Total synthesis of the phytotoxic agent herbarumin II using butane diacetals of glycolic acid as building blocks

Article abstract of DOI:10.1055/s-2003-39892

The total synthesis of the phytotoxic agent herbarumin II has provided an ideal stage to exploit the utility of butane diacetal (BDA) desymmetrised glycolic acid as a primary building block.

Full text of DOI:10.1055/s-2003-39892

1
186
LETTER
Total Synthesis of the Phytotoxic Agent Herbarumin II Using Butane Diacetals
of Glycolic Acid as Building Blocks
T
E
otal
S
ynthesis
l
of
H
er
e
barumin II na Diez, Darren J. Dixon, Steven V. Ley,* Alessandra Polara, Felix Rodriguez
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 9 April 2003
ploit the use of both enantiomers of these glycolic acid
Abstract: The total synthesis of the phytotoxic agent herbarumin II
has provided an ideal stage to exploit the utility of butane diacetal
species, employing alkylation or aldol reactions to set up
the key coupling compounds required for the synthesis.5
b,c
(BDA) desymmetrised glycolic acid as a primary building block.
Key words: acetals, aldol, alkylation, asymmetric synthesis, natu-
ral products, metathesis
The quest for novel potential herbicidal agents led in the
year 2000 to the isolation of two new nonenolides, her-
barumin I (1) and II (2), from the culture of Phoma er-
Figure 1 Structures of herbarumin I (1) and herbarumin II (2).
1
barum fungus (Figure 1). These lactones showed high
levels of phytotoxic effect on seedling growth and proved
to be closely related to other known compounds such as
The synthetic plan for herbarumin II (2) (Scheme 1) relies
on the union of two fragments 3 and 4 in a convergent
fashion to give, after esterification, ring closing meta-
thesis and deprotection, the desired natural product. The
protected triol component 3 was expected to be derived by
a non-chelation controlled addition of a propyl-metal re-
agent to aldehyde 5, which, in turn, should be readily ob-
tained from an aldol reaction between (R,R)-glycolate 6b
2
3
pinolidoxin, lethaloxin. The typical structure of these
natural products is characterised by a ten-membered mac-
rolide core, a vicinal diol, a trans-substituted double bond
and an appended n-propyl unit. Owing to their activity as
potential new herbicides, these nonenolides have recently
4
become attractive synthetic targets. Here we report the
synthesis of herbarumin II since it provides an ideal plat-
form to demonstrate the utility of butane diacetal (BDA)
desymmetrised glycolic acid as a building block for the
stereoselective synthesis of functionalised a-hydroxyac-
6
and acrolein. Fragment 4 on the other hand should be
easily obtained by alkylation of the enantiomeric (S,S)-
glycolate 6a with iodide 7.7
5
ids and polyol motifs. In particular, our plan was to ex-
Scheme 1 Synthetic plan.
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1186,1188,ftx,en;D08703ST.pdf.
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Herbarumin II
1187
Accordingly, the aldol reaction between (R,R)-glycolate- give 11 in 56% yield. Deprotection of the acetal using
b and acrolein was performed in the usual way5 by TFA/H O in the normal fashion gave hydroxy acid 12 in
c
6
2
deprotonation of the glycolate in THF at –78 °C followed 87% yield and the following protection of the hydroxyl
by addition of the aldehyde to give alcohol 8 in 86% yield group as the TBS ether gave the desired fragment 4 in
