Convergent synthesis of (-)-quinocarcin based on the combination of sonogashira coupling and gold(I)-catalyzed 6-endo-dig hydroamination

Article abstract of DOI:10.1002/chem.201300687

The total synthesis of the pentacyclic tetrahydroisoquinoline alkaloid quinocarcin, which possesses intriguing structural and biological features, has been achieved through a gold(I)-catalyzed regioselective hydroamination reaction. It is noteworthy that the regioselectivity of the intramolecular hydroamination of an unsymmetrical alkyne could be completely switched through substrate control. Other key features of this synthesis include the highly stereoselective synthesis of 2,5-cis-pyrrolidine through the intramolecular amination of the bromoallene and the Lewis acid mediated ring opening of dihydrobenzofuran. Golden(I): A convergent asymmetric total synthesis of quinocarcin employed Sonogashira and Au-catalyzed hydroamination reactions (see scheme). The regioselectivity of the intramolecular hydroamination of an unsymmetrical alkyne was switched by substrate control. Copyright

Full text of DOI:10.1002/chem.201300687

FULL PAPER
DOI: 10.1002/chem.201300687
Convergent Synthesis of (À)-Quinocarcin Based on the Combination of
Sonogashira Coupling and Gold(I)-Catalyzed 6-endo-dig Hydroamination
Hiroaki Chiba, Yuki Sakai, Ayako Ohara, Shinya Oishi, Nobutaka Fujii,* and
Hiroaki Ohno*[a]
Abstract: The total synthesis of the
pentacyclic tetrahydroisoquinoline al-
kaloid quinocarcin, which possesses in-
triguing structural and biological fea-
tures, has been achieved through a
gold(I)-catalyzed regioselective hydro-
lecular hydroamination of an unsym-
metrical alkyne could be completely
switched through substrate control.
Other key features of this synthesis in-
clude the highly stereoselective synthe-
sis of 2,5-cis-pyrrolidine through the in-
tramolecular amination of the bro-
moallene and the Lewis acid mediated
ring opening of dihydrobenzofuran.
Keywords: allenes · cross-coupling ·
gold
· natural products · total
ACHTUNGTRENNUNGamination reaction. It is noteworthy
that the regioselectivity of the intramo-
synthesis
Introduction
(À)-Quinocarcin is a pentacyclic tetrahydroisoquinoline al-
kaloid that was first isolated by Tomita, Takahashi, and Shi-
mizu in 1983 from Streptomyces melanovinaceus
(Figure 1).[1] This material was reported to exhibit remarka-
ble levels of antiproliferative activity against lymphocytic
leukemia. Further in vitro studies with the more stable cit-
rate salt KW2152[2] and the aminonitrile DX-52-1[3] revealed
that these compounds exhibited inhibitory activity towards
non-small cell-lung cancer and adenocarcinoma. A large
number of different natural products within this structural
class, from a variety of different environments, have been
reported.[4] For example, renieramycin G[5] was obtained
from Fijian sea sponges, whereas ecteinascidin 743 (Et-743,
Yondelis)[6] was isolated from Caribbean sea squirts. Fur-
thermore, lemonomycin[7] and saframycin B[8] were isolated
from the cultures of Streptomyces strains. Some of the com-
pounds that belong to this family have been evaluated as an-
ticancer agents in advanced human clinical trials. It is note-
worthy that Et-743 exhibited high levels of activity towards
a broad range of tumor cell-lines at pm and low nm concen-
trations.[9] Therefore, this class of tetrahydroisoquinoline al-
kaloids has been the subject of considerable renewed inter-
est from the drug-discovery community because of their po-
tential use as anti-cancer agents.
Figure 1. Quinocarcin and related tetrahydroisoquinoline alkaloids.
These tetrahydroisoquinoline alkaloids share a common
skeleton that is composed of a piperizinohydroisoquinoline
motif. In addition to their potent biological properties, their
fascinating and challenging molecular architectures have in-
spired many synthetic groups to develop creative ap-
proaches towards their total synthesis. Although several effi-
cient methods have been reported for the specific synthesis
of these alkaloids, the development of a new and convergent
route that is capable of providing general access to several
tetrahydroisoquinolines in this class is still desirable.
