Total synthesis of aburatubolactam A

Article abstract of DOI:10.1002/anie.200803593

(Chemical Equation Presented) An ocean of possibilities: Aburatubolactam A, a natural product isolated from the culture broth of a marine mollusk, was the target of a total synthesis (see scheme). Key transformations include tandem ring-opening/ring-closing metathesis, Lacey-Dieckmann cyclization, and macrolactamization.

Full text of DOI:10.1002/anie.200803593

Angewandte
Chemie
DOI: 10.1002/anie.200803593
Natural Product Synthesis
Total Synthesis of Aburatubolactam A**
James A. Henderson and Andrew J. Phillips*
Recently, Uemura and co-workers described the structure of
aburatubolactam A (1; Scheme 1), a macrolactam isolated
from the culture broth of a Streptomyces sp. bacterium,
sioned to arise from a tandem ring-opening/ring-closing
(ROM/RCM) metathesis of functionalized bicyclo-
[2.2.1]heptene 4.[3,4]
The synthesis commenced with a Diels–Alder reaction of
commercially available ketone 6 with cyclopentadiene in the
presence of MacMillanꢀs catalyst 8 (20 mol%) to give ketone
7 in 65% yield (endo/exo > 98:2, 93% ee; Scheme 2).[5]
Scheme 2. Synthesis of the bicyclo[3.3.0]octene. Reagents and condi-
tions: a) 20 mol% 8, H2O, 65%; b) LiHMDS, TMSCl, THF; then
Scheme 1. Structure of aburatubolactam A (1) and synthetic strategy.-
Boc=tert-butoxycarbonyl, TBS=tert-butyldimethylsilyl.
=
Pd(OAc)2, MeCN, 80%; c) 2.5 mol% 9; CH2 CH2 (1 atm), CH2Cl2,
90%. Cy=cyclohexyl, HMDS=hexamethyldisilazide, TMS=trimethyl-
silyl.
SCRC-A20, which was separated from a marine mollusk
collected near Aburatubo, Kanagawa Prefecture, Japan.[1a]
Aburatubolactam A is a member of a growing class of
tetramic acid containing macrolactams that include cylindra-
mide A,[1b] geodin A,[1c] xanthobaccin A,[1d] ikarugamycin,[1e]
discodermide,[1f] and the alteramides.[1g] These mixed poly-
ketide amino acid metabolites have been isolated from a
number of sources including marine sponges and bacteria, as
well as terrestrial bacteria.[2] These compounds display a
diverse range of biological activities including cytotoxicity,
antimicrobial activity, and the inhibition of superoxide
generation. Herein, we describe a synthesis of aburatubolac-
tam A.
Conversion of the trimethylsilyl enol ether derived from 7
into the enone 4 was readily achieved in 80% yield by using
the oxidation procedure developed by Ito and Saegusa.[6]
When enone 4 was treated with first-generation Grubbs
catalyst 9 (2.5 mol%) under an atmosphere of ethylene, rapid
and smooth reorganization to the desired bicyclo[3.3.0]octene
5 occurred in 90% yield.[7]
Further elaboration of 5 was accomplished by reduction of
both alkene groups (Pd/C, H2) to give fused bicyclic ketone 10
in 94% yield (Scheme 3). Introduction of the C6 and C13 side
chains was achieved by a sequence beginning with enolate
acylation using Manderꢀs reagent[8] and subsequent reduction
of the ketone with NaBH4. Elimination of the resultant
alcohol by mesylation and treatment with sodium hydride in
MeOH/THF (5:1) provided 11 in 64% overall yield from 10.
The side chain at C13 was introduced by employing Maje-
tichꢀs fluoride-mediated Sakurai allylation,[9] carried out in
DMF/DMPU to give 12 in 78% yield as a 4:1 mixture of
inseparable C6 diastereomers in favor of the undesired
configuration (12a). This ratio could be improved to 2:1 in
favor of the desired configuration (12b) by protonation (1n
HCl) of the silylketene acetal derived from 12a. Subsequent
iodolactonization facilitated separation of the diastereoiso-
mers, and gave 13 in 58% yield (over 2 steps), along with
recovered 12a. This sequence also provided a means for
recycling of material. Treatment of iodolactone 13 with Zn
dust in AcOH, THF/H2O and subsequent reduction of the
Our strategy for the synthesis of 1 is based on the coupling
of two domains: a subunit containing the bicyclo[3.3.0]octane
(2), and a 3-hydroxyornithine-derived subunit (3; Scheme 1).
The bicyclo[3.3.0]octane ring system was ultimately envi-
[*] Dr. J. A. Henderson, Prof. Dr. A. J. Phillips
Department of Chemistry and Biochemistry
University of Colorado
Boulder, CO 80309-0215 (USA)
Fax: (+1)303-492-0439
E-mail: andrew.phillips@colorado.edu
[**] This research was supported by the National Cancer Institute (NCI
CA110246). We thank Prof. Daisuke Uemura (Nagoya University)
for providing an authentic sample of aburatubolactam A.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803593.
