Relevance of the C-5 Position to Schweinfurthin Induced Cytotoxicity

Abstract

The schweinfurthins are an intriguing group of anti-proliferative agents that display low nanomolar activities against several cell types, including the human-derived glioblastoma cell line SF-295, but have little impact on other cell lines even at micromolar concentrations. This activity has inspired the synthesis of seven of the natural schweinfurthins, all with the correct absolute stereochemistry, and a variety of analogues designed to probe different facets of the pharmacophore. Reported herein is the synthesis of several new schweinfurthin analogues varied at the C-5 position along with data on their biological activity in the NCI 60 cell-line assay.

1. Introduction

In 1998 the structures of schweinfurthins A and B (1 and 2, Figure 1) were reported as part of the National Cancer Institute's (NCI) search for anti-proliferative agents with new mechanisms of action. These compounds were isolated from an extract of Macaranga schweinfurthii through bioassay guided fractionation,¹ and subsequently were subjected to the NCI 60 cell-line screen. This assay revealed a unique pattern of activity which does not correlate to any known mechanism of cell growth inhibition. Several cell lines were particularly sensitive to the schweinfurthins, including the human glioblastoma line SF-295, while other cell lines (e.g. the lung cancer line A549) were only marginally affected even at elevated doses. These observations led to the hypothesis that further exploration of the schweinfurthins might uncover a new target for treatment of specific malignancies, especially for conditions with poor clinical prognoses such as glioblastoma multiforme.

Figure 1.

Key schweinfurthins and current understanding of the pharmacophore

At this time seven of the eleven natural schweinfurthins^1–4 have been synthesized, including specifically schweinfurthins A (1),⁵ B (2),⁶ C,⁷ E (3),⁶ F (4),⁸ and G (5),⁸ as well as vedelianin⁹ (6). Our group also has synthesized numerous schweinfurthin analogues and in the process has gained considerable knowledge of the schweinfurthin pharmacophore. Several portions of the schweinfurthin structure have shown tolerance to modification, including the presence or absence of a hydroxyl group at C-3,¹⁰ methylation of one D-ring phenol¹¹ (Figure 1, “tolerant”), and especially incorporation of substituents at the para position of the D-ring, including hydrogen or an alkyl, allyl, prenyl, or geranyl group (“highly tolerant”).^12–15 Conversely, modification of other regions resulted in a significant loss of activity, including a cis-fused A/B system,¹⁶ a cis-stilbene or a saturated linkage,¹³ and simultaneous methylation of both D-ring phenols (Figure 1, “intolerant”).¹¹

Investigations of the schweinfurthin mechanism¹⁷ have revealed that schweinfurthin A can phenocopy the tumor suppressor NF1 in CNS and peripheral nervous system tumor cell lines,^17a although a proximate target has not yet been identified conclusively. Recent work by the Shair group has implicated oxysterol binding proteins in the action of schweinfurthins and other apparently similar natural products, but the evidence for schweinfurthins is less compelling than for OSW-1 and cephalostatin 1.^17b A recent study more specific to the schweinfurthins found that the synthetic analogue 3-deoxyschweinfurthin B had a pronounced impact on isoprenoid homeostasis,^17c but more work is clearly needed before the mechanism(s) will be understood in any detail.

An increased understanding of the pharmacophore has allowed synthesis of schweinfurthins for use as fluorescent^12,14 or biotinylated¹⁵ probes that may allow more specific determination of the basis of schweinfurthins' cellular activity. However, one region of the schweinfurthin structure that, until now, has remained relatively unexplored is the C-5 position. Within the natural family, this position has been found only as a free phenol or a methoxy group, with the free phenol typically 2–4 fold more potent. Given this difference in potency, it appeared to be worthwhile to explore the effect that various substituents at the C-5 position might have on activity. Reported herein is the synthesis of a small set of C-5 modified schweinfurthins with an evaluation of their relative activity in the NCI's 60 cell-line assay.

2. Synthesis

Our strategy for schweinfurthin synthesis is based on a late stage Horner-Wadsworth-Emmons (HWE) condensation between an aryl aldehyde, usually representing the hexahydroxanthene side of the target, and a benzylic phosphonate.¹⁰ To use this approach to obtain C-5 analogues required preparation of several key aldehydes (Scheme 1). The first aldehyde prepared carried only a hydrogen substituent at C-5. To pursue this compound, protection of the previously reported arene 7¹⁸ as the TBS ether afforded compound 8, which was epoxidized under Shi conditions¹⁹ to obtain the nonracemic compound 9. Removal of the silyl group in epoxide 9 afforded the phenol 10, and subsequent treatment with BF₃·OEt₂ brought about cyclization to afford the hexahydroxanthene 11 in very good yield. After reduction of this methyl ester to the benzylic alcohol 12, oxidation with MnO₂ gave the parent aldehyde 13. While aldehyde 13 underwent direct bromination at the C-5 position in modest yield (23%), a longer sequence provided the MOM-protected bromide 18 in much better yield. Thus, bromination of the methyl ester 11 in methylene chloride and acetic acid provided a mixture of bromides 14 and 15, but cleavage of the acetate could be accomplished in near-quantitative yield. After protection of the hydroxyl group of compound 14 through reaction with MOMCl, reduction provided the benzylic alcohol 17 and a final oxidation with MnO₂ gave the desired aldehyde 18. This aldehyde was condensed with a “right-half” phosphonate (vide infra) that was also MOM-protected, so a separate step was not required for the eventual removal of the C-2 MOM group.

Scheme 1.

Synthesis of four intermediate aldehydes for the “left half” of the schweinfurthins.

A substantial number of important drugs bear a fluorine substituent, at least in part because fluorine's electronic properties are significantly different from hydrogen but its size is sufficiently similar that there is minimal potential for introduction of unfavorable steric interactions in a monofluoro compound.²⁰ To prepare a C-5 fluorinated schweinfurthin analogue, synthesis of the requisite aldehyde began with ester 19, obtained in three steps from commercial 3-fluoro-4-hydroxybenzoic acid (esterification, bromination and protection as the MOM acetal).²¹ After this ester was reduced to alcohol 20 it was converted to the methyl ether 21 via a standard Williamson synthesis. Halogen metal exchange and reaction of the resulting aryl lithium intermediate with geranyl bromide provided compound 22 in low yield. Application of a Shi epoxidation furnished epoxide 23 in moderate yield and good enantiomeric excess. Cyclization of this epoxide afforded the hexahydroxanthene 24. The benzyl methyl ether has been utilized as a latent benzaldehyde in other schweinfurthin syntheses,^5,8 and in this specific case DDQ oxidation provided aldehyde 25 cleanly in a single step from the methyl ether 24.

A slightly different approach based on sequential and selective directed ortho metallation was employed to gain access to the C-5 methylthio schweinfurthin analogue. In this case, after alcohol 26 was converted to the methyl ether 27, deprotonation with n-BuLi followed by treatment with (CH₃S)₂ provided the thiomethyl ether 28. A second ortho metallation and copper-mediated coupling with the known²² epoxide of geranyl bromide provided epoxide 29. Cyclization to compound 30 proceeded in reasonable yield, and DDQ oxidation of the benzyl methyl ether provided aldehyde 31 smoothly without detectable oxidation of the thiomethyl group.

We also prepared compounds with carbon-containing substituents at C-5 (Scheme 2). During the course of these studies, the benzyl alcohol 32 became available through a cascade cyclization terminated by electrophilic aromatic substitution.⁵ Treatment of compound 32 with DDQ preferentially oxidized the benzyl methyl ether in the presence of the free benzyl alcohol to provide aldehyde 33, corroborating previous observations on the regioselectivity of this oxidation.⁵ Protection of the benzyl alcohol as a TBS ether afforded aldehyde 34 for use as a partner in HWE reactions.

Scheme 2.

Synthesis of C-5 alkyl compounds

The right half of the new schweinfurthin analogues was prepared as shown in Scheme 3. Directed ortho metallation of alcohol 35²³ occurred upon exposure to multiple equivalents of n-BuLi, and subsequent reaction with geranyl bromide afforded the expected geranylated arene 38 in 47% yield.²⁴ This approach presumably involves formation of an intermediate dianion, and was more efficient than the 34% overall yield if alcohol 35 was protected as the TBS ether 36, alkylated to obtain compound 37, and then deprotected to afford alcohol 38. Conversion of benzyl alcohol 38 to the phosphonate 39 was conducted by a classical Arbuzov reaction²⁵ after formation of the mesylate and iodide. This provided phosphonate 39 which was used as an HWE coupling partner throughout this series.

Scheme 3.

Synthesis of phosphonate 39

With phosphonate 39 and a set of aldehydes now available, stilbene formation was accomplished by standard HWE olefination (Table 1). Treatment of the new aldehydes 13, 18, 25, 31, and 34, as well as the known aldehydes 40,⁵41,⁸ and 42,¹⁰ with phosphonate 39 and base provided stilbenes 43–50 in moderate to high yield. Hydrolysis of the MOM acetals 43–49 was accomplished by exposure to methanolic p-TsOH to provide schweinfurthin analogues 51–57.

Table 1.

HWE Condensations and subsequent hydrolysis.

Entry	RCHO	R =	HWE (% Yield)	Stilbene	Hydrolysis (% Yield)	Schwein.	R =
1	13	H	66%	43	53%	51	H
2	18 a	Br	54%	44 a	92%	52	Br
3	25	F	53%	45	77%	53	F
4	31	SCH3	74%	46	40%	54	SCH3
5	40	CH2OCH3	50%	47	41%	55	CH2OCH3
6	41	OMOM	77%	48	61%	56	OH
7	42	OCH3	90%	49	92%	57	OCH3
8	34	CH2OTBS	36%	50

^aIn this series, the aldehyde and stilbene bear a C-2 MOM group that is cleaved in the final hydrolysis.

The benzylic C-5 position of compound 50 allowed the possibility of further elaboration and this intermediate was exploited to obtain several additional analogues. After cleavage of the silyl ether through treatment with TBAF, several analogues were obtained through straightforward reactions of the resulting benzyl alcohol 58 (Scheme 4). Exposure of alcohol 58 to MnO₂ resulted in aldehyde 60. Further oxidation of this intermediate with sodium chlorite²⁶ provided the carboxylic acid 61, while reductive amination of aldehyde 60 with NaCNBH₃ and dimethylamine resulted in the tertiary amine 62. The D-ring MOM group of compound 58 could be removed via hydrolysis to afford schweinfurthin 59, but this reaction proceeded in low yield. Given this disappointing yield, and because MOM groups can sometimes be cleaved in vivo during cellular assays, hydrolysis of the other MOM acetals in this small set was not pursued pending the results of bioassays on two representative members of this group, the alcohol 58 and the corresponding aldehyde 60.

Scheme 4.

3. Biological results and discussion

Nine of these new schweinfurthin analogues have been submitted to the NCI's 60 cell-line screen,²⁷ compounds 51–58, and 60. The current protocol for this assay requires initial testing at a single dose, and then the more active compounds are subjected to the full 5-dose assay. Of these nine schweinfurthins, compounds 52 and 55 did not pass the single dose assay with a level of activity sufficient to justify the full screen. Given the substantial size of the bromide substituent, it may not be surprising that compound 52 showed little activity, but the limited activity of the fluoride 55 was disappointing. This may suggest that a C-5 substituent capable of hydrogen bond donation is important to activity, or that the limited ability of fluorine²⁸ to serve as hydrogen bond acceptor diminishes activity.