[a] H. Chiba, Y. Sakai, A. Ohara, Dr. S. Oishi, Prof. Dr. N. Fujii,
Prof. Dr. H. Ohno
Graduate School of Pharmaceutical Sciences, Kyoto University
Sakyo-ku, Kyoto 606-8501 (Japan)
Fax : (+81)75-753-4570
E-mail: nfujii@pharm.kyoto-u.ac.jp
hohno@pharm.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300687.
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Scheme 2. Regioselectivity issue in the total synthesis of (À)-quinocarcin
through the alkyne-hydroamination reaction.
Scheme 1. Total syntheses of quinocarcin, reported by Fukuyama and
Nunes[10] and by Allan and Stoltz.[11f] Cbz=benzyloxycarbonyl.
potential issues that were associated with this strategy in-
volved the regioselectivity of the reaction, in that the alkyne
carbon atom at the benzylic position would be a highly reac-
tive site for the hydroamination reaction, which would lead
to the formation of the undesired isoindoline-type product
B through a 5-exo-dig cyclization reaction. With this issue in
mind, a precise optimization of the reaction conditions
would be required, in conjunction with any appropriate
modifications to the structures of the substrates. Herein, we
report a complete account of our investigation towards the
construction of the core structure of quinocarcin by using a
gold(I)-catalyzed hydroamination reaction, including a de-
scription of the complete switch that is observed in the re-
gioselectivity (5-exo-dig to 6-endo-dig) of the transformation
following changes to the substrate structure.[15] The stereose-
lective construction of an alkyne synthon of type A, through
a bromoallene-cyclization reaction, and the unusual cleav-
age of a dihydrobenzofuran moiety, thus allowing for the
completion of the total synthesis, are also presented.
In the majority of the reported syntheses of quinocar-
cin,[10,11] including the first total synthesis by Fukuyama and
Nunes (Scheme 1a),[10] and the syntheses of other related al-
kaloids, the Pictet–Spengler condensation reaction has been
used as one of the most reliable procedures for the construc-
tion of the isoquinoline core.[10,11d,e,12] In an alternative strat-
egy, Allan and Stoltz[11f] accomplished their total synthesis
based on a unique annulation reaction of an N-acyl enamine
with an aryne to generate the isoquinoline skeleton (Sche-
me 1b). It is noteworthy that this new approach allows the
development of the shortest synthetic route to the assembly
of the core tetrahydroisoquinoline ring system reported to
date.
The transition-metal-catalyzed intramolecular hydroami-
nation reaction of alkynes is currently recognized as one of
the most synthetically useful and straightforward approaches
for the construction of nitrogen-containing heterocycles.[13]
Several research groups have made significant contributions
to this area, which have resulted in the development of a va-
riety of different catalytic systems. Of the many transition-
metal catalysts that are available, gold has been reported to
be particularly effective for activating alkynes towards nu-
cleophilic attack.[14] Unfortunately, noble gold was for a long
time considered to be catalytically inactive and its potential
in organic chemistry was, consequently, overlooked. Howev-
er, over the course of the last decade, gold catalysis has rap-
idly become a topic of considerable interest in chemistry.
The soft character of this large atom provides a pronounced
affinity towards alkynes that ultimately translates into mild
reaction conditions and high yields of the desired addition
products.[14]
Results and Discussion
Preparation of 2,5-cis-pyrrolidine 5 through the highly cis-
selective intramolecular amination of bromoallene 6: Our
retrosynthetic analysis is shown in Scheme 3. It was envis-
aged that known lactam 1[11e,f] could be synthesized from di-
hydroisoquinoline 2 through a diastereoselective hydrogena-
tion reaction, followed by intramolecular amide formation.
