͐̕ő˜˶ĹDiels–AlderĔƜLͣÇ!( ņɘƄəɐȯƟɐ̂4šǖãĝƫɺʋ Research on Enantioselective Total Synthesis of Biologically Active Polycyclic Compounds Utilizing Inverse-Electron-Demand Diels–Alder Reaction

͐̕ő˜˶Ĺ Diels–Alder ĔƜLͣÇ!(

ņɘƄəɐȯƟɐ̂4šǖãĝƫɺʋ

Research on Enantioselective Total Synthesis of Biologically Active Polycyclic Compounds

Utilizing Inverse-Electron-Demand Diels–Alder Reaction

2014 Ž 2 Ǭ

ŦǠų Ü

Yu KOBAYAKAWA

͐̕ő˜˶Ĺ Diels–Alder ĔƜLͣÇ!(

ņɘƄəɐȯƟɐ̂4šǖãĝƫɺʋ

Research on Enantioselective Total Synthesis of Biologically Active Polycyclic Compounds

Utilizing Inverse-Electron-Demand Diels–Alder Reaction

2014 Ž 2 Ǭ

ǠʊɜŇŕŇŕͅ Þ̛ɗŴŕɺʋʅ ăŕ • əħăŕŤǎ ăŕĝƫȪɺʋ

ŦǠų Ü

Yu KOBAYAKAWA

ɡ˰˗

Ac : acetyl

aq : aqueous

BBB : blood-brain barrier BHT : di-t-butyl-p-cresol

Bn : benzyl

Bu : butyl

Bz : benzoyl

CAIMCP : catalytic asymmetric intramolecular cyclopropanation

cat. : catalyst

CBS : Corey–Bakshi–Shibata DABCO : 1,4-diazabicyclo[2.2.2]octane

DBU : 1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL : diisobutylaluminum hydride

DMAP : 4-N,N-dimethylaminopyridine DMF : N,N-dimethylformamide

DMP : Dess–Martin periodinane EDG : electron donating group

ee : enantiomeric excess eq : equivalent

Et : ethyl EWG : electron withdrawing group

GAPDH : glyceraldehyde-3-phosphate dehydrogenase HMBC : hetero-nuclear multiple-bond connectivity

HMPA : hexamethylphosphoric acid triamide HMQC : hetero-nuclear multiple quantum coherence HOMO : highest occupied molecular orbital

IEDDA : inverse-electron-demand Diels–Alder

IEDHDA : inverse-electron-demand hetero-Diels–Alder IR : infrared absorption spectrometry

KPB : potassium phosphate buffer LDA : lithium diisopropylamide lit. : literature

LUMO : lowest unoccupied molecular orbital M : mol/L

mCPBA : m-chloroperbenzoic acid

Me : methyl ME : methyl ester MOB : masked o-benzoquinone MOM : methoxymethyl mp : melting point MS : mass spectrograph Ms : methanesulfonyl

ND : no data

NGF : nerve growth factor

NMO : N-methylmorpholine N-oxide NMR : nuclear magnetic resonance

NOESY : nuclear overhauser effect spectroscopy NR : no reaction

Ph : phenyl PMB : p-methoxyphenyl benzyl Pr : propyl

PTLC : preparative thin-layer chromatography RCM : ring-closing metathesis

recryst : recrystallization rt : room temperature SN2 : bimolecular nucleophilic substitution TBAF : tetra-n-butylammonium fluoride TBDPS : tert-butyldiphenylsilyl

TBS : tert-butyldimethylsilyl temp. : temperature

TEMPO : 2,2,6,6-tetramethylpiperidine 1-oxyl TES : triethylsilyl

Tf : trifluoromethanesulfonyl TFA : trifluoroacetic acid

THF : tetrahydrofuran TIPS : triisopropylsilyl

TLC : thin-layer chromatography

Tsdpen : 2-amino-1,2-diphenylethyl-4-toluenesulfonyl-amido

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̱ă I(sarcodonin͝⁴⁾Cɘ˜3xyloseʩĝ!(erinacine͝⁵⁾C̱ʢŘʽļă3E +.ɘɒ}„Ofi•Ȏ̙Ƌƫ I.Hscabronine͝⁶⁾HIF4ņ5ȏ 2əɐȯƟLǭ!.HB4ņcyanthiwigin͝⁷⁾5ƳˀɩȯƟLǭ!cyathin͝¹⁾5 Ƴˌ•ƳˀɩȯƟ0ǫ̒ƳɇɧÆɛLƺ,0ĽĤ I⁸⁾scabronine͝erinacine

͝5ʂʨȃ͡ijő4ĝƫÍ̛ȯƟLǭ!.H

CHO HO₂C

H O

(–)-scabronine G

HO₂C H

OMe O

OH H H

OMe

(–)-scabronine A H

O O

H

OHOH OH OH

(–)-erinacine E H

OH

CHO

(+)-allocyathin B₂

OH

CHO

(+)-cyrneine A

HO O

H H

OH

(+)-cyanthiwigin U CHO

H O

(–)-sarcodonin G OH

H H

(–)-cyanthiwigin U O

H

(–)-cyathin A₃ O

OH OH

cyathane skeleton

1 2

9

3 4 5

6 7 8

10 11

17 12

16 14 13

15

18 20 19

A

B C CHO

H O

(–)-cyathin B₂

(+)-erinacine A O OH

O

OH OH

CHO

Figure 2-1. Selected members of cyathane diterpenoids.

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E4ï4šǖãĝƫ3ƫü!.H^9m)ͫScheme 2-1ͬ

Scheme 2-1. Convergent total syntheses of (+)-allocyathin B2, and (–)-erinacines E.

SO₂Mes O

O

HO OBn via CAIMCP

via baker's yeast reduction

OH

CHO

(+)-allocyathin B₂

H O

O

H

OHOH

OH OH H

original chiral

building blocks ring expansion

intramolecular aldol reaction coupling

addition of isopropenyl lithium

via glycosylation and Bz migrated aldol reaction

O

OH HO

HO OH

+

xylose

(–)-erinacine E

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CHO RO₂C

H O

(–)-scabronine G (3, R = H) (–)-scabronine G-ME (4, R = Me) HO₂C

H

OMe O

OH H H

OMe

(–)-scabronine A (1)

HO₂C

OR

CHO

(+)-scabronine E (8, R = Ac) (+)-scabronine F (9, R = H) H

HO₂C

OH

OBz OBz

11

HO₂C H

OMe O

OH H H

OMe

(–)-episcabronine A (2)

(+)-scabronine B (5)

H HO₂C

O

OBz OBz

(–)-scabronine C (6)

H HO₂C

OH

OBz

(–)-scabronine D (7)

17

O

Figure 2-2. Structures of scabronines.

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\ĔƜ3E+.ťâ!.GC ɘ̬Lĝƫʦɱ/ɘƸŇ#H0/šǖãĝƫL̠ƫ!

