Recent Progress in the Synthesis of Morphine Alkaloids

18 Pages·2005·0.44 MB·English

388 ACCOUNT
Recent Progress in the Synthesis of Morphine Alkaloids
RJecent Proogress in thes Synthesise of Morphifne Alkal oidsZezula,a Tomas Hudlicky*b
a NIH/NIDDK, 9000 Rockville Pike, Bldg. 8/Rm. B1-25, Bethesda, MD 20892-0815, USA
b Department of Chemistry, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada
Fax [phone]; E-mail: [email protected]
Received 15 June 2004
2
Abstract: Recent accomplishments in the field of total synthesis of HO MeO 3 AcO
1
morphine alkaloids are reviewed. Approaches to the skeleton of A
4 11
morphine are included as are various efforts towards related medic- B 10
inally important agents. The literature coverage begins after the O O 12 15 16 O
D
pthurboluicgaht i2o0n0 4o.f our last update in 2000 and continues mid-way C NMe 5 13 149 NMe NMe
1 Introduction HO HO 6 8 AcO
7
2 Total Syntheses of Morphine
1 2 3
2.1 Taber
2.2 Trost
HO HO
2.3 Ogasawara
3 Approaches to the Morphine Skeleton
3.1 Vollhardt
O O
3.2 Ogasawara
3.3 Cheng N N
3.4 Passarella OH OH
O O
3.5 Hudlicky
3.6 Hudlicky 4 5
4 Unnatural Analogs and Mimics
Figure 1 Morphine, congeners, and synthetic derivatives
4.1 Rice
4.2 Grauert
20% of morphine in their latex. The antagonists 4 and 5
4.3 Trost
are manufactured from morphine by semisynthesis in sev-
4.4 Ohno
4.5 Schmidhammer eral steps. To date there is no reported synthesis of the al-
5 Conclusions and Outlook kaloid (excepting perhaps that of Rice, see Table1) that
would show promise for a large-scale manufacturing.
Key words: morphine, total synthesis, alkaloids, approaches to
morphine skeleton, morphine analogs and mimics The possibility of a fully synthetic supply of morphine is
nevertheless important as the availability of natural
morphine depends on the political stability of a very few
regions of the world. Political unrest or ecological
1 Introduction
disasters could jeopardize the availability of morphine for
medical use, which is important as an analgesic and as an
Morphine (1) and codeine (2), the principal constituents
anesthetic.2,3
of opium, continue to attract the attention of synthetic
chemists. The use of opium has been documented as far Several reviews have been published on the total synthesis
back as 3000 B.C., to the Sumerians, who lived in the of morphine alkaloids;4 our own most recent update ap-
Mesopotamian region now a part of southern Iraq.1 Most peared in 2000.4d Since then at least three total syntheses
people are familiar with compounds such as morphine and and several approaches have appeared attesting to the un-
heroin (3), as well as some of the morphine antagonists diminished interest of synthetic chemists in this fascinat-
such as naltrexone (4) and naloxone (5), see Figure1. The ing molecule. A concise feature article discussing history,
legal medicinal use of morphine in the U.S. exceeds use, and synthesis of morphine by White was published in
80,000 kg/year, and the world-wide illicit market for 2002.4e
narcotics is estimated at more than $760 billion – a sum
Morphine seems to be a simple alkaloid compared to, for
exceeding the combined GNP of all but a few economies
example, diterpene alkaloids such as atisine, but a close
on the planet.1,2 All morphine used today originates in
examination of its structure (with an eye for an efficient
natural opium, which is supplied primarily from India,
design) reveals problems in connectivity. This is especial-
Afghanistan, and Turkey where the poppies contain up to
ly true for derivatives oxygenated at C-14.
Following Evans’s terminology of consonance and
SYNLETT 2005, No. 3, pp0388–040516.02.2005 dissonance5 and taking into account that morphine itself
Advanced online publication:04.02.2005
functions as an amino acid, the two disconnection analy-
DOI: 10.1055/s-2005-862383; Art ID:A35604ST
© Georg Thieme Verlag Stuttgart · New York
ACCOUNT Recent Progress in the Synthesis of Morphine Alkaloids 389
ceive an incorrect charge. This ‘dissonance’ no doubt ex-
HO HO presses itself in almost all published syntheses where one
or another part of the molecule suffers during the execu-
tion of the synthesis. The more arduous design elements
O O
in the structures of morphine (1) and noroxymorphone (6)
N N
are shown in Figure3.
HO HO
2 Total Syntheses
A B
Figure 2 Dissonant relationships in morphine connectivity Our 1996 review covered all total syntheses of morphine
(A=phenol priority, B=amine priority) including approaches and references to dissertations.4a An
updated list of all total and formal syntheses as of this
ses in terms of polarization begin with either the phenolic writing is shown in Table1. Since the publication of our
oxygen (A) or the tertiary amine (B), as shown in 2000 update4d three total syntheses have been reported;
Figure2. It is immediately obvious that there can be no these are discussed in detail in this review along with
possible assignment in which the alternating charges other approaches to the morphine ring system.
match or in which one of the priority atoms does not re-
Biographical Sketches
Josef Zezula was born in received his MSc degree in tion of arenes in approaches
1976 in Czechoslovakia, 1999, he moved to the Unit- towards the morphine skele-
now the Czech Republic. In ed States to pursue graduate ton. Currently he is a visit-
1994 he was accepted at the studies at the University of ing fellow at the National
Institute of Chemical Tech- Florida, Gainesville, under Institutes of Health in Be-
nology, Prague, where he the direction of Tomas thesda, Maryland, working
worked in research group of Hudlicky. In 2003 he com- in the research group of Dr.
