Stereoselective Addition of Chiral Titanium Enolates to 5-Substituted Five-Membered Oxocarbenium Ions

O curso estereoquímico da adição de enolatos de titânio quirais a -lactóis derivados do ácido (S)-glutâmico foi investigado. Quando -lactóis 5-substituídos foram tratados com enolatos de titânio quirais derivados de N-acetil-, N-propionil-, N-bromoacetile N-fenilacetil oxazolidin-2onas somente dois diastereoisômeros foram obtidos, revelando um completo controle facial pelo enolato de titânio, enquanto que a discriminação facial do íon oxocarbênio mostrou-se dependente da natureza do grupo R do enolato. Dessililação com HF/CH 3 CN aquoso, seguida de redução com LiBH 4 , forneceu eficientemente dióis tetraidrofurânicos trans-2,5-dissubstituídos e recuperação do auxiliar quiral.


Introduction
3][4][5][6][7] These substances exhibit a diverse range of biological activities including antitumor, antihelmintic, antimalarial, antimicrobial, and antiprotozoal activities.Due to the importance of these molecules, considerable effort has been devoted toward the development of methods for the stereoselective construction of 2,5-substituted tetrahydrofurans.][14] Recent studies have led to the development of models to explain and predict the stereochemical outcome of nucleophilic additions to oxocarbenium ions.6][17][18] This rationalization was based on the extension of the Felkin-Anh [19][20] model and do not encompass a wide range of substrates, nucleophiles and conditions.
2][23][24][25] The preference for the 'inside attack' from the concave face is believed to result from stereoelectronic effect.This model requires attack of the nucleophile to the face of the oxocarbenium ion that provides the products in their lowest energy staggered conformations.Small nucleophiles add to the 'inside' of the lower energy ground-state conformer of the oxocarbenium ion.In contrast, sterically demanding nucleophiles add to the inside of the envelope conformer where approach is anti to the substituent of the oxocarbenium ion, regardless of the ground-state conformer population.
Although a variety of nucleophiles have been utilized for 2,5-substituted tetrahydrofuran synthesis via addition to cyclic oxocarbenium ions, studies involving the stereoselective addition of chiral and prochiral nucleophiles are scarce. 26uring the course of our study of stereoselective synthesis of 2,5-substituted tetrahydrofurans through nucleophilic addition to five-membered ring oxocarbenium ions, we have reported the stereoselective Lewis acid-promoted allylsilane substitution reaction at the anomeric carbon of -lactol 1a with preparatively useful trans-2,5 selectivity being observed when a more hindered nucleophile was employed (Scheme 1). 27king into account the high facial discrimination displayed by stereochemically defined titanium enolates in aldol reaction 28 and in their addition to cyclic N-acyliminium ions, 29,30 we have previously studied the reactivity of the titanium enolate of chiral oxazolidinones with the chiral oxocarbenium ion derived from 5-substituted--lactol 1a regarding the generation of the stereogenic centers (C-2 and C-2' in Scheme 2). 11In continuation of our work on the synthesis of trans-2,5-disubtituted tetrahydrofurans, we report here full details of the diastereoselective additions of stereochemically defined titanium enolates of chiral oxazolidinones to cyclic oxocarbenium ions together with the dependence of the diastereoselectivity on the substitution pattern of -lactol and the nature of the R 3 group in the enolate.A model which accounts for the observed diastereoselectivity is proposed.
The reaction of lactol 1b with achiral titanium (IV) enolate 10 from oxazolidinone 9 was first examined.The chlorotitanium enolate was generated by the sequential addition of 1.1 equiv. of TiCl 4 and 1.1 equiv. of diisopropylethylamine (DIPEA) to a cold solution (-23 o C) of N-propionyl oxazolidin-2-one 9 in CH 2 Cl 2 , followed by the addition of a CH 2 Cl 2 solution of lactol 1b at -23 o C.Under these conditions the OTES group proved to be labile and we were not able to isolate the coupling products.We then moved to a more robust and bulkier silyl group (OTBS) and the reaction of chlorotitanium enolate 10 and lactol 1c, under the same experimental conditions, afforded a 4:4:1:1 mixture of the four possible adducts (trans-11/trans-12/ cis-11/cis-12, determined by 1 H NMR) in 52% yield Scheme 1. Scheme 2.
The major isomers trans-13 and trans-14 were separated by column chromatography on silica gel and had their configuration determined after conversion to the corresponding diols (TBDPS deprotection and reduction with LiBH 4 ) which were shown to be identical to 15 and 16, respectively (Scheme 5), derived from trans-6 and trans-7 which were synthesized and had their structures established by X-ray diffraction analyses in a preceding work. 11Compounds trans-11 and trans-12 afforded the same diols 15 and 16, obtained previously from trans-13 and trans-14, respectively.
These results confirm complete facial control by the chiral chlorotitanium enolates derived from (R)-4 and (R)-14 as only two out of the four possible diastereoisomers were formed in their reactions with lactol 1d.
][30] Furthermore, upon inspection of the 1 H NMR spectra of the 2,5-disubstituted tetrahydrofurans obtained previously, 11 it became apparent that the vicinal coupling constant 3 J 2,2ẃ as diagnostic of their relative stereochemistry with 3 J 2,2´b eing larger in the syn series (9.0-10.0Hz) than in the anti series (6.0-8.2Hz) which suggests that these compounds exhibit a conformational preference.
The major diastereoisomer syn-17 was separated by column chromatography and the configuration 2'S,2S was tentatively assigned based on the magnitude of the vicinal coupling constant ( 3 J 2,2´= 9.7 Hz) while for the minor isomer anti-17 ( 3 J 2,2´= 7.0 Hz), the configuration 2'S,2R was proposed.The absolute configuration at C-2' was conserved in both of them.On the other hand, the chiral oxocarbenium ions derived from 1a and 1c were less efficient in chiral discrimination as a mixture of the four possible stereoisomers were formed in their reactions with achiral chlorotitanium enolate 10 with the silyloxymethyl group at C-5 steering the preferential trans addition of the nucleophile.
