Angewandte

Synthetic Methods DOI: 10.1002/anie.200503863

Chemie

Asymmetric Sequential Allylic Transfer Reaction for the Synthesis of 2-(1-Stannylvinyl)-1,3-diols: Concise Synthesis of ()-Avenaciolide and ()-Isoavenaciolide**
Chan-Mo Yu,* Jinsuop Youn, and Juyoung Jung
Stereocontrolled consecutive processes can offer advantages over stepwise transformations by increasing chemical efficacy and saving efforts as a result of a simple operation.[1] During the course of our research program aimed at developing new synthetic methods for the stereoselective construction of pyran rings through stepwise allylic transfer reactions,[2] we disclosed our investigations on transition-metal-catalyzed intramolecular allylations mainly between allene and carbonyl functionalities to afford cyclic compounds with high levels of stereoselectivity.[3] With these observations in hand, we became interested in designing a sequential allylic transfer reaction from 1 with two aldehydes to form acyclic 2-(1stannylvinyl)-1,3-diols 2, which contain versatile functional groups (Scheme 1).

Scheme 1. General strategy for the synthesis of 2, and thus natural products 3 and 4, by a sequential approach. L* = chiral ligand.

It was envisaged that the sequential allylic transfer reaction starting from 1 could be realized by a three-step sequence as shown in Scheme 1. To provide direct access to 2, we considered the bis(stannyl) compound A as a crucial intermediate. The transformation involves propargylboration
[*] Prof. Dr. C.-M. Yu, J. Youn, J. Jung Department of Chemistry and Institute of Basic Sciences Sungkyunkwan University Suwon 440-746 (Korea) Fax: (+ 82) 31-290-7075 E-mail: [email protected] [**] Generous financial support from the Korea Science & Engineering Foundation (R01-2005-000-10381-0) and the Center for Molecular Design and Synthesis (CMDS, KOSEF-SRC) at KAIST is gratefully acknowledged. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 1553 1556  2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1553

Communications
with an aldehyde to yield an allenic species, distannation of the allene moiety using a palladium catalyst to form the allylic tin reagent A, and a second allylic transfer reaction with another aldehyde by activation of the existing boronyl group. Thus, the boronyl moiety would play two important rolesas a chiral controller and a Lewis acid promoterto regulate reactivity and stereoselectivity during the reaction sequence. Herein, we report a one-pot sequential transformation for the stereoselective synthesis of 2-(1-stannylvinyl)-1,3-diols with the generation of three contiguous stereogenic centers, and application of this method to the synthesis of ()-avenaciolide and ()-isoavenaciolide in three steps. We began with 5 and 6 for the first allylic transfer, as developed by Corey et al.,[4] to give easy access to 7 with excellent enantioselectivity (Scheme 2). Initial attempts of a at 40 8C. After cooling to 78 8C, benzaldehyde (1 equiv) was added. Aqueous workup and silica gel chromatography afforded 9 a as a single stereoisomer in 77 % isolated yield. Note that although an excess of propargylborane 6 (1.3 equiv) was used, the formation of allenyl carbinol resulting from its reaction with benzaldehyde was not observed. A control experiment clearly revealed that the propargylborane 6 was poisoned during the distannation process presumably by the formation of 2,3-distannylallylborane, which does not react with benzaldehyde at 78 8C. With the notion that this approach might lead to a general and efficient method, we set out to determine the scope of the reaction (Table 1). Indeed, the method is successful with a
Table 1: Scope of the sequential allylic transfer reaction of 5 and (R,R)6.[a]

Entry 1 2 3 4 5 6 7 8 9 10 11

R1 PhCH2CH2 Ph PhCH2CH2 PhCH2CH2 C5H11 Me2CHCH2 PhCH2CH2 PhCH2CH2 PhCH2CH2 Me2CH PhCH2CH2

R2 Ph PhCH2CH2 PhCH2CH2 C5H11 Ph C5H11 Me2CHCH2 4-BrPh C3H7CH=CH C5H11 Me2CH

9 a b c d e f g h i j k

Yield [%][b] 77 68 78 81 73 68 71 72 63 66 74

Scheme 2. Preliminary investigations of the asymmetric sequential allylic transfer reaction. Ts = p-toluenesulfonyl.

