Triphenylmethyl Group as a Highly Diastereoselective exo,endo-Auxiliary in Double Diels–Alder Reactions with 2H-Pyran-2-ones

Abstract

The influence of steric hindrance caused by the dienophiles on the stereoselectivity of cycloadditions of 2H-pyran-2-ones with maleimides was investigated in this study. It was found that sufficiently bulky N-substituents on the maleimides (such as N-triphenylmethyl) can cause the cycloaddition to proceed differently than expected, thus yielding asymmetric exo,endo-bicyclo[2.2.2]octenes instead of the commonly obtained symmetric exo,exo products. Furthermore, the incorporation of an N-triphenylmethyl group, which induces highly diastereoselective formation of asymmetric exo,endo adducts and can later be easily removed under acidic conditions, can be described as an example of an efficient exo,endo-diastereoselective auxiliary.

1. Introduction

The high importance of pericyclic reactions in general and, in particular, the Diels–Alder reaction, as versatile tools for constructing novel C–C bonds as fragments of larger scaffolds [1,2,3,4,5], stems in great part from detailed knowledge of their theoretical background [6,7,8,9,10,11,12]. This knowledge, rooted in the pioneering work of Woodward and Hoffmann [6,9], is directly reflected in the ability to reliably predict the reactivity of dienes and dienophiles in such transformations, as well as their regio- and stereoselectivities. This is obviously of utmost importance for the successful application of Diels–Alder reactions, but there are still some cases where certain surprises might lurk, and the observed stereoselectivity differs from what is anticipated. Recently, it was demonstrated that the kinetic preference for the endo attack in cycloadditions (the so-called endo rule) is often not (only) a consequence of orbital interactions, but is mainly caused by the unfavorable steric arrangement encountered in the transition state arising from an exo attack [8,11]. One of the rare and unusual cases where insurmountable steric hindrance causes a switch in the stereochemical course of a cycloaddition of 2H-pyran-2-ones from the otherwise preferred endo attack to an exo attack is described in the present article.

Primary cycloadducts 3 containing a CO₂-bridge, formed by the Diels–Alder reactions of substituted 3-acylamino-2H-pyran-2-ones 1 and suitable dienophiles such as N-substituted maleimides 2, often undergo a retro-hetero-Diels–Alder cycloaddition, resulting in the elimination of a CO₂ molecule (Scheme 1) [13]. The resulting cyclohexadiene intermediates 4 can be further transformed either into isoindole products 6 (through an additional oxidation step, often accelerated by suitable heterogeneous dehydrogenation catalysts) [14,15,16] or into bicyclo[2.2.2]octenes 5 (via a second cycloaddition step with 2) [17,18,19]. These compounds 5, also known as double cycloadducts or “butterfly”-like diazatetradecenes [19], are of great interest as they provide important insights into the stereoselectivity of these transformations and can be used for the subsequent synthesis of various compounds of pharmacological interest [13,20]. So far, in most cases, symmetric products exo,exo-5 have been obtained [17,18,19]; only in special cases involving sterically highly demanding 2H-pyran-2-ones 1, such as those fused with a cyclooctane ring (1, R²–R³ = -[CH₂]₆-) and with dienophiles 2 of sufficient size (R⁴ at least a Me group), have asymmetric cycloadducts exo,endo-5 been isolated [21]. The only other approach leading to asymmetric bicyclo[2.2.2]octene adducts from 2H-pyran-2-ones is the application of photochemical conditions [22]. An alternative, though more circuitous, route to some exo,endo derivatives relies on chemical desymmetrization methods starting from various symmetric bicyclo[2.2.2]octene derivatives [23].

Scheme 1.

General reaction pathway of cycloadditions between 2H-pyran-2-ones 1 and maleimides 2, yielding bicyclo[2.2.2]octenes 5 or isoindoles 6.

In addition to using conventional reaction conditions for the formation of 5 and 6 (e.g., heating under reflux), many of these adducts have also been successfully prepared under microwave irradiation [18,24,25] or at high pressures (13–15 kbar) [26,27]. Notably, the latter approach was the only suitable method for the synthesis of thermally sensitive intermediates of types 3 and 4 [27]. Moreover, a recent shift toward the use of conditions more consistent with the paradigms of modern green chemistry [28,29,30] is evident.

Herein we report the first example of a Diels–Alder reaction in which the significant steric hindrance of dienophiles 2 prevents the second cycloaddition step between 4 and 2 from proceeding with the same stereocourse as the first step, which, according to the literature data, preferentially occurs via the kinetically favored endo attack; where endo refers to the tendency for dienophile substituents to be oriented in the favored transition state so that they lie directly above the residual unsaturation of the diene, as described in [31]. Instead, the stereochemistry of the second step follows the opposite pathway to yield asymmetric exo,endo-5 adducts. From a synthetic point of view, this strategy, which employs the N-triphenylmethyl-substituted 2 as an effective diastereoselective auxiliary that can be easily removed after the cycloaddition, provides a facile entry into the class of asymmetric exo,endo-5. This new pathway is highly complementary to our previously described strategy, in which asymmetric adducts are formed due to the steric effects of a large ring fused to the pyran-2-one system [21], and represents a substantial addition to the often-described synthetic applications of 2H-pyran-2-one derivatives [32,33,34,35].

2. Results and Discussion

Based on our previous experience in this field [13,15,16,18,21,27], we anticipated that an approach to the synthesis of asymmetric cycloadducts exo,endo-5 that is complementary to the one described previously [21] could be realized by starting from sterically undemanding substituted 2H-pyran-2-ones 1 [36]. However, we recognized that this objective could only be achieved if the dienophile partners 2 are sufficiently sterically bulky. Therefore, we initially examined the reactions between the 5-methoxyphenyl derivative 1A, an example of an electron-rich 2H-pyran-2-one previously shown to form only symmetric bicyclo[2.2.2]octene adducts (exo,exo-5) upon cycloaddition of N-ethyl- or N-phenylmaleimide [18]. For the sterically demanding dienophiles 2 in this study, we selected the following substituted maleimides: N-[4-(tert-butyl)phenyl]- (2b), N-[2-(tert-butyl)phenyl]- (2c), N-(tert-butyl)- (2d), and N-triphenylmethylmaleimide (2e). For all these dienophiles 2, we found that they provided sufficient steric hindrance in the second cycloaddition step (i.e., 4 ⟶ 5) to yield asymmetric bicyclo[2.2.2]octenes (exo,endo-5), either as exclusive products or as mixtures with the symmetric exo,exo-5 derivatives. To evaluate the effects of steric hindrance in 2, preliminary reactions with 2a–e were conducted in closed vessels using toluene as the solvent and under microwave irradiation (1 h at 180 °C), which was sufficient for the complete conversion of 1a (Table 1).

Table 1.

Steric effect of dienophile 2 on the stereochemical outcome of the double Diels–Alder reaction with 1A ^a.

Entry	Dienophile 2 (R)		Product 5A	exo,endo-5A : exo,exo-5A b,c	Isolated Yields exo,endo-5A (exo,exo-5A) [%]
1	H	2a	5Aa	1 : 4.9 d	— e (82)
2	4-t-Bu-C6H4-	2b	5Ab	1 : 3.6 d	17 (65)
3	2-t-Bu-C6H4-	2c	5Ac	1 : 1.6 d	23 (38)
4	t-Bu	2d	5Ad	1 : 1.1 d	39 (43)
5	Ph3C-	2e	5Ae	1 : 0.04 d	87 (—) e

^a Reaction conditions: 2H-pyran-2-one 1A (0.5 mmol) and maleimide 2 (1.1 mmol) in toluene (2.2 mL), MW (1 h, 180 °C, power set to 300 W). ^b Determined by ¹H NMR spectroscopic analysis of the crude reaction mixture. ^c Conversion of starting 1A was quantitative. ^d Accompanied by a minor amount (<5%) of isoindoles 6A. ^e Not isolated.

As expected, the results of these cycloadditions show that as the steric demand of dienophiles 2 increases and the distance between the reacting double bond of dienophiles 2 and the site of highest steric congestion decreases, the amount of the asymmetric exo,endo adduct 5A increases. The most sterically congested dienophile, 2e, which possesses a triphenylmethyl group, displays the highest stereoselectivity, yielding nearly exclusively asymmetric exo,endo-5Ae when cycloadded on 1A (Table 1, Entry 5). In contrast, the other dienophiles 2b–d, which are less sterically congested, provide only mixtures of exo,endo and exo,exo cycloadducts 5Ab–d upon reaction with 1A (Table 1, Entries 2–4). We were able to separate these mixtures by column chromatography on silica gel and characterize each stereoisomer of product 5A individually. Specifically, 2b, which has the tert-butyl group at the position most distant from the maleimide nitrogen atom, gives the smallest amount of the asymmetric adduct (exo,endo-5Ab : exo,exo-5Ab = 1 : 3.6); 2d, with the tert-butyl group directly attached to the maleimide nitrogen, provides the largest amount of the asymmetric adduct (exo,endo-5Ad : exo,exo-5Ad = 1 : 1.1); and 2c, with the tert-butyl group at an intermediate position, gives an amount of the asymmetric adduct between the other two values (exo,endo-5Ac : exo,exo-5Ac = 1 : 1.6). On the other hand, the absence of the N-substituent on the dienophile (i.e., 2a) led primarily to the formation of the symmetric exo,exo-5Aa product (Table 1, Entry 1). It should also be noted that an insignificant amount (less than 5%) of the corresponding isoindole product 6A was formed in the cases discussed above.

To develop reaction conditions favorable for yielding asymmetric exo,endo adducts, we conducted a model reaction of 1A and 2c under microwave irradiation, while screening the effects of various additives, temperature changes, and solvents used on the outcome of this reaction (Table 2). Unfortunately, none of the additives previously known to influence the stereoselectivity of Diels–Alder reactions [37,38] increased the amount of exo,endo-5Ac (Table 2, Entry 1). The amount of exo,endo adduct did not increase with the addition of a Brønsted acid such as benzoic acid (Table 2, Entry 2), a Lewis acid such as ZnCl₂ (Table 2, Entry 3), the ionic liquid [emim]BF₄ (Table 2, Entry 4), or various organocatalysts (Table 2, Entries 5–7). Although the addition of bases such as Et₃N, quinine, or cinchonine (Table 2, Entries 8–10) slightly increased the amount of the desired exo,endo-5Ac, it also led to a significant increase in the formation of the undesired isoindole 6Ac (as demonstrated by ¹H NMR spectroscopy).

Table 2.

Optimization of reaction conditions ^a.

Entry	Additive	Solvent	T [°C]	t [h]	Conversion of 1A [%] b	Ratio of Products in Crude Reaction Mixture b
						exo,endo-5Ac	exo,exo-5Ac	6Ac
1	—	toluene	120	0.5	66	1	3.3	0.04
2	benzoic acid	toluene	120	0.5	62	1	3.7	0.06
3	ZnCl2	toluene	120	0.5	60	1	3.7	0.42
4	[emim]BF4	toluene	120	0.5	56	1	4.1	0.09
5	N,N′-diphenylthiourea	toluene	120	0.5	76	1	3.5	0.10
6	L-prolinol	toluene	120	0.5	65	1	3.8	0.58
7	L-proline	toluene	120	0.5	72	1	3.3	0.04
8	Et3N	toluene	120	0.5	72	1	2.6	5.8
9	quinine	toluene	120	0.5	70	1	2.9	5.7
10	cinchonine	toluene	120	0.5	66	1	2.9	8.3
11	—	toluene	120	2	89	1	2.6	0.08
12	—	toluene	140	2 c	93	1	2.2	0.08
13	—	toluene	160	2 c	99	1	2.0	0.09
14	—	toluene	180	1 d	>99	1	1.6	0.06
15	—	xylene e	180	1 d	>99	1	1.7	0.44
16	—	anisole	180	1 d	>99	1	2.4	0.25
17	—	n-heptane	180	1 d	>99	1	2.4	0.04
18	—	3-pentanone	180	1 d	>99	1	3.3	0.22
19	—	n-butanol	180	1 d	99	1	3.3	0.10
20	—	isobutanol	180	1 d	99	1	3.8	0.06
21	—	n-propanol	180	1 d	97	1	4.1	0.16
22	—	H2O	180	1 d	>99	1	6.1	0.03
23	—	MeCN	180	1 d	98	1	6.4	1.7
24	—	1,4-dioxane	180	1 d	79	1	3.7	1.1

^a Reaction conditions: 2H-pyran-2-one 1A (0.5 mmol), maleimide 2c (1.1 mmol), additive (0.1 mmol), solvent (2.2 mL), and MW (power set to 100 W). ^b Determined by ¹H NMR spectroscopic analysis of the crude reaction mixture. ^c MW power set to 150 W. ^d MW power set to 300 W. ^e Mixture of isomers.

