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Some chemical transformations of norditerpene dilactones from podocarpus sellowii
Tetrahedrom Letters Bo. 8, pp 675 - 678, 1974.
Perporn
Press.
Primted in &eat
Rrikim.
SOME CREMICAL TRANSFORMATIONS OF NORDITERPENR DILACTORRS FROM PODOCARPUS SELLOWII Keith S. Brown, Jr. *
and
Centro de Pesquisas de Produtos Naturais ICB, CCM, Universidade Federal do Rio de Janeiro Ilha do Fundao, Rio de Janeiro X-32, Brazil
Wolfango E. S&chez
L.
(0)
Institute de Quimica Universidade Estadual de Campinas C.P. 1170, Campinas, Sao Paulo, Brazil
(Received in USA 14 Rovember 1973; received in UK for publication
9 January 1974)
Although twenty-six nor- and bisnor-diterpene dilactones have been reported since 1968 as hydrophilic constituents of nine species of Podocarpus,l the organic chemistry of these compounds has been relatively little investigated.2
We have confirmed that many standard reactions on these
polyfunctional substances give unexpected and frequently uninterpretable results. rial is frequently recovered, even under vigorous reaction conditions.
3
Starting mate-
The lactone and epoxide
groups show an unusual stability to many acids and bases, hydroxyls are often sterically protected from attack by normal reagents , and even a vinyl group (present in some members of the series) resists well-known double bond attacking reagents such as diborane and mercuric acetate.
The in-
solubility of many of the compounds in any solvents other than pyridine, dimethylsulfoxide, or acetone (and often very sparing solubility even in these), has undoubtedly also contributed to the paucity of chemical transformations reported. In the course of several years' work on the three new compounds (I-III) isolated from the Brazilian Podocarpus sellowii Klotssch,4 we have observed some new reactions which, together with observations on the mass spectral fragmentations of the products, merit discussion here. Certain acid conditions give selective attack on the epoxy group in ring A of Sellowins A and B, without affacting the other epoxide in the molecule.
For example, solution of Sellowin
B (II) in trifluoroacetic acid gave slow modification of the portion of the NMR spectrum corresponding to the ring A protons, with formation of an easily hydrolyzed diol monotrifluoroacetate (M+ 444 = C20Hlg08F3).
The corresponding diol showed coupling of the 2a-proton (6 4.36 in pyri-
dine-d5) to the 18-proton (6 3.84) with J = 11 Hz, and to the 38 and 3a protons with J - 12.5 and 5 Hz, respectively, showing that the first three of these protons possess approximately trans7 antiparallel relative dispositions.
This requires a twist-boat conformation for ring A (Na).
Indeed, a Dreiding model of IV with ring A in the chair conformation either openaor flips to a
(0)
Taken in part from the M.S. thesis of W.E.S.L., C.P.P.N./U.F.R.J., October 1973. 675
676
No. 8
R-OE, 8’4
a,
b, R=Br, R’ICH3CO a, R-H Inumakilactone twist-boat
with
Attempted
great
derived
and 3a protons In both is evident lease
independent formation
group
of substitution
by electrophilic
showed coupling identical
cases,
gave very
patterns
to those
attack
of
in the structure
observed
(IV)
with
Inumakilactone
A (V) and related
the nucleophile ous epoxide itatively
with
recently
the 3S-hydroxyl C (VIIa)
with
of a stable
and 205)
benzo-pyrylium
in the spectra
may have a similar
origin
of
3-hydroxy (Scheme 2).
for
leaving
is
acid
(Scheme I).
opening
acid
the epoxide
of
IW.
the ring
resistant). A epoxide
in
at the l-position.
must be provided
In
by interaction
attempted
opening
(as used for
Sellowin
of
of
the analog-
B) led quant-
intact.
the 2-fionotrifluoroacetate fragmentation
A related
epoxide
formed by slow re-
group is
attack
and 3g
the protonated
apparently vinyl
which still
2a (6 4.74),
of
B with
The more tractable
structure
2-position
Interestingly,
of
(by IR).
indicating
VI by selective
trifluoroacetic
to retro-Diels-Alder ion
IVa,
a substance
in pyridine-d5),
of the reaction
(m/e 203) in the mass spectrum --
IVa, may be attributed
a bromohydrin
to whose attackthe
group in V.
