Synlett 2021; 32(07): 685-688
DOI: 10.1055/a-1297-6838
letter

Concise Total Synthesis of Curvulone B

Shivalal Banoth
a   Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b   Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
,
Utkal Mani Choudhury
a   Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b   Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
,
Kanakaraju Marumudi
c   Centre for NMR and Structural Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
,
Ajit C. Kunwar
c   Centre for NMR and Structural Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
,
Debendra K. Mohapatra
a   Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b   Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
› Author Affiliations
The authors gratefully acknowledge financial support received from the Science and Engineering Research Board (SERB), a statutory body of the Department of Science & Technology (DST), New Delhi, Government of India, through Grant No. EMR/2017/002298.
 


Abstract

A concise and convergent stereoselective synthesis of curvulone B is described. The synthesis utilized a tandem isomerization followed by C–O and C–C bond-forming reactions following Mukaiyama-type aldol conditions for the construction of the trans-2,6-disubstituted dihydropyran ring system as the key steps. Other important features of this synthesis are a cross-metathesis, epimerization, and Friedel–Crafts acylation.


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Marine fungi have been long recognized as a rich source of novel secondary metabolites with such biological properties as antitumor, phytotoxic, or antifungal activities, as well as cytotoxicity against human cancer cell lines.[1] In connection with the search for biologically active metabolites from fungi, Krohn and Kurtán and their co-workers isolated two new curvularin-type metabolites, curvulone A (1) and curvulone B (2; Figure [1]) from a Curvularia sp. obtained from the marine alga Gracilaria folifera.[1] Curvulone B (2) features a 2,6-disubstituted cis-tetrahydropyran ring, and displays antitumor, antifungal, and cytotoxic activities.[2]

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Figure 1 Structures of curvulone A (1) and curvulone B (2)

The structure of curvulone B was determined by 2D NMR spectroscopy, and its absolute configuration was deduced by comparison of the experimental electronic circular dichroism spectra in acetonitrile with the Boltzman-averaged spectrum.[3] Total syntheses of curvulone B (2) have been reported by the groups of Takahashi,[2] Bates,[4] and, more recently, He.[5] None of these syntheses involved fewer than ten linear steps, and all employed an intramolecular oxa-Michael addition for the formation of THP ring.

We recently reported the synthesis of 2,6-trans-disubstituted tetrahydropyrans with a keto functionality by means of a Mukaiyama-type aldol reactions of 1-phenyl-1-(trimethylsiloxy)ethylene with six-membered cyclic hemiacetals in the presence of iodine.[6] As a further application of this Mukaiyama-type aldol reaction, and as a part of our ongoing research on the total synthesis of biologically active natural products containing pyran rings,[7] we report an efficient and convergent synthesis of curvulone B in seven steps.

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Scheme 1 Retrosynthetic analysis of curvulone B (2)

Our retrosynthetic analysis of curvulone B is outlined in Scheme [1]. It was envisaged that curvulone B might be prepared by a Friedel–Crafts acylation reaction of aromatic ester 3 and the acid fragment 4 (Scheme [1]). We planned to obtain intermediate 4 from the trans-2,6-disubstituted dihydropyran 5 that, in turn, would be accessed from a δ-hydroxy α,β-unsaturated aldehyde through tandem isomerization followed by C–O and C–C bond-forming reactions of a silyl enol ether under Mukaiyama-type aldol reaction conditions. The δ-hydroxy α,β-unsaturated aldehyde would be obtained from the commercially available chiral homoallylic alcohol 6.

The synthesis of the key intermediate 5 began with the commercially available homoallylic alcohol 6 and acrolein, which, on treatment with the Hoveyda–Grubbs catalyst (10 mol%) in CH2Cl2 gave the cross-metathesis[8] product, the δ-hydroxy α,β-unsaturated aldehyde 7, in 87% yield (Scheme [2]). Tandem isomerization followed by a C–O and C–C bond-formation protocol under Mukaiyama-type conditions was performed by treating 7 with trimethyl(vinyloxy)silane in the presence of a catalytic amount of molecular iodine in anhydrous CH2Cl2 at room temperature to furnish the trans-2,6-disubstituted-3,4-dihydropyran 5 as the sole product in 81% yield.[6] [9] [10]

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Scheme 2 Synthesis of compound 5

The next task was to reduce the internal double bond and then to perform the isomerization reaction. Accordingly, the double bond in compound 5 was reduced in the presence of a catalytic amount of Adams’s catalyst under hydrogen in anhydrous ethyl acetate to furnish compound 8 in excellent yield (Scheme [3]). Epimerization was performed by a retro-oxa-Michael/oxa-Michael reaction with potassium tert-butoxide in THF at 0 °C; this reaction was highly stereoselective, favoring the desired C-β-epimer 9, which was obtained in 92% yield.[11] Acid 4, a key fragment for the Friedel–Crafts acylation strategy, was then synthesized in 86% yield from cis-pyran aldehyde 9 by Pinnick oxidation[12] with NaClO2, NaH2PO4, t-BuOH–H2O (1:1), and 2-methylbut-2-ene.

