Studies of intramolecular Diels–Alder reactions of nitroalkenes for the stereocontrolled synthesis of trans-decalin ring systems

Abstract

Studies of thermal IMDA cyclizations of (1E,7E)-1-nitro-deca-1,7,9-trienes and (1E,3Z,7E)-1-nitro-deca-1,3,7,9-tetraenes have been examined. Reactions of these nitroalkenes proceed via transition states featuring characteristics of asymmetric stretch asynchronicity and result in stereoselective formation of trans-fused decalin products. A substantial rate acceleration is observed for IMDA cyclizations exemplified by triene 14 due to steric repulsions of substituents in the tethering chain which promote facile stereocontrolled formation of trans-fused 26.

The intramolecular Diels–Alder reaction (IMDA) has been extensively utilized as a powerful strategy for the efficient construction of polycyclic systems.¹ Applications of transannular versions of IMDA reactions, as well as a number of creative IMDA strategies, have been featured for natural product synthesis.² Nevertheless, there are surprisingly few examples of IMDA processes which describe the use of nitroalkenes as dienophilic components. An early precedent illustrated the thermal cyclizations of 1-nitro-1,6,8-decatrienes for the synthesis of hexahydroindenes,³ and Kunesch and Tillequin described the cycloaddition of a 1,1-dinitroalkene with a tethered furan to produce 3,7-dinitro-11-oxatricycloundec-9-ene.⁴ In 2000, we reported the first study of IMDA reactions of (E)-1-nitro-1,7,9-decatrienes leading to substituted decalins as a preliminary investigation towards the synthesis of the AB ring system of norzoanthamine.⁵ Alternatively, the use of the nitroalkene moiety as a heterodiene in formal [4+2] cyclizations leading to nitronates has been extensively exploited by Denmark and coworkers as an effective strategy for the synthesis of alkaloids.⁶ In this communication, we describe studies of IMDA reactions of nitroalkenes which detail factors affecting the relative reactivity of these substrates as well as the observed stereoselectivity of the cyclization process.

A comparative summary is compiled in Table 1 for reports of thermal IMDA cyclizations of several representative decatrienes 1a–d. Houk has previously noted that the unactivated and unsubstituted (E)-deca-1,3,9-triene (1a) displays very little stereoselectivity in the production of nearly equal amounts of trans-fused and cis-fused decalins 2a and 3a.⁷ Four concerted synchronous transition state arrangements stemming from 4–7 are feasible in which the staggered conformations of the tethering carbon chain are compatible with a minimization of ring strain in the developing chair-like B ring. Thus cis-fused decalins are derived from arrangements 5 and 6 in which the transition state positions the diene in an axial orientation with respect to the developing cyclohexane of the tether. The incorporation of the ester in methyl (E,E)-undeca-2,8,10-trienoate (1b) does not significantly alter the product distribution even though this electron-withdrawing functionality increases the relative rate of the IMDA process.⁸ Further enhancement of the rate of the reaction is observed by the inclusion of the terminal nitro group in 1c and 1d, and these examples display a modest improvement in stereoselectivity which favors the trans-fused products 2c and 2d.⁵ Finally, the precoordination of Lewis acids result in powerful electron-withdrawing effects which dramatically alter the LUMO of the dienophile in 1e, and result in high trans-stereoselectivity (2e:3e ratio 97:3).⁹ These aspects of stereocontrol appear to correlate with a change from a concerted and highly synchronous reaction to a concerted, asynchronous pathway with increasing polarization of the dienophile. Indeed, Houk and Brown first described asymmetric stretch asynchronicity¹⁰ as a relevant concept leading to internal compression of the reacting C₂ and C₇ loci which proceeds to a greater preference for the trans-fused endo-transition states from 4 and 7.

Table 1.

A comparison study of the formation of trans- and cis-decalins via thermal IMDA cyclizations

Entry	Triene	Conditions	Yield % (ratio 2:3)	Literature Reference
1	1a EWG = H; R = H	220 °C/cyclohex	92 (48:52)	Ref. 7
2	1b EWG = COOMe; R = H	155 °C/toluene	92 (51:49)	Ref. 8
3	1c EWG = NO2; R = H	85 °C/benzene	63 (73:27)	Ref. 5
4	1d EWG = NO2; R = CH3	85 °C/benzene	80 (73:27)	Ref. 5
5		Me2AlCl (1.4 eq) −30 °C/CH2Cl2	88 (97:3)	Ref. 9

Our recent studies have examined the intramolecular [4π + 2π] cycloaddition of the 1-nitro-deca-1,3,6,8-tetraene system 8 (Scheme 1).¹¹

Scheme 1.

Studies of tetraene 8

Investigations of IMDA reactions of related tetraenes have not been previously explored. However, the incorporation of the (Z)-C₃–C₄ double bond in 8 was expected to provide an important element of conformational constraint which, in addition to the presence of the fully substituted C₆ carbon, would facilitate the cyclization process. One caveat is posed by the potential for thermal (Z) → (E) isomerization in 8. Mulzer and coworkers have recently addressed this issue by the design of an exo-selective transannular Diels–Alder reaction yielding cis-decalin products.¹²

In the event, we have observed slow cyclizations of 8 proceeding to 50% conversion upon heating at 90 °C under argon atmosphere in toluene (or xylenes) over a period of 12–15 hours. Small quantities of BHT are added to curtail radical decomposition processes, but longer reaction times lead to side products from destruction of the starting tetraene. In practice, we have routinely isolated a 50% yield of the substituted decalins 9 and 10 as a 88:12 ratio of diastereomers with the recovery of 45% yield of the starting material. In this fashion, approximately 72% yield of the trans-decalins 9 and 10 can be achieved after one recycle of starting tetraene.

