Formal and total syntheses of herbarumin i and II, respectively from (R)-2,3-cyclohexylideneglyceraldehyde

Article abstract of DOI:10.1016/j.tetasy.2012.05.011

Vinyl Grignard addition to 2, obtained via a nitroaldol reaction of (R)-2,3-cyclohexylideneglyceraldehyde 1, afforded 3 with absolute stereoselectivity. This was transformed into 7, a known intermediate for the formal synthesis of herbarumin I A. Condensation of 7 with 10, another intermediate obtained from 1 afforded 11. The RCM reaction of 11 in the presence of Grubbs second generation catalyst Ru II and global debenzylation of the product in the presence of TiCl₄ furnished B. The efficacy of the entire route was due to its operational simplicity, the easy accessibility of 1, all of the reactions being inexpensive and the high stereoselectivity of the asymmetric C-C bond forming reactions involved, as well as E-selectivity of the RCM reaction.

Full text of DOI:10.1016/j.tetasy.2012.05.011

Tetrahedron: Asymmetry 23 (2012) 764–768
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Formal and total syntheses of herbarumin I and II, respectively from
(R)-2,3-cyclohexylideneglyceraldehyde
⇑
Dibakar Goswami, Angshuman Chattopadhyay
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 April 2012
Accepted 15 May 2012
Vinyl Grignard addition to 2, obtained via a nitroaldol reaction of (R)-2,3-cyclohexylideneglyceraldehyde
1, afforded 3 with absolute stereoselectivity. This was transformed into 7, a known intermediate for the
formal synthesis of herbarumin I A. Condensation of 7 with 10, another intermediate obtained from 1
afforded 11. The RCM reaction of 11 in the presence of Grubbs second generation catalyst Ru II and global
debenzylation of the product in the presence of TiCl4 furnished B. The efficacy of the entire route was due
to its operational simplicity, the easy accessibility of 1, all of the reactions being inexpensive and the high
stereoselectivity of the asymmetric C–C bond forming reactions involved, as well as E-selectivity of the
RCM reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
comparison, only a very few reports7b,h–j are available for the syn-
thesis of B. Among these, Furstner et al.7b reported the synthesis of
Herbarumin-I A and herbarumin-II B are two nonenolides that
were discovered by Mata et al.1 through bioassay guided fraction-
ation of a culture broth fungus Phoma herbarum. These macrolides
showed high levels of phytotoxic effects on seedling growth and
were found to be structurally closely related to several other
recently discovered2 naturally occurring 10-membered macrolides,
such as herbarumin III C,1b microcarpalide D,3 lethaloxin E,4
decarestrictine D F5 as shown in Figure 1. Both herbarumin-I A
and herbarumin-II B exhibited significant phytotoxic effects in
assay monitoring germination and the growth of Amaranthus
hypochondriacus seedlings, with IC50 values as low as 5.43 ꢀ 10ꢁ5
for compound A.6 The discovery of this class of macrolides gave
rise to promising new lead structures in the search for novel
herbicidal agents.
both A and B and their structural characterization.
In our ongoing research related to the synthesis of bioactive
compounds, we have been exploiting (R)-2,3-cyclohexylideneglyc-
eraldehyde 18a as a useful template for the asymmetric construc-
tion of different structural units that are present in a wide range
of target biomolecules.8 Herein we report our successful exploita-
tion of 1 to develop a simple and stereoselective route leading to
the formal synthesis of A and an easy access to B.
2. Results and discussion
Retrosynthetic analysis (Scheme 1) of both A and B suggested
that both could be obtained via an appropriate chain extension
of common intermediate 7, which in turn could be derived from
a known aldehyde 28n obtained from 1. Accordingly, our synthesis
began with O-silylated hydroxyaldehyde 2, which was obtained by
the nitroaldol reaction of 1 in an aqueous medium.8n Compound 2
was subjected to vinyl Grignard addition, which produced isomer 3
stereoselectively. Desilylation of 3, followed by benzylation of both
hydroxyls of diol 4 produced 5 in good yield. Deketalisation of 5
under acidic conditions produced the known diol 6,7d in almost
quantitative yield. With regards to the preparation of 6, it is worth
mentioning that our protocol is simpler and more straightforward
involving the generation of both hydroxyls at C-3 and C-4 with
absolute stereoselectively via the corresponding nucleophilic addi-
tions [nitroaldol8n reaction of 1 and vinyl Grignard addition of 2
(Scheme 2, step ii), respectively] compared to the reported
method7d where C-3 hydroxyl was produced by starting from
In addition to their remarkable biological activities as men-
tioned above, both A and B bear a novel structural feature due to
the presence of three consecutive oxygenated stereocenters at
the C7, C8, and C9 positions in the lactone ring with an anti
relationship between any two adjacent oxygens in this scaffold.
