Three-Component Betti Condensation for Synthesis of Aminomethylnaphthols Incorporating Deoxy-isoequilenine Scaffold-Absolute Configuration and Application

Abstract

Chiral aminomethylnaphthols have been prepared highly diastereoselective by means of three-component “Betti condensation”, using steroidal 2-naphthol analogue, synthesized from estrone. The use of 2-methoxybenzaldehyde or 2-pyridinecarboxaldehyde as aldehyde component and (S)-(–)-1-phenylethan-1-amine or (S)-(–)-1-(naphthalen-2-yl)ethan-1-amine, as chiral non-racemic amine component providing the diastereoselectivity, allowed the synthesis of structurally diverse aminomethylnaphthols. The latter easily form 1,3-dihydronaphthoxazines through reaction with formaldehyde. The absolute configurations of the new aminomethylnaphthols synthesized have been determined through advanced nuclear magnetic resonance (NMR) experiments and confirmed by X-ray crystallography. The chiral steroidal aminomethylnaphthols obtained as pure diastereoisomers have been evaluated as pre-catalysts in the enantioselective addition of diethylzinc to aldehydes with enantioselectivities of up to 97% enantiomeric excess (ee).

Keywords:
Betti condensation; chiral ligands; NOESY spectra; absolute configuration; enantioselectivity

Introduction

In the modern organic synthesis, the preparation of enantiomerically pure products is of general importance due to their applications in medicinal chemistry and in catalytic enantioselective processes. The so-called “Betti condensation” (three-component condensation first studied by Mario Betti¹ leading to 1-(α-aminobenzyl)-2-naphthol, referred to as “Betti base”) offers practicable approach for the synthesis of aminobenzylnaphthols.¹ The Betti reaction is one of the early examples of a multicomponent reaction (MCR). It is necessary to emphasize that MCR have become in recent years an indispensable tool for synthesis of multifunctional compounds with diverse fields of application (comprehensive review articles have been recently published).²,³,⁴ The interest in this easy to perform reaction has been awakened by Naso and co-workers⁵,⁶ who synthesized new “Betti base” analogues, realizing efficient resolution into enantiomers with defined configuration⁵ and applied them as valuable catalyst in the enantioselective addition of diethylzinc to arylaldehydes (enantioselectivity up to 99% ee).⁶ In a further development, the use of commercial available chiral non-racemic amines within the three-component condensation resulted in highly diastereoselective synthesis of chiral 1,3-aminobenzylnaphthols with excellent properties as ligands for enantioselective organozinc additions to aldehydes.⁷,⁸,⁹,¹⁰ A new synthetic pathway of enantiomerically pure Betti bases has recently been described involving Zr-mediated reduction of chiral pyrrolidine-2-ones to cyclic imines and their further reaction with phenolic derivatives.¹¹ The scope of the current knowledge on the synthesis and application of aminobenzylnaphthols has recently been demonstrated in review articles.¹²,¹³,¹⁴,¹⁵,¹⁶,¹⁷ In most cases, various chiral amines are used in combination with different aldehydes to prepare chiral non-racemic aminobenzylnaphthols.⁷,⁸,⁹,¹⁸,¹⁹ As a third component 2-naphthol is commonly used in the condensation reaction. Recently we have described the utilization of 2,3-, 2,6- and 1,5-dihydroxynaphthalenes¹⁰ and the use of deoxy-isoequilenine as a new steroidal 2-naphthol analogue,²⁰ in condensation reactions with aromatic aldehydes and (S)-(–)-1-phenylethan-1-amine. The aminobenzylnaphthols thus synthesized were formed with high diastereoselectivity.

In the current work, we aimed to study the ability of 2-methoxybenzaldehyde (2) and 2-pyridinecarboxaldehyde (3) to efficiently perform the three component condensation with (S)-(–)-1-phenylethan-1-amine (4), (S)-(–)-1-(naphthalen-2-yl)ethan-1-amine (7) and deoxyisoequilenine (1). The diastereoselectivity of the reactions and the configuration of the newly formed stereogenic centers were of particular interest. The capability of the targeted compounds to serve as chiral auxiliaries was evaluated within the model reaction of enantioselective addition of diethylzinc to aldehydes.

Results and Discussion

Synthesis of aminomethylnaphthols by three component condensation

The synthetic approach for the condensation is focused on application of deoxy-isoequilenine (1) as 2-naphthol component (Scheme 1), since the utility of this chiral compound has been recently demonstrated.²⁰ The choice of 2-methoxybenzaldehyde (2) and 2-pyridinecarboxaldehyde (3) is motivated by the presence of additional heteroatom in the corresponding structure, which could bring advantage within the planned catalytic applications.

Scheme 1
Three component condensation of deoxy-isoequilenine (1), aromatic aldehydes 2 and 3, and amines 4 and 7 (the numbering of the C-atoms is tentative and applied for the assignment of nuclear magnetic resonance (NMR) signals and is introduced in the Supplementary Information (SI) section).

The readily available chiral amines (S)-(–)-1-phenylethan-1-amine (4) and (S)-(–)-1-(naphthalen-2-yl)ethan-1-amine (7) are the corresponding amine components to induce diastereoselectivity in the condensation reaction leading to aminomethylnaphthols 5, 6, 8 and 9 (Scheme 1). It should be noted that in all reactions the use of solvent was not necessary and the condensations were performed by simply mixing the three components and heating them. The yields of the aminomethylnaphthols got worse when using of solvents (tetrahydrofuran (THF) or EtOH). The condensation reactions performed with 2-methoxybenzaldehyde (2), naphthol 1 and amines 4 or 7, respectively at 80 °C, were slow with an optimized duration of 96 h to obtain acceptable yields of compounds 5 (50%) and 8 (32%). The diastereoselectivity determined by ¹H nuclear magnetic resonance (NMR) spectroscopy of the crude reaction mixtures for the formation of both compounds 5a/5b and 8a/8b was high (79:21) in favor of the corresponding S,S-diastereoisomer (in the following the configuration description refer to the atoms C-19 and C-20; compare Schemes 1 and 2, and for configuration determination Figure 1). Noteworthy, the diastereoisomeric ratio within 5 and 8 formed was always the same regardless of the reaction time (the condensation was evaluated in the range between 24 and 96 h). The individual diastereoisomers could be isolated in pure form by column chromatography in the yields, given as follows (S,S)-5a (47%), (R,S)-5b (3%), (S,S)-8a (26%) and (R,S)-8b (6%). It should be noted that the isolation of the diastereoisomers 5a and 5b, 8a and 8b in pure form required several column chromatographies due to their close Rf value.

Scheme 2
Synthesis of 1,3-dihydronaphthoxazines 10a, 11a, 12a and 13a.

Figure 1
Main proton proximities of compounds 5a/5b, 6a/6b, 8a, 9a/9b and 10a-13a, observed in the NOESY spectra (images with arbitrary molecular conformations were created using Spartan for Windows;²⁸ blue arrows present proton proximities formally in front of C-19, whereas the red ones behind it).

The condensations of 2-pyridinecarboxaldehyde (3) with 1 and amines 4 and 7 was high yielding (78% in both cases), respectively, providing compounds 6 and 9 within shorter reaction times (Scheme 1). The diastereoselectivities observed by ¹H NMR spectroscopy of the crude reaction mixtures were similar, 6a/6b = 80:20 and 9a/9b = 81:19. The predominantly formed 6a- and 9a-diastereoisomers showed the same sense of chirality, compared with compounds 5a and 8a, for the newly formed stereogenic center at C-19 (the same relative space arrangement of substituents attached to C-19), although according the Cahn, Ingold, Prelog (CIP) convention the configuration is determined as R for both 6a and 9a. The individual diastereoisomers were isolated in pure form by means of column chromatography realizing the yields, as follows (R,S)-6a (61%), (S,S)-6b (17%), (R,S)-9a (69%) and (S,S)-9b (9%). Also, in this case, due to the close Rf values of the diastereoisomers 6a and 6b, 9a and 9b the use of several column chromatographies is required to isolate them in pure form.

It is important to note that the defined configuration of the corresponding chiral amine applied in the condensation reaction allows to predict the configuration of the predominantly formed diastereoisomer (e.g., the S-configured amines 4 and 7 produce predominantly 5a and 8a with (S)-C-19 configuration. The situation in the case of compounds 6a and 9a is similar, however, due to the CIP rules the descriptor for stereogenic center C-19 is formally (R). The predictable diastereoselectivity, emphasized also in previous articles,¹⁰,²¹ is a significant advantage intrinsically connected with the mechanism of the reaction which has been discussed in recent studies.²²

Synthesis of the corresponding 1,3-dihydronaphthoxazines

The aminomethylnaphthols 5a, 6a, 8a and 9a were further used in the course of the very efficient reaction with aqueous formaldehyde to provide the corresponding 1,3-dihydronaphthoxazines (Scheme 2). The reactions were performed by gently heating the reactants in THF solution for several hours. The isolation of 1,3-dihydronaphthoxazines 10a-13a occurred in high yields by column chromatography. One reason for the synthesis of these compounds is the systematic generation in recent years of a library containing critical mass of structurally diverse aminomethylnaphthols and the corresponding 1,3-dihydronaphthoxazines for evaluation of the possible biological activity.²³,²⁴,²⁵,²⁶,²⁷ The main reason for the synthesis of compounds 10a-13a in the present study is to analyze and compare the NMR data of the prepared aminomethylnaphthols and their 1,3-dihydronaphthoxazines in order to establish the relative configuration of the newly formed stereogenic center at C-19. The introduction of the pro-stereogenic methylene group between the N- and O-atom leading to 10a-13a is a convenient synthetic method that does not affect the existing stereogenic centers. The methylene-bridge caused reduction of the conformational flexibility within the dihydronaphthoxazine structures providing the opportunity to attain proper information about the space position of substituents attached to C-19 relative to each other by means of NMR experiments.

