A stereoselective aldol approach for the total synthesis of herbarumin I and stagonolide A

Article abstract of DOI:10.1055/s-0029-1218775

A stereoselective total synthesis of phytotoxic compounds herbarumin I and stagonolide A has been achieved utilizing Crimmins protocol for non-Evans anti-aldol approach and a ring-closing olefin metathesis reaction as the key steps. Georg Thieme Verlag St

Full text of DOI:10.1055/s-0029-1218775

PAPER
2407
A Stereoselective Aldol Approach for the Total Synthesis of Herbarumin I and
Stagonolide A
Total
S
ynthesi
.
s
of
H
erbaru
S
min I and Sta
r
iA
hari,* G. Maheswara Rao, R. Srinivasa Rao, J. S. Yadav
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500607, India
Fax +91(40)27160512; fax +91(40)27160387; E-mail: srihari@iict.res.in
Received 8 March 2010; revised 23 March 2010
R5
Abstract: A stereoselective total synthesis of phytotoxic com-
pounds herbarumin I and stagonolide A has been achieved utilizing
Crimmin’s protocol for non-Evans anti-aldol approach and a ring-
closing olefin metathesis reaction as the key steps.
R4
R3
R2
O
R6
R1
O
Key words: macrolide, phytotoxic, Evans aldol, olefin metathesis
herbarumin I (1): R1 = α-Pr, R2 = β-OH, R3 = α-H, R4 = β-OH, R5 = H, R6 = H
herbarumin II (2): R1 = α-Pr, R2 = β-OH, R3 = α-H, R4 = β-OH, R5 = H, R6 = β-OH
herbarumin III (3): R1 = α-Pr, R2 = H, R3 = α-H, R4 = β-OH, R5 = H, R6 = H
stagonolide A (4): R1 = α-Pr, R2 = β-OH, R3 = O, R4 = O, R5 = H, R6 = H
stagonolide B (5): R1 = α-Pr, R2 = α-OH; R3 = β-H, R4 = α-OH, R5 = β-OH, R6 = H
stagonolide C (6): R1 = α-Me, R2 = H, R3 = α-OH, R4 = β-H, R5= β-OH, R6 = H
Recently, there has been increased attention in ten-mem-
bered ring containing macrolides that display potent bio-
logical activity.1 Herbarumins I–III,2 stagonolides A–I,3
and modiolides A and B4 are recent examples that have
been isolated and found to display potent biological activ-
ity (Figure 1). Herbarumins I–III have been isolated from
fermentation broth and mycelium of the fungus Phoma
herbarum and were found to show phytotoxic effects
against the seedlings of Amaranthus hypochondriacus at
very low concentrations. Herbarumin I also displayed po-
tent antifungal activity. Stagonolide A isolated recently
from the fungus Stagonospora cirsii, a pathogen of Cirsi-
um arvense was found to cause necrotic lesions on leaves.
The impressive biological activity and scarce availability
of these natural materials have attracted several synthetic
chemists to take up their total synthesis for further evalu-
ation towards biological screening.5–9
OH
OH
OH
O
O
O
O
O
O
O
stagonolide D (7)
stagonolide E (8)
stagonolide F (9)
OH
OH
OH
HO
O
O
O
O
HO
O
O
O
stagonolide G (10)
stagonolide H (11)
stagonolide I (12)
In continuation of our programme towards the total syn-
thesis of natural products containing lactone moi-
eties,7k,8d,10 we have recently described the total synthesis
of herbarumin I and stagonolide A following a chiron ap-
proach.5g Herein, we describe a stereoselective aldol route
for the total synthesis of herbarumin I and stagonolide A.
R
HO
modiolide A (13): R = OH
modiolide B (14): R = H
O
O
Figure 1 Ten-membered-ring-containing macrolides
Our synthetic strategy relies on Crimmins’ protocol for
non-Evans anti-aldol product starting from n-butyralde-
hyde to generate two chiral centers. The third chiral center
is created by a stereoselective Grignard reaction and is
then followed by the well-known ring-closing-metathesis
reaction to obtain the desired skeleton for the target mol-
ecule. Thus, our retrosynthetic analysis revealed a key
fragment 15 which could be coupled to hex-2-enoic acid
and subjected to intramolecular Grubbs metathesis reac-
tion followed by benzyl deprotection to realize the target
molecule herbarumin I (1). The key fragment 15 was ob-
tained from 16 in a four-step sequence involving auxiliary
cleavage to yield the aldehyde, Grignard reaction with vi-
nylmagnesium bromide followed by benzyl protection
and TBS-deprotection. The compound 16 in turn was ob-
tained by modified Evans aldol reaction of n-butyralde-
hyde
with
(S)-2-(benzyloxy)-1-(4-benzyl-2-
thioxooxazolidin-3-yl)ethanone (Scheme 1).
