Enantioselective addition of vinylzinc reagents to 3,4-dihydroisoquinoline N-oxide

Article abstract of DOI:10.1021/ol0614525

Ligand 2a promotes the enantioselective addition of vinylzinc reagents to 3,4-dihydroisoquinoline N-oxide to yield chiral allylic hydroxylamines. With 0.1 equiv of the ligand, the product is obtained in up to 84% ee, whereas with 1.2 equiv of the ligand,

Full text of DOI:10.1021/ol0614525

ORGANIC
LETTERS
2006
Vol. 8, No. 18
3979-3982
Enantioselective Addition of Vinylzinc
Reagents to 3,4-Dihydroisoquinoline
N-Oxide
Sa Wang and Christopher T. Seto*
Department of Chemistry, Brown UniVersity, 324 Brook Street Box H,
ProVidence, Rhode Island 02912
christopher_seto@brown.edu
Received June 13, 2006
ABSTRACT
Ligand 2a promotes the enantioselective addition of vinylzinc reagents to 3,4-dihydroisoquinoline N-oxide to yield chiral allylic hydroxylamines.
With 0.1 equiv of the ligand, the product is obtained in up to 84% ee, whereas with 1.2 equiv of the ligand, the ee is increased to the 90 95%
range with a variety of aliphatic, cyclic, and aromatic vinylzinc reagents. This method was used to synthesize the protected unnatural amino
acid N-Cbz- -1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid in three steps from the allylic hydroxylamine.
−
D
Tetrahydroisoquinoline (THIQ) alkaloids, especially 1-sub-
stituted THIQs, are important synthetic targets because of
their potent pharmacological properties.1 Members of this
family of alkaloids have diverse activities that include
agonism of the â-adrenoceptor,2 antagonism of D1 and
NMDA receptors,3 inhibition of R-glucosidase,4 and neuro-
toxicity associated with Parkinson’s disease.5 A majority of
these compounds possess a chiral center at the C-1 position
of the isoquinoline core, and stereoisomers at this position
exhibit very different activities (Scheme 1). Thus, enantio-
selective synthesis of 1-substituted THIQs is an important
goal in both synthetic and medicinal chemistry.
Syntheses of THIQs most often employ the Pictet-
Spengler reaction, which entails the intramolecular cycliza-
tion of an electron-rich aryl group onto an imine or iminium
Scheme 1. THIQ-Based Bioactive Structures and
Enantioselective Approaches to 1-Substituted THIQs
(1) Chrzanowska, M.; Rozwadowska, M. D. Chem. ReV. 2004, 104,
3341-3370.
(2) Nikulin, V. I.; Rakov, I. M.; De Los Angeles, J. E.; Mehta, R. C.;
Boyd, L. Y.; Feller, D. R.; Miller, D. D. Bioorg. Med. Chem. 2006, 14,
1684-1697.
(3) (a) Wanner, K. T.; Beer, H.; Ho¨fner, G.; Ludwig, M. Eur. J. Org.
Chem. 1998, 2019-2029. (b) Gao, M.; Kong, D.; Clearfield, A.; Zheng,
Q.-H. Bioorg. Med. Chem. Lett. 2006, 16, 2229-2233.
(4) Takada, K.; Uehara, T.; Nakao, Y.; Matsunaga, S.; van Soest, R. W.
M.; Fusetani, N. J. Am. Chem. Soc. 2004, 126, 187-193.
(5) (a) Shinohara, T.; Takada, A.; Toda, J.; Terasawa, N.; Sano, T.
Heterocycles 1997, 46, 555-565. (b) Nagatsu, T. Neurosci. Res. 1997, 29,
99-111 and references therein.
10.1021/ol0614525 CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/04/2006

