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Synthesis 2014; 46(19): 2663-2671
DOI: 10.1055/s-0034-1378282
paper
© Georg Thieme Verlag Stuttgart · New York

[2+2] Photocycloaddition Studies on Complex Tetronic Acid Esters Related to the Synthesis of Cembranoid Diterpenes

Roland Weixler
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany   Fax: +49(89)28913315   Email: thorsten.bach@ch.tum.de
,
Thorsten Bach*
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany   Fax: +49(89)28913315   Email: thorsten.bach@ch.tum.de
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Further Information

Publication History

Received: 25 April 2014

Accepted: 12 May 2014

Publication Date:
24 June 2014 (online)

 
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Abstract

Twelve different tetronic acid esters bearing two potentially reactive olefinic groups were prepared and subjected to [2+2] photocycloaddition reactions by irradiation at λ = 254 nm in tert-butanol (5 mM). The diastereoselectivity and regioselectivity of the reaction was studied with regard to the synthesis of cembranoid diterpenes. When the tetronic acid core carried an alk-3-enyl substituent in the γ-position and an alk-3-enyloxy substituent in the β-position, the undesired γ-products prevailed and were formed in 48–81% yield. Altering the γ-alk-3-enyl substituent into an alk-3-ynyl or alk-2-ynyl substituent, resulted in formation of the desired β-photocycloaddition products. The latter products were obtained in yields of 56–88%, with two out of three products exhibiting very high regio- and diastereoselectivity.


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Key words

[2+2] cycloadditions - cyclobutanes - regioselectivity - heterocycles - photochemistry

Photochemical reactions possess a fascinating potential for synthetic chemistry and, above all, for total synthesis because they facilitate reaction pathways that cannot be accessed by conventional methods. Highly complex molecules can be prepared by astonishing transformations in a very fast and economical way.[1] Among the wide range of photochemical reactions, the [2+2] photocycloaddition of olefins has shown the largest impact on natural product synthesis.[2] Cyclic α,β-unsaturated carbonyl compounds can undergo [2+2] photocycloaddition by direct excitation via the ππ*-triplet state to form cyclobutanes,[3] which have frequently been subjected to fragmentation reactions. In this context, the widely used de Mayo reaction,[4] which is a combination of a [2+2] photocycloaddition and a retro-aldol reaction, or radical fragmentation reactions, offer outstanding opportunities.[5] In recent years, tetronic acid esters (tetronates) have proven to be readily available, robust precursors for [2+2] photocycloadditions, facilitating various subsequent modifications for natural product synthesis.[6] In studies towards the total synthesis of cembranoid diterpenes, we considered a fragmentation reaction of cyclobutane B, which in turn should be accessible by a [2+2] photocycloaddition of complex tetronate C (Scheme [1]).

The fragmentation reaction has already been carried out with a test substrate utilizing a Grob-type fragmentation.[7] However, in contrast to earlier studies, the generic tetronate substrate C bears two double bonds that are capable of reacting with the excited enone in a [2+2] photocycloaddition reaction. Both the desired cyclic olefin (attached to the β-carbon atom) and the terminal olefin in the alk-3-enyl side chain (attached to the γ-carbon atom) are in five-membered-ring distance to the chromophore. In this account, we summarize the results of our investigations on the [2+2] photocycloaddition of substrate class C. Such reactions led, through a substrate modification, to products of type B and thus facilitate potential access to the basic­ skeleton (A) of cembranoid diterpenes of the asbestinin and briarellin class.[8]

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Scheme 1 Retrosynthetic considerations for the synthesis of the cembranoid diterpene skeleton A from substrate C via cyclobutane B

As described above, model studies were carried out using complex tetronates to verify the feasibility of the planned [2+2] photocycloaddition shown in Scheme [1]. Tetronates of type C should be readily accessible by Mitsunobu reactions of tetronic acids and – preferentially – primary alcohols.[9] For the synthesis of primary alcohol 3, which already bears the correct configuration for the construction of the diterpene skeleton, a four-step synthesis was established. Starting from crotonylated Evans auxiliary 1 (accessible from the respective oxazolidinone and crotonic acid chloride),[10] an aldol reaction with di-n-butylboryl trifluoromethanesulfonate (n-Bu2BOTf) and triethylamine (Et3N) in CH2Cl2 was applied to obtain syn-product 2 in 71% yield as a single diastereoisomer (Scheme [2]).

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Scheme 2 Synthesis of primary alcohol 3 by an aldol reaction and ring-closing metathesis

Subsequent ring-closing olefin metathesis (RCM) with Grubbs catalyst [Cl2(Cy3P)2Ru=CHPh] in CH2Cl2, tert-butyldimethylsilyl (TBS) protection with tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and 2,6-lutidine in CH2Cl2, and cleavage of the auxiliary with lithiumborohydride in tetrahydrofuran (THF) afforded primary alcohol 3 in 63% yield over three steps.

The synthesis of optically active tetronic acids has previously been accomplished by various approaches, for example, lipase-catalyzed kinetic resolution, oxidation of dihydrofuranones, Reformatsky reactions, or Dieckmann cyclizations.[11] In our case, we chose the Seebach alkylation protocol to install the quaternary C2-center with the desired configuration,[12] followed by acetylation (R1 = H) or Steglich esterification[13] with carbodiimides (R1 = CO2Et) in CH2Cl2 and Dieckmann cyclization to close the dihydrofuran ring.

As depicted in Scheme [3], dioxolanone 4 was deprotonated with lithium diisopropylamide (LDA) and the resulting enolate was trapped with primary iodides (R2I) to install the but-3-enyl, but-3-ynyl, or but-2-ynyl side chains. The iodides were accessible from the corresponding primary alcohols by Mukaiyama redox condensation.[14] A low substrate concentration and an excess of dioxolanone were required to avoid self-addition and to ensure high yields in the alkylation reaction.[12] In the case of but-3-ynyl iodide, lower yields were observed due to the high tendency for elimination reactions.

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Scheme 3 Preparation of esters 5a–e starting from dioxolanone 4 by Seebach alkylation

After alkylation, the dioxolanones were converted into the methyl esters with sodium methoxide (NaOMe) at 0 °C in methanol. Subsequent acylation with acetic acid anhydride (R1 = H) in toluene at 80 °C or mono-ethylmalonate and N,N-dicyclohexylcarbodiimide (DCC) as coupling reagent (R1 = CO2Et) afforded the Dieckmann cyclization precursors 5a–e in good yields over three steps. For the Dieckmann cyclization of esters 5a and 5b, lithium bis(trimethylsilyl)amide (LHMDS) in THF at –78 °C was used to afford the tetronic acids 6a and 6b in high yields (Scheme [4]). The tetronic acids were extracted from the acidified aqueous solution (pH 1) and purified by recrystallization. The coupling of tetronic acids with primary alcohols [cyclohex-2-enylmethanol (7a),[15] alcohol 3, but-3-enol (7b), or 3-methylbut-3-enol (7c)] was successfully accomplished by the Mitsunobu protocol (Scheme [5]).

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Scheme 4 Preparation of tetronic acids 6a and 6b by Dieckmann cyclization
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Scheme 5 Preparation of tetronates 8a–g by Mitsunobu reaction of alcohols 3 and 7a–c and tetronic acids 6a and 6b

Under standard conditions using triphenylphosphine and diisopropyl azodicarboxylate (DIAD) in THF, but-3-enyl substituted tetronates 8a–g were prepared in 36–82% yield. The low yield for the Mitsunobu reaction of tetronic acid 6b and alcohol 7a (product 8d) was caused by separation problems. Secondary alcohols were also tested as substrates in Mitsunobu reactions of tetronic acids 6, but no substitution products could be isolated.

