Enantioselective addition of terminal alkynes to isolated isoquinoline iminiums

Article abstract of DOI:10.1021/ol0526165

(Chemical Equation Presented) The asymmetric, catalytic addition of terminal alkynes to discrete alkyliminium species in the presence of copper bromide, QUINAP ligand, and triethylamine is reported. The reaction proceeds in high yield and high enantiomeri

Full text of DOI:10.1021/ol0526165

ORGANIC
LETTERS
2006
Vol. 8, No. 1
143-146
Enantioselective Addition of Terminal
Alkynes to Isolated Isoquinoline
Iminiums
Alexander M. Taylor and Stuart L. Schreiber*
Howard Hughes Medical Institute, Broad Institute of HarVard and MIT,
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
stuart_schreiber@harVard.edu
Received October 28, 2005
ABSTRACT
The asymmetric, catalytic addition of terminal alkynes to discrete alkyliminium species in the presence of copper bromide, QUINAP ligand,
and triethylamine is reported. The reaction proceeds in high yield and high enantiomeric excess with a variety of substrates in solution and
is also amenable to solid-phase synthesis.
A recently reported diversity-oriented synthetic pathway
(Figure 1) uses the addition of a nucleophile to an isolated
current study, we were not aware of a satisfactory method
to control the absolute stereochemistry of this key reaction.
Recently, Knochel and co-workers reported the copper-
catalyzed, asymmetric addition of terminal alkynes to enam-
ines and, in one pot, to aldehydes and amines.2 Since these
reaction conditions, involving the generation of an alky-
liminium species generated in situ, are not directly applicable
to our substrate, we investigated their modifcation for
application to the isolated iminium intermediates of our
pathway. Here, we report enantioselective additions of
terminal alkynes to isolated alkylisoquinoliniums catalyzed
by copper bromide and QUINAP. These conditions afford
propargylamine products in high yield and high enantiomeric
excess with substrates in solution. These conditions are also
compatible with solid-phase synthesis and lead to resin-bound
tetrahydroisoquinolines in high yield and purity with good
enantioselectivity.
Figure 1. Previously reported diversity-oriented synthesis (DOS)
of isoquinoline-derived alkaloids.1 No general method existed to
control the absolute stereochemistry of the addition reaction prior
to the studies reported here.
In the DOS pathway depicted in Figure 1, alkylisoquino-
linium intermediate 1 undergoes nucleophilic addition to
alkylisoquinolinium ion (1) to set the absolute stereochem-
istry of all the products of the pathway.1 At the outset of the
(2) (a) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed.
2002, 41, 2535. (b) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel,
P. Angew. Chem., Int. Ed. 2003, 42, 5763.
(1) Taylor, S. J.; Taylor, A. M.; Schreiber, S. L. Angew. Chem., Int. Ed.
2004, 43, 1681.
10.1021/ol0526165 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/14/2005

Table 1. CuBr-Catalyzed Addition of Terminal Alkynes to Selected Alkylisoquinolinium Salts
a Based on the average of two experiments, each with the opposite enantiomer of the ligand. b Isolated yield of spectroscopically pure compound.
c Enantiomeric excess determined by chiral HPLC. d Based on an experiment with only one enantiomer of ligand. e Conducted at -20 °C.
form enamine 2, which is the branching substrate that leads
to a number of different alkaloid skeletons. The lack of an
accessible coordination site in the iminium species, such as
from the lone pairs of a carbonyl (as in the system developed
by Shibasaki and co-workers3), precludes asymmetric induc-
tion by the coordination of a chiral Lewis acid. Instead, we
explored an enantioface-selective addition using a chiral
(3) Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 10784.
144
Org. Lett., Vol. 8, No. 1, 2006