distannation reaction of 7 (R1 = PhCH2CH2) with Bu3SnSnBu3 in the presence of a palladium complex followed by addition to benzaldehyde to give 9 a were unsuccessful under various reaction conditions, presumably owing to a lack of reactivity caused by the steric bulkiness of the tributylstannyl group.[5] We subsequently observed that the use of Me3SnSnMe3 in the presence of [(p-allyl)2Pd2Cl2], which was previously utilized for the cyclization of allene-aldehydes,[3a] could also be employed for this purpose. Upon surveying numerous conditions, the following observations emerged: 1) for the first allylic transfer, the use of 1.3 equivalents of 5 and 6 was optimum to prevent subsequent addition of the same aldehyde; 2) for the distannation reaction, the use of 3 mol % of [(p-allyl)2Pd2Cl2] in CH2Cl2 at 40 8C for 4 h was most efficient in terms of reaction yields; 3) the formation of 8 was confirmed by NMR spectroscopy after quenching with pH 7 buffer solution; 4) only Me3SnSnMe3 proved to be effective for the transformation; and 5) the use of CH2Cl2 resulted in optimum chemical yields in comparison to other solvents. Under optimal conditions, the reaction was conducted by dropwise addition of 5 (1.3 equiv) to (R,R)-6 (1.3 equiv) at 10 8C in CH2Cl2. After 11 h at 10 8C the reaction mixture was cooled to 78 8C, and PhCH2CH2CHO (1 equiv) was added during 2 h. To the resulting mixture was then added Me3SnSnMe3 (1.3 equiv) followed by [(p-allyl)2Pd2Cl2] (3 mol %), and the reaction mixture was maintained for 4 h

[a] Reactions were run in CH2Cl2. Reagents and conditions: a) 10 8C, 11 h; b) 78 8C, 2 h; c) Me3SnSnMe3 (1.3 equiv), [(p-allyl)2Pd2Cl2] (3 mol %), 40 8C, 4 h; d) 78 8C, 4 h. [b] Refers to yield after purification.

variety of aldehydes to yield the 2-(1-stannylvinyl)-1,3-diols 9 in good yields. It is important to note that the reaction produced no, or only detectable amounts (less than 1 %), of minor stereoisomers according to analysis by 1H NMR spectroscopy and HPLC with chiral column (Chiralcel ODH or OD-RH) in comparison with authentic samples prepared from (S,S)-6. The stereochemical outcome for the transformations can be explained by the analysis of stereochemical models as depicted in Scheme 3.[6] There are two possibilities governing the stereocontrol of the second allylic transfer reaction. First, the remote stereogenic center attached to R1 was envisioned to impact stereoselectivity during the allylic transfer through the favored model 8 C for 11. However, the results obtained (Table 1, entries 13) did not support this claim: the stereochemical relationship between 9 a and 9 b turned out to be diastereomeric rather than enantiomeric, and 9 c is an optically active species. Therefore, the preference for the absolute and relative configurations for adducts from (R,R)-8 with aldehydes could be explained on the basis of the geometrical preference of the chairlike stereochemical model 8 A (Scheme 3). The stereoselectivity for both the
Angew. Chem. Int. Ed. 2006, 45, 1553 1556

1554

www.angewandte.org

 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angewandte

Chemie

Scheme 3. Stereochemical routes. Scheme 4. Synthesis of ()-avenaciolide (3) and ()-isoavenaciolide (4): a) NIS, 78 8C, 2 h, CH2Cl2 ; b) [Pd(PPh3)4] (2 mol %), CO (100 atm), K2CO3, CH3CN, 70 8C, 1 h; c) NIS, 78 8C, 1 h, CH2Cl2, then CF3CO2H (10 mol %), 2 h. NIS = N-iodosuccinimide.

first and second allylic transfer reactions must be controlled by the chiral ligand. The exceptional stereoselectivity can also be explained by assuming that a tight coordination of the aldehyde to the boronyl moiety must be required for the formation of the new CC bond, such that the overlap between the carbonyl group and the double bond leads to optimum stereoelectronic effects and minimum steric repulsions. In light of the above results for the stereospecific sequential allylic transfer reaction, we next turned our attention to the application of this approach to the synthesis of the natural products ()-avenaciolide (3) and ()-isoavenaciolide (4 ; Scheme 1), which exhibit antifungal activities.[7] Interestingly, the diastereomer 10 can be obtained simply by changing the addition sequence of the aldehydes as illustrated in Scheme 3. Thus, we envisaged that the enantioselective synthesis of 3 and 4 could be realized by the sequential addition of aldehydes and appropriate selection of the chiral bromoborane 6 to obtain the correct absolute configurations. Even though the COH stereogenic center in 13 is not matched with that in 3, we predicted that it could be epimerized to the desired product owing to the greater thermodynamic stability of a cis-fused bicyclic ring relative to the trans isomer. We undertook the synthesis of 3 from the allenylstannane 5 and (S,S)-6 as shown in Scheme 4. Lactone 13 was cleanly obtained under standard conditions in 75 % yield through the sequential allylic transfer reaction. Conversion of 13 into 14 was achieved in 88 % yield by using NIS.[8] Surprisingly, our attempts to convert 14 into 3 under a CO atmosphere using palladium catalysis according to standard procedures[9] were not efficient in terms of the desired epimerization from 15 to
Angew. Chem. Int. Ed. 2006, 45, 1553 1556

