Synthesis of the enantiomer of the structure assigned to the natural product nobilisitine A

Article abstract of DOI:10.1021/ol102249q

The synthesis of the enantiomer of the structure, 1, assigned to the natural product nobilisitine A has been accomplished using the enantiomerically pure cis-1,2-dihydrocatechol 4 as starting material. The ¹H and ¹³C NMR spectral data derived from compound ent-1 do not match those reported for the natural product, thus suggesting its structure has been incorrectly assigned.

Full text of DOI:10.1021/ol102249q

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5210-5213
Synthesis of the Enantiomer of the
Structure Assigned to the Natural
Product Nobilisitine A
Brett D. Schwartz, Matthew T. Jones, Martin G. Banwell,* and Ian A. Cade
Research School of Chemistry, Institute of AdVanced Studies, The Australian National
UniVersity, Canberra ACT 0200, Australia
mgb@rsc.anu.edu.au
Received September 20, 2010
ABSTRACT
The synthesis of the enantiomer of the structure, 1, assigned to the natural product nobilisitine A has been accomplished using the
1
enantiomerically pure cis-1,2-dihydrocatechol 4 as starting material. The H and 13C NMR spectral data derived from compound ent-1 do not
match those reported for the natural product, thus suggesting its structure has been incorrectly assigned.
In 1999 Evidente and his colleagues reported on the isolation
of the natural product nobilisitine A from the Egyptian
ornamental plant CliVia nobilis.1 On the basis of the recorded
NMR, infrared, and mass spectral data, they concluded that the
compound was a masanane- or lycorenine-type alkaloid pos-
sessing structure 1 (Figure 1) in which there is an “all-cis”
arrangement of non-hydrogen substituents about the cyclohex-
ane C-ring. Structure 1 represents a diastereoisomer of clivonine
(2),2 arguably the “signature” member of this small subset of
Amaryllidaecae alkaloids. Given our interest3 in the biogeneti-
cally and structurally related lycorine alkaloids (e.g., 3),4 we
sought to develop syntheses of compound 1 and related systems
Figure 1. Structures of compounds 1-3.
for the purposes of checking Evidente’s structural assignment
and to obtain materials for biological evaluation. In this
connection, we now describe the first total synthesis of the
structure ent-1 and report that the derived spectral data do not
match those recorded for nobilisitine A.
The opening stages of our synthesis of compound ent-1
started (Scheme 1) with cis-1,2-dihydrocatechol 4, an
enantiomerically pure compound that is available in large
(1) Evidente, A.; Abou-Donia, A. H.; Darwish, F. A.; Amer, M. E.;
Kassem, F. F.; Hammoda, H. A. M.; Motta, A. Phytochemistry 1999, 51,
1151.
(2) Jeffs, P. W.; Hansen, J. F.; Do¨pke, W.; Bienert, M. Tetrahedron
1971, 27, 5065.
(3) Jones, M. T.; Schwartz, B. D.; Willis, A. C.; Banwell, M. G. Org.
Lett. 2009, 11, 3506.
(4) Man˜as, C. G.; Paddock, V. L.; Bochet, C. G.; Spivey, A. C.; White,
A. J. P.; Mann, I.; Oppolzer, W. J. Am. Chem. Soc. 2010, 132, 5176, and
references cited therein.
10.1021/ol102249q  2010 American Chemical Society
Published on Web 10/26/2010

