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Synlett 2013; 24(9): 1117-1120
DOI: 10.1055/s-0032-1317805
letter
© Georg Thieme Verlag Stuttgart · New York

First Total Synthesis of (3R,4S)-4-Hydroxylasiodiplodin: A Facile and Stereoselective Approach

Sheshurao Bujaranipalli
Natural Products Chemistry Division, CSIR Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, AP, India   Fax: +91(40)27160512   Email: saibal@iict.res.in
,
Gyan Chander Eppa
Natural Products Chemistry Division, CSIR Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, AP, India   Fax: +91(40)27160512   Email: saibal@iict.res.in
,
Saibal Das*
Natural Products Chemistry Division, CSIR Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, AP, India   Fax: +91(40)27160512   Email: saibal@iict.res.in
› Author Affiliations
Further Information

Publication History

Received: 05 March 2013

Accepted: 19 March 2013

Publication Date:
12 April 2013 (online)

 
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Abstract

A first total synthesis of (3R,4S)-4-hydroxylasiodiplodin is described starting from methyl acetoacetate and a commonly available carbohydrate, d-mannitol, which is regularly used in organic synthesis. The facile and stereoselective approach involves the Barbier allylation and a ring-closing metathesis as key steps.


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Key words

Hydroxylasiodiplodin - Barbier allylation - metathesis - carbohydrate - total synthesis - natural product

A number of naturally occurring orsellinic acid (2,4-dihydroxy-6-methyl benzoic acid)-type macrolides are known in the literature, including radicicol,[1] zearalenone,[2] lasiodiplodin,[3] resorcylide,[4] and have been shown to possess a variety of interesting biological properties.[5] Many among these lasiodiplodins are unique fungal metabolites of lasiodiplodia theobromae that acts in the inhibition of prostaglandin biosynthesis,[6] potent antileukemic activity,[7] cytotoxic,[8] potent nonsteroidal antagonist of the mineralocorticoid receptor (MR),[9] antimicrobial activity,[10] potato microtuber inducing activities, plant-gowth inhibitor[3] and also acts as a Hill reaction inhibitor.[11] In particular, (3R,4S)-4-hydroxylasiodiplodin (1) is a 12-membered macrolide (Figure [1]) isolated from IFO 31059[12] and was found to show strong potato microtuber inducing activity at a concentration of 10–4 M.

Zoom Image
Figure 1 (3R,4S)-4-Hydroxylasiodiplodin (1)

Owing to the growing importance of this family of compounds and our ongoing interest in the total synthesis of biologically active natural products,[13] we report the first total synthesis of (3R,4S)-4-hydroxylasiodiplodin (1) that involves a simple strategy using Barbier allylation and ring-closing metathesis (RCM) as the key steps starting from very common and inexpensive starting materials: methyl acetoacetate and d-mannitol.

As outlined below, the retrosynthetic approach (Scheme [1]) suggests that the construction of the 12-membered macrolide could be obtained using a RCM approach of compound 2 which could be envisaged from esterification of compound 3 with 4. Finally, compounds 3 and 4 may be prepared from easily available methyl acetoacetate 5 and d-mannitol, respectively, using well-established protocols in good yields.

Zoom Image
Scheme 1 Retrosynthesis for compound 1

To begin our synthesis, aromatic subunit 3 was constructed (Scheme [2]) starting from methyl acetoacetate which was transformed into the desired aromatic ester[14] 6 in one pot in 50% yield. Then, regioselective protection of the 4-hydroxy group as its ether 7 was achieved using MOMCl in the presence of DIPEA in 85% yield. The 1H NMR spectrum shows a singlet at δ = 11.65 ppm that indicates the presence of a hydroxyl group ortho to the internal keto functionality, suggesting that the protection of only the 4-hydroxy group as its MOM ether was attained. Compound 7 was then treated with dimethyl sulfate to obtain 2-methoxy compound 8 in 80% yield.[15] Lithiation of compound 8 at the benzylic position with LDA at –78 °C followed by reaction with homoallylbromide afforded the expected compound 9 in 62% yield, which was then ­saponified to furnish the desired acid 10 [16] in 86% yield.

Zoom Image
Scheme 2 Reagents and conditions: (a) NaH, n-BuLi, 0 °C to –78 °C to r.t., 12 h, reflux, 24 h, 50%; (b) MOMCl, DIEPA, CH2Cl2, 0 °C to r.t., 3 h, 85%; (c) K2CO3, Me2SO4, dry acetone, reflux, 12 h, 80%; (d) LDA, homoallyl bromide, –78 °C, 30 min, 62%; (e) KOH, (MeOH–H2O, 1:1), reflux, 2 d, then 1 M HCl, 86%.

