AcOLeDMAP and BnOLeDMAP: Conformationally Restricted Nucleophilic Catalysts for Enantioselective Rearrangement of Indolyl Acetates and Carbonates

Abstract

The rate of indolyl O- to C-acetyl or carboxyl rearrangement is accelerated by the electron withdrawing N-diphenylacetyl group (DPA) using the conformationally restricted chiral catalysts AcOLeDMAP (12b) and BnOLeDMAP (13b). Highly enantioselective conversion to quaternary C-acetylated and C-carboxylated oxindoles is observed, even for substrates containing branched substituents. The rearrangement of the carboxylate substrates 19 occurs with complementary enantiofacial selectivity using catalyst 13b compared to the acetyl migrations of 16 catalyzed by 12b. Access to N-unsubstituted oxindoles is demonstrated by DPA cleavage with Et₂NH.

The catalytic asymmetric synthesis of all-carbon oxindole quaternary centers has been a difficult challenge. Significant advances have been described using phase-transfer,¹ transition metal,^2–5 and chiral nucleophilic catalysts.^6–9 Examples of the latter process include the highly enantioselective rearrangement of indolyl carbonates 1 to the oxindoles 2 catalyzed by planar-chiral pyridines (2 days, 35 °C, 10 mol% catalyst).⁶ Catalyst 3 (TADMAP) also promoted the rearrangement, but a marginal enantioselectivity/reactivity profile at 10% catalyst loading discouraged detailed optimization.⁷ Herein, we report a dramatic substitution effect that solves the reactivity problem. We also describe the development of practical new catalysts featuring a chiral sidechain that prefers a uniquely advantageous conformation. These advances enable enantioselective acyl as well as carboxyl migration in the oxindole series.

Preparation of versatile substrates related to 1 from N-protected oxindoles was challenging due to competing reaction at O and C, but kinetic O-acetylation of oxindole 4 with acetyl chloride/2,6- lutidine afforded enol acetate 5 in acceptable 81% yield.¹⁰ Deprotonation of 5 followed by trapping with reactive electrophiles then gave differentially protected indolyl acetates 6 for initial evaluation. Upon catalysis with DMAP (3%), the N-benzyl (6a) or N-alkoxcarbonyl (6b) derivatives rearranged slowly to the oxindoles rac-7 (89% and 78% conversion, 5h, rt). On the other hand, the N-nosyl (6c) or N-acyl (6d–f; 8) analogues rearranged completely within 20 min (>95%) while 6g rearranged to the extent of 84%. Therefore, reactivity increases when more electron-withdrawing substituents are placed at indole nitrogen.

When 3 was used to catalyze the rearrangement of indolyl acetate 6d to 7d, much improved reactivity was indeed observed (98% isolated after 3 h, rt; 10% catalyst), but the 20% ee prompted a re-evaluation of the catalyst. One concern was that synthesis of enantiopure 3 requires classical resolution. Another issue is that the trityl group offers few options for catalyst modification short of repeating the entire 5-step synthesis/ resolution sequence. Accordingly, a new family of catalysts was designed that incorporates both electronic and steric factors expected to favor a specific sidechain conformer. Thus, (S)-N-benzoylvalinol¹¹ was oxidized to aldehyde 10a and 3-Li- DMAP (from the bromide)⁷ was added to afford the alcohol 11a. Subsequent acylation yielded 12a (AcOVaDMAP, 6:1 dr, 72% from 10a, Scheme 2). A similar route from (S)-tert-leucinol afforded 12b (AcOLeDMAP, >98:2 dr; 60% from 10b). Because diastereomer separation was not necessary with 12b, this catalyst was used for most of the optimization studies. A third catalyst 13b (BnOLeDMAP) was prepared by O-benzylation of isolated 11. The stereochemistry and the expected geometry of 12 and 13 (anti DMAP and tBu groups; gauche OAc and NHBz substituents) were confirmed by X-ray crystallography as shown in 12b*, and by J_1,2 < 1Hz for the OCHCHNBz protons of 12b and 13b. This evidence points to a strong preference for a well-defined catalyst geometry having the benzamido substituent near the catalytic site at the nucleophilic pyridine nitrogen.

Scheme 2.

Catalyst 12b effected rearrangement of the N-acetyl substrate 6d to 7d with promising 61% ee (THF, rt). The N-nosyl indole 6c gave similar results (58% ee), while the N-i-butyryl indole 6e rearranged with increased selectivity (77% ee). Reactivity dropped significantly with the N-pivalyl analogue 6g, but the N-diphenylacetyl (N-DPA) indole 6f gave good enantioselectivity in THF (89% ee) without impeding the reaction. Optimal 92% ee was otained in ethyl acetate at 0 °C, although other common solvents also gave good results.