ion electrophile. A number of diastereoselective syntheses
of THIQs have been reported using this approach,1 and
Jacobsen has recently developed an enantioselective thiourea-
based catalyst for an acyl-Pictet-Spengler reaction.6 Other
approaches to chiral THIQs include enantioselective addition
of ketene silyl acetals to acylisoquinolines or nitrones,7
addition of alkynes to isoquinoline iminium ions,8 reaction
of an allylsilane with 3,4-dihydro-6,7-dimethoxyisoquinoline
catalyzed by chiral Cu(I) complexes,9 and the asymmetric
hydrogenation of cyclic imines prepared by the Bischler-
Napieralski reaction.10
are modular structures with three potential sites of diversity.
The amino acid side chain provides the source of chirality.
The tertiary amine and the carbamate, upon deprotonation
of the carbamate N-H, could provide a bidentate coordina-
tion site for a metal. Both the alkyl groups on the tertiary
amine and the acyl group on the primary amine can be varied
to tune the steric and electronic environment surrounding
the metal atom. As shown in Scheme 2, the N-acylethylene-
Scheme 2. Synthesis of N-Acylethylenediamine Ligandsa
An alternative approach that could provide efficient access
to a wide variety of isoquinoline derivatives for biological
screening is the catalytic enantioselective addition of organo-
metallic reagents to the C-1 position of the isoquinoline ring
system (the C1-CR connection, Scheme 1). Ukaji and
Nakamura11 described the synthesis of chiral THIQs with
several organozinc reagents using tartrate ester or bisoxazo-
line ligands. These methods often give modest enantio-
selectivities or require stoichiometric amounts of the chiral
controller. Here we report a convenient method to access
chiral THIQs by the enantioselective addition of vinylzinc
reagents to 3,4-dihydroisoquinoline N-oxide promoted by
N-acylethylenediamine ligands. The reaction gives moderate
to good enantioselectivities with 0.1 equiv of the chiral ligand
and excellent enantioselectivities (90-95% ee) with 1.2 equiv
of the ligand with a range of vinylzinc reagents.
We recently demonstrated that N-acylethylenediamine-
based ligands catalyze the enantioselective addition of
vinylzinc reagents to aldehydes to give chiral allylic alco-
hols.12 To extend the utility of these chiral ligands, we
investigated whether a similar reactivity and selectivity could
be obtained using other electrophiles. In particular, nitrones
provide interesting opportunities because they are more
reactive than most unactivated imines, and the resulting
hydroxylamine products can be easily reduced to the cor-
responding chiral allylic amines.
a For R2 ) CH2STrt, EDC and HOBt were used in place of
HBTU in the first coupling step.
diamines were prepared by coupling Boc-protected amino
acids with secondary amines to give the corresponding
amides 1a-f.14 For N-BocCys(Trt), EDC and HOBt gave a
significantly higher yield in the coupling reaction with
morpholine when compared to HBTU. The amides were
reduced with borane-THF, followed by cleavage of the
resulting B-N bond with ethylenediamine to give ligands
2a-f. During the last step, we found that microwave heating
gave higher yields and much shorter reaction times than
conventional heating methods. This synthesis can be used
to prepare a variety of ligands on a multigram scale.
The substrate for the addition reactions, 3,4-dihydroiso-
quinoline N-oxide, was prepared by the Na2WO4-catalyzed
oxidation of 1,2,3,4-tetrahydroisoquinoline with H2O2.15 We
used the method developed by Oppolzer to generate the
vinylzinc reagents.16 In this procedure, terminal alkynes are
first hydroborated with dicyclohexylborane to give (E)-
vinylboranes. Transmetalation with diethylzinc then yields
the corresponding (E)-vinylzinc reagents. Our preliminary
screening studies indicated the use of a modified Oppolzer
procedure in which the vinylborane was slowly added via
syringe pump to a cooled (-48 °C) solution of nitrone,
diethylzinc, and the ligand in methylene chloride. Reactions
were allowed to proceed for 24 h at this temperature. This
inverse addition procedure increased both the yield and
stereoselectivity of the reaction. Reactions that were per-
formed with an excess of alkyne resulted in both alkynyl
and vinyl addition to the nitrone. If the reaction was
performed at higher temperatures (-20 °C), we began to
Amino acids provide an inexpensive and readily available
starting material for the preparation of chiral ligands.13 The
N-acylethylenediamines, which are derived from amino acids,
(6) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558-10559. For a Lewis acid-mediated Pictet-Spengler reaction, see:
(b) Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.;
Nakagawa, M. J. Org. Chem. 1998, 63, 6348-6354. (c) Hino, T.;
Nakagawa, M. Heterocycles 1998, 49, 499-531.
(7) (a) Taylor, M. S.; Tokunaga, N. T.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2005, 44, 6700-6704. (b) Murahashi, S.-I.; Imada, Y.; Kawakami,
T.; Harada, K.; Yonemushi, Y.; Tomita, N. J. Am. Chem. Soc. 2002, 124,
2888-2889.
(8) Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143-146.
(9) Itoh, T.; Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A. Org.
Lett. 2006, 8, 1295-1297.
(10) Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahedron: Asymmetry
1998, 9, 183-187.
(11) (a) Ukaji, Y.; Shimuzu, Y.; Kenmoku, Y.; Ahmed, A.; Inomata, K.
Chem. Lett. 1997, 1, 59-60. (b) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.;
Ahmed, A.; Inomata, K. Bull. Chem. Soc. Jpn. 2000, 73, 447-452. (c)
Ukaji, Y.; Yoshida, Y.; Inomata, K. Tetrahedron: Asymmetry 2000, 11,
733-736.
(14) Richmond, M. L.; Seto, C. T. J. Org. Chem. 2003, 68, 7505-7508.
(15) (a) Murahashi, S.-I.; Shiota, T.; Imada, Y. Org. Synth. 1998, 9, 632-
637. (b) Murahashi, S. I.; Shiota, T. Tetrahedron Lett. 1987, 28, 6469-
6472.
(16) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170-
173.
(12) (a) Sprout, C. M.; Richmond, M. L.; Seto, C. T. J. Org. Chem.
2005, 70, 7408-7417. (b) Richmond, M. L.; Seto, C. T. J. Org. Chem.
2005, 70, 8835-8840.
(13) Vicario, J. L.; Bad´ıa, D.; Carrillo, L.; Etxebarria, J. Curr. Org. Chem.
2003, 7, 1775-1792.
3980
Org. Lett., Vol. 8, No. 18, 2006

