lable at ScienceDirect

Tetrahedron 71 (2015) 1023e1035

Contents lists avai

Tetrahedron

journal homepage: www.elsevier .com/locate/ tet

Stereoselective acetate aldol reactions of a-silyloxy ketones

Adriana Lorente, Miquel Pellicena, Pedro Romea *, F�elix Urpí *

Departament de Química Org�anica and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Carrer Martí i Franqu�es,1-11, 08028 Barcelona, Catalonia, Spain

a r t i c l e i n f o

Article history:Received 13 November 2014Received in revised form 18 December 2014Accepted 29 December 2014Available online 3 January 2015

Keywords:Stereoselective reactionsAcetate aldol reactionsTitanium enolatesChiral ketones

* Corresponding authors. Tel.: þ34 93 4039106;tel.: þ34 93 4021247; fax: þ34 93 3397878 (F.U.); e-mub.edu (P. Romea), felix.urpi@ub.edu (F. Urpí).

http://dx.doi.org/10.1016/j.tet.2014.12.0990040-4020/� 2015 Elsevier Ltd. All rights reserved.

a b s t r a c t

TiCl4-mediated aldol reactions of chiral methyl a-silyloxy ketones with a variety of aldehydes provide thecorresponding 1,4-syn aldol adducts with moderate to high stereocontrol. This transformation representsa new approach to substrate-controlled acetate aldol reactions and complements the 1,4-anti asymmetricinduction produced by the related a-benzyloxy ketones. This new approach could be useful in the designof more efficient syntheses of natural products.

� 2015 Elsevier Ltd. All rights reserved.

1. Introduction

The coupling of elaborate fragments in the advanced steps ofa synthesis requires full knowledge of the particular trends of thereacting species.1,2 This is especially important in asymmetricsynthesis, in which the configurations of the new chirality centresusually rely on subtle steric and electronic influences due to severalgroups within the reactants.3 Acetate aldol reactions illustrate sucha scenario.4,5 Indeed, the resultant b-hydroxy carbonyl structuresare found in a large array of natural products and, in principle, theycould be easily synthesized by aldol addition of methyl ketones toaldehydes.5,6 Nevertheless, and despite recent advances in catalyticasymmetric-based5g,h,7 and chiral auxiliary-based5g,h,8 approaches,there is still a shortage of methods to achieve such transformationsboth in structurally simple as well as structurally complex in-termediates in advanced steps of a synthesis.9 Thus, substrate-controlled aldol reactions based on metal enolates from chiralmethyl ketones are an appealing way to address this challengeprovided that one has a thorough understanding of the asymmetricinduction that the enolate and the aldehyde undergo.5g,h,10e12 Un-fortunately, this is much more demanding than it is in relatedprocesses from ethyl ketones since metal enolate-mediated aldolreactions involving chiral methyl ketones can proceed throughseveral six-membered cyclic transition states of similar energy.13

Therefore, prediction of the stereochemical outcome of these

fax: þ34 93 3397878 (P.R.);ail addresses: pedro.romea@

reactions is always problematic and requires comprehensive anal-ysis of the influence of both the ketone and the aldehyde on theconfiguration of the new stereocentre.

Keeping these challenges in mind, some years ago we launcheda project to develop stereoselective aldol reactions from titaniu-m(IV) enolates of chiral methyl ketones.14,15 These titanium(IV)enolates can be prepared by simple treatment of methyl ketoneswith titanium(IV) Lewis acids in the presence of a tertiaryamine,16,17 and they can react with a large array of aldehydes undermild conditions. Furthermore, we envisaged that the relativelyshort TieO distances and the possibility of attaching different li-gands to the metal might furnish the tight transition states that areessential for highly stereocontrolled transformations.18 This provedto be the case in the aldol additions of b-as well as a-benzyloxymethyl ketones (see Eqs. 1 and 3 in Scheme 1).14,15 A parallel pro-cess based on b-silyloxy methyl ketones turned out to be nonstereoselective (Eq. 2 in Scheme 1), so the benzyl protecting groupseemed to be crucial for the success of these reactions. Neverthe-less, preliminary studies of the addition of titanium(IV) enolatesfrom a-tert-butyldimethylsilyloxy methyl ketones to aliphatic,aromatic and a,b-unsaturated aldehydes showed that the corre-sponding 1,4-syn aldols could be obtained in good yields (see Eq. 4in Scheme 1).19 Encouraged by these results, we have now carriedout a comprehensive analysis of such a transformation that com-plements the 1,4-anti induction observed for the related a-benzy-loxy methyl ketones (compare Eqs. 3 and 4 in Scheme 1). Herein,we report our findings on the substrate-controlled titanium-me-diated aldol reactions of a-silyloxy methyl ketones that produce1,4-syn aldol adducts with moderate to high diastereoselectivitydepending on the steric hindrance of the R group and the aldehyde.

Scheme 1. Titanium-mediated substrate-controlled aldol reactions from chiral b- and a-hydroxy methyl ketones.

A. Lorente et al. / Tetrahedron 71 (2015) 1023e10351024

On the whole, these studies provide valuable knowledge for de-vising more efficient synthesis routes for complex natural products.

2. Results and discussion

2.1. Preliminary results

Lactate-derived a-tert-butyldimethylsilyloxy methyl ketone 120

was chosen to assess the feasibility of stereoselective acetate al-dol reactions. Considering the influence of titanium(IV) Lewis acidson the stereochemical outcome of related processes,18 we initiallystudied the effect of the enolization conditions on the titanium-mediated aldol reaction of 1 with isobutyraldehyde (a). Thesepreliminary experiments were disappointing; experimental con-ditions optimized for related ethyl ketones based on the enolizationof 1 with mild Lewis acids such as (i-PrO)2TiCl2 and (i-PrO)TiCl3yielded the self-condensation adduct 5 as the major component ofthe reacting mixtures instead of 1,4-syn aldol 2a (entries 1 and 2 inTable 1).21 This suggested that the enolization step was slowenough to allow the resulting enolate to attack the activated ketoneand produce the undesired aldol 5. Even the stronger TiCl4 pro-duced a significant amount of this adduct at�78 �C (entry 3 in Table1). The formation of 5 was finally minimized by lowering theenolization temperature to �94 �C and carrying out the aldol re-action at �78 �C.22 Thereby, aldols 2a and 3a (1,4-syn and 1,4-anti,respectively) were obtained with a 71% overall yield as well as tinyamounts of hemiacetal 4a, which was isolated as a single di-astereomer after chromatographic purification (entry 4 in Table 1).Hence, the diastereoselectivity of the formation of 2a was estab-lished as dr 77:23 assuming that 4a results from 2a (entry 4 inTable 1).

Table 1Influence of titanium(IV) Lewis acids on the aldol reaction of 1 and isobutyraldehyde (a)

Entry TiL4 Tenol (�C) dr (2aþ4a)/3aa

1 Ti(i-PrO)2Cl2 �78 75:252 Ti(i-PrO)Cl3 �78 76:243 TiCl4 �78 74:264 TiCl4 �94 77:23

a Determined by 1H NMR analysis of isolated products.b Isolated yield.c Not determined.

2.2. TiCl4-mediated aldol reactions of lactate-derived ketone 1

Having established the feasibility of the titanium-mediated al-dol addition of 1 to isobutyraldehyde (a), we next examined parallelreactions with other aldehydes under the previously optimizedexperimental conditions. The results summarized in Table 2 provethat the TiCl4-mediated aldol reactions of 1 with aliphatic alde-hydes aeg are fairly diastereoselective (entries 1e7 in Table 2).Indeed, 1,4-syn aldols 2aeg were isolated in good yields and di-astereomeric ratios close to 80:20 irrespective of the steric bulk ofthe R1 group. Even aldol adduct 2d from the smallest acetaldehyde(d) was obtained with a reasonably good diastereomeric ratio andyield (dr 71:29 and 73%, entry 4 in Table 2). It is noteworthy thatsignificant amounts of hemiacetals 4b and 4c from iso-valeraldehyde and butanal were isolated after chromatographicpurification (entries 2 and 3 in Table 2, respectively), whereas thecorresponding hemiacetals from acetaldehyde or aldehydes eegcontaining other functional groups in R1 were never observed(entries 4e7 in Table 2). Benzaldehyde (h) and methacrolein (i) didnot form such hemiacetals either (entries 8 and 9 in Table 2). Un-fortunately, the diastereoselectivity for these conjugated aldehydeswas poorer than that achieved with the aliphatic counterparts,being particularly low with benzaldehyde (dr 55:45, entry 8 inTable 2).

The isolation of hemiacetals 4aec as a single diastereomer in-dicated that kinetic discriminationwas operating on the mixture ofaldol diastereomers,23,24 so there was room to improve the iso-lation of pure 1,4-syn adducts 2 provided that 4 could be obtainedin good yields to be subsequently converted back into 2. Thus, wewere pleased to observe that the use of 2 equiv of butanal (c)yielded up to 45% of pure hemiacetal 4c. Higher loadings were notnecessary, as 3 equiv afforded a similar yield (compare entries 1e3

Yield 2a and 3ab (%) Yield 4ab (%) Yield 5b (%)

5 d 6827 ndc 2965 ndc 1571 5 d

Table 2TiCl4-mediated aldol reactions of 1 with achiral aldehydes

Entry Aldehyde R1 Yield 4a (%) Yield 2 and 3a (%) dr (2þ4)/3

1 a i-Pr 5 71 77:23b

2 b i-Bu 19 63 76:24b

3 c n-Pr 18 65 76:24b

4 d Me d 73 71:29c

5 e CH2OTIPS d 71 78:22c

6 f CH2CH2OTIPS d 72 77:23c

7 g CH2CH2NPhth d 68 80:20c

8 h Ph d 75 55:45c

9 i C(CH3)]CH2 d 80 65:35c

a Overall isolated yield.b Determined by 1H NMR analysis of isolated products.c Determined by 1H NMR analysis of the reaction mixture.

A. Lorente et al. / Tetrahedron 71 (2015) 1023e1035 1025

in Table 3). Finally, stirring 4c and a catalytic amount of p-TsOH inTHF/MeOH at room temperature produced 2c with a 98% yield(entry 3 in Table 3). Application of this experimental procedure toisovaleraldehyde (b) allowed us to isolate diastereomerically pure1,4-syn aldol 2b in a straightforward manner (entry 4 in Table 3),but isobutyraldehyde (a) turned out to be less amenable and pro-duced hemiacetal 4a in a low yield (entry 5 in Table 3).

Table 3Synthesis and hydrolysis of hemiacetals 4

Entry Aldehyde R1 Equivalents Hemiacetal dra 4 Yield 4b (%) Aldol Yield 2b (%)

1 c n-Pr 1.5 4c >97:3 18 2c d

2 c n-Pr 2 4c >97:3 45 2c d

3 c n-Pr 3 4c >97:3 43 2c 984 b i-Bu 2 4b >97:3 42 2b 845 a i-Pr 2 4a >97:3 17 2a d

a The minor diastereomer was not detected in the isolated products by 1H NMR analysis (400 MHz).b Isolated yield.

Therefore, while it is true that such a protocol is restricted tocertain aliphatic aldehydes, it easily produces configurationallypure 1,4-syn aldol adducts, which are difficult to obtain by othermethods. Moreover, it also suggests that subtle structural detailscan determine the outcome of these aldol reactions.

2.3. TiCl4-mediated aldol reaction of chiral a-silyloxy methylketones

The aim of expanding the scope of such a substrate-controlledtransformation led us to test the reaction of other a-tert-butyldi-methylsilyloxy methyl ketones with several representative alde-hydes. Thus, ketones 6e8 were prepared in an enantiomericallypure form through acylation of MeLi with N-acyl pyrrolidines 9e11

derived from the corresponding a-hydroxy esters, as shown inScheme 2.25 Moreover, 6 and 8 were also obtained by treatment ofthe corresponding Weinreb amides 12 and 13 with MeMgBr.26

With a straightforward and reliable multigram supply of a-tert-butyldimethylsilyloxy methyl ketones to hand, we evaluated theirtitanium-mediated aldol reactions with isobutyraldehyde (a),benzaldehyde (h), and methacrolein (i) under the previously opti-

mized experimental conditions. The results are summarized inTable 4, including those for lactate-derived ketone 1.

Most of these acetate aldol reactions provided the corre-sponding 1,4-syn aldol adducts in high yields and with moderateto excellent diastereoselectivities. Lactate-derived methyl ketone1 underwent the poorest stereocontrolled reactions, whereas thevaline-derived ketone 8 produced diastereomeric ratios of up to96:4 (compare entries 1e3 and 10e12 in Table 4). Thus, the stericbulk of the R group plays a crucial role in the diastereoselectivityof the reaction, although the pace at which the latter increasesalso depends on aldehyde. Indeed, aldol reactions of 1, 6 and 7with isobutyraldehyde (a) and methacrolein (i) produce similardiastereomeric ratios (approximately dr 75:25 and 65:35, re-spectively, compare entries 1, 4 and 7 with 3, 6 and 9) whereas

Scheme 2. Synthesis of a-OTBS ketones 6e8. Reagents and conditions: (a) C4H9N, rt;(b) TBSCl, Et3N, DMAP, THF, rt; (c) MeLi, THF, �78 �C; (d) MeONHMe$HCl, i-PrMgCl,THF, �20 �C; (e) MeMgBr, THF, 0 �C.