Needless to say, due to these structural characteristics, both A
and B are challenging synthetic targets. As a result, there are
several reports in the literature for the synthesis of A, which ex-
ploit different chiral templates, such as D L
-ribose,7a,b -arabinose,7c
D
-(ꢁ)-isoascorbic acid7d and
L
-ascorbic acid,7e by employing an
asymmetric aldol,7f or asymmetric epoxidation7g protocols. In
⇑
Corresponding author.
E-mail
addresses:
achat@barc.gov.in,
achat@apsara.barc.ernet.in
D-isoascorbic acid following either a longer route or through
(A. Chattopadhyay).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.05.011

D. Goswami, A. Chattopadhyay / Tetrahedron: Asymmetry 23 (2012) 764–768
765
HO
HO
HO
HO
HO
O
O
O
OH
O
O
O
herbarumin II B
herbarumin I A
herbarumin III C
HO
O
OH
OH
O
O
HO
O
HO
OH
O
O
OH
OH
F
dacarestrictine D
microcarpalide D
(+)-lethaloxin E
Fig. 1.
HO
HO
O
OH
OBn
O
A
O
O
O
CHO
OTBS
O
CHO
OBn
7
1
HO
2
O
HO
OH
O
B
Scheme 1.
hydride reduction of a ketone, which did not take place with abso-
lute stereoselectivity. Furthermore, due to our reaction being a ser-
ies of operationally simple and inexpensive reactions starting from
easily accessible 1, the present route appears to be more viable
with respect to the reported one.7d Next, with a modification of
the reported protocol,7d 6 was transformed into the known inter-
mediate 7 thus constituting a formal synthesis of A.
3. Conclusion
Compound 1 has been utilized as a novel template in the devel-
opment of a divergent route to the formal synthesis of herbarumin
I A and herbarumin II B, respectively. In our approach, 1 has been
transformed stereoselectively into 7, a known intermediate to give
product 11, which was finally utilized for the synthesis of B via an
RCM approach. It is worth noting that two of the three oxygenated
stereocenters of the common intermediate 7 were generated
through crucial asymmetric C–C bond forming reactions, the nitro-
aldol reaction of 18n and vinyl-Grignard addition to 2 (step ii,
Scheme 2) which took place with absolute stereoselectivity, while
the third stereocenter was inherited from 1. Regarding the synthe-
sis of B, the only stereocenter of intermediate 10 originated from
8a, which itself was prepared from 1 with absolute stereoselectiv-
ity.8h Lastly, the selective formation of the desired E-olefin in the
RCM reaction9 of 11 (step xii, Scheme 2) further established the
novelty of this approach for the preparation of B. The easy avail-
ability of 7 is of high importance in the synthesis due to the fact
that in addition to this work, it could also be utilized as a useful
chiral template for the synthesis of lethaloxin following a reported
approach7j and gives access to several other biologically relevant
macrolides that have some structural resemblance with A and B.
