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Toward the synthesis of amphidinolide P: optimization of a model ene–yne metathesis fragment coupling
Accepted Manuscript Towards the Synthesis of Amphidinolide P: Optimization of a Model Ene-Yne Metathesis Fragment Coupling Edgars Jecs, Steven T. Diver PII: DOI: Reference:
S0040-4039(14)01137-X http://dx.doi.org/10.1016/j.tetlet.2014.06.113 TETL 44839
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
27 May 2014 23 June 2014 30 June 2014
Please cite this article as: Jecs, E., Diver, S.T., Towards the Synthesis of Amphidinolide P: Optimization of a Model Ene-Yne Metathesis Fragment Coupling, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet. 2014.06.113
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Towards the Synthesis of Amphidinolide P: Optimization of a Model EneYne Metathesis Fragment Coupling Edgars Jecs and Steven T. Diver * Department of Chemistry, University at Buffalo, Amherst, NY 14260 USA
Ru2 (10 mol %)
O TBSO
+ OH (1.5 equiv)
PhCH3, 40
oC,
O
Me
Me
1 h TBSO
ene-yne metathesis fragment coupling
Me N
OH
Cl
Me N
Me
Cl Me Ru O
(70% NMR yield, 59% isolated) Ru2 = Hoveyda-Grubbs precatalyst
ABSTRACT Ene-yne cross metathesis was assessed for use as a key fragment coupling in a planned total synthesis of amphidinolide P. A terminal alkyne containing a β,γ-epoxide was synthesized and employed as the alkyne partner in an intermolecular ene-yne metathesis. In the alkene substrate, optimal functionality and reaction conditions were determined. An unprotected allyl alcohol was found to be critical for both high yield and high E-selectivity. Fewer equivalents of the alkene resulted in incomplete reaction and side reactions consumed the terminal alkyne. The best ruthenium carbene precatalysts were found to be the Hoveyda-Grubbs carbene complexes.
*
Corresponding author. Tel. (716) 645-4208; fax: (716) 645-6963. Email address: [email protected]
1
1.
Introduction
Ene-yne metathesis (EYM) is a powerful catalytic method for C-C bond construction.1 It has been used in complex molecule total synthesis, primarily as a ring closure method, utilizing an alkene and alkyne reactant in the same molecule.2 The few examples of cross EYM in total synthesis use ethylene, to form butadienes3 which may be followed by a cross metathesis with excess 1-alkene4 or by a ring-closing metathesis (RCM) reaction.5 Cross ene-yne metathesis is used less frequently in complex molecule synthesis. A cross-EYM requires an excess of the alkene which accelerates the slow step of EYM6 and prevents side reactions such as alkyne polymerization7 and other undefined pathways that may result in catalyst decomposition. Recently, our group demonstrated an atom economical cross EYM8a where only 1.2 equivalents of an alkene can be used. In the case of secondary allylic alcohol derivatives as alkene reaction partners, a free hydroxyl group performed the best, supporting earlier findings by Hoye in RCM8b and consistent with a rate acceleration effect found by Imahori.8c Our goal is to disconnect amphidinolide P by a macrocyclization of the seco-ester, the latter of which can be made by a cross EYM (Scheme 1, panel a). Studies reported herein focus on the key carbon-carbon bond coupling between model alkyne 1 and representative alkenes. Amphidinolide P is a marine antibiotic with a unique macrocyclic backbone which contains the 1,3-diene subunit. In Nature, (+)-amphidinolide P is found in a marine dinoflagellate Amphidinium sp. First isolated by Kobayashi,9 amphidinolide P is moderately cytotoxic against murine lymphoma L1210 and carcinoma KB cells in vitro (IC50: 1.6 and 5.8 µg/mL). Both enantiomers of amphidinolide P have been previously synthesized. Williams et al. employed a Stille cross coupling to synthesize the 1,3-diene in a stereoselective fashion.10 Trost and Papillion employed a rutheniumcatalyzed alkene-alkyne coupling, developed in Trost’s labs, as their key step.11 We envisioned a synthesis of amphidinolide using an ene-yne metathesis as the key step. However, due to the paucity of data on the success of intermolecular EYM in total synthesis, we thought it prudent to perform exploratory studies in order to define optimized reaction conditions for use in our total synthesis. This paper reports our results of ene-yne metathesis cross coupling to make a key fragment of amphidinolide P. 2.
Results and Discussion
The required alkyne was synthesized as illustrated in Scheme 2. The sequence commenced with radical bromination of the γ-position of methyl crotonate, followed by reduction using excess DIBAL with subsequent protection of the resulting allylic alcohol as its tetrahydropyranyl (THP) ether,12 giving 3. Cu(I)-catalyzed coupling13 of allyl bromide 3 with lithiated (trimethylsilyl)acetylene produced the skipped enyne 4 in good yield. The THP ether was removed to unmask the allylic alcohol, which was used to direct Sharpless asymmetric epoxidation giving epoxyalkyne 5 in good yield. Either enantiomer of diethyltartrate can be employed in this step, which might be useful for the synthesis of analogs of amphidinolide. The enantiomeric excess (% ee) of 5 could not be directly determined using several different chiral hplc columns. The % ee of the epoxide was established via the benzoate 5B which proved separable by hplc using a chiral stationary phase. In addition, enantiomeric excess of the alcohol 5A was established by Mosher ester analysis.14 These methods indicated a 92 % ee. Protection of alcohol 6 as its tert-butyldimethyl silyl (TBS) ether completed the synthesis of the requisite alkyne 1.
