Chiral Allylsilane Additions to Chiral alpha-Substituted Aldehydes

Abstracts

Chiral allylsilane 3 reacted with chiral alpha-methyl-beta-siloxy-aldehydes to afford the corresponding 1,4-syn-products with good diastereoselectivities independent of the absolute stereochemistry of these aldehydes. The best selectivities are observed when the reactions are carried out by transmetallation of the allylsilane 3 using Tin (IV) Chloride in CH2Cl2, at -78 °C, before addition of the aldehydes.

chiral allylsilane; transmetallation; 1,4-asymmetric induction; polyacetate derived natural products

Reação do alilsilano quiral 3 com alfa-metil-beta-siloxi-aldeídos fornece os produtos correspondentes com estereoquímica relativa 1,4-syn com boa diastereosseletividade, independente da estereoquímica absoluta dos aldeídos. As melhores seletividades são observadas quando ocorre transmetalação do alilsilano 3 usando SnCl4 em CH2Cl2, a -78 °C, antes da adição dos aldeídos.

Article

Chiral Allylsilane Additions to Chiral a-Substituted Aldehydes

Luiz C. Dias*, and Rosana Giacomini

Instituto de Química, Universidade Estadual de Campinas, Unicamp, C.P. 6154, 13083-970 Campinas - SP, Brazil; e-mail: [e-mail]

Received: August 10, 1998

Reação do alilsilano quiral 3 com a-metil-b-siloxi-aldeídos fornece os produtos correspondentes com estereoquímica relativa 1,4-syn com boa diastereosseletividade, independente da estereoquímica absoluta dos aldeídos. As melhores seletividades são observadas quando ocorre transmetalação do alilsilano 3 usando SnCl₄ em CH₂Cl₂, a -78 °C, antes da adição dos aldeídos.

Chiral allylsilane 3 reacted with chiral a-methyl-b-siloxy-aldehydes to afford the corresponding 1,4-syn-products with good diastereoselectivities independent of the absolute stereochemistry of these aldehydes. The best selectivities are observed when the reactions are carried out by transmetallation of the allylsilane 3 using Tin (IV) Chloride in CH₂Cl₂, at -78 °C, before addition of the aldehydes.

Keywords: chiral allylsilane, transmetallation, 1,4-asymmetric induction, polyacetate derived natural products

Introduction

The Lewis acid-mediated reaction of allylsilanes with aldehydes is a well-known procedure for the preparation of homoallylic alcohols¹. The stereochemical outcome of this reaction has been occasionally explained by considering Lewis acid-carbonyl complexation. This type of complexation mainly occurs through two discrete pathways, chelation and non-chelation controlled, depending on the nature of the Lewis acid and on the steric requirements of the carbonyl ligand. Condensation of allylic metals (e.g. M: Si, Ti, Sn, B, Cr) with various carbonyl compounds can be used to achieve acyclic stereoselection, and has been applied to the synthesis of natural products¹. Chiral allylmetal reagents may be thought of as acetate-enolate equivalents for diastereoselective construction of stereochemically well-defined homoallylic alcohols. Because these reactions complement the aldol reactions, they are among the most important groups of organometallic reagents available for the control of acyclic stereochemistry. Many methods can be used to control the configurations of stereogenic centers that are close to each other^2,3. However relatively few methods are available for control of the stereochemistry of more remote stereogenic centers^4,5.

We describe herein a divergently stereocontrolled reaction between chiral aldehydes and a chiral allylic silane bearing an ethereal functionality, whose coordination to the Lewis acid was found to play a very important role⁶. These allylsilanes offer an attractive site for metal ligation with a benzyloxyl substituent and undergo Lewis acid promoted reactions with chiral aldehydes with efficient 1,4-asymmetric induction⁶.

The preparation of chiral allylsilane 3 from methyl ester 1 is detailed in Scheme 1. Allylsilanes can be obtained by the reaction of esters with a-silyl substituted Grignard reagents, but yields in this reaction are typically low due to kinetically-preferred enolization of the intermediate a-silylketone rather than addition of a second equivalent of Grignard reagent⁷.In 1987 Bunnelle and Narayanan reported that this complication can be circumvented in cases of simple esters by premixing the a-silyl Grignard reagent with anhydrous cerium (III) chloride⁸. The yields in this reaction are greatly increased presumably due to suppression of the enolization process⁹. The cerium reagent generated from cerium (III) chloride and trimethylsilylmethyl-magnesium chloride reacts with ester 1 to give bis-(silylmethyl)-carbinol 2¹⁰, which after treatment with silica gel in CH₂Cl₂ affords allylsilane 3 in 70% isolated yield after flash chromatography (Scheme 1)¹¹.

It seems unlikely that the above reaction proceeds via the intermediacy of an alkylcerium species, but it is clear that the presence of cerium (III) chloride is essential. It may be that cerium is involved in a direct interaction with the intermediate ketone species which enhances nucleophilic attack at the carbonyl and limits competitive enolization. Control experiments established that the Grignard reagent alone reacts very sluggishly at low reaction temperatures (starting ester along with small amounts of a-silylketone are obtained).

Chiral aldehydes 9, 10 and 13 and their enantiomers were prepared from methyl 3-hydroxy-2-methylpropionate 4, both enantiomers of which are commercially available^10,12. Standard literature methods were employed. The final step in each case was Swern oxidation of alcohols 7, 8 and 12. Attempts to purify 9, 10 and 13 by silica-gel chromatography resulted in partial racemization. Since the diastereoselectivity of the reactions of these aldehydes with allylsilane 3 depends on their enantiomeric purity, crude aldehydes 9, 10 and 13 were used in all of the studies described in this text. In aldehydes 9 and 10, chelation is presumably prevented by the use of bulky silyl protecting groups, since silyl ethers, with few exceptions, are recognized generally for their poor coordinating and chelating abilities¹³.

All of the studies were carried out on aldehydes and allylsilane 3 with SnCl₄ as the Lewis acid. Tin(IV) chloride promoted reactions of chiral allylsilane 3 with these aldehydes were carried out at 4 different conditions: 1. Aldehyde and SnCl₄ were mixed for 5 min. before the allylsilane addition; 2. Allylsilane and SnCl₄ were mixed for 1 h before the addition of the aldehyde solution; 3. SnCl₄ was added to a mixture of allylsilane and aldehyde in CH₂Cl₂ at -78 °C; 4. Allylsilane and SnCl₄ were mixed for 1 h at -78 °C before the addition of a solution of the aldehyde pre-mixed with SnCl₄ at -78 °C.

At this juncture, a comprehensive experimental study of the SnCl₄-mediated coupling of chiral allylsilane 3 with achiral aldehydes 14 and 15 was initiated to test the facial selectivity of this allylsilane. Precomplexation of aldehyde 14 or 15 with SnCl₄ (1.0 eq.) in CH₂Cl₂ at -78 °C (condition 1) followed by the dropwise addition of allylsilane 3 in CH₂Cl₂ solution led to the isolation of a mixture of diastereomeric homoallylic alcohols 16/17 or 18/19, respectively, in moderate yields (Scheme 3, Table 1)¹⁴. Changing the order of addition of allylsilane 3 to SnCl₄ (1.0 eq.) for varying periods of time at -78 °C followed by addition of aldehydes 14 or 15 led to the same selectivities as previously observed. Under condition 2, the same selectivity was observed for aldehyde 14 but aldehyde 15 afforded adduct 18 in better selectivity when compared with condition 1. Based on these results we conclude that allylsilane 3 prefers to add to the aldehyde re face affording 1,4-syn as the major product.

