Mukaiyama-Michael reactions with acrolein and methacrolein: A catalytic enantioselective synthesis of the C17-C28 fragment of pectenotoxins

Article abstract of DOI:10.1021/ol203486p

Enantioselective iminium-catalyzed reactions with acrolein and methacrolein are rare. A catalytic enantioselective Mukaiyama-Michael reaction that readily accepts acrolein or methacrolein as substrates, affording the products in good yields and 91-97% ee, is presented. As an application of the methodology, an enantioselective route to the key C17-C28 segment of the pectenotoxin using the Mukaiyama-Michael reaction as the key step is described.

Full text of DOI:10.1021/ol203486p

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1086–1089
MukaiyamaÀMichael Reactions with
Acrolein and Methacrolein: A Catalytic
Enantioselective Synthesis of the
C17ÀC28 Fragment of Pectenotoxins
Eeva K. Kemppainen, Gokarneswar Sahoo, Arto Valkonen,† and Petri M. Pihko*
€
Department of Chemistry and Nanoscience Center, University of Jyvaskyla, POB 35,
€
FIN-40014 JYU, Finland
Petri.Pihko@jyu.fi
Received December 30, 2011
ABSTRACT
Enantioselective iminium-catalyzed reactions with acrolein and methacrolein are rare. A catalytic enantioselective MukaiyamaÀMichael reaction
that readily accepts acrolein or methacrolein as substrates, affording the products in good yields and 91À97% ee, is presented. As an application
of the methodology, an enantioselective route to the key C17ÀC28 segment of the pectenotoxin using the MukaiyamaÀMichael reaction as the key
step is described.
The 1985 report by Yasumoto describing the isolation
and characterization of a novel marine natural product,
pectenotoxin-1 (PTX1),1 has been followed up by studies
characterizing more than 20 structurally related pecteno-
toxins.2 Originally isolated from scallops (Patinopecten
yessoensis),1 the actual producers of PTXs are the Dino-
physis dinoflagellates, found in coastal areas worldwide.3
PTXs are cytotoxic compounds that interact with the actin
cytoskeleton;4 however, for further studies into their
biological activity, only microgram amounts of the com-
pounds are commercially available.
PTX4 and PTX8 are the only members of the PTX
family that have been produced synthetically.5 We have
previously recorded efforts6 aimed at the synthesis of the
most active congener, PTX2, which bears as an additional
synthetic challenge a thermodynamically unstable “non-
anomeric” spiroketal.7
Our previous work has identified the building blocks
such as 2 and 3 as well as a methyl ketone such as 4
(Scheme 1, a) as versatile building blocks that allow the
construction of the sensitive AB ring spiroketal in a com-
plex setting.6d However, the model methyl ketones used in
our previous studies6b,d could not realistically be projected
to be carried forward in the actual total synthesis route.
The installment of the solitary methyl-bearing stereocenter
at C27 and the development of a highly stereocontrolled
route to the F ring stereochemistry were viewed as key
† X-ray crystallography.
(1) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.; Matsumoto,
G. K.; Clardy, J. Tetrahedron 1985, 41, 1019.
(2) (a) Sasaki, K.; Wright, J. L. C.; Yasumoto, T. J. Org. Chem. 1998,
63, 2475. (b) Daiguji, M.; Satake, M.; James, K. J.; Bishop, A.;
Mackenzie, L.; Naoki, H.; Yasumoto, T. Chem. Lett. 1998, 7, 653. (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.
(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 and references therein.
r
10.1021/ol203486p
Published on Web 02/01/2012
2012 American Chemical Society

