RUTHENIUM CATALYZED ENYNE METATHESIS

Reported by Justin I. Montgomery October 8, 2001

INTRODUCTION With the discovery of new, well-defined and mild catalysts, has transcended its original application to polymer chemistry and has become a powerful synthetic tool used in the preparation of many complex target molecules.1 However, the related enyne metathesis, involving reaction between an and an , has received much less attention. Intramolecular enyne metathesis involves the transition metal catalyzed carbon-carbon bond formation between an alkyne and an alkene (C-1 to C-3, Scheme 1). Subsequent alkylidene migration from the alkene to the other alkyne carbon (C-4) yields the 1,3- product.2 Overall, two new C=C bonds are formed and the starting alkyne is reduced to a single bond. Unlike olefin metathesis, all carbons from the starting material are retained in the product, and this product contains a synthetically useful 1,3-diene moiety that can be elaborated through a Diels-Alder reaction or other transformations. Scheme 1. Enyne Metathesis.

RA RA A 1 2 1 R RB RB 3 M 2 B RA 4 R 3 C 4 R C RC R RB

In the short time since its discovery in 1985,3 the scope and limitations of enyne metathesis have been studied extensively. Today, the importance of enyne metathesis in synthetic organic chemistry is evident by its application towards several complex molecule targets.

DISCOVERY AND EARLY WORK Intramolecular Enyne Metathesis Catalyzed by Tungsten Carbene Complexes Enyne metathesis was first described by Katz3 in 1985 (Equation 1). Treatment of enyne 1 with a catalytic amount of tungsten carbene complex 2 gives rearranged diene 3 in 31% yield. Me (OC)5W 2 OMe 1 mol % (1) toluene, 75 °C, 18 h 31% yield 1 3

Copyright  2001 Justin I. Montgomery 1

The proposed mechanism for this transformation (Scheme 2) involves [2+2] cycloaddition of the active catalyst 4 and the alkyne functionality of enyne 1 to give metallocyclobutene 5, which undergoes electrocyclic ring opening to provide the vinyl substituted carbenoid complex 6. Intramolecular [2+2] cycloaddition of carbene 6 forms metallocyclobutane 7, which collapses to give diene 3, regenerating the active catalyst.

Scheme 2. Proposed Mechanism.

W W W 1 3

H W 5 6 7 H 4

Katz4 and Hoye5 published further studies that extended the scope of tungsten and chromium catalyzed enyne metathesis, but low yields and multiple reaction pathways prevented this reaction from becoming synthetically useful. Intramolecular Enyne Metathesis Catalyzed by Palladium and Platinum In 1988, while investigating palladium-catalyzed enyne cyclizations, Trost isolated an unexpected rearrangement product (Equation 2).6 Enyne 8, when treated with dimethyl acetylenedicarboxylate (DMAD, 9), tri-o-tolylphosphite, and tetracarbomethoxypalladacyclopentadiene (TCPC, 10), gives a 1:1.2 ratio of the expected [2+2+2] cycloadduct 11 and unexpected vinylcyclopentene 12 in an overall yield of 97%.

E Me E

Pd PO CH E 3 CH E E E E 3 E 3 (2) + E 10 + CH3 E E E E E ClCH2CH2Cl, 60 °C 11 12 8 9 44% yield 53% yield E = CO2Me

Diene 12 is clearly the product of enyne metathesis. However, the proposed mechanism is quite different from that proposed for the tungsten carbene metathesis. Instead, a PdII - PdIV catalytic cycle, related to the competing enyne cycloisomerization mechanism, was advanced (Scheme 3).7 Enyne 13 coordinates to TCPC, forming complex 14, which undergoes oxidative cyclization to afford metallocyclopentene 15. Reductive elimination of the Pd catalyst from 15 generates cyclobutene 16. Subsequent electrocyclic ring opening of 16 provides the enyne metathesis product 17. Unfortunately, 2 this transformation lacks generality, because the balance between the two competing pathways is very sensitive to minor changes in the structure of enyne substrates.

Scheme 3. Catalytic Cycle of Palladium Catalyzed Enyne Metathesis.

II Pd L2 16 13 17

II IV Pd L2 Pd L2 15 14

Murai has published a PtCl2 catalyzed enyne metathesis involving intermediates similar to those 8 shown in Scheme 3. These results led Fürstner to a PtCl2- or acid-catalyzed enyne metathesis believed to proceed via a novel pathway involving “nonclassical” cations as intermediates.9 At this point, the scope and utility of the Pd- and Pt-catalyzed enyne metatheses have not been investigated as thoroughly as ruthenium catalyzed enyne metatheses.