8
and better than 96% de.
80% yield.
Deprotection of the butane diacetal using TMSCl in meth-
anol gave the corresponding anti-1,2-diol methyl ester in
7
2% yield. Protection of the hydroxyl groups as their TBS
ethers occurred in 96% yield to obtain 9. From here, the
desired aldehyde 10 was obtained in a two step procedure.
Thus, DIBAL reduction of the ester functionality in THF
at –30 °C gave the corresponding alcohol in 90% yield.
This alcohol was immediately oxidised to the aldehyde 10
using PCC in dichloromethane at room temperature
(
Scheme 2).
Scheme 3 Synthesis of fragment 4. a) LHMDS, THF, –78 °C, 20
min, 4-iodo-1-butene, –78° C to –20 °C, 20 h (56%); b) TFA/H O
2
(87%); c) TBSCl, Imidazole, DMF (80%).
The union of fragments 3 and 4 initially proved to be dif-
ficult and methods involving the use of coupling reagents
such as DCC and HATU gave the desired ester 16 but in
low yields and involved long reaction times. Nevertheless
the esterification step finally proved to be successful using
10
the Yamaguchi protocol, affording the coupled fragment
in good yield (Scheme 4).
Once obtained, the ester 16 was subjected to ring closing
metathesis reactions using different catalysts (Figure 2).
The results obtained were congruent with our predictions
based on semi-empirical calculations, which indicated
Scheme 2 Synthesis of fragment 3. a) LHMDS, THF, –78 °C, 20
min, acrolein, –78 °C, 1 h (86%); b) HCl, MeOH, r.t., 1 h (72%); c)
TBSCl, Imidazole, DMF, r.t., on (96%); d) DIBAL, CH Cl , –30 °C,
–1
that compound (E)-17 was ca. 2.5 Kcalmol more stable
that the corresponding (Z)-17 isomer.11 Therefore our
choice to protect with a TBS group was expected to lead
to the desired E-isomer.
2
2
1
2
h (90%); e) PCC, CH Cl , r.t., 1.5 h; f) n-PrMgCl, toluene, –78 °C,
h (dr >12:1, 68% over two step).
2 2
The only step remaining to obtain fragment 3 required a
non-chelation controlled addition of an appropriate pro-
pylmetal nucleophile to aldehyde 10. After several at-
tempts using different organometallic compounds (n-
PrLi, n-PrLi/CeCl , n-PrMgCl) under various reaction
3
conditions and alternative solvents (THF, diethyl ether,
toluene) it was found that the addition of n-PrMgCl in tol-
uene at –78 °C gave the best results. Under these condi-
tions the reaction proceeded with better than 12:1
Figure 2 Ring closing metathesis catalysts used.
12
diastereoselectivity ratio to give the alcohol 3 in 68% iso- Specifically, the use of catalyst 13 in boiling CH Cl af-
2
2
lated yield over the last two steps (Scheme 2). The relative forded the desired (E)-isomer as the major product but in
and absolute configuration of 3 was determined by exam- less that 50% yield after 48 h, while the exposure of diene
ining Mosher ester derivatives of related compounds.9
13
16 to the ‘second generation’ metathesis catalyst 14
gave rise to selective formation of the thermodynamically
more stable (E)-lactone 17 that was isolated in an excel-
Coupling partner 4 was obtained in just three steps from
the enantiomeric (S,S)-glycolate 6a (Scheme 3). The cor-
responding lithium enolate was obtained as before and
then was allowed to react with an excess of iodide 7 to
1
4
lent 85% yield. On the other hand catalyst 15 afforded a
:1 mixture of Z:E isomers, indicating competing kinetic
2
Synlett 2003, No. 8, 1186–1188 ISSN 1234-567-89 © Thieme Stuttgart · New York

