Asymmetric synthesis of 3-substituted isoindolinones: Application to the total synthesis of (+)-lennoxamine

Article abstract of DOI:10.1021/ol047824w

(Chemical Equation Presented) An anionic chiral auxiliary mediated asymmetric alkylation of carbamate 2 provides 3-substituted isoindolinones 4 in high ee. This methodology was used in the first asymmetric synthesis of (+)-lennoxamine.

Full text of DOI:10.1021/ol047824w

ORGANIC
LETTERS
2005
Vol. 7, No. 1
95-98
Asymmetric Synthesis of 3-Substituted
Isoindolinones: Application to the Total
Synthesis of (+)-Lennoxamine
Daniel L. Comins,* Stefan Schilling, and Yanchen Zhang
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received October 22, 2004
ABSTRACT
An anionic chiral auxiliary mediated asymmetric alkylation of carbamate 2 provides 3-substituted isoindolinones 4 in high ee. This methodology
was used in the first asymmetric synthesis of ( )-lennoxamine.
+
Various heterocyclic compounds containing the isoindolinone
skeleton (1) have important biological activities, and many
of these have been prepared and examined as antihyperten-
sive,1 antipsychotic,2 antiinflammatory,3 anesthetic,4 anti-
ulcer,5 and vasodilatory6 agents. Antiviral,7 antileukemic,8a1,b
and platelet aggregation inhibitory8c properties have also been
observed in this class of structures. Isoindolinones have been
widely used as building blocks for the synthesis of various
drugs9 and natural products10 and have recently found
application as templates for combinatorial library preparation.10c
Although there are several methods available for making
racemic 3-alkylisoindolinones, enantioselective syntheses are
few. These involve a resolution of racemic material,11 an
intramolecular Heck reaction,12 asymmetric Diels-Alder
reactions,13 a ring-closure procedure of chiral hydrazones,14
chiral acyliminium ion reactions,15 and a chiral appendage
(7) (a) Govindachari, T. R.; Ravindranath, K. R.; Viswanathan, N. J.
Chem. Soc., Perkin Trans. 1 1974, 1215. (b) Pendrak, I.; Barney, S.;
Wittrock, R.; Lambert, D. M.; Kingsbury, W. D. J. Org. Chem. 1994, 59,
2623. (c) De Clercq, E. J. Med. Chem. 1995, 38, 2491.
(8) (a) Taylor, E. C.; Zhou, P.; Jenning, L. D.; Mao, Z.; Hu, B.; and
Jun, J.-G. Tetrahedron Lett. 1997, 38, 521. (b) Fuska, J.; Fuskova, A.;
Proksa, B. Zb. Pr. Chemickotechnol Fak, SVST, 1979-1981 (pub. 1986),
