Preparation and Double Michael Addition Reactions of a Synthetic Equivalent of the Nazarov Reagent

A synthetic equivalent of the Nazarov reagent, the silyl derivative 2, able to undergo base-catalyzed double Michael addition reactions with α,β-unsaturated carbonyl compounds has been developed. The new reagent satisfactorily reacts with unsaturated indolo[2,3-a]quinolizidine lactams to give pentacyclic yohimbinone-type derivatives.

Scheme 1. A synthetic equivalent of the Nazarov reagent imines, 6 enamines, 7 dienamines, 8 and (thio)imidates, 9 in which the reagent undergoes an initial Michael addition   and the resulting β-keto ester enolate acts as a nucleophile.
However, the instability of 1 under basic conditions 10 has restricted its use in annulations with α,β-unsaturated carbonyl derivatives, in which the reagent successively acts as a Michael donor and a Michael acceptor. 11,12 To overcome this limitation, as well as the difficulties associated with the preparation and purification of the Nazarov reagent, more stable modified reagents substituted at the olefinic carbons 13 and suitable precursors allowing its in situ generation 14 have been developed. In contrast with the original Nazarov reagent, the substituted reagents, extensively used by Deslongchamps, react in their enolate form, smoothly undergoing base-catalyzed double Michael addition reactions to give cis-decalin derivatives. 13 In this letter we present a stable and practical synthetic equivalent of the Nazarov reagent, the silyl derivative 2, that we have developed in the context of our studies on the use of tryptophanol-derived lactams in the enantioselective synthesis of indole alkaloids. 15 We envisaged a straightforward approach to pentacyclic yohimbine-type derivatives, in which the carbocyclic E ring would be assembled by a double Michael addition of the Nazarov reagent (1) to unsaturated indoloquinolizidine lactams 4. These lactams, which incorporate an additional activating electron-withdrawing substituent, were prepared in good overall yields by conventional methods from the known lactam 3, 16 as outlined in Scheme 2.
Initial attempts to perform the annulation of the Nazarov reagent 1 with unsaturated lactam 4a (Cs 2 CO 3 / CH 2 Cl 2 or KF/MeOH) were unsuccessful, resulting in complete degradation of 1. When using lactam 4b, which bears a benzenesulfonyl activating substituent, annulation occurred to some extent, pentacycle 5b being isolated in very low yield from the resulting complex mixture.
Scheme 2. Attempted double Michael addition with the Nazarov reagent, 1 Despite these unsatisfactory results, the viability of our double Michael addition strategy was confirmed by the successful Cs 2 CO 3 -mediated reaction of the more stable methyl substituted Nazarov reagent 6 17 with the above lactams 4a and 4b to give the respective pentacyclic derivatives 8a and 8b as single stereoisomers in excellent yields 18 (Scheme 3). Although it was possible to stereoselectively remove the benzenesulfonyl group of 8b with retention of the configuration, 19 the presence of the methyl substituent in the carbocyclic E ring makes pentacyclic derivative 9 unsuitable for the synthesis of yohimbine-type natural products.
At this point, we decided to design a synthetic equivalent of the Nazarov reagent that would overcome the inconveniences and limitations of the original reagent 1. Bearing in mind that α-silylated vinyl ketones have been extensively used as surrogate vinyl ketones in (16) (6) annulation reactions, 20 we planned to prepare a Nazarovtype reagent, such as 2, silylated at the α-position of the enone (Scheme 4). The α-trimethylsilyl group would increase the electrophilicity of the β-carbon, stabilize the α-anion formed upon Michael addition, and slow down the polymerization due to its steric bulk. Additionally, being α-ketonic in the final compound, the silyl substituent could readily be removed by nucleophiles. The silyl derivative 2 was prepared from (1bromovinyl)trimethylsilane (10) via the known 21 allylic alcohol 11, by a route inspired in the preparation of the Nazarov reagent 1. 2b,c Dess-Martin oxidation of 11, followed by acylation of the unstable acrolein derivative 12 with the enolate of methyl acetate, and IBX oxidation of the resulting β-hydroxy ester 13 gave 2 in 53% overall yield for the four steps. This silylated Nazarov reagent was stable in storage at -20 °C under nitrogen for several months. 22 (22) Reagent 2 was stable enough to be purified by flash chromatography. Although TLC showed that no significant decomposition occurred on stirring a CH2Cl2 solution of 2 at 0 ºC for 2 h in the presence of Cs2CO3, extensive polymerization was observed when the experiment was performed at r.t.
