., 33, 4927. (c) Evans, D.A. and Connell, B.T. 101. Kiyooka, S.-i., Hena, M.A., Yabukami, (2003) J. Am. Chem. Soc., 125, 10899; T., Murai, K., and Goto, F. (2000) (d) Evans, D.A., Trenkle, W.C., Zhang, Tetrahedron Lett., 41, 7511. J., and Burch, J.D. (2005) Org. Lett., 102. For other synthetic applications, see: 7, 3335; (e) Evans, D.A., Nagorny, P., (a) Kiyooka, S.-i., Goh, K., Nakamura, Reynolds, D.J., and McRae, K.J. (2007) Y., Takesue, H., and Hena, M.A. Angew. Chem. Int. Ed., 46, 541; (f) (2000) Tetrahedron Lett., 41, 6599; (b) Evans, D.A., Burch, J.D., Hu, E., and Shomaker, J.M. and Borhan, B. (2008) Jaeschke, G. (2008) Tetrahedron, 64, J. Am. Chem. Soc., 130, 12228; (c) 4671; (g) Evans, D.A., Carter, P.H., Frein, J.D., Taylor, R.E., and Sackett, Carreira, E.M., Charette, A.B., Prunet, D.L. (2009) Org. Lett., 11, 3186; (d) J.A., and Lautens, M. (1999) J. Am. Yokoyama, T., Yokoyama, R., Nomura, Chem. Soc., 121, 7540; (h) Evans, D.A., S., Matsumoto, S., Fujiyama, R., and Trotter, B.W., Coleman, P.J., Cotˆ e,´ B., References 75

Dias, L.C., Rajapakse, H.A., and Tyler, Tetrahedron Lett., 42, 5195; (c) Snider, A.N. (1999) Tetrahedron, 55, 8671. B.B. and Song, F. (2001) Org. Lett., 115. For related Cu(II)-box complexes, see: 3, 1817; (d) Fettes, A. and Carreira, (a) Orlandi, S., Mandoli, A., Pini, D., E.M. (2003) J. Org. Chem., 68, 9274; and Salvadori, P. (2001) Angew. Chem. (e) Szpilman, A.M., Cereghetti, D.M., Int. Ed., 40, 2519; (b) Le, J.C.-D. and Manthorpe, J.M., Wurtz, N.R., and Pagenkopf, B.L. (2004) Org. Lett., 6, Carreira, E.M. (2009) Chem. Eur. J., 15, 4097; (c) Le Engers, J. and Pagenkopf, 7117. B.L. (2009) Eur. J. Org. Chem., 6109; 124. (a) Bluet, G. and Campagne, J.M. For Zn-pybox complexes, see: (d) (2001) J. Org. Chem., 66, 4293; (b) Jankowska, J. and Mlynarski, J. (2006) Bazan-Tejada,´ B., Bluet, G., Broustal, J. Org. Chem., 71, 1317. G., and Campagne, J.-M. (2006) Chem. 116. For a review on aldol additions to ke- Eur. J., 12, 8358. tones, see: (a) Adachi, S. and Harada, 125. (a) Gondi, V.B., Gravel, M., and Rawal, T. (2009) Eur. J. Org. Chem., 3661; for V.H. (2005) Org. Lett., 7, 5657; (b) recent communications, see: (b) Zhao, Gondi, V.B., Hagihara, K., and Rawal, J.-F., Tan, B.-H., and Loh, T.-P. (2011) V.H. (2010) Chem. Commun., 46, 904. Chem. Sci., 2, 349; (c) Zhao, J., Zheng, 126. In the same context, see also: (a) K.,Yang,Y.,Shi,J.,Lin,L.,Liu,X., Villano, R., Acocella, M.R., Massa, and Feng, X. (2011) Synlett, 903. A., Palombi, L., and Scettri, A. (2007) 117. For related remarkable contributions to Tetrahedron Lett., 48, 891; (b) Villano, ene reactions catalyzed by Cr(III) and R., Acocella, M.R., Massa, A., Palombi, Pd(II)-complexes, see respectively: (a) L., and Scettri, A. (2009) Tetrahedron, Ruck, R.T. and Jacobsen, E.N. (2003) 65, 5571. Angew. Chem. Int. Ed., 42, 4771; (b) 127. Cheon, C.H. and Yamamoto, H. (2010) Mikami, K., Kawakami, Y., Akiyama, Org. Lett., 12, 2476. K., and Aikawa, K. (2007) J. Am. Chem. 128. Garc´ıa-Garc´ıa, P., Lay, F., Soc., 129, 12950. Garc´ıa-Garc´ıa, P., Rabalakos, C., and 118. (a) Langner, M., Remy,´ P., and Bolm, List, B. (2009) Angew. Chem. Int. Ed., C. (2005) Chem. Eur. J., 11, 6254; (b) 48, 4363. Remy,´ P., Langner, M., and Bolm, 129. Ratjen, L., Garc´ıa-Garc´ıa, P., Lay, F., C. (2006) Org. Lett., 8, 1209; (c) Beck, M.E., and List, B. (2011) Angew. Sedelmeier, J., Hammerer, T., and Chem. Int. Ed., 50, 754. Bolm, C. (2008) Org. Lett., 10, 917; (d) 130. For an account of recent advances on Frings, M., Goedert, D., and Bolm, C. this area, see Pansare, S.V. and Paul, (2010) Chem. Commun., 5497. E.K. (2011) Chem. Eur. J., 17, 8770. 