Reduction of some adducts allowed the efficient recovery of the chiral auxiliaries and provided diols 15, 16, 25 and 26 in good yields (Table 2).Having established the nature of the matched pair in the coupling reaction, we investigated the use of the chlorotitanium enolate derived from (R)-20 in the reaction with lactol 1a, which afforded a mixture of the two possible stereoisomers trans-24/cis-24, in a 2:1 ratio, due to the poor facial discrimination of the unsubstituted chlorotitanium enolate (Table 1 -entry 6).However, compound trans-24 can be efficiently obtained when the bromo derivative trans-21 is treated with n-Bu 3 SnH (Scheme 7).
Furthermore, bromo derivative trans-21 is a versatile intermediate for -amino acids synthesis.Reaction of trans-21 with sodium azide in DMF afforded the corresponding azide 27 in 73% yield (Scheme 8) which can be converted directly to the corresponding amine by hydrogenation. 32inally, we examined the reactivity of --insaturated oxocarbenium ion derived from -lactol 1e prepared via reduction of lactone 8e 33 with DIBAL-H at -78 o C (Scheme 9).
The stereochemical outcome of the reactions investigated seems to be ruled by an open transition state with the favored approach of the less hindered face of a Z-configured internally coordinated titanium enolate to the sterically more available Re face of a putative oxocarbenium ion.Either an antiperiplanar or a synclinal approach of the nucleophile to the oxocarbenium ion seems to be available (Scheme 11).
Similar results observed for the addition of titanium enolate derived of achiral oxazolidinone 9 to lactols 1a and 1c revealed that the protecting group is located at a remote position from the electrophilic center and low steric interactions with the nucleophile are expected.The absence of a chiral substituent in the titanium enolate 10 led to no discrimination between the two faces (Scheme 11).
When the titanium enolate derived from (R)-4 was added to lactol 1d, the absence of a substituent at the 5-position of the oxocarbenium ion produced syn-18/anti-18 in good yield and without diastereoselection (1:1).However, when the titanium enolate derived from bromoacetyl oxazolidinone (R)-14 was added to lactol 1d, the adducts syn-17 and anti-17 were obtained in good yield and low diastereoselection (2.3:1).From the body of information described above it emerges that the oxazolidin-2-one moiety is efficiently discriminating its approach to the oxocarbenium ion: in every case, both major and minor isomers displayed the same stereochemistry at the stereogenic center arising from the nucleophile when (R)-4-benzyl oxazolidin-2-one was employed as chiral auxiliary revealing the preferential approach of the less hindered face of the corresponding titanium (IV) enolate.
The preferential formation of syn-17 can be rationalized either through a synclinal (I) or an antiperiplanar (J) approach while K and L approaches seem to be less favored due to the electronically disfavored interaction involving non-bonded electron pairs in the bromine and oxygen atoms of the enolate and the oxygen atom of the oxocarbenium ion (Scheme 12).
Addition of titanium (IV) enolates derived from (R)-4 and (R)-19 to lactol 1a afforded only two diastereoisomers trans-7/cis-7, 8:1 ratio and trans-23/cis-23, 7:1 ratio, respectively.The preferential formation of trans-7 and trans-23 can be rationalized either through a synclinal (M) or an antiperiplanar (N) approach of the titanium enolate Re face to the Re face of the oxocarbenium ion derived from 1a (Scheme 13).While the former arrangement minimizes the steric interaction between the methyl group of the enolate and the methylene groups of the oxocarbenium ion, the later one alleviates steric interaction between the oxazolidinone ring and the oxocarbenium ion.
The formation of the minor isomers cis-7 and cis-23 requires the antiperiplanar approach of titanium enolate Re face to the sterically hindered oxocarbenium ion Si face (O).In this case, the synclinal approach (P) seems to be less favored due not only to steric interactions involving the R 3 group in the enolate and the -CH 2 OTBDPS group of the oxocarbenium ion but also to the electronically disfavored interaction involving non-bonded electron pairs in closely spaced oxygen atoms (Scheme 13).
The high diastereoselection observed in the addition of bromoenolate derived from (R)-14 to lactol 1a (trans-21/ cis-21 10:1) results from severe steric interaction between the bromine atom and the -CH 2 OTBDPS group in the synclinal approach (P, Scheme 13) leading to cis-21, as well as to the repulsive electronic interactions in the antiperiplanar approach involving non-bonded electron pairs of the bromine atom and the oxygen atom of the oxocarbenium ion (O, Scheme 13).
Accordingly, the decrease in the diastereoselection observed for the non-substituted enolate (R)-20 is accounted for based on the lack of a discriminating group at the nucleophilic center of (R)-20 (R 3 =H) and denotes the poor facial selectivity of the oxocarbenium ion.
The low diastereoselections observed in the addition of titanium enolates (S)-4 and (S)-19 to lactol 1a (trans-6/ cis-6 3.5:1 ratio and trans-22/cis-22 5:1 ratio, respectively) can be assigned to non-bonded electron repulsion during the synclinal approach leading to trans-6 and trans-22 (Q, Scheme 14), which is not present both in the antiperiplanar and in the synclinal approaches leading to cis-6 and cis-22 (S and T, Scheme 14).
Finally, the low diastereoselection observed in the reaction of titanium enolate (R)-14 with the --insaturated oxocarbenium ion derived from 1e (3.5:1) can be understood by the planarity of the oxocarbenium ion ring.The -CH 2 OTBDPS group is positioned rather remote from the reaction centre.Thus, a decrease in steric interactions led to the loss of stereoselectivity.

