Skip to main content
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2008 Dec 4.
Published in final edited form as: J Org Chem. 2006 Sep 1;71(18):6915–6922. doi: 10.1021/jo061059c

Studies on the Synthesis of Quartromicins A3 and D3: Synthesis of the Vertical and Horizontal Bis-Spirotetronate Fragments

Tony K Trullinger a, Jun Qi a, William R Roush b,
PMCID: PMC2593838  NIHMSID: NIHMS60240  PMID: 16930045

Abstract

Syntheses of the vertical (3) and horizontal (4) bis-spirotetronate units of quartromicins A3 and D3 are described, along with an efficient synthesis of α-hydroxy aldehyde exo-8b, a precursor to the exo-spirotetronate fragments 19 and 21.

Introduction

The quartromicins (Figure 1) are a group of structurally complex macrocyclic natural products that display activity against herpes simplex virus (HSV) type 1, influenza, and HIV.13 Quartromicins A3 and D3 possess a novel 32-membered carbocyclic ring system containing four spirotetronic acid subunits connected in a head-to-tail arrangement via enone linkers. Our laboratory has proposed a stereochemical assignment4, 5 for the quartromicins and we have developed chemistry to access the two distinct spirotetronate subunits of these complex targets.5, 6 We refer to the two spirotetronate fragments as the endo (also known as the galacto fragment) and exo (or the agalacto fragment) spirotetronate units, by virtue of the Diels-Alder chemistry that we have employed for their synthesis.5, 6 Other work on the synthesis of the quartromicins has recently appeared.7

Figure 1.

Figure 1

Structures of quartromicins A3 (1) and D3 (2)

The quartromicins are formidable synthetic targets owing to the presence of contiguous quaternary centers in each of the spirotetronate fragments (C4/C12 and C4’/C12’ in the exo fragments; C22/C30 and C22’/C30’ in the endo fragments). The high steric congestion at these positions greatly complicates syntheses of the endo- and exo-spirotetronate fragments, much more so than in syntheses of the spirotetronic acid fragments of other spirotetronate natural products (e.g., chlorothricolide,8, 9 kijanolide,1016 and tetronolide1720). Other spirotetronate natural products that have attracted interest as synthetic targets include okilactomycin,21, 22 and tetronothiodin.23

Our synthetic strategy aims to exploit the C2 symmetry of the natural products by generation of the carbocycle via a late stage dimerization of either the vertical (3) or horizontal (4) exo-endo bis-tetronate fragments (Figure 2). Towards this end, we have developed and report herein syntheses of the “exo-endo” bis-spirotetronate units 3 and 4. The vertical “dimer” 3 contains an enone unit linking the two spirotetronate fragments,whereas the horizontal “dimer” 4 contains a dienone linker.

Figure 2.

Figure 2

Structures of the Vertical (3) and Horizontal (4) Bis-Spirotetronate Units of Quartromicin D3

A significant bottle-neck in the synthesis of 3 and 4 is access to synthetically useful quantities of precursors of the monomeric endo- and exo-spirotetronate units. While synthesis of the endo (or galacto) fragment in either racemic or single enantiomeric form proved to be relatively straightforward, development of a brief, highly stereoselective synthesis of the exo-spirotetronate subunit present in the agalacto fragment of quartromicin A3 has proven to be challenging.5

We have previously accomplished the enantioselective synthesis of 5 via the Lewis acid catalyzed Diels-Alder reaction of an acyclic (Z)-1,3-diene.5, 6, 24 Endo α-hydroxy aldehyde 6—a precursor to the endo (or galacto) spiroteronate fragment of the quartromicins—was then easily prepared by the DMDO epoxidation of the enol silane prepared from 5 (Scheme 1).5 However, conversion of 5 to the exo α-hydroxy aldehyde 8a (formally the (C)-2 epimer of 6, and the targeted precursor of the exo-spirotetronate subunit of the quartromicins) proceeded in low overall yield owing to an inefficient inversion of configuration of the C(2)-Br substituent of 7.5 Consequently, before initiating work on the synthesis of fragments 3 and 4, it was necessary to develop a more efficient synthesis of exo-8.

Scheme 1.

Scheme 1

Summary of Previous Syntheses of 6 and 8

Results and Discussion

An improved synthesis of exo-α-hydroxy aldehyde 8b began by converting aldehyde 5 into an enol silyl ether which was oxidized under Saegusa conditions25 to give the corresponding enal (Scheme 2). Reduction of the enal by using DIBAL-H then gave allylic alcohol 9. All attempts to effect a highly diastereoselective reagent-controlled epoxidation of 9 were unsuccessful (e.g., Sharpless asymmetric epoxidation).26 However, epoxidation of 9 using VO(acac)2 and t-BuOOH gave the β-face epoxy alcohol with >20:1 d.r.27 Subsequent treatment of the resulting epoxyalcohol with phenyl isocyanate and triethylamine furnished urethane 10 in 88% yield over two steps. Exposure of 10 to BF3·OEt2 led to rapid and highly diastereoselective intramolecular epoxide opening28 to furnish carbonate 11, possessing the C(2) stereochemistry required for the exo-spirotetronate fragment. Reductive removal of the hydroxyl group in 11 via Barton deoxygenation29, 30 proceeded in >90% yield. Cleavage of the carbonate with potassium carbonate in methanol followed by Parikh-Doering oxidation31 of the primary alcohol furnished aldehyde exo- 8b. The overall yield from 5 to 8b (47%) is more than five times higher than from previous routes. This sequence has been scaled to provide gram quantities of precursors to 8b.

Scheme 2.

Scheme 2

Synthesis of exo-8b

While the synthesis of 8b summarized in Scheme 2 is chemically efficient, the length of this sequence is unattractive (10 steps from 5). This prompted us to develop a more direct synthesis of exo-8b via the exo-selective Diels-Alder reaction of 12 and 13, a dienophile that we designed for this purpose.32 Details of the design and synthesis of 13 have been reported elsewhere.32, 33 Thus, the MeAlCl2 mediated Diels-Alder reaction of (Z)-diene 1224 with the conformationally constrained α-alkoxyacrylate dienophile 13 provided a 5 : 1 mixture of cycloadducts favoring exo-14. Reduction of this mixture with LiAlH4 and then oxidation of the resulting mixture of diols under Parikh-Doering conditions31 provided the targeted α-hydroxy aldehyde exo-8b in 51% yield, along with 10% of ent-endo-6 (the enantiomer of endo-6 as presented in Scheme 1) which were separated chromatographically.

The synthesis of exo-8b summarized in Scheme 3 is more step-wise efficient than the much longer synthesis summarized in Scheme 2, starting in both cases from diene 12, the closest common precursor for both routes.5 The synthesis of exo-8b in Scheme 3 proceeds in 36% yield over three steps from diene 12, whereas the synthesis of exo-8b from 12 via Scheme 2 proceeds in 23% yield over a 12 step sequence. An implicit trade-off, however, is that our current synthesis of dienophile 13 is lengthy (13 steps from commercially available L-valine, 7% overall yield). 32, 33 Nevertheless, we are using the sequence of Scheme 3 for bringing up starting materials, and have already prepare ca. 1 g quantities of exo-8b from single runs (see Experimental).

