First stereoselective total synthesis of (-)-stagonolide A

Article abstract of DOI:10.1016/j.tetasy.2009.12.015

The first stereoselective total synthesis of the nonenolide (-)-stagonolide A is described. Olefin metathesis and epoxide opening reaction are the key steps involved.

Full text of DOI:10.1016/j.tetasy.2009.12.015

Tetrahedron: Asymmetry 21 (2010) 106–111
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
First stereoselective total synthesis of (ꢀ)-stagonolide A
*
Pabbaraja Srihari , Boyapelly Kumaraswamy, Gokada Maheswara Rao, Jhillu Singh Yadav
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first stereoselective total synthesis of the nonenolide (ꢀ)-stagonolide A is described. Olefin metath-
esis and epoxide opening reaction are the key steps involved.
Received 23 November 2009
Accepted 21 December 2009
Available online 11 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
R5
R4
R3
Ten-membered macrolides with significant biological proper-
ties continue to attract the attention of both biologist and chem-
ists.1 The scarcity coupled with complexity of the natural
materials poses a great challenge for synthetic chemist. Herbaru-
min I–III2 are recent examples with potent phytotoxic properties,
and have been well addressed by several groups.3 Our own interest
in these types of natural products has allowed us to accomplish the
total synthesis of herbarumin III3l in a concise manner. Stagono-
lides (Fig. 1) are other examples, which have been isolated recently
from the fungus Stagonospora cirsii, a pathogen of Cirsium arvense
causing necrotic lesions on leaves.4 To the best of our knowledge,
there are no reports so far on the total synthesis of the toxic metab-
olite stagonolide A, and in continuation of our investigations for
concise synthetic routes for the total synthesis of biologically ac-
tive lactone containing natural products, we herein report the first
stereoselective total synthesis of stagonolide A.
Interestingly, we observed that both herbarumin I and stagono-
lideA have a similar skeleton butdifferby thepresence of anoxidized
carbon in stagonolide (C7). Retrosynthetically, we identified lactone
10as thekeyintermediate, whichcanbe manipulated furtherbyace-
tonide deprotection and selective allyl alcohol oxidation to give the
target compound stagonolide A. The macrolactone 10 can be synthe-
sized by coupling two fragments 11 and 12 via an olefin metathesis
followed by macrolactonization or esterification followed by an ole-
fin metathesis. While the 5-hexenoic acid fragment is commercially
available, the second fragment with three stereogenic centers 11 can
be easily synthesized from trans-2-hexenol (a non-carbohydrate
O
R6
R2
O
R1
R1 = α-CH2CH2CH3, R2 = β-OH, R3 = α-H, R4 = β-OH,
R5 = H, R6 = H : Herbarumin I 1
R1 = α-CH2CH2CH3, R2 = β-OH, R3 = α-H, R4 =β-OH,
R5 = H, R6 = β-OH : Herbarumin II 2
R1 = α-CH2CH2CH3, R2 = H, R3 = α-H, R4 = β-OH,
R5 = H, R6 = H : Herbarumin III 3
R1= α-CH2CH2CH3, R2 = β-OH, R3 + R4 = O, R5 = H,
R6 = H : Stagonolide A 4
R1 = α-CH2CH2CH3, R2 = α-OH; R3 = β-H, R4 = α-H,
R6 = H : Stagonolide B 5
R1 = α-Me, R2 = H, R3 = α-OH, R4 = β-H, R5 = β-OH,
R6 = H : Stagonolide C 6
OH
OH
OH
O
O
O
Me
O
O
Me
O
Me
O
Stagonolide F 9
Stagonolide D 7
Stagonolide E 8
route) or D-ribose (chiral pool strategy) (Scheme 1).
Figure 1.
2. Results and discussion
epoxy chloride 16 with triphenylphosphine and CCl4 and then sub-
jected to our earlier reported procedure to give chiral propargyl
alcohol 17.6 The newly generated chiral secondary alcohol was
protected as TBS ether 18 and the terminal acetylene was then
treated with n-BuLi followed by quenching with ethyl chlorofor-
Initially we started with the commercially available trans-2-
hexenol, which was epoxidized under Sharpless conditions5 to pro-
vide chiral epoxy alcohol 15. The epoxy alcohol was converted to
mate to yield
a,b-unsaturated ester 19. The cis reduction under
* Corresponding author. Tel.: +91 40 27161490; fax: +91 40 27160512.
E-mail addresses: srihari@iict.res.in, sriharipabbaraja@yahoo.com (P. Srihari).
Lindlar’s condition gave Z olefin 13, which was subjected to dihydr-
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.015

P. Srihari et al. / Tetrahedron: Asymmetry 21 (2010) 106–111
107
uct 24. Silyl deprotection with TBAF yielded the key fragment 11
with the required stereogenic centers (Scheme 2).
O
O
O
O
O
Alternatively, in a concise manner, we also synthesized the key
intermediate 11 utilizing a chiral pool synthetic strategy. This syn-
thesis is a departure from the prior work at the readily available
epoxide intermediate 14.8 The epoxide 14 is treated with ethyl
magnesium bromide in the presence of copper iodide to give the
key intermediate 11.
HO
O
O
10
Stagonolide A 4
OH
O
Coupling of alcohol 11 with 5-hexenoic acid under standard
DCC, DMAP conditions gave ester 25 which in turn allowed us to
proceed further for the metathesis reaction. We observed that 1st
generation Grubb’s catalyst works efficiently to produce the de-
sired lactone ring 10 as a diastereomeric mixture E/Z (8:2).9 The
diastereomers were not separated at this stage due to very close
Rf values but were separated after performing the next reaction.
