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DOI: 10.1055/s-0035-1561348
Diels–Alder Reactions of γ-Hydroxybutenolides: Approach to the Himbacine Tricyclic Core
Publication History
Received: 19 November 2015
Accepted after revision: 10 January 2016
Publication Date:
02 February 2016 (online)
Abstract
The Diels–Alder reaction of γ-hydroxybutenolides with dienes gave good yields of cycloadducts under thermal and Lewis acid catalyzed conditions. The application of this methodology to a more complex system was demonstrated by the synthesis of a model system for the tricyclic himbacine core. The stereo- and regioselective Diels–Alder reaction established three of the stereogenic centers, with the fourth stereogenic center secured by diastereoselective alkylation of the cycloadduct.
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Key words
γ-hydroxybutenolide - Diels–Alder reaction - himbacine - Lewis acid catalysis - isomerizationThe Diels–Alder reaction is a powerful method for the stereoselective synthesis of cyclic compounds.[1] Alkenes possessing two electron-withdrawing groups are attractive dienophiles, but selectivity, both stereochemical and regiochemical, becomes an issue for many of these reactive alkenes.[2] In some cases, stereochemical selectivity for the reaction of these dienophiles is markedly improved with the use of Lewis acid catalysis.[2a] [3]
At first inspection, γ-hydroxybutenolides 1 would not appear to be ideal dienophiles since they resemble substituted γ-lactones,[4] which usually require more forcing conditions for the Diels–Alder reaction compared to dienophiles with two electron-withdrawing groups (Scheme [1]). The representation of the ring tautomer belies the reactivity of γ-hydroxybutenolides since there is interconversion to the chain tautomer (taut-1), which is also present in significant quantities at equilibrium.[5] In addition, several reactions of γ-hydroxybutenolides, including the Diels–Alder reaction, suggests that the rate of interconversion between the ring and chain tautomer is relatively fast on the laboratory timescale.[6] The reactive tautomer taut-1 is a substituted acrylic acid, a functional group that possesses some challenges in its use as a dienophile, but several studies have shown that acrylic acids can be employed in stereoselective and regioselective Diels–Alder reactions.[2a] [7]
The reaction of γ-hydroxybutenolides as dienophiles in the Diels–Alder reaction is limited to the reactions of the parent system 1e (R1 = H) with cyclopentadienes[8] and two other special cases.[9] Given the ready availability of γ-hydroxybutenolides 1 from several methods (photooxidation of substituted 2-silylfurans[10a] [b] and 2-furaldehydes,[10c,d] and perchlorate oxidation of 2-substituted furans[10e]), we undertook a systematic study of their potential as dienophiles in the Diels–Alder reaction. In particular, we were interested in developing conditions that would lead to high regio- and stereoselectivity in the Diels–Alder reaction. Further, we were interested in investigating their potential in addressing the challenges of synthesizing the himbacine tricyclic core, a topic of continued interest.[11]
The thermal Diels–Alder reaction of several γ-hydroxybutenolides 1 with cyclopentadiene, 1,3-cyclohexadiene, 2,3-dimethyl-1,3-butadiene, isoprene, and (E)-3-methyl-1-phenyl-1,3-butadiene[12] (Scheme [2]) are summarized in Table [1]. γ-Hydroxybutenolides 1a–e were readily prepared either by the photolysis of the corresponding trimethylsilylfuran, in the case of 1a–c [10a] [b] [acetone (1% H2O); polymer-supported rose bengal; 200 W flood lamps; 0 °C], or the photolysis of the corresponding furaldehyde, in the case of 1d [10d] and 1e [10c] (MeOH; rose bengal; 200 W flood lamps; 0–25 °C; 1e is also available by photolysis of 2-trimethylsilylfuran and is a commercial product) according to literature procedures. They were good dienophiles, reacting with cyclopentadiene to give Diels–Adler adducts in high yields and endo-selectivity at room temperature (Table [1], entries 1, 6, 11, 15, and 18). The less reactive 1,3-cyclohexadiene required more forcing conditions (entries 2, 7, 12, and 19), leading to some isomerization of γ-hydroxybutenolides 1b and 1c to the corresponding (E)-β-acylacrylic acids, which then reacted to give trans-products. 2,3-Dimethyl-1,3-butadiene reacted with 1a–e (entries 3, 8, 13, 16, and 20) without isomerization and in good yields. The use of isoprene as a diene probed the issue of regiochemistry (entries 4, 9, and 14); there was little or no selectivity for the formation of 10, in which the acyl group acted as a ‘para’-directing group relative to the methyl substituent of isoprene. The reaction of 1a, 1b, and 1d with (E)-3-methyl-1-phenyl-1,3-butadiene gave diastereomer 11 with approximately 90–95% regio- and diastereoselectivity, the consequence of endo-selectivity and the acyl group acting as a strong ‘ortho/para’-directing group (entries 5, 10, and 17).
a Yields refer to cycloadducts purified by flash chromatography; diastereomeric ratio (dr) refers to the dr of crude reaction mixtures determined by 1H NMR spectroscopy.
b Purification gave diastereomerically pure products.
The identification of the Diels–Alder products by NMR spectroscopy was complicated by the tautomerization process of the cycloadducts. Unlike the Diels–Alder products of the reaction of (E)-β-acylacrylic acids with dienes in which there is a trans-relationship between the acyl group and carboxylic acid and no significant formation of the corresponding ring tautomer, the ring tautomer for the Diels–Alder products of γ-hydroxybutenolides 1 with dienes was evident, particularly in the case of bicyclic compounds and cycloadducts of 1e. For bicyclic compounds 3 and 4, the ring tautomers 5/7 and 6/8 were the major tautomeric species. For cycloadducts 9–11 derived from 1a–d, however, there was very little evidence for significant amounts of the ring tautomer. In order to reduce the complexity of the NMR spectra, DABCO was added to catalyze the tautomerization process, leading to fast exchange and averaged spectra of the chain tautomer and the two diastereomeric ring tautomers. We have previously shown that the amine-catalyzed tautomerization of γ-hydroxybutenolides facilitates the identification of epimeric γ-hydroxybutenolides.[13] [14] The assignment of the regiochemistry for the isoprene cycloadducts was determined by the isomerization (NaOH in MeOH) of 10a to the known trans-isomer of 10a;[2a] [7a] the assignment of regiochemistry for 10b and 10c was based on the similarity of common features observed in the 1H and 13C NMR spectra for these compounds. The assignment of regiochemistry for cycloadducts 11 was based on a strong NOE enhancement observed for the ortho-protons of the phenyl ring when the alkenyl proton at δ = 5.4 was irradiated. The magnitudes for the coupling constants observed for 11 are best explained by a conformation in which the phenyl and carboxylic acid groups occupy a pseudo-equatorial position and the acyl group is pseudo-axial.
In order to increase the reaction rate and improve the regio- and stereoselectivity for the Diels–Alder reactions of 1, we looked at a variety of Lewis acid catalyzed conditions, with some of the results summarized in Table [2]. The two catalyst systems that worked best for the catalyzed Diels–Alder reaction of 1 were DIPEA/SnCl4 and Sc(OTf)3. In our previous studies of the Diels–Alder reactions of (E)-β-acylacrylic acids,[2a] we found that deprotonation of the acrylic acid moiety by DIPEA and addition of two equivalents of SnCl4 led to an enhanced directing effect by the acyl group and a faster reaction. The use of the DIPEA/SnCl4 protocol greatly enhanced the rate of reaction, which alleviated the isomerization issues that occurred in the thermal reactions of 1a–c with 1,3-cyclohexadiene (Table [2], entries 1, 3, and 7). The use of the DIPEA/SnCl4 protocol greatly enhanced reaction rate for the reaction of 1b and 1c with 2,3-dimethyl-1,3-butadiene without isomerization (entries 5 and 9). Unfortunately, there was no enhancement in the regioselectivity and lower yields in the Sn-catalyzed reaction of 1a–c with isoprene (data not shown). Sc(OTf)3 was an effective catalyst, with faster reaction rates for the reaction of 1b with 1,3-cyclohexadiene and no evidence for isomerization (entry 4). We saw an enhancement of the regioselectivity for the reaction of isoprene with 1a–c (entries 2, 6, and 10), although longer reaction times led to lower yields due to unidentified side reactions. The cycloadducts of 1c, which have a phenyl group, decomposed to complex mixtures in the presence of Sc(OTf)3 (entries 8 and 10), so its usefulness was severely limited for the reactions of 1c. Low yields of cycloadducts 11 were obtained for the reaction of 1a–d with (E)-3-methyl-1-phenyl-1,3-butadiene catalyzed by Sc(OTf)3 or the DIPEA/SnCl4 protocol, also presumably due to the side reactions caused by the presence of the phenyl ring.
a All reactions were performed in CH2Cl2 for 1 h; DIPEA/SnCl4 reactions were performed at 0 °C and Sc(OTf)3 reactions at 22 °C.
b Yields refer to cycloadducts purified by flash chromatography; diastereomeric ratio (dr) refers to the dr of crude reaction mixtures determined by 1H NMR spectroscopy.
