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CEM 852 Total Synthesis Project:

(+)-Preuisolactone A

Behrad MasoudiSpring-Home 2020

O

MeO

OO

HH

O

OHH

O

CEM 852 Total Synthesis Project

Background

(+)- and (−)-Preuisolactone A: A Pair of Caged NorsesquiterpenoidalEnantiomers with a Tricyclo[4.4.01,6.02,8]decane Carbon Skeletonfrom the Endophytic Fungus Preussia isomeraLu-Lin Xu,†,‡,∥ Hai-Li Chen,†,‡,∥ Ping Hai,⊥ Yuan Gao,⊥ Chuan-Dong Xie,‡ Xiao-Long Yang,*,†,‡and Ikuro Abe*,§

†School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, People’s Republic of China‡Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, ChongqingUniversity, Chongqing 401331, People’s Republic of China§Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan⊥Department of Chemical Engineering, Yibin University, Yibin 644000, People’s Republic of China

*S Supporting Information

ABSTRACT: A pair of enantiomeric norsesquiterpenoids, (+)- and (−)-preuisolactone A (1) [(+)-1 and (−)-1)] featuring anunprecedented tricyclo[4.4.01,6.02,8]decane carbon scaffold were isolated from Preussia isomera. Their structures weredetermined by spectroscopic and computed methods and X-ray crystallography. Compounds (+)-1 and (−)-1 are two rarenaturally occurring sesquiterpenoidal enantiomers. A plausible biosynthetic pathway for 1 is proposed. Additionally, (±)-1exhibited remarkable antibacterial activity against Micrococcus luteus with an MIC value of 10.2 μM.

Plant endophytic fungi, the major group of special eco-environmental fungi inhabiting living plants without any

negative effects, have an excellent capacity for secreting diversebiological secondary metabolites with a variety of uniquestructures and with potential therapeutic applications.1−5 Fungiof the Preussia genus, belonging to the family Sporormiaceae,have been frequently found as plant endophytes.6,7 Previousphytochemical investigations of some species have affordedmany novel bioactive secondary metabolites, such as six novelbicyclic polyketides, preussilides A−F, with antiproliferativeactivity from Preussia similis,8 two novel polyketides, mini-moidiones A and B, as α-glucosidase inhibitors from Preussiaminimoides,9 two novel dibenzofurans, preussiafurans A and B,possessing antiplasmodial and cytotoxic activities from Preussiasp.,10 an unusual thiopyranchromenone, preussochromone A,with cytotoxic activity from Preussia af ricana,11 six aromatic bis-ketals, preussomerins A−F, with antifungal and antibacterialactivities from Preussia isomera,12,13 etc. Accordingly, thefascinating properties of the secondary metabolites producedby fungi of the Preussia genus stimulated us to search foradditional novel bioactive compounds for new drug develop-ment.In the course of our ongoing efforts to explore the unique

structurally bioactive compounds from the plant endophyticfungi, one of the isolates, Preussia isomera XL-1326, obtained

from the stems of Panax notoginseng, gained our attentionbecause of its significant antimicrobial properties. Furtherbioassay-guided fractionations afforded a pair of enantiomericnorsesquiterpenoids, (+)- and (−)-preuisolactone A (1) [(+)-1and (−)-1)] (Figure 1). Herein, we describe the details of theisolation, structural elucidation, biological activities, andplausible biosynthetic pathway of 1.(±)-Preuisolactone A (1) was obtained as colorless crystals

with a molecular formula of C15H14O7 as evident from thepositive HRESIMS (m/z 329.0630 [M + Na]+, calcd for

Received: December 26, 2018Published: February 7, 2019

Figure 1. Structures of (+)- and (−)-preuisolactone A (1).

