Chemoenzymatic enantiodivergent total syntheses of (+)- and (-)-codeine

Article abstract of DOI:10.1016/j.tet.2009.09.052

Whole-cell fermentation of β-bromoethylbenzene with the recombinant strain Escherichia coli JM109 (pDTG601) that over-expresses toluene dioxygenase provided the corresponding cis-dihydrodiol 19, which served as a starting material for both enantiomers of

Full text of DOI:10.1016/j.tet.2009.09.052

Tetrahedron 65 (2009) 9862–9875
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemoenzymatic enantiodivergent total syntheses of (þ)- and (ꢀ)-codeineq
Hannes Leisch, Alvaro T. Omori, Kevin J. Finn, Jacqueline Gilmet, Tyler Bissett,
*
´ ˇ
´
David Ilceski, Tomas Hudlicky
Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Whole-cell fermentation of b-bromoethylbenzene with the recombinant strain Escherichia coli JM109
Received 3 September 2009
Received in revised form 9 September 2009
Accepted 10 September 2009
Available online 16 September 2009
(pDTG601) that over-expresses toluene dioxygenase provided the corresponding cis-dihydrodiol 19,
which served as a starting material for both enantiomers of codeine. The key intermediate for the
synthesis of (þ)-codeine was diol 25b, whose Mitsunobu coupling with bromoisovanillin was followed
by an intramolecular Heck cyclization to aldehyde 35b. Elaboration of this material to vinyl bromide 27b
allowed for the second Heck cyclization 36b. Adjustment of the C-6 stereogenic center and hydro-
amination completed the synthesis of ent-codeine in 14 steps from b-bromoethylbenzene. Diol 33b was
converted via Mitsunobu reaction to epoxide 29, whose allylic opening with bromoisovanillin provided
ether 54, the enantiomer of 35b. The synthesis of (ꢀ)-codeine was completed via two Heck cyclizations
and a hydroamination protocol, in an analogous manner as that of ent-codeine. In addition, both en-
antiomers of epoxide 29, convenient precursors for the coupling with bromoisovanillin, were prepared
from diol 33b by Mitsunobu reactions and cyclizations of the trans-diol moiety. Spectral and experi-
mental data are provided for all compounds.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
namely the latex of opium poppies, grown primarily in Afghanistan,
Turkey, India, and Tasmania. A number of records can be ascribed to
Morphine (1), codeine (2), and other naturally occurring mor-
phinans serve as starting materials for the semisynthesis of all 4,5-
epoxymorphinans used in the practice of medicine such as the an-
algesic oxycodone (3) and the antagonists naloxone (5) and nal-
trexone (6), shown in Figure 1.2 The legal consumption of morphine
and morphine-derived agents approaches 400 metric tons annually
while only estimates are available for the illicit use of opiates such as
heroin, hydrocodone, and oxycodone.3 Morphine, codeine, the-
baine, and other morphinans originate from natural sources,
morphine. It is probably the world’s oldest known drug, with re-
cords of consumption of opium dating to 1500 BC.4 It was the first
natural product isolated in a pure state, by Sertu¨rner in 1806.5 His
efforts showed that morphine had the same effect on animals (dogs)
as opium and in a follow-up paper in 1817 he published the pro-
cedure for its isolation from opium. Sertu¨rner also reported the
preparation of morphine salts (sulfate, hydrochloride, and nitrate)
and investigated their chemical properties. The first human subjects
studies are also credited to him; he and three boys almost overdosed
RO
HO
RO
HO
A
11
10
D
B
O
O
O
O
13
9
5
N
NMe
NR
OH
C 14
NMe
OH
H
OH
6
HO
O
O
O
1 morphine, R = H
2 codeine, R = Me
6 naltrexone
3 oxycodone, R = Me
4 noroxymorphone, R = H
5 naloxone, R = allyl
Figure 1. Morphine, codeine, and their C-14 hydroxylated derivatives.
during the experiments with pure morphine. It may hold the record
as the compound that evaded complete structure elucidation for the
longest timedfrom 1806 to 1925 when Robinson and Gulland
proposed the correct structure, lacking only the relative and
q
See Ref. 1.
* Corresponding author.
E-mail address: thudlicky@brocku.ca (T. Hudlicky).
´
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.052

H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
9863
absolute stereochemistry.6 The stereochemical assignment was
essentially complete by 1952 and confirmed also by the first total
synthesis by Gates.7 The absolute stereochemistry was established
by degradation studies8 as well as by X-ray analysis9 in 1955. Finally,
it is probably one of the most frequently synthesized alkaloids on
record: as of this writing there have been more than 25 total syn-
theses of morphine (or codeine) reported in the literature10; the
most recent syntheses are those of Fukuyama (Mannich-type clo-
sure),11 Guillou (Heck reaction/hydroamination),12 and Stork (Diels–
Alder of benzofuran).13
cyclization approach, for example, the one reported by Parker that
provided codeine with full stereocontrol at C-14 and C-9.16
Our 1998 adaptation of Parker’s design to our own radical cycli-
zation approach to morphine resulted in the production of morphine
skeleton, but epimeric at C-14.17 In subsequent generations, we
modified the radical cyclization strategy to one that would employ
the Heck reaction with the expectation that the process was more
likely to be stereoselective. Overman,18 Cheng,19 Hsin,20 and Trost21
have already used the Heck reaction successfully for assembling the
morphine skeleton; these approaches are summarized in Figure 2.
Parker (1992)
MeO
MeO
MeO
R3SnH, AIBN,
SPh PhH, 130 °C, 35 h
Li, NH3, THF, tBuOH
O
O
O
Br
NMe
NTsMe
NTsMe
HO
HO
HO
9
8
7
Overman (1993)
MeO
MeO
BnO
Pd(OCOCF3)2(PPh3)2
pentamethylpiperidide,
toluene, 120 °C
BnO
X
NDBS
NDBS
11
10
Cheng (2000) and Hsin (2005):
MeO
O
MeO
MeO
MeO
R
R = CH2Cl
(Cheng)
R
O
O
O
Br
NMe
NMe
NMe
N
R = H, CH2OH
R = H, CH2Cl
13
12
14
15
Trost (2002):
MeO
MeO
O
MeO
O
Br
NHMe
CN
O
CHO
CN
Br
HO
16
18
17
Figure 2. Radical (Parker) and Heck cyclization strategies employed in design of morphinan syntheses.
Despite its popularity as a target for synthesis, only one practical
preparation with commercial potential exists to date. The most
efficient synthesis of morphine, performed in either enantiomeric
form, was reported by Rice in 1980,14 and this accomplishment
offers hope for a solution to potential supply problem on a scale
needed by the medical community.
The very real possibility of a natural or a political disaster in
those regions producing morphine and codeine jeopardizes the
supply of this important agent and its derivatives. A practical
synthetic or biosynthetic solution would obviate a potential
problem.
Morphine is an example of a very complex molecule for its size
owing to its completely dissonant connectivity.15 Solutions to an
effective design are consequently plagued with arduous in-
troduction of functionalities as well as problems in the control of
the five contiguous stereogenic centers. One possible solution to
the efficient assembly of morphine or codeine is a cascade
We have examined several chemoenzymatic strategies com-
mencing with the enantiopure diol 19 and involving Heck cycli-
zations.22 In the ent-series, pentacycle 21 was obtained by Heck
cyclization from aryl bromide 20, and in the natural series 10-
hydroxy-14a-dihydrocodeinone was prepared from 24 by C-10/
C-11 closure.23 The combination of elements of the double Heck
cyclization reported by Trost with a chemoenzymatic approach
resulted in the synthesis of ent-codeine in 13 operations from
b
-bromoethylbenzene, as shown in Figure 3.
Our enantiodivergent approach to codeine is based on the
generation of diene diol 19 via enzymatic dihydroxylation of
-bromoethylbenzene, whose side chain becomes the ethyl amino
b
bridge of morphine. The retrosynthetic reasoning shown in Figure 4
relies on the recognition that the configuration of the C-5 stereo-
genic center is the controlling element for all of the subsequent
carbon–carbon bond-forming events. The C-6 stereochemistry is
often adjusted by an oxidation–reduction sequence, which is well

9864
H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
Hudlicky (1999):
MeO
MeO
Br
O
H
Br
ent series
HO
HO
O
TBSO
N
O
O
N
O
TBSO
19
20
O
21
MeO
MeO
Hudlicky (2007):
OR
O
O
natural series
O
Br
TBSO
NMe
N
N
O
TBSO
O
O
22
Hudlicky (2007):
HO
O
23
24
MeO
MeO
Br
NMeBoc
CHO
O
O
Br
ent-2
TBSO
NMeBoc
TBSO
NMeBoc
TBSO
26
25
27
Figure 3. Chemoenzymatic approaches to morphine alkaloids via Heck cyclizations.
MeO
O
CHO
MeO
NMeBoc
Br
O
HO
NMe
NMeBoc
H
TBSO
HO
TBSO
25
26
ent-2
Br
HO
HO
19
MeO
O
CHO
MeO
Br
NMeBoc
O
NMeBoc
NMe
O
HO
HO
29
28
2
Figure 4. Disconnection analysis for enantiodivergent synthesis of codeine.
developed and guaranteed to deliver the C-6 configuration syn to
the C-5 bridge. The C-13 center will be formed syn to the C-5 ether
linkage, and the fate of C-14 and C-9 configuration is then de-
termined by the structural constraints of intermediates containing
fixed configurations at C-13 and C-5 (for example, compounds of
type 27a, b, Scheme 1). Finally, the C-9 center is created by
hydroamination or a similar reaction; its configuration is, by defi-
nition, predefined by the existing framework.
This analysis then requires efficient approach to the connection
of the aryl ether fragment to the enantiopure ring C, which can be
accomplished by means of either a single or a double Mitsunobu
reaction. The single Mitsunobu attachment of an aryl fragment to
25 has been shown to work well and has been reduced to practice
in the synthesis of ent-codeine (2). The double Mitsunobu inversion
of C-5 has been plagued, however, with difficulties arising from the
severe steric influence of the C-6 TBSO group. In several of our past

H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
9865
Br
OR
Br
Br
OH
E. coli JM109 (pDTG601A)
phosphate buffer
PAD, AcOH/MeOH,
0 °C, (60%)
OR
31 R= H
32 R= Ac
OH
30
Ac2O, TEA, DMAP,
CH2Cl2, 0 °C to rt, (79%)
19
MeNH2, K2CO3, THF,
-40 °C to rt, then Ac2O or Boc2O,
CH2Cl2, DMAP
[1N MeONa/MeOH for 33a]
MeO
CHO
NMeR
n-Bu3P, DIAD, THF,
NMeR
OH
NMeR
OH
Br
0 °C to rt
O
TBSCl, imidazole, CH2Cl2,
-78 °C to rt
MeO
34
OTBS
OH
TBSO
HO
CHO
33a R = Ac (63%)
33b R = Boc (50%)
26a R = Ac (58%)
26b R = Boc (55%)
Br
25a R = Ac (66%)
25b R = Boc (88%)
Pd(OAc)2, Ag2CO3,
dppf, toluene, 110 °C
MeO
MeO
MeO
Br
PPh3CH2Br2, t-BuOK,
Pd(OAc)2, Ag2CO3,
dppp, Toluene, 107 °C
THF, -60 °C
CHO
NMeR
O
O
O
NMeR
H
NMeR
TBSO
TBSO
TBSO
36a R = Ac (46%)
36b R = Boc (44%)
27a R = Ac (38%)
27b R = Boc (49%)
35a R = Ac (79%)
35b R = Boc (82%)
1. TBAF, THF, rt, (88%)
2. IBX, DMF, rt, (92%)
3. NaBH4, CeCl3 H2O,
For R = Boc
.
MeOH, 0 °C, (89%)
MeO
MeO
MeO
TFA/CH2Cl2 (1:4),
0 °C to rt, (88%)
Hg(OAc)2, TEA, THF, 48 h,
then LiAlH4, 2 h, rt, (18%)
O
O
O
NHMe
NMeR
H
NMe
H
HO
HO
HO
ent-2
38
37 R = Boc
Scheme 1.
approaches, especially in the synthesis of
a
C-10-hydroxy-
presence of n-Bu3P. (No reaction occurred with PPh3.) With the aryl
bromide 26a in hand, the first of the two Heck reactions was carried
out and mediated by Pd(0), generated in situ, and in the presence of
a free ligand (diphenylphosphinoferrocene or dppf) with silver
carbonate as base. The cyclization produced the tricyclic ether 35a in
79% yield.
morphinan by a radical cascade approach,17,24 this step was the
lowest yielding transformation in the sequence, so an alternative
solution had to be found. The generation of the allylic epoxide 29
would solve the problem of attachment of the ring A moiety pro-
vided the regiochemistry of the epoxide opening could be
controlled.
Conversion of the aldehyde to vinyl bromides 27a was accom-
plished in modest yield by treatment with bromomethyl-
triphenylphosphonium bromide and t-BuOK at ꢀ55 ꢁC, as we were
unable to repeat the procedure published by Trost, who prepared
the vinyl bromide in two steps by first Corey–Fuchs homologation
(91%) of the aldehyde followed by chemoselective radical debro-
mination (88%) to the required Z-vinyl bromide. Because the ap-
plication of the same conditions for the first step to compound 35a
led to the recovery of only trace amounts of product, we used the
Wittig protocol instead. The second Heck cyclization produced, in
moderate yield, the complete phenanthrene core of the target
compound under conditions similar to the first Heck sequence
except that the ligand was changed to diphenylphosphinopropane
(dppp). The rather modest yield can be explained by the fact that
we obtained a mixture of Z- and E-isomers (approximately 2:1, Z:E,
vide NMR analysis) after the Wittig reaction and only the Z-isomer
can further react to produce the desired compound. Trost obtained
a 65% yield of the cyclized product when only the Z-isomer was
2. Results and discussion
The synthesis of ent-codeine began with the saturation of the cis
olefin in diene diol 19 with potassium azadicarboxylate to produce
diol 31, which was converted to diacetate 32, Scheme 1. Exposure of
this material to methylamine resulted in the displacement of the
bromide and generation of the N-methylamine moiety with con-
comitant deacylation of the protected diol. In our initial approach to
(þ)-codeine, we chose to protect the N-methyl moiety as an acet-
amide, a choice that was later shown to have been less than fortu-
nate. It was found that the best yield of 33a was obtained by
exhaustive acylation of the initially obtained N-methylamine fol-
lowed by base-catalyzed hydrolysis (NaOMe, MeOH, and THF) of the
diacetate to 33a, whose distal hydroxyl group was then protected as
its TBS ether (25a). The connection of the ring A fragment to C-5 was
accomplished by Mitsunobu reaction of bromoisovanillin (34) in the