1
188
E. Diez et al.
LETTER
(
(
3) Arone, A.; Assante, M.; Nasini, G.; Ragg, E. Gazz. Chim.
Ital. 1993, 123, 71.
4) For previous synthesis of herbarumin I and II: (a) Fürstner,
A.; Radkowski, K. Chem. Commun. 2001, 671.
(
b) Fürstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.;
Lehmann, C. W.; Mynott, R. J. Am. Chem. Soc. 2002, 124,
7061. (c) Sabino, A. A.; Pilli, R. Tetrahedron Lett. 2002, 43,
2819.
(5) (a) Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.;
Ley, S. V.; Priepke, H. W. M.; Reynolds, D. J. Chem. Rev.
2001, 101, 53. (b) Diez, E.; Dixon, D. J.; Ley, S. V. Angew.
Chem. Int. Ed. 2001, 40, 2906. (c) Dixon, D. J.; Ley, S. V.;
Polara, A.; Sheppard, T. S. Org. Lett. 2001, 3, 3749.
(d) Dixon, D. J.; Ley, S. V.; Rodriguez, F. Org. Lett. 2001,
3, 3753. (e) Dixon, D. J.; Ley, S. V.; Rodriguez, F. Angew.
Chem. Int. Ed. 2001, 40, 4763. (f) Ley, S. V.; Michel, P.
Synlett 2001, 1793. (g) Michel, P.; Ley, S. V. Angew. Chem.
Int. Ed. 2002, 41, 3898. (h) Dixon, D. J.; Guarna, A.; Ley, S.
Scheme 4 End game. a) Acid 4, NEt , 2,4,6-trichlorobenzoyl chlo-
3
V.; Polara, A.; Rodriguez, F. Synthesis 2002, 1973.
ride, DMAP, r.t., 16 h (78%); b) catalyst 16, CH Cl , reflux, 8 h
25
2
2
(
(
(
6) Data for (R,R): [a]D –211.5 (c 0.4, CHCl ); mp 40–41 °C in
3
(
85%); b) TBAF, THF, r.t., 1.5 h (quantitative).
agreement with the following reference: Michel, P.; Ley, S.
V. Synthesis 2003, in press.
2
5
7) Data for (S,S): [a]D +208.3 (c 1.2, CHCl ); mp 41–42 °C in
3
agreement with the following reference: Michel, P.; Ley, S.
control that allows the selective formation of the thermo-
dynamically less stable (Z)-isomer.
V. Synthesis 2003, in press.
8) Minor diastereomer was not detected by H NMR.
1
Finally treatment of 17 with tetrabutylammonium fluoride
in THF afforded herbarumin II 2 in quantitative yield and
(9) (a) Othani, I.; Kusumi, T.; Kashman, K.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092. (b) Kouda, K.; Ooi, T.;
Kusumi, T. Tetrahedron. Lett. 1999, 40, 3005.
10) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
11) Calculated from Macromodel’s version of MM2 forcefield,
see: Mohamadi, F.; Richards, N. G. J.; Guida, W. C.;
Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.;
Hendrickson, T.; Still, W. C. J. Comp. Chem. 1990, 11, 440.
12) (a) Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem.
Soc. 1993, 115, 9858. (b) Schwab, P.; France, M. B.; Ziller,
J. W.; Grubbs, R. H. Angew. Chem. Int. Ed. Engl. 1995, 34,
1
13
identical by H NMR (600 MHz), C NMR (100 MHz)
analysis and X-ray crystallography to the natural prod-
(
(
1
5
uct.
In summary we have demonstrated the power of using
both enantiomeric butane-diacetal glycolic acid building
blocks to set up all the stereogenic centres formed in the
polyol, phytotoxic agent herbarumin II. Clearly these
methods could be readily adapted to the synthesis of the
enantiomeric series and novel analogues.
(
2039. (c) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am.
Chem. Soc. 1996, 118, 100.
(
13) (a) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247. (b) Scholl, M.; Ding, S.;
Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
14) Fürstner, A.; Guth, O.; Duffels, A.; Seidel, G.; Liebl, M.;
Gabor, B.; Mynott, R. Chem.–Eur. J. 2001, 7, 4811.
15) Data for herbarumin II: d (600 MHz, MeOH-d ) 5.57 (1 H,
Acknowledgment
We gratefully acknowledge financial support from the EPSRC (to
D. J. D.), the EU (Marie Curie Fellowship to E. D. and to F. R.) and
the Novartis Research Fellowship (to S.V. L.). We also thank
Professor A. Fürstner for providing a sample of catalyst 15, Dr J. E.
Davies for X-ray structure determination, Dr J. M. Goodman and
S. Oliver for assistance with molecular modelling and Dr F. Stelzer
for helpful advice and discussion.
(
(
H
4
ddd, J = 15.6 Hz, 2.0 Hz, 1.0 Hz, CH=CH), 5.51 (1 H, dddd,
J = 15.6 Hz, 9.9 Hz, 4.1 Hz, 2.0 Hz, CH=CH), 5.17 (1 H, td,
J = 9.3 Hz, 2.6 Hz, CHOCO), 4.34 (1 H, quint, J = 1.9 Hz,
CHOH), 3.85 (1 H, dd, J = 10.5 Hz, 2.9 Hz, CHOHCH2),
3.52 (1 H, dd, J = 9.6 Hz, 2.3 Hz, CHOH), 2.28 (1 H, m,
CH=CHCH H ), 2.08 (1 H, m, CH H ), 1.87 (1 H, m,
References
a
b
a
b
CH H CH H ) 1.80 (1 H, m, CHCH H ), 1.76 (1 H, m,
a
b
c
d
e
f
(
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c
d
e
f
g
h
3
1
.34 (1 H, m, CH H ), 0.93 (3 H, t, J = 7.4 Hz, CH ); d (100
g h 3 C
(
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4
7
3
4.5 (CH), 74.3 (CH), 74.0 (CH), 72.3 (CH), 35.6 (CH2),
5.4 (CH ), 30.1 (CH ), 19.1 (CH ), 14.8 (CH ).
2
2
2
3
Synlett 2003, No. 8, 1186–1188 ISSN 1234-567-89 © Thieme Stuttgart · New York