Asymmetric total synthesis of (+)-codeine via intramolecular carbenoid insertion

Article abstract of DOI:10.1021/jo990905z

A strategy was devised for the synthesis of codeine that employed intramolecular insertion of a carbenoid into a benzylic methine CH bond for creation of the C13 quaternary center and construction of the pentacyclic skeleton of the alkaloid. The synthesis began from isovanillin, and asymmetry was introduced through catalytic hydrogenation of its Stobbe condensation product 7 over a chiral catalyst (8). The product (S)-9 was advanced to tetralone 12, which underwent Robinson annulation to give the phenanthrenone 33. The latter was brominated and treated with base to afford the fused benzofuran 35. Reduction with hydride followed by catalytic hydrogenation produced the tetracycle 44, which was converted to diazoketone 48. The latter was reacted in the presence of catalytic Rh₂(OAc)₄ to furnish the pentacyclic product 49. Beckmann rearrangement of the derived oxime brosylate 59 gave lactam 57, and the synthesis of (+)-1 (the nonnatural enantiomer of codeine) was completed after oxidation to 63, introduction of Δ^7,8 unsaturation, and exhaustive reduction.

Full text of DOI:10.1021/jo990905z

J . Org. Chem. 1999, 64, 7871-7884
7871
Asym m etr ic Tota l Syn th esis of (+)-Cod ein e via In tr a m olecu la r
Ca r ben oid In ser tion
J ames D. White,* Peter Hrnciar, and Frank Stappenbeck
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331-4003
Received J une 2, 1999
A strategy was devised for the synthesis of codeine that employed intramolecular insertion of a
carbenoid into a benzylic methine CH bond for creation of the C13 quaternary center and
construction of the pentacyclic skeleton of the alkaloid. The synthesis began from isovanillin, and
asymmetry was introduced through catalytic hydrogenation of its Stobbe condensation product 7
over a chiral catalyst (8). The product (S)-9 was advanced to tetralone 12, which underwent Robinson
annulation to give the phenanthrenone 33. The latter was brominated and treated with base to
afford the fused benzofuran 35. Reduction with hydride followed by catalytic hydrogenation produced
the tetracycle 44, which was converted to diazoketone 48. The latter was reacted in the presence
of catalytic Rh2(OAc)4 to furnish the pentacyclic product 49. Beckmann rearrangement of the derived
oxime brosylate 59 gave lactam 57, and the synthesis of (+)-1 (the nonnatural enantiomer of codeine)
was completed after oxidation to 63, introduction of ∆7,8 unsaturation, and exhaustive reduction.
The unique position of codeine (1) and morphine (2) in
contemporary medicine continues to inspire efforts to-
ward an understanding of its analgesic and euphoriant
properties.1 Central to this endeavor is the development
in view of recent advances in methodology that could
permit elaboration of the pentacyclic framework of 1 from
this tricyclic nucleus.9 For reasons associated with our
interest in examining the pharmacological properties of
the unnatural enantiomorph, we chose (+)-codeine (1) as
the goal of this synthesis.10
The most important strategic decision made at the
outset of this work was that the C13-C15 bond of 1
would be set in place after the phenanthrene nucleus was
established. Of the many successful approaches to mor-
phine, only that of Ginsburg has employed this design.11
The means for achieving the pivotal C13-C15 bond of
morphine was to be an intramolecular carbenoid reaction
that would generate ketone 3 from a tricyclic precursor
4. The piperidine ring of 1 would then be elaborated
of new synthetic routes that not only lead to these
alkaloids in enantiomerically pure form but also provide
access to useful structural analogues.2 Approaches to the
synthesis of morphine began even before its structure
was revealed by Robinson in 1925,3 yet it was not until
1993 that the first asymmetric synthesis of the alkaloid
was reported.4 Our own preoccupation with codeine and
morphine5 has lately focused on a synthesis capable of
delivering either enantiomer and which exploits a concept
adopted by the pioneering efforts that envisioned a
phenanthrene as an easily accessible platform for con-
structing the pentacyclic skeleton of morphine.6 Although
subsequent investigations abandoned this strategy, fa-
voring biomimetic7 and other approaches,8 a revisitation
of the classical phenanthrene route seemed appropriate
(1) Lednicer, D. Central Analgesics; Wiley: New York, 1982; pp 137-
213.
(2) Hudlicky, T.; Butora, G.; Fearnley, S. P.; Gum, A. G.; Stabile,
M. R. Studies in Natural Products Chemistry; Rahman, A.-u., Ed.;
Elsevier: Amsterdam, 1996; pp 43-154.
(3) Gulland, J . M.; Robinson, R. Mem. Proc. Manch. Lit. Soc. 1925,
69, 79.
(4) Hong, C. Y.; Kado, N.; Overman, L. E. J . Am. Chem. Soc. 1993,
115, 11028.
through ring expansion of 3. Acquisition of 4 was
envisioned from tetralin 5 bearing a single stereogenic
(5) (a) White, J . D.; Caravatti, G.; Kline, T. B.; Edstrom, E.; Rice,
K. C.; Brossi, A. Tetrahedron 1983, 39, 2393. (b) White, J . D.; Butlin,
R. J .; Hahn, H.-G.; J ohnson, A. T. J . Am. Chem. Soc. 1990, 112, 8595.
(6) (a) Pschorr, A. T. Ber. 1896, 29, 496. (b) Fieser, L. F.; Holmes,
H. L. J . Am. Chem. Soc. 1936, 58, 2319. (c) Robinson, R.; Ghosh, R. J .
J . Chem. Soc. 1944, 506.
(8) (a) Evans, D. A.; Mitch, C. H. Tetrahedron Lett. 1982, 23, 285.
(b) Moos, W. H.; Gless, R. D.; Rapoport, H. J . Org. Chem. 1983, 48,
227. (c) Butora, G.; Hudlicky, T.; Fearnley, S. P.; Gum, A. G.; Stabile,
M. R.; Abboud, K. Tetrahedron Lett. 1996, 37, 8155. (d) Toth, J . E.;
Hamann, P. R.; Fuchs, P. L. J . Org. Chem. 1988, 53, 4694. (e) Parker,
K. A.; Fokas, D. J . Am. Chem. Soc. 1992, 114, 9688. (f) Tius, M. A.;
Kerr, M. A. J . Am. Chem. Soc. 1992, 114, 5959.
(7) Schwartz, M. A.; Pham, P. T. K. J . Org. Chem. 1988, 53, 2318
and references cited.
10.1021/jo990905z CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/25/1999

7872 J . Org. Chem., Vol. 64, No. 21, 1999
White et al.
Ta ble 1. Effect of Ca ta lyst-Su bstr a te Ra tio on th e
Asym m etr ic Hyd r ogen a tion of 7
catalysta-substrateb
reaction time
(h)
yield of 9
ee of 9c
(%)
ratio
(%)
2.0 × 10-3
3.8 × 10-3
5.6 × 10-3
10
10
7
10
50
100
90
92
94
a
Based on [RhCl(COD)]2; (MOD-DIOP/Rh(I) ratio was 2:1).
Maintained at 0.6M in MeOH. c Determined by chiral HPLC
b
analysis (Chiralpak AD, hexane-i-PrOH (90:10) containing 5%
CF3CO2H, flow rate 0.9 mL/min).
center, and it is this center that directs all subsequent
stereochemical events leading to 1.
The route to 5 began with Stobbe condensation12 of
isovanillin (6) with dimethyl succinate. The resultant
cinnamate half-acid 7 was subjected to asymmetric
hydrogenation using a chiral rhodium catalyst based on
the MOD-DIOP ligand 8 of Achiwa.13 Although both the
neutral [(ClRhCOD)2-MOD-DIOP] and cationic [(RhCOD-
MOD-DIOP)+ BF4-] versions of this catalyst are reported
to give good stereoselectivity in the asymmetric reduction
of substituted benzylidenesuccinate half esters,14 the
neutral complex was found to be easier to prepare.
Nevertheless, satisfactory asymmetric hydrogenation of
7 with the Rh complex of (4R,5R)-8 required considerable
optimization. Using a catalyst-to-substrate ratio of 2 ×
10-3, as suggested by Achiwa,14 necessitated long reaction
times and resulted in 9 of low optical purity. Chiral
HPLC analysis of the reaction course revealed that
enantiomeric purity of the product decreased over time,
suggesting that the chiral catalyst was chemically trans-
formed to a species that, while still catalytically active,
possessed lower or no selectivity. This observation is
consistent with results published by Glaser on asym-
metric hydrogenation using a (ClRhCOD)2-DIOP sys-
tem.15 For optimization, it was necessary to increase the
catalyst-to-substrate ratio nearly 3-fold to obtain good
enantioselectivity (see Table 1), and under these condi-
tions, 7 was reduced in quantitative yield to (S)-9 in 94%
enantiomeric excess. However, for practical reasons,
exploratory reactions with 9 were carried out on racemic
material, prepared by hydrogenation of 7 over 10% Pd/C
catalyst.
sis over Pearlman’s catalyst18 to afford 13 in virtually
quantitative yield. As subsequent events unfolded, how-
ever, this bromine substituent would be recalled for a
different role.
The next stage of the synthesis required conversion of
keto ester 13 to a phenanthrenone derivative through
Robinson annulation with methyl vinyl ketone. To effect
this annulation, it was first necessary to convert 13 to
its R-formyl derivative 14, since this tactic facilitated
Michael addition of the anion from 14 to MVK.19 In-
tramolecular condensation, deformylation, and saponi-
fication of 15 occurred in a single step to yield carboxylic
acid 16 as the sole stereoisomer. The relative configura-
tion of 16 was confirmed in the course of a subsequent
series of transformations (vide infra). This set the stage
for constructing the tetracyclic core of morphine, for
which the phenolic hydroxyl group of 16 was first blocked
as its acetate 17 and the carboxylic acid was converted
through its acyl chloride to diazoketone 18. Unexpectedly,
decomposition of 18 in the presence of Rh2(OAc)4 gave
norcaradiene 19,20 indicating that the electron-rich aro-
Not surprisingly, direct transformation of 9 to a
tetralone led to the undesired isomer 10 in which
intramolecular Friedel-Crafts acylation had occurred
para to the free phenol. The simple expedient of bromi-
nation blocked this pathway,16 and Friedel-Crafts cy-
clization17 of brominated phenol 11 afforded tetralone 12
in good yield. The bromine substituent in 12, having
served its present purpose, was removed by hydrogenoly-
(9) For a recent synthesis of morphine based on this strategy, see
Mulzer, J .; Duerner, G.; Trauner, D. Angew. Chem., Int. Ed. Engl.
1996, 35, 2830.
(10) White, J . D.; Hrnciar, P.; Stappenbeck, F. J . Org. Chem. 1997,
62, 5250.
(11) (a) Ginsburg, D.; Pappo, R. J . Chem. Soc. 1953, 1524. (b) Elad,
D.; Ginsburg, D. J . Chem. Soc. 1954, 3052.
(12) J ohnson, W. S.; Daub, G. H. Org. React. 1951, 6, 1.
(13) Morimoto, T.; Chiba, M.; Achiwa, K. Tetrahedron Lett. 1989,
30, 735.
(14) Morimoto, T.; Chiba, M.; Achiwa, K. Chem. Pharm. Bull. 1993,
41, 1149
(15) Glaser, R.; Geresh, S.; Blumenfeld, J . J . Organomet. Chem.
1976, 112, 355.
(16) Stock, L. M.; Himoe, A. J . Am. Chem. Soc. 1961, 83, 4605.
(17) Eaton, P. E.; Carlson, G. R.; Lee, J . T. J . Org. Chem. 1973, 38,
4071.
(18) Prugh, J . D.; Rooney, C. S.; Deana, A. A.; Ramjit, H. G.
Tetrahedron Lett. 1985, 26, 2947.
(19) Banwell, M. G.; Lambert, J . N.; Corbett, M.; Greenwood, R. J .;
Gulbis, J . M.; Mackay, M. F. J . Chem. Soc., Perkin Trans 1 1992, 1415.
(20) For an analogous example, see Adams, J .; Spero, D. M.
Tetrahedron 1991, 47, 1765.

Asymmetric Total Synthesis of (+)-Codeine
J . Org. Chem., Vol. 64, No. 21, 1999 7873
rearrangement in the presence of BF3‚OEt2 to give the
bridged tetracycle 28, albeit in low yield.23 The latter was
characterized as ketone 29, obtained by oxidation of the
pair of stereoisomeric alcohols with Dess-Martin perio-
dinane.24 Unfortunately, efficient chemical differentiation
of the two olefins of the cyclohexadiene moiety of 29
proved insurmountable and effectively terminated this
route.
matic ring is more receptive than the enone moiety to
attack by the keto carbenoid. The structure of 19 was
readily apparent from the chemical shifts of the olefinic
and cyclopropane carbons and protons in its NMR
spectrum.
The formation of 19 from diazoketone 18 implied that
a useful morphine precursor would only be accessible if
carbene addition to the benzenoid ring could be sup-
pressed. It was surmised that a bromine substituent at
C8 could accomplish this, since on both steric and
electronic grounds the aryl ring would become less
reactive when it bears a bulky halogen. This conjecture
led us back to 12, which was taken through the same
Robinson annulation sequence previously used on 13. The
R-formyl tetralone 20 was transformed via 21 to carboxy-
lic acid 22, which after acetylation produced 23. The ethyl
ester 24 of 23 was a highly crystalline compound, the
structure of which was determined by X-ray analysis.
This not only proved the relative configuration of 23 but
also confirmed the same stereochemical relationship in
16. Carboxylic acid 23 was converted to diazoketone 25,
but treatment of the latter with Rh2(OAc)4 produced
another surprise, affording cyclobutanone 26.21 This
substance was also highly crystalline, and its structure
readily yielded to X-ray crystallographic analysis. Thus,
although carbene attack had been diverted from the aryl
ring by the bromine substituent, insertion into the γ C-H
bond of the enone was now the preferred outcome. The
optimistic conjecture that 26 did not represent a cul-de-
sac was entertained briefly when it was found that diol
27, obtained as a mixture of all four stereoisomers by
Luche reduction22 of 26, underwent Wagner-Meerwein
A different strategy for fashioning the morphine C13-
C15 bond from 22 is conceivable if the double bond of
the enone is first reduced so that a hydrogen atom is
installed at the 13R position. In this plan, carbene
insertion into the resulting benzylic CH bond should lead
(21) Cyclobutanone formation via intramolecular decomposition of
a
R-diazoketone has been observed previously, albeit as a minor
(22) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981, 103, 5454.
(23) For a related example see White, J . D.; Matsui, T.; Thomas, J .
A. J . Org. Chem. 1981, 46, 3376.
pathway (Wenkert, E.; Davis, L. L.; Mylari, B. L.; Solomon, M. F.; da
Silva, R. R.; Shulman, S.; Warnet, R. J .; Ceccherelli, P.; Curini, M.;
Pellicciari, R. J . Org. Chem. 1982, 47, 3242).
(24) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.