Consequently, we continued studying the model reaction without additives to evaluate the effect of reaction temperature. Increasing the temperature (while reducing the reaction time) resulted in a higher yield of the asymmetric adduct 5Ac, while the formation of isoindole 6Ac remained favorably low (Table 2, Entries 11–14). We then performed a series of experiments to determine the influence of the solvent on the model reaction (Table 2, Entries 15–24). In xylene (a mixture of isomers), the reaction proceeded less efficiently than in toluene, yielding a similar ratio of 5Ac stereoisomers, but a larger amount of isoindole 6Ac (Table 2, Entries 14 and 15). In contrast, anisole and n-heptane, the least-polar among the tested solvents, produced a higher amount of undesired exo,exo-5Ac with a moderately low quantity of 6Ac (Table 2, Entries 16 and 17). Switching to a more polar and protic reaction medium disrupted the previously observed ratio between exo,endo- and exo,exo-5Ac. Neither 3-pentanone (Table 2, Entry 18) nor various alcohols (Table 2, Entries 19–21) improved selectivity toward the asymmetric product. Water was even less effective than previous examples (Table 2, Entry 22). Acetonitrile, on the other hand, yielded the largest amount of aromatic 6Ac (Table 2, Entry 23), while the amount of the desired asymmetric product was the lowest among all solvents tested. When 1,4-dioxane was used (Table 2, Entry 24), conversion was very low, and the amount of asymmetric product was mediocre. Comparing these results, it is evident that non-polar solvents combined with high temperature are essential for achieving preferential formation of asymmetric exo,endo-5Ac adducts.

To further investigate the factors responsible for the stereoselectivity of these transformations, we studied the cycloaddition of various 2 with other 3-benzoylamino-2H-pyran-2-ones 1B–K (Table 3, Entries 1–5, 7, 9, 11–17) under microwave irradiation (in toluene at 160 or 180 °C for 1 or 2 h in most cases). With maleimides 2a–d, which are less sterically hindered than 2e, symmetric exo,exo-5Ba–d were obtained as the major products (Table 3, Entries 1–4), with ratios of asymmetric to symmetric products ranging from 1 : 5.6 to 1 : 1.1. However, regardless of the electronic or steric properties (i.e., substituents at position 5) of the dienes 1, the outcome of the cycloaddition with 2e was analogous in all cases: highly dominant formation of the asymmetric exo,endo-5B–Je double cycloadducts.

Table 3.

Products 5 prepared by the Diels–Alder reaction of substituted 2H-pyran-2-ones 1 and maleimides 2 ^a.

Entry	2H-Pyran-2-ones 1			1	2	R4	t [h]	T [°C]	Product 5	exo,endo-5 : exo,exo-5 b,c	Isolated Yields exo,endo-5 (exo,exo-5) [%]
	R1	R2	R3
1	Ph	3,4-(MeO)2-C6H3-	Me	1B	2a	H	1	180	5Ba	1 : 4.9	— d (85)
2	Ph	3,4-(MeO)2-C6H3-	Me	1B	2b	4-t-Bu-C6H4-	1	180	5Bb	1 : 5.6	11 (70)
3	Ph	3,4-(MeO)2-C6H3-	Me	1B	2c	2-t-Bu-C6H4-	1	180	5Bc	1 : 2.5	19 (49)
4	Ph	3,4-(MeO)2-C6H3-	Me	1B	2d	t-Bu	1	180	5Bd	1 : 1.1	38 (44)
5	Ph	3,4-(MeO)2-C6H3-	Me	1B	2e	Ph3C-	1	180	5Be	1 : 0.05	85 (—) d
6	Ph	COPh	Me	1C	2a	H	2	160	5Ca	1 : 4.0	— d (75)
7	Ph	COPh	Me	1C	2e	Ph3C-	4	140	5Ce	1 : 0	79 (—) d
8	Ph	CO2Et	Me	1D	2a	H	2	180	5Da	1 : 8.4	— d (86)
9	Ph	CO2Et	Me	1D	2e	Ph3C-	1	180	5De	1 : 0	81 (—) d
10	Ph	-[CH2]4-		1E	2a	H	2	160	5Ea	1 : 4.1	— d (80)
11	Ph	-[CH2]4-		1E	2e	Ph3C-	2	160	5Ee	1 : 0.1	70 (—) d
12	Ph	COMe	Me	1F	2e	Ph3C-	1	180	5Fe	1 : 0	75 (—) d
13	Ph	CH2CO2Me	CO2Me	1G	2e	Ph3C-	3	160	5Ge	1 : 0	72 (—) d
14	Ph	-[CH2]5-		1H	2e	Ph3C-	1	180	5He	1 : 0	77 (—) d
15	Ph	-[CH2]3-		1I	2e	Ph3C-	1	180	5Ie	1 : 0.4	55 (—) d
16	Ph	Ph	Ph	1J	2e	Ph3C-	5	160	5Je	1 : 0.3	56 (—) d
17	Me	4-MeO-C6H4-	Me	1K	2e	Ph3C-	2	160	5Ke	1 : 0.1	77 (—) d

^a Reaction conditions: 2H-pyran-2-one 1 (0.5 mmol) and maleimide 2 (1.1 mmol), toluene (2.2 mL), and MW (power set to 300 W). ^b Determined by ¹H NMR spectroscopic analysis of the crude reaction mixture. ^c Conversion of starting 1 was quantitative. ^d Not isolated.

It is important to note that in one case (the reaction of 1C with 2e, Scheme 2), we had to modify the general reaction conditions to obtain pure 5Ce, as the conditions used in other cases were not suitable. Specifically, when the cycloaddition of 1C and 2e was carried out at 160 °C in toluene under microwave irradiation for 2 h, a substantial amount of the undesired isoindole product 6Ce was observed (exo,endo-5Ce : 6Ce = 1 : 0.25). Changing the solvent from toluene to the more polar acetonitrile was detrimental for our purpose, as after 2 h of microwave irradiation at 160 °C, no double cycloadduct 5Ce was formed; however, the isoindole 6Ce and its N-deprotected derivative 6Ca were detected in the crude reaction mixture (6Ce : 6Ca = 1 : 2). Therefore, we further varied the reaction time and temperature (using toluene as the solvent) and found that increasing the time to 4 h and decreasing the temperature to 140 °C was sufficient to yield predominantly the desired asymmetric double cycloadduct exo,endo-5Ce (accompanied by approximately 10% of the isoindole adduct 6Ce) (Table 3, Entry 7). Another case where the general reaction conditions required slight modification was the cycloaddition of 2e with 1J (Table 3, Entry 16). Here, due to the very low reactivity of the starting 2H-pyran-2-one 1J, the reaction time was increased to 5 h (at 160 °C to minimize the formation of the undesired isoindole 6Je), but the yield of the asymmetric exo,endo-5Je remained below average (56%).

Scheme 2.

Synthesis of the bicyclo[2.2.2]octene derivative exo,endo-5Ce and isoindoles 6C.

The results of these cycloadditions, along with data from the literature [21,27], show that the first cycloaddition step (i.e., 1 ⟶ 3) should occur via an endo attack as expected, since it is kinetically favored over an exo attack. However, the elimination of CO₂ that follows erases the stereochemical information from the first step; the two pairs of enantiomers of endo-3 and exo-3 initially formed [21,27] are reduced to a single pair of enantiomeric cyclohexadiene systems 4 (Scheme 3). The second cycloaddition step (i.e., 4 ⟶ 5) can yield asymmetric exo,endo-5 if it proceeds via a stereocourse opposite to the first step; therefore, if the first step took place via an endo attack, the second step must follow an exo attack from the opposite side of the diene system, where the previously incorporated dienophile ring is located, yielding the observed asymmetric exo,endo-5. Significant steric hindrance and congestion in the second transition state minimize the formation of symmetric exo,exo-5 and instead favor the attack that yields asymmetric exo,endo-5, which are, understandably, formed as racemates [8,11].

Scheme 3.

Schematic representation of the theoretically possible stereochemical pathways leading to four stereoisomeric bicyclo[2.2.2]octenes 5, via endo-3 or exo-3 (each of which exists as a pair of enantiomers) and an enantiomeric pair of 4. The attacks in the final cycloaddition step (i.e., 4 ⟶ 5) that are presumed to be sterically favorable are highlighted in bold.

The rather harsh reaction conditions required for the cycloadditions between 1 and 2, as well as for the elimination of CO₂, in certain cases also enable the aromatization of the cyclohexadiene intermediates 4 (at least in the reaction between 1C and 2e), resulting in the formation of isoindoles 6 as side products. Notably, pure isoindoles 6 can be prepared via direct cycloaddition between the corresponding 2H-pyran-2-ones 1 and maleimides 2, facilitated by the application of a heterogeneous dehydrogenation catalyst such as active carbon Darco KB (which prevents the formation of bicyclo[2.2.2]octenes 5), as demonstrated previously [16]. Although this approach with maleimide (2a) is feasible, the use of N-triphenylmethylmaleimide (2e) has proven inappropriate because the heterogeneous catalyst causes cleavage of the N–C bond in 2e, consequently favoring the formation of a deprotected derivative 6Ca (R⁴ = H).

To determine whether the symmetric adducts exo,exo-5 can eventually convert into the corresponding asymmetric adducts exo,endo-5 during the reactions, we investigated the transformation of pure exo,exo-5Ad under conditions analogous to those applied for the cycloadditions (i.e., microwave irradiation at 160 °C for 2 h in toluene). ¹H NMR analysis of the crude reaction mixture showed that, at best, only a trace of exo,endo-5Ad was formed, with the vast majority of the starting material remaining unchanged and only a negligible amount of additional degradation material observed. This proves that the asymmetric exo,endo-5 are formed directly and not via symmetric adducts followed by (intramolecular) isomerization.

On the other hand, we have observed that prolonging reaction times, especially at higher temperatures, consistently increases the amount of isoindole products 6 formed via thermal dehydrogenation of 4 (predominantly taking place via the hydrogen transfer to the maleimides 2, which are reduced to the corresponding succinimides [16] or possibly also partially via the acceptorless mechanism [39,40,41]), consequently decreasing the yields of 5.

For our further studies, we were eager to obtain asymmetric bicyclo[2.2.2]octenes exo,endo-5 with less bulky R⁴ groups. Direct cycloaddition of the appropriate maleimides 2 has already proven inadequate for accessing these compounds. For example, cycloaddition between 1A and maleimide (2a) yields exclusively symmetric exo,exo-5Aa (Table 1, Entry 1). To obtain the desired asymmetric counterpart, we devised an alternative route: a thermal, acid-promoted elimination of the N-triphenylmethyl substituent from asymmetric bicyclo[2.2.2]octenes exo,endo-5 (Table 4). We established that 1 h of microwave irradiation at 100 °C in a mixture of trifluoroacetic acid (TFA) and n-BuOH (1 : 3) was appropriate, as it resulted in complete conversion to N-unsubstituted exo,endo-5Aa in high yield (Table 4, Entry 1). It is important to note that no isomerization to the symmetric exo,exo-5Aa was observed in the ¹H NMR spectrum of the crude reaction mixture. Therefore, cycloaddition of N-triphenylmethyl group-containing dienophiles (i.e., 2e) leads to diastereospecific formation of asymmetric bicyclo[2.2.2]octene frameworks (exo,endo-5) as racemates, and the triphenylmethyl group can be easily removed after cycloaddition; thus, it acts as a diastereospecific exo,endo-auxiliary. Besides the formation of exo,endo-5Aa, the same strategy was applied to exo,endo-5B–Ea, which were prepared under nearly identical conditions as above from exo,endo-5B–Ee in excellent yields (Table 4, Entries 2–5). In these cases, as well, direct cycloaddition between 1B–E and 2a is not applicable, as symmetric exo,exo-5B–Ea are formed overwhelmingly.

Table 4.

Preparation of exo,endo-5A–Ea via removal of N-triphenylmethyl groups from exo,endo-5A–Ee ^a.

Entry	Bicyclo[2.2.2]Octene exo,endo-5A–Ee			T (°C)	Product exo,endo-5A–Ea b	Isolated Yield [%]
	R1	R2
1	4-MeO-C6H4-	Me	5Ae	100	5Aa	85
2	3,4-(MeO)2-C6H3-	Me	5Be	100	5Ba	87
3	COPh	Me	5Ce	100	5Ca	93
4	CO2Et	Me	5De	140 c	5Da	88
5	-[CH2]4-		5Ee	140	5Ea	91

^a Reaction conditions: bicyclo[2.2.2]octene exo,endo-5A–Ee (0.33 mmol), n-BuOH (3 mL), TFA (1 mL), and MW (power set to 100 W, 1 h). ^b Conversion of starting exo,endo-5A–Ee was quantitative. ^c Reaction was conducted in EtOH; the amount of TFA added was reduced to 0.3 mL.

We also wanted to investigate the possible effects of the size of the 3-acylamino moieties (i.e., groups bound to position 3 of the starting compounds 1). To this end, we replaced the benzoyl group in 1A (R¹ = Ph) with the much smaller acetyl group (1, R¹ = Me) and reacted the resulting 1K (prepared by removing the 3-benzoyl group from 1A under acidic conditions, followed by the introduction of a 3-acetyl group, according to a modified procedure as described previously [42]) with N-triphenylmethylmaleimide (2e), obtaining a result analogous to those observed for 1A–J, namely, predominantly asymmetric exo,endo-5Ke was formed (Table 3, Entry 17). Clearly, the size of the 3-acylamino group (i.e., R¹) does not play a significant role in determining the stereoselectivity of these transformations; the R⁴ group of the maleimides 2 has a much greater impact. This is not surprising, as the NHCOR¹ group is much more flexible (due to the –NH–CO– linker) than R⁴, making it easy to imagine that its conformational freedom does not interfere with the attack of the dienophile during the cycloaddition, and therefore does not influence the ratio of asymmetric exo,endo-5 to symmetric exo,exo-5 formation.

