New Aporphinoid 5-HT_2A and α_1A Antagonists via Structural Manipulations of Nantenine

Abstract

A series of C1, C2, C3 and N6 analogs of nantenine (2) was synthesized and evaluated in 5-HT_2A and α_1A receptor functional assays. Alkyl substitution of the C1 and N6 methyl groups of nantenine provided selective 5-HT_2A and α_1A antagonists respectively. The C2 alkyloxy analogs studied were generally selective for α_1A vs 5-HT_2A. The C3 bromo analog 15 is one of the most potent aporphinoid 5-HT_2A antagonists known presently.

1. Introduction

Aporphines are a group of tetracyclic alkaloids that are a subset of the ubiquitous tetrahydroisoquinoline family. The aporphine template is known to be associated with a range of biological activities. For example, aporphines have been explored as antituberculosis and cytotoxic agents.^{1, 2} In the realm of central nervous system (CNS) activity, members of the aporphine class are known to inhibit the enzyme acetylcholinesterase - an important therapeutic target in current treatment modalities for Alzheimers disease.^3-5 Behavioral and physiological effects of the designer drug MDMA (“Ecstasy”, 1) are antagonized by nantenine (2), an isolate of a number of Lauraceous plants. With regards to clinically available aporphine drugs, apomorphine (3) is a potent dopamine D1/D2 agonist that is used to treat symptoms of Parkinson’s disease.⁶

Naturally occurring aporphines and their synthetic derivatives are known to have affinity for dopaminergic, adrenergic and serotonergic receptors.^7-14 The aporphine chemotype may be regarded as a “privileged” CNS receptor template. Indeed, this scaffold represents an attractive opportunity to identify and develop selective mono-potent as well as multi-potent CNS receptor ligands for dopaminergic, adrenergic and serotonergic receptors. Such molecules will be useful as interrogative chemical tools and potential therapeutic interventions for a variety of neuropsychiatric conditions such as stress, depression, anxiety, psychosis and psychostimulant abuse.

As indicated earlier, a number of groups have investigated the structure-activity properties of aporphines (particularly apomorphine derivatives) as dopamine D1 and D2 receptor ligands. In contrast, the structure-activity relationships (SAR) of aporphines as 5-HT_2A receptor ligands have been little explored. We are particularly interested in “tooling” aporphines as 5-HT_2A and α_1A dual antagonists and as probes to study antagonism of MDMA’s behavioral and physiological effects. Our interest is propelled by abundant literature studies that implicate 5-HT_2A and α₁ adrenergic receptors in mediating physiological and psychobehavioral effects of MDMA in animals and humans. ^15-21 Currently, no medications are specifically approved to treat adverse effects of “Ecstasy” overdose although the muscle relaxant, dantrolene, has been effectively used as an antidote in cases of hospitalization due to “Ecstasy”- induced hyperthermia.²²

Prior to our forays in this area, only one SAR study on aporphines at the 5-HT_2A receptor was reported. In that study, conducted with (±)-nantenine (2) as the lead, it was revealed that replacement of the C1 methoxy group with a hydroxyl group gave decreased 5-HT_2A affinity.²³ Replacement of the N6 methyl group with a hydrogen or ethyl group also gave reduced affinity. We have recently reported further investigations at the C1 position and have identified new 5-HT_2A antagonists up to 12 times more potent than nantenine.^{24, 25}

In addition, we have screened (±)-nantenine in a CNS panel of over 30 receptors, ion-channels and transporters and determined that the molecule is a potent and selective α_1A ligand.²⁶ Others have documented the affinity trends of aporphines at the α_1A receptor, but no study has done so with nantenine as the lead.¹² One prior study has investigated the structure-affinity relationships of nantenine at α₁ receptors.²⁷ Here it was reported that replacement of the C1 methoxy group with a hydroxyl group gave improved α₁ affinity. Substitution of the N6 methyl group of nantenine with a hydrogen or ethyl group gave reduced affinities however.

Taken together, the results of previous investigations of (±)-nantenine suggest that the substituents on the aporphine core are important determinants of its 5-HT_2A and α_1A activity. While the ultimate goal of optimizing aporphines as 5-HT_2A/α_1A dual antagonist probes seems achievable, more extensive SAR studies are necessary. In this manuscript, we describe an SAR study to further probe the effects of structural manipulations in the ring A and N6 regions of the molecule on antagonism of 5-HT_2A and α_1A receptors. For comparison to our prior work, all evaluations in the following discussion were conducted with racemic aporphine derivatives.

2. Results and Discussion

2.1 Chemistry

The ring A C1 modified racemic analogs were prepared using methods analogous to that previously described via the key phenolic precursor 5.^{24, 28} Standard Williamson ether O-alkylation of 5 followed by reduction of the carbamate group gave the C1 analogs 6a-i. Synthesis of the ring A C2 analogs is shown in Scheme 1. The key intermediate 12 was synthesized from readily available 7 and used to prepare C2 analogs as shown. Thus, coupling of 7 with readily available bromomethylenedioxyphenylacetic acid gave amide 8.²⁹ Bischler-Napieralski cyclization of 8 gave an imine which was subsequently reduced to secondary racemic amine 9 ³⁰ (without purification of the imine). Reaction of 9 with Boc anhydride gave the carbamate 10, which was then cyclized via a palladium-mediated microwave-assisted procedure to afford the aporphine 11. Removal of the benzyl protecting group of 11 then gave phenol 12. Alkylation of 12 with respective alkyl bromides afforded the boc protected aporphines 13a-13f. Removal of the Boc group with ZnBr₂ and standard reductive amination gave the target C2 derivatives 14a-14f. (We attempted to reduce the Boc group directly to the N-methyl group with lithium aluminium hydride but found that this gave competing cleavage of the Boc group).

Scheme 1.

Synthesis of C2 ring A analogs

Bromination of (±)-nantenine with bromine/acetic acid (Figure 3) gave the C3-bromo analog 15. This reaction also produced a substantial amount of tribromo derivative 16.

Figure 3.

Bromination of nantenine

The preparation of N6 analogs was achieved by N-alklyation of secondary (±)-amine 17 (see ref 4) under reductive amination conditions (Figure 4)

Figure 4.

