Total synthesis of phytophthora mating hormone α1

Article abstract of DOI:10.1021/ol102177j

Total synthesis of Phytophthora mating hormone α1 (1) has been demonstrated. The required stereochemistries (methyl) are achieved by applying CuI-(S)-Tol-BINAP-catalyzed conjugate addition of Grignard reagents to α,β-unsaturated esters.

Full text of DOI:10.1021/ol102177j

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5166-5169
Total Synthesis of Phytophthora Mating
Hormone r1
Shun-Yi Wang,† Ping Song,† Li-Yan Chan, and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371
teckpeng@ntu.edu.sg
Received September 11, 2010
ABSTRACT
Total synthesis of Phytophthora mating hormone r1 (1) has been demonstrated. The required stereochemistries (methyl) are achieved by
applying CuI-(S)-Tol-BINAP-catalyzed conjugate addition of Grignard reagents to r,ꢀ-unsaturated esters.
Phytophthora are mostly water molds that can extensively
destroy important agricultures and cause high economical
loss. Therefore, they are often considered as one of the most
threatened phytopathogens in the world.1 This can be seen
from the Irish potato famine arising from phytopathogens
that caused potato diseases, known as late blight, in the mid
1840s.2 Interestingly, hormone R1 (1) (Figure 1) is found to
be a universal mating hormone as it induces oospore
formation not only in the A1 mating type of P. nicotianae
but also in A2 mating types of P. capsici, P. cambiVora,
and P. infestans.3 The isolation of hormone R1 was made
possible from P. nicotianae by Ojika’s group,3 which has
attracted tremendous interest among chemists.4 Qin and co-
workers first confirmed its absolute configuration and
reported the total synthesis of 1.5 Almost at the same time,
Feringa and co-workers have reported the synthesis of its
Figure 1. Structures of Phytophthora mating hormone R1 1, its
hemiacetal 1′, enantiomer 2, and diastereomer 3.
† S.-Y. Wang and P. Song have made equal contributions to this paper.
(1) Andrivon, D. Plant Pathol. 1996, 45, 1027–1035.
(2) Fry, W. E.; Goodwin, S. B. Bioscience 1997, 47, 363–371.
(3) Qi, J.; Asano, T.; Jinno, M.; Matsui, K.; Atsumi, K.; Sakagami, Y.;
Ojika, M. Science 2005, 309, 1828–1828.
(4) For synthesis and biological activities of the stereoisomeric mixture
of 1, see: (a) Yajima, A.; Kawanishi, N.; Qi, J.; Asano, T.; Sakagami, Y.;
Nukada, T.; Yabuta, G. Tetrahedron Lett. 2007, 48, 4601–4603. (b) Ojika,
M.; Qi, J.; Kito, Y.; Sakagami, Y. Tetrahedron: Asymmetry 2007, 18, 1763–
1765. (c) Ojika, M.; Qi, J.; Kito, Y.; Sakagami, Y. Tetrahedron: Asymmetry
2007, 18, 2497–2497. (d) Bajpai, R.; Yang, F.; Curran, D. P. Tetrahedron
Lett. 2007, 48, 7965–7968.
enantiomer (2) and diastereomer (3) and evaluated their
biological activities, independently.6 Due to its fascinating
hormone structure and biological activities, our group has
been interested in the total synthesis of (3R,7R,11R,15R)-
hormone R1 (1).
10.1021/ol102177j  2010 American Chemical Society
Published on Web 10/25/2010

Recently, our group has developed a highly enantioselec-
tive method using CuI-Tol-BINAP-catalyzed conjugate ad-
dition of Grignard reagents to R,ꢀ-unsaturated esters to afford
the desired ꢀ-methyl-substituted methyl ester with excellent
enantioselectivity (Scheme 1).7,8 In this report, application
The total synthesis of hormone R1 (1) started from 1,4-
conjugate addition (CA) of MeMgBr to R,ꢀ-unsaturated ester
9 catalyzed by CuI-(S)-Tol-BINAP (Scheme 3). The desired
Scheme 3. Synthesis of 4
Scheme 1
.
General Strategy to the Synthesis of Chiral ꢀ-Methyl
Esters
of this method to the synthesis of (3R,7R,11R,15R)-hormone
R1 (1) will be expounded.
The key steps of our total synthesis of hormone R1 (1)
involve the assembly of the two fragments 4 and 5 by cross-
metathesis reaction (Scheme 2).9 The fragment 4, in turn,
Scheme 2. Retrosynthetic Analysis of 1
ester 10 was obtained in 63% yield with 92% ee. A simple
DIBAL-H reduction furnished the primary alcohol 11, which
was then protected with TBDPS to yield 12. TBS was
selectively deprotected, and the resulting primary alcohol 13
was allowed to react with Dess-Martin reagent to afford
the aldehyde intermediate. Freshly prepared but-3-enylmag-
nesium bromide was injected smoothly to the aldehyde
leading to a mixture of diastereomers 14 (dr ) 58:42).
Following cross-metathesis with methyl acrylate using
second-generation Hoveyda-Grubbs catalyst and TES pro-
tection, (E)-enoate 6 (E/Z > 99:1) was obtained in 60% yield
over two steps. Methyl ester 15 was obtained via a similar
asymmetric conjugate addition of MeMgBr catalyzed by (S)-
Tol-BINAP.10 A further DIBAL-H reduction, followed by
can be obtained by two iterative CuI-(S)-Tol-BINAP-
catalyzed conjugate additions of MeMgBr to 9. The fragment
5 can be generated via cross-metathesis reaction of 7 and 8.
8 also can be obtained from the CuI-(S)-Tol-BINAP-
catalyzed conjugate addition of MeMgBr to 9.
(5) Yajima, A.; Qin, Y.; Zhou, X.; Kawanishi, N.; Xiao, X.; Wang, J.;
Zhang, D.; Wu, Y.; Nukada, T.; Yabuta, G.; Qi, J.; Asano, T.; Sakagami,
Y. Nat. Chem. Biol. 2008, 4, 235–237
.
(6) Harutyunyan, S. R.; Zhao, Z.; den Hartog, T.; Bouwmeester, K.;
Minnaard, A. J.; Feringa, B. L. Proc. Natl. Acad. Sci. U.S.A. 2008, 105,
8507–8512
.
(7) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. J. Am. Chem. Soc. 2007, 129, 276–
277
.
Org. Lett., Vol. 12, No. 22, 2010
5167

