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Synthesis 2009(12): 2009-2014  
DOI: 10.1055/s-0029-1216824
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Chiral Cyclobutanols and Cyclopentane Dimers via Samarium(II) Iodide Induced Keto-Olefin Cyclisations of Carbohydrate-Derived Unsaturated Ketones

D. Bradley G. Williams*, Judy Caddy, Kevin Blann, J. J. Cronjé Grové, Cedric W. Holzapfel
Department of Chemistry, University of Johannesburg, P.O. Box 524, Auckland Park, Johannesburg 2006, South Africa
Fax: +27(11)4892819; e-Mail: bwilliams@uj.ac.za;

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Publication History

Received 18 February 2009
Publication Date:
19 May 2009 (online)

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Abstract

Some pentose and hexose sugars were converted into unsaturated ketone derivatives, which themselves served as substrates for 4-exo-trig radical cyclisation reactions mediated by SmI2. Depending on the order of addition of reagents, the keto-olefins could also be made to undergo a surprising tandem 5-endo-trig cyclisation/dimerisation reaction to a cyclopentane dimer or a cyclobutane monomer.

Key words

carbocycles - carbohydrates - radical reactions - samarium - ring closure

Carbohydrates are ubiquitous in nature and chemists have recognised the potential of these flexible starting materials, applying them to their use as starting materials in the synthesis of chiral products. [¹] The use of carbohydrates as precursors for the synthesis of cyclopentane derivatives was recognised some time ago. [²] Since then, significant attention has been paid to this strategy, resulting in many new syntheses of substituted stereodefined cyclopentanes. [¹] In addition to the SmI2-mediated synthesis of cyclopentanes in our group, [³] we have also recently reported on the synthesis of cyclobutanes, using that reagent. [4] A number of routes toward the synthesis of compounds 1-3 (Figure  [¹] ), which contain thymine or guanine moieties and which are bioactive (antiviral agents), have been devised. [5] It is the synthesis of analogues of the guanine-containing cyclobutane derivative 3 that our strategy attempts to address. Therefore, we decided to utilise the methodology developed in our laboratories, [4] [6] revolving around SmI2, a selective single-electron reductant, towards the synthesis of functionalised cyclobutanes from carbohydrate precursors in 4-exo-trig ‘keto-olefin’ cyclisation reactions of some carbohydrate derivatives.

Our previous work has shown that a conformationally restricted system is required before cyclisations to small rings will take place. [4] With this in mind, 2,3:5,6-di-O-isopropylidene-d-mannofuranose (4) was subjected to a Wittig­ reaction [7] and in situ (to prevent unwanted Michael addition reactions [8] ) Dess-Martin oxidation [9] to provide keto-olefins 5a (63%) and 5b (5%) (Scheme  [¹] ).

Figure 1 Bioactive compounds 1-3 containing thymine or guanine moieties

Scheme 1

Reaction of 5a with SmI2 by slow dropwise addition of the sugar substrate to the SmI2/HMPA-THF mixture at -78 ˚C gave the desired chiral cyclobutane products 6a (50%) and 6b (33%), arising from a favoured 4-exo-trig cyclisation according to Baldwin’s rules, [¹0] in good yields (Figure  [²] ). Reversal of the mode of addition, that is, addition of the SmI2 solution to the keto-olefin substrate, again afforded products 6a and 6b, but also allowed the isolation of a third isomer 7c in trace amounts. The keto-olefin coupling reaction [¹¹] has been used in many guises, to effect, for example, 3-exo-trig, [¹²] 4-exo-trig [4] , and 5-exo-trig [5] cyclisation reactions. For unactivated alkene systems and for most α,β-unsaturated ester substrates, the mechanism is generally held to proceed via the ketyl radical anion [³] [4] [¹¹-¹³] cyclising onto the alkene, although there is some evidence that the process may proceed via initial reduction of the enoate system followed by cyclisation onto the keto moiety in certain instances. [¹²]

Figure 2 Cyclobutane derivatives 6a-c prepared from keto-enoate 5a

The diastereoselectivity observed presumably relates to the steric bulk of the two acetonide protecting groups preferring a trans set-up in the transition state, which would select 6a as the major product with 6b as the minor. In the event, the 4-exo-trig cyclisation reactions typically proceed such that the hydroxyl group and the ester function maintain a trans relative stereochemistry in the product. [4c] [d] [¹¹c]