2
(a)
(b) O
O
O
H
OH
O
O O
O +
H O
EYM
HO
EYM TBSO
CO2Me
HO
MODEL SYSTEM
OH
R TBSO 1
(–)-amphidinolide P
Scheme 1. (a) Key Retrosynthetic Disconnections of Amphidinolide P and (b) the Model Cross Ene-Yne Metathesis of this Study
Scheme 2. Synthesis of alkyne 1. Reagents and conditions: a) 0.6 equiv. NBS, 0.0139 mol % AIBN, CCl4, reflux, 3.5 h, 75 %; b) 2.2 equiv. DIBAL, CH2Cl2, -78 oC, 74 %; c) 30 mol % D-CSA, 3.0 equiv. 3,4-dihydro-2H-pyran, CH2Cl2, rt, 78 %; d) 1.26 equiv. n-BuLi, 1.2 equiv. TMSCCH, then 10 mol % CuCl, -78 to -15 oC, rt, 12 h, 65 %; e) 5 mol % TsOH-H2O, MeOH, 1 h, 94 %; f) 0.6 equiv. (-)-DET, 0.5 equiv. Ti(Oi-Pr)4, 2 equiv. t-BuOOH, 4Å MS, CH2Cl2, , -40 oC, 2.5 h, -40 oC, then 12 h at -20 oC, 78 % (92 % ee); g) 1.1 equiv. TBAF, THF, rt, 40 min, 92 %, h) 1.1 equiv. TBSCl, 1.2 equiv. imidazole, CH2Cl2, 0 oC, 1.5 h, 96 %. The cross ene-yne metathesis of alkyne 1 was evaluated first with two model alkenes. Optimization studies began using 10 mol % Ru1 and 6 equiv alkene 7A using conditions which were previously found to give a complete reaction (Table 1). In this case, however, a low yield was found at incomplete conversion (Table 1, entry 1). The product mixtures were analyzed by quenching with methanolic KO2CCH2NC, elution through a plug of silica gel, evaporation and addition of mesitylene in CDCl3. Not surprisingly, dropping the catalyst loading had a deleterious effect on the yield of 1,3-diene 8A (entry 2). A significant solvent effect was observed. Applying the same reaction conditions in toluene gave three times the yield as found in 1,2-dichloroethane (DCE) solvent (entry 3). Further improvements were found in moving to the Hoveyda-Grubbs complex Ru2 (Scheme 3). Similar yields were found in DCE and toluene (entries 4 and 5) but in DCE there was incomplete conversion with 15% recovery of unreacted alkyne 1. The reaction conducted in toluene went to full conversion and remarkably, gave complete E-selectivity (entry 5). The high E-selectivity could be explained by two processes: Z/E isomerization by secondary alkene metathesis and through possible decomposition of the Z-isomer. As the mass balance is far from 100%, alkyne polymerization or decomposition of products seemed likely. We considered that the side reactions might be suppressed at lower reaction temperatures. Lower temperature also resulted in poor mass balance: at 0 ˚C, 28% diene product and 28% unreacted alkyne were found after a 2 h reaction time (entry 6). Since few by-products could be seen by 1H NMR spectroscopy, the remaining 44% material is lost as intractable material. Using 4pentenol as the alkene partner resulted in similar yields of diene 8B (cf. entries 5 vs 7) obtained with lower E/Z selectivity. Given the propensity for excess alkenol to decompose the Grubbs catalyst to ruthenium hydrides,15 the fact that the yields
3
are similar to that of 1-octene is somewhat surprising and might be explained by the short reaction times.16 Longer reaction times (up to 14 h) improved the E/Z selectivity, but gave diminished yield of the diene 8B. Fewer alkene equivalents resulted in incomplete alkyne conversion (entry 8). Table 1. Optimized EYM using Alkene Partners 1-Octene and 4-Penten-1-ol
Entrya 1 2b 3 4 5 6
Cat. Ru1 Ru1 Ru1 Ru2 Ru2 Ru2
Alkene 7A (6 equiv) 7A (6 equiv) 7A (6 equiv) 7A (6 equiv) 7A (6 equiv) 7A (6 equiv)
Solvent DCE DCE PhCH3 DCE PhCH3 PhCH3
Temp/oC 60 60 60 60 60 0
Time/h 1 1 1 1 1 2
Yield/% 33 13 55 60 (59%)c 61 28
E/Z 1.2/1 2.3/1 1.3/1 1.5/1 1/0 1/1
1/% 24 57 12 15 0 28
7
Ru2
7B (6 equiv)
PhCH3
60
1
65 (50%)c
2.8/1
0
8
Ru2
7B (3 equiv)
PhCH3
0
2
16
1.3/1
43
(a) Conditions: 0.06 M 1, 3-6 equiv 7, 10 mol % RuX, solvent, temperature, time. Product yield and ratio were determined by 1H NMR spectroscopy vs. mesitylene internal standard. (b) 5 mol % Ru1 used. (c) Isolated yield (see Experimental).
