Novel 4,5-seco-Abietane-Type Diterpenes from Salvia prattii

Abstract

Eight new 4,5-seco-abietane-type diterpenes, salpratones B–I, along with two analogues, featuring diverse 6/5/6, 6/6/6, 6/6/7, and 6/6/8 ring systems, were isolated from Salvia prattii. Notably, salpratone B is the first example of a 4,5;13,14-bis-seco-abietane diterpene characteristic with a rare rearranged 6/5/6 tricyclic core skeleton. Their structures were determined by comprehensive NMR spectroscopy, single-crystal X-ray diffraction, and electronic circular dichroism. Moreover, salpratones B–D were resolved into optically pure enantiomers. Partial diterpenes were evaluated for their in vitro anticoagulant activities. While salpratones B, E, F can weakly prolong the clotting times of human plasma in the activated partial thromboplastin time (APTT) assays with concentrations of 100 μM, showing no appreciable anticoagulant activities.

Salvia is a renowned herb with a rich history of use in both Western and Asian countries.[1] Particularly, S. miltiorrhiza (‘Danshen’) is one of the most famous herbs for invigorating the blood and eliminating stasis in traditional Chinese medicine and for ameliorating the symptoms of cardiovascular diseases in modern medicine.[2] [3] [4] Research into Salvia species has unveiled an impressive array of bioactive secondary metabolites, predominantly comprising abietane and clerodane diterpenes, along with polyphenols.[1] Pharmacological studies on tanshinone IIA and salvianolic acid have revealed their multiple biological activities, such as improving reginal blood flow, decreasing myocardial oxygen consumption, and inhibiting platelet aggregation and thrombosis, which have been utilized to relieve myocardial infarction and angina pectoris.[5] [6] [7] [8] [9]

Recently, we reported that several novel diterpenes were isolated from S. prattii that showed significant antiplatelet aggregation activity.[10] [11] Among them, salpratone A showed a dose-dependent and potent inhibition of platelet aggregation triggered by various inducers without affecting platelet membrane integrity. Additionally, it showed effective antithrombotic in vivo FeCl₃-induced rat thrombosis model.[11] Despite these promising findings, there is a scarcity of literature on the anticoagulant effects of abietane diterpenes.[1] Given their traditional use in medicine, it is imperative that we focus on this area to uncover their potential biological activities.

Among abietane diterpenes, the 4,5-seco-abitane diterpenes constitute a small yet fascinating subgroup characterized by variable structure and a wide range of biological activities.[1] ^, [12] [13] [14] [15] [16] In this work, we detail the structural identification and biological evaluation of eight new 4,5-seco-abietane diterpenes, named salpratones B–I (1–8, Figure [1]), obtained from Salvia prattii (a relative of Danshen widely utilized in Tibetan). Their structures were elucidated through a combination of comprehensive NMR spectroscopy, single-crystal X-ray diffraction, and electronic circular dichroism analysis. Significantly, 1 represents the first instance of a 4,5;13,14-bis-seco-abietane diterpene sharing an unprecedented rearranged 6/5/6 tricyclic skeleton. A bioactivity study showed that 1, 4, and 5 weakly prolonged the clotting times of human plasma in the activated partial thromboplastin time (APTT) assays with concentrations of 100 μM.

