Studies toward the synthesis of Amaryllidaceae alkaloids from Morita-Baylis-Hillman adducts: a straightforward synthesis of functionalized dihydroisoquinolin-5(6H)-one core

ARTICLE

Studies toward the synthesis of Amaryllidaceae alkaloids from Morita-Baylis-Hillman adducts. A straightforward synthesis of functionalized dihydroisoquinolin-5(6H)-one core

Elizandra C.S. Lopes; Fernando Coelho^*

Instituto de Química, Universidade Estadual de Campinas, CP 6154, 13083-970 Campinas-SP, Brazil

ABSTRACT

We disclose herein our results concerning a study aiming at the synthesis of the highly substituted carbon skeleton of alkaloids isolated from plants of the Amaryllidaceae family. The total synthesis of the functionalized dihydroisoquinolin-5(6H)-one core, which is the bottom part of the structure of alkaloids isolated from this botanic family, is described, using Morita-Baylis-Hillman adducts as substrate. This compound should be a useful and valuable intermediate for the total synthesis of alkaloids isolated from Amaryllidaceae.

Keywords: Morita-Baylis-Hillman adducts, Amaryllidaceae, dihydroisoquinolinones

RESUMO

Descrevemos neste trabalho, os resultados de um estudo que teve como objetivo a síntese de esqueletos de carbono altamente funcionalizados de alcalóides de plantas da família das Amaryllidaceae. A partir de adutos de Morita-Baylis-Hillman, descrevemos a síntese total do núcleo diidroisoquinolin-5(6H)-ona funcionalizado, que é a parte inferior da estrutura de vários alcalóides dessa classe. Essa substância pode ser um intermediário útil e valioso para a síntese total dos alcalóides isolados de plantas da família Amaryllidaceae.

Introduction

Plants from the Amaryllidaceae family are spread all over the world and due to its pharmacological relevance some representatives of this botanic family are known by humans since antiquity.¹

Among the chemical constituents present in these plants, the alkaloids are the most important and, normally, they are responsible for the biological activities exhibited. As a matter of fact, the biological importance of the plants from this family led to an intense phytochemical research activity, which culminated with the isolation and chemical characterization of several structurally different classes of alkaloids.²

Galanthamine (1),³ pancratistatin (2),⁴ narciclasine (3),⁵ hippadine (4),⁶ anhydrolycorinone (5),^6,7 and plicamine (6)⁸ are examples that clearly show the structurally rich diversity of these alkaloids (Figure 1). Besides structural complexity, these alkaloids exhibit different biological activities. Galantamine (1), for example, is a specific, competitive and reversible acetyl cholinesterase inhibitor, being used in the clinical treatment of Alzheimer disease.³ Pancratistatin (2), narciclasine (3), hippadine (4) and anhydrolycorinone (5) exhibit antiproliferative activity.^9,10

The highly sophisticated substitution pattern of the carbon skeleton of these alkaloids, associated with their relevant biological and pharmacological significance, induced the interest of synthetic organic chemists in establishing strategies aiming at their total syntheses, in both racemic and asymmetric versions.The results of these efforts can be easily measured by the countless reports available in the literature describing successful syntheses of several types of alkaloids isolated from Amaryllidaceae.¹¹

Particularly, the alkaloids which are structurally related to pantacristatin (2) were synthesized successfully by using the strategy of joining the two suitably substituted fragments, in a convergent way, as shown in the Scheme 1.

This coupling generates two new bonds (10b and 4a, see numeration in Scheme 1), and introduces functional groups at the proper places for the formation of ring B.

Despite its elegance and efficiency, this synthetic strategy suffers from several drawbacks: occurrence of atropoisomers after the formation of the C10 bond renders completion of the synthesis troublesome;¹² difficulties in carrying out a systematic study on the structure-activity relationships since the coupling fragments provide advanced intermediates of a great resemblance with the target alkaloid itself.

In an ongoing research program directed to the utilization of Morita-Baylis-Hillman adducts (MBH) as versatile starting materials for the synthesis of different classes of natural and non-natural products¹³ we envisaged developing an alternative strategy to prepare alkaloids from Amaryllidaceae, mostly those structurally related to plicamine (6).^14,15 Our interest was focused on the establishment of a linear synthetic strategy that should fulfill two basic requirements. Firstly, it should use a simple set of reactions and a readily available starting material, in order to be easily scaled up. Secondly, the alkaloid carbon skeleton should be constructed step by step, thus permitting us to carry out, in a subsequent phase, a structure-activity relationship study of some synthetic intermediates.

From our point of view, the carbon skeleton of the alkaloids in which we were particularly interested (e.g., plicamine (6) and derivatives), should be prepared by a schematic sequence as shown in Scheme 2.

The synthesis of alkaloid skeletons could be accomplished from an intermediate such as 10, which could be used in the preparation of the skeleton of plicamine (6) through a spiroannelation protocol as previously described by Martin et al.¹⁵ and Kane et al.¹⁶ for the synthesis of alkaloids structurally related to it. The synthesis of dihydroisoquinolin-5(6H)-one derivative 11 could be secured from the carbamate 12, which in turn should be prepared from Morita-Baylis-Hillman adducts.

As part of a study directed towards to the total synthesis of alkaloids from Amaryllidaceae, we describe herein a straightforward total synthesis of the racemic dihydroisoquinolone 11, which we consider an important advanced intermediate in our approach towards the preparation of Amaryllidaceae alkaloids.

Results and Discussion

We started our sequence with the Morita-Baylis-Hillman reaction^17,18 between piperonal and methyl acrylate, in the presence of ultrasound,¹⁹ which gave the adducts 13, in 73% yield. In the next step of our sequence, the methyl ester group of 13 was chemoselectively reduced. Searching to shorten the synthetic sequence and avoid unnecessary protective steps, we first attempted to run this reduction directly on MBH adducts using DIBAL-H. However the diol 14 was afforded in only 40% yield. This low yield was promptly overcome by protecting the secondary hydroxyl group as a silyl ether (tertbutyldimethylsilyl, TBS) ether 15. Subsequent reduction of 15 with DIBAL-H provided the allyl derivative 16, in an overall yield of 86 % (for two steps) (Scheme 3).

The preparation of the lactam ring present in alkaloid structures could be readily secured by an intramolecular acylation reaction using a carbamate like 12 as acylating agent (see Scheme 2). This carbamate was readily prepared from 16 following the sequence shown in Schemes 4 and 5.

The synthesis of keto-amide 10 (see Scheme 2) requires the selective removal of the protecting group from the secondary hydroxyl group. At this stage of the work, it was important to differentiate the protecting group of the secondary hydroxyl group from that used to protecting the primary hydroxyl group. Thus, allyl diol 16 was treated with triisopropylsilyl triflate in the presence of CH₂Cl₂/DMAP to give the silyl ether 17 in 92% yield. Subsequent hydroboration of the double bond of 17 with 9-BBN gave alcohols 18a/b in 76% yield, as a mixture of diastereoisomers, in which the syn is the major one (18a, Scheme 4).¹³ The unprotected hydroxyl of the diastereoisomeric mixture was oxidized to the carboxylic acid 20 in two steps. All attempts to oxidize the alcohol 18a/b directly to the corresponding acid 20a/b failed.¹³We observed an extensive degradation of 18a/b under several different experimental conditions. Thus the alcohols 18a/b were treated with TPAP in the presence of NMO to furnish the corresponding aldehyde 19a/b, in 96% yield.²⁰ Oxidation of the aldehydes with sodium chlorite provided the acid 20a/b, in 90% yield (Scheme 4).^13,21 After chromatographic purification the minor diastereoisomer (20b) was no longer detected.

Acid 20a was then submitted to a Curtius rearrangement in order to incorporate the nitrogen atom of the lactam unit present in the skeleton of the Amaryllidaceae alkaloids.²² The rearrangement was carried out in a one pot sequence to furnish the carbamate 24. Treatment of 20a successively with ethyl chloroformate and sodium azide gave the acylazide intermediate 22, which was rearranged to the corresponding isocyanate 23 (not isolated) by refluxing in toluene. After evaporation of the toluene, 23 was treated with methanol to furnish the carbamate 24, with an overall yield of 65% from the acid 20a (4 steps) (Scheme 5).²³

With the carbamate 24 in our hands, we promoted the internal acylation. To drive this reaction in the direction of the protected dihydroisoquinolin-5(6H)-one (11), carbamate 24 was treated under several different Bischler-Napieralski experimental protocols (triflic anhydride in the presence of DMAP,²⁴ POCl₃/py, toluene;²⁵ P₂O₅/POCl₃,²⁵ etc.). However we were unable to detect the formation of compound 11 (Scheme 5).

In all trials we observed either the degradation of the starting materials or its almost total recuperation. The degradation could be related to the lability of the silyl group in the Bischler-Napieralski protocols. During the synthesis of some Licoridine derivatives, McNulty and Mo²⁶ have already described the unsucessfull cyclization of some methoxycarbamates, using Banwell´s method,²⁵ when a secondary hydroxyl group was protected as a TBS ether. To circumvent this problem, we changed our synthetic strategy. Instead of a silyl ether, the secondary hydroxyl of the Morita-Baylis-Hillman adduct 13 was now protected as a PMB ether (25) and a more acid-resistant silyl protecting group was chosen to protect the primary hydroxyl group. Using the same reaction sequence described above, PMB-ether 25 was transformed into the carbamate 31. When we tried to perform the Bischler-Napieralski reaction with 31 we were able to isolate either the oxazolidin-2-one 32 or isoquinolol 33, in 30 and 37% yields, respectively. Compound 33 was afforded after removal of the silylated protecting group presents on primary hydroxyl group. No trace of the required isoquinolinone 11 was detected in either reaction (Scheme 6).

During development of the asymmetric total synthesis of (+)-pantacristatin, Trost and Pulley²⁷ found similar problems when they tried to prepare the isoquinolinone ring of the alkaloid. To solve this problem, bromine was incorporated into the aromatic ring and this was then used as substrate for a halogen-lithium exchange. The aryl lithium compound generated in situ participated in an intramolecular nucleophilic attack on the isocyanate to furnish the required isoquinolinone ring in a good yield (Figure 2).

This simple idea inspired us and we again started our sequence, now using a brominated derivative of piperonal as starting material. The Morita-Baylis-Hillman reaction between 6-bromopiperonal and methyl acrylate in the presence of ultrasound and a catalytic quantity of an ionic liquid (1-methyl methylimidazolium, [bmin]PF₆) furnished 34 in 80% yield, as the sole product.^28,29 At this stage of the work and having the results of the sequence with piperonal in mind, we decided to prepare some derivatives in which the difference among them was only concerning the groups used for protecting the primary and secondary hydroxyl groups. Our interest in doing this was to evaluate which combination of protecting groups would be the most adequate for the cyclization step. Adduct 34 was then treated with TBSOTf or TIPSOTf to give the corresponding silyl ethers 35 and 36, in 98 and 87% yields, respectively. Both silylated compounds were reduced with DIBAL-H, at -78 ºC to provide the mono-silylated alcohols 37 and 38 in excellent chemical yields (97 and 95%, respectively). Compounds 37 and 38 were both submitted to another protecting step. Compound 37 was treated with TBDPSCl and imidazole to give 39 in 93% yield. Two different protecting groups were introduced in the primary hydroxyl group of 38. First, 38 was allowed to react with PMB trichloroimidate in dichloromethane to furnish compound 40, in 98% yield. The compound 38 was also treated with TBDPSCl and imidazole to give the compound 41, in 93% yield. Hydroboration reactions of compounds 39, 40 and 41 gave the alcohols 42, 43 and 44, in 82, 76 and 77% yields, respectively. These alcohols were used as substrates for the oxidation steps. First, alcohols 42-44 were reacted with TPAP to give the aldehydes 45, 46 and 47 in 98, 85 and 95% yields, respectively. Finally, the aldehydes 4547 were oxidized according to Pinnick conditions²¹ to give acids 48, 49 and 50, in 92, 80 and 85% yields (Scheme 7).

The acids 48-50 were easily prepared in six steps with overall yields of 66, 42 and 54%, respectively. Following our sequence the three acids were submitted to the Curtius rearrangement. To our delight, the treatment of the isocyanate intermediates with t-BuLi in diethyl ether gave the required dihydroisoquinolinone 11, in good overall yield (Scheme 8).

A careful spectroscopic analysis of the data recorded for 11 confirmed the proposed structure of this intermediate. At this stage , we have accomplished the syntheses of the isoquinolinone skeleton (51-53) in 8 steps with overall yields of 25, 20 and 16% from the Morita-Baylis-Hillman adduct 34.The next step of our sequence would be N-alkylation to provide the required bottom part of the plicamine skeleton. To carry out this alkylation reaction, the alkylating agent need to be prepared from commercial 4-hydroxy-phenyl acetic acid (54). Thus, acid 54 was first transformed to the corresponding ethyl ester 55, followed by protection of the phenolic hydroxyl group with TIPSOTf or methyl iodide to furnish the silylated ester 56 or the methoxy derivative 57. Reduction of ester furnished the homobenzylic alcohols 58 and 59, which were converted to the aryl bromides 60 and 61, in 4 steps with an overall yield of 77% (Scheme 9).

All spectroscopic data of 60 and 61 are compatible with the proposed structures. Isoquinolinone 51 was then treated with NaH at room temperature, followed by the addition of the bromide 60. To our surprise, no N-alkylated product was detected in the reaction medium, even after 24 h. After isolation, the only recovered product was the starting material 51. To solve this problem, we tried different experimental conditions; unfortunately, no N-alkylated product was detected.

Trying to surmount this problem, we changed the alkylating agent. Instead of aryl bromide an aryl iodide was used,³⁰ however no N-alkylation product was detected even when a more efficient alkylating agent was employed.

During the development of this work, Ley and coworkers¹⁴ described the first asymmetric total synthesis of plicamine (6). These authors also had the same problem for alkylating the nitrogen atom of the isoquinolinone ring. This problem was solved by reducing the isoquinolinone to the corresponding tetrahydroquinoline, which was now sucessfully alkylated in good yield. Most probably, the electron pair of this nitrogen is in resonance with the carbonyl group and with the aromatic ring, which compromise its nucleophilicity. This is confirmed by the fact that when the carbonyl group was removed the N-alkylation reaction worked very well.

Owing to this problem in the last step of our sequence, we decided to consider a synthetic alternative to prepare the required advanced intermediate 11. From our point of view, the N-alkylation step could be carried out in the middle of the sequence and the cyclization step could then be effected as the last step, with an already N-alkylated intermediate. To do this it was necessary to have a modification during the Curtius rearrangement in order to produce an amine instead of a carbamate.