In exploring the Lewis acid catalyzed Diels–Alder reaction of 1, we uncovered the tendency for some of the cycloadducts, especially the bicyclic compounds 3 and 4, to undergo isomerization to give the acyl group in the exo-position. Several studies have noted the tendency for cis-di-endo cycloadducts of cyclopentadiene to isomerize to the more stable trans-compounds.[15] When NaOH is added to methanolic solutions of 3a–c and 4a–c, there is epimerization at the α-carbon to the acyl group to give 12a–c (57–88% yield) and 13a–c (51–86% yield), respectively (Scheme [3]). The epimerization of nonbicyclic compounds (e.g., 9b) occurs more slowly (1 h vs 24 h) and in lower yields under similar reaction conditions. A simple one-pot procedure was developed, in which the Diels–Alder reaction was run in methanol and the base is added directly to the crude cycloadduct, for the synthesis of 12a–c from 1a–c (78–81% yield).[16] [17] [18] [19] [20] Amine bases such as DIPEA and triethylamine also gave isomerization but at slower rates. With the Diels–Alder reaction of γ-hydroxybutenolides and β-acylacrylic acids, and this isomerization reaction, three of the possible four diastereomers of these bicyclic compounds are readily prepared.
In considering the application of the Diels–Alder reaction of γ-hydroxybutenolides to the synthesis of biologically important molecules, we immediately recognized compounds such as himbacine and related pharmaceuticals (e.g., vorapaxar) as potential targets (Figure [1]).[21] [22] [23] [24] [25] [26] [27] [28] Himbacine, a powerful muscarinic receptor antagonist that was proposed as a potential candidate for treating Alzheimer’s disease, and vorapaxar,[22] a thrombin receptor antagonist recently approved by the FDA for reducing the risk of cardiovascular events, have a tricyclic core attainable using the methodology described herein. We envisioned a regio- and diastereoselective Diels–Alder reaction establishing the stereogenic centers of the A/B ring and C-4, with the stereogenic center at C-3 established by the reduction or alkylation of the Diels–Alder products. Employing the Diels–Alder reaction in the synthesis of himbacine and their derivatives has been a common and highly successful strategy, with most approaches using an intramolecular Diels–Alder reaction to prepare the tricyclic core,[23–26] although there are reports using an intermolecular Diels–Alder reaction.[27] [28]
For our model studies, we prepared diene 14 in three steps from cyclohexanone (see Supporting Information), which incorporated a simple isobutyl group that was a stand-in for the more complicated substituents normally found at C-4 in himbacine-related compounds. The Diels–Alder reaction of 1a and 1e with diene 14 gave Diels–Alder products 15a and 15b, respectively, in good yields (Scheme [4]). In both cases, the dr of the crude products was >90:10, which upon purification gave cycloadducts 15a and 15b free of diastereomeric impurities. The selective formation of 15a and 15b reflects an endo transition state as well as the formyl or acyl group acting as a strong ‘ortho’-directing group.
With access to both 15a and 15b, the stage was set for the establishment of the C-3 stereogenic center of the lactone ring. The reduction of cyclic γ-keto acids developed by Rovis[29] and others[30] for the formation of the C-3 stereogenic center was clearly relevant and served as a guide for our studies. The γ-keto acids of these studies, most lacking a substituent at the stereogenic center of ‘C-4’, gave anti-products (corresponding to compound 16a) with Ph2MeSiH/ CF3CO2H, and syn-products (corresponding to compound 16b) with hydride reagents. Our studies with the additional stereogenic center at ‘C-4’ gave the opposite stereochemical results. Reduction of 15a with typical hydride reagents [NaBH4, DIBAL, Zn(BH4)2] gave good yields and high diastereoselectivity (>95:5) of 16b (Scheme [4]). Employing Rovis’ protocol using silanes (Et3SiH, Ph2MeSiH) with CF3CO2H, 16a was obtained with modest stereoselectivity but in low yields. Our results clearly show the importance of the ‘C-4’ stereogenic center in determining the stereochemical outcome for the reduction of cyclic γ-keto acids.[29] The alkylation of 15b was then explored as an alternative approach to the desired lactone 16a. The addition of MeLi in Et2O gave a 78% yield of the lactone products but with poor diastereoselectivity (77:23 dr; 16a:16b). Excellent diastereoselectivity (>95:5) for the desired lactone was achieved using MeMgBr, Me2CuLi, and MeTi(O-iPr)3, with the highest yields achieved using the in situ-generated titanium reagent (93% yield). Recrystallization of 16a from hexanes gave crystals suitable for X-ray diffraction studies, which conclusively established the stereochemical assignment of 16a and 16b (Figure [2]).
This study establishes γ-hydroxybutenolides as excellent dienophiles in the Diels–Alder reaction. Reactive dienes gave good yields of cycloadducts under thermal conditions, although isomerization of the γ-hydroxybutenolides was evident with less reactive dienes such as 1,3-cyclohexadiene and isoprene. In some cases, this issue was overcome by employing Lewis acids, which also lead to enhanced stereo- and regioselectivity. The tendency for γ-hydroxybutenolides to isomerize to the more stable (E)-acylacrylic acids is a problem that still needs to be addressed in the case for less reactive dienes. These cycloadducts have the potential for transformation to stereochemically defined γ-lactones as evidenced by the stereoselective reduction of 15a and the alkylation of 15b. Even though the completion of the synthesis of the tricyclic core of himbacine awaits the development of a stereoselective trans-reduction of the alkenyl moiety, the potential for the synthesis of himbacine derivatives has been demonstrated. The development of an enantioselective version to give scalemic cycloadducts will be the next challenge. In conclusion, this study demonstrates some of the potential of γ-hydroxybutenolides as dienophiles in the Diels–Alder reaction, which promises to be an important contributor to the synthesis of γ-lactones and related compounds.
All reactions were carried out under argon. All glassware was dried in the oven (110 °C) before use. Yields refer to isolated compounds that are greater than >95% pure as determined by 1H and 13C NMR spectroscopy. IR spectra were obtained on an FT-IR spectrophotometer. The 1H and 13C NMR were recorded at 400 MHz and 100 MHz, respectively. All chemical shifts in the 1H NMR are reported in ppm relative to TMS (δ = 0.00) or CHCl3 (δ = 7.26) and in the 13C NMR are reported in ppm relative to CDCl3 (δ = 77.16). Flash chromatography was performed on 60 Å silica gel (40–75 μm). CH2Cl2 and toluene were dried over molecular sieves. Single crystals of 16a were prepared by recrystallization from hexanes. X-ray data were acquired at 173 K on a Bruker Smart Apex CCD diffractometer employing graphite monochromated MoKα radiation (δ = 0.71073 Å). The Bruker Apex2 suite of program[31] was used to process the data and the Bruker SAINT software package[32] was used to integrate the frames with a narrow-frame algorithm. The multi-scan method (SADABS)[33] was used to correct the data for absorption effects. The Bruker SHELXTL software package[34] was used to perform structure solution by direct methods, and refinement by full-matrix least-squares on F2. All non-hydrogen atoms were refined anisotropically with suggested weighting factors and the hydrogens were calculated on a riding model. All cif files were validated with the checkCIF/Platon facility of IUCr that was accessed with the software program enCIFer. High-resolution mass spectra were obtained using a direct analysis in real time – time-of-flight (DART-TOF) mass spectrometer.
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Thermal Diels–Alder Reaction of 1 with Dienes; General Procedure (Table [1])
A solution of 1 (1.0–1.3 mmol) and respective diene (3–5 equiv) in CH2Cl2 (5 mL) or toluene (5 mL) was stirred for the time and temperature specified in Table [1]. The reactions employing toluene at 110 °C were done in a sealed tube. The volatiles were removed on the rotary evaporator and the crude product was purified by flash chromatography (silica gel; hexanes → 50% EtOAc in hexanes) to give 3, 4, 9, 10, or 11. For convenience, the Diels–Alder products are listed as the chain tautomer even when the ring tautomers are the major species. NOE experiments established the major ring tautomers of 3a and 4a as 7a and 8a, respectively; the assignment of the ring tautomers of 3b–d, 4b, and 4c was based on chemical shift arguments of the alkenyl protons of these compounds compared to the alkenyl protons of 3a and 4a.
