Cp₂TiCl-catalyzed highly stereoselective intramolecular epoxide allylation using allyl carbonates

Abstract

A useful method for the diastereoselective synthesis of vinyl substituted carbo- and heterocycles is described. Highly functionalized structures difficult to achieve by other methodologies are obtained in a single step by this procedure.

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Epoxides are highly versatile functional groups in organic synthesis owing to the fact that their manipulation yields many attractive final products. Thus, for example, diverse carbon nucleophiles, such as Grignard and organolithium reagents or organocuprates, have been used in ring-opening reactions to install a new C–C bond.^1,2 The intramolecular version of this reaction would allow the preparation of different carbo- and heterocycles with different sizes and functionalities. Nevertheless, the synthesis of suitable polyfunctionalized starting materials is not simple taking into account the chemical incompatibilities between the required reactive partners. In this context, neutral pronucleophiles like olefins or allylsilanes (I, LG = SiR₃, Scheme 1) are more convenient since they allow better control of the reaction and functional group compatibility.³ A valuable advantage of the reactions of epoxides with allylsilanes, compared with alkenes, is their ability to stabilize β-carbocations (III, Scheme 1), thereby controlling which carbon of the alkene is the nucleophilic carbon.⁴ Moreover the allylsilane can control the direction of the final elimination acting as a good leaving group that stabilizes the generated positive charge (IV, Scheme 1). On the other hand, its main drawback is related to the electrophilic character of the reaction, which implies the use of Lewis acids, such as TiCl₄, and strict control over the temperature. Another disadvantage of allylsilanes relative to simple alkenes is that extra synthetic steps are necessary because they are generally prepared from oxygenated-allyl groups. Therefore, the direct employment of allylic oxygenated functionalities in epoxide ring-opening reactions retaining the favourable characteristics of allyl silane analogues using very mild reaction conditions would represent an important advance in organic synthesis.

Scheme 1 Working hypothesis.

The limitation of this approach is that the corresponding β-carbocations (Scheme 1, III, LG = OCOR) would not be stabilized and the control of the direction of elimination would remain a challenge due to the lack of a carbocation stabilizing group and also a good leaving group. As a result, a cationic pathway can be discarded in this case, and an alternative reaction pathway based on carbon-centered radicals was considered. Cp₂TiCl⁵-mediated homolytic epoxide opening is a well-known reaction,^6–19 which has allowed many remarkable transformations, including a highly successful bioinspired approach to different natural products.^20–26 Epoxyallylcarboxylates I (LG = OCOR, Scheme 1) are expected to react with Cp₂TiCl, yielding radical intermediate type-V. After the homolytic opening of the epoxide, the β-titanoxy radical generated V would undergo further radical cyclization generating a carbon-centered radical VI. At this point, we expected that an oxygenated function in the β-position would act as a good leaving group, thus directing the final elimination towards IV assisted by Cp₂TiCl as the Lewis acid.^27,28 In fact, we had previously observed the Cp₂TiCl-mediated radical fragmentation of β-acetoxy alkyl radicals toward the corresponding alkenes.^21,29

In this alternative radical pathway, Cp₂TiCl would play a crucial dual role in the intramolecular epoxide allylation with oxygenated-allyl groups: (i) starting the reaction by homolytic opening of the oxirane ring and (ii) controlling the final product obtained by radical fragmentation.

Here we wish to communicate that epoxides can formally be allylated intramolecularly in a highly diastereoselective manner under smooth reaction conditions using easily prepared and handled allylic carbonates as allylation reagents. This approach also allows the preparation of different carbo- and heterocycles with different functionalities.

Due to the known oxophilic character of Ti(III), our initial studies began testing different allyl pronucleophiles 1a–d and 3, including different oxygenated functional groups such as carbonate, acetate, benzoate, methoxyl or hydroxyl groups. Moreover, an epoxyallylsilane 6 was also tested in order to compare the observed results with oxygenated functions. Remarkably, the new developments in titanocene(III)-regenerating agents now allow the use of substoichiometric amounts of Cp₂TiCl₂ as a precatalyst. In this context, the combination of 2,4,6-collidine and trimethylsilyl chloride developed in our lab³⁰ has been extensively used, and it was the choice in this case.

Treatment of compounds 1a–d with Cp₂TiCl led to the expected cyclic compound 2 with variable yields from 50 to 85% (Scheme 2). It is noteworthy that compound 2 was obtained as a single diastereomer in all cases. NOE-diff. experiments (see the Experimental section) showed a cis relationship between the hydroxyl group at C-3 and the vinyl group at C-5.

Scheme 2 Ti(III)-mediated cyclization of model compounds 1a–d. Reaction conditions: (i) 1a–d (1.0 mmol) Cp₂TiCl₂ (0.2 mmol), Mn (8.0 mmol), Me₃SiCl (4.0 mmol), 2,4,6-collidine (6.0 mmol), THF, RT, 16 h. Isolated yields after column chromatography.

When epoxyallylic alcohol 3 was treated with Cp₂TiCl, cyclic compounds 4 and 5 were isolated in a 2/1 ratio (Scheme 3). In this case, the lack of a better leaving group resulted in a different final process. After homolytic oxirane-opening and subsequent cyclization, Ti(III)-mediated hydrogen abstraction in the radical intermediate yields aldehyde 4 (Scheme 3, process a).³¹ Besides, the radical intermediate can abstract a hydrogen-atom from the solvent (THF) leading to reduced product 5 (Scheme 3, process b).³²

Scheme 3 Ti(III)-mediated cyclization of compound 3. Reaction conditions: (i) 3 (1.0 mmol) Cp₂TiCl₂ (0.2 mmol), Mn (8.0 mmol), Me₃SiCl (4.0 mmol), 2,4,6-collidine (6.0 mmol), THF, RT, 16 h. Isolated yields after column chromatography.

Silyl derivative 6 was assayed under the same reaction conditions, leading to a mixture of trimethylsilyl containing compounds 7 and 8 in a 1/0.6 ratio (Scheme 4).²³ These two compounds were obtained by similar hydrogen-atom abstractions mentioned above. Ethyl carbonate derivative 1a (85% yield, Scheme 2) resulted in the best yield and therefore ethyl carbonate was the leaving group of choice for the following reactions.

Scheme 4 Ti(III)-mediated cyclization of compound 6. Reaction conditions: (i) 6 (1.0 mmol) Cp₂TiCl₂ (0.2 mmol), Mn (8.0 mmol), Me₃SiCl (4.0 mmol), 2,4,6-collidine (6.0 mmol), THF, RT, 16 h. Isolated yield after column chromatography. Compounds 7 and 8 were not separated.

With the optimized conditions in hand, we explored substrates with different linkers, functionalities and substitution patterns. The results are summarized in Table 1.