To distinguish between the asymmetric and symmetric structures of 5, NMR data were crucial (Figure 1). For exo,endo-5, four sets of doublets (each integrated as 1H) corresponding to the four aliphatic protons of the bicyclo[2.2.2]octene skeleton are observed. Two sets of doublets appear at δ 1.28–3.63 ppm (mean 2.55, range 2.35) and δ 0.84–3.26 ppm (mean 2.24, range 2.42), corresponding to the two protons (3a-H and 8a-H) being anti to the double bond. The other two doublets appear at δ 2.74–3.73 ppm (mean 3.10, range 0.99) and δ 3.90–4.85 ppm (mean 4.29, range 0.95), corresponding to the two protons (4a-H and 7a-H) being syn to the double bond. The coupling constant ranges are 7.8–9.0 Hz and 9.8–10.5 Hz for the pairs being anti and syn to the double bond, respectively. On the other hand, for symmetric exo,exo-5, only two doublets (each integrated as 2H) are observed at δ 2.74–3.44 ppm (mean 3.08, range 0.70) and δ 4.10–4.78 ppm (mean 4.40, range 0.68) in the ¹H NMR spectra (coupling constants 8.3–8.8 Hz). All these data, corroborated by the ¹³C, ¹H–¹³C gs-HSQC, and ¹H–¹³C gs-HMBC 2D NMR spectra, clearly show the difference between the two structural types; furthermore, they are in agreement with previously published results for cyclooctane-fused asymmetric systems exo,endo-5 (R² – R³ = -[CH₂]₆-) [21]. Additionally, some of the exo,endo adducts were structurally characterized by single-crystal X-ray diffraction spectroscopy [43].

Figure 1.

Comparison of the structural features of asymmetric and symmetric adducts 5, highlighting the key differences reflected in the ¹H NMR data.

3. Materials and Methods

3.1. General

Melting points were determined on a micro hot stage apparatus and are uncorrected. NMR spectra were recorded with a Bruker (Zürich, Switzerland) Avance III 500 spectrometer at 29 °C, using TMS as the internal standard at 500 MHz for ¹H NMR and 126 MHz for ¹³C NMR. Chemical shifts are provided as ppm values on the δ scale, and the coupling constants (J) are given in Hertz. ¹³C NMR spectra are referenced against the central line of the solvent signal (CDCl₃ at 77.0 ppm and DMSO-d₆ at 39.5 ppm). ¹H NMR peak assignments are additionally based on analyses of ¹H–¹³C gs-HSQC and ¹H–¹³C gs-HMBC 2D NMR spectra. IR spectra of compounds as powders were obtained with a Bruker (Zürich, Switzerland) Alpha Platinum ATR FT-IR spectrophotometer. Mass spectra were recorded using an Agilent (Santa Clara, CA, USA) 6624 Accurate Mass TOF LC/MS spectrometer via ESI ionization. Elemental analyses were performed using a Perkin Elmer 2400 Series II CHNS/O analyzer (PerkinElmer, Inc., Waltham, MA, USA). TLC was carried out on silica gel TLC cards with a fluorescent indicator, and visualization was accomplished with UV light (254 nm). Reagents and solvents were used as received from commercial suppliers with a purity of 98% or higher. The xylene used was a commercially available mixture of all three isomers.

Microwave reactions were conducted in air using a focused microwave unit (Discover by CEM Corporation, Matthews, NC, USA). The instrument features a continuous, focused microwave power delivery system with operator-selectable power output from 0 to 300 W. Reactions were carried out in darkness in glass vessels (10 mL capacity) sealed with a septum. The pressure was controlled by a load cell connected to the vessel via the septum. The temperature of the vessel contents was monitored using a calibrated infrared temperature controller mounted beneath the reaction vessel, measuring the temperature of the vessel’s outer surface. The mixtures were stirred with a Teflon-coated magnetic stirring bar in the vessel. Temperature, pressure, and power profiles were recorded using commercially available software provided by the microwave unit manufacturer.

3.2. Synthesis and Characterization of Starting 2H-Pyran-2-Ones 1

The starting compounds 1A–I were prepared from appropriate compounds containing activated CH₂ groups (such as 1,3-diketones, β-ketoesters, substituted acetones, etc.), a C₁-synthon (DMFDMA, trimethyl or triethyl orthoformate, etc.) and hippuric acid, as described in [36]; compounds 2b,c,e were prepared according to the procedures described previously [44,45]. The new 2H-pyran-2-one 1J was synthesized by refluxing 1,2-diphenylethanone (5.89 g, 30 mmol) and DMFDMA (7.15 g, 60 mmol) for 4 h; thereafter, the volatile components were removed under reduced pressure. The crude residue was then reacted with hippuric acid (5.38 g, 30 mmol) in acetic anhydride (35 mL) at 90 °C for 4 h. After the removal of the volatile components, the residue was treated with ethanol (20 mL) and, after prolonged cooling (5 days), the precipitate was filtered off, washed with ethanol, and dried to afford the corresponding product 1J.

3-Benzamido-5,6-diphenyl-2H-pyran-2-one (1J): yellow solid (8.69 g, 79%); mp 195–197 °C (EtOH); IR (ATR) ν_max 3392, 1698, 1677, 1634, 1513, 1482, 1379, 1249, 1152, 1071 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 8.78 (s, 1H, NH), 8.64 (s, 1H, CH), 7.90–7.94 (m, 2H, ArH), 7.57–7.62 (m, 1H, ArH), 7.50–7.55 (m, 2H, ArH), 7.27–7.38 (m, 8H, ArH), 7.22–7.26 (m, 2H, ArH); ¹³C NMR (CDCl₃, 126 MHz) δ 166.0, 159.6, 150.9, 136.4, 133.5, 132.5, 131.8, 129.5, 129.4, 129.0, 128.94, 128.88, 128.3, 128.2, 128.0, 127.2, 123.7, 119.1; HRMS (ESI-TOF) m/z 368.1279 (calcd for C₂₄H₁₈NO₃ (M + H)⁺ 368.1281); Anal. C, 78.35; H, 4.53; N, 3.85 (calcd for C₂₄H₁₇NO₃ C, 78.46; H, 4.66; N, 3.81).

For the synthesis of 1K, the mixture of 3-benzoylamino-2H-pyran-2-one derivative 1A (3.35 g, 10 mmol), ethanol (250 mL), and concentrated aq. HCl (150 mL) was refluxed for 21 h. After cooling, the filtrate was neutralized with NaHCO₃, and the volatile components were removed under reduced pressure. Water (200 mL) was added, and the mixture was extracted with CH₂Cl₂ (3 × 200 mL). The combined extracts were dried over Na₂SO₄ and concentrated in vacuo to give a solid residue. This was then dissolved in CH₂Cl₂ (40 mL) and left to react with acetyl chloride (735 μL, 10.3 mmol) and pyridine (840 μL, 10.4 mmol) for 4 h at room temperature. The volatile components were removed under reduced pressure, and water (20 mL) was added to the oily residue. The precipitated material was filtered off, washed with water and diethyl ether, and dried to yield the product 1K.

3-Acetamido-5-(4-methoxyphenyl)-6-methyl-2H-pyran-2-one (1K): ochre solid (2.07 g, 76%); mp 179–181 °C (EtOH/CH₂Cl₂); IR (ATR) ν_max 3312, 1705, 1683, 1509, 1383, 1290, 1244, 1174, 1128, 1031 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 8.29 (s, 1H, CH), 7.94 (s, 1H, NH), 7.20 and 6.94 (AA’XX’, J = 8.5 Hz, 2H each, 4-OCH₃-C₆H₄), 3.84 (s, 3H, OCH₃), 2.25 (s, 3H, CH₃), 2.20 (s, 3H, COCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.2, 159.8, 159.2, 151.4, 130.1, 128.2, 127.7, 122.7, 118.2, 114.0, 55.3, 24.6, 17.8; HRMS (ESI-TOF) m/z 274.1066 (calcd for C₁₅H₁₆NO₄ (M + H)⁺ 274.1074); Anal. C, 66.04, H, 5.23; N, 5.18 (calcd for C₁₅H₁₅NO₄ C, 65.92; H, 5.53; N, 5.13).

3.3. Synthesis of Bicyclo[2.2.2]Octenes exo,endo/exo,exo-5 via Microwave Cycloaddition of 2H-Pyran-2-Ones 1 with Maleimides 2

A mixture of 2H-pyran-2-one 1 (0.5 mmol), the corresponding N-substituted maleimide 2 (1.1 mmol), and toluene (2.2 mL) was irradiated in the focused microwave equipment for the time and at the temperature specified in Table 3. The power was set to 300 W with a ramp time of 5 min. After irradiation, the reaction mixture was cooled to room temperature, and the volatile components were removed under reduced pressure, yielding crude products 5.

The products exo,endo-5Ae and exo,endo-5Be were purified by crystallization from EtOAc, yielding pure exo,endo adducts. In all cases of the synthesis of 5Ab–d and 5Bb–d, mixtures of both stereoisomers were separated by column chromatography (SiO₂, petroleum ether : EtOAc = 10 : 1), yielding both types of adducts: exo,endo-5Ab–d,Bb–d and exo,exo-5Ab–d,Bb–d. Products exo,endo-5C–Ke were purified by column chromatography (SiO₂, petroleum ether : EtOAc = 10 : 1). For the analyses, all products were recrystallized from the appropriate solvents. For ¹H, ¹³C NMR and representative example of ¹H–¹³C gs-HSQC and ¹H–¹³C gs-HMBC 2D NMR NMR spectra of all new products 1 and 5, see Supplementary Materials.

rel-N-((3aR,4R,4aS,7aR,8S,8aS)-9-(4-methoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,exo-5Aa): white solid (199 mg, 82%); mp 348–349 °C (EtOH); IR (ATR) ν_max 3364, 3153, 3063, 1697, 1648, 1543, 1510, 1346, 1307, 1207, 1181 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 11.26 (s, 2H, 2 × NH), 8.61 (s, 1H, 4-NH), 7.87–7.90 (m, 2H, ArH), 7.53–7.57 (m, 1H, ArH), 7.48–7.52 (m, 2H, ArH), 6.92 and 6.87 (AA’XX’, J = 8.5 Hz, 2H each, 4-OCH₃-C₆H₄), 6.30 (s, 1H, C=CH), 4.23 (d, J = 8.5 Hz, 2H, 3a-CH, 4a-CH), 3.75 (s, 3H, OCH₃), 3.08 (d, J = 8.5 Hz, 2H, 7a-CH, 8a-CH), 1.66 (s, 3H, CH₃); ¹³C NMR (DMSO-d₆, 126 MHz) δ 178.0, 176.4, 167.6, 158.8, 145.2, 135.7, 131.0, 130.0, 128.9, 128.0, 127.7, 127.3, 113.6, 57.8, 55.1, 50.2, 44.6, 42.1, 18.6; HRMS (ESI-TOF) m/z 486.1659 (calcd for C₂₇H₂₄N₃O₆ (M + H)⁺ 486.1660); Anal. C, 66.17; H, 4.53; N, 8.35 (calcd for C₂₇H₂₃N₃O₆ · 1/4 H₂O C, 66.18; H, 4.83; N, 8.58).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-2,6-Bis(4-(tert-butyl)phenyl)-9-(4-methoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Ab): white solid (64 mg, 17%); R_f = 0.58 (PE/EtOAc 1/1); mp 247–249 °C (EtOH); IR (ATR) ν_max 2957, 2916, 2848, 1709, 1655, 1509, 1374, 1246, 1183 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.67 (s, 1H, NH), 7.87–7.91 (m, 2H, ArH), 7.49–7.60 (m, 7H, ArH), 7.30 and 7.11 (AA’XX’, J = 8.5 Hz, 2H each, ArH), 7.09 and 6.93 (AA’XX’, J = 9.0 Hz, 2H each, ArH), 6.39 (s, 1H, C=CH), 4.26 (d, J = 9.8 Hz, 1H, 4a-CH), 3.76 (s, 3H, OCH₃), 3.63 (d, J = 8.3 Hz, 1H, 3a-CH), 3.37 (d, J = 9.8 Hz, 1H, 7a-CH), 3.24 (d, J = 8.3 Hz, 1H, 8a-CH), 1.69 (s, 3H, CH₃), 1.32 (s, 9H, C(CH₃)₃), 1.30 (s, 9H, C(CH₃)₃); ¹³C NMR (DMSO-d₆, 126 MHz) δ 175.6, 175.3, 175.2, 174.0, 166.6, 158.8, 151.2, 145.7, 134.8, 132.3, 131.6, 129.8, 129.54, 129.48, 129.2, 128.4, 127.3, 126.9, 126.2, 126.0, 125.6, 113.6, 57.3, 51.1, 50.9, 45.9, 45.5, 43.7, 41.5, 34.5, 31.1, 31.0, 19.3; HRMS (ESI-TOF) m/z 750.3525 (calcd for C₄₇H₄₈N₃O₆ (M + H)⁺ 750.3538); Anal. C, 73.30; H, 6.59; N, 5.53 (calcd for C₄₇H₄₇N₃O₆ · H₂O C, 73.51; H, 6.43; N, 5.47).