9866
H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
used, thus the yields of the Heck cyclizations to the phenanthrene
core compare favorably.
the yield of the product substantially. This approach was therefore
abandoned in favor of pursuing the preparation of epoxide 29.
To accomplish this transformation, we reacted diol 33b with
p-nitrobenzoic acid under Mitsunobu conditions reported by Ban-
well27 in order to invert either hydroxyl. To our surprise the Mit-
sunobu reaction provided exclusively 42, Scheme 3, via inversion at
the proximal hydroxyl, perhaps delivered to this site by anchimeric
assistance of the carbamate via an intramolecular hydrogen-
bonded intermediate. To confirm this result 33b was converted to
tosylate 43. Mitsunobu reaction of this material yielded the ben-
zoate ester 44, which was also obtained by tosylation of alcohol 42.
Treatment of p-nitrobenzoate 44 with sodium methoxide furnished
directly the desired allylic epoxide (ꢀ)-29 suitable for coupling
with bromoisovanillin (34).
At this point we wished to establish whether the failure of the
double Mitsunobu was strictly the function of the steric hindrance
of the TBS group in 40. Hydrolysis of p-nitrobenzoate 42 provided
the trans-diol 45. Another attempt was made at the coupling of
bromoisovanillin at the allylic site. No aryl ether was detected in the
reaction mixture, but epoxide (þ)-29 was isolated in 45% yield.
Although there is some precedent for the formation of epoxides
from 1,2-trans-diols,28 we were delighted by this result as it pro-
vided an enantiomer of the epoxide that could be used in the
preparation of ent-codeine. With both enantiomers of 29 available,
the coupling of the ring A fragment was now possible in both en-
antiomeric series by an allylic opening (certainly a more convenient
method) instead of Mitsunobu coupling.
With the required epoxide 29 in hand, we turned to the in-
vestigation of conditions for coupling of 29 with bromoisovanillin.
After extensive model studies, we determined that the optimal
conditions for SN2 opening of the vinyl oxirane required the use of
rigorously dry potassium phenoxide in the presence of 18-crown-6
and a chelating solvent such as DME. Under these conditions the aryl
ether 46 was obtained in 78% yield, Scheme 4. These conditions,
however, initially failed with the potassium phenoxide 47 derived
from bromoisovanillin, perhaps because of the electron-withdrawing
effect of the aldehyde moiety. Thus the potassium phenoxide derived
from the acetal of bromoisovanillin, namely 48, was used in the re-
action with 29. To our surprise, the desired ether 49 was obtained in
low yield, with the free aldehyde 28 as the major product; however, it
is not clear how the acetal hydrolysis occurred under the reaction
conditions. Further optimization of the conditions (DME/DMF, 1:1,
18-crown-6, 80 ꢁC) led to the desired aryl ether 28 in 75% yield along
with a low yield of an interesting byproduct, the tricyclic dioxane
derivative 50, presumably formed by an intramolecular addition to
the isovanillin ring, as shown in Scheme 4. This material was formed
exclusively at higher reaction temperatures.
With the attainment of 36a our attention was turned to the
removal of the acetamide group so that we could apply Trost’s
photochemical hydroamination protocol to styrene 38 once the
standard adjustment of stereochemistry at C-6 was accomplished.
To our dismay we were never able to generate the secondary amine
from 36a under any conditions (hydrazine, KOH, t-BuOK/KOH, etc.).
Under forceful conditions and elevated temperatures, isomeriza-
tion of the olefins or elimination of the C-6 ether took place, and we
were forced to abandon this particular approach. We repeated the
synthesis with a less robust protecting group in place. (Similar
problems with amide hydrolysis plagued also our first synthesis of
pancratistatin and greatly complicated the completion of the
synthesis.25
)
Returning to diacetate 32, we discovered that its amination with
methylamine, followed by protection with Boc anhydride, led
cleanly to 33b without the over-acylation observed with acetic
anhydride. Protection of 33b as its TBS ether 25b was followed by
Mitsunobu reaction with bromoisovanillin 3426 to provide alde-
hyde 26b, Scheme 1. The Heck cyclization to 35b was followed by
the Wittig reaction and a second Heck cyclization of 27b to 36b.
Both proceeded in reasonable yields and without the attendant
C-14 epimerization observed in the acetate series during the sec-
ond Heck cyclization.
At this stage the stereochemistry at C-6 was adjusted by desi-
lylation, IBX oxidation, and reduction to attain the allylic alcohol 37,
which was deprotected with trifluoroacetic acid to yield the sec-
ondary amine 38, whose enantiomer had been reported by Trost.
Although the attainment of 38 formalized the synthesis, we de-
cided to repeat Trost’s hydroamination protocol consisting of irra-
diating the solution of lithium amide derived by treatment of 38
with LDA. In our hands, we never observed a closure to codeine
under these conditions after many attempts, even with complete
details provided to us by Professor Tang. It is clear that the re-
producibility of this closure is questionable and does not constitute
a general method. To solve this problem we resorted to oxy-
mercuration procedure followed by a reductive workup with lith-
ium aluminum hydride. This sequence yielded ent-codeine (2) in
a total of 14 steps (13 operations) from b-bromoethylbenzene.
To approach the synthesis of the natural enantiomer of codeine
we first considered a double Mitsunobu inversion at C-5 (morphine
numbering) despite the rather poor results obtained in our 1998
radical cyclization approach. Thus diol 33b was silylated to 25 at the
distal hydroxyl with TBSCl and a Mitsunobu inversion with benzoic
acid provided benzoate 39, which was hydrolyzed to the free al-
cohol 40, Scheme 2. Standard Mitsunobu conditions with bromo-
isovanillin (34) yielded at best w5% yield of the aryl ether 41.
Various modifications of the Mitsunobu protocol failed to increase
With the required aryl ether 28 in hand we turned to the
completion of the synthesis of natural (ꢀ)-codeine by following
NMeBoc
OH
NMeBoc
OBz
NMeBoc
OH
DIAD, n-Bu3P, C6H5CO2H,
THF, 0 °C (83%)
TBSCl, imidazole,
CH2Cl2, rt (88%)
OTBS
OTBS
OH
39
33b
25
NaOMe, MeOH,
0 °C, (55%)
MeO
CHO
NMeBoc
OH
Mitsunobu with 34
various conditions, (~5%)
Br
O
NMeR
OTBS
TBSO
40
41
Scheme 2.

H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
9867
NMeBoc
TsCl, Et3N,DMAP,
CH2Cl2, 0 °C to rt,
(35%)
DIAD, PPh3,THF,
pNO2C6H4CO2H,
0 °C, (78%)
OH
OTs
NMeBoc
OpNO2Bz
NMeBoc
OH
43
OTs
OH
NMeBoc
33b
44
OpNO2Bz
TsCl, Et3N,DMAP,
CH2Cl2, 0 °C to rt,
(73%)
DIAD, PPh3,THF,
pNO2C6H4CO2H,
0 °C, (71%)
OH
42
NaOMe, MeOH,
THF, 0 ¡C, (88%)
NaOMe, MeOH,
0 °C, (76%)
NMeBoc
NMeBoc
OH
NMeBoc
NMeBoc
O
NMeBoc
DIAD, nBu3P, THF,
[34], 0 °C, (45%)
O
O
O
OH
45
(-)-29
(+)-29
Scheme 3.
MeO
KO
MeO
MeO
O
O
48
Br
O
CHO
NMeBoc
O
DME-DMF (1:1), 90 °C, 4d
Br
Br
+
O
O
NMeBoc
NMeBoc
HO
HO
28 (21%)
49(7%)
Br
MeO
O
47
MeO
KO
CHO
Br
29
DME-DMF (1:1), 18-crown-6,
80 °C, 48 h, (75%)
NMeBoc
CHO
NMeBoc
OHC
O
Br
O
+
Model study:
O
PhOK, DME, 18-crown-6,
reflux, 16 h, (78%)
HO
28
50
NMeBoc
O
O
H
HO
H
Br
NMeBoc
Br
O
O
NMeBoc
46
O
O
O
MeO
MeO
52
51
Scheme 4.
closely the sequence used to attain ent-2. The alcohol in 28 was
protected as its TBS ether 53 (identical in all respects to 26b,
Scheme 1, except for the optical rotation), then the first Heck cy-
clization was performed to provide the tricycle 54 in 91% yield,
nearly identical to the yield obtained in the (þ)-series as well as in
Trost’s synthesis, Scheme 5. The aldehyde was converted to a mix-
ture of vinyl bromides 55 in a ratio of approximately 2:1 (identical
to the ratio obtained in the ent-series), and the second Heck cy-
clization yielded the complete phenanthrene skeleton 56 with the
C-14 stereogenic center correctly established.
C-6. In contrast to the similar maneuver executed during the syn-
thesis of ent-2 where this oxidation proceeded nearly quantitatively,
enone 58 was obtained as an inseparable mixture (1:1) with another
compound, probably resulting from the use of excess oxidizing agent.
The mixture was therefore taken through the remaining steps: re-
duction of the enone with sodium borohydride, hydrolysis of the Boc
carbamate with trifluoroacetic acid, and an oxymercuration protocol
to establish C-9 stereogenic center. In each of these steps the addi-
tional byproduct carried over from the IBX oxidation proved in-
separable from the main component of the reaction. The final
mixture was purified by careful flash column chromatography.
(ꢀ)-Codeine was isolated in low yield and matched with a sample of
Deprotection of the silyl ether furnished allylic alcohol 57, which
was subjected to IBX oxidation in order to adjust the configuration at

9868
H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
MeO
MeO
MeO
TBSCl, imidazole,
CH2Cl2, (61%)
Pd(OAc)2, Ag2CO3,
dppf, toluene, 110 °C, (91%)
CHO
NMeBoc
CHO
NMeBoc
CHO
NMeBoc
O
Br
Br
O
O
TBSO
TBSO
HO
54
53
28
PPh3CH2Br2, t-BuOK,
THF, -30 °C, (40%)
MeO
MeO
MeO
Br
Pd(OAc)2, Ag2CO3,
dppp, Toluene, 110 °C, (45%)
TBAF, THF, rt, (72%)
NMeBoc
O
O
O
NMeBoc
NMeBoc
TBSO
TBSO
HO
56
55
57
IBX, DMF, rt, (46%)
MeO
MeO
O
1. NaBH4, CeCl3.7H2O,
MeOH, 0 °C, (76%)
O
NMeBoc
2. TFA/CH2Cl2 (1:4),
0 °C to rt, (90%)
NMe
3. Hg(OAc)2, TEA, THF, 48 h,
then LiAlH4, 2 h, rt, (24%)
HO
O
2
58
Scheme 5.
MeO
O
MeO
NaHDMS, THF,
HMPA, Ph3PCh2I2,
-78 °C to rt, (72%)
MeO
Pd(OAc)2, Ag2CO3,
dppp, PhMe, 110 °C,
(31%)
X
CHO
NMeBoc
O
O
NMeBoc
NMeBoc
TBSO
TBSO
TBSO
54
59 X = I (Z:E = 2:1)
Scheme 6.
56
the natural product. The identity of the byproduct has not been
established at this time and will have to await the repetition of the
synthesis along with optimization of the last several steps.
coupling of ring A moiety to the enantiopure ring C fragment that
involved a regioselective allylic opening of vinyl oxirane 29 (gen-
erated in both enantiomeric series) with the phenoxide of ring A.
The accessibility of either (þ)- or (ꢀ)-29 from the same precursor
simplifies the coupling procedure especially in the natural series
where Mitsunobu conditions proved completely ineffective be-
cause of severe steric hindrance and represents a major improve-
ment in the chemoenzymatic strategy toward morphine alkaloids.
Further refinements and optimization need to be made in the
control of isomeric ratios of the vinyl halides required for the sec-
ond Heck coupling step as well as in the hydroamination protocol.
The latter issue appears to have been solved in the recent synthesis
of codeine by Guillou12 who used Parker’s conditions (a dissolved
metal reduction of N-methyltosylamide) to accomplish the con-
struction of C-9 stereogenic center in 51% yield. These are the major
issues that require investigation for the next generation approach
to codeine and derivatives.
In an attempt to improve the yield and the isomeric ratios in the
generation of the vinyl bromide precursor to the second Heck cy-
clization, we searched for conditions to produce only the desired
Z-isomer. We were able to produce the desired isomer in a better
ratio (but at the expense of somewhat lower yields in the sub-
sequent Heck cyclization) by following a protocol published by
Stork.29 His procedure employs (Ph3PþCH2I)Iꢀ and leads to pre-
dominantly Z-1-iodo-1-alkenes. When we subjected aldehyde 54 to
the conditions shown in Scheme 6, we obtained the iodo alkene 59
in 72% yields as a mixture of Z/E isomers (2:1). (Stork reported ra-
tios of Z/E of 13:1 for the iodo olefin derived from benzaldehyde.)
We have repeated the reaction with benzaldehyde and obtained the
same result; however, application of the procedure to the more
complex aldehyde 54 led to only a slight improvement.
3. Conclusions
4. Experimental section
4.1. General
In summary, we have completed enantiodivergent syntheses of
(þ)- and (ꢀ)-codeine from a single enantiomer of the cis-diol 19,
which was obtained by the toluene dioxygenase hydroxylation of
4.1.1. (1S,2R)-3-(2-Bromoethyl)-3-cyclohexene-1,2-diol, 1,2-diacetate
b-bromoethylbenzene. A new procedure was developed for the
(32). To a solution of diol 3130 obtained by diimide reduction of diol

