A stereodivergent strategy for the preparation of corynantheine and ipecac alkaloids, their epimers, and analogues: Efficient total synthesis of (-)-dihydrocorynantheol, (-)-corynantheol, (-)-protoemetinol, (-)-corynantheal, (-)-protoemetine, and related

Article abstract of DOI:10.1002/chem.201102012

Here we present a general and common catalytic asymmetric strategy for the total and formal synthesis of a broad number of optically active natural products from the corynantheine and ipecac alkaloid families, for example, indolo[2,3-a]- and benzo[a]quino

Full text of DOI:10.1002/chem.201102012

DOI: 10.1002/chem.201102012
A Stereodivergent Strategy for the Preparation of Corynantheine and Ipecac
Alkaloids, Their Epimers, and Analogues: Efficient Total Synthesis of (À)-
Dihydrocorynantheol, (À)-Corynantheol, (À)-Protoemetinol, (À)-
Corynantheal, (À)-Protoemetine, and Related Natural and Nonnatural
Compounds
Wei Zhang, Juho Bah, Andreas Wohlfarth, and Johan Franzꢀn*[a]
Abstract: Here we present a general
and common catalytic asymmetric
strategy for the total and formal syn-
thesis of a broad number of optically
active natural products from the cory-
nantheine and ipecac alkaloid families,
four possible epimers of the quinolizi-
dine alkaloids that begin from common
and easily accessible starting materials
by using a common synthetic route.
Focus has been made on excluding pro-
tecting groups and limiting isolation
and purification of synthetic intermedi-
ates. This methodology is applied in
the total synthesis of the natural prod-
ucts (À)-dihydrocorynantheol, (À)-hir-
sutinol, (À)-corynantheol, (À)-proto-
metinol, (À)-dihydrocorynantheal, (À)-
corynantheal, (À)-protoemetine, (À)-
(15S)-hydroxydihydrocorynantheol,
and an array of their nonnatural epi-
mers. The potential of this strategy is
also demonstrated in the synthesis of
biologically interesting natural product
analogues not accessible through syn-
thetic elaboration of alkaloid precur-
sors available from nature, for exam-
for example, indoloACTHNUGRTNEUNG[2,3-a]- and ben-
zo[a]quinolizidines. Construction of the
core alkaloid skeletons with the correct
absolute and relative stereochemistry
relies on an enantioselective and dia-
stereodivergent one-pot cascade se-
quence followed by an additional dia-
stereodivergent reaction step. This
allows for enantio- and diastereoselec-
tive synthesis of three out of
ple, thienoACTHNUTRGNEUNG[3,2-a]quinolizidine deriva-
tives. We also report the formal synthe-
sis of (+)-dihydrocorynantheine, (À)-
emetine, (À)-cephaeline, (À)-tubulo-
sine, and (À)-deoxytubulosine.
Keywords: alkaloids · asymmetric
catalysis · diastereodivergency · nat-
ural products · total synthesis
Introduction
The corynantheine and ipecac
alkaloid families contain a vast
number of naturally occurring
compounds that share a quino-
lizidine structural motif. They
are mainly isolated from the
leaves of Uncaria tomentosa
(cat claw) and the root of Cepa-
haelis ipecacuanha (Rubiaceae)
and have
a long history of
usage as herbal drugs to treat
inflammation, rheumatism, gas-
tric ulcers, tumors, dysentery, as
birth control, and to promote
wound healing. Over the years
there have been several studies on the pharmacological
properties of the individual alkaloids, which have been
shown to possess considerably diverse and interesting bio-
logical activity. For example, high antiviral activity is ob-
served for the indoloquinolizidines of the corynantheine
group, dihydrocorynantheine and hirsutine, towards influen-
za virus type A.[1] The corynantheine family also exhibits
anti-inflammatory,[2] antiarthritic,[3] antibacterial,[4] analge-
[a] Dr. W. Zhang, J. Bah, A. Wohlfarth, Dr. J. Franzꢀn
Department of Chemistry, Organic Chemistry
Royal Institute of Technology (KTH)
Teknikringen 30, 100 44 Stockholm (Sweden)
E-mail: jfranze@kth.se
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102012.