rel-N-((3aR,4R,4aS,7aR,8S,8aS)-2,6-Bis(4-(tert-butyl)phenyl)-9-(4-methoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,exo-5Ab): white solid (243 mg, 65%); R_f = 0.35 (PE/EtOAc 1/1); mp 233–235 °C (EtOH); IR (ATR) ν_max 3312, 2956, 1709, 1643, 1551, 1511, 1374, 1193, 1179, 1159 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.77 (s, 1H, NH), 7.82–7.86 (m, 2H, ArH), 7.45–7.56 (m, 7H, ArH), 7.03 (AA’BB’, J = 9.0 Hz, 4H, ArH), 6.93–6.98 (m, 4H, ArH), 6.45 (s, 1H, C=CH), 4.54 (d, J = 8.5 Hz, 2H, 3a-CH, 4a-CH), 3.76 (s, 3H, OCH₃), 3.44 (d, J = 8.5 Hz, 2H, 7a-CH, 8a-CH), 1.82 (s, 3H, CH₃), 1.28 (s, 18H, 2 × C(CH₃)₃); ¹³C NMR (DMSO-d₆, 126 MHz) δ 175.7, 174.1, 168.2, 159.0, 151.0, 145.3, 135.8, 131.0, 129.7, 129.5, 128.8, 128.0, 127.6, 127.3, 126.4, 125.8, 113.9, 58.3, 55.2, 49.2, 43.9, 42.7, 34.5, 31.0, 18.9; HRMS (ESI-TOF) m/z 750.3533 (calcd for C₄₇H₄₈N₃O₆ (M + H)⁺ 750.3538); Anal. C, 74.82; H, 6.04; N, 5.67 (calcd for C₄₇H₄₇N₃O₆ · 1/5 H₂O C, 74.92; H, 6.34; N, 5.58).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-2,6-Bis(2-(tert-butyl)phenyl)-9-(4-methoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Ac): white solid (86 mg, 23%); R_f = 0.60 (PE/EtOAc 1/1); mp 341–342 °C (EtOH); IR (ATR) ν_max 2964, 1713, 1655, 1522, 1509, 1489, 1372, 1196, 1176 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 8.18 (s, 1H, NH), 7.89–7.92 (m, 2H, ArH), 7.61 (td, J = 8.5, 1.5 Hz, 2H, ArH), 7.46–7.50 (m, 1H, ArH), 7.37–7.45 (m, 4H, ArH), 7.33 (td, J = 7.5, 1.5 Hz, 1H, ArH), 7.19 (td, J = 7.5, 1.5 Hz, 1H, ArH), 7.14 and 6.86 (AA’XX’, J = 8.8 Hz, 2H each, 4-OCH₃-C₆H₄), 6.70 (dd, J = 8.0, 1.3 Hz, 1H, ArH), 6.57 (dd, J = 8.0, 1.5 Hz, 1H, ArH), 6.54 (s, 1H, C=CH), 4.83 (d, J = 10.3 Hz, 1H, 4a-CH), 3.82 (s, 3H, OCH₃), 3.39 (d, J = 8.5 Hz, 1H, 3a-CH), 3.26 (d, J = 8.5 Hz, 1H, 8a-CH), 3.14 (d, J = 10.3 Hz, 1H, 7a-CH), 1.95 (s, 3H, CH₃), 1.35 (s, 9H, C(CH₃)₃), 1.29 (s, 9H, C(CH₃)₃); ¹³C NMR (CDCl₃, 126 MHz) δ 176.5, 176.3, 175.9, 175.0, 167.7, 159.5, 148.4, 148.2, 147.8, 134.1, 132.5, 131.9, 130.4, 130.3, 130.1, 129.91, 129.89, 129.7, 129.5, 129.4, 129.1, 128.9, 128.6, 127.7, 127.4, 127.2, 113.7, 57.9, 55.3, 51.1, 45.7, 45.4, 43.1, 42.8, 35.9, 35.8, 31.8, 31.7, 18.6; HRMS (ESI-TOF) m/z 750.3536 (calcd for C₄₇H₄₈N₃O₆ (M + H)⁺ 750.3538); Anal. C, 75.10; H, 6.45; N, 5.62 (calcd for C₄₇H₄₇N₃O₆ C, 75.28; H, 6.32; N, 5.60).

rel-N-((3aR,4R,4aS,7aR,8S,8aS)-2,6-Bis(2-(tert-butyl)phenyl)-9-(4-methoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,exo-5Ac): white solid (142 mg, 38%); R_f = 0.42 (PE/EtOAc 1/1); mp 338–340 °C (EtOAc); IR (ATR) ν_max 2960, 1711, 1510, 1488, 1440, 1369, 1285, 1248, 1201, 1176, 1155 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.85–7.89 (m, 2H, ArH), 7.54–7.58 (m, 2H, ArH), 7.44–7.48 (m, 1H, ArH), 7.33–7.42 (m, 4H, ArH), 7.18–7.23 (m, 2H, ArH), 7.13 and 6.86 (AA’XX’, J = 8.8 Hz, 2H each, 4-OCH₃-C₆H₄), 6.61–6.67 (m, 3H, ArH, NH), 6.11 (s, 1H, C=CH), 4.77 (d, J = 8.5 Hz, 2H, 3a-CH, 4a-CH), 3.81 (s, 3H, OCH₃), 3.18 (d, J = 8.5 Hz, 2H, 7a-CH, 8a-CH), 2.08 (s, 3H, CH₃), 1.28 (s, 18H, 2 × C(CH₃)₃); ¹³C NMR (CDCl₃, 126 MHz) δ 175.7, 174.7, 169.7, 159.8, 148.4, 147.9, 135.1, 131.6, 130.4, 129.9, 129.7, 129.2, 129.1, 128.6, 127.3, 127.1, 126.9, 114.0, 58.2, 55.3, 50.1, 44.0, 43.8, 35.8, 31.7, 19.4 (1 signal hidden); HRMS (ESI-TOF) m/z 750.3531 (calcd for C₄₇H₄₈N₃O₆ (M + H)⁺ 750.3538); Anal. C, 74.00; H, 6.48; N, 5.48 (calcd for C₄₇H₄₇N₃O₆ · 2/3 H₂O C, 74.09; H, 6.39; N, 5.52).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-2,6-Di-tert-butyl-9-(4-methoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Ad): white solid (116 mg, 39%); R_f = 0.61 (PE/EtOAc 1/1); mp 267–268 °C (EtOH/Me₂CO); IR (ATR) ν_max 3390, 2975, 1765, 1690, 1667, 1528, 1509, 1339, 1263, 1174 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.41 (s, 1H, NH), 7.86–7.90 (m, 2H, ArH), 7.54–7.64 (m, 3H, ArH), 7.03 and 6.91 (AA’XX’, J = 9.0 Hz, 2H each, 4-OCH₃-C₆H₄), 6.13 (s, 1H, C=CH), 3.95 (d, J = 10.0 Hz, 1H, 4a-CH), 3.75 (s, 3H, OCH₃), 3.08 (d, J = 8.3 Hz, 1H, 3a-CH), 2.92 (d, J = 10.0 Hz, 1H, 7a-CH), 2.74 (d, J = 8.3 Hz, 1H, 8a-CH), 1.58 (s, 3H, CH₃), 1.53 (s, 9H, C(CH₃)₃), 1.46 (s, 9H, C(CH₃)₃); ¹³C NMR (DMSO-d₆, 126 MHz) δ 177.4, 177.1, 176.8, 175.7, 166.1, 158.7, 145.8, 134.7, 131.9, 131.7, 129.8, 129.4, 128.6, 127.1, 113.4, 57.8, 57.6, 57.2, 55.1, 50.3, 45.0, 44.6, 42.8, 41.4, 28.0, 27.8, 19.4; HRMS (ESI-TOF) m/z 598.2908 (calcd for C₃₅H₄₀N₃O₆ (M + H)⁺ 598.2912); Anal. C, 69.71; H, 6.50; N, 6.99 (calcd for C₃₅H₃₉N₃O₆ · 1/4 H₂O C, 69.81; H, 6.61; N, 6.98).

rel-N-((3aR,4R,4aS,7aR,8S,8aS)-2,6-Di-tert-butyl-9-(4-methoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,exo-5Ad): white solid (128 mg, 43%); R_f = 0.42 (PE/EtOAc 1/1); mp 307–308 °C (EtOH/H₂O); IR (ATR) ν_max 3310, 2985, 2937, 1762, 1699, 1636, 1549, 1512, 1334, 1252, 1178, 1152 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.61 (s, 1H, NH), 7.86–7.91 (m, 2H, ArH), 7.50–7.59 (m, 3H, ArH), 6.91–6.97 (AA’BB’, J = 9.0 Hz, 4H, 4-OCH₃-C₆H₄), 6.28 (s, 1H, C=CH), 4.14 (d, J = 8.5 Hz, 2H, 3a-CH, 4a-CH), 3.75 (s, 3H, OCH₃), 2.97 (d, J = 8.5 Hz, 2H, 7a-CH, 8a-CH), 1.71 (s, 3H, CH₃), 1.40 (s, 18H, 2 × C(CH₃)₃); ¹³C NMR (DMSO-d₆, 126 MHz) δ 177.1, 175.6, 167.7, 158.8, 144.4, 135.9, 131.0, 129.8, 128.8, 128.1, 127.7, 126.9, 113.6, 58.3, 57.1, 55.1, 48.7, 42.8, 42.4, 28.1, 19.0; HRMS (ESI-TOF) m/z 598.2908 (calcd for C₃₅H₄₀N₃O₆ (M + H)⁺ 598.2912); Anal. C, 70.55; H, 6.43; N, 7.06 (calcd for C₃₅H₃₉N₃O₆ C, 70.33; H, 6.58; N, 7.03).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-9-(4-methoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,6-ditrityl-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Ae): white solid (422 mg, 87%); mp 276–277 °C (EtOH); IR (ATR) ν_max 3058, 1713, 1704, 1648, 1510, 1450, 1322, 1249, 1154, 1030 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.72–7.75 (m, 2H, ArH), 7.61 (s, 1H, NH), 7.36–7.49 (m, 9H, ArH), 7.14–7.24 (m, 21H, ArH), 7.06–7.11 (m, 3H, ArH), 6.87 and 6.77 (AA’XX’, J = 8.5 Hz, 2H each, 4-OCH₃-C₆H₄), 6.18 (s, 1H, C=CH), 4.45 (d, J = 10.3 Hz, 1H, 4a-CH), 3.80 (s, 3H, OCH₃), 2.88 (d, J = 10.3 Hz, 1H, 7a-CH), 1.82 (d, J = 9.0 Hz, 1H, 8a-CH), 1.67 (s, 3H, CH₃), 1.46 (d, J = 9.0 Hz, 1H, 3a-CH); ¹³C NMR (CDCl₃, 126 MHz) δ 175.7, 174.94, 174.92, 174.4, 167.4, 159.3, 148.2, 142.0, 141.5, 134.1, 131.80, 131.79, 130.4, 129.0, 128.6, 128.2, 128.0, 127.63, 127.56, 127.3, 126.74, 126.73, 113.2, 75.2, 74.3, 57.8, 55.3, 49.7, 45.5, 45.0, 42.5, 41.9, 18.9; HRMS (ESI-TOF) m/z 970.3878 (calcd for C₆₅H₅₂N₃O₆ (M + H)⁺ 970.3856); Anal. C, 79.92; H, 5.25; N, 4.32 (calcd for C₆₅H₅₁N₃O₆ · 1/4 H₂O C, 80.10; H, 5.33; N, 4.31).

