-
Tetrahedron:
Tetrahedron: Asymmetry 15 (2004) 1203–1237
Asymmetry
TETRAHEDRON: ASYMMETRY REPORT NUMBER 63
Synthetic pathways to salsolidine
Teodoro S. Kaufman*
Instituto de Qu�ımica Org�anica de S�ıntesis (CONICET-UNR) and
Facultad de Ciencias Bioqu�ımicas y Farmac�euticas,Universidad
Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina
Received 5 January 2004; accepted 6 February 2004
Dedicated to Professor Edmundo A. R�uveda on occasion of his
70th birthday
Abstract—Salsolidine is a simple 1-substituted
tetrahydroisoquinoline isolated from many natural sources as the
racemate and in itsenantiomeric modifications. The wide variety of
synthetic strategies leading to this natural product, mainly in its
optically activeforms, is discussed.� 2004 Elsevier Ltd. All rights
reserved.
Contents
* Tel./fax:
0957-4166/
doi:10.101
1. Introduction 1204
2. Isolation, natural occurrence, and interaction of salsolidine
with biomolecules and biological
systems 1205
3. Synthetic strategies leading to salsolidine in racemic form
1207
4. Syntheses of the salsolidines in their optically active forms
1210
4
+54
$ - s
6/j.te
4.1. Resolution of racemates and separation of diastereomeric
mixtures 1210
4.2. Hydride reduction and catalytic hydrogenation of C@N and
C@C double bonds 1211
4.2.1. General 1211
4.2.2. Enantioselective reduction of 3,4-dihydroisoquinolines.
Chiral borohydrides 1212
4.2.3. Diastereoselective reduction of chiral activated
azomethines
(chiral iminium ions) 1213
4.2.4. Enantioselective borane reduction of azomethines
activated
with chiral Lewis acids 1214
4.2.5. Catalytic enantioselective reduction of
1-alkyl-3,4-dihydroisoquinolines 1216
4.2.6. Diastereoselective catalytic hydrogenation or hydride
reduction
of chiral enamides 1219
4.2.7. Enantioselective reduction of enamides with chiral
catalysts 1220
4.3. Metallation of tetrahydroisoquinoline derivatives 1222
4.3.1. Diastereoselective alkylation of metallated chiral
tetrahydroisoquinoline
derivatives 1222
4.3.2. Enantioselective protonation of metallated
tetrahydroisoquinoline derivatives 1223
.4. Alkylation of azomethines 1223
4
4.4.1. Enantioselective alkylation of azomethines in the
presence of
chiral auxiliaries 1223
4.4.2. Diastereoselective alkylation of chiral activated
azomethines
(chiral iminium ions) 1226
.5. Syntheses employing organochalcogen derivatives 1232
5. Conclusion 1233
Acknowledgements 1234
References and notes 1234
-341-4370477; e-mail: [email protected]
ee front matter � 2004 Elsevier Ltd. All rights
reserved.tasy.2004.02.021
mail to: [email protected]
mail to: [email protected]
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1204 T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004)
1203–1237
1. Introduction
Isoquinolines comprise of the largest family of
naturallyoccurring alkaloids, being found abundantly but
notexclusively in the plant kingdom. The
1-substitutedtetrahydroisoquinolines constitute an important
groupamong the isoquinolines; while many of them have beenisolated
as both of their enantiomers from independentsources or just as the
racemate, most of these naturalproducts have been characterized as
only one enantio-mer with either the (1S)-absolute configuration
orthe opposite (1R)-geometry. The construction of
the1,2,3,4-tetrahydroisoquinoline ring system has been apopular
area of research in natural products chemistrysince the early
1900s, with activity in this field almost asold as the discovery of
the isoquinoline system itself.
Despite its simplicity, the elaboration of the isoquinolinering
has been approached in various ways. In a sys-tematic
classification of the methods for the synthesis ofthe isoquinoline
ring system, Kametani1 described fivedifferent types, according to
the mode of formation ofthe pyridine ring (Fig. 1). The first type
involves the ringclosure between the carbon atom, which constitutes
theC-1 position of the isoquinoline and the aromatic ring,while in
the second type the heterocycle is formed be-tween C-1 and the
nitrogen. Type 3 necessitates C–Nbonding between the nitrogen and
the atom, whichforms the C-3 position in the resulting
isoquinoline.
N N NN N
Type 1 Type 3 Type 5Type 2 Type 4
Figure 1. Classification of the synthetic strategies toward the
iso-
quinoline ring system, according to Kametani.N
MeO
MeOMe
HN
MeO
MeOMe
H
1S-(-)-Salsolidine, (-)-1 1R-(+)-Salsolidine, (+)-1
1 2
345
6
78
N
MeO
MeOMe
HN
MeO
MeOMe
H
1S-(-)-Salsolidine, (-)-1 1R-(+)-Salsolidine, (+)-1
1 2
345
6
78
Figure 2.
Likewise, the fourth type involves cyclization at the C-3and C-4
level while the fifth type is meant to describe theprocess in which
the isoquinoline ring is concluded bythe generation of a C–C bond
between the aromaticmoiety and the C-4 position. Although the
literaturerecords examples of all of the five types, synthetic
pro-tocols of types 1, 2, and 5 have been demonstrated to bethe
most widely used for the elaboration of
tetrahy-droisoquinolines.
Among the protocols of the currently available meth-odological
arsenal, some are only suitable for thesynthesis of 1-substituted
tetrahydroisoquinolines asracemic compounds, while others, in spite
of havingbeen tested for only one enantiomer, can provide eachone
of the constituents of the enantiomeric pair of 1-substituted
tetrahydroisoquinolines, in some cases withtheir absolute
stereochemistry known in advance.
The enantioselective synthesis of simple isoquinolinealkaloids
was pioneered by Brossi et al.,2 Kametaniet al.,3 Yamada et al.,4
and others in the 1970s andgained strong interest as a consequence
of their initialbreakthroughs, while some simple alternatives
for
accessing tetrahydroisoquinolines in enantiomericallypure forms,
such as the resolution of racemates, can betraced back to an
earlier time. Many novel strategieshave been explored with a range
of approaches becom-ing useful over the past few years. Most
importantly, aconsiderable group of the newly developed
syntheticprotocols are general and have already found use in
theelaboration of other related alkaloids and even morecomplex
structures. A recent review by Rozwadowska5
shows the many different strategies devised for
theenantioselective synthesis of simple 1-substituted
tetra-hydroisoquinoline alkaloids.
Strikingly, as early as in 1987, Huber and Seebach6
pointed out that all possible methods of
synthesizingenantiomerically pure compounds have been applied tothe
elaboration of homochiral 1-substituted tetrahy-droisoquinolines,
including resolution, catalytic, andstoichiometric enantioselective
reactions as well as theincorporation of components from the pool
of chiralbuilding blocks.
Salsolidine 1
(1-methyl-6,7-dimethoxy-1,2,3,4-tetrahy-dro-isoquinoline, CAS
493-48-1) is a simple tetrahy-droisoquinoline alkaloid (Fig. 2),
which can be isolatedfrom different natural sources, mainly
Cactaceae andChenopodiaceae and has been the subject of
numeroustotal syntheses, both as racemate and in its
homochiralforms up to the point that nowadays, the observationmade
by Huber and Seebach also holds true for theenantioselective
synthesis of salsolidine itself, as thisreview will make
evident.
On the other hand, there are no examples recording
theelaboration of salsolidine by Kametani’s type 4 synthe-sis; only
one publication discloses the elaboration of thenatural product
following a type 3 strategy while manyreports describe the
syntheses of salsolidine in which thestarting material is already
an isoquinoline derivative,built according to one of the five above
mentioned types.
The variety of syntheses of salsolidine reported to
date,especially those leading to the natural product in
itsoptically active form, can be accounted for in manyways. First,
the cardinal significance of chiral amines inthe pharmaceutical and
agrochemical industries, as wellas their increasing importance
among flavors and fra-gances, which have placed great demand and
strongpressure for the search of new strategies for their
effi-cient and cost-effective syntheses. Thus, in light of
theresulting developments over the past 25 years and sincethe
salsolidine enantiomers have often been used astargets for testing
newly developed synthetic methods, it
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T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004) 1203–1237
1205
is not surprising that the enantioselective preparation ofthe
salsolidines has been thoroughly studied and,therefore, experienced
an enormous growth in this time.Methods for the asymmetric
preparation of amines haverecently been reviewed by Johansson.7
Secondly, the continuous expansion of the arsenal ofreagents and
reactions at the disposal of the modernsynthetic organic chemist,
coupled to the structuralfeatures and simplicity of salsolidine,
constitute anadditional reason for chemists being inclined to
preparethe natural product, especially in its homochiral forms.
On the other hand,
1-methyl-6,7-dimethoxy-3,4-dihy-droisoquinoline 2, which is readily
accessible by theBischler–Napieralski reaction,8a–e;9a as well as
by oxi-dation of salsolidine itself (81% yield) with 3 equiv
ofdiphenylselenium bis(trifluoroacetate),8f is a represen-tative
cyclic imine, which has been repeatedly employedfor testing the
efficiency, scope, and limitations of manynew hydride reducing
agents and hydrogenation cata-lysts, with salsolidine being the
expected reactionproduct of these transformations.
Moreover, the related and easily available N-acetyl en-amine
3a9a (Fig. 3) has been employed as a representa-tive enamide,
having been often used as a startingmaterial for the elaboration of
the natural product,while enamides 3b and 3c9b;c have also found
some useas starting materials for the synthesis of 1.
N
MeO
MeOMe
N
MeO
MeOCH2
2 R= Me3b R= H3c R= OMe
O
a
R
3
Figure 3.
Additionally, there is general interest in
enantiopuretetrahydroisoquinoline systems, since many
isoquinolinealkaloids exhibit valuable physiological activities
orunique structures.10 Such a situation has continuouslyattracted
the attention of the synthetic organic chemists.
Finally, multiple syntheses of salsolidine can also beconsidered
in part by the use of salsolidine itself andother related simple
tetrahydroisoquinolines as startingmaterials for the elaboration of
bioactive substances11a–c
and in biological studies,11d mostly associated to
thepathogenesis of Parkinson’s disease and other patho-genic
processes of the central nervous system.
Most of the enantioselective syntheses of salsolidinereported to
date are based on more or less subtle butgenerally highly
interesting modifications of a handful ofdifferent basic strategic
schemes, including the resolutionof diastereomeric mixtures,
stoichiometric chiralitytransfer through hydride reduction of
optically activea-alkylbenzylamine derivatives and structurally
related
compounds (chiral iminium ions), diastereoselectivehydrogenation
of chiral enamides, enantioselectivehydrogenation of imines and
enamides with chiral cat-alysts, catalytic asymmetric reduction of
imines, diaste-reoselective addition of organometallic reagents
tochiral iminium compounds, addition of organometallicsto iminium
compounds in the presence of chiral ligands,and the addition of
chiral organometallic reagents toiminium derivatives, as shown in
Scheme 1. Otherstrategies include the intramolecular addition of
aminesto chiral vinyl sulfoxides, the asymmetric Pictet–Spen-gler
reaction, and the reduction of 1-alkyl-3,4-dihydro-isoquinolines by
chiral sodium(triacyloxy)borohydrides.
