Total synthesis of dihydrocodeine and hydrocodone via a double claisen rearrangement and C-10/C-11 closure strategy

Article abstract of DOI:10.1055/s-0032-1318114

Dihydrocodeine and hydrocodone were synthesized from bromobenzene in 16 and 17 transformations, respectively. The key steps involved the toluene dioxygenase-mediated dihydroxylation of bromobenzene by whole-cell fermentation with E. coli JM109(pDTG601A), Kazmaier-Claisen rearrangement of glycinate ester, Claisen rearrangement to set the C-13 quaternary center, and C-10-C-11 closure. Experimental procedures are provided for the key steps. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0032-1318114

LETTER
▌369
letter
Total Synthesis of Dihydrocodeine and Hydrocodone via a Double Claisen
Rearrangement and C-10/C-11 Closure Strategy
Total Synthesis of Dihydrocodeine and Hydrocodone
Vimal Varghese, Tomas Hudlicky*
Chemistry Department and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada
Fax +1(905)9844841; E-mail: thudlicky@brocku.ca
Received: 06.12.2012; Accepted after revision: 04.01.2013
1). Ireland reported that cyclohexenyl derivatives contain-
Abstract: Dihydrocodeine and hydrocodone were synthesized
ing substituents on the ring frequently undergo the Ire-
from bromobenzene in 16 and 17 transformations, respectively. The
land–Claisen rearrangement through both chair and boat
key steps involved the toluene dioxygenase-mediated dihydroxy-
lation of bromobenzene by whole-cell fermentation with E. coli
transition states and therefore result in isomeric mixtures.7
JM109(pDTG601A), Kazmaier–Claisen rearrangement of glyci-
nate ester, Claisen rearrangement to set the C-13 quaternary center,
ylation of bromobenzene with E. coli JM109
and C-10–C-11 closure. Experimental procedures are provided for
When diol 1 (X = Br),8 obtained by enzymatic dihydrox-
(pDTG601A),9 was subjected to the sequence depicted in
Scheme 1, two diastereomers of amino acid 4 were ob-
tained in approximately 2:1 ratio. After esterification with
the key steps.
Key words: enzymatic dihydroxylation of arenes, whole-cell
fermentation, Kazmaier–Claisen rearrangement, hydrocodone,
diazomethane and separation of the isomers, 5b was sub-
jected to base-catalyzed equilibration to provide a mixture
of 5a (39%) and 5b (49%), which was separated by col-
umn chromatography. This process was repeated until all
of the material was converted into pure 5a with the correct
absolute configuration at C-9 (morphine numbering). We
speculated that such equilibration is possible because of a
more stable, weakly hydrogen-bonded, conformation in
cases where X = Br, Cl, as shown in Scheme 1. The ester
functionality is axial in 5a and equatorial in 5b. In both
orientations it experiences steric hindrance (cyclohexene
methylene in 5a and Boc group in 5b) and hence equili-
bration of either diastereomer yields an approximately 1:1
mixture, with eventual production of 5a by recycling. The
corresponding isomeric mixtures where X = Me or aryl
were not responsive to the base-catalyzed equilibration,10
presumably because of steric hindrance and reduced
availability of the C-9 proton in the less rigid conforma-
tion.
dihydrocodeine, morphine alkaloids
The effort aimed at the total synthesis of morphine and re-
lated alkaloids has continued unabated over the 60 years
since Gates’s milestone preparation.1 The more than 30
published total syntheses of morphine, codeine, and their
congeners have been summarized in several reviews.2 As
creative as many of the published approaches are, none
compare in efficiency to that reported by Rice in 1980;3
however, even that one falls short of competing in price
with morphine obtained from natural sources. Although
morphine is not a particularly complex molecule, it is
completely dissonant in its connectivity, and thus any syn-
thetic strategy employed requires tactical adjustments to
overcome these issues. Such adjustments invariably lead
to longer sequences.
We have pursued diverse approaches to morphine alka-
loids for many years and have succeeded in several total
syntheses;4 however, we have not yet achieved a truly
practical approach. Nevertheless, our exploitation of dif-
ferent strategies provides us with an opportunity for fur-
ther improvements through multi-generational design.
Herein we report an approach to hydrocodone and di-
hydrocodeine based on a sequential Claisen rearrange-
ment and a C-10/C-11 closure, one that has not been
extensively used for morphine alkaloids.5
Ester 5a was subjected to Suzuki coupling with 2,3-dime-
thoxyboronic acid to produce cleanly the amino ester 6.