The stereochemical assignment of compound 16 was determined by analysis of the coupling constants in the ¹H-NMR spectrum of the tetrahydropyran derivative 23. The conversion of 16 to this derivative is illustrated in Scheme 4. Subjection of 16 to standard silylation conditions (TBSOTf, 2,6-lutidine, CH₂Cl₂, 0 °C, 20 min) afforded the bis-silyl ether 20 in 88% yield. Cleavage of the benzyl ether of 20 by the utilization of the lithium 4,4’-tert-butylbiphenyl (LiDBB) radical anion in THF at -78 °C, afforded the primary alcohol 21 in 50% yield. Tosylation of the primary hydroxyl in 21 gave tosylate 22 in 88% yield. Treatment of 22 with TBAF in THF at room temperature effected smooth deprotection of both silyl ethers with concomitant intramolecular etherification to provide tetrahydropyran 23 in 88% yield. Coupling constants of 11,0 and 3,30 Hz for Hb, and 11,0 and 1,83 Hz for Hc are indicative of the axial orientation of the methyl group in the ring. In addition, coupling constants of 13,55 and 2,93 Hz for He and 13,2 and 11,0 Hz for Hf are indicative of the axial orientation of Hd, thereby confirming the 1,4-syn relationship in homoallylic alcohol 16.

In order to check the facial selectivity of chiral a-substituted aldehydes they were reacted with commercial allyltrimethylsilane under conditions 1 and 2 (Scheme 5, Table 2). We always isolated a 50:50 mixture of both possible diastereomers in low yields. Based on these results we might conclude that aldehyde 9 has no preference for Felkin or anti-Felkin addition under the present reaction conditions.

The tin (IV) chloride promoted reactions of chiral allylsilane 3 with (S)-a-methyl chiral aldehydes 9 (OTBS) and 10 (OTBDPS) were carried out at the same 4 different experimental conditions described before. Under these conditions the allylsilane 3 reacted with (S)-aldehydes 9 and 10 to give a mixture of the 1,4-syn and 1,4-anti-diastereomers with useful diastereoselectivities (Scheme 6, Table 3), favoring the 1,4-syn-isomer (anti-Felkin addition)¹⁴. It should be noted that this reaction affords a very important subunit with different protecting groups at the terminus. All of the percentage values represent data obtained from three individual trials. It should be noted that partial racemization of the aldehydes probably occurs during reaction since we observed small peaks at d 1.0-1.2.

Under the same conditions as described above, allylsilane 3 reacted with the enantiomers of aldehydes 9 and 10 to give 1,4-syn-products with Felkin addition (Scheme 7 and Table 4)^10b,11.

In all cases the 1,4-syn products were formed stereoseletively in good yields. Confirmation that the same products were obtained with both TBS and TBDPS protected aldehydes was gained by desylation of 26 and 30 and comparison of these diols with those generated from 28 and 32, respectively¹⁴. Based on these results, the chiral aldehydes 9 and 10 would not appear to prefer to react in the Felkin-Anh mode, since similar selectivities for the 1,4-syn isomer were obtained with both enantiomers. Although the (R)-aldehydes are matched with (R)-allylsilane 3, whereas the (S)-enantiomer of these aldehydes are mismatched, it looks as though the allylsilane alone is responsible for the control of the relative stereochemistry.

In some of these experiments we observed the formation of small amounts of a by-product (5% yield, 1:1 mixture of diastereomers) that was characterized as being compound 34 (Scheme 8). We believe this compound is formed by the addition of the allylsilane to methacrolein, in situ formed from aldehydes and SnCl₄. To confirm the structure of this by-product we reacted allylsilane 3 with methacrolein and observed the formation of a 2:1 mixture of adducts 34 in 70% isolated yield (Scheme 8).

The selectivity in this reaction can be explained by invoking transmetalation of the allylsilane 3 with SnCl₄ to generate the allyltrichlorotin intermediate 35, in which the benzyl-protected oxygen atom is coordinated intramolecularly to the electron-deficient tin(Scheme 9)¹⁵. This species reacts with aldehydes at reasonable levels of 1,4-asymmetric induction in favor of the syn-diastereoisomer.

The formation of 1,4-syn-products from reactions of the allylsilanes and aldehydes is consistent with the participation of the transition structure involving a coordinated allyltin thrichloride. We believe that entrance of an aldehyde into the coordination sphere of tin does not disrupting the intramolecular chelation to the proximal oxygen. Under these circumstances, p-facial selectivity for attack at the aldehydes is ultimately governed by approach to the less hindered surface of the allyltin reagent. With the -CH₂OBn locked below the developing chair, the methyl substituent could become the key factor in dictating p-facial diastereoselection. One might anticipate that the internally-chelated allylstannane might afford the 1,4-syn-diastereoisomer.

The intermediate allyltin trichloride is stabilized by tin-oxygen interaction, and then reacts with the aldehyde via a chair-like six-membered ring transition state in which the aldehyde approaches the complex opposite to the methyl group. The preference of the alkyl group of the aldehyde to adopt an equatorial position controls the aldehyde facial selectivity, resulting in the favored 1,4-syn stereochemistry in the adduct, independent of the aldehyde absolute configuration (Scheme 10).

A very interesting experiment was done in order to prove the intermediacy of an allylstannane. Addition of SnCl₄ to a solution of chiral allylsilane 3 in CH₂Cl₂ at -78 °C, stirring for 1 h and quenching with Et₃N/NH₄Cl, without the addition of aldehyde, afforded alkene 36 in 87% yield (Scheme 11).

The relative stereochemical assignments of the homoallylic alcohols 26/28 and 30/32 were based on ¹H-NMR coupling constant analysis of the derived cyclic p-methoxybenzylidene acetals. The indicated vicinal coupling constant data for the benzylidene acetals unambiguously established the configuration of the newly formed stereocenter of the anti-felkin adducts 26/28 and the Felkin adducts 30/32. Average coupling constants of 11 Hz indicate that protons Ha-Hc in 41 are on opposite faces of the heterocyclic ring, and therefore the acetonide is derived from an 1,2-anti adduct. In contrast, coupling constants of 1-3 Hz for Ha-Hc in 39 are characteristic of protons residing on the same face of the ring, indicative of a 1,2-syn product. In some instances the relative ring stereochemistry was further supported by ¹H-¹H NOESY measurements. The illustrated NOE measurements on benzylidene acetal established the syn relationship between the newly formed hydroxyl and adjacent methyl bearing stereocenter, thereby securing the stereochemical assignment of these adducts (Scheme 12). Having confirmed the relative (syn or anti) relationship between allylsilane derived stereogenic centers, the absolute stereochemistry of the newly formed hydroxyl substituent was determined by ascertaining its relationship to the stereocenter originating from the aldehydes, which are of known configuration.

It is interesting to note that reactions of allylsilane 3 with both (R)- and (S)-aldehydes 13 protected with b-OPMB afforded exactly the same mixture of products 42 and 43 in a 50:50 ratio. This result was confirmed by conversion to the corresponding acetonides and comparison to the acetonides obtained in Scheme 12. These results can be explained by racemization of the aldehydes in the presence of SnCl₄ and selective reaction of chiral allylsilane with each enantiomer of these aldehydes.

For allylsilane adducts derived from aldehydes possessing the b-OPMB moiety, the strategy to prove the stereochemistry relied on intramolecular oxidative formation of the p-methoxybenzylidene acetals 39/41 (Scheme 13)¹⁶. This was accomplished by treatment of the PMB-ether in 42 and 43 under anhydrous conditions with 2,3-dichlor-5,6-dicyano-benzoquinone (DDQ).