Accordingly, our synthesis started with n-butyraldehyde
which was subjected to Crimmins’ protocol11 for non-
Evans anti-aldol reaction with (S)-2-(benzyloxy)-1-(4-
benzyl-2-thioxooxazolidin-3-yl)ethanone (17) in the pres-
ence of titanium(IV) chloride and (–)-sparteine at –78 °C
to give the corresponding chiral a,b-dihydroxy amides 18
and 18¢ as a mixture of diastereomers (non-Evans-anti/
Evans-anti, 95:5) in 65% yield. The diastereomeric ratios
were determined by combined analysis of crude 1H NMR
SYNTHESIS 2010, No. 14, pp 2407–2412
x
x.
x
x
.
2
0
1
0
Advanced online publication: 05.05.2010
DOI: 10.1055/s-0029-1218775; Art ID: Z05710SS
© Georg Thieme Verlag Stuttgart · New York

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P. Srihari et al.
PAPER
BnO
OH
ing allylic alcohols 20 and 20¢ as an inseparable mixture
of diastereomers (anti/syn, 90:10) in 95% yield.12 Howev-
er, upon protection of the secondary alcohol with benzyl
bromide, the desired product 21 (85%) was easily separat-
ed. TBS deprotection with tetrabutylammonium fluoride
yielded the intermediate 15. With the key intermediate 15
in hand, the stage was set for coupling with hex-5-enoic
acid (22) and to proceed further for ring-closing metathe-
sis. Thus, coupling of alcohol 15 with hex-5-enoic acid
(22) proceeded smoothly under Yamaguchi’s conditions
employing trichlorobenzoyl chloride and 4-(dimethylami-
no)pyridine to yield diolefin 23.13 Ring-closing metathe-
sis of compound 23 worked well with Grubbs’ 2nd-
generation catalyst in benzene at reflux temperature for 12
hours to yield the desired trans-isomer 24 as the major
product.14 Deprotection of the two benzyl moieties was
achieved using titanium(IV) chloride15 to yield herbaru-
min I (1). Consequently herbarumin I (1) was converted
into stagonolide A (4) on allylic oxidation with manga-
nese dioxide, thus, we have also accomplished the total
synthesis of stagonolide A (Scheme 2). The products her-
barumin I (1) and stagonolide A (4) obtained were charac-
terized by spectroscopic analysis and also confirmed by
O
HO
O
O
HO
HO
OBn
O
O
15
stagonolide A (4)
herbarumin I (1)
S
O
OTBS
CHO
O
N
n-butyraldehyde
OBn
Ph
16
Scheme 1 Retrosynthesis
spectroscopy and LCMS analysis. Due to difficulties in
separating anti-aldol products from the starting material,
we carried out the TBS-protection directly with tert-bu-
tyldimethylsilyl triflate to afford the corresponding TBS
ether 16. Treatment of compound 16 with diisobutylalu-
minum hydride afforded aldehyde 19, which was then
subjected to Grignard reaction with vinylmagnesium bro-
mide at –78 °C to room temperature to yield correspond-
S
O
O
N
S
OBn
17
S
OH
O
OH
O
Ph
TBSOTf, 2,6-lutidine
O
N
CHO
O
N
+
CH2Cl2, 0 °C to r.t.
3 h, 90%
TiCl4, sparteine,
dry CH2Cl2, –78 °C
2 h, 65%
OBn
18′
OBn
18
n-butyraldehyde
Ph
Ph
(95:5)
(non-Evans anti: Evans anti)
S
O
OTBS
O
OTBS
OH
OTBS
OH
OTBS
DIBAL-H, CH2Cl2
MgBr
O
N
+
H
–78 °C to r.t.,
30 min, 95%
THF, –78 °C to r.t.
3 h, 95 %
OBn
16
OBn
OBn
OBn
20
20′
19
Ph
90:10
inseparable mixture
O
OBn OTBS
OBn OH
HO
22
NaH, BnBr
TBAF, THF
2,4,6-trichlorobenzoyl chloride
Et3N, THF; then 15, DMAP, toluene,
r.t., 3 h, 80%
THF, 0 °C to r.t.
12 h, 85%
0 °C to r.t.,
5 h, 90%
OBn
OBn
15
21
O
BnO
BnO
HO
OBn
O
TiCl4, CH2Cl2
Grubbs II catalyst
O
0 °C to r.t.,
2 h, 70%
benzene, reflux,
12 h, 65%
O
HO
OBn
O
O
23
24
herbarumin I (1)
O
MnO2, CH2Cl2
r.t., 24 h, 92%
O
HO
O
stagonolide A (4)
Scheme 2 Total synthesis of herbarumin I (1) and stagonolide A (4)
Synthesis 2010, No. 14, 2407–2412 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Herbarumin I and Stagonolide A
2409
addition of aq sat. NH4Cl (15 mL). The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The
combined organic extracts were washed with brine (2 × 50 mL),
dried (anhyd Na2SO4), filtered, and concentrated to afford the dia-
stereomeric mixture 18/18¢ (2.4 g, 65%) ratio non-Evans anti/Evans
comparing the data with the earlier known literature and
was found to be identical in all respects.2,3,5,8d
In conclusion, we have achieved the total synthesis of her-
barumin I and stagonolide A by utilizing Crimmins’ pro-
tocol for non-Evans anti-aldol product, stereoselective
Grignard reaction, and Grubbs’ olefin metathesis as the
key steps with an overall yield of 12.6% and 11.6% for
herbarumin I (1) and stagonolide A (4), respectively.
