Total synthesis of (+)-cylindramide A

Article abstract of DOI:10.1021/ja057899a

A total synthesis of cylindramide A has been completed in 19 steps. The key step of the synthesis is a tandem ring-opening-ring-closing-cross metathesis that converts a readily available norbornene into an advanced intermediate. Copyright

Full text of DOI:10.1021/ja057899a

Published on Web 01/10/2006
Total Synthesis of (+)-Cylindramide A
Amy C. Hart and Andrew J. Phillips*
Department of Chemistry and Biochemistry, UniVersity of Colorado, Boulder, Colorado 80309-0215
Received December 1, 2005; E-mail: Andrew.Phillips@colorado.edu
Scheme 1 a
In 1993, Fusetani and co-workers described the structure of
cylindramide A, a macrocyclic tetramic acid isolated from the
sponge Halichondria cylindrata that was cytotoxic to B16 mela-
noma cells with an IC50 of 0.8 µg mL-1 1a
Cylindramide A is
.
structurally related to a number of other tetramic acid-containing
macrolactams that have been isolated from a variety of sources,
including aburatubolactam A,1b geodin A,1c xanthobaccin A,1d
ikarugamycin,1e discodermide,1f and the alteramides.1g Because of
their complex structures and diverse biological activities including
cytotoxicity, antimicrobial activity, and inhibition of superoxide
generation, these compounds have generated a significant degree
of interest in the synthesis community,2 and in this Communication
we report a synthesis of cylindramide A.
a Reagents and conditions: (1) 10% Grubbs’s II catalyst, 7, CH2Cl2, 40
°C, 59%; (2) cyclopentadiene, Et2AlCl, CH2Cl2, -78 °C, 96%, dr ) 45:1;
(3) (a) LiOH, H2O2, THF, H2O, -10 °C; (b) HCl‚HN(OMe)Me, DMAP,
EDCI, CH2Cl2, 52% (two steps); (4) H2CdCHMgBr, THF, 67 °C, 98%.
Our strategy for the synthesis of cylindramide A is outlined in
Figure 1. We planned to couple two large domains: a subunit
containing the bicyclo[3.3.0]octene (4), and a 3-hydroxyornithine-
derived subunit (5). The bicyclo[3.3.0]octene ring system was
envisioned to arise from a tandem ring-opening-ring-closing-cross
metathesis (ROM-RCM-CM) of readily available norbornene 2
to give 3.3
Scheme 2 a
a Reagents and conditions: 4% Grubbs’s catalyst, 11 (3.0 equiv), CH2Cl2,
40 °C, 59%.
Conversion of 3 to 4 commenced with installation of the C17
methyl group and ∆15,16 olefin by a sequence consisting of conjugate
addition (Me2CuLi, 90%, Scheme 3) followed by ketone reduction
and elimination of the resultant secondary alcohol (NaBH4 and then
Martin sulfurane,5 53%) to give 16. Removal of the triisopropylsilyl
(TIPS) ether with HF/pyridine provided alcohol 17 in 86% yield.
Oxidation with tetrapropylammonium perruthenate/N-methylmor-
pholine N-oxide (TPAP/NMO), followed by immediate reaction
with [bis(2,2,2-trifluoroethoxy)phosphoryl]acetic acid (2-trimeth-
ylsilyl)ethyl ester6 under Still-Gennari conditions,7 yielded 18 in
51% yield for the two steps. Cleavage of the 2-(trimethylsilyl)ethyl
(TMSE) group with tetrabutylammonium fluoride (TBAF) and
reduction of the isobutyl chloroformate-derived mixed anhydride
with NaBH4 (18f19, 51% over two steps), followed by Dess-
Martin oxidation, gave 4 and completed the synthesis of the bicyclo-
[3.3.0]octene domain.
Coupling of key fragments 4 and 58 was achieved by Horner-
Wadsworth-Emmons reaction, which led to 20 in 90% overall yield
from allylic alcohol 19. Heating 20 in toluene at reflux under dilute
conditions resulted in macrocyclization to give the expected
â-ketoamide in 65% yield as a complex mixture of tautomers.
Removal of the tert-butyldimethylsilyl (TBS) ether with HF
provided 21 in 95% yield. The synthesis was completed by Lacey-
Dieckmann cyclization9 to form the tetramic acid (NaOMe, 90%),
and finally removal of the 2,4-dimethoxylbenzyl protecting group
(trifluoroacetic acid (TFA), 67 °C, 65%) provided cylindramide
Figure 1. Structure of cylindramide A (1) and synthetic strategy.
Norbornene 2 was obtained by a five-step sequence that was
initiated by the cross metathesis of acryloyl oxazolidinone 6 with
alkene 7 to give 8 in 59% yield (Scheme 1). Diels-Alder reaction
with cyclopentadiene under the conditions described by Evans led
to 9 (96%, dr ) 45:1).4 Although direct conversion of the
oxazolidinone to Weinreb amide 10 was not possible, simple
hydrolysis to the acid and a 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide hydrochloride (EDCI)-mediated coupling provided a
suitable alternative (52% over two steps). Addition of vinylmag-
