RCM/PCC oxidation strategy for synthesis of functionalized cyclic α,β-unsaturated lactones: synthesis of (+)-triacetoxygoniotriol and its diastereomers

Article abstract of DOI:10.1016/j.tet.2006.09.016

A novel methodology leading to the synthesis of (+)-triacetoxygoniotriol 2 from d-glucose is described. Construction of the core six-membered α,β-unsaturated lactone moiety involved ring closing metathesis (RCM) followed by a PCC oxidation. Later exploiti

Full text of DOI:10.1016/j.tet.2006.09.016

Tetrahedron 62 (2006) 11165–11171
RCM/PCC oxidation strategy for synthesis of functionalized cyclic
a,b-unsaturated lactones: synthesis of (D)-triacetoxygoniotriol
and its diastereomers
a
a
b
G. S. C. Srikanth,a, Urlam Murali Krishna, Girish K. Trivedi and John F. Cannon
*
aDepartment of Chemistry, Indian Institute of Technology, Powai, Mumbai 400 076, India
bDepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84604, USA
Received 7 July 2006; revised 22 August 2006; accepted 8 September 2006
Available online 12 October 2006
Abstract—A novel methodology leading to the synthesis of (+)-triacetoxygoniotriol 2 from D-glucose is described. Construction of the core
six-membered a,b-unsaturated lactone moiety involved ring closing metathesis (RCM) followed by a PCC oxidation. Later exploiting the
pseudo-symmetry of D-glucose three other diastereomers of triacetoxygoniotriol were synthesized using the developed methodology.
Ó 2006 Elsevier Ltd. All rights reserved.
O
O
1. Introduction
OR
O
OAc O
Styryllactones, isolated from the stem bark of Goniothala-
mus gigeanteus (Annanoceae) have interesting heterocyclic
skeletons.1 They show significant murine toxicity toward
lymphocytic leukemia systems. Goniotriol 1a is one of the
important members of styryllactone family. It showed signif-
icant cytotoxicity in the potato disc test and brine shrimp
test. Interestingly both enantiomers of goniotriol occur in
nature and its stereochemistry varies with the source of
extraction.2 Syntheses of (+)-goniotriol adopting both chiral
pool and enantioselective approaches (including our own
approach) and its analogues have been reported and their
bioactivities were studied.3,4 Also, synthesis of other styryl-
lactones from goniotriol has been reported. Taking into
account the various approaches reported in the literature
we embarked on developing a novel unified approach for
synthesis of various diastereomers of (+)-goniotriol from
D-glucose. In our approach, which is described here we con-
structed the core a,b-unsaturated lactone moiety by using
RCM and PCC oxidation of dialkenyl derivatives. We also
showed that the allyl group, which is generally known to
be a protection group could be used as a masked acrylic ester
moiety during our synthesis. Herein, we wish to report
complete details of our approach along with the synthesis
of both the enantiomers of goniotriol, thus demonstrating
the versatility of our approach (Fig. 1).
C6H5
C6H5
OR OR
OAc OAc
(+)-7-epi-Triacetoxygoniotriol 2
(+)-Goniotriol 1a (R = H)
(+)-Triacetoxygoniotriol 1b (R = OAc)
O
O
OAc O
OAc O
C6H5
C6H5
OAc OAc
OAc OAc
(-)-7-epi-Triacetoxygoniotriol 4
(-)-Triacetoxygoniotriol 3
Figure 1.
2. Results and discussion
Retrosynthetic analysis of our approach for the synthesis of go-
niotriols 1–4 is depicted in Scheme 1. The recognition that the
core six-membered a,b-unsaturated lactone moiety of the
goniotriol could be constructed by ring closing metathesis fol-
lowed by PCC oxidation guided our planning from the outset.
In the synthetic direction (ꢀ)-triacetoxygoniotriols 3 and 4
could be synthesized from RCM product of dialkene 5 by
a PCC oxidation reaction.5 Dialkene 5 could originate from
the acetonide 6 by incorporation of the required phenyl group.
Finally theacetonide 6can be synthesized from diol 7, whichin
turn could be obtained from D-glucose by known steps.6
Our synthesis commenced as outlined in Scheme 2. Di-
alkenyl acetonide 6 was subjected to hydrolysis using acetic
Keywords: Styryllactones; Goniotriol; RCM and PCC oxidation.
* Corresponding author. E-mail: sriks74@yahoo.com
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.016

11166
G. S. C. Srikanth et al. / Tetrahedron 62 (2006) 11165–11171
O
OAc O
O
3 / 4
C6H5
O
O
OAc OAc
5
6
OH
O
O
HO
O
O
7
OH
O
O
O
OAc O
C6H5
1b / 2
C6H5
O
OAc OAc
8
9
Scheme 1.
OAc O
d
(-)-Triacetoxygoniotriol 3
c
C6H5
C6H5
from 12
OAc OAc
14
R2
R1
C6H5
O
a
6
OAc O
d
R3 R3
c
(-)-7-epi-Triacetoxygoniotriol 4
10 : R1 = H, R2 R3 = OH
11 : R1 R3 = OH, R2 = H
from 13
OAc OAc
15
b
12 : R2 = H, R1 R3= OAc
13 : R2 R3 = OAc, R1 = H
Scheme 2. (a) (i) CH3CO2H–H2O (4:1), reflux, 12 h (86% yield); (ii) PhMgBr, THF, 0 ꢁC to rt, 30 h (74% yield, a:b¼3:1); (b) Ac2O, Et3N, DMAP, 24 h
(88% yield); (c) Grubb’s catalyst (5 mol %), DCM, rt, 24 h (90% yield); (d) PCC, Py, DCM, reflux, 8 h (64% yield).
acid in water at 90 ꢁC to furnish an inseparable mixture of
anomeric diols in 86% yield. Diols were subjected to
a Grignard reaction with phenyl magnesium bromide in
dry THF at 0 ꢁC resulting in an inseparable mixture of dia-
stereomeric triols 10 and 11 in 3:1 ratio. The diastereomeric
diols on acetylation followed by column chromatography
afforded essentially pure triacetates 12 and 13 in 49%
combined yield (for two steps). The stereochemistry of the
major diastereomer 13 was deduced by the literature analogy
and was later unambiguously corroborated by the single
crystal X-ray structure of (ꢀ)-7-epi-triacetoxygoniotriol 4,
which was derived from 13.4,7 Treatment of triacetate 12
to ring closing metathesis conditions using Grubb’s catalyst
[benzylidene-bis(tri-cyclohexylphosphine)-dichlororuthenium
(5 mol %)] in dry DCM yielded allyl ether 15 in 90% yield.