Synthesis of N-alkyl analogs

2.2 Pharmacology

All analogs were screened at 10 μM in multi-well format for intrinsic (agonist) and antagonist activity at the human 5-HT_2A receptor using FLIPR Tetra (Molecular Devices, Sunnydale, CA) functional assays that detect receptor-mediated mobilization of internal calcium with a calcium sensitive fluorescent dye. Compounds that showed no intrinsic activity in the functional assay and inhibited the increase in basal fluorescence elicited by the EC₈₀ of 5-HT by at least 50%, had their K_e (apparent affinity in a functional assay) determined. K_e values were determined by running an 8-point half-log 5-HT concentration response curve in the presence and absence of a single concentration of antagonist. EC₅₀ values were calculated for 5-HT (A) and 5-HT + test compound (A’), and these used to calculate the test compound K_e using the formula: K_e = [L]/(DR-1), where [L] equals the concentration of test compound in the assay and DR equals the dose ratio or A’/A. A similar set of assays was performed for the α_1A-adrenergic receptor.

In our previous SAR study, we found that successive alkyl homologation of the C1 methyl group of nantenine resulted in a progressive increase in 5-HT_2A antagonist activity (ethyl to n-pentyl: 890 to 171 nM). ²⁴ Additionally, the C1 cyclopropylmethyloxy analog was the most potent 5-HT_2A antagonist (68 nM) identified in that study. Therefore, we continued our exploration of this position by investigating other alkyloxy, and cycloalkyloxy analogs. n-Hexyloxy analog 6a (K_e=71 nM, Table 1), showed activity comparable to the cyclopropylmethyloxy compound and 2-fold improved activity as compared to the previously reported n-pentyloxy analog. Compound 6b was prepared as a ring-opened analog for comparison to the cyclopropylmethyloxy compound but this had 5-fold lower 5-HT_2A antagonist activity. Nevertheless, we anticipated that homologation of 6b would cause a rebound in antagonist activity as seen with the C1 n-alkyloxy series and so we prepared and evaluated isopentyloxy analog 6c and 2-ethylbutyloxy analog 6d. However, homologation did not improve the antagonist activity. In fact in the case of 6c, this compound had weak agonist activity (19% of 5-HT E_max). Next we decided to investigate other cycloalkyloxy analogs. The cyclohexylmethyloxy analog (6g) showed moderate activity, albeit 25-fold lower than the cyclopropyloxy analog. Other cycloalkyloxy derivatives tested showed weak agonist activity (25% and 35% of 5-HT E_max for 6e and 6f respectively). However, we were pleased to observe that the allyloxy analog (6h) had activity comparable to the cyclopropylmethyloxy analog. Since the alkene functionality of 6h is electronically similar to a cyclopropyloxy group, this may account for the similar activities seen; this is in need of further investigation. We then decided to test the tolerance for a polar group in this region. Addition of a hydroxypropyloxy moiety (6i) was associated with a reduction in 5-HT_2A antagonist activity. Compounds 6a-6i were evaluated in α_1A assays but were devoid of activity.

Table 1.

K_e values for ring A and N6 analogs at 5-HT_2A and α_1A receptors

Compd	R1	R2	R3	X1	X2	Ke ± SEM (nM)a
						5-HT2A	α 1A
6a	n-Hex	Me	Me	H	H	71±19	>10,000
6b	Isobu	Me	Me	H	H	367±82	>10,000
6c	Isopen	Me	Me	H	H	NDb	>10,000
6d	2-EthylBu	Me	Me	H	H	806±152	>10,000
6e	CyclobutylMe	Me	Me	H	H	NDb	>10,000
6f	CyclopentylMe	Me	Me	H	H	NDb	>10,000
6g	CyclohexylMe	Me	Me	H	H	1722±258	>10,000
6h	Allyl	Me	Me	H	H	70±15	>10,000
6i	HydroxyPr	Me	Me	H	H	708±316	>10,000
14a	Me	Et	Me	H	H	378±92	52±13
14b	Me	n-Pr	Me	H	H	389±93	133±45
14c	Me	n-Bu	Me	H	H	943±283	234±52
14d	Me	n-Pen	Me	H	H	>10,000	449±169
14e	Me	CyclopropylMe	Me	H	H	484±123	195±86
14f	Me	Benzyl	Me	H	H	154±76	1917±226
15	Me	Me	Me	Br	H	53±14	>10,000
16	Me	Me	Me	Br	Br	43±11	>10,000
18a	Me	Me	Et	H	H	>10,000	26±6
18b	Me	Me	n-Pr	H	H	>10,000	38±3
18c	Me	Me	n-Bu	H	H	>10,000	210±50
18d	Me	Me	n-Pen	H	H	>10,000	720±204
18e	Me	Me	CyclopropylMe	H	H	>10,000	319±60
2	Me	Me	Me	H	H	850±6c	36±7
prazosin							1.1 ± 0.4
ketanserin						32c,d

^aValues represent mean ± SEM for three independent experiments.

^bND = K_e not determined (compounds were weak agonists).

^cData from reference 25

^dIC₅₀ determined in the presence of 5-HT EC₈₀

We then progressed to examine C2 nantenine analogs. With regards to 5-HT_2A activity, the ethyloxy and n-propyloxy analogs (14a and 14b respectively) were equipotent. Further extension of the alkyl chain resulted in decreased antagonist activity with a plummet in activity in going from the n-butyloxy analog to the n-pentyloxy homolog (14c to 14d). The C2 cyclopropylmethyloxy analog was found to have moderate activity that was comparable to 14a and 14b. Benzyloxy analog (14f) was the most potent C2 analog tested. In the α_1A assay a clear SAR trend was observed. The C2 ethyloxy analog had the highest activity though this was slightly lower than that obtained for nantenine in this assay. Increasing the alkyl chain length at this position led to a progressive decrease in α_1A antagonist activity. The C2 alkyloxy analogs (14a-14d) are generally more selective for α_1A vs 5-HT_2A. Interestingly, this selectivity is reversed with the benzyloxy analog 14e.

The C3 bromo analog (15) had high 5-HT_2A antagonist activity (K_e=53 nM). Polybromination of ring D (16) did not affect this activity. Compounds 15 and 16 are the most potent 5-HT_2A aporphine antagonists identified up to now. Both of these halogenated analogs were found to be highly selective for the 5-HT_2A receptor vs the α_1A receptor.