The aim of this review is to consider the literature andmost
relevant advances achieved over the past 25 yearsconcerned with the
synthesis of salsolidine, emphasizingthe enantioselective
preparation of the natural product.Accordingly, synthetic
strategies are divided into pro-tocols leading to racemic
salsolidine and those furnish-ing this product in its homochiral
form. Among thelatter, the methods covered are divided into five
maincategories: (1) resolution of racemates and separation
ofdiastereomeric mixtures, (2) reduction of C@N andC@C double
bonds, (3) metallation of isoquinolinederivatives with or without
formation of new C–Cbonds, (4) alkylation of azomethines, and (5)
the use oforganochalcogen derivatives. A brief comment on
theoccurrence of salsolidine in nature, as well as a summaryof the
reported effects of salsolidine, mainly on enzy-matic systems are
also reported herein.
2. Isolation, natural occurrence, and interaction ofsalsolidine
with biomolecules and biological systems
Salsolidine was first isolated by Proskurnina and Or�e-khov from
Salsola richteri (Chenopodiaceae) as thelevorotatory enantiomer
(�)-1 [(S)-salsolidine];12 acouple of years later, the same group
reported theoccurrence of this natural product in Salsola
arbuscula.13
The originally proposed structure for the natural prod-uct was
confirmed by chemical tests and a series ofspecific rotation
measurements and mixed melting pointdeterminations with
semi-synthetic (S)-salsolidine, pre-pared via (þ)-tartaric
acid-assisted resolution of racemicsalsoline 4, followed by
methylation of the free levoro-tatory base with ethereal
diazomethane. Additionalevidence of identity was gained from mixed
meltingpoint measurements of the hydrochloride, picrate
andpicrolonate of both, natural and semi-synthetic (�)-1,which
showed no melting point depression.
Both enantiomers of the natural product, as well as theracemate,
have been isolated from natural sources.14
Thus, (R)-(þ)-salsolidine was found in the leaf, fruit,and stem
of Genista pungens (Leguminosae),15 while theracemate (or the
natural product without disclosure ofthe characteristics of its
stereogenic center) wasfound, among others, in Carnegiea gigantea
(the firstreport of its occurrence in cacti)16 and Pachicereus
-
N
MeO
MeOMe
H*N
MeO
MeO R*
N
MeO
MeOMe
N
MeO
MeOCH3
R
N
MeO
MeO
N+
MeO
MeOMe
R*
N
MeO
MeOCH2
R*
N
MeO
MeOCH2
R
N
MeO
MeOMe
(H, R*)
Resolution
R*M or RM/L*
Na(OAc)3BH
L*M/H2
BuLi/MeI
R'M/L*
H2,catalyst
L*M/H2LA*, BH3
NaBR*3H
NaBH4
Scheme 1.
1206 T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004)
1203–1237
pectenaboriginum (Cactaceae) from Mexico and USA,16
Bienertia cycloptera,17 Corispermum leptopyrum,18
Salsola kali,19 S. soda,20 and S. ruthenica20 from Poland,Hamada
articulata ssp. Scoparia,21 Haloxylon articula-tum,22 and H.
scoparium (Chenopodiaceae), as well as inthe stem of Alhagi
pseudalhagi from India,23 and Cal-ycotome spinosa,24 Desmodium
cephalotes,25 and D. tili-aefolium15 among the Leguminosae. The
recentdetection of trace amounts of salsolidine and othersimple
tetrahydroisoquinolines in Neobuxbaumia mul-tiareolata, N.
scoparia, and N. tetetzo (Cactaceae)employing GC–MS techniques is a
finding with highchemotaxonomic significance; it suggests that
genusCarnegiea is different from Neobuxbaumia and is prob-ably
derived from it.26
Relevant physical properties and spectral data of thenatural
product in racemic and homochiral formshave been recently compiled
by Shamma et al.27a ItsNMR spectra were interpreted27a–c as well as
its massspectrum27d and other relevant data being disclosed.27e
Additionally, its chiroptical properties were examined aspart of
the development of a new semiempirical quad-rant rule based on
one-electron theory, useful forpredicting the configuration of
1-methyl tetrahydroiso-quinolines.28 Finally, X-ray diffraction
data of thehydrochloride hydrate as well as the
hydrochloridedihydrate have also been published.29
Experiments using tissue-cultured cells from Calluspallida var.
tenuis and Callus incisa fed with (�)-[1-D
and 1-methyl-CD3]-salsolinol (salsolinol-D4), allowedthe HPLC,
mass spectra, and 1H NMR detection ofminor amounts of salsolidine
among the resultingmetabolites; it was also shown that
(�)-salsolinol 5metabolized to produce salsolidine, among other
relatedtetrahydroisoquinolines, in the tissue-cultured cells
ofCorydalis ochotensis var. raddeana, Corydalis ophio-carpa, and
Macleaya cordata R. Br. Moreover, it wasfound that (�)-5
metabolized in live whole plants withresults similar to those
observed in tissue-culturedcells.30a
Furthermore, by using an LC/API-MS system, it wasshown that
3,4-dihydroxy-phenethylamine (dopamine)condenses with acetaldehyde
to give salsolinol 5, whichis further metabolized to produce
6-O-methylsalsolinol6a (isosalsoline), which in turn, is O- and
N-methylatedto provide salsolidine 1 and N-methylisosalsoline
6b,respectively, in several plant tissue cultures of Papaver-aceae
(Fig. 4).30b
The earliest preparations of 1 in homochiral form weremade by
the chemical manipulation of products ac-cessed by classical
Bischler–Napieralski8a–e as well asPictet–Spengler31 condensations,
which furnished theracemate, followed by resolution with
(þ)-tartaricacid.12 It was Battersby and Edwards in the early
1960swho unequivocally determined that natural (�)-salsol-idine had
an (S)-configuration, by its degradation
to2-carboxyethyl-LL-alanine and comparison with thisaminoacid
derivative.32
-
N
MeH
HO
MeON
MeH
HO
HO
N
MeMe
MeO
MeON
MeR
MeO
HO
4 5
S-(-)-7R= H, R-(+)-6aR= Me, R-(+)-6b
Figure 4.
T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004) 1203–1237
1207
Some efforts toward the measurement of salsolidine asan analyte
have already been published. Interestingly, aspectrophotometric
assay of 1 based on its reaction withammoniacal copper sulfate in
carbon disulfide, leadingto the production of a
copper–dithiocarbamate complexsoluble in benzene, has been
reported. The complex canbe extracted from the reaction medium and
measured atits absorbance maximum of 448 nm.33a An
alternativespectrophotometric procedure for the quantification of
1and 4 was disclosed earlier by Russian authors33b withthe
fluorometric determination of salsolidine as animpurity in the
preparations of 4 also being reported.33c
Interestingly, the HPLC separations of the enantiomersof
salsolidine as N-a-naphthoyl (a ¼ 1:21)34a and N-b-naphthoyl (a ¼
1:83)34b derivatives, employing 3,5-dini-trobenzoyl phenylglycine
and
(S,S)-[N-(3,5-dinitro-benzoyl)]-amino-3-methyl-1,2,3,4-tetrahydrophenanth-rene-based
chiral stationary phases, respectively, wererecently reported.
However, the chiral HPLC with b-cyclodextrin as chiral selector was
unable to separatesalsolidine enantiomers as previously reported
byStammel et al.34c Additionally, the production of highlyspecific
antibodies, with a high affinity against (�)-sal-solidine (K ¼ 1:5�
109 M�1) by immunization of rabbitswith bovine serum
albumin–salsolidine conjugates, wasdemonstrated.34d These
antibodies were employed todevelop a radioimmunoassay for the
alkaloid and thusmay find use in the determination of trace amounts
oftetrahydroisoquinolines in organic tissues and
biologicalfluids.
Several biological activities have been ascribed to (orinvolved)
the natural product. A study by Oxenkrugdemonstrated that 1 and
other alkaloids such as 4 (Fig.4) and papaverine, inhibit the
uptake of 5-hydroxytryptamine by human blood platelets,35 showing a
30–60% inhibition at a concentration of 10�4 M. The ste-reospecific
N-methylation of (S)-1 [to (S)-(�)-carnegine,7] and of the
endogenous alkaloid (R)-isosalsoline (R)-6a by the enzyme amine
N-methyl transferase frombovine liver has been shown by Bahnmaier
et al. Thisgroup found the enantiomers (S)-1 and (R)-6a to bethose
preferentially methylated.36 These authors alsorevealed that
certain tetrahydroisoquinolines are capa-ble of mimicking direct
but not receptor-mediatedinhibitory effects of estrogens and
phytoestrogens on
testicular endocrine function; salsolidine, however,was
ineffective in this assay.37 Moreover, Brossi et al.studied the
effect of simple isoquinoline alkaloids onmonoamine oxidase (MAO)
inhibition, finding that 3,4-dihydroisoquinolines were more potent
than isoquino-lines and their 1,2,3,4-tetrahydro- congeners in MAO
Ainhibition, while only a few heterocycles inhibited MAOB. Among
the dihydro- and tetrahydroisoquinolines, astereoselective
competitive inhibition of MAO A causedby the (R)-enantiomers was
observed. These results weresupportive of the view that the
topographies of MAO Aand MAO B inhibitor binding sites are
different.38
Salsolidine was also reported to inhibit competitively
themethylation of the catecholamine metabolite
3,4-di-hydroxybenzoic acid by an enriched rat liver prepara-tion of
the enzyme catechol-O-methyltransferase, withKi ¼ 0:19mM.39 Dostert
et al.40 reviewed the role ofdopamine-derived alkaloids in
alcoholism and Hun-tington’s disease and the group of Airaksinen,
afterstudying the binding of b-carbolines and
tetrahydro-isoquinolines to opiate receptors of the d-type,
con-cluded that tetrahydroisoquinolines, like salsolidine,with Ki
values higher than 100 lM, were less potent thanb-carbolines and
that opiate receptors do not appear tobe the major sites of action
of simple tetrahydroiso-quinolines.41a The neurotoxicity of several
tetrahydro-isoquinoline derivatives against SH-SY5Y cells has
alsorecently been studied; salsolidine proved to be lessneurotoxic
than the dihydroxylated compound 5, con-trasting with the tendency
observed among the mono-substituted 1-methyl
tetrahydroisoquinolines.41b On theother hand, a trimethoprim
analogue made by theincorporation of a 2,4-diaminopyrimidine unit
tothe salsolidine nucleus provided an active dihydrofolatereductase
inhibitor41c and
phenylpropionylamido-diph-enylalkyl-tetrahydroisoquinolines,
including the salsoli-dine moiety, have been reported as
luteinizing hormonereleasing hormone (LHRH) antagonists.41d
Dibenzo-18-crown-6 derivatives of salsolidine, prepared by
conden-sation of the crown acid dichloride with the naturalproduct,
have also been described.41e
3. Synthetic strategies leading to salsolidine inracemic
form
Racemic salsolidine has been elaborated in several
ways,including the reduction of isoquinolines and their
ben-zopyrylium precursors, metallation–alkylation of
tetra-hydroisoquinoline derivatives and modifications of
theclassical Bischler–Napieralski, Pictet–Spengler,
andPomeranz–Fritsch isoquinoline syntheses.
Despite that racemic salsolidine (�)-1 being the result ofmany
published syntheses, some of these can be modi-fied in order to
become synthetic protocols suitable forthe elaboration of
salsolidine in optically active form,transforming this into a
highly attractive test field fornovel synthetic methodology.