The allylic methylene moiety in ether 15 was oxidized with
3 equiv of PCC and pyridine in dry DCM furnished the
required styryllactone, [7R,6S,5S,4R]-7-epi-triacetoxy-(ꢀ)-
goniotriol 4.5 It is appropriate to mention that this is the
first example wherein such an oxidation was conducted on
densely functionalized intermediate. The minor isomer 12
was converted into (ꢀ)-triacetoxygoniotriol 3 under the
same conditions.
Accordingly, the synthesis of (+)-7-epi-triacetoxygoniotriol
2 is outlined in Scheme 3. The aldehyde generated by the
oxidative cleavage of diol 7 using NaIO4 in MeOH, when
allowed to react with phenyl magnesium bromide in dry
THF at 0 ꢁC resulted in the formation of the diastereomeric
alcohols 16 and 17 in a 8:2 ratio with 77% overall yield. The
stereochemistry at the C-5 center in two diastereomers was
established by the literature analogy (Fig. 2).8 The proton
on C-3 in the case of alcohol 16 (major diastereomer) having
L-ido configuration appeared approximately d 0.4 upfield
than that in the alcohol 17 with the D-gluco configuration
due to the anisotropy of the phenyl moiety. The benzylic
alcohol in 16 was then converted to PMB ether 19 using stan-
dard reaction conditions. Conversion of the PMB ether 19 to
dialkene 20 involved a two-step reaction sequence of acid
hydrolysis followed by Wittig reaction. While the Wittig
reaction preceded without any complication, albeit moderate
yield, the acid hydrolysis was complicated as a result of
cleavage of PMB group under the hydrolysis conditions.
The most efficient protocol entailed conducting acidic
hydrolysis using 4 M HCl in THF at 55 ꢁC and halting the
reaction prior to completion (52% yield based on the isolated
yield of the anomeric diols after column chromatography;
88% based on the recovered 19). The recovered diol was
resubjected to acidic hydrolysis. Acidic hydrolysis under
prolonged reaction conditions or use of strong acids resulted
in low yields of the desired product. Peracetylation of diol 20
gave diacetate 21, which was then exposed to DDQ in moist
CH2Cl2 to afford alcohol 22 in overall 88% yield. It was then
converted into the triacetate 23, followed by a ring closing
metathesis reaction using Grubb’s catalyst gave allyl ether
24 in 92% yield. Oxidation of the allyl ether 24 using PCC
and pyridine in dry DCM furnished the required lactone in
In order to synthesize (+)-triacetoxygoniotriols 1b and 2,
which are enantiomers of 3 and 4, respectively, we decided
to exploit the pseudo-symmetry of D-glucose. It was envi-
sioned that the intermediate generated by the addition of
phenyl magnesium bromide onto the aldehyde generated
by the oxidative cleavage of diol 7 could be converted to
triacetoxydialkene 8, which is enantiomeric to triacetoxy-
dialkene 5. Intermediate 8 could be converted to triacetoxy-
goniotriols 1b and 2 using the conditions described earlier.

G. S. C. Srikanth et al. / Tetrahedron 62 (2006) 11165–11171
11167
R2
R1
C6H5
OPMB
OPMB
OAc
O
OH
O
d, e
from 19
f
a, b
C6H5
C6H5
7
O
OH
OAc
O
O
O
16 : R1 = OH, R2 = H
17 : R1 = H, R2 = OH
20
21
c
18 : R1 = H, R2 = OPMB
19 : R1 = OPMB, R2 = H
OR
OAc O
OAc
j
(+)-7-epi-Triacetoxy
goniotriol 2
g
i
C6H5
C6H5
OAc
22 : R = H
23 : R = Ac
O
OAc OAc
24
h
Scheme 3. (a) NaIO4, MeOH–H2O (10:1), 0 ꢁC, 4 h (88% yield); (b) PhMgBr, THF, 0 ꢁC to rt, 12 h (74% yield, a:b¼8:2); (c) NaH, PMBCl, Bu4NI (cat), DMF,
0 ꢁC to rt, 18 h (quant); (d) 4 M HCl–THF (1:4), 55 ꢁC, 4 h (88%); (e) Ph3P]CH2, THF, ꢀ10 ꢁC to rt, 24 h (55% yield); (f) Ac2O, Et3N, DMAP, 0 ꢁC to rt, 24 h
(quant); (g) DDQ, moist DCM, rt, 2 h (88%); (h) Ac2O, Et3N, DMAP, 0 ꢁC to rt, 24 h (quant); (i) Grubb’s catalyst (5%) DCM, rt, 24 h (92% yield); (j) PCC,
C5H5N, DCM, reflux, 7 h (65% yield).
Figure 3.
Figure 2.
65% yield. The (+)-7-epi-triacetoxygoniotriol thus obtained
showed same optical rotation but with opposite sign as that
of (ꢀ)-7-epi-triacetoxygoniotriol 4 ([a]2D2 +134.1 (c 0.2,
MeOH)).4 The absolute stereochemistry of (ꢀ)-7-epi-triace-
toxygoniotriol 4 was further confirmed from single crystal
X-ray of the 8-O-benzyl derivative of the compound 24.8
3. Conclusion
Synthesis of natural products containing six-membered a,b-
unsaturated lactones as a core feature using RCM reactions
has been reported.11 These approaches involve intramolec-
ular RCM reactions of appropriately substituted acrylyl
alkenylic esters. However, in some cases acrylyl esters are
known to be reluctant to undergo a ring closing metathesis
reaction due to the formation of stable seven-membered
metal chelates formed between the ester carbonyls and
the intermediate metal carbene species.12 In the present
case we have used allyl ether as a masked acrylic ester
moiety to overcome such difficulties. Since allyl ethers
withstand many harsher reaction conditions the developed
The reversal of the stereochemistry at the C-6 center of 16
was accomplished by first oxidizing the benzylic alcohol
in acetonide 16 followed by reduction with NaBH4 at
0 ꢁC.9 Single crystal X-ray structure of the PMB ether of
17 unambiguously ascertained the stereochemistry at the
benzylic position (Fig. 3).10 Alcohol 17 was later converted
to (+)-triacetoxygoniotriol 1b using the same reaction
sequence as described in Scheme 4.
