Synthesis of enantiomerically pure morphine alkaloids: The hydrophenanthrene route

Article abstract of DOI:10.1021/jo9805394

A concise, linear, total synthesis of (-)-dihydrocodeinone - a close synthetic precursor of (-)-codeine and (-)-morphine - has been achieved. The carbocyclic core of the alkaloid was provided in the form of a phenanthrenone, which was resolved by chromatography on cellulose triacetate. A cuprate conjugate addition was used to establish the crucial benzylic quaternary stereocenter and to introduce the C₂-side chain. Dimeric byproducts provide evidence for a single electron transfer (SET) mechanism. Unusual S(N)2 and radical cyclizations were employed for the formation of the dihydrobenzofuran and the piperidine ring, respectively.

Full text of DOI:10.1021/jo9805394

5908
J . Org. Chem. 1998, 63, 5908-5918
Syn th esis of En a n tiom er ica lly P u r e Mor p h in e Alk a loid s: Th e
Hyd r op h en a n th r en e Rou te
Dirk Trauner,† J an W. Bats,‡ Andreas Werner,† and J ohann Mulzer*,†,§
Institut fu¨r Organische Chemie, Universita¨t Wien, Wa¨hringerstrasse 38, A-1090 Vienna, Austria, and
Institut fu¨r Organische Chemie, J ohann Wolfgang Goethe-Universita¨t, Marie-Curie-Strasse 11,
D-60439 Frankfurt, Germany
Received March 23, 1998
A concise, linear, total synthesis of (-)-dihydrocodeinonesa close synthetic precursor of (-)-codeine
and (-)-morphineshas been achieved. The carbocyclic core of the alkaloid was provided in the
form of a phenanthrenone, which was resolved by chromatography on cellulose triacetate. A cuprate
conjugate addition was used to establish the crucial benzylic quaternary stereocenter and to
introduce the C2-side chain. Dimeric byproducts provide evidence for a single electron transfer
(SET) mechanism. Unusual SN2 and radical cyclizations were employed for the formation of the
dihydrobenzofuran and the piperidine ring, respectively.
Sch em e 1
In tr od u ction
The morphine alkaloids represent a family of structur-
ally related natural products of eminent importance in
medicine.1 Total syntheses of the parent compound, (-)-
morphine (1), and derivatives thereof have attracted the
interest of organic chemists for many decades.2 These
efforts have resulted in numerous successful routes,
which, however, mostly led to racemic material and were
too long to be of practical use. Our approach is unusually
direct and is based on considerations which are derived
from the early degradation studies of morphine.3
and a two carbon “side chain” linked with the nitrogen,
whose other point of attachment was under debate for
many years until Robinson established the C13-linkage
in 1926.4
Zinc-dust distillation of 1 was observed to afford
phenanthrene as early as 1881. Subsequently, milder
methods allowed the isolation of intermediates which
provided more insight into the substitution pattern of the
phenanthrene core (Scheme 1). Hofmann-type degrada-
tions, for instance, led to cleavage of the C9-N bond and
introduction of a ∆9,10-double bond to yield so-called
morphimethines (2). Further degradation under more
drastic conditions usually resulted in elimination of the
C2-chain and full aromatization of the tricyclic nucleus.
Accordingly, the carbon skeleton has been conceptually
disconnected into an oxygenated hydrophenanthrene core
Hence, many attempts to synthesize morphine were
based on the idea to provide a suitably substituted
hydrophenanthrenone and to mount the ethanamine
bridge onto this platform subsequently. This deceptively
simple concept, however, requires a reaction which is
powerful enough to introduce the crucial benzylic qua-
ternary carbon (C13) against considerable steric
hindrancesan issue that has been solved by an intramo-
lecular strategy in approaches by Ginsburg5 and White.6
In contrast, our approach is characterized by an inter-
molecular addition to create the quaternary C13 center.
We report now full details of our synthesis, which is
essentially a reversal of the degradation shown above,
and give an account of its gradual evolution.7
† Universita¨t Wien.
‡ J ohann Wolfgang Goethe-Universita¨t
§ E-mail: dixi@felix.orc.univie.ac.at; mulzer@felix.orc.univie.ac.at.
(1) Iversen, L. Nature 1996, 383, 759, and references cited therein.
(2) For reviews on the total synthesis of morphine alkaloids, see:
(a) Hudlicky, T.; Butora, G.; Fearnley, S. P.; Gum, A. G.; Stabile, M.
R. In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 1996; pp 43 ff. (b) Maier, M. In Organic
Synthesis Highlights II; Waldmann, H., Ed.; VCH: Weinheim, Ger-
many, 1995; p 357 ff. (c) Sza´ntay, G.; Do¨rnyei, G. In The Alkaloids;
Cordell, G.A., Brossi, A., Eds.; Academic Press: New York, 1994; Vol.
45, pp 127 ff.
(4) Gulland, J . M; Robinson, R. Mem. Proc. Manchester Lit. Phil.
Soc. 1925, 69, 79.
(5) Ginsburg, D.; Elad, D. J . Am. Chem. Soc. 1954, 76, 312; J . Chem.
Soc. 1954, 3052.
(6) White, J . D.; Hrnciar, P.; Stappenbeck, F. J . Org. Chem. 1997,
62, 5250.
(7) For preliminary accounts of this work, see: (a) Mulzer, J .;
Du¨rner, G.; Trauner, D. Angew. Chem., Int. Ed. Engl. 1996, 35, 2830
[Angew. Chem. 1996, 108, 3046]. (b) Mulzer, J .; Bats, J . W.; List, B.;
Opatz, T.; Trauner, D. Synlett 1997, 441.
(3) Fieser, L.; Fieser, M. Natural Products Related to Phenanthrene,
3rd ed.; Reinhold: New York, 1949.
S0022-3263(98)00539-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/05/1998

Enantiomerically Pure Morphine Alkaloids
J . Org. Chem., Vol. 63, No. 17, 1998 5909
Sch em e 2
Sch em e 3
a
(a) NaBH4, MeOH (98%). (b) MeC(OMe)2NMe2, xylenes, ∆
(maximum 25%). (c) (i) H2CdCHMgCl, 5% CuBr-SMe2, (TMS)Cl;
(ii) 2 N HCl (87% from 6).
Sch em e 4a
In itia l Stu d ies: Develop m en t of th e
P h en a n th r en on e Ap p r oa ch
Initially, our approach was based on a completely
different strategy, which is shown in Scheme 2 (path A).
It was planned to establish the benzylic quaternary and
the adjacent tertiary stereocenter by consecutive Claisen
rearrangements of an allylic diol 3 (Scheme 1, path A),
which was retrosynthetically derived from D-(-)-quinic
acid.
However, in model studies with simple racemic allylic
alcohols, the envisioned [3,3]-sigmatropic rearrangements
proceeded with unacceptably low yields. For instance,
the Claisen-Eschenmoser rearrangement of 7, which is
readily available by reduction of the known enone 6,8
afforded amide 8 in only 25% yield (Scheme 3). The
Ireland and J ohnson variation of the Claisen reaction
failed completely.
A more elaborate substrate, 13, was prepared in three
steps from the vinylogous ester 10 by addition of ortho
lithiated veratrole followed by hydrolysis and dehydration
to afford enone 12 (Scheme 4). Alternatively, 12 was
obtained from the addition of veratrole-lithium to 2-allyl-
2-cyclohexen-1-one (11),9 followed by oxidation of the
resulting tertiary alcohol with concomitant allylic trans-
position. 1,2-Reduction of 12 then furnished 13.
Although allylic alcohol 13 did afford the desired
rearrangement product 14 upon treatment with several
equivalents of N,N-dimethylacetamide dimethyl acetal,
the yields obtained were, again, unacceptable. Notwith-
standing, the resulting amide 14 was selectively cleaved
at the terminal double bond to afford aldehyde 15.
Unfortunately, 15 failed to undergo the desired B-ring
closure upon treatment with various Lewis acids.
a
(a) (i) (2,3-Dimethoxyphenyl)lithium, Et2O, 0 °C; (ii) saturated
aqueous NH4Cl (56%). (b) (i) (2,3-Dimethoxyphenyl)lithium, Et2O,
0 °C; (ii) PCC, CH2Cl2 (44%). (c) NaBH4, MeOH (94%). (d)
MeC(OMe)2NMe2, xylenes, ∆ (maximum 24%). (e) (i) OsO4, NMO,
acetone, H2O; (ii) NaIO4, EtOH (87%).
Our third model compound, 18a , prepared from enone
16 as shown in Scheme 5 did not undergo [3,3]-sigmat-
ropic rearrangements at all.
Being aware that Claisen rearrangements and 1,4-
additions of vinyl cuprates complement one another, we
also explored the conjugate addition of organocuprates
to enones 6, 12, and 17. Indeed, the copper(I) catalyzed
reaction of vinyl magnesium chloride in the presence of
(TMS)Cl with 6 followed by acidic hydrolysis of the
intermediary silyl enol ether gave ketone 9 in good
overall yield (Scheme 3). Unfortunately, the application
(8) McMurry, J . E.; Farina, V.; Scott, W. J .; Davidson, A. H.;
Summers. D. R.; Shenvi, A. J . Org. Chem. 1984, 49, 3803.
(9) Taber, D. F.: Gunn, B. P.; Chiu, I. C. Org. Syntheses Collect.
Vol. VII; Wiley: New York, 1990; p 249.