119. Akullian, L.C., Snapper, M.L., and 131. Denmark, S.E. and Stavenger, R.A. Hoveyda, A.H. (2006) J. Am. Chem. (2000) J. Am. Chem. Soc., 122, 8837. Soc., 128, 6532. 132. Molawi, K., Delpont, N., and 120. (a) Kruger,¨ J. and Carreira, E.M. (1998) Echavarren, A.M. (2010) Angew. Chem. J. Am. Chem. Soc., 120, 837; (b) Int. Ed., 49, 3517. Pagenkopf, B.L., Kruger,¨ J., Stojanovic, 133. Denmark, S.E., Fujimori, S., and A., and Carreira, E.M. (1998) Angew. Pham, S.M. (2005) J. Org. Chem., 70, Chem.Int.Ed., 37, 3124. 10823. 121. Moreau, X., Bazan-Tejada,´ B., and 134. Denmark, S.E., Pham, S.M., Stavenger, Campagne, J.-M. (2005) J. Am. Chem. R.A., Su, X., Wong, K.-T., and Soc., 127, 7288. Nishigaichi, Y. (2006) J. Org. Chem., 122. Tenenbaum, J.M., Morris, W.J., Custar, 71, 3904. D.W., and Scheidt, K.A. (2011) Angew. 135. Denmark, S.E. and Heemstra, J.R. Jr. Chem.Int.Ed., 50, 5892. (2003) Org. Lett., 5, 2303. 123. For other synthetic applications, see: 136. (a) Denmark, S.E., Beutner, G.L., (a) Kruger,¨ J. and Carreira, E.M. Wynn, T., and Eastgate, M.D. (2005) (1998) Tetrahedron Lett., 39, 7013; (b) J. Am. Chem. Soc., 127, 3774; (b) Brennan, C.J. and Carreira, E.M. (2001) Villano, R., Acocella, M.R., Massa, 76 1 Stereoselective Acetate Aldol Reactions

A., Palombi, L., and Scettri, A. (2006) R.S., Sekerke, C.S., Sliskovic, D.R., Tetrahedron: Asymmetry, 17, 3332. Stratton, C.D., and Wilson, M.W. 137. For an application to the asymmet- (1991) J. Med. Chem., 34, 357; (b) ric synthesis of natural products, see: Tempkin, O., Abel, S., Chen, C.-P., Fang, L., Xue, H., and Yang, J. (2008) Underwood, R., Prasad, K., Chen, Org. Lett., 10, 4645. K.-M., Repic, O., and Blacklock, T.J. 138. For an outstanding report on hyper- (1997) Tetrahedron, 53, 10659. vinylogous Mukaiyama aldol reactions 145. A chiral phenol reported by Yamamoto of extended furan–based silyl enolates also affords high yields and diastereose- using this phosphoramide catalyst, lectivities under milder conditions, but see: Curti, C., Battistini, L., Sartori, it has been scarcely used, see: Saito, S., A., Lodola, A., Mor, M., Rassu, G., Hatanaka, K., Kano, T., and Yamamoto, Pelosi, G., Zanardi, F., and Casiraghi, H. (1998) Angew. Chem. Int. Ed., 37, G. (2011) Org. Lett., 13, 4738. 3378. 139. Denmark, S.E., Eklov, B.M., Yao, P.J., 146. It is worth recalling that N-propanoyl and Eastgate, M.D. (2009) J. Am. Chem. counterpart was absolutely successful Soc., 131, 17770. under the same experimental con- 140. Denmark, S.E., Fan, Y., and Eastgate, ditions and provided the Evans-syn M.D. (2005) J. Org. Chem., 70, 5235. diastereomer in dr 99.4:0.6. See Evans, 141. (a) Mekelburger, H.B. and Wilcox, D.A., Bartroli, J., and Shih, T.L. (1981) C.S. (1992) in Comprehensive Organic J. Am. Chem. Soc., 103, 2127. Synthesis,Vol.2 (eds B.M. Trost and 147. For recent examples, see: (a) Maggiotti, I. Fleming), Pergamon, Oxford, pp. V., Wong, J.