Structure determination

The configuration determination of the aminomethylnaphthols 5a/5b, 6a/6b, 8a and 9a/9b was of particular interest and was performed using NMR experiments. The ¹H and ¹³C signals of the compounds were assigned by means of 1D and 2D spectra (distortionless enhancement by polarization transfer (DEPT), heteronuclear single quantum correlation (HSQC), heteronuclear multiple bond correlation (HMBC) and nuclear overhauser effect spectroscopy (NOESY)). The implementation of the NOESY data was the approach applied¹⁰,²⁰,²² to obtain extensive information about the proton neighborhood around the newly formed stereogenic center at C-19. The data attained permitted elucidation of the relative arrangement of the fragments within the molecules (Figure 1) in respect of the C-19 stereogenic center. Consequently, by using this basic approach the relative configurations of newly formed stereogenic centers in the studied compounds could be determined. Taking into account the known absolute configuration of the fragments originating from (S)-(–)-1-phenylethan-1-amine (4) or (S)-(–)-1-(naphthalen-2-yl)ethan-1-amine (7), the absolute configuration at C-19 for the respective compound was deduced.

In the NOESY spectra of 5a, 6a, 8a and 9a, similar proton proximities could be observed for the relative positions of the steroidal naphthyl fragment, the (S)-(–)-1-phenylethan-1-amine or (S)-(–)-1-(naphthalen-2-yl)ethan-1-amine and the corresponding ortho-methoxyphenyl or 2-pyridyl parts of the structures. The most important proton interactions are indicated by means of arrows in Figure 1. The proton at C-19 is in close proximity to the following nuclei: the peri-proton from the steroidal naphthyl fragment, the C-20 methine proton and an ortho-proton of the phenyl moiety for all a-diastereoisomers (5a, 6a, 8a and 9a), as well as, the NH proton for 5a and 6a, and the ortho-naphthyl proton for 8a and 9a. It is important to note that the OH protons for all a-diastereoisomers are involved in strong intramolecular O–H···N hydrogen bonding, confirmed by the singlets with the following δ-values in ppm: 13.75 (5a), 13.28 (6a), 13.71 (8a) and 13.24 (9a). The data are consistent with the conformations presented and the configurations are strongly supported by the NOESY data obtained for the corresponding 1,3-dihydronaphthoxazines 10a-13a (Figure 1). The CH₂-bridge between the O- and N-atoms generate a conformationally rigid structure, providing additional arguments for a reliable configuration elucidation. Complementary information for the proximity of the H_a and H_b protons of the CH₂-bridge relative to the methyl group attached to C-20 and/or to the ortho-protons of the methoxyphenyl moiety additionally supports the configuration of the C-19 stereogenic center as presented in Figure 1.

Furthermore, the NOESY data for the minor diastereoisomers 5b, 6b and 9b indicating the opposite configuration of C-19 could be considered as additional proof for validity of the NMR approach presented above for configuration determination. The discussion of the NOESY spectra of 8b was abandoned due to the presence of impurities and possible adulteration of the interpretation.

The conformations of the aminomethylnaphthols presented in Figure 1 require some comments. It seems that the hydrogen bonding observed within 5a, 6a, 8a and 9a has a significant impact on the most favored conformations thus providing reliable NOESY data for configuration determination. The NOESY data strongly support comparable conformations of the a-diastereoisomers (5a, 6a, 8a and 9a) with the corresponding dihydronaphthoxazines (10a-13a), where the CH₂-bridge force the molecules to adopt a conformationally rigid structure. The strong hydrogen bonding observed in the case of compound 5a, 6a, 8a and 9a could be considered as formed in the course of the condensation reaction, which mechanism has been discussed in previous articles.²¹,²²

Single-crystal X-ray structure analyses were performed to precisely assign the structures of compounds 5a and 11a (suitable crystals were obtained by slow evaporation from ethanol). The absolute configurations of compounds 5a (S for C-19) and 11a (R for C-19) were independently and unequivocally confirmed by single-crystal X-ray structure analyses (see Experimental section). Consequently, the NMR approach for the determination of the configuration, which is presented in Figure 1, is fully confirmed by the results of the X-ray crystallography. Views of the molecules are shown in Figure 2 and the data collection, and refinement parameters are given in the Supplementary Information (SI) section. The values for the bond lengths and bond angles in 5a and 11a do not deviate significantly from the observed within similar structures of previously synthesized compounds.¹⁰,²⁰,²²

Figure 2
Atomic displacement ellipsoid plots of the molecular structures present in the asymmetric units of (a) (19S,20S)-5a and (b) (19R,20S)-11a. Atomic displacement parameters (ADP) are drawn at the 50% probability level. Hydrogen atoms are shown as spheres with arbitrary radii.

Compound 5a crystallizes in P2₁2₁2₁ and the only molecule present in the asymmetric unit exhibits a disorder over two positions for the cyclopentane ring of the steroidal fragment (major component of 75%) (Figure 2). An intramolecular hydrogen bond O1–H1∙∙∙N1 (2.585 Å) supports the relative orientation of the aromatic moieties around the C-19 center. Compound 11a crystallizes in the hexagonal P6₁ space group as hydrate.

For the crystal structure to fully accommodate the water molecule, disorder over two position is observed (major component of 75%). Interestingly, the water molecules do not show close contacts with the molecule of 11a. There is an interaction between the water molecules forming chains propagating along the c axis (Figure 3).

Figure 3
Three-dimensional view of 11a showing the water neighborhood along the c axis.

Application of aminomethylnaphthols as chiral ligands in enantioselective addition of diethylzinc to aldehydes

The newly synthesized compounds 5a, 6a, 8a and 9a were evaluated as pre-catalysts (3 mol%) in the enantioselective addition of diethylzinc (Et₂Zn) to various aldehydes (Table 1) by following a standard procedure.¹⁰,²⁰,²²,²⁹,³⁰

Table 1
Enantioselective addition of Et₂Zn to aldehydes catalyzed by ligands 5a, 6a, 8a and 9a

entry	Aldehyde	Ligand	Yielda / %	ee (config.)b / %
1	benzaldehyde	5a	34	33 (R)c
2	2-methoxybenzaldehyde	5a	99	90 (R)c
3	2,4,6-trimethylbenzaldehyde	5a	65	73 (unknown)d
4	cinnamaldehyde	5a	90	56 (R)d
5	2-naphthaldehyde	5a	88	97 (R)c
6	4-chlorobenzaldehyde	5a	39	33 (R)c
7	2,6-dichlorobenzaldehyde	5a	88	81 (unknown)d
8	benzaldehyde	6a	25	20 (S)c
9	2-methoxybenzaldehyde	6a	93	3 (S)c
10	cinnamaldehyde	6a	52	1 (S)d
11	2-naphthaldehyde	6a	63	26 (S)c
12	benzaldehyde	8a	45	22 (R)c
13	2-methoxybenzaldehyde	8a	50	77 (R)c
14	cinnamaldehyde	8a	57	64 (R)d
15	2-naphthaldehyde	8a	59	76 (R)c
16	4-chlorobenzaldehyde	8a	38	27 (R)c
17	2,6-dichlorobenzaldehyde	8a	90	72 (unknown)d
18	benzaldehyde	9a	69	24 (S)c
19	2-methoxybenzaldehyde	9a	47	7 (S)c
20	2-naphthaldehyde	9a	51	26 (S)c

• ^aYield of isolated pure products after column chromatography; ^bthe configuration was determined by comparison of the measured specific rotation with literature data; ^cenantiomeric excess (ee) was determined by GC (see SI section); ^denantiomeric excess was determined by HPLC (see SI section); unknown configuration, since no literature data about the specific rotation available.

The reactions catalyzed by the aminomethylnaphthols proceeded in the range of moderate to very good yields. The reaction times varied from 22 to 72 h. The best enantioselectivities were realized by using compound 5a as ligand. The addition of Et₂Zn to 2-methoxybenzaldehyde and 2-naphthaldehyde occurred with enantioselectivity of 90 and 97%, respectively (entries 2 and 5). The reactions with 2,4,6-trimethylbenzaldehyde and 2,6-dichlorobenzaldehyde using 5a could also be considered as acceptable, 73% ee and 81% ee, respectively (entries 3 and 7). Compounds 6a, 8a and 9a applied as ligands provided low to moderate enantioselectivity apart from 8a realizing with three of the aldehydes (entries 13, 15 and 17) enantioselectivities near the 77%. Notably, the enantioselectivities obtained with benzaldehyde were low with all ligands applied. Interestingly, comparing the enantioselectivity provided by ligand 5a by using 2-methoxybenzaldehyde and 2-naphthaldehyde (90 and 97% ee, respectively), there is a dramatic decrease of asymmetric induction in the case of 6a with the same aldehydes (3 and 26% ee, respectively). It should be noted that ligands 5a and 8a delivered products possessing R-configuration whereas compounds 6a and 9a the S-configured substituted 1-aryl-1-propanols. These results indicate a possible role of the pyridyl fragment providing additional coordination site within the active catalyst. In the established mechanistic model, described by Noyori and Kitamura,³⁰ for the addition of Et₂Zn to aldehydes catalyzed by chiral aminoalcohols, the addition reaction takes place within a transition complex formed by the actually catalyst (aminoalkoxy-Zn-Et intermediate formed in situ), Et₂Zn and the corresponding aldehyde. An additional coordinating N-atom (of the pyridyl fragment), as in the case of ligands 6a and 9a can significantly influence the stereochemistry within the transition complex and consequently also the outcome of the addition reaction.