.HͫScheme 2-2ͬ>(ůȺF5Ǟɷ4O_•12LìɫĎǗ0!134íőæ

̚ʭMichaelĔƜ3E+.2,44ʡšǖžƙL–Ƽ3Ȏʙ!.H^15b)ͫScheme 2-3ͬ&

4ƑC5 Â4Tyă0[‘dWk|Ž“\Lɛ( 4 ʳDžVzP“4ȎʙɈʢ-Ɉʢ ʩĝ4̀˘ĔƜ0PrinsɘăLʨɝ!.šǖãĝƫL̠ƫ!.H

Scheme 2-2. Total Synthesis of (–)-scabronine G (3) by S. J. Danishefsky.

O H

MeO₂C

HOPhS OMe

SPr

H O NC^–

(–)-scabronine G (3) O O

O O

6

ring expansion

cross coupling

10 11

Michael addition

enolate trapping

9 9

Tf⁺

Scheme 2-3. Total Synthesis of (–)-scabronine G (3) by Y. Iwabuchi.

(–)-scabronine G (3)

9

Prins cyclization

cross coupling OTBS

CO2Et HO

CO2Et TBSO

O

TBSO O

CO2Me

6

intramolecular double Michael

reaction

CHO MeO₂C

H

TBDPSO

5

5

12 13

H

O

5

O OH

H

MeO₂C H

O

OTBDPS oxidative

fragmentation

YxnP“\{‘k[Lòɛ!(scabronine͝4ĝƫƭɡͱ

–ǚƊɺʋŜ4ȼ̨5(–)-scabronine Aͫ1ͬ4šǖãĝƫLɲƻ!.˜̓4ĕǷĹĝ ƫȪ3EHscabronine ͝4ͥȇȎʙȪL̀ɫ!(¹⁶⁾ͫScheme 2-4ͬO_•14 Lìɫ ĎǗ0!ǓŴʈ4ŃDž3E+.cOhăĝɐ15LƓ(ƑƊɺʋŜ/̀ɫ I(ˢŐɭ

šǖíőæb[‘|‘v“ăͫcatalytic asymmetric intramolecular cyclopropanation, CAIMCPͬ ĔƜ3E+.C9Â44ʡšǖžƙLƺ,YxnP“\{‘k[16Lĝƫ!(16 LOnwp173ťv“̰ȝ̧Ý3EGñ̖˵˙!(B–,4YxnP“\

{‘k[18 0ʩĝ % 19 Lĝƫ!(íőæOp•ĔƜ3E+.B ɘ̬L̿ɘƑ C5Â4šǖžƙ5CrabtreeˢŐLɛ(ȢʢȷýĔƜ3E+.Ȏʙ!2046Īɘ̬Lɘ ƸŇ#H0/214šǖĝƫ3ƫü!.H

ǴĝƫȪ5ȌA.ßŕʠƂ4ͦ16 018Lɛ.H(Aßŕɭ3ʠʛ2ňɌɐ Ē8&4͝ʰÅLƓH0ęʽ02H!!2Ferinacine͝4ĝƫ/5C2-3Â FC3-4Â:4¨̳ʩĝ4ɣƟăçɁ3̛˔#H43ţ!.C17Â̱ʢŘʽļă I

( scabronine Ĺ4aQOi“ăĝɐ/5¨̳ʩĝ4ɣƟăĔƜ3èɖƟƓFI20

Ǵăĝɐɑǭ4ĭ͛+(

&/ʒʸ5C3-4ÂVzP“Ȏ̙4ɣƟăLʨɝ%$ F3̵ɭÉʪLBęʽ3

#Hÿɕɭ2aQOi“ͥȇȎʙȪLˤɟ#H03!(

Scheme 2-4. Convergent method for the synthesis of scabronine-type cyathane skeleton.

O O

OPMB

TBSO I

OPMB

CHO

O O HO

OTBS CO₂Et

OH

SO₂Mes O

N₂ O

SO₂Mes OTBDPS

TBDPSO TBDPSO

CAIMCP

TBDPSO

OH

H HO

OH

HO

TBDPSO

TBDPSO

H H2

Crabtree's cat

O

H TBDPSO H H

I CO2Me

H TBDPSO

H O

CO₂Me

9 9

6

5 ring expansion

2 3

4

14

15

18 (> 99% ee)

87% (93% ee)

16

17

19

20 21

IEDDAĔƜLòɛ#HǙ(2scabronine͝4ĝƫƭɡͱ

scabronine ͝4Ǚ(2ĝƫƭɡL·™3ɾ#ͫScheme 2-5ͬǴĝƫɺʋ/5ňɌɐ4š

ǖãĝƫ4?2F$&IF4˯ťÅLɛ(Ȏ̙ȯƟɴ͂ɺʋ:4ũ̀L˟̴3âI

ͥȇȎʙƑ3Řʽļ̱ăL˔ƭɡLˤɟ!(#2K*ïA3aQOi“ͥȇLǭ#

H̻ž́Å22 L˧ř!4ž́Å22 4̱ăƂL&I'I4Ȑɭăĝɐ3ĝK%.˵ʗ

#H03E+.(–)-scabronine Aͫ1ͬC(–)-scabronine Gͫ3ͬʓ4ňɌɐE8&4³͝

ʰÅLBÿɕɭ3ĝƫ#H0/H0ʷ(ͫC ɘ˜4̱ʢŘʽļă4ƭɡ3,.

5ʑ7ʗĐɍͬ

Scheme 2-5. Retrosynthesis of scabronines via oxidative dearomatization/IEDDA reaction cascade.

OHC H

O

OR

key intermediate (22) (R = TBDPS) (–)-scabronine G (3)

HO₂C H

O OMe OH H H

(–)-scabronine A (1)

OHC H

O OR

HO

OR

chirality transfer

•

OBn HO OMe

MeO TIPSO

OR

OBn

MeO HO

CHO OMe

[O]

stereocontrolled [O]

RCM

MeO TIPSO

23

24 (R = TBDPS) 25 26

27 28 29

BnO

OOMe MeO

&

oxidative dearomatization/

IEDDA cascade HO

(R = TBDPS) A

B C

A

B C

4̻ž́Å224Cɘ̬5234̿ɘ†ifbdͫring-closing metathesis, RCMͬ3E+

.Ȏʙ/HB40!(4ăĝɐ235ãɈʢ4ʡšǖžƙ2,Lġ@3,šǖžƙ0 ʎÅɭ3ȶ?â+(4ʳDžVzP“Ȏ̙Lǭ!.H˜̓!((–)-scabronine Gͫ3ͬ4 ĝƫȪ 2È0ƊɺʋŜ/̀ɫ I(ĕǷĹĝƫȪ5$IB4 ABɘ̬4šǖžƙĒ 8 4 ʳDžVzP“Ȏ̙LȜ͇ɭ3Ȏʙ!.ǚȪ/+(4̬íȎ̙4ÿɕɭ 2ȎʙȪLɲƻ!. ABɘ̬3Œĸ#Hã.4šǖžƙĒ84 ʳDžVzP“Ȏ̙Lɘă

ĔƜ4͈3–Ƽ3Ȏʙ#HǚȪLʎȈ!(#2K*zSt•264̱ăɭʾˉ͢ǝă /͐̕ő˜˶ĹDiels–Alderͫinverse-electron-demand Diels–Alder, IEDDAͬ̚ʭĔƜ3E+.