Contemporary with the Minter synthesis of N-carb-oxymethyl
salsolidine 8 from 1-methyl-6,7-dimethoxy
-
N
MeCO2Me
MeO
MeON
Me
MeO
MeO
N
CNCO2Et
MeO
MeON
H
MeO
MeO
8
10 11OH
9
Figure 5.
O+
MeO
MeOMe
N+
MeO
MeOMe
Bn
N
MeO
MeOMe
Bn
1. BnNH22. HClO4
NaBH4
H2, Pd/C
(±)-1
12 13
14
N
MeO
MeOMe
H
ClO4-
Scheme 2.
1208 T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004)
1203–1237
isoquinoline 9 by DIBAL-H mediated reduction of
itsisoquinoline–borane complex and subsequent reactionwith methyl
chloroformate (Fig. 5),42 Rozwadowskaand Br�ozda described the
synthesis of (�)-1 by inter-mediacy of
6,7-dimethoxy-2-ethoxycarbonyl-1,2-di-hydroisoquinaldonitrile 10, a
Reissert compound,43
which proved to be a convenient starting material forthe
elaboration of related 1-substituted tetrahydroiso-quinoline
natural products, such as the ubiquitous caly-cotomine 11 and
carnegine 7.
The reaction of 2-benzopyrylium salts with amines hasbeen
reported by Russian scientists as an alternativeapproach to (�)-1.
In their sequence, submission
of6,7-dimethoxy-1-methyl-2-benzopyrylium salt 12 to areaction with
benzylamine formed a mixture of thecorresponding N-benzyl
isoquinolinium salt 13, isolatedas the perchlorate, and the related
naphthylamine(Scheme 2); reduction of the former with sodium
boro-
HN
MeO
MeOMe
S N+
MeO
MeOS
MeO
N
MeO
MeOCH2 O
Me
MeO
MeOM
N
MeO
MeOO
t-Bu
MeO
MeOM
15 17
Raney Nickel
BrCH2COCl
3a 1
20 21a R=21b R
No
(98%)
(71%)
(96%, de
1. t-BuLi, TMEDA, THF, -40ºC
2. MeI
(99%)
Scheme 3.
hydride to N-benzylsalsolidine 14,44a followed by
hy-drogenolytic cleavage of the N-benzyl group affordedthe natural
product, albeit in a moderate overall yield.44b
As an example of the usefulness of thio N-acyliminiumions as
electrophilic partners in cationic p-cyclizations,Padwa et al.45
have recently shown that the reactiveN-acyliminium ions, formed
from thioamides like 15and bromoacetyl chloride, can react with
activated p-nucleophiles in the form of an appropriately
substitutedaromatic ring tethered on the nitrogen of a
thioamide.Upon cyclization, the resulting N,S-acetals can be
fur-ther manipulated leading to different products; amongthem
1-substituted tetrahydroisoquinolines.
A Kametani type 1 formal synthesis of salsolidine,shown in
Scheme 3, was employed to demonstrate this
N
MeO
MeOR
O
Me
N
eH
N
MeO
MeOMe O
N
e
N
MeO
MeOO
Ot-BuR
O
16 R= S18 R= S-O
Raney Nickel
H2O2
19NaOH, EtOH, reflux, 5 days
t-BuO= t-Bu
22
aAlH4, THF (76%)r TFA
= 25%)
(55%)
(95%)
10b
1. t-BuLi, TMEDA,2. MeI
(70%)
-
N
MeO
MeO H
N
MeO
MeO
N
OMe
NMe2
PhMe, 110ºC, 36 h(99%)
N
MeO
N
MeO
MeON
MeO
Li
N
MeO
MeON
MeO
Me
N
MeO
MeO HMe
NO2
OMe
23
24 25
1. H2-Pd2. Me2NCH(OMe)2
(90%)
2627
28 (±)-1
n-BuLi-100ºC
MeI (>72%)
N2H4(84%)
Scheme 4.
T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004) 1203–1237
1209
principle. To this end, thioamide 15 was converted intothe
related N,S-acetal 16 by way of an iminium ionderivative 17. In
turn, 16 was transformed into theknown N-acetyl enamine 3a with
Raney nickel, in 71%yield. As mentioned above, this enamide has
beenrepeatedly employed as a key precursor of salsolidine,including
the enantioselective synthesis of the naturalproduct.46
Recently, a Polish team led by Rozwadowska et al.47
disclosed a variant of Padwa�s group strategy in one oftheir
syntheses of (�)-salsolidine, using the
thiazo-lino[2,3-a]isoquinoline (S)-oxide 18, easily prepared inhigh
yield and 25% de (in favor of the anti-diastereomerwith an
a-oriented sulfoxide oxygen and a b-position forthe 10b methyl
substituent) by a 30% hydrogen perox-ide-mediated oxidation of 16,
as intermediate. Raneynickel treatment of sulfoxide 18, furnished
55% of N-acetyl salsolidine 19 instead of the related enamide
3a,which afforded the natural product in an almost quan-titative
yield upon basic hydrolysis.
As alternative strategies, the elaboration of
salsolidinederivatives by alkylation of a-sulfoxide carbanions
hasalso been reported47 and Indian researchers havedescribed an
AcOH-promoted Pictet–Spengler typesynthesis of (�)-1 in 60% yield
from 3,4-dimethoxy-phenethylamine, employing a perhydro-oxazine as
thecarbonyl equivalent.48 A different approach, consistingof a
heteroatom-facilitated metallation process followedby alkylation,
was taken by Coppola49a and more re-cently by Simpkins et al.49b In
the former case, N-Boc-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
22 waslithiated with the t-BuLi–TMEDA complex, leadingto N-Boc
salsolidine 21a (yield �70%), which affordedthe natural product
upon a facile TFA-mediateddeprotection.
Analogously, in the latter synthesis racemic
N-pivaloylsalsolidine 21b was obtained as part of a sequenceleading
to (�)-1, by MeI alkylation of the 1-lithioderivative of
N-pivaloyl-6,7-dimethoxy-tetrahydroiso-quinoline 20. The pivaloyl
protecting group was reduc-tively removed in high yield, by
treatment with sodiumaluminum hydride.
In a series of elegant studies, Meyers et al. experimentedduring
the 1980s and the beginning of the 1990s with thealkylation of
a-amino carbanions derived from form-amidines, the repeated
formation of salsolidine, amongother relevant targets.50 Thus,
transformamidination oftetrahydroisoquinoline 23 with formamidine
25, readilyaccessible from 2-methoxymethyl nitrobenzene 24,
fur-nished almost quantitative yield of formamidine 26.After
metallation with n-BuLi at �100 �C and alkylationwith MeI, 26
afforded the methylated derivative 28,probably through intermediacy
of lithiated species 27, inover 72% yield; final hydrazinolysis of
28 provided 84%of racemic salsolidine, as shown in Scheme 4.50a
Thechiral version of their developments in the area
ofdiastereoselective carbon–carbon bond forming strate-gies
employing chiral formamidines, is discussedbelow.
As an example of their proposed modification of theoriginal
Pomerantz–Fritsch isoquinoline synthesis lead-ing to
tetrahydroisoquinolines, Bobbitt et al.51 describeda preparation of
(�)-1 starting from veratraldehyde 29,involving methyllithium
addition to the intermediateSchiff base 30 formed by condensation
of 29 withaminoacetal, to furnish 31 (Scheme 5). Salsolidine
wasisolated in good yield as its hydrochloride salt after
Pd/C-mediated hydrogenolysis of the epimeric
tetrahydro-isoquinolin-4-ols 32, the overall sequence involving
aKametani type 5 synthesis.
The Pummerer sulfoxide rearrangement, coupled to anelectrophilic
aromatic cyclization reaction, devised byJapanese scientists,
constitute the key steps of anotherexample of a Kametani type 5
tetrahydroisoquinolinesynthetic strategy. The general protocol has
beendeveloped only recently, as a special case of the
Bobbittstrategy and thus has been explored not as extensivelyas
other classical cyclizations leading to tetrahydro-isoquinoline
derivatives. Initial work was done byTakano et al. and Sano et
al.,52 inspired in other sulf-oxide-mediated electrophilic
reactions.53
For the synthesis of (�)-1, the required N-acylsulfoxide35 was
prepared (Scheme 6) in 87% overall yield from3,4-dimethoxy
acetophenone 33. Thus, reductive
-
MeO
MeOMe
O
MeO
MeOMe
N
SPh
H
MeO
MeOMe
N
SPh
CHO
O
MeO
MeOMe
N
+SHPh
CHO
MeO
MeOMe
N
SPh
CHOMe
NH
R(±)-1
1. PhS(CH2)2NH2,(i-PrO)4Ti
2. NaBH4
1. HCOOH, Ac2O2. NaIO4, MeOH/H2O
TFAA,PhH
1. NiCl2,NaBH4
2. NaOH
33 34
35
36 37 R= H38 R= Me
(96%)
(80%)
(87%from 33)
Scheme 6.
CHO
MeO
MeO
MeO
MeON
OEt
OEt
MeO
MeON
OEt
OEt
MeH
MeO
MeON
MeH
OH
PhH, ∆(95%)
NH2OEt
OEt
MeMgBr,Et2O
29 30
31
4N HCl14-18 h
5% Pd/C
(66%)
(±)-1.HCl32
MeO
MeON
MeHHCl
Scheme 5.
1210 T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004)
1203–1237
amination of the latter with 2-phenylthioethylamineunder
titanium isopropoxide promotion54 in an EtOH–AcOH medium furnished
34, which in turn was acylatedwith mixed formyl–acetyl anhydride
and then oxidized tothe diastereomeric mixture of sulfoxides 35
with NaIO4in aqueous MeOH. Treatment of 35 with TFAA inbenzene at
room temperature for 18 h, gave 96% of the
cyclized product 36, which was reductively desulfurizedin 88%
yield with the sodium borohydride–nickel chlo-ride reagent and then
subsequently deformylated to thenatural product in 91% yield by
alkaline hydrolysis.55
In a systematic study,56 it was demonstrated that thistype of
cyclization is sensitive to the solvent and thenature of the N-acyl
substituent. In CH2Cl2, a complexmixture of products was obtained
with the formylmoiety as an N-protecting group apparently playing
animportant role in facilitating the intramolecular cycli-zation to
take place. Despite that only the elaboration ofracemic salsolidine
has been reported following thisroute to date, the strategy has
been adapted to largescale preparation of both enantiomers of
1-methyl tet-rahydroisoquinoline 3757a as well as the four
stereo-isomers of 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline38,57b
which suggests its potential applicability to anenantioselective
synthesis of salsolidine. This routeseems to be very attractive for
preparing substrates foruse in biological studies, since isotope
labeling at the C-4position is possible by reductive elimination of
thephenylthio group.