285-291; Chem. Abstr. 1987, 106, 95582k. (c) Egbertson, M. S.; Hartman,
G. D.; Gould, R. J.; Bednar, B.; Bednar, R. A.; Cook, J. J.; Gaul, S. L.;
Holahan, M. A.; Libby, L. A.; Lynch, R. J.; Sitko, G. R.; Stranieri, M. T.;
Vassallo, L. M. Bioorg. Med. Chem. Lett. 1996, 6, 2519.
(9) (a) Brever, E.; Zbaida, Z. Tetrahedron Lett. 1975, 31, 499. (b)
Inubushi, Y.; Tsuda, Y.; Konita, T.; Matsumoto, S. Chem. Pharm. Bull.
Tokyo 1964, 12, 749; 1968, 16, 1014. (c) Abramovitch, R. A.; Shinkai, I.;
Mavunkel, B. J.; More, K. M.; O’Connor, S.; Ooi, G. H.; Pennington, W.
T.; Srinivason, P. C.; Stowers, J. R. Tetrahedron 1996, 52, 3339. (d) Pigeon,
P.; Decroix, B. Tetrahedron Lett. 1997, 38, 2985.
(10) For recent references, see: (a) Heaney, H.; Shuhaibar, K. F. Synlett
1995, 47. (e) Othman, M.; Decroix, B. Synth. Commun. 1996, 2803. (b)
Othman, M.; Pigeon, P.; Decroix, B. Tetrahedron 1997, 53, 2495. (c). Boger,
D. L.; Lee, J. K.; Goldberg, J.; Jin, Q. J. Org. Chem. 2000, 65, 1467.
(11) Belliotti, T. R.; Brink, W. A.; Kesten, S. R.; Rubin, J. R.; Wustrow,
D. J.; Zoski, K. T.; Whetzel, S. Z.; Corbin, A. E.; Pugsley, T. A.; Heffner,
T. G.; Wise, L. D. Bioorg. Med. Chem. Lett. 1998, 8, 1499.
(1) Ferland, J.-M.; Demerson, C. A.; Humber, L. G. Can. J. Chem. 1985,
63, 361.
(2) (a) Linden, M.; Hadler, D.; Hofmann, S. Hum. Psychopharmacol.
1997, 12, 445. (b) Zhuang, Z.-P.; Kung, M.-P.; Mu, M.; Kung, H. F. J.
Med. Chem. 1998, 41, 157. (c) Norman, M. H.; Minick, D. J.; Rigdon, G.
C. J. Med. Chem. 1996, 39, 149.
(3) Li, S.; Wang, X.; Guo, H.; Chen, L. Yiyano Gongye 1985, 16, 543;
Chem. Abstr. 1986, 105, 6378n.
(4) Laboratori Baldacci, S. P. A. Japanese Patent 5,946,268, 1984; Chem.
Abstr. 1984, 101, 54922.
(5) Lippmann, W. U.S. Patent 4,267,189, 1981; Chem. Abstr. 1981, 95,
61988m.
(6) Achinami, K.; Ashizawa, N.; Kobayasui, F. Japanese Patent
03,133,955, 1991; Chem. Abstr. 1991, 115, 255977j.
(12) Grigg, R.; Dorrity, M. J. R.; Malone, J. F.; Mongkolaus-savaratana,
T.; Norbert, W. D. J. A.; Sridharan, V. Tetrahedron Lett. 1990, 31, 3075.
(13) McAlonan, H.; Murphy, J. P.; Nieuwenhuyzen, M.; Reynolds, K.;
Sarma, P. K. S.; Stevenson, P. J.; Thompson, N. J. Chem. Soc., Perkin
Trans 1 2002, 69, and references therein.
(14) Enders, D.; Braig, V.; Raabe, G. Can. J. Chem. 2001, 79, 1528.
10.1021/ol047824w CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/15/2004

