Tetrahedron Letters 54 (2013) 6349–6351

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Tetrahedron Letters

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Asymmetric total synthesis of (+)-monocerin

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⇑ Corresponding author. Tel.: +86 931 8912276; fax: +86 931 8912583.E-mail address: shexg@lzu.edu.cn (X. She).

O

O

MeO

MeO

OH

H

O

H

(+)-monocerin (1)

OMeMeO

MeOO

OH

OMeMeO

MeOOH

OH OH

OMeMeO

MeOOBn

OH

OMeMeO

MeOOH

O

2

3 4

5

OMeMeO

MeO CHO

6

SS

Scheme 1. Retrosynthetic plan for the synthesis of (+)-monocerin (

Bowen Fang a, Xingang Xie a, Huilin Li a, Peng Jing a, Jixiang Gu a, Xuegong She a,b,⇑a State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of Chinab State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, People’s Republic of China

a r t i c l e i n f o

Article history:Received 22 July 2013Revised 30 August 2013Accepted 13 September 2013Available online 21 September 2013

Keywords:Asymmetric synthesis(+)-Monocerincis-Fused furobenzopyranones

a b s t r a c t

A concise asymmetric total synthesis of (+)-monocerin has been accomplished. The cis-fused furobenzo-pyranone of monocerin was efficiently constructed via a Lewis acid-mediated stereoselective cyclizationof 1,2,4-triols intermediate.

� 2013 Elsevier Ltd. All rights reserved.

1).

Monocerin is a polyketide natural product isolated from severalfungal sources.1 The structural feature of monocerin includes a2,3,5-trisubstituted tetrahydrofuran, which is embedded with all-cis stereochemistry. Along with the elucidation of structure, stud-ies regarding its biological property have also been performedshowing various antifungal, insecticidal, plant pathogenic proper-ties, and phytotoxic activity1f,g,2 Due to the potential for applica-tion in the pharmaceutical industry, this natural productattracted the attention of synthetic chemists and several total syn-theses of monocerin (1) have been reported.3

The first asymmetric total synthesis of monocerin was reportedby Mori in 1989,3a which was followed by Simpson, who employeda radical benzylic bromination to initiate the formation of cis-tetra-hydrofuran.3b The cis-fused sub-unit was constructed via a radicalcyclization of vinylic ether intermediate by Lee in 2008,3d andthrough a stereoselective oxylactonization of ortho-alkenylbenzo-ate with chiral hypervalent iodine by Fujita in 2012.3e Recently,we have completed total synthesis of monocerin by a biomimeti-cally inspired procedure.4 In that work, the cis-fused furobenzopyr-anone arose by intramolecular nucleophilic trapping of aquinonemethide intermediate by a pendant alcohol.

Herein, we describe a concise asymmetric total synthesis ofmonocerin (1). The retrosynthetic pathway of this compoundwas depicted in Scheme 1. We envisioned that the 4-oxyisochro-man-1-one skeleton of monocerin (1) could be readily obtainedfrom trisubstituted tetrahydrofuran 2 via an oxa-Pictet–Spenglercyclization followed by a proper oxidation. The cis-fused tetrahy-

drofuran 2 would be established by a Lewis acid-mediated cycliza-tion of cyclic ortho esters from triol 3, which in turn could beprepared from b-hydroxydithiane 4. And the requisite chiralepoxyalcohol 5 could be easily accessed by several steps from com-mercially available 3,4,5-trimethoxybenzaldehyde 6.

The synthesis of monocerin (1) commenced from 3,4,5-trimeth-oxybenzaldehyde 6 (Scheme 2), which was converted into the cor-responding allylic alcohol 7 in 90% yield using a known procedure.5

The enantioselective epoxidation of the racemic allyl alcohol 7gave, in the presence of L-diisopropyl tartarate, the epoxy alcohol