1
anti, 95:5 (determined by combined analysis of crude H NMR
spectroscopy and LCMS). The diastereomeric mixture was used di-
rectly in the next step without further purification.
(2R,3R)-2-(Benzyloxy)-1-[(S)-4-benzyl-2-thioxooxazolidin-3-
yl]-3-(tert-butyldimethylsilyloxy)hexan-1-one (16)
To a stirred soln of aldol compound 9 (1.0 g, 2.4 mmol) in anhyd
CH2Cl2 (15 mL) at 0 °C under N2 was added 2,6-lutidine (0.36 mL,
3.1 mmol) and TBSOTf (0.83 mL, 3.6 mmol) sequentially and the
mixture was stirred at r.t. for 3 h. Then the mixture was quenched
with aq sat. NaHCO3 (5 mL). The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The com-
bined organic extracts were washed with 10% NaHSO4 (2 × 10 mL)
and brine (1 × 20 mL), dried (anhyd Na2SO4), filtered, and concen-
trated. The residue was purified by column chromatography (silica
gel, 60–120 mesh, PE–EtOAc, 95: 5) to afford 16 (1.15 g, 90%) as
a yellow oil.
Column chromatography was performed using silica gel 60–120
mesh. All the solvents were dried and distilled prior to use. IR spec-
tra were recorded on a Perkin-Elmer Infrared spectrophotometer as
KBr wafers or neat or in CHCl3 as a thin film. 1H and 13C NMR were
recorded on a Bruker Avance 300 MHz instrument using TMS as an
internal standard. Mass spectra were recorded on Micro mass VG
7070H mass spectrometer for EI, VG Autospec mass spectrometer
for FABMS and micromass Quatro LC triple quadrupole mass spec-
trometer for ESI analysis. The optical rotations were recorded on
Jasco DIP-360 digital polarimeter. PE = petroleum ether.
[a]D25 +50.3 (c 2.8, CHCl3).
(S)-2-(Benzyloxy)-1-(4-benzyl-2-thioxooxazolidin-3-yl)ethan-
one (17)
IR (neat): 2956, 2930, 2858, 1704, 1366, 1323, 1196, 1155, 834
cm–1.
To a stirred soln of 2-(benzyloxy)acetic acid (17.20 g, 103.0 mmol)
and DMF (0.394 mL, 5.10 mmol) in anhyd CH2Cl2 (100 mL) at 0
°C under N2 was added slowly 2.0 M oxalyl chloride in CH2Cl2 (9.5
mL, 112.0 mmol). The resulting mixture was allowed to warm up to
25 °C and stirred for 1 h. Evaporation of most of the solvents yield-
ed the crude 2-(benzyloxy)acetyl chloride, which was added to a
stirred soln of (S)-4-benzyloxazolidine-2-thione (10.00 g, 51.0
mmol) and 1.6 M n-BuLi in hexanes (38.1 mL, 61.0 mmol) in anhyd
THF (200 mL) at –78 °C under N2. The mixture was allowed to
warm up to r.t. and stirred for 1.5 h. The mixture was quenched with
sat. NaHCO3 (60 mL) and extracted with EtOAc (3 × 60 mL). The
combined organic extracts were washed with brine (2 × 60 mL),
dried (anhyd Na2SO4), filtered, and concentrated. The residue was
purified by column chromatography (silica gel, 60–120 mesh, PE–
EtOAc, 80:20) to afford pure 17 (12.5 g, 71%) as a colorless solid;
17 could also be recrystallized (Et2O–n-hexane) for enhanced puri-
ty.
1H NMR (300 MHz, CDCl3): d = 7.36–7.15 (m, 10 H), 6.24 (d,
J = 5.2 Hz, 1 H), 4.73–4.68 (m, 1 H), 4.58–4.46 (m, 2 H), 4.26–4.21
(m, 1 H), 4.12 (dd, J = 9.3, 3.1 Hz, 1 H), 3.89 (t, J = 8.3 Hz, 1 H),
3.31 (dd, J = 12.4, 3.1 Hz, 1 H), 2.51 (ABq, J = 12.4, Hz, 1 H),
1.81–1.71 (m, 1 H), 1.63–1.55 (m, 1 H), 1.54–1.44 (m, 2 H), 0.95 (t,
J = 7.2 Hz, 3 H), 0.87 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 184.8, 173.4, 137.8, 135.3, 129.2,
129.0, 128.4, 128.2, 127.9, 127.3, 78.1, 73.6, 72.9, 70.4, 60.3, 37.7,
35.1, 25.8, 17.6, 14.4, –4.35, –4.31.
MS (ESI): m/z = 528 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C29H42NO4SiS: 528.2603;
found: 528.2612.