Table 1 Substrate scope of [Ti]-catalyzed intramolecular epoxide allylations

Entry	Substrate	Product	Yield^a (%)
a Isolated yield after column chromatography. b 7/3 mixture of cis/trans diastereoisomers. c Compounds 14 and 15 were obtained in a 1/1 ratio. Both compounds were obtained as diastereomeric mixture in 2/1 dr. d Additional 12% of cyclic compound S43 in which the carbonate group is eliminated was also obtained (see ESI for further details). e 1/1 mixture of cis/trans diastereoisomers. f Additional 15% of cyclic compound S44 in which the carbonate moiety is eliminated was also obtained (see ESI for further details).
1		2	65%
2			53%
3			60%^b
4			55%^c
5			50%^d
6			54%
7			58%
8			76%
9			74%
10			71%^e
11			62%^f
12			73%

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The reaction successfully gave different five- and six-membered carbo- and heterocycles with excellent diastereoselectivities in almost all the tested substrates. Titanium-induced cyclization of compound E-1a (Table 1, entry 1) led to compound 2 as Z-1a (Scheme 2), revealing the stereoconvergent nature of the process. Additionally, the reaction proved to be compatible with different functional groups, including esters (Table 1, entries 1–7 and 11–12), sulfones (Table 1, entry 10), sulphonamides (Table 1, entries 8 and 9) or free hydroxyl groups (Table 1, entry 11), and permitted different substitution patterns in the oxirane ring (Table 1, entries 1–4) as well as in the involved alkene (Table 1, entries 5 and 11).

The regiochemistry of the radical epoxide opening mainly depends upon the substitution pattern³³ and controls the size of the obtained final cycle (Table 1, entries 1 vs. 2 and entries 8 vs. 9). As shown in entry 4, treatment of compound 13 with Cp₂TiCl led to the formation of a 1/1 mixture of five- and six-membered rings, as expected from a 1,2-disubstituted oxirane ring.^8,9 However in compound 18 electronic effects control the homolytic epoxide opening, thus only affording the six-membered ring 19. Stereoconvergency was further demonstrated, as diastereomeric mixture 28 (entry 11) gave rise to a single cyclic diastereomer 29. It is also noteworthy that the stereoselectivity of this cyclization allows the setting up of two stereocenters in six-membered and notably five-membered rings (entries 2 and 9). When the stereocenters are located in 1,3-relative positions a cis stereochemistry between the hydroxyl group at C-3 and the vinyl group at C-5 is observed as in the case of compounds 2, 17 and 23 (entries 1, 5 and 8). On the other hand, compounds presenting contiguous stereocenters showed a trans (entries 2, 7, 9 and 12) or cis relationship (entry 3) between the vinyl and hydroxymethyl groups depending on the substitution pattern of the intermediate radical. Interestingly, in more functionalized substrates even three stereocenters can be allocated stereoselectively (entries 6 and 11). In the case of 1,3-relative positions, cis stereochemistry between the hydroxyl group at C-3 and the vinyl group at C-5 is preserved. The additional stereocenter at C-4 presents a trans stereochemistry with respect to the other two stereocenters.

All these stereochemical findings can be rationalized invoking the Beckwith–Houk rules.^34,35cis Substituted five-membered rings are expected for 5-exo-trig cyclizations (entry 3). Trisubstituted radicals proceed disposing the bulkier substituent (R₂ in Scheme 5a) in a pseudoequatorial position (Scheme 5) thus yielding the observed cyclopentanes 10 and 25 (entries 2 and 9).

Scheme 5 (a) Ring-closure of 5-hexenyl radicals. (b) Selected examples from Table 1.

Although cyclizations of 6-heptenyl radicals are less studied, a similar reasoning explains the experimental results. In the chair-like transition states all the bulkier substituents (R₁ and R₃ in Scheme 6) are disposed in the equatorial positions. Additional template effects cannot be ruled out in cyclization of compound 28 (entry 11).^20–23

Scheme 6 (a) Schematic ring-closure of 6-heptenyl radicals. (b) Selected examples from Table 1.

In the case of entries 4 and 10, the structures of compounds 13 and 26 do not follow these stereochemical trends and mixtures of diastereoisomers are obtained. The intrinsic reactivity of a 1,2-disubstituted epoxide in compound 13 (entry 4) precludes a clear analysis of its stereoselectivity. In compound 26 (entry 10), the transition state may be affected by bulky phenyl sulphonyl groups avoiding a clear chair-like transition state and leading to the formation of both isomers.

Conclusions

A useful method for the diastereoselective synthesis of vinyl substituted carbo- and heterocycles is presented. The protocol is based on the radical opening of an epoxide and subsequent intramolecular addition to an allyl carbonate. Formally, the reaction yields similar products as the allylation of epoxides by the appropriate nucleophile but with several significant advantages. Firstly, the polyfunctionalized substrates required are very easily obtained and handled. Secondly, the cyclization reaction occurs at room temperature and under very smooth conditions highly compatible with diverse functional groups. And lastly, the diastereoselectivity observed is quite remarkable giving rise in most of the cases to a single diastereomer even when three stereogenic centres are generated in the final product. Highly functionalized structures difficult to achieve by other methodologies are obtained in a single step by this procedure. Thus, this method is an interesting tool in the context of organic synthesis.

Experimental section

General remarks

Unless otherwise stated, all reagents and solvents (CH₂Cl₂, Et₂O, MeCN, EtOAc, hexane, DMF, and MeOH) were purchased from commercial sources and used without further purification. Dry THF was freshly distilled over Na/benzophenone. Flash column chromatography was carried out using Silica Gel 60 (230–400 mesh, Scharlab, Spain) as the stationary phase. Analytical TLC was performed on aluminium sheets coated with silica gel with the fluorescent indicator UV₂₅₄ (Alugram SIL G/UV₂₅₄, Mackerey-Nagel, Germany) and observed under UV light (254 nm) and/or staining with Ce/Mo reagent or phosphomolybdic acid solution and subsequent heating. All ¹H and ¹³C NMR spectra were recorded on Varian 300, 400 or 500 MHz spectrometers at a constant temperature of 298 K. Chemical shifts are reported in ppm and referenced to residual solvent. Coupling constants (J) are reported in hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: m = multiplet, quint. = quintet, q = quartet, t = triplet, d = doublet, s = singlet, b = broad. Assignment of the ¹³C NMR multiplicities was accomplished by DEPT techniques.

Characterization data of substrates Z-1a, 1b–d, E-1a, 3, 6, 9, 11, 13, 16, 18, 20, 22, 24, 26, 28 and 30

Compound Z-1a. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 5.75–5.59 (m, 1H), 5.59–5.43 (m, 1H), 4.64 (d, J = 6.7 Hz, 2H), 4.15 (q, J = 7.0 Hz, 3H), 3.71 (s, 3H), 3.70 (s, 3H), 2.80 (d, J = 7.5 Hz, 2H), 2.70 (dd, J = 7.3, 4.2 Hz, 1H), 2.21 (dd, J = 14.8, 4.2 Hz, 1H), 1.95 (dd, J = 14.8, 7.3 Hz, 1H), 1.27 (t, J = 7.0 Hz, 3H), 1.24 (s, 3H), 1.20 (s, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 171.1 (C), 171.0 (C), 155.1 (C), 128.3 (CH), 127.2 (CH), 64.1 (CH₂), 63.2 (CH₂), 59.8 (C), 57.9 (C), 56.4 (C), 52.8 (CH₃), 52.7 (CH₃), 32.5 (CH₂), 31.6 (CH₂), 24.7 (CH₃), 18.8 (CH₃), 14.3 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₇H₂₆O₈ [M + Na]⁺: 381.1519, found: 381.1525.

