An asymmetric synthesis of 7-hydroxy-9-propylnonenolide (herbarumin III)

Article abstract of DOI:10.1016/j.tetasy.2006.01.027

An asymmetric synthesis of herbarumin III has been developed using (R)-cyclohexylidene glyceraldehyde 1 as the chiral template. The key steps of the synthesis were the enantioselective preparation of the required homoallylic alcohol from 1, an asymmetric

Full text of DOI:10.1016/j.tetasy.2006.01.027

Tetrahedron: Asymmetry 17 (2006) 325–329
An asymmetric synthesis of
7-hydroxy-9-propylnonenolide (herbarumin III)
Avinash Salaskar, Anubha Sharma and Subrata Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 21 September 2005; revised 27 December 2005; accepted 5 January 2006
Abstract—An asymmetric synthesis of herbarumin III has been developed using (R)-cyclohexylidene glyceraldehyde 1 as the chiral
template. The key steps of the synthesis were the enantioselective preparation of the required homoallylic alcohol from 1, an asym-
metric dihydroxylation, and a ring-closing metathesis reaction for the macrolactonization.
ꢀ 2006 Published by Elsevier Ltd.
1. Introduction
modulin and inhibits the activation of the calmodulin-
dependent enzyme cAMP phosphodiesterase.2a
Lactone functionality is ubiquitous amongst natural
products.1a Of these, c- and d-lactones are abundant
as insect pheromones, constituents of butter fats, fruits,
etc. Even large ring macrolides can be extensively found
in various natural sources, showing a diverse array of
bioactivity.1b,c However, lactones with a medium ring
size (8–10 membered) are rare, while their syntheses
are also challenging. One such compound, (7R,9R,5E)-
7-hydroxy-9-propylnonenolide I has been isolated from
the mycelium and culture broth of the fungus Phoma
herbarum Westend (Sphaeropsidaceae).2a Previously,
two other similar macrolides, one containing a hydroxyl
group at C-8 and another with two hydroxyl groups at
C-8 and C-2, were also isolated from the same fungus.2b
The last two compounds and compound I have been
trivially named as herbarumins I, II, and III, respec-
tively. In an assay monitoring the radical elongation of
Amaranthus hypochondriacus seedlings, all these com-
pounds exhibited significant phytotoxic effects at very
low concentrations.2b Compound I inhibited radical
growth with 10 times higher potency than 2,4-dichloro-
phenoxyacetic acid,2a its antifungal activity was equal to
that of herbarumin I and better than herbarumin II. The
level of activity, together with the fact that closely re-
lated compounds such as pinolidoxin3a and lethaloxin,3b
also show significant phytotoxicity renders this class of
compounds as promising herbicidal agents. Further-
more, compound I also interacts with bovine-brain cal-
2. Results and discussion
In view of the above importance of I, we attempted its
enantiomeric synthesis (Scheme 1). So far the asymmet-
ric syntheses of the herbarumins I and II using various
sugars, such as D-ribonolactone and L-arabinose,4a–c
and asymmetric reactions4d have been reported. While
the present work was under completion, three asymmet-
ric syntheses of I have been reported from D-glucose.4e–g
The present synthesis is based upon using (R)-cyclo-
hexylidene glyceraldehyde 15a–c as a chiral template
and a substrate-controlled asymmetric dihydroxylation
(ADH)6 with the Sharpless’ reagent to incorporate the
asymmetric centers, while the formation of the macro-
lide skeleton was accomplished by a ring-closing metath-
esis (RCM)7 of a suitable diene. The cyclohexylidene
group in 1 also provided one of the alkene groups
required for the RCM reaction.