nucleophile. For this addition, copper acetylides proved
optimal because they can be generated in situ and because
copper is known to bind well to a number of chiral ligands.4
tions but reacted only at relatively elevated temperatures
(-20 °C). Careful handling of the enamine product allowed
for the isolation of 6b in modest yield and enantiomeric
excess (Table 1, entry 7).
To apply this method to the synthesis of a collection of
diverse small molecules, we focused our attention to its
optimization on substrates linked to a 500 µm diameter
polystyrene resin (macrobeads) (Scheme 1). Using reported
Although our studies began with investigations into the
control of nucleophilic additions to isoquinolinium ions
similar to 1, such substrates proved unsuitable for optmiza-
tion due to the instability of their enamine products.5 Instead,
2-(2-bromo-5-methoxybenzyl)-6,7-dimethoxy-3,4-dihydroiso-
quinolinium bromide 3 was selected as a model substrate
because of the commercial availability of the precursor
dihydroisoquinoline and the ease with which the propargylic
amine products could be analyzed by chiral HPLC and SFC.
These iminium salts were generated in high yield (typically
greater than 90%) by isolation of the precipitate following
treatment of commercially available 6,7-dimethoxy-3,4-
dihydroisoquinoline with an alkylating agent such as 2-bromo-
5-methoxy-3,4-dihydroisoquinoline in refluxing diethyl ether.6
Scheme 1. Solid-Phase Addition of Terminal Alkynes to
Iminiumsa
Methylene chloride was chosen as the solvent for the
copper-catalyzed additions because of its ability to solvate
the starting iminium salts completely, which proved neces-
sary for high yields. After a series of optimization experi-
ments with various chiral ligands and copper(I) salts, we
selected the ligand and metal system arrived at by Knochel:
5 mol % of CuBr, 5.5 mol % of QUINAP.4a Exposure of a
0.1 M solution of dihydroisoquinolinium 3 to excess phe-
nylacetylene under these conditions in the presence of 1 equiv
of triethylamine at -55 °C for 48 h afforded propargylamine
3a in 85% isolated yield and 95% enantiomeric excess (Table
1, entry 1). The absolute stereochemistry of the addition
products was inferred by comparison to that of homo-
laudanosine, a related natural product synthesized using the
same conditions (see below).
a Purity of the final compound was determined by UV/vis and
TLC analysis. All intermediates were analyzed by MAS 1H NMR.
Enantiomeric excess is reported as the average of experiments with
each ligand enantiomer.
procedures, we attached 7-hydroxy-6-methoxy-3,4-dihy-
droisoquinoline to the macrobeads (7) and generated the
corresponding iminium salt 8 by exposing the adducts to
2-bromobenzyl-bromide in ether.7 Treatment of this alky-
liminium salt with phenylacetylene in the presence of 5 mol
% of CuBr, 5.5 mol % of QUINAP, triethylamine, and
methylene chloride at -78 °C yielded propargylamine 9a,
We next examined the reactivity of these dihydroisoquino-
linium salts with various alkynes under these conditions.
Iminium 3 reacted with both trimethylsilylacetylene and
methylpropargyl ether to afford propargylamines 3b and 3d
in high yield and enantiomeric excess (Table 1, entries 2
and 4). Iminium 3 reacted with the electron-rich ethoxyethyne
in high yield but with diminished enantiomeric excess (Table
1, entry 3), perhaps because of the actions of a more reactive,
less selective corresponding copper acetylide. N-methyldihy-
droisoquinolinium 4 also reacted with methyl propargyl ether
to form 4d in good yield and high enantiomeric excess, which
suggests that the conditions tolerate a degree of variation of
the N-subsitutent (Table 1, entry 5). Treatment of 1-substi-
tuted dihydroisoquinolinium 5 with methylpropiolate under
the reaction conditions proceeded in good yield but without
stereoselection (Table 1, entry 6). Isoquinolinium 6 was
exposed to trimethylsilylacetylene under the reaction condi-
1
which was characterized by H magic angle spin (MAS)
NMR prior to cleavage from the resin with HF-py for full
characterization. Propargylamine 9b was isolated in 84%
yield (all steps), 75% enantiomeric excess, and >90% purity
(as determined by UV/Vis and TIC analysis). Despite the
diminished enantioselectivity of the solid-phase reaction, we
anticipate that these conditions will be suitable for the
synthesis of a collection of enantioenriched small molecules.
To determine the absolute configuration of the stereocenter
established by this addition, we synthesized (S)-(-)-homo-
laudanosine (11), an isoquinoline-based natural product from
a family of alkaloids with neurologic activity (Scheme 2).
Commercially available 3,4-dihydro-6,7-dimethoxyisoquino-
line hydrochloride was neutralized and alkylated with me-
thyliodide to form isoquinolinium 4. Addition of 3,4-
dimethoxyphenylacetylene under the above reaction conditions
(4) Examples of copper-catalyzed enantioselective reactions include: (a)
Koradin, C.; Gommermann, N.; Polborn, K.; Knochel, P. Chem. Eur. J.
2003, 9, 2797. (b) Li, C.-J.; Wei, C. J. Am. Chem. Soc. 2002, 124, 5638.
(c) Fu, G. C.; Sua´rez, A.; Downey, C. W. J. Am. Chem. Soc. 2005, 127,
11244.
(5) (a) Bo¨hme, H.; Haake, M. In Iminium Salts in Organic Chemistry;
Taylor, E. C., Ed.; Advances in Organic Chemistry: Methods and Results;
John Wiley & Sons: New York, 1976; Vol. 1, p 112. (b) Thiessen, L. M.
Tetrahedron Lett. 1974, 15, 59. (c) Onaka, T. Tetrahedron Lett. 1971, 12,
4395.
(7) (a) Blackwell, H. E.; Perez, L.; Stavenger, R. A.; Tallarico, J. A.;
Eatough, E. C.; Foley, M. A.; Schreiber, S. L. Chem. Biol. 2001, 8, 1167.
(b) Clemons, P. A.; Koehler, A. N.; Wagner, B. K.; Sprigings, T. G.; Spring,
D. R.; King, R. W.; Schreiber, S. L.; Foley, M. A. Chem. Biol. 2001, 8,
1183. (c) Reference 1.
(6) See the Supporting Information for a general procedure.
Org. Lett., Vol. 8, No. 1, 2006
145

