Intramolecular Diels-Alder Reactions of Siloxacyclopentene Constrained Trienes

Abstract

The synthesis of siloxacyclopentene-constrained trienes 7 and 10 and studies of their IMDA cycloadditions are described. The use of appropriately chosen thermal or Lewis-acid conditions allows for cycloadducts 3-6 to be obtained with high levels of diastereoselectivity. These adducts possess trans-relationships between the hydroxyl group and the adjacent ring fusion proton, a stereochemical relationship not previously attainable in IMDA reactions.

Intramolecular Diels-Alder (IMDA) reactions of 1,3,8-nonatrienes and 1,3,9-decatrienes have been extensively applied to the synthesis of perhydroindene and octahydronaphthalene substructures found in a wide array of natural products.^1-4 Temporary addition of stereochemical directing groups has been used to increase stereoselectivity in certain cases. Boeckman and our group developed the steric directing group strategy which allows for selective access to trans-fused cycloadducts where the ring fusion is flanked by a heteroatom functionality in a cis-relationship with the ring fusion proton (Scheme 1).^5,6

Scheme 1.

Steric Directing Group Strategy

For example, by application of the steric directing group strategy, trienes 1 (X = −Br or −SiMe₃) react through transition state A to give cycloadducts 2 with excellent selectivity. Our group has applied this technology to the synthesis of chlorothricolide^6-8 and spinosin A model systems.^9,10 However, some natural products have the opposite stereochemical arrangement, with a heteroatom substitutent trans to the ring fusion proton as in cycloadducts 3-6 (e.g., FR182877),^11-13 but this stereochemical relationship has proven difficult to achieve with consistently high levels of stereocontrol.

In order to access the anti-hydroxyl/ring fusion stereochemical relationship in trans-fused cycloadducts such as 3 and 5, we sought to develop a strategy that would constrain the diene and adjacent hydroxyl functionality into coplanarity in the IMDA transition state(s). The diversity of methods for synthesizing five membered siloxacycles,¹⁴ as well as the ease of their removal with fluoride ion sources, led us to explore the use of siloxacyclopentene units for this purpose. We report herein the successful development and implementation of the siloxacyclopentene-constrained strategy for IMDA reactions, which provides cycloadducts 3-6 in a manner complimentary to the steric directing group strategy that has previously given access to cycloadducts such as 2.

We targeted terminally active trienes 7a-e and 10a-e to illustrate this strategy. By virtue of the constaining siloxacyclopentene unit, trienes 7 would be forced to cyclize through the half-chair-like transition states endo B or exo C to give either trans-fused cycloadduct 8 or cis-fused cycloadduct 9. Similarly, cyclization of the undecatriene homologs 10 would proceed either through chair-like transition state D or boat-like transition state E to give trans-fused 11 or cis-fused 12 respectively (Scheme 2).

Scheme 2.

Siloxacyclopentene Directing Group Strategy for IMDA Reactions

Synthesis of trienes 7a and 10a began with comercially available alcohols 13 and 14 (Scheme 3). Swern oxidation¹⁵ of 13 or 15 followed by addition of the lithium acetylide generated from 3-methylbutenyne gave propargyl alcohols 15 and 16. Alcohols 15 and 16 were then treated with tetramethyldisilazane (neat), followed by 10 mol% of KOt-Bu according to Lee's hydrosilylation procedure.^14e This sequence provided trienes 7a and 10a in excellent yields, and could easily be preformed on multigram scale.

Scheme 3.

Synthesis of Trienes 7a and 10a

Trienes 7a and 10a were further functionalized via olefin cross-metathesis¹⁶ by using the Hoveyda catalyst 17¹⁷ in order to access terminally activated trienes 7b-e and 10b-e. Methyl esters 7b and 10b and methyl ketones 7d and 10d were obtained in 88-92% yield via cross metatheses using methyl acrylate and methyl vinyl ketone, respectively. Similarly, cross metatheses of 7a and 10a with acrolein or acrolein acetals provided trienes 7c,e and 10c,e,f in good yield when the reactions were performed in the presence of 1,4-benzoquinone (71-84%).¹⁸

Results of the intramolecular Diels-Alder reactions of trienes 7 and 10 are summarized in Table 2. Thermal cycloadditions were performed at the indicated reaction temperatures in toluene (0.03 to 0.05M) in a sealed tube. Lewis-acid promoted cycloadditions were carried out in CH₂Cl₂ (0.01M). A solution of the Lewis-acid was added via syringe to the solution of triene at −78 °C, then the solution was warmed to the final reaction temperature. In both cases, the crude cycloadducts were immediately subjected to protiodesilylation by treatment with TBAF (typically in THF at 60 °C) to aid in product isolation and purification.¹⁹ Stereochemistry of the cycloadducts was assigned by using ¹H NOSEY and J data (see Supporting Information).