We have previously observed analogous cyclisations based on ribose-derived materials. [4] Here, identical reactions could be carried out to prepare cyclobutane derivatives of opposite stereochemistry, when making use of d-lyxose (7) as starting material. Synthesis of the lyxose derivative 10 for treatment with SmI2 was carried out with ease, using known chemistry (Scheme  [²] ) (53% total yield over three steps, cis/trans = 2:7). [4]

Scheme 2

Carrying out the SmI2-mediated ring-closing reaction by adding the trans substrate to the SmI2/HMPA-THF mixture gave four monomers 11a-d in a total yield of 65% (5%:30%:13%:17%) (Figure  [³] ), the major products having the alcohol and ester groups cis with respect to each other, as anticipated from our previous work. [4a] The change in the selectivity from trans to cis in the present instance presumably relates to the large size of the TBDMS group dominating steric interactions in the cyclisation transition state.

Figure 3 Cyclobutane derivatives 11a-d prepared from enoate 10

In all of the cases shown above, the stereochemistry of the isomers obtained was deduced and assigned on the basis of extensive NOE NMR experiments. A single crystal X-ray structure determination [¹4] of the fully deprotected lactone 12 (Scheme  [³] ), derived from 11c by acid-catalysed hydrolysis, offered conclusive evidence of the stereo­chemistry of this product. Indeed, triol 12 [¹4] (and its ribose­-derived analogue [¹5] ) is now perfectly set up for further manipulation towards a nucleoside, which is part of our ongoing studies in this area.

Scheme 3

A remarkable change in the selectivity of the reaction occurred, for some substrates, when the order of the addition of reagents was reversed. As already stated, keto-olefin 5b provided essentially identical product distributions, irrespective of whether the substrate was added to the SmI2 solution or the SmI2 solution was added to the substrate. However, when the SmI2 solution was added to either the ribose-derived substrate 13 [4a] or the lyxose-derived analogue 10, we unexpectedly isolated dimeric materials 14 (Scheme  [4] ).

Scheme 4

Even more surprising was the fact that these products were not dimeric cyclobutanes (i.e., simple dimers of, for example, 11b), but were dimeric cyclopentanes, the products of a tandem cyclisation/dimerisation reaction. This was unexpected in the face of Baldwin’s rules [¹0] of cyclisation, under which it is anticipated that a 4-exo-trig cyclisation dominates over a 5-endo-trig competing possibility. The structure of one of the ribose-derived dimeric products 14a was confirmed by X-ray crystallography. [¹6]

Interestingly, the ribose-derived trityl-protected keto-olefin 15 [4a] failed to afford the dimeric product (Scheme  [5] ), instead producing only the monomeric cyclobutane products already described elsewhere, [4a] regardless of the order of addition. This was also the case for the mannose derivative 5, as described above.

Scheme 5

From these data, it appears as if the outcome of the reaction is dependent on two factors. Firstly, the reaction is sensitive to the order of addition of substrate and reagent: addition of the keto-olefin substrates to SmI2 facilitates monomer formation only, in all cases, while the reverse addition allows the possibility of generating dimers. Secondly, in instances in which dimerisation is at all a possibility, namely when the SmI2 is slowly added to the keto-olefin substrate, steric factors may inhibit the dimerisation reaction altogether, as was found to be the case with the sterically demanding enoate substrates 5 and 15. The reason why dimer formation occurs probably lies in a change in the mechanism of the reaction. Literature reports have indicated that the cyclisation of keto-enoate substrates may also be initiated at the enoate group. [¹²] [¹³] Since the reduction of the ketone to the ketyl radical is reversible, [¹7] and the fact that 4-exo-trig reactions are held to be relatively slow, [¹8] the reaction may well favour reaction at the enoate under the particular reaction conditions cited here. Such cyclisations to monomeric systems have previously been observed when the reactions are performed in the presence of a proton source. [¹9] (Proton sources have been shown to dramatically effect SmI2-mediated reactions, also permitting stereoselective reactions to be secured from chiral alcohols. [²0] ) Furthermore, such reactions at the enoate are also known to lead to dimerisation products in some instances. [²¹] Here, the process is generally believed to proceed via radical addition, but one different mechanism has also been proposed. [²¹c] In any case, a recent detailed study by Flowers [²²] indicates that the keto-olefin reaction, particularly the role of HMPA therein, is difficult to predict. In the present case, it is quite possible that the mechanism switches from the usual ketyl radical cyclisation to an anion cyclisation/radical dimerisation or similar mechanism of the enoate moieties to produce 16 and 17 and so generate the five-membered rings (Scheme  [6] ). In this way, the preferred 5-exo-trig cyclisation is followed.