Conclusions

The three-component condensation of deoxy-isoequilenine with 2-methoxybenzaldehyde or 2-pyridine carboxaldehyde as aldehyde component, and (S)-(–)-1-phenylethan-1-amine or (S)-(–)-1-(naphthalen-2-yl)ethan-1-amine as amine component, has been efficiently applied for the highly diastereoselective synthesis of functionalized aminomethylnaphthols. The diastereoselectivity was induced by the readily available chiral amines applied, which makes the approach economically relevant. The significant advantage of this reaction was the opportunity to predict the configuration of the newly generated stereogenic center, which is directly dependent on the configuration of the amine component in the condensation. The absolute configuration of the newly formed stereogenic center within the synthesized compounds was determined by applying an effective approach based on NMR NOESY experiments. This approach was validated by corresponding X-ray crystal-structure determinations. The aminomethylnaphthols were evaluated as pre-catalysts in the enantioselective addition of Et₂Zn to aldehydes, providing secondary alcohols with up to 97% enantioselectivity.

Experimental

General information

Reagents were commercial grade and used without further purification (2 -methoxybenzaldehyde, 2-pyridinecarboxaldehyde, (S)-(–)-1-phenylethan-1-amine, (S)-(–)-1-(naphthalene-2-yl)ethan-1-amine and 37% aq solution of formaldehyde, Sigma-Aldrich, supplier FOT LTD, Sofia, Bulgaria). The reactions with Et₂Zn (1 mol L^-1 solution in hexane, Sigma-Aldrich, supplier FOT LTD, Sofia, Bulgaria) were carried out in flame-dried Schlenk flasks under an argon atmosphere. The toluene (high-performance liquid chromatography (HPLC) grade, Sigma-Aldrich, supplier FOT LTD, Sofia, Bulgaria) for the enantioselective organozinc additions was dried by refluxing over LiAlH₄ and distilled under an argon atmosphere. Thin layer chromatography (TLC) was performed on aluminum sheets pre-coated with Merck Kieselgel 60 F₂₅₄ 0.25 mm (Merck, supplier FOT LTD, Sofia, Bulgaria). Flash column chromatography was carried out using silica gel 60 230-400 mesh, (Merck, supplier FOT LTD, Sofia, Bulgaria). Solvents: petroleum ether (PE), methyl tert-butyl ether (MTBE) and tetrahydrofuran (THF) (Sigma-Aldrich, supplier FOT LTD, Sofia, Bulgaria). The melting points of the compounds were determined by using BOETIUS, type PHMK 05, manufacturer VEB Kombinat NAGEMA, Dresden, East Germany, (uncorrected). Optical rotation [α]_D²⁵ measurements were obtained using a PerkinElmer 241 polarimeter, supplier PerkinElmer, Vienna, Austria. The NMR spectra were recorded at ambient temperature (298 K) on a Bruker Avance II+ 600 (600 MHz for ¹H NMR, 150 MHz for ¹³C NMR) spectrometer, manufacturer Brucker BioSpin GmbH, Rheinstetten, Germany, with tetramethylsilane (TMS) as internal standard for chemical shifts (δ, ppm). ¹H and ¹³C NMR data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), integration, coupling constants (J, Hz), and identification.

The assignment of the ¹H and ¹³C NMR spectra was made on the basis of DEPT, HSQC, HMBC, and NOESY experiments. All assignments marked with an asterisk are tentative. Mass spectra (ESI-MS) were recorded on an API QSTAR PULSAR I spectrometer (AB Sciex LLC, Framingham, USA), and reported in m/z with relative intensities (%) in parentheses. High performance liquid chromatography (HPLC) separations were performed with an Agilent 1100 System (supplier T.E.A.M. Ltd.-CAG, Sofia, Bulgaria) fitted with a diode array detector and a manual injector with a 20 µL injection loop. Gas chromatography (GC) was performed with a Shimadzu GC-17A (supplier Shimadzu Handelsgesellschaft mbH Korneuburg, branch Sofia, Bulgaria). Elemental analyses were performed by Microanalytical Service Laboratory of the Institute of Organic Chemistry, Bulgarian Academy of Sciences. Crystallographic measurements and data collection of compounds 5a and 11a were performed on an SupernovaDual diffractometer equipped with an Atlas CCD detector using micro-focus Mo Kα radiation (λ, = 0.71073 Å) at 290 K (Oxford Diffraction/ Agilent Technologies UK Ltd, Yarnton, England). The determinations of the unit cell parameters, data collection and reduction were performed with Crysalis-Pro software.³¹ The structures were solved by direct methods ShelxS³² and refined by the full-matrix least-squares method with the ShelxL-2013 programs.³² All non-hydrogen atoms, were located successfully from Fourier maps and were refined anisotropically. Hydrogen atoms on C and N atoms were generated geometrically and their positional parameters were refined with C—H = 0.9600, N—H = 0.9300 Å with Uiso(H) = 1.2Ueq (C or N). Most important crystallographic and refinement indicators are listed in Table S1 (see SI section).

General procedure for the synthesis of aminomethyl-naphthols⁷,¹⁰,²⁰,²²

A mixture of the steroidal naphthol 1 (1 equiv), (S)-(–)-1-phenylethan-1-amine (4) or (S)-(–)-1-(naphthalene-2-yl)ethan-1-amine (7) (1.3 equiv) and 2 -methoxybenzaldehyde (2) or 2-pyridine-carboxaldehyde (3) (1.2 equiv) was heated at 80 °C for a period up to 96 h. The crude mixture was chromatographed twice to isolate the corresponding compounds in pure form.

(13S, 14S)-4-((2-Methoxyphenyl)(((S)-1-phenylethyl) amino)methyl)-13-methyl-12,13,14,15,16,17-hexahydro-11H-cyclopenta[a]phenanthren-3-ol (5)

According to the general procedure a mixture of 1 (0.292 g, 1.157 mmol), (S)-(–)-1-phenylethan-1-amine (4) (0.182 g, 0.19 mL, 1.504 mmol) and 2-methoxybenzaldehyde (2) (0.189 g, 1.388 mmol) was heated for 96 h. After column chromatography (eluent PE:acetone = 20:1) 0.054 g (18%) of the starting compound 1, 0.265 g (47%) of the major diastereoisomer (S,S)-5a and 0.017 g (3%) of the minor diastereoisomer (R,S)-5b were isolated. The total yield of 5 is 50%.

Data of (19S,20S)-5a

mp 146-149 °C (colorless crystals); [α]_D²⁵ = +197.5 (c 1.00, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ 1.09 (s, 3H, H-C(18)), 1.46 (d, 3H, J 6.8 Hz, H-C(27)), 1.49-1.54 (m, 1H, H-C(15)), 1.56-1.69 (m, 5H, H-C(12), H-C(16), H-C(17)), 1.78 (ddd, 1H, J 13.1, 11.1, 5.7 Hz, H-C(12)), 2.12-2.18 (m, 1H, H-C(15)), 2.45 (br s, 1H, NH), 2.68 (t, 1H, J 9.1 Hz, H-C(14)), 3.02 (ddd, 1H, J 16.8, 11.0, 5.7 Hz, H-C(11)), 3.15 (ddd, 1H, J 16.9, 5.3, 4.1 Hz, H-C(11)), 3.69 (s, 3H, H-C(34)), 3.88 (q, 1H, J 6.2 Hz, H-C(20)), 5.87 (s, 1H, H-C(19)), 6.69 (td, 1H, J 7.6, 0.9 Hz, H-C(30)), 6.81 (dd, 1H, J 8.2, 0.7 Hz, H-C(32)), 6.93 (dd, 1H, J 7.7, 1.6 Hz, H-C(29)), 6.99 (d, 1H, J 8.9 Hz, H-C(7)), 7.13-7.16 (m, 1H, H-C(31)), 7.18 (d, 1H, J 8.8 Hz, H-C(6)), 7.21-7.24 (m, 3H, H-C(22), H-C(26), H-C(2)), 7.31-7.34 (m, 1H, H-C(24)), 7.35-7.38 (m, 2H, H-C(23), H-C(25)), 7.97 (d, 1H, J 9.1 Hz, H-C(1)), 13.75 (br s, 1H, OH); ¹³C NMR (150 MHz, CDCl₃) δ 22.6 (q, C(27)), 23.0 (t, C(16)), 23.4 (t, C(11)), 26.0 (q, C(18)), 31.8 (t, C(12)), 35.5 (t, C(15)), 39.3 (s, C(13)), 40.8 (t, C(17)), 50.5 (d, C(14)), 54.6 (d, C(19)), 55.1 (q, C(34)), 57.0 (d, C(20)), 110.4 (d, C(32)), 114.0 (s, (C_ar)), 119.2 (d, C(2)), 119.5 (d, C(6)), 121.2 (d, C(30)), 124.8 (d, C(1)), 127.2 (s, (C_ar)), 127.4 (2d, C(22), C(26)), 127.64 (d, (C_ar)), 128.4 (2d, C(23), C(25)), 128.7 (s, (C_ar)), 129.2 (d, C(31)), 129.3 (d, C(7)), 129.7 (d, C(29)), 130.5 (s, (C_ar)), 131.3 (s, (C_ar)), 134.2 (s, (C_ar)), 143.3 (s, (C_ar)), 156.5 (s, (C_ar)), 157.2 (s, (C_ar)); MS (ESI) m/z, 492 ([M + H]⁺, 5), 371 (100), 275 (7), 265 (47), 169 (5); anal. calcd. for C₃₄H₃₇NO₂: C 83.06, H 7.59, N 2.85, found: C 82.93, H 7.63, N 2.69.

