Unified Enantioselective Synthesis of 5-Phenylmorphans and Cis-Octahydroisoquinolines

Abstract

Modifications of morphine have delivered novel opioid scaffolds, such as 5-phenylmorphans and cis-octahydroisoquinolines, that exhibit various pharmacological profiles. To date, these substructures have only been prepared using chiral resolution strategies that require purging of 50% of the material at a late stage of a synthesis. Herein, we disclose the first enantioselective synthesis of both scaffolds. This unified synthesis exploits an enantioselective conjugate addition, followed by conversion of the ester to a common amine intermediate. Subsequently, a diastereoselective aza-Michael reaction generates 5-phenylmorphans, while a γ-regio- and diastereoselective Mannich reaction generates cis-octahydroisoquinolines.

Graphical Abstract

Opioid receptors (ORs), a subclass of G-protein-coupled receptors, are widely distributed in the nervous system and play key roles in pain modulation, mood regulation, and stress response.^1,2 Clinically, exogenous opioids have been exploited for the management of pain, as well as disorders such as depression, and substance use disorders, despite well-known adverse effects, including respiratory depression, tolerance, and addiction.³ Among clinically approved opioids, morphine (Figure 1a) has long served as the prototypical opioid and a cornerstone for medicinal chemistry efforts aimed at improving its pharmacological and pharmacokinetic properties.^4–7 In this context, scaffolds such as the octahydroisoquinolines and 5-phenylmorphans frameworks (Figure 1a) have emerged as promising templates for the development of opioid modulators selective for the μ-, δ-, and κ-ORs (Figure 1b).^8–19

Figure 1. 5-Phenylmorphans and cis-Octahydroisouqionline Containing Opioids and Key Disconnections.^{12–17,19,25}.

So far, several syntheses have been developed to access various 5-phenylmorphans and cis-octahydroisoquinolines; however, these syntheses only generate racemic material and often employ early-stage intermediates that are structurally similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxic compound that causes Parkinson’s Disease.^20–22 As part of our efforts to develop opioid modulators with innovative signaling profiles, we identified 5-phenylmorphans and octahydroisoquinolines as promising scaffolds for further optimization.^20,21,23 To streamline analogs and enable their late-stage functionalization and rapid diversification, we pursued an efficient enantioselective, scalable synthesis to access these privileged scaffolds. Herein, we disclose the first enantioselective synthesis of both 5-phenylmorphan (2) and cis-octahydroisoquinolinone (3). Notably, both sequences exploit common amine intermediate 1 that can be accessed in multigram quantities, thereby facilitating direct access to both scaffolds. Additionally, the presence of the ketone groups on both products enables subsequent late-stage functionalization, which not only enables direct access to previously reported opioid modulators,^13–15,24 but also provides opportunities to access novel derivatives.

Our retrosynthetic analyses exploited strategic disconnections that trace both scaffolds back to common amine retron 1 (Figure 1c). For the 5-phenylmorphan system, disconnection of the C1–amine bond in the [3.3.1] bicyclic framework suggested a diastereoselective aza-Michael transformation. In contrast, the cis-octahydroisoquinolines was simplified by disconnecting the C8a–C1 bond of the [4.4.0] bicyclic system using a rarely utilized intramolecular γ-selective vinylogous-Mannich transformation, which further expands the use of vinylogous-Mannich annulation methodology²⁶ to the construction of opioid alkaloids regio and diastereoselectively. The common amine retron 1 would be accessed from an ester through functional group interconversion. Finally, to enantioselectively set the all-carbon quaternary stereocenter, a Pd-catalyzed enantioselective conjugate addition of an aryl boronic acid to the α,β-unsaturated ketone 4 was used.

In our optimized sequence, amine intermediate 1 was synthesized on gram scales over 6 steps with 56% yield (Scheme 1). Initially, the quaternary stereocenter was established by an enantioselective conjugate addition reaction of aryl boronic acids to α,β-unsaturated ketones.^27,28 Importantly, this stereocenter would be used to form all the subsequent stereocenters. Initial attempts to execute this strategy with cyclohexenone substrates bearing a nitrile (R = CN) or protected alcohol (R = OTBS) substituents were unsuccessful (Scheme 1A), though substrates bearing an ester side chain (R = CO₂Et) proved effective, affording ketone 5 in 90% yield with >95% ee on scales up to 10 g using (R)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (L1) as a ligand. Subsequent Pd-catalyzed dehydrogenation of 5 furnished the corresponding α,β-unsaturated ketone 6 in up to 88% yield on an 11 g scale, following a modified protocol.²⁹

Scheme 1. Synthesis of 5-Phenylmorphans.

