Constructing densely functionalized Hajos–Parrish-type ketones with six contiguous stereogenic centers and two quaternary carbons in a formal [2 + 2 + 2] cycloaddition cascade

Abstract

A [2 + 2 + 2] annulation of 2-methylcyclopentane-1,3-dione and nitrostyrenes has been achieved via a cascade double Michael–Henry reaction that provides densely functionalized Hajos–Parrish-type ketones with two quaternary carbons and six contiguous stereogenic centers. An uncommon and intriguing example of the high self-disproportionation of enantiomers (SDE) in the crystallization of racemic 3i was observed. The spontaneous high resolution of racemic mixture of 3i into its enantiopure forms via regular crystallization without the need to utilize a chiral resolving agent or external stimuli has achieved. The structures of the appropriate derivatives, (±)-3a, (±)-5a, (±)-3f, and (−)-3i, were further confirmed by their single-crystal X-ray crystallographic analyses.

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Introduction

The widely known Hajos–Parrish ketone (HPK)¹ prepared from the Hajos–Parrish–Eder–Sauer–Wiechert reaction (HPESW reaction)² has been generally utilized in the total synthesis of naturally occurring compounds and biologically active molecules, especially terpenoids and steroids (Fig. 1).³ For example, Shair and coworkers completed the total synthesis of cortistatin A beginning from a Hajos–Parrish ketone,⁴ and Deslongchamps and coworkers achieved the total synthesis of ouabagenin starting from a Hajos–Parrish ketone in a 41-step transformation.⁵ In addition to these applications in total synthesis, the study of the synthesis of highly functionalized HPK derivatives, e.g.,“iso-Hajos–Parrish” ketones,⁶ continues to be of great interest. However, despite these developments, a multicomponent domino reaction employing 2-methylcyclopentane-1,3-dione for the construction of highly functionalized HPK derivatives, especially those with nitro substitutents,⁷ known as a “synthetic chameleon” functional group, has rarely been attained.⁸ On the other hand, to our knowledge, the cascade reaction of 2-alkylcyclopentane-1,3-dione with two equivalents of nitroalkene⁹ via a formal [2 + 2 + 2] annulation,¹⁰ providing the synthesis of highly functionalized HPK analogues has not been revealed (Scheme 1).¹¹ Such a unique domino reaction is a fascinating theme of discovery. With the stated background and with the goal to broaden our investigations^12,13 of multicomponent organocatalytic asymmetric annulations¹⁴ via domino reactions¹⁵ or one-pot syntheses,¹⁶ we were prompted to examine the practicality of the double Michael–Henry cascade reaction of 2-methylcyclopentane-1,3-dione (1), and two equivalents of nitroalkene (2), Scheme 1. Herein, we report the details of our exploratory results, which afford high diastereoselectivity for the structurally distinct class of highly functionalized HPK (3) containing six contiguous stereogenic centers and two quaternary stereocenters.¹⁷

Fig. 1 Selected illustrations of the synthesis of natural occurring compounds employing the Hajos–Parrish ketone and its analogues.

Scheme 1 [2 + 2 + 2] annulation transformation of HPK derivative 3.

Results and discussion

The extremely low solubility of 2-methylcyclopentane-1,3-dione (1) in most organic solvents was troublesome for the reaction; after many attempts, CH₃CN was observed to be the best solvent medium for assessing the reaction, although 1 in CH₃CN was still poorly soluble.¹⁸

