Asymmetric allylboration of cyclic imines and applications to alkaloid synthesis

Article abstract of DOI:10.1021/ja0636791

Treatment of cyclic imines with 3,3′-disubstituted binaphthol modified allylboronates provides the expected allylated products in good yields and with high stereoselectivities (91-99% ee). The products may be readily transformed into various alkaloids. Copyright

Full text of DOI:10.1021/ja0636791

Published on Web 07/11/2006
Asymmetric Allylboration of Cyclic Imines and Applications to Alkaloid
Synthesis
T. Robert Wu and J. Michael Chong*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry,
UniVersity of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Received May 25, 2006; E-mail: jmchong@uwaterloo.ca
Table 1. Allylation of 1a with Allylboronates 2a-h
The enantioselective allylboration of carbonyl compounds has
become a prominent tool for asymmetric synthesis, with many
reported applications to the synthesis of natural products.1,2 In
contrast, the corresponding reaction with imines as a route to
homoallylic amines is much less developed: There are only a few
examples of asymmetric allylborations with acyclic imines as
substrates3 and no examples with cyclic imines. With acyclic imines
(or other CdN functionalities), other elegant allylation strategies
have been developed4 to access homoallylic amines, compounds
which are important synthetic intermediates.5 However, the analo-
gous enantioselective allylation of cyclic imines is very rare,6,7 even
though the chiral R-allyl cyclic amines produced are also valuable
building blocks. Previously, such compounds have been prepared
by less direct routes for syntheses of numerous natural products
and bioactive molecules.8 To the best of our knowledge, there has
been only one report of successful enantioselective allylations of
cyclic imines: 10 years ago, Nakamura and co-workers observed
high selectivities with allylzinc reagents,9 but there have been no
published synthetic applications of this chemistry. Very recently,
Itoh reported the first catalytic asymmetric allylation of a cyclic
imine, but the selectivity was only modest (71% ee).10 We now
report the first enantioselective allylboration of cyclic imines along
with some illustrative examples of applications to the synthesis of
alkaloids.
entry
X
yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
H (2a)
Me (2b)
I (2c)
CF3 (2d)
Ph (2e)
4-MeO-C6H4- (2f)
<50
94
87
83
90
94
88
92
10
75
77
84
87
88
87
95
3,5-(CH3)2-C6H3- (2g)
3,5-(CF3)2-C6H3- (2h)
a Isolated yields after acid-base extraction. b Determined by chiral HPLC
analysis of the trifluoroacetamide. Absolute configuration based on rotation.9
It has been demonstrated that 3,3′-disubstituted binaphthol
modified allylboronates can be used for enantioselective allylations
of aldehydes and ketones (up to 98% yield and >99% ee).11 Based
on analysis of proposed transition state models, it was anticipated
that acyclic (E) imines would be poor substrates, while cyclic (Z)
imines would be good substrates for these reagents. When a
prototypical cyclic imine, 3,4-dihydroisoquinoline (1a), was treated
with these allylboronates (2a-h, toluene, -78 °C to room tem-
perature), reactions proceeded smoothly to give homoallylic amine
3a in good yields (Table 1).
All of the 3,3′-disubstituted systems examined gave reasonable
to excellent selectivities, while the unsubstituted parent binaphthol
(2a) exhibited essentially no stereoselectivity. This lack of stereo-
selectivity and the sense of asymmetric induction observed may
be explained using a six-membered chair transition-state model
(Figure 1). The repulsion between one of the substituents on the
BINOL and the methylene protons R to the imine nitrogen is the
major destabilizing interaction in transition state B.
Figure 1. Proposed transition states.
A variety of substituted dihydroisoquinolines (Table 2, entries
1-5) were subjected to allylboration using 2h. Reactions of
electron-rich substrates (Table 2, entries 2 and 3) were much slower
than those of electron-poor substrates (Table 2, entries 4 and 5),
so longer reaction times were required to get satisfactory yields.
Nonetheless, good yields could be obtained in all cases, and
selectivities observed were uniformly excellent (95 to 99% ee). 3,4-
Dihydro-â-carboline (1f) could be allylated using 2h without
protecting the acidic indole functionality (Table 2, entry 6).