This strategy is similar to that reported by Fukuyama and
Nunes[10] and by Allan and Stoltz[11f] for the late-stage con-
struction of the piperidine ring. As described above, dihy-
droisoquinoline 2 could be synthesized by using the transi-
tion-metal-catalyzed intramolecular hydroamination of al-
We have designed a new strategy for the preparation of
the tetrahydroisoquinoline core of quinocarcin (Scheme 2),
based on the idea that the gold-catalyzed hydroamination of
an alkyne would provide a powerful alternative to the exist-
ing repertoire of synthetic strategies. One of the attractive
features of this strategy is that the reactant alkyne A could
be prepared by using the Sonogashira coupling of two ad-
vanced fragments during the latter stages of the synthesis,
which would effectively facilitate the preparation of quino-
carcin derivatives and other related alkaloids. One of the
ACHTUNGTRENkNUGN yne 3. A review of the literature revealed that no prece-
dent existed for retrosynthetically disconnecting the tetrahy-
droisoquinoline skeleton of these alkaloids in this particular
manner. We envisaged that alkyne 3 could be constructed
by the Sonogashira coupling of phenylglycinol 4 with 2,5-cis-
pyrrolidine 5. Compound 5 itself could be prepared stereo-
selectively through a 2,5-cis-selective pyrrolidine-formation
reaction through the intramolecular amination of bromoal-
lene 6, which contained a sulfonamide group, according to a
method that was originally developed by our group.[16]
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Convergent Synthesis of (À)-Quinocarcin
FULL PAPER
To improve our understanding of the scope of this pro-
AHCTUNGTRENNUNG
Scheme 3. Retrosynthetic analysis of (À)-quinocarcin.
The development of a highly stereoselective method for
the preparation of cis-pyrrolidine 5 would be vital to the
success of our synthetic strategy. Just over a decade ago, we
reported the intramolecular amination reactions of bromoal-
lenes 7 and 9, as shown in Scheme 4.[16] Thus, 2,3-cis-2-ethy-
Scheme 5. Model experiment for the cyclization of the bromoallene.
Reagents and conditions: a) tert-butyldiphenylsilyl chloride (TBDPSCl),
imidazole, DMF, 208C; b) lithium hexamethyldisilazide (LHMDS), TsCl,
THF, 208C; c) DIBAL-H, CH2Cl2, 208C; d) ethynylmagnesium bromide,
THF, 208C; e) MsCl, Et3N, CH2Cl2, 08C; f) CuBr·SMe2, LiBr, THF,
208C; g) NaH, DMF, 208C.[16] Ms=methanesulfonyl, Ts=4-toluenesul-
fonyl.
erature report,[17] 11 was converted into compound 12
through the successive protection of the hydroxy and amide
functionalities with tert-butyldiphenylsilyl (TBDPS) and 4-
toluenesulfonyl (Ts) groups, respectively. The subsequent re-
duction of compound 12 with diisobutylaluminum hydride
(DIBAL-H), followed by the addition of ethynylmagnesium
bromide to the resulting hemiaminal, afforded the propargyl
alcohol 13 in 79% yield as a mixture of diastereomers.
Then, the corresponding mesylate, which was prepared by
the treatment of 13 with MsCl and Et3N, was reacted with
CuBr·SMe2/LiBr[18] to give the bromoallene 14. The ratio of
1
diastereomers was determined to be 86:14 by H NMR spec-
Scheme 4. Our previous results on the highly cis-selective intramolecular
amination of bromoallenes.[16] DMF=N,N-dimethylformamide, Mts=
2,4,6-trimethylbenzenesulfonyl.
troscopy. The treatment of bromoallene 14 with NaH in
DMF afforded the desired 2,5-cis-pyrrolidine 15 with good
stereoselectivity (cis-15/trans-15, 88:12). In contrast, the re-
action of the corresponding mesylate 16 under identical con-
ditions gave 2,5-trans-pyrrolidine 15 (cis-15/trans-15=12:88),
through an inversion of the configuration, which reflected
the original ratio of the stereoisomers of mesylate 16
(87:13). This result demonstrated that the tert-butyldiphenyl-
siloxymethyl moiety at the 6-position and the tosyl group on
the nitrogen atom effectively induced the cis-selective cycli-
zation reaction, although their influences were relatively
smaller than those of the isopropyl and/or Mts groups in
compound 9 (Scheme 4).
nylaziridines 8 were obtained from both (S,aS)- and (S,aR)-
bromoallenes 7, which contained an N-sulfonylated amino
group, following their treatment with NaH in DMF or THF.