H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
9869
19 (1.45 g, 6.55 mmol) in DCM (20 mL) at 0 ꢁC were added tri-
ethylamine (5.50 mL, 39.30 mmol), acetic anhydride (1.85 mL,
19.65 mmol), and DMAP (0.16 g, 1.31 mmol). The reaction mixture
was warmed to ambient temperature, stirred for 16 h, and then
quenched by the addition of a saturated aqueous solution of
NaHCO3 (20 mL). The layers were separated, and the aqueous layer
was extracted with DCM. The organic layers were combined and
washed three times with cold 1 N aqueous HCl, three times with
saturated aqueous solution of NaHCO3, and brine. The organic layer
was dried over anhydrous magnesium sulfate. Filtration and
evaporation of the solvent gave a crude oil, which was purified by
flash column chromatography (hexanes/ethyl acetate, 15:1–3:1) to
aqueous HCl, saturated aqueous solution of NaHCO3, then dried over
anhydrous magnesium sulfate. Evaporation of the solvent gave
a crude oil, which was purified by flash column chromatography
(hexanes/ethyl acetate, 1:1–0:1) to give the mono-silyl derivative
25b as a clear and colorless oil (678 mg, 88%). Rf 0.47 (DCM/ethyl
24
acetate, 96:4); [
a
]
ꢀ22.6 (c 0.5, CHCl3); IR (film) nmax: 3556, 3475,
D
2953, 2857, 1692, 1472, 1392, 1253, 1085 cmꢀ1
;
1H NMR (600 MHz,
CDCl3) (mixture of rotamers) : 5.54 (s, 1H), 5.52 (s, 1H), 3.98 (s, 1H),
d
3.90 (s, 1H), 3.79 (s, 1H), 3.77 (s, 1H), 3.26–3.20 (m, 2H), 2.85 (s, 3H),
2.82 (s, 3H), 2.39–2.32 (m, 2H), 2.30–2.23 (m, 2H), 2.13 (br s, 2H),1.98
(br s, 2H) 1.80–1.72 (m, 2H),1.54 (s, 2H),1.44 (s,18H), 0.9 (s,18H), 0.11
(s, 6H), 0.10 (s, 6H) ppm; 13C NMR (150 MHz, CDCl3)
d: 155.7, 134.8,
give diacetate 32 as a clear and colorless oil (1.58 g, 79%). Rf 0.50
126.6, 79.0 (br), 71.0, 68.8, 48.4, 47.2, 34.1, 33.3, 32.8, 28.4, 25.8, 25.4,
25.3, 24.3, 24.1, 18.1, ꢀ4.4, ꢀ4.8 ppm; MS (EI) m/z (%): 228 (21), 197
(21), 136 (12), 74 (22), 73 (15), 57 (63), 44 (100); HRMS (EI) (Mþꢀ57)
calcd for C12H30NO4Si: 328.1944, found 328.1946; Anal. Calcd for
C20H39NO4Si: C 62.10% H 10.22%, found C 62.29% H 10.19%.
22
(hexanes/ethyl acetate, 3:1); [
a
]
ꢀ120.5 (c 0.9, CH2Cl2); IR (film)
D
nmax: 2947, 1738, 1434 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d: 5.80 (t,
J¼3.3 Hz, 1H), 5.47 (d, J¼3.3 Hz, 1H), 4.99 (dt, J¼11.7, 3.6 Hz, 1H),
3.39 (td, J¼7.2, 2.4 Hz, 2H), 2.47–2.56 (m, 2H), 2.20–2.24 (m, 2H),
2.08 (s, 3H), 1.99 (s, 3H), 1.83–1.90 (m, 1H), 1.71–1.77 (m, 1H) ppm;
13C NMR (75 MHz, CDCl3)
d
: 170.7, 170.2, 131.2, 130.4, 70.0, 67.3,
4.1.4. N-[2-[(5S,6S)-6-(2-Bromo-3-formyl-6-methoxyphenoxy)-5-
[[(1,1-dimethylethyl) dimethylsilyl]oxy]-1-cyclohexen-1-yl]ethyl]-N-
methyl-carbamic acid-1,1-dimethylethylester (26b). To a solution of
DIAD (1.02 mL, 5.21 mmol) in THF (10 mL) at ꢀ10 ꢁC, was added
tributylphosphine (1.69 mL, 5.21 mmol) dropwise. The solution
was stirred at ꢀ10 ꢁC for 10 min, then it was transferred dropwise
to a solution of bromoisovanillin 34 (0.93 g, 4.01 mmol) and
monoprotected diol 25b (1.39 g, 3.61 mmol) in THF (2 mL) at
ꢀ78 ꢁC. Once the addition was completed, the reaction vessel was
warmed to rt and stirred at ambient temperature for 48 h. The
solvent was removed under reduced pressure and the crude mix-
ture was subjected to column chromatography (DCM/ethyl acetate,
37.4, 30.6, 24.0, 22.2, 20.9, 20.9 ppm; HRMS (EI) (Mþ) calcd for
C12H17NO4Br: 304.0310, found 304.0317; Anal. Calcd for
C12H17NO4Br: C 47.23% H 5.62%, found C 47.42% H 5.67%.
4.1.2. N-[2-[(5S,6R)-5,6-Dihydroxy-1-cyclohexen-1-yl]ethyl]-N-
methyl-carbamic acid-1,1-dimethylethyl ester (33b). Bromide 32
(6.34 g, 20.8 mmol) was dissolved in THF (20 mL) and transferred to
a 50 mL thick-walled reaction vessel containing K2CO3 (1.61 g,
11.6 mmol) and a magnetic stirring bar. The reaction vessel was
cooled to ꢀ40 ꢁC, and the solution was saturated with methylamine
by bubbling gaseous methylamine from a lecture bottle through
the solution for 15 min. The reaction vessel was sealed, and the
mixture stirred at rt for 48 h. The vessel was cooled to ꢀ40 ꢁC be-
fore it was carefully opened. Potassium salts were removed by fil-
tration and rinsed with DCM (20 mL). The solvent was removed and
the residue was dissolved in DCM (50 mL). Boc anhydride (8.53 g,
37.4 mmol) was added to the solution and the reaction mixture was
cooled to 0 ꢁC. Triethylamine (5.20 mL, 37.4 mmol) and DMAP
(0.24 g, 2.0 mmol) were added to the reaction mixture, which was
warmed to rt over 24 h. A saturated aqueous solution of NH4Cl
was added and the layers were separated. The aqueous layer was
extracted with DCM and the organic extracts were combined. The
organic layer was washed three times with a saturated aqueous
solution of Na2CO3, brine, and then dried over anhydrous sodium
sulfate. The solution was filtered and the solvent was removed
under reduced pressure. Purification of the crude residue by flash
column chromatography (hexanes/ethyl acetate, 6:1–1:2) afforded
the title compound 33b as colorless oil (2.79 g, 50%). Rf 0.20 (hex-
anes/ethyl acetate,1:1); IR (film) nmax: 3383, 2974, 2930,1693,1672,
100:0–98:2). Compound 26b was isolated as colorless oil (1.19 g,
22
55%). Rf 0.81 (DCM/EtOAc, 96:4); [
a
]
þ59.1 (c 0.35, CHCl3); IR
D
(film) nmax: 3007, 2952, 2929, 2857, 1688, 1578, 1481, 1275, 1252,
1173, 1085, 1028, 1005, 836 cmꢀ1 1H NMR (600 MHz, CDCl3) (two
rotamers)
;
d
: 10.30 (s, 1H), 7.75 (d, J¼8.6 Hz, 1H), 7.00 (d, J¼8.6 Hz,
1H), 5.79–5.90 (m, 1H), 4.57 (br s, 1H), 3.94–4.04 (m, 4H), 3.40–3.65
(m,1H), 3.22 (br s,1H), 2.85 (s, 3H), 2.37–2.57 (m, 2H), 2.17–2.28 (m,
2H), 2.02–2.10 (m, 1H), 1.65–1.74 (m, 1H), 1.46 (s, 9H), 0.76 (s, 9H),
ꢀ0.12 (s, 3H), ꢀ0.17 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3)
d:
191.3, 157.9, 155.8, 144.6, 130.9, 130.3, 127.7, 125.9, 123.5, 110.9, 80.3,
79.1, 67.7, 56.1, 48.9, 48.3, 41.5, 35.0, 33.4, 32.7, 28.5, 25.6, 25.4, 20.8,
18.0, ꢀ4.9, ꢀ5.1 ppm; MS (EI) m/z (%): 312 (28), 269 (10), 268 (45),
237 (24),136 (31),109 (14), 75 (27), 73 (33), 57 (47), 44 (100); HRMS
(EI) (Mþꢀ73) calcd for C24H35NO5BrSi: 524.1468, found 524.1464;
Anal. Calcd for C28H44NO6BrSi: C 56.18% H 7.41%, found C 56.09% H
7.65%.
4.1.5. N-[2-[(5aS,6S,9aR)-6-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-
1-formyl-6,7-dihydro-4-methoxy-9a(5aH)-dibenzofuranyl]ethyl]-N-
methyl-carbamic acid-1,1-dimethylethyl ester (35b). To aryl bromide
26b (205 mg, 0.34 mmol) dissolved in degassed (N2) toluene (5 mL)
were added sequentially silver carbonate (283 mg, 1.03 mmol),
diphenylphosphino ferrocene (57 mg, 0.10 mmol), and Pd(OAc)2
(12 mg, 0.05 mmol). The reaction mixture was heated to 110 ꢁC
(preheated oil bath) in a Teflon-sealed Schlenk tube (10 mL) for 1 h,
before it was cooled to rt. The remaining black reaction mixture was
filtered through Celite and washed with several portions of CHCl3.
The filtrate was concentrated and adsorbed onto a mixture of silica
gel and charcoal. Purification by flash column chromatography
1396, 1158, 988 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d: 5.43 (br s, 1H),
4.87 (br s, 1H), 3.96 (br s, 2H), 3.56 (br s, 1H), 2.99 (d, J¼8.8 Hz, 1H),
2.91 (br s, 1H), 2.86 (s, 3H), 2.42–2.30 (m, 1H), 2.18 (d, J¼13.4 Hz,
1H), 2.03 (br s, 2H), 1.74–1.63 (m, 1H), 1.60–1.45 (m, 1H), 1.43 (s, 9H)
ppm; 13C NMR (150 MHz, CHCl3)
d: 157.0, 133.9, 128.8, 79.9, 70.0,
69.8, 48.3, 34.8, 34.0, 28.3, 25.4, 24.8 ppm; MS (EI) m/z (%): 144 (12),
110 (110), 57 (71), 44 (100); HRMS (EI) (Mþꢀ57) calcd for
C14H25NO4: 271.1784, found 271.1787.
4.1.3. N-[2-[(5S,6R)-5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-6-hy-
droxy-1-cyclohexen-1-yl]ethyl]-N-methyl-carbamic acid-1,1-dimethyl-
ethyl ester (25b). To a solution of diol 33b (656 mg, 2.0 mmol) in
DCM (8 mL) at ꢀ78 ꢁC was added imidazole (272 mg, 4.0 mmol)
followed by the addition of TBDMS-chloride (330 mg, 2.2 mmol).
The reaction mixture was warmed to rt over 14 h and then quenched
by the addition of a saturated aqueous solution of NH4Cl. The layers
were separated, and the aqueous layer was extracted twice with
DCM. The organic layers were combined and washed with cold 2%
(DCM/ethyl acetate, 4:1) gave 146 mg (82%) of the title compound
24
35b as colorless oil. Rf 0.80 (DCM/ethyl acetate, 96:4); [
a]
þ12.5 (c
D
0.6, CHCl3); IR (film) nmax: 3008, 2953, 2930, 2856, 2734, 1692, 1610,
1571, 1436, 1366, 1285, 1250, 1170, 1155, 1046, 837 cmꢀ1 1H NMR
(600 MHz, CDCl3) (two rotamers) : 9.90 (s, 1H), 9.89 (s, 1H), 7.38 (d,
;
d
J¼8.2 Hz, 2H), 6.86–6.93 (m, 2H), 6.40–6.49 (m, 1H), 6.32–6.40 (m,
1H), 5.65–5.72 (m, 2H), 4.54–4.80 (m, 2H), 3.95 (s, 6H), 3.91 (br s,