oxidation using Dess-Martin reagent, and Wittig olefination
afforded the terminal olefin 4 in 60% yields over three steps.
Scheme 5. Synthesis of 5
Scheme 4. Synthesis of 7
deprotected and subjected to oxidation with Dess-Martin
reagent, followed by Wittig olefination, leading to the
terminal olefin 5 in 64% yield over three steps (Scheme 5).
Ensuing cross-metathesis of the two fragments 4 and 5
catalyzed by second-generation Hoveyda-Grubbs catalyst,
hydrogenation over Pd/C, selective deprotection of TES, and
Dess-Martin oxidation, 26 was obtained in 40% yield over
four steps (Scheme 6). Finally, TBDPS deprotection using
TBAF yields the desired (3R,7R,11R,15R)-hormone R1 (1)
in 90% yield.14
As shown in Scheme 4, our synthesis of the fragment 7
utilizes an L-proline-catalyzed aldol reaction of commercially
available 17 and 18 to give anti-diol 19 with very high
enantioselectivity and moderate yield.11 After protection of
diol, tertiary 21 was obtained with 82% de by the reaction
of ketone 20 with vinyl magnesium bromide.12 After Bn
protection, acetal deprotection, periodate cleavage, NaBH4
reduction, and subsequent submittal to benzyl protection
reaction, 24 was formed (68%, from 21). The desired
precursor 7 was obtained in 79% yield by deprotection of
24 using DDQ.12
Scheme 6. Total Synthesis of 1
The synthesis of precursor 8, as shown in Scheme 5, was
achieved from 11 by Dess-Martin oxidation followed by
Wittig olefination in 72% yield. By means of cross metathesis
between 7and 8 using second-generation Hoveyda-Grubbs-2
catalyst,9d 23 was generated predominately in the (E)-
configuration in 62% yield as shown in Scheme 5.13
Hydrogenation of (E)-olefin 25 over Pd/C catalyst afforded
the corresponding primary alcohol, which was then protected
with TBDPS to give 24. Next, the Bz group was selectively
(8) (a) Wang, S.-Y.; Lum, T.-K.; Ji, S.-J.; Loh, T.-P. AdV. Synth. Catal.
2008, 350, 673–677. (b) Lum, T.-K.; Wang, S.-Y.; Loh, T.-P. Org. Lett.
2008, 10, 761–764.
(9) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168–8179. (b) Hoye, T. R.; Zhao, H. Org.
Lett. 1999, 1, 1123–1125. (c) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.;
Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–11370. (d) Kanada,
R. M.; Itoh, D.; Nagai, M.; Niijima, J.; Asai, N.; Mizui, Y.; Abe, S.; Kotake,
Y. Angew. Chem., Int. Ed. 2007, 46, 4350–4355.
(10) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386–7387.
(11) (a) Wang, S.-Y.; Chin, Y.-J.; Loh, T.-P. Synthesis 2009, 3557–
3564. (b) Chin, Y.-J.; Wang, S.-Y.; Loh, T.-P. Org. Lett. 2009, 11, 3674–
3676.
(12) See Supporting Information. The absolute stereochemistry of 21
was determined by comparison with our previous results (ref 11).
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Org. Lett., Vol. 12, No. 22, 2010

Inconclusion,wedescribedthetotalsynthesisof(3R,7R,11R,15R)-
hormone R1 (1) using the asymmetric conjugate addition
(CA) of MeMgBr, and cross-metathesis R1 (1) was con-
structed using the asymmetric conjugate addition (CA) of
the simple Grignard reagents, of which three stereogenic
centers were controlled using only one chiral ligand (S)-Tol-
BINAP. This method could be applied to the synthesis of
all the stereoisomers of hormone R1 (1) as well as other
natural products with stereogenic centers bearing methyl
groups.
Acknowledgment. We gratefully acknowledge the Nan-
yang Technological University, Ministry of Education and
Biomedical Research Council (A*STAR grant M47110006),
for the funding of this research.
(13) The cross metathesis reaction of 8 with other functionalized tertiary
alcohols such as 7a-7c or 22 under the same conditions affords the
corresponded products in much lower yields (< 10%).
Supporting Information Available: Additional experi-
mental procedures, all chromatograms, and spectral data for
reaction products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) It was known that there existed an equilibrium between hormone
R1 (1) and its hemiacetal 1′.5,6
OL102177J
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