Professor I. Stibor in the pleted PhD studies, which K. C. Rice.
area of calixarene-based were focused on the use of
macromolecules. After he products of microbial oxida-
Tomas Hudlicky was born lowing his PhD in 1977, he prokaryotic enzymes in gen-
in 1949 in Prague, Czecho- spent a year as a postdoctor- erating useful chiral metab-
slovakia, where he received al fellow with Professor olites for asymmetric
his elementary and middle Wolfgang Oppolzer at the synthesis. In 1995 he moved
school education. He was university of Geneva work- to the University of Florida
denied access to higher ing on the synthesis of iso- and in 2003 he accepted a
forms of education beyond comene. In 1978 he joined position at Brock University
grade 9 and worked for a the faculty at Illinois Insti- as Canada Research Chair
number of years in odd jobs tute of Technology to start Professor of Chemistry and
around the city as well as a his independent career in the Biocatalysis.
process chemist apprentice field of general methods of His current research inter-
in pharmaceutical industry. synthesis for triquinane ses- ests include the develop-
In 1968 he emigrated to the quiterpenes and other natu- ment of enantioselective
U.S. with his family and ral products containing five- synthetic methods, biocatal-
continued his educational membered rings. The devel- ysis, total synthesis of mor-
experience by attending opment of [4+1] and [3+2] phine and amaryllidaceae
Blacksburg High School, annulation methodologies alkaloids, isolation and use
dropping out in the spring of dates to this period of time. of metabolites derived by
1969. Accepted as a proba- In 1982 he moved back to enzymatic dihydroxylation
tional student at Virginia his alma mater, Virginia of aromatics, design of inos-
tech in the fall of that year Tech where he rose to the itol-containing oligomers,
he graduated with a BSc in rank of Professor in 1988. and organic electrochemis-
chemistry in 1973 and pur- One year later at the 20-year try. His hobbies include ski-
sued graduate studies at reunion of his High School ing, martial arts, music, and
Rice University under the class of ’69 he was awarded hockey and he enjoys all of
direction of Professor his High School Diploma. these with his 14-year old
Ernest Wenkert in indole The next phase of his re- son Jason.
alkaloid total synthesis. Fol- search involved the use of
Synlett 2005, No. 3, 388–405 © Thieme Stuttgart·New York
390 J. Zezula, T. Hudlicky ACCOUNT
HO C-10/C-11 bond HO Br O
a–d
HO MeO
O 13 9 O Br OMe
N NH
14 14 7 8
C-9/C-14 stereocenters OH
HO O
1 6 e–g
C-13 quarternary center C-14 alcohol
cis-1,2-aminoalcohol
Figure 3 Key design considerations for morphine and noroxymor-
O
phone
h
Table 1 Total and Formal Syntheses of Morphine and its Deriva- MeO
tives
OMe Br
Principle Date Product (no. of steps) Yield
9
author (%)
Gates 1952 (–)-Morphine (23) 0.016
Ph Ph
Ginsberg 1954 rac-Dihydrothebainone (21) 8.86a,7 O O
Ph Ph
Grewe 1967 rac-Dihydrothebainone (9) 0.818
O + O
Rice 1980 (–)-Dihydrocodeinone (10) 29.009 MeO MeO
OMe Br OMe Br
Evans 1982 rac-O-Me-thebainone-A (12) 16.6710
10 11
Rapoport 1983 rac-Codeine (26) 1.1511
Scheme 1 Reagents and conditions: (a) MeI, K CO , DMF (97%);
Fuchs 1988 rac-Codeine (22) 1.5312 2 3
(b) MeONa, collidine, CuI, MeOH, D (89%); (c) Na, EtOH, D; (d)
Tius 1992 rac-Thebainone-A (28) 0.9713 HCl, H2O, D (76%, 2 steps); (e) (MeO)2CO, MeONa, D (76%); (f)
LDA (2 equiv), THF, 0°C; (g) LiCl, DMSO, HO, D (80%, 2 steps);
2
Parker 1992 rac-Dihydrocodeinone (12) 9.4214 (h) p-TsOH, (S,S)-(–)-hydrobenzoin, HC(OEt), CH Cl (86%).
3 2 2
Overman 1993 (–)-Dihydrocodeinone (14) 4.4315
1,6-dibromo-2-naphthol (7) in 7 steps utilizing modified
Mulzer 1996 (–)-Dihydrocodeinone (15) 11.5016 literature procedures.25
Parsons 1996 Morphine 0.88b,17 Several issues deserve mention from strategic as well as
tactical viewpoints. First, the incorporation of asymmetry
White 1997 (+)-Morphine (28) 3.0018
was accomplished by resolution of racemic 9 via dia-
Hudlicky 1998 10-Hydroxy-ent-epi-dihydro- 2.7019 stereomeric ketals derived from (S,S)-(–)-hydrobenzoin to
codeinone (14)
give 10 and 11, which were separated by column chroma-
Cheng 2000 rac-Desoxycodeine-D (15) 13.2620 tography (Scheme1).