9870
H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
2H), 3.32 (br s, 1H), 3.16–3.25 (m, 1H), 2.93–3.03 (m, 2H), 2.78 (s,
6H), 2.01–2.29 (m, 8H), 1.43 (s, 18H), 0.91 (s, 18H), 0.14 (s, 6H), 0.04
(d, J¼8.0 Hz, 1H), 6.63 (d, J¼8.0 Hz, 1H), 6.40–6.48 (m, 1H), 5.85 (dd,
J¼9.2, 5.8 Hz,1H), 5.59–5.73 (m,1H), 5.55 (d, J¼9.8 Hz,1H), 4.64–4.74
(m, 1H), 4.04–4.15 (m, 1H), 3.90 (s, 3H), 3.16–3.28 (m, 1H), 3.05–3.14
(m, 2H), 2.68–2.80 (m, 3H), 1.92–2.01 (m, 1H), 1.80–1.91 (m, 1H),
1.38–1.46 (m, 10H), 0.92 (s, 9H), 0.16 (s, 3H), 0.07 (s, 3H) ppm; 13C
(s, 6H) ppm; 13C NMR (150 MHz, CDCl3) (two rotamers)
d: 190.6,
155.5, 150.2, 147.5, 133.6, 130.4, 129.8, 129.2, 126.5, 124.1, 110.4, 90.9,
89.9, 79.5, 68.8, 68.4, 56.0, 55.9, 51.8, 45.3, 44.6, 36.4, 35.5, 34.7,
34.6, 34.1, 31.6, 30.5, 29.1, 28.4, 25.8, 25.7, 25.3, 22.7, 20.7, 18.1, 14.1,
11.4, ꢀ4.7, ꢀ5.2 ppm; MS (EI) m/z (%): 162 (12), 144 (17), 136 (12),
118 (13), 117 (18), 92 (32), 91 (38), 88 (11), 75 (46), 73 (38), 57 (87),
44 (100); HRMS (EI) (Mþꢀ57) calcd for C24H34NO6Si: 460.2155,
found 460.2150; Anal. Calcd for C28H43NO6Si: C 64.96% H 8.37%,
found C 64.87% H 8.46%.
NMR (150 MHz, CDCl3) (two rotamers) d: 155.5, 144.7, 141.7, 129.6,
128.2, 128.0, 127.7, 124.1, 117.8, 113.0,102.1, 95.0, 85.7, 79.3, 68.8, 56.5,
45.1, 38.8, 36.4, 34.7, 34.2, 28.4, 25.8, 25.3, 18.1, ꢀ4.7, ꢀ4.9 ppm; MS
(EI) m/z (%): 440 (2), 370 (10), 356 (11), 355 (12), 299 (10), 281 (8),
238 (18), 225 (17), 224 (83), 223 (14), 158 (9) 117 (8),102 (54), 75 (41),
73 (63), 59 (38), 58 (59), 57 (99), 44 (100), 41 (22); HRMS (EI)
(Mþꢀ73) calcd for C25H34NO4Si: 440.2257, found 440.2250.
4.1.6. N-[2-[(5aS,6S,9aR)-1-(2-Bromoethenyl)-6-[[(1,1-dimethyl-
ethyl)dimethylsilyl]oxy]-6,7-dihydro-4-methoxy-9a(5aH)-dibenzofur-
anyl]ethyl]-N-methyl-carbamic acid-1,1-dimethylethyl ester (27b).
Potassium tert-butoxide (2.91 g, 26.0 mmol) was added to a solution
of ylide (prepared by refluxing a solution of triphenylphosphine
(15 g, 57.0 mmol)) and methylene bromide (22.3 g, 115 mmol) in
toluene (100 mL) for 24 h. The mixture was cooled to 0 ꢁC, the pre-
cipitate was collected by filtration, washed with toluene, and dried
under reduced pressure (12.2 g, 28.0 mmol) in THF (100 mL) at
ꢀ30 ꢁC. The solution was stirred at ꢀ30 ꢁC for 5 min and then al-
dehyde 35b (4.05 g, 7.8 mmol) was added. The mixture was stirred at
ꢀ30 ꢁC until TLC analysis indicated full conversion (20 min). The
reaction mixture was quenched with brine (40 mL) and the aqueous
layer was extracted twice with ethyl acetate (50 mL). The organic
layers were combined, dried over anhydrous magnesium sulfate, and
filtered. The concentrated residue was purified by flash column
chromatography (hexanes/ethyl acetate, 9:1–4:1) to give the title
4.1.8. N-[2-[(3R,3aS,9aS,9bR)-3,9a-Dihydro-3-hydroxy-5-methoxy-
phenanthro[4,5-bcd]furan-9b(3aH)-yl]ethyl]-N-methyl-carbamic
acid-1,1-dimethylethyl ester (37). To compound 36b (278 mg,
0.54 mmol) dissolved in THF (3 mL) was added TBAF (0.6 mL,1 M in
THF) and the reaction mixture was stirred at ambient temperature
for 1 h. The solvent was removed under reduced pressure and the
residue was purified by flash column chromatography (DCM/
MeOH, 95:5) to give the free alcohol N-[2-[(3S,3aS,9aS,9bR)-3,9a-
dihydro-3-hydroxy-5-methoxyphenanthro[4,5-bcd]furan-9b(3
aH)-
yl]ethyl]-N-methyl-carbamic acid-1,1-dimethylethyl ester as
a
21
colorless oil (190 mg, 88%). Rf 0.50 (DCM/MeOH, 95:5); [
(c 1.2, CHCl3); IR (film) nmax: 3417, 2974, 2933, 1675, 1633, 1507,
1438, 1366, 1280, 1162, 1051, 878 cmꢀ1 1H NMR (600 MHz, CDCl3)
(two rotamers)
a]
ꢀ80.5
D
;
d
: 6.68 (d, J¼9.1 Hz,1H), 6.64 (d, J¼6.0 Hz,1H), 6.40–
6.50 (m, 1H), 5.83 (br s, 1H), 5.75 (d, J¼9.91 Hz, 1H), 5.61 (br s, 1H),
4.70–4.82 (m, 1H), 4.14 (br s, 1H), 3.89 (s, 3H), 3.21–3.42 (m, 1H),
3.05–3.20 (m, 2H), 2.72–2.80 (m, 3H), 2.38–2.65 (m, 1H), 1.90–2.08
(m, 1H), 1.75–1.90 (m, 1H), 1.35–1.50 (m, 9H) ppm; 13C NMR
compound as colorless oil (2.05 g, 49%). Rf 0.56 (hexanes/ethyl ace-
21
tate, 4:1); [
a
]
þ46.6 (c 1.2, CHCl3); IR (film) nmax: 2952, 2929, 2855,
D
1691, 1620, 1502, 1366, 1282, 1156, 1122, 837 cmꢀ1
(300 MHz, CDCl3) (two isomers, ratio 2:1)
;
1H NMR
: 7.10 (d, J¼8.4 Hz, 1H),
(150 MHz, CDCl3) (two rotamers) d: 155.5, 145.4, 144.1, 128.3, 128.0,
d
127.6, 127.2, 123.9, 123.3, 118.1, 117.9, 112.5, 95.2, 79.4, 68.7, 68.6,
56.2, 44.9, 44.4, 43.2, 43.0, 39.3, 38.6, 36.1, 37.0, 34.2, 28.4 ppm; MS
(EI) m/z (%): 399 (1), 256 (10), 242 (21), 241 (47), 238 (21), 225 (25),
224 (89), 223 (23), 213 (11), 209 (17), 181 (12), 152 (10), 102 (30), 88
(11), 85 (14), 83 (20), 59 (27), 58 (35), 57 (100), 44 (27); HRMS (EI)
calcd for C23H29NO5: 399.2046, found 399.2043.
The free alcohol (157 mg, 0.39 mmol) obtained by desilylation of
36b was dissolved in DMF (2 mL) and IBX (110 mg, 0.42 mmol) was
added at rt. After complete consumption of starting material (TLC)
the reaction mixture was quenched with water (20 mL). The phases
were separated and the aqueous phase was extracted with DCM
(3ꢂ20 mL). The organic layers were combined, washed with a sat-
urated aqueous solution of NaHCO3, then dried over anhydrous
sodium sulfate. Filtration and removal of the solvent under reduced
pressure gave the crude product, which was purified by flash
column chromatography (DCM/ethyl acetate, 4:1) to afford the
corresponding enone N-[2-[(3aS,9aS,9bR)-3,9a-dihydro-5-methoxy-
6.70–6.86 (m, 3H), 6.56 (d, J¼13.9 Hz, 1H), 6.52 (d, J¼7.9 Hz, 1H),
5.86–5.99 (m, 2H), 5.66–5.81 (m, 2H), 4.46–4.60 (m, 2H), 3.94–4.03
(m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.18–3.48 (br s, 2H), 2.89–3.04 (m,
2H), 2.80 (s, 3H), 2.76 (s, 3H), 2.31 (t, J¼4.5 Hz, 1H), 2.25 (t, J¼2.8 Hz,
1H), 2.03–2.18 (m, 2H),1.80–2.03 (m, 4H),1.43–1.48 (m, 20H), 0.92 (s,
18H), 0.15 (s, 3H), 0.14 (s, 3H), 0.05 (s, 3H), 0.05 (s, 3H) ppm; 13C NMR
(150 MHz, CDCl3) (two isomers, ratio 2:1) d: 155.5, 147.1, 145.3, 145.0,
130.2, 129.0, 128.6, 124.7, 122.5, 119.5, 111.7, 110.9, 108.6, 106.7, 89.8,
89.1, 79.5, 68.9, 68.3, 65.9, 55.9, 55.8, 55.7, 51.0, 50.9, 45.2, 37.1, 34.2,
30.4, 30.3, 29.7, 28.5, 28.5, 25.8, 25.7, 25.7, 18.1, 15.3, ꢀ3.5, ꢀ4.7,
ꢀ5.2 ppm; MS (EI) m/z (%): 536 (4), 436 (7), 144 (8), 118 (6), 88 (14),
86 (29), 84 (44), 75 (21), 73 (38), 59 (33), 57 (61), 47 (10), 44 (100), 41
(18), MS (ES-pos) m/z (%): 618 (100), 616 (92), 553 (20), 477 (14), 476
(52); HRMS (EI) (Mþꢀ57) calcd for C25H35NO5BrSi: 536.1467, found
536.1461; Anal. Calcd for C29H44NO5BrSi: C 58.57% H 7.46%, found C
59.48% H 7.87%.
3-oxophenanthro[4,5-bcd]furan-9b(3aH)-yl]ethyl]-N-methyl-carba-
4.1.7. N-[2-[(3S,3aS,9aS,9bR)-3-[[(1,1-Dimethylethyl)dimethylsilyl]-
mic acid-1,1-dimethylethyl as a colorless oil (142 mg, 92%). Rf
21
oxy]-3,9a-dihydro-5-methoxyphenanthro[4,5-bcd]furan-9b(3
a
H)-
0.68 (DCM/ethyl acetate, 90:10); [
nmax 2928, 1683, 1508, 1438, 1393, 1366, 1281, 1153, 1050,
808 cmꢀ1 1H NMR (600 MHz, CDCl3) (two rotamers)
: 6.70 (br s,
a]
D
þ61.4 (c 1.4, CHCl3); IR (film)
yl]ethyl]-N-methyl-carbamic acid-1,1-dimethylethyl ester (36b). Vinyl
bromide 27b (788 mg, 1.33 mmol) was dissolved in degassed (N2)
toluene (20 mL) and transferred to a 50 mL Teflon-sealed Schlenk
tube containing a magnetic stirring bar. Silver carbonate (1.10 g,
4.0 mmol), diphenylphosphinopropane (164 mg, 0.4 mmol), and
Pd(OAc)2 (45 mg, 0.2 mmol) were added sequentially. The tube was
flushed with nitrogen, sealed, and placed in a preheated oil bath at
110 ꢁC for 3 h. The black reaction mixture was filtered through Celite
and washed with several portions of CHCl3. The filtrate was adsorbed
onto a mixture of silica gel and charcoal and loaded onto a silica gel
column. Elution with DCM/ethyl acetate, 4:1 gave compound 36b as
a yellow oil (300 mg, 44%). Rf 0.55 (hexanes/ethyl acetate, 4:1); IR
(film) nmax: 2954, 2929, 2856,1697,1507,1438,1391,1365,1279,1162,
:
;
d
1H), 6.58–6.66 (m, 1H), 6.58 (dd, J¼11.8, 1.3 Hz, 1H), 6.08–6.18 (m,
1H), 5.87 (t, J¼7.5 Hz, 1H), 4.90 (s, 1H), 3.91 (s, 3H), 3.68–3.74 (br s,
1H), 3.28–3.77 (m, 2H), 3.05–3.23 (m, 1H), 2.78 (s, 3H), 1.86–2.04
(m, 2H), 1.37–1.48 (m, 9H) ppm; 13C NMR (150 MHz, CDCl3) (two
rotamers) d: 194.0, 155.4, 146.1, 145.7, 145.0, 144.7, 129.0, 128.6,
127.8, 126.3, 124.6, 124.2, 122.1, 119.2, 119.0, 113.9, 87.3, 79.6, 56.6,
45.0, 44.8, 44.4, 38.5, 37.6, 35.2, 34.2, 29.7, 28.4 ppm; MS (EI) m/z
(%): 397 (1), 254 (23), 241 (14), 240 (77), 239 (38), 238 (12), 225
(17), 211 (14), 149 (12), 102 (21), 97 (13), 85 (27), 83 (35), 71 (20), 70
(10), 69 (18), 59 (24), 58 (23), 57 (100), 56 (13), 55 (23), 44 (31), 43
(38), 41 (31); HRMS (EI) calcd for C23H27NO5: 397.1889, found
397.1895.
1094, 865 cmꢀ1 1H NMR (600 MHz, CDCl3) (two rotamers)
; d: 6.69