None of the N6 analogs tested had activity at the 5-HT_2A receptor. The N6 ethyl (18a) and N6 n-propyl (18b) congeners had activities that were comparable to nantenine in the α_1A assay. Further lengthening of the alkyl chain gave reduced α_1A antagonist activity.

The preceding evaluations were conducted with the compounds in racemic form. It will be interesting to evaluate enantiomers of these molecules to ascertain whether there is any enantio-preference with respect to selectivity and activity. This is especially necessary in light of the fact that series of aporphine enantiomers have been shown to have opposing effects (agonism and antagonism) at the related 5-HT_1A receptor.^{11, 31, 32}

3. Conclusions

In summary, we have identified a number of new aporphine 5-HT_2A and α_1A antagonists via manipulation of the ring A and N6 substituents of nantenine. The results of our SAR study suggest that C1 and C3 substituents may be modified to develop potent 5-HT_2A antagonists that are highly selective vs the α_1A receptor. In contrast, the C2 alkyloxy analogs are generally more selective for the α_1A receptor vs. 5-HT_2A. However, it would appear that only relatively small alkyl groups are tolerated at this position for optimal activity at either receptor. Similarly, at N6 the relatively small methyl group is best tolerated. Compounds 15 and 16 are the most potent aporphine 5-HT_2A antagonists known. It is clear that the aporphine skeleton is sensitive to structural changes and that this template is amenable to the development of selective 5-HT_2A vs α_1A and selective α_1A vs 5-HT_2A antagonists.

Altogether, these results suggest that it is possible to synthesize potent dual-acting 5-HT_2A/α_1A aporphine ligands because the receptor selectivity can be directed through modifications of different substituents. Evaluation of the aporphine enantiomers is an important direction for future work. Our research team is actively investigating these avenues.

4. Experimental section

4.1 General experimental procedures

Reagent grade chemicals and solvents were purchased from Sigma-Aldrich Inc. or Fisher Scientific Inc. Reactions were monitored by TLC with Analtech Uniplate silica gel G/UV 254 precoated plates (0.2 mm). TLC plates were visualized by UV (254 nm), by iodine vapour or by staining with phosphomolybdic acid reagent followed by heating. Microwave reactions were conducted on a CEM Discover microwave reactor. Flash column chromatography was performed with Silicagel 60 (EMD Chemicals, 230-400 mesh, 0.04-0.063 μm particle size). High Resolution Electrospray Mass Spectra (HRESIMS) were obtained using an Agilent 6520 Q-TOF instrument. NMR data were collected on a Bruker 500 MHz machine with TMS as internal standard. Chemical shift (δ) values are reported in ppm and coupling constants in Hertz (Hz). Melting points were obtained on a Mel-Temp capillary electrothermal melting point apparatus.

4.2 Synthesis of C1 analogs (6)

C1 analogs were prepared from 4 using methods as described in reference 25.

4.2.1 1-(Hexyloxy)domesticine (6a)

Off white solid; mp: 68-70 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.95 (s, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 5.97 (d, J = 1.5 Hz, 1H), 5.95 (d, J = 1.5 Hz, 1H), 3.84 (s, 3H), 3.83.3.81 (m, 1H), 3.61-3.59 (m, 1H), 3.16-3.11 (m, 1H), 3.03 (dd, J=11.3, 6.0 Hz, 1H), 2.98-2.95 (m, 2H), 2.68-2.64 (br d, J = 16 Hz, 1H), 2.54-2.49 (m, 5H), 1.74-1.60 (m, 2H), 1.45-1.26 (m, 6H), 0.88-0.85 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 152.2, 146.48, 143.9, 130.8, 129.9, 128.8, 128.5, 127.5, 126.0, 110.8, 109.5, 108.3, 101.0, 73.4, 64.5, 56.0, 53.4, 44.1, 35.3, 31.8, 30.3, 29.3, 26.0, 22.8, 14.2 ; HRMS (ESI) m/z calcd. for C₂₅H₃₁NO₄ ([M+H]⁺), 410.2326, found 410.2330

4.2.2 1-(Isobutyloxy)domesticine (6b)

Brown Oil; ¹H NMR (500 MHz, CDCl₃) δ 7.95 (s, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 5.97 (s, 1H), 5.94 (s, 1H), 3.84 (s, 3H), 3.61 (t, J=7.6 Hz, 1H), 3.36 (t, J = 7.6 Hz, 1H), 3.16-3.10 (m, 1H), 3.04-2.95 (m, 2H), 2.67-2.64 (br. d, J=15.7 Hz, 1H), 2.54-2.48 (m, 5H), 2.04-1.99 (m, 1H), 1.01-0.95 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 152.2, 146.4 (×2), 144.1, 130.7, 128.4, 127.4, 125.8, 110.9, 109.6, 108.2, 101.0, 100.84, 79.8, 62.8, 56.1, 53.5, 44.2, 35.3, 29.3, 29.2, 19.7, 19.5; HRMS (ESI) m/z calcd for C₂₃H₂₇NO₄ ([M+H]⁺), 382.2013, found 382.2017.

4.2.3 1-(Isopentyloxy)domesticine (6c)

Brown Oil; ¹H NMR (500 MHz, CDCl₃) δ 7.95 (s, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 5.96 (s, 1H), 5.95 (s, 1H), 3.86-3.82 (m, 4H), 3.66-3.61 (m, 1H), 3.17-3.10 (m, 1H), 3.04-3.01 (m, 1H), 2.98-2.94 (m, 2H), 2.68-2.64 (m, 1H), 2.55-2.48 (m, 5H), 1.84-1.76 (m, 1H), 1.63-1.52 (m, 2H), 0.88-0.87 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 152.1, 146.4, 144.1, 143.7, 130.7, 129.7, 128.5, 127.3, 125.7, 110.5, 109.2, 108.1, 100.8, 71.5, 62.5, 55.8, 53.2, 40.3, 39.1, 35.1, 24.7, 22.6, 22.4; HRMS (ESI) m/z calcd for C₂₄H₂₉NO₄ ([M+H]⁺), 396.4914, found 396.4914

4.2.4 1-(2-Ethylbutyloxy)domesticine (6d)