OH
O
OH
O
O
O
O
c
a, b
C6H5
C6H5
(+)-Triacetoxygoniotriol 1b
O
O
O
17
16
Scheme 4. (a) PDC, DCM, rt, 4 h (80% yield); (b) NaBH4, 0 ꢁC, 4 h (90% yield, 9:1 (17:16)); (c) Scheme 2c–j.

11168
G. S. C. Srikanth et al. / Tetrahedron 62 (2006) 11165–11171
methodology offers an attractive alternative to acrylyl ester
derived synthesis of cyclic lactones. Also D-glucose offers
possibility of manipulating the stereochemistry around a
given carbon atom at a time. Hence it is possible to synthe-
size all stereoisomers of goniotriol from D-glucose using the
developed methodology.
1H NMR of compound 23 was similar to that of compound
13 ([a]2D2 ꢀ8.4 (c 2, CHCl3)).
Compound 12: 0.10 g, [a]2D2 ꢀ18.5 (c 2, CHCl3); nmax (liquid
1
film) 3110, 1740, 1638, 1610, 1444, 1342 cmꢀ1. H NMR
(CDCl3, 500 MHz) d 7.36–7.28 (m, 5H, Ph), 6.03 (d,
J¼8.0 Hz, 1H, PhCH(OAc)), 5.94–5.81 (m, 2H,
CH]CH2), 5.46 (q, J¼3.5 Hz, 1H, CH]CH2), 5.42–5.40
(m, 1H, CH]CH2), 5.30 (d, J¼2.0 Hz, 1H, CH]CH2),
5.27 (d, J¼2.0 Hz, 1H, CH]CH2), 5.24 (dd, J¼2.0,
7.0 Hz, 1H, OCHCH]CH2), 5.19 (dd, J¼2.0, 10.5 Hz,
1H, CHOAc), 4.15 (dd, J¼5.0, 10.0 Hz, 1H,
OCH2CH]CH2), 3.89 (dd, J¼4.0, 10.0 Hz, 1H,
OCH2CH]CH2), 3.51 (dd, J¼3.0, 7.0 Hz, 1H, CHOallyl),
2.06 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.03 (s, 3H, OAc).
13C NMR (CDCl3, 125 MHz) d 170.1, 169.6, 169.4, 136.6,
134.4, 132.4, 128.5, 128.4, 128.0, 118.5, 118.3, 77.8, 74.5,
73.6, 73.4, 72.5, 21.6, 21.3, 20.6.
4. Experimental
4.1. General
Optical rotations were measured with a JASCO DIP-370
digital polarimeter using a sodium lamp (l¼589 nm) at
24 ꢁC. 1H and 13C NMR spectra were recorded in CDCl3 us-
ing Me4Si as an internal standard on a Varian spectrometer.
Thin-layer chromatography was performed on E. Merck
glass plates silica gel sheets (Silica Gel F254) and visualized
under UV light and/or stained with ceric ammonium molyb-
date–aqueous H2SO4 solution. Column chromatography
was carried out on silica gel (E. Merck 230–400 mesh). All
solvents were distilled before use.
1H NMR of (8R) diastereomer of compound 23 was similar
to that of compound 12 ([a]2D2 +18.4 (c 2, CHCl3)).
4.1.2. 1,2,4-Tri-O-acetyl-3,7-anhydro-5,6-dideoxy-1-O-
phenylhept-5-enitol 14/15. To a degassed solution of di-
alkene 12/13/23 (0.10 g, 0.25 mmol) in anhydrous DCM
(3 ml) was added Grubb’s catalyst (10 mg, 0.012 mmol)
and stirred for 24 h at rt. The reaction mixture was diluted
with DCM (2 ml) and air was bubbled through the solution
to deactivate the catalyst. The reaction mixture was filtered
through Celite and concentrated in vacuo. Flash column
chromatography (10% EtOAc in hexane) afforded pyran
14/15/24 (82 mg, 0.23 mmol, 90% yield) as a colorless
semi solid. HRMS (FAB) m/z 362.3737 (MH+, C19H22O7,
requires 362.3729).
4.1.1. 2,4,5-Tri-O-acetyl-3-O-allyl-5,6-dideoxy-1-O-phen-
yl-hex-1-enitol 12/13. Dialkene 6 (0.5 g, 2.2 mmol) was dis-
solved in aqueous AcOH (10 ml, 1:4) and refluxed for 12 h.
Removal of the solvents in vacuo yielded a yellow oil, which
was then dissolved in DCM (10 ml) and washed with satd
aqueous NaHCO3 solution (5 ml). The organic layer was
dried (Na2SO4) and concentrated in vacuo. The resultant
crude diol was dissolved in dry THF (10 ml) and was added
drop wise (15 min) to a solution of phenyl magnesium bro-
mide (2 g, 11.0 mmol) in THF (15 ml) at 0 ꢁC. After stirring
for 2 h at 0 ꢁC and then for 30 h at rt, cold 1 M HCl (5 ml)
was added and extracted with EtOAc (10 ml). The combined
organic layers were dried (Na2SO4) and concentrated
in vacuo. Flash column chromatography (1:1, hexane–
EtOAc) afforded triols 10/11 (0.36 g, 1.36 mmol, 74%)
as a 3:1 mixture of diastereomers. The triols 10 and 11
(0.36 g, 1.36 mmol) were dissolved in Et3N (2 ml) at 0 ꢁC
and DMAP (20 mg) was added. Acetic anhydride (0.83 g,
8.1 mmol) was added and the resultant mixture was stirred
for 24 h at rt. Et3N was evaporated and flash column chroma-
tography of the resultant crude mixture afforded triacetoxy-
dialkenes 12 and 13 (0.46 g, 1.20 mmol, 88% yield) in 3:1
ratio, respectively, as a pale viscous oil. HRMS (FAB) m/z
391.1741 (MH+, C21H27O7, requires 391.1757).
