Synthesis of the c1-c20 and c15-c27 segments of aplyronine a

Article abstract of DOI:10.1021/ol2024746

The synthesis of C1-C20 and C15-C27 segments of Aplyronine A is described. Oxidative cleavage of cyclic vinyl sulfones has been used to prepare key fragments of Aplyronine A. Key precursors are united by Horner-Wadsworth-Emmons and Julia-Kociensky olefination for the respective elaboration of the C1-C20 and C15-C27 segments.

Full text of DOI:10.1021/ol2024746

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6342–6345
Synthesis of the C1ÀC20 and C15ÀC27
Segments of Aplyronine A
Wan Pyo Hong, Mohammad N. Noshi, Ahmad El-Awa, and Philip L. Fuchs*
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
pfuchs@purdue.edu
Received September 15, 2011
ABSTRACT
The synthesis of C1ÀC20 and C15ÀC27 segments of Aplyronine A is described. Oxidative cleavage of cyclic vinyl sulfones has been used to
prepare key fragments of Aplyronine A. Key precursors are united by HornerÀWadsworthÀEmmons and JuliaÀKociensky olefination for the
respective elaboration of the C1ÀC20 and C15ÀC27 segments.
Aplyronine macrolides were first isolated in 1993 from
the sea hare Aplysia kurodai collected on the Japanese
coast.1 Among them, aplyronine A (Figure 1) exhibited
potent cytotoxicity against HeLa S3 cells with an IC50 of
0.48 ng/mL and impressive antitumor activities against
various cell lines.2 Although aplyronine inhibits polymer-
ization of actin3 and the X-ray cocrystal structure of
aplyronine A•actin is known, micromolar concentrations
are necessary to depolymerize actin. Nanomolar concen-
trations show in vivo anticancer activity, suggesting that
Figure 1. Aplyronine A: mixture of four side chain diastereomers.
aplyronine A exerts its antineoplastic activity via a yet-
to-be-deteremined mechanism.
To date, only one total synthesis of aplyronine A has been
reported by Yamada et al.4 Recently, Kigoshi reported the
synthesis of the C1ÀC19 segment, featuring an asymmetric
NozakiÀHiyamaÀKishi (NHK) coupling reaction.5 Apart
from these two syntheses, there have been several reports
directed toward aplyronine A.6
Aplyronine A is an attractive synthetic target bearing three
stereotetrads (dipropionates): (C7ÀC10) is anti, syn, anti
while (C23ÀC26 and C29ÀC32) bear anti, anti, syn stereo-
chemistries. Recently, all eight possible diastereomeric cyclic
stereotetrads were prepared from enantiopure cycloheptadie-
nyl sulfones via a diastereoselective epoxidation/methylation
sequence.7 Specifically, it was demonstrated that oxidative
cleavage of cyclic stereoenriched vinyl sulfones afforded the
requisite termini-differentiated fragments, viz C5ÀC11,
C15ÀC20, C21ÀC27, and C28ÀC34 of aplyronine A.8
(1) Syntheses via Vinyl Sulfones 101. Chiral Carbon Catalog 23. For
review on aplyronine natural products, see: Yamada, K.; Ojika, M.;
Kigoshi, H.; Suenaga, K. Nat. Prod. Rep 2009, 26, 27.
(2) (a) Yamada, K.; Ojika, M.; Ishigaki, T.; Yoshida, Y.; Ekimoto,
H.; Arakawa, M. J. Am. Chem. Soc. 1993, 115, 11020. (b) Ojika, M.;
Kigoshi, H.; Ishigaki, T.; Tsukada, I.; Tsuboi, T.; Ogawa, T.; Yamada,
K. J. Am. Chem. Soc. 1994, 116, 7441.
(3) Hirata, K.; Muraoka, S.; Suenaga, K.; Kuroda, T.; Kato, K.;
Tanaka, H.; Yamamoto, M.; Takata, M.; Yamada, K.; Kigoshi, H.
J. Mol. Biol. 2006, 356, 945.
(4) Kigoshi, H.; Ojika, M.; Ishigaki, T.; Suenaga, K.; Mutou, T.;
Sakakura, A.; Ogawa, T.; Yamada, K. J. Am. Chem. Soc. 1994, 116, 7443.
(5) Kobayashi, K.; Fujii, Y.; Hayakawa, I.; Kigoshi, H. Org. Lett.
2011, 13, 900.
(6) (a) Paterson, I.; Cowden, C. J.; Woodrow, M. D. Tetrahedron
Lett. 1998, 39, 6037. (b) Paterson, I.; Woodrow, M. D.; Cowden, C. J.
Tetrahedron Lett. 1998, 39, 6041. (c) Paterson, I.; Blakey, S. B.; Cowden,
C. J. Tetrahedron Lett. 2002, 43, 6005. (d) Calter, M. A.; Guo, X.
Tetrahedron 2002, 58, 7093. (e) Calter, M. A.; Zhou, J. Tetrahedron Lett.
2004, 45, 4847. (f) Marshall, J. A.; Johns, B. A. J. Org. Chem. 2000, 65,
1501.
r
10.1021/ol2024746
Published on Web 11/22/2011
2011 American Chemical Society