objectives. Herein we present an expedient synthesis of the
C17ÀC28 fragment of the PTXs using an enantioselective
iminium-catalyzed MukaiyamaÀMichael reaction with
methacrolein.
when the product is cyclized during the reaction. The
process required herein is an example of a noncyclizing
iminium-catalyzed process. With acrolein, this process
effectively generates new stereogenicity solely at the nu-
cleophile (Scheme 1 b).
In principle, an iminium-catalyzed MukaiyamaÀMichael
reaction should allow the construction of a building
block such as 5. However, although a wide range
of iminium-catalyzed enantioselective reactions are
known,8 in the vast majority of cases the reactions have
been restricted to β-substituted enals,9 and methacrolein
is typically an unreactive substrate.10 Indeed, only very
recently have iminium-catalyzed reactions been expanded
to R-substituted enals,11 but to the best of our knowledge,
high enantioselectivities have only been obtained in
iminium-catalyzed reactions with β-unsubstituted aldehydes
Scheme 1. (a) Partial Retrosynthetic Analysis of Pectenotoxin-2
and (b) a Missing Link in Enantioselective Catalysis
(3) For selected examples, see: (a) Japan: see refs 1, 2a, 2b. (b) Korea:
Jung, J. H.; Sim, C. J.; Lee, C.-O. J. Nat. Prod. 1995, 58, 1722. (c) New
Zealand and Norway: see ref 2d. (d) Ireland: see ref 2c. (e) Finland:
ꢀ
Kuuppo, P.; Uronen, P.; Petermann, A.; Tamminen, T.; Graneli, E.
Limnol. Oceanogr. 2006, 51, 2300.
(4) (a) Spector, I.; Braet, F.; Schochet, N. R.; Bubb, M. R. Microscop.
Res. Technol. 1999, 47, 18. (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.
(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.
(b) Evans, D. A.; Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew.
Chem., Int. Ed. 2002, 41, 4573. For a review covering all synthetic studies
towards the pectenotoxins until year 2006, see: (c) Halim, R.; Brimble,
M. A. Org. Biomol. Chem. 2006, 4, 4048–4058. For synthetic studies
published after this review, see: (d) 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. (e)
Kolakowski, R. V.; Williams, L. J. Tetrahedron Lett. 2007, 48, 4761. (f)
O’Connor, P. D.; Knight, C. K.; Friedrich, D.; Peng, X.; Paquette, L. A.
J. Org. Chem. 2007, 72, 1747. (o) Vellucci, D.; Rychnovsky, S. D. Org.
Lett. 2007, 9, 711. (g) Lotesta, S. D.; Hou, Y.; Williams, L. J. Org. Lett.
2007, 9, 869. (h) Heapy, A. M.; Wagner, T. W.; Brimble, M. A. Synlett
2007, 2359. (i) Carley, S.; Brimble, M. A. Org. Lett. 2009, 11, 563. (j)
Heapy, A. M.; Brimble, M. A. Tetrahedron 2010, 66, 5424. (k)
Joyasawal, S.; Lotesta, S. D.; Akhmedov, N. G.; Williams, L. J. Org.
Lett. 2010, 12, 988. (l) Vassilikogiannakis, G.; Alexopoulou, I.; Tofi, M.;
Montagnon, T. Chem. Commun. 2011, 47, 259. (m) Canterbury, D. P.;
Micalizio, G. C. Org. Lett. 2011, 13, 2384. (n) Fujiwara, K.; Suzuki, Y.;
Koseki, N.; Murata, S.-i.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron
Lett. 2011, 52, 5589.
We reasoned that although it might be difficult to
control the stereochemistry at C27 of PTX via protona-
tion, the MukaiyamaÀMichael reaction between a silylo-
xyfuran such as 17 and methacrolein 7 should irreversibly
set the stereochemistry at the C25 tertiary center. For
this reaction, we screened a number of known iminium/
enamine type catalysts and some of their more bulky
variants (Table 1).12
(6) (a) Pihko, P. M.; Aho, J. E. Org. Lett. 2004, 6, 3849. (b)
Helmboldt, H.; Aho, J. E.; Pihko, P. M. Org. Lett. 2008, 10, 4183. (c)
€
Aho, J. E.; Salomaki, E.; Rissanen, K.; Pihko, P. M. Org. Lett. 2008, 10,
4179. (d) Aho, J. E.; Piisola, A.; Krishnan, K. S.; Pihko, P. M. Eur. J.
Although most secondary amine catalysts screened were
able to promote the desired reaction, the enantioselectiv-
ities were typically only modest (entries 1À8). However,
we were delighted to find that the C2-symmetric 2,5-
diphenylpyrrolidine 16 catalyst13 afforded the products 18a
and 18b with excellent enantiopurity.14 Furthermore, the
aldehyde diastereomers 18a and 18b were readily separable
by chromatography, and the undesired isomer 18a could
Org. Chem. 2011, 1682.
(7) Aho, J. E; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406.
€
(8) Erkkila, A.; Majander., I.; Pihko, P. M. Chem. Rev. 2007, 107,
5416.
(9) For the pioneering study of MukaiyamaÀMichael reactions with
β-substituted enals, see: Brown, S. P.; Goodwin, N. C.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2003, 125, 1192.
(10) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
3240.
(11) Examples of iminium-catalyzed reactions with R-substituted
acroleins where the products are cyclized during the reaction: Epoxida-
€
tions: (a) Erkkila, A.; Pihko, P. M.; Clarke, M.-R. Adv. Synth. Catal.
(12) (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212. (b) Marigo, M.; Wabnitz, T. C.;
Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44,
794. (c) Groselj, U.; Seebach, D.; Badine, D. M.; Schweizer, W. B.;
Beck, A. K. Helv. Chim. Acta 2009, 92, 1225.
(13) (a) Higashiyama, K.; Inoue, H; Takahashi, H. Tetrahedron 1994,
53, 1083. (b) For the use of 16 in enamine catalysis, see: Halland, N.;
Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J. Am.
Chem. Soc. 2004, 126, 4790.
(14) The identification of the diastereomers 18a and 18b is based
on NMR analysis of their cyclic derivatives (see the Supporting
Information).
2007, 349, 802. (b) Lifchits, O.; Reisinger, C. M.; List, B. J. Am. Chem.
Soc. 2010, 132, 10227. Cyclopropanations: (c) Terrasson, V.; van der
Lee, A.; de Figueiredo, R. M.; Campagne, J. M. Chem.;Eur. J. 2010,
7875. Cycloadditions: (d) Ishihara, K.; Nakano, K. J. Am. Chem. Soc.
2005, 127, 10504. (e) Sakakura, A.; Suzuki, K.; Nakano, K.; Ishihara, K.
Org. Lett. 2006, 8, 2229. (f) Sakakura, A.; Suzuki, K.; Ishihara, K. Adv.
Synth. Catal. 2006, 348, 2457. (g) Ishihara, K.; Nakano, K.; Akakura,
M. Org. Lett. 2008, 10, 2893. (h) Ishihara, K.; Nakano, K. J. Am. Chem.
Soc. 2007, 129, 8930. (i) Kano, T.; Tanaka, Y.; Osawa, K.; Yurino, T.;
Maruoka, K. Chem. Commun. 2009, 15, 1956. (j) Aziridinations: Deiana,
L.; Dziedzic, P.; Zhao, G.-L.; Vesely, J.; Ibrahem, I.; Rios, R.; Sun, J.;
ꢁ
ꢀ
Cordova, A. Chem.;Eur. J. 2011, 17, 7904.
Org. Lett., Vol. 14, No. 4, 2012
1087

