Chemoenzymatic formal total synthesis of ent-codeine and other morphinans via nitrone cycloadditions and/or radical cyclizations. comparison of strategies for control of C-9/C-14 stereogenic centers

Article abstract of DOI:10.1002/adsc.201400016

Formal total syntheses of ent-codeine and other morphinans were accomplished from 1- phenyl-2-acetoxyethane, which was subjected to enzymatic dihydroxylation by toluene dioxygenase overexpressed in Eschericia coli JM109 (pDTG601A). The resulting cis-dihyd

Full text of DOI:10.1002/adsc.201400016

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DOI: 10.1002/adsc.201400016
Chemoenzymatic Formal Total Synthesis of ent-Codeine and
Other Morphinans via Nitrone Cycloadditions and/or Radical
Cyclizations. Comparison of Strategies for Control of C-9/C-14
Stereogenic Centers
Mary Ann A. Endoma-Arias,a Jason Reed Hudlicky,a Razvan Simionescu,a
and Tomas Hudlickya,*
a
Department of Chemistry and Centre for Biotechnology, Brock University, St. Catharines, ON L2S 3A1, Canada
E-mail: thudlicky@brocku.ca
Received: January 4, 2014; Published online: February 7, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400016.
Abstract: Formal total syntheses of ent-codeine and
other morphinans were accomplished from 1-
phenyl-2-acetoxyethane, which was subjected to en-
zymatic dihydroxylation by toluene dioxygenase
strategies understand that the stereochemistry of the
C-5 center, if established early, controls the subse-
quent stereochemical events and can therefore be ex-
ploited in enantiodivergent design, as illustrated in
some of our recent papers.[4]
overexpressed
in
Eschericia
coli
JM109
(pDTG601A). The resulting cis-dihydroarenediol
was coupled with a phenol derived from bromoiso-
vanillin and a subsequent Heck reaction was used
to establish the C-13 quaternary center. Two strat-
egies were employed to set the C-14 center: nitrone
and nitrile oxide cycloadditions to the C-8/C-14
olefin and a radical cyclization of an aldehyde to C-
14. Both strategies yielded tetracyclic products that
were converted to known intermediates for the syn-
thesis of ent-codeine, ent-codeinone, and ent-hydro-
codone. Experimental and spectral data are provid-
ed for all new compounds.
One of the challenges in any design of the mor-
phine skeleton is the relative stereochemistry at C-9/
C-14 – this can be controlled by employing cycloaddi-
tions. In 1984 Parsons published a model study of an
intramolecular nitrone cycloaddition, which produced
the correct C-9/C-14 relationship,[5] followed by a com-
plete total synthesis of morphine by this strategy.[6] In
2011 Metz reported a total synthesis of racemic co-
deine via a nitrone cycloaddition that yielded the cor-
rect relationship at C-9/C-14.[7] In a recent publication
by Trost describing the enantioselective synthesis of
galanthamine and morphine, it was noted that all at-
À
tempts to achieve C-9 C-14 bond formation via car-
Keywords: aldehyde-olefin radical cycloaddition;
bonyl ene cyclization failed.[8]
codeine synthesis; enzymatic dihydroxylation; Heck
In this paper we report the results of the stereo-
chemical course of a nitrone cycloaddition, nitrile
oxide cycloaddition, and a radical cyclization ap-
proach to ent-codeine and other morphinans, as
shown in Figure 1.
reaction;
ACHTUNGTRENNUNG[3+2] nitrile oxide cycloaddition; ACHTUGNTREN[NUGN 3+2] ni-
trone cycloaddition
The synthesis begins with the enzymatic dihydroxy-
lation of 1-phenyl-2-acetoxyethane (5) by means of
New approaches to the synthesis of morphine alka- whole-cell fermentation with Eschericia coli JM109
loids continue to appear in the literature with more (pDTG601A), a recombinant organism that overex-
than 40 total or formal syntheses published since the presses toluene dioxygenase. The resulting cis-dihy-
first total synthesis by Gates in 1952.[1] Many reviews drodiol 6,[9] obtained in 5 gLÀ1 yield, was converted to
have compared the various strategies for control of silyl ether 8 prior to Mitsunobu coupling with phenol
the five contiguous stereogenic centers of morphine 9, which was prepared from isovanillin in four steps
and congeners.[2] One reason for the continuing activi- by a slight modification of a previously published pro-
ty in this field is the challenge of designing a practical cedure (Scheme 1).[10] The overall yield over the four-
synthesis of this important molecule; of all the report- step sequence was 55–65% (see the Supporting Infor-
ed syntheses only that published by Rice approaches mation for an experimental description of this se-
such a goal.[3] The authors of most of the synthetic quence). The aryl ether 10, prepared via a Mitsunobu
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Mary Ann A. Endoma-Arias et al.
