Synthetic studies toward pectenotoxin 2. Part I. Stereocontrolled access to the C10-C22 fragment

Article abstract of DOI:10.1021/ol8015868

(Chemical Equation Presented) A highly stereocontrolled and efficient synthesis for a fully functionalized C₁₀-C₂₂ fragment of pectenotoxin 2 Is described using a convergent sequence involving a stereoselective methylation of β-hydroxyketone as a key step.

Full text of DOI:10.1021/ol8015868

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4179-4182
Synthetic Studies Toward Pectenotoxin
2. Part I. Stereocontrolled Access to the
C10-C22 Fragment
Jatta E. Aho,‡ Elina Saloma¨ki,‡ Kari Rissanen,†,§ and Petri M. Pihko*,§
Department of Chemistry, Helsinki UniVersity of Technology, POB 6100, FI-02015
TKK, Finland, and Department of Chemistry, UniVersity of JyVa¨skyla¨, POB 35,
FI-40014 UniVersity of JyVa¨skyla¨, Finland
petri.pihko@jyu.fi
Received July 12, 2008
ABSTRACT
A highly stereocontrolled and efficient synthesis for a fully functionalized C10-C22 fragment of pectenotoxin 2 is described using a convergent
sequence involving a stereoselective methylation of ꢀ-hydroxyketone as a key step.
In 1985, the Yasumoto group reported the isolation and
characterization of a family of polyether macrolactones, the
pectenotoxins (PTXs).1 The pectenotoxin family has since
grown to comprise over 20 structurally related compounds.2
Originally isolated from scallops (Patinopecten yessoensis),1
the actual producers of PTXs are the Dinophysis dinoflagel-
lates, found in coastal areas worldwide.3 PTXs are cytotoxic
compounds that interact with the Actin cytoskeleton.4 The
scarcity of the compounds has hampered further studies into
their biological activity and their roles in the marine
ecosystems, and as such, access to synthetic PTXs would
be immensely helpful.
PTX4 and PTX8 are the only members of the PTX family
that have been produced synthetically.5 The most toxic PTX2
† X-ray crystallography.
(5) For total synthesis of PTX4 and PTX8, see: (a) Evans, D. A.;
Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4569–
4573. (b) Evans, D. A.; Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew.
Chem., Int. Ed. 2002, 41, 4573–4576. For other synthetic approaches, see:
(c) Amano, S.; Fujiwara, K.; Murai, A. Synlett 1997, 1300–1302. (d)
Awakura, D.; Fujiwara, K.; Murai, A. Synlett 2000, 1733–1736. (e)
Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949–1952. (f) Paquette,
L. A.; Peng, X.; Bondar, D. Org. Lett. 2002, 4, 937–940. (g) Peng, X.;
Bondar, D.; Paquette, L. A. Tetrahedron 2004, 60, 9589–9598. (h) Bondar,
D.; Liu, J.; Mu¨ller, T.; Paquette, L. A. Org. Lett. 2005, 7, 1813–1816. (i)
Halim, R.; Brimble, M. A.; Merten, J. Org. Lett. 2005, 7, 2659–2662. (j)
Fujiwara, K.; Kobayashi, M.; Yamamoto, F.; Aki, Y.; Kawamura, M.;
Awakura, D.; Amano, S.; Okano, A.; Murai, A.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2005, 46, 5067–5069. (k) Halim, R.; Brimble, M. A.;
Merten, J. Org. Biomol. Chem. 2006, 4, 1387–1399. (l) Fujiwara, K.; Aki,
Y.; Yamamoto, F.; Kawamura, M.; Kobayashi, M.; Okano, A.; Awakura,
D.; Shiga, S.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2007,
48, 4523–4527. (m) Kolakowski, R. V.; Williams, L. J. Tetrahedron Lett.
2007, 48, 4761–4764. (n) O’Connor, P. D.; Knight, C. K.; Friedrich, D.;
Peng, X.; Paquette, L. A. J. Org. Chem. 2007, 72, 1747–1754. (o) Vellucci,
D.; Rychnovsky, S. D. Org. Lett. 2007, 9, 711–714. (p) Lotesta, S. D.;
Hou, Y.; Williams, L. J. Org. Lett. 2007, 9, 869–872.
‡ Helsinki University of Technology.
§ University of Jyva¨skyla¨.
(1) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.; Matsumoto, G. K.;
Clardy, J. Tetrahedron 1985, 41, 1019–1025.
(2) (a) Sasaki, K.; Wright, J. L. C.; Yasumoto, T. J. Org. Chem. 1998,
63, 2475–2480. (b) Daiguji, M.; Satake, M.; James, K. J.; Bishop, A.;
Mackenzie, L.; Naoki, H.; Yasumoto, T. Chem. Lett. 1998, 7, 653–654. (c)
Wilkins, A. L.; Rehmann, N.; Torgersen, T. R.; Keogh, M.; Petersen, D.;
Hess, P.; Rise, F.; Miles, C. O. J. Agric. Food. Chem. 2006, 54, 5672–
5678. (d) Miles, C. O.; Wilkins, A. L.; Hawkes, A. D.; Jensen, D. J.;
Selwood, A. I.; Beuzenberg, V.; MacKenzie, A. L.; Cooney, J. M.; Holland,
P. T. Toxicon 2006, 48, 152–159, and refs therein.
(3) For selected examples, see: (a) Japan: see ref 1, 2a,b. (b) Korea:
Jung, J. H.; Sim, C. J.; Lee, C.-O. J. Nat. Prod. 1995, 58, 1722–1726. (c)
New Zealand and Norway: see ref 2d. (d) Ireland: see ref 2c. (e) Finland:
Kuuppo, P.; Uronen, P.; Petermann, A.; Tamminen, T.; Grane´li, E. Limnol.
Oceanogr. 2006, 51, 2300–2307.
(4) (a) Spector, I.; Braet, F.; Schochet, N. R.; Bubb, M. R. Microscop.
Res. Technol. 1999, 47, 18–37. (b) Leira, F.; Cabadon, A. G.; Vieytes, M. R.;
Roman, Y.; Alfonso, A.; Botana, L. M.; Yasumoto, T.; Malaguti, C.; Rossini,
G. P. Biochem. Pharmacol. 2002, 63, 1979–1988.
10.1021/ol8015868 CCC: $40.75
Published on Web 09/03/2008
2008 American Chemical Society