Table 1. Catalyst Screen for the MukaiyamaÀMichael Reaction
Scheme 2. Synthesis of the C17ÀC28 Fragment
duration
(h)
conv
(%)a
eeb (%)
(18a/b)
drb
entry
cat.
(18a/b)
1
2
3
4
5
6
7
8
9
8
23
1.5
24
24
10
24
20
24
8
33
<5/<5
37/23
20/28
54/53
61/63
29/64
59/59
30/37
À93/À93c
55/45
64/36
65/35
57/43
56/44
59/41
56/44
58/42
56/44
9
>95
65
10
11
12
13
14
15
16
94
>95
>95
>95
76
>95
a Determined by GC, monitoring the conversion of silyloxyfuran 17
to 18a/18b during the reaction. b Determined by GC (Supelco Astec
CHIRALDEX B-DM column). c Designates the opposite enantiomers
of 18a/18b.
easily be recycled to the thermodynamic 56:44 mixture
upon brief exposure to DBU.15
The new methodology was immediately put to use in the
synthesis of the F ring fragment 28 of PTXs (Scheme 2). The
aldehyde product 18a was subjected to Luche reduction,18
hydrogenation, and benzyl protection, affording the saturated
lactone 23. Reduction with DIBAL-H, followed by Grignard
reaction with vinylmagnesium bromide, gave the allylic alco-
hol 24, setting the stage for a JohnsonÀClaisen rearrangement
cleanly affording the olefin 25 as an essentially pure E isomer.
The Sharpless asymmetric dihydroxylation with AD-mix
R ((DHQ)2PHAL ligand) led to the formation of the diol
26 in 9:1 diastereoselectivity. The secondary hydroxyl group
was then selectively mesylated. Cyclization of the F ring was
readily achieved under the conditions reported by Wu and
Sun19 to yield compound 27. Finally, formation of the
Weinreb amide, Ley oxidation, Wittig reaction, and the
Weinreb ketone synthesis afforded the ketone 28.
A preliminary study of the reaction scope revealed
that the scope is not limited to the combination of
methacrolein and furan 17. Acrolein 6 was also a viable
electrophile for this reaction, and silyloxyfurans bear-
ing a hydrogen in the R-position could also be used as
nucleophiles, affording the products in good enantio-
selectivities (Table 2).16,17
(15) See the Supporting Information for details.
(16) The enantioselectivities were slightly improved when the reac-
tion was carried out at 0 °C instead of rt (see Table 2).
(17) Although several different possible approaches for the union of
17 and 7 consistent with the observed stereochemistry can be presented,
the uniformly high enantioselectivities in Table 2 suggest that the
stereochemistry-determining step is similar in all cases. A possible
rationalization for the observed stereochemistry is depicted below.
The stereochemistry of the adducts 18a and 18b was
assignedby the X-ray analysis of 29, derivedfrom alternate
asymmetric dihydroxylation of olefin 25 with AD-mix
(18) The use of Luche conditions was found to prevent a competing
Michael addition of the alcohol to the unsaturated lactone. Although the
use of Luche conditions results in a slower rate of reduction (as a result of
a competing reversible acetal formation reaction), the chemoselectivity
of the reduction is improved compared to standard NaBH4 reduction.
(19) Wu, Y.; Sun, Y.-P. Org. Lett. 2006, 8, 2831.
(20) Other MukaiyamaÀMichael products have been assigned by
analogy.
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Org. Lett., Vol. 14, No. 4, 2012