Five of the compounds that did pass this test carried one phenol and one methoxy substituent in the D-ring, and these five compounds displayed a range of activity (Table 2). Compound 56 was the most potent, with a mean GI₅₀ of 0.47 μM, and this compound also showed the greatest difference in activity between the most and least sensitive cell lines (2.84 log units). Reflecting the same trend as the natural products schweinfurthin A and B, introduction of a methyl ether at the C-5 position (i.e. compound 57) resulted in about a 3-fold loss of potency as measured by the mean GI₅₀ values. The difference in activity is even more striking if one considers just the sensitive SF-295 and insensitive A549 cell lines. For these two cell lines, compound 56 was more than 30-fold more potent against SF-295 cells than against A549 cells, while compound 57 showed only about 13-fold greater activity in the SF-295 assay. A lesser differential activity also is observed in the full 60 cell-line data for compound 57 versus compound 56 (1.58 versus 2.84).

Table 2.

Activity of Schweinfurthin Analogues in the NCI 60 Cell Line Screen.²⁷

Entry	Schweinfurthin	R =	R' =	Mean GI50 (μM)	Differential (log units)	SF-295 GI50 (μM)	A-549 GI50 (μM)
1	51 a	H	H	10.15	1.56	1.66	13.2
2	53 a	F	H	6.23	1.40	5.01	2.14
3	54 a	SCH3	H	7.95	1.58	3.80	6.03
4	56 b	OH	H	0.47	2.84	0.022	0.72
5	57 a	OCH3	H	1.67	1.58	0.19	2.45
6	58 b	CH2OH	MOM	1.66	2.56	0.15	1.41
7	60 a	CHO	MOM	6.30	2.46	1.20	7.8

^aDuplicate wells were run for each of these compounds in one assay.

^bDuplicate wells were run for each of these compounds in each of two independent assays and the average value is given in this table.

By some measures, compound 57 also is an interesting compound: it has a relatively low mean GI₅₀ (1.67 μM) and shows a 13-fold difference in activity between the SF-295 and A549 cells. However, perhaps the most surprising compound is the benzyl alcohol 58. As noted above, because attempted hydrolysis of the D-ring MOM group in compound 58 was accompanied by extensive decomposition, both compounds 58 and 60 were submitted for this assay with the D-ring MOM group still in place. Thus there are two points of difference between compounds 58 and 57 which complicates any direct comparison of their biological activity. Nevertheless, the fact that compound 58 displays potency comparable to compound 57 and high differential activity (2.56 log units in the 60 cell assay) is intriguing. If one assumes that the D-ring MOM group is lost after cell uptake, the resulting compound would be simply isomeric to compound 56 at C-5 and it is nearly equivalent in mean GI₅₀. However compound 58 may be significantly more stable to metabolism. Because ortho quinone formation in the C-ring would require extensive metabolism with any carbon substituent at C-5, it may be worthwhile to explore other schweinfurthin analogues that include a C-5 hydroxymethyl group.

4. Conclusions

In conclusion, several C-5 modified schweinfurthin analogues have been prepared through new variations on the strategies that have been used to prepare the natural products in this family. These syntheses required sequences of varied length and gave varied yields, but averaged 11 linear steps and proceeded in an average yield of ~5%. Of the nine schweinfurthin analogues synthesized for this study and tested in the NCI 60 cell assay, only compounds 56 and 58 have in vitro potency comparable to schweinfurthin A (1),¹ although most of them show selectivity for inhibition of CNS tumor cell growth. From these studies, it appears that the phenol group at C-5 is one structural feature that preserves both good potency and a high differential activity. Perhaps surprisingly, incorporation of a hydroxymethyl group at this position also led to an analogue with good activity. Thus the contribution of the C-5 substituent may be more reliant on its ability to undergo hydrogen bonding than on its electronic effect on the extended π system. It is now apparent that preservation of a C-5 substituent capable of H-bonding will be important during studies that probe other aspects of the schweinfurthin pharmacophore. Furthermore, the activity observed for compound 58, despite the presence of a D-ring MOM acetal, suggests that this group is biodegradable upon cell uptake and/or that there is more flexibility to substituents at this position than previously recognized. Thus it is reasonable to conclude that there is still more to be learned about the activity of synthetic compounds modeled upon the natural schweinfurthins, and further studies in this vein will be forthcoming.

5. Experimental procedures and methods

5.1 General Experimental Conditions

Tetrahydrofuran was freshly distilled from sodium/benzophenone, while methylene chloride was distilled from calcium hydride prior to use. All other reagents and solvents were purchased from commercial sources and used without further purification. All reactions in nonaqueous solvents were conducted in flame-dried glassware under a positive pressure of argon and with magnetic stirring. All NMR spectra were obtained at 300 MHz for ¹H, and 75 MHz for ¹³C with CDCl₃ as solvent, and (CH₃)₄Si (1H, 0.00 ppm) or CDCl₃ (¹³C, 77.0 ppm) as internal standards unless otherwise noted. The ³¹P chemical shifts were reported in ppm relative to 85% H₃PO₄ (external standard). High resolution mass spectra were obtained at the University of Iowa Mass Spectrometry Facility. Silica gel (60 Å, 0.040–0.063 mm) was used for flash chromatography.

5.2 Silyl ether 8

To a solution of phenol 7 (1.86 g, 6.4 mmol) in CH₂Cl₂ (200 mL) was added imidazole (2.19 g, 32.2 mmol), followed by TBSCl (1.15 g, 7.7 mmol) in one portion at 0 °C. The solution was allowed to stir for 12 h, and then the reaction was quenched by addition of water. The resulting solution was extracted with CH₂Cl₂, dried (MgSO₄), and concentrated in vacuo. Purification by column chromatography (1–5% EtOAc in hexanes) produced ester 8 as an oil (2.46 g, 95%): ¹H NMR δ 7.83 (d, J = 2.2 Hz, 1H), 7.78 (dd, J = 8.4, 2.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.34–5.29 (m, 1H), 5.14–5.09 (m, 1H), 3.86 (s, 3H), 3.32 (d, J = 6.8 Hz, 2H), 2.12–2.01 (m, 4H), 1.69 (s, 3H), 1.67 (s, 3H), 1.60 (s, 3H), 1.02 (s, 9H), 0.26 (s, 6H); ¹³C NMR δ 167.2, 157.8, 136.7, 132.5, 131.4, 129.6, 128.8, 124.3, 122.9, 122.0, 117.9, 51.8, 39.8, 28.5, 26.7, 25.7 (3C), 25.7, 18.3, 17.7, 16.3, −3.7 (2C). Anal. Calcd for C₂₄H₃₈O₃Si: C, 71.59; H, 9.51. Found C, 71.44; H, 9.58.

5.3 Epoxide 9

To a solution of ester 8 (879 mg, 2.2 mmol), CH₂Cl₂ (6 mL), CH₃CN (3 mL), EtOH (3 mL), and aqueous buffer (2 M K₂CO₃, 4 × 10⁻³ M EDTA, 12 mL), and the Shi catalyst (140 mg, 0.5 mmol) was added H₂O₂ (30% wt. in H₂O, 1.2 mL, 10.6 mmol) via syringe pump (0.14 mL/h) at –10 °C. After 17 h, the reaction was quenched by addition of Na₂SO₃. The resulting solution was extracted with ether, dried (MgSO₄), and concentrated in vacuo. Final purification by column chromatography (2–5% EtOAc in hexanes) provided recovered ester 8 (318 mg, 36%) and epoxide 9 (459 mg, 50%) as oils: ¹H NMR δ 7.81 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.4, 2.4 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 5.38–5.33 (m, 1H), 3.86 (s, 3H), 3.33 (d, J = 6.9 Hz, 2H), 2.72 (t, J = 6.4 Hz, 1H), 2.28–2.09 (m, 2H), 1.77–1.56 (m, 2H), 1.71 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H), 1.01 (s, 9H), 0.26 (s, 6H); ¹³C NMR δ 167.1, 157.8, 135.8, 132.2, 131.4, 128.9, 122.8, 122.5, 117.9, 64.2, 58.4, 51.9, 36.3, 28.5, 27.4, 25.7 (3C), 24.9, 18.7, 18.3, 16.3, −3.7 (2C). Anal. Calcd for C₂₄H₃₈O₄Si: C, 68.86; H, 9.15. Found C, 69.09; H, 9.19.

5.4 Phenol 10

To a solution of epoxide 9 (459 mg, 1.1 mmol) in THF (20 mL) at rt was added TBAF (1 M in THF, 2.2 mL, 2.2 mmol). After 3 h, the reaction was quenched by addition of water. The resulting solution was extracted with ether, dried (MgSO₄), and concentrated in vacuo. Final purification by column chromatography (10–15% EtOAc in hexanes) afforded phenol 10 (333 mg, 100%) as an oil: ¹H NMR δ 7.81–7.77 (m, 2H), 6.84–6.81 (m, 1H), 5.36 (td, J = 7.1, 1.4 Hz, 1H), 3.87 (s, 3H), 3.38 (d, J = 6.9 Hz, 2H), 2.74 (t, J = 6.2 Hz, 1H), 2.29–2.12 (m, 2H), 1.77 (s, 3H), 1.71–1.64 (m, 2H), 1.29 (s, 3H), 1.27 (s, 3H); ¹³C NMR δ 167.3, 158.7, 137.0, 131.8, 129.6, 127.2, 122.2, 122.0, 115.4, 64.4, 58.9, 51.9, 36.4, 29.1, 27.2, 24.8, 18.7, 16.2. Anal. Calcd for C₁₈H₂₄O₄: C, 71.03; H, 7.95. Found C, 70.73; H, 7.96.

5.5 Hexahydroxanthene 11

To a solution of epoxide 10 (353 mg, 1.16 mmol) in CH₂Cl₂ (125 mL) at −78 °C was added BF₃·OEt₂ (0.73 mL, 5.76 mmol). After 6 min, the reaction was quenched by addition of triethylamine (TEA, 1.5 mL). Water was added, the resulting solution was extracted with CH₂Cl₂, dried (MgSO₄), and concentrated in vacuo. Purification by column chromatography (25% EtOAc in hexanes) afforded compound 11 (332 mg, 94%) as a white solid: [α]^26.4_D = +66.8 (c 7.3, CHCl₃, 93% ee by HPLC); ¹H NMR δ 7.82 (d, J = 1.8 Hz, 1H), 7.77 (dd, J = 8.4, 2.1 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H), 3.44 (dd, J = 11.3, 4.2 Hz, 1H), 2.82–2.66 (m, 2H), 2.03 (dt, J = 12.4, 3.3 Hz, 1H), 1.92–1.54 (m, 5H), 1.23 (s, 3H), 1.11 (s, 3H), 0.89 (s, 3H); ¹³C NMR (CDCl₃) δ 167.1, 157.3, 131.9, 129.2, 121.7, 117.0, 77.9, 76.7, 51.8, 46.7, 38.4, 37.6, 28.2, 27.3, 22.9, 20.0, 14.3; ¹³C NMR (75.5 MHz, acetone-d₆) δ 167.4, 158.7, 132.9, 129.9, 123.6, 122.8, 118.0, 78.8, 78.0, 52.2, 48.0, 39.5, 38.9, 29.4, 28.1, 23.9, 20.6, 15.2. Anal. Calcd for C₁₈H₂₄O₄: C, 71.03; H, 7.95. Found C, 70.82; H, 8.10.

5.6 Hexahydroxanthene 12

To a solution of ester 11 (108 mg, 0.4 mmol) in THF (20 mL) at 0 °C was added LiAlH₄ (74 mg, 2.0 mmol). After 2 h, the reaction was quenched by addition of H₂O, acidified (pH 2), extracted into ethyl acetate, dried (MgSO₄), and concentrated in vacuo to afford alcohol 12 (98 mg, 100%) as a white solid: ¹H NMR δ 7.10–7.06 (m, 2H), 6.75 (d, J = 8.1 Hz, 1H), 4.58 (s, 2H), 3.41 (dd, J = 11.5, 4.4 Hz, 1H), 2.72 (bd, 1H), 2.69 (d, J = 3.9 Hz, 1H), 2.00 (dt, J = 12.3, 3.2 Hz, 1H), 1.88–1.82 (m, 1H), 1.80–1.50 (m, 4H), 1.25 (br s, 1H), 1.21 (s, 3H), 1.09 (s, 3H), 0.88 (s, 3H); ¹³C NMR δ 152.8, 132.3, 129.0, 126.6, 122.0, 117.1, 78.0, 76.5, 65.3, 46.9, 38.4, 37.8, 28.3, 27.4, 23.1, 19.9, 14.3. Anal. Calcd for C₁₇H₂₄O₃: C, 69.84; H, 8.27. Found C, 70.16; H, 7.92.