Scheme 3. Grubbs Precatalysts Evaluated in the Key Cross EYM
4
Next we examined the alkene partner 3-buten-2-ol, a secondary allylic alcohol similar to the cross partner needed in the amphidinolide fragment coupling. With this alkene, optimization began with 1.5 equiv alkene using 10 mol % Hoveyda-Grubbs complex Ru2. As above, solvent was found to have a major effect on chemical yield (entries 1-5, Table 2). At 40 ˚C, dichloromethane proved superior to THF. In THF, a fast alkene metathesis dimerization of 3-buten-2-ol was observed. THF has been found to be effective for Z-selective Grubbs catalysts, and gave a twofold increased initiation rate with ethyl vinyl ether relative to toluene. Percy et al. found that methyl t-butyl ether gave a twofold increase in initiation rate relative to dichloromethane, and comparable to that in toluene.17 Under the same conditions, toluene gave yields twice that of DCE (entries 4 vs 5). In each of these cases, the E-selectivity was moderate to good. Previously, we found that high E-selectivity could be achieved with an excess alkene used at higher temperatures, yet neither of these conditions apply. Dropping the temperature in toluene gave lower yields of the diene; at 0 ˚C incomplete conversion was noted (entries 6 and 7). Slightly higher temperatures (60 ˚C) resulted in lower yields compared to entry 5 either at 0.5 or 1 h reaction times (entries 8,9). With higher alkene equivalents (3-6 equivalents), the reaction temperature could be reduced to 0 ˚C with yields comparable to entry 5, albeit with some unreacted alkyne present (entries 10-12). The E-selectivities are comparable. Table 2. Optimized EYM Using the Alkene Partner 3-Buten-2-ol
Entrya 1 2 3 4 5 6
7 / Equiv 7C, 1.5 7C, 1.5 7C, 1.5 7C, 1.5 7C, 1.5 7C, 1.5
Solvent CH2Cl2 THF THF DCE PhCH3 PhCH3
Temp/oC 40 40 0 40 40 rt
Time/h 1 1 5 1 1 2
Yield/% 45 28 11 38 70 (59%)b 60
E/Z 11/1 6/1 8.5/1 8.4/1 6.5/1
1 /% 14 20 70 19 5 1
7
7C, 1.5
PhCH3
0
5
47
8.4/1
30
8
7C, 1.5
PhCH3
60
0.5
60
7.6/1
0
9
7C, 3
PhCH3
60
1
57
10.4/1
0
10
7C, 3
PhCH3
0
2
63
5.3/1
12
11
7C, 6
PhCH3
0
1
68
4.7.1
7
12 7C, 3 PhCH3 0 5 59 6.4/1 32 13 7D, 3 PhCH3 60 2 0 100 14 7E, 3 DCE 60 6 0 0 15 7F, 3 DCE 60 6 0 63 (a) Conditions: 0.06 M 1, 1.5-6 equiv 7C, 10 mol % RuX, solvent, temperature, time. Product yield and ratio were determined by 1H NMR spectroscopy vs. mesitylene internal standard. (b) Isolated yield (see Experimental). When alkenol 7C was protected, it failed to give ene-yne metathesis. To limit catalyst decomposition, the allylic alcohol was protected and subjected to ene-yne metathesis under standard conditions. Conventional protecting groups such as trimethylsilyl, tert-butyldimethylsilyl (TBS) and acetyl failed to give ene-yne metathesis as no 1,3-diene product was obtained (entries 13-15, Table 2 above). For instance, with the TBS protecting group, 100% recovered starting material was obtained. The reactions performed in dichloroethane resulted in variable alkyne decomposition. These results are consistent with earlier studies from our group,8a and related observations in the literature.8 Bulky silyl groups retard the reaction between the alkene and the catalyst.
5
With optimized reaction conditions, additional Grubbs catalysts were screened to see if further improvements could be obtained (Table 3). The various ruthenium carbene complexes are illustrated in Scheme 3. Since reaction conditions were optimized for the Hoveyda-Grubbs catalyst Ru2, we expected the best results with this family of precatalysts (Ru2-6, Ru10-11). The best case from Table 2, entry 5 is listed as the first entry in Table 3. Use of benzoquinone to limit possible decomposition due to a ruthenium hydride8a, 15c had a deleterious effect on the yield and conversion (entry 2, Table 3). Incomplete conversion was found with the Grubbs catalyst Ru1 (entry 3). Next, a series of sterically-permissive Hoveyda-type catalysts were screened, with similar results to that of Ru2, although with some unreacted alkyne remaining after the standard period of 1 h (entries 4,5). Greater NHC bulk reduced the yield somewhat (entry 6) and the carbamate appendage lowered the activity of the catalyst (entry 7). The Grela catalyst Ru3 and its position isomer Ru4 gave similar results (entries 8, 9) as obtained with Ru2 and entries 4,5. The ruthenium indenylidenes gave only low conversions (entries 10-12). The results with Ru7 and Ru8 correlate with initiation rates, so we can speculate that these precatalysts did not initiate significantly due to the low reaction temperatures and short reaction times. In some cases, higher yields might be achievable with further catalyst-specific optimization, but the above studies point to diminishing returns at higher temperatures or at longer reaction times, where mass balance is decreased. Table 3. Catalyst Screening Results
Entrya Cat. Yield 9, % E/Z 1/%b 1 70 0 Ru2 2c 34 10.3/1 41 Ru2 3 38 4.4/1 29 Ru1 4 61 2.6/1 9 Ru5 5 68 3.5/1 8 Ru6 6 52 12/1 4 Ru11 7 42 7.4/1 18 Ru10 8 58 5.4/1 8 Ru3 9 64 6.1/1 2 Ru4 10 0 80 Ru9 11 1 71 Ru7 12 36 4.1/1 34 Ru8 (a) Conditions: 0.06 M 1, 10 mol % RuX, toluene, 40 ˚C, 1 h. Product yield and ratio were determined by 1H NMR spectroscopy vs. mesitylene internal standard. (b) Recovered starting material. (c) Also used benzoquinone (20 mol %). Under standard conditions, the allylic alcohol gave the best yields compared to the other alkenes used in this study. We used the optimized conditions found in Table 2 employing 1.5 equivalents alkene, 10 mol % Ru2 and toluene at 40 ˚C for 1 h. 1-octene and 4-pentenol gave comparatively low yields and conversions (Table 4). In both cases, the diene is formed as an E/Z mixture and unreacted alkyne was present indicative of incomplete conversion. In contrast, a 70 % yield of diene 9 was obtained. Since 1-octene and 4-pentenol are linear alkenes with no allylic substitution, that 3-buten-2ol give a yield three times higher over a 1 h period supports an acceleration effect as proposed by Imahori et al. in ref 10.
Table 4. Comparision of Different Alkene Reaction Partners
Entrya
alkene/R
Yield, %
E/Z
6
Recov.
