New strategy for the synthesis of tetrahydroisoquinoline alkaloids

Article abstract of DOI:10.1021/ol034683+

(Matrix presented) A general strategy for the formation of 1,3-cis-substituted tetrahydroisoquinolines is described from ortho-iodo imines involving Larock isoquinoline synthesis, addition of organolithium compounds to unactivated isoquinolines, and ionic

Full text of DOI:10.1021/ol034683+

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2181-2184
New Strategy for the Synthesis of
Tetrahydroisoquinoline Alkaloids
Philip Magnus,* Kenneth S. Matthews, and Vince Lynch†
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin,
Austin, Texas 78712
p.magnus@mail.utexas.edu
Received April 23, 2003
ABSTRACT
A general strategy for the formation of 1,3-cis-substituted tetrahydroisoquinolines is described from ortho-iodo imines involving Larock
isoquinoline synthesis, addition of organolithium compounds to unactivated isoquinolines, and ionic hydrogenation. In addition, a new synthesis
of lactams via an unprecedented azide cyclization in the presence of a sulfonium ion is described.
Methods for the stereoselective synthesis of tetrahydroiso-
quinolines1 have elicited wide interest because of their
potential application to the synthesis of naturally occurring
potent antitumor antibiotics such as saframycin A 1,2
lemonomycin 2,3 and ecteinascidin 743 3.4,5
the C1 and C3 positions. The intermolecular Pictet-Spengler
reaction depicted in Scheme 1 converts 4 into 4â- and 4R-
Scheme 1. Pictet-Spengler Approach
with wide variations in the ratio of the diastereomers, but
under mild reaction conditions, 4â- is the major (but not
exclusive) product.2,5 An elegant solution to this problem
was reported by Corey in the course of his synthesis of
ecteinascidin 743,4a which utilized an intramolecular Pictet-
Spengler reaction to convert 5 into 6, Scheme 1.
One of the key stereochemical issues, which is common
to all of these compounds, is the cis relationship between
† Author for inquiries concerning the X-ray data.
10.1021/ol034683+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/21/2003

We have examined a new strategy that uses the C1
stereogenic center to induce the required cis relationship
between C1 and C3, Scheme 2. The strategy starts with a
DABCO and TMEDA; however, no enantioselectivity was
observed in the formation of 12 under a variety of condi-
tions.10 Exposure of 12 to trifluoroacetic acid in dichlo-
romethane containing triethylsilane at -10 °C and then
warming to 25 °C resulted in the formation of 13 (97%).11
We could not detect any other stereoisomers (1H NMR). The
C1-C3 cis relative stereochemistry of 13 was demonstrated
by treatment of 13 with N-chlorosuccinimide/PhCl followed
by stannic tetrachloride (catalytic) resulting in 14 (76%,
Scheme 2. C1 Nucleophilic Addition Approach
Scheme 4. Synthesis of Imine 25a
3-substituted isoquinoline 7 and adds LiCH2X followed by
acylation to give 8. Ionic hydrogenation (CF3CO2H/Et3SiH)
of 8 should give 9. The C1 substituent in 8 and in the
iminium ion 8a should be in an axial conformation to avoid
steric interactions with the -NCOR1 group and the peri-H,
thus favoring hydride addition from the least sterically
encumbered face resulting in 9.6
The synthesis of the 3-substituted isoquinoline 11 was
readily achieved using the recently reported Larock meth-
odology, Scheme 3.7 Phenylthiomethyllithium,8 formed by
reacting thioanisole with n-BuLi in the presence of a tertiary
diamine, was added to a solution of 11 in toluene at -78 °C
followed by warming to 25 °C, and quenching with methyl
chloroformate gave 12 (75%).9 Using (-)-sparteine as the
tertiary diamine gave the best results when compared to
a Reaction Conditions: (a) (i) MCPBA; (ii) NaOH, MeOH (94%
overall). (b) (HCHO)n, Et2AlCl, CH2Cl2. (c) BnBr, K2CO3, acetone
(89% over two steps). (d) AgO2CCF3, I2, CHCl3 (82%, 23). (e)
PCC, CH2Cl2 (98%). (f) tert-butylamine, 4 Å molecular sieves,
toluene.
structure by X-ray). Treatment of 13 with BCl3 in dichlo-
romethane at -78 °C followed by warming the solution to
0 °C removed the benzyl protecting group, resulting in 15
(95%). Exposure of 15 to (PhO)2P(O)N3/DEAD/PPh3 in THF
Scheme 3
2182
Org. Lett., Vol. 5, No. 12, 2003