Table 4TiCl4-mediated aldol reactions of a-OTBS methyl ketones

Entry Ketone R Aldehyde R1 Adduct dra (1,4-syn/1,4-anti) Yieldb (%)

1 1 Me a i-Pr 2a 77:23c 712 1 Me h Ph 2h 55:45 753 1 Me i C(Me)]CH2 2i 65:35 804 6 i-Bu a i-Pr 14a 73:27 955 6 i-Bu h Ph 14h 72:28 756 6 i-Bu i C(Me)]CH2 14i 64:36 747 7 Bn a i-Pr 16a 77:23 958 7 Bn h Ph 16h 75:25 949 7 Bn i C(Me)]CH2 16i 68:32 9310 8 i-Pr a i-Pr 18a 96:4 8511 8 i-Pr h Ph 18h 83:17 8412 8 i-Pr i C(Me)]CH2 18i 90:10 83

a Determined by 1H NMR analysis of the reaction mixture.b Overall isolated yield. Diastereomeric aldol adducts cannot be separated by column chromatography.c Determined by 1H NMR analysis of isolated products.

A. Lorente et al. / Tetrahedron 71 (2015) 1023e10351026

similar reactions of 8 result in much better stereocontrol (dr 96:4and 90:10, respectively, entries 10 and 12 in Table 4). In contrast,the diastereomeric ratios for benzaldehyde steadily increase from55:45 to 83:17 (compare entries 2, 5, 8 and 11 in Table 4). Alltogether, these results show that a-OTBS methyl ketoneswith a bulky R group can participate in highly diastereoselectiveacetate aldol reactions and provide access to 1,4-syn di-astereomers that are difficult to obtain by any other syntheticmethod.5g,h,27

Finally, the influence of other silyl protecting groups was alsotested. To this end, a-silyloxy methyl ketones 20 and 21 wereprepared25 as was 7 and their aldol reactions with iso-butyraldehyde (a) were examined. Importantly, the results sum-marized in Table 5 show that all those ketones produced excellentyields (91e98%) and diastereoselectivities close to 80:20. Therefore,

the silyl-protecting groups have no influence on such reactions andeven the labile TES can safely be used. In short, TiCl4-mediatedacetate aldol additions of a-silyloxy methyl ketones to a wide arrayof achiral aldehydes provide the corresponding 1,4-syn aldol ad-ducts with remarkable stereocontrol.

2.4. Configuration

The stereochemical outcomes of such titanium-mediated aldolreactions of a-silyloxy methyl ketones were established by chem-ical correlation of the aldol adducts 2a,18a and 18h. Removal of theTBS protecting group and further oxidation of the resultant a-hy-droxy ketones gave the corresponding b-hydroxy acids 26 and 27(Scheme 3).

Comparison of the physical and spectroscopic data for the car-boxylic acids 26 and 27 with those previously reported in the lit-erature proved the 1,4-syn configuration of the aldol adducts(Scheme 4).

The moderate to high 1,4-syn stereochemical induction pro-vided by such a wide range of a-silyloxy ketones is a pleasingcomplement to the 1,4-anti trend observed for related a-benzyloxy

ketones.14 So titanium-mediated aldol reactions from a-hydroxymethyl ketones can provide either configuration merely bya change of the protecting group (Scheme 1).18 This is especiallyremarkable since most of the acetate aldol reactions from a-hy-droxy methyl ketones supply the corresponding 1,4-anti configu-ration.27 Therefore, these substrate-controlled aldol reactions froma-silyloxy methyl ketones may be a valuable tool for the totalsynthesis of natural products. With this in mind, we finally testedthe reactions in a more complex scenario involving chiralaldehydes.

2.5. Double asymmetric aldol reactions

Conventional wisdom states that double asymmetric reactionsbecome more or less diastereoselective than those of the two

Scheme 3. Chemical correlation of aldols 2 and 18.

Table 5Influence of the protecting group on the TiCl4-mediated aldol reactions of a-silyloxy ketones

Entry Ketone R3Si Adduct dra (1,4-syn/1,4-anti) Yieldb (%)

1 7 TBS 16a 77:23c 952 20 TES 22a 76:24 913 21 TBDPS 24a 80:20 98

a Determined by 1H NMR analysis of the reaction mixture.b Overall isolated yield. Diastereomeric aldol adducts cannot be separated by column chromatography.c Determined by 1H NMR analysis of isolated products.

Scheme 4. 1,4-syn Configuration of aldols 2 and 18.

A. Lorente et al. / Tetrahedron 71 (2015) 1023e1035 1027

reacting depending on the stereochemical induction imparted byeach of them. Thus, if they cooperate and produce the same di-astereomer (matched case) the stereocontrol increases; whereas inthe opposite situation (mismatched case) the stereocontrol is re-duced.29 This occurs for most aldol additions of chiral enolates tochiral aldehydes and it is currently used in the accounts of suchreactions. Nonetheless, we had previously observed that doubleasymmetric acetate aldol reactions from a-benzyloxy methyl ke-tones are highly diastereoselective, irrespective of the configura-tion of the ketone and the aldehyde.14b Therefore, thestereochemical outcome of this sort of reactions deserve to be ex-amined carefully.

Keeping such precedents in mind, we examined the TiCl4-me-diated aldol reaction of lactate-derived ketone 1 with a-Me chiralaldehydes 28 and ent-28 (Scheme 5).30 Since it is well documentedthat chiral aldehydes favour the Felkin diastereomer in acetate aldolreactions under non-chelating conditions,5,10,31 aldehyde 28 wasexpected to produce the most diastereoselective process. Surpris-ingly, just the contrary was observed: the enantiomer of aldehyde28, ent-28, produced a better diastereomeric ratio (dr 72:28 vs62:38) with a higher yield (81% vs 67%, see Eqs. 5 and 6 in Scheme5). Moreover, the diastereoselectivity of the putative matched pairwas slightly lower than that with isobutyraldehyde (dr 77:23),which is the most similar achiral aldehyde used in previous ex-periments (see Table 2).

To gain further insight into such unforeseen behaviour, weassessed double asymmetric aldol reactions of methyl ketones 1and 8 with chiral a-OTBDPS aldehydes 33 and ent-33.32 These areknown to impart a remarkable Felkin bias and are often employedas probes to evaluate such transformations.33e35 As shown inScheme 6, these aldehydes confirmed the trend observed in theformer reactions. Indeed, the putative matched pair involvinglactate-derived ketone 1 and chiral aldehyde 33 produced a roughlyequimolecular mixture of two diastereomers in an excellent yield(see Eq. 7 in Scheme 6). Instead, anti-Felkin aldol adduct 36 wasobtained from ent-33 with a high diastereomeric ratio (dr 80:20)and with a 92% yield (see Eq. 8 in Scheme 6). Valine-derivedmethylketone 8 exhibited the same trend. Contrary to what was expected,its addition to 33 produced Felkin adduct 38 in a 84:16 di-astereomeric ratio with a 93% yield whereas the parallel reactionwith ent-33 produced anti-Felkin adduct 40 in a higher di-astereomeric ratio (dr 93:7) than with a 95% yield (compare Eqs. 9and 10 in Scheme 6).

These puzzling results highlight the difficulty in providinga simple mechanistic model that accounts for the overall trans-formations and reveal the necessity of further studies to shed lighton the intricacies of these reactions. In turn, they also emphasizethe fact that sterically hindered a-OTBS methyl ketones are anexcellent platform from which 1,4-syn aldol adducts can be ob-tained in a highly diastereoselective and straightforward mannerirrespective of the configuration of the aldehyde, which can beexploited to devise more efficient synthesis.

3. Conclusions

To summarize, TiCl4-mediated acetate aldol reactions of chiral a-silyloxy methyl ketones with a variety of aldehydes produce the

Scheme 5. Double asymmetric aldol reactions with chiral a-Me aldehydes.

Scheme 6. Double asymmetric aldol reactions with chiral a-OTBDPS aldehydes.

A. Lorente et al. / Tetrahedron 71 (2015) 1023e10351028

corresponding 1,4-syn adducts with moderate to high diaster-eoselectivities and yields. Importantly, sterically hindered a-sily-loxy methyl ketones participate in highly stereocontrolledtransformations irrespective of the aldehyde; this nicely comple-ments the 1,4-anti induction provided by related a-benzyloxymethyl ketones. Thus, the titanium-based methodology reportedhere represents a new and complementary approach to substrate-controlled acetate aldol reactions, which may be helpful to designmore efficient syntheses.

4. Experimental section

4.1. General information

Unless otherwise noted, all oxygen and moisture-sensitive re-actions were conducted in oven-dried glassware under inert at-mosphere of N2 with anhydrous solvents. The solvents andreagents were dried and purified when necessary according tostandard procedures. All commercial reagents were used as

A. Lorente et al. / Tetrahedron 71 (2015) 1023e1035 1029

received. Analytical thin-layer chromatography (TLC) was carriedout on Merck silica gel 60 F254 plates and analyzed by UV (254 nm)and stained with p-anisaldehyde or phosphomolybdic acid; Rfvalues are approximate. Column chromatographies were carriedunder low pressure (flash) conditions and performed on SDS silicagel 60 (35e70 mm). Specific rotations ([a]D) were determined at20 �C on a PerkineElmer 241 MC polarimeter. IR spectra wererecorded on a Nicolet 6700 FT-IR Thermo Scientific spectrometerand only the more representative frequencies (n) are reported incm�1. 1H NMR (400 MHz) and 13C NMR (100.6 MHz) spectra wererecorded on a Varian Mercury 400. Chemical shifts (d) are quotedin parts per million (ppm) and referenced to internal TMS (d 0.00for 1H NMR), or CDCl3 (d 77.0 for 13C NMR); coupling constants (J)are quoted in hertz (Hz); data are reported as follows: s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet (and their correspond-ing combinations); where necessary, 2D techniques (NOESY, COSY,HSQC) were also used to assist on structure elucidation. High-resolution mass spectra (HRMS) were obtained with an Agilent1100 spectrometer by the Unitat d’Espectrometria deMasses at theCentres Científics i Tecnol�ogics de la Universitat de Barcelona(CCiTUB).

4.2. Synthesis of (S)-tert-butyldimethylsilyloxy-2-butanone (1)

MeLi (1.6 M in THF, 4.0 mL, 6.5 mmol) was added dropwise toa solution of (S)-2-tert-butyldimethylsilyloxy-N,N-tetramethylen-propanamide (1.12 g, 4.4 mmol) in THF (40 mL) at �78 �C. Theresulting mixture was stirred at �78 �C for 45 min, quenched byaddition of saturated NH4Cl (10 mL) and vigorously stirred at roomtemperature for 10 min. The mixture was diluted with Et2O(60 mL) and the layers were separated. The organic layer waswashed with saturated NH4Cl (30 mL), brine (30 mL), dried(MgSO4) and carefully concentrated at 0 �C (Alert: concentration athigher temperatures led to lower yields due to the volatility ofcompound). The resulting oil was purified by column chromatog-raphy (50:50 hexanes/CH2Cl2) to afford 707 mg (80% yield) of (S)-tert-butyldimethylsilyloxy-2-butanone (1) as a colourless oil. Rf(50:50 hexanes/CH2Cl2) 0.35. [a]D �6.8 (c 1.0, CHCl3) [lit.12d [a]D�7.1 (c 2.16, CHCl3)]. IR (film) n 2956, 2931, 2887, 2858, 1720, 1254,1125. 1H NMR (400 MHz, CDCl3) d 4.11 (1H, q, J¼6.8, CHOTBS), 2.18(3H, s, COCH3), 1.27 (3H, d, J¼6.8, CH3CHOTBS), 0.90 (9H, s,(CH3)3C), 0.08 (6H, s, Si(CH3)2). 13C NMR (100.6 MHz, CDCl3) d 212.6(C), 75.0 (CH), 25.7 (CH3), 24.8 (CH3), 20.6 (CH3), 18.0 (C), �4.7(CH3), �5.1 (CH3).

4.3. General procedure for the TiCl4-mediated aldol reaction

Neat TiCl4 (120 mL, 1.1 mmol) was added dropwise to a solutionof the corresponding a-silyloxymethyl ketone (1.0 mmol) in CH2Cl2(5.0 mL) at �94 �C, and the mixture was stirred for 5 min. Then,anhydrous i-Pr2NEt (190 mL, 1.1 mmol) was added dropwise and theresulting dark red solution was stirred for 30 min at �94 �C. Afterdropwise addition of the freshly distilled aldehyde (1.5 mmol),stirring was continued for 30 min at �78 �C. The reaction wasquenched by the addition of saturated NH4Cl (5 mL) and vigorouslystirred at room temperature for 10 min. Then it was diluted withEt2O (50 mL), and washed with H2O (50 mL), saturated NaHCO3(50 mL) and brine (50 mL). The combined organic extracts weredried (MgSO4) and concentrated. The resulting crude was analysedby 1H NMR and purified by column chromatography.

4.4. TiCl4-mediated aldol reactions of lactate-derived ketone 1

4.4.1. (2S,5R)-2-tert-Butyldimethylsilyloxy-5-hydroxy-6-methyl-3-heptanone (2a). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.25. [a]Dþ9.2 (c 1.0, CHCl3, 50% de). IR (film) n 3487 (br), 2957, 2935, 2858,

1714, 1471, 1366, 1254, 1120, 1044. 1H NMR (400 MHz, CDCl3) d 4.14(1H, q, J¼6.9, CHOTBS), 3.82e3.72 (1H, m, CHOH), 2.78 (1H, dd,J¼17.9, 3.0, COCHxHy), 2.66 (1H, dd, J¼17.9, 9.3, COCHxHy), 1.80e1.64(1H, m, CH(CH3)2), 1.29 (3H, d, J¼6.9, CH3CHOTBS), 0.96 (3H, d,J¼6.9, CH3), 0.92 (9H, s, (CH3)3C), 0.91 (3H, d, J¼6.9, CH3), 0.09 (3H,s, SiCH3), 0.08 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 215.9,75.0, 72.1, 40.6, 33.2, 25.6, 20.6, 18.2, 18.1, 17.9, �4.7, �5.0. HRMS(þESI): m/z calcd for C14H31O3Si [MþH]þ: 275.2036, found:275.2035.