5910 J . Org. Chem., Vol. 63, No. 17, 1998
Trauner et al.
Sch em e 5a
Sch em e 7a
a
(a) (i) (2,3-Dimethoxyphenyl)lithium, Et2O, 0 °C; (ii) 0.5 N
H2SO4 (72%). (b) NaBH4, MeOH (82%), separation of diastereo-
mers.
Sch em e 6
a
(a) Cl2, AcOH (99%). (b) (i) (COCl)2, PhH, ∆; (ii) SnCl4, PhH,
0 °C (71%). (c) HCOOMe, NaOMe, PhH (95%). (d) (i) MVK, Et3N,
MeOH; (ii) KOH, dioxane, H2O (81% 23; 8% 24).
Tota l Syn th esis of (-)-Dih yd r ocod ein on e, F or m a l
Syn th esis of (-)-Mor p h in e
Our synthesis starts with the known tetralone 21,10
which was prepared from 19 as described (Scheme 7).
The introduction of the chlorine (19 f 20) serves to direct
the Friedel-Crafts cyclization into the less reactive
aromatic position. Activation of 21 as its formyl deriva-
tive 22 followed by Robinson annulation and retro-
Claisen cleavage provided the crystalline key phenan-
threnone 23 in good overall yield. The achiral ketone
24, a double bond isomer of 23, was isolated as a
byproduct (∼10% with respect to 23). This ketone 24 was
recycled by prolonged treatment under the Robinson
annulation conditions to afford the 10:1 equilibrium
mixture of 23 and 24.
of this reaction to the more advanced intermediates 12
and 17 was unsuccessful. Despite many attempts to
perform the conjugate addition under various conditions,
only products of 1,2-addition were isolated.
The discouraging results of these model studies may
be explained by repulsive interactions between the o-
methoxy group on the one hand and the corresponding
substituents R and R′ on the other hand which twist the
aromatic ring out of conjugation with the double bond
1
(Scheme 6). This assumption was based on the H-NMR
Compound 23 was resolved by chromatography on
cellulose triacetate (CTA, either on a 1 g scale by flash
chromatography (eluent: MeOH) or on a 10 g scale by
MPLC (eluent: EtOH:H2O ) 96:4).11 Under basic condi-
tions the undesired enantiomer (+)-23 underwent rapid
racemization and partial deconjugation to afford the
usual mixture of rac-23 and 24.
Single crystal X-ray diffraction12 gave some insight into
the ground-state conformation of (-)-23 and allowed the
assignment of its absolute configuration. The four crys-
tallographically independent, homochiral molecules in
the unit cell fall into two classes of atropisomers, 23R
and 23â (Figure 1).
spectra of allylic alcohol 13, which clearly demonstrate
the existence of two rotamers. The whole situation bears
some resemblance to the well-known atropisomerism of
biphenyls. With the aromatic residue more or less
perpendicular to the double bond, any attack on the
benzylic sp2-hybridized carbon is obviously highly unfa-
vorable for steric reasons. The intramolecular hydroxy-
alkylation of 15 probably failed for similar reasons.
An obvious solution to this problem was to restrict the
conformational flexibility of the aromatic ring by means
of a tether which would also provide for the missing two
carbon B-ring fragment. This idea led to a phenan-
threnone of type 4. A conjugate addition/enolate trapping
sequence would then not only establish the quaternary
center but also activate C5 toward dihydrofuran ring
formation (Scheme 2). Furthermore, the valuable car-
bonyl function at C6 would be be retained with this
strategy. The exact scenario for the functionalization of
C9 and closure of the piperidine ring was left undefined
at this stage of our planning. Phenanthrenones of type
4 can be prepared in a straigtforward manner via
tetralones of type 5, as shown in Scheme 2.
In both cases the 4-methoxy group tends to avoid the
vinylic hydrogen at C5 for steric reasons. As these
atropisomers, however, are not visible in the NMR
spectra at room temperature, the rotational barrier
(10) Robinson, R.; Gosh, R. J . Chem. Soc. 1944, 506.
(11) For an excellent review on the chromatographic resolution on
polysaccharide derivatives, see: Okamoto, Y.; Yashima, E. Angew.
Chem., Int. Ed. Engl. 1998, 37, 1020 [Angew. Chem. 1998, 110, 1072].
(12) Details of the crystal structure determinations of compounds
23, 26, 27, 31, 37, 38a , 43, 44, and 45 may be obtained from: The
Director, Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1 EZ, U.K.

Enantiomerically Pure Morphine Alkaloids
J . Org. Chem., Vol. 63, No. 17, 1998 5911
F igu r e 1.
Sch em e 8
diffraction confirmed the C2 symmetry of 26 and 27
(Figure 2).12 The central bond of 27 is very crowded, and
its homolytic cleavage would generate two stabilized
radicals. Nevertheless, it is not much longer than a
“normal” C,C-bond (1.573 ( 0.002 Å).
The formation of 26 and 27 under these aprotic
conditions can be rationalized by single electron transfer
(SET) from the organocuprate to the enone 23, which
generates the stable radical anion 28 and a labile copper-
(II) species (Scheme 9).14 Radical anion 28 reacts with
the chlorosilane ((TMS)Cl, (TBS)Cl) to the neutral radical
29, which either dimerizes (see 26) or combines with the
copper(II) species to form the copper(III) intermediate 30,
commonly postulated in the conjugate addition of cu-
prates. Reductive elimination of vinyl copper(I) then
generates the silyl enol ether 31, which is hydrolyzed in
a separate step. The formation of the sterically congested
copper(III) intermediate may be so slow that the destruc-
tion of the copper(II) species via reductive elimination
can compete. The remaining silylated radical then
dimerize despite extreme steric hindrance.
Due to Coulombic repulsion, radical anion 28 should
be much less prone to dimerization than its neutral
counterpart 29. In the absence of (TMS)Cl the dimer-
ization should, therefore, not be observed. Indeed, under
these conditions, 25 was formed as a single diastereomer
in excellent yields without any dimeric byproducts (Table
1, entries 6 and 7). As a final optimization, the simple
magnesiocuprate (H2CdCH)2CuMgCl was introduced
(entry 7). Despite its convenient preparation from a
commercially available Grignard compound and copper-
(I) iodide, this reagent has not found many applications
in chemical synthesis so far.15
appears to be rather small. Due to the W-shaped
arrangement of the saturated C7-C10 periphery, the
diastereoface opposite to the angular hydrogen (re-face)
is sterically more hindered than the si-face in both
conformers. In particular, the pseudo-axial hydrogens
at C8 and C9 exert a stereocontrolling effect and direct
any attack at C13 to the si-face to provide the natural
cis linkage of the B- and C-ring. Apart from its primary
purpose of blocking the C1 position, the chlorine sub-
stituent deactivates the electron-rich aromatic A-ring
toward electrophiles and oxidants. Furthermore, it al-
lows the determination of the absolute configuration of
enantiomerically pure (-)-23 by anomalous X-ray disper-
sion.
With gram quantities of racemic and enantiomerically
pure phenanthrenone 23 at hand, the conjugate addition
of functionalized organocuprates was explored. Consid-
ering the results with compounds 6, 12, and 17 (see
above), we felt that only a sophisticated reagent would
undergo the reaction and that some kind of activation
would be mandatory. Indeed, the “(TMS)Cl-accelerated”
vinyl cuprates described by Kuwajima and Nakamura
(H2CdCHMgCl, 5-10% CuBrMe2S, (TMS)Cl did provide
the desired 1,4-adduct 25, which represents the entire
carbon skeleton of morphine, after hydrolysis of the
intermediary silyl enol ether with strong acid (Scheme
8, Table 1). The average yields obtained, however, were
low, and the experiments proved difficult to reproduce
and scale up. Other vinyl cuprates [e.g. (H2CdCH)2CuLi/
(TMS)Cl and (H2CdCH)2Cu(CN)Li/(TMS)Cl] also gave
erratic results. Unpolar byproducts were consistently
observed which were partially destroyed during acidic
workup. The nature of these compounds became appar-
ent when the hydrolysis was conducted under milder
conditions. Brief treatment of the crude material with
tetrabutylammonium fluoride ((TBA)F) in tetrahydrofu-
ran (THF) gave low yields of 25 along with ca. 20% of
the C2 symmetrical dimer 26. Similar results were
obtained with other vinyl cuprates (Table 1, entries 2-4)
and (TBS)Cl (entry 5).
The success of the conjugate addition to the phenan-
threnone was found to be critically dependent on the
substitution pattern of the aromatic ring. Whereas the
“correctly” substituted phenanthrenones 25 and 3216
Since our relevant experiments were carried out with
racemic 23, the pinacols 26 and 27 represent one out of
6 possible diastereomeric dimers in each case. Highly
C2 selective electrochemical pinacol dimerizations of
similar racemic phenanthrenones have been previously
observed by Dana and Esktra.13 Single crystal X-ray
underwent clean conjugate addition of our standard vinyl
cuprate (H2CdCH)2CuMgCl (91 and 85% yields, respec-
tively) to afford 25 and 37,17 respectively, the simpler
(13) Dana, G.; Estera, T. J . Org. Chem. 1979, 44, 1397.

5912 J . Org. Chem., Vol. 63, No. 17, 1998
Trauner et al.