For the synthesis, syn-homoallylic alcohol 2 was pre-
pared conveniently on a multi-gram scale following a
known procedure.8 The stereochemistry of 2 was con-
firmed from the 1H NMR resonances of its –CH2O
and –CHO groups.5a
The presence of cyclohexylidene protection in the start-
ing chiron increased its hydrophobicity, as well as that
of the product carbinol, ensuring easy isolation by
extraction with apolar organic solvents. Moreover, the
*
Corresponding author. Fax: +91 22 25505151; e-mail: schatt@
apsara.barc.ernet.in
0957-4166/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2006.01.027

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A. Salaskar et al. / Tetrahedron: Asymmetry 17 (2006) 325–329
O
O
O
iii
ii
O
O
O
i
OH
O
O
O
OR OH
4 R = TBDPS
CHO
OTBDPS
3
OH
2
1
OH
O
O
viii
HO
vii
iv
v
O
O
OR
O
OR
5 R = TBDPS
OR OR'
9 R = TBDPS
O
6 R = TBDPS, R' = H
vi
8 R = TBDPS, R' = CO(CH2)3CH=CH2
HO
x
O
O
OR
O
O
O
O
10 R = TBDPS
OR
2a R = H; 2b R = TBS
I
ix
11 R =H
Scheme 1. Reagents and conditions: (i) Ref. 8, (ii) TBDPSCl/imidazole/CH2Cl2 (88%), (iii) AD mix-b/t-BuOH–H2O (1:1) (78%), (iv) p-TsCl/pyridine
(94%); K2CO3/MeOH (86%), (v) EtMgBr/Cu2Br2/THF/ꢀ78 ꢁC (72%), (vi) CH2@CH(CH2)3COOH (7)/DCC/DMAP (cat.)/CH2Cl2 (69%), (vii)
aqueous TFA (81%), (viii) MsCl/pyridine; Zn/NaI/DMF/D (63%), (ix) TBAF/THF/ꢀ78 ꢁC (88%), (x) Grubb’s second generation catalyst/CH2Cl2
(63%).
1
protecting group was quite stable, even under weakly
acidic conditions allowing the required addition to be
carried out in aqueous NH4Cl solution.
comparison of its H and 13C NMR spectra with those
of the product obtained earlier by the ADH reaction
of 2b.9 This was further confirmed at a latter stage.
Compound 2 was silylated with TBDPSCl to furnish 3.
Previously, we found9 that irrespective of the ADH
reagent6 (AD mix-a[K2OsO2(OH)4 and (DHQ)2-PHAL]
or AD mix-b[K2OsO2(OH)4 and (DHQD)2-PHAL])
used, the asymmetric dihydroxylation of the TBS-deriv-
ative 2b, an epimer of 2 with a less bulky silyl substitu-
tion proceeds predominantly from the a-face, furnishing
the 2,4-syn-product. However, while the syn:anti ratio
was 77.5:22.5 with the AD mix-a reagent, the same
was 95.5:4.5 with the b-reagent. It was of interest to
investigate whether the reaction also follows a similar
stereochemical course with the syn-compound 3 contain-
ing the b-silyloxy group. This observation was critical
for the synthesis of I. Given that the AD mix-b reagent
gave a better syn-selectivity with 2b, compound 3 was
subjected to the ADH reaction with the same reagent.
It was gratifying to note that the reaction not only pro-
ceeded as per our expectation, but the bulky silyl protec-
tion (OTBDPS) actually ensured absolute 2,4-syn-
selectivity and furnished 4 as the sole product. The
2,4-syn-stereochemistry of 4 could easily be assessed by
Regioselective monotosylation of the primary hydroxyl
group of 4 with p-toluenesulfonyl chloride (p-TsCl)/pyr-
idine, followed by base treatment, furnished epoxide 5.
The reaction of 5 with EtMgBr in the presence of cata-
lytic CuBr proceeded smoothly thus furnishing alcohol 6
as the only product. There was no trace of the formation
of the primary carbinol due to the ring opening at the
secondary epoxide-site. The syn-stereochemistry at C-3
and C-5 centers of 6 was determined by its derivatization
to the corresponding acetonide 6b and analyzing the 13C
NMR resonances. Thus, desilylation of 6 afforded 6a,
which was converted to 6b by acetalization with 2,2-
dimethoxypropane (Scheme 2). In its 13C NMR spec-
trum, the signals at d 19.6 and 31.3 (two methyls) and
at d 98.4 (acetal carbon) of the six-membered acetonide
moiety confirmed the 2,4-syn relationship10a,b of 6b, and
thus of 6.
1,3-Dicyclohexylcarbodiimide (DCC) promoted the
esterification of 6 with 5-hexenoic acid 7, which pro-
ceeded very slowly. After stirring for 5 days at room
O
O
O
ii
i
O
O
O
O
O
OH OH
6a
OR OH
6 R = TBDPS
6b
Scheme 2. Reagents and conditions: (i) TBAF/THF/ꢀ78 ꢁC, (ii) 2,2-dimethoxypropane/p-TsOH.