Table 2.

Thermal and Lewis-Acid Promoted Intramolecual Diels-Alder Cycloadditions of Trienes 7 and 10.

entry	substrate	R	reaction conditions	product yield (%)a	products	ratiob
1	7a	-H	1) c 180 °C, 24 h; 2) TBAF, THF, 60 °C, 1.5 h	75	3a:4a	<1:20
2	7b	-CO2Me	1) c 140 °C, 20 h; 2) TBAF, THF, 60 °C, 1.5 h	81	3b:4b	1:1
3	7b	-CO2Me	MeAlCl2, −78 → 23 °C, 16 h d	0
4	7b	-CO2Me	SnCl4, −78 → 23 °C, 16 h e	0
5	7c	-CHO	1) c 100 °C, 20 h; 2) TBAF, THF, 12 h	60	3c:4c	2.5:1f
6	7c	-CHO	1) d MeAlCl2, −78 → −20 °C, 3 h; 2) TBAF, THF, 12 h	55	3c:4c	>20:1f
7	7d	-COMe	1) c 100 °C, 20 h; 2) TBAF, THF, 60 °C, 1.5 h	85	3d:4d	2:1
8	7d	-COMe	1) d MeAlCl2, CH2Cl2, −78 → −20 °C, 3 h; 2) TBAF, THF, 60 °C, 1.5 h	75	3d:4d	94:6
9	7e	-CH(-OCH2CH2O-)	1) c 160 °C, 20 h; 2) TBAF, THF, 60 °C, 1.5 h	74	3e:4e	<1:20
10	10a	-H	1) c 190 °C, 72 h; 2) TBAF, THF, 60 °C, 1.5 h	65	5a:6a	1.25:1
11	10b	-CO2Me	1) c 140 °C, 20 h; 2) TBAF, THF, 60 °C, 1.5 h	92	5b:6b	>20:1
12	10b	-CO2Me	MeAlCl2, −78 → 23 °C, 16 h d	0
13	10b	-CO2Me	SnCl4, −78 → 23 °C, 16 h e	0
14	10c	-CHO	1) c 120 °C, 24 h; 2) TBAF, THF, 12 h	57	5c:6c	>20:1f
15	10c	-CHO	1) d MeAlCl2, −78 → −20 °C, 6 h; 2) TBAF, THF, 12 h	55	5c:6c	>20:1f
16	10d	-COMe	1) c 120 °C, 24 h; 2) TBAF, THF, 60 °C, 1.5 h	93	5d:6d	97:3
17	10d	-COMe	1) d MeAlCl2, −78 → 0 °C 6 h; 2) TBAF, THF, 60 °C, 1.5 h	60	5d:6d	>20:1
18	10e	-CH(-OCH2CH2O-)	1) c 190 °C, 72 h; 2) TBAF, THF, 60 °C, 1.5 h	57	5e:6e	1.8:1

^aCombined yield of products after purification by silica gel chromatography.

^bProduct ratios determined by ¹H NMR analysis of crude reaction mixtures prior to protiodesilylation.

^c0.03-0.05 M PhMe solution in a sealed tube.

^d0.01 M solution in CH₂Cl₂ with 1.0 equiv of MeAlCl₂.

^e0.01 M solution in CH₂Cl₂ with 0.2 equiv of SnCl₄.

^fCa. 10 % epimerization alpha to the aldehyde ocurred during protiodesilation and chromatography.

Stereostructures were assigned by ¹H NOESY and J data (see Supporting Information).

The thermal cyclization of unactivated triene 7a gave cis-fused cycloadduct 4a with ≥20 : 1 selectivity (entry 1). This result suggests that the siloxacyclopentene unit destabilizes the trans-fused transition state B, since it is known that thermal cycloadditions of conformationally unconstrained, unactivated nonatrienes provide the cis-fused cyloadducts with ca. 2-3 : 1 selectivity.²⁰

The high intrinsic selectivity preference for the cis-ring fusion exhibited in the IMDA reaction of 7a proved difficult to overcome, as thermal cycloaddition of terminally activated trienes 7b-d proved to be unselective (entries 2, 5, and 7). Thermal IMDA reactions of trienes analogous to 7b-d but lacking the siloxacyclopentane unit generally display useful selectivities for the trans-fused product (especially with terminal ketone or aldehyde dienophile activiating groups).²¹

Attempts to effect the cycloaddition of trienoate 7b by using Lewis acid catalysis gave no observable cycloadducts, with substrate decomposition occurring above 0 °C in the experiment performed with SnCl₄ (entries 3 and 4). However, Lewis-acid promoted cycloadditions of trienal 7c and trienone 7d were highly selective for the trans-fused cycloadducts 3c and 3d, respectively (entries 6 and 8).