observe small amounts of products from ethyl and cyclohexyl
addition. Finally, because the yield and stereoselectivity
appeared to depend on the amount of ligand present in the
reaction, subsequent screening studies were performed using
1.2 equiv of the ligand.
With optimized reaction conditions in hand, we next
examined how the ligand structure influenced the yield and
ee of the allylic hydroxylamine product (Table 1). In terms
center, such as CH2STrt (ligand 2d), gave an intermediate
level of enantioselectivity.
With entries 1, 5, and 6, we examined the influence of
the tertiary amine. Ligands that incorporated cyclic amines,
such as those derived from morpholine and piperidine, were
preferred over noncyclic analogues (2f). Because the yield
of the reaction with ligand 2a was higher than that with 2b,
we chose 2a as the optimized structure for further experi-
ments.
The data in Table 2 show that both the yield and ee of the
reaction correlate with the equivalent of ligand 2a. As 2a is
increased from 0.1 to 1.2 equiv, the yield increases from 60
to 74% and the ee increases from 84 to 95%. We have found
that, although the highest levels of enantioselectivity are
observed with 1.2 equiv of the ligand, in practice the ligand
can be isolated from the reaction by chromatography and
recycled up to three times without erosion of product ee.
To investigate the scope of this reaction, we prepared seven
vinylzinc reagents and reacted them with 3,4-dihydroiso-
quinoline N-oxide in the presence of either 0.1 or 1.2 equiv
of ligand 2a. As shown in Table 3, using 1.2 equiv of 2a,
Table 1. Effect of Ligand Structure on Addition of Vinylzinc
Reagents to 3,4-Dihydroisoquinoline N-Oxide
R2 ) side yield
ee
entry ligand
R1
-(CH2)2O(CH2)2- Chg
-CH2)2O(CH2)2- Ile
chain of
(%)a
(%)b
Table 3. Enantioselective Addition of Vinylzinc Reagents to
3,4-Dihydroisoquinoline N-Oxide
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
74
68
60
72
63
58
95
95
84
90
90
72
-(CH2)2O(CH2)2- Phe
-(CH2)2O(CH2)2- Cys(Trt)
-(CH2)5-
-CH2CH3-
Chg
Chg
a Isolated yield. b Measured by HPLC (Chiralcel OD-H). Cy ) cyclo-
hexyl. Chg ) cyclohexylglycine.
1.2 equiv of 2aa
0.1 equiv of 2ab
yield
(%)c
ee
(%)
yield
(%)c
ee
(%)
of stereoselectivity, comparison of ligands 2a-d (entries
1-4) demonstrated that â-branched amino acid side chains
were optimal. Ligands derived from cyclohexylglycine and
isoleucine both gave the product in 95% ee. Ligands with
less bulky substituents that lack â-branching, such as the
benzyl side chain of Phe, reduced the ee to 84%. Side chains
with a sterically demanding group more distal from the chiral
entry
R (product)
1
2
3
4
5
6
7
tert-butyl (3a)
n-butyl (3b)
cyclopropyl (3c)
cyclohexyl (3d)
CH2CH2Ph (3e)
Ph (3f)
69
66
79
62
74
74
85
93
94
94
94
95
90
92
61
66
77
63
60
81
74
41
80
72
64
84
71
75
4-MeO-Ph (3g)
a Reactions performed using 2.4 equiv of Et2Zn. b Reactions performed
using 1.3 equiv of Et2Zn. c Isolated yield.
Table 2. Effect of Ligand Loading on the Enantioselectivity of
the Addition of a Vinylzinc Reagent to 3,4-Dihydroisoquinoline
N-Oxide
we obtained excellent ee values with a range of aliphatic,
cyclic, and aromatic vinylzinc reagents. For catalytic reac-
tions using 0.1 equiv of the chiral ligand, good enantio-
selectivities in the range of 71-84% ee were obtained with
five of the nucleophiles. However, vinylzinc reagents derived
from cyclohexylacetylene and tert-butylacetylene gave poor
enantioselectivities.
To highlight the utility of this method and to confirm the
absolute configuration of the allylic hydroxylamine products,
we performed a short synthesis of the unnatural amino acid
N-Cbz-D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (N-
Cbz-D-Tiq). This conformationally constrained amino acid
has been used in the design of thrombin inhibitors and to
entry
equiv of ligand 2a
yield (%)
ee (%)
1
2
3
4
0.10
0.25
0.50
1.20
60
63
68
74
84
90
93
95
Org. Lett., Vol. 8, No. 18, 2006
3981

