Chemoenzymatic total synthesis of the phytotoxic lactone herbarumin III

Article abstract of DOI:10.1016/j.tetlet.2005.03.139

Asymmetric total synthesis of phytotoxic nonenolide herbarumin III was accomplished by a chemoenzymatic approach. The main highlight of the synthesis was to fix the hydroxyl stereocenters (C7 and C9) by lipase catalyzed irreversible transesterification.

Full text of DOI:10.1016/j.tetlet.2005.03.139

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3661–3663
Chemoenzymatic total synthesis of the phytotoxic lactone
herbarumin III
Samik Nanda*
Biotechnology Research Center, Toyama Prefectural University, 5180 Kurokawa, Kosugi, Toyama 939-0398, Japan
Received 3 March 2005; revised 17 March 2005; accepted 22 March 2005
Available online 8 April 2005
Abstract—Asymmetric total synthesis of phytotoxic nonenolide herbarumin III was accomplished by a chemoenzymatic approach.
The main highlight of the synthesis was to fix the hydroxyl stereocenters (C7 and C9) by lipase catalyzed irreversible
transesterification.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Bioassay guided fractionation of a culture broth of the
fungus Phoma herbarum Westend (Sphaeropsidaceae)
led to a new nonenolide with the two previously iso-
lated compounds named herbarumin I (1) and II (2).1
According to the previous nomenclature,2 this com-
pound was named herbarumin III (3) and possessing
the nonenolide core with one hydroxyl group (Fig. 1).
Its structural features and conformational analysis were
established perfectly.1 Herbarumin III (3) showed rele-
vant phytotoxic effects when tested against seedlings of
A. hypochondriacus using the Petri dish bioassay.3
The lactone (IC50 = 2 · 10À5 M) inhibited radicle
growth with higher potency than 2,2-dichlorophenoxy-
acetic acid (IC50 = 2 · 10À4 M), used as positive control.
Herbarumin III (3) also interacted with bovine brain
calmodulin and has an inhibitory effect same as those
of herbarumin I (1) and II (2). Thus, compounds 1–3
are calmodulin inhibitors and should have physiological
effects of agrochemical and medicinal interest. Both
herbarumin I and II were recently synthesized by a con-
cise approach involving RCM or Nozaki–Hiyama–
Kishi coupling reaction as the key step for the formation
of the medium-sized ring.4
The first total synthesis of herbarumin III was reported
last year,5 which also involves RCM as a key step. In
this letter, I wish to report the asymmetric total synthe-
sis of herbarumin III by a chemoenzymatic approach.
The two stereocenters (C7 and C9) both were installed
by lipase catalyzed irreversible transesterification, and
in the final step macrolactonization, by applying Yama-
guchiÕs protocol as well as lipase catalyzed irreversible
acyl transfer method yielded herbarumin III.
The synthesis starts from the trans cinamaldehyde (1a–
c), which on addition with propylmagnesium bromide
yields the allylic alcohol 2a–c. The allylic alcohol 2a–c
was subjected to lipase catalyzed irreversible transesteri-
fication with vinyl acetate and CAL-B (immobilized on
macroporous acrylic resin) to afford (R)-acetate and
the slow reacting enantiomer (S)-alcohol. The mixture
of (R)-acetate and (S)-alcohol was converted to (R)-ace-
tate by employing an elegant strategy reported by
Kanerva and Vanttinen6 involving Mitsunobu inversion,
thus effectively converting a racemic alcohol to (R)-ace-
tate (whereas in traditional enzymatic transesterification
reaction maximum 50% possible yield was obtained).
The absolute configuration of the product acetate in
the enzyme catalyzed transesterification can be predicted
by Kazlauskas empirical model7 where the sizes of the
two side chains determine which enantiomer will
HO
O
R1
R2
O
R1 = OH, R2 = H; Herbarumin I
R1 = R2 = OH; Herbarumin II
R1 = R2 = H; Herbarumin III
Figure 1.
Keywords: Herbarumin III; Asymmetric synthesis; Lipase-mediated
transesterification.
*
Tel.: +81 766567500; fax: +81 766 56 7500x532; e-mail: snanda@
sunny.ocn.ne.jp
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.139

