The Stereochemistry of the Nozaki-Hiyama-Kishi Reaction and the Construction of 10-Membered Lactones . The Enantioselective Total Synthesis of (-)-Decarestrictine D .

O uso da reação de Nozaki-Hiyama-Kishi para a formação de lactonas de 10 membros é descrita. A influência dos grupos de proteção em C4 e C5 sobre a estereoquímica do novo centro estereogênico formado em C7 foi investigada. A utilidade desta metodologia ficou demonstrada com a síntese total e estereosseletiva da (-)-decarestrictina D a partir do 1,3-propanodiol e poliidroxibutirato (PHB) em 13 etapas e 6,3% de rendimento total.


Introduction
Decarestrictine D (1) is a 10-membered lactone isolated from Penicillium corylophilum, simplicissimum 1a-c and independently from the Canadian Tuckahoe fungi Polyporus tuberaster 1d and named as tuckolide.A general panel of whole cell screening demonstrated that decarestrictine D inhibits cholesterol biosynthesis in HEP-G2 liver cells and this beneficial effect was corroborated by in vivo studies with normolipidemic rats.In addition, it appears that decarestrictine D is highly selective in that it exhibits no significant antibacterial, antifungal, antiprotozoal, or antiviral activity.However, recent studies 2 revealed DNA-binding activity for decarestrictine D and the corresponding bisglycosylated derivatives, disclosing new avenues of opportunities in structure-activity relationship.Such significant biological properties exhibited by decarestrictine D contributed much to the interest in devising synthetic approaches to this family of natural products.
While the relative stereochemistry was provided by Xray analysis 1b , its absolute configuration has been recently established by total synthesis 3 and X-ray analysis of a chiral derivative 2 .Other members of the 10-membered lactone family 4 include decarestrictines A (2) and B (3), phoracantholide I (4) 5 and pyrenolide A (5) 6 .
The synthetic approach to lactones has traditionally focused mainly on the use of fragmentation/ring expansion reactions and on lactonization strategies in order to build the lactone ring 7 .Recently, examples of the construction of lactones through the formation of C-C bond appeared 8 and the intramolecular Nozaki-Hiyama-Kishi (NHK) coupling reaction 9 stands as a promising protocol 10 .Moreover, the factors controlling the stereochemical outcome of the C-C bond forming step are unknown which prompted us to investigate how the conformational bias in the acyclic precursor influences the stereochemical course of the reaction.
According to our synthetic plan, the construction of the decanolide ring would arise from the formation of the C6-C7 bond.The stereogenic centers at C3 and C4 could conceivably come from the chiral pool by de novo contruction through asymmetric methodology such as Sharpless asymmetric dihydroxylation (Scheme 1).The C7-C10 fragment 8 was planned to be prepared from natural biopolymer polyhydroxybutyrate 11 (PHB, 11) while the C1-C6 fragment 7 could be obtained either from tartaric acid 9 (path A) or through Sharpless asymmetric dihydroxylation 12 (path B).The choice of fragment 7 poses the additional opportunity to investigate the influence of the protecting groups at C3 and C4 (cyclic or acyclic) on the stereochemical outcome of the Nozaki-Hiyama-Kishi cyclization.The different local conformations that might be enforced by the protecting groups at C3 and C4 were expected to impart changes on the geometry of the transition state as proposed by Kishi 13 and Schreiber 14 .
At this stage we faced the preparation of the corresponding vinylic iodides from alcohol 14 and/or ester 20 and the Takai protocol was elected as our first choice 17 .This method employs the addition of organochromium species to an aldehyde and for that purpose alcohol 14 was oxidized to aldehyde 21 under Swern conditions (Scheme 4).When aldehyde 21 was treated with iodoform (2.0 equiv.)and CrCl 2 (6.0 equiv.) at 0 o C iodide 22 was isolated in low yield (23%, 2 steps) as a 3:1 mixture of the E and Z isomers, as determined by 1 H NMR analyses 18 , while no reaction was observed when a mixture of 1,4-dioxane-THF (6:1) was employed 19 .