Ta ble 1
chlorosilane
entry
vinyl cuprate
workup
2 N HCl
(TBA)F, THF
(TBA)F, THF
(TBA)F, THF
(TBA)F, THF
H2O/NH4Cl
H2O/NH4Cl
yield of 25 (%)
1
2
3
4
5
6
7
H2CdCHMgCl, 5-20% CuBr-Me2S
H2CdCHMgCl, 10% CuBr-Me2S
(H2CdCH)2CuLi
(H2CdCH)2Cu(CN)Li
(H2CdCH)2Cu(CN)Li
(TMS)Cl
(TMS)Cl
(TMS)Cl
(TMS)Cl
(TBS)Cl
none
5-21
23
11
21
24
73
(H2CdCH)2Cu(CN)Li
(H2CdCH)2CuMgCl
none
91
These results can be explained in terms of the above-
mentioned 1,4-strain between the vinylic hydrogen at C5
and the 4-methoxy substituent of 23 and 32, which is
apparent in the X-ray structure of 23 (Figure 1). This
strain, which does not exist in 33-36, is relieved as the
benzylic carbon is pyramidalized in the transition state
of the reaction. Additionally, the crucial o-methoxy group
might stabilize the hypothetical copper(III) intermediate
(cf. 30) by coordination to the metal.
Once the problem of the quaternary stereocenter had
been overcome, the synthesis progressed quickly. The
conjugate addition not only provided the key quaternary
center but also functionalized the neopentylic position
(C5), which is otherwise difficult to access, as an enolate
or enol ether. In order to achieve the E-ring closure by
nucleophilic attack of the proximate oxygen, some kind
of “umpolung”, transforming the nucleophilic enolate into
an electrophilic species, had to be achieved. This could
be done by trapping it as an R-bromoketone. Attempted
direct bromination of the enolate gave unsatisfactory
results in terms of yield and diastereoselectivity. It was
therefore necessary to use silyl enol ether 31, which was
now prepared by subsequent addition of (TMS)Cl to the
enolate resulting from conjugate addition (Scheme 10).
Racemic 3112 was purified by twofold recrystallization
from n-pentane (84% yield). Bromination of 31 with NBS
in THF at low temperature afforded a 3:1 mixture of the
isomeric R-bromoketones 38a and 38b. This ratio could
not be improved by variation of the reagent, the solvent,
or the temperature. Attempted direct epimerizaton of
38b was unsuccessful as well. However, the undesired
isomer 38b could be recycled by reductive removal of
bromide with zinc and concomitant silylation of the
resultant enolate (Scheme 10).18
F igu r e 2. Crystal structure of dimer 27. Hydrogens are
omitted for clarity.
Sch em e 9
Interestingly, the two epimeric R-bromoktones 38a and
38b adopt two completely different overall conformations,
as shown in Scheme 10.19 These conformations, which
were elucidated by detailed NMR analysis and a single
crystal X-ray structure analysis12 of 38a , can be inter-
(14) For lead references on the mechanism of organocuprate con-
jugate additions, see: (a) Nakamura, E.; Mori, S.; Morokuma, K. J .
Am. Chem. Soc. 1997, 119, 4900. (b) Lipshutz, B. H.; Sengupta, S. Org.
React. 1992, 41, 135. (c) Organocopper Reagents, A Practical Approach;
Taylor, R. K., Ed.; Oxford University Press: Oxford, 1994. For a recent
example of a (TMS)Br mediated cuprate addition to form a quaternary
center, see: (d) Piers, E.; Renaud, J .; Rettig, S. J . Synthesis 1998, 590.
(15) (a) Harding, K. E.; Clement, B. A.; Moreno, L.; Peter-Katalinic,
J . J . Org. Chem. 1981, 46, 940. (b) Wege, P. M.; Clark, R. D.; Heathcock,
C. H. J . Org. Chem. 1976, 41, 3144.
(16) Compound 32 was prepared along similar lines starting from
the corresponding chlorine-free tetralone (Bruce, B. H.; Thomson, R.
F. J . Chem. Soc. 1955, 1089).
(17) Interestingly, 37, underwent spontaneous resolution upon
crystallization.12 Bats, J . W.; Trauner, D. Unpublished results.
(18) (a) Rubottom, G. M.; Mott, R. C.; Krueger, D. S. Synth.
Commun. 1977, 7, 333. (b) J oshi, G. C.; Pande, L. M. Synthesis 1975,
451.
model compounds 33, 34, 35, and 36 which lack the
4-methoxy substituent failed to produce significant
amounts of 1,4-adducts under identical conditions. Com-
pounds 34, 36, and, most notably, enone 33, which is
electronically very similar to 25 and 32, underwent 1,2-
addition exclusively. In the case of 35, the corresponding
1,4-adduct was formed in low yield (14%).
(19) Trauner, D.; Opatz, T.; Porth, S.; Bats. J . W.; Giester, G.;
Mulzer, J . Synthesis 1998, 653.

Enantiomerically Pure Morphine Alkaloids
J . Org. Chem., Vol. 63, No. 17, 1998 5913
Sch em e 10a
Sch em e 11a
a
(a) (i) (H2CdCH)2CuMgCl, THF, -78 °C f 0 °C; (ii) (TMS)Cl,
Et3N, 0 °C f 25 °C. (b) NBS, THF (60% 38a , 21% 38b; two steps).
(c) Zn, (TMS)Cl, TMEDA, Et2O (71%).
preted in terms of the R-haloketone effect.20 In 38a , the
bromine and the aromatic A-ring are axial with respect
to the cyclohexanone chair (C-ring). The other two
substituents adopt equatorial positions. Epimerization
of the bromine triggers inversion of the C-ring chair and
leads to 38b wherein the aromatic substituent is equato-
rial and all other ring substituents axial.
The R-bromoketone in 38a not only provides the
required functionality for the subsequent ring closure but
also forces the carbon skeleton of the molecule into a
morphine-like, L-shaped conformation which ensures a
suitable SN2 trajectory for the intramolecular nucleophilic
attack of the proximate methoxy group. In fact, when
heated in dimethylformamide (DMF) at 140 °C, bromoke-
tone 38a afforded the dihydrobenzofuran derivative 39
within 20 min in virtually quantitative yield (Scheme 11)!
This clean intramolecular transetherification most likely
proceeds through a methoxonium ion.19,21 Bromination
and ring closure could also be performed in one flask.
Thus, treatment of 31 with NBS in DMF at low temper-
ature followed by brief heating of the solution to 140 °C
produced an easily separable 1:2 mixture of 39 and 38b
in excellent overall yield (91%).
a
(a) DMF, 140 ˚C (99%). (b) (TMS)Cl, (CH2OH)2, CH2Cl2 (92%).
(c) (i) BH3.SMe2, THF; (ii) H2O2, OH- (70%). (d) RaNi, MeOH, KOH
(98%). (e) PhSO2NHMe, ADDP, Bu3P (81%). (f) NBS, (PhCOO)2,
CCl4, reflux, Et3N (67%). (g) Li, NH3, THF, t-BuOH, -78 °C (79%).
(h) 3 N HCl, 90 °C (95%).
Sch em e 12a
The next stage of our synthesis involved the introduc-
tion of the nitrogen and the functionalization of C9.
Ketone 39 was protected as ethylene ketal 40 under
Chan’s conditions.22 Hydroboration of the vinyl group
with BH3‚SMe2 followed by oxidation then gave the
primary alcohol 41. At this point, it was time to get rid
of the “dummy” chlorine substituent by catalytic hydro-
genation. The resultant alcohol 42 was directly con-
verted to the benzenesulfonamide 43 using a novel
variant of the Mitsunobu reaction [N-methylbenzene-
sulfonamide, 1,1′-azodicarbonyldipiperidine (ADDP),
Bu3P].23
a
(a) PhSO2Br, H2O, K2CO3 (91%). (b) H2, Pd-CaCO3 (97%). (c)
(TMS)Cl, (CH2OH)2, CH2Cl2 (91%).
Alternatively, the sulfonamide 43 was prepared in only
three steps from (-)-thebaine (Scheme 12). Quaterniza-
tion of the tertiary nitrogen with benzenesulfonyl bro-
mide in aqueous potassium carbonate induced cleavage
of the C9-N bond to afford a good yield of dienone 47.24
Hydrogenation of 47 in the presence of palladium on
calcium carbonate occurred with remarkable stereose-
lectivity, furnishing ketone 48 as a single diastereomer
in excellent yield. Finally, 48 was protected as the
ethylene ketal to give relay compound 43. A third route
to 43 involved a Claisen-Eschenmoser rearrangement
(20) Eliel; E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley-Interscience: New York, 1995; pp 731 ff.
(21) Kawabata, T. K.; Grieco, P. A.; Sham, H. L.; Kim, H.; J aw, J .
Y.; Tu, S. J . Org. Chem. 1987, 52, 3347.
(22) Chan, T. H.; Brook, M. A.; Chaly, T. Synthesis 1983, 203.
(23) Tsuda, T.; Yamamiya, Y.; Itoˆ, S. Tetrahedron Lett. 1993, 34,
1639.
(24) (a) Bertgen, C.; Fleischhacker, W.; Viebo¨ck, F. Chem. Ber. 1967,
100, 3002. (b) Toth, J . E.; Fuchs, P. L. J . Org. Chem. 1986, 51, 2594.

5914 J . Org. Chem., Vol. 63, No. 17, 1998
Trauner et al.
of an allylic alcohol derived from 23 and Lewis-acid
promoted opening of a 5,6-epoxide by the 4-methoxy
group.7b
4-(2-Ch lor o-3,4-dim eth oxyph en yl)bu tyr ic Acid (20).