Figure 1. Cycloaddition and radical cyclization strategy for morphinans.
Scheme 1. Synthesis of ent-codeinone and ent-codeine via nitrone cycloaddition. i) E. coli JM109 (pDTG601A), 5 gLÀ1; ii)
potassium azodicarboxylate (PAD), HOAc, MeOH, 84%; iii) TBSCl, imidazole, DMF, 54%; iv) DIAD, (n-Bu)3P, THF,
phenol 9, 79.5%; v) Pd
NHMeOH·HCl, Hꢁnigꢂs base, toluene, reflux, 38%; viii) Meerwein salt, CH2Cl2, then LiAlH4, THF, 76% over 2 steps; ix)
Dess–Martin periodinane, CH2Cl2, 75%; x) NH2Me·HCl, NEt3,Ti(i-PrO)4, MeOH, then NaBH4; xi) BOC anhydride, EtOH,
ACHTNUGTRNEUN(GN dba)2, K2CO3, (t-Bu)3P, toluene, reflux, 64%; vi) 50% aqueous TFA, toluene, 508C, 92%; vii)
AHCTUNGTRENNUNG
66% over 3 steps; xii) TBAF, THF; xiii. Dess–Martin Periodinane, CH2Cl2, 51% over 2 steps.
reaction, was subjected to an intramolecular Heck TFA provided the required aldehyde 4, which was not
cyclization to afford the tricyclic compound 11 in isolated but used immediately in the next step. The
64% yield. Deprotection of the acetal with aqueous key nitrone 3, generated from the aldehyde in situ,
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Chemoenzymatic Formal Total Synthesis of ent-Codeine
Scheme 2. Synthesis of 12 via nitrile oxide cycloaddition. i) 50% aqueous TFA, toluene, 508C; ii) NH2OH·HCl, pyridine; iii)
10–15% aqueous NaOCl, CH2Cl2, 37.5% over 3 steps; iv) Meerwein salt, CH2Cl2, then NaBH4, MeOH, 65%.
underwent [2+3] cycloaddition to afford the adduct trialkylammonium salt] afforded the Hofmann elimi-
12 exclusively (Scheme 1).
nation product 13. Conversion of the ethyl alcohol
The NMR assignment of compound 12 was estab- side-chain to the Boc-protected amine was accom-
1
lished by H,13C, homonuclear (COSY) and heteronu- plished by oxidation of the alcohol 13 to aldehyde 14
clear (HSQC) correlation spectroscopy. The stereo- with Dess–Martin periodinane followed by reductive
chemistry was established by NOE correlation spec- amination with methylamine using titanium isoprop-
troscopy. A two-dimensional NOE pulse sequence oxide as catalyst and Boc protection of the amine.
with gradient selection was employed with a mixing Deprotection of the silyl ether 15 followed by oxida-
time of 600 ms tuned for small molecules.
tion of the resulting secondary alcohol and a concomi-
Negative (inverse to diagonal) strong NOEs were tant elimination of dimethylamino alcohol moiety re-
observed between H-8/H-14, H-14/H9 and also sulted in the formation of the known compound 16 to
a weaker direct NOE between H-8 and H-9. These complete the formal synthesis of ent-codeinone and
data support the conclusion that all protons at these ent-codeine.[4a]
vicinal positions are on the same face of the molecule.
