Synthesis of Organotin Substituted Tricyclic Macrodiolides

Abstract

The radical addition of triorganotin hydrides, R₃SnH (R =n-butyl, phenyl, neophyltin), to four unsaturated diesters of (11R,12R)-9,10-dihydro-9,10-ethaneanthracene-11,12-dimethanol leads to products of cyclohydrostannation with an average yield of around 80%. Whereas the addition of these hydrides to diacrylate and dimethacrylate leads to the expected mixtures containing two and four distereoisomeric cyclized products respectively, the addition to di-2-methyl- and di-2-phenylcinnamate yields only four out of the sixteen possible stereoisomers. The observed high stereoselectivity is consistent with a radical tandem cyclohydrostannation mechanism. Full proton (¹H), carbon 13 (¹³C) and tin 119 (¹¹⁹Sn) nuclear magnetic resonance (NMR) data are given.

Keywords:
organotin substituted macrodiolides; cyclohydrostannation; stereoselective tandem cyclization

Introduction

Macrocyclic structures are commonly found in natural products and pharmaceutical molecules and provide privileged scaffolds for medicinal chemistry programs in modern drug discovery.¹ They have had an enormous impact on the fields of chemistry, biology and medicine.^1-5 Macrocyclic natural products continue to serve as invaluable starting points and to drive and inspire organic and medicinal chemists to discover new and better drugs.^1,6,7 Different from synthetic small molecule drugs, characteristics macrocyclic natural products typically include 10 or more membered ring architecture. This unique structural feature and conformational flexibility of the macrocyclic ring can offer subsequent functional advantages, e.g., it has the potential of being highly potent, as well as selective when key functional groups interact with biological targets.¹ In addition, from a chemistry point of view, macrocyclic compounds can offer diverse functionality and stereochemical complexity in a conformationally restricted fashion. Moreover, they may have favorable druglike properties, including good solubility, increased lipophilicity, enhanced membrane penetration, improved metabolic stability and good oral bioavailability with desirable pharmacokinetic and pharmacodynamic properties.^1,4 Their biological and medicinal activities have made the macrolides very important target molecules of synthetic studies.⁸ A number of synthetic strategies and methodologies have been developed for macrolide synthesis.⁹ Commonly, these syntheses involve many steps and the global yields are very low.¹⁰ On the other hand, organotin(IV) compounds have various biocidal activities and show a toxicity, which is dependent on both the number and nature of the organic groups attached to the tin atom. They have found applications as fungicides, acaricides, antifoulings, disinfectants, wood preservatives and others.¹¹ The compounds include both alkyl and aryl organotin derivatives. In addition, some of them, like triphenyltin carbohydrates, have antitumor activity.¹² However, we have not found reports of the biological activity of stannilated macrodiolides.

We have recently reported a method for the synthesis of new 11 membered macrodiolides.¹³ The starting materials for building these cycles are open-chain systems with two carbon-carbon double bonds conjugated with electron withdrawing substituents, like ester group, i.e., activated for radical reactions, as shown in Figure 1.

Figure 1
Carbon-carbon double bonds conjugated with electron withdrawing ester group.

Another feature of the systems employed is that they are chiral and therefore can exert asymmetric induction on the products of subsequent reactions. As starting material, we used α,α,α',α'-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL) unsaturated diesters compounds with C₂ symmetry.¹⁴ We found that the addition of triorganotin hydrides (R₃SnH) to the unsaturated diesters leads to stannylated macrocycles with high stereoselectivity through a cyclohydrostannation tandem mechanism.¹³

In order to determine the effect of the structural features of unsaturated diesters on cyclohydrostannation reactions, we considered it of interest to carry out a study on the addition of organotin hydrides to some unsaturated diesters of (11R,12R)-9,10-dihydro-9,10-ethaneanthracene-11,12-dimethanol with C₂ symmetry,¹⁵ and to compare the results obtained with those of other C₂ symmetry unsaturated diesters with different structural arrangements.