Finally, the clean indium metal-mediated reduction
of3,4-dihydroisoquinoline 2 to salsolidine in a quantitativeyield
has recently been reported by Moody et al.58a
Contrary to the outcome of related heterocyclic ringsystems when
zinc metal was employed as reducingagent, no evidence of any
dimeric products formed bycoupling of the heterocyclic rings was
found by theseauthors.58b
4. Syntheses of the salsolidines in their opticallyactive
forms
Stereoselective synthesis is one of the most relevantadvances in
synthetic organic chemistry over the last fewdecades. In addition
to the resolution of racematesthrough the formation of
diastereomeric salts with chiralacids and the separation of
diastereomeric mixturesprepared with the aid of chiral derivatizing
agents, ac-cess to salsolidines in their homochiral forms has
beenrepeatedly achieved by diastereo- and
enantioselectivesyntheses, exploiting strategies such as C@N and
C@Cdouble bond reduction (hydrogenation, hydrosilylation,and
hydride addition), C@N double bond alkylation,diastereoselective
alkylation of chiral tetrahydroiso-quinoline derivatives, and
enantioselective protonation.Other alternatives involving
enantioselective C@Oreduction and chiral aminoselenenylation have
alsosuccessfully yielded chiral modifications of the
naturalproduct.
4.1. Resolution of racemates and separation of diaste-reomeric
mixtures
The resolution of racemic salsolidine or related
simpletetrahydroisoquinolines by the formation of tartratesalts,
was the first strategy aimed at the acquisition ofthe natural
product in optically active form.12
-
N
MeH
MeO
MeO
N
MeH
MeO
MeO
N
MeH
MeO
MeO(R) N
Me
MeO
MeONH
(R)
O Me
NaOBu,BuOH
NaOBu,BuOH
OCN (R) Ph
Crystallizationi-Pr2O-CH2Cl2
(5:1)
41, Non-crystalline (44%)
40, Crystalline (46%)(-)-1
(+)-1
39
(±)-1
(74%)(S) N
Me
MeO
MeONH
(R)
O Me
Scheme 7.
N
R1
RN
R1
RSiHPh2
H+
Ph2SiH2 *
Cat.
T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004) 1203–1237
1211
A modern example of the resolution of (�)-1 by theformation of
diastereomeric mixtures was provided byBrossi et al.59 Their
strategy was based on the prepara-tion, separation, and
decomposition of diastereomericureas by a reaction of (�)-1 with an
optically activeisocyanate.
Reaction of (�)-1, prepared by the Bischler–Napieralskiroute
involving the related 3,4-dihydroisoquinoline 2,8;9
with (R-(þ)-a-phenethylisocyanate 39, furnished amixture of
diastereomeric products (Scheme 7), whichonce submitted to
crystallization in an isopropyl ether–methylene chloride (5:1)
solvent mixture, afforded thecrystalline urea 40, while its
diastereomer 41 remained inthe mother liquors; basic hydrolysis of
the purifieddiastereomers with 2M BuONa in BuOH, providedboth
enantiomers of salsolidine in around 35% overallyields each, and
enantiomeric excesses comparable tothose obtained by the tartaric
acid resolution procedure.
The same group prepared diastereomeric p-nitrophenylurea
derivatives of (�)-1 employing the known
(R)-[1-(p-nitro-phenyl)ethyl]amine as the derivatizing
agent;60a
these diastereomeric compounds were easily separatedby HPLC.
Interestingly, the same principle was alsoemployed in the opposite
sense; Russian scientists re-ported the use of (S)-salsolidine as a
reagent for theconfigurational determination of isocyanates such as
a-phenethylisocyanate, by kinetic resolution. This strategycan also
be applied to alcohols with stereogenic cen-ters.60b
N
R1
RH
PRh
P
Solvent (PhH)ClO
O
Ph
Ph
Ph
Ph
H
H *Cat.=
Scheme 8.
4.2. Hydride reduction and catalytic hydrogenation ofC@N and C@C
double bonds
4.2.1. General. Being complementary to the C@O reduc-tion, the
asymmetric reduction of heterotopic C@N
double bonds to diastereo- or enantio-enriched
aminefunctionalities is an important approach for accessingchiral
amines, as is the enantioselective reduction of theC@C double bond
of enamine derivatives.
Hydride reduction of the C@N bond of 3,4-dihydro-isoquinolines
and 3,4-dihydroisoquinolinium derivativesconstitutes one of the
first strategies, which have beenevaluated for the enantioselective
elaboration of chiral1-substituted tetrahydroisoquinolines. As it
has madestriking progress over the last two decades, driven by
theubiquity of amine groups in natural products, pharma-ceuticals,
herbicides, and other bioactive materials, itstill remains an
actively explored strategy and an activearea of research. This
topic has recently been re-viewed.61a–c
Nowadays being a core technology, catalytic enantio-selective
processes have also been explored.61d In thefield of isoquinoline
alkaloids, several examples of cat-alytic enantioselective
syntheses have appeared in theliterature by which a large quantity
of nonracemiccompounds can be secured using small amounts of
achiral catalyst. The performances of the catalysts basedon Ti, Ru,
Rh, and Ir were tested through enantiose-lective syntheses of
salsolidine. Most of them were usedto carry out C@N hydrogenations,
while others such asthose based on Rh and Ru have been employed for
thesomewhat less explored enantioselective reduction of theC@C bond
of enamides.
Although less successful, other processes have also
beeninvestigated for the enantioselective reduction of C@Ndouble
bonds. Cho and Chun were the first to report theasymmetric
reduction of N-substituted ketimine deriv-atives with
stoichiometric amounts of chiral oxazabor-olidines and borane;
however, their procedure proved tobe effective only for aromatic
ketimines, since N-substituted alkyl ketimines gave poor results
(9% ee with2-butanone-phenylimine).62
Furthermore (although it has not been applied to theelaboration
of salsolidine itself) Kagan provided the firstexample toward
catalytic enantioselective synthesis of 1-substituted
tetrahydroisoquinolines by assembling anenantioselective
hydrosilylation of 1-alkyl-3,4-dihydro-isoquinolines catalyzed by a
DIOP–Rh(I) complex(Scheme 8). The transformation, however,
proceeded atbest with a modest enantioselectivity of 39%.63
-
1212 T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004)
1203–1237
Interestingly however, Kutney et al. disclosed
that1-alkyl-3,4-dihydroisoquinolines were nonreducible
with(R)-(þ)-Cycphos-Rh, a reagent which proved useful as acatalyst
for the asymmetric hydrogenation of prochiralnoncyclic Schiff
bases, furnishing amines with up to 91%ee (enantiomeric
excess).64
N
Me
MeO
MeO
N
MeO
MeO B ON
O
Me H
O
OR H
ZnClCl
N
Me
MeO
MeO H
(-)-1
N
Me
MeO
MeO H
(+)-1
2
Re-face attack (favored)
N
OO
HOR H O
42a R= Me42b R= Bn42c R= CH2CHMe2
MeO
MeOZn
ON
O
Me
O
OR HCl Cl
NH
B
Si-face attack (disfavored)
Scheme 9.
4.2.2. Enantioselective reduction of 3,4-dihydroisoquino-lines.
Chiral borohydrides. While in the seventies theasymmetric reduction
of prochiral ketones with chirallymodified metal hydrides was
capable of deliveringoptically active alcohols with reasonable
enantiomericexcess, the asymmetric reduction of cyclic imines
stillremained unsuccessful.65
In 1971, Grundon et al. reported that the reduction
of3,4-dihydropapaverine with lithium
hydro(methyl)-dipinan-3-a-ylborate followed by a reaction with
methyliodide provided (�)-laudanosine methiodide in 8.9%ee.66
Sometime later and based on the reports of Gribbleand Ferguson,
Brown and Rao, Liberatore and Morr-acci,67a–c on the synthesis and
isolation of triacyloxy-borohydrides, Iwakuma et al. disclosed the
asymmetricreduction of cyclic imines with isolated chiral
sodiumtriacyloxy borohydrides, easily obtained from the reac-tion
of NaBH4 and 3 equiv of N-acyl derivatives ofoptically active
a-aminoacids.68 These authors improvedthe enantiomeric excess of
chiral laudanosine, reportingthe synthesis of the (þ)-enantiomer in
71% ee with thehelp of an N-benzyloxycarbonyl-proline derived
catalystin methylene chloride at room temperature. Resorting tothe
same strategy, (S)-salsolidine was acquired in 85%yield and 70% ee,
with the chiral auxiliary being recov-ered nearly
quantitatively.
By analogy with earlier observations of Reetz69 alongwith
results of the analysis of the reaction products be-tween picoline
and trifluoroacetoxyborohydrides, theformation of an intermediate
borane–amine complexupon reaction of the reductant with the
starting 3,4-di-hydroisoquinoline 2 was postulated as a first step
forthis transformation. In this proposal, products aregenerated in
a second stage by inter- or intra-molecularhydride reduction of the
imine.
Evidence favoring this proposed mechanism was gainedfrom the
reaction of trifluoroacetoxyborohydride
with1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline 2 inTHF at 0 �C,
which afforded 80% yield of the imine–
Table 1. Reduction of 2 with chiral triacyloxyborohydride 42c,
derived from
Entry no Solvent Time (h) Ad
1 THF 5 ––
2 THF 8 ––
3 Et2O 12 ––
4 CH2Cl2 144 ––
5 DME 123 ––
6 ClCH2CH2Cl 40 ––
7 THF 8 Zn
8 –– 1 Al
borane complex. Upon reflux in THF for 48 h, thisproduced
racemic salsolidine in only 30% yield.70
A recent and highly improved variation of this strategywas
contributed by Hajipour and Hantehzadeh.71 TheseIranian authors
prepared bulky triacyloxyborohydridesderived from N,N-phthaloyl
aminoacids 42a–c,72 whichinitially provided up to 78% of
salsolidine in only 71% eestarting from dihydroisoquinoline 2, when
the reactionwas run in THF at room temperature (Table 1).
Important solvent and additive effects were observed(entries
1–7), with the transformations run in THF beingthe quickest and
more selective ones; moreover, in thepresence of ZnCl2, the
selectivity of the catalyst showeda slight improvement, leading to
salsolidine in 70% yieldand 79% ee. Interestingly, however, when
this asym-metric reduction was carried out with the
reagentsimpregnated on alumina, under solid state conditions(entry
8), 90% salsolidine was produced, exhibiting aremarkable 100% ee.
In all reductions, the (S)-enantio-mer was predominant; Scheme 9
provides a mechanistic
N,N-phthaloyl valine
ditive Yield (%) Ee (%)
78 71
79 75
45 52
50 56
55 58
65 62
Cl2 (1.2 equiv) 72 80
2O3 (solid state) 90 100
-
MeO MeO RNH2
X Me
T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004) 1203–1237
1213
explanation accounting for the enhanced selectivity ob-served
when the transformation was carried out in thepresence of
ZnCl2.
COR
MeO MeON Ar
HH
Me
MeO
MeON Ar
HMe
Me
O
MeO
MeON+ Ar
HMe
Me
Cl2PO2-
MeO
MeON Ar
HMe
Me
MeO
MeON
MeH
Ac2OTEA
44a X=Y= H44b X= H, Y= Cl44c X=Y= Cl
Y
43a R= H43b R= OH
45a-c R= O46a-c R= H, H
47a-c
POCl3, PhH90ºC
NaBH4, EtOH,-78ºC(97-99%)
Pd/C, EtOH,10% HCl
48a-c
49a-c (-)-1
(97-99%)
(83-90%)
BH3.THF,BF3.Et2O
(97-99%)
Scheme 10.