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Communications
acid with LAH provided alcohol 14 in 86% yield (over 2
steps).
Advancement of alcohol 14 to 2 involved the cross-
metathesis of butene-1,4-diol derivative 16 catalyzed by the
second-generation Grubbs catalyst 15 to give 18 in 95% yield
(Scheme 4). Oxidation with Dess–Martin periodinane fol-
lowed by olefination with (iodomethylene)triphenylphos-
phorane under the conditions developed by Stork and
Zhao[10] provided vinyl iodide 19 in 82% yield. Conversion
of 19 into the stannane by treatment with tBuLi in the
presence of tributyltin chloride also resulted in removal of the
pivalate group to give alcohol 20 in 85% yield. Treatment of
this alcohol with Dess–Martin periodinane and a subsequent
Horner–Wadsworth–Emmons reaction yielded stannyl diox-
enone 2 in 60% yield (over 2 steps).
The synthesis of the b-hydroxyornithine subunit 3 began
with the Sharpless asymmetric dihydroxylation of a,b-unsa-
turated ester 21 to give diol 22 in 90% yield and > 98% ee
(Scheme 5). Introduction of the nitrogen functionality was
achieved by formation of the cyclic sulfite and ring-opening
with sodium azide. Subsequent silylation provided ether 23 in
80% yield (over 3 steps). Reduction of the azide and
nosylation[11] led to 24 in 94% yield, and subsequent
introduction of the methyl group by the Mitsunobu reaction
Scheme 4. Completion of the carbocyclic domain 2. Reagents and
conditions: a) 16, 10 mol% 15, CH2Cl2, 95%; b) 1. Dess–Martin per-
iodinane, CH2Cl2; 2. [Ph3P+CH2I]IÀ, NaHMDS, THF, 82% (over 2
steps); c) tBuLi, Bu3SnCl (internal quench), THF, 85%; d) 1. Dess–
Martin periodinane, CH2Cl2; 2. 17, KHMDS, THF, 60% (over 2 steps).
Piv=pivalate.
Scheme 5. Synthesis of the b-hydroxyornithine subunit 3. Reagents and
conditions: a) AD-mix-a, 90%; b) 1. SOCl2, Et3N; 2. NaN3, DMF, 558C;
3. TBSOTf, 2-6-lutidine, CH2Cl2, 80% (over 3 steps); c) 1. Pd/C, H2,
EtOAc; 2. NsCl, iPr2NEt, CH2Cl2, 94% (over 2 steps); d) MeOH, Ph3P,
DEAD, THF; e) PhSH, K2CO3, DMF, 82% (over 2 steps). DEAD=
diethyl azodicarboxylate, DMF=N,N-dimethylformamide, Ns=o-nitro-
phenylsulfonyl.
gave 25; then removal of the nosyl group with thiophenoxide
provided amine 3 (82% from 24).
After exploring a number of unsuccessful end-game
strategies that paralleled those employed for the preparation
of the natural product cylindramide, we completed the
synthesis as shown in Scheme 6.[12] Coupling of the two
halves of the molecule was achieved by heating dioxenone 2
with amine 3 in toluene under reflux for 6 hours. The sensitive
b-ketoamide product was subjected to Stille coupling with
tert-butyl-b-iodoacrylate, and subsequent Lacey–Dieckmann
cyclization led to tetramic acid 26 in 50% yield (over 3 steps
from 2). Macrolactamization was achieved by simultaneous
removal of the Boc and tert-butyl ester groups with TFA, and
treatment of the resulting compound with DEPC and Et3N in
DMF for 12 hours.[13] Removal of the TBS group with HF
Scheme 3. Elaboration of the bicyclo[3.3.0]octene. Reagents and con-
ditions: a) 10% Pd/C (10 wt%), EtOAc, H2, 94%; b) 1. LDA,
NCCO2Me, THF/DMPU; then NaBH4, MeOH, 74% (over 2 steps);
2. MsCl, DMAP, Et3N, CH2Cl2; then NaH, MeOH/THF (5:1), 87%
(over 2 steps); c) allyltrimethylsilane, TBAF, DMF/DMPU, 78%,
d.r. 4:1; d) LDA, TMSCl, THF; then HCl (1n), d.r. 2:1; e) I2, MeCN, RT,
58% (over 2 steps); f) 1. Zn, AcOH, THF/H2O; 2. LAH, THF, 86%
(over 2 steps). DMAP=4-dimethylaminopyridine, DMPU=1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, LAH=lithium alumi-
num hydride, LDA=lithium diisopropylamide, Ms=methanesulfonyl,
TBAF=tetra-n-butylammonium fluoride.
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[1] a) M. A. Bae, K. Yamada, Y. Ijuin, T. Tsuji, K. Yazawea, Y.
Tomono, D. Uemura, Heterocycl. Commun. 1996, 2, 315; b) S.