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S. Nanda / Tetrahedron Letters 46 (2005) 3661–3663
undergo fast reaction. The enantioselectivity (ee) was
measured by chiral HPLC and it was observed that sub-
strates 1b and 1c provide better ee than 1a (Table 1; due
to presence of bulky substituents in para position in 1b
and 1c). The choice of benzyl and 4-methoxybenzyl
was judiciously done to have an effective steric difference
between the two side chains in the allylic alcohols. And
from Table 1, it shows that substrate 1c provides best
enantioselectivity (98% ee for the acetate and 96% for
the remaining alcohol which was inverted by using
Mitsunobu protocol).
deprotection and formation of TBDPS ether were
achieved to afford 10. Removal of 4-methoxybenzyl
group with DDQ12 furnished alcohol 11. The alcohol
11 was converted to acid 12 by a two-step procedure,
first Swern oxidation followed by oxidation with
NaClO2/NaH2PO4 using PinnickÕs protocol.13 Finally,
removal of benzyl group with Li–NH3 (l) afforded
hydroxyacid, the desired lactone precursor 13 in good
yield.
The formation of medium-sized ring lactone was re-
ported by Lobell and Schneider14 by lipase catalyzed
irreversible intramolecular acyl transfer method. When
the hydroxyacid 13 itself was subjected to lactonization
(lipase) in TBME, no product lactone was detected from
the reaction mixture. It was established by Lobell et al.
that the hydroxyacid itself was a poor substrate and
yields no lactone. Following a similar method reported
by them, it is possible to obtain the required nonenolide
from the corresponding carboxy vinylester of 13. The
vinylester of 13 was prepared successfully by employing
Pd catalyzed transesterification with vinyl acetate. The
vinylester when employed with lipase catalyzed intramo-
lecular acyl transfer reaction, moderate yield of required
nonenolide was observed with some other oligomeric
product. Immobilized lipase from Pseudomonas sp. pro-
vides best yield, where as TBME is the solvent choice.
The yield of products is summarized in Table 2. To
the best of our knowledge, this is the first report of lipase
catalyzed macrolactonization approach for total synthe-
sis of a natural product precursor. The major drawback
associated with lipase catalyzed intramolecular acyl
transfer reaction leading to medium-sized lactone is
mainly the formation of oligomeric rings, which cause
less yield for the required lactone precursor of herbaru-
min III. So finally lactonization was achieved by apply-
ing YamaguchiÕs protocol.15 The hydroxyacid 13 when
treated with 2,4,6-trichlorobenzoylchloride in refluxing
benzene, the required lactone 14 was obtained in overall
Acetate group in 1c was deprotected and benzyl protec-
tion was achieved by using benzylimidate to yield 3c.8
Ozonolysis of 3c and reduction of the generated alde-
hyde functionality with NaBH4 produced alcohol 4.
Compound 4 was converted to sulfone derivative 5 by
a two-step method, first making the iodo compound
and then treating it with paratoluenesulfenic acid
sodium salt yielded 5 (Scheme 1).
The sulfone 5 was then condensed with (E)-7-(4-meth-
oxybenzyloxy)hept-2-enal9 in presence of LDA at
À78 ꢁC to yield compound 6 in 78% yield.10 The para-
toluene sulfone group was removed by treating com-
pound 6 with amalgamated aluminum (Al/Hg) by
Trost protocol11 to furnish compound 7. Compound 7
was subjected to second enzymatic kinetic transesterifi-
cation with VAC in DIPE. In this case, the side chain
bearing the paramethoxybenzyl group acts as a large
substituent compared to the other one. Thus, the fast-
reacting enantiomer can be predicted according to Kazl-
auskas rule. The previous strategy of Mitsunobu inver-
sion was applied in tandem to yield the acetate 8 with
required stereochemistry in 88% overall yield from 7.
The enantioselectivity (diastereoselection) was deter-
mined by chiral HPLC and it was observed that overall
good de (90%) was obtained. After fixing the two stereo-
centers (C7 and C9), the remaining task was to construct
the lactone ring in an efficient manner. Acetate group
Table 2. Enzyme catalyzed irreversible acyl transfer for nonenolide
formation
Table 1. Enzymatic transesterification of 1a–c
Substrate
Lipase
ee-Acetate (%)
ee-Alcohol (%)
E16
Substrate
Lipase
Solvent
Yield (%)
1a
1b
1c
CAL-B
CAL-B
CAL-B
90
97
98
88
94
96
55
213
412
Vinyl ester of 13
Vinyl ester of 13
Vinyl ester of 13
PSL
CAL-B
PSL
TBME
TBME
TBME/hexane (8:2)
31
11
28
OH
OR'
CHO
a
b
C3H7
C3H7
3a-3c
R
R
R
1a-1c
2a-2c
c
R' = Ac
R = H, OBn, OPMB
R' = H
d
R' = Bn
OBn
OBn
e
f
SO2Tol
HOH2C
4
5
Scheme 1. Reagents and conditions: (a) nPrMgBr, ether, rt; (b) (i) VAC, CAL-B, DIPE; (ii) TPP, DIAD, AcOH, THF; (c) K2CO3, MeOH;
(d) BnO(C@NH)CCl3, CSA; (e) O3, DCM, Me2S; NaBH4/MeOH, 82%; (f) (i) I2, TPP, Im, 88%; (ii) TolSO2Na, DMF, 65%.