Ogasawara 2000 rac-3,4-Dimethoxy-6-mor- 0.2521 The undesired diastereomer 11 was easily recycled to ra-
phinanone (29) cemic 9 by reflux in aqueous acetic acid. Second, the cy-
clization of ketal 10 via alkylidene carbene C–H
Ogasawara 2001 (–)-Dihydrocodeinone ethyl- 0.3722
insertion26 followed by hydrolysis gave the enantiomeri-
ene ketal (24)
cally pure ketone 12, which, unlike tetralone 9, cannot ra-
Taber 2002 (–)-Morphine (27) 0.5123 cemize because of the large energy difference between
Trost 2002 (–)-Codeine (15) 6.7824 cis- and trans-fused hydrindanones (Scheme2).
Taber introduced the nitrogen atom along with the re-
a First 16 steps.
b Last 5 steps. maining two carbons necessary for the construction of the
D-ring to provide the key intermediate, keto aldehyde 14
Note: Key transformations in the Schemes are depicted in as shown in Scheme2. Third, both C- and D-rings were
blue. closed in a single operation, as shown in Scheme3.
The introduction of the nitrogen atom required the stereo-
2.1 Taber selective reduction of ketone 12 with L-Selectride to the
a-alcohol, which was converted, with inversion of config-
In 2002 Taber23 published a total synthesis of (–)-mor-
uration, to the corresponding azide by Mitsunobu cou-
phine starting from tetralone 9, which provided the AB-
pling.27 Reduction and protection gave sulfonamide 13.
ring system and the carbon atoms needed for the construc-
The key intermediate in Taber’s synthesis, the keto alde-
tion of the C-ring. Compound 9 had been prepared from
Synlett 2005, No. 3, 388–405 © Thieme Stuttgart·New York
ACCOUNT Recent Progress in the Synthesis of Morphine Alkaloids 391
aromatic ring. Regioselective opening of the epoxide pro-
H
O N vided selenide 17, whose oxidation followed by elimina-
a,b c–f SO2Ph
10 tion gave alcohol 18, with the incorrect configuration of
MeO MeO the hydroxyl at the C-6 (Scheme3).
OMe 13 OMe Codeine was prepared by the known oxidation–reduction
12
sequence, and morphine was obtained by further treat-
g, h ment with BBr3 by the procedure reported by Rice28 in a
total of 27 steps from naphthol 7 and in 0.5% overall yield.
Br
2.2 Trost
N SO2Ph
Trost’s enantioselective total synthesis of (–)-codeine and
(–)-morphine24 appeared in 2002 soon after Taber’s re-
MeO
O port. Chirality was introduced via asymmetric allylic
OMe
O alkylation of phenol 2112 with ester 2029 (readily available
14 H
in two steps from glutaraldehyde), catalyzed by palladium
Scheme 2 Reagents and conditions: (a) KHMDS, Et2O (77%); (b) in the presence of chiral bis-phosphine ligand 19 to give
HOAc, H2O, D (80%); (c) L-Selectride, THF, 0°C (97%); (d) the aryl ether 22 in good yield and ee (72 and 88%, respec-
(PhO)P(O)N, DEAD, PhP, THF; (e) LiAlH, EtOH, EtO; (f)
2 3 3 4 2 tively, Scheme4).
PhSO Cl, EtN, CHCl (43%, 3 steps); (g) BrCHCHBr, NaOH,
2 3 2 2 2 2
TBAB, PhMe, D (83%); (h) O3, CH2Cl2, –70°C, PPh3 (85%). The key features of Trost’s synthesis are the Heck cycliza-
tion of nitrile 23, which contain the A- and C-rings, to the
hyde 14, was prepared by alkylation of 13 and subsequent tricyclic ether 24 and the Heck vinylation of 25 to furnish
ozonolysis of the methylcyclopentene ring (Scheme2). the tetracycle 26 (Scheme5). The D-ring was closed by an
intramolecular hydroamination to produce codeine.
Tetracyclic morphinan 15 was prepared by a selective
double cyclization of 14, the first step of which involved Nitrile 23 was prepared in four steps as described in
the intramolecular alkylation of the aldehyde enolate to Trost’s earlier report on the synthesis of alkaloid (–)-gal-
close the D-ring. In the second step, a Robinson annula- anthamine.30 The optical purity of 23 was improved to
tion provided enone 15 in excellent yield (Scheme3). Re- 96% ee by recrystallization. The key step, establishing the
duction of 15 with NaBH gave a single alcohol, which C-13 quarternary center, was accomplished by Heck cou-
4
upon brief exposure to BBr provided the ether bridge to pling of 23 to give tricyclic ether 24 in excellent yield
3
yield pentacycle 16. Deprotection of phenylsulfonamide (Scheme4).
16 by dissolving metal reduction failed, but Red-Al in re- Cyclization precursor 25 was prepared in two steps by
fluxing toluene was found effective, and the resulting Corey–Fuchs olefination31 followed by chemoselective
amine was immediately protected as its carbamate. reduction to the (Z)-vinylbromide.32 Intramolecular Heck
The oxidation state of ring C was adjusted by stereoselec- vinylation gave olefin 26, completing the construction of
tive epoxidation directed by the steric hindrance from the the phenanthrene core of morphine (Scheme5).