Salpratone B (1) was obtained as a colorless crystal with the molecular formula of C₂₀H₂₈O₅, which was deduced by the ¹³C NMR and HRMS (ESI) (m/z = 371.1837, [M + Na]⁺) data, indicating 7 degrees of unsaturation. The ¹³C and DEPT NMR (Table [1]) spectroscopic data of 1 revealed 20 carbon signals, comprising 8 quaternary carbons, 5 methines, 2 methylenes, and 5 methyls. The ¹H NMR spectrum of 1 exhibited the presence of three methyl groups at δ_H = 1.37 (3 H, s), 1.18 (3 H, s), and 2.21 (3 H, s) ppm, and an isopropyl group at δ_H = 3.49 (1 H, sept, J = 6.9 Hz), 1.06 (3 H, d, J = 6.9 Hz), and 0.90 (3 H, d, J = 6.9 Hz) ppm, typical of a 4,5-seco-abietane diterpene.[12] [13] [14] [15] [16] The relationships between the proton signals in 1 were established from the ¹H–¹H COSY spectrum, which disclosed the following connectivity: H-1/H-2/H-3, H-6/H-7, H-16/H15/H-17, and H-14/OH-14 (Figure [2]). The HMBC correlations from H-1 to C-9 and C-10, from OH-11 to C-3/C-9, and from H18/H-19/OH-4 to C-3/C-4 indicated the presence of ring A. The second part of the molecule was characterized by six aromatic carbons at δ_C = 136.8, 130.2, 124.1, 139.1, 146.8, and 133.8 (C-5/C-6/C-7/C-8/C-9/C-10) ppm, indicating a substituted benzene ring B. Additional signals for carbonyl carbon (δ_C = 215.4 ppm), an oxidized quaternary carbon (δ_C = 90.0 ppm), an oxidized methine (δ_C = 77.2 ppm), and an isopropyl group were assigned to the substituted five-membered carbon ring C. The assignments were corroborated by the HMBC correlations of OH-12 with C-11 (δ_C = 82.5 ppm)/C-13 (δ_C = 215.4 ppm)/C-14 (δ_C = 77.2 ppm), of OH-14 with C-9/C-12 (δ_C = 90.0 ppm), and of H-16/H-17 with C-13 (Figure [2]).

Given that the ROESY spectra failed to yield conclusive correlations, we proceeded with a single-crystal X-ray diffraction analysis to obtain the necessary structural information (Figure [3]). Interestingly, the X-ray crystallographic structure of 1 (CCDC: 2333505) confirmed the above conjecture, and it was also proved to be racemic mixture by the space group P-1. After HPLC analysis and isolation with a chiral column (COS-MOSIL CHiRAL 3C), a pair of enantiomerically pure (+)-1 and (–)-1 were obtained.

The CD spectrum of (+)-1 exhibited positive effects at 195 (Δε +8.25), 201 (Δε +15.33), and 300 (Δε +1.07) nm and negative effect at 233 (Δε –3.46) nm (Figure [4]). Conversely, (–)-1 presented the inverse Cotton effects at the same wavelengths. We compared the experimental ECD with the calculated ones, which were performed at the B3LYP/6-311G (d,p) level in MeOH. As a result, the calculated ECD spectrum of 3R,11S,12R,14R corresponded well with the experimental curve of (+)-1, as the 3S,11R,12S,14S to (–)-1 (Figure [4]). Consequently, the structures of (+)-1 and (–)-1 were determined to feature a unique rearranged 6/5/6 tricyclic framework that probably originates via the retro-aldol reaction of the precursor prionopid A (9).[17] This is the first case of a 4,5-seco-abietane diterpene containing a cyclopentene ring C fragment.

The positive-ion HRMS (ESI) analyses (m/z = 337.1780 [M + Na]⁺, calcd 337.1774) established the molecular formula C₂₀H₂₆O₃, which accounted for 8 degrees of unsaturation. ¹H NMR spectrum of 2 displayed the presence of an isopropyl group, with signals at δ_H = 1.15 and 1.12 (each 3 H, d, J = 6.9 Hz, H-16/H-17) ppm and a methine septet at δ_H = 2.86 (1 H, J = 6.9 Hz, H-15) ppm. Again, two methyl singlets were at δ_H = 1.33 and 1.30 ppm for H-18 and H-19, and another diagnostic signal methyl singlet was observed at δ_H = 2.22 ppm, being typical for H-20 and indicative of a rearranged abietane diterpene similar to analogous signals saprirearine (10).[12] The NMR spectrum of 2 was similar to that of 10, except for the chemical shifts of the terminal double-bond signals. The HMBC correlations from H-18/H-19/OH-4 to C-3 (δ_C = 47.3 ppm)/C-4 (δ_C = 73.6 ppm) indicated that the hydroxyl group of 2 was attached to C-4 (Figure [2]). The relative configurations of 2 were established through ROESY correlations of OH-11/H-18 (Figure [5]). The architecture of 2 was further confirmed by Cu Κα X-ray crystallographic analysis and outlined in Figure [3]. In addition, the crystal of 2 had a P21/n space group, indicating its racemic nature, which was also supported by the absence of CD absorption. Subsequently, 2 was successfully separated via chiral HPLC to two optically pure enantiomers, (+)-2 and (–)-2. Their absolute configurations were defined by correlating the experimental and calculated ECD spectra. Thus, (+)-2 and (–)-2 were determined to be (3R,11S)-2 and (3S,11R)-2, with the names (+)-salpratone C and (–)-salpratone C, respectively.

