Stereoselective Double Alkylation of the Acetoacetate Ester α-Carbon on a d-Glucose-Derived Template: Application to the Synthesis of Enantiopure Cycloalkenones Bearing an Asymmetric Quaternary Carbon

Abstract

The previously developed d-glucose derivative, i.e., ­methyl 6-deoxy-2,3-di-O-(tert-butyldimethylsilyl)-α-d-glucopyranoside, served as a significant stereocontrolling element for the ­diastereoselective alkylation of the α-carbon in its acetoacetate at C-4 with two types of alkyl halides. The thus obtained doubly ­alkylated acetoacetate moiety bearing both methyl and allyl groups was efficiently converted into functionalized cycloalk-2-en-1-one derivatives by means of an intramolecular aldol strategy. Furthermore, the synthetic utility of the cycloalkenones was exemplified through the 1,4-addition to the thus obtained cyclopentenone ­derivative.

d-glucose derivatives - chiral auxiliary - double alkylation - asymmetric quaternization - intramolecular aldol reactions

References and Notes

1 Totani K. Takao K. Tadano K. Synlett  2004,  2066 

2 Munakata R. Totani K. Takao K. Tadano K. Synlett  2000,  979 

3a Totani K. Asano S. Takao K. Tadano K. Synlett  2001,  1772 

3b Asano S. Tamai T. Totani K. Takao K. Tadano K. Synlett  2003,  2252 

3c

Sasaki, D.; Sawamoto, D.; Takao, K.; Tadano, K.; Okue, M.; Ajito K., Heterocycles, 2007, 72, in press.

4a Nagatsuka T. Yamaguchi S. Totani K. Takao K. Tadano K. Synlett  2001,  481 

4b Nagatsuka T. Yamaguchi S. Totani K. Takao K. Tadano K. J. Carbohydr. Chem.  2001,  20:  519 

4c Tamai T. Asano S. Totani K. Takao K. Tadano K. Synlett  2003,  1865 

Some recent prominent papers on this subject:

5a Trost BM. Pissot-Soldermann C. Chen I. Schroeder GM. J. Am. Chem. Soc.  2004,  126:  4480 

5b Trost BM. Xu J. J. Am. Chem. Soc.  2005,  127:  2846 

5c Mohr JT. Behenna DC. Harned AM. Stoltz BM. Angew. Chem. Int. Ed.  2005,  44:  6924 

Some recent prominent papers on this subject:

6a Bella M. Jørgensen KA. J. Am. Chem. Soc.  2004,  126:  5672 

6b Wilson RM. Jen WS. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  11616 

7 A recent review on this subject: Arya P. Qin H. Tetrahedron  2000,  56:  917 

8

All new compounds were fully characterized by spectral means (¹H NMR and ¹³C NMR, IR, and HRMS). Yields refer to isolated products after purification by column chromatography on silica gel.

9

We examined the following bases for the second benzylation, which was carried out in THF. The yield of 7 using NaHMDS (-78 °C to r.t.), 18%; using LiHMDS
(-18 °C to r.t.), 35%; and using NaH (-78 °C to r.t.), 74%.

10

The yield of the first benzylation (BnBr, EtONa, THF, 0 °C to r.t.) was 97%. The conditions and yields of the second methylation for the two diastereomers, i.e., 7 and its epimer at the α-carbon, were as follows: a) MeI and KHMDS in THF at -18 °C to r.t., 46% and 10%; b) EtONa as the base at -78 °C to r.t., 64% and 16%; c) MeONa as the base at -78 °C to r.t., 63% and 14%. In all cases, the major product was 7.

11a

(4R)-4-Benzyl-3,4-dimethyl-2-pyrazolin-5-one (8): [α]_D ²² -186 (c 1.24, CHCl₃). For the reported [α]_D for 8 [α]_D ¹⁵ -186 (c 1.24, CHCl₃) see ref. 11b. In this paper, the Vallribera group reported the asymmetric construction of a quaternary carbon using d-ribolactone acetonide or its cyclohexanone ketal as a sugar-based chiral template. Their sugar templates also served as good stereocontrolling elements, which provided the doubly α-alkylated (both Me and Bn) acetoacetates installed at C-5 in the sugar templates in 56-69% yield with 80:20 to 75:25 diastereomeric ratios in favor of the respective R-isomer. Thus, the diastereo-selectivities observed in their cases were lower than those in ours with the use of the pyranose-type template 1.

11b Moreno-Mañas M. Trepat E. Sebastián RM. Vallribera A. Tetrahedron: Asymmetry  1999,  10:  4211 

12

We also synthesized the S-antipode of 8 from the minor α-dialkylated acetoacetate obtained by the reverse double alkylation of 5 with the same alkyl halides followed by the analogous pyrazoline formation used for the case of 7. The synthesized S-isomer possessed the following optical rotation: [α]_D ²¹ +180 (c 0.30, CHCl₃).

13a

We synthesized the antipode of 10, i.e., (S)-10, as follows. As a substrate for the pyrazoline formation, enantioenriched ethyl (S)-2-acetyl-2-methyl-4-pentenoate was prepared at first by the α-allylation of racemic ethyl 2-methyl-acetoacetate using l-valine tert-butyl ester as a chirality inducer, according to a known procedure reported by Koga and co-workers, see ref. 13b. The thus obtained α-disubstituted acetoacetate ester was then treated with N₂H₄·H₂O, providing enantioenriched (S)-10. The comparison of the sign and magnitude of the optical rotatory property for (S)-10 {[α]_D ²⁷ +128 (c 0.49, CHCl₃)} with our (R)-10 {[α]_D ²⁶ -123 (c 0.78, CHCl₃)} clearly established the R-configuration for the new stereogenic carbon center in 9.

