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Total synthesis of (±)-neplanocin F
Tetrahedron Letters,Vo1.30,No.37,pp Printed in Great Britain
TOTAL Michael
SYNTHESIS
Cancer
Institute,
(t)-Neplanocin
was available
Of the natural
fermentation
and its potent
naturally
occurring
(-)-neplanocin
patent
literature,5
An undesired
(compound
benzyl
F would
regarding
F, however,
ether,
interest. firmly
of Health,
(3J$), which
for compound
followed
reqularis
of its novel
properties.2
Among
F (2), the allylic
In addition,
three
the stereochemistry obtained
because
as both a synthetic
published
the other
rearranged
target
isomer of
and as a
structure
of this
communications2-4
of the 2'-hydroxyl synthesis
intermediate
enantiomer
A11079,I
carbocyclic
it was felt that a total
the chemical
from the scale-up
cyclopentenone
it is the opposite
and the
group.
of (-)-neplanocin
3. 6
A,
For the synthesis
in this racemic
mixture
precursor. 3, the racemic
and stereoselectively
form is shown
from amoullariella
establish
between
is the critical
earlier
isolated
(-)-neplanocin
(3J/4) of a pivotal
regioselectively
enantiomeric
Institutes
Treatment,
20892
and antitumor
a discrepancy
side product,
A), which
As reported
of Cancer
in 12 steps from the racemate
our attention
biological
of neplanocin
was the racemate
reduced
attracted
and resolve
of neplanocin
E. Marquez*
the most attention
antiviral
neplanocins,
A,3y4
of potential
compound
products
A (I) has received
structure
synthesis
F
from D-ribonolactone.
(-)-neplanocin
molecule
National Maryland
F was synthesized
+ .oo
Chemistry,
Division
Program,
Bethesda, Abstract:
and Victor
of Medicinal
Therapeutics
National
OF (+)-NEPLANOCIN
Bodenteich
Laboratory Developmental
0040-4039/89 $3.00 Pergamon Press plc
4909-4912,1989
in Scheme
1).6
by the acid-catalyzed
cyclopentenone
to the a-allylic
Protection removal
alcohol
(3/J) was 2 (only one
of the newly formed of the isopropylidine
OH
4909
mixture
alcohol moiety,
as a gave
4910
Scheme
1
0% ;
BnO
-7
/@OR2
\
\ bh
IR
Rl
ec$ t ;,
dClH
BACAC P&H
t ‘lJH
f32 H
Ac
.-OR,
t
\ b” Rl jj
t1,2
Oh
R2
AC
MS
MI
Ac Cl
OR1 I
BnO
R2
11
g_
w
i-k
\ \
Rl
) \ OBn
%
AC %
H Bn t- Bn
Na N N k2
a. #I NaH. DMF. tt, 30 mtn. (II PhCH26r (&t&l, OMF. rt. 1 h: b. TFA (aql, rt, 16 min; c. %O Il.2 aqulv.L B$N. DMAP, CH924. rt. 30 min; d. NaOMe/MeOH. rt. r) min: e. MaOSO,Cl [M&I, 1.2 W@V.), Et& cH2c4. rt, 30 min; f. LiNJ. DMBO, rt, 30 min; g. LiNI. DMSO, lllPC, 3 dm; h. Undlar wt. [H& MeOH. rt. 1 h; i. 2,6-diamino-bchloropyrimidina I2 equhr.1, E@, n-BuOH, A, 3 claw: j. IEtOl&H. HCI. rt. 8 h; k. BC4, CH2C$, -7WC. 2.6 h: I. NHS/MeOH, lloOC, 3 days.
4912
256-7-C dec, IH NMR (Me2SD-d6)
6 3.90-4.19
(m,
2 H, Cti20H), 4.30 (t, J = 6.6 Hz, 1 H, H-
I'), 4.82 (t, J = 5.5 Hz, 1 H, CH20li), 4.55-5.01(m, 2 H, H-2', H-5'), 5.40-5.50 (overlapping
doublets,
H, H-8), 8.18 264.1099)].10 from a sample
2 H, 2 x Oil), 5.65
(s, 1 H, H-2); The proton of natural
from the Toyo Jozo Co.,
toward
example
investigation
of our previously
developed
Buckberg
Evaluation
We are grateful
(LMC) for secretarial Program
toward
4. 5. 6. 7.
::
cyclopentenone
particularly potential
the preparation
to Dr. James A. Kelley,
spectral
Yaginuma,
from the
support.
A travel
grant
Laboratory
(u/4)
belonging
of neplanocin
of optically
awarded
represents synthon
those
to
F is under
pure material.
of Medicinal
data and Drs. John S. Driscoll
(LMC) and Joseph
We thank Mrs. Yetta to M. Bodenteich
under
CIES is also acknowledged.
References
::
to the one
in this work,
Jr. (LMC), for their helpful comments and suggestions.
the Fulbright
1.
nucleosides,
of the biological
with efforts
(LMC), for the mass
J. Barchi,
(s, 1
in Japan.
of novel carbocyclic
family.