Initial attempts to install the methylamine group using an amide coupling approach followed by reduction failed to convert ester intermediate 6 (or its ketal-protected derivative) to an amide by reacting with methylamine at reflux in THF or ethanol in a sealed tube (Scheme 1B), as were attempts to react N-methyl aminoacetonitrile with various ester derivatives under basic and Lewis acidic conditions. However, protection of the ketone and reduction of the ester yielded alcohol 7 in 85% yield. From alcohol 7, attempts to introduce an acidic boc- or nosyl-protected methylamine precursor using a Mitsunobu reaction using DIAD and PPh₃ were unsuccessful (Scheme 1C), as were attempts to couple N-methyl aminoacetonitrile derivatives with a recently reported system ³⁰ However, a sequence involving the mesylation of alcohol 7 followed by nucleophilic amination afforded the desired methylamine-bearing intermediate 1 in 75% yield over two steps. Finally, treatment of methylamine 1 with 1 N HCl deprotected the ketal and promoted the diastereoselective aza-Michael reaction to deliver 5-phenylmorphan 2 in 90% yield (99% ee) in a single step (Scheme 1). The retention of enantiopurity for 2, implicates retention of stereochemsitry for intermediates 6, 7, 8, and 1.

The other enantiomer of 5-phenylmorphan 2 was also produced using the same synthetic route, albeit by employing (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (L2) for the enantioselective conjugate addition step. The 1D NMR spectra match the previously reported spectra,¹⁴ and further 2D NMR analysis reconfirmed the structures (See SI For Details). Of note, the preparation of product 2 represents a formal synthesis of several pharmacologically active compounds, as the C₇ ketone provides opportunities for further synthetic transformations at a site that has previously been proven useful in structure-function studies.^{13,14,24,31,32}

The cis-decahydroisoquinoline scaffold was delivered in 28% yield in 3 steps from methylamine intermediate 1. Initially, amine 1 was reacted with bromoacetonitrile followed by an acidic workup to to deliver the α-aminoacetonitrile 9 (Scheme 1), which can generate an electrophilic iminium ion under mild conditions (Table 1). Having installed the pro-electrophile, the nucleophilic γ-silylenol ether 10 would need to be selectively prepared to promote the regioselective intramolecular vinylogous Mannich reaction. Though the synthesis of γ-silylenol ethers has been reported,^33–39 application of prior methods that performed well on simple model systems failed to perform on the more complex substrate (9) that bears three acidic protons (α and γ to the carbonyl, and α to the nitrile), in addition to steric effects presented by the quaternary stereocenter. These features introduced considerable sensitivity to small changes in conditions and made the system unusually challenging, which necissitated the screening of various conditions to access γ-silylenol ether 10. Initial screening of a mild base (TEA) in the presence of silylating reagents (TBSOTf or TBSCl)^33,34 demonstrated an innate instability of our substrate, as the reactions formed undesired dimerized side products (entries 1–2). To avoid forming the side products, we explored methods that use stronger bases to discretely form the enolate at cryogenic temperatures. Initially, the use of TBSCl with LHMDS and HMPA^34–36,39 regioselectively formed the γ-silylenol ether without degradation, albeit with low conversion (entry 3). Surprisingly, use of KHMDS as the base in the presence of TBSCl converted 9 to 10 while minimizing degradation, albeit with eroded regioselectivity (entry 4). The greater regioselectivity using LHMDS may arise from the lower reactivity of the lithium enolate (30 min) vs. the potassium enolate (7 h) needed for complete conversion, allowing kinetic control and favoring the transition state leading to the γ-product. On the other hand, use of a stronger base, LDA (entry 5), predominantly degraded the starting material. Subseuqently, , different chlorosilanes were screened using LHMDS/HMPA, though these other silanes unexpectedly reacted with poor selecivity (entries 6–8).^40–42 Finally, further optimization of stoichiometry, time, and temperature using TBSCl-LHMDS (entry 9) improved the reaction to deliver the product with >99:1 regioselectivity, 48% yield, and 20% recovered starting material.

