Stereoselective formal synthesis of herbarumin III via prins cyclization

Article abstract of DOI:10.1055/s-0028-1083249

The total synthesis of herbarumin III is described, proving the versatility of the Prins cyclization in the synthesis of natural products. The approach is convergent and highly stereoselective. Ring-closing metathesis and alkene-rearrangement reactions ar

Full text of DOI:10.1055/s-0028-1083249

PAPER
3945
Stereoselective Formal Synthesis of Herbarumin III via Prins Cyclization
S
tereosele
.
ctive
F
ormal
S
Synthesis of
H
.
erbaruminI
Y
II adav,* Hissana Ather, K. Uma Gayathri, N. Venkateswar Rao, A. R. Prasad
Pheromone Group, Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 9 July 2008; revised 18 July 2008
HO
Abstract: The total synthesis of herbarumin III is described, prov-
ing the versatility of the Prins cyclization in the synthesis of natural
products. The approach is convergent and highly stereoselective.
Ring-closing metathesis and alkene-rearrangement reactions are
utilized as key steps in the synthesis of the macrolactone.
O
R2
R1
O
Key words: herbarumins, Prins cyclization, alkene rearrangement,
ring-closing metathesis
R1 = R2 = H; herbarumin III (1)
R
1 = OH, R2 = H; herbarumin I (2)m
R1 = R2 = OH; herbarumin II (3)
Figure 1
Herbarumin III (1) isolated1a from the fermentation broth
and mycelium of the fungus Phoma herbarum displays
significant phytotoxic effects against seedlings of Ama-
ranthus hypochondriacus.1b The herbarumin macrolides
1–3 (Figure 1) interact with bovin brain calmodulin and
inhibit the activation of the calmodulin-dependent en-
zyme cAMP phosphodiesterase. Construction of the ten-
membered lactone ring and the stereocontrolled formation
of the syn-1,3-diol unit are two major issues in the total
synthesis of herbarumin III (1). In previous total syntheses
of 1,2 the ten-membered lactone ring was synthesized by
ring-closing metathesis (RCM) reaction2a,b,d,e and
Yamaguchi’s lactonization method.2c Asymmetric syn-
thesis of the syn-1,3-diol moiety has been achieved using
chiral pool methods,2c a chemoenzymatic method,2c an
asymmetric allylation/Sharpless epoxidation method,2e
and Jacobsen’s hydrolytic kinetic resolution (HKR) meth-
od.2f,g Recently our group has developed a concise stereo-
selective total synthesis of herbarumin III utilizing
Crimmins’s aldol approach.2i Herein, we describe the ste-
reoselective synthesis of herbarumin III (1) via Prins cy-
clization.
Prins cyclization in the synthesis of various polyketide in-
termediates and has utilized the Prins cyclization in the
synthesis of various natural products.4 As a part of this on-
going programme, we have investigated the synthesis of
herbarumin III (1).
In our retrosynthetic analysis (Scheme 1), we envisaged
that the target molecule could be prepared from 15
through ring-closing metathesis. Compound 15 is viewed
as being obtained from 12 via Mitsunobu inversion. It is
proposed to obtain the 1,3-diol 12 from the iodide 8 via
silica gel rearrangement and in turn pyran derivative 8
would be obtained via Prins cyclization of the homoallylic
alcohol 4 and butyraldehyde.
In view of the importance of the macrolide 1, we have at-
tempted its enantiomeric synthesis (Scheme 2). The
asymmetric total synthesis of herbarumin III (1) started
with chiral homoallyl alcohol 4. Copper-mediated regio-
selective opening5 of benzyl (S)-glycidyl ether with vinyl-
magnesium bromide followed by debenzylation through
treatment with lithium or sodium in liquid ammonia pro-
duced homoallylic alcohol 4. Prins cyclization of 4 with
butyraldehyde in the presence of trifluoroacetic acid fol-
lowed by hydrolysis of the resulting trifluoroacetate gave
trisubstituted pyran 5.4c The stereochemistry was assumed
to be in accordance as it was well examined and has been
The Prins cyclization has emerged as a powerful synthetic
tool for the construction of multi-substituted tetrahydro-
pyran systems and has been utilized in the course of the
synthesis of several natural products.3 Our group has
made a significant effort to explore the synthetic utility of
OMOM
HO
MOMO
OH
1
O
HO
I
OH
O
O
15
12
7
4
Scheme 1
SYNTHESIS 2008, No. 24, pp 3945–3950
x
x.
x
x
.