SM 1 7A, C6H13 8A, 12 0.7/1 45 2 7B, C3H7OH 8B, 18 1/1 43 3 7C, CH(OH)CH3 9, 70 5.4/1 5 (a) Conditions: 0.06 M 1, 10 mol % RuX, toluene, 40 ˚C, 1 h. Product yield and ratio were determined by 1H NMR spectroscopy vs. mesitylene internal standard. The reactions above also produced a 1,3-butadiene by-product, which was independently synthesized by alkyneethylene cross metathesis as shown in Scheme 4. Under an ethylene balloon, alkyne 1 was transformed to the corresponding butadiene 10 in 44 % isolated yield. The terminal vinyl group of 10 has characteristic resonances at δ 6.43 (dd, J =17.5, 11.0 Hz), 5.25 (d, J = 17.5 Hz) and 5.11 (d, J = 11.0 Hz), which are distinctive from those of the 1,3-dienes 8A, 8B and 9. This authentic product was used to assign butadiene by-product yields in the reactions above (see Experimental section for details). The butadiene 10 is thought to arise due to a small amount of alkene self-metathesis which produces a highly reactive LnRu=CH2 species. Scheme 4. Preparation of 2-Substituted Butadiene from Alkyne 1
A product stability study showed that the 1,3-dienes were somewhat unstable under prolonged reaction conditions. The lost alkyne mass in all the trials above suggested that decomposition of the products could be occurring. A control experiment was carried out by subjecting diene 9 to heating with catalyst Ru2 for a 24 h period. The results are shown in Scheme 5. Note that these conditions are slightly more forcing than the optimized conditions (40 ˚C, 1 h). Analyzing the reaction mixture showed that only 52 % of the initial amount of diene was found. In addition, an oxidized byproduct was detected as ketone 11 (12 % by 1H NMR vs. internal standard). Authentic material of 11 was synthesized independently by MnO2 oxidation of 9, which was isolated and fully characterized (see Experimental). The presence of 11 could be detected in the crude product mixture of Scheme 5, and its yield determined by integration of the appropriate peaks. The balance of the mass is presumably decomposed to more polar material or the dienone 11 may have undergone partial polymerization. Oxidation of alcohol should produce a Ru hydride species, but no isomerized 1,3-dienes (dienyl isomerization)18 were observed in this reaction. Scheme 5. 1,3-Diene Product Stability
3.
Conclusions
A difficult cross ene-yne metathesis was optimized to set the stage for a fragment coupling to be used in the late stages of a total synthesis of amphidinolide P. Of the alkene reaction partners, a free allylic alcohol performed the best, giving significantly higher yields than simple, unfunctionalized alkenes such as 1-octene. With 3-buten-2-ol, near atom economy could be achieved, with only 1.5 equiv of alkene used. The cross ene-yne metatheses showed moderate E-
7
selectivity, highest in the case of 3-buten-2-ol. A significant solvent effect was found, with toluene outperforming the rest. Higher equivalents of alkene allowed lower reaction temperatures to be used. Though many different precatalysts were screened, the Hoveyda-Grubbs type catalysts performed the best and further catalyst structural changes within this family did not further improve the yields. Longer periods of heating had a deleterious effect on the yield as shown in a control study. In all cases, ca. 25% loss of mass was attributed to a combination of alkyne oligomerization, 1,3-diene instability and other undefined decomposition pathways. Application of these optimized conditions to a key fragment coupling in amphidinolide P total synthesis is underway and will be reported in due course. 4.
Acknowledgement
This work was supported by the NSF (CHE-1012839). We are grateful to Dr. Dick Pederson (Materia) for a gift of the Grubbs and Grubbs-Hoveyda-type complexes used in this study. We would also like to thank Dr. Christophe LeRet (Umicore) for supplying the ruthenium indenylidene precatalysts used. 5.
References
8
1
(a) Clark, J. R.; Diver, S. T. “Ene-Yne Metathesis” In: Comprehensive Organic Synthesis II, Fürstner, A. Ed. Elsevier: London, 2014. (b) Diver, S. T.; Griffiths, J. R. “Ene-Yne Metathesis (Chapter 4)” In: Olefin Metathesis– Theory and Practice, Grela, K., Ed. Wiley: New York, 2014. (c) Li, J.; Lee, D. Eur. J. Org. Chem. 2011, 2011, 4269-4287. (d) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317-1382. 2
(a) Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356-8357. (b) Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773-775. (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4490-4527. (d) Metathesis in Natural Product Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: 2010, p 261-285. 3
(a) Fürstner, A.; Larionov, O.; Flügge, S. Angew. Chem., Int. Ed. 2007, 46, 5545-5548 (b) Nicolaou, K. C.; Brenzovich, W. E.; Bulger, P. G.; Francis, T. M. Org. Biomol. Chem. 2006, 4, 2119. 4
Kim, C. H.; An, H. J.; Shin, W. K.; Yu, W.; Woo, S. K.; Jung, S. K.; Lee, E. Angew. Chem., Int. Ed. 2006, 45, 8019-8021. 5
Gao, X.; Woo, S. K.; Krische, M. J. J. Am. Chem. Soc. 2013, 135, 4223-4226.
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(a) Galan, B. R.; Giessert, A. J.; Keister, J. B.; Diver, S. T. J. Am. Chem. Soc. 2005, 127, 5762-5763. (b) Hoye, T. R.; Donaldson, S. M.; Vos, T. J. Org. Lett. 1999, 1, 277-279. (c) Grotevendt, A. G. D.; Lummiss, J. A. M.; Mastronardi, M. L.; Fogg, D. E. J. Am. Chem. Soc. 2011, 133, 15918-15921. 7
2+2+1 reaction: (a) Diver, S. T.; Kulkarni, A. A.; Clark, D. A.; Peppers, B. P. J. Am. Chem. Soc. 2007, 129, 58325833. 2+2+2 reactions: (b) Peters, J.-U.; Blechert, S. Chem. Commun. 1997, 0, 1983-1984. (c) Das, S. K.; Roy, R. Tetrahedron Lett. 1999, 40, 4015-4018. 8
(a) Clark, J. R.; Diver, S. T. Org. Lett. 2011, 13, 2896-2899. (b) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 11231125. (c) Imahori, T.; Ojima, H.; Yoshimura, Y.; Takahata, H. Chem. Eur. J. 2008, 14, 10762-10771. (d) Hoveyda, A. H.; Lombardi, P. J.; O’Brien, R. V.; Zhugralin, A. R. J. Am. Chem. Soc. 2009, 131, 8378-8379. 9
Ishibashi, M.; Takahashi, M.; Kobayashi, J. i. J. Org. Chem. 1995, 60, 6062-6066.