We next turned our attention to the synthesis of B for which
we chose to start with syn alcohol 8a, which had been derived
from 1.8h This was benzylated to produce 8b, which upon deke-
talisation under acidic conditions produced diol 9. Sodium perio-
date cleavage of 1,2-dihydroxyl in 9, followed by PDC oxidation
of the resulting aldehyde afforded 10 in reasonably good yield in
two steps. Compound 10 has recently been prepared,7j however
our protocol seems simpler and scaleable since it is originated
from 1. In the next step, 10 was condensed with 7 in the pres-
ence of DCC in dichloromethane to afford diolefin 11 in good
yield. In the next crucial step, compound 11 was subjected to
a ring closing metathesis reaction (RCM) in boiling CH2Cl2 using
Grubbs second generation catalyst Ru II.9 The RCM product, thus
obtained was used without further purification and subjected to
exhaustive debenzylation upon treatment with TiCl4 to furnish B
in good yield. Its optical and spectroscopic data were in good
agreement with the reported values.7b,h This suggested that the
metathesis reaction of diolefin 11 with Ru II (Scheme 2, step
xii) produced only the (E)-lactone, which was similar to what
had been observed earlier7h in the same reaction with the corre-
sponding tri-O-silylated substrate. It is worth mentioning that
the RCM reaction of another terminal bisolefin compound with
Grubbs first generation catalyst Ru I predominantly afforded
the E-olefin.10
4. Experimental
4.1. General
Chemicals used as starting materials were commercially
available and used without further purification. All solvents used

766
D. Goswami, A. Chattopadhyay / Tetrahedron: Asymmetry 23 (2012) 764–768
O
O
O
O
OH
i
ii
O
OH
iii
iv
O
CHO
OTBS
O
O
vi
O
CHO
2
1
3
4
OTBS
OH
HO
OH
OBn
3
OH
OBn
vii
v
OBn
4
1
6
O
HO
HO
7
5
O
8
2
OBn
OBn
O
6
A
7
5
BnO
OH
HO2C
ix, x
viii
v
O
HO
1
O
OBn
10
9
OBn
OR
8a, R= H
8b,
iv
R= Bn
BnO
O
HO
xii, xiii
xi
O
OBn
7
O
OH
HO
O
B
OBn
11
i) Reference 8n; ii) vinylmagnesiumbromide, dry THF, -78 oC to RT; iii) TBAF, THF, 0 oC to RT; iv) NaH, BnBr, THF,
reflux; v) Aq. TFA, CH2Cl2, 0 oC; vi) (a)TsCl, py, 0oC; then K2CO3, MeOH; (b) Ethylmagnesiumbromide, Cu2Br2, -50 o
C
to RT; vii ) Reference 7d; viii) Reference 8h; ix) NaIO4, 60% aq. MeCN ; x) PDC, DMF; xi) 10, DCC, CH2Cl2; xii) Grubbs
catalyst-II, CH2Cl2, 50 oC; xiii) TiCl4, CH2Cl2, 0 oC.
Scheme 2.
for extraction and chromatography were distilled twice at atmo-
spheric pressure prior to use. The 1H and 13C NMR spectra were re-
corded with a Bruker Ac-200 (200 MHz) instrument. The organic
extracts were desiccated over dry Na2SO4.
THF), and the mixture stirred for approximately 2 h (TLC). Next,
the mixture was poured into water, and extracted with EtOAc
(15 mL). The organic extract was washed with H2O (5 mL) and
brine, and dried. Removal of solvent in vacuo followed by column
chromatography (silica gel, 0–5% MeOH/CHCl3) of the residue fur-
4.2. (2R,3S,4S)-1,2-Cyclohexylidene-3-O-tert-butyldimethylsilyl
hex-5-ene-1,2,3,4-tetrol 3
nished pure diol 4. Yield: 1.56 g (78%); colorless oil; ½a D22
¼ þ23:4
ꢂ
(c 1.4, CHCl3); 1H NMR: 1.39–1.65 (m, 10H), 2.37 (broad s, 1H),
2.75 (broad s, 1H), 3.70 (t, J = 4.2 Hz, 1H), 3.93–4.08 (m, 3H),
4.32 (t, J = 5.7 Hz, 1H), 5.28–5.44 (m, 2H), 5.88–5.99 (m, 1H);
13C NMR: d 23.9, 24.1, 25.1, 34.9, 36.3, 66.1, 73.7, 74.5, 76.1,
109.7, 118.1, 136.0. Anal. Calcd for C12H20O4: C, 63.14; H, 8.83%.
Found, C, 63.29; H, 8.61%.