7874 J . Org. Chem., Vol. 64, No. 21, 1999
White et al.
13, formylation of the trianion of 30 produced 31.
Annulation of the latter with MVK took a course different
from that observed with 14 and afforded lactol 32 as an
intermediate, but this substance underwent smooth
intramolecular condensation in the presence of base to
yield the crystalline keto acid 16. Treatment of 16 with
diazomethane in ethyl acetate then gave optically pure
methyl ester 33.
Closure of the furanoid ring of morphine from 33
required R bromination of the enone followed by intramo-
lecular displacement of bromide by the phenoxide oxygen.
However, before this displacement can occur, rehybrid-
ization of the R carbon of the enone toward sp3 must take
place. The mechanism proposed by Seshadri for this
process in a conversion of 3-halocoumarins to benzo[b]-
furans is temporary, reversible conjugate addition of a
nucleophile (hydroxide) to the R-bromoenone.25 With this
precedent in mind, 33 was treated with bromine in
chloroform containing NaHCO3. Addition followed by
elimination of HBr occurred as expected, but it was not
possible to suppress aromatic bromination under these
conditions, and dibromo compound 34 therefore became
the obligatory candidate for benzofuran formation. Sev-
eral basic media were investigated for this purpose, but
most led to epimerization at both stereogenic centers in
34. In the event, DBU in hot benzene proved to be the
most satisfactory method for the transformation of 34 to
35. These conditions are not consonant with Seshadri’s
reversible 1,4-addition mechanism,25 and we believe a
more plausible scenario involves isomerization of 34 to
the â,γ-enone 36 prior to cyclization. The return of C14
to its original R configuration in 35 is in accord with our
observation that the trans stereoisomer of 16 and 24 is
thermodynamically favored. In fact, analysis of 35 showed
that <3% epimerization had occurred during its forma-
tion from 34.
F igu r e 1. (a) AM1-optimized conformation of a tricyclic
diazoketone showing pseudoequatorial orientation of diazo
function and hydrogen atom. (b) AM1-optimized conformation
of a tetracyclic diazoketone showing pseudoaxial orientation
of diazo function and hydrogen atom.
directly to the desired configuration at the C13 quater-
nary center. There are, however, two important require-
ments for this approach to be productive. First, the enone
must be reduced stereoselectively from the R face to
afford a cis BC ring fusion, and second, the C13-H bond
and diazoketone moiety must occupy a diaxial relation-
ship. Even if the first of these requirements is met, the
AM1-optimized geometry of the reduced structure reveals
that the diazoketone moiety and the hydrogen atom it
must target are both pseudoequatorial (Figure 1a). On
the other hand, a structure in which the furanoid ring of
morphine is closed enforces the necessary diaxial orienta-
tion of reacting partners (Figure 1b). This conformational
analysis predicts that continuation of our original phenan-
threne approach toward a tetracyclic diazoketone would
lead to successful intramolecular CH insertion at C13 by
the carbene generated from this species.
A return to 16 for the purpose of redirecting the
synthesis along this line brought another unpleasant
surprise; it was discovered that partial racemization of
this compound had occurred en route from 13! Fortu-
nately, the problem was easily solved by a simple
modification to the Robinson annulation sequence using
carboxylic acid 30 rather than the corresponding methyl
ester 13 as the substrate. Thus, after saponification of
Our initial plan for saturation of the 5,13-double bond
of 35 envisioned a thermodynamically controlled reduc-
(25) Saroja, T.; Seshadri, T. R.; Muckerjee, S. K. Indian J . Chem.
1971, 9, 1316.

Asymmetric Total Synthesis of (+)-Codeine
J . Org. Chem., Vol. 64, No. 21, 1999 7875
decided to explore this option. Exposure of 35 to sodium
borohydride gave the desired 6R alcohol 43 in quantita-
tive yield and, as predicted, the parallel alignment of the
alcohol substituent with the aromatic π system in this
isomer resulted in complete suppression of hydrogenoly-
sis. Thus, catalytic hydrogenation of 43 afforded mainly
44, accompanied by a small amount of its stereoisomer
45 (44:45 ) 22:1).
tion, since calculations had convinced us that the desired
cis,syn isomer (5S,13R) was the most stable of the four
possible stereoisomeric products. In fact, reduction of 35
with sodium amalgam did give a single product, but after
esterification with diazomethane this was found to be 37,
in which reductive R cleavage as well as saturation of
the double bond had taken place. The same keto ester
was obtained upon exposure of 35 to lithium-ammonia.
In an attempt to avoid R cleavage, 35 was treated with
triethylsilane in the presence of TiCl4 in the hope that
only conjugate reduction would occur. In this case, the
deoxygenated tetracycle 38 was the sole product. By
contrast, hydrogenation of 35 over a palladium catalyst
in MeOH afforded 39 accompanied by alcohol 40 and
methyl ether (39:40:41 ) 6:1:1). The cis relationship
between hydrogens at C13 and C14 in 39 was apparent
from an NOE (7%) between these protons in its NMR
spectrum. The major product 39 presumably arises from
initial reduction of the keto group of 35, leading to a
pseudoaxial alcohol 42 that undergoes subsequent hy-
drogenolysis.26 The perpendicular orientation of the
alcohol of 42 with respect to the plane of the benzofuran
would facilitate both hydrogenolysis and explain the
solvolytic origin of 41. Hydrogenation of the benzofuran
is thus the terminal event in this scenario.
It became clear from the foregoing results that if both
the tetracyclic framework of 35 and an oxygen substitu-
ent at C6 were to be preserved during hydrogenation of
the benzofuran, a substrate bearing a pseudoequatorial
alcohol at C6 would have better prospects. Although a
6R hydroxyl group would eventually require inversion to
the natural â configuration of 1, it was nevertheless
(26) Analogous reduction was observed by Gates in the course of
his studies on thebaine (Gates, M.; Klein, D. A. J . Med. Chem. 1967,
10, 380).
Acquisition of 44 brought us to the pivotal C9-C13
bond construction needed to secure the pentacyclic

7876 J . Org. Chem., Vol. 64, No. 21, 1999
White et al.
framework of morphine. Ample precedent exists to sug-
gest that a keto carbenoid derived from an ester such as
44 should undergo insertion into the CH bond of the
benzylic methine to afford a bridged cyclopentanone,27
and with the diversionary pathways seen with 18 and
25 now effectively blocked, preparation of a substrate for
this key cyclization became our next objective. First,
alcohol 44 was protected as its MOM ether 46, after
which saponification of the ester gave 47. Conversion of
this carboxylic acid to its acyl chloride, followed by
treatment with diazomethane furnished diazoketone 48.
Decomposition of 48 was carried out in the presence
of several Rh(II) catalysts with varying success. The
Doyle catalyst, dirhodium(II) tetrakisacetamide [Rh2-
(acam)4],28 is known to favor insertion by carbenes into
electron-rich, methine CH bonds, and indeed this catalyst
provided the highest yield (65%) of pentacyclic ketone 49.
A detailed discussion of the decomposition of 48 with
various rhodium(II) catalysts will be presented else-
where,29 but it should be noted that the transformation
48 f 49 represents a unique method for setting config-
uration at the quaternary carbon of morphine and for
creating its pentacyclic skeleton.
In a parallel study that examined intramolecular
carbene insertion into the C13-H bond of ketone 50,
alcohol 44 was first oxidized to keto ester 51. The latter
was saponified, and keto acid 52 was converted to
diazoketone 50 by the same protocol used for the prepa-
ration of 48. Decomposition of 50 using Rh2(OAc)4 as
catalyst furnished diketone 53 in 53% yield. Our hope
was that this pathway could be continued from 53,
thereby avoiding protection of the C6 hydroxyl function
and affording a more direct route to the 6R configuration
required for 1. The first objective in this plan was
introduction of a ∆7,8 double bond, a task that was
accomplished by acid-catalyzed phenylselenylation30 of
53 followed by oxidation of R-selenyl ketone 54 with
periodate. Unfortunately, the R,â-unsaturated ketone 55
proved to be a cul-de-sac, for although we had envisioned
construction of the piperidine ring of 1 via Beckmann
rearrangement of the cyclopentanone oxime derived from
55, this diketone could not be induced to form the desired
oxime without involvement of the enone moiety.
In contrast to 55, however, ketone 49 yielded oxime
56 quite readily, and although the latter was produced
as an inseparable 1.2:1 mixture of anti and syn isomers,
respectively, progression to the δ-lactam 57 appeared to
be straightforward. In practice, neither 56 nor the
corresponding oxime tosylate31 could be induced to un-
dergo Beckmann rearrangement under a variety of
conditions, including exposure to elevated tempera-
tures.32 The oxime derivative 58, prepared in high yield
by treatment of 56 with carbonyldiimidazole, did afford
a low yield of 57 upon reaction with MeI in hot benzene,33
but it became clear from these studies that a successful
transformation of 56 to 57 would necessitate careful
examination of factors impeding this crucial Beckmann
rearrangement. One of these is the poor alignment of the
migrating bond with the breaking N-O linkage in either
stereoisomer of this rigid framework. However, if the
oxime carbon of 56 is rehybridized to sp3, the stereoelec-
tronic impediment to rearrangement is largely removed.
It follows that conditions favoring addition across the
CdN bond of the oxime prior to solvolysis and migration
should facilitate Beckmann rearrangement.34 This logic
led us to examine the reactivity of brosylate 59 in glacial
acetic acid, and to our delight, this resulted in smooth
Beckmann rearrangement at room temperature. The
desired δ-lactam 57 was accompanied by its isomer 60,
initially in the ratio 6.5:1, respectively, if 59 was prepared
and used in situ. However, if brosylate 59 was warmed
to 75 °C in toluene before exposure to acetic acid, the ratio
57:60 improved to 11:1, respectively. This temperature
dependence reflects equilibration of the mixture of oxime
brosylates toward the less sterically crowded anti stere-
oisomer and specifically sets the tetrahedral intermediate
61 in a configuration that favors migration of the
bridgehead carbon. Lactam 57 was separated from the
minor isomer 60 by chromatography on silica and was
converted to its N-methyl derivative 62 in high yield with
methyl iodide and sodium hydride.
(27) Burke, S. D.; Grieco, P. A. Org. React. 1979, 26, 361.
(28) Doyle, M. P.; Bagheri, V.; Wandless, T. J .; Harn, N. K.; Brinker,
D. A.; Eagle, C. T.; Loh, K.-L.J . Am. Chem. Soc. 1990, 112, 1906.
(29) The product distribution from decomposition of 48 was found
to depend markedly on the Rh(II) catalyst employed as well as on small
structural variations in the substrate (Hrnciar, P. Ph.D. Thesis 1999,
Oregon State University).
(30) Iijima, I.; Rice, K. C.; Silverton, J . V. Heterocycles 1977, 6, 1157.
(31) Oppolzer, W.; Fehr, C.; Warneke, J . Helv. Chim. Acta 1977,
60, 48.
To complete the synthesis of 1, it was necessary to
reverse the configuration of the C6 oxygen substitutent
and introduce unsaturation into position C7-C8 of the
C ring of 62. Inspection of molecular models suggested
that, whereas hydride reduction of 35 had given the 6R
(32) Corey, E. J .; Arnett, J . F.; Widiger, G. N. J . Am. Chem. Soc.
1975, 97, 430.
(33) Kamijo, T.; Harada, H.; Iizuka, K. Chem. Pharm. Bull. 1984,
32, 2560.
(34) For a contemporary view of the classical Beckmann rearrange-
ment, see: Nguyen, M. T.; Raspoet, G.; Vanquickenborne, L. G. J . Am.
Chem. Soc. 1997, 119, 2552.

Asymmetric Total Synthesis of (+)-Codeine
J . Org. Chem., Vol. 64, No. 21, 1999 7877
alcohol 43 exclusively, similar reduction of the C6 ketone
of a pentacyclic structure such as 63 should yield the 6â
hydroxyl configuration. The reason for anticipating this
reversal is that the presence of the lactam ring forces 63
to adopt a conformation in which the â face of the
cyclohexanone carbonyl is shielded by the aryl ring.
Ketone 63 was prepared by Dess-Martin oxidation of
alcohol 64, obtained after removal of the MOM protecting
group from 62, and was first explored as a vehicle for
introducing the ∆7,8 unsaturation required for 1. Depro-
tonation of 63 with LDA or with NaHMDS, followed by
reaction of the enolate with phenylselenyl chloride,
produced a 1:1 mixture of 65 and 66, but deprotonation
under thermodynamic conditions with potassium tert-
butoxide gave exclusively the desired enolate, resulting
in the R-phenylselenyl ketone 66. Elimination of the
selenoxide derived from 66 led to R,â-unsaturated ketone
67 in good overall yield. As expected, exhaustive treat-
ment of 67 with lithium aluminum hydride resulted in
conversion of the δ-lactam to a piperidine as well as
reduction of the keto group to the desired 6â alcohol. The
product, (+)-codeine (68), was shown to be enantiomeric
with natural (-)-codeine (1) by comparison of 1H and 13C
NMR spectra and optical rotation. O-Demethylation of
natural codeine is known,35 and by extension exposure
of 68 to boron tribromide would provide (+)-morphine (2).
It can be seen from the foregoing results that the
complete stereogenicity of 1 arises from the single asym-
metric center in (S)-9. Inversion of the latter reverses the
absolute sense of the entire synthetic sequence and would
therefore lead to natural (-)-codeine. Thus, either enan-
tiomer of codeine and morphine is available in principle
by selection of the appropriate enantiomer of the MOD-
DIOP ligand14 used for the asymmetric hydrogenation of
7. A further attribute of the synthetic pathway disclosed
here is that pentacyclic ketones 49 and 53 afford conve-
nient entry points to certain analogues of the morphine
structure that are not readily accessible by other routes.
This aspect will be the subject of a future publication.
Exp er im en ta l Section
Melting points are uncorrected. Chemical ionization (CI)
high- and low-resolution mass spectra (HRMS and MS) were
obtained using a source temperature of 120 °C and CH4 as
the ionizing source. Perfluorokerosene was used as a reference.
X-ray crystallographic structures were solved using the direct
methods program contained in the SHELXTL software pack-
age.
(E)-4-(3-Hyd r oxy-4-m eth oxyp h en yl)-3-m eth oxyca r bon -
yl-3-bu ten oic Acid (7). To a solution of NaOCH3, prepared
from sodium metal (12.0 g, 0.52 mol) and MeOH (150 mL),
were added isovanillin (20.0 g, 0.13 mol) and dimethyl succi-
nate (25 g, 0.17 mol). The mixture was refluxed for 6 h, poured
into stirred, aqueous HCl (5%, 250 mL) at 0 °C, and extracted
with EtOAc. The extract was washed with water and was
extracted with saturated aqueous NaHCO3 (450 mL). The
aqueous phase was separated, washed with EtOAc, and
(35) Rice, K. C. J . Med. Chem. 1977, 20, 164.