4.2.3. Diastereoselective reduction of chiral
activatedazomethines (chiral iminium ions). The
stereoselectivenucleophilic addition of hydride ion to the
endocyclicC@N bond of chiral iminium ions derived from opti-cally
active amines constitutes a powerful tool for theelaboration of
saturated nitrogen heterocycles with highdiastereomeric excess. The
mechanism accounting forthat success was most probably the
stereocontrolledformation of an iminium ion–borohydride ion pair
priorto reduction, followed by a diastereoselective attack of
ahydride ion to the activated iminium moiety, with con-comitant
generation of a new stereogenic center. Facileremoval of chiral
auxiliaries was critical for the successof this strategy, leading
to products with excellent levelsof enantiomeric excess.
The numerous stereoselective syntheses of enantio-enriched
salsolidine and related alkaloids accomplishedover the past 25
years with the aid of hydride reductionof optically active iminium
ions, attest to how thisstrategy has also evolved into a chirally
efficient process,making use of various chiral auxiliaries and
reagents.The use of such a strategy can be traced back to a
seriesof studies on the syntheses of heterocyclic
compoundsperformed by Kametani et al.
This Japanese group discovered that when
N-alkyl-3,4-dihydroisoquinolinium compounds, prepared
from3,4-dimethoxyphenyl acetaldehyde 43a by the POCl3-assisted
Bischler–Napieralski closure of their N-acyl-b-phenethylamine
derivatives, were reduced with NaBH4at 0 �C or hydrogenolyzed over
10% palladiumhydroxide on charcoal, the corresponding
tetrahydro-isoquinolines were obtained in moderate yields;73
mostinterestingly, however, was the discovery that whenthe N-alkyl
groups were chiral, diastereomeric mixturesof optically active
compounds were produced. In thisway, after removal of the chiral
auxiliary, (R)- and (S)-salsolidine were accessed in 15–44% ee
employing chiraldihydroisoquinolinium precursors 48 derived from
(R)-(þ)-a-phenethylamine, (S)-(�)-a-phenethylamine
44a,(S)-(�)-a-ethylbenzylamine, and
(S)-(�)-1-(1-naphthyl)-ethylamine, being the products arising from
the chirala-methylbenzylamines those obtained in better
enan-tiomeric excess (36–44% ee). In spite of the excellentchemical
yields attained, the performance of the overallsequence in terms of
diastereoselection, however, wasrather poor.
Sometime later, while studying the conformationalpreference of
these iminium ions whose asymmetryoriginates from a stereogenic
center appended to thenitrogen atom of the iminium ion moiety,
Polniaszekand McKee74a described an interesting improvement
toKametani’s original procedure (Scheme 10). Carryingout the
reduction of the 3,4-dihydroisoquinolinium saltderived from 44a
with sodium borohydride at �78 �C,(1S)-49a was obtained in 77%
yield and 86% de. To
complete the synthesis, the N-benzyl moiety was effi-ciently
removed by palladium on carbon-mediated hy-drogenolysis.
In a further improvement, Polniaszek prepared ‘secondgeneration’
chiral amines such as (S)-(�)-1-(2-chloro-phenyl)ethylamine 44b and
(S)-(�)-1-(2,6-dichloro-phenyl) ethylamine 44c via directed
metallation of silylderivatives of commercially available
(S)-(�)-a-phen-ethylamine.75 For comparative purposes, the
chiralinductors 44a–c, which possess enhanced steric differ-ences
between the aryl and methyl groups, were incor-porated into
dihydroisoquinolinium type iminium ions48a–c.
To that end, a carbonyldiimidazole-mediated reaction of44a–c
with 3,4-dimethoxy phenylacetic acid 43b wasfollowed by a reduction
of the resulting amides 45a–c tothe corresponding amines 46a–c with
a BH3ÆTHF/BF3ÆEt2O reagent. These were conveniently acylatedwith
acetic anhydride furnishing 47a–c and then sub-jected to a
POCl3-mediated cyclization to the corre-sponding iminium salts
48a–c, which upon NaBH4reduction at �78 �C afforded chiral
1-substituted tetra-hydroisoquinolines 49a–c. Conventional
catalytichydrogenolysis of their N-benzyl group provided
(S)-(�)-salsolidine, showing that the reduction proceededwith great
diastereoselection. Diastereomeric ratios (1S/1R) of salsolidine
derivatives were 91:9 for 44a, 100:0 for44b and 98.4:1.6 for 44c,
representing efficient examplesof 1,3-asymmetric induction.
Interestingly enough, when
-
1214 T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004)
1203–1237
bulkier substituents were placed at the C-1 position ofthe
resulting tetrahydroisoquinoline, the 2,6-dichloro-phenyl
derivative was at least as efficient as its mono-chloro
congener.
In this monotonic series of 2,6-diH, 2-Cl, and
2,6-diClderivatives, it was seen that the degree of
diastereoselec-tion observed in the reduction of iminium ions
48a–cseemed to be governed by steric factors; apparently, thesingle
stereogenic center appended to the nitrogen atomof the iminium ion
moiety creates different stericenvironments at the two iminium ion
diastereofaces in thetransition state of this nucleophilic addition
reaction.
This transformation is ionic in nature, in which a rea-sonable
first step may be an ion metathesis, with theformation of an
iminium ion–borohydride ion pair priorto the second step,
consisting in a hydride addition tothe iminium. Since these
compounds possess a C@Ndouble bond embedded in a rather rigid
six-memberedring, it appears that only two conformational degrees
offreedom are accessible to these structures: (1) rotationabout the
C–N bond linking the N to the stereogeniccenter and (2) rotation
about the C–C bond linking thestereocenter to the aromatic
moiety.
The data provided by these researchers supports theview that
iminium ions prefer transition state confor-mations in which the si
face is more hindered to nucle-ophilic approach (Scheme 25).
Substitution withchlorine increases the net steric shielding of the
si dia-stereoface, thus increasing the diastereoselection.
A chirally complementary, modification of the strategydepicted
in the above sequence was reported by Ki-bayashi et al.76 This
consisted of the synthesis andreduction of isoquinolinium salts,
such as 51, bearing anhydrazonium moiety derived from natural
proline.
With different precursors, easily elaborated by the
Bis-chler–Napieralski cyclization of conveniently substi-
Table 2. Synthesis of salsolidine derivatives 52 by reduction of
51
N
MeO
MeO NR
Me
O
50
N+
MeO
MeO NR
Me
51
POCl3, PhH,reflux
Hydride,Solvent
Entry R Hydride Solvent
1 Me NaBH4 MeOH
2 CH(CH3)2 NaBH4 MeOH
3 CH2OBn NaBH4 MeOH
4 CH2OBn NaBH4 MeOH
5 CH2OBn NaBH4 MeOH
6 CH2OBn LiBEt3 H THF
7 CH2OBn Vitride THF
8 CH2OBn DIBAL-H THF
9 CH2OBn K-Selectride THF
tuted b-phenethylamides 50, salsolidine derivatives 52carrying a
(1R)-configuration were isolated in 42–88%yield and 84–96% de. As
shown in Table 2, solvent,reducing agent, and reduction temperature
were moreinfluential in the recovery yields than in the
enantio-meric excesses recorded for the isolated products.Removal
and recovery of the proline derived chiralauxili-aries were carried
out by refluxing first withBH3ÆTHF, followed by the destruction of
the resultingtetrahydroisoquinoline–borane complexes with
refluxingHCl.
The preferential formation of one of the enantiomers ofthe
natural product was rationalized on the basis of thepyramidal
stability of the trivalent nitrogen of the chiralpyrrolidine ring,
constituting an efficient asymmetryinducing a stereogenic center,
and the existence ofan energetically favored conformer, which can
beattacked from its less hindered face.77 An alternativestrategy
involving hydrazonium ions, which is discussedbelow, was reported
to lead to the opposite enantiomerof the natural product; this
entails the nucleo-philic addition of carbon nucleophiles to
hydrazoniumsalts.
4.2.4. Enantioselective borane reduction of azomethinesactivated
with chiral Lewis acids. A fundamentally dif-ferent approach to
that consisting of reduction of chiralactivated azomethines was
reported by Kang et al.78
Their protocol employed a borane-mediated reductionof
1-alkyl-3,4-dihydroisoquinoline derivatives
usingenantioface-selective coordination on the amine nitro-gen
assisted by chiral Lewis acids, which producesactivated iminium
species. These authors tested variousLewis acids, such as
thiazazincolidine complexes 53aand 53b,79 TADDOL–Ti complex 54,80
Ohno’s catalyst5581 and LL-DPMPM–Zn complex 56 (Fig. 6),82 andfound
that the zinc complex 53a gave the optimalenantioselectivity.
N
MeO
MeO HMe
N
MeO
MeO NR
Me
(+)-152
N RH
+
1. BH3.THF,2. HCl
Temperature (�C) De 52 (%) Yield 52 (%)
�50 84 73�50 86 71�10 90 88�50 92 84�90 94 81�50 92 68�50 92
63�50 92 42�50 96 44
-
NS
Zn
PhMe
R
EtR O
TiOO
O O iPr
iPrOPhPh
Ph Ph
N
N
O iPr
iPrOTf
Tf
NZn O Ph
Ph
MeEt
53a R, R= -(CH2)5-53b R, R= Me, Me
54
55 56
Figure 6.
T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004) 1203–1237
1215
The borane source proved to be influential in the reac-tion’s
outcome. Good chemical yields (60–81%) andenantiomeric excesses
ranging from 62% to 86% wereachieved when BH3.THF was employed;
other boranesexamined, such as borane–dimethylsulfide
complex,bis(2,6-dimethylphenoxy)borane (BDMPB), and pina-col borane
furnished enantiomeric excesses in the range4–45%. Interestingly,
the reaction provided a mixture ofsalsolidine and a second
compound, presumably a bor-ane complex of dihydroisoquinoline 2,
which could notbe forced to undergo reduction but reverted to
thestarting material upon aqueous work-up.
Selectivity [(R)-salsolidine was obtained in all cases]
wasexplained (Scheme 11) on the basis of the coordination
N
MeH
MeO
MeON
MeH
MeO
MeO
(-)-1 (+)-1
OMeMeO
SN
HH
Ph Me
+N
MeOMeO
Zn
Me
S EtN
HH
Ph Me
R
R
R
R
-Favored+N
Zn
Me
Et-
Disfavored
Scheme 11.
Table 3. Reduction of 2 with boranes in toluene, in the presence
of thiazazi
Entry no Borane (equiv) Temperature (�C)
1 BH3ÆTHF (2) 102 BH3ÆTHF (2) 03 BH3ÆTHF (2) �54 BDMPB (3) �105
BH3ÆSMe2 (3) �206 Pinacolborane (2) �5
of the chiral Lewis acid to the nitrogen lone pair of
thedihydroisoquinoline, which can occur in two ways;the preferred
one is that in which the unfavorable A1;3
strain between the bulky methyl group and the ethylgroup on zinc
is minimized. In addition to this stericreason, the
anti-relationship between the C@N bondin the dihydroisoquinoline
and the C–Zn bond in thecatalyst, seems to make the complex leading
to (þ)-1 thelower energy species, presumably due to
electronicreasons.78
This model also explains the lower enantioselectivityfound when
coordinating solvents such as dimethylsulfide or THF are used, on
the basis of interference ofthe coordination of the chiral catalyst
to the substrate inthe transition state.
The enantiomeric excess (Table 3) was found to improveas the
reaction temperature was lowered from 10 to�5 �C (entries 1–3);
conversely, chemical yields droppedfrom 81% to 65% as a result of
this change in reactionconditions. BH3ÆTHF seemed to be the most
efficientreducing reagent within this system.