Results and Discussion

The addition, under free radical conditions, i.e., argon atmosphere, 75 ºC and azobisisobutyronitrile (AIBN) as radical initiator, of tri-n-butyl- (5), triphenyl- (6), and trineophyltin (7) hydrides, to [(9R,10R,11S,12S)-9,10-dihydro-9,10-ethanoanthracene-11,12-diyl)bis(methylene)] diacrylate (1) in toluene leads, in all cases, to products of cyclohydrostannation (type I compounds, Scheme 1). These results were obtained using ratios organotin hydride/diester1 = 2.1 (tin hydride concentration = 0.12 mol L^-1) as well as 1.3 (tin hydride concentration = 0.074 mol L^-1, Scheme 1). It is to note that in these cases neither products of double addition (II, Scheme 1) nor products of polymerization were obtained.

Scheme 1
Triorganotin hydrides additions to unsaturated diesters 1-4. Me,n-Bu, Ph and Neoph represents methyl,n-butyl, phenyl and neophyl, respectively.

Because with substrate 1 the cyclohydrostannation leads to the creation of only one new stereogenic center, a maximum of two diastereomers are expected in each case. The tin 119 nuclear magnetic resonance (¹¹⁹Sn NMR) spectroscopic analysis of the crude products obtained in the additions of triorganotin hydrides 5, 6, and 7 to diester1 showed, in each case, the anticipated two signals corresponding to the ¹¹⁹Sn atom present in each diastereomer. It also showed that the stereoisomers were formed in different proportions, clearly indicating some degree of diastereoselection (Table 1). It is to add that the proportion among the diastereomers in the mixtures (8a-8b,9a-9b and 10a-10b) was almost the same in the three cases studied, as shown in Table 1.

Table 1
Addition of triorganotin hydrides to unsaturated diesters1-4 ( Scheme 1)

entry No.	Mixture No.	Radical	Diester No.	time / h	Yield a/ %	Diastereomer No.	119Sn b/ (δ, ppm)	D c / %
1	8	n -Bu	1	24	87	8a	-12.0	33
						8b	-12.7	67
2	9	Ph	1	48	80	9a	-104	36
						9b	-105	64
3	10	Neoph	1	72	76	10a	-42	36
						10b	-43	64
4	11	n -Bu	2	24	86	11a	-16.8	23
						11b	-18.7	48
						11c	-19.2	15
						11d	-20.1	14
5	12	Ph	2	48	72	12a	-104.4	37
						12b	-104.6	32
						12c	-112.9	12
						12d	-113.1	19
6	13	Neoph	2	72	74	13a	-42.7	9
						13b	-44.8	62
						13c	-48.7	20
						13d	-49.5	9
7	14	n -Bu	3	48	82	14a	-8.0	43
						14b	-8.4	36
						14c	-10.3	11
						14d	-10.5	10
8	15	Ph	3	48	75	15a	-114.3	8
						15b	-115.8	43
						15c	-116.1	42
						15d	-116.9	7
9	16	n -Bu	4	48	80	16a	-5.0	61
						16b	-5.4	23
						16c	-8.6	6
						16d	-9.2	10
10	17	Ph	4	72	72	17a	-110.7	9
						17b	-111.6	54
						17c	-113.1	8
						17d	-113.6	29

• ^a
  After column chromatography;
• ^b
  ¹¹⁹Sn NMR in CDCl₃, in ppm with respect to Me₄Sn;
• ^c
  percentage of diastereoisomer in the mixture (from ¹¹⁹Sn NMR spectra); n -Bu: n -butyl; Ph: phenyl; Neoph: neophyl.

The hydrostannation of dimethacrylate 2 with triorganotin hydrides5-7 (Table 1, entries 4-6) creates two new stereocenters and leads to the four diastereomers expected. In all the cases studied, one of the four diastereomers was formed in higher proportion than the other ones.

Thus, the addition of tri-n-butyltin hydride 5 to diester 2 leads to a mixture of four products that contains diastereomer 11b (Table 1) in 48%. Similarly, in the mixture of products resulting from the addition of triphenyltin hydride 6 to ester 2 predominates the stereoisomer 12a (37%). The hydrostannation of 2 with trineophyltin hydride 7 to compound 2 leads to a mixture containing diastereomer 13b in 62%. The latter suggests that both the slow speed of the attack and the bulk of the neophyl substituent combine to achieve a higher selectivity in the cyclohydrostannation.