-B., Razet, R., Cowley, A.R., 99–131; (b) Heathcock, C.H. (1992) and Gouverneur, V. (2002) Tetrahedron: in Comprehensive Organic Synthesis, Asymmetry, 13, 1789; (b) Liang, Q., Vol. 2 (eds B.M. Trost and I. Fleming), Zhang, J., Quan, W., Sun, Y., She, X., Pergamon, Oxford, pp. 181–235; and Pan, X. (2007) J. Org. Chem., 72, (c) Kim, B.M., Williams, S.F., and 2694. Masamune, S. (1992) in Comprehensive 148. Nagao, Y., Yamada, S., Kumagai, T., Organic Synthesis,Vol.2 (eds B.M. Ochiai, M., and Fujita, E. (1985) J. Trost and I., Fleming), Pergamon, Ox- Chem. Soc., Chem. Commun., 1418. ford, pp. 237–273; (d) Rathke, M.W. 149. Nagao, Y., Hagiwara, Y., Kumagai, T., and Weipert, P. (1992) in Compre- Ochiai, M., Inoue, T., Hashimoto, K., hensive Organic Synthesis,Vol.2 (eds and Fujita, E. (1986) J. Org. Chem., 51, B.M. Trost and I. Fleming), Pergamon, 2391. Oxford, pp. 275–298; (e) Paterson, 150. For the use of Sn(II)-mediated aldol I. (1992) in Comprehensive Organic reaction based on N-acetyl oxazo- Synthesis,Vol.2 (eds B.M. Trost and lidinethiones and thiazolidinethiones in I. Fleming), Pergamon, Oxford, pp. the synthesis of natural products, see: 301–318. (a) Paquette, L.A. and Zuev, D. (1997) 142. (a) Braun, M., Graf,¨ S., and Herzog, S. Tetrahedron Lett., 38, 5115; (b) Romo, (1995) Org. Synth., 72, 32; (b) Braun, D., Rzasa, R.M., Shea, H.A., Park, K., M. and Graf,¨ S. (1995) Org. Synth., 72, Langenhan, J.M., Sun, L., Akhiezer, 38. A., and Liu, J.O. (1998) J. Am. Chem. 143. (a) Schinzer, D., Bauer, A., Bohm,¨ Soc., 120, 12237; (c) Sinz, C.J. and O.M., Limberg, A., and Cordes, M. Rychnovsky, S.D. (2002) Tetrahedron, (1999) Chem. Eur. J., 5, 2483; (b) 58, 6561; (d) Paterson, I., Steven, Lentsch, C. and Rinner, U. (2009) Org. A., and Luckhurst, C.A. (2004) Org. Lett., 11, 5326. Biomol. Chem., 2, 3026; (e) Frenzel, 144. Occasionally, high diastereoselectivities T., Brunjes,¨ M., Quitschalle, M., and ◦ have been also achieved at −78 C, Kirschning, A. (2006) Org. Lett., 8, see: (a) Roth, B.D., Blankley, C.J., 135; (f) Ciblat, S., Kim, J., Stewart, Chucholowski, A.W., Ferguson, E., C.A.,Wang,J.,Forgione,P.,Clyne,D., Hoeﬂe, M.L., Ortwine, D.F., Newton, and Paquette, L.A. (2007) Org. Lett., 9, References 77

719; (g) Scheerer, J.R., Lawrence, J.F., Chem., 71, 6262; (d) Zhang, Y., Arpin, Wang, G.C., and Evans, D.A. (2007) C.C., Cullen, A.J., Mitton-Fry, M.J., and J. Am. Chem. Soc., 129, 8968; (h) Sammakia, T. (2011) J. Org. Chem., 76, Smith, T.E., Kuo, W.-H., Balskus, E.P., 7641. Bock, V.D., Roizen, J.L., Theberge, 160. (a) Crimmins, M.T. and Dechert, A.B., Carroll, K.A., Kurihara, T., and A.-M.R. (2009) Org. Lett., 11, 1635; (b) Wessler, J.D. (2008) J. Org. Chem., 73, Crimmins, M.T. and O’Bryan, E.A. 142; (i) Riatto, V.B., Pilli, A.A., and (2010) Org. Lett., 12, 4416. Victor, M.M. (2008) Tetrahedron, 64, 161. (a) Osorio-Lozada, A. and Olivo, 2279; (j) Muller,¨ S., Mayer, T., Sasse, H.F. (2008) Org. Lett., 10, 617; (b) F., and Maier, M.E. (2011) Org. Lett., Tello-Aburto, R. and Olivo, H.F. (2008) 13, 3940. Org. Lett., 10, 2191; (c) Numajiri, Y., 151. Interestingly, the second-generation Takahashi, T., Takagi, M., Shin-ya, approach described in Scheme 1.65 in- K., and Doi, T. (2008) Synlett, 2483; volves an improvement of the aldol re- (d) Osorio-Lozada, A. and Olivo, H.F. action reported in the ﬁrst-generation, (2009) J. Org. Chem., 74, 1360. see: Smith, A.B. III, Razler, T.M., 162. For related studies on an Ciavarri, J.P., Hirose, T., Ishikawa, T., N-acetyl-1,3-oxazolidine-2-selone, see: and Meis, R.M. (2008) J. Org. Chem., Silks, L.A. III, Kimball, D.B., Hatch, 73, 1192, and references therein. D., Ollivault-Shiﬂett, M., Michalczyk, 152. Yan, T.-H., Hung, A.