In summary, good levels of 1,4-asymmetric induction were obtained in the reactions of chiral allylsilane 3 and aldehydes. A chelate transition state model, which takes into account dual coordination of tin intramolecularly to nearby oxygen and intermolecularly to activate the aldehyde carbonyl, is proposed to explain the observed sense of 1,4-asymmetric induction.

The examples presented here show that the levels of p-facial selection are independent of the absolute stereochemistry of the aldehydes. The data support the notion that the stereocenter in allylsilane is primarily responsible for the observed diastereoselection and that these chiral allylsilanes can be used as an effective stereocontrolling element in acyclic diastereoselection. Other Lewis acids could be used to promote this reaction in order to improve yields and selectivities and reduce the amount of racemization in these aldehydes.

We believe that the chemistry involved is truly significant in the context of acyclic diastereoselection and will prove to be exceptionally useful in the synthesis of complex organic molecules like polypropionate and polyacetate-derived natural products. Further exploration of these reagents and their applications is now underway in our laboratories as well as investigations of the mechanistic details.

Experimental

General

All experiments were carried out under an argon atmosphere in flame-dried glassware. Dichloromethane, triethylamine, cyclohexane, pyridine, and 2,6-lutidine were distilled from CaH₂. Tin tetrachloride was distilled from P₂O₅ and stored in a Schlenk flask. THF and toluene were distilled from sodium/benzophenone ketyl. Dimethyl sulfoxide was distilled under reduced pressure from calcium hydride and stored over molecular sieves. Trimethylsilil chloride and oxalyl chloride were distilled immediately prior to use. TLC plates were obtained of silica gel 60 and GF (5-40-mm thickness) and visualization was accomplished with either a UV lamp and I₂ staining. ¹H-NMR spectra were recorded on a Bruker AC 300/P (300 MHz) or Varian Gemini (300 MHz) spectrometers. Chemical shifts are recorded in ppm with the solvent resonance as the internal standard (deuterochloroform: d 7.26). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qt = quintet, st = sextet, br = broad, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, br d = broad doublet, ddd, doublet of doublet of doublets), integration, coupling constants (Hz), and assignment. ¹³C-NMR spectra were recorded on a Bruker AC 300/P (75 MHz) or Varian Gemini (75 MHz) spectrometers with complete proton decoupling. Chemical shifts are recorded in ppm with the solvent resonance as the internal standard (deuterochloroform: d 77.00). Infrared spectra were recorded on a Perkin-Elmer 1600 FTIR spectrophotometer. Mass spectra were obtained on a GC/MS HP-5988-A. Optical rotations were measured on a polarimeter Polamat A Carl Zeiss Jene using 1 mL capacity quartz cell, using a mercury or sodium lamp, and are reported as follows: [a]^t(°C)l, (c = g/100 mL, solvent). Chromatography on silica-gel (230-400 mesh) was performed using a forced-flow of the indicated solvent system (flash chromatography)

2-[(1R)-2-benzyloxy-1-methylethyl]allyl(trimethyl)silane (3)

In a 3-necked 500 mL round bottomed flask, powdered CeCl₃.7H₂O (17.6 g, 48 mmol) was heated under vacuum (3 mm Hg) at 160 °C for 10 h with vigorous stirring, resulting in the formation of a white mobile solid. The reaction flask was flushed with argon and allowed to cool to room temperature when 96 mL of dry THF was added to vigorously stirred anhydrous cerium (III) chloride forming a uniform white suspension, which was left stirring for 2 h. During this time, a separate 3-necked 100 mL flask, fitted with a condenser and a pressure equalized dropping funnel, was charged with 1.17 g (48 mmol) of magnesium turnings, and the whole apparatus was flame dried under a flow of argon. A solution of ClCH₂TMS (6.7 mL, 48 mmol) was added to this flask dropwise in 45 mL of dry THF. This mixture was stirred for 1.5 h until almost all of the magnesium was dissolved. The dry cerium (III) chloride suspension was now cooled to -78 °C. To this suspension Grignard reagent (prepared above) was added dropwise forming na off-white suspension which was stirred at -78 °C for 1 h. At this time ester 1 (2.0 g, 9,6 mmol) in 10 mL of THF was added dropwise over 5 min, and the resulting mixture was warmed gradually to room temperature. When consumption of starting ester was complete by TLC (3 h), the resulting gray solution was cooled to 0 °C and quenched by the addition of 10 mL aqueous solution saturated of NH₄Cl (0 °C). The organic layer was separated, and the aqueous layer was extracted with diethyl ether (2 x 50 mL). The combined organic layer was washed with saturated brine (2 x 50 mL) and dried over anhydrous MgSO₄. The solvent was removed under reduced pressure affording a slightly yellow liquid which was dissolved in 100 mL of CH₂Cl₂. To this flask 10 g of silica gel was added and this mixture was stirred at room temperature until complete consumption of starting material. The silica gel was then removed by filtration and washed with 300 mL of CH₂Cl₂. The solvent was removed under reduced pressure to give a colorless liquid which was purified by flash chromatography on silica gel (hexanes:ethyl acetate 99:01) to afford 1.76 g in 70% yield. [a]²⁰_D = + 12.6 (c 1.3, CHCl₃). TLC: Rf: 0.26, hexanes:diethyl ether 99:01). ¹H-NMR (CDCl₃, 300 MHz): d: 0.03 (9H, s), 1.12 (3H, d, ³J = 6.59), 1.57 (2H, d, ³J = 5.86), 2.28 (1H, m), 3.26 (1H, dd, ²J = 9.15, ³J = 8.06), 3.54 (1H, dd, ²J = 9.15, ³J = 4.76), 4.53 (2H, d, ³J = 2.56), 4.63 (2H, d, ³J = 6.96), 7.36 (5H, m). ¹³C-NMR (CDCl₃, 75 MHz): d: -1.5 (CH₃), 17.0 (CH₃), 26.6 (CH₂), 40.9 (CH), 72.9 (CH₂), 75.0 (CH₂), 106.5 (CH₂), 127.5 (CH), 127.6 (CH), 128.4 (CH), 138.8 (C₀), 149.9 (C₀). IR (film):3066, 3030, 2957, 2856, 1631, 1496, 1454, 1419, 1364, 1248, 1158, 1099, 1028, 958, 854, 734, 696, 634 cm^{- 1}.

MS (70eV): 45 (13%), 73 (100%), 91 (91%), 156 (14%), 179 (10%).

General procedures for allylsilane reactions

Condition 1

To a solution of 0.25 mmol of aldehyde in 2 mL of dry CH₂Cl₂ at -78 °C was added 0.25 mmol of SnCl₄. The resulting solution was stirred at -78 °C for 5 min when 0.25 mmol of allylsilane 3 in 1 mL of CH₂Cl₂ was added. This mixture was stirred at -78 °C for 30 min and quenched by the slow addition of 0.30 mmol of Et₃N, followed by 5 mL of saturated NaHCO₃ solution.The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2 x 5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (10% EtOAc/hexanes) afforded the corresponding homoallylic alcohols.

Condition 2

To a solution of 0.25 mmol of allylsilane 3 in 2 mL of dry CH₂Cl₂ at -78 °C was added 0.25 mmol of SnCl₄. The resulting solution was stirred at -78 °C for 1 h when 0.25 mmol of aldehyde in 1 mL of CH₂Cl₂ was added. This mixture was stirred at -78 °C for 30 min and quenched by the slow addition of 0.30 mmol of Et₃N, followed by 5 mL of saturated NaHCO₃ solution.The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2 x 5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (10% EtOAc/hexanes) afforded the corresponding homoallylic alcohols.