rel-N-((3aR,4R,4aS,7aR,8S,8aS)-9-(3,4-dimethoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,exo-5Ba): white solid (219 mg, 82%); mp 349–350 °C (MeOH); IR (ATR) ν_max 3221, 1703, 1671, 1514, 1346, 1302, 1253, 1202, 1153, 1136 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 11.28 (s, 2H, 2 × NH), 8.62 (s, 1H, 4-NH), 7.87–7.91 (m, 2H, ArH), 7.54–7.58 (m, 1H, ArH), 7.48–7.53 (m, 2H, ArH), 6.93 (d, J = 8.2 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.51 (d, J = 2.0 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.48 (dd, J = 8.2, 2.0 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.32 (s, 1H, C=CH), 4.23 (d, J = 8.3 Hz, 2H, 3a-CH, 4a-CH), 3.75 (s, 3H, OCH₃), 3.70 (s, 3H, OCH₃), 3.08 (d, J = 8.3 Hz, 2H, 7a-CH, 8a-CH), 1.67 (s, 3H, CH₃); ¹³C NMR (DMSO-d₆, 126 MHz) δ 178.1, 176.4, 167.7, 148.4, 147.9, 145.3, 135.7, 131.0, 130.2, 128.1, 127.7, 127.2, 120.2, 111.6, 111.5, 57.8, 55.5, 55.4, 50.2, 44.6, 42.2, 18.6; HRMS (ESI-TOF) m/z 516.1768 (calcd for C₂₈H₂₆N₃O₇ (M + H)⁺ 516.1765); Anal. C, 64.49; H, 4.80; N, 7.96 (calcd for C₂₈H₂₅N₃O₇ · 1/3 H₂O C, 64.49; H, 4.96; N, 8.06).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-2,6-Bis(4-(tert-butyl)phenyl)-9-(3,4-dimethoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Bb): white solid (43 mg, 11%); R_f = 0.42 (PE/EtOAc 1/1); mp 194–196 °C (EtOAc); IR (ATR) ν_max 2960, 1710, 1664, 1514, 1488, 1381, 1310, 1255, 1189, 1175, 1138, 1024 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 8.10 (s, 1H, NH), 7.90–7.93 (m, 2H, ArH), 7.41–7.52 (m, 7H, ArH), 7.22 and 7.11 (AA’XX’, J = 9.0 Hz, 2H each, 4-C(CH₃)₃-C₆H₄), 6.82 (d, J = 8.2 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.73 (dd, J = 8.2, 2.0 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.60 (d, J = 2.0 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.47 (s, 1H, C=CH), 4.84 (d, J = 10.0 Hz, 1H, 4a-CH), 3.89 (s, 3H, OCH₃), 3.74 (s, 3H, OCH₃), 3.35 (d, J = 8.3 Hz, 1H, 3a-CH), 3.21 (d, J = 8.3 Hz, 1H, 8a-CH), 3.17 (d, J = 10.0 Hz, 1H, 7a-CH), 1.93 (s, 3H, CH₃), 1.33 (s, 9H, C(CH₃)₃), 1.31 (s, 9H, C(CH₃)₃); ¹³C NMR (CDCl₃, 126 MHz) δ 175.5, 174.9, 174.7, 174.1, 167.7, 152.6, 152.2, 148.9, 148.4, 147.8, 134.1, 132.2, 131.9, 129.3, 128.6, 128.5, 128.2, 127.1, 126.4, 126.3, 125.7, 125.6, 121.1, 111.4, 110.8, 57.9, 55.9, 55.8, 51.0, 45.3, 45.1, 43.2, 42.9, 34.79, 34.78, 31.21, 31.17, 18.9; HRMS (ESI-TOF) m/z 780.3647 (calcd for C₄₈H₅₀N₃O₇ (M + H)⁺ 780.3643); Anal. C, 73.32; H, 6.24; N, 5.33 (calcd for C₄₈H₄₉N₃O₇ · 1/3 H₂O C, 73.36; H, 6.37; N, 5.35).

rel-N-((3aR,4R,4aS,7aR,8S,8aS)-2,6-Bis(4-(tert-butyl)phenyl)-9-(3,4-dimethoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,exo-5Bb): white solid (273 mg, 70%); R_f = 0.23 (PE/EtOAc 1/1); mp 323–325 °C (EtOAc); IR (ATR) ν_max 3313, 2958, 1709, 1636, 1558, 1514, 1377, 1247, 1203, 1187, 1160, 1142 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.84–7.88 (m, 2H, ArH), 7.36–7.49 (m, 7H, ArH), 7.06–7.11 (m, 4H, ArH), 6.80 (d, J = 8.3 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.74 (s, 1H, NH), 6.63 (dd, J = 8.3, 2.0 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.54 (d, J = 2.0 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.00 (s, 1H, C=CH), 4.72 (d, J = 8.5 Hz, 2H, 3a-CH, 4a-CH), 3.87 (s, 3H, OCH₃), 3.63 (s, 3H, OCH₃), 3.13 (d, J = 8.5 Hz, 2H, 7a-CH, 8a-CH), 2.00 (s, 3H, CH₃), 1.29 (s, 18H, 2 × C(CH₃)₃); ¹³C NMR (CDCl₃, 126 MHz) δ 174.6, 173.9, 169.5, 152.0, 149.2, 148.6, 147.7, 135.1, 131.6, 129.0, 128.61, 128.58, 127.1, 126.8, 126.2, 125.7, 120.4, 111.0, 58.3, 55.9, 55.7, 49.8, 44.0, 43.7, 34.7, 31.2, 19.3 (1 signal hidden); HRMS (ESI-TOF) m/z 780.3636 (calcd for C₄₈H₅₀N₃O₇ (M + H)⁺ 780.3643); Anal. C, 73.36; H, 6.33; N, 5.36 (calcd for C₄₈H₄₉N₃O₇ · 1/3 H₂O C, 73.36; H, 6.37; N, 5.35).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-2,6-Bis(2-(tert-butyl)phenyl)-9-(3,4-dimethoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Bc): white solid (74 mg, 19%); R_f = 0.58 (PE/EtOAc 1/1); mp 353–355 °C (EtOAc); IR (ATR) ν_max 3419, 2960, 1714, 1658, 1513, 1490, 1441, 1372, 1251, 1196, 1137, 1028 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 8.19 (s, 1H, NH), 7.89–7.92 (m, 2H, ArH), 7.61 (td, J = 8.3, 1.0 Hz, 2H, ArH), 7.37–7.50 (m, 5H, ArH), 7.34 (td, J = 7.5, 1.3 Hz, 1H, ArH), 7.18 (td, J = 7.6, 1.2 Hz, 1H, ArH), 6.83 (d, J = 8.0 Hz, 1H, ArH), 6.78 (dd, J = 8.3, 1.8 Hz, 1H, ArH), 6.68–6.72 (m, 2H, ArH), 6.61 (dd, J = 7.8, 1.3 Hz, 1H, ArH), 6.55 (s, 1H, C=CH), 4.85 (d, J = 10.3 Hz, 1H, 4a-CH), 3.90 (s, 3H, OCH₃), 3.78 (s, 3H, OCH₃), 3.40 (d, J = 8.5 Hz, 1H, 3a-CH), 3.26 (d, J = 8.5 Hz, 1H, 8a-CH), 3.15 (d, J = 10.3 Hz, 1H, 7a-CH), 1.95 (s, 3H, CH₃), 1.35 (s, 9H, C(CH₃)₃), 1.29 (s, 9H, C(CH₃)₃); ¹³C NMR (CDCl₃, 126 MHz) δ 176.4, 176.3, 175.9, 175.0, 167.8, 148.9, 148.43, 148.39, 148.2, 147.9, 134.1, 132.7, 131.9, 130.4, 130.3, 130.1, 129.9, 129.7, 129.5, 129.4, 129.2, 128.6, 127.5, 127.4, 127.2, 121.3, 111.4, 110.8, 57.9, 55.91, 55.85, 51.1, 45.5, 45.4, 43.1, 42.8, 35.9, 35.8, 31.74, 31.68, 18.6 (1 signal hidden); HRMS (ESI-TOF) m/z 780.3650 (calcd for C₄₈H₅₀N₃O₇ (M + H)⁺ 780.3643); Anal. C, 73.50; H, 6.28; N, 5.33 (calcd for C₄₈H₄₉N₃O₇ · 1/4 H₂O C, 73.50; H, 6.36; N, 5.36).

rel-N-((3aR,4R,4aS,7aR,8S,8aS)-2,6-Bis(2-(tert-butyl)phenyl)-9-(3,4-dimethoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,exo-5Bc): white solid (191 mg, 49%); R_f = 0.44 (PE/EtOAc 1/1); mp 336–338 °C (EtOAc); IR (ATR) ν_max 2959, 1713, 1646, 1514, 1490, 1369, 1247, 1195, 1140, 1023 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.85–7.89 (m, 2H, ArH), 7.57 (dd, J = 8.0, 1.0 Hz, 2H, ArH), 7.44–7.48 (m, 1H, ArH), 7.34–7.41 (m, 4H, ArH), 7.18 (td, J = 7.5, 0.8 Hz, 2H, ArH), 6.82 (d, J = 8.5 Hz, 1H, ArH), 6.72 (dd, J = 8.5, 2.0 Hz, 1H, ArH), 6.65–6.70 (m, 4H, ArH, NH), 6.12 (s, 1H, C=CH), 4.78 (d, J = 8.8 Hz, 2H, 3a-CH, 4a-CH), 3.88 (s, 3H, OCH₃), 3.74 (s, 3H, OCH₃), 3.19 (d, J = 8.8 Hz, 2H, 7a-CH, 8a-CH), 2.08 (s, 3H, CH₃), 1.28 (s, 18H, 2 × C(CH₃)₃); ¹³C NMR (CDCl₃, 126 MHz) δ 175.7, 174.6, 169.7, 149.2, 148.63, 148.60, 148.0, 135.1, 131.6, 130.4, 129.9, 129.7, 129.3, 128.9, 128.6, 127.1, 127.0, 120.3, 111.0, 110.8, 58.3, 55.9, 55.8, 50.1, 44.0, 43.7, 35.8, 31.7, 19.4 (1 signal hidden); HRMS (ESI-TOF) m/z 780.3649 (calcd for C₄₈H₅₀N₃O₇ (M + H)⁺ 780.3643); Anal. C, 73.11; H, 6.39; N, 5.31 (calcd for C₄₈H₄₉N₃O₇ · 1/2 H₂O C, 73.08; H, 6.39; N, 5.33).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-2,6-Di-tert-butyl-9-(3,4-dimethoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Bd): white solid (119 mg, 38%); R_f = 0.44 (PE/EtOAc 1/1); mp 278–280 °C (EtOH); IR (ATR) ν_max 3401, 2963, 2936, 1701, 1688, 1660, 1510, 1335, 1260, 1168, 1135 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 8.16 (s, 1H, NH), 7.93–7.96 (m, 2H, ArH), 7.47–7.56 (m, 3H, ArH), 6.79 (d, J = 8.3 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.68 (dd, J = 8.3, 2.0 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.64 (d, J = 2.0 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.28 (s, 1H, C=CH), 4.42 (d, J = 10.3 Hz, 1H, 4a-CH), 3.88 (s, 3H, OCH₃), 3.87 (s, 3H, OCH₃), 2.88 (d, J = 8.8 Hz, 1H, 3a-CH), 2.74 (d, J = 10.3 Hz, 1H, 7a-CH), 2.72 (d, J = 8.8 Hz, 1H, 8a-CH), 1.80 (s, 3H, CH₃), 1.59 (s, 9H, C(CH₃)₃), 1.55 (s, 9H, C(CH₃)₃); ¹³C NMR (CDCl₃, 126 MHz) δ 177.5, 177.2, 176.6, 175.9, 167.3, 148.8, 148.3, 147.4, 134.4, 131.9, 131.8, 129.6, 128.7, 127.2, 121.3, 111.6, 110.6, 59.5, 58.9, 57.7, 55.9, 55.8, 50.6, 44.64, 44.60, 42.5, 42.4, 28.40, 28.36, 19.0; HRMS (ESI-TOF) m/z 626.2893 (calcd for C₃₆H₄₀N₃O₇ (M − H)⁻ 626.2872); Anal. C, 69.13; H, 6.58; N, 6.63 (calcd for C₃₆H₄₁N₃O₇ C, 68.88; H, 6.58; N, 6.69).