Cho et al. found that 3,4-dihydroisoquinoline 2 wasinert to
Itsuno’s reagent 57a;83a interestingly,
however,oxazaborolidine-type catalysts have been employed forthe
elaboration of 1-substituted tetrahydroisoquinolinealkaloids.83b;c
More recently, Bolm and Felder reportedthat 2 was refractory to the
b-hydroxy sulfoximine-cat-alyzed enantioselective reduction with
borane, when 57bwas employed as catalyst (Fig. 7);84 it is believed
thatunder the reaction conditions, cyclic imines like 2 formborane
adducts, which prevent hydride reduction.
ncolidine catalyst 53a
Time (h) Yield (%) Ee, % (config.)
12 81 62 (R)
12 75 79 (R)
12 65 86 (R)
15 32 87 (R)
12 4 60 (R)
12 45 82 (R)
N+BH
Ph
PhH
H3B
HNS
OH
PhPh
OPh
OMeOMeO
BO
H
Me Me
MeMe
57a 57b 57c
N
Me
MeO
MeO
R
RO
BOH
HH
N
Me
MeO
MeO
Si-face attack (favored)
R
R
OB O
H
HH
Re-face attack (disfavored)
Figure 7.
-
RArSO2
1216 T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004)
1203–1237
Interestingly, chiral oxaborolidines of the dialkoxy-borane
type, like 57c available from the commercialdimethyl LL-tartrate,
were observed to reduce cyclic andacyclic azomethines.85 However,
57c is a stoichiometricreductant, which has to be used in
approximately five-fold excess in the presence of 1.2 equiv of a
mild Lewisacid, such as MgBr2ÆOEt2 for the reaction to be
morestereoselective. In this way, (þ)-1 (isolated as
theN-carboxymethyl derivative, 8) was accessed in verymodest 50%
yield and 28% ee.
The si-face directing effect leading to the
preferentialformation of the (1R)-enantiomer can be explained
(Fig.7) by considering a transition state, which avoids non-bonding
interactions between the methylene protons (H-3) of 2 and the bulky
substituent of the dialkoxyboranering.
N
MeO
MeO
Me
NRu
N
Cl
n
H H59a η6-arene= p-cymene; Ar= 4-MeC6H459b η6-arene= p-cymene;
Ar= 2,4,6-Me3C6H259c η6-arene= benzene; Ar= 2,4,6-Me3C6H259d
η6-arene= benzene; Ar= 1-naphthyl(S,S)-59
(S,S)-59"H2"
+
Si-face attack
(R,R)-59 "H2"
Re-face attack
4.2.5. Catalytic enantioselective reduction of
1-alkyl-3,4-dihydroisoquinolines. The catalytic
enantioselectivereduction of 1-alkyl-3,4-dihydroisoquinolines has
beenachieved with different degrees of success employingtitanium,
ruthenium, and iridium-based catalysts. Whilestudying the viability
of titanium catalysts for the cat-alytic reduction of unsaturated
organic compounds,Willoughby and Buchwald discovered a
titanocene-derived catalytic system (Scheme 12) valuable for
theasymmetric hydrogenation of imines.86 Their catalyst58b was
generated in situ by metallation with n-BuLi ofthe
1,10-binaphth-2,20-diolate derivative 58a, a previ-ously described
ansa-titanocene precatalyst,87 and asubsequent reaction of the
metallated species with phe-nyl silane under a hydrogen
atmosphere.
58a 58b
1. BuLi (2 equiv.)2. PhSiH3 (2.5 equiv.)O
OTi Ti H
Scheme 12.
Figure 8.
This catalytic system does not require a coordinatinggroup on
the substrate and impressive levels of selec-tivity are achieved,
taking into account that the catalystoperates by discrimination on
the basis of the shape ofthe substrate. In the reaction cycle, the
titanium(III)hydride form of the catalyst 58b reacts with the
imineproducing a 1,2-insertion and forming a titanium aminecomplex,
which is then hydrogenolyzed via a sigmabond metathesis reaction to
regenerate the catalyst,releasing the amine product.
Reactions were typically run at 65 �C and,
interestingly,enantiomeric excesses achieved by the use of this
catalystwere higher with cyclic imines than with their
acycliccounterparts; they also required less pressure and
thehydrogenation outcome was less sensitive to changes inhydrogen
pressure. In the case of the Z-imine 1-methyl-
6,7-dimethoxy-3,4-dihydroisoquinoline 2, however, asmall
pressure effect was observed; at 2000 psig theobserved ee of the
product was 98%, while at 80 psig theee obtained was 95%. This
substrate, which has a syngeometry, upon hydrogenation with the
(R,R,R)-cata-lyst gave (�)-1, which is consistent with the
generalreaction mechanism proposed for the catalyst.
In recent publications, Noyori et al.88a;b studied theasymmetric
transfer hydrogenation of 1-substituted-3,4-dihydroisoquinolines
with different preformed chiralRu(II) catalysts of general
structure 59 (Fig. 8),employing formic acid–triethylamine
media.
Transfer hydrogenation with stable organic hydrogendonors is
highly attractive because of its operationalsimplicity, high cost
performance and the less hazardousproperties of the reducing
agents. Screening experimentsrevealed that the transformation was
best effected with a5:2 formic acid–triethylamine azeotropic
mixture inacetonitrile at 28 �C, a substrate concentration of
0.5M,a substrate/catalyst ratio of 200 and 6 equiv of HCO2H;these
conditions provided a stereodirected synthesis of(þ)-1 in
remarkable 99% yield and 95% ee (Table 4,entries 1 and 2).
Interestingly, the reaction did not take place without
theaddition of triethylamine or in alcoholic and etherealmedia with
the rate and enantioselectivity of the reac-tion being influenced
by the g6-arene and 1,2-diamineligands. It is also known that the
alkyl substituents onthe p-cymene ligand as well as the free amine
and tosylgroup play crucial roles with regards to the
reactivity.The general sense of asymmetric induction with
thiscatalytic system is illustrated in Figure 8; it has
beenproposed that in the stereodetermining hydrogen-transfer step,
the chiral Ru species (probably a hydride)formally discriminates
the enantiofaces at the sp2
nitrogen atom of the imine, generating a stereogenic sp3
carbon (a-control according to the latent trigonal
centerrule).88c
-
Table 4. Reaction of 2 and 60 with catalyst 59a in MeCN to
enantioselectively afford salsolidine 1
N
Me
MeO
MeON
Me
MeO
MeO H
Catalyst
HCO2H-Et3N
21
O
Me
MeO
MeO
NHBoc
1. HCO2H, 9 vol. 16 h2. Et3N (to give 5:2 ratio with HCO2H)3.
Catalyst
60
*
Entry no Substrate Catalyst S/C ratio Time (h) Yield (%) Ee, %
(config.)
1 2 (S,S)-59a 200 3 >99 95 (R)
2 2 (S,S)-59a 1000 12 97 94 (R)
3 2 (R,R)-59a 400 120 95 88 (S)
4 60 (R,R)-59a 400 20 85 88 (S)
T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004) 1203–1237
1217
Very recently, Wills et al. reported a one-pot process forthe
enantioselective synthesis of salsolidine from
theBoc–phenethylamine derivative 60,9c employing areductive
amination strategy, under transfer hydroge-nation
conditions.88d
These authors were able to demonstrate that formicacid-mediated
removal of the Boc protecting group of60, followed by the addition
of enough triethylamine togive a 5:2 ratio with the formic acid,
and submissionof the mixture to an enantioselective transfer
hydro-genation reaction in acetonitrile, in the presenceof the
ruthenium(II)-based catalyst (R,R)-59a (pre-pared in situ) provided
the natural product withthe same enantiomeric excess obtained when
2 washydrogenated under similar conditions (Table 4,entries 3 and
4). For the synthesis of certain amines,this is a potentially
valuable procedure, since imineformation and imine reduction are
carried out in onesynthetic step, avoiding the isolation of the
imineintermediate.
Cobley et al.89 disclosed another series of ruthenium-based
complexes involving chiral diphosphines and di-amines as ligands,
as robust and highly useful tools forthe catalytic asymmetric
hydrogenation of imines. Oneof these optically active complexes was
considered thepreferred one for the enantioselective hydrogenation
of2; this transformation employed (R,R)-1,2-diamino-
Table 5. Catalytic hydrogenation of 2 leading to salsolidine
with the (R,R)-
N
Me
MeO
MeO
MeO
MeO
H2, 15 BarCatalyst, KtBuO,
2-PrOH
S/C/B= 100:1:20
2 1
Catalyst Temperature (�C)
(R,R)-Et–DuPHOS–RuCl2 (R,R)-DACH 65
(R,R)-Et–DuPHOS–RuCl2 (R,R)-DACH 80
cyclohexane [(R,R)-DACH, 61a] as a diamine, while(R,R)-Et–DuPHOS
61b, a phosphethane type auxiliary,was used as chiral diphosphine;
unlike others, this cat-alytic system requires a strong base, such
as potassiumtert-butoxide. In this work, conversions were
deter-mined by 1H NMR, while the percentages of ee wereobtained by
chiral GC analysis of volatile derivatives,with the results shown
in Table 5.
Using for asymmetric catalytic hydrogenation catalystssimilar to
those employed in the pioneering hydrosily-lation work of Kagan et
al. (Scheme 8),63 James et al.disclosed64 that when imine 2 was
treated with a rho-dium catalyst, including DIOP 62a as ligand in
MeOH,the reaction did not proceed to salsolidine, evidencingthe
formation of 63. Under different reduction condi-tions (H2, 1 atm,
CH2Cl2), a related complex, whichexisted as a couple of isomers 64a
and 64b in solutionstate, was also observed (Fig. 9). These authors
alsofound that no reduction product was obtained when(þ)-cycphos
62b (1mol%, PhH–MeOH, 1:1, H2, 1000–1500 psig) was employed as
chiral ligand.
For acyclic imines, these researchers64b suggested thatthe
coordination of the nitrogen atom of the imine tothe rhodium center
is the first step of the reaction. Dueto the importance of the
solvent system in the reactionsstudied (PhH–MeOH, 1:1), the
existence of a five-coordinated Rh(I) intermediate and its
transformation
Et–DuPHOS–RuCl2-(R,R)-DACH catalytic system
NH2
NH2
61a
PEtEt
P
Et
Et
61b
N
MeH*
Time (h) Conversion (%) Ee (%)
68.5 79.5 79
68.5 96 76
-
N
MeMeO
Rh
MeO
MeO
63
PPh2
PPh2
62b
P
PPhPh
Ph Ph
N
MeCl
Rh
MeO
MeO
64a
P
PPhPh
Ph Ph
N
Me
ClRh
MeOOMe
64b
P
PPhPh
Ph PhO
O
O
O
O
O
O
O
PPh2PPh2
62a
H
Figure 9.
1218 T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004)
1203–1237
into a monohydride species was assumed, as shownin Scheme 13. In
the case of cyclic imines suchas 2, the reaction would not proceed
beyond the firststep.
Rh(I)P
P S
S+
Rh(III)P
P H
S
+O
H
HMe
Rh(III)P
P H
N
+O
H
HMe R1
R3
R2
Rh(III)P
P H
N
+O
H
HMe R1
R3
R2
RhP
P S
N
+O
H
HMe R1
R3
R2H
RhP
P S
NO
S
HMe R1
R3
R2H
H
H2
R3
N
R2
R1
H-Transfer
+
H-Transfer
H R2
NR1H
R3 H2
S= SolventP= Tertiary Phosphine
Solvent
Solvent
MeOH(Solvent)
Scheme 13.