3. For example, treatment of 14 with CO (10 atm) in the presence of [Pd(PPh3)4] (2 mol %) and Et3N in CH3CN at 50 8C for 5 h afforded 3 and 15 in a ratio of 2:1 (71 %). Longer reaction times resulted in decomposition of the products. Fortunately, we found that modified Stille conditions were effective for our purpose.[10] Thus, treatment of 14 under an atmosphere of CO (100 atm) in the presence of [Pd(PPh3)4] (2 mol %) and K2CO3 in CH3CN at 70 8C for 1 h afforded ()avenaciolide (3, 67 %) along with 15 in a ratio of 95:5 as judged by 1H NMR spectra of the crude mixture. We then turned our attention to the synthesis of ()isoavenaciolide (4). Compound 16 was obtained in moderate (54 %) yield, probably because intramolecular chelation of the boronyl group with the ester in 8 resulted in diminished reactivity with nonanal (12 h at 78 8C; Scheme 4). Treatment of 16 with NIS to obtain the corresponding vinyl iodide 17 afforded a 1:1 mixture of 17 and the lactone 18. However, after complete consumption of 16 in its reaction with NIS at 78 8C for 1 h, addition of CF3CO2H (10 mol %) at 78 8C resulted in the formation of 18 in 77 % yield. A modified Stille reaction of 18 completed the synthesis of 4. In summary, we have described a sequential allylic transfer reaction for the synthesis of enantiomerically enriched 2-(1-stannylvinyl)-1,3-diols which provides three contiguous stereogenic centers through a four-component assembly. The approach is efficient and promises to be synthetically useful, as demonstrated here with the concise syntheses of ()-avenaciolide and ()-isoavenaciolide. www.angewandte.org

