Concise enantioselective synthesis of diospongins A and B

Abstract

Ether transfer methodology is capable of stereoselectively generating 1,3-diol mono- and diethers in good yield. Surprisingly, allylic and benzylic substrates provide none of the desired products when exposed to previously optimized conditions of iodine monochloride. Herein, second-generation activation conditions for ether transfer have been developed that circumvents undesired side reactions for these substrates. The application of this chemistry to the enantioselective synthesis of diospongins A and B has now been accomplished.

1. Introduction

Polyketide natural products have attracted the attention of numerous academic laboratories for their potential use as chemotherapeutic agents. Often limited by natural supplies, the community has harnessed powerful synthetic methods for practical syntheses of complex molecules to enable exploration of their therapeutic potential. The repeating pattern of 1,3-oxygenation is very common to polyketides. We have recently developed an ether transfer methodology that enables the formation of syn-1,3-diol mono- or diethers through electrophilic activation of a homoallylic alkoxyether.¹ As highlighted in Scheme 1, activation of 1a with iodine monochloride in toluene at low temperature led to the formation of ether transfer product 4a in excellent yield and diastereoselectivity. The use of iodine monochloride proved critical by generating the chloromethyl ether intermediate 3 in situ, as observed by NMR analysis.

Scheme 1.

Electrophile-induced ether transfer.

However, during the course of these studies we observed that certain substrates failed to provide the expected reactivity. A comparison of substrates 1a and 1b demonstrated a remarkable effect of the proximity of phenyl substitution on the ether transfer. In fact, subjecting 1b to the identical conditions led predominantly to the isolation of a complex mixture of ICl addition products, 5b (Scheme 1). Similarly, in planned application of this methodology to the syntheses of synthetic fragments related to zampanolide and peluroside A, undesired ICl addition products were also observed with diene substrates 6 and 7. Thus, the proximity of sp²-hybridized substituents adjacent to the reacting alkoxymethyl ether had a significant effect on the rate of cyclization. Application of ether transfer to the syntheses of the diastereomeric pyran natural products, diospongins A and B, would require a solution to this issue.

Diospongins A and B were isolated in 2004 from rhizomes of Dioscorea spongiosa,² a Chinese plant used for the treatment of rheumatism as well as urethra and renal infections in traditional medicine.³ Diospongin B has shown significant antiosteoporotic activity and potent inhibitory activities on bone resorption by inhibiting calcium release. Due to their relatively simple structure and their potential application to the treatment of osteoporosis, diospongins A and B have attracted the attention of the synthetic community leading to several syntheses.⁴ We envisioned a divergent synthetic strategy that would allow access to both diospongins from a common intermediate, such as 1,3-syn-diol monoether 4b. As proposed in Scheme 2, complementary methods for pyran generation would provide stereoselective access to each of the diastereomeric natural products.

Scheme 2.

Divergent strategy for the syntheses of diospongins.

2. Results and discussion

2.1. Access to syn-1,3-diol monoether

Iodine monochloride has shown unique ability to affect stereo-selective ether transfer in good yield. However, it has also shown limitations with some substrates, vide supra. For example, significant amount of ICl addition was observed with 1b leading to lower yield of the desired ether transfer product 4b. The inductively electron-withdrawing aryl or vinyl group is likely to slow the rate of cyclization and formation of the intermediate oxonium ion 2. However, an alternative rationale includes the potentially stabilizing cationic-pi interaction, such as intermediate 8, which would populate an unproductive conformation and allow intermolecular chloride addition to compete with the ether transfer (Scheme 3). Sterics were eliminated as a factor by substituting the aromatic ring in 1b with a cyclohexyl group. Here, only trace amounts of dihalogenation products were detected and the syn-1,3-diol monoether 10 was isolated in good yield and excellent diastereoselectivity.⁵

Scheme 3.

Through-space stabilization of the iodonium ion.

We envisioned that modulating the nucleophilicity and availability of counterions in solution, such as chloride, could eliminate undesired olefin addition products. We thus focused our efforts on finding alternative electrophilic activating conditions, to induce ether transfer in substrate 1b and the results are listed in Table 1. Substitution of ICl by other sources of I⁺, such as Ipy₂BF₄, I(collidine)₂PF₆, bromodiethylsulfonium bromopentachloroantimonate (BDSB), and the iodine analogue (IDSI) led to either poor reactivity or decomposition (Entries 3–7). However, much to our delight, we found that conditional adjustments to N-iodosuccinimide enabled the formation of syn-1,3-diol monoether 4b in higher yield and satisfactory diastereoselectivity (Entry 8). Unfortunately, an appreciable amount of the water addition product 11 was also observed. However, changing the solvent to nitromethane not only diminished the formation of this undesired product but also increased the yield and diastereoselectivity of the transformation (Entry 12).

Table 1.

Ether transfer activated with N-iodosuccinimide

Entry	Conditions	4b Yielda (dr)b	4b:11c
1	ICl, PhCH3, −78 °C, 10 min	22% (20:1)	–
2	IBr, PhCH3, −78 °C, 10 min	20% (20:1)	–
3	I2, PhCH3, −78 °C	NR	–
4	Ipy2BF4, DCM, rt	NR	–
5	I(collidine)2PF6, DCM, rt	NR	–
6	IDSI, CH3NO2, rt	Decomp.	–
7	BDSB, CH3NO2, rt	Decomp.	–
8	NIS, 10% H2O in CH3CN, rt, 1 h	40%	3:2
9	NIS, 10% H2O in PhCH3, rt, 1 h	0%	0:1
10	NIS, 10% H2O in DCM, rt, 1 h	75% (11:1)	1:1
11	NIS, 10% H2O in CH3NO2, rt, 1 h	72% (6:1)	3.5:1
12	NIS, H2O (2 equiv), CH3NO2, rt, 6 h	64% (6:1)	5:1
13	NIS, H2O (5 equiv), CH3NO2, rt, 5 h	64% (6:1)	5:1
14	NIS, CH3NO2, 4 ÅMS	NR	–

^aIsolated yield.