The late transition metal complexes in which a coordi-nating
group is often necessary for the catalytic asym-metric
hydrogenation of cyclic imines, thought time agoto be somehow less
successful, have also been employedfor the enantioselective
synthesis of salsolidine, as ademonstration of the remarkable
progress made in thisarea.
Iridium–iodine based catalytic systems like Ir(I)–MOD–DIOP–TBAI
and Ir(I)–BCPM–bismuth(III) iodide,which are efficient for the
asymmetric hydrogenation ofcertain cyclic ketimines leading to
enantiomeric excessesup to 91%, were found unable to hydrogenate
1-alkyl-3,4-dihydroisoquinolines with enantiomeric excesseshigher
than 20%.90a;b
These systems seem to require fine tuning; it has beenrecorded
that addition of phthalimide 65 (4mol%) to aniridium(I)–(R,R)-BICP
66a system gave high conversionto salsolidine but with very poor
enantiomeric excess(94.6% and ee¼ 4.0%), while addition of
benzylamine(5%) to the same catalytic system provided the
naturalproduct in no more than 41.3% ee,91a while the use of
aniridium(I)–BINAP-phthalimide complex for the suc-cessful
elaboration of the related (S)-calycotomine (S)-11 in 86% ee has
been recorded91b and a modified DIOPligand (R,R)-MOD-DIOP, 62d was
used as part of aneutral iridium complex, which in the presence of
TBAIgave 91% of (R)-1, in 27.5 ee (S/C¼ 100, H2 at100 atm).91d
On the other hand, Morimoto et al. recently demon-strated that
the addition of imides as co-catalysts al-lowed a remarkable
improvement in the asymmetrichydrogenation of
1-alkyl-3,4-dihydroisoquinolines whenthe BCPM 66b type of chiral
diphosphine–iridium(I)complex catalysts was employed (Table
6).90c–e Theseimprovements have found uses in other, related
sys-tems.91c
Enantiomeric excesses of (�)-1 of up to 93% (entry 6)were
obtained with 4 equiv of phthalimide as additive;the reaction was
run in toluene at 2–5 �C, under aninitial hydrogen pressure of 100
atm and 1mol%of catalyst, conveniently prepared in situ
from[Ir(COD)Cl]2 and (2S,4S)-BCPM (Scheme 14).
N
Me
MeO
MeON
Me
MeO
MeO H
2 (+)-1
N H
O
O
[Ir(COD)Cl]2, 65
N
(c-C6H11)2P
PPh2O O
tBu
66b65
66a or 66b, H2
H
H
Ph2P
PPh2
66a
Scheme 14.
-
Table 6. Asymmetric hydrogenation of 2 with the
diphosphine–iridium(I) catalyst system, employing (2S,4S)-BCPM 66b
as the chiral ligand
Entry no Additive Solvent Temperature (�C) Time (h) Conversion
(%) Ee, % (config.)
1 None PhH–MeOH 20 24 90 18 (R)
2 None PhMe 20 24 22 14 (S)
3 Succinimide PhH–MeOH �10 72 94 67 (S)4 Phthalimide PhH–MeOH
�10 48 98 76 (S)5 Phthalimide PhH 20 24 96 70 (S)
6 Phthalimide PhMe 2–5 24 95 85–93 (S)
7 Phthalimide THF 20 20 95 41 (S)
8 Phthalimide CH2Cl2 20 20 94 70 (S)
9 Succinimide PhH–MeOH �10 72 94 67 (S)10 Saccharin PhH–MeOH 20
45 82 4 (R)
11 Hydantoin PhH–MeOH 20 30 96 49 (S)
12 4-Cl-Phthalimide PhMe 20 20 97 81 (S)
13 4-Cl-Phthalimide PhH–MeOH 20 30 95 56 (S)
14 4,4-Cl2-Phthalimide PhMe 20 20 95 76 (S)
NEtN
Et
N
NEt
Et O
Me
OHH
PhCH2CH2
T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004) 1203–1237
1219
Clear solvent effects were observed, with less polarsolvents
showing higher enantioselectivities; the eeobserved in toluene
(>85%) dropped to 41% when THFwas employed, under similar
conditions. Five memberedcyclic imides proved to be the best
co-catalysts, while theuse of benzamide as co-catalyst provided
(þ)-1, in only25% ee.
As mentioned above, the hydrosilylation reactions forthe
enantioselective elaboration of 1-substituted
tetra-hydroisoquinolines were pioneered by Kagan et al. withlimited
success and so this strategy was not applied tothe elaboration of
salsolidine.63
More recently, however, a two-step synthesis of (S)-salsolidine
by means of the asymmetric hydrosilylationof the precursor nitrone
67 using the Ru2Cl4[S-(�)-p-tolbinap]2–Et3N–Ph2SiH2 catalyst
system, has beenreported.92 The intermediate hydroxylamine
(2-hydroxysalsolidine, 68), obtained in 99% chemical yield and
56%ee after a 2 h reaction period at 35 �C, was finallyreduced with
zinc–HCl to the natural product (Scheme15).
N+
Me
MeO
MeO
N
Me
MeO
MeO H
67
(-)-1
N
Me
MeO
MeO OH
S-68
Ru2Cl4[(S)-(-)-p-tolbinap]2,Et3N, CH2Cl2, 35ºC,
Ph2SiH2
O-
Zn, HCl
PP
Tol
TolTolTol
(S)-(-)-p-Tolbinap
(99%, ee= 56%)
Scheme 15.
NHN CH2OH
N
NH
HOH2C OCH2Ph
Me
OCH2PhH
H
HH
Et
74
69
NEtN
Et
N
NEt
EtO
Me
OH
PhCH2CH2
N
O
MeMeO
MeO
69a
H
Mg+2
Figure 10.
Production of N-hydroxylamine (S)-68 was rationalizedby assuming
a mechanism, which involved insertion ofthe Ru–phosphine complex
into the Si–H bond of the
silane to give a silylhydridoruthenium species. In turn,this
underwent enantioselective insertion into thenitrone, depending on
the configuration of the latter.Both, the silane and the catalyst
had an influence on theenantiomeric excess of the product, with
Ph2SiH2 beingthe most appropriate silane.
The biomimetic reduction of 2 with the NADH ana-logue 69 (Fig.
10) was achieved, yielding salsolidine in36% yield.93 Surprisingly,
in spite of the availability ofchiral NADH models, its
enantioselective reduction wasnot reported in this work. Finally,
it is worth mention-ing that the reduction of 2 with baker’s yeast
has alsobeen attempted, but proved to be unsuccessful.94
4.2.6. Diastereoselective catalytic hydrogenation or hy-dride
reduction of chiral enamides. A series of reports by
-
1220 T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004)
1203–1237
Czarnocki et al.95 indicated the achievement of
theenantiodivergent syntheses of (R)- and (S)-N-acetylsalsolidine
19 and its related compounds by catalytichydrogenation or
borohydride reduction of enamides 70and 71. The starting enamides
were prepared in 50–80%overall yield by acylation of 2, which is
readily accessibleby the Bischler–Napieralski reaction,8;9 with
acetonidederivatives of the natural (R,R)-tartaric acid as
chiralauxiliaries (Scheme 16).
Hydrogenation of the enamides over Adams catalystprovided a
mixture of diastereomers 72 and 73 enrichedin the C-1 (R)-isomers
(ee¼ 9.7–42.4% after hydrazi-nolysis and N-acylation), while a
mixture enriched in theC-1 (S)-isomer (81% chemical yield, ee¼ 15%)
wasrecovered from enamides bearing unprotected hydroxylgroups on
the 2-tartaroyl moiety, upon reduction withNaBH4 in acidic EtOH at
�5 �C.
4.2.7. Enantioselective reduction of enamides with
chiralcatalysts. The enantioselective reduction of enamideswith
chiral catalysts was accomplished (in several caseswith a high
degree of enantioselectivity) with NADHmimics as well as by
catalytic hydrogenation employingchiral rhodium(I) and
ruthenium(II) complexes as cat-alysts.
N
MeO
MeO
O
NO
O
OOMe
OMe
N
MeO
MeO
O
OEtO
O
O
R1 R2
N
MeO
MeO
N
MeO
MeOMe O
PtO2, H2, 1
70
71a R1, R2= -(CH2)5-71b R1, R2= Me
PtO2, H2,1 atm.
73a R1, R273b R1, R2
1. NaBH4, acidic EtOH2. N2H4, KOH, (CH2OH)2, ∆3. Ac2O, KOH
S-19
MeO
MeO
3a
N
Ph2P
CH2PPh2Piv
66d, Rh+, H2(92%, ee= 45%)
66d
Scheme 16.
The hydrogenation of enamide 3a was repeatedly em-ployed as the
model reaction, furnishing N-acetyl sal-solidine 19, the
transformation of which into salsolidinein high chemical yield and
without loss of stereochemi-cal integrity, is known (Scheme 3).
Bourguignon et al. studied the reduction of enamideswith NADH
models as hydride donors. The chiralNADH mimic 74 (Fig. 10),
derived from (S)-phenyla-laninol, reduces C@O and C@N bonds in the
presenceof a large excess (8 equiv) of Mg(ClO4)2; in this
way,enamide 3a was reduced to give 95% of (1R)-N-acetyl-salsolidine
(R)-19 in up to 87% ee. Addition of excessMg(ClO4)2 to the reaction
medium was critical, since theuse of 1 equiv of the salt provided
the product in only32% ee;93 however, the related methyl carbamate
3c wasreduced to furnish 95% of (R)-8, but in only 26%
ee.Curiously, inversion of selectivity, which was dependentupon the
amount of Mg(ClO4)2 employed, occurredduring the reduction of
methyl benzoyl formate to me-thyl mandelate; however, no such
inversion was ob-served when the reduction of
3,4-dihydroisoquinolineenamides was carried out.
The use of nonchiral NADH models, such as 69 toprovide racemic
19 and its conversion to racemic sal-solidine, have also been
described by this group in ear-
N
MeO
MeO
O
NO
O
OOMe
OMe
O
OEtO
O
O
R1 R2
N
MeO
MeOMe O
atm.
72
= -(CH2)5-= Me
1. Acidic EtOH2. N2H4, KOH, (CH2OH)2,∆
3. Ac2O, KOH
R-19
N
O
N
Ph2P
CH2PPh2Boc
66c, Rh+, H2(82%, ee= 34%)
1. N2H4, KOH,(CH2OH)2, ∆
2. Ac2O, KOH(28%, overall)
(75-85%)
66c
-
T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004) 1203–1237
1221
lier publications.96 A ternary complex 69a between thesubstrate,
the NADH mimic 69, and Mg2þ was assumedto be responsible for the
hydride transfer; in the case ofthe chiral NADH mimic 74, this
model correctly ex-plains the preferential si-face hydrogen
transfer to 3a,leading to enantioenriched (R)-19.
Rhodium and ruthenium-based chiral catalysts havebeen employed
for the catalytic enantioselective hydro-genation of N-acyl
enamines. In a pioneering commu-nication by Achiwa97 on the
hydrogenation of enamide3a catalyzed by chiral bisphosphine–Rh
complexes, theenantioenriched elaboration of both enantiomers
ofsalsolidine by simple modifications in reaction condi-tions was
reported (Scheme 16).