10
(a) Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945-948. (b) Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett. 2013, 15, 2070-2070. (c) Williams, D. R.; Myers, B. J.; Mi, L.; Binder, R. J. J. Org. Chem. 2013, 78, 4762-4778. 11
(a) Trost, B. M.; Papillon, J. P. N. J. Am. Chem. Soc. 2004, 126, 13618-13619 (b) Trost, B. M.; Papillon, J. P. N.; Nussbaumer, T. J. Am. Chem. Soc. 2005, 127, 17921-17937. 12
(a) Baeckström, P.; Jacobsson, U.; Norin, T.; Rikard Unelius, C. Tetrahedron 1988, 44, 2541-2548. (b) Takami, H.; Taniguchi, M.; Tamai, T. Bull. Chem. Soc. Jpn. 1987, 60, 2151-2161. (c) Kuk, J.; Kim, B. S.; Jung, H.; Choi, S.; Park, J.-Y.; Koo, S. J. Org. Chem. 2008, 73, 1991-1994. 13
Sellès, P.; Lett, R. Tetrahedron Lett. 2002, 43, 4621-4625.
14
(a) Dounay, A. B.; Urbanek, R. A.; Frydrychowski, V. A.; Forsyth, C. J. J. Org. Chem. 2001, 66, 925-938. (b) Watanabe, T.; Imaizumi, T.; Chinen, T.; Nagumo, Y.; Shibuya, M.; Usui, T.; Kanoh, N.; Iwabuchi, Y. Org. Lett. 2010, 12, 1040-1043. 15
(a) Dinger, M. B.; Mol, J. C. Organometallics 2003, 22, 1089-1095. Thermal decomposition of Ru=CH2: (b) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004, 126, 7414-7415. (c) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 17160-17161. 16
The shorter reaction times likely minimize the extent of decomposition and limit the formation of methylidene intermediates. 17
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18
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S0040-4039(14)01137-X http://dx.doi.org/10.1016/j.tetlet.2014.06.113 TETL 44839
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
27 May 2014 23 June 2014 30 June 2014
Please cite this article as: Jecs, E., Diver, S.T., Towards the Synthesis of Amphidinolide P: Optimization of a Model Ene-Yne Metathesis Fragment Coupling, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet. 2014.06.113
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Towards the Synthesis of Amphidinolide P: Optimization of a Model EneYne Metathesis Fragment Coupling Edgars Jecs and Steven T. Diver * Department of Chemistry, University at Buffalo, Amherst, NY 14260 USA
Ru2 (10 mol %)
O TBSO
+ OH (1.5 equiv)
PhCH3, 40
oC,
O
Me
Me
1 h TBSO
ene-yne metathesis fragment coupling
Me N
OH
Cl
Me N
Me
Cl Me Ru O
(70% NMR yield, 59% isolated) Ru2 = Hoveyda-Grubbs precatalyst
ABSTRACT Ene-yne cross metathesis was assessed for use as a key fragment coupling in a planned total synthesis of amphidinolide P. A terminal alkyne containing a β,γ-epoxide was synthesized and employed as the alkyne partner in an intermolecular ene-yne metathesis. In the alkene substrate, optimal functionality and reaction conditions were determined. An unprotected allyl alcohol was found to be critical for both high yield and high E-selectivity. Fewer equivalents of the alkene resulted in incomplete reaction and side reactions consumed the terminal alkyne. The best ruthenium carbene precatalysts were found to be the Hoveyda-Grubbs carbene complexes.
*
Corresponding author. Tel. (716) 645-4208; fax: (716) 645-6963. Email address: [email protected]
1
1.
Introduction
Ene-yne metathesis (EYM) is a powerful catalytic method for C-C bond construction.1 It has been used in complex molecule total synthesis, primarily as a ring closure method, utilizing an alkene and alkyne reactant in the same molecule.2 The few examples of cross EYM in total synthesis use ethylene, to form butadienes3 which may be followed by a cross metathesis with excess 1-alkene4 or by a ring-closing metathesis (RCM) reaction.5 Cross ene-yne metathesis is used less frequently in complex molecule synthesis. A cross-EYM requires an excess of the alkene which accelerates the slow step of EYM6 and prevents side reactions such as alkyne polymerization7 and other undefined pathways that may result in catalyst decomposition. Recently, our group demonstrated an atom economical cross EYM8a where only 1.2 equivalents of an alkene can be used. In the case of secondary allylic alcohol derivatives as alkene reaction partners, a free hydroxyl group performed the best, supporting earlier findings by Hoye in RCM8b and consistent with a rate acceleration effect found by Imahori.8c Our goal is to disconnect amphidinolide P by a macrocyclization of the seco-ester, the latter of which can be made by a cross EYM (Scheme 1, panel a). Studies reported herein focus on the key carbon-carbon bond coupling between model alkyne 1 and representative alkenes. Amphidinolide P is a marine antibiotic with a unique macrocyclic backbone which contains the 1,3-diene subunit. In Nature, (+)-amphidinolide P is found in a marine dinoflagellate Amphidinium sp. First isolated by Kobayashi,9 amphidinolide P is moderately cytotoxic against murine lymphoma L1210 and carcinoma KB cells in vitro (IC50: 1.6 and 5.8 µg/mL). Both enantiomers of amphidinolide P have been previously synthesized. Williams et al. employed a Stille cross coupling to synthesize the 1,3-diene in a stereoselective fashion.10 Trost and Papillion employed a rutheniumcatalyzed alkene-alkyne coupling, developed in Trost’s labs, as their key step.11 We envisioned a synthesis of amphidinolide using an ene-yne metathesis as the key step. However, due to the paucity of data on the success of intermolecular EYM in total synthesis, we thought it prudent to perform exploratory studies in order to define optimized reaction conditions for use in our total synthesis. This paper reports our results of ene-yne metathesis cross coupling to make a key fragment of amphidinolide P. 2.