The [2+3] cycloaddition was repeated with nitrile
NOEs were also observed between both H-8 and H-9 oxide generated from 11, as shown in Scheme 2. The
with H-17 proving that the N-methyl group is also reduction of the imine bond in 17 proceeded to give
pointing in the same direction. No NOE were ob- 12 with identical stereochemistry as that obtained
served from any of H-8, H-9 or H-14 to the acetate from the nitrone addition. Metz reported that the cy-
tail methylene protons H-15 or H-16.
cloaddition of 18 proceeded anti to the C-13 substitu-
The stereochemistry of the cycloadduct 12 was ent to produce the correct C-9/C-14 relationship in
shown to have the incorrect C-9/C-14 relationship, re- 19. In our case, the cycloaddition also took place anti
sulting from a different transition state geometry than to the C-13 substituent and syn to the C-5 dihydrofur-
that operating on the substrate reported by Metz.[7] an bridge (absent in the substrate 18 in which free ro-
We therefore converted the adduct 12 to styrene 13 to tation around the C-13 aryl bond is permitted). Metz
allow for the introduction of the C-9 center by hydro- also investigated the cycloaddition of 20, which pro-
amination at a later stage of the synthesis. Thus, treat- duced the adduct 21 possessing the incorrect stereo-
ment of 12 with excess Meerwein salt, followed by ad- chemistry at C-9.[11]
dition of LiAlH4, [which reduced the acetate and also
We also investigated the radical cyclization of alde-
led to the base-catalyzed elimination of the resulting hyde 4 by SmI2-mediated closures of the type report-
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Mary Ann A. Endoma-Arias et al.
Scheme 3. Radical cyclization approach to ent-hydrocodone (27). i) 50% aqueous TFA, toluene, 508C, ~92%; ii) SmI2,
HMPA, THF, 50%; iii) H2, Pd/C, MeOH, 92%; iv) MsCl, NEt3, CH2Cl2; v) aqueous NaOH, MeOH, 69% over 2 steps;; vi)
Dess–Martin periodinane, CH2Cl2, 72%.
Scheme 4. Ene approaches to C-9/C-14 stereogenic centers. i) SmI3, HMPA, THF.
ed by Curran[12] in his approach to coriolin, Reissig[13] the C-6 alcohol,[17] attaining Chidaꢂs intermediate also
in his synthesis of strychnine, and Banwell in his syn- formalized the synthesis of ent-hydrocodone (27).
thesis of patchoulenone.[14] Aldehyde 4 was generated
Following the completion of the formal total syn-
from the acetal immediately prior to use and treated theses, we returned to the investigation of the produc-
with freshly prepared SmI2 in THF and HMPA,[15] tion of olefinic alcohol 22 during the radical cycliza-
producing a mixture of 22 and 23 (1:8) in addition to tion. The compound could be the formal product of
the unreacted starting material, as shown in either radical disproportionation, (a similar event
Scheme 3. The generation of 22 is interesting. If its took place in Banwellꢂs synthesis of parchoulene
production can be optimized, a more direct synthesis where an olefin was a by-product of the radical clo-
of codeine will become available. The hydrogenation sure unless a radical scavenger was used in the reac-
of the mixture of 22 and 23 to produce 23 as a single tion[14]), an ene reaction, or a Prins reaction. It was
isomer proved that 22 and 23 possessed identical ster- suggested to us that 22 could originate from an ene
eochemistries at C-9/C-14. Mesylation of 23 followed reaction catalyzed by the samariumACTHNUTRGNE(NUG III) that would
by base-catalyzed elimination afforded alcohol 24, be present in small amounts during the Sm(II)-cata-
whose oxidation provided the enantiomer of the lyzed radical closures.[18] In spite of the results report-
Chida intermediate 25,[16] thus formalizing the synthe- ed by Trost for the ene reaction of 28, we studied the
sis of ent-dihydroisocodeine. Because this compound Lewis acid-catalyzed ene reaction of 4 (Scheme 4).
was also converted to hydrocodone by oxidation of
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Chemoenzymatic Formal Total Synthesis of ent-Codeine
The only product isolated from treatment of 4 with 2-{(5aS,5a1S,7aS,9S,9aS,9a1R)-9-[(tert-Butyldimethyl-
SmI3 was keto alcohol 30, probably resulting from iso- silyl)oxy]-2-methoxy-6-methyl-5a,5a1,6,7a,8,9,9a,9a1-
merization of the corresponding a-hydroxy aldehyde octahydro-5H-furo[2’,3’,4’,5’:4,5]phenanthro
produced in the reaction by benzylic oxidation of 4. isoxazol-9a1-yl}ethyl Acetate (12)
The structure of 30 was elucidated by NMR spectros-
ACHTUNGTRENN[UNG 10,1cd]-
A – From nitrone cycloaddition: Deprotection of aldehyde:
To a stirred solution of Heck coupling product 11 (100 mg,
0.20 mmol) in toluene (2 mL) was added 50% aqueous TFA
(0.20 mL). The resulting biphasic mixture was heated to
508C for 30 min. The cooled reaction mixture was diluted
with EtOAc (10 mL) and was washed with saturated
NaHCO3 solution (5 mL). The aqueous layer was back-ex-
tracted with EtOAC (10 mL). The combined organic ex-
tracts were dried with anhydrous Na2SO4. Filtration of the
dehydrating agent followed by concentration via rotary
evaporation afforded the intermediate aldehyde 4 as an oil
which was used as crude substrate in the next step; yield:
85 mg (92.0%).