rel-N-((3aR,4R,4aS,7aR,8S,8aS)-2,6-Di-tert-butyl-9-(3,4-dimethoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,exo-5Bd): white solid (138 mg, 44%); R_f = 0.33 (PE/EtOAc 1/1); mp 293–295 °C (EtOH); IR (ATR) ν_max 3377, 2936, 1698, 1646, 1537, 1516, 1461, 1332, 1265, 1250, 1180, 1142 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.90–7.94 (m, 2H, ArH), 7.45–7.55 (m, 3H, ArH), 6.79 (d, J = 8.3 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.65–6.67 (m, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.62 (d, J = 8.3 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.53 (s, 1H, NH), 5.82 (s, 1H, C=CH), 4.33 (d, J = 8.8 Hz, 2H, 3a-CH, 4a-CH), 3.88 (s, 3H, OCH₃), 3.86 (s, 3H, OCH₃), 2.74 (d, J = 8.8 Hz, 2H, 7a-CH, 8a-CH), 1.92 (s, 3H, CH₃), 1.50 (s, 18H, 2 × C(CH₃)₃); ¹³C NMR (CDCl₃, 126 MHz) δ 176.5, 175.6, 169.0, 149.1, 148.4, 146.9, 135.3, 131.6, 129.5, 128.7, 127.2, 126.5, 120.7, 111.2, 110.7, 58.6, 58.2, 55.9, 55.8, 49.6, 43.6, 43.2, 28.5, 19.4; HRMS (ESI-TOF) m/z 626.2893 (calcd for C₃₆H₄₀N₃O₇ (M − H)⁻ 626.2872); Anal. C, 68.67; H, 6.57; N, 6.74 (calcd for C₃₆H₄₁N₃O₇ C, 68.88; H, 6.58; N, 6.69).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-9-(4-methoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,6-ditrityl-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Be): white solid (425 mg, 85%); mp 292–293 °C (EtOAc); IR (ATR) ν_max 3390, 3062, 2930, 1704, 1656, 1528, 1514, 1334, 1316, 1201, 1162, 1027 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.17 (s, 1H, NH), 7.71–7.75 (m, 2H, ArH), 7.53–7.57 (m, 1H, ArH), 7.47–7.52 (m, 8H, ArH), 7.23–7.29 (m, 12H, ArH), 7.17–7.22 (m, 9H, ArH), 7.10–7.15 (m, 3H, ArH), 6.68–6.72 (m, 2H, 3,4-(OCH₃)₂-C₆H₃), 5.97 (s, 1H, C=CH), 5.70 (dd, J = 8.3, 1.8 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 4.20 (d, J = 10.5 Hz, 1H, 4a-CH), 3.75 (s, 3H, OCH₃), 3.66 (s, 3H, OCH₃), 3.27 (d, J = 10.5 Hz, 1H, 7a-CH), 2.13 (d, J = 9.0 Hz, 1H, 3a-CH), 1.54 (d, J = 9.0 Hz, 1H, 8a-CH), 1.44 (s, 3H, CH₃); ¹³C NMR (DMSO-d₆, 126 MHz) δ 175.9, 174.9, 173.8, 173.7, 165.9, 148.3, 147.7, 146.7, 142.5, 141.6, 134.3, 132.0, 131.8, 129.5, 128.6, 128.03, 127.97, 127.6, 127.4, 127.0, 126.5, 126.3, 120.6, 112.1, 111.2, 74.2, 73.2, 57.1, 55.5, 55.4, 49.4, 44.82, 44.77, 42.5, 41.2, 19.3; HRMS (ESI-TOF) m/z 998.3826 (calcd for C₆₆H₅₂N₃O₇ (M − H)⁻ 998.3811); Anal. C, 77.86; H, 5.34; N, 4.12 (calcd for C₆₆H₅₃N₃O₇ C, 77.86; H, 5.45; N, 4.13).

rel-N-((3aR,4R,4aS,7aR,8S,8aS)-9-benzoyl-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,exo-5Ca): white solid (181 mg, 75%); mp decomposes at 350 °C (EtOH); IR (ATR) ν_max 3374, 3181, 3063, 1770, 1709, 1686, 1661, 1533, 1347, 1300, 1277, 1210, 1187 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 11.35 (s, 2H, 2 × NH), 8.72 (s, 1H, 4-NH), 7.84–7.88 (m, 2H, ArH), 7.68–7.72 (m, 1H, ArH), 7.63–7.66 (m, 2H, ArH), 7.51–7.57 (m, 3H, ArH), 7.46–7.50 (m, 2H, ArH), 6.94 (s, 1H, C=CH), 4.33 (d, J = 8.3 Hz, 2H, 3a-CH, 4a-CH), 3.12 (d, J = 8.3 Hz, 2H, 7a-CH, 8a-CH), 1.84 (s, 3H, CH₃); ¹³C NMR (DMSO-d₆, 126 MHz) δ 192.0, 177.0, 176.0, 167.4, 141.8, 138.5, 136.3, 135.3, 133.6, 131.2, 129.3, 128.8, 128.1, 127.6, 57.9, 50.3, 44.6, 41.1, 17.3; HRMS (ESI-TOF) m/z 484.1500 (calcd for C₂₇H₂₂N₃O₆ (M + H)⁺ 484.1503); Anal. C, 66.66; H, 4.24; N, 8.73 (calcd for C₂₇H₂₁N₃O₆ · 1/6 H₂O C, 66.66; H, 4.42; N, 8.64).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-9-benzoyl-8-methyl-1,3,5,7-tetraoxo-2,6-ditrityl-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Ce): white solid (382 mg, 79%); R_f = 0.57 (PE/EtOAc 1/1); mp 283–285 °C (EtOAc); IR (ATR) ν_max 3388, 3055, 3023, 1708, 1651, 1526, 1490, 1448, 1321, 1264, 1200, 1162 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.89–7.92 (m, 2H, ArH), 7.70–7.74 (m, 2H, ArH), 7.61–7.65 (m, 1H, ArH), 7.51–7.55 (m, 3H, ArH, NH), 7.45–7.49 (m, 1H, ArH), 7.35–7.41 (m, 8H, ArH), 7.27–7.30 (m, 6H, ArH), 7.21–7.26 (m, 6H, ArH), 7.11–7.20 (m, 9H, ArH), 7.02–7.06 (m, 3H, ArH), 6.73 (s, 1H, C=CH), 4.63 (d, J = 10.3 Hz, 1H, 4a-CH), 3.06 (d, J = 10.3 Hz, 1H, 7a-CH), 1.82 (d, J = 9.0 Hz, 1H, 3a-CH), 1.68 (s, 3H, CH₃), 1.23 (d, J = 9.0 Hz, 1H, 8a-CH); ¹³C NMR (CDCl₃, 126 MHz) δ 192.7, 174.6, 174.5, 174.4, 172.7, 167.7, 144.1, 141.8, 141.5, 139.9, 136.6, 133.8, 133.7, 132.0, 129.9, 128.9, 128.6, 128.4, 127.9, 127.7, 127.5, 127.3, 126.9, 126.7, 75.5, 75.0, 57.0, 49.6, 44.6, 44.1, 42.8, 41.8, 17.1; HRMS (ESI-TOF) m/z 966.3560 (calcd for C₆₅H₄₈N₃O₆ (M − H)⁻ 966.3549); Anal. C, 80.47; H, 4.88; N, 4.34 (calcd for C₆₅H₄₉N₃O₆ C, 80.64; H, 5.10; N, 4.34).

Ethyl rel-(3aR,4R,4aS,7aR,8S,8aS)-4-Benzamido-8-methyl-1,3,5,7-tetraoxo-1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-ethenopyrrolo[3,4-f]isoindole-9-carboxylate (exo,exo-5Da): white solid (194 mg, 86%); mp 339–341 °C (EtOH); IR (ATR) ν_max 3357, 3207, 3044, 1716, 1693, 1654, 1548, 1340, 1307, 1267, 1184, 1154, 1045 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 11.18 (s, 2H, 2 × NH), 8.80 (s, 1H, 4-NH), 7.89–7.93 (m, 2H, ArH), 7.55–7.59 (m, 1H, ArH), 7.49–7.53 (m, 2H, ArH), 7.42 (s, 1H, C=CH), 4.25 (d, J = 8.3 Hz, 2H, 3a-CH, 4a-CH), 4.10 (q, J = 7.3 Hz, 2H, CH₃CH₂), 3.03 (d, J = 8.3 Hz, 2H, 7a-CH, 8a-CH), 1.91 (s, 3H, CH₃), 1.19 (t, J = 7.3 Hz, 3H, CH₃CH₂); ¹³C NMR (DMSO-d₆, 126 MHz) δ 176.9, 175.8, 167.5, 163.1, 139.8, 135.3, 134.8, 131.2, 128.1, 127.6, 60.6, 57.9, 50.3, 44.1, 40.8, 18.2, 14.0; HRMS (ESI-TOF) m/z 452.1456 (calcd for C₂₃H₂₂N₃O₇ (M + H)⁺ 452.1452); Anal. C, 60.83; H, 4.43; N, 9.20 (calcd for C₂₃H₂₁N₃O₇ C, 61.19; H, 4.69; N, 9.31).

Ethyl rel-(3aR,4R,4aR,7aS,8S,8aS)-4-Benzamido-8-methyl-1,3,5,7-tetraoxo-2,6-ditrityl-1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-ethenopyrrolo[3,4-f]isoindole-9-carboxylate (exo,endo-5De): white solid (379 mg, 81%); R_f = 0.59 (PE/EtOAc 1/1); mp 286–288 °C (EtOH); IR (ATR) ν_max 3399, 3057, 3033, 1708, 1667, 1519, 1488, 1449, 1308, 1267, 1196, 1156, 1034 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.73–7.76 (m, 2H, ArH), 7.47–7.51 (m, 1H, ArH), 7.47 (s, 1H, NH), 7.35–7.42 (m, 8H, ArH), 7.28 (s, 1H, C=CH), 7.16–7.26 (m, 15H, ArH), 7.09–7.13 (m, 6H, ArH), 6.96–7.00 (m, 3H, ArH), 4.33 (d, J = 10.5 Hz, 1H, 4a-CH), 4.24 (q, J = 7.1 Hz, 2H, CH₃CH₂), 2.98 (d, J = 10.5 Hz, 1H, 7a-CH), 1.79 (s, 3H, CH₃), 1.70 (d, J = 9.0 Hz, 1H, 3a-CH), 1.27 (t, J = 7.1 Hz, 3H, CH₃CH₂), 1.10 (d, J = 9.0 Hz, 1H, 8a-CH); ¹³C NMR (CDCl₃, 126 MHz) δ 174.5, 174.4, 174.0, 172.9, 167.6, 163.3, 143.7, 141.8, 141.4, 138.2, 133.6, 132.1, 128.7, 128.1, 127.8, 127.6, 127.5, 127.3, 126.84, 126.75, 75.6, 74.6, 61.4, 57.3, 50.0, 44.7, 43.8, 42.5, 41.2, 18.4, 14.1; HRMS (ESI-TOF) m/z 966.3560 (calcd for C₆₁H₄₈N₃O₇ (M − H)⁻ 966.3549); Anal. C, 77.89; H, 5.06; N, 4.60 (calcd for C₆₁H₄₉N₃O₇ C, 78.27; H, 5.28; N, 4.49).

rel-N-((3aS,4R,9aS,9bR,10R,14S)-1,3,11,13-tetraoxo-2,3,3a,6,7,8,9,9b-octahydro-4,9a-[3,4]epipyrrolobenzo[e]isoindol-4(1H)-yl)benzamide (exo,exo-5Ea): white solid (168 mg, 80%); mp 335–337 °C (EtOH); IR (ATR) ν_max 3345, 3137, 3052, 2940, 1718, 1698, 1640, 1543, 1346, 1309, 1213, 1197 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 11.11 (s, 2H, 2 × NH), 8.49 (s, 1H, 4-NH), 7.85–7.89 (m, 2H, ArH), 7.52–7.56 (m, 1H, ArH), 7.46–7.51 (m, 2H, ArH), 6.12 (s, 1H, C=CH), 4.10 (d, J = 8.3 Hz, 2H, 3a-CH, 10-CH), 2.96 (d, J = 8.3 Hz, 2H, 9b-CH, 14-CH), 2.58 (t, J = 6.8 Hz, 2H, 9-CH₂), 2.16 (t, J = 5.8 Hz, 2H, 6-CH₂), 1.55–1.61 (m, 2H, 8-CH₂), 1.31–1.38 (m, 2H, 7-CH₂); ¹³C NMR (DMSO-d₆, 126 MHz) δ 178.3, 176.4, 167.5, 140.8, 135.7, 130.9, 128.0, 127.7, 123.6, 57.2, 50.3, 44.8, 40.3, 29.2, 26.3, 22.9, 21.0; HRMS (ESI-TOF) m/z 420.1546 (calcd for C₂₃H₂₂N₃O₅ (M + H)⁺ 420.1554); Anal. C, 65.54; H, 5.22; N, 10.00 (calcd for C₂₃H₂₁N₃O₅ C, 65.86; H, 5.05; N, 10.02).