^bDiastereomeric ratio determined by NMR analysis.

^cRegioisomeric ratio of 11 was 1:1 by ¹³C NMR analysis.

2.2. Access to syn-1,3-diol diether

The results of this study make clear that the presence of water was crucial in the transfer as it likely both activates N-iodosuccinimide and also serves as a nucleophilic trap for the intermediate oxonium ion (Scheme 4). Intrigued by this transformation, we thought to access syn-1,3-diol diethers by replacing water with other weak Brønsted acids.

Scheme 4.

Activation of N-iodosuccinimide with water.

Successful demonstration of this concept is highlighted in Table 2. In the presence of N-iodosuccinimide, a variety of activating agents, such as acetic acid, 1-phenyl-1H-tetrazole-5-thiol, benzyl imidate, or propionaldehyde oxime were able to initiate the ether transfer providing access to syn-1,3-diol diethers in good yield and diastereomeric ratio. In some cases a significant amount of byproduct 13 was observed, although sensitivity of the reaction to the counterion remains unclear. Unfortunately attempts to use sulfur or phosphorus as nucleophiles were unsuccessful.

Table 2.

Activation of NIS with a variety of electrophiles

Entry	Nuc-H	12	Yielda (dr)b	12:13
1	AcOH		12a 74% (5:1)	5:1
2			12b 64% (6:1)	5:1
3			12c 45% (8:1)	10:1
4			4b 64% (3:1)	10:1

Regioisomeric ratio of 13 was 1:1 by ¹³C NMR analysis.

^aIsolated yield.

^bDiastereomeric ratio determined by NMR analysis.

2.3. Synthesis of diospongins A and B

With the reliable methodology in hand, we focused our efforts on the synthesis of diospongins A and B. Starting from the MOM protected homoallylic alcohol 1b, obtained in two steps from benzaldehyde, we realized the challenge of a late stage cleavage of the methyl group in the total synthesis. Unable to execute the deprotection, even at various points along the synthesis, we chose to investigate alternative transferring ethers, which would readily be deprotected when desired. Previous efforts from our group reported that the use of benzyloxy methyl ether (BOM) and, more recently, 2-naphtylmethoxymethyl ether (Naph)^1b as a substrates for ether transfer proved to be particularly useful since these groups can be removed under hydrogenolysis or mild aqueous oxidation conditions, respectively. Surprisingly, we found that the newly developed NIS conditions with BOM and Naph-protected versions of 1b, provided products with relatively poor diastereomeric ratio and low yields.

We found that the 2-bromoethoxymethyl ether 14 transferred efficiently to provide 15 in good yield and satisfactory diastereoselectivity when activated with NIS/1-phenyl-1H-tetrazole-5-thiol (Scheme 5).⁶ Oxidative cleavage with m-CPBA enabled quick access to the syn-1,3-diol monoether 15.⁷ Tributylphosphine catalyzed conjugate addition of 15 to phenyl ketone 16 provided access to the vinylogous ester 17.⁸ Selective radical generation and cyclization⁹ provided exclusively the 4-alkoxy-2,6-cis-trisubsituted pyran. A final reductive deprotection of the 2-bromoethyl ether yielded diospongin A.

Scheme 5.

Synthesis of diospongin A.

We have recently demonstrated that quenching the ether transfer process with nucleophiles, such as sulfide can provide access to 2-sulfonyl pyrans as intermediates to 2,6-cis or 2,6-trans pyran systems via an anionic cyclization.^1e While sulfur nucleophiles were not compatible with these NIS activation conditions, the identical intermediate 19 was available from ether transfer product 15 through alkylation with ((diazomethyl)sulfonyl)toluene 18 (Scheme 6).¹¹ The sulfonyl pyran was then generated as an inconsequential mixture of diastereomers by treatment of 19 with lithium bis(trimethylsilyl)amide. In analogy to our previously published procedures, exposure to aluminum chloride, in the presence of the TBS-enol ether derived from acetophenone, provided the 2,6-trans-pyran through axial attack on an intermediate oxonium ion. A final zinc-mediated deprotection of the 2-bromoethyl group yielded diospongin B.

Scheme 6.

Synthesis of diospongin B.

In conclusion we have achieved a divergent synthesis of diospongins A and B from common intermediate 15. Stereoselective access to 15 required further development of our ether transfer methodology since iodine monochloride cannot be employed with sp²-hybridized substituents adjacent to the reacting alkoxymethyl ether. We identified N-iodosuccinimide in wet nitromethane as useful in obtaining the desired ether transfer products in good yields and diastereoselectivities for the benzylic substrates presented above. Moreover, preliminary studies suggest that the new conditions also promote ether transfer in allylic substrates. These additional efforts as well as the results of our continued investigation of the scope and mechanism of the ether transfer will be reported in due course.