7878 J . Org. Chem., Vol. 64, No. 21, 1999
White et al.
acidified with aqueous HCl (10%). The aqueous solution was
extracted with EtOAc, and the extract was washed with H2O
and saturated aqueous NaCl, dried (Na2SO4), and concentrated
under reduced pressure. The residue was recrystallized from
EtOAc-hexane (2:1) to afford 23.8 g (68%) of 7 as pale yellow
prisms: mp 182-183 °C; IR (KBr) 3347, 2883, 2939, 1733,
1687, 1606, 1588, 1511, 1444, 1278, 1212, 1163, 1126, 1022,
(1.30 g, 3.40 mmol), NaHCO3 (1.60 g), and Pd(OH)2 catalyst
(40 mg) in MeOH (100 mL) was stirred vigorously for 45 min
under an H2 atmosphere at ambient temperature and pres-
sure. The mixture was filtered, and the filtrate was concen-
trated under reduced pressure. To the residue was added
aqueous HCl (5%, 10 mL), and the product was extracted with
EtOAc. The extract was washed with H2O and saturated
aqueous NaCl, dried (Na2SO4), and concentrated under re-
duced pressure to afford 1.00 g (99%) of pure 13 as a yellow
1
811 cm-1; H NMR (300 MHz, CDCl3) δ 3.65 (m, 2H), 3.82 (s,
3H), 3.90 (s, 3H), 6.60-6.95 (m, 3H), 7.81 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 33.5, 52.3, 55.9, 110.7, 115.3, 121.9, 123.4,
127.9, 142.4, 145.6, 147.5, 168.2, 177.0; MS (EI) m/z 266 (M+),
222, 175, 167, 163, 162, 147, 131, 119, 103, 91; HRMS (EI)
m/z 266.0790 (calcd for C13H14O6 266.0790). Anal. Calcd for
oil: [R]23 +42.5 (c 1.04, CHCl3); IR (neat) 2960, 1733, 1645,
D
1422, 1263 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.85-2.90 (m,
2H), 3.04-3.17 (m, 3H), 3.69 (s, 3H), 3.84 (s, 3H), 6.65 (d, J )
8 Hz, 1H), 6.97 (d, J ) 8 Hz, 1H), 12.50 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 31.8, 40.2, 40.6, 52.4, 56.5, 116.5, 118.1, 118.3,
133.2, 147.3, 153.2, 173.6, 203.2; MS m/z 250 (M+), 191, 159,
147, 131, 103, 91, 85, 83; HRMS m/z 250.0840 (calcd for
C
13H14O6: C, 58.65; H, 5.30. Found: C, 58.54; H, 5.27.
(3S)-4-(3-Hydr oxy-4-m eth oxyph en yl)-3-m eth oxycar bon -
ylbu ta n oic Acid (9). Chlororhodium(I) (4R,5R)-MOD-DIOP
complex was prepared from chloro(1,5-cyclooctadiene)rhodium-
(I) dimer (18 mg, 0.036 mmol) and (4R,5R)-MOD-DIOP (8, 54
mg, 0.074 mmol) in THF (4 mL). The complex was prehydro-
genated for 10 min, and a solution of 7 (1.75 g, 6.57 mmol) in
MeOH (8 mL) was added via syringe. The resulting mixture
was stirred under an H2 atmosphere at room temperature until
TLC indicated complete consumption of 7 (ca. 10 h). The
mixture was concentrated under reduced pressure, and the
residue was chromatographed on silica (EtOAc-hexane-
HCOOH, 1:1:0.01) to afford 1.77 g (100%) of 9 as a colorless
C
13H14O5 250.0841). Anal. Calcd for C13H14O5: C, 62.39; H,
5.64. Found: C, 62.07; H, 5.57.
(()-3-Ca r bom eth oxy-2-for m yl-8-h yd r oxy-7-m eth oxy-1-
oxo-1,2,3,4-tetr a h yd r on a p h th a len e (14). To a suspension
of NaH (0.98 g, 40 mmol) in toluene (10 mL) was added methyl
formate (6.13 g, 10.2 mmol) followed by a solution of 13 (2.55
g, 10.2 mmol) in toluene (20 mL). The mixture was stirred for
10 h at ambient temperature, poured into ice-cold aqueous HCl
(10%), and extracted with EtOAc. The extract was washed with
saturated aqueous NaCl, dried (Na2SO4), and concentrated to
leave 2.76 g (98%) of pure 14 as a pale orange oil: 1H NMR
(300 MHz, CDCl3) δ 3.05 (dd, J ) 10, 1 Hz, 1H), 3.20 (dd, J )
12, 3 Hz, 1H), 3.49 (m, 1H), 3.60 (s, 3H), 3.85 (s, 3H), 6.64 (d,
J ) 8 Hz, 1H), 6.97 (d, J ) 8 Hz, 1H), 11.90 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 30.5, 40.5, 52.3, 56.1, 107.4, 115.7, 117.5,
118.0, 130.9, 147.1, 152.4, 167.2, 173.0, 193.9. This material
was unstable and was used immediately for the next reaction.
(()-3-Ca r bom eth oxy-2-for m yl-8-h yd r oxy-7-m eth oxy-1-
oxo-2-[3-oxob u t yl]-1,2,3,4-t et r a h yd r on a p h t h a len e (15).
To a solution of 14 (2.70 g, 9.74 mmol) in CH2Cl2 (30 mL) was
added methyl vinyl ketone (3.41 g, 42.5 mmol) followed by Et3N
(1 mL), and the mixture was stirred for 36 h at ambient
temperature. The mixture was concentrated in vacuo, and the
residue was taken up into EtOAc (100 mL). The solution was
washed with dilute HCl (100 mL) and saturated aqueous NaCl
and was dried (Na2SO4). Removal of the solvent and chroma-
tography of the residue on silica (hexanes-EtOAc, 2:1) af-
forded 2.67 g (79%) of 15 as a mixture of two stereoisomers
(ca 1:1). This material was used immediately for the next
reaction.
(()-4-Acetoxy-3-m eth oxy-6-oxo-6,7,8,8a,9,10-h exah ydr o-
9-p h en a n th r en eca r boxylic Acid (17). To a stirred suspen-
sion of 16 (0.50 g, 1.36 mmol) in CH2Cl2 (20 mL) were added
Et3N (1.9 mL), DMAP (9 mg), and Ac2O (1.3 mL). The mixture
was stirred under Ar for 10 h at ambient temperature, during
which time the solution became dark. The mixture was poured
into aqueous 10% HCl (70 mL) and was extracted with EtOAc.
After removal of the solvent in vacuo, the residue was
chromatographed on silica (hexane/EtOAc, 1:2) to give 0.22 g
(40%) of 17 as an oil: 1H NMR (300 MHz, CDCl3) δ 1.91 (dq,
J ) 10, 2 Hz, 1H), 2.10 (dq, J ) 9, 1 Hz, 1H), 2.23 (dq, J ) 10,
2 Hz, 1H), 2.27 (s, 3H), 2.40-2.53 (m, 2H), 2.71 (m, 1H), 2.95
(dd, J ) 11, 2 Hz, 1H), 3.06 (m, 1H), 3.13 (dd, J ) 11, 6 Hz,
1H), 3.82 (s, 3H), 6.70 (d, J ) 1 Hz,1H), 6.93 (d, J ) 7 Hz,
1H), 7.05 (d, J ) 7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 20.8,
28.2. 31.7, 36.8, 38.0, 45.7, 56.2, 113.9, 126.2, 127.4, 129.7,
137.8, 139.9, 150.4, 153.0, 168.6, 174.8, 199.5.
oil: [R]23 -27.2 (c 1.34, MeOH); IR (neat) 3447, 3234, 2980,
D
1724, 1715, 1513, 1274 cm-1
;
1H NMR (300 MHz, CDCl3) δ
2.44 (dd, J ) 5, 17 Hz, 1H), 2.63-2.73 (m, 2H), 2.98 (dd, J )
6, 13 Hz, 1H), 3.03-3.11 (m, 1H), 3.69 (s, 3H), 3.86 (s, 3H),
6.02 (dd, J ) 2, 8 Hz, 1H), 6.70 (d, J ) 2 Hz, 1H), 7.00 (d, J )
8 Hz, 1H) 7.21 (br, 2H); 13C NMR (75 MHZ, CDCl3) δ 32.3,
36.9, 42.8, 52.0, 55.9, 110.8, 115.2, 120.5, 131.1, 145.4, 145.5,
174.7, 177.0; MS m/z 268 (M+), 208, 137, 131, 122, 103, 94,
77; HRMS m/z 268.0947 (calcd for C13H16O6 268.0947).
(3S)-4-(2-Br om o-5-h yd r oxy-4-m eth oxyp h en yl)-3-m eth -
oxyca r bon ylbu ta n oic Acid (11). To a stirred solution of 9
(2.50 g, 9.3 mmol) in AcOH (50 mL) was added dropwise a
solution of Br2 (0.5 mL, 9.4 mmol) in AcOH (10 mL) during 30
min. The mixture was stirred at room temperature for 10 min,
and 5 M aqueous Na2S2O3 (5 mL) was added. The resulting
mixture was poured onto ice, and the product was extracted
with EtOAc. The extract was washed with H2O and saturated
aqueous NaCl, dried (Na2SO4), and concentrated under re-
duced pressure to yield 3.10 g (92%) of 11, which was not
further purified: [R]23 -32.7 (c 1.48, MeOH); IR (neat) 3315,
D
3238, 2983, 1715, 1502, 1441, 1277, 1230, 1183, 1161 cm-1
;
1H NMR (300 MHz, CDCl3) δ 2.48 (dd, J ) 4, 17 Hz, 1H), 2.71-
2.85 (m, 2H), 3.09 (dd, J ) 6, 13 Hz, 1H), 3.14-3.23 (m, 1H),
3.70 (s, 3H), 3.87 (s, 3H), 6.76 (s, 1H), 7.00 (s, 1H); 13CNMR
(100 MHz, CDCl3) δ 34.7, 37.0, 41.4, 52.1, 56.2, 113.5, 115.2,
116.7, 130.2, 145.0, 146.1, 174.4, 177.4; MS m/z 346 (M+), 269,
267, 216, 191, 159, 127, 118; HRMS m/z 346.0054 (calcd for
C
13H15BrO6 346.0052).
Meth yl (2S)-8-Br om o-5-h ydr oxy-6-m eth oxy-4-oxo-1,2,3,4-
tetr a h yd r o-2-n a p h th a len eca r boxyla te (12). To a solution
of 11 (3.00 g, 8.61 mmol) in MeSO3H (50 mL) was added P2O5
(ca. 0.5 g), and the mixture was stirred for 10 h at ambient
temperature. After addition of MeOH (30 mL), the mixture
was poured onto ice, and the product was extracted with
EtOAc. The extract was washed with saturated aqueous
NaHCO3 (3 × 70 mL) and saturated aqueous NaCl, dried (Na2-
SO4), and concentrated under reduced pressure to give 2.10 g
(75%) of pure 12 as a pale yellow solid: mp 95-96 °C; [R]23
(()-5-Acetoxy-10-R-d ia zoa cetyl-6-m eth oxy-3-oxo-1,2,9,-
10-tetr a h yd r op h en a n th r en e (18). To a solution of 17 (160
mg, 0.483 mmol) in dry benzene (25 mL) was added oxalyl
chloride (0.21 mL, 4 equiv), and the mixture was stirred for
12 h at ambient temperature. The solvent was evaporated, and
the residue was taken up into dry benzene (20 mL). To this
solution was added an excess of ethereal CH2N2, and the yellow
solution was stirred for 1 h at ambient temperature. The
remaining CH2N2 was decomposed with AcOH, and the solu-
tion was concentrated to leave a yellow oil that was chromato-
graphed on silica (hexane-EtOAc, 1:1). This yielded 79 mg
(47%) of 18 as a pale yellow oil: IR (neat) 3089, 2931, 2106,
D
+22.6 (c 1.68, CHCl3); IR (neat) 2928, 1731, 1643, 1465, 1435,
1
1281, 1245, 1181 cm-1; H NMR (CDCl3, 300 MHz,) δ 2.85-
3.30 (m, 5H), 3.74, (m, 3H), 3.87 (s, 3H), 7.20, (s, 1H), 12.7 (s,
1H); 13C NMR (CDCl3, 75 MHz) δ 31.8, 39.0, 39.9, 52.3, 56.3,
111.4, 116.9, 121.3, 131.3, 147.6, 152.7, 172.9, 202.9; MS m/z
328 (M+), 298, 296, 271, 269, 253, 239, 191, 189, 175, 119;
HRMS m/z 327.9946 (calcd for C13H13BrO5 327.9946). Anal.
Calcd for C13H13BrO5: C, 47.44; H, 3.98. Found: C, 47.52; H,
3.76.
Met h yl (2S)-5-H yd r oxy-6-m et h oxy-4-oxo-1,2,3,4-t et -
r a h yd r o-2-n a p h th a len eca r boxyla te (13). A mixture of 12