nesium bromide to a solution of 10 at reflux provided 2 in 98%
yield and set the stage for the key tandem ROM-RCM-CM
sequence.
When 2 was treated with 4 mol % Grubbs’s catalyst in the
presence of 3.0 equiv of 11, tandem ROM-RCM-CM occurred
to give 3 in 59% yield and as a 2:1 mixture of separable
diastereoisomers (Scheme 2).
9
1094
J. AM. CHEM. SOC. 2006, 128, 1094-1095
10.1021/ja057899a CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
a Reagents and conditions: (1) (a) Me2CuLi, Et2O, -78 °C, 90%; (b) NaBH4, MeOH, 0 °C; (c) Martin sulfurane, CH2Cl2, 0 °C, 53% (two steps); (2)
HF/pyr, THF, 86%; (3) (a) TPAP, NMO, CH2Cl2, 4 Å MS; (b) [bis(2,2,2-trifluoroethoxy)phosphoryl]acetic acid (2-trimethylsilyl)ethyl ester, KHMDS,
18-C-6, THF, -78 °C, 51% (two steps); (4) (a) TBAF, THF; (b) IBCF, NMM, THF, 0 °C, then NaBH4, MeOH, H2O, 50% (two steps); (5) Dess-Martin
periodinane, CH2Cl2; (6) 5, NaHMDS, then add 4, THF, -78 °C f rt, 90% (from 19); (7) (a) PhMe, 105 °C, 65%; (b) HF, MeCN, 95%; (8) (a) NaOMe,
MeOH, 90%; (b) TFA, 67 °C, 65%.
Weidner, C. H.; Perni, R. B.; Napier, J. J. J. Am. Chem. Soc. 1989, 111,
A. Synthetic cylindramide A had physical and spectroscopic
8036. (c) Paquette, L. A.; Macdonald, D.; Anderson, L. G.; Wright, J. J.
properties in accord with those reported.10
Am. Chem. Soc. 1989, 111, 8037. (d) Roush, W. R.; Wada, C. K. J. Am.
Chem. Soc. 1994, 116, 2151.
In conclusion, we have delineated a synthesis of cylindramide
A that proceeds in 19 steps (longest linear sequence) and highlights
the utility of the tandem ROM-RCM-CM of simple norbornenes
in the context of complex natural products synthesis.
(3) For other examples of tandem metathesis sequences of this general type,
see: (a) Stragies, R.; Blechert, S. Synlett. 1998, 169. (b) Wrobleski, A.;
Sahasrabudhe, K.; Aube´, J. J. Am. Chem. Soc. 2002, 124, 9974. (c) Arjona,
O.; Csakye, A. G.; Medel, R.; Plumet, J. J. Org. Chem. 2002, 67, 1380.
(d) Stille, J. R.; Santarsiero, B. D.; Grubbs, R. H. J. Org. Chem. 1990,
55, 843. (e) Minger, T. L.; Phillips, A. J. Tetrahedron Lett. 2002, 43,
5357 and references therein.
Acknowledgment. We thank Dr. Gillian Nicholas for experi-
mental assistance and Professor Nobuhiro Fuestani for copies of
spectra for cylindramide A. This research was supported by the
National Cancer Institute (NCI CA110246) and in part by The
American Chemical Society Petroleum Research Fund (ACS PRF#
38856-G1) and was facilitated by NMR facilities purchased partly
with a NSF Shared Instrumentation Grant (CHE-0131003).
(4) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1984, 106,
4261.
(5) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327.
(6) Boger, D. L.; Sakya, S. M.; Yohannes, D. J. Org. Chem. 1991, 56, 4204.
(7) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(8) Amine 5 was synthesized by the sequence shown below:
Supporting Information Available: Experimental procedures, data,
and spectra for compounds 1-3, 8-10, and 16-21. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Kanazawa, S.; Fusetani, N.; Matsunaga, S. Tetrahedron Lett. 1993,
34, 1065. (b) Bae, M. A.; Yamada, K.; Ijuin, Y.; Tsuji, T.; Yazawea, K.;
Tomono, Y.; Uemura, D. Heterocycl. Commun. 1996, 2, 315. (c) Capon,
R. J.; Skene, C.; Lacey, E.; Gill, J. H.; Wadsworth, D.; Friedel, T. J. Nat.
Prod. 1999, 62, 1256. (d) Hashidoko, Y.; Nakayama, T.; Homma, Y.;
Tahara, S. Tetrahedron Lett. 1999, 40, 2957. (e) Jomon, K.; Kuroda, Y.;
Ajisaka, M.; Sakai, H. J. Antibiot. 1972, 25, 271. (f) Gunasekera, S. P.;
Gunasekera, M.; McCarthy, P. J. Org. Chem. 1991, 56, 4830. (g)
Shigemori, H.; Bae, M. A.; Yazawa, K.; Sasaki, T.; Kobayashi, J. J. Org.
Chem. 1992, 57, 4317.
Reagents and conditions: (1) AD mix R, MeSO2NH2, H2O/t-BuOH, 90%,
>98% ee; (2) (a) SOCl2, NEt3, CH2Cl2; (b) NaN3, DMF, 55 °C; (c)
TBSOTf, CH2Cl2, 80% (three steps); (3) (a) H2(g), Pd/C, EtOAc, (b) 2,4-
dimethoxybenzaldehyde, 4 Å MS, MeOH, then NaBH3CN, 70% (two
steps); (4) TFA, CH2Cl2, then diethylphosphonoacetic acid, thiazolidine-
2-thione, EDCI, DMAP, Et3N, 61% (two steps).
(9) Lacey, R. N. J. Chem. Soc. 1954, 850.
(10) See the Supporting Information for details.
(2) For a previous synthesis of cylindramide A, see: (a) Cramer, N.; Laschat,
S.; Baro, A.; Schwalbe, H.; Richter, C. Angew. Chem., Int. Ed. 2005, 44,
820. For syntheses of ikarugamycin, see: (b) Boeckman, R. K., Jr.;
JA057899A
9
J. AM. CHEM. SOC. VOL. 128, NO. 4, 2006 1095