13814
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FULL PAPER
sic,[5] and antiallergenic[6] activity. Tubulosine, emetine, and
cephaeline, from the ipecac alkaloid families, are potent in-
hibitors of protein biosynthesis.[7] Remarkable activities
against several cancer-cell lines,[8] for example, lymphatic
leukemia,[9] HIV reverse-transcriptase inhibitory activities,[10]
antiprotozoic properties,[11] as well as antiamoebic activity
have also been observed. Emetine also has a history as a
therapeutic emetic. In nature, both corynantheine and
ipecac alkaloids share the same biosynthetic pathway and
are formed through the enzymatic condensation of the mon-
oterpene secologanin with tryptamine and dopamine, re-
spectively.[12,13] From a synthetic point of view, construction
of the fused-ring system with control of the relative and ab-
solute stereochemistry on the quinolizidine core structure
represents a significant challenge and considerable research
focus has been placed on its laboratory preparation. Tradi-
tionally, the majority of previously reported strategies for
the asymmetric total synthesis of quinolizidine alkaloids
have required a multistep synthesis that relies on starting
materials from the chiral pool.[14] These strategies often in-
clude several functional group transformations and tedious
protection/deprotection steps. As a consequence, the enan-
tioselective total syntheses of corynantheine and ipecac al-
kaloids and analogues thereof are demanding and proceed
in low overall yield. Lately, there have been a few scattered
reports of efficient synthesis of optically active quinolizidine
natural products and different analogues based on asymmet-
ric catalysis.[15–18] Worthy of mention is the elegant total syn-
thesis of ent-dihydrocorynantheol by Itoh et al.[17f] The key
step in their strategy is based on an enantioselective proline-
catalyzed annulation of 3-ethyl-3-buten-2-one to 9-tosyl-3,4-
dihydro-b-carboline, which provides the target alkaloid in
only three additional steps. Although highly efficient and
productive, the majority of the synthetic strategies devel-
oped is target-specific with respect to the relative configura-
tion of the quinolizidine stereocenters and only allow for se-
lective formation of one specific epimer of the alkaloid.[19]
Keeping in mind the structural similarity of the quinolizi-
dine alkaloids, we anticipated that an array of naturally oc-
curring quinolizidine alkaloids, their epimers, and analogues,
including those not accessible through the synthetic elabora-
tion of naturally occurring alkaloids, could be prepared by
means of a single and general synthetic strategy. Our plan
was to develop a common synthetic route to a series of func-
tionalized quinolizidine intermediates with skeletal and ste-
reochemical variation. These epimerically different inter-
mediates are to be designed in such a way that they can be
rapidly modified in a few synthetic operations to the desired
alkaloids with correct absolute and relative stereochemistry.
We were also determined to put considerable focus on the
overall efficiency of the synthetic strategy through the im-
plementation of asymmetric one-pot and cascade/tandem re-
actions.[20,21] Such strategies will have the advantage of
avoiding traditional stop-and-go synthesis,[22] which will
reduce the tedious isolation and purification of synthetic in-
termediates and result in higher-yielding processes that will
allow for practical quantitative preparation of the alkaloids.
To meet the requirements for efficient and diverse quanti-
tative total synthesis, we set the following objectives:
1) readily available starting materials, not limited by the
chiral pool; 2) easily manageable operational protocols on a
multigram scale; 3) selective access to different diastereoiso-
mers through stereodivergent reaction steps; 4) low number
of synthetic operations, isolationism and purifications of re-
action intermediates; 5) no protection/deprotection of func-
tional groups; and 6) easy access to nonnatural quinolizidine
alkaloid analogues.
Here we wish to report an enantioselective and diastereo-
divergent synthetic strategy for quantitative preparation of a
broad variety of alkaloids that contain a quinolizidine sub-
structure that we believe fulfills the above-mentioned crite-
ria.
Results and Discussion
Retrosynthetic analysis: The common structural unit for the
corynantheine and ipecac alkaloids is the quinolizidine ring,
which contains a fused aromatic group and three stereocen-
ters wherein one is a ring-junction stereocenter. The ring-
junction stereocenter has a great impact on the conforma-
tion of the alkaloid as can be seen through comparison of
the two naturally occurring ring-junction epimers, dihydro-
corynantheine and hirsutine, in which the former is the ther-
modynamically most stable form and has all groups on the
quinolizidine substructure in the equatorial position
(Scheme 1).[23] Hirsutine, on the other hand, has the aromat-
Scheme 1. Conformations of the epimeric natural products 12b-a-H dihy-
drocorynantheine and 12b-b-H hirsutine.
ic group in an axial position that forces a V-shaped form. In-
terestingly, dihydrocorynantheine and hirsutine have been
found to have differing biological activities,[24] thus stereose-
lective formation of different epimers is highly desired. This
requires special considerations during synthesis and has
been one of the bottlenecks in previously reported total syn-
theses of quinolizidine alkaloids.[14i] We came to the conclu-
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J. Franzꢀn et al.