Acid 48 was again submitted to Curtius rearrangement conditions, however now the isocyanate intermediate was allowed to react with NaOH in THF to produce the required amine 62, as depicted in Scheme 10, with an overall yield of 62%.

Before starting the N-alkylation reaction with amine 62, we altered the structure of the alkylating agent in order to have good selectivity when the removal of the protecting group was necessary (see Scheme 9). Then, ester 55 was treated with MeI in acetone to furnish the O-methoxy ethyl ester 57, which was reduced with DIBAL-H to give alcohol 59. Bromide 61 was prepared from alcohol 59 by treatment with CBr₄/PPh₃, in 3 steps from ester 55, in 84% overall yield.

Then amine 62 was allowed to react with Na₂CO₃ in acetonitrile under reflux, followed by the addition of the bromide 61 to smoothly provide the N-alkylated product 63, in 85% yield. The secondary amine 63 was then treated with methyl chloroformate to give carbamate 64, in 90% yield. Finally, the treatment of 64 with t-BuLi in THF at –78 ºC afforded the N-alkylated isoquinolinone 65, in 60% yield (Scheme 11).

Based on this modification, isoquinolinone 65 was prepared in 10 steps with an overall yield of 19%. To achieve our target, the TBS protecting group should be removed. To our surprise, selective removal of this group was revealed to be particularly troublesome, independent of the experimental conditions employed. Trying to finding the best way to selectively removed one of the silylated groups, we have carried out some experiments with different conditions, using as substrate some isoquinolinones prepared during the development of our synthetic study (51-53, see Scheme 8). The results achieved are summarized in Table 1.

For most of the cases, no selectivity was observed. For one case, the protecting group of the primary hydroxyl was surprisingly removed faster than that attached on the secondary hydroxyl (entry 1). Under three different experimental conditions it was possible to selectively removed the secondary protecting group, as required, however in two of them the yields are really low (entries 4 and 8), in the third case an elimination reaction occurred (entry 5). Degradation of starting material as well as its recovery was also observed under some experimental conditions (entries 2, 6 and 9, respectively)

These results obliged us to change our initial sequence and to add an unexpected step. Thus, isoquinolinone 65 was treated with TBAF in anhydrous THF at room temperature to provide diol 70, in 75% yield. Now, the primary hydroxyl group of diol 70 was selectivity protected to give 71, in 80% yield, as the sole detectable product (Scheme 12).

The structure of isoquinolinone 70 sucessfully incorporates all the groups needed to accomplish the preparation of the skeleton of Amaryllidaceae alkaloids. The highly functionalized isoquinolinone 70 was synthesized in 9 steps with an overall yield of 11% from Morita-Baylis-Hillman adduct 34.

In summary, this strategy has permitted us to prepare an advanced intermediate which could be used in a racemic or asymmetric total synthesis of Amaryllidaceae alkaloids. The structure of isoquinolinone 70 exhibits all substituents that are found on the bottom part of the structure of alkaloid plicamine (6). Studies to accomplish the total synthesis of an Amaryllidaceae alkaloid through this strategy are ongoing in our laboratory and will be disclosed in due time.

Experimental

The ¹H and ¹³C spectra were recorded on a Varian GEMINI BB-300 at 300 MHz and 75.4 MHz, respectively, or on an Inova instrument at 500 MHz and 125 MHz, respectively. The mass spectra were recorded using a HP 5988A GC/MS with a High Resolution Autospec-Micromass/EBE. IR were obtained with a Nicolet model Impact 410. Melting points were measured in open capillary tubes using an Electrothermal model 9100 apparatus, and are uncorrected. Yields were determined from GC analyses on a HP6890 equipment with a flame ionization detector, using a HP-5 capillary (crosslinked 5% phenylmetylsiloxane, 28 m) column. Manipulations and reactions were not performed under dry atmospheres or employing dry solvents, unless otherwise specified. Purification and separations by column chromatography were performed on silica gel, using normal or flash chromatography. TLC visualization was achieved by spraying with 5% ethanolic phosphomolybdic acid and heating. All Baylis-Hillman reactions were sonicated in an ultrasonic cleaner, UNIQUE model GA 1000 (1000 W, 25 kHz). Aromatic aldehydes were purchased from Aldrich, Acros or Lancaster and were used without previous purification

General procedure for the preparation of Morita-Baylis-Hillman adducts

A mixture of aromatic aldehyde (3 g, 18-20 mmol), methyl acrylate (14-20 mmol) and DABCO (11-13 mmol) in methanol, dichloromethane or acetonitrile (2 cm³ mmol^-1, indicated for each aldehyde), was sonicated for 16-96 hours. The ultrasound bath temperature was constantly monitored and kept at 30-45 ºC during the reaction, through ice addition or by using a refrigerated recirculator. After the reaction time, the mixture was diluted with dichloromethane (50 mL). The organic solution was washed with 10% aqueous HCl (2 × 20 mL), concentrated under reduced pressure and dried over MgSO₄. After filtration and solvent removal, the residue was filtered through a pad of silica gel (eluent indicated for each adduct).

(±)-Methyl 2-[1,3-benzodioxol-5-yl(hydroxy)methyl] acrylate (13)

Reaction time: 96 h, methanol solvent; 73% of a white solid (yield based on recovered aldehyde), purified by silica gel column chromatography (eluting with hexane/ethyl acetate 75:25); mp 40-41 ºC; IR n_max/cm^-1: 3492, 3119, 1706, 1620; ¹H NMR (500MHz, CDCl₃): d 2.87 (bs, 1H, OH), 3.78 (s, 3H), 5.45 (s, 1H), 5.82 (s, 1H), 5.87 (s, 2H, OCH₂O), 6.3 (s, 1H), 6.77 (d, J 8.0 Hz, 1H), 6.84 (ddd, J 8.0 Hz, J 1.8Hz, J 0.5 Hz, 1H), 6.87 (dd, J 1.9 Hz and J 0.5 Hz, 1H), ¹³C NMR (125MHz, CDCl₃) d 51.9, 72.9, 101, 107.1, 108.1, 120.1, 125.9, 135.2, 141.9, 147.2, 147.7, 166.7. MS (70 eV, m/e, %) 236 (M+, 84), 204 (30), 176 (27), 151 (40), 149 (100), 93 (55), 65 (44); HRMS (EI, 70 eV) calc. for C₁₂H₁₂O₅ [M⁺] 236.0684. Found: 236.0679. Anal. Calc. for C₁₂H₁₂O₅: C, 61.01; H, 5.12%. Found: C, 60.81; H, 4.93%.

(±)-Methyl 2-[(6-bromo-1,3-benzodioxol-5-yl)(hydroxy) methyl]acrylate (34)

Reaction time: 96 h methanol solvent; a catalytic amount (0.03 mL) of 1-methyl-3-butylimidazolium hexafluorophosphate [(bmim)PF₆] was used in this reaction; 80% yield of a white solid, purified by silica gel column chromatography, eluting with hexane/ethyl acetate, (75:25); mp 101-102 ºC; IR n_max/cm^-1: 3483, 2954, 2920, 2854, 1720, 1631, 1477, 1261, 1234, 1038; ¹H NMR (500 MHz, CDCl₃): d 2.87 (bs, 1H, OH), 3.80 (s, 3H) 5.62 (s, 1H), 5.82 (s, 1H), 6.01 (s, 2H, OCH₂O), 6.26 (s, 1H), 7.0 (s, 1H aromatic), 7.02 (s, 1H aromatic). ¹³C NMR (125 MHz, CDCl₃) d 52.1, 71.4, 101.8, 108.2, 112.6, 113.6, 126.8, 133.1, 140.6, 147.6, 147.9, 166.9. MS (70eV, m/z, %) 315(M+2, 17), 313 (M+, 15), 235 (87), 203 (43), 175 (24), 149 (100), 122 (81), 113 (66), 63 (60); HRMS (EI, 70 eV) Calc. for C₁₂H₁₁BrO₅ [M⁺] 313.9790. Found: 313.9771.

(±) Methyl 3-(tert-butyldimethyl-silanyloxy)-3-(1,3-benzodioxol-5-yl)2-methyl propanoate (15)

To a solution of 13 (0.5g, 2.12 mmol) in 15 mL of anhydrous dichloromethane was added successively, at room temperature and under an atmosphere of argon, anhydrous triethylamine (0.6 mL, 4.24 mmol) and tertbutyldimethylsilyl triflate (0.52 mL, 2.75 mmol). The resulting mixture was stirred for 1 h at room temperature. Then, the reaction was diluted with dichloromethane and the organic layer was washed with a saturated solution of NaHCO₃ (2 × 50 mL) and brine (2 × 50 mL). After separation, the organic phase was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash silica-gel colum chromatography, using as eluent a mixture of hexane/ethyl acetate 2%, to furnish 0.71 g of silyl ether 15 as a colorless oil in 96% yield.

IR n_max/cm^-1: 2954, 1723, 1631, 1488, 1443, 1247, 1079; ¹H NMR (500 MHz, CDCl₃): d –0.08 (s, 3H), 0.06 (s, 3H), 0.88 (s, 9H), 3.70 (s, 3H), 5.52 (s, 1H), 5.96 (d, J 1.5 Hz, 2H, OCH₂O), 6.06 (bs, 1H), 6.23 (bs, 1H), 6.7-6.85 (m, 3H aromatics); ¹³C NMR (125 MHz, CDCl₃): d –5.1, –4.9, 18.1, 25.7, 51.6, 72.3, 100.9, 107.4, 107.7, 120.6, 123.5, 136.6, 143.9, 146.7, 147.3, 166.3; HRMS (EI, 70eV) m/z Calc. for C₁₈H₂₆O₅Si [M⁺]: 350.1550. Found: 293.0845 [M⁺ -t-butyl].

(±)-2-[ 1,3-Benzodioxol-5-yl(tert-butyldimetylsilyloxy) methyl]prop-2-en-1-ol (16)

To a solution of silyl ether 15 (0.35 g, 1 mmol) in anhydrous dichloromethane, at –78 ºC and under an atmosphere of argon, was added of solution 1.0 mol L^-1 of DIBAL-H (2.4 mL, 2.4 mmol) The reaction mixture was stirred for 2 h at –78 ºC. After this time, a saturated solution of sodium acetate was added and the reaction mixture was dropped into a mixture of ethyl ether (50 mL) and a saturated solution of NH₄Cl (4.6 mL). The resulting two phase system was stirred for 1 h, which led to formation of a gel that was filtered over a pad of Celite®. The solid was washed with ethyl ether (5 × 15 mL) and the organic phases were combined, dried over MgSO₄ and removed under reduced pressure. The residue was purified by flash silica gel column chromatography to afford alcohol 16, as a colorless viscous oil, in 98% yield.

IR n_max/cm^-1: 3389, 2955, 2929, 1655, 1487, 1441, 1248, 1041; ¹H NMR (300 MHz, CDCl₃): d –0.07 (s, 3H), 0.09 (s, 3H), 0.93 (s, 9H, t-butyl), 1.86 (bs, 1H, OH), 3.85 (d, J 13.5 Hz, 1H), 4.02 (d, J 13.5 Hz, 1H), 5.05 (s, 1H), 5.11 (s, 1H), 5.15 (s, 1H), 5.95 (s, 2H, OCH₂O), 6.7-6.8 (m, 3H aromatics); ¹³C NMR (75 MHz, CDCl₃): d –4.8, 0.2, 18.5, 26.0, 63.4, 77.3, 101.2, 106.9, 108.1, 112.0, 119.6, 136.9, 147.0, 147.8, 150.7. HRMS (EI, 70eV) m/z: Calc. for C₁₇H₂₆O₄Si [M⁺]: 322.1600. Found: 265.0896 [M⁺ -t-butyl].

(±)-5-[1-Tert-butyl-dimethyl-silanyloxy)-2-triisopropylsilanyloxymethyl-allyl]-benzo[1,3]dioxol (17)

To a solution of silyl ether 16 (0.68 g, 2.12 mmol) in 15 mL of dry dichloromethane, under an atmosphere of argon, was added anhydrous triethylamine (0.6 mL, 4.24 mmol), followed by triisopropylsilyl triflate (0.74 mL,

2.75 mmol). The resulting mixture was stirred for 1 h at room temperature. Then the reaction was diluted with dichloromethane (25 mL) and the organic phase was washed with a saturated solution of (2 × 50 mL) and brine (2 x 50 mL). The organic phase was then dried over anydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash silica-gel column chromatography (eluent: hexane/ethyl acetate 2%) to give 17 as colorless viscous oil in 92% yield.

IR n_max/cm^-1: 2948, 2865, 1650, 1487, 1246, 1068, 881. ¹H NMR (500 MHz, CDCl₃): d –0.03 (s, 3H), 0.06 (s, 3H), 0.86 (s, 9H, t-butyl), 1.05 (m, 21H, 3 x isopropyl), 4.0 (d, J 14.2Hz, 1H), 4.17 (d, J 14.2Hz, 1H), 5.19 (s, 1H, CH), 5.2 (bs, 2H), 5.93 (d, ²J 1.5Hz, 2H), 6.72-6.85 (3H, m, aromatics). ¹³C NMR (125 MHz, CDCl₃): d –5.0; –0.02; 11.9, 18.0, 18.3, 25.8, 62.6, 75.5, 100.8, 106.8, 107.6, 108.8, 119.5, 137.3, 146.5, 147.4, 151.0. MS (EI, 70eV) m/z: 478 (M⁺), 435, 304, 265, 203, 173, 115, 73. HRMS (IE, 70eV) m/z Calc. for C₂₆H₄₆O₄Si₂ [M]⁺: 478.2935. Found: 478.2970.

(±)-3-Benzo[1,3]dioxol-5-yl-3-(tert-butyldimethylsilanyloxy)-2-triisopropyl-silanyloxymethyl-1-propanol (18a/18b)

To a solution of compound 17 (0.20 g, 0.42 mmol) in 4 mL of dry tetrahydrofuran, at 0 ºC, was added a solution of 9-BBN in THF (0.5 mol L^-1) (6 mL, 3 mmol). The resulting mixture was stirred for 16 h, at room temperature. After that, the mixture was cooled to 0 ºC followed by the slow addition of NaOH solution (5.0 mL, 3 mol L^-1) and 30% H₂O₂ (5.0 mL). The mixture was stirred for 45 min, at room temperature. Then, a saturated solution of NaHCO₃ (5.0 mL) was added. The final mixture was poured into a separatory funnel filled with dichloromethane (50 mL). The phases were separated, and the organic one was successively washed with a saturated solution of NaHCO₃ (10 mL), distilled water (10 mL) and brine (10 mL). Finally, the organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica-gel column chromatography (using as eluting mixture hexane/ ethyl acetate 5%) to give alcohols 18a/b as a mixture of diastereoisomers in 75% yield.