In another attempt, ester (-)-20 was reduced with DIBAL-H to aldehyde 23 (Scheme 5) 20 which was treated under the conditions mentioned above for aldehyde 21 but even after a large reaction time, iodide 24 was obtained in low yield (12% overall and 24% yield based on recovered aldehyde) but fortunately a single stereoisomer was formed 21 .In summary, due to the low selectivity observed in the olefination of aldehyde 21 and the need of homologation imposed by route A we decided to concentrate our efforts on route B.
Upon changing the amounts of CrCl 2 (12 equiv.)and iodoform (4 equiv.),iodide 24 was obtained in 53% yield when the reaction was carried out at 55 o C (Table 1).
The reason for the high diastereoselectivity in the Takai olefination of aldehyde 23 is not totally clear at this point but it can be rationalized through the intervention of the geminal organochromium species 25, as proposed by Hodgson 22 .The addition of this species to the aldehyde would be followed by syn elimination.The preferential formation of olefin E-28 would arise from the relief of steric interactions between the R group in 23 and the iodine atom upon changing conformation 27a to 27b.The corresponding Z olefin would be less favoured due to the expected higher steric energy associated to conformer 27a which displays staggered R group and iodine (Scheme 6).The presence of bulky TBS groups in the aldehyde would not only enforce conformation 27b but could conceivably slow down the reaction 23 .
With the preparation of the key intermediate 24 secured, we focused on its conversion to carboxylic acid 7.The primary OTBS group was removed with HF.pyridine to afford the primary alcohol in 64% yield which was converted to the corresponding carboxylic acid with Jones reagent (79% yield) 24,25 .Considering that partial deprotection of the OTBS group in 24 was observed during column chromatography on silica gel and the report by Evans e coworkers 26 on the one-pot primary OTBS deprotection-Jones oxidation sequence, we decided to carry out the oxidation step directly from crude iodide 24.Ester (-)-20 was reduced to aldehyde 23 and homologated under the condition developed by Takai 17 .Crude iodide was taken up in acetone and treated with Jones reagent at 0 o C to yield carboxylic acid (-)-7, in 53% overall yield (3 steps, Scheme 7).Scheme 6. Mechanistic rationale for the stereoselective formation of (E)-vinylic iodide 28.a) (i) DIBAL-H (2.5 eq), toluene, -95 °C, 1h; (ii) CrCl 2 (12 eq.), THF, 55 °C; (iii) Jones reagent, acetone, 0 °C (3 steps, 53% overall yield).The C7-C10 fragment 8 The preparation of this moiety began with the reduction of PHB (11) with LiAlH 4 27 to afford diol (-)-29, in 85% yield.Selective silylation of the primary hydroxyl group afforded (+)-8, in 83% yield.The enantiomeric excess of this intermediate was determined to be >99% ee by GC analysis with chiral column 16 (Scheme 8).

Coupling of the C1-C6 and C7-C10 fragments
Our expectation to control the stereogenic center to be created at C7 was based on the interplay of transannular interactions, known to be proeminent in medium-size rings 28 , and on the proposal by Overman and coworkers of a well organized arrangement in the transition state of the Nozaki-Hiyama-Kishi reaction.During the synthesis of (-)-7-deacetoxyalcionine 29 , Overman and coworkers proposed the chelation of the vinylic chromium species to the carbonyl of the aldehyde to explain the outstanding diastereoselectivity observed in the formation of the 9membered ring (>20:1).Carbonyl facial selection would then be dictated by a preferential endo positioning of the hydrogen in the formyl group of the aldehyde to minimize transannular interactions.
As applied to our case, the ideas above allow one to expect that: i) the methyl group at C9 would adopt a pseudo-equatorial orientation in the transition state thus determining the relative position of the C9-C7 moiety and influencing carbonyl facial selection; ii) the judicious choice of the protecting group at the oxygens atoms at C3 and C4 could dictate the relative positioning of the C5-C6 and C2-O-C7 fragments (Figure 1): OTBS protecting groups which are bound to adopt anti relative orientation would enforce gauche orientation (conformation A) while isopropylideneacetal as protecting group would keep the side chains apart (conformation B).
