Stereocontrolled total synthesis of (-)-aurisides A and B

Article abstract of DOI:10.1002/anie.200462267

An expedient total synthesis of aurisides A and B (1), unusual cytotoxic macrolide glycosides isolated from the Japanese sea hare D. auricularia, takes advantage of a highly convergent aldol-based route for the stereocontrolled construction of the common

Full text of DOI:10.1002/anie.200462267

Communications
growing interest in these compounds as synthetic targets.[1b,3]
In 1998, the Yamada group reported a synthesis of the aglycon
unit, confirming their initial stereochemical assignment. The
low yield of their route was the result of several problematic
steps in its late stages.[1b] Herein, we report the first total
synthesis of aurisides A (1) and B (2) by appropriate
attachment of the required sugar residue, which involves a
highly convergent and expedient aldol-based route for the
stereocontrolled construction of the common macrolide core.
As outlined in Scheme 1, our synthetic strategy relied on a
late-stage, a-selective glycosylation of the equatorial C5
Natural Product Synthesis
Stereocontrolled Total Synthesis of
(ꢀ)-Aurisides A and B**
Ian Paterson,* Gordon J. Florence,
Annekatrin C. Heimann, and Angela C. Mackay
Aurisides A (1) and B (2) are unique marine polyketides
isolated in 1996 by Yamada and co-workers from the Japanese
sea hare Dolabella auricularia,[1a] an organism that has proved
to be a rich source of bioactive secondary metabolites.[2]
Initial biological screening of 1 and 2 highlighted significant
cytotoxicity, with IC50 values against HeLa S3 cervical cancer
cell lines of 0.17 and 1.2 mgmLꢀ1, respectively. The aurisides
are 14-membered glycosylated macrolides that contain a six-
membered hemiacetal ring, an E-trisubstituted enone with an
E,E bromodiene side chain appended at C13, and different
sugar moieties attached at C5 (Scheme 1).
Scheme 1. Retrosynthetic analysis for the aurisides.
The unusual structure of the aurisides, combined with
their biological activity and low natural abundance (0.8 mg of
1 was obtained from 278 kg of D. auricularia), has generated
alcohol in lactone 5 with the fluorosugar 3 or 4, each derived
from l-rhamnose. The macrocyclic lactone, in turn, was
envisaged to arise from a stereocontrolled Mukaiyama aldol
coupling between aldehyde 6 (C1–C7) and silyl enol ether 7
(C8–C17) containing a bromodiene terminus, followed by a
suitable macrolactonization step. Introduction of the remote
C13 stereocenter in 7 was planned to rely on the application
of an asymmetric vinylogous Mukaiyama (AVM) aldol
reaction,[4] while the C5 center in 6 would also be installed
by a suitable aldol reaction.[5]
[*] Prof. Dr. I. Paterson, Dr. G. J. Florence, A. C. Heimann,
Dr. A. C. Mackay
University Chemical Laboratory
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax: (+44)1223-336-362
E-mail: ip100@cam.ac.uk
[**] This research was supported by the EPSRC, Emmanuel College,
Cambridge (Research Fellowship to G.J.F), the EC (Network HPRN-
CT-2000-18), and Merck Research Laboratories.
As shown in Scheme 2, the synthesis of the C1–C7 subunit
6 began with a highly stereoselective boron-mediated aldol
reaction of the readily available methyl ketone 8[6] with 3-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 2. Synthesis of the C1–C7 subunit 6. a) NaIO4, CH2Cl2, pH 4
buffer, 08C, 3 h; b) 1. (+)-Ipc2BCl, Et3N, Et2O, 08C, 1 h; 2. 9, CH2Cl2,
ꢀ78 ! ꢀ278C, 2.5 h; 3. H2O2 (30% aq), pH 7 buffer, MeOH, 08C!