Scheme 5
at 0-25 °C gave 16 (82%). When 16 was treated with NCS
It was found that treatment of 25 with 2% PdCl2(PPh3)2,
1% CuI, benzylpropargyl ether, and TEA/55 °C followed
by 10% CuI and DMF/100 °C (Larock isoquinoline synthe-
sis) gave 26 in 38% yield, Scheme 5, whereas treatment of
25 with stoichiometric CuI and Et3N/benzylpropargyl ether
at 25 °C followed by warming to 80 °C gave 26 in 91%
yield. Addition of phenylthiomethyllithium in the presence
of (-)-sparteine followed by methyl chloroformate gave 27
(83%), but again no enantioselectivity was observed for the
addition. Reduction of the enecarbamate double bond in 27
using Et3SiH/TFA in dichloromethane was complicated by
the competitive formation of 28b (61%) as well as the
required product 28 (31%). The formation of 28b presumably
results from the extended oxonium ion 28a (a pathway not
available in the unsubstituted version, Scheme 3). Conducting
the above reduction, but now in the presence of benzyl
alcohol (15 equiv), increased the yield of 28 to 71%, while
28b was formed in 22% yield. The primary alcohol benzyl
ether protecting group in 28 was selectively removed by
in PhCl followed by SnCl4 (stoichiometric) at 0 °C, the
thiophenyl imino ether 17 was rapidly formed (5 min).12 Mild
acid hydrolysis readily converted 17 into the lactam 18,
whose structure was confirmed by X-ray crystallography.
To explore the application of this new strategy to a more
highly substituted isoquinoline pertinent to the synthesis of
1 and/or 2 required the synthesis of 25, Scheme 4. Com-
mercially available 19 was converted into 25 via 20-24
using standard procedures.13
(1) (a) The Chemistry of Heterocyclic Compounds. Isoquinolines; Grethe,
G., Ed.; John Wiley: New York, 1981; Part 1. The Chemistry of
Heterocyclic Compounds. Isoquinolines; Kathawala, F. G., Coppola, G. M.,
Schuster, H. F., Eds.; John Wiley, New York, 1990; Part 2. The Chemistry
of Heterocyclic Compounds. Isoquinolines; Coppola, G. M., Schuster, H.
F., Eds.; John Wiley, New York, 1995; Part 3. (b) For a recent review of
these alkaloids, see: Ozturk, T. The Alkaloids. Cordell, G. A., Ed.; Academic
Press, San Diego, 2000; Vol. 53, p 120.
(2) For a comprehensive account of the chemistry and biology of these
compounds, see: (a) Scott, J. D.; Williams, R. M. Chem. ReV. 2002, 102,
1669. (b) Myers, A. G.; Kung, D. W. J. Am. Chem. Soc. 1999, 121, 10828.
(c) Myers, A. G.; Kung, D. W.; Zhong, B.; Movassaghi, M.; Kwon, S. J.
Am. Chem. Soc. 1999, 121, 8401. (d) Kubo, A.; Saito, N.; Yamato, H.;
Masubuchi, K.; Nakamura, M. J. Org. Chem. 1988, 53, 4295. (e) Saito,
N.; Harada, S.; Yamashita, M.; Saito, T.; Yamaguchi, K.; Kubo, A.
Tetrahedron 1995, 51, 8213. (f) Fukuyama, T.; Sachleben, R. A. J. Am.
Chem. Soc. 1982, 104, 4957. (g) Fukuyama, T.; Yang, L.; Ajeck, K. L.;
Sachleben, R. A. J. Am. Chem. Soc. 1990, 112, 3712. (h) Zhou, B.;
Edmondson, S.; Padron, J.; Danishefsky, S. J. Tetrahedron Lett. 2000, 41,
2039. (i) Zhou, B.; Guo, J.; Danishefsky, S. J. Tetrahedron Lett. 2000, 41,
2043. (j) Zhou, B.; Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4, 43.
(3) He, H.; Shen, B.; Carter, G. T. Tetrahedron Lett. 2000, 41, 2067.
(4) (a) Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996,
118, 9202. (b) Martinez, E. J.; Corey, E. J. Org. Lett. 1999, 1, 75. (c) Endo,
A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am.
Chem. Soc. 2002, 124, 6552.
(7) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86. In this
paper, the yield of 3-hydroxymethylisoquinoline was 0% when propargyl
alcohol was used (Table 3, entry 5 in the above reference). Simply using
protected derivatives as in Scheme 3 works well.
(8) Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097.
(9) For the addition of organolithium reagents to isoquinoline, see:
Alexakis, A.; Amiot, F. Tetrahedron: Asymmetry 2002, 13, 2117.
(10) Enantiomers were separated using chiral HPLC.
(11) For ionic hydrogenation of aryleneamides, see: Molinksi, T. F.;
Masuno, M. N. Tetrahedron Lett. 2001, 42, 8263.
(12) Closest analogy to the type of reaction is the intramolecular Schmidt
rearrangement. (a) Milligan, G. L.; Mossman, C. J.; Aube´, J. J. Am. Chem.
Soc. 1995, 117, 10449. (b) Mossman, C. J.; Aube´, J. Tetrahedron 1996,
52, 3403.
(5) Herberich, B.; Kinugawa, M.; Vazquez, A.; Williams, R. M.
Tetrahedron Lett. 2001, 42, 543.
(6) Deslongchamps, P. Stereoelectronic Effects in Organic Synthesis;
Pergamon Press: Elmsford, NY, 1983; p 211 and references therein.
(13) Saito, D. T.; Morimoto, M.; Akiyama, C.; Matsumoto, T.; Suzuki,
K. J. Am. Chem. Soc. 1995, 117, 10757.
Org. Lett., Vol. 5, No. 12, 2003
2183

treatment with BCl3 in dichloromethane at -78 °C to -20
°C, and the resulting alcohol 29 was converted into the azide
30. Treatment of 30 with NCS followed by SnCl4 (stoichio-
metric) gave 31, which was directly hydrolyzed to the lactam
32 (51% from 30).
In summary, a new strategy for the synthesis of 1,3-cis-
substituted tetrahydroisoquinolines has been developed that
relies on the stereoselctive reduction of 1,2-dihydroisoquino-
lines under ionic hydrogenation conditions. The [3.3.1] ring
system present in 1 and 3 was made by an unprecedented
intramolecular trapping of a sulfonium ion with an alkyl
azide.
Acknowledgment. We thank the National Institutes of
Health (GM32718) and Merck Research Laboratories for
their support of this research
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 11-18,
22-24, 26-30, and 32 and X-ray data (CIF) for compounds
14 and 18. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL034683+
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