Scheme 3.

Scheme 3

Synthesis of exo-8b via the Exo-Selective Diels-Alder Reaction of 12 and 13

We turned next to elaboration of 8b to exo-spirotetronates 19 and 21 needed for the synthesis of 3 and 4, respectively (Scheme 4). α-Hydroxy aldehyde exo-8b was oxidized by exposure to KOH and I2 in MeOH,34 and then the primary TBS ether was cleaved by treatment with PPTs in MeOH. The diol exo-16 was acylated by treatment with Ac2O and catalytic Sc(OTf)3,35 and then the primary acetate was selectively cleaved by treatment with DIBAL-H. The resulting α-acetoxy ester 17 was then elaborated to exo-18 by using our previously published sequence.5, 6 Treatment of 18 with LHMDS in THF-HMPA at −78 °C with warming to 0 °C followed by addition of NBS provided the 2-bromo spirotetronic acid. Treatment of this intermediate with CH2N2 afforded the methyl ether derivative exo-19 in 86% yield. This compound was destined to serve as the nucleophilic component (after lithium-halogen exchange) in the synthesis of the horizontal bis-spirotetronate unit 4. Alternatively, standard Dieckmann cyclization of 18 followed by methylation using CH2N2 provided 20. Deprotection of the TBS ether of 20 by treatment with PPTS in methanol, followed SO3-pyridine oxidation31 gave enal exo-21, which ultimately served as the electrophilic coupling partner in the synthesis of the vertical bis-spirotetronate fragment 3.

Scheme 4.

Scheme 4

Elaboration of exo-8b to exo-19 and exo-21

Endo α-acetoxy ester 22, deriving from endo-6,5, 6 was elaborated to 2-bromo spirotetronate 23 (Scheme 5) by using the same Dieckmann cyclization-bromination conditions used for the synthesis of exo-19 from 18 (Scheme 4). Intermediate 23 was designed to serve as the nucleophilic component in the synthesis of the vertical bis-spritetronate unit 3. Deprotection of the primary TBS ether of 24, which derives from the non-oxidative Dieckmann cyclization of 22,5, 6 was accomplished by treatment with PPTS in MeOH. Oxidation of the resulting alcohol to the corresponding enal, and then olefination with a stabilized ylide afforded dienal 25 in the endo-spirotetronate series. The latter compound was targeted to serve as the electrophilic fragment in a synthesis of the horizontal bis-spirotetronate 4.

Scheme 5.

Scheme 5

Elaboration of endo-6 to endo-23 and endo-25

With viable synthetic routes to all four coupling partners in hand, we were ready to investigate the synthesis of the vertical and horizontal halves of quartromicin. In previous studies, we directly metallated endo-24 by treatment with mesityllithium,17 and the resulting α-lithio spirotetronate added in good yield to an α, β-unsaturated aldehyde.5 However, attempts to apply this protocol to the metallation of exo-20 under a variety of conditions met with poor results. Consequently, we elected to generate the 2-lithio-exo-spirotetronate via lithium/halogen exchange36 by treatment of exo-19 with n-BuLi (Scheme 6). Unfortunately, while the requisite 2-lithiotetronate was efficiently generated under these conditions, it failed to add to dienal 25 in good yield. However, when the 2-lithiotetronate (generated from 3 equiv of 19) was transmetallated using CeCl3,37, 38 the resulting vinylcerium species underwent smooth and efficient 1,2-addition to dienal 25 (1 equiv), thus providing 26 in 92% yield (Scheme 6). The addition product 26 was oxidized to the ketone by using activated MnO2 which provide the horizontal fragment 4 of quartromicin.

Scheme 6.

Scheme 6

Synthesis of the Horizontal exo-endo Bis-tetronate 4

This coupling protocol was also applied to the synthesis of the vertical fragment 3 (Scheme 7). Thus, sequential treatment of 2-bromo-endo-spirotetronate 23 with n-BuLi, activated CeCl3, and finally aldehyde exo-21 gave addition product 27 in ca. 65% yield. The secondary hydroxyl group of 27 was oxidized by using MnO2 to give the complete vertical fragment 3 of quartromicin.

Scheme 7.

Scheme 7

Synthesis of the Vertical endo-exo Bis-Tetronate 3

In summary, we have developed an improved synthetic route to exo-α-hydroxy aldehyde 8b via the Diels-Alder reaction of 12 and 13. Exo-8b and endo-6 were elaborated into the corresponding 2-bromospirotetronates exo-19 and endo-23 and the unsaturated aldehydes exo-21 and endo-25 needed for the coupling experiments. Finally, we have shown that both the vertical (3) and horizontal (4) halves of quartromicins A3 and D3 can be accessed via the 1,2-addition of organocerium intermediates derived from 19 and 23 onto the requisite enals 25 and 21, respectively. Attempts to utilize these intermediates in the completion of the total synthesis of the proposed structure of quartromicin D3 (2) are in progress and will be reported in due course.

Experimental Section39

Spiro (1’R, 2’S, 5’S, 8αR)-6-[2’-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-4’-(tert-butyl-diphenyl-silanyloxymethyl)-2’,5’-dimethyl-cyclohex-3’-ene]-8α-isopropyl-dihydro-oxazolo[4,3-c][1,4]oxazine-3,5,8-trione (14) and Spiro (1’R, 2’R, 5’R, 8αR)-6-[2’-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-4’-(tert-butyl-diphenyl-silanyloxymethyl)-2’,5’-dimethyl-cyclohex-3’-ene]-8α-isopropyl-dihydro-oxazolo[4,3-c][1,4]oxazine-3,5,8-trione (15). To a −78 °C solution of diene 12 (2.32 g, 4.4 mmol) and dienophile 13 (1.20 g, 5.3 mmol) in CH2Cl2 was added 5.3 mL of MeAlCl2 (1.0 M solution in hexanes, 5.3 mmol) over 30 min. The resulting yellow solution was stirred at −78 °C for 6 d. The reaction was quenched by the slow addition of saturated aq. NaHCO3 and allowed to warm to room temperature. The mixture was diluted with diethyl ether and 1N HCl, and the layers were separated after the white solids had dissolved. The aqueous layer was extracted with Et2O (3 x). The combined organic layers were washed with saturated aq. NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The crude product was then purified by chromatography on silica gel (20% EtOAc-hexane). The mixture of diastereomeric products so obtained (5 :1 mixture, 2.32 g, 70%) was inseparable by silica gel chromatography (20% EtOAc-hexane), or by HPLC. Data for the mixture of 14 and 15: Rf 0.46 (33% EtOAc-hexane); [α]23 D +24.7 (c 1.8, CH2Cl2); 1H NMR for major diastereomer 14 (500 MHz, CDCl3) δ 7.51 (m, 10H), 5.40 (s, 1H), 4.37 (s, 2H), 4.13 (m, 2H), 3.54 (m, 2H), 2.66 (m, 1H), 2.34 (dd, J=13.9, 7.3 Hz, 1H), 2.23 (m, 1H), 1.99 (dd, J=13.9, 7.3 Hz, 1H), 1.52 (m, 4H), 1.03 (m, 21H), 0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 165.1, 164.7, 149.5, 137.7, 135.6, 135.5, 135.4, 133.6, 133.5, 129.7, 129.6, 127.7, 127.6, 125.5, 91.6, 66.3, 65.2, 65.0, 63.4, 44.3, 37.7, 37.0, 34.8, 29.0, 27.4, 27.0, 26.8, 26.7, 26.0, 25.9, 21.7, 19.3, 19.2, 18.3, 16.2, 15.7, –5.3; FT-IR (thin film) 2930, 2857, 1822, 1756, 1715, 1472, 1428, 1358, 1297, 1258, 1188, 1111, 1056, 835, 776, 703 cm−1; HRMS (ESI) calcd. for C42H61NO7Si2Na [M+Na]+ 770.3884, found 770.3903 m/z