Condition 3

To a solution of 0.25 mmol of allylsilane 3 in 2 mL of dry CH₂Cl₂ at -78 °C was added 0.25 mmol of aldehyde. To the resulting solution was added 0.25 mmol of SnCl₄. This mixture was stirred at -78 °C for 30 min and quenched by the slow addition of 0.30 mmol of Et₃N, followed by 5 mL of saturated NaHCO₃ solution. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2 x 5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (10% EtOAc/hexanes) afforded the corresponding homoallylic alcohols.

Condition 4

To a solution of 0.25 mmol of allylsilane 3 in 2 mL of dry CH₂Cl₂ at -78 °C was added 0.25 mmol of SnCl₄. The resulting solution was stirred at -78 °C for 1 h when was added to a solution 0.25 mmol of aldehyde pre-mixed with SnCl₄ in 1 mL of CH₂Cl₂. This mixture was stirred at -78 °C for 30 min and quenched by the slow addition of 0.30 mmol of Et₃N, followed by 5 mL of saturated NaHCO₃ solution. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2x5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (10% EtOAc/hexanes) afforded the corresponding homoallylic alcohols.

(3R)-5-[(1R)-2-benzyloxy-1-methylethyl]-1-[tert-butyl(dimethyl)silyloxy]-5-hexen-3-ol (16)

To a solution of 0.25 mmol of allylsilane 3 in 2 mL of dry CH₂Cl₂ at -78 °C was added 0.25 mmol of SnCl₄. The resulting solution was stirred at -78 °C for 1 h when 0.25 mmol of aldehyde 14 in 1 mL of CH₂Cl₂ was added. This mixture was stirred at -78 °C for 30 min and quenched by the slow addition of 0.30 mmol of Et₃N, followed by 5 mL of saturated NaHCO₃ solution. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2x5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (10% EtOAc/hexanes) afforded 50 mg of the homoallylic alcohol 16 in 50% yield. [a]²⁰_D = +9.9 (c 0.8, CHCl₃). TLC: Rf: 0.46, hexane:diethyl ether 99:01). ¹H-NMR(CDCl₃, 300 MHz): d: 0.06 (6H, s), 0.89 (9H, s), 1.04 (3H, d, ³J = 6.96), 1.66 (2H, m), 2.20 (2H, d, ³J = 6.96), 2.48 (1H, sext, ³J = 6.96), 3.35 (1H, dd, ²J = 9.15, ³J = 6.59), 3.49 (1H, dd, ²J = 9.15, ³J = 7.32), 3.80 (3H, m), 3.99 (1H, m), 4,50 (2H, s), 4.92 (2H, d, ³J = 1.46), 7.32 (5H, m). ¹³C-NMR (CDCl₃, 75 MHz): d: -5.8 (CH₃), 17.2 (CH₃), 18.0 (C_o), 25,7 (CH₃), 38.4 (CH₂), 38.9 (CH), 43.7 (CH₂), 61.7 (CH₂), 68.4 (CH), 73.0 (CH₂), 74.6 (CH₂), 112.0 (CH₂), 127.7 (CH), 127.8 (CH), 128.5 (CH), 138.4 (C_o), 149.3 (C_o). IR (film): 3482, 2956, 2927, 2855, 1652, 1472, 1456, 1361, 1255, 1092, 1005, 897, 836, 776, 734, 697 cm^-1. MS (70eV): 77 (23%), 183 (80%), 191 (100%), 239 (51%),269 (73%).

2-[(2R,5R)-5-methyl-4-methylenetetrahydro-2H-2-pyranyl]-1-ethanol (23)

To a solution of compound 16 (60 mg, 0.16 mmol) in 2 mL of CH₂Cl₂ was added 2,6-lutidine (43 mg, 0.4 mmol). This mixture was cooled to -10 °C, and tert-butyldimethylsilyl triflate (48 mg, 0.2 mmol) was added dropwise. After 30 min at -10 °C, the reaction was quenched by the addition of 1.0 mL of H₂O. The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (2 x 3 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated under reduced pressure. Purification by flash chromatography (hexanes:ethyl acetate 95:05) afforded 68.2 mg of 20 in 88% yield. TLC: Rf: 0.68, hexanes/ethyl acetate 85:15: IR (film): 2955, 2928, 2856, 1734, 1640, 1471, 1389, 1360, 1255, 1091, 1033, 1005, 966, 939, 893, 836, 774, 732, 696 cm^-1. To a solution of 4,4-di-tert-butylbiphenyl (0.32 g, 1.2 mmol) in 5 mL of THF at room temperature was added lithium metal (0.17 g, 2.4 mmol) which had been washed with MeOH and THF under argon. This mixture was sonicated at room temperature for 6 h during which time the dark blue color of the anion radical developed. To a -78 °C stirred solution of 20 (60 mg, 0.12 mmol) in 3 mL of THF was added dropwise the LiDBB radical anion solution until a blue color persisted in the reaction mixture. The dark blue solution was then stirred for another 30 min at -78 °C before being quenched by careful addition of 3 mL of a saturated aqueous NH₄Cl solution. The colorless mixture was extracted with diethyl ether (2 x 5 mL). The combined organic extract was dried over MgSO₄, filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (hexane:ethyl acetate 90:10) gave 24 mg of alcohol 21 in 50% yield. TLC: Rf: 0.40, hexane:ethyl acetate 85:15. IR (film): 3359, 3081, 2955, 2857, 2738, 1641, 1472, 1463, 1388, 1361, 1255, 1187, 1093, 1033, 1006, 984, 965, 938, 895, 836, 800, 774, 716, 663 cm^-1. To a solution of alcohol 21 (20 mg, 0.05 mmol) in 2 mL of CH₂Cl₂ at 0 °C was added pyridine (0.1 mmol), followed by addition of 14 mg (0.07 mmol) of p-toluenesulfonyl chloride. The resulting mixture was warmed to room temperature and stirred for 18 h. The reaction was quenched by the addition of ethyl ether (1.0 mL) and H₂O (1 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2 x 5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification of the crude product by silica gel flash chromatography (hexanes:ethyl acetate 95:05) afforded 24 mg of 22 in 88% yield. TLC: Rf = 0.60, hexanes:ethyl acetate 85:15. ¹H-NMR(CDCl₃, 300 MHz): d: 0.0 (6H, d, ³J = 7.69), 0.02 (6H, s), 0.85 (9H, s), 0.87 (9H, s) 1.04 (3H, d, ³J = 6.96), 1.48 (1H, m) 1.65 (1H, m), 2.11 (2H, d, ³J = 6.59), 2.44 (3H, s), 3.61 (1H, d, ³J = 5,86), 3.64 (1H, d, ³J = 5.86), 3.74 (1H, m), 3.82 (1H, dd, ²J = 9.15, ³J = 7.69), 3.91 (1H, m), 4.00 (1H, dd, ²J = 9.15, ³J = 5.12), 4.82 (2H, d, ³J = 17.95), 7.33 (2H, d, ³J = 8.06), 7.77 (2H, d, ³J = 8.06). IR (film): 2955, 2928, 2856, 1735, 1642, 1598, 1472, 1363, 1256, 1189, 1178, 1097, 1034, 1006, 968, 900, 836, 813, 775, 666 cm^-1. To a solution of 20 mg (0.04 mmol) of 22 in 1 mL of THF at 0 °C was added 0.16 mL of a 1.0 M solution of TBAF. The solution was warmed to room temperature and stirred for 18 h. The solution was diluted with 2 mL of ethyl ether and washed with aqueous saturated solution of NH₄Cl. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2 x 5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification of the crude product by silica gel flash chromatography (hexanes:ethyl acetate 95:05) afforded 5 mg of 23 in 88% yield. [a]²⁰_D = + 30.4 (c 0.1, CHCl₃). TLC: Rf: 0.1, hexanes:ethyl acetate 85:15. ¹H-NMR(CDCl₃, 300 MHz): d: 1.18 (3H, d, ³J = 6.96), 1.63 ( 1H, br), 1.71 (1H, m), 1.85 (1H, m), 2.07 (1H, d, ²J = 13.0) 2.29 (1H, d, ²J = 13.0), 2.35 (1H, m), 3.50 (1H, m), 3.57 (1H, dd, ²J = 10.6, ³J = 3.29), 3.77 (1H, d, ²J = 10.6), 3.81 (2H, d, ³J = 5.13), 4.72 (2H, d, ²J = 27.1). ¹³C-NMR (CDCl₃, 75 MHz): d: 17.7 (CH₃), 37.2 (CH₂), 37.5 (CH₂), 38.2 (CH), 61.3 (CH₂), 73.5 (CH₂), 79.3 (CH), 108.2 (CH₂), 148.3 (C₀). IR (film): 3407, 3071, 2928, 2853, 1724, 1651, 1461, 1430, 1382, 1258, 1178, 1112, 1055, 991, 963, 891 cm^-1.

