Concise synthesis of reduced propionates by stereoselective reductions combined with the Kobayashi reaction

Article abstract of DOI:10.1021/ol401406m

A concise and straightforward synthesis of 2,4,6-trimethyloctanoates was established by using the sequence of the vinylogous Mukaiyama aldol reaction and regio- and stereoselective reduction reactions. All isomers were obtained selectively in a few steps. The short step synthesis of septoriamycin A, an antimalarial and antileishmanial agent, has been achieved by this methodology.

Full text of DOI:10.1021/ol401406m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Concise Synthesis of Reduced Propionates
by Stereoselective Reductions Combined
with the Kobayashi Reaction
Tatsuya Nakamura, Mio Harachi, Takaaki Kano, Yuki Mukaeda, and Seijiro Hosokawa*
Department of Applied Chemistry, Faculty of Advanced Science and Engineering,
Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
seijiro@waseda.jp
Received May 18, 2013
ABSTRACT
A concise and straightforward synthesis of 2,4,6-trimethyloctanoates was established by using the sequence of the vinylogous Mukaiyama aldol
reaction and regio- and stereoselective reduction reactions. All isomers were obtained selectively in a few steps. The short step synthesis of
septoriamycin A, an antimalarial and antileishmanial agent, has been achieved by this methodology.
Reduced polypropionates are frequently seen in natural
products. A variety of synthetic methods have been devel-
oped to achieve the structures.1 Some of them include
Scheme 1. Synthetic Plan to Reduced Propionates Using the
Kobayashi Reaction
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in one pot by transition metal catalysts.3 The methods
to realize the short step synthesis of the reduced polypro-
pionates should be powerful tools to obtain bioactive
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10.1021/ol401406m
XXXX American Chemical Society