-W., Lee, H.-C., R., and Moody, E. (2009) Synth. Com- Chang, C.-S., and Liu, W.-H. (1995) J. mun., 39, 641. Org. Chem., 60, 3301. 163. For the use of Ti(IV)–mediated 153. Gonzalez,´ A., Aiguade,´ J., Urp´ı, F., and aldol reactions from chiral Vilarrasa, J. (1996) Tetrahedron Lett., 37, N-acetyl-4-alkyl-1,3-thiazolidine-2- 8949. thiones in the synthesis of natural 154. For the preparation of products, see: (a) Crimmins, M.T. N-acyl-1,3-thiazolidine-2-thiones, see: and Emmitte, K.A. (1999) Org. Lett., Galvez,´ E., Romea, P., and Urp´ı, F. 1, 2029; (b) Crimmins, M.T. and (2009) Org. Synth., 86, 70. Siliphaivanh, P. (2003) Org. Lett., 5, 155. Le Sann, C., Munoz,˜ D.M., Saunders, 4641; (c) Sugiyama, H., Yokokawa, F., N., Simpson, T.J., Smith, D.I., Soulas, and Shioiri, T. (2003) Tetrahedron, 59, F., Watts, P., and Willis, C.L. (2005) 6579; (d) Yurek-George, A., Habens, Org. Biomol. Chem., 3, 1719. F., Brimmell, M., Packham, G., and 156. (a) Hintermann, T. and Seebach, D. Ganesan, A. (2004) J. Am. Chem. Soc., (1998) Helv. Chim. Acta, 81, 2093; 126, 1030; (e) Smith, T.E., Djang, (b) Doi, T., Iijima, Y., Shin-ya, K., M., Velander, A.J., Downey, C.W., Ganesan, A., and Takahashi, T. (2006) Carroll, K.A., and van Alphen, S. (2004) Tetrahedron Lett., 47, 1177. Org. Lett., 6, 2317; (f) Kobayashi, Y., 157. (a) Guz, N.R. and Phillips, A.J. (2002) Fukuda, A., Kimachi, T., Motoharu, Org. Lett., 4, 2253; (b) Crimmins, M.T. J.-i., and Takemoto, Y. (2005) Tetra- and DeBaillie, A.C. (2003) Org. Lett., 5, hedron, 61, 2607; (g) Smith, A.B. III 3009; (c) Chen, Y., Gambs, C., Abe, and Simov, V. (2006) Org. Lett., 8, Y., Wentworth Jr., P., and Janda, K.D. 3315; (h) Jogireddy, R. and Maier, (2003) J. Org. Chem., 68, 8902; (d) M.E. (2006) J. Org. Chem., 71, 6999; Carrick, J.D. and Jennings, M.P. (2009) (i) White, J.D., Lincoln, C.M., Yang, Org. Lett., 11, 769. J., Martin, W.H.C., and Chan, D.B. 158. Crimmins, M.T. and Shamszad, M. (2008) J. Org. Chem., 73, 4139; (j) (2007) Org. Lett., 9, 149. Skaanderup, P.R. and Jensen, T. (2008) 159. (a) Zhang, Y., Phillips, A.J., and Org. Lett., 10, 2821; (k) Ren, Q., Dai, Sammakia, T. (2004) Org. Lett., 6, L., Zhang, H., Tan, W., Xu, Z., and Ye, 23; (b) Zhang, Y. and Sammakia, T. T. (2008) Synlett, 2379; (l) Bock, M., (2004) Org. Lett., 6, 3139; (c) Zhang, Dehn, R., and Kirschning, A. (2008) Y. and Sammakia, T. (2006) J. Org. Angew. Chem. Int. Ed., 47, 9134; (m) 78 1 Stereoselective Acetate Aldol Reactions

Pabbaraja, S., Rajendar, G., Rao, R.S., 171. (a) Kageyama, M., Tamura, T., Nantz, and Yadav, J.S. (2008) Tetrahedron Lett., M.H., Roberts, J.C., Somfai, P., 49, 5590; (n) Yadav, J.S., Kumar, V.N., Whritenour, D.C., and Masamune, Rao, R.S., and Pabbaraja, S. (2008) S. (1990) J. Am. Chem. Soc., 112, 7407; Synthesis, 1938; (o) She, J., Lampe, (b) Oertle, K., Beyeler, H., Duthaler, J.W., Polianski, A.B., and Watson, R.O., Lottenbach, W., Riediker, M., and P.S. (2009) Tetrahedron Lett., 50, 298; Steiner, E. (1990) Helv. Chim. Acta, (p) White, J.D. and Yang, J. (2009) 73, 353; (c) Gennari, C., Moresca, Synlett, 1713; (q) Crimmins, M.T., D., Vulpetti, A., and Pain, G. (1997) Ellis, J.M., Emmitte, K.A., Haile, P.A., Tetrahedron, 53, 5593; (d) Mart´ın, McDougall, P.J., Parrish, J.D., and M.,Mas,G.,Urp´ı, F., and Vilarrasa, Zuccarello, J.L. (2009) Chem. Eur. J., J. (1999) Angew. Chem. Int. Ed., 38, 15, 9223; (r) Brodmann, T., Janssen, 3086; (e) Lee, C.B., Wu, Z., Zhang, D., Sasse, F., Irschik, H., Jansen, R., F., Chappell, M.D., Stachel, S.J., Chou, Muller,¨ R., and Kalesse, M. (2010) T.