Stemona Alkaloids

  • View
    222

  • Download
    2

Embed Size (px)

Text of Stemona Alkaloids

  • Stemona Alkaloids

    1

    Baran Lab Tom Maimone

    N

    1 2

    3

    567

    8

    99a

    The Stemonaceae plant family, which comprises over 30 species, produces a large class of structurally diverse alkaloids featuring a conserved pyrrolo [1,2-a] azepine = perhydroazaazulene = 4-azazaulene nucleusTheir roots have been used for centuries in traditional chinese medicince for a variety of purposes including (but not limited to): treatment of bronchitis, tuberculosis, pertussis, as well as anti-parasitic agentsOver 80 members have been discovered and many more are likely to be isolated (restriction is limited to only 8 species, mostly from the Stemona genus)

    N

    O

    O

    I. Stenine Group

    N

    O

    O

    H

    HH

    HH

    stenine

    N

    O

    O

    H

    HH

    HH

    H

    OH O N

    O

    O

    H

    H

    HOOH O

    H

    N

    O

    O

    HOOH O

    H

    H

    N

    O

    O

    HHOH O

    HH

    H

    H

    neotuberostemonine

    3

    1112

    10

    tuberostemonine (H3 = ) tuberostemonine A (H3 = )

    tuberostemonol

    didehydrotuberostemonine (H11 = , H12 = , Et = )bisdehydroneotuberostemonine (H11 = , H12 = )

    N OH O

    HO

    O

    HHO

    oxotuberostemonine

    N

    II. Stemoamide GroupO

    NH

    O

    OH

    H

    O

    stemoamide

    NH

    OH

    H

    OOH

    H

    O

    stemonine

    NH

    OH

    H

    OO

    OMe

    neostemonine

    N

    OH

    H

    OO

    OMe

    bisdehydroneostemonine

    N

    OH

    H

    OO

    OMe

    HO

    H

    HO

    protostemonine

    N

    OH

    H

    OO

    OMe

    HO

    H

    HO

    protostemonine

    N

    OH

    H

    OO

    OMe

    OHO

    didehydroprotostemonin

    I. Introduction

    For excellent reviews see (and references therein): Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127. Seger et al. Chemistry & Biodiversity. 2004. 1, 265-279.

  • Stemona Alkaloids

    2

    Baran Lab Tom Maimone

    N

    II. Stemoamide Group (Con't)

    O

    N

    OH

    HOO OH

    OH

    H

    OMe

    isoprotostemonine

    N

    OH

    H

    H

    OOO

    tuberstemoamide

    N

    OH

    HOH

    OH

    H

    OO

    stemoninine

    NH

    OHOH

    H

    HO

    OO

    OMe

    OH

    stemodiol

    III. Tuberostemospironine Group

    NO

    ON

    OO

    OOH

    tuberstemospironine

    NO

    O OO

    H

    H

    H H

    R

    NO

    OO

    H

    H

    O

    O

    NO

    OO

    H

    H

    O

    O

    NO

    OO

    H

    H

    O NO

    OO

    HO

    MeOH

    didehydrocroomine

    stemonidine

    croomine (R = H)stemospironine (R = OMe)

    stemotinine isostemotinine

    N

    IV. Stemonamine (maistemonine) Group

    OO

    O

    N

    OO

    O

    OMe

    Me

    N

    OO

    O

    OMe

    Me

    N

    OO

    O

    OMe

    Me

    ON

    OO

    O

    OMe

    Me

    O N

    OO

    O

    OMe

    Me

    O

    H

    H ON

    OO

    O

    OMe

    Me

    HO

    O

    H

    H O

    stemonamine isostemonamine

    stemonamideisostemonamidemaistemonine oxymaistemonine

    Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127.

  • Stemona Alkaloids

    3

    Baran Lab Tom Maimone

    N

    O

    OO

    H

    H H

    N

    V. Parvistemoline

    O

    OOH

    parvistemoline

    N

    O

    OO

    H

    H H

    HO

    H

    H O

    H

    parvistemonine

    N

    O

    OO

    H

    H

    HOH O

    H

    didehydroparvistemonine

    VI. Miscellaneous?

    NO

    OR

    HOO

    OMe

    N

    O

    H

    OOO

    OMeR

    NH

    O

    O

    OH

    H

    O

    O

    H

    H O

    N

    O

    OO

    H

    H

    O

    OH OH

    ONH

    O

    H

    H

    OH

    O

    parvistemoamidetuberostemoninol

    tuberostemononeparvistemoninine (R = H)parvistemoninol (R = OH)

    stemofoline (R = H)oxystemofoline (R = OH)methoxystemofoline (R = OMe

    Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127.

  • Stemona Alkaloids

    4

    Baran Lab Tom Maimone

    II. Biosynthetic ConsiderationsConsider the following carbocyclic skeletons where the C5 units of presumed terpene origin are drawn in bold:

    N

    O

    O

    N

    O

    O

    O

    O

    O

    OMe Me

    O

    O

    N

    O

    O

    O

    N

    O

    O

    O

    O

    N

    O

    O

    O

    OHN

    O

    OO

    O

    Stemofoline protostemonine tuberostemonine

    O

    stemonine tuberstemonamide tuberostemospironine

    This leaves the following fragment unaccounted for:

    N

    Recall pyrrolizidine biosynthesis:

    HN

    H2NNH2

    N

    O

    mannich

    N

    O

    homospermidineAn analagous pathway could produce the stemona alkaloids

    HN

    H2NH2N

    spermidineN

    O

    Thus the following biosynthetic picture emerges:

    X

    N

    O

    X

    N

    [O]

    [O]

    [O]

    N

    O

    O

    OMe

    O

    O

    O

    N

    O

    O

    O

    O

    OMe

    stemofoline-CO2

    Seger et al. Chemistry & Biodiversity. 2004. 1, 265-279.

