Total Synthesis of 7-N-Acetyl-6Ethyl-Lavendamycin Methyl Ester
An Honors 499 Thesis
by
Brian CUnningham
Mentor
Dr. Mohammad Behforouz
Ball State University
Muncie, IN
May 8, 1998
-
Expected Date of Graduation: May 9, 1998
Abstract
The research detailed within concerns the synthesis of
an analog of lavendamycin; 7-N-acetyl-6-ethyl-Iavendamycin
methyl ester.
This synthesis is part of a continuing
structure-activity relationship study of various analogs of
lavendamycin as possible chemotherapeutic agents.
The
eventual screening of this analog for biological activity
will further the knowledge of the effects of structure on
various biological activities.
-
-
The molecules selected in
this SAR study are chosen in hopes that they will show
selective toxicity for ras k oncogene transformed cells.
2
Table of Contents
I. Acknowledgments
3
II. Background Information
4
III. Synthesis of Lavendamycin Analogs
5
IV. 7-N-Acetyllavendamycin Esters
7
V. Total Synthesis
7
A. 7-N-Acetyl-6-ethyl-lavendamycin methyl ester
B. Reaction of Diethylaluminum Cyanide with
7
a,~-
Unsaturated Ketones
VI. Experimental
9
10
A. General Information
10
B. Solvent Purification
11
C. Procedures
11
8-Hydroxy-2-methyl-S,7-dinitroquinoline
11
S,7-Diacetamido-8-acetoxy-2-methylquinoline
11
7-Acetamido-2-methylquinoline-S,8-dione
12
7-Acetamido-6-ethyl-2-methylquinoline-S,8-dione
13
7-Acetamido-6-ethyl-2-formylquinoline-S,8-dione
13
7-N-Acetyl-6-ethyl-lavendamycin Methyl Ester
14
Appendix A
VII. Works Cited
IR, NMR Spectroscopy
16
17
3
I. Acknowledgments
I would first like to thank Dr. Mohammad Behforouz, without
whom this project would not have been possible.
I have a
tremendous amount of respect for Dr. Behforouz and his combined
strengths of strong character, vast knowledge, and genuine
kindness.
Another very special person to thank is Mrs. Wen Cai,
whose unselfishness and unwavering work ethic has been key to the
completion of this project.
I am also grateful to Adrian Adams
and MaryAnn Knott for providing me with employment and
friendship.
Thanks to the Ball State Chemistry Department and
all faculty for giving me a quality education that has prepared
me for a successful future in chemistry.
Recognition goes to the
National Institute of Health and the American Cancer Society for
providing the major funding for the project.
Thank you to the
Ball State University Honors College for awarding me an
Undergraduate Honors Fellowship, thus allowing me to commit more
time to the project.
Above all, I would like to thank God 'for
these and the many other blessings in my life.
4
-
II. Background Information
Lavendamycin (1), a naturally occurring compound produced by the
soil bacterium Streptomyces lavendulae, was first isolated and described
in 1981 by Doyle and associates at Bristol Laboratories.
1
The
similarity in structure of lavendamycin and a known
antitumor/antibiotic, streptonigrin (2), was noted.
The two compounds
also displayed similar biological activities, with lavendamycin showing
limited antimicrobial action and significant activity against ras
k
leukemia cells in mice. 2
o
MeO
COOH
H2N
COOH
H2N
0
CH 3
CH 3
1
2
OMe
Figure 1: Lavendamycin and Streptonigrin
The prospect of anti-tumor activity, coupled with the extreme difficulty
in isolating the natural product, sparked several research groups to
begin efforts at a total synthesis of lavendamycin.
In 1984, Kende and
Ebetino were the first to report synthesis of lavendamycin methyl
ester. 3 • 4
Their synthesis pathway used a Friedlander condensation to
produce the A-B ring portion and a Bischler-Napierski cyclodehydration
to complete the five-ring system.