C diacetate
group of Sellowin
producing
(the bromohydrin
giving
control
to the 7-O_monotrifluoroacetate,
the diol
slow reaction,
published5
compounds,
on the vinyl
at the exposed
reagent,
regiospecific
in Nagilactone
The base peak
mation
the results
the different
attack
in the diol
of the product
C
at C-Z.
the 18 (6 5.66
the nucleophile
of HBr from the N-bromoacetamide
case,
for
Nagilactone
b, R-COCH3 Nagilactone
(by NMR) but was nevertheless
This contrasts
this
(lc-i:;Br.or OH)
in 90% aqueous acetone
the vinyl acetate
ease,
bromohydrin
N-bromoacetamide possessed
rl
A
pair
compounds such as Nagilactone
of ring
precursor A with
of significant C (VIIa)
subsequent peaks
and Sellowin
of for-
(m/e 203 -C (III)
677
Ho. 8
Successful dine.
oxidation
The starting
element
of the vinyl
material,
of these
and its
the product,
B was achieved
diacetate
mass spectrometry.
mapping in high-resolution
fragmentations
group of Sellowin
6
compounds (Scheme 3) suggests
were subjected
A speculative that
furan
portant
even in compounds where principal
peaks come from cleavage
SCHEME
3
c
Formulae
Cl,Hl705
C18H1806 ‘ym:‘“’
T
Further C (III) rect,
and measured
has led producing
3~1:~J;~““)
$02’ ‘16’17’6
investigation
of
.
c 01025
the reported4
to the unexpected III
from VIIa
maSSi
discovery
in high yield
9
calculated
only with
mass fraction;
f I
that
‘+
.
of Nagilactone
the reduction
under a variety
the principal
in ring
C4 may be im-
- relative
intensity
C15H1303 ‘Al:;,“;;‘“‘)
c .0970
interconversion
of
of the sidechain.
C16H1304 289:;;s”“)
@:961 C15H1504
to computer-assisted
outline
formation
0s04 in pyri-
by Cr
II
E(62) C14H1205
C (VIIa)
and Sellowin
or the Zn-Cu couple
of experimental
conditions.
7
is
di-
While
100. 8
removal of an epoxide to form a double bond,a and saturationof a conjugateddouble bond,9 are known in Cr" reductions,the direct reductionof a non-conjugated epoxide to a saturatedderivative has not been previouslyobservedwith this reagent;with the Zn-Cu couple,it is rarely seen. Significantly, CrCl2 treatmentof NagilactoneC diacetate(VIIb)did not give any epoxide removal or reduction,even under forcingconditions. Apparently,the free hydroxyl at C-3 is participatingin the four-electron reductionobserved,possiblyvia a mechanismsuch as that representedin a simplifiedfashionin Scheme 4
(actually,it is unlikelythat a "free"radical
exists, and hydrogenatoms are probablytransferreddirectly-fromwater moleculesin complex chromiumligands associatedwith the 3B-hydroxylproup).
