Catalytic enantioselective synthesis of tetrahydroisoquinolines and their analogues bearing a C4 stereocenter: Formal synthesis of (+)-(8S,13R)- cyclocelabenzine

Article abstract of DOI:10.1002/chem.201301065

A one-pot wonder: 1,2,3,4-Tetrahydroisoquinolines with a C4 stereocenter can be formed by using a one-pot multicomponent chiral phosphoric acid catalyzed transformation of a mixture of oxetane-tethered benzaldehydes, amines, and the dimethyl ester derivative of the Hantzsch ester (see scheme). This transformation can be used to prepare the spermidine alkaloid (+)-(8S,13R)-cyclocelabenzine. Copyright

Full text of DOI:10.1002/chem.201301065

DOI: 10.1002/chem.201301065
Catalytic Enantioselective Synthesis of Tetrahydroisoquinolines and
Their Analogues Bearing a C4 Stereocenter: Formal Synthesis of
(+)-(8S,13R)-Cyclocelabenzine
Zhilong Chen†, Zhaobin Wang†, and Jianwei Sun*[a]
1,2,3,4-Tetrahydroisoquinoline (THIQ) is a ubiquitous
subunit found in numerous alkaloids and therapeutic agents
with significant biological activities, such as antitumor and
antimicrobial activities.[1] Thus, intensive efforts have been
directed to the development of methods for the stereoselec-
tive incorporation of this important unit. Among the various
strategies that have been developed, the majority are fo-
cused on the incorporation of THIQs with a C1 stereocen-
ter.[2] In contrast, direct and general asymmetric methods
Scheme 2. Synthesis of THIQs bearing a C4 stereocenter.
for the preparation of a THIQ skeleton with concomitant
formation of the C4 stereocenter are scarce.[3–5] However,
THIQs of this type are by no means less important. For ex-
ample, many natural products and drug leads, such as cri-
nine, lycorine, and a type of H3 antagonist/serotonin-trans-
porter inhibitors (Scheme 1) have a stereogenic center at
Intrigued by the versatility of the oxetane functional
group in organic synthesis and medicinal chemistry[8] as well
as our initial success in employing it for ring-expansion and
oxetane-directed aza-Diels–Alder reactions,[9] we envisioned
that a benzylamine tethered with an ortho-oxetane moiety
could undergo ring formation leading to THIQ (Scheme 2).
The intramolecular oxetane ring opening by the nitrogen
atom could be enantioselective in the presence of a chiral
catalyst, thus furnishing the C4 stereocenter. The benzyla-
mine could be generated in situ by reductive amination of
the corresponding aldehyde. In this multicomponent cascade
process, the proper choice of chiral catalyst is crucial not
only for the efficient bond formation in both steps, but also
for the chiral induction in the oxetane desymmetrization.[10]
In view of the known difficulty in oxetane ring opening by
amine nucleophiles,[11] and the high enantioselectivity that
can be achieved with Lewis acid catalysis,[11c] we planned to
examine the use of chiral Brønsted acid catalysts.[12,13]
We began the evaluation of our hypothesis with aldehyde
1a and 3,4,5-trimethoxyaniline 2a as the reaction partners
and Hantzsch ester 3a as the reductant.[14] In the presence
of 5 mol% of racemic phosphoric acid A1, we were pleased
to find that the desired THIQ, 4a, formed in quantitative
yield (Table 1, entry 1). This result prompted us to screen
various enantiopure chiral phosphoric acids with different
chiral backbones and substituents at the 3- and 3’-positions.
Although all of the evaluated catalysts are capable of pro-
moting the desired formation of 4a in essentially quantita-
tive yield, SPINOL-derived phosphoric acid C1 gives the
highest enantioselectivity (Table 1, entry 6).[15] In the ab-
sence of molecular sieves, a slight decrease in enantioselec-
tivity was observed (Table 1, entry 8). Further solvent
screening revealed that etherate solvents are superior, with
cyclopentyl methyl ether (CPME) being the best (94:6 er;
Scheme 1. Selected natural products and drug leads containing THIQs
with a C4 stereogenic center.
the C4 position.[6] As a result of the limited availability of
such methods, current approaches for the synthesis of these
core structures typically involve multistep sequences, for ex-
ample, initial installation of the C4 stereocenter followed by
ring closure at the C1 position (Scheme 2).[7] Herein, we
report the first multicomponent strategy to address this
unmet challenge by establishing the THIQ skeleton as well
as the C-4 stereogenic center in one step.