This was followed in 1985 by Hibino
reporting the synthesis of lavendamycin methyl ester by first
constructing the complete ring system with a Pictet-Spengler
condensation between a quinoline analog and
~-methyl
tryptophan,
followed by several steps to functionalize the five ring system. 5
Also
in 1985 Boger reported a complicated synthesis involving twenty steps
with an overall yield less than 1%.6
Then in 1993, Behforouz reported a
synthesis of only five steps to an overall yield of 33%.7
This five
step route involved a Diels-Alder condensation to produce the A-B ring
system, along with a Pictet-Spengler condensation similar to that
-
reported by Hibino, with all functionalizations occurring before the
Pictet-Spengler condensation.
Behforouz then improved on the method in
5
-
1996, producing lavendamycin methyl ester in six steps with a yield of
40%, this time using 8-hydroxyquinaldine as the starting material and
avoiding the Diels-Alder condensation. B • 9
Since 1993, Behforouz's group
has been conducting a structure-activity relationship (SAR) study on
analogs of lavendamycin in order to better understand the mechanism of
these compounds in biological activity.
II. Synthesis of Lavendamycin Analogs
The potent antitumor capacity of both lavendanmycin and
streptonigrin was originally overshadowed by their high toxici ty 2,10.11
and lavendamycin's low solubility in pharmaceutical solvents. 1
An SAR
study of lavendamycin analogs allows researchers to select for more
soluble analogs and search for compounds with more selective
cytotoxicity.
cleavage
12
,
Quinones often are highly cytotoxic, resulting in DNA
and many have shown anti-cancer potential.
It has also been
suggested that the quinone toxicity is due to effects on the electron
transport system in mitochondria. 13-17
In hopes of gaining a better
understanding of these mechanisms and possibly discovering a useful
chemotherapeutic agent, Behforouz and his group at Ball State University
began an SAR study on lavendamycin analogs, using the five step
syntheses reported in 1993 and 1996.
It is the concise and practical
nature of these synthesis routes that has allowed the SAR study to take
place.
In 1993 7 (Scheme 1a) Behforouz reported the use of a Diels-Alder
condensation between the bromoquinone (3) and the azadiene (4), to
produce the quinolinedione (5) portion of lavendamycin.
Oxidation of
the methyl group on the quinolinedione provided the aldehyde (6) used in
a Pictet-Spengler condensation with ~-methyl tryptophan methyl ester (7)
to produce 7-N-acetyllavendamycin methyl ester (8), which was then
hydrolyzed to give the final product (9).
6
0
+
1
CeHsCI
heat
b-~
AcHN
•
W
N~
CH 3
0
5
4
3
~
+
ACHNVN~HO
o
Xyfene
Reflux
7
6
AcHN
..
600
•
Scheme 1a
10
11
10
ACHNV~CH3
o
5
138: R=OH
13b: R=OAc
Scheme 1b
In 1996 8 ,9 Behforouz modified the method (Scheme 1b) and increased the
yield from 33% to 40% by using 8-hydroxyquinaldine (10) as starting
7
In 1996 8 ,9 Behforouz modified the method (Scheme 1b) and increased the
yield from 33% to 40% by using 8-hydroxyquinaldine (10) as starting
material for the A-B portion of the ring system, and thus avoiding the
relatively low-yield Diels-Alder reaction.
It is this improved method
that has been used for the research presented in this thesis.
IV. 7-N-acetyllavendamycin esters
It has been discovered in the SAR study that the 7-N-acetyl
analogs of lavendamycin proved a much more selective toxicity
against the rask tumor cells than the amino counterparts. 18
The
7-N-acetyl compound 8 displayed 9-fold selectivity against the
tumor cells compared to the much lower O.S-fold selectivity
displayed by 9.
Because the 7-N-acetyl analogs are more
selective and are produced in one less step than the amino
counterpart, the target molecule for this project was chosen to
be a 7-N-acetyl analog.
V. Total Synthesis:
A. 7-N-Acetyl-6-ethyl-lavendamycin methyl ester
The key reaction in Behforouz's synthesis route to
lavendamycin analogs is the Pictet-Spengler condensation of a
formylquinolinedione and a tryptophan.