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(1R*,2S*,3R*,4S*)-3-Acetylbicyclo[2.2.1]hept-5-ene-2-carboxylic Acid (3a)[16]
White solid; yield: 0.205 g [99% based on 0.131 g (1.15 mmol) of 1a]; >96:4 dr; 3a:5a:7a = 40:15:45; mp 76–77.5 °C.
1H NMR (400 MHz, CDCl3; 8% DABCO): δ = 6.99 (br s, 1 H), 6.23 (dd, J = 2.9, 5.5 Hz, 1 H), 6.20 (dd, J = 2.9, 5.5 Hz, 1 H), 3.39 (dd, J = 4.0, 9.2 Hz, 1 H), 3.22 (br s, 1 H), 3.17 (dd, J = 3.6, 9.2 Hz, 1 H), 3.12 (br s, 1 H), 1.83 (s, 3 H), 1.54 (br d, J = 8.4 Hz, 1 H), 1.39 (br d, J = 8.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3; 8% DABCO): δ = 177.3, 135.7, 134.4, 54.0, 50.7, 49.2, 46.1, 45.6, 44.4, 28.4.
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(1R*,2S*,3R*,4S*)-3-Acetylbicyclo[2.2.2]oct-5-ene-2-carboxylic Acid (4a)
Off-white solid; yield: 0.186 g [74% based on 0.147 g (1.29 mmol) of 1a]; >96:4 dr; 6a:8a = 30:70; mp 126–127.5 °C.
IR (CH2Cl2): 3567, 1771 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.38 (m, 0.3 H), 6.31 (m, 0.3 H), 6.25–6.20 (m, 1.4 H) 3.75 (br s, 0.7 H), 3.24 (br s, 0.3 H), 3.18–3.08 (m, 1.7 H), 3.02 (dd, J = 3.7, 9.9 Hz, 0.3 H), 2.92 (m, 0.3 H), 2.79 (m, 0.7 H), 2.56 (dd, J = 2.6, 9.9 Hz, 0.3 H), 2.51 (dd, J = 2.4, 8.6 Hz, 0.7 H), 1.592 (s, 2.1 H), 1.585 (s, 0.9 H), 1.56–1.49 (m, 12 H), 1.33–1.24 (m, 2 H).
13C NMR (100 MHz, CDCl3; 30% DABCO): δ = 177.9, 133.3, 132.5, 114.6 (br), 49.6, 47.5, 32.0, 30.7, 26.5, 25.0, 22.7.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C11H15O3: 195.1021; found: 195.1023.
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(1S*,6R*)-6-Acetyl-3,4-dimethylcyclohex-3-enecarboxylic Acid (9a)
White solid; yield: 0.570 g [94% based on 0.352 g (3.08 mmol) of 1a in 15 mL of CH2Cl2]; mp 110.5–113 °C.
IR (CH2Cl2): 3300–2700, 1746, 1709 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.04 (dt, J = 3.6, 6.2 Hz, 1 H), 2.84 (dt, J = 3.6, 6.8 Hz, 1 H), 2.51–2.22 (m, 4 H), 2.19 (s, 3 H), 1.64 (s, 3 H), 1.62 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 208.3, 179.0, 123.7, 122.5, 46.9, 39.1, 31.1, 30.7, 26.8, 18.2, 18.0.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C11H17O3: 197.1178; found: 197.1179.
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(1S*,6R*)-6-Acetyl-3-methylcyclohex-3-enecarboxylic Acid (10a)
Pale yellow oil; yield: 0.214 g [93% based on 0.144 g (1.26 mmol) of 1a]; 10a:iso-10a (15% trans-isomers) = 70:30.
IR (CH2Cl2): 3400–2800, 1746, 1709 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.95 (br s, 1 H), 5.39 (br s, 1 H), 3.04 (m, 1 H), 2.85 (m, 1 H), 2.54–2.20 (m, 4 H), 2.17 (s, 3 H), 1.65 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 209.3, 179.9, 133.3, 118.6, 47.0, 39.9, 30.6, 27.8, 25.8, 23.4.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C10H15O3: 183.1021; found: 183.1023.
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(1R*,2R*,3S*)-2-Acetyl-5-methyl-3-phenylcyclohex-4-ene-1-carboxylic Acid (11a)
White solid; yield: 0.139 g [51% based on 0.120 g (1.05 mmol) of 1a]; 11a:iso-11a = 89:11 (crude); mp 140 °C (dec.).
IR (CH2Cl2): 3300–2700, 1744, 1711, 1603 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.32 (br t, J = 7.1 Hz, 2 H), 7.24 (m, 1 H), 7.17 (d, J = 7.0 Hz, 2 H), 5.42 (br s, 1 H), 3.85 (br s, 1 H), 3.60 (dd, J = 3.7, 6.6 Hz, 1 H), 3.01 (m, 1 H), 2.86 (m, 1 H), 2.33 (dd, J = 6.2, 17.2 Hz, 1 H), 1.84 (s, 3 H), 1.39 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 210.9, 180.3, 142.0, 135.6, 128.8, 128.4, 127.2, 120.7, 49.9, 44.5, 43.2, 33.7, 29.8, 23.6.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C16H19O3: 259.1334; found: 259.1337.
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(1R*,2S*,3R*,4S*)-3-Hexanoylbicyclo[2.2.1]hept-5-ene-2-carboxylic Acid (3b)
White solid; yield: 0.263 g [90% based on 0.211 g (1.24 mmol) of 1b]; >96:4 dr; 3b:5b:7b = 61:18:21; mp 69–71 °C.[17]
IR (CH2Cl2): 3536, 1765, 1712 cm–1.
1H NMR (400 MHz, CDCl3; 8 mol% DABCO): δ = 7.44 (br s, 1 H), 6.26 (dd, J = 2.9, 5.5 Hz, 1 H), 6.18 (dd, J = 2.9, 5.5 Hz, 1 H), 3.32 (dd, J = 3.6, 9.2 Hz, 1 H), 3.26 (br d, J = 8.8 Hz, 1 H), 3.20 (br s, 1 H), 3.12 (br s, 1 H), 2.16 (br s, 2 H), 1.55–1.23 (m, 8 H), 0.89 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3; 30 mol% DABCO): δ = 177.0, 135.3, 134.6, 54.1, 49.8, 49.7, 46.4, 46.2, 42.8, 31.7, 23.5, 22.7, 14.1.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C14H21O3: 237.1491; found: 237.1495.
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(1R*,2S*,3R*,4S*)-3-Hexanoylbicyclo[2.2.2]oct-5-ene-2-carboxylic Acid (4b)
White solid; yield: 0.245 g [79% based on 0.211 g (1.24 mmol) of 1b]; 92:8 dr; 6b:8b (~5% trans-isomers) = 59:41; mp 105–107 °C.
IR (CH2Cl2): 3570, 1768 cm–1.
1H NMR (400 MHz, CDCl3; 12 mol% DABCO): δ = 6.32–6.24 (m, 2 H), 4.12 (br s, 1 H), 3.11 (br s, 1 H), 3.01 (dd, J = 3.7, 9.5 Hz, 1 H), 2.81 (br s, 1 H), 2.55 (br d, J = 9.5 Hz, 1 H), 1.84–1.74 (m, 2 H), 1.55–1.24 (m, 10 H), 0.90 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3; 12 mol% DABCO): δ = 177.4, 133.5, 132.9, 116.0, 48.7, 47.8, 40.4, 32.0, 31.9, 30.4, 24.9, 22.9, 22.8, 22.7, 14.1.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C15H23O3: 251.1647; found: 251.1651.
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(1S*,6R*)-6-Hexanoyl-3,4-dimethylcyclohex-3-enecarboxylic Acid (9b)
White solid; yield: 0.231 g [74% based on 0.211 g (1.24 mmol) of 1b]; mp 75–77 °C.
IR (CH2Cl2): 3300–2700, 1746, 1706 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.99 (dt, J = 3.5, 6.6 Hz, 1 H), 2.87 (dt, J = 3.7, 6.6 Hz, 1 H), 2.54–2.21 (m, 4 H), 2.46 (t, J = 7.3 Hz, 2 H), 1.64 (s, 3 H), 1.62 (s, 3 H), 1.56 (pent, J = 7.4 Hz, 2 H), 1.34–1.20 (m, 4 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 211.5, 179.9, 124.9, 123.5, 47.4, 40.1, 40.0, 32.1, 31.8, 31.5, 23.4, 22.6, 19.2, 19.0, 14.1.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C15H25O3: 253.1804; found: 253.1809.
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(1S*,6R*)-6-Hexanoyl-3-methylcyclohex-3-enecarboxylic Acid (10b)
Oil; yield: 0.273 g [93% based on 0.211 g (1.24 mmol) of 1b]; 10b:iso-10b (20% trans-isomers) = 71:29.