It proved necessary to use mild conditions for the protiodesilylation of the siloxacyclopentane intermediate 8c in the IMDA reactions of 7c, as treatment the crude cycloadduct with TBAF at 60 °C led to decomposition of the products (c.f., 3c), presumably due to competing reactions of the aldehyde function. Fortunately, decreasing the protiodesilylation reaction temperature to 23 °C minimized side reactions, although a small amount of aldehyde epimerization was observed (ca. 10 %).

Thermal cyclization of acetal 7e was highly selective, giving the cis-fused cycloadduct 4e as the only observable cycloadduct. This result is important, as this exo-selective cycloaddition provides access to a cis-fused cycloadduct series not previously obtainable with synthetically useful selectivity from intramolecular Diels-Alder reactions (entry 9).^1-4

A remarkably different trend of diastereoselectivity was found for IMDA reactions of decatrienes 10. Unlike 7a, thermal cycloaddition of unactivated triene 10a was sluggish and relatively non-selective, giving slightly more trans-fused cycloadduct 5a than cis-fused 6a (entry 10).

Thermal cycloadditions of terminally activated trienes 10b-d gave primarily the trans-fused cycloadducts 5b-d (entries 11, 14, and 16). Aldehyde cycloadduct 5c, as with aldehyde 3c, was prone to decomposition when exposed to TBAF at 60 °C, so here also the protiodesilylation of the product mixture (11c/12c) obtained from the IMDA reactions of trienal 10c was performed at ambient temperature (entries 14, 15).

As with 7b, attempts to promote the IMDA cyclization of trienoate 10b with MeAlCl₂ failed to give any observable cycloadducts, and use of SnCl₄ resulted in decomposition above 0 °C (entries 12 and 13). Lewis-acid promoted cycloadditions of trienal 10c and trienone 10d gave exclusively the trans-fused cycloadducts 5c and 5d, respectively (entries 15 and 17), but in lower yields than under thermal conditions.

In contrast to the results obtained with 7e, the thermal cycloaddition of acetal 10e was unselective, exhibiting only a slight preference for the trans-fused cycloadduct 5e (entry 18).

In summary, we have developed a strategy for the stereocontrolled synthesis of perhydroindene and octahydronaphthalene cycloadducts with trans-relationships between the ring fusion proton and an adjacent hydroxyl group, as in structures 3-6, via the intramolecular Diels-Alder cyclizations of siloxacyclopentene-constrained trienes 7 and 10. Cycloadducts 3-6 have not previously been accessible with synthetically useful levels of stereoselectivity from intramolecular Diels-Alder reactions. Moreover, this procedure is completely complementary to the stereochemical control achieved by application of the steric directing group strategy.^5,6 Key to the successful demonstration of this new siloxacyclopentene-contraining strategy were the application of Lee's alkoxide-promoted intramolecular hydrosilylation of alkynes to the synthesis of the siloxacyclopentene-containing trienes 7a and 10a, and the utility of 7a and 10a as substrates for cross olefin metathesis leading to trienes 7b-e and 10b-e. Applications of this new strategy for stereochemical control of the intramolecular Diels-Alder reaction towards the synthesis of biologically active natural products synthesis will be reported in due course.

Table 1.

Synthesis of Terminally-Substituted Trienes 7b-e and 10b-f

entry	n =	R =	yield (%)a	product
1	1	-CO2Me	94	7b
2	2	-CO2Me	94	10b
3	1	-CHO	84b	7c
4	2	-CHO	83b	10c
5	1	-COMe	92	7d
6	2	-COMe	88	10d
7	1	-CH(-OCH2CH2O-)	81b	7e
8	2	-CH(-OCH2CH2O-)	71b	10e

^aYield of product after purification by silica gel chromatography.

^breaction performed with 10 mol % 1,4-benzoquinone.

^cpin = 2,2,3,3-tetramethylethylene acetal