2
3
À
thus achieving the C
C
cis or trans configuration. From
À
compound B, our first C C bond disconnection leads back
to the N-acyliminium ion C. On the basis of our previous
developments in stereoselective N-acyliminium ion cycliza-
tions, we proposed that the annulation could be controlled
to give either the a- or b-epimer in a second diastereodiver-
gent reaction.[25,26,27b] Further disconnections led back to the
a,b-unsaturated aldehyde 1 and b-ketoamide 2. We rea-
soned that optical activity could be introduced in the first
step through an enantioselective organocatalytic conjugate
addition (Scheme 2).[28] The catalytic asymmetric conjugate
addition of amidomalonates to a,b-unsaturated aldehydes
has been previously studied by Rios et al.[29] and our
group.[27] However, this reaction is limited to cinnamic alde-
hyde derivatives, and attempts to use alkyl-substituted a,b-
unsaturated aldehydes resulted in decomposition of the al-
dehyde. This drastically limits the potential use of this reac-
tion in quinolizidine natural-product synthesis. We reasoned
that the reluctance of amidomalonates to undergo conjugate
addition to alkyl-substituted a,b-unsaturated aldehydes was
mainly due to the poorer stability of alkyl-substituted a,b-
unsaturated aldehydes relative to cinnamic aldehydes and
the low nucleophilicity of the amidomalonate. To circum-
vent this, we attempted to use the more nucleophilic b-ke-
toamide in the conjugate addition.
One-pot stereoselective construction of the quinolizidine
carbon skeleton: Our retrosynthetic analysis leads back to
the a,b-unsaturated aldehyde 1, which was easily accessible
through the cross-metathesis of acroleine and 3-butenol by
using only 0.7 mol% Grubbs second-generation catalyst in
almost quantitative yield. The b-ketoamides 2a–c were ac-
cessed through the condensation of tert-butyl acetoacetate
with the corresponding 2-arylethanamine (Scheme 4).
Scheme 2. Stereodivergent retrosynthetic analysis of quinolizidine alka-
loids.
sion that the four different epimers of quinolizidine deriva-
tives A would be prominent precursors for a broad series of
corynantheine and ipecac alkaloids, their epimers, and dif-
ferent analogues (Schemes 2 and 3). The strategy should be
based on asymmetric catalysis, and we also envisioned a
Scheme 4. Starting material synthesis. DCM=dichloromethane.
Gratifyingly, we found that b-ketoamides 2a–c smoothly
reacted with the a,b-unsaturated aldehyde 1 in the presence
of catalyst 3 to give a white precipitate that indicated that
the conjugate addition had gone to completion. An analyti-
cal sample of the formed precipitate was analyzed by
1H NMR spectroscopy, which established it as a diastereo-
meric mixture of lactols 5a–c (Scheme 5). The crude reac-
tion mixture that contained the lactol 5a–c was quenched by
addition of trifluoroacetic acid (TFA) to give a 1:1 mixture
of the two ring-junction isomers a-7a–c and b-7a–c, which
could be isolated in good yields and high enantioselectivity
Scheme 3. Nomenclature used through this paper (a and b refers to the
ring-junction configuration, trans and cis refers to the relative relation-
ship between C2 and C3).
stereodivergent introduction of the following stereocenters
by taking advantage of thermodynamic and kinetic reaction
conditions. This will allow for fast construction of different
epimeric intermediates from common starting materials. We
anticipated that it would be possible to hydrolyze the enol
ether moiety of compound B in a diastereodivergent matter,
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Corynantheine and Ipecac Alkaloids
FULL PAPER
voring the nucleophilic attack of the b-ketoamides from the
Si face and generating the C1 stereocenter with the desired
absolute configuration.[31] Spontaneous cyclization gives the
intermediate lactol 5 (Scheme 5). The addition of TFA to
lactol 5 triggers an acid-catalyzed cascade reaction that con-
sists of lactol ring opening, enol ether formation, hemiami-
nal formation, and acid-catalyzed elimination of water to
give N-acyliminium ion 6. Subsequent N-acyliminium ion
cyclization gives a mixture of a-7a–c and b-7a–c.[32]
The ring-junction stereocenter is formed through the N-
acyliminium ion cyclization: reactions that are known to be
under kinetic control.[33] Through examination of the expect-
ed transition states in the N-acyliminium ion cyclization, we
reasoned that the kinetically favored ring-junction configu-
ration should be formed through Si face addition to lead to
formation of the b-epimer (Scheme 6). Confident that the
Scheme 5. Proposed mechanism for one-pot quinolizidine synthesis.
in a two-step one-pot process (Scheme 5 and Table 1).[30]
The mechanism for this reaction is proposed to proceed
through iminium ion activation and conjugate addition to
give 4. The sterically shielding groups on the catalyst will
shield the Re face of the intermediate iminium ion, thus fa-
Table 1. Enantio and diastereoselective one-pot formation of both ring-
junction epimers of the indolo
[2,3-a]-, benzo[a]-, and thieno
E
Scheme 6. Proposed transition states in the formation of thermodynami-
cally and kinetically favored ring-junction epimers in N-acyliminium ion
cyclization.
