Cascade cyclization, dipolar cycloaddition to bridged tricyclic amines related to the daphniphyllum alkaloids

Article abstract of DOI:10.1021/ol102961x

A tandem one-pot reaction of an aldehyde with a primary amine involving condensation and then cyclization (N-alkylation), followed by intramolecular dipolar cycloaddition of the resulting nitrone or azomethine ylide, provides a synthesis of bridged tricyclic amines. The reaction was most successful using hydroxylamine, and when the dipolarophile was an unsaturated ester, subsequent reduction of the N-O bond and cyclization to the lactam provided the core ring system of the yuzurimine, daphnilactone B, and bukittinggine type Daphniphyllum alkaloids.

Full text of DOI:10.1021/ol102961x

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1267–1269
Cascade Cyclization, Dipolar
Cycloaddition to Bridged Tricyclic Amines
Related to the Daphniphyllum Alkaloids
,†
†
†
‡
ꢀ ꢁ
Iain Coldham,* Adam J. M. Burrell, Helene D. S. Guerrand, 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
Received December 7, 2010
ABSTRACT
A tandem one-pot reaction of an aldehyde with a primary amine involving condensation and then cyclization (N-alkylation), followed by
intramolecular dipolar cycloaddition of the resulting nitrone or azomethine ylide, provides a synthesis of bridged tricyclic amines. The reaction
was most successful using hydroxylamine, and when the dipolarophile was an unsaturated ester, subsequent reduction of the N-O bond and
cyclization to the lactam provided the core ring system of the yuzurimine, daphnilactone B, and bukittinggine type Daphniphyllum alkaloids.
The Daphniphyllum alkaloids are a large and growing
group of complex natural products. There are several
structural types of these alkaloids, including the daph-
niphylline, secodaphniphylline, yuzurimine, yuzurine,
daphnilactone A, daphnilactone B, bukittinggine,
daphnezomine, daphnicyclidin, daphmanidin, daph-
niglaucin, calyciphyllin, and paxdaphnine alkaloids.1
Other than an inspired biomimetic synthesis of some of the
members of these alkaloids,2 there are only a few approaches
to the core ring systems of these structurally complex alka-
loids.3
We have recently reported an efficient entry to tricyc-
lic products by a cascade of condensation, cyclization,
and then cycloaddition.4 This chemistry has allowed
access to fused tricyclic products, and we wondered if a
similar approach would be successful for the synthesis of
bridged tricyclic compounds, as found in many Daphni-
phyllum alkaloids. For example, yuzurimine B, daphni-
lactone B, and bukittinggine have a bridged core ring
system, of which compound 1 is representative (Scheme 1).
Denmark and co-workers have reported some elegant
cascade cycloaddition-cycloaddition chemistry for the
preparation of the core of daphnilactone B.3a Discon-
nection of the core ring system 1 to the aldehyde 2 would
allow us to probe whether our cascade cyclization-
cycloaddition chemistry would be amenable to the
synthesis of the core bridged ring system of these alka-
loids. In this paper we report our successful preliminary
results using such chemistry.
† University of Sheffield.
‡ Eli Lilly and Company.
(1) (a) Kobayashi, J.; Kubota, T. Nat. Prod. Rep. 2009, 26, 936. (b)
Dong, M.; Zhang, M. L.; Shi, Q. W.; Gu, Y. C.; Kiyota, H. Curr. Org.
Chem. 2009, 13, 646. (c) Kobayashi, J.; Morita, H. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: San Diego, 2003; Vol. 60, pp 165-205.
(2) (a) Heathcock, C. H.; Hansen, M. M.; Ruggeri, R. B.; Kath, J. C.
J. Org. Chem. 1992, 57, 2544. (b) Heathcock, C. H.; Stafford, J. A. J.
Org. Chem. 1992, 57, 2566. (c) Heathcock, C. H.; Stafford, J. A.; Clark,
D. L. J. Org. Chem. 1992, 57, 2575. (d) Heathcock, C. H.; Ruggeri, R. B.;
McClure, K. F. J. Org. Chem. 1992, 57, 2585. (e) Heathcock, C. H.;
Kath, J. C.; Ruggeri, R. B. J. Org. Chem. 1995, 60, 1120.
(3) (a) Denmark, S. E.; Baiazitov, R. Y.; Nguyen, S. T. Tetrahedron
2009, 65, 6535. (b) Denmark, S. E.; Nguyen, S. T.; Baiazitov, R. Y.
Heterocycles 2008, 76, 143. (c) Denmark, S. E.; Baiazitov, R. Y. J. Org.
Chem. 2006, 71, 593. (d) Ueda, M.; Walczak, M. A. A.; Wipf, P.
ꢀ
Tetrahedron Lett. 2008, 49, 5986. (e) Sole, D.; Urbaneja, X.; Bonjoch,
(4) (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, 2290. (c) Burrell, A. J. M.; Coldham, I.; Oram, N. Org. Lett.
2009, 11, 1515. (d) Burrell, A. J. M.; Watson, L.; Martin, N. G.; Oram,
N.; Coldham, I. Org. Biomol. Chem. 2010, 8, 4530.
J. Org. Lett. 2005, 7, 5461. (f) Cordero-Vargas, A.; Urbaneja, X.;
Bonjoch, J. Synlett 2007, 2379. (g) Ikeda, S.; Shibuya, M.; Kanoh, N.;
Iwabuchi, Y. Org. Lett. 2009, 11, 1833. (h) Tanabe, K.; Fujie, A.;
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r
10.1021/ol102961x
2011 American Chemical Society
Published on Web 02/11/2011