Data of (19R,20S)-5b

¹H NMR (600 MHz, CDCl₃) δ 1.04 (s, 3H, H-C(18)), 1.61 (d, 3H, J 6.6 Hz, H-C(27)), 1.57-1.83 (m, 6H, H-C(12), H-C(15), H-C(16), H-C(17)), 1.80 (ddd, 1H, J 12.9, 11.5, 5.6 Hz, H-C(12)), 2.22-2.28 (m, 1H, H-C(15)), 2.66 (dd, 1H, J 9.2, 8.8 Hz, H-C(14)), 3.01 (ddd, 1H, J 16.9, 11.1, 5.7 Hz, H-C(11)), 3.14 (ddd, 1H, J 17.0, 5.2, 4.0 Hz, H-C(11)), 3.93 (q, 1H, J 6.5 Hz, H-C(20)), 4.02 (s, 3H, H-C(34)), 6.42 (s, 1H, H-C(19)), 6.74 (t, 1H, J 7.3 Hz, H-C(30)), 6.94 (d, 1H, J 7.9 Hz, H-C(32)), 7.02 (dd, 1H, J 7.7, 1.4 Hz, H-C(29)), 7.10 (d, 1H, J 8.8 Hz, H-C(7)), 7.16 (d, 1H, J 9.2 Hz, H-C(2)), 7.19-7.23 (m, 2H, H-C(31), H-C(24)), 7.26-7.30 (m, 4H, H-C(22), H-C(26), H-C(23), H-C(25)), 7.50 (d, 1H, J 8.9 Hz, H-C(6)), 7.93 (d, 1H, J 9.2 Hz, H-C(1)); ¹³C NMR (150 MHz, CDCl₃) δ 20.0 (q, C(27)), 23.0 (t, C(16)), 23.5 (t, C(11)), 25.9 (q, C(18)), 31.8 (t, C(12)), 35.8 (t, C(15)), 39.4 (s, C(13)), 41.0 (t, C(17)), 50.6 (d, C(14)), 54.1 (d, C(19)), 55.4 (d, C(20)), 55.6 (q, C(34)), 110.5 (d, C(32)), 113.8 (s, (C_ar)), 119.4 (d, C(6)), 119.5 (d, C(2)), 121.4 (d, C(30)), 124.8 (d, C(1)), 126.5* (2d, C(23), C(25)), 127.2 (d, C(24)), 127.3 (s, (C_ar)), 128.6 (s, (C_ar)), 128.7* (2d, C(22), C(26)), 129.3 (d, C(7)), 129.4 (d, C(31)), 129.8 (d, C(29)), 130.8 (s, (C_ar)), 131.4 (s, (C_ar)), 134.2 (s, (C_ar)), 144.2 (s, (C_ar)), 156.4 (s, (C_ar)), 157.0 (s, (C_ar)).

(13S,14S)-13-Methyl-4-((((S)-1-phenylethyl)amino) (pyridin-2-yl)methyl)-12,13,14,15,16,17-hexa-hydro-11 H-cyclopenta[a]phenanthren-3-ol (6)

According to the general procedure a mixture of 1 (0.290 g, 1.149 mmol), (S)-(–)-1-phenylethan-1-amine (4) (0.181 g, 0.19 mL, 1.494 mmol) and 2-pyridinecarboxaldehyde (3) (0.148 g, 0.13 mL, 1.379 mmol) was heated for 24 h. After column chromatography (eluent PE:acetone:ammonia = 10:0.5:0.01) 0.322 g (61%) of the major diastereoisomer (R,S)-6a and 0.089 g (17%) of the minor diastereoisomer (S,S)-6b were isolated. The total yield of 6 is 78%.

Data of (19R,20S)-6a

mp 80-84 °C (colorless crystals); [α]_D²⁵ = –20.7 (c 1.00, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ 1.10 (s, 3H, H-C(18)), 1.52 (d, 3H, J 6.8 Hz, H-C(27)), 1.57-1.75 (m, 6H, H-C(15), H-C(12), H-C(16), H-C(17)), 1.83 (ddd, 1H, J 13.0, 11.2, 5.7 Hz, H-C(12)), 2.20-2.25 (m, 1H, H-C(15)), 2.72 (dd, 1H, J 9.1, 9.0 Hz, H-C(14)), 3.04 (ddd, 1H, J 16.9, 11.0, 5.7 Hz, H-C(11)), 3.18 (ddd, 1H, J 17.0, 5.2, 4.1 Hz, H-C(11)), 3.90 (q, 1H, J 6.6 Hz, H-C(20)), 4.24 (br s, 1H, NH), 5.54 (s, 1H, H-C(19)), 6.65 (d, 1H, J 8.0 Hz, H-C(29)), 7.05 (d, 1H, J 8.8 Hz, H-C(7)), 7.08 (dd, 1H, J 7.2, 5.1 Hz, H-C(31)), 7.18 (d, 1H, J 9.1 Hz, H-C(2)), 7.26-7.30 (m, 4H, H-C(6), H-C(22), H-C(26), H-C(24)), 7.33-7.36 (m, 3H, H-C(30), H-C(23), H-C(25)), 7.99 (d, 1H, J 9.2 Hz, H-C(1)), 8.57 (dd, 1H, J 4.8, 0.8 Hz, H-C(32)), 13.28 (br s, 1H, OH); ¹³C NMR (150 MHz, CDCl₃) δ 23.0 (t, C(16)), 23.4 (t, C(11)), 23.9 (q, C(27)), 25.9 (q, C(18)), 31.8 (t, C(12)), 35.6 (t, C(15)), 39.4 (s, C(13)), 40.9 (t, C(17)), 50.5 (d, C(14)), 55.6 (d, C(20)), 58.9 (d, C(19)), 114.3 (s, (C_ar)), 119.3 (d, C(6)), 119.5 (d, C(2)), 122.1 (d, C(29)), 122.4 (d, C(31)), 125.1 (d, C(1)), 127.0 (2d, C(22), C(26)), 127.1 (s, (C_ar)), 127.6 (d, C(24)), 128.9 (2d, C(23), C(25)), 129.7 (d, C(7)), 130.7 (s, (C_ar)), 132.2 (s, (C_ar)), 134.4 (s, (C_ar)), 136.9 (d, C(30)), 143.5 (s, (C_ar)), 148.7 (d, C(32)), 156.7 (s, (C_ar)), 159.6 (s, (C_ar)); MS (ESI) m/z, 463 ([M + H]⁺, 33), 342 (100); anal. calcd. for C₃₂H₃₄N₂O: C 83.08, H 7.41, N 6.06, found: C 83.45, H 7.76, N 6.34.

Data of (19S,20R)-6b

¹H NMR (600 MHz, CDCl₃) δ 1.09 (s, 3H, H-C(18)), 1.61 (d, 3H, J 6.6 Hz, H-C(27)), 1.59-1.77 (m, 6H, H-C(12), H-C(15), H-C(16), H-C(17)), 1.83 (ddd, 1H, J 13.0, 11.2, 5.7 Hz, H-C(12)), 2.26-2.32 (m, 1H, H-C(15)), 2.73 (dd, 1H, J 9.2, 8.8 Hz, H-C(14)), 3.04 (ddd, 1H, J 16.9, 11.8, 5.7 Hz, H-C(11)), 3.16 (ddd, 1H, J 17.0, 5.3, 4.0 Hz, H-C(11)), 3.94 (q, 1H, J 6.6 Hz, H-C(20)), 6.06 (s, 1H, H-C(19)), 6.85 (d, 1H, J 8.0 Hz, H-C(29)), 7.14 (d, 1H, J 9.2 Hz, H-C(2)), 7.14 (m, 1H, H-C(31)), 7.19 (d, 1H, J 8.8 Hz, H-C(7)), 7.19-7.22 (m, 1H, H-C(24)), 7.27-7.30 (m, 2H, H-C(23), H-C(25)), 7.31-7.33 (m, 2H, H-C(22), H-C(26)), 7.44 (td, 1H, J 7.7, 1.8 Hz, H-C(30)), 7.69 (d, 1H, J 8.8 Hz, H-C(6)), 7.95 (d, 1H, J 9.2 Hz, H-C(1)), 8.60-8.61 (m, 1H, H-C(32)); ¹³C NMR (150 MHz, CDCl₃) δ 20.3 (q, C(27)), 23.0 (t, C(16)), 23.5 (t, C(11)), 25.9 (q, C(18)), 31.8 (t, C(12)), 35.8 (t, C(15)), 39.4 (s, C(13)), 40.9 (t, C(17)), 50.6 (d, C(14)), 54.7 (d, C(20)), 59.6 (d, C(19)), 114.1 (s, (C_ar)), 119.1 (d, C(6)), 119.7 (d, C(2)), 122.4 (d, C(29)), 122.6 (d, C(31)), 125.2 (d, C(1)), 126.8 (2d, C(22), C(26)), 127.2 (s, (C_ar)), 127.4 (d, C(24)), 128.7 (2d, C(23), C(25)), 129.7 (d, C(7)), 131.0 (s, (C_ar)), 132.0 (s, (C_ar)), 134.5 (s, (C_ar)), 137.3 (d, C(30)), 144.0 (s, (C_ar)), 148.9 (d, C(32)), 156.3 (s, (C_ar)), 159.8 (s, (C_ar)).