To a vigorously stirred solution of 4-(3,4-dimethoxyphen-
yl)butyric acid (50.0 g, 224 mmol) in glacial acetic acid
(150 mL) at 10 °C was added dropwise chlorine (19.0 g,
268 mmol) in acetic acid (200 mL) within 1 h. After being
stirred 1 h further, the solution was heated to reflux for
10 min, cooled, diluted with ice water (300 mL), and
extracted with methylene chloride (7 × 100 mL). The
combined organic phases were dried (MgSO4) and evapo-
rated in vacuo to afford the chloro acid 20 (58.3 g, 224
mmol, >99%) as colorless crystals (mp 112 °C).
With ready access to 43, we investigated the introduc-
tion of a ∆9,10 double bond by benzylic radical bromination
and ensuing dehydrobromination. Exposure of 43 to 1
equiv of NBS and a catalytic amount of dibenzoyl
peroxide in refluxing carbon tetrachloride, afforded the
“morphimethine” 44 in 67% yield (Scheme 11). On the
basis of recovered starting material, the overall yield was
81%. Although the dehydrobromination occurred spon-
taneously on prolonged heating, the yields were usually
better if triethylamine was added after 10-15 min.
The stage was now set for the final heterocyclization
and the completion of the synthesis. Treatment of
styrene 44 under the conditions of Parker and Focas (Li,
THF/NH3) cleanly effected the desired heterocyclization
and afforded dihydrocodeinone ethyleneketal (45)12 in
good yield. Hydrolysis of 45 with aqueous hydrogen
chloride at 90 °C afforded an excellent yield of (-)-
dihydrocodeinone (46), which was identical with an
1H-NMR (250 MHz, CDCl3): δ ) 1.95 (m, 2H), 2.45 (t,
2H, J ) 7.1 Hz), 2.72 (t, 2H, J ) 7.0 Hz), 3.83 (s, 3H),
3.86 (s, 3H), 6.67 (s, 1H), 6.85 (s, 1H 11.10 (s br, 1H).
13C-NMR (63 MHz, CDCl3): δ 24.9, 32.3, 33.2, 56.1 (2C),
112.7, 113.1, 124.7, 130.6, 147.8, 147.9, 179.5. MS (EI,
70 eV, 200 °C): m/ z 260 (M
•+, 22), 260 (70), 198 (23),
187 (34), 185 (100). IR (KBr, cm-1): ν˜ ) 2966, 1703,
1507, 1382, 1278, 1164. Anal. Calcd for C12H15ClO4 (Mr
) 258.701 g‚mol-1): C, 55.71; H, 5.84. Found: C, 55.58;
H, 5.87.
1
authentic sample according to the H-, 13C-NMR, IR, MS
5-Ch lor o-7,8-d im et h oxy-3,4-d ih yd r on a p h t h a lin -
1(2H)-on e (21). Oxalyl chloride (36.5 mL, 425 mmol)
was added to a solution of 20 (50 g, 193 mmol) in
refluxing anhydrous benzene (500 mL). After the vigor-
ous evolution of gases ceased, the solution was stirred
for 2 h at 50 °C and then cooled to 0 °C. Stannic chloride
(80 mL, 680 mmol) was added, and the mixture was
stirred at 0 °C for another 36 h. The reaction was
quenched by careful addition of concentrated hydrochloric
acid (100 mL), followed by ether (250 mL) and ice water
(100 mL). The organic phase was washed with diluted
hydrochloric acid (2 N, 100 mL), saturated aqueous
NaHCO3 (100 mL), and brine (100 mL), dried (MgSO4),
and concentrated in vacuo. Purification of the residue
by flash chromatography (silica gel, hexanes:EtOAc )
7:1) afforded 21 (33.0 g, 137 mmol, 71%) as yellow
crystals (mp 77-78 °C).
spectra, DC, [R]2D0, and mp.
Dihydrocodeinone is a well-known precursor of codeine
and morphine and has served as a relay in several
previous formal syntheses of morphine and other opium
alkaloids. Its conversion to codeine and morphine, first
reported by Gates, has been reinvestigated and optimized
by Rice and Rapoport.25 Unfortunately, all our attempts
to perform this transformation independently via Pd(0)
mediated Saegusa oxidation of the known dihydroco-
deinone silyl enol ether26 were unsuccessful. The failure
of this reaction may be attributed to the well-known
competing oxidation of the tertiary amine followed by
polymerization.27
Con clu sion
Our synthesis requires only 13 isolated intermediatess
all of which are crystallinesfrom commercially available
4-(3,4-dimethoxyphenyl)butyric acid (19) to (-)-dihydro-
codeinone, (46; total yield, 11.5%). The stereochemical
course of all additions is efficiently controlled by the
growing ring template in the sequence of ring closures A
f AB f ABC f ABCE f ABCDE. The reagents and
building blocks employed are inexpensive and readily
available. In the end, the carbons and heteroatoms of
morphine are derived from veratrol, succinic anhydride,
vinyl magnesium chloride, methyl vinyl ketone, and
methylamine. The use of protecting groups is confined
to the ethylene ketal. Undesired isomers [(+)-23, 24,
38b] are recycled. Therefore, the synthesis shows a high
degree of atom economy and efficiency. As the resolution
is performed at the earliest stage possible and the
undesired enantiomer can be racemized, it shows chiral
economy as well. Both enantiomers and the racemate
are accessible equally well.
Rf ) 0.30 (hexanes:EtOAc ) 4:1). 1H-NMR (250 MHz,
CDCl3): δ 2.04 (mc, 2H), 2.58 (mc, 2H), 2.82 (t, 2H, J )
7.5 Hz), 3.78 (2s, 6H) 7.08 (s, 1H). 13C-NMR (63 MHz,
CDCl3): δ 22.1, 27.0, 40.1, 56.2, 61.3, 117.6, 127.9, 128.3,
133.6, 148.5, 152.2, 196.8. MS (EI, 70 eV, 120 °C): m/ z
242 (61), 241 (61), 240 (M•+, 100), 211 (41), 169 (32), 155
(24). IR (KBr; cm-1): ν˜ 2943, 2862, 1694, 1582, 1480,
1426, 1349, 1266, 1029. Anal. Calcd for C12H13ClO3 (Mr
) 240.69 g‚mol-1): C, 59.88; H, 5.44. Found: C, 59.82;
H, 5.35.
5-Ch lor o-7,8-d im et h oxy-2-(h yd r oxym et h ylen e)-
3,4-d ih yd r on a p h th a lin -1(2H)-on e (22). Methyl for-
mate (10.3 mL, 165 mmol) in anhydrous ether (40 mL)
was added to a suspension of sodium methoxide (6.70 g,
123 mmol) in anhydrous benzene (125 mL). After stir-
ring for 30 min, tetralone 21 (19.8 g, 82.3 mmol) was
added in one portion. The mixture was heated to reflux
for 3 h, cooled, and stirred for another 12 h at room
temperature. Ice cold water was added to the mixture
to dissolve the precipitated sodium salt. The organic
phase was separated and extracted with aqueous 5%
KOH (3 × 100 mL). The combined alkaline phases were
washed with ether (100 mL) and acidified (pH 3) with
cold 2 M HCl. The resulting mixture was extracted with
methylene chloride (5 × 200 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo to
afford pure 22 (21.5 g, 80.0 mmol, 97%) as light brown
solid (mp 100-102 °C).
Exp er im en ta l Section
Gen er a l Meth od s. See Supporting Information.
(25) (a) Gates, M.; Tschudi, G. J . Am. Chem. Soc. 1956, 78, 1380.
(b) Ijima, I.; Minamikawa, J .; J acobson, A. E.; Brossi, A.; Rice, K. C.
J . Org. Chem. 1978, 43, 1463. (c) Rice, K. C. J . Org. Chem. 1980, 45,
3135. (d) Weller, D. D.; Rapoport, H. J . Med. Chem. 1976, 19, 1173.
(26) Gao, P.; Portoghese, P. S. J . Org. Chem. 1995, 60, 2276.
(27) For
a successful Saegusa oxidation in the presence of a
bridgehead tertiary amine, see: J in, J .; Weinreb, S. M. J . Am. Chem.
Soc. 1997, 119, 2050.

Enantiomerically Pure Morphine Alkaloids
J . Org. Chem., Vol. 63, No. 17, 1998 5915
Rf ) 0.57 (hexanes:EtOAc ) 1:2). 1H-NMR (250 MHz,
CDCl3): δ 2.42-2.47 (m, 2H), 2.83-2.88 (m, 2H), 3.88
(s, 3H), 3.93 (s, 3H), 7.05 (s, 1H), 8.60 (s br, 1H), 13.89 (s
br, 1H). 13C-NMR (63 MHz, CDCl3): δ 15.14, 20.9 (br),
25.6, 56.2, 70.3, 110.7, 116.3, 125.8, 127.5, 130.9, 146.5,
152.0, 180.3 (br). MS (EI, 70 eV, 200 °C): m/ z 271 (16),
270 (34), 269 (M•+, 55), 268 (100), 89 (33). IR (KBr; cm-1):
ν˜ ) 3198, 2967, 1628, 1445, 1316, 1262, 1195, 1083.
Anal. Calcd for C13H13ClO4 (Mr ) 268.696 g‚mol-1): C,
58.11; H, 4.88. Found: C, 58.06; H, 4.85.