Ʈǯ4šǖžƙĒ8C3-4ẤVzP“Ȏ̙Lƺ,ɘăƫʲÅ25LƓ(Ƒ244̱ăɭ

̀˘ĔƜLʨɝ!.23 Lÿɕɭ3ƓFIHB40ʷ(^18,19) F3ǴIEDDAĔƜ3 .ßŕȯƟ2O“Ȏ̙Lǭ#HzSt•26LɛI6&4YŽmP•ɘă ƫʲÅ25 3̊é IßŕȯƟ2̻ž́Å223˯ť/HB40¦ƥ!(4zSt

•26 4ßŕȯƟ2O“̬Â5|‘vZO_•˯ťÅ27 4YŽmP•L

̊é %H0/Ȏʙ/HB40!27 5Ǟɷ4Onwp 29 F͗ȕťHB40 ʷ(

̻ĔƜ/H̱ăɭʾˉ͢ǝă/IEDDA̚ʭĔƜ4ļ̂265ˉ͢ɘ˜4Ȣ̱ļĒ8†

oYbļ4Âʳ3E+. IEDDA ĔƜ4ĔƜƟĒ8ʎÅ̤ƴƟLŃă %FIH0¦

ƥ/HÞ426 0ˉ͢ɘ˜4&I'I4ʳDžļ̕4B4L300!†it•ž

/̱ăɭ3ʾˉ͢ǝă#H0310324E2MOBͫmasked o-benzoquinoneͬ&I'I ə"H0ʷFIHͫScheme 2-6ͬIEDDAĔƜ3͂›#H¨̳ʩĝ4HOMOLUMO3 H̟̉4ÌǓL¦Ⱦ!(ǦŇ2ÌǓ5ƺ,45Ÿ/˦!(Ɉʢ/H0DFT ˤʕ²⁰⁾0LiaoF4ĽĤ²¹⁾F¦Ⱦ/HIFz‘“mPỎ̟4ɴ©ÆɛLʷH0

MOB 324ǚŇ2ÌǓĞłƒkj!IEDDAĔƜ3.EGͦĔƜƟLɾ#

0¦ƥ IH!!2Fʒʸ5MOB 314ʳDžļĞł4ʎÅɭƍ͔IEDDAĔƜ 4ʎÅ̤ƴƟ3Ň͂›#H0ʷ.zSt•26L̻ĔƜ4ļ̂0!.̤ƴ!(

Scheme 2-6. Comparison of presumable reactivity of MOBs in IEDDA reactions.

•

OBn HO OMe

26

•

OBn OMeO

OMe

•

OBn MeO

MeO O HOMO

LUMO

HOMO LUMO

•

OBn MeO OH

30

[O]

in MeOH

31

32 MOB : masked o-benzoquinone

[O]

in MeOH more reactive

ʑ

ʑ 4ʗ IEDDA̚ʭĔƜ3EH ABɘ̬4Ȏʙ

O_•˯ťÅ274ĝƫͱ

ïA3ßŕȯƟ2O_•˯ťÅ27a027b4ĝƫL˔+(ͫScheme 2-7ͬǞɷ4O

nwp29²²⁾4zSt•ƟȢ̱ļLTIPSļ/Ï˻#H0/330!|‘vZ{

‘„pF˵˙ I(ǭȔ¬̸˪ːL TiCl4ˢŐŒĸ™/Æɛ %H03EGO_•

34LƓ(²³⁾O_•344¨ʡȢ̱ļLb“̧Ý#H0/OY“28L2Ŵʈ 84%/ĝƫ!(4OY“28F˵˙ I(ŽjR…OfjŽp3ţ!.ñ̖˵˙

!(WeinrebO„p35²⁴⁾LÆɛ %H0/Qt“36 3ť(ʭ.4Qt“36

Lɛ.šǖ̧ÝL˪?(&4ʩǾCoreyF3E+.ĽĤ I(CBŞݲ⁵⁾/589%

eeĕɕ 87%/ɲɭ4O_• 37 ƓFIH0K+(–ǚ̴Ê-ɻŨˢŐL

ɛ(šǖ̧ݲ⁶⁾L˪?(0JͦĕɕͦTq“jV̤ƴɭ3O_•37ƓFI H0K+(ǫƑ395% ee4O_•LOfjăđ5Ž“̱Tdmă#H 0/O_•˯ťÅ27a027bL&I'Iͦĕɕ/ƓH0/(

Scheme 2-7. Enantioselective preparation of 27a and 27b.

MeO TIPSO

OH

OBn MeO

HO CHO

MeO TIPSO 83%

a. TIPSCl MeO

TIPSO CHO

b. propargyl bromide, Zn

BnO N

O OMe 35 Me

84% (2 steps)

29 33 34

d. , ⁿBuLi

89%

MeO TIPSO

OBn O

MeO TIPSO

OR

OBn e. Ru[(R,R)-Tsdpen]-

(p-cymene) (6 mol%) 92% (95% ee) c. Et₃SiH, BF₃•OEt₂

HO

MeO TIPSO

28

f. Ac₂O or

g. (EtO)₂P(O)Cl

27a (R = Ac, 96%) 27b (R = P(O)(OEt)₂, 97%)

36

37

Reagents and conditions: (a) TIPSCl, imidazole, DMF, 40 °C, 83%; (b) propargyl bromide, Zn, TiCl₄ (5 mol%), THF, 0 °C, (c) Et₃SiH, BF₃·OEt₂, CH₂Cl₂, 0 °C, 84% (2 steps); (d) n-BuLi, 35, THF, –78 °C to rt, 89%; (e) Ru[(R,R)-Tsdpen](p-cymene) (6 mol%), i-PrOH, rt, 92% (95% ee); (f) Ac₂O, DMAP, Et₃N, CH₂Cl₂, rt, 96%; (g) (EtO)₂P(O)Cl, DMAP, Et₃N, CH₂Cl₂, rt, 97%.

šǖ̊éL¿+(O“38:4Ȏ̙ŃDž4Ȋ˥ͱ

ʭ.O_•˯ťÅ27a027bLɛ.šǖ̊éL¿+(O“:4Ȏ̙ŃDžL Ȋ˥!(ͫTable 2-1ͬ

Table 2-1. Conversion of alcohol derivatives to allene 38 with concomitant chirality transfer.

•

OBn TIPSO OMe

iPrMgCl (3 eq) THF, –78 ºC, 30 min MeO

TIPSO

OR

OBn 27a (R = Ac) 38

27b (R = P(O)(OEt)2)

Entry R CuX (eq) additive (eq) yield (%)^a ee^b

1 Ac CuCN (3) – 21^c 93% ee 2 Ac CuBr (3) LiBr (3) 49^c 95% ee 3 Ac CuCN (3) LiCl (6) NR – 4 P(O)(OEt)2 CuCN (3) – 70^c 95% ee 5 P(O)(OEt)2 CuBr (3) LiBr (3) 80^c 95% ee 6 P(O)(OEt)2 CuI (1.5) – 9^c ND 7 P(O)(OEt)2 CuI (3) – 7^c ND 8 P(O)(OEt)2 CuBr (3) – 35^c ND 9 P(O)(OEt)2 CuCN (3) LiCl (6) 88^c ND 10^d P(O)(OEt)2 CuCN (3) LiCl (6) quant. 95% ee

a Isolated yield.

b Ee was determined with phenol 26 after TIPS deprotection of 38 (see scheme 2-8).

c Reacting material was remained.

d The organocopper reagent was prepared at – 40 ºC.