compounds. In the search for efficient routes to the poly-
propionates, we have developed the vinylogous Mukaiyama
aldol reactions using the chiral dienol ether 14 (the
Kobayashi reaction, Scheme 1) and applied it to the
syntheses of natural products.5,6 Since the vinylogous
Mukaiyama aldol reaction gave the polypropionate skele-
ton 3 directly, the sequential regio- and stereoselective
reductions of olefins would provide an efficient method
to synthesize reduced polypropionate 4 (Scheme 1). This
method is also applicable to the synthesis of deoxypropio-
nates because we have already succeeded in deoxygenation
at the C5 position in the total synthesis of lagunamycin.
Herein, we present the concise and stereochemically flex-
ible synthesis of 2,4,6-trimethyloctanoates.
tiglic aldehyde 5 to give adduct 6 as a single isomer,
which was determined by the absolute configuration by
X-ray crystallography of TBS ether 7 (Scheme 2).5c,g The
ORTEP drawing in Figure 17 shows that the TBS group
covers the one face of the olefins. Thus, hydrogenation of
compound 7 would proceed from the face opposite to
the TBS group to give 4,6-anti product 8 (Scheme 3). On
the other hand, a cationic catalyst might promote hydro-
genation directed by the hydroxyl group of the adduct 6,8
which would produce 4,6-syn product 9 having another
stereochemistry.
Scheme 2. Synthesis of the TBS Ether 5 in the Total Synthesis of
Actinopyrone A
In the course of the total synthesis of actinopyrone A, we
performed the vinylogous Mukaiyama aldol reaction with
(3) For the synthesis of deoxypropionates using the stereoselective
hydrogenation, see: (a) Evans, D. A.; Morrissey, M. M.; Dow, R. L.
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Pischl, M. C.; Pfaltz, A.; Schneider, C. J. Org. Chem. 2012, 77, 1477–
1488. (f) Diez, P. S.; Micalizio, G. C. Angew. Chem. 2012, 124, 5242–
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Nakazaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 13604–13605. (b) Mukaeda, Y.; Kato, T.; Hosokawa, S. Org. Lett.
2012, 14, 5298–5301. (c) Tsukada, H.; Mukaeda, Y.; Hosokawa, S. Org.
Lett. 2013, 15, 678–681. For other syn selective Kobayashi reactions,
see: (d) Shinoyama, M.; Shirokawa, S.; Nakazaki, A.; Kobayashi, S.
Org. Lett. 2009, 11, 1277–1280. (e) Wang, L.; Gong, J.; Deng, L.; Xiang,
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Z. Org. Lett. 2011, 13, 74–77. (g) Symkenberg, G.; Kalesse, M. Org. Lett.
2012, 14, 1608–1611.
(5) (a) Hosokawa, S.; Ogura, T.; Togashi, H.; Tatsuta, K. Tetrahe-
dron Lett. 2005, 46, 333–337. (b) Tatsuta, K.; Hosokawa, S. Chem. Rev.
2005, 105, 4707–4729. (c) Hosokawa, S.; Yokota, K.; Imamura, K.;
Suzuki, Y.; Kawarasaki, M.; Tatsuta, K. Tetrahedron Lett. 2006, 47,
5415–5418. (d) Hosokawa, S.; Kuroda, S.; Imamura, K.; Tatsuta, K.
Tetrahedron Lett. 2006, 47, 6183–6186. (e) Nakamura, T.; Shirokawa,
S.; Hosokawa, S.; Nakazaki, A.; Kobayashi, S. Org. Lett. 2006, 8, 677–
679. (f) Shirokawa, S.; Shinoyama, M.; Ooi, I.; Hosokawa, S.; Nakazaki,
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Yokota, K.; Imamura, K.; Suzuki, Y.; Kawarasaki, M.; Tatsuta, K.
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Figure 1. ORTEP drawing of the TBS ether 7.
Scheme 3. Suggested Stereochemical Courses toward 8 and 9
(6) Application to the natural product synthesis by other groups: (a)
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(7) Crystallographic data (excluding structure factor(s) for the struc-
tures of TBS ether 7) have been deposited with the Cambridge Crystal-
lographic Data Center as supplementary publication number CCDC
602830. Copies of the data can be obtained, free of charge, on applica-
tion to CCDC, 12 Union Road, Cambridge, CB2 1EZ, U.K. [fax:
þ44(0)-1223-336033 or E-mail: deposit@ccdc.cam.ac.uk].
According to the hypothesis, we achieved the stereose-
lective synthesis of 2,4,6-trimethyloctanoates (Scheme 4).
(8) Hydrogenation with the directing group: (a) Evans, D. A.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 4. Stereoselective Synthesis of 2,4,6-Trimethyloctanoates
Compound ent-6, the product of the vinylogous Mukaiyama
aldol reaction using dienolate 1 and tiglic aldehyde 5, was
submitted to hydrogenation using the SchrockꢀOsborn
catalyst to give ent-9 selectively. After protection of the
hydroxyl group as methoxymethyl ether, Birch reduction
afforded the 2,4,6-syn compound 10 in high yield and
stereoselectivity. On the other hand, ent-9 was submitted
to hydrogenation using palladium on alumina, which
proceeded in quantitative yield in a ratio of 1:6.7. The
major product was 2,4-anti-4,6-syn product 11, which was
isolated by column chromatography on silica gel in 87%
yield. The stereoselectivity of these reductions is explained
by using the models in Figure 2. In the Birch reduction, the
intermediate enolate should be A including chelation of the
alkali ion, of which the isopropyl group interfered with the
protonation from the upper face to give all syn product 10.
On the other hand, in the major conformation of ent-9, the
carbonyl groups of the oxazolidone and imide would direct
the opposite sides due to the dipole moment, which would
make the isopropyl group of the chiral auxiliary covering
the lower face of the double bond as B. Thus, the catalyst
would approach from the opposite face of the isopropyl
group to give 2,4-anti product 11 as a major product.
Next, TBS ether ent-7 was submitted to hydrogenation
with a platinum catalyst, which proceeded regio- and stereo-
selectively to give 4,6-anti product ent-8 as expected. Un-
saturated imide ent-8 was submitted to Birch reduction to
give 2,4-syn product 12. The best result was obtained in the
presence of bis(methoxyethyl)amine to give 12 in 71%
isolated yield. Finally, hydrogenation of ent-8 proceeded
to give reduced products in a ratio of 1:5.2, from which
2,4,6-anti product 13 was isolated in 81% yield. Therefore,
all stereoisomers of 2,4,6-trimethyloctanoate were obtained
stereoselectively in a short sequence consisting of the
Kobayashi reaction and regio- and stereoselective reductions.
Figure 2. Proposed intermediate of the Birch reduction (A) and
the conformation of the R,β-unsaturated imide moiety (B).
Upon establishing efficient methodology to construct
2,4,6-trimethyloctanoates, we applied it to the natural
product synthesis (Scheme 5). Septoriamycin A has been
isolated from the culture broth of plant pathogen Septoria
pistaciarum as an antiplasmodial agent by Nanayakkara’s
group in 2010.9 Septoriamycin A was also reported to have
potent antileishmanial activity in 2012.10 Herein, we pre-
sent the first and efficient synthesis of septoriamycin A. As
shown in Scheme 5, ent-9 was directly reduced by the Birch
reduction, which was followed by lactonization under
the acidic conditions to give δ-lactone 14 in good yield.
Lactone 14 was obtained as crystals which allowed the
X-ray crystallography to determine the configuration.
DIBAL reduction afforded the corresponding lactol,
which was submitted to the Knoevenagel condensation
with pyridone 1611 in the presence of amine 15. The
Knoevenagel condensation was followed by oxa-Michael
addition in one pot, and this sequence directly gave
(9) Kumarihamy, M.; Fronczek, F. R.; Ferreira, D.; Jacob, M.;
Khan, S. I.; Nanayakkara, N. P. D. J. Nat. Prod. 2010, 73, 1250–1253.
(10) Kumarihamy, M.; Jacob, M.; Tekwani, B. L; Duke, S. O.;
Ferreira, D.; Nanayakkara, N. P. D. J. Nat. Prod. 2012, 75, 883–889.
(11) Sugawara, K.; Imanishi, Y.; Hashiyama, T. Heterocycles 2007,
71, 597–607.
Org. Lett., Vol. XX, No. XX, XXXX
C

