Synlett 2004(11): 1891-1896  
DOI: 10.1055/s-2004-831296
LETTER
© Georg Thieme Verlag Stuttgart · New York

Proline-Catalyzed Ketone-Aldehyde Aldol Reactions are Accelerated by Water

Annika I. Nyberg, Annina Usano, Petri M. Pihko*
Laboratory of Organic Chemistry, Helsinki University of Technology, P.O.Box. 6100, FI-02015 HUT, Finland
Fax: +358(9)4512538; e-Mail: Petri.Pihko@hut.fi;
Further Information

Publication History

Received 8 April 2004
Publication Date:
06 August 2004 (online)

Abstract

Proline-catalyzed aldol reactions between acetone or 4-thianone and different aldehydes are accelerated by addition of 1-10 equivalents of water to the reaction medium, allowing stoichiometric aldol reactions to proceed at acceptable rates.

    References

  • 1a Sakthivel K. Notz W. Bui T. Barbas CF. J. Am. Chem. Soc.  2001,  123:  5260 
  • 1b List B. Lerner RA. Barbas CF. J. Am. Chem. Soc.  2000,  122:  2395 
  • 1c List B. Pojarliev P. Castello C. Org. Lett.  2001,  3:  573 
  • 1d Notz W. List B. J. Am. Chem. Soc.  2000,  122:  7386 
  • 1e Córdova A. Notz W. Barbas CF. Chem. Commun.  2002,  3024 
  • 1f For a review of proline-catalyzed asymmetric reactions, see: List B. Tetrahedron  2002,  58:  5573 
  • Only one proline molecule is involved in the transition state:
  • 2a Hoang L. Bahmanyar S. Houk KN. List B. J. Am. Chem. Soc.  2003,  125:  16 
  • 2b For density functional studies of the mechanism and quantum mechanical predictions of the stereoselectivities, see: Arnó M. Domingo LR. Theor. Chem. Acc.  2002,  108:  232 
  • 2c Rankin KN. Gauld JW. Boyd RJ. J. Phys. Chem.  2002,  106:  5155 
  • 2d Bahmanyar S. Houk KN. Martin HJ. List B. J. Am. Chem. Soc.  2003,  125:  2479 
  • 3 See for example: Zhong G. Lerner RA. Barbas CF. Angew. Chem. Int. Ed.  1999,  38:  3738 ; and references therein
  • 4a Guthrie JP. Cossar J. Taylor KF. Can. J. Chem.  1984,  62:  1958 
  • 4b Guthrie JP. Wang X.-P. Can. J. Chem.  1992,  70:  1055 
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  • 5d Orsini F. Pelizzoni F. Forte M. Destro R. Gariboldi P. Tetrahedron  1988,  44:  519 
  • 6a Hayashi T. Tetrahedron Lett.  1991,  32:  5369 
  • 6b Ward DE. Sales M. Sasmal PK. Org. Lett.  2001,  3:  3671 
  • 6c Ward DE. Sales M. Man CC. Shen J. Sasmal PK. Guo C. J. Org. Chem.  2002,  67:  1618 
  • 6d Karisalmi K. Rissanen K. Koskinen AMP. Org. Biomol. Chem.  2003,  1:  3193 
  • 12a The assignment of the stereochemistry of 5a and 5b is based on the 1H NMR coupling constants of the COCHCH(OH)Ph proton of the product (400 MHz, CDCl3), characteristic shifts of 5a: δ = 4.90 [d, J = 9.9 Hz, 1 H, COCHCH(OH)Ph], 2.61 [br ddd, J = 9.9, 6.0, 4.9 Hz, 1 H, COCHCH(OH)Ph]; shifts of 5b: δ = 5.19 [d, J = 4.9 Hz, 1 H, COCHCH(OH)Ph], 2.68 [br q, J = 5 Hz, 1 H, COCHCH(OH)Ph)], indicating that the cyclohexanone ring does not adopt the chair conformation, as would be expected for the equatorial products. The major products also do not match the data reported for the corresponding equatorial product, see: Busch-Petersen J. Corey EJ. Tetrahedron Lett.  2000,  41:  6941 
  • 12b

    In addition, the stereochemical model presented in ref. [2d] clearly predicts an axial attack of the carbonyl electrophile to the enamine intermediate. Only minor amounts (<5% each) of the corresponding equatorial isomers were formed.