H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
9871
To the enone (123 mg, 0.31 mmol) dissolved in methanol (3 mL),
(600 MHz, CDCl3)
d
: 6.69 (d, J¼8.2 Hz, 1H), 6.60 (d, J¼8.2 Hz, 1H),
was added CeCl3$7H2O (182 mg, 0.62 mmol). The reaction mixture
was stirred at ambient temperature for 5 min and then cooled to
0 ꢁC. NaBH4 (13 mg, 0.34 mmol) was added portion-wise and the
mixture was stirred at 0 ꢁC for 20 min. The solvent was removed
under reduced pressure and the residue was suspended in DCM
(15 mL). The organic layer was washed with a saturated aqueous
solution of NH4Cl (15 mL), dried over anhydrous sodium sulfate,
filtered, and the volatiles were removed under reduced pressure.
The residue was purified by flash column chromatography (DCM/
5.74 (m, 1H), 5.31 (m, 1H), 4.93 (d, J¼6.5 Hz, 1H), 4.20–4.23 (m, 1H),
3.87 (s, 3H), 3.72 (m, 1H), 3.41–3.46 (m, 1H), 3.08 (d, J¼18.5 Hz,
1H), 2.74–2.81 (m, 1H), 2.65–2.72 (m, 1H), 2.51 (s, 3H), 2.44–2.50
(m, 1H), 2.34–2.42 (m, 1H), 2.11–2.21 (m,1H), 1.92 (d, J¼12.4 Hz,1H)
ppm; 13C NMR (150 MHz, CDCl3)
d: 146.3, 142.3, 133.7, 130.8, 127.9,
119.7, 112.9, 91.2, 66.3, 59.0, 56.3, 46.5, 42.9, 42.8, 40.4, 35.4, 29.9,
20.6 ppm; MS (EI) m/z (%): 300 (21), 299 (100), 298 (14), 229 (19),
188 (13), 162 (23), 124 (22), 115 (12), 59 (14), 42 (13); HRMS (EI)
calcd for C18H21NO3: 299.1521, found 299.1520.
MeOH, 95:5) to give 110 mg (89%) of alcohol 37. Rf 0.48 (DCM/
22
MeOH, 95:5); [
a
]
þ98 (c 0.5, CHCl3); IR (film) nmax: 3449, 2973,
4.1.11. N-[2-[(5S,6R)-5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-6-
benzoyloxy-1-cyclohexen-1-yl]ethyl]-N-methyl-carbamic acid-1,1-di-
methylethyl ester (39). To a stirred solution of alcohol 25b (360 mg,
0.94 mmol) and benzoic acid (171 mg, 1.40 mmol) in THF (12 mL) at
0 ꢁC, was added a solution of the Mitsunobu reagent [previously
prepared by addition of DIAD (568 mg, 2.81 mmol) to a stirred
solution of freshly distilled tributylphosphine (736 mg, 2.81 mmol)
in THF (10 mL) at 0 ꢁC], and the mixture was warmed to rt. After
16 h, silica gel was added to the reaction mixture and the solvent
was removed under reduced pressure. The crude residue was
subjected to flash column chromatography (hexanes/ethyl acetate,
D
2932, 1690, 1637, 1507, 1457, 1393, 1366, 1269, 1160, 1089, 1051,
798 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d: 6.63 (d, J¼8.0 Hz, 1H), 6.58
(d, J¼8.0 Hz, 1H), 6.51 (d, J¼9.3 Hz, 1H), 6.00 (dd, J¼9.3, 6.2 Hz, 1H),
5.81 (d, J¼10.0 Hz, 1H), 5.28 (dd, J¼10.0, 2.3 Hz, 1H), 5.15 (br s, 1H),
4.17–4.28 (m, 1H), 3.85 (s, 3H), 3.22–3.45 (m, 1H), 2.80–2.99 (m,
2H), 2.76 (s, 3H), 2.05–2.22 (m, 1H), 1.76–1.99 (m, 1H), 1.42 (s, 9H)
ppm; 13C NMR (150 MHz, CDCl3) (two rotamers)
d: 178.4, 155.5,
145.4, 144.1, 128.3, 128.0, 127.2, 123.9, 118.1, 117.9, 112.5, 95.2, 79.4,
68.7, 56.2, 44.9, 44.4, 43.2, 43.0, 39.3, 36.9, 34.2, 28.4 ppm; MS (EI)
m/z (%): 399 (14), 343 (12), 246 (43), 242 (34), 241 (87), 240 (11),
252 (13), 224 (12), 223 (11), 213 (16), 209 (16), 181 (16), 88 (23), 86
(56), 84 (56), 59 (25), 58 (33), 57 (100), 55 (12); HRMS (EI) calcd for
C23H29NO5: 399.2046, found 399.2044.
15:1–1:1) to give compound 39 as a clear and colorless oil (380 mg,
23
83%). Rf 0.55 (hexanes/ethyl acetate, 1:1); [
a]
ꢀ5.6 (c 0.8, CHCl3);
D
IR (film) nmax: 3030, 2956, 2859, 1718, 1692, 1472, 1392, 1253,
1085 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d
: 8.08 (d, J¼7.8 Hz, 2H), 7.59
4.1.9. (3R,3aS,9aS,9bR)-3,3a,9a,9b-Tetrahydro-5-methoxy-9b-[2-
(methylamino)ethyl]-phenanthro[4,5-bcd]furan-3-ol (38). To com-
pound 37 (105 mg, 0.26 mmol) dissolved in DCM (3 mL) was added
trifluoroacetic acid (0.5 mL) dropwise at 0 ꢁC. The reaction mixture
was stirred at 0 ꢁC for 2 h and then the solvent was removed under
reduced pressure. The residue was suspended in CHCl3 and washed
with a saturated aqueous solution of Na2CO3 and brine. The aque-
ous layers were combined and extracted with CHCl3. The organic
layers were combined, dried over anhydrous magnesium sulfate,
filtered, and then the solvent was evaporated. The crude product
(t, J¼7.8 Hz, 1H), 7.47 (t, J¼7.8 Hz, 2H), 5.79–5.68 (m, 1H), 5.52 (br s,
1H), 4.03 (br s, 1H), 3.18–3.35 (m, 2H), 2.69–2.81 (m, 3H), 2.20–2.29
(m, 2H), 2.09–2.20 (m, 2H), 1.81–1.91 (m, 1H), 1.71–1.80 (m, 1H),
1.45 (s, 9H), 0.89 (s, 9H), 0.07 (s, 3H), 0.02 (s, 3H) ppm; 13C NMR
(150 MHz, CDCl3) d: 166.2, 155.7, 133.0, 131.5, 130.3, 129.7, 129.1,
128.7, 128.4, 79.3, 74.6, 74.3, 69.9, 48.2, 47.7, 34.8, 34.4, 32.4, 31.6,
31.5, 28.5, 27.9, 25.7, 22.7, 22.5, 17.9, 14.2, ꢀ4.76, ꢀ4.82 ppm; HRMS
(EI) (Mþꢀ57) calcd for C27H43NO5Si: 489.2911, found 428.2916.
4.1.12. N-[2-[(5S,6S)-5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-6-
hydroxy-1-cyclohexen-1-yl]ethyl]-N-methyl-carbamic acid-1,1-dime-
thylethyl ester (40). To a solution of compound 39 (370 mg,
0.76 mmol) in MeOH (5 mL) was added 1 M NaOH (2.3 mL,
2.3 mmol) and the resulting reaction mixture was stirred at rt for
18 h. Brine was added and MeOH was removed on the rotary
evaporator. The aqueous layer was extracted five times with ethyl
acetate and the organic layers were combined and dried over an-
hydrous sodium sulfate. The solution was filtered and the solvent
was removed under reduced pressure to yield a colorless oil, which
was purified by flash column chromatography (hexanes/ethyl ac-
was purified by flash column chromatography (DCM/MeOH, 4:1) to
22
give 69 mg (88%) of amine (þ)-38. [
a
]
þ112.5 (c 0.4, CHCl3); (lit.21d
D
ꢀ118.1 (c 0.7, CHCl3)); IR (film) nmax: 3583, 3311, 3032, 2931, 2851,
1635, 1573, 1506, 1457, 1381, 1270, 1194, 1161, 1050 cmꢀ1
(300 MHz, CDCl3)
;
1H NMR
d
: 6.64 (d, J¼7.9 Hz, 1H), 6.58 (d, J¼7.9 Hz, 1H),
6.50 (d, J¼9.0 Hz, 1H), 6.00 (dd, J¼9.3, 6.4 Hz, 1H), 5.77–5.85 (m,
1H), 5.29 (dt, J¼10.1, 2.5 Hz,1H), 5.16 (d, J¼6.1 Hz,1H), 4.19–4.26 (m,
1H), 3.85 (s, 3H), 2.78–2.86 (m, 1H), 2.71 (td, J¼5.2, 2.9 Hz, 1H),
2.31–2.49 (m, 2H), 2.36 (s, 3H), 2.06–2.19 (m, 2H), 1.78–1.92 (m, 1H)
ppm; 13C NMR (75 MHz, CDCl3)
d: 146.2, 143.8, 132.0, 129.2, 127.6,
125.1, 123.7, 117.8, 112.0, 90.5, 66.0, 56.0, 57.9, 45.4, 37.7, 36.4, 35.9,
25.8 ppm; MS (EI) m/z (%): 299 (9), 242 (53), 240 (16), 225 (24), 197
(13), 152 (10), 59 (100), 44 (54); HRMS (EI) calcd for C18H21NO3:
299.1521, found 299.1517.
etate 8:1–5:1) to yield compound 40 as a colorless oil (160 mg,
23
55%). Rf 0.62 (hexanes/ethyl acetate, 2:1); [
a
]
ꢀ12.6 (c 0.8, CHCl3);
D
IR (film) nmax: 3584, 2976, 2931, 1698, 1482, 1393, 1365, 1162 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d: 5.42 (br s,1H), 3.87–4.11 (m,1H), 3.69–
3.87 (m, 2H), 2.88 (s, 3H), 2.25–2.45 (m, 1H), 2.08–2.22 (m, 2H),
1.85–2.01 (m, 1H), 1.65–1.79 (m, 1H), 1.58–1.62 (m, 2H), 1.44 (s, 9H),
0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H) ppm; 13C NMR (150 MHz,
4.1.10. (þ)-Codeine (ent-2). Amine (þ)-38 (50 mg, 0.17 mmol) dis-
solved in THF (5 mL) was added to a mixture of Hg(OAc)2 (80 mg,
0.25 mmol) and triethylamine (60
mL, 0.40 mmol) in THF (2 mL).
CDCl3) d: 155.5, 129.3, 122.0, 80.1, 75.9, 75.6, 49.9, 48.4, 34.3, 33.5,
The mixture was stirred for 48 h and then a solution of LiAlH4 in
THF (0.46 mL (1 M THF), 0.46 mmol) was added dropwise. The re-
action mixture was stirred for 2 h and then quenched with satu-
rated aqueous solution of Na2CO3 (2 mL). The aqueous phase was
extracted with CHCl3 (3ꢂ3 mL). The organic layers were combined
and dried over anhydrous sodium sulfate. The mixture was filtered
and the solvent was evaporated under reduced pressure. The con-
centrated product was purified by flash column chromatography
32.6, 28.2, 25.4, 25.2, 25.2, 24.3, 24.0, 17.9, ꢀ4.6, ꢀ4.8 ppm; MS (EI)
m/z (%): 367 (1), 272 (16), 228 (55), 197 (35), 185 (19), 153 (13), 144
(24), 136 (22), 127 (12), 88 (20), 75 (60), 73 (36), 57 (87), 45 (11), 44
(100); HRMS (EI) (Mþꢀ18) calcd for C20H37NO3Si: 367.2543, found
367.2542.
4.1.13. N-[2-[(5S,6S)-5-Hydroxy-6-(4-nitro-benzoyloxy)-1-cyclo-
hexen-1-yl]ethyl]-N-methyl-carbamic acid-1,1-dimethylethyl ester
(42). A magnetically stirred suspension of cis-diol 33b (200 mg,
0.74 mmol) in toluene (5 mL) at 0 ꢁC was treated with p-nitrobenzoic
acid (369 mg, 2.21 mmol) and triphenylphosphine (291 mg,
1.11 mmol). DIAD (209 mg, 1.04 mmol) was added dropwise and the
(DCM/MeOH/NH4OH, 80:20:1) affording (þ)-codeine ent-2 (10 mg,
22
0.03 mmol, 17.6%). Rf 0.75 (DCM/MeOH, 4:1); [
a
]
D
þ130 (c 0.3,
EtOH) (lit.31 þ137.5 (c 0.16, EtOH)); IR (film) nmax: 3402, 2930, 2839,
1634, 1603, 1504, 1452, 1277, 1254, 1121, 1054, 942 cmꢀ1 1H NMR
;