The major diastereomer was found to be the desired E-isomer
based on the comparison of the crude data with earlier literature3b
and was characterized fully after deprotection of the acetonide
moiety. Thus, we proceeded further for acetonide deprotection
by TFA in CH2Cl2 to give the easily separable diastereomers to pro-
vide herbarumin I 1, whose analytical data were compared with
those of the natural product2 and the synthetic products from ear-
lier reports.3b Further oxidation of herbarumin I with MnO2 yielded
the new nonenolide stagonolide A 4 in a good yield (Scheme 3).
The spectroscopic data were found to be identical to those of the
natural product.4a
O
O
+
HO
11
O
12
OTBS
O
O
OEt
O
14
13
trans 2-hexenol
D-Ribose
Scheme 1. Retrosynthesis.
oxylation with OsO4 to give the polyhydroxylated ester 20 along
with undesired 20a as an easily separable diastereomeric mixture
(85:15).7 Isopropylidination of the desired major diol 20 with 2,2-
DMP in CH2Cl2 yielded ester 21, which was reduced with LiAlH4 to
afford alcohol 22. Oxidation of 22 with PCC provided aldehyde 23,
which was subsequently treated with iodomethyltriphenylphos-
phine in the presence of n-BuLi to give the 1-C homologated prod-
3. Conclusion
In conclusion, the first total synthesis of stagonolide A has been
achieved in nine steps with an overall yield of 24%. Two synthetic
O
O
(-)DIPT, Ti(OiPr)4
TPP, CCl4
Cl
OH
OH
TBHP, CH2Cl2
reflux, 3 h, 85%
15
16
º
2 h, -25 C, 90%
OTBS
OH
Li/liq NH3
TBS-Cl, imidazole
n-BuLi, Cl-COOEt
º
º
-78 C, THF, 87%
º
CH2Cl2, 0 C,
THF, -25 C, 2 h, 75%
18
2 h, 95%
17
OTBS
OTBS
O
OsO4, NMO
aq acetone : t-BuOH
rt, 12 h, 88%
Pd-CaCO3/quinoloine
EtOAc,1h, 95%
OEt
OEt
19
13
O
OH
OTBS
O
OTBS
O
OTBS OH
OEt
LAH, THF
2,2-DMP, PPTS
OEt
OEt
+
º
CH2Cl2, rt,
12 h, 77%
15 min, 0-5 C,
O
O
O
O
20a
OH
OH
21
20
22
91%
(85:15)
O
OTBS
O
OTBS
O
OTBS
O
ICH3PPh3, n-BuLi
PCC/CH3COONa
OH
H
º
THF, 0 C- rt,
CH2Cl2, rt,
3 h, 75%
O
24
23
O
1 h, 70%
O
OH
TBAF, THF
rt, 2 h, 90%
O
11
Scheme 2.

108
P. Srihari et al. / Tetrahedron: Asymmetry 21 (2010) 106–111
O
O
O
OH
O
O
O
O
CuI, EtMgBr
ref. 8
HO
O
D-Ribose
º
THF, -40 C,
DCC, DMAP
11
14
O
O
º
3 h, 92%
CH2Cl2, 0 C- rt,
25
6 h, 84%
O
O
HO
HO
O
Grubbs 1st generation
TFA, CH2Cl2
rt, 8 h, 88%
MnO2, CH2Cl2
30 h, rt, 96%
O
O
O
O
CH2Cl2, reflux
6h, 82%
HO
O
O
10
E : Z (80 : 20)
herbarumin-I 1
stagonolide A 4
Scheme 3.
routes for the synthesis of the key intermediate 11 with three ste-
reogenic centers have been provided, which could be utilized for
the synthesis of herbarumin I and stagonolide A. The key reactions
involved are the epoxide opening, the generation of chiral propar-
gyl alcohol from a chiral epoxy chloride, Lindlar’s reduction, and
Grubb’s olefin metathesis. Application of this strategy to the prep-
aration of other analogues toward investigation for biological
activity is currently being pursued.
CDCl3): d 0.94 (t, J = 6.8 Hz, 3H), 1.35–1.58 (m, 4H), 2.48 (br s,
1H), 2.80–2.92 (m, 2H), 3.53 (dd, J = 12.8, 4.5 Hz, 1H), 3.83 (dd,
J = 12.8, 2.3 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 13.5, 18.9, 33.3,
55.8, 58.5, 61.8. Anal. Calcd for C6H12O2: C, 62.04; H, 10.41. Found:
C, 62.12; H, 10.38.
4.1.2. (2R,3R)-trans-3-Propyloxiranemethylchloride 16
A stirred solution of alcohol 15 (1.0 g, 8 mmol), triphenyl phos-
phine (Ph3P) (3.39 g, 12 mmol), and NaHCO3 (362 mg, 4 mmol) in
CCl4 (15 mL) under nitrogen atmosphere was refluxed for 3 h. The
solvent was removed in vacuo and the residue was purified by silica
gel column chromatography (5% EtOAc/hexane) to yield the epoxy
4. Experimental
4.1. General
chloride 16 (0.91 mg, 85%) as a yellow oil. ½a D27
ꢂ
¼ þ10:0 (c 2.8,
CHCl3); IR (neat)
m ;
max: 1637, 1219, 913, 771 cmꢀ1 1H NMR
The reactions were carried out under an N2 atmosphere in
anhydrous solvents such as CH2Cl2, THF, and EtOAc. THF used
was freshly distilled over benzophenone prior to use. All reactions
were monitored by TLC (silica-coated plates and visualized under
UV light). Yields refer to isolated yields. Air-sensitive reagents were
transferred by a syringe or a double-ended needle. 1H and 13C NMR
spectra were recorded in CDCl3 solution on Bruker Avance 300
spectrometers. Chemical shifts are reported relative to TMS as an
internal standard. Column chromatography was performed on Sil-
ica Gel (60–120 mesh) supplied by Acme Chemical Co., India. TLC
was performed on Merck 60 F-254 silica gel plates. IR (FT-IR) spec-
tra were recorded either on KBr pellets or neat as thin film. Optical
rotations were recorded on JASCO DIP-360 digital polarimeter.