Asymmetric Total Synthesis of (+)-Codeine
J . Org. Chem., Vol. 64, No. 21, 1999 7879
1778, 1667, 1638, 1504, 1381, 1194; 1H NMR (300 MHz, CDCl3)
1.09-1.85 (m, 1H), 2.20-2.31 (m, 1H), 2.32 (s, 3H), 2.39-2.64
(m, 3H), 2.96 (dd, J ) 5, 6 Hz, 1H), 2.88-3.12 (m, 2H), 3.83
(s, 3H), 5.33 (s, 1H), 6.82 (d, J ) 1 Hz, 1H), 6.97 (d, J ) 8 Hz,
1H), 7.03 (d, J ) 8 Hz, 1H).
(200 mL, 2.0 mmol), Et3N (0.5 mL, 7 mmol), and a catalytic
amount of 4-(dimethylamino)pyridine. The mixture was stirred
at ambient temperature for 12 h, after which time aqueous
0.1 N HCl (50 mL) was added and the mixture was extracted
with Et2O. The extract was washed with brine, dried (Na2-
SO4), and concentrated in vacuo. Recrystallization of the
residue from Et2O afforded 250 mg (92%) of 23 as a colorless
solid: mp 196 °C; IR (KBr) 2946, 1769, 1733, 1664, 1470, 1436,
1284, 1263, 1185, 713 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.95
(m, 1H), 2.18 (m, 1H), 2.50 (m, 2H), 2.28 (s, 3H), 3.05 (m, 2H),
2.78 (m, 1H), 3.20 (dd, J ) 16, 7 Hz, 1H), 3.82 (s, 3H), 6.62 (s,
1H), 7.22 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 20.7, 27.4, 32.0,
36.4, 39.9, 45.6, 56.4, 117.9, 121.3, 128.1, 128.4,129.0, 137.1,
150.6, 152.6, 168.3, 178.0, 199.4; MS (EI) m/z 410, 408 (M+),
368, 366, 323, 321, 214, 212, 186, 185, 171, 169; HRMS m/z
408.0207 (calcd for C18H17BrO6 408.0208).
(()-Dik eton e 19. To a solution of 18 (70 mg, 0.20 mmol)
in CH2Cl2 (15 mL) was added Rh2(OAc)4 (1 mg), and the
mixture was stirred under Ar for 0.5 h at ambient tempera-
ture. The solvent was evaporated in vacuo, and the residual
oil was chromatographed on silica (hexane/EtOAc, 1:1) to give
33 mg (52%) of 19: IR (neat) 3063, 2956, 1758, 1729, 1670,
1623, 1245, 1204, 1174 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.67 (d, J ) 1 Hz, 1H), 1.74-1.89 (m, 2H), 1.95 (d, J ) 13 Hz,
1H), 2.16 (s, 3H), 2.24 (d, J ) 5 Hz, 1H), 2.34-2.42 (m, 2H),
2.48-2.57 (m, 1H), 2.73-2.82 (m, 1H), 3.63 (s, 3H, 6.17 (s, 2H),
6.22 (d, J ) 2 Hz, 1H);13C NMR (75 MHz, CDCl3) δ 21.0, 28.2,
28.4, 32.3, 37.5, 42.9, 46.0, 47.4, 48.6, 57.1, 121.3, 128.1, 129.2,
131.7, 144.0, 157.9, 168.8, 198.9, 212.0; MS (EI) m/z 326 (M+),
284, 256, 241,228, 213, 128,115; HRMS m/z 326.1153 (calcd
for C19H18O5 326.1154).
(()-5-Acetoxy-8-br om o-10-car beth oxy-6-m eth oxy-3-oxo-
1,2,9,10-tetr a h yd r op h en a n th r en e (24): IR (KBr) 2942,
1770, 1730, 1670, 1601, 1558, 1472, 1287, 1262, 1124, 912, 713
cm-1 1H NMR (300 MHz, CDCl3) δ 1.21 (t, J ) 7 Hz, 3H),
;
(()-5-Br om o-3-ca r b om et h oxy-2-for m yl-8-h yd r oxy-1-
oxo-7-m eth oxy-1,2,3,4-tetr a h yd r on a p h th a len e (20). To a
suspension of NaH in mineral oil (60 wt %, 38 mg, 1.0 mmol)
in toluene (0.5 mL) was added methyl formate (1 mL, 12.4
mmol) followed by a solution of 12 (101 mg, 0.31 mmol) in
toluene (3 mL). The suspension was stirred at room temper-
ature for 18 h, after which time aqueous 0.1 N HCl (10 mL)
was added. The layers were separated, and the aqueous layer
was extracted with Et2O. The extract was washed with brine,
dried (Na2SO4), and concentrated in vacuo to give 110 mg of
crude 20. Due to its sensitivity to air, this material was used
immediately without further purification: IR (neat) 2928,
1.85 (m, 1H), 2.18 (s, 1H), 2.26 (s, 3H), 2.50 (m, 2H), 2.71 (m,
1H), 2.98 (m, 2H), 3.20 (dd, J ) 16, 10 Hz, 1H), 3.80 (s, 3H),
4.15 (q, J ) 7 Hz, 2H), 6.55 (s, 1H), 7.18 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 14.1, 15.2, 20.7, 27.5, 31.9, 36.0, 37.3, 45.7,
56.4, 61.1, 117.6, 121.0, 128.0, 128.6, 129.3, 136.9, 150.5, 152.6,
168.2, 173.2, 199.0; MS (EI) m/z 438, 436 (M+), 396, 394, 323,
321, 279, 277, 265, 263, 242, 240, 214, 213, 185, 128; HRMS
m/z 436.0521 (calcd for C20H21BrO6 436.0521).
Compound 24 crystallized in the tetragonal space group
I4(1)/a with a ) 26.878(4) Å, b ) 26.878(4) Å, c ) 10.870(3) Å,
V ) 7852.78 Å3, Z ) 16, Dcalc ) 1.479 g/cm3. All 2187
nonequivalent reflections in the range of 3.5° < 2Θ < 95° were
measured. The structure was solved by direct methods (SHELX-
TL) using 1536 unique reflections with F > 3σ(F). Full-matrix
least-squares refinement with anisotropic temperature factors
for all non-H atoms and calculated H atom positions led to
the final discrepancy indices of R ) 0.0749 and Rw ) 0.0776.
(()-5-Acetoxy-8-br om o-10-R-d ia zoa cetyl-6-m eth oxy-3-
oxo-1,2,9,10-tetr a h yd r op h en a n th r en e (25). To a solution
of 23 (85 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added (COCl)2
(50 µL, 0.60 mmol), and the mixture was stirred at ambient
temperature for 18 h. The solvent and residual (COCl)2 were
evaporated in vacuo, and the residue was taken up into Et2O
(3 mL). A solution of CH2N2 in Et2O (1 mL) was added, and
the resulting yellow solution was stirred for 1 h at ambient
temperature. The solvent was evaporated, and the residue was
chromatographed on silica (hexanes-EtOAc, 1:1) to yield 63
mg (70%) of 25: IR (neat) 2918, 2108, 1769, 1666, 1640, 1469,
1726, 1613, 1467, 1439, 1409, 1356, 1242, 1215, 1182 cm-1
;
1H NMR (300 MHz, CDCl3) δ 2.90 (dd, J ) 4.0, 1 Hz, 1H),
3.60 (m, 2H), 3.74 (s, 3H), 3.94 (s, 3H), 7.16 (s, 1H), 7.53 (d, J
) 10 Hz, 1H), 12.18 (s, 1H).
(()-5-Br om o-3-ca r b om e t h oxy-2-[1-(3-b u t a n on e )]-2-
for m yl-8-h yd r oxy-1-oxo-7-m et h oxy-1, 2, 3, 4-t et r a h y-
d r on a p h th a len e (21). To a solution of crude 20 (110 mg, 0.28
mmol) in CH2Cl2 (4 mL) at 0 °C was added freshly distilled
methyl vinyl ketone (300 µL, 5 mmol) followed by Et3N (10
µL, 0.14 mmol). The mixture was stirred at ambient temper-
ature for 5 h, after which time the volatile components were
evaporated in vacuo. Chromatography of the residue afforded
116 mg (86% from 12) of 21 as a mixture of two stereoiso-
mers: IR (neat) 2928, 1721, 1638, 1465, 1435, 1311, 1258,
1206, cm-1; 1H NMR (300 MHz, CDCl3) δ 2.02 (s, 1H), 2.10 (s,
3H), 2.50 (m, 1H), 2.90 (m, 1H), 3.15 (m, 1H), 3.45 (m, 1H),
3.60 (s, 3H), 3.80 (m, 3H), 3.94 (s, 3H), 7.20 (s, 1H), 10.31 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 21.0, 28.7, 30.0, 36.9, 45.6,
52.8, 56.4, 57.0, 60.4, 111.8, 121.8, 127.8, 148.2, 153.5, 171.1,
173.2, 200.0, 202.1; MS (CI) m/z 428, 426 (M+), 383, 381, 368,
1
1375, 1288, 1260, 1184, 1123, 1019, 713 cm-1; H NMR (300
MHz, CDCl3) δ 1.80 (m, 1H), 2.20 (m, 1H), 2.28 (s, 3H), 2.49
(m, 2H), 2.61 (m, 1H), 3.05 (m, 3H), 3.81 (s, 3H), 5.39 (s, 1H),
6.66 (s, 1H), 7.21 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 20.8,
27.1, 33.1, 35.9, 37.4, 50.7, 55.5, 56.4, 117.8, 121.3, 128.2, 128.6,
128.7, 137.3, 150.6, 152.8, 168.2, 194.3, 199.1. Anal. Calcd for
366, 343, 341, 283, 281; HRMS m/z 426.0313 (calcd for C18H19
-
Br O7426.0314).
(()-8-Br om o-10-ca r boxyl-5-h yd r oxy-6-m eth oxy-3-oxo-
1,2,9,10-tetr a h yd r op h en a n th r en e (22). A solution of 21
(2.00 g, 4.54 mmol) in aqueous 1.0 M KOH (100 mL) was
stirred at ambient temperature for 7 h. The mixture was
acidified with aqueous 10% HCl (50 mL), during which time
the red color of the solution disappeared and a white precipi-
tate was formed. Filtration of the mixture through a Bu¨chner
funnel provided 1.40 g (86%) of pure 22 as a colorless solid:
C19H17BrN2O5 C; 52.77; H; 3.97; N; 6.48. Found: C; 52.59; H;
3.94; N; 5.78.
(()-8-Acetoxy-11-br om o-2,3,4,5,6,7-h exadeh ydr o-9-m eth -
oxy-4-oxo-15-oxot e t r a cyclo[12.2.01,6.07,12.01,14]-5-h e xa -
d ecen e (26). To a suspension of rhodium(II) acetate dimer
(10 mg, 0.02 mmol) in CH2Cl2 (20 mL) was added dropwise
during 4 h a solution of 25 (340 mg, 0.78 mmol) in CH2Cl2 (60
mL). After addition was complete, the solvent was evaporated
in vacuo. Column chromatography of the residue on silica
(hexanes-EtOAc, 1:1) gave 170 mg (53%) of 26: IR (neat)
2925, 1781, 1668, 1470, 1187 cm-1; 1H NMR (300 MHz, CDCl3)
δ 2.20 (s, 3H), 2.50 (m, 4H), 2.92 (dd, J ) 18, 4 Hz, 1H), 3.20
(dd, J ) 18, 4 Hz, 1H), 3.43 (m, 1H), 3.55 (m, 2H), 3.83 (s,
3H), 6.38 (s, 1H), 7.22 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
20.6, 27.3, 34.1, 34.7, 35.3, 56.4, 56.6, 63.9, 118.0, 121.0, 127.9,
128.7, 129.3, 137.4, 150.9, 153.4, 168.5, 198.2, 206.9; MS (EI)
m/z 406, 404 (M+), 364, 362, 322, 320, 307, 305, 279, 277, 265,
263, 261, 242, 240, 213, 211, 198, 197, 169, 167, 116, 113;
HRMS m/z 404.0259 (calcd for C19H17BrO5 404.0259).
Compound 26 crystallized in the triclinic space group P-1
with a ) 9.489(2) Å, b ) 11.102(2) Å, c ) 16.969(3) Å, V )
mp 264 °C; IR (KBr) 2928, 1702, 1609, 1466, 1245, 1181, cm-1
;
1H NMR (400 MHz, DMSO-d6) δ 1.75 (m, 1H), 2.11 (m, 1H),
2.41 (m, 2H), 2.85 (m, 2H), 3.82 (s, 3H), 7,15 (s, 1H), 7.27 (s,
1H), 9.71 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 27.6, 32.8,
36.3, 37.8, 45.2, 56.5, 112.0, 116.5, 120.9, 127.5, 128.4, 145.9,
146.9, 153.2, 174.9, 199.2; MS (EI) m/z 368, 366 (M+), 323, 321,
242, 240, 215, 214, 209, 199, 186, 185, 153, 152, 139, 119;
HRMS m/z 366.0103 (calcd for C16H15BrO5 366.0103). Anal.
Calcd for C16H15Br O5 C; 52.34; H; 4.12. Found: C; 52.74; H;
4.00.
(()-5-Acet oxy-8-b r om o-10-ca r b oxyl-6-m et h oxy-3-oxo-
1,2,9,10-tetr a h yd r op h en a n th r en e (23). To a suspension of
22 (238 mg, 0.65 mmol) in CH2Cl2 (20 mL) were added Ac2O