For the preparation of alk-3-ynyl or alk-2-ynyl substituted tetronates 8h–l, the reaction conditions had to be optimized (Scheme [6]). Under standard conditions, as previously used for the synthesis of the alkenyloxy-substituted tetronates, only a very sluggish reaction was observed. Instead of LHMDS, potassium tert-butoxide (t-BuOK) was used in N,N-dimethylformamide (DMF) at ambient temperature to achieve the desired Dieckmann cyclization. Furthermore, the tetronic acids were directly used for the Mitsunobu reactions without further purification. The long reaction times for the Mitsunobu reactions were decreased by applying tris(4-chlorophenyl)phosphine to increase the electrophilicity of the intermediate alkoxyphosphoniumion salt.[16] Additionally, DEAD was added slowly over twelve hours. Under these conditions, tetronates 8h–l were isolated in moderate yields over two steps (32–47%). For the synthesis of tetronates 8j and 8l the two-step synthesis started with ester 5d, which underwent an alkyne isomerization[17] under basic work-up conditions (NaOH in H2O/Et2O) to form the but-2-ynyl substituted tetronic acid. When directly subjected to the Mitsunobu reaction, the ethoxycarbonyl tetronates were isolated. When the base treatment was omitted during work-up, the terminal alkyne remained unchanged (product 8h).

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Scheme 6 Synthesis of tetronates 8h–l over two steps

It has been reported that tetronates undergo a clean [2+2] photocycloaddition reaction upon irradiation with a conventional low-pressure mercury (λ = 254 nm) lamp to afford cyclobutanes.[18] To synthesize useful products for the synthesis of cembranoid diterpenes, the alkenyloxy side chain in the β-position was required to react selectively – but not the alkenyl or alkynyl side chain in the γ-position. The results of the [2+2] photocycloaddition reactions for all alkenyl-substrates 8a–g are summarized in Scheme [7]. The [2+2] photocycloaddition reactions were carried out in tert-butanol (c = 5 mm) at λ = 254 nm. Under these conditions, tetronates 8a and 8b, without a substituent in the α-position (R1 = H), produced exclusively the undesired straight products 9a and 9b, albeit in high yields (78–81%). When a methyl group was installed in the β-alken­yl­oxy side chain (8c), again only the undesired straight product 9c was obtained.

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Scheme 7 Formation of straight products 9a–d,f,h,j by [2+2] photocycloaddition of tetronates 8a–g, and crossed products 9i and 9k from tetronate 8a and 8b. All reactions were conducted at a substrate concentration of 5mm in t-BuOH as the solvent and were stopped at full conversion. Yields are given for isolated products. a The product was obtained as a 50:50 mixture of diastereoisomers. b The yield was determined by 1H NMR spectroscopic analysis because the product could not be isolated in pure form. The structure assignment is tentative. c The product was obtained as a ca. 75:25 mixture of diastereoisomers.

To investigate the influence of steric hindrance on the regioselectivity, we also irradiated tetronate 8f, with two but-3-en-1-yl chains but without further substitution. With this substrate a mixture of two products was isolated (9d and 9e), both as straight products, resulting from a [2+2] photocycloaddition with either one of the olefinic double bonds. Clearly, the but-3-en-1-yl group that is attached to the tetronate γ-carbon atom reacted with significant preference (product 9d) over the second but-3-en-1-yl group (product 9e) attached to the tetronate via the oxygen atom at the β-carbon atom. The same trend was observed for tetronate 8g, which bears an ester group at the α-carbon atom. In this case, product 9f prevailed over its positional isomer 9g. The intrinsic preference is apparently further enhanced by steric hindrance; thus, when the β-alkenyoxy substituent is further substituted (substrates 8a–c) only a single product is observed, which results from attack at the γ-linked but-3-en-1-yl group. In other words, the photoexcited tetronate chromophore does not react with the more substituted double bond but, rather, selects the conformationally more accessible bond. The reason for this preference appears to be entropic, because the quaternary center in the γ-position leaves little rotational flexibility and forces the side chain to fold in the direction of the photoexcited enone double bond. The β-alkenyloxy side chain is more flexible and conformations that are compatible with an attack at the enone double bond seem to be less heavily populated. In addition, as depicted in Figure [1] for substrate 8f, the required orientation of the alkenyloxy group may also suffer from steric repulsion (conformation 8f′), whereas the conformation 8f′′, required for formation of product 9d, is readily accessed.

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Figure 1 Possible conformations 8f′ and 8f′′ leading to regioisomeric [2+2] photocycloaddition products 9e and 9d

In previous studies[19] it was observed that an electron-withdrawing group (R1 = CO2Et) in the α-position of the tetronate causes a bathochromic shift in the absorption of the chromophores. In addition, it was found that the additional stabilization of the intermediate 1,4-biradical can cause selectivity changes. In the present case, irradiation of substrates 8d and 8e, however, did not significantly alter the selectivity. The products of attack at the γ-linked but-3-en-1-yl group 9h and 9j remained the main products. Interestingly, the minor products were found to be crossed products (9i and 9k). The unexpected formation of crossed products has already been investigated in earlier studies and correlates with the stabilization of the intermediate biradicals by the additional electron-withdrawing substituent.[19] The structural assignment of the photocycloaddition products was based on two-dimensional NMR experiments (NOE and HMBC experiments, see the Supporting Information for further details). As expected, the facial diastereoselectivity of the [2+2] photocycloaddition reactions was high.

To change the regioselectivity, the alkenyl side chain at the γ-position was replaced by an alkynyl side chain. Although there are some examples for the formation of annulated cyclobutenes,[20] their formation was expected to be disfavored in a [2+2] photocycloaddition of tetronates. The further conversion of the nonreactive alkynes into alkenes of type B by hydrogenation – after [2+2] photocycloaddition at the other position – seemed feasible.[21] As expected, photocycloaddition products of the tetronate chromophore with the alkyne were not observed and we were pleased to obtain a single product in 88% yield after irradiation of substrate 8i (R1 = H). Again, NMR experiments helped to assign the product as straight product 10 (Scheme [8]). Likewise, the [2+2] photocycloaddition of tetronate 8h (R1 = CO2Et) only occurred at the cyclic double bond. However in the latter case, two products, the straight product 11 (26% yield) and the crossed product 12 (31% yield), were formed.

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Scheme 8 Formation of products 10–12 by [2+2] photocycloaddition of tetronates 8h and 8i

For further investigations, the photochemical behavior of alk-2-ynyl tetronates 8j–l was tested. In this case, the products could serve as promising starting points for further studies on the synthesis of cembranoid diterpenes.

The [2+2] photocycloaddition of the enone with the alk-2-ynyl side chain is highly unlikely because of the short distance between the reactive centers. Irradiation should only lead to the formation of the desired products with the β-positioned alkenyloxy tether. Indeed, irradiation of tetronate 8l was very promising, as only the straight product 13 was observed (72%; Scheme [9]). Much to our surprise, tetronates 8j and 8k did not react in a [2+2] photocycloaddition to give the expected photoproducts 14, but resulted in a mixture of various side products due to hydrogen abstraction. Attempts to utilize sensitizers to irradiate the tetronates at longer wavelength (λ = 300 nm) led to the same result. The substrates completely decomposed within ten minutes, indicating very fast side reactions. It appears that the methyl group at the alkyne is particularly prone to hydrogen abstraction from the photoexcited tetronate.

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Scheme 9 Irradiation of tetronates 8j–l under standard conditions

In summary, twelve complex tetronates were synthesized by employing a Mitsunobu reaction as the key step. The irradiation of β-alkenyloxy- and γ-alkenyl-substituted tetronates was shown to occur preferentially at the γ-alkenyl side chain. To alter the regioselectivity, substrates with alk-3-ynyl substituents in the γ-position were prepared and, at least for substrates 8h and 8i, it was shown that [2+2] photocycloaddition reactions occur cleanly at the β-alkenyloxy site. Surprisingly, some β-alkenyloxy- and γ-alk-2-ynyl-substituted tetronates did not show a clean [2+2] photocycloaddition. Hydrogen abstraction intervened with the desired reaction pathway. Regarding a projected use in further synthetic efforts, product 10 holds the greatest promise.