Salpratone D (3) was isolated as colorless crystals. The molecular formula was determined as C₂₀H₂₄O₃ based on its ¹³C NMR and HRMS (ESI) (m/z = 313.1803, [M + H]⁺) data, requiring 9 indices of hydrogen deficiency. The 1D NMR spectra of 3 were similar to the spectra of 2. However, its NMR data revealed the absence of hydroxy (OH-4) and aromatic hydrogen (H-14) signals instead of an excess of unsaturation in 2. Therefore, compared with 2, 3 may form a new ring. The HMBC correlations from H-8/H-15 to C-14 (δ_C = 186.5 ppm) indicated a key difference: the carbonyl is located at C-14 instead of C-12 (Figure [2]). Further, the furan ring was constructed based on the HMBC correlations of OH-11 with C-3/C-12 and of H-18/H-19 with C-4/C-3, as well as the characteristic chemical shift of C-4 (δ_C = 93.2 ppm) and C-12 (δ_C = 176.0 ppm). Moreover, ROESY correlations between OH-11 and H-3 indicated the cofacial nature of these groups (Figure [5]). The planar structure and relative configurations of 3 were rigorously assigned by X-ray crystal diffraction (Figure [3]). Ultimately, with the aid of chiral resolution and calculated electronic circular dichroism analysis, the absolute configurations of (±)-3 were determined using the same methodology as used for 1 and 2.

The molecular formula of salpratone E (4) was established to be C₂₀H₂₂O₃ based on its ¹³C NMR and HRMS (ESI) (m/z = 333.1467, [M + Na]⁺) data, which required 10 degrees of unsaturation. The ¹H and ¹³C NMR spectroscopic data (Table [2]) for 4, which includes the α-hydroxy ketone moiety, an isopropyl group, and the terminal double bonds, closely resemble the corresponding data for candidissiol.[18] Carefully comparing the NMR data of 4 with those of candidissiol revealed that a methylene (δ_C = 25.8 ppm) in candidissiol was substituted by carbonyl (δ_C = 209.2 ppm) in 4, which was further determined by the HMBC correlations from H-2 (δ_H = 2.94/2.67 ppm, m) to C-1 (δ_C = 209.2 ppm, Figure [2]). A subsequent X-ray crystal diffraction allowed the full assignment of 4 (Figure [4]), and it was also proved to be a racemic mixture by the space group P-1. In conclusion, 4 was identified as a 4,5-seco-abietane diterpene with a 6/6/8 ring system and was assigned the trivial name salpratone E.

HRMS (EI) spectrum measured for 5 revealed a molecular formula C₂₁H₂₆O₃ consistent with an OCH₃ homologue of saprirearine (10), with NMR data revealing the principal difference as replacement of the methylene moiety in 10 with a methoxyl and oxidized methine signals in 5, confirmed by diagnostic HMBC correlations of OMe-1 (δ_H = 3.43 ppm, s) with C-1 (δ_C = 74.0 ppm, Figure [6]). ROESY correlations of OH-11 with H-19, of OH-11 with H-2α, and of H-2β with H-3/OMe-1 revealed the relative configurations of 5 as shown in Figure [7]. Thus, the structure of 5 was proposed, as illustrated in Figure [1], and named salpratone F.

