A synthesis of the bicyclo[3.3.0]octene core of geodin A

Article abstract of DOI:10.1016/j.tetlet.2006.03.124

A synthesis of the bicyclo[3.3.0]octene core of the macrolactam tetramic acid geodin A is described. The key steps are a tandem metathesis and a Wharton rearrangement.

Full text of DOI:10.1016/j.tetlet.2006.03.124

Tetrahedron Letters 47 (2006) 3743–3745
A synthesis of the bicyclo[3.3.0]octene core of geodin A
Andrew J. Phillips,* Amy C. Hart and James A. Henderson
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA
Received 11 February 2006; revised 19 March 2006; accepted 20 March 2006
Available online 17 April 2006
Abstract—A synthesis of the bicyclo[3.3.0]octene core of the macrolactam tetramic acid geodin A is described. The key steps are a
tandem metathesis and a Wharton rearrangement.
Ó 2006 Elsevier Ltd. All rights reserved.
In 1999, Capon et al. described the structure of geodin A
magnesium salt (Fig. 1), a tetramic acid-containing
macrolactam isolated from a Geodia sp. sponge collected
from the Great Australian Bight.1
report a concise synthesis of the bicyclo[3.3.0]octadiene
core of geodin A.
Our strategy for the synthesis of geodin A is based on
the coupling of two domains: a subunit containing the
bicyclo[3.3.0]octene 1, and a 3-hydroxyornithine-derived
subunit (Fig. 2, 2). The bicyclo[3.3.0]octene was envi-
sioned to arise from 3, which would ultimately arise
from a tandem ring-opening–ring-closing–cross meta-
thesis of functionalized bicyclo[2.2.1]heptene 4 with
alkenyl ester 5.10
Geodin A is the most recently isolated member of a
growing class of tetramic acid-containing macrolactams
including cylindramide A,2 aburatubolactam A,3 xan-
thobaccin A,4 ikarugamycin,5 discodermide,6 and the
alteramides.7 These mixed polyketide-amino acid
metabolites have been isolated from a number of sources
including marine sponges, marine bacteria, and terres-
trial bacteria,8 and display a diverse range of biological
activities including cytotoxicity, anti-microbial activity,
and inhibition of superoxide generation. Intrigued by
the questions relating to the biogenesis of compounds
in this class, and motivated by their synthetically chal-
lenging structures and potent biological activity, we
have initiated a program directed toward the synthesis
of several of these compounds,9 and in this letter we
O
H
HN
HO
H
O
NH
0.5 Mg2+
SnBu3
O
O
H
H
NHDMB
CO2Et
H
N
O
I
H
O
HN
+
O
OTBS
O
O
2
1
HO
H
O
O
NH
OTIPS
0.5 Mg2+
OTIPS
H
H
O
O
4
+
Figure 1. Geodin A.
CO2Me
CO2Me
3
5
*
Corresponding author. Tel.: +1 303 735 2049; fax: +1 303 492
5894; e-mail: Andrew.Phillips@colorado.edu
Figure 2. Abbreviated retrosynthesis of geodin A.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.124

