Asymmetric domino synthesis of indanes bearing four contiguous stereocentres catalyzed by sub-mol% loadings of a squaramide in minutes

Abstract

An efficient diastereo- and enantioselective synthesis of polyfunctionalized indanes bearing four contiguous stereogenic centres in generally very short reaction times and sub-mol% squaramide catalyst loadings has been developed. The novel methodology creates a maximum of two stereocentres per bond formation via an organocatalytic Michael–Henry domino reaction.

In recent years, asymmetric organocatalytic domino reactions have developed into a fascinating research area at the forefront of synthetic chemistry leading to diverse and complex molecular structures with very high asymmetric inductions. For the formation of multiple bonds and stereogenic centres in a domino fashion, various organocatalytic activalion modes including enamine, iminium, Brønsted acid, Lewis base, hydrogen bonding as well as NHC catalysis are used.¹ However, some common disadvantages the majority of such reactions still encounter are the rather high catalyst loadings often ranging between 5 and 20 mol%,² long reaction times of more than one day, as well as the loss of stereogenic information due to the elimination of water, especially in aldol condensations. With these limitations in mind, we wanted to design a domino reaction fulfilling all of the following four criteria: (l) useful molecular architectures should be assembled with sub-mol% catalyst loadings rivalling transition metal catalysis, (2) maximum stereogenic information should be generated per bond formed (2 stereocentres formed per C-C bond),³ (3) very short reaction times,⁴ and (4) ambient room temperature conditions without temperature control.

Due to our recent interest in accessing synthetically useful chiral indane frameworks via chiral thioamide catalyzed Michael–Henry domino reactions (Scheme 1, eqn (l)),^5,6 we envisioned that N-Boc-protected oxindoles containing an sp³ nucleophilic carbon (Scheme 1, eqn (2)) could ensure that the nucleophilic carbon forms a stereogenic center in the domino sequence to achieve a maximum conservation of stereogenic information per bond formed,⁷ in contrast with the previously published report resulting in only a calculated 1.5 stereogenic centers per bond formed in the domino reaction.⁵

Scheme 1.

Domino efficiency comparison of current with previously reported work.

We would now like to report on an asymmetric Michael–Henry domino reaction that proceeds in a very short reaction time catalyzed by sub-mol% amounts of a squaramide, which allows a facile access to cis-nitroindanols bearing four contiguous stereogenic centres with excellent diastereo- and enantioselectivities.⁸ Our initial intention was to test chiral Brønsted base catalysis by employing TMS-protected dialkylprolinol 4⁹ used previously by our group,^10-12 To our delight, 4 (Table 1, entry 1] catalyzed the Michael–Henry domino reaction of oxindole la with nitrovinyl benzaldehyde 2a to form the indane cascade product 3a at room temperature in moderate enantioselectivities (44%). A lower temperature of −25 °C gave only a modest increase in ee to 59% with a virtually quantitative yield (Table 1, entry 2). Encouraged by these results, we screened the commonly utilized TMS-protected diphenylprolinol derived catalysts 5 and 6. However, this change from alkyl to aryl substitution on the praline-derived catalyst resulted in a decrease in enantioselectivities (Table 1, entries 3 and 4).

Table 1.

Optimisation of the reaction conditions^a,b

Entry	Cat.	t	Cat. loading (mol%)	Yieldc (%)	d.rd	eee (%)
1	4	18 h	10	77	>20:1	44
2f	4	18 h	10	99	>20:1	59
3	5	23 h	10	97	>20:1	−17
4	6	2 h	10	78	>20:1	27
5	7	16.5 h	10	32	8:1	80
6	8	16.5 h	20	66	7:1	−91
7	9	2.5 h	10	98	>20:1	−93
8	10	1.5 h	10	99	>20:1	95
9	10	15 min	5	96	20:1	91
10g	10	40 min	1	68	>20:1	90
11g	10	45 min	0.5	81	>20:1	91
12h	10	45 min	0.5	93	>20:1	93

^aConducted on a 0.1 mmol scale of la (1 equiv.) and 0.12 mmol scale of 2a (1.2 equiv.).

^bThe relative and absolute configurations of 3a were assigned by analogy to 2D NOESY of 3a and b and comparing with literature data.¹⁰

^cYields of isolated 3a after flash column chromatography.

^dDetermined by ¹H NMR.

^eDetermined by HPLC analysis on a chiral stationary phase.

^fThis reaction was conducted at −25 °C.

^gReactions were conducted on a 0.5 mmol scale of la (l equiv.) and 0.6 mmol scale of 2a (1.2 equiv.).

^hReaction was conducted on a 0.55 mmol scale of la (1.1 equiv.) and 0.5 mmol scale of 2a (1 equiv.).

Subsequently, the quinine-derived primary amine 7 was tested in this domino reaction (Table 1, entry 5). While the enantioselectivity in this case showed a marked increase in ee to 80%, yields dropped to 32% and the d.r, also decreased to 8:1. We then screened bi-functional hydrogen bonding catalysts. Upon utilizing the Takemoto thiourea catalyst 8, excellent enantioselectivities were achieved (Table 1, entry 6), albeit with only moderate yields and lower d.r. (66%, 7:1 d.r.].