N-Protected dihydro-â-carboline 1g gave a similar result, indicating
that the enantioselectivity of the reaction is not affected by the steric
or electronic nature of the indole ring (Table 2, entry 7).
Aliphatic cyclic imines 1-pyrroline (1i) and ∆1-piperideine (1h)
were also subjected to the allylboration, giving the desired chiral
cyclic pyrrolidine and piperidine with 92 and 91% ee, respectively
(Table 2, entries 8 and 9). Slightly lower yields were obtained in
both cases, likely due to the propensity of the starting imines to
undergo rapid trimerization.12 In these cases, products were isolated
as Boc or tosyl derivatives to avoid possible problems with volatility
or water solubility.
The desired amine was isolated by simple aqueous acid-base
extraction, and the chiral ligands were recycled from the organic
phases without detectable loss of enantiomeric purities. Thus,
although stoichiometric amounts of reagents are employed, these
reactions are quite practicable. Of the chiral boronates tested, 2h
gave the best enantioselectivity (Table 1, entry 8) and was chosen
for further studies.
The allylation products can serve as building blocks for the
synthesis of natural products. For instance, hydroboration of 3b
(9-BBN then H2O2/NaOH) followed by an intramolecular Mit-
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10.1021/ja0636791 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Allylation of Cyclic Imines Using (S)-2h
converted to R,â-unsaturated ester 7. n-BuLi induced intramolecular
Michael addition led to the formation of all-cis trisubstituted
δ-lactam 8.16 ent-Corynantheidol (9) was finally obtained after a
global reduction using LAH. Of course, use of (R)-2h, readily
prepared from (R)-1,1′-bi(2-naphthol), would have produced natural
corynantheidol. These syntheses compare very favorably with
previous syntheses in terms of both length and overall yields.13b,14,17
In summary, a general methodology for the enantioselective
allylation of cyclic imines has been developed. The versatility of
the allylation products has been demonstrated through efficient total
syntheses of several naturally occurring alkaloids, and we expect
that more applications of this methodology will be forthcoming.
Acknowledgment. We thank the Natural Sciences and Engi-
neering Research Council of Canada (NSERC) for financial support.
Supporting Information Available: Procedures for allylborations
and spectroscopic data for compounds 3-9. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Isolated yields after flash column chromatography on silica gel.
b Isolated yields after acid-base extraction. c Determined by chiral HPLC
analysis of trifluoroacetamides. d Determined by 19F NMR of its R-MTPA
amide. e The reaction was quenched using TsCl/pyridine/DMAP or (Boc)2O/
Et3N/DMAP, and the ee of the product was determined by chiral HPLC
analysis.
References
(1) Reviews: (a) Chemler, S. R.; Roush, W. R. In Modern Carbonyl
Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, Germany, 2000;
Chapter 11. (b) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763-
2793.
(2) Recent developments: (a) Canales, E.; Prasad, K. G.; Soderquist, J. A. J.
Am. Chem. Soc. 2005, 127, 11572. (b) Rauniyar, V.; Hall, D. G. Angew.
Chem., Int. Ed. 2006, 45, 2426.
Scheme 1. Synthesis of (+)-Crispine A (4)
(3) Chen, G. M.; Ramachandran, P. V.; Brown, H. C. Angew. Chem., Int.
Ed. 1999, 38, 825 and references therein.
(4) For recent examples, see: (a) Kobayashi, S.; Ogawa, C.; Konishi, H.;
Sugiura, M. J. Am. Chem. Soc. 2003, 125, 6610. (b) Berger, R.; Rabbat,
P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596. (c) Fernandes,
R. A.; Stimac, A.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 14133.
(d) Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126,
5686. (e) Ogawa, C.; Sugiura, M.; Kobayashi, S. Angew. Chem., Int. Ed.
2004, 43, 6491. (f) Ramachandran, P. V.; Burghardt, T. E.; Bland-Berry,
L. J. Org. Chem. 2005, 70, 7911.
Scheme 2. Synthesis of R-(-)-Coniine‚HCl (5)
(5) For recent reviews, see: (a) Ding, H.; Friestad, G. K. Synthesis 2005,
2815. (b) Kobayashi, S.; Sugiura, M.; Ogawa, C. AdV. Synth. Catal. 2004,
346, 1023.