2
0
0
8
Advanced online publication: 01.12.2008
DOI: 10.1055/s-0028-1083249; Art ID: Z15808SS
© Georg Thieme Verlag Stuttgart · New York

3946
J. S. Yadav et al.
PAPER
previously established.4,5 However, it was proved after that the elimination reaction itself did not result in the re-
1
elaborating the compound 5 to the target molecule 1, arranged product, we have analyzed the H NMR of the
which in all respects was identical with that reported. To- crude product of the elimination reaction, which clearly
sylation with 1.1 equivalents of tosyl chloride in the pres- revealed the presence of two doublets at d = 4.33 and 4.09
ence of triethylamine in dichloromethane produced the (J = 2.2 Hz, geminal coupling) and the absence of any
corresponding primary tosylate 6.4a Protection of the sec- characteristic signal for the rearranged product.
ondary alcohol as the methoxymethyl ether 7 was per-
Then, the substrate 10 was subjected to ozonolysis to ob-
formed with methoxymethyl chloride in dichloromethane
tain the corresponding acetoxy aldehyde, which without
in the presence of N,N-diisopropylethylamine.6 Treatment
purification was treated with a one-carbon ylide to furnish
of tosylate 7 with sodium iodide in refluxing acetone gave
the open-chain alkene 11.4e Hydrolysis of the acetate
the corresponding iodo compound 8. Elimination of HI7
group in 11 using potassium carbonate in methanol result-
from 8 using sodium hydride in N,N-dimethylformamide
ed in the alcohol 12. Alcohol 12, when subjected to stan-
produced enolic exocyclic alkene 9, which on column
dard Mitsunobu inversion conditions (DEAD, Ph3P, 4-
chromatography revealed rearranged product 10.
nitrobenzoic acid, THF then K2CO3, MeOH),8 yielded 13
In fact, we anticipated that rearranging the exocyclic alk- with the required syn-1,3-diol system. Esterification of the
ene 9 proceeds to the more stable endocyclic alkene 10 in free hydroxy group of 13 with hex-5-enoic acid in the
acidic medium after column chromatography. Incidental- presence of N,N¢-dicyclohexylcarbodiimide and a catalyt-
ly, we ended up with the compound with rearrangement ic amount of 4-(dimethylamino)pyridine readily provided
on silica gel during flash chromatography. To confirm the diene 142e and set the stage for macrocyclization by
OH
OH
a
b
HO
TsO
HO
OH
O
O
4
5
OMOM
O
6
OMOM
c
d
TsO
I
O
7
8
OMOM
O
OMOM
f
g
e
O
9
10
MOMO
OAc
MOMO
MOMO
OH
i
h
12
11
O
MOMO
OH
O
j
k
13
14
HO
HO
l
O
O
O
O
15
1
Scheme 2 Reagents and conditions: (a) 1. PrCHO, TFA, CH2Cl2; 2. K2CO3, MeOH, r.t., 3 h, 52%; (b) Et3N, TsCl, CH2Cl2, 0 °C to r.t., 3 h,
95%; (c) MOMCl, DIPEA, DMAP, CH2Cl2, 0 °C to r.t., 3 h, 98%; (d) NaI, acetone, reflux, 24 h, 95%; (e) NaH, DMF, r.t., 6 h; (f) silica gel
rearrangement, 83%; (g) 1. O3, Ph3P, CH2Cl2, 2. Ph3P=CH2, THF, –78 to 0 °C, 74%; (h) K2CO3, MeOH, r.t., 2 h, 96%; (i) 4-O2NC6H4CO2H,
DEAD, Ph3P, THF, 0 °C to r.t., 30 min, then K2CO3, MeOH, r.t., 4 h, 75%; (j) hex-5-enoic acid, DCC, DMAP, CH2Cl2, 86%; (k) TFA–CH2Cl2
(1:4), 25 °C, 2 h, 85%; (l) Grubbs II catalyst, CH2Cl2, 25 °C, 12 h, 62%.
Synthesis 2008, No. 24, 3945–3950 © Thieme Stuttgart · New York

PAPER
Stereoselective Formal Synthesis of Herbarumin III
3947
removed under reduced pressure. Purification of the crude product
by column chromatography (silica gel) yielded 5 (2.65 g, 52%) as a
colorless liquid; Rf = 0.3 (silica gel, 60% EtOAc–hexane).
[a]D20 –0.2 (c 1.88, CHCl3).
ring-closing metathesis. At the outset, the macrocycliza-
tion, deprotection of the methoxymethyl ether 14 using
trifluoroacetic acid in dichloromethane (1:4) provided the
corresponding alcohol 15.4g
IR (neat): 3386, 2932, 2871, 1705, 1460, 1380, 1333, 1259, 1218,
1185, 1111, 1052, 980, 920, 847, 627 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.89 (t, J = 6.61 Hz, 3 H), 1.09–
1.60 (m, 6 H), 1.78–1.95 (m, 2 H), 2.27 (s, 2 H), 3.27–3.62 (m, 4 H),
3.69–3.85 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 13.98, 18.63, 36.77, 37.47, 40.90,
65.55, 67.71, 75.45, 75.93.
