Toward the synthesis of (+)-peloruside A via an intramolecular vinylogous aldol reaction

Article abstract of DOI:10.1021/ol202966m

The use of the intramolecular vinylogous aldol reaction for the preparation of an advanced intermediate for the synthesis of peloruside A is described. The reaction was applied to compound 19 and proceeds in high yield and good levels of diastereoselectiv

Full text of DOI:10.1021/ol202966m

ORGANIC
LETTERS
2012
Vol. 14, No. 1
178–181
Toward the Synthesis of (þ)-Peloruside
A via an Intramolecular Vinylogous Aldol
Reaction
Jeffrey A. Gazaille, Joseph A. Abramite, and Tarek Sammakia*
Department of Chemistry and Biochemistry, University of Colorado, Boulder,
Colorado 80309-0215, United States
sammakia@colorado.edu
Received November 3, 2011
ABSTRACT
The use of the intramolecular vinylogous aldol reaction for the preparation of an advanced intermediate for the synthesis of peloruside A is
described. The reaction was applied to compound 19 and proceeds in high yield and good levels of diastereoselectivity. Application of the
Achmatowicz reaction to this intermediate provided the corresponding pyranone, a late stage intermediate well positioned for conversion to the
natural product.
Peloruside A is a polyoxygenated 16-membered macro-
lide isolated from the marine sponge Mycale hentscheli by
Northcote and co-workers (Figure 1).1 It displays potent
antimitotic activity, arresting cells at the G2-M boundary
with low nanomolar activity against several cancer cell lines.2
Its combination of potent biological activity and complex
structure has led to intense interest by the synthetic organic
(1) West, L. M.; Northcote, P. T.; Battershill, C. N. J. Org. Chem.
Figure 1. (þ)-Peloruside A.
2000, 65, 445.
(2) (a) Hood, K. A.; West, L. M.; Rouwe, B.; Northcote, P. T.;
Berridge, M. V.; Wakefield, S. J. Cancer Res. 2002, 62, 3356. (b)
Gaitanos, T. N.; Buey, R. M.; Diaz, J. F.; Northcote, P. T.; Teesdale-
Spittle, P.; Andreu, J. M.; Miller, J. H. Cancer Res. 2004, 64, 5063. (c)
Miller, J. H.; Rouwe, B.; Gaitanos, T. N.; Hood, K. A.; Crume, K. P.;
Baeckstroem, B. T.; La Flamme, A. C.; Berridge, M. V.; Northcote, P. T.
Apoptosis 2004, 9, 785. (d) Page, M.; West, L.; Northcote, P.; Battershill,
C.; Kelly, M. J. Chem. Ecol. 2005, 31, 1161.
(3) (a) Liao, X.; Wu, Y.; De Brabander, J. K. Angew. Chem., Int. Ed.
2003, 42, 1648. (b) Jin, M.; Taylor, R. E. Org. Lett. 2005, 7, 1303–1305.
(c) Ghosh, A. K.; Xu, X.; Kim, J.-H.; Xu, C.-X. Org. Lett. 2008, 10,
1001. (d) Evans, D. A.; Welch, D. S.; Speed, A. W. H.; Moniz, G. A.;
Reichelt, A.; Ho, S. J. Am. Chem. Soc. 2009, 131, 3840. (e) Hoye, T. R.;
Jeon, J.; Kopel, L. C.; Ryba, T. D.; Tennakoon, M. A.; Wang, Y. Angew.
Chem., Int. Ed. 2010, 49, 6151. (f) McGowan, M. A.; Stevenson, C. P.;
Schiffler, M. A.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2010, 49, 6147.
community with six total syntheses reported to date.3 We
describe herein our progress toward the synthesis of peloru-
side A using the intramolecular vinylogous aldol4 reaction
in a novel approach to the construction of the macrocycle.
One of the challenges associated with the synthesis of
peloruside A is the construction of the macrocycle, and all
previous total syntheseshaveutilizeda macrolactonization
(4) Recent reviews: Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.;
Zanardi, F. Chem. Rev. 2011, 111, 3076. (b) Denmark, S. E.; Heemstra,
J. R.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682.
r
10.1021/ol202966m
Published on Web 12/12/2011
2011 American Chemical Society