Although the pyrrolidine formation of bromoallenes 9 also
proceeded in
a
highly cis-selective manner (>99:1,
Scheme 4), the formation of the five-membered ring was
only investigated as an isolated example. Therefore, the ef-
fects of the relatively small alkoxymethyl (at the 6-position)
and tosyl groups (on the nitrogen atom) of bromoallene 6
(Scheme 3) on this reaction, as well as of the additional sub-
stituent at the 4-position, remain unclear.
Based on the success of this model reaction, we focused
on the preparation of the target pyrrolidine 5 (Scheme 3),
which contained an ester functionality at its 3-position. We
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N. Fujii, H. Ohno et al.
initially expected that the diastereoselective aldol reaction
of g-butyrolactone 18 with aldehyde 19 would provide a
convenient route to bromoallene 6 with the requisite func-
tionality and stereochemistry (Scheme 6). Disappointingly,
the stereoselectivity of this reaction was not satisfactory
(3,5-trans-20/cis-20, 80:20) and the separation of these iso-
mers was difficult.[19] Therefore, we decided to modify the
synthetic route.
oxidation produced propargyl alcohol 25 as a mixture of dia-
stereomers. The treatment of 25 with MsCl and Et3N gave
the corresponding mesylate, which was subsequently reacted
with CuBr·SMe2/LiBr,[18] followed by removal of the tert-bu-
toxycarbonyl (Boc) group with trifluoroacetic acid (TFA),
to afford bromoallene 6 (d.r.=55:45; as determined by
1H NMR spectroscopy).
The formation of the 2,5-cis-selective pyrrolidine was ini-
tially attempted by performing the intramolecular amina-
tion[16] of bromoallene 6 (Scheme 8). The treatment of com-
Scheme 6. Attempted synthesis of compound 6 from the aldol reaction of
g-butyrolactone 18. Reagents and conditions: a) TBDPSCl, imidazole,
DMF, 208C; b) LHMDS, THF, À788C. TMS=trimethylsilyl.
Our modified synthetic route for the construction of bro-
moallene 6 is shown in Scheme 7. We expected that sequen-
tial diastereoselective propargylation and selenium-mediat-
ed oxidation reactions would provide access to the desired
propargyl alcohol of type 21. In contrast to the aldol reac-
Scheme 8. Preparation of 2,5-cis-pyrrolidine 5 by the highly cis-selective
intramolecular amination of bromoallene 6. Reagents and conditions:
a) TBAF, THF, 208C; b) K2CO3, MeOH, 208C; c) Dess–Martin periodi-
nane, CH2Cl2, 208C; d) NaClO2, 2-methylbut-2-ene, NaH2PO4·2H2O,
tBuOH/CH2Cl2/H2O (8:3:8), 08C; e) 1-hydroxybenzotriazole, EDC·HCl,
MeOH, 208C; f) Mg, MeOH, À208C; g) MeI, Cs2CO3, acetone, 208C.
EDC=N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide.
pound 6 with NaH in DMF at room temperature successful-
ly provided the desired 2,5-cis-pyrrolidine 26 in 95% yield
with excellent diastereoselectivity (cis-26/trans-26, 96:4). In
a similar manner to the model system shown in Scheme 5,
the intramolecular SN2 reaction of mesylate 27 under identi-
cal reaction conditions afforded compound 26 as a mixture
of diastereomers in a ratio that corresponded to the initial
ratio in the mesylate (cis-26/trans-26, 55:45). Then, the de-
sired pyrrolidine 5 was prepared from cis-26 by the removal
of the TBDPS and Ac groups, followed by sequential oxida-
tion, esterification, detosylation, and N-methylation reac-
tions by using standard procedures.
Scheme 7. Modified synthetic route to bromoallene 6. Reagents and con-
ditions: a) LHMDS, propargyl bromide, THF, À808C; b) LiBH4, MeOH,
Et2O, 20 8C; c) AcCl, 2,4,6-collidine, CH2Cl2, À208C; d) TsBocNH, PPh3,
diisopropyl azodicarboxylate, THF, 208C; e) SeO2, tert-butylhydroperox-
ide, DCE, 608C; f) MsCl, Et3N, CH2Cl2, 208C; g) CuBr·SMe2, LiBr, THF,
508C; h) TFA, CH2Cl2, À208C. DCE=1,2-dichloroethane, TFA=tri-
fluoroacetic acid, Ac=acetyl.