(13S,14S)-4-((2-Methoxyphenyl)(((S)-1-(naphthalen-2-yl)ethyl)amino)methyl)-13-methyl-12,13,14,15,16,17-hexahydro-11H-cyclopenta[a] phenanthren-3-ol (8)

According to the general procedure a mixture of 1 (0.312 g, 1.236 mmol), (S)-(–)-1-(naphthalene-2-yl)ethan-1-amine (7) (0.275 g, 1.607 mmol) and 2-methoxybenzaldehyde (2) (0.202 g, 1.483 mmol) was heated for 96 h. After column chromatography (eluent PE:acetone:ammonia = 20:1:0.05) 0.138 g (44%) of the starting deoxy-isoequilenine (1), 0.174 g (26%) of the major diastereoisomer (S,S)-8a and 0.042 g (6%) of the minor diastereoisomer (R,S)-8b were isolated. The total yield of 8 is 32%.

Data of (19S,20S)-8a

mp 101-104 °C (colorless crystals); [α]_D²⁵ = +159 (c 1.00, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ 1.11 (s, 3H, H-C(18)), 1.47-1.69 (m, 6H, H-C(12), H-C(15), H-C(16), H-C(17)), 1.55 (d, 3H, J 6.9 Hz, H-C(31)), 1.79 (ddd, 1H, J 13.1, 11.2, 5.7 Hz, H-C(12)), 2.11-2.17 (m, 1H, H-C(15)), 2.58 (br s, 1H, NH), 2.69 (t, 1H, J 9.1 Hz, H-C(14)), 3.05 (ddd, 1H, J 16.8, 11.0, 5.7 Hz, H-C(11)), 3.17 (ddd, 1H, J 16.9, 5.3, 4.0 Hz, H-C(11)), 3.55 (s, 3H, H-C(38)), 4.00-4.06 (m, 1H, H-C(20)), 5.91 (s, 1H, H-C(19)), 6.69 (td, 1H, J 7.7, 0.8 Hz, H-C(33)), 6.77 (d, 1H, J 8.2 Hz, H-C(36)), 6.93 (d, 1H, J 8.8 Hz, H-C(7)), 6.95 (dd, 1H, J 7.7, 1.6 Hz, H-C(35)), 7.13 (d, 1H, J 8.9 Hz, H-C(6)), 7.12-7.15 (m, 1H, H-C(34)), 7.26 (d, 1H, J 9.2 Hz, H-C(2)), 7.42 (dd, 1H, J 8.4, 1.7 Hz, H-C(30)), 7.47-7.51 (m, 2H, H-C(25), H-C(26)), 7.57 (s, 1H, H-C(22)), 7.72-7.74 (m, 1H, H-C(24)), 7.87-7.90 (m, 2H, H-C(27), H-C(29)), 8.00 (d, 1H, J 9.2 Hz, H-C(1)), 13.71 (s, 1H, OH); ¹³C NMR (150 MHz, CDCl₃) δ 22.7 (q, C(31)), 23.0 (t, C(16)), 23.4 (t, C(11)), 26.0 (q, C(18)), 31.9 (t, C(12)), 35.5 (t, C(15)), 39.4 (s, C(13)), 40.9 (t, C(17)), 50.5 (d, C(14)), 54.5 (d, C(19)), 55.1 (q, C(38)), 56.9 (d, C(20)), 110.3 (d, C(36)), 114.0 (s, (C_ar)), 119.2 (d, C(2)), 119.6 (d, C(6)), 121.2 (d, C(33)), 124.9 (d, C(1)), 124.9 (d, C(30)), 125.9* (d, C(25)), 126.3* (d, C(26)), 126.7 (d, C(22)), 127.3 (s, (C_ar)), 127.8 (d, C(25)), 128.0 (d, C(24)), 128.2 (d, C(29)), 128.5 (s, (C_ar)), 129.2 (d, C(34)), 129.3 (d, C(7)), 129.8 (d, C(35)), 130.5 (s, (C_ar)), 131.4 (s, (C_ar)), 133.1 (s, (C_ar)), 133.4 (s, (C_ar)), 134.2 (s, (C_ar)), 140.4 (s, (C_ar)), 156.5 (s, (C_ar)), 157.2 (s, (C_ar)); MS (ESI) m/z, 542 ([M + H]⁺, 43), 408 (21), 371 (100), 275 (20), 265 (75); anal. calcd. for C₃₈H₃₉NO₂: C 84.25, H 7.26, N 2.59, found: C 84.43, H 7.05, N 2.41.

Data of (19R,20S)-8b

¹H NMR (600 MHz, CDCl₃) δ 1.03 (s, 3H, H-C(18)), 1.69 (d, 3H, J 6.6 Hz, H-C(27)), 1.54-1.80 (m, 7H, H-C(12), H-C(15), H-C(16), H-C(17)), 2.22-2.29 (m, 1H, H-C(15)), 2.66 (t, 1H, J 9.1 Hz, H-C(14)), 2.98 (ddd, 1H, J 16.9, 11.5, 5.7 Hz, H-C(11)), 3.09 (ddd, 1H, J 16.6, 5.5, 3.8 Hz, H-C(11)), 4.00 (s, 3H, H-C(38)), 4.11 (q, 1H, H-C(20)), 6.44 (s, 1H, H-C(19)), 6.75 (t, 1H, J 7.5 Hz, H-C_ar), 6.95 (d, 1H, J 8.2 Hz, H-C_ar), 7.05 (dd, 1H, J 7.7, 1.4 Hz, H-C_ar), 7.10 (d, 1H, J 8.8 Hz, H-C(7)), 7.12 (d, J = 9.2 Hz, 1H, H-C(2)), 7.21-7.22 (m, 2H, H-C(31), H-C(24)), 7.39-7.42 (m, 2H, H-C_ar), 7.51 (d, 1H, J 9.0 Hz, H-C(6)), 7.66 (s, 1H, H-C(22)), 7.70-7.73 (m, 1H, H-C_ar), 7.74-7.77 (m, 2H, H-C_ar), 7.85-7.90 (m, 1H, H-C_ar), 13.37 (br s, 1H, OH).

(13S,14S)-13-Methyl-4-((((S)-1-(naphthalen-2-yl)ethyl) amino)(pyridin-2-yl)methyl)-12,13,14,15,16,17-hexahydro-11 H-cyclopenta[a]phenanthren-3-ol (9)

According to the general procedure a mixture of 1 (0.168 g, 0.666 mmol), (S)-(–)-1-(naphthalene-2-yl)ethan-1-amine (7) (0.148 g, 0.866 mmol) and 2-pyridinecarboxaldehyde (3) (0.085 g, 0.076 mL, 0.799 mmol) was heated for 48 h. After column chromatography (eluent PE:acetone:ammonia = 20:1:0.01) 0.011 g (7%) of the starting deoxy-isoequilenine (1), 0.236 g (69%) of the major diastereoisomer (R,S)-9a and 0.030 g (9%) of the minor diastereoisomer (S,S)-9b were isolated. The total yield of 9 is 78%.