5.7 Aldehyde 13

To a solution of diol 12 (98 mg, 0.35 mmol) in CH₂Cl₂ (25 mL) at rt was added MnO₂ (812 mg, 8.22 mmol). After 2 h, the reaction was diluted, filtered through a pad of celite, and the filtrate was concentrated in vacuo. Final purification by crystalization (hexanes) afforded aldehyde 13 (78 mg, 90%) as white needles: ¹H NMR δ 9.83 (s, 1H), 7.64–7.61 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 3.45 (d, J = 12.0 Hz, 1H), 2.79–2.75 (m, 2H), 2.07–2.02 (m, 1H), 1.92–1.60 (m, 5H), 1.25 (s, 3H), 1.12 (s, 3H), 0.90 (s, 3H); ¹³C NMR δ 191.0, 158.9, 132.2, 129.7, 129.2, 122.5, 117.7, 78.0, 77.8, 46.6, 38.4, 37.6, 28.2, 27.3, 22.9, 20.1, 14.3; HRMS (EI) m/z calcd for C₁₇H₂₂O₃ (M⁺) 274.1570, found 274.1579.

5.8 C5-Bromo hexahydroxanthene 14

Method A

To a flask containing unsubstituted hexahydroxanthene 11 (107 mg, 0.4 mmol), glacial acetic acid (1 mL), and CH₂Cl₂ (35 mL) was added Br₂ (0.02 mL, 0.4 mmol) in CH₂Cl₂ (1 mL) dropwise at room temperature. The solution was allowed to stir for 24 h, and then the reaction was quenched by addition of Na₂SO₃. Water was added and the product was extracted into CH₂Cl₂, dried (MgSO₄), and concentrated under reduced pressure. Final purification by flash chromatography produced bromide 14 as a white solid (48 mg, 36%): ¹H NMR δ 8.03 (d, J = 2.1 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H), 3.88 (s, 3H), 3.44 (dd, J = 11.4, 4.1 Hz, 1H), 2.78–2.75 (m, 2H), 2.17–2.10 (m, 1H), 1.94–1.55 (m, 5H), 1.24 (s, 3H), 1.11 (s, 3H), 0.88 (s, 3H); ¹³C NMR δ 166.0, 154.0, 132.5, 130.7, 123.1, 122.4, 111.2, 79.0, 77.7, 52.1, 46.5, 38.4, 37.3, 28.1, 27.3, 23.3, 20.2, 14.3; HRMS (EI) m/z calcd for C₁₈H₂₃O₄Br (M⁺) 382.0780, found 382.0777. In addition the acetate-protected compound 15 was isolated as a white solid (78 mg, 52%): ¹H NMR δ 8.04 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 2.1 Hz, 1H), 4.66 (dd, J = 11.5, 3.9 Hz, 1H), 3.88 (s, 3H), 2.78–2.75 (m, 2H), 2.18–1.37 (m, 5H), 2.09 (s, 3H), 1.37 (s, 3H), 1.00 (s, 3H), 0.96 (s, 3H); ¹³C NMR δ 170.6, 165.9, 153.9, 132.5, 130.6, 122.8, 122.5, 111.3, 79.0, 78.5, 52.0, 46.6, 37.4, 37.0, 27.2, 24.6, 23.1, 21.2, 20.2, 15.4; HRMS (EI) m/z calcd for C₂₀H₂₅O₅Br (M⁺) 424.0886, found 424.0889.

Method B

To a flask containing acetate 15 (76 mg, 0.2 mmol), and CH₃OH (10 mL) was added potassium carbonate (137 mg, 1.0 mmol) at room temperature. The solution was allowed to stir for 6 h, the CH₃OH was removed in vacuo and then the reaction was quenched by addition of NH₄Cl. The product was extracted into CH₂Cl₂, dried (MgSO₄), and concentrated under reduced pressure. Final purification by flash chromatography produced the bromide 14 as a white solid (66 mg, 96%).

5.9 MOM-protected bromide 16

To a flask containing alcohol 14 (174 mg, 0.5 mmol), and CH₂Cl₂ (10 mL) was added DIPEA (0.5 mL, 2.9 mmol) followed by MOMCl (0.08 mL, 1.1 mmol) at room temperature. The solution was allowed to stir for 24 h, and then the reaction was quenched by addition of water. The product was extracted into CH₂Cl₂, dried (MgSO₄), and concentrated under reduced pressure. Final purification by flash chromatography produced 16 as a yellow oil (185 mg, 82%): ¹H NMR δ 8.03 (d, J = 1.8 Hz, 1H), 7.76–7.75 (m, 1H), 4.78 (d, J = 6.9 Hz, 1H), 4.65 (d, J = 7.1 Hz, 1H), 3.88 (s, 3H), 3.41 (s, 3H), 3.28 (dd, J = 11.7, 4.1 Hz, 1H), 2.80–2.68 (m, 2H), 2.12 (dt, J = 12.8, 3.3 Hz, 1H), 2.05–1.97 (m, 1H), 1.85–1.51 (m, 3H), 1.25 (s, 3H), 1.09 (s, 3H), 0.90 (s, 3H); ¹³C NMR δ 166.0, 154.0, 132.5, 130.7, 123.2, 122.4, 111.2, 96.2, 83.7, 78.9, 55.7, 52.0, 46.8, 38.2, 37.3, 27.4, 25.2, 23.3, 20.2, 15.1; HRMS (EI) m/z calcd for C₂₀H₂₇O₅Br (M⁺) 426.1042, found 426.1051.

5.10 Benzyl alcohol 17

To a flask containing ester 16 (185 mg, 0.4 mmol) and THF (10 mL) was added DIBAL-H (2.2 mL, 5.2 mmol) at 0 °C. The solution was allowed to stir for 3 hours, and then the reaction was quenched by addition of saturated NH₄Cl. The product was extracted into ether, dried (MgSO₄), and concentrated under reduced pressure. Final purification by flash chromatography produced alcohol 17 (158 mg, 92%): ¹H NMR δ 7.36 (d, J = 1.8 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 4.77 (d, J = 7.1 Hz, 1H), 4.65 (d, J = 6.6 Hz, 1H), 4.56 (s, 2H), 3.41 (s, 3H), 3.28 (dd, J = 11.4, 4.2 Hz, 1H), 2.72 (d, J = 9.5 Hz, 2H), 2.09 (dt, J = 12.6, 3.0 Hz, 1H), 1.95–1.43 (m, 5H), 1.22 (s, 3H), 1.08 (s, 3H), 0.89 (s, 3H); ¹³C NMR δ 149.5, 133.2, 129.9, 127.9, 123.7, 111.3, 96.2, 84.0, 77.7, 64.6, 55.7, 47.1, 38.2, 37.4, 27.4, 25.2, 23.4, 20.0, 15.1; HRMS (EI) m/z calcd for C₁₉H₂₇O₄Br (M⁺) 398.1093, found 398.1093.

5.11 Brominated aldehyde 18

To a flask containing benzyl alcohol 17 (76 mg, 0.2 mmol) in methylene chloride (52 mL) was added MnO₂ (88% precipitated active, 315 mg, 3.2 mmol). The mixture was allowed to stir for 3.25 h and then the reaction was quenched by filtration through celite. Final purification by flash chromatography produced aldehyde 18 (61 mg, 81%) as a white solid: [α]^26.4_D = +75.9 (c 0.61, CHCl₃, 96% ee by HPLC); ¹H NMR δ 9.71, (s, 1H), 7.81 (d, J = 1.7 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 4.71 (d, J = 7.1 Hz, 1H), 4.58 (d, J = 7.1 Hz, 1H), 3.34 (s, 3H), 3.22 (dd, J = 11.7, 4.3 Hz, 1H), 2.77–2.65 (m, 2H), 2.07 (dt, J = 12.7, 3.2 Hz, 1H), 2.01–1.45 (m, 4H), 1.20 (s, 3H), 1.03 (s, 3H), 0.84 (s, 3H); ¹³C NMR δ 189.8, 155.5, 132.8, 130.8, 129.7, 123.9, 112.3, 96.2, 83.7, 79.4, 55.7, 46.8, 38.3, 37.2, 27.4, 25.2, 23.3, 20.3, 15.1. Anal. Calcd for C₁₉H₂₅O₄Br: C, 57.44; H, 6.34. Found C, 57.54; H, 6.37.

5.12 Benzyl alcohol 20

To a solution of ester 19 (254 mg, 0.9 mmol) in THF (3 mL) at 0 °C was added LiAlH₄ (35 mg, 0.9 mmol). After 20 min, the reaction was quenched by slow addition of saturated NH₄Cl. The resulting solution was extracted with ether, dried (MgSO₄), and concentrated in vacuo. Final purification by column chromatography afforded alcohol 20 (208 mg, 90%) as a colorless oil: ¹H NMR δ 7.26–7.23 (m, 1H), 6.97 (dd, J_HF = 11.3 Hz, J = 2.0 Hz, 1H), 5.09 (s, 2H), 4.50 (s, 2H), 3.56 (s, 3H), 2.68 (br s, 1H); ¹³C NMR δ 156.0 (d, J_CF = 254 Hz), 141.1 (d, J_CF = 14.0 Hz), 138.7 (d, J_CF = 7.0 Hz), 126.5 (d, J_CF = 2.3 Hz), 117.8 (d, J_CF = 3.4 Hz), 114.3 (d, J_CF = 21.2 Hz), 98.9 (d, J_CF = 5.6 Hz), 63.5, 57.8; ¹⁹F NMR (280 MHz, CDCl₃) δ −125.8. Anal. Calcd for C₉H₁₀O₃BrF: C, 40.93; H, 3.82. Found C, 41.17; H, 3.85.