OMeMeO

MeO CHO

6

OMeMeO

MeOOH

7

OMeMeO

MeOOH

O

5

OMeMeO

MeOOBn

O

8

OMeMeO

MeOOBn

OH

4

OMeMeO

MeOOBn

OH O

9

OMeMeO

MeOOBn

OH OH

10

OMeMeO

MeOOH

OH OH

3

OMeMeO

MeOO

OAc

11

OMeMeO

MeOO

OH

2

OMeMeO

MeOO

O

O

12

OHMeO

MeOO

O

O

(+)-monocerin (1)

ref 4 a

b c dSS

e f

g h

i j

Scheme 2. Synthesis of monocerin (1), Reagents and conditions: (a) diisopropyl L-tartarate, Ti(i-PrO)4, tert-butyl hydroperoxide, CH2Cl2, �20 �C, 30 h, 27%; (b) NaH,BnBr, TBAI, THF, 0 �C, 83%; (c) 2-propyl-1,3-dithiane, t-BuLi, THF/HMPA, �20 �C, 1 h,then 8 in THF was added, �20 �C to rt, 76%; (d) I2, CaCO3, THF/H2O, 0 �C, 80%; (e)Me4NBH(OAc)3, CH3CN/AcOH, �30 �C, 91%; (f) 5% Pd/C, H2 (1 atm), CH3OH, rt, 95%;(g) trimethyl orthoacetate, PPTS, CH2Cl2, rt, 15 min, then BF3�OEt2, 0 �C, 85%; (h)K2CO3, CH3OH, rt, 100%; (i) (1) CH(OMe)3, TMSOTf, CH2Cl2, 0 �C; (2) Jones oxid.,Acetone, 0 �C, 82% (over two steps); (j) BCl3, CH2Cl2, �10 �C, 68%.

6350 B. Fang et al. / Tetrahedron Letters 54 (2013) 6349–6351

5 in 27% yield,6 then the hydroxyl group of 5 was protected asbenzyl ether 8. Treatment of 2-propyl-1,3-dithiane7 with t-BuLiin THF and HMPA, followed by the ring opening of 8 affordb-hydroxydithiane 4 in 76% yield. Removal of the 1,3-dithianegroup was achieved under mild conditions by I2 and CaCO3 to giveb-hydroxyketone 9. Me4NBH(OAc)3 reduction8 of 9 gave thedesired 1,3-anti diol 10, which was converted into triol 3 upondebenzylation with Pd/C in 95% overall yield.

With triol 3 in hand, we set out to investigate synthesis of thecis 2,3,5-trisubstituted tetrahydrofuran in monocerin. It was foundthat after treatment of 3 with trimethyl orthoacetate and a cata-lytic amount of PPTS in dichloromethane, followed by addition ofBF3�OEt2, the cyclization proceeded to deliver product 11 as asingle diastereomer in 85% yield. The strategy depends on the gen-eration of an ortho ester via trans-ortho esterification of trimethylorthoacetate with a 1,2-diol. The subsequent ionization of theintermediate ortho ester with a Lewis acid leads to a reactive ace-toxonium species, which upon intramolecular displacement withthe pendant hydroxyl yields the cyclized ether.9 The acetyl groupof compound 11 was removed under slight basic conditions to givealcohol 2. Subsequently, treatment of alcohol 2 with trimethylorthoformate and TMSOTf, the oxa-Pictet–Spengler reaction10

was found to be reliable and the resulting cyclic acetal was directly

treated with Jones reagent11 to afford d-valerolactone 12 in 85%yield for two consecutive steps. Finally, (+)-monocerin was ob-tained from 12 by partial demethylation12 with boron trichloridein 68% yield. The characterization data of (+)-monocerin13 is con-sistent with the prior reported 1 (see the Supporting Information).

In summary, we have achieved a concise asymmetric totalsynthesis of (+)-monocerin from commercially available 3,4,5-tri-methoxybenzaldehyde with an overall yield of 5% over 11 steps.

Acknowledgments

Financial support for this research was provided by the NSFC(21125207, 21102062, 21072086), the MOST (2010CB833203),PCSIRT (IRT1138), the FRFCU (lzujbky-2013-49, lzujbky-2013-ct02) and Program 111.

Supplementary data

Supplementary data (all experimental procedures, NMR spectra(1H, 13C NMR)) associated with this article can be found, in the on-line version, at http://dx.doi.org/10.1016/j.tetlet.2013.09.055.These data include MOL files and InChiKeys of the most importantcompounds described in this article.

