Studies directed toward the synthesis of the guanidine alkaloid, spiroleucettadine: Some observations at the level of structure

Article abstract of DOI:10.1016/j.tetlet.2005.11.002

Studies toward the synthesis of the novel guanidine alkaloid spiroleucettadine are described.

Full text of DOI:10.1016/j.tetlet.2005.11.002

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 385–387
Studies directed toward the synthesis of the guanidine alkaloid,
spiroleucettadine: some observations at the level of structure
Chaomin Lia and Samuel J. Danishefskya,b,
*
aDepartment of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, NY 10027, USA
bLaboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10021, USA
Received 24 October 2005; accepted 1 November 2005
Available online 28 November 2005
Abstract—Studies toward the synthesis of the novel guanidine alkaloid spiroleucettadine are described.
Ó 2005 Elsevier Ltd. All rights reserved.
Marine natural products, particularly those isolated
from sponges, often exhibit interesting and diverse bio-
logical profiles in the context of novel structural frame-
works. Crews and co-workers recently isolated a number
of structurally related guanidinium natural products
from a calcareous Leucetta sponge (Fig. 1).1 Among
these, we were particularly drawn to the unusual struc-
ture of spiroleucettadine (1), which was assigned a rare
5,5-trans fused bicyclic core moiety in the context of a
2-aminoimidazole oxalane. Furthermore, compound 1
is reported to exhibit in vitro antibacterial activity
against Enterococcus durans, with a minimum inhibitory
concentration (MIC) of <6.25 lg/mL.1b In keeping with
our ongoing research program devoted to the reaching
of biologically and structurally novel natural products,
we sought to accomplish the total synthesis of spiroleu-
cettadine (1).
In designing a synthesis of 1, we were particularly mind-
ful of the potential challenges associated with the diaste-
reoselective construction of the trans-5,5-bicyclic core
structure. In this regard, we postulated that a cationic
intermediate of the type 6 might be induced to selectively
undergo hydration at the desired a-face in light of the
steric constraints imposed on the b-face by the benzylic
moiety (Scheme 1). In turn, we envisioned gaining access
to the cationic intermediate (cf. 6) through hypervalent
iodide oxidation2 of a phenol (5), with subsequent intra-
molecular amide attack of the acyl guanidine to form
the spirocycle.
The synthesis of the key phenol intermediate (11) com-
menced with Knoevenagel condensation of creatinine
(7) with 4-methoxybenzaldehyde (Scheme 2). Thus, under
optimized solvent- and base-free thermolysis conditions,
OMe
O
O
N
OMe
Me
N
OMe
HO
Me
Me
N
H2N
N
OMe
HN
O
OR
N
N
Me
O
OH
H2N
HO
Spiroleucettadine (1)
Proposed Structure
Spirocalcaridine A (3, R = H)
Spirocalcaridine B (4, R = Me)
Calcaridine (2)
Figure 1. Guanidine alkaloids isolated from Leucetta sponge.
*
Corresponding author. Tel.: +1 212 639 5501; fax: +1 212 772 8691; e-mail: s-danishefsky@mskcc.org
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.002