Initially, a solution of 1 and 3.5 equivalents of nitrostyrene 2a in CH₃CN was treated with Jørgensen–Hayashi catalyst I–HOAc (20 mol%), with no observation of the formation of product 3a, Table 1, entry 1. The same outcomes were observed in the reactions with catalyst I with an excess of HOAc (150 mol%) or DIPEA (20 mol%), Table 1, entries 2 and 3. The reactions with pyrrolidine (II, 150 mol%) or prolinol (III, 20 mol%) in CH₃CN or CH₃CN–H₂O were also in vain, Table 1, entries 4 and 5. Therefore, we were delighted to observe that the reaction with Takemoto catalyst (IV) and DIPEA (20 mol%) for 70 h afforded an 20% yield of the product 3a, Table 1, entry 6. Treatment with DIPEA (20 mol%) and the other bifunctional chiral thiourea derivatives, e.g. V, VI, gave lesser yields, 22% and 15%, respectively (table entries 7 and 8). Surprisingly, the product 3a obtained in the above reactions had no enantioselectivity (∼0% ee). This outcome suggested that the reaction may be facilitated by DIPEA, but not by the organocatalyst. This hypothesis was strengthened by the fact that the same reaction with an excess amount of DIPEA (150 mol%) in the absence of catalysts gave 64% yield of 3a in 12 h, Table 1, entry 9. However, the reaction with a catalytic amount of DIPEA (20 mol%) only provided 23% yield of adduct 3a, Table 1, entry 10. Although the solubility of the starting compounds was a pivotal issue, the reaction with an excess amount of DIPEA (150 mol%) in water gave no sign of reaction after 18 h (Table 1, entry 11). Other attempts to conduct the reaction in CH₃CN–H₂O (1 : 2) were fruitless and we observed only trace amounts of product 3a, Table 1, entry 12–16. The reaction conditions of DIPEA (150 mol%) at 0.2 M scale of 1 (Table 1, entry 9) were the best ones since the reactions at diluted conditions provided lower yields, (Table 1, entries 17–19). The reaction of two equivalents of 1 and one equivalent of 2a with DIPEA (80 mol%) in CH₃CN for 2 h afforded 22% yield of the intermediate 4a (Table 1, entry 20). Notably, 4a was unstable and it gradually decomposed back to 1 and 2a after standing at room temperature for a few days.

Table 1 A screening of the catalysts, additives, solvents, and other reaction conditions for the cascade reactions^a

Entry	Solvent	Cat (mol%)	Additive (mol%)	t (h)	Yield^b (%)
a Unless otherwise noted, the reactions were performed on a 0.2 M scale of 1 (1.0 equiv.) and 2a (3.5 equiv.) in CH3CN at ambient temperature.b Yields of 3a isolated.c On a 0.1 M scale of 1.d On a 0.05 M scale of 1.e On a 0.01 M scale of 1.f 1 (2.0 equiv.) and 2a (1.0 equiv.), 22% of 4a was isolated. nr = no reaction.
1	CH3CN	I (20)	HOAc (20)	72	∼0
2	CH3CN	I (20)	HOAc (150)	72	∼0
3	CH3CN	I (20)	DIPEA (20)	72	∼0
4	CH3CN	II (150)		72	∼0
5	CH3CN–H2O (1 : 2)	III (20)		72	∼0
6	CH3CN	IV (20)	DIPEA (20)	70	20
7	CH3CN	V (20)	DIPEA (20)	70	22
8	CH3CN	VI (20)	DIPEA (20)	70	15
9	CH3CN		DIPEA (150)	12	64
10	CH3CN		DIPEA (20)	72	23
11	H2O		DIPEA (150)	18	nr
12	CH3CN–H2O (1 : 2)		DIPEA (20)	72	Trace
13	CH3CN–H2O (1 : 2)		DIPEA (150)	72	Trace
14	CH3CN–H2O (1 : 2)	IV (20)		72	Trace
15	CH3CN–H2O (1 : 2)	VI (20)		72	Trace
16	CH3CN–H2O (1 : 2)	VII (20)		72	Trace
17^c	CH3CN		DIPEA (150)	24	51
18^d	CH3CN		DIPEA (150)	72	40
19^e	CH3CN		DIPEA (150)	240	Trace
20	CH3CN		DIPEA (80)	2	Trace^f