Letter

pubs.acs.org/OrgLettCite This: Org. Lett. 2019, 21, 1078−1081

© 2019 American Chemical Society 1078 DOI: 10.1021/acs.orglett.8b04123Org. Lett. 2019, 21, 1078−1081

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Preussia isomera

C15H14O7Na 329.0632), requiring 9 degrees of unsaturation.The IR spectra exhibited typical absorptions suggesting thepresence of hydroxy (3289 cm−1), γ-lactone (1795 cm−1),conjugated carbonyl (1640 cm−1), and olefinic (1581 cm−1)functionalities. An analysis of the 1H NMR spectroscopic data(Table 1) of 1 displayed the characteristic signals, assigned to

three singlet methyl groups including one oxygenated at δH 1.09(H-11), 1.37 (H-13), and 3.88 (H-15), one olefinic proton at δH5.48 (d, H-4), and three methine groups including oneoxygenated at δH 3.03 (brs., H-6), 2.85 (brs., H-7), and 4.34(s, H-9). In agreement with its molecular formula, 15 resolvedC-atom resonances were observed in the 13C NMR spectrum,which were categorized by DEPT and HSQC experiments asfour sp2 quaternary carbons (δC 188.9, 184.3, 175.6, and 174.0),one protonated olefinic carbon (δC 100.1), three methyl groupsincluding one oxygenated (δC 58.6, 13.9, and 10.5), three sp3

methines including one oxygenated (δC 82.5, 52.6, and 49.5),and four sp3 quaternary carbons including two oxygenated (δC93.2, 85.6, 63.1, and 60.5). The above unsaturated function-alities accounted for four of the nine indices of hydrogendeficiency, illustrating that compound 1 had a pentacyclic ringsystem (rings A−E).In the HMBC spectrum (Figure 2), the observed correlations

of H-4 with C-2, C-3, and C-6, H-6 with C-2 and C-4, H-11 with

C-1, C-2, and C-6, and H-15 with C-5 suggested the presence ofa 3-methoxy-5-methylcyclohex-2-en-1-one substructure (frag-ment A, ring A). Furthermore, the observed key HMBCcorrelations from H-6 to C-8 and C-10, from H-7 to C-1 and C-9, fromH-9 to C-1 and C-7, and fromH-13 to C-2, C-7, C-8, and

C-9, as well as the 1H−1H COSY correlation of H-6 with H-7,facilitated the construction of an 8-methyl-bicyclo[2.2.15,7]-heptane moiety (fragment B, rings B and C). The fusing patternof fragments A and B was determined through C-1 and C-6 toform a tricyclo[4.4.01,6.02,8]decane carbon scaffold, as evidentfrom the key HMBC correlations of H-7 with C-1 and C-5. Theremaining two ester carbonyls at δC 174.0 (C-12) and 175.6 (C-14) were determined to be attached to C-7 and C-10,respectively, as supported by the HMBC correlations of H-6with C-14, andH-9 with C-12. The keyHMBC correlation of H-9 with C-14 allowed us to construct the five-membered lactone(ring E). Analysis of HMBC correlations was not sufficient todetermine the remaining five-membered lactone (ring D), dueto the lack of a hydrogen atom at C-2. Considering the chemicalshift of C-2 as well as the ring tension factor, we finallyconstructed the remaining five-membered lactone (ring D) bythe linkage of C-2 and C-12 via an oxygen atom. Finally, thegross structure of 1 was elucidated, as shown in Figure 1.In the NOESY spectrum (Figure 3), the observed NOE

