Synthesis of fused tricyclic amines from enolizable acyclic aldehydes by cyclization then dipolar cycloaddition cascade: Synthesis of myrioxazine A

Article abstract of DOI:10.1021/ol9001653

A tandem one-pot reaction involving a condensation, then cyclization (N-alkylation), followed by an azomethine ylide or nitrone dipolar cycloaddition allows a synthesis of tricyclic amines from acyclic enolizable aldehydes. The reaction was unsuccessful u

Full text of DOI:10.1021/ol9001653

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1515-1518
Synthesis of Fused Tricyclic Amines
from Enolizable Acyclic Aldehydes by
Cyclization then Dipolar Cycloaddition
Cascade: Synthesis of Myrioxazine A
Adam J. M. Burrell,*,† Iain Coldham,*,† and Niall Oram‡
Department of Chemistry, UniVersity of Sheffield, Brook Hill, Sheffield, S3 7HF, U.K.,
and Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, U.K.
i.coldham@sheffield.ac.uk; adam.burrell@pfizer.com
Received January 26, 2009
ABSTRACT
A tandem one-pot reaction involving a condensation, then cyclization (N-alkylation), followed by an azomethine ylide or nitrone dipolar
cycloaddition allows a synthesis of tricyclic amines from acyclic enolizable aldehydes. The reaction was unsuccessful using amino acids or
esters but was successful with (tributylstannyl)methylamine or hydroxylamine. One of the products was converted in two steps to the alkaloid
(()-myrioxazine A. The chemistry also provides a formal synthesis of the antimalarial alkaloids myrionidine and schoberine.
Reactions where multiple bonds are formed in one sequence
without isolating intermediates, changing the reaction condi-
tions or adding reagents, represent efficient and economic
processes.1 Multiple bond forming reactions, or multicom-
ponent reactions, are often termed cascade, tandem, or
domino reactions and can be used for the formation of
complex products.2 For example, the formation of a 1,3-
dipole followed by an in situ intramolecular cycloaddition
represents a powerful way of accessing bicyclic compounds.3
In addition, such processes generally offer high levels of
regio- and stereocontrol. Cascade reactions where three rings
can be formed in one reaction are particularly efficient and
(3) For reviews, see: (a) Mehta, G.; Muthusamy, S. Tetrahedron 2002,
58, 9477. (b) Coldham, I.; Hufton, R. Chem. ReV. 2005, 105, 2765.
(4) For some recent examples, see: (a) Shin, S.; Gupta, A. K.; Rhim,
C. Y.; Oh, C. H. Chem. Commun. 2005, 4429. (b) Hodgson, D. M.; Angrish,
D.; Labande, A. H. Chem. Commun. 2006, 627. (c) Zhang, X.; Ko, R. Y. Y.;
Li, S.; Miao, R.; Chiu, P. Synlett 2006, 1197. (d) Geng, Z.; Chen, B.; Chiu,
P. Angew. Chem., Int. Ed. 2006, 45, 6197. (e) Mejia-Oneto, J. M.; Padwa,
A. Org. Lett. 2006, 8, 3275. (f) Nakamura, S.; Sugano, Y.; Kikuchi, F.;
Hashimoto, S. Angew. Chem., Int. Ed. 2006, 45, 6532. (g) Hong, X.; France,
S.; Padwa, A. Tetrahedron 2007, 63, 5962. (h) England, D. B.; Padwa, A.
Org. Lett. 2007, 9, 3249. (i) Lam, S. K.; Chiu, P. Chem.-Eur. J. 2007, 13,
9589. (j) England, D. B.; Egan, J. M.; Merey, G.; Anac, O.; Padwa, A.
Tetrahedron 2008, 64, 988. (k) Padwa, A.; Chughtai, M. J.; Boonsombat,
J.; Rashatasakhon, P. Tetrahedron 2008, 64, 4758. (l) Mejia-Oneto, J. M.;
Padwa, A. HelV. Chim. Acta 2008, 91, 285. (m) Oh, C. H.; Lee, J. H.; Lee,
S. J.; Kim, J. I.; Hong, C. S. Angew. Chem., Int. Ed. 2008, 47, 7505.
† University of Sheffield.
‡ Eli Lilly and Company.
(1) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(2) For recent reviews, see: (a) Nicolau, K. C.; Edmonds, D. J.; Bulger,
P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (b) Albert, M.; Fensterbank,
L.; Lacoˆte, E.; Malacria, M. Top. Curr. Chem. 2006, 264, 1. (c) Enders,
D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
(d) Tietze, L. F.; Brasche, G.; Gerike, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 2006. (e) Chapman, C. J.;
Frost, C. G. Synthesis 2007, 1.
10.1021/ol9001653 CCC: $40.75
Published on Web 03/02/2009
2009 American Chemical Society