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Scheme 3 Synthesis of compound 4

The aromatic coupling fragment 3 was synthesized by methylation of commercially available methyl 2-(3,5-dihydroxyphenyl)acetate (10) with potassium carbonate and dimethyl sulfate in acetone to afford methyl 2-(3,5-dimethoxyphenyl)acetate (3) in 95% yield (Scheme [4]).[13]

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Scheme 4 Synthesis of fragment 3

With cis-pyran acid 4 and methyl 2-(3,5-dimethoxyphenyl)acetate (3) in hand, our next objective was to combine both fragments by using the key Friedel–Crafts acylation reaction. Accordingly, treatment of cis-pyran acid 4 with methyl 2-(3,5-dimethoxyphenyl)acetate (3) in TFA/TFAA, afforded the desired ketone 11 in 93% yield (Scheme [5]).[14]

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Scheme 5 Completion of the total synthesis of curvulone B (2)

The structure of compound 11 was confirmed by extensive NMR experiments, including DQF-COSY, TOCSY, NOESY, HSQC, and HMBC experiments. The distinctive AB spin system of double doublets at δ = 2.97 and 3.04 ppm, due to 10-H and 10-H′ displaying a HMBC correlation with the carbonyl carbon (δ = 204.3 ppm), was used to initiate the assignments. The DQF-COSY experiment helped us to assign the protons from 11-H to 15-H and the 16-CH3 protons. The 2-CH2 protons appear as a broad singlet at δ = 3.60 ppm. The nOe correlations 11-H/15-H, 11-H/13-H, 13-H/15-H, and 12-H′/14-H′ strongly supported the syn orientation of the 11-H and 15-H protons, as well as the 14C11 chair conformation of the six-membered ring. Furthermore, nOe correlations between 10-H/2-CH2, 2-CH2/4-H, and 7′-OCH3/10-H provided strong evidence that the pyran ring occupies an position ortho to methyl ester of the benzene ring, providing firm support for the proposed structure of 11 (Figure [2]).

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Figure 2 Energy-minimized structure of 11, along with key nOe correlations (double-headed arrows)

Finally, demethylation of the methoxy group of 11 was successfully achieved under Maier’s conditions (AlI3, TBAI, phloroglucinol)[15] in benzene at 0 °C to furnish curvulone B (2) in 91% yield.[16] The spectroscopic and analytical data for synthetic compound 2 were in good agreement with those reported for the natural product.[1]

In summary, a concise and stereoselective synthesis of the curvulone B (2) was achieved in seven steps and a 46% overall yield by using iodine-catalyzed tandem isomerization followed by C–O and C–C bond-formation through a Mukaiyama-type aldol reaction for the construction of the trans-2,6-disubstituted dihydropyran ring system as the key step. The other important reactions involved in the current synthetic approach were cross-metathesis, epimerization, and Friedel–Crafts acylation reactions.


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Acknowledgment

We are grateful to the Director, CSIR-IICT for his kind support and for providing research facilities (Manuscript communication number IICT/ Pubs/2020/305). S.B., U.M.C., and K.M. thank UGC, New Delhi, India, for financial assistance in the form of fellowships.