(1R, 2S, 5S)-2-[3-(tert-butyldimethyl-silanyloxy)-propyl]-4-(tert-butyldiphenyl-siloxylmethyl)-1-hydroxy-2,5-dimethyl-cyclohex-3-enecarbaldehyde (exo-8b) and (1R, 2R, 5R)-2-[3-(tert-butyldimethyl-silanyloxy)-propyl]-4-(tert-butyldiphenyl-siloxylmethyl)-1-hydroxy-2,5-dimethyl-cyclohex-3-enecarbaldehyde (endo-6). To a solution of the 5 : 1 mixture of 14 and 15 (2.33 g, 3.1 mmol) in THF (23 mL) was added LiAlH4 (236 mg, 6.2 mmol) portion-wise at 0 °C. The mixture was stirred at room temperature for 6 h. Diethyl ether and saturated aq. Rochelle’s salt solution were then added, and the mixture was further stirred overnight until both layers became clear. The layers were then separated and the aqueous layer was extracted with ether (3 x). The combined organic layers was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was then purified by chromatography on silica gel (50% EtOAc-hexane) provided exo-8b (231mg, 12%), endo-6 (46 mg, 3%) and a mixture of endo andexo diols (923mg, 50% yield).

To a solution of diol mixture (923 mg, 1.5 mmol) in CH2Cl2 (15 mL) was added sequentially DMSO (1.1 mL, 15.5 mmol), i-Pr2NEt (1.4 mL, 7.8 mmol), and SO3•Pyridine (740 mg, 4.6 mmol). The reaction was judged complete in 15 min by TLC analysis, and was quenched by addition of EtOAc (20 mL) and 1M aq. HCl (5 mL). The organic layer was separated and washed with saturated aq. NaHCO3, brine, dried with MgSO4, filtered, and concentrated. The crude productwas purified by flash column chromatography on SiO2 (10% EtOAc-hexane) to afford the known α-hydroxy aldehyde exo-8b (694 mg, 75% from the diol mixture; 38% from Diels-Alder adducts 14-15) and ent-endo-6 (132 mg, 14% from diol mixture; 7% from 14–15). Overall, 925 mg (51% yield) of exo-8b and 178 mg (10%) of ent-endo-6 were obtained for the three step sequence starting with the 5 : 1 mixture of Diels-Alder adducts 14 and 15.

Data for exo-8b: Rf 0.56 (10% EtOAc-hexane); [α]23 D –2.7 (c 3.1, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 7.66 (m, 4H), 7.40 (m, 6H), 5.52 (br, 1H), 4.27 (d, J=13.2 Hz, 1H), 4.18 (d, J=13.2 Hz, 1H), 3.57 (m, 2H), 3.27 (s, 1H), 2.46 (m, 1H), 1.92 (dd, J=13.9, 11.7 Hz, 1H), 1.65 (dd, J = 13.9, 7.3 Hz, 1H), 1.51 (m, 4H), 1.08 (s, 7H), 1.05 (d, J = 6.6 Hz, 3H), 0.89 (s, 9H), 0.82 (s, 3H), 0.04 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 206.5, 138.9, 135.5, 133.6, 133.5, 129.8, 129.3, 127.7, 80.9, 65.4, 63.8, 39.4, 38.2, 34.5, 30.1, 27.0, 26.8, 25.9, 20.5, 19.5, 19.2, 18.3, –5.3; FT-IR (thin film) 3948, 3070, 2956, 2930, 2857, 1718, 1471, 1427, 1389, 1361, 1333, 1255, 1112, 1006, 934, 835, 775, 738, 701 cm−1; HRMS (ESI) calcd. for C35H54O4Si2Na [M+Na]+ 617.3458, found 617.3456 m/z.

Data for the minor product ent-endo-6: Rf 0.52 (10% EtOAc-hexane); [α]23 D –9.3 (c 0.8, CH2Cl2); H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 7.69 (m, 4H), 7.40 (m, 6H), 5.46 (br, 1H), 4.23 (d, J=13.2 Hz, 1H), 4.14 (d, J=13.2 Hz, 1H), 3.55 (m, 2H), 3.16 (s, 1H), 2.53 (m, 1H), 1.80 (m, 2H), 1.53 (m, 4H), 1.06 (s, 7H), 1.02 (d, J = 6.6 Hz, 3H), 0.99 (s, 3H), 0.87 (s, 9H), 0.03 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 205.5, 138.5, 135.55, 133.51, 133.71, 133.70, 129.63, 129.61, 127.64, 127.60, 127.4, 80.4, 65.5, 63.4, 41.5, 36.0, 35.9, 27.7, 27.2, 26.8, 25.9, 20.5, 19.3, 19.2, 18.3, –5.3; FT-IR (thin film) 3510, 3071, 3049, 2956, 2930, 2857, 1717, 1589, 1472, 1389, 1361, 1255, 1112, 1006, 938, 835, 775, 740, 701 cm−1; HRMS (ESI) calcd. for C35H54O4Si2Na [M+Na]+ 617.3458, found 617.3459 m/z. These spectroscopic data matched previously reported data for endo-(+)-6.5

Synthesis of exo-16

A solution of aldehyde 8b (676 mg, 1.1 mmol) in MeOH (11 mL) was cooled to 0 °C and methanolic solutions of potassium hydroxide (11.6 mL of a 0.78 M solution, 9.0 mmol) and iodine (5.8 mL of a 0.78M solution, 4.5 mmol) were added successively. The resulting dark brown mixture was stirred at 0 °C for 45 min, after which time second portions of potassium hydroxide (2.3 mL, 1.8 mmol) and iodine (1.1 mL, 0.9 mmol) solution were added successively. The starting material was completely consumed 30 min after the second addition. The reaction mixture was diluted with 2N H2SO4 and Et2O, and stirred at room temperature for 30 min. The layer was separated and the aqueous layer was extracted with Et2O (3 x). The combined layers were washed with saturated aq. Na2S2O3 and brine, dried over MgSO4, filtered and concentrated. The crude product was filtered through a short column of silica gel (50% EtOAc-hexane) to afford a mixture of exo-16 and the corresponding TBS ether.