has not yet yielded to synthetic efforts, presumably because
both PTX2 and PTX1 include a relatively labile nonanomeric
spiroketal that readily isomerizes under acidic conditions to
more stable isomers. We have already reported the synthesis
of the nonanomeric spiroketal unit via kinetic spiroketaliza-
tion.6 More recently, the Rychnovsky group has also
synthesized the nonanomeric spiroketal of PTX2 using a
reductive cyclization approach.5o
Scheme 1. Synthesis of the C10-C16 Fragment
A successful route to the most interesting PTX congeners,
PTX2 and PTX1, must therefore be compatible with the acid-
labile nonanomeric spiroketal unit. More specifically, the
presence of another ketal group, embedded in the DE ring
system in the PTXs, is a cause for concern. In this
communication, we present a highly stereocontrolled route
to the C10-C22 acyclic precursor. The following communica-
tion describes the synthesis of the CDE and the CDEF ring
systems of PTX2 and also addresses the issue of compat-
ibility of the ketal forming event with the nonanomeric
spiroketal unit.
Our approach for the synthesis of the C10-C22 fragment,
constituting the carbon chain of the CDE ring system, is
based on convergent addition of aldehyde 3 and ketone 4
(Figure 1). Among the possible strategies for the construction
(E)-isomer 6 in 92% yield (Scheme 1).8 Reduction with
DIBAL-H afforded allylic alcohol 7 which under Katsuki-
Sharpless asymmetric epoxidation conditions furnished
Scheme 2. Synthesis of Aldehyde 3
Figure 1. Retrosynthetic analysis of the C10-C22 fragment.
of the C18 quaternary center, a hydroxyl-directed methylation
of the C18 ketone with organometallic reagents was selected.
A key feature of this strategy was that after a mild ozonolytic
cleavage of the C21 masking olefin the ketalization to form
the DE ring would take place under very mild conditions,
without the need to unmask any protecting groups. Poten-
tially, these mild conditions would also tolerate the presence
of the nonanomeric AB spiroketal system in more advanced
intermediates. Although hydroxyl-directed alkylations have
rarely been used in total synthesis, the literature precedents
were nevertheless encouraging.7
epoxide 8 in 90% yield and 93% ee. The terminal olefin
was reacted with methylacrylate in the presence of Hoveyda-
Grubbs second-generation catalyst followed by TBS protec-
tion to afford ester 10 in 83% yield over two steps.
Asymmetric dihydroxylation with the Sharpless’ ligand
(DHQD)2PYR was used to introduce the remaining two
stereocenters, giving the desired diol 11 in excellent (95%)
yield and 9:1 diastereoselectivity.
The synthesis began with an addition of allylcopper reagent
to commercially available tetrolate 5 to provide the desired
(6) Pihko, P. M.; Aho, J. E. Org. Lett. 2004, 6, 3849–3852.
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Org. Lett., Vol. 10, No. 19, 2008