3744
A. J. Phillips et al. / Tetrahedron Letters 47 (2006) 3743–3745
O
O
O
O
O
1
N
O
TIPSO
N
O
OTIPS
[Ru]Ln
Bn
Bn
4
6
7
O
2
3-4
ring-opening
metathesis
Xc
O
O
OTIPS
H
H
OTIPS
OTIPS
8
O
O
Ln[Ru]
[Ru]Ln
H
H
15
5
N(OMe)Me
OTIPS
14
OTIPS
ring-closing
metathesis
cross
metathesis
9
4
O
H
O
Mes
Cl
N
N
Mes
TIPSO
H
OTIPS
OTIPS
OTIPS
Ru
PCy3
10
11
Cl
Ph
H
17
H
Scheme 1. Reagents and conditions: (1) 5 mol % 11, 1.2 equiv 10,
CH2Cl2, 45 °C, 81%, >99:1 E:Z; (2) cyclopentadiene, Et2AlCl, CH2Cl2,
À78 °C, 96%, dr > 45:1; (3) LiOH, H2O2, THF–H2O, À10 °C to 0 °C,
77%; (4) HN(OMe)Me. HCl, EDCI, CH2Cl2, 75%; (5) vinylmagnesium
bromide, THF, reflux, 98%.
CO2Me
16
ring-closing
metathesis
slow
O
O
H
H
OTIPS
The synthesis of the metathesis precursor 4 is detailed in
Scheme 1. Cross metathesis of N-acryloyl oxazolidinone
6 with triisopropylsilyl-protected butenol 10 in the pres-
ence of 5 mol % of 11 provided 7 in 81% yield and with
>99:1 E:Z selectivity.11 Diels–Alder reaction of 7 with
cyclopentadiene in the presence of Et2AlCl12 proceeded
to give 8 in excellent yield and diastereoselectivity (96%,
>45:1). Norbornene 8 was converted to the correspond-
ing Weinreb amide 9 by a two step sequence consisting
of hydrolysis with LiOH–H2O2 (77% yield),13 followed
by EDCI-mediated coupling with N-methoxy-N-methyl-
amine (75% yield). Subsequent reaction of amide 9 with
excess vinylmagnesium bromide in THF at reflux pro-
vided the desired enone 4 in 98% yield, and set the stage
for the key tandem ROM-RCM-CM sequence.
[Ru]Ln
H
H
18
CO2Me
12
Scheme 3. Pathways for the tandem ring-opening–ring-closing–cross
metathesis.
>95:5 E:Z by radical isomerization employing PhSH
and AIBN in toluene.
Preliminary mechanistic studies suggest that the tandem
ring-opening–ring-closing–cross metathesis occurs via
the sequence shown in Scheme 3. Initial non-selective
ring-opening metathesis of the norbornene leads to
intermediates 14 and 15. Compound 14 can undergo
productive cross metathesis to yield 16, which can be
readily ring-closed to yield the desired product 12. Inter-
When a solution of enone 4 and 2.5 equiv of alkene 5, in
CH2Cl2 at reflux, was exposed to 4 mol % of catalyst 13,
tandem ring-opening–ring-closing–cross metathesis
occurs to provide the bicyclo[3.3.0]octene 12 in 54% yield
and with an E:Z ratio of 1.5:1, along with 30% of 17
(Scheme 2). The E:Z ratio for 12 could be improved to
O
O
H
H
1
OTIPS
OTIPS
O
H
H
CO2Me
CO2Me
12
19
OTIPS
O
O
H
H
O
1
OTIPS
3
2
1.5:1 E:Z
>95:5 E:Z
2
HO
H
OTIPS
H
CO2Me
4
+
20
CO2Me
12
+
H
H
H
CO2Me
OTIPS
OTIPS
OTIPS
PCy3
Ru
4
5
Cl
Cl
13
O
Ph
H
H
H
PCy3
CO2Me
CO2Me
17
21
3
Scheme 2. Reagents and conditions: (1) 4 mol % 13, 2.5 equiv of 5,
CH2Cl2, 45 °C, 54% of 12, and 30% of 17; (2) PhSH, AIBN, PhMe,
110 °C, 84%.
Scheme 4. Reagents and conditions: (1) 30% H2O2, NaOH, MeOH–THF,
À5 °C, 92% (dr > 95:5); (2) H2NNH2, AcOH, EtOH, rt; (3) Dess–Martin
periodinane, CH2Cl2, rt, 80% (two steps); (4) Cp2TiMe2, PhMe, 58%.