(EI, 70 eV, 120 °C): m/ z 292 (M•+, 100), 277 (5), 250 (7),
235 (23). IR (KBr; cm-1): ν˜ ) 2913, 2829, 1702, 1584,
1467, 1426, 1248, 1117, 1093. Anal. Calcd C16H17ClO3
(Mr ) 292.762 g‚mol-1): C, 65.64; H, 5.85. Found: C,
65.61; H, 5.82.
4a (R),10a (R)-8-Ch lor o-5,6-d im eth oxy-4a -eth en yl-
1,4,4a ,9,10,10a -h exa h yd r op h en a n t h r en -3(2H )-on e
(25). Vinylmagnesium chloride (1.6 M in THF, 25 mL,
40 mmol) was added to a suspension of CuI (3.81 g, 20
mmol) in THF (100 mL) at -78 °C. The mixture was
briefly warmed to -10 °C until it became almost homo-
geneous and became brown in color. It was then rapidly
cooled to -78 °C. Enone 23 (2.93 g, 10 mmol) in THF
(50 mL) was added dropwise at -78 °C. The mixture
was warmed to room temperature within 1 h, diluted
with hexanes (100 mL), and then quenched with satu-
rated aqueous NH4Cl/25% aqueous NH3 (9:1, 10 mL).
After filtration through a pad of Celite, the organic layer
was washed with saturated aqueous NH4Cl/25% aqueous
NH3 (9:1, 2 × 50 mL) and brine (50 mL), dried (MgSO4),
and evaporated in vacuo. The crude, crystalline product
was purified by column chromatography (silica gel,
hexanes:EtOAc ) 10:1) to afford ketone 25 (2.91 g, 9.1
mmol, 91%) as colorless crystals (mp: 140-142 °C
(racemic); 142 °C (enantiomerically pure).
Rf ) 0.22 (hexanes:EtOAc ) 10:1). 1H-NMR (270 MHz,
CDCl3): δ 1.74-2.04 (m, 4H), 2.16-2.31 (m, 2H), 2.39
(mc, 1H), 2.53 (d, 1H, J ) 15.2 Hz), 2.70 (mc, 1H), 3.02
(ddd, 1H, J ) 3.1 Hz, 5.1 Hz, 17.2 Hz), 3.22 (d, 1H, J )
15.2 Hz), 3.71 (s, 3H), 3.79 (s, 3H), 4.94 (d, 1H, J ) 17.6
Hz), 5.15 (d, 1H, J ) 10.8 Hz), 5.91 (dd, 1H, J ) 10.8 Hz.
17.6 Hz), 6.88 (s, 1H). 13C-NMR (63 MHz, CDCl3): δ
24.0, 27.2, 27.9, 37.3, 39.3, 46.5, 48.3, 55.8, 60.2, 112.5,
113.3, 126.5, 128.1, 137.2, 146.2, 146.8, 151.4, 211.1. MS
(EI, 70 eV, 120 °C): m/ z 321 (22), 320 (M+•, 100), 237
(23), 55 (42). IR (KBr; cm-1): ν˜ 2937, 1710, 1585, 1471,
1426, 1294. [R]2D0 ) + 37.7° (c ) 2, CHCl3). Anal. Calcd
for C18H21ClO3 (Mr ) 320.816 g‚mol-1) C, 67.39; H, 6.60.
Found: C, 67.47; H, 6.58.
10a (R)-8-Ch lor o-5,6-d im eth oxy-1,9,10,10a -tetr a h y-
d r op h en a n th r en -3(2H)-on e (23) a n d 8-Ch lor o-5,6-
d i m e t h o x y -1,4,9,10-t e t r a h y d r o -3(2H )-p h e n a n -
th r en on e (24). To a vigorously stirred solution of 22
(49 g, 182 mmol) in anhydrous methanol (700 mL) was
added dropwise at 0 °C anhydrous Et3N (50 mL, 364
mmol), followed by MVK (17.9 mL, 218 mmol). After
stirring at room temperature for 2 days, additional MVK
(1.5 mL, 18 mmol) was added. After 3 days the solution
was neutralized with acetic acid (21 mL, 370 mmol). The
solvent was evaporated in vacuo, and the resulting solid
was dissolved in methylene chloride (1000 mL) and
washed with H2O (5 × 100 mL). The organic phase was
evaporated in vacuo, and the resulting material was
redissolved in a mixture of dioxane (400 mL) and a
solution of KOH (33.6 g, 728 mmol) in H2O (400 mL).
After 3 h stirring at room temperature, the resulting
suspension was diluted with H2O (1000 mL), saturated
with NaCl, and extracted with CH2Cl2 (7 × 200 mL). The
organic layer was dried (MgSO4) and concentrated to give
the crude mixture of products. Purification by chroma-
tography (silica gel, hexanes:EtOAc ) 10:1 f 5:1) af-
forded 24 (4.47 g, 15.3 mmol; 8.3%) and racemic 23 (43.3
g, 148 mmol; 81.2%) as colorless crystals.
MP LC Resolu tion . A 1 g amount of racemic 23 was
dissolved in EtOH:H20 (96:4, 40 mL) and separated on
swollen microcrystalline cellulose triacetate (Merck).
Separation was effected by a single run through a 63 ×
660 mm column thermostated at 40 °C, eluting with
EtOH:H20 (96:4). Fraction 1: k1′ ) 0.77; ee > 99%.
Fraction 2: k2′ ) 1.29; ee > 96 %. Enantioselectivity R
) 1.68. Resolution Rs ) 1.15 was calculated using the
tangent method. Throughput was 2 g per day with 95%
recovery.
4a (R),10a (R)-8-Ch lor o-5,6-d im eth oxy-4a -eth en yl-
3-(t r im e t h ylsilyloxy)-1,2,4a ,9,10,10a -h e xa h yd r o-
p h en a n th r en e (31). Vinylmagnesium chloride (1.6 M
in THF, 25 mL, 40 mmol) was added to a suspension of
CuI (3.81 g, 20 mmol) in THF (100 mL) at -78 °C. The
mixture was briefly warmed to -10 °C until it became
almost homogenous and became dark brown in color. It
was then rapidly cooled to -78 °C. Enone 23 (2.93 g, 10
mmol) in THF (50 mL) was added dropwise at -78 °C,
and the reaction mixture was allowed to warm to 0 °C
within 3 h. (TMS)Cl (50 mmol, 6.34 mL) was added,
followed by Et3N (60 mmol, 8.36 mL). The mixture was
warmed to room temperature, stirred for 1 additional
hour, diluted with hexanes (100 mL), and then quenched
with saturated aqueous NH4Cl/25% aqueous NH3 (9:1,
10 mL). After filtration through a pad of Celite, the
organic layer was washed with saturated aqueous NH4Cl/
25% aqueous NH3 (9:1, 2 × 50 mL) and brine (50 mL),
dried (MgSO4), and evaporated in vacuo. The crystalline
crude product (4.58 g) was recrystallized from n-pentane
(100 mL) to yield pure 31 as large colorless crystals (3.033
g, 77.2 mmol, 77%). A second recrystallization afforded
additional 269 mg of 31 (total yield: 8.42 mmol, 84 %).
The enantiomerically pure material remained an oil and
could neither be purified by recrystallization nor by
chromatography (mp 99-100 °C (racemic)).
Com p ou n d 23. Mp: 101-103 °C (racemic); 113-115
°C (enantiomerically pure). Rf ) 0.10 (hexanes:EtOAc
) 10:1). 1H-NMR (270 MHz, CDCl3): δ 1.73 (mc, 1H),
1.83 (dddd, 1H, J ) 5.9 Hz, 10.0 Hz, 11.9 Hz, 13.2 Hz),
2.03 (mc, 1H), 2.24 (mc, 1H), 2.40-2.62 (m, 3H), 2.72-
2.84 (m, 1H), 2.92 (ddd, 1H, J ) 4.3 Hz, 5.5 Hz, 17.1 Hz),
3.74 (s, 3H), 3.86 (s, 3H), 6.99 (s, 1H), 7.16 (d, 1H, J )
2.1 Hz). 13C-NMR (63 MHz, CDCl3): δ 27.0, 29.5, 29.7,
36.1, 36.5, 56.2, 60.1, 114.8, 127.6, 128.4, 128.5, 129.7,
147.8, 151.7, 154.5, 200.7. MS (EI, 70 eV, 120 °C): m/ z
292 (M•+, 100), 264 (51), 249 (43), 233 (19), 115 (28). IR
(KBr; cm-1): ν˜ ) 2938, 1656, 1471, 1450, 1423, 1296,
1255. [R]20) -245.1° (c ) 2, CHCl3). Anal. Calcd for
D
C16H17ClO (Mr ) 292.762 g‚mol-1): C, 65.64; H, 5.85.
Found: C, 65.44; H, 5.69.
Com p ou n d 24. Mp: 107-109 °C. Rf ) 0.11 (hexanes:
EtOAc ) 10:1). 1H-NMR (270 MHz, CDCl3): δ 2.16 (t,
2H, J ) 5.0 Hz), 2.56-2.78 (m, 6H), 3.53 (s, 2H), 3.75 (s,
3H), 3.86 (s, 3H), 6.81 (s, 1H). 13C-NMR (63 MHz,
CDCl3): δ 25.2, 28.1, 31.2, 37.9, 42.8, 55.8, 60.7, 111.4,
124.5, 126.7, 127.3, 129.8, 136.1, 144.8, 151.9, 210.6. MS

5916 J . Org. Chem., Vol. 63, No. 17, 1998
Trauner et al.