On the other hand, in the case of the disubstituted acrylates 3 and4 where four new stereogenic centers are created and therefore 16 diastereomers should be expected, only four diastereomers are formed instead. This indicates that the addition to these substrates take place with very high diastereoselectivity (Table 1, entries 7-10). As shown in Table 1, the yields of these reactions were in a range of 72-87%. Reaction's times for the hydrostannations withn-Bu₃SnH 5 were 24 h for the less substituted esters 1 and 2, and 48 h for the more crowded diesters 3 and 4. Whereas the addition of Ph₃SnH 6 to diesters 1-3 took 48 h and 72 h to ester 4, the hydrostannations with trineophyltin hydride7 needed 72 h with diesters 1 and 2, and no reaction was observed with diesters 3 and 4 after 96 h. These results would indicate that it is the steric volume rather than the reactivity of the organotin hydrides the factor that rules the cyclohydrostannations. It should be noted that we were unable to separate by column chromatography (silica-gel 60, 70-230 mesh) the mixtures of diastereomers generated in these reactions.

The main proton (¹H) and carbon 13 (¹³C) NMR characteristics of the mixtures 8-17 are summarized in Tables 2- 4. The¹³C NMR chemical shifts were assigned through the analysis of the multiplicity of the signals by means of polarization transfer (DEPT) experiments and taking into account the magnitude of ⁿJ(¹³C,¹¹⁹Sn) coupling constants.¹⁶The use of some key signals in the ¹³C NMR spectra enabled us to establish a quick structural assignment of the stannylated macrocycles. Thus, the formation of the cycles gives rise to the existence of two carbonyl signals, only one of them showing ³J(¹¹⁹Sn,¹³C) coupling constants. Other key signals are those corresponding to the carbons resulting from the ring closure (C-15 in Tables 2 and 3). These signals show second order ²J(¹¹⁹Sn,¹³C) coupling constants, and the DEPT experiments indicate that these carbons are either tertiary, when the starting diester is 1; or quaternary, when the starting diesters are 2-4.

Table 2
Selected ¹³C NMR values for the mixtures of cyclohydrostannation products of diesters 1 and2^a

Table 3
Selected ¹³C NMR values for the mixtures of cyclohydrostannation products of diesters 3 and4^a

Table 4
¹H NMR characteristics of the mixtures of diastereomers obtained from diesters 1-4

Mixture No.	Chemical shift / (δ, ppm) a
8ab	0.64-0.90 (m, 30H), 1.62-1.71 (m, 1H), 1.82-2.00 (m, 1H), 2.04-2.28 (m, 2H), 2.97 (c, 2H), 4.06 (s, 2H), 4.23-4.41 (m, 4H), 6.93-7.27 (m, 8H)
9ab	1.12-1.62 (m, 2H), 2.16-2.38 (m, 2H), 2.47-2.74 (m, 2H), 1.77-3.00 (m, 2H), 3.56-3.64 (m, 1H), 3.86-3.98 (m, 4H), 4.22-4.28 (m, 2H), 6.89-7.51 (m, 23H)
10abd	0.57-0.71 (m, 1H), 1.01 (m, 2H), 1.22-1.29 (m, 1H), 1.47 (s, 9H), 1.67 (s, 9H), 1.84-2.42 (m, 3H), 2.95-3.49 (m, 8H), 4.14 (s, 2H), 4.19- 4.26 (m, 2H), 4.35-4.49 (m, 2H), 7.04-7.31 (m, 23H)
11a-d	0.49-0.88 (m, 17H), 0.95-1.56 (m, 18H), 2.07-2.24 (m, 2H), 2.26-2.66 (m, 1H), 2.69-3.44 (m, 2H), 4.04-4.07 (m, 2H), 4.16-4.48 (m, 4H), 6.96-7.22 (m, 8H)
12a-d	1.16-1.19 (m, 1H), 1.47 (m, 2H), 1.61 (s, 3H), 1.76-2.27 (m, 2H), 2.68-2.90 (m, 3H), 3.03-3.65 (m, 2H), 3.81-4.23 (m, 4H), 4.48-4.53 (m, 2H), 6.94-7.48 (m, 23H)
13a-d	0.68-1.05 (m, 6H), 1.08 (s, 18H), 1.12 (s, 3H), 1.16 (s, 3H), 1.29-1.38 (m, 2H), 1.82-2.33 (m, 2H), 2.63-3.15 (m, 3H), 4.01 (d, 2H), 4.08- 4.39 (m, 4H), 6.77-7.47 (m, 23H)
14a-d	0.93-1.42 (m, 33H), 2.02 (m, 1H), 2.65-2.91 (m, 2H), 3.07-3.19 (m, 2H), 3.98-4.15 (m, 4H), 4.18-4.25 (m, 2H), 6.78-7.62 (m, 18H)
15a-d	1.98-2.07 (m, 3H), 2.09-2.27 (m, 6H), 3.35-3.53 (s, 1H), 3.74-3.86 (m, 1H), 4.04-4.09 (m, 4H), 4.33-4.46 (m, 2H), 6.96-7.74 (m, 33H)
16a-d	0.62-0.77 (m, 15H), 1.11-1.32 (m, 8H), 1.45-1.61 (m, 2H), 2.10-2.21 (m, 2H), 3.21-3.45 (m, 2H), 3.68 (s, 1H), 3.74-3.96 (m, 2H), 4.12- 4.15 (m, 2H), 4.21-4.41 (m, 4H), 6.52-7.83 (m, 28H)
17a-d	2.11-2.25 (m, 2H), 3.48 (s, 1H), 3.60 (t, 1H), 3.77-3.96 (m, 4H), 4.28-4.48 (m, 2H), 6.57 (s, 1H), 6.67-7.89 (m, 43H)