Grignard ˪ː0ȿŐĒ8ĔƜȽƂLĶř!.ʾ͎ļ OR 0̹ĿĒ8ȷýɐ4Ȋ˥L˔

+(ïA3Ofm•o27a3ţ!.CuCN0Qg|‘yƒ\sbR…[‘ŽpF

˵˙ IHǭȔ̹˪ːLÆɛ %(0J21%0Ãĕɕ2Fɲɭ0#HO“38LƓ H0/(ͫEntry 1ͬ&!.ƓFI(O“384TIPSļLʾÏ˻!&4Tq“

jV̞øɕLȾř!(0J93% ee0O_•˯ťÅ4Tq“jV̞øɕL<=Ïƺ

!.H0K+(ʭ.KrauseFĽĤ!.HLiBr•CuBr²⁷⁾Lɛ.ĔƜL˔

+(0JˊŻ4ĕɕǍĮ˝FI(ͫEntry 2ͬ–ǚEntries 1, 24ĔƜǸ¹LŽ“̱

Tdm27b3̢ɛ!(ʩǾ$I4ľĝ3.B27aLɛ(ľĝEGBˇŌ2ĕ

ɕ/ɲɭ4O“ƓFIǴO_•˯ťÅ5Ofm•o27a EGBŽ“̱Tdm

27b4ǚͦĔƜƟLǭ!.H0K+(ͫEntry 4,5ͬ&/27bLɛ.Ǫ 2HĔƜǸ¹4ǫ̢ăL˔+(,4ʩǾKnochelFĂûɭ3ɺʋL˔+.H

2LiCl•CuCN²⁸⁾Lɛ(0J˄Ħȵ03Ofm•o27a/5ãĔƜ̛˔!2

B44Ž“̱Tdm27b3Æɛ %(0JI>//ǫBˇĕɕ/ɲɭ4O

“ 38 LƓH0/(ͫEntry 3,9ͬ&!.Ǫ2HȊ˥4ʩǾǴǭȔ̹˪ː4˵˙Ƚ ƂB̳˜2˜ij/H0ðǢ!ǫʦɭ35ǭȔ̹˪ːL–40 ºC/˵˙!(Ƒ3 27b

L–78 ºC/Æɛ %H0/ɲɭ4Y2O“38Lř̵ɭ,Tq“jV̞øɕL

ŗã3Ïƺ!(ɒƨ/ƓH03ƫü!(ͫEntry 10ͬ

̱ăɭʾˉ͢ǝă/͐̕ő˜˶ĹDiels–Alder̚ʭĔƜͱ

·˜4Ȋ˥3E+.ßŕȯƟ2O“38LƓH0/(4/̻ĔƜ/H̱ăɭ ʾˉ͢ǝă/IEDDA̚ʭĔƜL˪?H03!(ͫScheme 2-8ͬ

Scheme 2-8. Oxidative dearomatization/inverse-electron-demand Diels–Alder reaction cascade.

•

OBn RO OMe

BnO

OOMe MeO

HO

OOMe MeO

b. PhI(OAc)₂ MeOH, 0 ºC, 15min

38 (R = TIPS) 26 (R = H)

c. H₂, Pd/C 92%

•

OBn OMeO

OMe

rt, 7 days 97% (95%ee)

31 25

39

X-ray structure of 39 a. TBAF

97%

Reagents and conditions: (a) TBAF, THF, 0 °C, 97%; (b) PhI(OAc)₂, MeOH, 0 ºC to rt, 7 days, 97%; (c) H₂, Pd/C (5 mol%), EtOAc, rt, 92% (95% ee, >99% ee (recryst)).

O“384TIPSļLʾÏ˻!ƓFI(zSt•263ţ!.PhI(OAc)2L†it•

ž/Æɛ %(&4ʩǾzSt•26 4̱ăɭ2ʾˉ͢ǝăĔƜ0 ºC /ʢǠ

̛˔!.MOB 31ə"ʭIEDDAĔƜŜȽ/D+G0̛˔#H0K+(

&!.ǴIEDDAĔƜ57ǟ́/ŗʩ!Ċ–4ɣƟÅ0!.ɘăƫʲÅ25L97%0<

=ř̵ɭ3ƓH03ƫü!(&!.25LÂʳ̤ƴɭ2ȢʢȷýĔƜĒ8~“cļ LýȢʢíˡ#H0/ƓFIHO_• 39 4 X ʯʩǨȎ̙ˡǼ3E+.ɘăƫʲ Å255ǯ?4ɴţĒ8ʫţʎÅ̮ʳLǭ!.H0K+(²⁹⁾ F3èʩǨõ4 394Tq“jV̞øɕLȾř!(ʩǾ95% ee0O“4Tq“jV̞øɕLÏƺ!.

H0&!.èʩǨ3E+.395Şǣ3&4Tq“jV̞øɕLĠ˜ %FIH0 ɼˮ I(

ǴIEDDAĔƜ5ŜȽ/57ǟ́0Ǧ́H–ǚ/ͦĔƜȽƂ/ȌA.çɁ3̛

˔#H0Lɼˮ!.H(06ʾˉ͢ǝăƑ4IEDDAĔƜL50 ºC/˔+(0

JIEDDA ĔƜ5 17 Ǧ́/ŗʩ!(!!2FȎ̙Dzȥř4÷əƫɐ˚Ǔəƫ

#H0ɼˮ IɘăƫʲÅ254ĕ̵592%0ˊŻ4ÙˮAFI(4ɗɝ5 ʾˉ͢ǝă4(A4̱ăöPhI(OAc)2L̞ø̵ɛ.H(A̱ăö3EH÷ĔƜ̃

.H4/520ʷFIH&4(AǴIEDDAĔƜ4ǫ̢ȽƂLŜȽ0!(

IEDDAĔƜ4ʎÅ̤ƴƟ3,.4ʷšͱ

·˜4Ȋ˥3E+.zSt•264̱ăɭʾˉ͢ǝă/IEDDA̚ʭĔƜEGɘăƫ ʲÅLĬ–4əƫɐ0!.ƓH03ƫü!(ǴIEDDAĔƜ3HȌA.ͦʎÅ̤

ƴƟ5·™4E3ʷ.HͫScheme 2-9ͬ>$264zSt•̬Â̱ăɭʾˉ͢

ǝăLė.MOB 31ə"H4314IEDDAĔƜ3HcT“4̤͒ƴƟ531a 0C1-9Ấ/4Ɉʢ-Ɉʢʩĝ/ 180ºIJ̊!(31b4¨,4ʎÅ̮ƃʷFIH4

¨,4ʎÅ̮ƃLȟ̋!(ǦIEDDAĔƜ3.ǭò245ʾˉ͢ǝă4͈3ə"(c

†oYbOfi•0O“dzʐÙ4Ù̼4ʎÅĔɫŦ 31a/H0ʷFIH

#2K*ʎÅɭ3ǭò231aLʨɝ!.IEDDAĔƜ̛˔!Ʈǯ4ɘăƫʲÅ25 ƓFI(0ʷ.H

Scheme 2-9. Presumable stereoselectivity in IEDDA reaction.