Compound 1b. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 5.70–5.55 (m, 1H), 5.55–5.40 (m, 1H), 4.57 (d, J = 6.6 Hz, 1H), 3.70 (s, 3H), 3.68 (s, 3H), 2.78 (d, J = 7.5 Hz, 2H), 2.68 (dd, J = 7.3, 4.3 Hz, 1H), 2.19 (dd, J = 14.9, 4.3 Hz, 1H), 1.99 (s, 3H), 2.00–1.89 (m, 1H), 1.23 (s, 3H), 1.19 (s, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 171.1 (C), 170.8 (C), 127.7 (CH), 60.1 (CH₂), 59.8 (CH), 57.9 (C), 56.3 (C), 52.8 (CH₃), 52.6 (CH₃), 32.3 (CH₂), 31.4 (CH₂), 24.6 (CH₃), 20.9 (CH₃), 18.7 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₆H₂₄O₇Na [M + Na]⁺: 351.1414, found: 351.1415.

Compound 1c. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 8.00 (d, J = 7.4 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.4 Hz, 2H), 5.87–5.71 (m, 1H), 5.64–5.50 (m, 1H), 4.86 (d, J = 6.7 Hz, 2H), 3.73 (s, 3H), 3.71 (s, 3H), 2.89 (d, J = 7.5 Hz, 2H), 2.74 (dd, J = 7.4, 4.1 Hz, 1H), 2.25 (dd, J = 14.8, 4.1 Hz, 1H), 2.08–1.94 (m, 1H), 1.24 (s, 3H), 1.21 (s, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 171.2 (C), 171.1 (C), 166.4 (C), 133.0 (CH), 130.2 (C), 129.6 (CH), 128.4 (CH), 128.0 (CH), 127.8 (CH), 60.6 (CH₂), 59.9 (CH), 58.0 (C), 56.4 (C), 52.8 (CH₃), 52.7 (CH₃), 32.4 (CH₂), 31.6 (CH₂), 24.7 (CH₃), 18.8 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₂₁H₂₆O₇Na [M + Na]⁺: 413.1570, found: 413.1569.

Compound 1d. ¹H-NMR (300 MHz, C₆D₆) δ(ppm): 5.85–5.68 (m, 1H), 5.60–5.43 (m, 1H), 3.86 (d, J = 6.3 Hz, 2H), 3.39 (s, 3H), 3.36 (s, 3H), 3.06 (s, 3H), 3.09–3.02 (m, 2H), 2.87 (dd, J = 8.0, 3.8 Hz, 1H), 2.45 (dd, J = 14.8, 3.8 Hz, 1H), 2.20 (dd, J = 14.8, 8.0 Hz, 1H), 1.05 (s, 3H), 1.03 (s, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 171.2 (C), 171.1 (C), 130.4 (CH), 125.9 (CH), 67.9 (CH₂), 59.8 (CH), 58.0 (CH₃), 57.9 (C), 56.3 (C), 52.7 (CH₃), 52.6 (CH₃), 32.2 (CH₂), 31.5 (CH₂), 24.6 (CH₃), 18.7 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₅H₂₄O₆Na [M + Na]⁺: 323.1465, found: 323.1474.

Compound 3. ¹H-NMR (300 MHz, C₆D₆) δ(ppm): 5.84–5.68 (m, 1H), 5.51–5.34 (m, 1H), 4.21–4.06 (m, 1H), 4.06–3.91 (m, 1H), 3.36 (s, 3H), 3.34 (s, 3H), 3.12 (dd, J = 14.8, 8.5 Hz, 1H), 2.98 (dd, J = 14.8, 6.8 Hz, 1H), 2.80 (dd, J = 8.3, 3.2 Hz, 1H), 2.48 (dd, J = 14.9, 3.2 Hz, 1H), 2.12 (dd, J = 14.9, 8.3 Hz, 1H), 1.00 (s, 3H), 0.99 (s, 3H). ¹³C-NMR (75 MHz, C₆D₆) δ(ppm): 171.5 (C), 171.3 (C), 134.0 (CH), 125.0 (CH), 60.1 (CH), 58.1 (CH₂), 57.7 (C), 57.1 (C), 52.4 (CH₃), 52.3 (CH₃), 32.8 (CH₂), 31.6 (CH₂), 24.5 (CH₃), 18.6 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₄H₂₂O₆Na [M + Na]⁺: 309.1308, found: 309.1307.

Compound 6. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 5.62–5.45 (m, 1H), 5.18–5.01 (m, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 2.80–2.72 (m, 1H), 2.71 (d, J = 7.0 Hz, 2H), 2.20 (dd, J = 14.8, 4.6 Hz, 1H), 2.00 (dd, J = 14.8, 7.3 Hz, 1H), 1.42 (d, J = 8.0 Hz, 2H), 1.28 (s, 3H), 1.24 (s, 3H), −0.02 (s, 9H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 171.6 (C), 132.0 (CH), 121.3 (CH), 60.1 (CH), 58.0 (C), 56.8 (C), 52.6 (CH₃), 52.5 (CH₃), 36.9 (CH₂), 32.0 (CH₂), 24.8 (CH₃), 23.1 (CH₃), 18.8 (CH₃), −1.9 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₇H₃₁O₅Si [M + H]⁺: 343.1941, found: 343.1951.

Compound E-1a. ¹H-NMR (300 MHz, acetone) δ(ppm): 5.75–5.65 (m, 2H), 4.69 (d, J = 6.4 Hz, 2H, Z-isomer), 4.54 (d, J = 6.4 Hz, 2H, E-isomer), 4.19 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 3.73 (s, 3H), 2.84 (d, J = 7.2 Hz, 2H, Z-isomer), 2.81–2.69 (m, 3H), 2.22 (dd, J = 14.9, 4.2 Hz, 1H), 1.99 (dd, J = 14.9, 7.6 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.28 (s, 3H), 1.25 (s, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 171.0 (C), 170.9 (C), 154.8 (C), 129.7 (CH), 128.4 (CH), 67.5 (CH₂), 63.9 (CH₂), 59.7 (CH), 57.8 (C), 56.5 (CH), 52.6 (CH₃), 52.5 (CH₃), 36.2 (CH₂), 32.2 (CH₂), 24.6 (CH₃), 18.7 (CH₃), 14.2 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₇H₂₆O₈Na [M + Na]⁺: 381.1519, found: 381.1516.

Compound 9. ¹H-NMR (300 MHz, C₆D₆) δ(ppm): 5.74–5.46 (m, 2H), 4.63 (d, J = 5.7 Hz, 2H), 3.91 (q, J = 7.1 Hz, 2H), 3.35 (s, 6H), 3.00–2.89 (m, 2H), 2.31 (d, J = 3.9 Hz, 2H), 2.26 (d, J = 5.1 Hz, 1H), 2.11 (d, J = 5.1 Hz, 1H), 1.10 (s, 3H), 0.93 (t, J = 7.1 Hz, 3H). ¹³C-NMR (75 MHz, C₆D₆) δ(ppm): 171.2 (C), 171.0 (C), 155.5 (C), 128.9 (CH), 127.4 (CH), 63.7 (CH₂), 63.1 (CH₂), 56.7 (C), 54.0 (CH₂), 53.9 (C), 52.2 (CH₃), 52.2 (CH₃), 39.9 (CH₂), 32.1 (CH₂), 21.6 (CH₃), 14.2 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₆H₂₄O₈Na [M + Na]⁺: 367.1363, found: 367.1372.