(2R,3R)-5-[(1R)-2-benzyloxy-1-methylethyl]-1-[tert-butyl(dimethyl)silyloxy]-2-methyl-5-hexen-3-ol (26)

To a solution of 0.25 mmol of allylsilane 3 in 2 mL of dry CH₂Cl₂ at -78 °C was added 0.25 mmol of SnCl₄. The resulting solution was stirred at -78 °C for 1 h when 0.25 mmol of aldehyde (S)-9 in 1 mL of CH₂Cl₂ was added. This mixture was stirred at -78 °C for 30 min and quenched by the slow addition of 0.30 mmol of Et₃N, followed by 5 mL of saturated NaHCO₃ solution.The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2 x 5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (10% EtOAc/hexanes) afforded 68 mg of the alcohol 26 in 70% yield. [a]²⁰_D = -8.7 (c 0.5, CHCl₃). TLC: Rf = 0.4, hexanes:diethyl ether 8:2. ¹H-NMR(CDCl₃, 300 MHz): d: 0.08 (3H, s), 0.91 (9H, s), 0.94 (3H, d, ³J = 6.98), 1.08 (3H, d, ³J = 6.96), 1.75 ( 1H, m), 2.12 (1H, dd, ²J = 14.1, ³J = 9.86), 2.34 (1H, dd, ²J = 14.1, ³J = 2.95), 2.51 (1H, m), 3.29 (1H, d, ³J = 3.16), 3.38 (1H, dd, ²J = 9.11, ³J = 6.63), 3.52 (1H, dd, ²J = 9.11, ³J = 7.36), 3.66 (1H, dd, ²J = 9.95, ³J = 5.84), 3.73 (1H, dd, ²J = 9.95, ³J = 5.35), 3.74 (1H, m), 4.52 (2H, s), 4.96 (2H, d, ³J = 12.21), 7.33 (5H, m). ¹³C-NMR (CDCl₃, 75 MHz): d: -5.5 (CH₃), 13.5 (CH₃), 17.6 (CH₃), 18.2 (C₀), 25.9 (CH₃), 38.9 (CH), 40.2 (CH), 41.2 (CH₂), 66.4 (CH₂), 72.2 (CH), 73.0 (CH₂), 74.6 (CH₂), 111.6 (CH₂), 127.5 (CH), 127.6 (CH), 128.3 (CH), 138.3 (C₀), 149,5 (C₀). IR (film): 3482, 2956, 2928, 2857, 1639, 1472, 1389, 1362, 1255, 1093, 1028, 894, 837, 776, 735, 698 cm^-1.

1-(2R)-3-[(2R,3S)-4-(tert-butyl(dimethyl)silyloxy)-2-(trimethyl)silyloxy-3-methylbutyl]-2-methyl-3-butenyloxymethylbenzene (26, TMS protected)

To a solution of 26 (100 mg, 0.26 mmol) in 2 mL of dry CH₂Cl₂ at room temperature was added 2 eq. of TMS-imidazole. The resulting solution was stirred for 1 h and filtered in silica gel with CH₂Cl₂. Concentration of the filtrate under reduced pressure and purification by flash chromatography on silica gel (5% EtOAc/hexanes) afforded 83 mg of 26 (TMS protected) in 70% yield). [a]²⁰_D = + 4.2 (c 2.0, CHCl₃). TLC: Rf = 0.6, hexanes:ethyl ether 8:2. ¹H-NMR(CDCl₃, 300 MHz): d: 0.04 (6H, s), 0.09 (9H, s), 0.79 (3H, d,³J = 6.96), 0.90 (9H, s), 1.11 (3H, d, ³J = 6.96), 1.70 ( 1H, m), 2.19 (1H, dd, ²J = 14.1, ³J = 6.04), 2.29 (1H, dd, ²J = 14.1, ³J = 8.24), 2.44 (1H, m), 3.31 (1H, dd, ²J = 9.52, ³J = 7.69), 3.37 (1H, dd, ²J = 9.52, ³J = 6.23), 3.49 (2H, m), 4.10 (1H, m), 4.53 (2H, d, ³J = 1.83), 4.86 (2H, d, ³J = 6.59), 7.34 (5H, m). ¹³C-NMR (CDCl₃, 75 MHz): d: -5.7 (CH₃), 0.2 (CH₃), 9.3 (CH₃), 16.8 (CH₃), 18.0 (C_o), 25.7 (CH₃), 39.0 (CH), 39.1 (CH), 41.1 (CH₂), 65.1 (CH₂), 69.8 (CH), 72.9 (CH₂), 74.8 (CH₂), 111.4 (CH₂), 127.6 (CH), 127.7 (CH), 128.5 (CH), 138.9 (C_o), 149.2 (C_o). IR (film): 2955, 2856, 1474, 1360, 1250, 1096, 939, 838, 775, 748, 696 cm^-1. MS (70eV): 73 (59%), 91 (100%), 147 (20%), 275 (42%).

