Highly efficient synthesis of tricyclic amines by a cyclization/ cycloaddition cascade: Total syntheses of aspidospermine, aspidospermidine, and quebrachamine

Article abstract of DOI:10.1002/anie.200701943

(Chemical Equation Presented) Three in one: Three new rings can be made in one pot with complete control of the regio- and stereochemistry by a tandem cyclization/cycloaddition cascade reaction. Treatment of a chloroaldehyde with an amine gives a cyclic azomethine ylide that undergoes intramolecular cycloaddition onto a tethered alkene. The method was applied to the shortest known synthesis of aspidospermine (see scheme).

Full text of DOI:10.1002/anie.200701943

Angewandte
Chemie
DOI: 10.1002/anie.200701943
Alkaloid Synthesis
Highly Efficient Synthesis of Tricyclic Amines by a Cyclization/
Cycloaddition Cascade: Total Syntheses of Aspidospermine,
Aspidospermidine, and Quebrachamine**
Iain Coldham,* Adam J. M. Burrell, Laura E. White, Harry Adams, and Niall Oram
Reactions that occur in a single pot to form more than two
chemical bonds or new ring systems provide the means to
prepare complex compounds in a highly efficient manner.
Multicomponent reactions or multiple-bond formations
through cascade processes can be exploited for such chemis-
try.[1] For example, a powerful method to access bicyclic
compounds involves the formation of a 1,3-dipole followed by
intramolecular cycloaddition.[2] Such processes are generally
atom economic and occur with very high levels of regio- and
stereocontrol, in addition to saving time and effort in
comparison with sequential formation of each ring. Even
more efficient, however, are processes that allow the for-
mation of three rings in a single pot. There are few examples
of this type of method, yet this approach has the potential to
provide a rapid access to tricyclic compounds with significant
structural and stereochemical complexity.[3,4] This strategy has
recently received considerable attention for the synthesis of
various oxygen-containing products using cyclic carbonyl
ylides (often generated by reaction of a carbenoid with a
carbonyl group).[4] Herein, we describe an important devel-
opment of this method that leads to tricyclic amines in one pot
from acyclic precursors. Nitrogen-containing compounds are
prevalent in natural products and biologically active com-
pounds. Therefore this procedure has significant potential,
illustrated here by the shortest total synthesis to date of the
alkaloid (Æ )-aspidospermine, together with efficient synthe-
ses of the related alkaloids (Æ )-aspidospermidine and (Æ )-
quebrachamine.
and contains a pentacyclic ring system (Scheme 1). The
alkaloids aspidospermine and quebrachamine were first
synthesized by Stork and Dolfini over 40 years ago.[6] In
their classic synthesis, the ketone 1 was prepared as a key
intermediate in approximately 13steps. Since then many
other syntheses or formal syntheses have been reported.[7]
Scheme 1. Aspidosperma alkaloid targets.
Our strategy to tricyclic amine products was based on the
reasoning that if an azomethine ylide can be formed from an
aldehyde and a secondary amine, then it should be possible to
form the ylide from an aldehyde and a primary amine,
together with in situ N alkylation. Indeed, such a process has
been reported by Pearson et al. using (2-azaallyl)stannanes
and silanes, and used in intermolecular cycloadditions to give
two new rings.[8] By preparing the substrate in which the
dipolarophile is tethered to the ylide dipole, intramolecular
cycloaddition should ensue to give tricyclic products.[9] This is
illustrated by the general reaction depicted in Scheme 2. To
Many Aspidosperma alkaloids are known and have
attracted considerable attention, not least because of their
complex structures and interesting biological activities.[5]
Aspidospermidine is one of the simplest of these alkaloids
[*] Dr. I. Coldham, A. J. M. Burrell, L. E. White, H. Adams
Department of Chemistry
Scheme 2. Planned synthesis of tricyclic amines. X=leaving group;
Y=SiMe3, SnBu3, or CO2H.
University of Sheffield
Brook Hill, Sheffield S37HF (UK)
Fax: (+44)114-222-9346
E-mail: i.coldham@sheffield.ac.uk
Homepage: http://www.shef.ac.uk/chemistry/staff/profiles/cold-
ham.html
test this procedure, we required a method to access aldehyde
substrates that bear a dipolarophile (for example, an alkene)
and a leaving group (X) to allow ylide formation (for
example, after loss of Y by desilylation, destannylation, or
decarboxylation).