(300 MHz, CDCl3): d 0.99 (t, J = 7.6 Hz, 3H), 1.22–1.37 (m, 2H),
1.43–1.59 (m, 2H), 2.78–2.83 (m, 1H), 2.91–2.96 (m, 1H), 3.38 (dd,
J = 11.0, 5.9 Hz, 1H), 3.61 (dd, J = 11.0, 5.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d 13.7, 19.0, 33.3, 44.7, 57.0, 58.8. Anal. Calcd for
C6H11OCl: C, 53.54; H, 8.24. Found: C, 54.56; H, 8.26.
4.1.3. (3R)-Hex-1-yn-3-ol 17
To
a solution of LiNH2 [prepared from lithium (1.03 g,
148 mmol) in liquid NH3 (50 mL) at ꢀ35 °C, and catalytic amount
of ferric nitrate] was added epoxy-choloride 16 (2.5 g, 18.5 mmol)
in THF (100 mL) and was allowed to stir for 2 h. The reaction was
quenched with solid NH4Cl and allowed to warm to room temper-
ature. The reaction mixture was diluted with water and extracted
with diethyl ether (2 ꢁ 10 mL). The combined organic phase was
washed with water and brine, and evaporated in vacuo. The crude
product was purified by silica gel column chromatography (10%
4.1.1. (2R,3R)-(3-Propyl-oxiranyl)-methanol 15
A mixture of
D
-(ꢀ)-diisopropyl tartrate (15.92 mL, 75 mmol)
and Ti(OiPr)4 (17.85, 60 mmol) in CH2Cl2 (100 mL) containing 4 Å
molecular sieves was stirred for 15 min at ꢀ25 °C under a nitrogen
atmosphere. After 15 min at the same temperature, t-BuOOH
(150 mL, 4 M in toluene, 600 mmol) was added over a period of
10 min and the mixture was stirred for 30 min. A solution of
trans-2-hexene-1-ol (30 g, 300 mmol) in dry CH2Cl2 (100 mL) was
slowly added at ꢀ25 °C. The mixture was stirred for 1 h at
ꢀ25 °C and then to this was added 10% NaOH (50 mL) followed
by aq satd NaCl solution (100 mL) at 0 °C. The reaction mixture
was warmed to room temperature for 1 h and diluted with CH2Cl2.
The mixture was filtered through Celite and extracted with CH2Cl2
(2 ꢁ 200 mL). The combined organic phases were washed with
water and brine solution and were concentrated under reduced
pressure. Purification by silica gel column chromatography (30%
EtOAc/hexane) provided the epoxy alcohol 15 (31.5 g, 90%) as a
EtOAc/hexane) to give yellow liquid 17 (1.36 g, 75%). ½a D27
¼
ꢂ
þ15:8 (c 0.3, CHCl3); IR (neat): mmax 3421, 2959, 2855,
1458 cmꢀ1 1H NMR (300 MHz, CDCl3): d 0.87 (t, J = 7.3 Hz, 3H),
;
1.31–1.48 (m, 2H), 1.53–1.72 (m, 2H), 2.39 (d, J = 2.0 Hz, 1H),
3.02–3.13 (br s, 1H), 4.30 (td, J = 6.4, 1.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d 13.5, 18.1, 39.4, 61.7, 72.5, 85.0. Anal. Calcd
for C6H10O: C, 73.43; H, 10.27. Found: C, 73.32; H, 10.65.
4.1.4. (3R)-3-tert-Butyldimethylsilyloxy-hex-1-yne 18
Imidazole (2.7 g, 40 mmol) was added to a solution of alcohol
17 (2.0 g, 20 mmol) in dry CH2Cl2 (100 mL) and the mixture was
stirred at 0 °C under nitrogen. After 30 min TBDMSCl (4.6 g,
30 mmol) was added to the reaction mixture and stirred at the
same temperature for 2 h. After complete consumption of the
starting material, the reaction was quenched with the addition of
water, and the reaction mixture was extracted with CH2Cl2
colorless oil; ½a D28
ꢂ
¼ þ40:5 (c 1.0, CHCl3); IR (neat)
mmax: 3406,
2961,2872, 1462, 1223, 1068, 897 cmꢀ1
;
1H NMR (300 MHz,

P. Srihari et al. / Tetrahedron: Asymmetry 21 (2010) 106–111
109
(2 ꢁ 25 mL). The organic extract was washed with water and brine.
The organic layer was concentrated using a rotaevaporator to give
the crude product, which was purified by silica gel column chro-
matography (5% EtOAc/hexane) to provide TBS protected ether
EtOAc/hexane) provided diol 20 as a yellow liquid (2.2 g, 88%).