1
copy: H and 13C, as well as HSQC and COSY, were
employed to establish the backbone structure. A sig-
nificant change in proton NMR chemical shift of
about 0.5 ppm downfield was noticed for the H-
1 proton, indicating the presence of an electronega-
tive functionality near the aromatic. Further investiga-
tion was completed by HMBC spectroscopy. It re-
vealed J3 correlation H-1–C-10 and J2 correlation H-
9–C-10, which established the substituent as a benzylic
À
À
À
ketone (Ar CO CH2 OH).
In summary, we have achieved the synthesis of sev-
eral ent-morphinans by [2+3] cycloaddition and radi-
cal closures, both of which were used to establish the
correct mutual relationship of stereogenic centers at
C-9/C-14.
Nitrone cycloaddition of aldehyde: To a refluxing mixture
of
N-methylhydroxylamine
hydrochloride
(20 mg,
0.22 mmol), Hꢁnigꢂs base ( 48 mL, 0.28 mmol) in toluene
(1 mL) was added the aldehyde 4 (85 mg, 0.19 mmol) dis-
solved in toluene (1 mL). The resulting mixture was further
refluxed for 5 h. After allowing the mixture to reach room
temperature, toluene was removed using rotary evaporation
and the resulting residue was chromatographed on silica gel
using 2:1 EtOAc/hexanes as eluent to afford 12 as a yellow
heavy oil; yield: 34 mg (38.0%). [a]2D0: +32.1 (c=1.0,
CHCl3); Rf =0.58 (1:2; hexanes/EtOAc); IR (film): v=2953,
Experimental Section
Selected experimental procedures are presented below; all
others can be found in the Supporting Information, along
with the corresponding NMR spectral data.
2930, 2856, 1739, 1509, 1455, 1282, 1242, 1076, 837 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=6.71 (d, J=7.8 Hz, 1H, 1-
H), 6.65 (d, J=7.8 Hz, 1H, 2-H), 4.63 (d, J=1.5 Hz, 1H, 5-
H), 4.57 (m, 1H, 6-H), 4.15–4.17 (m, 1H, CH2OAc), 4.10–
4.12 (m, 1H, CH2OAc), 3.90–3.92 (m, 1H, 6-H), 3.86 (s, 3H,
OMe), 3.11 (t, J=8.4 Hz, 1H, 14-H), 2.92 (dd, J=15.7,
3.9 Hz, 1H, 10-H), 2.74–2.79 (m, 1H, 10-H), 2.65 (s, 3H,
NMe), 2.20–2.40 (m, 2H, 15-H), 1.94–2.11 (s, 2H, 7-H), 0.92
(s, 9H, OTBS), 0.15 (s, 3H, OTBS), 0.10 (s, 3H, OTBS);
13C NMR (150 MHz, CDCl3): d=171.2, 145.2, 142.6, 129.5,
125.8, 119.7, 112.6, 91.5, 72.5, 68.9, 60.4, 56.0, 48.1, 43.8, 39.2,
29.7, 25.7, 21.1, 20.9, 18.0, 14.2, À4.9, À5.1; MS (EI+): m/z
(%)=432 (6), 167 (18), 149 (55), 136 (24), 67 (100), 55 (66),
43 (73), 41 (62); HR-MS (EI+): m/z=489.2549, calcd. for
C26H39O6NSi: 489.2547.