SO2Ph
N N
SO2Ph b,c
a
14
O
MeO
OMe
O
OMe
15 16
d–g
Me CO2Et CO2Et
N N N SePh
OH OH OH
O j–l O h,i O
OH OMe OMe
1 18 17
Scheme 3 Reagents and conditions: (a) KCO, TBAB, toluene, D (92%); (b) NaBH, EtOH (92%); (c) BBr, CHCl, –40°C (70%); (d)
2 3 4 3 2 2
Red-Al, toluene, D; (e) ClCOEt, EtN, CHCl (78%); (f) {[(CH )NCH]+}{PO [W(O)(O)]}3–, H O, DCE, D (75%); (g) PhSeSePh,
2 3 2 2 8 173 3 3 4 224 2 2
NaBH , EtOH, D (75%); (h) NaIO , THF, HO; (i) NaCO , toluene, HO (58%); (j) MnO , CH Cl; (k) LiAlH, THF, D (75%); (l) BBr (86%).
4 4 2 2 3 2 2 2 2 4 3
Synlett 2005, No. 3, 388–405 © Thieme Stuttgart·New York
392 J. Zezula, T. Hudlicky ACCOUNT
Ph Ph
O O
NH N
H
TrocO
20 CO2Me PPh2 Ph2P 19 MeO O BCrO2Me
+
OH a
MeO Br CHO
22
CHO
21 b–e
OMe
O
O CN
f
OHC MeO Br
NC
CHO
24 23
Scheme 4 Reagents and conditions: (a) 19, {[h3-CHPdCl]}, EtN, CHCl, r.t. (72%); (b) TsOH, CH(OMe), MeOH; (c) DIBALH, toluene,
3 3 2 3 2 2 3
–78°C (85%); (d) PPh, acetonecyanohydrin, DIAD, EtO; (e) TsOH, THF, H O (76%); (f) Pd(OAc), dppp, AgCO, toluene, 107°C (91%).
3 2 2 2 2 3
Troc=2,2,2-trichloroethoxycarbonyl, DIAD=diisopropyl azodicarboxylate, dppp=bis(diphenylphosphonyl)propane.
OMe Intramolecular hydroamination of 27, promoted by irradi-
OMe
ation of the basic solution by an ordinary tungsten lamp,
yielded (–)-codeine in good yield. Morphine was obtained
a,b O c
24 Br O by O-demethylation, following the procedure of Rice.28
(–)-Codeine was obtained in 15 steps from guaiacol deriv-
NC
ative 21 in an overall yield of 7%. It should be mentioned
NC 25 26
that compound 24 also served as an intermediate for total
synthesis of (–)-galanthamine (29) as shown in Scheme6.
d,e
OH OH
OMe OMe H H
1 g O f O 24 a MeO O b–d MeO O
N CN
OH H OH
N CHO NMe
2 27 28 29
S(bc)h ePmde(P 5Ph3R)4e,a gne-nBtus 3aHn,d ctoolnudeintieo n(s8: 8(a%) )C; B(rc4),% Ph 3PPd, (COHA2cC)l22, (9d1p%pp);, Soxcahneem (e6 46%)R; e(ba)g eMntesN aHn2d, McoenOdiHti;o n(cs): D(aI)B SAeLOH2, (N4 ae2qHuPivO)4, , th1e,4n- daiq-
Ag2CO3, toluene (65%); (d) SeO2, 1,4-dioxane, 75°C, then DMP, r.t. NaH2PO4; (d) NaCNBH3 (b–d in one pot, 62%).
(58%); (e) DIBALH, CHCl, EtO, then NH Br, MeNH, then
2 2 2 4 2
NaBH (89%); (f) LDA, THF with tungsten bulb (57%); (g) BBr.
4 3
2.3 Ogasawara
Allylic oxidation with SeO and treatment with Dess– In 2001 Ogasawara published22 a concise route to the
2
Martin periodinane gave the corresponding enone, which ethylene ketal of (–)-dihydrocodeinone starting from
was reduced, along with the nitrile, in a one-pot procedure enantiopure bicyclic enone 30,34 a compound that exhibits
by DIBALH to give an imine–aluminum complex. Addi- convex-face selectivity because of its sterically biased
tion of ammonium bromide in dry methanol quenched the framework. Enone 30 has served the author well in several
excess hydride and furnished the free imine, which was other syntheses, most notably in his preparation of vernol-
reacted with methylamine. Finally, the addition of sodium epin.35 In this approach to the morphine skeleton, rings A
borohydride resulted in the formation of the desired and C were constructed in two steps via the attack of lithi-
secondary amine 27 in good overall yield from olefin 26 ated veratrol (ring A) onto the carbonyl to give the tertiary
(Scheme5). alcohol, which was oxidized with concomitant transposi-
tion to enone 31. The vinyl moiety was introduced accord-
Synlett 2005, No. 3, 388–405 © Thieme Stuttgart·New York
ACCOUNT Recent Progress in the Synthesis of Morphine Alkaloids 393
ing to Mulzer’s conditions16a via a diastereoselective 1,4- MeO MeO
addition of vinyl cuprate followed by bromination with
NBS to give bromoketone 32 (Scheme7).
The ether bridge was constructed by heating 32 in di- 37 a,b O c O
methylformamide to provide dihydrobenzofuran 33. After NMe
O O
protection of the ketone as a ketal, the hydroboration– NMeSO2Ph
oxidation sequence was carried out to give the primary O 38 O 39
alcohol, protected as pivalate 34 (Scheme7).