[a] Z. Chen, Z. Wang, Prof. J. Sun
Department of Chemistry
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong SAR, China
Fax : (+852)23581594
E-mail: sunjw@ust.hk
[†] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301065.
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COMMUNICATION
Table 1. Optimization of reaction conditions.[a]
phene (4g), pyrrole (4h-i), and indole (4j) ring can also par-
ticipate in the enantioselective cascade process to furnish a
diverse set of heterocyclic compounds. Notably, pyrrolopi-
perazine and indolopiperazine are both key subunits of a
range of important drug leads and bioactive natural prod-
ucts, such as longamide B, agelastatin F, and palauꢁ
amine (Scheme 3).[16] In addition, as shown in Table 3, a
Entry
Catalyst
Solvent
3 (R1,R2)
er (4a)
Scheme 3. Representative pyrrolopiperazine-containing alkaloids.
1
2
3
4
5
6
7
(Æ)-A1
(R)-A2
(R)-A3
(R)-A4
(R)-B
(S)-C1
(S)-C2
(S)-C1
(S)-C1
(S)-C1
(S)-C1
(S)-C1
(S)-C1
(S)-C1
(S)-C1
(S)-C1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
3a (Et,Et)
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
–
73:27
64:36
88:12
70:30
92:8
84:16
91:9
range of aryl amines are suitable reaction partners. The mild
reaction conditions are compatible with typical functional
groups, such as ethers, esters, halides, and free alcohols. Fi-
nally, the hydroxymethyl group in the 4-position of the prod-
ucts is poised for further functionalizations, such as oxida-
tion and coupling reactions.
We have carried out several control experiments to probe
the reaction mechanism. In the absence of the reductant 3d,
the reaction between 1a and 2a affords 5 in quantitative
yield as a single diastereomer [Eq. (1)], presumably result-
ing from formation of the N,O-acetal followed by oxetane
ring opening by attack of the nitrogen atom. Because the C4
8[b]
9
70:30
91:9
10
11
12
13
14
15
16[c]
THF
Et2O
93:7
94:6
90:10
92:8
95:5
97:3
CPME
CPME
CPME
CPME
CPME
3b (tBu,tBu)
3c (tBu,Me)
3d (Me,Me)
3d
[a] The ratio, 1/2/3, is 1:1:1.2; GC analysis using an internal standard
showed that all products were obtained in quantitative yield. [b] Without
5 ꢂ MS. [c] Run at À208C. CPME=cyclopentyl methyl ether, Tf=tri-
fluoromethanesulfonyl.
Table 2. Aldehyde scope.[a]
Table 1, entry 12). The steric bulk of the Hantzsch ester
also has an effect on enantioselectivity. When the rela-
tively small dimethyl ester, 3d, is used, a slight increase
in enantiomeric ratio was observed. Finally, at a lower
temperature (À208C), the reaction proceeds with both
high efficiency and excellent enantioselectivity
(Table 1, entry 16).
With standard reaction conditions established, we
next examined the scope of the multicomponent reac-
tion (Table 2). A range of THIQ products with elec-
tron-withdrawing and electron-donating groups can be
formed with high efficiency and good to excellent
enantioselectivity (4a–e). A gram-scale reaction was
also carried out, and no erosion in efficiency and enan-
tioselectivity were observed (4a), relative to the small-
er scale reactions, thus suggesting that our protocol is
amenable to large-scale multistep synthesis. THIQs
with a stereogenic quaternary center at the C4 position
can also be obtained in high yield, albeit with moderate
enantioselectivity (4 f). Substrates having oxetanes teth-
[a] Yield of isolated product. [b] Reaction performed at 08C. [c] Reaction performed
ered on a heterocyclic aryl ring, for example, on thio- at room temperature.
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J. Sun et al.
Table 3. Amine scope.[a]
Entry
Ar
Product
Yield [%]
er of 4
1
2
3
4
3-OH-C6H4
4k
4l
4m
4n
95
96
89
96
96:4
96:4
94:6
93:7
3,5-(OMe)2-C6H3
4-OMe-C6H4
4-SMe-C6H4
5
6
4o
4p
95
96
88:12
90:10
2-napthyl
[a] Yield of isolated product.
stereogenic center has been already established, compound
5 was subjected to reduction by Hantzsch ester 3d in the
presence of racemic phosphoric acid A1. Product 4a was ob-
tained in quantitative yield and the enantioselectivity is
comparable to that obtained using the one-pot standard re-
action conditions. However, we could not observe any inter-
mediate, such as 5, under our standard one-pot procedure.
These results suggest that if compound 5 is an intermediate,
the second step might be the faster step. In contrast to 1a,
pyrrole-linked substrate 1h could not lead to a similar inter-
mediate. Indeed, no reaction was observed between 1h and
2a in the presence of catalyst C1 [Eq. (2)]. However, during
the one-pot reaction of 1h under our standard reaction con-
ditions, we were able to observe one intermediate that is ini-
tially generated and then consumed at the end. When race-
mic catalyst A1 was used, the same intermediate, which
proved to be the reductive amination product 6, was also
observed and isolated at partial conversion of substrate as
an inseparable mixture with racemic product 4h [Eq. (3)].
This mixture was next subjected to the standard reaction
conditions, thus forming enantioenriched 4h (81:19 er). The
enantiomeric ratio (er) of 4h that was formed solely in the
second step was calculated as being 95:5, which is similar to
Scheme 4. Plausible mechanisms.
that of the product obtained by using the one-pot standard
reaction conditions.
From the above experimental results, we proposed possi-
ble mechanisms (Scheme 4). As depicted in path a, through
mediation of the acid catalyst, the aldehyde and the amine
forms N,O-acetal I, an intermediate for imine formation.
Rather than undergoing dehydration to form an imine, I un-
dergoes intramolecular oxetane ring opening through attack
of the amine group, which is more nucleophilic than the al-
cohol group, to give intermediate II. Subsequent reduction
of the resulting N,O acetal group, presumably via iminium
III, affords the desired product, 4. Alternatively, the alde-
hyde and the amine may first undergo reductive amination
to form amine V via the imine intermediate IV (path b).
Next, enantioselective ring opening of the oxetane delivers
product 4. It is also possible for imine IV to undergo enan-
tioselective oxetane ring opening to form iminium III
(path b’). According to the experimental results, all these
mechanisms may function, the one dominating being de-
pendent on the substrate.
To demonstrate the application of our method for THIQ
synthesis, we completed a formal asymmetric synthesis of
the spermidine alkaloid, (+)-(8S,13R)-cyclocelabenzine
(Scheme 5).[17] The enantioenriched product 4m obtained
from our multicomponent reaction was converted into
phthalimide 7 under Mitsunobu conditions. Subsequent oxi-
dation at the C1 position delivered dihydroisoquinolinone 8.
Oxidative cleavage of the para-methoxyphenyl (PMP) group
followed by alkylation afforded 10, a known intermediate in
a previously completed synthesis of (+)-(8S,13R)-cyclocela-
benzine.[17b]
In summary, we have developed a direct multicomponent
method for the efficient assembly of tetrahydroisoquinoline;
the transformation involves concomitant formation of a C4
stereocenter by means of enantioselective desymmetrization
of oxetanes with amine nucleophiles. Thus, tetrahydroisoqui-
nolines, privileged structures that are typically synthesized
by a multistep sequence, can now be prepared using a one-
step catalytic asymmetric method with high efficiency and
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Synthesis of Tetrahydroisoquinolines
COMMUNICATION
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Scheme 5. A formal synthesis of (+)-(8S,13R)-cyclocelabenzine. brsm=
based on recovered starting material, CAN=cerium ammonium nitrate,
DIAD=diisopropylazodicarboxylate.
enantioselectivity. The present method can also be applied
to the asymmetric synthesis of other heteroaryl-fused ana-
logs, such as pyrrolopiperazines and indolopiperazines,
which are also core structures of many important alkaloids
and drug lead compounds. This multicomponent reaction
may proceed by two possible mechanisms, either of which
could be dominant depending on the substrate. Finally, we
have applied our protocol in the formal synthesis of the al-
kaloid, (+)-(8S,13R)-cyclocelabenzine. We anticipate that
the present method will find more applications in drug dis-
covery and alkaloid synthesis.
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Acknowledgements
Financial support was provided by Hong Kong RGC (GRF604411 and
ECS605812).
Keywords: alkaloids · asymmetric catalysis · nucleophilic
addition · organocatalysis · strained molecules
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Received: March 19, 2013
Published online: May 15, 2013
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