To a solution of this mixture in 5 mL of MeOH was added PPTS (553 mg, 2.2 mmol). The reaction was stirred at room temperature for 2 h, at which point the TBS ether was fully deprotected. Water (50 mL) and diethyl ether (50 mL) were added. The layers were separated and the aqueous layer was extracted by Et2O (3 x). The combined organic layers were then washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by column chromatography (50% EtOAc-hexane) to afford exo-16 (423 mg, 75%) as a colorless oil: Rf 0.40 (50% EtOAc-hexane); [α]23 D –16.2 (c 2.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.70 (m, 4H), 7.39 (m, 6H), 5.36 (s, 1H), 4.27 (d, J=12.7 Hz, 1H), 4.09 (d, J=12.7 Hz, 1H), 3.71 (s, 3H), 3.59 (t, J=5.9 Hz, 2H), 3.54 (br, 1H), 2.64 (m, 1H), 1.98 (dd, J=14.2, 6.8 Hz, 1H), 1.78 (dd, J=14.2, 8.8 Hz, 1H), 1.56 (m, 5H), 1.06 (m, 12H), 0.93 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 177.3, 138.5, 135.5, 135.4, 133.9, 133.8, 129.6, 129.5, 128.2, 128.1, 127.6, 127.5, 78.7, 66.0, 63.7, 52.5, 52.4, 40.3, 38.3, 34.5, 29.4,27.6, 26.7, 21.5, 19.3; FT-IR (thin film) 3501, 2955, 2932, 2858, 1716, 1472, 1456, 1428, 1247, 1111, 1062, 824, 738, 702, 614 cm−1; HRMS (ESI) for C30H42O5SiNa [M+Na]+ calcd. 533.2699, found 533.2701 m/z.

Synthesis of exo-17

A solution of diol exo-16 (421.8 mg, 0.83 mmol) in acetic anhydride (6.6 mL) was cooled to 0 °C and a CH3CN solution of Sc(OTf)3 (215.4 mg, 0.44 mmol in 1.7 mL of CH3CN) was added quickly. The resulting solution was stirred at 0 °C for 40 sec, after which time saturated aq.NaHCO3 (40 mL) was added with 10 g of solid NaHCO3. The reaction mixture was stirred at room temperature for overnight, and then was diluted with ether and water. The layer was separated and the aqueous layer was extracted with ether (3 x). The combined layers were washed with saturated aq.NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The product was purified by column chromatography (25% EtOAc-hexane) to afford the 1°–3° diacetate intermediate (436 mg, 89%) as a colorless oil; 10% of a triacetate (deriving from deprotection/acylation of the primary TBDPS ether) was also observed. Data for the diacetate: Rf 0.20 (25% EtOAc-hexane); [α]23 D −48.4 ° (c 3.2, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.68 (m, 4H), 7.38 (m, 6H), 5.43 (s, 1H), 4.19 (d, J=13.2 Hz, 1H), 4.13 (d, J=13.9 Hz, 1H), 4.02 (t, J=6.6 Hz, 2H), 3.71 (s, 3H), 2.47 (m, 2H), 2.34 (m, 1H), 2.03 (s, 3H), 2.02 (s, 3H), 1.78–1.56 (m, 4H), 1.06 (s, 9H), 0.93 (d, J=7.3 Hz, 3H), 0.88 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.1, 171.0, 170.2, 138.4, 135.44, 135.41, 133.6, 133.5, 129.6, 129.5, 127.6, 127.6, 124.8, 84.4, 65.6, 65.2, 51.8, 40.1, 31.7, 31.1, 27.6, 26.7, 24.0, 23.8, 21.5, 20.9, 19.4, 19.2; FT-IR (thin film) 3071, 2959, 2934, 2892, 2858, 1739, 1472, 1463, 1429, 1368, 1113, 1072, 1030, 824, 741, 704, 610 cm−1; HRMS (ESI) calcd. for C34H46O7SiNa [M+Na]+ 617.2911, found 617.2911 m/z.

To a −78 °C solution of the above diacetate (436 mg, 0.73 mmol) in THF (7.3 mL) was added DIBAL-H (1.96 mL of a 1.5M solution in toluene, 2.9 mmol) slowly down the side of the flask. The resulting solution was stirred at −78 °C for 2 h; pH 7 buffer (10 mL) and ether (20 mL) were then added. The mixture was allowed to warm to room temperature, diluted with saturated aq. Rochelle’s salt solution, and stirred for 5 h. The layer was separated and the aqueous layer was extracted with ether (3 x). The combined layers were washed with saturated aq. NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The product was purified by column chromatography (50% EtOAc-hexane) to afford exo-17 (410 mg, 99%) as colorless oil: Rf 0.20 (50% EtOAc-hexane); [α]23 D –61.8 (c 1.0, CHCl3); the spectroscopic data for this intermediate were identical to data for the same compound previously prepared in our laboratory.5

exo-Bromotetronate, exo-19

To a solution of the α-acetoxy ester exo-18 (196 mg, 0.295 mmol) in THF (6.0 mL) was added HMPA (1.0 mL). The solution was cooled to −78 °C, and LHMDS (0.87 mL, 1.0 M in THF, 0.87 mmol) was added. The solution was stirred for 1.5 h at which point complete conversion of exo-18 to the tetronic acid was observed (TLC analysis). A solution of NBS (0.60 mL, 0.5 M in THF, 0.30 mmol) was then added dropwise to the −78 °C solution. The flask was wrapped with aluminum foil and the mixture stirred for 30 min. The reaction was quenched by addition of EtOAc and aq. 1M HCl, the solution was allowed to warm to 23 °C, the layers were separated, and the organic layer was washed with water (3 x), dried over MgSO4, filtered, and concentrated.

To a 0 °C solution of the tetronic acid in ether (3.0 mL) was added ethereal CH2N2 (~ 10 equiv); gas evolution occurred. The reaction mixture was allowed to warm to 23 °C and stirred for 30 min. A few drops of HOAc were added until the yellow color dissipated, then ether and saturated aq. NaHCO3 were added. The layers were separated, the aqueous layer was extracted with ether (2 x), and the combined organic extracts were dried over MgSO4, filtered, concentrated. Purification of the crude product by chromatography on SiO2 (20 to 30% EtOAc-hexane) provided bromotetronate exo-19 (181 mg, 86%) as an oil. Small amounts of the regioisomeric methyl tetronate were also detected (ratio = 10 : 1 favoring 19). Data for 19: Rf 0.28 (20% EtOAc-hexane); [α]27D +52.3 (c 2.7, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.71 (m, 4H), 7.40 (m, 6H), 7.69 (d, J=15.6 Hz, 1H), 5.45 (dt, J=15.4, 5.1 Hz, 1H), 5.26 (s, 1H), 4.29 (d, J=12.4 Hz, 1H), 4.21 (s, 3H), 4.20-4.10 (3H), 2.72 (m, 1H), 1.98 (dd, J=13.4, 10.2 Hz, 1H), 1.83 (dd, J=13.5, 6.6 Hz, 1H), 1.06 (15H), 0.88 (s, 9H), 0.045 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 176.9, 168.4, 140.5, 135.5, 135.4, 134.7, 133.7, 133.6, 132.0, 129.8, 129.7, 127.7, 127.6, 125.8, 88.4, 79.2, 65.2, 63.8, 59.6, 43.6, 37.6, 29.3, 26.7, 25.9, 21.7, 19.3, 18.9, 18.3, –5.0, –5.1; FT-IR (neat) 2956, 2930, 2857, 1768, 1634, 1258, 1112, 836, 703 cm−1; HRMS (ESI) calcd. for C38H53BrO5Si2Na [M+Na]+ 747.2513, found 747.2523 m/z.