Purification by flash silica gel chromatography afforded complete characterizations of 9 and 10, and NMR studies showed key NOESY correlations as depicted in Figure 1, which led to the assignments of relative stereochemistry.

Figure 1.

Key NOESY correlations for 9 and 10

Under basic conditions, product 9 underwent isomerization to give a separable mixture of C₁ epimers (99%, dr 5:1) in which the axial diastereomer 11 was identified as the major component. A number of bases produced the same unanticipated result. Indeed, our calculations confirm that 11 is less stable than the starting equatorial 9 by approximately 2.0 kcal/mol. This outcome suggests that the accumulation of 11 is the result of an unanticipated kinetic effect. Removal of the PMB ether and esterification yielded a highly crystalline sample of 12 (mp 111–112 °C), and X-ray diffraction studies of 12 provided an unambiguous stereochemical assignment.¹³ In addition, selective reduction with zinc in methanolic HCl yields the amino-substituted trans-decalins, such as 13 (70%) for further derivations.

Based on the cyclization results, we postulate that features of extended conjugation in tetraene 8, which lower the LUMO energy of the nitroalkene dienophile, have very little effect on the rate of this IMDA reaction. However, geometrical constraints imposed by the additional C=C benefit the asynchronous, endo-transition state affording higher trans-selectivity as compared with corresponding exo transition states leading to cis-decalins as seen in Table 1.

The observed stereochemical preference favoring the production of trans-fused decalins provided encouragement for studies of increasing structural complexity within the tethering chain as a prelude for efforts toward biologically significant natural products. In this regard, Scheme 2 illustrates a pathway of general utility which has led to the Diels–Alder nitroalkene precursors 14 and 15. The optically active (Z)-allylic alcohol 16 affords nearly quantitative esterification with (+)-3-methylnonanoic acid (17) to yield 18 as a single, nonracemic diastereomer.¹⁴

Scheme 2.

Preparation of trienes 14 and 15

A Claisen rearrangement protocol, featuring the slow addition of 18 into a THF solution of LDA and freshly distilled TMS-Cl, provides for conversion to an intermediate (E)-silylketene acetal which is heated to reflux in toluene (12 h). The methyl ester 19 is obtained in 86% yield following an aqueous workup and esterification. Subsequent cleavage of the silyl ether gave a primary alcohol and mesylation provided an unstable homoallylic mesylate for elimination, yielding the desired diene 19 (91% yield; 3 steps). Elongation of the carbon chain via an aldol condensation of the enolate of tert-butylacetate with aldehyde 20 leads to 21 (dr approximately 1:1) in excellent overall yield. However, further manipulations incorporating the (E)-nitroalkene dienophile required a selection of conditions to avoid β-elimination of the C-4 MOM ethers. This is accomplished by DIBAL reduction of 21 at −78 °C and buffered Dess–Martin oxidation of the resulting primary alcohols to give the aldehydes 22. Finally, Henry reactions¹⁵ with nitromethane are effectively achieved using KF in isopropanol at 22 °C (98% yields) and resulted in the isolation of the diastereomeric β-hydroxynitroalkane adducts. Subsequently, mild dehydrations are accomplished with methanesulfonyl chloride and Et₃N to produce the triene precursors 14 and 15, respectively, as unstable species which readily undergo the IMDA reaction.

Based upon our mechanistic analysis of these IMDA cyclizations, we anticipated a transition state B-ring anchored by the branched alkyl group at C₅ as an equatorial substituent of a preferred chair arrangement. The protected hydroxyl functionality was viewed as less significant although there were initial concerns about the propensity for elimination reactions under the thermal conditions. These fears proved to be unwarranted since the IMDA reaction of triene 23, as described in our previous efforts toward norzoanthamine, proceeded at 80 °C in refluxing benzene over 65 hours to yield 24 and 25 in 92% yield [dr 91:9].⁵ On the other hand, we were surprised to observe a remarkable rate enhancement in studies of the trienes 14 and 15 which resulted in production of small amounts of cyclization products at room temperature during silica gel chromatography of the IMDA precursors. Upon heating to reflux in benzene (containing BHT), the triene 14 was completely converted to 26 (85% yield) and 27 (4% yield) within 4 hours.¹⁶ Under identical conditions, the C-4 diastereomer 15 yielded three cyclization products (dr 25:55:20). The more polar, minor component was readily separated by flash chromatography and identified as cis-fused 29.¹⁷ Preparative HPLC led to the separation and purification of the trans-fused decalin 28 as the major product,¹⁷ and an additional isomer, which is assumed to be the alternative trans-fused system based on previous trends. Unfortunately, an unambiguous assignment of this third diastereomer was not feasible because key ¹H signals were overlapping and insufficiently resolved for correlations in 2D-COSY and 2D-NOESY spectra.

The presence of the branched C-5 alkyl substituent in trienes 14 and 15 leads to a substantial IMDA rate acceleration as a consequence of a Thorpe–Ingold effect from which steric repulsions of C-5 and C-6 substituents result in the compression of internal C-2 and C-7 loci in the Diels-Alder endo-transition states. The presentation of an axial OMOM substituent in the transition state from 15 destabilizes the B-ring chair arrangement owing to the 1,3-diaxial interaction with the C-6 methyl group and diminishes trans-selectivity in this IMDA example.

In conclusion, investigations of IMDA reactions using nitroalkene dienophiles have demonstrated the production of trans-fused decalin systems with high stereoselectivity. Our mechanistic rationale considers the benefits of geometrical constraints and steric repulsions within the tethering carbon chain which facilitate asynchronous, endo-transition states. Applications for the synthesis of natural products are underway.

Scheme 3.

IMDA cyclization of 23

Scheme 4.

IMDA cyclizations of trienes 14 and 15