Results and Discussion
The required alkyne was synthesized as illustrated in Scheme 2. The sequence commenced with radical bromination of the γ-position of methyl crotonate, followed by reduction using excess DIBAL with subsequent protection of the resulting allylic alcohol as its tetrahydropyranyl (THP) ether,12 giving 3. Cu(I)-catalyzed coupling13 of allyl bromide 3 with lithiated (trimethylsilyl)acetylene produced the skipped enyne 4 in good yield. The THP ether was removed to unmask the allylic alcohol, which was used to direct Sharpless asymmetric epoxidation giving epoxyalkyne 5 in good yield. Either enantiomer of diethyltartrate can be employed in this step, which might be useful for the synthesis of analogs of amphidinolide. The enantiomeric excess (% ee) of 5 could not be directly determined using several different chiral hplc columns. The % ee of the epoxide was established via the benzoate 5B which proved separable by hplc using a chiral stationary phase. In addition, enantiomeric excess of the alcohol 5A was established by Mosher ester analysis.14 These methods indicated a 92 % ee. Protection of alcohol 6 as its tert-butyldimethyl silyl (TBS) ether completed the synthesis of the requisite alkyne 1.
2
(a)
(b) O
O
O
H
OH
O
O O
O +
H O
EYM
HO
EYM TBSO
CO2Me
HO
MODEL SYSTEM
OH
R TBSO 1
(–)-amphidinolide P
Scheme 1. (a) Key Retrosynthetic Disconnections of Amphidinolide P and (b) the Model Cross Ene-Yne Metathesis of this Study
Scheme 2. Synthesis of alkyne 1. Reagents and conditions: a) 0.6 equiv. NBS, 0.0139 mol % AIBN, CCl4, reflux, 3.5 h, 75 %; b) 2.2 equiv. DIBAL, CH2Cl2, -78 oC, 74 %; c) 30 mol % D-CSA, 3.0 equiv. 3,4-dihydro-2H-pyran, CH2Cl2, rt, 78 %; d) 1.26 equiv. n-BuLi, 1.2 equiv. TMSCCH, then 10 mol % CuCl, -78 to -15 oC, rt, 12 h, 65 %; e) 5 mol % TsOH-H2O, MeOH, 1 h, 94 %; f) 0.6 equiv. (-)-DET, 0.5 equiv. Ti(Oi-Pr)4, 2 equiv. t-BuOOH, 4Å MS, CH2Cl2, , -40 oC, 2.5 h, -40 oC, then 12 h at -20 oC, 78 % (92 % ee); g) 1.1 equiv. TBAF, THF, rt, 40 min, 92 %, h) 1.1 equiv. TBSCl, 1.2 equiv. imidazole, CH2Cl2, 0 oC, 1.5 h, 96 %. The cross ene-yne metathesis of alkyne 1 was evaluated first with two model alkenes. Optimization studies began using 10 mol % Ru1 and 6 equiv alkene 7A using conditions which were previously found to give a complete reaction (Table 1). In this case, however, a low yield was found at incomplete conversion (Table 1, entry 1). The product mixtures were analyzed by quenching with methanolic KO2CCH2NC, elution through a plug of silica gel, evaporation and addition of mesitylene in CDCl3. Not surprisingly, dropping the catalyst loading had a deleterious effect on the yield of 1,3-diene 8A (entry 2). A significant solvent effect was observed. Applying the same reaction conditions in toluene gave three times the yield as found in 1,2-dichloroethane (DCE) solvent (entry 3). Further improvements were found in moving to the Hoveyda-Grubbs complex Ru2 (Scheme 3). Similar yields were found in DCE and toluene (entries 4 and 5) but in DCE there was incomplete conversion with 15% recovery of unreacted alkyne 1. The reaction conducted in toluene went to full conversion and remarkably, gave complete E-selectivity (entry 5). The high E-selectivity could be explained by two processes: Z/E isomerization by secondary alkene metathesis and through possible decomposition of the Z-isomer. As the mass balance is far from 100%, alkyne polymerization or decomposition of products seemed likely. We considered that the side reactions might be suppressed at lower reaction temperatures. Lower temperature also resulted in poor mass balance: at 0 ˚C, 28% diene product and 28% unreacted alkyne were found after a 2 h reaction time (entry 6). Since few by-products could be seen by 1H NMR spectroscopy, the remaining 44% material is lost as intractable material. Using 4pentenol as the alkene partner resulted in similar yields of diene 8B (cf. entries 5 vs 7) obtained with lower E/Z selectivity. Given the propensity for excess alkenol to decompose the Grubbs catalyst to ruthenium hydrides,15 the fact that the yields
3
are similar to that of 1-octene is somewhat surprising and might be explained by the short reaction times.16 Longer reaction times (up to 14 h) improved the E/Z selectivity, but gave diminished yield of the diene 8B. Fewer alkene equivalents resulted in incomplete alkyne conversion (entry 8). Table 1. Optimized EYM using Alkene Partners 1-Octene and 4-Penten-1-ol
Entrya 1 2b 3 4 5 6
Cat. Ru1 Ru1 Ru1 Ru2 Ru2 Ru2
Alkene 7A (6 equiv) 7A (6 equiv) 7A (6 equiv) 7A (6 equiv) 7A (6 equiv) 7A (6 equiv)
Solvent DCE DCE PhCH3 DCE PhCH3 PhCH3
Temp/oC 60 60 60 60 60 0
Time/h 1 1 1 1 1 2
Yield/% 33 13 55 60 (59%)c 61 28
E/Z 1.2/1 2.3/1 1.3/1 1.5/1 1/0 1/1
1/% 24 57 12 15 0 28
7
Ru2
7B (6 equiv)
PhCH3
60
1
65 (50%)c
2.8/1
0
8
Ru2
7B (3 equiv)
PhCH3
0
2
16
1.3/1
43
(a) Conditions: 0.06 M 1, 3-6 equiv 7, 10 mol % RuX, solvent, temperature, time. Product yield and ratio were determined by 1H NMR spectroscopy vs. mesitylene internal standard. (b) 5 mol % Ru1 used. (c) Isolated yield (see Experimental).