exo-Spirotetronate 20

To a THF solution (2.0 mL) of exo-α-acetoxy ester 18 (79 mg, 0.12 mmol) was added HMPA (0.47 mL) and the resulting solution was cooled to −78 °C. Next a solution of LHMDS (0.68 mL, 1.0 M in THF) was added over 2 min. The solution was stirred for 2 h at which point complete conversion of 18 to the tetronic acid was observed (TLC analysis). The reaction was quenched by addition of EtOAc and aq. 1M HCl, the solution was allowed to warm to 23 °C; the layers were separated, the organic layer was washed with water (3 x), dried over MgSO4, filtered, and concentrated to give an oil.

To a 0 °C solution of the crude tetronic acid in ether (3.0 mL) was added ethereal CH2N2 (ca. 10 equiv), gas evolution occurred. The reaction mixture was allowed to warm to 23 °C and stir for 30 min. A few drops of AcOH were added until the yellow color dissipated, then ether and saturated aq. NaHCO3 were added. The layers were separated, the aqueous layer was extracted with ether (2 x), and the combined organic extracts were dried over MgSO4, filtered, concentrated, and purified by chromatography on SiO2 (15 to 30% EtOAc-hexane) to afford the spirotetronate exo-20 (40 mg pure major diastereomer, and 21 mg which was 1.7:1 mixture of major and minor tetronate methylation regioisomers for a 78% total yield) as a clear semi-solid. The ratio of the two O-methyl tetronates was approximately 7 : 1. Data for exo-20: Rf 0.35 (35% EtOAc-hexane); [α]27D +51.9 (c 0.42, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.72 (m, 4H), 7.40 (m, 6H), 5.75 (d, J=15.6 Hz, 1H), 5.45, dt, J=15.6, 5.6 Hz, 1H), 5.26 (br s, 1H), 5.05 (s, 1H), 4.32 (AB, J=12.4 Hz, 1H), 4.16 (m, 2H), 4.13 (AB, J=13.0 Hz, 1H), 3.73 (s, 3H), 2.75 (m, 1H), 2.02 (dd, J=13.2, 10.8 Hz, 1H), 1.79 (dd, J=13.2, 6.6 Hz, 1H), 1.06 (overlapping s and d, 12H), 1.01 (s, 3H), 0.88 (s, 9H), 0.049 (s, 3H), 0.047 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 185.4, 171.9, 140.7, 135.5, 133.8, 131.7, 129.7, 129.6, 127.7, 127.6, 125.9, 89.4, 87.7, 65.6, 64.0, 59.1, 43.2, 37.8, 29.7, 29.4, 26.7, 26.0, 21.7, 19.3, 18.8, −5.0; FT-IR (neat) 2956, 2930, 2856, 1760, 1627, 1361, 1112, 1057, 835, 702 cm−1; HRMS (ESI) calcd. for C38H54O5Si2Na [M+Na]+ 669.3408, found 669.3411 m/z.

exo-Enal 21

To a solution of TBS ether exo-20 (48 mg, 0.074 mmol) in MeOH (0.60 mL) and THF (0.10 mL) was added PPTS (37 mg, 0.15 mmol) in one portion. The reaction was stirred for 2 h, then the mixture was concentrated to a white precipitate. This material was purified by chromatography on SiO2 (50% EtOAc-hexane) to afford the allylic alcohol (33 mg, 83% yield) as a white foam.

The above allylic alcohol (32 mg, 0.060 mmol) was oxidized via the SO3•pyridine protocol described for the synthesis of 8b (see SI) to give the crude enal which was purified by chromatography on SiO2 (35 to 50% EtOAc-hexane) to give exo-21 (28 mg, 71%): Rf 0.38 (50% EtOAc-hexane); [α]27D +95.6 (c 2.7, CHCl3); 1H NMR (500 MHz, CDCl3) δ 9.58 (d, J=7.8 Hz, 1H), 7.69 (m, 4H), 7.40 (m, 6H), 6.97 (d, J=15.6 Hz, 1H), 6.00 (dd, J=15.5, 7.8 Hz, 1H), 5.31 (br s, 1H), 5.12 (s, 1H), 4.29 (AB, J=13.2 Hz, 1H), 4.16 (AB, J=13.2 Hz, 1H), 3.78 (s, 3H), 2.76 (m, 1H), 1.89 (overlapping dd, 2H), 1.12 (s, 3H), 1.06 (s, 9H), 1.03 (d, J=6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 193.8, 184.5, 171.1, 161.7, 142.7, 135.4, 135.3, 133.5, 133.4, 133.3, 129.8, 129.7, 127.7, 127.6, 123.2, 89.6, 86.7, 65.1, 59.4, 44.2, 38.2, 29.5, 26.7, 20.9, 19.3, 18.7; FTIR 2932, 2857, 1761, 1691, 1628, 1361, 1112, 960, 704 cm−1; HRMS (ESI) calcd. for C32H38O5SiNa [M+Na]+ 553.2386, found 553.2378 m/z.

endo-Bromotetronate 23

The brominative Dieckmann cyclization of endo-225 (177 mg) was performed using the procedure described for preparation of exo-19. This gave bromotetronate endo-23 (111 mg, 58% yield) after purification by chromatography on SiO2 (30 to 40% EtOAc-hexane): Rf 0.50 (30% EtOAc-hexane). Small amounts of the regioisomeric methyl tetronate were also detected (ratio = 10 : 1 favoring 23). Data for endo-23: [α]27D +40.4 (c 2.8, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.70 (m, 4H), 7.40 (m, 6H), 5.65 (d, J=15.4 Hz, 1H), 5.46 (dt, J=15.4, 4.4 Hz, 1H), 5.30 (br s, 1H), 4.30 (s, 3H), 4.19 (4H), 2.56 (m, 1H), 1.96 (dd, J=13.6, 10.7 Hz, 1H), 1.72 (dd, J=13.9, 6.6 Hz, 1H); 1.04 (s, 12H), 0.98 (d, J=7.3 Hz, 3H), 0.91 (s, 9H), 0.069 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 175.7, 168.4, 135.6, 135.5, 134.1, 130.5, 129.7, 129.6, 127.7, 127.6, 125.7, 88.1, 65.1, 63.5, 59.5, 44.6, 36.2, 28.7, 26.8, 25.9, 20.5, 19.3, 18.6, –5.1; FT-IR (thin film) 2955, 2930, 2857, 1768, 1635, 1601, 1111, 1011, 837, 703 cm−1; HRMS (ESI) calcd. for C38H53BrO5Si2Na [M+Na]+ 747.2513, found 747.2513 m/z.