N. Oram
Eli Lilly & Co. Ltd
Lilly Research Centre, Erl Wood Manor
Windlesham, Surrey GU206PH (UK)
The aldehyde substrates were prepared readily by alky-
lation of butanenitrile. This preparation allows the formation
of quaternary centers in high yield.[10] Thus, deprotonation of
butanenitrile with LDA and alkylation with 4-bromo-1-
[**] We thank the EPSRC, the University of Sheffield, and Lilly UK for
support of this work.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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butene, followed by a second deprotonation then alkylation
with 1-bromo-3-chloropropane gave the nitrile 2a (n = 0,
Scheme 3). Simple reduction of the nitrile using DIBAL-H
then gave the aldehyde 3a. Likewise the product 3b (n = 1)
was prepared in only three steps via the nitrile 2b.
Scheme 5. Cyclization/cycloaddition of 3a and 3b with hydroxylamine.
a) Cl·H3NOH, toluene, iPr2NEt, heat, 18 h; 6 67% or 7 64%.
zoyl chloride) and X-ray analysis. In line with the results using
glycine ethyl ester described above, the reactions led to
different stereoisomers of the products for n = 0 and n = 1.
Of particular relevance is the cycloaddition of aldehydes
3a and 3b using glycine as the primary amine. With aldehyde
3b (n = 1) and glycine, an inseparable mixture of products was
obtained (NMR spectroscopy showed the presence of the
alkene in the mixture). The aldehyde 3a (n = 0) did however
Scheme 3. Preparation of the aldehyde substrates. a) LDA (0.5 equiv),
THF, À788C, 1 h; then (n=0) 4-bromo-1-butene (0.25 equiv), 80% or
(n=1) 5-bromo-1-pentene, 99%; b) LDA (2 equiv), THF, À788C, 1 h;
then 1-bromo-3-chloropropane, n=0, 95% or n=1, 96%; c) DIBAL-H
(1.2 equiv), CH2Cl2, À788C; then aq HCl, n=0, 87% or n=1, 89%.
DIBAL-H=diisobutylaluminum hydride, LDA=lithium diisopropyl-
amide.
Treatment of the aldehydes 3a and 3b with glycine ethyl
ester gave the products 4 or 5, respectively, each as a single
stereoisomer (Scheme 4). Yields were very good (72–74%)
Scheme 6. Cyclization/cycloaddition of 3a with amino acids.
a) H2NCH(R)CO2H, toluene, heat, 18–36 h; 8 82%, 9 78%, 10 60%.
give the product 8 (Scheme 6). Using alanine and phenyl-
alanine, the cycloadducts 9 and 10 were obtained. A single
stereoisomer of the tricyclic amines 8–10 was formed in each
case and these were assigned the all cis configuration based on
NMR spectroscopy.
A comparison of the reactions of 3b with glycine ethyl
ester (to give 5) and with glycine (no cycloaddition) suggests
that the electronics of the cycloaddition are important. To test
this, a further substrate 11 was prepared by cross-metathesis
and reduction (Scheme 7). A cyclization/cycloaddition cas-
cade was now successful using glycine and gave a mixture of
Scheme 4. Cyclization/cycloaddition of 3a and 3b with glycine ethyl
ester that includes possible transition-state conformation.
a) Cl·H3NCH2CO2Et, toluene, iPr2NEt, heat, 2 h; 4 72% or 5 74%.
for a process that involved the formation of four new s bonds,
three new rings, and three new stereocenters with complete
selectivity. The stereochemistry was confirmed by reduction
of the ester, conversion into the para-bromobenzoate, and X-
ray analysis of the HCl salt (see the Supporting Information).
The configuration of the products indicates that cycloaddi-
tions occur through the azomethine ylides with S-shaped
geometry, and this conforms to other examples of cyclo-
additions that use ester-stabilized ylides.[2b] The difference in
the stereochemistry at the ring junction must be a reflection of
the greater conformational freedom in the longer tethered
substrate (n = 1) which allows preferential formation of the
trans product 5, whereas the shorter chain length necessarily
leads to the all cis product 4.
Scheme 7. Cyclization/cycloaddition of 11 with glycine. a) phenyl vinyl
sulfone, Grubbs II cat. (5 mol%), CH2Cl2, heat, 24 h, 88%; b) DIBAL-
H, CH2Cl2, À788C; then aq HCl, 86%; c) H2NCH2CO2H, toluene, heat,
24 h; 12 36% and 13 38%; d) Na/Hg, Na2HPO4, MeOH, 08C; 14 57%
or 15 73%.