The authorswish to thank the NationalInstitutesof Health, the NationalScienceFoundation (GrantsGB 5389X/X1),the U.S. Army, the UniversidadAut&oma de Puebla, the ConselhoNacional de Pesquisas,CAPES, the OAS (fellowshipto WESL, 1967-a),the Banco Nationaldo Desenvolvimento Econ&ico (FUNTEC47 and 101). the Ministhriode Planejamento(convehio14O/CT),and the CPEG of the UFRJ for financialsupportat various stages of this work. Mass and NMR spectrawere obtainedthroughthe kindnessof Drs. Lois J. Durham,ToshiakiNishida,and Alan M. Duffieldof StanfordUniversity,and Dr. Paul M. Baker of the CPPN. REFERENCESAND NOTES 1. For recent reviews see M.N. Galbraith,D.H.S. Horn, Shs It;, M. Kodama and J.M. Sasse, Agr. Biol. Chem.. 36, 2393 (1972);and K.S. Brown Jr. and W.E. S&chez L., submittedto BiochemicalSysteaics. 2. The majority of known reactiontypes were reportedin the initial communications:ShiiIt;, M. Kodama,M. Sunagawa,T. Takahashi,H. Imamuraand 0. Honda, TetrahedronLetters, 2065 (1968);and Y. Hayashi,S. Takahashi,II.Oua and T. Sakan, TetrahedronLetters,2071 (1968). 3. The failure of standardreactionson 16-sulfoxides(Podolactones C and D) has been reported 1362 (1971). by M.N. Galbraith,D.E.S. Horn and J.M. Sasse, Chem. Consnun., 4. W.B. S&rchez L., K.S. Brown, Jr., T. Nishida,L.J. Durham and A.M. Duffield,Pnais Acad. Bras. Ci&cias, g:, supplement,77 (1971). 5. T. Hayashi,H. Kakisawa,Sh; It;, Y.P. Chen and H.-Y. Hsii,TetrahedronLetters,3365 (1972). 6. Kindly measuredfor us by S. Enomoto of JBOL Ltd., on a JMS-0156-2spectrometersystem. 7. G. Rosenkranz,0. Mancera,J. Gatica and C. Djerassi.J. Am. Chsm. Sot., 72, 4077 (1950);W. Cole and P.L. Julian,J. Org. Chem., 19, 132 (1954);J.K. Kochi, D.M. Sinzeton and L.J. Andrews, Tetrahedron,z, 3503 (1968);??%. Kupchanand M. Maruyama,J. Org. Chem.,36,1187(l97l). 8. P. Crabbz,M. Pe'rezand G. Vera, Canad. J. Chem.,4& 156 (1963);D. Lavie, E. Glotter and Y. Shvo. J. Chem. Sot., 7517 (1965). 9. J.R. Hanson and E. Premuzic,Angew. Chem., 271 (1968);C.E. Castro,R.D. Stephensand S. Mojh, J. Am. Chem. Sot., 88, 3016 (1966).
Perporn
Press.
Primted in &eat
Rrikim.
SOME CREMICAL TRANSFORMATIONS OF NORDITERPENR DILACTORRS FROM PODOCARPUS SELLOWII Keith S. Brown, Jr. *
and
Centro de Pesquisas de Produtos Naturais ICB, CCM, Universidade Federal do Rio de Janeiro Ilha do Fundao, Rio de Janeiro X-32, Brazil
Wolfango E. S&chez
L.
(0)
Institute de Quimica Universidade Estadual de Campinas C.P. 1170, Campinas, Sao Paulo, Brazil
(Received in USA 14 Rovember 1973; received in UK for publication
9 January 1974)
Although twenty-six nor- and bisnor-diterpene dilactones have been reported since 1968 as hydrophilic constituents of nine species of Podocarpus,l the organic chemistry of these compounds has been relatively little investigated.2
We have confirmed that many standard reactions on these
polyfunctional substances give unexpected and frequently uninterpretable results. rial is frequently recovered, even under vigorous reaction conditions.
3
Starting mate-
The lactone and epoxide
groups show an unusual stability to many acids and bases, hydroxyls are often sterically protected from attack by normal reagents , and even a vinyl group (present in some members of the series) resists well-known double bond attacking reagents such as diborane and mercuric acetate.
The in-
solubility of many of the compounds in any solvents other than pyridine, dimethylsulfoxide, or acetone (and often very sparing solubility even in these), has undoubtedly also contributed to the paucity of chemical transformations reported. In the course of several years' work on the three new compounds (I-III) isolated from the Brazilian Podocarpus sellowii Klotssch,4 we have observed some new reactions which, together with observations on the mass spectral fragmentations of the products, merit discussion here. Certain acid conditions give selective attack on the epoxy group in ring A of Sellowins A and B, without affacting the other epoxide in the molecule.