Vinylmagnesium bromide (1 M solution in THF, 19.20 ml,
19.20 mmol) was added dropwise to a cooled (ꢁ78 °C) solution
of aldehyde 2 (4.0 g, 12.74 mmol) in dry THF under an argon atmo-
sphere. The solution was stirred for 6 h (TLC) and then gradually
brought to room temperature. Water and EtOAc were added to
the mixture, the organic layer separated and the aqueous layer ex-
tracted with EtOAc (3 ꢀ 40 mL). The combined organic extracts
were washed with aqueous HCl, water and brine, and dried. Sol-
vent removal in vacuo and chromatographic purification (silica
gel, 0–10% EtOAc/Hexane) of the crude residue afforded pure alco-
4.4. (2R,3S,4S)-1,2-Cyclohexylidene-3,4-O-dibenzylhex-5-ene-1,2,3,4-
tetrol 5
To a suspension of sodium hydride (0.74 g, 50% suspension in
oil, 15.35 mmol) in dry THF (50 ml), a solution of 4 (1.40 g,
6.14 mmol) in dry THF (50 ml) was added dropwise over a period
of 10 min under an argon atmosphere. The mixture was heated
at 60 °C for 1 h. Then the mixture was cooled to room temperature
followed by the addition of benzyl bromide (2.62 g, 15.35 mmol) in
THF (50 ml). The mixture was stirred for a further 1 h and then
heated at 60 °C for 2 h. Upon completion of the reaction (TLC), it
was cooled with ice-water, quenched by the addition of water,
and extracted with EtOAc. The organic layer was washed succes-
sively with water, 5% aqueous HCl, water, brine, and then dried
over Na2SO4. Solvent removal under reduced pressure and column
chromatography of the residue (silica gel, 0–5% EtOAc in hexane)
hol 3. Yield: 3.14 g (72%); colorless oil; ½a D24
¼ þ11:3 (c 1.2, CHCl3);
ꢂ
1H NMR: d 0.10 (s, 6H), 0.88 (s, 9H), 1.19–1.59 (m, 10H), 2.03
(broad s, 1H), 3.78–3.88 (m, 2H), 3.92–4.04 (m, 2H), 4.23–4.25
(m, 1H), 5.17–5.37 (m, 2H), 5.80–5.92 (m, 1H); 13C NMR: d ꢁ4.4,
ꢁ4.2, 18.2, 23.9, 24.1, 25.3, 25.9, 35.1, 36.3, 65.9, 75.3, 75.5, 75.7,
109.1, 116.8, 136.2. Anal. Calcd for C18H34O4Si: C, 63.11; H,
10.00%. Found, C, 63.32; H, 10.14%.
4.3. (2R,3S,4S)-1,2-Cyclohexylidenehex-5-ene-1,2,3,4-tetrol 4
To a cooled (0 °C) and stirred solution of 3 (3.0 g, 8.77 mmol)
in THF (30 mL) was added Bu4NF (14.90 ml, 14.90 mmol, 1 M in
afforded pure 5. Yield: 2.25 g (90%); colorless oil; ½a D24
¼ þ38:8 (c
ꢂ

D. Goswami, A. Chattopadhyay / Tetrahedron: Asymmetry 23 (2012) 764–768
767
1.06, CHCl3); 1H NMR: 1.35–1.59 (m, 10H), 3.74 (dd, J = 3.0 Hz and
6.3 Hz, 1H), 3.87–3.98 (m, 2H), 4.03–4.13 (m, 2H), 4.40 (d,
J = 12.3 Hz, 1H), 4.67 (dd, J = 9.3 Hz and 11.4 Hz, 2H), 4.83 (d,
J = 11.4 Hz, 1H), 5.30–5.38 (m, 2H), 5.86–5.98 (m, 1H), 7.26–7.34
(m, 10H); 13C NMR: d 23.9, 24.1, 25.3, 35.0, 36.4, 66.3, 70.6, 74.2,
74.9, 81.6, 81.7, 109.5, 119.5, 127.5, 127.6, 127.7, 128.1, 128.4,
134.9, 138.7. Anal. Calcd for C26H32O4: C, 76.44; H, 7.90%. Found,
C, 76.12; H, 7.80%.
NMR: 0.89 (t, J = 6.9 Hz, 3H), 1.25–1.64 (m, 4H), 2.41 (d, J = 4.8 Hz,
1H), 3.44 (t, J = 6.0 Hz, 1H), 3.70–3.82 (m, 1H), 4.00–4.05 (m, 1H),
4.37 (d, J = 12.0 Hz, 1H), 4.54–4.74 (m, 3H), 5.34–5.40 (m, 2H),
5.88–6.01 (m, 1H), 7.26–7.37 (m, 10H); 13C NMR: d 14.2, 18.9,
34.9, 70.4, 72.5, 74.3, 82.0, 83.9, 119.5, 127.7, 127.8, 127.9, 128.1,
128.4, 128.5, 136.1, 138.1, 138.4.