endo-Spirotetronate 24

To a THF solution (18 mL) of endo-α-acetoxy ester 225 (0.54 g, 0.81 mmol) was added HMPA (2.8 mL) and the resulting solution was cooled to −78 °C. To this solution was then added a solution of LHMDS (0.41 g, 2.4 mmol, 1.0 M THF) over 2 min. The solution was stirred for 1.5 h at which point complete conversion to the tetronic acid was observed (TLC analysis). The reaction was quenched by addition of EtOAc and aq. 1M HCl, the solution was allowed to warm to 23 °C, the layers were separated, the organic layer was washed with water (3 x), dried over MgSO4, filtered, and concentrated to give an oil.

To a 0 °C solution of the tetronic acid in ether (10 mL) was added ethereal CH2N2 (~ 10 equiv), gas evolution occurred and the solution was allowed to warm to 23 °C. After 30 min the reaction was complete (TLC analysis). The solvent was removed under reduced pressure, and the residue was purified by chromatography on SiO2 (20 to 30% EtOAc-hexane) to afford spirotetronate endo-24 (0.36 g, 69%) as a clear semi-solid: Rf 0.31 (30% EtOAc-hexane); [α]27D +42.2 (c 1.1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.72 (m, 4H), 7.43 (m, 6H), 5.69 (dt, J=15.4, 1.7 Hz, 1H), 5.47 (dt, J=15.4, 4.9 Hz, 1H), 5.34 (app d, J=1.5 Hz, 1H), 5.08 (s, 1H), 4.20 (br s, 2H), 4.17 (dd, J=4.6, 1.7 Hz, 2H), 3.83 (s, 3H), 2.56 (m, 1H), 1.94 (dd, J=13.4, 10.7 Hz, 1H), 1.71 (dd, J=13.7, 6.1 Hz, 1H), 1.05 (s, 9H), 1.05 (s, 3 H), 0.98 (d, J=7.1 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 184.0, 171.8, 139.4, 135.5, 135.5, 134.3, 133.7, 133.6, 130.7, 129.6, 129.5, 127.7, 127.6, 125.6, 89.4, 87.1, 65.1, 65.1, 63.5, 59.2, 44.0, 36.4, 28.6, 26.7, 25.9, 20.7, 19.2, 18.6, 18.3, 18.3, –5.2, –5.2; FT-IR (neat) 3071, 3049, 2956, 2930, 2889, 2856, 1759, 1629, 1590, 1462, 1428, 1359, 1251, 1113, 836, 777, 703 cm−1; HRMS (ESI) calcd. for C38H54O5Si2Na [M+Na]+ 669.3408, found 669.3385 m/z.

endo-α-Methyl-Dienal 25

To a solution of TBS ether endo-24 (21.5 mg, 0.33 mmol) in MeOH (0.30 mL) was added PPTS (25 mg, 0.99 mmol). The reaction mixture was stirred for 2 h, then was concentrated to an oil and titrated with ether. The heterogeneous solution was filtered through Celite and washed multiple times with ether. The ether extracts were washed with saturated aq. NaHCO3 (1 x), aq.1M HCl (1 x), brine (1 x), dried over MgSO4, filtered, and concentrated. This crude material was oxidized by using the SO3•pyridine oxidation procedure described for the synthesis of 8b, giving the corresponding enal (12 mg, 68%) as a flaky white precipitate after purification by chromatography on SiO2 (50 to 60% EtOAc-hexane): Rf 0.49 (80% EtOAc-hexane); [α]27 D +114.9 (c 0.47, CHCl3); 1H NMR (500 MHz, CDCl3) δ 9.58 (d, J=7.9 Hz, 1H), 7.68 (m, 4H), 7.42 (m, 6H), 6.82 (d, J=15.6 Hz, 1H), 6.02 (dd, J=15.6, 7.5 Hz, 1H), 5.34 (s, 1H), 5.14 (s, 1H), 4.20 (app s, 2H), 3.86 (s, 3H), 2.60 (m, 1H), 1.86 (dd, J=14.2, 10.8 Hz, 1H), 1.80 (dd, J=14.2, 6.6 Hz, 1H), 1.16 (s, 3H), 1.05 (s, 9H), 0.99 (d, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 193.7, 182.8, 171.1, 160.7, 141.6, 135.4, 133.3, 133.2, 131.9, 129.7, 127.7, 122.9, 89.7, 85.6, 64.6, 59.5, 44.9, 36.5, 28.6, 26.7, 19.4, 19.2, 18.4; FT-IR (neat) 2955, 2932, 2857, 1756, 1688, 1633, 1428, 1358, 1113, 957, 705 cm−1; HRMS (ESI) calcd. for C32H38O5SiNa [M+Na]+ 553.2386, found 553.2386 m/z.

To a solution of the above enal (12 mg, 0.023 mmol) in toluene (1.00 mL) was added formylethylidenetriphenylphosphorane (7 mg, 0.023 mmol). The flask was fitted with reflux condenser and heated to ca 110 °C overnight (~16 h). Conversion was only ca 50%, so more ylide (7 mg) was added and the reaction was heated for 8 h. The conversion was not complete so more ylide (7 mg) was added, and the reaction was stirred for an additional ca. 16 h. Evaporation of the solvents and purification of the product by preparative TLC on SiO2 (80% EtOAc-hexane) gave the dienal endo-25 (8.5 mg, 62%): Rf 0.41 (80% EtOAc-hexane); [α]27 D +265 (c 0.3, CHCl3) 1H NMR (500 MHz, CDCl3) δ 9.46 (s, 1H), 7.70 (m, 4H), 7.40 (m, 6H), 6.87 (d, J=11.3 Hz, 1H), 6.45 (dd, J=15.1, 11.0 Hz, 1H), 6.23 (d, J=15.1 Hz, 1H), 5.39 (br s, 1H), 5.13 (s, 1H), 4.23 (app br s, 2H), 3.87 (s, 3H), 2.62 (m, 1H), 1.91 (dd, J=13.9, 10.7 Hz, 1H), 1.14 (s, 3H), 1.05 (s, 9H), 1.03 (d, J=7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 194.7, 183.4, 171.3, 148.0, 141.0, 137.6, 135.6, 135.5, 133.6, 133.5, 129.7, 129.7, 127.8, 127.7, 125.7, 124.6, 89.8, 86.4, 65.1, 59.4, 45.3, 36.7, 29.7, 28.8, 26.8, 20.2, 19.3, 18.8, 9.6; FT-IR (neat) 2925, 2854, 1756, 1683, 1630, 1457, 1359, 1179, 1112, 703 cm−1; HRMS (ESI) calcd. for C35H42O5SiNa [M+Na]+ 593.2699, found 593.2705 m/z.

