1. Art and Diseño

Tetrahedron Letters,Vol.23,No.3,pp
Printed In Great Britain
285-288,1982
0040-4039/82/030285-04$03.00/O
01982 Pergamon Press Ltd.
STUDIES DIRECTED TOWARDS THE TOTAL SYNTHESIS
OF MORPHINE ALKALOIDS
D. A. EVANS* AND C. H. MITCH
Contrlbutlon
No. 6546from theLaboratorIes
of Chemistry
Callforrua
Institute
Pasadena,
Abstract:
Appkatlon
IS reported.
A recent
morphman
which
outlmed
Scheme
have
of metallated
A formal
pubkatlon
this laboratory
outhned
toward
the development
congeners
has been completed.
an efflclent
The purpose of this commumcatlon
been dlrected
91125
enammes to the synthesis of morphme related
total synthesis of (+ )-morphme
from
derlvatlves.1
of Technology
Cahforma
approach
to the constructlon
of a morphme
total
synthesis
accordmg
m Scheme I.
I
OMe
OH
X
2
le
2,
x-o
a,
X = CHe
Br
H2C
H,C
Br
t
br
6
5
285
of simple
IS to expand upon the scope of our earher
4
studies
to the
plan
286
Pursuant
In the
to executmg
followmg
cyclopropane
the desired
fashion.
dlcarboxyhc
subsequent
brommatlon3
8b In 75% yield.
plan, the Illustrated
dlbromlde
acld2 as Illustrated
dlbromlde
cyclopropylcarbmyl
synthesis
The requlslte
structural
6 was convemently
below (eq 1). Borane reduction
The
reqwslte
C02H
II
FiH,
allyhc
dlbromlde
of 8b (1.0 equlv.
ZnBr2,
CH2X
THF
C02H
D<
HzC
-7
cs”,
CHzX
b,
the
Acid catalyzed
Br
E?r
r
X=OH
X=Br [SO%1
80,
96 h) afforded
-via Lewis
w
2) Per,
from
SO”C, 36 h) m 80% yleld.fiThesynthesls
ZllBr,
-
steps
of 7 (BH3, THF, 25OC, 75%) and
6 was prepared
C6H6,
were constructed
In three
of dlol 8a (1.1 molar equlv PBr3, 0.1 equlv 48% HBr, CH2CI2,
rearrangement4
D<
components
synthesized
2
(1)
[75%1
OMe
_
(2)
9
of
the required
methyl
tetrahydropyrldme
4-plperldone
9 was executed
O’C,
45-50%)
1 lO”C, 2 h, 95%) of the resultant
alcohol
was
of
carried
cannulatlon
Scheme
out
(Et20,
by metallatlon
analogy
to the blcycllc
with earher
crystallme
(mp
equlhbrated
to the thermodynamlcally
149-ISI’C)
95%) which
was readily
m anhydrous
azlrldmlum
salts deserves
further
process
-78’C).
lmmomum
which,
salt
ieadmg
-lO”c,
The resultant
10 m the presence
protonatlon
(3 equiv.
to the blcychc
30 mm)
monocyclic
to N-
TsOH, toluene,
enamme
enamme
4 (c.f.
of sodium lodlde (MeCN, K2CO3 Sot,
of 10 (HC104-MeOH,
upon dlssolutlon
Et20) afforded
m MeOH
(50°C,
three-step
Into the a-ammo
sulfoxlde
attention
sequence.
the dlastereomerlcally
(25°C).
aldehyde
The reaction
13 m vu-tually
This exceptionally
as a potentially
of 11 (CH2Cl2,
pure azlrldmlum
the
24 h),
generahzable
efficient
method
25’C) with
salt 12 (mp 186-188 C,
quantitative
“Kornblum
yield upon Its
oxldatlon”
for the constructlon
ammo aldehydes.
Ar
Nu
‘Me
CH2Nu
12
10
and subsequent
-cls-Isomer II (cls:trans = 95:5) as an amorphous powder In an
of the -cls-fused lmmonlum perchlorate
11 to the morphman skeleton
afforded
transformed
dimethyl
dehydration
preferred
of dlazomethane
dlssolutlon
of 2,3-dlmethoxyphenylhth:um6
9 (n-BuLI,THF,
6 (Et20,
enamme
m 72% yield by the followmg
solution
The annelation
studies, l kmetlc
trans-fused
yield of 60% from 9. Conversion
was accomplished
an ethereal
(eq 2).
by the addltlon
by acid catalyzed
tetrahydropyrldme
of the anion Into 2 equlv of dlbromlde
I) was then cychzed
2 h). In complete
overall
followed
= Cl-,
-OH,
-O&a),
(3)
of
of o-
287
In the present
facile
Instance,
regloselectlve
the oxldatlve
substltutlon
reactlons
converslon
of 13 to the morphman
BF3 Et20,
toluene,
derived
-IO”c,
cleavage
of this salt
carbmol
afforded
perchlorate
Successive
morphman
I2 by DMSO
by both hydroxide
14 was affected
3 h) In 80% yield.
from 14 (LlBEt3H)
of azlrldmlum
was suggested by the
and chloride
by Lewis Acid catalyzed
methanesulfonatlon
15a m excellent
Ions (eq 3).
cycllzatlon
and reduction
The
(2.5 equlv
of the mesylate
yield.
Scheme II
HCIO.,
MIOH.
A
c
C&NC
CHcCIe
?Me
OMSO
25=X
I
-Ma&
clo;
-12 [95%1
I) MaCI, TEA
2) LIEt+H
3) 0.0..
NaIO,
I
OMe
OMe
8Me
Me0
0
a.
-ij,x=o
From our earller
morphman
careful
lfia.
exammatlon
small
observations
dlazomethane
oxldatlon
previously
that
of
of II
for the direct
With a sample of the direct
with dlazomethane
morphman
this rmg system
E
noted
m this
could be directly
revealed
Instance
constructed
converslon of lmmoruum salt 11 to
cycllzatlon
product l5a m hand, a
the presence of approximately
IS In marked
from
lmmomum
contrast
1% of
to our earller
Ions related
to 11 upon
treatment.1
completion
(0~04,
of a formal
NaI04)
employed
total
synthesis
of 15a under acldlc
by Gates m his ploneermg
by Its converslon
of unsaturated
with authentic
had been established
treatment.1
of the reactlon
l5b was accompllshed
reduction
studies precedent
percentage
N
Me
16
Ce
[SO%]
c
[SO%1
15a upon dlazomethane
The
The
X = CHz
c
\@
Yl
.
17 obtamed
ketone
total
was accomphshed
(THF:H2O:HOAc,
3:1:1)7
17 via base catalyzed
l3C NMR and Infrared
sources, generously
by Lemleux-Johnson
to ketone
synthesis of morphme. 8 Verlflcatlon
to the Cl4-eplmer
16. 9 The lo,
from natural
of (+ )-morphme
condltlons
lfib which
of the structure
equlhbratlon
was
of
and subsequent
spectra of 17 were found to be ldentlcal
provided by A. Brossl and I+. SchmldhammerJO
288
Acbowledgement.
Lilly
This work has been supported
Company.
The
use
of
the
Southern
by the Natlonal
Callfornla
lnstltutes
Reglonal
NMR
of Health (GM-261 I I) and the El1
Faclhty
(NSF-7916324AI)
IS also
acknowledged.
REFERENCES AND NOTES
D. A. Evans, C. H. Mitch,
(I)
R. C. Thomas,
D. M. Zimmerman,
and R. L. Robey,
J. Am. Chem. Sot.,
102,
5955 (1980).
R. K. Smgh and S. Damshefsky,
J. Org. Chem.,
(3)
R. 0. Hutchms,
and C. Maryanoff,
(4)
D. E. Applequlst
(2)
D. Masllamaru,
and J. D. Roberts,
40, 2969 (1975).
J. Am. Chem.
ZnBr2 and anhydrous condltlons
J. Org. Chem.,
(5)
Subhmed
(6)
H. Cllman,
(7)
H. Vorbrueggen
(8)
M. Gates and G. Tschudi,
(9)
M. Gates and R. Helg, J. Am. Chem. Sot., 75, 379 (1953).
J. SWISS, and L. C. Cheney,
and C. Dlerassl,
(a) A. Brossl et.,
(IO)
41, 1071 (1976).
Sot., 78, 874 (1956).
were found to be essential
for the desired
transformation.
J. Am. Chem. Sot., 62, 1963 (1940).
J. Am. Chem.
J. Am. Chem.
Helv. Chum. Acta,
Sot., 84, 2990 (1962).
Sot., 78, 1380 (1956).
64, 1298 (1981).
(b) C. Oheman,
L. Maat, and H. C. Beyerman,
Rec. Trav. Chum., 99, 169 (1980).
Selected
17:
13C NMR Data:
(CDC13)
6 210.5,
(22.5 MHz)
151.5,
148.9,
130.4,
130.2,
122.9,
111.4, 60.3,
57.0, 55.8,
51.3,
46.5,
45.6, 42.6,
41.5,
41.1, 40.0, 27.0, 24.0.
1%:
(C6D6)
6 209.6 (s), 151.9 (s), 148.7 (s), 136.8 (s), 131.1 (s), 123.2 (d), 111.8 (d), 60.0 (q), 57.8 (d), 55.6 (q),
51.9 (t), 47.9 (t), 42.8 (q), 41.7 (d), 40.8 (t), 40.4 (s), 31.3 (t), 28.5 (t), 26.9 (t).
14:
6 152.7, 147.4, 137.0, 136.3, 123.8, 111.8, 110.1, 69.7, 63.3, 60.1, 55.4, 47.0, 46.7, 45.5,42.4,
(C6D6)
40.3,
35.4, 30.2, 25.4.
11 _trans:
(CD3CN)
6 182.4,
154.6, 148.8, 145.1, 131.2, 123.9, 122.3, 113.7, 111.8, 61.3, 56.5, 52.4, 48.8, 45.7,
43.0, 35.2, 34.7, 27.0.
11 -as:
(CD3CN)
6 181.4,
154.6,
148.9,
144.6,
136.2,
124.8,
120.2,
113.7,
111.9,
61.2,
56.5,
52.2, 49.3, 43.1,
42.6, 39.3, 33.2, 27.6, 27.1.
12:
(CD3CN)
6 154.5,
148.8,
145.7,
138.3,
124.1,
121.3,
113.3,
111.4, 60.8, 56.5, 53.5, 50.8, 50.7, 46.2, 43.3,
39.4, 34.8, 30.8, 30.4, 27.6.
10:
(CDC13)
6 153.2,
147.7,
147.3,
138.9, 133.7,
42.7, 37.8, 36.1, 31.8.
‘(Received
in
USA
9 October
1981)
125.1, 122.0, 112.8, 110.9, 108.4, 60.2, 55.7, 46.7, 46.2, 44.5,