7880 J . Org. Chem., Vol. 64, No. 21, 1999
White et al.
1786.28 Å3, Z ) 2, Dcalc ) 1.507 g/cm3. All 2340 nonequivalent
reflections in the range of 3.5° < 2Θ < 95° were measured.
The structure was solved by direct methods (SHELXTL) using
2155 unique reflections with F > 3σ(F). Full-matrix least-
squares refinement with anisotropic temperature factors for
all non-H atoms and calculated H atom positions led to the
final discrepancy indices of R ) 0.1093 and Rw ) 0.1051.
(()-8-Acetoxy-11-br om o-2,3,4,5,6,7-h exa d eh yd r o-4-h y-
dr oxy-15-h ydr oxy-9-m eth oxytetr acyclo[12.2.01,6.07,12.01,14]-
5-h exa d ecen e (27). To a solution of 26 (95 mg, 0.23 mmol)
in aqueous 0.4 M CeCl3 (0.5 mL) was added NaBH4 (20 mg,
0.54 mmol) in small portions. The mixture was stirred at
ambient temperature for 15 min, treated with aqueous 0.1 N
HCl (5 mL), and extracted with Et2O. The extract was washed
with brine, dried, and concentrated in vacuo. Column chro-
matography of the residue on silica (hexanes-EtOAc, 1:4)
yielded 58 mg (60%) of 27 as a mixture of four stereoisomers:
3.18 (m, 3H), 3.78 (s, 3H), 6.65 (d, J ) 8 Hz, 1H), 7.04 (d, J )
8 Hz, 1H), 12.5 (s, 1H); 13C NMR (75 MHz, THF-d8) δ 35.1,
43.3, 44.0, 59.3, 120.0, 120.9, 122.4, 137.4, 150.8, 157.3, 177.1,
207.3; MS m/z 236 (M+), 191, 159, 131, 80, 78, 69; HRMS m/z
236.0684 (calcd for C12H12O5 236.0685).
(2S)-5-H yd r oxy-3-h yd r oxym et h ylid en e-6-m et h oxy-4-
oxo-1,2,3,4-tetr ah ydr o-2-n aph th alen ecar boxylic Acid (31).
To a suspension of KH (35 wt % suspension in mineral oil,
540 mg, 4.6 mmol) in THF (15 mL) was added a solution of 30
(110 mg, 0.46 mmol) in dry THF (15 mL), and the mixture
was stirred for 4 h at ambient temperature. Freshly distilled
HCO2Me (1 mL, 16 mmol) was added dropwise during 40 min.
(The apparatus must be equipped with an outlet of sufficient
size to accommodate the large volume of gas liberated during
addition.) Stirring was continued for 3 h at ambient temper-
ature, the reaction was quenched with saturated aqueous NH4-
Cl, and the solution was acidified with aqueous HCl (5%). The
mixture was extracted with EtOAc, and the extract was
washed with H2O and saturated aqueous NaCl, dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was washed with hexane to leave crude 31, which
was not further purified: IR (neat) 3218 (br), 2954, 1709, 1626,
1450, 1254, 1025 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.88 (br,
1H), 3.09 (dd, J ) 7, 15 Hz, 1H), 3.22 (dd, J ) 3, 15 Hz, 1H),
3.52 (m, 1H), 3.87 (s, 3H), 6.65 (d, J ) 8 Hz, 1H), 6.96 (d, J )
8 Hz, 1H), 7,49 (d, J ) 3 Hz, 1H), 11.91 (s, 1H); MS m/z 264
(M+), 220, 204, 191, 159, 131, 97, 71; HRMS m/z 264.0633
(calcd for C13H12O6 264.0634).
IR (neat) 3392, 2927, 1760, 1469, 1198 cm-1 1H NMR (300
;
MHz, CDCl3) δ 1.20 (m, 1H), 1.57 (m, 2H), 2.02 (m, 2H), 2.27
(m, 4H), 2.47 (m, 1H), 2.69 (m, 1H), 3.35 (m, 1H), 3.40 (m,
1H), 3‚82 (s, 3H), 4.35 (m, 2H), 6.00 (s, 1H), 7.11 (s, 1H), 7.13
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 20.6, 20.8, 26.6, 26.9,
29.4, 29.6, 32.5, 34.1, 34.7, 35.0, 43.0, 43.5, 46.5, 56.2, 64.7,
64.8, 66.0, 67.1, 115.2, 115.4, 119.9, 120.0, 129.1, 130.4, 130.5,
133.1, 135.5, 137.0, 150.4, 150.5, 168.9; MS (EI) m/z 410, 408
(M+), 392, 390, 366, 364, 350, 287, 251, 226, 224, 193, 192,
181, 178, 153, 152, 115, 197, 169, 167, 116, 113; HRMS m/z
408.0572 (calcd for C19H21BrO5 408.0572).
(()-3-Acetoxy-6-br om o-2,3,4,5,6,7-h exa d eh yd r o-15-h y-
d r oxy-4-m et h oxyt et r a cyclo-[7.5.2.02,7.01,10]-10,13-h exa -
d eca d ien e (28). To a solution of 27 (21 mg, 0.05 mmol) in
toluene (2 mL) at reflux was added a 0.1 M solution of BF3‚
OEt2 (10 µL) in CH2Cl2. After 30 s, the mixture was poured
into ice-water, the layers were separated, and the aqueous
layer was extracted with Et2O. The extract was washed with
brine, dried, and concentrated in vacuo, and the residue was
chromatographed on silica (hexanes-EtOAc, 3:1) to give 7 mg
(36%) of 28 as a mixture of stereoisomers: IR (neat) 3312,
2927, 1761, 1472, 1198, 1169, 1143, 1017 cm-1; 1H NMR (300
MHz, CDCl3) δ 2.02 (s, 3H), 2.52-2.80 (m, 4H), 3.01 (m, 1H),
3.30 (m, 1H), 3.80 (s, 3H), 3.82 (m, 2H), 5.60 (s, 1H), 5.74 (m,
3H), 7.13 (s, 1H); MS (EI) m/z 392, 390 (M+), 330, 304, 258,
207, 178, 165, 152, 139, 131, 120, 117, 107, 106, 105; HRMS
m/z 390.0457 (calcd for C19H19BrO4 390.0467).
(3R,3aR,9aS)-3,5-Dih ydr oxy-6-m eth oxy-3a-(3-oxobu tyl)-
3,3a ,9,9a -tetr a h yd r on a p h th o[2,3-c]fu r a n -1,4-d ion e (32).
A solution of 31 (130 mg, 0.49 mmol), methyl vinyl ketone (0.4
mL, 4.90 mmol), and Et3N (0.15 mL, 1.0 mmol) in CH2Cl2 (30
mL) was stirred for 12 h at ambient temperature. The solution
was concentrated under reduced pressure, and the residue was
chromatographed on silica (40 g, EtOAc-hexane-HCO2H,
1:1:0.005) to afford 161 mg (80%) of 32 as a pale yellow oil:
IR (neat) 3418, 3022, 2944, 1782, 1718, 1635, 1435, 1254 cm-1
;
1H NMR (300 MHz, CDCl3) δ 2.08-2.30 (m, 5H), 2.55-2.72
(m, 2H), 3.09-3.22 (m, 2H), 3.34 (d, J ) 15 Hz, 1H), 3.85 (s,
3H), 6.04 (s, 1H), 6.70 (d, J ) 8 Hz, 1H), 7.05 (d, J ) 8 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 23.6, 25.7, 30.1, 38.2, 42.1,
55.8, 56.6, 99.7, 116.0, 118.9, 120.0, 131.3, 147.3, 154.1, 176.1,
202.9, 208.6; MS m/z 334 (M+), 316, 288, 260, 242, 203, 191,
175, 163, 159, 131, 98; HRMS m/z 334.1051 (calcd for C17H18O7
334.1053).
(()-3-Acetoxy-6-br om o-2,3,4,5,6,7-h exadeh ydr o-11-m eth -
oxy-15-oxot et r a cyclo[7.5.2.02,7.01,10]-10,13-h exa d eca d i-
en e (29). To a solution of 28 (7 mg, 0.018 mmol) in CH2Cl2 (1
mL) was added Dess-Martin periodinane (15 mg, 0.054 mmol),
and the mixture was stirred at ambient temperature for 0.5
h. The solution was diluted with Et2O (2 mL), and aqueous
Na2S2O3 (2 mL) was added. The organic layer was separated,
the aqueous layer was extracted with Et2O, and the extract
was washed with brine, dried, and concentrated in vacuo. The
residue was chromatographed on silica (hexanes-EtOAc, 3:1)
to give 5 mg (70%) of 29: IR (neat) 2971, 2933, 2929, 1768,
(8a R ,9S )-4-H yd r oxy-3-m e t h oxy-6-oxo-6,7,8,8a ,9,10-
h exa h yd r o-9-p h en a n th r en eca r boxylic Acid (16). To a
stirred solution of 32 (420 mg, 1.25 mmol) in THF-H2O (1:1,
30 mL) was added NaOH (250 mg, 6.3 mmol). The mixture
was stirred for 10 h at ambient temperature and then was
acidified with aqueous HCl (5%). The precipitated solid was
filtered off and was washed with MeOH to give 253 mg (70%
from 31) of pure 16 as a yellow crystalline solid: [R]23D +235.0
(c 0.31, DMSO); IR (neat) 3325, 2925, 1718, 1620, 1567, 1484,
1294 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 1.70-1.81 (m, 1H),
2.02-2.16 (m, 1H), 2.38-2.46 (m, 3H), 2.79-2.86 (m, 1H), 2.92
(d, J ) 7 Hz, 2H), 3.80 (s, 3H), 6.67 (d, J ) 8 Hz, 1H), 6.99 (d,
J ) 8 Hz, 1H), 7.35 (d, J ) 2 Hz, 1H), 9.50 (s, 1H), 12.58 (br
s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 33.2, 38.2, 41.9, 50.9,
61.4, 118.3, 123.4, 123.7, 131.8, 135.7, 151.4, 151.9, 159.3,
191.8, 207; MS m/z 288 (M+), 243, 215, 187, 183; HRMS m/z
1752, 1477, 1195, 1175 cm-1 1H NMR (300 MHz, CDCl3) δ
;
2.02 (s, 3H), 2.70-3.25 (m, 5H), 3.75 (s, 3H), 3.80 (m, 1H),
5,71 (d, J ) 8 Hz, 1H), 5.80 (m, 3H), 6.97 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 20.5, 27.5, 34.7, 44.4, 57.8, 60.4, 60.7, 115.0,
115.7, 116.4, 120.0, 124.8, 126.4, 127.6, 135.4, 139.4, 151.6,
168.2, 216; MS (EI) m/z 390, 388 (M+), 348, 346, 306, 304, 267,
225, 224, 223, 207, 165, 152, 139, 115, 91; HRMS m/z 388.0310
(calcd for C19H17BrO4 (M+) 388.0310).
288.0998 (calcd for
C16H16O5 288.0998). Anal. Calcd for
C
16H16O5: C, 66.66; H, 5.59. Found: C, 66.61; H, 5.45. An
(2S)-5-Hyd r oxy-6-m eth oxy-4-oxo-1,2,3,4-tetr a h yd r o-2-
n a p h th a len eca r boxylic Acid (30). To a solution of 13 (400
mg, 1.70 mmol) in THF-H2O (1:1, 10 mL) was added LiOH
(360 mg, 8.6 mmol), and the solution was stirred for 12 h at
ambient temperature. The mixture was acidified with aqueous
HCl (5%), and the product was extracted with EtOAc. The
extract was washed with H2O and saturated aqueous NaCl,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure to leave 402 mg (100%) of pure 30 as a yellow
crystalline solid: mp > 203 °C dec; [R]23D +38.4 (c 0.66, THF);
IR (neat) 3047, 2969, 1728, 1611, 1445, 1347, 1259, 1195, 1039
cm-1; 1H NMR (300 MHz, THF-d8) δ 2.81-2.85 (m, 2H), 3.01-
additional 20-25% of 16 could be obtained by extraction of
the filtrate with ether and chromatography of the residue after
evaporation of the solvent.
Meth yl (8aR,9S)-4-Hydr oxy-3-m eth oxy-6-oxo-6,7,8,8a,9,-
10-h exa h yd r o-9-p h en a n th r en eca r boxyla te (33). To a sus-
pension of 16 (1.00 g, 3.47 mmol) in EtOAc (30 mL) was added
a 0.7 M solution of CH2N2 in Et2O (10 mL), and the mixture
was stirred at ambient temperature until a homogeneous
solution was obtained. To this solution was added AcOH (0.5
mL), and stirring was continued for 10 min. The mixture was
concentrated under reduced pressure, and the residue was
chromatographed on silica (60 g, CH2Cl2-EtOAc-hexane, 1:2:

Asymmetric Total Synthesis of (+)-Codeine
J . Org. Chem., Vol. 64, No. 21, 1999 7881
1) to give 0.94 g (90%) of 33 as a colorless crystalline solid:
mp 178-179 °C; [R]23D +176.0 (c 1.27, CHCl3); IR (neat) 2940,
2846, 1729, 1650, 1480, 1289 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.80-1.90 (m, 1H), 2.04-2.16 (m, 1H), 2.42-2.65 (m, 3H),
2.87-3.00 (m, 2H), 3.10 (dd, J ) 12, 15 Hz, 1H), 3.76 (s, 3H),
3.91 (s, 3H), 6.69 (d, J ) 8 Hz, 1H), 6.79 (s, 1H), 6.84 (d, J )
8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 28.5, 34.0, 37.3, 39.9,
46.7, 52.2, 56.7, 112.2, 118.2, 119.4, 128.2, 131.0, 145.6, 146.7,
153.6, 175.0, 201.0; MS m/z 303 (M+), 243, 193, 183, 113;
HRMS m/z 303.1238 (calcd for C17H19O5 303.1233). Anal. Calcd
for C17H19O5: C, 67.54; H, 6.00. Found: C, 67.25; H, 5.57.
Meth yl (8a R,9S)-1,5-Dibr om o-4-h yd r oxy-3-m eth oxy-6-
oxo-6,7,8,8a ,9,10-h e xa h yd r o-9-p h e n a n t h r e n e ca r b oxy-
la te (34). To a suspension of 33 (0.10 g, 0.31 mmol) and
NaHCO3 (0.29 g, 3.31 mmol) in CHCl3 (30 mL) at 0 °C was
added dropwise a solution of Br2 in CHCl3 (10%, 3.40 mL, 0.62
mmol) during 30 min. Stirring was continued for 1 h, the
mixture was filtered through Celite, and the filtrate was
concentrated under reduced pressure. Chromatography of the
residue on silica (CH2Cl2-EtOAc-hexane, 1:2:1) afforded 0.11
g (70%) of 34 as a yellow crystalline solid: mp 129 °C dec;
[R]23D +39.7 (c 0.35, CHCl3); IR (neat) 3394, 3301, 2939, 1429,
1682, 1481, 1439, 1268, 1129 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.91-2.05 (m, 1H), 2.25-2.34 (m, 1H), 2.54 (dd, J ) 5, 15
Hz, 1H), 2.65-2.88 (m, 3H), 3.49-3.42 (m, 1H), 3.57 (dd, J )
3, 15 Hz, 1H), 3.61 (s, 3H), 3.91 (s, 3H), 6.13 (s, 1H), 7.06 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 28.8, 29.9, 37.2, 41.0, 45.6,
56.2, 111.2, 115.2, 123.5, 124.3, 129.0, 141.1, 145.0, 153.0,
173.3, 190.8; MS (CI) m/z 461 (M+ + 1), 383, 303, 229, 221,
213, 135 (100). Anal. Calcd for C17H16Br2O5: C, 44.37; H, 3.51.
Found: C, 44.12; H, 3.43.
IR (neat) 2925, 2832, 1743, 1494, 1440, 1279, 1157, 1108, 1020
1
cm-1; H NMR (300 MHz, CDCl3) δ 1.01-1.17 (m, 1H), 1.68
(pent, J ) 4 Hz, 1H), 1.88-2.08 (m, 1H), 2.14-2.26 (m, 1H),
2.32 (d t, J ) 5, 9 Hz, 1H), 2.59-2.75 (m, 1H), 2.78-2.90 (m,
1H), 2.92-3.11 (m, 3H), 3.19 (dd, J ) 5, 16 Hz, 1H), 3.80 (s,
3H), 4.01 (s, 3H), 6.79 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
23.4, 23.5, 28.1, 31.4, 33.6, 48.9, 52.1, 57.1, 111.1, 113.8, 116.4,
121.1, 130.1, 141.1, 144.5, 154.2, 174.9; MS (CI) m/z 365 (M+
+ 1), 335, 314, 307, 285, 217, 205, 189, 159, 123, 115, 103;
HRMS (CI) m/z 365.0373 (calcd for C17H18BrO4 365.0388).
Catalytic Hydr ogen ation of 35. Meth yl (4a S*,7aS*,8S*,-
9cR*)-3-Meth oxy-4a,5,6,7,7a,8,9,9c-octah ydr oph en an th r o-
[4,5-bcd ]fu r a n -8-ca r boxyla te (39). A suspension of 35 (12.8
mg, 0.0337 mmol) and 10% Pd/C (5 mg) in MeOH (5 mL) was
stirred under H2 at ambient temperature and pressure for 9
h. The mixture was filtered through a short column of silica,
and the filtrate was concentrated under reduced pressure.
Chromatography of the residue on silica (5 g, EtOAc-hexane,
1:3) afforded 9.8 mg (68%) of 39 as a colorless oil: IR (neat)
2930, 2858, 1733, 1507, 1440, 1277, 1200, 1161, 1104, 1065
cm-1; 1H NMR (300 MHz, CDCl3) δ 0.92-1.05 (m, 1H), 1.06-
1.24 (m, 2H), 1.50-1.68 (m, 2H), 1.93-2.03 (m, 1H), 2.64-
2.73 (m, 2H), 2.85-2.91 (m, 1H), 3.20 (d, J ) 17 Hz, 1H), 3.37
(t, J ) 6 Hz, 1H), 3.68 (s, 3H), 3.86 (s, 3H), 4.96-5.04 (m, 1H),
6.66 (d, J ) 8 Hz, 1H), 6.73 (d, J ) 8 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 21.7, 23.5, 26.3, 27.9, 34.6, 37.8, 44.4, 52.2,
56.9, 85.9, 113.8, 119.9, 124.8, 127.0,143.6, 145.6, 175.4; MS
(CI) m/z 288 (M+), 257, 229, 197, 97, 84, 69; HRMS (CI) m/z
288.1363 (calcd for C17H20O4 288.1362);
There was also obtained 2.3 mg (18%) of methyl (4aS*,5R*,-
7aS*,8S*,9cR*)-3,5-dimethoxy-4a,5,6,7,7a,8,9,9c-octahydro-
phenanthro[4,5-bcd]furan-8-carboxylate (41) [IR (neat) 3366,
2923, 1724, 1508, 1445, 1281, 1152, 1089 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.25-1.47 (m, 2H), 1.52-1.61 (m, 1H), 1.82-
1.92 (m, 1H), 2.63-2.85 (m, 3H), 3.09 (d, J ) 14 Hz, 1H), 3.28
(s, 3H), 3.50 (t br, J ) 6 Hz, 1H), 3.58 (t br, J ) 4 Hz, 1H),
3.69 (s, 3H), 3.87 (s, 3H), 5.02 (dd, J ) 5, 9 Hz, 1H), 6.62 (d,
J ) 8 Hz, 1H), 6.72 (d, J ) 8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.2, 24.7, 26.4, 33.7, 37.0, 45.1, 52.2, 57.1, 59.1, 76.1,
86.4, 114.1, 119.4, 124.3, 127.7, 142.1, 148.1, 175.6; MS (CI)
m/z 318 (M+), 287, 259, 247, 227, 195, 187, 123, 97, 83; HRMS
(CI) m/z 318.1471 (calcd for C18H22O5 318.1467)] and 2.0 mg
(15%) of methyl (4aS*,5R*,7aS*,8S*,9cR*)-5-hydroxy-3-meth-
oxy-4a,5,6,7,7a,8,9,9c-octahydrophenanthro[4,5-bcd]furan-8-
carboxylate (40): IR (neat) 3443, 2928,1 734, 1503, 1435, 1277,
1147, 1060, 940 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.36-1.49
(m, 1H), 1.51-1.63 (m, 1H), 1.85-1.97 (m, 2H), 2.63-2.87 (m,
3H), 3.10 (dd, J ) 1, 16 Hz, 1H), 3.51 (t, J ) 8 Hz, 1H), 3.69
(s, 3H), 3.87 (s, 3H), 4.08-4.11 (m, 1H), 4.97 (dd, J ) 5, 9 Hz,
1H), 6.65 (d, J ) 8 Hz, 1H), 6.71 (d, J ) 9 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 19.6, 24.6, 28.2, 33.9, 36.6, 48.1, 52.3, 56.7,
66.2, 86.0, 113.5, 120.3, 124.4, 127.6, 141.7, 147.0, 175.5; MS
(CI) m/z 304 (M+), 287, 273, 245, 227, 215, 187; HRMS (CI)
m/z 304.1306 (calcd for C17H20O5 304.1311).
Meth yl (7a R,8S)-1-Br om o-3-m eth oxy-6-oxo-5,6,7,7a ,8,9-
h exa h yd r op h en a n th r o[4,5-bcd ]fu r a n -8-ca r boxyla te (35).
A solution of 34 (235 mg, 0.51 mmol) and DBU (0.23 mL, 1.53
mmol) in benzene (50 mL) was stirred for 4 h at 68 °C. The
mixture was cooled to room temperature and filtered through
a short column of silica, which was subsequently rinsed with
hexanes-EtOAc (2:1). The eluant was concentrated under
reduced pressure to yield 174 mg (90%) of 35 as colorless
crystals: mp 172 °C dec; [R]23 + 140.8 (c 0.70, CH2Cl2); IR
D
(neat) 2949, 1728, 1674, 1503, 1269, 1171, 1103 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.80-1.94 (dq, J ) 12, 4 Hz, 1H), 2.50-
2.88 (m, 5H), 3.03 (dd, J ) 12, 17 Hz, 1H), 3.31 (dd, J ) 4, 17
Hz, 1H), 3.45 (dt, J ) 12, 4 Hz, 1H), 3.83 (s, 3H), 4.06 (s, 3H),
7.05 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 31.1, 31.6, 32.6, 33.8,
39.9, 48.4, 52.5, 57.7, 115.1, 117.5, 123.6, 128.0, 137.7, 142.9,
145.5, 145.7, 173.6, 186.3; MS (CI) m/z 381 (100), 380 (M+
1), 301, 243, 239, 95; HRMS (CI) m/z 379.0181 (calcd for C17H16
+
-
BrO5 379.0181).
Meth yl (2S*,8a R*,9S*)-1-Br om o-4-h yd r oxy-3-m eth oxy-
6-oxo-2,5,6,7,8,8a ,9,10-octa h yd r o-9-p h en a n th r en eca r box-
yla te (37). A suspension of 35 (100 mg, 0.275 mmol) in 0.3 M
NaOH (20 mL) was stirred at ambient temperature until a
homogeneous solution was obtained. To the mixture was added
Hg-(10%)Na, and stirring was continued for 1 h. The solution
was acidified with aqueous HCl (5%) and was extracted with
CH2Cl2. The extract was washed with saturated aqueous NaCl,
dried over anhydrous Na2SO4, and filtered. The filtrate was
treated with CH2N2 (0.6 M in Et2O), and the solution was
concentrated under reduced pressure. Chromatography of the
residue on silica (10 g, EtOAc-hexane, 2:1) afforded 88 mg
(85%) of 37 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
1.95-2.07 (m, 2H), 2.13-2.39 (m, 3H), 2.47-2.62 (m, 1H),
2.81-2.95 (m, 2H), 3.04-3.27 (m, 2H), 3.50-3.63 (m, 1H), 3.78
(s, 3H), 3.87 (s, 3H), 5.70 (s, 1H), 7.00 (s, 1H).
Meth yl (7aR*,8S*)-Br om o-3-m eth oxy-5,6,7,7a,8,9-h exah y-
d r op h en a n th r o[4,5-bcd -fu r a n -8-ca r boxyla te (38). To a
solution of 35 (50 mg, 0.110 mmol) in CH2Cl2 (5 mL) were
added Et3SiH (50 mL, 0.31 mmol) and 1 M TiCl4 in CH2Cl2
(0.543 mL, 0.543 mmol). The mixture was stirred for 4 h at
ambient temperature, poured onto ice, and extracted with
EtOAc. The extract was washed with saturated aqueous NaCl,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. Chromatography of the residue on silica (3 g,
EtOAc-hexane, 1:3) gave 38 mg (90%) of 38 as a colorless oil:
Met h yl (5S,7a R,8S)-1-Br om o-5-h yd r oxy-3-m et h oxy-
5,6,7,7a ,8,9-h exa h yd r op h en a n t h r o[4,5-bcd ]fu r a n -8-ca r -
boxyla te (43). To a solution of 35 (0.34 g, 0.90 mmol) in
CH2Cl2-i-PrOH (3:1, 40 mL) was added sodium borohydride
(0.34 g, 9.01 mmol), and the mixture was stirred for 12 h at
ambient temperature. The reaction was quenched with aque-
ous HCl (5%), and the organic layer was separated, washed
with saturated aqueous NaHCO3 and saturated aqueous NaCl,
and dried over anhydrous Na2SO4. Removal of the solvent
under reduced pressure furnished 0.35 g (99%) of 43 as
colorless crystals: mp 171 °C dec; [R]23D +105.8 (c 1.15, CHCl3);
IR (neat) 3400, 2947, 2834, 1729, 1493, 1432, 1272, 1164 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.26-1.38 (m, 1H), 1.85-1.99
(m, 1H), 2.21-2.37 (m, 2H), 2.45-2.53 (m, 1H), 2.94 (dd, J )
12, 16 Hz, 1H), 3.10-3.21 (m, 1H), 3.18 (dd, J ) 4, 16 Hz,
1H), 3.80 (s, 3H), 4.02 (s, 3H), 4.94-4.99 (m, 1H), 6.85 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 29.8, 31.2, 33.7, 34.2, 48.7, 52.3,
57.2, 65.4, 112.4, 114.1, 120.0, 122.0, 129.2, 141.7, 144.7, 153.2,
174.5; MS m/z 381(M+), 365, 303, 285, 278, 224, 149; HRMS
m/z 380.0260 (calcd for C17H17BrO5 380.0259). Anal. Calcd for
C
17H17BrO5: C, 53.56; H, 4.49. Found: C, 53.75; H, 4.62.