The novel work presented
in this thesis involves new functionalization on the
quinolinedione portion of the lavendamycin molecule.
The final
product, 7-N-acetyl-6-ethyl-lavendamycin methyl ester was
produced as follows.
8-hydroxyquinaldine (lO), available
commercially, was nitrated with a 70:30 mixture of concentrated
nitric and sulfuric acids.
The reaction was quite exothermic, so
an ice bath was used to maintain room temperature.
The hydroxy
group on the 8-hydroxyquinaldine acts as an ortho-para director,
and the nitrogen on the opposite ring deactivates the positions
on that ring, so the nitro groups are added only ortho and para
to the hydroxy group.
8
-
The resulting yellow 5,7-dinitro-8-hydroxy-2-methylquinoline
(11) was then hydrogenated using a Parr hydrogenator.
The
dinitro is mixed with 5% Pd-C and a 10% HCI solution, and shaken
under H2 at 30 psi for 20 hours to give the dark red
dihydrochloride salt 12.
amino group,
This salt, which protects the sensitive
is not isolated, but is reacted immediately with
sodium sulfite, sodium acetate, and a slow addition of acetic
anhydride to give the diacetamido compound 13.
The reaction
proceeds by nucleophilic attack of the amino groups to the
carbonyl carbons in the acetic anhydride.
There was possibly a
mixture of the hydroxy and acetoxy groups at the 8 position, but
these do not need to be separated as they do not affect the next
step.
This white acetoxy/hydroxy mixture was then oxidized with
K2Cr207 in acetic acid solution, extracted with dichloromethane,
and neutralized with 5% NaHC0 3 to give the bright yellow
quinolinedione 5.
-
The mechanism for this reaction is unknown.
The remainder of the steps in the synthesis can be seen in
Scheme 2.
Compound 5 was reacted with a 1M diethylaluminum
cyanide/toluene solution to give, surprisingly, a major product
of the ethylated compound 14.
This most likely occurred by way
of a 1,4-Michael addition, rather than the previously reported
1,2-addition resulting in 17 19 , or the originally expected 1,4conjugate addition of HCN.
There was also recovery of a smaller
amount of starting material.
The methyl group of this quinolinedione was then oxidized
with selenium dioxide in 1,4-dioxane and a small amount of water
to give the aldehyde 15.
The water and Se02 react, forming a
reactive selenium oxide, which then reacts selectively to oxidize
only the methyl group on the quinolinedione.
9
Scheme 2
-EVoICN (1 M!Toluene)
5
..
8e02 • heat
..
Dioxane
15
14
15
+
oJ;:
~~ I
N
H
0
C02CH3
NH2
7
Xylene
Reflux
..
CH3 CH2
C02CH 3
0
CH3
Next, the Pictet-Spengler condensation was performed with the
aldehyde and the commercially available p-methyl tryptophan
methyl ester (7), refluxing in xylene, to yield the final product
16.
In the Pictet-Spengler condensation, the aldehyde of the
quinolinedione and the amine group of the tryptophan react, are
thought to form a spiroindolenine intermediate 20 , and result in a
new carbon-carbon bond.
B. Reaction of Diethylaluminum Cyanide with
a,~­
unsaturated Ketones
For many years, diethylaluminum cyanide has been known to
produce p-cyano carbonyl compounds by way of a conjugate addition
to a,p-unsaturated ketones. 21
In early 1998 Behforouz reported
from our own research group a reaction in which diethylaluminum
cyanide added to the quinolinedione 5 in a 1,2 fashion, resulting
in the quinoline quinol 17 and a small amount of recovered
starting material. 19
10
-
W
I /-
I
AcHN
f0
CH2~3
HO
N
o
• //
CH3
ACHNyN~CH3
o
17
+
E~
//.