 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1555

Communications
Experimental Section
General procedurepreparation of 9 a from (R,R)-6 : A flame-dried 20-mL Schlenk flask containing (+)-(1R,2R)-1,2-diphenyl-1,2-bis-ptoluenesulfonylamide (0.50 g, 0.96 mmol) was charged with dry CH2Cl2 (7 mL), and the resulting mixture was cooled to 0 8C and treated with BBr3 (1.1 mL of a freshly prepared 1m solution in CH2Cl2, 1.1 mmol). The solution was stirred at 0 8C for 1 h, warmed to 20 8C and maintained at this temperature for 5 h, and then concentrated under vacuum (1 mm Hg). Dryness of the vacuum line was maintained with a drying tube containing anhydrous CaSO4 and two traps (one containing NaOH pellets, and the other a cold trap at 78 8C). Freshly distilled CH2Cl2 (5 mL) was added and evaporated under vacuum as above. Freshly distilled CH2Cl2 (4 mL) was again added to the residue, and the homogeneous solution of (R,R)-6 was cooled to 10 8C and treated dropwise with 1,2-propadienyl-tributylstannane (5, 0.33 g, 1.00 mmol) in CH2Cl2 (1 mL). The reaction mixture was maintained at 10 8C overnight (ca. 11 h) and then cooled to 78 8C. A solution of hydrocinnamaldehyde (purified and distilled, 100 mg, 0.74 mmol) in CH2Cl2 (1 mL) was added over 10 min to the cooled reaction mixture along the wall of the flask while keeping the temperature below 78 8C. The mixture was then stirred for 2 h, then hexamethyldistannane (0.21 mL, 0.33 g, 1.01 mmol) in CH2Cl2 (0.5 mL) was added followed by [(p-allyl)2Pd2Cl2] (8.3 mg, 0.022 mmol) in CH2Cl2 (0.5 mL). The mixture was then allowed to warm to 40 8C and was stirred for 4 h. The resulting solution of 8 was cooled to 78 8C, and a solution of benzaldehyde (0.08 mL, 83.6 mg, 0.78 mmol) in CH2Cl2 (1 mL) was added dropwise to the flask. The reaction was allowed to proceed for 4 h at 78 8C and then quenched by addition of aqueous buffer solution (pH 7, 10 mL) followed by CH2Cl2 (ca. 10 mL) to dissolve the white bis(sulfonamide) precipitate. The aqueous layer was extracted with CH2Cl2 (ca. 10 mL 2), and the combined organic extracts were washed with saturated solutions of NaHCO3 (1 ) and NaCl (1 ), dried over anhydrous Na2SO4, and filtered. The solvents were evaporated, and the residue was taken up in diethyl ether (ca. 30 mL). The solution was cooled to 0 8C for 20 min to complete the precipitation of (+)-(1R,2R)-1,2-diphenyl-1,2-bis-p-toluenesulfonylamide, which was then removed by filtration through a sintered glass funnel. The filtrate was washed with cold 20 % KF solution (1 ) and saturated aqueous NaHCO3 solution (1 ). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. Final purification was effected by SiO2 chromatography (4:1 hexanes/EtOAc) to afford pure 9 a as a colorless oil (0.255 g, 0.57 mmol, 77 %). Received: November 1, 2005 Revised: November 29, 2005 [3] a) C.-M. Yu, J. Youn, M.-K. Lee, Org. Lett. 2005, 7, 3733 3736; b) C.-M. Yu, J. Youn, S.-K. Yoon, Y.-T. Hong, Org. Lett. 2005, 7, 4507 4510; c) C.-M. Yu, Y.-T. Hong, J. Lee, J. Org. Chem. 2004, 69, 8506 8509; d) S. Kang, Y.-T. Hong, J.-H. Lee, W.-Y. Kim, I. Lee, C.-M. Yu, Org. Lett. 2003, 5, 2813 2816. [4] a) E. J. Corey, C.-M. Yu, D.-H. Lee, J. Am. Chem. Soc. 1990, 112, 878 879; b) E. J. Corey, C.-M. Yu, S. S. Kim, J. Am. Chem. Soc. 1989, 111, 5495 5496. [5] For reviews, see: a) T. N. Mitchell, Synthesis 1992, 803 815; b) R. Zimmer, C. U. Dinesh, E. Nandann, F. A. Khan, Chem. Rev. 2000, 100, 3067 3125; c) T. Mandai, in Modern Allene Chemistry, Vol. 2 (Eds.: N. Krause, A. S. K. Hashmi), WileyVCH, Weinheim, 2004, pp. 925 972. [6] For discussions on the mechanism of allylations, see: a) M. Santelli, J.-M. Pons, Lewis Acids and Selectivity in Organic Synthesis, CRC Press, Boca Raton, 1996, pp. 91 184; b) S. E. Denmark, N. G. Almstead in Modern Carbonyl Chemistry (Ed.: J. Otera), Wiley-VCH, Weinheim, 2000, pp. 299 401; c) S. R. Chemler, W. R. Roush in Modern Carbonyl Chemistry (Ed.: J. Otera), Wiley-VCH, Weinheim, 2000, pp. 403 490; d) J. A. Marshall, Chem. Rev. 2000, 100, 3163 3185. [7] a) V. K. Aggarwal, P. W. Davies, A. T. Schmidt, Chem. Commun. 2004, 1232 1233; b) E. Alcazar, M. Kassou, I. Metheu, S. Castillon, Eur. J. Org. Chem. 2000, 2285 2289; c) M.-J. Chen, K. Narkuran, R.-S. Liu, J. Org. Chem. 1999, 64, 8311 8318; d) V. S. Martin, C. M. Rodriguez, T. Martin, Org. Prep. Proced. Int. 1998, 30, 291 323, and references therein. [8] a) R. A. Britton, E. Piers, B. O. Patrick, J. Org. Chem. 2004, 69, 3068 3075; b) R. S. Paley, A. De Dios, L. A. Estroff, J. A. Lafontaine, C. Montero, D. J. McCulley, M. B. Rubio, M. P. Ventura, H. L. Weers, R. F. de la Pradilla, S. Castro, R. Dorado, M. Morente, J. Org. Chem. 1997, 62, 6326 6343. [9] V. Farina, M. Eriksson in Handbook of Organopalladium Chemistry for Organic Synthesis, Vol. II (Eds.: E. Negishi, A. de Meijere), Wiley-Interscience, New York, 2002, pp. 2351 2355. [10] L. D. Martin, J. K. Stille, J. Org. Chem. 1982, 47, 3630 3633.

Keywords: asymmetric synthesis boranes natural products synthetic methods tin

[1] For recent examples, see: a) E. Flamme, W. R. Roush, J. Am. Chem. Soc. 2002, 124, 13 644 13 645; b) X. Wang, Q. Meng, A. J. Nation, J. L. Leighton, J. Am. Chem. Soc. 2002, 124, 10 672 10 673; c) M. Nakamura, T. Hatekeyama, K. Hara, H. Hukudome, E. Nakamura, J. Am. Chem. Soc. 2004, 126, 14 344 14 345; d) N. H. Halland, P. S. Aburel, K. A. Jorgensen, Angew. Chem. 2004, 116, 1292 1297; Angew. Chem. Int. Ed. 2004, 43, 1272 1277, and references therein. [2] a) C.-M. Yu, J.-Y. Lee, B. So, J. Hong, Angew. Chem. 2002, 114, 169 171; Angew. Chem. Int. Ed. 2002, 41, 161 163; b) C.-M. Yu, J.-M. Kim, M.-S. Shin, M.-O. Yoon, Chem. Commun. 2003, 1744 1745.

1556

www.angewandte.org

 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2006, 45, 1553 1556