(2R,3R)-2-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)hexanal
(19)
[a]D25 +59.4 (c 1.1, CHCl3).
To a stirred soln of 16 (1.5 g, 2.8 mmol) in anhyd CH2Cl2 (15 mL)
at –78 °C under N2 was added dropwise 20% DIBAL-H in toluene
(4.07 mL, 5.7 mmol). The resulting mixture was stirred at –78 °C
for 30 min. Then the mixture was quenched with sat. sodium potas-
sium tartrate soln (5 mL) and allowed to warm up to r.t. and stirred
for 2 h. The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (2 × 10 mL). The combined organic extracts
were washed with brine (1 × 10 mL), dried (anhyd Na2SO4), fil-
tered, and concentrated. The residue was purified by column chro-
matography (silica gel, 60–120 mesh; PE–EtOAc, 97: 3) to afford
pure 19 (0.9 g, 95%) as a yellow oil.
IR (KBR): 3029, 2919, 1710, 1494, 1366, 1325, 1208 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.42–7.19 (m, 10 H), 5.02 (dd,
J = 29.4, 18.1 Hz, 2 H), 4.94–4.86 (m, 1 H), 4.67 (s, 2 H), 4.37–4.30
(m, 2 H), 3.31 (dd, J = 12.8, 3.0 Hz, 1 H), 2.82–2.71 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 184.3, 170.5, 136.7, 134.5, 129.0,
128.6, 128.1, 127.7, 127.6, 127.0, 73.0, 71.1, 71.0, 59.3, 37.0.
MS (ESI): m/z = 364 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H19NNaO3S: 364.0983;
found: 364.0986.
[a]D25 +16.1 (c, 3.0, CHCl3).
(2R,3R)-2-(Benzyloxy)-1-[(S)-4-benzyl-2-thioxooxazolidin-3-
yl]-3-hydroxyhexan-1-one (18)
IR (neat): 2957, 2932, 2859, 1731, 1463, 1364, 1254, 1122, 835,
776 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.68 (d, J = 2.2 Hz, 1 H), 7.39–
7.28 (m, 5 H), 4.63 (ABq, J = 11.8 Hz, 2 H), 4.06–4.00 (m, 1 H),
3.69 (dd, J = 2.2, 3.5 Hz, 1 H), 1.71–1.57 (m, 1 H), 1.54–1.41 (m, 1
H), 1.40–1.22 (m, 2 H), 0.92–0.86 (m, 12 H), 0.07 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 203.2, 137.3, 128.3, 128.0, 127.8,
86.0, 72.7, 73.5, 35.8, 25.7, 18.8, 18.2, 14.0, –4.6, –4.7.
MS (ESI): m/z = 359 [M + Na]+.
To a stirred soln of 17 (3.0 g, 8.79 mmol) in anhyd CH2Cl2 (25 mL)
at –78 °C under N2 was added TiCl4 (1.17 mL, 10.5 mmol) dropwise
and the resulting reddish brown color soln was allowed to stir for 10
min. Then a freshly prepared soln of 2.0 M (–)-sparteine in CH2Cl2
(2.41 mL, 10.5 mmol) was added dropwise and stirring was contin-
ued for an additional 40 min. Additional TiCl4 (2.25 mL, 20.2
mmol) was added to the enolate mixture, the mixture was stirred for
1 min, and a freshly distilled soln of butyraldehyde (1.05 mL, 11.4
mmol) in CH2Cl2 (2 mL) was added. The mixture was stirred at this
temperature for 15 min, and then the reaction was quenched by the
Synthesis 2010, No. 14, 2407–2412 © Thieme Stuttgart · New York

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P. Srihari et al.
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(3S,4S,5R)- and (3R,4S,5R)-4-(Benzyloxy)-5-(tert-butyldimeth-
ylsilyloxy)oct-1-en-3-ol (20 and 20¢)
washed with brine (1 × 20 mL), dried (anhyd Na2SO4), filtered, and
concentrated. The residue was purified by column chromatography
(silica gel, PE–EtOAc, 90:10) to afford pure 15 (0.37 g, 90%) as a
yellow oil.
[a]D25 –4.4 (c 2.2, CHCl3).
IR (neat): 3452, 2956, 2924, 2862, 1637, 1456, 1069, 751 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.21 (m, 10 H), 5.97–5.87
(m, 1 H), 5.38–5.29 (m, 2 H), 4.72–4.52 (m, 3 H), 4.35 (d, J = 12.4
Hz, 1 H), 4.02 (t, J = 5.8 Hz, 1 H), 3.71–3.65 (m, 1 H), 3.37 (t,
J = 5.8 Hz, 1 H), 2.45 (d, J = 5.1 Hz, 1 H, OH), (1.57–1.42 (m, 1 H),
1.40–1.23 (m, 3 H), 0.89 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 134.6, 128.4, 128.3, 128.0, 127.9,
127.8, 127.6, 119.1, 82.8, 80.9, 73.7, 70.8, 70.5, 34.9, 29.6, 18.7,
14.0.