Compound 15: [a]D22 ꢀ152.1 (c 0.2, MeOH); nmax (liquid
film) 3080, 1742, 1646, 1430, 1335 cmꢀ1 1H NMR
.
(CDCl3, 300 MHz) d 7.38–7.31 (m, 5H), 6.04–5.98 (m,
3H), 5.52 (t, J¼5.4 Hz, 1H), 5.00–4.95 (m, 1H), 4.30
(d, J¼19.8 Hz, 1H), 4.08 (d, J¼19.8 Hz, 1H), 3.55 (dd,
J¼2.5, 5.5 Hz, 1H), 2.09 (s, 3H), 2.08 (s, 3H), 2.07 (s,
3H). 13C NMR (CDCl3, 125 MHz) d 170.3, 169.6, 136.5,
131.8, 128.6, 126.9, 122.2, 74.2, 73.5, 73.1, 66.1, 65.5,
21.0, 20.9, 20.8.
1H NMR of compound 24 was similar to that of compound
15 ([a]2D2 +152.1 (c 0.2, MeOH)).
Compound 14: [a]D22 +90.2 (c 0.2, MeOH); nmax (KBr) 3100,
1740, 1644, 1440, 1320 cmꢀ1. 1H NMR (CDCl3, 300 MHz)
d 7.38–7.29 (m, 5H), 6.04–5.96 (m, 2H), 5.83 (d, J¼5.5 Hz,
1H), 5.52 (d, J¼6.0 Hz, 1H), 5.01–4.97 (m, 1H), 4.33
(d, J¼18.0 Hz, 1H), 4.10 (d, J¼18.0 Hz, 1H), 3.57 (dd,
J¼4.0, 8.0 Hz, 1H), 2.09 (s, 3H), 2.07 (s, 3H), 2.05 (s,
3H). 13C NMR (CDCl3, 125 MHz) d 170.2, 169.8, 136.5,
131.6, 128.9, 126.7, 122.0, 74.1, 73.5, 73.2, 66.2, 65.3,
21.1, 20.9, 20.7.
Compound 13: 0.35 g, [a]2D2 +8.5 (c 2, CHCl3); nmax (liquid
film) 3120, 1743, 1643, 1604, 1434, 1335, 1130 cmꢀ1
.
1H NMR (CDCl3, 500 MHz) d 7.38–7.30 (m, 5H, Ph),
5.95–5.81 (m, 2H, CH]CH2), 5.86 (d, J¼8.0 Hz,
1H, PhCH(OAc)), 5.40–5.35 (m, 2H, CH(OAc) and
AcOCHCH]CH2), 5.30–5.19 (m, 4H, CH]CH2), 4.25
(dd, J¼4.5, 13.0 Hz, 1H, OCH2CH]CH2), 4.10 (dd,
J¼5.5, 13.0 Hz, 1H, OCH2CH]CH2), 3.69 (dd, J¼3.0,
7.5 Hz, 1H, CHOallyl), 2.09 (s, 3H, OAc), 2.02 (s, 3H,
OAc), 1.81 (s, 3H, OAc). 13C NMR (CDCl3, 125 MHz)
d 170.0, 169.5, 169.4, 136.6, 134.5, 132.4, 128.8, 128.4,
127.9, 118.5, 118.2, 77.7, 74.3, 73.9, 73.4, 72.3, 21.4,
21.3, 20.8.
1H NMR of (8R) diastereomer of compound 24 was similar
to that of compound 15 ([a]2D2 ꢀ90.0 (c 0.2, MeOH)).
4.1.3. General procedure for the oxidation of cyclic allyl
ethers to lactones. To a solution of pyran 14/15/24 (80 mg,

G. S. C. Srikanth et al. / Tetrahedron 62 (2006) 11165–11171
11169
0.20 mmol) in anhydrous DCM were added PCC (142 mg,
0.6 mmol) and pyridine (0.1 ml) and refluxed for 7 h. The
solvent was evaporated and ethyl ether (5 ml) was added
and filtered through Celite. The solvent was evaporated
and flash column chromatography (5–20% EtOAc in
hexane, gradient elution) afforded triacetoxygoniotriol 3/4/2
(54.5 mg, 65% yield) as a white solid. HRMS (FAB) m/z
376.1158 (MH+, C19H20O8, requires 376.1164).
(dd, J¼6.0, 13.0 Hz, 1H, PhCH(OH)CH), 4.04 (dd, J¼5.5,
12.5 Hz, 1H, OCH2CHCH2), 3.77 (dd, J¼5.5, 12.5 Hz,
1H, OCH2CHCH2), 3.50 (d, J¼5.0 Hz, 1H, CHOallyl),
2.89 (d, J¼2.5 Hz, 1H, OH), 1.51 (s, 3H, C(CH3)2), 1.33
(s, 3H, C(CH3)2). 13C NMR (CDCl3, 125 MHz) d 140.0,
133.8, 128.6, 128.4, 127.5, 118.0, 112.1, 105.5, 84.9, 82.4,
82.2, 72.8, 71.1, 27.0, 26.5.
(5R)-Isomer 17: [a]D22 ꢀ34.9 (c 1, MeOH); nmax (liquid film)
1
7-epi-7,6,4-Triacetoxy-(ꢀ)-goniotriol 4: [a]2D2 ꢀ135.0
(c 0.2, MeOH); nmax (KBr) 3100, 1742, 1640, 1448,
3450–3050 (br), 1620, 1424, 1340, 1140 cmꢀ1. H NMR
(CDCl3, 500 MHz) d 7.42–7.35 (m, 4H, Ph), 7.31–7.26
(m, 1H, Ph), 6.02 (d, J¼5.5 Hz, 1H, OCHO), 5.95–5.86
(m, 1H, CH]CH2), 5.32 (d, J¼17.0 Hz, 1H, CH]CH2),
5.25 (d, J¼10.5 Hz, 1H, CH]CH2), 5.11 (t, J¼6.5 Hz,
1H, PhCH(OH)), 4.55 (d, J¼2.5 Hz, 1H, CHOCMe2), 4.33
(t, J¼2.5 Hz, 1H, PhCH(OH)CH), 4.16–4.12 (m, 1H,
OCH2CH]CH2), 3.96–3.92 (m, 1H, OCH2CH]CH2),
3.88–3.86 (m, 1H, CHOallyl), 3.51 (d, J¼7.0 Hz, 1H,
OH), 1.47 (s, 3H, C(CH3)2), 1.31 (s, 3H, C(CH3)2).