Herein we communicate the advancement of two stereo-
tetrads to an acyclic intermediate and its union with other
segments to yield the C1ÀC20 and C15ÀC27 segments of
aplyronine A.
increase of the concentration of the actual oxidant [HOCl]
was required. After extensive experimentation at different
pH ranges,11 pH 9.0À9.512 was found to be optimal for
clean conversion to 18 in 2 h.
Scheme 2. Large Scale Synthesis of 11 and 913
Scheme 1. Retrosynthetic Analysis
As outlined in Scheme 1, the synthetic approach is based
on the disconnection of macrocyclic lactone 2 and side
chain 3. Macrocyclic core 2 is accessed from building
blocks 4, 5, 6, 7, and 8. Segments 4, 7, and 8 are derived
by vinyl sulfone strategies creating stereodefined polypro-
pionate fragments. Side chain 3 was projected to be con-
structed from 11-enantiomer.
To obtain stereotetrads 9 and 11 reproducibly, a strate-
gic protecting group switch from ÀOTBS to ÀOTES was
crucial to avoid problems in regioselective deprotection of
the final bis-OTBS stereotetrad.9 Epoxide 12 was con-
verted to vinylsulfide 14 on a 100 g scale. Improved
procedures based on our previous report7a afforded die-
nylsulfone 17 on a 60 g scale. In contrast to our previous
methodology,itwasobservedthatearlyÀOTES protection
(14 to 15) performed better for the elimination to dienyl-
sulfide 16 employing AlMe3. Jacobsen epoxidation of 17
proved challenging due to rapid onset followed by stalling
after 72 h. Adding more catalyst and/or oxidant resulted
only in product decomposition.10 It was envisaged that an
Due to the sensitivity of 18 to silica, removal of the
Mn-salen without chromatography was crucial. Conveni-
ently, adding hexanes (300% v/v) quantitatively precipi-
tated the Mn-salen, cleanly affording 18 after pad
filtration.14 After treating 18 with 3,5-dimethylpyrazole
(DMP), silica filtration of adduct 19 was a “must” due to
the sensitivity of the next reaction. Syn-directed methyla-
tion to 20 was not trivial.15 The best procedure employed
(7) (a) Noshi, M. N.; El-Awa, A.; Fuchs, P. L. J. Org. Chem. 2008, 73,
3274. (b) El-Awa, A.; Noshi, M. N.; Mollat du Jourdin, X.; Fuchs, P. L.
Chem. Rev. 2009, 109, 2315. (c) El-Awa, A.; Mollat du Jourdin, X.;
Fuchs, P. L. J. Am. Chem. Soc. 2007, 129, 9086. (d)Hong, W. P.; El-Awa,
A.; Fuchs, P. L. J. Am. Chem. Soc. 2009, 131, 9150.
(11) For buffer preparation and pH calculation, see Table 1 in
Supporting Information.
(12) At this pH range, no chlorinated products were observed.
(13) See detailed experiments and extended discussion in the Sup-
porting Information.
(8) (a) El-Awa, A.; Fuchs, P. L. Org. Lett. 2006, 8, 2905. (b) Noshi,
M. N.; El-Awa, A.; Torres, E.; Fuchs, P. L. J. Am. Chem. Soc. 2007, 129,
11242.
(9) For such deprotection, a delicate balance must be achieved
between TBAF and MeOH. While excess TBAF resulted in elimination
and lack of regioselectivity, excess MeOH completely deactivated
TBAF. Thus it was not a “robust” process for scale-up purposes.
(10) For similar observations, see: Zhang, W.; Jacobsen, E. N. J. Org.
Chem. 1991, 56, 2296.
(14) See Figure 3 in Supporting Information.
(15) Adding MeMgBr at 23À35 °C resulted in partial conversion and
stalling. Adding more MeMgBr resulted in over methylation of 20 rather
than 19. See optimization Table 2 in Supporting Information.
Org. Lett., Vol. 13, No. 24, 2011
6343