8.09
(MH+, calcd.
to us by Dr. Satoshi
of the utility
together
(s, 2 H, NH2),
F was identical
provided
F, achieved
Acknowledqement. Chemistry
(f)-neplanocin
F kindly
of (+)-neplanocin
the synthesis
the neplanocin
NMR of synthetic (-)-neplanocin
7.21
FAB MS, m/z 264.1097
the synthesis
In summary, another
(s, 1 H, H-4'),
high resolution
and Notes
J. S. Yaginuma, N. Muto, M. Tsujino, Y. Sudate, M. Hayashi and M. Otani, Antibiot. 1981, 34, 359. 1986, 6, 1 and references therein. V. E. Marquez and M.-I. Lim, Med. &. &y. S. Yaginuma, M. Tusjino, N. Muto, M. Otani, M. Hayashi, 3. Ishimura, T. Jujii, S. of Infectious Watanabe, T. Matsuda, T. Watanabe and J. Abe, "Current Chemotherapy Diseases", Proc. 11th Intl.Congress Chemother., 1979, 2, 1558. M. Hayashi, S. Yaginuma, N. Muto and M. Tsujino, Nucl. Acids Res. Symposium Series No. 8, 1980, ~65. M. Otani, S. Yaginuma, M. Tsujino, N. Muto, S. Tagata, German patent, Offenlegungsschrift 29 17 000, Nov. 29, 1979, Toyo Jozo (Japan). V. E. Marquez, M.-I. Lim, C.K.-H. Tseng, A. Markovac, M.A. Priest, M.S. Khan and B. kaskar, 4. m. m. 1988, 53, 5709. When the carbocyclic amine obtained from compound 14 was used in the condensation acyl group migration from the ester reaction with 2,4-dichloro-5_aminopyrimidine, to the amine interfered with the reaction. On the other hand, use of the carbocyclic amine generated from compound Is, gave the desired condensation product in acceptable yields. However, the final cyclization step did not go to completion due to the ease with which the free allylic alcohol reacted with triethyl orthoformate. Y. F. Shealy and J. D. Clayton, J. Am. m. a. 1969, 9l, 3075. M. Arita, K. Adachi, Y. Ito, H. Sawai and M. Ohno, J. Am. Chem. &g. 1983,105,
4049. 10.
Combustion neplanocin calculated
analyses for C, H, and N, performed on the final product F, as well as in the intermediate compounds, were within values.
(Received in USA 7 June 1989)
(k)f 0.4% of the
TOTAL Michael
SYNTHESIS
Cancer
Institute,
(t)-Neplanocin
was available
Of the natural
fermentation
and its potent
naturally
occurring
(-)-neplanocin
patent
literature,5
An undesired
(compound
benzyl
F would
regarding
F, however,
ether,
interest. firmly
of Health,
(3J$), which
for compound
followed
reqularis
of its novel
properties.2
Among
F (2), the allylic
In addition,
three
the stereochemistry obtained
because
as both a synthetic
published
the other
rearranged
target
isomer of
and as a
structure
of this
communications2-4
of the 2'-hydroxyl synthesis
intermediate
enantiomer
A11079,I
carbocyclic
it was felt that a total
the chemical
from the scale-up
cyclopentenone
it is the opposite
and the
group.
of (-)-neplanocin
3. 6
A,
For the synthesis
in this racemic
mixture
precursor. 3, the racemic
and stereoselectively
form is shown
from amoullariella
establish
between
is the critical
earlier
isolated
(-)-neplanocin
(3J/4) of a pivotal
regioselectively
enantiomeric
Institutes
Treatment,
20892
and antitumor
a discrepancy
side product,
A), which
As reported
of Cancer
in 12 steps from the racemate
our attention
biological
of neplanocin
was the racemate
reduced
attracted
and resolve
of neplanocin
E. Marquez*
the most attention
antiviral
neplanocins,
A,3y4
of potential
compound
products
A (I) has received
structure
synthesis
F
from D-ribonolactone.
