Total synthesis of (+)-phomopsolide C by ring-size selective ring-closing metathesis/cross-metathesis

Article abstract of DOI:10.1021/ol052332k

(Chemical Equation Presented) A new strategy for the synthesis of chiral 6-substituted 5,6-dihydro-5-hydroxypyran-2-ones by ring-size selective ring-closing metathesis (RCM) and its application to a short total synthesis of (+)-phomopsolide C are describe

Full text of DOI:10.1021/ol052332k

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5513-5516
Total Synthesis of (+)-Phomopsolide C
by Ring-Size Selective Ring-Closing
Metathesis/Cross-Metathesis
Simon Michaelis and Siegfried Blechert*
Institut fu¨r Chemie, Technische UniVersita¨t Berlin,
Strasse des 17.Juni 135, 10623 Berlin, Germany
blechert@chem.tu-berlin.de
Received September 26, 2005
ABSTRACT
A new strategy for the synthesis of chiral 6-substituted 5,6-dihydro-5-hydroxypyran-2-ones by ring-size selective ring-closing metathesis (RCM)
and its application to a short total synthesis of (
chemoselective cross-metathesis (CM) and RCM.
+)-phomopsolide C are described. The key bond-forming reactions in this approach are a
Dutch elm disease can destroy a healthy 100-year-old
American elm in as little as two weeks.1 The fungus
responsible for this disease would be quite innocuous, save
for its association with the elm bark beetle (Scolytid beetle).
The prevention of Dutch elm disease by chemical deterrence
of this beetle is therefore of current interest.
The phomopsolides2 are a new class of natural products
possessing an effective antiboring/antifeeding activity against
the elm bark beetle (Figure 1). Phomopsolide C is part of a
series of related 6-substituted 5,6-dihydro-5-hydroxypyran-
2-ones, which were first isolated from fungi found in the
bark of the Pacific yew in 1997 by Stierle.3 In addition to
phomopsolides, there exist other natural products possessing
a similarly substituted 5,6-dihydro-5-hydroxypyran-2-one
core, an example being (+)-diplopyrone (Figure 1).4
To date, however, only one synthesis of (+)-phomopsolide
C has been reported.5
Figure 1. 6-substituted 5,6-dihydro-5-hydroxypyran-2-ones.
CM and a ring-size selective RCM.6 Our approach is outlined
in Scheme 1. To allow for flexibility in our synthetic plan,
we envisaged two pathways to phomopsolide C. Pathway A
was based on a tandem RCM/CM of 3 and 4. Selectivity in
this conversion would require RCM to occur first, giving
exclusively the six-membered ring with only one pendant
double bond available for CM.
We describe herein the total synthesis of phomopsolide
C, the key steps of which involve a regio- and chemoselective
(1) Santamour, F. S.; Bentz, S. E. J. Arboricult. 1995, 21, 122.
(2) Grove, J. F. J. Chem. Soc., Perkin Trans. 1 1985, 865.
(3) Stierle, D. B.; Stierle, A. A.; Ganser B. J. Nat. Prod. 1997, 60, 1207.
(4) (a) Evidente, A.; Maddau, L.; Spanu, E.; Franceschini, A.; Lazzaroni,
S.; Motta, A. J. Nat. Prod. 2003, 66, 313. (b) Giorgio, E.; Maddau, L.;
Spanu, L.; Evidente, A.; Rosini, C. J. Org. Chem. 2005, 70, 7.
(5) O’Doherty, G. A.; Harris, J. M. Tetrahedron Lett. 2002, 43, 8195.
(6) For reviews, see: (a) Connon, S. J.; Blechert, S. Top. Organomet.
Chem. 2004, 11, 93. (b) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed.
2003, 42, 1900.
10.1021/ol052332k CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/04/2005