Supporting Information

  • References and Notes

  • 1 Dai J, Krohn K, Flörke U, Pescitelli G, Kerti G, Papp T, Kövér KE, Bényei AC, Draeger S, Schulz B, Kurtán T. Eur. J. Org. Chem. 2010; 6928 ; and references therein
  • 2 Takahashi S, Akita Y, Nakamura T, Koshino H. Tetrahedron: Asymmetry 2012; 23: 952 ; and references therein
  • 3 Guo Y.-W, Kurtán T, Krohn K, Pescitelli G, Zhang W. Chirality 2009; 21: 561
  • 4 Bates RW, Wang K, Zhou G, Kang DZ. Synlett 2015; 26: 751
  • 5 Allu SR, Banne S, Jiang J, Qi N, Guo J, He Y. J. Org. Chem. 2019; 84: 7227
  • 6 Bharath Y, Choudhury UM, Sadhana N, Mohapatra DK. Org. Biomol. Chem. 2019; 17: 9169
    • 7a Mallampudi NA, Srinivas B, Reddy JG, Mohapatra DK. Org. Lett. 2019; 21: 5952
    • 7b Srinivas B, Reddy DS, Mallampudi NA, Mohapatra DK. Org. Lett. 2018; 20: 6910
    • 7c Reddy GS, Padhi B, Bharath Y, Mohapatra DK. Org. Lett. 2017; 19: 6506
    • 7d Maity S, Kanikarapu S, Marumudi K, Kunwar AC, Yadav JS, Mohapatra DK. J. Org. Chem. 2017; 82: 4561
    • 7e Banoth S, Maity S, Kumar SR, Yadav JS, Mohapatra DK. Eur. J. Org. Chem. 2016; 2300
    • 7f Thirupathi B, Mohapatra DK. Org. Biomol. Chem. 2016; 14: 6212
    • 7g Padhi B, Reddy DS, Mohapatra DK. Eur. J. Org. Chem. 2015; 542
    • 7h Reddy DS, Padhi B, Mohapatra DK. J. Org. Chem. 2015; 80: 1365
    • 8a Garber SB, Kingsbury JS, Gray BL, Hoveyda AH. J. Am. Chem. Soc. 2000; 122: 8168
    • 8b Dinh M.-T, Bouzbouz S, Peglion J.-L, Cossy J. Tetrahedron 2008; 64: 5703
  • 9 Mohapatra DK, Das PP, Pattanayak MR, Yadav JS. Chem. Eur. J. 2010; 16: 2072
  • 10 [(2R,6R)-6-Methyl-5,6-dihydro-2H-pyran-2-yl]acetaldehyde (5) I2 (0.89 g, 3.51 mmol) was added to a stirred solution of aldehyde 7 (2.0 g, 17.54 mmol) and trimethyl(vinyloxy)silane (3.85 mL, 26.31 mmol) in anhyd CH2Cl2 (50 mL) at 0 °C, and the mixture was allowed to warm to rt. When the reaction was complete (TLC), it was quenched with sat. aq Na2S2O3 (30 mL), and the mixture was extracted with CH2Cl2 (2 × 50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:5)] to give a pale-yellow liquid; yield: 1.99 g (81%); [α]D 20 –68.0 (c = 0.85, CHCl3). IR (neat): 3033, 2971, 2928, 1721, 1636, 1373, 1187, 1137, 1090 cm–1. 1H NMR (300 MHz, CDCl3): δ = 9.81 (s, 1 H), 5.87 (m, 1 H), 5.70 (d, J = 11.7 Hz, 1 H), 4.78 (m, 1 H), 3.83 (m, 1 H), 2.76 (ddd, J = 16.2, 8.8, 3.0 Hz, 1 H), 2.55 (dd, J = 16.2, 4.7 Hz, 1 H), 2.06–1.91 (m, 2 H), 1.21 (d, J = 6.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 201.0, 127.5, 125.2, 67.6, 64.1, 47.9, 31.5, 20.6. HRMS (ESI): m/z [M + Na]+ calcd for C8H12NaO2: 163.0728; found: 163.0724.
  • 11 Yakambram P, Puranik VG, Gurjar MK. Tetrahedron Lett. 2006; 47: 3781
    • 12a Ballakrishna SB, Childers WE. Jr, Pinnick HW. Tetrahedron 1981; 37: 2091
    • 12b Dalcanale E, Montanari F. J. Org. Chem. 1986; 51: 567
  • 13 Liang Q, Zhang J, Quan W, Sun Y, She X, Pan X. J. Org. Chem. 2007; 72: 2694
  • 14 Tauber J, Rudolph K, Rohr M, Erkel G, Opatz T. Eur. J. Org. Chem. 2015; 3587
  • 15 Rink C, Sasse F, Zubrienė A, Matulis D, Maier ME. Chem. Eur. J. 2010; 16: 14469
  • 16 Curvulone B (2) A suspension of Al powder (192 mg, 7.37 mmol) in anhyd benzene (5 mL) was treated with I2 (0.7 g, 2.74 mmol) under argon, and the violet mixture was stirred under reflux for 30 min until the mixture became colorless. The mixture was then cooled to 0 °C, and TBAI (12.7 mg, 0.034 mmol) and phloroglucinol (108 mg, 0.85 mmol) were added, followed by a solution of 11 (60 mg, 0.17 mmol) in anhyd benzene (2 mL) added in one portion. The resulting green–brown suspension was stirred for 30 min at 0 °C. When the reaction was complete (TLC), it was quenched with sat. aq aqueous Na2S2O3 (10 mL), and the mixture was diluted with EtOAc (15 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine (25 mL), filtered, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:1)] to give a colorless liquid; yield: 50 mg (91%); [α]D 20 –18.2 (c = 0.2, EtOH). IR (neat): 3410, 2928, 1713, 1613, 1451, 1334, 1166 cm1. 1H NMR (400 MHz, CDCl3): δ = 9.79 (s, 1 H), 6.28 (d, J = 2.3 Hz, 1 H), 6.22 (d, J = 2.3 Hz, 1 H), 6.08 (br s, 1 H), 4.13 (brtt, J = 10.5, 2.3 Hz, 1 H), 3.92 (d, J = 16.5 Hz, 1 H), 3.70 (s, 3 H), 3.57 (m, 1 H), 3.51 (d, J = 16.6 Hz, 1 H), 3.30 (dd, J = 14.3, 10.1 Hz, 1 H), 2.56 (dd, J = 14.3, 3.1 Hz, 1 H), 1.85 (m, 1 H), 1.65–1.50 (m, 3 H), 1.42 (m, 1 H), 1.25 (m, 1 H), 1.17 (d, J = 6.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 204.2, 172.4, 159.4, 135.7, 120.7, 111.7, 104.0, 77.8, 74.8, 52.0, 49.0, 39.7, 32.6, 30.7, 23.1, 21.5. HRMS (ESI): m/z [M + H]+ calcd for C17H23O6: 323.1489; found: 323.1494.