Scheme 6

In summary, chiral cyclobutane derivatives can be readily prepared from chiral carbohydrate precursors of varying carbon number and chirality using a reductive cyclisation protocol. Furthermore, depending on the steric bulk around the ketone functionality and the order of addition of reagents, cyclopentane dimers may also be prepared from common intermediates. Excessive steric bulk prevents the formation of such dimers, regardless of the order of addition of the reagents, producing cyclobutane derivatives in all instances. We are currently in the process of preparing analogues of 3, from products of this study, with the view to their biological evaluation, the results of which will be disclosed in due course.

TLC was conducted quantitatively on Merck GF254 precoated silica gel glass plates (0.25 mm layer). Various solvent mixtures were used to elute the chromatograms with the mixture of hexanes and EtOAc usually being the eluent of choice. Aromatic derivatives were visualised by their fluorescence under UV light (254 nm) while carbohydrate substrates were detected after spraying the TLC plate with a chromic acid solution and then heating it over an open flame. Flash column chromatography refers to column chromatography under N2 pressure (ca. 50 kPa). The columns were loaded with Merck Kieselgel 60 (230-400 mesh) and eluted with appropriate solvent mixtures in a volume per volume ratio. THF was predried over freshly ground KOH. The KOH was then filtered off and the solvent distilled from sodium-benzophenone under N2 immediately prior to use, and once a sustained blue colour was present. HMPA was heated over CaH2 under argon for one week prior to its use. The solvent was only used if freshly distilled. NMR-spectra were recorded using a Varian Gemini 2000, 300 MHz spectrometer. The samples were usually made up in CDCl3 and for more polar samples D2O was used. The ¹H NMR data are listed in order: Chemical shift (δ, reported in ppm and referenced to the residual solvent peak of CDCl3 [δ = 7.24]), the multiplicity, the coupling constant J expressed in Hz, the proton integration, and finally the specific hydrogen allocation. Spin-decoupling experiments aided in the determination of the coupling constants and hydrogen allocation. The relative stereochemistry was determined after studying nuclear Overhauser effect spectra (1D NOE difference). ¹³C NMR data are listed in the order: chemical shift (δ, reported in ppm referenced to the solvent peak of CDCl3 [(δ = 77.0]) and the specific carbon atom allocation. DEPT and HETCOR spectroscopy were used to assist in the allocation of difficult spectra where necessary. Mass spectra were recorded on a Finnigan Matt 8200 spectrometer at an electron impact of 70 eV, while FAB-HRMS spectra were recorded on a Varian E7070 using glycerol or nitrobenzyl alcohol as the matrix. A PerkinElmer 881 spectrometer was used to record IR spectra using anhyd CHCl3 as the solvent. The data are listed with characteristic peaks indicated in wavenumbers (cm-¹). A Jasco model DIP-730 spectropolarimeter having a cell with a 10 mm path length was used to determine optical rotations. The concentration (c) indicates the concentration of the sample in grams per 100 mL of solution. All reactions were performed in flamed out glass apparatus using anhyd solvents unless otherwise stated. All SmI2 reactions were carried out under argon using degassed solvents while standard chemistry was done under N2.

Keto-Enoate 5a

To a solution of 2,3:5,6-di-O-isopropylidene-d-mannofuranose (4; 100 mg, 0.37 mmol) in anhyd CH2Cl2 (1.5 mL) [4a] was added ethyl(triphenylphosphoranylidene)acetate (157 mg, 0.45 mmol) and the reaction mixture stirred at r.t. Upon completion of the reaction (6 d, TLC), the mixture was diluted with CH2Cl2 (1.5 mL), treated with Dess-Martin periodinane (191 mg, 0.45 mmol) and stirred at r.t. for 3 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (5:1 hexanes-EtOAc) to afford the trans title compound as a colourless oil; yield: 76 mg (63%); R f = 0.67 (2:1 hexanes-EtOAc).