IR n_max/cm^-1: 3407, 2927, 2864, 1487, 1246, 1059. ¹H NMR (300 MHz, CDCl₃) Major diastereoisomer (±)-18a: d –0.17 (s, 3H), 0.07 (s, 3H), 0.87 (s, 9H, t-butyl), 1.01-1.10 (m, 21H, 3 x isopropyl group), 1.78-1.88 (m, 1H, CH), 3.64 (dd, J 10 Hz, J 6.2 Hz, 1H_a, CH₂), 3.68 (dd, J 10 Hz, J 5.9 Hz, 1H_b, CH₂), 3.76-3.90 (m, 2H, CH₂), 4.90 (d, J 5.9 Hz, 1H, CH), 5.92 (d, J 1.5 Hz, 1H_a, CH₂), 5.96 (d, J 1.5 Hz, 1H_b, CH₂), 6.74-6.84 (m, 3H aromatics). Minor diastereoisomer (±)-18b: d –0.19 (s, 3H), 0.03 (s, 3H), 0.87 (s, 9H, t-butyl), 1.01-1.10 (m, 21H, 3 × isopropyl group), 2.13-2.20 (m, 1H, CH), 3.57 (dd, J 10.2 Hz, J 4.7 Hz, 1H_a, CH₂,), 3.6 (dd, J 10.2 Hz, J 4.0 Hz, 1H_b, CH₂), 3.76-3.90 (m, 2H, CH₂), 4.72 (d, J 6.6 Hz, 1H, CH), 5.94 (d, J 1.4 Hz, 1H_a, CH₂), 5.95 (d, J 1.4 Hz, 1H_b, CH₂), 6.74-6.84 (m, 3H aromatics). ¹³C NMR (75 MHz, CDCl₃) Major diastereoisomer (±)-18a: d –5.1, –4.5, 12.0 18, 18.1, 25.3, 51, 63, 63.8, 74.8, 100.8, 106.7, 107.7, 119.6, 137.5, 146.5, 147.4. Minor diastereoisomer (±)-18b: d –5.1, –4.4, 11.9, 18, 18.1, 24.8, 50.3, 63.4, 64.1, 74.2, 100.9, 107, 107.7, 119.9, 136.3, 146.5, 147.4.

(±)-3-Benzo[1,3]dioxol-5-yl-3-(tert-butyl-dimethylsilanyloxy)-2-triisopropyl-silanyloxymethylpropionaldehyde (19)

To a mixture of diastereoisomeric alcohols 18a/b (0.17g, 0.5 mmol), N-methylmorpholine oxide (NMO) (0.068g, 0.75 mmol), ammonium tetrapropylperruthenate (TPAP) (0.011g, 10 mmol %, 0.03 mmol), molecular sieves 4Å (500 mg per mmol of substrate, freshly activated and triturated) was added 4.0 mL of dry dichloromethane. The heterogeneous mixture was stirred, at room temperature, for 30 min. After that, the mixture was filtered over a column filled with silica gel (230400 mesh), which was washed with dichloromethane. The filtrates were combined and the solvent was removed under reduced pressure to give aldehyde 19a/b as a mixture of diastereoisomers in 85% yield. No additional purification was necessary and the product was used directly in the next step.

IR n_max/cm^-1: 2943, 2866, 1726, 1504, 1488, 1247. ¹H NMR (300 MHz, CDCl₃): d –0.17 (s, 3H, CH₃), 0.06 (s, 3H, CH₃), 0.86 (s, 9H, t-butyl), 0.98-1.05 (m, 21H, 3 ×isopropyl), 2.55 (m, 1H), 3.83 (dd, J 10.2 Hz, J 5.1 Hz, 1H), 3.87 (dd, J 10.2 Hz, J 5.1 Hz, 1H), 5.2 (d, J 6.9 Hz, 1H, CH), 5.98 (s, 2H, OCH₂O), 6.7-6.8 (m, 3H, aromatics), 9.8 (d, J 2.9 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃): d –5.1, –4.3, 12, 17.7, 18, 25.8, 61, 62.7, 72.1, 101, 106.8, 107.8, 119.9, 136.4, 146.9, 147.6, 204. MS (EI, 70eV) m/z: 494 (M⁺), 437, 265, 145, 73. HRMS (EI, 70eV) m/z Calc. for C₂₆H₄₆O₅Si₂ [M⁺ -t-butyl]: 437.2174. Found: 437.2249.

(±)-3-(Benzo[1,3]dioxol-5-yl-3-(tert-butyl-dimethylsilanyloxy)-2-triisopropylsilanyloxymethyl-propanoic acid (20)

To a mixture of aldehyde 19a/b (0.26 g, 0.52 mmol), 4.3 mL of t-butanol and 2-methyl-but-2-ene (48.4 equiv.; 25.42 mmol), cooled to 0 ºC, was added a solution of NaClO₂ (0.44 g, 9.2 equiv., 2.42 mmol) and NaH₂PO₄ (0.44 g, 6.9 equiv., 1.82 mmol) in 1.5 mL of distilled water. The resulting heterogeneous mixture was stirred for 5 h at room temperature. Then the reaction mixture was concentrated under reduced pressure, the residue was diluted with distilled water (30 mL), which was acidified to pH 3 (using a 10% HCl solution). The aqueous phase was extracted with ethyl ether (3 × 20 mL) and after separation, the organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 8%) to provide the enriched acid 20a (syn) as a yellow viscous oil in 87% yield.

IR n_max/cm^-1: 3448, 2933, 2864, 1704, 1490, 1248. ¹H NMR (300 MHz, CDCl₃): d –0.15 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H, t-butyl), –1.0-1.09 (m, 21H, 3 × isopropyl), 2.86 (m, 1H), 3.73 (dd, J 10.2 Hz, J 5.1 Hz, 1H), 3.75 (dd, J 10.2 Hz, J 5.1 Hz, 1H), 5.0 (d, J 6.6 Hz, 1H), 5.96 (d, J 1.5 Hz, OCH₂O), 6.75-6.84 (m, 3H, aromatics.). ¹³C NMR (75 MHz, CDCl₃): d –5.3, –4.5, 11.9, 17.6, 18, 25.7, 57.3, 61.6, 72.7, 101, 106.7, 107.9, 119.9, 135.6, 147.1, 147,6, 173.9. HRMS (EI, 70 eV) m/z Calc. for C₂₆H₄₆O₆Si₂ [M⁺ t-butyl]: 453.2123. Found: 453.2279.

(±)-[2-Benzo[1,3]dioxol-5-yl-2-(tert-butyl-dimethylsilanyloxy)-1-triisopropylsilanyloxymethyl-ethyl]methoxycarboxamide (24)

To a solution of acid 20a (0.1g, 0.195 mmol) in acetone (1.9 mL) cooled at 0 ºC was added anhydrous triethylamine (54 mL, 0.39 mmol) and ethyl chloroformate (28 mL, 0.29 mmol). The mixture was stirred for 45 min at 0 ºC. After this time, the formation of an acyl carbonate was observed by tlc (R_f = 0.6; hexane/ethyl acetate 20%). To this mixture was then added 57 mL of a solution of sodium azide (0.019 g, 0.29 mmol) in distilled water (3 mL). The mixture was stirred for 2 h, at room temperature. After this time, an acylazide was formed (R_f = 0.62, hexane/ethyl acetate 20%). Then the mixture was diluted with dichloromethane (20 mL) and the organic phase was washed with distilled water (5 mL) and brine (5 mL), dried over sodium sulfate and finally the solvent was removed under reduced presurre. The residue was dissolved in anhydrous toluene (10 mL) and refluxed for 2 h, under an argon atmosphere. The reaction was followed by infrared spectroscopy. At the end of reaction the absorption band at 2136 cm^-1 (atributted to acylazide) had disappeared and a new absorption band at 2254 cm^-1 confirmed the formation of an isocyanate. Toluene was evaporated and the residue was dissolved in anhydrous methanol (5 mL). The resulting mixture was refluxed for 12 h. Then, the solvent was removed under reduced pressure and the residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 15%) to provide the carbamate 24 as a viscous colorless oil in an overall yield of 65 % (for 4 steps).

IR n_max/cm^-1: 3450, 2947, 2866, 1731, 1251, 1101, 776.¹H NMR (300 MHz, CDCl₃): d –0.11 (s, 3H), 0.07 (s, 3H), 0.85 (s, 9H, t-butyl), 0.91-1.07 (m, 21H, 3 ×isopropyl), 3.58 (bs, 3H), 3.60-3.72 (m, 3H), 5.02 (m, 2H, benzylic CH and NH), 5.95 (s, 2H, OCH₂O), 6.74-6.8 (m, 3H, aromatics).¹³C NMR (75 MHz, CDCl₃): d –5.1, –4.5, 12.1, 17.8, 18.1, 25.9, 52, 59.2, 62, 71.4, 100.8, 106.7, 107.8, 119.3, 136.5, 146.6, 147.3, 156.5. MS (EI, 70eV) m/z: 496 (M⁺), 364, 267, 265, 135, 73. HRMS (EI, 70eV) m/z Calc. for C₂₇H₄₉NO₆Si₂ [M⁺ -t-butyl]: 482.2389. Found: 482.2491.

(±)-Methyl 2-{1,3-benzodioxol-5-yl[(4-methoxybenzyl) oxy]methyl}acrylate (25)

To a solution of adduct 13 (0.47 g, 2 mmol) in dry dichloromethane (4.5 mL) was added p-methoxybenzyl trichloroacetimidate (0.85 g, 3 mmol) and a catalytic amount of camphorsulfonic acid (0.023 g, 0.1 mmol). The resulting solution was stirred for 18 h at room temperature. Then, the reaction mixture was diluted with diethyl ether (25 mL) and the organic phase was washed with a saturated solution of NaHCO₃ (2 × 10 mL), distilled water (2 × 10 mL) and brine (2 × 10 mL). The organic phase was then dried over sodium sulfate and the solvent was evaporated. The residue was purified by flash silica gel colum chromatography (hexane/ethyl acetate 5%) to afford PMB ether 25 as a colorless viscous oil in 93% yield.

IR n_max/cm^-1: 2952, 2901, 2840, 1721, 1612, 1513, 1486, 1441, 1247, 1068. ¹H NMR (500 MHz, CDCl₃): d 3.68 (s, 3H), 3.80 (s, 3H), 4.39 (dd, J 19 and 11.5 Hz, 2H), 5.22 (s, 1H), 5.94 (s, 2H, CH₂OCH₂), 6.01 (s, 1H), 6.32 (s, 1H), 6.75-6.98 (m, 5H aromatics), 7.26 (d, J 8.8 Hz, 2H aromatics). ¹³C NMR (125 MHz, CDCl₃): d 51.7, 55.2, 70.2, 77.8, 101, 107.9, 108, 113.7, 121.6, 124.9, 129.3, 130.1, 133.5, 141.2, 147.2, 147.7, 159.1, 166.2. MS (EI, 70eV) m/z: 356 (M⁺), 220, 160, 149, 137, 121, 102, 77. HRMS (EI, 70eV) m/z Calc. for C₂₀H₂₀O₆ [M⁺]: 356.1260. Found: 356.1262.

(±)-2-{1,3-Benzodioxol-5-yl[(4-methoxybenzyl) oxy]methyl}prop-2-en-1-ol (26)

A solution of ether 25 (0.35 g, 1 mmol) in dry dichloromethane (7 mL) was cooled to –78 ºC, under an atmosphere of argon. Then a solution of DIBAL-H in toluene (1.0 mol L^-1) (2.4 mL, 2.4 mmol) was slowly added. The resulting solution was stirred for 2 h, at –78 ºC. After that a saturated solution of sodium acetate was added (2.2 mL) and the reaction was allowed to warm to the room temperature. The reaction medium was then poured into a beaker filled with ethyl ether (50 mL) and a saturated solution of NH₄Cl (4.6 mL). The mixture was stirred for 1 h until we observed the formation of a gel, which was then filtered over a pad of Celite^®. The solid was washed with small portions of diethyl ether and the organic phases were combined, dried over magnesium sulfate and finally the solvent was removed under reduced pressure. The residue was purified by flash silica gel column chromatography (hexane/ ethyl acetate 5%) to furnish 26 as a colorless fluid oil in 72% yield.

IR n_max/cm^-1: 3417, 2897, 2840, 1612, 1513, 1441, 1247, 1038. ¹H NMR (300 MHz, CDCl₃): d 2.04 (bs, 1H, OH), 3.80 (s, 3H), 4.01 (d, ²J 12.8 Hz, 1H), 4.11 (d, ²J 12.8 Hz, 1H), 4.38 (d, ²J 11.5 Hz, 1H), 4.45 (d, ²J 11.5 Hz, 1H), 4.88 (s, 1H, benzylic CH), 5.11 (s, 1H), 5.24 (s, 1H), 5.96 (s, 2H, OCH₂O), 6.78-6.97 (m, 5H aromatics), 7.22 (d, J 8.0 Hz, 2H aromatics). ¹³C NMR (75 MHz, CDCl₃): d 55.2, 63.7, 70, 81.9, 101, 107.4, 108, 113.7, 113.8, 120.6, 129.4, 130, 133.7, 147.1, 147.9, 148.3, 159.2. HRMS (EI, 70 eV) m/z Calc. for C₁₉H₂₀O₅ [M⁺]: 328.1311. Found: 328.1289.

5-[1-[(4-Methoxybenzyl)oxy]-2-(tert-butyl-diphenyl silyloxy)prop-2-enyl]-1,3-benzodioxole (27)

To a solution of 26 (0.328 g, 1 mmol) in dichloromethane (6.0 mL), under an atmosphere of argon, was added N,N-dimethylaminopyridine (DMAP) (0.003 g, 0.024 mmol), dry triethylamine (0.20 mL, 1.5 mmol) and tert-butyldiphenylsilyl chloride (0.4 mL, 1.5 mmol). The resulting mixture was stirred for 16 h, at room temperature. After that the mixture was diluted with dichloromethane (25 mL) and the organic phase was washed with a saturated solution of NaHCO₃ (2 × 20 mL). The phases were separated. The organic layer was dried over magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 2%) to provide 27 as colorless viscous oil in an almost quantitative yield.