Synthesis of Horizontal Bis-Tetronate Fragment 4 from 19 and 25

To a solution of exo-bromospirotetronate 19 (35 mg, 0.048 mmol) in THF (0.20 mL) was added cat. 1,10-phenanthroline indicator and ca. 10 mg of 4 Å molecular sieves. The mixture was stirred at 23 °C for 30 min, then was cooled to −78 °C and n-BuLi (2.5 M hex) was added until a deep red/brown color persisted. The resulting solution was stirred for 30 min, then a suspension of CeCl3 (0.78 mL, 0.68 M THF) was added dropwise. [CeCl3 was activated as follows.37, 38 To powdered CeCl3 (167 mg, 0.677 mmol) (>99+% anhydrous Aldrich) was added THF (1.00 mL) and H2O (0.002 mL, 0.11 mmol) the flask was fitted with a reflux condenser and heated to 70 °C for 2 h. After being cooled to 23 °C the suspension was stirred vigorously overnight (ca 16 h). Microscopy showed rod-shaped crystals indicative of properly activated CeCl3 as described by Conlon.38] This mixture was stirred for 1 h, then a solution of the dienal endo-25 (8 mg, 0.016 mmol) in THF (0.20 mL plus 0.10 mL wash) was added dropwise via canula. The mixture was stirred at −78 °C for 30 min, at which point TLC analysis indicated the reaction was complete. Methanol (0.2 mL) was added to the solution and after 3 min the flask was pulled from the dewer and ether and saturated aq NH4Cl were added. The mixture was stirred for 5 min, then EtOAc was added, the layers were separated, and the aqueous layer was extracted with EtOAc (1 x). The combined organic extracts were combined, dried over MgSO4, filtered, and concentrated. Purification of the crude product by chromatography on SiO2 (30 to 50% EtOAc-hexane) afforded the exo-spirotetronate 20 (18 mg), and two new spots corresponding to the two diastereomers of allylic alcohol 26: Rf 0.38, 3.7 mg, >90% pure by 1H NMR analysis, and Rf 0.30, 12.0 mg (50% EtOAc-hexane), 15.7 mg total, 92% yield.

To a solution of allylic alcohol 26 (mixture of both Rf spots from above, 5.5 mg, 0.0045 mmol) in ether (0.15 mL, 0.03 M) at 0 °C was added activated MnO2 (ca 10 mg, 25 equiv) in one portion. After 5 min, the black suspension reaction mixture was allowed to warm to 23 °C and was vigorously stirred for 2 h. This cycle was repeated two more times until TLC analysis showed complete consumption of 26. Ether (2 mL) was added and the suspension was filtered through Celite with washing of the Celite bed (4 x 2 mL). Concentration of the combined filtrate afforded ketone 4 (3.2 mg, 58%): Rf 0.41 (40% EtOAc-hexane); [α]27D +137.1 (c 0.35, CHCl3) 1H NMR δ 7.70 (m, 8H), 7.42 (m, 12H), 7.00 (d, J=10.3 Hz, 1H), 6.41 (dd, J=15.1, 11.0 Hz, 1H), 6.11 (d, J=15.2 Hz, 1H), 5.77 (app d, J=15.6 Hz, 1H), 5.48 (dt, J=15.4, 5.6 Hz, 1H), 5.40 (app br s, 1H), 5.30 (br s, 1H), 5.11 (s, 1H), 4.30 (app d, J=12.5 Hz, 1H), 4.23 (dd, J=20.0, 14.0 Hz, 2H), 4.17 (3H), 3.84 (s, 3H), 3.72 (s, 3H), 2.75 (m, 1H), 2.60 (m, 1H), 2.06 (dd, J=13.5, 11.0 Hz, 1H), 1.95 (s, 3H), 1.91 (overlapping dd, 2H), 1.76 (dd, J=13.9, 6.1 Hz, 1H), 1.15 (s, 3H), 1.14 (s, 3H), 1.05 (s, 21H), 1.02 (d, J=7.1 Hz, 3 H), 0.89 (s, 9H), 0.053 (s, 3H), 0.050 (s, 3H); 13C NMR 191.9, 183.4, 181.1, 171.6, 169.4, 148.6, 144.4, 141.0, 136.6, 135.5, 135.1, 133.7, 133.6, 133.5, 133.4, 132.1, 129.7, 127.8, 127.7, 127.6, 126.3, 125.3, 124.1, 104.3, 89.6, 65.4, 64.9, 63.8, 61.1, 59.3, 45.3, 43.7, 37.7, 36.6, 29.7, 29.5, 28.7, 26.8, 26.7, 25.9, 21.9, 20.4, 19.3, 18.8, 18.7, 11.8, −5.0; FT-IR (neat) 2956, 2929, 2856, 1757, 1630, 1456, 1361, 1112, 703; HRMS (ESI) calcd for C73H94O10Si3Na [M+Na] 1237.6053, found 1237.6053.

Vertical Bis-Tetronate Fragment 3

Bromotetronate endo-23 (30 mg) and enal exo-21 (8.0 mg) were coupled by using the procedure described for synthesis of 26. This afforded 13.4 mg of a 6 : 1 mixture (not separable) of addition product 27 and aldehyde 21. Based on 1H NMR integration of this mixture, the yield of 27 was estimated to be 65% (ca. 12 mg).

Treatment of this mixture (13.4 mg) with MnO2 according to the procedure described for synthesis of 4 provided a crude product mixture that was separated by chromatography. The mixture was first purified by conventional chromatography on SiO2, which provided 6.7 mg of pure 3. The impure fractions were purified by HPLC to give an additional 2.3 mg of 3 (total 9.0 mg, 78% yield; 50% overall from 21): Rf 0.38 (40% EtOAc-hexane); [α]27D +105.5 (c 0.4, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.70 (m, 8H), 7.40 (m, 12H), 6.97 (d, J=15.7 Hz, 1H), 6.67 (d, J=15.6 Hz, 1H), 5.65 (dt, J=15.4, 1.5 Hz, 1H), 5.47 (dt, J=15.4, 4.8 Hz, 1H), 5.31 (app br s, 2H), 5.09 (s, 1H), 4.35 (app d, J=12.7, 1H); 4.17 (5H), 4.00 (s, 3H), 2.82 (m, 1H), 2.55 (m, 1H), 1.96 (3 overlapping dd, 3H), 1.75 (dd, J=13.7, 6.4 Hz, 1H), 1.12 (s + d overlapping, 6H), 1.07 (s, 3H), 1.06 (s, 9H), 1.04 (s, 9H), 0.98 (d, J=7.4 Hz, 3H), 0.90 (s, 9H), 0.063 (s, 3H), 0.060 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 186.6, 184.7, 183.8, 171.3, 169.5, 152.5, 142.3, 139.3, 135.6, 135.5, 134.1, 133.7, 133.6, 130.6, 130.2, 129.8, 129.7, 129.6, 129.5, 127.7, 127.6, 125.7, 124.3, 104.8, 89.7, 87.1, 86.3, 65.6, 65.0, 63.6, 62.9, 59.3, 44.6, 44.0, 37.9, 36.2, 29.7, 29.4, 28.6, 26.8, 25.9, 21.0, 20.6, 19.3, 19.2, 18.7, 18.6, −5.1; FT-IR (neat) 2956, 2929, 2856, 1758, 1660, 1627, 1455, 1360, 1250, 1112, 703 cm−1; HRMS (ESI) calcd. for C70H90O10Si3Na [M+Na]+ 1197.5740, found 1197.5763 m/z.