IR (CHCl3): 3026, 1723, 1664 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 6.76 (dd, J = 15.2, 3.4 Hz, 1 H), 6.09 (d, J = 15.2 Hz, 1 H), 5.03 (s, 2 H), 4.71 (dd, J = 8.1, 6.3 Hz, 1 H), 4.21-4.11 (m, 3 H), 3.87 (dd, J = 8.7, 6.3 Hz, 1 H), 1.59 (s, 3 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.35 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).

¹ ³C NMR (75 MHz, CDCl3): δ = 204.1, 165.2, 141.5, 123.3, 110.7, 110.6, 81.2, 75.6, 75.8, 64.9, 60.5, 26.6, 25.5, 24.7, 24.5, 14.1.

MS (FAB): m/z = 329 ([M + 1]+, 100%).

HRMS-FAB: m/z calcd for C16H24O7: 329.1600 ([M]+); found: 329.1611.

Mannofuranose Monomers 6a-c

Keto-enoate 5a (69 mg, 0.21 mmol) was dissolved in degassed THF (5 mL) and the solvent removed by vacuum distillation to ensure an oxygen-free system. The residue was then dissolved in THF (20 mL) and added dropwise over 20 min with stirring to a freshly prepared solution of SmI2 in THF (8.8 mL of a 0.1 M solution, 0.88 mmol, 4.2 equiv) and HMPA (0.21 mL, 1.43 mmol, 6.8 equiv) at -78 ˚C. The mixture was stirred at -78 ˚C for 2 h, after which it was diluted with EtOAc (20 mL) and filtered through a thin pad of silica gel. The solvent was removed in vacuo and the residue was purified by flash column chromatography (3:1 hexanes-EtOAc). Two isomeric monomers 6a and 6b were obtained as oils (total yield: 83%). Reversed addition allowed 6c to be isolated in a separate reaction as a colourless oil.

Cyclobutane 6a

Yield: 35 mg (50%); R f = 0.47 (2:1 hexanes-EtOAc); [α]D +61.1 (c 1.0, CHCl3).

IR (CHCl3): 3568, 2949, 1733, 1730, 1066 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 4.46 (t, J = 6.9 Hz, 1 H), 4.41 (s, 1 H), 4.40 (s, 1 H), 4.12 (q, J = 7.1 Hz, 2 H), 3.99 (dd, J = 8.4, 6.9 Hz, 1 H), 3.75 (dd, J = 8.4, 6.9 Hz, 1 H), 2.61-2.48 (m, 2 H), 2.53 (d, J = 6.0 Hz, 1 H, OH), 2.47-2.38 (m, 1 H), 1.56 (s, 3 H), 1.42 (s, 3 H), 1.37 (s, 3 H), 1.25 (s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H).

¹ ³C NMR (75 MHz, CDCl3): δ = 172.1, 114.9, 109.3, 81.0, 76.2, 75.9, 71.9, 63.9, 60.7, 42.1, 31.5, 26.5, 26.3, 25.6, 24.9, 14.2.

MS (FAB): m/z = 331 ([M + 1]+).

HRMS-FAB: m/z calcd for C16H26O7: 331.1757 ([M]+); found: 331.1756.

Cyclobutane 6b

Yield: 23 mg (33%); R f = 0.29 (2:1 hexanes-EtOAc); [α]D +19.5 (c 0.5, CHCl3).

IR (CHCl3): 3429, 3033, 2935, 1735, 1222 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 4.84 (dd, J = 6.3, 5.4 Hz, 1 H), 4.43 (t, J = 7.2 Hz, 1 H), 4.38 (dd, J = 5.4, 2.1 Hz, 1 H), 4.13 (q, J = 7.2 Hz, 2 H), 3.92 (dd, J = 7.5, 7.2 Hz, 1 H), 3.77 (dd, J = 7.5, 7.2 Hz, 1 H), 2.77-2.66 (m, 1 H), 2.55 (dd, J = 16.2, 11.4 Hz, 1 H), 2.55 (br s, 1 H, OH), 2.13 (dd, J = 16.2, 5.9 Hz, 1 H), 1.54 (s, 3 H), 1.45 (s, 3 H), 1.37 (s, 3 H), 1.26 (s, 3 H), 1.23 (t, J = 7.2 Hz, 3 H).