(2R,3R)-5-[(1R)-2-benzyloxy-1-methylethyl]-1-[tert-butyl(diphenyl)silyloxy]-2-methyl-5-hexen-3-ol (28)

To a solution of 0.25 mmol of allylsilane 3 in 2 mL of dry CH₂Cl₂ at -78 °C was added 0.25 mmol of aldehyde (S)-10. To the resulting solution was added 0.25 mmol of SnCl₄ . This mixture was stirred at -78 °C for 30 min and quenched by the slow addition of 0.30 mmol of Et₃N, followed by 5 mL of saturated NaHCO₃ solution.The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2 x 5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (10% EtOAc/hexanes) afforded 91 mg the alcohol 28 in 72% yield. [a]²⁰_D = +13.8 (c 1.8, CHCl₃). TLC: Rf = 0.38, hexanes:EtOAc 85:15. ¹H-NMR(CDCl₃, 300 MHz): d: 0.96 (3H, d,³J = 6.96), 1,06 (3H, d,³J = 7.32), 1.07 (9H, s), 1.86 (1H, m), 2.11 (1H, dd, ²J = 14.1, ³J = 10.0), 2.23 (1H, br d, ³J = 6.28), 2.33 (1H, dl, ³J = 13.92), 2.51 (1H, m), 3.15 (1H, d, ³J = 2.93), 3.38 (1H, dd, ²J = 9.15, ³J = 6.23), 3.51 (1H, dd, ²J = 9.15, ³J = 7.69), 3.70 (1H, dd, ²J = 10.00, ³J = 5.86), 3.76 (1H, dd, ²J = 10.00, ³J = 5.31), 3.85 (1H, m), 4.52 (2H, s), 4.96 (2H, br d, ³J = 8.79), 7.38 (10H, m), 7.71 (5H, m). ¹³C-NMR (CDCl₃, 75 MHz): d: 13.2 (CH₃), 17.4 (CH₃), 19.0 (C_o), 26.7 (CH₃), 38.7 (CH), 40.3 (CH), 40.7 (CH₂), 66.8 (CH₂), 71.5 (CH), 73.0 (CH₂), 74.5 (CH₂), 112.0 (CH₂), 127.7 (CH), 127.8 (CH), 128.5 (CH), 129.8 (CH), 133.7 (C_o), 135.0 (CH), 138.4 (C_o), 149.7 (C_o). IR (film): 3069, 2958, 2929, 2856, 1958, 1887, 1821, 1643, 1588, 1471, 1389, 1361, 1308, 1260, 1188, 1111, 1028, 998, 939, 897, 874, 823, 739, 701, 613 cm^-1. MS (70eV): 45 (8%), 77 (9%), 199 (100%), 256 (5%).

1-(2R)-3-[(2R,3R)-4-(tert-butyl(dimethyl)silyloxy)-2-(trimethyl)silyloxy-3-methylbutyl]-2-methyl-3-butenyloxymethylbenzene (30, TMS protected)

To a solution of 30 (100 mg, 0.26 mmol) in 2 mL of dry CH₂Cl₂ at room temperature was added 2 eq. of TMS-imidazole. The resulting solution was stirred for 1 h and filtered in silica gel with CH₂Cl₂. Concentration of the filtrate under reduced pressure and purification by flash chromatography on silica gel (5% EtOAc/hexanes) afforded 83 mg of 30 (TMS protected) in 70% yield). [a]²⁰_D = -5.8 (c 2.9, CHCl₃). TLC: Rf = 0.6, hexanes:ethyl ether 8:2. ¹H-NMR(CDCl₃, 300 MHz): d: 0.05 (6H, s), 0.08 (9H, s), 0.87 (3H, d,³J = 6.96), 0.91 (9H, s), 1.12 (3H, d, ³J = 6.96), 1.71 (1H, br d, ³J = 5.86), 2.06 (1H, dd, ²J = 14.10, ³J = 8.24), 2.25 (1H, dd, ²J = 14.1, ³J = 3.84), 2.48 (1H, m), 3.32 (1H, dd, ²J = 9.06, ³J = 7.87), 3.46 (1H, dd, ²J = 10.16, ³J = 6.59), 3.53 (1H, dd, ²J = 9.06, ³J = 5.13), 3.58 (1H, dd, ²J = 10.16, ³J = 6.96), 3.92 (1H, m), 4.53 (2H, d, ³J = 1.83), 4.86 (2H, d, ³J = 6.59), 7.35 (5H, m). ¹³C-NMR (CDCl₃, 75 MHz): d: -5.7 (CH₃), 0.2 (CH₃), 12.2 (CH₃), 16.9 (CH₃), 18.0 (C_o), 25.7(CH₃), 38.7 (CH₂), 39.4 (CH), 41.4 (CH), 64.9 (CH₂), 72.9 (CH₂), 73.3 (CH), 74.6 (CH₂), 111.2 (CH₂), 127.6 (CH), 127.7 (CH), 128.6 (CH), 138.9 (C_o), 149.6 (C_o). IR (film): 2957, 2857, 1472, 1362, 1250, 1086, 938, 838, 775, 747, 697 cm^-1.

(2S,3R)-5-[(1R)-2-benzyloxy-1-methylethyl]-1-[tert-butyl(diphenyl)silyloxy]-2-methyl-5-hexen-3-ol (32)

To a solution of 0.25 mmol of allylsilane 3 in 2 mL of dry CH₂Cl₂ at -78 °C was added 0.25 mmol of SnCl₄. The resulting solution was stirred at -78 °C for 1 h when 0.25 mmol of aldehyde (R)-10 in 1 mL of CH₂Cl₂ was added. This mixture was stirred at -78 °C for 30 min and quenched by the slow addition of 0.30 mmol of Et₃N, followed by 5 mL of saturated NaHCO₃ solution.The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2 x 5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (10% EtOAc/hexanes) afforded 113 mg of the alcohol 32 in 90% yield. [a]²⁰_D = +2.9 (c 2.9, CHCl₃). TLC: Rf = 0.38, hexanes:EtOAc 85:15. ¹H-NMR(CDCl₃, 300 MHz): d: 0.99 (3H, d,³J = 7.32), 1.09 (3H, d,³J = 6.59), 1.11 (9H, s), 1.81 (1H, m), 2.24 (1H, br), 2.27 (1H, sl), 2.54 (1H, q, ³J = 6.96), 2.85 (1H, d, ³J = 2.56), 3.40 (1H, dd, ²J = 8.97, ³J = 6.59), 3.53 (1H, dd, ²J = 8,97, ³J = 7.32), 3.72 (1H, s), 3.74 (1H, s), 4.09 (1H, m), 4.54 (2H, s), 4.98 (2H, m), 7.45 (10H, m), 7.73 (5H, m). ¹³C-NMR (CDCl₃, 75 MHz), d: 10.5 (CH₃), 17.3 (CH₃), 19.0 (C_o), 26.7 (CH₃), 38.8 (CH), 39.5 (CH), 40.7 (CH₂), 67.7 (CH₂), 70.5 (CH), 73.0 (CH₂), 74.5 (CH₂), 111.9 (CH₂), 127.7 (CH), 127.8 (CH), 127.9 (CH), 128.0 (CH), 128.5 (CH), 129.9 (CH), 133.6 (C_o), 133.7 (C_o), 135.8 (CH), 135.9 (CH), 138.5 (C_o), 149.5 (C_o). IR (film), 3774, 3070, 2958, 2929, 2856, 1959, 1886, 1643, 1589, 1474, 1454, 1427, 1390, 1361, 1307, 1258, 1188, 1112, 1028, 998, 898, 874, 823, 739, 701, 613 cm^-1. MS (70eV), 77 (14%), 91 (82%), 135 (18%), 199 (100%), 239 (13%), 269 (52%).