for this purpose. While macrolactonization has become a
reliable method for the synthesis of medium- to large-
membered rings, it can at times provide modest yields, and
there can be strategic advantages to other methods of
macrocycle formation. We have recently described the
application of the Yamamoto vinylogous aldol reaction5
for the synthesis of medium-membered rings using non-
enolizable aldehydes.6 These reactions proceed in good to
excellent yields and with high levels of remote stereo-
control, and we wished to demonstrate the utility of this
method in the context of natural products synthesis. The
vinylogous aldol reaction produces an R,β-unsaturated
ester, the alkene of which can be subjected to functionali-
zation, and we targeted peloruside A for synthesis as this
compound contains functionality that can be installed
from the product of an intramolecuar vinylogous aldol
reaction. Our retrosynthesis is shown in Figure 2.
Scheme 1. Synthesis of Aldehyde 6
The preparation of cyclization precursor 3 began with
the synthesis of aldehyde 6 as follows. 5-Bromo-2-furoic
acid (4) was reduced with BH3•THF to provide the corre-
sponding alcohol which was protected as the TBS ether to
provide bromofuran 5in 94% yield over two steps (Scheme 1).
Methyl isobutyrate was then subjected to R-arylation with
bromofuran 5 under Hartwig’s conditions8 (Pd(dba)2,
P(t-Bu)3, and Cy2NLi) and then reduced with DIBAL-H
to provide aldehyde 6. This aldehyde was then coupled
to ketone 9 using a 1,5-anti-aldol reaction,9 as shown in
Scheme 3.
Scheme 2. Synthesis of Ketone 9
Figure 2. Retrosynthetic analysis.
Ketone 9 was prepared from (ꢀ)-ethyl lactate by protec-
tion as the benzyl ether (benzyltrichloroacetimidate, cata-
lytic TfOH) and reduction (DIBAL-H) to provide aldehyde
7 (Scheme 2). Subjection of this aldehyde to a chelation-
controlled ene-reaction using 2-methyl propene as described
by Mikami10 selectively provided alcohol 8 (>30:1 dr).
Protection as the PMB ether (NaH, PMBCl) and oxidative
cleavage (OsO4, NaIO4, 2,6-lutidine)11 provided methyl
ketone 9 ready for coupling with aldehyde 6.
The coupling of aldehyde 6 and methyl ketone 9 was
accomplished using Evans’ conditions12 (n-Bu2BOTf,i-Pr2
NEt) to provide 10 in 87% yield and 7:1 diastereoselectivity
(Scheme 3). Anti-selective hydroxyl-directed reduction
The most straightforward disconnection utilizing the
intramolecular vinylogous aldol reaction involves the use
of an enolizable aldehyde to make the C4ꢀC5 bond;
however, this reaction is currently limited to nonenolizable
aldehydes. We therefore chose to utilize a nonenolizable
furfural derivative (3) lacking the C16ꢀC17 alkene and
which upon cyclization would provide a furyl alcohol (2)
that could be subjected to the Achmatowicz oxidative
rearrangement7 to provide a pyranone (1) with a handle
to install the requisite functionality in the natural product
(Figure 2).
(5) (a) Saito, S.; Shiozawa, M.; Ito, M.; Yamamoto, H. J. Am. Chem.
Soc. 1998, 120, 813. (b) Saito, S.; Shiozawa, M.; Yamamoto, H. Angew.
Chem., Int. Ed. 1999, 38, 1769. (c) Saito, S.; Shiozawa, M.; Nagahara, T.;
Nakadai, M.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 7847. (d)
Saito, S.; Nagahara, T.; Shiozawa, M.; Nakadai, M.; Yamamoto, H.
J. Am. Chem. Soc. 2003, 125, 6200. (e) For an asymmetric variation, see:
Takikawa, H.; Ishihara, K.; Saito, S.; Yamamoto, H. Synlett 2004, 732.
(6) Abramite, J. A.; Sammakia, T. Org. Lett. 2007, 9, 2103.
(7) (a) Coombs, T. C.; Lee, M. D.; Wong, H.; Armstrong, M.; Cheng,
B.; Chen, W.; Moretto, A. F.; Liebeskind, L. S. J. Org. Chem. 2008, 73,
882. (b) Henderson, J. A.; Jackson, K. L.; Phillips, A. J. Org. Lett. 2007,
9, 5299. (c) Achmatowicz, O., Jr.; Bukowski, P.; Szechner, B.; Zwierzchowska,
Z.; Zamojski, A. Tetrahedron 1971, 27, 1973.
(8) Jørgensen, M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F.
J. Am. Chem. Soc. 2002, 124, 12557.
(9) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996,
37, 8585.
(10) Mikami, K.; Loh, T. P.; Nakai, T. Tetrahedron: Asymmetry
1990, 1, 13.
(11) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217.
(12) Evans, D. A.; Cote, B.; Coleman, P. J.; Connell, B. T. J. Am.
Chem. Soc. 2003, 125, 10893.
(13) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
Org. Lett., Vol. 14, No. 1, 2012
179