¹ ³C NMR (75 MHz, CDCl3): δ = 171.3, 113.9, 108.9, 81.2, 75.9, 74.5, 71.3, 63.9, 60.7, 39.5, 29.7, 26.2, 25.3, 25.2, 24.5, 14.2.

MS (FAB): m/z = 331 ([M + 1]+, 100%).

HRMS-FAB: m/z calcd for C16H26O7: 331.1757 ([M]+); found: 331.1753.

Cyclobutane 6c

Yield: 11 mg (16%); R f = 0.56 (2:1 hexanes-EtOAc); [α]D +17.4 (c 0.5, CHCl3).

IR (CHCl3): 3400, 3026, 2942, 1702, 1045 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 4.77 (dd, J = 5.7, 5.4 Hz, 1 H), 4.33 (dd, J = 8.4, 6.6 Hz, 1 H), 4.28-3.99 (m, 5 H, 4 × CH, OH), 3.69 (t, J = 8.6 Hz, 1 H), 2.91 (dd, J = 12.6, 6.6 Hz, 1 H), 2.27 (ddd, J = 13.2, 12.6, 5.4 Hz, 1 H), 2.09 (dd, J = 13.2, 6.6 Hz, 1 H), 1.41 (s, 3 H), 1.35 (s, 3 H), 1.34 (s, 3 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.26 (s, 3 H).

¹ ³C NMR (75 MHz, CDCl3): δ = 174.5, 110.3, 107.9, 85.6, 82.9, 78.9, 78.6, 65.3, 61.2, 42.8, 35.3, 26.0, 25.9, 25.3, 23.7, 14.0.

MS (FAB): m/z = 331 ([M + 1]+, 100%).

HRMS-FAB: m/z calcd for C16H26O7: 331.1757 ([M]+); found: 331.1757.

Keto-Enoate 10

The general procedure to perform a Wittig reaction with ethyl(tri­phenylphosphoranylidene)acetate in CH2Cl2 [4a] was carried out on protected lyxose derivative 8 (1.050 mg, 3.44 mmol) followed by in situ Dess-Martin oxidation. The solvent was removed in vacuo and the residue was purified by flash column chromatography (7:1 hexanes-EtOAc) to afford the trans title compound as a colourless oil; yield: 749 mg (56%); R f = 0.57 (5:1 hexanes-EtOAc). The cis isomer (224 mg, 17%) was obtained as a by-product.

IR (CHCl3): 1723, 1386, 1313, 1267, 1191, 1111, 1080, 1034, 982, 847 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 6.73 (dd, J = 15.6, 4.5 Hz, 1 H), 6.07 (dd, J = 15.6, 1.7 Hz, 1 H), 5.02-4.94 (m, 2 H), 4.42 (d, J = 18.8 Hz, 1 H), 4.13 (d, J = 18.8 Hz, 1 H), 4.12 (q, J = 7.2 Hz, 2 H), 1.59 (s, 3 H), 1.37 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 0.88 (s, 9 H), 0.05 (s, 3 H), 0.03 (s, 3 H).

¹ ³C NMR (75 MHz, CDCl3): δ = 205.7, 165.2, 140.9, 123.5, 110.8, 81.6, 75.9, 68.3, 60.5, 26.8, 25.8, 24.8, 18.3, 14.2, -5.5.

HRMS-FAB: m/z calcd for C18H33SiO6: 373.2046 ([M + 1]+); found: 373.2037.

Lyxose Monomers 11a-d

The general procedure to form monomers with SmI2 in THF in the presence of HMPA via normal addition was used to form monomers from enoate 10 (78 mg, 0.21 mmol). The residue was purified by flash column chromatography (3:1 hexanes-EtOAc). Four monomer isomers were obtained as oils; total yield: 55%.

Cyclobutane 11a

Yield: 4 mg (5%); [α]D -28.2 (c 2.0, CHCl3); R f = 0.56 (5:1 hexanes-EtOAc).