  • Stemona Alkaloids

    5

    Baran Lab Tom Maimone

    III. Synthesis

    NO

    O OO

    H

    H

    H

    Croomine(D.R. Williams et al, 1989)

    J. Am. Chem. Soc. 1989, 111, 1923 -1925.

    MEMO

    1

    1) n-buLi, THF, ClCO2CH3, -78C

    MEMO

    O

    O MgBr

    OBn

    MEMO

    H3CO2C

    OBn

    MEMO

    OBn

    OOH

    MEMO

    OBn

    O

    CO2CH3

    MEMO

    OBn

    O

    OBz

    MEMO

    OBn

    OBz

    HO N3

    OO

    N3H

    OH

    Ph3POBz

    OO

    N3H OBz

    N3H CO2CH3

    OO

    (63%)CuBr DMSTMEDA, Et2O

    -78C23

    2)

    3) DIBAL, CH2Cl2, -78C4) D-DIPT, t-BuOOH, CH2Cl2 -50C

    4

    5) Swern, -78C

    (83%)

    (95%)

    then PPh3=CHCO2CH3-78C 25C

    (89%)

    567

    6) LiBH4, MeOH Et2O

    5% Rh/Al2O3 H2

    (60%)

    7) BzCl, Et3N

    8) LiN3, DMPU 110C

    (94%)

    9) BF3 OEt2, OC10) LiOH, MeOH

    (79%)

    11) Swern, then

    8 9 10(70-81%)

    12) HBF4, MeOH then LiOH, MeOH: H2O

    13) Jones reagent14) CH2N2

    (78%)OBn

    OBn OBn

  • Stemona Alkaloids

    6

    Baran Lab Tom Maimone

    NO

    O OO

    H

    H

    H

    Croomine(D.R. Williams et al, 1989)

    N3H CO2CH3

    OO N3

    H CO2CH3O

    O

    O

    CO2CH3O

    O NHHO

    O NH

    O

    H

    H O

    mechanism ?

    N OO

    H

    H

    HO

    H

    H

    O

    Stemonine(D.R. Williams et al, 2003)

    Org. Lett. 2003, 5, 3361-3364

    A Similar iodination cascade was used here as well

    O

    OCH3

    OOTBS N3H

    TBSONH

    TBSO

    MeOOTBSO

    H

    NH

    O

    H

    H O

    TBSO

    TBSO

    CH3

    NH

    O

    H

    H O

    O

    H

    H

    HON

    HO

    H

    H O

    O

    H

    H

    O

    15) BCl3, CH2Cl2, -78C

    16) swern(71%)

    1011

    17) PPh3, 25C then NaBH4, MeOH

    (90%)18) I2, Et2O, CH2Cl2 25C

    (25C)

    prepared in many steps

    1) EtPPh2, PhH, 18h, 25C, then NaBH4, MeOH

    (70%)

    12

    13

    2) I2, Et2O:CH2Cl2, 48 h, 25C42%

    14

    4) TBAF5) DMP

    (69%)

    15

    6) Jones Reagent

    (68%)

    OBn

  • Stemona Alkaloids

    7

    Baran Lab Tom Maimone

    NO

    O OO

    H

    H

    H

    Croomine(Martin et al, 1989)

    J. Am. Chem. Soc. 1996, 118, 3299-3300.

    OO OTIPSO OTIPSO Br

    OO

    Br

    NH

    CO2Me

    N CO2MeMeO

    Boc

    BocO

    O

    Br

    NHH

    CO2MeNOO

    H

    CO2H

    NO

    O

    HOH

    H

    O

    NO

    O

    HOH

    H

    O

    NH

    O

    O

    H

    H

    O

    Stemoamide(Jacobi et al, 2000)

    J. Am. Chem. Soc. 2000, 122, 4295-4303

    racemic synthesis:

    O

    ClCl

    N

    OMeO

    Cl

    N

    OMeO

    NO

    O

    1) TIPSOTf, Et3N 0C 25C

    (99%)

    2) s-BuLi, TMEDA THF, 0C

    then Br(CH2)4Br

    (83%)3) 5% TIPS-OTf, 0C

    1 2 3

    4

    5

    (32%)

    4) TFA

    5) 3% Rh/C, H2 EtOAc:EtOH

    (96%)

    6) NMM, DMF,

    (74%)7) 3M HBr, 60CHBr

    8) POCl3, DMF

    OTIPSO

    9) 10% Pd-C/H2

    10% HCl/EtOH

    (47%)

    (85%)

    6

    7

    8

    1) Methyl alaninate

    2) P2O5(80%)

    3) NaH, then succinimide

    (97%)

    1 2 3

  • Stemona Alkaloids

    8

    Baran Lab Tom Maimone

    N

    OMeO

    NO

    ONH

    O

    O

    H

    H

    O

    Stemoamide(Jacobi et al, 2000) N

    OMeO

    NO

    MeO

    N

    OMeO

    NO

    H

    N

    MeO O

    NH

    O

    NH

    O

    OH

    ON

    H

    O

    OH

    O

    H

    rationalize the following by-products formed in the IMDA cascade

    NH

    O

    O

    NH

    O

    OO

    MeO2C

    NH

    O

    OO

    NH

    O

    OO

    an enantioselective route was alsodeveloped using L-pyroglutamic acid

    NH

    O

    HO2CN

    O

    R

    NH

    O

    OH

    O

    3

    4) NaBH4, Me