Scheme 1. Synthesis of N-Methyl Carbamate 14
quantities via the whole-cell biotransformation of bro-
mobenzene.5 Thus, diol 4 was converted, under standard
conditions, into the well-known6 acetonide 5 (93%) that
was then subjected to electrophilic epoxidation with
m-chloroperbenzoic acid (m-CPBA). The resulting and
previously reported6 epoxide 6 (95%), which was obtained
in a completely regio- and diastereoselective manner, was
then treated with the acetonitrile anion, thereby affording
the γ-hydroxynitrile 73 (96%) as the only isolable product
of reaction. Subjection of the latter compound to a
Barton-McCombie deoxygenation reaction sequence7
provided, via the intermediate xanthate ester 8 (94%), the
desired methylene-containing derivative 93 (82% from 8).
Suzuki-Miyaura cross-coupling8 of compound 9 with the
readily available boronate ester 103 then gave the arylated
cyclohexene 113 (75%), a key intermediate associated with
our recently reported3 synthesis of a lycorine degradation
product.
the corresponding primary amine 12 using dihydrogen in the
presence of Raney cobalt.9 Reaction of the latter compound
with Alloc-Cl in the presence of pyridine gave carbamate
13 (88% from 11) that could be N-methylated through its
successive treatment with lithium hexamethyldisilazide (LiH-
MDS) and methyl iodide. Compound 14 was thereby
obtained in 98% yield.
The D-ring of target ent-1 was formed using a nitrogen-
centered radical cyclization process.10 The substrate required
for this purpose was prepared as shown in Scheme 2. Thus,
the Alloc group associated with compound 14 was cleaved
Scheme 2. Completion of the Synthesis of Lactone ent-1
As a prelude to installing the D-ring and associated methyl
group of target ent-1, the nitrile moiety within compound
11 was reduced, in a completely chemoselective manner, to
(5) For reviews on methods for generating compounds such as 4 by
microbial dihydroxylation of the corresponding aromatics, as well as the
synthetic applications of these metabolites, see: (a) Hudlicky, T.; Gonzalez,
D.; Gibson, D. T. Aldrichimica Acta 1999, 32, 35. (b) Banwell, M. G.;
Edwards, A. J.; Harfoot, G. J.; Jolliffe, K. A.; McLeod, M. D.; McRae,
K. J.; Stewart, S. G.; Vo¨gtle, M. Pure Appl. Chem. 2003, 75, 223. (c)
Johnson, R. A. Org. React. 2004, 63, 117. (d) Hudlicky, T.; Reed, J. W.
Synlett 2009, 685.
(6) Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. J. Am. Chem. Soc.
1990, 112, 9439.
(7) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1
1975, 1574.
(8) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
(9) For a related reduction process involving Raney cobalt, see: Janey,
J. M.; Orella, C. J.; Njolito, E.; Baxter, J. M.; Rosen, J. D.; Palucki, M.;
Sidler, R. R.; Li, W.; Kowal, J. J.; Davies, I. W. J. Org. Chem. 2008, 73,
3212.
Org. Lett., Vol. 12, No. 22, 2010
5211