3. Experimental section

3.1. General

Unless otherwise noted, all materials were used as received from a commercial supplier without further purification. All anhydrous reactions were performed using oven-dried or flame-dried glassware under nitrogen atmosphere. Tetrahydrofuran (THF), dichloromethane (CH₂Cl₂), toluene, and diethyl ether (Et₂O) were filtered through activated alumina under nitrogen. Nitromethane was distilled over CaH₂, and kept over 4 Å molecular sieves. All reactions were monitored by Whatman analytical thin layer chromatography (TLC) plates (AL SIL G/UV, aluminum back) and analyzed with 254 nm UV light and/or anisaldehyde/sulfuric acid treatment. Silica gel for column chromatography was purchased from E. Merck (Silica Gel 60, 230–400 mesh). Unless otherwise noted, all ¹H and ¹³C NMR spectra were obtained in CDCl₃ on Varian Unity Plus 300, 500 or 600 spectrometers (operating at 299.701, 499.864 MHz, 599.876 MHz for ¹H and 75.368 MHz, 125.706 MHz and 150.84 MHz for ¹³C, respectively). Chemical shifts (δ) were reported in parts per million relative to residual CDCl₃ as an internal reference (¹H: 7.27 ppm, ¹³C: 77.23 ppm) and coupling constants (J) were reported in hertz (Hz). Peak multiplicity is indicated as follows: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartet), b (broad). Mass spectra (FAB) were obtained at the Department of Chemistry and Biochemistry, University of Notre Dame. Substrates 1a, 4a, 5a, 6, 7, and 9 have been prepared according to previously reported procedures.^1,5

3.2. (±)-1-Cyclohexyl-4-iodo-3-methoxybutan-1-ol (10)

Iodine monochloride (0.832 ml, 1.0 M in DCM) was added dropwise to a solution of 9 (0.110 g, 0.555 mmol) in toluene (10 ml) at −78 °C under inert atmosphere. The reaction was quenched after 20 min by addition of 1:10 mixture of H₂O/diisopropylamine (11 ml), warmed to room temperature, and stirred for 1 h. The mixture was diluted with water (10 ml), extracted with AcOEt (3 × 10 ml), and washed with brine (20 ml). The combined organic layers were dried over MgSO₄ and concentrated. Purification by column chromatography on silica gel (Hexane/AcOEt 6:1) provided 10 (95 mg, 55% yield, >20:1 dr) as an oil. ¹H NMR (600 MHz, CDCl₃): δ (ppm)=3.55 (1H, ddd, J=1.8, 5.4, 10.2 Hz), 3.40 (3H, s), 3.32 (1H, dd, J=1.2, 4.8 Hz), 3.31 (1H, dd, J=2.4, 4.8 Hz), 3.27 (1H, m), 1.83 (1H, dd, J=1.8, 3.6 Hz),1.80 (1H, dd, J=1.8, 3.6 Hz),1.73–1.79 (2H, m),1.70 (1H, m), 1.63–1.67 (2H, m), 1.33 (1H, m), 1.15–1.25 (3H, m), 1.15 (1H, m), 1.03 (1H, m). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=80.4, 75.1, 56.8, 44.1, 38.5, 28.9, 28.1, 26.7, 26.4, 26.3, 9.2. HRMS calculated for C₁₁H₂₂IO₂ [M+H]⁺ 313.0665, found 313.0659.

3.3. (±)-(1-(Methoxymethoxy)but-3-en-1-yl)benzene (1b)

To a solution of benzaldehyde (20 g, 196 mmol) in diethyl ether (300 ml) was added allylmagnesium chloride (117 ml, 2.0 M) dropwise at 0 °C over 30 min and stirred for 1 h under inert atmosphere. Saturated NH₄Cl (300 ml) was added and the aqueous layer extracted with diethyl ether (3×50 ml). The combined organic layers were dried over MgSO₄ and concentrated to provide 29 g (99% yield) of the corresponding allylic alcohol as an oil.

The allylic alcohol (29 g, 195 mmol) was diluted in dry DCM (200 ml), followed by addition of DIPEA (68 ml, 392 mmol) and n-Bu₄NI (0.72 g, 0.19 mmol). A solution of MOMCl¹⁰ (115 ml, 2.21 M in toluene) was added dropwise at 0 °C over 30 min and stirred overnight at reflux. Saturated NH₄Cl (300 ml) was added and extracted with diethyl ether (3 × 100 ml). The combined organic layers were dried over MgSO₄ and concentrated. Purification by column chromatography on silica gel (hexane/AcOEt 10:1) provided 1b (32 g, 85% yield) as an oil. ¹H NMR (600 MHz, CDCl₃): δ (ppm)=7.26–7.34 (5H, m), 5.80 (1H, dddd, J=7.2, 7.2, 10.2, 13.8 Hz), 5.08 (1H, m), 5.04 (1H, m), 4.63 (1H, dd, J=5.4, 7.8 Hz), 4.55 (1H, d, J=6.6 Hz), 4.53 (1H, d, J=6.6 Hz), 3.36 (3H, s), 2.44–2.63 (2H, m). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=141.5, 134.8, 128.4, 127.7, 126.9, 117.1, 94.1, 77.6, 55.5, 42.4. HRMS calculated for C₁₂H₁₆NaO₂ [M+Na]⁺ 215.1043, found 215.1067.

3.4. (±)-4-Iodo-3-methoxy-1-phenylbutan-1-ol (4b)

Iodine monochloride (2.10 ml, 1.0 M in DCM) was added drop-wise to a solution of 1b (0.309 g, 1.607 mmol) in toluene (50 ml) at −78 °C under inert atmosphere. The reaction was quenched after 10 min by addition of 1:5 mixture of H₂O/diisopropylamine (25 ml) and warmed to room temperature. The mixture was diluted with water (20 ml) and extracted with AcOEt (3 × 15 ml). The combined organic layers were dried over MgSO₄ and concentrated. Purification by column chromatography on silica gel (hexane/AcOEt 10:1–4:1) provided 4b (108 mg, 22% yield, >20:1 dr) as an oil. ¹H NMR (600 MHz, CDCl₃): δ (ppm)=7.26–7.37 (5H, m), 4.87 (1H, dd, J=4.2, 9.0 Hz), 3.39 (3H, s), 3.36 (1H, br), 3.28–3.33 (2H, m), 3.22 (1H, dddd, J=3.6, 5.4, 7.2, 12.6 Hz), 1.94–2.07 (2H, m). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=144.1, 128.5, 127.6, 125.8, 78.9, 72.8, 56.6, 43.9, 8.9. HRMS calculated for C₁₁H₁₅INaO₂ [M+Na]⁺ 329.0014, found 329.0023.