To our delight, reagent 2 satisfactorily reacted with unsaturated lactams 4a and 4b to give double Michael addition products, in which the trimethylsilyl group had undergone in situ protodesilylation. 23 Thus, treatment of 4a with 2 under the reaction conditions outlined in Scheme 5 stereoselectively led to a single pentacycle 14a in excellent yield. A subsequent removal of the Boc protecting group provided 15. A similar reaction from 4b afforded a diastereoisomeric mixture of pentacycles 14b and 5b (2:1 ratio; 64%), 24 the latter being stereoselectively converted to the epi-allo-yohimbinone derivative 16 by reductive removal of the activating benzenesulfonyl group. 19 The absolute configuration of 5b was unambiguosly established by X-ray crystallography. In turn, the 3-H/15-H cis relationship in the isomers 14a and 14b (as well as in 19; see Scheme 6) was deduced from the positive NOE effect between these protons. Taking into account these assignments, the NMR chemical shifts of the protons and carbons at the 3-and 14-positions were of diagnostic value to assign the C-3, C-15, and C-20 relative stereochemistry of the pentacyclic derivatives reported in this work (see Tables in the Supporting Information). Similar satisfactory results were obtained in the reaction of the silylated Nazarov reagent 2 with unsaturated lactams 18 (Scheme 6), which lacks the O-Boc hydroxymethyl substituent, and 20 (Scheme 7), unprotected at the hydroxy function and indole nitrogen. The former was prepared from the known saturated lactam 17 25 as outlined in Scheme 6, whereas the latter by TFA treatment of the above lactam 4a. Scheme 6. Double Michael addition of the Nazarov reagent equivalent 2 to unsaturated lactam 18 Scheme 7. Double Michael addition of the Nazarov reagent equivalent 2 to unsaturated lactam 20 Somewhat surprisingly, whereas lactam 18 behaved like lactams 4, stereoselectively leading to an all-cis pentacycle, 19, the annulation from 20 took place with opposite facial selectivity, giving pentacycle 21 as the major product. 26 The stereochemical outcome of the double Michael additions deserves comment. The configuration of the C-15 stereocenter is generated in the initial attack of the Nazarov enolate, and it is known that conjugate addition to unsaturated indolo[2,3-a]quinolizidine lactams usually leads to trans 3-H/15-H derivatives, although, for steric reasons, a reversal of the facial selectivity is observed when the indole nitrogen is  On the other hand, the cis D/E ring junction 28 results from the  Tetrahedron Lett. 2006, 47, 1961-1964 (26) Trace amounts of the 15,20-epimer were also formed. (28) All pentacyclic derivatives prepared in this work were predominantly (or completely) enolic in solution, as expected for a cis-D/E ring junction in yohimbinone-type systems: (a) Albright, J. D.; stereoelectronic control during the second Michael addition. 29 To further illustrate the synthetic usefulness of the silylated Nazarov reagent 2 as a synthetic equivalent of the original reagent 1, we also studied Cs 2 CO 3 -promoted double Michael annulations from cyclohexenones 22a and 22b (Scheme 8). Earlier attempts to perform the annulation of 22a with 1 had only resulted in a very poor yield of 23a. In contrast, the silylated derivative 2 satisfactorily gave the respective highly functionalized cis-decalins 23a 30 and 23b in acceptable yields. In summary, we have developed a synthetic equivalent of the Nazarov reagent, the silyl derivative 2, which is able to participate in Cs 2 CO 3 -promoted double Michael annulations with α,β-unsaturated carbonyl compounds, avoiding the polymerization problem associated with the original Nazarov reagent. Starting from unsaturated indolo[2,3-a]quinolizidine lactams, this silylated Nazarov reagent allows the straightforward construction of pentacyclic yohimbinone-type systems.