Scheme 1. Some Daphniphyllum Alkaloids and Disconnection of
the Core Bridged Tricyclic Amine
Scheme 2. Synthesis of Aldehyde 2
Our cascade strategy relies on the ability to form a 1,3-
dipole from an aldehyde using a condensation with a
primary amine and in situ cyclization (N-alkylation) of
the imine.5 This is followed by dipolar cycloaddition with
an alkene. For the core of these Daphniphyllum alkaloids,
we needed access to the aldehyde 2 to test this chemistry.
This has a one-carbon bridging atom between the aldehyde
and the branch-point for the alkyl halide and the dipolar-
ophile, and we chose this bridging atom to have a gem-
dimethyl group to mimic the natural products and to avoid
problems of diastereomers of the substrate and potential
enolization or enamine formation on reaction of the
aldehyde and amine.
The aldehyde 2 was prepared as shown in Scheme 2. Our
strategy involved conjugate addition to the known unsat-
urated aldehyde 3,6 using the method of Yamamoto and
co-workers with a silyl ketene acetal in the presence of a
bulky Lewis acid catalyst.7 This gave the aldehyde 4
selectively by 1,4- rather than 1,2-addition. The aldehyde
4 was reduced (in the presence of the ester) to the alcohol 5
withNaBH4.8 Care mustbetaken toavoid heat or traces of
the aluminum catalyst from the previous step, as otherwise
cyclization to the lactone occurs readily. Conversion of the
alcohol 5 to the bromide 6 was achieved via the intermedi-
ate mesylate. Finally, reduction of the ester to the alcohol 7
and then Swern oxidation gave the aldehyde 2.
Scheme 3. Treatment of Aldehyde 2 with Amines
high yield (Scheme 3). This product must arise from
condensation to give the oxime, cyclization with formation
of the nitrone 8, and then intramolecular cycloaddition.
However, heating the aldehyde 2 with glycine in toluene or
xylene failed to give any of the desired pyrrolidine product
resulting from the expected azomethine ylide intermediate.
Heating with glycine ethyl ester gave a mixture of products
containing some of the desired cycloadduct 10, formed as a
1
single stereoisomer (stereochemistry determined by H
NOESY experiments) resulting from cycloaddition
through the expected S-shaped ylide.9
The low yields for the reactions of the azomethine ylides
are probably due to their slow reaction with an unactivated
alkene combined with the requirement for the alkenyl
tether to be located in a pseudoaxial position for successful
cycloaddition. Therefore, we anticipated that direct for-
mation of the desired product 1 (by cycloaddition of the
azomethine ylide generated using glycine and a Z-methyl-
substituted alkene) would be unsuccessful. To increase the
rate of cycloaddition, an electron-withdrawing group
could be located on the alkene. To test this, the aldehydes
11 and 12 were prepared by cross metathesis of 2 with
phenyl vinyl sulfone or methyl acrylate, catalyzed by
Grubbs’ second generation catalyst (Scheme 4). The acti-
vated substrate 11 did undergo the in situ condensation,
cyclization, and cycloaddition using glycine to give the
tricyclic product 13; however the yield was very poor. An
We were pleased to find that heating aldehyde 2 with
hydroxylamine hydrochloride and iPr2NEt in toluene gave
the desired bridged tricyclic product 9 as a single isomer in
(5) 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) Levesque, F.;
ꢀ
Belanger, G. Org. Lett. 2008, 10, 4939. (g) Coldham, I.; Jana, S.; Watson,
L.; Martin, N. G. Org. Biomol. Chem. 2009, 7, 1674.
(6) (a) Bestmann, H. J.; Koschatzky, K. H.; Platz, H.; Suess, J.;
Vostrowsky, O.; Knauf, W.; Burghardt, G.; Schneider, I. Liebigs Ann.
1982, 1359. (b) Whittaker, M.; McArthur, C. R.; Leznoff, C. C. Can. J.
Chem. 1985, 63, 2844.
(7) Maruoka, K.; Imoto, H.; Saito, S.; Yamamoto, H. J. Am. Chem.
Soc. 1994, 116, 4131.
(8) For a related sequence of reactions starting with an aldehyde-
ester, see: Cheney, D. L.; Paquette, L. A. J. Org. Chem. 1989, 54, 3334.
(9) (a) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765. (b)
Burrell, A. J. M.; Coldham, I. Curr. Org. Synth. 2010, 7, 312.
1268
Org. Lett., Vol. 13, No. 6, 2011