Corresponding Author

Debendra K. Mohapatra
Centre for NMR and Structural Chemistry, CSIR-Indian Institute of Chemical Technology
Hyderabad 500 007
India   

Publication History

Received: 08 October 2020

Accepted after revision: 26 October 2020

Accepted Manuscript online:
26 October 2020

Article published online:
24 November 2020

© 2020. Thieme. All rights reserved

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  • References and Notes

  • 1 Dai J, Krohn K, Flörke U, Pescitelli G, Kerti G, Papp T, Kövér KE, Bényei AC, Draeger S, Schulz B, Kurtán T. Eur. J. Org. Chem. 2010; 6928 ; and references therein
  • 2 Takahashi S, Akita Y, Nakamura T, Koshino H. Tetrahedron: Asymmetry 2012; 23: 952 ; and references therein
  • 3 Guo Y.-W, Kurtán T, Krohn K, Pescitelli G, Zhang W. Chirality 2009; 21: 561
  • 4 Bates RW, Wang K, Zhou G, Kang DZ. Synlett 2015; 26: 751
  • 5 Allu SR, Banne S, Jiang J, Qi N, Guo J, He Y. J. Org. Chem. 2019; 84: 7227
  • 6 Bharath Y, Choudhury UM, Sadhana N, Mohapatra DK. Org. Biomol. Chem. 2019; 17: 9169
    • 7a Mallampudi NA, Srinivas B, Reddy JG, Mohapatra DK. Org. Lett. 2019; 21: 5952
    • 7b Srinivas B, Reddy DS, Mallampudi NA, Mohapatra DK. Org. Lett. 2018; 20: 6910
    • 7c Reddy GS, Padhi B, Bharath Y, Mohapatra DK. Org. Lett. 2017; 19: 6506
    • 7d Maity S, Kanikarapu S, Marumudi K, Kunwar AC, Yadav JS, Mohapatra DK. J. Org. Chem. 2017; 82: 4561
    • 7e Banoth S, Maity S, Kumar SR, Yadav JS, Mohapatra DK. Eur. J. Org. Chem. 2016; 2300
    • 7f Thirupathi B, Mohapatra DK. Org. Biomol. Chem. 2016; 14: 6212
    • 7g Padhi B, Reddy DS, Mohapatra DK. Eur. J. Org. Chem. 2015; 542
    • 7h Reddy DS, Padhi B, Mohapatra DK. J. Org. Chem. 2015; 80: 1365
    • 8a Garber SB, Kingsbury JS, Gray BL, Hoveyda AH. J. Am. Chem. Soc. 2000; 122: 8168
    • 8b Dinh M.-T, Bouzbouz S, Peglion J.-L, Cossy J. Tetrahedron 2008; 64: 5703
  • 9 Mohapatra DK, Das PP, Pattanayak MR, Yadav JS. Chem. Eur. J. 2010; 16: 2072
  • 10 [(2R,6R)-6-Methyl-5,6-dihydro-2H-pyran-2-yl]acetaldehyde (5) I2 (0.89 g, 3.51 mmol) was added to a stirred solution of aldehyde 7 (2.0 g, 17.54 mmol) and trimethyl(vinyloxy)silane (3.85 mL, 26.31 mmol) in anhyd CH2Cl2 (50 mL) at 0 °C, and the mixture was allowed to warm to rt. When the reaction was complete (TLC), it was quenched with sat. aq Na2S2O3 (30 mL), and the mixture was extracted with CH2Cl2 (2 × 50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:5)] to give a pale-yellow liquid; yield: 1.99 g (81%); [α]D 20 –68.0 (c = 0.85, CHCl3). IR (neat): 3033, 2971, 2928, 1721, 1636, 1373, 1187, 1137, 1090 cm–1. 1H NMR (300 MHz, CDCl3): δ = 9.81 (s, 1 H), 5.87 (m, 1 H), 5.70 (d, J = 11.7 Hz, 1 H), 4.78 (m, 1 H), 3.83 (m, 1 H), 2.76 (ddd, J = 16.2, 8.8, 3.0 Hz, 1 H), 2.55 (dd, J = 16.2, 4.7 Hz, 1 H), 2.06–1.91 (m, 2 H), 1.21 (d, J = 6.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 201.0, 127.5, 125.2, 67.6, 64.1, 47.9, 31.5, 20.6. HRMS (ESI): m/z [M + Na]+ calcd for C8H12NaO2: 163.0728; found: 163.0724.