To a stirred soln of aldehyde 19 (1.40 g, 4.1 mmol) in anhyd THF
(13 mL) at –78 °C under N2 was added dropwise 1.0 M vinylmag-
nesium bromide in THF (12.00 mL, 12.00 mmol). The resulting
mixture was warmed up to r.t. and stirred for 3 h and then it was
quenched with sat. aq NH4Cl (5 mL) and extracted with EtOAc
(3 × 5 mL). The combined organic extracts were washed with brine
(1 × 5 mL), dried (anhyd Na2SO4), filtered, and concentrated. The
residue was purified by column chromatography (silica gel, 60–120
mesh, PE–EtOAc, 90:10) to afford a pure, inseparable diastereo-
meric mixture of 20 and 20¢ (1.45 g, 95%) as a yellow oil; anti/syn
90:10.
[a]D25 –9.3 (c 3.5, CHCl3).
IR (neat): 3449, 2955, 2929, 2858, 1638, 1462, 1077, 773 cm–1.
MS (ESI): m/z = 363 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H28NaO3: 363.1931;
1H NMR (300 MHz, CDCl3): d = 7.36–7.24 (m, 5 H), 6.08–5.85 (m,
1 H), 5.41–5.29 (m, 1 H), 5.24–5.16 (m, 0.9 H), 5.14–5.08 (m, 0.1
H), 4.78–4.54 (m, 2 H), 4.29–4.13 (m, 1 H), 3.94–3.84 (m, 0.9 H),
3.82–3.75 (m, 0.1 H), 3.35–3.30 (m, 0.9 H), 3.29–3.25 (m, 0.1 H),
2.79 (d, J = 4.5 Hz, 0.3 H, OH), 2.37 (d, J = 3.5 Hz, 0.7 H, OH),
1.72–1.50 (m, 1 H), 1.49–1.28 (m, 3 H), 0.96–0.86 (m, 12 H), 0.12–
0.06 (m, 6 H).
13C NMR (75 MHz, CDCl3): d (major and minor) = (138.2, 138.4),
(137.9, 139.3), (128.2, 128.3), (127.9, 127.8), (127.7, 127.5),
(115.6, 116.4), (84.4, 84.0), (74.1, 73.9), (73.5, 73.4), (71.8, 72.6),
(35.7, 35.1), (25.86, 25.85), (18.3, 19.1), (18.2, 17.9), (14.25,
14.24), (–4.4, –4.61), (–4.5, –4.64).
found: 363.1941.
(4R,5S,6S)-5,6-Bis(benzyloxy)oct-7-en-4-yl Hex-5-enoate (23)
To a stirred soln of hex-5-enoic acid (22, 0.139 mL, 1.17 mmol) in
anhyd THF (7 mL) under N2 was added Et3N (0.181 mL, 1.29
mmol) and 2,4,6-trichlorobenzoyl chloride (0.183 mL, 1.17 mmol)
at r.t. The resulting mixture was allowed to stir at r.t. for 2 h and then
it was filtered through a pad of silica gel. The filtrate was concen-
trated to dryness to give the acid anhydride. The residue was dis-
solved in toluene (8 mL) and 15 (0.40 g, 1.17 mmol) and DMAP
(0.717 g, 5.88 mmol) were added. The mixture was stirred at r.t. for
3 h and then it was diluted with EtOAc and the organic layer was
separated. The aqueous layer was extracted with EtOAc (2 × 5 mL).
The combined organic extracts were washed with sat. aq NaHCO3
(2 × 5 mL) and brine (1 × 10 mL), dried (anhyd Na2SO4), filtered,
and concentrated. The residue was purified by column chromatog-
raphy (silica gel, PE–EtOAc, 95:5) to afford pure 23 (0.41 g, 80%)
as a yellow oil.
MS (ESI): m/z = 365 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H37O3Si: 365.2511; found:
365.2519.
[(4R,5S,6S)-5,6-Bis(benzyloxy)oct-7-en-4-yloxy]tert-butyldi-
methylsilane (21)
To a well-stirred soln of NaH (0.219 g, 5.4 mmol) in anhyd THF (5
mL) at 0 °C under N2 atmosphere, a soln of mixture of compounds
20 and 20¢ (1.0 g, 2.74 mmol) in anhyd THF (5 mL) was added
dropwise. After 30 min, a soln of BnBr (0.45 mL, 3.80 mmol) in an-
hyd THF (4 mL) was added dropwise and the mixture was allowed
to warm up to r.t. and stirred for 12 h. The mixture was quenched
with ice flakes and extracted with EtOAc (3 × 10 mL) and the com-
bined organic extracts were washed with brine (1 × 20 mL), dried
(anhyd Na2SO4), filtered, and concentrated. The residue was puri-
fied by column chromatography (silica gel, 230–400 mesh, PE) to
afford pure 21 (1.07 g, 85%) as a yellow oil.
[a]D25 +28.0 (c 0.6, EtOH).
