Total synthesis of (+)-herbarumin I via intermolecular Nozaki-Hiyama-Kishi reaction

Article abstract of DOI:10.1016/S0040-4039(02)00359-3

The phytotoxin herbarumin I, isolated from Phoma herbarum, was stereoselectively synthesized in 17 steps and 6% yield from L-arabinose featuring the intermolecular Nozaki-Hiyama-Kishi coupling and modified Yamaguchi macrolactonization as key steps.

Full text of DOI:10.1016/S0040-4039(02)00359-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2819–2821
Total synthesis of (+)-herbarumin I via intermolecular
Nozaki–Hiyama–Kishi reaction
Ada˜o Aparecido Sabino and Ronaldo A. Pilli*
Instituto de Qu´ımica, UNICAMP, P.O. Box 6154, 13083-970 Campinas, SP, Brazil
Received 8 November 2001; revised 19 February 2002; accepted 20 February 2002
Abstract—The phytotoxin herbarumin I, isolated from Phoma herbarum, was stereoselectively synthesized in 17 steps and 6% yield
from -arabinose featuring the intermolecular Nozaki–Hiyama–Kishi coupling and modified Yamaguchi macrolactonization as
L
key steps. © 2002 Elsevier Science Ltd. All rights reserved.
Recently, Mata and co-workers1 have isolated two new
phytotoxic lactones, named herbarumin I and II, from
the culture of Phoma herbarum fungus. Related 10-
membered lactones have also been isolated from fungi
with phytotoxic activity such as pinolidoxin,2
lethaloxin3 and putaminoxin.4
Starting from -arabinose (2), lactol 4 was prepared in
L
65% overall yield according to the procedure by Ballou
and Wightman.8 Wittig olefination9 afforded the corres-
ponding olefin as a 3.2:1 mixture (Z/E) that was
subsequently hydrogenated on Pd/C to give acetonide 6
in 85% yield for two steps.
HO
HO
Removal of the acid labile acetonide group and re-
acetalization of the corresponding triol under thermo-
dynamic conditions with 3-pentanone provided acetal 8
in 79% yield. This one was transformed in the corre-
sponding benzylic ether10 and then converted to the
corresponding bis-silyl ether 11 in 78% overall yield
from 8 (three steps). Selective deprotection11 of the
primary silyl group with HF·pyridine in buffered THF,
followed by mild oxidation of the corresponding alco-
hol with Dess–Martin periodinane12 provided aldehyde
13 in 64% yield over two steps (Scheme 2).
O
O
HO
HO
OH
O
O
Herbarumin I
Herbarumin II
Among the substances isolated from P. herbarum
extract, herbarumin I displayed pronounced phytotoxic
activity on the seedling of Amaranthus hypochondria-
cus,1 holding promise as a lead compound for the
discovery of new herbicides. Recently, Fu¨rstner and
co-workers5 reported the first total synthesis of
herbarumin I taking advantage of an (E)-selective ring
closing olefin metathesis (RCM) approach to prepare
the lactone ring.
Hydrostannylation of 5-hexyn-1-ol (14) catalyzed by
13
Pd(PPh3)2Cl2 stereoselectively provided vinylic stan-
nane 15 in 74% yield. Tin–iodine exchange was accom-
Our ongoing interest in the stereoselective preparation
of 10-membered lactones6 through the Nozaki–
Hiyama–Kishi (NHK) reaction7 led us to explore this
approach in the total synthesis of herbarumin I. Here
we disclose our results on the total synthesis of
herbarumin I based on the Felkin-type intermolecular
NHK reaction between a,b-alkoxy aldehyde B and
vinylic iodide C, followed by macrolactonization
(Scheme 1).
* Corresponding author. E-mail: pilli@iqm.unicamp.br
Scheme 1. Retrosynthetic analysis for herbarumin I.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00359-3