4.7. (2R,3R)-1,2-Cyclohexylidene-3-O-benzylhept-6-ene-1,2,3-
triol 8b
4.5. (2R,3S,4S)-3,4-O-Dibenzylhex-5-ene-1,2,3,4-tetrol 6
To a suspension of sodium hydride (0.576 g, 50% suspension in
oil, 12.0 mmol) in dry THF (50 ml), a solution of 8a8h (2.26 g,
10.0 mmol) in dry THF (40 ml) was added dropwise over a period
of 10 min under an argon atmosphere. The mixture was heated
at 60 °C for 1 h. Then the mixture was cooled to room temperature
followed by the addition of benzyl bromide (2.05 g, 12.0 mmol) in
THF (50 ml). The mixture was stirred for a further 1 h and then
heated at 60 °C for 2 h. Upon completion of the reaction (TLC), it
was cooled with ice-water, quenched by the addition of water
and extracted with EtOAc. The organic layer was washed succes-
sively with water, 5% aqueous HCl, water, brine, and then dried
over Na2SO4. Solvent removal under reduced pressure and column
chromatography of the residue (silica gel, 0–5% EtOAc in hexane)
To a stirred and cooled (0 °C) solution of 5 (2.0 g, 4.90 mmol) in
CH2Cl2 (30 mL) was added portionwise 80% aqueous trifluoroacetic
acid (15 mL). The mixture was stirred for 2.5 h at 0 °C until comple-
tion of the reaction (TLC). Solid NaHCO3 (5.0 g) was then added in
order to decompose the excess TFA, followed by the addition of
water. The mixture was extracted with CHCl3 (3 ꢀ 30 ml). The
combined organic extracts were washed with water and brine,
and dried over Na2SO4. Removal of the solvent in vacuum followed
by column chromatography (silica gel, 5% MeOH in CHCl3) of the
residue afforded pure 6. Yield: 1.16 g (72%); colorless oil;
½
a 2D4
ꢂ
¼ þ47:4 (c 1.6, CHCl3); lit.7d
½
a 2D0
ꢂ
¼ þ47:8 (c 0.7, CHCl3); 1H
NMR: 2.32 (broad s, 1H), 3.19 (broad s, 1H), 3.62 (t, J = 6.0 Hz,
1H), 3.68–3.82 (m, 3H), 4.05–4.09 (m, 1H), 4.38 (d, J = 11.7 Hz,
1H), 4.57–4.72 (m, 3H), 5.37–5.44 (m, 2H), 5.85–5.97 (m, 1H),
7.26–7.39 (m, 10H); 13C NMR: d 63.5, 70.6, 72.4, 74.2, 81.2, 82.1,
120.1, 127.9, 128.2, 128.5, 128.6, 135.4, 137.8, 137.9.
afforded pure 8b. Yield: 2.68 g (85%); colorless oil; ½a D24
¼ þ13:4
ꢂ
(c 1.0, CHCl3); 1H NMR: 1.39–1.68 (m, 12H), 2.08–2.16 (m, 1H),
2.23–2.30 (m, 1H), 3.44–3.48 (m, 1H), 3.67 (t, J = 7.5 Hz, 1H), 3.99
(dd, J = 6.5 and 8.0 Hz, 1H), 4.21 (q, J = 7.0 Hz, 1H), 4.62 (d,
J = 11.5 Hz, 1H), 4.83 (d, J = 11.5 Hz, 1H), 4.95–5.01 (m, 2H), 5.74–
5.82 (m, 1H), 7.26–7.38 (m, 5H); 13C NMR: d 23.9, 24.0, 25.2,
29.7, 30.1, 34.9, 36.3, 65.7, 73.0, 78.3, 79.4, 109.9, 114.9, 127.5,
128.0, 128.3, 138.3. Anal. Calcd for C20H28O3: C, 75.91; H, 8.92%.
Found, C, 76.12; H, 8.80%.
4.6. (4R,5R,6S)-5,6-O-Dibenzyl-oct-7-en-4-ol 7
To a cooled (0 °C) solution of 6 (1.0 g, 3.05 mmol) in pyridine
(10 mL) containing DMAP (50 mg), p-toluenesulfonylchloride
(0.581 g, 3.05 mmol) was slowly added over a period of 2 h. The
mixture was then stirred at 0 °C for 2 h. After completion of the
reaction (TLC), it was quenched by the addition of water and ex-
tracted with CHCl3. The organic layer was washed successively
with 5% aqueous HCl, water, brine, and then dried over Na2SO4.
The solvent was removed under reduced pressure to obtain the
crude residue, which was quickly purified by passing through a
short silica gel column eluting with 5–15% EtOAc in hexane to ob-
tain the product in quantitative yield. This was immediately dis-
solved in MeOH (15 mL) and mixed with solid K2CO3 (0.635 g,
4.60 mmol). The mixture was stirred at room temperature for three
hours until the reaction was complete (TLC). The solvent was re-
moved under reduced pressure and the residue was dissolved in
CHCl3. The organic layer was washed successively with water, 5%
aqueous HCl, water, brine, and then dried over Na2SO4. Solvent re-
moval under reduced pressure afforded the corresponding termi-
nal epoxide7d (0.65 g) in its crude form. This was used as such
for the next reaction without further purification.