•

OBn

HO OMe BnO

OOMe MeO

BnO

OMe O OMe IEDDA

rt, 7 days 97%

PhI(OAc)₂ MeOH, 0 ºC

15 min

• H

MeO OBn O OMe

rotation at C1–C9 bond sterically favored

sterically disfavored

• H

OBn OMe

OMe O

9

26 ⁹

1

1

25

31b 31a

undesired

ļ̂30Lɛ(̱ăɭʾˉ͢ǝă/IEDDA̚ʭĔƜͫͭͬļ̂ĝƫͱ

·˜4Ȋ˥3E+.Ʈǯ4ɘăƫʲÅ25LͦʎÅ̤ƴɭ,ͦĕɕ3.ƓH03ƫ

ü!(ǴIEDDAĔƜ/5ĔƜ4̣ʇɒƨ3.MOB 314c†oYbOfi•0

O“dzʐÙ4Ɉʢ̼4ʎÅɭƍ͔ͦʎÅ̤ƴƟ3͂›#H0ʷ.ăĝɐ26LĔ Ɯļ̂0!.̤ƴ!(ͫScheme 2-9ͬ–ǚIEDDAĔƜ/5z‘“mPỎ̟4HOMO LUMO4ÌǓ4¦ȾFļ̂30ɝǹ4MOB 32 4ǚͦĔƜƟLɾ#0¦ƥ I .(ͫScheme 2-6ͬʒʸ4ɷḦ́GI>/íőæ4IEDDAĔƜ3HMOB˜4ʳ Džļ4Âʳ4̡0&4ĔƜƟ3,.4ĽĤ52Ś͈3Ȋ˨#H05ǭȔĝƫă ŕ˜̳˜,ȌA.˄Ħȵ&/Ȣ̱ļ0†oYbļ4ʳDžÂʳ4ɣ2Hļ̂30Lĝ ƫ!&4ĔƜƟ0ʎÅ̤ƴƟLȊ˨#H03!(

ļ̂304ĝƫȪ5ăĝɐ264ĝƫȪLļǴ0!EGɸ˔ʈ/30ƓFIHE3

f„Å430Lĝƫ#H03!(ͫScheme 2-10ͬŶ˾4zSt•404Ȣ̱ļLTIPS Ï˻3EG410!VoŽjVăLʨɝ!.Onwp42LƓ(Onwp42F O_•43Lʨɝ!.OY“44Lĝƫ!(ʭ.OY“44F˵˙!(Of jŽp3Onwp 45 LÆɛ %ə"(ŽjR…O_Ybp3ţ!.PO(OEt)2ClL Æɛ %H0/f„Å4Ž“̱Tdm46L’“‚ko/˵˙!(O“47:5 Þ0Ğȏ4Ǹ¹/˔03EGͦĕɕ/ŃDž#H0/TIPSļ4ʾÏ˻L#H 0/2605ˉ͢ɘ˜4Ȣ̱ļ0†oYbļ4ʳDžÂʳ4ɣ2Hăĝɐ30Lĝƫ!(

Scheme 2-10. Preparation of substrate 30.

HO MeO

a. TIPSCl 99%

TIPSO MeO

b. DMF, ⁿBuLi 81%

BnO CHO 45

40 41

e. , ⁿBuLi

then PO(OEt)2Cl, 67%

TIPSO MeO

44

TIPSO MeO

CHO 42

c. propargyl bromide, Zn

TIPSO MeO

OP(O)(OEt)₂

46 OBn

•

OBn MeO OH

f. ⁱPrMgCl, 2LiCl•CuCN

98%

30

•

OBn MeO OTIPS

47

g. TBAF 92%

HO

d. Et3SiH, BF3•OEt2

92% (2 steps)

TIPSO MeO

43

Reagents and conditions: (a) TIPSCl, imidazole, CH₂Cl₂, rt, 99%; (b) n-BuLi, DMF, hexane, rt, 81%; (c) propargyl bromide, Zn, TiCl₄ (5 mol %), THF, 0 °C, (d) Et₃SiH, BF₃·OEt₂, CH₂Cl₂, 0 °C, 92% (2 steps); (e) n-BuLi, BnO(CH₂)₂CHO (45), then PO(OEt)₂Cl, THF, –78 °C to rt, 67%; (f) i-PrMgCl, 2LiCl•CuCN, THF, –78 °C, 98%; (g) TBAF, THF, 0 ºC, 92%.

ļ̂30Lɛ(̱ăɭʾˉ͢ǝă/IEDDA̚ʭĔƜͫͮͬIEDDA̚ʭĔƜ4Ȋ˥0ʩǾͱ

ļ̂30Lĝƫ#H0/(4/Þ0Ğȏ4Ǹ¹/̱ăɭʾˉ͢ǝă/IEDDA̚ʭ ĔƜL˪?(ͫScheme 2-11ͬ&4ʩǾʾˉ͢ǝă5Þʈ4ļ̂ 260Ğ"15í<1 /̛˔!(ʭIEDDAĔƜ5ļ̂264ľĝ05ɣ2GȌA.çɁ3̛˔#H0

KGŜȽ3Ǧ́/IEDDAĔƜŗ¥!ɘăƫʲÅ48049Lí͎ęʽ2cOdm

Vƒ•ȶĝɐ0!.ͦĕɕ/ƓH03ƫü!(ƓFI(ɘăƫʲÅ48049 4ɴţʎ Å̮ʳ5¡əƫɐ48 4Âʳ̤ƴɭ2Ȣʢȷý3E+.ƓFIHăĝɐ50 4 NOESYȾ ř3E+.ȥř!(

ļ̂304IEDDAĔƜȌA.Ǡ̛˔!(ɗɝ5¦ƥ!(̗GMOB 324z‘“m

PỎ̟4Ň2ÌǓĞłƒkj!(ʩǾ/H0ʷFIH&!.†oYbļĒ 8Ȣ̱ļ4ÂʳƮǯ4ɘăƫʲÅLƓH(A3ȌA.̳˜/H0Bļ̂ 30 Lɛ (ŚͤFðǢ!(ɖĸļ̂30Lɛ(IEDDAĔƜ4ʎÅ̤ƴƟ3,.ʷšL˔

+.HIEDDAĔƜ3HMOB 324ʎÅ̮ƃLʷH0c†oYbOfi•0

O“dzʐÙ4Ɉʢ̼35͎̅G&4ʳDžļĞł4ʎÅɭƍ͔ʎÅ̤ƴƟ3ƍ͔

LĒ=!(05ʷ340FƠFʎÅɭ2˜ij/52̟̉4 2ȕɭ2 ɴ©Æɛ3E+.ʎÅ̤ƴƟɫɖ!(4/520ʷ.H³⁰⁾

Scheme 2-11. Oxidative dearomatization/IEDDA cascade with 30.

