Stereocontrolled Total Synthesis of Antimalarial (+)-Axisonitrile-3

Abstract

Here we describe the total synthesis of the antimalarial sesquiterpene, (+)-axisonitrile-3. Three key features of this synthesis are: (i) non-Evans syn-aldol reaction of an isovaleric acid derivative bearing a chiral oxazolidinethione and crotonaldehyde with high diastereoselectivity, (ii) Claisen rearrangement of alkenyl dihydropyran affording spiro[4.5]decane with requisite functionalities, and (iii) highly stereoselective reduction in the sterically congested O-methyl oxime system.

Key words

antimalarial activity - (+)-axisonitrile-3 - Claisen rearrangement - O-methyl oxime - total synthesis

References and Notes

• 1 Di Blasio B. Fattorusso E. Magno S. Mayol L. Pedone C. Santacroce C. Sica D. Tetrahedron  1976,  32:  473 
• 2 For a review on marine isocyanides and related natural products, see: Garson MJ. Simpson JS. Nat. Prod. Rep.  2004,  21:  164 
• 3a Angerhofer CK. Pezzuto JM. König GM. Wright AD. Sticher O. J. Nat. Prod.  1992,  55:  1787 
• 3b Wright AD. Wang H. Gurrath M. König GM. Kocak G. Neumann G. Loria P. Foley M. Tilley L. J. Med. Chem.  2001,  44:  873 
• 3c Marrero-Ponce Y. Iyarreta-Veitía M. Montero-Torres A. Romero-Zaldivar C. Brandt CA. Ávila PE. Kirchgatter K. Machado Y. J. Chem. Inf. Model.  2005,  45:  1082 
• 4 Hirota H. Tomono Y. Fusetani N. Tetrahedron  1996,  52:  2359 
• 5 Caine D. Deutsch H. J. Am. Chem. Soc.  1978,  100:  8030 
• 6a Nakazaki A. Era T. Kobayashi S. Chem. Pharm. Bull.  2007,  55:  1606 
• 6b Nakazaki A. Era T. Kobayashi S. Chem. Lett.  2008,  37:  770 
• 7 Crimmins MT. King BW. Tabet EA. J. Am. Chem. Soc.  1997,  119:  7883 
• 9 Wu Y. Yang Y.-Q. Hu Q. J. Org. Chem.  2004,  69:  3990 
• 12a Reisman SE. Ready JM. Hasuoka A. Smith CJ. Wood JL. J. Am. Chem. Soc.  2006,  128:  1448 
• 12b Reisman SE. Ready JM. Weiss MM. Hasuoka A. Hirata M. Tamaki K. Ovaska TV. Smith CJ. Wood JL. J. Am. Chem. Soc.  2008,  130:  2087 
• 15 Jumaryatno P. Stapleton BL. Hooper JNA. Brecknell DJ. Blanchfield JT. Garson MJ. J. Nat. Prod.  2007,  70:  1725 

8

In the previous synthesis of (-)-gleenol, the use of SuperQuat-type oxazolidine-2-one was necessary to minimize the cleavage of the oxazolidin-2-one during the removal of chiral auxiliary. Even employing SuperQuat, substantial amount of undesired byproduct caused by the ring opening of SuperQuat was formed.

10

The absolute stereochemistry of (2S,3R)-aldol adduct 6 was established by comparison of the specific rotation of the primary alcohol derived from ester 7.

11

An S_N2 reaction of tosylate 16a prepared from axenol 4 with potassium azide has been reported by Caine and co-workers (Scheme  [4] ). [5] However, we were unable to observe the formation of tosylate 16a using their protocol. Thus we chose mesylate as an alternative leaving group. Unfortunately, azidation of 16b under various reaction conditions (i.e., NaN₃, 15-crown-5, benzene, 80 ˚C; NaN₃, DMF, 100 ˚C; aq LiN₃, DMF, 100 ˚C; n-Bu₄NCl, NaN₃, NMP, 60 ˚C) was found to be unsuccessful. In each case, only a trace amount of the desired azide 17 was detected. Therefore we chose an alternative approach as shown in Scheme  [³] .

13

NOESY analysis of O-methyl oxime 18 indicated that 18 exists predominantly as the chair conformer A at r.t. in a CDCl₃ solution, see Supporting Information. Further, molecular mechanics calculations (SPARTAN) also supported the above observation.

14

Spectral Data for (+)-1
White solid; mp 94-95 ˚C; [α]_D ^²4 +54.4 (c 0.107, CHCl₃); lit. [¹] [α]_D +68.4 (c 1.0, CHCl₃); lit. [¹5] [α]_D +43.4 (c 0.006, CHCl₃); R _f = 0.45 (hexane-i-Pr₂O = 20:1). ^¹H NMR (400 MHz, CDCl₃): δ = 5.14 (q, J = 1.4 Hz, 1 H), 3.59 (br s, 1 H), 2.31-2.17 (m, 2 H), 2.01-1.90 (m, 2 H), 1.85-1.76 (m, 2 H), 1.74 (d, J = 1.4 Hz, 3 H), 1.59 (dqq, J = 9.4, 6.7, 6.7 Hz, 1 H), 1.51 (ddt, J = 13.4, 4.0, 3.5 Hz, 1 H), 1.33 (ddt, J = 12.8, 4.0, 13.4 Hz, 1 H), 1.20-1.11 (m, 1 H), 1.06 (ddt, J = 12.8, 4.0, 13.4 Hz, 1 H), 0.94 (d, J = 6.7 Hz, 3 H), 0.91 (d, J = 6.7 Hz, 3 H), 0.77 (d, J = 6.7 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 155.7, 144.8, 123.6, 64.5, 57.1, 43.8, 35.8, 34.9, 34.3, 31.2, 29.7, 24.9, 20.7, 20.3, 16.9, 16.1. IR (neat): 2925, 2131, 1541, 1456 cm^-¹. ESI-HRMS: m/z calcd for C₁₆H₂₆N: 232.2055; found: 232.2059.