Rf ) 0.10 (hexanes). 1H-NMR (250 MHz, CDCl3): δ
0.16 (s, 9H), 1.45-2.13 (m, 7H), 2.57 (ddd, 1H, J ) 3.0,
9.1, 17.0 Hz), 2.84 (dt, 1H, J ) 5.5, 17.0 Hz), 3.71 (s, 3H),
3.79 (s, 3H), 4.92 (dd, 1H, J ) 1.4, 17.1 Hz), 5.10 (dd,
1H, J ) 1.4, 10.2 Hz), 5.14 (s, 1H), 5.80 (dd, 1H, J ) 10.2,
17.1 Hz), 6.85 (s, 1H). 13C-NMR (63 MHz, CDCl3): δ
-4.9, 18.5, 18.6, 21.6, 21.7, 32.6, 41.8, 50.7, 55.0, 104.2,
107.0, 107.5, 122.2, 122.7, 132.3, 142.5, 142.7, 144.8,
146.1. MS (EI, 70 eV, 30 °C): m/ z 394 (18), 392 (M+•,
54), 377 (60), 365 (61), 363 (72), 361 (100), 73 (80). IR
(KBr; cm-1): ν˜ 2931, 2864, 1652, 1631, 1591, 1468, 1251,
1206. HRMS. Calcd for C21H29ClO3Si (Mr ) 392.997 g‚
mol-1): 392.1575. Found: 392.1575 ( 0.002.
4(S),4a(S),10a(S)-4-Br om o-5,6-dim eth oxy-10a-ethen -
yl-1,4,4a ,9,10,10a -h exa h yd r op h en a n th r en -3(2H)-on e
(38a ) a n d 4(R),4a (S),10a (S)-4-Br om o-5,6-d im eth oxy-
10a -eth en yl-1,4,4a ,9,10,10a -h exa h yd r op h en a n th r en -
3(2H)-on e (38b). NBS (2.14 g, 12 mmol) was added in
one portion at -78 °C to a solution of crude enantiomeri-
cally pure silyl enol ether 31 (4.9 g), which was prepared
from 23 (2.93 g, 10 mmol) as described above, in anhy-
drous THF (100 mL). The mixture was allowed to warm
to room temperature within 4 h. After addition of
saturated NaHCO3 solution (50 mL), the resulting mix-
ture was thoroughly extracted with Et2O. The combined
organic layers were washed with saturated NaHCO3
solution and brine, dried (MgSO4), and evaporated in
vacuo. Purification of the residue by silica gel chroma-
tography, eluting with hexanes/ethyl acetate (10:1) fol-
lowed by HPLC [Macherey-Nagel Nucleosil 50-10 (250 ×
20), n-hexane:MeOAc ) 10:0.5, 2 mL‚min-1] provided
enantiomerically pure bromoketones 38a (2.36 g, 6.0
mmol, 60%) and 38b (0.84 g, 2.1 mmol, 21%) as pale
brown crystals and colorless oil, respectively.
C18H20BrClO3 (Mr ) 399.712 g‚mol-1): C, 54.09; H, 5.04.
Found: C, 54.30; H, 5.19.
1,3a (R),8,9,9a (R),9b (S)-H exa h yd r o-9b -et h en yl-5-
m eth oxy[4,4a ,4b,5-bcd ]fu r a n -3(2H)-on e (39). A solu-
tion of 38a (3.99 g, 10 mmol) in anhydrous DMF (50 ml)
was heated to 140 °C for 20 min. After cooling to room
temperature, the solvent was removed in vacuo. The
crystalline crude product was purified by chromatogra-
phy on silica gel, eluting with hexanes/ethyl acetate (1:
1), to afford dihydrofuran 39 (2.99 g, 9.8 mmol, 98%) as
colorless crystals. (Mp: 147-148 °C (racemic); 178-179
°C (enantiomerically pure)).
Rf ) 0.25 (hexanes:EtOAc ) 3:1). 1H-NMR (250 MHz,
CDCl3): δ 1.29 (dq, 1H, J ) 4.9 Hz, 12.6 Hz), 1.70-2.20
(m, 3H), 2.23-2.45 (m, 4H), 2.61 (ddd, 1H, J ) 0.9 Hz,
7.3 Hz, 18.0 Hz), 3.82 (s, 3H), 4.52 (dd, 1H, J ) 0.7 Hz,
17.0 Hz), 4.71 (s, 1H), 5.14 (dd, 1H, J ) 0.7 Hz, 10.2 Hz),
5.97 (dd, 1H, J )10.2 Hz, 17.0 Hz), 6.71 (s, 1H). 13C-
NMR (63 MHz, CDCl3): δ 19.9, 22.9, 26.5, 36.1, 39.4,
55.2, 56.6, 91.7, 114.7, 117.1, 123.9, 125.0, 126.8, 141.8,
142.9, 145.6, 206.5. MS (EI, 70 eV, 30 °C): m/ z 306 (57),
304 (M+•, 99), 244 (87), 174 (76), 69 (100). IR (Si; cm-1):
ν˜ 2938, 1729, 1631, 1491, 1436, 1186, 1147, 1096, 1037.
[R]2D0 ) -35.7° (c ) 2, CHCl3). Anal. Calcd for C17H17
-
ClO3 (Mr ) 304.773 g‚mol-1): C, 67.00; H, 5.62. Found:
C, 66.92; H, 5.55.
1,2,3,3a (R),8,9,9a (S),9b(S)-Octa h yd r o-7-ch lor o-9b-
et h en yl-5-m et h oxy-3-(et h ylen ed ioxy)p h en a n t h r o-
[4,4a ,4b ,5-bcd ]fu r a n (40). To a vigorously stirred
biphasic mixture of anhydrous CH2Cl2 (20 mL) and
ethylene glycol (20 mL) was added 39 (790 mg, 2.59
mmol) and (TMS)Cl (1.5 mL, 12 mmol). After stirring
for 18 h at room temperature, saturated aqueous NaH-
CO3 (50 mL) was added, and the mixture was thoroughly
extracted with CH2Cl2 (5 × 30 mL). The combined
organic layers were dried (MgSO4) and concentrated in
vacuo. Purification of the resulting residue by chroma-
tography (silica gel, hexanes:EtOAc ) 10:1) gave diox-
olane 40 (831 mg, 2.4 mmol, 92%) as colorless crystals
(mp: 121-123 °C (racemic); 94-95 °C (enantiomerically
pure)). 1H-NMR (250 MHz, CDCl3): δ 1.30 (mc, 1H),
1.49-1.78 (m, 4H), 1.95-2.10 (m, 2H), 2.38 (mc, 1H), 2.66
(mc, 1H), 3.55-3.99 (m, 3H), 3.85 (s, 3H), 4.17 (mc, 1H),
4.53 (dd, 1H, J ) 1.0, 17.0 Hz), 4.57 (s, 1H), 5.13 (dd,
1H, J ) 0.9, 10.2 Hz), 5.88 (dd, 1H, J ) 10.2, 17.0 Hz),
6.80 (s, 1H). 13C-NMR (63 MHz, CDCl3): δ 20.2, 22.8,
23.3, 33.1, 35.8, 51.3, 56.6, 64.8, 66.3, 94.7, 107.9, 113.9,
116.2, 123.7, 124.2, 128.83 142.2, 143.8, 146.8. MS (EI,
70 eV, 40 °C): m/ z 350 (33), 348 (M+•, 72), 112 (38), 99
(100). IR (Si; cm-1): ν˜ 2936, 1630, 1489, 1436, 1286,
1190, 1070. [R]2D0 ) -44.2° (c ) 1, CHCl3). Anal. Calcd
for C19H21ClO4 (Mr ) 348.826 g‚mol-1): C, 65.42; H, 6.07.
Found: C, 65.44; H, 6.20.
Ma jor Isom er 38a . Mp: 102-104 °C (racemic); 102-
104 °C (enantiomerically pure). Rf ) 0.65 (hexanes:
EtOAc ) 10:1). 1H-NMR (270 MHz, CDCl3): δ 1.64-1.82
(m, 2H), 1.94-2.16 (m, 3H), 2.61-2.75 (m, 3H), 3.14 (ddd,
1H, J ) 6.6 Hz, 10.7 Hz, 10.8 Hz), 3.80 (s, 3H), 3.81 (s,
3H), 4.47 (dd, 1H, J ) 1.1 Hz, 17.2 Hz), 5.21 (dd, 1H, J
) 1.1 Hz, 10.5 Hz), 5.87 (s, 1H), 6.34 (dd, 1H, J ) 10.5
Hz, 17.2 Hz), 6.93 (s, 1H). 13C-NMR (68 MHz, CDCl3):
δ 22.6, 23.8, 24.9, 32.2, 34.6, 50.9, 55.9, 57.8, 60.3, 113.8,
116.8, 127.8, 128.7, 128.8, 142.2, 147.9, 151.3, 203.5. MS
(EI, 70 eV, 60 °C): m/ z 400 (M•+, 100), 398 (73), 320 (46),
319 (46), 304 (47), 228 (30), 165 (26), 149 (23), 115 (36).
IR (Si; cm-1): ν˜ 2941, 1718, 1587, 1465, 1424, 1292, 1214,
1063, 912. [R]2D0 ) -1.2° (c ) 2, CHCl3), [R]20 +33.7° (c
436
) 2, CHCl3). Anal. Calcd for C18H20BrClO3 (Mr
)
399.712 g‚mol-1): C, 54.09; H, 5.04. Found: C, 54.11;
H, 5.01.