A. Salaskar et al. / Tetrahedron: Asymmetry 17 (2006) 325–329
327
temperature, ester 8 was obtained in ꢁ45% yield. The
overall yield could be improved upon to 69% by re-ester-
ification of the recovered 6 with acid 7. Its deacetalization
in the presence of aqueous trifluoroacetic acid (TFA)
furnished diol 9 uneventfully. Mesylation of 9 with
excess mesyl chloride furnished the corresponding di-
mesylate, which on heating with NaI in the presence of
Zn-dust in DMF, gave the olefin 10.
of 28 (2.8 g, 13.21 mmol) and imidazole (1.1 g,
16.1 mmol) in CH2Cl2 (40 mL) was added TBDPSCl
(4.39 g, 16.0 mmol) in CH2Cl2 (20 mL) and the mixture
was stirred overnight. This was then poured into water,
the organic layer separated, and the aqueous layer
extracted with CHCl3. The combined organic extracts
were washed with water and brine, and dried. Solvent
removal and column chromatography of the residue (sil-
ica gel, 0–10% EtOAc/hexane) afforded 3 (5.23 g, 88%).
25
Compound 10 possessed all the structural requirements,
as well as the sense of chirality to be converted to the
target macrolide, via a ring closing metathesis (RCM)
reaction. The RCM reaction provides remarkable scope
for the synthesis of medium-sized rings and macrocyclic
products, and is being used extensively.7 Although due
to the inherent ring strain, construction of the medium
sized 8–11-membered cycloalkenes via the RCM
reaction is very challenging,11a some precedents
exist.11b–k The presence of a suitable functionality and
its distance from the olefins play key roles in the success
of the reaction. It has been reported7c that the RCM
reaction proceeds satisfactorily with substrates possess-
ing a 5-hexenoate ester moiety as is present in 10. All
these considerations made us feel confident in the pres-
ent endeavor.
Colorless liquid; ½aꢂD ¼ ꢀ2:7 (c 1.04, CHCl3); IR: 3049,
991, 910 cmꢀ1; H NMR: d 1.09 (s, 9H), 1.27–1.61 (m,
1
10H), 2.18–2.24 (m, 2H), 3.68–3.72 (m, 1H), 3.82–3.94
(m, 2H), 4.08–4.15 (m, 1H), 4.88–4.97 (m, 2H), 5.65–
5.73 (m, 1H), 7.38–7.42 (m, 6H), 7.71–7.75 (m, 4H);
13C NMR: d 19.5, 23.8, 25.3, 26.6, 26.8, 27.0, 34.5,
36.0, 37.9, 65.2, 73.8, 77.8, 109.8, 117.4, 127.7, 129.1,
129.6, 130.1, 133.9, 134.2, 134.9, 135.2, 136.1, 137.2;
MS (EI, 70 eV): m/z (%) 450 (7.9, M+), 394 (50), 295
(36), 278 (27), 253 (19), 218 (59), 200 (58), 183 (46),
140 (65), 136 (100), 117 (24), 83 (25), 59 (75). Anal.
Calcd for C28H38O3Si: C, 74.62; H, 8.50. Found: C,
74.77; H, 8.32.
3.1.2. (2S,4R,5R)-4-tert-Butyldiphenylsilyloxy-5,6-cyclo-
hexylidenedioxyhexane-1,2-diol 4. A solution of 3
(2.25 g, 5.0 mmol) in a solvent mixture of t-BuOH/water
(1:1, 25 mL) was added to a cooled (0 ꢁC) and stirred
suspension of AD mix-b (7.0 g) in the same solvent mix-
ture (120 mL). The mixture was stirred at 0 ꢁC for 18 h,
treated with solid Na2SO3 (7.0 g), stirred for a further
1 h at room temperature, and extracted with CHCl3.