IR (CHCl3): 3040, 2960, 2870, 1790, 1740, 1660, 1540, 1390, 1270 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 4.75 (t, J = 5.6 Hz, 1 H), 4.21 (d, J = 5.7 Hz, 1 H), 4.20-4.06 (m, 2 H), 3.97 (br s, 1 H, OH), 3.80 (d, J = 1.5 Hz, 2 H), 2.80 (dd, J = 12.5, 6.6 Hz, 1 H), 2.26 (td, J = 13.5, 5.1 Hz, 1 H), 2.03 (dd, J = 13.6, 6.6 Hz, 1 H), 1.41 (s, 3 H), 1.24 (s, 3 H), 1.25 (t, J = 6.9 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H).

¹ ³C NMR (75 MHz, CDCl3): δ = 173.9, 110.0, 85.4, 83.1, 78.9, 66.1, 60.7, 45.7, 34.8, 26.2, 25.9, 23.8, 18.4, 14.1, -5.40.

MS (EI, 70 eV): m/z (%) = 375 ([M + 1]+, 4), 359 ([M - CH3]+, 31), 329 ([M - OEt]+, 40), 317 ([M - C4H9]+, 72), 259 ([M - TBDMS]+, 53), 28 (100).

HRMS-FAB: m/z calcd for C18H35O6Si: 3754.2203 ([M + 1]+); found: 375.2202.

Cyclobutane 11b

Yield: 27 mg (30%); [α]D -138.9 (c 16.0, CHCl3); R f = 0.46 (5:1 hexanes-EtOAc).

IR (CHCl3): 3040, 2960, 2880, 1790, 1740, 1715, 1660, 1560, 1390, 1270, 1220 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 4.37 (s, 1 H), 4.36 (s, 1 H), 4.10 (q, J = 7.2 Hz, 2 H), 3.84 (d, J = 9.9 Hz, 1 H), 3.51 (d, J = 9.9 Hz, 1 H), 3.02 (br s, 1 H, OH), 2.56 (dd, J = 16.2, 9.0 Hz, 1 H), 2.44 (dd, J = 16.2, 6.9 Hz, 1 H), 2.34 (ddd, J = 9.0, 6.9, 1.8 Hz, 1 H), 1.50 (s, 3 H), 1.22 (s, 3 H), 1.22 (t, J = 7.2 Hz, 3 H), 0.87 (s, 9 H), 0.60 (s, 3 H), 0.56 (s, 3 H).

¹ ³C NMR (75 MHz, CDCl3): δ = 172.4, 114.4, 80.7, 75.8, 73.2, 64.7, 60.4, 43.2, 31.7, 26.4, 25.9, 25.8, 18.4, 14.2, -5.31, -5.33.

HRMS-FAB: m/z calcd for C18H35O6Si: 375.2203 ([M + 1]+); found: 375.2203.

Cyclobutane 11c

Yield: 15 mg (13%); [α]D +57.7 (c 2.0, CHCl3); R f = 0.31 (5:1 hexanes-EtOAc).

IR (CHCl3): 3040, 2960, 2880, 1780, 1740, 1715, 1660, 1390, 1272, 1230 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 4.76 (t, J = 5.5 Hz, 1 H, H-5′), 4.41 (dd, J = 5.5, 1.7 Hz, 1 H, H-1′), 4.11 (q, J = 7.2 Hz, 2 H,), 3.71 (d, J = 10.2 Hz, 1 H,), 3.57 (d, J = 10.2 Hz, 1 H), 3.18 (br s, 1 H, OH), 2.64-2.56 (m, 2 H), 2.50 (dd, J = 5.7, 3.9 Hz, 1 H), 1.47 (s, 3 H), 1.24 (s, 3 H), 1.23 (t, J = 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.07 (s, 3 H), 0.05 (s, 3 H).

¹ ³C NMR (75 MHz, CDCl3): δ = 172.2, 113.6, 80.5, 71.9, 63.1, 60.5, 40.6, 28.8, 25.9, 25.3, 25.2, 18.3, 14.2, -5.4.

HRMS-FAB: m/z calcd for C18H35O6Si: 375.2203 ([M + 1]+); found: 375.2212.

