Intramolecular Diels–Alder route to angularly oxygenated hydrindanes. Synthesis of the functionalized bicylic skeleton present in galiellalactone

Accepted Manuscript Intramolecular Diels-Alder Route to angularly oxygenated hydrindanes. Synthesis of the functionalized bicylic skeleton present in galiellalactone Md. Firoj Hossain, Ram Naresh Yadav, Sujit Mondal, Anupam Jana, Subrata Ghosh PII:

S0040-4020(13)01095-8

DOI:

10.1016/j.tet.2013.07.014

Reference:

TET 24595

To appear in:

Tetrahedron

Received Date: 30 April 2013 Revised Date:

3 July 2013

Accepted Date: 4 July 2013

Please cite this article as: Hossain MF, Yadav RN, Mondal S, Jana A, Ghosh S, Intramolecular DielsAlder Route to angularly oxygenated hydrindanes. Synthesis of the functionalized bicylic skeleton present in galiellalactone, Tetrahedron (2013), doi: 10.1016/j.tet.2013.07.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

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Md. Firoj Hossain, Ram Naresh Yadav, Sujit Mondal, Anupam Jana and Subrata Ghosh*

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Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India

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Intramolecular Diels-Alder route to angularly oxygenated hydrindanes. Synthesis of the functionalized bicylic skeleton present in galiellalactone

OH H

O O (+)-Galiellalactone

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Tetrahedron j o u r n a l h o m e p a g e : w w w . e l s e vi e r . c o m

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Intramolecular Diels-Alder Route to angularly oxygenated hydrindanes. Synthesis of the functionalized bicylic skeleton present in galiellalactone Md. Firoj Hossain, Ram Naresh Yadav, Sujit Mondal, Anupam Jana and Subrata Ghosh*

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Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India

ABSTRACT

Article history: Received Received in revised form Accepted Available online

Intramolecular Diels-Alder reaction of trienones embedded in a sugar derivative with or without Me substituents on the diene part has been investigated for synthesis of hydrindanes with angular oxygen functionality. One of these adducts has been transformed to a functionalized bicyclic skeleton present in galiellalactone.

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ARTICLE INFO

Keywords: Carbohydrate Diels-Alder reaction Hydrindanes Metathesis

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1. Introduction

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Hydrindanes with angular oxygen functionality is found in several natural products. Galiellalactone 11 and acremostrictin 22 (Fig. 1) are two representative examples. Galiellalactone 1 was isolated first by Anke and Hautzel from cultures of the ascomycete Galiella rufa A75-86. Subsequently, it was found in the ascomycete strain A111-95 collected from dead wood in Chile. 4 H 3 5 2a OH H O 2 O 7b 5a 6 7a OH O 1 7 O OH O H 2 1 Figure 1. Structures of galiellalactone 1 and acremostrictin 2

Galiellalactone and its analogues may be of great importance for uncovering the biochemical pathway of IL-6 signalling and may serve as lead structures for development of new drugs for treating diseases linked to this pathway. Thus development of an efficient and flexible synthetic route to 1 and its analogues is necessary. Preliminary structure-activity relationship studies have established that the angular hydroxyl group is one of the fundamental features for the biological activity of 1. It has also been demonstrated that (+)-galiellalactone and C4-epigaliellalactone are equally active with (-)-galiellalactone.  ∗ Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805; E-mail address: [email protected] (S. Ghosh).

2009 Elsevier Ltd. All rights reserved.

H

H

1

HO 2C HO H OH

O O

3

H

O O

4 CH O

O O

O O

O

O O

5 6 Scheme 1. Retrosynthetic approach to galiellalactone The most difficult task in the synthesis of 1 and 2 is the introduction of the hydroxyl group at the angular position. A number of synthetic attempts3 to 1 have been reported in literature. Only one of them has been successful in accomplishing the total synthesis of (+)-galiellalactone.3a The other approaches have led to synthesis of either the C-7b de-oxy analogue3d of 1 or the 7, 7-dimethyl analogue3c of 1 or pre-galieallactone,3b a biosynthetic precursor of 1. None of these approaches dealt with direct construction of the hydrindane moiety with angular hydroxyl group. Our synthetic plan was based on designing a route that introduces directly the angular oxygen functionality in the hydrindane moiety so as to address the synthesis of both 1 and 2. Retrosynthetically 1 may be obtained through lactonization of the dihydroxy acid 3 which in principle should be available from 4 (Scheme 1). The sugar residue in 4 will

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Tetrahedron

provide the carboxylic acid to be required for lactonization as well as the angular hydroxyl group. It will also impart enantiopurity in the molecule. Compound 4 should be available through an intramolecular Diels-Alder (IMDA) reaction of the trienone 5 to be available from the sugar derivative 6.

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H O O O O

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∆ ref . 6

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IMDA reaction4 provides a unique way to construct hydrindanes with good diastereoselectivity and has been used extensively in organic synthesis. However, use of IMDA to create hydrindane with angular hydroxyl group5 is a formidable task. To the best of our knowledge there is no report on synthesis of hydrindanes with angular oxygen functionality employing

substrates leading to hydrindanes. The substrates 14a, b and 5 required for this purpose were prepared from the sugar derived unsaturated aldehyde 67 using the general protocol as depicted in Scheme 3. Addition of Grignard reagent prepared from 4-bromo-1-butene to the aldehyde 6 gave the hydroxy compound 10 as a diastereoisomeric mixture (ca. 5:1 by 1H NMR spectrum of the corresponding acetate derivative 11) in 80% yield. As the asymmetry at the center bearing the hydroxyl group will be destroyed during its transformation to the trienone, subsequent reactions were carried out with this mixture. The hydroxyl group in 10 was then acetylated to produce the acetate 11 in excellent yield. The acetate 11 was subjected to cross metathesis8 with crotonaldehyde in presence of Grubbs’ second generation catalyst (G II) to provide the aldehyde 12a in 87% yield. Wittig olefination of the aldehyde 12a with the ylide generated from methyltriphenylphosphonium bromide and nBuLi provided the diene 13a in 65% yield. Deacetylation of 13a followed by oxidation of the corresponding hydroxy compound with Dess-Martin periodinane9 (DMP) afforded the trienone 14a in 95% yield. Similarly cross metathesis of 11 with methacrolein and methyl vinyl ketone (MVK) under identical condition gave the enones 12b and 12c respectively in excellent yields. The enones 12b and 12c were then converted to the trienones 14b and 5 respectively in over all excellent yield following Wittig olefination-deacetylation-DMP oxidation sequence as described above for transformation of 13a to 14a. With the trienones ready in hand, these were subjected to Diels-Alder reaction by heating a toluene solution in a sealed tube at 150-160 OC for 24 hr. The trienone 14a without any methyl substituent on the diene moiety gave adducts 15a as an inseparable mixture in 1.3:1 ratio. The trienone 14b gave a 1:1 mixture of adducts 15b. On the other hand the trienone 5 gave a mixture of two adducts 4 in ca. 1.5:1 ratio. It may be noted that unlike the diastereoselectivity observed in IMDA of the trienones 7a and 7b to form exclusively the trans- and cis-decalins 8a and 9b respectively, IMDA reaction of the corresponding lower homolog (i.e. the trienones 14b and 5) proceeded with poor diastereoselectivity to form mixture of cis- and trans-hydrindanes 15b and 4 respectively. None of the components in these mixtures of adducts could be separated by column chromatography.

a, R1=Me, R2=H, b, R 1=H, R2=Me, c, R1=R2=H Scheme 2. IMDA reaction of the trienones 7 to decalins

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IMDA reaction. We have recently reported an IMDA approach to construct decalins6 stereoselectively with angular oxygen functionality. It was noted that the position of the substituents on the diene moiety has a profound influence on the stereochemical outcome at the ring junction. Thus, while the trienone 7a gave exclusively the trans-fused ring system 8a, the trienone 7b gave exclusively the cis-fused ring system 9b (Scheme 2). The trienone 7c, on the other hand, led to a mixture of both cis- and tran-fused ring systems 8c and 9c. Encouraged by this observation, we expected that trienone 5, the lower homolog of 7b, would provide the desired cis-fused hydrindane 4. Herein, we report the results of our investigation on IMDA reaction of the trienones 14a, b and 5 leading to hydrindanes with angular oxygen functionality along with our attempt towards the synthesis of 1 culminating in the synthesis of the fully functionalized bicyclic skeleton present in galiellalactone. 2. Results and Discussion

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We initially focussed on determining the influence of methyl substituents on the stereochemical outcome in IMDA reaction of

CH 2:CH(CH2) 2Br 6

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Mg, Et2O, 80%

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Crotonaldehyde f or 12a Methacrolein for 12b

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13a, R1=R2=H b, R1=Me, R2=H c, R1=H, R2=Me

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Ph 3PCH 2Br,THF, n-BuLi for 12a , b KHMDS f or 12c 55-60%

12a, R 1=R2=H b , R1=Me, R2=H c, R1=H, R2=Me

11, R=OAc

OAc 2. DMP, DCM, 90-95%

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1. K 2CO3, MeOH, 90-95%

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Scheme 3. Synthesis of angularly oxygenated hydrindanes

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O O 18 (64%) Scheme 4 . Hydrogenation of 4 and 17 EtOH, 78%

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Figure 2. Ellipsoid representation of compounds 17 and 19 (at 30% probability level) We next focussed on transformation of 18 towards the synthesis of 1 (Scheme 5). Reduction of the carbonyl group in 18 with lithium aluminium hydride in diethyl ether provided exclusively the carbinol 20 in 98% yield as a crystalline solid, m.p. 54-56 OC. Stereochemical assignment to 20 is based on analysis of 2 D NMR spectra (COSY, NOESY and HSQC) of the compound 28 prepared from it as described below. Treatment of the acetonide 20 with aqueous sulphuric acid effected smooth deketalization to afford 21 in 98% yield. Treatment of the triol 21 with sodium metaperiodate provided an aldehyde in 81% yield. Examination of the 1H NMR spectrum of the product revealed that the C-7a proton (adjacent to the secondary OH group) which appeared as a triplet (J 8.4 Hz) at δ 5.37 is deshielded by 1.341.37 ppm over those observed for 20 (δ 4.01) and 21 (δ 3.90). This indicated that the resulting product is the compound 23 and not the expected product 22.11 The migration of the formyl group from the formate at C-7b to the OH group at C-7a in 22 probably proceeds through the transition state 24 to produce 23 during periodic acid oxidation of 21. The driving force for this migration is probably the greater stability of the formate ester 23 over 22. Pinnick oxidation12 (NaClO2) of the hydroxy-aldehyde 23 provided in 88% yield the carboxylic acid 25. The latter was characterized as its methyl ester 26 prepared by treatment with ethereal diazomethane solution. The formate 25 was then treated with aqueous methanolic KOH to provide the dihydroxy-acid 27 in 71% yield. When the ester 26 was treated with dimethoxy methane in the presence of BF3.Et2O as catalyst at rt, the ketal 28 was obtained in 61% yield. The facile formation of the ketal 28 from 26 indicated that the C-7a OH group is syn to the C-7b oxygen functionality. A cross peak observed in the NOESY spectrum between C-2a H at δ 3.01 (dd, J 2, 5 Hz) and C-7a H at δ 4.42 (d, J 7Hz) confirmed the syn stereochemical assignment of these protons. The assignment of stereochemistry to 28 also confirmed the structure of the hydroxy compound 20. In order to make 3 an attempt was then made to introduce a double bond conjugated to the ester unit in 28 through phenyl selenenylationoxidative elimination following the procedure of Sharpless et al13 leading to an intractable mixture.

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Inspection of the structures of adducts reveals that adducts 4 have the methyl substituent at position required for synthesis of galiellalactone 1. Thus we decided to proceed with this mixture for synthesis of galiellalactone anticipating that at a late stage in the synthesis, purification would be possible. Attempted hydrogenation of an ethanolic solution of the mixture of adducts 4 over 10% Pd/C as catalyst provided a mixture of two compounds in nearly 1:1 ratio. Column chromatography of this mixture afforded the pure compounds one of which was a crystalline solid, m.p. 96-98 OC (Scheme 4). 1H and 13C NMR spectra of these compounds revealed that both of these compounds are unsaturated ketones with double bond isomerized. Single crystal X-ray10 diffraction (Fig. 2) of the solid component showed that it has the cis-hydrindane structure as depicted in 17. Thus the liquid component was assigned the trans hydrindane structure 16. The compounds 16 and 17 were isolated in 38% and 42% yields respectively. Hydrogenation of the unsaturated ketone 17 with an excess of 10% Pd/C for prolonged time afforded after column chromatography the saturated ketones 18 (64%) as a liquid and 19 (14%) as a crystalline solid, m.p. 102-104 OC. Structure of the minor component 19 was established through X-ray (Fig. 2). Thus the major component was assigned the structure 18. The compound 18 has the Me group anti to the ring junction i.e. the desired stereochemistry at three of the four stereocenters as in galiellalactone 1.

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28 27 Scheme 5. Synthesis of (+)-dihydro seco-galiellalactone (27)

3. Conclusion IMDA reaction of trienones embedded in a sugar derivative with or without Me substituent on the diene moiety proceeds with moderate diastereoselectivity to produce hydrindanes with angular oxygen functionality. An attempt was made for synthesis of galiellalactone using the appropriate Diels-Alder adduct but ended up with a synthesis of (+)-dihydro-C-7a-epi-secogaliellalactone (27). The present route can be extended for synthesis of analogues without Me group as well as with Me group at positions other than that present in galiellalactone.

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4.1 General

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Melting points were taken in open capillaries in sulfuric acid bath and are uncorrected. Petroleum refers to the fraction of petroleum ether having bp 60-80 oC. A usual work up of the reaction mixture consists of extraction with diethyl ether, washing with brine, drying over Na2SO4, and removal of the solvent in vacuo. Column chromatography was carried out with silica gel (60-120 mesh). Peak positions in 1H and 13C NMR spectra are indicated in ppm downfield from internal TMS in δ units. Unless otherwise stated NMR spectra were recorded in CDCl3 solution at 300 MHz for 1H and 75 MHz for 13C on Bruker-Avance DPX300 instrument. 13C Peaks assignment is based on DEPT experiment. IR spectra were recorded as liquid film for liquids and in KBr plate for solids on Shimadzu FTIR8300 instrument. Optical rotations were measured using Jasco P1020 digital polarimeter and [α]D values are given in units of 10-1 deg cm2 g-1. Mass spectra were measured in a QTOF I (quadrupole-hexapole-TOF) mass spectrometer with an orthogonal Z-spray-electrospray interface on Micro (YA-263) mass spectrometer (Manchester, UK). Unless otherwise indicated, all reactions were carried out under a blanket of Ar.

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4. Experimental section

Hz), 1.44 (3 H, s), 1.42 (3 H, s); δC (125 MHz, CDCl3) 170.0 (CO), 159.7 (C), 137.2 (CH), 115.6 (CH2), 112.5 (C), 106.5 (OCHO), 99.5 (CH), 83.5 (OCH), 68.6 (OCH), 31.02 (CH2), 29.3 (CH2), 28.2 (CH3), 28.0 (CH3), 21.0 (CH3); HRMS (ESI) m/z calcd for C14H20O5Na (M+Na)+, 291.1208; found 291.1208. 4.1.3. (E)-1-((3aR,6aR)-2,2-dimethyl-3a,6a-dihydrofuro[3,2d][1,3]dioxol-5-yl)-6-oxohex-4-enyl acetate (12a) To a solution of the acetate 11 (118 mg, 0.44 mmol) in anhydrous degassed DCM (10 mL) and crotonaldehyde (0.06 mL, 0.66 mmol) was added G II (37 mg, 0.044 mmol). The reaction mixture was refluxed for 15 min. The crude mass obtained after removal of the solvent was purified by column chromatography [petroleum-diethyl ether (6:1)] to afford the aldehyde 12a (117 mg, 90%) as light yellow oil; Rf (20% EtOAc/petroleum) 0.25; [α]D26 –16.44 (c 5.57, CHCl3); νmax(liquid film) 1748 cm-1; δH (500 MHz, CDCl3) (for major diastreoisomer) 9.50 (1 H, d, J 7.5 Hz), 6.80 (1 H, dt, J 6.7, 15.5 Hz), 6.10 (1 H, dd, J 7.5, 15.8 Hz), 6.04 (1 H, d, J 5.0 Hz), 5.37 (1 H, t, J 6.0 Hz), 5.26 (1 H, dd, J 2.0, 5.0 Hz), 5.13 (1 H, br s), 2.39 (2 H, dd, J 7.0, 15.0 Hz), 2.07 (3 H, s), 1.95 (2 H, dd, J 7.5, 14.3 Hz), 1.43 (3 H, s), 1.41 (3 H, s); δC (125 MHz, CDCl3) 193.7 (CHO), 169.9 (CO), 158.9 (C), 156.3 (CH), 133.5 (CH), 112.5 (C), 106.6 (OCHO), 99.5 (CH), 83.3 (OCH), 68.2 (OCH), 30.0 (CH2), 28.2 (CH2), 28.1 (CH3), 27.9 (CH3), 20.9 (CH3); HRMS (ESI) m/z calcd for C15H20O6Na (M+Na)+, 319.1158; found 319.1158. 4.1.4. (E)-1-((3aR,6aR)-2,2-dimethyl-3a,6a-dihydrofuro[3,2d][1,3]dioxol-5-yl)-5-methyl-6-oxohex-4-enyl acetate (12b) Following the procedure for synthesis of 12a, compound 11 (750 mg, 2.8 mmol) on cross metathesis with methacrolein (0.35 mL, 4.2 mmol) using G II (36 mg, 0.042 mmol) afforded the aldehyde 12b (755 mg, 87%); [α] D23 –13.0 (c 7.2, CHCl3); νmax(liquid film) 1744 cm-1; δH (500 MHz, CDCl3) (for major diastreoisomer) 9.35 (1 H, s), 6.41 (1 H, t, J 7.5 Hz), 6.0 (1 H, t, J 6.0 Hz), 5.36-5.23 (2 H, m), 5.12 (1 H, brs), 2.38 (2 H, q, J 7.5 Hz), 2.06 (3 H, s), 1.93 (1 H, q, J 7.5 Hz), 1.74 (1 H, q, J 7.5 Hz), 1.70 (3 H, s), 1.41 (3 H, s), 1.39 (3 H, s); δC (125 MHz, CDCl3) 194.9 (CHO), 169.9 (CO), 158.95 (C), 152.3 (CH), 140.1 (C), 129.7 (CH), 112.5 (C), 106.5 (OCHO), 99.4 (CH), 83.3 (OCH), 68.3 (OCH), 30.2 (CH2), 28.1 (CH3), 28.0 (CH3), 20.9 (CH3), 9.26 (CH3); HRMS (ESI) m/z calcd for C16H22O6Na (M+Na)+, 333.1314; found 333.1314. 4.1.5. (E)-1-((3aR,6aR)-2,2-dimethyl-3a,6a-dihydrofuro[3,2d][1,3]dioxol-5-yl)-6-oxohept-4-enyl acetate (12c) Following the procedure for synthesis of 12a, compound 11 (600 mg, 2.23 mmol) on cross metathesis with methyl vinyl ketone (0.28 mL, 3.36 mmol) using G II (28 mg, 0.033 mmol) afforded the compound 12c (625 mg, 90%); [α]D26 – 10.67 (c 3.5, CHCl3); νmax(liquid film) 1744 cm-1; δH (500 MHz, CDCl3) (for major diastreoisomer) 6.75-6.68 (1 H, m), 6.06-6.02 (2 H, m ), 5.33 (1 H, d, J 6.0 Hz), 5.24 (1 H, dd, J 2.0, 5.0 Hz), 5.10 (1 H, br s), 2.30-2.22 (2 H, m), 2.20 (3 H, s), 2.05 (3 H, s), 1.90 (2 H, dd, J 7.0, 14.3 Hz), 1.40 (6 H, s); δC (125 MHz, CDCl3) 198.3 (CO), 169.9 (CO), 159.0 (C), 146.2 (CH), 131.8 (CH), 112.5 (C), 106.5 (OCHO), 99.7 (CH), 83.3 (OCH), 68.3 (OCH), 30.1 (CH2), 29.8 (CH2), 28.1 (CH3), 27.9 (CH3), 27.1 (CH3), 20.8 (CH3); HRMS (ESI) m/z calcd for C16H22O6Na (M+Na)+, 333.1314; found 333.1314. 4.1.6. (E)-1-((3aR,6aR)-2,2-dimethyl-3a,6a-dihydrofuro[3,2d][1,3]dioxol-5-yl)hepta-4,6-dienyl acetate (13a)

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4.1.1. 1-((3aR,6aR)-2,2-dimethyl-3a,6a-dihydrofuro[3,2d][1,3]dioxol-5-yl)pent-4-en-1-ol (10) To the Grignard reagent [prepared from 4-bromo-1butene (3.8 mL, 35.3 mmol) and magnesium (847 mg, 37.0 mmol) in 30 ml of diethyl ether] cooled at -30 oC was added a solution of the aldehyde 6 (3.0 g, 17.6 mmol) in diethyl ether (20 mL) over a period of 10 min. After addition of the aldehyde the reaction mixture was stirred for 1 h at 0 oC. The reaction mixture was quenched by addition of saturated aqueous NH4Cl solution (6 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (3x10 mL). The combined organic layer was dried and concentrated to give a light yellow liquid. The crude compound was then chromatographed using petroleum-diethyl ether (8:1) as the eluent to afford the alcohol 10 (3.19 g, 80%); Rf (30% EtOAc/petroleum) 0.60; [α]D26 –14.2 (c 2.0, CHCl3); δH (300 MHz, CDCl3) (for major diastreoisomer) 6.04 (1 H, d, J 4.4 Hz), 5.81-5.75 (1 H, m), 5.27 (1 H, br s), 5.134.95 (3 H, m), 4.18 (1 H, br s), 2.26–2.15 (3 H, m), 1.73 (2 H, dt, J 7.5, 15.0 Hz), 1.44 (3 H, s), 1.41 (3 H, s); δC (75 MHz, CDCl3) 163.3 (C), 137.8 (CH), 115.5 (CH2), 112.3 (C), 106.4 (OCHO), 97.6 (CH), 83.7 (OCH), 67.4 (OCH), 33.4 (CH2), 29.6 (CH2), 28.3 (CH3), 27.9 (CH3); HRMS (ESI) m/z calcd for C12H18O4Na (M+Na)+, 249.1103; found 249.1103. 4.1.2. (1-((3aR,6aR)-2,2-dimethyl-3a,6a-dihydrofuro[3,2d][1,3]dioxol-5-yl)pent-4-enyl acetate (11) To a solution of the alcohol 10 (750 mg, 3.32 mmol) in DCM (20 mL) was added sequentially triethylamine (0.92 mL, 6.64 mmol), DMAP (36 mg, 1.0 mmol) and acetic anhydride (0.47 mL, 5.0 mmol). The mixture was then stirred at rt for 2 h. The reaction mixture was made alkaline with saturated aqueous NaHCO3 solution (1 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (3x5 mL). The combined organic layer was dried and concentrated. The crude mass was purified through column chromatography with petroleum-diethyl ether (9:1) as eluent to provide the acetate 11 (845 mg, 95%) as a light yellow oil; Rf (20% EtOAc/petroleum) 0.60; [α]D26 –24.00 (c 5.14, CHCl3); νmax(liquid film) 1746 cm-1; δH (500 MHz, CDCl3) (for major diastreoisomer) 6.05 (1 H, d, J 5.5 Hz), 5.80-5.74 (1 H, m), 5.34 (1 H, dd, J 7.5, 13.3 Hz), 5.26 (1 H, dd, J 2.5, 4.5 Hz), 5.12 (1 H, br s), 5.03 (1 H, br s), 4.98 (1 H, d, J 11.0 Hz), 2.14-2.07 (4 H, m), 1.81 (3 H, dd, J 7.5, 14.5

To a suspension of methyltriphenylphosphonium bromide (724 mg, 2.02 mmol) in anhydrous THF (8 mL) at 0 oC, n-BuLi (1.1 mL, 1.82 mmol, 1.6 M in hexane) was added drop wise and stirred for 30 min at the same temperature. A solution of the aldehyde 12a (300 mg, 1.01 mmol) in THF (2 mL) was

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133.9 (CH), 132.0 (CH), 115.5 (CH2), 112.4 (C), 106.4 (OCHO), 97.7 (CH), 83.7 (OCH), 67.3 (OCH), 33.7 (CH2), 28.3 (CH2), 28.2 (CH3), 28.0 (CH3); HRMS (ESI) m/z calcd for C14H20O4Na (M+Na)+, 275.1259; found 275.1259. A solution of this alcohol (50 mg, 0.2 mmol) in DCM (5 mL) was stirred with DMP (127 mg, 0.3 mmol) for 30 min at 0 o C. The reaction mixture was stirred for additional 1 h at rt, quenched by Na2S2O3 solution doped with NaHCO3 and was stirred vigorously. After usual work up, the crude mass was column chromatographed using petroleum-diethyl ether (4:1) to give the adduct 14a (45 mg, 90%); [α]D25 16.4 (c 1.37, CHCl3); νmax(liquid film) 1699 cm-1; δH (500 MHz, CDCl3) 6.25 (1 H, dt, J 9.0, 17.0 Hz), 6.12 (1 H, d, J 5.5 Hz), 6.05 (1 H, dd, J 11.0, 15.3 Hz), 5.98 (1 H, d, J 2.5 Hz), 5.7-5.63 (1 H, m), 5.36 (1 H, dd, J 2.5, 5.5 Hz), 5.1 (1 H, d, J 17.0 Hz), 4.96 (1 H, d, J 10.0 Hz), 2.75 (2 H, t, J 7.0 Hz), 2.4 (2 H, q, J 7.0 Hz), 1.43 (3 H, s), 1.40 (3H, s); δC (125 MHz, CDCl3) 192.9 (CO), 156.0 (C), 136.9 (CH), 132.6 (CH), 132.2 (CH), 115.9 (CH2), 113.1 (C), 108.8 (CH), 106.7 (OCHO), 83.0 (OCH), 38.8 (CH2), 28.1 (CH3), 27.8 (CH3), 26.4 (CH2); HRMS (ESI) m/z calcd for C14H18O4Na (M+Na)+, 273.1103; found 273.1102. 4.1.10. (E)-1-((3aR,6aR)-2,2-dimethyl-3a,6a-dihydrofuro[3,2d][1,3]dioxol-5-yl)-5-methylhepta-4,6-dien-1-one (14b) Following the procedure for the synthesis of 14a, the compound 13b (100 mg, 0.32 mmol) was deacetylated with K2CO3 (90 mg, 0.65 mmol) in MeOH to afford the corresponding alcohol (82 mg, 95%); [α] D24 –5.6 (c 3.27, CHCl3); δH (500 MHz, CDCl3) 6.35 (1H, dd, J 10.5, 17.3 Hz), 6.5 (1H, d, J 5.0 Hz), 5.47 (1 H, t, J 7.5 Hz), 5.28 (1 H, d, J 5.0 Hz), 5.1 (1 H, brs), 5.1 (1 H, d, J 17.5 Hz), 4.93 (1 H, d, J 10.5 Hz), 4.18 (1 H, t, J 6.5 Hz), 2.28 (2 H, dd, J 7.5, 15.0 Hz), 2.0 (1 H, brs), 1.81–1.69 (2 H, m), 1.74 (3 H, s), 1.46 (3 H, s), 1.43 (3 H, s); δC (125 MHz, CDCl3) 163.2 (C), 141.4 (CH), 135.1 (C), 131.7 (CH), 112.3 (C), 111.1 (CH2), 106.4 (OCHO), 97.7 (CH), 83.7 (OCH), 67.5 (OCH), 34.0 (CH2), 28.4 (CH3), 28.0 (CH3), 24.0 (CH2) , 11.8 (CH3); HRMS (ESI) m/z calcd for C15H22O4Na (M+Na)+, 289.1416; found 289.1418. A solution of this alcohol (60 mg, 0.22 mmol) in DCM (5 mL) was oxidized with DMP (144 mg, 0.34 mmol) following the above procedure to afford after column chromatography the compound 14b (54 mg, 90%) as a viscous liquid; [α]D24 –21.4 (c 1.1, CHCl3); νmax(liquid film) 1697 cm-1; δH (500 MHz, CDCl3) 6.31 (1 H, dd, J 10.5, 17.3 Hz), 6.15 (1 H, d, J 5.0 Hz), 5.99 (1 H, s), 5.41 (1 H, t, J 7.5 Hz), 5.36 (1 H, t, J 2.5 Hz), 5.1 (1 H, d, J 17.5 Hz), 4.93 (1 H, d, J 10.5 Hz), 2.73 (2 H, t, J 7.5 Hz), 2.45 (2 H, q, J 7.5 Hz), 1.73 (3 H, s), 1.43 (3 H, s), 1.41 (3 H, s); δC (125 MHz, CDCl3) 193.0 (CO), 156.0 (C), 141.2 (CH), 135.4 (C), 130.37 (CH), 113.08 (C), 111.45 (CH2), 108.7 (CH), 106.7 (OCHO), 83.0 (OCH), 39.0 (CH2), 28.1 (CH3), 27.78 (CH3), 22.4 (CH2), 11.7 (CH3); HRMS (ESI) m/z calcd for C15H20O4Na (M+Na)+, 287.1259; found 287.1258. 4.1.11. (E)-1-((3aR,6aR)-2,2-dimethyl-3a,6a-dihydrofuro[3,2d][1,3]dioxol-5-yl)-6-methylhepta-4,6-dien-1-one (5) Following the procedure for the synthesis of 14a,b the compound 13c (150 mg, 0.49 mmol) was deacetylated with K2CO3 (135 mg, 0.97 mmol) in MeOH to afford the corresponding alcohol (123 mg, 95%); [α]D25 0.86 (c 3.62, CHCl3); δH (300 MHz, CDCl3) 6.18 (1 H, d, J 15.6 Hz), 6.05 (1 H, d, J 5.2 Hz), 5.63 (1 H, td, J 7.5, 15.6 Hz), 5.28 (1 H, dd, J 1.8, 5.0 Hz), 5.14 (1 H, d, J 1. 5 Hz), 4.90 (2 H, br s), 4.21-4.19 (1 H, m), 2.26 (2 H, td, J 7.2, 14.5 Hz), 2.02 (1 H, br s), 1.82 (3 H, s), 1.80-1.68 (2 H, m), 1.46 (3 H, s), 1.43 (3 H, s); δC (75 MHz, CDCl3) 163.2 (C), 142.0 (C), 133.9 (CH), 129.4 (CH), 115.0 (CH2), 112.4 (C), 106.4 (OCHO), 97.7 (CH), 83.7 (OCH), 67.5 (OCH), 33.9 (CH2), 28.4 (CH2), 27.9 (CH3), 27.8 (CH3),

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then added to the reaction mixture and was stirred for 2 h. The reaction mixture was quenched by addition of water. After usual work up the crude mass was purified through column chromatography [petroleum-diethyl ether (4:1)] to afford the acetate 13a (179 mg, 60%) as light yellow oil; [α]D25 –11.9 (c 7.2, CHCl3); νmax(liquid film) 1746 cm-1; δH (300 MHz, CDCl3) (for major diastreoisomer) 6.29-6.20 (1 H, m), 6.06-5.98 (2 H, m), 5.67-5.60 (1 H, m), 5.33 (1 H, t, J 6.3 Hz), 5.24 (1 H, dd, J 1.8, 5.1 Hz), 5.10 (1 H, d, J 1.1 Hz), 5.05 (1 H, s), 4.95 (1 H, d, J 10.1 Hz), 2.16-2.08 (2 H, m), 2.06 (3 H, s), 1.89–1.79 (2 H, m), 1.42 (3 H, s), 1.40 (3 H, s); δC (75 MHz, CDCl3) 170.0 (CO), 159.5 (C), 136.9 (CH), 133.1 (CH), 132.0 (CH), 115.6 (CH2), 112.4 (C), 106.4 (OCHO), 99.1 (CH), 83.4 (OCH), 68.5 (OCH), 31.2 (CH2), 28.2 (CH2), 28.05 (CH3), 27.9 (CH3), 21.0 (CH3); HRMS (ESI) m/z calcd for C16H22O5Na (M+Na)+, 317.1365; found 317.1366. 4.1.7. (Z)-1-((3aR,6aR)-2,2-dimethyl-3a,6a-dihydrofuro[3,2d][1,3]dioxol-5-yl)-5-methylhepta-4,6-dienyl acetate (13b) Following the procedure described for Wittig reaction of the aldehyde 12a, the aldehyde 12b (1.6 g, 5.16 mmol) on treatment with the ylide generated from methyltriphenylphosphonium bromide (5.5 g, 15.48 mmol) gave the diene 13b (1.03 g, 65%); [α]D24 –11.66 (c 5.0, CHCl3);νmax (liquid film) 1715 cm-1; δH (500 MHz, CDCl3) (for major diastreoisomer) 6.32 (1 H, dd, J 10.5, 17.5 Hz), 6.0 (1 H, d, J 5.0 Hz), 5.4 (1 H, t, J 7.5 Hz), 5.31 (1 H, t, J 6.5 Hz), 5.25 (1 H, dd, J 2.0, 5.0 Hz), 5.1 (1 H, d, J 2.0 Hz), 5.0 (1 H, d, J 17.5 Hz), 4.9 (1 H, d, J 10.5 Hz), 2.17 (2 H, dd, J 7.0, 15.0 Hz), 2.06 (3 H, s), 1.83–1.78 (2 H, m), 1.68 (3 H, s), 1.42 (3 H, s), 1.40 (3 H, s); δC (125 MHz, CDCl3) 170.0 (CO), 159.6 (C), 141.3 (CH), 135.1 (C), 131.1 (CH), 112.4 (C), 111.25 (CH2), 106.5 (OCHO), 99.1 (CH), 83.4 (OCH), 68.7 (OCH), 31.3 (CH2), 28.1 (CH3), 27.9 (CH3), 23.7 (CH2), 20.90 (CH3), 14.2 (CH3); HRMS (ESI) m/z calcd for C17H24O5Na (M+Na)+, 331.1521; found 331.1522. 4.1.8. (E)-1-((3aR,6aR)-2,2-dimethyl-3a,6a-dihydrofuro[3,2d][1,3]dioxol-5-yl)-6-methylhepta-4,6-dienyl acetate (13c) Following the procedure described for Wittig reaction of the aldehyde 12a,b the ketone 12c (400 mg, 1.29 mmol) on treatment with the ylide generated from methyltriphenylphosphonium bromide (1.38 g, 3.87 mmol) gave the diene 13c (238 mg, 60%) as light yellow oil; [α]D25 –17.4 (c 1.13, CHCl3); νmax(liquid film) 1746 cm-1; δH (500 MHz, CDCl3) (for major diastreoisomer) 6.07 (1 H, d, J 15.0 Hz), 6.0 (1 H, d, J 5.0 Hz), 5.53 (1 H, td, J 7.5, 15.5 Hz), 5.31-5.27 (1 H, m), 5.21 (1 H, dd, J 2.0, 5.0 Hz), 5.07 (1 H, d, J 2.0 Hz), 4.81 (2 H, br s), 2.13-2.10 (2 H, m), 2.08 (3 H, s), 1.89–1.82 (1 H, m), 1.81 (3 H, s), 1.45-1.44 (4 H, m), 1.43 (3 H, s); δC (125 MHz, CDCl3) 169.0 (CO), 158.7 (C), 140.9 (C),133.0 (CH), 128.8 (CH), 114.1 (CH2), 111.5 (C), 105.5 (OCHO), 98.1 (CH), 82.5 (OCH), 67.7 (OCH), 30.5 (CH2), 27.5 (CH2), 27.02 (CH3), 27.0 (CH3), 20.0 (CH3), 17.8 (CH3); HRMS (ESI) m/z calcd for C17H24O5Na (M+Na)+, 331.1521; found 331.1520. 4.1.9. (E)-1-((3aR,6aR)-2,2-dimethyl-3a,6a-dihydrofuro[3,2d][1,3]dioxol-5-yl)hepta-4,6-dien-1-one (14a) To a solution of the acetate 13a (100 mg, 0.34 mmol) in MeOH (3 mL) was added K2CO3 (94 mg, 0.68 mmol) at rt. The reaction mixture was stirred at rt for 2h. The excess methanol was evaporated and the crude mass was worked up as usual. The crude mass after column chromatography [petroleum-diethyl ether (5:1)] afforded the corresponding alcohol (77 mg, 90%) as colorless liquid; [α]D26 –3.2 (c 4.1, CHCl3); δH (500 MHz, CDCl3) 6.30 (1 H, td, J 10.0, 17.0 Hz), 6.01-6.04 (2 H, m), 5.67 (1 H, td, J 7.0, 15.0 Hz), 5.27 (1 H, d, J 5.0 Hz), 5.12 (1 H, br s), 5.07 (1 H, d, J 17.0 Hz), 4.95 (1 H, d, J 10.5 Hz), 4.20-4.15 (1 H, m), 2.27-2.16 (2 H, m), 2.07 (1 H, br s), 1.81–1.68 (2 H, m), 1.44 (3 H, s), 1.41 (3 H, s); δC (125 MHz, CDCl3) 163.2 (C), 137.1 (CH),

ACCEPTED MANUSCRIPT Tetrahedron

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1.66 (5 H, s), 1.44 (3 H, s), 1.35 (3 H, s), 1.27 (3 H, s); δC (75 MHz, CDCl3) 215.0 (CO), 211.4 (CO), 136.24 (C), 136.1 (C), 123.8 (CH), 123.88 (CH), 114.2 (C), 112.9 (C), 105.8 (OCHO), 105.2 (OCHO), 92.4 (C), 89.9 (C), 88.8 (OCH), 88.38 (OCH), 44.5 (CH), 43.7 (CH), 42.0 (CH), 41.0 (CH), 35.2 (CH2), 34.8 (CH2), 32.6 (CH2), 30.9 (CH2), 27.7 (CH3) , 27.5 (CH3), 26.6 (CH3), 26.4 (CH3), 25.5 (CH2), 23.6 (CH3), 23.2 (CH3), 22.5 (CH2); HRMS (ESI) m/z calcd for C15H20O4Na (M+Na)+, 287.1259; found 287.1263. 4.1.15. Synthesis of the tricyclic ketones (16) and (17) To a solution of a mixture of the Diels-Alder adducts 4 (60 mg, 0.22 mmol) in ethanol (2 mL) was added 10% Pd/C (15 mg). The reaction mixture was stirred under hydrogen atmosphere for 6 h and then the catalyst was filtered off. Removal of ethanol under reduced pressure followed by column chromatography [petroleum-diethyl ether (19:1)] gave the compounds 16 (23 mg, 38%) as colorless liquid; [α] D27 -226.4 (c 1.75, CHCl3); νmax(liquid film) 1753 cm-1; δH (500 MHz, CDCl3) 5.67 (1 H, d, J 4.0 Hz), 5.18 (1 H, s), 4.43 (1 H, d, J 4.0 Hz), 3.1 (1 H, s), 2.69-2.62 (1 H, m), 2.16-2.1 (2 H, m), 1.96-1.90 (3 H, m), 1.77-1.75 (1 H, m), 1.71 (3 H, s), 1.46 (3 H, s), 1.24 (3 H, s); δC (125 MHz, CDCl3) 211.68 (CO), 137.3 (C), 118.8 (CH), 112.5 (C), 105.2 (OCHO), 87.6 (C), 86.0 (OCH), 43.4 (CH), 40.7 (CH), 34.2 (CH2), 30.0 (CH2), 26.1 (CH3) , 25.5 (CH3), 23.8 (CH3), 23.6 (CH2); HRMS (ESI) m/z calcd for C15H20O4Na (M+Na)+, 287.1259; found 287.1254 and 17 (25 mg, 42%) as white solid; m. p. 96-98 oC, [α]D27 -78.2 (c 1.1, CHCl3); νmax (KBr plate) 1757 cm-1; δH (500 MHz, CDCl3) 5.81 (1 H, d, J 3.5 Hz), 5.27 (1 H, s), 4.42 (1 H, d, J 3.5 Hz), 2.89 (1 H, s), 2.46-2.34 (2 H, m), 2.29-2.17 (2 H, m), 1.85-1.76 (2 H, m), 1.74 (3 H, s), 1.72 (3 H, s), 1.69-1.60 (1 H, m), 1.27 (3 H, s); δC (125 MHz, CDCl3) 213.9 (CO), 134.3 (C), 116.8 (CH), 113.3 (C), 106.3 (OCHO), 90.1 (C), 86.0 (OCH), 42.6 (CH), 37.8 (CH), 32.8 (CH2), 28.9 (CH2), 26.3 (CH3) , 25.9 (CH3), 24.1 (CH3), 21.5 (CH2); HRMS (ESI) m/z calcd for C15H20O4Na (M+Na)+, 287.1259; found 287.1254. 4.1.16. Synthesis of the tricyclic ketones (18) and (19) A solution of the enone 17 (28 mg, 0.10 mmol) in ethanol (2 mL) was stirred under hydrogen atmosphere in presence of 10% Pd/C (30 mg) for 24 h. The catalyst was filtered off. Removal of ethanol from the filtrate under reduced pressure followed by column chromatography [petroleum-diethyl ether (20:1)] gave the saturated the ketones 18 (18 mg, 64%) ; [α] D27 34.12 (c 2.0, CHCl3); νmax(liquid film) 1751 cm-1; δH (500 MHz, CDCl3) 5.68 (1 H, d, J 4.5 Hz), 4.65 (1 H, t, J 5.0 Hz), 2.73 (1 H, ddd, J 1.5, 5.5, 5.6 Hz), 2.42 (1 H, dd, J 9.0, 18.5 Hz), 2.34-2.26 (1 H, m), 2.18 (1 H, td, J 10, 19.5 Hz), 2.08 (1 H, td, J 6.5, 13.5 Hz), 1.94-1.91 (1 H, m), 1.66-1.62 (2 H, m), 1.61 (3 H, s), 1.491.45 (1 H, m), 1.39 (3 H, s), 1.0 (1 H, dddd, J 6.0, 12.0, 14.1 Hz), 0.89 (3 H. d, J 6.5 Hz), 0.56 (1 H, q, J 12.5 Hz); δC (125 MHz, CDCl3) 214.6 (CO), 114.4 (C), 105.2 (OCHO), 87.1 (OCH), 87.04 (C), 43.6 (CH), 41.4 (CH), 36.8 (CH2), 33.67 (CH2), 33.02 (CH2), 28.3 (CH3) , 28.2 (CH3), 26.9 (CH), 24.45 (CH2), 21.89 (CH3); HRMS (ESI) m/z calcd for C15H22O4Na (M+Na)+, 289.1416; found 289.1421 and 19 (4 mg, 14%) ; m. p. 102-104 O C, [α] D27 -19.6 (c 5.6, CHCl3); νmax(KBr plate) 1755 cm-1; δH (500 MHz, CDCl3) 5.94 (1 H, d, J 3.5 Hz), 4.31 (1 H, t, J 4.0 Hz), 2.48-2.33 (2 H, m), 2.22 (1 H, td, J 9.5, 19.0 Hz), 1.88-1.82 (2 H, m), 1.77-1.74 (2 H, m), 1.72 (3 H, s), 1.52-1.50 (1H, m), 1.31-1.25 (2 H, m), 1.28 (3 H, s), 0.94 (3H. d, J 6.5 Hz), 0.62 (1 H, q, J 13.0 Hz); δC (125 MHz, CDCl3) 214.6 (CO), 112.9 (C), 106.2 (OCHO), 91.5 (C), 86.2 (OCH), 41.0 (CH), 38.0 (CH), 35.2 (CH2), 32.7 (CH2), 32.7 (CH2), 25.9 (CH3), 24.9 (CH3), 24.0 (CH), 22.4 (CH3), 20.9 (CH2); HRMS (ESI) m/z calcd for C15H22O4Na (M+Na)+, 289.1416; found 289.1412. 4.1.17. Synthesis of the tricyclic hydroxy compound (20)

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18.8 (CH3); HRMS (ESI) m/z calcd for C15H22O4Na (M+Na)+, 289.1416; found 289.1416. A solution of this alcohol (100 mg, 0.38 mmol) in DCM (10 mL) was oxidized with DMP (207mg, 0.49 mmol) using the above procedure to afford after column chromatography the trienone 5 (94 mg, 95%) as a viscous liquid; [α] D26 -17.5 (c 1.94, CHCl3); νmax(liquid film) 1699 cm-1; δH (300 MHz, CDCl3) 6.15 (1 H, d, J 5.4 Hz), 6.0 (1 H, d, J 2.5 Hz), 5.86 (1 H, d, J 11.7 Hz), 5.36 (1 H, dd, J 2.2, 5.3 Hz), 5.34-5.32 (1 H, m), 4.96 (1 H, s), 4.83 (1 H, s), 2.74 (2H, t, J 7.0 Hz), 2.60 (2 H, t, J 7.0 Hz), 1.86 (3 H, s), 1.45 (3 H, s), 1.43 (3 H, s); δC (75 MHz, CDCl3) 193.0 (CO), 155.9 (C), 141.5 (C), 132.3 (CH), 128.9 (CH), 115.8 (CH2), 113.1 (C), 108.7 (CH), 106.6 (OCHO), 83.0 (OCH), 39.7 (CH2), 28.1 (CH3), 27.8 (CH3), 23.3 (CH3), 22.8 (CH2); HRMS (ESI) m/z calcd for C15H20O4Na (M+Na)+, 287.1259; found 287.1259. 4.1.12. Synthesis of the tricyclic ketone (15a) A solution of the trienone 14a (50 mg, 0.2 mmol) in toluene (2 mL) was heated at 150 0C in a sealed tube in the presence of [2,6-bis (1,1-dimethylethyl)-4-methyl phenol] (BHT) as catalyst for 24 h. Excess toluene was removed under vacuum and the residual mass was chromatographed [ petroleum-diethyl ether (4:1) ] to give the tricyclic enone 15a (35 mg, 70%) as an inseparable mixture of two diastereoisomers in 1.3:1 ratio; [α] D27 -88.1 (c 2.7, CHCl3); νmax(liquid film) 1735 cm-1; δ (500 MHz, CDCl3) (for the mixture) 5.93 (1 H, ddd, J 3.0, 6.0, 9.0 Hz), 5.87-5.84 (2 H, m), 5.75-5.73 (1 H, m), 5.71 (1 H, dd, J 2.0, 3.5 Hz), 5.57 (1 H, d, J 3.5 Hz), 4.5 (1 H, t, J 3.5 Hz), 4.35 (1 H, d, J 3.5 Hz), 2.91 (1 H, dd, J 2.0, 6.5 Hz), 2.70-2.64 (3 H, m), 2.422.08 (11 H, m), 1.71-1.63 (1 H, m), 1.65 (3 H, s), 1.44 (3 H, s), 1.35 (3 H, s), 1.24 (3 H, s); δC (125 MHz, CDCl3) 214.5 (CO), 211.2 (CO), 130.6 (CH), 130.5 (CH), 128.0 (CH), 127.5 (CH), 114.2 (C), 112.9 (C), 105.8 (OCHO), 105.4 (OCHO), 92.8 (C), 90.1 (C), 88.8 (OCH), 88.4 (OCH), 44.0 (CH), 43.3 (CH), 41.4 (CH), 41.2 (CH), 35.0 (CH2), 34.9 (CH2), 27.7 (CH3), 27.6 (CH3), 27.1 (CH2), 26.7 (CH3), 26.5 (CH3), 25.7 (CH2), 25.3 (CH2), 22.4 (CH2); HRMS (ESI) m/z calcd for C14H18O4Na (M+Na)+, 273.1103; found 273.1102. 4.1.13. Synthesis of the tricyclic ketone (15b) Following the procedure for the synthesis of 15a, the compound 14b (50 mg, 0.20 mmol) afforded the tricyclic enone 15b (33 mg, 65%) as an inseparable 1:1 diastereoisomeric mixture; [α]D23 -24.3 (c 7.2, CHCl3);νmax(liquid film) 1755 cm-1; δH (500 MHz, CDCl3) (for the mixture) 5.67 (1 H, d, J 4.0 Hz), 5.59-5.58 (2 H, m), 5.54 (1 H, d, J 3.0 Hz), 4.48 (1 H, t, J 3.5 Hz), 4.34 (1 H, d, J 3.5 Hz), 2.86 (1 H, d, J 8.0 Hz), 2.69-2.64 (2 H, m), 2.54 (1 H, t, J 7.5 Hz), 2.44-2.34 (2 H, m), 2.32-2.16 (5 H, m), 2.15-2.02 (5 H, m), 1.8-1.79 (5 H, m), 1.70 (3 H, s), 1.45 (3 H, s), 1.35 (3 H, s), 1.25 (3 H, s), 1.29-1.20 (1 H, m); δC (125 MHz, CDCl3) 215.0 (CO), 211.6 (CO), 138.0 (C), 137.9 (C), 120.0 (CH), 119.8 (CH), 114.3 (C), 113.0 (C), 106.1 (OCHO), 105.6 (OCHO), 93.6 (C), 90.2 (C), 89.9 (OCH), 89.0 (OCH), 46.6 (CH), 46.4 (CH), 44.7 (CH), 41.2 (CH), 35.9 (CH2), 35.3 (CH2), 27.7 (CH2), 27.6 (CH2), 27.2 (CH3) , 26.8 (CH3), 26.8 (CH3), 25.3 (CH3), 23.5 (CH2), 22.1 (CH3), 20.5 (CH3), 19.7 (CH2); HRMS (ESI) m/z calcd for C15H20O4Na (M+Na)+, 287.1259; found 287.1259. 4.1.14. Synthesis of the tricyclic ketone (4) Following the procedure for the synthesis of 15a,b the compound 5 (50 mg, 0.19 mmol) afforded the tricyclic enone 4 (30 mg, 60%) as an inseparable mixture in 1.5:1 ratio; [α]D27 76.3 (c 3.0, CHCl3); νmax(liquid film) 1753 cm-1; δH (300 MHz, CDCl3, for the mixture) 5.74 (1 H, d, J 4.0 Hz), 5.55 (1 H, d, J 3.2 Hz), 5.50 (1 H, s), 5.38 (1 H, s), 4.47 (1 H, t, J 3.4 Hz), 4.35 (1 H, d, J 3.3 Hz), 2.86 (1 H, d, J 3.2 Hz), 2.69-2.62 (3 H, m), 2.34-2.19 (6 H, m), 2.08-2.0 (4 H, m), 1.80 (3 H, s), 1.72 (3 H, s),

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1726, 1710 cm–1; δH (300 MHz, CDCl3) 8.14 (1 H, s), 5.37 (1 H, t, J 8.4 Hz), 2.87 (1 H, dd, J 2.7, 5.4 Hz), 2.36-2.23 (3 H, m), 2.06-2.00 (2 H, m), 1.82-1.67 (3 H, m), 1.48-1.38 (1 H, m), 1.331.20 (2 H, m), 0.89 (3 H, d, J 6.3 Hz), 0.85-0.76 (1 H, m); δC (75 MHz, CDCl3) 178.8 (CO), 160.8 (CO), 79.4 (C), 75.5 (OCH), 45.3 (CH), 42.0 (CH), 39.6 (CH2), 34.0 (CH2), 27.6 (CH2), 27.0 (CH), 26.0 (CH2), 21.7 (CH3); HRMS (ESI) m/z calcd for C12H18O5Na (M+Na)+, 265.1052; found 265.1055. 4.1.21. (3R,3aR,4S,6R,7aS)-methyl 3-(formyloxy)-3a-hydroxy-6methyloctahydro-1H-indene-4-carboxylate (26) A solution of the carboxylic acid 25 in diethyl ether (1 mL) was treated with ethereal diazomethane for 15 min. Removal of ether followed by column chromatography (30% diethyl ether –petroleum) provided the hydroxy ester 26 (10 mg, 90%) as an oil; [α] D26 9.7 (c 3.75 CHCl3); υmax(liquid film) 1728, 1713 cm–1; 1 H (500 MHz, CDCl3) δ 8.13 (1 H, s), 5.32 (1 H, t, J 8.5 Hz), 3.7 (3 H, s), 3.18 (1 H, s), 3.10 (1 H, s), 2.84 (1 H, dd, J 3.0, 5.5 Hz), 2.36-2.20 (2 H, m), 1.92-1.89 (1 H, m), 1.82-1.65 (3 H, m), 1.441.38 (1 H, m), 1.29-1.25 (1 H, m), 0.87 (3 H, d, J 6.0 Hz), 0.76 (1 H, q, J 12.5 Hz); δC (125 MHz, CDCl3) 175.4 (CO), 161.0 (CO), 79.1 (C), 75.5 (OCH), 51.9 (CH), 45.4 (CH), 42.3 (CH), 39.7 (CH2), 34.0 (CH2), 27.5 (CH2), 27.0 (CH), 26.0 (CH2), 21.8 (CH3); HRMS (ESI) m/z calcd for C13H20O5Na (M+Na)+, 279.1208; found 279.1205. 4.1.22. (3R,3aR,4S,6R,7aS)-methyl 3,3a-dihydroxy-6methyloctahydro-1H-indene-4-carboxylate (27) The formate 25 (8 mg) was treated with 5% aqueous methanolic solution (0.1 mL) for 1h at rt. After disappearance of the formate (TLC), the solvent was removed by purging N2 and the crude mass was diluted with diethyl ether. The solution was acidified with 10% aqueous HCl. The organic layer was separated, dried and concentrated in vacuum to afford the dihydroxy carboxylic acid 27 as a viscous liquid (5 mg, 71%); [α]D27 14.0 (c 0.5 CHCl3); υmax(liquid film) 1710 cm–1; δH (500 MHz, CDCl3) 4.54 (1 H, d, J 5.5 Hz), 2.99 (1 H, s), 2.5 (1 H, t, J 5.5 Hz), 2.12-1.97 (2 H, m), 1.77-1.66 (3 H, m), 1.39-1.38 (1 H, m), 1.25-1.20 (2 H, m), 0.88 (3 H, d, J 6.0 Hz), 0.69 (1 H, q, J 12.5 Hz); δC (125 MHz, CDCl3) 177.3 (CO), 91.6 (C), 85.3 (OCH), 46.7 (CH), 42.8 (CH), 36.7 (CH2), 33.3 (CH2), 31.7 (CH2), 29.3 (CH2), 25.3 (CH), 21.9 (CH3); HRMS (ESI) m/z calcd for C11H18O4Na (M+Na)+, 237.1103; found 237.1107. 4.1.23. (3aR,5aS,7R,9S,91R)-methyl 7-methyloctahydroindeno[1d][1,3]dioxole-9-carboxylate (28) To a magnetically stirred solution of the hydroxy ester 26 (7 mg, 0.03 mmol) in DCM (0.5 mL), dimethoxy methane (0.007 mL, 0.08 mmol) and BF3.Et2O (0.003 mL, 0.03 mmol) was added at 0 OC. The reaction mixture was stirred for 12h at rt. The reaction mixture was worked up in the usual way to afford after column chromatography (10% diethyl ether/petroleum) the compound 28 (4 mg, 61%) as colorless liquid; [α]D26 18.3 (c 0.5 CHCl3); υmax(liquid film) 1743 cm–1; δH (500 MHz, CDCl3) 5.02 (1 H, s), 4.98 (1 H, s), 4.44 (1 H, d, J 7.0 Hz), 3.7 (3 H, s), 3.03 (1 H, dd, J 2.0, 5.0 Hz), 2.68 (1 H, td, J 6.0, 12.5 Hz), 2.07-1.95 (3 H, m), 1.92-1.89 (1 H, m), 1.70-1.66 (1 H, m), 1.64-1.59 (1 H, m), 1.39-1.34 (1 H, m), 1.22-1.13 (1 H, m), 0.85 (3 H, d, J 6.5 Hz), 0.67 (1 H, q, J 12.5 Hz); δC (125 MHz, CDCl3) 173.9 (CO), 94.96 (CH2), 91.04 (C), 84.3 (OCH), 51.65 (CH3), 45.58 (CH), 41.6 (CH), 37.9 (CH2), 35.2 (CH2), 30.6 (CH2), 29.4 (CH2), 25.5 (CH), 21.9 (CH3); HRMS (ESI) m/z calcd for C13H20O4Na (M+Na)+, 263.1259; found 263.1257.

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To a magnetically stirred suspension of LAH (6.4 mg, 0.17 mmol) in diethyl ether (4 mL) at 0 oC was added the ketone 18 (30 mg, 0.11 mmol) in diethyl ether (1 mL). The resulting mixture was stirred at the same temperature for 0.5 h. The reaction mixture was then quenched with the addition of 0.01 mL water, 0.01 mL 15% NaOH solution and 0.03 mL water at 0 oC. The precipitated solid was filtered off and washed with diethyl ether. The filtrate and the washings were concentrated in vacuum. The residue was chromatographed [petroleum-diethyl ether (4:1)] to afford the alcohol 20 (30 mg, 99%) as a white solid; m. p. 5456 OC, [α]D26 6.24(c 2.75, CHCl3); δH (500 MHz, CDCl3) 5.71 (1 H, t, J 2.5 Hz), 4.60-4.58 (1 H, m), 4.02 (1 H, dd, J 6.0, 7.0 Hz), 2.43-2.35 (1 H, m), 2.27 (1 H, brs), 2.09-2.05 (1 H, m), 2.0-1.99 (1 H, m), 1.94-1.84 (1 H, m), 1.78-1.76 (1 H, m), 1.64-1.57 (2 H, m), 1.68 (3 H, s), 1.31 (3 H, s), 1.23-1.16 (3 H, m), 0.89 (3 H, dd, J 2.0, 4.5 Hz), 0.68 (1 H, q, J 12.0 Hz); δC (125 MHz, CDCl3) 113.0 (C), 104.0 (OCHO), 93.2 (OCH), 86.5 (C), 73.7 (OCH), 43.3 (CH), 41.1 (CH), 39.0 (CH2), 33.0 (CH2), 31.3 (CH2), 30.7 (CH3), 28.1 (CH3), 27.5 (CH2), 26.8 (CH), 21.7 (CH3); HRMS (ESI) m/z calcd for C15H24O4Na (M+Na)+, 291.1572; found 291.1576. 4.1.18. (3R,3aR,5R,6aS,9S,91R)-5-methyldecahydroindeno[4b]furan-2,3,9-triol (21) To a solution of the hydroxy compound 20 (30 mg, 0.11 mmol) in THF (0.5 mL), 4% aqueous H2SO4 (0.2 mL) was added. The reaction mixture was heated at 60 oC for 0.5 h. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and after usual work up the residual mass was purified through column chromatography [petroleum-diethyl ether (2:3)] to afford the triol 21 (25 mg, 98%) as an epimeric mixture; [α]D26 13.17 (c 2.5 CHCl3); δH (500 MHz, CDCl3) (for the major epimer) 5.07 (1 H, d, J 2.5 Hz), 4.10-4.09 (1 H, m), 3.90 (2 H, t, J 9.0 Hz), 2.7-2.64 (1 H, m), 2.54-2.48 (3 H, brs), 1.67-1.52 (5 H, m), 1.47-1.09 (2 H, m), 0.93-0.83 (1 H, m), 0.88 (3 H, d, J 6.0 Hz), 0.62 (1 H, q, J 12.5 Hz); δC (125 MHz, CDCl3) 95.3 (OCHO), 92.0 (C), 77.67 (OCH), 73.0 (OCH), 42.7 (CH), 41.5 (CH2), 40.25 (CH), 32.0 (CH2), 30.4 (CH2), 27.0 (CH2), 26.8 (CH), 21.7 (CH3); HRMS (ESI) m/z calcd for C12H20O4Na (M+Na)+, 251.1259; found 251.1259. 4.1.19. (1R,3aS,5R,7S,7aR)-7-formyl-7a-hydroxy-5methyloctahydro-1H-inden-1-yl formate (23) A solution of this triol 21 (25 mg, 0.11 mmol) in THFH2O (2:1) (0.3 mL) at 0 oC was treated with NaIO4 (35 mg, 0.16 mmol). The reaction mixture was stirred for 0.5 h at 0 oC. On completion (TLC), the reaction mixture was extracted with diethyl ether (3 X 3 mL). The extract was washed with water, brine and dried. Removal of solvent afforded the compound 23 (21 mg, 85%) as a viscous liquid; [α] D23 1.4 (c 1.0 CHCl3); υmax(liquid film) 1724, 1713 cm–1; δH (300 MHz, CDCl3) 9.86 (1 H, d, J 1.8 Hz), 8.13 (1 H, s), 5.36 (1 H, t, J 8.4 Hz), 3.05 (1 H, brs), 2.7-2.69 (1 H, m), 2.38-2.05 (3 H, m), 2.02-1.85 (1 H, m), 1.84-1.62 (2 H, m), 1.56-1.4 (2 H, m), 1.38-1.22 (1 H, m), 0.89 (3 H, d, J 6.0 Hz), 0.87-0.74 (1 H, m); δH (75 MHz, CDCl3) 205.7 (CO), 160.7 (CO), 79.8 (C), 75.5 (OCH), 51.8 (CH), 42.8 (CH), 39.7 (CH2), 32.1 (CH2), 28.0 (CH), 27.6 (CH2), 25.6 (CH2), 21.9 (CH3); HRMS (ESI) m/z calcd for C12H18O4Na (M+Na)+, 249.1103; found 249.1107. 4.1.20. (3R,3aR,4S,6R,7aS)-3-(formyloxy)-3a-hydroxy-6methyloctahydro-1H-indene-4-carboxylic acid (25) To a solution of the aldehyde 23 (15 mg, 0.06 mmol) in t-BuOH (0.3 mL) was added β-isoamylene (0.15 mL) followed by NaH2PO4 (12 mg, 0.099 mmol) and NaClO2 (9 mg, 0.1 mmol) in water (0.3 mL). After 1h, the reaction mixture was quenched by saturated aqueous NH4Cl solution (0.3 mL) and extracted with ethyl acetate. The solvent was removed under vacuum to afford 25 (14 mg, 88%); [α]D23 9.5 (c 6.1 CHCl3); υmax(liquid film)

Acknowledgments Financial support from DST, Government of India is gratefully acknowledged. MFH, RNY, SM and AJ are thankful to CSIR, New Delhi for research fellowships. We are grateful to

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Hautzel, R.; Anke, H. Z. Naturforsch. 1990, 45c, 68-73. Julianti, E.; Oh, H.; Jang, K. H.; Lee, J. K.; Lee, S. K.; Oh, D. –C.; Oh, K. –B.; Shin, J. J. Nat. Prod. 2011, 74, 2592-2594. (a) Johansson, M.; Sterner, O. Org. Lett. 2001, 3, 2843-2845. (b) Johansson, M.; Köpcke, B.; Anke, H.; Sterner, O. Tetrahedron 2002, 58, 2523-2528. (c) Lebel, H.; Parmentier, M. Org. Lett. 2007, 9, 3563-3566. (d) Gidlof, R.; Johansson, M.; Sterner, O. Org. Lett. 2010, 12, 5100-5103. For reviews on IMDA reaction see: (a) Oppolzer, W. Angew. Chem. Int. Engl. 1977, 16, 10-23. (b) Brieger, G.; Bennet, J. N. Chem. Rev. 1980, 80, 63-97. (c) Fallis, A. G. Can. J. Chem. 1984, 62, 183-234; (d) Singh, V.; Iyer, S. R.; Pal, S. Tetrahedron 2005, 61, 9197-9231. (e) Juhl, M.; Tanner, D. Chem. Soc. Rev. 2009, 38, 2983-2992. For selected non-IMDA approaches to hydrindanes with angular hydroxyl group see: (a) Chiu, P.;Szeto, C.-P.; Geng, Z.; Cheng, K.-F. Org. Lett. 2001, 3, 1901-1903. (b) Huddleston, R. R.; Krische, M. J. Org.Lett. 2003, 5, 1143-1146. (c) Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6, 691-694. (d) Chiu, P.; Leung, S. K. Chem.Commun. 2004, 2308-2309. (e) Deschamp, J.;Riant, O. Org.Lett. 2009, 11, 1217-1220. (f) Ressault, B.; Jaunet, A.; Geoffroy, P.; Goudedranche, S.; Miesch, M. Org.Lett. 2012, 14, 366-369. Mondal, S.; Yadav, R. N.; Ghosh, S. Org. Lett. 2011, 13, 60786081. Sun, K. M.; Fraser-Reid, B. Synthesis, 1982, 28-29. (a) For a review on olefin cross metathesis see: Cannon, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003 42, 1900-1923. For reviews on olefin metathesis and its applications see: (b) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446−452. (c) Fürstner, A. Top. Catal. 1997, 4, 285−299. (d) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2036−2056. (e) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413−4450. (f) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371−388. (g) Fürstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012−3043. (h) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199−2238. (i) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed.

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2005, 44, 4490−4527. (j) Ghosh, S.; Ghosh, S.; Sarkar, N. J. Chem. Sci. 2006, 118, 223−235. (k) Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919−3952. (l) Kotha, S.; Dipak, M. K. Tetrahedron 2012, 68, 397-421. (a) Dess, D. B.; Martin, J. C. J. Org. Chem 1983, 48, 4156-4158. (b) Dess, D. B.; Martin, J. J. Am. Chem. Soc. 1991, 113, 72777287. Crystal data: Compound 17. colorless block shaped crystal (0.32 X 0.27 X 0.14 mm). Empirical formula C15H20O4, Mr = 264.31, orthorhombic space group P212121 , a = 8.9307(5), b = 14.1263(8), c = 21.9670(12)Å, V = 2771.3(3) Å3, T = 150 K, Z = 8. ρcalcd = 1.267 g cm-3. F (000) = 1136, λ(Mo–Kα) = 0.71073 Å, µ Mo Kα/mm-1 = 0.091, 2θmax = 61.6°, 32819 total reflections, 8010 unique reflections 503 parameters; R1 = 0.0437; wR2 = 0.1077 with GOF = 0.986. Compound 19. C15H22O4, M = 266.33, orthorhombic, space group P212121, a = 9.063(5), b = 14.126(5), c = 22.079 (5)Å, V = 2827(2) Å3, T = 150 K, Z = 8. ρcalcd = 1.252 g cm-3 , F (000) = 1152, µ = 0.089 mm-1, 2θmax = 62.22°, 8786 reflections were collected, 5917 observed (I>2σ (I)) 349 parameters; R1 = 0.0521; wR2 = 0.1706 with GOF = 0.883. X-ray single crystal data were collected using MoKα (λ = 0.7107 Å) radiation on a SMART APEX II diffractometer equipped with CCD area detector. Data collection, data reduction, structure solution/refinement were carried out using the software package of SMART APEX. The structures were solved by direct method and refined in a routine manner. Non hydrogen atoms were treated anisotropically. The hydrogen atoms were geometrically fixed. CCDC (CCDC Nos. 885013 for 17 and 924255 for 19) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: (+44) 1223-336-033; or [email protected]. We are thankful to one of the reviewers for correcting the assignment of the structure of the periodate oxidation product of 21 as 23 instead of 22. Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091-2096. Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J. Am. Chem. Soc. 1973, 95, 6137-6139.

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O

O

OAc O 13a O

ACCEPTED MANUSCRIPT

O

O

AC C

EP

TE D

M AN U

SC

RI PT

O

OAc 13b

O

O O

OAc 13c

ACCEPTED MANUSCRIPT

O

O

OH

AC C

EP

TE D

M AN U

SC

RI PT

O

O

O O

OH

ACCEPTED MANUSCRIPT

O

O

OH

AC C

EP

TE D

M AN U

SC

RI PT

O

O

O O

O 14a

ACCEPTED MANUSCRIPT

O O O 14b

AC C

EP

TE D

M AN U

SC

RI PT

O

O O 1

O O 5

H NMR in CDCl3, 300 MHz

ACCEPTED MANUSCRIPT

O O

15a

AC C

EP

TE D

M AN U

SC

RI PT

O

H

H

O

O O

H O O

H 15b

ACCEPTED MANUSCRIPT

H

H

O

O O

4

AC C

EP

TE D

M AN U

SC

RI PT

O

O O

H O O

H 16

ACCEPTED MANUSCRIPT

O O

17

AC C

EP

TE D

M AN U

SC

O

H

RI PT

H

O

O O

H O O

H 18

ACCEPTED MANUSCRIPT

H

H

RI PT

O

O O

19

AC C

EP

TE D

M AN U

SC

O

O O

H

H

O OH

20

ACCEPTED MANUSCRIPT

H

HO

O 21 H OH

AC C

EP

TE D

M AN U

SC

RI PT

HO

H

H

H

OHC HO H OCHO

23

ACCEPTED MANUSCRIPT

H

H

HO 25 H OCHO

AC C

EP

TE D

M AN U

SC

RI PT

HO2C

H H MeO2C HO 26 H OCHO

ACCEPTED MANUSCRIPT

M AN U

SC

RI PT

H H HO2C HO H OH 27

AC C

EP

TE D

MeO2C

H O O

H 28