7882 J . Org. Chem., Vol. 64, No. 21, 1999
White et al.
Meth yl
(4a S,5S,7a S,8S,9cR)-5-Hyd r oxy-3-m eth oxy-
MS m/z 334 (M+), 304, 289, 271, 260, 243, 227, 215, 199, 183,
161, 115; HRMS m/z 334.1415 (calcd for C18H22O6 334.1417).
(4a S,5S,7a S,8S,9cR)-3-Meth oxy-5-(m eth oxym eth oxy)-
4a ,5,6,7,7a ,8,9,9c-octa h yd r op h en a n th r o[4,5-bcd ]fu r a n -8-
yl]-2-d ia zo-1-eth a n on e (48). A solution of 47 (90 mg, 0.27
mmol) and oxalyl chloride (0.2 mL, 2.2 mmol) in dry benzene
(30 mL) was stirred for 18 h at ambient temperature. The
solvent and excess oxalyl chloride were removed under reduced
pressure, and the residue was taken up into benzene (25 mL).
The solution was added dropwise to CH2N2 (6 M in Et2O, 30
mL), and the mixture was stirred at ambient temperature for
1 h. Excess CH2N2 was removed in a stream of N2, and the
solvent was removed under reduced pressure. The residue was
chromatographed on silica (30 g, EtOAc-hexane, 1:1) to yield
61 mg (63%) of 48 as a yellow oil: [R]23D -36.7 (c 0.95, CHCl3);
IR (neat) 3091, 2930, 2099, 1630, 1503, 1445, 1362, 1152, 1112,
4a ,5,6,7,7a ,8,9,9c-octa h yd r op h en a n th r o[4,5-bcd ]fu r a n -8-
ca r boxyla t e (44). A suspension of 43 (0.35 g, 0.91 mmol),
NaHCO3 (75 mg, 091 mmol), and 10% Pd/C (30 mg) in MeOH
(20 mL) was stirred under H2 at ambient temperature and
pressure for 24 h. The mixture was filtered through a short
column of silica, and the filtrate was concentrated under
reduced pressure. The residue was taken up into CH2Cl2 (20
mL), and the solution was washed with H2O and saturated
aqueous NaCl. The solvent was removed under reduced
pressure, and the residue was chromatographed on silica (300
g, EtOAc-hexane, 1:1.5) to give 0.21 g (75%) of 44 as a
colorless oil: [R]23D -4.1 (c 1.02, CHCl3); IR (neat) 3428, 2939,
2861, 1729, 1503, 1440, 1279, 1064 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.05-1.18 (m, 1H), 1.29-1.43 (m, 1H), 1.66-1.72 (m,
1H), 1.78-1.85 (m, 1H), 2.40 (br, 1H), 2.65-2.75 (m, 2H),
2.90-2.91 (m, 1H), 3.18 (d, J ) 17 Hz, 1H), 3.37-3.49 (m, 2H),
3.68 (s, 3H), 3.86 (s, 3H), 4.67-4.72 (m, 1H), 6.65 (d, J ) 8
Hz, 1H), 6.73 (d, J ) 8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
23.5, 25.1, 29.8, 34.2, 38.4, 43.7, 52.3, 56.8, 71.7, 93.2, 113.9,
120.3, 124.1, 127.2, 143.5, 145.4, 175.2; MS m/z 304 (M+, 100),
287, 273, 245, 227, 187, 149, 119, 107, 102; HRMS m/z
304.1309 (calcd for C17H20O5 304.1307).
1
1054 cm-1; H NMR (300 MHz, CDCl3) δ 1.05-1.39 (m, 2H),
1.63-1.70 (m, 1H), 1.85-1.92 (m, 1H), 2.52-2.58 (m, 1H),
2.69-2.81 (m, 2H), 2.93 (d, J ) 17, 1H), 3.35-3.41 (m,1H),
3.36 (s, 3H), 3.51 (t, J ) 7 Hz, 1H), 3.87 (s, 3H), 4.67 (d, J )
7 Hz, 1H), 4.73 (d, J ) 7 Hz, 1H), 4.76 (t, J ) 8 Hz, 1H), 5.31
(s, 1H), 6.64 (d, J ) 8 Hz, 1H), 6.73 (dd, J ) 1, 8 Hz, 1H); 13
C
NMR(75 MHz, CDCl3) δ 23.5, 25.3, 28.5, 35.3, 38.4, 49.3, 54.3,
55.3, 57.2, 76.1, 91.3, 95.5, 115.1, 120.2, 123.6, 127.6, 143.8,
145.8, 197.2.
There was also obtained 9.5 mg (3%) of 45: IR (neat) 3511,
2954, 1733, 1513, 1445, 1284, 1205, 1176, 1054 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.37-1.47 (m, 2H), 1.88-2.00 (m, 2H),
2.66-2.85 (m, 3H), 3.07-3.13 (m, 1H), 3.51-3.60 (m, 1H), 3.70
(s, 3H), 3.87 (s, 3H), 4.10-4.14 (m, 1H), 4.95-5.00 (m, 1H),
6.66 (d, J ) 8 Hz, 1H), 6.72 (d, J ) 8 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 19.6, 24.5, 28.1, 33.8, 36.5, 45.1, 52.2, 56.7,
66.2, 86.0, 113.4, 120.2, 124.4, 127.6, 141.7, 147.0, 175.5; MS
m/z 304 (M+), 244, 227, 215, 201, 199, 195, 187, 121, 119, 115,
86, 84; HRMS m/z 304.1309 (calcd for C17H20O5 304.1311).
(1R,4S,12S,13S,16R)-9-Meth oxy-13-(m eth oxym eth oxy)-
11-oxa p en ta cyclo[8.6.1.01,12.04,16.06,17]h ep ta d eca -6(17),7,9-
tr ien -3-on e (49). To a solution of 48 (47 mg, 0.13 mmol) in
CH2Cl2 (50 mL) under argon was added Rh2(OAc)4 (1 mg), and
the mixture was stirred for 1 h at ambient temperature. The
mixture was concentrated under reduced pressure, and the
residue was chromatographed on silica (10 g, EtOAc-hexane,
1:2) to afford 22 mg (51%) of 49 as a colorless oil: [R]23D +12.0
(c 0.44, CHCl3); IR (neat) 2941, 1755, 1509, 1447, 1283, 1262,
Me t h yl
(4a S ,7a S ,8S ,9cR )-3-Me t h oxy-5-(m e t h ox)-
1
1041 cm-1; H NMR (300 MHz, CDCl3) δ 1.21-1.31 (m, 1H),
m et h oxy)-4a ,5,6,7,7a ,8,9,9c-oct a h yd r op h en a n t h r o[4,5-
bcd ]fu r a n -8-ca r boxyla te (46). A mixture of 44 (130 mg, 0.43
mmol), CH2(OMe)2 (1.9 mL, 21.3 mmol), and P2O5 (30 mg) in
dry CHCl3 (30 mL) was stirred for 4 h at ambient temperature.
The solid residue was filtered off, and the filtrate was neutral-
ized with solid NaHCO3 (200 mg). The neutral mixture was
filtered, and the filtrate was concentrated under reduced
pressure. Chromatography of the residue on silica (30 g,
hexanes-EtOAc, 2:1) afforded 129 mg (86%) of 46 as a
colorless oil: [R]23D -9.2 (c 0.78, CHCl3); IR (neat) 2939, 1733,
1.34-1.57 (m, 1H), 1.73-1.83 (m, 1H), 1.86-1.95 (m, 1H),
2.47-2.55 (m, 1H), 2.49 (s, 2H), 2.72-2.76 (m, 1H), 2.85-2.93
(m, 2H), 3.40 (s, 3H), 3.57-3.64 (m, 1H), 3.87 (s, 3H), 4.72 (d,
J ) 7 Hz, 1H), 4.75 (d, J ) 6 Hz, 1H), 4.79 (d, J ) 7 Hz, 1H),
6.58 (d, J ) 8 Hz, 1H), 6.72 (d, J ) 8 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 19.7, 27.5, 28.4, 42.2, 49.1, 50.1, 53.9, 55.5,
57.0, 77.9, 90.9, 95.9, 115.3, 120.7, 122.4, 133.1, 144.0, 144.2,
217.9; MS m/z 330 (M+), 285, 257, 243, 199, 113, 83, 69, 55,
49, 45; HRMS m/z 330.1469 (calcd for C19H22O5 330.1467).
Analogous decomposition of 48 using Rh2(acam)4 as the
catalyst gave 49 in 65% yield.
1503, 1445, 1108, 1054 cm-1 1HNMR (300 MHz, CDCl3) δ
;
1.05-1.19 (m, 1H), 1.25-1.38 (m, 1H), 1.63-1.70 (m, 1H),
1.85-1.93 (m, 1H), 2.65-2.74 (m, 2H), 2.89-2.91 (m, 1H), 3.18
(d, J ) 18 Hz, 1H), 3.34-3.42 (m, 1H), 3.37 (s, 3H), 3.48 (t, J
) 7 Hz, 1H), 3.68 (s, 3H), 3.87 (s, 3H), 4.69 (d, J ) 7 Hz, 1H),
4.75 (d, J ) 7 Hz, 1H), 4.77 (t, J ) 8 Hz, 1H), 6.64 (d, J ) 8
Hz, 1H), 6.72 (d, J ) 8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
23.5, 24.9, 29.9, 34.2, 38.6, 43.7, 52.3, 55.4, 57.2, 76.1, 91.3,
95.6, 115.0, 120.2, 124.2, 127.2, 143.6, 145.7, 175.1; MS m/z
348 (M+), 302, 243, 227, 215, 199, 183, 161, 115, 86, 84 69;
HRMS m/z 348.1574 (calcd for C19H24O6 348.1573).
(3a S*,9R*,9a S*,9b R*)-9-(2-Dia zoa cet yl)-5-m et h oxy-1,-
3a ,8,9,9a ,9b-h exa h yd r op h en a n th r o[4,5-bcd ]fu r a n -3(2H)-
on e (50). A solution of 52 (210 mg, 0.73 mmol) and oxalyl
chloride (325 µL, 3.72 mmol) in dry benzene (20 mL) was
stirred for 18 h at ambient temperature, after which time the
solvent and excess oxalyl chloride were removed under reduced
pressure. The residue was taken up into benzene (25 mL), and
the solution was added dropwise to a 0.6 M solution of CH2N2
in Et2O (100 mL). The mixture was stirred for 1 h, and N2
was passed through the solution for 2 h to remove excess
CH2N2. Most of the solvent was evaporated under reduced
pressure, and the residual oil was chromatographed on silica
(18 g, EtOAc-hexane, 1:1) to provide 190 mg (83%) of 50 as a
yellow oil: IR (neat) 3086, 2930, 2109, 1728, 1636, 1504, 1440,
(4a S,5S,7a S,8S,9cR)-3-Meth oxy-5-(m eth oxym eth oxy)-
4a ,5,6,7,7a ,8,9,9c-octa h yd r op h en a n th r o[4,5-bcd ]fu r a n -8-
ca r boxylic Acid (47). To a solution of 45 (100 mg, 0.29 mmol)
in THF-H2O (30 mL, 1:1) was added LiOH (50 mg, 1.2 mmol),
and the mixture was stirred for 20 h at ambient temperature.
The mixture was acidified with aqueous HCl (10%) and
extracted with EtOAc. The extract was washed with saturated
aqueous NaCl, dried over anhydrous Na2SO4, and concentrated
under reduced pressure to give 100 mg (100%) of pure 46 as a
1362, 1284, 1157, 113 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.37-1.51 (m, 1H), 1.94-1.99 (m, 1H), 2.36-2.48 (m, 2H), 2.72
(dd, J ) 6, 18 Hz, 1H), 2.84-2.88 (m, 1H), 2.96 (d, J ) 18,
1H), 2.98-3.03 (m, 1H), 3.91 (s, 3H), 3.96 (t, J ) 6 Hz, 1H),
5.05 (d, J ) 9 Hz, 1H), 5.38 (s, 1H), 6.67 (d, J ) 8 Hz, 1H),
6.74 (d, J ) 8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 23.8,27.4,
35.0, 39.6, 41.7, 48.8, 54.7, 57.1, 87.3, 115.3, 121.0, 123.3, 124.6,
143.2, 147.0, 196.7, 207.7.
Meth yl (4a S*,7a S*,8S*,9cR*)-3-Meth oxy-5-oxo-4a ,5,6,7,-
7a ,8,9,9c-octa h yd r op h en a n th r o[4,5-bcd ]fu r a n -8-ca r boxy-
la te (51). A mixture of 44 (30 mg, 0.099 mmol) and Dess-
Martin periodinane (50 mg, 0.12 mmol) in CHCl3 (5 mL) was
stirred for 1 h at ambient temperature. A solution of Na2S2O3-
NaHCO3 (5 mL, 50 g of Na2S2O3 in 200 mL of saturated
aqueous NaHCO3) was added, and stirring was continued for
colorless oil: [R]23 -8.5 (c 1.55 CHCl3); IR (neat) 3174 (br),
D
2930, 1733, 1708, 1508, 1445, 1283, 1156, 1103, 1049 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.05-1.18 (m, 1H), 1.25-1.38
(m, 1H), 1.62-1.71 (m, 1H), 1.87-1.92 (m, 1H), 2.64-2.75 (m,
2H), 2.91-2.96 (m, 1H), 3.16 (d, J ) 17 Hz, 1H), 3.34-3.42
(m, 1H), 3.38 (s, 3H), 3.54 (t, J ) 7 Hz, 1H), 3.86 (s, 3H), 4.69
(d, J ) 7 Hz, 1H), 4.75 (d, J ) 7 Hz, 1H), 4.78 (t, J ) 8 Hz,
1H), 6.63 (d, J ) 8 Hz, 1H), 6.72 (d, J ) 8 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 23.2, 24.9, 28.4, 34.0, 38.5, 43.5, 55.3, 57.2,
76.0, 91.2, 95.5, 115.0, 120.2, 123.9, 127.0, 143.7, 145.7, 180.7;

Asymmetric Total Synthesis of (+)-Codeine
J . Org. Chem., Vol. 64, No. 21, 1999 7883
another 20 min. The CHCl3 layer was separated, washed with
saturated aqueous NaCl, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. Chromatography of the
residue on silica (5 g, EtOAc-hexane, 1:2) gave 27 mg (92%)
of 51 as a colorless oil: IR (neat) 2946, 1733, 1684, 1504, 1435,
193.3, 215.3; MS m/z 282 (M+), 254, 226, 211, 201, 185, 85,
83; HRMS m/z 282.0891 (calcd for C17H14O4 282.0892).
(1R,4S,12S,13S,16R)-9-Meth oxy-13-(m eth oxym eth oxy)-
11-oxa p en ta cyclo[8.6.1.01,12.04,16.06,17]h ep ta d eca -6(17),7,9-
tr ien on e Oxim e (56). A solution of 49 (20 mg, 0.062 mmol),
NH2OH‚HCl (6.3 mg, 0.091 mmol), and NaOAc (16.5 mg, 0.12
mmol) in MeOH (10 mL) was stirred for 6 h at ambient
temperature. The mixture was concentrated under reduced
pressure, and the residue was taken up into CHCl3 (15 mL).
The resulting solution was washed with H2O and saturated
aqueous NaCl, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. Chromatography of the residue on
silica (20 g, EtOAc-hexane 1:1) afforded 18.8 mg (90%) of 56
as a colorless oil: IR (neat) 1073, 1284, 1440, 1507, 1606, 1640,
1552, 2935, 3374 cm-1; 1H NMR (300 Mz, CDCl3) δ 1.16-1.24
(m, 1H), 1.39-1.51 (m, 1H), 1.66-1.75 (m, 1H), 1.73-1.91 (m,
1H), 1.87 (d, J ) 13 Hz, 1H), 2.12-2.26 (m, 1H), 2.57 (m, 1H),
2.73-3.10 (m, 3H), 3.40 (s, 3H), 3.51-3.58 (m, 1H), 3.87 (s,
3H), 4.69-4.81 (m, 3H), 6.58 (d, J ) 8 Hz, 1H), 6.71 (d, J ) 8
Hz, 1H); MS (EI) m/z 345(M+), 241, 199, 167, 149, 115; HRMS
m/z 345.1575 (calcd for C19H23NO5 345.1576).
1
1271, 1206, 1167 cm-1; H NMR (300 MHz, CDCl3) δ 1.37-
1.50 (m, 1H), 1.92-1.99 (m, 1H), 2.38-2.43 (m, 2H), 2.67 (d,
J ) 7, 18 Hz, 1H), 2.94-2.98 (m, 1H), 3.17-3.10 (m, 1H), 3.22
(d, J ) 18 Hz, 1H), 3.72 (s, 3H), 3.89 (s, 3H), 3.88-3.92 (m,
1H), 5.05 (d, J ) 9 Hz, 1 H), 6.65 (d, J ) 8 Hz, 1H), 6.71 (d, J
) 8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 23.5, 26.9, 34.0,
39.5, 41.8, 43.3, 52.5, 57.1, 87.3, 115.0, 121.0, 123.8, 124.1,
142.9, 146.8, 174.7, 207.8; MS m/z 302 (M+), 248, 231, 214,
187, 161, 119, 86, 84; HRMS m/z 302.1154 (calcd for C17H18O5
302.1154).
(4a S*,7a S*,8S*,9cR*)-3-Meth oxy-5-oxo-4a ,5,6,7,7a ,8,9,-
9c-octah ydr oph en an th r o[4,5-bcd]fu r an -8-car boxylic Acid
(52). To a solution of 51 (50 mg, 0.165 mmol) in THF-H2O
(1:1.3, 35 mL) was added LiOH (28 mg, 0.66 mmol), and the
mixture was stirred for 18 h at ambient temperature. The
mixture was acidified with aqueous HCl (10%) and was
extracted with CH2Cl2. The extract was washed with saturated
aqueous NaCl, dried over anhydrous Na2SO4, and concentrated
under reduced pressure to afford 47 mg (99%) of 52 as a
colorless oil: IR (neat) 3209, 2945, 1728, 1509, 1450, 1284,
(1R,5S,13S,14S,17S)-10-Meth oxy-14-(m eth oxym eth oxy)-
12-oxa -4-a za p e n t a cyclo[9.6.1.01,13.05,17.07,18]oct a d e ca -
7(18),8,10-tr ien -3-on e (57). A solution of 56 (25 mg, 0.072
mmol), p-bromobenzenesulfonyl chloride (28 mg, 0.11 mmol),
Et3N (16 µL, 0.12 mmol), and a catalytic amount of DMAP in
CH2Cl2 (5 mL) was stirred for 1 h at ambient temperature.
The solvent was removed under reduced pressure, and the
residue was taken up into AcOH (2 mL). The resulting solution
was stirred for 1 h and was neutralized with saturated,
aqueous NaHCO3. The mixture was extracted with CH2Cl2,
and the extract was washed with saturated aqueous NaCl,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. Chromatography of the residue on silica (6 g,
EtOAc-MeOH, 12:1) gave 17 mg (69%) of 57 as a colorless
1196, 1167, 1108, 917 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.38-1.48 (m, 1H), 1.95-1.99 (m, 1H), 2.37-2.46 (m, 2H), 2.86
(dd, J ) 7, 18 Hz, 1H), 3.00 (d, J ) 8 Hz, 1H), 3.11-3.18 (m,
1H), 3.22 (d, J ) 18 Hz, 1H), 3.90 (s, 3H), 3.97 (t, J ) 7 Hz,
1H), 5.06 (d, J ) 9 Hz, 1H), 6.66 (d, J ) 8 Hz, 1H), 6.72 (d, J
) 8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 23.3, 26.9, 33.9,
39.5, 41.7, 43.2, 57.2, 87.2, 115.6, 121.0, 123.6, 124.2, 143.0,
146.9, 180.1, 207.7; MS m/z 288 (M+), 260, 232, 215, 187, 183,
161, 115; HRMS m/z 288.0996 (calcd for C16H16O5 288.0998).
(1 R *,1 2 S *,1 6 R *)-9 -M e t h o x y -1 1 -o x a p e n t a c y c l o -
[8.6.1.01,12.04,14.06,17]h e p t a d e ca -6(17),7,9-t r ie n e -3,13-d i-
on e (53). To a stirred solution of 50 (0.19 g, 0.605 mmol) in
dry CH2Cl2 (200 mL) under argon was added Rh2(OAc)4 (ca. 2
mg), and the mixture was stirred for 1 h at ambient temper-
ature. The solvent was removed under reduced pressure, and
the residue was chromatographed on silica (30 g, EtOAc-
hexane, 1:2) to furnish 91 mg (53%) of 53 as a colorless oil:
oil: [R]23 +114.2 (c 1.47, CHCl3); IR (neat) 3271, 2932, 1673,
D
1509, 1437, 1288, 1119, 1037, 1021 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.92-1.05 (m, 1H), 1.25-1.41 (m, 1H), 1.69-1.80 (m,
1H), 1.92-2.01 (m, 1H), 2.29 (dt, J ) 4, 13 Hz, 1H), 2.52 (d, J
) 17 Hz, 1H), 2.68 (d, J ) 17 Hz, 1H), 2.75 (br s, 2H), 3.38 (s,
3H), 3.35-3.39 (m, 1H), 3.83 (br s, 1H), 3.88 (s, 3H), 4.41 (d,
J ) 7 Hz, 1H), 4.68 (d, J ) 7 Hz, 1H), 4.75 (d, J ) 7 Hz, 1H),
6.62 (d, J ) 8 Hz, 1H), 6.76 (d, J ) 8 Hz, 1H), 6.78 (br s, 1H);
13C NMR (75 MHz, CDCl3) δ 23.0, 28.0, 28.3, 31.1, 38.2, 42.6,
43.8, 51.3, 55.4, 57.1, 76.4, 95.3, 95.6, 115.7, 121.5, 130.3, 144.6,
144.9, 170.9; MS (CI) m/z 346 (M++1), 339, 323, 284, 246, 185,
169, 141, 125, 89, 86, 84, 78, 75, 73; HRMS m/z 345.1575 (calcd
for C19H23NO5 345.1576).
IR (neat) 2941, 2839, 1740, 1721, 1503, 1442, 1283, 1088 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.48-1.63 (m, 1H), 2.03-2.11
(m, 1H), 2.39-2.50 (m, 1H), 2.55-2.64 (m, 2H), 2.72 (d, J )
17 Hz, 1H), 2.84-2.92 (m, 4H), 3.90 (s, 3H), 4.92 (s, 1H), 6.62
(d, J ) 8 Hz, 1H), 6.72 (d, J ) 8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 21.7, 27.5, 40.7, 42.6, 49.9, 52.0, 53.3, 56.9, 88.2,
115.5, 121.7, 121.9, 129.9, 143.5, 145.1, 207.3, 216.6; MS m/z
284 (M+), 256, 242, 227, 213, 199, 185, 181, 128, 121, 115;
HRMS m/z 284.1047 (calcd for C17H16O4 284.1048).
(1R,5S,13S,14S,17S)-10-Meth oxy-14-(m eth oxym eth oxy)-
4-m e t h yl-12-oxa -4-a za p e n t a cyclo[9.6.1.01,13.05,17.07,18]-
octa d eca -7(18),8,10-tr ien -3-on e (62). To a solution of 57 (24
mg, 0.069 mmol) in dry benzene (3 mL) were added NaH (55
wt % suspension in mineral oil, 12 mg, 0.28 mmol) and CH3I
(43 µL, 0.69 mmol), and the mixture was heated at reflux for
5 h. The mixture was diluted with EtOH (40 mL) and H2O (2
mL), and the organic phase was separated. The aqueous layer
was extracted with CH2Cl2, and the combined organic phase
was washed with saturated aqueous NaCl, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure.
Chromatography of the residue on silica (4 g, EtOAc-MeOH,
(1R *,4S *,12S *,16R *)-9-Me t h oxy-11-oxa p e n t a cyclo-
[8.6.1.01,12.04,16.06,17]h ep ta d eca -6(17),7,9,14-tetr a en e-3,13-
d ion e (55). To a stirred solution of 52 (48 mg, 0.17 mmol) in
EtOAc (7 mL) was added PhSeCl (46 mg, 0.24 mmol), followed
by aqueous HCl (36%, 5 drops), and the mixture was stirred
for 5 h at ambient temperature. The mixture was neutralized
with solid NaHCO3 (30 mg) and was stirred for another 30
min. The mixture was filtered, and the filtrate was concen-
trated under reduced pressure. The residue was taken up into
THF-H2O (1:1.5, 25 mL), NaIO4 (150 mg, 0.70 mmol) was
added, and the solution was stirred for 30 h at room temper-
ature, after which time most of the THF was removed under
reduced pressure. The residue was extracted with EtOAc, and
the extract was washed with saturated aqueous NaCl, dried
over anhydrous Na2SO4, and concentrated under reduced
pressure. Chromatography of the residue on silica (5 g,
EtOAc-hexane, 2:1) gave 19 mg (46%) 55 as a colorless oil:
IR (neat) 2959, 2842, 1748, 1684, 1503, 1450, 1284, 1264, 1176,
1084, 927, 805 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.89 (dd, J
) 5, 17 Hz, 1H), 3.02 (dd, J ) 2, 17 Hz, 1H), 3.07-3.10 (m,
1H), 3.46-3.50 (m, 1H), 3.85 (s, 3H), 5.05 (s, 1H), 6.24 (d, J )
2, 10 Hz, 1H), 6.70 (d, J ) 8 Hz, 1H), 6.95 (dd, J ) 2, 10 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 28.3, 41.0, 49.5, 49.6, 52.1,
56.9, 86.3, 115.6, 121.3, 122.0, 132.3, 134.7, 143.1, 144.6, 145.3,
12:1) furnished 24 mg (95%) of 62 as a colorless oil: [R]23
D
+148.9 (c 0.092, CHCl3); IR (neat) 2935, 1655, 1636, 1509,
1440, 1284, 1108, 1054, 1005 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.98-1.26 (m, 1H), 1.28-1.38 (m, 1H), 1.68-1.78 (m, 1H),
1.91-1.97 (m, 1H), 2.34 (dt, J ) 4, 13 Hz, 1H), 2.56 (d, J ) 17
Hz, 1H), 2.95 (d, J ) 18 Hz, 1H), 3.00 (s, 3H), 3.31-3.38 (m,
1H), 3.38 (s, 3H), 3.69-3.72 (m, 1H), 3.88 (s, 3H), 4.41 (d, J )
7 Hz, 1H), 4.68 (d, J ) 7 Hz, 1H), 4.75 (d, J ) 7 Hz, 1H), 6.62
(d, J ) 8 Hz, 1H), 6.75 (d, J ) 8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 23.0, 26.8, 28.0, 34.2, 39.2, 43.1, 44.9, 55.4, 57.2, 59.0,
76.4, 95.1, 95.6, 115.7, 121.2, 121.5, 130.4, 144.6, 144.9, 168.4;
MS m/z 359 (M+), 329, 314, 298, 286, 256, 243, 225, 211, 199,
185; HRMS m/z 359.1733 (calcd for C20H25NO5 359.1733).
(1R,5S,13S,14S,17S)-14-Hyd r oxy-10-m eth oxy-4-m eth yl-
12-oxa -4-a za p e n t a cyclo[9.6.1.01,13.05,17.07,18]oct a d e ca -