Min or Isom er 38b . Mp: 63-68 °C (racemic, oil if
enantiomerically pure). Rf ) 0.58 (hexanes:EtOAc ) 10:
1). 1H-NMR (250 MHz, CDCl3): δ 1.72-1.99 (m, 3H),
2.17-2.33 (m, 2H), 2.62-2.88 (m, 2H), 3.05-3.315 (m,
2H), 3.77 (s, 3H), 3.82 (s, 3H), 4.92 (d, 1H, J ) 17.8 Hz),
5.16 (d, 1H, J ) 11.0 Hz), 5.24 (s, 1H), 5.96 (dd, 1H, J )
11.0, 17.8 Hz), 6.95 (s, 1H). 13C-NMR (63 MHz, CDCl3):
δ 24.1, 27.3, 27.7, 32.1, 39.9, 50.5, 54.6, 55.8, 60.2, 113.2,
113.5, 127.6, 128.0, 135.0, 144.8, 146.4, 150.7, 205.0. MS
(EI, 80 eV, 60 °C): m/ z 400 (M•+, 100), 398 (77), 320 (38),
263 (65), 228 (30), 165 (27), 149 (29), 115 (31). IR (Si;
cm-1): ν˜ 2941, 1718, 1587, 1465, 1424, 1292, 1214, 1063,
1044. [R]2D0 ) -93.9° (c ) 2, CHCl3). Anal. Calcd for
1,2,3,3a (R),8,9,9a (R),9b (S)-Oct a h yd r o-7-ch lor o-5-
m e t h oxy-9b -(2-h yd r oxye t h yl)-3-(e t h yle n e d ioxy)-
p h en a n th r o[4,4a ,4b,5-bcd ]fu r a n (41). BH3‚SMe2 (2 M
THF, 6.25 mL, 12.5 mmol) was added dropwise to a
solution of 40 (888 mg, 2.5 mmol) in anhydrous THF (20
mL) at -15 °C. The mixture was warmed to room
temperature within 3 h and stirred at this temperature
for a further 18 h. Water (3 mL), NaOH (3 N, 6 mL)
and 30% aqueous H2O2 H2O2 (6 mL) were carefully added,
and the mixture was stirred at room temperature for 20
h. Subsequently, 10% aqueous Na2S2O3 (20 mL) was
added, and the mixture was stirred for 30 min. The

Enantiomerically Pure Morphine Alkaloids
J . Org. Chem., Vol. 63, No. 17, 1998 5917
organic phase was separated, and the aqueous phase was
extracted with ethyl acetate (5 × 10 mL). The combined
organic phases were washed with brine (2 × 25 mL),
dried, and evaporated in vacuo. Purification of the
residue by chromatography (silica gel, hexanes:EtOAc )
5:1 f 3:1) afforded 41 (714 mg, 78%) as colorless crystals
(mp: 149-150 °C (racemic); 103 °C (enantiomerically
pure)). Rf ) 0.14 (hexanes:EtOAc ) 5:1). 1H-NMR (250
MHz, CDCl3): δ 1.18-1.34 (m, 1H), 1.44- 1.68 (m, 3H),
1.75-1.98 (m, 4H), 2.04-2.22 (m, 2H), 2.42 (mc, 1H), 2.70
(mc, 1H), 3.61-3.96 (m, 5H), 3.84 (s, 3H), 4.15 (mc, 1H),
4.78 (s, 1H), 6.77 (s, 1H). 13C-NMR (63 MHz, CDCl3): δ
20.0, 23.4 (2C), 32.9, 34.8, 42.1, 46.5, 56.5, 59.3, 64.7,
66.23, 94.5, 108.1, 113.6, 123.3, 124.1, 131.4, 142.2, 146.1.
MS (EI, 70 eV, 110 °C): m/ z 368 (14), 366 (M+•, 48), 321
(34), 112 (22), 99 (100). IR (Si; cm-1) 3460, 2939, 1631,
1489, 1437, 1287, 1190, 1150, 1065. [R]2D0 ) -62.5° (c )
1, CHCl3). Anal. Calcd for C19H23ClO5 (Mr ) 366.841
g‚mol-1): C 62.21; H, 6.32. Found: C, 62.41; H, 6.35.
1,2,3,3a (R),8,9,9a (R),9b(S)-Octa h yd r o-5-m eth oxy-
9b-(2-h yd r oxyeth yl)-3-(eth ylen ed ioxy)p h en a n th r o-
[4,4a ,4b,5-bcd ]fu r a n (42). A suspension of Raney nickel
(1 g) in methanol (25 mL) was thoroughly saturated with
H2. Potassium hydroxide (164 mg, 3 mmol) was added,
followed by 41 (125 mg, 0.34 mmol). The mixture was
stirred under a hydrogen atmosphere at room tempera-
ture for 5 h. Ammonium chloride (500 mg) was added,
and the resulting mixture was filtered through a pad of
Celite and concentrated in vacuo. The residue was taken
up in H2O/CH2Cl2 and extracted with CH2Cl2 (3 × 20
mL). The combined organic phases were dried (MgSO4)
and concentrated under reduced pressure to produce the
alcohol 42 (111 mg, 33 mmol, 98%) as colorless crystals
(mp: 115 °C (racemic); 113-114 °C (enantiomerically
pure)). Rf ) 0.14 (hexanes:EtOAc ) 5:1). 1H-NMR (250
MHz, CDCl3): δ 1.21-2.24 (m, 10H), 2.47-2.74 (m, 2H),
3.56-3.99 (m, 5H), 3.85 (s, 3H), 4.17 (mc, 1H), 4.74 (s,
1H), 6.61 (d, 1H, J ) 8.2 Hz), 6.74 (d, 1H, J ) 8.2 Hz).
13C-NMR (63 MHz, CDCl3): δ 21.0, 23.5, 23.8, 32.9, 35.2,
42.5, 46.1, 56.5, 59.5, 64.7, 66.2, 94.3, 108.3, 113.6, 120.2,
125.3, 130.1, 141.8, 147.2. MS (EI, 70 eV, 120 °C): m/ z
332 (M+•, 80), 287 (76), 260 (61), 199 (62), 99 (100), 55
(97). IR (KBr; cm-1): 3440, 2941, 1607, 1503, 1440, 1275,
1189, 1059. [R]2D0 ) -60.8° (c ) 1, CHCl3). Anal. Calcd
for C19H24O5 (Mr ) 332.396 g‚mol-1): C, 68.66; H, 7.28.
Found: C, 68.81; H, 7.11.
NMR (400 MHz, CDCl3): δ 1.29 (mc, 1H), 1.46-1.53 (m,
2H), 1.61 (mc, 1H), 1.70-1.82 (m, 2H), 1.90 (ddd, 1H, J
) 5.2, 10.3, 15.1 Hz), 2.03-2.16 (m, 2H), 2.54 (mc, 1H),
2.68 (mc, 1H), 2.70 (s, 3H), 2.88 (ddd, 1H, J ) 5.2, 10.5,
15.7 Hz), 3.34 (ddd, 1H, J ) 5.6, 10.5, 16.1 Hz), 3.75 (mc,
1H), 3.84 (mc, 1H), 3.85 (s, 3H), 3.94 (mc, 1H), 4.17 (mc,
1H), 4.59 (s, 1H), 6.60 (d, 1H, J ) 8.2 Hz), 6.74 (d, 1H, J
) 8.2 Hz), 7.48-7.58 (m, 3H), 7.72-7.74 (m, 2H). 13C-
NMR (63 MHz, CDCl3): δ 21.1, 23.6, 23.9, 32.9, 34.5,
34.9, 37.0, 46.2, 46.5, 56.7, 64.9, 66.4, 93.4, 108.3, 113.9,
120.3, 125.4, 127.3, 129.0, 129.9, 132.5, 137.7, 141.9,
147.1. MS (EI, 80 eV, 120 °C): m/ z 485 (M•+, 53), 287
(100), 99 (99), 84 (30). IR (Si; cm-1): ν˜ 2946, 1503, 1445,
1337, 1274, 1190, 1162, 1092, 1057. [R]2D0 ) -15.0° (c )
1, CHCl3). Anal. Calcd for C26H31NO6S (Mr ) 485.601
g‚mol-1): C, 64.31; H, 6.43; N, 2.88. Found: C, 64.33;
H, 6.48; N, 3.01.
1,2,3,3a (R),9a (R),9b(S)-Hexa h yd r o-5-m eth oxy-9b-
[2-[N -m e t h yl-N -(p h e n ylsu lfon yl)a m in o]e t h yl]-3-
(eth ylen edioxy)ph en an th r o[4,4a,4b,5-bcd]fu r an (44).
A solution of 43 (486 mg, 1 mmol), NBS (187 mg, 1.05
mmol) and a catalytic amount of benzoyl peroxide (5 mg,
0.02 mmol, recrystallized from chloroform/methanol) in
anhydrous CCl4 (150 mL) was kept at reflux for 30 min.