BnO

OMe OMe

O H

H

50 NOESY correlations

H

•

OBn MeO OH

a. PhI(OAc)₂ MeOH, 0 ºC to rt

3 h 30

BnO

OMe OMe

O

BnO MeO OMe

O

49 (11%) 48 (87%)

b. H₂, Pd(OH)₂ 40%

•

OBn MeO

MeO O

HOMO LUMO

32

+

Reagents and conditions: (a) PhI(OAc)2, MeOH, 0 ºC to rt, 3h, 48 (87%), 49 (11%); (b) H2, Pd(OH)2 (10 mol%), THF, 40%.

ʑ

ʑ 5ʗ aQOi“ͥȇLǭ#H̻ž́Å 224ĝƫ

̻ž́Å224ĝƫͫͭͬcV•244ĝƫͱ

·˜4Ȋ˥3E+.Ʈǯ439 LƓH0/(4/̻ž́Å22 :4˯ťLȊ˥!

(5"A339FcV•24:4˯ťL˔+(ͫScheme 2-12ͬăĝɐ3941ʡO

_•L Swern ̱ă!.Onwp0!Wittig ĔƜ3E+.dzʐVzP“Ȏ̙Lťâ

!( 51 Lĝƫ!(ʭ.WrļL NaBH43E+.̧Ý!(Ƒ3Ŀ̱/Ƒëɗ#

H0/wp‘Yb]o“52LĊ–4ɣƟÅ0!.Ɠ(4523ţ!.{‘„p53³¹⁾

0ZnLɛHBarbielĹ4OYă3E+.Ʈǯ4cV•24LĊ–4ʎÅɣƟÅ0

!.ͦĕɕ/ƓH03ƫü!(cV•244ʎÅ̮ʳ52Ŵʈ4ŃDž3E+.ƓF IHăĝɐ554NOESYˡǼ3E+.ȥř!.H

Scheme 2-12. Preparation of diol 24.

HO

OOMe MeO

39 (>99% ee, recryst)

HOHO

OR a. Swern oxidation

b. Ph3PCH3Br, ^tBuOK 97% (2 steps)

O OMe MeO

c. NaBH₄, then 3M HClaq 95%

HO O

d. , ZnBr OTBDPS

53

(R = TBDPS) 51

52

24

HO

(R =TBDPS) 54 single diastereomer

HO

OR

(91%) (7%)

HOHO

OR

(R = TBDPS) 24

e. TBAF f. p-BrCH₄COBr 90%

HO

HO H

O O

HH H

55

NOESY correlations

+

Br

Reagents and conditions: (a) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, –78 to 0 °C, 98%; (b) Ph₃PCH₃Br, t-BuOK, THF, 0 °C, 99%; (c) NaBH4, MeOH, 0 °C; then, 3M HCl aq, 95%; (d) 53, Zn, THF, rt, 24 (91%), 54 (7%); (e) TBAF, THF, rt; (f) p-BrCH₄COBr, DMAP, CH₂Cl₂, rt, 90% (2 steps).

–ǚOYă4͈3C14Â4ʎÅɣƟÅ·Ņ4÷əƫɐƓFIH0ðǢ!

ÂʳɣƟÅ 54 /H0 HMQCHMBC Ē8 NOESY ˡǼ3E+.ǢF32+(

ͫScheme 2-12, 13ͬ4ăĝɐ544əƫ†Wre…5ÂʳɣƟÅ564əƫLʨɝ#H

ȕ42,4ʨ̇Lʷ.H1,ɲ4ʨ̇5ĔƜʞž/ə"H0ʷFIH524¬̸

O_Ybp41,2-wpŽpbzoEHʨ̇/Gͫpath AͬB–,5¬̸Tt•o 4əƫ0è|‘o“ă3EHʨ̇/Hͫpath Bͬ4÷əƫɐ545ZnĒ8{‘„p53 4Ɗ̵ŧ2ľĝCZn4ȯƟăšĆí2ľĝ3ņəƫ#H0K+(

,4Ȋ˥4ʩǾmg ĊÂ4ĔƜd]•3.5 50 Ɗ̵0̞̄ø̵4ȯƟă Zn 4 THF ƪɅȴž3ăĝɐ 52 0{‘„p 53 4 THFȿȴLʢǠýH0/÷əƫɐ 544əƫLƱ.ĕɕEcV•24LƓH03ƫü!(

>(24 054L›HǴOYă3HʎÅ̤ƴƟ5ŲͦAɘ̬Ē8dzʐV

zP“Ù4Ɉʢ̼4ʎÅɭƍ͔3E+.ɫɖ!.HB40ʷ.H Scheme 2-13. Structural determination of 54, and presumable mechanism.

52

HO

54 HO

OTBDPS

NOESY correlations HO

54 HO

OR H O O

H

O O Zn Br

H

H

H H

H HO

HO

OR H

HMBC correlations 54

1,2-H shift

HO HO

O ZnBrO H⁺ H

protonation

HOO

56

addition RBr (53)

Zn R' ZnBr

R' ZnBr

deprotonation

R' = alkoxide (from 24) or alkyl (from 53) [path A]

[path B]

52

̻ž́Å224ĝƫͫͮͬcV•244̱ăɭ̀˘4Ȋ˥ͱ

ƓFI(24Lɛ.̱ăɭ̀˘LȊ˥!(ͫTable 2-2ͬcV•245ciscV•/

H0FïA3–ˆɭ2̱ăö/H NaIO4L˪?(!!2FãĔƜ

̛˔%$ĎǗLIJĕ#H4?/+(ͫEntry 1ͬ4ɗɝ0!.2452ʡ3ʡ4cV

•/G F3O_•5 4ʡšǖɈʢ3ƽ>IʎÅɭ3ȌA.ȶ?â+.

H0F˪ː3ţ#HĔƜƟÃ0ʷFI(&/˪ː4ĔƜƟEG

ͦ0ʷFIHı̸̯̱Lɛ(0JˇŌ2ĕɕ/̀˘ăĝɐ 23 LƓH0/

(ͫEntry 2ͬ>(˄Ħȵ03245Dess–Martin˪ːLɛ(ľĝ̗Ź42ʡO

_•4̱ăĔƜ5̃F$̀˘ĔƜ̛˔!ɲɭ0#H23žʈƂ4ĕɕ/ƓFIH 0K+(ͫEntry 3ͬ&!.3Ë4̄ĎőˌRʢ/HPhI(OAc)2Lɛ(0 J90%0ͦĕɕ/ɲɭ423LƓH03ƫü!(³²⁾ͫEntry 4ͬ

Table 2-2. Oxidative cleavage of diol 24.

HOHO

OTBDPS

24

OHC H

O OTBDPS

23

Entry reagent (eq) solvent temp. time yield (%)^a

1 NaIO4 (3) MeOH/H2O = 1:1 rt to 60 ºC ovn NR 2 Pb(OAc)4 (3) CH2Cl2 0 ºC 30 min 84

3 DMP (3) CH2Cl2 rt 12 h 53 4 PhI(OAc)2 (3) CH2Cl2 rt 1.5 h 90

a Isolated yield.