Preparation of 6f according to Scheme 1 afforded modest yields, so a new route to N-DPA indolyl esters was developed. Heating 4 in neat Ph₂CHCOCl (1.5 eq) yielded 14 (85%), and reaction with AcCl/Et₃N afforded the easily purified, crystalline indolyl acetate 15a as well as ca. 5% of the C-acetylated isomer (Scheme 3). Various indolyl acetates prepared in this way were then subjected to catalysis by 12b (Table 1). Unbranched alkyl groups at the 3-position promoted rearrangement to 16 with good selectivity and reactivity (entries 1–6). A branched alkyl group (i-Pr) decreased the rate, but gave oxindole 16f with 94% ee, while the more reactive 3-phenyl derivative 15g rearranged with lower selectivity (entry 8).¹² The 5-bromoindolyl acetate 17 reacted completely within 20 min, and the purified major oxindole 18 was found to have the (S) configuration by X-ray crystallography (anomalous dispersion). Since the oxindoles 16 and 18 have the same sign of optical rotation and similar chromophores, and also have similar relative mobility for major vs. minor enantiomers on chiral hplc supports, 16a–g and 18 were assigned the same configuration by analogy.

Scheme 1.

Scheme 3.

Table 1.

Table 1A. Rearrangement of indolyl acetates catalyzed by 12b
Entry	indole	R4	time	product	ee
1	15a	Me	2 h a	16a 94%	92%
2	15a	"	24 hb	16a 99%	92%
3	15b	Et	2.5 h a	16b 98%	91%
4	15c	Bn	3 h a	16c 96%	94%c
5	15d	(CH2)2OTBDPS	3 h a	16d 94%	91%
6	15e	Allyl	2.5 h a	16e 98%	86%
7	15f	i-Pr	42 h a	16f 82%	94%
8	15g	Ph	2 h a	16g 98%	66%
9	17	Me	.33 h a	18 95%	85%

Table 1B. Rearrangement of indolyl carbonates catalyzed by 13b
Entry	indole	R4	time	product	ee
10	21a	Me	23 h d	22a 91%	−90%
11	21b	Bn	23 h d	22b 98%	−92%
12	21c	(CH2)2OTBDPS	23 h d	22c 99%	−94%
13	21d	Ph	2 h d,e	22d 98%	−91%
14	23a	Me	5 h d,e	24a 90%	−90%

^a10 mol % 12b, 0.2M, EtOAc, 0 °C

^b1 mol % 12b

^cee of deprotected NH oxindole

^d10 mol% 13b, 0.8M, CHCl₃, −20 °C

^e0.2M

Using 1 mol% of catalyst 12b, 15a rearranged on gram scale within 24 h (entry 2) and recrystallization upgraded the resulting oxindole 16a to 99% ee. The valine derived catalyst 12a (AcOVaDMAP) was also effective (16a: 88% yield, 90% ee). If desired, the N-DPA products 16 can be deprotected to the N-H oxindoles 19. Strong base¹³ or primary amines removed DPA as well as acetyl groups in 16, but diethyl amine selectively cleaved DPA to give the parent oxindole (19a, 75%; 19c 65%). Retention of configuration was confirmed in the latter case (94% ee). To further illustrate synthetic potential, 16a (88% ee) was converted into 20a (73% yield; 87% ee) under Baeyer-Villiger conditions (MCPBA/NaHCO₃, CH₂Cl₂/reflux).

Catalyst 12b was also evaluated with the indolyl carbonate substrates. Rearrangement from 8 to 9 occurred readily (5 h, rt), but enantioselectivity was low (4 % ee). The reason became clear when NMR/MS assay of recovered catalyst revealed clean conversion of 12b to an oxazoline resulting from loss of the O-acetyl group.¹⁴ The stable catalyst 13b (BnOLeDMAP) catalyzed the conversion from 8 to 9 with modest 33% ee, but good enantioselectivity was achieved by optimizing substituents. Thus, the N-DPA indolyl carbonates 21 or 23 (available from 1-naphthylmethyl chloroformate) were converted into oxindoles 22 or 24 with 90–94% ee using 13b in several representative examples (entries 10–14; CHCl₃, −20 °C). Remarkably, these reactions afforded oxindoles having the opposite configuration compared to 16 or 18 obtained using catalyst 12b according to X-ray crystallography data for 25, obtained in 94% yield by treatment of 24a with diethyl amine.¹⁵

In summary, carboxyl and acetyl migration of indolyl esters is strongly accelerated by N-acyl groups. Easily accessible AcOLeDMAP (12b) and BnOLeDMAP (13b) are the most practical and versatile nucleophilic catalysts reported to date for enantioselective rearrangement of indolyl acetates and carbonates to oxindoles containing chiral quaternary carbon. The interplay between migrating group substituents and catalyst modifications at the benzylic oxygen has striking consequences, as illustrated by the complementary enantiofacial selectivity for 13b with 21/23 vs. 12b with 15/17.¹⁶ Furthermore, the catalyst design highlights a conformationally restricted sidechain that may have other uses in situations where convergent functionality in a chirotopic environment is required.

Supplementary Material

1_si_001. Supporting Information Available.

Experimental procedures and characterization (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

Scheme 4.