treating 19 at 50À60 °C with MeMgBr at rates of 1À2 mL/
min, effecting clean conversion to 19. Treatment with
TBSOTf, followed by chemoselective deprotection of
ÀOTES, afforded stereotetrad 11 on scales up to 4.5 g
(Scheme 2A). Similarly, alcohol 21 was converted to
stereotetrad 9 on scales up to 8 g (Scheme 2B).
aldehyde-ester 34 was quite troublesome since it was
exceptionally prone to air oxidation giving the carboxylic
acid. Fortunately, it was found that aldehyde-PMB ether 7
is inert to air oxidation. The aldehyde 7 was obtained in
four steps from vinyl sulfone 10 (Schemes 4 and 7).
Fragment 4, possessing the stereotetrad (C7ÀC10), can
be obtainedfrom cyclic vinyl sulfone 9. Similarly, fragment
8 with C23ÀC26 can be prepared from cyclic vinyl sulfone
11. Following our previous report, fragment 10 was chosen
to introduce the C15ÀC20 array 7. Notably, β-ketopho-
sphonate 6 was adopted for joining iodide 4 and aldehyde 7
as developed by Paterson and Calter.6b,6e
Scheme 4. Synthesis of C15ÀC20 Terminii-Differentiated Seg-
mentsa
The synthesis starts with vinyl sulfone 9 which was
converted to lactone 30 upon ozonolysis followed by
reductive workup (Scheme 3). After protection of the
primary alcohol in 30 as the silyl ether, the lactone was
converted to acyclic dimethylamide16 31 using a protocol
developed for making Weinreb amides.17 Interestingly,
synthesis of the specific methoxymethyl amide failed under
these conditions. Super-Hydride (LiBEt3H) reduction of
the dimethylamide yielded the primary alcohol18 in vir-
tually quantitative yield, which was subsequently converted
to iodide 4 (71% yield over three steps).
a Ozonolysis was performed in CH2Cl2/MeOH (4:1).
Scheme 3. Synthesis of Iodide 4
The synthesis of C21ÀC27 intermediate 8 commences
with ozonolysis20 of 11 followed by reduction to afford
lactone-alcohol 35 (Scheme 5). DCAD Mitsunobu
coupling21 of 35 followed by lactone opening generated
Weinrebamide 37, which was transformed to alcohol 38via
the intermediate aldehyde. Initial attempts to protect the
alcohol with a benzyl group were unsuccessful due to the
TBS migration and TES deprotection. To circumvent these
difficulties, TIPS protection was adopted. Final m-CPBA
oxidation delivered the C21ÀC27 fragment sulfone 8.
With 8 and 32 in hand, JuliaÀKocienski olefination
(Scheme 6) was investigated to construct the C15ÀC27
subunit of aplyronine A. Low E/Z ratios were obtained,
using Li or KMHDS in THF (entries 1 and 3). Changing
the solvent to DME22 gave a better ratio (E/Z = 5.5:1)
(entry 2). Much to our delight, application of Jacobsen’s
solvent combination (DMF/HMPA)23 gave the best selec-
tivity (E/Z = 12:1) in a yield of 60%, 83% based upon
recovered starting material. Subsequent DIBAL reduction
afforded aldehyde 40 in 92% yield.
The synthesis of the C15ÀC20 target starts with known
vinyl sulfone 10 that underwent ozonolysis to give acyclic
ester-aldehyde 32 as the JuliaÀKocienski olefination sub-
strate (Schemes 4 and 6).8b
In 2007, our group reported a variant of the Taber
reaction,19 in which cyclic vinyl sulfone 10 was converted
to transposed vinyl phosphate 33 featuring a formal end-
for-end REDOX transposition. Treatment of 10 with the
sodium salt of diethylphosphite gave vinyl phosphonate 33
in 93% yield. Oxidative cleavage of 33 provided aldehyde-
ester 34 desired for the HornerÀWadsworthÀEmmons
(HWE) coupling step (Schemes 4 and 7). Handling
With compounds 4, 5, 6, and 7 in hand, attention was
directed to the C1ÀC20 segment synthesis (Scheme 7). The
(20) Ozonolysis was performed successfully in CH2Cl2 and in acet-
one, based on “the added aldehyde effect”. For ozonolysis in acetone,
see: (a) Su, J.; Murray, R. W. J. Org. Chem. 1980, 45, 678. (b) Schiaffo,
C. E.; Dussault, P. H. J. Org. Chem. 2008, 73, 4688. (c) For stabilization
of carbonyl oxide with acetone, see Figure 4 in Supporting Information.
(21) Lipshutz, B. H.; Chung, D. W.; Rich, B.; Corral, R. Org. Lett.
2006, 8, 5069.
(16) Occasionally, quenching with aqueous NH4Cl resulted in some
global elimination. See Figure 5 in Supporting Information for sug-
gested mechanism and characterization.
(17) Levin, J. I.;Turos, E.;Weinreb, S. M. Synth. Commun. 1982, 12, 989.
(18) Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J. Org. Chem.
1980, 45, 1.
ꢀ
(22) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26.
(23) (a) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772.
(b) Smith, A. B.; Dong, S.; Brenneman, J. B.; Fox, R. J. J. Am. Chem.
Soc. 2009, 131, 12109.
(19) Taber, D. F.; Saleh, S. A. J. Org. Chem. 1981, 46, 4817.
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Org. Lett., Vol. 13, No. 24, 2011