correlations of H3-13 with H-7 andH-9 suggested that H-7, H-9,

and H3-13 should be in the same orientation, while H-6 and H3-11 should be opposite, as evident by the NOE correlations of H-6 withH3-11. Due to the existence of four contiguous quaternarycarbons in 1, the relative configurations of C-1, C-2, C-8, and C-10 could not be directly determined by the NOESY experiment.Fortunately, a single crystal was successfully obtained from asolvent mixture of toluene/MeOH/CH2Cl2 (4:2:1, v/v/v), aftermany attempts using different solvents. The single-crystal X-raycrystallographic analysis (MoKα radiation) (Figure 3) con-firmed the above proposed structure, and the relativec o n fi g u r a t i o n o f 1 w a s d e t e r m i n e d t o b e1R*,2R*,6R*,7R*,8S*,9R*,10S*. However, the X-ray structureperformed with Cu Kα radiation (Table S5 and Figure S11)revealed the presence of a racemic mixture. Further chiral HPLCanalysis indicated that compound 1 contained two enantiomers(+)-1 and (−)-1) with a ratio of about 1:1.05 (Figure S12). Wetried to separate this partially racemic mixture (±)-1 by chiralHPLC to afford (−)-1 (0.25 mg) and (+)-1 (0.16 mg).Unfortunately, we only obtained the experimental CD spectra of(−)-1 but failed for (+)-1 due to trace sample amount. Thecalculated ECD spectra of (−)-1 was in good agreement with itsexperimental data (Figure 4), suggesting that the absoluteconfiguration in (−)-1 is 1S,2S,6S,7S,8R,9S,10R. The specificrotations ([α]D24 +69 for (+)-1 and [α]D23 −80 for (−)-1)] wereopposite. Furthermore, the specific rotation calculations of(+)-1 (+53.85) and (−)-1 (−53.85) supports that the absoluteconfigurations of (+)-1 and (−)-1 are 1R,2R,6R,7R,8S,9R,10Sand 1S,2S,6S,7S,8R,9S,10R, respectively. Finally, compounds

Table 1. 1H (400 MHz) and 13C (100 MHz) NMR Data for(±)-Preuisolactone A (1) in Methanol-d4

no. δH (J in Hz) δC

1 63.1, C2 93.2, C3 188.9, C4 5.48, d (1.8) 100.1, CH5 184.3, C6 3.03, brs 49.5, CH7 2.85, brs 52.6, CH8 60.5, C9 4.34, s 82.5, CH10 85.6, C11 1.09, s 10.5, CH3

12 174.0, C13 1.37, s 13.9, CH3

14 175.6, C15 3.88, s 58.6, CH3

Figure 2. Structural fragments A−B of (±)-preuisolactone A (1) andkey HMBC and 1H−1H COSY correlations.

Figure 3. NOESY correlations and X-ray crystallographic structure of(±)-preuisolactone A (1).

Organic Letters Letter

DOI: 10.1021/acs.orglett.8b04123Org. Lett. 2019, 21, 1078−1081

1079

OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H

1) SbF5, Freon-1132) AgNO2

HO

MeO

OO

HH

OAcAcO O

H

1) n-BuLi (2 equiv)2) H2O

HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

O MeO

OH

O

OH

HO

MeO

OH O

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAc AcOO

H


HO

MeO

OO

HH

O AcO

OHH

OO

MeO

OO

HH

O AcO

OHH

O

DMP

131415

161718

O

MeO

OO

HH

O AcO

OTMSH

O

TMSCl

O

MeO

OO

HH

O HO

OTMSH

OO

MeO

OO

HH

O Br

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O


(+)-Preuisolactone A (–)-Preuisolactone A

2


Proposed Retrosynthesis


aldoladdition

Halolactonization

O

OHMeO

OH

Diels-Alder +

∫

O

O

MeO

OO

HH

O

OHH

O

O

MeO

OO

HH

OAcO

OHH

OGrignardReaction

HO

MeO

OO

HH

OAcAcO O

H

HO

MeO

OO

HH

OAc

Cl

AcO

H

HO

MeO

OHO

HH

O

∫

∫

O

OHMeO

OH

OH

O

OH

OO O+

3

Proposed Synthesis The Two Fragments


OH

O

Ph N OMe

(0.1 equiv)

oxalyl bromide (1.0 equiv) OBr

Brmethyl formate

CAS No.: 107-31-3

n-BuLiBr

OPPh3

PPh3 Br

HOPPh3

Br

TBSOPPh3

H2SO4, CH3I TBSCl

O

HCl

BrTBSO(Z)