5.13 Benzyl ether 21

To a solution of benzyl alcohol 20 (198 mg, 0.7 mmol) in THF (5 mL) at 0 °C was added NaH (60% wt. in mineral oil, 35 mg, 0.9 mmol) followed by iodomethane (0.06 mL, 1.0 mmol). After 10 h, the reaction was quenched by addition of water, the resulting solution was extracted with ether, dried (MgSO₄), and concentrated in vacuo. Final purification by column chromatography (8% EtOAc in hexanes) afforded ether 21 (158 mg, 76%) as an oil: ¹H NMR δ 7.25–7.24 (m, 1H), 6.98 (dd, J_HF = 11.1 Hz, J = 2.0 Hz, 1H), 5.11 (s, 2H), 4.29 (s, 2H), 3.56 (s, 3H), 3.31 (s, 3H); ¹³C NMR δ 155.9 (d, J_CF = 250 Hz), 141.4 (d, J_CF = 13.4 Hz), 136.1 (d, J_CF = 6.7 Hz), 127.3 (d, J_CF = 3.5 Hz), 117.8 (d, J_CF = 3.5 Hz), 115.1 (d, J_CF = 20.9 Hz), 99.0 (d, J_CF = 6.1 Hz), 72.9 (d, J_CF = 1.8 Hz), 58.3, 57.8 (d, J_CF = 1.7 Hz); ¹⁹F NMR (280 MHz, CDCl₃) δ −126.1. Anal. Calcd for C₁₀H₁₂BrF O₃: C, 43.03; H, 4.33. Found C, 42.87; H, 4.33

5.14 Geranylated Arene 22

To a solution of ether 21 (153 mg, 0.6 mmol) in THF (10 mL) at −78 °C was added n-BuLi (0.27 mL, 0.6 mmol). After 10 min, CuBr·DMS (136 mg, 0.7 mmol) was added. After an additional 30 min, geranyl bromide (0.11 mL, 0.6 mmol) was added and after an additional 1 h, the reaction was quenched by addition of water. The resulting solution was extracted with ether, dried (MgSO₄), and concentrated in vacuo. Final purification by column chromatography afforded arene 22 (31 mg, 17%) as an oil: ¹H NMR δ 6.94–6.79 (m, 2H), 5.21 (t, J = 7.2 Hz, 1H), 5.04 (s, 2H), 5.04–5.00 (m, 1H), 4.28 (s, 2H), 3.51 (s, 3H), 3.34–3.27 (m, 2H), 3.30 (s, 3H), 2.09–1.84 (m, 4H), 1.63 (s, 3H), 1.60 (s, 3H), 1.52 (s, 3H); ¹³C NMR δ 155.3 (d, J_CF = 247 Hz), 141.7 (d, J_CF = 10.8 Hz), 136.8, 136.7, 134.4 (d, J_CF = 6.9 Hz), 131.5, 124.2, 124.0 (d, J_CF = 2.9 Hz), 122.0, 113.6 (d, J_CF = 20.6 Hz), 99.1 (d, J_CF = 6.0 Hz), 73.9 (d, J_CF = 1.1 Hz), 58.2, 57.4 (d, J_CF = 1.0 Hz), 39.7, 28.3 (d, J_CF = 2.5 Hz), 27.6, 25.7, 17.7, 16.2; ¹⁹F NMR (280 MHz, CDCl₃): δ −130.6; HRMS (EI) m/z calcd for C₂₀H₂₉O₃F (M⁺) 336.2102, found 336.2106.

5.15 (R)-Epoxide 23

To a solution of benzyl ether 22 (30 mg, 0.1 mmol) in CH₂Cl₂ (1 mL), CH₃CN (0.5 mL), EtOH (0.5 mL), aqueous buffer (2 M K₂CO₃, 4 × 10⁻³ M EDTA, 2 mL), and Shi catalyst (24 mg, 0.1 mmol) at 0 °C, H₂O₂ (30% wt. in H₂O, 0.05 mL, 0.44 mmol) was added over 2 h. After an additional 45 min the reaction was quenched by addition of Na₂SO₃. The resulting solution was extracted with CH₂Cl₂, dried (MgSO₄), and concentrated in vacuo. Final purification by column chromatography afforded epoxide 23 (17 mg, 54%) as an oil: ¹H NMR δ 6.91–6.82 (m, 2H), 5.26 (t, J = 7.1 Hz, 1H), 5.04 (s, 2H), 4.23 (s, 2H), 3.51 (s, 3H), 3.34 (d, J = 7.1 Hz, 2H), 3.30 (s, 3H), 2.64 (t, J = 6.3 Hz, 1H), 2.29–1.86 (m, 4H), 1.66 (s, 3H), 1.21 (s, 3H), 1.19 (s, 3H); ¹³C NMR δ 155.3 (d, J_CF = 246 Hz), 141.7 (d, J_CF = 12.4 Hz), 136.5 (d, J_CF = 1.8 Hz), 135.8, 134.5 (d, J_CF = 7.4 Hz), 124.0 (d, J_CF = 2.8 Hz), 122.6, 113.6 (d, J_CF = 20.4 Hz), 99.1 (d, J_CF = 6.5 Hz), 73.9 (d, J_CF = 1.9 Hz), 64.1, 58.4, 58.2, 57.5, 36.4, 28.4, 27.4, 24.9, 18.8, 16.2; ¹⁹F NMR (280 MHz, CDCl₃) δ −130.6; HRMS (EI) m/z calcd for C₂₀H₂₉O₃F (M⁺) 352.2051, found 352.2048.

5.16 5-Fluoro-hexahydroxanthene 24

To a solution of epoxide 23 (16 mg, 0.05 mmol) in CH₂Cl₂ (6 mL) at −78 °C was added BF₃·OEt₂ (0.03 mL, 0.2 mmol). After 6 min, the reaction was quenched by addition of TEA. Water was added and the product was extracted into CH₂Cl₂, dried (MgSO₄), and concentrated in vacuo. Final purification by column chromatography (20% EtOAc in hexanes) produced hexahydroxanthene 24 (8 mg, 57%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 6.91–6.85 (m, 2H), 4.33 (s, 2H), 3.44 (dd, J = 11.3, 6.9 Hz, 1H), 3.38 (s, 3H), 2.79–2.66 (m, 2H), 2.12–1.58 (m, 5H), 1.25 (s, 3H), 1.11 (s, 3H), 0.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 151.8 (d, J_CF = 246 Hz), 141.0 (d, J_CF = 11.3 Hz), 129.4 (d, J_CF = 5.6 Hz), 124.4 (d, J_CF = 2.8 Hz), 124.0 (d, J_CF = 2.8 Hz), 113.4 (d, J_CF = 18.3 Hz), 77.9, 74.1 (d, J_CF = 1.5 Hz), 58.1, 46.7, 38.4, 37.5, 28.3, 27.3, 23.0, 22.9, 19.8, 14.3; ¹⁹F NMR (CDCl₃) δ −136.9; HRMS (EI) m/z calcd for C₁₈H₂₅O₃F (M⁺) 308.1789, found 308.1782.

5.17 5-Fluorinated aldehyde 25

To a solution of methyl ether 24 (7 mg, 0.02 mmol) in CH₂Cl₂ (1.0 mL) and water (0.1 mL) at rt was added DDQ (12 mg, 0.05 mmol). After 4 h, the reaction was quenched by addition of saturated NaHCO₃. The resulting solution was extracted with CH₂Cl₂, dried (MgSO₄), and concentrated in vacuo. Final purification by radial chromatography (40% EtOAc in hexanes) produced aldehyde 25 (6 mg, 90%) as a film: ¹H NMR (400 MHz, CDCl₃) δ 9.81 (d, J_HF = 1.9 Hz, 1H), 7.45–7.42 (m, 2H), 3.47 (dd, J = 11.7, 4.0 Hz, 1H), 2.88–2.75 (m, 2H), 2.17–1.58 (m, 5H), 1.30 (s, 3H), 1.14 (s, 3H), 0.92 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 189.9 (d, J_CF = 2.0 Hz), 152.0 (d, J_CF = 249 Hz), 147.3 (d, J_CF = 11.0 Hz), 128.4 (d, J_CF = 5.2 Hz), 127.8 (d, J_CF = 2.6 Hz), 124.6 (d, J_CF = 2.6 Hz), 113.7 (d, J_CF = 19.5 Hz), 78.8, 77.5, 46.3, 38.3, 37.1, 28.0, 27.1, 22.7, 19.9, 14.1; ¹⁹F NMR (CDCl₃) δ −134.7. HRMS (EI) calcd for C₁₇H₂₁O₃F (M⁺) 292.1477, found 292.1478.

5.18 Ether 27

To a solution of alcohol 26²⁹ (2.66 g, 15.8 mmol) in THF (50 mL) at 0 °C was added NaH (750 mg, 18.8 mmol, 60% dispersion oil). After 30 min, MeI (1.09 mL, 17.5 mmol) was added dropwise and the reaction mixture was allowed to stir overnight. The reaction was quenched by the addition of NH₄Cl (sat), and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO₄), filtered, and concentrated in vacuo. Final purification by flash column (15% to 40% ethyl acetate in hexanes) afforded arene 27 (2.34 g, 81%) as a colorless oil: ¹H NMR δ 7.25 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 5.15 (s, 2H), 4.38 (s, 2H), 3.46 (s, 3H), 3.35 (s, 3H); ¹³C NMR δ 156.7, 131.5, 129.1 (2C), 116.0 (2C), 94.3, 74.1, 57.7, 55.8; HRMS (ESI⁺) calcd for C₁₀H₁₄O (M⁺) 182.0943, found 182.0949.

5.19 Thiol Ether 28

To a solution of arene 27 (2.34 g, 12.8 mmol) in THF (60 mL) at 0°C was added n–BuLi (6.0 mL, 2.2 M in hexanes) and after 5 minutes dimethyldisulfide (1.23 mL, 14 mmol) was added dropwise. After 5 h the reaction mixture was quenched by addition of NH₄Cl (sat), extracted with EtOAc, washed with brine, dried (MgSO₄), and filtered, and the filtrate was concentrated in vacuo. Final purification by flash column chromatography (13% EtOAc in hexanes) afforded 28 (1.29 g, 44%) as an oil: ¹H NMR δ 7.13 (s, 1H), 7.04 (m, 2H), 5.22 (s, 2H), 4.38 (s, 2H), 3.49 (s, 3H), 3.36 (s, 3H), 2.43 (s, 3H); ¹³C NMR δ 153.2, 132.2, 128.2, 125.2, 125.2, 113.9, 94.7, 74.1, 57.5, 56.0, 14.4; HRMS (EI⁺) calcd for C₁₁H₁₆O₃S (M⁺) 228.0820, found 228.0822.

5.20 Epoxide 29

To a solution of arene 28 (829 mg, 3.63 mmol), in THF (15 mL) at to 0 °C was added n–BuLi (1.6 mL, 3.68 mmol). After 1 h, the solution was cooled to –20 °C and CuBr·DMS (784 mg, 3.81 mmol) was added. After an additional 1 h, epoxygeranyl bromide²² (887 mg, 3.93 mmol) was added dropwise as a THF solution (2 mL). After 2 h, the reaction mixture was quenched by addition of NH₄Cl (sat), diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried (MgSO₄), filtered, and then concentrated in vacuo. Final purification by column chromatography (15% EtOAc in hexanes) afforded epoxide 29 (522 mg, 38%) as a light yellow oil: ¹H NMR δ 6.99 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 1.6 Hz, 1H), 5.36 (m, 1H), 5.03 (s, 2H), 4.37 (s, 2H), 3.63 (s, 3H), 3.43 (d, J = 7.2 Hz, 2H), 3.38 (s, 3H), 2.71 (t, J = 6.2 Hz, 1H), 2.43 (s, 3H), 2.04 (m, 2H), 1.73 (s, 3H), 1.69–1.62 (m, 2H), 1.28 (s, 3H), 1.25 (s, 3H); ¹³C NMR δ 151.6, 135.4, 134.8, 134.8, 132.6, 125.9, 123.1, 123.0, 99.2, 74.3, 64.0, 58.2, 58.0, 57.6, 36.3, 28.4, 27.3, 24.7, 18.6, 16.1, 14.8; HRMS (EI) calcd for C₂₁H₃₂O₄S (M⁺) 380.2120, found 380.2127.

5.21 Hexahydroxanthene 30

To a solution of epoxide 29 (207 mg, 0.54 mmol) in CH₂Cl₂ (136 mL) at −78 °C was added BF₃·OEt₂ (0.40 mL, 3.3 mmol). After 10 minutes, the reaction was quenched by addition of TEA (0.3 mL), allowed to warm to room temperature, and the solvent was removed in vacuo. Final purification by flash column chromatography (25–30% EtOAc in hexanes) gave hexahydroxanthene 30 (93 mg, 51%) as an oil: ¹H NMR δ 6.93 (d, J = 1.6 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 4.34 (s, 2H), 3.40–3.35 (m, 1H), 3.74 (s, 3H), 2.71–2.68 (m, 2H), 2.40 (s, 3H), 2.09–2.04 (m, 1H), 1.87–1.77 (m, 2H), 1.71–1.57 (m, 3H), 1.21 (s, 3H), 1.07 (s, 3H), 0.86 (s, 3H); ¹³C NMR δ 149.6, 129.6, 126.3, 126.2, 123.6, 121.2, 77.9, 77.2, 74.6, 57.9, 46.8, 38.3, 37.5, 28.2, 27.2, 23.1, 19.9, 14.6, 14.2; HRMS (EI) calcd for C₁₉H₂₈O₃S (M⁺) 336.1759, found 336,1750.