4.8. (2R,3R)-3-O-Benzylhept-6-ene-1,2,3-triol 9
To a stirred and cooled (0 °C) solution of 8b (2.5 g, 7.91 mmol)
in CH2Cl2 (30 mL) was added portionwise 80% aqueous trifluoro-
acetic acid (15 mL). The mixture was stirred for 2.5 h at 0 °C until
completion of the reaction (TLC). Solid NaHCO3 (5 g) was then
added in order to decompose the excess TFA, followed by the addi-
tion of water. The mixture was extracted with CHCl3 (3 ꢀ 30 ml).
The combined organic extracts were washed with water and brine,
and dried over Na2SO4. Removal of the solvent in vacuum followed
by column chromatography (silica gel, 5% CHCl3/MeOH) of the
residue afforded pure 9. Yield: 1.27 g (68%); colorless oil; ½a D24
¼
ꢂ
þ18:2 (c 1.2, CHCl3); 1H NMR: 1.67–1.82 (m, 2H), 2.15–2.20 (m,
2H), 2.42 (broad s, 1H), 2.74 (broad s, 1H), 3.51 (q, J = 5.5 Hz, 1
H), 3.59–3.63 (m, 1H), 3.67–3.69 (m, 2H), 4.50 (d, J = 11.0 Hz,
1H), 4.66 (d, J = 11.0 Hz, 1H), 4.98–5.06 (m, 2H), 5.80–5.87 (m,
1H), 7.27–7.38 (m, 5H); 13C NMR: d 29.3, 29.4, 64.0, 72.3, 72.8,
79.1, 115.0, 127.9, 128.5, 138.0. Anal. Calcd. for C14H20O3: C,
71.16; H, 8.53%. Found, C, 71.33; H, 8.71%.
A Grignard suspension of bromoethane in THF (50 mL) was pre-
pared from ethyl bromide (0.467 ml, 6.30 mmol) and Mg (0.202 g,
8.40 mmol) in the usual manner. The suspension was cooled
(ꢁ50 °C) and Cu(I) bromide (0.452 g, 3.15 mmol) was added. The
mixture was stirred at ꢁ50 °C for 15 min. To this cooled organome-
tallic suspension, a solution of epoxide (0.650 g, 2.10 mmol) in THF
(40 mL), prepared as above, was added. The mixture was stirred at
the same temperature for 1 h and then gradually brought to room
temperature. The mixture was then stirred overnight at room tem-
perature. The reaction was quenched by the addition of aqueous
saturated NH4Cl (10 mL) and extracted with EtOAc. The organic
layer was washed with 5% aqueous HCl, water, brine and then
dried over Na2SO4. Solvent removal under reduced pressure and
column chromatography of the residue (silica gel, 0–10% EtOAc
in hexane) afforded pure 7. Yield: 0.54 g (52% in 3 steps); colorless
4.9. (R)-2-O-Benzylhex-5-enoic acid 10
To a stirred solution of 9 (1.20 g, 5.1 mmol) in 60% aqueous
CH3CN (20 mL) was added portionwise NaIO4 (1.86 g, 8.67 mmol).
After stirring for 2 h, the mixture was filtered, and the filtrate ex-
tracted with CHCl3. The organic layer was washed with water
and brine, and concentrated in vacuo to give the aldehyde, which
was utilized for next reaction without further purification.
This aldehyde (1.0 gm, 4.9 mmol) was added to a stirred solu-
tion of pyridinium dichromate (9.21 g, 24.5 mmol) in DMF (5 ml),
and stirring was continued at rt. The reaction was monitored by
TLC. When no starting material could be detected, water (10 ml)
and ether (20 ml) were added to the reaction. The organic layer
oil; ½a 2D5
ꢂ
¼ þ9:3 (c 2.4, MeOH); lit.7d
½
a 2D0
ꢂ
¼ þ9:1 (c 3.0, MeOH); 1H

768
D. Goswami, A. Chattopadhyay / Tetrahedron: Asymmetry 23 (2012) 764–768
was separated and the aqueous phase was extracted with ether.
The combined ether phases were dried over MgSO4 and concen-
trated, to yield an oil, which was subjected to column chromatog-
raphy (silica gel, 0–15% MeOH/CHCl3) to afford pure 10. Yield:
washed with saturated aqueous sodium bicarbonate (10 mL) and
water (10 mL), dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, 0–30% EtOAc/hexane) to afford B.