Model experiments for the regioselective hydroamination of
the alkyne: With key building block 5 in hand, our attention
turned to the regioselective hydroamination reaction. Thus,
model substrates 30a–30 f were prepared by using a copper-
free Sonogashira coupling reaction[23] from racemic aryl io-
dides 4 and readily available propargyl amines 29, as shown
in Scheme 9. It is noteworthy that the application of stand-
ard Sonogashira coupling conditions, with a copper co-cata-
lyst, resulted in the generation of significant quantities of
the homocoupled alkyne products.
tion, the propargylation reaction proceeded in a highly ster-
eoselective manner to exclusively afford 3,5-trans-lactone
22. Following the reduction of the lactone 22 with LiBH4,[20]
the primary hydroxy group of the resulting diol was selec-
tively acetylated[21] to give alcohol 23. The Mitsunobu reac-
tion[22] of 23 with TsBocNH allowed for the introduction of
a nitrogen functionality and subsequent selenium-mediated
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Convergent Synthesis of (À)-Quinocarcin
FULL PAPER
À
lyzed C N bond formation occurred preferentially at the
more cationic carbon atom, which contained an aryl sub-
stituent.
Based on the unsuccessful results of these model experi-
ment, we turned our attention towards modifying the sub-
strate structure (Scheme 10). The use of seven-membered
Scheme 9. Preparation of model substrates 30a–30 f for the hydroamina-
tion reactions of the alkynes. MOM=methoxymethyl.
Our initial efforts were focused on investigating the hy-
droamination reaction of the alkynes by using simple model
substrates 30a and 30b (Table 1). Following the optimiza-
Table 1. Investigation of the regioselective hydroamination reaction
(6-endo-dig versus 5-exo-dig).
Scheme 10. Substrate-controlled 6-endo-dig hydroamination of alkynes.
acetonide-type substrate 30c partially overcame the inherent
preference for the 5-exo-dig cyclization, thereby leading to
the desired 6-endo-dig product 31c in 61% yield, together
with the 5-exo-dig product 32c (32% yield). However, dis-
appointingly, the regioselectivities were decreased when ace-
tonide-type substrates 30d and 30e, which contained methyl
and tert-butyl ester groups, respectively, were used. In sharp
contrast, the desired 6-endo-dig product 31 f was obtained
exclusively in 73% yield when dihydrobenzofuran-type sub-
strate 30 f was used with gold catalyst 33. This difference in
reactivity was attributed to the ring strain in the 5-exo-dig
product 32 f. Gold catalyst 34, which was generated in situ
from IPrAuCl (IPr=1,3-bis(diisopropylphenyl)imidazol-2-
ylidene) and AgNTf2 in DCE afforded compound 31 f in
96% yield. These model experiments demonstrated that a
dihydrobenzofuran-type aryl iodide would be the target
building block for the phenylglycinol derivative 4 for this
synthesis.
Entry
Alkyne
Metal cat.
Solvent
T
[8C]
Yield
[%][a]
31
32
1[b]
2[c]
3[c]
4[c]
5
30a
30a
30a
30a
30b
30b
30b
CuBr
PtCl2
PPh3AuCl
JohnPhosAuCl
DMF
100
25
25
25
80
80
25
–
–
–
6
–
–
–
21
–
43
72
–
CH2Cl2
CH2Cl2
CH2Cl2
DCE
DCE
DCE
In
[{RhCl
cat. 33
ACHTUNGTRENNUNG
6
7
G
U
–
74
[a] Yield of isolated product. [b] TBAF (5 mol%) was used as an addi-
tive. [c] AgNTf2 (5 mol%) was used as an additive. JohnPhos=(2-biphe-
nyl)di-tert-butylphosphine.
tion of the reaction conditions, cationic gold(I) catalysts
were found to be the most efficient among the variety of dif-
ferent transition-metal catalysts that we tested for promot-
ing the hydroamination reaction (Table 1, entries 1–6). How-
ever, disappointingly, the undesired 5-exo-dig cyclization
products 32a and 32b were obtained exclusively in most
cases.[24] This observed regioselectivity was attributed to the
electronic properties of the alkyne, in that the gold(I)-cata-
Our efforts towards the preparation of optically active di-
hydrobenzofuran (R)-4d began with the formylation of 3-
fluoroiodobenzene 35 through its treatment with lithium di-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
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N. Fujii, H. Ohno et al.