IR n_max/cm^-1: 3071, 2956, 2857, 1612, 1513, 1486, 1246, 1073. ¹H NMR (300 MHz, CDCl₃): d 1.03 (s, 9H), 3.78 (s, 3H), 4.05 (d, ²J 14.2 Hz, 1H), 4.13 (d, ²J 14.2 Hz, 1H), 4.35 (s, 2H, CH₂), 4.80 (s, 1H, CH), 5.25 (s, 1H_b, CH₂,), 5.43 (s, 1H_a, CH₂), 5.92 (s, 2H, CH₂), 6.7-7.64 (m, 17H, aromatics). ¹³C NMR (75 MHz, CDCl₃): d 19.2, 26.8, 55.2, 63.7, 69.8, 80.5, 100.9, 107.4, 107.9, 111.5, 113.7, 120.6, 127.6, 129.2, 129.6, 130.4, 133.5, 134.1, 135.5, 146.9, 147.6, 147.9, 159.1. MS (EI, 70eV) m/z: 566 (M⁺), 200, 199, 121. HRMS (EI, 70eV) m/z Calc. for C₃₅H₃₈O₅Si [M]⁺: 566.2489. Found: 566.2475.

3-(1,3-Benzodioxol-5-yl)-3-[(4-methoxybenzyl)oxy]-2(tert-butyl-diphenylsilyloxy)propan-1-ol (28)

A solution of 27 (0.2 g, 0.35 mmol) in anhydrous THF (3.0 mL) was cooled at 0 ºC and then a solution of 9-BBN (0.5 mol L^-1) in THF (5.0 mL, 2.5 mmol) was added drop by drop under an argon atmosphere. After finishing the addition, the solution was stirred for 16 h at room temperature. After that time, the reaction mixture was cooled to 0 ºC and then a solution 3 mol L^-1 of NaOH (3.6 mL) was slowly added, followed by 30% H₂O₂ (3.6 mL). The resulting mixture was stirred at 0 ºC for 45 min. After that, a saturated solution of NaHCO₃ was added (5.0 mL) and the resulting mixture was transferred to a separatory funnel with dichloromethane (50 mL). The phases were separated and the organic one was washed with a saturated solution of NaHCO₃ (2 × 10 mL), distilled water (2 × 10 mL) and brine (2 × 10 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 5%) to afford alcohols 28a/b, as a mixture of diastereoisomers, in 67% yield.

IR n_max/cm^-1: 3433, 2930, 2856, 1486, 1245, 1112, 1037, 702. ¹H NMR (300 MHz, CDCl₃) major diastereoisomer (±)-28a: d 1.03 (s, 9H), 1.96 (m, 1H, CH), 3.43 (dd, ²J 10.3 Hz, ³J 5.3 Hz, 1H), 3.57 (dd, ²J 10.4 Hz, ³J 4.2 Hz, 1H), 3.81 (s, 3H, CH₃), 3.85-4.1 (m, 2H, CH₂), 4.14 (d, ²J 11 Hz, 1H_a, CH₂), 4.4 (d, ²J 11 Hz, 1H_b, CH₂), 4.53 (d, ³J 8.4 Hz, 1H, CH), 5.99 (s, 2H), 6.79-6.82 (m, 4H aromatics), 6.84 (bs, 1H aromatic), 7.06 (d, J 8.7 Hz, 1H aromatic), 7.32-7.72 (m, 10H aromatics). Minor diastereoisomer (±)-28b: d 1.07 (s, 9H, 3CH₃), 2.08 (m, 1H, CH), 3.5 (dd, ²J 11.4 Hz, ³J 5.5 Hz, 1H), 3.64 (dd, ²J 11.4 Hz, ³J 4.2 Hz, 1H), 3.80 (s, 3H), 3.85-4.1 (m, 2H), 4.11 (d, ²J 11.3 Hz, 1H), 4.33 (d, ²J 11.3 Hz, 1H), 4.49 (d, ³J 8.4 Hz, 1H), 5.99 (s, 2H), 6.79-6.82 (m, 4H aromatics), 6.84 (bs, 1H aromatic), 7.06 (d, J 8.7 Hz, 1H aromatic), 7.32-7.72 (m, 10H aromatics). ¹³C NMR (75 MHz, CDCl₃) Major diastereoisomer (±)-28a: d 19.2, 26.9, 49.7, 55.6, 63.1, 63.9, 70.2, 81.5, 101, 107.3, 107.9, 113.9, 121.1, 127.7, 129.6, 129.8, 129.9, 133.1, 134.2, 135.6, 147.2, 148, 159.3. Minor diastereoisomer (±)-28b: d 19.2, 26.8, 48.8, 55.3, 62.8, 63.7, 70.1, 79.2, 101, 107.4, 108, 113.7, 121.1, 127.6, 129.3, 129.7, 130.3, 133.2, 133.9, 135.6, 147.2, 148, 159.1. HRMS (EI, 70eV) m/z Calc. for C₃₅H₄₀O₆Si [M⁺]: 584.2594. Found: 584.2620.

(±)-3-(1,3-Benzodioxol-5-yl)-3-[(4-methoxybenzyl)oxy]-2(tert-butyl-diphenylsilyloxy)propanal (29)

To a mixture of diastereoisomeric alcohols 28a/b (0.2 g, 0.34 mmol), N-methyl morpholine oxide (NMO) (0.068 g, 0.5 mmol), ammonium tetrapropylperruthenate (TPAP) (0.011 g, 10 mmol %, 0.03 mmol) and triturated and activated 4Å molecular sieves (0.16 g, 0.5 g per mmol of substrate) was added anydrous dichloromethane (4.0 mL). The resulting heterogenous mixture was stirred for 1 h at room temperature. After that time, the mixture was filtered on a column containing flash silica gel (approximately 5.0 cm of silica gel) and the solid was washed with CH₂Cl₂. The organic phases were combined and the solvent evaporated to obtain 29a/b as colorless oil in 80% yield. No additional purification was necessary and the product was used in next step without any purification.

IR n_max/cm^-1: 2928, 2859, 1725, 1604, 1499, 1247, 1104. ¹H NMR (500 MHz, CDCl₃) Major diastereoisomer (±)-29a: d 1.01 (s, 9H, 3CH₃), 2.64 (m, 1H, CH), 3.82 (s, 3H, CH₃), 3.76 (dd, ²J 10.5 Hz, ³J 3.8 Hz, 1H_a, CH₂), 3.95 (dd, ²J 10.5 Hz, ³J 4.5 Hz, 1H_b, CH₂), 4.18 (d, ²J 11.3 Hz, 1H _a, CH₂), 4.44 (d, ²J 11.3 Hz, 1H_b, CH₂), 4.88 (d, ³J 9.1 Hz, 1H, CH), 5.99 (bs, 2H), 6.62-6.85 (m, 4H aromatics), 7.16-7.68 (m, 13H aromatics), 9.87 (d, ³J 3.0 Hz, 1H). Minor diastereoisomer (±)-29b: d 1.05 (s, 9H, 3CH₃), 2.88 (m, 1H, CH), 3.81 (s, 3H, CH₃), 3.57 (dd, ²J 10.4 Hz, ³J 4.9 Hz, 1H_a, CH₂), 3.87 (dd, ²J 10.4 Hz, ³J 4.9 Hz, 1H_b, CH₂), 4.22 (d, ²J 11.3 Hz, 1H_a, CH₂), 4.40 (d, ²J 11.3 Hz, 1H_b, CH₂), 4.82 (d, ³J 7.6 Hz, 1H, CH,), 5.98 (s, 2H), 6.62-6.85 (m, 4H aromatics), 7.16-7.68 (m, 13H aromatics), 9.73 (d, ³J 2.4 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) Major diastereoisomer (±)-29a: d 19.1, 26.7, 55.2, 60.3, 61.2, 69.9, 77.1, 101.1, 107.3, 108, 113.8, 121.4, 127.7, 129.3, 129.7, 129.8, 132.6, 132.8, 135.5, 147.5, 148.1, 159.2, 203.7. Minor diastereoisomer (±)-29b: d 19.2, 26.7, 55.2, 60.3, 60.4, 70, 77.2, 101.1, 107.3, 108.2, 113.7, 121, 127.6, 129.6, 129.7, 129.8, 132.5, 132.9, 135.4, 147.4, 148.1, 159.1, 202.7. MS (EI, 70eV) m/z: 582 (M⁺), 199, 149, 135, 121, 77, 57. HRMS (EI, 70eV) m/z Calc. for C₃₅H₃₈O₆Si [M⁺]: 582.2438. Found: 582.2489.

(±)-3-(1,3-Benzodioxol-5-yl)-3-[(4-methoxybenzyl)oxy]-2(tert-butyl-diphenylsilyloxymethyl)propanoic acid (30)

A mixture of diastereoisomeric aldehydes (±)-29a/29b (0.11 g, 0.18 mmol), t-butanol (3.85 mL) and 2-methylbut-2-en (0.95 mL, 8.85 mmol) was cooled to 0 ºC , then a solution of NaClO₂ (0.15 g, 1.68 mmol) and NaH₂PO₄ (0.15 g, 1.26 mmol) dissolved in 1 mL of distilled water was slowly added. The resulting mixture was stirred for 1 h at room temperature. After that, the volative components were evaporated and the residue was dissolved in distilled water (20 mL), acidified to pH 3 with a 10% solution of HCl. The aqueous phase was extracted with ethyl ether. The organic phases were combined, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 8%) to give 30 as a mixture of diastereoisomers in 88% yield.

IR n_max/cm^-1: 3058, 2937, 2891, 1711, 1609, 1487, 1245, 1105, 815, 700. ¹H NMR (500 MHz, CDCl₃) Major diastereoisomer (±)-30a: d 1.02 (s, 9H, 3CH₃), 3.04-3.08 (m, 1H, CH), 3.8 (s, 3H, CH₃), 3.5-4.02 (m, 2H, CH₂), 4.13 (d, ²J 11.3 Hz, 1H), 4.34 (d, ²J 11.3 Hz, 1H), 4.62 (d, ³J 9.4 Hz, 1H, CH), 5.98 (s, 2H, CH₂), 6.6-7.7 (m, 17H, aromatics). Minor diastereoisomer (±)-30b: d 0.98 (s, 9H, 3CH₃), 2.9-2.95 (m, 1H, CH), 3.77 (s, 3H, CH₃), 3.5-4.02 (m, 2H, CH₂), 4.18 (d, ²J 11.3 Hz, 1H_a, CH₂), 4.37 (d, ²J 11.3 Hz, 1H_b, CH₂), 4.56 (d, ³J 8.5 Hz, 1H, CH), 5.92 (s, 2H, CH₂), 6.6-7.7 (m, 17H, aromatics). ¹³C NMR (125 MHz, CDCl₃) Major diastereoisomer (±)-30a: d 19.1, 26.7, 55.1, 62.3, 70, 77.9, 101, 107.2, 108, 113.7, 121.4, 127.7, 129.5, 129.6, 132.3, 132.5, 133.1, 135.5, 147.5, 147.9, 159.1, 177.4. Minor diastereoisomer (±)-30b: d 19.1, 26.6, 55.2, 55.5, 62.1, 69.9, 78.4, 101.1, 107.4, 108, 113.7, 121.5, 127.6, 129.6, 132.4, 132.7, 134, 135.4, 147.6, 148, 159.2, 176.1. HRMS (EI, 70 eV) Calc. for C₃₅H₃₈O₆Si [M⁺ -t-butyl] 524.16552. Found: 524.16533.

[2-Benzo[1,3]dioxol-5-yl)-1-(tert-butyl-diphenylsilanyloxymethyl)-2-(4-methoxy-benzyloxy)-ethyl]methoxycarboxamide, (±)-31a/b

To a solution of diastereoisomeric acids 30a/b (0.1 g, 0.167 mmol) in acetone (1.6 mL), at 0 ºC, was added anhydrous triethylamine (24 µL, 0.33 mmol) and ethyl chloroformate (24µL, 0.25 mmol). The mixture was then stirred for 45 min at 0 ºC. After observing the formation of an acyl carbonate (by TLC), a solution of sodium azide (49 µL, 0.0163 g, 0.25 mmol) in distilled water (3 mL) was added. The resulting mixture was stirred for 2 h, until the formation of an acyl azide (observed by IR spectroscopy). Then, the reaction was diluted with dichloromethane and the organic phase was washed with distilled water (5 mL) and brine (5 mL), dried over anydrous sodium sulfate and finally the solvent was evaporated. To the residue was added dry toluene (10 mL) and the solution was refluxed for 2 h, under an argon atmosphere. The reaction was followed by IR spectroscopy until the appearance of an absorption band at 2259 cm^-1, atributted to the isocyanate formed after the Curtius rearrangement. Then, the solvent was evaporated and to the residue was added anhydrous methanol. The solution was refluxed for 12 h. After solvent evaporation, the residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 15%) to afford carbamate 31a/b as a viscous colorless oil in an overall yield of 60% (four steps).

IR n_max/cm^-1: 3436, 2928, 2857, 1725, 1612, 1513, 1247, 1112, 707. ¹H NMR (300 MHz, CDCl₃) d(ppm) Diastereoisomeric mixture: d 1.07 (s, 9H), 3.41-3.6 (m, 1H, NH), 3.80 (s, 3H), 3.82 (s, 3H), 3.9-4.52 (m, 5H), 4.84 (d, ³J 8.8 Hz, 1H), 5.97 (bs, 2H, OCH₂O), 6.77-7.65 (m, 17H aromatics). ¹³C NMR (75 MHz, CDCl₃) Diastereoisomeric mixture: d 19.4, 27, 52, 55.3, 56.8, 62.4, 70.5, 79.6, 100.9, 107.5, 107.9, 113.7, 120.5, 127.6, 129.2, 129.6, 130, 132.3, 133.1, 135.4, 147.4, 147.7, 156.1, 159. HRMS (EI, 70 eV) Calc. for C₃₆H₄₁NO₆Si: 553.19207 [M⁺ -t-butyl]. Found: 553.19200.