̻ž́Å224ĝƫͫͯͬͱ̿ɘ†ifbd

ʭ.ăĝɐ234̿ɘ†ifbdL˔+(ͫScheme 2-14ͬ&4ʩǾGrubbsʑ¨œ¶

RuˢŐ³³⁾Œĸ™c[‘‘†i“žýɎ̧Ȱ#H0/23 4̿ɘ†ifbd5çɁ3

̛˔!¨̳ʩĝ4ɣƟăCOnwp:4÷ĔƜL¿K$ɲɭ0#H̻ž́Å22Lͦĕ ɕ/ƓH03ƫü!(2Ǵɺʋ/5ňɌɐ4šǖãĝƫ0͝ʰÅĝƫ4ã.4ļ ɱ02H̻ž́Å22L3g·˜ĝƫ#H03ƫü!.H

Scheme 2-14. Ring-closing metathesis of 23.

OHC H

O

OTBDPS OHC

H

O OTBDPS

23

a. Grubbs 2nd (2.5 mol %) 98%

22

Reagents and conditions: (a) Grubbs 2nd (2.5 mol %), CH₂Cl₂, reflux, 98%.

ʑ

ʑ 6ʗ (–)-Scabronine Gͫ3ͬ4šǖãĝƫ

·˜4Ȋ˥3E+.aQOi“ͥȇLǭ#H̻ž́Å 22 Lĝƫ#H0/(4/

scabornine͝4ž/ǫBȎ̙ʚɃ2(–)-scabronine Gͫ3ͬ4šǖãĝƫLȊ˥!(ͫScheme 2-15̻ͬž́Å224TBDPSļL̯̱Œĸ™TBAFLɛ.ʾÏ˻#H0/ăĝɐ57 LƓ(&!.574Onwp̬Â01ʡO_•LPinnicḵăĒ8Dess–Martiṉ ă3E+.&I'I1Ȝ͇$,̱ă#H0/(–)-scabronine Gͫ3ͬ4šǖãĝƫLìɫ ĎǗ29EG19Ŵʈʮĕɕ21%/̠ƫ!(ĝƫ!((–)-scabronine Gͫ3ͬ4Ĝʉd[

on•iͫ¹H-, ¹³C-NMR, HRMS, IR, [α]Dͬ5DanishefskyFĒ8ůȺFĽĤ¹⁵⁾!.

HB40ȟ̋!.ˇ–˃Lɾ#0Lɼˮ!(ͫʑ5ʏŚ͖ͤĐɍͬ

Scheme 2-15. Total synthesis of (–)-scabronine G (3).

OHC H

O

OTBDPS

22

a. TBAF, AcOH 70%

b. Pinnick oxidation 97%

c. DMP 89%

OHC H

O

OH

57

HO₂C H

O

OH

58

CHO HO₂C

H O

(–)-scabronine G (3)

19 steps from 29, 21% overall yield

Reagents and conditions: (a) TBAF, AcOH, THF, rt, 70%; (b) NaClO₂, NaH₂PO₄, 2-methyl-2-butene, THF, t-BuOH, H₂O, rt, 97%; (c) DMP, CH₂Cl₂, 0 °C, 89%.

ʑ

ʑ 7ʗ əĝƫLȑÔ!( Cɘ˜4̱ʢŘʽļăƭɡ

·˜4Ȋ˥3E+.̱ăɭʾˉ͢ǝă/IEDDA̚ʭĔƜLʨɝ!.̻ž́Å22Lĝƫ!

224̱ăƂL˵ʗ#H0/scabronine͝4ž/ǫBʚɃ2Ȏ̙Lƺ,(–)-scabronine Gͫ3ͬ 4šǖãĝƫL̠ƫ#H0/(&/ȕ4Ȑɭăĝɐ0!.ǫBȎ̙4˚͍2

(–)-scabronine Aͫ1ͬ4ĝƫɺʋ3ɶƯ#H03!(·™3¦ƥ IHscabronine͝

4əĝƫʨ̇0&ILȑÔ!(Cɘ˜4ʎÅ̤ƴɭ2̱ʢŘʽļăƭɡ3,.̓;H

¦ƥ IHscabronine͝4əĝƫʨ̇ͱ

scabronine͝5ʑ2ʗ/ɾ!(̗GCɘ˜4̱ʢŘʽļɣ2HňɌɐ/HͫFigure

2-2ͬ&I'I4Ȏ̙5(–)-scabronine Gͫ3ͬǫBʚɃ2ăŕȎ̙Lǭ!.G

(–)-scabronine Aͫ1ͬ0&4C11ÂTyƒ•/H(–)-episcabronine Aͫ2ͬǫB˚͍3̱

ʢŘʽļă I.H(+)-scabronine Bͫ5ͬ014C11ÂĒ8C14Â3ȫɲ#H0Ğ"ɴ ţ̮ʳLǭ#H0KH40Fʒʸ53 4E2ăĝɐəĝƫ4̞ʈ/

ʎÅ̤ƴɭ2̱ʢŘʽļăLė.(+)-scabronine Bͫ5ͬ4E2̱ăɒƨLʨɝ!EG

̱ʢŘʽļă I((–)-scabronine Aͫ1ͬəĝƫ I.HB40¦ƥ!(ͫScheme 2-16ͬ F3(–)-scabronine Aͫ1ͬ(–)-episcabronine Aͫ2ͬ&!.(+)-scabronine Eͫ8ͬFͫ9ͬ 5ăĝɐ594E2̱ăɒƨ4əĝƫž́ÅF̱ʢŘʽļă4ʦɱ/íŭ!&I' Iñʨ̇/əĝƫ I.HB40ʷ(

Scheme 2-16. Presumable biogenesis of scabronines.

CHO HO₂C

H O

(–)-scabronine G (3)

HO2C H

OMe O

OH H H

OMe

(–)-scabronine A (1) H

HO₂C

OH

OBz OBz

(+)-scabronine B (5)

H HO₂C

OH

CHO OH 59

14 14

11 11

[O] [O]

HO₂C H

OMe O

OH H H

(–)-scabronine A (1, R¹ = OMe, R² = H) (–)-episcabronine A (2, R¹ = H, R² = OMe)

14 11

advanced intermediate in biogenesis

R₁R₂ HO₂C

OR

CHO

(+)-scabronine E (8, R = Ac) (+)-scabronine F (9, R = H)

əĝƫLȑÔ!((–)-scabronine Aͫ1ͬ0(–)-episcabronine Aͫ2ͬ4ĝƫƭɡͱ

·˜4ʷšFÞ3ĝƫ!(̻ž́Å22 F(–)-scabronine Aͫ1ͬ:4ĝƫƭɡLȕ 4E3ˤɟ!(ͫScheme 2-17ͬïA3̻ž́Å224C11-C12ÂVzP“Ȏ̙L̃

ɉ3C11Â:4ʎÅ̤ƴɭ2Ȣ̱ļ4ťâ0C12-C13ÂVzP“Ȏ̙4ťâ#2K*

(–)-scabronine Cͫ6ͬ0Ğȏ4̱ăƂLB,ăĝɐ 60 :4˯ťL˔ʭ.C14 ÂW

rļ4ʎÅ̤ƴɭ2̧Ý3EG(+)-scabronine Bͫ5ͬ4̱ăɒƨLB,ăĝɐ61 L ʨ.Þ4əĝƫʨ̇4ž́Å59 0Ğȏ4̱ăɒƨLǭ#Hăĝɐ62 3ť&!.