¼ ꢀ4:5 (c 1.0, CHCl3); IR (neat): mmax 3451, 2957, 2931,
2858, 1733, 1638, 1255, 1070, 772 cmꢀ1 1H NMR (300 MHz,
CDCl3): d 0.07 (s, 6H), 0.83–0.92 (m, 12H), 1.20–1.48 (m, 6H),
1.58–1.72 (m, 1H), 2.70 (d, J = 8.8 Hz, 1H), 3.21 (d, J = 7.9 Hz, 1H),
3.48–3.56 (m, 1H), 3.88–3.95 (m, 1H), 4.02 (t, J = 7.8 Hz, 1H),
4.15–4.30 (m, 2H); 13C NMR (75 MHz, CDCl3): d ꢀ4.8, ꢀ4.2, 14.0
(2 C), 17.9, 18.2, 25.7, 35.8, 61.4, 71.0, 71.9, 73.5, 173.7; MS-ESI:
m/z 343 (M++Na); HRMS (ESI): m/z calcd for C15H32O5NaSi:
343.1916, found: 343.1927.
½ ꢂ
a 2D7
;
18 as a colorless oil, yield (4.0 g, 95%). ½a D29
¼ þ27:9 (c 1.2, CHCl3);
ꢂ
IR (neat): mmax 3311, 2958, 2933, 2859, 1466, 1255, 1114, 1084,
896, 778 cmꢀ1 1H NMR (300 MHz, CDCl3): d 0.10 (s, 3H), 0.13 (s,
;
3H), 0.88–0.95 (m, 12H), 1.35–1.54 (m, 2H), 1.58–1.73 (m, 2H),
2.36 (d, J = 2.26 Hz, 1H), 4.34 (td, J = 6.4, 2.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d ꢀ5.0, ꢀ4.5, 13.7, 18.2, 18.4, 25.7, 40.7, 62.5,
71.8, 85.7. Anal. Calcd for C12H24OSi: C, 67.86; H, 11.39. Found: C,
67.95; H, 11.52.
4.1.8. (2R,3S,4R)-5-[1-(tert-Butyl-dimethyl-silanyloxy)-butyl]-
2,2dimethyl-[1,3]dioxolane-4-carboxylic acid ethyl ester 21
Pyridinium p-toluenesulfonate (PPTS) (39 mg, 0.15 mmol) was
added to the stirred solution of diol 20 (500 mg, 1.56 mmol) in
dry CH2Cl2 (100 mL) under nitrogen at room temperature. 2,2-
Dimethoxy propane (1 g, 3 mmol) was added to the reaction mix-
ture and stirred at room temperature for 12 h. The solvent was re-
moved under reduced pressure, purified by silica gel column
chromatography gel (5% EtOAc/hexane) to give a colorless liquid
4.1.5. (4R)-(tert-Butyl-dimethyl-silanyloxy)-hept-2-ynoicacid
ethyl ester 19
n-Butyllithium (10.5 mL, 1.6 M in hexane 16.9 mmol) was
added to a stirred solution of alkyne 18 (3 g, 11.4 mmol) in THF
(100 mL) at ꢀ78 °C. After 30 min, ethyl chloroformate (3 mL,
21 mmol) was added at the same temperature for 30 min. After
completion of the reaction (judged by TLC analysis), the reaction
was quenched with saturated aqueous NH4Cl solution and the
reaction mixture was extracted with ethyl acetate. (2 ꢁ 30 mL).
The extract was washed with water and brine, and dried over
anhydrous Na2SO4. The organic layer was concentrated under re-
duced pressure. The residue was purified by silica gel column chro-
matography (10% EtOAc/hexane) to give ester 19 (2.7 g, 87%) as a
21 (100 mg, 77%). ½a D30
ꢂ
¼ þ25:8 (c 1.2, CHCl3); IR (neat): mmax
2958, 2933, 2858, 1756, 1733, 1251, 1104, 777 cmꢀ1
;
1H NMR
(300 MHz, CDCl3):d 0.04 (s, 3H), 0.06 (s, 3H), 0.84–0.91 (m, 12H),
1.21–1.54 (m, 10H), 1.58 (s, 3H), 3.61 (td, J = 8.4, 2.0 Hz, 1H),
4.06–4.27 (m, 3H), 4.43 (d, J = 6.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d ꢀ4.7, ꢀ3.9, 13.9, 14.0, 18.4, 18.6, 25.5, 25.9, 26.5, 36.1,
60.9, 71.2, 76.0, 81.8, 110.5, 170.2; MS-ESI: m/z 361 (M++H); HRMS
(ESI): m/z calcd for C18H36O5NaSi: 383.2229, found: 383.2229.
yellow liquid. ½a D30
ꢂ
¼ þ8:0 (c 1.0, CHCl3); IR (neat): mmax 2959,
2933, 2860,1716,1248 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 0.12
(s, 3H), 0.15 (s, 3H), 0.90 (s, 9H), 0.95 (t, J = 6.8 Hz, 3H), 1.33 (t,
J = 6.8 Hz, 3H), 1.38–1.54 (m, 2H), 1.65–1.77 (m, 2H), 4.21 (q,
J = 6.8 Hz, 2H), 4.44 (t, J = 6.8 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d ꢀ5.2, ꢀ4.6, 13.5, 13.9, 18.0, 18.2, 25.6, 39.8, 61.8, 62.3, 76.5,
88.7, 153.5; MS-ESI: m/z 307 (M++Na); HRMS (ESI): m/z calcd for
C15H28O3NaSi: 307.1705, found: 307.1704.