The molecular formula of salpratone F (6) was established as C₂₀H₂₄O₃ from ¹³C NMR (Table [3]) and HRMS (ESI) data. Analysis of the HSQC spectrum enabled the assignment of all proton signals to their corresponding carbons, with the exception of two signals at δ_H = 4.00 and 4.61 ppm, indicating that these protons likely belong to two hydroxy groups. A detailed comparison of the 1D NMR spectra of 6 with those of saprirearine (10) suggested that the substructures of rings A/B/C remained intact in 6. However, it was obvious that the characteristic signals for 6 at C-1 (δ_C = 64.4 ppm) were absent in 10. Therefore, the observed differences could be rationalized by the change in the epoxidation state of ring A in 6. The hydroxy group at δ_H = 4.00 ppm was located at C-1 (δ_C = 64.4 ppm) on the basis of the ¹H–¹H COSY correlations of OH-1 with H-1 (Figure [6]). Furthermore, ROESY correlations of OH-11/H-18 and OH-1/H-3 suggested the relative configurations of 6 as those in 5 (Figure [7]).

Compound 7 was obtained as colorless gum. Its molecular formula, C₂₀H₂₂O₂, was established by ¹³C NMR (Table [4]) and HRMS (EI) (m/z = 294.1635 [M]⁺) data, indicating 10 indices of hydrogen deficiency. Structurally, 7 was similar to 3, differing by the presence of additional double bond (δ_C = 154.6, 124.9 ppm) instead of methylene (δ_C = 54.7 ppm, C-3) and quaternary carbon (δ_C 76.1, C-11) in the latter. The HMBC correlations from H-2 (δ_H = 2.93 ppm, m) to C-3/C-4, and from H-18/H-19 (δ_H = 1.61 ppm, s) to C-3 further supported this elucidation (Figure [6]). Thus, the planar structure of 7 was assigned and named salpratone H.

Salpratone I (8) was analyzed by HRMS (ESI) (m/z = 337.1779 [M + Na]⁺, calcd for C₂₀H₂₆O₆Na) and ¹³C NMR as C₂₀H₂₆O₆. By carefully analyzing the characteristic resonances (Table [4]), one carbonyl carbon (δ_C = 205.7, C-12 ppm), an isopropyl (δ_C = 27.8/22.2/21.5 ppm, C-15/16/17), an oxidized quaternary carbon (δ_C = 84.8 ppm, C-11), and a quaternary carbon (δ_C = 39.5 ppm, C-4) were clearly observed, which indicated that 8 possessed a similar 6/6/7 ring system to 4,5-seco-abietane diterpene microstegiol.[19] The major differences were the presence of an oxidized methine (δ_C = 71.0 ppm) in 8 instead of a methylene group (δ_C = 44.5 ppm) in microstegiol. Additionally, the planar structure of 8 was corroborated by the ¹H–¹H COSY correlations of OH-1 with H-1 and the HMBC correlations as shown in Figure [6]. In the ROESY spectrum, the cross peak between H-1 and OH-11 indicated the cis orientation of H-1 and OH-11 (Figure [7]). Structurally, salpratone I (8) was a 4,5-seco-abietane diterpene that processes a 6/6/7 tetracyclic skeleton.

To evaluate the anticoagulant properties of 4,5-seco-abietane diterpenes derived from S. prattii, in vitro anticoagulant effects of compounds 1–5 and 9, 10 were assessed using the activated partial thromboplastin time (APTT) assay.[20] [21] As detailed in Table [5], compounds 1, 4, and 5 demonstrated a slight prolongation of APTT relative to the DMSO control.