386
C. Li, S. J. Danishefsky / Tetrahedron Letters 47 (2006) 385–387
OMe
requisite bicyclic system 13 were unsuccessful. Treat-
ment of 11 with PIFA led to the formation of inter-
mediate 12, which corresponds to the ring-opened isomer
of 13.5 In our hands, there was no indication of cycliza-
tion of 12 to 13.
Me
N
OMe
RN
O
N
O
Me
N
Me
H2O
I(III)
1
Given the resistance of 12 to undergo the spirocycliza-
tion reaction expected on the basis of the structural
formulation of spiroleucettadine,1 we next considered
a modified approach which would involve the inter-
mediacy of a compound of the type 14. We hoped to
determine whether this intermediate, containing the
preconstructed spirocyclic modality, would be suscepti-
ble to intramolecular guanidine attack to afford the req-
uisite bicyclic adduct. We were not unaware that the
guanidine would be unlikely to approach the lactone
from the b-face to form the desired trans-fused bicyclic
adduct. Nonetheless, for the moment, we concerned
ourselves primarily with issues of chemical connectivity
(Fig. 2).
RN
OMe
N
Me
O
OH
Me
5
N
RN
O
N
O
R = Acyl
Me
6
Scheme 1.
OMe
OMe
Me
Me
N
N
H2N
Me
Me
The synthesis of spirolactone 20 commenced with the
preparation of the diaryl amino ester 17 from imine 16
by two successive alkylations under phase transfer cataly-
sis conditions.6 The latter was readily converted to the
Boc-protected amino acid 18 as shown. We were pleased
to find that benzyl deprotection followed by iodonium
oxidation afforded the spirocyclic intermediate 19. N-
Methylation followed by removal of the Boc-protecting
group provided the key intermediate 20, as shown. After
a number of unsuccessful attempts at guanylation, we
a
d
b, c
N
N
H2N
HN
O
N
N
O
O
7
8
9
3:1 of Z:E
OMe
OMe
Me
N
Me
N
HN
N
g
e,f
BocN
N
Me
O
7
OH
OMe
O
OBn
identified conditions in which AgNO3 was employed
Me
11
10
to facilitate the coupling of 20 with Boc-methylisothio-
urea (21). Interestingly, although guanidine cyclization
did occur, none of the anticipated amino hemiketal com-
pound (cf. 15) was detected. Instead, compound 12, in
which the spirocycle had undergone acyl transfer, was
observed as the sole reaction product.
OMe
Me
Me
Me
N
N
O
X
BocN
O
BocN
HO
N
O
N
Me
O
OH
12
13
We postulated that perhaps the rather weak nucleophilic
character of the lactam functionality might be responsi-
ble for the failure of intermediate 11 to undergo the req-
uisite spirocyclization. Accordingly, we sought to
evaluate spirocyclization with a potentially more nucleo-
philic hemiaminal. Thus, intermediate 23 was prepared
through reduction of acyl guanidine 22, followed by
removal of the benzyl ether. We were encouraged to find
that upon exposure to PIFA oxidation conditions, 23
readily underwent spirocyclization to afford the 5,5-bicy-
clic compound 24 in 75% yield.8 Unfortunately, however,
extensive efforts to oxidize 24 to the amino hemiketal 13
were unsuccessful. This finding suggested that at least the
Scheme 2. Reagents and conditions: (a) 4-methoxybenzaldehyde
(3 equiv), 170 °C, 20 min (89%); (b) MeI, DMF, rt, 20 h (98%); (c)
H2, Pd (10% on carbon), MeOH, 3 h, quant.; (d) LiHMDS, 4-
BnOC6H4CH2Br, THF, 0 °C, 1 h (91%); (e) n-BuLi, Boc2O, THF,
0 °C, 30 min (91%); (f) H2, Pd (10% on carbon), MeOH, 3 h, (99%);
(g) PIFA, CH3CN/H2O (2:1), 0 °C, 5 min, 56%. DMF = dimethyl
formamide, HMDS = hexamethyldisilazane, PIFA = [bis(trifluoro-
acetoxy)iodo]benzene.
intermediate 8 was formed as a 3:1 mixture of Z and E
olefin isomers.3 N-Methylation4 followed by hydrogena-
tion provided the acyl dimethyl guanidine 9 in excellent
yield. We were pleased to find that LiHMDS-mediated
alkylation of 9 proceeded smoothly to afford the diben-
zyl intermediate 10 without any observed N-alkylated
side product. At this stage, N-Boc protection, followed
by removal of the benzyl group afforded phenol 11.
OMe
OMe
Me
Me
N
N
?
RN
O
RN
O
O
N
Me
O
NH
Me
With this key intermediate in hand, we were now pre-
pared to explore the viability of our projected oxidative
cyclization/hydration sequence. Unfortunately, how-
ever, all attempts to transform intermediate 11 to the
O
OH
14
15
Figure 2. Alternative approaches toward spiroleucettadine.