B – From nitrile oxide cycloaddition product 17: To
a stirred solution of 17 (25 mg, 0.05 mmol) in CH2Cl2 (2 mL)
was added Meerwein salt (20 mg, 0.14 mmol). The reaction
mixture was stirred for 2 h at room temperature. The solvent
was removed via rotary evaporation. The residue was dis-
solved in MeOH (2 mL), cooled to 08C and was treated in
one portion with NaBH4 (15 mg, 0.40 mmol). Once the evo-
lution of gas has ceased, the reaction mixture was stirred at
room temperature for 30 min. It was quenched by the addi-
tion of acetone (5 mL). The solvents were removed via
rotary evaporation and the resulting residue was partitioned
between water and Et2O (10 mL). The layers were separated
and the organic was further extracted with Et2O (3ꢃ10 mL).
The combined organic extracts were dried over MgSO4, fil-
tered and concentrated via rotary evaporation. Chromatog-
raphy on silica gel (1:1 hexanes/EtOAc as eluent) afforded
the product 12 as an oil; yield: 20 mg (77.5% over two
steps).
2-{(5aS,6S,9aR)-6-(tert-Butyldimethylsilyloxy)-1-(2,2-
dimethoxyethyl)-4-methoxy-5a,6,7,9a-tetrahydro-
dibenzoACHTUNGTRENNUNG[b,d]furan-9a-yl}ethyl Acetate (11)
To a stirred solution of ether 10 (2 g, 3.41 mmol) in toluene
(35 mL) was added Pd(dba)2 (200 mg, 0.35 mmol), K2CO3
AHCTUNGTRENNUNG
(707 mg, 5.12 mmol) and (t-Bu)3P (135 mg, 0.67 mmol). The
resulting mixture was heated to reflux for 16 h. The cooled
reaction mixture was filtered through a pad of Celite to
remove the catalyst and the filtrate was concentrated using
rotary evaporation to afford a crude mixture that was chro-
matographed on silica gel (2:1 hexanes/EtOAc as eluent) to
afford Heck coupling product 11 as an oil; yield: 1.1 g
(63.6%). [a]20: 28.2 (c=1.2, CHCl3); Rf =0.75 (2:1; hexanes/
EtOAc); IRD(film): v=3034, 2952, 2911, 2855, 2834, 1712,
1
1622, 1506, 1235, 1119, 1064, 837 cmÀ1; H NMR (300 MHz,
CDCl3): d=6.73 (m, 2H, 1-H, 2-H), 5.99 (d, J=10.2 Hz,
1H, 14-H), 5.72 (dt, J=10.2, 3.6 Hz, 1H, 8-H), 4.55 (t, J=
5.7 Hz, 1H, 9-H), 4.51 (d, J=6.9 Hz, 1H, 5-H), 4.10–4.15
(m, 1H, 6-H), 3.99–4.01 (m, 2H, 16-H), 3.85 (s, 3H, OMe),
3.39 (s, 3H, OMe), 3.35 (s, 3H, OMe), 2.90 (m, 2H, 10-H),
2.27 (m, 2H, 15-H), 2.10–2.19 (m, 2H, 7-H), 2.00 (s, 3H,
OAc), 0.91 (s, 9H, OTBS), 0.15 (s, 3H, OTBS), 0.04 (s, 3H,
OTBS); 13C NMR (75 MHz, CDCl3): d=170.7, 146.3, 143.8,
132.0, 129.3, 125.4, 124.6, 122.8, 111.8, 105.2, 89.1, 68.0, 61.3,
55.8, 53.8, 53.1, 51.1, 37.5, 35.2, 30.6, 25.8, 20.8, 18.1, À4.8,
À5.3; MS (EI+): m/z (%)=260 (7), 180 (6), 117 (11), 84 (7),
133 (22), 75 (100), 57 (8), 43 (41); HR-MS (EI+): m/z=
506.2692, calcd. for C27H42O7Si: 506.2699; anal. calcd.: C
64.00, H 8.35; found: C 64.02, H 8.20.
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Mary Ann A. Endoma-Arias et al.
3.94 (d, J=6.6 Hz, 1H, 9-H), 3.88 (s, 3H, OMe), 3.26 (m,
1H, 6-H), 2.76–2.83 (m, 2H, 10-H), 2.54–2.56 (m, 1H, 14-
H), 1.96–2.05 (m, 2H, 15-H), 2.00 (s, 3H, OAc), 0.90 (s, 9H,
OTBS), 0.13 (s, 3H, OTBS), 0.02 (s, 3H, OTBS); 13C NMR
(75 MHz, CDCl3): d=171.0, 144.7, 144.0, 132.2, 129.0, 125.7,
119.7, 114.0, 94.8, 78.1, 68.3, 61.0, 56.7, 47.5, 45.0, 40.4, 36.7,
25.8, 21.0, 18.2, À4.7, À5.5.
