A New Reaction Motif: “Homo-S_N2′-Like” Direct Nucleophilic Addition to Neutral η³-Allylmolybdenum Complexes. Total Synthesis of the Antimalarial (+)–Isofebrifugine

Abstract

Charge neutral TpMo(CO)₂(5-acyloxy-η³-pyranyl) and TpMo(CO)₂(5-acyloxy-η³-pyridinyl) scaffolds undergo a novel intermolecular “homo-S_N2′-like” reaction with a variety of carbon nucleophiles. Combined with an annulative demetalation, the homo-S_N2′-like substitution/annulative demetalation sequence rapidly generates 2,7-dioxabicyclo[4.3.0]nonane and 2-aza-7-oxabicyclo[4.3.0]nonane frameworks in good to excellent yields with high enantiopurity. An enantiocontrolled total synthesis of the antimalarial alkaloid (+)-isofebrifugine was achieved utilizing this reaction cascade.

Enantiomerically pure, air and moisture-stable TpMo(CO)₂(η³-pyranyl) and TpMo(CO)₂(η³-pyridinyl) complexes, 1 and 2 (Scheme 1), are powerful scaffolds for the enantiocontrolled construction of substituted heterocycles.¹ Readily available in multigram quantities,^1m they provide not only new bond construction strategies to access a variety of natural products, but they also constitute platforms from which to explore novel reactivity. A survey of the literature shows that a TpMo(CO)₂-stabilized carbocation is a requisite intermediate in almost all synthetic transformations of the scaffolds.1a–i,1k,l,1n It was only recently that a new, non-cationic pathway taking place through the direct nucleophilic addition of an internal enolate to a terminal π-carbon of neutral 5-oxo-η³-pyranyl (and pyridinyl) moiety was reported.1j,1o This synthetically useful 1,5-Michael-like functionalization mode was explained, in part, by the tendency of TpMo(CO)₂ systems to favor 6-coordinate over 7-coordinate structures,² and also because the nucleophilic addition generates a characterizable anionic TpMo(CO)₂ intermediate (5 in Scheme 1), which possesses three good π-back-bonding ligands to delocalize the anionic charge: 2 terminal CO’s and the η²-enone ligand. These observations led us to wonder if the preference for 6-coordinate over 7-coordinate structures alone would be sufficient to enhance a more general nucleophilic addition pathway by which TpMo(CO)₂(η³-allyl) systems that are less-activated than the 5-oxo-η³-pyranyl/pyridinyl complexes could be functionalized. Following these considerations, we report herein the first examples of the “homo-S_N2′-like” intermolecular nucleophilic substitution of charge neutral TpMo(CO)₂(5-acyloxy-η³-pyranyl) and TpMo(CO)₂(5-acyloxy-η³-pyridinyl) complexes (3 and 4, Scheme 1). This mechanistically new enantiocontrolled carbon-carbon bond forming reaction occurs enantiospecifically with excellent anti stereoselectivity.

Scheme 1.

Nucleophilic Functionalization of Neutral TpMo(CO)₂(η³-pyranyl/pyridinyl) Complexes.

The requisite substrates 3a–c, 4a,b (Table 1) are prepared in high yields from the readily available TpMo(CO)₂(5-oxo-η³-pyranyl) and TpMo(CO)₂(5-oxo-η³-pyridinyl) complexes 1 and 2 through hydride or Grignard reagent addition to the carbonyl group followed by acylation.³ Initial experiments were conducted on the racemic forms of TpMo(CO)₂(5-acetoxy-η³-pyranyl) and TpMo(CO)₂(5-acetoxy-η³-pyridinyl) complexes. Treatment of 3a–c,4a,b with anionic carbon nucleophiles (pKa range = 13.3–18.0 in DMSO)⁴ in the presence of catalytic 15-crown-5 ether afforded substitution products 6 – 14 in good to excellent yields (Table 1). Moreover, as indicated in entry 1, the use of the high enantiopurity scaffold 3a led to the corresponding substitution product without loss of enantiopurity. Reactions of carbanions generated from precursors that are more acidic than dimethyl malonate benefited from the use of acetonitrile rather than THF as solvent (compare entry 2 and 3). When R on the scaffold is hydrogen, higher product yields were obtained using p-nitrobenzoate rather than acetate as the leaving group.

Table 1.

“Homo S_N2′-Like” Substitution Reactions

entry	reactant	NuH	solvent	% yield
1	3a	CH2(COOMe)2	THF	6, 99a
2	3a	CH3COCH2COOMe	ACN	7, 69(99)b,c
3	3a	CH3COCH2COOMe	THF	7, 31(99)b,c
4	3a	CH3CH(COOEt)2	THF	8, 66(94)b
5	3a	CH3NO2	DMSO	9, 80d
6	3b	CH3COCH2COOMe	ACN	10, 94c
7	3b	CH3COCH2COMe	ACN	11, 68
8	3c	CH2(COOMe)2	THF	12, 90
9	4a	CH2(COOMe)2	ACN	13, 94
10	4b	CH3COCH2COOMe	ACN	14, 91c

^a96% ee product from 96% ee starting material. The enantiopurity was determined by chiral HPLC.

