A flexible organocatalytic enantioselective synthesis of heptadeca-1-ene-4,6-diyne-3S,8R,9S,10S-tetrol and its congeners

Article abstract of DOI:10.1016/j.tet.2011.10.058

A unified enantioselective route is developed for the synthesis of heptadeca-1-ene-4,6-diyne-3S,8R,9S,10S-tetrol and its synthetic congeners. A proline-catalyzed aminoxylation, cross-metathesis, Wittig reaction, and catalytic dihydroxylation are key steps

Full text of DOI:10.1016/j.tet.2011.10.058

Tetrahedron 68 (2012) 262e271
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Tetrahedron
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A flexible organocatalytic enantioselective synthesis of heptadeca-1-ene-4,6-
diyne-3S,8R,9S,10S-tetrol and its congeners
*
Gullapalli Kumaraswamy , Kadivendi Sadaiah
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 August 2011
Received in revised form 12 September 2011
Accepted 14 October 2011
Available online 25 October 2011
A
unified enantioselective route is developed for the synthesis of heptadeca-1-ene-4,6-diyne-
3S,8R,9S,10S-tetrol and its synthetic congeners. A proline-catalyzed aminoxylation, cross-metathesis,
Wittig reaction, and catalytic dihydroxylation are key steps of this synthesis. This new approach is en-
visioned to facilitate the synthesis of every representative member of the family with skeletal and ste-
reochemical variation.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
The conjugated diynes with successive hydroxylated stereo-
genic centers are a common structural motif in many natural
products such as heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol 1,
oploxyne B 2, panaxytriol 3, and oploxyne A 4. Due to its intriguing
structural motif, these natural products exhibit diverse biological
profiles including potent cytotoxicity (Fig. 1).1
In addition, these natural compounds are of significance both in
their natural form and also as templates for synthetic modification,
as well as considered potential leads for the treatment of various
cancers.2 In view of wide pharmacological profiles, a plethora of
approaches has been recorded for this class of compounds.3
Among them, the putative structure proposed for the conjugated
diyne tetrol 1, with relative stereochemistry assigned as 8R,9R,10R
based on Kishi’s protocol, isolated from Hydrocotyle leucocephala
by Ramos et al.4 has received considerable interest. Shortly, the
total synthesis of this heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol, 1
was ensued by Ghosh et al.5a to validate the proposed initial
structure and their relative and absolute stereochemistry of hy-
droxyl functional groups. While comparing the NMR data of syn-
thetic sample with that of natural product revealed a number of
discrepancies and also further, proposed that the natural product
could be one of the possible six diastereomers.5b En route to the
synthesis of 1, Prasad et al.6 also accomplished the syntheses of
possible diastereomers and further unambiguously assigned the
absolute stereochemistry of hydroxyl functionalities of 1. Thus far,
applied strategies for the synthesis of 1 and their diastereomers
were based on chiron approach. The requisite stereogenic centers
Fig. 1. Conjugated diynes with successive hydroxylated stereogenic centers.
in tetrol were introduced by transforming mannitol,
tartaric acid.
D-ribose, and
With our continued interest in developing catalytic enantiose-
lective routes to biologically important molecules,7 we were
attracted to the enantioselective total synthesis of heptadeca-1-
ene-4,6-diyne-3,8,9,10-tetrol congeners (Fig. 2). At the outset, we
intended to develop a unified, flexible alternative strategy for the
synthesis of the tetrols 5ae5d and also consequent view to validate
the putative structure proposed by Ramos et al.4,8 In addition, all
the possible diastereomers of the heptadeca-1-ene-4,6-diyne-
3,8,9,10-tetrol family could be synthesized, in principle, by varying
chirality inducing ligands with high stereocontrol and a predictable
absolute stereochemistry. Our retrosynthetic analysis is delineated
in Scheme 1.
* Corresponding author. Tel.: þ91 40 27193154; fax: þ91 40 27193275;
e-mail address: gkswamy_iict@yahoo.co.in (G. Kumaraswamy).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.058

G. Kumaraswamy, K. Sadaiah / Tetrahedron 68 (2012) 262e271
263
with a catalytic amount of CuSO4 afforded the required diol 14 in
60% yield from 12.10d The optical purity of 14 found to be w97%12
and the absolute configuration was determined by comparing the
chirooptical data reported in the literature.13 The conversion of diol
14 to epoxide 1514 was achieved by tosylation of primary alcohol
followed by treatment with K2CO3 in methanol. Then, opening of
epoxide 15 with dimethyl sulphonium methylide, generated in dry
THF at ꢀ20 ꢁC employing trimethylsulphonium iodide in the
presence of n-BuLi provided the enantioenriched secondary allylic
alchol (S)-11 in 85% yield.15 The secondary alcohol was converted as
TBDPS ether 16 and then oxidative cleavage of olefin led to an al-
dehyde in 85% yield (after two steps). The reaction of triphenyl-
phosphonium salt 1716 and p-methoxybenzyloxy propanal in THF
with n-BuLi generated (Z)-olefin 9 (Z/E 92:8, judged by 1H NMR)17
in 74% yield for two steps. Then, cis-hydroxylation was achieved
under the Upjohn conditions18 and the resultant diol was protected
as acetonide to give 18 as separable mixture with 9:1 di-
astereomeric ratio. The terminal acetylenic functionality was in-
Fig. 2. Heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol diastereomers.
Scheme 1. Retrosynthetic analysis of heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol.
2. Results and discussion
stalled by a four-step sequence. Consequently, compound 19 was
subjected to oxidation using DMP in DCM and subsequent trans-
formation of crude aldehyde using the CoreyeFuchs protocol19
provided the corresponding alkyne 20 in 78% yield (over three
steps). Removal of the TBDPS group with TBAF gave 7 in 94% yield
(Scheme 2).
Then, we sought an efficient enantioselective synthesis of ad-
vanced intermediate (S)-6. However, all attempts to reduce the
corresponding enynone of 6 by means of Noyori’s protocol20 failed
to yield the required advanced intermediate (S)-6. Alternatively, the
conversion of enantioenriched (S)-11, generated through organo-
catalysis via a four-step sequence was furnished only to trace the
amount of required compound (S)-2221 (Scheme 3). At this point
we considered Lipase PS catalyzed resolution of (ꢂ)-23.3c Thus, the
reaction of (ꢂ)-23 and vinylacetate in hexane with 0.3 mass equiv
of Lipase PS at ambient temperature resulted in acylated compound
(R)-23 in 35% yield with 98% optical purity leaving enriched (S)-23
in 36% yield with 98% optical purity.3c After the protection of al-
cohol as TBS-ether followed by Isobe’s22 one-pot procedure led to
the desired (S)-6 in 92% yield (Scheme 4).
As illustrated in Scheme 1, the pivotal advanced intermediates
are envisioned to be 5-bromopent-1-ene-3-ol, (S)-6 and the ter-
minal acetylenic compound 7 or 8, which would be cross-coupled
employing CadioteChodkiewich conditions9 anticipated to deliver
the target molecule. The terminal acetylenic compounds 7 and 8
could be accessed through a catalytic dihydroxylation of enan-
tioenriched secondary alcohol with well defined cis or trans alkene
9 or 10, which in turn could be generated either cis-Wittig reaction
or cross-metathesis reaction. Eventually, the critical intermediate
(S)-11 is considered to obtain via an organocatalyzed aminoxylation
of 12. To this end, the enantioenriched advanced intermediate 7
synthesis is described in Scheme 2.
We proposed to install hydroxyl stereogenic center in 7 by
employing
Accordingly, the reaction of propanal 12 (1 equiv) with nitro-
sobenzene (1.2 equiv) in the presence of 20 mol % of -proline at
ambient temperature resulted in labile -aminoxy aldehyde, which
was reduced to
-aminoxy alcohol 13.11 Then, subsequent reaction
a
proline-catalyzed
a
-aminoxylation strategy.10
L
a
a

264
G. Kumaraswamy, K. Sadaiah / Tetrahedron 68 (2012) 262e271
Scheme 2. Synthesis of advanced intermediate 7.
Scheme 3. Synthesis of TBDMS protected pent-1-ene-4-yne-3-ol, 22.
Scheme 4. Lipase PS catalyzed kinetic resolution of (ꢂ)-23.