Compound 11. ¹H-NMR (300 MHz, C₆D₆) δ(ppm): 5.69–5.54 (m, 1H), 5.56–5.38 (m, 1H), 4.61 (d, J = 6.7 Hz, 2H), 3.90 (q, J = 7.1 Hz, 2H), 3.35 (s, 3H), 3.33 (s, 3H), 2.93 (d, J = 7.8 Hz, 2H), 2.87–2.76 (m, 1H), 2.33–2.20 (m, 2H), 1.98 (dd, J = 5.2, 2.4 Hz, 1H), 1.88 (dd, J = 14.7, 7.8 Hz, 1H), 0.90 (t, J = 7.1 Hz, 3H). ¹³C-NMR (75 MHz, C₆D₆) δ(ppm): 171.0 (C), 170.9 (C), 155.5 (C), 128.5 (CH), 127.8 (CH), 63.8 (CH₂), 63.1 (CH₂), 56.7 (CH₂), 52.3 (CH₃), 48.2 (CH), 46.0 (CH₂), 36.8 (CH₂), 31.9 (CH₂), 14.2 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₅H₂₂O₈Na [M + Na]⁺: 353.1206, found: 353.1197.

Compound 13. 5.69–5.56 (m, 1H), 5.56–5.41 (m, 1H), 4.61 (d, J = 6.9 Hz, 2H), 3.89 (q, J = 7.1 Hz, 2H), 3.36 (s, 3H), 3.34 (s, 3H), 2.94 (d, J = 7.8 Hz, 2H), 2.76–2.68 (m, 1H), 2.44–2.34 (m, 1H), 2.28 (dd, J = 14.6, 4.2 Hz, 1H), 2.02 (dd, J = 14.6, 7.4 Hz, 1H), 0.96 (d, J = 5.2 Hz, 3H), 0.90 (t, J = 7.1 Hz, 3H). ¹³C-NMR (75 MHz, C₆D₆) δ(ppm): 170.9 (C), 155.0 (C), 128.2 (CH), 127.2 (CH), 64.0 (CH₂), 63.1 (CH₂), 56.2 (C), 55.4 (CH), 54.3 (CH), 52.8 (CH₃), 52.7 (CH₃), 35.9 (CH₂), 31.6 (CH₂), 17.3 (CH₃), 14.3 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₆H₂₄O₈ [M + Na]⁺: 367.1363, found: 367.1377.

Compound 16. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 5.56 (t, J = 7.0 Hz, 1H), 4.40 (s, 2H), 3.93 (q, J = 7.1 Hz, 2H), 3.38 (s, 3H), 3.36 (s, 3H), 3.00 (t, J = 7.0 Hz, 2H), 2.86 (dd, J = 7.9, 4.1 Hz, 1H), 2.43 (dd, J = 14.8, 4.1 Hz, 1H), 2.20 (dd, J = 14.8, 7.9 Hz, 1H), 1.51 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H), 0.93 (t, J = 7.1 Hz, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 171.4 (C), 171.2 (C), 155.4 (C), 134.4 (C), 122.9 (CH), 72.6 (CH₂), 63.7 (CH₂), 59.7 (CH), 57.3 (C), 56.8 (C), 52.3 (CH₃), 52.2 (CH₃), 32.9 (CH₂), 32.1 (CH₂), 24.6 (CH₃), 18.7 (CH₃), 14.2 (CH₃), 13.9 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₈H₂₈O₈Na [M + Na]⁺: 395.1676, found: 395.1667.

Compound 18. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 7.36–7.25 (m, 3H), 7.26–7.16 (m, 2H), 5.78–5.61 (m, 2H), 4.52 (d, J = 4.5 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.73 (s, 3H), 3.69 (s, 3H), 3.56 (d, J = 1.8 Hz, 1H), 2.96 (ddd, J = 6.7, 5.0, 1.8 Hz, 1H), 2.77 (d, J = 5.7 Hz, 2H), 2.27 (dd, J = 14.7, 5.0 Hz, 1H), 2.14 (dd, J = 14.7, 6.7 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 170.9 (C), 154.9 (C), 136.9 (C), 129.6 (CH), 128.6 (CH), 128.5 (CH), 128.3 (CH), 125.6 (CH), 67.5 (CH₂), 64.0 (CH₂), 58.8 (CH), 58.5 (CH), 56.4 (C), 52.8 (CH₃), 36.7 (CH₂), 36.2 (CH₂), 14.3 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₂₁H₂₆O₈Na [M + Na]⁺: 429.1519, found: 429.1529.

Compound 20. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 5.76–5.59 (m, 2H), 4.54 (d, J = 4.5 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.72 (s, 6H), 2.95–2.85 (m, 1H), 2.79–2.70 (m, 1H), 2.65 (d, J = 5.5 Hz, 2H), 2.51–2.42 (m, 1H), 2.11–1.91 (m, 2H), 1.54–1.38 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 171.1 (C), 154.9 (C), 129.7 (CH), 128.1 (CH), 67.5 (CH₂), 63.9 (CH₂), 57.1 (C), 52.5 (CH₃), 51.7 (CH), 46.9 (CH₂), 35.9 (CH₂), 28.9 (CH₂), 27.3 (CH₂), 14.2 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₆H₂₄O₈Na [M + Na]⁺: 367.1363, found: 367.1362.

Compound 22. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 7.71 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 5.79–5.64 (m, 1H), 5.64–5.51 (m, 1H), 4.68 (d, J = 6.7 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 4.09–3.90 (m, 2H), 3.65 (dd, J = 14.8, 3.7 Hz, 1H), 2.95 (dd, J = 14.8, 5.7 Hz, 1H), 2.87 (dd, J = 5.7, 3.7 Hz, 1H), 2.43 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.28 (s, 3H), 1.24 (s, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 154.9 (C), 143.6 (C), 136.6 (C), 129.8 (CH), 129.6 (CH), 127.2 (CH), 127.1 (CH), 64.1 (CH₂), 62.7 (CH₂), 61.9 (CH), 57.8 (C), 47.1 (CH₂), 45.3 (CH₂), 24.4 (CH₃), 21.5 (CH₃), 18.8 (CH₃), 14.2 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₉H₂₈NO₆S [M + H]⁺: 398.1637, found: 398.1627.

Compound 24. ¹H-NMR (300 MHz, C₆D₆) δ(ppm): 7.65 (d, J = 8.2 Hz, 2H), 6.78 (d, J = 8.2 Hz, 2H), 5.55–5.34 (m, 2H), 4.63 (d, J = 6.2 Hz, 2H), 3.91 (d, J = 6.1 Hz, 2H), 3.88 (q, J = 7.1 Hz, 2H), 3.35 (d, J = 14.5 Hz, 1H), 2.79 (d, J = 14.5 Hz, 1H), 2.25 (d, J = 4.8 Hz, 1H), 2.10 (d, J = 4.8 Hz, 1H), 1.90 (s, 3H), 1.20 (s, 3H), 0.90 (t, J = 7.1 Hz, 3H). ¹³C-NMR (75 MHz, acetone) δ(ppm): 155.7 (C), 144.4 (C), 138.2 (C), 130.7 (CH), 130.1 (CH), 128.1 (CH), 127.9 (CH), 64.4 (CH₂), 63.5 (CH₂), 56.2 (CH₂), 53.6 (CH), 51.9 (CH₂), 46.3 (CH₂), 21.5 (CH₃), 19.2 (CH₃), 14.6 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₈H₂₆NO₆S [M + H]⁺: 384.1481, found: 384.1476.