We initially attempted to elicit the C-10/C-11 closure to a
complete phenanthrene skeleton by treating the carboxyl-
ic acid derived from 6 with polyphosphoric acid (PPA) or
TsOH but under these conditions we have observed only
addition of the carboxylate to C-13 forming a lactone with
the concomitant elimination of the C-6 siloxy group.11 We
have previously demonstrated that the full epimerization
of the C-9 substituent is possible in bicyclic lactones of
the type obtained by acid treatment of the carboxylic acid
derived form 6.6,10 We reasoned that the C-9 substituent
would be more amenable to equilibration to its more sta-
ble, exo-configuration in the rigid phenanthrene cyclic
system. Had this approach been successful, the isomeric
mixtures of 5a/5b could be carried to this stage without
the arduous equilibration and recycling.
In 1997 we reported the Kazmaier–Claisen rearrangement
of glycinate esters derived from diols of type 1 (R = Cl,
Me, aryl).6 This rearrangement provided a mixture of dia-
stereomers at C-9 (morphine numbering) presumably be-
cause the rearrangement proceeded through both chair
and boat transition states despite the fact that only the Z-
enolate species was generated from glycinates 2 (Scheme
SYNLETT 2013, 24, 0369–0374
Advanced online publication: 21.01.2013
DOI: 10.1055/s-0032-1318114; Art ID: ST-2012-S1047-L
© Georg Thieme Verlag Stuttgart · New York
After removal of the silyl protecting group, the C-6 hy-
droxyl group was subjected to the Mitsunobu inversion
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

370
V. Varghese, T. Hudlicky
LETTER
X
X
X
OH
O
O
i
NHBoc
NBoc
Zn
ii
O
O
68%
OH
OR
OR
1
2
3
X = Br, Cl, Me, aryl
R = TDS
X
CO2Me
NHBoc
X
CO2H
9
HO2C
X
iii
65% over 2 steps
RO
NHBoc
BocHN
H
H
RO
OR
4
5a X = Br (C-9 = S)
5b X = Br (C-9 = R) 5a/5b = 1:1.8
iv
v
92–94%
2
H
MeO
MeO
H
1
Br
NBoc
CO2Me
Br
NBoc
H
H
11
10
H
14
14
CO2Me
9
9
13
9
H
CO2Me
5a (9S)
NHBoc
14
H
5b (9R)
6
RO
6
Scheme 1 Reagents and conditions: (i) (a) potassium azodicarboxylate, AcOH, MeOH; (b) thexyldimethylsilyl chloride, imidazole, CH2Cl2, –
78 °C to r.t.; (c) N-Boc-glycine, DCC, DMAP, CH2Cl2; (ii) ZnCl2, LDA, THF, –78 °C to r.t.; then quench with 1 N HCl, 0 °C; (iii) CH2N2,
Et2O; (iv) DBU, THF, reflux; (v) 2,3-dimethoxyphenylboronic acid, Pd(dppf)2Cl2, Cs2CO3, THF, reflux.
MeO
MeO
MeO
MeO
MeO
MeO
O
N
OH
iv, v
57%
i, ii, iii
74%
CO2Me
NHBoc
O
NHBoc
H
H
Me
H
HO
TDSO
6
HO
7
8
51%
vi
MeO
MeO
MeO
O
OH
NHMe
O
N
MeO
O
MeO
vii
MeO
viii, ix
58%
O
HO2C
EtO2C
NMe
or
x, xi, ix
H
H
H
Me
54%
11
10
9
xii, xiii
50%
MeO
MeO
MeO
MeO
O
O
O
NMe
xv
xiv
O
O
NMe
NMe
84%
54%
H
H
H
O
HO
14
13
12
Scheme 2 Reagents and conditions: (i) Bu4NF, THF; (ii) n-Bu3P, DEAD, BzOH, THF, 0 °C to r.t.; (iii) LiAlH4, THF, 0 °C to r.t.; (iv) NaH,
DMF, 0 °C to r.t.; (v) NaH, MeI, THF, 0 °C; (vi) MeC(OEt)3, cat. 2-nitrophenol, 130 °C; (vii) 50% aq NaOH, MeOH, 80 °C; (viii) HBTU,
DIPEA, CH2Cl2, r.t.; (ix) DMP, CH2Cl2; (x) TMSCl, MeOH; (xi) cat. AcOH, EtOH; (xii) BF3·OEt2, CH2Cl2, –20 °C to r.t.; (xiii) Ph2SiHCl, cat.