IR (neat): 2926, 2864, 1730, 1638, 1455, 1067, 737 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.38–7.22 (m, 10 H), 5.93–5.68
(m, 2 H), 5.39–5.26 (m, 2 H), 5.05–4.95 (m, 3 H), 4.73 (ABq,
J = 11.7 Hz, 2 H), 4.60 (d, J = 11.7 Hz, 1 H), 4.37 (d, J = 11.7 Hz,
1 H), 3.87 (t, J = 6.7 Hz, 1 H), 3.65 (dd, J = 3.2, 6.6 Hz, 1 H), 2.29–
2.11 (m, 2 H), 2.09–2.02 (m, 2 H), 1.86–1.63 (m, 3 H), 1.62–1.49
(m, 1 H), 1.42–1.14 (m, 2 H), 0.87 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 173.0, 138.6, 138.2, 137.6, 135.0,
128.2, 128.1, 127.9, 127.8, 127.5, 127.4, 119.4, 115.3, 82.7, 82.4,
74.8, 74.0, 70.4, 33.6, 33.0, 30.6, 23.9, 18.7, 13.8.
[a]D25 +23.0 (c 0.7, CHCl3).
IR (neat): 3449, 2926, 2856, 1635, 1459, 1252, 1107, 832, 772 cm–1.
MS (ESI): m/z = 459 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C28H36NaO4: 459.2511;
1H NMR (300 MHz, CDCl3): d = 7.35–7.22 (m, 10 H), 5.96–5.84
(m, 1 H), 5.38–5.28 (m, 2 H), 4.73 (ABq, J = 12.0 Hz, 2 H), 4.63 (d,
J = 12.0 Hz, 1 H), 4.35 (d, J = 12.0 Hz, 1 H), 3.94–3.86 (m, 2 H),
3.58–3.54 (m, 1 H), 1.67–1.55 (m, 1 H), 1.40–1.20 (m, 3 H), 0.91–
0.81 (m, 12 H), 0.05 (s, 3 H), 0.04 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 135.8, 128.2, 128.1, 127.8, 127.7,
127.4, 127.2, 118.7, 84.2, 80.4, 74.0, 72.5, 70.1, 34.2, 29.6, 25.9,
18.1, 14.3, –4.2, –4.4.
found: 459.2501.
(8S,9S,10R,E)-8,9-Bis(benzyloxy)-10-propyl-3,4,5,8,9,10-
hexahydro-2H-oxecin-2-one (24)
A soln of 23 (0.065 g, 0.149 mmol) and Grubbs II catalyst (0.029
mmol) in degassed anhyd benzene (125 mL) was refluxed for 12 h
under an argon atmosphere; the mixture was concentrated in vacuo.
The residue was purified by column chromatography (silica gel,
PE–EtOAc, 92:8) to afford pure 24 (0.039 g, 65%); as a yellow oil.
MS (ESI): m/z = 455 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C28H43O3Si: 455.3011; found:
455.2989.
[a]D25 +47.0 (c 2.5, CHCl3).
IR (neat): 2923, 2853, 1736, 1458, 1260, 1093, 1022, 800 cm–1.
(4R,5R,6S)-5,6-Bis(benzyloxy)oct-7-en-4-ol (15)
1H NMR (300 MHz, CDCl3): d = 7.40–7.22 (m, 10 H), 5.76–5.59
(m, 1 H), 5.46 (td, J = 9.2, 2.6 Hz, 1 H), 5.38 (d, J = 15.4 Hz, 1 H),
4.78 (d, J = 12.6 Hz, 1 H), 4.58 (d, J = 12.6 Hz, 1 H), 4.40 (ABq,
J = 11.7 Hz, 2 H), 4.31–4.25 (m, 1 H), 3.33 (dd, J = 9.4, 2.0 Hz, 1
To a stirred soln of 21 (0.55 g, 1.21 mmol) in anhyd THF (5 mL) at
25 °C was added TBAF (3.6 mL, 3.63 mmol) and the mixture was
stirred for 5 h. Then it was diluted with H2O (5 mL) and extracted
with EtOAc (3 × 10 mL). The combined organic extracts were
Synthesis 2010, No. 14, 2407–2412 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Herbarumin I and Stagonolide A
2411
H), 2.45–2.26 (m, 2 H), 2.03–1.78 (m, 4 H), 1.73–1.58 (m, 2 H),
1.51–1.21 (m, 2 H), 0.90 (t, J = 7.3 Hz, 3 H).
References
(1) (a) Dräger, G.; Kirschning, A.; Thiericke, R.; Zerlin, M. Nat.
Prod. Rep. 1996, 365. (b) Riatto, V. B.; Pilli, R. A.; Victor,
M. M. Tetrahedron 2008, 64, 2279. (c) Boonphong, S.;
Kittakoop, P.; Isaka, M.; Pittayakhajonwut, D.;
13C NMR (75 MHz, CDCl3): d = 174.8, 129.7, 128.3, 128.1, 127.9,
127.7, 127.6, 127.4, 127.2, 125.1, 80.8, 74.7, 72.0, 71.9, 70.1, 34.6,
33.7, 33.6, 29.6, 24.3, 17.7, 14.0.