IR (CH2Cl2): 1746, 1707 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.37 (m, 1 H), 3.00 (m, 1 H), 2.91 (m, 1 H), 2.60–2.20 (m, 5 H), 1.67 (s, 3 H), 1.61–1.52 (m, 3 H), 1.35–1.20 (m, 5 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 211.4, 179.9, 133.4, 119.08, 46.4, 39.9, 31.4, 30.5, 25.8, 23.41, 23.38, 22.6, 14.0.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C14H23O3: 239.1647; found: 239.1696.
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(1R*,2R*,3S*)-2-Hexanoyl-5-methyl-3-phenylcyclohex-4-ene-1-carboxylic Acid (11b)
White solid; yield: 0.183 g [65% based on 0.153 g (0.90 mmol) of 1b]; >96:4 dr; mp 160 °C (dec).
IR (CH2Cl2): 3300–2700, 1745, 1711 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.29 (br t, J = 7.1 Hz, 2 H), 7.23 (m, 1 H), 7.14 (m, 2 H), 5.41 (br s, 1 H), 3.82 (br s, 1 H), 3.52 (dd, J = 3.6, 7.0 Hz, 1 H), 3.01 (m, 1 H), 2.87 (m, 1 H), 2.33 (dd, J = 5.9, 17.2 Hz, 1 H), 2.06 (m, 1 H), 1.83 (s, 3 H), 1.25–0.78 (m, 7 H), 0.74 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 212.4, 180.3, 142.1, 135.6, 128.7, 128.4, 127.1, 120.8, 49.6, 46.3, 44.7, 43.2, 31.0, 30.0, 23.6, 22.4, 22.2, 14.0.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C20H27O3: 315.1960; found: 315.1975.
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(1R*,2S*,3R*,4S*)-3-(3-Phenylpropanoyl)[2.2.1]hept-5-ene-2-carboxylic Acid (3c)
White solid; yield: 0.257 g [83% based on 0.234 g (1.15 mmol) of 1c]; >96:4 dr; 3c:5c:7c = 62:18:20; mp 84–86 °C.
IR (CH2Cl2): 3565, 1768, 1714 cm–1.
1H NMR (400 MHz, CDCl3; 20 mol% DABCO): δ = 7.92 (br s, 1 H), 7.27 (m, 2 H), 7.21–7.16 (m, 3 H), 6.23 (dd, J = 2.8, 5.3 Hz, 1 H), 6.13 (dd, J = 2.9, 5.5 Hz, 1 H), 3.34 (dd, J = 3.7, 9.5 Hz, 1 H), 3.24 (dd, J = 3.3, 9.5 Hz, 1 H), 3.18 (br s, 1 H), 3.07 (br s, 1 H), 2.93–2.76 (m, 2 H), 2.62–2.47 (m, 2 H), 1.47 (d, J = 8.4 Hz, 1 H), 1.33 (d, J = 8.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3; 20 mol% DABCO): δ = 177.3, 141.4, 135.3, 134.6, 128.6, 128.4, 126.1, 54.3, 49.8, 49.4, 46.4, 46.1, 44.2, 29.9.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C17H19O3: 271.1334; found: 271.1343.
#
(1R*,2S*,3R*,4S*)-3-(3-Phenylpropanoyl)[2.2.2]oct-5-ene-2-carboxylic Acid (4c)
White solid; yield: 0.244 g [78% based on 0.224 g (1.10 mmol) of 1c]; 92:8 dr; 6c:8c (~5% trans-isomers) = 59:41; mp 115.5–118 °C.
IR (CH2Cl2): 3564, 1769 cm–1.
1H NMR (400 MHz, CDCl3; 30 mol% DABCO): δ = 7.32–7.17 (m, 5 H), 6.31–6.25 (m, 2 H). 4.14 (br s, 1 H), 3.11 (m, 1 H), 3.05 (dd, J = 3.7, 9.5 Hz, 1 H), 2.84–2.78 (m, 3 H), 2.59 (dd, J = 2.2, 9.5 Hz, 1 H), 2.23–2.10 (m, 2 H), 1.57–1.45 (m, 2 H), 1.36 (m, 2 H).
13C NMR (100 MHz, CDCl3; 30 mol% DABCO): δ = 177.4, 141.2, 133.6, 132.8, 128.7, 128.5, 126.3, 120.9, 49.5, 48.0, 42.2, 32.2, 30.5, 29.6, 24.9, 23.0.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C18H21O3: 285.1491; found: 285.1497.
#
(1S*,6R*)-3,4-Dimethyl-6-(3-phenylpropanoyl)cyclohex-3-enecarboxylic Acid (9c)
White solid; yield: 0.286 g [85% based on 0.241 g (1.18 mmol) of 1c]; mp 102–104 °C.
IR (CH2Cl2): 3300–2700, 1746, 1708 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.27 (m, 2 H), 7.21–7.16 (m, 3 H), 3.01 (m, 1 H), 2.93–2.78 (m, 5 H), 2.50 (dd, J = 5.2, 17.5 Hz, 1 H), 2.42–2.12 (m, 3 H), 1.61 (br s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 210.2, 179.8, 141.4, 128.6, 128.5, 126.2, 124.9, 123.4, 47.6, 41.8, 40.1, 32.1, 31.7, 29.7, 19.2, 19.0.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C18H23O3: 287.1647; found: 287.1658.
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(1S*,6R*)-3-Methyl-6-(3-phenylpropanoyl)cyclohex-3-enecarboxylic Acid (10c)
White solid; yield: 0.260 g [87% based on 0.225 g (1.10 mmol) of 1c]; 10c:iso-10c (20% trans-isomers) = 55:45; mp 64–72 °C.
IR (CH2Cl2): 1745, 1708 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.16 (m, 5 H), 5.33 (br s, 1 H), 3.08–2.78 (m, 6 H), 2.50–2.20 (m, 4 H), 1.66 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 210.2, 179.8, 141.3, 133.4, 128.5, 128.4, 126.1, 118.5, 46.5, 41.7, 39.9, 30.5, 29.7, 25.6, 23.5.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C17H21O3: 273.1491; found: 273.1491.
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(1R*,2S*,3R*,4S*)-3-(2-Acetoxyacetyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic Acid (3d)
Off-white solid; yield: 0.233 g [81% based on 0.206 (1.21 mmol) of 1d]; 3d:5d:7d = 4:53:43; mp 66–70 °C.
IR (CH2Cl2): 3552, 1775, 1751 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.37 (dd, J = 2.9, 5.5 Hz, 0.55 H), 6.28 (dd, J = 3.3, 5.9 Hz, 0.45 H), 6.22 (dd, J = 2.9, 5.5 Hz, 0.55 H), 6.15 (dd, J = 2.8, 5.6 Hz, 0.45 H), 4.28 (d, J = 12.1 Hz, 0.45 H), 4.25 (d, J = 12.1 Hz, 0.55 H), 4.13 (d, J = 11.7 Hz, 0.45 H), 4.04 (d, J = 11.7 Hz, 0.55 H), 3.88 (br s, 0.45 H), 3.63 (br s, 0.55 H), 3.55 (dd, J = 5.0, 8.6 Hz, 0.45 H), 3.43 (dd, J = 5.0, 8.9 Hz, 0.55 H), 3.32 (m, 1 H), 3.18 (m, 1 H), 3.03 (m, 1 H), 2.16 (s, 1.35 H), 2.12 (s, 1.65 H), 1.71–1.61 (m, 1 H), 1.49-1.43 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 177.0, 175.6, 170.82, 170.76, 136.9, 136.7, 134.1, 133.7, 104.4, 103.8, 69.0, 65.8, 53.2, 52.0, 50.6, 49.9, 47.9, 47.6, 45.8, 45.0, 44.8, 43.9, 20.83, 20.76.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C12H15O5: 239.0919; found: 239.0921.
#
(1S*,6R*)-6-(2-Acetoxyacetyl)-3,4-dimethylcyclohex-3-enecarboxylic Acid (9d)
Tan solid; yield: 0.211 g [67% based on 0.206 g (1.24 mmol) of 1d]; 9d:9d-ring tautomers = 93:7; mp 102–103.5 °C.
IR (CH2Cl2): 1783, 1750, 1707 cm–1.
1H NMR (400 MHz, CDCl3): δ = 11.05 (br s, 1 H), 4.82 (s, 2 H), 3.06 (m, 1 H), 2.98 (m, 1 H), 2.51 (dd, J = 5.0, 17.4 Hz, 1 H), 2.36–2.27 (m, 3 H), 2.15 (s, 3 H), 1.64 (br s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 203.7, 179.5, 170.5, 125.0, 122.9, 66.9, 44.3, 40.1, 31.8, 30.7, 20.5, 19.0, 18.9.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C13H19O5: 255.1232; found: 255.1239.