Compound 26. ¹H-NMR (300 MHz, C₆D₆) δ(ppm): 8.22–8.11 (m, 4H), 7.09–6.93 (m, 6H), 6.08 (dt, J = 11.0, 6.5 Hz, 1H), 5.55 (dt, J = 11.0, 6.6 Hz, 1H), 4.43 (d, J = 6.8 Hz, 2H), 3.88 (q, J = 7.1 Hz, 2H), 3.49 (t, J = 4.9 Hz, 1H), 3.36 (d, J = 6.5 Hz, 2H), 2.81 (dd, J = 16.1, 4.9 Hz, 1H), 2.50 (dd, J = 16.1, 4.9 Hz, 1H), 1.16 (s, 3H), 1.02 (s, 3H), 0.91 (t, J = 7.1 Hz, 3H). ¹³C-NMR (75 MHz, C₆D₆) δ(ppm): 155.4 (C), 137.4 (C), 137.2 (C), 134.6 (CH), 134.5 (CH), 132.0 (CH), 131.9 (CH), 128.8 (CH), 128.7 (CH), 127.6 (CH), 126.8 (CH), 89.8 (C), 63.9 (CH₂), 62.8 (CH₂), 58.7 (CH), 58.5 (C), 30.6 (CH₂), 28.9 (CH₂), 24.5 (CH₃), 18.8 (CH₃), 14.2 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₂₅H₃₀O₈S₂Na [M + Na]⁺: 545.1274, found: 545.1260.

Compound 28. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 5.31 (t, J = 7.3 Hz, 1H), 4.42 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.69 (s, 3H), 3.68 (s, 3H), 3.57 (s, 2H), 2.80 (dd, J = 6.9, 5.2 Hz, 1H), 2.71 (d, J = 7.3 Hz, 2H), 2.19 (dd, J = 14.9, 5.2 Hz, 1H), 2.03 (dd, J = 14.9, 6.9 Hz, 1H), 1.63 (s, 3H), 1.30 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 171.3 (C), 171.2 (C), 155.0 (C), 134.1 (C), 122.6 (CH), 72.7 (CH₂), 64.0 (CH₂), 63.5 (CH₂), 60.6 (CH), 60.4 (C), 56.3 (C), 52.8 (CH₃), 52.7 (CH₃), 32.0 (CH₂), 31.6 (CH₂), 19.9 (CH₃), 14.2 (CH₃), 14.0 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₈H₂₈O₉Na [M + Na]⁺: 411.1625, found: 411.1624.

Compound 30. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 5.72–5.59 (m, 1H), 5.53–5.40 (m, 1H), 4.61 (d, J = 6.8 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.67 (s, 6H), 2.65 (d, J = 7.6 Hz, 2H), 2.53 (dd, J = 11.9, 4.7 Hz, 2H), 1.92 (t, J = 8.3 Hz, 2H), 1.51–1.31 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.25 (s, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 171.2 (C), 155.0 (C), 128.3 (CH), 127.0 (CH), 64.0 (CH₂), 63.0 (CH₂), 57.0 (C), 56.4 (C), 53.5 (CH₂), 52.6 (CH₃), 31.3 (CH₂), 30.8 (CH₂), 28.2 (CH₂), 20.8 (CH₃), 14.3 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₇H₂₇O₈ [M + H]⁺: 359.1706, found: 359.1719.

General procedure for the intramolecular epoxide allylation

Rigorously deoxygenated dry THF (10 mL) was added to a previously deoxygenated mixture of Cp₂TiCl₂ (0.2 mmol) and Mn (8.0 mmol) under an Ar atmosphere, and the suspension was stirred at room temperature until it turned green (about 10 min). A solution of the previously synthesized polyfunctionalized substrate (1.0 mmol) in THF (2 mL), Me₃SiCl (4.0 mmol) and 2,4,6-collidine (6.0 mmol) was then added. The reaction mixture was stirred at room temperature for 16 h and then diluted with EtOAc, washed with HCl (10%), dried over anhydrous Na₂SO₄ and the solvent removed. The residue was subjected to flash column chromatography (SiO₂, EtOAc–hexane mixtures) to give the corresponding cyclic products.

Characterization data of cyclic products 2, 4, 5, 7, 8, 10, 12, 14, 15, 17, 19, 21, 23, 25, 27, 29, and 31

(See ESI† for numbering and copies of ¹H-NMR and ¹³C-NMR spectra.)

Compound 2. Colorless oil; 65–85% yield. ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 5.69 (ddd, J = 17.2, 10.4, 8.1 Hz, 1H), 5.06 (dd, J = 10.4, 1.8 Hz, 1H), 5.03 (d, J = 17.2 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 3.40 (dd, J = 12.1, 4.2 Hz, 1H), 2.37 (ddd, J = 12.1, 4.2, 2.4 Hz, 1H), 2.10 (dt, J = 13.6, 2.7 Hz, 1H), 1.90 (ddd, J = 12.7, 8.1, 2.7 Hz, 1H), 1.82 (t, J = 12.7 Hz, 1H), 1.80 (t, J = 13.2 Hz, 1H), 0.95 (s, 3H), 0.77 (s, 3H); NOE-diff. experiment: proton irradiated, (NOEs observed): H-7, (H₂-8, H-5), H-3, (H-2b H-5). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 171.9 (C), 171.5 (C), 137.7 (CH), 116.6 (CH₂), 74.4 (CH), 54.9 (C), 52.9 (CH₃), 52.8 (CH₃), 47.0 (CH), 38.0 (C), 34.7 (CH₂), 31.9 (CH₂), 25.6 (CH₃), 12.3 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₄H₂₂O₅Na [M + Na]⁺: 293.1359, found: 293.1351.

Compound 4. Colorless oil; 40% yield. ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 9.74 (s, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 3.46 (dd, J = 11.9, 3.8 Hz, 1H), 2.57 (dd, J = 16.8, 2.4 Hz, 1H), 2.39 (ddd, J = 13.2, 4.0, 2.3 Hz, 1H), 2.17 (dd, J = 10.0, 2.9 Hz, 1H), 2.12 (dt, J = 13.2, 3.5 Hz, 1H), 1.97–1.86 (m, 1H), 1.80 (t, J = 12.6 Hz, 1H), 1.61 (t, J = 13.4 Hz, 1H), 0.99 (s, 3H), 0.77 (s, 3H); NOE-diff. experiment: proton irradiated (NOEs observed): H-7a (H-7b, H-5), H-3 (H-2a, H-5), H-2a (H-2b, H-3). ¹³C-NMR (125 MHz, CDCl₃) δ(ppm): 201.8 (C), 171.5 (C), 171.2 (C), 73.9 (CH), 54.7 (C), 53.0 (CH₂), 52.9 (CH₂), 44.6 (CH₂), 38.0 (C), 36.5 (CH), 34.7 (CH₂), 32.5 (CH₂), 25.1 (CH₃), 12.4 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₄H₂₂O₆Na [M + Na]⁺: 309.1308, found: 309.1308.