RT, 1 h; c) PMBTCA, TfOH (0.3 mol%), Et2O, room temperature, 3 h;
d) PMBTCA, Sc(OTf)3 (1 mol%), PhMe, 08C, 15 min; e) O3, NaHCO3,
CH2Cl2, ꢀ788C, 10 min; then PPh3, ꢀ788C!RT, 3 h. Ipc=-
Scheme 3. Synthesis of the C8–C17 subunit 7. a) Br2, PPh3, CH2Cl2,
08C!RT, 4 h; b) Ti(OiPr)4 (50 mol%), (R)-binol (50 mol%), CaH2,
THF, ꢀ788C, 72 h; c) TBSCl, imidazole, CH2Cl2, room temperature,
4 h; d) DIBAL, CH2Cl2, ꢀ788C, 2 h; e) MnO2, Et2O, room temperature,
=
3 h; f) CH2 CH(Me)MgBr, THF, ꢀ78!08C, 1.5 h; g) MnO2, Et2O,
isopinocampheyl, PMBTCA=para-methoxybenzyltrichloroacetimidate,
Tf =trifluoromethanesulfonyl, TIPS=triisopropylsilyl.
room temperature, 5 h; h) L-Selectride, CaH2, THF, ꢀ788C, 15 min;
TMSCl·Et3N, ꢀ78!ꢀ208C, 45 min. Binol=1,1’-bi(2-naphthol),
TBS=tert-butyldimethylsilyl, DIBAL=diisobutylaluminum hydride,
L-Selectride=lithium tri-sec-butylborohydride, TMS=trimethylsilyl.
butenal (9), derived from the oxidative cleavage of 1,2-glycol
10.[7] Enolization of 8 with (+)-Ipc2BCl/Et3N,[6,8] followed by
the addition of a freshly prepared anhydrous solution of 9 at
ꢀ788C, provided the corresponding 1,4-syn aldol adduct 11
(94%, > 97:3 d.r.). Treatment of 11 with PMBTCA in the
presence of catalytic TfOH in Et2O at room temperature
afforded the PMB ether 12 in 85% yield.[9] Alternatively, use
of Sc(OTf)3 in toluene at 08C provided 12 in 76% yield on a
multigram scale,[10] with decreased by-product formation.
Subsequent ozonolysis of 12 with reductive PPh3 workup gave
the 1,5-ketoaldehyde 6 in 97% yield.
enone 18 (86%), anticipated as a direct precursor to the
silyl enol ether 7. Initial attempts at this transformation
employing Chan hydrosilylation,[15] LiAlH4/CuI/TMSCl,[16] or
the Stryker reagent[17] proved unsuccessful. However, when
18 was subjected to L-Selectride in THF at ꢀ788C, regiose-
lective 1,4-reduction of the less sterically encumbered enone
was observed. The resultant enolate was quenched with
TMSCl to provide the C8–C17 subunit 7, which was used
directly in the subsequent coupling step.
Synthesis of the C8–C17 subunit 7 (Scheme 3) com-
menced with the bromination of potassium glutaconaldehyde
(13),[11] according to the method of Duhamel and co-work-
ers.[12] Treatment of 13 with Br2 and PPh3 provided the
corresponding E,E bromodienal 14 (68%). The stage was
now set for the critical AVM reaction between 14 and silyl
dienolate 15[13] to introduce the C13 stereocenter, along with
the 10E-trisubstituted alkene functionality.[5,14] Gratifyingly,
treatment of aldehyde 14 with [(R)-binol-Ti(OiPr)2]
(50 mol%) in THF at ꢀ788C, generated in situ from (R)-
binol and Ti(OiPr)4, followed by addition of silyl dienolate 15
provided the vinylogous aldol adduct 16 exclusively in 89%
yield and 94% ee.
With key subunits 6 and 7 in hand, attention was focused
on their Mukaiyama-type aldol union to introduce the C7
stereocenter, relying on 1,3-anti induction from the C5 ether
through an open transition state, following the Evans polar
model,[18] thus completing the carbon backbone of aglycon 5
(Scheme 4). In practice, exposure of 6 and 7 to BF3·Et2O in
CH2Cl2 at ꢀ958C provided the adduct in 66% yield (from 18)
with 95:5 d.r. which was present in solution in the closed
hemiacetal form 19. Treatment of 19 with PPTS, (MeO)3CH,
and MeOH cleanly provided methyl acetal 20. To confirm the
stereochemistry of 20, irradiation of 5-H provided a diagnos-
tic NOE interaction with the C3-OMe, consistent with their
1,3-diaxial relationship, whereas irradiation of the C3-OMe in
turn, provided a further NOE interaction with 7-H. Cleavage
of the silyl ethers with TASF in wet DMF gave diol 21
(72%).[19] Selective oxidation of the C1 terminus to seco acid
22 was next attempted and required careful optimization.