All reactions involving water-sensitive chemicals were carried out in flame-dried glassware under positive pressure of argon with magnetic stirring. THF was purified using a SPS-800 solvent purification system (M. Braun). Et3N was distilled over CaH2. All other chemicals were either commercially available or prepared according to the cited references. For photochemical reactions, the reaction mixture was degassed by purging with argon in an ultrasonicating bath. Subsequently, the solution was transferred into quartz tubes (diameter: 1 cm, volume: 10 mL) and irradiated in a Rayonet RPR100 reactor, equipped with 16 Rayonet RPR2537 Å (λ = 254 nm) lamps. The reactor was cooled with an internal fan, the operating temperature for photochemical reactions was ca. 35 °C. Thin-layer chromatography (TLC) was performed on silica-coated glass plates (silica gel 60 F254) with detection by UV (λ= 254 nm) or KMnO4 (0.5% in H2O) with subsequent heating. Flash chromatography was performed on silica gel 60 (Merck, 230–400 mesh) with the indicated eluent. Common solvents for chromatography [pentane (P), ethyl acetate (EtOAc), diethyl ether (Et2O)] were distilled prior to use. IR spectra were recorded with a JASCO IR-4100 (ATR) or Perkin–Elmer 1600 FT/IR, MS / HRMS-measurements were performed with a Finnigan MAT 8200 (EI) / Finnigan MAT 95S (HR-EI). 1H and 13C NMR spectra were recorded in CDCl3 at 303 K with a Bruker AV-250, Bruker AV-360, or Bruker AV-500. Chemical shifts are reported relative to CHCl3 (δ = 7.26 ppm). Apparent multiplets that occur as a result of the accidental equality of coupling constants to those of magnetically nonequivalent protons are market as apparent (app). The multiplicities of the 13C NMR signals were determined by DEPT experiments, assignments are based on COSY, HMBC and HMQC experiments.

Analytical data are provided for representative compounds. A complete set of data for all new compounds can be found in the Supporting Information.


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Mitsunobu Reactions with Tetronic Acids; General Procedure I

The tetronic acid (1.0 mmol) was dissolved in THF (10 mL) followed by addition of the primary alcohol (1.1 mmol). The mixture was cooled to 0 °C, triphenylphosphine (1.1 mmol) or tris(4-chlorophenyl)phosphine (1.1 mmol) were added and diisopropyl azodicarboxylate (1.1 mmol) or diethyl azodicarboxylate (1.1 mmol) were slowly dropped into the solution. The mixture was allowed to warm to r.t. overnight, then the solvent was removed under reduced pressure and the residue was purified by column chromatography.


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(5R,1′R,6′R)-5-(But-3-en-1-yl)-4-{6′-[(tert-butyldimethylsilyl)oxy]cyclohex-2′-en-1′-ylmethoxy}-5-methyl-2-oxo-2,5-dihydrofuran (8b)

The reaction was performed with alcohol 3 (50.0 mg, 0.21 mmol) and tetronic acid 6a (76.3 mg, 0.45 mmol) in THF (5 mL) according to General Procedure I.

Yield: 42.0 mg (0.11 mmol, 52%); yellow oil; Rf = 0.27 (P–Et2O, 3:1); [α]D 22 +37.1 (c 0.50, CHCl3).

IR (ATR): 2951, 2928, 2855, 1754, 1628, 1461 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 0.08 (s, 3 H), 0.10 (s, 3 H), 0.91 (s, 9 H), 1.49 (s, 3 H), 1.65–1.98 (m, 4 H), 2.01–2.30 (m, 4 H), 2.65–2.69 (m, 1 H), 3.97 (dd, 2 J = 9.5 Hz, 3 J = 7.7 Hz, 1 H), 4.12 (ddd, 3 J = 7.6, 4.2, 2.7 Hz, 1 H), 4.21 (dd, 2 J = 9.5 Hz, 3 J = 5.7 Hz, 1 H), 4.97–5.05 (m, 2 H), 4.99 (s, 1 H), 5.52 (ddt, 3 J = 9.8, 4.1 Hz, 4 J = 1.9 Hz, 1 H), 5.74–5.81 (m, 1 H), 5.84 (dtd, 3 J = 9.8, 3.7 Hz, 4 J = 1.9 Hz, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = –5.0 (q), –4.4 (q), 18.1 (s), 22.5 (t), 23.4 (q), 25.8 (q), 27.4 (t), 28.8 (t), 36.0 (t), 40.4 (d), 67.2 (d), 73.9 (t), 84.1 (s), 88.0 (d), 115.1 (t), 124.0 (d), 129.2 (d), 137.2 (d), 172.0 (s), 184 (s).

MS (ESI): m/z (%) = 1199 (6) [3M + Na]+, 807 (13) [2M + Na]+, 785 (100) [2M + H]+, 393 (27) [M + H]+, 335 (14) [M – C4H9]+.

HRMS (ESI): m/z [M + H]+ calcd for C22H36O4Si+: 393.24556; found: 393.24575.


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(5R)-5-(But-3-en-1-yl)-4-(3-methylbut-3-en-1-yloxy)-5-methyl-2-oxo-2,5-di-hydrofuran (8c)

The reaction was performed with alcohol 7c (48.0 μL, 39.6 mg, 0.46 mmol) and tetronic acid 6a (70.0 mg, 0.42 mmol) in THF (2 mL) according to General Procedure I.

Yield: 81.4 mg (0.34 mmol, 82%); light-yellow oil; Rf = 0.39 (P–EtOAc, 1:1); [α]D 22 +24.0 (c 0.50, CHCl3).

IR (ATR): 2977, 2933, 1746, 1620, 1456 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 1.47 (s, 3 H), 1.75–1.80 (m, 1 H), 1.81 (s, 3 H), 1.84–1.99 (m, 2 H), 2.05–2.16 (m, 1 H), 2.50 (t, 3 J = 6.5 Hz, 2 H), 4.06–4.16 (m, 2 H), 4.75–4.79 (m, 1 H), 4.86–4.98 (m, 1 H), 4.94–5.02 (m, 2 H), 4.98 (s, 1 H), 5.75 (ddt, 3 J = 17.1, 10.2, 6.4 Hz, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = 22.5 (q), 23.5 (q), 27.4 (t), 28.2 (t), 35.9 (t), 70.8 (t), 84.2 (s), 88.1 (d), 113.0 (t), 115.2 (t), 137.2 (d), 140.5 (s), 171.9 (s), 183.5 (s).

MS (EI, 70 eV): m/z (%) = 236 (1) [M+], 181 (5) [C4H7]+, 69 (100) [C5H9]+.

HRMS (EI, 70 eV): m/z [M+] calcd for C14H20O3 +: 236.1407; found: 236.1409.


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(5R,1′R,6′R)-(But-3-en-1-yl)-3-ethoxycarbonyl-4-{6′-[(tert-butyldimethylsilyl)oxy]cyclohex-2′-en-1′-ylmethoxy}-5-methyl-2-oxo-2,5-dihydrofuran (8e)

The reaction was performed with alcohol 3 (19.1 mg, 79.3 μmol) and tetronic acid 6b (56.6 mg, 0.24 mmol) in THF (2.5 mL) according to General Procedure I.

Yield: 19.2 mg (41.0 μmol, 53%); light-yellow oil; Rf  = 0.33 (P–Et2O, 3:1); [α]D 22 +31.0 (c 0.50, CHCl3).