  • 14a A slight erosion in the diastereopurity of the product (12:1 to 8:1 anti:syn) was observed during the purification of the product by preparative TLC. The spectroscopic data of 8 match those reported earlier by Paterson and co-workers. See: Paterson I. Wallace DJ. Cowden CJ. Synthesis  1998,  639 
  • 14b

    [α]D 23 +29 (c 1.0, CHCl3, 96% ee, 8:1 anti:syn), lit.: [α]D 23 +12.3 (c 0.6, CHCl3).

  • 15a

    l-Proline is not racemized in this process (see ref. [5a] ). Very recently, List and co-workers [15b] have reported that ketones may also condense with proline to form the oxazolidinones. Our inability to detect these ketone-derived oxazolidinones may simply reflect the fact that the equilibrium constants for oxazolidinone formation are higher with aldehydes than with ketones. The observation by List et al. that cyclohexanone forms the oxazolidinone with an equilibrium constant ca. five times that of acetone (0.68 vs. 0.12) fits very nicely with our observations that the effect of added water is more dramatic with cyclic ketones such as 4-thianone.

  • 15b List B. Hoang L. Martin HJ. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  5839 
  • 17a Itoh T. Yokoya M. Miyauchi K. Nagata K. Ohsawa A. Org. Lett.  2003,  5:  4301 
  • 17b In contrast with these results, related proline-catalyzed Mannich reactions with glyoxylate-derived imine electrophiles were not improved by the addition of water. See: Notz W. Tanaka F. Watanabe S.-i. Chowdari NS. Turner JM. Thayumanavan R. Barbas CF. J. Org. Chem.  2003,  68:  9624 
  • 18 Brown SP. Goodwin NC. MacMillan DWC. J. Am. Chem. Soc.  2003,  125:  1192 
  • 19 Torii H. Nakadai M. Ishihara K. Saito S. Yamamoto H. Angew. Chem. Int. Ed.  2004,  43:  1983 
  • 20 4-Thianone is an excellent surrogate for 3-pentanone, which is unreactive under proline catalysis (see ref.1a). For an earlier example of the 4-thianone strategy in polypropionate synthesis, see: Woodward RB. Logusch E. Nambiar KP. Sakan K. Ward DE. Au-Yeung B.-W. Balaram P. Browne LJ. Card PJ. Chen CH. Chênevert RB. Fliri A. Frobel K. Gais H.-J. Garrat DG. Hayakawa K. Heggie W. Hesson DP. Hoppe D. Hoppe I. Hyatt JA. Ikeda D. Jacobi PA. Kim KS. Kobuke Y. Kojima K. Krowicki K. Lee VJ. Leutert T. Malchenko S. Martens J. Matthews RS. Ong BS. Press JB. Rajan Babu TV. Rousseau G. Sauter HM. Suzuki M. Tatsuta K. Tolbert LM. Truesdale EA. Uchida I. Ueda Y. Uyehara T. Vasella AT. Vladuchick WC. Wade PA. Williams RM. Wong HN.-C. J. Am. Chem. Soc.  1981,  103:  3210 
7

General Experimental Procedure. To ensure that all reactions were performed under otherwise identical conditions, all reactions were conducted in flame-dried glassware under an argon atmosphere. DMF and DMSO were dried by distillation over 4 Å molecular sieves, and acetone was dried over anhyd CaSO4. To a mixture of 1 mL anhyd DMF or DMSO, ketone donor (1 mmol) and l-proline (10 mol% or 30 mol%) was added aldehyde (1 mmol) and H2O (0-1500 mol%). The flask was capped and the reaction mixture was stirred at r.t. under argon for 3-13 d. The reaction was then quenched with H2O (10 mL, Table [3] ) or with a sat. NH4Cl solution (10 mL, Table [1] and Table [2] ) and then extracted with Et2O (3 × 10 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The pure aldol products were obtained by flash column chromatography [silica gel, pentane-Et2O (Table [1] ), hexane-EtOAc (Table [2] ) or hexane-MTBE (Table [3] )].