Subsequently, Et3N (10 mL) was added, and the mixture
was refluxed for 10 more minutes. After cooling to room
temperature, the reaction mixture was washed with
saturated aqueous NaHCO3 (2 × 50 mL) and saturated
aqueous Na2S2O3 (50 mL). The organic phase was dried
(MgSO4) and concentrated in vacuo. The residue was
purified by HPLC [Macherey-Nagel Nucleosil 50-10 (250
× 20), n-hexane:MeOAc ) 10:4, 10 mL‚min-1; Merck Si-
60, n-hexane:MeOAc ) 10:4, 2 mL‚min-1] to afford the
starting sulfonamide 43 (102 mg, 0.21 mmol, 21%) and
styrene 44 (324 mg, 0.67 mmol, 67%, 85% based on
recovered starting material) as colorless crystals (mp:
115-117 °C (enantiomerically pure)). 1H-NMR (400
MHz, CDCl3): δ 1.24 (dq, 1H, J ) 2.7, 12.8 Hz), 1.38-
1.62 (m, 2H), 1.66-1.93 (m, 3H), 2.43 (mc, 1H), 2.62 (s,
3H), 2.86 (ddd, 1H, J ) 5.4, 10.7, 16.0 Hz), 3.18 (ddd,
1H, J ) 5.4, 10.7, 16.0 Hz), 3.66-3.90 (m, 2H), 3.87 (s,
3H), 4.00 (mc, 1H), 4.20 (mc, 1H), 4.69 (s, 1H), 5.79 (dd,
1H, J ) 5.7, 9.6 Hz), 6.36 (dd, 1H, J ) 0.8, 9.6 Hz), 6.63
(d, 1H, J ) 8.1 Hz), 6.71 (d, 1H, J ) 8.1 Hz), 7.44-7.58
(m, 3H), 7.67-7.72 (m, 2H). 13C-NMR (100 MHz,
CDCl3): δ 25.2, 31.3, 34.7, 36.5, 38.8, 45.3, 46.1, 56.3,
64.8, 66.4, 94.1, 108.0, 112.9, 117.6, 123.0, 123.1, 127.1,
128.9, 129.6, 132.3, 137.6, 143.8, 146.1. MS (EI, 70 eV,
80 °C): m/ z ) 483 (M•+, 44), 342 (79), 286 (74), 285 (53),
199 (67), 99 (100), 77 (58). IR (KBr; cm-1): ν˜ 2948, 1636,
1,2,3,3a (R),8,9,9a (R),9b(S)-Octa h yd r o-5-m eth oxy-
9b-[2-[N-m eth yl-N-(p h en ylsu lfon yl)a m in o]eth yl]-3-
(eth ylen edioxy)ph en an th r o[4,4a,4b,5-bcd]fu r an (43).
To a solution of 42 (332 mg, 1 mmol), tributylphosphane
(370 µl, 303 mg, 1.5 mmol) and N-methylbenzenesulfona-
mide (257 mg, 1.5 mmol) in anhydrous benzene (10 mL)
at 0 °C was added 1,1′-(azodicarbonyl)dipiperidine (ADDP,
378 mg, 1.5 mmol). After stirring for 10 min, at 0 °C
and 24 h at room temperature, n-hexane (20 mL) was
added to the reaction mixture. The dihydro-ADDP
separated out was filtered off, and the clear solution was
concentrated in vacuo. Purification of the residue by
chromatography (silica gel, hexanes:EtOAc ) 5:1) af-
forded a mixture of N-methylbenzenesulfonamide and 43.
Further purification by HPLC [Macherey-Nagel Nucleosil
50-10 (250 × 20), n-hexane:EtOAc ) 10:6.7, 2 mL ×
min-1] provided 43 (428 mg, 88 mmol, 88 %) as colorless
crystals (mp: 174-175 °C (racemic); 175 °C (enantio-
merically pure)). Rf ) 0.15 (hexanes:EtOAc ) 5:1). 1H-
1622, 1505, 1446, 1338, 1278, 1163, 1092. [R]D20
)
-24.1° (c ) 1, CHCl3); [R]20 ) -23.8° (c ) 0.5, CHCl3).
D
Anal. Calcd for C26H29NO6S (Mr ) 483.578 g‚mol-1): C,
64.58; H, 6.04; N, 2.90. Found: C, 64.61; H, 6.08; N, 2.75.
(-)-Dih yd r ocod ein on e Eth ylen ek eta l (45). To a
mixture of liquid ammonia (20 mL) and anhydrous THF
(20 mL) at -78 °C was added tert-butanol (400 µL, 4.2
mmol) followed by lithium metal (200 mg, 28.8 mmol).
The resulting dark blue solution was stirred for 10 min,
and then styrene 44 (200 mg, 0.41 mmol) in THF (10 mL)
was added dropwise. The blue color was rapidly dis-
charged, and additional lithium (200 mg, 28.8 mmol) was
added. After 30 min, the reaction was quenched with a
mixture of saturated aqueous ammonium chloride (25
mL) and methanol (25 mL). After dilution with ethyl

5918 J . Org. Chem., Vol. 63, No. 17, 1998
Trauner et al.
acetate (50 mL) and separation of the basic aqueous
phase, the organic phase was washed with saturated
sodium bicarbonate (10 mL) and brine (10 mL), dried
(MgSO4), and concentrated in vacuo. The residue was
purified by chromatography (silica gel, CHCl3:MeOH )
5:1) to give morphinane 45 (111 mg, 0.32 mmol, 79%) as
colorless crystals (mp: 173-175 °C (enantiomerically
pure)). 1H-NMR (400 MHz, CDCl3): δ 1.16 (dq, 1H, J )
2.3, 12.8 Hz), 1.50-1.56 (m, 2H), 1.64-1.71 (m, 2H), 1.88
(td, 1H, J ) 4.9, 12.3 Hz), 2.19-2.24 (m, 2H), 2.36 (dd,
1H, J ) 5.4, 18.3 Hz), 2.41 (s, 3H), 2.53 (dd, 1H, J ) 3.8,
12.2 Hz), 3.00 (d, 1H, J ) 18.3 Hz), 3.11 (dd, 1H, J )
2.6, 5.4 Hz), 3.79 (mc, 1H), 3.87 (s, 3H), 3.88 (mc, 1H),
4.11 (mc, 1H), 4.18 (mc, 1H), 4.48 (s, 1H), 6.62 (d, 1H, J
) 8.2 Hz), 6.74 (d, 1H, J ) 8.2 Hz). 13C-NMR (100 MHz,
CDCl3): δ 20.0, 22.2, 33.2, 36.3, 42.4, 42.7, 43.5, 47.0,
56.4, 59.5, 64.8, 66.3, 94.2, 108.4, 113.4, 118.5, 126.2,
129.0, 142.1, 146.4. MS (EI, 70 eV, 120 °C): m/ z 343
(M+•, 100), 286 (23), 244 (18), 168 (17), 115 (16), 99 (40).
IR (Si; cm-1): ν˜ 2924, 1638, 1614, 1503, 1446, 1276, 1246,
1194, 1058. [R]2D0 ) -173.3° (c ) 1, CHCl3). Anal.
Calcd for C20H25NO4 (Mr ) 343.422 g‚mol-1): C, 69.95;
H, 7.34; N, 4.08. Found: C, 69.82; H, 7.21; N, 3.83.
(-)-Dih yd r ocod ein on e. A solution of dihydroco-
deinone ethyleneketal 45 (100 mg, 0.29 mmol) in dilute
aqueous hydrochloric acid (3 N, 2 mL) was kept at 90 °C
for 1 h. The reaction mixture was cooled, diluted with
ice water (5 mL), neutralized carefully with sodium
carbonate, and extracted with chloroform (5 × 5 mL). The
organic phase was dried (MgSO4) and concentrated in
vacuo. Filtration through a pad of silica, eluting with
chloroform, and concentration of the filtrate afforded
synthetic (-)-dihydrocodeinone (83 mg, 0.28 mmol, 95%)
as colorless crystals (mp: 194-197 °C (enantiomerically
pure)). 1H-NMR (400 MHz, CDCl3): δ 1.17 (dq, 1H, J )
5.9, 13.0 Hz), 1.70-1.80 (m, 2H), 1.96-2.33 (m, 5H), 2.35
(s, 3H), 2.46-2.54 (m, 2H), 2.95 (d, 1H, J ) 18.5 Hz),
3.11 (dd, 1H, J ) 2.7, 5.2 Hz), 3.82 (s, 3H), 4.59 (s, 1H),
6.55 (d, 1H, J ) 8.2), 6.62 (d, 1H, J ) 8.2). 13C-NMR
(100 MHz, CDCl3): δ 19.8, 25.4, 35.3, 40.0, 42.4, 42.7,
46.6, 46.7, 56.6, 59.0, 91.2, 114.5, 119.6, 126.1, 127.1,
142.6, 145.2, 207.6. MS (EI, 80 eV, 80 °C): m/ z 299 (M•+,
100), 243 (27), 242 (42), 215 (15), 185 (14), 115 (8), 96
(12), 83 (10), 71 (9). IR (Si; cm-1): ν˜ 2935, 2790, 1718,
1501, 1444, 1318, 1271, 1058. [R]2D0 ) -206.8° (c ) 1,
CHCl3). HRMS. Calcd for 299.1521. Found: 299.1521
( 0.0015.
Ack n ow led gm en t. This article is dedicated to Pro-
fessor Ulrich Eder on the occasion of his 60th birthday.
We thank Dr. G. Du¨rner for helping us with the
chromatographic resolution of compound 23.
Su p p or tin g In for m a tion Ava ila ble: Tables of full ex-
perimental details and spectra for 9, 26, 27, 47, and 48; details
of the chromatographic resolution of 23, and X-ray crystal-
lographic data for 27 (29 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
J O9805394