We had initially protected the 4-hydroxy group in compound 6 as its benzyl ether using benzyl bromide in the presence of K2CO3 to afford compound 7a in 60% yield, followed by methylation on the 2-hydroxy group using dimethyl sulfate to give 8a in 82% yield (Scheme [3]). In compound 8a two benzylic positions are found: 1) one ­ortho to the ester group, and 2) a second one that is part of the benzyl ether protecting group. Since toluene derivatives with heteroatom-containing substituents in the ortho position undergo site-selective benzylic lithiation for further functionalization,[17] we expected lithiation to occur at one benzylic position and not the other. Unfortunately, lithiation did not occur at either of the benzylic positions with LDA at –78 °C and only starting material was recovered. Hence, the search for other protecting groups came into play. The protecting groups must be stable under basic and mild acidic conditions and will be used under saponification conditions in the later stage of the approach. Therefore, we opted for methoxymethyl ether as the protecting group which is stable under the above-mentioned conditions and serves the purpose.

Zoom Image
Scheme 3 Reagents and conditions: (a) BnBr, K2CO3, dry acetone, reflux, 12 h, 60%; (b) K2CO3, Me2SO4, dry acetone, reflux, 12 h, 82%; (c) LDA, homoallyl bromide, –78 °C, 30 min.

Having compound 10 in hand, the synthesis towards compound 4 was focused upon (Scheme [4]). d-mannitol, a carbohydrate precursor was deployed for the preparation of enantiomerically pure (R)-2,3-O-cyclohexylidine glyceraldehyde (11) using a literature procedure.[18] Then compound 11 was subjected to Barbier allylation conditions (Zn, allyl bromide and aq NH4Cl) to obtain the anti-­homoallylic alcohol 12 in 91% yield with 94% de.

Zoom Image
Scheme 4 Reagents and conditions: (a) Zn, allyl bromide, aq NH4Cl, 0 °C, 4 h, 91%; (b) NaH, BnBr, THF, 0 °C to r.t., 6 h, 93%; (c) 60% AcOH in H2O, r.t., overnight, 86%; (d) TPP, DEAD, CHCl3, reflux, 12 h, 85%; (e) LAH, THF, 0 °C to r.t., 6 h, 89%.

The diastereomers were easily separated by column chromatography,[19] and homoallylic alcohol 12 was protected using benzyl bromide in the presence of NaH in THF to afford the corresponding benzyl ether 13 in 93% yield. The cyclohexylidine protection was then removed using 60% AcOH in water to afford the desired 1,2-diol 14 in 86% yield which was converted into the epoxide 15 under Mitsunobu conditions.[20] Afterwards reductive opening of the epoxide 15 with LAH furnished the secondary alcohol 16 in 89% yield.

The next steps were to couple the two intermediate compounds 10 and 16 and to construct the 12-membered ring (Scheme [5]). Accordingly, the ester 17 was obtained under stoichiometric conditions via an acyl activation[21] of the acid intermediate 10 using DCC and DMAP at room temperature in 62% yield, followed by treatment with 5 mol% of Grubbs second-generation catalyst under dilute conditions[22] to afford the desired lactone 18 in 81% yield with a E/Z ratio of 7:3 based on HPLC analysis observations, which upon treatment with 10% palladium on carbon provided 19 in 87% yield. Finally, deprotection of MOM ether with aqueous HCl in methanol afforded the target compound 1 in 91% yield. The spectral data of thus synthesized target compound was in agreement with the natural product[12] [23] and was further confirmed by NOE experiment under irradiation of the proton present at position 4. Enhancement of CH3 protons was observed, suggesting they are cofacial, and no enhancement of the proton present at position 3 indicated their anti relationship as well.

Zoom Image
Scheme 5 Reagents and conditions: (a) DCC, DMAP, CH2Cl2, 0 °C to r.t., 5 h, 62%; (b) Grubbs II catalyst (5 mol%), CH2Cl2, reflux, 12 h, 81%; (c) H2, 10% Pd/C, EtOAc, 6 h, 87%; (d) 1 N HCl–MeOH (1:1), r.t., 24 h, 91%.

In conclusion, the first total synthesis of (3R,4S)-4-hydoxylasiodiplodin has been accomplished by employing ­Barbier allylation and ring-closing metathesis as the key steps. This method can be conveniently utilized for the synthesis of different other resorcylic macrolides towards the development of such class of compounds.


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Acknowledgment

B.S. thanks UGC and E.G.C. thanks CSIR, New Delhi, India for fellowships. Authors thank CSIR, New Delhi for financial supports through Project ORIGIN under 12th Five Year Plan.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.
  • Supporting Information

  • References and Notes

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  • 23 Spectral Data for Representative Compounds Methyl 2-Hydroxy-4-(methoxymethoxy)-6-methyl-benzoate(7) Mp 55–58 °C. IR (KBr): 2956, 2855, 2831, 1726, 1657, 1618, 1579, 1446, 1422, 1369, 1324, 1261, 1215, 1152, 1111, 1080, 1062, 1020, 942, 845, 803, 770, 700, 673, 606, 578, 528 cm–1. 1H NMR (300 MHz, CDCl3): δ = 11.65 (s, 1 H), 6.47 (d, J = 3.0 Hz, 1 H), 6.36 (s, J = 2.3 Hz, 1 H), 5.15 (s, 2 H), 3.90 (s, 3 H), 3.45 (s, 3 H), 2.48 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 172.1, 165.2, 161.4, 143.3, 111.8, 101.5, 93.8, 56.3, 51.9, 29.7, 24.4. ESI-MS: m/z = 227 [M + H]+. ESI-HRMS: m/z calcd for C11H18O6Na: 269.1001; found: 269.0992. Methyl 2-Methoxy-4-(methoxymethoxy)-6-methyl-benzoate (8) IR (neat): 2944, 2846, 1727, 1602, 1585, 1459, 1434, 1321, 1268, 1231, 1189, 1149, 1096, 1078, 1026, 962, 928, 836, 814, 773 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.47 (d, J = 1.7 Hz, 1 H), 6.45 (d, J = 2.0 Hz, 1 H), 5.17 (s, 2 H), 3.88 (s, 3 H), 3.80 (s, 3 H), 3.48 (s,3 H), 2.27 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 168.5, 158.9, 157.9, 138.0, 117.3, 109.2, 94.2, 97.7, 55.9, 55.8, 51.9, 19.7. ESI-MS: m/z = 241 [M + H]+. ESI-HRMS: m/z calcd for C12H16O5Na: 263.0890; found: 263.0894. Methyl 2-Methoxy-4-(methoxymethoxy)-6-(pent-4-enyl)benzoate (9) IR (neat): 2951, 3004, 2907, 2838, 1739, 1709, 1615, 1577, 1431, 1297, 1219, 1137, 1103, 1037, 966, 930, 823, 772, 640 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.48 (m, 2 H), 5.89–5.71 (m, 1 H), 5.17 (s, 2 H), 5.07–4.87 (m, 2 H), 3.88 (s, 3 H), 3.47 (s, 3 H), 2.62–2.50 (m, 2 H), 2.15–2.07 (ABq, J = 14.0, 6.8 Hz, 2 H), 1.74–1.62 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 168.7, 158.9, 157.8, 142.5, 138.3, 125.5, 114.8, 108.4, 97.8, 94.3, 56.0, 55.9, 33.4, 33.1, 30.2. ESI-MS: m/z = 295 [M + H]+. 2-Methoxy-4-(methoxymethoxy)-6-(pent-4-enyl)benzoic Acid (10) IR (neat): 3076, 2932, 1697, 1603, 1460, 1425, 1297, 1218, 1193, 1151, 1113, 1081, 1021, 918, 837, 772 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.58 (d, J = 1.8 Hz, 1 H), 6.53 (d, J = 2.1 Hz 1 H), 5.93–5.76 (m, 1 H), 5.50–5.40 (m, 1 H), 5.21 (s, 2 H), 5.08–4.92 (m, 1 H), 3.93 (s, 3 H), 3.49 (s, 3 H), 2.92–2.80 (m, 2 H), 2.12 (ABq, J = 14.2, 7.17 Hz, 2 H), 1.79–1.64 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 171.8, 159.4, 158.4, 144.4, 138.3, 115.3, 114.7, 109.3, 97.8, 94.1, 55.9, 33.5, 33.4, 30.3. ESI-MS: m/z = 281 [M + H]+. ESI-HRMS: m/z calcd for C15H21O5Na: 281.1384; found: 281.1369. (R)-2-[(S)-1-(Benzyloxy)but-3-enyl]oxirane (15) [α]D 30 +5.40 (c 1, CHCl3). IR (neat): 3032, 3065, 2989, 2925, 2867, 1955, 1824, 1642, 1495, 1454, 1434, 1391, 1344, 1306, 1252, 1207, 1159, 1098, 1074, 1028, 995, 917, 851, 739, 698, 609, 2982, 2933, 1647, 1608, 1574, 1445, 1376, 1357, 1319, 1257, 1211, 1159, 1103, 1034, 967, 864, 757 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.32–7.20 (m, 5 H), 5.94–5.82 (m, 1 H), 5.17–5.06 (m, 2 H), 4.62–4.52 (m, 2 H), 3.32–3.28 (m, 1 H), 2.92–2.88 (m, 1 H), 2.73–2.70 (m, 1 H), 2.68–2.65 (m, 1 H), 2.47–2.35 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 138.3, 133.9, 128.3, 127.6, 117.4, 77.7, 72.1, 53.1, 45.6, 37.2. ESI-MS: m/z = 227[M + Na]+. ESI-HRMS: m/z calcd for C13H16O2Na: 227.1402; found: 227.1402. (2R,3S)-3-(Benzyloxy)hex-5-en-2-ol (16) [α]D 30 +3.8 (c 0.3, CHCl3). IR (neat): 3432, 3070, 3031, 2977, 2931, 2874, 1718, 1641, 1496, 1453, 1396, 1370, 1258, 1215, 1092, 1070, 1028,996, 913, 772, 738, 698 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.36–7.20 (m, 5 H), 5.96–5.76 (m, 1 H), 5.18–5.05 (m, 2 H), 4.65 (m, 2 H), 3.98–3.89 (m, 1 H), 3.46–3.39 (m, 1 H), 2.48–2.37 (m, 1 H), 2.33–2.23 (m, 1 H), 1.18 (d, J = 6.6 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 138.4, 135.1, 127.7, 128.4, 127.8, 116.9, 82.4, 72.1, 68.2, 34.0, 17.8. ESI-MS: m/z = 229 [M + Na]+. ESI-HRMS: m/z calcd for C13H18O2Na: 229.1199; found: 229.1199. (2R,3S)-3-(Benzyloxy)hex-5-en-2-yl 2-Methoxy-4-(methoxymethoxy)-6-(pent-4-en-1-yl)benzoate (17) [α]D 30 –7.0 (c 0.3, CHCl3). IR (neat): 3073, 2927, 2855, 1725, 1640, 1604, 1588, 1458, 1426, 1317, 1261, 1216, 1191, 1150, 1085, 1023, 966, 917, 838, 772, 698 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H), 6.49 (d, J = 2.1 Hz, 1 H), 6.45 (d, J = 2.1 Hz, 1 H), 5.98–5.70 (m, 2 H), 5.45–5.22 (m, 2 H), 5.17 (s, 2 H), 5.12–4.91 (m, 3 H), 4.63 (m, 2 H), 3.81–3.74 (m, 3 H), 3.69–3.62 (m, 1 H), 3.48 (s, 3 H), 2.64–2.54 (m, 2 H), 2.44–2.35 (m, 2 H), 2.06 (ABq, J = 7.0, 14.1 Hz, 2 H), 1.73–1.64 (m, 2 H), 1.38 (d, J = 6.4 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 167.6, 158.8, 157.7, 142.2, 138.3, 134.6, 128.2, 127.7, 127.4, 117.3, 108.3, 97.7, 94.3, 80.4, 72.6, 72.5, 56.0, 55.6, 35.5, 33.5, 33.0, 30.3, 15.0. ESI-MS: m/z = 491 [M + Na]+. ESI-HRMS: m/z calcd for C28H36O6Na: 491.2404; found: 491.2405. (3R,4S)-4-(Benzyloxy)-14-methoxy-12-(methoxymethoxy)-3-methyl-3,4,5,8,9,10-hexahydro-1H-benzo[c][1]oxacyclododecin-1-one (18) Mp 86–90 °C. [α]D 30 32 (c 1, CHCl3). IR (KBr): 2925, 2854, 1724, 1604, 1586, 1456, 1373, 1346, 1311, 1261, 1230, 1212, 1191, 1149, 1091, 1070, 1017, 964, 932, 830, 738, 698 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.40–7.27 (m, 5 H), 6.51 (d, J = 1.9 Hz, 1 H), 6.42 (d, J = 1.9 Hz, 1 H), 5.70–5.51 (m, 1 H), 5.42–5.24 (m, 2 H), 5.16 (d, J = 1.3 Hz, 2 H), 4.82–4.44 (m, 2 H), 3.75 (s, 3 H), 3.62–3.53 (m, 1 H), 3.50 (s, 3 H), 2.62–2.49 (m, 2 H), 2.32–2.19 (m, 2 H), 2.15–1.96 (m, 2 H), 1.91–1.77 (m, 2 H), 1.43 (d, J = 5.9 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 167.4, 158.8, 157.2, 142.1, 138.3, 132.6, 128.7, 128.4, 128.3, 127.7, 127.6, 124.8, 108.3, 107.3, 97.7, 94.4, 80.5, 73.6, 71.3, 55.9, 56.1, 30.9, 31.8, 29.7, 29.5, 17.7. ESI-MS: m/z = 463 [M + Na]+. ESI-HRMS: m/z calcd for C26H32O6Na: 463.2091; found: 463.2091. (3R,4S)-4-Hydroxy-14-(methoxymethoxy)-3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-benzo[c][1]oxacyclo-dodecin-1-one (19) Mp 105–107 °C. [α]D 30 +7(c 1, CHCl3). IR (KBr): 3422, 2950, 2853, 2923, 1718, 1604, 1587, 1462, 1377, 1265, 1218, 1150, 1088, 1023, 771, 722 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.47 (m, 2 H), 5.17 (s, 2 H), 5.05–4.84 (m, 1 H), 3.78–3.80 (m, 4 H), 3.48 (s, 3 H), 2.83–2.69 (m, 1 H), 2.62–2.51 (m, 1 H), 1.93–1.83 (m, 1 H), 1.74–1.56 (m, 5 H), 1.48 (d, J = 6.0 Hz, 3 H), 1.45–1.36 (m, 4 H). 13C NMR (75 MHz, CDCl3): δ = 168.3, 158.9, 157.6, 142.6, 118.4, 108.7, 97.7, 94.3, 74.3, 73.9, 56.1, 55.9, 33.6, 31.9, 29.9, 25.9, 24.8, 21.4, 17.9. ESI-MS: m/z = 375 [M + Na]+. ESI-HRMS: m/z calcd for C19H28O6Na: 375.1778; found: 375.1776. (3R,4S)-4-Hydoxylasiodiplodin (1) Mp 213–215 °C. [α]D 30 +3.5 (c 0.7, MeOH). IR (KBr): 3355, 2924, 2853, 1691, 1603, 1462, 1263, 1219, 1162, 1093, 1026, 772 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.28 (d, J = 2.0 Hz, 1 H), 6.23 (d, J = 2.0 Hz 1 H), 4.76–4.71 (m, 1 H), 3.75 (s, 3 H), 3.66–3.61 (m, 1 H), 2.68 (ddd, J = 13.9, 7.9, 3.9 Hz, 1 H), 2.51 (ABq, J = 12.9, 7.0 Hz, 1 H), 1.85–1.78 (m, 1 H), 1.74–1.67 (m, 1 H), 1.67–1.58 (m, 2 H), 1.57–1.50 (m, 2 H), 1.42 (d, J = 6.0 Hz, 3 H), 1.37–1.32 (m, 2 H), 1.31–1.27 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 170.5, 160.9, 159.5, 143.7, 117.4, 109.4, 97.9, 75.0, 74.9, 56.3, 31.4, 31.3, 31.2, 27.3, 25.6, 22.5, 18.5. ESI-MS: m/z = 331 [M + Na]+. ESI-HRMS: m/z calcd for C17H24O5Na: 331.1516; found: 331.1518.