4.1.9. (2S,3S,4R)-5-[1-(tert-Butyl-dimethyl-silanyloxy]-2,2-
dimethyl-[1,3]dioxolan-4-yl-methanol 22
To the stirred solution of compound 21 (1.2 g, 3.3 mmol) in dry
THF (10 mL) was added LiAlH4 (164 mg, 4.3 mmol) under nitrogen
at ꢀ15 °C for 15 min. The reaction was quenched with saturated
Na2SO4 (3 mL) and stirred at rt for 1 h. The reaction mixture was
filtered through Celite and extracted with EtOAc (2 ꢁ 10 mL). The
combined organic layer was washed with water and brine and con-
centrated under reduced pressure. Residue was purified by chro-
matography over silica gel (20% EtOAc/hexane) to give alcohol as
4.1.6. (4R)-(tert-Butyl-dimethyl-silanyloxy)-hept-2-enoic acid
ethylester 13
To a stirred solution of alkyne 19 (2 g, 7 mmol) in EtOAc (15 mL)
were added Pd–CaCO3 (50 mg) and 10 mL ethyl acetate/quinoline
(10:3) and the mixture was stirred under a hydrogen atmosphere
for 1 h at room temperature. The resultant mixture was filtered
through a short pad of Celite. The filter cake was washed with ethyl
acetate and the filtrate was concentrated under reduced pressure.
The crude product was purified by column chromatography on sil-
ica gel (10% EtOAc/hexane) to afford unsaturated ester 13 (1.9 g,
a yellow liquid 22 (950 mg, 91%). ½a D28
ꢂ
¼ þ39:1 (c 1.0, CHCl3); IR
(neat):
m
max3455, 2956, 2932, 2857, 1464, 1250, 776 cmꢀ1 1H
;
NMR (300 MHz, CDCl3): d 0.07 (s, 3H), 0.08 (s, 3H), 0.87–0.97 (m,
12H), 1.24–1.57 (m, 10H), 2.05 (br s, 1H), 3.54 (m, 2H), 3.70–3.79
(m, 1H), 3.98–4.12 (m, 2H); 13C NMR (75 MHz, CDCl3): d ꢀ4.6,
ꢀ4.0, 14.0, 18.3, 19.0, 25.3, 25.9, 28.0, 36.2, 61.5, 70.8, 77.5, 80.2,
108.2; MS-ESI: m/z 341 (M++Na); HRMS (ESI): m/z calcd for
C16H34O4NaSi: 341.2124, found: 341.2120.
95%) as a pale yellow liquid; ½a D30
ꢂ
¼ ꢀ14:8 (c 1.9, CHCl3); IR (neat):
mmax 2957, 2932, 2859, 1721, 1465, 1410, 1187 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 0.01 (s, 3H), 0.03 (s, 3H), 0.81–0.91 (m, 12H),
1.24 (td, J = 7.1, 0.9 Hz, 3H), 1.28–1.58 (m, 4H), 4.12 (qd, J = 7.1,
0.9 Hz, 2H), 5.22–5.31 (m, 1H), 5.63 (dt, J = 12.8, 7.7 Hz, 1H); 6.10
(dt, J = 12.8, 0.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): d ꢀ4.9, ꢀ4.6,
13.9, 14.1, 18.0, 18.3, 25.7, 39.7, 59.9, 68.5, 117.1, 153.7, 165.7;
MS-ESI: m/z 309 (M++Na); HRMS (ESI): m/z calcd for C15H30O3NaSi:
309.1861, found: 309.1867.
4.1.10. (2R,3S,4R)5-[1-(tert-Butyl-dimethyl-silanyloxy)-butyl]-
2,2dimethyl-[1,3]dioxolane-4-carbaldehyde 23
At first, PCC (311 mg, 1.4 mmol) and anhydrous sodium ace-
tate (118 mg, 1.4 mmol) were added to a solution of alcohol 22
(400 mg, 1.2 mmol) in dry CH2Cl2 (10 mL). The reaction mixture
was stirred under a nitrogen atmosphere at room temperature
for 3 h. The reaction mixture was filtered through a Celite pad
and concentrated under reduced pressure, the crude product
was purified by column chromatography over silica gel (10%
EtOAc/hexane) to give aldehyde 23 (306 mg, 88%) as a colorless
4.1.7. (2R,3S,4R)-4-(tert-Butyldimethylsilyloxy)-2,3-dihydroxy-
heptanoicacid ethylester 20
4-Methylmorpholine N-oxide (NMO) (2 g, 17.4 mmol) and OsO4
(8.74 mL, 0.1 M in t-BuOH, 0.4 mmol) were added to a stirred solu-
tion of unsaturated ester 13 (2.5 g, 1 mmol) in t-BuOH, water, ace-
tone (24 mL, 1:1:1) at room temperature and were stirred for 12 h.
The reaction was quenched with solid sodium sulfite. The solvent
was removed under reduced pressure and the compound was ex-
tracted with ethyl acetate. (3 ꢁ 20 mL) The combined organic layer
was washed with water and brine and dried over sodium sulfate.
Purification by column chromatography over silica gel (15%
liquid. ½a 3D0
ꢂ
¼ ꢀ13:6 (c 1.1, CHCl3); IR (neat): mmax 2957, 2932,
2858, 1738, 1465, 1253, 773 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d 0.05 (s, 3H), 0.06 (s, 3H), 0.76–0.98 (m, 12H), 1.37 (s, 3H),
1.38–1.56 (m, 4H), 1.57 (s, 3H), 4.04 (td, J = 2.3 Hz, 1H), 4.32
(d, J = 3.2 Hz, 1H), 4.36 (d, 2.0, J = 2.4 Hz, 1H), 9.56 (d,
J = 3.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): d ꢀ4.8, ꢀ4.1, 14.1,
18.0, 19.1, 25.1, 25.8, 27.1, 36.7, 70.8, 80.6, 82.7, 110.0, 198.8;
MS-ESI: m/z 317 (M++H).