diastereoselectivity while reduction with the (R)-CBS cat-
alyst provided the C-5 S-alcohol (17-S) in 4:1 diastereos-
electivity. The spectral data of 17-R were identical to those
of 17, indicating that the product of the intramolecular
vinylogous aldol reaction (16) bears the undesired config-
uration at C-5. While it is feasible that the stereochemistry
at C-5 in compound 16 can be inverted, we instead studied
a different cyclization precursor in order to directly obtain
the desired stereochemical outcome as described below.
Scheme 3. Synthesis of Cyclization Precursor 15
Scheme 4. Intramolecular Vinylogous Aldol Reaction and
Proof of Stereochemistry
(Me4NBH(OAc)3)13 of 10 provided diol 11 which was
protected as the diisopropyl silylene (12). Compound 12
was then treated with methyl lithium in the presence of
HMPA followed by methyl iodide to provide 13 bearing a
methyl ether at C-13 and a diisopropyl methyl silyl ether at
C-11 as a single constitutional isomer to the limits of 1H
NMR detection.14 Deprotection of the C-16 PMB group
(DDQ) resulted in simultaneous oxidation of the TBS
ether at C-5 to provide hydroxy aldehyde 14. This fortu-
itous result is likely the result of oxidation of the electron-
rich furan by a mechanism similar to that of DDQ oxida-
tion of a PMB ether to provide a silyl oxocarbenium ion
which upon attack by water would provide the aldehyde.15
Acylation with crotonic anhydride provided cyclization
precursor 15 ready for the key intramolecular CꢀC bond
forming reaction.
We were pleased to find that subjection of compound 15
to our standard intramolecular vinylogous aldol reaction
conditions (lithium 2,2,6,6-tetramethyl-piperidine (LTMP),
2.0 equiv; aluminum tris(2,6-diphenylphenoxide) (ATPH),
2.2 equiv; toluene/THF, ꢀ48 °C) provided the cyclized
product in 86% yield as a 6:1 diastereomeric mixture
(Scheme 4). In order to determine the stereochemistry at
C-5 of this material, the alkene was reduced (H2, Pd/C, 17)
and the alcohol oxidized to provide ketone 18. Reduc-
tion of the C-5-ketone with the (S)-CBS catalyst16 pro-
vided the C-5 R-alcohol (17-R) in greater than 25:1
We reasoned that the stereochemistry of the cyclization
could be dictated by the conformation of the forming
macrocycle and that a different conformation could pro-
vide the desired stereochemical outcome. We therefore
studied cyclization of silylene 19, which was prepared from
silylene 12 by subjection to DDQ (Scheme 5). Again, this
resulted in the simultaneous deprotection of the PMB
ether and oxidation at C-5 to provide the corresponding
hydroxy aldehyde as observed on compound 13. Acylation
with crotonic anhydride then provided cyclization precur-
sor 19. Subjection of compound 19 to our intramolecular
vinylogous aldol reaction conditions provided macrolide
20 in 84% yield, again as a 6:1 diastereomeric mixture . The
stereochemistry of the C-5 alcohol in 20 was determined by
chemical correlation as described for macrolide 16 in
Scheme 4 and was found to have the desired S-configura-
tion (see Supporting Information).
(14) (a) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura,
T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y-i.; Hasegawa, M.;
Yamada, K.; Saitoh, K. Chem.;Eur. J. 1999, 5, 121. (b) Van den Bossche,
J.; Shin, J.; Thompson, D. H. J. Org. Chem. 2007, 72, 5005.
(15) Piva, O.; Amougay, A.; Peter, J. P. Tetrahedron Lett. 1991, 32,
3993.
(16) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53,
2861.
180
Org. Lett., Vol. 14, No. 1, 2012