enhance the biological activities and stabilities of peptides
and peptidomimetics.17 The ee of hydroxylamine 3f was
increased from 90% to 96% by recrystallization from
hexanes, which removes racemic 3f from the sample as a
crystalline solid. Reduction of the hydroxylamine with Zn/
AcOH followed by protection of the free amine with CbzCl
afforded 4 in 67% yield over the two steps (Scheme 3).18
Thus, ligand 2a catalyzes the addition of vinylzinc reagents
to the si face of the nitrone CdN double bond. This
procedure represents a significant improvement over reported
syntheses of D-Tiq, which require separation of the racemic
compound by recrystallization of a diastereomeric salt.20
In summary, we have developed a new method for the
addition of vinylzinc reagents to 3,4-dihydroisoquinoline
N-oxide using chiral N-acylethylenediamine ligands. This
method should be applicable to the asymmetric synthesis of
tetrahydroisoquinoline alkaloids and derivatives of the con-
formationally constrained amino acid Tiq. Our current work
is directed toward broadening the scope of the process
through the use of other nucleophiles and gaining a better
understanding of the reaction’s mechanism and basis for
stereoselectivity.
Scheme 3. Synthesis of
N-Cbz-D-1,2,3,4-Tetrahydroisoquinoline-1-carboxylic Acid
Acknowledgment. We thank Dr. Russell Hopson of the
Brown University Department of Chemistry for assistance
with NMR spectroscopy.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0614525
Oxidative cleavage of the alkene with RuCl3 and NaIO4 gave
N-Cbz-D-Tiq in 61% yield.19 The absolute configuration of
the product was confirmed by comparing the sign of its
specific optical rotation with a value from the literature.20
(18) (a) Merino, P.; Franco, S.; Lafuente, D.; Merchan, F.; Revuelta, J.;
Tejero, T. Eur. J. Org. Chem 2003, 15, 2877-2881. (b) Cong, X.; Liao,
Q. J.; Yao, Z. J. J. Org. Chem. 2004, 69, 5314-5321.
(19) (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936-3938. (b) Chen, Y. K.; Lurain, A. E.; Walsh,
P. J. J. Am. Chem. Soc. 2002, 124, 12225-12231.
(17) (a) Shuman, R. T.; Rothenberger, R. B.; Campbell, C. S.; Smith,
G. F.; Gifford-Moore, D. S.; Gesellchen, P. D. J. Med. Chem. 1993, 36,
314-319. (b) Shuman, R. T.; Rothenberger, R. B.; Campbell, C. S.; Smith,
G. F.; Gifford-Moore, D. S.; Paschal, J. W.; Gesellchen, P. D. J. Med. Chem.
1995, 38, 4446-4453.
(20) Observed for compound 5: [R]24 ) -24.8° (c ) 0.5, MeOH).
D
Literature value: [R]24 ) -40.1° (c ) 1.0, MeOH). Bajusz, S.; Mohai,
D
L.; Feher, A.; Lavich, J.; Szell, G.; Veghelyi, B. PCT Int. Appl. WO
9312091 A1 930624, 1993 (36 pp).
3982
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