The organic extract was washed with water, brine and
dried. Solvent removal and column chromatography of
the residue (silica gel, 0–5% MeOH/CHCl3) afforded 4
However, the attempted RCM of 10 in the presence of
Grubb’s second generation catalyst led to undesired
dimerization. Consequently, compound 10 was desilyl-
ated to 11 and subjected to the RCM reaction using
the Grubb’s second generation catalyst. We were
pleased to find that the reaction proceeded smoothly
under dilute conditions to afford the title compound I
as the only major product, which was isolated in its pure
form by chromatography over a AgNO3-silica gel col-
umn. The compound was characterized from its chirop-
as the sole product (1.89 g, 78%). Colorless viscous oil;
25
½aꢂD ¼ þ11:9 (c 0.94, CHCl3); IR: 3418, 3071,
tical and spectral data. Compared to the reported2a
933 cmꢀ1 1H NMR d 1.06 (s, 9H), 1.25–1.75 (m,
;
22
½aꢂD ¼ þ22:0 (c 0.1, EtOH) of I, the specific rotation
12H), 2.68 (br s, 2H), 3.18–3.42 (m, 2H), 3.63–3.80 (m,
1.5H), 3.89–3.97 (m, 1.5H), 4.07–4.23 (m, 2H), 7.37–
7.40 (m, 6H), 7.67–7.70 (m, 4H); 13C NMR: d 13.8,
19.2, 23.7, 24.9, 26.7, 26.9, 34.6, 35.7, 37.7, 38.5, 66.6,
71.9, 73.4, 73.7, 75.5, 109.9, 126.0, 127.0, 127.7, 128.1,
129.9, 130.3, 133.2, 133.4, 134.5, 135.6, 135.8, 136.9;
MS (EI, 70 eV): m/z (%) 484 (22, M+), 427 (20), 350
(25), 298 (31), 269 (58), 252 (96), 234 (92), 221 (62),
200 (100), 181 (31), 139 (62), 117 (54), 113 (58), 81
(46), 57 (33). Anal. Calcd for C28H40O5Si: C, 69.38; H,
8.32. Found: C, 69.52; H, 8.15.
25
ð½aꢂD Þ of our synthetic compound was +21.9 (c 0.88,
EtOH).
It is worth mentioning that although the synthesis of
alcohol 3 requires three steps, we have been preparing
this very conveniently in multi-gram scales for its appli-
cation in various syntheses. Overall, we have developed
a highly asymmetric synthesis of I employing operation-
ally simple reactions.
3. Experimental
3.1.3. (2S,4R,5R)-4-tert-Butyldiphenylsilyloxy-5,6-cyclo-
hexylidenedioxy-1,2-epoxyhexane 5. To a cooled (0 ꢁC)
and stirred solution of 4 (1.7 g, 3.51 mmol) and pyridine
(2.0 mL) in CH2Cl2 (20 mL) was added p-toluenesulfo-
nyl chloride (p-TsCl) (0.669 g, 3.5 mmol) in portions.
After stirring for 12 h, the mixture was poured into
ice-water, the organic layer separated, and the aqueous
portion was extracted with CHCl3. The combined or-
ganic extracts were washed with aqueous 2 M HCl,
water, and brine and dried. Removal of the solvent fol-
lowed by column chromatography (silica gel, 0–20%
EtOAc/hexane) of the residue afforded the monotosylate
(2.10 g, 94%) as a colorless liquid; IR: 3450, 1588, 1364,
3.1. General methods
General information regarding instruments, techniques,
and source of chemicals used were the same as men-
1
tioned in our previous publications.5a–c The H NMR
(200 MHz) and 13C NMR (50 MHz) spectra were
recorded in CDCl3 with a Bruker AC 200. The optical
rotations were recorded with
polarimeter.
a Jasco 364 DIP
3.1.1.
(4R,5R)-4-tert-Butyldiphenylsilyloxy-5,6-cyclo-
hexylidenedioxyhex-1-ene 3. To a well stirred solution
1176 cmꢀ1 1H NMR: d 1.02 (s, 9H), 1.30–1.60 (m,
;

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A. Salaskar et al. / Tetrahedron: Asymmetry 17 (2006) 325–329
10H), 1.60–1.71 (m, 2H), 2.44 (s, 3H), 3.48–3.57 (m,
1H), 3.60–3.77 (m, 4H), 3.80–4.13 (m, 2H), 7.28–7.40
(m, 8H), 7.42–7.74 (m, 6H); 13C NMR: d 19.2, 21.5,
26.5, 26.7, 26.9, 37.4, 69.7, 70.9, 72.9, 74.8, 76.2, 109.1,
117.7, 127.7, 127.9, 129.2, 129.7, 129.9, 130.3, 132.4,
132.5, 133.2, 135.5, 135.8, 145.1.