may or may not contain a substituent in the C8 position,
according to our different retrosynthetic pathways. Our
results are summarized in Table 1.
Scheme 1
Table 1. Ring-Size Selectivity of RCM
cat.
5 mol %
time
(h)
ring
size 8/9a
conva
(%)
entry R1
R2
R3
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
Mom
Mom
Mom
Mom
H
H
H
H
H
H
H
H
H
H
H
H
CORf
Ab
Bc
Cd
De
A
B
C
D
B
96
17
96
17
96
96
96
96
17
17
96
6
5
80
60
99
16
70
7
55
75
1/7
<1/>99
1/6.5
<1/>99
1/9
1/2.7
<5/>95
<5/>95
Me
Me
Me Mom
In pathway B, a regioselective CM provides an intermedi-
ate that can be converted to the 8-substituted RCM precursor
5 by deprotection and esterification. It was envisaged that
the selectivety in the CM of 6 and 4 could be controlled
either by chelating effects or by the steric hindrance of the
protecting group PG′.7 Following the synthesis of intermedi-
ate 2 by either pathway A or B, esterification and deprotec-
tion would then give phomopsolide C.
The main challenge in this strategy is controlling the ring-
size selectivity of RCM, because of the possibility of either
forming the desired six- or the undesired five-membered ring.
A number of examples where a six-membered ring has been
formed selectively are known, e.g., natural (5′-oxoheptene-
1′E,3′E-dienyl)-5,6-dihydro-2H-pyran-2-one,8 (+)-strictifo-
lione,9 and spicigerolide10 by using either the Grubbs catalyst
I or II. These examples have two important structural
differences to our precursor for RCM as given in pathway
A: (1) no substitution in the C5 position and (2) a substituent
in the C8 position (see Scheme 1). It has been demonstrated
in related systems having no substitution in the C8 position
that mixtures of five- and six-membered rings are obtained.11
RCM of precursors with a protected hydroxy group at the
C5 position and no substitution in postion C8 (e.g., (-)-
muricatacin12 and rollicosin13) result in the formation of the
five-membered ring exclusively when using Grubbs catalyst
II.
10
11
12
H
D
A-D
D
>95
<5
>99
H
H
>99/<1
1
a Estimated from H NMR of the crude reaction mixure. In each case,
the remainder was the starting material. b Grubbs I: PhCHdRuCl2(PCy3)2.
c Grubbs II: PhCHdRuCl2(PCy3)(IHMes). d Hoveyda: o-isopropoxy-
PhCHdRuCl2(PCy3). e See Scheme 2. f See 5 (Scheme 1)
In the case where R1 ) R2 ) R3 ) H (entries 1-4), the
first-generation Grubbs and Hoveyda catalysts gave exclu-
sively the five-membered ring, in agreement with previously
reported studies.12,13 Interestingly, though, the second-genera-
tion catalysts yielded appreciable amounts of 8. We hypoth-
esised that the double bond on which metathesis commenced
governed the size selectivity of the RCM. For this reason,
we investigated the use of the methoxymethylene protecting
group (Mom) in order to pre-coordinate the catalyst at OR2
(entries 5-8). We hoped that this would encourage reaction
at the neighboring alkene, favoring six-membered ring
formation. In most cases, the amount of 8 was increased
appreciably. This is the first time that formation of a six-
membered ring, for a system substituted at the C5 position
but with no substitution at the C8 position, has been
observed. We were also interested in the effect of incorporat-
ing an electron withdrawing enone at R3 (entry 12). Gratify-
ingly, it was found that metathesis with this substrate led
exclusively to the six-membered ring 8 in excellent yield.
We now had conditions for RCM that we hoped would
give us the core of phomopsolide C. Our model studies
indicated that the electron-withdrawing side chain of the
natural product precursor 5 would control the reaction
outcome, directing the metathesis to the sterically less
hindered, more electron rich double bond of the allylic
alcohol. This would give the six-membered ring 16 (Scheme
2).
Bearing these results in mind, we first investigated reaction
conditions for the exclusive formation of the six-membered
ring 8 when starting from a 5-substituted precursor 7 which
(7) BouzBouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 20, 3465.
(8) BouzBouz, S.; de Lamos, E.; Cossy, J.; Saez, J.; Franck, X.; Figadere,
B. Tetrahedron Lett. 2004, 45, 2615.
(9) BouzBouz, S.; Cossy, J. Org. Lett. 2003, 5, 1995.
(10) Falomir, E.; Murga, J.; Ruiz, P.; Carda, M.; Marco, J. A. J. Org.
Chem. 2003, 68, 5672.
(11) Virolleaud, M.-A.; Piva, O. Synlett. 2004, 12, 2087.
(12) Quinn, K. J.; Isaacs, A. K.; Arvary R. A. Org. Lett. 2004, 23, 4143.
(13) Quinn, K. J.; Isaacs, A. K.; DeChristopher, B. A.; Szklarz, S. C.;
Arvary R. A. Org. Lett. 2005, 7, 1243.
The precursor for CM 12 was available in a few steps
starting from commercial diethyl L-tartrate 10. After protec-
5514
Org. Lett., Vol. 7, No. 24, 2005