(±)-(4-Chloro-3-iodo-1-(methoxymethoxy)butyl)benzene

5b (438 mg, 77% yield, 1:1 mixture of regioisomers) was isolated. ¹H NMR (600 MHz, CDCl₃): δ (ppm)=7.28–7.38 (5H, m), 4.85 (1H, dd, J=2.4, 10.2 Hz), 4.60 (1H, dddd, J=3.0, 4.8, 7.2, 12.0 Hz), 4.56 (1H, d, J=6.6 Hz), 4.55 (1H, d, J=6.6 Hz), 4.09 (1H, dd, J=4.8, 11.4 Hz), 3.82 (1H, dd, J=9.6, 11.4 Hz), 3.43 (3H, s), 2.42 (1H, ddd, J=2.4, 10.2, 15.0 Hz), 1.95 (1H, ddd, J=2.4, 11.4, 15.0 Hz). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=141.0, 128.6, 128.1, 126.9, 94.3, 77.5, 56.3, 50.6, 45.9, 29.9. HRMS calculated for C₁₂H₁₆ClINaO₂ [M+Na]⁺ 376.9776, found 376.9801.

3.4.1. NIS/H₂O activation

Water (4.7 μl, 261 μmol) was added to a mixture of 1b (50 mg, 260 μmol) and N-iodosuccinimide (71 mg, 312 μmol) in dry nitromethane (3 ml) and stirred overnight in the dark. The reaction was quenched by addition of half saturated Na₂S₂O₃ (5 ml) and diluted with AcOEt (5 ml). The mixture was extracted with AcOEt (5×3 ml), dried over MgSO₄, and concentrated. Purification by column chromatography on silica gel (hexane/AcOEt 6:1–2:1) provided 4b (63 mg, 65% yield, 6:1 dr) as an oil.

3.4.2. NIS/oxime activation

E/Z Propionaldehyde oxime (0.171 g, 2.34 mmol) was added to a mixture of 1b (45 mg, 234 μmol) and N-iodosuccinimide (0.536 g, 2.34 mmol) in dry nitromethane (3 ml) and stirred 48 h in the dark under inert atmosphere. The reaction was quenched by addition of half saturated Na₂S₂O₃ (5 ml) and diluted with AcOEt (5 ml). The mixture was extracted with AcOEt (5 × 3 ml), dried over MgSO₄, and concentrated. Purification by column chromatography on silica gel (hexane/AcOEt 6:1–2:1) provided 4b (46 mg, 64% yield, 99% br sm, 5:1 dr) as an oil.

3.5. (±)-(4-Iodo-3-methoxy-1-phenylbutoxy)methyl acetate (12a)

Acetic acid (30 μl, 531 μmol) was added to a solution of 1b (51 mg, 265 μmol) and NIS (120 mg, 531 μmol) in dry nitromethane (3 ml). The mixture was stirred in the dark for 2 h under inert atmosphere, quenched by addition of half saturated Na₂S₂O₃ (5 ml), and diluted with AcOEt (5 ml). The mixture was extracted with AcOEt (5 × 3 ml), dried over MgSO₄, and concentrated. Purification by column chromatography on silica gel (hexane/AcOEt 8:1) provided 12a (74 mg, 74% yield, 6:1 dr) as an oil. ¹H NMR (600 MHz, CDCl₃): δ (ppm)=7.29–7.37 (5H, m), 5.31 (1H, d, J=6.6 Hz), 4.99 (1H, d, J=6.6 Hz), 4.72 (1H, dd, J=7.2, 7.2 Hz), 3.34 (1H, dd, J=5.5,10.8 Hz), 3.27 (3H, s), 3.24 (1H, dd, J=3.6, 10.8 Hz), 2.81 (1H, dddd, J=3.6, 4.8, 4.8, 7.2 Hz), 2.20 (1H, ddd, J=7.2, 13.8, 14.4 Hz), 1.94 (3H, s), 1.89 (1H, ddd, J=5.4, 7.2, 14.4 Hz). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=170.5, 140.6, 128.6, 128.2, 126.9, 86.9, 78.1, 75.9, 56.6, 42.4, 20.9, 9.6. HRMS calculated for C₁₄H₁₉INaO₄ [M+Na]⁺ 401.0220, found 401.0227.

3.6. (±)-1-((4-Iodo-3-methoxy-1-phenylbutoxy)methyl)-4-phenyl-1H-tetrazole-5(4H)-thione (12b)