(±)-5-Benzo[1,3]dioxol-5-yl-4-(tert-butyl-diphenylsilanyloxymethyl)-2-oxazolidinone (32)

To a mixture of the diastereoisomeric carbamates 31a/b (0.03 g, 0.048 mmol) and DMAP (0.018 g, 0.144 mmol) in dry dicloromethane (3.0 mL) at 0 ºC was slowly added trifluoromethane sulfonic anhydride (TF₂O) (40 µL, 0.244 mmol). The resulting mixture was stirred for 2 h at 5 ºC. After that time, the reaction medium was transfered to a separatory funnel and diluted with dichloromethane (10 mL). The phases were separated and the organic one was washed with a 10% solution of HCl (2 × 10 mL), distilled water (2 × 10 mL) and brine (2 × 10 mL). The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash silica gel colum chromatography (hexane/ethyl acetate 40%) to give oxazolidinone 32 as a colorless oil in 30% yield.

IR n_max/cm^-1: 3224, 2929, 2856, 1758, 1587, 1493, 1250, 1111, 702. ¹H NMR (300 MHz, CDCl₃): d 1.07 (s, 9H, 3CH₃), 3.70-3.80 (m, 3H), 5.18 (d, ²J 5.0 Hz, 1H), 5.44 (bs, 1H, NH), 5.98 (s, 2H, OCH₂O), 6.65-6.85 (m, 3H aromatics), 7.35-7.67 (m, 10H aromatics). ¹³C NMR (75 MHz, CDCl₃): d 19.1, 26.7, 61.5, 64.9, 79.8, 101.4, 106.2, 108.4, 119.7, 128.1, 130.2, 132.5, 132.7, 135.6, 148.2, 148.4, 158.6. HRMS (EI, 70eV) m/z Calc. for C₂₇H₂₉NO₅Si [M⁺]: 475.1815. Found: 475.1811.

7-Hydroxymethyl-[1,3]dioxol[4,5-g]isoquinolin-5-ol (33)

To a solution of carbamate 31 (0.086 g. 0.13 mmol) in a mixture of anydrous toluene (5.0 mL) and dry pyridine (0.5 mL) at 0 ºC was added, drop by drop, phosphorus oxychloride (0.36 mL, 3.88 mmol). The resulting mixture was stirred for 2 h at room temperature and then refluxed for 16 h, under an argon atmosphere. After that, the mixture was cooled to 0 ºC followed by the addition of distilled water (5.0 mL). The phases were separated and the aqueous one was extracted with ethyl acetate. The organic phase was separated and washed with a 1 mol L^-1 solution of HCl (2 × 10 mL), a saturated solution of NaHCO₃ (2 × 10 mL), distilled water (2 × 10 mL) and brine (2 × 10 mL). The organic phase was then dried over anhydrous magnesium sulfate and the solvent was evaporated to provide a silylated intermediate as a yellow oil in 50% yield. This crude intermediate was dissolved in anhydrous THF and the solution was cooled to 0 ºC. After that a solution 1.0 mol L^-1 of tetrabutylammonium fluoride in THF (0.3 mL, 0.3 mmol) was added. The resulting mixture was stirred for 2 h at room temperature. Then the solvent was evaporated and residue was dissolved in ethyl acetate, the organic layer was washed with a saturated solution of ammonium chloride (2 × 10 mL), distilled water (2 × 10 mL) and brine (2 × 10 mL) and finally dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by flash silica gel column chromatography (ethyl acetate/methanol 10%) to afford the isoquinoline 33 as colorless oil in 75% yield.

IR n_max/cm^-1: 3400-3300, 2920, 2851, 1726; 1588, 1477, 1245, 1034, 883; 722; 611. ¹H NMR (300 MHz, CDCl₃): d 1.83 (bs, 1H, OH), 4.74 (s, 2H, CH₂), 6.17 (s, 2H, OCH₂O), 7.10 (s, 1H), 7.59 (s, 2H). ¹³C NMR (75 MHz, CDCl₃): d 66.1, 102.3, 102.7, 103.1, 119.1, 123.4, 136.8, 148, 149.3, 149.9, 152.1.

HRMS (EI, 70eV) m/z Calc. for C₁₁H₉NO₄ [M⁺]: 219.0532. Found: 219.0491.

General procedure for protection of brominated MBH adduct (34)

To a solution of MBH adducts 34 (3-4g) in dry dichloromethane (ca. 20 mL) was added dry triethylamine (2.0. equiv.) and triisopropylsilyl triflate or tertbutyldimethylsilyl triflate (1.3 equiv.) at room temperature. The resulting mixture was stirred for 1 h at room temperature. After that, the mixture was diluted with dichloromethane (ca. 30 mL) and the organic phase was washed with a saturated solution of NaHCO₃ (2 × 50 mL) and brine (2 × 50 mL), dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified by flash silica gel column chromatography to provide the corresponding silylated ether in very good yield (for details see below).

(±) Methyl 2-[(6-bromo-benzo[1,3]dioxol-5-yl-(tert-butyldimethyl-silanyloxy)-methyl]acrylate (35)

98% yield, a colorless viscous oil. IR n_max/cm^-1: 2953, 2929, 2894, 2856, 1727, 1630, 1474, 1257, 1230, 1076, 1039, 837. ¹H NMR (300 MHz, CDCl₃): d -0.06 (s, 3H), 0.11 (s, 3H), 0.87 (s, 9H), 3.70 (s, 3H, CH₃), 5.83 (t, ²J 1.0 Hz, 1H), 5.90 (d, ²J 1.0 Hz, 1H), 5.94 (d, ²J 1.46 Hz, 1H), 5.97 (d, ²J 1.46 Hz, 1H), 6.26 (t, ⁴J 1.0 Hz), 6.87 (s, 1H aromatic), 6.94 (s, 1H aromatic). ¹³C NMR (75 MHz, CDCl₃): d -4.8, -4.5, 18.1, 25.9, 51.8, 71.5, 101.6, 108.8, 112.1, 113.3, 124.9, 134.6, 143, 147.2, 147.5, 166.1. HRMS (EI, 70eV) m/z Calc. for C₁₈H₂₅BrO₅Si [M⁺]: 428.0654. Found: 372.9949 [M -t-butyl].

(±) Methyl 2-[(6-bromo-benzo[1,3]dioxol-5-yl-(triisopropylsilanyloxy-methyl]-acrylate (36)

87% yield, a colorless viscous oil. IR n_max/cm^-1: 2945, 2865, 1730, 1610, 1475, 1265, 1230, 1086, 1065, 1039, 881, 814. ¹H NMR (300 MHz, CDCl₃): d 0.92-1.17 (m, 21H), 3.70 (s, 3H), 5.94 (d, ²J 1.1 Hz, 1H_a), 5.98 (d, ²J 1.1 Hz, 1H), 6.01 (bs,1H), 6.10 (bs, 1H), 6.3 (bs, 1H), 6.92 (s, 1H aromatic), 6.93 (s, 1H aromatic). ¹³C NMR (75 MHz, CDCl₃): d 12.5, 18.1, 51.7, 71.5, 101.6, 108.9, 112, 113.4, 124.8, 135.1, 143.3, 147.2, 147.5, 166. HRMS (ESI) m/z Calc. for C₂₁H₃₁BrO₅Si [M⁺]: 470.1124. Found: 493.1020 [M + Na]⁺.

General procedure for the reduction of silylated ether 35 and 36 with DIBAL-H

A solution of silyl ether 35 (2.20 g, 5.12 mmol) or silyl ether 36 (4.07 g, 8.64 mmol) in dry dichloromethane (20 mL), under an atmosphere of argon, was cooled to –78 ºC and then a solution of DIBAL-H (1.5 mol L^-1, 2.4 equiv.) was slowly added. At the end, the resulting solution was stirred for 2 h, at –78 ºC. After that time, a saturated solution of sodium acetate in distilled water was added (15-26 mL) and the temperature was allow to warm to room temperature. Then, the reaction medium was poured into a beaker containing a mixture of ethyl ether (50-100mL) and a saturated solution of ammonium chloride (30-54 mL). The mixture was stirred until the formation of a gel (approximately 1 h). The gel was then filtered over a pad of Celite® and the solid was washed with portions of ethyl ether (3 × 20 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 15%) to provide the corresponding mono-protected diols 37 and 38 (for spectroscopic data see below).

(±)-[6-Bromo-benzo[1,3]dioxol-5-yl-(tert-butyl-dimethylsilanyloxy)-methyl]-2-propen-1-ol (37)

97% yield, as a colorless oil. IR n_max/cm^-1: 3376, 2943, 2892, 2866, 1503, 1475, 1405, 1233, 1106, 1041, 882, 683. ¹H NMR (300 MHz, CDCl₃): d –0.05 (s, 3H), 0.10 (s, 3H), 0.89 (s, 9H), 1.84 (bs, 1H, OH), 4.03 (d, ²J 14 Hz_, 1H), 4.10 (d, ²J 14 Hz, 1H), 5.16 (s, 1H), 5.18 (s, 1H), 5.59 (s, 1H, CH), 5.96 (d, ²J 1.0 Hz, 1H), 5.99 (d, ²J 1.0 Hz, 1H), 6.93 (s, 1H aromatic), 7.0 (s, 1H aromatic). ¹³C NMR (75 MHz, CDCl₃): d –4.9, –4.7, 18.2, 25.8, 63.4, 75, 101.7, 108.4, 112, 112.3, 112.5, 135, 147.5, 147.6, 148.8.

(±)-2-[(6-Bromo-benzo[1,3]dioxol-5-yl)-triisopropylsilanyloxy-methyl]-2-propen-1-ol (38)

95% yield, as a colorless oil. IR n_max/cm^-1: 3383, 2943, 2866, 1509, 1473, 1388, 1234, 1107, 1045, 942, 888, 825. ¹H NMR (300 MHz, CDCl₃): d 0.92-1.16 (m, 21H), 2.02 (bs, 1H, OH), 4.0 (d, ²J 13.6 Hz, 1H), 4.13 (d, ²J 13.6 Hz, 1H), 5.19 (s, 1H), 5.45 (s, 1H), 5.7 (s, 1H), 5.96 (d, ²J 1.5 Hz, 1H), 6.0 (d, ²J 1.5 Hz, 1H), 6.93 (s, 1H aromatic), 7.09 (s, 1H aromatic). ¹³C NMR (75 MHz, CDCl₃): d 12, 18.8, 19.9, 62.7, 75.2, 101.7, 108.1, 111.9, 112, 112.1, 135.4, 147.5, 147.6, 148.6. HRMS (ESI) m/z Calc. for C₂₀H₃₁BrO₄Si [M⁺]: 442.1175. Found: 465.1071 [M + Na]⁺.

(±)-5-Bromo-6-[1-(tert-butyl-dimethyl-silanyloxy)-2-(tertbutyl-diphenyl-silanyloxymethyl)-allyl]-benzo[1,3]dioxol (39)

To a mixture of mono protected diol 37 (2.0 g, 5 mmol), N,N-dimethylaminopyridine (DMAP) (0.015 g, 0.125 mmol) and dry triethylamine (1.4 mL, 10 mmol) in anhydrous dichloromethane (20 mL) was added tertbutyldimethyl silyl chloride (2.0 mL, 7.5 mmol). The resulting solution was stirred for 16 h, at room temperature. After that, the mixture was diluted with hexane (50 mL) and the organic layer was washed with a saturated solution of NaHCO₃. The organic layer was separated, dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 5%) to provide 39 as colorless viscous oil in 93% yield.

IR n_max/cm^-1: 2954, 2929, 2856, 1613, 1473, 1232, 1109, 1069, 1040, 874, 836. ¹H NMR (300 MHz, CDCl₃): d –0.09 (s, 3H), 0.03 (s, 3H), 0.84 (s, 9H), 1.05 (s, 9H), 4.13 (m, 2H), 5.19 (s, 1H), 5.33 (s, 1H), 5.50 (s, 1H), 5.94 (d, ²J 1.5 Hz, 2H), 6.88 (s, 1H aromatic), 6.9 (s, 1H aromatic), 7.37-7.64 (m, 10H aromatics). ¹³C NMR (75 MHz, CDCl₃): d –4.9, –4.7, 18.2, 19.3, 25.8, 26.8, 63.5, 73.6, 101.5, 108.5, 110, 111.7, 112.4, 127.4, 129.4, 133.5, 135.3, 135.5, 147.3, 147.3, 149.2. HRMS (ESI) m/z Calc. for C₃₃H₄₃BrO₄Si₂ [M⁺]: 638.1883. Found: 661.1779 [M + Na]⁺.

(±)-[1,6-Bromo-benzo[1,3]dioxol-5-yl-2-(4-methoxybenzyloxymethyl)-allyloxy] triisopropylsilane (40)

To a solution of 38 (0.89 g, 2 mmol) in dry dichloromethane (5.0 mL) was added, at room temperature, p-methoxybenzyl trichloroacetoimidate (0.85g, 3 mmol) and a catalytic amount of camphorsulfonic acid (0.023g, 0.1 mmol). The resulting solution was stirred for 18 h at room temperature. Then, the reaction medium was diluted with ethyl ether (25 mL), washed with a saturated solution of NaHCO₃ (2 × 10mL), distilled water (2 ×10 mL) and brine (2 × 10 mL). The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 5%) to provide 40 as a colorless oil in 98% yield.

IR n_max/cm^-1: 3422, 2943, 2865, 1513, 1474, 1247, 1039. ¹H NMR (300 MHz, CDCl₃): d 0.92-1.14 (m, 21H, 3 ×isopropyl), 3.81(s, 3H), 3.92 (s, 2H), 4.37 (s, 2H), 5.26 (bs, 1H), 5.56 (bs, 1H), 5.68 (bs, 1H), 5.94 (d, ²J 1.5 Hz, 1H), 5.98 (d, ²J 1.5 Hz, 1H), 6.85 (d, ³J 8.8 Hz, 2H), 6.92 (s, 1H), 7.02 (s, 1H), 7.2 (d, ³J 8.8 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃): d 12.3, 18.1, 55.3, 68.9, 71.7, 74, 101.5, 108.4, 111.7, 111.8, 113.5, 113.7, 129, 129.6, 130.4, 135.9, 146.9, 147.3, 158.8. HRMS (ESI) m/z Calc. for C₂₈H₃₉BrO₅Si [M⁺]: 562.1750. Found: 585.1645 [M + Na]⁺.

(±)-5-Bromo-6-[2-tert-butyl-diphenyl-silanyloxymethyl)1-triisopropyl-silanyloxy-allyl]-benzo[1,3]dioxol (41)

To a mixture of 38 (0.887 g, 2 mmol), N,Ndimethylaminopyridine (DMAP) (0.006 g, 0.05 mmol) and dry triethylamine (0.56 mL, 4 mmol) in dry dichloromethane (8.0 mL), at room temperature and under an atmosphere of argon, was added tert-butyldiphenylsilane chloride (0.8 mL, 3 mmol). The resulting mixture was stirred for 16 h at room temperature and under an argon atmosphere. After that, the reaction medium was diluted with hexane (50 mL) and the organic layer was washed with a saturated solution of NaHCO₃ (2 × 20 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 2%) to afford 41 as a colorless oil in 91% yield.