Having obtained advanced intermediates (S)-6 and 7, we pro-
Next, to generate stereochemical diversity, we explored the
synthesis of E-allylic alcohol 10 from a common intermediate (S)-11
under the same set of conditions (vide infra). Consequently, we
considered to conduct cross-metathesis between (S)-11 and 1-
nonene using the second generation Grubbs catalyst.23 To our de-
light, the required E-allylic alcohol 10 was generated (E/Z 95:5)16 in
81% yield. The secondary alcohol was converted as TBDPS ether
followed by oxidative cleavage resulted in the primary alcohol 25.24
Oxidation of primary alcohol under the Swern conditions furnished
aldehyde, which was converted to corresponding acetylene using
the CoreyeFuchs protocol to give 26 in 74% yield. Fluoride ion in-
duced deprotection followed by catalytic asymmetric dihydrox-
ylation25 led the desired critical intermediate 8 in 36% yield.26 The
triol 8 was cross-coupled with (S)-6 employing CadioteChodkie-
wicz conditions and subsequent acid-catalyzed deprotection
resulted in 5c (Scheme 6).
ceeded for their coupling. Initially, TBDMS ether 20 and (S)-6 were
subjected to CadioteChodkiewicz conditions (CuCl/NH2OH$HCl/
EtNH2) but no trace of expected coupled product was observed.
Whereas, corresponding alcohol 7 and (S)-6 under otherwise
identical conditions as above led to the target compound 24. Finally,
acid-catalyzed deprotection of acetonide and TBS group furnished
the desired molecule 5a in 44% yield (Scheme 5).
Scheme 5. Synthesis of final molecule tetrol 5a.

G. Kumaraswamy, K. Sadaiah / Tetrahedron 68 (2012) 262e271
265
Scheme 6. Synthesis of final molecule tetrol 5c.
Correspondingly, the diastereomers 5b and 5d were generated
by coupling (R)-6 with 7 and 8, respectively, making use of
complementary sense of chirality that induces ligand and to this
end, further work is under progress.
CadioteChodkiewicz conditions and subsequent acid-catalyzed
23
deprotection. Moreover, the optical data of 5a ([
a
]
]
þ9.6 (c 1.3,
4. Experimental section
4.1. General procedures
MeOH) {lit.6 [
MeOH) {lit.6
a
]
23 þ11.9 (c 1.4, MeOH)}) and 5b ([
a
2D3 ꢀ38.6 (c 0.3,
D
D
23
[a
]
ꢀ41.7 (c 2.3, MeOH)}) were in full accord with
D
those reported in the literature.6 The structures of 5c and 5d were
confirmed by spectral data (1H and 13C NMR). Furthermore, the
optical rotation of 5c and 5d was found to be equal in magnitude
but opposite in sign with those reported in the literature,6 and
hence was considered as their enantiomers. To the best of our
knowledge, synthesis of 5c and 5d is described here for the first
time (Schemes 6 and 7).
1H NMR spectra were recorded at 300 and 500 MHz and 13C
NMR 75 MHz, in CDCl3 and D3CCN. IR (FTIR) spectrometer, mea-
sured as neat. Mass spectral data were compiled using MS (ESI),
HRMS mass spectrometers. Optical rotations recorded on HORIBA
high sensitive polarimeter, 10 mL cell. Column chromatography
carried out with silica gel, grade 60e120 and 100e200 mesh.
Scheme 7. Cu-catalyzed oxidative coupling of (R)-6 with 7 and 8.
3. Conclusions
Starting materials: CH2Cl2 was distilled from P2O5, THF from so-
dium benzophenone ketyl. All other chemicals used were com-
mercially available. All reactions were conducted under an
atmosphere of nitrogen (IOLAR Grade I). Organic extracts were
dried over anhydrous Na2SO4.
In conclusion, we have developed a unified stereochemical
diversity-oriented synthesis of 5ae5d through the tactical appli-
cation of established chemistry. The salient features of this concise
synthesis are (i) the genesis of chirality through an organocatalytic
reaction; (ii) the consecutive hydroxyl motif were generated from
the same synthone, which in turn was accessed by two catalytic
reactions with perfect stereocontrol and a predictable relative
stereochemistry. Moreover, the flexibility built into the synthesis to
generate a library of analogues will be amenable to a large-scale
synthesis with easy skeletal and stereogenic diversity using
4.2. (S)-3-(4-Methoxybenzyloxy)-2-(phenylaminooxy)
propan-1-ol (13)
To a solution of aldehyde 12 (2.55 g, 13.14 mmol) in DMSO
(50 mL), nitrasobenzene (1.41 g, 13.17 mmol) followed by
L-proline
(310 mg, 2.7 mmol) were added at room temperature.

266
G. Kumaraswamy, K. Sadaiah / Tetrahedron 68 (2012) 262e271
The resultant reaction mixture was allowed to stir for 3 h at same
temperature. Reaction mixture was diluted with anhydrous
methanol (20 mL), then temperature was lowered to 0 ꢁC, followed
by addition of excess NaBH4 (2.4 g). After 30 min, reaction was
quenched with a 1:1 biphasic solution of ether and 1 N HCl
(50 mL). The organic layer was separated and aqueous layer was
extracted with ethyl acetate (4ꢃ50 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The resultant residue was purified by silica gel
rotary evaporation, and extracted with ethyl acetate (3ꢃ10 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The resultant residue was
purified by silica gel column chromatography using hexane/ethyl
acetate (9:1) as eluent to obtain epoxide 15 as colorless oil 412 mg
(82% over two steps). [
a
]
D
24 ꢀ5.5 (c 5.4, CHCl3); IR (neat) 2909, 2362,
1513, 1244, 1085, 817 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
7.22 (d,
J¼8.3 Hz, 2H, ArH), 6.83 (d, J¼9.1 Hz, 2H, ArH), 4.48 (dd, J¼18.9,
11.3 Hz, 2H, ArOCH2), 3.80 (s, 3H, ArOMe), 3.65 (dd, J¼11.3, 3.0 Hz,
1H, OCHaHbCH), 3.39 (dd, J¼11.3, 5.3 Hz, 1H, OCHaHbCH), 3.13e3.07
(m, 1H, OCHCH2), 2.74 (t, J¼4.5 Hz, 1H, OCHCHaHb), 2.55 (dd, J¼5.3,
column chromatography using hexane/ethyl acetate (5:1) as elu-
24
ent to yield title compound 13 as yellow syrup (65% yield). [a]
D
ꢀ2.45 (c 2.0, CHCl3); IR (neat) 3442, 3393, 2865, 2333, 1513, 1089,
757 cmꢀ1 1H NMR (300 MHz, CDCl3)
7.34e7.23 (m, 5H, ArH),
2.3 Hz, 1H, OCHCHaHb); 13C NMR (75 MHz, CDCl3)
d 159.0, 129.7,
;
d
129.1, 113.5, 72.6, 70.3, 54.9, 50.6, 43.9; ESIMS (m/z) 217 (Mþ23)þ;
7.02e6.97 (m, 2H, ArH), 6.93e6.85 (m, 2H, ArH), 4.51 (s, 2H,
OCH2Ar), 4.16e4.07 (m, 1H, CH(CH2)2), 3.95e3.87 (m, 2H, CH2eO),
3.81 (s, 3H, MeO), 3.76e3.72 (m, 2H, CH2eO); 13C NMR (75 MHz,
ESIHRMS calcd for C11H14O3Na 217.0840, found 217.0837.
4.6. (S)-1-(4-Methoxybenzyloxy) but-3-en-2-ol ((S)-11)
CDCl3)
d 165.7, 130.9, 129.4, 129.2, 129.0, 122.3, 114.6, 113.8, 82.4,
73.2, 69.0, 62.9, 55.2; ESIMS (m/z) 304 (MþH)þ; ESIHRMS calcd for
To
a
solution of trimethylsulphonium iodide (9.87 g,
C17H22NO4 304.1543, found 304.1543.