bromide to form alkyliminium 12 in 71% yield over two
steps. Exposure to trimethylsilyacetylene under the above
reaction conditions (using R-QUINAP) afforded in 89% yield
the corresponding propargylamine, which was globally
deprotected under basic conditions to form amine 13 (ster-
eochemistry inferred from homolaudanosine synthesis).
Partial hydrogenation formed 14 in 40% yield. These steps
were repeated with S-QUINAP to yield S-14. Both enanti-
omers were isolated in 98% enantiomeric excess. Prelminary
screens of 14 and S-14 indicate that 14 has little effect on
yeast growth, while S-14 has activity comparable to the
racemic mixture of 15. S-13 shows greater activity than either
S-14 or racemic 15. Neither enantiomer of 16, which differs
only in substitution at the isoquinoline 7 position, had any
detectable activity against yeast growth, suggesting that the
active compounds of this series are acting in a specific
manner on their target(s). Further experiments to determine
basic structure-activity relationships and to identify the
target(s) of these compounds are underway.
Scheme 2. Enantioselective Synthesis of Homolaudanosine
with S-QUINAP afforded the corresponding propargylamine
tetrahydroisoquinoline 10 in good yield and high enantiose-
lectivity. Complete reduction of this alkyne afforded homo-
laudanosine (11) in 76% yield. Synthetic homolaudanosine
exhibited an optical rotation in the same direction as that
reported for the natural product.8 (R)-(+)-homolaudanosine
was synthesized by the identical route using R-QUINAP and
demonstrated a similar but opposite optical rotation.
In ongoing small-molecule screens at the Broad Institute
Chemical Biology (BCB) Program using racemic tetrahy-
droisoquinoline products derived from the reported DOS
pathway, we identified a small-molecule inhibitor of yeast
proliferation (15).9 As part of ongoing efforts to elucidate
the target(s) of this compound, we synthesized both enan-
tiomers of the derivative 14 (Scheme 3). Commercially
In summary, guided by earlier studies of Knochel and co-
workers, we report the development of conditions for the
asymmetric addition of terminal alkynes to discrete alkyl-
isoquinolinium and alkyldihydroisoquinolinium ions in the
presence of triethylamine and catalytic copper bromide and
QUINAP. These conditions proceed with a variety of alkynes
to yield propargylic amines in up to 95% isolated yield and
99% enantiomeric excess. Similar treatment of polystyrene
resin-bound alkyliminiums also leads to highly pure prop-
argylic amines in high yield and good enantiomeric excess.
These conditions were used in solution to synthesize both
enantiomers of naturally occurring homolaudanosine. Also,
highly enantioenriched derivatives of a compound discovered
to interfere with yeast proliferation were synthesized, indicat-
ing the applicability of these conditions toward resynthesis
of active compounds from future screens. These conditions
should allow for control of the absolute stereochemistry of
a collection of isoquinoline-derived alkaloids derived from
a previously reported DOS pathway, so that enantioenriched
products can be screened directly soon.
Scheme 3. Enantioselective Synthesis of Compounds
Previously Discovered in Screens Using Proliferating Yeast
Cells
Acknowledgment. We thank the National Institute for
General Medical Sciences for their support of this research
via the Broad Institute Center of Excellence in Chemical
Methodology and Library Development (BI-CMLD). We are
indebted to members of the Broad Chemical Biology (BCB)
Scientific Platform for the resin used in the solid-phase
experiments. Ethan Perlstein conducted the initial yeast
growth assays. Dr. Steven Taylor, Nilesh Kumar, and Dr.
Ryan Looper contributed helpful discussions. A.M.T. was
supported by a training grant managed by the Molecular,
Cellular, and Chemical Biology (MCCB) Program at Harvard
University. S.L.S. is an Investigator at the Howard Hughes
Medical Institute.
available 7-hydroxy-6-methoxy-3,4-dihydroisoquinoline was
protected as a silyl ether and alkylated with 2-bromobenzyl
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(8) (a) Aladesamm, A. J., et al. J. Nat. Prod. 1983, 46, 127. (b) Meyers,
A. I., et al. Tetrahedron. 1987, 43, 5095.
(9) Data shown in the Supporting Information. Preliminary experiments
conducted with Ethan Perlstein.
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