IR (ATR): 2980, 2931, 1720, 1466 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 0.09 (s, 3 H), 0.10 (s, 3 H), 0.91 (s, 9 H), 1.37 (t, 3 J = 7.1 Hz, 3 H), 1.51 (s, 3 H), 1.69 (dtd, 2 J = 13.3 Hz, 3 J = 6.8, 3.4 Hz, 1 H), 1.74–1.85 (m, 2 H), 1.90 (dt, 2 J = 10.6 Hz, 3 J = 5.0 Hz, 1 H), 1.96–2.02 (m, 1 H), 2.04–2.17 (m, 2 H), 2.20–2.28 (m, 1 H), 2.61–2.65 (m, 1 H), 4.11 (ddd, 3 J = 7.8, 4.8, 2.9 Hz, 1 H), 4.33 (q, 3 J = 7.1 Hz, 2 H), 4.37 (dd, 2 J = 9.5 Hz, 3 J = 6.9 Hz, 1 H), 4.63 (dd, 2 J = 9.5 Hz, 3 J = 5.7 Hz, 1 H), 4.94 –4.98 (m, 1 H), 5.03 (dd, 2 J = 1.6 Hz, 3 J = 17.1 Hz, 1 H), 5.49–5.52 (m, 1 H), 5.74 (ddt, 3 J = 17.1, 10.2, 6.3 Hz, 1 H), 5.83 (dtd, 3 J = 9.8, 3.4 Hz, 4 J = 1.9 Hz, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = –5.0 (q), –4.4 (q), 14.1 (q), 18.0 (s), 22.7 (t), 23.5 (q), 25.8 (q), 27.3 (t), 28.8 (t), 36.2 (t), 41.1 (d), 61.7 (t), 67.1 (d), 76.0 (t), 83.2 (s), 97.1 (s), 115.4 (t), 123.8 (d), 129.4 (d), 136.9 (d), 162.1 (s), 168.1 (s), 181.7 (s).

MS (ESI): m/z (%) = 951 (21) [2M + Na]+, 946 (23) [2M + NH4]+, 465 (100) [M + H]+, 243 (18) [C13H27O2Si]+.

HRMS (ESI): m/z [M + H]+ calcd for C25H41O6Si+: 465.26669; found: 465.26673.


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(5R,1′R,6′R)-5-(But-3-yn-1-yl)-3-ethoxycarbonyl-4-{6′-[(tert-butyldimethylsilyl)oxy]cyclohex-2′-en-1′-ylmethoxy}-5-methyl-2-oxo-2,5-dihydrofuran (8h)

The reaction was performed with alcohol 3 (90.0 mg, 0.37 mmol) and tetronic acid (78.6 mg, 0.33 mmol; accessible by cyclization of acetate 5d in 67% yield) in THF (4 mL) according to General Procedure I.

Yield: 85.5 mg (185 μmol, 56%); yellow oil; Rf  = 0.29 (P–Et2O, 3:1); [α]D 22 +81.1 (c 0.50, CHCl3).

IR (ATR): 3285, 2956, 2931, 2857, 1767, 1715, 1644, 1458 cm–1.

1H NMR (360 MHz, CDCl3): δ = 0.07 (s, 3 H), 0.09 (s, 3 H), 0.90 (s, 9 H), 1.36 (t, 3 J = 7.1 Hz, 3 H), 1.51 (s, 3 H), 1.64–1.72 (m, 1 H), 1.73–1.80 (m, 1 H), 1.94 (t, 4 J = 2.6 Hz, 1 H), 1.98–2.19 (m, 4 H), 2.20–2.32 (m, 2 H), 2.61–2.65 (m, 1 H), 4.10 (ddd, 3 J = 8.0, 4.9, 2.9 Hz, 1 H), 4.32 (q, 3 J = 7.1 Hz, 2 H), 4.37 (dd, 2 J = 9.8 Hz, 3 J = 7.4 Hz, 1 H), 4.63 (dd, 2 J = 9.8 Hz, 3 J = 5.8 Hz, 1 H), 5.49 (ddt, 3 J = 9.8, 4.1 Hz, 4 J = 1.9 Hz, 1 H), 5.83 (dtd, 3 J = 9.8, 3.6 Hz, 4 J = 2.1 Hz, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = –5.0 (q), –4.4 (q), 12.9 (t), 14.1 (q), 18.0 (s), 22.8 (t), 23.3 (q), 25.8 (q), 28.8 (t), 36.0 (t), 41.1 (d), 61.7 (t), 67.2 (d), 69.1 (d), 76.1 (t), 82.5 (s), 82.5 (s), 97.1 (s), 123.8 (d), 129.5 (d), 161.9 (s), 167.7 (s), 181.0 (s).

MS (ESI): m/z (%) = 947 (51) [2M + Na]+, 485 (15) [M + Na]+, 463 (100) [M + H]+.

HRMS (ESI): m/z [M + H]+ calcd for C25H39O6Si+: 463.25104; found: 463.25083.


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(5R,1′R,6′R)-5-(But-3-yn-1-yl)-4-{6′-[(tert-butyldimethylsilyl)oxy]cyclohex-2′-en-1′-ylmethoxy}-5-methyl-2-oxo-2,5-dihydrofuran (8i)

The reaction was performed with alcohol 3 (89.0 mg, 0.37 mmol) and tetronic acid (55.4 mg, 0.33 mmol; accessible by cyclization of acetate 5c in 81% yield) in THF (4 mL) according to General Procedure I.

Yield: 52.3 mg (134 μmol, 40%); yellow oil; Rf  = 0.43 (P–Et2O, 3:1); [α]D 22 +79.1 (c 0.15, CHCl3).

IR (ATR): 3309, 2956, 2928, 2854, 1757, 1630 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 0.08 (s, 3 H), 0.10 (s, 3 H), 0.91 (s, 9 H), 1.48 (s, 3 H), 1.64–1.83 (m, 2 H), 1.94 (t, 4 J = 2.6 Hz, 1 H), 1.95–2.05 (m, 2 H), 2.06–2.31 (m, 4 H), 2.65–2.69 (m, 1 H), 3.97 (app t, 2 J ≈ 3 J = 9.3 Hz, 1 H), 4.11–4.12 (m, 1 H), 4.21 (dd, 2 J = 9.3 Hz, 3 J = 6.0 Hz, 1 H), 4.97 (s, 1 H), 5.45–5.55 (m, 1 H), 5.84 (dtd, 3 J = 9.8, 3.4 Hz, 4 J = 1.9 Hz, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = –5.0 (q), –4.3 (q), 12.9 (t), 18.1 (s), 22.5 (t), 23.3 (q), 25.8 (q), 28.8 (t), 35.7 (t), 40.3 (d), 67.1 (d), 68.8 (d), 74.1 (t), 83.0 (s), 83.4 (s), 88.2 (d), 123.9 (d), 129.3 (d), 171.7 (s), 183.4 (s).

MS (EI, 70 eV): m/z (%) = 333 (6) [M – C4H9]+, 57 (100).

HRMS (EI): m/z [M – C4H9]+ calcd for C18H25O4Si+: 333.1517; found: 333.1512.


#

[2+2] Photocycladdition Reaction; General Procedure II

The tetronic acid ester (0.10 mmol) was dissolved in t-BuOH (20 mL, 5 mM), degassed by purging with Ar in an ultrasonicator for 15 min and irradiated in a Rayonet RPR 100 merry-go-round reactor, equipped with 16 Rayonet RPR 2537 Å lamps (λ = 254 nm). Unless otherwise stated, the reaction was stopped when the starting material was fully consumed according to TLC analysis. The solvent was then removed and the residue was purified by flash chromatography.


#

(1R,1′RS,4S,6R,9S)-9-(Cyclohex-2′-en-1′-ylmethoxy)-1-methyl-2-oxatricyclo[4,2,1,04,9]-non-3-one (9a)

The reaction was performed with tetronic acid ester 8a (20.0 mg, 76.2 μmol) in t-BuOH (15 mL) according to General Procedure II.

Yield: 16.2 mg (62.0 μmol, 81%); colorless amorphous solid; mixture of two diastereoisomers (dr 50:50); Rf  = 0.81 (P–Et2O, 1:1).

IR (ATR): 2931, 2861, 1774, 1447 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 1.30–1.40 (m, 1 H), 1.45 (s, 3 H), 1.54–1.62 (m, 2 H), 1.66–1.75 (m, 2 H), 1.80–1.82 (m, 1 H), 1.94 (app dt, 2 J = 14.1 Hz, 3 J ≈ 3 J = 7.9 Hz, 1 H), 1.99–2.05 (m, 2 H), 2.12 (app dtd, 2 J = 13.7 Hz, 3 J ≈ 3 J = 7.9 Hz, 3 J = 6.1 Hz, 1 H), 2.25 (ddd, 2 J = 14.1 Hz, 3 J = 7.9, 4.0 Hz, 1 H), 2.34–2.44 (m, 1 H), 2.62–2.69 (m, 1 H), 2.95–3.04 (m, 1 H), 3.19–3.22 (m, 1 H), 3.37–3.42 (m, 2 H), 5.60 (ddt, 3 J = 9.8, 4.3 Hz, 4 J = 1.9 Hz, 1 H), 5.80 (dtd, 3 J = 9.8, 3.4 Hz, 4 J = 2.0 Hz, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = 20.0 (q), 20.7 (t), 24.8 (t), 25.3 (t), 25.9 (t), 29.9 (t), 36.0 (d), 38.5 (d), 39.5 (d), 40.0 (t), 69.9 (t), 90.8 (s), 96.1 (s), 127.6 (d), 129.1 (d), 177.4 (s). Two signal sets for each peak due to the existence of two diastereoisomers.

MS (EI, 70 eV): m/z (%) = 262 (1) [M+], 168 (5) [C9H12O2]+, 95 (100).

HRMS (EI): m/z [M+] calcd for C16H22O3 +: 262.1563; found: 262.1554.


#

(1R,1′R,4S,6R,6′R,9S)-9-{6′-[(tert-Butyldimethylsilyl)oxy]cyclohex-2′-en-1′-ylmethoxy}-1-methyl-2-oxatricy­clo[4,2,1,04,9]non-3-one (9b)

The reaction was performed tetronic acid ester 8b (30.7 mg, 78.0 μmol) in t-BuOH (16 mL) according to General Procedure II.

Yield: 23.9 mg (60.8 μmol, 78%); colorless amorphous solid; Rf  = 0.42 (P–Et2O, 3:1); [α]D 20 +87.2 (c 0.20, CHCl3).

IR (ATR): 2952, 2928, 2884, 1765, 1463 cm –1 .

1H NMR (500 MHz, CDCl3): δ = 0.07 (s, 3 H), 0.09 (s, 3 H), 0.91 (s, 9 H), 1.44 (s, 3 H), 1.58–1.73 (m, 3 H), 1.75–1.84 (m, 1 H), 1.92 (app dt, 2 J = 13.9 Hz, 3 J ≈ 3 J = 7.9 Hz, 1 H), 1.99–2.29 (m, 4 H), 2.41–2.48 (m, 1 H), 2.64 (ddd, 2 J = 12.8 Hz, 3 J = 11.3, 2.2 Hz, 1 H), 2.98–3.06 (m, 1 H), 3.22 (ddd, 3 J = 11.2, 3.7 Hz, 4 J = 2.2 Hz, 1 H), 3.40 (app t, 2 J ≈ 3 J = 8.4 Hz, 1 H), 3.74 (dd, 2 J = 8.4 Hz, 3 J = 6.0 Hz, 1 H), 4.07–4.10 (m, 1 H), 5.45 (ddt, 3 J = 9.8, 4.3 Hz, 4 J = 1.9 Hz, 1 H), 5.76 (dtd, 3 J = 9.7, 3.6 Hz, 4 J = 2.2 Hz, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = –5.0 (q), –4.4 (q), 18.1 (s), 20.0 (q), 22.6 (t), 25.1 (t), 25.8 (q), 28.9 (t), 30.0 (t), 38.6 (d), 39.6 (d), 40.0 (t), 41.6 (d), 66.8 (t), 67.5 (d), 91.1 (s), 96.1 (s), 125.6 (d), 127.9 (d), 177.4 (s).

MS (ESI): m/z (%) = 1199 (6) [3M + Na]+, 785 (100) [2M + H]+, 415 (8) [M + Na]+, 410 (22) [M + NH4]+, 393 (70) [M + H]+.

HRMS (ESI): m/z [M + H]+ calcd for C22H37O4Si+: 393.24556; found: 393.24570.


#

(1R,4S,6R,9R)-9-(3-Methylbut-3-en-1-yloxy)-1-methyl-2-oxa­tricyclo[4,2,1,04,9]non-3-one (9c)

The reaction was performed with tetronic acid ester 8c (25.6 mg, 108 μmol) in t-BuOH (22 mL) according to General Procedure II.

Yield: 14.4 mg (61.0 μmol, 56%); colorless amorphous solid; Rf  = 0.45 (P–Et2O, 3:1); [α]D 22 +11.4 (c 0.25, CHCl3).

IR (ATR): 2956, 2939, 1761, 1447 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 1.41 (s, 3 H), 1.58 (app dt, 2 J = 12.8 Hz, 3 J ≈ 3 J = 3.7 Hz, 1 H), 1.67 (app dtd, 2 J = 13.6 Hz, 3 J ≈ 3 J = 7.9 Hz, 3 J = 4.0 Hz, 1 H), 1.75 (s, 3 H), 1.91 (app dt, 2 J = 14.1 Hz, 3 J ≈ 3 J = 7.9 Hz, 1 H), 2.09 (app dtd, 2 J = 13.6 Hz, 3 J ≈ 3 J = 7.9, 3 J = 6.1 Hz, 1 H), 2.17–2.28 (m, 1 H), 2.30 (t, 3 J = 6.7 Hz, 2 H), 2.64 (ddd, 2 J = 12.8 Hz, 3 J = 11.3, 2.2 Hz, 1 H), 2.95–3.02 (m, 1 H), 3.18 (ddd, 3 J = 11.2, 3.7 Hz, 4 J = 2.2 Hz, 1 H), 3.56–3.60 (m, 2 H), 4.71–4.73 (m, 1 H), 4.79–4.80 (m, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = 20.0 (q), 22.9 (q), 24.8 (t), 29.9 (t), 38.1 (t), 38.5 (d), 39.4 (d), 40.1 (t), 64.7 (t), 90.9 (s), 96.1 (s), 112.0 (t), 142.4 (s), 177.3 (s).

MS (EI, 70 eV): m/z (%) = 236 (1) [M+], 69 (100) [C5H9]+.

HRMS (EI): m/z [M+] calcd for C14H20O3 +: 236.1407; found: 236.1407.


#

(1R,4S,6R,9R)-9-(But-3-en-1-yloxy)-1-methyl-2-oxatricy­clo[4,2,1,04,9]non-3-one (9d)

The reaction was performed with tetronic acid ester 8f (20.0 mg, 90.0 μmol) in t-BuOH (18 mL) according to General Procedure II. The product 9d was obtained as colorless amorphous solid (13.2 mg, 59.3 μmol, 66%) and 9e was obtained as a mixture with 9d (3.5 mg, 15.8 μmol, 18%). Combined yield: 84%; regioisomer ratio 79:21.

Rf  = 0.55 (P–Et2O, 3:1); [α]D 20 +14.6 (c 0.39, CHCl3).

IR (ATR): 2999, 2871, 1761, 1447 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 1.44 (s, 3 H), 1.60 (app dt, 2 J = 12.8 Hz, 3 J ≈ 3 J = 3.7 Hz, 1 H), 1.69 (app dtd, 2 J = 13.6 Hz, 3 J ≈ 3 J = 7.9 Hz, 3 J = 4.0 Hz, 1 H), 1.93 (app dt, 2 J = 14.1 Hz, 3 J ≈ 3 J = 7.9 Hz, 1 H), 2.02–2.18 (m, 1 H), 2.18–2.28 (m, 1 H), 2.31–2.39 (m, 2 H), 2.66 (ddd, 2 J = 12.8 Hz, 3 J = 11.3, 2.2 Hz, 1 H), 2.90–3.03 (m, 1 H), 3.19 (ddd, 3 J = 11.2, 3.7 Hz, 4 J = 2.2 Hz, 1 H), 3.47–3.58 (m, 2 H), 5.06–5.10 (m, 1 H), 5.12 (dd, 2 J = 1.7 Hz, 3 J = 17.1 Hz, 1 H), 5.83 (ddt, 3 J = 17.1, 10.2, 6.4 Hz, 1 H).