Minor aldol (3a). 1H NMR (400 MHz, CDCl3) d 2.84 (1H, dd,J¼18.1, 2.3, COCHxHy), 2.58 (1H, dd, J¼18.1, 9.8, COCHxHy), 0.09 (3H,s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 74.9, 40.9, 17.6.

4.4.2. (2S,4S,6R)-4[(S)-1-tert-Butyldimethylsilyloxyethyl]-2,6-diisopropyl-1,3-dioxan-4-ol (4a). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.85. [a]D �18.4 (c 0.25, CHCl3). IR (film) n 3532 (br), 2958,2858, 1472, 1377, 1363, 1252, 1105, 1016. 1H NMR (400 MHz,CDCl3) d 4.73 (1H, d, J¼5.2, OCHO), 3.69 (1H, q, J¼6.4, CHOTBS),3.54 (1H, ddd, J¼11.7, 6.8, 2.5, CH2CHO), 3.44 (1H, d, J¼2.3, OH),1.80e1.69 (1H, m, CH(CH3)2), 1.69e1.58 (1H, m, CH(CH3)2), 1.51(1H, dd, J¼12.7, 2.5, CHxHyCHO), 1.20 (1H, ddd, J¼12.7, 11.7, 2.3,CHxHyCHO), 1.06 (3H, d, J¼6.4, CH3CHOTBS), 0.95 (3H, d, J¼6.7,CH3), 0.92 (3H, d, J¼6.9, CH3), 0.91 (3H, d, J¼6.9, CH3), 0.90 (9H, s,(CH3)3C), 0.88 (3H, d, J¼6.8, CH3), 0.10 (3H, s, SiCH3), 0.09 (3H, s,SiCH3). 13C NMR (100.6 MHz, CDCl3) d 98.3, 96.5, 76.8, 73.5, 33.4,33.1, 32.4, 25.8, 18.1 (�2), 18.0, 17.6, 17.4, 16.8, �4.6, �4.8. HRMS(þESI): m/z calcd for C18H38NaO4Si [MþNa]þ: 369.2431, found:369.2435.

4.4.3. (2S,5S)-2-tert-Butyldimethylsilyloxy-5-hydroxy-7-methyl-3-octanone (2b). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.30. [a]Dþ9.7 (c 1.15, CHCl3). IR (film) n 3475 (br), 2956, 2931, 2859, 1715,1471,1367,1259,1121. 1H NMR (400MHz, CDCl3) d 4.13 (1H, q, J¼6.8,CHOTBS), 4.15e4.05 (1H, m, CHOH), 2.74 (1H, dd, J¼18.4, 3.2,COCHxHy), 2.67 (1H, dd, J¼18.4, 8.8, COCHxHy), 1.88e1.74 (1H, m,CH(CH3)2), 1.55e1.45 (1H, m, CHxHyCH(CH3)2), 1.28 (3H, d, J¼6.8,CH3CHOTBS), 1.20e1.12 (1H, m, CHxHyCH(CH3)2), 0.93 (3H, d, J¼6.1,CH3), 0.91 (3H, d, J¼6.1, CH3), 0.91 (9H, s, (CH3)3C), 0.08 (3H, s,SiCH3), 0.08 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 215.8,75.0, 65.5, 45.7, 44.0, 25.7, 24.4, 23.3, 22.0, 20.6, 18.0, �4.7, �5.1.HRMS (þESI): m/z calcd for C15H32NaO3Si [MþNa]þ: 311.2013,found: 311.2009.

Minor aldol (3b). 1H NMR (400 MHz, CDCl3) d 2.82 (1H, dd,J¼18.4, 2.8, COCHxHy), 2.58 (1H, dd, J¼18.4, 9.2, COCHxHy), 1.29 (3H,d, J¼6.8, CH3CHOTBS), 0.09 (3H, s, SiCH3), 0.08 (3H, s, SiCH3). 13CNMR (100.6 MHz, CDCl3) d 215.9, 74.9, 65.6, 45.7, 44.4, 24.4, 23.3,22.0, 18.0, �4.7, �5.1.

4.4.4. (2S,4S,6S)-4[(S)-1-tert-Butyldimethylsilyloxyethyl]-2,6-diisobutyl-1,3-dioxan-4-ol (4b). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.85. [a]D �20.7 (c 1.0, CHCl3). IR (film) n 3522 (br), 2955,2929, 2897, 2869, 1470, 1377, 1251, 1155, 1120, 1080, 1004. 1H NMR(400 MHz, CDCl3) d 4.73 (1H, dd, J¼6.4, 4.8, OCHO), 4.01e3.92 (1H,m, CH2CHO), 3.67 (1H, q, J¼6.4, CHOTBS), 3.47 (1H, d, J¼2.4, OH),1.88e1.76 (2H, m, CH2), 1.52e1.36 (3H, m, O2CCHxHy & CH2),1.28e1.22 (1H, m, O2CCHxHy), 1.20e1.12 (2H, m, 2�CH(CH3)2), 1.04(3H, d, J¼6.4, CH3CHOTBS), 0.92e0.89 (12H, m, 4�CH3), 0.89 (9H,s, (CH3)3C), 0.08 (3H, s, SiCH3), 0.07 (3H, s, SiCH3). 13C NMR(100.6 MHz, CDCl3) d 96.4, 93.9, 73.5, 70.4, 45.2, 43.4, 37.0, 25.8,24.0, 23.9, 23.2, 22.9, 22.6, 22.1, 18.1, 17.5, �4.6, �4.9. HRMS(þESI): m/z calcd for C20H42NaO4Si [MþNa]þ: 397.2744, found:397.2751.

4.4.5. (2S,5S)-2-tert-Butyldimethylsilyloxy-5-hydroxy-3-octanone(2c). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.35. [a]Dþ18.7 (c 1.0,CHCl3). IR (film) n 3473 (br), 2958, 2932, 2859, 1716, 1472, 1464,

A. Lorente et al. / Tetrahedron 71 (2015) 1023e10351030

1367, 1255, 1120, 1006. 1H NMR (400 MHz, CDCl3) d 4.13 (1H, q,J¼6.8, CHOTBS), 4.07e3.98 (1H, m, CHOH), 2.76 (1H, dd, J¼18.2, 3.2,COCHxHy), 2.67 (1H, dd, J¼18.2, 8.8, COCHxHy), 1.57e1.32 (4H, m,(CH2)2CH3), 1.28 (3H, d, J¼6.8, CH3CHOTBS), 0.93 (3H, t, J¼6.9, CH3),0.91 (9H, s, (CH3)3C), 0.08 (3H, s, SiCH3), 0.07 (3H, s, SiCH3). 13C NMR(100.6 MHz, CDCl3) d 215.5, 75.0, 67.1, 43.6, 38.7, 25.7, 20.6, 18.7,18.0, 14.0, �4.7, �5.1. HRMS (þESI): m/z calcd for C14H31O3Si[MþH]þ: 275.2036, found: 275.2045.

Minor aldol (3c). 1H NMR (400 MHz, CDCl3) d 2.85 (1H, dd,J¼18.4, 2.4, COCHxHy), 2.58 (1H, dd, J¼18.4, 9.2, COCHxHy), 1.28 (3H,d, J¼6.8, CH3CHOTBS), 0.09 (3H, s, SiCH3), 0.08 (3H, s, SiCH3). 13CNMR (100.6 MHz, CDCl3) d 215.6, 74.9, 67.2, 43.8, 38.7, 18.6.

4.4.6. (2S,4S,6S)-4[(S)-1-tert-Butyldimethylsilyloxyethyl]-2,6-dipropyl-1,3-dioxan-4-ol (4c). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.90. [a]D �20.9 (c 1.0, CHCl3). IR (film) n 3520 (br), 2958,2930, 2874, 2858, 1464, 1377, 1253, 1148, 1119, 1005. 1H NMR(400 MHz, CDCl3) d 5.03 (1H, t, J¼5.3, OCHO), 3.91e3.83 (1H, m,CH2CHO), 3.68 (1H, q, J¼6.4, CHOTBS), 3.46 (1H, d, J¼2.3, OH),1.62e1.32 (9H, m, O2CCHxHy & 4�CH2), 1.27e1.18 (1H, m,O2CCHxHy), 1.05 (3H, d, J¼6.4, CH3CHOTBS), 0.94e0.88 (6H, m,2�CH2CH3), 0.89 (9H, s, (CH3)3C), 0.08 (3H, s, SiCH3), 0.07 (3H, s,SiCH3). 13C NMR (100.6 MHz, CDCl3) d 96.3, 94.8, 73.4, 71.9, 38.3,36.8, 36.4, 25.8, 18.3, 18.1, 17.5, 17.4, 14.0 (�2), �4.6, �4.9. HRMS(þESI): m/z calcd for C18H38NaO4Si [MþNa]þ: 369.2431, found:369.2436.

4.4.7. (2S,5S)-2-tert-Butyldimethylsilyloxy-5-hydroxy-3-hexanone(2d). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.20. IR (film) n 3448(br), 2957, 2931, 2897, 2859,1716,1472,1463,1368,1258,1119,1058.1H NMR (400 MHz, CDCl3) d 4.25e4.16 (1H, m, CHOH), 4.13 (1H, q,J¼6.8, CHOTBS), 2.77 (1H, dd, J¼18.2, 3.2, COCHxHy), 2.68 (1H, dd,J¼18.2, 8.6, COCHxHy), 1.29 (3H, d, J¼6.8, CH3CHOTBS), 1.22 (3H, d,J¼6.3, CHOHCH3), 0.92 (9H, s, (CH3)3C), 0.09 (3H, s, SiCH3), 0.08 (3H,s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 215.4, 74.9, 63.6, 45.1, 25.7,22.5, 20.7, 18.0, �4.7, �5.1.

Minor aldol (3d). 1H NMR (400 MHz, CDCl3) d 2.86 (1H, dd,J¼18.4, 2.8, COCHxHy), 2.58 (1H, dd, J¼18.4, 9.0, COCHxHy), 1.21(3H, d, J¼6.8, CH3CHOTBS), 0.92 (9H, s, (CH3)3C), 0.09 (3H, s,SiCH3), 0.09 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 74.8,63.8, 45.2, 22.4.

4.4.8. (2S,5R)-2-tert-Butyldimethylsi lyloxy-5-hydroxy-6-triisopropylsilyloxy-3-hexanone (2e). Colourless oil. Rf (90:10 hex-anes/EtOAc) 0.30. IR (film) n 3487 (br), 2943, 2893, 2866, 1717,1464, 1387, 1367, 1254, 1121. 1H NMR (400 MHz, CDCl3)d 4.19e4.08 (1H, m, CHOH), 4.16 (1H, q, J¼6.8, CHOTBS), 3.72e3.62(2H, m, CH2OTBDPS), 2.87 (1H, dd, J¼18.0, 7.8, COCHxHy), 2.77(1H, dd, J¼18.0, 4.5, COCHxHy), 1.29 (3H, d, J¼6.8, CH3CHOTBS),1.15e1.03 (21H, m, Si(CH(CH3)2)3), 0.91 (9H, s, (CH3)3C),0.08 (3H, s, SiCH3), 0.07 (3H, s, SiCH3). 13C NMR (100.6 MHz,CDCl3) d 214.0, 75.0, 68.1, 66.6, 40.4, 25.7, 20.6, 17.9, 17.8, 11.9,�4.5, �5.1.

Minor aldol (3e). 1H NMR (400 MHz, CDCl3) d 2.92 (1H, dd,J¼17.9, 4.5, COCHxHy), 2.77 (1H, dd, J¼17.9, 8.0, COCHxHy), 1.29 (3H,d, J¼6.8, CH3CHOTBS), 0.92 (9H, s, (CH3)3C), 0.09 (3H, s, SiCH3), 0.09(3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 74.9, 68.0, 66.5, 40.6,�4.7, �5.1.

4.4.9. (2S,5S)-2-tert-Butyldimethylsi lyloxy-5-hydroxy-7-triisopropylsilyloxy-3-heptanone (2f). Colourless oil. Rf (90:10 hex-anes/EtOAc) 0.35. IR (film) n 3489 (br), 2943, 2892, 2866,1716,1464,1388, 1366, 1254, 1115. 1H NMR (400 MHz, CDCl3) d 4.34e4.27 (1H,m, CHOH), 4.15 (1H, q, J¼6.8, CHOTBS), 3.92e3.86 (2H, m,CH2OTBDPS), 2.85 (1H, dd, J¼17.8, 7.8, COCHxHy), 2.70 (1H, dd,J¼17.8, 4.6, COCHxHy), 1.79e1.65 (2H, m, CH2CH2OTBDPS), 1.29 (3H,

d, J¼6.8, CH3CHOTBS), 1.15e1.03 (21H, m, Si(CH(CH3)2)3), 0.91 (9H,s, (CH3)3C), 0.08 (6H, s, Si(CH3)2). 13C NMR (100.6 MHz, CDCl3)d 213.6, 75.0, 67.0, 62.0, 44.0, 38.6, 25.7, 21.1, 20.6, 18.0, 11.8,�4.7, �5.1.

Minor aldol (3f). 1H NMR (400 MHz, CDCl3) d 4.14 (1H, q, J¼6.8,CHOTBS), 2.85 (1H, dd, J¼18.4, 5.8, COCHxHy), 2.73 (1H, dd, J¼18.4,7.4, COCHxHy), 1.28 (3H, d, J¼6.8, CH3CHOTBS), 0.92 (9H, s, (CH3)3C),0.09 (6H, s, Si(CH3)2). 13C NMR (100.6 MHz, CDCl3) d 74.9, 67.0, 62.0,44.3, 38.5, 11.9.