mediated carbanion method.16 Both the carbocationic ap-
proach developed by Allin15c and the carbanion method
reported by Royer16 use an (R)-phenylglycinol unit as a chiral
appendage to control diastereoselectivity. Modest to high
stereoselectivity can be obtained using these two asymmetric
methods. A disadvantage to using an incorporated phenyl-
glycinol unit as the chiral appendage is that its cleavage is
harsh (concentrated H2SO4)15d or tedious requiring three steps
(mesylation, elimination, and acid hydrolysis).15c As a re-
sult of our interest in pursuing the synthesis of isoindo-
line-containing natural products, we decided to investigate
an asymmetric synthesis of 3-substituted isoindolinones
via a carbanion method using an easily cleaved and recover-
able chiral auxiliary. Given our success at using (+)- and
(-)-trans-2-(R-cumyl)cyclohexanol (TCC) as the chiral
auxiliary for 1-acylpyridinium salt reactions,17 we prepared
N-acylisoindolinone 2 (R* ) (+)-TCC) and studied its
deprotonation and asymmetric alkylation (Scheme 1).
Figure 1. Low energy conformation of the sodium enolate of 2
(MMFF).
tion depicted in Figure 1. The phenyl ring of the TCC
auxiliary clearly blocks the bottom face of the stabilized
anion.
Scheme 1
We next looked at the removal of the chiral auxiliary
(Table 2). Initial attempts using lithium methoxide (entry 2)
Table 2. Removal of the Chiral Auxiliary from 3
Isoindolinone 1 was treated with n-butyllithium and
(+)-TCC chloroformate to give the N-acyl derivative 2 in
90% yield. A deprotonation study indicated that NaHMDS
was the base of choice. Anion formation at -78 °C in THF
and addition of an electrophile provided the 3-substituted
isoindolinones 3 in high yield and with excellent diastereo-
selectivity as shown in Table 1. The stereochemistry of 3d
was established by single-crystal X-ray analysis.
yielda
b
entry
3
conditions
(%)
[R]D
eec (%)
1
2
3
4
5
6
7
8
9
3a LiOMe, MeOH, rt
0
sm
3a LiOMe, MeOH, reflux 85
racemization
3d 10% HCl, MeOH, rt
3d K2CO3, MeOH, rt
3d K2CO3, MeOH, reflux
3d LiOMe, 30% H2O2, rt
3a Mg(OMe)2, MeOH, rt
3b Mg(OMe)2, MeOH, rt
3c Mg(OMe)2, MeOH, rt
0
0
93
0
sm
sm
racemization
sm
Table 1. Asymmetric Alkylation of 2
92 -70° (c 0.63) >99
99 -65° (c 0.53) 99
98 -40° (c 0.38) >99
92 -34° (c 0.26) >99
93 -57° (c 0.43) 99
90 -44° (c 0.40) 99
b
entry
R-X
3
yielda (%)
[R]D
dec (%)
10 3d Mg(OMe)2, MeOH, rt
11 3e Mg(OMe)2, MeOH, rt
12 3f Mg(OMe)2, MeOH, rt
1
2
3
4
5
6
CH2dCHCH2Br 3a
83
89
76
86
84
74
+35° (c, 1.35)
+91° (c, 0.70)
+79° (c, 0.45)
+38° (c, 0.86)
+90° (c, 1.28)
+47° (c, 0.80)
97
97
97
99
98
97
BnBr
3b
3c
3d
3e
3f
(CH3)2CHI
MeI
a Purified by radial PLC. b Solvent was CH2Cl2. c The ee was determined
by chiral column HPLC analysis.
CHtCCH2Br
I(CH2)4Cl
a Yields are for the major diastereoisomer isolated. b The solvent was
CHCl3. c The de was determined by HPLC analysis of the crude product.
and K2CO3/MeOH (entry 5) resulted in efficient cleavage
of the N-acyl group, but significant racemization at C-3
occurred. Fortunately, the racemization problem was cir-
cumvented by using magnesium methoxide in methanol at
room temperature. In this manner, (S)-3-alkylisoindolinones
4 were isolated enantiopure in excellent yield. In addition,
the TCC auxiliary can be readily recovered (90-95%). All
of the products (entries 7-12) exhibited a minus specific
rotation value which corresponds to the 3S configuration.11,15e
With the asymmetric synthesis worked out, we decided
to test the methodology against the rigor of natural product
The high degree of asymmetric induction observed was
anticipated on the basis of the molecular mechanics calcula-
(15) (a) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z.
Tetrahedron Lett. 1997, 38, 3627. (b) Allin, S. M.; Northfield, C. J.; Page,
M. I.; Slawin, A. M. Z. Tetrahedron Lett. 1998, 39, 4905. (c) Allin, S. M.;
Northfield, C. J.; Page, M. I.; Slawin, A. M. Z. Tetrahedron Lett. 1999, 40,
141; Tetrahedron Lett. 1999, 40, 143. (d) Allin, S. M.; Northfield, C. J.;
Page, M. I.; Slawin, A. M. Z. J. Chem. Soc., Perkin Trans. 1 2000, 1715.
(e) Deniau, E.; Enders, D.; Couture, A.; Grandclaudon, P. Tetrahedron:
Asymmetry 2003, 14, 2253. (f) Bahajaj, A. A.; Vernon, J. M.; Wilson, G.
D. Tetrahedron 2004, 60, 1247. (g) Chen, M-D.; Zhou, X.; He, M-Z.; Ruan,
Y-P.; Huang, P-Q. Tetrahedron 2004, 60, 1651.
(16) (a) Pe´rard, J.; Prange´, T.; Tomas, A.; Royer, J. Tetrahedron 2002,
5103.
96
Org. Lett., Vol. 7, No. 1, 2005