1-phenyl-1H-tetrazole-5-thiol (104 mg, 583 μmol) was added to a solution of 1b (56 mg, 291 μmol) and NIS (131 mg, 583 μmol) in dry nitromethane (3 ml). The mixture was stirred in the dark for 12 h under inert atmosphere, quenched by addition of half saturated Na₂S₂O₃ (5 ml), and diluted with AcOEt (5 ml). The mixture was extracted with AcOEt (5×3 ml), dried over MgSO₄, and concentrated. Purification by column chromatography on silica gel (hexane/AcOEt 8:1) provided 12b (91 mg, 63% yield, 6:1 dr) as an oil. ¹H NMR (600 MHz, CDCl₃): δ (ppm)=7.83–7.85 (2H, m), 7.26–7.55 (8H, m), 5.70 (1H, d, J=11.4 Hz), 5.56 (1H, d, J=11.4 Hz), 4.90 (1H, dd, J=7.8, 7.8 Hz), 3.32 (1H, dd, J=5.4,10.8 Hz), 3.26 (3H, s), 3.20 (4.2, 10.8 Hz), 2.82 (1H, dddd, J=4.2, 5.4, 5.4, 7.8 Hz), 2.26 (1H, ddd, J=7.2, 7.2, 14.4 Hz), 1.94 (1H, ddd, J=5.4, 7.2, 14.4 Hz). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=164.3, 139.8, 134.5, 129.7, 129.3, 129.2, 128.6, 128.6, 128.4, 127.0, 126.8, 123.9, 123.6, 79.1, 76.0, 74.6, 56.6, 42.5, 9.5. IR (cm⁻¹): f=2984, 2940, 2907, 1740, 1498, 1446, 1373, 1298, 1241, 1096, 1047, 938, 847, 634, 607. HRMS calculated for C₁₉H₂₂IN₄O₂S [M+H]⁺ 497.0503, found 497.0524.

3.7. (±)-2,2,2-Trichloro-N-((4-iodo-3-methoxy-1-phenylbutoxy)methyl)acetamide (12c)

Benzyl imidate (168 μg, 905 μmol) was added to a solution of 1b (58 mg, 302 μmol) and NIS (204 mg, 905 μmol) in dry nitromethane (3 ml). The mixture was stirred in the dark for 12 h under inert atmosphere, quenched by addition of half saturated Na₂S₂O₃ (5 ml), and diluted with AcOEt (5 ml). The mixture was extracted with AcOEt (5 × 3 ml), dried over MgSO₄, and concentrated. Purification by column chromatography on silica gel (hexane/AcOEt:8:1) provided 12c (65 mg, 45% yield, 8:1 dr) as an oil. ¹H NMR (600 MHz, CDCl₃): δ (ppm)=7.23–7.37 (5H, m), 7.12 (1H, br s), 4.79 (1H, dd, J=7.2, 10.8 Hz), 4.71 (1H, dd, J=6.6, 10.8 Hz), 4.60 (1H, dd, J=5.4, 7.2 Hz), 3.31 (1H, dd, J=5.4,10.8 Hz), 3.26 (3H, s), 3.22 (1H, dd, J=4.2, 10.8 Hz), 2.83 (1H, dddd, J=4.2, 5.4, 5.4, 7.8 Hz), 2.19 (1H, ddd, J=7.2, 7.2, 13.8 Hz), 1.89 (1H, ddd, J=5.4, 6.6, 13.8 Hz). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=162.1, 140.6, 128.7, 128.2, 127.0, 78.1, 76.0, 70.7, 56.6, 42.5, 9.4. HRMS calculated for C₁₄H₁₇Cl₃INNaO₃ [M+Na]⁺ 501.9216, found 501.9214.

3.8. 1-Bromo-2-(chloromethoxy)ethane

A suspension of paraformaldehyde (3.51 g, 111.10 mmol), 2-bromoethanol (7.50 ml, 105.81 mmol) in 10:1 mixture of pentane/DCM (65 ml) was cooled to 0 °C. HCl gas was bubbled under vigorous stirring until the mixture became homogeneous (approximatively 30 min). In a separatory funnel, the aqueous solution was removed and distillation over CaCl₂ (82–87 °C/10 mmHg) provided 1-bromo-2-(chloromethoxy)ethane (18 g, 99% yield) as an oil, which can be kept over CaCl₂ for months in a freezer. ¹H NMR (600 MHz, CDCl₃): δ (ppm)=5.52 (2H, s), 4.00 (2H, t, J=5.4 Hz), 3.51 (2H, t, J=5.4 Hz). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=82.3, 70.1, 29.0.

3.9. (S)-(1-((2-Bromoethoxy)methoxy)but-3-en-1-yl)benzene (14)

1-Bromo-2-(chloromethoxy)ethane (2.82 g, 16.31 mmol) was added slowly to a solution of (S)-1-phenylbut-3-en-1-ol (1.86 g, 12.55 mmol) and DIPEA (3.93 ml, 22.59 ml) in dry DCM (25 ml). The mixture is stirred for 24 h under argon at room temperature. Saturated NH₄Cl (50 ml) was added and the aqueous layer was extracted with AcOEt (3×10 ml). The organic layers were combined, dried over MgSO₄, and concentrated. After purification by column chromatography on silica gel hexane/AcOEt (12:1), 14 was obtained as an oil (2.68 g, 77% yield). ¹H NMR (600 MHz, CDCl₃): δ (ppm)= 7.26–7.35 (5H, m), 5.78 (1H, dddd, J=7.2, 7.2, 10.2, 17.4 Hz), 5.03–5.10 (2H, m), 4.68 (1H, m), 4.68 (1H, d, J=7.2 Hz), 4.61 (1H, d, J=7.2 Hz), 3.96 (1H, ddd, J=6.0, 6.0, 10.8 Hz), 3.74 (1H, ddd, J=6.0, 6.0,10.8 Hz), 3.41 (2H, ddd, J=1.2, 6.0, 6.0 Hz), 2.43–2.63 (2H, m). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=141.3, 134.6, 128.4, 127.8, 127.0, 117.4, 93.0, 78.2, 67.9, 42.3, 30.7. HRMS calculated for C₁₃H₁₇BrNaO₂ [M+Na]⁺ 307.0304, found 307.0313. ${[\alpha ]}_{\text{D}}^{20}$−116.8 (c 0.75, CHCl₃).