In order to test our working hypothesis, alcohol (-)-35 was prepared from (-)-30: removal of the primary OTBS group afforded unstable alcohol 31 which was immediately protected as the PMB ether to afford (-)-32 in 74% overall yield (two steps) 31 .The secondary hydroxyl groups at C3 e C4 were removed with a large excess of HF.pyridine complex and the unstable diol 33 was immediately protected as the corresponding isopropylidene acetal with dimethoxypropane and catalytic PPTS in DMF to afford (-)-34 in 85% overall yield (two steps) 32 .Oxidative cleavage of the PMB ether 33 provided alcohol (-)-35, in 70% yield.Surprisingly, alcohol (-)-35 turned out to be rather stable as compared to alcohol 31 as no sign of transesterification was detected by 1 H-NMR even after monitoring the same sample in CDCl 3 for 7 days.Such behaviour was assigned to conformational changes upon changing from a sterically demanding protecting group (OTBS) to a conformationally constrained one (isopropylidene acetal).

The macrolactonization step: stereoselective Nozaki-Hiyama-Kishi cyclization (NHK)
At this point we were ready to apply the intramolecular NHK reaction to the aldehydes derived from conformationally biased alcohols 31 and 35.Due to the labile nature of alcohol 31, a method was sought to oxidize it as soon as it was liberated from (-)-30: our first choice was the use of Swern conditions [i) (COCl) 2 , DMSO, CH 2 Cl 2, -78 o C; ii) Et 3 N, rt] which led mainly to carboxylic acid (-)-7 through base-promoted elimination, probably at the aldehyde stage.We were then forced to try Dess-Martin periodinane 34 which only circumvented the formation of (-)-7 and efficiently provided aldehyde 36 when the modified conditions described by Meyer and Schreiber 34c were employed (Scheme 10).
Scheme 10.The Nozaki-Hiyama-Kishi coupling and the formation of decanoides protocol required the use of 15 equiv. of CrCl 2 in degassed DMF at room temperature which afforded decanolide (-)-38a as a single isomer in 30% overall yield (3 steps) from ester (-)-30.Attempts to improve the yield without decrease of the diastereoselectivity were not successfull as the use of DMSO as solvent afforded similar overall yield (35%) but a 2:1 mixture of (-)-38a and 38b (C-7 epimer), as determined by 1 H NMR of the crude mixture.Modification in the workup of the reaction (use of triethanolamine or ethylenediamine to complex chromium salts) or the use of modified conditions for the chromium-mediated Reformatzky reation 35 were not successfull.The above reaction condition was applied to alcohol (-)-35 and decanolides 39a and 39b were isolated in 41% yield (two steps) as a 1:2 mixture ( 1 H NMR).
At this point we were not able to carry out an unambiguous assignement of (-)-38a but its 1 H-NMR data suggested the 7S configuration: H-7 appeared as a triple doublet at d 4.21 with two large coupling constants (10.8 and 8.4 Hz) and a small one (3.4Hz).The two large coupling constants were assigned to its trans orientation to H-6 and H-8 ax in chair-chair-chair conformation of (-)-38a while the small one was due to H-8 eq .Such assignment was supported by some nOe experiments: a 4.3% increment at H-7 was observerd upon irradiation of H-9 (d 5.08) In the spectra of the isopropylidene derivatives 39a and 39b, H-7 appeared as a multiplet and the information on the relative configuration of this stereogenic center had to be retrieved from the data of H-8 and H-6: in the major diastereoisomer 39b, H-8ax appeared as a triple doublet at d 1.87 with two large ( 2 J 14.9 and 3 J(H8 ax -H7) 7.3 Hz) and a small one ( 3 J(H8 ax -H9 eq ) 3.7 Hz) while H-6 displayed a double doublet at d 5.69 with two large coupling constants in 39b ( 3 J 16.4 and 7.3 Hz) and appeared as a multiplet in minor 39a.Additionally, isomers 39a and 39b could not be separated by chromatography on silicagel and only circunstancial evidence on the sterochemical assignement at C-7 could be provided at this stage for 39a and 39b.