dimethyl sulfate or methyl iodide giving 44a (78%) and 44b
(94%), respectively. Deprotection of the primary TBS
group in 44b using 10 mol % CSA gave 45 in 91% yield.
Scheme 5. Synthesis of C21ÀC27 Tetrazole Sulfone 8
Scheme 7. Synthesis of C1ÀC20 Carboxylic Acid 47
Scheme 6. JuliaÀKociensky Olefination of Fragment 8 and 32a
Application of Kigoshi’s oxidation of 45,28 followed by
R,β,γ,δ-unsaturated ester formation (LiHMDS29 and
(EtO)2P(O)CH2CHdCHCO2Et), led to the C1ÀC20 seg-
ment of aplyronine A as a 4E/4Z mixture (12:1). Finally,
completion of the C1ÀC20 acid 47 was achieved by LiOH
hydrolysis in 78% yield.
In conclusion, synthesis of the C1ÀC20 and C15ÀC27
segments of aplyronine A was accomplished via a con-
vergent strategy. The use of vinyl sulfone chemistry was
pivotal for the synthesis of three key precursors. The total
synthesis and biological activity of aplyronine A analogs
will be communicated in due course.
a Isolated yields (entries 1 and 3) were not calculated due to the low E/
Z selectivity. bDetermined by crude 1H NMR.
sodium/lithium dianion of β-ketophosphonate 6 reacted
smoothly with iodide 4 to give 41 in 86% yield. HWE
reaction with 34 was performed best using Myer’s
protocol24 affording enone 42a in 66% yield.25 When
barium hydroxide mediated HWE coupling6b was utilized
with 7, a similar yield (67%, 77% based upon recovered
starting material) was obtained providing enone 42b.
Chemo- and stereoselective reduction of enones 42a, 42b to
alcohols 43a, 43b respectively was achieved using the (R)-
MeCBS26 catalyst (43a; de = 96%). The absolute stereo-
chemistries of product 43a were determined by analysis of
the 1H NMR of their Mosher’s esters.27 Methylation of the
secondary alcohol was achieved using sodium hydride and
Acknowledgment. We thank Dr. Karl Wood and
Dr. Douglas Lantrip (Purdue University) for providing
MS and HPLC data.
Supporting Information Available. Spectroscopic (1H
NMR, 13C NMR, HRMS), analytical data, and experi-
menatal details. This material is available free of charge
via the Internet at http://pubs.acs.org.
(24) Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281.
(25) The (E) stereochemistry of the newly formed double bond was
confirmed by NOE difference spectroscopy, and the (Z) stereoisomer
was not observed in the crude mixture.
(26) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K.
J. Am. Chem. Soc. 1987, 109, 7925.
(27) See Supporting Information.
(28) Partial MTM elimination (enal formation) was observed with a
DessÀMartin periodinane (DMP)/10 equiv pyridine reaction.
(29) HWE reaction with LDA, employed by the Kigoshi group in
their approach to the C1ÀC19 segment of Aplyronine A, afforded
dienoate in 86% yield with 5% (4Z)-isomer; see ref 5.
Org. Lett., Vol. 13, No. 24, 2011
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