  • References and Notes

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  • 4 Oyama H, Sassa T, Ikeda M. Agric. Biol. Chem. 1978; 42: 2407
    CrossrefSearch in Google Scholar
  • 6 Xin-Sheng Y, Ebizuka Y, Noguchi H, Kiuchi F, Litaka Y, Sankawa U, Seto H. Tetrahedron Lett. 1983; 24: 2407
    CrossrefSearch in Google Scholar
  • 7 Lee K.-H, Hayashi N, Okhano M, Hall IH, Wu R.-Y, Mchail AT. Phytochemistry 1982; 21: 1119
    CrossrefSearch in Google Scholar
  • 8 Buayairaksa M, Kanokmedhakul S, Kanokmedhakul K, Moosophon P, Hahnvajanawong C, Soytong K. Arch. Pharm. Res. 2011; 34: 2037
    CrossrefSearch in Google Scholar
  • 9 Jiang C.-S, Zhou R, Gong J.-X, Chen L.-L, Kurtan T, Shen X, Guo Y.-W. Bioorg. Med. Chem. Lett. 2011; 21: 1171
    CrossrefSearch in Google Scholar
  • 10 Yang R-Y, Li C.-Y, Lin Y.-C, Peng G.-T, She Z.-G, Zhou S.-N. Bioorg. Med. Chem. Lett. 2006; 16: 4205
    CrossrefSearch in Google Scholar
  • 11 Veiga TA. M, Silva SC, Francisco A.-C, Filho ER, Vieira PC, Ferndes JB, Silva MF. G. F, Müller MW, Lotina-Hennsen B. J. Agric. Food. Chem. 2007; 55: 4217
    CrossrefSearch in Google Scholar
  • 12 Yang Q, Asai M, Matsuura H, Yoshihara T. Phytochemistry 2000; 54: 489
    CrossrefSearch in Google Scholar
  • 14 Chiarello J, Joullie MM. Tetrahedron 1988; 44: 41
    CrossrefSearch in Google Scholar
  • 15 Harris EM, Roberson JS, Harris TM. J. Am. Chem. Soc. 1976; 17: 5380
    Search in Google Scholar
  • 16 Vu NQ, Chai CL. L, Lim KP, Chia SC, Chen A. Tetrahedron 2007; 63: 7053
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  • 17 For a general review of benzylic anions, see: Clark RD, Jahangin A. Org. React. 1995; 47: 1
    Search in Google Scholar
  • 18 Chattopadhyay A, Mamdapur VR. J. Org. Chem. 1995; 60: 585
    CrossrefSearch in Google Scholar
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  • 23 Spectral Data for Representative Compounds Methyl 2-Hydroxy-4-(methoxymethoxy)-6-methyl-benzoate(7) Mp 55–58 °C. IR (KBr): 2956, 2855, 2831, 1726, 1657, 1618, 1579, 1446, 1422, 1369, 1324, 1261, 1215, 1152, 1111, 1080, 1062, 1020, 942, 845, 803, 770, 700, 673, 606, 578, 528 cm–1. 1H NMR (300 MHz, CDCl3): δ = 11.65 (s, 1 H), 6.47 (d, J = 3.0 Hz, 1 H), 6.36 (s, J = 2.3 Hz, 1 H), 5.15 (s, 2 H), 3.90 (s, 3 H), 3.45 (s, 3 H), 2.48 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 172.1, 165.2, 161.4, 143.3, 111.8, 101.5, 93.8, 56.3, 51.9, 29.7, 24.4. ESI-MS: m/z = 227 [M + H]+. ESI-HRMS: m/z calcd for C11H18O6Na: 269.1001; found: 269.0992. Methyl 2-Methoxy-4-(methoxymethoxy)-6-methyl-benzoate (8) IR (neat): 2944, 2846, 1727, 1602, 1585, 1459, 1434, 1321, 1268, 1231, 1189, 1149, 1096, 1078, 1026, 962, 928, 836, 814, 773 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.47 (d, J = 1.7 Hz, 1 H), 6.45 (d, J = 2.0 Hz, 1 H), 5.17 (s, 2 H), 3.88 (s, 3 H), 3.80 (s, 3 H), 3.48 (s,3 H), 2.27 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 168.5, 158.9, 157.9, 138.0, 117.3, 109.2, 94.2, 97.7, 55.9, 55.8, 51.9, 19.7. ESI-MS: m/z = 241 [M + H]+. ESI-HRMS: m/z calcd for C12H16O5Na: 263.0890; found: 