9872
H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
23
reaction mixture was warmed to rt and stirred for 18 h. The reaction
was quenched by the addition of a saturated aqueous solution of
NaHCO3. The layers were separated and the aqueous layer was
extracted with ethyl acetate. The organic layers were combined and
washed with brine, dried over anhydrous sodium sulfate, and fil-
tered. The solvent was evaporated and the residue was purified by
flash column chromatography (hexanes/ethyl acetate, 12:1–1:1) to
0.48 (hexanes/ethyl acetate, 2:1); [
a
]
þ81.6 (c 0.9, CHCl3); IR (film)
D
nmax: 3112, 3054, 2976, 2931, 1730, 1691, 1599, 1529, 1454, 1350, 1266,
1190, 1101, 914 cmꢀ1 1H NMR (600 MHz, CDCl3) (two rotamers)
;
d:
8.28 (d, J¼7.9 Hz, 2H), 8.10 (d, J¼8.8 Hz, 2H), 7.71 (d, J¼7.9 Hz, 2H),
7.11–7.18 (m, 2H), 5.80–5.88 (m, 1H), 5.73–5.76 (m, 1H), 4.88–4.93 (m,
1H), 3.28–3.45 (m, 1H), 3.08–3.16 (m, 1H), 2.70–2.78 (m, 3H), 2.30 (s,
3H), 2.22–2.28 (m, 2H), 2.09–2.19 (m, 2H), 1.95–2.09 (m, 2H), 1.43 (s,
give the title compound 42 as a colorless oil (220 mg, 71%). Rf 0.38
9H) ppm; 13C NMR (150 MHz, CDCl3) (two rotamers)
d: 164.0, 155.6,
22
(hexanes/ethyl acetate, 1:1); [
a
]
ꢀ41.6 (c 0.6, CHCl3); IR (film) nmax
:
150.6, 144.7, 134.0, 131.0, 130.9, 129.2, 129.7, 128.6, 127.6, 123.4, 79.9,
79.6, 79.2, 72.8, 72.4, 47.6, 47.0, 34.2, 31.3, 30.7, 28.5, 26.7, 23.2, 23.0,
21.6 ppm; HRMS (EI) (Mþ-73) calcd for C24H25N2O8S: 501.1326, found
501.1330; Anal. Calcd for C28H34N2O9S: C 58.52% H 5.96%, found C
58.78% H 6.02%.
D
3424, 2977, 2931, 1722, 1692, 1529, 1396, 1270, 1161, 1102 cmꢀ1
NMR (600 MHz, acetone-d6) (two rotamers)
8.32 (d, J¼8.4 Hz, 4H), 5.64–5.81 (m, 4H), 4.38 (br s, 1H), 4.24 (br s,
1H), 4.02 (br s, 2H), 3.60 (br s,1H), 3.41 (br s, 1H), 3.23 (br s,1H), 3.08
(br s, 1H), 2.88 (br s, 1H), 2.82 (s, 3H), 2.76 (s, 3H), 2.12–2.39 (m, 8H),
1.88–1.99 (m, 2H), 1.71–1.82 (m, 2H), 1.46 (s, 18H) ppm; 13C NMR
;
1H
d: 8.39 (d, J¼8.4 Hz, 4H),
4.1.15.2. By Mitsunobu reaction of alcohol 43. To a solution of
TBS-protected diol 43 (450 mg, 1.06 mmol) in toluene (10 mL) at
0 ꢁC were added p-nitrobenzoic acid (531 mg, 3.18 mmol) and tri-
phenylphosphine (417 mg, 1.59 mmol), followed by the dropwise
addition of DIAD (299 mg, 1.48 mmol). The reaction mixture was
warmed to rt and stirred for 18 h. The reaction was quenched by the
addition of a saturated aqueous solution of NaHCO3. The layers
were separated and the aqueous layer was extracted with ethyl
acetate. The organic layers were combined and washed with brine,
dried over anhydrous sodium sulfate, and filtered. The solvent was
evaporated and the residue was purified by flash column chroma-
tography (hexanes/ethyl acetate, 15:1–1:1) to give the title com-
pound 44 as a colorless solid (474 mg, 78%). Data (mp, Rf value, 1H
(150 MHz, acetone-d6) (two rotamers) d: 164.6, 156.3, 150.7, 130.90,
130. 86, 129.1, 123.6, 78.4, 76.5, 75.3, 69.2, 68.8, 68.3, 47.7, 46.6, 33.6,
33.4, 31.6, 31.4, 27.6, 27.5, 22.7, 22.5, 21.9 ppm; MS (EI) m/z (%): 420
(1), 167 (14), 144 (35), 120 (14), 118 (11), 110 (29), 109 (13), 103 (43),
88 (10), 76 (51), 65 (15), 59 (17), 57 (83), 45 (13), 44 (100); HRMS (EI)
calcd for C21H28N2O7: 420.1897, found 420.1901; Anal. Calcd for
C21H27N2O7: C 59.99% H 6.71%, found C 60.02% H 7.24%.
4.1.14. N-[2-[(5S,6R)-[6-Hydroxy-5-(4-methylbenzenesulfonyl)-1-
cyclohexen-1-yl]ethyl]-N-methyl-carbamic acid-1,1-dimethylethyl es-
ter (43). To a solution of diol 33b (2.0 g, 7.4 mmol) and tosylchloride
(2.5 g, 13.3 mmol) in DCM (20 mL) were added triethylamine (1.9 g,
18.5 mmol) and DMAP (catalytic amount) at 0 ꢁC. The reaction
mixture was warmed to rt and was stirred until complete con-
sumption of starting materials (TLC, 18 h). The solution was diluted
with DCM (20 mL) and washed three times with a saturated aqueous
solution of Na2CO3, three times with a saturated aqueous solution of
NH4Cl, and brine. The organic layer was dried over anhydrous so-
dium sulfate, filtered, and the solvent was removed under reduced
pressure. Purification of the crude residue by flash column chro-
matography afforded the tile compound 43 as colorless oil (1.1 g,
NMR and 13C spectra, [
a]D) were found identical to those of com-
pound 44 obtained by tosylation of alcohol 42.
4.1.16. N-[2-[(5S,6R)-[5,6-Dihydroxy-1-cyclohexen-1-yl]ethyl]-N-
methyl-carbamic acid-1,1-dimethylethyl ester (45). To a solution of
compound 42 (200 mg, 0.48 mmol) in MeOH (3 mL) was added 1 M
NaOH (1.43 mL, 1.43 mmol) and the resulting reaction mixture was
stirred at rt for 18 h. Brine was added and MeOH was removed on
the rotary evaporator. The aqueous layer was extracted five times
with ethyl acetate and the organic layers were combined and dried
over anhydrous sodium sulfate. The solution was filtered and the
solvent was removed under reduced pressure to yield a colorless
oil, which was purified by flash column chromatography (hexanes/
35%) and 0.9 g (45%) of recovered starting material. Rf 0.48 (hexanes/
22
ethyl acetate, 1:1); [
a
]
þ107.1 (c 0.10, CHCl3); IR (film) nmax: 3400,
D
2918, 2849, 1689, 1672, 1599, 1483, 1453, 1395, 1364, 1180, 1123,
1098 cmꢀ1 1H NMR (600 MHz, CDCl3) (two rotamers)
;
d: 7.78–7.92
(m, 2H), 7.31–7.39 (m, 2H), 5.38–5.59 (m, 1H), 4.56–4.69 (m, 1H),
4.00–4.23 (m, 2H), 3.58–3.70 (m, 1H), 3.18–3.39 (m, 1H), 3.00–3.13
(m, 1H), 2.82 (s, 3H), 2.45 (s, 3H), 2.26–2.37 (m, 1H), 2.08–2.19 (m,
2H), 1.95–2.07 (m, 2H), 1.41 (br s, 9H) ppm; 13C NMR (150 MHz,
ethyl acetate, 4:1–1:3) to yield compound 45 as a colorless oil
23
(98 mg, 76%). Rf 0.10 (hexanes/ethyl acetate, 1:1); [
a
]
þ17.6 (c 1.0,
D
CHCl3); IR (film) nmax: 3430, 2975, 2929, 1695, 1673, 1484, 1397,
1366, 1158, 1048 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d: 5.34 (br s, 1H),
CDCl3)
d
: (two rotamers): 156.4, 144.5, 134.3, 134.0, 129.8, 127.8,
3.96–4.06 (m, 1H), 3.62–3.78 (m, 2H), 3.58 (br s, 2H), 2.98–3.18 (m,
1H), 2.82 (s, 3H), 2.31–2.43 (m, 1H), 2.20–2.31 (m, 1H), 1.95–2.20
(m, 2H), 1.82–1.95 (m, 1H), 1.55–1.71 (m, 1H), 1.45 (s, 9H) ppm; 13C
NMR (75 MHz, CDCl3) d: 156.7, 134.6, 126.7, 79.8, 74.7, 73.2, 47.8,
34.1, 32.6, 28.5, 28.3, 27.2, 23.7 ppm; HRMS (EI) calcd for
C14H25NO4: 271.1784, found 271.1782.
127.4, 81.4, 79.6, 68.1, 47.6, 34.0, 33.8, 28.3, 24.3, 23.9, 22.5, 21.7 ppm;
HRMS (EI) (Mþꢀ73) calcd for C17H22NO5S: 352.1219, found 352.1228;
Anal. Calcd for C21H31NO6S: C 59.27% H 7.34%, found C 59.34% H
7.18%.
4.1.15. N-[2-[(5S,6S)-[5-(4-Methylbenzenesulfonyl)-6-(4-nitro-benzo-
yloxy)-1-cyclohexen-1-yl]ethyl]-N-methyl-carbamic acid-1,1-dimethyl-
ethyl ester (44). 4.1.15.1. By tosylation of alcohol 42. To a solution of
nitrobenzoate 42 (2.3 g, 5.5 mmol) in DCM (30 mL) were added
tosylchloride (5.2 g, 27.4 mmol), triethylamine (7.6 mL, 54.8 mmol),
and DMAP (60 mg) at 0 ꢁC. The reaction mixture was warmed to rt
and stirred for 22 h, before it was quenched by the addition of water
(20 mL). The layers were separated and the aqueous layer was
extracted three times with DCM (20 mL). The organic extracts were
combined, washed three times with a saturated aqueous solution of
Na2CO3, three times with a saturated aqueous solution of NH4Cl, and
brine. The organic layers were dried over anhydrous sodium sulfate,
filtered, and the solvent was evaporated under reduced pressure.
Purification of the crude residue by flash column chromatography
(hexanes/ethyl acetate, 9:1–1:1) gave the title compound 44 as col-
orless solid (2.5 g, 78%). Mp 135–136 ꢁC (hexanes/ethyl acetate); Rf
4.1.17. tert-Butyl-2-(7-oxa-bicyclo[4.1.0]hept-2-en-2-yl)ethylmethyl-
carbamate (þ)-(29). 4.1.17.1. From trans-diol 45. A solution of trans-
diol 45 (80 mg, 0.30 mmol) in THF (1 mL) at 0 ꢁC was treated with
bromoisovanillin 34 (205 mg, 0.89 mmol) and triphenylphosphine
(116 mg, 0.44 mmol). DIAD (89 mg, 0.44 mmol) was added dropwise
and the reaction mixture was warmed to rt and stirred for 18 h. The
reaction was quenched by the addition of a saturated aqueous so-
lution of NaHCO3. The layers were separated and the aqueous layer
was extracted with ethyl acetate. The organic layers were combined
and washed with brine, dried over anhydrous sodium sulfate, and
filtered. The solvent was evaporated and the residue was purified by
flash column chromatography (hexanes/ethyl acetate, 5:1–1:1) to
give the title compound (þ)-29 as a colorless oil (30 mg, 45%). Rf 0.40
22
(hexanes/ethyl acetate, 2:1); [
a
]
þ20.6 (c 0.25, CHCl3); IR (film)
D
nmax: 2976, 2931, 1692, 1482, 1393, 1365. 1134 cmꢀ1 1H NMR
;