4.4.10. (2S,5S)-7-Amino-2-tert-butyldimethylsilyloxy-5-hydroxy-N-phtaloyl-3-heptanone (2g). Colourless oil. Rf (60:40 hexanes/EtOAc) 0.60. IR (film) n 3519 (br), 2954, 2930, 2895, 2857, 1772,1715, 1468, 1443, 1397, 1372, 1253, 1121, 1089. 1H NMR (400 MHz,CDCl3) d 7.87e7.82 (2H, m, ArH), 7.74e7.68 (2H, m, ArH), 4.13 (1H,q, J¼6.8, CHOTBS), 4.12e4.03 (1H, m, CHOH), 3.86 (2H, t, J¼6.6,CH2NPhth), 2.83 (1H, dd, J¼18.0, 8.9, COCHxHy), 2.66 (1H, dd,J¼18.0, 3.2, COCHxHy), 1.81 (2H, q, CH2CH2NPhth), 1.27 (3H, d,J¼6.8, CH3CHOTBS), 0.89 (9H, s, (CH3)3C), 0.06 (3H, s, SiCH3),0.05 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 213.9, 168.6,133.9, 132.0, 123.2, 74.9, 64.8, 43.7, 35.3, 34.6, 25.6, 20.5, 18.0,�4.7, �5.1.

Minor aldol (3g). 1H NMR (400MHz, CDCl3) d 2.81 (1H, dd, J¼18.1,3.4, COCHxHy), 2.70 (1H, dd, J¼18.1, 8.6, COCHxHy), 0.07 (3H, s,SiCH3), 0.06 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 74.8, 64.8,43.9, 35.2, 20.6.

4.4.11. (1R,4S) and (1S,4S)-5-tert-Butyldimethylsilyloxy-1-hydroxy-3-pentanone (2h and 3h). Colourless oil. Rf (90:10 hexanes/EtOAc)0.25. IR (film) n 3481 (br), 2955, 2930, 2895, 2858, 1717, 1472, 1463,1363, 1254, 1159, 1118, 1090. 1H NMR (400 MHz, CDCl3) d 7.42e7.25(10H, m, 2�ArH), 5.17e5.10 (1H, m, 2�CHOH), 4.16 (1H, q, J¼6.9,2�CHOTBS), 3.05 (1H, dd, J¼17.9, 9.1, COCHxHy), 3.04 (1H, dd,J¼18.1, 3.5, COCHxHy), 2.97 (1H, dd, J¼18.1, 8.8, COCHxHy), 2.95 (1H,dd, J¼17.9, 3.2, COCHxHy), 1.27 (3H, d, J¼6.9, CH3CHOTBS), 1.21 (3H,d, J¼6.9, CH3CHOTBS), 0.83e0.82 (18H, m, 2�(CH3)3C), 0.07 (3H, s,SiCH3), 0.06 (6H, s, SiCH3), 0.06 (3H, s, SiCH3). 13C NMR (100.6 MHz,CDCl3) d 214.3, 214.1, 143.0, 142.9, 128.5, 128.5, 127.6, 127.5, 125.7,125.6, 75.0, 74.9, 69.8, 69.7, 45.7, 45.5, 25.7 (�2), 20.6, 20.5, 18.0(�2), �4.7 (�2), �5.0 (�2).

4.4.12. (2S,5R)-2-tert-Butyldimethylsilyloxy-5-hydroxy-6-methyl-6-hepten-3-one (2i). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.30. IR(film) n 3482 (br), 2956, 2931, 2887, 2858, 1717, 1472, 1463, 1389,1367, 1256, 1161, 1119, 1006. 1H NMR (400 MHz, CDCl3)d 5.05e5.02 (1H, m, ]CHxHy), 4.89e4.87 (1H, m, ]CHxHy),4.52e4.46 (1H, m, CHOH), 4.16 (1H, q, J¼6.8, CHOTBS), 2.86 (1H,dd, J¼17.8, 8.5, COCHxHy), 2.79 (1H, dd, J¼17.8, 3.7, COCHxHy), 1.76(3H, s, H2C]CCH3), 1.30 (3H, d, J¼6.8, CH3CHOTBS), 0.93 (9H, s,(CH3)3C), 0.09 (6H, s, SiCH3), 0.08 (6H, s, SiCH3). 13C NMR(100.6 MHz, CDCl3) d 214.7, 145.8, 111.0, 75.0, 70.8, 42.3, 25.7, 20.5,18.4, 18.0, �4.7, �5.1.

Minor aldol (3i). 1H NMR (400 MHz, CDCl3) d 4.16 (1H, q, J¼6.8,CHOTBS), 2.91 (1H, dd, J¼18.0, 2.8, COCHxHy), 2.76 (1H, dd, J¼18.0,9.4, COCHxHy), 1.31 (3H, d, J¼6.8, CH3CHOTBS), 0.92 (9H, s, (CH3)3C),0.10 (3H, s, SiCH3), 0.09 (6H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3)d 145.8, 111.2, 74.9, 70.9, 42.6, 20.6, 18.3, �4.7.

4.5. Hydrolysis of hemiacetals 4aec

A mixture of hemiacetal 4aec (0.1 mmol) and p-TsOH$H2O(25 mmol) in 4:1 THF/H2O (1.5 mL) was stirred at room temperaturefor 20 min. Then, it was partitioned with Et2O and saturatedNaHCO3. The organic layer was washed with brine, dried(MgSO4) and concentrated. The resulting crude was purified by

A. Lorente et al. / Tetrahedron 71 (2015) 1023e1035 1031

column chromatography (90:10 hexanes/EtOAc) to afford pure al-dol adducts 2aec.

4.6. Synthesis of a-OTBS methyl ketones 6e8

4.6.1. Acylation of pyrrolidine-amides 9e11. Experimental pro-cedure reported for methyl ketone 1 was used for the acylation ofpyrrolidine-amides 9e11,20 with the following results.

4.6.1.1. (S)-3-tert-Butyldimethylsilyloxy-5-methyl-2-hexanone(6). Starting from 9 (585 mg, 2.0 mmol), the acylation was carriedout for 1.5 h to afford 200 mg (42% yield) of 6 as a colourless oil. Rf(CH2Cl2) 0.65. [a]D �31.3 (c 1.1, CHCl3). IR (film) n 2953, 2928, 2897,2857, 1716, 1474, 1351, 1255, 1140, 1092. 1H NMR (400 MHz, CDCl3)d 4.02 (1H, dd, J¼8.4, 4.9, CHOTBS), 2.15 (3H, s, COCH3), 1.79e1.67(1H, m, CH(CH3)2), 1.52 (1H, ddd, J¼13.5, 8.4, 5.5, CHxHy), 1.35 (1H,ddd, J¼13.5, 8.2, 4.9, CHxHy), 0.93 (3H, d, J¼7.0, CH3), 0.92 (9H, s,(CH3)3C), 0.91 (3H, d, J¼7.0, CH3), 0.06 (3H, s, SiCH3), 0.04 (3H, s,SiCH3). 13C NMR (100.6 MHz, CDCl3) d 212.3 (C), 77.6 (CH), 43.7(CH2), 25.7 (CH3), 24.6 (CH3), 23.9 (CH), 23.3 (CH3), 22.0 (CH3), 18.1(C), �4.9 (CH3), �5.1 (CH3). HRMS (þESI): m/z calcd for C13H29O2Si[MþH]þ: 245.1931, found: 245.1928.

4.6.1.2. (S)-3-tert-Butyldimethylsilyloxy-4-phenyl-2-butanone(7). Starting from 10 (3.18 g, 9.5 mmol), the acylation was carriedout for 15 min to afford 1.28 g (48% yield) of 7 as a colourless oil. Rf(CH2Cl2) 0.65. [a]D �45.0 (c 1.0, CHCl3). IR (film) n 2953, 2929, 2854,1714, 1651, 1557, 1470, 1453, 1255, 1099. 1H NMR (400 MHz, CDCl3)d 7.34e7.14 (5H, m, ArH), 4.15 (1H, dd, J¼8.3, 4.0, CHOTBS), 2.91(1H, dd, J¼13.4, 4.0, PhCHxHy), 2.79 (1H, dd, J¼13.4, 8.3, PhCHxHy),2.11 (3H, s, COCH3), 0.84 (9H, s, (CH3)3C),�0.11 (3H, s, SiCH3),�0.29(3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 212.0 (C), 137.3 (C),137.0 (C), 129.9 (CH), 128.2 (CH), 126.6 (CH), 80.2 (CH), 41.2 (CH2),25.7 (CH3), 25.5 (CH3), 18.0 (C), �5.3 (CH3), �5.6 (CH3). HRMS(þESI): m/z calcd for C16H27O2Si [MþH]þ: 279.1775, found:279.1773.

4.6.1.3. (S)-3-tert-Butyldimethylsilyloxy-4-methyl-2-pentanone(8). Starting from 11 (1.42 g, 5.0 mmol), the acylation was carriedout for 1 h at�40 �C to afford 565mg (49% yield) of 8 as a colourlessoil. Rf (95:5 hexanes/EtOAc) 0.35. [a]D �49.6 (c 0.9, CHCl3). IR (film)n 2960, 2930, 2857, 1715, 1471, 1252, 1088. 1H NMR (400 MHz,CDCl3) d 3.68 (1H, d, J¼5.8, CHOTBS), 2.14 (3H, s, COCH3), 1.97e1.84(1H, m, CH(CH3)2), 0.94 (9H, s, (CH3)3C), 0.91 (3H, d, J¼6.7, CH3),0.89 (3H, d, J¼6.9, CH3), 0.05 (3H, s, SiCH3), 0.02 (3H, s, SiCH3). 13CNMR (100.6 MHz, CDCl3) d 212.4 (C), 83.8 (CH), 32.8 (CH), 25.8(CH3), 25.7 (CH3), 18.8 (CH3), 18.1 (C), 17.5 (CH3), �4.9 (CH3), �5.1(CH3). HRMS (þESI): m/z calcd for C12H27O2Si [MþH]þ: 231.1775,found: 231.1772.

4.6.2. Acylation of Weinreb-amides 12e13

4.6.2.1. (S)-2-tert-Butyldimethylsilyloxy-5-methyl-2-hexanone(6). A 1.4 M solution of MeMgBr in 75:25 toluene/THF (3.0 mL,4.1 mmol) was added dropwise to a solution of 12 (396 mg,1.4 mmol) in THF (3.0 mL) at 0 �C. The resulting mixture was stirredat 0 �C for 2 h, quenched by addition of saturated NH4Cl (5 mL) andvigorously stirred at room temperature for 10 min. The layers wereseparated and the aqueous layer was extracted with Et2O(2�10 mL) and CH2Cl2 (2�10 mL). The combined organic extractswere dried (MgSO4) and concentrated. The resulting oil was puri-fied by column chromatography (CH2Cl2) to afford 282 mg (84%yield) of 6.

4.6.2.2. (S)-3-tert-Butyldimethylsilyloxy-4-methyl-2-pentanone(7). The aforementioned experimental procedure was followed,

starting from 1310c (1.94 g, 7.0 mmol) to afford 1.39 g (86% yield)of 7.

4.7. TiCl4-mediated aldol reactions of a-OTBS methyl ketones

4.7.1. (3R,6S)-6-tert-Butyldimethylsilyloxy-3-hydroxy-2,8-dimethyl-5-nonanone (14a). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.35. IR(film) n 3479 (br), 2954, 2928, 2897, 2855, 1711, 1472, 1255, 1089,1042, 1003. 1H NMR (400 MHz, CDCl3) d 4.05 (1H, dd, J¼8.4, 5.0,CHOTBS), 3.82e3.73 (1H, m, CHOH), 2.99 (1H, br s, CHOH), 2.82 (1H,dd, J¼18.1, 2.0, COCHxHy), 2.53 (1H, dd, J¼18.1, 9.9, COCHxHy),1.78e1.64 (2H, m, 2�CH(CH3)2), 1.58e1.48 (1H, m, CHxHyCHOTBS),1.43e1.33 (1H, m, CHxHyCHOTBS), 0.95 (3H, d, J¼6.8, CH3), 0.93 (3H,d, J¼6.5, CH3), 0.92 (9H, s, (CH3)3C), 0.91 (3H, d, J¼6.6, CH3), 0.91(3H, d, J¼7.3, CH3), 0.07 (3H, s, SiCH3), 0.04 (3H, s, SiCH3). 13C NMR(100.6 MHz, CDCl3) d 215.9 (C), 77.7 (CH), 72.1 (CH), 43.7 (CH2), 40.2(CH2), 33.1 (CH), 25.7 (CH3), 24.0 (CH), 23.2 (CH3), 22.1 (CH3), 18.3(CH3), 18.1 (C), 18.0 (CH3), �4.8 (CH3), �5.0 (CH3).

Minor aldol (15a). 1H NMR (400 MHz, CDCl3) d 4.07 (1H, dd,J¼8.0, 5.0, CHOTBS), 3.07 (1H, br s, CHOH), 2.76 (1H, dd, J¼18.1, 2.2,COCHxHy), 2.57 (1H, dd, J¼18.1, 9.9, COCHxHy), 0.93 (9H, s, (CH3)3C),0.06 (6H, s, Si(CH3)2). 13C NMR (100.6 MHz, CDCl3) d 216.0 (C), 77.5(CH), 72.1 (CH), 43.9 (CH2), 40.7 (CH2), 33.0 (CH), 25.7 (CH3), 24.0(CH), 23.2 (CH3), 22.1 (CH3), 18.3 (CH3), 18.1 (C), 18.0 (CH3), �4.8(CH3), �4.9 (CH3).