• ^a
  In CDCl₃; chemical shifts, δ, in ppm with respect to tetramethylsilane.

These cyclohydrostannations have been explained assuming that the triorganotin radical will add to the backbone of one of the unsaturated groups leading to the alkyl radical A (Scheme 2), which in turn adds to the less substituted carbon of the other olefinic group, leading to the product of endocyclization, i.e, the radical B. The final step is hydrogen transfer from the organotin hydride to the cyclic radical to give the product of cyclohydrostannation C (Scheme 2).¹³

Scheme 2
Mechanism of the cyclohydrostannations.

It is known that when this tandem radical cyclization process takes place with very high regio- and diastereoselectivity, the endocyclization mode is favored.¹⁷ Both polar and steric effects may affect radical cyclization. Since carbon radicals are nucleophilic, the presence of electron-withdrawing substituents activates alkenes toward addition by such radicals. Steric effects are also critical in determining the ease of carbon radical addition to alkenes, so that substitution at the olefin site of radical attack reduces the rate of addition.¹⁸

In the case of esters 1 and 2, the two factors that dominate the rate of addition to the olefins, i.e., electronic and steric, are both favorable: the alkene substituent (ester group) is electron withdrawing and the β carbon of acrylate and methacrylate esters are unsubstituted and therefore there is no steric hindrance for the addition. The addition of tri-n-butyl- and triphenyltin hydrides to esters 3and 4 follows a similar pattern, even though the α and β carbons of both esters are substituted. On the other hand, the fact that the trineophyltin hydride does not add to unsaturated diesters 3 and4 is not surprising, because we have found that, due to steric factors, this hydride also do not add to β-substituted methyl propenoates.¹⁹ This could be attributed to the steric blocking effect exerted by this substituent to the approach of the bulky trineophylestannyl radical. Also, the presence of two bulky substituents (diester 4, R¹ = R² = Ph) leads to an increase in the stereoselectivity of the cycloaddition (Table 1, entries 9 and 10).

The additions of the triorganotin hydrides used, R₃SnH (R = tri-n-butyltin, triphenyl, trineophyltin), to diacrylate1 leads to the two expected diastereomers, one of them in higher proportion, an average diastereomeric excess of around 30%. The additions of the same hydrides to dimetacrylate 2 yield the normal mixture of four diastereomers, again with one of them in higher proportion than the other three. In the case of the hydrostannation with trineophyltin hydride, one of the four diastereomers is formed in a 62% proportion, due, probably, to the steric volume of the neophyl groups. The additions of Bu₃SnH and Ph₃SnH to the more substituted dimethyl- 3 and diphenylcinnamtes 4showed a higher diastereoselectivity than those to esters 1 and2: only four of the sixteen possible diastereomers were formed. Here, again, one of the four diastereomers was formed in higher proportion than the other three: an average of 43% in the case of the additions to diester3 and of 57% in the additions to diester 4.