Employing the rhodium complex of (2S,4S)-N-Boc-4-diphenyl
phosphino-2-diphenyl phosphinomethyl-pyr-rolidine 66c (BPPM),
(S)-salsolidine was prepared in34% ee. However, when the same
catalytic cycle wasperformed with PPPM 66d, the enantiomeric
(R)-sal-solidine was obtained in 45% ee after deacetylation;
inrelated work, the catalytic enantioselective hydrogena-tion of 3a
with the Rh–BICP 66a complex acting as acatalyst to (R)-19 in
quantitative yield and ee¼ 77.8%,was also reported,91c as well as
the elaboration of (R)-1and (S)-1 by asymmetric hydrogenation of 3a
with dif-ferent Rh(I) complexes based on DIOP 62a,c,d and
(2R,3S)-MOCBP, 75, and diarylphosphino-pyrrolidine 66eand 66f
motifs, as shown in Table 7.91d
A cationic rhodium(I) complex was found to exhibitbetter
enantioselectivity than the related neutral one
Table 7. Asymmetric hydrogenation of enamide 3a to N-acetyl
salsolidine 1
O
O PAr2PAr2
62a (R,R)-DIOP, Ar= C6H562c (R,R)-p-MeO-DIOP, Ar= 4-MeO-C6H462d
(R,R)-MOD-DIOP, Ar= 3,3'-Me2-4MeO-C6H2
PPh2
MeOMeO PPh2
75
N
MeO
MeO
3a
O
EtOH, 50
H2, Cat
Entry no Ligand Rh source S/C ratio
1 62b Rhþ(COD)BF�4 1000
2 62c Rhþ(COD)BF�4 1000
3 62c Rhþ(COD)BF�4 200
4 62c [Rhþ(COD)Cl]2 200
5 62d Rhþ(COD)BF�4 200
6 66e Rhþ(NBD)ClO�4 200
7 66f Rhþ(NBD)ClO�4 200
8 75 Rhþ(COD)BF�4 200
9 75 Rhþ(COD)BF�4 500
10 75 Rhþ(COD)BF�4 200
(entries 3 and 4) and pressure (entries 2 and 3) as well
asligand (entries 2, 5, and 6) effects on enantiomericexcesses were
also observed.
In several contributions, Noyori et al. reported thehighly
enantioselective synthesis of 1-substituted
tetra-hydroisoquinolines by the BINAP–Ru(II)-catalyzedhydrogenation
(Fig. 11) of N-acyl-1-alkylidene-tetrahy-droisoquinolines. In this
way, (�)-1 was quantitativelyaccessed from the precursor N-acetyl
enamide 3a, in97% ee employing D-(S)-76, while use of the related
N-formyl enamide 3b as starting material furnished theproduct in
quantitative yield and 96% ee.98 A mnemonicpicture for the
prediction of the sense of the enantio-selective hydrogenation of
N-acyl-1-benzylidene-1,2,3,4-tetrahydroisoquinolines with
BINAP–Ru(II) catalystswas derived from experimental data; catalytic
hydroge-nation of acyl-enamines such as 3a seem to obey thesame
principles.46
Hydrogenation conditions are rather mild and verypractical,
employing 0.5–1% of catalyst and hydrogen(4 atm) at room
temperature in EtOH–CH2Cl2 (5:1)mixtures. Since both enantiomers of
the catalyst arereadily available, the synthesis is
stereochemically flexi-ble with either of the enantiomers of the
natural productcan be potentially synthesized with equal ease,
bychoosing the appropriate handedness of the catalyst.
The synthetic scheme is also general, with other
tetra-hydroisoquinolines being obtained in high chemicalyield and
enantiomeric excess following analogoussequences. Interestingly
however, with a given
9 catalyzed by bis-phosphine–Rh(I) complexes
N
PPh2Ph2P
COPhN
Ph2P
CO2t-Bu
P(4-MeO-C6H4)2
66e 66f
N
Me
MeO
MeO
19
O
ºC, 20h
alyst
H2 (atm) Conversion (%) Ee, % (config.)
5 72 40.5 (S)
5 100 51.6 (S)
1 100 62.4 (S)
1 100 48.4 (S)
1 100 29.1 (S)
1 100 25.6 (S)
1 98 46.2 (R)
1 100 80.6 (R)
1 100 80.6 (R)
5 100 76.6 (R)
-
P
PRu
O
OMe
Me
OO
Ph
PhPh
Ph
P
PRh+
L
L
Ph
PhPh
Ph
L= MeOH
ClO4-
∆-(S)-76 R-77
(R)-BINAP-Ru(II)
N
MeO
MeO
HH Me
O
(S)-BINAP-Ru(II)
Figure 11.
NH
MeO
MeON
MeO
MeON
Me3CO
N
MeO
MeON
Me3CO
Me
N
MeO
N
MeO
MeOOMe
N
MeO
1. t-BuLi2. MeI
Me3CO
N
Me2N
23
79
80
1. Boc2O2. tBuLi-TMEDA3. MeI (99%)
21b
N2H4, AcOH
NaAlH4(76%)
PhHN Ph
BuLi,TMEDA
(94%,ee= 86%)
81
(96%)
(60-63%overall)
78
1222 T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004)
1203–1237
handedness, the related rhodium-based BINAP catalystssuch as 77
deliver the opposite configuration at theC-1 position through
hydrogenation; therefore, notsurprisingly, hydrogenation of the
same N-acetylderivative 3a with the rhodium catalyst (R)-77 gave
(S)-N-acetylsalsolidine (S)-19 in 82% chemical yield and60%
ee.46
It was also found that the N-acyl function is crucial forthe
appropriate reaction with Rh(I) catalysts becauseit acts like a
tether, binding the heterocycle to thecatalytic metal center.
Another interesting differencebetween Ru(II) and Rh(I) catalysts is
that when 77is employed, the N-formyl substrates, such as 3b,
arenot hydrogenated under conditions where 3a is easilyreduced.
HMeOMe
MeOOMe
S-21b (-)-1
Scheme 17.
4.3. Metallation of tetrahydroisoquinoline derivatives
4.3.1. Diastereoselective alkylation of metallated
chiraltetrahydroisoquinoline derivatives. Substituents can
beintroduced at the a-position of secondary amines viametallation,
followed by treatment of the metallatedspecies with the appropriate
electrophile, by alkylationof azomethines as well as their
synthetic equivalents oractivated forms, or by catalytic oxidation
and sub-sequent treatment of the oxidized intermediates
withappropriate nucleophiles.99;100
Throughout their studies on the alkylation of a-aminocarbanions
derived from chiral formamidines, carriedout during the 1980s and
the beginning of the 1990s,Meyers et al. were among the first to
study the enan-tioselective formation of new C–C bonds adjacent
tonitrogen atoms.101 As a result, several model
tetrahy-droisoquinolines were enantioselectively alkylated
withvarious alkyl halides in 50–70% yields and
excellentenantiomeric excesses, employing different chiral
form-
amidines, and many natural products were synthesizedin this
way.102
The most consistent results were observed with thechiral
auxiliary derived from (S)-valinol tert-butyl ether,while others
gave products in 80–99% ee. For instance,(S)-1 was obtained by this
procedure in 60–63% yieldand >97% ee, by way of the formamidine
derivative 79,easily available from the known
6,7-dimethoxytetra-hydroisoquinoline 23 and formamidine 78
(Scheme17).103a
Removal of the chiral auxiliary from the resultingalkylated
derivative 80 was conveniently carried out byhydrazinolysis.
Formamidines derived from (S)-salsoli-dine itself were also
employed for the elaboration ofasymmetric 1,1-disubstituted
tetrahydroisoquino-lines.103b
By analogy with models proposed for other opticallyactive
formamidines,101c the high stereoselectivity ob-served for the
(S)-valinol tert-butyl ether chiral auxiliaryin 80 may be
attributed to the different conformationalpreferences of the
diastereomeric lithium salts 82a and82b; in the former, the chiral
auxiliary appeared to lieover the plane of the isoquinoline ring,
while in thelatter, the auxiliary was placed out and away from
the
-
NEtO
T. S. Kaufman / Tetrahedron: Asymmetry 15 (2004) 1203–1237
1223
isoquinoline, as a consequence of the (S)-configurationof the
stereogenic center (Fig. 12).
N
H
(S)
N
MeO
MeO
MeO
MeOLi
N
(S)
MeI
Me3CO
H
82a 82b
Solvent
SolventH
N
Me3CO
Li
Figure 12.
NH
MeO
MeON
MeO
MeON
1. t-BuLi, -78ºC2. MeI, -100ºC
(93%)
O
23 84
85(+)-1
O
N
MeO
MeON
O
Me
NH
MeO
MeOMe
N2H4(100%)
83PhH, TsOH (cat.)
Scheme 18.
Steric factors disfavored the production of 82a, whilethe steric
blockade of the bottom side of the preferreddiastereomer 82b,
resulted in alkylation occurring fromthe top side, furnishing the
observed (S)-configurationof the product. The role of the chiral
auxiliary versusthe configurational stability of the C–Li bond
wasstudied. Interestingly, metallation and alkylation ofoptically
active salsolidine carrying an achiral form-amidine moiety afforded
completely racemic mate-rial.103c
Resorting to an analogous sequence of transformations,Gawley et
al. reported the synthesis of (R)-salsolidine bythe use of
oxazolines as chiral auxiliaries for the asym-metric alkylation of
amines,104 thus providing a chirallycomplementary sequence to that
disclosed by Meyerset al. for the synthesis of the natural
product.
To that end, tetrahydroisoquinoline 23 was transformedinto 84
via reaction with (S)-ethoxyoxazoline 83, derivedfrom (S)-valine.
In turn, this was metallated with t-BuLiat �78 �C and the resulting
species quenched withMeI at �100 �C, to furnish 93% of a
chromato-graphically separable mixture (9:1) of
diastereomericoxazolines 85. Hydrazinolysis of 85 caused removalof
the oxazoline moiety, providing (þ)-1 quantita-tively, as shown in
Scheme 18, in excellent enantio-meric purity.34a Similarly, Quirion
et al.104c were ableto prepare (+)-1 in 53% yield and up to 93%
eefrom the tetrahydroisoquinoline 23 through the
dia-stereoselective alkylation of amides derived fromgulonic
acid.
4.3.2. Enantioselective protonation of metallated
tetrahy-droisoquinoline derivatives. Recently, Simpkins et
al.disclosed another interesting and complementary strat-egy toward
chiral salsolidine (Scheme 17), involving theenantioselective
protonation of metallated tetrahydro-isoquinoline derivatives.50
Thus, metallation of N-piva-loyl salsolidine 21b with the
t-BuLi–TMEDA complexat �40 �C in the presence of 81, a chiral amine
derivedfrom a-phenethylamine provided 94% of
N-pivaloyl-(S)-salsolidine (S)-21b in 86% ee, an enantiomeric
excess,
which was raised to 96% upon crystallization frompetroleum
ether. Reductive deprotection of the N-piva-loyl moiety with sodium
aluminum hydride afforded(�)-1 in 76% yield. The asymmetric
reactions oforganolithium reagents under control of chiral
ligandshave recently been reviewed.105
4.4. Alkylation of azomethines
4.4.1. Enantio