Kanazawa, N. Fusetani, S. Matsunaga, Tetrahedron Lett. 1993,
34, 1065; c) R. J. Capon, C. Skene, E. Lacey, J. H. Gill, D.
Wadsworth, T. Friedel, J. Nat. Prod. 1999, 62, 1256; d) Y.
Hashidoko, T. Nakayama, Y. Homma, S. Tahara, Tetrahedron
Lett. 1999, 40, 2957; e) K. Jomon, Y. Kuroda, M. Ajisaka, H.
Sakai, J. Antibiot. 1972, 25, 271; f) S. P. Gunasekera, M.
Gunasekera, P. McCarthy, J. Org. Chem. 1991, 56, 4830; g) H.
Shigemori, M. A. Bae, K. Yazawa, T. Sasaki, J. Kobayashi, J.
Org. Chem. 1992, 57, 4317.
[2] The true biogenetic source of the compounds derived from
marine sponges has not been determined, although they are
likely to be bacterial metabolites.
[3] While our studies were in progress, Aubꢁ and co-workers
reported this transformation in the course of their elegant
synthesis of the alkaloid 251F; a) A. Wrobleski, K. Sahasra-
budhe, J. Aubꢁ, J. Am. Chem. Soc. 2002, 124, 9974; b) A.
Wrobleski, K. Sahasrabudhe, J. Aubꢁ, J. Am. Chem. Soc. 2004,
126, 5475.
[4] For other examples of tandem metathesis sequences of this
general type, see: a) J. R. Stille, B. D. Santarsiero, R. H. Grubbs,
J. Org. Chem. 1990, 55, 843; b) R. Stragies, S. Blechert, Synlett
1998, 169; c) O. Arjona, A. G. Csaky, R. Medel, J. Plumet, J. Org.
Chem. 2002, 67, 1380; d) T. L. Minger, A. J. Phillips, Tetrahedron
Lett. 2002, 43, 5357; e) A. C. Hart, A. J. Phillips, J. Am. Chem.
Soc. 2006, 128, 1094; f) A. J. Phillips, A. C. Hart, J. A. Hender-
son, Tetrahedron Lett. 2006, 47, 3743; g) C. L. Chandler, A. J.
Phillips, Org. Lett. 2005, 7, 3493; h) M. W. B. Pfeiffer, A. J.
Phillips, J. Am. Chem. Soc. 2005, 127, 5334.
Scheme 6. Completion of the synthesis. Reagents and conditions:
a) 1. toluene, 1108C; 2. tert-butyl-b-iodoacrylate, [Pd2(dba)3], Ph3As,
NMP; 3. NaOMe, MeOH, 50% (over 3 steps); b) 1. TFA, CH2Cl2;
2. DEPC, Et3N, DMF, 08C; 3 HF, MeCN, 46% (over 3 steps).
NMP=N-methylpyrrolidinone, TFA=trifluoroacetic acid, DEPC=
diethylphosphoryl cyanide.
[5] A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 2458.
[6] Y. Ito, T. Saegusa, J. Org. Chem. 1978, 43, 1011.
[7] In the absence of an ethylene atmosphere the reaction proceeds
in 41% yield (at reflux, 12 h). The presence of Ti(iPrO)4 also
failed to appreciably affect the yield of reactions carried out in
the absence of ethylene (46% yield, at reflux, 12 h); for the
original report of this additive, see: A. Fꢂrstner, K. Langemann,
J. Am. Chem. Soc. 1997, 119, 9130.
[8] a) L. N. Mander, S. P. Sethi, Tetrahedron Lett. 1983, 24, 5425;
b) S. R. Crabtree, W. L. A. Chu, L. N. Mander, Synlett 1990, 169.
[9] G. Majetich, A. Casares, D. Chapman, M. Behnke, J. Org. Chem.
1986, 51, 1745; although the original procedure calls for the use
of hexamethyl phosphoramide (HMPA), we found DMPU to be
a suitable alternative.
provided aburatubolactam A in 46% yield (over 3 steps).
Data for an analytical sample of the synthetic aburatubolac-
tam A obtained by semi-preparative HPLC methods matched
those obtained for an authentic sample, which was provided
by Prof. Daisuke Uemura.
In conclusion, we have described a 23-step route that leads
to aburatubolactam A. This sequence further highlights the
utility of tandem metathesis reactions in a target-oriented
setting.
Received: July 23, 2008
Published online: September 29, 2008
[10] G. Stork, K. Zhao, Tetrahedron Lett. 1989, 30, 2173.
[11] T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36,
6373.
[12] A detailed account of these efforts will be forthcoming in a full
disclosure of the results.
[13] S. Yamada, Y. Kasai, T. Shioiri, Tetrahedron Lett. 1973, 14, 1595.
Keywords: cross-coupling · metathesis · natural products ·
total synthesis
.
Angew. Chem. Int. Ed. 2008, 47, 8499 –8501
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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