Cyclobutane 11d

Yield: 12 mg (17%); [α]D +61.7 (c 5.0, CHCl3); R f = 0.27 (4:1 hexanes-EtOAc).

IR (CHCl3): 3040, 2960, 2880, 1790, 1740, 1715, 1660, 1560, 1390, 1270, 1220 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 4.58 (d, J = 4.8 Hz, 1 H), 4.12 (q, J = 7.2 Hz, 2 H), 4.04 (t, J = 4.8 Hz, 1 H), 3.64 (d, J = 10.1 Hz, 1 H), 3.59 (d, J = 10.1 Hz, 1 H), 2.92 (br s, 1 H, OH), 2.71-2.55 (m, 3 H), 1.58 (s, 3 H), 1.31 (s, 3 H), 1.23 (t, J = 7.2 Hz, 3 H), 0.89 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H).

¹ ³C NMR (75 MHz, CDCl3): δ = 172.4, 114.3, 79.4, 73.6, 69.0, 64.2, 60.5, 52.6, 31.9, 27.4, 26.4, 25.8, 18.2, 14.2, -5.6.

HRMS-FAB: m/z calcd for C18H35O6Si: 3754.2203 ([M + 1]+); found: 375.2205.

Dimers 14a-d; General Procedure

The keto ester 10 or 13 (0.21 mmol) was dissolved in degassed THF (5 mL) and the solvent removed by vacuum distillation to ensure an oxygen-free system. The residue was then dissolved in THF (20 mL) and HMPA (0.21 mL, 1.43 mmol, 6.8 equiv) and subsequently cooled to -78 ˚C. A freshly prepared solution of SmI2 in THF (6.3 mL of a 0.1 M solution, 0.63 mmol, 3.0 equiv) was then added dropwise over 20 min with stirring. The stirring was continued at -78 ˚C for 2 h, after which it was diluted with EtOAc (20 mL) and filtered through a thin pad of silica gel. The solvent was removed in vacuo and the residue purified by flash column chromatography.

Ribose-Derived Pivaloyl Dimer 14a [¹6]

Yield: 24 mg (0.035 mmol, 33%); colourless oil; R f = 0.37 (2:1 hexanes-EtOAc).

IR (CHCl3): 3520, 3040, 3000, 2960, 1740, 1715, 1570, 1220, 1170 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 4.88 (dd, J = 6.8, 2.8 Hz, 2 H), 4.50 (d, J = 6.8 Hz, 2 H), 4.25 (q, J = 7.2 Hz, 2 H), 4.22 (d, J = 12.2 Hz, 2 H), 4.10 (d, J = 12.2 Hz, 2 H), 4.05 (q, J = 7.2 Hz, 2 H), 3.80 (br s, 2 H, OH), 3.04 (m, 2 H), 2.67 (t, J = 2.8 Hz, 2 H), 1.43 (s, 6 H), 1.28 (s, 6 H), 1.26 (t, J = 7.2 Hz, 6 H), 1.20 (s, 18 H).

¹³C NMR (75 MHz, CDCl3): δ = 178.4, 172.6, 111.9, 85.5, 83.1, 81.2, 67.1, 61.1, 51.6, 46.8, 38.9, 27.1, 26.4, 24.3, 14.1.

HRMS-FAB: m/z calcd for C34H56O14: 688.3670 ([M + 2]+); found: 688.3672.

Ribose-Derived Pivaloyl Dimer 14b

Yield: 20 mg (0.030 mmol, 28%); white needle-like, gummy crystals; R f = 0.25 (2:1 hexanes-EtOAc).

IR (CHCl3): 3600, 3040, 2960, 1740, 1715, 1390, 1220, 1170 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 4.56 (dd, J = 6.8, 4.2 Hz, 2 H), 4.44 (d, J = 6.8 Hz, 2 H), 4.36 (d, J = 11.7 Hz, 2 H), 4.23 (d, J = 11.7 Hz, 2 H), 4.16 (q, J = 7.2 Hz, 4 H), 2.87-2.76 (m, 6 H, 4 × CH, 2 × OH), 1.42 (s, 6 H), 1.258 (s, 6 H), 1.264 (t, J = 7.2 Hz, 6 H), 1.19 (s, 18 H).