was filtered through a short pad of silica gel, which
was washed with ether. After concentration, the residue
was chromatographed (0–10% ether/hexane) to afford
pure 8 (45%) and unreacted 6 (0.427 g, 43%). After a sec-
ond acylation of the unreacted 6 with 7 as above, com-
pound 8 (0.817, overall 69% from two reactions) was
25
obtained as a colorless liquid; ½aꢂD ¼ þ7:4 (c 2.3,
1
To a stirred and cooled (0 ꢁC) solution of the above tos-
ylate (2.1 g, 3.29 mmol) in MeOH (15 mL) was added
solid anhydrous K2CO3 (0.92 g, 6.5 mmol) and the mix-
ture stirred at 0 ꢁC for 3 h (cf. TLC). The mixture was
filtered, concentrated in vacuo, the residue was extracted
with EtOAc, the organic extract was washed with H2O
and brine, and dried. Removal of solvent and column
chromatography (0–10% EtOAc/hexane) of the residue
CHCl3); IR: 3060, 1730, 990, 910 cmꢀ1; H NMR: d
0.84 (t, J = 6.6 Hz, 3H), 1.02 (s, 9H), 1.27–1.80 (m,
12H), 1.83–2.04 (m, 6H), 2.21–2.35 (m, 2H), 2.51–2.77
(m, 2H), 3.59–3.87 (m, 4H), 4.45–4.59 (m, 1H), 4.85–
5.10 (m, 2H), 5.65–5.81 (m, 1H), 7.25–7.36 (m, 6H),
7.57–7.75 (m, 4H); 13C NMR: d 14.1, 18.9, 19.5, 23.7,
25.3, 25.7, 26.9, 27.2, 32.8, 34.5, 35.9, 67.8, 74.9, 75.4,
78.1, 109.8, 116.1, 127.5, 128.1, 132.6, 134.8, 135.9,
174.1; MS (EI, 70 eV): m/z (%) 592 (25, M+), 550 (13),
535 (26), 492 (16), 421 (28), 412 (26), 350 (37), 296
(66), 235 (51), 198 (96), 140 (92), 136 (100), 108 (74),
99 (98), 56 (51). Anal. Calcd for C36H52O5Si: C, 72.93;
H, 8.84. Found: C, 73.12; H, 8.88.
afforded the pure epoxide 5 (1.32 g, 86%) as a colorless
25
liquid; ½aꢂD ¼ ꢀ13:6 (c 1.14, CHCl3); IR: 1483, 1427,
1
1369, 1163 cmꢀ1; H NMR: d 1.05 (s, 9H), 1.25–1.73
(m, 12H), 2.25–2.29 (dd, J = 2.6 and 5.0 Hz, 1H),
2.63–2.67 (m, 1H), 2.93–3.15 (m, 1H), 3.60–3.75 (m,
1H), 3.87–3.94 (m, 2H), 4.05–4.20 (m, 1H), 7.37–7.44
(m, 6H), 7.66–7.73 (m, 4H); 13C NMR: d 19.4, 23.9,
25.2, 26.9, 27.1, 34.8, 36.1, 37.4, 48.9, 55.2, 66.5, 72.4,
75.1, 109.6, 127.7, 129.9, 133.5, 136.1; MS (EI, 70 eV):
m/z (%) 466 (77, M+), 423 (26), 409 (41), 384 (38), 351
(71), 334 (87), 322 (100), 310 (100), 294 (100), 266
(100), 254 (30), 225 (61), 200 (98), 183 (57), 136 (88),
117 (77), 84 (99), 69 (60), 56 (100). Anal. Calcd for
C28H38O4Si: C, 72.06; H, 8.21. Found: C, 72.24; H, 8.37.
3.1.6.
(2R,3R,5R)-3-tert-Butyldiphenylsilyloxy-5-(50-
hexenoyloxy)octane-1,2-diol 9. A mixture of 8 (0.500
g, 0.84 mmol) and 15% aqueous TFA was stirred
at room temperature for 12 h. Most of the solvent
was removed in vacuo, the residue taken in CHCl3,
the organic extract washed with water and brine,
and dried. Solvent removal followed by column
chromatography (silica gel, 0–5% MeOH/CHCl3) of
the residue gave 9 (0.350 g, 81%) as a colorless
25
3.1.4. (4R,6R,7R)-6-tert-Butyldiphenylsilyloxy-7,8-cyclo-
hexylidenedioxyoctan-4-ol 6. A solution of EtMgBr
[prepared from EtBr [0.86 g, 7.9 mmol] and Mg
[0.19 g, 7.8 mmol]] in dry THF (20 mL) was added drop-
wise to a stirred and cooled (ꢀ30 ꢁC) suspension of
Cu2Br2 (0.5 g) in THF (20 mL). After stirring for
10 min, epoxide 5 (1.22 g, 2.62 mmol) in THF (15 mL)
was added. Stirring was continued overnight, gradually
warming the mixture to 0 ꢁC. The mixture was poured
into saturated NH4Cl solution (20 mL) and extracted
with ether. The extract was dried and concentrated in
vacuum. The residue was purified by column chroma-
liquid; ½aꢂD ¼ þ2:7 (c 1.16, CHCl3); IR: 3440, 3060,
1727 cmꢀ1; H NMR: d 0.86 (dist. t, 3H), 1.04–1.25 (m
1
containing a s at d 1.05, 13H), 1.40–1.65 (m, 4H),
1.87–2.25 (m, 4H), 2.36 (br s, D2O exchangeable, 2H),
3.61–3.66 (m, 4H), 4.48–4.65 (m, 1H), 4.95–5.02 (m,
2H), 5.62–5.77 (m, 1H), 7.38–7.42 (m, 6H), 7.54–7.62
(m, 4H); 13C NMR: d 14.2, 18.9, 23.7, 25.3, 25.5, 26.3,
27.2, 35.9, 67.3, 72.9, 73.1, 77.9, 116.1, 127.5, 128.1,
132.5, 134.7, 135.8, 171.8; MS (EI, 70 eV): m/z (%) 512
(22, M+), 455 (17), 412 (15), 349 (26), 271 (32), 252
(61), 136 (92), 113 (30), 97 (100), 81 (68), 56 (55). Anal.