lizidine skeleton.[a]
diastereoselectivity in this step could be controlled to favor
selective formation of the a- or the b-ring-junction epimer
through kinetic or thermodynamic control, we set out to
find a series of acid conditions for the one-pot cascade. This
turned out to be a considerably challenging task and no real
trends could be observed, with most acids giving a close to
1:1 diastereomeric ratio.[34] After extensive screening, we
found a series of conditions that allowed for a diastereo-
meric switch (Table 1). Thus, quenching the reaction of b-
ketoamide 2a with acetyl chloride resulted in the formation
of a precipitate that was found to be the thermodynamically
Ar
Product
Acid
d.r.[b]
ee [%][c]
Yield
[%][d]
1
2
3
TFA
AcCl
50:50
>95:5
18:82
92
80
85
70
a-7a
ß-7a
92 (99)[f]
92 (95)[f]
BzCl[e]
4
5
a-7b
ß-7b
Et3O·BF4
SnCl4
70:30
22:78
92
92
73
76
favored indoloACTHUNTGRNEUNG[2,3-a]quinolizidine a-7a as the only observa-
ble isomer (Table 1, entry 2). Interestingly, when using ben-
zoyl chloride, we observed a switch in diastereoselectivity
and the kinetically favored product b-7a was obtained as
the major isomer in 82:18 diastereoselectivity (entry 3). It is
6
7
a-7c
ß-7c
Et3O·BF4
BzCl
67:33
33:67
95
94
94
78
also worth noting that the kinetically favored b-indoloACHTUNGTRENNUNG[2,3-
[a] A solution of aldehyde 1 (1.2 equiv), amide 2 (1 equiv), and catalyst 3
(20 mol%) in CH2Cl2 (1m) was stirred at room temperature. After full
conversion of 2, the given acid was added to the reaction mixture. [b] De-
termined by 1H NMR spectroscopy on the crude reaction mixture. [c] De-
termined by chiral HPLC on the major diastereoisomer. [d] Isolated com-
bined yields of both epimers. [e] Benzoyl chloride was added at À788C
and stirred for 4 h before being slowly allowed to reach room tempera-
a]quinolizidine b-7a could be epimerized to the thermody-
namically favored a-7a epimer by treatment with TFA
heated at reflux to give a ratio of 85:15 in favor of the a-
epimer (Scheme 7). When subjecting the pure thermody-
namically favored a-7a epimer to TFA heated at reflux, the
same thermodynamic equilibrium was reached. Since a
higher preference for the a-7a epimer was obtained by
using acetyl chloride than under thermodynamic equilibrium
ture over 4 h. [f] A solution of aldehyde
1 (1.2 equiv), amide 2a
(1 equiv), and catalyst 3 (20 mol%) in CH2Cl2 (1m) was stirred at À208C
for 72 h.
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J. Franzꢀn et al.
Scheme 7. Acid-catalyzed epimerization of a- and b-indolo
zidine 7a.
ACHTUNGTREN[NGNU 2,3-a]quinoli-
conditions (see Table 1, entry 2 and Scheme 7), it appears as
the acetyl chloride-promoted N-acyliminium ion cyclization
is not under thermodynamic control, which leads us to be-
lieve that the high selectivity observed is due to the precipi-
tation of the thermodynamically favored a-7a epimer
during the reaction. Unfortunately, the optimized acid con-
ditions for the indole compound could not be directly ap-
plied to selective ring-junction formation of the benzo[a]- or
Scheme 8. Enantio- and diastereoselective synthesis of the quinolizidine
skeleton.
b-ketoamide 2 (Scheme 8). At this stage, the a- and b-epi-
mers of amines 8a,b could be easily separated by flash
column. Next we needed to open the dihydropyran moiety,
bearing in mind selective formation of the final stereocenter.
Treatment of the a-epimers of amines a-8a–c with HCl in
water/THF at room temperature gave the trans ring junction
of the lactol a-trans-9a–c exclusively (Table 2, entries 1, 4,
the thienoACHTUNGTRENNUNG[3,2-a]quinolizidines 7b,c, so a new acid screening
was conducted. As for the initial screening of the indole
compound, the one-pot cascade using the phenyl- and thio-
phenyl-ketoamides 2b,c gave poor selectivity in the forma-
tion of the ring-junction stereocenter by using a variety of
different acid conditions. Eventually, we found that triethy-
loxonium tetrafluoroborate promoted the formation of the
thermodynamically favored ring-junction stereocenter a-
7b,c with moderate selectivity (entries 4–6). One-pot condi-
tions that favored the kinetic epimers benzo[a]- and thieno-
Table 2. Diastereodivergent lactol formation.[a]
ACHTUNGTRENNUNG[3,2-a]quinolizidines b-7b,c with moderate selectivity were
identified to be tin(IV) chloride and benzoyl chloride, re-
spectively (entries 5–7). The exact role of the acid with re-
spect to selectivity in the formation of the ring-junction ste-
reocenter is not clear, and we have not been able to detect
any obvious trends between different acids during screen-
ing.[34]
Ar
Starting
material
T [8C]
ratio[b]
trans/cis
Product
1
2
3
a-8a
ß-8a
ß-8a
RT
65
0
>95:5
83:17
20:80
a-trans-9a
ß-trans-9a
ß-cis-9a
Preparation of functionalized quinolizidine intermediates:
After establishing an efficient and stereoselective method
for the preparation of alkaloid carbon skeletons 7a–c, we
started to investigate how these intermediates could be ap-
plied in total synthesis. To obtain the desired natural prod-
ucts, we needed to reduce both the amide carbonyl and the
masked carbonyl group in the dihydropyran moiety. Our
main focus from this point on was to develop an efficient
methodology that used as few reaction steps as possible, and
to limit the number of isolations and purifications of reac-
tion intermediates. We also needed to consider separation of
the undesired ring-junction diastereoisomers as early as pos-
sible in the reaction sequence. It appeared that the a- and
b-epimers of amides 7a–c could not be easily separated on
flash column; however, reduction of the crude reaction mix-
ture from the one-pot cascade was accomplished by initial
alkylation with triethyloxonium tetrafluoroborate, followed
by NaBH4 reduction to give the corresponding amines 8a–c
in high to moderate overall yields from their corresponding
4
5
6
a-8b
ß-8b
ß-8b
RT
65
0
>95:5
71:29
<5:95
a-trans-9b
ß-trans-9b
ß-cis-9b
7
8
9
a-8c
ß-8c
ß-8c
RT
65
0
>95:5
72:28
<5:95
a-trans-9c
ß-trans-9c
ß-cis-9c
[a] Compound 6 was dissolved in 2m HCl(aq)/THF (1:3 c=0.1m) at the
given temperature. [b] Determined by 1H NMR spectroscopy on the
crude reaction mixture.