rel-N-((3aR,4R,9aS,9bS,10R,14S)-1,3,11,13-tetraoxo-2,12-ditrityl-2,3,3a,6,7,8,9,9b-octahydro-4,9a-[3,4]epipyrrolobenzo[e]isoindol-4(1H)-yl)benzamide (exo,endo-5Ee): white solid (316 mg, 70%); R_f = 0.53 (PE/EtOAc 1/1); mp 271–272 °C (EtOH/Me₂CO); IR (ATR) ν_max 3438, 3271, 3054, 2937, 1706, 1641, 1486, 1449, 1316, 1305, 1199, 1153 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.71–7.75 (m, 2H, ArH), 7.53 (s, 1H, NH), 7.43–7.48 (m, 1H, ArH), 7.34–7.42 (m, 8H, ArH), 7.13–7.26 (m, 21H, ArH), 7.02–7.07 (m, 3H, ArH), 5.95 (s, 1H, C=CH), 4.29 (d, J = 10.5 Hz, 1H, 10-CH), 2.99 (d, J = 10.5 Hz, 1H, 9b-CH), 2.38–2.45 (m, 1H, 9-CH₂), 2.27–2.35 (m, 1H, 9-CH₂), 2.18–2.25 (m, 1H, 6-CH₂), 2.02–2.11 (m, 1H, 6-CH₂), 1.64–1.74 (m, 2H, 7-CH₂, 8-CH₂), 1.57 (d, J = 8.8 Hz, 1H, 14-CH), 1.54–1.62 (m, 1H, 8-CH₂), 1.39–1.48 (m, 1H, 7-CH₂), 1.38 (d, J = 8.8 Hz, 1H, 3a-CH); ¹³C NMR (CDCl₃, 126 MHz) δ 176.0, 175.0, 174.8, 174.2, 167.4, 145.9, 142.0, 141.5, 134.1, 131.7, 128.5, 128.1, 127.9, 127.6, 127.5, 127.2, 127.0, 126.70, 126.68, 75.2, 74.2, 57.4, 45.1, 44.4, 43.6, 42.6, 42.2, 27.0, 22.9, 19.8, 17.8; HRMS (ESI-TOF) m/z 902.3596 (calcd for C₆₁H₄₈N₃O₅ (M − H)⁻ 902.3599); Anal. C, 80.14; H, 5.53; N, 4.71 (calcd for C₆₁H₄₉N₃O₅ · 1/2 H₂O C, 80.24; H, 5.52; N, 4.60).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-9-acetyl-8-methyl-1,3,5,7-tetraoxo-2,6-ditrityl-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Fe): white solid (340 mg, 75%); R_f = 0.45 (PE/EtOAc 1/1); mp 216–218 °C (Me₂CO); IR (ATR) ν_max 3364, 3062, 1701, 1673, 1527, 1488, 1324, 1313, 1200, 1163 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.52 (s, 1H, NH), 7.80–7.84 (m, 2H, ArH), 7.54–7.59 (m, 1H, ArH), 7.42–7.52 (m, 8H, ArH), 7.07–7.28 (m, 25H, ArH, C=CH), 4.07 (d, J = 10.5 Hz, 1H, 4a-CH), 2.96 (d, J = 10.5 Hz, 1H, 7a-CH), 2.39 (d, J = 9.0 Hz, 1H, 3a-CH), 2.03 (s, 3H, COCH₃), 1.55 (s, 3H, CH₃), 1.03 (d, J = 9.0 Hz, 1H, 8a-CH); ¹³C NMR (DMSO-d₆, 126 MHz) δ 196.8, 175.0, 174.5, 173.1, 172.9, 166.2, 144.3, 143.2, 142.5, 141.7, 133.9, 131.9, 128.5, 127.93, 127.90, 127.5, 127.37, 127.36, 126.4, 126.3, 74.3, 73.3, 56.6, 49.3, 43.9, 43.5, 42.8, 40.5, 28.4, 17.7; HRMS (ESI-TOF) m/z 904.3387 (calcd for C₆₀H₄₆N₃O₆ (M − H)⁻ 904.3392); Anal. C, 79.46; H, 5.13; N, 4.66 (calcd for C₆₀H₄₇N₃O₆ C, 79.54; H, 5.23; N, 4.64).

Methyl rel-(3aR,4R,4aR,7aS,8S,8aS)-4-Benzamido-8-(2-methoxy-2-oxoethyl)-1,3,5,7-tetraoxo-2,6-ditrityl-1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-ethenopyrrolo[3,4-f]isoindole-9-carboxylate (exo,endo-5Ge): white solid (353 mg, 72%); R_f = 0.53 (PE/EtOAc 1/1); mp 278–280 °C (EtOAc/Me₂CO); IR (ATR) ν_max 3372, 3056, 1721, 1698, 1672, 1519, 1488, 1325, 1313, 1273, 1201, 1168 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.77 (s, 1H, NH), 7.82–7.86 (m, 2H, ArH), 7.54–7.58 (m, 1H, ArH), 7.42–7.51 (m, 8H, ArH), 7.05–7.27 (m, 25H, ArH, C=CH), 4.04 (d, J = 10.3 Hz, 1H, 4a-CH), 3.73 (d, J = 10.3 Hz, 1H, 7a-CH), 3.65 (d, J = 18.3 Hz, 1H, CH₂), 3.58 (s, 3H, CO₂CH₃), 3.57 (s, 3H, CO₂CH₃), 2.95 (d, J = 18.3 Hz, 1H, CH₂), 2.57 (d, J = 8.8 Hz, 1H, 3a-CH), 0.84 (d, J = 8.8 Hz, 1H, 8a-CH); ¹³C NMR (DMSO-d₆, 126 MHz) δ 175.6, 174.6, 172.6, 172.2, 171.8, 166.3, 163.5, 146.4, 142.3, 141.5, 133.7, 132.8, 131.9, 128.4, 127.9, 127.8, 127.5, 127.4, 126.5, 126.4, 74.5, 73.6, 56.5, 52.0, 51.4, 44.9, 42.9, 42.61, 42.57, 40.8, 32.4 (1 signal hidden); HRMS (ESI-TOF) m/z 978.3395 (calcd for C₆₂H₄₈N₃O₉ (M − H)⁻ 978.3396); Anal. C, 75.71; H, 4.88; N, 4.28 (calcd for C₆₂H₄₉N₃O₉ C, 75.98; H, 5.04; N, 4.29).

rel-N-((3aR,4R,10aS,10bS,11R,15S)-1,3,12,14-tetraoxo-2,13-ditrityl-2,3,3a,7,8,9,10,10b-octahydro-1H-4,10a-[3,4]epipyrrolocyclohepta[e]isoindol-4(6H)-yl)benzamide (exo,endo-5He): white solid (353 mg, 77%); R_f = 0.52 (PE/EtOAc 1/1); mp 271–272 °C (EtOH); IR (ATR) ν_max 3412, 3058, 2923, 1704, 1650, 1514, 1487, 1450, 1317, 1198, 1156 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.71–7.75 (m, 2H, ArH), 7.57 (s, 1H, NH), 7.45–7.49 (m, 1H, ArH), 7.35–7.42 (m, 8H, ArH), 7.14–7.24 (m, 21H, ArH), 7.04–7.08 (m, 3H, ArH), 5.90 (s, 1H, C=CH), 4.33 (d, J = 10.5 Hz, 1H, 11-CH), 3.25 (d, J = 10.5 Hz, 1H, 10b-CH), 2.27–2.37 (m, 3H, 6-CH₂, 10-CH₂), 2.00 (t, J = 12.8 Hz, 1H, 6-CH₂), 1.81–1.93 (m, 3H, 7-CH₂, 8-CH₂, 9-CH₂), 1.55–1.63 (m, 1H, 9-CH₂), 1.51 (d, J = 8.5 Hz, 1H, 3a-CH), 1.43 (d, J = 8.5 Hz, 1H, 15-CH), 1.13–1.32 (m, 2H, 7-CH₂, 8-CH₂); ¹³C NMR (CDCl₃, 126 MHz) δ 175.3, 175.1, 174.0, 167.3, 149.5, 142.1, 141.5, 134.1, 131.8, 128.8, 128.6, 128.1, 128.0, 127.6, 127.5, 127.3, 126.7, 75.2, 74.2, 57.4, 46.4, 45.5, 44.6, 44.1, 42.8, 35.3, 31.0, 29.5, 29.2, 24.3 (2 signals hidden); HRMS (ESI-TOF) m/z 918.3915 (calcd for C₆₂H₅₂N₃O₅ (M + H)⁺ 918.3907); Anal. C, 80.28; H, 5.63; N, 4.55 (calcd for C₆₂H₅₁N₃O₅ · 1/2 H₂O C, 80.32; H, 5.65; N, 4.53).

rel-N-((3aR,4R,8aS,8bS,9R,13S)-1,3,10,12-tetraoxo-2,11-ditrityl-2,3,3a,7,8,8b-hexahydro-1H-4,8a-[3,4]epipyrrolocyclopenta[e]isoindol-4(6H)-yl)benzamide (exo,endo-5Ie): white solid (245 mg, 55%); R_f = 0.46 (PE/EtOAc 1/1); mp 305–307 °C (EtOH); IR (ATR) ν_max 3056, 1706, 1650, 1521, 1488, 1450, 1319, 1306, 1198, 1154 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.22 (s, 1H, NH), 7.74–7.77 (m, 2H, ArH), 7.52–7.56 (m, 1H, ArH), 7.43–7.50 (m, 8H, ArH), 7.08–7.28 (m, 24H, ArH), 5.86 (s, 1H, C=CH), 3.99 (d, J = 10.5 Hz, 1H, 9-CH), 2.87 (d, J = 10.5 Hz, 1H, 8b-CH), 2.02–2.23 (m, 4H, 3a-CH, 6-CH₂, 8-CH₂), 1.65–1.73 (m, 1H, 6-CH₂), 1.54–1.63 (m, 1H, 7-CH₂), 1.27–1.37 (m, 1H, 7-CH₂), 1.18 (d, J = 8.8 Hz, 1H, 13-CH); ¹³C NMR (DMSO-d₆, 126 MHz) δ 176.7, 175.2, 174.3, 173.9, 165.9, 148.8, 142.5, 141.6, 134.4, 131.6, 128.5, 127.94, 127.87, 127.5, 127.3, 127.1, 126.4, 126.2, 124.6, 74.0, 73.2, 57.9, 48.3, 48.2, 44.4, 44.1, 40.8, 30.2, 28.9, 25.1; HRMS (ESI-TOF) m/z 888.3456 (calcd for C₆₀H₄₆N₃O₅ (M − H)⁻ 888.3443); Anal. C, 80.32; H, 5.25; N, 4.70 (calcd for C₆₀H₄₇N₃O₅ · 1/3 H₂O C, 80.43; H, 5.36; N, 4.69).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-1,3,5,7-tetraoxo-8,9-diphenyl-2,6-ditrityl-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Je): white solid (281 mg, 56%); R_f = 0.59 (PE/EtOAc 1/1); mp 248–250 °C (EtOH); IR (ATR) ν_max 3388, 3057, 1710, 1669, 1533, 1490, 1449, 1316, 1197, 1148 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.73–7.77 (m, 2H, ArH), 7.48–7.61 (m, 3H, ArH, NH), 7.38–7.42 (m, 2H, ArH), 7.31–7.34 (m, 6H, ArH), 6.96–7.19 (m, 29H, ArH), 6.85–6.95 (m, 1H, ArH), 6.79–6.83 (m, 2H, ArH), 6.60 (s, 1H, C=CH), 6.42–6.58 (m, 1H, ArH), 4.46 (d, J = 10.5 Hz, 1H, 4a-CH), 3.51 (d, J = 10.5 Hz, 1H, 7a-CH), 2.92 (d, J = 8.3 Hz, 1H, 8a-CH), 1.28 (d, J = 8.3 Hz, 1H, 3a-CH); ¹³C NMR (CDCl₃, 126 MHz) δ 174.7, 174.0, 173.80, 173.78, 167.5, 147.8, 142.0, 141.5, 137.0, 136.4, 134.0, 133.3, 132.0, 131.0, 130.0, 129.5, 128.6, 128.0, 127.9, 127.6, 127.50, 127.46, 127.3, 126.7, 126.58, 126.57, 75.3, 74.7, 58.1, 53.0, 50.9, 45.3, 43.8, 41.9 (1 signal hidden); HRMS (ESI-TOF) m/z 1000.3746 (calcd for C₆₉H₅₀N₃O₅ (M − H)⁻ 1000.3756); Anal. C, 82.07; H, 5.16; N, 4.15 (calcd for C₆₉H₅₁N₃O₅ · 1/3 H₂O C, 82.20; H, 5.17; N, 4.17).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-9-(4-methoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,6-ditrityl-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)acetamide (exo,endo-5Ke): white solid (350 mg, 77%); R_f = 0.37 (PE/EtOAc 1/1); mp 216–218 °C (EtOH); IR (ATR) ν_max 3397, 3057, 1705, 1675, 1510, 1492, 1449, 1323, 1288, 1245, 1198, 1182, 1154, 1034 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.42–7.47 (m, 6H, ArH), 7.11–7.26 (m, 24H, ArH), 6.91 (s, 1H, NH), 6.72 and 6.66 (AA’XX’, J = 9.0 Hz, 2H each, 4-OCH₃-C₆H₄), 5.97 (s, 1H, C=CH), 4.32 (d, J = 10.5 Hz, 1H, 4a-CH), 3.79 (s, 3H, OCH₃), 2.81 (d, J = 10.5 Hz, 1H, 7a-CH), 1.97 (s, 3H, COCH₃), 1.78 (d, J = 9.0 Hz, 1H, 8a-CH), 1.60 (s, 3H, CH₃), 1.44 (d, J = 9.0 Hz, 1H, 3a-CH); ¹³C NMR (CDCl₃, 126 MHz) δ 175.7, 174.71, 174.68, 174.6, 170.6, 159.1, 148.0, 142.1, 141.4, 132.1, 130.1, 129.0, 128.2, 128.0, 127.7, 127.6, 126.78, 126.77, 113.2, 75.2, 74.1, 57.4, 55.2, 49.8, 45.1, 44.3, 42.3, 41.7, 24.2, 19.0; HRMS (ESI-TOF) m/z 906.3549 (calcd for C₆₀H₄₈N₃O₆ (M − H)⁻ 906.3549); Anal. C, 78.13; H, 5.21; N, 4.57 (calcd for C₆₀H₄₉N₃O₆ · 2/3 H₂O C, 78.33; H, 5.51; N, 4.57).