¹³C NMR (75 MHz, CDCl3): δ = 178.2, 170.3, 113.0, 86.0, 81.2, 81.0, 65.3, 61.1, 56.4, 48.4, 38.9, 27.2, 26.2, 24.9, 14.2.

HRMS-FAB: m/z calcd for C34H55O14: 687.3592 ([M + 1]+); found: 687.3588.

Ribose-Derived OTBDMS Dimer 14c

Yield: 47 mg (0.063 mmol, 60%); colourless oil; R f = 0.37 (4:1 hexanes-EtOAc).

IR (CHCl3): 3040, 2960, 1740, 1715, 1660, 1570, 1220, 1100 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 4.50 (dd, J = 6.7, 4.4 Hz, 2 H), 4.42 (d, J = 6.7 Hz, 2 H), 4.20-4.02 (m, 4 H), 3.84 (d, J = 10.2 Hz, 2 H), 3.72 (d, J = 10.2 Hz, 2 H), 3.39 (br s, 2 H, OH), 2.78 (d, J = 9.3 Hz, 2 H), 2.55-2.71 (m, 2 H), 1.39 (s, 6 H), 1.24 (s, 6 H), 1.23 (t, J = 7.2 Hz, 6 H), 0.88 (s, 18 H), 0.06 (s, 6 H), 0.04 (s, 6 H).

¹³C NMR (75 MHz, CDCl3): δ = 170.6, 112.6, 85.3, 81.1, 80.7, 63.3, 60.5, 55.9, 47.9, 26.3, 25.9, 24.9, 18.5, 14.2, -5.5, -5.3.

HRMS-FAB: m/z calcd for C36H67Si2O12: 747.4171 ([M + 1]+); found 747.4171.

Lyxose-Derived OTBDMS Dimer 14d

Yield: 34 mg (0.045 mmol, 43%); colourless oil; [α]D +29.5 (c 0.5, CHCl3); R f = 0.32 (4:1 hexanes-EtOAc).

IR (CHCl3): 3041, 2960, 1740, 1714, 1662, 1220, 1100 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 4.81 (t, J = 5.6 Hz, 1 H), 4.73 (t, J = 5.6 Hz, 1 H), 4.36 (d, J = 5.4 Hz, 1 H), 4.19 (d, J = 5.7 Hz, 1 H), 4.16-4.10 (m, 4 H), 3.88 (d, J = 9.6 Hz, 1 H), 3.75 (d, J = 9.6 Hz, 1 H), 3.46 (d, J = 1.2 Hz, 2 H), 3.17 (br s, 1 H, OH), 2.99 (d, J = 12.9 Hz, 1 H), 3.02-2.91 (m, 1 H), 2.73-2.64 (m, 1 H), 2.68 (d, J = 12.0 Hz, 1 H), 1.56 (br s, 1 H, OH), 1.52 (s, 3 H), 1.39 (s, 3 H), 1.35 (s, 3 H), 1.25 (s, 3 H), 1.26 (t, J = 6.6 Hz, 3 H), 1.24 (t, J = 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0.06 (s, 6 H), 0.04 (s, 6 H).

¹ ³C NMR (75 MHz, CDCl3): δ = 172.3, 171.3, 110.3, 109.6, 84.3, 82.6, 80.5, 80.4, 80.3, 80.2, 66.1, 63.8, 60.6, 60.5, 54.8, 50.5, 42.4, 40.3, 26.5, 26.4, 25.9, 25.8, 24.8, 24.3, 18.4, 18.3, 14.2, 14.1, -5.54, -5.52, -5.37, -5.30.

HRMS-FAB: m/z calcd for C36H66O12Si2: 747.4171 ([M]+); found: 747.4172.

Acknowledgment

The authors thank the NRF and the University of Johannesburg for funding this project.

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CCDC 294062.

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CCDC 294062.

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Figure 1 Bioactive compounds 1-3 containing thymine or guanine moieties

Scheme 1

Figure 2 Cyclobutane derivatives 6a-c prepared from keto-enoate 5a

Scheme 2

Figure 3 Cyclobutane derivatives 11a-d prepared from enoate 10

Scheme 3

Scheme 4

Scheme 5

Scheme 6