IR n_max/cm^-1: 3070, 3051, 2939, 2862, 1504; 1473, 1388, 1234, 1107, 1045, 937, 883, 825, 702. ¹H NMR (500 MHz, CDCl₃): d 0.98-1.08 (m, 30H, t-butyl + 3 × isopropyl), 4.17 (s, 2H), 5.42 (bs, 1H), 5.53 (bs, 1H) 5.65 (bs, 1H), 5.93 (d, ²J 1.5 Hz, 1H), 5.97 (d, ²J 1.5 Hz, 1H), 6.84 (s, 1H aromatic), 6.9 (s, 1H aromatic), 7.36-7.68 (m, 10H aromatics). ¹³C NMR (125 MHz, CDCl₃): d 12.2, 18, 19.2, 26.8, 62.9, 73.9, 101.5, 108.4, 109.5, 111.7, 112.3, 127.5, 129.5, 133.6, 133.7, 135.4, 135.5, 136.1, 147.4, 147.4, 149.6. HRMS (EI, 70 eV) m/z calc. for C₃₆H₄₉BrO₄Si₂ [M⁺]: 680.2353. Found: 680.2328.

General procedure for hydroboration reaction of 39, 40 and 41

To a solution of compounds 39 (2.98 g, 4.66 mmol), 40 (1.1 g, 1.96 mmol) or 41 (1.24 g, 1.82 mmol) in anhydrous THF (15, 15 or 5 mL, respectively) was slowly added, at 0 ºC, a solution of 9-BBN in THF (0.5 mol L^-1) (5 equiv.). The reaction was then stirred for 16 h at room temperature. After that, the reaction was cooled to 0 ºC and a 3.0 mol L^-1 solution of NaOH (55, 16 and 15 mL, respectively for the reactions with 39, 40 and 41) was added, followed by the addition of 30% H₂O₂ (55, 15 and 16 mL, respectively). The mixture was stirred for 45 min at 0 ºC and 45 min at room temperature. Then, a saturated solution of NaHCO₃ was added and the mixture was transferred to a separatory funnel and diluted with dichloromethane (80 mL). The phases were separated amd the organic one was washed with NaHCO₃ (2 × 20 mL), distilled water (2 × 20 mL) and brine (2 × 20 mL), dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash silica gel column chromatography to furnish the corresponding alcohol (see the analytical and spectroscopic data for each compound below).

(±)-3-(6-Bromo-benzo[1,3]dioxol-5-yl)-3-(tert-butyldimethylsilanyloxy)-2-(tert-butyl-diphenyl silanyloxymethy)-1-propanol (42a/b-syn/anti)

Colorless oil, 82% yield. IR n_max/cm^-1: 3425, 3070, 2930, 2866, 1503, 1473, 1391, 1238, 1112, 1045, 937, 879. ¹H NMR (500 MHz, CDCl₃) Diastereoisomeric mixture: d –0.19 (s, 3H), 0.01 (s, 3H), 0.85 (s, 9H), 1.06 (s, 9H), 1.97 (m, 1H), 3.73-3.90 (m, 4H), 5.21 (d, ³J 3.7 Hz, 1H), 5.97 (d, ²J 1.5 Hz, 1H), 5.99 (d, ²J 1.5 Hz, 1H), 6.91 (s, 1H aromatic), 6.99 (s, 1H aromatic), 7.39-7.66 (m, 10H aromatics). ¹³C-NMR (125 MHz, CDCl₃) Diastereoisomeric mixture: d –5.4, –4.8, 14.14, 17.9, 19.1, 25.7, 26.5, 26.9, 48.1, 60.3, 61.8, 63.9, 74, 101.7, 108.3, 111.6, 112.2, 127.6, 127.7, 129.6, 129.7, 133.2, 133.3, 134.7, 135.4, 135.5, 135.6, 147.4; 147.5. HRMS (EI, 70 eV) m/z Calc. for C₃₃H₄₅BrO₅Si [M⁺]: 656.1989. Found: 656.1926.

(±)-3-(6-Bromo-benzo[1,3]dioxol-5-yl)-2-(tert-butyldiphenyl-silanyloxy-methyl)-3-triisopropylsilanyloxy-1propanol (43a/b-syn/anti)

Colorless oil (mixture of diastereoisomers), 77% yield. IR n_max/cm^-1: 3406, 2940, 2865, 1612, 1513, 1476, 1240, 1170, 1105, 1037, 934. ¹H NMR (500 MHz, CDCl₃) Major diastereoisomer (±)-syn-43a: d 0.95-1.06 (m, 21H, 3 ×isopropyl), 2.08 (m, 1H), 2.4 (bs, 1H, OH), 3.72-3.78 (m, 2H), 3.81 (s, 3H), 3.82-3,87 (m, 2H), 4.44 (dd, J 15.3 and 11.7 Hz, 2H), 5.25 (d, ³J 5.5 Hz, 1H), 6.01 (d, J 1.5Hz, 2H), 6.87 (d, J 8.7 Hz, 2H aromatics), 6.94 (s, 1H aromatic), 7.05 (s, 1H aromatic), 7.24 (d, J 8.7 Hz, 2H aromatics). Minor diastereoisomer (±)-anti-43b: d 0.95-1.06 (m, 21H, 3 × isopropyl), 2.27 (m, 1H), 2.4 (bs, 1H, OH), 3.58-3.7 (m, 2H), 3.8 (s, 3H), 3.82-3.87 (m, 2H), 4.44 (bs, 2H), 5.35 (d, ³J 7 Hz, 1H), 6.01 (d, J 1.5Hz, 2H), (d, J 8.7 Hz, 2H aromatics), 6.94 (s, 1H aromatic), (s, 1H aromatic), 7.24 (d, J 8.7 Hz, 2H aromatics). ¹³C NMR (125 MHz, CDCl₃) Major diastereoisomer (±)-syn-43a: d 12.5, 18, 48.6, 55.3, 63.9, 69.9, 72.9, 74.1, 101.7, 108.5, 112, 112.3, 113.7, 129.2, 129.9, 130.1, 135.6, 147.4, 159. Minor diastereoisomer (±)-anti-43b: d 12.5, 18, 47.6, 55.3, 62.3, 70.3, 73.1, 73.3, 101.7, 108.4, 112.1, 112.3, 113.6, 129, 129.4, 130.1, 135.9, 147.4, 159. HRMS (ESI) m/z Calc. for C₂₈H₄₁BrNaO₆Si⁺ [M + Na]⁺: 603.1748. Found: 603.1739.

(±)-3-(6-Bromo-benzo[1,3]dioxol-5-yl)-2-(tert-butyldiphenyl-silanyloxy-methyl)-3-triisopropylsilanyloxy-1propanol (44)

Colorless oil, 77% yield. IR n_max/cm^-1: 3425, 3070, 2930, 2866, 1504, 1473, 1426, 1391, 1238, 1111, 1045, 937, 879, 706. ¹H NMR (300 MHz, CDCl₃) Major diastereoisomer (±)-syn-44: d 0.80-1.01 (m, 21H, 3 ×isopropyl), 1.05 (s, 9H, t-butyl), 1.90 (m, 1H), 2.0 (bs, 1H, OH), 3.78-3.90 (m, 4H), 5.31 (d, ³J 3.7 Hz, 1H, CH), 5.97 (d, ²J 1.5 Hz, 1H), 6.01 (d, ²J 1.5 Hz, 1H), 6.91 (s, 1H aromatic), 7.03 (s, 1H aromatic), 7.37-7.68 (m, 10H aromatics). ¹³C NMR (75 MHz. CDCl₃) Major diastereoisomer (±)-40a: d 12.6, 18, 19.2, 27, 48.9, 61.9, 64.5, 74.4, 101.7, 108.4, 111.7, 112.2, 127.6, 129.6, 133.2, 134.7, 135.5, 135.8, 147.4. HRMS (ESI) m/z Calc. for C₃₆H₅₁BrNaO₆Si₂⁺ [M + Na]⁺: 721.2351. Found: 721.2347.

General procedure for the preparation of aldehydes of 45, 46 and 47

A mixture of alcohol 42 (3.67 g, 5.58 mmol), alcohol 43 (0.8 g, 1.37 mmol) or alcohol 44 (0.95, g, 1.40 mmol), N-methyl-morpholine oxide (NMO) (1.5 equiv.), tetrapropylammonium perruthenate (10 mol%), molecular sieves 4Å (previously triturated and activated, 0.5 g mmol^-1) in anhydrous dichloromethane (4 mL mmol^-1) was stirred for 1 h at room temperature. After that, the reaction medium was filtered on a silica gel column and the solid was washed twice with dichloromethane. Filtrates were combined and the solvent was evaporated. The residue was used in the next step without any additional purification.

(±)-3-(6-Bromo-benzo[1,3]dioxol-5-yl)-3-(tert-butyldimethyl-silanyloxy)-2-(tert-butyl-diphenyl-silanyloxymethyl)-propionaldehyde (45)

Colorless oil, 98% yield. IR n_max/cm^-1: 3070, 2956, 2930, 2890, 2857, 1727, 1475, 1239, 1112, 1099, 837, 702. ¹H NMR (300 MHz, CDCl₃) Mixture of diastereo-isomers: d –0.19 (s, 3H), 0.05 (s, 3H), 0.83 (s, 9H), 1.03 (s, 9H), 2.72 (m, 1H), 2.81 (m, 1H, CH), 3.74 (m, 1H, CH₂), 3.92 (m, 1H, minor diastereoisomer), 4.06 (m, 1H, CH₂), 4.22 (m, 1H, minor diastereoisomer), 5.38 (d, ³J 5.1 Hz, 1H), 5.46 (d, ³J 6.2 Hz, 1H, minor diastereoisomer), 5.91 (d, ²J 1.5 Hz, 1H), 5.97 (d, ²J 1.5 Hz, 1H), 6.91 (s, 1H aromoatic), 6.93 (s, 1H aromatic), 7.32-7.62 (m, 10H aromatics), 9.75 (d, ³J 3.3 Hz, 1H, C(O)H). ¹³C NMR (75 MHz, CDCl₃) Mixture of diastereoisomers: d –5.4, –5.3, –4.7, –4.6, 17.9, 18, 19.1, 25.6, 26.7, 59.8, 60.9, 70.6, 101.7, 102.8, 108.3, 111.4, 112.2, 127.6, 127.6, 127.7, 129.6, 129.7, 133, 133.1, 134.4, 135.5, 135.6, 147.5, 147.7, 202.7, 202.8. HRMS (ESI) m/z Calc. for C₃₃H₄₃BrNaO₅Si⁺ [M + Na]⁺: 677.1725. Found: 677.1718.

(±)-3-(6-Bromo-benzo[1,3]dioxol-5-yl)-2-(4-methoxybenzyloxymethyl)-3-triisopropylsilanyloxy-propionaldehyde (46)

Colorless oil, 85% yield. IR n_max/cm^-1: 2944, 2867, 1752, 1613, 1513, 1476, 1247; 1084, 1039, 934, 882, 828, 683. ¹H NMR (500 MHz, CDCl₃) Mixture of diastereoisomers: d 0.95-1.06 (m, 21H, 3 × isopropyl), 3.58 (m, 1H), 3.68 (m, 1H), 3.81 (s, 3H), 4.4 (m, 2H), 5.57 (d, ³J 5.5 Hz, 1H, major diastereoisomer), 5.67 (d, ³J 4.3 Hz, 1H, minor diastereoisomer), 5.96 (d, ²J 1.2 Hz, 1H, minor diastereoisomer), 5.98 (d, ²J 1.2 Hz, 1H), 6.01 (d, ²J 1.5 Hz, 1H, minor diastereoisomer), 6.02 (d, ²J 1.5 Hz, 1H), 6.83-7.21 (m, 6H aromatics), 9.83 (d, ³J 3.1 Hz, 1H,C(O)H). ¹³C NMR (125 MHz, CDCl₃) Major diastereoisomer: d 12.4, 17.9, 55.2, 58.9, 66.4, 72.1, 72.8, 101.9, 108.3, 112.2, 113.5, 113.7, 129.1, 130, 135.1, 147.6, 147.9, 159.1, 202.5. Minor diastereoisomer: d 12.3, 17.9, 55.2, 59.7, 64.8, 71.5, 72.9, 101.8, 108.4, 112, 113.4, 113.7, 129.2, 130, 134.8, 147.5, 147.8, 159, 202.4. HRMS (ESI) m/z Calc. for C₂₈H₃₉BrNaO₆Si [M + Na]⁺: 601.1591. Found: 601.1579.

(±)-3-(6-Bromo-benzo[1,3]dioxol-5-yl)-2-(tert-butyldiphenyl-silanyloxy-methyl)-3-triisopropylsilanyloxypropionaldehyde (47)

Colorless oil, 95% yield. IR n_max/cm^-1: 2944, 2866, 2892, 1727, 1503, 1475, 1239, 1112, 1039, 882, 702. ¹H NMR (300 MHz, CDCl₃): d 0.92-1.04 (m, 30H, t-butyl + 3 × isopropyl), 2.82 (m, 1H), 3.78 (dd, ²J 10.4 Hz, ³J 5.5 Hz, 1H), 4.1 (dd, ²J 10.4 Hz, ³J 5.5 Hz), 5.52 (d, ³J 5.1 Hz, 1H, CH), 5.97 (d, ²J 1.5 Hz, 1H), 6.0 (d, ²J 1.5 Hz, 1H), 6.91 (s, 1H aromatic), 6.93 (s, 1H aromatic), 7.36-7.63 (m, 10H aromatics), 9.82 (d, ³J 3.3 Hz, 1H, C(O)H). ¹³C NMR (75 MHz, CDCl₃): d 12.6, 18, 19.2, 26.9, 61.1, 61.6, 72, 101.8, 108.3, 111.8, 112.2, 127.6, 129.6, 133.1, 134.7, 135.5, 147.4, 147.7, 202.5. HRMS (ESI) m/z Calc. for C₃₆H₄₉BrNaO₅Si₂ [M + Na]⁺: 719.2194. Found: 719.2183.