5.22 Aldehyde 31

To a solution of methyl ether 30 (84 mg, 0.25 mmol) in a 9:1 mixture of CH₂Cl₂ and H₂O (10 mL) at rt was added DDQ (79 mg, 0.35 mmol). After 20 min, the reaction was quenched by the addition of NaHCO₃ (sat.), diluted with water and extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried (MgSO₄), filtered, and concentrated in vacuo to afford aldehyde 31 (61 mg, 76%) as a white solid: ¹H NMR δ 9.82 (s, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.42 (d, J = 1.1 Hz, 1H), 3.45 (dd, J = 11.2, 3.6 Hz, 1H), 2.80–2.76 (m, 2H), 2.45 (s, 3H), 2.16–2.10 (m, 1H), 1.94–1.81 (m, 2H), 1.76–1.56 (m, 3H), 1.27 (s, 3H), 1.12 (s, 3H), 0.90 (s, 3H); ¹³C NMR δ 190.9, 155.2, 130.0, 129.5, 128.9, 123.6, 121.5, 79.1, 77.9, 46.7, 38.5, 37.5, 28.3, 27.4, 23.1, 20.4, 14.4, 14.4; HRMS (EI) calcd for C₁₈H₂₄O₃S (M⁺) 320.1446, found 320.1447.

5.23 Aldehyde 33

To a solution of methyl ether 32⁵ (350 mg, 1.1 mmol), in CH₂Cl₂/water (10:1) at rt was added DDQ (320 mg, 1.4 mmol). After 15 min, the reaction was quenched by addition of brine and NaHCO₃. The resulting solution was extracted with CH₂Cl₂, and the combined organic extracts were washed with a small amount of water followed by brine. After the organic phase was dried (MgSO₄) and concentrated in vacuo, aldehyde 33 was obtained as a faintly yellow wax that was used without further purification: ¹H NMR δ 9.76 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 5.26 (s, 1H), 4.64 (d, J = 13.2 Hz, 1H), 4.60 (d, J = 13.6 Hz, 1H), 3.38 (dd, J = 11.4, 4.2 Hz, 1H), 2.79–2.67 (m, 2H), 2.34 (br, 1H), 2.04–1.99 (m, 1H), 1.87–1.57 (m, 4H), 1.20 (s, 3H), 1.07 (s, 3H), 0.85 (s, 3H); ¹³C NMR δ 191.2, 156.2, 131.3, 129.6, 128.6, 127.7, 122.2, 78.4, 77.5, 60.7, 46.4, 38.3, 37.5, 27.9, 27.1, 22.7, 20.2, 14.2; HRMS (EI) calcd for C₁₈H₂₄O₄ (M⁺) 304.1675, found 304.1668.

5.24 Silyl Ether 34

To a solution of alcohol 33, in CH₂Cl₂ at rt was added TBSCl (485 mg, 3.2 mmol) followed by imidazole (394 mg, 5.8 mmol). After 45 min, the reaction was quenched by addition of water. The resulting solution was extracted with CH₂Cl₂, and the combined organic extracts were washed with a small amount of water followed by brine. After which the organic phase was dried (MgSO₄) and concentrated in vacuo. Final purification by column chromatography (30% EtOAc in hexanes) afforded aldehyde 34 (321 mg, 70% over 2-steps) as a colorless oil: ¹H NMR (CDCl₃) δ 9.82 (s, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 4.70 (d, J = 14.4 Hz, 1H), 4.62 (d, J = 14.1 Hz, 1H), 3.40 (dd, J = 11.4, 3.9 Hz, 1H), 2.77–2.72 (m, 2H), 2.07–2.00 (m, 1H), 1.89–1.62 (m, 4H), 1.20 (s, 3H), 1.09 (s, 3H), 0.94 (s, 9H), 0.87 (s, 3H), −0.11 (s, 6H); ¹³C NMR δ 191.5, 155.3, 130.1, 130.0, 128.6, 127.4, 121.6, 77.9, 77.6, 59.7, 46.4, 38.3, 37.5, 28.0, 27.1, 25.9 (3C), 22.8, 20.2, 18.4, 14.2, −5.4 (2C); HRMS (EI) calcd for C₂₄H₃₈O Si (M⁺–tBu) 362.1869, found 362.1861.

5.25 Silyl ether 36

To a flask containing benzyl alcohol 35 (1.81 g, 9.2 mmol) and CH₂Cl₂ (150 mL) was added imidazole (3.19 g, 46.9 mmol), followed by TBSCl (1.61 g, 10.7 mmol) at room temperature. The solution was allowed to stir for 9 h, and then the reaction was quenched by addition of saturated NH₄Cl. The product was extracted into CH₂Cl₂, dried (MgSO₄), and concentrated under reduced pressure. Final purification by flash chromatography produced the silyl ether 36 as an oil (2.40 g, 84%): ¹H NMR δ 6.62–6.57 (m, 2H), 6.49–6.48 (m, 1H), 5.15 (s, 2H), 4.68 (s, 2H), 3.78 (s, 3H), 3.47 (s, 3H), 0.94 (s, 9H), 0.10 (s, 6H); ¹³C NMR δ 160.9, 158.5, 144.4, 106.2, 105.2, 101.2, 94.7, 65.0, 56.2, 55.5, 26.2 (3C), 18.6, −5.0 (2C); HRMS (EI) calcd for C₁₆H₂₈O₄Si (M⁺) 312.1757, found 312.1753.

5.26 Geranylated benzyl alcohol 38

To a flamed dried Schlenk flask under argon, ether (30 mL) was added via syringe followed by TMEDA (3.8 mL, 25 mmol) and n-BuLi (12 mL, 29 mmol, 2.4 M solution in hexanes) and this solution was cooled to 0 °C. Compound 35 (2.97 g, 12.6 mmol) was dissolved in ether (20 mL) and transferred via cannula to the reaction vessel, which gave a white precipitate. After 20 min, solid CuI (2.64 g, 13.8 mmol) was added in one portion leading to an immediate color change to black. The resulting mixture was allowed to stir for 20 min and then geranyl bromide (3.3 mL, 16.3 mmol) was added dropwise over a 10 min period. The reaction mixture was allowed to stir for 4 h, and then was quenched by addition of water. The product was extracted into diethyl ether, dried (MgSO₄), and concentrated under reduced pressure. Final purification by column chromatography (30% EtOAc in hexanes) produced alcohol 38 (1.98 g, 47%) as an oil: ¹H NMR δ 6.72 (s, 1H), 6.61 (s, 1H), 5.20–5.06 (m, 1H), 5.18 (s, 2H), 5.06–5.04 (m, 1H), 4.63 (s, 2H), 3.82 (s, 3H), 3.46 (s, 3H), 3.36 (d, J = 6.9 Hz, 2H), 2.05–2.00 (m, 2H), 1.96–1.91 (m, 2H), 1.77 (s, 3H), 1.64 (s, 3H), 1.57 (s, 3H); ¹³C NMR δ 158.3, 155.6, 139.9, 134.6, 131.1, 124.4, 122.6, 118.6, 105.6, 103.3, 94.4, 65.6, 55.9, 55.7, 39.8, 26.7, 25.6, 22.3, 17.6, 16.0; HRMS (EI) calcd for C₂₀H₃₀O₄ (M⁺) 334.2144, found 334.2141.

5.27 Phosphonate 39

To a solution of alcohol 38 (1.00 g, 3.0 mmol) in CH₂Cl₂ (200 mL) at 0 °C was added TEA (1.70 mL, 12.2 mmol), followed by MsCl (0.93 mL, 12.0 mmol). After 20 h, the reaction was quenched by addition of saturated NH₄Cl. The resulting solution was extracted with CH₂Cl₂, dried (MgSO₄), and concentrated in vacuo to yield the intermediate mesylate as an oil which was used without further purification.

To a solution of the crude intermediate mesylate in acetone (11 mL) in a foil-wrapped flask at rt was added sodium iodide (1.81 g, 12.1 mmol). After 30 min, the reaction was concentrated in vacuo. The residue was diluted with water and the resulting solution was extracted with ether, dried (MgSO₄), and concentrated in vacuo to yield the intermediate iodide as a yellow oil, which was used without further purification.

To a flask containing the intermediate iodide, triethylphosphite (1.1 mL, 12.1 mmol) was added at rt. The solution was heated to 62 °C, and after 16 h the reaction was quenched by addition of water. The resulting solution was extracted with ethyl acetate, dried (MgSO₄), and concentrated in vacuo. Final purification by column chromatography afforded phosphonate 39 (1.36 g, 100% for 3 steps) as a colorless oil: ¹H NMR δ 6.65–6.64 (m, 1H), 6.55–6.54 (m, 1H), 5.19–5.14 (m, 1H), 5.16 (s, 2H), 5.09–5.04 (m, 1H), 4.08–4.00 (m, 4H), 3.81 (s, 3H), 3.45 (s, 3H), 3.33 (d, J = 7.1 Hz, 2H), 3.10 (d, J_HP = 21.5 Hz, 2H), 2.07–1.91 (m, 4H), 1.75 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.26 (t, J = 7.0 Hz, 6H); ¹³C NMR δ 158.0, 155.5, 134.6, 131.2, 130.0, 124.5, 122.7, 118.0 (d, J_CP = 3.9 Hz), 108.7 (d, J_CP = 6.6 Hz), 106.4 (d, J_CP = 6.1 Hz), 94.4, 62.1 (d, J_CP = 7.4 Hz, 2C), 55.9, 55.8, 39.8, 34.0 (d, J_CP = 138.2 Hz), 26.7, 25.7, 22.2, 17.7, 16.4 (d, J_CP = 6.1 Hz, 2C), 16.0; ³¹P NMR δ 27.1; HRMS (EI) m/z calcd for C₂₄H₃₉O₆P (M⁺) 454.2486, found 454.2471.

5.28 Stilbene 43

Under the general conditions for HWE condensations (vide infra), the reaction of aldehyde 13 (36 mg, 0.1 mmol), phosphonate 39 (31 mg, 0.1 mmol), and NaH (60% wt. in mineral oil, 34 mg, 0.9 mmol) provided stilbene 43 as a white solid (49 mg, 66%): ¹H NMR (400 MHz, CDCl₃) δ 7.26–7.25 (m, 1H), 6.99–6.86 (m, 4H), 6.74 (d, J = 8.3 Hz, 1H), 6.70 (s, 1H), 5.22 (s, 2H), 5.20–5.18 (m, 1H), 5.07 (t, J = 6.7 Hz, 1H), 3.86 (s, 3H), 3.49 (s, 3H), 3.43 (dd, J = 11.8, 4.6 Hz, 1H), 3.37 (d, J = 7.0 Hz, 2H), 2.76–2.66 (m, 2H), 2.07–1.48 (m, 9H), 1.78 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.23 (s, 3H), 1.11 (s, 3H), 0.89 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 158.1, 155.6, 152.7, 136.5, 134.4, 131.0, 129.2, 127.7, 127.2, 126.3, 125.4, 124.3, 122.5, 121.8, 118.6, 117.1, 105.2, 102.4, 94.4, 77.9, 76.5, 55.8, 55.6, 46.7, 39.7, 38.2, 37.6, 28.1, 27.2, 26.6, 25.5, 22.9, 22.3, 19.8, 17.5, 15.9, 14.1; HRMS (EI) m/z calcd for C₃₇H₅₀O₅ (M⁺) 574.3660, found 574.3651.