0.79 g (71% over two steps); colorless oil; ½a D24
ꢂ
¼ þ20:8 (c 1.2,
Yield: 0.055 g (54% over 2 steps); colorless solid; ½a D24
¼ þ16:8 (c
ꢂ
CHCl3); lit7j
½
a 2D4
ꢂ
¼ þ22:3 (c 0.45, CHCl3); 1H NMR: d 1.88–1.95
1.0, MeOH); lit7b
data were in agreement with the literature.
½
a 2D0
ꢂ
¼ þ17:3 (c 0.63, MeOH); The spectroscopic
7b,h
(m, 2H), 2.18–2.24 (m, 2H), 4.02 (t, J = 6.0 Hz, 1H), 4.48 (d,
J = 11.4 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.98–5.04 (m, 2H), 5.71–
5.84 (m, 1H), 7.28–7.42 (m, 5H); 13C NMR: d 29.4, 32.0, 72.9,
77.7, 116.0, 128.4, 128.8, 137.3, 177.4.
References
1. (a) Rivero-Cruz, J. F.; Macias, M.; Gerda-Garcia-Rojas, C. M.; Mata, R.
Tetrahedron 2000, 56, 5337–5344; (b) Rivero-Cruz, J. F.; Macias, M.; Gerda-
Garcia-Rojas, C. M.; Mata, R. J. Nat. Prod. 2003, 66, 511.
2. (a) Gerald, D.; Andreas, K.; Ralf, T.; Marion, Z. Nat. Prod. Rep. 1996, 13, 365; (b)
Valeria, B. R.; Ronaldo, A. P.; Mauricio, M. V. Tetrahedron 2008, 64, 2279.
3. Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. Org. Lett. 2001,
3, 3479.
4.10. (2R)-(4R,5R,6S)-5,6-Dibenzyloct-7-en-4-yl-2-benzylhex-5-
enoate 11
To a stirred solution of compound 7 (0.20 g, 0.59 mmol) in dry
CH2Cl2 (5 ml), DCC (0.243 g, 1.18 mmol), 10 (0. 150 g, 0.68 mmol)
and DMAP (catalytic amount) were added at 0 °C and stirred at
room temperature for 3 h. After completion of the reaction (TLC),
the reaction mixture was filtered through Celite and extracted with
CHCl3, dried over anhydrous Na2SO4 and concentrated under re-
duced pressure. The residue was purified by column chromatogra-
phy (silica gel, 0–5% EtOAc/hexane) to afford 11. Yield: 0.262 g
4. Arnone, A.; Assante, G.; Montorsi, M.; Nasini, G.; Ragg, E. Gazz. Chim. Ital. 1993,
123, 71.
5. (a) Grabley, S.; Granzer, E.; Hütter, K.; Ludwig, D.; Mayer, M.; Thiericke, R.; Till,
G.; Wink, J.; Phillips, S.; Zeeck, A. J. Antibiot. 1992, 45, 56; (b) Hütter, K.;
Thiericke, R.; Kirsch, R.; Kluge, H.; Göhrt, A.; Zeeck, A. J. Antibiot. 1992, 45, 66;
(c) Hütter, K.; Thiericke, R.; Kirsch, R.; Kluge, H.; Grabley, S.; Hammann, P.;
Mayer, M.; Zeeck, A. J. Antibiot. 1992, 45, 1176; (d) Ayer, W. A.; Sun, M.; Browne,
L. M.; Brinen, L. S.; Clardy, J. J. Nat. Prod. 1992, 55, 649.
(82%); colorless oil; ½a D22
ꢂ
¼ þ68:4 (c 1.1, CHCl3); 1H NMR: 0.92 (t,
6. Mata, R.; Macias, M. L.; Rojas, I. S.; Lotina-Hennsen, B.; Toscano, R. A.; Anaya, L.
A. Phytochemistry 1998, 49, 441.
J = 6.9 Hz, 3H), 1.18–1.39 (m, 2H), 1.41–1.75 (m, 4H), 2.20–2.26
(m, 2H), 3.62 (t, J = 4.5 Hz, 1H), 3.82 (dd, J = 6.0 Hz and 7.5 Hz,
1H), 4.12 (t, J = 6.9 Hz, 1H), 4.34 (d, J = 12.0 Hz, 1H), 4.45–4.73
(m, 5H), 4.94–5.07 (m, 2H), 5.14–5.20 (m, 1H), 5.28–5.41 (m,
2H), 5.65–5.89 (m, 2H), 7.26–7.33 (m, 15H); 13C NMR: d 15.0,
19.1, 24.2, 32.9, 68.1, 70.0, 73.7, 74.1, 80.3, 82.1, 83.3, 115.6,
119.8, 127.7, 128.1, 128.2, 128.4, 128.4, 133.4, 133.6, 135.4,
137.3, 138.3, 138.6, 170.8. Anal. Calcd. for C35H42O5: C, 77.46; H,
7.80%. Found, C, 77.54; H, 7.66%.