-C., Guan, Y., and Danishefsky, S. Eur. J. Org. Chem., 5155; (s) Li, W., (2001) J. Am. Chem. Soc., 123, 5249; Schlecker, A., and Ma, D. (2010) Chem. (f) Bauer, M., and Maier, M.E. (2002) Commun., 46, 5403; (t) Shekhar, V., Org. Lett., 4, 2205; (g) Burova, S.A. Reddy, D.K., Reddy, S.P., Prabhakar, and McDonald, F.E. (2004) J. Am. P., and Venkateswarlu, Y. (2011) Eur. J. Chem. Soc., 126, 2495; (h) Amans, D., Org. Chem., 4460; (u) Yadav, J.S. and Bellosta, V., and Cossy, J. (2009) Chem. Rajendar, G. (2011) Eur. J. Org. Chem., Eur. J., 15, 3457; (i) Park, H., Kim, 6781; (v) Yajima, A., van Brussel, H., and Hong, J. (2011) Org. Lett., 13, A.A.N., Schripsema, J., Nukada, T., 3742; (j) El Marrouni, A., Joolakanti, and Yabuta, G. (2008) Org. Lett., 10, S.R., Colon, A., Heras, M., Arseniyadis, 2047; (w) Frenzel, T., Brunjes,¨ M., S., and Cossy, J. (2010) Org. Lett., 12, Quitschalle, M., and Kirschning, A. 4074. (2006) Org. Lett., 8, 135. 172. (a) Yamada, Y.M.A., Yoshikawa, N., 164. Pabbaraja, S., Satyanarayana, K., Sasai, H., and Shibasaki, M. (1997) Ganganna, B., and Yadav, J.S. (2011) J. Angew. Chem. Int. Ed. Engl., 36, Org. Chem., 76, 1922. 1871; (b) Groger,¨ H., Vogl, E.M., 165. Gesinski, M.R. and Rychnovsky, S.D. and Shibasaki, M. (1998) Chem. Eur. J., (2011) J. Am. Chem. Soc., 133, 9727. 4, 1137. 166. Masamune, S., Sato, T., Kim, B.M., 173. For a catalytic resolution of a racemic and Wollmann, T.A. (1986) J. Am. compound in an aldol reaction using Chem. Soc., 108, 8279. this catalyst in the context of the total 167. Corey, E.J., Imwinkelried, R., Pikul, S., synthesis of epothilones A and B, see: and Xiang, Y.B. (1989) J. Am. Chem. Sawada, D., Kanai, M., and Shibasaki, Soc., 111, 5493. M. (2000) J. Am. Chem. Soc., 122, 168. (a) Paterson, I., and Goodman, J.M. 10521. (1989) Tetrahedron Lett., 30, 997; (b) 174. For mechanistic studies and an im- Paterson, I., Goodman, J.M., Lister, proved catalyst, see: Yoshikawa, N., M.A., Schumann, R.C., McClure, C.K., Yamada, Y.M.A., Das, J., Sasai, H., and and Norcross, R.D. (1990) Tetrahedron, Shibasaki, M. (1999) J. Am. Chem. Soc., 46, 4663; (c) Ramachandran, P.V., 121, 4168. Xu, W.-c., and Brown, H.C. (1996) 175. Trost, B.M. and Ito, H. (2000) J. Am. Tetrahedron Lett., 37, 4911. Chem. Soc., 122, 12003. 169. Gennari, C., Moresca, D., Vieth, S., and 176. (a) Trost, B.M., Silcoff, E.R., and Ito, Vulpetti, A. (1993) Angew. Chem. Int. H. (2001) Org. Lett., 3, 2497; (b) Trost, Ed. Engl., 32, 1618. B.M., Shin, S., and Sclafani, J.A. (2005) 170. Duthaler, R.O., Herold, P., Lottenbach, J. Am. Chem. Soc., 127, 8602. W., Oertle, K., and Riediker, M. (1989) 177. Maki, K., Motoki, R., Fujii, K., Kanai, Angew. Chem. Int. Ed. Engl., 28, 495. M., Kobayashi, T., Tamura, S., and References 79

Shibasaki, M. (2005) J. Am. Chem. Soc., C.-M. and Loh, T.-P. (2006) Tetrahedron 127, 17111. Lett., 47, 4485. 