RUTHENIUM CATALYZED ENYNE METATHESIS Intramolecular Dienyne Metathesis The discovery of the well-defined ruthenium carbene complex 18 (Equation 3) by Grubbs10 revolutionized enyne metathesis chemistry. Even though it was developed for alkene metathesis, complex 18 can be used to catalyze tandem enyne metathesis/ring-closing metathesis, yielding a fused bicyclic ring system such as 20.11 Furthermore, unsymmetrical dienynes with varying tether lengths and sterically differentiated olefins allow access to other [4.3.0], [5.4.0], [4.4.0], and [5.3.0] bicyclic ring systems.

OSiEt3 OSiEt3 Ph PCy3 3 mol% 18, Cl Ru (3) Cl Ph CH Cl , 25 °C, 8 h 18 19 2 2 20 PCy3 Me 95% yield Me

Ruthenium Catalyzed Intramolecular Enyne Metathesis Mori first reported the use of the for intramolecular enyne metathesis in 1994 (Equation 4).12 Treatment of enyne 21 with 1 mol% of catalyst 18 gives cyclized diene 22. Electron donating functionality on the alkyne is crucial to attaining high yields (22b vs. 22a). Five-, six-, and seven-membered heterocycles can be accessed through reactions of 1,6- , 1,7- , and 1,8-enynes, respectively. 3 1 mol% 18 TsN TsN benzene, reflux (4) R R 22 21 21a, 22a - R = H, 6 h, 36% yield 21b, 22b - R = Me, 35 min, 91% yield

Two mechanistic pathways for this Scheme 4. Mechanistic Possibilities. transformation have been proposed (Scheme 4).13 First, in pathway A, which is similar to that proposed by Katz,3 enyne 23 reacts with active catalyst 24 at the 23 alkyne to form a metallocyclobutene 25. Electrocyclic Path A Path B ring opening provides the diene 26. [2+2] cyclo- addition yields metallocyclobutane 27, which opens to Ru give diene 28 and regenerate the active catalyst. Ru 23 Alternatively, route B begins with reaction of the 25 29 alkene. Carbenoid 29 undergoes intramolecular Ru cycloaddition providing bicyclic metallocyclobutene Ru Ru 24 30, which collapses to carbenoid 31. Subsequent 30 reaction with another molecule of 23 generates product 26 28 and continues the catalytic cycle. Evidence supporting pathway A has been Ru 12 23 Ru provided by Mori through two competition 31 experiments (one intramolecular and one 27 intermolecular), leading to the conclusion that reaction

of the alkyne part of an enyne is faster than that of the 28 alkene moiety. However, an NMR experiment by all steps are reversible Hoye13 suggests that pathway B is active. Two carbene proton resonances that were attributed to the intermediates type 29 and 31 were immediately observed. While these findings provide evidence that path B is viable, they do not rule out the possibility that both pathways are active. Currently, more evidence is needed before a solid conclusion can be attained. Recently, Mori and coworkers have extended the scope of intramolecular enyne metathesis to include the construction of eight-membered rings (Table 1).14 Various eight-membered heterocycles are formed through metathesis of the general type enynes 33. However, yields are substrate dependent, as illustrated in the reactions of 33b and 33c. This methodology has not been successful in the synthesis of larger rings.

4 Table 1. Synthesis of Eight-Membered Rings.

PCy3 Cl Ph Me 10 mol% Ru Cl X X1 1 PCy3 32 X 2 X2 33 (a-c) CH2Cl2, rt 34 (a-c)

SubstrateX1 X2 Ring TimeProduct Yield

33a O N-Ts Ph 24 h 34a 84%

33b N-Ts N-Ts None 14.5 h 34b 95%

None 33c N-Ts CH2 14.5 h 34c 11%

Ruthenium Catalyzed Intermolecular Enyne Metathesis Due to multiple competing reaction pathways, intermolecular enyne metathesis of complex and can lead to a range of alkene, alkyne, and polymeric compounds.2 However, researchers have been able to carry out this transformation on simple systems. The simplest of alkenes, ethylene, was used by Mori to convert alkynes to 2,3-substituted (Table 2).15

Table 2. Intermolecular Enyne Metathesis Using Ethylene.

H CCH 2 2 32 H2CCH2 + CH Cl , 25 °C, 45 h 1 2 R1 R2 2 2 R R 1 atm ethylene

Entry Substrate 32 (mol %) Product Yield (Conversion)

1 Et 3 Et OBz 62% (100%) 35 OBz 36

OTBS 60% (86%) 2 BzO37 OTBS 10 BzO 38 O O OAc 3 3 74% (89%) 39 OAc 40

Yields are moderate and products of this transformation have been used in the type-two intramolecular Diels-Alder reaction to synthesize bridgehead olefins.15 The Mes NMesN Cl Ph scope of the ethylene-alkyne cross-metathesis has recently been expanded, using the Ru Cl 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ruthenium carbene complex 41 (Figure PCy3 41 1),16 to include compounds with unprotected heteroatoms at the propargylic position. Figure 1. New Catalyst. Blechert and coworkers have reported an intermolecular enyne metathesis

5 that transforms terminal alkynes and alkenes to 1,3 disubstituted dienes (Scheme 5).17 Yields of dienes 44a-h are generally high when only 2-3 equivalents of alkene 43 are used. Unfortunately, the olefin geometry of products 44 cannot be controlled.