13b Ando K. Takemasa Y. Tomioka K. Koga K. Tetrahedron  1993,  49:  1579 

14

Compound 12: TLC: R _f = 0.50 (EtOAc-hexane, 1:3); [α]_D ²⁵ +64.1 (c 1.49, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 0.09, 0.10 (2 s, each 6 H), 0.84, 0.91 (2 s, each 9 H), 1.05 (d, 3 H, J = 6.3 Hz), 1.42 (s, 3 H), 2.53, 3.45 (2 ddd, each 1 H, J = 19.2, 2.2, 2.2 Hz), 3.33 (s, 3 H), 3.56-3.64 (m, 1 H), 3.66 (dd, 1 H, J = 8.7, 3.5 Hz), 3.87 (t, 1 H, J = 8.7 Hz), 4.60 (d, 1 H, J = 3.5 Hz), 4.72 (dd, 1 H, J = 9.8, 8.7 Hz), 6.17 (ddd, 1 H, J = 5.6, 2.2, 2.2 Hz), 7.74 (ddd, 1 H, J = 5.6, 2.2, 2.2 Hz). ¹³C NMR (68 MHz, CDCl₃): δ = -4.2 × 2, -3.2, -2.6, 17.5, 17.9, 18.5, 21.9, 26.0 × 3, 26.2 × 3, 42.1, 53.7, 54.8, 65.3, 72.0, 74.6, 78.2, 99.8, 131.5, 163.0, 170.3, 205.8. IR (neat): 2950, 2850, 2750, 2710, 1730, 1715, 1590, 1450, 1360 cm^-1. HRMS (EI): m/z calcd for C₂₂H₃₉O₇Si₂ [M⁺ - t-Bu]: 471.2234; found: 471.2233.

15

(1S,5S)-5-Hydroxymethyl-5-methyl-2-cyclopenten-1-ol (14): TLC: R _f = 0.44 (EtOAc); [α]_D ²³ +65.6 (c 0.14, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.09 (s, 3 H), 1.98 (d, 1 H, J = 17.1 Hz), 2.48 (dd, 1 H, J = 17.1, 2.1 Hz), 3.63, 3.70 (2 d, each 1 H, J = 11.1 Hz), 4.44 (br s, 1 H), 5.74-5.76 (m, 1 H), 5.95-5.97 (m, 1 H). ¹³C NMR (68 MHz, CDCl₃): δ = 24.0, 41.9, 45.2, 68.3, 85.4, 131.6, 134.9. IR (neat): 3250, 3060, 2930, 1730, 1460 cm^-1. HRMS (EI): m/z calcd for C₇H₁₂O₂ [M⁺]: 128.0837; found: 128.0841

16a

(1S,5R)-5-Hydroxymethyl-5-methyl-2-cyclopenten-1-ol, the 5-epimer of 14, is a known compound that was synthesized by Kato and co-workers using a chiral acetal-mediated asymmetric alkylation, see ref. 16b. The ¹H NMR and ¹³C NMR spectra of the 5-epimer were distinctly different from those of 14. Furthermore, the NOE experiment of the 5-epimer revealed a 2.9% signal enhancement for the methylene of the hydroxymethyl group at C-5 when the proton at C-1 (H-1) was irradiated. On the other hand, the irradiation of H-1 in 14 resulted in a 1.3% signal enhancement of the methyl protons at C-5.

16b Kato K. Suzuki H. Tanaka H. Miyasaka T. Baba M. Yamaguchi K. Akita H. Chem. Pharm. Bull.  1999,  47:  1256 

17

We explored the removal of the sugar template from 12 directly by methanolysis (MeONa in MeOH). In this case, compound 12 was quantitatively recovered. The removal of the sugar template from the protected forms of the allylic alcohol 13 as its TBS or MOM ethers was also fruitless. For these ethers, saponification or hydride attack resulted in the recovery of the starting material.

18 Gemal AL. Luche JL. J. Am. Chem. Soc.  1981,  103:  5454 

19

The configuration of newly introduced allylic carbinol carbon in 19 as depicted was confirmed by the NOE experiment in which a significant (7.3%) signal enhancement of the proton at the allylic carbinol carbon was observed when the adjacent methyl group was irradiated.

20

The DIBAL-H reduction of 18 (1.5 equiv, CH₂Cl₂, -78 °C) also provided 19 as a single product in a less effective yield of 63%.

21 The observed dextrorotatory property for 20 {[α]_D ²¹ +138,7 (c 0.355, CHCl₃)} confirmed the absolute stereochemistry of 20. For the reported enantioenriched 20 (94% ee), [α]_D +104.1 (c 0.95, CHCl₃) was reported, see: Mikami K. Motoyama Y. Terada M. J. Am. Chem. Soc.  1994,  116:  2812 

22

In this case, the sugar template 1 was recovered in 19% yield. Under the harsh DIBAL-H reduction of 19, the silyl group at C-2 in 1 was unexpectedly deprotected to a large extent. Thus, the 3-O-TBS derivative was obtained in a significant yield of 75%.

23

We also examined the 1,4-addition using n-Bu₂CuLi under analogous conditions as those used for the Me₂CuLi addition. The 1,4-addition proceeded with complete stereoselectivity to provide a single 1,4-adduct in 75% yield. Unfortunately, we could not establish the configuration at the β-carbon of this adduct unambiguously from ¹H NMR spectral analysis.

24a Sato K. Suzuki S. Kojima Y. J. Org. Chem.  1967,  32:  339 

24b Lee K.-H. Mar E.-C. Okamoto M. Hall IH. J. Med. Chem.  1978,  21:  819 

24c

Practically, we prepared racemic 22 by the Ito-Saegusa oxidation of 2-methyl-2-(carboethoxy)cyclopentanone for the introduction of the C=C bond.