C. Li, S. J. Danishefsky / Tetrahedron Letters 47 (2006) 385–387
OEt
387
alcohol 12, which is actually the ring opened isomeric
form of the reported spiroleucettadine structure. In fact,
in the route shown in Scheme 3, the formation of 12 vir-
tually requires the intermediacy of a structure of the
general type 15. Indeed, even in the case of Scheme 2,
a structure of the type 15 is a likely, though not obliga-
tory intermediate. The fact that we observe only the iso-
meric compound 12 would appear to invite caution as to
the stability of the (trans) bicyclic core moiety reported
for spiroleucettadine (1). We note that our data do not
rule out the validity of the structural assignment. Per-
haps we have failed to find a kinetically accessible path-
way to the trans isomer, which would be stable if it
could be formed. The spiroleucettadine problem contin-
ues to be of keen interest to our group.
NH2
O
Cl
O
a
b,c
N
EtO
H
16
BnO
OMe
OMe
17
OH
NHBoc
O
d, e
f, g
BocHN
O
O
O
BnO
OMe
OMe
19
18
OMe
Me
N
Acknowledgements
h
O
MeHN
BocN
HO
O
O
NBoc
N
This work was supporting by a Grant from the National
Institutes of Health (HL25848). Additional support was
provided by the Eli Lilly Corporation.
O
Me
O
MeHN
SMe
12
20
21
Scheme 3. Reagents and conditions: (a) 4-BnOC6H4CH2Br, Bu4NBr,
CsOHÆH2O, toluene, À5 °C, 45 min; then 4-MeOC6H4CH2Br, rt, 1 h;
then 0.5 M citric acid, THF, 1.5 h, (85%); (b) KOH, EtOH, reflux,
40 h, (91%); (c) Me4NOHÆ5H2O, Boc2O, CH3CN, (80%); (d) H2, Pd
(10% on carbon), MeOH, 3 h; (e) PIFA, CH3CN, (19% for two steps);
(f) NaH, MeI, DMF, 0 °C, 2.5 h; (g) TFA, CH2Cl2, rt, 1 h (68% for
two steps); (h) 21, Et3N, AgNO3, 88% brsm, CH3CN. TFA = triflu-
oroacetic acid.
Supplementary data
Experimental procedures and characterization data are
provided for all new compounds (PDF). Supplementary
data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2005.11.002.
OMe
OMe
References and notes
Me
Me
a, b
OBn
c
N
N
1. (a) Edrada, R. A.; Stessman, C. C.; Crews, P. J. Nat. Prod.
2003, 66, 939; (b) Ralifo, P.; Crews, P. J. Org. Chem. 2004,
69, 9025.
BocN
BocN
N
Me
N
Me
OH
23
O
OH
22
2. Vargolis, A. Tetrahedron 1997, 53, 1179.
OMe
3. Because both Z and E olefin isomers are transformed into
the same product (9) at the olefin hydrogenation step, the
two isomers were carried through the next two steps
without separation. For the assignment of the Z and E
stereochemistry, see: Villemin, D.; Martin, B. Synth.
Commun. 1995, 25, 3135.
OMe
Me
Me
Me
Me
[O]
N
N
N
BocN
O
BocN
O
X
N
O
O
OH
24
4. Kenyon, G. L.; Rowley, G. L. J. Am. Chem. Soc. 1971, 93,
5552, and references cited therein.
13
Scheme 4. Reagents and conditions: (a) LiEt3BH, THF, 0 °C, 30 min,
quant.; (b) H2, Pd (10% on carbon), MeOH, 3 h, quant.; (c) PIFA,
CH3CN (75%).
5. We also note that when the non-Boc-protected congener of
11 was subjected to the oxidation conditions, the analogous
quinol intermediate was observed, in 21% yield.
6. Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am.
Chem. Soc. 2000, 122, 5228.
7. (a) Burgess, K.; Lim, D.; Ho, K. K.; Ke, C. Y. J. Org.
Chem. 1994, 59, 2179; (b) Ma, D.; Xia, C.; Jiang, J.; Zhang,
J.; Tang, W. J. Org. Chem. 2003, 68, 442.
cis fused version of the ring system proposed by Crews
was not prohibitively strained (Scheme 4).
In conclusion, we have investigated three strategies
toward spiroleucettadine. It is of note that two of these
approaches led to the formation of the stable tertiary
8. On the basis of NMR analysis, 24 exists as a 1.8:1 isomeric
mixture of products, which are inseparable by silica gel
column chromatography.