Calcd for C30H44O5Si: C, 70.27; H, 8.65. Found: C,
70.12; H, 8.59.
tography (silica gel, 0–10% EtOAc/hexane) to give
25
6 (0.935 g, 72%) as a colorless liquid; ½aꢂD ¼ þ6:5
(c 0.42, CHCl3); IR: 3384, 1478, 1061 cmꢀ1; 1H NMR:
d 0.84 (dist. t, 3H), 1.03 (s, 9H), 1.20–1.66 (m, 14H),
1.79–2.04 (m, 2H), 3.06–3.31 (m, 1H), 3.44–3.69 (m,
1H), 3.75–3.90 (m, 1H), 3.93–4.06 (m, 1H), 4.07–4.19
(m, 1H), 7.27–7.50 (m, 6H), 7.66–7.75 (m, 4H); 13C
NMR: d 14.0, 18.7, 19.5, 23.7, 25.2, 26.9, 27.2, 34.5,
35.9, 39.8, 67.5, 73.1, 74.8, 75.2, 109.9, 125.8, 127.5,
128.1, 129.1, 131.7, 134.8, 135.9; MS (EI, 70 eV): m/z
(%) 496 (27, M+), 439 (26), 410 (29), 351 (47), 297
(56), 279 (62), 264 (99), 253 (100), 225 (98), 208 (69),
190 (99), 176 (98), 52 (89). Anal. Calcd for C30H44O4Si:
C, 72.53; H, 8.93. Found: C, 72.29; H, 8.78.
3.1.7. (3R,5R)-3-tert-Butyldiphenylsilyloxy-1-octen-5-yl
50-hexenoate 10. To a cooled (0 ꢁC) and stirred solu-
tion of 9 (0.350 g, 0.68 mmol) in pyridine (5.0 mL) was
injected mesyl chloride (0.160 mL, 2.10 mmol) and the
mixture stirred for 12 h at room temperature. The mix-
ture was poured into ice-cold water, the organic layer
separated, and the aqueous layer washed with water
and brine, and dried. Removal of solvent gave the di-
mesylate, which was used for the next step. IR: 1740,
1375, 1175 cmꢀ1
.
A mixture of the above mesylate, NaI (0.600 g,
4.0 mmol) and Zn-dust (0.670 g, 10.0 mmol) in DMF
(15 mL) was heated at 90 ꢁC for 8 h. The mixture was
cooled to room temperature, ether then added, and the
supernatant passed through a pad (200 · 200) of silica
gel. Water was added to the eluent, the mixture was ex-
tracted with ether, and the ethereal layer was washed
with water and brine, and dried. Removal of solvent
3.1.5. (4R,6R,7R)-6-tert-Butyldiphenylsilyloxy-7,8-cyclo-
hexylidenedioxyoctan-4-yl 50-hexenoate 8. A mixture of
6 (0.992 g, 2.0 mmol), acid 7 (0.365 g, 3.2 mmol), DCC
(0.659 g, 3.2 mmol), and N,N-dimethylaminopyridine
(DMAP) (0.122 g, 1.0 mmol) in CH2Cl2 (10 mL) was
stirred at room temperature for 5 days. The mixture

A. Salaskar et al. / Tetrahedron: Asymmetry 17 (2006) 325–329
329
S.; Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem.