5.29 Schweinfurthin analogue 51

Under general conditions for the removal of MOM-ethers from protected stilbenes (vide infra), stilbene 53 (33 mg, 0.1 mmol) was treated with methanol (0.3 mL) and p-TsOH·H₂O (56 mg, 0.3 mmol) for 2.5 h to provide analogue 51 as a clear oil (16 mg, 53%): ¹H NMR (400 MHz, CDCl₃) δ 7.25–6.61 (m, 7H), 5.33 (br s, 1H), 5.25 (t, J = 7.0 Hz, 1H), 5.07 (t, J = 6.7 Hz, 1H), 3.87 (s, 3H), 3.47–3.42 (m, 3H), 2.80–2.68 (m, 2H), 2.18–1.55 (m, 10H), 1.82 (s, 3H), 1.69 (s, 3H), 1.60 (s, 3H), 1.24 (s, 3H), 1.13 (s, 3H), 0.90 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 157.8, 155.5, 152.8, 138.1, 136.9, 131.7, 129.1, 128.0, 127.7, 126.0, 125.4, 123.7, 121.8, 121.6, 117.1, 114.3, 106.7, 101.1, 77.9, 77.0, 55.6, 46.7, 39.5, 38.2, 37.6, 28.1, 27.2, 26.3, 25.5, 22.9, 22.1, 19.8, 17.5, 16.0, 14.1; HRMS (EI) m/z calcd for C₃₅H₄₆O₄ (M⁺) 530.3398, found 530.3399.

5.30 C-5 Bromostilbene 44

Under the general conditions for HWE condensations, the reaction of aldehyde 18 (60 mg, 0.2 mmol), phosphonate 39 (72 mg, 0.2 mmol), and NaH (60% wt. in mineral oil, 33 mg, 0.8 mmol) provided stilbene 44 as a white solid (57 mg, 54%): [α]^26.4_D = +64.2 (c 0.25, CHCl₃, 96% ee by HPLC); ¹H NMR δ 7.46 (d, J = 1.9 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 6.82–6.79 (m, 3H), 6.62 (s, 1H), 5.15 (s, 2H), 5.12 (t, J = 7.0 Hz, 1H), 5.00 (t, J = 6.4 Hz, 1H), 4.71 (d, J = 6.9 Hz, 1H), 4.58 (d, J = 7.0 Hz, 1H), 3.79 (s, 3H), 3.42 (s, 3H), 3.35 (s, 3H), 3.30 (d, J = 7.0 Hz, 1H), 3.22 (dd, J = 11.6, 4.1 Hz, 1H), 2.81 (d, J = 9.5 Hz, 2H), 2.06–1.36 (m, 9H), 1.70 (s, 3H), 1.57 (s, 3H), 1.50 (s, 3H), 1.17 (s, 3H), 1.02 (s, 3H), 0.83 (s, 3H); ¹³C NMR δ 158.2, 155.8, 149.5, 136.2, 134.7, 131.2, 130.3, 128.8, 127.6, 127.0, 126.5, 124.5, 123.6, 122.6, 119.1, 111.7, 105.4, 102.7, 96.2, 94.5, 83.9, 77.9, 56.0, 55.7, 55.7, 47.1, 38.8, 38.2, 37.3, 27.4, 26.7, 25.7, 25.2, 23.4, 22.5, 20.1, 17.6, 16.1, 15.1; HRMS (EI) m/z calcd for C₃₉H₅₃O₆Br (M⁺) 696.3027, found 696.3098.

5.31 5-Bromoschweinfurthin analogue 52

Under the general conditions for removal of MOM-acetals, the reaction of stilbene 44 (10 mg, 0.01 mmol), methanol (1.5 mL), and p-TsOH·H₂O (11 mg, 0.06 mmol) for 96 h provided analogue 52 as a white solid (8 mg, 92%): [α]^26.4_D = +29.2 (c 0.27, CHCl₃, 96% ee by HPLC); ¹H NMR (400 MHz, CDCl₃) δ 7.53–6.60 (m, 6H), 5.33 (br s, 1H), 5.25 (t, J = 6.6 Hz, 1H), 5.07 (t, J = 6.6 Hz, 1H), 3.87 (s, 3H), 3.48–3.38 (m, 3H), 2.79–2.70 (m, 2H), 2.14–1.35 (m, 10H), 1.82 (s, 3H), 1.69 (s, 3H), 1.60 (s, 3H), 1.25 (s, 3H), 1.12 (s, 3H), 0.90 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 157.8, 155.6, 149.4, 138.2, 136.5, 131.7, 130.1, 128.7, 127.1, 126.8, 126.6, 123.7, 123.3, 121.5, 114.6, 111.6, 106.9, 101.2, 77.8, 77.7, 55.6, 46.6, 39.5, 38.2, 37.3, 28.1, 27.1, 26.2, 25.5, 23.2, 22.1, 19.9, 17.5, 16.0, 14.0; HRMS (EI) m/z calcd for C₃₅H₄₅O₄Br (M⁺ 608.2503, found 608.2498.

5.32 5-Fluoro stilbene 45

Under the general conditions for HWE reactions, aldehyde 25 (6 mg, 0.02 mmol), phosphonate 39 (10 mg, 0.02 mmol), and NaH (60% wt. in mineral oil, 5 mg, 0.1 mmol), and purification by column chromatography (25% EtOAc in hexanes) provided stilbene 45 as a white solid (6 mg, 53%): ¹H NMR (400 MHz, CDCl₃) δ 7.11–6.70 (m, 6H), 5.23 (s, 2H), 5.23–5.19 (m, 1H), 5.08 (t, J = 6.7 Hz, 1H), 3.88 (s, 3H), 3.51 (s, 3H), 3.46 (dd, J = 11.1, 3.6 Hz, 1H), 3.38 (d, J = 6.9 Hz, 2H), 2.81–2.68 (m, 2H), 2.13–1.60 (m, 9H), 1.78 (s, 3H), 1.66 (s, 3H), 1.58 (s, 3H), 1.28 (s, 3H), 1.13 (s, 3H), 0.91 (s, 3H); ¹³C NMR (CDCl₃) δ 158.1, 155.7, 151.9 (d, J_CF = 244 Hz), 140.9 (d, J_CF = 10.3 Hz), 136.0, 134.5, 131.0, 129.0 (d, J_CF = 8.3 Hz), 127.5, 126.8 (d, J_CF = 2.3 Hz), 125.3, 124.3, 122.8 (d, J_CF = 2.3 Hz), 122.4, 119.0, 111.0 (d, J_CF = 19.0 Hz), 105.3, 102.6, 94.3, 77.7, 77.3, 55.8, 55.6, 46.6, 39.6, 38.2, 37.3, 28.1, 27.1, 26.6, 25.5, 22.8, 22.3, 19.7, 17.5, 15.9, 14.1; ¹⁹F NMR (CDCl₃) δ −136.8; HRMS (EI) m/z calcd for C₃₇H₄₉O₅F (M⁺) 592.3566, found 592.3574.

5.33 5-Fluoro schweinfurthin analogue 53

Under the general conditions for MOM hydrolysis, stilbene 45 (6 mg, 0.01 mmol), methanol (0.6 mL), and p-TsOH·H₂O (12 mg, 0.1 mmol) were allowed to react for 24 h. Final purification by column chromatography provided analogue 53 as a white solid (4 mg, 72%): ¹H NMR (400 MHz, CDCl₃) δ 7.09 (dd, J = 12.1, 1.7 Hz, 1H), 6.99 (s, 1H), 6.91 (d, J = 16.3 Hz, 1H), 6.84 (d, J = 16.3 Hz, 1H), 6.64 (d, J = 1.3 Hz, 1H), 6.60 (d, J = 1.3 Hz, 1H), 5.34 (br s, 1H), 5.27–5.23 (m, 1H), 5.09–5.05 (m, 1H), 3.87 (s, 3H), 3.48–3.42 (m, 3H), 2.82–1.84 (m, 11H), 1.82 (s, 3H), 1.69 (s, 3H), 1.60 (s, 3H), 1.27 (s, 3H), 1.13 (s, 3H), 0.90 (s, 3H); ¹³C NMR (CDCl₃) δ 157.8, 155.6, 151.9 (d, J_CF = 243 Hz), 141.0 (d, J_CF = 11.3 Hz), 138.2, 136.5, 131.7, 129.0 (d, J_CF = 7.5 Hz), 127.1, 127.1 (d, J_CF = 2.3 Hz), 124.3 (d, J_CF = 1.6 Hz), 123.7, 122.9 (d, J_CF = 2.1 Hz), 121.5, 114.6, 111.0 (d, J_CF = 19.2 Hz), 106.8, 101.2, 77.7, 77.3, 55.6, 46.6, 39.5, 38.2, 37.3, 28.1, 27.1, 26.3, 25.5, 22.8, 22.1, 19.7, 17.5, 15.9, 14.1; ¹⁹F NMR (CDCl₃) δ −136.8; HRMS (EI) m/z calcd for C₃₅H₄₅O₄F + 35 45O₄F (M⁺) 548.3304, found 548.3299.

5.34 Stilbene 46

Under the general conditions for HWE condensations, aldehyde 31 (23 mg, 0.07 mmol), phosphonate 39 (40 mg, 0.09 mmol), THF (0.7 mL), and NaH (50 mg, 1.25 mmol, 60% dispersion oil) were allowed to react for 18 h. Final purification by flash column chromatography (25% EtOAc in hexanes) afforded stilbene 46 (33 mg, 74%) as a colorless oil; ¹H NMR δ 7.11 (d, J = 1.7 Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H), 6.96 (d, J = 16.3 Hz, 1H), 6.92–6.88 (m, 2H), 6.71 (s, 1H), 5.23 (s, 2H), 5.23–5.18 (m, 1H), 5.09–5.05 (m, 1H), 3.87 (s, 3H), 3.50 (s, 3H), 3.43 (dd, J = 11.5, 3.8 Hz, 1H), 3.37 (d, J = 7.0 Hz, 2H), 2.74–2.70 (m, 2H), 2.45 (s, 3H), 2.11–1.57 (m, 10H), 1.78 (s, 3H), 1.64 (s, 3H), 1.57 (s, 3H), 1.24 (s, 3H), 1.10 (s, 3H), 0.88 (s, 3H); ¹³C NMR δ 158.3, 155.8, 149.8, 136.5, 134.6, 131.1, 129.5, 127.7, 126.8, 126.6, 124.7, 124.4, 122.6, 122.0, 121.4, 118.9, 105.4, 102.6, 94.5, 77.8, 77.5, 55.9, 55.7, 46.8, 39.8, 38.4, 37.5, 28.2, 27.3, 26.7, 25.6, 23.1, 22.4, 20.0, 17.6, 16.0, 14.8, 14.2 HRMS (EI) calcd for C₃₈H₅₂O₅S (M⁺) 620.3535, found 620.3536.

5.35 Schweinfurthin analogue 54

Under general conditions for MOM hydrolysis, stilbene 46 (16.5 mg, 0.03 mmol), methanol (1.5 mL), and TsOH (25 mg, 0.13 mmol) were allowed to react for 18 h. Final purification by column chromatography (25% EtOAc in hexanes) afforded analogue 54 (6 mg, 40%) as an off-white solid: ¹H NMR δ 7.11 (d, J = 1.5 Hz, 1H), 7.06 (d, J = 1.4 Hz, 1H), 6.95 (d, J = 16.2 Hz, 1H), 6.86 (d, J = 16.2 Hz, 1H), 6.64 (d, J = 1.1 Hz, 1H), 6.60 (d, J = 1.0 Hz, 1H), 5.26–5.23 (m, 1H), 5.08–5.04 (m, 1H), 3.86 (s, 3H), 3.47–3.41 (m, 3H), 2.74–2.71 (m, 2H), 2.45 (s, 3H), 2.10–2.03 (m, 4H), 1.90–1.63 (m, 5H), 1.81 (s, 3H), 1.68 (s, 3H), 1.59 (s, 3H), 1.24 (s, 3H), 1.11 (s, 3H), 0.89 (s, 3H); ¹³C NMR (CDCl₃) δ 158.0, 155.8, 153.0, 138.3, 137.2, 131.9, 129.3, 128.2, 127.9, 126.2, 125.6, 123.9, 122.0, 121.8, 117.4, 114.5, 106.9, 101.3, 78.1, 77.2, 55.8, 46.9, 39.8, 38.4, 37.8, 30.3, 28.3, 27.4, 26.5, 25.7, 23.1, 22.3, 20.0, 17.7, 16.2, 14.3; HRMS (EI) calcd for C₃₆H₄₈O₄S (M⁺) 576.3273, found 576.3279.