Compound 5. Colorless oil; 23% yield. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 3.75 (s, 3H), 3.71 (s, 3H), 3.71–3.57 (m, 2H), 3.34 (dd, J = 11.8, 4.0 Hz, 1H), 2.39 (ddd, J = 13.2, 3.9, 2.3 Hz, 1H), 2.25 (dt, J = 13.8, 2.7 Hz, 1H), 1.86 (t, J = 12.0 Hz, 1H), 1.85–1.77 (m, 1H), 1.63–1.57 (bs, 2H), 1.51 (t, J = 13.0 Hz, 1H), 1.38–1.17 (m, 2H), 1.00 (s, 3H), 0.77 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) δ(ppm): 171.9 (C), 171.5 (C), 74.6 (CH), 61.5 (CH₂), 54.9 (C), 53.0 (CH₂), 52.9 (CH₂), 38.6 (CH), 38.3 (C), 34.7 (CH₂), 32.2 (CH₂), 31.7 (CH₂), 24.9 (CH₃), 12.2 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₄H₂₄O₆Na [M + Na]⁺: 311.1465, found: 311.1468.

Compounds 7 and 8. Compounds 7 and 8 were isolated as a mixture in a 7/8 ratio of 1.6/1. Colorless oil; 53% yield. (Compounds 7 (33% yield) and 8 (20% yield) were not separated.) ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 5.89 (dd, J = 18.7, 7.0 Hz, 1H, 7), 5.67 (d, J = 18.7 Hz, 1H, 7), 3.75 (s, 3H, 7), 3.74 (s, 3H, 8), 3.71 (s, 3H), 3.40 (dd, J = 12.0, 4.1 Hz, 1H, 7), 3.34 (dd, J = 12.0, 4.0 Hz, 1H, 8), 2.37 (ddd, J = 12.6, 4.0, 2.2 Hz, 1H), 2.11 (dt, J = 12.8, 2.0 Hz, 1H), 1.96–1.74 (m, 3H), 1.60–1.50 (m, 1H, 8), 1.40 (t, J = 13.0 Hz, 1H, 8), 0.99 (s, 3H, 8), 0.95 (s, 3H, 7), 0.94–0.80 (m, 2H, 8) 0.77 (s, 3H, 7), 0.73 (s, 3H, 8), 0.72–0.61 (m, 1H, 8), 0.35–0.20 (m, 1H, 8), 0.04 (s, 9H, 7), 0.03 (s, 9H, 8). ¹³C-NMR (100 MHz, CDCl₃) δ(ppm): 172.2 (C), 171.9 (C), 171.6 (C), 171.5 (C), 145.2 (CH, 7), 132.6 (CH, 7), 74.6 (CH), 74.4 (CH), 54.9 (C), 54.8 (C), 53.0 (CH₃), 52.9 (CH₃), 52.8 (CH₃), 52.7 (CH₃), 49.1 (CH), 45.7 (CH), 38.7 (C), 38.1 (C), 34.8 (CH₂), 34.6 (CH₂), 31.7 (CH₂), 31.2 (CH₂), 25.6 (CH₃), 25.0 (CH₃), 23.2 (CH₂, 8), 15.1 (CH₂, 8), 12.4 (CH₃), 12.1 (CH₃), −1.6 (CH₃), −1.1 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₇H₃₀O₅Si [M]⁺: 342.1863, found: 342.1867. HRMS for compound 8 was not found.

Compound 10. Colorless oil; 53% yield. ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 5.74–5.62 (m, 1H), 5.06 (d, J = 16.1 Hz, 1H), 5.05 (d, J = 11.3 Hz, 1H), 3.71 (s, 6H), 3.41 (d, J = 10.9 Hz, 1H), 3.36 (d, J = 10.9 Hz, 1H), 2.59–2.49 (m, 1H), 2.43 (d, J = 14.2 Hz, 1H), 2.42–2.37 (m, 1H), 2.28 (t, J = 12.8 Hz, 1H), 2.06 (d, J = 14.2 Hz, 1H), 0.82 (s, 3H); NOE-diff. experiment: proton irradiated, (NOEs observed): H₃-8, (H-2b, H₂-9, H-6), H-6, (H₂-5, H-4, H₃-8), H-4, (H-6, H₂-7, H₂-5, H₂-9). ¹³C-NMR (125 MHz, CDCl₃) δ(ppm): 173.5 (C), 172.9 (C), 137.3 (CH), 116.7 (CH₂), 69.3 (CH₂), 57.9 (C), 53.1 (CH₃), 52.9 (CH₃), 48.1 (CH), 46.9 (C), 43.5 (CH₂), 38.5 (CH₂), 19.3 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₃H₂₀O₅Na [M + Na]⁺: 279.1202, found: 279.1200.

Compound 12. Compound 12 was obtained as a 7/3 mixture of cis/trans diastereoisomers. Colorless oil; 60% yield. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 5.85 (ddd, J = 17.3, 10.2, 8.5 Hz, 1H, cis-12), 5.70 (ddd, J = 17.4, 10.1, 8.1 Hz, 1H, trans-12), 5.09 (d, J = 16.6 Hz, 1H, cis-12), 5.05 (d, J = 8.6 Hz, 1H, cis-12), 5.07–4.95 (m, 2H, trans-12), 3.72 (bs, 6H), 3.68–3.52 (m, 2H, trans-12), 3.61 (dd, J = 11.1, 6.4 Hz, 1H, cis-12), 3.48 (dd, J = 11.1, 6.3 Hz, 1H, cis-12), 2.88–2.74 (m, 1H), 2.54–2.23 (m, 3H), 2.19–1.98 (m, 2H). ¹³C-NMR (75 MHz, CDCl₃) δ(ppm): 173.1 (C), 173.0 (C), 172.9 (C), 172.0 (C), 140.3 (CH), 137.8 (CH), 116.1 (CH₂), 115.9 (CH₂), 64.4 (CH₂), 63.2 (CH₂), 59.2 (C), 58.8 (C), 53.0 (CH₃), 52.9 (CH₃), 47.3 (CH), 46.5 (CH), 45.1 (C), 44.9 (CH), 40.9 (CH₂), 39.1 (CH₂), 37.1 (CH₂), 36.5 (CH₂). HRMS (TOF MS ES+) m/z calcd for C₁₂H₁₈O₅Na [M + Na]⁺: 265.1046, found: 265.1054. Compound 12 was oxidized to simplify the ¹H-NMR spectrum and confirm the ratio of diastereomers obtained. See ESI† for further details.