Collectively, eight undescribed 4,5-seco-abietane-type diterpenes (1–8), together with two known analogues (9 and 10), were purified and identified from S. prattii.[22] Among them, a 4,5;13,14-bis-seco-abietane diterpene (1) with a unique rearranged 6/6/5 tricyclic skeleton that probably originates via the retro-aldol reaction of the precursor prionopid A (9) was characterized. Single-crystal X-ray diffraction, spectroscopic data interpretation, and computed electronic circular dichroism analysis were used to determine the structures. Assays of anticoagulant activity showed that 1, 4, and 5 weakly prolonged the clotting times of human plasma in the activated partial thromboplastin time (APTT) assays with concentrations of 100 μM. These findings will contribute to the enrichment of the structural diversity and bioactivity profiles of Salvia diterpenes.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

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• 22 Salpratone B (1) Colorless crystals; mp 174–176 °C. UV (MeOH): λ_max (log ε): 200 (4.69), 248 (2.31), 266 (2.63) nm. IR (KBr): ν_max = 3397, 3339, 2967, 2919, 1709, 1469, 1384, 1194, 1057, 914, 822 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₂₈O₅Na: 371.1829; found: 371.1837 [M + Na]⁺. [α]_D ²¹  + 17  (c  0.24,  MeOH)  for  (+)-1;  [α]_D ²¹ –20 (c  0.24,  MeOH) for (–)-1. CD (0.00039 M, MeOH): λ_max (Δε): 195 (+8.25), 201 (+15.33), 233 (–3.46), 300 (+1.07) nm for (+)-1; CD (0.00036 M, MeOH): λ_max (Δε): 195 (–7.73), 201 (–13.17), 233 (+4.90), 300 (–0.15) nm for (–)-1. Salpratone C (2) Colorless crystals; mp 96–97 °C. UV (MeOH): λ_max (log ε): 203 (4.33), 242 (4.20), 280 (3.22), 334 (3.67) nm. IR (KBr): ν_max = 3441, 2963, 2927, 1632, 1383, 1046, 581 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₂₆O₃Na: 337.1774; found: 337.1780 [M + Na]⁺. [α]_D ²¹ +2.2 (c 0.12, MeOH) for (+)-2; [α]_D ²¹ –32.2 (c 0.12, MeOH) for (–)-2. CD (0.00086 M, MeOH): λ_max (Δε): 195 (–9.19), 220 (+8.37), 244 (–4.74), 337 (–2.70), 380 (+1.31) nm for (+)-2. CD (0.00079 M, MeOH): λ_max (Δε): 195 (+7.36), 220 (–7.97), 244 (+3.92), 337 (+2.26), 380 (–1.60) nm for (–)-2. Salpratone D (3) Colorless crystals; mp 162–164 °C. UV (MeOH): λ_max (log ε): 204 (4.45), 237 (4.02), 265 (3.95), 306 (3.60) nm. IR (KBr): ν_max = 3415, 2964, 2938, 1619, 1571, 1361, 1265, 1112, 1026 