allow rapid access to structural and stereochemical complex-
ity. One such cascade class involves a cyclization to form a
dipole which can then undergo an intramolecular cycload-
dition. This strategy has been used for the synthesis of
polycyclic oxygen-containing products, where cyclic carbo-
nyl ylides (often generated by the reaction of a carbenoid
with an intramolecular carbonyl group) undergo a cycload-
dition with an internal dipolarophile.4 In a similar way, an
intramolecular 1,3-dipolar cycloaddition reaction of a nitrone
ylide with a dipolarophile can lead to a range of polycyclic
compounds.5 Another class of cascades, again forming
multiple rings in one reaction, involves tandem [4 + 2]/[3
+ 2] cycloadditions of either 1,3,4-oxadiazoles (coupled with
nitrogen extrusion)6 or nitroalkenes.7
led to inseparable mixtures of mono- and dialkylated
products. To circumvent this problem, the trimethylsilyl ether
of 3-bromopropan-1-ol was used as the alkylating agent.
Following an acidic workup, the alcohols 4a and 4b could
be separated easily from the dialkylated diol products
(Scheme 2). Subsequent chlorination of the alcohols with
Scheme 2. Synthesis of Aldehydes 6
Our cascade strategy relies on the ability to form an
azomethine or nitrone ylide from an aldehyde and a primary
amine (e.g., glycine, glycine ethyl ester, or hydroxylamine)
using an in situ N-alkylation.8 In our recent synthesis of three
Aspidosperma alkaloids, we demonstrated such a process
using aldehyde 1, where treatment with glycine generates a
cyclic azomethine ylide which then undergoes an intramo-
lecular cycloaddition on the tethered alkene, to give amine
2 (Scheme 1).9
PPh3 and N-chlorosuccinimide (NCS), then reduction with
DIBAL-H, gave the aldehydes 6a and 6b.
Treatment of aldehydes 6a and 6b with glycine or glycine
ethyl ester (to form the unstabilized or stabilized ylides,
respectively) gave an inseparable mixture of products (in each
case, NMR spectroscopy showed the presence of alkene in
the mixture) (Scheme 3). The failure of this chemistry
Scheme 1
.
Synthesis of Tricyclic Amine 2 Using a Cyclization/
Cycloaddition Cascade
Scheme 3. Treatment of Aldehydes 6 with Amines
A number of possible tricyclic amine targets lack the ring
junction ethyl group. Thus, to use the cascade chemistry as
a general method for total synthesis, the use of enolizable
aldehydes must be evaluated. We report here our results with
such aldehydes.
Deprotonation of 5-hexenenitrile (3a) or 6-heptenenitrile
(3b) with LDA and alkylation with 1-bromo-3-chloropropane
(5) (a) Turariello, J. J.; Trybulski, E. J. J. Org. Chem. 1974, 39, 3378.
(b) Grigg, R.; Markandu, J.; Surendrakumar, S.; Thornton-Pett, M.;
Warnock, W. J. Tetrahedron 1992, 48, 10399. (c) Markandu, J.; Ali Dondas,
H.; Frederickson, M.; Grigg, R. Tetrahedron 1997, 53, 13165. (d)
Frederickson, M.; Grigg, R.; Markandu, J.; Thornton-Pett, M.; Redpath, J.
Tetrahedron 1997, 53, 15051. (e) Davison, E. C.; Fox, M. E.; Holmes,
A. B.; Roughley, S. D.; Smith, C. J.; Williams, G. M.; Davies, J. E.; Raithby,
P. R.; Adams, J. P.; Forbes, N. J.; Thompson, M. J. J. Chem. Soc., Perkin
Trans. 1 2002, 1494. (f) Arini, L. G.; Szeto, P.; Hughes, D. L.; Stockman,
R. A. Tetrahedron Lett. 2004, 45, 8371. (g) Stockman, R. A.; Sinclair, A.;
Arini, L. G.; Szeto, P.; Hughes, D. L. J. Org. Chem. 2004, 69, 1598. (h)
Horseley, H. T.; Holmes, A. B.; Davies, J. E.; Goodman, J. M.; Silva, M. A.;
Pascu, S. I.; Collins, I. Org. Biomol. Chem. 2004, 2, 1258. (i) Sinclair, A.;
Arini, L. G.; Rejzek, M.; Szeto, P.; Stockman, R. A. Synlett 2006, 2321.
(j) Karatholuvhu, M. S.; Sinclair, A.; Newton, A. F.; Alcaraz, M.-L.;
Stockman, R. A.; Fuchs, P. L. J. Am. Chem. Soc. 2006, 128, 12656.
contrasts with that of the analogous nonenolizable substrates.9
As an alternative to the use of glycine or glycine ethyl ester,
it is sometimes possible to generate azomethine ylides from
enolizable aldehydes via their imines then desilylation or,
preferably, destannylation, which is thought to be faster than
(6) (a) Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.;
Sorensen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem.
Soc. 2002, 124, 11292. (b) Elliott, G. I.; Fuchs, J. R.; Blagg, B. S. J.;
Ishikawa, H.; Tao, H.; Yuan, Z.-Q.; Boger, D. L. J. Am. Chem. Soc. 2006,
128, 10589. (c) Ishikawa, H.; Elliott, G. I.; Velicicky, J.; Choi, Y.; Boger,
D. L. J. Am. Chem. Soc. 2006, 128, 10596.
1516
Org. Lett., Vol. 11, No. 7, 2009