by treating it with Pd(Ph3P)4 in the presence of an excess of
dimedone.11 The resulting secondary amine 15 (99%) was
then subjected to chlorination, at nitrogen, using N-chloro-
succinimide (NCS), and the N-chloroamine 16 so formed
(88%) was treated with tri-n-butylstannane (n-Bu3SnH, 1.1
mol equiv) and AIBN (5 mol %) in benzene at reflux. This
resulted in the coproduction of the chromatographically
separable reductive cyclization product 17 (23% or 77%
based on recovered 15) and the direct reduction product 15
(71% recovery).
The initial assignment of stereochemistry to the two new
stereogenic centers, C11b and C11c, established within
product 17 during the radical cyclization process was based
on mechanistic arguments. Thus, in keeping with outcomes
observed in analogous cyclization reactions involving carbon-
centered radicals,12 the formation of a cis-ring-fused system
would be expected. Furthermore, the benzylic radical created
as a result of the cyclization process would be expected to
react with n-Bu3SnH at the sterically less congested ꢀ-face,
thereby establishing the illustrated R-orientation of the aryl
group at C11b in compound 17.
Figure 2. ORTEP derived from the single-crystal X-ray analysis
of compound ent-1. Thermal ellipsoids are drawn at the 50%
probability level. H atoms are shown as spheres of arbitrary radius.
A comparison of the 1H and 13C NMR spectral data derived
from lactone ent-1 with those reported1 for nobilisitine A is
presented in Table 1. This quite clearly reveals that the two
compounds are different and, therefore, that the structure
assigned to the title natural product is incorrect. The large
difference in the chemical shifts of the resonances due to
the methyl group protons (δH 1.45 for ent-1 vs δH 2.24 for
nobilisitine A) is particularly notable. The high-field nature
of the former chemical shift can be attributed to the shielding
of the N-methyl group in lactone ent-1 by the adjacent cis-
related arene unit. It is tempting, therefore, to assume that
in the natural product a trans-relationship exists between the
The conversion of product 17 into target ent-1 was
effected, in 93% yield, by treating the former compound with
acidified DOWEX-50WX8-100 ion-exchange resin in water/
methanol. All of the spectral data derived from lactone ent-1
were in complete accord with the assigned structure, and
final confirmation of the relative stereochemistry followed
from a single-crystal X-ray analysis.13 The ORTEP arising
from this analysis is shown in Figure 2, while further details
are presented in the Supporting Information, including the
full assignment of the 1H and 13C NMR spectral data recorded
for the compound.
1
Table 1. Comparison of the 13C and H NMR Data Recorded for Synthetically-Derived Lactone ent-1 with those Reported for
Nobilisitine A
13C NMR (δC)
1H NMR (δH)
lactone ent-1a
nobilisitine Ab
lactone ent-1c
nobilisitine Ad
164.7
151.9
147.6
137.8
121.0
109.8
106.6
101.9
78.0
69.7
67.7
55.0
45.2
164.0
152.6
147.2
137.3
118.6
109.7
106.5
102.0
81.4
68.6
66.6
54.9
41.8
7.54, s, 1H
6.70, s, 1H
6.05, m, 2H
7.53, s, 1H
7.05, s, 1H
6.05, broad s, 2H
4.65, dd, J ) 6.6 and 5.0 Hz, 1H
3.96, ddd, J ) 9.9, 6.6, and 5.0 Hz, 1H
3.34, dd, J ) 5.0 and 5.0 Hz, 1H
3.24, ddd, J ) 13.6, 6.6, and 5.0 Hz, 1H
2.67, dd, J ) 5.8 and 5.0 Hz, 1H
2.30, m, 1H
2.24, s, 3H
2.27, m, 1H
2.02, m, 1H
2.00, m, 1H
1.62, m, 2H
-
4.61, app. t, J ) 2.5 Hz, 1H
3.74, ddd, J ) 11.7, 3.7, and 2.9 Hz, 1H
3.31, td, J ) 10.6 and 6.8 Hz, 1H
2.87, dd, J ) 4.6 and 3.0 Hz, 1H
2.60, app. t, J ) 4.9 Hz, 1H
2.37-2.33, complex m, 1H
2.26-2.22, complex m, 1H
1.95-1.90, complex m, 1H
1.88, app. q, J ) 12.4 Hz, 1H
1.78, dt, J ) 10.3 and 4.9 Hz, 1H
1.47-1.44, complex m, 1H
1.45, s, 3H
41.0
39.4
36.6
34.7
30.9
29.8
33.7
30.1
signal due to OH proton not observed
-
signal due to OH proton not observed
-
a Data recorded in CDCl3 at 200 MHz. b Data obtained from ref 1 and recorded in CDCl3 at unspecified field strength. c Data recorded in CDCl3 at 800
MHz. d Data obtained from ref 1 and recorded in CDCl3 at unspecified field strength.
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Org. Lett., Vol. 12, No. 22, 2010

equivalent moieties. Certainly, the chemical shift of the
N-methyl group protons reported for nobilisitine A is more
consistent with the presence of a cis B/C anti, cis C/D
arrangement14 of the constituent ring systems (assuming, of
course, that the basic lycorenine framework assigned to this
natural product is indeed correct). Efforts are now underway
to determine the true structure of nobilisitine A.
Acknowledgment. We thank the Institute of Advanced
Studies and the Australian Research Council for financial
support.
(10) For relevant examples of nitrogen-centered radical cyclization
processes, see, for example: (a) Cassayre, J.; Gagosz, F.; Zard, S. Z. Angew.
Chem., Int. Ed. 2002, 41, 1783. (b) Banwell, M. G.; Lupton, D. W.
Heterocycles 2006, 68, 71.
Supporting Information Available: Full experimental
procedures; data derived from the single-crystal X-ray
analysis of compound ent-1; and 1H and 13C NMR spectra
of compounds 12-17 and ent-1. This material is available
free of charge via the Internet at http://pubs.acs.org.
(11) Kunz, H.; Unverzagt, C. Angew. Chem., Int. Ed. 1984, 23, 436.
(12) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073.
(13) CCDC 793455 contains the supplementary crystallographic data
for compound ent-1. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
(14) Jeffs, P. W.; Mueller, L.; Abou-Donia, A. H.; Seif El-Din, A. A.;
Campau, D. J. Nat. Prod. 1988, 51, 549.
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