Compound 15 possessed all the structural requirements,
as well as the sense of chirality to be converted into the
target macrolide 1 via a ring-closing metathesis reaction.
The ring-closing metathesis reaction provides a remark-
able scope for the synthesis of medium-sized rings and
macrocyclic products and has been used extensively.9 Al-
though due to the inherent ring strain, the construction of
medium-sized (8–11-membered) cycloalkenes via the
ring-closing metathesis reaction is very challenging, some
precedents exist.9 The presence of a suitable functionality
and its distance from the C=C bonds play a key role in the
success of the metathesis reaction. It has been reported2
that the ring-closing metathesis proceeds satisfactorily
with substrates possessing a hex-5-enoate ester moiety,
which is present in the dienic derivative 15. All these con-
siderations gave us confidence in this endeavor. The diene
15 upon treatment with 5 mol% Grubbs II catalyst (II) un-
der high dilution conditions (0.001 M in CH2Cl2) produc-
es only herbarumin III (1) in 62% yield,2f,9 which in all
respects was identical to the reported natural product.2
HRMS (ESI): m/z [M+ + Na] calcd for C9H18NaO3: 197.2374;
found: 197.1153.
(2S,4S,6S)-2-Propyl-6-(tosyloxymethyl)tetrahydro-2H-pyran-
4-ol (6)
To soln of 5 (2.5 g, 14.3 mmol) in anhyd CH2Cl2 (25 mL) at 0 °C
was added Et3N (3.99 mL, 28.7 mmol). Then TsCl (2.87 g, 15.1
mmol) was added over 2 h, the mixture was allowed to warm to r.t.
and stirred for 3 h. The mixture was treated with aq 1 M HCl (10
mL) and extracted with CH2Cl2 (3 × 30 mL). The organic layer was
washed with sat. NaHCO3 (15 mL) and H2O (15 mL). The com-
bined organic phases were dried (Na2SO4) and concentrated under
reduced pressure. Flash chromatography of the crude afforded 6
(4.47 g, 95%) as a gummy liquid; Rf = 0.6 (silica gel, 40% EtOAc–
hexane).
[a]D20 +2.5 (c 0.96, CHCl3).
In conclusion, we have proved the versatility of the Prins
cyclization in natural product synthesis by achieving the
stereoselective formal synthesis of herbarumin III (1) em-
ploying an eleven-step sequence. Further applications of
the Prins cyclization in the synthesis of natural products
are in progress and will be disclosed in due course.
IR (neat): 3425, 2957, 2869, 1781, 1739, 1598, 1454, 1360, 1243,
1176.6, 1189, 1096, 976, 815, 668 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 7.03 Hz, 3 H), 1.00–
1.84, (m, 8 H), 2.42 (s, 3 H), 3.14–3.23 (m, 1 H), 3.42–3.54 (m, 1
H), 3.61–3.77 (m, 1 H), 3.89–3.94 (m, 2 H), 7.30–7.40 (d, J = 7.18
Hz, 2 H), 7.60–7.85 (d, J = 8.59 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.88, 18.40, 21.43, 36.68, 37.73,
All reactions were carried out under an inert atmosphere unless
mentioned following standard syringe/septum techniques. Solvents
were dried and purified by conventional methods prior to use. The
progress of reactions was monitored by TLC using glass plates pre-
coated with silica gel 60 F254 to a thickness of 0.5 mm (Merck).
Column chromatography was performed on silica gel (60–120
mesh) and neutral alumina using Et2O, EtOAc, and hexane as elu-
ents. Optical rotation values were measured with a Perkin-Elmer
P241 polarimeter and Jasco DIP-360 digital polarimeter at 25 °C. IR
spectra were recorded with a Perkin-Elmer FT-IR spectrophotome-
ter. 1H and 13C NMR spectra were recorded with Varian Gemini 200
MHz, Bruker Avance 300 MHz, Varian Unity 400 MHz, or Varian
Inova 500 MHz spectrometer using TMS as an internal standard in
CDCl3. MS were recorded on Micro mass VG-7070H for EI and VG
Autospec M for FAB-MS.
40.48, 67.30, 72.08, 72.63, 75.42, 127.75, 129.64, 132.78, 144.65.
HRMS (ESI): m/z [M+ + Na] calcd for C16H24NaO5S: 351.4248;
found: 351.1238.