The second photocycloaddition product 9e could only be isolated as a mixture with 9d. An unambiguous structure determination was not possible.

13C NMR (90.6 MHz, CDCl3): δ = 20.0 (q), 24.8 (t), 29.9 (t), 34.4 (t), 38.5 (d), 39.4 (d), 40.1 (t), 65.3 (t), 90.9 (s), 96.1 (s), 117.0 (t), 134.6 (s), 177.3 (s).

MS (EI, 70 eV): m/z (%) = 222 (1) [M+], 167 (15) [M – C4H7]+, 55 (100) [C4H7]+.

HRMS (EI): m/z [M+] calcd for C13H18O3 +: 222.1250; found: 222.1252.


#

(1R,4S,6R,9R)-9-(But-3-en-1-yloxy)-4-ethoxycarbonyl-1-methyl-2-oxatricyclo[4,2,1,04,9]non-3-one (9f)

The reaction was performed with tetronic acid ester 8g (15.0 mg, 51.0 μmol) in t-BuOH (10 mL) according to General Procedure II. The product 9f was obtained as colorless amorphous solid (10.5 mg, 35.7 µmol, 70%) and 9g was obtained as a mixture with 9f (3.0 mg, 10.2 µmol, 20% yield). Combined yield: 90%, regioisomer ratio 72:28.

Rf  = 0.27 (P–Et2O, 3:1); [α]D 20 +61.0 (c 0.50, CHCl3).

IR (ATR): 3076, 2980, 2940, 1767, 1733 cm–1.

1H NMR (360 MHz, CDCl3): δ = 1.31 (t, 3 J = 7.1 Hz, 3 H), 1.48 (s, 3 H), 1.65–1.90 (m, 3 H), 2.19–2.34 (m, 4 H), 3.03–3.08 (m, 1 H), 3.17 (dd, 2 J = 12.8 Hz, 3 J = 10.2 Hz, 1 H), 3.47 (dt, 2 J = 8.5 Hz, 3 J = 6.5 Hz, 1 H), 3.52 (dt, 2 J = 8.5 Hz, 3 J = 6.6 Hz, 1 H), 4.16–4.35 (m, 2 H), 5.05 (dd, 2 J = 1.6 Hz, 3 J = 10.2 Hz, 1 H), 5.08 (dd, 2 J = 1.6 Hz, 3 J = 17.1 Hz, 1 H), 5.79 (ddt, 3 J = 17.1, 10.2, 6.4 Hz, 1 H).

The second photocycloaddition product 9g could only be isolated as a mixture with 9f. Therefore an unambiguous structure determination was not possible.

13C NMR (90.6 MHz, CDCl3): δ = 14.1 (q), 19.4 (q), 29.2 (t), 29.9 (t), 34.4 (t), 35.4 (d), 40.0 (t), 55.3 (s), 61.9 (t), 65.2 (t), 94.1 (s), 95.6 (s), 117.0 (t), 134.3 (d), 166.6 (s), 173.6 (s).

MS (ESI): m/z (%) = 589 (11) [2M + H]+, 317 (23) [M + Na]+, 312 (100) [M + NH4]+, 295 (74) [M + H]+.

HRMS (ESI): m/z [M + H]+ calcd for C16H23O5 +: 295.15400; found: 295.15401.


#

(1R,1′RS,4S,6R,9S)-Ethyl 9-(Cyclohex-2′-en-1′-ylmethoxy)-4-ethoxycarbonyl-1-methyl-2-oxatricyclo[4,2,1,04,9]non-3-on-4-carbonate (9h) and (1S,2S,3R,6S,7R,8RS)-3-(But-3-en-1-yl)-6-ethoxy-carbonyl-3-methyl-2,8-oxathano-4-oxatricy­clo[5.4.0.02,6]undecan-5-one (9i)

The reaction was performed with tetronic acid ester 8d (10.0 mg, 29.9 μmol) in t-BuOH (6 mL) according to General Procedure II. Products 9h (6.5 mg, 19.3 μmol, 65% yield) and 9i (1.0 mg, 3.1 μmol, 10% yield) were obtained as colorless amorphous solids (75% yield, regioisomeric ratio 86:14).


#

Straight Product 9h

Mixture of two diastereoisomers (dr 50:50); Rf  = 0.36 (P–Et2O, 3:1).

IR (ATR): 2928, 2850, 1765, 1718 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 1.31 (t, 3 J = 7.1 Hz, 3 H), 1.26–1.39 (m, 2 H), 1.49 (s, 3 H), 1.64–1.82 (m, 5 H), 1.98–2.02 (m, 2 H), 2.19–2.37 (m, 4 H), 3.01–3.13 (m, 1 H), 3.14–3.20 (m, 1 H), 3.29–3.36 (m, 1 H), 4.18–4.32 (m, 2 H), 5.55 (ddt, 3 J = 9.8, 4.3 Hz, 4 J = 1.9 Hz, 1 H), 5.77 (dtd, 3 J = 9.8, 3.5 Hz, 4 J = 1.8 Hz, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = 14.1 (q), 19.5 (q), 20.7 (t), 25.3 (t), 25.6 (t), 29.2 (t), 29.9 (t), 31.9 (d), 36.0 (d), 40.0 (t), 55.4 (s), 61.9 (t), 69.7 (t), 94.0 (s), 95.7 (s), 127.4 (d), 129.2 (d), 166.6 (s), 173.8 (s). Two signal sets for each peak due to the existence of two diastereoisomers.

MS (EI, 70 eV): m/z (%) = 334 (1) [M+], 186 (100), 95 (26) [C7H11]+.

HRMS (EI): m/z [M+] calcd for C19H26O5 +: 334.1775; found: 334.1767.


#

Crossed Product 9i

Mixture of two diastereoisomers (dr ca.75:25); Rf  = 0.58 (P–Et2O, 3:1).

IR (ATR): 2935, 2831, 1760, 1718 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 1.33 (t, 3 J = 7.1 Hz, 3 H), 1.47–1.54 (m, 3 H), 1.68 (s, 3 H), 1.69–2.39 (m, 8 H), 2.65–2.72 (m, 1 H), 2.92–2.95 (m, 1 H), 3.81–3.87 (m, 1 H), 4.05–4.11 (m, 1 H), 4.22–4.34 (m, 2 H), 5.01 (dd, 2 J = 1.6 Hz, 3 J = 10.2 Hz, 1 H), 5.06 (dd, 2 J = 1.6 Hz, 3 J = 17.1 Hz, 1 H), 5.77–5.89 (m, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = 13.9 (q), 17.3 (t), 18.3 (q), 20.1 (t), 20.7 (t), 28.2 (t), 32.7 (t), 34.5 (t), 36.2 (d), 40.0 (d), 59.8 (s), 62.1 (t), 70.2 (t), 88.3 (s), 96.0 (s), 115.0 (t), 137.5 (d), 166.7 (s), 171.8 (s). Two signal sets for each peak due to the existence of a second diastereoisomer.

MS (EI, 70 eV): m/z (%) = 334 (1) [M+], 186 (100), 95 (26) [C7H11]+.

HRMS (EI): m/z [M+] calcd for C19H26O5 +: 334.1775; found: 334.1767.