Under the conditions developed by Piancatelli and co-work-
TBS ether formation on the alcohol 16 was followed by
conversion into aldehyde 17 by treatment with DIBAL.
Subsequent reoxidation with MnO2 proceeded in 87% yield.
Addition of isopropenyl magnesium bromide to 17 and
oxidation of the resulting alcohol with MnO2 provided
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Scheme 5. Synthesis of fluorosugar units 3 and 4. a) DAST, NBS,
ꢀ158C, 15 min; b) TBAF, THF, 08C!RT, 4 h; c) SnCl2, AgClO4,
molecular sieves (4 ꢀ), Et2O, 08C!RT, 4 h; d) Cl3CC(O)NCO, CH2Cl2,
room temperature, 1 h; K2CO3, MeOH, room temperature, 2 h.
DAST=(diethylamino)sulfur trifluoride, NBS=N-bromosuccinimide,
TBAF=tetrabutylammonium fluoride.
used to access common precursor 24.[22,23] Formation of the
disaccharide 3 began with the activation of 24 with DAST/
NBS to provide exclusively a-fluorosugar 25 in 60% yield.[24]
Mukaiyama glycosylation between 25 and 26,[25] obtained by
deprotection of 24 with TBAF, provided 27 as the a-anomer
exclusively (84%). Activation of 27 with DAST/NBS then
afforded 3 in 79% yield. The fluorosugar 4 required for
auriside B (2) was readily synthesized in 77% yield by
treatment of 26 with trichloroacetyl isocyanate to afford
carbamate 28 (99%),[26] followed by activation with DAST/
NBS.
Completion of the total synthesis, as shown in Scheme 6,
required the coupling of aglycon 5 with either activated sugar
3 or 4 to directly provide auriside A (following silyl
deprotection) and auriside B, respectively. Under the
Mukaiyama protocol, the reaction of 3 and 5 followed by
desilylation with HF·pyr afforded (ꢀ)-auriside A (1) in 37%
yield ([a]2D0 = ꢀ16.3 (c = 0.033 in MeOH) Ref. [1a] ꢀ43.0 (c =
0.050 in MeOH)). Similarly, the reaction of 4 and 5 proceeded
smoothly to afford (ꢀ)-auriside B in 74% yield ([a]2D0 = -21.6
(c = 0.10 in MeOH), Ref. [1a] ꢀ30.0 (c = 0.090 in MeOH)). In
each case, analytical data (1H, 13C NMR and IR spectroscopy,
MS, and specific rotation) for the synthetic material were in
excellent agreement with those reported for natural aurisides
A and B, allowing confirmation of the relative and absolute
configurations of these compounds.[27]
Scheme 4. Synthesis of the auriside aglycon 5. a) BF3·OEt2, CaH2,
CH2Cl2, ꢀ958C, 10 min; b) PPTS (20 mol%), CH(OMe)3, MeOH, room
temperature, 4 h; c) TASF, H2O, DMF, 0!158C, 5 h; d) 1. TEMPO,
PhI(OAc)2, MeCN, pH 7 buffer, 6 h; 2. NaClO2, NaH2PO4, tBuOH,
H2O, 2-methyl-2-butene, room temperature, 30 min; e) 1. 2,4,6-
trichlorobenzoyl chloride, Et3N, PhMe, room temperature, 1 h;
2. DMAP, room temperature, 4 h; f) DDQ, CH2Cl2, pH 7 buffer, room
temperature, 30 min; g) pTsOH·H2O, THF, H2O, room temperature,
16 h. PPTS=pyridinium p-toluenesulfonate, TASF=(diethylamino)sul-
fur trifluoride, DMF=N,N-dimethylformamide, TEMPO=4-amino-
2,2,6,6-tetramethylpiperidine-1-oxyl, DMAP=4-N,N-dimethylaminopyri-
dine, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, pTsOH=para-
tolunenesulfonic acid.