InCl3, DCE, reflux; (xiv) (a) mCPBA, CH2Cl2, 0 °C to r.t.; (b) CSA, THF, reflux; (xv) DMP, CH2Cl2.
Synlett 2013, 24, 369–374
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Dihydrocodeine and Hydrocodone
371
MeO
MeO
MeO
O
xvi
xvii
O
O
O
NMe
NMe
NMe
70%
83%
H
H
H
O
HO
HO
hydrocodone (17)
13
16
2
MeO
MeO
1
11
O
xvi
71%
10
O
O
9
NMe
NMe
5
H
14
H
6
O
HO
14
dihydrocodeine (15)
Scheme 3 Reagents and conditions: (xvi) LiAlH4, dioxane, reflux; (xvii) DMP, CH2Cl2.
and the amino ester 6 was reduced to alcohol 7 in 74% The chemoenzymatic syntheses of dihydrocodeine and
yield over three steps and transformed by intramolecular hydrocodone were attained in enantioselective manner
closure and methylation to oxazoline 8 (57%, over two from bromobenzene. This accomplishment also formaliz-
steps), which already contains the N-17 methyl group es the synthesis of codeine and morphine. The Kazmaier–
(Scheme 2). These transformations were essential in order Claisen rearrangement, expected to control the C-14/C-9
to prevent side reactions at either C-13 or C-6 emanating relationship, provided diastereomeric mixtures as a result
from the nucleophilic character of the secondary amide ni- of mixed chair–boat transition states operating during this
trogen. The orthoester Claisen rearrangement of 8 was process. The undesired isomer was subjected to equilibra-
performed under conditions previously used by Chida5a,d tion and recycling to provide the correct S-configuration
to provide ester 9 in 51% yield. Hydrolysis to acid 10, cy- of the substituent at C-9. A second Claisen rearrangement
clization to the amide, and oxidation furnished the crucial was used to set the C-13 quaternary center followed by the
substrate for the C-10/C-11 closure, namely aldehyde 11 relatively uncommon C-10/C-11 closure. Future improve-
in 58% yields over three steps. Cyclization under condi- ments in this synthesis will address the scale-up and com-
tions employed by Evans5c followed by the reduction of bination of several sequences into one-pot
the benzylic hydroxyl using a known protocol12 furnished transformations. We will report these improvements and
12 in 50% over two steps. The one-step deoxygenation further details in an upcoming full paper.
proceeded through the initial formation of a hydrodiphe-
nylsilyl ether and generation of the oxonium complex by
the Lewis acid, followed by the desiloxylation through the
donation of hydrogen. Tetracycle 12 was subjected to ep-
oxidation and epoxide opening to establish the C-5 center
in 13 with 54% overall yield according to the method pre-
viously published by Overman.13 Mulzer14 and Chida5a
also used a similar strategy in their approach towards the
morphine core.
Selected Experimental Procedures
(S)-Methyl 2-[(1S,4S)-2-bromo-4-{[(2,3-dimethylbutan-2-yl)di-
methylsilyl]oxy}cyclohex-2-en-1-yl)-2-[(tert-butoxycarbon-
yl)amino]acetate (5a)
A solution of glycinate ester 2 (55 g, 0.11 mol) in THF (200 mL)
along with a solution of ZnCl2 (18.3 g, 0.13 mol) in THF (200 mL)
was added dropwise to freshly prepared LDA (0.31 mol) in THF
(400 mL) at –78 °C over a period of 2 h. The reaction mixture was
slowly warmed to r.t. and stirred for 18 h. The reaction mixture was
then diluted with Et2O (800 mL), quenched with H2O (25 mL), and
the pH value was adjusted to approximately 2.5 using 1 N HCl at 0
°C. The organic layer was separated, the aqueous layer was washed
with Et2O (3 × 500 mL), the combined organics were dried over
Na2SO4, and the solvent was evaporated under reduced pressure to
provide amino acid 4 as a mixture of two diastereomers. A solution
of excess of diazomethane in Et2O (generated from N-nitrosomethyl
urea and KOH solution) was treated with the crude amino acid so-
lution in Et2O at 0 °C, and the resulting diastereomeric mixture of
esters was separated by column chromatography on silica gel with
hexane/EtOAc (95:5) as eluent to yield 5a and 5b (36 g, 1:1.8 ratio,
0.07 mol, 65% combined yield).