and 7; for nomenclature, see Scheme 3). The selective for-
mation of this stereocenter is due to the thermodynamic sta-
bility of the all-equatorial quinolizidine structure, and at-
tempts to access the a-cis configuration have failed
(Scheme 9). However, hydration of the dihydropyran in the
kinetic b-epimer series turned out to be under kinetic and
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Corynantheine and Ipecac Alkaloids
FULL PAPER
and the b-cis-9a–c could again be epimerized to a 2:1 mix-
ture of b-trans-9a–c and b-cis-9a–c through treatment with
HCl in water/THF at 658C. The lactols were isolated by ex-
traction with CH2Cl2. The CH2Cl2 solution was partially con-
centrated, and the resulting solution was treated with acetic
anhydride to promote ring opening of the lactol to give the
ketones 10a–c. The excess amount of acetic anhydride was
quenched by the addition of methanol before the reaction
mixture was treated with tosyl hydrazide in AcOH/MeOH
(1:3) to give the corresponding hydrazones (Scheme 10).
Any undesired epimer from the previous hydration of enol
ether 8 was separated by flash column, and the hydrazones
11a–c were isolated as a single isomer in good to excellent
overall yields from amine 8a–c without purification of syn-
thetic intermediates. All reactions from b-ketoamide 2 to
the hydrazone intermediate 11 were remarkably clean, and
in most cases, no byproducts could be observed in the crude
reaction mixtures by 1H NMR spectroscopy. However, it
should also be pointed out that the b-trans-quinolizidine
series was more difficult to handle than the a-trans- and b-
Scheme 9. Stereoselective hydration of enol ether.
thermodynamic control, and
treatment of benzo[a]quinolizi-
dine and thienoACHTUNGTRENNUNG[3,2-a]quinolizi-
dine b-9b,c with HCl in water/
THF at room temperature fa-
vored the cis configuration be-
2
3
À
tween C
C and gave a 2:1
mixture of b-cis-9b,c and b-
trans-9b,c. Further optimization
of the hydration revealed that
treatment of b-8b,c with HCl in
water/THF at 08C exclusively
2
3
À
gave the C
C cis configura-
tion and b-cis-9b,c were ob-
tained as the only observed iso-
mers (entries 6 and 9). The
Scheme 10. Stereodivergent syntheses of hydrazone intermediates 11a–c.
indoloACHTUNGTRENNUNG[2,3-a]quinolizidine b-8a
reacted with lower selectivity in
this reaction and gave a 4:1 mixture of b-cis-9a and b-trans-
9a (entry 3). Interestingly, lactol formation at elevated tem-
peratures (HCl in water/THF at 658C) reversed the selectiv-
ity and favored formation of benzo[a]quinolizidine and
cis-quinolizidine derivatives, in particular during purification
by flash column, which is also reflected in the lower isolated
yields of these compounds. The entire reaction sequence
starting from b-ketoamide 2a,b and a,b-unsaturated alde-
hyde 1 was also performed without any purification of syn-
thetic intermediates on a multigram scale to give 12b-a-
trans-11a as a single isomer in 63% overall yield and 11b-a-
trans-11a,b and 11b-b-cis-11a,b as a 1:1 mixture in 62%
combined overall yield (Scheme 11).