Brown solid; mp: 62-64 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.91 (s, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 5.95 (d, J= 1.4 Hz, 1H), 5.94 (d, J= 1.4 Hz, 1H), 3.84 (s, 3H), 3.74 (dd, J= 9.1, 5.3 Hz, 1H), 3.49 (dd, J= 9.0, 5.3 Hz, 1H), 3.17-3.10 (m, 1H), 3.03 (dd, J=11.3, 5.1 Hz, 1H), 2.98-2.94 (m, 2H), 2.66 (dd, J=16.3, 3.4 Hz, 1H), 2.54-2.48 (m, 5H), 1.56-1.34 (m, 5H), 0.86 (d, J= 7.2 Hz, 3H), 0.83 (d, J=7.2 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 152.1, 146.4, 146.3, 144.1, 130.6, 128.3, 127.5, 127.4, 125.8, 110.8, 109.6, 108.2, 100.9, 75.2, 62.7, 55.9, 53.4, 44.1, 42.1, 35.2, 29.3, 23.4, 23.2, 11.3, 11.1; HRMS (ESI) m/z calcd for C₂₅H₃₁NO₄ ([M+H]⁺), 410.2326, found 410.2329.

4.2.5 1-(cyclobutylmethoxy)domesticine (6e)

Brown Oil; ¹H NMR (500 MHz, CDCl₃) δ 7.93 (s, 1H), 6.74 (s, 1H), 6.56 (s, 1H), 5.98 (d, J=1.5 Hz 1H), 5.94 (d, J=1.5 Hz, 1H), 3.85 (s, 3H), 3.83 (dd, J=9.4, 6.7 Hz, 1H), 3.59 (dd, J=9.4, 7.4 Hz, 1H), 3.18-3.11 (m, 1H), 3.05 (dd, J=6.0, 5.5 Hz, 1H), 3.0-2.95 (m, 2H), 2.69-2.64 (m, 2H), 2.56-2.50 (m, 5H), 2.06-1.95 (m, 2H), 1.92-1.85 (m, 1H), 1.83-1.66 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 152.1, 146.4, 146.7, 143.7, 130.7, 128.4, 127.5, 127.2, 125.9, 110.7, 109.7, 108.2, 101.0, 62.6, 56.1, 53.3, 44.0, 35.5, 35.2, 29.8, 29.1, 25.5, 25.0, 18.6; HRMS (ESI) m/z calcd for C₂₄H₂₇NO₄ ([M+H]⁺), 394.2013, found 394.2017.

4.2.6 1-(cyclopentylmethoxy)domesticine (6f)

Brown Oil; ¹H NMR (500 MHz, CDCl₃) δ 7.97 (s, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 5.97 (d, J=1.3 Hz, 1H), 5.94 (d, J=1.3 Hz, 1H), 3.85 (s, 3H), 3.73 (dd, J = 7.0, 7.0 Hz, 1H), 3.47 (dd, J = 7.6, 7.6 Hz, 1H), 3.16-3.10 (m, 1H), 3.03 (dd, J = 11.6, 5.5 Hz, 1H), 2.98-2.94 (m, 2H), 2.66 (br. d, J = 16.1 Hz, 1H), 2.54-2.47 (m, 4H), 2.31-2.25 (m, 1H), 1.92-1.85 (m, 1H), 1.80-1.71 (m, 2H), 1.55-1.49 (m, 4H), 1.33-1.22 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 152.1, 146.4, 146.3, 144.0, 130.7, 128.4, 127.4, 127.2, 125.9, 110.8, 109.7, 108.2, 101.0, 62.7, 56.0, 53.4, 44.1, 40.2, 35.2, 29.9, 29.4, 29.3, 25.6, 25.0, 25.5; HRMS (ESI) m/z calcd for C₂₅H₂₉NO₄ ([M+H]⁺), 408.2169, found 408.2172.

4.2.7 1-(cyclohexylmethoxy)domesticine (6g)

Yellow Oil; ¹H NMR (500 MHz, CDCl₃) δ 7.94 (s, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 5.97 (s, 1H), 5.94 (s, 1H), 3.84 (s, 3H), 3.60 (dd, J = 8.7, 6.1 Hz, 1H), 3.40 (t, J = 7.6 Hz, 1H), 3.17-3.10 (m, 1H), 3.05-2.94 (m, 3H), 2.66 (br. d. J = 16.0 Hz, 1H), 2.53-2.49 (m, 5H), 1.90-1.63 (m, 10H), 1.17-1.10 (m,1H); ¹³C NMR (125 MHz, CDCl₃) δ 152.2, 146.49, 146.45, 144.2, 130.7, 128.4, 127.4 (× 2), 125.8, 110.9, 109.7, 108.2, 101.0, 78.7, 62.7, 56.1, 53.4, 44.1, 38.7, 35.2, 30.2, 29.9, 29.1, 26.7, 26.1, 26.0 ; HRMS (ESI) m/z calcd for C₂₆H₃₁NO₄ ([M+H]⁺), 422.2326, found 422.2329.

4.2.8 1-(allyloxy)domesticine (6h)

Brown solid; mp: 63-65 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.95 (s, 1H), 6.74 (s, 1H), 6.58 (s, 1H), 6.01-5.93 (m, 3H), 5.27 (ddd, J= 17.3, 3.0, 1.4 Hz, 1H), 5.14 (dd, J=10.4, 1.4 Hz, 1H), 4.37-4.33 (m, 1H), 4.22-4.21 (m, 1H), 3.86 (s, 3H), 3.17-3.10 (m, 1H), 3.04-2.94 (m, 3H), 2.66 (dd, J = 16.3, 3.35 Hz, 1H), 2.54-2.48 (m, 2H), 2.53 (s, 3H) ; ¹³C NMR (125 MHz, CDCl₃) δ 152.2, 146.5, 146.4, 143.1, 134.4, 130.8, 128.8, 127.6, 127.3,125.8, 117.6, 110.7, 109.4, 108.3, 101.0, 73.8, 62.6, 56.0, 53.3, 44.1, 35.2, 29.3; HRMS (ESI) m/z calcd for C₂₂H₂₃NO₄ ([M+Na]⁺), 388.1519, found 388.1520.

