Spiroleucettadine: synthetic studies and investigations towards structural revision

Article abstract of DOI:10.1016/j.tetlet.2007.01.088

Synthetic efforts towards spiroleucettadine are described, including the enantioselective synthesis of the presumed biosynthetic precursor. High level density functional theory calculations were used to predict the ¹³C NMR shifts of possible al

Full text of DOI:10.1016/j.tetlet.2007.01.088

Tetrahedron Letters 48 (2007) 2199–2203
Spiroleucettadine: synthetic studies and investigations
towards structural revision
Nicholas Aberle,a,b Simon P. B. Ovenden,c Guillaume Lessene,a
Keith G. Watsona,* and Brian J. Smitha
aThe Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Victoria, Australia
bDepartment of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia
cDefence Science and Technology Organisation, 506 Lorimer Street, Fishermans Bend 3207, Victoria, Australia
Received 25 October 2006; revised 8 January 2007; accepted 17 January 2007
Available online 23 January 2007
Abstract—Synthetic efforts towards spiroleucettadine are described, including the enantioselective synthesis of the presumed biosyn-
thetic precursor. High level density functional theory calculations were used to predict the 13C NMR shifts of possible alternative
structures and, along with a re-evaluation of the available NMR data, allow the proposal of revised structures for this spirocyclic
alkaloid.
Ó 2007 Elsevier Ltd. All rights reserved.
Structurally interesting and biologically useful marine
natural products have provided stimulation for ad-
vances in both synthetic chemistry and disease treat-
ment. Recent work by Crews and co-workers on the
bright yellow Leucetta sponge furnished the cyclic gua-
nidine alkaloid spiroleucettadine (1, Fig. 1), possessing
both anti-bacterial activity (a minimum inhibitory con-
centration of <6.25 lg/mL against Enterococcus durans)
and a highly strained trans-fused imidazolidine–oxolane
core ring system featuring an unusual orthoamide func-
tionality.1 Continuing our interest in 2-aminoimidazole
alkaloids,2 we sought to develop a synthetic route to
the proposed structure and, following two recent papers
also dealing with synthetic studies towards 1, were
inspired to report our own findings which include
offering alternative structures for the alkaloid.
Teams led by Danishefsky3 and Ciufolini4 both pursued
the final structure via the presumed biosynthetic pre-
cursor, glycocyamidine 2 (Fig. 1), in anticipation that
oxidative intramolecular cyclisation in the fashion per-
formed by Wong5 would afford the ring system of 1.
Use of a hypervalent iodine species such as bis(trifluoro-
acetoxy)iodobenzene (‘PIFA’) to effect such a transfor-
mation also formed the final step in our synthetic
plans, but we note that neither group of researchers
could entice the desired cyclisation to occur. The pres-
ence of the free hydroxyl in the orthoamide moiety of
Figure 1. Original structure of spiroleucettadine 1, presumed biosynthetic precursor 2 and ring-opened isomer 3.
Keywords: Spiroleucettadine; Density functional theory; Oxidative cyclisations; 13C NMR Predictions; Biosynthesis.
*
Corresponding author. E-mail: kwatson@wehi.edu.au
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.088