#
(1R*,2R*,3S*)-2-(2-Acetoxyacetyl)-5-methyl-3-phenylcyclohex-4-ene-1-carboxylic Acid (11d)
White solid; yield: 0.174 g [55% based on 0.172 g (1.01 mmol) of 1d]; 95:5 dr; mp 144–148 °C.
IR (CH2Cl2): 1745, 1727, 1702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.33 (t, J = 7.3 Hz, 2 H), 7.26 (m, 1 H), 7.14 (d, J = 7.7 Hz, 2 H), 5.43 (br s, 1 H), 4.46 (d, J = 17.2 Hz, 1 H), 3.85 (br s, 1 H), 3.50 (m, 1 H), 3.16 (d, J = 16.8 Hz, 1 H), 3.10 (m, 1 H), 2.81 (m, 1 H), 2.39 (dd, J = 6.2, 17.6 Hz, 1 H), 1.99 (s, 3 H), 1.84 (br s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 204.5, 179.0, 169.9, 141.3, 136.0, 129.0, 128.8, 128.2, 127.5, 127.1, 120.5, 69.9, 46.3, 44.5, 43.1, 30.0, 23.5, 20.5.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C18H21O5: 317.1389; found: 317.1394.
#
(1R*,2S*,3R*,4S*)-3-Formylbicyclo[2.2.1]hept-5-ene-2-carboxylic Acid (3e)[8]
White solid; yield: 0.154 g [77% based on 0.120 g (1.00 mmol) of 1e]; >96:4 dr; 7e:5e = >98:2; mp 99–100 C (hexanes).
1H and 13C NMR spectra match with those described in the literature.[8]
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(1R*,2S*,3R*,4S*)-3-Formylbicyclo[2.2.2]oct-5-ene-2-carboxylic Acid (4e)
White solid; yield: 0.076 g [42% based on 1.00 g (1.00 mmol) of 1e]; >96:4 dr; 8e:6e = 95:5; mp 147–149 °C.
IR (CH2Cl2): 3578, 1773 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.29 (m, 1 H), 6.24 (m, 1 H), 5.34 (dd, J = 1.8, 4.0 Hz, 1 H), 3.61 (d, J = 4.4 Hz, 1 H), 3.08 (m, 1 H), 2.95 (dd, J = 3.7, 9.5 Hz, 1 H), 2.86 (m, 1 H), 2.50 (dt, J = 9.5, 2.4 Hz, 1 H), 1.58–1.50 (m, 2 H), 1.36–1.25 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 179.0, 134.1, 132.7, 102.7, 47.2, 45.9, 31.9, 31.8, 23.6, 23.3.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C10H13O3: 181.0865; found: 181.0861.
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(1S,6R)-6-Formyl-3,4-dimethylcyclohex-3-enecarboxylic Acid (9e)[35]
Colorless oil; yield: 0.146 g [79% based on 0.102 g (1.02 mmol) of 1e]; >96% ring tautomer.
IR (CH2Cl2): 3577, 1778 cm–1.
1H NMR (400 MHz, CDCl3; 4 mol% DABCO): δ = 6.34 (br s, 1 H), 4.15 (br s, 1 H), 3.06 (dt, J = 7.5, 3.9 Hz, 1 H), 2.63 (q, J = 7.2 Hz, 1 H), 2.39 (m, 1 H), 2.29–2.15 (m, 2 H), 1.96 (dd, J = 16.9, 6.6 Hz, 1 H), 1.65 (s, 6 H).
13C NMR (100 MHz, CDCl3; 4 mol% DABCO): δ = 178.9, 125.0, 123.9, 44.6, 41.1, 37.7, 30.1, 29.2, 19.4, 19.1 (hemi-acetal carbon was not observed).
HRMS (DART-TOF): m/z [M + 1]+ calcd for C10H15O3: 183.1021; found: 183.1023.
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SnCl4-Promoted Diels–Alder Reaction of 1 with Dienes; General Procedure (Table [2])
A solution of 1a, 1b, or 1c (1.20 mmol) with the respective diene [3–5 equiv; 1.3 equiv in the case of (E)-3-methyl-1-phenyl-1,3-butadiene] in CH2Cl2 (5 mL) was cooled to 0 °C. DIPEA (0.22 mL, 1.26 mmol) and SnCl4 (0.29 mL, 2.5 mmol) were added dropwise and the reaction mixture was stirred for the 1 h at 0 °C. The mixture was quenched with H2O (10 mL), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were washed with H2O (50 mL) and brine (50 mL), and dried over Na2SO4. The volatiles were removed on the rotary evaporator and the crude product was purified by flash chromatography (silica gel; hexanes → 50% EtOAc in hexanes). The yields and dr are summarized in Table [2].
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Sc(OTf)3-Catalyzed Diels–Alder Reaction of 1 with Dienes; General Procedure (Table [2])
To a solution of 1 (1.2 mmol) and the respective diene (3–5 equiv) in CH2Cl2 (5 mL) was added Sc(OTf)3 (0.12 g, 0.24 mmol) and the reaction mixture was stirred for the time and temperature specified in Table [2]. The mixture was washed with H2O (2 × 20 mL), the volatiles were removed on the rotary evaporator, and the crude product was purified by flash chromatography (silica gel; hexanes → 50% EtOAc in hexanes). The yields and dr are summarized in Table [2].
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Isomerization of Diels–Alder Products 3a–c and 4a–c; General Procedure
To a solution of 3a–c or 4a–c (0.5–1.1 mmol) in MeOH (1 mL) was added NaOH (4–6 equiv) in MeOH (1.0 M). The reaction mixture was stirred for 2 h and then quenched with 1.0 M aq HCl (4–6 mL). Brine (10 mL) and EtOAc (10 mL) were added and the organic phase was separated. The aqueous phase was extracted with EtOAc (2 × 10 mL), the combined organic phases were washed with brine (10 mL), and dried over Na2SO4. The crude product was purified by flash chromatography (silica gel; hexanes → 50% EtOAc in hexanes) to give 12a–c and 13a–c.
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(1R*,2S*,3S*,4S*)-3-Acetylbicyclo[2.2.1]hept-5-ene-2-carboxylic Acid (12a)[2a]
White solid; yield: 0.085 g [57% based on 0.149 g (0.083 mmol) of 3a]; mp 103–105 °C.
1H and 13C NMR spectra match with those described in the literature.[2a]
#
(1R*,2S*,3S*,4S*)-3-Hexanoylbicyclo[2.2.1]hept-5-ene-2-carboxylic Acid (12b)
White solid; yield: 0.221 g [88% based on 0.250 (1.06 mmol) of 3b]; mp 92–94 °C.
IR (CH2Cl2): 3300–2750, 1744, 1703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.31 (dd, J = 2.9, 5.5 Hz, 1 H), 6.17 (dd, J = 2.7, 5.7 Hz, 1 H), 3.46 (t, J = 4.2 Hz, 1 H), 3.27 (br s, 1 H), 3.01 (br s, 1 H), 2.77 (m, 1 H), 2.64–2.48 (m, 2 H), 1.64–1.25 (m, 8 H), 0.89 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 210.8, 179.9, 137.8, 135.9, 54.6, 47.0, 46.7, 46.6, 45.4, 42.6, 31.5, 23.7, 22.6, 14.0.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C14H21O3: 237.1491; found: 237.1497.
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(1R*,2S*,3S*,4S*)-3-(3-Phenylpropanoyl)[2.2.1]hept-5-ene-2-carboxylic Acid (12c)
Off-white solid; yield: 0.202 g [74% based on 0.271 g (1.00 mmol) of 3c]; mp 60.5–62 °C.
IR (CH2Cl2): 3300–2700, 1744, 1706 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.28 (m, 2 H), 7.19 (m, 3 H), 6.26 (dd, J = 3.3, 5.5 Hz, 1 H), 6.15 (dd, J = 2.9, 5.5 Hz, 1 H), 3.42 (t, J = 4.0 Hz, 1 H), 3.25 (br s, 1 H), 2.97–2.82 (m, 5 H), 2.75 (dd, J = 1.1, 4.4 Hz, 1 H), 1.47 (br d, J = 8.8 Hz, 1 H), 1.36 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 209.6, 179.4, 141.1, 137.8, 135.9, 128.6, 128.5, 126.3, 54.8, 46.8 (2 C), 46.5, 45.4, 44.2, 30.1.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C17H19O3: 271.1334; found: 271.1343.
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(1R*,2S*,3S*,4S*)-3-Acetylbicyclo[2.2.2]oct-5-ene-2-carboxylic Acid (13a)[2a]
White solid; yield: 0.089 g [86% based on 0.104 g (0.53 mmol) of 4a]; mp 104–106 °C.