Scheme 3. Grubbs Precatalysts Evaluated in the Key Cross EYM
4
Next we examined the alkene partner 3-buten-2-ol, a secondary allylic alcohol similar to the cross partner needed in the amphidinolide fragment coupling. With this alkene, optimization began with 1.5 equiv alkene using 10 mol % Hoveyda-Grubbs complex Ru2. As above, solvent was found to have a major effect on chemical yield (entries 1-5, Table 2). At 40 ˚C, dichloromethane proved superior to THF. In THF, a fast alkene metathesis dimerization of 3-buten-2-ol was observed. THF has been found to be effective for Z-selective Grubbs catalysts, and gave a twofold increased initiation rate with ethyl vinyl ether relative to toluene. Percy et al. found that methyl t-butyl ether gave a twofold increase in initiation rate relative to dichloromethane, and comparable to that in toluene.17 Under the same conditions, toluene gave yields twice that of DCE (entries 4 vs 5). In each of these cases, the E-selectivity was moderate to good. Previously, we found that high E-selectivity could be achieved with an excess alkene used at higher temperatures, yet neither of these conditions apply. Dropping the temperature in toluene gave lower yields of the diene; at 0 ˚C incomplete conversion was noted (entries 6 and 7). Slightly higher temperatures (60 ˚C) resulted in lower yields compared to entry 5 either at 0.5 or 1 h reaction times (entries 8,9). With higher alkene equivalents (3-6 equivalents), the reaction temperature could be reduced to 0 ˚C with yields comparable to entry 5, albeit with some unreacted alkyne present (entries 10-12). The E-selectivities are comparable. Table 2. Optimized EYM Using the Alkene Partner 3-Buten-2-ol
Entrya 1 2 3 4 5 6
7 / Equiv 7C, 1.5 7C, 1.5 7C, 1.5 7C, 1.5 7C, 1.5 7C, 1.5
Solvent CH2Cl2 THF THF DCE PhCH3 PhCH3
Temp/oC 40 40 0 40 40 rt
Time/h 1 1 5 1 1 2
Yield/% 45 28 11 38 70 (59%)b 60
E/Z 11/1 6/1 8.5/1 8.4/1 6.5/1
1 /% 14 20 70 19 5 1
7
7C, 1.5
PhCH3
0
5
47
8.4/1
30
8
7C, 1.5
PhCH3
60
0.5
60
7.6/1
0
9
7C, 3
PhCH3
60
1
57
10.4/1
0
10
7C, 3
PhCH3
0
2
63
5.3/1
12
11
7C, 6
PhCH3
0
1
68
4.7.1
7
12 7C, 3 PhCH3 0 5 59 6.4/1 32 13 7D, 3 PhCH3 60 2 0 100 14 7E, 3 DCE 60 6 0 0 15 7F, 3 DCE 60 6 0 63 (a) Conditions: 0.06 M 1, 1.5-6 equiv 7C, 10 mol % RuX, solvent, temperature, time. Product yield and ratio were determined by 1H NMR spectroscopy vs. mesitylene internal standard. (b) Isolated yield (see Experimental). When alkenol 7C was protected, it failed to give ene-yne metathesis. To limit catalyst decomposition, the allylic alcohol was protected and subjected to ene-yne metathesis under standard conditions. Conventional protecting groups such as trimethylsilyl, tert-butyldimethylsilyl (TBS) and acetyl failed to give ene-yne metathesis as no 1,3-diene product was obtained (entries 13-15, Table 2 above). For instance, with the TBS protecting group, 100% recovered starting material was obtained. The reactions performed in dichloroethane resulted in variable alkyne decomposition. These results are consistent with earlier studies from our group,8a and related observations in the literature.8 Bulky silyl groups retard the reaction between the alkene and the catalyst.
5
With optimized reaction conditions, additional Grubbs catalysts were screened to see if further improvements could be obtained (Table 3). The various ruthenium carbene complexes are illustrated in Scheme 3. Since reaction conditions were optimized for the Hoveyda-Grubbs catalyst Ru2, we expected the best results with this family of precatalysts (Ru2-6, Ru10-11). The best case from Table 2, entry 5 is listed as the first entry in Table 3. Use of benzoquinone to limit possible decomposition due to a ruthenium hydride8a, 15c had a deleterious effect on the yield and conversion (entry 2, Table 3). Incomplete conversion was found with the Grubbs catalyst Ru1 (entry 3). Next, a series of sterically-permissive Hoveyda-type catalysts were screened, with similar results to that of Ru2, although with some unreacted alkyne remaining after the standard period of 1 h (entries 4,5). Greater NHC bulk reduced the yield somewhat (entry 6) and the carbamate appendage lowered the activity of the catalyst (entry 7). The Grela catalyst Ru3 and its position isomer Ru4 gave similar results (entries 8, 9) as obtained with Ru2 and entries 4,5. The ruthenium indenylidenes gave only low conversions (entries 10-12). The results with Ru7 and Ru8 correlate with initiation rates, so we can speculate that these precatalysts did not initiate significantly due to the low reaction temperatures and short reaction times. In some cases, higher yields might be achievable with further catalyst-specific optimization, but the above studies point to diminishing returns at higher temperatures or at longer reaction times, where mass balance is decreased. Table 3. Catalyst Screening Results
Entrya Cat. Yield 9, % E/Z 1/%b 1 70 0 Ru2 2c 34 10.3/1 41 Ru2 3 38 4.4/1 29 Ru1 4 61 2.6/1 9 Ru5 5 68 3.5/1 8 Ru6 6 52 12/1 4 Ru11 7 42 7.4/1 18 Ru10 8 58 5.4/1 8 Ru3 9 64 6.1/1 2 Ru4 10 0 80 Ru9 11 1 71 Ru7 12 36 4.1/1 34 Ru8 (a) Conditions: 0.06 M 1, 10 mol % RuX, toluene, 40 ˚C, 1 h. Product yield and ratio were determined by 1H NMR spectroscopy vs. mesitylene internal standard. (b) Recovered starting material. (c) Also used benzoquinone (20 mol %). Under standard conditions, the allylic alcohol gave the best yields compared to the other alkenes used in this study. We used the optimized conditions found in Table 2 employing 1.5 equivalents alkene, 10 mol % Ru2 and toluene at 40 ˚C for 1 h. 1-octene and 4-pentenol gave comparatively low yields and conversions (Table 4). In both cases, the diene is formed as an E/Z mixture and unreacted alkyne was present indicative of incomplete conversion. In contrast, a 70 % yield of diene 9 was obtained. Since 1-octene and 4-pentenol are linear alkenes with no allylic substitution, that 3-buten-2ol give a yield three times higher over a 1 h period supports an acceleration effect as proposed by Imahori et al. in ref 10.