7884 J . Org. Chem., Vol. 64, No. 21, 1999
White et al.
7(18),8,10-tr ien -3-on e (64). A solution of 62 (22 mg, 0.061
mmol) in MeCN (2 mL) and aqueous HBr (36%, 10 mL) was
stirred for 2 h at ambient temperature. The mixture was
neutralized with solid NaHCO3 (30 mg) and filtered, and the
filtrate was concentrated under reduced pressure. Chroma-
tography of the residue on silica (3 g, EtOAc-MeOH, 9:1) gave
taken up into THF-H2O (1:1, 4 mL), NaIO4 (180 mg, 0.88
mmol) was added, and the mixture was stirred for 30 h at
ambient temperature. The mixture was extracted with CHCl3,
and the extract was washed with saturated aqueous NaCl,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. Chromatography of the residue on silica (3 g,
EtOAc-EtOH, 11:1) produced 22 mg (64%) of 67 as a colorless
oil: [R]23D +168.4 (c 0.012, CHCl3); IR (neat) 1159, 1287, 1449,
1505, 1634, 1681, 2859, 2929 cm-1; 1H NMR (300 MHz, CDCl3)
δ 2.56 (dd, J ) 4, 18 Hz, 1H), 2.78 (d, J ) 17 Hz, 1H), 2.89 (d,
J ) 17 Hz, 1H), 3.05 (s, 3H), 3.12 (m, 2H), 3.42 (br s, 1H),
3.87 (s, 3H), 4.05 (m, 1H), 4.71 (s, 1H), 6.19 (dd, J ) 3, 10 Hz,
1H), 6.63 (d, J ) 8 Hz, 1H), 6.69 (d, J ) 10 Hz, 1H), 6.74 (d,
J ) 8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 29.9, 34.4, 38.4,
43.1, 43.2, 57.3, 58.5, 87.7, 118.2, 121.0, 122.3, 129.0, 134.1,
143.9, 144.2, 145.2, 167.6, 193.7; MS (CI) m/z 321 (M+ + H),
201, 130, 121, 115, 111, 102, 97 86, 83, 69; HRMS (CI) m/z
312.1235 (calcd for C18H18NO4 312.1236).
18 mg (95%) of 64 as a colorless oil: [R]23 +148.9 (c 0.092,
D
CHCl3); IR (neat) 3394, 2936, 1620, 1509, 1440, 1280, 1097
cm-1; 1H NMR (300 MHz, CDCl3) δ 1.00-1.10 (m, 1H), 1.28-
1.48 (m, 1H), 1.73-1.80 (m, 2H), 1.84-1.90 (m, 1H), 2.36 (dt,
J ) 4, 13 Hz, 1H), 2.54 (m, 1H), 2.56 (d, J ) 17 Hz, 1H), 2.65
(dd, J ) 4, 18 Hz, 1H), 2.70 (d, J ) 17 Hz, 1H), 2.95 (d, J ) 18
Hz, 1H), 3.01 (s, 1H), 3.33-3.43 (m, 1H), 3.70-3.73 (m, 1H),
3.87 (s, 3H), 4.34 (d, J ) 7 Hz, 1H), 6.63 (d, J ) 8 Hz, 1H),
6.76 (d, J ) 8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 23.2, 26.8,
29.4, 34.2, 39.2, 42.9, 44.9, 56.8, 59.0, 72.3, 97.0, 114.8, 121.3,
121.5, 130.5, 144.4, 144.7, 168.4; MS m/z 315 (M+), 301, 286,
258, 243, 229, 213, 199, 185, 178; HRMS m/z 315.1472 (calcd
for C18H21NO4 315.1471).
(+)-Cod ein e (1). To a stirred suspension of LiAlH4 (6.10
mg, 0.16 mmol) in dry THF (0.5 mL) was added a solution of
67 (5 mg, 0.0196 mmol) in THF (1 mL), and the mixture was
refluxed for 6 h. After being cooled to ambient temperature,
the mixture was treated with a saturated aqueous solution of
Rochelle’s salt (1 mL) and extracted with CH2Cl2. The extract
was washed with saturated aqueous NaCl, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure.
Chromatography of the residue on silica (2 g, CHCl3-Et2NH,
20:1) yielded 4.1 mg (70%) of 1 as a colorless solid: mp 149-
152 °C; [R]23D +137.5 (c 0.16, EtOH); 1HNMR (400 MHz,CDCl3)
δ 1.90 (d, J ) 12 Hz), 2.11-2.17 (m, 1H), 2.36 (dd, J ) 6, 18
Hz, 1H), 2.44-2.47 (m, 1H), 2.49 (s, 3H), 2.65-2.68 (m, 1H),
2.78 (br s, 1H), 3.05 (d, J ) 18 Hz, 1H), 3.41 (br s, 1H), 3.84
(s, 3H), 4.17-4.19 (m, 1H), 4.90 (d, J ) 6 Hz, 1H), 5.26-5.30
(m, 1H), 5.72 (d, J ) 10 Hz, 1H), 6.57 (d, J ) 8 Hz, 1H), 6.67
(d, J ) 8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.8, 35.6,
40.6, 43.0, 43.1, 46.8, 56.6, 59.3, 66.5, 91.3, 113.3, 119.9, 128.0,
131.0, 133.9, 139.6, 142.6, 146.5. This material was spectro-
scopically identical with a sample of natural (-)-codeine.5a
(1R ,5S ,13S ,17S )-10-M e t h o x y -4-m e t h y l-12-o x a -4-
a za p e n t a cyclo[9.6.1.01,13.05,17.07,18]oct a d e ca -7(18),8,10-
tr ien e-3,14-d ion e (63). A mixture of 64 (16 mg, 0.051 mmol)
and Dess-Martin periodinane (26 mg, 0.061 mmol) in CHCl3
(3 mL) was stirred for 1 h at ambient temperature. The
suspension was treated with a Na2S2O3-NaHCO3 solution (4
mL, 50 g of Na2S2O3 in 200 mL of saturated aqueous NaHCO3),
and the chloroform layer was separated, washed with satu-
rated aqueous NaCl, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. Chromatography of the
residue on silica (4 g, EtOAc-MeOH, 11:1) gave 15 mg (96%)
of 63 as a colorless oil: [R]23D +181.3 (c 0.71, CHCl3); IR (neat)
2935, 1738, 1636, 1504, 1440, 1284, 1101, 771 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.26-1.39 (m, 1H), 2.01-2.08 (m, 1H),
2.40-2.48 (m, 2H), 2.62 (dd, J ) 4, 18 Hz, 1H), 2.76-2.80 (m,
3H), 2.98 (d, J ) 18 Hz, 1H), 3.04 (s, 3H), 3.78-3.80 (m, 1H),
3.91 (s, 3H), 4.70 (s, 1H), 6.64 (d, J ) 8 Hz, 1H), 6.75 (d, J )
8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 25.3, 26.9, 34.3, 39.1,
39.2, 44.5, 46.9, 57.2, 58.7, 91.6, 116.2, 121.2, 122.1, 127.3,
143.9, 146.2, 167.7, 206.0; MS m/z 313 (M+), 256, 241, 231,
212, 198, 181, 131, 121, 97, 83, 71; HRMS m/z 313.1314 (calcd
for C18H19NO4 313.1341).
(1R ,5S ,13S ,17S )-10-M e t h o x y -4-m e t h y l-12-o x a -4-
a za p en ta cyclo[9.6.1.01,13.05,17.07,18]octa d eca -7(18),8,10,15-
tetr a en e-3,14-d ion e (67). To a solution of 63 (35 mg, 0.11
mmol) in THF (5 mL) at 0 °C under argon was added a 1 M
solution of KO-t-Bu in t-BuOH (130 mL, 0.13 mmol), and the
mixture was stirred for 30 min at 0 °C. A solution of PhSeCl
(28.7 mg, 0.15 mmol) in THF (0.4 mL) was added, and the
mixture was allowed to warm to room temperature during 1
h. The mixture was diluted with saturated aqueous NH4Cl (0.5
mL) and was extracted with CHCl3. The extract was washed
with saturated aqueous NaCl, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The residue was
Ack n ow led gm en t. We are indebted to Professor
J ohn Block, College of Pharmacy, Oregon State Uni-
versity, for a sample of (-)-codeine and to Dr. Alex
Yokochi for assistance with the determination of X-ray
crystal structures of 24 and 26. Financial support was
provided by the National Science Foundation (9711187-
CHE), by DuPont Pharmaceutical Co., and by Pfizer Inc.
Su p p or tin g In for m a tion Ava ila ble: Complete X-ray
crystallographic data for 24 and 26 and NMR spectra (1H and
13C) of synthesized compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O990905Z