4.7.2. (1R,4S)-4-tert-Butyldimethylsilyloxy-1-hydroxy-6-methyl-1-phenyl-3-heptanone (14h). Colourless oil. Rf (CH2Cl2) 0.35. IR (film)n 3456 (br), 2956, 2927, 2893, 2856, 1718, 1470, 1389, 1363, 1253,1092,1056. 1H NMR (400MHz, CDCl3) d 7.38e7.26 (5H, m, ArH), 5.15(1H, dd, J¼8.7, 3.3, CHOH), 4.07 (1H, dd, J¼8.3, 5.2, CHOTBS), 3.35(1H, br s, OH), 2.99 (1H, dd, J¼18.0, 3.3, COCHxHy), 2.91 (1H, dd,J¼18.0, 8.7, COCHxHy), 1.75e1.62 (1H, m, CH(CH3)2), 1.48 (1H, ddd,J¼13.8, 8.3, 5.8, CHxHyCHOTBS), 1.33 (1H, ddd, J¼13.8, 8.0, 5.2,CHxHyCHOTBS), 0.91 (3H, d, J¼6.7, CH3), 0.89 (9H, s, (CH3)3C), 0.88(3H, d, J¼6.3, CH3), 0.05 (3H, s, SiCH3), 0.03 (3H, s, SiCH3). 13C NMR(100.6 MHz, CDCl3) d 214.2 (C), 143.0 (C), 128.5 (CH), 127.5 (CH),125.5 (CH), 77.6 (CH), 69.8 (CH), 45.3 (CH2), 43.5 (CH2), 25.7 (CH3),23.9 (CH), 23.2 (CH3), 22.1 (CH3), 18.1 (C), �4.8 (CH3), �5.0 (CH3).

Minor aldol (15h). 1H NMR (400 MHz, CDCl3) d 5.12 (1H, dd,J¼7.5, 4.9, CHOH), 4.08 (1H, dd, J¼8.2, 5.1, CHOTBS), 3.33 (1H, br s,OH), 3.02e2.92 (2H, m, COCH2), 0.90 (9H, s, (CH3)3C), 0.05 (6H, s,SiCH3). 13C NMR (100.6 MHz, CDCl3) d 214.2 (C), 142.9 (C), 128.5(CH), 127.6 (CH), 125.8 (CH), 77.5 (CH), 69.9 (CH), 45.7 (CH2), 43.7(CH2), 25.7 (CH3), 23.9 (CH), 23.2 (CH3), 22.1 (CH3), 18.1 (C), �4.8(CH3), �5.0 (CH3).

4.7.3. (3R,6S)-6-tert-Butyldimethylsilyloxy-3-hydroxy-2,8-dimethyl-1-nonen-5-one (14i). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.25.IR (film) n 3487 (br), 2955, 2929, 2896, 2858, 1711, 1468, 1386, 1257,1095. 1H NMR (400 MHz, CDCl3) d 5.04e5.02 (1H, m, C]CHxHy),4.89e4.85 (1H, m, C]CHxHy), 4.51e4.46 (1H, m, CHOH), 4.07 (1H,dd, J¼8.3, 4.8, CHOTBS), 3.01 (1H, d, J¼3.4, OH), 2.84 (1H, dd, J¼17.9,2.6, COCHxHy), 2.71 (1H, dd, J¼17.9, 9.5, COCHxHy), 1.77e1.67 (1H,m, CH(CH3)2), 1.75 (3H, br s, CH3C]CH2), 1.57e1.48 (1H, m,CHxHyCHOTBS), 1.43e1.34 (1H, m, CHxHyCHOTBS), 0.93 (3H, d,J¼6.4, CH3), 0.92 (9H, s, (CH3)3C), 0.91 (3H, d, J¼6.5, CH3), 0.07 (3H,s, SiCH3), 0.04 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 214.7(C), 145.7 (C), 111.0 (CH2), 77.6 (CH), 70.8 (CH), 43.6 (CH2), 42.1(CH2), 25.7 (CH3), 23.9 (CH), 23.2 (CH3), 22.1 (CH3), 18.5 (CH3), 18.0(C), �4.8 (CH3), �5.0 (CH3).

Minor aldol (15i). 1H NMR (400 MHz, CDCl3) d 5.03e5.00 (1H, m,C]CHxHy), 4.48e4.44 (1H, m, CHOH), 4.08 (1H, dd, J¼8.2, 4.9,CHOTBS), 3.10 (1H, d, J¼3.2, OH), 2.82 (1H, dd, J¼18.1, 3.2, COCHxHy),2.74 (1H, dd, J¼18.1, 9.0, COCHxHy), 0.93 (3H, d, J¼6.3, CH3), 0.92(9H, s, (CH3)3 C), 0.92 (3H, d, J¼6.5, CH3), 0.07 (6H, s, SiCH3). 13C

A. Lorente et al. / Tetrahedron 71 (2015) 1023e10351032

NMR (100.6MHz, CDCl3) d 214.8 (C),145.8 (C),111.3 (CH2), 77.4 (CH),71.0 (CH), 43.8 (CH2), 42.4 (CH2), 25.7 (CH3), 24.0 (CH), 23.2 (CH3),22.1 (CH3), 18.2 (CH3), 18.1 (C), �4.8 (CH3), �5.0 (CH3).

4.7.4. (2S,5R)-2-tert-Butyldimethylsilyloxy-5-hydroxy-6-methyl-1-phenyl-3-heptanone (16a). Colourless oil. Rf (90:10 hexanes/EtOAc)0.20. IR (film) n 3492 (br), 2953, 2927, 2887, 2856, 1712, 1466, 1257,1094, 1044. 1H NMR (400 MHz, CDCl3) d 7.31e7.16 (5H, m, ArH), 4.17(1H, dd, J¼8.6, 4.1, CHOTBS), 3.78 (1H, ddd, J¼9.8, 5.8, 1.9, CHOH),2.97e2.76 (3H, m, COCHxHy & PhCH2), 2.89 (1H, br s, OH), 2.57e2.45(1H, m, COCHxHy), 1.74e1.62 (1H, m, CH(CH3)2), 0.93 (3H, d, J¼6.8,CH3), 0.89 (3H, d, J¼6.8, CH3), 0.84 (9H, s, (CH3)3C), �0.12 (3H, s,SiCH3),�0.32 (3H, s, SiCH3). 13C NMR (100.6MHz, CDCl3) d 215.2 (C),136.9 (C), 129.9 (CH), 128.3 (CH), 126.7 (CH), 80.3 (CH), 71.9 (CH),41.3 (CH2), 41.1 (CH2), 33.1 (CH), 25.7 (CH3), 18.2 (CH3), 18.0 (C), 17.9(CH3), �5.3 (CH3), �5.6 (CH3).

Minor aldol (17a). 1H NMR (400 MHz, CDCl3) d 4.22 (1H, dd,J¼7.5, 4.1, CHOTBS), 3.65 (1H, ddd, J¼8.7, 5.5, 3.2, CHOH), 3.02 (1H,br s, OH), 1.67e1.57 (1H, m, CH(CH3)2), 0.87 (9H, s, (CH3)3C), �0.06(3H, s, SiCH3), �0.23 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3)d 215.9 (C), 136.7 (C), 129.9 (CH), 128.2 (CH), 126.7 (CH), 79.8 (CH),71.7 (CH), 41.7 (CH2), 41.4 (CH2), 32.9 (CH), 25.7 (CH3), 18.2 (CH3),17.7 (CH3), �5.2 (CH3), �5.4 (CH3).

4.7.5. (1R,4S)-4-tert-Butyldimethylsilyloxy-1-hydroxy-1,5-diphenyl-3-pentanone (16h). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.20. IR(film) n 3449 (br), 2953, 2924, 2858, 1717, 1454, 1256, 1093. 1H NMR(400 MHz, CDCl3) d 7.30e7.06 (10H, m, ArH), 5.09e5.02 (1H, m,CHOH), 4.11 (1H, dd, J¼8.6, 4.2, CHOTBS), 3.18 (1H, d, J¼3.2, CHOH),2.93e2.65 (4H, m, COCH2 & PhCH2), 0.73 (9H, s, (CH3)3C),�0.22 (3H,s, SiCH3), �0.40 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 213.6(C), 143.0 (C), 136.7 (C), 129.9 (CH), 128.5 (CH), 128.3 (CH), 127.6(CH), 126.7 (CH), 125.6 (CH), 80.3 (CH), 69.6 (CH), 46.1 (CH2), 41.0(CH2), 25.7 (CH3), 18.0 (C), �5.3 (CH3), �5.6 (CH3).

Minor aldol (17h). 1H NMR (400MHz, CDCl3) d 4.95e4.88 (1H, m,CHOH), 4.16 (1H, dd, J¼7.7, 4.1, CHOTBS), 3.24 (1H, d, J¼2.6, CHOH),0.75 (9H, s, (CH3)3C), �0.16 (3H, s, SiCH3), �0.32 (3H, s, SiCH3). 13CNMR (100.6 MHz, CDCl3) d 129.9 (CH), 128.4 (CH), 128.3 (CH), 126.8(CH), 125.7 (CH), 79.8 (CH), 69.6 (CH), 46.7 (CH2), 41.3 (CH2), 25.7(CH3).

4.7.6. (2S,5R)-2-tert-Butyldimethylsilyloxy-5-hydroxy-6-methyl-1-phenyl-6-hepten- 3-one (16i). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.15. IR (film) n 3486 (br), 2950, 2926, 2855,1713,1468,1256,1096. 1H NMR (400 MHz, CDCl3) d 7.31e7.16 (5H, m, ArH), 5.02 (1H,br s, C]CHxHy), 4.87 (1H, br s, C]CHxHy), 4.48 (1H, d, J¼9.5, CHOH),4.19 (1H, dd, J¼8.7, 4.1, CHOTBS), 3.06 (1H, br s, CHOH), 2.99e2.56(4H, m, COCH2 & PhCH2), 1.73 (3H, br s, CH3C]CH2), 0.84 (9H, s,(CH3)3C), �0.12 (3H, s, SiCH3), �0.32 (3H, s, SiCH3). 13C NMR(100.6 MHz, CDCl3) d 214.0 (C), 145.8 (C), 136.8 (C), 129.9 (CH), 128.3(CH), 126.7 (CH), 111.0 (CH2), 80.3 (CH), 70.7 (CH), 42.9 (CH2), 41.1(CH2), 25.7 (CH3), 18.4 (CH3), 18.0 (C), �5.3 (CH3), �5.6 (CH3).

Minor aldol (17i). 1H NMR (400 MHz, CDCl3) d 4.96 (1H, br s, C]CHxHy), 4.83 (1H, br s, C]CHxHy), 4.34 (1H, dd, J¼8.6, 2.3, CHOH),4.24 (1H, dd, J¼7.6, 4.1, CHOTBS), 1.66 (3H, br s, CH3C]CH2), 0.87(9H, s, (CH3)3C), �0.05 (3H, s, SiCH3), �0.23 (3H, s, SiCH3). 13C NMR(100.6 MHz, CDCl3) d 214.8 (C), 145.6 (C), 136.6 (C), 129.9 (CH), 128.3(CH), 126.8 (CH), 111.1 (CH2), 79.8 (CH), 70.7 (CH), 43.5 (CH2), 41.3(CH2), 25.7 (CH3), 18.2 (CH3), 18.0 (C), �5.2 (CH3), �5.4 (CH3).

4.7.7. (3S,6R)-3-tert-Butyldimethylsilyloxy-6-hydroxy-2,7-dimethyl-4-octanone (18a). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.30.[a]D �17.0 (c 1.1, CHCl3, 92% de). IR (film) n 3510 (br), 2955, 2930,2879, 2859, 1707, 1475, 1388, 1252, 1089. 1H NMR (400 MHz, CDCl3)d 3.79 (1H, ddd, J¼10.1, 5.9, 1.9, CHOH), 3.70 (1H, d, J¼6.0, CHOTBS),3.02 (1H, br s, OH), 2.85 (1H, dd, J¼18.3, 1.9, COCHxHy), 2.45 (1H, dd,

J¼18.3, 10.1, COCHxHy), 2.00e1.86 (1H, m, TBSOCHCH(CH3)2),1.77e1.63 (1H, m, CHOHCH(CH3)2), 0.95 (3H, d, J¼6.8, CH3), 0.94(9H, s, (CH3)3C), 0.92 (3H, d, J¼6.8, CH3), 0.91 (3H, d, J¼6.6, CH3),0.89 (3H, d, J¼6.6, CH3), 0.06 (3H, s, SiCH3), 0.01 (3H, s, SiCH3). 13CNMR (100.6MHz, CDCl3) d 215.8 (C), 83.9 (CH), 72.1 (CH), 41.3 (CH2),33.1 (CH), 32.5 (CH), 25.7 (CH3), 18.6 (CH3), 18.2 (CH3), 18.1 (C), 18.0(CH3),17.6 (CH3),�4.8 (CH3),�5.1 (CH3). HRMS (þESI):m/z calcd forC32H68NaO6Si2 [2MþNa]þ: 627.4447, found: 627.4441.

Minor aldol (19a). 1H NMR (400 MHz, CDCl3) d 2.72 (1H, dd,J¼18.4, 2.0, COCHxHy), 2.53 (1H, dd, J¼18.4, 9.9, COCHxHy), 0.04 (3H,s, SiCH3).