Scheme 8 Reagents and conditions: (a) LiAlH, THF, r.t. (100%);
4
Closure of ring B was accomplished by heating 34 in ben- (b) PhSO NHMe, 1,1¢-(azodicarbonyl)dipiperidine, Bu P, THF
2 3
zene and ethylene glycol in the presence of a catalytic (78%); (c) Li, NH3, t-BuOH, THF (70%).
amount of TsOH. Ogasawara proposed that the ketal is
first converted into its oxonium ion 35, which then under-
3 Approaches to the Morphine Skeleton
goes a retro-aldol cleavage of the bicyclic system to afford
the corresponding protonated aldehyde 36. The final cy-
3.1 Vollhardt
clization, accelerated by the para-methoxy group, occurs
at this stage to form the B-ring. The presence of ethylene In his approach published in 2000, Vollhardt envisioned
glycol in the reaction mixture seemed to accelerate this simultaneous closure of the B- and the C-rings in the
cyclization. Tetracycle 37 was obtained in good yield as a morphine skeleton by a CpCo-mediated [2+2+2] cyclo-
single isomer (Scheme7). addition of functionalized 4-(3-butynyl)-benzofurans37
such as 42 with arynes 43 (Scheme9).
O O
MeO MeO
Br X
O a,b OMe c,d OMe
R
O
MOM MOM O OMe MOM O OMe O O +
NMe X
30 31 32
O R
R R
e CoCp
OPiv R R OMe
40 41
O O 42 43
O Scheme 9
i O f,g,h O
OH O The precursor for the required 4-(3-butynyl)-benzofurans
OMe MOM OMe was prepared from the readily available38 acid 44 by its
conversion into the (S)-ethylthioester. Reduction with
34 33
Et SiH–Pd/C39 gave the corresponding aldehyde, which
3
OPiv OH MeO H MeO was transformed into alcohol 45 by the reaction with lith-
ium trimethylsilylacetylene. The requisite benzofurans
O O
42a–e were obtained from 45 by standard procedures
O O
(Scheme10).
O
O OPiv O Reactions of 42a–e with bis(trimethylsilyl)acetylene
H OMe O OPiv (BTMSA) in the presence of CpCo(C H ) successfully
O 2 4 2
OH yielded the corresponding crystalline cobalt complexes
35 36 37 47a–e in good yields (Scheme11). The [2+2+2] cycliza-
tions proceeded in a remarkably diastereospecific fashion
Scheme 7 Reagents and conditions: (a) 3-Li-veratrol, THF, –78°C;
providing only one of four possible diastereomers and se-
(b) PCC, CHCl (81% for 2 steps); (c) CHCHMgCl, CuBr·SMe ,
2 2 2 2 curing the correct configurations at C-5, C-13, and C-9.
TMSCl, HMPA, THF (75%); (d) NBS, CHCl, r.t. (99%); (e) DMF,
2 2
D (82%); (f) (CHOTMS), TfOTMS (cat.), CH Cl (71%); (g) Oxidative removal of the metal in complex 47e furnished
2 2 2 2
BH·SMe, then H O , NaOH (72%); (h) Piv-Cl, pyridine (87%); (i) dihydrophenanthrene 48. Future adjustments in the strate-
3 2 2 2
(CHOH), TsOH (cat.), toluene, D (50%). gy toward morphine therefore should rely on derivatives
2 2
of 42 substituted at the 3-position. Such functionalization
Synthesis of the complete pentacyclic skeleton was ac- would serve a double purpose: to provide the required
complished by the introduction of the tosylamide moiety carbons for the ethylamino bridge (ring D) and, more im-
in two steps followed by reductive detosylation with con- portantly, to prevent the aromatization of ring C following
comitant cyclization14 to give the ethylene ketal of (–)- the removal of the cobalt complex. One can assume that
dihydrocodeine 39 (Scheme8). The key intermediate 39 the stereochemical fate of C-13 center in such functional-
was prepared in 12 steps from the bicyclic ketone 30 in ized benzofurans will parallel that observed in the forma-
6% overall yield. tion of 47.
Synlett 2005, No. 3, 388–405 © Thieme Stuttgart·New York
394 J. Zezula, T. Hudlicky ACCOUNT
OH X three days in the presence of the lipase PS (Pseudomonas
cepacia, Amano) provided the enantiopure acetate of (+)-
CO2H
(R)-49 (47%) along with the enantioenriched alcohol (–)-
TMS (S)-49 (97% ee, 48%). The diastereoselective synthesis
a–c d
described below was carried out with the racemate of 49.
O O O
The C-13 quarternary center was constructed by a radical
OMe OMe OMe cyclization of the Stork bromoacetal, which was intro-
44 45
duced by alkylation of 49 with ethyl vinyl ether in the
42a X = OH
e presence of N-bromosuccinimide to provide the key pre-
42b X = OTMS cursor 50. With the C-13 center set, the cyclic hemiacetal
f–h
was oxidized to lactone 51.
O
Reductive cleavage and selective protection of the prima-
X NH2 N
ry alcohol as its pivalate allowed the conversion of the
secondary alcohol to its xanthate, the pyrolysis of which
i TMS k,l in the original b-configuration in 51 did not yield the de-
sired olefin. The stereochemistry of the secondary alcohol
O O O was inverted by an oxidation–reduction sequence to give
the a-isomer 52 (Scheme12). The xanthate derived from
OMe OMe OMe
52 eliminated upon pyrolysis to give olefin 53. Allylic ox-
42c X = NH2 46 42e idation of 53 provided the corresponding enone, which
j
42d X = NMe2 was treated with allyl trimethylsilane under Sakurai’s
conditions to give 54.33 The phenanthrene core of mor-
Scheme 10 Reagents and conditions: (a) EtSH, DMAP, DCC,
phine was completed by oxidative cleavage of the olefin
CH Cl, 0–23°C (99%); (b) TES, 10% Pd/C, CHCl (88%); (c)
2 2 2 2
TMSCCLi, THF, –78°C to 23°C (79%); (d) aq 10% KOH, THF in 54, followed by cyclization under acidic conditions in
(100%); (e) (TMS) NH, TMSCl, toluene, D (90%); (f) MsCl, pyri- the presence of ethylene glycol to furnish the tricyclic
2
dine, –15°C to 23°C (99%); (g) NaN3, DMF, 23°C (94%); (h) ketal 55 (Scheme12).