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N. Aberle et al. / Tetrahedron Letters 48 (2007) 2199–2203
Scheme 1. Synthesis of chiral precursor.
1 presents the concern that the preferred form of the
proposed structure might be the amide-containing p-qui-
nol 3, a fact confirmed in both of the aforementioned
papers where N-protected derivatives of this species
were isolated in variable yields. In the circumstance
where the imine is unprotected, it appears that poly-
merisation through Michael additions to the dienone
prevents isolation of 3 itself.4
the 5-oxazolidinone to the a,a-disubstituted amino acid
7 under basic hydrolysis conditions was followed by
selective N-methylation. The formation of amino-amide
8 was achieved through in situ preparation of the
acid fluoride using DAST before addition of excess
methylamine. Simultaneous removal of both the Cbz
and Bn protecting groups provided compound 9 which,
upon treatment with cyanogen bromide, cyclised to the
desired precursor 10.
Our stereospecific preparation of the precursor (Scheme
1) began with a commercially available and suitably
protected tyrosine residue 4, present as the unnatural
enantiomer so as to provide, ultimately, the correct ori-
entation of the benzyl groups about the sp3 quaternary
carbon of the imidazolidinone ring. To enable introduc-
tion of the p-methoxybenzyl moiety in a stereoselective
manner, the protected tyrosine was first converted to
the dominant cis-epimer of 5-oxazolidinone 5 by expo-
sure to benzaldehyde dimethyl acetal in the presence
of BF3ÆEt2O.6,7 Alkylation with 4-methoxybenzyl bro-
mide proceeded smoothly to afford 6. Ring opening of
In light of the results disclosed in Refs. 3 and 4 and after
several unsuccessful attempts at performing the oxida-
tive spirocyclisation, we turned to a model system
(Scheme 2). While not affected by the concerns of the
peculiar ring-strain evident in spiroleucettadine, the
model was aimed at determining whether amino-ketal 13
(R = alkyl) might support the unusual orthoamide ring
system better than the required hemiketal (13, R = H).
For this investigation, model compound 12 was pre-
pared in two steps from p-hydroxycinnamic acid 11.
Unfortunately, under all attempted conditions only 14

N. Aberle et al. / Tetrahedron Letters 48 (2007) 2199–2203
2201
Scheme 2. Model system for oxidative spirocyclisation.
or 15 (R = CH3), or mixtures thereof, were isolated,
casting further doubt on the ability to isolate such an
orthoamide functionality via hyper-valent iodine-medi-
ated oxidative cyclisation.
ment8 and, after their recent use to propose structural
revision of the natural product hexacyclinol,9 were used
here to support an alternative structure of spiroleucetta-
dine. The hybrid functional MPW1PW91 has been shown
to perform particularly well in this regard, especially
when employed with the 6-311+G(2d,p) basis set.10–13
Our experience with both the model system and the actual
precursor 10, along with the comments in both the Dani-
shefsky and Ciufolini papers, led us to examine the avail-
able spectroscopic data of spiroleucettadine in greater
detail. This highlighted several areas of concern with the
initial structure assignment, based around the observed
13C chemical shift values of C-4 (102.5 ppm) and C-5
(82.5 ppm) (and hence the regiochemistry of the oxygen
in the oxolane ring), and the interpretation of the
gHMBC and ROESY data. In particular, Ralifo and
Crews state that there is a gHMBC correlation observed
between H2-8 and C-6. Our analysis of the available
gHMBC data suggested that this correlation is in fact a
The minimum energy conformation of each structure
was located on the B3LYP/6-31G(d) potential energy
surface, and the nuclear shielding determined at the
MPW1PW91/6-311+G(2d,p) level upon these geo-
metries. The 13C chemical shifts were obtained by sub-
tracting the predicted nuclear shielding for each atom
from the predicted shielding for tetramethylsilane
(TMS). The nuclear shielding of the carbon nucleus in
TMS at this level, 186.49, compares very favourably
with the experimental value, 186.4.14 The calculated
shifts were corrected from a least-squares correlation
of the predicted and experimental shifts.9,15
1
coincidental correlation from H2-8 into the JC–H of
the 13C resonance of MeOH, the solvent in which
the two-dimensional NMR data were collected. Thus, in
the absence of any evidence linking C-6 and C-8, we con-
sidered the possibility that the actual structure of spiro-
leucettadine has C-6 and the oxygen in the oxolane ring
reversed (16, Fig. 2). This change in structure is consistent
with the absence of gHMBC correlations between C-8
and C-6, and was also expected to better explain the
observed 13C resonances for both C-4 and C-5.
The differences in experimental and calculated (cor-
rected) 13C chemical shifts for 1 and 16 are presented
in Figure 3. The mean absolute error (MAE) for 1 is
4.3, whereas for 16 the MAE is 3.4 ppm. The error in
13C shift for atoms C-4, -5, -6 and -7 of 1 are quite large,
between 7.8 and 14.0 ppm. The error in 13C shift for
three of these four atoms in 16 remains high, but C-5 is
within 0.6 ppm of the experimental value. Despite this,
16 appears to be a biosynthetically feasible alternative.
Density functional calculations of 13C NMR chemical
shifts generally show good agreement with the experi-
Performing the same calculations on various known
structures (Fig. 4)16–18 confirmed the accuracy of the
predictions (with the exception of brominated carbons,
due to the omission in the calculations of relativistic
and spin–orbit coupling effects19) to within about
5 ppm. These results also provided evidence that the pre-
viously unassigned rings of spirocalcaridines A and B
(17 and 18)16 are likely to be cis-fused (MAEs 2.4 and
2.7 ppm, respectively) rather than trans-fused (MAEs
3.9 and 4.3 ppm, respectively).
A range of structural and conformational variants of 1
and 16 were then modelled following the method outlined
Figure 2. Spiroleucettadine 1 and oxolane-inverted version 16.