Data of (19R,20S)-9a

mp 97-101 °C (colorless crystals); [α]_D²⁵ = –18 (c 1.00, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ 1.13 (s, 3H, H-C(18)), 1.55-1.74 (m, 6H, H-C(15), H-C(12), H-C(16), H-C(17)), 1.61 (d, 3H, J 6.8 Hz, H-C(31)), 1.84 (ddd, 1H, J 13.0, 11.2, 5.7 Hz, H-C(12)), 2.20 (ddd, 1H, J 13.0, 8.1, 3.9 Hz, H-C(15)), 2.72 (t, 1H, J 9.1 Hz, H-C(14)), 3.06 (ddd, 1H, J 16.9, 11.1, 5.7 Hz, H-C(11)), 3.19 (ddd, 1H, J 16.9, 5.4, 3.8 Hz, H-C(11)), 4.06 (q, 1H, J 6.8 Hz, H-C(20)), 4.33 (br s, 1H, NH), 5.58 (s, 1H, H-C(19)), 6.64 (d, 1H, J 8.0 Hz, H-C(33)), 6.97 (d, 1H, J 8.8 Hz, H-C(7)), 7.08 (dd, 1H, J 7.2, 0.5 Hz, H-C(35)), 7.20 (d, 1H, J 9.1 Hz, H-C(2)), 7.21 (d, 1H, J 8.8 Hz, H-C(6)), 7.34 (td, 1H, J 7.8, 1.8 Hz, H-C(34)), 7.46-7.49 (m, 2H, H-C(25), H-C(26)), 7.51 (dd, 1H, J 8.5, 1.7 Hz, H-C(30)), 7.62 (s, 1H, H-C(22)), 7.71-7.73 (m, 1H, H-C(24)), 7.83-7.86 (m, 1H, H-C(27)), 7.88 (d, 1H, J 8.5 Hz, H-C(29)), 8.01 (d, 1H, J 9.1 Hz, H-C(1)), 8.57 (ddd, 1H, J 4.9, 1.6, 0.8 Hz, H-C(36)), 13.24 (br s, 1H, OH); ¹³C NMR (150 MHz, CDCl₃) δ 23.0 (t, C(16)), 23.5 (t, C(11)), 23.7 (q, C(31)), 25.9 (q, C(18)), 31.8 (t, C(12)), 35.6 (t, C(15)), 39.4 (s, C(13)), 40.9 (t, C(17)), 50.5 (d, C(14)), 55.6 (d, C(20)), 58.9 (d, C(19)), 114.5 (s, (C_ar)), 119.4 (d, C(6)), 119.6 (d, C(2)), 122.1 (d, C(33)), 122.4 (d, C(35)), 124.4 (d, C(30)), 125.2 (d, C(1)), 125.9* (d, C(26)), 126.3* (d, C(25)), 126.5 (d, C(22)), 127.1 (s, (C_ar)), 127.8 (d, C(27)), 128.1 (d, C(24)), 129.0 (d, C(29)), 129.7 (d, C(7)), 130.7 (s, (C_ar)), 132.3 (s, (C_ar)), 133.1 (s, (C_ar)), 133.5 (s, (C_ar)), 134.5 (s, (C_ar)), 137.0 (d, C(4)), 140.7 (s, (C_ar)), 148.6 (d, C(36)), 156.7 (s, (C_ar)), 159.5 (s, (C_ar)); MS (ESI) m/z, 513 ([M + H]⁺, 48), 342 (100); anal. calcd. for C₃₆H₃₆N₂O: C 84.34, H 7.08, N 5.46, found: C 84.01, H 7.37, N 5.35.

Data of (19S,20S)-9b

mp 110-114 °C (colorless crystals); ¹H NMR (600 MHz, CDCl₃) δ 1.07 (s, 3H, H-C(18)), 1.51-1.83 (m, 7H, H-C(15), H-C(12), H-C(16), H-C(17)), 1.70 (d, 3H, J 6.6 Hz, H-C(27)), 2.30 (ddd, 1H, J 12.4, 8.0, 3.9 Hz, H-C(15)), 2.71 (t, 1H, J 9.1 Hz, H-C(14)), 2.98 (ddd, 1H, J 16.8, 10.9, 5.6 Hz, H-C(11)), 3.04-3.08 (m, 1H, H-C(11)), 4.13 (q, 1H, J 6.6 Hz, H-C(20)), 6.06 (s, 1H, H-C(19)), 6.85 (d, 1H, J 8.0 Hz, H-C(33)), 7.06 (d, 1H, J 9.1 Hz, H-C(2)), 7.14 (dd, 1H, J 7.2, 5.0 Hz, H-C(35)), 7.17 (d, 1H, J 8.7 Hz, H-C(7)), 7.37-7.40 (m, 2H, H-C(24), H-C(25*)), 7.41-7.46 (m, 2H, H-C(30), H-C(34)), 7.66-7.68 (m, 3H, H-C(6), H-C(22), H-C(26*)), 7.72 (d, 1H, J 8.6 Hz, H-C(29)), 7.74 (dd, 1H, J 9.4, 2.3 Hz, H-C_ar), 7.85 (d, 1H, J 9.16 Hz, H-C_ar), 8.61-8.62 (m, 1H, H-C(36)); ¹³C NMR (150 MHz, CDCl3) δ 20.7 (q, C-27), 23.0 (t, C-16), 23.4 (t, C-11), 25.9 (q, C-18), 31.8 (t, C-12), 35.7 (t, C-15), 39.4 (s, C-13), 40.9 (t, C-17), 50.5 (d, C-14), 55.5 (d, C-20), 59.9 (d, C-19), 114.6 (s, (C_ar)), 119.1 (d, (C_ar)), 119.7 (d, C-2), 122.4 (d, C-33), 122.7 (d, C-35), 125.1 (d, C-1), 125.2 (d, (C_ar)), 125.3 (d, (C_ar)), 125.7 (d, (C_ar)), 126.0 (d, (C_ar)), 127.2 (s, (C_ar)), 127.6 (d, (C_ar)), 128.0 (d, (C_ar)), 128.3 (d, (C_ar)), 129.7 (d, C-7), 131.0 (s, (C_ar)), 131.9 (s, (C_ar)), 132.9 (s, (C_ar)), 133.3 (s, (C_ar)), 134.4 (s, (C_ar)), 137.3 (d, (C_ar)), 141.1 (s, (C_ar)), 148.9 (d, C-36), 156.1 (s, (C_ar)), 159.8 (s, (C_ar)).

General procedure for the enantioselective addition of diethylzinc to aldehydes

To a solution of the corresponding ligand 5a, 6a, 8a and 9a (3 mol% based on the aldehyde used in the reaction) in dry toluene (4 mL) Et₂Zn (1.7 equiv of 1 mol L¹ solution in hexane) was added dropwise at 0 °C. The mixture was stirred for 30 min at 0 °C and then the corresponding aldehyde (1 equiv) was added at -20 °C. The reaction was stirred and allowed to warm up to 20 °C, and monitored by TLC (PE/Et2O = 4:1) until the aldehyde was consumed. The mixture was quenched (aq NH₄Cl), extracted with Et2O (3 × 20 mL), and dried. After evaporation of the solvent, the crude product was purified by column chromatography (eluent PE/Et₂O = 20:1). The enantiomeric excess of the obtained secondary alcohols was determined by GC or HPLC with chiral columns. Conditions for determination of enantiomeric excess are described in the SI section.

General procedure for the synthesis of 1,3-dihydro-naphthoxazines

To a solution of the chiral aminomethylnaphthols 5a, 6a, 8a and 9a (0.200 mmol) in THF (4 mL) 37% aq solution of formaldehyde (calculated to provide 2 equiv of formaldehyde) was added. The reaction mixture was stirred at 50 °C for 5 h for the formation of compounds 5a and 6a, and 24 h for the compounds 8a and 9a. After evaporation of the solvent the crude product was chromatographed (eluent PE to PE/acetone = 20:1 for compound 10a; eluent PE to PE/MTBE = 10:1 for compound 11a; eluent PE/MTBE = 15:1 for compounds 12a and 13a).

(1 S,8aS,11aS)-1-(2-Methoxyphenyl)-8a-methyl-2-((S)-1-phenylethyl)-1,2,3,7,8,8a,9,10,11,11a-decahydrocyclopenta[7,8]phenanthro[1,2-e][1,3]oxazine (10a)

According to the general procedure 10a was isolated in 92% yield. mp 103-106 °C (colorless crystals); [α]_D²⁵ = +204 (c 1.00, CHCl3); 1H NMR (600 MHz, CDCl3) δ 1.07 (s, 3H, H-C(18)), 1.52 (d, 3H, J 6.7 Hz, H-C(27)), 1.48-1.70 (m, 6H, H-C(12), H-C(15), H-C(16), H-C(17)), 1.80 (ddd, 1H, J 13.0, 11.3, 5.7 Hz, H-C(12)), 2.10-2.17 (m, 1H, H-C(15)), 2.66 (t, 1H, J 9.1 Hz, H-C(14)), 3.02 (ddd, 1H, J 16.9, 11.2, 5.7 Hz, H-C(11)), 3.14 (ddd, 1H, J 17.0, 5.4, 3.6 Hz, H-C(11)), 3.63 (s, 3H, H-C(34)), 4.10 (q, 1H, J 6.7 Hz, H-C(20)), 4.99 (dd, 1H, J 10.8, 1.7 Hz, H-C(35)), 5.12 (d, 1H, J 10.8 Hz, H-C(35)), 5.68 (s, 1H, H-C(19)), 6.66 (td, 1H, J 7.5, 0.9 Hz, H-C(30)), 6.80 (dd, 1H, J 7.6, 1.6 Hz, H-C(29)), 6.86 (dd, 1H, J 8.2, 0.8 Hz, H-C(32)), 6.90 (d, 1H, J 8.7 Hz, H-C(6)), 6.94 (d, 1H, J 8.7 Hz, H-C(7)), 7.13 (d, 1H, J 9.2 Hz, H-C(2)), 7.17 (td, 1H, J 8.2, 1.7 Hz, H-C(31)), 7.27-7.30 (m, 1H, H-C(24)), 7.31-7.34 (m, 4H, H-C(22), H-C(26), H-C(23), H-C(25)), 7.92 (d, 1H, J 9.2, H-C(1)); ¹³C NMR (150 MHz, CDCl₃) δ 20.7 (q, C-27), 22.9 (t, C-16), 23.3 (t, C-11), 25.8 (q, C-18), 31.7 (t, C-12), 35.5 (t, C-15), 39.3 (s, C-13), 41.0 (t, C-17), 50.6 (d, C-14), 52.5 (d, C-19), 54.9 (q, C-34), 60.2 (d, C-20), 75.2 (t, C-35), 110.3 (d, C-32), 113.7 (s, C_ar), 117.7 (d, C-2), 119.8 (d, C-30), 120.5 (d, C-6), 124.0 (d, C-1), 127.1 (d, C-24), 127.7 (s, C_ar), 128.0* (2d, C-22, C-26), 128.5* (2d, C-23, C-25), 128.6 (d, C-31), 129.5 (d, C-7), 130.5 (s, C_ar), 130.9 (s, C_ar), 131.4 (s, C_ar), 131.5 (d, C-29), 134.8 (s, C_ar), 144.6 (s, C_ar), 152.3 (s, C_ar), 156.9 (s, C_ar); MS (ESI) m/z, 504 ([M + H]⁺, 3), 371 (100), 265 (6).