For example, solution of Sellowin
B (II) in trifluoroacetic acid gave slow modification of the portion of the NMR spectrum corresponding to the ring A protons, with formation of an easily hydrolyzed diol monotrifluoroacetate (M+ 444 = C20Hlg08F3).
The corresponding diol showed coupling of the 2a-proton (6 4.36 in pyri-
dine-d5) to the 18-proton (6 3.84) with J = 11 Hz, and to the 38 and 3a protons with J - 12.5 and 5 Hz, respectively, showing that the first three of these protons possess approximately trans7 antiparallel relative dispositions.
This requires a twist-boat conformation for ring A (Na).
Indeed, a Dreiding model of IV with ring A in the chair conformation either openaor flips to a
(0)
Taken in part from the M.S. thesis of W.E.S.L., C.P.P.N./U.F.R.J., October 1973. 675
676
No. 8
R-OE, 8’4
a,
b, R=Br, R’ICH3CO a, R-H Inumakilactone twist-boat
with
Attempted
great
derived
and 3a protons In both is evident lease
independent formation
group
of substitution
by electrophilic
showed coupling identical
cases,
gave very
patterns
to those
attack
of
in the structure
observed
(IV)
with
Inumakilactone
A (V) and related
the nucleophile ous epoxide itatively
with
recently
the 3S-hydroxyl C (VIIa)
with
of a stable
and 205)
benzo-pyrylium
in the spectra
may have a similar
origin
of
3-hydroxy (Scheme 2).
for
leaving
is
acid
(Scheme I).
opening
acid
the epoxide
of
IW.
the ring
resistant). A epoxide
in
at the l-position.
must be provided
In
by interaction
attempted
opening
(as used for
Sellowin
of
of
the analog-
B) led quant-
intact.
the 2-fionotrifluoroacetate fragmentation
A related
epoxide
formed by slow re-
group is
attack
and 3g
the protonated
apparently vinyl
which still
2a (6 4.74),
of
B with
The more tractable
structure
2-position
Interestingly,
of
(by IR).
indicating
VI by selective
trifluoroacetic
to retro-Diels-Alder ion
IVa,
a substance
in pyridine-d5),
of the reaction
(m/e 203) in the mass spectrum --
IVa, may be attributed
a bromohydrin
to whose attackthe
group in V.
C diacetate
group of Sellowin
producing
(the bromohydrin
giving
control
to the 7-O_monotrifluoroacetate,
the diol
slow reaction,
published5
compounds,
on the vinyl
at the exposed
reagent,
regiospecific
in Nagilactone
The base peak
mation
the results
the different
attack
in the diol
of the product
C
at C-Z.
the 18 (6 5.66
the nucleophile
of HBr from the N-bromoacetamide
case,
for
Nagilactone
b, R-COCH3 Nagilactone
(by NMR) but was nevertheless
This contrasts
this
(lc-i:;Br.or OH)
in 90% aqueous acetone
the vinyl acetate
ease,
bromohydrin
N-bromoacetamide possessed
rl
A
pair
compounds such as Nagilactone
of ring
precursor A with
of significant C (VIIa)
subsequent peaks
and Sellowin
of for-
(m/e 203 -C (III)
677
Ho. 8
Successful dine.
oxidation
The starting
element
of the vinyl
material,
of these
and its
the product,
B was achieved
diacetate
mass spectrometry.
mapping in high-resolution
fragmentations
group of Sellowin
6
compounds (Scheme 3) suggests
were subjected
A speculative that
furan
portant
even in compounds where principal
peaks come from cleavage
SCHEME
3
c
Formulae
Cl,Hl705
C18H1806 ‘ym:‘“’
T
Further C (III) rect,
and measured
has led producing
3~1:~J;~““)
$02’ ‘16’17’6
investigation
of
.
c 01025
the reported4
to the unexpected III
from VIIa
maSSi
discovery
in high yield
9
calculated
only with
mass fraction;
f I
that
‘+
.
of Nagilactone
the reduction
under a variety
the principal
in ring
C4 may be im-
- relative
intensity
C15H1303 ‘Al:;,“;;‘“‘)
c .0970
interconversion
of
of the sidechain.