178. (a) Trost, B.M., Fettes, A., and 185. For other examples on asymmetric Shireman, B.T. (2004) J. Am. Chem. induction imparted by chiral aldehydes, Soc., 126, 2660; (b) Trost, B.M., see: (a) Paterson, I., Florence, G.J., Frederiksen, M.U., Papillon, J.P.N., Gerlach, K., Scott, J.P., and Sereinig, Harrington, P.E., Shin, S., and N. (2001) J. Am. Chem. Soc., 123, 9535; Shireman, B.T. (2005) J. Am. Chem. (b) Scheidt, K.A., Bannister, T.D., Soc., 127, 3666. Tasaka, A., Wendt, M.D., Savall, B.M., 179. For comments and applications of this Fegley, G.J., and Roush, W.R. (2002) J. catalytic aldol reaction to the synthesis Am. Chem. Soc., 124, 6981. of natural products, see: (a) Amans, 186. For a preliminar report on the re- D., Bareille, L., Bellosta, V., and Cossy, activity of lithium enolate from J. (2009) J. Org. Chem., 74, 7665; (b) 2-acetylthiazole, see: Dondoni, A. Trost, B.M., Yang, H., Brindle, C.S., and Merino, P. (1991) J. Org. Chem., and Dong, G. (2011) Chem. Eur. J., 17, 56, 5294. 9777; (c) Trost, B.M., O’Boyle, B.M., 187. Kuranaga, T., Ohtani, N., Tsutsumi, R., and Hund, D. (2009) J. Am. Chem. Baden, D.G., Wright, J.L.C., Satake, M., Soc., 131, 15061. and Tachibana, K. (2011) Org. Lett., 13, 180. (a) Iwata, M., Yazaki, R., Suzuki, Y., 696. Kumagai, N., and Shibasaki, M. (2009) 188. For other application to the synthesis J. Am. Chem. Soc., 131, 18244; (b) of natural products, see: Aho, J.E., Iwata, M., Yazaki, R., Kumagai, N., Piisola, A., Krishnan, K.S., and Pihko, and Shibasaki, M. (2010) Tetrahedron: P.M. (2011) Eur. J. Org. Chem., 1682. Asymmetry, 21, 1688; (c) Iwata, M., 189. Halperin, S.D., Kang, B., and Britton, Yazaki, R., Chen, I.-H., Sureshkumar, R. (2011) Synthesis, 1946. D., Kumagai, N., and Shibasaki, M. 190. Ocejo, M., Carrillo, L., Vicario, J.L., (2011) J. Am. Chem. Soc., 133, 5554.; Bad´ıa, D., and Reyes, E. (2011) J. Org. (d)Kawato,Y.,Iwata,M.,Yazaki,R., Chem., 76, 460. Kumagai, N. and Shibasaki, M. (2011) 191. (a) Zhou, X.-T., Lu, L., Furkert, D.P., Tetrahedron, 67, 6539. Wells, C.E., and Carter, R.G. (2006) 181. See, for instance: (a) Gathergood, N., Angew. Chem. Int. Ed., 45, 7622; (b) Juhl, K., Poulsen, T.B., Thordrup, K., and Jørgensen, K.A. (2004) Org. Biomol. Nicolaou, K.C., Pihko, P.M., Bernal, F., Chem., 2, 1077; (b) Li, H., Da, C.-S., Frederick, M.O., Qian, W., Uesaka, N., Xiao, Y.-H., Li, X., and Su, Y.-N. (2008) Diedrichs, N., Hinrichs, J., Koftis, T.V., J. Org. Chem., 73, 7398; (c) Kobayashi, Loizidou, E., Petrovic, G., Rodriguez, S. and Matsubara, R. (2009) Chem. Eur. M., Sarlah, D., and Zou, N. (2006) J. J., 15, 10694. Am. Chem. Soc., 128, 2244. 182. For an example of high 1,2-Felkin in- 192. (a) Hassfeld, J., Eggert, U., and duction provided by a chiral aldehyde, Kalesse, M. (2005) Synthesis, 1183; see: Prantz, K. and Mulzer, J. (2010) (b) Ehrlich, G., Hassfeld, J., Eggert, U., Chem. Eur. J., 16, 485. and Kalesse, M. (2008) Chem. Eur. J., 183. For application of this anti bias to the 14, 2232. synthesis of natural products, see: (a) 193. Paterson, I., Goodman, J.M., and Isaka, De Brabander, J. and Vandewalle, M. M. (1989) Tetrahedron Lett., 30, 7121. (1994) Synthesis, 855; (b) Wender, 194. Paton, R.S. and Goodman, J.M. (2008) P.A., Koehler, M.F.T., and Sendzik, J. Org. Chem., 73, 1253. M. (2003) Org. Lett., 5, 4549; (c) 195. (a) Shotwell, J.B. and Roush, W.R. Nakagawa-Goto, K. and Crimmins, (2004) Org. Lett., 6, 3865; (b) Paterson, M.T. (2011) Synlett, 1413. I.,Findlay,A.D.,andFlorence,G.J. 184. (a) Dunetz, J.R., Julian, L.D., Newcom, (2006) Org. Lett., 8, 2131; (c) Paterson, J.S., and Roush, W.R. (2008) J. Am. I. and Paquet, T. (2010) Org. Lett., 12, Chem. Soc., 130, 16407; (b) Wong, 2158. 80 1 Stereoselective Acetate Aldol Reactions