110
P. Srihari et al. / Tetrahedron: Asymmetry 21 (2010) 106–111
4.1.11. tert-(3S,4S,5R)-Butyl-[-(2,2-dimethyl-5-vinyl-
[1,3]dioxolan-4-yl-butoxyl-dimethyl-silane 24
quickly. After 15 min stirring, alcohol 11 (1 g, 5.0 mmol) was added
as a solution in 9 mL CH2Cl2 along with a small amount of DMAP
(15 mg). The cooling bath was removed and stirring was continued
for 6 h. The solution was filtered and the solvent was removed un-
der reduced pressure. The resulting oil purified by column chroma-
tography (2% EtOAc/hexane) to give 25 (1.24 g, 84%) as colorless
To a stirred solution of iodomethyltriphenylphosphine (383 mg,
0.94 mmol) in THF (10 mL) was added n-BuLi (0.29 mL, 1.6 M,
0.47 mmol) dropwise at 0 °C. After 30 min, aldehyde 23 (100 mg,
0.31 mmol) was added and the reaction mixture was allowed to
warm to room temperature over 15 min. The resultant mixture
was quenched with saturated aqueous NH4Cl, diluted with ethyl-
acetate (2 ꢁ 5 mL). The combined organic layer was washed with
water and then brine. The organic layer was dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (10% EtOAc/hexane) to
oil; ½a 3D0
¼ þ19:7 (c 1.5, CH2Cl2): IR (neat): mmax 2961, 2933,
ꢂ
2873, 1738, 1642, 1459, 1376, 1246, 1217, 1169, 1100,
1065 cmꢀ1 1H NMR (300 MHz, CDCl3): d 0.91 (t, J = 7.4 Hz, 3H),
;
1.23–1.35 (m, 2H), 1.36 (s, 3H), 1.47 (s, 3H), 1.53–1.75 (m, 4H),
2.07 (q, J = 7.0 Hz, 2H), 2.16–2.33 (m, 2H), 4.17 (t, J = 7.4 Hz, 1H),
4.60 (t, J = 7.4 Hz, 1H), 4.92 (q, J = 7.4 Hz, 1H), 4.95–5.06 (m, 2H),
5.21 (d, J = 10.4 Hz, 1H), 5.32 (d, J = 17.0 Hz, 1H), 5.68–5.87 (m,
2H); 13C NMR (75 MHz, CDCl3): d 14.0, 17.9, 23.9, 25.2, 27.5,
33.0, 33.4, 33.7, 71.5, 78.4, 78.9, 108.7, 115.3, 118.5, 133.2, 137.6,
172.5; MS-ES: m/z 297 (M++1); HRMS (ESI); m/z calcd for
C17H28O4Na 319.1885, found 319.1872.
give compound 24 (78 mg, 70%) as a yellow liquid. ½a D27
¼ ꢀ19:6
ꢂ
(c 12.5, CHCl3); IR (neat): mmax 2956, 2933, 2860, 1465, 1374,
1251, 1078,773 cmꢀ1 1H NMR (300 MHz, CDCl3): d 0.03 (s, 3H),
;
0.05 (s, 3H), 0.87 (s, 9H), 0.90 (t, J = 7.2 Hz, 3H), 1.36 (s, 3H),1.37–
1.46 (m, 2H), 1.47 (s, 3H), 1.54–1.71 (m, 2H), 3.80–3.89 (m, 1H),
4.07 (t, J = 7.0 Hz, 1H), 4.55 (t, J = 7.0, 6.4 Hz, 1H), 5.20 (d,
J = 10.4 Hz, 1H), 5.31 (br d, J = 17.2 Hz, 1H), 5.96 (ddd, J = 17.2,
10.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d ꢀ4.3, ꢀ3.7, 14.3, 16.6,
25.3, 25.9, 27.8, 29.6, 36.0, 70.3, 79.0, 79.6, 108.0, 117.6, 134.9;
MS-ESI: m/z 337 (M++Na); HRMS (ESI): m/z calcd for C17H34O3NaSi:
337.2174, found: 337.2174.
4.1.15. Synthesis of herbarumin-1 1 via 10
A degassed solution of Grubbs’ first generation catalyst (0.055 g,
0.06) in CH2Cl2 (30 mL) was added over 30 min to a refluxing solu-
tion of compound 25 (0.1 g, 0.33) in CH2Cl2 (180 mL) and was stirred
for 8 h at reflux. After the starting material was completely
consumed (judged by TLC), the reaction was stopped and allowed
to cool to room temperature. The solvent was removed under re-
ducedpressureto giveadarkbrowncolored residue. Thecrudeprod-
uct was purified by silica gel column chromatography (7% EtOAc/
hexane) to afford E/Z (4:1) mixture of 10 (0.074 g, 82%) as a colorless
liquid.
4.1.12. (R)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl)butan-1-ol (11) from 24
To a stirred solution of TBS ether 24 (75 mg, 0.23 mmol) in THF
(5 mL) at 0 °C, TBAF (0.47 mL, 0.47 mmol, 1 M solution in THF) was
added dropwise at the same temperature. The mixture was al-
lowed to stir at room temperature over 3 h. The resultant mixture
was quenched with water and diluted with diethyl ether (5 mL).
The organic layer was washed with water and then with brine,
respectively. The combined organic layers was dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. The resi-
due was purified by chromatography on silica gel (15% EtOAc/
hexane) to give compound 11 (42 mg, 90%) as a yellow liquid.