263.0894. Methyl 2-Methoxy-4-(methoxymethoxy)-6-(pent-4-enyl)benzoate (9) IR (neat): 2951, 3004, 2907, 2838, 1739, 1709, 1615, 1577, 1431, 1297, 1219, 1137, 1103, 1037, 966, 930, 823, 772, 640 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.48 (m, 2 H), 5.89–5.71 (m, 1 H), 5.17 (s, 2 H), 5.07–4.87 (m, 2 H), 3.88 (s, 3 H), 3.47 (s, 3 H), 2.62–2.50 (m, 2 H), 2.15–2.07 (ABq, J = 14.0, 6.8 Hz, 2 H), 1.74–1.62 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 168.7, 158.9, 157.8, 142.5, 138.3, 125.5, 114.8, 108.4, 97.8, 94.3, 56.0, 55.9, 33.4, 33.1, 30.2. ESI-MS: m/z = 295 [M + H]+. 2-Methoxy-4-(methoxymethoxy)-6-(pent-4-enyl)benzoic Acid (10) IR (neat): 3076, 2932, 1697, 1603, 1460, 1425, 1297, 1218, 1193, 1151, 1113, 1081, 1021, 918, 837, 772 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.58 (d, J = 1.8 Hz, 1 H), 6.53 (d, J = 2.1 Hz 1 H), 5.93–5.76 (m, 1 H), 5.50–5.40 (m, 1 H), 5.21 (s, 2 H), 5.08–4.92 (m, 1 H), 3.93 (s, 3 H), 3.49 (s, 3 H), 2.92–2.80 (m, 2 H), 2.12 (ABq, J = 14.2, 7.17 Hz, 2 H), 1.79–1.64 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 171.8, 159.4, 158.4, 144.4, 138.3, 115.3, 114.7, 109.3, 97.8, 94.1, 55.9, 33.5, 33.4, 30.3. ESI-MS: m/z = 281 [M + H]+. ESI-HRMS: m/z calcd for C15H21O5Na: 281.1384; found: 281.1369. (R)-2-[(S)-1-(Benzyloxy)but-3-enyl]oxirane (15) [α]D 30 +5.40 (c 1, CHCl3). IR (neat): 3032, 3065, 2989, 2925, 2867, 1955, 1824, 1642, 1495, 1454, 1434, 1391, 1344, 1306, 1252, 1207, 1159, 1098, 1074, 1028, 995, 917, 851, 739, 698, 609, 2982, 2933, 1647, 1608, 1574, 1445, 1376, 1357, 1319, 1257, 1211, 1159, 1103, 1034, 967, 864, 757 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.32–7.20 (m, 5 H), 5.94–5.82 (m, 1 H), 5.17–5.06 (m, 2 H), 4.62–4.52 (m, 2 H), 3.32–3.28 (m, 1 H), 2.92–2.88 (m, 1 H), 2.73–2.70 (m, 1 H), 2.68–2.65 (m, 1 H), 2.47–2.35 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 138.3, 133.9, 128.3, 127.6, 117.4, 77.7, 72.1, 53.1, 45.6, 37.2. ESI-MS: m/z = 227[M + Na]+. ESI-HRMS: m/z calcd for C13H16O2Na: 227.1402; found: 227.1402. (2R,3S)-3-(Benzyloxy)hex-5-en-2-ol (16) [α]D 30 +3.8 (c 0.3, CHCl3). IR (neat): 3432, 3070, 3031, 2977, 2931, 2874, 1718, 1641, 1496, 1453, 1396, 1370, 1258, 1215, 1092, 1070, 1028,996, 913, 772, 738, 698 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.36–7.20 (m, 5 H), 5.96–5.76 (m, 1 H), 5.18–5.05 (m, 2 H), 4.65 (m, 2 H), 3.98–3.89 (m, 1 H), 3.46–3.39 (m, 1 H), 2.48–2.37 (m, 1 H), 2.33–2.23 (m, 1 H), 1.18 (d, J = 6.6 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 138.4, 135.1, 127.7, 128.4, 127.8, 116.9, 82.4, 72.1, 68.2, 34.0, 17.8. ESI-MS: m/z = 229 [M + Na]+. ESI-HRMS: m/z calcd for C13H18O2Na: 229.1199; found: 229.1199. (2R,3S)-3-(Benzyloxy)hex-5-en-2-yl 2-Methoxy-4-(methoxymethoxy)-6-(pent-4-en-1-yl)benzoate (17) [α]D 30 –7.0 (c 0.3, CHCl3). IR (neat): 3073, 2927, 2855, 1725, 1640, 1604, 1588, 1458, 1426, 1317, 1261, 1216, 1191, 1150, 1085, 1023, 966, 917, 838, 772, 698 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H), 6.49 (d, J = 2.1 Hz, 1 H), 6.45 (d, J = 2.1 Hz, 1 H), 5.98–5.70 (m, 2 