4ăĝɐ623ţ!.oxa-MichaelĔƜL̃ɉ0#H̚ʭĔƜL˔0/C12,13Â42

̚ʭšǖžƙ0ǿȓOfi•ɘȎ̙L–Ƽ3Ȏʙ!(–)-scabronine Aͫ1ͬ4šǖãĝƫ L̠ƫ/HB40ʷ(

>(Þ4əĝƫ4¸˲Făĝɐ 62 4Ȏ̙4–̬LŃDž!(ăĝɐ 63 :4

oxa-Michael ĔƜL̃ɉ0#H̚ʭĔƜL˔0/(–)-episcabronine Aͫ2ͬ4šǖãĝ

ƫL̠ƫ/HB40ʷ(

Scheme 2-17. Synthetic strategy of (–)-scabronine A (1) and (–)-episcabronine A (2).

HO2C H

OMe O

OH H H

OMe

(–)-scabronine A (1)

H MeO2C

OH

CHO OR' OHC

H O

OR

22 (R = TBDPS)

H MeO₂C

O

OH OR

12 11 12

11

13

H MeO₂C

OH

OH

14 OH

oxa-Michael cascade

60 (R = TBDPS) 61

62 (R' = H)

63 (R '= Bz) double oxa-Michael

cascade

11

HO₂C H

O OMe OH H H

OMe

(–)-episcabronine A (2) oxidized same as

(–)-scabronine C (6)

oxidized same as (+)-scabronine B (5)

oxidized same as advanced intermediate (59)

12 13

ʑ

ʑ 8ʗ (–)-Scabronine Aͫ1ͬ4šǖãĝƫ T‚YbăLʨɝ!(Cɘ˜4̱ʢŘʽļăͱ

Þ4ĝƫƭɡ3ƒ̻ž́Å22F60:4Ȏ̙ŃDž#2K*C11Â:4ʎÅ̤ƴɭ 2Ȣ̱ļ0 C12-13 Ấ4VzP“Ȏ̙4ťâLȊ˥!(ͫScheme 2-18̻ͬž́Å 22 4Onwp̬ÂLPinnicḵă3E+.W“̱3ŃDžƑ†jTdm643ť (ʭ.T‚YbăLʨɝ!(C11Â:4Ȣ̱ļ4ťâL˪?(!!2Fļ

̂643mCPBALÆɛ %(0JƮǯ4655ƓFI$C3-4Ấ44ʳDžVzP“

T‚Ybă I(66¡əƫɐ0!.ƓFIHʩǾ02+(ăĝɐ644C3-4Ấ4 4 ʳDžVzP“̒Ú35 4 ʡšǖɈʢĒ8Qg|‘yļŒĸ!.H0FʎÅ ɭ3ȌA.ȶ?â+.H(A̱ăö5ʎÅɭ3ʌ.HC11-12Ấ43ʳDžVz P“3ǁ̒!T‚Ybp65ƓFIHB40ʷ.(!!2F4ʳDžVz P“4͐őɭ2˜ijʎÅɭ˜ijEGÜÞ I66L¡əƫɐ0!.›(B4ʷFI H&/EGʎÅɭ2ƍ͔LėC#̱ăöLɛH03!(

Scheme 2-18. Attempted introduction of an oxygen atom at C11 position via epoxidation.

OHC H

O

OR

22 (R = TBDPS)

H MeO₂C

O

OH OR

12 11

13

60 (R = TBDPS) a. Pinnick oxidation

b. MeI

74% (2 steps)

MeO2C H

O

OR

64 (R = TBDPS)

c. mCPBA

MeO2C H

O

OR

66 (R = TBDPS) 80%

O

MeO2C H

O

OR

67 (R = TBDPS) trace

O O

MeO₂C H

O

OR

65 (R = TBDPS) not obtained

O

4 3

12 11

Reagents and conditions: (a) NaClO₂, NaH₂PO₄, 2-methyl-2-butene, THF, t-BuOH, H₂O, 10 ºC; (b) MeI, K₂CO₃, DMF, rt, 74% (2 steps); (c) mCPBA, CH₂Cl₂, 0 °C, 66 (80%), 67 (trace).

ı̱ăVd„R…Lɛ(cwp‘Ybă0íőæĔƜLòɛ!(60:4ŃDžͱ ˜4ʩǾLė.EGʎÅɭ2ƍ͔LėC#̱ăö/Hı̱ăVd„R…Lɛ

.644ÂʳĒ8ʎÅ̤ƴɭ2cwp‘YbăL˪?(ͫScheme 2-19ͬ&4ʩǾ ŗã2Âʳ̤ƴƟ/cwp‘Ybă̛˔!Ʈǯ4cV• 68aL¡əƫɐ0!.Ɠ H03ƫü!(cOdmVƒ•68b LW…[‘ƒo\zP•/í͎ƑcV•

 68a 4 3 ʡO_•:4ʾ͎ļ4ťâ4Ȋ˥L˔+(,4Ȋ˥4ʩǾC12 Â4 3ʡO_•5ȌA.ĔƜƟÃOfm•o214ʾ͎ļ4ťâ/#FĴ͏/

H0K+(>(ýɎ214Ʉ!ĔƜǸ¹™3.ăĝɐ 68a5̕O

p•ĔƜLʨɝ!(0ƞKIHăĝɐ71Lʨɝ!ļ̂4íˡ̃H0K+(

Scheme 2-19. Regio- and stereoselective dihydroxylation of 64 with OsO4, and attempted preparation of 60.

MeO₂C H

O

OR

64 (R = TBDPS)

MeO₂C H

O

OH OH

OTBDPS

H a. OsO₄, NMO

MeO₂C H

O

OH OH

OTBDPS

H 68a (major)

MeO₂C H

O

OH OH

OTBDPS

H

68a

b. Ac2O MeO₂C H

O

OH OAc

OTBDPS

H

69 (95%)

MeO₂C H

O

OAc OAc

OTBDPS

H 70 (not obtained)

MeO₂C H

O

O OAc

OTBDPS

H 71 c. Ac2O, reflux

retro-Aldol reaction

decomposed

68b (minor)

Reagents and conditions: (a) OsO₄ (2.5 mol %), NMO, THF, t-BuOH, H₂O, rt; (b) Ac₂O, Et₃N, DMAP, CH₂Cl₂, rt, 69 (95%); (c) Ac₂O, Et₃N, DMAP, CH₂Cl₂, reflux, decomposed.

4ĭ͛4ˡȥʔ0!.ʒʸ5oŽ€d^“LɛH03!(ͫScheme 2-20ͬ#

2K*cOdmVƒ•ȶĝɐ 68 4 2 ʡȢ̱ļ3oŽ€d^“LÆɛ %H0/72 0!ĔƜʞž/íőæĔƜ3ƺ*̐?ʾ͎ļLɘ˜W•s•o0!.ťâ!( 73 74Lí͎ęʽ2cOdmVƒ•ȶĝɐ0!.ƓH03ƫü!(ăĝɐ734βʾ͎5 DBULĿļ0!.ɛH0/çɁ3̛˔!(–)-scabronine Cͫ6ͬ0Ğ"̱ăɒƨLǭ#

HƮǯ4ăĝɐ60LƓH0/(