References and notes

1. (a) Aldridge, D. C.; Turner, W. B. J. Chem. Soc. Sect. C 1970, 18, 2598; (b) Grove, J.F.; Pople, M. J. Chem. Soc., Perkin Trans. 1 1979, 2048; (c) Scott, F. E.; Simpson, T.J.; Trimble, L. A.; Vederas, J. C. J. Chem. Sot. Chem. Commun. 1984, 756; (d) Cuq,F.; Herrmann-Gorline, S.; Klaebe, A.; Rossignol, M.; Petitprez, M. Phytochemistry1993, 34, 1265; (e) Lim, C.-H. Agric. Chem. Biotechnol. (Engl Ed.) 1999, 42, 45; (f)Sappapan, R.; Sommit, D.; Ngamrojanavanich, N.; Pengpreecha, S.; Wiyakrutta,S.; Sriubolmas, N.; Pudhom, K. J. Nat. Prod. 2008, 71, 1657; (g) Zhang, W.; Krohn,K.; Draeger, S.; Schulz, B. J. Nat. Prod. 2008, 1078, 71.

2. (a) Claydon, N.; Grove, J. F.; Pople, M. J. Intertebr. Pathol. 1979, 33, 364; (b)Grove, J. F.; Pople, M. Mycopathologia 1981, 76, 65.

3. (a) Mori, K.; Takaishi, H. Tetrahedron 1989, 45, 1639; (b) Dillon, M. P.; Simpson,T. J.; Sweeney, J. B. Tetrahedron Lett. 1992, 33, 7569; (c) Cassidy, J. H.; Farthing,C. N.; Marsden, S. P.; Pedersen, A.; Slater, M.; Stemp, G. Org. Biomol. Chem. 2006,4, 4118; (d) Kwon, H. K.; Lee, Y. E.; Lee, E. Org. Lett. 2008, 10, 2995; (e) Fujita,M.; Mori, K.; Shimogaki, M.; Sugimura, T. Org. Lett. 2012, 14, 1294.

4. Fang, B.; Xie, X.; Zhao, C.; Jing, P.; Li, H.; Wang, Z.; Gu, J.; She, X. J. Org. Chem.2013, 78, 6338.

5. Briot, A.; Baehr, C.; Brouillard, R.; Wagner, A.; Mioskowski, C. J. Org. Chem. 2004,69, 1374.

6. Bessodes, M.; Saiah, M.; Antonakis, K. J. Org. Chem. 1992, 57, 4441.7. For synthesis of 2-propyl-1, 3-dithiane, see: Abad, J.-L.; Fabriás, G.; Camps, F. J.

Org. Chem. 2000, 65, 8582.8. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560.9. Zheng, T.; Narayan, R. S.; Schomaker, J. M.; Borhan, B. J. Am. Chem. Soc. 2005,

127, 6946.10. For intramolecular oxa-Pictet-Spengler cyclization, see: (a) Giles, R. G. F.;

Rickards, R. W.; Senanayake, B. S. J. Chem. Soc., Perkin Trans. 1 1997, 3361; (b)Xu, Y.-C.; Kohlman, D. T.; Liang, S. X.; Erikkson, C. Org. Lett. 1999, 1, 1599; (c)Giles, R. G. F.; McManus, J. D. Tetrahedron Lett. 2009, 50, 6361; (d) Zheng, H.;Zhao, C.; Fang, B.; Jing, P.; Yang, J.; Xie, X.; She, X. J. Org. Chem. 2012, 77, 5656.

11. Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C. L. J. Chem. Soc. 1946,39.

12. Dean, F. M.; Goodchild, J.; Houghton, L. E.; Martin, J. A.; Morton, R. B.; Parton,B.; Price, A. W.; Somvichien, N. Tetrahedron Lett. 1966, 7, 4153.