ers,[20] treatment of 21 with TEMPO and PhI(OAc)2 in
MeCN/pH7 buffer (5:1) provided the intermediate aldehyde,
which was further oxidized with NaClO2 to give 22 in 60%
yield. This intermediate readily underwent Yamaguchi mac-
rolactonization to provide the desired 14-membered macro-
cycle 23 cleanly (86%).[21] Cleavage of the PMB ether with
DDQ and hydrolysis of the methyl acetal then afforded
1
auriside aglycon 5 in 74% yield. At this stage, the H and
13C NMR spectroscopic data and specific rotation agreed with
those reported by the Yamada group.[1b]
With aglycon 5 in hand, attention was now directed
toward the preparation of the activated fluorosugar units 3
and 4 (Scheme 5). Following work reported by the Nicolaou
group, a nine-step sequence starting from l-rhamnose was
In conclusion, we have completed an expedient total
synthesis of (ꢀ)-aurisides A and B that proceeds in 18 steps
(1.7% overall yield) and 17 steps (3.5% overall yield),
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[3] a) M. Romero-Ortega, D. A. Colby, H. F. Olivo, Tetrahedron
Lett. 2002, 43, 6439; b) H. F. Olivo, F. Velazquez, M. Romero, Y.
Rios, Abstr. Pap. Am. Chem. S. 225: 311-ORGN, Part 2, MAR
2003; c) D. Y. Gin, H. M. Nguyen, Abstr. Pap. Am. Chem. S. 225:
245-ORGN Part 2, MAR 2003.
[4] I. Paterson, R. D. M. Davies, A. C. Heimann, R. Marquez, A.
Meyer, Org. Lett. 2003, 5, 4477.
[5] For a review, see: C. J. Cowden, I. Paterson, Org. React. 1997, 51,
1.
[6] Methyl ketone 8 was prepared in 96% yield over three steps
from methyl(R)-3-hydroxy-2-methylpropionate: 1) TIPSCl, imi-
dazole, CH2Cl2, room temperature, 16 h; 2) MeONHMe·HCl,
iPrMgCl, THF, ꢀ208C, 1 h; 3) MeMgBr, THF, 08C, 1 h. We have
previously reported the use of ent-8 in the context of our
spongistatin work: I. Paterson, R. M. Oballa, Tetrahedron Lett.
1997, 38, 8241.
[7] 1,2-Glycol 10 was prepared from glyoxal (Sn, allyl bromide,
sonication, room temperature, 3 h): a) M. T. Crimmins, S. J.
Kirincich, A. J. Wells, A. L. Choy, Synth. Commun. 1998, 28,
3675; b) M. T. Crimmins, A. L. Choy, J. Am. Chem. Soc. 1999,
121, 5653.
[8] a) I. Paterson, J. M. Goodman, M. Isaka, Tetrahedron Lett. 1989,
30, 7121; b) I. Paterson, J. M. Goodman, M. A. Lister, R. C.
Schumann, C. K. McClure, R. D. Norcross, Tetrahedron 1990, 46,
4663.
[9] T. Iverson, D. R. Bundle, J. Chem. Soc. Chem. Commun. 1981,
1240.
Scheme 6. Completion of the total synthesis of aurisides A (1) and B
(2). a) SnCl2, AgClO4, molecular sieves (4 ꢀ), Et2O, 08C!RT, 16 h;
b) HF·py, THF, 08C!RT, 16 h; c) SnCl2, AgClO4, molecular sieves
(4 ꢀ), Et2O, 08C!RT, 8 h.
[10] A. N. Rai, A. Basu, Tetrahedron Lett. 2003, 44, 2267.
[11] Potassium glutaconaldehyde 13 was prepared from pyridinium-
1-sufonate in 61% yield: J. Becher, Synthesis 1980, 589.
[12] a) D. Soullez, G. Ple, L. Duhamel, P. Duhamel, J. Chem. Soc.
Chem. Commun. 1995, 563; b) D. Soullez, G. Ple, L. Duhamel, J.