(2S,4S,6S)-4-(Methoxymethoxy)-2-propyl-6-(tosyloxymeth-
yl)tetrahydro-2H-pyran (7)
To 6 (3.0 g, 9.13 mmol) in anhyd CH2Cl2 (30 mL) at 0 °C were add-
ed successively DIPEA (4.69 mL, 27.40 mmol), DMAP (cat.), and
MOMCl (1.47 g, 18.26 mmol). The mixture was stirred at r.t. for 3
h, quenched by addition of H2O (10 mL), and extracted with CH2Cl2
(3 × 20 mL). The combined organic extracts were washed with
brine (10 mL), dried (anhyd Na2SO4), and concentrated under vac-
uum to remove the solvent and the crude was purified by column
chromatography to afford pure 7 (3.33 g, 98%) as a viscous liquid;
Rf = 0.7 (silica gel, 10% EtOAc–hexane).
(2S,4S,6S)-2-(Hydroxymethyl)-6-propyltetrahydro-2H-pyran-
4-ol (5)
[a]D20 +6.3 (c 0.85, CHCl3).
IR (neat): 2955, 2876, 1630, 1598, 1451, 1362, 1210, 1179, 1143,
1098, 1039, 976, 939, 815, 668, 555 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 6.79 Hz, 3 H), 1.05–
1.41 (m, 2 H), 1.24–1.55 (m, 4 H), 1.86–1.96 (m, 2 H), 2.47 (s, 3 H),
3.24 (m, 1 H), 3.32 (s, 3 H), 3.48–3.70 (m, 2 H), 3.91–4.02 (m, 2 H),
4.62 (s, 2 H), 7.31 (d, J = 8.30 Hz, 2 H), 7.74 (d, J = 8.30 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.91, 18.43, 21.46, 34.36, 37.86,
38.07, 55.12, 72.03, 72.4, 72.72, 75.47, 75.5, 94.31, 127.81, 129.63,
132.97, 144.57.
TFA (43.78 mL) was added slowly to a soln of 4 (3 g, 29.37 mmol)
and butyraldehyde (6.35 g, 88.12 mmol) in CH2Cl2 (90 mL) at 25
°C under N2. The mixture was stirred for 3.0 h and then sat.
NaHCO3 soln (200 mL) was added and pH was adjusted to >7 by
addition of Et3N. The layers were separated and the aqueous layer
was extracted with CH2Cl2 (4 × 70 mL), the organic layers were
combined, and the solvent was removed under reduced pressure.
The trifluoroacetate obtained in this reaction was directly used in
the next reaction without purification. The residue was dissolved in
MeOH (40 mL) and stirred with K2CO3 (8.11 g) for 0.5 h. The
MeOH was then removed under reduced pressure and H2O (30 mL)
was added. The mixture was extracted with CH2Cl2 (3 × 30 mL), the
combined organic layers were dried (Na2SO4), and the solvent was
HRMS (ESI): m/z [M+ + Na] calcd for C18H28NaO6S: 395.4773;
found: 395.1515.
Synthesis 2008, No. 24, 3945–3950 © Thieme Stuttgart · New York

3948
J. S. Yadav et al.
PAPER
(2S,4S,6S)-2-(Iodomethyl)-4-(methoxymethoxy)-6-propyltetra-
hydro-2H-pyran (8)
1H NMR (200 MHz, CDCl3): d = 0.92 (t, J = 6.61 Hz, 3 H), 1.25–
1.74 (m, 6 H), 2.02 (s, 3 H), 3.30 (s, 3 H), 3.93–4.04 (m, 1 H), 4.39–
4.64 (dd, J = 7.34, 6.79 Hz, 2 H), 4.97–5.09 (m, 1 H), 5.14–5.24 (m,
2 H), 5.56–5.73 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.91, 18.21, 21.13, 36.88, 40.11,
55.66, 70.77, 73.98, 93.87, 117.14, 138.67, 170.54.
NaI (6.03 g, 40.27 mmol) was added to a soln of 7 (3.5 g, 9.4 mmol)
in acetone (60 mL) and the mixture was heated to reflux for 24 h.
Acetone was removed under reduced pressure. To the residue was
added H2O and CH2Cl2 and the organic layer was separated, dried
(Na2SO4), concentrated, and chromatographed to afford 8 (2.51 g,
95%) as a colorless liquid; Rf = 0.7 (silica gel, 10% EtOAc–hex-
ane).
HRMS (ESI): m/z [M+ + Na] calcd for C12H22NaO4: 253.3007;
found: 253.1424.
[a]D20 –22.0 (c 1.91, CHCl3).
(3R,5S)-3-(Methoxymethoxy)octadec-1-en-5-ol (12)
IR (neat): 3447, 2957, 2928, 1735, 1670, 1595, 1458, 1517, 1458,
1375, 1273, 1152, 1036, 918, 754 cm–1.