13. Spectral data for selected compounds: (S)-((R)-oxiran-2-yl)(3,4,5-trimethoxyphenyl)methanol (5): ½a�27

D +58 (c 1, CHCl3); 1H NMR (400 MHz,CDCl3) d 6.63 (s, 2H), 4.84 (d, J = 3.2 Hz, 1H), 3.88 (s, 6H), 3.85 (s, 3H), 3.23 (dd,J = 6.7, 3.2 Hz, 1H), 2.95 (dd, J = 5.0, 2.8 Hz, 1H), 2.79 (dd, J = 4.9, 4.0 Hz, 1H),2.29 (s, 1H); 13C NMR (100 MHz, CDCl3) d 153.4, 137.8, 135.1, 103.1, 71.1, 60.8,56.1, 55.0, 43.7; IR (KBr): tmax 3446, 2926, 1592, 1461, 1232, 1126, 1004 cm�1;HRMS (ESI) Calcd for C12H17O5 [M+H]+ 241.1071, found 241.1078.(1S,2R,4S)-1-(3,4,5-trimethoxyphenyl)heptane-1,2,4-triol (3): ½a�27

D +24 (c 1,CHCl3); 1H NMR (300 MHz, CDCl3) d 6.58 (s, 2H), 4.59 (d, J = 5.3 Hz, 1H),4.08–4.02 (m, 1H), 3.94–3.88 (m, 1H), 3.84 (s, 6H), 3.82 (s, 3H), 3.21 (s, 1H),3.01 (s, 1H), 2.64 (s, 1H), 1.69 (ddd, J = 14.5, 8.9, 2.8 Hz, 1H), 1.59–1.16 (m, 5H),0.89 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 153.2, 137.3, 136.4, 103.5,72.6, 69.2, 60.8, 56.1, 39.4, 37.4, 18.9, 13.9; IR (KBr): tmax 3377, 2927, 1592,1460, 1327, 1234, 1127, 1009, 755 cm�1; HRMS (ESI) Calcd for C16H26O6Na[M+Na]+ 337.1622, found 337.1616. (2R,3R,5S)-5-propyl-2-(3,4,5-trimethoxyphenyl)tetrahydrofuran-3-yl acetate (11): ½a�27

D �4 (c 1, CHCl3); 1HNMR (300 MHz, CDCl3) d 6.57 (s, 2H), 5.57–5.52 (m, 1H), 4.80 (d, J = 4.6 Hz, 1H),4.05–3.95 (m, 1H), 3.84 (s, 6H), 3.81 (s, 3H), 2.52 (dt, J = 14.2, 7.2 Hz, 1H), 1.73

B. Fang et al. / Tetrahedron Letters 54 (2013) 6349–6351 6351

(s, 3H), 1.91–1.37 (m, 5H), 0.99 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) d169.9, 152.7, 137.2, 132.4, 104.3, 83.2, 77.6, 74.9, 60.8, 56.0, 38.5, 37.8, 20.8,19.3, 14.1; IR (KBr): tmax 2925, 1740, 1592, 1461, 1375, 1237, 1128, 1010,756 cm�1; HRMS (ESI) Calcd for C18H27O6 [M+H]+ 339.1802, found 339.1819.(+)-monocerin (1): ½a�25

D +53 (c 1, CHCl3), (lit.,1 ½a�24D +53); 1H NMR (400 MHz,

CDCl3) d 11.28 (s, 1H), 6.59 (s, 1H), 5.05 (dd, J = 5.4, 3.0 Hz, 1H), 4.54 (d,J = 3.1 Hz, 1H), 4.12 (dq, J = 12.7, 6.3 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 2.59

(ddd, J = 14.6, 8.5, 6.2 Hz, 1H), 2.15 (dd, J = 14.5, 5.8 Hz, 1H), 1.72–1.64 (m, 1H),1.62–1.51 (m, 1H), 1.47–1.29 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR(100 MHz, CDCl3) d 167.7, 158.6, 156.2, 137.2, 131.1, 104.3, 102.0, 81.2, 78.7,74.4, 60.7, 56.2, 38.9, 38.0, 19.1, 13.9; IR (KBr): tmax 2925, 1663, 1520, 1459,1377, 1275, 1120, 1014, 735 cm�1; HRMS (ESI) Calcd. for C16H21O6 [M+H]+

309.1333, found 309.1328.