2820
A. A. Sabino, R. A. Pilli / Tetrahedron Letters 43 (2002) 2819–2821
O
O
OH
OH
O
OH
a - b
c - d
e - f
O
HO
O
O
4
6
OH
OH
L-arabinose (2)
BnO
O
OH
BnO
g - i
j - k
H
O
OTBS
OTBS
OTBS
8
O
Et
13
11
Et
Scheme 2. Reagents and conditions. (a) 2,2-Dimethoxypropane, DMF, PTSA; (b) NaBH4, EtOH, 2 h, then NaIO4, H2O (65%
overall); (c) C2H5PPh3Br, n-BuLi, THF, −78°C, 2 h, then 4 (89%); (d) H2, Pd/C, EtOH (96%); (e) 10% HCl, MeOH, quant.; (f)
3-pentanone, CSA, rt (79%); (g) NaH, BnBr, Et4NI, THF (82%); (h) 2 mol L−1 HCl, MeOH, quant.; (i) TBSCl, imidazole, DMF
(95%); (j) HF.pyridine, THF, pyridine (65%); (k) Dess–Martin periodinane, CH2Cl2 (99%).
1,6%
plished without isomerization of the double bound to
1,3%
afford the required vinylic iodide 16 in 93% yield. Jones
CH3
H8
oxidation followed by esterification14 with SOCl2 in
methanol, afforded ester 18 in 59% yield over two steps
(Scheme 3).
H7
H3C
3,0%
3,0%
O
O
BnO
H6
The intermolecular Nozaki–Hiyama–Kishi reaction of
vinylic iodide 18 and aldehyde 13 was successfully
carried out and provided allylic alcohol 19 together
with its C7 epimer (76% yield, 3.4:1 mixture). The anti
configuration at C7–C8 of the major isomer 19 was
established after nOe experiments with its acetonide 20:
among others, a 3.0% increment at the H7 signal
observed upon irradiation of H8 was diagnostic of the
H7–H8 cis relationship.
H5
nOe increments
in acetonide 20
Having secured the C7 configuration, the secondary
alcohol was protected as its TBS ether and the selective
removal of the benzylic group was investigated next.
While no reaction was observed with lithium
naphthalenide15 or LiDBB,16 hydrogenolysis under
Raney nickel17 promoted both the removal of the ben-
zyl group and reduction of the double bond. Eventu-
ally, alcohol 22 was successfully prepared via hydrogen
transfer reaction employing cyclohexene18 and Pd(OH)2
as catalyst, in 81% yield. Ester hydrolysis followed by
lactonization under modified Yamaguchi macro-
lactonization19 afforded 10-membered lactone 24 in
54% overall yield from 22. Removal of both TBS
groups with TBAF in THF as the fluoride source
Scheme 3. Reagents and conditions. (a) n-Bu3SnH, 2 mol%
Pd(PPh3)2Cl2, CH2Cl2 (74%); (b) I2, CCl4 (93%); (c) CrO3,
H2SO4, acetone (81%); (d) SOCl2, MeOH, 0°C (73%).
BnO
O
H
BnO
OH
O
13
OTBS
a
b - c
8
7
OCH3
+
OTBS
OCH3
19
I
Felkin adduct
O
18
HO
HO
TBSO
TBSO
HO
OTBS
O
d - e
f
O
O
OCH3
O
OTBS
22
O
24
Herbarumin I
Scheme 4. Reagents and conditions. (a) CrCl2 (1% NiCl2), DMSO (76%, 3.4:1 mixture); (b) TBSCl, DMF (77%); (c) Pd(OH)2,
EtOH/cyclohexene (2.5:1 v/v), 63°C (81%); (d) LiOH, THF/MeOH/H2O (3:1:1 v/v) (96%); (e) 2,4,6-Cl3PhCOCl, DIPEA, DMAP,
benzene, 3×10−4 mol L−1, 80°C (56%); (f) TBAF, 1.0 mol L−1, THF, quant.

A. A. Sabino, R. A. Pilli / Tetrahedron Letters 43 (2002) 2819–2821
2821
provided the corresponding diol in quantitative yield,
which proved to be identical to herbarumin I by 1H and
13C NMR spectroscopy and specific optical rotation
(Scheme 4).20
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In summary, the intermolecular Nozaki–Hiyama–Kishi
coupling provided the Felkin type allylic alcohol with
the correct configuration for the synthesis of the potent
phytotoxin herbarumin I in 17 steps (longest linear
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sequence) from L-arabinose and 6% overall yield. This
approach is currently under investigation in our labora-
tory for the synthesis of other 10-membered lactones.
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Acknowledgements
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The authors thank Fapesp for generous financial sup-
port and fellowship (A.A.S.) and CNPq for fellowship
(R.A.P.).
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20. Representative analytical data. Herbarumin I: [h]2D0 +18 (c
0.1; EtOH) {[h]2D0 +28 (c 0.1, EtOH), Ref. 1; [h]2D0 +10.8 (c
0.51, EtOH), Ref. 5}; IR (KBr, film): 3437, 2958, 2924,
2854, 1720, 1647, 1462, 1358, 1254, 1203, 1153, 1057
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