When the bi-functional squaramide catalyst 9 was utilized in the domino reaction, we observed a significant increase in the reaction rate (2.5 h), and the cascade product was obtained with excellent yields, d.r. and enantioseleclivities (Table 1, entry 7). When the quinine derived-squaramide catalyst 10 was tested, we noticed a slight increase in ee (95%) with an almost quantitative yield and d.r. within 1.5 h. Remarkably, the catalyst loading of 10 could be effectively decreased to sub-mol% quantities (Table 1, entries 9–11) with the optimal catalyst loading obtained at 0.5 mol%. Finally, the stoichiometric proportions of substrates 1 and 2 were optimized to provide excellent yields, ee and d.r. values of the cascade product 3a within 45 minutes (Table 1, entiy 12).

With the optimized conditions in hand, we then proceeded to screen the substrate scope of this rapid and highly efficient Michael–Henry domino reaction (Table 2).

Table 2.

Substrate scope of the Michael–Henry domino reaction^a,b

3	R1	R2	R3	eec (%)	Yieldd (%)
a	Me	Ph	H	93	93
b	Me	Ph	Cl	90	89
c	Me	Ph	MeO	90	95
d	Me	Ph	F	90	83
e	H	Ph	H	90	86
f	H	Ph	Cl	90	92
g	H	Ph	MeO	90	92
h	H	Ph	F	89	87
i	Me	p-Ph–Pb	H	98	87
j e	Me	p-Ph–Ph	Cl	99	83
k	Me	p-Ph–Ph	MeO	89	92
l	Me	p-Ph–Ph	F	91	90
m f	H	Me	Cl	39	39
n g	H	H	Cl	73	44
o	H	2-Thiophenyl	Cl	—	—

^aThe reaction was conducted on a 0.55 mmol scale of la-n (1.1 equiv.) and 0.5 mmol scale of 2a-d (1 equiv.).

^bThe relative and absolute configurations of 3a-n were assigned by analogy to 2D NOESY of 3a and b and comparison with literature data.¹⁰

^cDetermined by HPLC analysis on a chiral stationary phase.

^dYields of isolated 3a-n after flash column chromatography.

^eConducted with 1 mol% of catalyst 10 for 20 min.

^f3 Equiv. oxindole 1m was used; reaction time was extended to 220 min.

^g3 Equiv. oxindole 1n was used; d.r was 12:1 in this case.

We figured out that generally this protocol is highly efficient and tolerant towards a wide series of functional groups. These include compounds containing electron donating (Table 2, 3c, g and k) and electron withdrawing groups (Table 2, 3b, d, f, and h, j and l). Moreover, the enantioselectivities were generally excellent. The diastereomeric ratios of this Michael–Henry domino reaction were also excellent (≥20:l) for most of the examples tested (Table 2, 3a–l). For 3j a slight increase in catalyst loading to 1 mol% was required in order to obtain excellent ee, however, we also noticed that this reaction was completed in only 20 minutes at room temperature.

One limitation of this methodology is that R² requires a phenyl or a phenyl derivative substituent. When a methyl substituent (Table 2, 3m) or a hydrogen substituent (Table 2, 3n) was tested, yields and enantioselectivity became inferior. Decomposition was observed in the reaction and workup when a thiophene substituent was used in R² (Table 2, 3o) and the cascade product could not be isolated. One explanation is that the presence of a phenyl group on R² is crucial in this methodology to stabilize the carbanion formed at C3 of the oxindole.

The relative configuration of the cascade products 3a–n was determined by analogy to long range NOESY contacts of derivatives 3a and 3b, The absolute configuration was determined by comparing the relative topicity of this domino reaction using catalyst 10 with literature known Michael additions of N-Boc-oxindoles using catalyst 4 (Table 1, comparing entries 2 and 12, for a detailed mechanism, see ESI^†).¹⁰

We also tested a gram scale synthesis of the cascade product 3g. Interestingly, we noticed that the gram scale synthesis proceeded much faster in 15 minutes with reproducible results comparable to the 0.5 mmol scale (Table 2, 3g) with excellent yield and very good ee (Scheme 2).

Scheme 2.

Gram scale synthesis of the cascade product 3g and further transformation.

The gram scale reaction however resulted in a slight decrease of the d.r. to 17:1. This lower d.r. was overcome by triturating 3g in diethylether overnight thus raising the diastereoselectivity to >20:1 d.r. Furthermore, a Boc-deprotection was carried out on 3g by stirring it with TFA. The facile deprotection resulted in almost quantitative yield of the deprotected derivative 11 (96%).

In conclusion, an efficient asymmetric organocatalytic Michael–Henry domino reaction has been developed that generates polyfunctionalized indanes bearing four contiguous stereo-genie centers with sub-mol% catalyst loadings. This new scalable protocol is based on the hydrogen bonding activation of the squaramide catalyst and creates a maximum of two stereogenic centres per bond formation within minutes. Further investigations of the utility of the cascade products are currently underway in our laboratories.