Alcohol 13 was oxidized in 84% yield to keto amide 14,
from which several morphinan derivatives are easily at-
tained. Thus the reduction of 14 gave dihydrocodeine (15)
in 71% yield (Scheme 3), with the correct absolute stereo-
chemistry at C-6, which is known to result from the reduc-
tion of C-6 ketones already containing the dihydrofuran
bridge.15 Such a process is frequently used to adjust C-6
stereochemistry.4b,16 Finally, reduction of the amide moi-
ety in 13 followed by oxidation of the C-6 alcohol in 16
provided hydrocodone (17) in 58% yield over two steps.
The identity of both compounds was established by com-
parison of NMR spectra with those of authentic samples.
Compound 5a: colorless liquid; Rf = 0.14 (hexane/EtOAc, 95:5);
20
[α]D –27.7 (c 1, CHCl3). IR (KBr): ν = 3443, 2956, 2868, 1749,
1715, 1503 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.27 (dd, J = 5.6,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 369–374

372
V. Varghese, T. Hudlicky
LETTER
1.3 Hz, 1 H), 4.81–4.73 (m, 2 H), 4.12–4.09 (m, 1 H), 3.71 (s, 3 H),
2.96 (br s, 1 H), 1.86–176 (m, 1 H), 1.63–1.50 (m, 4 H), 1.40 (s, 9
H), 0.86 (d, J = 6.9 Hz, 6 H), 0.80 (s, 6 H), 0.06 (d, J = 5.3 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 171.7, 155.4, 135.5, 127.9, 79.7,
65.4, 55.2, 52.2, 43.7, 34.1, 29.5, 28.2, 24.8, 20.2, 19.9, 18.5, –2.6,
–3.0. LRMS (EI): m/z (%) = 370 (13), 366 (38), 364 (37), 348 (16),
346 (15), 231 (24), 229 (24), 162 (95), 75 (100). HRMS: m/z calcd
for C22H41NSiBrO5: 506.1920; found: 506.1937. Anal. Calcd for
C22H41NSiBrO5: C, 52.16; H, 7.96. Found: C, 52.34; H, 8.01.
CDCl3): δ = 7.26 (d, J = 8.7 Hz, 1 H), 6.85 (d, J = 8.7 Hz, 1 H), 6.41
(d, J = 10.2 Hz, 1 H), 5.69–5.65 (m, 1 H), 4.89 (d, J = 3.9 Hz, 1 H),
3.83 (s, 3 H), 3.81 (s, 3 H), 3.61 (t, J = 1.8 Hz, 1 H), 3.13 (s, 3 H),
2.88 (d, J = 17.7 Hz, 1 H), 2.40 (d, J = 17.7 Hz, 1 H), 2.14–2.04 (m,
3 H), 1.77–1.72 (m, 1 H), 1.50–1.36 (m, 1 H). 13C NMR (75 MHz,
CDCl3): δ = 170.5, 153.0, 147.4, 134.9, 133.9, 127.8, 125.7, 122.6,
112.0, 70.2, 63.0, 60.2, 55.8, 46.1, 41.5, 38.2, 38.0, 25.4, 23.0. MS
(FAB+): m/z (%) = 330 (81), 270 (20), 226 (20), 165 (28), 115 (40),
89 (68), 77 (100). HRMS (EI): m/z calcd for C19H23NO4:
329.16271; found: 329.16270. Anal. Calcd for C19H23NO4: C,
62.28; H, 7.04. Found: C, 61.61; H, 7.66.
Compound 5b: colorless liquid; Rf = 0.16 (hexane/EtOAc, 95:5);
[α]D20 –55.7 (c 1.0, CHCl3). IR (KBr): ν = 3439, 2955, 2867, 1753,
1720, 1498, 1365, 1251, 1164 cm–1. 1H NMR (300 MHz, CDCl3): δ
= 6.30 (dd, J = 5.6, 1.3 Hz, 1 H), 5.21 (d, J = 8.6 Hz, 1 H), 4.68 (dd,
J = 8.7, 2.3 Hz, 1 H), 4.11–4.09 (m, 1 H), 3.71 (s, 3 H), 3.05 (br s,
1 H), 1.86–1.78 (m, 2 H), 1.63–1.50 (m, 3 H), 1.43 (s, 9 H), 0.84 (d,
J = 6.9 Hz, 6 H), 0.80 (s, 6 H), 0.05 (d, J = 5.3 Hz, 6 H). 13C NMR
(75 MHz, CDCl3): δ = 171.8, 155.4, 136.3, 125.5, 80.0, 66.7, 55.9,
52.3, 45.1, 34.1, 29.2, 28.3, 25.8, 24.7, 23.4, 20.2, 18.6, –2.7, –2.9.