A. J. Phillips et al. / Tetrahedron Letters 47 (2006) 3743–3745
3745
5. Jomon, K.; Kuroda, Y.; Ajisaka, M.; Sakai, H. J.
Antibiot. 1972, 25, 271.
6. Gunasekera, S. P.; Gunasekera, M.; McCarthy, P. J. Org.
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mediate 15 can undergo ring-closing metathesis to yield
17, which does not readily undergo cross metathesis.14
At this juncture transposition of enone was necessary,
and we were attracted to the possibility of employing
the Wharton fragmentation15 of epoxy ketones to effect
this transformation. To this end, epoxidation of enone
12 with hydrogen peroxide under basic conditions
yielded a,b-epoxy ketone 19 in 92% yield and as a single
diastereoisomer (Scheme 4). Despite limited precedent
for the use of the Wharton fragmentation on complex
substrates,16 subjecting an ethanolic solution of 19 to
hydrazine and catalytic acetic acid resulted in hydrazone
formation and in situ Wharton fragmentation to give
the desired allylic alcohol 20. Subsequent Dess–Martin
oxidation yielded enone 21 in 80% yield for the two
steps. Olefination of compound 21 with the Petasis
reagent17 provided 318 in 58% yield, and completed the
synthesis of the carbocyclic core of geodin A.
7. Shigemori, H.; Bae, M. A.; Yazawa, K.; Sasaki, T.;
Kobayashi, J. J. Org. Chem. 1992, 57, 4317.
8. The true biogenetic source of the marine sponge-derived
compounds has not been determined, although it seems
likely that they are bacterial metabolites.
9. Hart, A. C.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128,
1094.
10. For other examples of tandem metathesis sequences of this
general type see: (a) Stille, J. R.; Santarsiero, B. D.;
Grubbs, R. H. J. Org. Chem. 1990, 55, 843; (b) Stragies,
R.; Blechert, S. Synlett 1998, 169; (c) Arjona, O.; Csaky,
A. G.; Medel, R.; Plumet, J. J. Org. Chem. 2002, 67, 1380;
´
(d) Wrobleski, A.; Sahasrabudhe, K.; Aube, J. J. Am.
Chem. Soc. 2002, 124, 9974; (e) Chandler, C. L.; Phillips,
A. J. Org. Lett. 2005, 7, 3493; (f) Pfeiffer, M. W. B.;
Phillips, A. J. J. Am. Chem. Soc. 2005, 127, 5334; (g)
Minger, T. L.; Phillips, A. J. Tetrahedron Lett. 2002, 43,
5357, and references cited therein.
11. Choi, T.-L.; Chatterjee, A. K.; Grubbs, R. H. Angew.
Chem., Int. Ed. 2001, 40, 1277.
12. Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem.
Soc. 1988, 110, 1238.
13. Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron
Lett. 1987, 28, 6141.
14. Resubjecting 17 to the reaction conditions results in less
than 10% conversion to the desired product and other
metathesis catalysts were also ineffective for this cross
metathesis.
In conclusion, we have described a concise 11-step syn-
thesis of the bicyclo[3.3.0]octadiene core of geodin A.
The synthesis features an efficient tandem ring-open-
ing–ring-closing–cross metathesis reaction and the
Wharton fragmentation of an a,b-epoxy ketone as the
key steps. Further progress towards the total synthesis
of geodin A will be reported in due course.
Acknowledgments
15. (a) Wharton, P. S.; Bohlen, D. H. J. Org. Chem. 1961, 26,
3615; (b) Wharton, P. S.; Dunny, S.; Krebs, L. S. J. Org.
Chem. 1964, 29, 958; (c) Stork, G.; Williard, P. J. Am.
Chem. Soc. 1977, 99, 7067.
16. For a rare example see: Liu, J.; Hsung, R. P.; Peters, S.
Org. Lett. 2004, 6, 3989.
Support for this research was provided by the National
Cancer Institute (NCI CA110246). This work was facil-
itated by NMR facilities purchased partly with funds
from an NSF Shared Instrumentation Grant (CHE-
0131003).
17. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
6392.
18. [a]D +84.4 (c 0.05, CHCl3); IR (thin film): 2919.59,
2862.51, 1749.49, 1455.95, 1097.17 cmÀ1
;
1H NMR
References and notes
(500 MHz, CDCl3): d 6.06–6.08 (m, 1H), 5.96–5.97 (m,
1H), 5.39–5.44 (m, 1H), 5.24–5.28 (m, 1H), 4.79 (d, 2H,
J = 66.0 Hz), 3.71–3.80 (m, 2H), 3.66 (s, 3H), 3.03–3.09
(m, 1H), 2.88–2.91 (m, 1H), 2.33–2.37 (m, 2H), 2.27–2.31
(m, 2H), 2.04–2.17 (m, 2H), 1.79–1.85 (m, 1H), 1.30–1.44
(m, 1H), 1.15–1.22 (m, 2H), 1.05–1.07 (m, 3H), 1.05 (s,
18H); 13C NMR (100 MHz, CDCl3): d 158.90, 142.38,
134.24, 131.60, 128.31, 103.08, 94.39, 90.03, 62.58, 57.62,
47.91, 45.64, 40.48, 37.05, 34.13, 29.69, 27.89, 18.04, 11.98;
HRMS (ESI) m/z calcd for C26H44O3SiNa (M++Na)
455.2951, found 455.2943.
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