H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
9873
(600 MHz, CDCl3)
d
: 5.63 (d, J¼6.6 Hz, 1H), 3.54 (br s, 1H), 3.38–3.53
2869, 2741, 1678, 1579, 1482, 1440, 1367, 1276, 1253, 1164, 1029,
938 cmꢀ1 1H NMR (600 MHz, CDCl3)
: 10.27 (s, 1H), 7.73 (d,
J¼8.6 Hz, 1H), 6.97 (d, J¼8.6 Hz, 1H), 5.71–5.75 (m, 1H), 4.78–4.82
(m, 1H), 3.98–4.06 (m, 2H), 3.95 (s, 3H), 3.53 (br s, 1H), 2.89 (s, 3H),
2.80–2.87 (m, 1H), 2.65–2.79 (m, 1H), 2.22–2.37 (m, 2H), 2.03–2.21
(m, 2H), 1.80–1.89 (m, 1H), 1.42 (s, 9H) ppm; 13C NMR (150 MHz,
(m, 1H), 3.12–3.30 (m, 2H), 2.89 (br s, 3H), 2.32–2.48 (m, 2H), 2.16–
2.28 (m, 1H), 1.88–2.04 (m, 2H), 1.52–1.60 (m, 1H), 1.48 (s, 9H) ppm;
;
d
13C NMR (150 MHz, CDCl3)
d: 155.7, 132.1, 127.3, 79.7, 55.4, 50.2; 48.4,
47.8, 34.8, 34.5, 34.2, 28.5, 20.8, 20.2 ppm; MS (EI) m/z (%): 253 (1),
144 (34), 110 (24), 88 (10), 57 (94), 44 (100); HRMS (EI) calcd for
C14H23NO3: 253.1678, found 253.1680; Anal. Calcd for C14H23NO3: C
66.37% H 9.15%, found C 66.37% H 9.09%.
CDCl3) d: 191.3, 158.1, 157.1, 144.7, 130.9, 130.4, 127.6, 126.1, 123.4,
111.0, 80.0, 76.9, 66.4, 56.1, 46.3, 34.0, 32.8, 28.5, 28.5, 24.3,
20.7 ppm; HRMS (EI) (Mþꢀ73) calcd for C18H21NO5: 410.0603,
found 410.0601; Anal. Calcd for C22H30BrNO6: C 54.55% H 6.24%,
found C 54.68% H 6.41%.
4.1.18. tert-Butyl-2-(7-oxa-bicyclo[4.1.0]hept-2-en-2-yl)ethylmethyl-
carbamate (ꢀ)-(29). 4.1.18.1. From compound 44. Compound 44
(1.70 g, 2.96 mmol) was dissolved in THF (30 mL) and 0.5 M sodium
methoxide solution in MeOH (7.1 mL) was added dropwise at 0 ꢁC.
The reaction mixture was stirred at 0 ꢁC for 1 h, before it was
quenched by the addition of a saturated aqueous solution of NH4Cl
(50 mL). The organic solvent was removed under reduced pressure
and the aqueous layer was extracted five times with ethyl acetate. The
organic extracts were combined and dried over anhydrous sodium
sulfate. The solution was filtered and the solvent was removed under
reduced pressure. The residue was purified by flash column chro-
4.1.21. tert-Butyl-2-((4aR,10aR)-6-bromo-7-formyl-1,2,4a,10a-tetrahy-
drodibenzo [b,e][1,4] dioxin-4-yl)ethylmethylcarbamate (50). Colorless
22
oil; Rf 0.42 (hexanes/ethyl acetate, 3:1); [
a
]
þ168.3 (c 0.5, CHCl3); IR
D
(film) nmax: 2975, 2931, 2873,1686, 1591, 1561, 1477, 1392,1280,1160,
1052, 969 cmꢀ1 1H NMR (600 MHz, DMSO-d6) (two rotamers)
;
d:
10.14 (s, 1H), 7.46 (d, J¼8.7 Hz, 1H), 7.12 (d, J¼8.7 Hz, 1H), 5.58–5.66
(m, 1H), 4.60–4.79 (m, 1H), 4.10–4.25 (m, 1H), 3.47–3.78 (m, 1H),
2.74–2.88 (m, 3H), 2.52–2.64 (m, 1H), 2.13–2.47 (m, 4H), 1.63–1.87
(m, 2H), 1.28–1.44 (s, 9H) ppm; 13C NMR (600 MHz based on HSQC,
matography (hexanes/ethyl acetate, 9:1–3:1) to give the title com-
pound (ꢀ)-29 as colorless oil (0.66 g, 88%). [
22
a]
ꢀ21.0 (c 0.25, CHCl3).
DMSO-d6) (two rotamers) d: 190.7, 127.9, 123.9, 117.2, 76.5, 75.5, 40.3,
D
34.1, 30.1, 28.3, 25.7, 23.9 ppm; HRMS (EI) calcd for C21H26BrNO5:
451.0994, found 451.0995; Anal. Calcd for C21H26BrNO5: C 55.76% H
5.79%, found C 56.51% H 5.96%.
4.1.19. N-[2-[(5R,6R)-[5-Hydroxy-6-phenoxy-1-cyclohexen-1-yl]-
ethyl]-N-methyl-carbamic acid-1,1-dimethylethyl ester (46). To a so-
lution of epoxide (ꢀ)-29 (50 mg, 0.20 mmol) in DME (0.5 mL) was
added potassium phenoxide (52 mg, 0.40 mmol) followed by the
addition of 18-crown-6-ether (catalytic amount). The reaction
mixture was heated at reflux for 16 h, before it was cooled to rt
and quenched by the addition of water (2 mL). The layers were
separated and the aqueous layer was extracted three times with
ethyl acetate. The organic layers were combined, washed three
times with a saturated aqueous solution of Na2CO3 and brine. The
organic layer was dried over anhydrous sodium sulfate, filtered,
and the solvent was removed under reduced pressure. The crude
residue was purified by flash column chromatography (hexanes/
ethyl acetate, 5:1–1:1) and the title compound 46 was isolated as
4.1.22. N-[2-[(5R,6R)-6-(2-Bromo-3-formyl-6-methoxyphenoxy)-5-
[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-cyclohexen-1-yl]ethyl]-N-
methyl-carbamic acid-1,1-dimethylethylester (53). To a solution of
alcohol 28 (15 mg, 0.03 mmol) in diethyl ether (0.5 mL) were added
imidazole (8.2 mg, 0.12 mmol) and TBDMSCl (9.1 mg, 0.06 mmol) at
ꢀ60 ꢁC. The reaction mixture was warmed to rt and stirred at
ambient temperature for 18 h. The reaction mixture was diluted
with DCM (5 mL) and extracted three times with a saturated
aqueous solution of NH4Cl. The organic layer was washed with
brine, dried over anhydrous sodium sulfate, and filtered. Evapora-
tion of the solvent and purification of the crude residue by flash
colorless oil (54 mg, 78%). Rf 0.35 (hexanes/ethyl acetate, 2:1);
column chromatography gave the title compound 53 as colorless oil
23
21
[
a
]
ꢀ33.2 (c 0.59, CHCl3); IR (film) nmax: 3429, 2975, 2928, 1694,
(11 mg, 61%). Data for 53 is identical to data of 26b except for [a]
D
D
22
1670, 1596, 1492, 1454, 1396, 1366, 1228, 1164, 1078 cmꢀ1; 1H NMR
(600 MHz, CDCl3)
ꢀ55.8 (c 0.325, CHCl3); 26b [
a
]
þ59.1 (c 0.35, CHCl3).
D
d
: 7.31 (t, J¼7.4 Hz, 2H), 7.07 (d, J¼7.4 Hz, 2H),
6.98 (t, J¼7.4 Hz, 1H), 5.70–5.73 (m, 1H), 4.69–4.72 (m, 1H), 4.15–
4.19 (m, 1H), 3.85–3.93 (m, 1H), 3.63 (d, J¼6.4 Hz, 1H), 2.86 (s, 3H),
2.73–2.80 (m, 1H), 2.13–2.32 (m, 3H), 2.04–2.11 (m, 1H), 1.77–1.85
4.1.23. N-[2-[(5aR,6R,9aS)-6-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-
1-formyl-6,7-dihydro-4-methoxy-9a(5aH)-dibenzofuranyl]ethyl]-N-
methyl-carbamic acid-1,1-dimethylethyl ester (54). Following the
same procedure as for the preparation of compound 35b, using
compound 53 (380 mg, 0.64 mmol), Pd(OAc)2 (22 mg, 0.10 mmol),
dppf (105 mg, 0.19 mmol), and Ag2CO3 (533 mg, 1.91 mmol) as
starting materials, gave 301 mg (91%) of compound (ꢀ)-54. Data for
(m, 2H), 1.46 (s, 9H) ppm; 13C NMR (150 MHz, CDCl3)
d: 158.6,
157.0, 130.6, 129.7, 121.1, 115.6, 79.9, 73.6, 66.0, 46.3, 34.0, 32.7,
28.5, 24.4, 20.7 ppm; HRMS (EI) calcd for C20H29NO4: 347.2097,
found 347.2084; Anal. Calcd for C20H29NO4: C 69.14% H 8.41%,
found C 68.85% H 8.49%.
(ꢀ)-54 (1H NMR spectra, Rf value) are identical to those of com-
22
pound 35b, except for optical rotation. 54: [
a]
ꢀ8.5 (c 0.60,
D
24
4.1.20. N-[2-[(5R,6R)-6-(2-Bromo-3-formyl-6-methoxyphenoxy)-5-
hydroxy-1-cyclohexen-1-yl]ethyl]-N-methyl-carbamic acid-1,1-dime-
CHCl3); 35b: [
a
]
þ12.5 (c 0.60, CHCl3).
D
thylethylester (28). To
a
solution of epoxide (ꢀ)-29 (90 mg,
4.1.24. N-[2-[(5aR,6R,9aS)-1-(2-Bromoethenyl)-6-[[(1,1-dimethyle-
thyl)dimethylsilyl]oxy]-6,7-dihydro-4-methoxy-9a(5aH)-dibenzofur-
anyl]ethyl]-N-methyl-carbamic acid-1,1-dimethylethyl ester (55).
Following the same procedure as for the preparation of compound
27b, using compound (ꢀ)-54 (0.75 g, 1.45 mmol), ylide (prepared by
refluxing a solution of triphenylphosphine (15 g, 57.0 mmol) and
methylene bromide (22.3 g, 115 mmol) in toluene (100 mL) for 24 h.
The mixture was cooled to 0 ꢁC and the precipitate was collected by
filtration. The product was washed with toluene and dried under
reduced pressure (1.26 g, 2.90 mmol), and potassium tert-butoxide
(0.31 g, 2.76 mmol), gave 344 mg (40%) of compound 55. Data for 55
(1H NMR spectra, Rf value) are identical to those of compound 27b,
0.375 mmol) in DME (0.5 mL) and DMF (0.5 mL) was added po-
tassium phenoxide derivative 47 (260 mg,1.126 mmol), followed by
the addition of 18-crown-6-ether (catalytic amount). The reaction
mixture was heated at 80 ꢁC for 48 h, before it was cooled to rt and
diluted with diethyl ether (20 mL). The organic layer was extracted
three times with a saturated aqueous solution of Na2CO3 (10 mL),
ten times with water (0.5 mL) and brine. The organic layer was
dried over anhydrous sodium sulfate, filtered, and the solvent was
removed under reduced pressure. Purification by flash column
chromatography (hexanes/ethyl acetate, 4:1–1:1) gave the title
compound 28 (130 mg, 75%) and tricyclic compound 50 (8 mg, 5%).
21
21
Compound 28: colorless oil; Rf 0.35 (hexanes/ethyl acetate, 3:2);
except for optical rotation. 55: [
a
]
ꢀ37.1 (c 1.30, CHCl3); 27b [
a]
D
D
23
[
a]
ꢀ93.0 (c 0.2, CHCl3); IR (film) nmax: 3428, 3088, 2975, 2931,
þ46.6 (c 1.20, CHCl3).
D