HRMS (EI): m/z calcd for C20H36NSiBrO5: 506.1920; found:
506.1937. Anal. Calcd for C20H36NSiBrO5: C, 52.16; H, 7.96.
Found: C, 52.28; H, 8.06.
To a solution of the intermediate alcohol (40 mg, 0.12 mmol) in 1,2-
dichloroethane (2 mL) chlorodiphenylsilane (66.4 mg, 0.3 mmol)
was added and heated for 1 h; then catalytic InCl3 (5.3 mg, 0.02
mmol) was added, and the mixture was heated to reflux for another
20 h. After complete consumption of the starting material (vide
TLC), the reaction mixture was diluted with CH2Cl2, washed with
H2O and brine and dried over Na2SO4. Solvent was evaporated un-
der reduced pressure to provide the crude product, and column chro-
matography on silica gel using EtOAc as eluent afforded amide
12(25 mg, 0.08 mmol, 67%) as a white solid.
To a solution of pure 5b (26.5 g, 0.52 mol) in THF (250 mL) DBU
(4.01 g, 0.26 mol) was added, and the reaction mixture was heated
to reflux for 36 h. Chromatographic separation on silica gel using
hexane/EtOAc (95:5) as eluent yielded 5a as a colorless liquid (10
g, 0.02 mol, 39%) along with 5b (colorless liquid, 12.8 g, 0.025 mol,
49%). After separation (as above) this process was repeated to con-
vert all of 5b into 5a.
Compound 12: mp 55–58 °C (EtOAc/hexane); Rf = 0.24 (EtOAc);
[α]D +48.7 (c 1.5, CHCl3). IR (CHCl3): ν = 3000, 2938, 2840,
20
1623, 1485, 1275, 1219, 1051 cm–1. 1H NMR (300 MHz, CDCl3): δ
= 6.78–6.75 (m, 2 H), 6.45 (d, J = 10.2 Hz, 1 H), 5.67 (d, J = 9.9 Hz,
1 H), 3.84 (s, 3 H), 3.81 (s, 3 H), 3.58 (s, 1 H), 2.99–2.94 (m, 4 H),
2.83 (d, J = 16.8 Hz, 2 H), 2.37 (d, J = 17.4 Hz, 1 H), 2.09–2.04 (m,
3 H), 1.69–1.66 (m, 1 H), 1.57–1.43 (m, 1 H). 13C NMR (75 MHz,
CDCl3): δ = 169.6, 151.9, 148.6, 134.7, 133.9, 125.5, 124.8, 123.7,
111.8, 60.1, 58.4, 55.9, 46.1, 40.2, 37.8, 33.4, 29.5, 25.2, 23.1. MS
(EI): m/z (%) = 313 (100), 240 (37), 225 (22), 192 (71), 85 (53), 83
(79). HRMS (EI): m/z calcd for C19H23NO3: 313.1677; found:
313.1673. Anal. Calcd for C19H23NO3: C, 72.82; H, 7.40. Found: C,
72.57; H, 7.46.
Ethyl 2-{(1S,6R)-1-(2,3-Dimethoxyphenyl)-6-[(S)-3-methyl-2-
oxooxazolidin-4-yl])cyclohex-2-enyl}acetate (9)
A solution of alcohol 8 (1 g, 2.99 mmol) and 2-nitrophenol (20 mg,
0.14 mmol) in triethyl orthoacetate (60 mL) was heated at 130 °C
for 6 d under argon with continuous removal of EtOH. Then the re-
action mixture was diluted with EtOAc, washed with 1 N HCl, sat.
NaHCO3 solution, brine, dried over Na2SO4, and the solvent was
evaporated under reduced pressure to yield the crude product,
which was purified by column chromatography on silica gel (hex-
ane/EtOAc, 50:50 → 30:70) to give 9 (618 mg, 1.53 mmol, 51%) as
a viscous yellow liquid.
(7aR,12bS)-9-Methoxy-3-methyl-4,4a,5,6-tetrahydro-1H-4,12-
methanobenzofuro[3,2-e]isoquinoline-2,7-(3H,7aH)-dione (14)
To a solution of 13 (12 mg, 0.038 mmol) in CH2Cl2 (1 mL), Dess–
Martin periodinane (32 mg, 0.08 mmol) was added at 0 °C, and the
mixture was stirred for 30 min whereupon it was allowed to warm
to r.t. and stirred for another 5 h. The reaction mixture was diluted
with CH2Cl2 and stirred with a 1:1 mixture of 10% Na2S2O3 and sat.