Table 1.

Synthesis of the γ-Silylenolether 10

Entry	Base (equiv.)	R3SiX (equiv.)	Additive (equiv.)	Time (h)	Temp. (°C)	SM:Pa	(γ:α)	Isolated Yield
1	TEA (1.3)	TBSCl (1.3)	KI (1.3)	18	50	17:83	>99:1	17%d
2	TEA (1.3)	TBSOTf (1.3)	-	3.5	0 to r.t.	-	-	-d
3 b	LHMDS (2)	TBSCl (5)	HMPA (2.5)	5	–78	60:40	>99:1	15%
4 b	KHMDS (2)	TBSCl (5)	HMPA (2.5)	0.5	–78	<1:99	50:50	43%
5 b	LDA (2)	TBSCl (5)	HMPA (2.5)	5	–78	20:80	>99:1	2%d
6 b	LHMDS (2)	TIPSCl (5)	HMPA (2.5)	5	–78	90:10	72:28	9%
7 b	LHMDS (2)	TESCl (5)	HMPA (2.5)	0.5	–78	<1:99	77:23	20%
8 b	LHMDS (2)	DMPSCl (5)	HMPA (2.5)	3	–78	<1:99	56:44	37%
9 b,c	LHMDS (3)	TBSCl (4)	HMPA (2.5)	7	–78 to –20	25:75	>99:1	48%

^a+APCI ratios;

^bAfter addition of base and HMPA, stir at 0 °C for 1 h;

^cAfter addition of TBSCl, reaction was let to warm slowly to –20 °C over 5 h;

^dDegradation and dimerization observed during the reaction

After delivering the precursor for the vinylogous-Mannich reaction, different reported conditions for the formation of iminium were screened to facilitate the subsequent cyclization to the cis-octahydroisoquinoline core (Table 2).^39–41 Notably, nearly all the conditions delivered the product with absolute regio- and diastereoselectivity except for Pd(PPh₃)₄ (entry 4).

Table 2.

Synthesis of cis-Octahydroisoquinoline

Entry*	Reagent (equiv.)	Solvent (Temp.)	Degradation	Yield
1	Cu(OTf)2 (1.2)	CHCl3 (r.t.)	partial	21%
2	Camphorsulfonic acid (1.2)	PhH (80 °C)	partial	44%
3	ZnCl2 (1.2)	THF (60 °C)	partial	27%
4	Pd(PPh3)4 (1.2)	THF (60 °C)	complete	-
5	AgTFA (1.2)	EtOH (r.t.)	not observed	68%
6	AgBF4 (2.0)	THF (r.t.)	not observed	81%

^*Complete conversion observed in all runs.

Out of the conditions explored, AgTFA (entry 5) and AgBF₄ (entry 6) delivered the desired product (3) in 68% and 81%, respectively. The regio- and stereochemistry of the product were confirmed using HMQC, HMBC, and NOESY NMR (See SI For Details). The excellent regio- and diastereoselectivity of this annulation represents an expansion in the vinylogous-Mannich annulation methodology²⁶ to include the construction of fused ring systems of opioid alkaloids.

In summary, we report the first enantioselective access to two privileged opioid scaffolds, 5-phenylmorphans and cis-octahydroisoquinolinones. This unified synthesis sequences exploited common amine intermediate 1, which divergently promote an aza-Michael reaction to access 5-phenylmorphans and a regioselective vinylogous-Mannich reaction to generate cis-octahydroisoquinolinones. Notably for both transformations, the inital quarternary stereocenter was exploited to set subsequent stereocenters with excellent disatereoselectivities. This synthesis not only provides medicinal chemists with improved access to these scaffolds for the development of novel opioid modulators but also introduces a synthetic paradigm for accessing these core structures embedded within various opioid alkaloids. Future directions in our laboratory include the synthesis and pharmacological evaluation of novel derivatives based on these scaffolds.

Supplementary Material

The Supporting Information is available free of charge at (___).

General synthetic information, experimental procedures, NMR spectra, HRMS, IR, chiral HPLC analyses, and specific rotation for compounds (PDF)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.