Compound 11 (0.5 g, 2.17 mmol) was dissolved in MeOH (10 mL)
and K2CO3 (0.6 g, 4.34 mmol) was added. The mixture was stirred
at r.t. for 4 h and then it was diluted with H2O (15 mL) and extracted
with CH2Cl2 (3 × 10 mL). Removal of solvent under reduced pres-
sure followed by flash chromatography afforded 12 (0.39 g, 96%)
as a colorless liquid; Rf = 0.4 (30% EtOAc–hexane).
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 6.79 Hz, 3 H), 1.09–
1.22 (m, 2 H), 1.31–1.62 (m, 4 H), 1.84–1.90 (dddd, J = 12.84, 2.26,
2.26 Hz, 1 H), 2.15–2.20 (dddd, J = 12.08, 2.26, 2.26 Hz, 1 H),
3.14–3.17 (m, 2 H), 3.29–3.39 (m, 5 H), 3.61–3.73 (m, 1 H), 4.63–
4.68 (m, 2 H).
[a]D20 –113.5 (c 1, CHCl3).
13C NMR (75 MHz, CDCl3): d = 8.75, 13.93, 18.65, 37.97, 38.13,
38.19, 55.17, 72.60, 74.99, 75.59, 94.35.
IR (neat): 3443, 2955, 2930, 1637, 1461, 1419, 1381, 1216, 1152,
1097, 1034, 922 cm–1.
HRMS (ESI): m/z [M+ + Na] calcd for C11H21INaO3: 351.1871;
found: 351.0418.
1H NMR (200 MHz, CDCl3): d = 0.91 (t, J = 7.03 Hz, 3 H), 1.35–
1.69 (m, 6 H), 3.39 (s, 3 H), 3.79–3.91 (m, 1 H), 4.25–4.34 (m, 1 H),
4.51–4.67 (dd, J = 7.03, 6.25 Hz, 2 H), 5.15–5.26 (m, 2 H), 5.66–
5.83 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.02, 18.78, 39.59, 42.34, 55.68,
67.74, 75.40, 94.40, 116.59, 137.91.
(2S,4R)-4-(Methoxymethoxy)-6-methyl-2-propyl-3,4-dihydro-
2H-pyran (10)
To a soln of 11 (2.5 g, 7.6 mmol) in DMF (100 mL) at 0 °C was
added NaH (60% in oil, 0.91 g, 38.0 mmol). The mixture was stirred
at r.t. 6 h and then the reaction was quenched with H2O at 0 °C. The
resultant mixture was diluted with EtOAc, washed with H2O and
brine, dried (Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by column chromatography
(silica gel, 10% EtOAc–hexane) gave 9, which on column chroma-
tography revealed rearranged product 10 (1.26 g, 83%) as a color-
less clear oil; Rf = 0.6 (silica gel, 10% EtOAc–hexane).
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J = 6.79 Hz, 3 H), 1.25–
1.71 (m, 7 H), 1.91–2.14 (m, 2 H), 3.53 (s, 3 H), 3.85 (m, 1 H), 4.24
(m, 1 H), 4.49 (s, 1 H), 4.63 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 147.06, 98.02, 94.74, 70.63, 70.46,
55.24, 42.53, 41.49, 22.08, 18.77, 14.13.
(3R,5R)-3-(Methoxymethoxy)octadec-1-en-5-ol (13)
To a stirred mixture of 12 (0.3 g, 1.53 mmol), Ph3P (1.33 g, 5.0
mmol), and 4-nitrobenzoic acid (0.34 g, 2.0 mmol) in anhyd THF
(10 mL) at 0 °C was added DEAD (0.88 g, 5.0 mmol) via a syringe.
The mixture was then stirred at r.t. for 0.5 h, diluted with H2O (10
mL), and extracted with EtOAc (2 × 15 mL). The solvent was re-
moved and the crude product was dissolved in MeOH (10 mL) and
K2CO3 (0.44 g, 3.18 mmol) was added. The mixture was stirred at
r.t. for 4 h and then it was diluted with H2O (15 mL) and extracted
with CH2Cl2 (3 × 10 mL). Removal of solvent under reduced pres-
sure followed by flash chromatography afforded 13 (0.22 g, 75%)
as a colorless liquid; Rf = 0.4 (30% EtOAc–hexane).
[a]D20 –100.5 (c 1, CHCl3).
LC-MS: m/z = 199 (M – 1), 169, 140, 139, 110, 102, 101, 81.