Exposure of the diol mixture to catalytic PPTS resulted
in cyclization to give the desired tetrahydrofuran ring 12
(Scheme 2). At this stage, the diastereomers could be easily
separated by chromatography to give crystalline 12 in 90%
yield as a single diastereomer. X-ray crystallographic analysis
confirmed the stereochemistry of the product (Scheme 2).
Finally, protection of the secondary hydroxyl groups, fol-
lowed by DIBAL-H reduction, furnished aldehyde 3 in 46%
overall yield for 9 steps.9
Several different reagents were explored for the methy-
lation of ꢀ-hydroxyketone 17 at C18. On the basis of the
precedent by Fujisawa,7a titanium reagents were considered
as prime candidates to achieve the desired anti selectivity
via internal delivery of the methyl group (Table 1).14
Pleasingly, our initial experiment at 0.25 mmol scale with
MeTi(OiPr)3 gave the desired anti diol product 210 in 8:1
diastereoselectivity. However, considerable difficulties were
encountered in reproducing this result. Experiments to screen
different conditions for this key transformation are sum-
marized in Table 1.15
The synthesis of the aldol partner 4 began with com-
mercially available methallyl dichloride 14, which was
selectively monoprotected as benzyl ether (Scheme 3). After
In comparison with methyltitanium reagents, Mg and Zn
reagents gave inferior selectivity (entries 2 and 3). Surpris-
16
ingly, predistilled MeTi(OiPr)3 turned out to be very
unreactive toward 17, even with 15 equiv of the reagent
(entry 4). Under comparable conditions, more Lewis acidic
reagents, MeTiCl3 or MeTi(OiPr)2Cl (entries 5 and 6), did
not help, and neither did the use of more reactive
Me2Ti(OiPr)2 or the less-hindered MeTi(OMe)3 (entries
Scheme 3. Synthesis of Ketone 4
17
7-9). Addition of excess Ti(OiPr)4 did not afford any
improvement in selectivity or reproducibility (entry 10).
Ultimately, the best reproducible selectivities (9:1) and yields
(91%) were obtained using an excess of the in situ prepared
MeTi(OiPr)3 at -78 °C followed by quick warming to 0 °C
(entry 11).
In summary, we have developed an efficient and highly
stereocontrolled synthesis for the C10-C22 fragment of PTX2
with the correct stereochemistry. The following communica-
(7) For additions of organometallic reagents to ꢀ-hydroxyketones, see:
(a) Ukaji, Y.; Kanda, H.; Yamamoto, K.; Fujisawa, T. Chem. Lett. 1990,
597–600. (b) Ruano, J. L. G.; Tito, A.; Culebras, R. Tetrahedron 1996, 52,
2177–2186.
conversion into bromide 15, monoalkylation of ethyl ac-
etoacetate afforded compound 16 in 62% yield. Finally, ester
hydrolysis followed by decarboxylation furnished ketone 4
in 92% yield.
The aldol addition of aldehyde 3 and ketone 4 proceeded
nicely to give a single anti product 17 in 82% yield (Scheme
4).10 The anti selectivity can be explained by a modified
(8) (a) Corey, E. J.; Kim, C. U.; Chen, R. H. K.; Takeda, M. J. Am.
Chem. Soc. 1972, 94, 4395–4396. (b) Lipshutz, B. H.; Ellsworth, E. L.;
Dimock, S. H.; Smith, R. A. J. J. Am. Chem. Soc. 1990, 112, 4404–4410.
(9) The entire synthetic sequence was successfully scaled up to ca. a
20 g scale.
(10) The stereochemistry of the aldol and the methyltitanation steps was
established by extensive NOE studies of the CDE and CDEF ring systems.
See the following paper in this issue: Helmboldt, H.; Aho, J. E.; Pihko,
P. M. Org. Lett. 2008, 10, 4183-4185.
(11) (a) Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem.
Soc. 1959, 11, 2–127. For excellent discussions and predictions in both
cyclic and acyclic systems, see: (b) Evans, D. A.; Cee, V. J.; Siska, S. J.
J. Am. Chem. Soc. 2006, 128, 9433–9441, and refs therein. The high level
of diastereoselection observed suggests that the R,ꢀ-syn relationship of the
oxygen substituents in 3 represents a stereochemically reinforcing case. For
a related highly selective aldol bond construction, see: (c) Anderson, O. P.;
Barrett, A. G. M.; Edmunds, J. J.; Hachiya, S.-I.; Hendrix, J. A.; Horita,
K.; Malecha, J. W.; Parkinson, C. J.; VanSickle, A. Can. J. Chem. 2001,
79, 1562–1592.
Scheme 4. Cornforth-Selective Aldol Union of 3 and 4
(12) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9,
2199–2204. (b) Che´rest, M.; Felkin, H. Tetrahedron Lett. 1968, 9, 2205–
2208. (c) Anh, N. T.; Eisenstein, O. NouV. J. Chim 1977, 1, 61–70. (d)
Anh, N. T. Top. Curr. Chem. 1980, 88, 145–162.
(13) See Supporting Information for further details.
(14) There are two possible modes to achieve 1,3-induction in hydroxyl-
directed additions: the nucleophile is delivered either externally (from an
external reagent) or internally (directed addition): (a) Evans, D. A.;
Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560–3578.
A chelation-controlled transition state model has also been suggested. (b)
Reetz, M. T.; Jung, A. J. Am. Chem. Soc. 1983, 105, 4833–4835. For a
review, see: (c) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191–1223.
(15) For further details, including screens for different solvents and
additives, see Supporting Information.
Cornforth11 transition state model, although the polar
Felkin-Ahn12 model also predicts the same stereochemical
outcome (Scheme 4). Similar selectivities, albeit with reduced
yields, were obtained by using a related enolsilane (TMS/
BF3·OEt2).13
(16) Reetz, M. T.; Westermann, J.; Steinbach, R.; Wenderoth, B.; Peter,
R.; Ostarek, R.; Maus, S. Chem. Ber. 1985, 118, 1421–1440.
(17) Excess Ti(OiPr)4 should facilitate the removal of the product from
the metal center and assist in the formation of an active complex: Wu,
K.-H.; Gau, H.-M. Organometallics 2004, 23, 580–588.
Org. Lett., Vol. 10, No. 19, 2008
4181