Addition of hydroxylamine to the aldehydes 3a and 3b
gave the tricyclic products 6 or 7 (Scheme 5). The relative
À
stereochemistry was confirmed by the reduction of the N O
bond (Zn, AcOH), followed by diacylation (para-bromoben-
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the tricyclic products 12 and 13. The structures and relative
stereochemistry of products 12 and 13 were verified by X-ray
analysis. Removal of the sulfone group was achieved using
sodium/mercury amalgam; from amine 12, the tricyclic
product 14 was obtained, although desulfonylation of 13
gave the bicyclic product 15, formed by b elimination.
To access the ketone 1, we needed to use a functionalized
version of substrate 3b or 11. We reasoned that using an
enone or masked enone in place of the alkene dipolarophile
could provide the necessary functionality and activation. The
bromide 17, which contains a protected enone, was prepared
from the known dibromoketone 16, itself readily prepared
from ethyl 3-bromopropionate (Scheme 8).[11]
Scheme 9. Synthesis of (Æ)-aspidospermine and (Æ)-quebrachamine.
a) 1. 2-MeOC6H4NHNH2, EtOH, RT, 3 h; 2. AcOH, 958C, 1 h;
3. LiAlH4, THF, 508C; 4. Ac2O, pyridine, 22% over 4 steps;
b) 1. PhNHNH2, benzene, heat, 2.5 h; 2. AcOH, 958C, 3 h; 3. KBH4,
KOH, MeOH, 39% over 3 steps.
spectroscopic data of this product corresponded with those
reported[7f,j] and it was converted into (Æ )-aspidospermidine
(Scheme 8) in three steps as previously reported.[7f,j,k] Sim-
ilarly, (Æ )-aspidospermine and (Æ )-quebrachamine were
prepared from the ketone 1 (Scheme 9).[6]
The method described here provides a rapid access to
complex tricyclic amines from acyclic precursors with regio-
and stereocontrol. Tertiary amines are formed from simple,
readily available primary amines. As far as we are aware, the
methodology provides the shortest known synthesis of
aspidospermine and consists of only six steps (40% yield)
from dibromide 16 to the ketone 1. This efficient method-
ology is likely to find application in the synthesis of various
nitrogen-containing heterocyclic compounds.
Experimental Section
Procedure for the cyclization/cycloaddition cascade with aldehyde 20:
The aldehyde 20 (0.27 g, 0.98 mmol), camphor sulfonic acid (25 mg,
0.1 mmol), and glycine (0.22 g, 2.9 mmol) were heated under reflux in
toluene (7.5 mL). After 18 h, the mixture was cooled to room
temperature and evaporated. Purification by column chromatography
on silica, eluting with CH2Cl2/MeOH/NH3 (95:5:0.1), gave the amine
21 (194 mg, 79%) which was recrystallized from light petroleum as
Scheme 8. Synthesis of (Æ)-aspidospermidine. a) HOCH2CH2OH, ben-
zene, TsOH, heat, 18 h; then tBuOK, THF/toluene (1:1), 08C, 2 h,
82%; b) EtCH2CN, LDA, THF, À788C; then 17, 88%; c) LDA, THF,
À788C, 1 h; then 1-bromo-3-chloropropane, 96%; d) DIBAL-H
(1.2 equiv), CH2Cl2, À788C; then oxalic acid (0.5m), 82%;
e) H2NCH2CO2H, toluene, camphor sulfonic acid (10 mol%), heat,
18 h, 79%; f) 5% aq HCl/THF (1:1), 808C, 1 h, 89%; g) 1. PhNHNH2,
benzene, heat, 2.5 h; 2. AcOH, 958C, 2.5 h; 3. LiAlH4, THF, heat, 13 h,
42% over 3 steps (the product from Fischer indole synthesis of the
regioisomeric enamine was isolated in 8% yield). Ts=toluene-p-
sulfonyl.
plates; m.p. 94–968C; Rf 0.27 (CH2Cl2/MeOH/NH3 (95:5:0.1)); nmax
=
1
2920, 2870 cmÀ1; H NMR (500 MHz, CDCl3) d = 3.96–3.84 (m, 4H,
2 ” CH2), 2.94 (ddd, J 12.5, 11.0, 5.5, 1H, CH), 2.61–2.56 (m, 1H, CH),
2.53(ddd, J 12.5, 9.0, 5.0, 1H, CH), 2.45–2.37 (m, 1H, CH), 2.33 (d, J
12.5, 1H, CH), 2.28–2.22 (m, 1H, CH), 1.98–1.90 (m, 1H, CH), 1.86–
1.78 (m, 1H, CH), 1.80–1.79 (m, 1H, CH), 1.87–1.26 (m, 8H, 8 ” CH),
1.22–1.13(m, 1H, CH), 0.78 ppm (t, J 7.5, 3H, CH3); 13C NMR
(125 MHz, CDCl3) d = 111.0, 68.9, 65.5, 64.2, 52.7, 48.7, 40.1, 34.9,
32.8, 31.9, 31.1, 23.2, 21.7, 21.7, 7.4 ppm; HRMS (ES) found: [M + H]+
(ES), 252.1970. C15H26NO2 requires [M + H]+, 252.1964; LRMS m/z
(ES) 252 (100%, [M + H]+); C15H25NO2 (251.19): calcd. C 71.67, H
10.02, N 5.57; found C 71.74, H 10.34, N 5.74.