IR (neat): 3443, 2956, 2930, 1637, 1461, 1419, 1381, 1216, 1152,
1097.83, 1034, 922 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 7.03 Hz, 3 H), 1.26–
1.79 (m, 6 H), 3.39 (s, 3 H), 3.74–3.85 (m, 1 H), 4.19–4.30 (m, 1 H),
4.48–4.73 (dd, J = 7.03, 6.25 Hz, 2 H), 5.18–5.27 (m, 2 H), 5.56–
5.74 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.05, 18.58, 39.74, 42.43, 55.72,
70.48, 77.58, 93.46, 117.82, 137.57.
HRMS (ESI): m/z [M+ + Na] calcd for C10H20NaO3: 211.2640;
found: 211.1306.
(3R,5S)-5-Acetoxy-3-(methoxymethoxy)octadec-1-ene (11)
Ozone was bubbled through a soln of 10 (1.0 g, 4.99 mmol) in
CH2Cl2 (12 mL) at –78 °C until no unreacted starting material was
observed (TLC). The mixture was purged with N2 to remove the ex-
cess ozone and cooled to 0 °C, Ph3P (2.61 g, 9.98 mmol) was added,
and the mixture was stirred for 2 h. The mixture was concentrated
in vacuo. After addition of hexane, the mixture was filtered through
a Celite pad; the residue was washed with hexane. The filtrate was
dried (Na2SO4), concentrated under reduced pressure, and the crude
aldehyde was subjected to the next reaction without further purifi-
cation.
(4R,6R)-6-(Methoxymethoxy)oct-7-en-4-yl Hex-5-enoate (14)
To a soln of 12 (0.2 g, 1.06 mmol) in CH2Cl2 (10 mL) was added
hex-5-enoic acid (0.13 g, 1.16 mmol) and DCC (0.24 g, 1.16 mmol)
at r.t. DMAP (0.06 g, 0.53 mmol) was added and the mixture was
stirred at r.t. for 15 h. Filtration of the mixture, evaporation of the
solvent, and column chromatography of the resulting crude afforded
14 (0.26 g, 86%) as a colorless oil; Rf = 0.2 (silica gel, 20% EtOAc–
hexane).
To the ylide generated from methylenetriphenylphosphorane (6.05
g, 14.97 mmol) and t-BuOK (2.80 g, 25.0 mmol) in anhyd THF was
added at 0 °C a soln of the aldehyde in anhyd THF (12 mL) and the
mixture was stirred for 2 h at this temperature. THF was removed
under reduced pressure and to the residue was added EtOAc (15
mL) and the soln was washed with brine (5 mL), dried (Na2SO4),
and concentrated in vacuo. Purification by column chromatography
afforded 11 (0.85g, 74%, 2 steps) as a colorless oil; Rf = 0.7 (silica
gel, 10% EtOAc–hexane).
[a]D20 –89.0 (c 1, CHCl3).
[a]D20 –122.6 (c 1, CHCl3).
IR (neat): 3168, 2928, 1732, 1631, 1384, 1244, 1154, 1100, 1033
cm–1.
IR (neat): 2959, 2932, 1738, 1463, 1372, 1241, 1155, 1098, 1031,
924 cm–1.
Synthesis 2008, No. 24, 3945–3950 © Thieme Stuttgart · New York

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Stereoselective Formal Synthesis of Herbarumin III
3949
1H NMR (200 MHz, CDCl3): d = 0.92 (t, J = 7.03 Hz, 3 H), 1.25–
1.40 (m, 4 H), 1.49–1.78 (m, 2 H), 1.84–1.98 (m, 2 H), 2.04–2.14
(m, 2 H), 2.23–2.30 (m, 2 H), 3.34 (s, 3 H), 3.93–4.04 (m, 1 H),
4.44–4.64 (dd, J = 7.03, 7.03 Hz, 2 H), 4.92–5.04 (m, 3 H), 5.13–
5.20 (m, 2 H), 5.53–5.82 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.91, 18.36, 24.15, 33.08, 33.81,
36.48, 39.89, 55.45, 70.81, 74.53, 93.65, 115.29, 118.03, 137.69,
172.95.
References
(1) (a) Rivero-Cruz, J. F.; Macias, M.; Cerda-Garcia-Rojas, C.
M.; Mata, R. J. Nat. Prod. 2003, 66, 511. (b) Mata, R.;
Macias, M.; Rojas, S.; Lotina-Hensen, B.; Toscano, R.;
Anaya, A. Phytochemistry 1998, 49, 441.
(2) (a) Gurjar, M. K.; Karmakar, S.; Mohapatra, D. K.