13C NMR (CDCl3, 125 MHz) d 141.5, 133.4, 128.6,
127.8, 126.2, 118.7, 105.4, 83.1, 82.5, 81.9, 72.4, 71.3,
26.9, 26.4.
1
1336 cmꢀ1. H NMR (CDCl3, 300 MHz) d 7.34 (m, 5H),
6.93 (dd, J¼5.4, 9.5 Hz, 1H), 6.16 (d, J¼9.5 Hz, 1H), 6.05
(d, J¼6.2 Hz, 1H), 5.62 (dd, J¼5.1, 6.2 Hz, 1H), 5.24 (dd,
J¼3.2, 5.1 Hz, 1H), 4.43 (dd, J¼3.2, 5.1 Hz, 1H), 2.1 (s,
6H), 2.08 (s, 3H). 13C NMR (CDCl3, 125 MHz) d 170.1,
169.4, 169.2, 140.3, 129.3, 129.2, 127.2, 124.7, 100.1,
75.7, 74.0, 71.8, 62.9, 21.1, 21.0.
1H NMR of 7-epi-7,6,4-triacetoxy-(+)-goniotriol 2 was sim-
ilar to that of compound 4 ([a]2D2 +135.0 (c 0.2, MeOH)).
7,6,4-Triacetoxy-(ꢀ)-goniotriol 3: [a]2D2 ꢀ121 (c 0.8,
MeOH); nmax (KBr) 3124, 1742, 1644, 1440, 1327 cmꢀ1
.
4.1.5. 1,2-O-(1-Methylethyledene)-5-O-(4-methoxybenz-
yl)-3-O-allyl-5-C-phenyl-5-O-a-D-xylo-furanoses 18
and 19. To pentane-washed NaH (0.16 g, 6.5 mmol) in
anhydrous DMF (5 ml) was added alcohol 16/17 (1 g,
3.2 mmol) at 0 ꢁC and stirred for 15 min. 4-Methoxybenzyl-
chloride (0.77 g, 4.9 mmol) and tetrabutylammonium iodide
(20 mg) were added and the resultant reaction mixture was
stirred for 18 h at rt. HCl (1 M, 10 ml) was added slowly
and extracted twice with DCM (10 ml). The organic layers
were collected dried and concentrated in vacuo. Flash
column chromatography (10% EtOAc in hexane) afforded
acetonide 18/19 (1.40 g, 3.13 mmol, 98% yield) as a color-
less oil. HRMS (FAB) m/z 449.1938 (MNa+, C25H30O6Na,
requires 449.1940).
1H NMR (CDCl3, 300 MHz) d 7.42–7.33 (m, 5H), 6.93
(dd, J¼6.0, 10.2 Hz, 1H), 6.16 (d, J¼9.8 Hz, 1H), 5.96 (d,
J¼5.2 Hz, 1H), 5.76 (dd, J¼4.8, 7.1 Hz, 1H), 5.30 (dd,
J¼3.2, 6.0 Hz, 1H), 4.53 (dd, J¼3.2, 6.8 Hz, 1H), 2.10
(s, 3H), 2.08 (s, 3H), 2.01 (s, 3H). 13C NMR (CDCl3,
125 MHz) d 170.2, 169.4, 169.1, 140.4, 129.4, 129.0,
127.3, 124.5, 100.3, 76.1, 74.2, 71.6, 62.7, 21.3, 21.1.
1H NMR of 7,6,4-triacetoxy-(+)-goniotriol 1b was similar to
that of compound 3 ([a]2D2 +121 (c 0.8, MeOH)).
4.1.4. 1,2-O-(1-Methylethyledene)-3-O-allyl-5-C-phenyl-
a-D-xylo-furanose 16/17. To vigorously stirred slurry of
silica gel (10 g, Acme 60–120 mesh) in DCM (100 ml) a
solution of NaIO4 (5.83 g, 22.27 mmol in 15 ml water)
was added and continued stirring at rt for 10 min after which
a solution of diol 7 (4 g, 18.18 mmol) in methanol (20 ml)
was added. The reaction mixture was further stirred for 4 h
and solids were filtered. Solvents were evaporated to give the
aldehyde as a colorless oil, which was dried in vacuo over
P2O5 (88% yield). The resultant crude aldehyde was dis-
solved in anhydrous THF (60 ml) and the solution was added
drop wise (30 min) to a solution of phenyl magnesium bro-
mide (6.8 g, 37.8 mmol) in anhydrous THF (150 ml) at 0 ꢁC.
After stirring for 4 h at 0 ꢁC and then 12 h at rt, cold 1 M HCl
(25 ml) was added and extracted with EtOAc (30 ml). The
combined organic layers were dried (Na2SO4) and concen-
trated in vacuo. Flash chromatography (1:1, hexane–EtOAc)
afforded diastereomeric alcohols 16/17 (3.9 g, 12.8 mmol,
74% yield) as 8:2 (16:17) mixtures of diastereomers as a yel-
low oil separable by column chromatography. HRMS (FAB)
m/z 329.1350 (MNa+, C17H22O5Na, requires 329.1365).
(5S)-Isomer 18: [a]D22 +18.2 (c 1, CHCl3); nmax (liquid film)
3110, 1634, 1595, 1410, 1340, 1044 cmꢀ1 1H NMR
.