S. Nanda / Tetrahedron Letters 46 (2005) 3661–3663
3663
OH
OBn
a
OH
OBn
C3H7
b
5
C3H7
BMPO(CH2)4
BMPO(CH2)4
SO2Tol
6
7
OR
OBn
c
OR
OBn
f
C3H7
BMPO(CH2)4
C3H7
HO(CH2)4
11
R = Ac, 8
R = H, 9
d
e
g
R = OTBDPS, 10
OR
OR
OBn
C3H7
i
O
HO2C(CH2)3
OBn, 12
OH, 13
h
O
R = TBDPS, 14
R = H, Herbarumin III
j
Scheme 2. Reagent and conditions: (a) LDA, À78 ꢁC, E-7-(4-methoxybenzyloxy)hept-2-enal, 78%; (b) Al/Hg, THF, 60%; (c) (i) CAL-B, VAC,
DIPE; (ii) TPP, DIAD, AcOH, 90% de; (d) K2CO3/MeOH; (e) TBDPS-Cl, imidazole, DMF, 86%; (f) DDQ, 82%; (g) (i) DMSO, (COCL)2, Et3N,
88%; (ii) NaClO2, NaH2PO4, 2-methyl-2-butene, 80%; (h) Li–NH3 (1), 3-hexyne; (i) (i) vinyl acetate, Pd(OAc)2, lipase, TBME, 31%; (ii) Et3N,
DMAP, pH, 80 ꢁC, 83%.
4. (a) Furstner, A.; Radkowski, K. Chem. Commun. 2001,
671; (b) Furstner, A.; Radkowski, K.; Wirtz, C.; Goddard,
R.; Lehmann, C. W.; Mynott, R. J. Am. Chem. Soc. 2002,
124, 7061; (c) Sabinu, A. A.; Pilli, R. A. Tetrahedron Lett.
2002, 43, 2819; (d) Diez, E.; Dixon, D. J.; Ley, S. V.;
Polara, A.; Rodriguez, F. Helv. Chim. Acta 2003, 86,
3717.
5. Gurjar, M. K.; Karmakar, S.; Mahapatra, D. K. Tetra-
hedron Lett. 2004, 45, 4525.
6. Kanerva, L. T.; Vanttinen, E. Tetrahedron: Asymmetry
1997, 8, 923.
good yield (Scheme 2). Finally, TBDPS group was
removed by TBAF treatment to yield herbarumin III
(3). The NMR (1H and 13C) spectra of synthesized
and natural herbarumin III are in perfect agreement,
its optical rotation value was little low {[a]D +16.7 (c
1.0, EtOH); Literature value [a]D +22.0 (c 1.0, EtOH)}
compared with the natural product, and that may be
due to the fact that the second enzymatic transesterifica-
tion method (to fix the C7) was not completely enantio-
selective (de, 90%).
7. Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in
Organic Synthesis: Regio- and Stereoselective Biotransfor-
mations; Wiley-VCH, 1999, Chapter 5, p 65.
8. Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.;
Danishefsky, S. J. J. Org. Chem. 1989, 54, 3378.
9. (E)-7-(4-Methoxybenzyloxy)hept-2-enal was synthesized
as described in the supporting information.
10. The separation of the diastereomes of compound 6 was
difficult, hence sulfone group was deprotected prior to
second enzymatic resolution.
In summary, an efficient asymmetric total synthesis of
herbarumin III is described for the first time by a
chemoenzymatic approach.
Supplementary data
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tetlet.
2005.03.139.
11. Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.
Tetrahedron Lett. 1976, 17, 3477.
12. Horita, K.; Yoshioka, T.; Tanaka, T.; Olikawa, Y.;
Yonemitsu, O. Tetrahedron 1986, 42, 3021.
References and notes
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1993, 4, 1027.
2. Rivero-Cruz, J. F.; Garcia-Aguirre, G.; Gerda-Garcia-
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