1H and 13C NMR spectra match with those described in the literature.[2a]
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(1R*,2S*,3S*,4S*)-3-Hexanoylbicyclo[2.2.2]oct-5-ene-2-carboxylic Acid (13b)
Pale yellow oil; yield: 0.0137 g [81% based on 0.169 g (0.67 mmol) of 4b].
IR (CH2Cl2): 3400–2700, 1741, 1707 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.39 (t, J = 7.1 Hz, 1 H), 6.25 (br t, J = 7.1 Hz, 1 H), 3.30 (dd, J = 2.1, 5.5 Hz, 1 H), 3.06 (m, 1 H), 2.93–2.87 (m, 2 H), 2.58–2.42 (m, 2 H), 1.64–1.56 (m, 3 H), 1.37–1.22 (m, 6 H), 1.07 (m, 1 H), 0.87 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 210.4, 180.7, 134.6, 133.2, 53.7, 43.4, 41.4, 32.4, 32.2, 31.5, 24.3, 23.7, 22.6, 20.1, 14.1.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C15H23O3: 251.1647; found: 251.1655.
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(1R*,2S*,3S*,4S*)-3-(3-Phenylpropanoyl)[2.2.2]oct-5-ene-2-carboxylic Acid (13c)
White solid; yield: 0.147 g [51% based on 0286 g (1.00 mmol) of 4c]; mp 113.5–115 °C.
IR (CH2Cl2): 3400–2800, 1742, 1705 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.28 (m, 2 H), 7.21–7.17 (m, 3 H), 6.36 (br t, J = 7.1 Hz, 1 H), 6.25 (br t, J = 7.0 Hz, 1 H), 3.30 (dd, J = 2.0, 5.6 Hz, 1 H), 3.05 (m, 1 H), 2.96–2.74 (m, 6 H), 1.59 (m, 1 H), 1.29–1.21 (m, 2 H), 1.01 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 209.1, 180.5, 141.1, 134.6, 133.2, 128.6, 128.5, 126.3, 53.4, 43.4, 43.1, 32.3, 32.2, 30.0, 24.3, 20.0.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C18H21O3: 285.1491; found: 285.1494.
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One-Pot Procedure for the Synthesis of 12a–c from 1a–c; General Procedure
To a solution of 1a, 1b, or 1c (1.0 mmol) in MeOH (5 mL) was added 1,3-cyclopentadiene (0.50 mL, 6.0 mmol) and the reaction mixture was stirred for 4 h at 22 °C. Aq 2 M NaOH (5.0 mL, 10 mmol) was added and the mixture was stirred 0.5 h at 22 °C. The mixture was quenched with aq 1 M HCl (15 mL). The aqueous phase was extracted with EtOAc (2 × 25 mL), the combined organic phases were gently washed with brine (50 mL), and dried over Na2SO4. The solvent was removed on the rotary evaporator, and the crude product was purified by flash chromatography (silica gel; hexanes → 50% EtOAc in hexanes) to give 12a (78%), 12b (56%) or 12c (78%).
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(2S*,3R*,4S*)-3-Acetyl-4-isobutyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-carboxylic Acid (15a)
A solution of (E)-1-(3-methylbutylidene)-2-methylidenecyclohexane (14; 1.026 g, 6.25 mmol; see Supporting Information) and 1a (0.530 g, 4.65 mmol) in CH2Cl2 (15 mL) was stirred at 40 °C for 20 h. After removing the volatiles on the rotary evaporator, the crude product (90:10 dr) was purified by flash chromatography (silica gel; 10 → 50% EtOAc in hexanes) to give 15a as the chain tautomer; white solid; yield: 1.04 g (80%); mp 104–107 °C.
IR (CH2Cl2): 3300–2500, 1752, 1708 1681 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.38 (br s, 1 H) 2.90 (m, 1 H), 2.50–2.37 (m, 2 H) 2.24 (s, 3 H), 1.18–2.15 (m, 12 H), 0.88 (d, J = 6.2, 6 H).
13C NMR (100 MHz, CDCl3): δ = 211.8, 178.8, 128.8, 127.5, 51.2, 41.6, 40.2, 38.2, 32.0, 30.7 (2 C), 28.2, 26.1, 23.8, 23.5, 22.7, 21.7.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C17H27O3: 279.1960; found: 279.1964.
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(2S*,3R*,4S*)-3-Formyl-4-isobutyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-carboxylic Acid (15b)
A solution of 14 (2.50 g, 15.2 mmol) and 1e (1.00 g, 10.0 mmol) in CH2Cl2 (30 mL) was heated to 40 °C for 18 h. After removing the volatiles on the rotary evaporator, the crude product was purified by flash chromatography (silica gel; hexanes → 50% EtOAc in hexanes) to give 15b as the ring tautomer; white solid; yield: 2.22 g (84%); mp 108–111 °C.
IR (CH2Cl2): 3570, 1775 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.40 (br s, 1 H), 3.80 (br s, 1 H), 3.11 (m, 1 H), 2.66 (m, 1 H), 2.34–2.13 (m, 3 H), 1.97 (br s, 4 H), 1.70 (m, 1 H), 1.61–1.50 (m, 4 H), 1.42–1.23 (m, 2 H), 0.93 (d, J = 6.6 Hz, 3 H), 0.89 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 180.8, 133.0, 130.8, 100.9, 46.3, 39.4, 37.0, 36.0, 30.7, 29.3, 27.7, 25.5, 23.4 (2C), 22.8, 22.5.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C16H25O3: 265.1804; found: 265.1807.
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(3S*,3aR*,4S*,9aS*)-4-Isobutyl-3-methyl-3a,4,5,6,7,8,9,9a-octahydronaphtho[2,3-c]furan-1(3H)-one (16a)
To a solution of ClTi(O-iPr)3 (0.81 mL 3.50 mmol) in anhyd THF (6 mL) at 0 °C was added MeLi (2.0 mL, 1.6 M in hexanes, 3.2 mmol) and the reaction mixture was stirred for 1 h. After the mixture was warmed to 22 °C, 15b (0.260 g, 0.985 mmol) was added and the mixture was stirred at 22 °C for 19 h. The mixture was quenched with aq 1 M HCl (40 mL), stirred vigorously for 15 min, and extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (50 mL) and dried over Na2SO4. The volatiles were removed on the rotary evaporator and the crude product was purified by flash chromatography (5% EtOAc in hexanes → 50% EtOAc in hexanes) to give 16a; white solid; yield: 0.241 g (93%); mp 81–84 °C.
IR (CH2Cl2): 1763 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.18 (dq, J = 4.2, 6.4 Hz, 1 H) 3.00 (qd, J = 2.9, 8.2, 10.5 Hz, 1 H), 2.44 (dt, J = 4.5, 10.5 Hz, 1 H), 2.33 (dd, J = 2.8, 15.6 Hz, 1 H), 2.24–2.13 (m, 2 H), 1.99 (br s, 3 H) 1.67–1.49 (m, 6 H), 1.36 (m, 1 H), 1.35 (d, J = 6.2 Hz, 3 H), 1.19 (m, 1 H), 0.93 (d, J = 6.6 Hz, 3 H), 0.89 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 180.6, 133.0, 130.7, 77.3, 45.3, 39.4, 37.3, 37.0, 30.6, 29.3, 28.3, 25.6, 23.4, 23.2, 22.9, 22.7.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C17H27O2: 263.2011; found: 263.2017.
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(3R*,3aR*,4S*,9aS*)-4-Isobutyl-3-methyl-3a,4,5,6,7,8,9,9a-octahydronaphtho[2,3-c]furan-1(3H)-one (16b)
To a solution 15a (0.094 g, 0.38 mmol) in EtOH (2 mL) was added NaBH4 (0.075 g, 0.19 mmol) and the reaction mixture was stirred for 1 h at 22 °C. H2O (10 mL) and aq 1 M HCl (10 mL) were added and the mixture was stirred vigorously for 1 h. The mixture was extracted with Et2O (3 × 30 mL), the combined organic extracts were washed with brine (30 mL), dried over NaSO4, and concentrated on the rotary evaporator. The crude product (16a:16b = 6:94) was purified by flash chromatography (silica gel; 10 → 25% EtOAc in hexanes) to give 16b; white solid; yield: 0.061 g (69%); mp 125–127 °C.
IR (CH2Cl2): 1765 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.67 (dq J = 5.0, 6.8 Hz, 1 H) 2.88 (ddd, J = 5.0, 8.4, 11.2 Hz, 1 H), 2.48 (m, 1 H), 2.38 (m, 1 H), 2.25–1.88 (m, 6 H) 1.70–1.40 (m, 5 H), 1.50 (d, J = 6.6 Hz, 3 H), 1.25–1.12 (m, 2 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.77 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 181.2, 134.6, 127.7, 79.0, 44.0, 39.6, 38.7, 37.0, 32,1, 30.6, 27.3, 26.3, 24.8, 23.4, 23.2, 21.3, 14.9.