Scheme 11. Preparation of optically active dihydrobenzofuran (R)-4d.
Reagents and conditions: a) LDA, DMF, THF, 208C; b) MePPh3Br,
LHMDS, THF, 08C; c) OsO4, hydroquinine 1,4-phthalazinediyl diether,
K2CO3, [K3Fe(CN)6], MeSO2NH2, tBuOH/H2O (1:1), 08C; d) TBSCl, 4-
(dimethylamino)pyridine, Et3N, CH2Cl2, 208C; e) DPPA, diethyl azodi-
carboxylate, PPh3, THF, 08C; f) TBAF, THF, 08C; g) tBuOK, THF,
208C; h) PhSH, SnCl2, Et3N, THF, 208C; i) Boc2O, Et3N, CH2Cl2, 208C.
brsm=based on recovered starting material.
diol 37 was obtained in good yield and moderate enantiose-
lectivity (83% yield, 81% ee). Pleasingly, diol 37 was ob-
tained with an excellent level of optical purity (>99% ee),
following a single recrystallization from CHCl3. The silyla-
tion of the primary alcohol of compound 37 by its treatment
with tert-butyldimethylsilyl chloride (TBSCl) and Et3N, fol-
lowed by a Mitsunobu reaction with diphenylphosphoryl
azide (DPPA)[26] and the removal of the TBS group with
tetra-n-butylammonium fluoride (TBAF), afforded azide al-
cohol 38 in excellent yield. The desired dihydrobenzofuran
derivative 39 was obtained in 51% yield through the intra-
molecular SNAr reaction of alcohol 38 in the presence of
tBuOK in THF at room temperature.[27] Although the Stau-
dinger reduction[28] of azide 39 did not provide satisfactory
results, the treatment of compound 39 with PhSH, SnCl2,
and Et3N in THF[29] successfully afforded the corresponding
amine, which was subsequently converted into optically pure
compound (R)-4d in 82% yield by treatment with Boc2O/
Et3N.
Scheme 12. Construction of the core structure of quinocarcin (42). Re-
agents and conditions: a) [PdACHTNUGTRNENUG(PPh3)4], CuSO4, sodium ascorbate, DMF/
Et3N (3:2), 808C. b) TFA, CH2Cl2, 08C; c) NaBH3CN, DCE/MeOH
(2:1), 1m HCl, 08C; d) AcOH, toluene, 808C.
Table 2. Gold(I)-catalyzed hydroamination of alkynes.
Entry
Alkyne
Gold cat.
[mol%]
T
[8C]
Yield
[%][a]
Recovery
[%][a]
N
1
2
3
4
5
6
3a
3a
3a
3a
3b
3b
34 (10)
33 (10)
33 (25)
33 (40)
33 (10)
33 (20)
45
70
70
60
45
45
3
17
38
9
37
–
–
–
46
61[b]
90[b]
Total synthesis of (À)-quinocarcin through a gold(I)-cata-
lyzed 6-endo-dig selective hydroamination reaction: With
both of the building blocks, that is compounds (R)-4d and
2,5-cis-5, in hand, the stage was set for their coupling and
for the construction of the quinocarcin core structure. Thus,
the treatment of compounds (R)-4d and 2,5-cis-5 with [Pd-
–
[a] Yield of isolated compound. [b] Yield after reduction with NaBH3CN
(Scheme 12).