196. (a) O’Sullivan, P.T., Buhr, W., Fuhry, J.M., Banuelos,˜ P., Tello, M., and M.A.M., Harrison, J.R., Davies, J.E., Linden, A. (2004) J. Org. Chem., 69, Feeder, N., Marshall, D.R., Burton, 4126. J.W., and Holmes, A.B. (2004) J. Am. 206. (a) Paterson, I., Gibson, K.R., and Chem. Soc., 126, 2194; (b) Paterson, Oballa, R.M. (1996) Tetrahedron Lett., I.,Anderson,E.A.,Dalby,S.M.,and 37, 8585; (b) Evans, D.A., Coleman, Loiseleur, O. (2005) Org. Lett., 7, P.J., and Cotˆ e,´ B. (1997) J. Org. Chem., 4125; (c) Paterson, I., Florence, 62, 788; (c) Evans, D.A., Cotˆ e,´ B., G.J., Heimann, A.C., and Mackay, Coleman, P.J., and Connell, B.T. (2003) A.C. (2005) Angew. Chem. Int. Ed., 44, J. Am. Chem. Soc., 125, 10893. 1130; (d) Paterson, I., Coster, M.J., 207. For a recent review, see: Dias, L.C. and Chen, D.Y.-K., Oballa, R.M., Wallace, Aguilar, A.M. (2008) Chem.Soc.Rev., D.J., and Norcross, R.D. (2005) Org. 37, 451. Biomol. Chem., 3, 2399; (e) Paterson, 208. For further applications to the syn- I., Gibson, L.J., and Kan, S.B.J. (2010) thesis of natural products, see: (a) Org. Lett., 12, 5530. Trieselmann, T. and Hoffmann, 197. Zambrana, J., Romea, P., Urp´ı, F., R.W. (2000) Org. Lett., 2, 1209; (b) and Lujan,´ C. (2011) J. Org. Chem., 76, Kozmin, S. (2001) Org. Lett., 3, 755; 8575. (c) Paterson, I. and Collett, L.A. 198. Furstner,¨ A., Kattnig, E., and Lepage, (2001) Tetrahedron Lett., 42, 1187; O. (2006) J. Am. Chem. Soc., 128, (d) Bhattacharjee, A., Soltani, O., and 9194. De Brabender, J.K. (2002) Org. Lett., 199. Pellicena, M., Solsona, J.G., Romea, P., 4, 481; (e) Paterson, I. and Tudge, and Urp´ı, F. (2008) Tetrahedron Lett., M. (2003) Tetrahedron, 59, 6833; (f) 49, 5265. Paterson, I., Coster, M.J., Chen, 200. Interestingly, lithium and sodium D.Y.-K., Gibson, K.R., and Wallace, enolates from α-(N,N-dibenzylamino) D.J. (2005) Org. Biomol. Chem., 3, 2410; methyl ketones undergo aldol reactions (g) Denmark, S.E. and Fujimori, S. delivering 1,4-syn aldols with very high (2005) J. Am. Chem. Soc., 127, 8971; diastereoselectivity, see: Lagu, B.R., and (h) Mitton-Fry, M.J., Cullen, A.J., and Liotta, D.C. (1994) Tetrahedron Lett., 35, Sammakia, T. (2007) Angew. Chem. 4485. Int. Ed., 46, 1066; (i) Paterson, I., 201. Lorente, A., Pellicena, M., Romea, P., Anderson, E.A., Dalby, S.M., Lim, and Urp´ı, F. (2010) Tetrahedron Lett., J.H., Loiseleur, O., Maltas, P., and 51, 942. Moessner, C. (2007) Pure Appl. Chem., 202. Paterson,I.,Findlay,A.D.,andNoti,C. 79, 667; (j) Guo, H., Mortensen, M.S., (2009) Chem. Asian J., 4, 594. and O’Doherty, G.A. (2008) Org. Lett., 203. (a) Lorenz, M. and Kalesse, M. (2008) 10, 3149; (k) Evans, D.A., Welch, Org. Lett., 10, 4371; (b) Lorenz, M., D.S., Speed, A.W.H., Moniz, G.A., Bluhm, N., and Kalesse, M. (2009) Reichelt, A., and Ho, S. (2009) J. Am. Synthesis, 3061. Chem. Soc., 131, 3840; (l) Paterson, 204. (a) Guerinot,´ A., Lepesqueux, G., Sable,´ I., Muhlthau,¨ F.A., Cordier, C.J., S., Reymond, S., and Cossy, J. (2010) J. Housden, M.P., Burton, P.M., and Org. Chem., 75, 5151. Loiseleur, O. (2009) Org. Lett., 11, 353; 205. (a) Palomo, C., Gonzalez,´ A., Garc´ıa, (m) Fu, F. and Loh, T.-P. (2009) Tetra- J.M., Landa, C., Oiarbide, M., hedron Lett., 50, 3530; (n) Li, S., Chen, Rodr´ıguez, S., and Linden, A. (1998) Z., Xu, Z., and Ye, T. (2010) Chem. Angew. Chem. Int. Ed., 37, 180; (b) Commun., 46, 4773; (o) Evans, D.A., Palomo, C., Oiarbide, M., Aizpurua, Trotter, B.W., Coleman, P.J., Cotˆ e,´ B., J.M., Gonzalez,´ A., Garc´ıa, J.M., Dias, L.C., Rajapakse, H.A., and Tyler, Landa, C., Odriozola, I., and Linden, A.N. (1999) Tetrahedron, 55, 8671; (p) A. (1999) J. Org. Chem., 64, 8193; (c) Paterson, I., Di Francesco, M.E., and Palomo, C., Oiarbide, M., Garc´ıa, J.M., Kuhn,¨ T. (2003) Org. Lett., 5, 599; (q) Gonzalez,´ A., Pazos, R., Odriozola, Fettes, A. and Carreira, E.M. (2003) J. References 81