HRMS (DART-TOF): m/z [M + 1]+ calcd for C17H27O2: 263.2011; found: 263.2019.
#
#
Acknowledgment
Acknowledgment is made to the Donors of the American Chemical Society Petroleum Research Fund for support of this research. We also thank Lafayette College’s Academic Research Committee for financial support. We gratefully acknowledge a grant from the Kresge Foundation for the purchase of a 400 MHz NMR spectrometer.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0035-1561348.
- Supporting Information
-
References
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- 2a Miles WH, Cohen EM, Naimoli BJ. Synth. Commun. 2013; 43: 1980 ; and references cited therein
- 2b Mukherjee S, Corey EJ. Org. Lett. 2010; 12: 1024
- 2c Kakushima M, Scott DG. Can. J. Chem. 1979; 57: 1399
- 2d Danishefsky S, Prisbylla MP, Hiner S. J. Am. Chem. Soc. 1978; 100: 2918
- 3a Kowalski CJ, Lal GS. J. Am. Chem. Soc. 1988; 110: 3693
- 3b Zhang YD, Tang YF, Luo TP, Shen J, Chen JH, Yang Z. Org. Lett. 2006; 8: 107
- 3c Hu QY, Zhou G, Corey EJ. J. Am. Chem. Soc. 2004; 126: 13708
- 4 Feringa BL, De Lange B, Jansen JF. G. A, De Jong JC, Lubben M, Faber W, Schudde EP. Pure Appl. Chem. 1992; 64: 1865
- 5 Simple γ-alkyl-γ-hydroxybutenolides are at slow exchange in the 1H NMR at ambient temperature, with the presence of the chain tautomer as high as 5%
- 6 For a review of the synthetic applications of γ-hydroxybutenolides, see: Miles WH. Curr. Org. Synth. 2014; 11: 244
- 7a Miller KK, Zhang P, Nishizawa-Brennen Y, Frost JW. ACS Sustain. Chem. Eng. 2014; 2: 2053
- 7b Furuta K, Miwa Y, Iwanaga K, Yamamoto H. J. Am. Chem. Soc. 1988; 110: 6254
- 7c Al-Zoubi RM, Marion O, Hall DG. Angew. Chem. Int. Ed. 2008; 47: 2876
- 7d Zheng HC, Hall DG. Tetrahedron Lett. 2010; 51: 3561
- 7e Ryu DH, Corey EJ. J. Am. Chem. Soc. 2003; 125: 6388
- 8a Magnus P, Cairns PM. J. Am. Chem. Soc. 1986; 108: 217
- 8b Magnus P, Cairns PM, Moursounidis J. J. Am. Chem. Soc. 1987; 109: 2469
- 9a Noutsias D, Vassilikogiannakis G. Org. Lett. 2012; 14: 3565
- 9b Tu NP. W, Yip JC, Dibble PW. Synthesis 1996; 77
- 9c Sánchez-Obregón R, Salmón M, Walls F. Bol. Inst. Quim. Univ. Nacl. Autón. Méx. 1970; 22: 16 ; Chem. Abstr. 1971, 74, 140602
- 10a Lee GC. M, Syage ET, Harcourt DA, Holmes JM, Garst ME. J. Org. Chem. 1991; 56: 7007
- 10b Adam W, Rodriguez A. Tetrahedron Lett. 1981; 22: 3505
- 10c Feringa BL. Recl. Trav. Chim. Pays-Bas 1987; 106: 469
- 10d Cottier L, Descotes G, Eymard L, Rapp K. Synthesis 1995; 303
- 10e Annangudi SP, Sun MJ, Salomon RG. Synlett 2005; 1468
- 11a Larson RT, Pemberton RP, Franke JM, Tantillo DJ, Thomson RJ. J. Am. Chem. Soc. 2015; 137: 11197
- 11b Chackalamannil S, Wang YG, Greenlee WJ, Hu ZY, Xia Y, Ahn HS, Boykow G, Hsieh YS, Palamanda J, Agans-Fantuzzi J, Kurowski S, Graziano M, Chintala M. J. Med. Chem. 2008; 51: 3061
- 12 Liu P, Pan YM, Hu K, Huang XC, Liang Y, Wang HS. Tetrahedron 2013; 69: 7925
- 13 Miles WH, Duca DG, Selfridge BR, De Sousa CA. P, Harriman KB, Goodzeit EO, Freedman JT. Tetrahedron Lett. 2007; 48: 7809
- 14 In some cases, broadening of the peaks in the NMR spectra of these cycloadducts may be attributable to hydrogen bonding; see: Klika KD, Tahtinen P, Dahlqvist M, Szabo JA, Stajer G, Sinkkonen J, Pihlaja K. J. Chem. Soc., Perkin Trans. 2 2000; 687
- 15a Suzuki J, Harada T. Synthesis 2006; 2483
- 15b Miklos F, Sohar P, Csampai A, Sillanpaa R, Peter M, Stajer G. Heterocycles 2002; 57: 2309
- 15c Rajsfus DE, Alter-Zilberfarb S, Frimer AA. J. Fluorine Chem. 2013; 148: 49
- 16 With the unequivocal synthesis of 3a and these isomerization studies, the lack of certainty about the assignment of the stereochemistry of compound ‘4’ in Pinnick’s paper is clarified.17 In Pinnick’s study, the addition of lithium dimethylcuprate to endo-Diels–Alder product of cyclopentadiene and maleic anhydride gave a product whose NMR spectra match the spectra of 12a, and not 3a. A similar study by Walton, in which cadmium reagents were added to above endo-Diels–Alder product, appears to lead to isomerization since the melting points of both 3a and 3b differ considerably from the values given in the paper but are very close to the melting points found for isomerized compounds 12a and 12b.18 A study of the addition of some Grignard reagents to anhydrides has previously been noted to cause isomerization of the resulting keto acids.19 The nickel-catalyzed reactions of zinc reagents to anhydrides, on the other hand, appears to occur without isomerization, since the product from the above endo-Diels–Alder product exhibited a complex 1H NMR spectra due to ‘rotomers,’ that is, ring and chain tautomers.20
- 17 Cornelius LA. M, Bone RG. A, Hastings RH, Deardorff MA, Scharlach RA, Hauptmann BE, Stankovic CS, Pinnick HW. J. Org. Chem. 1993; 58: 3188
- 18 Walton HM. J. Org. Chem. 1957; 22: 312
- 19 Canonne P, Plamondon J, Akssira M. Tetrahedron 1988; 44: 2903
- 20 Bercot EA, Rovis T. J. Am. Chem. Soc. 2002; 124: 174
- 21 Rinner U, Lentsch C, Aichinger C. Synthesis 2010; 3763
- 22 Chackalamannil S, Wang YG, Greenlee WJ, Hu ZY, Xia Y, Ahn HS, Boykow G, Hsieh YS, Palamanda J, Agans-Fantuzzi J, Kurowski S, Graziano M, Chintala M. J. Med. Chem. 2008; 51: 3061
- 23 Gao LJ, Waelbroeck M, Hofman S, Van Haver D, Milanesio M, Viterbo D, De Clercq PJ. Bioorg. Med. Chem. Lett. 2002; 12: 1909
- 24 Doller D, Chackalamannil S, Czarniecki M, McQuade R, Ruperto V. Bioorg. Med. Chem. Lett. 1999; 9: 901
- 25 Larson RT, Pemberton RP, Franke JM, Tantillo DJ, Thomson RJ. J. Am. Chem. Soc. 2015; 137: 11197
- 26 Howell JM, Liu W, Young AJ, White MC. J. Am. Chem. Soc. 2006; 136: 5750
- 27 Takadoi M, Katoh T, Ishiwata A, Terashima S. Tetrahedron 2002; 58: 9903
- 28 Takadoi M, Yamaguchi K, Terashima S. Bioorg. Med. Chem. 2003; 11: 1169
- 29 Bercot EA, Kindrachuk DE, Rovis T. Org. Lett. 2005; 7: 107
- 30a Shi H, Liu H, Bloch R, Mandville GR. Tetrahedron 2001; 57: 9335
- 30b Frenette R, Monette M, Bernstein MA, Young RN, Verhoeven TR. J. Org. Chem. 1991; 56: 3083
- 31 APEX2 . Bruker AXS Inc; Madison (WI, USA): 2009
- 32 Sheldrick GM. SADABS . University of Gottingen; Germany: 2008
- 33 Sheldrick GM. Acta Crystallogr., Sect. A 2008; 64: 112
- 34 Allen FH, Johnson O, Shields GP, Smith BR, Towler M. J. Appl. Crystallogr. 2004; 37: 335