^bThe number in the parentheses is the yield based on the recovery of starting material.

^cAn approximate 1.5:1 ratio of diastereomers was observed according to crude NMR.

^dNo 15-crown-5-ether was added.

The homo-S_N2′-like process does not appear to proceed by way of an in situ generated Mo-stabilized carbocation that is then trapped by the nucleophile. Exposure of 3a to TrPF₆ generates the molybdenum-stabilized carbocation 15, which upon treatment with sodium dimethylmalonate and 15-crown-5-ether shows a different reaction profile from the reactions in Table 1: only 18% of nucleophilic addition compound 6 is produced (Scheme 2). The reaction mostly forms the elimination product 16 in 55% yield. Additional observations are consistent with the postulate of direct attack of the nucleophile at the neutral η³-allylmolybdenum moiety: (1) compound 3a is recovered unchanged after stirring overnight in THF/Et₃N, (2) the homo-S_N2′-like substitution reaction proceeds faster with less substituted substrates: both 3b and the acetate corresponding to 3b (S2 in the Supporting Information) are faster reacting than the more substituted 3a, and (3) most reactions are significantly accelerated by the use of 15-crown-5 ether.

Scheme 2.

Control Experiment. The Reaction of Molybdenum-Stabilized Carbocation 15 with Sodium Dimethyl Malonate

An X-ray crystal structure of 8 (Table 1) unambiguously established direct anti nucleophilic attack at the neutral η³-allylmolybdenum (details are provided in the SI). In contrast some Mo-catalyzed allylic alkylations occur through a metal-centered attack,⁵ and Green has disclosed results consistent with the direct attack of a nucleophile at the molybdenum moiety of a neutral η³-lactonylmolybdenum complex.⁶

A represenative sampling of product molybdenum complexes were cleanly converted to bicyclic annulation products in high yields and with excellent stereoselectivity (Table 1). For example, treatment of 7, 10, 11, and 14 with NaH in DMSO in the presence of a catalytic amount of copper(II) 2-ethylhexanoate⁷ open to air provided the annulations products 17 – 20 in 83–92% isolated yields (Table 2). In earlier work, Pearson used different non-basic annulative demetalation reagents such as I₂⁸ or NOBF₄⁹ for related transformations, but exposing our substrates to these reagents (as well as prolonged standing in CDCl₃) yielded only the undesired elimination product (i.e., 16, Scheme 2) through ionization of the carbon nucleophile¹⁰ and subsequent proton loss. Mechanistically, we suggest that the reactions of Table 2 proceed through 1-electron oxidation of the stabilized enolate to a radical¹¹ that then reacts with the adjacent η³-allylmolybdenum moiety.

Table 2.

Cu-Catalyzed Aerobic Annulative Demetalation

entry	reactant	Z	EWG	R	% yield
1	7	O	COOMe	Me	17, 85
2	10	O	COOMe	H	18, 83
3	11	O	COMe	H	19, 92
4	14	NCbz	COOMe	H	20, 83

The synthetic potential of this methodology was demonstrated by an asymmetric synthesis of the antimalarial alkaloid (+)-isofebrifugine (Scheme 3).¹²

Scheme 3. Enantiocontrolled Synthesis of (+)-Isofebrifugine.

a/NaH, CH₃COCH₂SO₂Ph, DMSO, rt, overnight then NaH, Cu(ethylhexanoate)₂, air, overnight. b/(1) 10% Na/Hg, THF/MeOH, Na₂HPO₄, −35 °C to rt. (2) HCl, acetone. c/PtO₂, H₂. d/TIPSCl, imidazole, DMF. e/(1) TMSOTf, TEA, DCM then NBS. (2) 4-hydroxyquinazoline, NaH, THF, 15-C-5. f/6M HCl, reflux, 90 min.

Upon treatment of high enantiopurity (+)-4b³ in one pot with phenyl sulfonyl acetone anion in DMSO followed by a copper-catalyzed annulative demetalation, the bicyclic product (−)-21 was obtained in good yield without loss of enantiopurity. Desulfonylation with 10% Na/Hg and an acidic workup afforded the hemiketal (+)-22 in 86% yield. Hydrogenation on PtO₂ yielded (+)-23 which was subjected to standard TIPS protection conditions to furnish (+)-24 selectively in 75% yield (along with the recovery of 20% of the starting material). The ketone (+)-24 was monobrominated by subjecting its in situ generated silyl enol ether to NBS. The crude α-bromoketone was directly treated with 4-hydroxyquinazoline to afford (+)-25. Finally, deprotection with 6 M HCl delivered (+)-isofebrifugine, 26, in 63% yield ([α]_D²⁰ = +129, c = 0.3, CHCl₃, Lit.^12a [α]_D²⁰ = +131, c=0.35, CHCl₃).