4.2.9 1-(3-hydroxy-propanyloxy)domesticine (6i)

Brown Oil; ¹H NMR (500 MHz, CDCl₃) δ 7.95 (s, 1H), 6.74 (s, 1H), 6.59 (s, 1H), 5.98 (s, 1H), 5.96 (s, 1H), 3.97-3.92 (m, 2H), 3.90-3.84 (m, 5H), 3.82-3.77 (m, 1H), 3.19-3.13 (m, 1H), 3.07-2.95 (m, 3H), 2.68 (dd, J=16.2, 2.8 Hz, 1H), 2.54 (m, 5H), 2.05-1.97 (s, 1H), 1.85-1.78 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 151.8, 146.7, 146.6, 143.4, 130.8, 128.9, 127.4, 125.6, 110.6, 108.7, 108.5, 101.1, 71.0, 62.6, 61.2, 56.0, 53.3, 44.1, 44.0, 35.1, 29.9; HRMS (ESI) m/z calcd for C₂₂H₂₅NO₅ ([M+H]⁺), 384.4376, found 384.4376

4.3 3-(6-bromobenzo[d][1,3] dioxol-5-yl)-N-(3,4-dimethoxyphenethyl) ethanamide (8)

A solution of bromomethylenedioxyphenylacetic acid (4.76 g, 17.5 mmol) and 1,10-carbonyldiimidazole (2.84 g, 17.5 mmol) in anhydrous THF (40 mL) was stirred at 0 °C for 1.5 h and then at room temperature for 1 h. The mixture was cooled in an ice-bath and stirred for 1 h. Then 3-benzyloxy-4-methoxyphenethylamine (7) (4.50 g, 17.5 mmol) was added and the solution was stirred at 0 °C for 4 h and left to stir overnight at room temperature. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in EtOAc and washed sequentially with 1 N HCl (25 mL), water (50 mL), satd. NaHCO₃ solution (25 mL) and finally with brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was crystallized from EtOAc/diethylether to furnish amide 8 (6.65 g, 76.5%).

White solid; mp: 163-165 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.45 (m, 2H), 7.39 (m, 2H), 7.30 (m, 1H), 7.00 (s, 1H), 6.80 (d, J=8.2 Hz, 1H), 6.75 (s, 1H), 6.70 (br. s., 1H), 6.66 (d, J=8.2 Hz, 1H), 6.00 (s, 2H), 5.38 (br. s, 1H), 5.12 (s, 2H), 3.89 (s, 3H), 3.55 (s, 2H), 3.44 (dd, J=13.0, 6.5 Hz, 2H), 2.69 (dd, J=6.9, 6.9 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 169.5, 148.4, 148.3, 147.9, 147.7, 137.1, 131.0, 128.5, 127.9, 127.5, 127.4, 121.4, 115.3, 114.6, 112.9, 112.0, 110.9, 102.0, 71.1, 56.1, 43.8, 40.6, 34.9; HRMS (ESI) m/z calcd for C₂₅H₂₄BrNO₅ ([M+H]⁺), 498.0838, found 498.0840.

4.4 6-(benzyloxy)-1-((6-bromobenzo[d][1,3]dioxol-5-yl)methyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (9)

To a magnetically stirred ice-cooled solution of 8 (5.00 g, 10.05 mmol) in dry DCM (40 mL) was added solid phosphorus pentachloride (4.19 g, 20.1 mmol) in portions over 10 min. The reaction mixture was stirred at 0 °C for 1 h and then left to stir at room temperature for 20 h. The reaction mixture was then poured onto a saturated solution of aqueous NaHCO₃ (100 mL) and the contents of the flask were stirred for 1 h. The aqueous layer was extracted with dichloromethane (3 × 20 mL). The combined organic layer was washed with saturated NaHCO₃ solution (100 mL) and brine (40 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. To a magnetically stirred ice-cooled solution of the crude imine thus obtained in a mixture of dry MeOH (40 mL) and dry DCM (20 mL), was added powdered NaBH₄ (3.60 g, 98 mmol) in three portions over 10 min. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with water and extracted with dichloromethane (3 × 10 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography over deactivated silica gel using 0.7% MeOH/DCM as eluant to furnish pure 9 (3.92 g, 81 % yield from 8)

White solid; mp: 115-117 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.44 (m, 2H), 7.36 (m, 2H), 7.30 (m, 1H), 7.05 (s, 1H), 6.79 (s, 1H), 6.76 (s, 1H), 6.63 (s, 1H), 6.00 (s, 2H), 5.12 (s, 2H), 4.21 (t, J=6.5 Hz, 1H), 3.84 (s, 3H), 3.28-3.20 (m, 2H), 2.99-2.89 (m, 2H), 2.71 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 147.9, 147.3, 147.2, 147.0, 137.3, 131.6, 130.8, 128.5, 127.8, 127.3, 127.1, 115.0, 114.5, 112.9, 111.4, 110.4, 101.7, 71.1, 56.2, 55.2, 42.8, 40.0, 29.1; HRMS (ESI) m/z calcd for C₂₅H₂₄BrNO₄ ([M+H]⁺), 482.0889, found 482.0886.

4.5 tert-butyl-6-(benzyloxy)-1-((6-bromobenzo[d][1,3]dioxol-5-yl)methyl)-7-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (10)

To a stirred solution of 9 (3.67 g, 7.63 mmol) in DCM (30 mL) was added DIPEA (2.66 mL, 15.3 mmol), a catalytic amount of DMAP (0.01 g) followed by BOC anhydride (3.26 mL, 15.3 mmol) at room temperature and the solution stirred under inert atmosphere for 18 h. The reaction mixture was washed with saturated NH₄Cl solution and water, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 30% EtOAc/hexanes as eluant to furnish pure 10 (5.10 g, 65 %).

Off-white solid; mp: 128-130 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.43 (m, 2H), 7.36 (m, 2H), 7.29 (m, 1H), 7.02 (s, 1H), 6.96 (s,1H), 6.63 (s, 1H), 6.65 (s, 1H), 5.97 (s, 1H), 5.93 (s, 1H), 5.27 (m, 1H), 5.10-5.09 (s, 2H), 4.35 (dd, J = 13.2, 5.3 Hz, 1H), 3.85 (s, 3H), 3.21 (m, 2H), 2.89 (m, 2H), 1.40-1.23 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 154.9, 148.3, 147.2, 137.8, 131.3, 128.6, 127.9, 127.8, 127.3, 126.6, 115.3, 114.2, 112.5, 111.4, 111.0, 110.6, 101.6, 79.5, 71.1, 56.2, 54.0, 42.6, 36.4, 28.1; HRMS (ESI) m/z calcd for C₃₀H₃₂BrNO₆ ([M]⁺), 581.1413, found 581.1415.