2-{(1S,3S,3aS,3a1R,9aR)-3-[(tert-Butyldimethylsilyl)-
oxy]-1-[(dimethylamino)oxy]-5-methoxy-
1,2,3,3a,3a1,9a-hexahydrophenanthro
3a1-yl}ethanol (13)
ACHTUNGTREN[NGNU 4,5-bcd]furan-
To a stirred solution of nitrone cycloaddition product 12
(50 mg, 0.10 mmol) in CH2Cl2 (2 mL) was added Meerwein
salt (40 mg, mmol). The reaction mixture was stirred for 2 h
at room temperature. The solvent was removed via rotary
evaporation. The residue was dissolved in THF (2 mL),
cooled to 08C and was treated in one portion with LiAlH4
(20 mg, 0.53 mmol). Once the evolution of gas has ceased,
the reaction mixture was stirred at room temperature for
30 min. It was quenched by the addition of 1N NaOH
(5 mL), and the resulting biphasic mixture was extracted
with Et2O (3ꢃ10 mL). The combined organic extracts were
dried over MgSO4, filtered and concentrated via rotary
evaporation. Chromatography on silica gel (1:1 hexanes/
EtOAc as eluent) afforded the elimination product 13 as an
oil; yield: 36 mg (76.6% over two steps). [a]2D0: À113.8 (c=
0.3, CH2Cl2); Rf =0.31 (1:1 hexanes/ethyl acetate); IR (film):
n=3429, 2953, 2928, 2855, 1636, 1507, 1439, 1281, 1114,
3-{(3S,3aS,3a1R,9S,9aS)-3-[(tert-Butyldimethylsilyl)oxy]-
9-hydroxy-5-methoxy-1,2,3,3a,3a1,8,9,9a-octahydrophen-
anthroACHTUNGTRNEUNG
[4,5-bcd]furan-3a1-yl}ethyl acetate (23): [a]2D0: +29.3
(c=0.7, CH2Cl2); Rf =0.35 (2:1; hexanes/EtOAc); IR (film):
v=3434, 2929, 2856, 1738, 1634, 1504, 1439, 1258, 1115, 837,
778 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=6.77 (d, J=
8.2 Hz, 1H, 1-H), 6.63 (d, J=8.2 Hz, 1H, 2-H), 4.90 (d, J=
6.7 Hz, 1H, 5-H), 4.36 (m, 1H, 16-H), 4.23 (m, 1H, 16-H),
4.18 (m, 1H, 9-H), 3.90 (s, 3H, OMe), 3.26 (m, 1H, 6-H),
3.00 (dd, J=17.7, 6.0 Hz, 1H, 10-H), 2.80 (dd, J=17.7,
2.1 Hz, 1H, 10-H), 2.31 (m, 1H, 14-H), 2.16 (t, J=6.9 Hz,
2H, 15-H), 2.05 (s, 3H, OAc), 1.62–1.67 (m, 3H, 7-H, 8-H),
1.30 (m, 1H, 8-H), 0.90 (s, 9H, OTBS), 0.13 (s, 3H, OTBS),
0.02 (s, 3H, OTBS); 13C NMR (75 MHz, CDCl3): d=171.1,
145.2, 143.6, 131.2, 123.0, 120.3, 114.9, 96.8, 72.9, 72.5, 62.1,
57.0, 45.5, 42.2, 36.4, 32.4, 30.6, 25.8, 25.4, 21.0, 18.1, À4.6,
À5.1; MS (EI+): m/z (%)=345 (60), 327 (40), 315 (25), 149
(40), 117 (50), 73 (99), 57 (50), 43 (100); HR-MS (EI+): m/
z=462.24443, calcd. for C25H38O6Si: 462.24377.