~A
ACHNYN
o
5
CH3
18
1
CH3CH2~
I I ~
AcHN
N
0
CH3
14
Quinoline quinols have shown promise as chemotherapeutic agents,
so the project was begun intending to produce a lavendamycin
analog with a quinoline quinol portion.
Instead, working under
the same reaction conditions but with a different reagent bottle,
I repeated the published reaction with compound 7 and
diethylaluminum cyanide and obtained a major product of compound
14, along with a small amount of recovered starting material 7.
The proposed mechanism for this reaction would be a 1,4 conjugate
addition, but with an ethyl group acting as the nucleophile
,-
rather than the expected cyano group.
VI. Experimental
A. General Infor.mation
Reagents:
8-hydroxyquinaldine, selenium dioxide,
diethylaluminum cyanide (1M in toluene), and
~-methyl
ester were
purchased from the Aldrich Chemical Co.
Solvents:
All solvents used were reagent grade, excluding 1,4-
dioxane, xylene, and in specified instances, dichloromethane.
NMR Spectra:
The IH NMR spectra were recorded with a Varian
Gemini 200 spectrometer, and the samples were prepared in
CDCI 3 (w/TMS as internal standard) or DMSO.
IR Spectra:
The IR spectra were recorded with a Perkin-Elmer
Spectrum 1000 FT-IR Spectrometer and the samples were prepared in
--
KBr pellets.
11
--
B. Solvent Purification
For the reaction with diethylaluminum cyanide,
dichloromethane was distilled over CaH 2 and stored under argon.
l,4-dioxane was first refluxed with potassium hydroxide,
decanted, refluxed with benzophenone and sodium spheres until
dry, and then distilled.
The potassium hydroxide breaks down the
dioxane into monomers, and the sodium is a drying agent.
The
benzophenone acts as an indicator of complete dryness, and the
solution turns blue at such time.
The xylene is also purified by
refluxing with sodium spheres and benzophenone, followed by
distillation.
c. Procedures
Preparation of 8-Bydroxy-2-methyl-S,7-dinitroquinoline (11)
In a 1L erlenmeyer flask cooled by ice, concentrated nitric
acid (140 ml) and concentrated sulfuric acid (60 ml) were
combined and stirred.
In small portions over a one hour period
was added 8-hydroxyquinaldine (10; 20.00 g, 0.125 mol), while
keeping the solution at room temperature.
Once the addition was
complete, the reddish solution was allowed to stir in the ice
bath for an additional two hours.
This solution was then poured
into a 2L beaker containing ice water(l:l, 1200 ml), and stirred
with a glass rod.
The solution immediately precipitated a bright
yellow solid, which was then vacuum filtered, washed with water
and diethyl ether to yield 17.68 g (56%) of product 11.
mp 292-296 °c.
lH NMR(DMSO):a 9.68(lH, d,J=9.1Hz,C-4H),9.22(lH,s,
C-6B),8.15(lH,d,J=9.1Hz,C-3B),2.95(3H,s,CB3 )
•
Preparation of S,7-Diacetamido-8-acetoxy-2-methylquinloine (13)
In a thick walled 500 ml hydrogenation flask, 2.0 g 5% Pd-C
catalyst was added to a suspension of finely powdered 8-hydroxy2-methylquinoline-5,7-dinitroquinoline (11; 5.98 g,
.024 mol) in
12
-
100 ml 10% hydrochloric acid.
This mixture was placed on a Parr
hydrogenator and shaken under 30 psi for 21 hours.
The resulting
red solution was immediately filtered to remove the Pd-C, and the
filter cake rinsed with 10-20 ml water.
Immediately, 20.0 g
sodium acetate and 10.0 g sodium sulfite was added to the dark
red filtrate and stirred.
Then 67 ml acetic anhydride was added
dropwise while stirring and cooling in an ice bath.
turned yellow as precipitate formed.
The solution
Once the addition was
complete, the solution was allowed to stir for an additional 30
minutes,
then the precipitate was filtered off and rinsed with 20
ml water.
The filtrate was then concentrated to approximately
25-30 ml, and an extra 13 ml acetic anhydride was added dropwise
over fifteen minutes, causing more precipitate to form.
The
solution was filtered again, and the filter cakes were combined
and dried to give 6.10 g
--
(81%) of 13.
Preparation of 7-Acetamido-2-methylquinoline-s,8-dione(s)
In a 500 ml erlenmeyer flask,
methylquinoline (13; 3.15 g,
5,7-diacetamido-8-acetoxy-2-
.01 mol) was dissolved and stirred
in 120 ml glacial acetic acid.
Potassium dichromate (8.75 g,
.03
mol) was then dissolved in 100 ml water and added to the acetic
acid solution.
This solution was then stirred at room
temperature for 24 hours.
the resulting black solution was
poured into 900 ml water in a 2L separatory funnel, and extracted
with dichloromethane (4 x 250 ml).
The yellow organic extracts
were then combined and washed with 5% sodium carbonate in
saturated sodium chloride solution (3 x 200 ml) to neutralize the
acid.
The organic solution was then dried over magnesium sulfate
overnight.
The next day, the solution was rota-evaporated to
dryness and dried under vacuum to yield 1.18 g
solid 5.
mp 216-218 °C.
(52%) of yellow
lH NMR(CDCI 3 ):0 8.41(lH,s,C-7NH),8.32
(lH,d,J=8.1Hz,C-4H),7.92(lH,s,C-6H),7.57(lH,d,J=8.1Hz,C-3H),
2.78(3H,s,C-2CH3 ) ,2.33 (3H,s,NHCOCH3 )
•
13
-
Preparation of 7-Acetamido-6-ethyl-2-methylquinoline-S,8-dione (14)
7-acetamido-2-methylquinoline-5,S-dione (5; 230 mg, 1 mmol)
was dissolved and stirred in 10 ml of dichloromethane (distilled
over CaH 2 ) .
To this bright yellow solution was added a 1M
solution of diethylaluminum cyanide in Toluene (5 ml,5mmol,5 eq),
which immediately turned the solution to a thick brown mixture.
The mixture was then stirred in an argon atmosphere for one hour.
Next, 40 ml of ice-cooled saturated sodium potassium tartrate was
added and stirred for 20 minutes.
Then 100 ml dichloromethane
and another 40 ml saturated sodium potassium tartrate was added
and stirred for an additional 20 minutes.
The resulting mixture
was extracted with dichloromethane (3 x 100 ml) and the yellow
organic layers combined, washed with 200 ml water, and dried over
magnesium sulfate.
5 mI.
The extracts were then concentrated to about
Flash chromatography (silica gel
40~,
2.5 x 15 cm, EtOAc
eluent) afforded 21 mg (9%) of recovered starting material 3, and
-
76.4 mg (30%) of 14 as a dull yellow solid.
m.p. 159-162 °C.
(CH2C12-Pet. Ether)
IR(KBr) 344S(br), 3265, 2964, 2935, 1670, 1655,
15SS,150S,1304,1256,cm- 1 ; IH NMR (CDCI 3 )O S.32(lH,d,J=S.lHz,C-4H),
7.75 (lH,s,C-7N-H),7.50(lH,d,J=S.lHz,C-3H),2.74(3H,s,C-2CH3 ),
2.64 (2H,q,J=7.45Hz,CH2 CH3 ),2.2S(3H, s, COCB3),l.14(3H,t,J=7.47Hz,
CH2 CB3 )
Preparation of 7-Acetamido-6-ethyl-2-formylquinoline-5,8dione(15)
In a 10 ml pear-shaped flask, 4 ml of dried and purified
l,4-dioxane and 0.025 ml of water were added to a mixture of 7acetamido-6-ethyl-2-methylquinoline-5,S-dione (14, 51.6 mg, 0.2
mmol) and selenium dioxide (27.S mg, 0.25 romol, white crystal
only).
The resulting mixture was gently stirred under an argon
atmosphere and slowly heated to reflux at 115-120 °c over a 2
hour period.
The now dark orange-black solution was allowed to
14
reflux for 16 hours, until the reaction is complete when checked
by TLC (1:1 CH 2 C1 2 :Acetone).
At this time 4 ml more 1,4-dioxane
was added to the solution and refluxed for 15 minutes.
The
solution was the decanted from the black selenium and vacuum
filtered while hot.
5 ml of dichloromethane was added to the
residue in the reaction flask and refluxed for 10 minutes.
This
solution was then filtered hot, the filtrates combined, and rotaevaporated to dryness, leaving an orange-yellow solid which is
dried to yield 38.6 mg (71%) of 15.
(CH 2 C1 2 :Pet. Ether).
m.p.
180-185 °c IR(KBr) 3455 (br), 3280, 1675, 1652, 1581, 1500, 1240i
lH NMR (CDC1 3 )O 10.33(lH,s,CHO),8.67 (lH,d,J=8.1Hz,C-4H),
8.34(lH,d,J=8.1Hz,C-3H),7.83(lH,s,C-7NH),2.72(2H,q,J=7.5Hz,
CH2 CH 3 ) ,2.37(3H,s,COCH3 ),l.22(3H,t,J=7.5Hz,CH2 CH3 ) ·
Preparation of
7-N-Acetyl-6-ethyl-lavend~cin
methyl ester (16)
In a 100 ml round bottom flask, 7-acetamido-6-ethyl-2formylquinoline-5,8-dione (15, 35.3 mg, 0.13 romol) was dissolved
in 42 ml of dried xylene and stirred under argon flow.
~-methyl
tryptophan methyl ester (30.1 mg, 0.13 romol) was added and the
mixture heated slowly to reflux at 160°C.
The pale yellow
solution was refluxed for 21 hours, and completion of reaction
was then checked by TLC (6ml CH2 C1 2 : 4 drops MeOH).
The solution
was concentrated to one-fifth its original volume, vacuum
filtered and the yellow crystals were washed with petroleum ether
to remove the xylene.
The solid is dried and weighed to yield
41.4 mg (66%) of rather impure 16.
cm, 40
~
Flash chromatography (1 x 7.5
silica gel, 50:1 CH2 C1 2 iMeOH eluent) results in pure 16
as dark orange solid. IR(KBr) 3350, 3244, 2962, 2925, 1717, 1690,
1662, 1589, 1508, 1334, 1262, 1099, 1077, 1020, 802 cm-1i
lH NMR (CDC1 3 ) 0 11.82(lH,s,NH) ,9.04(lH,d, J=8.1Hz,C-4H), 8.50
(lH,d,J=8.1Hz,C-3H),8.33(lH,d,J=8.1Hz) ,7.75 (lH,d),7.72
(lH,br s,
NHCOCH 3 ),7.60(lH,t,J=8.1Hz),7.35(lH,t,J=8.1 Hz), 4.03(3H, s,
15
-
-
COOCH3 ) ,3.17(3H,s,-CH3 ) ,2.64(2H,q,CH2 CH 3 ),2.29(3H, s, NCOCH 3 ) , 1.18
( 3 H, t , CH2 CH3 )
•
16
Index of Spectra
8-Hydroxy-2-methyl-5,7-dinitroquinoline ......... (NMR) ... (11)
7-Acetamido-2-methylquinoline-5,8-dione ......... (NMR) ... (5)
7-Acetamido-6-ethyl-2-methylquinoline-5,8-dione .. (NMR) .. (14)
(IR) . . . (14)
7-Acetamido-6-ethyl-2-formylquinoline-5,8-dione .. (NMR) .. (15)
(IR) . . . (15)
7-N-Acetyl-6-ethyl-lavendamycin methyl ester ..... (NMR) .. (16)
. . . . (IR) . . . (16)
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17
Works Cited
-.
1. Doyle, T.W.; Balitz, D.M.; Grulich, R.E.; Nettleton, D.E.;
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18
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19
--
--
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