entry 1). Although some improvement was observed in the
hydroamination reaction by using gold catalyst 33, the de-
sired dihydroisoquinoline 40a was obtained in a low yield of
17% (Table 2, entry 2). Increased loading of the gold cata-
lyst was unsuccessful and resulted in poor levels of catalyst
turnover (Table 2, entries 3 and 4). It was assumed that the
methoxycarbonyl group at the C-5 position of the 2,5-cis-
pyrrolidine was located near to the N-Boc group in the con-
former required for the hydroamination reaction and this
steric repulsion could have impaired the formation of com-
pound 40a. Therefore, we examined the reaction of the cor-
responding amine 3b. Fortunately, the desired 6-endo-dig
hydroamination reaction proceeded efficiently upon the
treatment of compound 3b with gold catalyst 33 (>90%
yield; Table 2, entry 6). The desired 6-endo-dig product was
ACHTUNGTRENNUNG
(PPh3)4], CuSO4, and sodium ascorbate[30] in DMF and Et3N
at 808C provided the coupling product (3a) in 92% yield
(Scheme 12). It is noteworthy that the use of CuSO4/sodium
ascorbate, in an equimolar amount to alkyne 5, was critical
to the success of this coupling reaction and it effectively pre-
vented the generation of the undesired homocoupled alkyne
product.
Then, we proceeded with the construction of the dihydro-
ACHTUNGTRENNUNGisoquinoline skeleton according to our established gold(I)-
catalyzed hydroamination of compound 3a (Table 2). Our
initial attempt at the hydroamination of compound 3a by
using gold catalyst 34, which was the most efficient catalyst
for the hydroamination of model substrate 30 f, resulted in
the substantial decomposition of compound 3a (Table 2,
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Convergent Synthesis of (À)-Quinocarcin
FULL PAPER
isolated in 90% yield as its tetrahydroisoquinoline form 41,
following the stereoselective reduction of compound 40b
with NaBH3CN (Scheme 12), because the resulting enamine
product 40b was found to be particularly unstable. When
compound 41 was heated in the presence of AcOH at 808C,
the secondary amine underwent a selective condensation re-
action with one of the ester groups to form 42 bearing the
mation) to afford lactam 42. The use of other silyl chlorides,
such as TMSCl and TESCl, also led to the recovery of dihy-
drobenzofuran 42. Although the reduction of compound 43
with Et3SiH for the preparation of the N,O-acetal 45 repre-
sented another attractive approach, over-reduction of com-
pound 45 occurred and the resulting phenol was isolated as
its methyl ether 46 following methylation with Me2SO4. In
contrast, treatment of the suspension with tert-butylamine
afforded amidine 47. However, disappointingly, all of our at-
tempts to convert compound 47 into quinocarcin were un-
successful.
Despite these unsuccessful results, the formation of oxa-
zolidinium intermediate 43 was supported by the isolation
of alcohol 46 and amidine 47. We envisaged that the trap-
ping of intermediate 43 with an external nucleophile would
prevent the reverse reaction. In practice, the treatment of
the ring-opening reaction mixture with LiOAc in MeCN
provided chlorinated phenol 48 in 20% yield, together with
the recovery of compound 42 in 57% yield (Table 3,
diazabicycloACHTUNGTRENNUNG[3.2.1]octane core in 96% yield. For the comple-
tion of the total synthesis, we had to overcome the newly
À
and challenging task of cleaving the C O bond of the dihy-
drobenzofuran and converting it into the phenylglycinol
moiety of quinocarcin.
In a related transformation, Zewge et al.[31] reported the
LiI-mediated ring-opening halogenation of dihydrobenzofur-
an in the presence of SiCl4 and BF3·AcOH. With this proce-
dure in mind, we envisaged that the treatment of lactam 42
with a Lewis acid would afford oxazolidinium intermediate
À
43, which would result from the cleavage of the C O bond
of the dihydrobenzofuran, assisted by the neighboring
lactam carbonyl group in compound 42. The resulting inter-
mediate 43 could then be converted into phenylglycinol de-
rivative 44 by hydrolysis (Scheme 13). Our initial synthetic
Table 3. Lewis acid mediated ring-opening chlorination of dihydrobenzo-
furan 42.
Entry
Additive
[equiv]
T
[8C]
t
Yield
[%][a]
Recovery
[%][a]
G
[h]
1
2
3
4
5
LiOAc (10)
LiOAc (20)
LiOAc (50)
CsOAc (10)
CsCl (10)
45
60
80
60
60
33
24
12
20
10
20
45
–
86
92
57
50
89
trace
–
[a] Yield of isolated compound.
entry 1). Following optimization of the reaction conditions,
the use of CsCl gave the most promising result and phenol
48 was obtained in 92% yield (Table 3, entry 5). NOE ex-
periments on this compound confirmed the relative stereo-
chemistry.