4.7.8. (1R,4S)-4-tert-Butyldimethylsilyloxy-1-hydroxy-5-methyl-1-phenyl-3-hexanone (18h). Colourless oil. Rf (90:10 hexanes/EtOAc)0.20. IR (film) n 3471 (br), 2953, 2925, 2891, 2857, 1715, 1474, 1388,1252,1073. 1H NMR (400MHz, CDCl3) d 7.41e7.23 (5H, m, ArH), 5.16(1H, dd, J¼9.4, 2.8, CHOH), 3.72 (1H, d, J¼6.2, CHOTBS), 3.03 (1H, dd,J¼18.2, 2.8, COCHxHy), 2.84 (1H, dd, J¼18.2, 9.4, COCHxHy),1.99e1.84 (1H, m, CH(CH3)2), 0.91 (9H, s, (CH3)3C), 0.90 (3H, d,J¼6.3, CH3), 0.88 (3H, d, J¼6.9, CH3), 0.05 (3H, s, SiCH3), 0.01 (3H, s,SiCH3). 13C NMR (100.6 MHz, CDCl3) d 214.2 (C), 143.0 (C), 128.5(CH), 127.5 (CH), 125.5 (CH), 83.9 (CH), 69.7 (CH), 46.4 (CH2), 32.4(CH), 25.7 (CH3), 18.6 (CH3), 18.1 (C), 17.6 (CH3), �4.8 (CH3), �5.1(CH3).

Minor aldol (19h). 1H NMR (400 MHz, CDCl3) d 5.12 (1H, dd,J¼9.0, 3.2, CHOH), 3.77 (1H, d, J¼5.6, CHOTBS), 2.99 (1H, dd, J¼18.4,9.0, COCHxHy), 2.89 (1H, dd, J¼18.4, 3.2, COCHxHy), 0.92 (9H, s,(CH3)3C), 0.03 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 127.6(CH), 125.8 (CH), 83.5 (CH), 46.8 (CH2), 32.6 (CH), 18.8 (CH3), 17.4(CH3).

4.7.9. (3S,6R)-3-tert-Butyldimethylsilyloxy-6-hydroxy-2,7-dimethyl-7-octen-4-one (18i). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.25.[a]D �26.7 (c 1.0, CHCl3, 80% de). IR (film) n 3486 (br), 2955, 2931,2892, 2860, 1715, 1471, 1386, 1252, 1071. 1H NMR (300 MHz, CDCl3)d 5.03 (1H, br s, C]CHxHy), 4.87 (1H, br s, C]CHxHy), 4.49 (1H, d,J¼9.1, CHOH), 3.72 (1H, d, J¼6.0, CHOTBS), 3.00 (1H, br s, OH), 2.87(1H, dd, J¼18.2, 2.4, COCHxHy), 2.62 (1H, dd, J¼18.2, 9.6, COCHxHy),2.03e1.85 (1H, m, CH(CH3)2), 1.75 (3H, br s, CH3C]CH2), 0.93 (9H, s,(CH3)3C), 0.92 (3H, d, J¼6.4, CH3), 0.90 (3H, d, J¼6.5, CH3), 0.06 (3H,s, SiCH3), 0.02 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 214.6(C),145.8 (C), 110.9 (CH2), 83.8 (CH), 70.7 (CH), 43.1 (CH2), 32.5 (CH),25.7 (CH3), 18.7 (CH3), 18.5 (CH3), 18.1 (C), 17.5 (CH3), �4.8 (CH3),�5.1 (CH3). HRMS (þESI): m/z calcd for C32H64NaO6Si2 [2MþNa]þ:623.4134, found: 623.4125.

Minor aldol (19i). 1H NMR (300 MHz, CDCl3) d 5.01 (1H, br s, C]CHxHy), 4.45 (1H, d, J¼4.3, CHOH), 3.78 (1H, d, J¼5.4, CHOTBS), 0.94(9H, s, (CH3)3C), 0.05 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3)d 111.3 (CH2), 83.4 (CH), 43.5 (CH2), 32.7 (CH), 18.9 (CH3), 18.2 (C),17.3 (CH3), �4.8 (CH3), �5.0 (CH3).

4.8. TiCl4-mediated aldol reactions of a-silyloxy methylketones

4.8.1. (2S,5R)-2-Triethylsilyloxy-5-hydroxy-6-methyl-1-phenyl-3-heptanone (22a). Colourless oil. Rf (90:10 hexanes/EtOAc) 0.25. IR(film) n 3503 (br), 2955, 2937, 2908, 2887, 1709, 1468, 1239, 1102,1004. 1H NMR (400 MHz, CDCl3) d 7.31e7.16 (5H, m, ArH), 4.23 (1H,dd, J¼8.1, 4.6, CHOTES), 3.79e3.72 (1H, m, CHOH), 3.03e2.74 (4H,m, OH& COCHxHy & PhCH2), 2.52e2.42 (1H, m, COCHxHy),1.73e1.62(1H, m, CH(CH3)2), 0.92 (3H, d, J¼6.8, CH3), 0.89 (3H, d, J¼6.3, CH3),0.84 (9H, t, J¼7.9, Si(CH2CH3)3), 0.48e0.38 (6H, m, Si(CH2CH3)3). 13CNMR (100.6 MHz, CDCl3) d 215.1 (C), 136.8 (C), 129.7 (CH), 128.3(CH), 126.7 (CH), 80.1 (CH), 72.0 (CH), 41.4 (CH2), 41.1 (CH2), 33.1(CH), 18.2 (CH3), 17.9 (CH3), 6.6 (CH3), 4.5 (CH2). HRMS (þESI): m/z

A. Lorente et al. / Tetrahedron 71 (2015) 1023e1035 1033

calcd for C20H34NaO3Si [MþNa]þ: 373.2169, found: 373.2184; m/zcalcd for C40H68NaO6Si2 [2MþNa]þ: 723.4447, found: 723.4453.

Minor aldol (23a). 1H NMR (400 MHz, CDCl3) d 4.27 (1H, dd,J¼7.1, 4.5, CHOTES), 3.66e3.59 (1H, m, CHOH), 1.68e1.58 (1H, m,CH(CH3)2), 0.53e0.45 (6H, m, Si(CH2CH3)3). 13C NMR (100.6 MHz,CDCl3) d 215.9 (C), 136.6 (C), 129.8 (CH), 128.2 (CH), 126.7 (CH), 79.6(CH), 71.8 (CH), 41.7 (CH2), 41.5 (CH2), 32.9 (CH), 18.2 (CH3), 17.7(CH3), 6.7 (CH3), 4.6 (CH2).

4.8.2. (2S,5R)-2-tert-Butyldiphenylsilyloxy-5-hydroxy-6-methyl-1-phenyl-3-heptanone (24a). Colourless oil. Rf (90:10 hexanes/EtOAc)0.30. IR (film) n 3512 (br), 3074, 2955, 2930, 2893, 2856, 1707, 1469,1427, 1112, 1046. 1H NMR (400 MHz, CDCl3) d 7.60e7.55 (2H, m,ArH), 7.45e7.21 (11H, m, ArH), 7.15e7.10 (2H, m, ArH), 4.35 (1H, t,J¼6.4, CHOTBDPS), 3.32e3.26 (1H, m, CHOH), 2.91e2.83 (2H, m,PhCH2), 2.67 (1H, d, J¼3.1, OH), 2.40 (1H, dd, J¼18.2, 1.9, COCHxHy),2.11 (1H, dd, J¼18.2, 10.0, COCHxHy), 1.52e1.41 (1H, m, CH(CH3)2),1.08 (9H, s, (CH3)3C), 0.76 (3H, d, J¼6.8, CH3), 0.72 (3H, d, J¼6.8,CH3). 13C NMR (100.6 MHz, CDCl3) d 214.3 (C), 136.4 (C), 135.9 (CH),135.8 (CH), 132.9 (C), 132.6 (C), 130.1 (CH), 130.0 (CH), 129.8 (CH),128.4 (CH), 127.9 (CH), 127.6 (CH), 126.8 (CH), 80.5 (CH), 71.5 (CH),41.5 (CH2), 41.4 (CH2), 32.8 (CH), 26.9 (CH3), 19.1 (C), 18.0 (CH3), 17.8(CH3). HRMS (þESI): m/z calcd for C60H76NaO6Si2 [2MþNa]þ:971.5073, found: 971.5079.

Minor aldol (25a). 1H NMR (400 MHz, CDCl3) d 4.39 (1H, t, J¼5.7,CHOTBDPS), 3.40e3.34 (1H, m, CHOH), 2.74 (1H, d, J¼2.8, OH),2.15e2.05 (2H, m, COCH2), 1.09 (9H, s, (CH3)3C), 0.73 (3H, d, J¼6.8,CH3), 0.69 (3H, d, J¼6.8, CH3). 13C NMR (100.6 MHz, CDCl3) d 214.6(C), 136.3 (C), 135.9 (CH), 132.8 (2�C), 130.1 (CH), 129.9 (CH), 128.3(CH), 127.9 (CH), 127.7 (CH), 79.7 (CH), 71.4 (CH), 42.3 (CH2), 41.2(CH2), 32.7 (CH), 26.9 (CH3), 19.2 (C), 17.9 (CH3), 17.7 (CH3).

4.9. Double asymmetric aldol reactions

4.9.1. (2S,5R,6R)-2-tert-Butyldimethylsilyloxy-7-tert-butyldiphe-nylsilyloxy-5-hydroxy-6-methyl-3-heptanone (29). Colourless oil. Rf(90:10 hexanes/EtOAc) 0.25. IR (film) n 3516 (br), 3070, 3048, 2955,2933, 2886, 2856,1712,1468. 1H NMR (400MHz, CDCl3) d 7.69e7.63(4H, m, ArH), 7.45e7.35 (6H, m, ArH), 4.36e4.26 (1H, m, CHOH),4.15 (1H, q, J¼6.8, CHOTBS), 3.69 (2H, d, J¼5.6, CH2OSi), 3.11 (1H, d,J¼3.5, OH), 2.85 (1H, dd, J¼17.7, 9.3, COCHxHy), 2.64 (1H, dd, J¼17.7,3.2, COCHxHy), 1.83e1.72 (1H, m, CHCH2OSi), 1.29 (3H, d, J¼6.8,CH3CHOTBS), 1.06 (9H, s, (CH3)3C), 0.93 (3H, d, J¼7.0, CH3CHCH2),0.91 (9H, s, (CH3)3C), 0.08 (3H, s, SiCH3), 0.07 (3H, s, SiCH3). 13C NMR(100.6 MHz, CDCl3) d 214.4 (C), 135.6 (CH), 135.5 (CH), 134.8 (CH),133.4 (C), 133.2 (C), 129.7 (2�CH), 127.7 (CH), 75.1 (CH), 68.7 (CH),67.2 (CH2), 41.3 (CH2), 39.8 (CH), 26.9 (CH3), 25.7 (CH3), 20.6 (CH3),19.2 (C), 18.0 (C), 10.9 (CH3), �4.7 (CH3), �5.0 (CH3).

Minor aldol (30). 1H NMR (400 MHz, CDCl3) d 4.18e4.08 (1H, m,CHOH), 4.16 (1H, q, J¼6.8, CHOTBS), 3.73 (1H, dd, J¼10.2, 5.0,CHxHyOSi), 3.65 (1H, dd, J¼10.2, 6.2, CHxHyOSi), 3.49 (1H, d, J¼3.4,OH), 2.87 (1H, dd, J¼17.7, 3.0, COCHxHy), 2.67 (1H, dd, J¼17.7, 9.2,COCHxHy), 1.91e1.79 (1H, m, CHCH2OSi), 1.29 (3H, d, J¼6.8,CH3CHOTBS), 1.05 (9H, s, (CH3)3C), 0.92 (9H, s, (CH3)3C), 0.90 (3H, d,J¼6.9, CH3CHCH2), 0.09 (3H, s, SiCH3), 0.08 (3H, s, SiCH3). 13C NMR(100.6 MHz, CDCl3) d 214.7 (C), 135.6 (2�CH), 133.3 (2�C), 129.6(CH), 75.0 (CH), 70.2 (CH), 66.9 (CH2), 41.7 (CH2), 40.3 (CH), 26.8(CH3), 25.7 (CH3), 20.6 (CH3), 13.1 (CH3), �4.7 (CH3), �5.0 (CH3).

4.9.2. (2S,5R,6S)-2-tert-Butyldimethylsilyloxy-7-tert-butyldiphe-nylsilyloxy-5-hydroxy-6-methyl-3-heptanone (31). Colourless oil. Rf(90:10 hexanes/EtOAc) 0.35. IR (film) n 3511 (br), 3069, 3047, 2960,2927, 2889, 2856, 1714, 1469. 1H NMR (400MHz, CDCl3) d 7.69e7.64(4H, m, ArH), 7.45e7.35 (6H, m, ArH), 4.16 (1H, q, J¼6.8, CHOTBS),4.14e4.07 (1H, m, CHOH), 3.73 (1H, dd, J¼10.2, 5.1, CHxHyOSi), 3.67(1H, dd, J¼10.2, 6.0, CHxHyOSi), 3.49 (1H, d, J¼3.4, OH), 2.90e2.60

(2H, m, COCH2), 1.90e1.78 (1H, m, CHCH2OSi), 1.29 (3H, d, J¼6.8,CH3CHOTBS), 1.05 (9H, s, (CH3)3C), 0.91 (9H, s, (CH3)3C), 0.89 (3H, d,J¼7.0, CH3CHCH2), 0.08 (3H, s, SiCH3), 0.07 (3H, s, SiCH3). 13C NMR(100.6 MHz, CDCl3) d 214.6 (C), 135.6 (2�CH), 134.7 (CH), 133.3(2�C), 129.7 (2�CH), 127.7 (CH), 75.1 (CH), 70.1 (CH), 66.9 (CH2),41.5 (CH2), 40.3 (CH), 26.8 (CH3), 25.7 (CH3), 20.6 (CH3), 19.2 (C),18.0 (C), 13.4 (CH3), �4.7 (CH3), �5.0 (CH3).