#

(1R,1′R,4S,6R,6′R,9S)-9-{[(6′-tert-Butyldimethylsilyl)oxy]cyclohex-2′-en-1′-ylmethoxy}-4-ethoxycarbonyl-1-methyl-2-oxatricyclo[4,2,1,04,9]non-3-one (9j) and (1S,2S,3R,6S,7R,8R,9R)-9-[(tert-Butyldimethylsilyl)oxy]-3-(but-3-en-1-yl)-6-ethoxycarbonyl-3-methyl-2,8-oxathano-4-oxatricyclo[5.4.0.02,6]undecan-5-one (9k)

The reaction was performed with tetronic acid ester 8e (12.0 mg, 25.8 μmol) in t-BuOH (5 mL) according to General Procedure II. Products 9j (5.6 mg, 12.1 μmol, 47% yield) and 9k (2.2 mg, 4.7 μmol, 18% yield) were obtained as colorless amorphous solids (65% yield, regioisomeric ratio 72:28).


#

Straight Product 9j

Rf  = 0.41 (P–Et2O, 3:1); [α]D 22 +65.4 (c 0.50, CHCl3).

IR (ATR): 2980, 2924, 2857, 1771, 1729 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 0.06 (s, 3 H), 0.09 (s, 3 H), 0.91 (s, 9 H), 1.30 (t, 3 J = 7.1 Hz, 3 H), 1.50 (s, 3 H), 1.62–1.81 (m, 5 H), 1.95–2.06 (m, 1 H), 2.13–2.31 (m, 3 H), 2.35–2.39 (m, 1 H), 3.04–3.09 (m, 1 H), 3.17 (dd, 2 J = 12.8 Hz, 3 J = 10.2 Hz, 1 H), 3.36 (app t, 2 J ≈ 3 J = 8.4 Hz, 1 H), 3.68 (dd, 2 J = 8.4 Hz, 3 J = 5.8 Hz, 1 H), 4.05 (ddd, 3 J = 7.4, 4.3, 2.5 Hz, 1 H), 4.24 (q, 3 J = 7.1 Hz, 2 H), 5.52 (ddt, 3 J = 9.8, 4.3 Hz, 4 J = 1.9 Hz, 1 H), 5.73 (dtd, 3 J = 9.8, 3.4 Hz, 4 J = 1.9 Hz, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = –5.0 (q), –4.4 (q), 14.0 (q), 18.1 (s), 19.4 (q), 22.6 (t), 25.8 (q), 28.9 (t), 29.4 (t), 29.9 (t), 35.4 (d), 40.0 (t), 41.7 (d), 55.3 (s), 61.9 (t), 66.9 (t), 67.4 (d), 94.4 (s), 95.5 (s), 125.6 (d), 127.7 (q), 166.4 (s), 173.7 (s).

MS (ESI): m/z (%) = 951 (67) [2M + Na]+, 946 (66) [2M + NH4]+, 487 (7) [M + Na]+, 482 (6) [M + NH4]+, 465 (100) [M + H]+.

HRMS (ESI): m/z [M + H]+ calcd for C25H41O6Si+: 465.26669; found: 465.26654.


#

Crossed Product 9k

Rf  = 0.58 (P–Et2O, 3:1); [α]D 22 +44.3 (c 0.50, CHCl3).

IR (ATR): 2980, 2928, 2861, 1771, 1729 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 0.06 (s, 3 H), 0.08 (s, 3 H), 0.89 (s, 9 H), 1.34 (t, 3 J = 7.1 Hz, 3 H), 1.65 (s, 3 H), 1.68–1.84 (m, 5 H), 1.95 (dt, 2 J = 11.6 Hz, 3 J = 6.1 Hz, 1 H), 2.16–2.20 (m, 2 H), 2.24–2.26 (m, 1 H), 2.53–2.57 (m, 1 H), 3.05 (app t, 3 J ≈ 3 J = 5.4 Hz, 1 H), 3.77–3.80 (m, 1 H), 3.86 (ddd, 3 J = 12.4, 5.8 Hz, 4 J = 1.2 Hz, 1 H), 4.25–4.35 (m, 3 H), 5.00 (dd, 2 J = 1.6 Hz, 3 J = 10.2 Hz, 1 H), 5.06 (dd, 3 J = 1.6, 17.1 Hz, 1 H), 5.82 (ddt, 3 J = 17.1, 10.2, 6.4 Hz, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = –4.7 (q), –4.5 (q), 13.8 (q), 18.0 (s), 18.2 (q), 20.9 (t), 25.7 (q), 27.5 (t), 28.1 (t), 34.6 (t), 35.5 (d), 40.5 (d), 41.6 (d), 59.6 (s), 62.2 (t), 64.9 (d), 69.8 (t), 88.4 (s), 96.2 (s), 115.0 (t), 137.4 (d), 166.5 (s), 171.5 (s).

MS (ESI): m/z (%) = 951 (75) [2M + Na]+, 946 (60) [2M + NH4]+, 482 (6) [M + NH4]+, 465 (100) [M + H]+.

HRMS (ESI): m/z [M + H]+ calcd for C25H41O6Si+: 465.26669; found: 465.26673.


#

(1S,2R,5R,6R,9R,10R,13S)-10-[(tert-Butyldimethylsilyl)oxy]-5-(but-3-yn-1-yl)-5-methyl-4,7-dioxatetracyclo[7.3.1.02,6.06,13]tridecan-3-one (10)

The reaction was performed with tetronic acid ester 8i (4.0 mg, 10.2 μmol) in t-BuOH (2 mL) according to General Procedure II.

Yield; 3.5 mg (9.0 μmol, 88%); colorless amorphous solid; Rf  = 0.37 (P–Et2O, 3:1); [α]D 22 +8.6 (c 0.50, CHCl3).

IR (ATR): 3312, 2956, 2925, 2854, 1767 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 0.07 (s, 3 H), 0.07 (s, 3 H), 0.89 (s, 9 H), 1.30–1.36 (m, 1 H), 1.48 (s, 3 H), 1.65–1.71 (m, 1 H), 1.76–1.83 (m, 1 H), 1.87–1.93 (m, 1 H), 1.97 (t, 4 J = 2.6 Hz, 1 H), 1.99–2.11 (m, 2 H), 2.26–2.30 (m, 1 H), 2.33 (dddd, 2 J = 10.8 Hz, 3 J = 7.8, 5.1, 2.2 Hz, 1 H), 2.42 (dddd, 2 J = 10.8 Hz, 3 J = 16.2, 5.3, 2.7 Hz, 1 H), 2.69–2.76 (m, 1 H), 2.94 (d, 3 J = 6.6 Hz, 1 H), 3.04 (app t, 3 J ≈ 3 J = 9.6 Hz, 1 H), 3.94 (ddd, 3 J = 10.7, 5.9, 4.3 Hz, 1 H), 4.06 (app t, 2 J ≈ 3 J = 9.9 Hz, 1 H), 4.12 (dd, 3 J = 9.9, 8.6 Hz, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = –4.6 (q), –4.6 (q), 13.7 (t), 18.0 (s), 22.4 (q), 24.7 (t), 25.7 (q), 26.4 (t), 28.2 (t), 36.9 (d), 41.0 (d), 41.8 (d), 45.3 (d), 68.4 (d), 69.3 (d), 69.7 (t), 83.9 (s), 86.3 (s), 87.9 (s), 176.4 (s).

MS (ESI): m/z (%) = 803 (10) [2M + Na]+, 781 (23) [2M + H]+, 413 (11) [M + Na]+, 391 (100) [M + H]+.

HRMS (ESI): m/z [M + H]+ calcd for C22H35O4Si+: 391.22991; found: 391.22966.


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(1S,2R,5R,6R,6R,10R,13S)-10-[(tert-Butyldimethylsilyl)oxy]-5-(but-3-yn-1-yl)-5-methyl-2-ethoxycarbonyl-4,7-dioxatetracy­clo[7.3.1.02,6.06,13]tridecan-3-one (11) and (1S,2S,3R,6S,7R,8R,9R)-9-[(tert-Butyldimethylsilyl)oxy]-3-(but-3-yn-1-yl)-6-ethoxycarbonyl-3-methyl-2,8-oxathano-4-oxatricyclo­[5.4.0.02,6]undecan-5-one (12)

The reaction was performed with tetronic acid ester 8h (12.0 mg, 26.4 μmol) in t-BuOH (5 mL) according to General Procedure II. Products 11 (3.2 mg, 6.9 μmol, 26% yield) and 12 (3.8 mg, 8.2 μmol, 31% yield) were obtained as colorless amorphous solids (58% yield, regioisomeric ratio 46:54).