Scheme 2
tion of the 1,2-diol in 10 as a cyclic ketal,14 subsequent ester
chemoselectivity may result from steric hindrance by the
bulky trityl group.6 CM with an ester substituent as a
chelating controlling feature instead of the trityl group led
to a 4:1 mixture in favor of the desired regioisomer.
reduction and double Wittig olefination15 were conducted
in one pot due to the instability of the intermediate aldehyde.
Deprotection16 leading to the C2-symmetric dienediol and
monotritylation of one of the hydroxy groups afforded diene
12 in 43% yield over five steps.
Acrylation and trityl removal of 14 gave the precursor for
RCM 15. Migration of the acryl group during the deprotec-
tion under either too acidic or basic conditions (i.e., during
the workup process) was suppressed by using a saturated
HCl solution in CHCl3, and the deprotection succeeded under
these conditions in good yield.
Starting with methyl S-(-)-lactate 11, the coupling partner
1317 was synthesized by protection of the hydroxy functional
group,17 followed by Grignard reaction18 of the Weinreb
amide19 in 68% overall yield.
The ruthenium-catalyzed cross metathesis of 12 and 13
occurred with exclusive formation of the desired regioisomer
using catalyst D (Scheme 2), giving 14 in 73% yield,
exclusively as the trans isomer, as well as the dimer of 12
in 24% yield. Recycling of the dimer by CM with 13 gave
additional cross product 14, increasing the yield to 89%. The
Using the optimized reaction conditions, RCM of 15
proceeded in complete conversion, although the isolated yield
of 16 was 68%, suggesting partial decomposition during
chromatography. Esterification with tiglic acid and subse-
quent deprotection then yielded phomopsolide C, the spec-
troscopic data of which was identical (IR, 1H and 13C NMR)
to the literature.5 Thus, a concise synthesis of (+)-phomop-
solide C has been achieved in good overall yield.
(14) Onoda, T.; Shirai, J.; Kawai, N.; Iwasaki, S. Tetrahedron 1996, 52,
13327.
(15) Knief, A.; Dumont, W.; Pasau, P.; Lecomte, P. Tetrahedron 1989,
45, 3039.
(16) Green, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999.
(17) Stammen, B.; Berlage, U.; Kindermann, R.; Kaiser, M.; Gu¨nther,
B.; Sheldrick, W.; Wenzel, W.; Roth, W. J. Org. Chem. 1992, 57, 6566.
(18) Hiyamizu, H.; Ooi, H.; Inomoto, Y.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. Org. Lett. 2001, 3, 473.
This synthesis demonstrates the power of CM and RCM
in skeletal C-C bond-forming. Selectivity in CM was ob-
tained by tuning the relative steric environments of the double
bonds. Furthermore, we have shown that we are able to con-
trol the size selectivity of the RCM by altering the electronic
environment of double bonds. We are currently working on
(19) Sakai, A.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 2000, 41, 6859.
Org. Lett., Vol. 7, No. 24, 2005
5515

establishing control of the ring size in RCM with R3 ) H.
We are also synthesising further natural products with related
structures to expand the scope of this methodology.
Supporting Information Available: Full experimen-
tal details and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.
org.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for supporting this work.
OL052332K
5516
Org. Lett., Vol. 7, No. 24, 2005