General procedure for the preparation of acids 48, 49 and 50

A mixture of aldehyde 45 (1.58, 2.41 mmol), aldehyde 46 (0.63, 1.09 mmol) or aldehyde 47 (0.83 g, 1.19 mmol) in t-butanol (20 mL for 45 and 10 mL for 46 and 47) and 2-methyl-but-2-ene (48.4 equiv.) was cooled to 0 ºC. Then a solution of NaClO₂ (9.2 equiv.) and NaH₂PO₄ (6.9 equiv.) dissolved in distilled water (6 mL for 45 and 2.5 mL for aldehydes 46 and 47) was added. The resulting mixture was stirred for 1 h, at room temperature. After that, the volatile components were evaporated and the residue was dissolved in distilled water (20 mL), which was acidified to pH 3 with a 10% solution of HCl. The acidified aqueous phase was then extracted with ethyl ether (2 × 20 mL). The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 20%) to furnish the corresponding acids. The yields and spectroscopic data for each acid are shown below.

(±)-3-(6-Bromo-benzo[1,3]dioxol-5-yl)-3-(tert-butyldimethyl-silanyloxy)-2-(tert-butyl-diphenyl-silanyloxymethyl)-propanoic acid (48)

Colorless oil, 92% yield. IR n_max/cm^-1: 3530, 3070, 3049, 2955, 2931, 2886, 2857, 1712, 1504, 1478, 1428, 1239, 1113, 1076, 1039, 934, 839, 777, 702. ¹H NMR (300 MHz, CDCl₃): d –0.2 (s, 3H), 0.05 (s, 3H), 0.82 (s, 9H), 1.01 (s, 9H), 2.96 (m, 1H), 3.48 (dd, ²J 10.3 Hz, ³J 5.5 Hz, 1H), 4.03 (t, ²J 9.3 Hz, 1H), 5.26 (d, ³J 7.7 Hz, 1H), 5.97 (d, ²J 1.5 Hz, 1H), 5.99 (d, ²J 1.5 Hz, 1H), 6.83 (s, 1H aromatic), 6.87 (s, 1H aromatic), 7.33-7.6 (m, 10H aromatics). ¹³C NMR (75 MHz, CDCl₃): d –5.2, –4.7, 18, 19.2, 25.7, 26.8, 58.3, 62.1, 71.6, 101.6, 108, 111.7, 112.2, 127.5, 129.4, 132.9, 134.6, 135.4, 147.4, 147.6, 177.5. HRMS (ESI) m/z Calc. for C₃₃H₄₃BrNaO₆Si₂ [M + Na]⁺: 693.1674. Found: 693.1661.

(±)-3-(6-Bromo-benzo[1,3]dioxol-5-yl)-2-(4-methoxybenzyloxymethyl)-3-triisopropylsilanyloxy-propanoic acid (49)

Yellow tinged oil, 80% yield. IR n_max/cm^-1: 3430, 2944, 2867, 1712, 1611, 1513, 1476, 1408, 1389, 1242, 1173, 1088, 882. ¹H NMR (300 MHz, CDCl₃) Diastereoisomers mixture: d 0.95-1.02 (m, 21H, 3 × isopropyl), 3.12 (m, 1H), 3.37-3.78 (m, 2H), 3.81(s, 3H), 4.39 (m, 2H), 5.48 (d, ³J 6.9 Hz, 1H major diastereoisomer), 6.01(d, ²J 1.5 Hz, 2H), 6.82-7.26 (m, 6H, aromatics). ¹³C NMR (75 MHz, CDCl₃) Diastereoisomers mixture: d 12.4, 15.5, 50.7, 55.3, 71.6, 78.6, 101.7, 108.9, 112.4, 113.1, 113.6, 128.2, 128.5, 135.1, 136.6, 146.8, 144.5, 146.8, 159.8, 179.7. HRMS (ESI) m/z Calc. for C₂₈H₃₉BrNaO₇Si [M + Na]⁺: 617.1541. Found: 617.1522.

(±)-3-(6-Bromo-benzo[1,3]dioxol-5-yl)-2-(tert-butyldiphenyl-silanyloxy-methyl)-3-triisopropylsilanyloxypropanoic acid (50)

Colorless oil, 85 % yield. IR n_max/cm^-1: 3359, 2943, 2866, 1712, 1473, 1238, 1149, 1111, 937, 883. ¹H NMR (300 MHz, CDCl₃): d 0.91-1.02 (m, 30H, t-butyl + 3 ×isopropyl), 2.99 (m, 1H), 3.56 (dd, ²J 10 Hz. ³J 5.2 Hz, 1H), 4.02 (dd, ²J 10 Hz, ³J 5.2 Hz, 1H), 5.43 (d, ³J 6.2 Hz, 1H, CH), 5.95 (d, ²J 1.1 Hz, 1H_a, CH₂), 5.98 (d, ²J 1.5 Hz, 1H_b, CH₂), 6.83 (s, 1H aromatic), 6.9 (s, 1H aromatic), 7.33-7.6 (m, 10H aromatics). ¹³C NMR (75 MHz, CDCl₃): d 12.6, 17.9, 19.2, 26.9, 57.1, 62.3, 72, 101.7, 108.2, 111.8, 112.2, 127.5, 129.5, 133, 134.8, 135.4, 147.4, 147.7, 176.4. HRMS (EI, 70 eV) m/z Calc. for C₃₆H₄₉BrO₆Si₂ [M]⁺: 712.2251. Found: 712.2262.

General procedure for the preparation of isoquinolinones 51, 52 and 53

To a solution of (0.87 mmol) of the corresponding acids 48, 49 and 50 in acetone (8 mL), cooled at 0 ºC, was added anydrous triethylamine (2.0 equiv.) and ethyl chloroformate (1.5 equiv.) and the resulting solution was stirred for 40 min. After this time, an aqueous solution of NaN₃ (1.5 equiv., 1.0 NaN₃ per 3 mL of distilled H₂O) was added and the mixture was stirred for 2 h at 0 ºC. Then the reaction mixture was diluted with dichloromethane (10 mL) and the organic layer was washed with brine (5 mL). The organic phase was dried over Na₂SO₄ and the solvent was evaporated. To the residue was added 15 mL of anhydrous toluene and the solution was refluxed for 2 h under an argon atmosphere. The reaction evolution was followed by IR. The disappearance of the absorption band at 2137 cm^-1 attributed to the azide, accompanied by the appearance of an absorption band at 2260 cm^-1, confirmed the formation of the isocyanate. After that, the solvent was evaporated and to the residue was added, under an argon atmosphere, anydrous ethyl ether (10 mL) and the reaction temperature was lowered to –78 ºC. Then, a solution of sec-butyl lithium (3.0 equiv.) in ether was added. The resulting mixture was stirred for 2 h at –78 ºC. After that time, distilled water was slowly added and the reaction medium was extracted with ethyl ether (3 × 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄ and the solvent was evaporated. The residue was purified by flash silica gel column chromatography to furnished the corresponding isoquinolinones.

(±)-8-(tert-Butyl-dimethyl-silanyloxy)-7-(tert-butyldiphenyl-silanyloxymethyl)-7,8-dihydro-6H[1,3] dioxol[4,5-g]-isoquinolin-5-one (51)

Colorless oil, 50% overall yield. IR n_max/cm^-1: 3415, 3070, 2956, 2930, 2857, 1670, 1612, 1264, 1112, 1038, 837, 701.¹H-NMR (500 MHz, CDCl₃): d –0.06 (s, 3H), –0.01 (s, 3H), 0.77 (s, 9H), 1.02 (s, 9H), 3.73 (m, 1H), 3.82 (d, ³J 6.1 Hz, 2H), 4.82 (d, ³J 4.3 Hz, 1H), 6.04 (s, 2H, OCH₂O), 6.77 (s, 1H aromatic), 7.15 (bs, 1H, NH), 7.36-7.64 (m, 10H, aromatics), 7.49 (s, 1H aromatic). ¹³CNMR (125 MHz, CDCl₃): d –4.8, –4.6, 18, 19.1, 25.6, 26.7, 57.7, 62.6, 67, 101.9, 106.3, 108.1, 121.1, 127.9, 129.9, 132.8, 135.5, 136.3, 147.8, 151.6, 165.5. HRMS (ESI) m/z Calc. for C₃₃H₄₃NNaO₅Si₂ [M + Na]⁺: 612.2572. Found: 612. 2389.

(±)-7-(4-Methoxy-benzyloxymethyl)-8-triisopropylsilanyloxy-7,8-dihydro-6H-[1,3]dioxol-[4,5-g]-isoquinolin5-one (52)

Yellow-tinged oil, 50% overall yield. IR n_max/cm^-1: 3371, 3011, 2956, 2931, 2858, 1670, 1612, 1513, 1474, 1250, 1111, 1038, 822, 755, 707.¹H NMR (500 MHz, CDCl₃) Diastereoisomers mixture: d 0.96-1.05 (m, 21H, 3 × isopropyl), 3.26-3.51 (m, 1H), 3.77 (m, 2H), 3.80 (s, 3H), 4.32-4.45 (m, 2H), 4.85 (d, ³J 3.3 Hz, 1H major diastereoisomer), 5.04 (d, ³J 3.6 Hz, 1H, minor diastereoisomer), 6.02 (m, 2H, CH₂), 6.35 (bs, 1H, NH), 6.41 (bs, 1H, NH), 6.72 (s, 1H aromatic), 6.85-7.22 (m, 4H aromatics), 7.49 (s, 1H aromatic). ¹³C NMR (125 MHz, CDCl₃) Major diastereoisomer: d 12.7, 17.9, 55.2, 56.5, 68, 68.7, 73, 101.6, 107.7, 108.2, 113.8, 122.4, 129.5, 129.6, 136, 147.9, 150.7, 159.3, 164.4. Minor diastereoisomers: d 12.7, 18, 55.2, 58, 67.7, 69.9, 73.2, 101.6, 106, 108, 113.8, 122.2, 129.2, 129.6, 134.5, 147.6, 150.6, 159.3, 164.2. HRMS (ESI) m/z Calc. for C₂₈H₃₉NNaO₆Si [M + Na]⁺: 536.2439. Found: 536.2412.

(±)-7-(tert-Butyl-diphenyl-silanyloxymethyl)-8-triisopropylsilanyloxy-7,8-dihydro-6H-[1,3]dioxol[4,5-g]isoquinolin-5-one (53)

Colorless oil, 50% overall yield. IR n_max/cm^-1: 3204, 3070, 2943, 2866, 1670, 1612, 1511, 1467, 1250, 1110, 1037, 934, 822, 752.¹H NMR (300 MHz, CDCl₃): d 0.95-1.15 (m, 30H, t-butyl + 3 × isopropyl), 3.72-3.88 (m, 2H), 4.21-4.24 (m, 1H), 5.0 (d, ³J 2.9 Hz, 1H), 6.01 (s, 2H), 6.41 (bs, 1H, NH), 6.83 (s, 1H aromatic), 7.5 (s, 1H aromatic), 7.33-7.64 (m, 10H aromatics).¹³C NMR (75 MHz, CDCl₃): d 12.7, 18.1, 19.1, 26.8, 58.2, 62.9, 67.9, 101.7, 106.2, 108.2, 121.9, 127.8, 129.8, 132.9, 135.5, 136.2, 147.6, 151, 164.9. HRMS (EI, 70eV) m/z Calc. for C₃₆H₄₉NO₅Si₂ [M]⁺: 631.3149. Found: 631.3100 [M]⁺.

(±)-8-Hydroxy-7-hydroxymethyl-7,8-dihydro-6H-[1,3] dioxol[4,5-g]-isoquinolin-5-one (11)

To a cooled solution of 51 (0.23g, 0.4 mmol) in THF (6 mL), at 0 ºC, was added a 1.0 mol L^-1 solution of tetrabutyl ammonium fluoride (TBAF, 1.6 mL, 1.6 mmol) and the resulting solution was stirred at 0 ºC for 5 min, then the bath was removed and the reaction was stirred for 2h at room temperature. After that, the solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL). The organic layer was washed with a saturated solution of NH₄Cl (2 × 10 mL), distilled water (2 × 10 mL), brine (2 × 10 mL) and dried over anhydrous sodium. After filtration, the solvent was removed and the residue was purified by flash silica gel column chromatography (ethyl acetate/methanol; 90:10) to provide 11, as a white solid, in 76% yield.

mp 198-200 ºC; IR n_max/cm^-1: 3423, 3196, 2917, 1669, 1611, 1503, 1465, 1408, 1383, 1262, 1038, 932, 903, 787, 695, 490, 432. ¹H NMR (300 MHz, DMSO-d₆): diastereoisomers mixture, d 3.34-3.70 (m, 1H, CH), 3.63 (bs, 2H, CH₂), 4.61 (d, ³J 4.8 Hz, 1H), 4.78 (bs,1H, OH), 4.89 (bs, 1H, OH), 6.10 (s, 2H, CH₂OCH₂), 6.99 (s, 1H aromatic), 7.29 (s, 1H aromatic), 7.48 (bs, 1H, NH). ¹³C NMR (125 MHz, DMSO-d₆): Major diastereoisomer, d 59.8, 62.3, 65.7, 102.4, 107.1, 107.9, 122.8, 137.3, 147.7, 150.9, 163.6. Minor diastereoisomer, d 57.8, 60.8, 65.4, 102.4, 107.2, 108.2, 123.7, 137.4, 147.9, 150.7, 164.3. HRMS (EI, 70 eV) m/z Calc. for C₁₁H₁₁NO₅ [M⁺]: 237.0637. Found: 237.0622.

(±)-2-(6-Bromo-benzo[1,3]dioxol-5-yl)-2-(tert-butyldimethyl-silanyloxy)-1-(tert-butyl-diphenyl-silanyloxymethyl)-ethylamine (62)

To a solution of acid 48 (1.0 g, 1.48 mmol) in acetone (10 mL), cooled at 0 ºC, was added anhydrous triethylamine (0.41 mL, 2.96 mmol, 2.0 equiv.) and freshly distilled ethyl chloroformate (0.22 mL, 2.2 mmol, 1.5 equiv.). The resulting solution was stirred for 40 min at 0 ºC. After this time, an aqueous solution of NaN₃ (0.43 mL, 1.0 g NaN₃ per 3 mL of distilled H₂O) was added. The mixture was stirred for 1h. The mixture was diluted with dichloromethane (10 mL) and, after separation, the organic phase was successively washed with distilled water (10 mL) and brine (10 mL). The organic phase was then dried over Na₂SO₄ and the solvent was evaporated. To the residue was added anydrous toluene (15 mL) and the resulting solution was refluxed for 2 h under an argon atmosphere. The evolution of the reaction was followed by IR. The disappearance of the absorption band at 2137 cm^-1, atributted to the acylazide associated with the appearance of the absorption band at 2255 cm^-1, confirmed isocyanate formation. The solvent was then evaporated and the residue was dissolved in THF (10 mL). The solution was cooled to 0 ºC and a solution of NaOH (1.5 mL, 1.5 mol L^-1) was slowly added. After that the resulting solution was stirred for 4 h at 70 ºC. After cooling to the room temperature, the reaction medium was diluted with ethyl ether (30 mL) and distilled water (10 mL). The phases were separated and the organic one was dried over Na₂SO₄ and the solvent was evaporated. The residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 50%) to furnish 62, as a colorless oil, in 62% overall yield.