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Straight Product 11

Rf  = 0.31 (P–Et2O, 3:1); [α]D 22 +8.5 (c 0.50, CHCl3).

IR (ATR): 3270, 2952, 2931, 2854, 1765, 1733, 1461 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 0.05 (s, 3 H), 0.06 (s, 3 H), 0.87 (s, 9 H), 1.31 (t, 3 J = 7.1 Hz, 3 H), 1.40 (s, 3 H), 1.65–1.76 (m, 2 H), 1.95 (t, 4 J = 2.6 Hz, 1 H), 2.03–2.08 (m, 2 H), 2.23–2.29 (m, 1 H), 2.35–2.47 (m, 2 H), 2.49–2.52 (m, 2 H), 2.71–2.76 (m, 1 H), 3.20 (dd, 3 J = 10.2, 9.2 Hz, 1 H), 3.96 (app td, 3 J ≈ 3 J = 10.7 Hz, 3 J = 5.0 Hz, 1 H), 4.10 (app t, 2 J ≈ 3 J = 9.2 Hz, 1 H), 4.18 (app t, 2 J ≈ 3 J = 9.2 Hz, 1 H), 4.26–4.33 (m, 2 H).

13C NMR (90.6 MHz, CDCl3): δ = –4.6 (q), –4.9 (q), 13.1 (t), 14.1 (q), 18.0 (s), 18.8 (q), 23.6 (t), 25.7 (q), 26.4 (t), 32.3 (t), 34.1 (d), 35.6 (d), 41.7 (d), 56.9 (s), 61.7 (t), 68.4 (d), 68.6 (d), 71.1 (t), 84.0 (s), 85.8 (s), 93.9 (s), 164.9 (s), 173.2 (s).

MS (ESI): m/z (%) = 1409 (5) [2M + Na]+, 947 (25) [2M + Na]+, 925 (25) [2M + H]+, 485 (100) [M + Na]+, 463 (93) [M + H]+.

HRMS (ESI): m/z [M + H]+ calcd for C25H39O6Si+: 463.25104; found: 463.25176.


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Crossed Product 12

Rf  = 0.41 (P–Et2O, 3:1); [α]D 22 +94.8 (c 0.25, CHCl3).

IR (ATR): 3284, 2953, 2931, 2857, 1771, 1726, 1461 cm –1 .

1H NMR (360 MHz, CDCl3): δ = 0.04 (s, 3 H), 0.07 (s, 3 H), 0.86 (s, 9 H), 1.34 (t, 3 J = 7.1 Hz, 3 H), 1.64 (s, 3 H), 1.68–1.78 (m, 2 H), 1.84–1.90 (m, 2 H), 1.94–1.99 (m, 2 H), 2.00 (t, 4 J = 2.6 Hz, 1 H), 2.23–2.27 (m, 1 H), 2.31–2.35 (m, 2 H), 2.53–2.57 (m, 1 H), 3.03 (app t, 3 J ≈ 3 J = 5.0 Hz, 1 H), 3.76–3.81 (m, 1 H), 3.82 (dd, 2 J = 12.5 Hz, 3 J = 5.9 Hz, 1 H), 4.22–4.30 (m, 3 H).

13C NMR (90.6 MHz, CDCl3): δ = –4.7 (q), –4.5 (q), 13.6 (t), 13.8 (q), 17.9 (s), 18.0 (q), 20.8 (t), 25.7 (q), 27.5 (t), 34.6 (t), 35.5 (d), 40.5 (d), 41.6 (d), 59.5 (s), 62.2 (t), 65.0 (d), 68.8 (d), 69.8 (t), 83.2 (s), 87.4 (s), 95.9 (s), 166.3 (s), 171.2 (s).

MS (ESI): m/z (%) = 947 (100) [2M + Na]+, 485 (78) [M + Na]+, 480 (27) [M + NH4]+, 463 (96) [M + H]+.

HRMS (ESI): m/z [M + H]+ calcd for C25H39O6Si+: 463.25204; found: 463.25180.


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(1R,3S,7R,8R)-8-(But-2-yn-1-yl)-1-ethoxycarbonyl-8-methyl-6,9-dioxatricyclo[5.3.1.03,7]non-10-one (13)

The reaction was performed with tetronic acid ester 8i (10.0 mg, 34.2 μmol) in t-BuOH (7 mL) according to General Procedure II.

Yield: 7.2 mg (24.6 μmol, 72%); colorless amorphous solid; Rf  = 0.39 (P–Et2O, 3:1); [α]D 20 +6.8 (c 0.32, CHCl3).

IR (ATR): 2956, 2925, 2855, 1775, 1733, 1454 cm–1.

1H NMR (360 MHz, CDCl3): δ = 1.30 (t, 3 J = 7.1 Hz, 3 H), 1.45 (s, 3 H), 1.81 (t, 5 J = 2.6 Hz, 3 H), 1.79–1.90 (m, 2 H), 2.31 (dd, 2 J = 13.3 Hz, 3 J = 8.6 Hz, 1 H), 2.49 (dd, 2 J = 13.3 Hz, 3 J = 7.0 Hz, 1 H), 2.50–2.57 (m, 1 H), 2.81–2.86 (m, 1 H), 3.15–3.21 (m, 1 H), 4.09–4.16 (m, 1 H), 4.20–4.32 (m, 3 H).

13C NMR (90.6 MHz, CDCl3): δ = 3.7 (q), 14.1 (q), 18.0 (q), 26.6 (t), 26.8 (t), 30.7 (t), 37.7 (d), 53.3 (s), 62.2 (t), 70.4 (s), 73.6 (t), 78.3 (s), 85.0 (s), 94.4 (s), 166.0 (s), 172.8 (s).

MS (ESI): m/z (%) = 315 (12) [M + Na]+, 293 (100) [M + H]+.

HRMS (ESI): m/z [M + H]+ calcd for C16H21O5 +: 293.13835; found: 293.13818.


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Supporting Information

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Scheme 1 Retrosynthetic considerations for the synthesis of the cembranoid diterpene skeleton A from substrate C via cyclobutane B
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Scheme 2 Synthesis of primary alcohol 3 by an aldol reaction and ring-closing metathesis
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Scheme 3 Preparation of esters 5a–e starting from dioxolanone 4 by Seebach alkylation
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Scheme 4 Preparation of tetronic acids 6a and 6b by Dieckmann cyclization
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Scheme 5 Preparation of tetronates 8a–g by Mitsunobu reaction of alcohols 3 and 7a–c and tetronic acids 6a and 6b
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Scheme 6 Synthesis of tetronates 8h–l over two steps
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Scheme 7 Formation of straight products 9a–d,f,h,j by [2+2] photocycloaddition of tetronates 8a–g, and crossed products 9i and 9k from tetronate 8a and 8b. All reactions were conducted at a substrate concentration of 5mm in t-BuOH as the solvent and were stopped at full conversion. Yields are given for isolated products. a The product was obtained as a 50:50 mixture of diastereoisomers. b The yield was determined by 1H NMR spectroscopic analysis because the product could not be isolated in pure form. The structure assignment is tentative. c The product was obtained as a ca. 75:25 mixture of diastereoisomers.
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Figure 1 Possible conformations 8f′ and 8f′′ leading to regioisomeric [2+2] photocycloaddition products 9e and 9d
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Scheme 8 Formation of products 10–12 by [2+2] photocycloaddition of tetronates 8h and 8i
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Scheme 9 Irradiation of tetronates 8j–l under standard conditions