1993, 58, 7535; (c) Sharma, A.; Sankaranarayanan, S.;
Chattopadhyay, S. J. Org. Chem. 1996, 61, 1814.
in vacuo followed by column chromatography of the
residue (silica gel, 0–10% EtOAc/hexane) gave pure 10
25
(0.205 g, 63%) as a colorless liquid; ½aꢂD ¼ ꢀ15:2
(c 0.72, CHCl3); IR: 1740, 1230, 990, 910 cmꢀ1 1H
;
´
´
2. (a) Rivero-Cruz, J. F.; Macıas, M.; Cerda-Garcıa-Rojas,
C. M.; Mata, R. J. Nat. Prod. 2003, 66, 511–514; (b)
NMR: d 0.86 (dist. t, 3H), 1.04–1.28 (m containing a s
at d 1.06, 13H), 1.47–1.62 (m, 4H), 1.95–2.38 (m, 4H),
4.18–4.26 (m, 1H), 4.41–4.56 (m, 1H), 4.89–5.04 (m,
4H), 5.71–5.82 (m, 2H), 7.36–7.44 (m, 6H), 7.54–7.64
(m, 4H); 13C NMR: d 13.8, 18.8, 23.7, 25.3, 25.5, 26.3,
27.1, 35.7, 74.8, 77.3, 116.1, 116.4, 127.5, 128.1, 132.5,
134.5, 135.8, 173.1; MS (EI, 70 eV): m/z (%) 478 (19,
M+), 421 (27), 381 (36), 378 (18), 365 (22), 236 (30),
218 (66), 113 (35), 102 (96), 97 (71), 81 (100), 56 (55).
Anal. Calcd for C30H42O3Si: C, 75.26; H, 8.84. Found:
C, 75.52; H, 8.62.
´
´
Rivero-Cruz, J. F.; Garcıa-Aguirre, G.; Cerda-Garcıa-
Rojas, C. M.; Mata, R. Tetrahedron 2000, 56, 5337–
5344.
3. (a) de Napoli, L.; Messere, A.; Palomba, D.; Piccialli, V.;
Evidente, A.; Piccialli, G. J. Org. Chem. 2000, 65, 3432; (b)
Arnone, A.; Assante, G.; Montorsi, M.; Nasini, G.; Ragg,
E. Gazz. Chim. Ital. 1993, 123, 71.
4. (a) Furstner, A.; Radkowski, K. Chem. Commun. 2001,
671–672; (b) Furstner, A.; Radkowski, K.; Wirtz, C.;
Goddard, R.; Lehmann, C. W.; Mynott, R. J. Am. Chem.
´
Soc. 2002, 124, 7061–7069; (c) Dıez, E.; Dixon, D. J.; Ley,
S. V.; Polara, A.; Rodrıguez, F. Helv. Chim. Acta 2003, 86,
´
3717–3729; (d) Sabino, A. A.; Pilli, R. A. Tetrahedron
Lett. 2002, 43, 2819–2822; (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, part 3, 237–257.
5. (a) Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104–6107;
(b) Sharma, A.; Chattopadhyay, S. Tetrahedron: Asym-
metry 1999, 10, 883–890; (c) Sharma, A.; Chattopadhyay,
S. Enantiomer 2000, 5, 175–179.
3.1.8. (3R,5R)-5-(50-Hexenoyloxy)-1-octen-3-ol 11. To
a cooled (ꢀ78 ꢁC) and stirred solution of 10 (0.4 g,
0.84 mmol) in THF (10 mL) was injected TBAF
(1.0 mL, 1.0 M in THF mL). After stirring for 3 h, the
mixture was concentrated in vacuo and the residue sub-
jected to preparative TLC (silica gel, 10% EtOAc/hex-
ane) to furnish 114e (0.177 g, 88%). Colorless liquid;
25
½aꢂD ¼ þ5:7 (c 1.12, CHCl3); IR: 3380, 1740, 1230,
990, 910 cmꢀ1 1H NMR: d 0.84 (dist. t, 3H), 1.04–
;
6. Kolb, H. C.; van Nieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547.
1.24 (m, 4H), 1.51–1.63 (m, 4H), 1.95–2.16 (m, 2H),
2.31 (t, J = 7.2 Hz, 2H), 2.70 (br s, 1H), 4.14–4.19 (m,
1H), 4.39–4.48 (m, 1H), 4.91–5.04 (m, 4H), 5.72–5.86
(m, 2H); 13C NMR: d 14.1, 17.6, 23.7, 25.5, 26.3, 33.7,
35.7, 67.9, 72.5, 116.1, 116.4, 132.5, 171.4; MS (EI,
70 eV): m/z (%) 240 (21, M+), 222 (36), 197 (16), 179
(78), 171 (32), 153 (100), 113 (38), 97 (72), 61 (51), 55
(71).
