Concise enantioselective total synthesis of neopeltolide macrolactone highlighted by ether transfer

Article abstract of DOI:10.1021/ol802254z

(Chemical Equation Presented) A concise total synthesis of neopeltolide macrolactone has been accomplished in 14 steps in the longest linear sequence, 15 steps overall from commercially available materials. The present synthesis was highlighted by successful exploitation of ether transfer methodology and a radical cyclization reaction to directly establish the requisite stereochemistry of the tetrahydropyran core.

Full text of DOI:10.1021/ol802254z

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5047-5050
Concise Enantioselective Total
Synthesis of Neopeltolide Macrolactone
Highlighted by Ether Transfer
Rendy Kartika, Thomas R. Gruffi,† and Richard E. Taylor*
Department of Chemistry and Biochemistry and the Walther Cancer Research Center,
UniVersity of Notre Dame, 251 Nieuwland Science Hall,
Notre Dame, Indiana 46556-5670
taylor.61@nd.edu
Received September 27, 2008
ABSTRACT
A concise total synthesis of neopeltolide macrolactone has been accomplished in 14 steps in the longest linear sequence, 15 steps overall
from commercially available materials. The present synthesis was highlighted by successful exploitation of ether transfer methodology and
a radical cyclization reaction to directly establish the requisite stereochemistry of the tetrahydropyran core.
Polyketide natural products are biosynthesized by microor-
ganisms for their antibiotic activity and thus create an
environmental advantage for the producing organism. Their
structures evolve during the ancestral history of the producing
organism through modification in the PKS gene clusters and
the development or sequestration of post-PKS processing
enzymes. Our laboratory is particularly interested in the
correlation between unique polyketide structures and their
corresponding biological activities. Many cyanobacteria-
derived polyketides contain methyl substitution at odd-
number carbons proposedly due to an HMG-CoA synthase
embedded in the PKS gene cluster.1 This unique structural
feature presumably evolved as an additional conformational
control element and to enhance structural diversity.
fied, the sponge was most closely related to Daedalopelta
sollas. Neopeltolide is a fully saturated, tetrahydropyran-
containing 14-membered macrolide exhibiting ornamentation
at C5 hydroxyl with a pendant oxazole carbamate side chain
identical to that of leucascandrolide A 2.3 The original
stereochemical configuration of the neopeltolide macrolac-
tone was revised by recent total syntheses.4-6
(2) Wright, A. E.; Botelho, J. C.; Guzman, E.; Harmody, D.; Linley,
P.; McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J. Nat. Prod.
2007, 70, 412–416.
(3) Dambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1996, 79, 51–60.
(4) (a) Youngsaye, W.; Lowe, J. T.; Pohlki, F.; Ralifo, P.; Panek, J. S.
Angew. Chem., Int. Ed. 2007, 46, 9211-9214; Angew. Chem. 2007, 119,
9371-9374. (b) Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am. Chem.
Neopeltolide 1 is one example of these interesting
compounds. In 2007, Wright and co-workers reported the
isolation of neopeltolide from a deepwater sponge of the
family Neopeltidae collected off the north Jamaican coast.2
Although the exact species of the specimen was not identi-
Soc. 2008, 130, 804–805
.
(5) (a) Woo, S. K.; Kwon, M. S.; Lee, E. Angew. Chem., Int. Ed. 2008,
47, 3242-3244; Angew. Chem. 2008, 120, 3286-3288. (b) Vintonyak,
V. V.; Maier, M. E. Org. Lett. 2008, 10, 1239–1242. (c) Fuwa, H.; Naito,
S.; Goto, T.; Sasaki, M. Angew. Chem., Int. Ed. 2008, 47, 4737-4739;
Angew. Chem. 2008, 120, 4815-4817. (d) Paterson, I.; Miller, N. A. Chem.
Commun. 2008, DOI: 10.1039/b812914b (Advance Article)
.
(6) Ulanovskaya, O. A.; Janjic, J.; Suzuki, M.; Sabharwal, S. S.;
† Undergraduate research participant.
(1) Calderone, C. T. Nat. Prod. Rep. 2008, 25, 845–853.
Schumacker, P. T.; Kron, S. J.; Kozmin, S. A. Nat. Chem. Biol. 2008, 4,
418–424.
10.1021/ol802254z CCC: $40.75
Published on Web 10/15/2008
2008 American Chemical Society