thieno
ACHTUNGTRENNUNG
tries 5 and 8). The indoloAHCTNUGTRENNNUG
higher selectivity under these reaction conditions, and b-
trans-9a was favored with a corresponding 5:1 diastereo-
meric ratio (d.r.; entry 2). Furthermore, we found that the
pure b-cis-9a–c epimers could be smoothly epimerized in
HClaq/THF at 658C to give b-trans-9a–c in the same diaste-
reomeric ratio as was observed for the acid catalyzed hydra-
tion of b-9a–c, thereby indicating that b-trans-9a–c is the
thermodynamically favored isomer. Our assumption is that
the epimerization is driven through the open keto form to
the more favored cyclohexane trans configuration followed
by relactonization (Scheme 9). The b-cis-9a–c and the b-
trans-9a–c epimers were easily separated by flash column,
Applications in total synthesis: We decided to proceed
through the hydrazone intermediate because from here we
have a choice of full reduction to the saturated C3 alkyl
chain or partial reduction under Shapiro conditions to give
the C3 vinyl group. The full reduction of benzo[a]quinolizi-
dine-hydrazones a-trans-11b and b-cis-11b to the ethyl
group and the simultaneous reductive cleavage of the ace-
tate moiety was accomplished by using diisobutylaluminium
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J. Franzꢀn et al.
nolizidine (10b-a-trans-14) were prepared in high yields
(Scheme 12). On the other hand, DIBAL-H reduction of
benzo[a]- and thienoACTHNUTRGNE[UNG 3,2-a]quinolizidine-hydrazones a-trans-
11b,c was sluggish and after 10 min reaction time only the
intermediate hydrazine 15 could be isolated, along with sev-
eral unidentified byproducts. Prolonged reaction time at ele-
vated temperature (DIBAL-H, 3 h, RT) slowly decomposed
the hydrazine intermediate to the product in low yields. The
hydrazine intermediate 15 was remarkably stable and could
be isolated before it was thermally decomposed at 708C to
the desired product in low yields. The a-trans- and b-trans-
indoloACTHNURTGNEU[GN 2,3-a]quinolizidine hydrazones 11a also reacted with
poor selectivity with DIBAL-H and gave low yields and
mixtures of product and byproducts. After screening of dif-
ferent reducing agents we found that NaBH3CN in the pres-
ence of 3 equivalents of HCl cleanly reduced indolo
a]quinolizidine hydrazones 12b-a-trans-11a and 12b-b-
trans-11a, benzo[a]- and thieno[3,2-a]quinolizidine hydra-
ACHTUNGTRENNUNG[2,3-
AHCTUNGTRENNUNG
zones b-trans-11b,c to the corresponding hydrazines 15. The
intermediate hydrazines 15 were isolated by extraction and
heated in DMF (1008C) to decompose the hydrazine inter-
mediate, followed by addition of KOHaq/methanol/CH2Cl2
to hydrolyze the acetate group, thereby giving the natural
product (À)-dihydrocorynantheol (12b-a-trans-13) and
(+)-hirsutinol (12b-b-trans-13) as well as the analogues
Scheme 11. Multigram syntheses of hydrazone intermediates 11a,b.
hydride (DIBAL-H). Full consumption of the starting mate-
rial was observed after 10 min at À788C in a clean and high-
yielding reaction to give the natural product (À)-protoeme-
tinol (11b-a-trans-12) in 92% yield from 11b-a-trans-11b
and 49% overall yield from b-ketoamide 2b. In the same
manner, the analogues 3-epi-11b-epi-protoemetinol (11b-b-
(+)-11b-epi-protoemetinol (11b-b-trans-12) and thienoACHTUNGTRENNUNG[3,2-
a]quinolizidine 10b-b-trans-14 in good overall yields
cis-12), 3-epi-hirsutinol (12b-b-cis-13), and thieno
G
(Scheme 12). As previously mentioned, the hydrazone
Scheme 12. Preparation of a series of natural products, their analogues and epimers through full and partial hydrazone reduction.
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Corynantheine and Ipecac Alkaloids
FULL PAPER
moiety also provides access to a vinyl group at the C3 posi-
tion through partial reduction under Shapiro conditions.
Thus, treatment of hydrazones a-trans-11 and b-trans-11
with nBuLi resulted in the elimination of the hydrazone and
deacetylation to provide access to the natural product (À)-
corynantheol (12b-a-trans-16) and the analogues dehydro-
protoemetinol (11b-a-trans-17), 11b-epi-dehydroprotoeme-
tinol (11b-b-trans-17), and thienoACTHNUGTRNEUNG[3,2-a]quinolizidine 10b-a-
trans-18 in moderate to good yields (Scheme 12).
The hydroxyquinolizidines were smoothly oxidized by
using Dess–Martin periodinane to give the naturally occur-
ring alkaloids (À)-dihydrocorynantheal (12b-a-trans-19),
(À)-corynantheal (12b-a-trans-20) and (À)-protoemetine
Scheme 14. The formal synthesis of (À)-emetine, cephaeline, (À)-tubulo-
sine, and (À)-deoxytubulosine from (À)-protoemetine 11b-a-trans-21.