Scheme 5. Crossed Enyne Metathesis.

5-7 mol% 32 1 R + R2 CH Cl , 25 °C, 12-48 h 1 2 42 43 2 2 R R 2 - 3X excess of alkene 44 (a-h)

SiMe BnO R1 3 R2

1 2 44a R = CH2OTHP (81%) 44e R = CH2SiMe3 (86%) 1 2 44b R = CH2OAc (90%) 44f R = CH2t-Bu (82%) 1 2 44c R = CH(CH3)OAc (63%) 44g R = (CH2)2CH(CO2Me)2 (76%) 1 2 44d R = CH2OCO2Me (89%) 44h R = CH2OTBDMS (83%)

Ruthenium Catalyzed Tethered Enyne Metathesis To access intermolecular enyne metathesis products while still retaining the stereo- and regiochemical control allowed by its intramolecular variant, tethered enyne metathesis has been developed (Scheme 6).18 Treatment of tethered enyne 45 with catalyst 32 gives silyl ether 46. Oxidative cleavage of the tether in 46 affords the trisubstituted diene 47 in 88% overall yield. This new methodology can be used to generate seven-membered tethered dienes by simply changing the catalyst to the more active carbene complex 41.

Scheme 6. Tethered Enyne Metathesis.

Me Me HO Me Me OH Si Si KF, H2O2, O O 3 mol% 32 KHCO3 Ph Ph 47 CH2Cl2, reflux Me Me MeOH/THF 45 46 Ph Me 88% yield for 2 steps

APPLICATION TO SYNTHESIS Small Molecule Synthesis In addition to the synthesis of the various dienes and cyclic compounds already mentioned, enyne metathesis has found utility in numerous small molecule syntheses. Highly functionalized bicyclic19 and tricyclic20 β-lactams (Chart 1, 48–49), as well as a solid-supported library of hexahydroisoindoles21 50, have been synthesized using enyne metathesis. Blechert and coworkers have used enyne cross metathesis combined with the aza-Diels-Alder reaction to construct substituted

6 tetrahydropyridines 51.22 Finally, a concise route to afford 1,3-dienylboronic esters 52 through enyne metathesis has been described.23 These syntheses demonstrate the exceptional functional group tolerance of this transformation and provide compounds that have been used in pharmaceutical (48–50) and cross-coupling (52) applications. Chart 1. Small Molecules through Enyne Metathesis

4 O OTBDMS R2 R O 5 CCl3 Ph O R N Me Ts O O N N N O B N Ph OR1 1 2 O O R R Me O R3 48 49 50 51 52

Complex Molecule Synthesis In 1996, (–)-stemoamide was successfully synthesized through an enyne metathesis approach (Scheme 7). 24 The key step involved metathesis of enyne 54 to diene 55 in 87% yield and in only 5 hours. (–)-Stemoamide 56 was completed in 14 steps in 9% overall yield from (–)-pyroglutamic acid 53. Scheme 7. Synthesis of (-)-Stemoamide. Me CO2Me O MeO2C H H2C O HO2C H N 4 mol% 31 O O N O N O H N H C H H 2 54 H 56 CH2Cl2, 25 °C, 5h 55 53 87% yield (-)-stemoamide

In addition, approaches to various complex molecules (Chart 2) including the cyclic enol ethers of gambeirol 5725 and the AB ring system of the manzamine alkaloids 5826 using enyne metathesis have 27 been described. The completed syntheses of a previtamin D3 to vitamin D3 transition state analog 59 and the natural product (±)-differolide 6013 through enyne metathesis have also been reported.

CONCLUSION Enyne metathesis is an efficient carbon-carbon bond forming reaction that leads to a variety of useful organic molecules. 1,3-Dienes are available through simple transformations involving enyne or

Chart 2. Enyne Metathesis for the Construction of Complex Molecules

N R O H H N Me H H H H HO Me O O H H Me O O OH O AB OH O N H Me OH H O H Me O H HMe O O H H 57 N O OH gambeirol 60 59 (±)-differolide 58 manzamine A 7 alkyne starting materials. In addition, unsaturated carbo- and heterocycles can be formed from acyclic precursors. The development of novel ruthenium catalysts by Grubbs has significantly impacted the scope of the transformation. Enyne metathesis has proven to be useful in the synthesis of small organic molecules and complex targets.

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