(CDCl3, 500 MHz) d 7.42–7.35 (m, 5H, Ph), 7.23 (d,
J¼9.0 Hz, 2H, Ph of PMB), 6.83 (d, J¼8.0 Hz, 2H, Ph
of PMB), 6.02 (d, J¼4.0 Hz, 1H, OCHO), 5.76–5.68
(m, 1H, CH]CH2), 5.22 (d, J¼17.5 Hz, 1H, CH]CH2),
5.14 (d, J¼10.5 Hz, 1H, CH]CH2), 4.68 (d, J¼9.0 Hz,
1H, PhCH(OPMB)), 4.48–4.45 (m, 2H, CHOCMe2,
PhCH(OPMB)CH), 4.49 (d, J¼11.5 Hz, 1H, OCH2PhOMe),
4.32 (d, J¼11.5 Hz, 1H, OCH2PhOMe), 3.82 (dd, J¼5.0,
12.0 Hz, 1H, OCH2CHCH2), 3.77 (s, 3H, OMe), 3.48 (dd,
J¼6.0, 12.5 Hz, 1H, OCH2CHCH2), 3.20 (d, J¼3.5 Hz,
1H, CHOallyl), 1.50 (s, 3H, CMe2), 1.29 (s, 3H, CMe2).
13C NMR (CDCl3, 125 MHz) d 159.1, 138.7, 133.9, 130.7,
129.5, 128.4, 117.6, 113.7, 111.7, 105.7, 84.1, 82.2, 81.6,
79.9, 70.9, 70.2, 55.4, 27.0, 26.4.
(5R)-Isomer 19: [a]D22 ꢀ45.0 (c 1, MeOH); nmax (liquid film)
3120, 1640, 1602, 1420, 1344, 1045 cmꢀ1 1H NMR
.
(5S)-Isomer 16: [a]D22 ꢀ5.0 (c 1, MeOH); nmax (liquid film)
(CDCl3, 500 MHz) d 7.46–7.31 (m, 5H, Ph), 7.18 (d,
J¼14.5 Hz, 2H, Ph of PMB), 6.84 (d, J¼15.0 Hz, 2H, Ph
of PMB), 5.80–5.86 (m, 1H, CH]CH2), 5.84 (d,
J¼6.5 Hz, 1H, OCHO), 5.34–5.20 (m, 2H, CH]CH2),
4.65 (d, J¼15.0 Hz, 1H, PhCH(OPMB)), 4.55 (d,
J¼6.5 Hz, 1H, CHOCMe2), 4.31 (d, J¼18.5 Hz, 1H,
1
3480–3060 (br), 1610, 1434, 1335, 1130 cmꢀ1. H NMR
(CDCl3, 500 MHz) d 7.49–7.34 (m, 5H, Ph), 6.03 (d,
J¼6.5 Hz, 1H, OCHO), 5.92–5.78 (m, 1H, CH]CH2),
5.35–5.20 (m, 2H, CH]CH2), 5.06 (dd, J¼3.0, 13.0 Hz,
1H, PhCH(OH), 4.57 (d, J¼6.0 Hz, 1H, CHOCMe2), 4.33

11170
G. S. C. Srikanth et al. / Tetrahedron 62 (2006) 11165–11171
OCH2Ph(OMe2)),
4.27
(d,
J¼5.0 Hz,
1H,
anhydride (53 mg, 0.52 mmol). The resultant mixture was
stirred for 24 h at rt. Et3N was evaporated and flash column
chromatography of the resultant crude mixture gave diace-
tate (60 mg, 0.12 mmol, 98% yield) as a pale yellow oil.
HRMS (FAB) m/z 491.2052 (MNa+, C27H32O7Na, requires
491.2045).
PhCH(OPMB)CH), 4.20 (d, J¼17.5 Hz, 1H, OCH2-
Ph(OMe)), 4.16 (d, J¼9.0 Hz, 1H, OCH2CHCH2), 4.10 (d,
J¼4.0 Hz, 1H, CHOallyl), 4.06 (dd, J¼9.0, 21.0 Hz, 1H,
OCH2CHCH2), 3.79 (s, 3H, OMe), 1.39 (s, 3H, CMe2),
1.26 (s, 3H, CMe2). 13C NMR (CDCl3, 125 MHz) d 159.4,
139.8, 134.6, 130.6, 129.7, 128.6, 128.2, 128.1, 117.6,
114.0, 111.7, 105.3, 83.1, 82.5, 81.8, 78.2, 71.8, 70.3,
55.5, 27.0, 26.5.
(6S)-Isomer 21: [a]D22 ꢀ15.5 (c 2, CHCl3); nmax (liquid film)
3180, 1742, 1610, 1550, 1320 cmꢀ1 1H NMR (CDCl3,
.
500 MHz) d 7.39–7.28 (m, 5H), 7.20 (d, J¼8.0 Hz, 2H),
6.87 (d, J¼8.0 Hz, 2H), 5.93–5.87 (m, 1H), 5.85–5.78 (m,
1H), 5.35 (t, J¼6.5 Hz, 1H), 5.24 (d, J¼17.0 Hz, 1H), 5.20
(d, J¼17.0 Hz, 1H), 5.18–5.16 (m, 3H), 4.57 (d, J¼9.5 Hz,
1H), 4.37 (d, J¼11.5 Hz, 1H), 4.24–4.18 (m, 2H), 4.05
(dd, J¼4.5, 12.0 Hz, 1H), 3.98 (d, J¼8.5 Hz, 1H), 3.80
(s, 3H), 2.07 (s, 3H), 1.70 (s, 3H). 13C NMR (CDCl3,
125 MHz) d 170.0, 169.1, 159.1, 138.0, 135.0, 132.6,
130.0, 129.9, 128.6, 128.4, 118.4, 117.3, 114.0, 78.8, 74.7,
74.5, 73.9, 70.3, 55.5, 21.4, 20.8.
4.1.6. 3-O-Allyl-5,6-dideoxy-1-O-(4-methoxybenzyl)-1-
O-phenyl-hex-5-enitol (6S)-20 and (6R)-20. To acetonide
18/19 (0.3 g, 0.7 mmol) dissolved in THF (3 ml) was added
4 M HCl (2 ml) and the resultant mixture was heated to
55 ꢁC for 4 h. The reaction mixture was cooled, neutralized
with satd aqueous NaHCO3 solution (5 ml) and extracted
twice with EtOAc (5 ml). The combined organic layers
were dried (Na2SO4) and concentrated in vacuo. Flash col-
umn chromatography (10–30% gradient elution) afforded
diol (0.13 g, 52%) as anomeric mixture and acetonide
18/19 (0.10 g, 44%) was recovered. The diol (0.1 g,
0.2 mmol) was dissolved in anhydrous THF (0.5 ml) and
added drop wise to methylenetriphenylphosphine ylide (pre-
pared from methyltriphenylphosphonium bromide (0.46 g,
1.3 mmol) and n-BuLi (0.79 ml of 1.6 M in hexane,
1.2 mmol) at ꢀ5 ꢁC) at ꢀ10 ꢁC. The reaction mixture was
stirred at ꢀ10 ꢁC for 2 h and then at rt for 24 h, then
quenched with cold satd aqueous NH4Cl (2 ml), and ex-
tracted twice with EtOAc (5 ml). The combined organic
layers were dried (Na2SO4) and concentrated in vacuo. Flash
column chromatography (10–20% EtOAc in hexane, gra-
dient elution) afforded pure dialkene (6S)-20/(6R)-20
(54.6 mg, 1.4 mmol, 55% yield) as a colorless liquid.
HRMS (FAB) m/z 407.1826 (MNa+, C23H28O5Na, requires
407.1835).
(6R)-Isomer 21: [a]D22 +32.5 (c 2, CHCl3); nmax (liquid film)
3210, 1740, 1605, 1520, 1142 cmꢀ1 1H NMR (CDCl3,
.
500 MHz) d 7.39–7.30 (m, 5H), 7.19 (d, J¼9.0 Hz, 2H),
6.87 (d, J¼8.5 Hz, 2H), 5.95–5.80 (m, 2H), 5.35–5.30 (m,
2H), 5.24–5.19 (m, 2H), 5.14 (dd, J¼4.0, 8.5 Hz, 1H),
4.60 (d, J¼5.0 Hz, 1H), 4.43 (d, J¼11.5 Hz, 1H), 4.16 (d,
J¼12 Hz, 2H), 4.12 (dd, J¼6.0, 12.5 Hz, 1H), 3.93 (dd,
J¼6.0, 12.5 Hz, 1H), 3.82 (s, 3H), 3.47 (t, J¼5.0 Hz, 1H),
2.08 (s, 3H), 2.00 (s, 3H). 13C NMR (CDCl3, 125 MHz)
d 170.2, 170.0, 159.4, 138.0, 134.7, 133.0, 130.4, 130.2,
129.5, 128.8, 128.6, 128.0, 118.1, 117.1, 114.0, 79.5, 79.0,
74.9, 74.0, 73.9, 70.4, 55.5, 21.3, 21.2.
4.1.8. General procedure for PMB cleavage: synthesis of
2-4-di-O-acetyl-3-O-allyl-5,6-dideoxy-1-O-phenyl-hex-5-
enitol 22 and its (6R)-diastereomer. To a stirred solution of
diacetate 21 (55 mg, 0.11 mmol) in wet DCM (0.2 ml) was
added DDQ (35.0 mg, 0.15 mmol) and stirred for 2 h at rt.
DCM (2 ml) and satd aqueous NaHCO3 (1 ml) were added
to the reaction mixture and extracted. The combined organic
layers were dried (Na2SO4) and concentrated in vacuo. Flash
column chromatography afforded alcohol (6S)-isomer 22/
(6R)-isomer 22 (34 mg, 0.096 mmol, 88% yield) as a color-
less oil. HRMS (FAB) m/z 371.1486 (MNa+, C19H24O6Na,
requires 371.1471).
Compound (6S)-20: [a]2D2 ꢀ88.0 (c 1, CHCl3); nmax (liquid
film) 3450–3100 (br), 1638, 1610, 1450, 1342, 1145 cmꢀ1
.
1H NMR (CDCl3, 500 MHz) d 7.42–7.36 (m, 5H), 7.23
(d, J¼14.0 Hz, 2H), 6.90 (d, J¼12.0 Hz, 2H), 5.90–5.83
(m, 2H), 5.40–5.18 (m, 4H), 4.43–4.37 (m, 2H), 4.32
(t, J¼10.5 Hz, 1H), 4.20 (d, J¼19.0 Hz, 1H), 4.19 (d,
J¼19.0 Hz, 1H), 4.07 (dd, J¼9.0, 20.5 Hz, 1H), 3.83 (s,
3H), 3.82–3.76 (m, 2H). 13C NMR (CDCl3, 125 MHz)
d 159.6, 139.3, 137.4, 134.9, 130.0, 128.8, 128.5, 128.1,
117.4, 117.3, 114.0, 81.4, 80.3, 75.2, 74.6, 74.5, 70.2, 55.5.
(6S)-Isomer 22: [a]D22 ꢀ32.0 (c 2, CHCl3); nmax (liquid film)
1
Compound (6R)-20: [a]2D2 +47.0 (c 2, CHCl3); nmax (liquid
3550–3100 (br), 1740, 1605, 1450, 1140 cmꢀ1. H NMR
film) 3500–3100 (br), 1640, 1610, 1440, 1135, 1095 cmꢀ1
.
(CDCl3, 500 MHz) d 7.41–7.30 (m, 5H), 6.03–5.93 (m,
1H), 5.82–5.73 (m, 1H), 5.42–5.29 (m, 2H), 5.27–5.22 (m,
2H), 5.17–5.12 (m, 1H), 4.97–4.95 (m, 1H), 4.32–4.28 (m,
1H), 4.19–4.11 (m, 1H), 3.81 (dd, J¼2.5, 7.0 Hz, 1H),
2.10 (d, J¼4.5 Hz, 1H), 2.06 (s, 3H), 1.92 (s, 3H). 13C
NMR (CDCl3, 125 MHz) d 169.9, 169.7, 140.5, 134.4,
132.5, 128.6, 128.3, 126.7, 118.7, 118.2, 78.5, 74.3, 74.1,
73.3, 21.3, 21.1.