NaHCO3 solution for 10 min. Then the organic layer was separated
and washed with sat. NaHCO3 solution and brine and dried over
Na2SO4. Then the solvent was evaporated under reduced pressure,
and the crude product was purified by column chromatography on
silica gel using CH2Cl2/MeOH (98:2) as eluent to provide 14 (10
mg, 0.03 mmol, 84%) as a colorless oil.
20
Rf = 0.3 (hexane/EtOAc, 40:60); [α]D +25.6 (c 1, CHCl3). IR
(CHCl3): ν = 3008, 2978, 2939, 2836, 1737, 1466, 1425, 1264, 1230
cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.01–6.96 (m, 1 H), 6.90–
6.86 (m, 1 H), 5.98–5.89 (m, 2 H), 4.39 (t, J = 8.7 Hz, 1 H), 4.13–
4.08 (m, 1 H), 4.03 (dd, J = 14.1, 6.9 Hz, 2 H), 3.93–3.81 (m, 7 H),
3.14 (dd, J = 19.2, 14.4 Hz, 2 H), 2.41–2.36 (m, 1 H), 2.20–2.09 (m,
2 H), 2.02 (s, 3 H), 1.79–1.69 (m, 1 H), 1.58–1.45 (m, 1 H), 1.16 (t,
J = 7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 171.5, 159.8,
153.5, 148.4, 134.2, 133.1, 127.3, 123.9, 123.0, 112.0, 69.4, 60.7,
60.1, 56.9, 55.8, 47.9, 45.5, 45.2, 30.9, 24.7, 18.5, 14.2. MS (EI):
m/z (%) 403 (2), 100 (22), 83 (100), 47 (34), 43 (29). HRMS (EI):
m/z calcd for C22H29NO6: 403.1995; found: 403.2006. Anal. Calcd
for C22H29NO6: C, 65.49; H, 7.24. Found: C, 65.78; H, 7.32.
20
Compound 14: Rf = 0.15 (CH2Cl2/MeOH, 95:5); [α]D –178.0 (c
0.17, CHCl3). IR (CHCl3): ν = 3005, 2933, 1735, 1636, 1507, 1439,
1400, 1279, 1157 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.75 (d,
J = 8.4 Hz, 1 H), 6.64 (d, J = 8.4 Hz, 1 H), 4.70 (s, 1 H), 3.90 (s, 3
H), 3.80–3.79 (m, 1 H), 3.04 (s, 3 H), 3.01–2.95 (m, 1 H), 2.80–2.77
(m, 3 H), 2.62 (dd, J = 18.0, 3.9 Hz, 1 H), 2.47–2.42 (m, 2 H), 2.08–
2.02 (m, 1 H), 1.39–1.30 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ =
206.1, 167.6, 146.1, 143.6, 127.1, 121.9, 121.1, 115.8, 91.5, 58.8,
57.2, 46.7, 44.5, 38.9, 34.3, 30.0, 26.8, 25.2. MS (EI): m/z (%) = 313
(21), 248 (100), 231 (59), 203 (18), 156 (18), 149 (13), 139 (18),
127 (10), 111 (16), 105 (13). HRMS (EI): m/z calcd for C18H19NO4:
313.1314; found: 313.1308.
(4bS)-3,4-Dimethoxy-11-methyl-8,8a,9,10-tetrahydro-7H-9,4b-
(epiminoethano)phenanthren-12-one (12)
Aldehyde 11 (50 mg, 0.15 mmol) was dissolved in CH2Cl2 (2 mL)
and cooled to –10 °C, then BF3·OEt2 (54 mg, 0.38 mmol) was add-
ed. The reaction mixture was stirred for 3 h, then quenched with
H2O and diluted with CH2Cl2. It was then washed with H2O and
brine and dried over Na2SO4. The solvent was evaporated under re-
duced pressure, and the crude product was purified by column chro-
matography on silica gel using CH2Cl2/MeOH (95:5) as eluent to
furnish the intermediate alcohol as a colorless liquid (38 mg, 0.12
mmol, 76%).