44.86 mmol) in THF (100 mL), n-BuLi (1.6 M, 27 mL) was added
drop wise at ꢀ20 ꢁC under inert atmosphere. After stirring 1 h at
the same temperature, epoxide 15 (2.9 g, 14.95 mmol) in THF
(20 mL) was added drop wise over 10 min. Then, the resultant re-
action mixture was shifted to the room temperature and allowed to
stir for 6 h, then quenched with water (50 mL) and extracted with
ethyl acetate (3ꢃ75 mL). The combined organic layers were washed
with brine (50 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The resultant residue was
purified by silica gel column chromatography using hexane/ethyl
4.3. (S)-3-(4-Methoxybenzyloxy)propane-1,2-diol (14)
To a solution hydroxyamino alcohol 13 (1.8 g, 6.59 mmol) in
methanol (20 mL) CuSO4$5H2O (496 mg, 2 mmol) was added at
0 ꢁC, the mixture was stirred at same temperature for 12 h and then
quenched with satd NH4Cl (20 mL). Methanol was removed by
rotary evaporation, and reaction mixture was extracted with ethyl
acetate (5ꢃ20 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
resultant residue was purified by silica gel column chromatography
acetate (7:1) as eluent to give title compound (S)-11 as pale yellow
24
oil, 2.64 g (85%). [
a
]
ꢀ2.0 (c 2.0, CHCl3); IR (neat) 3448, 2860,
D
using hexane/ethyl acetate (1:2) as eluent to obtain diol 14 as pale
2362, 1613, 1462, 1096, 820 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.26
24
yellow oil 1.28 g (92% yield). [
a
]
þ1.0 (c 0.110, MeOH); IR (neat)
D
(d, J¼8.5 Hz, 2H, ArH), 6.89 (d, J¼8.5 Hz, 2H, ArH), 5.83 (ddd, J¼16.4,
10.4, 5.5 Hz, 1H, CH]CH2), 5.35 (d, J¼17.4 Hz, 1H, CHaHb]CH), 5.19
(d, J¼10.6 Hz, 1H, CHaHb]CH), 4.50 (s, 2H, ArOCH2), 4.33 (br s, 1H,
CH(CH)CH2O), 3.81 (s, 3H, ArOMe), 3.52 (dd, J¼9.6, 3.4 Hz, 1H,
OCHaHbCH), 3.44 (dd, J¼9.4, 7.9 Hz, 1H, OCHaHbCH), 2.45 (br s, 1H,
3392, 2930, 2362, 1242, 1028 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
7.20 (d, J¼8.5 Hz, 2H, ArH), 6.82e6.80 (d, J¼8.7 Hz, 2H, ArH), 4.41
(s, 2H, OCH2Ar), 3.82e3.74 (m, 4H, OMe, CHeCH2), 3.61e3.56 (dd,
J¼11.5, 3.6 Hz, 1H, OCHaHbCH), 3.51e3.46 (dd, J¼11.3, 5.8 Hz, 1H,
OCHaHbCH), 3.42e3.40 (m, 2H, OCH2); 13C NMR (75 MHz, CDCl3)
OH); 13C NMR (75 MHz, CDCl3)
d 159.1, 136.5, 129.7, 129.3, 116.2,
d
159.2, 129.7, 129.4, 113.7, 73.0, 71.2, 70.6, 63.9, 55.2; ESIMS (m/z)
113.7, 73.6, 72.8, 55.1, 25.5; ESIMS (m/z): 231 (Mþ23)þ; HRMS calcd
235 (Mþ23)þ; ESIHRMS calcd for C11H16O4Na 235.0946, found
for C12H16O3Na 231.0997, found 231.1000.
235.0953.
4.4. (R)-((R)-1-(tert-Butyldimethylsilyloxy)-3-(4-
methoxybenzyloxy)propan-2-yl)3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate
4.7. (S)-tert-Butyl(1-(4-methoxybenzyloxy)but-3-en-2-yloxy)
diphenylsilane (16)
TBDPSCl (1.5 mL, 5.77 mmol) was added to solution of alcohol
(S)-11 (1.0 g, 4.81 mmol) and imidazole (0.98 g, 14.42 mmol) in
dichloromethane (15 mL) at 0 ꢁC. This resultant reaction mixture
was stirred at 0 ꢁC to room temperature for 2 h. Then the reaction
was quenched with water (20 mL). The organic layer was separated
and aqueous layer was extracted with dichloromethane (2ꢃ15 mL).
The combined organic layers were washed with brine (30 mL),
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. The resultant residue was purified by silica gel column chro-
matography using hexane/ethyl acetate (97:3) as eluent gave title
1H NMR
d
7.55 (d, J¼7.9 Hz, 2H, ArH), 7.36e7.31 (m, 3H, ArH),
7.10 (d, J¼7.9 Hz, 2H, ArH), 6.79 (d, J¼8.9 Hz, 2H, ArH), 5.29e5.24
(m, 1H, OCH(CH2)2), 4.35 (t, J¼13.9 Hz, 2H, OCH2Ar), 3.84e3.77 (m,
5H, ArOMe, OCH2), 3.55e3.50 (m, 5H, OMe, OCH2), 0.88 (s, 9H, t-
BuSi), 0.06e0.05 (m, 6H, Me2Si).
4.5. (S)-2-((4-Methoxybenzyloxy)methyl)oxirane (15)
To a solution of diol 14 (550 mg, 2.59 mmol) in dichloromethane
(10 mL), dry pyridine (0.4 mL) follwed by tosyl-Cl (542 mg,
2.85 mmol) were added at 0 ꢁC. This reaction mixture was allowed
to stir at same temperature 12 h. The reaction was quenched with
1 N HCl (5 mL), then organic layer was separated and aqueous layer
was extracted with dichloromethane (2ꢃ10 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The resultant residue was passed through
a small plug of silica gel. Removal of the solvent under reduced
pressure afforded corresponding tosylated alcohol, which was im-
mediately dissolved in anhydrous MeOH (10 mL) and was treated
with K2CO3 (268 mg, 1.94 mmol) at 0 ꢁC. After completion of the
reaction (2 h) water was added (5 mL), methanol was removed by
compound 16 as dense oil 2.04 g (95%). [
a]
24 ꢀ22.0 (c 1.7, CHCl3); IR
D
(neat) 3069, 2933, 2857, 2362, 1513, 1247, 1108, 1034, 810,
701 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.68e7.60 (m, 4H, ArH),
7.41e7.27 (m, 6H, ArH), 7.05 (d, J¼8.7 Hz, 2H, ArH), 6.76 (d,
J¼8.69 Hz, 2H, ArH), 5.85 (ddd, J¼16.2, 10.4, 5.7 Hz, 1H, CH]CH2),
5.15 (dt, J¼17.2, 1.5 Hz, 1H, CHaHb]CH), 5.04 (dt, J¼10.4, 1.5 Hz, 1H,
CHaHb]CH), 4.33e4.27 (m, 3H, ArOCH2, CH(CH)CH2O), 3.79 (s, 3H,
ArOMe), 3.32 (qd, J¼9.6, 5.8 Hz, 2H, OCH2CH), 1.07 (s, 9H, t-BuSi);
13C NMR (75 MHz, CDCl3)
d 159.0, 138.3, 136.0, 135.9, 134.2, 133.8,
130.4,129.5,129.1,127.4,115.4,113.6, 74.3, 73.3, 72.7, 55,2, 27.0,19.3;
ESIMS (m/z) 469 (Mþ23)þ; ESIHRMS calcd for C28H34O3NaSi
469.2174, found 469.2184.

G. Kumaraswamy, K. Sadaiah / Tetrahedron 68 (2012) 262e271
267
4.8. (S,Z)-tert-Butyl(1-(4-methoxybenzyloxy)undec-3-en-2-
yloxy) diphenylsilane (9)
(s, 3H, MeC), 1.29e1.19 (m, 12H, eCH2CH2e), 1.0 (s, 9H, t-BuSi), 0.88
(t, J¼6.8 Hz, 3H, MeCH2); 13C NMR (75 MHz, CDCl3)
d 158.8, 136.2,
135.8,134.7,133.2,130.5, 129.6, 129.3,129.1,127.4,127.2,113.4,107.8,
78.1, 77.7, 72.4, 72.3, 71.6, 55.2, 31.8, 29.8, 29.5, 29.1, 28.3, 27.0, 26.0,
25.9, 22.6, 19.3, 14.1; ESIMS (m/z) 636 (Mþ18)þ; ESIHRMS calcd for
C38H54O5NaSi 641.3638, found 641.3635.
To a solution of olefin (S)-11 (1.5 g, 3.36 mmol) in acetone/water
(8:2, 20 mL) NMO 50% aq solution (1.18 mL) followed by 0.004 M
OsO4 in t-BuOH solution (5 mL) were added and stirred it for 8 h at
room temperature. Then the reaction was quenched with solid
Na2SO3 and stirred it for 1 h at room temperature. The resultant
reaction mixture was filtered and concentrated under reduced
pressure. The resultant residue was dissolved in ethyl acetate,
water, and brine washes were given. The organic layer was dried
over dried Na2SO4, filtered, and concentrated under reduced pres-
sure. To this diol solution in dichloromethane (30 mL), NaIO4
(1.08 g, 5.04 mmol) adsorbed on silica gel was added at 0 ꢁC. The
resultant mixture was stirred at room temperature for 30 min, fil-
tered, and concentrated under reduced pressure afforded corre-
sponding aldehyde, which was used for next step without any
purification.