Compounds 14 and 15. Compounds 14 and 15 were both obtained as a mixture of diastereoisomers. Yellowish oil; 55% yield. Compounds 14 and 15 were not separated. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 5.90–5.73 (m, 1H, 14 or 15), 5.63–5.48 (m, 1H, 14 or 15), 5.10–4.96 (m, 2H), 3.82–3.72 (m, 1H, 14 or 15), 3.73 (bs, 3H, 14 or 15), 3.71 (bs, 3H), 3.69 (bs, 3H, 14 or 15), 3.37–3.26 (m, 1H, 14 or 15), 2.61–2.39 (m, 2H), 2.35–2.14 (m, 2H), 2.08–1.96 (m, 1H), 1.93–1.72 (m, 1H), 1.69–1.54 (m, 1H), 1.15 (d, J = 4.3 Hz, 3H, 15), 0.96 (d, J = 6.0 Hz, 3H, 14). HRMS (TOF MS ES+) m/z calcd for C₁₃H₂₀O₅Na [M + Na]⁺: 279.1202, found: 279.1210. The mixture of compounds 14 and 15 was oxidized to simplify the ¹H-NMR spectrum and confirm both compounds and dr obtained. See ESI† for further details.

Compound 17. Colorless oil; 50% yield. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 5.29 (s, 1H), 5.02 (s, 1H), 4.54 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 3.70 (s, 3H), 3.42 (dd, J = 12.0, 4.0 Hz, 1H), 2.39 (ddd, J = 13.2, 4.0, 2.3 Hz, 1H), 2.14 (dt, J = 13.7, 2.6 Hz, 1H), 2.00 (t, J = 14.2 Hz, 1H), 1.91–1.85 (m, 1H), 1.84 (t, J = 14.2 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.95 (s, 3H), 0.87 (s, 3H); NOE-diff. experiment: proton irradiated (NOEs observed): H-3, (H-2a, H-5). ¹³C-NMR (100 MHz, CDCl₃) δ(ppm): 171.7 (C), 171.3 (C), 155.1 (C), 143.5 (C), 115.3 (CH₂), 74.7 (CH), 71.1 (CH₂), 64.2 (CH₂), 54.9 (C), 53.0 (CH₃), 52.8 (CH₃), 44.6 (CH), 39.1 (C), 34.6 (CH₂), 32.5 (CH₂), 25.7 (CH₃), 14.4 (CH₃), 12.7 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₈H₂₈O₈Na [M + Na]⁺: 395.1676, found: 395.1668.

Compound 19. Colorless oil; 54% yield. ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 7.31 (t, J = 7.3 Hz, 2H), 7.25–7.20 (m, 1H), 7.14 (dd, J = 8.3, 1.4 Hz, 2H), 5.43 (ddd, J = 17.5, 10.4, 7.1 Hz, 1H), 4.83 (d, J = 16.1 Hz, 1H), 4.81 (d, J = 9.4 Hz, 1H), 3.86 (td, J = 11.2, 4.7 Hz, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 2.74 (ddd, J = 13.1, 4.7, 2.2 Hz, 1H), 2.55–2.44 (m, 2H), 2.27 (dd, J = 11.2, 10.6 Hz, 1H), 1.82 (dd, J = 13.1, 11.2 Hz, 1H), 1.74 (dd, J = 13.4, 12.2 Hz, 1H). NOE-diff. experiment: proton irradiated (NOEs observed): H-7 (H₂-8, H-4, H-6b), H-4 (H-2b, H-6b), H-3 (H₂-2, H-5). ¹³C-NMR (125 MHz, CDCl₃) δ(ppm): 171.8 (C), 171.4 (C), 140.1 (C), 139.6 (CH), 128.8 (CH), 127.3 (CH), 115.5 (CH₂), 71.2 (CH), 57.4 (CH), 54.8 (C), 53.1 (CH₃), 52.9 (CH₃), 42.3 (CH), 38.1 (CH₂), 36.6 (CH₂). HRMS (TOF MS ES+) m/z calcd for C₁₈H₂₂O₅Na [M + Na]⁺: 341.1359, found: 341.1359.

Compound 21. Colorless oil; 58% yield. ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 5.64 (ddd, J = 17.2, 10.1, 9.0 Hz, 1H), 5.10 (dd, J = 17.2, 1.5 Hz, 1H), 5.03 (dd, J = 10.1, 1.5 Hz, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.62 (dd, J = 11.0, 4.4 Hz, 1H), 3.40 (dd, J = 11.0, 6.1 Hz, 1H), 2.41 (ddd, J = 13.5, 6.0, 3.2 Hz, 1H), 2.35–2.27 (m, 1H), 2.10–1.96 (m, 1H), 1.84 (ddd, J = 13.6, 7.1, 3.9 Hz, 1H), 1.71 (td, J = 13.6, 3.9 Hz, 1H), 1.63–1.53 (m, 1H), 1.39–1.14 (m, 2H). 2D-NOESY spectra observed: H-5 (H-9), H-5 (H-6), H-5 (H-3a), H-4 (H₂-11), H-4 (H-3b). ¹³C-NMR (125 MHz, CDCl₃) δ(ppm): 172.69 (C), 171.52 (C), 141.76 (CH), 115.87 (CH₂), 66.33 (CH₂), 54.90 (C), 52.85 (CH₃), 52.67 (CH₃), 43.34 (CH), 41.80 (CH), 37.44 (CH₂), 30.73 (CH₂), 25.59 (CH₂). HRMS (TOF MS ES+) m/z calcd for C₁₃H₂₀O₅Na [M + Na]⁺: 279.1201, found: 279.1215.

Compound 23. White solid; m.p. 121–123 °C. 76% yield. ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 7.65 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 5.58 (ddd, J = 17.1, 10.4, 8.6 Hz, 1H), 5.12 (d, J = 10.4 Hz, 1H), 5.09 (d, J = 17.1 Hz, 1H), 3.65 (ddd, J = 11.2, 4.8, 1.7 Hz, 1H), 3.54 (dd, J = 10.5, 4.8 Hz, 1H), 3.46 (ddd, J = 11.8, 4.2, 1.7 Hz, 1H), 2.44 (s, 3H), 2.35 (dd, J = 23.9, 11.4 Hz, 2H), 2.21–2.14 (m, 1H), 0.97 (s, 3H), 0.65 (s, 3H). NOE-diff. experiment: proton irradiated (NOEs observed): H-5 (H-6, H-3), H-3 (H-2, H-5). ¹³C-NMR (125 MHz, CDCl₃) δ(ppm): 143.7 (C), 134.3 (CH), 129.8 (CH), 127.7 (CH), 118.7 (CH₂), 74.2 (CH), 49.2 (CH), 47.4 (CH₂), 46.0 (CH₂), 37.1 (C), 25.2 (CH₃), 21.7 (CH₃), 12.3 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₆H₂₄NO₃S [M + H]⁺: 310.1471, found: 310.1481.

Compound 25. Colorless oil; 74% yield. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 7.70 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 5.51 (ddd, J = 17.1, 10.3, 8.5 Hz, 1H), 5.06 (d, J = 10.3 Hz, 1H), 5.00 (d, J = 17.1 Hz, 1H), 3.49 (dd, J = 9.9, 8.0 Hz, 1H), 3.34 (dd, J = 17.9, 10.9 Hz, 2H), 3.29 (d, J = 9.8 Hz, 1H), 3.13 (t, J = 9.9 Hz, 1H), 3.06 (d, J = 9.8 Hz, 1H), 2.57 (dd, J = 17.1, 8.0 Hz, 1H), 2.42 (s, 3H), 0.71 (s, 3H). NOE-diff. experiment: proton irradiated (NOEs observed): H-6 (H-5, H₂-9, H₃-8), H-4 (H-6, H₂-7, H-5, H₂-9), H₃-8 (H-2, H₂-9, H-6). ¹³C-NMR (100 MHz, CDCl₃) δ(ppm): 143.6 (C), 134.3 (CH), 129.7 (CH), 127.5 (CH), 118.4 (CH₂), 67.0 (CH₂), 56.6 (CH₂), 51.0 (CH₂), 47.1 (CH), 46.4 (C), 21.6 (CH₃), 16.9 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₅H₂₂NO₃S [M + H]⁺: 296.1314, found: 296.1326.