The diastereomeric mixture of compound 10 (70 mg, 0.26 mmol)
and trifluoroacetic acid (0.03 mL) in CH2Cl2 (3 mL) was stirred at
room temperature for 8 h until TLC showed complete consumption
of the starting material. The reaction mixture was concentrated un-
der reduced pressure and the resulting residue was purified by col-
umn chromatography (25% EtOAc/hexane) to obtain Herbarumin-
1 (30 mg, 88%), as a low melting solid along with a mixture of E/Z dia-
stereomers 22.4 mg. ½a D31
ꢂ
¼ þ11:2 (c 0.7, EtOH); Lit.3b
½
a 2D0
ꢂ
¼ þ10:8
4.1.13. Synthesis of compound 11 from 14
(c 0.51, EtOH); IR (neat): mmax = 3451, 2959, 2929, 1730, 1455, 1206,
To a solution of an epoxide 14 (600 mg, 3.5 mmol) in THF (8 mL)
at ꢀ40 °C was added CuI (0.134, 0.7 mmol) and stirred at the same
temperature for 15 min. After this time, the pre cooled ethyl mag-
nesium bromide (10.5 ml of 1 M solution in THF, 10.5 mmol) was
added by a cannula. The resulting mixture was stirred at ꢀ40 °C
for 3 h and the reaction was quenched by the addition of aqueous
NH4Cl solution and warmed to room temperature. The layers were
separated and the aqueous layer was extracted with ethyl acetate
(2 ꢁ 20 mL). The combined organic layer was washed with brine,
dried over anhydrous Na2SO4, and concentrated to provide the
crude product. Silica gel column chromatography (15% EtOAc/hex-
ane) afforded the pure product 11 (649 mg, 92%) as a colorless oil.
1061, 811 cmꢀ1; 1H NMR (300 MHz, CDCl3); d 0.91 (t, J = 7.2 Hz, 3H),
1.20–1.40 (m, 2H), 1.50–1.54 (m, 1H), 1.72 (m, 1H), 1.82–2.00 (m,
4H), 2.16 (br s, 1H), 2.38–2.50 (m, 3H), 3.51 (dd, J = 9.8, 1.9 Hz, 1H),
4.42 (br s, 1H,), 4.94 (dt, J = 9.6, 2.4 Hz, 1H), 5.45–5.57 (m, 1H),5.61
(d, J = 15.9, Hz, 1H,); 13C NMR (75 MHz, CDCl3): d 13.8, 18.0, 24.6,
33.3, 33.7, 34.4, 70.2, 73.3, 73.7, 120.8, 130.6, 176.4; MS-ES: m/z
251 (M++Na); HRMS (ESI) m/z calcd for C12H20O4Na, 251.1259, found
251.1248.
4.1.16. Stagonolide A
To a solution of herbarumin-1 (30 mg, 0.13 mmol) in CH2Cl2
(6.0 mL) was added manganese dioxide (229 mg, 2.6 mmol) at
room temperature. After being stirred at the same temperature
for 20 h, the reaction mixture was filtered through a pad of Celite.
The solvent was concentrated under reduced pressure and the
resulting residue was purified by column chromatography (10%
EtOAc/hexane) to obtain stagonolide A (28.5 mg, 96%, based on
recovery of starting material) as a colorless crystalline solid.
½
a 3D0
ꢂ
¼ þ8:8 (c 1.6, CH2Cl2); lit.3a
½
a 2D0
ꢂ
¼ þ8:8 (c.1.2, CH2Cl2). IR
(neat): mmax 3467, 2983, 2959, 2932, 2873, 1642, 1217, 1065,
872 cmꢀ1 1H NMR (300 MHz, CDCl3): d 0.94 (t, J = 7.2 Hz, 3H),
;
1.37 (m, 1H), 1.37 (s, 3H),1.45 (m, 1H), 1.48 (s, 3H), 1.57 (m, 1H),
1.69 (m, 1H), 1.80 (br s, 1H), 3.67 (dt, J = 2.6, 2.3 Hz, 1H), 3.97
(dd, J = 8.1, 6.4 Hz, 1H), 4.63 (t, J = 7.4 Hz, 1H), 5.31 (d, J = 10.4 Hz,
1H), 5.43 (d, J = 17.2 Hz, 1H), 6.04 (ddd, J = 17.2, 10.4, 7.4 Hz, 1H);
13C NMR (75 MHz, CDCl3): d 14.0, 18.3, 25.3, 27.8, 35.8, 69.7,
78.9, 80.7, 108.6, 118.9, 134.7; MS-ES: m/z 223 (M++Na); HRMS
(ESI): m/z calcd for C11H20O3Na, 223.1305, found 223.1304.
Mp = 71–72 °C. ½a 3D2
ꢂ
¼ ꢀ60 (c 0.2, EtOH); IR (neat):
mmax = 3417,
2960, 2930, 2869, 1727, 1692, 1632, 1438, 1398, 1152, 1075,
824 cmꢀ1 1H NMR (300 MHz, CDCl3); d 0.93 (t, J = 7.3 Hz, 3H),
;
1.24–1.50 (m, 2H), 1.58–1.73 (m, 1H), 1.86–2.03 (m, 3H), 2.05
(m, 1H), 2.13 (dd, J= 14.0, 2.3 Hz, 1H), 2.44 (d, J = 5.7 Hz, 1H),
2.47–2.55 (m, 1H), 4.05 (dd, J = 9.5, 6.2 Hz, 1H), 4.65 (dt, J = 9.6,
2.4 Hz, 1H), 6.24–6.37 (m, 1H), 6.42 (d, J = 16.0, Hz, 1H); 13C NMR
(75 MHz, CDCl3); d 13.7, 18.0, 25.0, 33.5, 34.0, 34.2, 74.5, 76.5,
131.9, 143.1, 174.1, 199.6; MS-ES: m/z 249 (M++Na); HRMS (ESI)
m/z calcd for C12H18O4Na, 249.1102, found 249.1095.
