Asymmetric Total Synthesis of Attenol A and B

Abstract

The asymmetric total synthesis of attenol A (1) and B (2), which possess challenging structures and an interesting biological activity, was accomplished in a convergent and highly stereo­selective manner (de, ee ≥ 96%) with good overall yield. The short total synthesis is based on asymmetric alkylations of SAMP-hydrazones as well as a Sharpless asymmetric dihydroxylation as key steps.

asymmetric dihydroxylation - dithianes - natural products - SAMP-hydrazone methodology - total synthesis

References

<A NAME="RG21803ST-1">1</A> Takada N. Suenaga K. Yamada K. Zheng S.-Z. Chen H.-S. Uemura D. Chem. Lett.  1999,  1025 

<A NAME="RG21803ST-2A">2a</A> Suenaga K. Araki K. Sengoku T. Uemura D. Org. Lett.  2001,  3:  527 

<A NAME="RG21803ST-2B">2b</A> Araki K. Suenaga K. Sengoku T. Uemura D. Tetrahedron  2002,  58:  1983 

<A NAME="RG21803ST-2C">2c</A> Van de Weghe P. Aoun D. Boiteau J.-G. Eustache J. Org. Lett.  2002,  4:  4105 

For reviews concerning the chemistry of dithianes, see:

<A NAME="RG21803ST-3A">3a</A> Seebach D. Synthesis  1969,  17 

<A NAME="RG21803ST-3B">3b</A> Gröbel B.-T. Seebach D. Synthesis  1977,  357 

<A NAME="RG21803ST-3C">3c</A> Bulman Page PC. van Niel MB. Prodger JC. Tetrahedron  1989,  45:  7643 

<A NAME="RG21803ST-4">4</A> The introduction of keto groups using dithianes as acylanion equivalents followed by intramolecular ketalization is a very common approach in spiroketal synthesis. For a review about spiroketals, see: Perron F. Albizati KF. Chem. Rev.  1989,  89:  1617 

For reviews about the SAMP/RAMP-hydrazone methodology in asymmetric synthesis see:

<A NAME="RG21803ST-5A">5a</A> Enders D. In Asymmetric Synthesis   Vol. 3:  Morrison JD. Academic Press; Orlando: 1984.  p.275 

<A NAME="RG21803ST-5B">5b</A> Job A. Janeck CF. Bettray W. Peters R. Enders D. Tetrahedron  2002,  58:  2253 

Compound 6 is a versatile chiral dihydroxy acetone dicarbanion equivalent. For its applications see:

<A NAME="RG21803ST-6A">6a</A> Enders D. Bockstiegel B. Synthesis  1989,  493 

<A NAME="RG21803ST-6B">6b</A> Enders D. Gatzweiler W. Jegelka U. Synthesis  1991,  1137 

<A NAME="RG21803ST-6C">6c</A> Enders D. Jegelka U. Synlett  1992,  999 

<A NAME="RG21803ST-7">7</A> Vader J. Sengers H. De Groot A. Tetrahedron  1989,  45:  2131 

<A NAME="RG21803ST-8">8</A> For a review about the cleavage of N,N-dialkylhydrazones see: Enders D. Peters R. Wortmann L. Acc. Chem. Res.  2000,  33:  157 

<A NAME="RG21803ST-9">9</A> Since the hydrazone cleavage of 8 proceeded without epimerisation, the ee of the anti-2,2-dimethyl-1,3-dioxan-5-one 4 is assumed to be at least as high as its de. The absence of epimerization can be proved on the stage of the anti-2,2-dimethyl-1,3-dioxane 10, whose ¹³C NMR resonance is at δ = 100.2 in accordance to Rychnovsky’s criteria. See: Rychnovsky SD. Rogers B. Yang G. J. Org. Chem.  1993,  58:  3511 

<A NAME="RG21803ST-10A">10a</A> Barton DHR. McCombie SW. J. Chem. Soc., Perkin Trans. 1  1975,  1574 

<A NAME="RG21803ST-10B">10b</A> Hartwig W. Tetrahedron  1983,  39:  2609 

<A NAME="RG21803ST-10C">10c</A> Motherwell WB. Crich D. Free Radical Chain Reactions in Organic Synthesis   Academic Press; London: 1992. 

<A NAME="RG21803ST-11A">11a</A> Enders D. Hundertmark T. Lampe C. Jegelka U. Scharfbillig I. Eur. J. Org. Chem.  1998,  2839 

<A NAME="RG21803ST-11B">11b</A> For an application in natural product synthesis, see: Enders D. Hundertmark T. Eur. J. Org. Chem.  1999,  751 

<A NAME="RG21803ST-12">12</A>

Experiments towards higher stereoselectivities in the reduction step were not conducted since the newly formed stereogenic center had to be removed afterwards.

<A NAME="RG21803ST-13">13</A>

A large excess of Bu₃SnH was necessary to sufficiently reduce the occuring side reactions. Under optimized conditions 10 contained only 3 mol% of an isomerization product in which the terminal double bond had migrated between C-19 and C-20 (the numbering refers to the final natural products).

<A NAME="RG21803ST-14">14</A> Ishikawa T. Ikeda S. Ibe M. Saito S. Tetrahedron  1998,  54:  5869 

<A NAME="RG21803ST-15">15</A>

The de of 13 and the ee of 5 were verified by HPLC on chiral stationary phase. In order to do so, the 1:1-epimeric mixture of 13 and the racemate of 5 had to be synthesized which was performed starting from the N,N-dimethyl-hydrazone of 12. Alkylation with MeI and ozonolysis gave the α-alkylated racemic aldehyde which was treated with SAMP and Ph₃PCHCO₂Et to obtain the desired mixtures of compounds.

<A NAME="RG21803ST-16">16</A> Kolb HC. VanNieuwenhze MS. Sharpless KB. Chem. Rev.  1994,  94:  2483 

<A NAME="RG21803ST-17">17</A>

The ee of 15 was verified by HPLC on chiral stationary phase. For this, ent-15 had to be synthesized analogously to 15 starting from the RAMP-hydrazone ent-7 and performing the Sharpless asymmetric dihydroxylation of ent-5 with the AD-mix α.

<A NAME="RG21803ST-18">18</A>

The reaction sequence leading to 15 was also conducted starting with 5 of much lower enantiomeric purity (i.e. ee = 83%). After HPLC, 15 (obtained in lower yield) was still diastereomerically and enantiomerically pure (de, ee ≥ 98%) which indicates the high stereoselectivity of the Sharpless asymmetric dihydroxylation.

<A NAME="RG21803ST-19">19</A> Posner GH. Weitzberg M. Hamill TG. Asirvatham E. He CH. Clardy J. Tetrahedron  1986,  42:  2919 

<A NAME="RG21803ST-20">20</A>

Our synthetic material was identical in all respects with physical and spectroscopic data provided for the natural products. Compound 1: [α]_D ²⁶ -8.2 (c 0.35, CHCl₃) {(ref. [2a] , [α]_D ²⁸ -9.7 (c 0.35, CHCl₃) and [α]_D ²⁸ -8.0 (c 0.38, CHCl₃) for natural 1. Compound 2: [α]_D ²⁶ 37 (c 0.072, CHCl₃) {(ref. [2a] , [α]_D ²⁹ 34 (c 0.073, CHCl₃) and [α]_D ²⁸ 31
(c 0.065, CHCl₃) for natural 2}.
All new compounds gave satisfactory spectral data and correct elemental analyses.