MS (ESI): m/z = 431 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H32NaO4: 431.2198;
Tankicharoen, M.; Thebtaranonth, Y. J. Nat. Prod. 2001, 64,
965. (d) Ishigami, K. Biosci. Biotechnol. Biochem. 2009, 73,
971. (e) Greve, H.; Schupp, P. J.; Eguereva, E.; Kehraus, S.;
König, G. M. J. Nat. Prod. 2008, 71, 1651.
found: 431.2190.
(2) (a) Rivero-Cruz, J. F.; Garcia-Aguieee, G.; Cerda-Garcia-
Rojas, C. M.; Mata, R. Tetrahedron 2000, 56, 5337.
(b) Rivero-Cruz, J. F.; Martha, M.; Cerda-Garcia-Rojas, C.
M.; Mata, R. J. Nat. Prod. 2003, 66, 511.
(3) For isolation of stagonolides: (a) Yuzikhin, O.; Mitina, G.;
Berestetskiy, A. J. Agric. Food Chem. 2007, 55, 7707.
(b) Evidente, A.; Cimmino, A.; Berestetskiy, A.; Mitina, G.;
Andolfi, A.; Motta, J. Nat. Prod. 2008, 71, 31.
(8S,9S,10R,E)-8,9-Dihydroxy-10-propyl-3,4,5,8,9,10-hexahy-
dro-2H-oxecin-2-one (Herbarumin I; 1)
To a stirred soln of 24 (0.025 g, 0.061 mmol) in anhyd CH2Cl2 (5
mL) at 0 °C under N2 was added TiCl4 (0.013 mL, 0.122 mmol) and
the resulting mixture was allowed to stir at r.t. for 2 h. The mixture
was diluted with H2O (5 mL) and extracted with CH2Cl2 (2 × 5 mL).
The combined organic extracts were washed with sat. aq NaHCO3
(2 × 5 mL) and brine (1 × 10 mL), dried (anhyd Na2SO4), filtered,
and concentrated. The residue was purified by column chromatog-
raphy (silica gel, PE–EtOAc, 80:20) to afford pure herbarumin I (1)
(0.009 g, 70%) as a colorless solid.
(c) Evidente, A.; Cimmino, A.; Berestetskiy, A.; Andolfi,
A.; Motta, A. J. Nat. Prod. 2008, 71, 1897.
(4) Tsuda, M.; Mugishima, T.; Komatsu, K.; Sone, T.; Tanaka,
M.; Mikami, Y.; Kobayashi, J. J. Nat. Prod. 2003, 66, 412.
(5) For syntheses of herbarumin I, see: (a) Furstner, A.;
Radkowski, K. Chem. Commun. 2001, 671. (b) Furstner,
A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, W.
C.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061.
(c) Sabino, A. A.; Pilli, R. A. Tetrahedron Lett. 2002, 43,
2819. (d) Nagaiah, K.; Sreenu, D.; Rao, R. S.; Yadav, J. S.
Tetrahedron Lett. 2007, 48, 7173. (e) Selvam, P. J. J.;
Rajesh, K.; Suresh, V.; Chanti, B. D.; Venkateshwarlu, Y.
Tetrahedron: Asymmetry 2009, 20, 1115. (f) Kamal, A.;
VenkataReddy, P.; Prabhakar, S. Tetrahedron: Asymmetry
2009, 20, 1120. (g) Srihari, P.; Kumaraswamy, B.;
Maheswara Rao, G.; Yadav, J. S. Tetrahedron: Asymmetry
2010, 21, 106.
(6) For syntheses of herbarumin II, see: (a) Diez, E.; Dixon, D.
J.; Ley, S. V.; Polara, A.; Rodriguez, F. Helv. Chim. Acta
2003, 86, 3717. (b) Diez, E.; Dixon, D. J.; Ley, S. V.; Polara,
A.; Rodriguez, F. Synlett 2003, 1186.
(7) For syntheses of herbarumin III, see: (a) Gurjar, M. K.;
Karmakar, S.; Mohapatra, D. K. Tetrahedron Lett. 2004, 45,
4525. (b) Nanda, S. Tetrahedron Lett. 2005, 46, 3661.
(c) Salaskar, A.; Sharma, A.; Chattopadhyay, S.
[a]D25 +13.0 (c, 0.3, EtOH).
IR (neat): 2958, 2923, 2854, 1716, 1440, 1359, 1255, 1203, 1089,
806 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.61 (dd, J = 15.8, 0.7 Hz, 1 H),
5.56–5.44 (m, 1 H), 4.94 (td, J = 9.6, 2.4 Hz, 1 H), 4.42 (br s, 1 H),
3.50 (dd, J = 9.8, 2.0 Hz, 1 H), 2.46–2.27 (m, 3 H), 2.06–1.86 (m, 3
H), 1.64–1.50 (m, 2 H), 1.45–1.21 (m, 2 H), 0.91 (t, J = 7.3 Hz, 3
H).