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₂₅O₃, 313.1804; found: 313.1803 [M + H]⁺. ECD (MeOH): λ_max (Δε): 195 (–10.78), 208 (–6.51), 213 (–6.81), 237 (–2.37), 253 (–3.46), 282 (+0.74), 320 (+6.84), 360 (+0.09) nm. [α]_D ²¹ +3.6 (c 0.08, MeOH) for (+)-3; [α]_D ²¹ –27.5 (c 0.08, MeOH) for (–)-3. CD (0.00102 M, MeOH): λ_max (Δε): 207 (+5.59), 240 (–5.58), 295 (–1.78), 325 (+4.65), 363 (–3.54), 450 (–0.27) nm for (+)-3. CD (0.001 M, MeOH): λ_max (Δε): 207 (–6.61), 240 (+6.45), 295 (+1.89), 325 (–5.87), 363 (+3.71), 450 (–0.28) nm for (–)-3. Salpratone E (4) Colorless crystals; mp 197–200 °C; [α]_D ¹⁹ –104.2 (c 0.03, MeOH). UV (MeOH): λ_max (log ε): 197 (4.18), 236 (3.78), 274 (3.19), 322 (3.43) nm. IR (KBr): ν_max = 3388, 2960, 2920, 2851, 1683, 1261, 1097, 1029, 802 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₂₂O₃Na, 333.1461; found: 333.1467 [M + Na]⁺. Salpratone F (5) Colorless gum; [α]_D ²⁰ –75.6 (c 0.05, MeOH). UV (MeOH): λ_max (log ε): 197 (4.77), 220 (4.29), 242 (4.55), 269 (3.46), 335 (4.06) nm. IR (KBr): ν_max = 3418, 2960, 2927, 1693, 1460, 1383, 1072, 969 cm^–1. HRMS (EI): m/z calcd for C₂₁H₂₆O₃, 326.1882; found: 326.1883 [M]⁺. Salpratone G (6) Colorless solid; [α]_D ¹⁹ –119.7 (c 0.06, MeOH). UV (MeOH): λ_max (log ε): 197 (4.57), 221 (4.08), 242 (4.34), 270 (3.23), 335(3.85) nm. IR (KBr): ν_max = 3412, 2960, 2925, 2852, 1693, 1462, 1383, 1260, 966, 815 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₂₄O₃Na, 335.1618; found: 335.1615 [M + Na]⁺. Salpratone H (7) Colorless gum; UV (MeOH): λ_max (log ε): 204 (4.54), 226 (4.39), 265 (3.96), 294 (4.05), 357 (3.98) nm. IR (KBr): ν_max = 2961, 2926, 1606, 1563, 1433, 1287, 1136 cm^–1. HRMS (EI): m/z calcd for C₂₀H₂₂O₂, 294.1620; found: 294.1635 [M]⁺. Salpratone I (8) Colorless solid; [α]_{20 DD} ²⁰ +460 (c 0.06, MeOH). UV (MeOH): λ_max (log ε): 202 (4.64), 2.32 (4.12), 247 (4.22), 271 (3.24), 338 (4.08) nm. IR (KBr): ν_max = 3427, 2962, 2930, 1651, 1466, 1386, 1080, 986 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₂₆O₃Na, 337.1774; found: 337.1779 [M + Na]⁺. Crystallographic Data Crystallographic data of 1–4 were collected at 100 K on a Bruker APEX DUO diffractometer equipped with an APEX II CCD using Cu Kα radiation. CCDC 2333505 (1), CCDC 2333506 (2), CCDC 2333510 (3), and CCDC 2333511 (4) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures

Corresponding Authors

Publication History

Received: 26 October 2024

Accepted after revision: 29 November 2024

Article published online:
23 January 2025

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• References and Notes

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• 22 Salpratone B (1) Colorless crystals; mp 174–176 °C. UV (MeOH): λ_max (log ε): 200 (4.69), 248 (2.31), 266 (2.63) nm. IR (KBr): ν_max = 3397, 3339, 2967, 2919, 1709, 1469, 1384, 1194, 1057, 914, 822 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₂₈O₅Na: 371.1829; found: 371.1837 [M + Na]⁺. [α]_D ²¹  + 17  (c  0.24,  MeOH)  for  (+)-1;  [α]_D ²¹ –20 (c  0.24,  MeOH) for (–)-1. CD (0.00039 M, MeOH): λ_max (Δε): 195 (+8.25), 201 (+15.33), 233 (–3.46), 300 (+1.07) nm for (+)-1; CD (0.00036 M, MeOH): λ_max (Δε): 195 (–7.73), 201 (–13.17), 233 (+4.90), 300 (–0.15) nm for (–)-1. Salpratone C (2) Colorless crystals; mp 96–97 °C. UV (MeOH): λ_max (log ε): 203 (4.33), 242 (4.20), 280 (3.22), 334 (3.67) nm. IR (KBr): ν_max = 3441, 2963, 2927, 1632, 1383, 1046, 581 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₂₆O₃Na: 337.1774; found: 337.1780 [M + Na]⁺. [α]_D ²¹ +2.2 (c 0.12, MeOH) for (+)-2; [α]_D ²¹ –32.2 (c 0.12, MeOH) for (–)-2. CD (0.00086 M, MeOH): λ_max (Δε): 195 (–9.19), 220 (+8.37), 244 (–4.74), 337 (–2.70), 380 (+1.31) nm for (+)-2. CD (0.00079 M, MeOH): λ_max (Δε): 195 (+7.36), 220 (–7.97), 244 (+3.92), 337 (+2.26), 380 (–1.60) nm for (–)-2. Salpratone D (3) Colorless crystals; mp 162–164 °C. UV (MeOH): λ_max (log ε): 204 (4.45), 237 (4.02), 265 (3.95), 306 (3.60) nm. IR (KBr): ν_max = 3415, 2964, 2938, 1619, 1571, 1361, 1265, 1112, 1026 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₂₅O₃, 313.1804; found: 313.1803 [M + H]⁺. ECD (MeOH): λ_max (Δε): 195 (–10.78), 208 (–6.51), 213 (–6.81), 237 (–2.37), 253 (–3.46), 282 (+0.74), 320 (+6.84), 360 (+0.09) nm. [α]_D ²¹ +3.6 (c 0.08, MeOH) for (+)-3; [α]_D ²¹ –27.5 (c 0.08, MeOH) for (–)-3. CD (0.00102 M, MeOH): λ_max (Δε): 207 (+5.59), 240 (–5.58), 295 (–1.78), 325 (+4.65), 363 (–3.54), 450 (–0.27) nm for (+)-3. CD (0.001 M, MeOH): λ_max (Δε): 207 (–6.61), 240 (+6.45), 295 (+1.89), 325 (–5.87), 363 (+3.71), 450 (–0.28) nm for (–)-3. Salpratone E (4) Colorless crystals; mp 197–200 °C; [α]_D ¹⁹ –104.2 (c 0.03, MeOH). UV (MeOH): λ_max (log ε): 197 (4.18), 236 (3.78), 274 (3.19), 322 (3.43) nm. IR (KBr): ν_max = 3388, 2960, 2920, 2851, 1683, 1261, 1097, 1029, 802 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₂₂O₃Na, 333.1461; found: 333.1467 [M + Na]⁺. Salpratone F (5) Colorless gum; [α]_D ²⁰ –75.6 (c 0.05, MeOH). UV (MeOH): λ_max (log ε): 197 (4.77), 220 (4.29), 242 (4.55), 269 (3.46), 335 (4.06) nm. IR (KBr): ν_max = 3418, 2960, 2927, 1693, 1460, 1383, 1072, 969 cm^–1. HRMS (EI): m/z calcd for C₂₁H₂₆O₃, 326.1882; found: 326.1883 [M]⁺. Salpratone G (6) Colorless solid; [α]_D ¹⁹ –119.7 (c 0.06, MeOH). UV (MeOH): λ_max (log ε): 197 (4.57), 221 (4.08), 242 (4.34), 270 (3.23), 335(3.85) nm. IR (KBr): ν_max = 3412, 2960, 2925, 2852, 1693, 1462, 1383, 1260, 966, 815 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₂₄O₃Na, 335.1618; found: 335.1615 [M + Na]⁺. Salpratone H (7) Colorless gum; UV (MeOH): λ_max (log ε): 204 (4.54), 226 (4.39), 265 (3.96), 294 (4.05), 357 (3.98) nm. IR (KBr): ν_max = 2961, 2926, 1606, 1563, 1433, 1287, 1136 cm^–1. HRMS (EI): m/z calcd for C₂₀H₂₂O₂, 294.1620; found: 294.1635 [M]⁺. Salpratone I (8) Colorless solid; [α]_{20 DD} ²⁰ +460 (c 0.06, MeOH). UV (MeOH): λ_max (log ε): 202 (4.64), 2.32 (4.12), 247 (4.22), 271 (3.24), 338 (4.08) nm. IR (KBr): ν_max = 3427, 2962, 2930, 1651, 1466, 1386, 1080, 986 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₂₆O₃Na, 337.1774; found: 337.1779 [M + Na]⁺. Crystallographic Data Crystallographic data of 1–4 were collected at 100 K on a Bruker APEX DUO diffractometer equipped with an APEX II CCD using Cu Kα radiation. CCDC 2333505 (1), CCDC 2333506 (2), CCDC 2333510 (3), and CCDC 2333511 (4) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures

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