Table 4. Comparision of Different Alkene Reaction Partners
Entrya
alkene/R
Yield, %
E/Z
6
Recov.
SM 1 7A, C6H13 8A, 12 0.7/1 45 2 7B, C3H7OH 8B, 18 1/1 43 3 7C, CH(OH)CH3 9, 70 5.4/1 5 (a) Conditions: 0.06 M 1, 10 mol % RuX, toluene, 40 ˚C, 1 h. Product yield and ratio were determined by 1H NMR spectroscopy vs. mesitylene internal standard. The reactions above also produced a 1,3-butadiene by-product, which was independently synthesized by alkyneethylene cross metathesis as shown in Scheme 4. Under an ethylene balloon, alkyne 1 was transformed to the corresponding butadiene 10 in 44 % isolated yield. The terminal vinyl group of 10 has characteristic resonances at δ 6.43 (dd, J =17.5, 11.0 Hz), 5.25 (d, J = 17.5 Hz) and 5.11 (d, J = 11.0 Hz), which are distinctive from those of the 1,3-dienes 8A, 8B and 9. This authentic product was used to assign butadiene by-product yields in the reactions above (see Experimental section for details). The butadiene 10 is thought to arise due to a small amount of alkene self-metathesis which produces a highly reactive LnRu=CH2 species. Scheme 4. Preparation of 2-Substituted Butadiene from Alkyne 1
A product stability study showed that the 1,3-dienes were somewhat unstable under prolonged reaction conditions. The lost alkyne mass in all the trials above suggested that decomposition of the products could be occurring. A control experiment was carried out by subjecting diene 9 to heating with catalyst Ru2 for a 24 h period. The results are shown in Scheme 5. Note that these conditions are slightly more forcing than the optimized conditions (40 ˚C, 1 h). Analyzing the reaction mixture showed that only 52 % of the initial amount of diene was found. In addition, an oxidized byproduct was detected as ketone 11 (12 % by 1H NMR vs. internal standard). Authentic material of 11 was synthesized independently by MnO2 oxidation of 9, which was isolated and fully characterized (see Experimental). The presence of 11 could be detected in the crude product mixture of Scheme 5, and its yield determined by integration of the appropriate peaks. The balance of the mass is presumably decomposed to more polar material or the dienone 11 may have undergone partial polymerization. Oxidation of alcohol should produce a Ru hydride species, but no isomerized 1,3-dienes (dienyl isomerization)18 were observed in this reaction. Scheme 5. 1,3-Diene Product Stability
3.
Conclusions
A difficult cross ene-yne metathesis was optimized to set the stage for a fragment coupling to be used in the late stages of a total synthesis of amphidinolide P. Of the alkene reaction partners, a free allylic alcohol performed the best, giving significantly higher yields than simple, unfunctionalized alkenes such as 1-octene. With 3-buten-2-ol, near atom economy could be achieved, with only 1.5 equiv of alkene used. The cross ene-yne metatheses showed moderate E-
7
selectivity, highest in the case of 3-buten-2-ol. A significant solvent effect was found, with toluene outperforming the rest. Higher equivalents of alkene allowed lower reaction temperatures to be used. Though many different precatalysts were screened, the Hoveyda-Grubbs type catalysts performed the best and further catalyst structural changes within this family did not further improve the yields. Longer periods of heating had a deleterious effect on the yield as shown in a control study. In all cases, ca. 25% loss of mass was attributed to a combination of alkyne oligomerization, 1,3-diene instability and other undefined decomposition pathways. Application of these optimized conditions to a key fragment coupling in amphidinolide P total synthesis is underway and will be reported in due course. 4.
Acknowledgement
This work was supported by the NSF (CHE-1012839). We are grateful to Dr. Dick Pederson (Materia) for a gift of the Grubbs and Grubbs-Hoveyda-type complexes used in this study. We would also like to thank Dr. Christophe LeRet (Umicore) for supplying the ruthenium indenylidene precatalysts used. 5.
References
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1
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(a) Dinger, M. B.; Mol, J. C. Organometallics 2003, 22, 1089-1095. Thermal decomposition of Ru=CH2: (b) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004, 126, 7414-7415. (c) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 17160-17161. 16
The shorter reaction times likely minimize the extent of decomposition and limit the formation of methylidene intermediates. 17
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Clark, J. R.; Griffiths, J. R.; Diver, S. T. J. Am. Chem. Soc. 2013, 135, 3327-3330.
9