3.10. (1S,3R)-3-(2-Bromoethoxy)-4-iodo-1-phenylbutan-1-ol (15)

To a solution of 14 (1.00 g, 3.51 mmol) in dry nitromethane (70 ml) was successively added NIS (6×0.78 g, 24.54 mmol) and 1-phenyl-1H-tetrazole-5-thiol (6×0.62 g, 24.54 mmol) every 6 h in the dark at room temperature under inert atmosphere. AcOEt (100 ml) was added, and the solvent evaporated. The crude material was portioned in half saturated NaS₂O₃/Et₂O (200 ml:200 ml) and stirred for 30 min. After extraction with AcOEt (5×20 ml), the organic layers were combined, dried over MgSO₄, and concentrated. Purification by column chromatography on silica gel (hexane/AcOEt 10:1–6:1) provided the ether transfer product (1.19 g, 64% yield) as an oil. ¹H NMR (500 MHz, CDCl₃): δ (ppm)=7.84–7.86 (2H, m), 7.30–7.58 (8H, m), 5.71 (1H, d, J=10.8 Hz), 5.55 (1H, d, J=10.8 Hz), 4.96 (1H, dd, J=6.6, 6.6 Hz), 3.80 (1H, ddd, J=5.4, 5.4, 10.2 Hz), 3.60 (1H, ddd, J=5.4, 5.4, 10.2 Hz), 3.42 (2H, m), 3.26 (1H, dd, J=4.8, 11.4 Hz), 3.22 (1H, dd, J=4.8, 11.4 Hz), 3.09 (1H, dddd, J=4.8, 4.8, 4.8, 7.2 Hz), 2.28 (1H, ddd, J=7.2, 7.2,14.4 Hz), 2.00 (5.4, 7.2,14.4 Hz).¹³C NMR (150 MHz, CDCl₃): δ (ppm)=164.3, 139.6, 134.5, 129.7, 129.3, 129.2, 128.7, 128.6, 127.1, 126.9, 123.9, 123.6, 78.8, 75.5, 74.5, 69.2, 42.7, 30.5, 9.2. HRMS calculated for C₂₀H₂₃BrIN₄O₂S [M+H]⁺ 588.9764, found 588.9745. ${[\alpha ]}_{\text{D}}^{20}$−43.0 (c 1.5, CHCl₃).

m-CPBA (0.475 g, 2.121 mmol) was added to a mixture of the ether transfer product (0.625 g, 1.061 mmol) and NaHCO₃ (0.445 g, 5.311 mmol) in AcOEt (30 ml) and vigorously stirred at room temperature open to air. After 1 h, a 1:1 mixture of saturated NaHCO₃/Na₂S₂O₃ (30 ml) was added and stirred for 10 min. The aqueous layer was extracted with DCM (5×5 ml), dried over MgSO₄, and concentrated (without heating the water bath). Purification by column chromatography on silica gel (hexane/AcOEt 4:1) provided 15 (275 mg, 65% yield) as an oil. ¹H NMR (600 MHz, CDCl₃): δ (ppm)=7.27–7.40 (5H, m), 4.95 (1H, dd, J=3.6, 8.4 Hz), 3.99 (1H, ddd, J=5.4, 5.4, 10.8 Hz), 3.68 (1H, ddd, J=5.4, 5.4, 10.8 Hz), 3.51 (2H, m), 3.44 (1H, dddd, 4.2, 4.2, 6.0, 7.8 Hz), 3.31 (2H, m), 3.00 (1H, br s), 2.00–2.15 (2H, m). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=143.9, 128.5, 127.7, 125.8, 78.1, 72.7, 69.0, 44.1, 30.5, 8.7. HRMS calculated for C₁₂H₁₇BrIO₂ [M+H]⁺ 398.9451, found 398.9459. ${[\alpha ]}_{\text{D}}^{20}$−41.5 (c 1.2, CHCl₃). Remark: compound 15 proved to be fairly unstable and cannot be kept as an oil. It can be stored in benzene solution in a freezer for a long period of time.

3.11. (E)-3-(3-(2-Bromoethoxy)-4-iodo-1-phenylbutoxy)-1-phenylprop-2-en-1-one (17)

To a mixture of 15 (260 mg, 650 μmol) and 1-phenylprop-2-yn-1-one (0.17 g, 1.30 mmol) in dry DCM (65 ml) was added PBu₃ (0.32 ml, 1.30 mmol) dropwise at 0 °C over 15 min under inert atmosphere. After 1 h, the mixture was concentrated and purified by column chromatography on silica gel (hexane/AcOEt 7:1) provided 17 (292 mg, 85% yield) as an oil.¹H NMR (MHz, CDCl₃): δ (ppm)=7.80–7.82(2H, m), 7.67 (1H, d, J=12.0 Hz), 7.48–7.52 (1H, m), 7.32–7.43 (7H, m), 6.45 (1H, d, J=12.0 Hz), 5.27 (1H, dd, J=6.0, 7.8 Hz), 3.91 (1H, ddd, J=4.8, 4.8, 10.2 Hz), 3.54 (1H, ddd, J=4.8, 4.8,10.2 Hz), 4.49 (2H, m), 3.29 (1H, dd, J=6.0,10.8 Hz), 3.25 (1H, dd, J=3.6,10.8 Hz), 3.08 (1H, dddd, J=4.2, 4.2, 5.4, 7.8 Hz), 2.44 (1H, ddd, J=6.0, 8.4,14.4 Hz), 2.19 (1H, ddd, J=3.6, 8.4, 14.4 Hz). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=190.4, 162.6, 140.0, 138.6, 132.3, 129.0, 128.4, 128.00, 126.8, 126.0, 104.0, 81.9, 75.1, 69.1, 42.0, 30.7, 8.0. HRMS calculated for C₂₁H₂₃BrIO₃ [M+H]⁺ 528.9870, found 529.9881. ${[\alpha ]}_{\text{D}}^{20}$−43.5 (c 0.75, CHCl₃).