C16H1304 289:;;s”“)
@:961 C15H1504
to computer-assisted
outline
formation
0s04 in pyri-
by Cr
II
E(62) C14H1205
C (VIIa)
and Sellowin
or the Zn-Cu couple
of experimental
conditions.
7
is
di-
While
100. 8
removal of an epoxide to form a double bond,a and saturationof a conjugateddouble bond,9 are known in Cr" reductions,the direct reductionof a non-conjugated epoxide to a saturatedderivative has not been previouslyobservedwith this reagent;with the Zn-Cu couple,it is rarely seen. Significantly, CrCl2 treatmentof NagilactoneC diacetate(VIIb)did not give any epoxide removal or reduction,even under forcingconditions. Apparently,the free hydroxyl at C-3 is participatingin the four-electron reductionobserved,possiblyvia a mechanismsuch as that representedin a simplifiedfashionin Scheme 4
(actually,it is unlikelythat a "free"radical
exists, and hydrogenatoms are probablytransferreddirectly-fromwater moleculesin complex chromiumligands associatedwith the 3B-hydroxylproup).
The authorswish to thank the NationalInstitutesof Health, the NationalScienceFoundation (GrantsGB 5389X/X1),the U.S. Army, the UniversidadAut&oma de Puebla, the ConselhoNacional de Pesquisas,CAPES, the OAS (fellowshipto WESL, 1967-a),the Banco Nationaldo Desenvolvimento Econ&ico (FUNTEC47 and 101). the Ministhriode Planejamento(convehio14O/CT),and the CPEG of the UFRJ for financialsupportat various stages of this work. Mass and NMR spectrawere obtainedthroughthe kindnessof Drs. Lois J. Durham,ToshiakiNishida,and Alan M. Duffieldof StanfordUniversity,and Dr. Paul M. Baker of the CPPN. REFERENCESAND NOTES 1. For recent reviews see M.N. Galbraith,D.H.S. Horn, Shs It;, M. Kodama and J.M. Sasse, Agr. Biol. Chem.. 36, 2393 (1972);and K.S. Brown Jr. and W.E. S&chez L., submittedto BiochemicalSysteaics. 2. The majority of known reactiontypes were reportedin the initial communications:ShiiIt;, M. Kodama,M. Sunagawa,T. Takahashi,H. Imamuraand 0. Honda, TetrahedronLetters, 2065 (1968);and Y. Hayashi,S. Takahashi,II.Oua and T. Sakan, TetrahedronLetters,2071 (1968). 3. The failure of standardreactionson 16-sulfoxides(Podolactones C and D) has been reported 1362 (1971). by M.N. Galbraith,D.E.S. Horn and J.M. Sasse, Chem. Consnun., 4. W.B. S&rchez L., K.S. Brown, Jr., T. Nishida,L.J. Durham and A.M. Duffield,Pnais Acad. Bras. Ci&cias, g:, supplement,77 (1971). 5. T. Hayashi,H. Kakisawa,Sh; It;, Y.P. Chen and H.-Y. Hsii,TetrahedronLetters,3365 (1972). 6. Kindly measuredfor us by S. Enomoto of JBOL Ltd., on a JMS-0156-2spectrometersystem. 7. G. Rosenkranz,0. Mancera,J. Gatica and C. Djerassi.J. Am. Chsm. Sot., 72, 4077 (1950);W. Cole and P.L. Julian,J. Org. Chem., 19, 132 (1954);J.K. Kochi, D.M. Sinzeton and L.J. Andrews, Tetrahedron,z, 3503 (1968);??%. Kupchanand M. Maruyama,J. Org. Chem.,36,1187(l97l). 8. P. Crabbz,M. Pe'rezand G. Vera, Canad. J. Chem.,4& 156 (1963);D. Lavie, E. Glotter and Y. Shvo. J. Chem. Sot., 7517 (1965). 9. J.R. Hanson and E. Premuzic,Angew. Chem., 271 (1968);C.E. Castro,R.D. Stephensand S. Mojh, J. Am. Chem. Sot., 88, 3016 (1966).