Org. Chem., 68, 9274; (r) Crimmins, Gaunt, M.J., Scolaro, A., Yamanoi, S., M.T. and Siliphaivanh, P. (2003) Org. and Ley, S.V. (2005) Synlett, 2031; (c) Lett., 5, 4641. Fu, F. and Loh, T.-P. (2009) Tetrahedron 209. (a) Paterson, I., Coster, M.J., Chen, Lett., 50, 3530; (d) Paterson, I., Coster, D.Y.-K., Acena,˜ J.L., Bach, J., Keown, M.J., Chen, D.Y.-K., Acena,˜ J.L., Bach, L.E., and Trieselmann, T. (2005) Org. J., Keown, L.E., and Trieselmann, T. Biomol. Chem., 3, 2420; (b) Crimmins, (2005) Org. Biomol. Chem., 3, 2420. M.T. and Siliphaivanh, P. (2003) Org. 217. (a) Chakraborty, T.K., Thippeswamy, Lett., 5, 4641. D., Suresh, V.R., and Jayaprakash, S. 210. Dias, L.C., de Marchi, A.A., Ferreira, (1997) Chem. Lett., 563; (b) Ishiyama, M.A.B., and Aguilar, A.M. (2008) J. H., Takemura, T., Tsuda, M., and Org. Chem., 73, 6299. Kobayashi, J. (1999) J. Chem. Soc. 211. Dias, L.C., de Lucca, E.C., Ferreira, Perkin Trans. 1, 1163; (c) Cid, M.B. M.A.B., Garcia, D.C., and Tormena, and Pattenden, G. (2000) Tetrahe- C.F. (2010) Org. Lett., 12, 5056. dron Lett., 41, 7373; (d) Furstner,¨ 212. For other examples, see: (a) Mulzer, J. A., Bouchez, L.C., Morency, L., and Berger, M. (2004) J. Org. Chem., Funel, J.-A., Liepins, V., Poree,´ F.-H., 69, 891; (b) Arefolov, A. and Panek, Gilmour, R., Laurich, D., Beauﬁls, F., J.S. (2005) J. Am. Chem. Soc., 127, and Tamiya, M. (2009) Chem. Eur. J., 5596; (c) Dias, L.C., Aguilar, A.M., 15, 3983. Salles, A.G. Jr., Steil, L.J., and Roush, 218. (a) Lu, L., Zhang, W., and Carter, R.G. W.R. (2005) J. Org. Chem., 70, 10461; (2008) J. Am. Chem. Soc., 130, 7253; (d) Kim, Y.J. and Lee, D. (2006) Org. For a recent example, see: (b) Hara, Lett., 8, 5219; (e) Li, P., Li, J., Arikan, A., Morimoto, R., Ishikawa, Y., and F., Ahlbrecht, W., Dieckmann, M., and Nishiyama, S. (2011) Org. Lett., 13, Menche, D. (2010) J. Org. Chem., 75, 4036. 2429. 219. Zhang, W. and Carter, R.G. (2005) Org. 213. (a) Dias, L.C., Bau,´ R.Z., de Sousa, Lett., 7, 4209. M.A., and Zukerman-Schpector, J. 220. Chakraborty, T.K. and Suresh, V.R. (2002) Org. Lett., 4, 4325; (b) Dias, L.C. (1998) Tetrahedron Lett., 39, 7775. and Aguilar, A.M. (2006) Org. Lett., 8, 221. (a) Liesener, F.P., Jannsen, U., and 4629. Kalesse, M. (2006) Synthesis, 2590; (b) 214. Dias, L.C., Pinheiro, S.M., de Oliveira, Deng, L., Ma, Z., and Zhao, G. (2008) V.M., Ferreira, M.A.B., Tormena, C.F., Synlett, 728. Aguilar, A.M., Zukerman-Schpector, J., 222. For an insightful account on the total and Tiekink, E.R.T. (2009) Tetrahedron, syntheses of discodermolide, see: (a) 65, 8714. Paterson, I. and Florence, G.J. (2003) 215. Roush, W.R., Bannister, T.D., Wendt, Eur. J. Org. Chem., 2193; (b) Florence, M.D., Jablonowski, J.A., and Scheidt, G.J., Gardner, N.M., and Paterson, I. K.A. (2002) J. Org. Chem., 67, 4275. (2008) Nat. Prod. Rep., 25, 342. 216. (a) Crimmins, M.T., Katz, J.D., 223. Paterson, I., Delgado, O., Florence, Washburn, D.G., Allwein, S.P., and G.J., Lyothier, I., Scott, J.P., and McAtee, L.F. (2002) J. Am. Chem. Sereinig, N. (2003) Org. Lett., 5, 35. Soc., 124, 5661; (b) Kawahara, S.,