3.12. Diospongin A

AIBN (0.5 mg, 2.8 μmol) was added to 17 (15.0 mg, 28.3 μmol) and n-Bu₃SnH (16 μl, 57 μmol) in dry benzene (3 ml). The mixture was rapidly brought to reflux and stirred for 5 min under argon. After cooling down, the reacting mixture was concentrated and purified by column chromatography on silica gel (hexane/AcOEt 10:1–6:1), to provide 2-((2R,4S,6S)-4-(2-bromoethoxy)-6-phenyltetrahydro-2H-pyran-2-yl)-1-phenylethanone as an oil (9.7 mg, 87% yield). ¹H NMR (600 MHz, CDCl₃): δ (ppm)=7.99 (2H, dd, J=1.2, 7.2 Hz), 7.55 (1H, m), 7.45 (2H, dd, J=7.2, 7.8 Hz), 7.26–7.30 (5H, m), 4.86 (1H, dd, J=1.8, 12.0 Hz), 4.57 (1H, dddd, J=1.8, 6.6, 6.6, 13.2 Hz), 3.86 (1H, p, 3.0 Hz), 3.50–3.64 (4H, m), 3.38 (1H, dd, J=6.0,15.6 Hz), 3.04 (1H, dd, J=6.6, 15.6 Hz), 2.12 (1H, q, J=3.0 Hz), 2.05 (1H, q, 3.0 Hz), 1.66 (1H, ddd, J=3.0,12.0,14.4 Hz),1.51 (1H, ddd, J=3.0,11.4,14.4 Hz). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=198.3, 142.7, 137.3, 133.1, 128.5, 128.3, 128.2, 127.2, 125.8, 74.1, 72.4, 69.4, 68.5, 45.1, 37.7, 35.1, 31.1. HRMS calculated for C₂₁H₂₄BrO₃ [M+ H]⁺ 403.0903, found 403.0928. ${[\alpha ]}_{\text{D}}^{20}$−21.5 (c 0.5, CHCl₃).

2-((2R,4S,6S)-4-(2-Bromoethoxy)-6-phenyltetrahydro-2H-py-ran-2-yl)-1-phenylethanone (11.0 mg, 27.3 μmol) was diluted in a 14:1 mixture of i-PrOH/H₂O (4 ml). Solid NH₄Cl (7.3 mg, 136.5 μmol) was added followed by purified zinc dust (0.178 g, 2.72 mmol) and the mixture was refluxed for 8 h. After concentration, the crude material was purified by column chromatography on silica gel (hexane/AcOEt 2:1) to provide diospongin A (6.0 mg, 75% yield). ¹H NMR (600 MHz, CDCl₃): δ (ppm)=7.98 (2H, dd, J=1.2, 7.8 Hz), 7.56 (1H, m), 7.46 (dd, 2H, J=7.2, 8.4 Hz), 7.30 (5H, m), 4.93 (1H, dd, J=1.8, 12.0 Hz), 4.65 (1H, m), 4.38 (1H, q, J=3 Hz), 3.42 (1H, dd, J=6.0, 15.6 Hz), 3.07 (1H, dd, J=6.6, 15.6 Hz), 1.94–1.98 (2H, m), 1.67–1.79 (2H, m), 1.64 (1H, br s). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=198.3, 142.6, 137.3, 133.1, 128.5, 128.3, 128.3, 127.2, 125.8, 73.8, 69.1, 64.7, 45.1, 40.0, 38.5. HRMS calculated for C₁₉H₂₁O₃ [M+H]⁺ 297.1485, found 297.1496. ${[\alpha ]}_{\text{D}}^{20}$−18.6 (c 0.12, CHCl₃); lit.: −21.2 (c 0.8, CHCl₃). The spectral data and optical rotation are in full agreement with that reported for both natural as well as synthetic sources of diospongin A.

3.13. 1-((((1S,3R)-3-(2-Bromoethoxy)-4-iodo-1-phenylbutoxy) methyl)sulfonyl)-4-methylbenzene (19)

HBF₄·OEt₂ (32 μl, 238 mmol) was added dropwise at 0 °C to a mixture of 15 (380 mg, 952 mmol) and 1-((diazomethyl)sulfonyl)-4-methylbenzene (0.280 mg, 1.428 mmol) in dry DCM (10 ml) under argon atmosphere. After 2 h, saturated NH₄Cl (10 ml) was added and the aqueous layer was extracted with DCM (3×5 ml), dried over MgSO₄, and concentrated. Purification by column chromatography on silica gel (hexane/AcOEt 6:1) provided 19 (355 mg, 66% yield) as an oil. ¹H NMR (600 MHz, CDCl₃): δ (ppm)=7.80 (2H, d, J=6.6 Hz), 7.22–7.40 (7H, m), 4.95 (1H, t, J=6.6 Hz), 4.40 (1H, d, J=12.0 Hz), 4.28 (1H, d, J=12.0 Hz), 3.41–3.77 (4H, m), 3.36 (1H, dd, J=4.8,10.8 Hz), 3.27 (1H, dd, J=4.8,10.8 Hz), 3.10 (1H, p, 5.4 Hz), 2.47 (3H, s), 2.17 (1H, ddd, J=6.6, 7.8, 14.4 Hz), 1.93 (1H, ddd, J=6.0, 6.0, 14.4 Hz). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=145.2, 138.7, 134.4, 130.0,128.9,128.8,127.2,125.5, 82.9, 80.5, 75.3, 69.1, 42.5, 30.3, 21.8, 9.5. HRMS calculated for C₂₀H₂₄BrINaO₄S [M+Na]⁺ 588.9516, found 588.9497. ${[\alpha ]}_{\text{D}}^{20}$−47.6 (c 1.5, CHCl₃).