By using the same method as before, the anion of
butanenitrile was treated with the bromide 17 to give the
nitrile 18. A second alkylation with 1-bromo-3-chloropropane
gave the nitrile 19 and reduction gave the desired substrate
20. Successful cyclization/cycloaddition was achieved with
this substrate using glycine in the presence of 10 mol%
camphor sulfonic acid to give the amine 21. The relative
stereochemistry was confirmed by X-ray analysis and showed
the cis/trans arrangement. On heating with aqueous acid, the
acetal was hydrolyzed with concomitant isomerization of the
adjacent stereocenter to provide the cis/cis ketone 1. The
Received: May 3, 2007
Published online: July 10, 2007
Keywords: alkaloids · amines · cyclization · cycloaddition · ylides
.
[1] For recent reviews, see: a) K. C. Nicolaou, D. J. Edmonds, P. G.
Bulger, Angew. Chem. 2006, 118, 7292 – 7344; Angew. Chem. Int.
Ed. 2006, 45, 7134 – 7186; ; b) M. Albert, L. Fensterbank, E.
Lacôte, M. Malacria, Top. Curr. Chem. 2006, 264, 1 – 62; c) D.
Enders, C. Grondal, M. R. M. Hüttl, Angew. Chem. 2007, 119,
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Communications
1590 – 1601; Angew. Chem. Int. Ed. 2007, 46, 1570 – 1581; d) L. F.
[4] For the formation of cyclic carbonyl ylides, followed by intra-
molecular cycloadditions, see: a) S. Shin, A. K. Gupta, C. Y.
Rhim, C. H. Oh, Chem. Commun. 2005, 4429 – 4431; b) T.
Graening, V. Bette, J. Neudꢀrfl, J. Lex, H.-G. Schmalz, Org.
Lett. 2005, 7, 4317 – 4320; c) D. M. Hodgson, D. Angrish, A. H.
Labande, Chem. Commun. 2006, 627 – 628; d) X. Zhang, R. Y. Y.
Ko, S. Li, R. Miao, R. Chiu, Synlett 2006, 1197 – 1200; e) Z. Geng,
B. Chen, P. Chiu, Angew. Chem. 2006, 118, 6343 – 6347; Angew.
Chem. Int. Ed. 2006, 45, 6197 – 6201; f) X. Hong, J. M. Mejier-
Oneto, S. France, A. Padwa, Synlett 2007, 775 – 779.
Tietze, G. Brasche, K. Gerike, Domino Reactions in Organic
Synthesis, Wiley-VCH, Weinheim, 2006; e) C. J. Chapman, C. G.
Frost, Synthesis 2007, 1 – 21.
[2] For reviews, see: a) G. Mehta, S. Muthusamy, Tetrahedron 2002,
58, 9477 – 9504; b) I. Coldham, R. Hufton, Chem. Rev. 2005, 105,
2765 – 2810.
[3] For some examples, in particular involving cycloaddition reac-
tions, see: a) K. C. Nicolaou, N. A. Petasis, R. E. Zipkin, J.
Uenishi, J. Am. Chem. Soc. 1982, 104, 5555 – 5557; b) K. C.
Nicolaou, N. A. Petasis, J. Uenishi, R. E. Zipkin, J. Am. Chem.
Soc. 1982, 104, 5557 – 5558; c) C. H. Heathcock, M. M. Hansen,
R. B. Ruggeri, J. C. Kath, J. Org. Chem. 1992, 57, 2544; d) S. A.
Frank, W. R. Roush, J. Org. Chem. 2002, 67, 4316 – 4324; e) G. D.
Wilkie, G. I. Elliott, B. S. J. Blagg, S. E. Wolkenberg, D. R.
Soenen, M. M. Miller, S. Pollack, D. L. Boger, J. Am. Chem. Soc.
2002, 124, 11292 – 11294; f) G. BØlanger, F.-T. Hong, L. E.
Overman, B. N. Rogers, J. E. Tellew, W. C. Trenkle, J. Org.