synthesis. We turned our attention to applying our method
to the total synthesis of (+)-lennoxamine,18 a naturally
occurring isoindolobenzazepine alkaloid.
Scheme 4
The synthesis plan followed the retrosynthetic analysis
shown in Scheme 2. The known isoindolinone 619 was
Scheme 2
lithium-bromide exchange, formylation, and reduction pro-
vided alcohol 14. Hydrogenation of the vinyl ether and
subsequent treatment of the resulting alcohol (15) with PBr3
afforded the desired benzyl bromide 16.
The joining of isoindolinone 11 and bromide 16 proved
to be more problematic than anticipated. As a result of the
presence of two methoxy groups in 11, the anion formed on
deprotonation was not very stable. The best conditions found
for the alkylation step involved adding a mixture of 11 and
16 to 1.1 equiv of NaHMDS at -78 °C. In this manner, a
56% yield of 17 was isolated as a white solid (Scheme 5).
prepared in four steps from commercially available 2,3-
dimethoxybenzoic acid by bromination using dibromodi-
methylhydantoin (DBDMH),20 esterification, cyanation, and
then hydrogenation as depicted in Scheme 3. N-Acylation
as before provided the TCC-carbamate 11. The required
Scheme 5
Scheme 3
benzyl halide was synthesized from 6-bromopiperonal (12)
in four steps (Scheme 4). Olefination using the Levine
reagent21 gave the vinyl ether 13 in high yield. One-pot
Selective demethylation and chiral auxiliary cleavage was
effected using AlCl3/NaI22 to give alcohol 18 in 60% yield.
Finally, mesylation and cyclization using NaH provided
(+)-lennoxamine (5) in high overall yield for the two steps.
Our synthetic 5 (mp 232-234 °C, [R]23D +28 (c 1.0, CHCl3))
was configurationally stable and shown to be enantiopure
by chiral column HPLC analysis.
(17) Kuethe, J. T.; Comins, D. L. J. Org. Chem. 2004, 69, 5219 and
references therein.
(18) For the isolation of racemic lennoxamine from Berberis darwinii,
see: (a) Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron
Lett. 1984, 25, 599. For recent racemic total syntheses and leading
references, see: (b) Sahakitpichan, P.; Ruchirawat, S. Tetrahedron 2004,
60, 4169. (c) Kim, G.; Kim, J. H.; Kim, W.-j; Kim, Y. A. Tetrahedron
Lett. 2003, 44, 8207. (d) Koseki, Y.; Katsura, S.; Kusano, S.; Sakata, H.;
Sato, H.; Monzene, Y.; Nagasaka, T. Heterocycles 2003, 59, 527. (e) Padwa,
A.; Beall, L. S.; Eidell, C. K.; Worsencroft, K. J. J. Org. Chem. 2001, 66,
2414. (f) Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3923 and references
therein.
In summary, an efficient and practical asymmetric syn-
thesis of 3-alkylisoindolinones has been developed. This
(20) Auerbach, J.; Weissman, S. A.; Blacklock, T. J.; Angeles, M. R.;
Hoogsteen, K. Tetrahedron Lett. 1993, 34, 931.
(21) Levine, S. G. J. Am. Chem. Soc. 1958, 80, 6150.
(22) Node, M.; Ohta, K.; Kajimoto, T.; Nishide, K.; Fujita, E.; Fuji, K.
Chem. Pharm. Bull. 1983, 31, 4178.
(19) Kametani, T.; Honda, T.; Inoue, H.; Fukumoto, K. J. Chem. Soc.,
Perkin Trans. 1 1976, 1221.
Org. Lett., Vol. 7, No. 1, 2005
97

method was used in the first enantioselective synthesis of
the isoindolobenzazepine alkaloid, lennoxamine.
the National Science Foundation (grants CHE-9509532,
CHE-0078253).
Supporting Information Available: General experimen-
tal procedures for the preparation of 3 and spectral data for
compounds 2, 3, 4e-f, 5, 11, 13-18. ORTEP plot and X-ray
crystal data for 3d in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The authors thank Professor Raymond
Funk for a sample of racemic lennoxamine. We thank Dr.
Paul Boyle for X-ray crystallographic analysis of 3d. NMR
and mass spectra and X-ray data were obtained at NCSU
instrumentation laboratories, which were established by
grants from the North Carolina Biotechnology Center and
OL047824W
98
Org. Lett., Vol. 7, No. 1, 2005