3.14. Diospongin B

LiHMDS (0.5 ml, 0.45 M in THF) was added slowly at −78 °C to a solution of 19 (86 mg, 152 mmol) and HMPA (80 μl, 455 mmol) in dry THF (6 ml) under argon. After 45 min, the reaction was quenched by addition of saturated NH₄Cl (10 ml) and extracted with Et₂O (3×5 ml). The organic layers were dried over MgSO₄, concentrated, and purified by column chromatography on silica gel (hexane/AcOEt 5:1) to provide the corresponding sulfonyl pyran (55 mg, 82% yield) as an oil. ¹H NMR (500 MHz, CDCl₃): δ (ppm)= 7.83 (2H, d, J=8.0 Hz), 7.23–7.34 (7H, m), 7.96 (1H, dd, J=2.0, 12.0 Hz), 4.86 (1H, d, J=10.5 Hz), 4.03 (1H, m), 3.51–3.91 (4H, m), 2.42–2.48 (5H, m), 1.87 (1H, ddd, 2.5, 14.0, 14.0 Hz), 1.63 (1H, ddd, J=2.0, 14.5, 14.5 Hz). ¹³C NMR (125 MHz, CDCl₃): δ (ppm)=145.3, 141.4, 133.4, 130.0, 129.8, 128.5, 127.8, 125.7, 88.1, 75.3, 71.7, 69.0, 37.6, 31.3, 28.1, 22.0. HRMS calculated for C₂₀H₂₃BrNaO₄S [M+Na]⁺ 461.0393, found 461.0395. ${[\alpha ]}_{\text{D}}^{20}$−1.2 (c 0.2, CHCl₃).

The sulfonyl pyran (51 mg, 116 μmol) in DCM (1 ml), dried over molecular sieves, was added to a suspension of AlCl₃ (46 mg, 348 μmol) in dry DCM (6 ml) and stirred for 5 min. tert-Butyldimethyl((1-phenylvinyl)oxy)silane (41 mg, 174 μmol) in dry DCM (1 ml) was added at −78 °C and slowly warmed to −40 °C, which showed complete consumption of the starting material. The reaction was quenched by addition of saturated Rochelles’ salt (10 ml) and stirred overnight. The aqueous layer was extracted with DCM (3 × 5 ml), and the combined organic layers dried over MgSO₄, and concentrated. Purification by column chromatography on silica gel (hexane/AcOEt 5:1) provided the corresponding 2,6-trans pyran (38 mg, 82% yield) as a single diastereomer. ¹H NMR (600 MHz, CDCl₃): δ (ppm)=8.00 (2H, dd, J=1.2, 8.4 Hz), 7.57 (1H, m), 7.47 (2H, m), 7.32–7.37 (5H, m), 5.17 (1H, t, J=4.8 Hz), 4.33 (1H, m), 3.77–3.81 (2H, m), 3.74 (1H, m), 3.47 (1H, dd, J=6.6, 16.2 Hz), 3.45–3.47 (2H, m), 3.51 (1H, dd, J=6.0, 16.2 Hz), 2.41 (1H, dddd, J=1.2, 4.8, 4.8, 4.8 Hz), 2.10 (1H, dddd, J=1.2, 3.6, 3.6, 7.8 Hz), 1.99 (1H, ddd, J=4.8, 8.5, 13.2 Hz), 1.61 (1H, m). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)= 198.4, 140.6, 137.2, 133.1, 128.6, 128.5, 128.2, 127.2, 126.2, 72.1, 71.6, 68.1, 67.3, 44.2, 36.2, 34.3, 31.1. HRMS calculated for C₂₁H₂₄BrO₃ [M+H]⁺ 403.0903, found 403.0928. ${[\alpha ]}_{\text{D}}^{20}$−45.5 (c 2.5, CHCl₃).

The 2,6-trans pyran (8.0 mg, 19.3 μmol) was diluted in a 14:1 mixture i-PrOH/H₂O (3 ml). Solid NH₄Cl (5.5 mg, 99.2 μmol) was added followed by purified zinc dust (0.130 g, 1.98 mmol) and the mixture was refluxed for 10 h. After concentration, the crude material was purified by column chromatography on silica gel (hexane/AcOEt 2:1) to provide diospongin B (4.5 mg, 76% yield). ¹H NMR (600 MHz, CDCl₃): δ (ppm)=7.98 (2H, d, J=7.8 Hz), 7.57 (1H, t, J=7.2 Hz), 7.47 (2H, t, J=7.8 Hz), 7.34 (5H, m), 5.20 (1H, t, J=4.2 Hz), 4.23 (1H, m), 4.03 (1H, m), 3.45 (1H, dd, J=7.2, 15.6 Hz), 3.18 (1H, dd, J=6.0, 15.6 Hz), 2.51 (1H, m), 2.05 (1H, m), 1.92 (1H, ddd, J=5.4, 10.2, 15.0 Hz), 1.62 (1H, br s), 1.50 (1H, dd, J=9.0, 12.0 Hz). ¹³C NMR (150 MHz, CDCl₃): δ (ppm)=198.3, 140.2, 137.2, 133.2, 128.6, 128.5, 128.3, 127.1, 126.3, 72.3, 66.9, 64.344.6, 40.2, 36.7. HRMS calculated for C₁₉H₂₁O₃ [M+H]⁺ 297.1485, found 297.1496. ${[\alpha ]}_{\text{D}}^{20}$−22.5 (c 0.08, CHCl₃); lit. −23.4 (c 0.6, CHCl₃). The spectral data and optical rotation are in full agreement with that reported for both natural as well as synthetic sources of diospongin B.