Compound trans-27. Vitreous solid; 39% yield. ¹H-NMR (500 MHz, CDCl₃) δ(ppm): 8.14 (dd, J = 8.5, 1.2 Hz, 2H), 8.02 (dd, J = 8.5, 1.2 Hz, 2H), 7.74 (dd, J = 15.3, 7.2 Hz, 2H), 7.63 (dd, J = 15.3, 7.2 Hz, 4H), 5.70 (ddd, J = 17.2, 10.9, 8.3 Hz, 1H), 5.14 (d, J = 10.9 Hz, 1H), 5.13 (d, J = 17.2 Hz, 1H), 4.27 (d, J = 11.4 Hz, OH), 3.60 (ddd, J = 11.4, 4.9, 2.0 Hz, 1H), 2.92 (dd, J = 16.5, 4.9 Hz, 1H), 2.81 (ddd, J = 12.4, 8.3, 3.8 Hz, 1H), 2.52 (d, J = 18.6 Hz, 1H), 2.49 (t, J = 13.0 Hz, 1H), 2.18 (ddd, J = 15.7, 3.8, 1.7 Hz, 1H), 1.04 (s, 3H), 0.82 (s, 3H). NOE-diff. experiment: proton irradiated, (NOEs observed): H-5, (H-7, H-6), H-3, (H-2, H-6). ¹³C-NMR (125 MHz, CDCl₃) δ(ppm): 137.47 (CH), 135.78 (C), 135.04 (CH), 134.94 (C), 134.84 (CH), 132.04 (CH), 131.75 (CH), 128.83 (CH), 128.79 (CH), 117.67 (CH₂), 89.02 (C), 74.24 (CH), 40.32 (CH), 36.98 (C), 28.59 (CH₂), 27.34 (CH₂), 25.57 (CH₃), 19.34 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₂₂H₂₆O₅S₂Na [M + Na]⁺: 457.1113, found: 457.1100

Compound cis-27. White solid; m.p. 153–156 °C. 32% yield. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 8.07 (d, J = 7.6 Hz, 2H), 8.02 (d, J = 7.6 Hz, 2H), 7.76–7.67 (m, 2H), 7.65–7.56 (m, 4H), 5.64 (ddd, J = 17.3, 10.8, 8.8 Hz, 1H), 5.11 (d, J = 10.8 Hz, 1H), 5.10 (d, J = 17.3 Hz, 1H), 4.24–4.09 (m, 1H), 2.68 (ddd, J = 12.5, 8.8, 3.8 Hz, 1H), 2.52–2.24 (m, 3H), 2.06–1.95 (m, 1H), 1.02 (s, 3H), 0.71 (s, 3H). NOE-diff. experiment: proton irradiated (NOEs observed): H-5, (H-7, H-3, H-6), H-3, (H-5, H-2). ¹³C-NMR (100 MHz, CDCl₃) δ(ppm): 137.0 (CH), 135.9 (C), 134.8 (CH), 134.6 (CH), 131.7 (CH), 131.3 (CH), 128.7 (CH), 117.7 (CH₂), 88.6 (C), 73.0 (CH), 45.8 (CH), 37.6 (C), 30.4 (CH₂), 27.0 (CH₂), 25.3 (CH₃), 11.7 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₂₂H₂₆O₅S₂Na [M + Na]⁺: 457.1113, found: 457.1092.

Compound 29. Colorless oil; 62% yield. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 5.30 (s, 1H), 5.07 (s, 1H), 4.54 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.87 (dd, J = 12.2, 4.2 Hz, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.60 (d, J = 10.8 Hz, 1H), 3.38 (d, J = 10.8 Hz, 1H), 2.42 (ddd, J = 13.2, 4.1, 2.2 Hz, 1H), 2.19 (dt, J = 13.5, 2.7 Hz, 1H), 2.16–2.12 (m, 1H), 2.01 (t, J = 13.1 Hz, 1H), 1.95 (t, J = 12.5 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 0.92 (s, 3H). 2D-NOESY spectra observed: H-3 (H-2a), H-3 (H-5), H-3 (H-11), H-5 (H-11). ¹³C-NMR (100 MHz, CDCl₃) δ(ppm): 171.6 (C), 171.2 (C), 155.2 (C), 143.3 (C), 116.1 (CH₂), 71.2 (CH), 71.1 (CH₂), 68.3 (CH₂), 64.4 (CH₂), 54.7 (C), 53.1 (CH₃), 52.9 (CH₃), 43.1 (C), 39.0 (CH), 34.2 (CH₂), 32.4 (CH₂), 14.4 (CH₃), 9.3 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₈H₂₈O₉Na [M + Na]⁺: 411.1625, found: 411.1627.

Compound 31. Yellowish oil; 73% yield. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 5.69 (ddd, J = 17.2, 10.2, 8.8 Hz, 1H), 5.09 (d, J = 17.2 Hz, 1H), 5.05 (d, J = 10.2 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.34 (d, J = 11.0 Hz, 1H), 3.29 (d, J = 11.0 Hz, 1H), 2.30–2.20 (m, 2H), 2.15 (ddd, J = 11.0, 3.5, 2.4 Hz, 1H), 1.89 (td, J = 13.7, 3.5 Hz, 1H), 1.82 (t, J = 13.0 Hz, 1H), 1.50 (td, J = 13.9, 3.7 Hz, 1H), 1.35 (dt, J = 13.9, 3.6 Hz, 1H), 0.84 (s, 3H). NOE-diff. experiment: proton irradiated, (NOEs observed): H-7, (H-8, H₃-9), H₂-10, (H-5, H₃-9), H₃-9, (H-7, H₂-10). ¹³C-NMR (100 MHz, CDCl₃) δ(ppm): 172.7 (C), 171.5 (C), 139.3 (CH), 116.4 (CH₂), 71.8 (CH₂), 55.0 (C), 52.8 (CH₃), 52.6 (CH₃), 42.8 (CH), 37.3 (C), 32.4 (CH₂), 31.5 (CH₂), 26.4 (CH₂), 14.9 (CH₃). HRMS (TOF MS ES+) m/z calcd for C₁₄H₂₂O₅Na [M + Na]⁺: 293.1365, found: 293.1359.

Acknowledgements

This research was funded by the Ministerio de Ciencia e Innovación (Spain) (project CTQ-2011.22455). I.R.M. thanks the MEC (Spain) for a predoctoral FPU fellowship. A.M. thanks the University of Granada for a postdoctoral contract (‘Contrato Puente’). A.G.C. thanks the MICINN (Spain) for a postdoctoral contract ‘Juan de la Cierva’ and University of Granada.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4qo00012a

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