4.10. (R)-2-(tert-Butyldiphenylsilyloxy)-2-((4S,5S)-5-heptyl-2,
2-dimethyl-1,3-dioxolan-4-yl)ethanol (19)
To a stirred solution of 18 (640 mg, 1.04 mmol) in dichloro-
methane/water (19:1, 15 mL), DDQ (259 mg, 1.14 mmol) was added
at 0 ꢁC. The reaction mixture was stirred at 0 ꢁC to room temper-
ature for 1 h, and then reaction mixture was diluted with
dichloromethane (15 mL) and quenched with satd NaHCO3 solution
(15 mL). The organic layer was separated and aqueous layer was
extracted with dichloromethane (3ꢃ10 mL). The combined organic
layers were washed with brine (10 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. The resultant crude
residue was purified by silica gel column chromatography using
To a solution of octyltriphenylphosphonium bromide (3.06 g,
6.73 mmol) in THF (20 mL) n-BuLi (4 mL, 1.6 M in hexane) was
added at 0 ꢁC. After 5 min DMSO (5 mL) followed by aldehyde in
THF (5 mL) were added at same temperature. The resulting mixture
was stirred for 30 min at room temperature. After completion of
the reaction, water was added and extracted with ethyl acetate
(3ꢃ30 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The resultant
residue was purified by silica gel column chromatography using
hexane/ethyl acetate (97:3) as eluent to afford title compound 9 as
hexane/ethyl acetate (3:1) gave title compound 19 as a pale yellow
24
oil 445 mg (86%). [
a]
ꢀ2.0 (c 2.0, CHCl3); IR (neat) 3565, 2926,
D
2857, 2362, 1463, 1372, 1110, 1061, 703 cmꢀ1
CDCl3)
;
1H NMR (300 MHz,
d
7.67 (td, J¼7.9, 1.5 Hz, 4H, ArH), 7.47e7.36 (m, 6H, ArH),
4.24e4.10 (m, 2H, OCH, OCH), 3.81e3.76 (m, 1H, OCH), 3.71e3.66
(m, 2H, OCH2), 2.10 (t, J¼6.4 Hz, 1H, OH), 1.36 (s, 3H, MeC), 1.33 (s,
3H, MeC),1.29e1.11 (m,12H, eCH2CH2e),1.05 (s, 9H, t-BuSi), 0.89 (t,
J¼6.6 Hz, 3H, MeCH2); 13C NMR (75 MHz, CDCl3)
d 135.8, 135.6,
colorless oil 1.13 g (62% over three steps). [
a
]
24 ꢀ8.4 (c 3.7, CHCl3);
133.8, 132.9, 129.9, 127.8, 108.1, 79.6, 78.0, 71.8, 65.6, 31.8, 29.8, 29.7,
29.4, 29.1, 28.0, 26.9, 25.9, 25.8, 22.6, 19.2, 14.1; ESIMS (m/z) 521
(Mþ23)þ; ESIHRMS calcd for C30H46O4NaSi 521.3063, found
521.3044.
D
IR (neat) 3002, 2927, 2856, 2362, 2334, 1708, 1513, 1249, 1109, 821,
702 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.69e7.62 (m, 4H, ArH),
7.39e7.28 (m, 6H, ArH), 7.10 (t, J¼8.9 Hz, 2H, ArH), 6.78 (d, J¼7.9 Hz,
2H, ArH), 5.40e5.36 (m, 1H, CH]CH), 5.30e5.24 (m, 1H, CH]CH),
4.58 (q, J¼6.9 Hz, 1H, CH(CH)CH2O), 4.34 (s, 2H, OCH2Ar), 3.80 (s,
3H, MeOAr), 3.47e3.42 (m, 1H, OCHaHbCH), 3.31e3.26 (m, 1H,
OCHaHbCH), 1.31e1.14 (m, 2H, OCH2CH2), 1.10e1.05 (m, 19H,
eCH2CH2e, t-Bu), 0.88 (t, J¼6.9 Hz, 3H, CH3CH2); 13C NMR (75 MHz,
4.11. tert-Butyl((R)-1-((4S,5S)-5-heptyl-2,2-dimethyl-1,3-
dioxolan-4-yl)prop-2-ynyloxy)diphenylsilane (20)
To a solution of alcohol 19 (380 mg, 0.76 mmol) in dichloro-
methane (15 mL) was added DMP (488 mg, 1.14 mmol) at 0 ꢁC. The
resulting reaction mixture was stirred at room temperature for 1 h,
and then, reaction mixture was further diluted with dichloro-
methane (10 mL) and washed with satd NaHCO3, hypo, brine, and
dried over Na2SO4. The contents were filtered and concentrated
under reduced pressure. The resultant crude residue was passed
through a small plug of silica gel ether as eluent. Removal of the
ether solvent under reduced pressure afforded aldehyde. To a 0 ꢁC
solution of PPh3 (517 mg, 1.98 mmol) and Zn (50 mg, 0.76 mmol) in
CH2Cl2 (10 mL) was added CBr4 (328 mg, 0.99 mmol). The reaction
mixture was warmed to room temperature for 30 min and then
cooled back to 0 ꢁC. To this mixture was added above aldehyde in
CH2Cl2 (2 mL). The reaction mixture was stirred for 1 h and then
diluted with hexane (50 mL), upon which a white precipitate
formed (Ph3P]O). The slurry was passed through a small plug of
silica gel using hexane/ether (95:5) and concentrated. The residual
oil was dissolved in THF (10 mL), cooled to ꢀ78 ꢁC, and treated with
n-BuLi (1.2 mL 1.6 M hexane solution, 1.9 mmol). The reaction
mixture was stirred for 1 h and then quenched with satd NH4Cl
(5 mL) and extracted with EtOAc (3ꢃ5 mL). The organic phase was
washed with brine, dried over Na2SO4, filtered, and concentrated.
The resultant residue was purified by silica gel column chroma-
CDCl3)
d 158.9, 136.0, 135.9, 134.3, 132.1, 131.9, 130.6, 129.8, 129.4,
129.0, 127.3, 127.2, 113.5, 74.6, 72.7, 68.9, 55.2, 32.2, 31.7, 29.7, 29.4,
27.7, 26.9, 22.6, 19,3, 14.0; ESIMS (m/z) 566.8 (Mþ23)þ; ESIHRMS
calcd for C35H48O3NaSi 567.3265, found 567.3252.
4.9. tert-Butyl(R)-1-((4S,5S)-5-heptyl-2,2-dimethyl-1,3-
dioxolan-4-yl)-2-(4-methoxybenzyloxy)ethoxy-
diphenylsilane (18)
For dihydroxylation, compound 9 procedure described above
was followed. The resultant residue was passed through a small
plug of silica gel using hexane/ethyl acetate (1:1) as eluent to give
the diastereomeric mixture of alcohols (9:1). To this diastereomeric
mixture of alcohols and 2,2-dimethoxypropane in dichloro-
methane PTSA$H2O (35 mg, 0.18 mmol) was added at 0 ꢁC. The
resultant mixture was allowed to stir at 0 ꢁC to room temperature
for 3 h, and then solid NaHCO3 was added. This reaction mixture
was filtered and concentrated under reduced pressure. The re-
sultant residue was purified by silica gel column chromatography
using hexane/ethyl acetate (95:5) as eluent to obtain title com-
pound 18 as major diastereomer 0.84 g (74% over two steps). [a]
24
D
ꢀ18.4 (c 3.7, CHCl3); IR (neat) 2928, 2857, 2362, 1719, 1610, 1513,
1463, 1252, 1107, 702 cmꢀ1 1H NMR (300 MHz, CDCl3)
7.66 (t,
;
d
tography using hexane/ethyl acetate (98:2) as eluent to obtain title
24
J¼6.8 Hz, 4H, ArH), 7.43e7.27 (m, 6H, ArH), 6.96 (d, J¼8.3 Hz, 2H,
ArH), 6.77 (d, J¼9.1 Hz, 2H, ArH), 4.23 (dd, J¼8.3, 6.0 Hz, 1H,
OCHaHbAr), 4,18 (d, J¼11.3 Hz, 1H, OCHaHbAr), 4.15e4.10 (m, 1H,
CHCHaHbCH), 4.03 (d, J¼11.3 Hz, 1H, OCHaHbCH), 3.89e3.84
(m, 1H, OCHaHbCH), 3.79 (s, 3H, MeOAr), 3.53 (dd, J¼9.8, 2.3 Hz, 1H,
OCHCH), 3.45 (dd, J¼9.8, 5.3 Hz, 1H, OCHCH), 1.34 (s, 3H, MeC), 1.33
compound 20 292 mg (78% over three steps). [
a]
ꢀ14.7 (c 6.0,
D
CHCl3); IR (neat) 3620, 3305, 3069, 2928, 2858, 2362, 1464, 1373,
1216, 1107, 1074, 702 cmꢀ1 1H NMR (500 MHz, CDCl3)
;
d
7.72e7.70
(m, 4H, ArH), 7.41e7.33 (m, 6H, ArH), 4.39 (dd, J¼6.4, 2.7 Hz, 1H,
CHOSi), 4.13e4.09 (m, 2H, OCH, OCH), 2.19 (d, J¼1.8 Hz, 1H, HCC),
1.55e1.46 (m, 2H, CH2CH2), 1.42 (s, 3H, MeC), 1.33 (s, 3H, MeC),

268
G. Kumaraswamy, K. Sadaiah / Tetrahedron 68 (2012) 262e271
1.31e1.21 (m, 10H, eCH2CH2e), 1.08 (s, 9H, t-BuSi), 0.90 (t, J¼6.4 Hz,
3H, MeCH2); 13C NMR (75 MHz, CDCl3)
136.2, 135.8, 133.2, 133.0,
129.8, 129.6, 127.5, 127.2, 108.2, 82.5, 80.1, 77.7, 75.3, 63.2, 31.8, 29.5,
29.4, 29.1, 27.8, 26.9, 26.4, 25.6, 22.6, 19.3, 14.1; ESIMS (m/z) 515
(Mþ23)þ; ESIHRMS calcd for C31H44O3NaSi 515.2957, found
515.2952.
(m, 1H, OCHCH2), 3.53e3.47 (m, 2H, OCH2CH), 1.90e1.80 (m, 2H,
CH2CH]), 1.29e1.19 (m, 10H, eCH2CH2e), 0.88 (t, J¼6.0 Hz, 3H,
d
MeCH2); 13C NMR (75 MHz, CDCl3)
d 135.9,135.7, 135.5, 134.2, 133.9,
133.7,129.7, 129.6, 128.8, 127.6,127.4, 75.2, 67.0, 32.3, 32.1, 31.8, 29.1,
29.0, 28.8, 27.0, 26.8, 22.6, 19.3, 14.1; ESIMS (m/z) 447 (Mþ23)þ;
ESIHRMS calcd for C27H40O2NaSi 447.2695, found 447.2686.
4.12. (R)-1-((4R,5S)-5-Heptyl-2,2-dimethyl-1,3-dioxolan-4-yl)
4.15. (S,E)-tert-Butyl(dodec-4-en-1-yn-3-yloxy)
prop-2-yn-1-ol (7)
diphenylsilane (26)
To a solution of 20 (275 mg, 0.56 mmol) in THF (10 mL), TBAF
1 M in THF (0.62 mL) was added at 0 ꢁC. The reaction mixture was
warmed to room temperature for 2 h, and then solvent was re-
moved under reduced pressure and purified by silica gel column
To a solution of oxalyl chloride (0.94 mL, 10.88 mmol) in
dichloromethane (15 mL) was added DMSO (1.6 mL, 21.75 mmol) in
dichloromethane (3 mL) at ꢀ78 ꢁC. The resulting reaction mixture
was stirred at same temperature for 15 min, and then, alcohol 25
(1.54 g, 3.62 mmol) in dichloromethane (15 mL) was added. After
45 min reaction mixture was quenched with triethylamine (5 mL,
36.25 mmol) and allowed to room temperature for 45 min. The
resultant reaction mixture was further diluted with dichloro-
methane (30 mL) and washed with water and brine and dried over
Na2SO4. The contents were filtered and concentrated under re-
duced pressure. The resultant crude residue was passed through
a small plug of silica gel hexane/ether (9:1) as eluent. Removal of
the solvent under reduced pressure afforded aldehyde.
chromatography using hexane/ethyl acetate (9:1) as eluent to ob-
24
tain title compound 7 134 mg (94%). [
a
]
þ35.2 (c 1.5, CHCl3); IR
D
(neat) 3442, 3308, 2926, 2858, 2362, 1516, 1375, 1249, 1052, 868,
656 cmꢀ1 1H NMR (500 MHz, CDCl3)
;
d
4.34e4.30 (m, 1H, OCH),
4.16 (dt, J¼9.9, 5.9 Hz, 1H, OCH), 4.04 (t, J¼5.9 Hz, 1H, OCH), 2.45 (d,
J¼2.0 Hz, 1H, HCC), 2.03 (d, J¼7.0 Hz, 1H, OH), 1.74e1.68 (m, 2H,
2(OH)), 1.49 (s, 3H, MeC), 1.35 (s, 3H, MeC), 1.34e1.27 (m, 10H,
eCH2CH2e), 0.90 (t, J¼7.0 Hz, 3H, MeCH2); 13C NMR (75 MHz,
CDCl3) d 108.4, 82.8, 79.6, 77.4, 74.8, 62.1, 31.7, 29.5, 29.2, 28.8, 27.4,
26.9, 25.3, 22.6, 14.0; ESIMS (m/z) 277 (Mþ23)þ; ESIHRMS calcd for
To install acetylene functionality, compound 20 procedure de-
24
C15H26O3Na 277.1779, found 277.1790.
scribed above was followed (74% over three steps). [
a
]
(c 1.5,
D
CHCl3); IR (neat) 3305, 3068, 2927, 2857, 2362, 1465, 1428, 1107,
4.13. (S,E)-1-(4-Methoxybenzyloxy)undec-3-en-2-ol (10)
1051, 701 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
7.76e7.64 (m, 4H,
ArH), 7.44e7.31 (m, 6H, ArH), 5.60e5.45 (m, 2H, CH]CH), 4.74 (dd,
J¼5.3, 2.3 Hz, 1H, HCOSi), 2.37 (d, J¼2.3 Hz, 1H, HCC), 1.98 (q,
J¼6.0 Hz, 2H, CH2C]), 1.37e1.39 (m, 10H, eCH2CH2e), 1.14e1.06
(m, 12H, t-BuSi), 0.91 (t, J¼6.0 Hz, 3H, MeCH2); 13C NMR (75 MHz,
To a solution of allyl alcohol (S)-11 (0.2 g, 0.96 mmol) and 1-
nonene (0.75 mL, 4.81 mmol) in dichloromethane (10 mL) was
added Grubbs second generation catalyst (0.082 g, 0.096 mmol).
The reaction mixture was heated at reflux for 24 h. The reaction
mixture was concentrated and purified silica gel column chroma-
tography using hexane as using hexane/ethyl acetate (8:1) as eluent
CDCl3)
d 136.0, 135.9, 135.8, 113.5, 133.3, 133.0, 129.7, 129.4, 129.0,
127.5, 84.0, 73.2, 64.4, 31.8, 29.1, 29.0, 28.9, 27.0, 26.8, 25.6, 22.6,
19.3, 14.1; ESIMS (m/z) 441 (Mþ23)þ; ESIHRMS calcd for
C28H38ONaSi 441.2584, found 441.2578.
to obtain title compound 10 as brown oil 0.238 g (81%). [
a]
24 þ7.2 (c
D
2.7, CHCl3); IR (neat) 3449, 2925, 2856, 2362, 2334, 1710, 1610, 1513,
1249, 1103, 1034, 822 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
7.21 (d,
4.16. (3R,4R,5S)-Dodec-1-yne-3, 4, 5-triol (8)
J¼8.8 Hz, 2H, ArH), 6.83 (d, J¼8.8 Hz, 2H, ArH), 5.72 (quintet, J¼14.6,
5.8 Hz, 1H, CH]CH), 5.37 (dd, J¼15.6, 6.8 Hz, 1H, CH]CH), 4.48 (d,
J¼2.0 Hz, 2H, OCH2Ar), 4.25e4.22 (m, 1H, OCHCH2), 3.80 (s, 3H,
MeOAr), 3.42 (dd, J¼9.8, 2.9 Hz, 1H, OCHaHbCH), 3.26 (t, J¼8.8 Hz,
1H, OCHaHbCH), 2.29 (br s,1H, OH), 2.02 (q, J¼5.8 Hz, 2H, CH2CH]),
1.38e1.27 (m, 10H, eCH2CH2e), 0.89 (t, J¼6.8 Hz, 3H, MeCH2); 13C
To a solution of 26 (540 mg,1.77 mmol) in THF (20 mL) TBAF 1 M
in THF (2.0 mL) was added at 0 ꢁC. The reaction mixture was
warmed to room temperature for 2 h, and then solvent was re-
moved under reduced pressure. The resultant residue was passed
through a small plug of silica gel hexane/ether (9:1) as eluent. Re-
moval of the solvent under reduced pressure afforded allyl alcohol.
NMR (75 MHz, CDCl3)
d 159.2, 134.0, 129.3, 127.9, 125.1, 113.8, 74.1,
72.9, 71.3, 55.2, 36.7, 32.3, 31.8, 29.1, 29.0, 22.6, 14.0; ESIMS (m/z)
329 (Mþ23)þ; ESIHRMS calcd for C19H30O3NaSi 329.2092, found
329.2098.
To a stirred solution of AD-mix-a (2.5 g, 2.48 mmol) and
methane sulphonamide (165 mg, 1.77 mmol) in t-BuOH/H2O (1:1,
18 mL) was added olefin in t-BuOH at 0 ꢁC. The resultant reaction
mixture was stirred for 48 h at same temperature. The reaction was
quenched by addition of sodium sulphite, and stirred for another
1 h at room temperature. This mixture was extracted with extrac-
ted with EtOAc (3ꢃ15 mL). The organic phase was washed with
brine, dried over Na2SO4, filtered, and concentrated. The resultant
residue was passed through small plug of silica gel using ethyl ac-
etate as eluent to give the diastereomeric mixture of alcohols.
Solvent was removed under reduced pressure. To this di-
astereomeric mixture of alcohols in DCM (15 mL), Et3N (0.99 mL,
7.08 mmol) followed by Ac2O (0.33 mL, 3.54 mmol) were added at
0 ꢁC. The resulting mixture was stirred 0 ꢁC to room temperature
for 1 h. Then the reaction was quenched with water (10 mL). The
organic layer was separated and aqueous layer was extracted with
dichloromethane (2ꢃ15 mL). The combined organic layers were
washed with brine (30 mL), dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The resultant acetyl protected
diastereomers were separated by silica gel column chromatography
using hexane/ethyl acetate (8:1) as eluent to obtain triacetate
190 mg (major)þ63 mg (minor) (42% over three steps). To the
4.14. (S,E)-2-(tert-Butyldiphenylsilyloxy)undec-3-en-1-ol (25)
For TBDPS protection, compound 16 procedure described above
was followed. For MPM deprotection, compound 18 procedure
described above was followed.
The resultant residue was dissolved in anhydrous methanol
(20 mL), then temperature was lowered to 0 ꢁC, followed by addi-
tion of NaBH4 (0.19 g, 4.9 mmol). After 30 min, reaction was
quenched with water and methanol was removed under reduced
pressure. The aqueous layer was extracted with ethyl acetate
(4ꢃ50 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The resultant
residue was purified by silica gel column chromatography using
hexane/ethyl acetate (25:1) as eluent to obtain title compound 25
24
as pale yellow oil 1.8 g (95% over three steps). [
a]
þ38.7 (c 3.5,
D
CHCl3); IR (neat) 3575, 3067, 2926, 2857, 2362, 1464, 1108, 965,
701 cmꢀ1 1H NMR (500 MHz, CDCl3)
7.68e7.66 (m, 4H, ArH),
7.44e7.33 (m, 6H, ArH), 5.37 (q, J¼2.3 Hz, 2H, CH]CH), 4.23e4.17
;
d

G. Kumaraswamy, K. Sadaiah / Tetrahedron 68 (2012) 262e271
269
solution of major triacetate (190 mg, 0.56 mmol) in methanol
4.21. (S)-(5-Bromopent-1-en-4-yn-3-yloxy)(tert-butyl)
dimethylsilane ((S)-6)
(5 mL) K2CO3 (116 mg, 0.84 mmol) was added in one portion at
room temperature, and the solution was stirred at 45 ꢁC for 1.5 h.
After the solution was cooled to room temperature, a cold satd
NH4Cl solution (5 mL) was added to the solution, and the resulting
mixture was extracted with EtOAc (3ꢃ5 mL). The organic layer was
washed with brine, dried over Na2SO4, and solvent was removed
under reduced pressure. The residue was purified by silica gel
column chromatography using hexane/ethyl acetate (3:1) as eluent
To a solution of alcohol (S)-23 (0.65 g, 4.22 mmol) and imidazole
(0.63 g, 9.3 mmol) in dichloromethane (20 mL) TBSCl (0.7 g,
4.64 mmol) was added at 0 ꢁC. The resultant reaction mixture was
stirred at 0 ꢁC to room temperature for 2 h. Then the reaction was
quenched with water (20 mL). The organic layer was separated and
aqueous layer was extracted with dichloromethane (2ꢃ15 mL). The
combined organic layers were washed with brine (30 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The resultant residue was passed through small plug of silica gel
using hexane as eluent and the solvent was distilled off under at-
mospheric pressure gave TBS protected alcohol as colorless oil. The
solution of TBS-ether in acetone (20 mL) was treated with N-bromo
succinimide (1.19 g, 6.33 mmol) and catalytic AgNO3 (0.143 g,
0.84 mmol). The reaction mixture was stirred at room temperature
for 1 h. The mixture was diluted with cold water and extracted with
Et2O (2ꢃ20 mL). The combined organic layers were dried (Na2SO4),
concentrated under reduced pressure, and purified by silica gel
to obtain desired alcohol 8 as colorless oil 103 mg (86%). [
(c 1.4, CHCl3); IR (neat) 3372, 3307, 2925, 2856, 2362, 2117, 1708,
a
]
24 ꢀ10.3
D
1459, 1067 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
4.43 (dd, J¼5.8,
1.9 Hz, 1H, OCH), 3.79 (t, J¼5.5 Hz, 1H, OCH), 3.48 (dd, J¼6.2, 1.5 Hz,
1H, OCH), 2.49 (d, J¼2.1 Hz, 1H, HCC), 1.63e1.49 (m, 2H, OHCeCH2),
1.36e1.26 (m, 10H, eCH2CH2e), 0.89 (t, J¼7.0 Hz, 3H, MeCH2); 13C
NMR (75 MHz, CDCl3)
d 82.1, 75.9, 74.7, 71.3, 64.1, 34.0, 31.8, 29.5,
29.2, 25.6, 22.6, 14.0; ESIMS (m/z) 237 (Mþ23)þ; ESIHRMS calcd for
C12H22O3Na 237.1461, found 237.1463.
4.17. (S)-5-(Trimethylsilyl)pent-1-en-4-yn-3-ol ((S)-23)
column chromatography using hexane/ethyl acetate (98:2) as elu-
ent to obtain title compound (S)-6 1.07 g (92% over two steps). [a]
24
D
To a stirred suspension of Lipase PS (0.545 g, 0.3 mass equiv),
ꢀ
ꢀ19.5 (c 2.0, CHCl3); IR (neat) 3418, 2933, 2858, 2363, 2179, 1706,
1623, 1255, 1085, 839 cmꢀ1; 1H NMR (300 MHz, CDCl3)
5.88 (ddd,
ground, activated 4 A molecular sieves (2 g, 1.0 mass equiv), and
d
racemic alcohol (ꢂ)-23 (2 g, 12.99 mmol) in dry hexane (100 mL)
was added vinylacetate (6.0 mL, 64.95 mmol) in one portion. The
suspension was allowed to stir under N2, at room temperature for
3.5 h, and the progress of the reaction was monitored by TLC
analysis. When the amount of the acetate was about the same as
the amount of the alcohol, the reaction was stopped. At the end of
this period, the mixture was filtered through a pad of Celite, and
evaporated to dryness under reduced pressure. The crude mixture
following flash chromatography gave (R)-acetate, (R)-23 (eluent: 3%
Et2O/hexane) 0.9 g (35%), and alcohol (S)-23 (eluent: 10% Et2O/
J¼15.1, 10.2, 5.1 Hz,1H, CH]), 5.38 (dt, J¼16.9, 3.2 Hz, 1H, CHaHb]),
5.16 (dt, J¼10.0, 1.1 Hz, 1H, CHaHb]), 4.90 (dt, J¼4.9, 1.5 Hz, 1H,
CHOSi), 1.65 (br s, 1H), 0.92 (s, 9H, t-BuSi), 0.14 (s, 3H, MeSi), 0.13 (s,
3H, MeSi); 13C NMR (75 MHz, CDCl3)
d 137.1, 115.2, 79.6, 64.5, 45.5,
25.7, 18.3, ꢀ4.7, ꢀ4.9.
4.22. (R)-(5-Bromopent-1-en-4-yn-3-yloxy)(tert-butyl)
dimethylsilane ((R)-6)
24 þ35.4 (c 3.0, CHCl3); IR
For deacetylation, compound 8 procedure described above was
followed. For TBS protection and acetylinic bromination, (S)-6
procedure described above was followed (78% over three steps).
hexane) 0.72 g (36%) as colorless oils. [
a
]
D
(neat) 3330, 2960, 2173, 1645, 1407, 1251, 986, 759 cmꢀ1
;
1H NMR
(500 MHz, CDCl3)
d
5.96 (ddd, J¼15.1, 9.8, 5.3 Hz,1H, CH]), 5.50 (dt,
[a
]
24 þ21.3 (c 2.0, CHCl3) for spectroscopic data, see (S)-6.
D
J¼16.6, 1.5 Hz, 1H, CHaHb]), 5.22 (dt, J¼9.8, 1.5 Hz, 1H, CHaHb]),
4.90e4.84 (m, 1H, OCHCH), 2.04e1.99 (m, 1H, OH), 0.18 (s, 9H,
Me3Si); 13C NMR (75 MHz, CDCl3)
d 136.6, 116.5, 104.0, 91.1, 63.4,
4.23. Typical experimental procedure for
CadioteChodkiewicz coupling
ꢀ0.3.
To a solution of CuCl (0.1 mmol), NH2OH$HCl (0.5 mmol), and
alkyne (1 mmol) in methanol (3 mL), bromoalkyne (1.2 mmol) in
methanol (3 mL) was added over 10 min at 0 ꢁC. The resulting re-
action mixture was warmed to ambient temperature (1 h). The
reaction mixture was quenched by water, and then methanol was
removed under reduced pressure. Aqueous layer was extracted
with ethyl acetate (3ꢃ5 mL). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated. The
resulting residue was purified by silica gel column chromatography
using hexane/ethyl acetate as eluent to obtain diyne.
4.18. (S)-((S)-5-(Trimethylsilyl)pent-1-en-4-yn-3-yl)3,3,3-
trifluoro-2-methoxy-2-phenylpropanoate
1H NMR (500 MHz, CDCl3)
d 7.56e7.54 (m, 2H, ArH), 7.42e7.37
(m, 3H, ArH), 6.08 (d, J¼5.5 Hz, 1H, HCO2C), 5.85 (ddd, J¼17.3, 10.0,
5.5 Hz, 1H, CH]), 5.53 (d, J¼16.4 Hz, 1H, CHaHb]), 5.33 (d,
J¼10.0 Hz, 1H, CHaHb]), 3.60 (s, 3H, OMe), 0.19 (s, 9H, Me3Si).
4.19. (R)-5-(Trimethylsilyl)pent-1-en-4-yn-3-yl acetate ((R)-23)
24
[
a]
ꢀ10.34 (c 1.4, CHCl3); IR (neat) 2928, 2856, 2362, 2180,
D
4.23.1. (1R,6S)-6-(tert-Butyldimethylsilyloxy)-1-((4R,5S)-5-heptyl-
1745, 1464, 1368, 1225, 1099, 841, 771 cmꢀ1
;
1H NMR (300 MHz,
2,2-dimethyl-1,3-dioxolan-4-yl)octa-7-en-2,4-diyn-1-ol
(24). The
CDCl3) 5.91e5.80 (m, 2H, CH], CHO2C), 5.56e5.48 (m, 1H,
d
above typical procedure was used for CadioteChodkiewicz cou-
24
CHaHb]), 5.34e5.27 (m, 1H, CHaHb]), 2.10 (s, 3H, MeCO), 0.19 (s,
pling with (S)-6 and 7 to obtain 24 (52% yield). [
CHCl3); IR (neat) 3443, 2928, 2858, 2362, 1740, 1693, 1516, 1463,
1374, 1255, 1064, 840 cmꢀ1; 1H NMR (300 MHz, CDCl3)
5.86 (ddd,
a
]
þ5.7 (c 1.4,
D
9H, Me3Si); 13C NMR (75 MHz, CDCl3)
d 169.5, 132.8, 118.9, 100.0,
92.3, 64.4, 21.0, ꢀ0.3.
d
J¼15.1, 9.8, 5.3 Hz, 1H, CH]), 5.38 (d, J¼16.6 Hz, 1H, CHaHb]), 5.17
(d, J¼9.8 Hz, 1H, CHaHb]), 4.93 (d, J¼5.3 Hz, 1H, HCOSi), 4.41 (t,
J¼5.3 Hz, 1H, HCO), 4.23e4.17 (m, 1H, HCO), 4.10 (t, J¼5.3 Hz, 1H,
HCO), 1.77e1.65 (m, 2H, OeCCH2), 1.51 (s, 3H, MeC), 1.36 (s, 3H,
MeC), 1.33e1.21 (m, 10H, eCH2CH2e), 0.94e0.84 (m, 12H, t-BuSi,
MeCH2), 0.14 (s, 3H, MeSi), 0.12 (s, 3H, MeSi); 13C NMR (75 MHz,
4.20. (R)-((R)-Pent-1-en-4-yn-3-yl)3,3,3-trifluoro-2-methoxy-
2-phenylpropanoate
1H NMR
d 7.74e7.48 (m, 2H, ArH), 7.40e7.36 (m, 3H, ArH),
6.06e6.03 (m, 1H, CHO2C), 5.86 (ddd, J¼16.8, 10.0, 5.48 Hz, 1H,
CH]), 5.54 (d, J¼17 Hz, 1H, CHaHb]), 5.34 (d, J¼10.0 Hz, 1H,
CHaHb]), 3.59 (s, 3H, MeO), 2.60 (d, J¼2.1 Hz, 1H, HCC).
CDCl3)
d 136.6, 115.6, 108.6, 79.7, 79.0, 78.0, 77.3, 70.9, 69.4, 64.0,
63.0, 31.8, 29.7, 29.6, 29.2, 28.8, 27.3, 27.0, 25.7, 25.3, 22.6, 18.3, 14.1,

270
G. Kumaraswamy, K. Sadaiah / Tetrahedron 68 (2012) 262e271
ꢀ4.6, ꢀ4.9; ESIMS (m/z) 466 (Mþ18)þ; ESIHRMS calcd for
10.6, 5.8 Hz, 1H, CH]), 5.38 (d, J¼17.4 Hz, 1H, CHaHb]), 5.19
(d, J¼10.6 Hz, 1H, CHaHb]), 4.90 (d, J¼4.8 Hz, 1H, HCOH), 4.56
(d, J¼3.9 Hz,1H, HCOH), 3.48e3.44 (m, 1H, HCOH), 3.38 (t, J¼3.9 Hz,
1H, HCOH), 1.71e1.68 (m, 1H, OeCCH2), 1.50e1.44 (m, 1H, OeCCH2),
1.36e1.24 (m, 10H, eCH2CH2e), 0.89 (t, J¼5.8 Hz, 3H, MeCH2); 13C
C26H44O4NaSi 471.2906, found 471.2884.
4.23.2. (1R,6R)-6-(tert-Butyldimethylsilyloxy)-1-((4R,5S)-5-heptyl-2,
2-dimethyl-1,3-dioxolan-4-yl)octa-7-en-2,4-diyn-1-ol
(28). The
above typical procedure was used for CadioteChodkiewich cou-
NMR (MHz, D3CCN)
d 137.8, 116.7, 80.6, 79.4, 77.8, 72,9, 69.9, 69.7,
24
pling with (R)-6 and 7 to obtain 28 (52% yield). [
CHCl3); IR (neat) 3396, 2892, 2858, 2362, 1740, 1634, 1516, 1463,
1374, 1255, 840, 680 cmꢀ1; 1H NMR (300 MHz, CDCl3)
5.86 (ddd,
a
]
þ45.6 (c 1.1,
65.6, 63.5, 34.2, 32.7, 30.5, 30.1, 26.0, 23.5, 14.5; ESIMS (m/z) 317
D
(Mþ23)þ; ESIHRMS calcd for C17H26O4Na 317.1728, found 317.1717.
d
J¼15.1, 10.0, 4.9 Hz, 1H, CH]), 5.38 (d, J¼17.0 Hz, 1H, CHaHb]), 5.17
(d, J¼10.0 Hz, 1H, CHaHb]), 4.94 (d, J¼4.5 Hz, 1H, HCO), 4.44e4.37
(m, 1H, HCO), 4.23e4.17 (m, 1H, HCO), 4.10 (t, J¼4.9 Hz, 1H, HCO),
1,77e1.57 (m, 2H, OeCCH2), 1.51 (s, 3H, MeC), 1.36 (s, 3H, MeC),
1.34e1.25 (m, 10H, eCH2CH2e), 0.94e0.86 (m, 12H, t-BuSi, MeCH2),
0.14 (s, 3H, MeSi), 0.12 (s, 3H, MeSi); 13C NMR (75 MHz, CDCl3)
4.24.2. (3R,8R,9S,10S)-Heptadeca-1-en-4,6-diyne-3,8,9,10-tetraol
(5b). The above typical procedure was used for the deprotection of
TBS and acetonide groups of 28 to give 5b (85% yield). [
0.3, MeOH); IR (neat) 3356, 2913, 2855, 1688, 1528, 1461, 1071, 1022,
a
]
24 ꢀ38.6 (c
D
780 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
5.93 (ddd, J¼16.2, 10.4,
4.6 Hz, 1H, CH]), 5.47 (d, J¼17.4 Hz, 1H, CHaHb]), 5.26 (d,
J¼10.4 Hz, 1H, CHaHb]), 5.13e5.10 (m, 1H, OH), 4.95e4.92 (m, 1H,
HCOH), 4.70 (br s, 1H, HCOH), 3.75e3.69 (m, 1H, HCOH), 3.63e3.57
(m, 1H, HCOH), 1.54e1.46 (m, 2H, OeCCH2), 1.40e1.20 (m, 10H,
eCH2CH2e), 0.88 (t, J¼6.9 Hz, 3H, MeCH2); 13C NMR (MHz, CDCl3)
d
136.6, 115.7, 108.6, 79.8, 79.5, 79.0, 78.0, 77.3, 69.4, 64.0, 63.1, 31.8,
29.7, 29.6, 29.2, 28.9, 27.3, 27.0, 25.7, 22.6, 18.3, 14.1; ESIMS (m/z)
466 (Mþ18)þ; ESIHRMS calcd for C26H44O4NaSi 471.2906, found
471.2892.
d
135.6, 117.4, 81.9, 78.3, 76.0, 73.2, 70.8, 68.1, 64.9, 63.3, 33.5, 31.8,
4.23.3. (3S,8R,9R,10R)-3-(tert-Butyldimethylsilyloxy)heptadeca-1-
en-4, 6-diyne-8,9,10-triol (27). The above typical procedure was
used for CadioteChodkiewicz coupling with (S)-6 and 8 to obtain
29.6, 29.2, 25.3, 22.6, 14.0; ESIMS (m/z) 317 (Mþ23)þ; ESIHRMS
calcd for C17H26O4Na 317.1728, found 317.1733.
27 (58% yield). [
a]
24 ꢀ22.9 (c 1.0, CHCl3); IR (neat) 3352, 2926, 2857,
4.24.3. (3S,8R,9R,10S)-Heptadeca-1-en-4,6-diyne-3,8,9,10-tetraol
(5c). The above typical procedure was used for the deprotection of
D
1742, 1462, 1068, 968, 724 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
5.86
(ddd, J¼15.1, 9.8, 5.3 Hz,1H, CH]), 5.38 (d, J¼16.6 Hz,1H, CHaHb]),
5.18 (d, J¼9.8 Hz, 1H, CHaHb]), 4.93 (d, J¼5.3 Hz, 1H, HCO), 4.54 (d,
J¼6.0 Hz, 1H, HCO), 3.80 (td, J¼6.0, 1.5 Hz, 1H, HCO), 3.53 (dd, J¼6.0,
2.3 Hz, 1H, HCO), 1.67e1.51 (m, 2H, OeCCH2), 1.33e1.22 (m, 10H,
eCH2CH2e), 0.95e0.86 (m, 12H, t-BuSi, MeCH2), 0.14 (s, 3H, MeSi),
TBS group of 27 to obtain 5c (85% yield). [
a
]
24 þ24.5 (c 1.2, MeOH);
D
IR (neat) 3336, 2923, 2855, 2362, 1693, 1515, 1461, 1071, 1020 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
5.94 (ddd, J¼16.8, 9.9, 5.0 Hz, 1H,
CH]), 5.47 (d, J¼17.8 Hz, 1H, CHaHb]), 5.26 (d, J¼9.9 Hz,
1H, CHaHb]), 4.94 (d, J¼5.0 Hz, 1H, HCOH), 4.56 (d, J¼6.0 Hz, 1H,
HCOH), 3.82e3.79 (m, 1H, HCOH), 3.53 (d, J¼4.0 Hz, 1H, HCOH),
1.64e1.51 (m, 2H, OeCCH2), 1.36e1.26 (m, 10H, eCH2CH2e), 0.88 (t,
0.12 (s, 3H, MeSi); 13C NMR (75 MHz, CDCl3)
d 136.5,115.7, 77.4, 77.2,
77.0, 76.5, 75.7, 71.2, 64.8, 63.9, 34.1, 31.7, 29.6, 29.4, 29.1, 25.6, 25.5,
22.6, 14.0, ꢀ4.7, ꢀ5.0; ESIMS (m/z) 431 (Mþ23)þ; ESIHRMS calcd for
C23H40O4NaSi 431.2593, found 431.2599.
J¼6.9 Hz, 3H, MeCH2). 13C NMR (MHz, CDCl3)
d 135.7, 117.3, 78.6,
78.1, 71.4, 70.3, 70.0, 64.6, 63.1, 33.9, 31.8, 29.6, 29.3, 25.7, 22.7, 14.1;
ESIMS (m/z) 317 (Mþ23)þ; ESIHRMS calcd for C17H26O4Na 317.1728,
found 317.1717.
4.23.4. (3R,8R,9R,10S)-3-(tert-Butyldimethylsilyloxy)heptadeca-1-
en-4,6-diyne-8,9,10-triol (29). The above typical procedure was
used for CadioteChodkiewicz coupling with (R)-6 and 8 to obtain
4.24.4. (3R,8R,9R,10S)-Heptadeca-1-en-4,6-diyne-3,8,9,10-tetraol
(5d). The above typical procedure was used for the deprotection of
24
29 (58% yield). [
a
]
D
þ2 (c 3.0, CHCl3); IR (neat) 3391, 2926, 2857,
1719, 1462, 1255, 1068, 839, 780 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
TBS group of 29 to obtain 5d (85% yield). [
a
]
24 ꢀ32.6 (c 0.6, MeOH);
D
d
5.86 (ddd, J¼14.8, 9.9, 5.0 Hz, 1H, CH]), 5.38 (d, J¼16.8 Hz, 1H,
IR (neat) 3352, 2923, 2858, 2362, 1663, 1518, 1418, 1081, 1033 cmꢀ1
;
CHaHb]), 5.17 (d, J¼10.9 Hz, 1H, CHaHb]), 4.93 (d, J¼5.0 Hz, 1H,
HCO), 4.53 (d, J¼5.9 Hz, 1H, HCO), 3.80 (t, J¼6.0 Hz, 1H, HCO), 3.52
(dd, J¼6.0, 2.0 Hz, 1H, HCO), 2.84 (br.s, 2H, OH), 1.64e1.53 (m, 2H,
OeCCH2), 1.36e1.25 (m, 10H, eCH2CH2e), 0.94e0.87 (m, 12H, t-
BuSi, MeCH2), 0.14 (s, 3H, MeSi), 0.12 (s, 3H, MeSi); 13C NMR
1H NMR (300 MHz, D3CCN)
d
5.91 (ddd, J¼15.7, 10.2, 5.5 Hz, 1H,
CH]), 5.38 (d, J¼17.2 Hz, 1H, CHaHb]), 5.19 (d, J¼10.0 Hz, 1H,
CHaHb]), 4.89 (m, 1H, HCOH), 4.39 (d, J¼5.8 Hz, 1H, HCOH),
3.75e3.72 (m, 1H, HCOH), 3.66e3.62 (m, 1H, HCOH), 3.37e3.35 (m,
1H, OH), 2.80 (br s, 1H, OH), 1.54e1.43 (m, 2H, OeCCH2), 1.36e1.23
(m, 10H, eCH2CH2e), 0.89 (t, J¼6.8 Hz, 3H); 13C NMR (MHz, D3CCN)
(75 MHz, CDCl3) d 136.5, 115.7, 79.3, 77.3, 75.8, 71.3, 70.5, 69.0, 64.8,
64.0, 34.1, 31.8, 29.7, 29.5, 29.2, 25.7, 25.6, 22.6, 14.1, ꢀ4.6, ꢀ5.0;
ESIMS (m/z) 431 (Mþ23)þ; ESIHRMS calcd for C23H40O4NaSi
431.2593, found 431.2582.
d 137.7, 116.6, 80.2, 79.9, 76.8, 71.5, 69.5, 69.4, 65.0, 63.3, 34.6, 32.5,
30.1, 29.9, 26.3, 23.3, 14.3; ESIMS (m/z) 317 (Mþ23)þ; ESIHRMS
calcd for C17H26O4Na 317.1728, found 317.1714.
4.24. Typical experimental procedure for deprotection of
acetonide and TBS group
Acknowledgements
To a methanolic (5 mL) solution of starting material (1 mmol)
was added PTSA$H2O (0.2 mmol) at 0 ꢁC. The resulting reaction
mixture was warmed to ambient temperature (1 h), and then solid
NaHCO3 (excess) was added, followed by silica adsorption and
purified by silica gel column chromatography using hexane/ethyl
acetate (6:4) as eluent to give tetraol.
We are grateful to Dr. J.S. Yadav, Director, IICT, for his constant
encouragement. Financial support was provided by the DST, New
Delhi, India (Grant No: SR/SI/OC-12/2007). CSIR (New Delhi) is
gratefully acknowledged for awarding the fellowship to K.S. Thanks
is also due to Dr. G.V.M. Sharma, Head, Organic III Division, for his
support.
4.24.1. (3S,8R,9S,10S)-Heptadeca-1-en-4,6-diyne-3,8,9,10-tetraol
(5a). The above typical procedure was used for the deprotection of
Supplementary data
24
TBS and acetonide groups of 24 to give 5a (85% yield). [
a
]
þ9.6
D
(c 1.4, MeOH); IR (neat) 3368, 2920, 2855, 1693, 1509, 1455, 1091,
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2011.10.058.
1020, 810 cmꢀ1 1H NMR (500 MHz, D3CCN)
;
d
5.91 (ddd, J¼17.4,

G. Kumaraswamy, K. Sadaiah / Tetrahedron 68 (2012) 262e271
271
the target compound (S)-11 and unprotected 10. Eventually, we have adopted
reduction/oxidation protocol.
References and notes
12. In order to estimate the ee, the 14 was converted as (R)-MTPA ester. The 1H
NMR analysis of (R)-MTP ester in comparison with the racemic (R)-MTPA ester
showed w97% ee, See Supplementary data.
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11. We have also attempted to capture the aminioxylated aldehyde by Wittig re-
action under various conditions. Regrettably, we could not succeed to generate