Materials and methods
1 H NMR and 13 C NMR spectra were recorded in CDCl 3 solution 300 and 75 MHz respectively, using a Varian Gemini 2000 spectrometer and at 500 and 125 MHz respectively, using a Varian Inova 500 spectrometer.Chemical shifts are expressed in ppm relative to tetramethylsilane followed by multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, Column chromatography was performed using silicagel (70-230 Mesh), except when stated otherwise, and reactions were monitored by TLC (plates from Macherey-Nagel, Germany).
Tetrahydrofuran was treated with sodium/benzophenone and distilled immediately prior to use.Dichloromethane, triethylamine and diisopropylethylamine were treated with calcium hydride and distilled immediately prior to use.TiCl 4 was distilled prior to use.The remaining reagents employed were purchased from commercial suppliers and used without further purification.The reactions involving anhydrous solvents were carried out under argon atmosphere.
The adduct was deprotected using HF/pyridine.To a solution of adduct (1.15 mmol) in THF (20 mL) in a Nalgene tube was added freshly prepared buffered pyridinium hydrofluoride (19.0 mL) (stock solution prepared from 2.0 g of Aldrich pyridinium hydrofluoride, 4.0 mL of pyridine and 16 mL of THF).After 3 h at room temperature, satd.aq.NaHCO 3 (20 mL) was added.The layers were separated, the aqueous layer was extracted with Et 2 O (3 5 mL), the combined organic layers were washed with brine (7 mL), dried over MgSO 4 and concentrated under reduced pressure.The product was purified by chromatography on silica gel (40% ethyl acetate-hexane) to afford a 10:1 mixture of trans-21:cis-21 (57% yield).The trans-21 isomer was separated by flash chromatography on silica gel (20% ethyl acetate-hexane).

General procedure for the reduction of N-acyloxazolidinones
To a suspension of LiBH 4 (5.0 mmol) in THF (10.0 mL) at 0 o C under argon, was added dropwise a solution of acyloxazolidinone (1.0 mmol) in THF (2.0 mL) and MeOH (4.0 mmol).The cooling bath was removed and the reaction was let to stir 3 h at room temperature.The reaction was then quenched with 1 M aqueous solution of sodium potassium tartarate (5 mL) and stirred until both layers were clear.The mixture was poured into ether and water, the layers were separated and the aqueous phase was extracted with Et 2 O (3 1 mL).The combined organic layers were dried over MgSO 4 and concentrated under reduced pressure.

Conclusion
The addition of chiral titanium (IV) enolates to oxocarbenium ions derived from 5-substituted -lactols occurred with good diastereoselectivity in most cases.These stereoselectivities can be understood by an open transition state with the favored approach of the less hindered face of a Z-configured internally coordinated titanium enolate to the sterically more available face of oxocarbenium ion.The products generated from these substitution reactions provide access to 2,5-transdisubstituted tetrahydrofuran rings with excellent recovery of the chiral auxiliary.The diastereoisomers were readily distinguishable by 1 H NMR spectroscopy as the vicinal coupling constants ( 3 J 2,2' ) for the hydrogens in the newly created stereogenic centers: J = 9.0-10.0Hz and J = 6.0-8.2Hz for syn and anti respectively.This methodology can be applied to synthesize polyoxygenated structures such as those embedded in biologically active natural products.

Table 2 .
Preparation of diols