Chem. 2002, 67, 7880 – 7883; g) D. A. Evans, J. T. Starr, J. Am.
Chem. Soc. 2003, 125, 13531 – 13540; h) C. D. Vanderwal, D. A.
Vosburg, S. Weiler, E. J. Sorensen, J. Am. Chem. Soc. 2003, 125,
5393 – 5407; i) S. E. Denmark, R. Y. Baiazitov, J. Org. Chem.
2006, 71, 593– 605; j) G. I. Elliott, J. R. Fuchs, B. S. J. Blagg, H.
Ishikawa, H. Tao, Z.-Q. Yuan, D. L. Boger, J. Am. Chem. Soc.
2006, 128, 10589 – 10595; k) H. Ishikawa, G. I. Elliott, J.
Velcicky, Y. Choi, D. L. Boger, J. Am. Chem. Soc. 2006, 128,
10596 – 10612; l) J. Gergely, J. B. Morgan, L. E. Overman, J.
Org. Chem. 2006, 71, 9144 – 9152; m) D. Enders, M. R. M. Hüttl,
J. Runsink, G. Raabe, B. Wendt, Angew. Chem. 2007, 119, 471 –
473; Angew. Chem. Int. Ed. 2007, 46, 467 – 469; n) H.-Y. Lee, W.-
Y. Kim, S. Lee, Tetrahedron Lett. 2007, 48, 1407 – 1410; o) P. J.
Parsons, A. J. Waters, D. S. Walter, J. Board, J. Org. Chem. 2007,
72, 1395 – 1398; p) Y. Zhou, J. A. Porco, Jr., J. K. Snyder, Org.
Lett. 2007, 9, 393 – 396; q) H.-T. Chang, M. Jeganmohan, C.-H.
Cheng, Org. Lett. 2007, 9, 505 – 508; r) N. A. Miller, A. C. Willis,
M. N. Paddon-Row, M. S. Sherburn, Angew. Chem. 2007, 119,
955 – 958; Angew. Chem. Int. Ed. 2007, 46, 937 – 940.
[5] J. E. Saxton, The Alkaloids, Vol. 51 (Ed.: G. A. Cordell),
Academic Press, New York, 1998, chap. 1.
[6] G. Stork, J. E. Dolfini, J. Am. Chem. Soc. 1963, 85, 2872 – 2873.
[7] For recent examples, see: a) O. Callaghan, C. Lampard, A. R.
Kennedy, J. A. Murphy, J. Chem. Soc. Perkin Trans. 1 1999, 995 –
1001; b) M.A. Toczko, C. H. Heathcock, J. Org. Chem. 2000, 65,
2642 – 2645; c) S. A. Kozmin, T. Iwama, Y. Huang, V. H. Rawal,
J. Am. Chem. Soc. 2002, 124, 4628 – 4641; d) J. P. Marino, M. B.
Rubio, G. Cao, A. de Dios, J. Am. Chem. Soc. 2002, 124, 13398 –
13399; e) Y. Fukuda, M. Shindo, K. Shishido, Org. Lett. 2003, 5,
749 – 751; f) D. Gnecco, E. Vꢁzquez, A. Galindo, J. L. Terꢁn, L.
Orea, S. Bernꢂs, R. G. Enrꢃquez, ARKIVOC 2003, 185 – 192;
g) H. Tanino, K. Fukuishi, M. Ushiyama, K. Okada, Tetrahedron
2004, 60, 3273 – 3282; h) M. G. Banwell, D. W. Lupton, Org.
Biomol. Chem. 2005, 3, 213– 215; i) M. G. Banwell, D. W.
Lupton, A. C. Willis, Aust. J. Chem. 2005, 58, 722 – 737; j) R.
Iyengar, K. Schildknegt, M. Morton, J. AubØ, J. Org. Chem. 2005,
70, 10645 – 10652; k) L. A. Sharp, S. Z. Zard, Org. Lett. 2006, 8,
831 – 834; l) W. H. Pearson, A. Aponick, Org. Lett. 2006, 8,
1661 – 1664.
[8] W. H. Pearson, P. Stoy, Y. Mi, J. Org. Chem. 2004, 69, 1919 – 1939.
[9] For a recent example, see: W. H. Pearson, J. E. Kropf, A. L.
Choy, I. Y. Lee, J. W. Kampf, J. Org. Chem. 2007, 72, 4135 – 4148.
[10] F. F. Fleming, Z. Zhang, Tetrahedron 2005, 61, 747 – 789.
[11] S. E. Denmark, L. R. Marcin, J. Org. Chem. 1997, 62, 1675 –
1686.
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