Neopeltolide (Figure 1) has demonstrated cytotoxic activity
against several cancer lines, including P388 murine leukemia,
A-549 human lung adenocarcinoma, and NCI-ADR-RES
human ovarian sarcoma, with their respective IC50 values
of 0.56, 1.2, and 5.1 nM.2 Recent efforts by Kozmin and
co-workers have suggested that the mode of action of
neopeltolide may involve inhibition of mitochondrial ATP
synthesis with cytochrome bc1 complex as the primary
cellular target.6 A related biological activity of leuscandrolide
A offers circumstantial support that their inherent activity is
primarily associated with their common oxazole carbamate
side chain.
Scheme 1. Retrosynthetic Analysis
able (R)-4-(methoxycarbonyl)-3-methylbutanoic acid10 8 with
borane dimethylsulfide complex. These conditions yielded
a mixture of alcohol 9 and lactone 10 in 92:8 ratio, which
were sequentially treated under Weinreb amidation11 and
Dess-Martin oxidation12 to produce amide-aldehyde 4 in
good yields. This compound represents an interesting syn-
thetic intermediate due to its dual electrophilic sites; however,
it exhibits an appreciable difference in reactivity. By exploit-
ing the more electrophilic aldehyde functionality, asymmetric
allylation should set the C7 stereochemistry necessary for
the neopeltolide macrolactone. Upon screening a variety of
allylation methods, the transformation to homoallylic alcohol
11 was found most effective with Soderquist’s chiral
bicyclodecane-allylborane reagent 5.13a Under modified
reaction conditions, which included an introduction of a
stoichiometric amount of BF3•OEt2, homoallylic alcohol 11
was readily produced in 60%.13b This external Lewis acid
was presumably necessary to sequester the much stronger
Lewis basic Weinreb amide functionality. Conversion of 11
to the corresponding benzyloxymethyl (BOM) ether 12,
necessary for the ether transfer, then proceeded in 92% yield
(Scheme 2).
Figure 1. Neopeltolide and Leucascandrolide A.
Biosynthetically, the C5 side chain is likely incorporated
by a post-PKS process. As post-PKS genes develop late in
the evolutionary history of the producing organism,7 we are
particularly interested in the structural significance of this
oxazole-containing side chain and the inherent activity of
the polyketide core. From the seven published total syntheses
of neopeltolide, only Panek’s route directly accessed the
natural stereochemistry of the neopeltolide macrolactone.4a
Alternatively, the rest involved the production of the C5
epimer followed by stereochemical inversion upon installa-
tion of the oxazole carbamate side chain by the method of
Mitsunobu.4b,5,6
Scheme 2. Synthesis of C4-C11 Segment
We envisioned an assembly of four simple fragments 4-7
for the construction of macrolide 3 (Scheme 1), with ethyl
propiolate 7 serving as a lynchpin for the macrolactonization.
The present total synthesis will be highlighted by the
utilization of our ether transfer methodology,8 which directs
the stereochemistry embedded within the tetrahydropyran
ring.9 More importantly, we have successfully implemented
a strategy that minimizes protecting group manipulation in
a unique fashion, a common and unavoidable practice in
polyketide syntheses. The result is a remarkably efficient,
14-step (longest linear sequence, 15 total steps) synthesis of
the neopeltolide core which will enable full biological
profiling.
Our synthesis then continued with an installation of the
C12-C16 segment by utilizing ꢀ-hydroxylsulfide 6.
The concise synthesis to neopeltolide macrolactone 3
began with chemoselective reduction of commercially avail-
(10) Commercially available from Aldrich or readily accessible in large
scale from enzymatic resolution of dimethyl-3-methylglutarate with porcine
liver esterase: Lam, L. K. P.; Hui, R. A. H. F.; Jones, J. B. J. Org. Chem.
1986, 51, 2047–50.
(7) Young, J.; Taylor, R. E. Nat. Prod. Rep. 2008, 25, 651–655.
(8) Liu, K.; Taylor, R. E.; Kartika, R. Org. Lett. 2006, 8, 5393–5395.
(9) Utilizations of electrophile-induced ether transfer in oxacycle
syntheses: (a) Kartika, R.; Taylor, R. E. Heterocycles 2007, 74, 447–459.
(b) Kartika, R.; Taylor, R. E. Angew. Chem., Int. Ed. 2007, 46, 6874-6877;
Angew. Chem. 2007, 119, 6998-7001. (c) Kartika, R.; Frein, J. D.; Taylor,
R. E. J. Org. Chem. 2008, 73, 5592–5594.
(11) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
(12) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(13) (a) Burgos, C. H.; Canales, E.; Matos, K.; Soderquist, J. A. J. Am.
Chem. Soc. 2005, 127, 8044–8049. (b) The minor diastereomer C7(R) was
separable by chromatography and isolated in 6% yield.
5048
Org. Lett., Vol. 10, No. 21, 2008