The final proof of the 7S configuration of (-)-38a came from its conversion to (-)-decarestrictine D (1).Tetrabutylammonium fluoride (TBAF) and acetic acid in THF 36 led to recovery of (-)-38a even after 24 h at room temperature while the use of hydrofluoric acid in acetonitrile-water mixture led to extensive decomposition.We reasoned that the acid lability of 1 would call for a buffered medium.We turned our attention to the HF.pyridine complex which provided 1 but only in 10% yield after 24 h at room temperature with recovery of (-)-38a and, finally, to a mixture of TBAF-HF in acetonitrile-water which successfully provided 1 in 83% yield, after 2.5 h at room temperature (Scheme 11).
In conclusion, the total synthesis of 1 was achieved in 13 steps and 6.3 % overall yield from 1,3-propanediol and provided the opportunity to uncover the effect of local conformations on the stereochemical outcome of the Nozaki-Hiyama-Kishi intramolecular cyclization as applied to the formation of 10-membered lactones.Further studies are underway in order to collect more data on such effects.

(3S,4S,5E)-3,4-bis-(tert-Butyldimethylsilyloxy)-6-iodo-5hexenoic acid (7)
To a solution of ester (-)-20 (0.582 g, 1.12 mmol) in toluene (2.3 cm 3 ) at -95 o C (liquid N 2 /hexane bath) was added dropwise a 1.0 mol L -1 DIBAL-H soln. in hexane (2.3 cm 3 , 2.3 mmol).The reaction mixture was stirred for 1 h at -95 o C , quenched with ethyl acetate (3.96 cm 3 ), followed by addition of a saturated solution of sodium and potassium tartrate (4.0 cm 3 ).The reaction mixture was allowed to warm to room temperature and stirred 2 h at this temperature.Addition of Et 2 O (10 cm 3 ) was followed by phase separation.The aqueous phase was further extracted with Et 2 O (4 x 5 cm 3 ), the combined organic layers were concentrated under reduced pressure, and the residue was filtered through Celite.Evaporation under reduced pressure afforded crude aldehyde 23 which was used in the next step without further purification.
To a suspension of CrCl 2 (1.62 g, 13.2 mmol) in THF (36 cm 3 ) were added via cannula a solution of iodoform (1.76 g, 4.47 mmol) and crude aldehyde 23 in THF (12 cm 3 ).The reaction mixture was stirred and warmed at 55-60 o C for 48 h.The reaction was quenched with brine (60 cm 3 ), and diluted with Et 2 O (60 cm 3 ).The organic layer was separated, and the aqueous one was extracted with Et 2 O until all iodoform has been extracted.The combined organic layers were washed with a 1 mol L -1 Na 2 S 2 O 3 (30 cm 3 ), brine (30 cm 3 ), and dried over MgSO 4 .Evaporation under reduced pressure afforded crude iodide 24 which was used in the next step without further purification.
A stirred ice-cold acetone solution (43 cm 3 ) of crude iodide 24 was treated dropwise with 8 mol L -1 Jones reagent.The excess of the Jones reagent was quenched by the addition of 2-propanol and the mixture was allowed to reach room temperature.The clear greenish solution was decanted and the remaining chromium salts were extracted with Et 2 O (4 x 10 cm 3 ).The combined extracts were washed with brine (20 cm 3 ) and dried over MgSO 4 .The solvents were removed in vacuum and the remaining crude product was purified by column chromatography (EtOAc:hexane 10:90, v/v) to give carboxilic acid (-)-7 (0.299 g, 53% overall) as a viscous oil.
To a suspension of Dess Martin periodinane (0.176 g, 0.42 mmol) in CH 2 Cl 2 (1.83 cm 3 ) containing water (0.008 cm 3 ) was added a solution of the alcohol above in CH 2 Cl 2 (0.50 cm 3 ).The reaction mixture was stirred 1 h, and it was diluted with EtOAc (12 cm 3 ).After the addition of saturated NaHCO 3 (12 cm 3 ), the organic layer was separated and aqueous layer was extracted with EtOAc (2 x 5 cm 3 ).The combined organic layer was washed with aqueous 1mo L -1 NaHSO 3 (10 cm 3 ), brine (10 cm 3 ) and dried over MgSO 4 .Concentration produced the crude aldehyde 6 that was used in next step without further purification.

Figure 1 .
Figure 1.Conformational bias imposed by the protecting groups.