1H NMR (CDCl3, 500 MHz) d 7.42–7.35 (m, 5H), 7.20 (d,
J¼8.5 Hz, 2H), 6.87 (d, J¼8.0 Hz, 2H), 5.93–5.85 (m, 1H),
5.83–5.76 (m, 1H), 5.33–5.21 (m, 2H), 5.15 (d, J¼10.0 Hz,
1H), 4.57 (d, J¼7.5 Hz, 1H), 4.41 (d, J¼11.5 Hz, 1H), 4.31
(m, 1H), 4.23 (d, J¼11.0 Hz, 1H), 4.23–4.17 (m, 2H),
3.95–3.91 (m, 2H), 3.81 (s, 3H), 3.05–3.02 (m, 1H), 2.99
(br s, 1H), 2.67 (br s, 1H). 13C NMR (CDCl3, 125 MHz)
d 159.6, 138.4, 138.0, 135.0, 130.0, 128.9, 128.7, 128.2,
117.0, 116.7, 114.1, 81.7, 80.8, 76.1, 73.8, 70.6, 55.5.
(6R)-Isomer 22: [a]D22 +28.0 (c 2, CHCl3); nmax (liquid film)
1
3500–3100 (br), 1738, 1610, 1450, 1245 cmꢀ1. H NMR
4.1.7. 2,4-O-Acetyl-3-O-allyl-5,6-dideoxy-1-O-(4-meth-
oxybenzyl)-1-O-phenyl-hex-5-enitol 21 and its (6R) dia-
stereomer. To a mixture of diol 20 (50 mg, 0.13 mmol)
and DMAP (7 mg) in Et3N (0.5 ml) at 0 ꢁC was added acetic
(CDCl3, 500 MHz) d 7.37–7.29 (m, 5H), 5.91–5.86 (m,
2H), 5.51–5.48 (m, 1H), 5.32–5.28 (m, 2H), 5.20 (dd,
J¼2.0, 11.0 Hz, 1H), 4.97 (d, J¼5.5 Hz, 1H), 4.22–4.18
(m, 1H), 4.15–4.10 (m, 2H), 4.02–3.98 (m, 1H), 3.58 (d,

G. S. C. Srikanth et al. / Tetrahedron 62 (2006) 11165–11171
11171
J¼4.5 Hz, 1H), 2.06 (s, 3H), 1.99 (s, 3H). 13C NMR (CDCl3,
125 MHz) d 171.4, 170.5, 140.4, 134.4, 132.5, 128.8, 126.7,
119.6, 118.3, 117.7, 117.5, 79.1, 75.3, 73.8, 60.6, 21.3, 21.1.
5. (a) Bonadies, F.; Romano, D. F.; Bonini, C. J. Org. Chem. 1984,
49, 1647; (b) Bonadies, F.; Bonini, C. Synth. Commun. 1988,
18, 1573.
6. Kaliappan, K. P.; Kumar, N. Tetrahedron 2005, 61, 7461.
7. Gracza, T.; Jager, V. Synthesis 1994, 1359.
Acknowledgements
8. We unambiguously determined the stereochemistry at the C-7
from the single crystal X-ray structure of 7-O-benzyl derivative
of 24. Detailed X-ray crystallographic data is available from
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK. CCDC no. 279045). Crystal data:
empirical formula, C24H26O6; formula weight, 410.45; crystal
color, habit, colorless, prism; crystal dimensions, 0.30ꢂ0.25ꢂ
0.20 mm; crystal system, monoclinic; lattice parameterꢁs,
G.S.C.S. would like to thank IIT Bombay and U.M.K. to the
DST for the fellowship. We wish to thank National Single
Crystal X-Ray Diffraction Facility at IIT Bombay and Brig-
ham Young University.
˚
References and notes
a¼12.8090(10), b¼8.7390(7), c¼10.1040(5) A a¼90.000(6) ,
3
ꢁ
ꢁ
˚
b¼99.536(6) , g¼90.000(6) ; vol. 1115.39 A ; Z¼2; calcu-
1. (a) Fang, X.-P.; Anderson, J. E.; Chang, C.-J.; Fanwich, P. E.;
McLaughlin, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 1655;
(b) Fang, X.-P.; Anderson, J. E.; Chang, C.-J.; McLaughlin,
J. L. J. Nat. Prod. 1991, 54, 1034; (c) Fang, X.-P.; Anderson,
J. E.; Chang, C.-J.; McLaughlin, J. L. Tetrahedron 1991, 47,
9751.
lated density¼1.222 mg/m3 (Fig. 2).
9. Prakash, K. R. C.; Rao, P. S. Tetrahedron 1993, 49, 1505.
10. Detailed X-ray crystallographic data is available from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK. CCDC no. 279939. Crystal data:
empirical formula, C25H30O6; formula weight, 426.49; crystal
color, habit, colorless, prism; crystal dimensions, 0.36ꢂ0.50ꢂ
0.56 mm; crystal system, monoclinic; lattice parameters,
2. Talapatra, S. K.; Goswami, D.; Talapatra, B. Indian J. Chem.,
Sect. B 1985, 24, 29.
˚
3. (a) Shing, T. K. M.; Zhou, Z.-H. Tetrahedron Lett. 1992, 33,
3333; (b) Shing, T. K. M.; Ysui, H.-C.; Zhou, Z.-H. J. Org.
Chem. 1995, 60, 3121; (c) Chen, W. P.; Roberts, S. M.
J. Chem. Soc., Perkin Trans. 1 1991, 103; (d) Tsubuki, M.;
Kanai, K.; Nagase, H.; Honda, T. Tetrahedron 1999, 55,
2493; (e) Yang, Z.-C.; Zhou, W.-S. Tetrahedron 1995, 51, 1429.
4. Srikanth, G. S. C.; Krishna, U. M.; Trivedi, G. K. Tetrahedron
Lett. 2002, 43, 5471.
a¼11.3632(7), b¼8.5797(7), c¼11.8583(9) A a¼90ꢁ,
3
ꢁ
ꢁ
˚
b¼97.968(6) , g¼90 ; vol. 1144.94(15) A ; Z¼2; calculated
density¼1.237 mg/m3.
11. Ramachandran, P. V.; Reddy, M. V.; Brown, H. C. J. Indian
Chem. Soc. 1999, 76, 739; (b) Ramachandran, P. V.; Reddy,
M. V.; Brown, H. C. Tetrahedron Lett. 1999, 41, 583.
12. Fustner, A.; Langermman, K. J. Am. Chem. Soc. 1997, 119,
9130.