SnCl·2HO, MeOH, 23°C (100%); (i) BnMeNF, THF, 23°C
2 2 3
(92%); (j) aq 37% HCHO, NaBHCN, MeCN, 23°C, then HOAc,
3
23°C (37%); (k) Ac2O, pyridine, CH2Cl2 (90%); (l) KOH, MeI, MeO MeO
DMSO, 23°C (97%).
Br
MeO a MeO b,c
MeO OH O OEt
X
49 50
a O
X MeO MeO MeO
O
OMe TMS TMSCoCp MeO h,i MeO d–g MeO O
42 47 OH O
OPiv
MeO
a, X = OH (63%)
b, X = OTMS (53%) 53 PivO 52 51
c, X = NH2 (66%) HO
d, X = NMe2 (43–72%) b
e, X = NMeAc (58–70%) 47e MeO MeO
NMe
Ac OPiv
TMS j,k MeO OPiv l–n MeO
TMS 48
H
Scheme 11 Reagents and conditions: (a) BTMSA, CpCo(CH),
2 42
EtO, 0°C or 23°C; (b) Fe(NO )·9H O, HO–MeCN–THF, –78°C
2 33 2 2 O O
to 23°C (92%). O 54 55
Scheme 12 Reagents and conditions: (a) ethyl vinyl ether, NBS,
3.2 Ogasawara
EtO (96%); (b) BuSnH, AIBN, benzene (48%); (c) MCPBA,
2 3
BF·OEt (89%); (d) LiAlH, THF (98%); (e) Piv-Cl, pyridine; (f)
In 2000 Ogasawara reported an interesting synthesis of 3 2 4
PDC, CH Cl, (96%); (g) NaBH, i-PrOH (82%); (h) MeI, CS, NaH;
3,4-dimethoxy-7-morphinanone21 starting from rac-2- 2 2 4 2
(i) o-CHCl, D (73%); (j) CrO·3,5-(Me)pyrazole (81%); (k)
(2,3-dimethoxyphenyl)cyclohexen-1-ol (49),7a,40 which CH CH6=C4H2TMS, TiCl, CHCl (731%); (l) (C2H OH), TsOH (cat.),
2 2 4 2 2 2 2
was resolved by an established protocol.40 Stirring rac-49 benzene, D (97%); (m) OsO (cat.), NaIO (83%); (n) (CH OH),
4 4 2 2
with vinyl acetate (1.0 equiv) in t-butyl methyl ether for TsOH (cat.), benzene, D (85%).
Synlett 2005, No. 3, 388–405 © Thieme Stuttgart·New York
ACCOUNT Recent Progress in the Synthesis of Morphine Alkaloids 395
The ethyl amino bridge was introduced in three steps: the duction, conversion to a carbamate, and oxidation with
reductive deprotection of the pivalate, conversion of the concomitant 1,3-transposition, as was done in his ap-
alcohol to sulfonamide 56 by the Mitsunobu reaction, and proach to dihydrocodeinone. The quaternary center in 62
the radical closure of the D-ring according to Parker’s was constructed by the regioselective 1,4-addition of an
conditions14 (reductive desulfonation followed by an in- aryl cuprate to the enone in 61 (Scheme14).
tramolecular cyclization, Scheme13). Hydrolysis of the
When ketone 62 was heated in benzene in the presence of
ketal to ketone 57 completed the synthesis of the tetracy-
p-toluenesulfonic acid and ethylene glycol cleavage of the
clic morphinan. Structural correlation with a known mate-
bicyclic ring system occurred to give intermediate alde-
rial was carried out by the conversion of 57 to its a-
hyde 63, which underwent cyclization, presumably via the
diketone monothioketal 58, which was reduced and pro-
quinone methide 64. Surprisingly, an intramolecular nu-
tected as the acetate 59 (Scheme13). The dithiane moiety
cleophilic attack of the carbamate nitrogen provided tetra-
was cleaved under oxidative conditions and the a-acetate
cycle 65, instead of the expected formation of C-9/C-10
was reductively removed by treatment with samarium(II)
double bond (Scheme14).
iodide to give the racemic morphinan 60, corresponding
Carbamate 65 was therefore reduced and subjected to sub-
to the known O-methylated derivative of Gates’s
sequent sulfonation with phenylsulfonyl chloride, result-
ketone.6,10 The unoptimized synthesis of 60 from alcohol
ing in the eliminative ring cleavage to give olefin 66
49 required 23 steps and proceeded with an overall yield
(Scheme15) possibly through the intermediacy of a
of 0.8%.
quinone methide. This result suggests that the formation
of 65 may have been avoided by allowing the initial reac-
tion to proceed under equilibrium conditions where the
MeO MeO
expected olefin might have formed from 64. Ring D was
closed using the well-established reductive protocol of
MeO MeO
Parker,14 followed by deprotection of the ketal moiety to
55 a,b NMeTs c,d NMe give ketone 67.