ClWittig Reaction

BrMeO

OHNaOH

O

OH

MeO

OH

O

OH

Et3NPd(OAc)2

PPh3

acrylic acid

fragment 1

O O1) LDA, -78 °C2) CH3I O

BrBr

OHBr, Br2 (2 equiv) NaOH (2 equiv)

fragment 2

TBAF

BrHO

Cl 1) NaH2) CH3Br

BrMeO

Cl

21 3 4

5 6 7 8

9

10 11 12


4

Proposed Synthesis The Rest

CEM 852 Total Synthesis Project (+)-Preuisolactone A

OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

DMP

23

O

MeO

OO

HH

O

OTMSH

OTBAF

24

O

MeO

OO

HH

O

OHH

O

K2CO3, MeOH

20

SOBr2pyridine

21 22

Mg0BrBr

5

OH

O

Ph N OMe

(0.1 equiv)

oxalyl bromide (1.0 equiv) OBr

Brmethyl formate

CAS No.: 107-31-3

OBr

Br

n-BuLi Br

OPPh3PPh3+

Kimura, Y.; Warashina, T., Convenient preparation of dichloromethyl alkyl ethers. Tetrahedron Letters 2017, 58 (49), 4598-4599.

Annadi, K.; Wee, A. G. H., An Alkylidene Carbene C–H Activation Approach toward the Enantioselective Syntheses of Spirolactams: Application to the Synthesis of (−)-Adalinine. The Journal of Organic Chemistry 2016, 81 (3), 1021-1038.

The Ylide


1

2


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

6

Br

OPPh3

Br

HOPPh3

Br

TBSOPPh3

H2SO4, CH3I TBSCl

BrTBSO

PPh3

O

HCl

BrTBSO(Z)

Cl

+

2-chloroacetaldehydeCAS No.: 107-20-0

Wittig Reactionbulkygroup

bulkygroup

The Ylide and to make sure we end up to (Z) product


3 4

5


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

7


Kim, J.-I. I.; Patel, B. A.; Heck, R. F., Palladium-catalyzed synthesis of 2,4-dienoic acid derivatives from vinylic halides. The Journal of Organic Chemistry 1981, 46 (6) 1067-1073.

BrTBSO(Z)

Cl

BrMeO

OHNaOHTBAF

BrHO

Cl 1) NaH2) CH3Br

BrMeO

Cl

6 7 8

Back to the Methoxy & Coupling

BrMeO

OH

O

OH

MeO

OH

O

OH

Et3NPd(OAc)2

PPh3

acrylic acid

fragment 19


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

8


Fragment 2

kinetic control

O O

BrBr

OHBr, Br2 (2 equiv) NaOH (2 equiv)

fragment 211 12

d'Angelo, J., Tetrahedron report number 25: Ketone enolates: regiospecific preparation and synthetic uses. Tetrahedron 1976, 32 (24), 2979-2990.

major product(tri-substituted)

• Montaña, Á. M.; Barcia, J. A.; Grima, P. M.; Kociok-Köhn, G., New methodology for the synthesis of tetrahydrofuro[3,2-b]furan-2(3H)-one derivatives, synthons of natural products with biological interest. Tetrahedron 2016, 72 (43), 6794-6806.• Quast, H.; Jakobi, H.; Seiferling, B., Photochemische Bildung von Heteromethylencyclopropanen, 20. Diastereomere 3,3,5,5-Tetraalkyl-3,5-dihydro-4H-pyrazol-4-one. Liebigs Annalen der Chemie 1991, 1991 (1), 41-46


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

O O1) LDA, -78 °C2) CH3I

102-methylcyclopentanone

CAS No: 1120-72-5

9


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

13

The Main Bicyclic Scaffold


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

10

HO

MeO

OHO

HH

OPh2SO(COCl)2

HO

MeO

OO

HH

O

ClH

14

Ding, R.; Lan, L.; Li, S.; Liu, Y.; Yang, S.; Tian, H.; Sun, B., A Novel Method for the Chlorolactonization of Alkenoic Acids Using Diphenyl Sulfoxide/Oxalyl Chloride. Synthesis 2018, 50 (13), 2555-2566.