7. For general reviews on olefin metathesis in organic
synthesis, see the following leading references: (a) Grubbs,
R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446–452; (b) Ivin, K. J.; Mol, J. C. Olefin Metathesis and
Metathesis Polymerization; Academic Press: New York,
1997; (c) Furstner, A.; Langemann, K. Synthesis 1997,
792–803; (d) Furstner, A. Top. Catal. 1997, 4, 285–299; (e)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–
4450; (f) Grubbs, R. H. Handbook of Metathesis, 1st ed.;
Wiley-VCH: Weinheim, 2003.
8. Dhotare, B.; Salaskar, A.; Chattopadhyay, A. Synthesis
2003, 2571–2575.
9. Chattopadhyay, A.; Salaskar, A. J. Chem. Soc., Perkin
Trans. 1 2002, 785–789.
10. (a) Richnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett.
1990, 31, 945–948; (b) Evans, D. A.; Rieger, D. L.; Gage,
J. R. Tetrahedron Lett. 1990, 31, 7099–7100.
11. (a) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073–
2077; (b) Furstner, A.; Muller, T. Synlett 1997, 1010–1012;
(c) Chang, S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38,
4757–4760; (d) Delgado, M.; Martin, J. D. J. Org. Chem.
1999, 64, 4798–4816; (e) Bamford, S. J.; Goubitz, K.; van
Lingen, H. L.; Luker, T.; Schenk, H.; Hiemstra, H. J.
Chem. Soc., Perkin Trans. 1 2000, 345–351; (f) Naka-
shima, K.; Ito, R.; Sono, M.; Tori, M. Heterocycles 2000,
53, 301–314; (g) Oishi, T.; Nagumo, Y.; Hirama, M.
3.1.9. (7R,9R,5E)-7-Hydroxy-9-propylnonenolide (her-
barumin III) I. A solution of 11 (0.175 g, 0.73 mmol)
and Grubb’s II catalyst (0.07 mmol) in CH2Cl2
(250 mL) were refluxed for 18 h. After quenching the
reaction with ethyl vinyl ether (1.0 mL), the mixture
was concentrated in vacuo, and the residue chromato-
graphed (silica gel, 0–10% ether/hexane) to give I
25
(0.142 g, 63%). Colorless liquid; ½aꢂD ¼ þ21:9 (c 0.88,
22
EtOH), (lit.2a ½aꢂD ¼ þ22:0 (c 0.1, EtOH)); IR: 3380,
1710, 980 cmꢀ1
;
1H NMR d 0.88 (dist. t, 3H),
1.32–1.42 (m, 2H), 1.49–1.76 (m, 2H), 1.77–1.85 (m,
2H), 1.98–2.02 (m, 3H), 2.02 (m, 1H), 2.24–2.29 (m,
1H), 2.37–2.42 (m partially D2O exchangeable, 2H),
4.42–4.47 (m, 1H), 5.10–5.21 (m, 1H), 5.34–5.44 (m,
1H), 5.59–5.64 (m, 1H); 13C NMR: d 14.1, 17.7, 24.2,
33.3, 33.9, 34.6, 39.7, 67.7, 70.1, 124.6, 134.1, 175.8;
MS (EI, 70 eV): m/z (%) 212 (12, M+), 194 (30), 169
(18), 151 (67), 143 (36), 125 (98), 113 (41), 97 (100), 55
(75), 41 (34).
Chem. Commun. 1998, 1041–1042; (h) Furstner, A.;
¨
Piquet, M.; Bruneau, C.; Dixneuf, P. H. Chem. Commun.
1998, 1315–1316; (i) Gerlach, K.; Quitschalle, M.; Kalesse,
M. Tetrahedron Lett. 1999, 40, 3553–3556; (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, 7893–7907; (k) Furstner, A.; Thiel, O. R.; Blanda, G.
Org. Lett. 2000, 2, 3731–3734.
References
1. (a) Belitz, H. D.; Grosch, W. In Food Chemistry; Springer:
Berlin, 1986; Chapter 5; (b) Pawar, A. S.; Chattopadhyay,