(-)-neplanocin
molecule
National Maryland
F was synthesized
+ .oo
Chemistry,
Division
Program,
Bethesda, Abstract:
and Victor
of Medicinal
Therapeutics
National
OF (+)-NEPLANOCIN
Bodenteich
Laboratory Developmental
0040-4039/89 $3.00 Pergamon Press plc
4909-4912,1989
in Scheme
1).6
by the acid-catalyzed
cyclopentenone
to the a-allylic
Protection removal
alcohol
(3/J) was 2 (only one
of the newly formed of the isopropylidine
OH
4909
mixture
alcohol moiety,
as a gave
4910
Scheme
1
0% ;
BnO
-7
/@OR2
\
\ bh
IR
Rl
ec$ t ;,
dClH
BACAC P&H
t ‘lJH
f32 H
Ac
.-OR,
t
\ b” Rl jj
t1,2
Oh
R2
AC
MS
MI
Ac Cl
OR1 I
BnO
R2
11
g_
w
i-k
\ \
Rl
) \ OBn
%
AC %
H Bn t- Bn
Na N N k2
a. #I NaH. DMF. tt, 30 mtn. (II PhCH26r (&t&l, OMF. rt. 1 h: b. TFA (aql, rt, 16 min; c. %O Il.2 aqulv.L B$N. DMAP, CH924. rt. 30 min; d. NaOMe/MeOH. rt. r) min: e. MaOSO,Cl [M&I, 1.2 W@V.), Et& cH2c4. rt, 30 min; f. LiNJ. DMBO, rt, 30 min; g. LiNI. DMSO, lllPC, 3 dm; h. Undlar wt. [H& MeOH. rt. 1 h; i. 2,6-diamino-bchloropyrimidina I2 equhr.1, E@, n-BuOH, A, 3 claw: j. IEtOl&H. HCI. rt. 8 h; k. BC4, CH2C$, -7WC. 2.6 h: I. NHS/MeOH, lloOC, 3 days.
4912
256-7-C dec, IH NMR (Me2SD-d6)
6 3.90-4.19
(m,
2 H, Cti20H), 4.30 (t, J = 6.6 Hz, 1 H, H-
I'), 4.82 (t, J = 5.5 Hz, 1 H, CH20li), 4.55-5.01(m, 2 H, H-2', H-5'), 5.40-5.50 (overlapping
doublets,
H, H-8), 8.18 264.1099)].10 from a sample
2 H, 2 x Oil), 5.65
(s, 1 H, H-2); The proton of natural
from the Toyo Jozo Co.,
toward
example
investigation
of our previously
developed
Buckberg
Evaluation
We are grateful
(LMC) for secretarial Program
toward
4. 5. 6. 7.
::
cyclopentenone
particularly potential
the preparation
to Dr. James A. Kelley,
spectral
Yaginuma,
from the
support.
A travel
grant
Laboratory
(u/4)
belonging
of neplanocin
of optically
awarded
represents synthon
those
to
F is under
pure material.
of Medicinal
data and Drs. John S. Driscoll
(LMC) and Joseph
We thank Mrs. Yetta to M. Bodenteich
under
CIES is also acknowledged.
References
::
to the one
in this work,
Jr. (LMC), for their helpful comments and suggestions.
the Fulbright
1.
nucleosides,
of the biological
with efforts
(LMC), for the mass
J. Barchi,
(s, 1
in Japan.
of novel carbocyclic
family.
8.09
(MH+, calcd.
to us by Dr. Satoshi
of the utility
together
(s, 2 H, NH2),
F was identical
provided
F, achieved
Acknowledqement. Chemistry
(f)-neplanocin
F kindly
of (+)-neplanocin
the synthesis
the neplanocin
NMR of synthetic (-)-neplanocin
7.21
FAB MS, m/z 264.1097
the synthesis
In summary, another
(s, 1 H, H-4'),
high resolution
and Notes
J. S. Yaginuma, N. Muto, M. Tsujino, Y. Sudate, M. Hayashi and M. Otani, Antibiot. 1981, 34, 359. 1986, 6, 1 and references therein. V. E. Marquez and M.-I. Lim, Med. &. &y. S. Yaginuma, M. Tusjino, N. Muto, M. Otani, M. Hayashi, 3. Ishimura, T. Jujii, S. of Infectious Watanabe, T. Matsuda, T. Watanabe and J. Abe, "Current Chemotherapy Diseases", Proc. 11th Intl.Congress Chemother., 1979, 2, 1558. M. Hayashi, S. Yaginuma, N. Muto and M. Tsujino, Nucl. Acids Res. Symposium Series No. 8, 1980, ~65. M. Otani, S. Yaginuma, M. Tsujino, N. Muto, S. Tagata, German patent, Offenlegungsschrift 29 17 000, Nov. 29, 1979, Toyo Jozo (Japan). V. E. Marquez, M.-I. Lim, C.K.-H. Tseng, A. Markovac, M.A. Priest, M.S. Khan and B. kaskar, 4. m. m. 1988, 53, 5709. When the carbocyclic amine obtained from compound 14 was used in the condensation acyl group migration from the ester reaction with 2,4-dichloro-5_aminopyrimidine, to the amine interfered with the reaction. On the other hand, use of the carbocyclic amine generated from compound Is, gave the desired condensation product in acceptable yields. However, the final cyclization step did not go to completion due to the ease with which the free allylic alcohol reacted with triethyl orthoformate. Y. F. Shealy and J. D. Clayton, J. Am. m. a. 1969, 9l, 3075. M. Arita, K. Adachi, Y. Ito, H. Sawai and M. Ohno, J. Am. Chem. &g. 1983,105,
4049. 10.
Combustion neplanocin calculated
analyses for C, H, and N, performed on the final product F, as well as in the intermediate compounds, were within values.
(Received in USA 7 June 1989)
(k)f 0.4% of the