(6) Diastereoselective syntheses of chiral R-allyl cyclic amines: (a) Meyers,
A. I.; Dickman, D. A.; Boes, M. Tetrahedron 1987, 43, 5095. (b) Suzuki,
H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 1995, 36, 6709. (c) Hatano,
B.; Haraguchi, Y.; Kozima, S.; Yamaguchi, R. Chem. Lett. 1995, 11, 1003.
(d) Adam, S.; Pannecoucke, X.; Combret, J.-C.; Quirion, J.-C. J. Org.
Chem. 2001, 66, 8744.
Scheme 3. Synthesis of ent-Corynantheidol (9)a
(7) An enantioselective allylation of activated cyclic iminium ions using a
chiral allylsilane has been reported: Yamaguchi, R.; Tanaka, M.; Matsuda,
T.; Fujita, K. Chem. Commun. 1999, 2213.
(8) Total syntheses involving chiral R-allyl cyclic amines: (a) Yamaguchi,
R.; Otsuji, A.; Uchimoto, K. J. Am. Chem. Soc. 1988, 110, 2186. (b)
Meyers, A. I.; Highsmith, T. K.; Buonora, P. T. J. Org. Chem. 1991, 56,
2960. (c) Yamaguchi, R.; Otsuji, A.; Uchimoto, K.; Kozima, S. Bull. Chem.
Soc. Jpn. 1992, 65, 298. (d) Birman, V. B.; Rawal, V. H. J. Org. Chem.
1998, 63, 9146.
(9) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 1996, 118,
8489.
(10) Itoh, T.; Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A. Org. Lett.
2006, 8, 1295.
(11) Wu, T. R.; Shen, L.; Chong, J. M. Org. Lett. 2004, 6, 2701.
(12) Scully, F. E., Jr. J. Org. Chem. 1980, 45, 1515.
a Reaction conditions: (a) (()-HO2CCH(Br)CH2CH3, DCC, CH2Cl2; (b)
OsO4, NaIO4, 2,6-lutidine, 1,4-dioxane/H2O; (c) Ph3PdCHCOOEt, CH2Cl2,
82% for 3 steps; (d) n-BuLi (1.2 equiv), THF, 63%; (e) LAH (15 equiv),
THF, 79%.
(13) (a) Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58, 6795.
(b) Szawkalo, J.; Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.;
Drabowicz, J.; Czarnocki, Z. Tetrahedron: Asymmetry 2005, 16, 3619.
(14) Recent enantioselective syntheses of coniine: (a) Sattely, E. S.; Cortez,
G. A.; Moebius, D. C.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2005, 127, 8526. (b) Gommermann, N.; Knochel, P. Chem. Commun.
2004, 2324. (c) Glorius, F.; Spielkamp, N.; Holle, S.; Goddard, R.;
Lehmann, C. W. Angew. Chem., Int. Ed. 2004, 43, 2850.
(15) Shellard, E. J.; Houghton, P. J. Planta Med. 1973, 24, 13.
(16) Mixtures of diastereomers were obtained from which compound 8 could
be isolated in 63% yield by flash chromatography. Other radical cyclization
methods (e.g., Bu3SnH/AIBN or SmI2) and a Reformatsky process (CuCN/
Zn) were attempted but gave low diastereselectivities or low yields.
(17) (a) Yu, S.; Berner, O. M.; Cook, J. M. J. Am. Chem. Soc. 2000, 122,
7827. (b) Beard, R. L.; Meyers, A. I. J. Org. Chem. 1991, 56, 2091.
sunobu reaction yielded (+)-crispine A (4), an antitumor alkaloid
isolated from C. crispus (Scheme 1).13
Coniine (5), an alkaloid that has been the target of innumerable
demonstrations of synthetic methodologies,14 could be obtained in
one pot from imine 1h (Scheme 2).
This allylboration methodology was also applied to the total
synthesis of the enantiomer of a more complex alkaloid corynan-
theidol, isolated from leaves of Mitragyna parVifolia (Roxb.) Korth
(Scheme 3).15 Thus, allylation product 3g was treated with (()-2-
bromobutyric acid and DCC to give amide 6, which was in turn
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