Stereoselective Total Synthesis of Zaragozic Acid A based on an Acetal [1,2] Wittig Rearrangement

Abstract

Die gleichzeitige Erzeugung der quartären Kohlenstoffzentren C4 und C5 durch eine Acetal‐[1,2]‐Wittig‐Umlagerung des O‐Glycosids 1, das sich vom L‐Arabino‐γ‐lacton ableitet, ist das Schlüsselelement beim Aufbau der zentralen 2,8‐Dioxabicyclo[3.2.1]octan‐Einheit von Saragossasäure A 2.

γ‐Silyl Group Effect in Hydroalumination and Carbolithiation of Propargylic Alcohols

“…We have found this unprecedented silyl effect during the course of our synthetic study of zaragozic acid A 4. As one of the key steps in this total synthesis, we faced the problem of group‐selective functionalization of intermediate 1 , which has three alkynyl groups on C4 and C5 [Eq.…”

Total Syntheses of Zaragozic Acids A and C by a Carbonyl Ylide Cycloaddition Strategy

“…After acetylation of the secondary alcohols at C6 and C4′, the exposure of selenide 100 to aqueous hydrogen peroxide effected an oxidative elimination to give alkene 101 in 57 % yield in three steps. Alcohol 3 , obtained by the selective transesterification of the C6 acetate with 0.2 % potassium carbonate in MeOH in 80 % yield, was identical in all respects ( 1 H NMR, 13 C NMR, IR, [ α ] D ) with the intermediate reported by Tomooka and co‐workers 14. We then proceeded to complete the total synthesis by acylation of the hydroxyl group at C6 with (2 E ,4 S ,6 S )‐4,6‐dimethyl‐2‐octenoic acid ( 102 )52 followed by global deprotection with TFA to give the fully synthetic zaragozic acid A ( 1 ) in 81 % yield in two steps.…”

“…[ α ]${{{22\hfill \atop {\rm D}\hfill}}}$ =+3.86 ( c =1.30 in CHCl 3 ) [lit. [ α ]${{{27\hfill \atop {\rm D}\hfill}}}$ =+1.6 ( c =0.83 in CHCl 3 );14 1 H NMR (500 MHz, CDCl 3 ): δ =0.81 (d, J =6.7 Hz, 3 H; C5′‐C H 3 ), 1.45 (s, 9 H; CO 2 C(C H 3 ) 3 ), 1.50 (s, 18 H; 2×CO 2 C(C H 3 ) 3 ), 1.59 (s, 9 H; OCO 2 C(C H 3 ) 3 ), 2.00–2.17 (m, 3 H; C1′‐ H 2 , C5′‐ H ), 2.09 (s, 3 H; COC H 3 ), 2.30–2.45 (m, 2 H; C2′‐ H 2 ), 2.35 (dd, J =9.4, 13.5 Hz, 1 H; C6′‐ H ), 2.72 (dd, J =5.2, 13.5 Hz, 1 H; C6′‐ H ), 2.84 (d, J =3.5 Hz, 1 H; C6‐O H ), 3.97 (s, 1 H; C4‐O H ), 4.65 (d, J =1.9 Hz, 1 H; C7‐ H ), 4.73 (s, 1 H; C3‐ H ), 4.97 (br s, 2 H; C14′‐ H 2 ), 5.12–5.14 (m, 2 H; C6‐ H , C4′‐ H ), 7.14–7.18 (m, 3 H; Ar H ), 7.24–7.27 (m, 2 H; Ar H ); 13 C NMR (125.8 MHz, CDCl 3 ): δ =13.6, 21.1, 25.4, 27.6, 27.97, 28.04, 28.1, 29.7, 33.9, 36.6, 40.0, 74.0, 75.3, 76.8, 77.2, 79.2, 83.2, 83.8, 83.9, 85.1, 85.6, 90.8, 103.6, 111.3, 125.9, 128.3, 129.2, 140.4, 145.6, 153.6, 165.1, 165.8, 168.5, 170.2; IR (film): $\tilde \nu $ =3461, 2980, 2932, 1732, 1456, 1395, 1372, 1279, 1157, 1036, 990, 916, 845 cm −1 ; HR‐MS (FAB): m / z : calcd for C 42 H 62 O 15 Na: 829.3986, found: 829.3979 [ M + +Na].…”

“…7 The first total syntheses of zaragozic acid C ( 2 ) and zaragozic acid A (squalestatin S1, 1 ) were reported from the Carreira8 and Nicolaou9 laboratories, respectively, in 1994. Since then, five additional total syntheses of zaragozic acids,10–14 including our first‐generation synthesis, have been reported 15. All of these approaches utilize internal ketalization in constructing the core structure; only Heathcock adopted a stepwise approach, wherein the full C1 alkyl side chain was installed after the ketalization event…”

Rearrangement Reactions

“…However, the following example instructively demonstrates that a radical mechanism does not necessarily preclude stereochemical control. It proceeds through a radical dissociation-recombination mechanism preferentially with retention of the configuration at the migration center, and was employed in the total synthesis of (+)-squalestatin S1 21 (Scheme 5.23) [40], [41] The stereochemical course of the rearrangement is apparently dictated by the configurational stability of the anomeric radical and the formation of a radical pair 80 held together by lithium coordination. Recombination of the two radicals then proceeds with substrate-induced diastereoselectivity.…”