13C NMR (75 MHz, CDCl3): d = 176.4, 130.5, 124.9, 73.6, 73.3,
70.1, 34.4, 33.6, 33.3, 24.6, 18.0, 13.8.
MS (ESI): m/z = 251 [M + Na]+.
HRMS (ESI): m/z [M + Na]+calcd for C12H20NaO4: 251.1259;
found: 251.1264.
(9R,10R,E)-9-Hydroxy-10-propyl-4,5,9,10-tetrahydro-2H-oxe-
cin-2,8(3H)-dione (Stagonolide A; 4)
To a stirred soln of herbarumin I (1, 0.03 g, 0.13 mmol) in CH2Cl2
(6.0 mL) was added MnO2 (0.229 mg, 2.60 mmol) at 25 °C and the
mixture was stirred at this temperature for 24 h. The mixture was fil-
tered through a pad of Celite, the solvent was concentrated under re-
duced pressure, and the resulting residue was purified by column
chromatography (silica gel, PE–EtOAc, 90:10) to afford pure
stagonolide A (4) (0.027 g, 92%) as a colorless solid.
Tetrahedron: Asymmetry 2006, 17, 325. (d) Gurjar, M. K.;
Nagaprasad, R.; Ramana, C. V.; Karmakar, S.; Mohapatra,
D. K. ARKIVOC 2005, (iii), 237. (e) Boruwa, J.; Gogoi, N.;
Barua, N. C. Org. Biomol. Chem. 2006, 4, 3521. (f) Chen,
X. S.; Da S, J.; Xu, B.-Y.; Xie, Z.-X.; Li, Y. Chem. J. Chin.
Univ. 2007, 28, 2086. (g) Chen, X. S.; Da S, J.; Yang, L. H.;
Xu, B. Y.; Xie, Z. X.; Li, Y. Chin. Chem. Lett. 2007, 18,
255. (h) Gupta, P.; Kumar, P. Tetrahedron: Asymmetry
2007, 18, 1688. (i) Lee, J.; Jung, Y. H.; Tae, J. Bull. Korean
Chem. Soc. 2007, 28, 513. (j) Mohapatra, D. K.; Ramesh, D.
K.; Giardello, M. A.; Chorghade, M. S.; Gurjar, M. K.;
Grubbs, R. H. Tetrahedron Lett. 2007, 48, 2621. (k) Yadav,
J. S.; Kumar, V. N.; Rao, R. S.; Srihari, P. Synthesis 2008,
1938.
[a]D25 –59.5 (c 0.2, EtOH).
IR (neat): 3417, 2960, 2930, 2869, 1727, 1692, 1632, 1438, 1398,
1152, 1075, 824 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.42 (d, J = 16.0 Hz, 1 H), 6.37–
6.24 (m, 1 H), 4.65 (dt, J = 9.6, 2.4 Hz, 1 H), 4.05 (dd, J = 9.5, 6.2
Hz, 1 H), 2.47–2.55 (m, 1 H), 2.44 (d, J = 5.7 Hz, 1 H), 2.13 (dd,
J = 14.0, 2.3 Hz, 1 H), 2.05 (m, 1 H), 2.03–1.86 (m, 3 H), 1.73–1.58
(m, 1 H), 1.50–1.24 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 199.6, 174.1, 143.1, 131.9, 76.5,
74.5, 34.2, 34.0, 33.5, 25.0, 18.0, 13.7.
(8) For syntheses of stagonolides see (a) Perepogu, A. K.;
Raman, D.; Murty, U. S. N.; Rao, V. J. Bioorg. Chem. 2009,
37, 46. (b) Jana, N.; Mahapatra, T.; Nanda, S. Tetrahedron:
Asymmetry 2009, 20, 2622. (c) Giri, A. G.; Mohabul, A.;
Mondal, M. A.; Vedava Puranik, V. G.; Ramana, C. V. Org.
Biomol. Chem. 2010, 8, 398. (d) Srihari, P.; Kumaraswamy,
B.; Somaiah, R.; Yadav, J. S. Synthesis 2010, 1039.
(9) For syntheses of modiolides, see: (a) Mohapatra, D. K.;
Dash, U.; Naidu, P. R. Synlett 2009, 2129. (b) Matsuda, M.;
Yamazaki, T.; Fuhshuku, K.; Sugai, T. Tetrahedron 2007,
63, 8752.
MS (ESI): m/z = 249 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H18NaO4: 249.1102;
found: 249.1095.
Synthesis 2010, No. 14, 2407–2412 © Thieme Stuttgart · New York

2412
P. Srihari et al.
PAPER
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(b) Srihari, P.; Vijaya Bhasker, E.; Bal Reddy, A.; Yadav, J.
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The coupling constant value of JH5–H6 = 15.8 Hz in the
multiplet at d = 5.59–5.76 confirmed the trans geometry.
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Synthesis 2010, No. 14, 2407–2412 © Thieme Stuttgart · New York