(4R,4aR,7S,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,6,7,7a-
octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ol
(15) – Dihydrocodeine
To a stirred suspension of LiAlH4 (3 mg, 0.079 mmol) in dioxane
(0.5 mL) was added a solution of 14 (5 mg, 0.016 mmol) in dioxane
(0.5 mL), and the mixture was refluxed for 6 h. Then the reaction
mixture was cooled to r.t., quenched by the addition of 2 drops of
H2O, followed by the addition of 2 drops of 15% NaOH solution
20
Rf = 0.20 (CH2Cl2/MeOH, 95:5); [α]D +48.7 (c 1.5, CHCl3). IR
(CHCl3): ν = 3583, 3004, 2940, 2840, 1626, 1484, 1415, 1399,
1
1320, 1279, 1096, 1054, 1029, 978 cm–1. H NMR (300 MHz,
Synlett 2013, 24, 369–374
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Dihydrocodeine and Hydrocodone
373
and 6 more drops of H2O. The white suspension formed was filtered
through a pad of Celite, washed with CH2Cl2, solvent was evaporat-
ed under reduced pressure, and the crude product was purified by
column chromatography on silica gel using EtOAc/Et2NH (20:1) as
eluent to provide 15 (3.4 mg, 0.011 mmol, 71%) as a white glassy
solid which provided crystalline dihydrocodeine (15) upon tritura-
tion with CH2Cl2.
Council of Canada (NSERC), (Idea to Innovation and Discovery
Grants); Canada Research Chair Program, Canada Foundation for
Innovation (CFI), TDC Research, Inc., TDC Research Foundation,
Brock University, and the Ontario Partnership for Innovation and
Commercialization (OPIC). Additional acknowledgments are due
David Gonzalez, Kofi Oppong, Thomas Metcalf, Tyler Bissett, Ke-
vin Finn, Dr. Petr Cankar, Dr. Scott Banfield, Dr. Lucilia
de los Santos, all of whom contributed in various ways to this pro-
ject and who will be co-authors on the full paper, when completed.
Compound 15: mp 110–112 °C (CH2Cl2) (lit.17 mp 111–112 °C);
20
Rf = 0.16 (EtOAc/Et2NH, 20:1); [α]D –212 (c 0.11, 1,4-dioxane)
21
{lit.18 [α]D –220 (c 0.246, 1,4-dioxane)}. IR (CHCl3): ν = 3590,
1
3010, 2936, 2909, 1504, 1449, 1440, 1322, 1278, 1157 cm–1. H
References and Notes
NMR (300 MHz, CDCl3): δ = 6.73 (d, J = 8.1 Hz, 1 H), 6.64 (d,
J = 8.1 Hz, 1 H), 4.61 (d, J = 5.4 Hz, 1 H), 4.05 (br s, 1 H), 3.87 (s,
3 H), 3.14 (br s, 1 H), 3.01 (d, J = 18.3 Hz, 1 H), 2.55–2.52 (m, 1
H), 2.32 (s, 4 H), 2.32–2.28 (m, 2 H), 2.05–1.84 (m, 2 H), 1.73–1.69
(m, 1 H), 1.60–1.54 (m, 1 H), 1.51–1.40 (m, 2 H), 1.18–1.12 (m, 1
H). 13C NMR (75 MHz, CDCl3): δ = 146.2, 141.7, 130.0, 126.5,
119.2, 113.3, 90.3, 67.1, 60.0, 56.4, 47.0, 42.8, 41.9, 40.4, 37.0,
27.2, 20.2, 18.9. MS (EI): m/z (%) = 301 (100), 286 (10), 244 (18),
242 (13), 199 (28), 185 (10), 164 (20), 91 (18), 73 (16), 60 (21), 58
(32), 45 (61), 44 (54); HRMS (EI): m/z calcd for C18H23NO3:
301.1678; found 301.1674.
(1) (a) Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1952, 74, 1109.
(b) Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1956, 78,
1380.
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F.; Neubert, T. D.; Schlecht, M. F. In Strategies and Tactics
in Organic Synthesis; Vol. 5; Harmata, M., Ed.; Elsevier:
London, 2004, 353. (d) Hudlicky, T. J. Heterocycl. Chem.
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Mulzer, J.; Trauner, D. Curr. Org. Chem. 2000, 4, 343.
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VCH: Weinheim, 1995, 357.