enamine formation.8a,10,11 Pearson and co-workers have
found that azomethine ylides can be generated readily from
N-(tri-n-butylstannyl)methyl iminium salts without the need
for an additive (such as fluoride) to initiate demetalation.8a
Following this procedure, we were pleased to find that
treatment of aldehyde 6a with (tri-n-butylstannyl)methy-
lamine gave tricyclic amine 8 as a single isomer (Scheme
In the case of aldehyde 10b, activation of the dipolarophile
facilitated the desired cycloaddition, and three tricyclic
amines with structure 12 were obtained in moderate yield
(dr 1:1:1) with no observable enamine product. The structures
of two of these cycloadducts (12b and 12c, Figure 1) were
1
3). The all cis configuration was confirmed by H NMR
spectroscopy. In addition to amine 8, enamine 7 was also
isolated, arising either from deprotonation of the iminium
salt followed by destannylation and protonation or by
tautomerization of the azomethine ylide after destannylation.
In the case of aldehyde 6b, the cycloaddition to form a new
six-membered ring must be slower than that to form a five-
membered ring, and as such, only the analogous enamine 9
was isolated (Scheme 3).
Figure 1. Structures of the products 12.
In attempts to increase the rate of cycloaddition relative
to the rate of enamine formation, aldehydes 10a and 10b
were prepared by cross metathesis with phenyl vinyl sulfone
catalyzed by Grubbs’ second-generation catalyst (Scheme
4). However, activation of the dipolarophile in aldehyde 10a
elucidated by single-crystal X-ray analysis and the third
isomer (12a) by H NMR spectroscopy. In similar studies
1
with nonenolizable aldehydes (using a substrate similar to
10 but with an ethyl group rather than a hydrogen atom R-
to the aldehyde), only products with stereochemistry analo-
gous to 12a and 12c were obtained.9a It therefore seems that
the trans-decalin moiety in product 12b can arise when using
an enolizable aldehyde.
In contrast to azomethine ylides, dipolar cycloaddition of
nitrone ylides derived from enolizable aldehydes is common,
and we were pleased to find that treatment of the aldehyde
6a with hydroxylamine gave the cycloadduct 13 in good yield
(Scheme 5). Similarly, treating aldehyde 6b with hydroxy-
Scheme 4
.
Cross Metathesis and Subsequent Cyclization/
Cycloaddition
Scheme 5. Cyclization/Cycloaddition Using Hydroxylamine
failed to give an increase in yield of the desired tricyclic
amine (11), which we ascribe to the inherent instability of
the aldehyde 10a.
lamine gave the cycloadduct 14 (together with some oxime
15, which could be converted to 14 on further heating). The
stereochemistry of the cycloadducts was confirmed by H
(7) For some recent examples, see: (a) Denmark, S. E.; Baiazitov, R. Y.
J. Org. Chem. 2006, 71, 593. (b) Denmark, S. E.; Gomez, L. J. Org. Chem.