7. (a) Fürstner, A.; Radkowski, K. Chem. Commun. 2001, 671; (b) Fürstner, 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) Selvam, J. J. P.; Rajesh, K.; Suresh, V.; Babu, D. C.; Venkateshwarlu, Y.
Tetrahedron: Asymmetry 2009, 20, 1115. and references cited therein; (e)
Nagaiah, K.; Sreenu, D.; Rao, S. S.; Yadav, J. S. Tetrahedron Lett. 2007, 48, 7173;
(f) Srihari, P.; Rao, G. M.; Rao, R. S.; Yadav, J. S. Synthesis 2010, 2407; (g) Srihari,
P.; Kumaraswamy, B.; Rao, G. M.; Yadav, J. S. Tetrahedron: Asymmetry 2010, 21,
106. and references cited therein; (h) Diez, E.; Dixon, D. J.; Ley, S. V.; Polara, A.;
Rodriguez, F. Synlett 2003, 1186; (i) Diez, E.; Dixon, D. J.; Ley, S. V.; Polara, A.;
Rodriguez, F. Helv. Chim. Acta. 2003, 86, 3717; (j) Krishna, P. D.; Ramana, D. V. J.
Org. Chem. 2012, 77, 674.
8. (a) Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem. 1995, 60, 585; (b)
Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104; (c) Chattopadhyay, A.;
Dhotare, B.; Hassarajani, S. A. J. Org. Chem. 1999, 64, 6874; (d) Dhotare, B.;
Chattopadhyay, A. Synthesis 2001, 1337; (e) Dhotare, B.; Chattopadhyay, A.
Tetrahedron Lett. 2005, 46, 3103; (f) Dhotare, B.; Goswami, D.;
Chattopadhyay, A. Tetrahedron Lett. 2005, 46, 6219; (g) Chattopadhyay, A.;
Salaskar, A. J. Chem. Soc., Perkin Trans. 1 2002, 785; (h) Chattopadhyay, A.;
Vichare, P.; Dhotare, B. Tetrahedron Lett. 2007, 48, 2871; (i) Chattopadhyay,
A.; Goswami, D.; Dhotare, B. Tetrahedron Lett. 2006, 47, 4701; (j) Goswami,
D.; Chattopadhyay, A. Lett. Org. Chem. 2006, 47, 4701; (k) Dhotare, B.;
Salaskar, A.; Chattopadhyay, A. Synthesis 2003, 8, 2571; (l) Dubey, A. K.;
Goswami, D.; Chattopadhyay, A. ARKIVOC 2010, 137; (m) Chattopadhyay, A.;
Goswami, D.; Dhotare, B. Tetrahedron Lett. 2010, 51, 4701; (n) Vichare, P.;
Chattopadhyay, A. Tetrahedron: Asymmetry 2010, 21, 1983; (o)
Chattopadhyay, A.; Tripathy, S. J. Org. Chem. 2011, 76, 5856; (p) Dubey, A.
K.; Chattopadhyay, A. Tetrahedron: Asymmetry 2011, 22, 1516.
4.11. Herbarumin II (B)
Second generation Grubbs’ catalyst (0.068 g, 0.08 mmol) was
added to a solution of diene ester 11 (0.228 g, 0.42 mmol) in de-
gassed anhydrous CH2Cl2 (150 ml) and the mixture was heated at
50 °C under an argon flow for 12 h. After completion of the reaction
(TLC), most of the solvent was evaporated and then air was bub-
bled to decompose catalyst. The remaining solvent was evaporated
under reduced pressure, to afford a dark brown oily residue, which
was quickly passed through a short silica gel column eluting with
30% EtOAc in hexane to obtain the RCM product (0.186 g) in its
crude form. This was used for the next step without further
purification.
9. (a)Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: New York, 2003.
Vols. 1–3; (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199; (c) Trnka, T.
M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
10. Garcia-Fortanet, J.; Murga, J.; Falomir, E.; Carda, M.; Marco, J. A. J. Org. Chem.
2006, 70, 9822.
A cooled (0 °C) solution of this crude RCM product (0.170 g,
0.33 mmol) in dry CH2Cl2 (5 ml), containing TiCl4 (0.073 ml,
0.66 mmol) was stirred for 15 min. After completion of the reaction
(cf. TLC), more CH2Cl2 (20 ml) was added to it. The mixture was