Halolactonization


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

HO

MeO

HOO

HH

O

Cl

Cl

HO

MeO

HOO

HH

O

Cl

Cl

lesscrowded face

ClS

Ph

PhHO

MeO

OO

HH

O

ClH

HO

MeO

CO2HH

O

11

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H15


Ketone to gem-diacetate

Sun, P.; Hu, Z., A simple and efficient method for the synthesis of gem-diacetates from aldehydes and ketones catalysed by gallium triiodide. Journal of Chemical Research 2005, 2005 (10), 659-660.


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

12


Oxygenation of alkyl halide

HO

MeO

OO

HH

OAc

Cl

AcO

HO

MeO

OO

HH

OAcAcO O

H H


16

Olah, G. A.; Ramaiah, P., Electrophilic reactions at single bonds. 26. Oxygenation of bicyclo[2.2.1]heptane and bicylo[2.2.2]octane with nitronium tetrafluoroborate. The Journal of Organic Chemistry 1993, 58 (17), 4639-4641.


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

13


Aldol Addition

HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

O

17

Citron, C. A.; Rabe, P.; Dickschat, J. S., The Scent of Bacteria: Headspace Analysis for the Discovery of Natural Products. Journal of Natural Products 2012, 75 (10), 1765-1776.

HO

MeO

OO

HH

OAcO O

H

OH

other possibledeprotonations


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

14


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

18

Oxidation


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

15


Alcohol Protection

OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

O

MeO

OO

HH

OAcO

OHH

O

TMSCl

19

O

MeO

OO

HH

OAcO

OTMSH

O

16


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

Deacetylation

O

MeO

OO

HH

OAcO

OTMSH

OO

MeO

OO

HH

OHO

OTMSH

OK2CO3, MeOH

20

17


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

OSOBr2pyridine

21

Thuring, J. W. J. F.; Nefkens, G. H. L.; Schaafstra, R.; Zwanenburg, B., Asymmetric synthesis of a D-ring synthon for strigol analogues and its application to the synthesis of all four stereoisomers of germination stimulant GR7. Tetrahedron 1995, 51 (17), 5047-5056.

Halogenation

18


OMeO

OH

O

OH

HO

MeO

OHO

HH

O

+Diels-Alder

Ph2SO(COCl)2

HO

MeO

OO

HH

O

ClH

(Ac)2OGaI3

HO

MeO

OO

HH

OAc

Cl

AcO

H


HO

MeO

OO

HH

OAcAcO O

H


HO

MeO

OO

HH

OAcO

OHH

OO

MeO

OO

HH

OAcO

OHH

O

DMP

13 14 15

16 17 18

O

MeO

OO

HH

OAcO

OTMSH

O

TMSCl

O

MeO

OO

HH

OHO

OTMSH

OO

MeO

OO

HH

OBr

OTMSH

O

19

OH

MeO

OO

HH

O

OTMSH

O

OH

MeO

OO

HH

O

OTMSH

ODMP

18

O

MeO

OO

HH

O

OTMSH

OTBAF

6

O

MeO

OO

HH

O

OHH

O

O

MeO

OO

HH

OBr

OTMSH

OOH

MeO

OO

HH

O

OTMSH

O

22

Mg0BrBr

Last Three Steps

OH

MeO

OO

HH

O

OTMSH

ODMP

23

O

MeO

OO

HH

O

OTMSH

OTBAF

24

O

MeO

OO

HH

O

OHH

O

19

Thank you for everything Dr. Wulff.

cem 852 total synthesis project - chemistry.msu.edu · cem 852 total synthesis project background...

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