(1R,S)-3-[(1R)-2-benzyloxy-1-methylethyl]-1-isopropenyl-3-butenyl alcohol (34)

To a solution of 0.28 mmol of allylsilane 3 in 2 mL of dry CH₂Cl₂ at -78 °C was added 0.28 mmol of SnCl₄. The resulting solution was stirred at -78 °C for 1 h when 0.28 mmol of methacrolein in 1 mL of CH₂Cl₂ was added. This mixture was stirred at -78 °C for 30 min and quenched by the slow addition of 0.35 mmol of Et₃N, followed by 5 mL of saturated NaHCO₃ solution.The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2 x 5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (20% EtOAc/hexanes) afforded 38 mg of alcohol 34 in 50% yield. TLC: Rf: 0.34, hexanes:ethyl acetate 85:15. ¹H-NMR(CDCl₃, 300 MHz): d: 1.05 (3H, d,³J = 6.96), 1.76 (3H, d, ³J = 5.13), 2.19 (1H, m), 2.39 (1H, m), 2.54 (1H, q, ³J = 6.96), 2.71 (1H, d, ³J = 2.56), 3.43 (2H, m), 4.21 (1H, m), 4.53 (2H, s), 4.85 (2H, br), 5.01 (2H, br). ¹³C-NMR (CDCl₃, 75 MHz): d: 7.3 (CH₃), 18.0 (CH₃), 38.6 (CH), 42.1 (CH₂), 73.0 (CH), 73.5 (CH₂), 74.3 (CH₂), 110.6 (CH₂), 112.6 (CH₂), 127.8 (CH), 127.9 (CH), 128.1 (CH), 128.5 (CH), 138.2 (C_o), 147.1(C_o), 149.1 (C_o). IR (film): 3438, 3069, 3028, 2963, 2922, 2858, 1644, 1495, 1453, 1369, 1254, 1204, 1090, 1028, 964, 898, 735, 697 cm^-1.

1-[(2R)-2,3-dimethyl-3-butenyloxymethyl]benzene (36)

To a solution of 0.25 mmol of allylsilane 3 in 2 mL of dry CH₂Cl₂ at -78 °C was added 0.25 mmol of SnCl₄. The resulting solution was stirred at -78 °C for 1 h the reaction was quenched by the slow addition of 0.30 mmol of Et₃N, followed by 5 mL of saturated NaHCO₃ solution. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2x5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (20% EtOAc/hexanes) afforded 40 mg of 36 in 84% yield. [a]²⁰_D = -15.0 (c 1.4, CHCl₃). TLC: Rf: 0.34, hexanes:ethyl acetate 85:15. ¹H-NMR(CDCl₃, 300 MHz), d: 1.07 (3H, d,³J = 6.96), 1.73 (3H, s), 2.52 (1H, m), 3.33 (1H, dd, ²J = 9.15, ³J = 6.96), 3.48 (1H, dd, ²J = 9.15, ³J = 6.59), 4.54 (2H, s), 4.79 (2H, m), 7.36 (5H, m). ¹³C NMR (CDCl₃, 75 MHz): d: 16.6 (CH₃), 20.1 (CH₃), 41.0 (CH), 72.9 (CH₂), 73.9 (CH₂), 110.4 (CH₂), 127.4 (CH), 127.6 (CH), 128.3 (CH), 138.6 (C_o), 147.7(C_o). IR (film): 3066, 3028, 2964, 2854, 1645, 1603, 1495, 1453, 1372, 1248, 1202, 1098, 1028, 1000, 964, 889, 855, 734, 697 cm^-1. MS (70 eV): 41 (15%), 69 (19%), 84 (30%), 91 (100%).

General procedure for the preparation of diols

To a solution of 0.08 mmol of the homoallylic alcohols in 2 mL of dry THF at 0 °C was added 0.24 mL of a 1.0 M solution of TBAF in THF. This mixture was stirred for 1 h at 0 °C and quenched by the addition of a saturated solution of NH₄Cl. The aqueous layer was extracted with 3 x 2 mL of ethyl ether and washed with brine (5 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica-gel (20% EtOAc/Hexanes) afforded the corresponding 1,3-diols:

(2R,3R)-5-[(1R)-2-benzyloxy-1-methylethyl]-2-methyl-5-hexene-1,3-diol (38)

Purification by flash chromatography on silica gel (25% EtOAc/hexanes) afforded 17 mg of diol 38 in 75% yield. TLC: Rf: 0.26, hexanes:ethyl acetate 1:1. ¹H-NMR(CDCl₃, 300 MHz): d: 0.95 (3H, d,³J = 6.96), 1.02 (3H, d, ³J = 6.96), 1.69 (1H, br), 1.87 (1H. m), 2,15 (1H, dd, ²J = 13.8, ³J = 3.38), 2.24 (1H, dd, ²J = 13.8, ³J = 10.0), 2.51 (1H, m), 3.07 (1H, s), 3.41 (1H, dd, ²J = 8.97, ³J = 5.49), 3.48 (1H, t, ³J = 8.97), 3.70 (2H, d , ³J = 5.49), 4.02 (1H, dt, ²J = 10.0, ³J = 3.38), 4.50 (2H, d, ³J = 1.1), 5.00 (2H, d, ³J = 2,2), 7.32 (5H, m). ¹³C-NMR (CDCl₃, 75 MHz): d: 10.5 (CH₃), 17.4 (CH₃), 38.5 (CH), 38.6 (CH), 39.5 (CH₂), 67.1 (CH₂), 72.0 (CH), 73.1 (CH₂), 74.4 (CH₂), 112.9 (CH₂), 128.0 (CH), 128.1 (CH), 128.6 (CH), 137.9 (C_o), 149.2 (C_o). IR (film): 3382, 2926, 1716, 1644, 1602, 1454, 1372, 1276, 1177, 1100, 1073, 1028, 901, 752, 714, 699 cm^-1.

(2S,3R)-5-[(1R)-2-benzyloxy-1-methylethyl]-2-methyl-5-hexene-1,3-diol (40)

Purification by flash chromatography on silica gel (25% EtOAc/hexanes), afforded 19 mg of diol 40 in 70% yield. [a]²⁰_D = -77.0 (c 0.2, CHCl₃). TLC: Rf: 0.26, hexanes:ethyl acetate 1:1. ¹H-NMR(CDCl₃, 300 MHz): d: 0.87 (3H, d,³J = 6.96), 1,01 (3H, d, ³J = 6.96), 1.73 (1H, m), 2.08 (1H, dd, ²J = 13.5, ³J = 10.6), 2.39 (1H, br d, ²J = 13.5), 2.49 (1H, m), 3.48 (4H, m), 3.65 (3H, m), 4.50 (2H, d, ³J = 4.03), 5.00 (2H, s), 7.31 (5H, m). ¹³C-NMR (CDCl₃, 75 MHz): d: 13.7 (CH₃), 17.5 (CH₃), 38.2 (CH), 40.1 (CH), 42.5 (CH₂), 68.3 (CH₂), 73.2 (CH₂), 74.7 (CH), 74.7 (CH₂), 113.2 (CH₂), 128.0 (CH), 128.1 (CH), 128.6 (CH), 137.7 (C_o), 149.1 (C_o). IR (film): 3382, 2926, 1716, 1644, 1602, 1454, 1372, 1276, 1177, 1100, 1073, 1028, 901, 752, 714, 699 cm^-1.