Table 2. Enantioselective MukaiyamaÀMichael Reactions with Acrolein or Methacrolein
entry
R1
R2
R3
yield (%)a
ee (%)c
drd
1
2
3
4
5
Me
Me
H
Me
H
TBS
TBS
TBS
TBS
TIPS
90b (80)a
65a
97/96e
94/93e
93
55/45
50/50
À
Me
H
65a
H
56a
71a
91
À
H
H
92
À
a Isolated yield of the derived alcohol, after Luche reduction of the aldehyde group. b Isolated yield of the aldehyde. c Determined by GC (Supelco
Astec CHIRALDEX B-DM column). d Determined by GC. e ee reported for both 18a/18b and 19a/19b.
as well as expansion of the scope of catalyst 16 are
underway.
Scheme 3. Proof of Stereochemistry
Acknowledgment. Financial support from the Academy
of Finland (Grant Nos. 217221, 217224, and 139046), and
€
€
Department of Chemistry, University of Jyvaskyla (JYU)
are gratefully acknowledged. A.V. thanks Academy Prof.
Kari Rissanen (JYU, AF-212588) for financial support.
€
We thank Ms. Mirja Lahtipera (JYU) and Mr. Esa
Haapaniemi (JYU) for assistance with the HRMS and
ꢀ
NMR analyses, and Dr. Imre Papai (Hungarian Academy
of Sciences) for highly valuable discussions throughout
this project.
Note Added after ASAP Publication. In the version posted
ASAP on February 1, 2012, the descriptors R and β for AD-
mix R and AD-mix β were interchanged. This error is now
corrected in the paper and in the Supporting Information.
The corrected version reposted on February 6, 2012.
β ((DHQD)2PHAL ligand) (Scheme 3).20 Furthermore,
diagnostic NOE enhancements were observed for com-
pound 27 (Scheme 2), consistent with the depicted stereo-
chemistry.
In summary, we have identified an enantioselective
iminium-catalyzed Mukaiyama-Michael-type reaction with
acrolein and methacrolein that could be readily applied
to the synthesis of the key C17ÀC28 segment of the pecte-
notoxins. Efforts toward the total synthesis of pectenotoxin-2
Supporting Information Available. Full experimental
details, characterization data, X-ray characterization data,
and copies of 1H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
1089