With phenol 48 in hand, only a short sequence of func-
tional manipulations was required to complete the total syn-
thesis of quinocarcin. The methylation of phenol 48 with di-
methyl sulfate afforded methyl ether 49 in 94% yield
(Scheme 14). Then, compound 49 was converted into alco-
hol 1a by using acetone/water in the presence of AgNO3
and Et3N and compound 1a was successfully converted into
quinocarcin by using the procedure reported by Allan and
Stoltz.[11f] The spectroscopic data for our synthetic (À)-qui-
nocarcin were identical to those in the original isolation
report[1] and to those provided in the reports concerning
synthetic quinocarcin.[11]
Scheme 13. Unsuccessful results of the Lewis acid mediated ring-opening
of dihydrobenzofuran (42). Reagents and conditions: a) BF3·Et2O, SiCl4,
DCE, 208C; b) NaHCO3, H2O, 0 8C; c) Et3SiH, MeCN, 08C; d) Me2SO4,
Cs2CO3, acetone, 208C; e) tBuNH2, 08C.
efforts revealed that the exposure of compound 42 to
BF3·Et2O and SiCl4 in DCE afforded a suspension that
could potentially contain the expected oxazolidinium inter-
mediate 43. However, disappointingly, the aqueous workup
of this suspension only resulted in the recovery of the start-
ing material 42. This disappointing result was attributed to
the hydrolysis of the transient silyl ether in compound 43
prior to the required cleavage of the oxazolidinium species,
thus promoting the reverse reaction (dihydrobenzofuran for-
Chem. Eur. J. 2013, 00, 0 – 0
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N. Fujii, H. Ohno et al.
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Scheme 14. Total synthesis of quinocarcin. Reagents and conditions:
a) Me2SO4, Cs2CO3, acetone, 208C; b) AgNO3, Et3N, acetone/H2O (3:1),
508C; c) LiOH·H2O, THF/H2O (2:1), 208C; d) Li, NH3 (liq.), THF,
À808C to À308C.
Conclusion
We have achieved an asymmetric total synthesis of quinocar-
cin, according to a new and convergent strategy that is
based on a combination of Sonogashira coupling and
gold(I)-catalyzed hydroamination reactions. The alkyne unit
for the coupling reaction was stereoselectively prepared
through a bromoallene-cyclization reaction. The trouble-
some issue of the regioselectivity of the intramolecular hy-
droamination reaction was completely resolved by the sub-
strate-controlled inversion of the selectivity and by a chlo-
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which predominantly involved the application of the Pictet–
Spengler condensation reaction for the construction of the
core tetrahydroisoquinoline structure. These findings could
potentially lead to the development of a general and diver-
gent synthetic strategy for the synthesis of related tetrahy-
droisoquinoline alkaloids.
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Acknowledgements
This work was supported by a Grant-in-Aid for the Encouragement of
Young Scientists (A) (H.O.) and a Strategic Young Researcher Overseas
Visits Program for Accelerating Brain Circulation from the Japan Society
for the Promotion of Science (JSPS) and a Platform for Drug Design,
Discovery, and Development from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of Japan. H.C. is grateful for
Research Fellowships for Young Scientists from JSPS.
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Convergent Synthesis of (À)-Quinocarcin
FULL PAPER
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Received: February 21, 2013
Published online: && &&, 0000
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N. Fujii, H. Ohno et al.
Total Synthesis
H. Chiba, Y. Sakai, A. Ohara, S. Oishi,
N. Fujii,* H. Ohno* ......... &&&& — &&&&
Convergent Synthesis of (À)-Quino-
carcin Based on the Combination of
Sonogashira Coupling and Gold(I)-
Catalyzed 6-endo-dig Hydroamination
Golden(I): A convergent asymmetric
total synthesis of quinocarcin
employed Sonogashira and Au-cata-
lyzed hydroamination reactions (see
scheme). The regioselectivity of the
intramolecular hydroamination of an
unsymmetrical alkyne was switched by
substrate control.
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These are not the final page numbers!