In order to complete the synthesis, the oxidation state of
O O the C-ring had to be adjusted. This was accomplished by
56 57 O reaction of ketone 67 with trimethylenedithiotosylate in
e the presence of base to give dithiane 68. The synthesis
was completed by oxidative cleavage of the thioketal fol-
lowed by installation of the a-methoxyenone. (–)-O-
MeO MeO
Methylpallidinine (69) was thus prepared in 12 steps from
the chiral building block 30 in an overall yield of 5% after
MeO MeO
i f–h correction for the recovered starting material isolated after
NMe NMe the final step (Scheme15).
S
O
S 3.3 Cheng
MeO OAc O
59 58
In 2000 Cheng published a total synthesis of rac-desoxy-
MeO codeine-D featuring an intramolecular Heck coupling as
the key step.20 Readily available substituted tetrahydro-
NMe isoquinoline derivative 70 was alkylated with methyl io-
O 60 dide and reduced with sodium borohydride to give the
desired octahydroisoquinoline skeleton.
Scheme 13 Reagents and conditions: (a) LiAlH , THF; (b)
4
MeNHTs, BuP, 1,1¢-(azodicarbonyl)dipiperidine (84%); (c) Na, The tertiary amine was converted to its carbamate and the
3
naphthalene, THF (89%); (d) TsOH, aq acetone (97%); (e) pyrroli- acetate hydrolyzed to alcohol 71. The aryl ether was intro-
dine, benzene, then TsS(CH2)3STs, Et3N (73%); (f) NaBH4, MeOH duced under Mitsunobu’s conditions to provide 72, the
(97%); (g) AcO, EtN (96%); (h) PhI(OTFA), aq MeCN (61%); (i)
2 3 2 precursor for the Heck cyclization (Scheme16). Alde-
SmI, THF (37%).
2 hyde 72 was reduced and the tertiary C-13 center was es-
tablished by Heck coupling in moderate yield (46%); the
Ogasawara has also reported a total synthesis of morphi- yield was significantly increased by the protection of the
nan alkaloid (–)-O-methylpallidinine,36 which possesses benzylic alcohol as the t-butyl dimethylsilyl ether 73 prior
the B/C-trans-hydrophenanthrene framework. The strate- to the Heck coupling. Tetracyclic enamine 74 was trans-
gy employed the versatile bicyclic enone 30. In this ap- formed to benzyl chloride 75 in two steps.
proach to morphinan skeleton, the nitrogen atom was
The attempted closure of ring B by palladium-catalyzed
introduced early in the synthesis by the condensation of
cyclization of the benzyl chloride onto the olefin resulted
the lithium salt of acetonitrile with the carbonyl in 30. The
in N-benzylation, and 76 was isolated. This setback
product was transformed in three steps to enone 61 via re-
was rectified by methylation of the amine to give the
Synlett 2005, No. 3, 388–405 © Thieme Stuttgart·New York
396 J. Zezula, T. Hudlicky ACCOUNT
OMe
O MeO
O a–d e O
R
O O
MOM MOM NH NH
R O
30 61 62
MOM
R = CO2Me
f
OMe OMe OMe
MeO MeO MeO
R
N
CHO
OH NH OH NH
O R R
O O
O
65 64 63
Scheme 14 Reagents and conditions: (a) MeCN, BuLi, THF, –78°C, (92%); (b) LiAlH, THF; (c) ClCOMe, EtN, CHCl (75%, 2 steps);
4 2 3 2 2
(d) PCC, CH Cl (89%); (e) 3,4-(MeO) CHMgBr, CuBr·SMe , TMSCl, HMPA, THF, then TBAF (75%); (f) (CHOH), TsOH (cat.), toluene,
2 2 2 6 3 2 2 2
D (77%).
OMe OMe MeO CHO
MeO MeO OAc OH
Me a–d e O Br
a,b c,d
65 NSO2Ph N N
CO2Et
NMe N
O 70 71 72 CO2Et
66 O 67 f,g
O
e
MeO OTBDMS
OTBDMS MeO
OMe OMe
MeO MeO O NCO2Et h O Br
i,j
f,g
N
74 73 CO2Et
NMe NMe
MeO O MeO MeO MeO
69 S S 68
O Cl k l,m
O NCO2Et O N O
Scheme 15 Reagents and conditions: (a) LiAlH , THF, D (95%); (b)
4 N
PhSO Cl, EtN, CHCl, 0°C to r.t. (82%); (c) Li, NH, t-BuOH,
2 3 2 2 3 Me
THF, –78°C (76%); (d) TsOH (cat.), aq acetone, D (90%); (e) pyrro-
lidine, CH(CH STs) (76%); (f) MCPBA, –30°C then dilute HCl, D 75 76 77
2 2 2
(69%); (g) TsOH, MeOH, D (44%, based on recovery of starting
Scheme 16 Reagents and conditions: (a) MeI, CHCl, r.t.; (b)
material). 2 2
NaBH , MeOH (85%); (c) ClCOEt, KHCO , DCE, D; (d) NaOH,
4 2 3
MeOH (86%); (e) 2-bromoisovanillin, DEAD, n-BuP, THF (85%);
3
(f) NaBH , MeOH (88%); (g) TBDMSCl, imidazole, THF; (h)
4
Pd(OAc), PPh, EtN, MeCN (62%, 2 steps); (i) TBAF, THF (95%);
2 3 3
corresponding quarternary salt, which upon exposure (j) NCS, PPh , THF (96%); (k) Pd(PPh), EtN, MeCN, (59%); (l)
3 34 3
to phenyllithium underwent Stevens’ rearrangement to MeI, CHCl; (m) PhLi, EtO (83%, 2 steps).