(1R, 8aS, 11aS)-8a-Methyl-2-((S)-1-phenylethyl)-1-(pyridin-2-yl)-1,2,3,7,8,8a,9,10,11,11a-deca-hydrocyclopenta [7,8]phenanthro[1,2-e][1,3]oxazine (11 a)

According to the general procedure 11a was isolated in 97% yield. mp 150-154 °C (colorless crystals); [α]_D²⁵ = +206 (c 1.00, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ 1.06 (s, 3H, H-C(18)), 1.53 (d, 3H, J 6.6 Hz, H-C(27)), 1.47-1.70 (m, 6H, H-C(12), H-C(15), H-C(16), H-C(17)), 1.77 (ddd, 1H, J 13.1, 11.2, 5.7 Hz, H-C(12)), 2.10-2.15 (m, 1H, H-C(15)), 2.64 (t, 1H, J 9.1 Hz, H-C(14)), 3.01 (ddd, 1H, J 16.9, 11.1, 5.7 Hz, H-C(11)), 3.12 (ddd, 1H, J 17.0, 5.5, 3.8 Hz, H-C(11)), 4.07 (q, 1H, J 6.6 Hz, H-C(20)), 5.11 (dd, 1H, J 10.7, 1.8 Hz, H-C(33)), 5.21 (d, 1H, J 10.7 Hz, H-C(33)), 5.30 (s, 1H, H-C(19)), 6.84 (d, 1H, J 8.7 Hz, H-C(6)), 6.89 (d, 1H, J 8.7 Hz, H-C(7)), 7.03 (d, 1H, J 7.9 Hz, H-C(29)), 7.09 (ddd, 1H, J 7.4, 4.9, 0.9 Hz, H-C(31)), 7.17 (d, 1H, J 9.3 Hz, H-C(2)), 7.29-7.32 (m, 1H, H-C(24)), 7.35-7.37 (m, 2H, H-C(23), H-C(25)), 7.42-7.43 (m, 2H, H-C(22), H-C(26)), 7.56 (td, 1H, J 7.7, 1.8 Hz, H-C(30)), 7.93 (d, 1H, J 9.3 Hz, H-C(1)), 8.50 (dd, 1H, J 4.8, 0.9 Hz, H-C(32)); ¹³C NMR (150 MHz, CDCl₃) δ 21.9 (q, C-27), 22.9 (t, C-16), 23.3 (t, C-11), 25.8 (q, C-18), 31.7 (t, C-12), 35.5 (t, C-15), 39.3 (s, C-13), 40.9 (t, C-17), 50.6 (d, C-14), 59.7 (d, C-20), 59.9 (d, C-19), 74.3 (t, C-33), 112.7 (s, C_ar), 117.9 (d, C-2), 120.5 (d, C-6), 122.1 (d, C-31), 123.9 (d, C-29), 124.3 (d, C-1), 127.5 (d, C-24), 127.8 (s, C_ar), 128.0 (2d, C-22, C-26), 128.6 (2d, C-23, C-25), 129.3 (d, C-7), 130.8 (s, C_ar), 131.1 (s, C_ar), 134.8 (s, C_ar), 136.4 (d, C-30), 145.3 (s, C_ar), 149.5 (d, C-32), 152.1 (s, C_ar), 162.49 (s, C_ar); MS (ESI) m/z, 475 ([M + H]⁺, 18), 342 (100).

(1S,8aS,11aS)-1-(2-Methoxyphenyl)-8a-methyl-2-((S)-1-(naphthalen-2-yl)ethyl)-1,2,3,7,8,8a,9,10,11,11a-decahydrocyclopenta[7,8]-phenanthro[1,2-e][1,3]oxazine (12a)

According to the general procedure 12a was isolated in 80% yield. mp 85-88 °C (colorless crystals); [α]_D²⁵ = +161 (c 1.00, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ 1.09 (s, 3H, H-C(18)), 1.47-1.53 (m, 1H, H-C(15)), 1.58-1.68 (m, 5H, H-C(12), H-C(16), H-C(17)), 1.60 (d, 3H, J 6.7 Hz, H-C(31)), 1.79 (ddd, 1H, J 13.1, 11.3, 5.7 Hz, H-C(12)), 2.12 (ddd, 1H, J 13.0, 8.5, 4.1 Hz, H-C(15)), 2.66 (t, 1H, J 9.1 Hz, H-C(14)), 3.03 (ddd, 1H, J 17.0, 11.2, 5.7 Hz, H-C(11)), 3.15 (ddd, 1H, J 16.9, 5.6, 3.6 Hz, H-C(11)), 3.40 (s, 3H, H-C(38)), 4.26 (q, 1H, J 6.7 Hz, H-C(20)), 5.04 (dd, 1H, J 10.8, 1.7 Hz, H-C(39)), 5.16 (d, 1H, J 10.6 Hz, H-C(39)), 5.75 (s, 1H, H-C(19)), 6.66 (td, 1H, J 7.5, 1.0 Hz, H-C(34)), 6.81 (dd, 1H, J 7.6, 1.7 Hz, H-C(33)), 6.82 (dd, 1H, J 8.3, 1.0 Hz, H-C(36)), 6.86 (d, 1H, J 8.7 Hz, H-C(6)), 6.92 (d, 1H, J 8.7 Hz, H-C(7)), 7.15 (d, 1H, J 9.2 Hz, H-C(2)), 7.16 (dd, 1H, J 8.1, 1.7 Hz, H-C(35)), 7.43-7.47 (m, 2H, H-C(25), H-C(26)), 7.56 (dd, 1H, J 8.5, 1.7 Hz, H-C(30)), 7.71 (s, 1H, H-C(22)), 7.75-7.76* (m, 1H, H-C(24)), 7.82 (d, 1H, J 8.5 Hz, H-C(29)), 7.84-7.86* (m, 1H, H-C(27)), 7.93 (d, 1H, J 9.2 Hz, H-C(1)); ¹³C NMR (150 MHz, CDCl₃) δ 20.8 (q, C-27), 22.9 (t, C-16), 23.3 (t, C-11), 25.8 (q, C-18), 31.7 (t, C-12), 35.5 (t, C-15), 39.4 (s, C-13), 41.0 (t, C-17), 50.6 (d, C-14), 52.6 (d, C-19), 54.8 (q, C-38), 60.4 (d, C-20), 74.2 (t, C-39), 110.2 (d, C-36), 113.7 (d, C_ar), 117.7 (d, C-2), 119.8 (d, C-34), 120.5 (d, C-6), 124.0 (d, C-1), 125.6 (d, C-25), 125.8 (d, C-26), 126.8 (d, C-22), 127.2 (d, C_ar), 127.4 (d, C_ar), 127.6 (d, C-30), 127.7 (d, C-29), 128.1 (d, C-27), 128.7 (d, C-35), 129.5 (d, C-7), 130.5 (d, C_ar), 130.9 (d, C_ar), 131.4 (d, C-33), 131.5 (d, C_ar), 133.0 (d, C_ar), 133.4 (d, C_ar), 134.9 (d, C_ar), 142.3 (d, C_ar), 152.3 (d, C_ar), 156.9 (d, C_ar); MS (ESI) m/z, 554 ([M + H]⁺, 11), 371 (46), 339 (45), 155 (100).