8

The racemic samples for the reactions with acetone, 4-tert-butylcyclohexanone and 4-thianone (entries 13-15, Table [3] ) as the donor were prepared by using racemic proline as catalyst. For other reactions with 4-thianone, the racemic samples were obtained using the procedure of Hayashi. [6a]

9

Reaction conditions: 14.0 mmol acetone, 0.5 mmol isobutyraldehyde, 30 mol% l-proline, 1 mL DMSO, r.t.,
50 h; 0 mol% H2O gave a conversion of 59% (ee 95%), 300 mol% H2O a conversion of 68% (ee 95%).

10

Reaction conditions: 27 mmol acetone, 1 mmol p-nitro-benzaldehyde, 20 mol% l-proline, 1 mL DMF, r.t., 24 h, 555 mol% (3 vol%) H2O; yield 90% (100% conversion), ee 76%. Previously, List and Barbas had obtained this aldol product in 68% yield and 76% ee in dry DMSO (see ref. [1a] [b] ).

11

As an example, under the List-Barbas conditions, the reactions with cyclohexanone and isobutyraldehyde require five days for reasonable yields (ref. [2d] ). It should be noted that the stoichiometric reactions with cyclohexanone and isobutyraldehyde were also accelerated (0% water: <30% conversion after 4 d; 300 mol% water: ca. 60% conversion).

13

All new compounds gave satisfactory analytical and spectral data. Selected characterization data: (3 S ,1′ S )-3-[(1′-hydroxy-2′-methyl)propyl]-tetrahydrothiopyran-4-one (Table 3, Entry 4): The ee was determined by HPLC (Chiralpak OD column, hexane-i-PrOH, 98:2, flow rate 0.7 mL/min; τminor = 26.1 min; τmajor = 20.7 min, λ = 254 nm). Rf (1:1, hexane-MTBE) = 0.27. [α]D 23 -72 (c 1.0, MeOH, 95% ee). 1H NMR: δ = 3.50 (t, J = 5.1 Hz, 1 H), 2.93-2.77 (m, 5 H), 2.70-2.65 (m, 2 H), 1.83-1.70 (m, 1 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H). 13C NMR: δ = 212.4, 76.1, 55.7, 44.9, 33.5, 30.9, 29.9, 19.9, 16.0. IR (film): 3488, 2960, 2874, 1704, 1426, 1274, 990 cm-1. HRMS (ESI): m/z calcd for C9H16O2NaS: 211.0769. Found: 211.0762.
(3 S ,1′ R )-3-[(1′-hydroxy-1′-phenyl)methyl]-tetrahydrothiopyran-4-one (Table 3, Entry 10): The ee was determined by HPLC (Chiralpak OD column, hexane-i-PrOH, 90:10, flow rate 0.5 mL/min; τminor = 40.8 min; τmajor = 31.0 min, λ = 254 nm). Rf (1:1, hexane-MTBE) = 0.19. Mp 126-127 °C. [α]D 23 -73 (c 1.1, MeOH, 98% ee). 1H NMR: δ = 7.32-7.22 (m, 5 H), 4.90 (dd, J = 8.9, 3.0 Hz, 1 H), 3.34 (s, 1 H), 2.96-2.86 (m, 3 H), 2.78 (m, 1 H), 2.70 (m, 1 H), 2.49 (dd, J = 13.8, 9.9 Hz, 1 H), 2.44 (ddd, J = 13.8, 5.2, 1.8 Hz, 1 H). 13C NMR: δ = 211.8, 140.2, 128.7, 128.3, 126.9, 73.8, 59.7, 44.5, 32.9, 30.9. IR (KBr pellet): ν = 3421, 2914, 1690, 1426, 1275, 1051, 706 cm-1. Anal. calcd for C12H14O2S: C, 64.8%; H, 6.4%. Found: C, 64.4%; H, 6.3%. HRMS (ESI): m/z calcd for C12H14O2NaS: 245.0612. Found: 245.0605.

16

Reaction conditions: 1 mmol 4-thianone, 1 mmol iso-butyraldehyde, 1 mL DMF, r.t., 10 d.