General procedure for p-methoxybenzylidene acetal formation

To a solution of 0.054 mmol of the corresponding diol in 2 mL of CH₂Cl₂ at room temperature was added 0.116 mmol of 4-methoxy-benzaldehyde dimethylacetal, followed by catalytic amounts of camphor sulfonic acid. The mixture was stirred for 3h at room temperature, diluted with 3 mL of CH₂Cl₂ and quenched by the addition of 5 mL of a saturated solution of NaHCO₃. The layers were separated and the aqueous layer was extracted with 3 x 2mL of CH₂Cl₂. The combined organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. An analytical sample was purified by preparative TLC (20% EtOAc/Hexanes) affording the corresponding p-methoxybenzylidene acetals:

(4R,5R)-4-2-[(1R)-2-benzyloxy-1-methylethyl]allyl-2-(4-methoxyphenyl)-5-methyl-1,3-dioxane (39)

[d]²⁰_D = +31.8 (c 0.5, CHCl₃). TLC: Rf: 0.45, hexanes/ethyl acetate 8:2. ¹H-NMR(C₆D₆, 300 MHz): d: 1.10 (3H, s), 1.12 (3H, s), 1.23 (1H, m), 2.05 (1H, dd, ²J = 14.66, ³J = 6.59), 2.44 (1H, dd, ²J = 14.66, ³J = 6.59), 2.53 (1H, q, ³J = 6.40), 3.18 (1H, dd, ²J = 9.06, ³J = 6.40), 3.40 (1H, dd, ²J = 9.06, ³J = 6.40), 3.65 (1H, d, ²J = 11.17), 3.74 (1H, d, ²J = 11.17), 3.88 (1H, t, ³J = 6.59), 4.28 (2H, s), 4.92 (2H, d, ³J = 10.25), 5.34 (2H, s), 6.77 (2H, m), 7.14 (5H, m), 7.59 (2H, m). ¹³C NMR (C₆D₆, 75 MHz): d: 10.9 (CH₃), 16.9 (CH₃), 31.8 (CH), 39.0 (CH₂), 39.7 (CH), 54.4 (CH₃), 72.8 (CH₂), 73.5 (CH₂), 74.9 (CH₂), 78.7 (CH), 101.8 (CH₃), 111.3 (CH₂), 113.6 (CH₃), 127.6 (CH), 127.8 (CH), 128.5 (CH), 132.4 (C_o), 139.4 (C_o), 149.1 (C_o), 160.4 (C_o). IR (film): 3065, 2962, 2916, 2849, 1734, 1642, 1616, 1588, 1518, 1455, 1395, 1358, 1302, 1249, 1172, 1154, 1118, 1035, 1002, 898, 827, 754, 698 cm^-1.

(5S,4R)-4-2-[(1R)-2-benzyloxy-1-methylethyl]allyl-2-(4-methoxyphenyl)-5-methyl-1,3-dioxane (41)

TLC: Rf: 0.45, hexanes/ethyl acetate 8:2. ¹H-NMR(C₆D₆, 300 MHz): d: 0.34 (3H, d,³J = 6.59), 1.17 (3H, d, ³J = 6.96), 1.67 (1H, m), 2.21 (1H, dd, ²J = 15.8, ³J = 8.9), 2.36 (1H, dd, ²J = 15.8, ³J = 2.2), 2.68 (1H, m), 3.14 (1H, t, ³J = 11.35), 3.26 (1H, dd, ²J = 7.69, ³J = 8.97), 3.36 (1H, td, ²J = 8.97, J = 2.2), 3.50 (1H, dd, ²J = 6.59, ³J = 8.97), 3.86 (1H, dd, ²J = 11.35, ³J = 4.76), 4.30 (2H, s), 4.98 (2H, d, ³J = 23.0), 5.31 (2H, s), 6.76 (2H, m), 7.14 (5H, m), 7.60 (2H, m). ¹³C-NMR (C₆D₆, 75 MHz): d: 12.4 (CH₃), 17.1 (CH₃), 33.8 (CH), 38.7 (CH₂), 39.4 (CH), 55.1 (CH₃), 72.8 (CH₂), 72.9 (CH₂), 74.7 (CH₂), 82.5 (CH), 100.7 (CH), 111.4 (CH₂), 113.6 (CH), 127.4 (CH), 127.6 (CH), 127.7 (CH), 128.5 (CH), 131.5 (C_o), 138.9 (C_o), 149.0 (C_o), 160.0 (C_o). IR (film): 3065, 2962, 2916, 2849, 1734, 1642, 1616, 1588, 1518, 1455, 1395, 1358, 1302, 1249, 1172, 1154, 1118, 1035, 1002, 898, 827, 754, 698 cm^-1.

Acknowledgments

We thank FAPESP for financial support and CNPq for a fellowship to Rosana Giacomini. We are grateful to Prof. Roy Edward Bruns from UNICAMP for helpful suggestions about English grammar and style, during the preparation of this manuscript.

References

1.(a) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97, 2063-2192; (b) Nishigaichi, Y.; Takuwa, A.; Naruta, Y.; Maruyama, K. Tetrahedron 1993, 49, 7395-7426.

2.Evans, D.A.; Dart, M.J.; Duffy, J.L.; Yang, M.G. J. Am. Chem. Soc. 1996, 118, 4322-4343.

3.(a) Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199-2204; (b) Anh, N.T.; Eisenstein, O. Nouv. J. Chem. 1977, 1, 61. (c) We use the “Felkin” descriptor to refer to the diastereomer predicted by the Felkin-Ahn paradigm. The “anti-Felkin” descriptor refers to diastereomers not predicted by this transition state model.

4.(a) Trost, B.M.; Urabe, H. J. Org. Chem. 1990, 55, 3982-3983; (b) Nishigaishi, Y.; Takuwa, A.; Jodai, A. Tetrahedron Lett. 1991, 32, 2383-2386.

5.Almendros, P.; Gruttadauria, M.; Helliwell, M.; Thomas, E.J. J. Chem. Soc. Perkin Trans. I 1997, 2549-2560.

6.Dias, L.C.; Giacomini, R. Tetrahedron Lett. 1998, 30, 5343-5346.

7.Demuth, M. Helv. Chim. Acta 1978, 61, 3136-3138.

8.(a) Bunnelle, W.H.; Narayanan, B.A. Tetrahedron Lett. 1987, 28, 6261-6264; (b) Mickelson, T.J.; Koviach, J.L.; Forsyth, C.J. J. Org. Chem. 1996, 61, 9617-9620.

9.Lee, T.V.; Channon, J.A.; Gregg, C.; Porter, J.R.; Roden, F.S.; Yeoh, H.T.L. Tetrahedron 1989, 45, 5877-5886.

10.For the preparation of ester 1, see: Paterson, I.; Norcross, R.D.; Ward, R.A.; Romea, P.; Lister, M.A. J. Am. Chem. Soc. 1994, 116, 11287-11314.

11.Evans, D.A.; Coleman, P.J.; Dias, L.C. Angew. Chem. Int. Ed. Engl. 1997, 36, 2737-2741.

12.Burke, S.D.; Cobb, J.E.; Takeuchi, K. J. Org. Chem. 1990, 55, 2138-2151.

13.Schreiber, S.L.; Shambayati, S.; Blake, J.F.; Wierschke, S.G.; Jorgensen, W.L. J. Am. Chem. Soc. 1990, 112, 697-703.

14.All new compounds were isolated as chromatographically pure materials and exhibited acceptable ¹H-NMR, ¹³C-NMR, IR, MS, and HRMS spectral data.

15.For reviews on remote asymmetric induction using allylstannanes see: a) Thomas, E.J. Chem. Tracts - Organic Chemistry 1994, 207-234; b) Nishigaishi, Y.; Takuwa, A.; Naruta, Y.; Maruyama, K. Tetrahedron 1993, 49, 7395-7426.

16.a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885-888; b) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 889-892.

FAPESP helped in meeting the publication costs of this article

Dedicated to Prof. José Tércio Barbosa Ferreira (in Memoriam) and to the Brazilian Chemical Society (SBQ)

Publication Dates

• Publication in this collection
  30 Oct 2002
• Date of issue
  Aug 1998

History

• Received
  10 Aug 1998