Scheme 5. Intramolecular Vinylogous Aldol Reaction of
Aldehyde 19
Scheme 6. Synthesis of Achmatowicz Precursor 23
The hydroxyl group at C-5 was protected as a TES ether,
and the alkene was subjected to dihydroxylation using
AD-mix-β17 to provide the diol bearing the natural stereo-
chemistry in a 12:1 diastereomeric ratio (Scheme 6). The
stereochemistry of the product was established by subjec-
tion of compound 20 to dihydroxylation using the Upjohn
conditions,18 which provided a 3:1 mixture of diastereo-
mers, and usage of AD-mix-R, which proved to be the
mismatched case and provided the product in a 1.4:1 dia-
stereomeric ratio. This indicates that intrinsic peripheral
attack provides the desired stereochemistry, which can be
enhanced using AD-mix-β. The C-2 hydroxyl group was
then selectively protected as the TBS ether (TBSCl, imid-
azole), and the C-3 alcohol was methylated (trimethyloxonium
tetrafluoroborate, proton sponge).
Scheme 7. Achmatowicz Reaction of Furan 24
With the installation of the protected diol complete, we
turned our attention to the Achmatowicz reaction. We found
that subjection of compound 23 to a mild acid (PPTS, MeOH/
DMF) selectively removed the TES group in preference to
the silylene (Scheme 7).19 Subjection of this material to
Achmatowicz reaction conditions7 (m-CPBA in the presence
of trichloroacetic acid) induced the oxidative rearrangement
and provided the desired pyranone in 64% yield which is in a
good position for conversion to the natural product.
product with handles for the installation of the required
functional groups. Other highlights of this synthesis in-
cludethe selectiveconversionofasilylene toa differentially
protected 1,3-diol and the oxidation of a furfuryl ether to
the corresponding aldehyde using DDQ. Completion of the
synthesis of peloruside A is currently under investigation.
This synthesis illustrates the utility of the intramolecular
vinylogous aldol reaction for the synthesis of medium-
membered rings. The key reaction is efficient and stereo-
selective and enables rapid entry into the cyclic core structure
of peloruside A. Further, application of the Achmatowicz
reaction allows the use of a furfural derivative that is
nonenolizable and provides the pyran ring of the natural
Acknowledgment. This work was supported by a generous
grant from the National Institutes of Health (GM 48498).
We thank Professor Andrew Phillips (Yale) for insightful
suggestions and conversations.
Note Added after ASAP Publication. This paper pub-
lished ASAP on December 12, 2011. Reference 3f was
added and the paper reposted on December 19, 2011.
(17) (a) VanNieuwenhze, M.; Sharpless, K. B. Tetrahedron Lett.
1994, 35, 843. (b) Ahmed, M. M.; O’Doherty, G. Carbohydr. Res.
2006, 341, 1505.
(18) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 23, 1973.
(19) Selective removal of the silylene in preference to the TES ether
could be accomplished using HF•pyridine in 75% yield.
Supporting Information Available. Experimental pro-
cedures for the synthesis of compounds 5ꢀ12 and 19ꢀ25
and full characterization. The material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
181