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After establishing the optimal reaction conditions (Table 1, entry 9), we next inspected the cascade reaction with a series of nitrostyrenes 2. The results were promising, generally with good stereoselectivities (Table 2). Most reactions were completed within one day to afford adducts 3 and 5 as the only isolable products along with the highly insoluble polymer solids, which arose from the self-polymerization of nitrostyrenes 2 with DIPEA. The reaction with an electron donating substituent (e.g., methyl) on the benzene ring of nitrostyrenes, 2b, gave a lesser yield of 3b (41%), and afforded much lower yield of 3c (20%) in the reaction with a much stronger electron donating substituent (e.g., methoxy) on the benzene ring of nitrostyrenes, 2c (Table 2, entries 2 and 3). Much more polymerized insoluble solids were observed in the above two reactions. The reaction of 1a with the 4-halo substituted nitrostyrenes 2d–2f afforded 60 to 46% yields of adduct 3d–3f (Table 2, entries 4–6). Interestingly, the reaction with 2-chloro substituted nitrostyrene, 2g, provided an excellent transformation and gave 81% yield of 3g, Table 2, entry 7. The reaction of the 4-nitro substituted nitrostyrene, 2h, with an electron withdrawing substituent, gave a good yield of 3h (77%), while the 2-nitro substituted nitrostyrene, 2i, gave 38% yield of 3i and 30% yield of 5i (Table 2, entries 8 and 9). The structures of 3a, 5a, 3f, and 3i were unequivocally determined by their single crystal X-ray crystallographic analyses (Fig. 2). It is interesting to note that the high self-disproportionation of enantiomers (SDE) effect^19,20 occurred during the crystallization process of racemic 3i. A chiral crystal of (−)-3i was obtained and its absolute stereochemistry was unequivocally established by its X-ray crystallographic analysis.²¹ Specifically, a sample of 15 mg of racemic 3i, prepared as described above, was dissolved with CH₂Cl₂ (15 mL) in a vial, followed by the slow addition of hexane (2 mL) down the inside of the vial and the two-layer solution was maintained throughout the addition process. The solution was capped and left to stand at room temperature for slow evaporation over 5 days to give some crystals (ca. 100 crystals) of the compound 3i. A crystal was subjected for the single crystal X-ray analysis (as shown in the Fig. S4 and Table S4, see ESI†). Surprisingly, a chiral space group: orthorhombic P2₁2₁2₁ was observed in the crystal! In order to understand the sign of its specific rotation and to probe the approximate frequency of occurrence of the SDE effect in the recrystallization process, another two crystals from the same batch were arbitrarily selected and subjected for single crystal X-ray analysis. Notably, each of them had the same chiral space group, orthorhombic P2₁2₁2₁, with the same absolute configuration as the previous crystal. The two single crystal X-ray analyses are shown in the Fig. S5, Table S5, Fig. S6, and Table S6, see ESI.† On the other hand, another batch of ca. 40 mg of racemic 3i was subject to the same recrystallization process as described previously to give ca. 150 crystals. From them, 46 crystals were arbitrarily selected and individually subjected to the HPLC analysis with a chiral column (Chiralpack IC). Eluent: 25% THF–hexane, flow rate: 1.0 mL min⁻¹. The two enantiomers were separated at R_t 5.6 min and R_t 8.0 min. For the 46 crystals analyzed, 16 of them eluted with R_t 5.6 min (>99% ee), 14 of them eluted with R_t 8.0 min (>99% ee), 2 of them displayed >80% ee, 4 of them were almost a racemate, and 10 of them had low ee. The pure enantiomer was individually collected, checking with the aid of the HPLC analysis, and subjected to optical rotation analysis. For R_t 5.6 min: [α]²⁹_D +10.2 (c 0.58, acetone); for R_t 8.0 min: [α]²⁹_D −9.1 (c 0.36, acetone).²² In addition, it has been suggested that compounds qualified for forming H-bonding would be exceptionally inclined to display a significant SDE effect in achiral chromatography separations. In this context, a SDE test was executed on a racemic mixture of 3i, but no SDE (Δee ≈ 0%) was detected in the fractions obtained from the achiral silica-gel chromatography. Furthermore, the chiral HPLC analysis of the arbitrarily selected six crystals from the crystallization of racemic 3a showed no SDE (Δee ≈ 0%). After the historical and special demonstration of tweezer-separation of sodium ammonium tartrate crystals by Pasteur in the 19^th century, the search for a convenient and high resolution protocol continues to be a pivotal subject in scientific studies. However, rare examples have been revealed regarding the high resolution of racemic mixtures into their enantiopure forms via regular crystallization without the need to utilize a chiral resolving agent or external stimuli. Furthermore, even with the advances of some technologies, the quest for enhanced chiral resolution methods is a long way from being complete, and this challenge remains to be conquered. As a result, the high magnitude of SDE in the crystallization process of racemic 3i is an unusual and intriguing example. The observation of a high SDE effect in the crystallization of racemic 3i not only yielded an enantiopure product,²³ but also established a new vista for potential application of this process in the resolution of various types of compounds,²⁴ and also may help to further our understanding of the origin of chirality in nature.²⁵ Since straightforward slow evaporation of the racemic 3i solution afforded self-resolution in crystalline form and provided substantial amounts of the enantiopure 3i in crystal form, it is highly reasonable to speculate that in the prebiotic era certain chemicals could also undergo a similar process to yield enantiopure substances followed by the subsequent asymmetric catalysis (amplification reaction) and produced the status quo with the surviving enantiopure natural products.²⁶