4.6 2-(benzyloxy)N-boc-nor-isodomesticine (11)

In a microwave reaction vial, compound 10 (0.12 g, 0.21 mmol), Pd(OAc)₂ (0.009 g, 0.04 mmol), triphenylphosphine (0.02 g, 0.08 mmol) and Cs₂CO₃ (0.13 g, 0.4 mmol),) were added and dissolved in degassed DMF (2 mL). The mixture was irradiated in the CEM microwave reactor for 15 min at 175 °C with the power level at 300W. After cooling to room temperature, the reaction mixture was loaded directly onto a deactivated silica gel column and eluted in gradient fashion with 15-30% EtOAc/hexanes to furnish compound 11 (0.05 g, 52%).

Off-white solid; mp: 170-172 °C; ¹H NMR (500 MHz, CDCl₃) δ 8.07 (s, 1H), 7.52-7.29 (m, 5H), 6.76 (s, 1H), 6.68 (s, 1H), 6.01 (s, 2H), 5.15 (m, 2H), 4.65 (m, 1H), 4.42 (m, 1H), 3.75 (s, 3H), 2.86-2.64 (m, 5H), 1.52 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 151.1, 146.6, 146.5, 145.5, 137.1, 129.7, 128.6, 127.9, 127.3, 125.2, 112.8, 109.1, 100.9, 79.9, 71.0, 60.1, 51.8, 30.3, 28.6; HRMS (ESI) m/z calcd for C₃₀H₃₁NO₆ ([M]⁺), 501.2151, found 501.2154.

4.7 N-boc-nor-isodomesticine (12)

To a solution of 11 (0.50 g, 1 mmol) in dry methanol (10 mL) was added 10% Pd/C (25 mg) under inert atmosphere. The reaction was purged with H₂ and stirred under a balloon of H₂ for 6 h. Pd/C was filtered through a Celite pad and the filtrate was evaporated to give the corresponding phenol 12 (0.38 g, 92%).

White solid; mp: 218-220 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.90 (s, 1H), 6.79 (s, 1H), 6.73 (s, 1H), 6.02 (s, 2H), 5.86 (s, 1H), 4.70-4.68 (m, 1H), 4.61 (m, 1H), 4.40 (m, 1H), 3.61 (s, 3H), 2.92-2.76 (m, 4H), 2.66-2.62 (m, 1H), 1.57-1.52 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 148.1, 146.9, 146.8, 142.6, 131.5, 131.1, 126.5, 125.4, 124.9, 124.8, 113.4, 108.6, 107.8, 101.0, 79.9, 60.2, 51.8, 30.2, 28.6; HRMS (ESI) m/z calcd for C₂₃H₂₅NO₆ ([M]⁺), 411.1682, found 411.1684.

4.8 General procedure for preparation of C2 analogs (14)

O-methylation of 12

To a stirred solution of phenol (1eq) in acetone (10 mL) was added solid K₂CO₃ (2 eq) and potassium iodide (2 eq) at r.t. The resulting mixture was stirred for 5 min and then alkyl halide (1.5 eq) was added and refluxed for 7h. The solvent was evaporated and the resulting solid dissolved in water and extracted with dichloromethane twice (20 mL each) . The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 12.5% EtOAc/hexanes.

N-Boc deprotection and reductive amination of 13

To a solution of the boc-protected amine (1 eq) in dichloromethane (15 mL) was added dry ZnBr₂ (2 eq) and the reaction allowed to stir at rt overnight under N₂. The mixture was diluted with dichloromethane (20 mL) and wahed with saturated aqueous NaHCO₃ twice (10 mL each). The organic layer was dried (Na₂SO₄), filtered and concentrated in vacuo. The crude amine product was purified by comlumn chromatography on water-deactivated silica gel in 5% methanol/dichloromethane.

To a solution of this amine (1 eq) in dichloromethane (10 mL) was added the aldehyde (3 eq) and sodium triacetoxyborohydride (3 eq) under N₂. The reaction mixture was allowed to stir at r.t. overnight. The reaction was quenched with water and extracted with dichloromethane twice (20 mL each) . The combined organic layer was washed with 10% aq. NaHCO₃, then with brine, dried over anhydrous Na₂SO₄, and concentrated to give crude product. The crude product was subjected to column chromatography over water-deactivated silica gel using methanol/dichloromethane (2:98) as eluant, to furnish N-alkylated final product.

4.8.1 2-(ethoxy)isodomesticine (14a)

Yellow solid; mp: 101-104 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.92 (s, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 5.96 (d, J = 1.4 Hz, 1H), 5.95 (d, J = 1.4 Hz, 1H), 4.12-4.02 (m, 2H), 3.67 (s, 3H), 3.15-3.08 (m, 1H), 3.02-2.94 (m, 3H), 2.66-2.62 (m, 1H), 2.54-2.45 (m, 5H), 1.47 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 151.5, 146.5, 146.4, 144.7, 130.5, 128.9, 127.3, 127.1, 125.6, 111.6, 109.1, 108.4, 100.9, 64.2, 62.4, 60.2, 53.4, 44.2, 35.3, 29.3, 15.1; HRMS (ESI) m/z calcd for C₂₁H₂₃NO₄ ([M+H]⁺), 354.4116, found 354.4120.