  • 11 Yakambram P, Puranik VG, Gurjar MK. Tetrahedron Lett. 2006; 47: 3781
    • 12a Ballakrishna SB, Childers WE. Jr, Pinnick HW. Tetrahedron 1981; 37: 2091
    • 12b Dalcanale E, Montanari F. J. Org. Chem. 1986; 51: 567
  • 13 Liang Q, Zhang J, Quan W, Sun Y, She X, Pan X. J. Org. Chem. 2007; 72: 2694
  • 14 Tauber J, Rudolph K, Rohr M, Erkel G, Opatz T. Eur. J. Org. Chem. 2015; 3587
  • 15 Rink C, Sasse F, Zubrienė A, Matulis D, Maier ME. Chem. Eur. J. 2010; 16: 14469
  • 16 Curvulone B (2) A suspension of Al powder (192 mg, 7.37 mmol) in anhyd benzene (5 mL) was treated with I2 (0.7 g, 2.74 mmol) under argon, and the violet mixture was stirred under reflux for 30 min until the mixture became colorless. The mixture was then cooled to 0 °C, and TBAI (12.7 mg, 0.034 mmol) and phloroglucinol (108 mg, 0.85 mmol) were added, followed by a solution of 11 (60 mg, 0.17 mmol) in anhyd benzene (2 mL) added in one portion. The resulting green–brown suspension was stirred for 30 min at 0 °C. When the reaction was complete (TLC), it was quenched with sat. aq aqueous Na2S2O3 (10 mL), and the mixture was diluted with EtOAc (15 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine (25 mL), filtered, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:1)] to give a colorless liquid; yield: 50 mg (91%); [α]D 20 –18.2 (c = 0.2, EtOH). IR (neat): 3410, 2928, 1713, 1613, 1451, 1334, 1166 cm1. 1H NMR (400 MHz, CDCl3): δ = 9.79 (s, 1 H), 6.28 (d, J = 2.3 Hz, 1 H), 6.22 (d, J = 2.3 Hz, 1 H), 6.08 (br s, 1 H), 4.13 (brtt, J = 10.5, 2.3 Hz, 1 H), 3.92 (d, J = 16.5 Hz, 1 H), 3.70 (s, 3 H), 3.57 (m, 1 H), 3.51 (d, J = 16.6 Hz, 1 H), 3.30 (dd, J = 14.3, 10.1 Hz, 1 H), 2.56 (dd, J = 14.3, 3.1 Hz, 1 H), 1.85 (m, 1 H), 1.65–1.50 (m, 3 H), 1.42 (m, 1 H), 1.25 (m, 1 H), 1.17 (d, J = 6.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 204.2, 172.4, 159.4, 135.7, 120.7, 111.7, 104.0, 77.8, 74.8, 52.0, 49.0, 39.7, 32.6, 30.7, 23.1, 21.5. HRMS (ESI): m/z [M + H]+ calcd for C17H23O6: 323.1489; found: 323.1494.

Zoom Image
Figure 1 Structures of curvulone A (1) and curvulone B (2)
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Scheme 1 Retrosynthetic analysis of curvulone B (2)
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Scheme 2 Synthesis of compound 5
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Scheme 3 Synthesis of compound 4
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Scheme 4 Synthesis of fragment 3
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Scheme 5 Completion of the total synthesis of curvulone B (2)
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Figure 2 Energy-minimized structure of 11, along with key nOe correlations (double-headed arrows)