Table 2 Examples of cascade double Michael–Henry reaction^a

Entry	Ar	Products	t (h)	Yield of 3^b (%)	dr (3 : 5)^c
a Unless otherwise noted, the reactions were conducted on a 0.2 M scale of 1 (1.0 equiv.) and 2a (3.5 equiv.) in CH3CN at rt.b Yields of 3 isolated.c Determined by ^1H NMR of the crude reaction mixture.d 38% yield of 3i and 30% yield of 5i.
1	Ph	3a, 5a	12	64	80 : 20
2	4-Me-Ph	3b, 5b	15	41	84 : 16
3	4-MeO-Ph	3c, 5c	20	20	80 : 20
4	4-F-Ph	3d, 5d	15	60	88 : 12
5	4-Cl-Ph	3e, 5e	14	56	87 : 13
6	4-Br-Ph	3f, 5f	20	46	80 : 20
7	2-Cl-Ph	3g, 5g	20	81	87 : 13
8	4-NO2-Ph	3h, 5h	24	77	81 : 19
9	2-NO2-Ph	3i, 5i	15	38 (30)^d	57 : 43

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Fig. 2 Stereo plots of the X-ray crystal structures of (±)-3a, (±)-5a, (±)-3f and (−)-3i: C, gray; O, red; N, blue; Br, purple.

To account for the stereochemical outcome of this transformation, we proposed a conceivable mechanism (Scheme 2). The initial conjugate addition of 1 on nitrostyrene 2a, activated by DIPEA, followed by the subsequent conjugate addition of the intermediate A to nitrostyrene 2a via TS B, and the subsequent Henry reaction via TS C would give the adduct 3a as the major isomer.²⁷ It is noteworthy that reasonable amounts of the polymer residue, which is highly insoluble in most of the organic solvents, were observed in these reactions. This residue arose from the DIPEA-triggered polymerization of nitrostyrene since the same residue was observed in the reaction in the absence of dione 1.

Scheme 2 Proposed reaction mechanism.

Conclusions

In summary, a [2 + 2 + 2] annulation of 2-methylcyclopentane-1,3-dione and nitrostyrenes has been achieved via a cascade double Michael–Henry reaction that provides densely functionalized Hajos–Parrish type ketones with six contiguous stereogenic centers, including two quaternary carbons. DIPEA was identified as the best reagent for accelerating the reaction and provided diastereoselectivities under benign reaction conditions. The exquisite execution of the cascade reaction represents a straightforward and efficient approach to synthesize highly functionalized Hajos–Parrish type ketones, which ought to find broad applications in organic synthesis (for examples of the compounds with the methyloctahydro-1H-indenol skeleton, (Fig. 3). The structures of the appropriate derivatives, (±)-3a, (±)-5a, (±)-3f, and (−)-3i, were individually confirmed by single-crystal X-ray crystallographic analyses. In addition, we succeeded in demonstrating, in an unusual and intriguing example, a spontaneous high resolution of a racemic mixture into its enantiopure forms via regular crystallization without the need to utilize a chiral resolving agent or external stimuli. The observation of a high SDE effect in the crystallization of the racemic mixture of 3i not only afforded an enantiopure product, but also pointed toward the potential application of this process in the resolution of various types of compounds, and in addition, may extend our understanding of the origin of chirality in nature.