Tetrahedron Lett. 2004, 45, 4525. (b) Gurjar, M. K.;
Nagaprasad, R.; Ramanna, C. V.; Karmakar, S.; Mohapatra,
D. K. ARKIVOC 2005, (iii), 237. (c) Nanda, S. Tetrahedron
Lett. 2005, 46, 3661. (d) Salaskar, A.; Sharma, A.;
Chattopadhyay, S. Tetrahedron: Asymmetry 2006, 17, 325.
(e) Boruwa, J.; Gogoi, N.; Barua, N. C. Org. Biomol. Chem.
2006, 4, 3521. (f) Jieun, L.; Young-Hee, J.; Jinsung, T. Bull.
Korean Chem. Soc. 2007, 28, 513. (g) Gupta, P.; Kumar, P.
Tetrahedron: Asymmetry 2007, 18, 1688. (h) Xue, S. C.;
Shi, J. D.; Li, H. Y.; Bo, Y. X.; Zhi, X. X.; Ying, L. Chin.
Chem. Lett. 2007, 18, 255. (i) Yadav, J. S.; Kumar, V. N.;
Rao, R. S.; Srihari, P. Synthesis 2008, 1938.
(3) For the Prins cyclization, see for example: (a) Barry, C. S.
J.; Crosby, S. R.; Harding, J. R.; Hughes, R. A.; King, C. D.;
Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429.
(b) Yang, X.-F.; Mague, J. T.; Li, C.-J. J. Org. Chem. 2001,
66, 739. (c) Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew.
Chem. Int. Ed. 2005, 44, 3485. (d) Barry, C. S.; Bushby, N.;
Harding, J. R.; Willis, C. S. Org. Lett. 2005, 7, 2683.
(e) Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126,
12216. (f) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker,
G. D.; Willis, C. L. Org. Lett. 2002, 4, 3407. (g)Marumoto,
S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett.
2002, 4, 3919. (h) Kozmin, S. A. Org. Lett. 2001, 3, 755.
(i) Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem.
2001, 66, 4679. (j) Kopecky, D. J.; Rychnovsky, S. D. J.
Am. Chem. Soc. 2001, 123, 8420. (k) Rychnovsky, S. D.;
Thomas, C. R. Org. Lett. 2000, 2, 1217. (l) Rychnovsky, S.
D.; Yang, G.; Hu, Y.; Khire, U. R. J. Org. Chem. 1997, 62,
3022. (m) Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126,
2425. (n) Yadav, J. S.; Reddy, B. V. S.; Sekhar, K. C.;
Gunasekar, D. Synthesis 2001, 885. (o) Yadav, J. S.; Reddy,
B. V. S.; Reddy, M. S.; Niranjan, N. J. Mol. Catal. A: Chem.
2004, 210, 99. (p) Yadav, J. S.; Reddy, B. V. S.; Reddy, M.
S.; Niranjan, N.; Prasad, A. R. Eur. J. Org. Chem. 2003,
1779.
HRMS (ESI): m/z [M+ + Na] calcd for C16H28NaO4: 307.3911;
found: 307.1882.
(3R,5R)-5-(Hex-5-enoyloxy)oct-1-en-3-ol (15)
Compound 14 (0.1 g, 0.35 mmol) was dissolved in CH2Cl2 (1 mL)
and TFA (0.10 mL, 1.40 mmol) was added dropwise at 25 °C. The
mixture was stirred at this temperature for 2 h and then quenched
with sat. NaHCO3 soln (8 mL) and extracted with CH2Cl2 (2 × 8
mL). The combined organic extracts were washed with brine (8 mL)
and concentrated in vacuo and the residue was subjected to column
chromatography to afford the pure 15 (0.071 g, 85%) as a colorless
oil; Rf = 0.5 (silica gel, 30% EtOAc–hexane).
[a]D20 +1.0 (c 1, CHCl3).
IR (neat): 3442, 2927, 2857, 1731, 1630, 1173 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (t, 3 H), 1.10–1.45 (m, 4 H),
1.5–1.90 (m, 4 H), 2.00 (s, 1 H), 2.00–2.18 (m, 2 H), 2.24–2.32 (m,
2 H), 4.20–4.30 (s, 1 H), 4.90–5.62 (m, 5 H), 5.68–5.90 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.98, 18.42, 24.06, 32.99, 33.88,
36.78, 41.61, 70.55, 71.59, 114.86, 115.34, 137.64, 140.50, 173.48.
HRMS (ESI): m/z [[M+ + Na]] calcd for C14H24NaO3: 263.3384;
found: 263.1622.
(7R,9R,5E)-7-Hydroxy-9-propylnon-5-en-9-olide (Herbarumin
III, 1)
Grubbs II catalyst (0.88 mg, 5 mol%) was dissolved in CH2Cl2 (10
mL) and was added dropwise to a soln of 15 (0.05 g, 0.20 mmol) in
CH2Cl2 (40 mL). The mixture was stirred at 25 °C for 12 h, by
which time all of the starting material had been consumed (TLC).