H), 5.45–5.22 (m, 2 H), 5.17 (s, 2 H), 5.12–4.91 (m, 3 H), 4.63 (m, 2 H), 3.81–3.74 (m, 3 H), 3.69–3.62 (m, 1 H), 3.48 (s, 3 H), 2.64–2.54 (m, 2 H), 2.44–2.35 (m, 2 H), 2.06 (ABq, J = 7.0, 14.1 Hz, 2 H), 1.73–1.64 (m, 2 H), 1.38 (d, J = 6.4 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 167.6, 158.8, 157.7, 142.2, 138.3, 134.6, 128.2, 127.7, 127.4, 117.3, 108.3, 97.7, 94.3, 80.4, 72.6, 72.5, 56.0, 55.6, 35.5, 33.5, 33.0, 30.3, 15.0. ESI-MS: m/z = 491 [M + Na]+. ESI-HRMS: m/z calcd for C28H36O6Na: 491.2404; found: 491.2405. (3R,4S)-4-(Benzyloxy)-14-methoxy-12-(methoxymethoxy)-3-methyl-3,4,5,8,9,10-hexahydro-1H-benzo[c][1]oxacyclododecin-1-one (18) Mp 86–90 °C. [α]D 30 32 (c 1, CHCl3). IR (KBr): 2925, 2854, 1724, 1604, 1586, 1456, 1373, 1346, 1311, 1261, 1230, 1212, 1191, 1149, 1091, 1070, 1017, 964, 932, 830, 738, 698 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.40–7.27 (m, 5 H), 6.51 (d, J = 1.9 Hz, 1 H), 6.42 (d, J = 1.9 Hz, 1 H), 5.70–5.51 (m, 1 H), 5.42–5.24 (m, 2 H), 5.16 (d, J = 1.3 Hz, 2 H), 4.82–4.44 (m, 2 H), 3.75 (s, 3 H), 3.62–3.53 (m, 1 H), 3.50 (s, 3 H), 2.62–2.49 (m, 2 H), 2.32–2.19 (m, 2 H), 2.15–1.96 (m, 2 H), 1.91–1.77 (m, 2 H), 1.43 (d, J = 5.9 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 167.4, 158.8, 157.2, 142.1, 138.3, 132.6, 128.7, 128.4, 128.3, 127.7, 127.6, 124.8, 108.3, 107.3, 97.7, 94.4, 80.5, 73.6, 71.3, 55.9, 56.1, 30.9, 31.8, 29.7, 29.5, 17.7. ESI-MS: m/z = 463 [M + Na]+. ESI-HRMS: m/z calcd for C26H32O6Na: 463.2091; found: 463.2091. (3R,4S)-4-Hydroxy-14-(methoxymethoxy)-3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-benzo[c][1]oxacyclo-dodecin-1-one (19) Mp 105–107 °C. [α]D 30 +7(c 1, CHCl3). IR (KBr): 3422, 2950, 2853, 2923, 1718, 1604, 1587, 1462, 1377, 1265, 1218, 1150, 1088, 1023, 771, 722 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.47 (m, 2 H), 5.17 (s, 2 H), 5.05–4.84 (m, 1 H), 3.78–3.80 (m, 4 H), 3.48 (s, 3 H), 2.83–2.69 (m, 1 H), 2.62–2.51 (m, 1 H), 1.93–1.83 (m, 1 H), 1.74–1.56 (m, 5 H), 1.48 (d, J = 6.0 Hz, 3 H), 1.45–1.36 (m, 4 H). 13C NMR (75 MHz, CDCl3): δ = 168.3, 158.9, 157.6, 142.6, 118.4, 108.7, 97.7, 94.3, 74.3, 73.9, 56.1, 55.9, 33.6, 31.9, 29.9, 25.9, 24.8, 21.4, 17.9. ESI-MS: m/z = 375 [M + Na]+. ESI-HRMS: m/z calcd for C19H28O6Na: 375.1778; found: 375.1776. (3R,4S)-4-Hydoxylasiodiplodin (1) Mp 213–215 °C. [α]D 30 +3.5 (c 0.7, MeOH). IR (KBr): 3355, 2924, 2853, 1691, 1603, 1462, 1263, 1219, 1162, 1093, 1026, 772 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.28 (d, J = 2.0 Hz, 1 H), 6.23 (d, J = 2.0 Hz 1 H), 4.76–4.71 (m, 1 H), 3.75 (s, 3 H), 3.66–3.61 (m, 1 H), 2.68 (ddd, J = 13.9, 7.9, 3.9 Hz, 1 H), 2.51 (ABq, J = 12.9, 7.0 Hz, 1 H), 1.85–1.78 (m, 1 H), 1.74–1.67 (m, 1 H), 1.67–1.58 (m, 2 H), 1.57–1.50 (m, 2 H), 1.42 (d, J = 6.0 Hz, 3 H), 1.37–1.32 (m, 2 H), 1.31–1.27 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 170.5, 160.9, 159.5, 143.7, 117.4, 109.4, 97.9, 75.0, 74.9, 56.3, 31.4, 31.3, 31.2, 27.3, 25.6, 22.5, 18.5. ESI-MS: m/z = 331 [M + Na]+. ESI-HRMS: m/z calcd for C17H24O5Na: 331.1516; found: 331.1518.