3.4. Synthesis of exo,endo-5A–Ea by Acid-Induced Elimination of the Triphenylmethyl Group from exo,endo-5A–Ee

A mixture of the starting bicyclo[2.2.2]octene exo,endo-5A–Ee (0.3 mmol), n-BuOH (3 mL), and TFA (1 mL) was irradiated in the focused microwave equipment for 1 h. The power was set to 100 W, the final temperature to 100 °C or 140 °C, and the ramp time to 5 min (Table 4). In the case of 5De, n-BuOH was replaced with ethanol (3 mL), and the volume of TFA was 0.3 mL. Afterward, the reaction mixture was cooled, and the precipitated material was filtered off and washed with cold EtOH (1 mL), yielding the destrityl exo,endo-5A–Ea products.

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-9-(4-methoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Aa): white solid (124 mg, 85%); mp 293–295 °C (EtOH); IR (ATR) ν_max 3392, 3200, 1724, 1699, 1642, 1541, 1508, 1340, 1316, 1241, 1194, 1177 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 11.63 (s, 1H, NH), 11.42 (s, 1H, NH), 8.42 (s, 1H, 4-NH), 7.86–7.91 (m, 2H, ArH), 7.58–7.63 (m, 1H, ArH), 7.52–7.57 (m, 2H, ArH), 7.00 and 6.90 (AA’XX’, J = 9.0 Hz, 2H each, 4-OCH₃-C₆H₄), 6.15 (s, 1H, C=CH), 4.09 (d, J = 10.0 Hz, 1H, 4a-CH), 3.75 (s, 3H, OCH₃), 3.28 (d, J = 7.8 Hz, 1H, 3a-CH), 3.11 (d, J = 10.0 Hz, 1H, 7a-CH), 2.91 (d, J = 7.8 Hz, 1H, 8a-CH), 1.56 (s, 3H, CH₃); ¹³C NMR (DMSO-d₆, 126 MHz) δ 178.0, 177.9, 177.7, 176.4, 166.1, 158.7, 145.8, 134.7, 132.1, 131.6, 129.9, 129.4, 128.6, 127.1, 113.4, 56.7, 55.1, 51.8, 46.6, 46.2, 44.5, 41.1, 18.8; HRMS (ESI-TOF) m/z 486.1653 (calcd for C₂₇H₂₄N₃O₆ (M + H)⁺ 486.1660); Anal. C, 66.31; H, 4.88; N, 8.50 (calcd for C₂₇H₂₃N₃O₆ · 1/5 H₂O C, 66.30; H, 4.82; N, 8.59).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-9-(3,4-dimethoxyphenyl)-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Ba): white solid (134 mg, 87%); mp 320–322 °C (EtOH/H₂O); IR (ATR) ν_max 3372, 3180, 1719, 1705, 1640, 1536, 1515, 1489, 1343, 1254, 1200, 1137 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 11.64 (s, 1H, NH), 11.41 (s, 1H, NH), 8.42 (s, 1H, 4-NH), 7.87–7.90 (m, 2H, ArH), 7.58–7.63 (m, 1H, ArH), 7.53–7.57 (m, 2H, ArH), 6.91 (d, J = 8.3 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.66 (d, J = 1.7 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.57 (dd, J = 8.3, 1.7 Hz, 1H, 3,4-(OCH₃)₂-C₆H₃), 6.16 (s, 1H, C=CH), 4.09 (d, J = 9.8 Hz, 1H, 4a-CH), 3.75 (s, 3H, OCH₃), 3.74 (s, 3H, OCH₃), 3.28 (d, J = 8.0 Hz, 1H, 3a-CH), 3.17 (d, J = 9.8 Hz, 1H, 7a-CH), 2.90 (d, J = 8.0 Hz, 1H, 8a-CH), 1.57 (s, 3H, CH₃); ¹³C NMR (DMSO-d₆, 126 MHz) δ 177.9, 177.8, 177.7, 176.5, 166.1, 148.3, 147.9, 146.0, 134.7, 132.0, 131.6, 130.2, 128.6, 127.1, 120.6, 112.1, 111.3, 56.7, 55.5, 55.4, 51.7, 46.6, 46.1, 44.6, 41.2, 18.8; HRMS (ESI-TOF) m/z 516.1766 (calcd for C₂₈H₂₆N₃O₇ (M + H)⁺ 516.1765); Anal. C, 64.98; H, 4.58; N, 8.07 (calcd for C₂₈H₂₅N₃O₇ C, 65.24; H, 4.89; N, 8.15).

rel-N-((3aR,4R,4aR,7aS,8S,8aS)-9-benzoyl-8-methyl-1,3,5,7-tetraoxo-2,3,3a,4a,5,6,7,7a,8,8a-decahydro-4,8-ethenopyrrolo[3,4-f]isoindol-4(1H)-yl)benzamide (exo,endo-5Ca): white solid (135 mg, 93%); mp 342–344 °C (EtOH); IR (ATR) ν_max 3367, 3254, 3052, 1726, 1708, 1660, 1552, 1346, 1324, 1207, 1188 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 11.70 (s, 1H, NH), 11.50 (s, 1H, NH), 8.66 (s, 1H, 4-NH), 7.86–7.90 (m, 2H, ArH), 7.72–7.76 (m, 2H, ArH), 7.66–7.71 (m, 1H, ArH), 7.57–7.61 (m, 1H, ArH), 7.50–7.56 (m, 4H, ArH), 6.68 (s, 1H, C=CH), 4.04 (d, J = 9.8 Hz, 1H, 4a-CH), 3.45 (d, J = 8.3 Hz, 1H, 3a-CH), 3.12 (d, J = 9.8 Hz, 1H, 7a-CH), 2.95 (d, J = 8.3 Hz, 1H, 8a-CH), 1.74 (s, 3H, CH₃); ¹³C NMR (DMSO-d₆, 126 MHz) δ 192.6, 177.14, 177.09, 176.9, 175.8, 166.5, 142.4, 141.6, 136.4, 134.3, 133.7, 131.7, 129.4, 128.8, 128.4, 127.4, 56.7, 51.8, 46.3, 46.1, 44.4, 40.1, 17.4; HRMS (ESI-TOF) m/z 484.1515 (calcd for C₂₇H₂₂N₃O₆ (M + H)⁺ 484.1503); Anal. C, 66.39; H, 4.16; N, 8.57 (calcd for C₂₇H₂₁N₃O₆ · 1/3 H₂O C, 66.25; H, 4.46; N, 8.58).

Ethyl rel-(3aR,4R,4aR,7aS,8S,8aS)-4-Benzamido-8-methyl-1,3,5,7-tetraoxo-1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-ethenopyrrolo[3,4-f]isoindole-9-carboxylate (exo,endo-5Da): white solid (119 mg, 88%); mp 334–336 °C (EtOH); IR (ATR) ν_max 3379, 3154, 3042, 2934, 1708, 1664, 1529, 1352, 1315, 1286, 1237, 1202, 1042 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 11.49 (s, 1H, NH), 11.45 (s, 1H, NH), 8.63 (s, 1H, 4-NH), 7.89–7.94 (m, 2H, ArH), 7.61–7.64 (m, 1H, ArH), 7.52–7.58 (m, 2H, ArH), 7.13 (s, 1H, C=CH), 4.06–4.15 (m, 2H, CH₃CH₂), 3.90 (d, J = 10.0 Hz, 1H, 4a-CH), 3.36 (d, J = 8.0 Hz, 1H, 3a-CH), 2.95 (d, J = 9.5 Hz, 1H, 7a-CH), 2.85 (d, J = 8.0 Hz, 1H, 8a-CH), 1.85 (s, 3H, CH₃), 1.20 (t, J = 7.0 Hz, 3H, CH₃CH₂); ¹³C NMR (DMSO-d₆, 126 MHz) δ 177.1, 176.9, 176.7, 175.8, 166.5, 163.5, 143.7, 135.8, 134.4, 131.7, 128.5, 127.4, 60.6, 56.6, 51.7, 46.4, 45.5, 44.0, 39.9, 17.7, 14.0; HRMS (ESI-TOF) m/z 452.1435 (calcd for C₂₃H₂₂N₃O₇ (M + H)⁺ 452.1452); Anal. C, 60.74; H, 4.48; N, 9.14 (calcd for C₂₃H₂₁N₃O₇ · 1/6 H₂O C, 60.79; H, 4.73; N, 9.25).

rel-N-((3aR,4R,9aS,9bS,10R,14S)-1,3,11,13-tetraoxo-2,3,3a,6,7,8,9,9b-octahydro-4,9a-[3,4]epipyrrolobenzo[e]isoindol-4(1H)-yl)benzamide (exo,endo-5Ea): white solid (114 mg, 91%); mp 335–337 °C (EtOH); IR (ATR) ν_max 3394, 3136, 3073, 2950, 1703, 1641, 1523, 1340, 1312, 1179 cm⁻¹; ¹H NMR (DMSO-d₆, 500 MHz) δ 11.50 (s, 1H, NH), 11.34 (s, 1H, NH), 8.28 (s, 1H, 4-NH), 7.83–7.87 (m, 2H, ArH), 7.58–7.63 (m, 1H, ArH), 7.53–7.57 (m, 2H, ArH), 5.98 (s, 1H, C=CH), 3.97 (d, J = 9.8 Hz, 1H, 10-CH), 3.13 (d, J = 8.0 Hz, 1H, 3a-CH), 3.07 (d, J = 9.8 Hz, 1H, 9b-CH), 2.83 (d, J = 8.0 Hz, 1H, 14-CH), 2.41–2.48 (m, 1H, 9-CH₂), 2.28–2.35 (m, 1H, 9-CH₂), 2.17–2.25 (m, 1H, 6-CH₂), 1.95–2.04 (m, 1H, 6-CH₂), 1.57–1.76 (m, 3H, 7-CH₂, 8-CH₂), 1.37–1.48 (m, 1H, 7-CH₂); ¹³C NMR (DMSO-d₆, 126 MHz) δ 178.16, 178.15, 177.7, 176.7, 165.9, 143.3, 134.7, 131.6, 128.6, 127.0, 126.7, 56.5, 47.3, 46.1, 44.9, 44.5, 41.1, 26.3, 22.7, 19.6, 17.5; HRMS (ESI-TOF) m/z 420.1535 (calcd for C₂₃H₂₂N₃O₅ (M + H)⁺ 420.1554); Anal. C, 65.34; H, 4.95; N, 9.89 (calcd for C₂₃H₂₁N₃O₅ · 1/6 H₂O C, 65.39; H, 5.09; N, 9.95).

4. Conclusions

In this study, we described the first examples where the steric hindrance of the diene (i.e., N-substituted maleimides 2) causes the double cycloaddition of 2H-pyran-2-one derivatives 1 to proceed via a different stereochemical pathway, yielding bicyclo[2.2.2]octenes with the asymmetric exo,endo-5 structure instead of the symmetric exo,exo-5 adducts obtained in all previous cases (with the only exception being when cyclooctane-fused pyran-2-one derivatives were applied). The work presented here clearly shows that steric interactions strong enough to reverse the stereoselectivity of these cycloadditions can arise solely from the bulkiness of the dienophiles 2, which, together with other groups in the reactants, results in steric hindrance sufficient to yield nearly exclusively asymmetric exo,endo products. Based on the experimental results, a qualitative correlation between the steric demand of the substituents present in 2 and the observed ratio of the asymmetric exo,endo- to symmetric exo,exo-cycloadducts 5 was established, showing that greater steric hindrance leads to the formation of a larger amount of asymmetric exo,endo-5 adducts, with stereospecific formation of exo,endo-5 when the sterically highly congested N-triphenylmethylmaleimide (2e) is used. Furthermore, we have shown that asymmetric exo,endo-5 with R⁴ = H, which cannot be accessed via direct cycloaddition of maleimide (2a) on 1A–E, can be obtained by acid-induced elimination of the triphenylmethyl group from the asymmetric bicyclo[2.2.2]octenes exo,endo-5A–Ee, which are easily obtained by cycloaddition of N-triphenylmethylmaleimide (2e). In these cases, the N-triphenylmethyl group acts as a diastereoselective exo,endo-auxiliary.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules31081301/s1, ¹H and ¹³C NMR spectra of all new products 1 and 5, a representative example of ¹H–¹³C gs-HSQC and ¹H–¹³C gs-HMBC 2D NMR spectra for the asymmetric/symmetric pair 5Aa, and the ¹H NMR spectrum of isolated 6Ac.

Author Contributions

Conceptualization, K.K.; methodology, M.K. (Marko Krivec), Ž.Š., M.K. (Marijan Kočevar) and K.K.; synthesis, M.K. (Marko Krivec) and Ž.Š.; formal analysis, M.K. (Marko Krivec) and K.K.; writing—original draft preparation, K.K.; writing—review and editing, M.K. (Marko Krivec), Ž.Š., M.K. (Marijan Kočevar) and K.K.; visualization, M.K. (Marko Krivec) and K.K. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors on request.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding Statement

This research was funded by the Ministry of Higher Education, Science and Innovation of the Republic of Slovenia and the Slovenian Research and Innovation Agency, grant number P1-0230, and by the Infrastructure Programme of the University of Ljubljana “Network of Research and Infrastructural Centres UL” (No. I0-0022).