9874
H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
4.1.25. N-[2-[(3R,3aR,9aR,9bS)-3-[[(1,1-Dimethylethyl)dimethylsily-
l]oxy]-3,9a-dihydro-5-methoxyphenanthro[4,5-bcd]furan-9b(3 H)-
This mixture of compounds (28 mg) dissolved in THF (1 mL) was
added to a mixture of Hg(OAc)2 (45 mg, 0.14 mmol) and triethyl-
a
yl]ethyl]-N-methyl-carbamic acid-1,1-dimethylethyl ester (56).
Following the same procedure as for the preparation of compound
36b, using compound (ꢀ)-55 (325 mg, 0.55 mmol), Pd(OAc)2
(31 mg, 0.14 mmol), dppp (111 mg, 0.27 mmol), and Ag2CO3
(451 mg, 1.64 mmol) as starting materials, gave 127 mg (45%) of
amine (33 mL, 0.23 mmol) in THF (1 mL). The mixture was stirred for
48 h and then a solution of LAH in THF (10 mg, 0.25 mmol in 1 mL of
THF) was added dropwise. The reaction mixture was stirred for 2 h
and then quenched with saturated aqueous solution of Na2CO3
(2 mL). The aqueous phase was extracted with CHCl3 (3ꢂ3 mL). The
organic layers were combined and dried over anhydrous sodium
sulfate. The mixture was filtered and the solvent was evaporated
under reduced pressure. The concentrated product (26 mg) was
purified by flash column chromatography (DCM/MeOH/NH4OH,
100:0:0–90:10:1) affording (ꢀ)-codeine (4.2 mg, 0.014 mmol, 8%
compound 56. Data for 56 (1H NMR spectra, Rf value) are identical
22
to those of compound 36b, except of optical rotation: [
(c 0.3, CHCl3).
a
]
þ22.1
D
4.1.26. N-[2-[(3S,3aR,9aR,9bS)-3,9a-Dihydro-3-hydroxy-5-methoxy-
phenanthro[4,5-bcd]furan-9b(3 H)-yl]ethyl]-N-methyl-carbamic
a
over four steps). Data for (ꢀ)-codeine (2) (1H NMR spectra, Rf value)
20
acid-1,1-dimethylethyl ester (57). Following the same procedure as
for the preparation of compound 37, using compound 56 (125 mg,
0.24 mmol) and TBAF (0.27 mL, 1 M in THF) as starting materials,
gave 72 mg (72%) of alcohol 57. Data for 57 (1H NMR spectra, Rf
value) are identical to those of compound 37, except for optical
are identical to those of (þ)-codeine (2); [
a
]
ꢀ124.6 (c 0.15, EtOH),
D
27
(lit.7b
[
a]
ꢀ137 (c 1.15, EtOH)).
D
Acknowledgements
21
21
rotation. 57: [
CHCl3).
a
]
þ68.5 (c 0.65, CHCl3); 37 [
a]
ꢀ80.5 (c 1.20,
D
D
The authors are indebted to Natural Sciences and Engineering
Research Council (NSERC) of Canada, Canadian Foundation for In-
novation (CFI), Ontario Innovation Trust (OIT), Coordenaça˜o de
Aperfeiçoamento de Pessoal de Nivel Superior (CAPES; postdoctoral
fellowship for A.T.O.), Research Corporation, Brock University, TDC
Research Inc., and TDC Research Foundation for financial support of
this work. We are also thankful to Professor Tang (U. Wisconsin) for
his help in supplying experimental and spectral data for the pho-
tolytic hydroamination conditions attempted by us in the first
generation approach to codeine.
4.1.27. (3S,3aR,9aR,9bS)-3,3a,9a,9b-Tetrahydro-5-methoxy-9b-[2-
(methylamino)ethyl]-phenanthro[4,5-bcd]furan-3-ol (58). To alcohol
57 (70 mg, 0.18 mmol) dissolved in DMF (2 mL) was added IBX
(49 mg, 0.18 mmol) at rt. The reaction mixture was stirred at rt for
2 h (TLC indicated unreacted starting material) and additional IBX
(15 mg, 0.05 mmol) was added. After complete consumption of
starting material (TLC) the reaction mixture was quenched with
water (20 mL). The phases were separated and the aqueous phase
was extracted with DCM (3ꢂ20 mL). The organic layers were
combined, washed with a saturated aqueous solution of NaHCO3,
then dried over anhydrous sodium sulfate. Filtration and removal of
the solvent under reduced pressure gave the crude product, which
was purified by flash column chromatography (DCM/ethyl acetate,
9:1–4:1) to afford 60 mg of a mixture of two compounds. Exhaus-
tive purification by flash column chromatography gave 7 mg in 90%
purity of compound 58 and 50 mg of a 1:1 mixture of compounds
(58 and a yet unidentified byproduct). Data for 58 (1H NMR spectra,
Supplementary data
General methods, experimental data for compounds 33a, 25a,
26a, 35a, 27a, 36a, 59, 56 (from 59), and copies of proton and
carbon spectra for all reported compounds are provided. Supple-
mentary data associated with this article can be found in online
version, at doi:10.1016/j.tet.2009.09.052.
Rf value) are nearly identical to its enantiomer obtained during the
References and notes
22
preparation of 37, except for optical rotation. 58: [
a
]
ꢀ59.2 (c 0.35,
D
1. For preliminary disclosure of this work see: Omori, T. A.; Finn, K. J.; Leisch, H.;
Carroll, R. J.; Hudlicky, T. Synlett 2007, 2859.
2. For a review of chemistry and pharmacology of opiates and their derivatives
see: (a) Opium Poppy: Botany, Chemistry, and Pharmacology; Kapoor, L. D., Ed.;
The Haworth: New York, NY, 1995; 326 pp; (b) Bryant, R. J. Chem. Ind. 1988, 5,
146.
3. (a) Report of the International Narcotics Control Board for 2005, ISBN 92-1-
148209-7 ISSN 0257-3717, p 17; (b) For production quotas of morphine alkaloids
for the U.S. see: http://www.deadiversion.usdoj.gov/quotas/quota_history.htm.
4. See for example:Opium: A History; Booth, M., Ed.; St. Martin’s: New York, NY,
1998; 381 pp.
CHCl3); corresponding enantiomer of the enone produced in the
21
conversion of 36b to 37: [
a
]
þ61.4 (c 1.4, CHCl3).
D
4.1.28. (ꢀ)-Codeine (2). To a mixture of compounds (1:1, 58 and
unidentified byproduct) (50 mg) dissolved in methanol (1 mL), was
added CeCl3$7H2O (70 mg, 0.19 mmol). The reaction mixture was
stirred at ambient temperature for 5 min and then cooled to 0 ꢁC.
NaBH4 (5 mg, 0.14 mmol) was added in one portion and the mix-
ture was stirred at 0 ꢁC for 20 min. The solvent was removed under
reduced pressure and the residue was suspended in DCM (10 mL).
The organic layer was washed with a saturated aqueous solution of
NH4Cl (10 mL), dried over anhydrous sodium sulfate, filtered and
the volatiles were removed under reduced pressure. The residue
was purified by flash column chromatography (DCM/MeOH, gra-
dient and DCM/ethyl acetate, gradient) to give 38 mg of a mixture
of compounds (1.25:1).
5. (a) Sertu¨rner, F. W. Trommsdorff’s J. Pharm.1806,14, 47; (b) Sertu¨rner, F. W. Gilbert’s
Ann. Phys. 1817, 25, 56.
6. For the historical account of morphine structure elucidation see: (a) Holmes, H. L.
In The Alkaloids, Chemistry and Physiology; Manske, R. H. F., Holmes, H. L., Eds.;
1952; Vol. 2, p 2; (b) Butora, G.; Hudlicky, T. In The Story of Morphine Structure
Elucidation: One Hundred Years of Deductive Reasoning; Hudlicky, T., Ed.; Organic
Synthesis: Theory and Applications; JAI: Stamford, CT, 1998; Vol. 4, pp 1–51;
(c) Gulland, J. M.; Robinson, R. Mem. Proc. Manchester Lit. Phil. Soc. 1925, 69, 79.
7. (a) Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1952, 74, 1109; (b) J. Am. Chem. Soc.
1956, 78, 1380.
8. Kalvoda, J.; Buchschacher, P.; Jeger, O. Helv. Chim. Acta 1955, 38, 1847.
9. Mackay, M.; Hodgin, D. C. J. Chem. Soc. 1955, 3261.
To this mixture of compounds (38 mg) dissolved in DCM (1 mL)
was added trifluoroacetic acid (0.25 mL) dropwise at 0 ꢁC. The re-
action mixture was stirred at 0 ꢁC for 2 h and then the solvent was
removed under reduced pressure. The residue was suspended in
CHCl3 and washed with a saturated aqueous solution of Na2CO3 and
brine. The aqueous layers were combined and extracted with CHCl3.
The organic layers were combined, dried over anhydrous magne-
sium sulfate, filtered, and then the solvent was evaporated. The
crude product was purified by flash column chromatography (DCM/
MeOH, 4:1) to give 28 mg of a mixture of compounds (1.25:1).
10. For reviews of morphine syntheses, see: (a) Zezula, J.; Hudlicky, T. Synlett 2005,
388; (b) Taber, D. F.; Neubert, T. D.; Schlecht, M. F. In Strategies and Tactics in
Organic Synthesis; Harmata, M., Ed.; 2004; Vol. 5, p 353; (c) Blakemore, P. R.;
White, J. D. Chem. Commun. 2002, 1159; (d) Novak, B. H.; Hudlicky, T.; Reed, J. W.;
Mulzer, J.; Trauner, D. Curr. Org. Chem. 2000, 4, 343; (e) Hudlicky, T.; Butora, G.;
Fearnley, S.; Gum, A.; Stabile, M. In Studies in Natural Products Chemistry; Atta-ur-
Rahman, Ed.; Elsevier: Amsterdam, 1996; Vol. 18, p 43; (f) Waldman, H. Organic
Synthesis Highlights II; 1995; p 407; (g) Maier, M. Organic Synthesis Highlights II;
1995; p 357.
11. Uchida, K.; Yokoshima, S.; Kan, T.; Fukuyama, T. Org. Lett. 2006, 8, 5311.
12. Varin, M.; Barre, E.; Iorga, B.; Guillou, C. Chem.dEur. J. 2008, 14, 6606.

H. Leisch et al. / Tetrahedron 65 (2009) 9862–9875
9875
13. Stork, G.; Yamashita, A.; Adams, J.; Schulte, G. R.; Chesworth, R.; Miyazaki, Y.;
Farmer, J. J. J. Am. Chem. Soc. 2009, 131, 11403.
Chem., Int. Ed. 2002, 41, 2795; (d) Trost, B. M.; Tang, W.; Toste, F. D. J. Am. Chem.
Soc. 2005, 127, 14785.
14. Rice, K. C. J. Org. Chem. 1980, 45, 3135.
22. (a) Frey, D. A.; Duan, C.; Hudlicky, T. Org. Lett. 1999, 1, 2085; (b) Frey, D. A.;
Duan, C.; Ghiviriga, I.; Hudlicky, T. Collect. Czech. Chem. Commun. 2000, 65,
561.
23. Zezula, J.; Rice, K. C.; Hudlicky, T. Synlett 2007, 2863.
24. Butora, G.; Hudlicky, T.; Fearnley, S. P.; Gum, A. G.; Stabile, M. R.; Abboud, K.
Tetrahedron Lett. 1996, 37, 8155.
25. Problems with benzamide hydrolysis complicated the first asymmetric syn-
thesis of pancratistatin and were only alleviated at the expense of additional
steps and functional manipulations. See: (a) Tian, X.; Hudlicky, T.; Ko¨nigsberger,
K. J. Am. Chem. Soc. 1995, 117, 3643; (b) Hudlicky, T.; Tian, X.; Konigsberger, K.;
Maurya, R.; Rouden, J.; Fan, B. J. Am. Chem. Soc. 1996, 118, 10752.
26. Large scale synthesis of bromoisovanillin was adapted from: Noire, P. D.;
Franck, R. W. Synthesis 1980, 882.
15. For definition of this term, coined by David Evans, see: (a) Hudlicky, T.; Reed, J.
W. In The Way of Synthesis: Evolution of Design and Methods for Natural Products;
Wiley-VCH: Weinheim, 2007; Chapter 2.4.5, p 186; (b) Wong, H. N. C.; Hon, M.
Y.; Tse, C. W.; Yip, Y. C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165.
16. (a) Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114, 9688; (b) Parker, K. A.;
Fokas, D. J. Org. Chem. 1994, 59 3927 and 3933; (c) Parker, K. A.; Fokas, D. J. Org.
Chem. 2006, 71, 449.
17. Butora, G.; Hudlicky, T.; Fearnley, S. P.; Stabile, M. R.; Gum, A. G.; Gonzalez, D.
Synthesis 1998, 665.
18. (a) Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 11028;
(b) Heerding, D. A.; Hong, C. Y.; Kado, N.; Look, G. C.; Overman, L. E. J. Org. Chem.
1993, 58, 6947.
19. Liou, J.-P.; Cheng, C.-Y. Tetrahedron Lett. 2000, 41, 915.
20. Hsin, L.-W.; Chang, L.-T.; Chen, C.-W.; Hsu, C.-H.; Chen, H.-W. Tetrahedron 2005,
61, 513.
27. Banwell, M. G.; Edwards, A. J.; Loong, D. T. J. Arkivoc 2004, x, 53.
28. Nakatani, K.; Okamoto, A.; Saito, I. Angew. Chem., Int. Ed. 1997, 36, 2794.
29. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
21. (a) Trost, B. M.; Tang, W. J. Am. Chem. Soc. 2002, 124, 14542; (b) Trost, B. M.;
Toste, F. D. J. Am. Chem. Soc. 2000, 122, 11262; (c) Trost, B. M.; Tang, W. Angew.
30. Stabile, M. R.; Hudlicky, T.; Meisels, M. L. Tetrahedron: Asymmetry 1995, 6, 537.
31. White, J. D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1999, 64, 7871.