Transformation14a,b of 6 to the corresponding dilithio species
13 followed by addition to Weinreb amide 12 according the
method of Rychnovsky14c cleanly produced ꢀ-hydroxy
ketone 14 in 92% yield without the necessity for protection
at the C13 hydroxy group. Elaboration of the C11 stereo-
chemistry and simultaneous differentiation of the C13
hydroxy group as a benzoate ester was realized by the
Evans-Tischenko reaction in 80% yield.15 Methylation of
the resulting C11 hydroxyl with Meerwein’s salt in the
presence of Proton Sponge then quantitatively afforded
methyl ether 15 (Scheme 3).16
Scheme 4. Construction of the Tetrahydropyran Core
Scheme 3. Preparation of Ether Transfer Precursor 15
The endgame strategy to neopeltolide macrolactone was
straightforward. Exposure of tetrahydropyran 18 to a mixture
of aqueous KOH and methanol saponified the ethyl ester
group to the corresponding carboxylic acid and at the same
time cleaved the C13 benzoate ester (Scheme 5). Macrolac-
Scheme 5. Endgame to Neopeltolide Macrolactone
The highlight of the present total synthesis resides in the
utilization of our ether transfer technology which directly
installed the requisite C5 stereochemistry as a benzyl-
protected ether. This was accomplished by simply treating
homoallylic BOM ether 15 with iodine monochloride.8 Upon
aqueous workup, 1,3-syn-diol monoether 16 was liberated
in 71% yield with excellent stereocontrol. In addition to our
previous work in phorboxazole A,9b this transformation once
again exemplifies the versatility and applicability of the ether
transfer reaction to complex substrates. The completion to the
carbon skeleton of neopeltolide macrolactone was realized via
tributylphosphine-promoted conjugate addition of the C7 hy-
droxyl to ethyl propiolate 7.17a This reaction proved challenging
since, under the established reaction conditions,17a,18 the
alternative tetrahydrofuran cyclization event of alcohol 16
was highly competitive. However, upon optimization,17b the
desired ꢀ-alkoxyacrylate 17 was selectively produced in 98%
yield. The ensuing construction of the tetrahydropyran core
was executed via radical cyclization with AIBN and
n-Bu3SnH in refluxing toluene (Scheme 4).19 These condi-
tions afforded 18 in 95% yield as nearly a single diastere-
omer.
tonization of the resulting seco acid was then realized under
the Yamaguchi protocol;20 both steps proceeded in good
yields. The ensuing hydrogenolysis in the presence of a
catalytic amount of Pd/C removed the C5 benzyl ether and
thus completed our total synthesis of neopeltolide macro-
lactone 3. The spectroscopic analyses of our synthetic
material were found in a complete agreement with those
presented by Panek.21 Considering Panek’s two-step conver-
sion of 3 to neopeltolide, the present route represents a formal
total synthesis.
In summary, we have accomplished a concise total
synthesis of neopeltolide macrolactone 3 with only 14 steps
in the longest linear sequence and 15 steps22 overall from
commercially available materials. The highly efficient route
outlined in this communication successfully implemented a
strategy that utilized sequential ether transfer and radical
cyclization reactions to directly install the requisite stereo-
chemistry within the tetrahydropyran ring. In addition, our
present route readily minimized protecting group manipula-
(14) (a) Mudryk, B.; Shook, C. A.; Cohen, T. J. Am. Chem. Soc. 1990,
112, 6389. (b) Foubelo, F.; Gutierrez, A.; Yus, M. Tetrahedron Lett. 1997,
38, 4837–4840. (c) Huckins, J. R.; de Vicente, J.; Rychnovsky, S. D. Org.
Lett. 2007, 9, 4757–4760
.
(15) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447–
6449.
(16) (a) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S.
Tetrahedron Lett. 1994, 35, 7171–7172. (b) It was essential to immediately
methylate the Evans-Tischenko product upon isolation to prevent the facile
C11-C13 benzoate migration.
(19) A recent review of ꢀ-alkoxyacrylate radical cyclization to oxacycle
systems in total syntheses: Lee, E. Pure Appl. Chem. 2005, 77, 2073–2081.
(20) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
(17) (a) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241–
244. (b) The reaction was optimized by simultaneous dropwise addition of
stoichiometric amounts of PBu3 and ethyl propiolate to a dilute solution of
ꢀ-alkoxyacrylate 17; see Supporting Information for a detailed experimental
protocol.
(21) We thank Professor James Panek for kindly providing us with their
NMR spectra for neopeltolide macrolactone 3.
(18) The use of amine-based promoters, such as DMAP, DABCO,
TEA, and NMM, also predominantly led to the tetrahydrofuran cycliza-
tion event.
(22) Preparation of ꢀ-hydroxysulfide 6 was achieved in one step via addition
of sodium thiophenoxide to commercially available (S)-2-propyloxirane; see
Supporting Information for a detailed experimental protocol.
Org. Lett., Vol. 10, No. 21, 2008
5049

tion. In fact, the two protecting groups (C5 benzyl ether and
C13 benzoate ester) were produced simultaneously upon
generation of a specific stereogenic center and, thus, allowed
differentiation of the resulting 1,3-diol products. The sig-
nificant quantities of material prepared by the route, >300
mg, will allow for detailed biological analysis of 3 as well
as analogues. Moreover, extensive conformational analyses23
are currently underway in our laboratories and will be
reported in due course.
Acknowledgment. R.K. thanks the University of Notre
Dame for financial support through the Reilly Fellowship.
T.R.G. thanks the University of Notre Dame for financial
support through the College of Science Summer Under-
graduate Research Fellowship (SURF) Program.
Supporting Information Available: Full experimental
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Taylor, R. E.; Zajicek, J. J. Org. Chem. 1999, 64, 7224–7228.
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