Supplementary Material

SI. Supporting Information Available.

Experimental procedures and full spectroscopic data for all new compounds in Scheme 2. This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgments

Financial support by the National Institutes of Health (GM026782) is gratefully acknowledged. T.K.T. thanks the NIH for a Postdoctoral Fellowship (GM068298).

References

  • 1.Kusumi T, Ichikawa A, Kakisawa H, Tsunakawa M, Konishi M, Oki T. J Am Chem Soc. 1991;113:8947. [Google Scholar]
  • 2.Tsunakawa M, Tenmyo O, Tomita K, Naruse N, Kotake C, Miyaki T, Konishi M, Oki T. J Antibiot. 1992;45:180. doi: 10.7164/antibiotics.45.180. [DOI] [PubMed] [Google Scholar]
  • 3.Tanabe-Tochikura A, Nakashima H, Murakami T, Tenmyo O, Oki T, Yamamoto N. Antiviral Chem & Chemother. 1992;3:345. [Google Scholar]
  • 4.Roush WR, Barda DA. Org Lett. 2002;4:1539. doi: 10.1021/ol025771h. [DOI] [PubMed] [Google Scholar]
  • 5.Roush WR, Barda DA, Limberakis C, Kunz RK. Tetrahedron. 2002;58:6433. doi: 10.1021/ol025772+. [DOI] [PubMed] [Google Scholar]
  • 6.Roush WR, Limberakis C, Kunz RK, Barda DA. Org Lett. 2002;4:1543. doi: 10.1021/ol025772+. [DOI] [PubMed] [Google Scholar]
  • 7.Bedel O, Franxais A, Haudrechy Y. Synlett. 2005:2313. [Google Scholar]
  • 8.Takeda K, Igarashi Y, Okazaki K, Yoshii E, Yamaguchi K. J Org Chem. 1990;55:3431. [Google Scholar]
  • 9.Roush WR, Sciotti RJ. J Am Chem Soc. 1998;120:7411. [Google Scholar]
  • 10.Marshall JA, Grote J, Audia JE. J Am Chem Soc. 1987;109:1186. [Google Scholar]
  • 11.Takeda K, Yano S, Sato M, Yoshii E. J Org Chem. 1987;52:4135. [Google Scholar]
  • 12.Takeda K, Yano S-g, Yoshii E. Tetrahedron Lett. 1988;29:6951. [Google Scholar]
  • 13.Marshall JA, Xie S. J Org Chem. 1992;57:2987. [Google Scholar]
  • 14.Roush WR, Brown BB. J Am Chem Soc. 1993;115:2268. [Google Scholar]
  • 15.Roush WR, Brown BB. J Org Chem. 1993;58:2151. [Google Scholar]
  • 16.Roush WR, Brown BB. J Org Chem. 1993;115:2162. [Google Scholar]
  • 17.Takeda K, Kawanishi E, Nakamura H, Yoshii E. Tetrahedron Lett. 1991;32:4925. [Google Scholar]
  • 18.Roush WR, Reilly ML, Koyama K, Brown BB. J Org Chem. 1997;62:8708. [Google Scholar]
  • 19.Boeckman RK, Jr, Barta TE, Nelson SG. Tetrahedron Lett. 1991;32:4091. [Google Scholar]
  • 20.Boeckman RK, Jr, Wrobleski ST. J Org Chem. 1996;61:7238. doi: 10.1021/jo961585b. [DOI] [PubMed] [Google Scholar]
  • 21.Paquette LA, Boulet SL. Synthesis. 2002:888. [Google Scholar]
  • 22.Boulet SL, Paquette LA. Synthesis. 2002:895. [Google Scholar]
  • 23.Page PCB, Vahedi H, Batchelor KJ, Hindley SJ, Edgar M, Beswick P. Synlett. 2003:1022. [Google Scholar]
  • 24.Roush WR, Barda DA. J Am Chem Soc. 1997;119:7402. [Google Scholar]
  • 25.Ito Y, Hirao T, Saegusa T. J Org Chem. 1978;43:1011. [Google Scholar]
  • 26.Katsuki T, Martin VS. Org React. 1996;48:1. [Google Scholar]
  • 27.Tanaka SY, Hisashi, Nozaki Hitosi, Sharpless KB, Michaelson RC, Cutting JD. J Am Chem Soc. 1974;96:5254. doi: 10.1021/ja00823a042. [DOI] [PubMed] [Google Scholar]
  • 28.Roush WR, Brown RJ, DiMare M. J Org Chem. 1983;48:5083. [Google Scholar]
  • 29.Barton DHR, Jaszberenyi JC. Tetrahedron Lett. 1989;30:2619. [Google Scholar]
  • 30.Hartwig W. Tetrahedron. 1983;39:2609. [Google Scholar]
  • 31.Parikh JR, von Doering EW. J Am Chem Soc. 1967;89:5505. [Google Scholar]
  • 32.Qi J, Roush WR. Org Lett. 2006;8:2795. doi: 10.1021/ol0609208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Complete details for the synthesis of dienophile 13 are provided in the Supporting Information to the paper cited as ref. 32.
  • 34.Yamada S, Morizono D, Yamamoto K. Tetrahedron Lett. 1992;33:4329. [Google Scholar]
  • 35.Ishihara K, Kubota M, Kurihara H, Yamamoto H. J Am Chem Soc. 1995;117:4413. [Google Scholar]
  • 36.Takeda K, Kubo H, Koizumi T, Yoshii E. Tetrahedron Lett. 1982;23:3175. [Google Scholar]
  • 37.Imamoto T, Takiyama N, Nakamura K, Hatajima T, Kamiya Y. J Am Chem Soc. 1989;111:4392. [Google Scholar]
  • 38.Conlon DA, Kumke D, Moeder C, Hardiman M, Hutson G, Sailer L. Advanced Synthesis and Catalysis. 2004;346:1307. [Google Scholar]
  • 39.New compounds and the isolated intermediates gave satisfactory 1H and 13C NMR, IR, and HRMS data. Yields refer to chromatographically and spectroscopically homogeneous materials. Tabulations of spectroscopic data are provided in the Supporting Information.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

SI. Supporting Information Available.

Experimental procedures and full spectroscopic data for all new compounds in Scheme 2. This material is available free of charge via the Internet at http://pubs.acs.org.

RESOURCES