(11b-a-trans-21), and the analogue thienoACHTNUTRGNEUNG[3,2-a]quinolizi-
dine 10b-a-trans-22 in overall high yields (Scheme 13). (À)-
mine, serotonin, and tryptamine, respectively (Scheme 14).
Furthermore, Jones oxidation of dihydrocorynantheal 19 in
methanol gives the corresponding methyl ester;[40] subse-
quent formylation and methylation provides an efficient
formal
synthesis
of
(+)-dihydrocorynantheine
(Scheme 15).[41] The same approach should also provide
access to hirsutine and corynantheine from hirsutinol and
corynantheal.
Scheme 15. The formal synthesis of (+)-dihydrocorynantheine from (À)-
dihydrocorynantheal 12b-a-trans-19.
This methodology was also applied in the protecting-
group-free total synthesis of (À)-(15S)-hydroxydihydrocory-
nantheol 12b-a-trans-23, an alkaloid isolated in 1999 from
an endemic tree of Puerto Rico, Antirhea portoricensis (Ru-
biaceae).[42] Lactol 12b-a-trans-9a was prepared without pu-
rification of intermediates and the crude compound was dis-
solved in methanol/CH2Cl2 and directly reduced with
NaBH4 to give an 81:19 mixture of diols in high yields
Scheme 13. Natural product synthesis.
1
(Scheme 16). By comparing the H NMR spectroscopic data
Protoemetine occupies a key position among the ipecac al-
kaloids since it is considered to be an intermediate in the
biogenesis of emetine and several related alkaloids.[35] Thus,
the quinolizidine aldehydes 19–22 are useful synthetic pre-
cursors for further transformation into a broad variety of
quinolizidine natural products of higher structural complexi-
ty. For example, the methodology described here represents
an efficient formal synthesis of (À)-emetine,[36] (À)-cephae-
line,[36,37] (À)-tubulosine,[38] and (À)-deoxytubulosine[39]
through the Pictet–Spengler annulation of (À)-protoemetine
21 with 3,4-dimethoxyphenylethylamine, O-methyldopa-
of the major isomer with literature data, we were able to
conclude that this was the nonnatural epimer (15R)-hydrox-
ydihydrocorynantheol 12b-a-trans-23. However, opening of
the lactol 12b-a-trans-9 to the ketone 12b-a-trans-10 and
subsequent reduction by using l-Selectride gave the natural
product (À)-(15S)-hydroxydihydrocorynantheol 12b-a-trans-
23 with 77:23 diastereoselectivity and 50% combined overall
yield from b-ketoamide 2a.[43]
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J. Franzꢀn et al.
series. This synthetic strategy also provides easy access to
the natural products (À)-dihydrocorynantheal, (À)-corynan-
theal, (À)-protoemetine, and different analogues thereof in
high overall yields. We also describe the total synthesis of
(À)-(15S)-hydroxydihydrocorynantheol and the formal syn-
thesis of (À)-emetine, (À)-cephaeline, (À)-tubulosine, (À)-
deoxytubulosine, and (+)-dihydrocorynantheine. The major
benefits of this strategy are the easily available starting ma-
terials, common synthetic strategy, stereodivergent reaction
steps, omission of protection groups, and limited isolations
and purifications of reaction intermediates. Due to efficien-
cy, product diversity, and operational simplicity, this protocol
has the potential to find important uses in natural product
synthesis, biochemistry, and pharmaceutical science.
Experimental Section
Purification-free multigram preparation of hydrazone 12b-a-trans-11a:
b-Ketoamide 2a (2.44 g, 10 mmol) and R catalyst 3 (650 mg, 2 mmol)
were dissolved in CH2Cl2 (10 mL). 5-Hydroxyl-pentaldehyde 1 (1.20 g,
1.2 mmol) was added to this solution, and the resulting reaction mixture
was stirred until a white or white/brown precipitate was formed that indi-
cated full conversion. Acetyl chloride (100 mmol, 7.10 mL) was added,
and the mixture was stirred overnight at room temperature. The reaction
was quenched by addition of saturated NaHCO3(aq), and the water phase
was extracted with CH2Cl2. The combined organic phases were dried
(Na2SO4), filtered, and concentrated under reduced pressure. The residue
was dissolved in CH2Cl2 (200 mL) followed by addition of di-tert-butyl-
pyridine (5.70 g, 35 mmol) and Et3O·BF4 (3.80 g, 25 mmol). After 4 h,
CH2Cl2 was removed under vacuum, and the residue was redissolved in
methanol (150 mL) and cooled to 08C. NaBH4 (2.30 g, 60 mmol) was
added in small portions, and the resulting mixture was stirred for 1 h at
room temperature. Methanol was removed under vacuum and the resi-
due was dissolved in THF (100 mL) and 2m HCl(aq) (100 mL). The mix-
ture was stirred overnight before being quenched with saturated
NaHCO3 and NaOH (10 mL, 5% aqueous solution). The water phase
was extracted with CH2Cl2, and the combined organic phases were dried
(Na2SO4). CH2Cl2 was removed under vacuum until approximately
100 mL remained. Pyridine (8.0 g, 100 mmol), 4-dimethylaminopyridine
(DMAP; 30 mg, 0.2 mmol), and acetic anhydride (10 g, 100 mmol) were
added to this solution in turn. The reaction was left for 4 h at room tem-
perature before saturated NaHCO3 was added. The water phase was ex-
tracted with CH2Cl2, and the combined organic phases were dried
(Na2SO4). The solvent was removed, then the residue was dissolved in
methanol (120 mL) and acetic acid (40 mL) followed by the addition of
tosylhydrazide (3.72 g, 20 mmol). The reaction was stirred overnight at
room temperature before being quenched with saturated NaHCO3. The
water phase was extracted with CH2Cl2, and the combined organic
phases were dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue was purified with column chromatography to give
12b-a-trans-11a as a yellow solid (2.77 g, overall yield: 53%).