Minor aldol (32). 1H NMR (400 MHz, CDCl3) d 4.36e4.29 (1H, m,CHOH), 4.15 (1H, q, J¼6.8, CHOTBS), 3.68 (2H, d, J¼5.6, CH2OSi), 3.10(1H, d, J¼3.3, OH), 1.81e1.71 (1H, m, CHCH2OSi), 1.29 (3H, d, J¼6.8,CH3CHOTBS), 1.05 (9H, s, (CH3)3C), 0.93 (3H, d, J¼7.0, CH3CHCH2),0.91 (9H, s, (CH3)3C), 0.08 (6H, s, SiCH3). 13C NMR (100.6 MHz,CDCl3) d 214.5 (C), 135.6 (CH), 135.5 (CH), 133.4 (C), 133.3 (C), 129.6(CH), 75.0 (CH), 68.6 (CH), 67.3 (CH2), 41.8 (CH2), 39.8 (CH), 26.9(CH3), 20.6 (CH3), 10.9 (CH3).

4.9.3. (2S,5R,6S)-2-tert-Butyldimethylsilyloxy-6-tert-butyldiphe-nylsilyloxy-5-hydroxy-3-heptanone (34). Colourless oil. Rf (hexanes/EtOAc 90:10) 0.20. IR (film) n 3511 (br), 2956, 2931, 2894, 2858,1716, 1472, 1463, 1428, 1390, 1363, 1254, 1112. 1H NMR (400 MHz,CDCl3) d 7.73e7.63 (4H, m, ArH), 7.46e7.34 (6H, m, ArH), 4.15 (1H, q,J¼6.8, CHOTBS), 4.05e3.95 (1H, m, CHOH), 3.91e3.83 (1H, m,CHOTBDPS), 2.67 (1H, dd, J¼17.8, 9.2, COCHxHy), 2.67 (1H, dd,J¼17.8, 3.2, COCHxHy), 2.70 (1H, d, J¼3.8, OH), 1.28 (3H, d, J¼6.8,CH3CHOTBS), 1.07 (9H, s, (CH3)3C), 0.99 (3H, d, J¼6.3,CH3CHOTBDPS), 0.90 (9H, s, (CH3)3C), 0.07 (3H, s, SiCH3), 0.05 (3H, s,SiCH3). 13C NMR (100.6 MHz, CDCl3) d 213.8 (C), 135.8 (2�CH), 134.3(C), 133.5 (C), 129.7 (CH), 129.6 (CH), 127.7 (CH), 127.5 (CH), 75.0(CH), 72.1 (CH), 71.4 (CH), 39.3 (CH2), 27.0 (CH3), 25.7 (CH3), 20.6(CH3), 19.3 (C), 18.4 (CH3), 18.0 (C), �4.7 (CH3), �5.0 (CH3).

Minor aldol (35). 1H NMR (400 MHz, CDCl3) d 2.95 (1H, dd,J¼17.8, 3.1, COCHxHy), 2.85 (1H, dd, J¼17.8, 9.3, COCHxHy), 2.81 (1H,d, J¼4.7, OH), 1.27 (3H, d, J¼6.8, CH3CHOTBS), 1.06 (9H, s, (CH3)3C),1.02 (3H, d, J¼6.3, CH3CHOTBDPS), 0.92 (9H, s, (CH3)3C), 0.09 (6H, s,SiCH3). 13C NMR (100.6 MHz, CDCl3) d 214.5 (C), 135.8 (CH), 135.7(CH), 134.1 (C), 133.5 (C), 129.8 (CH), 129.7 (CH), 127.7 (CH), 74.9(CH), 71.4 (CH), 71.0 (CH), 39.4 (CH2), 20.7 (CH3), 19.3 (C), �4.7(CH3).

4.9.4. (5R,6S)-6-tert-Butyldiphenylsilyloxy-5-hydroxy-2-methyl-3-heptanone (36). Colourless oil. Rf (80:20 hexanes/EtOAc) 0.30. IR(film) n 3480 (br), 3068, 2961, 2928, 2892, 2855, 1705, 1470, 1426,1384, 1115, 1092. 1H NMR (400 MHz, CDCl3) d 7.71e7.64 (4H, m,ArH), 7.46e7.34 (6H, m, ArH), 4.00e3.93 (1H, m, CHOH), 3.84 (1H,dq, J¼12.4, 6.2, CHOTBDPS), 2.84 (1H, d, J¼4.5, OH), 2.68e2.48 (3H,m, COCH2 & CH(CH3)2), 1.09 (3H, d, J¼6.9, CH3), 1.07 (3H, d, J¼6.9,CH3), 1.06 (9H, s, (CH3)3C), 1.05 (3H, d, J¼6.2, CH3CHO). 13C NMR(100.6 MHz, CDCl3) d 215.0 (C), 135.8 (CH), 135.7 (CH), 134.0 (C),133.5 (C), 129.8 (CH), 129.7 (CH), 127.7 (CH), 127.5 (CH), 71.4 (CH),71.3 (CH), 42.1 (CH2), 41.5 (CH), 27.0 (CH3), 19.3 (C), 18.5 (CH3), 18.0(2�CH3).

Minor aldol (37). 1H NMR (400 MHz, CDCl3) d 3.86e3.79 (1H, m,CHOTBDPS), 2.87 (1H, d, J¼3.4, OH), 1.07 (9H, s, (CH3)3C),1.04 (3H, d,J¼6.2, CH3CHO). 13C NMR (100.6 MHz, CDCl3) d 215.0 (C), 135.8 (CH),134.2 (C), 133.5 (C), 129.8 (CH), 129.7 (CH), 127.7 (CH), 72.0 (CH),71.9 (CH), 42.4 (CH2), 41.5 (CH), 19.3 (C), 18.6 (CH3), 18.0 (CH3), 17.9(CH3).

4.9.5. (3S,6R,7S)-3-tert-Butyldimethylsilyloxy-7-tert-butyldiphe-nylsilyloxy-6-hydroxy-2-methyl-4-octanone (38). Colourless oil. Rf(90:10 hexanes/EtOAc) 0.35. IR (film) n 3527 (br), 3068, 2957, 2931,2893, 2855, 1708, 1471, 1428, 1388, 1254, 1140, 1111, 1087. 1H NMR(400 MHz, CDCl3) d 7.72e7.62 (4H, m, ArH), 7.46e7.34 (6H, m, ArH),4.07e4.01 (1H, m, CHOH), 3.87 (1H, qd, J¼6.3, 4.1, CHOTBDPS), 3.71(1H, d, J¼5.8, CHOTBS), 2.72 (1H, d, J¼3.3, OH), 2.71 (1H, dd, J¼18.0,9.1, COCHxHy), 2.61 (1H, dd, J¼18.0, 3.0, COCHxHy), 1.98e1.88 (1H,

A. Lorente et al. / Tetrahedron 71 (2015) 1023e10351034

m, CH(CH3)2), 1.07 (9H, s, (CH3)3C), 0.99 (3H, d, J¼6.3,CH3CHOTBDPS), 0.92 (9H, s, (CH3)3C), 0.90 (3H, d, J¼6.7, CH3), 0.90(3H, d, J¼6.6, CH3), 0.04 (3H, s, SiCH3),�0.02 (3H, s, SiCH3). 13C NMR(100.6 MHz, CDCl3) d 213.5 (C), 135.9 (2�CH), 134.3 (C), 133.5 (C),129.7 (CH), 129.6 (CH), 127.7 (CH), 127.5 (CH), 83.8 (CH), 72.2 (CH),71.3 (CH), 40.1 (CH2), 32.4 (CH), 27.0 (CH3), 25.8 (CH3), 19.3 (C), 18.8(CH3), 18.3 (CH3), 18.1 (C), 17.4 (CH3), �4.8 (CH3), �5.1 (CH3). HRMS(þESI): m/z calcd for C62H100NaO8Si4 [2MþNa]þ: 1107.6387, found:1107.6377.

Minor aldol (39). 1H NMR (400 MHz, CDCl3) d 4.01e3.95 (1H, m,CHOH), 3.93e3.88 (1H, m, CHOTBDPS), 3.75 (1H, d, J¼5.4, CHOTBS),2.97 (1H, d, J¼3.9, OH), 2.89 (1H, dd, J¼18.1, 2.3, COCHxHy), 2.60 (1H,dd, J¼18.1, 8.0, COCHxHy), 1.05 (9H, s, (CH3)3C), 1.02 (3H, d, J¼6.3,CH3CHOTBDPS), 0.96 (9H, s, (CH3)3C), 0.89 (3H, d, J¼6.8, CH3), 0.89(3H, d, J¼6.7, CH3), 0.06 (6H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3)d 215.3 (C), 135.7 (2�CH), 134.8 (C), 130.0 (CH), 129.9 (CH), 127.8(2�CH), 83.5 (CH), 70.9 (CH), 70.6 (CH), 39.7 (CH2), 32.7 (CH), 26.9(CH3), 19.2 (C), 18.9 (CH3), 17.8 (CH3), 17.3 (CH3), e5.0 (CH3).

4.9.6. (3S,6R,7R)-3-tert-butyldimethylsilyloxy-7-tert-butyldiphe-nylsilyloxy-6-hydroxy-2-methyl-4-octanone (40). Colourless oil. Rf(90:10 hexanes/EtOAc) 0.25. [a]D þ5.2 (c 1.1, EtOH, 86% de). IR(film) n 3486 (br), 3070, 2958, 2929, 2890, 2856, 1713, 1470, 1428,1389, 1363, 1253, 1112, 1088. 1H NMR (400 MHz, CDCl3)d 7.70e7.63 (4H, m, ArH), 7.46e7.34 (6H, m, ArH), 4.10e4.03 (1H,m, CHOH), 3.85 (1H, qd, J¼6.3, 4.6, CHOTBDPS), 3.75 (1H, d, J¼5.7,CHOTBS), 2.80e2.62 (3H, m, COCH2 & OH), 1.99e1.89 (1H, m,CH(CH3)2), 1.05 (9H, s, (CH3)3C), 1.01 (3H, d, J¼6.3, CH3CHOTBDPS),0.93 (9H, s, (CH3)3C), 0.91 (3H, d, J¼6.9, CH3), 0.91 (3H, d, J¼6.7,CH3), 0.05 (3H, s, SiCH3), 0.01 (3H, s, SiCH3). 13C NMR (100.6 MHz,CDCl3) d 214.0 (C), 135.8 (2�CH), 134.1 (C), 133.4 (C), 129.8 (CH),129.7 (CH), 127.7 (CH), 127.5 (CH), 83.7 (CH), 71.5 (CH), 70.7 (CH),40.4 (CH2), 32.5 (CH), 27.0 (CH3), 25.8 (CH3), 19.3 (C), 18.8 (CH3),18.3 (CH3), 18.1 (C), 17.4 (CH3), �4.8 (CH3), �5.1 (CH3). HRMS(þESI): m/z calcd for C31H54NaO4Si2 [MþNH4]þ: 560.3586, found:560.3578.

Minor aldol (41). 1H NMR (400 MHz, CDCl3) d 3.74 (1H, d, J¼5.4,CHOTBS), 0.88 (3H, d, J¼6.8, CH3), 0.88 (3H, d, J¼6.9, CH3), 0.04 (3H,s, SiCH3), 0.03 (3H, s, SiCH3). 13C NMR (100.6 MHz, CDCl3) d 134.5(C), 130.0 (CH), 129.9 (CH), 127.8 (CH), 83.5 (CH), 40.6 (CH2), 32.7(CH), 26.9 (CH3), 26.6 (CH3).

4.10. Chemical correlation

48% HF (0.32 mL, 10 mmol) was added dropwise to a solution ofaldols 2 or 18 (1 mmol) in CH3CN (10 mL) at room temperature. Thereaction mixture was stirred for 2.5 h and partitioned with CH2Cl2(50 mL) and saturated NaHCO3 (25 mL). The layers were separatedand the organic layer was washed with NaHCO3 (2�25 mL), dried(MgSO4) and concentrated to obtain a colourless oil, which wasused in the next step without further purification. A mixture of thisoil and NaIO4 (2.25 g,10mmol) in 2:1MeOH/H2O (9mL) was stirredat room temperature for 1 h. Then, it was diluted with Et2O (20mL),cooled to 0 �C and 1 M HCl was slowly added to reach pH 1. Themixture was partitioned with Et2O (10 mL) and H2O (10 mL), thelayers were separated and the aqueous layer was extracted withEt2O (4�10 mL). The combined organic extracts were dried(MgSO4) and concentrated. The residue was purified by columnchromatography to afford b-hydroxy acids 26 or 27.

4.10.1. (R) 3-Hydroxy-4-methylpropanoic acid (26). Colourless oil. Rf(95:5 CH2Cl2/MeOH) 0.25. From 2a [a]D þ18.1 (c 1.0, CHCl3, 48% ee)[lit.28 [a]D þ39.8 (c 1.0, CHCl3)]. From 18a [a]D þ33.9 (c 0.9, CHCl3,92% ee) IR (film) n 3270 (br), 1715, 1418, 1182, 1044. 1H NMR(400 MHz, CDCl3) d 3.86e3.79 (1H, m, CHOH), 2.57 (1H, dd, J¼16.5,3.2, COCHxHy), 2.45 (1H, dd, J¼16.5, 9.3, COCHxHy), 1.80e1.69 (1H,

m, CH(CH3)2), 0.95 (6H, m, 2�CH3). 13C NMR (100.6 MHz, CDCl3)d 178.0 (C), 72.8 (CH), 38.3 (CH2), 33.2 (CH), 18.3 (CH3), 17.7 (CH3).