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N. Aberle et al. / Tetrahedron Letters 48 (2007) 2199–2203
Figure 3. Difference in ppm between calculated and experimental 13C NMR chemical shifts for 1 and 16.
Analysis of these results revealed that, in order to obtain
chemical shift predictions similar to the experimental val-
ues of 82.5 and 102.5 ppm for those two atoms, one of
these two carbons must be connected to three other car-
bon atoms and one nitrogen, and the other connected
to two other carbons, one nitrogen and one oxygen. It
was also observed that the accurate prediction of the shift
for C-7 required the fused [5,5] ring system to be cis-
fused. Further structures matching these rules were
investigated, with the lowest mean average error being
obtained for cis-22 (MAE 2.2 ppm, Fig. 5), which also
had the lowest maximum individual error (5.1 ppm).
Biosynthetically, 16 can be explained by a speculative
dihydroxylation of the common naamine-type skeleton
23, followed by intramolecular spirocyclisation and sub-
sequent methylations (Scheme 3). Such a dioxygenated
intermediate can also explain the spirocalcaridines 17
and 18 and, via a pinacol-type rearrangement, the car-
bon structure of calcaridine 19. Structure 22 could be
derived from an epoxidation of 23. Various states of
N- and O-methylation are known to exist amongst Leuc-
Figure 4. Related structures with acceptably low deviations from the
experiment. Spirocalcaridines A 17 and B 18, calcaridine 19, 6-bromo-
10-hydroxy-10,8-dihydroaplysinopsin 20 and slagenin A 21.
above, without significant improvements in either mean
average error or maximum individual atom error, focus-
sing primarily on the ring junction atoms C-4 and C-5.
Figure 5. Difference in ppm between calculated and experimental 13C NMR chemical shifts for cis-22. MAE = 2.2 ppm.

N. Aberle et al. / Tetrahedron Letters 48 (2007) 2199–2203
2203
Scheme 3. Possible biosyntheses of 16 and 22.
2. Aberle, N. S.; Lessene, G.; Watson, K. G. Org. Lett. 2006,
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etta alkaloids, and it is conceivable that the correspond-
ing introduction of the C-4 methyl would result in the
opening of epoxide 24 before an intramolecular cyclisa-
tion to give 22.
As an alternative structure, 16 appears to be more bio-
synthetically feasible, but the modelling results show
22 to be the best match of the 13C NMR data. In view
of the apparent error in the existing assignment of spiro-
leucettadine, our focus now shifts to providing synthetic
evidence for our proposals.
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Acknowledgements
This work was supported by an Australian Postgraduate
Award (N.A.). We thank Dr. Jonathan B. Baell for
helpful discussions.
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Supplementary data
15. The gradient and intercept for compound 1 are 0.9948 and
0.3311, respectively, and for compound 16, 0.9806 and
ꢀ3.8437, respectively.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.01.088.
16. Edrada, R. A.; Stessman, C. C.; Crews, P. J. Nat. Prod.
2003, 66, 939–942.
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References and notes
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