sequence that includes the vinylogous Mukaiyama aldol
reaction and regio- and stereoselective reduction reactions.
All isomers were obtained selectively in a few steps. Allylic
olefin underwent catalytic hydrogenation in a stereoselec-
tive manner. Additionally, we achieved the synthesis of
septoriamycin A using this methodology with minimal
steps. The present method is effective to synthesize poly-
propionates. Natural product syntheses using this metho-
dology are in progress in our laboratory.
Scheme 5. Synthesis of Septoriamycin A
Acknowledgment. Authors are grateful for financial
support from Grants for Excellent Graduate Schools for
‘Practical Chemical Wisdom’, Waseda University, and
Grant-in-Aid for Scientific Research B (#22350045) from
The Ministry of Education, Culture, Sports, Science and
Technology (MEXT). This research was also supported by
the Supporting Strategic Research Platform for Fusion
Biotechnology based on Biology, Chemistry, and Infor-
matics Project to Form the Strategic Research Platforms
for Private University, and a Matching Fund Subsidy from
MEXT, Japan.
septoriamycin A as a major compound of the separable
mixture of C2 epimers in a ratio of 8:1. The synthetic
septoriamycin A was identical in all respects with the
natural product including the optical rotation (synthetic:
Supporting Information Available. The experimental
procedure and physical properties of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
[R]D þ201° (c 0.55, MeOH), natural:9 [R]D þ201° (c 0.4,
MeOH)). Thus, septoriamycin A was synthesized in 35%
over six steps from silyl dienol ether 1.
29
26
In conclusion, we established the concise and straight-
forward synthesis of 2,4,6-trimethyloctanoates by a
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX