A simple entry into 1,3-diols from (R)-2,3-cyclohexylideneglyceraldehyde: synthesis of (-)-galantinic acid

Article abstract of DOI:10.1016/j.tetasy.2009.07.030

Aldehydes 5, 7, and 9 derived from easily accessible (R)-2,3-cyclohexylideneglyceraldehyde 1 were used as novel substrates to obtain both syn- and anti-1,3-diols in several individual reactions by subjecting each of them to some practically viable metal-m

Full text of DOI:10.1016/j.tetasy.2009.07.030

Tetrahedron: Asymmetry 20 (2009) 2007–2013
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A simple entry into 1,3-diols from (R)-2,3-cyclohexylideneglyceraldehyde:
synthesis of (ꢀ)-galantinic acid
*
Bhaskar Dhotare, Angshuman Chattopadhyay
Bio-Organic Division, Bhabha Atomic Research Center, 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:
Aldehydes 5, 7, and 9 derived from easily accessible (R)-2,3-cyclohexylideneglyceraldehyde 1 were used
as novel substrates to obtain both syn- and anti-1,3-diols in several individual reactions by subjecting
each of them to some practically viable metal-mediated Barbier-type allylations under moist conditions.
In this regard, a detailed investigation was made regarding the compatibility and stereoselectivity asso-
ciated with four such metal-mediated allylations of these aldehydes 5–7. Good yields with moderate
selectivity in several successful reactions with easy chromatographic separation of diastereoisomers of
the products have been elegantly exploited to isolate two pairs of enantiomerically pure syn-1,3 and
anti-1,3-diols (6a and 6b; 10a and 10b) in substantial amounts. Finally, 10b has been exploited to syn-
thesize (ꢀ)-galantinic acid A.
Received 30 June 2009
Accepted 16 July 2009
Available online 2 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
are likely to contribute significantly regarding the stereoselectivity
in all individual allylations.
The 1,3-skipped polyol systems with syn- or anti-configuration
are structural units of several classes of natural products including
clinically valuable polyene macrolide antibiotics. This has attracted
the attention of synthetic chemists to develop different strategies
for the construction of functionalized syn-1,3- and anti-1,3-diols.1
A very common approach to obtain chiral 1,3-diols is via the
stereo-differentiating allylation of b-hydroxy- or alkoxyaldehydes.
This route has the advantage of producing 1,3-polyols from re-
peated oxidative cleavage of the olefin of the resulting homoallylic
alcohol followed by allylation of the aldehyde produced. The ste-
reo-differentiation in each allylation step can be achieved in the
presence of a chiral auxiliary which exists in either the substrate
or the allylating agent or both. The reaction of b-oxygenated alde-
hydes with chiral allylating agents is associated with a very high
degree of stereoselectivity to obtain either 1,3-syn- or 1,3-anti-
diol.2 Due to the recent development of different innovative
strategies for the allylation of aldehydes,3 the stereoselective prep-
aration of 1,3-diols employing medal-mediated allylations of chiral
b-oxygenated aldehydes looked highly attractive.1 In this regard,
there is also a scope to explore the compatibility of various allyl-
metallations with many chiral b-oxygenated aldehydes and allow
stereochemical investigations for such reactions. Presumably, due
to the chelation control of all such allylation reactions, both the
metal of the allylmetal and the substrate b-oxygenated aldehyde
In our ongoing program regarding the synthesis of bioactive
compounds, we have exploited an easily accessible (R)-2,3-cyclo-
hexylideneglyceraldehyde 14a for the asymmetric construction
of several structural units such as alkanetriols,4,5a ribofuranos-
es,5a,b,g,h
c
-lactone,5c d-lactone,5d isonucleosides,5e and 2,5-disub-
stituted tetrahydrofurans5f. Herein we report out attempts to
explore the potential of 1 once again for asymmetric construction
of functionalized 1,3-diols.
2. Results and discussion
The olefin unit of anti-homoallylic alcohol 2 derived from it4b
was ozonolyzed and then reduced with PPh3 to obtain hydroxyal-
dehyde 5 in good yield. Compound 5, due to its unstability on
standing without being purified further, was immediately sub-
jected to Barbier-type allylations mediated with different metals
under various conditions as shown in Table 1. The Zn-mediated
allylation following Luche’s procedure6 did not take place (Table
1, entry A). The same disappointing results were obtained for the
allylation of 5 mediated with low valent Cu or Fe prepared follow-
ing bimetal redox strategy7 (Table 1, entries B and C). The In-med-
iated allylation8 of 5 took place successfully under two different
aqueous conditions (Table 1, entries D and E) producing 1,3-diol
6 with varied anti-selectivity; the selectivity using water as sol-
vent (Table 1, entry D) was found to be noteworthy (syn-6a:
anti-6b = 20:80). The diastereomeric diols 6a,b could be easily
separated from each other by column chromatography and their
stereochemistry was determined from 13C NMR spectra of the
* Corresponding author. Tel.: +91 22 2559 5422; fax: +91 22 2550 5151.
E-mail address: achat@barc.gov.in (A. Chattopadhyay).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.030

2008
B. Dhotare, A. Chattopadhyay / Tetrahedron: Asymmetry 20 (2009) 2007–2013
Table 1
Metal-mediated allylations of aldehydes 5, 7, and 9
Entry
R1CHO
RBr
Reagents
Time (h)
Products
Yield (%)
Products Ratio(syn/anti)
A
B
C
D
E
5
5
5
5
5
7
7
7
7
7
9
9
9
9
9
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Zn, NH4Cl(aq), THF
FeCl3, Zn, THF
CuCl2ꢁ2H2O, Zn, THF
In, H2O
24
24
24
24
24
6
—
—
—
No reaction
No reaction
No reaction
20:80a
—
—
6a and 6b
6a and 6b
8a and 8b
8a and 8b
8a and 8b
—
8a and 8b
10a and 10b
—
77.0
74.3
81.7
84.8
82.4
—
In, H2O:THF
38:62a
F
Zn, NH4Cl(aq), THF
FeCl3, Zn, THF
CuCl2ꢁ2H2O, THF
In, H2O
48:52b
G
H
I
J
K
L
M
N
O
4
35:65b
20
24
24
6
24
24
24
24
45:55b
No reaction
In, H2O:THF
15c
80.8
—
—
—
40: 60b
Zn, NH4Cl(aq), THF
FeCl3, Zn, THF
CuCl2ꢁ2H2O, THF
In, H2O
40:60a
No reaction
No reaction
No reaction
No reaction
—
—
—
In, H2O:THF
—
a
b
c
The ratio was determined after separation of diastereomers by column chromatography.
The ratio was determined after desilylation of the crude mixture followed by separation of diastereomer diols 6a and 6b by column chromatography.
The majority of the substrate remained unreacted.
corresponding acetonides 6c,d9 (Scheme 1). The signals of syn-diol
acetonide 6c were observed at d 98.4 for a quaternary carbon and
at 19.8 and 33.6 for the methyl carbons, respectively, whereas for
anti-diol acetonide 6d the same signals appeared at d 100.2 for a
quaternary carbon and at 24.7 and 25.1, respectively.
Our next attempt was to investigate the efficacy and stereose-
lectivity of similar allylations of the O-silylated 7 and O-benzoylat-
ed 9 hydroxyaldehydes, which were prepared, respectively, from
the corresponding protected homoallylic alcohols 3 and 4 derived
from 2 following similar reaction protocols viz. ozonolysis followed
by reduction with PPh3. Since both the aldehydes 7 and 9 are
unstable on long standing they were immediately used for the next
reaction. Very interestingly, the later allylations afforded results at
some variance with the earlier ones and are worth reporting (Table
1). For silyl derivative 7, Luche’s allylation took place but with poor
selectivity producing 8a and 8b in nearly equal proportions (syn-
8a:anti-8b = 48:52). (Table 1, entry F) Low valent Cu- and Fe-med-
iated reactions took place with excellent yields but with little
improved anti-selectivity in both the cases [for Cu syn-8a:anti-
8b = 45:55; for Fe syn-8a:anti-8b = 35:65] compared to that
obtained using Luche’s procedure (Table 1, entries G and H). The
In-mediated reaction in water gave poor results (Table 1, entry I).
ii or iii
i
O
O
O
O
O
O
3 R= TPS
4 R=Bz
CHO
2
1
OR
OH
O
iv
v
O
+
O
O
O
O
2, 3, 4
CHO
OH
OR
OR
OH
vii
OR
5 R = H
7 R= TPS
9 R=Bz
6b R = H
8b R= TPS
10b R=Bz
6a R = H
8a R= TPS
10a R=Bz
vi
vi
vii
O
O
O
O
viii
6a
6c
O
O
OH
OH
O
O
O
O
viii
6d
6b
O
O
OH
OH
Scheme 1. (i) Ref. 4; (ii) TBDPSCl/imidazole/CH2Cl2; (iii) BzCN, TEA/CH2Cl2; (iv) O3/CH2Cl2/PPh3; (v) allylBr/In, H2O/THF or Zn/aq NH4Cl/THF or FeCl3/Zn/THF or CuCl2, 2H2O/
Zn/THF; (vi) TBAF, THF; (vii) K2CO3, MeOH; (viii) 2,2-dimethoxypropane/PTSA.

B. Dhotare, A. Chattopadhyay / Tetrahedron: Asymmetry 20 (2009) 2007–2013
2009
Using water/THF as a solvent, the In-mediated reaction showed lit-
tle progress as the majority of aldehyde remained unreacted. (Ta-
ble 1, entry J). In this case the diastereoisomers 8a/b were
inseparable from each other by column chromatography. Hence
they were identified and quantified on desilylation of the mixture
with TBAF and chromatographic separation of the corresponding
diols 6a/b. Luche’s allylation of benzoylated derivative 9 (Table 1,
entry K), proceeded well to produce 10 with reasonable anti-selec-
tivity (syn-10a:anti-10b = 40:60) which could be separated by col-
umn chromatography to obtain both monoprotected 1,3-diols (10a
and 10b) in homochiral form. Both 10a/b could be identified after
converting them to the corresponding diols 6a/b by alkaline hydro-
lysis (Scheme 2). However, no reaction took place for allylations
mediated with low valent Cu or Fe (Table 1, entries L and M) or
In under both conditions (Table 1, entries N and O).
Thus, a detailed investigation on the compatibility of four differ-
ent metal-mediated Barbier-type allylations6–8 in wet media of
three b-oxygenated aldehydes (5, 7, and 9) derived from 1 was car-
ried out. As shown in Table 1, the aldehydes were found to be
inconsistently reactive toward all four allylations we attempted.
However, each aldehyde was found to be compatible with at least
one of the allylations (Table 1, entries D, E, F, G, H, and K). Due to
their moderate stereoselectivity, some successful allylations affor-
ded both syn-1,3-6a and anti-1,3-6b diols either directly (Table 1,
entries D and E) or through desilylation (Table 1, entries E, F, G,
H, and J) while some provided both diastereoisomers of monopro-
tected diols 10a and 10b (Table 1, entry K) in homochiral form. It is
worth mentioning that all the diastereoisomeric alcohols 6a and
6b, and 10a and 10b due to their possession of different types of
functionalities on both ends of the diol moiety are amenable for
versatile chemical manipulations. In conclusion, the good compat-
ibility of 5, 7, and 9 with moderate stereoselectivity under several
allylation reactions and the easy chromatographic separation of
the diastereoisomers of 6 and 10 enabled us to directly obtain sub-
stantial amounts of both syn- and anti-1,3 diols 6a and 6b or 10a
and 10b from each of them (Table 1, entries E, F, G, H, and K), in-
stead of performing the stereoselective allylation separately using
chiral allylating agents2 with the same aldehydes. Furthermore, the
isolation of homochiral monoprotected syn- and anti-1,3-diols
10a,b (Table 1, entry K) is worth mentioning as both their hydrox-
yls and other functionalities are individually amenable for a variety
of chemical elaborations, that will impart more versatility regard-
ing their synthetic potential.
Having achieved the preparation of homochiral 1,3-diols in
good yields following this approach we next turned our attention
to exploit the major isomer 10b to prepare (ꢀ)-galantinic acid A.
This is a non-protenogenic natural amino acid and a constituent
of the peptide antibiotic Galantanin 1. It was first isolated from
the culture broth of Bacillus pulvifaciens10 as a degradation product.
Its acyclic structure has been correctly assigned by Ohfume et al. in
199011 after correcting the wrong structure, which had been pro-
posed earlier. In support of their proposal regarding the structure
and absolute configuration of A, Ohfume et al. reported its first
synthesis.11 Later, due to its interesting biological properties, other
syntheses of A were reported employing several asymmetric
strategies.12
Benzoylation of 10b yielded 11, which on deketalization on
treatment with aqueous acid afforded diol 12. This was subjected
to monobenzoylation at its primary hydroxyl to afford tribenzoate
13 in good yield. Its remaining hydroxyl at C-2 was subjected to
SN2 invertive azidation in two steps comprising tosylation and
treatment of the corresponding tosylate 14 with NaN3 in good
overall yield. Next, the olefin of 15 was subjected to oxidative
cleavage on treatment with NaIO4/ RuCl3 to afford 16. This was
transformed into (ꢀ)-galantinic acid
A in two simple steps
(Scheme 2) involving exhaustive debenzoylation under alkaline
conditions followed by hydrogenation of the resulting triol 17.
The physical and spectroscopic data of our synthesized A are in
accordance with those reported in the literature (Scheme 2).11a
3. Conclusion
Thus, (R)-2,3-cyclohexylideneglyceraldehyde 1 could be effi-
ciently utilized to obtain a number of syn- and anti-1,3-diols 6
and 10 in homochiral form by employing several metal-mediated
Barbier-type allylations of aldehydes 5, 7, and 9 derived from it
in wet media. The novelty of this approach stems from its exhaus-
tive application of environmentally benign green chemistry by
preparing many compounds associated with it, viz. 1,4a 24b and
1,3-diols 6, 8, and 10 (Table 1). It is worth mentioning, that the
hydrophobicity of the cyclohexylidene moiety in the aldehydes 5,
7, and 9 did not inhibit their reactivity in a wet medium as each
of them could be successfully allylated under at least one of the
four conditions carried out herein. Conversely by protecting the
1,2-diol in 6a,b and 10a,b, the cyclohexylidene moiety is likely to
facilitate a wide range of chemical manipulations of all their
O
O
OH
HO
O
O
i
ii
10b
12
11
OBz
BzO
OH
OH
OBz
OBz
N3
OBz
OBz
OTs
BzO
iv
BzO
HO
iii
i
13
14
17
15
OBz
OBz
OBz
OBz
OBz
OBz
N3
BzO
N3
NH2
HO
vi
v
vii
COOH
COOH
COOH
16
OBz
OH
OBz
OH
OH
OH
(-)-A
Scheme 2. (i) BzCN/TEA/DCM; (ii) TFA:H2O/DCM; (iii) p-TsCl Py; (iv) NaN3, DMF, 90 °C; (v) RuCl3, NaIO4, H2O; (vi) K2CO3, MeOH; (vii) 10% Pd/C, H2 MeOH.

2010
B. Dhotare, A. Chattopadhyay / Tetrahedron: Asymmetry 20 (2009) 2007–2013
functionalities, thereby enhancing their synthetic utility. Finally, as
a representative application of the 1,3-diols constructed here, the
stereo-selective synthesis of galantinic acid A10 has been devel-
oped from a major anti-1,3-diol 10b. Our investigation on the effi-
cacy and stereoselectivity of several metal-mediated allylations
with a few more aldehydes derived from 1 is currently in progress.
eluting with different solvent systems (0–3% MeOH in CHCl3 for
5, 0–10% EtOAc in hexane for 7 and 0–15% EtOAc in hexane for
9) to afford aldehyde 5, 7, or 9, all of which tended to decompose
on long standing and hence were used immediately for the subse-
quent allylation reactions.
4.4. General method for Luche’s allylation of aldehydes 5, 7, and 9
4. Experimental
To a well-stirred mixture of the crude aldehyde 5 or 7 or 9
[obtained from ozonolysis of their respective olefin precursor
(5 mmol)], allyl bromide (10 mmol), and Zn dust (1 g, 15 mmol)
in THF (50 mL), was added saturated aqueous NH4Cl solution
(7 mL) in portions over a period of 20 min. For aldehyde 5, no reac-
tion took place (TLC) even after stirring the mixture for an addi-
tional 24 h. For aldehydes 7 and 9, the reaction mixture was
stirred for another 1.5 h until the complete disappearance of the
starting material (TLC). The mixture was filtered and washed thor-
oughly with EtOAc. The combined organic layer was washed with
5% HCl to dissolve the suspended turbid material and then with
water and brine and dried. Solvent removal under reduced pres-
sure and column chromatography (silica gel, 0–20% EtOAc/hexane)
of the residue afforded an inseparable diastereomeric mixture
(2.02 g of 8a/8b, 81.7%) and separable diastereomers (582 mg of
10a and 873 mg of 10b) in their respective cases.
Chemicals used as starting materials are commercially available
and were employed without further purification. All solvents used
for extraction and chromatography were distilled twice at atmo-
spheric pressure prior to use. The 1H NMR and 13C NMR spectra
were scanned with a Brucker Ac-200 (200 MHz) instrument in
CDCl3. The organic extracts were desiccated over dry Na2SO4.
4.1. (2R,3S)-1,2-O-Cyclohexylidene-3-(tert)-butyldiphenylsilyloxy-
5-hexene 3
To a stirred solution of 2 (2.5 g, 11.79 mmol) and imidazole
(0.962 g, 14.15 mmol) in CH2Cl2 (50 mL) was added TBDPSCl
(3.87 g, 14.15 mmol) in CH2Cl2 (15 mL) and the reaction mixture
was stirred overnight. It was then poured in water, and the organic
layer was separated and the aqueous layer was extracted with
CHCl3. The combined organic extracts were washed with water,
brine, and dried. Solvent removal under reduced pressure followed
by column chromatography of the residue (Silica gel, 0–10% EtOAc/
4.5. Desilylation of 8a/8b
A solution of tetrabutylammonium fluoride in THF (8 mL, 1 M
solution) was added to a solution of 8a/8b (2.02 g) obtained above
in THF (30 mL). The resulting solution was stirred overnight at
room temperature. The reaction was quenched by the addition of
saturated aqueous solution of NH4Cl (10 mL). The mixture was di-
luted with EtOAc, and phases were separated. The aqueous phase
was thoroughly extracted with EtOAc. The combined organic layer
was washed successively with water and brine and dried. Solvent
removal under reduced pressure and column chromatography of
the residue (silica gel, 0–5% MeOH/CHCl3) afforded pure diols 6a
(502 mg 39.2%) and 6b (544 mg, 42.5%).
hexane) afforded 3 (4.75 g, 89.6%); ½a D25
ꢂ
¼ þ15:3 (c 2.8, CHCl3); 1H
NMR: d 1.0 (s, 9H), 1.12–1.57 (m, 10H), 2.03–2.17 (m, 2H), 3.70–
3.77 (m,1H), 3.89–3.95 (m, 2H), 4.02–4.08 (m, 1H), 4.86–4.98 (m,
2H), 5.63–5.84 (m, 1H), 7.24–7.39 (m, 6H), 7.67–7.73 (m, 4H). 13C
NMR: 19.3, 23.8, 23.9, 25.1, 26.9, 34.7, 36.0, 38.6, 65.8, 73.0, 77.5,
109.2, 117.3, 127.37, 127.44, 129.5, 129.6, 133.5, 133.8, 133.9,
135.8, 135.9. Anal. Calcd for C28H38O3Si: C, 74.63; H, 8.49. Found:
C, 74.88; H, 8.70.
4.2. (2R,3S)-1,2-O-Cyclohexylidene-3-benzoyloxy-5-hexene 4
To a stirred and cooled (0 °C) solution of 2 (3.0 g, 14.15 mmol)
and TEA (2.88 g, 28.30 mmol) in CH2Cl2 (50 mL) was added benzoyl
cyanide (2.1 g, 16 mmol) in CH2Cl2 (20 mL). The mixture was
stirred at 0 °C for 5 h till the disappearance of starting material
(TLC). Mixture was then treated with H2O. The organic layer was
separated and the aqueous layer was extracted with CHCl3. The
combined organic extracts were washed successively with 5%
aqueous HCl, water, brine, and then dried. Solvent removal under
reduced pressure and column chromatography of the residue (sil-
ica gel, 0–15% EtOAc/hexane) afforded pure 4. Yield: 4.38 g (98%);
1H NMR: 1.2–1.60 (m, 10H), 2.38–2.52 (m, 2H), 3.85–3.93 (m,1H),
4.00–4.07 (m, 1H), 4.19–4.28 (m, 1H), 5.00–5.13 (m, 2H), 5.21–5.30
(m,1H), 5.71–5.91 (m, 1H), 7.35–7.51 (m, 3H), 8.01 (d, J = 7 Hz, 2H).
13C NMR: 23.7, 23.8, 25.0, 34.7, 35.5, 36.0, 65.7, 73.3, 75.8, 110.0,
118.1, 128.2, 129.5, 130.0, 132.9, 165.6. Anal. Calcd for C19H24O4:
C, 72.12; H, 7.64. Found: C, 71.88; H, 7.84.
4.6. General procedure for allylation of aldehydes 5, 7, and 9
employing bimetal redox strategy
To a cooled (10 °C) solution of crude aldehyde 5 or 7 or 9 [ob-
tained from ozonolysis of their respective olefin precursor
(5 mmol)], in THF (50 mL), CuCl2ꢁ2H2O (15 mmol) or anhydrous
FeCl3 (10 mmol) was added. The mixture was stirred well for
2 min. To this stirred suspension allyl bromide (15 mmol) was
added. Then Zn dust (30 mmol) was added to it in portions over
a period of 20 min. For aldehydes 5 and 9 no reaction took place
(TLC) even after stirring the mixture for an additional 24 h. For
aldehyde 7, the mixture was stirred further at the same tempera-
ture for an additional period of 10 h for CuCl2ꢁ2H2O and 1 h for
FeCl3 until the total disappearance of the starting material (TLC).
The reaction mixture was gradually brought to room temperature
and stirred for another 2 h. It was then treated successively with
water (25 mL) and EtOAc (50 mL). The mixture was stirred for
10 min and then filtered. The filtrate was treated with 2% aqueous
HCl to dissolve the small amount of suspended particles. The or-
ganic layer was separated and the aqueous layer was extracted
with EtOAc. The combined organic extract was washed with water
and brine and then dried. Solvent removal under reduced pressure
afforded residue which on column chromatography (silica gel, 0–
20% EtOAc/hexane) gave an inseparable mixture of diastereomers
(8a and 8b) [2.1 g for FeCl3/Zn; 2.04 g(82.4%) for CuCl2ꢁ2H2O/Zn]
of the resulting homoallylic alcohol in pure form. Desilylation of
the mixture of 8a/8b following a similar procedure as carried out
4.3. General method for ozonolysis
To a stirred and cooled (ꢀ78 °C) solution of 2 (1.06 g, 5 mmol)
or 3 (2.25 g, 5 mmol) or 4 (1.58 g, 5 mmol) in CH2Cl2 (50 mL) was
bubbled ozone gas until a blue color persisted. Excess ozone
was removed by flushing with argon. Next, PPh3 (2.0 g, 8 mmol)
was added to the mixture causing immediate disappearance of
the blue color. The solution was brought to room temperature
and stirred for an additional 5 h and concentrated under reduced
pressure. The residue was chromatographed through silica gel

B. Dhotare, A. Chattopadhyay / Tetrahedron: Asymmetry 20 (2009) 2007–2013
2011
above afforded individual diols [6a (380 mg (29.7%) and 6b
(706 mg (55.1%) for FeCl3/Zn; 6a (475 mg (37.1%) and 6b (580 mg
(45.3%) for CuCl2ꢁ2H2O /Zn].
4.11. (2R,3S,5S)-1,2-O-Cyclohexylidene-3-O-benzoyl-1,2,3,5-
tetrahydroxy-oct-7-ene 10a
½
a 2D6
ꢂ
¼ þ10:8 (c 1.04, CHCl3); 1H NMR: d 1.2–1.6 (m, 10H), 1.70–
1.84 (m, 2H), 2.22–2.28 (m, 2H), 2.55 (br s, 1H), 3.55–3.65 (m, 1H),
3.86–3.93 (m, 1H), 4.06–4.13 (m, 1H), 4.23–4.32 (m, 1H), 5.04–5.12
(m, 2H), 5.30–5.40 (m, 1H), 5.71–5.88 (m, 1H), 7.40–7.48 (m, 2H),
7.54–7.62 (m, 3H), 8.04 (dd, J = 7.2 Hz, 2H); 13C NMR: 23.7, 23.8,
25.0, 34.6, 35.9, 38.7, 41.8, 65.6, 66.5, 72.2, 77.8, 110.3, 117.5,
128.4, 129.5, 129.8, 133.3, 134.6, 166.8. Anal. Calcd for C21H28O5:
C, 69.97; H, 7.83. Found: C, 70.20; H, 7.64.
4.7. General method for Indium-mediated allylation of aldehydes
5, 7, and 9 in H2O
To a magnetically stirred solution of crude aldehyde 5 or 7 or 9
[obtained from ozonolysis of their respective olefin precursor
(5 mmol)], and allyl bromide (10 mmol) in water (8 mL) was added
indium metal (99.99% pure ingot, Alfa Aesar make, 632 mg,
5.5 mmol). The reaction mixture was stirred for 24 h. For aldehydes
7 and 9 no reaction took place (TLC). For aldehyde 5, the mixture
was treated with EtOAc (20 mL) and stirred for an additional 1 h.
The organic layer was separated and the aqueous layer was ex-
tracted with ethyl acetate. The combined organic extract was
washed with water and brine and then dried. Solvent removal un-
der reduced pressure and column chromatography of the residue
(silica gel, 0–5% MeOH/CHCl3) afforded pure diols 6a (191 mg,
15.3%) and 6b (788 mg, 61.7%).
4.12. (2R,3S,5R)-1,2-O-Cyclohexylidene-3-O-benzoyl-1,2,3,5-
tetrahydroxy-oct-7-ene 10b
½
a 2D5
ꢂ
¼ þ12:7 (c 1.76, CHCl3); 1H NMR: d 1.24–1.57 (m, 10H),
1.91–1.99 (m, 2H), 2.13–2.35 (m, 2H, overlapped with a br s, 1H),
3.83–3.92 (m, 2H), 4.05–4.12 (m, 1H), 4.26–4.35 (m, 1H), 5.07–
5.15 (m, 2H), 5.26–5.35 (m, 1H), 5.70–5.87 (m, 1H), 7.39–7.60
(m, 3H), 7.99–8.04 (m, 2H); 13C NMR: 23.7, 24.9, 34.6, 36.0, 37.9,
41.6, 65.5, 67.8, 72.0, 76.5, 110.1, 117.7, 128.2, 129.5, 129.9,
132.8, 134.3, 165.8. Anal. Calcd for C21H28O5: C, 69.97; H, 7.83.
Found: C, 70.19; H, 8.04.
4.8. General method for indium-mediated allylation in H2O/THF
4.13. (2R,3S,5S)-1,2-O-Cyclohexylidene-3,5-O-isopropylidene-
1,2,3,5-tetrahydroxy-oct-7-ene 6c
To a magnetically stirred solution of crude aldehyde 5 or 7 or 9
[obtained from ozonolysis of their respective olefin precursor
(5 mmol)], and allyl bromide (10 mmol) in a 1:1 solvent mixture
of water and THF (8 mL) was added indium (99.99% pure ingot,
Alfa Aesar, 632 mg, 5.5 mmol). The reaction mixture was stirred
for 24 h. For aldehyde 9 no reaction took place. For aldehyde 5,
the mixture was treated with EtOAc (20 mL) and stirred for an
additional 1 h. The organic layer was separated and the aqueous
layer was extracted with EtOAc. The combined organic extract
was washed with water and brine and then dried. Solvent re-
moval under reduced pressure and column chromatography of
the residue (silica gel, 0–20% EtOAc/hexane) afforded pure diols
6a (361 mg, 28.2%) and 6b (590 mg, 46.1%). For aldehyde 7, the
reaction took place to a slight extent after stirring the mixture
for an additional 10 h (TLC). The mixture was treated with EtOAc
and worked up in similar manner as carried out above for the In-
mediated reaction in water. Solvent removal under reduced pres-
sure, column chromatography (silica gel, 0–20% EtOAc/hexane) of
the residue to obtain a mixture of 8a and 8b, its desilylation with
TBAF as carried out earlier and column chromatography (silica
gel, 0–5% MeOH/CHCl3) of the product after the usual work-up
afforded diols 6a (78 mg, 6.0%) and 6b (115 mg, 9.0%) in pure
form.
A solution of 6a (100 mg, 0.39 mmol) in 2,2-dimethoxypropane
(5 mL) and containing para-toluenesulfonic acid (PTS) (50 mg) was
stirred for 1 h. After the completion of the reaction (cf. TLC), it was
diluted with ethyl acetate. The organic layer was separated and the
aqueous layer was extracted with ethyl acetate. The combined or-
ganic extract was washed water and brine and dried. Removal of
solvent under reduced pressure and column chromatography (sil-
ica gel, 0–15 EtOAc/hexane) of the residue afforded pure 6c
208 mg (90%); d 13C NMR: d 19.8, 23.7, 24.0, 25.0, 29.9, 33.6,
34.6, 36.4, 40.7, 65.8, 68.3, 70.7, 77.9, 98.4, 109.7, 117.1, 133.9.
4.14. (2R,3S,5R)-1,2-O-Cyclohexylidene-3,5-O-isopropylidene-
1,2,3,5-tetrahydroxy-oct-7-ene 6d
Compound 6d was prepared from 6b (100 mg, 0.39 mmol) fol-
lowing a similar procedure as described above for the preparation
of 6c. Yield 212 mg; 13C NMR: d 23.7, 23.9, 24.7, 24.9, 25.1, 34.4,
34.7, 36.3, 40.0, 65.7, 66.0, 66.9, 68.1, 100.2, 109.8, 116.9, 134.2.
4.15. (2R,3S,5RS)-1,2-O-Cyclohexylidene-3-O-tert-butyldiphen-
ylsilyl-1,2,3,5-tetrahydroxy-oct-7-enes 8a,b
4.9. (2R,3S,5S)-1,2-O-Cyclohexylidene-1,2,3,5-tetrahydroxy-oct-
7-ene 6a
1H NMR: d 1.06 (s, 9H), 1.28–1.61 (m, 10H), 1.67–1.71 (m, 2H),
2.0–2.2 (m, 2H), 2.70 (br s, 1H), 3.59–3.66 (m, 1H), 3.79–4.25 (m,
4H), 4.92–5.03 (m, 2H), 5.6–5.8 (m, 1H), 7.32–7.43 (m, 6H), 7.64–
7.73 (m, 4H); 13C NMR: 19.3, 23.7, 25.0, 26.9, 29.6, 34.7, 35.9,
41.5, 41.9, 42.1, 42.2, 66.9, 67.4, 67.5, 68.0, 72.3, 74.1, 76.4, 78.1,
78.5, 110.0, 117.2, 117.3, 127.6, 129.8, 133.1, 133.3, 133.4, 133.6,
134.7, 134.8, 135.5, 135.9.
½
a 2D6
ꢂ
¼ þ10:4 (c 2.0, CHCl3) 1H NMR: 1.3–1.8 (m, 12H), 2.2–2.3
(m, 2H), 3.2 (br s, 1H), 3.5 (br s, 1H), 3.84–3.98 (m, 5H), 5.0–5.1
(m, 2H), 5.6–5.9, (m, 1H); 13C NMR: 23.4, 23.6, 24.7, 34.4, 35.9,
38.1, 42.0, 65.0, 71.2, 72.3, 77.7, 109.4, 117.9, 133.8. Anal. Calcd
for C14H24O4: C, 65.59; H, 9.44. Found: C, 65.78; H, 9.66.
4.16. (2R,3S,5R)-1,2-O-Cyclohexylidene-3,5-O-di-benzoyl-
1,2,3,5-tetrahydroxy-oct-7-ene 11
4.10. (2R,3S,5R)-1,2-O-Cyclohexylidene-1,2,3,5-tetrahydroxy-
oct-7-ene 6b
To a cooled (0 °C) solution of 10b (2.5 g, 7 mmol) in CH2Cl2
(75 mL) containing triethylamine (3.5 mL) was added benzoyl cya-
nide (982 mg, 7.5 mmol). The mixture was stirred for 5 h at 0 °C
until the completion of the reaction (cf. TLC), after which it was
treated with water and extracted with CHCl3. The combined organ-
ic extract was washed with 5% HCl, then with water until acid free
½
a 2D6
ꢂ
¼ þ0:5 (c 1.2, CHCl3); 1H NMR: d 1.2–1.9 (m, 12H), 2.2–2.5
(m, 2H), 2.5 (br s, 1H), 2.9 (br s, 1H), 3.84–4.0 (m, 5H), 5.0–5.15 (m,
2H), 5.5–5.9, (m, 1H); 13C NMR: 23.4, 23.6, 24.8, 34.4, 35.9, 38.0,
41.7, 65.0, 67.7, 68.8, 77.6, 109.4, 118.0, 134.0. Anal. Calcd for
C14H24O4: C, 65.59; H, 9.44. Found: C, 65.38; H, 9.26.

2012
B. Dhotare, A. Chattopadhyay / Tetrahedron: Asymmetry 20 (2009) 2007–2013
and brine and dried. Solvent removal under reduced pressure and
column chromatography (silica gel, 0–10% EtOAc/hexane) of the
residue afforded pure 11 (3.06 g, 95%); 1H NMR: d 1.56–1.66 (m,
10H), 2.13–2.19 (m, 2H), 2.48–2.55 (m, 2H), 3.82–3.89 (m, 1H),
4.03–4.06 (m, 1H), 4.30–4.42 (m, 1H), 5.07–5.10 (m, 2H), 5.31–
5.35 (m, 2H), 5.70–5.87 (m, 1H), 7.25–7.54 (m, 10H).; 13C NMR:
23.7, 23.9, 25.1, 34.3, 34.7, 36.1, 38.9, 60.8, 65.9, 76.2, 110.3,
118.4, 128.1, 128.2, 128.2, 129.5, 129.6, 129.8, 130.2, 130.4,
132.7, 132.9, 165.6, 165.8.
(m, 1H), 5.08–5.17 (m, 2H), 5.23–5.25 (m, 1H), 5.55–5.59 (m, 1H),
5.74–5.82 (m, 1H), 7.31–7.58 (m, 9H), 7.93–8.00 (m, 6H); 13C
NMR: 34.7, 38.7, 62.3, 63.9, 69.4, 69.9, 118.7, 128.2, 128.3, 129.0,
129.4, 129.6, 129.7, 129.9, 132.5, 132.8, 133.2, 165.3, 165.7, 165.9.
Anal. Calcd for C29H27O6N3: C, 67.82; H, 5.29; N, 8.18. Found: C,
68.07; H, 5.11; N, 8.36.
4.20. (2S,3S,5S)-2-Azido-1,3,5-tribenzoyloxy-heptanoic acid 16
Compound 15 (800 mg, 1.56 mmol) was taken in a solvent mix-
ture of carbon tetrachloride (2 mL), acetonitrile (2 mL), and water
(3 mL). The biphasic mixture was stirred, treated with sodium
metaperiodate (1.34 g, 6.26 mmol), followed by the addition of
ruthenium trichloride hydrate (10 mg). The entire mixture was
stirred vigorously for 2 h at room temperature. After completion
of the reaction (TLC), CH2Cl2 (20 mL) was added. The organic layer
was separated and the aqueous layer was extracted with CH2Cl2.
The combined organic extract was washed with water and brine
and dried. Solvent removal under reduced pressure and column
chromatography (0–7% MeOH/CHCl3) of the residue afforded 16
(0.588 g, 71%); 1H NMR: d 2.39–2.49 (m, 2H), 2.73–2.97 (m, 2H),
4.03–4.25 (m, 1H), 4.41–4.65 (m, 2H), 5.56 (m, 2H), 7.27–7.54
(m, 9H), 7.89–7.99 (m, 6H), 8.36 (br s, 1H); 13C NMR: 35.04, 38.6,
62.2, 63.9, 70.9, 72.5, 128.2, 128.4, 128.7, 128.9, 129.0, 129.5,
129.6, 129.8, 133.0, 133.3, 134.1, 147.0, 157.9, 165.5, 165.6,
165.9, 174.9.
4.17. (2R,3S,5R)-3,5-O-Di-benzoyl-1,2,3,5-tetrahydroxy-oct-7-
ene 12
To a cooled (0 °C) solution of 11 (2.5 g, 5.38 mmol) in CH2Cl2
(50 mL) was added 80% aqueous trifluoroacetic acid (8 mL). The
mixture was stirred for 2.5 h until the completion of the reaction
(TLC), after which it was treated with water (50 mL) and the
organic layer was separated. The aqueous layer was extracted
with CHCl3. The combined organic extract was washed succes-
sively with water and brine and dried. Removal of the solvent
under reduced pressure and column chromatography (silica gel,
5% MeOH/CHCl3) of the crude afforded pure 12 (1.62 g, 78.2%);
½
a 2D4
ꢂ
¼ ꢀ13:2 (c 4.78, CHCl3); 1H NMR: d 2.15–2.36 (m, 2H), 2.42–
2.53 (m, 2H), 3.1 (br s, 2H), 3.54–3.78 (m, 3H), 5.05–5.15 (m,
3H), 5.31–5.35 (m, 1H), 5.74–5.82 (m, 1H), 7.28–7.50 (m, 6H),
7.50–7.93 (m, 4H).; 13C NMR: 34.4, 49.0, 62.6, 70.4, 71.1, 72.9,
118.5, 128.2, 128.3, 129.4, 129.5, 129.7, 130.0, 132.8, 132.9,
133.0, 133.2, 166.1, 166.7. Anal. Calcd for C22H24O6: C, 68.73; H,
6.29. Found: C, 68.51; H, 6.52.
4.21. Galantinic acid A
To a well-stirred and cooled (0 °C) solution of 16 (0.300 g,
0.584 mmol) in MeOH (25 mL) was added powdered K2CO3
(0.322 g, 2.34 mmol). This mixture was allowed to stir for 2.5 h. After
completion of reaction (TLC), MeOH was removed in vacuo to afford
a crude residue which was dissolved in CHCl3. The solution was
washed with water and brine and dried. Solvent removal under
reduced pressure afforded the residue containing 17. This was taken
in methanol (25 mL). To this methanolic solution, 10% Pd/C (100 mg)
was added. The mixture was subjected to hydrogenation for 2 h with
stirring. After completion of reaction (TLC) the reaction mixture was
passed through a small silica pad. The silica pad was washed with
methanol (70 mL). Solvent removal under reduced pressure and col-
umn chromatography (0–20% MeOH/CHCl3) of the residue afforded
A as colorless crystals (0.050 g (71%). Melting point: 122–126 °C;
4.18. (2R,3S,5R)-1,3,5-O-Tri-benzoyl-1,2,3,5-tetrahydroxy- oct-
7-ene-2-ol 13
Following a similar procedure as done for the preparation of 11,
compound 12 (1.5 g, 3.9 mmol) was benzoylated with benzoyl cya-
nide (524 mg, 4 mmol) in the presence of triethyl amine (2 mL) in
CH2Cl2 (75 mL) at 0 °C to obtain 13 (1.73 g, 91%); ½a D24
¼ ꢀ19:1 (c
ꢂ
1.57, CHCl3); 1H NMR: d 2.26–2.32 (m, overlapped with br s, 3H),
2.49–2.55 (m, 2H), 4.28–4.55 (m, 3H), 5.06–5.16 (m, 2H), 5.36–
5.39 (m, 2H), 5.74–5.83 (m, 1H), 7.29–7.57 (m, 10H), 7.89–8.09
(m, 5H).; 13C NMR: 33.7, 38.9, 65.5, 70.0, 70.2, 71.1, 71.8, 118.5,
128.0, 128.2, 128.2, 129.4, 129.6, 130.0, 132.7, 133.1, 165.9,
166.0, 166.7. Anal. Calcd for C29H28O7: C, 71.29; H, 5.77. Found:
C, 71.48; H, 5.98.
lit11a Melting point: 125–130 °C; ½a 2D2
ꢂ
¼ ꢀ25:0 (c 2.9, D2O); lit11a
½
a 2D5
ꢂ
¼ ꢀ29:0 (c 3.5, D2O), 1H NMR (D2O): d 1.51–1.65 (m, 2H),
4.19. (2S,3S,5R)-2-Azido-1,3,5-tri-benzoyloxy-oct-7-ene 15
2.27–2.29 (m, 2H), 3.05–3.07 (m, 1H), 3.52–3.61 (m, 1H), 3.68–
3.76 (m, 1H), 3.81–3.91 (m, 1H), 4.05–4.11 (m, 1H). 13C NMR
(D2O): 39.6, 45.4, 57.3, 59.6, 65.3, 180.0.
To an ice-cooled (0 °C) solution of 13 (1.5 g, 3.07 mmol) in pyri-
dine (20 mL) containing 4-(dimethylamino)pyridine (50 mg) was
added p-TsCl (700 mg, 3.67 mmol). The mixture was stirred at the
same temperature for 4.0 h. After completion of reaction (TLC), it
was treated with water and extracted with ethyl acetate. The organ-
ic layer was separated and the aqueous layer was washed with
ethyl acetate. The combined organic extracts were washed with
5% HCl, water, and brine and dried. Removal of the solvent under re-
duced pressure yielded a crude residue containing tosylate 14. This
was taken in dimethylformamide (DMF) (25 mL), after which so-
dium azide (NaN3) (280 mg, 4.3 mmol) was added to it. The reaction
mixture was heated at 90 °C for 4 h. After completion of the reac-
tion (TLC), it was brought to room temperature, treated with water
and extracted with EtOAc. The combined organic extract was
washed successively with water and brine and dried. Solvent re-
moval under reduced pressure and column chromatography (0–
15% EtOAc/hexane) of the residue afforded 15 (1.1 g, 70%);
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a 2D2
ꢂ
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