Scheme 16. Purification and protecting group free total synthesis of natu-
ral product (À)-(15S)-hydroxydihydrocorynantheol 12b-a-trans-23 and its
epimer (15R)-hydroxydihydrocorynantheol.
Conclusion
We have described the development of a highly efficient
and enantioselective synthetic strategy that allows for access
to a broad number of optically active quinolizidine alkaloids
of the corynantheine and ipecac families on a multigram
scale. The optical activity is introduced by asymmetric catal-
ysis that starts from easily available nonchiral starting mate-
rials, and the following two stereocenters are introduced
through diastereodivergent reactions. By employing diaster-
eodivergent steps, selective access to 3 out of 4 possible op-
tically active diastereomers can be realized from common
starting materials by using the same synthetic strategy. The
focus during the development of this strategy has been on
efficiency, and the majority of our attention has been devot-
ed to excluding protection groups and finding reaction con-
ditions compatible with a limited number of isolation and
purification steps. Most of the reaction steps are extremely
high yielding and the potential of this methodology in natu-
ral product synthesis is demonstrated by the total synthesis
of (À)-dihydrocorynantheol in 47% overall yield, (À)-proto-
emetinol in 49% overall yield, and (À)-corynantheol in
42% overall yield from easy accessible a,b-unsaturated al-
dehyde 1 and b-ketoamide 2. Furthermore, this methodolo-
gy also provides easy access to an array of epimers and ana-
logues not accessible through synthetic elaboration of natu-
rally occurring alkaloids, which is exemplified by the synthe-
(À)-Dihydrocorynantheol 12b-a-trans-15: HCl (3 equiv, 1m in Et2O) was
added dropwise at 08C to a solution of the hydrazone 12b-a-trans-11a
and NaBH3CN (2.2 equiv) in DMF (c=0.1m). The resulting mixture was
stirred at room temperature overnight and quenched with Na2CO3(aq)
(2m). The water phase was extracted with CH2Cl2, and the combined or-
ganic phases were dried (Na2SO4), filtered, and concentrated under re-
duced pressure to give a solution of the crude tosylhydrazine in DMF.
The DMF solution was heated at 1008C for 45 min before being cooled
to room temperature. CH2Cl2 (10 mLmmolÀ1), MeOH (10 mLmmolÀ1),
and KOH(aq) (1m, 10 mLmmolÀ1) were added, and the resulting mixture
was stirred vigorously for 2 h before being dispersed between CH2Cl2
and water. The water phase was extracted with CH2Cl2, and the com-
bined organic phases were dried (Na2SO4), filtered, and concentrated
sis of the thieno
ACHTUNGTRENNUNG[3,2-a]quinolizidine natural product ana-
logues as well as the synthesis of the b-cis-quinolizidine
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Corynantheine and Ipecac Alkaloids
FULL PAPER
under reduced pressure. The crude product was purified by flash chroma-
tography (EtOAc/MeOH) to give the title compound in 74% overall
yield. [a]2D0 =À13.5 (c=0.004 in CDCl3) (lit: [a]2D0 =À20.4 (c=0.25 in
CDCl3)). All characterization data was in accordance with those previ-
ously reported.[44,45]
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(À)-Corynantheol 12b-a-trans-16: The hydrazone compound 12b-a-
trans-11a was dissolved in anhydrous THF (c=0.1m) under nitrogen at-
mosphere and cooled down to À788C. nBuLi (5 equiv, 2.3m in hexane)
was added dropwise to this solution. During the addition, the reaction
mixture turned from yellow to brown, and the resulting solution was al-
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(5 mL) was added to quench the reaction and the water phase was ex-
tracted with CH2Cl2. The combined organic phases were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude product
was purified by flash chromatography (EtOAc/MeOH) to give the title
compound in 67% yield according to the general procedure described
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Acknowledgements
This work was made possible by a grant from the Swedish Research
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Received: June 30, 2011
Published online: November 3, 2011
13824
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Chem. Eur. J. 2011, 17, 13814 – 13824