The cyclohydrostannation of unsaturated diesters derived from TADDOL could be explained taking into account the high Thorpe-Ingold effect exerted by the four phenyl groups attached at C-6 and C-7 (type III compounds, R = Ph; Figure 2). This is supported by recent studies of our group on the addition of organotin hydrides to unsaturated diesters derived from (4S,5S)-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol (type III compounds, R = H; Figure 2) that lack of substituents at carbons C-6 and C-7. These hydrostannations lead to mixtures of products of diaddition and cyclohydrostannation in proportions that depend on the organotin hydride used. Thus, using triphenyltin hydride 6, the yield of diaddition product was 100%.

Figure 2
Unsaturated diesters of (4S,5S)-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol (III) and diesters 1 and 2 (type IV compounds).

If we compare, in Figure 2, the unsaturated diesters 1 and 2 (type IV compounds) with type III diesters, that possess R = H, it can be seen that diesters IV also lack substituents at the carbons equivalent to C-6 and C-7 of diesters III, i.e., the carbons attached to the ester oxygen atom (C-13). This would indicate that the effect exerted by the ligand (9S,10S)-9,10-dihydro-9,10-ethanoanthracene is higher than that of the dioxolane ring of type III compounds. Moreover, the Thorpe-Ingold's effect of the ligand (9S,10S)-9,10-dihydro-9,10-ethanoanthracene is similar to that exerted by the dioxolane plus four phenyl groups attached to C-6 and C-7 (TADDOL's derivatives) together.

Another point is that whereas the radical additions of triorganotin hydrides R₃SnH (R = tri-n-butyltin and triphenyl) to diesters3 and 4 lead to mixtures of the corresponding four diastereoisomeric medium-sized cycles, in the case of TADDOL's cinnamates only the triphenyltin hydride adds.¹³ The presence of four bulky phenyl groups at C₆ and C₇ in TADDOL derivatives (type III compounds, R = Ph; Figure 2) determines higher diastereoselectivities in the additions, facilitates intramolecular cyclization (Thorpe-Ingold effect) and increases the selectivity of the substrate so that the α,β-disubstituted unsaturated diesters react only with the more reactive hydride (Ph₃SnH).

Conclusions

In conclusion, the addition of triorganotin hydrides, R₃SnH (R = tri-n-butyltin, triphenyl, trineophyltin) to unsaturated diesters of (11R,12R)-9,10-dihydro-9,10-ethaneanthracene-11,12-dimethanol leads to products of cyclohydrostannation in the four unsaturated systems studied. If we compare the hydrostannation of the unsaturated diesters1-4 with that of the unsaturated diesteres of TADDOL that also possess C₂ symmetry, it could be said that both reactions follow the same pattern. However, one important difference is that whereas TADDOL's di(α-methyl) and di(α-phenyl) cinnamates do not react with tri-n-butyltin hydride 5,¹³ the unsaturated diesters 3 and 4do react, leading to the corresponding mixtures of tri-n-butyltin substituted macrocycles 14a-d and 16a-d in good yields. On the other hand, recent studies on the addition of organotin hydrides to unsaturated diesters derived from (4S,5S)-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol (type III compounds, R = H; Figure 2) indicate that in these systems predominate the products of diaddition rather than those of cyclohydrostannation. Considering our present and previous results, it would be possible that the effect of the ligand (9S,10S)-9,10-dihydro-9,10-ethanoanthracene should be similar to that exerted by the Thorpe-Ingold's effect of the four phenyl groups attached to C-6 and C-7 plus the dioxolane group in TADDOL's derivatives, together.

The results of these studies may bestow insight into the factors governing this type of intramolecular radical cyclization reactions. Although it was not possible to separate the mixtures obtained, these were achieved with high diastereoselectivity. The cyclohydrostannylation of unsaturated diesters of (11R, 12R)-9,10-dihydro-9,10-ethaneanthracene-11,12-dimethanol is a simple, fast and highly diastereoselective method to obtain new macrodiolides with potential biological applications.