2003, 68, 8015. (c) Denmark, S. E.; Juhl, M. HelV. Chim. Acta 2002, 85,
1
NMR spectroscopy.
3712. (d) Denmark, S. E.; Cottell, J. J. J. Org. Chem. 2001, 66, 4276
.
(8) For related chemistry, see: (a) Pearson, W. H.; Stoy, P.; Mi, Y. J.
Org. Chem. 2004, 69, 1919. (b) Pearson, W. H.; Kropf, J. E.; Choy, A. L.;
Lee, I. Y.; Kampf, J. W. J. Org. Chem. 2007, 72, 4135. (c) Dondas, H. A.;
Grigg, R.; Hadjisoteriou, M.; Markandu, J.; Thomas, W. A.; Kennewell, P.
Tetrahedron 2000, 56, 10087. (d) Coldham, I.; Jana, S.; Watson, L.; Pilgram,
C. D. Tetrahedron Lett. 2008, 49, 5408. (e) Yeom, H.-S.; Lee, J.-E.; Shin,
S. Angew. Chem., Int. Ed. 2008, 47, 7040. (f) Le´vesque, F.; Be´langer, G.
The N-O bond in cycloadduct 14 was cleaved by reaction
with zinc in acetic acid to give the amino alcohol 16 (Scheme
6). This amino alcohol was heated with paraformaldehyde
under acid catalysis to complete the total synthesis of (()-
myrioxazine A, a natural product isolated from Myrioneuron
nutans.12 The synthesis of the amino alcohol 16 also
Org. Lett. 2008, 10, 4939
.
(9) (a) Coldham, I.; Burrell, A. J. M.; White, L. E.; Adams, H.; Oram,
N. Angew. Chem., Int. Ed. 2007, 46, 6159. (b) Burrell, A. J. M.; Coldham,
I.; Watson, L.; Oram, N.; Pilgram, C. D.; Martin, N. G. J. Org. Chem.
2009, 74,DOI: 10.1021/jo8019913.
(12) Pham, V. C.; Jossang, A.; Chiaroni, A.; Se´venet, T.; Bodo, B.
Tetrahedron Lett. 2002, 43, 7565.
(10) Padwa, A.; Dent, W. J. Org. Chem. 1987, 52, 235
.
(13) Pham, V. C.; Jossang, A.; Grellier, P.; Se´venet, T.; Nguyen, V. H.;
Bodo, B. J. Org. Chem. 2008, 73, 7565.
(11) Torii, S.; Okumoto, H.; Genba, A. Chem. Lett. 1996, 25, 747
.
Org. Lett., Vol. 11, No. 7, 2009
1517

cade. As such, the methodology may find application in the
total synthesis of nitrogen-containing heterocyclic compounds
bearing ring junction protons. This is demonstrated by an
expedient synthesis of (()-myrioxazine A in six steps and
42% overall yield, starting from 6-heptenenitrile.
Scheme 6. Synthesis of Myrioxazine A from Cycloadduct 14
Acknowledgment. We thank the EPSRC, the University
of Sheffield, and Lilly UK for support of this work. Harry
Adams (University of Sheffield) is thanked for X-ray
crystallographic analysis.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of NMR spectra for
the products 4-14, 16, and myrioxazine A and X-ray
structures for 12b (CCDC-714564) and 12c (CCDC-714563).
This material is available free of charge via the Internet at
http://pubs.acs.org.
completes a formal synthesis of the antimalarial alkaloids
myrionidine and schoberine.13
In summary, the method described here allows the
formation of tricyclic amines from acyclic enolizable alde-
hydes, using a condensation/cyclization/cycloaddition cas-
OL9001653
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Org. Lett., Vol. 11, No. 7, 2009