Table 1. anti-Selective Addition of Methyl Nucleophiles with Different Reagents
methylation
reagenta
temperature
time [min at
-78/0 °C ]
entry
equiv
solvent
[°C]
drb
conversionb
1
2
3
4
5
6
7
8
MeTi(OiPr)3
MeLi/ZnBr2
MeMgBr
MeTi(OiPr)3
MeTiCl3
MeTi(OiPr)2Cl
Me2Ti(OiPr)2
Me2Ti(OMe)2
MeTi(OMe)3
MeTi(OiPr)3
MeTi(OiPr)3
5
4
1
Et2O
CH2Cl2
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
-78 to0
-78
-78
10/10
240
15
8/1 - 2/3
3/2
2/1
4/1
1/1
3/1
6/1
2/1
4/1
100
100
100
80
c
15
15
15
15
15
15
15
15
-78 to0
-78 to0
-78 to0
-78 to0
-78 to0
-78 to0
-78 to0
-78to0
10/10
10/10
10/10
10/10
10/10
10/10
10/10
10/10
20
100
100
100
100
100
100
9
10
11
d
4/1
9/1
a Reagents were prepered in situ. b Determined by 1H NMR from the crude reaction mixture. c MeTi(OiPr)3 was distilled prior to use. d Excess Ti(OiPr)4
(15 equiv) was used. e See ref 14a.
tion describes the use of this strategy for the assembly of
the CDE and the CDEF ring systems.
Reetz (MPI fu¨r Kohlenforschung, Mu¨lheim) for discussions
on titanium chemistry and Prof. G. Vassilikogiannakis and
Dr. T. Montagnon (both at University of Crete, Heraklion)
for their help with COST STSM of JEA.
Acknowledgment. We thank Helsinki University of
Technology (Outstanding Junior Research Group Award),
TEKES, and the Academy of Finland for support. JEA is
the recipient of an Undergraduate Stipend from the Onni
Rannikko Fund of the Finnish Foundation for Economic and
Technology Sciences (KAUTE), Tekniikan Edista¨missa¨a¨tio¨
(TES), Kordelin Foundation, COST D28, and Association
of Finnish Chemical Societies. We also thank Prof. M. T.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra
(PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
OL8015868
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Org. Lett., Vol. 10, No. 19, 2008