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Figure 1 (3R,4S)-4-Hydroxylasiodiplodin (1)
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Scheme 1 Retrosynthesis for compound 1
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Scheme 2 Reagents and conditions: (a) NaH, n-BuLi, 0 °C to –78 °C to r.t., 12 h, reflux, 24 h, 50%; (b) MOMCl, DIEPA, CH2Cl2, 0 °C to r.t., 3 h, 85%; (c) K2CO3, Me2SO4, dry acetone, reflux, 12 h, 80%; (d) LDA, homoallyl bromide, –78 °C, 30 min, 62%; (e) KOH, (MeOH–H2O, 1:1), reflux, 2 d, then 1 M HCl, 86%.
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Scheme 3 Reagents and conditions: (a) BnBr, K2CO3, dry acetone, reflux, 12 h, 60%; (b) K2CO3, Me2SO4, dry acetone, reflux, 12 h, 82%; (c) LDA, homoallyl bromide, –78 °C, 30 min.
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Scheme 4 Reagents and conditions: (a) Zn, allyl bromide, aq NH4Cl, 0 °C, 4 h, 91%; (b) NaH, BnBr, THF, 0 °C to r.t., 6 h, 93%; (c) 60% AcOH in H2O, r.t., overnight, 86%; (d) TPP, DEAD, CHCl3, reflux, 12 h, 85%; (e) LAH, THF, 0 °C to r.t., 6 h, 89%.
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Scheme 5 Reagents and conditions: (a) DCC, DMAP, CH2Cl2, 0 °C to r.t., 5 h, 62%; (b) Grubbs II catalyst (5 mol%), CH2Cl2, reflux, 12 h, 81%; (c) H2, 10% Pd/C, EtOAc, 6 h, 87%; (d) 1 N HCl–MeOH (1:1), r.t., 24 h, 91%.