The solvent was removed under vacuum and the crude product was
purified by column chromatography (silica gel) to give 1 (0.027 g,
62%) as a colorless oil; Rf = 0.3 (silica gel, 30% EtOAc–hexane).
[a]D20 +20.2 (c 1.24, EtOH).
(4) (a) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R.
Tetrahedron Lett. 2006, 47, 4397. (b) Yadav, J. S.; Reddy,
M. S.; Prasad, A. R. Tetrahedron Lett. 2006, 47, 4937.
(c) Yadav, J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron
Lett. 2005, 46, 2133. (d) Yadav, J. S.; Reddy, M. S.; Prasad,
A. R. Tetrahedron Lett. 2006, 47, 4995. (e) Yadav, J. S.;
Reddy, M. S.; Rao, P. P.; Prasad, A. R. Synlett 2007, 2049.
(f) Yadav, J. S.; Rao, P. P.; Reddy, M. S.; Rao, N. V.; Prasad,
A. R. Tetrahedron Lett. 2007, 48, 1469. (g) Yadav, J. S.;
Kumar, N. N.; Reddy, M. S.; Prasad, A. R. Tetrahedron
2007, 63, 2689. (h) Rao, A. V. R.; Reddy, E. R.; Joshi, B. V.;
Yadav, J. S. Tetrahedron Lett. 1987, 28, 6497.
IR (neat): 3442, 2959, 2927, 1725, 1630, 1383 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (t, 3 H), 1.32–1.42 (m, 2 H),
1.49–1.76 (m, 2 H), 1.77–1.85 (m, 2 H), 1.98–2.02 (m, 3 H), 2.02
(m, 1 H), 2.24–2.29 (m, 1 H), 2.37–2.42 (m, partially D2O ex-
changeable, 2 H), 4.42–4.47 (m, 1 H), 5.10–5.21 (m, 1 H), 5.34–
5.44 (m, 1 H), 5.59–5.64 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 18.4, 26.0, 33.7, 34.6, 37.4,
40.6, 67.8, 68.0, 124.9, 134.6, 176.7.
HRMS (ESI): m/z [M+ + Na] calcd for C12H20NaO3: 235.2854;
found: 235.1303.
(5) Bonini, C.; Chiummiento, L.; Lopardo, M. T.; Pullex, M.;
Colobert, F.; Solladie, G. Tetrahedron Lett. 2003, 44, 2695.
(6) Murai, M.; Ichimaru, N.; Abe, M.; Nishioka, T.; Miyoshi, H.
J. Pestic. Sci. 2006, 31, 156.
(7) Fuwa, H.; Okamura, Y.; Natsugari, H. Tetrahedron 2004,
60, 5341.
Acknowledgment
H.A., K.U.G. and N.V.R. thank CSIR, New Delhi for fellowships
and also thank DST for the financial assistance under the J. C. Bose
fellowship scheme.
(8) Mitsunobu, O. Synthesis 1981, 1.
(9) (a) Maier, M. E. Angew. Chem. Int. Ed. 2000, 39, 2073.
(b) Furstner, A.; Muller, T. Synlett 1997, 1010. (c) Chang,
S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757.
(d) Delgado, M.; Martin, J. D. J. Org. Chem. 1999, 64,
4798. (e) Bamford, S. J.; Goubitz, K.; van Lingen, H. L.;
Luker, T.; Schenk, H.; Hiemstra, H. J. Chem. Soc., Perkin
Synthesis 2008, No. 24, 3945–3950 © Thieme Stuttgart · New York

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Trans. 1 2000, 345. (f) Nakashima, K.; Ito, R.; Sono, M.;
Tori, M. Heterocycles 2000, 53, 301. (g) Oishi, T.;
Nagumo, Y.; Hirama, M. Chem. Commun. 1998, 1041.
(h) Furstner, A.; Piquet, M.; Bruneau, C.; Dixneuf, P. H.
Chem. Commun. 1998, 1315. (i) Gerlach, K.; Quitschalle,
M.; Kalesse, M. Tetrahedron Lett. 1999, 40, 3553.
(j) Barrett, A. G. M.; Baugh, S. P. D.; Braddock, D. C.;
Flack, K.; Gibson, V. C.; Giles, M. R.; Marshall, E. L.;
Procopiou, P. A.; White, A. J. P.; Williams, D. J. J. Org.
Chem. 1998, 63, 7893. (k) Furstner, A.; Thiel, O. R.;
Blanda, G. Org. Lett. 2000, 2, 3731.
Synthesis 2008, No. 24, 3945–3950 © Thieme Stuttgart · New York