4.8.2 2-(propyloxy)isodomesticine (14b)

Yellow solid; mp: 76-77 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.95 (s, 1H), 6.76 (s, 1H), 6.59 (s, 1H), 5.98 (d, J=1.4 Hz, 1H) 5.95 (d, J= 1.4 Hz, 1H), 4.04-3.90 (m, 2H), 3.69 (s, 3H), 3.17-3.10 (m, 1H), 3.04-2.96 (m, 3H), 2.65 (m, 1H), 2.55-2.48 (m, 5H), 1.93-1.85 (m, 3H), 1.09 (t, J = 7.4 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 151.6, 146.5, 146.4, 144.7, 131.0, 128.6, 127.3, 127.1, 125.8, 111.8, 109.1, 108.4, 101.0, 70.3, 62.6, 60.3, 53.4, 44.2, 35.3, 29.4, 22.9, 10.9; HRMS (ESI) m/z calcd for C₂₂H₂₅NO₄ ([M+H]⁺), 368.1882, found 368.1888

4.8.3 2-(butyloxy)isodomesticine (14c)

Yellow solid; mp: 95-97 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.95 (s, 1H), 6.76 (s, 1H), 6.60 (s, 1H), 5.98 (d, J = 1.4 Hz, 1H), 5.97 (d, J = 1.4 Hz, 1H), 4.05-3.94 (m, 2H), 3.68 (s, 3H), 3.17-3.10 (m, 1H), 3.04-2.95 (m, 3H), 2.68-2.64 (m, 1H), 2.55-2.46 (m, 5H), 1.92-1.78 (m, 2H), 1.63-1.47 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 151.6, 146.5, 146.4, 144.7, 130.9, 128.6, 127.3, 127.0, 125.8, 111.7, 109.1, 108.3, 100.9, 68.4, 62.6, 60.3, 53.4, 44.2, 35.3, 31.6, 27.4, 19.5, 14.0; HRMS (ESI) m/z calcd for C₂₃H₂₇NO₄ ([M+H]⁺), 382.2016 found 382.2013

4.8.4 2-(pentyloxy)isodomesticine (14d)

Yellow oil; ¹H NMR (500 MHz, CDCl₃) δ 7.94 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 5.97 (d, J = 1.4 Hz, 1H), 5.95 (d, J = 1.4 Hz, 1H), 4.05-3.94 (m, 2H), 3.68 (s, 3H), 3.15-3.09 (m, 1H), 3.03-2.95 (m, 3H), 2.67-2.63 (m, 1H), 2.54-2.46 (m, 5H), 1.92-1.81 (m, 2H), 1.55-1.37 (m, 4H), 0.96 (t, J=7.2 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 151.6, 146.5, 146.4, 144.7, 130.9, 128.6, 127.3, 127.1, 125.8, 111.8, 109.1, 108.4, 100.9, 68.7, 62.6, 60.3, 53.4, 44.2, 35.3, 29.4, 29.2, 28.4, 22.6, 14.2; HRMS (ESI) m/z calcd for C₂₄H₂₉NO₄ ([M+H]⁺), 396.2194, found 396.2192

4.8.5 2-(cyclopropylmethyloxy)isodomesticine (14e)

Yellow solid; mp: 91-92 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.93 (s, 1H), 6.74 (s, 1H), 6.56 (s, 1H), 5.97 (d, J=1.4 Hz, 1H), 5.95 (d, J=1.4 Hz, 1H), 3.94-3.90 (m, 1H), 3.79-3.75 (m, 1H), 3.70 (s, 3H), 3.14-3.07 (m, 1H), 3.02-2.94 (m, 3H), 2.65-2.61 (m, 1H), 2.54-2.45 (m, 5H), 1.37-1.24 (m, 1H), 0.64 (m, 2H), 0.37 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 151.6, 146.5, 146.4, 144.7, 130.9, 128.6, 127.3, 127.1, 125.8, 111.8, 109.1, 108.4, 100.9, 68.7, 62.6, 60.3, 53.4, 44.2, 35.3, 29.4, 29.2, 28.4, 22.6, 14.2; HRMS (ESI) m/z calcd for C₂₃H₂₅NO₄ ([M+H]⁺), 380.1872 found 380.1874.

4.8.6 2-(benzyloxy)isodomesticine (14f)

Brown solid; mp: 112-114 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.95 (s, 1H), 7.50-7.32 (m, 5H), 6.77 (s, 1H), 6.67 (s, 1H), 5.98 (d, J=1.4 Hz, 1H), 5.97 (d, J=1.4 Hz, 1H), 5.12 (d, J=11.8 Hz, 1H), 5.11 (d, J=11.8 Hz, 1H), 3.72 (s, 3H), 3.11 (m, 1H), 3.09-2.97 (m, 3H), 2.64 (m, 1H), 2.56-2.46 (m, 5H); ¹³C NMR (125 MHz, CDCl₃) δ 151.2, 146.5, 146.4, 145.0, 137.2, 130.8, 128.6, 128.5, 127.9, 127.8, 127.4, 127.3, 127.2, 125.6, 112.7, 109.0, 108.3, 100.9, 70.9, 62.5, 60.3, 53.2, 44.0, 35.1, 29.1; HRMS (ESI) m/z calcd for C₂₆H₂₅NO₄ ([M+H]⁺), 416.1784, found 416.1788.

4.9 Synthesis of 3-bromonantenine (15) and 3,8,11-tribromonantenine (16)

To a solution of nantenine (2) (25 mg, 1 eq) in acetic acid (5 mL) was slowly added a solution of bromine (3 eq) dissolved in acetic acid (2 mL) at room temperature. The mixture was stirred overnight at room temperature and the solvent evaporated in vacuo. The residue was dissolved in toluene and the solvent again removed by rotary evaporation. The residue was purified by column chromatography with elution in 2% MeOH/DCM to give compounds 15 (5 mg, 16%) and 16 (22 mg, 52%).

4.9.1 3-bromonantenine (15)

Off white solid; mp: 142-144 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.80 (s, 1H), 6.75 (s, 1H), 5.98 (d, J=1.2 Hz, 1H), 5.97 (d, J=1.2 Hz, 1H), 3.93 (s, 3H), 3.73 (s, 3H), 3.10-3.07 (dd, J=10.7, 5.2 Hz, 1H), 2.98-2.89 (m, 3H), 2.83-2.79 (m, 1H), 2.52 (s, 3H), 2.49-2.41 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 150.1, 149.3, 146.77, 146.76, 132.6, 130.7, 129.4, 127.0, 124.9, 118.5, 108.8, 108.3, 101.1, 62.9, 60.8, 60.6, 53.2, 44.0, 34.8, 30.5; HRMS (ESI) m/z calcd for C₂₀H₂₀BrNO₄ ([M+H]⁺), 418.0648, found 418.0651.