5.36 5-Methoxymethyl stilbene 47

Under the general conditions for HWE condensations, aldehyde 40 (26 mg, 0.1 mmol), phosphonate 39 (42 mg, 0.1 mmol), and NaH (60% wt. in mineral oil, 48 mg, 1.2 mmol) were allowed to react. Final purification by column chromatography provided stilbene 47 (26 mg, 50%) as a solid: [α]^26.4_D = +31.1 (c 0.30, CHCl₃, 81% ee by HPLC); ¹H NMR δ 7.30 (d, J = 1.6 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 6.89–6.64 (m, 4H), 5.15 (s, 2H), 5.19–5.10 (m, 1H), 5.02–4.97 (m, 1H), 4.38 (s, 2H), 3.79 (s, 3H), 3.42 (s, 3H), 3.37 (s, 3H), 3.35–3.38 (m, 3H), 2.67–2.63 (m, 2H), 2.02–1.75 (m, 5H), 1.70 (s, 3H), 1.57 (s, 3H), 1.50 (s, 3H), 1.14–1.13 (m, 4H), 1.13 (s, 3H), 1.03 (s, 3H), 0.81 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 158.2, 155.8, 150.4, 136.7, 134.6, 131.2, 128.9, 128.0, 127.0, 126.5 (2C), 124.5, 124.5, 122.7, 121.7, 118.7, 105.4, 102.6, 94.5, 78.1, 76.7, 69.2, 58.5, 56.0, 55.7, 46.8, 39.9, 38.7, 37.7, 28.3, 27.3, 26.8, 25.7, 23.1, 22.7, 20.2, 17.7, 16.1, 14.3; HRMS (EI) m/z calcd for C₃₉H₅₄O₆ (M⁺) 618.3922, found 618.3922.

5.37 5-Methoxymethyl schweinfurthin analogue 55

Under the general conditions for MOM hydrolysis, stilbene 47 (34 mg, 0.1 mmol), methanol (3.0 mL), and p-TsOH·H₂O (59 mg, 0.3 mmol) were allowed to react for 14 h. Purification by radial chromatography (20% EtOAc in hexanes) afforded analogue 55 (13 mg, 41%) as an oil: [α]^26.4_D = +40.0 (c 0.68, CHCl₃, 81% ee by HPLC); ¹H NMR (CDCl₃) δ 7.31–7.01 (m, 2H), 6.90 (d, J = 16.3 Hz, 1H), 6.80 (d, J = 16.3 Hz, 1H), 6.58–6.46 (m, 2H), 5.29 (br s, 1H), 5.21–5.11 (m, 1H), 5.00–4.97 (m, 1H), 4.38 (s, 2H), 3.78 (s, 3H), 3.37 (s, 3H), 3.34 (d, J = 6.7 Hz, 2H), 2.73–2.58 (m, 2H), 2.09–1.40 (m, 11H), 1.73 (s, 3H), 1.60 (s, 3H), 1.52 (s, 3H), 1.13 (s, 3H), 1.03 (s, 3H), 0.81 (s, 3H); ¹³C NMR (CDCl₃) δ 157.8, 155.5, 150.3, 138.1, 137.0, 131.7, 128.7, 128.1, 126.9, 126.3, 125.9, 124.3, 123.7, 121.6, 121.5, 114.2, 106.7, 101.1, 77.9, 77.0, 69.0, 58.3, 55.6, 46.6, 39.5, 38.2, 37.5, 28.1, 27.1, 26.3, 25.5, 22.9, 22.1, 20.0, 17.5, 16.0, 14.1; HRMS (EI) m/e calcd for C₃₇H₄₉O₅ (M-H)⁻ 573.3580, found 573.3560.

5.38 Stilbene 48. General Procedure for HWE Condensations

To a suspension of NaH (85 mg, 60% oil dispersion, 2.1 mmol) and 15-crown-5 (0.01 mL, 0.05 mmol) in THF (10 mL) at 0 °C was added a solution of phosphonate 39 (65 mg, 0.14 mmol) in THF (1.5 mL). The resulting mixture was stirred for 0.5 h. and aldehyde 41 (39 mg, 0.12 mmol) in THF (0.5 mL) was then added to the cooled solution. After the reaction was allowed to warm to room temperature and stirred for 16 h, it was quenched by addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (MgSO₄), concentrated in vacuo to a yellow liquid, and purified by flash column chromatography (2:1 hexanes/EtOAc) to afford stilbene 48 (57 mg, 77%) as a colorless oil: [α]^26.4_D = +38.4 (c 3.74, CHCl₃); ¹H NMR δ 7.13 (d, J = 1.8 Hz, 1H), 6.95 (d, J = 1.8 Hz, 1H), 6.94 (d, J = 15.9 Hz, 1H), 6.90–6.86 (m, 1H), 6.86 (s, 1H), 6.71 (s, 1H), 5.25–5.18 (m, 5H), 5.07 (t, J = 6.6 Hz,1H), 3.86 (s, 3H), 3.54 (s, 3H), 3.49 (s, 3H), 3.42 (dd, J = 11.4, 3.9 Hz, 1H), 3.39 (d, J = 6.9 Hz, 2H), 2.74 (s, 1H), 2.71 (d, J = 2.7 Hz, 1H), 2.15–2.05 (m, 1H), 2.00–1.80 (m, 5H), 1.78 (s, 3H), 1.75–1.70 (m, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.24 (s, 3H), 1.10 (s, 3H), 0.88 (s, 3H); ¹³C NMR δ 158.4, 155.9, 146.3, 143.9, 136.6, 134.7, 131.3, 129.2, 127.9, 126.9, 124.6, 123.3, 122.8, 122.1, 118.9, 113.6, 105.5, 102.7, 96.0, 94.6, 78.1, 77.1, 56.3, 56.1, 55.8, 46.9, 39.9, 38.5, 37.9, 28.4, 27.4, 26.8, 25.8, 23.3, 22.6, 20.0, 17.8, 16.2, 14.4; HRMS (EI⁺) m/z calcd for C₃₉H₅₄O₇ (M⁺) 634.3870, found 634.3876.

5.39 3-Deoxy-5'-O-Methylschweinfurthin A (56). General Procedure for MOM hydrolysis

To a solution of stilbene 48 (54 mg, 0.09 mmol) in MeOH (10 mL) was added TsOH (80 mg, 0.47 mmol) at room temperature and the solution was stirred for 23 h. The reaction was quenched by addition of NaHCO₃ (sat.) and extracted with EtOAc. The organic extracts were washed with H₂O and brine, dried (MgSO₄), and concentrated in vacuo to afford a yellow oil. Final purification by flash column chromatography (2:1 hexanes/EtOAc) gave compound 56 (29 mg, 61%) as a white solid: [α]^26.4_D = +44.7 (c 1.84, CH₃OH); ¹H NMR (CD₃OD) δ 6.89 (d, J = 16.2, 1H), 6.83 (d, J = Hz, 1H), 6.79 (d, J = 16.2, 1H), 6.73 (s, 1H), 6.58 (s, 2H), 5.19 (t, J = 7.2 Hz, 1H), 5.05 (t, J = 6.9 Hz, 1H), 3.81 (s, 3H), 3.37-3.33 (m, 1H), 3.31–3.28 (m, 2H), 2.70–2.67 (m, 2H), 2.05–2.00 (m, 2H), 1.95–1.90 (m, 2H), 1.82–1.78 (m, 2H), 1.78 (s, 3H), 1.70–1.65 (m, 3H), 1.61 (s, 3H), 1.55 (s, 3H), 1.21 (s, 3H), 1.08 (s, 3H), 0.86 (s, 3H); ¹³C NMR (CD₃OD) δ 159.9, 156.9, 147.0, 142.2, 137.8, 134.8, 131.9, 130.9, 128.9, 127.6, 125.5, 124.5, 123.9, 120.6, 117.1, 111.1, 107.1, 101.6, 78.7, 78.2, 56.1, 48.6, 41.0, 39.5, 38.9, 29.0, 27.9, 27.8, 25.9, 24.0, 23.1, 20.3, 17.7, 16.2, 14.9; HRMS (EI⁺) m/z calcd for C₃₅H₄₆O₅ (M⁺) 546.3345, found 546.3340.

5.40 Stilbene 49

Under the general conditions for HWE condensations, aldehyde 42 (98 mg, 0.32 mmol), phosphonate 39 (172 mg, 0.38 mmol), and NaH (130 mg, 3.2 mmol, 60% in oil) were allowed to react in THF (6.2 mL) for 15 h. Final purification by column chromatography (1:1 hexanes/ethyl acetate) afforded stilbene 49 (175 mg, 90%) as a yellow oil: ¹H NMR (CDCl₃) δ 7.00–6.72 (m, 6H), 5.23 (s, 2H), 5.23–5.21 (m, 1H), 5.08 (t, J = 8.5 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.50 (s, 3H), 3.46–3.37 (m, 3H), 2.73 (d, J = 9.2 Hz, 2H), 2.17–1.51 (m, 10H), 1.78 (s, 3H), 1.65 (s, 3H), 1.58 (s, 3H), 1.26, (s, 3H), 1.11 (s, 3H), 0.89 (s, 3H);¹³C NMR (CDCl₃) δ 158.2, 155.8, 148.9, 142.5, 136.5, 134.6, 131.1, 128.9, 128.0, 126.6, 124.4, 122.59, 122.56, 120.5, 118.7, 106.8, 105.3, 102.5, 94.4, 77.9, 77.1, 55.94, 55.92, 55.7, 46.7, 39.8, 38.3, 37.6, 28.2, 27.3, 26.7, 25.6, 23.1, 22.4, 19.8, 17.6, 16.0, 14.2; HRMS (ESI) m/z calcd for C₃₈H₅₂O₆ (M⁺) 604.3764, found 604.3754.

5.41 3-Deoxy-schweinfurthin B Analogue 57

Under the general conditions for MOM hydrolysis, stilbene 49 (80 mg, 0.13 mmol), MeOH (35 mL), and p-TsOH (75 mg, 0.42 mmol) were allowed to react for 4 days. Final purification by column chromatography (1:1 hexanes/ethyl acetate) afforded compound 57 (68 mg, 92%) as a yellow oil: ¹H NMR (CDCl₃) δ 7.00–6.60 (m, 6H), 5.28–5.24 (m, 1H), 5.07–5.05 (m, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.43–3.37 (m, 3H), 2.73 (d, J = 9.2 Hz, 2H), 2.17–1.51 (m, 10H), 1.80 (s, 3H), 1.68 (s, 3H), 1.59 (s, 3H), 1.26, (s, 3H), 1.11 (s, 3H), 0.88 (s, 3H); ¹³C NMR (CDCl₃) δ 158.0, 155.6, 148.8, 142.5, 137.7, 136.8, 131.7, 128.9, 128.2, 126.3, 123.9, 122.6, 121.9, 120.5, 114.7, 106.79, 106.77, 101.2, 77.9, 77.0, 55.94, 55.7, 46.7, 39.7, 38.3, 37.6, 28.2, 27.3, 26.4, 25.6, 23.1, 22.2, 19.8, 17.6, 16.1, 14.2; HRMS (ESI) m/z calcd for C₃₆H₄₈O₅ (M⁺) 560.3502, found 560.3481.