Chem. Soc. Perkin Trans. 1 1997, 1639.
[13] J. Savard, P. Brassard, Tetrahedron 1984, 40, 3455.
[14] For a review of the vinylogous aldol reaction, see: G. Casiraghi,
F. Zanardi, G. Appendino, G. Rassu, Chem. Rev. 2000, 100, 1929.
[15] T. H. Chan, G. Z. Zheng, Tetrahedron Lett. 1993, 34, 3095.
[16] E. C. Ashby, J.-J. Lin, R. Kovar, J. Org. Chem. 1976, 41, 1939.
[17] W. S. Mahoney, D. M. Brestensky, J. M. Stryker, J. Am. Chem.
Soc. 1988, 110, 291.
[18] D. A. Evans, M. J. Dart, J. L. Duffy, M. G. Yang, J. Am. Chem.
Soc. 1996, 118, 4322.
[19] K. A. Scheidt, H. Chen, B. C. Follows, S. R. Chemler, D. S.
Coffey, W. R. Roush, J. Org. Chem. 1998, 63, 6436; under other
silyl deprotection conditions, complete decomposition of 20 was
observed.
respectively. By building the E,E bromodiene of the side
chain into the silyl enol ether 7, the key Mukaiyama aldol
coupling with aldehyde 6 delivers the advanced intermediate
19 in a highly convergent manner. This can then be converted
into the aurisides by a-selective glycosylation of the derived
macrolide core 5 with the fluorosugars 3 and 4. This work also
highlights an efficient enantioselective vinylogous
Mukaiyama aldol reaction, which in tandem with our
diastereoselective boron-mediated aldol methodology pro-
vides a rapid synthetic entry into this structurally unique class
of bioactive marine macrolides.
Received: October 11, 2004
Published online: January 21, 2005
[20] A. DeMico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancatelli,
J. Org. Chem. 1997, 62, 6974.
[21] J. Inanaga, K. Hirata, T. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
Keywords: aldol reaction · antitumor agents · glycosylation ·
natural products · total synthesis
.
[22] For a Review, see: K. C. Nicolaou, H. J. Mitchell, Angew. Chem.
2001, 113, 1624; Angew. Chem. Int. Ed. 2001, 40, 1576.
[23] a) R. E. Dolle, K. C. Nicolaou, J. Am. Chem. Soc. 1985, 107,
1691; b) R. E. Dolle, K. C. Nicolaou, J. Am. Chem. Soc. 1985,
107, 1695.
[24] K. C. Nicolaou, A. Chucholowski, R. E. Dolle, J. L. Randall, J.
Chem. Soc. Chem. Commun. 1984, 1155.
[25] T. Mukaiyama, Y. Murai, S. Shoda, Chem. Lett. 1981,431.
[26] P. Kocovsky, Tetrahedron Lett. 1986, 27, 5521.
[27] Copies of 1H and 13C NMR spectra for aglycon 5 and aurisides A
(1) and B (2) are provided in the Supporting Information.
[1] a) H. Sone, H. Kigoshi, K. Yamada, J. Org. Chem. 1996, 61, 8956;
b) H. Sone, K. Suenaga, Y. Bessho, T. Kondo, H. Kigoshi, K.
Yamada, Chem. Lett. 1998, 85.
[2] For examples of other bioactive and structurally unique secon-
dary metabolites isolated from Dolabella auricularia, see:
a) dolastatins: G. R. Pettit, Y. Kamano, C. L. Herald, Y. Fujii,
H. Kizu, M. R. Boyd, F. E. Boettner, D. L. Doubek, J. M.
Schmidt, J.-C. Chapuis, C. Michel, Tetrahedron 1993, 49, 9151;
H. Sone, T. Shibata, T. Fujita, M. Ojika, K. Yamada, J. Am.
Chem. Soc. 1996, 118, 1874; b) dolabelides: M. Ojika, T. Nagoya,
K. Yamada, Tetrahedron Lett. 1995, 36, 7491; c) dolabellin: H.
Sone, T. Kondo, M. Kiryu, H. Ishiwata, M. Ojika, K. Yamada, J.
Org. Chem. 1995, 60, 4774.
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