Experimental

Materials and methods

¹H, ¹³C and ¹¹⁹Sn NMR spectra were obtained in a Bruker ARX 300 instrument at 300 K, in 5 mm diameter tubes, using 10% (m/v) solutions of the compounds and were recorded in CDCl₃ (300 MHz for¹H, 100 MHz for ¹³C and 111.8 MHz for¹¹⁹Sn). Chemical shifts (δ) was given in parts per million (ppm) downfield relative to tetramethylsilane (TMS), for ¹H and ¹³C; and relative to Me₄Sn, for ¹¹⁹Sn. Coupling constants (ⁿJ) were in Hz. Infrared (IR) spectra were recorded with a Nicolet Nexus FT 470/670/870 spectrophotometer. Irradiations were conducted in a reactor equipped with four 250 W lamps with peak emition at 350 nm. All the solvents and reagents used were analytical reagent grade. Triorganotin hydrides were prepared by reduction of the corresponding chlorides with lithium aluminum hydride following common procedures and the starting (11R,12R)-9,10-dihydro-9,10-ethaneanthracene-11,12-dimethanol unsaturated diesters were prepared as recently described.¹⁰ The reactions were performed under argon atmosphere.

Addition of triorganotin hydrides to [(9R,10R,11S,12S)-9,10-dihydro-9,10-ethanoanthracene-11,12-diyl)bis(methylene)] diesters

The same procedure was used in all the reactions between unsaturated esters and triorganotin hydrides. One experiment is described in detail to illustrate the methods used.

Addition of tri-n-butyltin hydride (5) to [(9R,10R,11S,12S)-9,10-dihydro-9,10-ethanoanthra-cene-11,12-diyl)bis(methylene)] diacrylate (1). Synthesis of (4R and 4S,9aR,10R,15S,15aS)-4-[(tributylstannyl)methyl]-5,6,9a,10,15,15a-hexahydro-1H-10,15-[1,2]benzenonaphtho[2,3-c][1,6]dioxacycloundecine-3,7(4H,9H)-diones (8ab)

Diester 1 (0.30 g, 0.80 mmol) in dry toluene (10 mL) was treated with tri-n-butyltin hydride (0.30 g, 1.04 mmol), using AIBN as radical initiator (0.049 g, 0.3 mmol), in argon atmosphere at 75 ºC, during 24 h. Optimal time of reaction and adequate excess of organotin hydride were determined in previous runs by both monitoring the reaction by taking samples at intervals and observing the disappearance of the n_Sn-H absorption in the IR spectrum, and also by checking that the ¹H NMR spectrum of the reaction mixture did not show the presence of unreacted olefin. The¹¹⁹Sn NMR spectrum of the crude product showed that, under these reaction conditions, two compounds were formed: one in 33% (compound8a) and the other in 67% yield (8b). The solvent was eliminated under reduced pressure and the crude product thus obtained was directly purified by column chromatography using silica-gel 60. The mixture of adducts 8ab (0.46 g, 0.69 mmol, 87%) was eluted with hexane:diethyl ether (80:20, v/v) as a dense oil. IR (film) ν_max / cm^-1 3071, 3040, 2966, 2920, 2867, 2848, 1731, 1467, 1455, 1372, 1255, 1070, 780, 761, 696.

Supplementary Information

Supplementary information (spectral data for IR, ¹H, ¹³C and¹¹⁹Sn NMR of the obtained compounds) is available free of charge athttp://jbcs.sbq.org.br as PDF file.

https://minio.scielo.br/documentstore/1678-4790/8PcywdXwjTs7qn99frpQ8WG/63997a28a78583714edc292840dab45e5c464d20.pdf

Acknowledgements

This work was supported by grants from ANPCyT (Capital Federal, Argentina / BID, PICT project No. 2644), CONICET (Buenos Aires, Argentina, PIP project No. 112-201101-00828), and Universidad Nacional del Sur (Bahía Blanca, Argentina, PGI 24/Q041). Fellowships from CONICET to F. C. Z. and R. A. O. are acknowledged.

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Publication Dates

• Publication in this collection
  Mar 2016

History

• Received
  06 July 2015
• Accepted
  22 Oct 2015