1
1060, 836 cmÀ1; H NMR (300 MHz, CDCl3): d=6.69 (d, J=
7.8 Hz, 1H, 1-H), 6.62 (d, J=1.8 Hz, 1H, 2-H), 6.53 (d, J=
9.3 Hz, 1H, 10-H), 5.77–5.82 (dd, J=9.3, 5.7 Hz, 1H, 9-H),
4.63 (d, J=7.5 Hz, 1H, 5-H), 3.99–4.00 (m, 1H, 8-H), 3.91
(s, 3H, OMe), 3.85–3.94 (m, 1H, 6-H), 3.55 (m, 2H, 16-H),
2.52 (t, J=5.4 Hz, 1H, 14-H), 2.30 (s, 6H, NMe2), 2.04–2.10
(m, 1H, 7-H), 1.90–1.94 (m, 2H, 15-H), 1.76–1.80 (m, 1H, 7-
H), 0.93 (s, 9H, OTBS), 0.17 (s, 3H, OTBS), 0.06 (s, 3H,
OTBS); 13C NMR (75 MHz, CDCl3): d=144.8, 143.8, 130.1,
126.2, 125.9, 124.9, 117.5, 113.3, 97.7, 77.4, 70.6, 68.1, 59.5,
56.7, 44.4, 43.9, 42.2, 35.0, 26.5, 25.8, 18.1, À4.49, À5.0; MS
(EI+): m/z (%)=461 (10), 269 (25), 225 (30), 185 (35), 115
(20), 73 (100), 57 (20), 41 (20); HR-MS (EI+): m/z=
461.26006, calcd. for C25H39O5NSi: 461.25975.
Conversion of 22 to 23
To a stirred mixture of 22 and 23 (62 mg, 0.13 mmol) in
MeOH (1 mL) was added 5% Pd/C (10 mg). The flask was
evacuated and refilled with hydrogen gas three times. Then
it was stirred under an atmosphere of hydrogen gas for 16 h.
The catalyst was removed by filtration through a plug of
Celite and the filtrate was concentrated under vacuum to
afford the product 23; yield: 57 mg (92%).
3-{(3S,3aS,3a1R,9S,9aS)-3-[(tert-Butyldimethylsilyl)-
oxy]-9-hydroxy-5-methoxy-3,3a,3a1,8,9,9a-hexa-
2-{(3S,3aS,3a1R,9aR)-3-[(tert-Butyldimethylsilyl)oxy]-
5-methoxy-1,2,3,3a,3a1,9a-hexahydrophenanthroACHTUNGTRENNUNG[4,5-
bcd]furan-3a1-yl)ethanol (24)
hydrophenanthroACHTUNGTRENNUNG[4,5-bcd]furan-3a1-yl}propyl Acetate
(22)
To a solution of alcohol 23 (25 mg, 0.05 mmol) dissolved in
CH2Cl2 (1 mL) at 08C was added NEt3 (18.7 mL,
0.14 mmol) followed by MsCl (8.4 mL, 0.11 mmol). The
cooling bath was removed and the reaction mixture was
stirred at room temperature for 30 min. It was diluted with
CH2Cl2 (5 mL) and 1N NaOH (5 mL). The layers were sep-
arated and the aqueous layer was further extracted with
CH2Cl2 (2ꢃ5 mL). The combined organic extracts were
dried over anhydrous MgSO4, filtered and concentrated via
rotary evaporation. The crude oily residue of mesylate prod-
uct was used as is in the next step.
To a solution of the crude mesylate prepared in the previ-
ous step in EtOH (3 mL) was added 3N NaOH (0.50 mL).
The resulting solution was heated to reflux for 1 h. It was
cooled to room temperature and the solvent was removed
via rotary evaporation. The residue was partitioned between
EtOAc (5 mL) and H2O (5 mL). The layers were separated
and the aqueous was further extracted with EtOAc (2ꢃ
5 mL). The combined organic extracts were dried over anhy-
drous MgSO4, filtered and concentrated via rotary evapora-
tion. The residue was chromatographed on silica gel using
In a flame-dried flask, a stream of argon was bubbled
through a solution of aldehyde 4 (104 mg, 0.23 mmol) and
HMPA (0.71 mL, 4.07 mmol) in THF (9 mL) for 20 min. A
deep-blue solution of SmI2 in THF (5.0 mL, 0.5 mmol) was
added to the degassed solution dropwise over 20 min. The
resulting orange-brown solution was stirred at room temper-
ature for 20 h, after which the reaction was quenched by ad-
dition of saturated aqueous NaHCO3 and diluted with Et2O
(20 mL). After separation of the organic and aqueous layers,
the aqueous phase was further extracted with Et2O (3ꢃ
20 mL). The combined organic extracts were then washed
with H2O and brine before drying over Na2SO4. After filtra-
tion and evaporation, the crude mixture was purified by
flash column chromatography (3:1, hexanes/ethyl acetate) to
afford the alcohols 22 (yield: 6 mg) and 23 (yield: 47 mg) as
oil; combined yield: 53 mg (50%).