(1R,8aS,11aS)-8a-Methyl-2-((S)-1-(naphthalen-2-yl) ethyl)-1-(pyridin-2-yl)-1,2,3,7,8,8a,9,10,11,11a-decahy-drocyclopenta[7,8]phenanthro[1,2-e][1,3]oxazine (13a)

According to the general procedure 13a was isolated in 97% yield. mp 101-104 °C (colorless crystals); [α]_D²⁵ = +216 (c 1.00, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ 1.05 (s, 3H, H-C(18)), 1.45-1.51 (m, 1H, H-C(15)), 1.55-1.69 (m, 5H, H-C(12), H-C(16), H-C(17)), 1.60 (d, 3H, J 6.6 Hz, H-C(31)), 1.76 (ddd, 1H, J 13.1, 11.3, 5.8 Hz, H-C(12)), 2.07-2.13 (m, 1H, H-C(15)), 2.62 (dd, 1H, J 9.2, 9.1 Hz, H-C(14)), 3.02 (ddd, 1H, J 17.0, 11.1, 5.7 Hz, H-C(11)), 3.13 (dd, 1H, J 17.0, 5.4, 3.9 Hz, H-C(11)), 4.25 (q, 1H, J 6.6 Hz, H-C(20)), 5.17 (dd, 1H, J 10.6, 1.7 Hz, H-C(37)), 5.27 (d, 1H, J 10.6 Hz, H-C(37)), 5.37 (s, 1H, H-C(19)), 6.78 (d, 1H, J 8.7 Hz, H-C(6)), 6.84 (dd, 1H, J 8.8 Hz, H-C(7)), 7.01 (d, 1H, J 7.9 Hz, H-C(33)), 7.09 (ddd, 1H, J 7.4, 4.9, 0.8 Hz, H-C(35)), 7.19 (d, 1H, J 9.3 Hz, H-C(2)), 7.45-7.49 (m, 2H, H-C_ar), 7.53 (dt, 1H, J 7.7, 1.8 Hz, H-C(34)), 7.65 (dd, 1H, J 8.5, 1.6 Hz, H-C(30)), 7.76-7.79 (m, 1H, H-C_ar), 7.84 (s, 1H, H-C(22)), 7.86-7.89 (m, 1H, H-C_ar), 7.89 (d, 1H, J 8.5 Hz, H-C(29)), 7.94 (d, 1H, J 9.3 Hz, H-C(1)), 8.50 (dd, 1H, J 4.8, 0.9 Hz, H-C(36)); ¹³C NMR (150 MHz, CDCl₃) δ 22.0 (q, C-27), 22.9 (t, C-11), 23.3 (t, C-16), 25.8 (q, C-18), 31.7 (t, C-12), 35.5 (t, C-15), 39.3 (s, C-13), 40.9 (t, C-17), 50.5 (d, C-14), 59.9 (d, C-20), 60.0 (d, C-19), 74.3 (t, C-37), 112.7 (s, C_ar), 118.0 (d, C-2), 120.6 (d, C-6), 122.1 (d, C-35), 123.9 (d, C-33), 124.4 (d, C-1), 125.8 (d, C_ar), 126.1 (d, C_ar), 126.2 (d, C-30), 126.7 (d, C-22), 127.7 (s, C_ar), 127.9 (d, C_ar), 128.1 (d, C_ar), 128.4 (d, C-29), 129.3 (d, C-7), 130.7 (s, C_ar), 131.1 (s, C_ar), 133.2 (s, C_ar), 133.6 (s, C_ar), 134.9 (s, C_ar), 136.4 (d, C-34), 142.8 (d, C_ar), 149.5 (s, C-36), 152.2 (s, C_ar), 162.4 (s, C_ar); MS (ESI) m/z, 525 ([M + H]⁺, 3), 353 (5), 344 (25), 183 (20), 155 (100), 145 (21), 60 (60).

Acknowledgments

This work was supported by Operational Program “Science and Education for Smart Growth” 2014-2020, co-financed by European Union through the European Structural and Investment Funds, Grant BG05M2OP001-1.002-0012.

The application of the equipment of INFRAMAT-project, part of the Bulgarian National Roadmap for Research Infrastructures, supported by Bulgarian Ministry of Education and Science is greatly acknowledged.

Supplementary Information

Crystallographic data (excluding structure factors) for the structures in this work were deposited in the Cambridge Crystallographic Data Centre as supplementary publication number CCDC-2095267 (5a), and 2095266 (11a). Copies of the data can be obtained, free of charge, via https://www.ccdc.cam.ac.uk/structures/.

Supplementary data (NMR spectra of the synthesized compounds, crystal structures data and conditions for the determination of enantiomeric excess (GC or HPLC)) are available free of charge at http://jbcs.sbq.org.br as PDF file.

References

• ¹
  Betti, M.; Gazz. Chim. Ital. 1900, 30 II, 310.
• ²
  Rodrigues, M. O.; Eberlin, M. N.; Neto, B. A. D.; Chem. Rec. 2021, 21, 2762. [Crossref]
• ³
  Graebin, C. S.; Ribeiro, F. V.; Rogério, K. R.; Kummerle, A. E.; Curr. Org. Synth. 2019, 16, 855. [Crossref]
• ⁴
  Insuasty, D.; Castillo, J.; Becerra, D.; Rojas, H.; Abonia, R.; Molecules 2020, 25, 505. [Crossref]
• ⁵
  Cardellicchio, C.; Ciccarella, G.; Naso, F.; Schingaro, E.; Scordari, F.; Tetrahedron: Asymmetry 1998, 9, 3667. [Crossref]
• ⁶
  Cardellicchio, C.; Ciccarella, G.; Naso, F.; Perna, F.; Tortorella, P.; Tetrahedron 1999, 55, 14685. [Crossref]
• ⁷
  Palmieri, G.; Tetrahedron: Asymmetry 2000, 11, 3361. [Crossref]
• ⁸
  Cimarelli, C.; Palmieri, G.; Volpini, E.; Tetrahedron: Asymmetry 2002, 13, 2417. [Crossref]
• ⁹
  Szatmári, I.; Sillanpää, R.; Fülöp, F.; Tetrahedron: Asymmetry 2008, 19, 612. [Crossref]
• ¹⁰
  Marinova, M.; Kostova, K.; Tzvetkova, P.; Tavlinova-Kirilova, M.; Chimov, A.; Nikolova, R.; Shivachev, B.; Dimitrov, V.; Tetrahedron: Asymmetry 2013, 24, 1453. [Crossref]
• ¹¹
  Speich, E.; Banfi, L.; Moni, L.; Riva, R.; Rocca, V.; Basso, A.; Chem. Heterocycl. Compd. 2018, 54, 329. [Crossref]
• ¹²
  Szatmári, I.; Fülöp, F.; Curr. Org. Synth. 2004, 1, 155. [Crossref]
• ¹³
  Cimarelli, C.; Palmieri, G.; Chirality 2009, 21, 218. [Crossref]
• ¹⁴
  Cardellicchio, C.; Capozzi, M. A. M.; Naso, F.; Tetrahedron: Asymmetry 2010, 21, 507. [Crossref]
• ¹⁵
  Szatmári, I.; Fülöp, F.; Tetrahedron 2013, 69, 1255. [Crossref]
• ¹⁶
  Olyaei, A.; Sadeghpour, M.; RSC Adv. 2019, 9, 18467. [Crossref ]
• ¹⁷
  Iftikhar, R.; Kamran, M.; Iftikhar, A.; Parveen, S.; Naeem, N.; Jamil, N.; Mol. Diversity 2022 [Crossref]
• ¹⁸
  Liu, D.-X.; Zhang, L.-C.; Wang, Q.; Da, C.-S.; Xin, Z.-Q.; Wang, R.; Choi, M. C. K.; Chan, A. S. C.; Org. Lett. 2001, 3, 2733. [Crossref]
• ¹⁹
  Ji, J.-X.; Qiu, L.-Q.; Yip, C. W.; Chan, A. S. C.; J. Org. Chem. 2003, 68, 1589. [Crossref]
• ²⁰
  Zagranyarska, I.; Kostova, K.; Zagranyarski, Y.; Nikolova, R.; Shivachev, B.; Dimitrov, V.; Mol. Diversity 2020, 24, 1343. [Crossref]
• ²¹
  Cardellicchio, C.; Capozzi, M. A. M.; Alvarez-Larena, A.; Piniella, J. F.; Capitelli, F.; CrystEngComm 2012, 14, 3972. [Crossref]
• ²²
  Dikova, K.; Kostova, K.; Simova, S.; Linden, A.; Chimov, A.; Dimitrov, V.; Polyhedron 2019, 165, 177. [Crossref]
• ²³
  Gyémánt, N.; Engi, H.; Schelz, Z.; Szatmári, I.; Tóth, D.; Fülöp, F.; Molnár, J.; de Witte, P. A. M.; Br. J. Cancer 2010, 103, 178. [Crossref]
• ²⁴
  Yadav, Y.; MacLean, E. D.; Bhattacharyya, A.; Parmar, V. S.; Balzarini, J.; Barden, C. J.; Too, C. K. L.; Jha, A.; Eur. J. Med. Chem. 2011, 46, 3858. [Crossref]
• ²⁵
  Capozzi, M. A. M.; Cardellicchio, C.; Tetrahedron: Asymmetry 2017, 28, 1792. [Crossref]
• ²⁶
  Capozzi, M. A. M.; Cardellicchio, C.; Magaletti, A.; Bevilacqua, A.; Perricone, M.; Corbo, M. R.; Molecules 2014, 19, 5219. [Crossref]
• ²⁷
  Ankit, L.; Bijoy, P. M.; Mahendra, N.; Curr. Org. Chem. 2021, 25, 133. [Crossref]
• ²⁸
  Spartan’08, version 1.2.0; Wavefunction, Inc., USA, 2008. [Link] accessed in September 2022
• ²⁹
  Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R.; J. Am. Chem. Soc. 1986, 108, 6071. [Crossref]
• ³⁰
  Noyori, R.; Kitamura, M.; Angew. Chem., Int. Ed. Engl. 1991, 30, 49. [Crossref]
• ³¹
  CrysAlis PRO, Agilent Technologies, UK Ltd, Yarnton, England, 2011.
• ³²
  Sheldrick, G. M.; Acta Crystallogr., Sect. A: Found. Adv. 2008, 64, 112. [Crossref]

Edited by

Editor handled this article: Brenno A. D. Neto (Associate)

Publication Dates

• Publication in this collection
  31 Mar 2023
• Date of issue
  2023

History

• Received
  17 Aug 2022
• Accepted
  28 Sept 2022