IR n_max/cm^-1: 3375, 2953, 2929, 2856, 1474, 1252, 1237, 1112, 1040, 837, 778, 702. ¹H NMR (300 MHz, CDCl₃): d –0.13 (s, 3H); 0.07 (s, 3H), 0.90 (s, 9H), 1.10 (s, 9H), 2.76 (bs, 2H, NH₂), 2.98 (m, 1H), 3.63 (d, ³J 6.6 Hz, 2H), 5.21 (d, ³J 2.9 Hz, 1H), 5.93 (d, ²J 1.5 Hz, 1H_a, CH₂), 5.99 (d, ²J 1.5 Hz, 1H_b, CH₂), 6.94 (s, 1H aromatic), 6.98 (s, 1H aromatic), 7.35-7.7 (m, 10H aromatics). ¹³CNMR (75 MHz, CDCl₃): d –4.9, –4.4, 18.2, 19.3, 26, 27.1, 57.8, 65.6, 72.3, 101.5, 108.9, 111.5, 112.1, 127.5, 129.5, 133.3, 134.8, 135.4, 135.5, 147, 147.3. HRMS (ESI) m/z Calc. for C₃₂H₄₄BrNO₄Si₂ [M+2]⁺ -t-butyl: 586.1268. Found: 586.1203.

(±)-[2-(6-Bromo-benzo[1,3]dioxol-5-yl)-2-(tert-butyldimethyl-silanyloxy)-1-(tert-butyl-diphenyl-silanyloxymethyl)-ethyl]-[2-(4-methoxy-phenyl)-ethyl]amine (63)

A mixture of amine 59 (0.62 g, 0.4 mmol), Na₂CO₃ (0.13 g, 1.2 mmol) and 2-bromoethyl-(4-methoxy)benzene (0.24g, 0.6 mmol) in anhydrous acetonitrile (15 mL), under an argon atmosphere, was refluxed for 24 h. After that time, the solvent was evaporated and to the residue was added distilled water (15 mL). The aqueous phase was extracted with dichloromethane (30 mL) and the organic phase was dried over anhydrous Na₂SO₄ and the solvent was evaporated. The residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 20%) to afford alkylated amine 63 as a yellow-tinged oil in 85% yield.

IR n_max/cm^-1: 3432, 2952, 2929, 2856, 1735, 1611, 1512, 1474, 1274, 1111, 1077, 1039, 937, 837, 702. ¹H NMR (500 MHz, CDCl₃): d –0.15 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H), 1.09 (s, 9H), 2.29 (m, 1H), 2.45 (m, 2H), 2.61 (m, 1H), 2.8 (m, 1H), 3.65 (m, 2H), 3.80 (s, 3H), 5.30 (d, ³J 5.2 Hz, 1H), 5.98 (d, ²J 1.5 Hz, 1H), 6.01 (d, ²J 1.5 Hz, 1H), 6.79 (s, 1H), 6.80 (d, ³J 8.2 Hz, 2H), 6.94 (d, ³J 8.2 Hz, 2H), 7.40 (s, 1H, CH), 7.36-7.66 (m, 10H, aromatics). ¹³C NMR (125 MHz, CDCl₃): d –5.9, –4.9, 18, 19.3, 25.4, 26.8, 34.6, 50.8, 54.7, 61.6, 64.3, 65.8, 101.9, 108.2, 109.8, 113.4, 127.5, 129.4, 129.7, 130, 131.9, 132, 132.7, 132.9, 135.4, 135.5, 136.3, 146.1, 146.6, 147, 158. HRMS (ESI) m/z Calc. for C₄₁H₅₄NNaBrO₅Si₂ [M + Na]⁺: 798.2616. Found: 798.2601.

(±)-[2-(6-Bromo-benzo[1,3]dioxol-5-yl)-2-(tert-butyldimethyl-silanyloxy)-1-(tert-butyl-diphenyl-silanyloxymethyl)-ethyl]-[2-(4-methoxy-phenyl)-ethyl]-methoxycarbamate (64)

To a solution of amine 63 (0.26 g, 0.2 mmol) in dry acetone (10 mL), cooled to 0 ºC, was added anhydrous triethylamine (56 mL, 0.4 mmol) and methyl chloroformate (46 mL, 0.6 mmol). The resulting solution was stirred for 40 min at 0 ºC. After this time, the solvent was evaporated and the residue was diluted with ethyl acetate (20 mL). The organic phase was successively washed with distilled water (2 × 20 mL) and brine (2 × 20 mL) and finally was dried over anhydrous Na₂SO₄. The solvent was evaporated and the residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 20%) to give methoxy carbamate 64 as a colorless oil in 90% yield.

IR n_max/cm^-1: 3012, 2998, 2945, 2929, 2891, 2864, 1704, 1699, 1608, 1510, 1476, 1471, 1464, 1259, 1238, 1073, 1039, 936, 837, 701. ¹H NMR (300 MHz, CDCl₃): d –0.24 (s, 3H), –0.01 (s, 3H), 0.82 (s, 9H), 1.08 (s, 9H), (s, 3H), 3.8 (s, 3H), 3.67 (d, ²J 11 Hz, 2H), 5.08 (d, ³J Hz, 1H), 5.95 (d, ²J 1.5 Hz, 1H), 5.98 (d, ²J 1.5 Hz, 1H), 6.8 (s, 1H), 6.83 (d, ³J 8.4 Hz, 2H), 6.84 (s, 1H), 7.11 (d, ³J 8.4 Hz, 2H), 7.34-7.7 (m, 10H aromatics). ¹³C NMR (75 MHz, CDCl₃): d –5.4, –4.8, 17.8, 19.2, 25.6, 26.8, 34.7, 46.9, 52, 53.9, 61.1, 61.8, 73.8, 101.9, 108.4, 111.7, 111.8, 119.8, 127.7, 129.6, 129.7, 132.4, 133.2, 134.2, 135.6, 147.2, 147.3, 156.2, 157.1. HRMS (ESI) m/z Calc. for C₄₃H₅₆BrNNaO₇Si₂ [M + Na]⁺: 856.2671. Found: 856.2589.

(±)-8-(tert-Butyl-dimethyl-silanyloxy)-7-(tert-butyldiphenyl-silanyloxymethyl)-6-[2-(4-methoxy-phenyl)ethyl]-7,8-dihydro-6H-[1,3]dioxol[4,5-g]-isoquinolin-5one (65)

To a solution of carbamate 64 (0.15 g, 0.18 mmol) in anhydrous ethyl ether (5 mL), under an orgon atmosphere and at -78 ºC, was slowly added a solution 0.8 mol L^-1 of tert-butyl lithium (0.7 mL, 0.54 mmol). The resulting solution was stirred for 1 h at –78 ºC. After this time, the reaction medium was diluted with ethyl ether (15 mL) and distilled water (10 mL). The phases were separated and the organic one was dried over anhydrous Na₂SO₄. The solvent was evaporated and the residue was purified by flash silica gel column chromatography (hexane/ethyl acetate, 25%) to give isoquinolinone 65 as a colorless oil in 60% yield.

IR n_max/cm^-1: 3069, 2952, 2929, 2893, 2856, 1654, 1611, 1512, 1467, 1416, 1272, 1248, 1177, 1111, 1038, 937, 839, 823, 702. ¹H NMR (300 MHz, CDCl₃): d –0.17 (s, 3H), 0.03 (s, 3H), 0.85 (s, 9H), 0.92 (s, 9H), 2.88 (m, 1H _a, CH₂), 3.05-3.18 (m, 2H, CH₂), 3.26 (m, 1H_b, CH₂), 3.61-3.76 (m, 2H), 3.79 (s, 3H), 4.61-4.68 (m, 1H), 4.77 (d, ³J 6.2 Hz, 1H), 5.94 (d, ²J 1.3 Hz, 1H), 5.97 (d, ²J 1.3 Hz, 1H), 6.73 (s, 1H), 6.85 (d, ³J 8.8 Hz, 2H), 7.16 (d, ³J 8.8 Hz, 2H), 7.49 (s, 1H), 7.30-7.57 (m, 10H aromatics).¹³C NMR (75 MHz, CDCl₃): d –5.6, -4.9, 17.9, 18.9, 25.7, 26.5, 33.6, 51, 55.1, 61.8, 64.1, 67.5, 101.3, 103.9, 107.9, 113.9, 121.7, 127.7, 129.6, 129.7, 130, 131.6, 132.7, 132.9, 135.4, 135.5, 136.3, 146.8, 150.6, 158.1, 163.1. HRMS (ESI) m/z Calc. for C₄₂H₅₃NNaO₆Si₂ [M + Na]⁺: 746.3304. Found: 746.3295.

(±)-8-Hydroxy-7-hydroxymethyl-6-[2-(4-methoxy-phenyl)ethyl]-7,8-dihydro-6H-[1,3]dioxol[4,5-g]-isoquinolin-5one (70)

To a solution of isoquinolinone 65 (0.04 g, 0.05 mmol) in THF (5 mL) at 0 ºC was added a solution of tetrabutyl ammonium fluoride (TBAF) in THF (0.25 mL, 0.25 mmol). After 5 min, the ice bath was removed and the reaction temperature was allow to warm to the room temperature. Finally the reaction was stirred for 1 h at this temperature. Then, the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic phase was successively washed with a saturated solution of NH₄Cl, distilled water (2 × 20 mL) and finally dried over anhydrous Na₂SO₄. The solvent was evaporated and the residue was purified by flash silica gel column chromatography (hexane/ethyl acetate/methanol, 50:40:10) to give isoquinolinone 70, as yellow-tinged solid, in 75% yield.

mp 96.1-96.7 ºC. IR n_max/cm^-1: 3418, 3070, 2957, 2929, 2888, 2856, 1592, 1471, 1463, 1427, 1362, 1114, 1001, 820, 739, 701. ¹H NMR(300 MHz, CDCl₃): d 2.0 (bs, 1H, OH), 2.93 (m, 1H), 3.02-3.08 (m, 2H), 3.50 (m, 1H), 3.68 (m, 1H), 3.80 (s, 3H), 3.86 (m, 1H), 4.32-4.40 (m, 1H), 5.04 (d, ³J 5.5 Hz, 1H), 6.02 (s, 2H), 6.85 (d, ²J 8.5 Hz, 2H), 7.04 (s, 1H), 7.17 (d, ³J 8.5 Hz, 2H), 7.44 (s, 1H). ¹³C NMR (125 MHz, CDCl₃): d 34.1, 50.9, 55.4, 62.5, 64.3, 67.8, 101.7, 104.3, 109.7, 115.1, 115.9, 122.2, 129.9, 130.2, 132.6, 136.2, 147, 151.2, 158.3, 163.5. HRMS (70 eV, EI) Calc. for C₂₀H₂₁NO₆ 371.1369. Found: 371.1360.

(±)-7-(tert-Butyl-diphenyl-silanyloxymethyl)-8-hydroxy-6-[2(4-methoxy-phenyl)-ethyl]-7,8-dihydro-6H-[1,3]dioxol[4,5g]-isoquinolin-5-one (71)

A mixture of dihydroisoquinoline 70 (0.025 g, 0.067 mmol), a crystal of DMAP, anhydrous triethylamine (100 µL, 0.1 mmol) and tert-butyldiphenylsilyl chloride (20 µL, 0.013 mmol) in dry dichloromethane was stirred for 24 h at room temperature. After this period of time, the mixture was diluted with dichloromethane (10 mL) and the organic phase was washed with a saturated solution of NaHCO₃ (2 × 10 mL). The phases were separated and the organic one was dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by flash silica gel column chromatography (hexane/ethyl acetate 20%) to give mono-protected isoquinolinone 70, as a colorless oil, in 80% yield.

IR n_max/cm^-1: 3336, 3009, 2949, 2930, 2853, 1650, 1634, 1602, 1513, 1471, 1427, 1272, 1248, 1112, 1076, 1038, 823, 756, 703. ¹H NMR (300 MHz, CDCl₃): d 1.02 (s, 9H), 2.63-2.82 (m, 2H), 3.50 (m, 1H), 3.63 (m, 1H), 3.61-3.76 (m, 2H); 3.80 (s, 3H); 4.12-4.20 (m, 1H); 5.01 (d, ³J 5.5 Hz, 1H), 6.03 (d, ²J 1.1 Hz, 1H), 6.06 (d, ²J 1.1 Hz, 1H), 6.85 (d, ³J 8.8 Hz, 2H aromatics), 7.07 (d, ³J 8.8 Hz, 2H aromatics), 7.15 (s, 1H), 7.40 (s, 1H), 7.31-7.62 (m, 10H aromatics).¹³C NMR (75 MHz, CDCl₃): d 18.8, 26.8, 34, 48.9, 55.3, 59.8, 63.3, 68.6, 101.8, 104.7, 108, 114, 121.7, 127.8, 127.5, 130.2, 130.4, 131.6, 131.8, 132.1, 135.2, 135.5, 136.3, 146.9, 150.4, 158.3, 163.2. HRMS (70eV, EI) Calc. for C₃₆H₃₉NO₆Si [M⁺ -t-Bu] 550.2547. Found: 550.2539.

Acknowledgments

The authors thank FAPESP for grants to ECSL (# 00/07938-4) and for financial support (98/14640-0 and 02/00461-3). The authors also thank CNPq for a research fellowship to FC (301369/87-9). We thank Prof. C.H. Collins for English revision of this text.

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Received: July 24, 2007

Web Release Date: November 15, 2007

FAPESP helped in meeting the publication costs of this article.

Publication Dates

• Publication in this collection
  08 Jan 2008
• Date of issue
  2007

History

• Received
  24 July 2007
• Accepted
  15 Nov 2007