4.9.2 3,8,11-tribromonantenine (16)

White solid; mp: 193-195 °C; ¹H NMR (500 MHz, CDCl₃) δ 6.18 (s, 1H), 6.14 (s, 1H), 3.95 (s, 3H), 3.54 (s, 3H), 3.08 (dd, J=11.5, 5.2 Hz, 1H), 2.96-2.90 (m, 1H), 2.85-2.77 (m, 2H), 2.54 (s, 3H), 2.49 (dt, J=11.8, 4.1 Hz, 1H), 2.18 (dd, J=14.5, 12.9 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 149.6, 145.9, 145.0, 133.8, 132.6, 128.7, 127.5, 127.1, 125.7, 119.7, 101.7, 101.5, 101.4, 63.0, 61.5, 61.1, 53.0, 44.1, 34.9, 30.3; HRMS (ESI) m/z calcd for C₂₀H₁₈ Br₃NO₄ ([M+H]⁺), 572.8859, found 572.8859.

4.10 Synthesis of N6 analogs (18)

These compounds were prepared by reductive amination on amine 17 using the procedure as described above for synthesis of the C2 analogs.

4.10.1 N-ethyl-nornantenine (18a)

Brown solid; mp: 220-222 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.92 (s, 1H), 6.76 (s, 1H), 6.60 (s, 1H), 5.98 (d, J=1.4 Hz, 1H), 5.95 (d, J=1.4 Hz, 1H), 3.88 (s, 3H), 3.65 (s, 3H), 3.27 (d, J=8 Hz, 1H), 3.19-3.17 (m, 1H), 3.12-3.08 (m, 2H), 2.99-2.96 (m, 1H), 2.71-2.48 (m, 4H), 1.15 (t, J=7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 152.0, 146.6, 146.4, 144.6, 131.0, 129.0, 127.3, 125.7, 110.7, 109.1, 109.0, 108.4, 101.0, 60.4, 59.2, 55.9, 48.4, 47.9, 35.0, 29.3, 10.8; HRMS (ESI) m/z calcd for C₂₁H₂₃NO₄ ([M+H]⁺), 354.4116, found, 354.4115.

4.10.2 N-propyl-nornantenine (18b)

Yellow Oil; ¹H NMR (500 MHz, CDCl₃) δ 7.91 (s, 1H), 6.76 (s, 1H), 6.59 (s, 1H), 5.98 (d, J =1.1 Hz, 1H), 5.97 (d, J =1.1 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.23-3.20 (d, 1H), 3.17-3.14 (m, 2H), 2.98-2.95 (m, 1H), 2.69-2.66 (d, 1H), 2.51-2.41 (m, 4H), 1.60-1.57 (m, 2H), 0.97 (t, J=7.4 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ; 151.9, 146.5, 146.4, 144.5, 131.2, 129.2, 128.2, 128.1, 127.3, 125.7, 110.8, 109.0, 108.3, 101.0, 60.3, 60.0, 56.4, 55.9, 49.3, 35.3, 29.8, 29.5, 19.7,12.2; HRMS (ESI) m/z calcd for C₂₂H₂₅NO₄ ([M+H]⁺), 368.4382, found, 368.4380

4.10.3 N-butyl-nornantenine (18c)

Yellow Oil; ¹H NMR (500 MHz, CDCl₃) δ 7.92 (s, 1H), 6.77 (s, 1H), 6.60 (s, 1H), 5.99 (d, J = 1.5 Hz, 1H), 5.97 (d, J = 1.5 Hz, 1H), 3.88 (s, 3H), 3.65 (s, 3H), 3.17-3.15 (m, 2H), 2.99-2.95 (m, 3H), 2.70 (m, 1H), 2.54-2.43 (m, 3H), 1.59-1.54 (m, 2H), 1.41-1.37 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 151.9, 146.6, 146.4, 144.5, 131.3, 129.3, 128.6, 127.3, 125.8, 110.7, 109.0, 108.4, 101.0, 60.4, 60.0, 56.0, 54.2, 49.3, 35.3, 29.6, 28.7, 21.0, 14.3; HRMS (ESI) m/z calcd for C₂₃H₂₇NO₄ ([M+H]⁺), 382.4648, found 382.4645

4.10.4 N-pentyl-nornantenine (18d)

Yellow Oil; ¹H NMR (500 MHz, CDCl₃) δ 7.91 (s, 1H), 6.77 (s, 1H), 6.59 (s, 1H), 5.99 (d, J =1.4 Hz, 1H), 5.97 (d, J=1.4 Hz, 1H), 3.87 (s, 3H), 3.65 (s, 3H), 3.20-3.15 (m, 1H), 2.98-2.94 (m, 4H), 2.69 (m, 1H), 2.54 (m, 1H), 2.45-2.42 (m, 2H), 1.57 (m, 2H), 1.39-1.33 (m, 4H), 0.93 (t, J=6.9 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 151.9, 146.6, 146.4, 144.54, 131.3, 129.2, 128.1, 127.3, 125.8, 110.7, 109.0, 108.4, 101.0, 60.4, 60.0, 56.0, 54.5, 49.3, 35.3, 30.1, 29.6, 26.2, 22.9, 14.3; HRMS (ESI) m/z calcd for C₂₄H₂₉NO₄ ([M+H]⁺), 396.4914, found 396.4918.

4.10.5 N-cyclopropylmethyl-nornantenine (18e)

Yellow Oil; ¹H NMR (500 MHz, CDCl₃) δ 7.92 (s, 1H), 6.76 (s, 1H), 6.60 (s, 1H), 5.98 (d, 1.5 Hz, 1H), 5.97 (d, 1.5 Hz, 1H), 3.88 (s, 3H), 3.65 (s, 3H) 3.38-3.37 (m, 1H), 2.99-2.92 (m, 4H), 2.72-2.71 (m, 1H), 2.57-2.56 (m, 1H), 2.53-2.47 (m, 1H), 2.40-2.36 (m, 1H), 0.96 (m, 1H), 0.59 (dd, J=8.0, 8.0 Hz, 1H), 0.54 (dd, J=8.0, 8.0 Hz, 1H), 0.19 (d, J=4.8 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 151.9, 146.6, 146.4, 144.5, 131.2, 129.2, 128.0, 127.2, 125.8, 110.7, 109.0, 108.3, 101.0, 60.4, 59.5, 59.2, 56.0, 49.5, 35.2, 29.5, 7.7, 5.2, 3.1; HRMS (ESI) m/z calcd for C₂₃H₂₅NO₄ ([M+H]⁺), 380.4489, found 380.4490

Figure 1.

Structures of MDMA (1), ( ±)-Nantenine (2) and Apomorphine (3)

Figure 2.

Preparation of C1 analogs