5.42 Stilbene 50

Under the general conditions for HWE condensations, aldehyde 34 (320 mg, 0.76 mmol) phosphonate 39 (560 mg, 1.23 mmol), and KHMDS (0.5 M in toluene, 5 mL, 2.5 mmol) were allowed to react in THF (10 mL) for 10 min. Final purification by column chromatography (30% EtOAc in hexanes) afforded stilbene 50 (195 mg, 36%) as a colorless oil: ¹H NMR (CDCl₃) δ 7.44 (d, J = 0.8 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 6.96 (d, J = 16.0 Hz, 1H), 6.90 (J = 16.0 Hz, 1H), 6.86 (d, J = 0.8 Hz, 1H), 6.71 (d, J = 0.8 Hz, 1H), 5.23 (s, 2H), 5.20 (t, J = 6.8 Hz, 1H), 5.07 (t, J = 6.8 Hz, 1H), 4.70 (d, J = 13.6 Hz, 1H), 4.63 (d, J = 13.6 Hz, 1H), 3.87 (s, 3H), 3.50 (s, 3H), 3.43 (dd, J = 11.6, 4.4 Hz, 1H), 3.37 (d, J = 6.8 Hz, 2H), 2.73–2.70 (m, 2H), 2.06–1.84 (m, 8H), 1.78 (s, 3H), 1.72–1.68 (m, 2H), 1.65 (s, 3H), 1.57 (s, 3H), 1.20 (s, 3H), 1.10 (s, 3H), 0.98 (s, 9H), 0.88 (s, 3H), – 0.13 (s, 6H); ¹³C NMR δ 158.2, 155.8, 149.6, 136.8, 134.6, 131.2, 129.4, 128.8, 128.4, 126.3, 126.3, 124.4, 123.4, 122.7, 121.1, 118.6, 105.3, 102.6, 94.5, 78.0, 76.5, 60.2, 56.0, 55.7, 46.8, 39.8, 38.3, 37.8, 28.2, 27.3, 26.7, 26.0, 25.7 (3C), 23.0, 22.4, 20.1, 18.5, 17.6, 16.0, 14.2, −5.2 (2C); HRMS (EI) calcd for C₄₄H₆₆O₆Si (M⁺) 718.4629, found 718.4631.

5.43 Alcohol 58

To a solution of silyl ether 50 (195 mg, 0.27 mmol) in THF at rt was added TBAF (0.5 mL, 1 M in THF, 0.5 mmol). After 4 h, the reaction was quenched by addition of water, the resulting solution was extracted with ethyl acetate, and the combined organic phases were washed with brine. The organic phase was dried (MgSO₄) and concentrated in vacuo, which provided nonracemic alcohol 58 (193 mg, 100% yield, 89% ee by HPLC) as a colorless oil: ¹H NMR (CDCl₃) δ 7.27 (d, J = 1.2 Hz, 1H), 7.18 (d, J = 1.2 Hz, 1H), 6.97 (d, J = 16.0 Hz, 1H), 6.92 (d, J = 16.0 Hz, 1H), 6.84 (s, 1H), 6.71 (s, 1H), 5.23 (s, 2H), 5.22 (m, 1H), 5.08 (t, J = 6.2 Hz, 1H), 4.66 (d, J = 13.2 Hz, 1H), 4.59 (d, J = 13.2 Hz, 1H), 3.87 (s, 3H), 3.50 (s, 3H), 3.40–3.37 (m, 3H), 2.75–2.64 (m, 2H), 2.08–1.95 (m, 5H), 1.86–1.80 (m, 2H), 1.79 (s, 3H), 1.75–1.67 (m, 3H), 1.66 (s, 3H), 1.58 (s, 3H), 1.22 (s, 3H), 1.10 (s, 3H), 0.88 (s, 3H); ¹³C NMR (CDCl₃) δ 158.1, 155.7, 150.5, 136.5, 134.4, 130.9, 129.0, 128.7, 127.7, 127.2, 126.6, 124.3, 124.2, 122.6, 121.8, 118.7, 105.3, 102.6, 94.4, 77.6, 77.1, 61.8, 55.8, 55.6, 46.7, 39.7, 38.2, 37.7, 28.0, 27.2, 26.6, 25.6, 22.8, 22.4, 20.1, 17.5, 15.9, 14.2; HRMS (EI) m/z calcd for C₃₈H₅₂O₆ (M⁺) 604.3764, found 604.3751.

5.44 Schweinfurthin analogue 59

Under the general conditions for MOM hydrolysis, stilbene 58 (14 mg, 0.025 mmol), methanol (1 mL), and p-TsOH·H₂O (68 mg, 0.37 mmol) were allowed to react for 24 h to provide analogue 59 (2 mg, 17%) as a white solid after purification by thin layer chromatography (50% EtOAc in hexanes): ¹H NMR (CDCl₃) δ 7.26 (s, 1H), 7.18 (s, 1H), 6.95 (d, J = 16.0 Hz, 1H), 6.86 (d, J = 16.0 Hz, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 5.23 (m, 1H), 5.06 (m, 1H), 4.67 (d, J = 12.4 Hz, 1H), 4.60 (d, J = 12.4 Hz, 1H), 3.85 (s, 3H), 3.46–3.40 (m, 3H), 2.76 (m, 2H), 2.09–1.88 (m, 8H), 1.80 (s, 3H), 1.75–1.70 (m, 2H), 1.66 (s, 3H), 1.59 (s, 3H), 1.25 (s, 3H), 1.11 (s, 3H), 0.89 (s, 3H); HRMS (EI) m/z calcd for C₃₆H₄₈O₅ (M⁺) 560.3502, found 560.3508.

5.45 Aldehyde 60

To a solution of alcohol 58 (50 mg, 0.10 mmol) in CH₂Cl₂ at rt was added activated MnO₂ (250 mg, 2.3 mmol). After 22 h at rt, the solution was diluted with ethyl acetate, filtered through celite, and concentrated in vacuo which afforded aldehyde 60 (49 mg, 98%) as a yellow oil: ¹H NMR (CDCl₃) δ 10.41 (s, 1H), 7.78 (s, 1H), 7.47 (s, 1H), 6.96 (s, 2H), 6.87 (s, 1H), 6.70 (s, 1H), 5.20 (s, 2H), 5.19 (m, 1H), 5.06 (m, 1H), 3.86 (s, 3H), 3.49 (s, 3H), 3.44 (dd, J = 11.4, 3.4 Hz, 1H), 3.37 (d, J = 6.8 Hz, 2H), 2.77–2.73 (m, 2H), 2.08–1.82 (m, 8H), 1.77 (s, 3H), 1.74–1.70 (m, 2H), 1.64 (s, 3H), 1.50 (s, 3H), 1.28 (s, 3H), 1.12 (s, 3H), 0.90 (s, 3H); ¹³C NMR (CDCl₃) δ 189.9, 158.2, 155.8, 155.6, 136.0, 134.6, 133.6, 131.1, 129.2, 128.0, 126.6, 124.4, 124.4, 123.8, 123.7, 122.5, 119.2, 105.4, 102.7, 94.5, 78.0, 77.7, 55.9, 55.7, 46.5, 39.7, 38.4, 37.4, 28.1, 27.2, 26.7, 25.6, 22.9, 22.4, 20.2, 17.6, 16.0, 14.2; HRMS (EI) m/z calcd for C₃₈H₅₀O₆ (M⁺) 602.3607, found 602.3616.

5.46 Acid 61

To a solution of aldehyde 60 (17 mg, 0.028 mmol) in (CH₃)₃COH (1 mL) at rt was added 2-methyl-2-butene (0.3 mL). Dropwise addition of NaH₂PO₄ (40 mg) and NaClO₂ (34 mg, 0.38 mmol) as an aqueous solution (0.3 mL) resulted in a darkening of the reaction solution. After 45 min, the reaction was quenched by addition of 1N HCl. The resulting solution was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (MgSO₄), and concentrated in vacuo to afford acid 61 (18 mg, 100%) as a yellow oil: ¹H NMR (CDCl₃) δ 8.23 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.09 (d, J = 16.8 Hz, 1H), 7.05 (d, J = 16.6 Hz, 1H), 6.97 (d, J = 0.8 Hz, 1H), 6.79 (d, J = 1.2 Hz, 1H), 5.30 (s, 2H), 5.27 (m, 1H), 5.15 (t, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.58 (s, 3H), 3.56 (m, 1H), 3.45 (d, J = 7.2 Hz, 2H), 2.92–2.87 (m, 2H), 2.20–1.88 (m, 8H), 1.85 (s, 3H), 1.81–1.74 (m, 2H), 1.72 (s, 3H), 1.65 (s, 3H), 1.44 (s, 3H), 1.23 (s, 3H), 1.00 (s, 3H); ¹³C NMR (CDCl₃) δ 165.7, 158.3, 155.9, 151.1, 135.8, 134.7, 132.8, 131.2, 130.9, 129.5, 129.1, 126.0, 124.4, 123.4, 122.5, 119.5, 117.4, 105.6, 102.9, 94.6, 81.3, 77.2, 56.0, 55.7, 46.4, 39.8, 38.5, 37.5, 28.0, 27.1, 26.7, 25.6, 22.9, 22.4, 20.3, 17.6, 16.0, 14.2; HRMS (EI) m/z calcd for C₃₈H₅₀O₇ (M⁺ 618.3557, found 618.3560.

5.47 Amine 62

Aldehyde 60 (7.5 mg, 0.012 mmol) was dissolved in dimethylamine (2 M solution in THF, 1 mL, 2 mmol) at rt and molecular sieves were added. After 2 h, additional dimethylamine (1 mL, 2 mmol) was added along with AcOH (0.05 mL). After an additional 5 h, NaBH(OAc)₃ (58 mg, 0.4 mmol) was added in one portion. After 15 h, the reaction was quenched by addition of 1N NaOH. The resulting solution was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. Final purification by preparative thin layer chromatography on a base-washed plate (75% EtOAc and 5% TEA in hexanes) afforded amine 62 (2.5 mg, 33%) as a colorless oil: ¹H NMR (CDCl₃) δ 7.34 (s, 1H), 7.30 (s, 1H), 6.95 (s, 2H), 6.86 (s, 1H), 6.70 (s, 1H), 5.22 (s, 2H), 5.19 (m, 1H), 5.05 (m, 1H), 3.88 (s, 3H), 3.64 (s, 2H), 3.50 (s, 3H), 3.44 (dd, J = 11.4, 7.6 Hz, 1H), 3.36 (d, J = 7.6 Hz, 2H), 2.76–2.73 (m, 2H), 2.59 (s, 6H), 2.06–2.03 (m, 6H), 1.97–1.88 (m, 2H), 1.81 (s, 3H), 1.73–1.68 (m, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 1.24 (s, 3H), 1.11 (s, 3H), 0.90 (s, 3H); ¹³C NMR (CDCl₃) δ 159.4, 156.9, 152.6, 137.3, 135.7, 132.2, 130.6, 130.3, 129.9, 129.7, 128.7, 128.6, 128.0, 125.5, 123.7, 120.2, 106.6, 103.8, 95.6, 78.9, 78.2, 71.6, 57.0, 56.8, 48.0, 43.9, 40.9 (2C), 39.5, 38.9, 29.3, 28.4, 27.8, 26.7, 24.3, 23.5, 21.3, 18.7, 17.1, 15.4; HRMS (EI) m/z calcd for C₄₀H₅₇NO₅ (M⁺) 631.4237, found 631.4232.