(4R,4aR,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,6-hexa-
hydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-
one (17) – Hydrocodone
To a solution of 16 (3.5 mg, 0.012 mmol) in CH2Cl2 (0.6 mL) Dess–
Martin periodinane (7.4 mg, 0.017 mmol) was added at 0 °C, and
the reaction mixture was stirred for 30 min whereupon it was al-
lowed to warm to r.t. and stirred for another 2 h. The reaction mix-
ture was diluted with CH2Cl2, and stirred with a 1:1 mixture of 10%
Na2S2O3 and sat. NaHCO3 solution for 10 min. Then organic layer
was separated and washed with sat. NaHCO3 solution, brine, and
dried over Na2SO4. Then the solvent was evaporated under reduced
pressure, and the crude product was purified by column chromatog-
raphy on silica gel using EtOAc–Et2NH (20:1) as eluent to provide
17 (2.9 mg, 0.01 mmol, 83%) as a white glassy solid. Trituration
with Et2O provided crystalline hydrocodone (17)
(3) Rice, K. C. J. Org. Chem. 1980, 45, 3135.
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Chem. 2011, 89, 709. (b) Leisch, H.; Omori, A. T.; Finn, K.
J.; Gilmet, J.; Bissett, T.; Ilceski, D.; Hudlicky, T.
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Leisch, H.; Carroll, R. J.; Hudlicky, T. Synlett 2007, 2859.
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2008, 49, 358. (b) Butora, G.; Hudlicky, T.; Fearnley, S. P.;
Stabile, M. R.; Gum, A. G.; Gonzalez, D. Synthesis 1998,
665. (c) Evans, D. A.; Mitch, C. H. Tetrahedron Lett. 1982,
23, 285. (d) Ichiki, M.; Tanimoto, H.; Miwa, S.; Saito, R.;
Saito, T.; Chida, N. Chem. Eur. J. 2013, 19, 264.
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Abboud, K. J. Org. Chem. 1997, 62, 1194.
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14940. For medium-scale preparation of 1 and other diene
cis-diols by fermentation, see: (b) Endoma, M. A.; Bui, V.
P.; Hansen, J.; Hudlicky, T. Org. Process Res. Dev. 2002, 6,
525.
Compound 17: mp 191–194 °C (Et2O) (lit.19 mp 194–197 °C];
Rf = 0.21 (EtOAc/Et2NH, 20:1); [α]D20 –195 (c 0.11, CHCl3) {lit.19
20
[α]D –206.8 (c 1, CHCl3)}. IR (CHCl3): ν = 3007, 2936, 1728,
1504, 1439, 1278, 1157, 1058 cm–1. 1H NMR (300 MHz, CDCl3): δ
= 6.70 (d, J = 8.1 Hz, 1 H), 6.63 (d, J = 8.1, 1 H), 4.66 (s, 1 H), 3.90
(s, 3 H), 3.20–3.17 (m, 1 H), 3.03 (d, J = 18.3 Hz, 1 H), 2.60–2.54
(m, 2 H), 2.43–2.40 (m, 4 H), 2.37–2.31 (m, 1 H), 2.28–2.15 (m, 2
H), 2.11–2.02 (m, 1 H), 1.89–1.79 (m, 2 H), 1.33–1.19 (m, 1 H). 13
C
NMR (75 MHz, CDCl3): δ = 207.8, 145.6, 142.9, 127.3, 126.3,
119.8, 114.6, 91.4, 59.2, 56.8, 46.9, 46.8, 42.9, 42.8, 40.2, 35.6,
25.6, 19.9. MS (EI): m/z (%) = 299 (100), 284 (14), 256 (11), 243
(29), 242 (47), 214 (19), 212 (18), 161 (12), 188 (14), 185 (20), 96
(26), 86 (17), 84 (24), 70 (18), 59 (30), 42 (15). HRMS (EI): m/z
calcd for C18H21NO3: 299.1521; found: 299.1518.
(10) Gonzalez, D. PhD Dissertation; University of Florida: USA,
1999, Diss. Abstr. 1999.9945971.
(11) Hudlicky, T.; Gonzalez, G. unpublished observations. The
following reactivity was observed upon treatment of acid i
with PPA or TsOH (Scheme 4).
Acknowledgment
The authors are grateful to the following agencies for financial sup-
port of this work: Natural Sciences and Engineering Research
MeO
MeO
MeO
MeO
MeO
O
PPA or
TsOH, CH2Cl2, r.t.
MeO
CO2H
NHBoc
PPA
X
O
O
50–60%
NHBoc
H
H
H
TDSO
TDSO
NHBoc
iii
i
ii
Scheme 4
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 369–374

374
V. Varghese, T. Hudlicky
LETTER
(12) Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba, A.
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Synlett 2013, 24, 369–374
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