- 35 Cycloadduct 9e has been previously reported, but likely to be the trans-compound: Andreev VM, Usova AV. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1966; 15: 1351
For representative examples of isomerization of [2.2.1]-bicyclic systems, see:
-
References
- 1 Nicolaou KC, Snyder SA, Montagnon T, Vassilikogiannakis G. Angew. Chem. Int. Ed. 2002; 41: 1668
- 2a Miles WH, Cohen EM, Naimoli BJ. Synth. Commun. 2013; 43: 1980 ; and references cited therein
- 2b Mukherjee S, Corey EJ. Org. Lett. 2010; 12: 1024
- 2c Kakushima M, Scott DG. Can. J. Chem. 1979; 57: 1399
- 2d Danishefsky S, Prisbylla MP, Hiner S. J. Am. Chem. Soc. 1978; 100: 2918
- 3a Kowalski CJ, Lal GS. J. Am. Chem. Soc. 1988; 110: 3693
- 3b Zhang YD, Tang YF, Luo TP, Shen J, Chen JH, Yang Z. Org. Lett. 2006; 8: 107
- 3c Hu QY, Zhou G, Corey EJ. J. Am. Chem. Soc. 2004; 126: 13708
- 4 Feringa BL, De Lange B, Jansen JF. G. A, De Jong JC, Lubben M, Faber W, Schudde EP. Pure Appl. Chem. 1992; 64: 1865
- 5 Simple γ-alkyl-γ-hydroxybutenolides are at slow exchange in the 1H NMR at ambient temperature, with the presence of the chain tautomer as high as 5%
- 6 For a review of the synthetic applications of γ-hydroxybutenolides, see: Miles WH. Curr. Org. Synth. 2014; 11: 244
- 7a Miller KK, Zhang P, Nishizawa-Brennen Y, Frost JW. ACS Sustain. Chem. Eng. 2014; 2: 2053
- 7b Furuta K, Miwa Y, Iwanaga K, Yamamoto H. J. Am. Chem. Soc. 1988; 110: 6254
- 7c Al-Zoubi RM, Marion O, Hall DG. Angew. Chem. Int. Ed. 2008; 47: 2876
- 7d Zheng HC, Hall DG. Tetrahedron Lett. 2010; 51: 3561
- 7e Ryu DH, Corey EJ. J. Am. Chem. Soc. 2003; 125: 6388
- 8a Magnus P, Cairns PM. J. Am. Chem. Soc. 1986; 108: 217
- 8b Magnus P, Cairns PM, Moursounidis J. J. Am. Chem. Soc. 1987; 109: 2469
- 9a Noutsias D, Vassilikogiannakis G. Org. Lett. 2012; 14: 3565
- 9b Tu NP. W, Yip JC, Dibble PW. Synthesis 1996; 77
- 9c Sánchez-Obregón R, Salmón M, Walls F. Bol. Inst. Quim. Univ. Nacl. Autón. Méx. 1970; 22: 16 ; Chem. Abstr. 1971, 74, 140602
- 10a Lee GC. M, Syage ET, Harcourt DA, Holmes JM, Garst ME. J. Org. Chem. 1991; 56: 7007
- 10b Adam W, Rodriguez A. Tetrahedron Lett. 1981; 22: 3505
- 10c Feringa BL. Recl. Trav. Chim. Pays-Bas 1987; 106: 469
- 10d Cottier L, Descotes G, Eymard L, Rapp K. Synthesis 1995; 303
- 10e Annangudi SP, Sun MJ, Salomon RG. Synlett 2005; 1468
- 11a Larson RT, Pemberton RP, Franke JM, Tantillo DJ, Thomson RJ. J. Am. Chem. Soc. 2015; 137: 11197
- 11b Chackalamannil S, Wang YG, Greenlee WJ, Hu ZY, Xia Y, Ahn HS, Boykow G, Hsieh YS, Palamanda J, Agans-Fantuzzi J, Kurowski S, Graziano M, Chintala M. J. Med. Chem. 2008; 51: 3061
- 12 Liu P, Pan YM, Hu K, Huang XC, Liang Y, Wang HS. Tetrahedron 2013; 69: 7925
- 13 Miles WH, Duca DG, Selfridge BR, De Sousa CA. P, Harriman KB, Goodzeit EO, Freedman JT. Tetrahedron Lett. 2007; 48: 7809
- 14 In some cases, broadening of the peaks in the NMR spectra of these cycloadducts may be attributable to hydrogen bonding; see: Klika KD, Tahtinen P, Dahlqvist M, Szabo JA, Stajer G, Sinkkonen J, Pihlaja K. J. Chem. Soc., Perkin Trans. 2 2000; 687
- 15a Suzuki J, Harada T. Synthesis 2006; 2483
- 15b Miklos F, Sohar P, Csampai A, Sillanpaa R, Peter M, Stajer G. Heterocycles 2002; 57: 2309
- 15c Rajsfus DE, Alter-Zilberfarb S, Frimer AA. J. Fluorine Chem. 2013; 148: 49
- 16 With the unequivocal synthesis of 3a and these isomerization studies, the lack of certainty about the assignment of the stereochemistry of compound ‘4’ in Pinnick’s paper is clarified.17 In Pinnick’s study, the addition of lithium dimethylcuprate to endo-Diels–Alder product of cyclopentadiene and maleic anhydride gave a product whose NMR spectra match the spectra of 12a, and not 3a. A similar study by Walton, in which cadmium reagents were added to above endo-Diels–Alder product, appears to lead to isomerization since the melting points of both 3a and 3b differ considerably from the values given in the paper but are very close to the melting points found for isomerized compounds 12a and 12b.18 A study of the addition of some Grignard reagents to anhydrides has previously been noted to cause isomerization of the resulting keto acids.19 The nickel-catalyzed reactions of zinc reagents to anhydrides, on the other hand, appears to occur without isomerization, since the product from the above endo-Diels–Alder product exhibited a complex 1H NMR spectra due to ‘rotomers,’ that is, ring and chain tautomers.20
- 17 Cornelius LA. M, Bone RG. A, Hastings RH, Deardorff MA, Scharlach RA, Hauptmann BE, Stankovic CS, Pinnick HW. J. Org. Chem. 1993; 58: 3188
- 18 Walton HM. J. Org. Chem. 1957; 22: 312
- 19 Canonne P, Plamondon J, Akssira M. Tetrahedron 1988; 44: 2903
- 20 Bercot EA, Rovis T. J. Am. Chem. Soc. 2002; 124: 174
- 21 Rinner U, Lentsch C, Aichinger C. Synthesis 2010; 3763
- 22 Chackalamannil S, Wang YG, Greenlee WJ, Hu ZY, Xia Y, Ahn HS, Boykow G, Hsieh YS, Palamanda J, Agans-Fantuzzi J, Kurowski S, Graziano M, Chintala M. J. Med. Chem. 2008; 51: 3061
- 23 Gao LJ, Waelbroeck M, Hofman S, Van Haver D, Milanesio M, Viterbo D, De Clercq PJ. Bioorg. Med. Chem. Lett. 2002; 12: 1909
- 24 Doller D, Chackalamannil S, Czarniecki M, McQuade R, Ruperto V. Bioorg. Med. Chem. Lett. 1999; 9: 901
- 25 Larson RT, Pemberton RP, Franke JM, Tantillo DJ, Thomson RJ. J. Am. Chem. Soc. 2015; 137: 11197
- 26 Howell JM, Liu W, Young AJ, White MC. J. Am. Chem. Soc. 2006; 136: 5750
- 27 Takadoi M, Katoh T, Ishiwata A, Terashima S. Tetrahedron 2002; 58: 9903
- 28 Takadoi M, Yamaguchi K, Terashima S. Bioorg. Med. Chem. 2003; 11: 1169
- 29 Bercot EA, Kindrachuk DE, Rovis T. Org. Lett. 2005; 7: 107
- 30a Shi H, Liu H, Bloch R, Mandville GR. Tetrahedron 2001; 57: 9335
- 30b Frenette R, Monette M, Bernstein MA, Young RN, Verhoeven TR. J. Org. Chem. 1991; 56: 3083
- 31 APEX2 . Bruker AXS Inc; Madison (WI, USA): 2009
- 32 Sheldrick GM. SADABS . University of Gottingen; Germany: 2008
- 33 Sheldrick GM. Acta Crystallogr., Sect. A 2008; 64: 112
- 34 Allen FH, Johnson O, Shields GP, Smith BR, Towler M. J. Appl. Crystallogr. 2004; 37: 335
- 35 Cycloadduct 9e has been previously reported, but likely to be the trans-compound: Andreev VM, Usova AV. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1966; 15: 1351
For representative examples of isomerization of [2.2.1]-bicyclic systems, see:
