Siloxacyclopentenes as Dienophile-Linked Directing Groups in Intramolecular Diels-Alder Reactions

Abstract

The synthesis and intramolecular Diels-Alder reactions of trienes 5 and 6 with a siloxacyclopentene-constrained dienophile are described. These reactions provide the primary cycloadducts 7 and 8 with high diastereoselectivity. These cycloadducts possess trans-relationships between the ring fusion proton and the adjacent C(1) alkoxy group, and can be further elaborated to alcohols 9 and 11 (via protiodesilylation), or to 10 and 12 (via Fleming-Tamao oxidation) depending on the substitutent R.

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 Addition of temporary stereochemical directing groups has been used to increase stereoselectivity of certain IMDA reactions.^5,6

Boeckman and our group introduced the steric directing group strategy for diastereocontrol of IMDA reactions of trienes with alkoxy substituents at the internal dienylic position (e.g., 1). Introduction of the diene substituent “X” in triene substrates allows for selective access to cycloadducts in which the alkoxy substituent of the product is in a cis-relationship with the adjacent ring fusion proton.^5,6 For example, trienes 1 (X = Br or SiMe₃) react through transition state A to give cycloadducts 2 with excellent diastereoselectivity. Our group has applied this methodology to the synthesis of chlorothricolide^6-8 and spinosin A model systems.^9,10

Complementary stereochemical control can be achieved by locking the diene and an adjacent hydroxyl group by way of a conformationally constraining siloxacyclopentene unit.¹¹ For example, trienes 3 react through transition state B to give cycloadducts 4 in which the heteroatom is in a trans-relationship with the adjacent ring fusion proton (Scheme 1).

Scheme 1.

Stereochemical Directing Group Strategies for IMDA Reactions

In connection with an ongoing effort in natural product synthesis, we became interested in the possibility that use of a dienophile-tethered siloxacyclopentene unit could provide a general strategy for control of the stereochemistry of bicycles 9-12 (Scheme 2). Based on the limited number of literature examples of IMDA reactions of trienes with unconstrained alkoxy units allylic to the dienophile,^1-4 it appears that synthetically useful control of the stereochemistry of the alkoxy group relative to the ring fusion in cycloadducts analogous to 9 and 11 cannot always be achieved.¹² In contrast, it was anticipated that IMDA cyclizations of 5 and 6 should proceed via transition states C and D to give trans-fused cycloadducts 7 and 8, respectively, with excellent stereochemical control. The constraint imposed by the siloxacyclopentene unit makes it impossible for these reactions to proceed with pseudoequatorial placement of the alkoxyl group, which would lead to the C(1)-epimers of 9-12. Moreover, it was anticipated that the IMDA cyclizations of 5 and 6 should show excellent control for trans-ring fused cycloadducts, as the alternative cis-fused transition states (not shown) suffer from non-bonded interactions between the diene and the dimethylsilyl unit. Elaboration of the primary cycloadducts 7 and 8, either by protiodesilylation¹³ or Fleming-Tamao oxidation,¹⁴ would then lead to 9-12. Cycloadducts 10 and 12 are of considerable interest as they are the formal products of intramolecular Diels-Alder reactions of enol-containing dienophiles.

Scheme 2.

Strategy for Intramolecular Diels-Alder Cyclizations of Siloxacyclopentene-Constrained Trienes 5 and 6

We report herein the synthesis and IMDA reactions of siloxacyclopentene-constrained trienes 5a-c and 6a-c to illustrate this strategy. The ethylene glycol acetal units in 5c and 6c serve as excellent dienophiles under Lewis-acidic conditions.¹⁵

Synthesis of nonatrienes 5a-c began with the known Claisen rearrangement¹⁶ of commerically available 1,4-pentadien-3-ol (13) (Scheme 3). Aldehyde 14 was then treated with the lithium acetylides generated from either phenylacetylene, 2-furylacetylene or propionaldehyde acetal 16¹⁷ to give alcohols 15a-c respectively. These intermediates were then elaborated to trienes 5a-c in good yield by treatment with tetramethyldisilazane, followed by catalytic potasium tert-butoxide in THF to effect intramolecular hydrosilylation (Scheme 3).¹⁸

Scheme 3.

Synthesis of Nonatrienes 5a-c

Syntheses of decatrienes 6a-c were performed by using similar procedures (Scheme 4). Comercially available 2-methoxytetrahydropyran (17) was converted into dienol 18 via the known procedure.¹⁹ Alcohol 18 was oxidized using the Swern protocol,²⁰ and the resulting aldehyde was treated with the lithium acetylide generated from either phenylacetylene, 2-furylacetylene or 16 to give alcohols 19a-c. Propargyl alcohols 19a-c were then converted to the trienes 6a-c by treatment with HN(SiMe₂H)₂ followed by catalytic KOtBu in THF.¹⁸

Scheme 4.

Synthesis of Decatrienes 6a-c

While the results summarized in Schemes 3 and 4 (as well as those in our previous study¹¹) demonstrate that the intramolecular hydrosilylation procedure, originally developed by Lee,¹⁸ works well for a range of substrates, one limitation is for substrates like 19d (Scheme 5). Attempted hydrosilylation of 19d under a variety of conditions gave only small amounts (<10%) of 6d, which proved to be highly unstable to attempted chromatographic purification, as well as to acidic, basic and thermal (e.g., Diels-Alder) reaction conditions. Consequently, acetals 5c and 6c serve as surrogates for conventional dienophile-activated trienes in this study.

Scheme 5.

Attempted Hydrosilylation of 19d

The results of intramolecular Diels-Alder reactions of trienes 5 and 6 are summarized in Table 1. Thermal cycloadditions were performed in toluene (0.03 M) in a sealed tube in the presence of a catalytic amount of BHT. Lewis acid promoted cycloadditions were carried out by addition of the reagent to a solution of triene in CH₂C1₂ (0.02 M) at -78 °C, then the solution was warmed to the final reaction temperature. In both sets of reactions, the crude cycloadducts were subjected either to protiodesilylation (TBAF in THF, 60 °C)¹³, or Fleming-Tamao oxidation (H₂O₂, KF, KHCO₃ in 1:1 THF:MeOH),¹⁴ as indicated.^21,22 Remarkably, all cycloadditions were highly stereoselective for the trans-fused cycloadducts, with no observable cis-fused cycloadducts by ¹H NMR analysis of the crude reaction mixtures (≥20:l dr).

Table 1.

Thermal and Lewis-Acid Promoted Intramolecular Diels-Alder Reactions of Trienes 5 and 6

entry	substrate	R	Diels-Alder conditions	workup conditions	producta	product yield (%)b
1	5a	Ph	190 °C 7 days	KF, KHCO3, H2O2	10a	72%
2	5b	2-furyl	190 °C 72 h	KF, KHCO3, H2O2	10b	43%
3	5c	-CH(OCH2)2	170 °C 72 h			0%
4	5c	-CH(OCH2)2	0.4 equiv. TMSOTf -78 °C to 0 °C 2 h	TBAF, THF, 60 °C, 2 h	9c	85%
5	6a	Ph	190 °C 5 days	KF, KHCO3, H2O2	12a	64%
6	6b	2-furyl	170 °C 48 h	KF, KHCO3, H2O2	12b	45%
7	6c	-CH(OCH2)2	170 °C 72 h		11c	0%
8	6c	-CH(OCH2)2	0.4 equiv. TMSOTf -78 °C to 0 °C 2 h	TBAF, THF, 60 °C, 2 h	11c	91%

^aEach cycloaddition was highly diastereoselective (≥20:l by ¹H NMR analysis of the crude reaction mixtures.)

^bYield of cycloadducts after purification by silica gel column chromatography.

The intramolecular cycloaddition of phenyl-substituted triene 5a required 7 days at 190 °C to preceed to completion, but nevertheless gave a single diastereomeric cycloadduct according to ¹H NMR analysis of the reaction mixture. Oxidation of crude 7a under standard Flemming-Tamao conditions gave diol 10a in 72% overall yield. The stereochemistry of 10a (as with all isolated cycloadducts in this study) was assigned by NMR methods (see Supporting Information). Thermal cycloaddition of 2-furyl-substituted triene 5b was also sluggish and required three days at 170 °C to go to completion. Again, standard Fleming-Tamao oxidation of the crude cycloadduct 7b gave a single diol 10b in 43% yield.

Attempted thermal cycloaddition of triene 5c led only to decomposition. Fortunately, TMS-OTf promoted cycloaddition of 5c proceeded smoothly at -78 to 0 °C. The resulting cycloadduct 7c was converted to alcohol 9c (85% yield) by treatment with TBAF in THF. Again 9c was obtained as a single isomer by ¹H NMR analysis of the crude reaction mixture. Unfortunately, all attempts to oxidize the carbon-silicon bond of 7c under a variety of conditions failed to give diol 10c. All attempted oxidations of 7c under conditions containing a fluoride source or a strong base led only to desilylated 9c (H₂O₂, KF, KHCO₃ in 1:1 THF:MeOH or t-BuOOH, NaH in THF), while no reaction was observed under milder conditions (Me₃NO in DMF).

Decatrienes 6a-c behaved analogously to their nonatriene counterparts. Thermal cycloaddition of 6a required five days at 190 °C. Fleming-Tamao oxidation of the primary cycloadduct 8a gave diol 12a in 64% yield. Thermal cycloaddition of 6b was complete after two days at 170 °C. Fleming-Tamao oxidation of 8b provided the diol 12b in 45% yield. Finally, treatment of decatriene 6c with TMS-OTf at -78 °C with warming to 0 °C led to smooth cycloaddition. Protiodesilylation of the primary cycloadduct 8c by treatment with TBAF in THF at 60 °C then provided alcohol 11c in 91% yield and as a single diastereomer. All attempts to effect Fleming-Tamao oxidation of 8c were unsuccessful.

In summary, we have developed a strategy for the stereocontrolled synthesis of hexahydroindene and octahydronaphthalene cycloadducts 9-12 via the intramolecular Diels-Alder cyclizations of siloxacyclopentene-constrained trienes 5 and 6. The silacyclopentene units of 5 and 6 permit the stereochemistry of the C(1) hydroxyl group of the cycloadducts to be controlled relative to the ring fusion, and also serve as a handle for subsequent Fleming-Tamao oxidation (in the case of cycloadducts 7a,b and 8a,b). Also of interest is the ability of triene acetals 5c and 6c to undergo TMS-OTf promoted cycloadditions to give cycloadducts 9c and 11c after protiodesilylation of the initial products, 7c and 8c. Applications of this new strategy for stereochemical control of the intramolecular Diels-Alder reaction in the synthesis of biologically active natural products synthesis will be reported in due course.

Supplementary Material

1_si_001. Supporting Information Available.

Experimental procedures and full charactization data (¹H NMR, ¹³C NMR, IR, and HRMS) for all new compounds as well as summaries of stereochemical assignments for cycloadducts. This material is available free of charge via the Internet at http://pubs.acs.org.