4.1.14. (R)-1-((4R,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl)butyl hept-6-enoate 25
A solution of 5-hexenoic acid (792 mg, 5.5 mmol) in CH2Cl2
(8 mL) was cooled to 0 °C. A sample of DCC (1.34 g, 6.5 mmol)
was added in several portions and a white precipitate formed

P. Srihari et al. / Tetrahedron: Asymmetry 21 (2010) 106–111
111
Asymmetry 2007, 18, 1688–1692; (k) Nagaiah, K.; Sreenu, D.; Rao, R. S.; Yadav, J.
S. Tetrahedron Lett. 2007, 48, 7173–7176; (l) Yadav, J. S.; Kumar, V. N.; Rao, R. S.;
Srihari, P. Synthesis 2008, 1938–1942; (m) Yadav, J. S.; Ather, H.; Gayathri, K. U.;
Rao, N. V.; Prasad, A. R. Synthesis 2008, 3945–3950; (n) Selvam, P. J. J.; Rajesh, K.;
Suresh, V.; Chanti, B. D.; Venkateswarlu, Y. Tetrahedron: Asymmetry 2009, 20,
1115–1119; (o) Kamal, A.; VenkataReddy, P.; Prabhakar, S. Tetrahedron:
Asymmetry 2009, 20, 1120–1124.
Acknowledgment
B.K. and G.M.R. thank CSIR, New Delhi, for financial assistance.
References
4. For the isolation of stagonolides: (a) Oleg, Y.; Galin, M.; Alexander, B. J. Agric.
Food Chem. 2007, 55, 7707–7711; (b) Antonio, E.; Alessio, C.; Alexander, B.;
Galina, M.; Anna, A.; Andera, M. J. Nat. Prod. 2008, 71, 31–34.
5. For Sharpless: Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780.
6. (a) Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron 1990, 46, 7033–
7046; For related work from other groups see: (b) Takano, S.; Samizu, K.;
Sugihara, T.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1989, 1344–1345; (c)
Takano, S.; Sugihara, T.; Ogasawara, K. Synlett 1991, 279–282.
7. (a) Seiki, S.; Yasuhisa, M.; Toshio, M. J. Org. Chem. 1990, 55, 5424–5426; (b)
Ludmila, E.; Andre, N. S. J. Org. Chem. 2006, 71, 693–703; (c) Cha, J. K.; Christ, W.
J.; Kishi, Y. Tetrahedron Lett. 1983, 24, 3943–3946; (d) Cha, J. K.; Christ, W. J.;
Kishi, Y. Tetrahedron 1984, 40, 2247–2255; (e) The compounds were easily
separated by silica gel column chromatography.
1. (a) Gerald, D.; Andreas, K.; Ralf, T.; Marion, Z. Nat. Prod. Rep. 1996, 365–375; (b)
Valeria, B. R.; Ronaldo, A. P.; Mauricio, M. V. Tetrahedron 2008, 64, 2279–2300;
(c) Surat, B.; Prasat, K.; Masahiko, I.; Daraporn, P.; Morakot, T.; Yodhathai, T. J.
Nat. Prod. 2001, 64, 965–967; (d) Ken, I. Biosci. Biotechnol. Biochem. 2009, 73,
971–979; (e) Hendrik, G.; Peter, J. S.; Ekaterina, E.; Stefan, K.; Gabriele, M. K. J.
Nat. Prod. 2008, 71, 1651–1653.
2. (a) Rivero-Cruz, J. F.; Garcia-Aguieee, G.; Cerda-Garcia-Rojas, C. M.; Mata, R.
Tetrahedron 2000, 56, 5337–5344; (b) Rivero-Cruz, J. F.; Martha, M.; Cerda-
Garcia-Rojas, C. M.; Mata, R. J. Nat. Prod. 2003, 66, 511–514.
3. (a) Furstner, A.; Radkowski, K. Chem. Commun. 2001, 671–672; (b) Furstner, A.;
Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, W. C.; Mynott, R. J. Am. Chem.
Soc. 2002, 124, 7061–7069; (c) Sabino, A. A.; Pilli, R. A. Tetrahedron Lett. 2002, 43,
2819–2821; (d) Diez, E.; Dixon, D. J.; Ley, S. V.; Polara, A.; Rodriguez, F. Helv.
Chim. Acta 2003, 86, 3717–3729; (e) Gurjar, M. K.; Karmakar, S.; Mohapatra, D. K.
Tetrahedron Lett. 2004, 45, 4525–4526; (f) Nanda, S. Tetrahedron Lett. 2005, 46,
3661–3663; (g) Gurjar, M. K.; Nagaprasad, R.; Ramana, C. V.; Mohapatra, D. K.
Arkivoc 2005, 3, 237–257; (h) Salaskar, A.; Sharma, A.; Chattopadhyay, S.
Tetrahedron: Asymmetry 2006, 17, 325–329; (i) Boruwa, J.; Gogoi, N.; Barua, N. C.
Org. Biomol. Chem. 2006, 4, 3521–3525; (j) Gupta, P.; Kumar, P. Tetrahedron:
8. Srihari, P.; Kumaraswamy, B.; Yadav, J. S. Tetrahedron 2009, 65, 6304–
6309.
9. (a) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043; (b) Grubbs, H. R.;
Chang, S. Tetrahedron 1998, 54, 4413–4450; (c) The diastereomeric mixture ratio
was determined based on GC–MS analysis.