Scheme 4. Cross Metathesis and Cyclization/Cycloaddition
Figure 1. X-ray structures of the products 16 and 19.
was not verified at this stage. This product was treated with
Raney nickel and then sodium methoxide in methanol (to
complete the partial cyclization) to give the lactam 16. The
stereochemistry of this compound was confirmed by single
crystal X-ray structure analysis (Figure 1). This was the
expected stereoisomer based on the anticipated concerted
cycloaddition across the E-alkene 12 (to give isomer 15).
Oxidation of the alcohol 16 gave the ketone 17, and Wittig
reaction gave the alkene 18.10 Finally, reduction of the
Scheme 5. Cyclization/Cycloaddition Using Hydroxylamine
alkene with Ni(OAc)2 4H2O/NaBH4 under an atmo-
3
sphere of hydrogen gave the desired ring system 19, as a
single stereoisomer. An X-ray single crystal structure of
product 19 (Figure 1) confirmed the configuration
of the methyl group, which matches that of the Daph-
niphyllum alkaloids.
In summary, cascade chemistry involving condensation,
cyclization, and then intramolecular dipolar cycloaddition
has been extended successfully to bridged tricyclic pro-
ducts. This has allowed the synthesis of the core bridged
ring system of the yuzurimine, daphnilactone B, and
bukittinggine type alkaloids.
Acknowledgment. We thank the EPSRC, the Univer-
sity of Sheffield, and Lilly UK for support of this work.
Harry Adams (University of Sheffield) is thanked for
X-ray crystallographic analyses.
attempted reaction of the activated substrate 12 with
glycine was unsuccessful (decomposition). However, with
glycine ethyl ester, the tricyclic products 14 were obtained
in good yield. These were formed as a mixture of stereo-
isomers at the carbon center bearing the ethyl ester group.
Cycloaddition through the S-shaped ylide may be less
favored in this case due to a steric clash with the methyl
ester in the transition state.
Supporting Information Available. Experimental proce-
dures, spectroscopic data, and copies of NMR spectra for
the products 2-7, 9-19, and X-ray structures for 16 (CCDC
802281) and 19 (CCDC 802282). This material is available
free of charge via the Internet at http://pubs.acs.org.
Heating the aldehyde 12 with hydroxylamine in toluene
gave the cycloadduct 15 in excellent yield (Scheme 5). A
single isomer was formed, although the stereochemistry
(10) For a related sequence of reactions, see ref 3c.
Org. Lett., Vol. 13, No. 6, 2011
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