Fig. 3 Examples of naturally occurring compounds or biologically active agents with a methyloctahydro-1H-indenol skeleton.

Conflict of interest

The authors declare no competing financial interest.

Acknowledgements

We acknowledge the financial support for this study from the Ministry of Science and Technology (MOST, Taiwan) and thank the instrument center of MOST for analyses of compounds.

Notes and references

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21. The data were collected using CuKα (λ = 1.54178 Å) X-ray radiation. The Flack parameter was in accordance with the absolute structure assigned, absolute structure parameter = 0.06(3). Crystal system: orthorhombic, space group: P2₁2₁2₁.
22. Moreover, the above two crystals investigated by X-ray (CCDC 1488798 and CCDC 1488808) were individually subjected to HPLC analysis, comparing and co-injecting with the previous samples, with the conclusion that the chiral X-ray structures obtained herein are (−)-3i.†.
23. For review in the separation of non-racemic mixtures of enantiomers using fractional crystallization, see: F. Faigl, E. Fogassy, M. Nógrádi, E. Pálovics and J. Schindler, Org. Biomol. Chem., 2010, 8, 947.
24. For select examples, see: (a) G. Springuel and T. Leyssens, Cryst. Growth Des., 2012, 12, 3374; (b) J. E. Hein, B. H. Cao, M. W. Meijden, M. Leeman and R. M. Kellogg, Org. Process Res. Dev., 2013, 17, 946; (c) Y. Wang and A. Chen, Crystallization-Based Separation Of Enantiomers, in Stereoselective Synthesis of Drugs and Natural Products, ed. V. Andrushko, and N. Andrushko, Wiley, 2013, ch. 56, pp. 1663–1682; (d) L. Pasteur, Ann. Chim. Phys., 1848, 24, 442.
25. (a) H. Zhao, W. Q. Ong, F. Zhou, X. Fang, X. Chen, S. F. Y. Li, H. Su, N.-J. Chob and H. Zeng, Chem. Sci., 2012, 3, 2042; (b) D. G. Blackmond, Cold Spring Harbor Perspect. Biol., 2010, 2, a002147; (c) O. J. Vogl, J. Polym. Sci., Part A: Polym. Chem., 2011, 49, 1299; (d) J. Bailey, A. Chrysostomou, J. H. Hough, T. M. Gledhill, A. McCall, S. Clark, F. Ménard and M. Tamura, Science, 1998, 281, 672; (e) J. Podlech, Angew. Chem., Int. Ed., 1999, 38, 477; (f) V. A. Pavlov and E. I. Klabunovskii, Curr. Org. Chem., 2014, 18, 93.
26. For an excellent example and a review, see: (a) R. R. E. Steendam, J. M. M. Verkade, T. J. B. van Benthem, H. Meekes, W. J. P. van Enckevort, J. Raap, P. J. T. Floris, F. P. Rutjes and E. Vlieg, Nat. Commun., 2014, 5, 5543; (b) I. Weissbuch and M. Lahav, Chem. Rev., 2011, 111, 3236.
27. With the internal standard of 1,3,5-trimethoxybenzene, the ratio of 3a/5a was found to remain similar along with the progress of the reaction time, i.e., the isomerization of 5a to 3a was not observed.

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Footnote

† Electronic supplementary information (ESI) available: Experimental detail, spectroscopic characterization, HPLC analysis. CCDC 1474917, 1495243, 1474865, 1485986, 1488798, 1488808. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra22430j

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