1
Alcohol 22: H NMR (300 MHz, CDCl3): d=6.73 (d, J=
7.8 Hz, 1H, 1-H), 6.65 (d, J=7.8 Hz, 1H, 2-H), 6.09 (m, 1H,
8-H), 5.69 (d, J=10.2 Hz, 1H, 7-H), 4.44 (d, J=3.6 Hz, 1H,
5-H), 4.16–4.19 (m, 1H, 16-H), 4.08–4.11 (m, 1H, 16-H),
338
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 333 – 339

COMMUNICATIONS
Chemoenzymatic Formal Total Synthesis of ent-Codeine
hexanes/EtOAc (2:1) as eluent to afford the alcohol 24 as
an oil; yield: 15 mg (69% over 2 steps). [a]2D0: +12.4 (c=0.5,
CH2Cl2); Rf =0.50 (2:1 hexanes/EtOAc); IR (film): v=3430,
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Carroll, T. Hudlicky, Synlett 2007, 2859–2862.
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Commun. 1984, 322–323.
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2929, 2856, 1634, 1505, 1437, 1275, 1109, 836, 777 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=6.71 (d, J=8.1 Hz, 1H, 1-
H), 6.63 (d, J=8.1 Hz, 1H, 2-H), 6.36 (d, J=9.6 Hz, 1H, 10-
H), 5.83 (dd, J=9.6, 5.7 Hz, 1H, 9-H), 4.59 (d, J=6.9 Hz,
1H, 5-H), 3.89 (s, 3H, OMe), 3.53 (m, 1H, 16-H), 3.40 (m,
1H, 16-H), 3.37 (m, 1H, 6-H), 2.37 (m, 1H, 14-H), 1.58–1.63
(m, 2H, 7-H), 1.23–1.27 (m, 2H, 8-H), 0.89 (s, 9H, OTBS),
0.12 (s, 3H, OTBS), 0.03 (s, 3H, OTBS); 13C NMR
(75 MHz, CDCl3): d=145.4, 144.7, 130.4, 128.7, 123.5, 122.9,
117.7, 113.7, 98.3, 73.9, 59.6, 56.7, 45.3, 41.2, 40.5, 29.8, 26.9,
25.8, 18.1, À4.6, À5.0; MS (EI+): m/z (%)=345 (10), 327
(20), 301 (20), 268 (15), 242 (15), 199 (30), 75 (100), 57 (30),
45 (50); HR-MS (EI+): m/z=402.22267, calcd. for
C23H34O4Si: 402.22264.
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Acknowledgements
[9] a) Diol 6 was previously reported: T. Hudlicky, M. A.
Endoma, G. Butora, J. Chem. Soc. Perkin Trans.
1 1996, 2187–2192; b) for medium-scale preparation of
arene-cis-dihydrodiols see: M. A. Endoma, V. P. Bui, J.
Hansen, T. Hudlicky, Org. Process Res. Dev. 2002, 6,
525–532.
[10] Procedure adapted from the preparation of ethylene
glycol acetal of 9: G. Duchek, J. Piercy, J. Gilmet, T.
Hudlicky, Can. J. Chem. 2011, 89, 709–728.
The authors are grateful to the following agencies for finan-
cial support of this work: Natural Sciences and Engineering
Research Council of Canada (NSERC), Canada Research
Chair Program, Canada Foundation for Innovation (CFI),
TDC Research, Inc., TDC Research Foundation, the Ontario
Partnership for Innovation and Commercialization (OPIC),
and The Advanced Biomanufacturing Centre (Brock Univer-
sity). We also thank Professors Kevin Brown and David Wil-
liams of Indiana University for helpful discussion and mech-
anistic insight.
[11] P. Metz, A. Hennig, unpublished observations. From
PhD thesis of A. Hennig, TU Dresden, 2008.
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[13] C. Beemelmanns, H.-U. Reissig, Pure Appl. Chem.
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asc.wiley-vch.de
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