2 2 2
afford rac-desoxycodeine-D (77) in good yield
(Scheme16).
Synlett 2005, No. 3, 388–405 © Thieme Stuttgart·New York
ACCOUNT Recent Progress in the Synthesis of Morphine Alkaloids 397
3.4 Passarella 3.5 Hudlicky
Passarella’s 2002 synthesis41 of 7,8-didehydro-6-mor- In 1999 we published an enantioselective synthesis of oc-
phinanone utilized the Grewe cyclization,8 a well-estab- tahydroisoquinoline intermediate 89 (Scheme18).45 The
lished synthetic sequence, as the key step. Condensation homochiral diol 87 was obtained in two steps from phen-
of neat 3-methoxyphenethylamine (78) with 3-benzyloxy- ethyl bromide 86 by whole-cell fermentation with E. coli
phenylacetic acid (79) gave the corresponding amide, JM 109 (pDTG 601)46 to give corresponding cyclohexadi-
which was cyclized under Bischler–Napieralski condi- ene diol, which was regioselectively reduced by diimide.
tions. Diol 87 was protected as the dibenzoate then treated with
oxazolidine-1,4-dione. Partial reduction of the oxazoli-
Reduction of the adduct to the corresponding tetrahy-
dine-1,4-dione moiety with sodium borohydride in meth-
droisoquinoline and Birch reduction provided, after the
anol gave the cyclization precursor 88. Hemiaminal 88,
formylation of the nitrogen atom, the key cyclization pre-
upon exposure to aluminium chloride in methylene chlo-
cursor 80. Grewe cyclization of 80 gave ketone 8142 in
ride, furnished a mixture of cis- and trans-decahydroiso-
good yield, and tetracycle 82 was attained following the
quinoline chlorides, which were subjected to elimination
hydrolysis of the formyl group and reductive amination
to give the tetrasubstituted olefin. Hydrolysis of the ben-
(Scheme17). Phenol 82 was converted to tetrazole deriv-
zoates yielded diol 89, which was used as a starting mate-
ative 83, which was hydrogenated over Pd/C in formic
rial in our new study of introducing the aryl ether at C-5
acid to give the corresponding deoxygenated aromatic
with the correct stereochemistry.
compound.42,43 Bromoketalization44 provided 84 and fur-
ther adjustments led to rac-7,8-didehydro-6-morphin-
anone (85) in a total of 13 steps and overall yield of 3.1%. Br OH
HO
a,b
MeO
MeO + CO2H a–e N 86 87 Br c–e
CHO
NH2
80
OH
OBz
78 79
HO
OBn BzO
f–h
Ph f OH N
N N O N O
HO
N O
O
O N OH OH 89 88
Scheme 18 Reagents and conditions: (a) E. coli JM 109 pDTG601;
(b) potassium azodicarboxylate, HOAc, MeOH (80%); (c) BzOH,
i g,h DCC, CH2Cl2 (83%); (d) oxazolidine-1,4-dione, (Me2N)2CNH, THF
(77%); (e) NaBH, MeOH (80%); (f) AlCl, CHCl (57%,
4 3 2 2
NMe NMe N cis:trans=3.7:1); (g) DBU, DMSO, 100°C (25%); (h) MeONa,
H H H MeOH, THF (85%).
CHO
O O O
83 82 81
To accomplish the attachment of the aryl fragment, diol
89 was monotosylated at C-6 (morphine numbering) to
90. The recovered starting material was recycled to im-
prove the overall yield of this step. Next, the benzoate was
j,k
introduced via the Mitsunobu reaction27 to give the trans-
l,m
tosylate-benzoate 91, which was converted to epoxide 92
by treatment with methanolic sodium methoxide in tet-
NMe NMe
O H H rahydrofuran (Scheme19). Opening of epoxide 92 with
O the potassium salt of bromoguaiacol gave corresponding
O
Br 84 85 aryl ether 93, with the correct stereochemistry at C-5. Pro-
tection of the alcohol as t-butyl dimethylsilyl ether gave
Scheme 17 Reagents and conditions: (a) 200°C, 5 h (80%); (b)
PCl, CHCl, r.t. (67%); (c) NaBH, MeOH (97%); (d) Li, NH , cyclization precursor 94 (Scheme19).
5 2 2 4 3
THF–t-BuOH, –78°C (95%); (e) HCO2Et, DMF (95%); (f) 80% The crucial C-13 quarternary center was established by an
H SO , Et O, 25°C (82%); (g) HCl, MeOH (96%); (h) HCHO,
2 4 2 intramolecular Heck coupling of 94, which led to the pen-
Pd/C (40%); (i) 5-chloro-1-phenyl-1H-tetrazole, K CO, DMF
2 3 tacyclic morphinan 95, which has the correct stereochem-
(65%); (j) H, HCOH, Pd/C (74%); (k) (CHOH), Br , 70°C (50%);
2 2 2 2 2
(l) t-BuOK, DMSO, 85°C; (m) 3 N HCl, MeOH (87%). istry at C-5, C-13 and C-9 and the neopine-type
unsaturation required in the C-ring of morphine. Reduc-
tive cleavage of carbamate 95 provided the amino alcohol
96,47 which is set up for the C-10–C-11 closure of the B-
ring to complete the carbocyclic skeleton of morphine.
Synlett 2005, No. 3, 388–405 © Thieme Stuttgart·New York