4.10.2. (R) 3-Hydroxy-3-phenylpropanoic acid (27). Viscous oil. Rf(20:80 hexanes/EtOAc) 0.30. From 18h [a]D þ10.7 (c 1.2, EtOH, 66%ee) [lit.12d [a]D þ15.5 (c 0.9, EtOH)]. IR (film) n 3286 (br), 2926 (br),1695, 1454, 1275, 1212, 1057, 1017. 1H NMR (400 MHz, CDCl3)d 7.41e7.28 (5H, m, ArH), 5.17 (1H, dd, J¼9.1, 3.7, CHOH), 2.85 (1H,dd, J¼16.6, 9.1, COCHxHy), 2.78 (1H, dd, J¼16.6, 3.7, COCHxHy). 13CNMR (100.6 MHz, CDCl3) d 177.1 (C), 142.0 (C), 128.7 (CH), 128.1(CH), 125.7 (CH), 70.2 (CH), 43.0 (CH2).

Acknowledgements

Financial support from the Spanish Ministerio de Ciencia eInnovaci�on (Grant No. CTQ2009-09692/BQU), Ministerio deEconomía y Competitividad (Grant No. CTQ2012-31034), and theGeneralitat de Catalunya (2009SGR825), as well as doctorate stu-dentship to M.P. (FPU, Ministerio de Educaci�on) is acknowledged.

References and notes

1. (a) Nicolaou, K. C.; Chen, J. S. Classics in Total Synthesis III: Further Targets,Strategies, Methods; Wiley-VCH: Weinheim, Germany, 2011; For overviews ofrecent advances in the synthesis of natural products, see: (b) Chem. Soc. Rev.2009, 38, 2981; (c) Nat. Prod. Rep. 2014, 31, 403.

2. For insightful analyses on natural product syntheses, see: (a) Wender, P. A.;Miller, B. L. Nature 2009, 460, 197; (b) Gaich, T.; Baran, P. S. J. Org. Chem. 2010,75, 4657.

3. Carreira, E. M.; Kvaerno, L. Classics in Stereoselective Synthesis; Wiley-VCH:Weinheim, Germany, 2009.

4. The term acetate aldol reaction refers to any aldol transformation involvingunsubstituted enolates, which encompasses the reactions from acetic acid orderivatives, methyl ketones, or acetaldehyde.

5. (a) Braun, M. In Houben-Weyl; Helmchen, G., Hoffmann, R. W., Mulzer, J.,Schaumann, E., Eds.; Thieme: Stuttgart, Germany, 1995; Vol. E21b, p 1603; (b)Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1; (c) Palomo, C.; Oiarbide, M.;García, J. M. Chem.dEur. J. 2002, 8, 36; (d) Palomo, C.; Oiarbide, M.; García, J. M.Chem. Soc. Rev. 2004, 33, 65; (e) Modern Aldol Reactions; Mahrwald, R., Ed.;Wiley-VCH: Weinheim, Germany, 2004; (f) Geary, L. M.; Hultin, P. G. Tetrahe-dron: Asymmetry 2009, 20, 131; (g) Ariza, X.; García, J.; Romea, P.; Urpí, F.Synthesis 2011, 2175; (h) Modern Methods in Stereoselective Aldol Reactions;Mahrwald, R., Ed.; Wiley-VCH: Weinheim, Germany, 2013.

6. For the application of aldol reactions to the total synthesis of natural products,see: (a) Yeung, K.-S.; Paterson, I. Angew. Chem., Int. Ed. 2002, 41, 4632; (b) Yeung,K.-S.; Paterson, I. Chem. Rev. 2005, 105, 4237; (c) Schetter, B.; Mahrwald, R.Angew. Chem., Int. Ed. 2006, 45, 7506; (d) Brodmann, T.; Lorenz, M.; Sch€ackel, R.;Simsek, S.; Kalesse, M. Synlett 2009, 174; (e) Li, J.; Menche, D. Synthesis 2009,2293.

7. (a) Pellissier, H. Tetrahedron 2007, 63, 9267; (b) Guillena, C.; N�ajera, C.; Ram�on,D. J. Tetrahedron: Asymmetry 2007, 18, 2249; (c) Mukherjee, S.; Yang, J. W.;Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (d) Trost, B. M.; Brindle, C. S.Chem. Soc. Rev. 2010, 39, 1600; (e) Kumagai, N.; Shibasaki, M. Angew. Chem., Int.Ed. 2011, 50, 4760.

8. For recent advances in chiral auxiliaries-based aldol reactions, see: Khatik, G. L.;Kumar, V.; Nair, V. A. Org. Lett. 2012, 14, 2442 and references therein.

9. For examples illustrating the complexity of acetate aldol reactions, see: (a)Paterson, I.; Findlay, A. D.; Anderson, E. A. Angew. Chem., Int. Ed. 2007, 46, 6699;(b) F€urstner, A.; Bouchez, L. C.; Funel, J.-A.; Liepins, V.; Por�ee, F.-H.; Gilmour, R.;Beaufils, F.; Laurich, D.; Tamiya, M. Angew. Chem., Int. Ed. 2007, 46, 9265; (c)Lorenz, M.; Kalesse, M. Org. Lett. 2008, 10, 4371; (d) Paterson, I.; Findlay, A. D.;Noti, C. Chem. Asian J. 2009, 4, 594; (e) Gu�erinot, A.; Lepesqueux, G.; Sabl�e, S.;Reymond, S.; Cossy, J. J. Org. Chem. 2010, 75, 5151; (f) Dias, L. C.; Polo, E. C.;Ferreria, M. A. B.; Tormena, C. F. J. Org. Chem. 2012, 77, 3766; (g) Lu, L.; Zhang,W.; Nam, S.; Horne, D. A.; Jove, R.; Carter, R. G. J. Org. Chem. 2013, 78, 2213; (h)Gregg, C.; Perkins, M. V. Tetrahedron 2013, 69, 6845; (i) Kretschmer, M.; Die-ckmann, M.; Li, P.; Rudolph, S.; Herkommer, D.; Troendlin, J.; Menche, D. Chem.dEur. J. 2013, 19, 15993.

10. For seminal analyses of substrate-controlled aldol reactions, see: (a) Evans, D.A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem. Soc.1995, 117, 9073; (b) Evans,D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322; (c)Evans, D. A.; Cee, V. J.; Siska, S. J. J. Am. Chem. Soc. 2006, 128, 9433.

11. For a recent example to illustrate the intricacies of substrate-controlled aldolreactions from chiral ethyl ketones, see: Ward, D. E.; Kundu, D.; Biniaz, M.; Jana,S. J. Org. Chem. 2014, 79, 6868.

12. For studies on stereoselective aldol reaction from a-hydroxy methyl ketones,see: (a) Trost, B. M.; Urabe, H. J. Org. Chem. 1990, 55, 3982; (b) Denmark, S. E.;Stavenger, R. A. J. Org. Chem. 1998, 68, 9524; (c) Evans, D. A.; Carter, P. H.;Carreira, E. M.; Charette, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem. Soc. 1999,

A. Lorente et al. / Tetrahedron 71 (2015) 1023e1035 1035

121, 7540; (d) Palomo, C.; Oiarbide, M.; Aizpurua, J. M.; Gonz�alez, A.; García, J.M.; Landa, C.; Odriozola, I.; Linden, A. J. Org. Chem. 1999, 64, 8193; (e) Denmark,S. E.; Stavenger, R. A. J. Am. Chem. Soc. 2000, 122, 8837; (f) F€urstner, A.; Kattnig,E.; Lepage, O. J. Am. Chem. Soc. 2006, 128, 9194; (g) Lorenz, M.; Bluhm, N.;Kalesse, M. Synthesis 2009, 3061.

13. (a) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Org. Chem. 1990, 55, 481; (b)Goodman, J. M.; Kahn, S. D.; Paterson, I. J. Org. Chem. 1990, 55, 3295; (c) Ber-nardi, A.; Capelli, A. M.; Gennari, C.; Goodman, J. M.; Paterson, I. J. Org. Chem.1990, 55, 3576; (d) Bernardi, A.; Gennari, C.; Goodman, J. M.; Paterson, I. Tet-rahedron: Asymmetry 1995, 6, 2613; (e) Liu, C. M.; Smith, W. J., III; Gustin, D. J.;Roush, W. R. J. Am. Chem. Soc. 2005, 127, 5770.

14. For studies on a-benzyloxy methyl ketones, see: (a) Pellicena, M.; Solsona, J. G.;Romea, P.; Urpí, F. Tetrahedron Lett. 2008, 49, 5265; (b) Pellicena, M.; Solsona, J.G.; Romea, P.; Urpí, F. Tetrahedron 2012, 68, 10338.

15. For studies on b-benzyloxy methyl ketones, see: Zambrana, J.; Romea, P.; Urpí,F.; Luj�an, C. J. Org. Chem. 2011, 76, 8575.

16. (a) Evans, D. A.; Urpí, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem.Soc. 1990, 112, 8215; (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpí, F. J. Am.Chem. Soc. 1991, 113, 1047; (c) Gonz�alez, A.; Aiguad�e, J.; Urpí, F.; Vilarrasa, J.Tetrahedron Lett. 1996, 37, 8949.

17. For the structure of titanium(IV) enolates of chiral a-alkoxy ketones, see:Moreira, I. de P. R.; Bofill, J. M.; Anglada, J. M.; Solsona, J. G.; Nebot, J.; Romea, P.;Urpí, F. J. Am. Chem. Soc. 2008, 130, 3242.

18. For studies on the influence of titanium(IV) Lewis acid on the stereochemicaloutcome of aldol reactions of chiral ketones, see: (a) Solsona, J. G.; Romea, P.;Urpí, F.; Vilarrasa, J. Org. Lett. 2003, 5, 519; (b) Solsona, J. G.; Romea, P.; Urpí, F.Tetrahedron Lett. 2004, 45, 5379; (c) Nebot, J.; Figueras, S.; Romea, P.; Urpí, F.; Ji,Y. Tetrahedron 2006, 62, 11090; (d) Rodríguez-Cisterna, V.; Villar, C.; Romea, P.;Urpí, F. J. Org. Chem. 2007, 72, 6631; (e) Nebot, J.; Romea, P.; Urpí, F. J. Org. Chem.2009, 74, 7518; (f) Zambrana, J.; Romea, P.; Urpí, F. Chem. Commun. 2013, 4507.

19. For a former communication, see: Lorente, A.; Pellicena, M.; Romea, P.; Urpí, F.Tetrahedron Lett. 2010, 51, 942.

20. Ketone 1 was easily prepared in an enantiomerically pure form through acyl-ation of methyl lithiumwith N-acyl pyrrolidine derived from lactate esters, see:Ferrer�o, M.; Galobardes, M.; Martín, R.; Montes, T.; Romea, P.; Rovira, R.; Urpí,F.; Vilarrasa, J. Synthesis 2000, 1608.

21. For highly stereoselective aldol additions of chiral a-hydroxy ketones to ke-tones, see: Alcoberro, S.; G�omez-Palomino, A.; Sol�a, R.; Romea, P.; Urpí, F.; Font-Bardia, M. Org. Lett. 2014, 16, 584.

22. When the aldol reaction was carried out at �94 �C it turned out to be toosluggish and required longer reaction times.

23. Kinetic resolution is one of the most important methods for the preparation ofenantiomerically pure compounds. For representative reviews on kinetic res-olution, see: (a) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001,343, 5; (b) Robinson, D. E. J. E.; Bull, S. D. Tetrahedron: Asymmetry 2003, 14,1407; (c) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974; (d) M€uller, C.E.; Schreiner, P. R. Angew. Chem., Int. Ed. 2011, 50, 6012; (e) Pellissier, H. Adv.Synth. Catal. 2011, 353, 1613; (f) Bartoszewicz, A.; Ahlsten, N.; Martín-Matute, B.Chem.dEur. J. 2013, 19, 7274.

24. For a rational design of aldol reactions proceeding via kinetic resolution, see:Ward, D. A.; Becerril-Jimenez, F.; Zahedi, M. M. J. Org. Chem. 2009, 74, 4447.

25. For the preparation of chiral ketones 6e8, and 20e21, see Ref. 20.26. For the preparation of Weinreb amides 12 and 13 and further acylation of

MeMgBr, see Ref. 10c.27. Acetate aldol reactions of a-hydroxy methyl ketones usually afford the 1,4-anti

diastereomers. Only a few examples based on lithium or boron-mediated aldolreactions have been reported to afford 1,4-syn diastereomers in low di-astereomeric ratio, see: (a) Ref. 9c; (b) Ref. 9e. For examples in Mukaiyama aldolreactions, see: (c) Ref. 12a; (d) Denmark, S. E.; Fujimori, S.; Pham, S. M. J. Org.Chem. 2005, 70, 10823.

28. Orsini, F.; Sello, G.; Manzo, A. M.; Lucci, E. M. Tetrahedron: Asymmetry 2005, 16,1913.

29. (a) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl.1985, 24, 1; (b) Kolodiazhnyi, O. I. Tetrahedron 2003, 59, 5953.

30. Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112, 6348.31. Roush, W. R. J. Org. Chem. 1991, 56, 4151.32. Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem. 1983, 48, 5180.33. Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pirrung, M. C.; White, C. T.; Van-

Derveer, D. J. Org. Chem. 1980, 45, 3846.34. For former studies on the aldol addition of titanium enolates to a-silyloxy al-

dehydes, see: (a) Esteve, C.; Ferrer�o, M.; Romea, P.; Urpí, F.; Vilarrasa, J. Tetra-hedron Lett. 1999, 40, 5079; (b) Esteve, C.; Ferrer�o, M.; Romea, P.; Urpí, F.;Vilarrasa, J. Tetrahedron Lett. 1999, 40, 5083.

35. For a recent analysis on chelation-controlled addition to a-silyloxy ketones,see: Stanton, G. R.; Koz, G.; Walsh, P. J. J. Am. Chem. Soc. 2011, 133, 7969.