Organocatalytic enantioselective synthesis of 1,3,5-polyols by means of iterative asymmetric epoxidation: Their application to the total synthesis of polyrhacitide A

Article abstract of DOI:10.1016/j.tet.2012.02.055

We have developed a pragmatic route to the stereogenic skipped 1,3,5-polyols. The strategic transformation includes an organocatalytic enantioselective asymmetric epoxidation, which is either syn- or anti-selective as genesis of chirality and successive S_N2 opening reaction by an appropriate functionalized nucleophile, followed by hydroboration/oxidation to generate stereoisomers in good yield. The critical intermediate generated en route to this process is employed in the total synthesis of polyrhacitide A.

Full text of DOI:10.1016/j.tet.2012.02.055

Tetrahedron 68 (2012) 3179e3186
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Tetrahedron
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Organocatalytic enantioselective synthesis of 1,3,5-polyols by means of iterative
asymmetric epoxidation: their application to the total synthesis of polyrhacitide A
,
a,
Gullapalli Kumaraswamya , Akula Narayana Murthy b, Kadivendi Sadaiah a
*
a Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b An Associate Institution of University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 January 2012
Received in revised form 20 February 2012
Accepted 22 February 2012
Available online 27 February 2012
We have developed a pragmatic route to the stereogenic skipped 1,3,5-polyols. The strategic trans-
formation includes an organocatalytic enantioselective asymmetric epoxidation, which is either syn- or
anti-selective as genesis of chirality and successive SN2 opening reaction by an appropriate functionalized
nucleophile, followed by hydroboration/oxidation to generate stereoisomers in good yield. The critical
intermediate generated en route to this process is employed in the total synthesis of polyrhacitide A.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
enantioselective organocatalytic MacMillan asymmetric epoxida-
tion protocol for the synthesis of enantiomerically pure terminal
1,3-Polyol is a distinctive array of functionality that exemplifies
in a wide range of natural products.1 The diversified stereogenic
skipped 1,3-polyol possessing bioactive molecules exhibit a broad
range of therapeutical properties.2 A plethora of synthetic strate-
gies have been developed for 1,3-syn and 1,3-anti polyol function-
alities and are subsequently utilized for the synthesis of 1,3-polyol
motif present in natural products. So far, the genesis of chirality for
these synthetic strategies has either been from the chiral pool,3 or
initiated through catalytic asymmetric transformations.4 Notable
among the representative catalytic asymmetric reactions there
were (a) Jacobsen’s hydrolytic kinetic resolution of racemic termi-
nal epoxides,5 (b) Cr-mediated catalytic asymmetric allylation,6 (c)
epoxide.13 Further, we envisaged that the stereo divergent 1,3-
polyol, which is either syn- or anti-selective could be synthesized
from a reactive intermediate of corresponding enantiomerically
pure terminal epoxide and successive SN2 opening reaction by an
appropriate functionalized nucleophile, to generate a functionality,
which enables to execute the next iteration.
2. Results and discussion
Accordingly, exposure of nonanal 1 to organocatalyzed asym-
metric epoxidation conditions provided the terminal epoxide 2 in
90% yield. To install the second stereogenic centre, the epoxide 2
proline-catalyzed
a-aminoxylation and HWE olefination of alde-
was treated with the carbanion of acetonitrile to give g-hydroxy
hydes,7 (d) iridium-catalyzed transfer hydrogenative carbonyl
allylation,8 (e) catalytic asymmetric Overman esterfication.9
Organocatalysis using small organic molecules to generate chi-
ral intermediates has become a powerful means in organic syn-
thesis.10 With our sustained interest in developing catalytic
enantioselective routes to bioactive molecules,11 we intended to
develop a common approach for the differently oriented 1,3-polyol.
At the outset, we became interested in the concept of ‘linchpin’
catalysis, a different approach wherein the chirality inducing step
leads to an enantioenriched reactive intermediate that can be
rapidly converted into an important structural motif.12 In this
regard we sought a critical intermediate, which could be used in the
synthesis of 1,3-polyol. Towards this goal, we planned to exploit the
nitrile 3,14 and the subsequent protection of secondary alcohol led
to TBS-ether 4 in 90% yield (over two steps). The nitrile function-
ality was converted to aldehyde using DIBALeH and the resulting
crude residue was subjected to organocatalyzed asymmetric ep-
oxidation using catalyst A, resulted in terminal epoxide 5 in 86%
yield (over two steps) with 7:1 diastereomeric ratio as estimated by
1H NMR. Then, 5 was reacted with the carbanion of acetonitrile, and
to our dismay, only 10% of expected product 6 was isolated. Alter-
natively, we explored the epoxide-opening with lithium acetylide
ethylenediamine complex. Thus, the reaction of 5 with lithium
acetylide ethylenediamine complex at ambient temperature in
DMSO led to homopropargyl alcohol, 7 in 92% yield. The 1,3-diol of
7 was converted to acetonide 8 and the relative stereochemistry
found to be syn using Rychnovsky’s15 method. To explore the
catalyst-directed diastereoselectivity, 4 was subjected to reduction
followed by epoxidation with catalyst ent-A resulting in the
diastereoisomer 5a in similar yield, with 10:1 dr as estimated by
* 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 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.055

3180
G. Kumaraswamy et al. / Tetrahedron 68 (2012) 3179e3186
1H NMR. The use of identical conditions as above furnished the
anti-acetonide 8a. The appearance of methyl carbons resonance
synthesis.9a,18 We outline herein, our pragmatic and high yielding
strategy, which involves organocatalytic iterative enantioselective
MacMillan asymmetric epoxidation as the pivotal step. For the
proposed synthetic strategy, the ideal advanced intermediate could
be enantioenriched 1,3,5-synesyn terminal acetylene 10 (Scheme 2).
Eventually, the synthesis began with 10. Exposure of synthon 10
to hydroboration/oxidation and asymmetric epoxidation gave 13 in
peaks at
98.7 ppm confirmed the presence of syn-acetonide 8. Similarly,
anti-acetonide 8a was confirmed by the appearance of the methyl
carbons resonance at 24.6 and 25.3 ppm and the acetal carbon at
100.4 ppm (Scheme 1).
d 19.8 and 30.1 ppm and acetal carbon resonating at
d
d
d
OH
O
a)
b)
O
CN
96%
90%
3
1
2, 93% ee
OR
OR
O
b)
d), a)
c)
CN
OH
86% (over 2 steps)
94%
10%
R = TBS
5, syn/anti = 7:1
4, R = TBS
OH
OH
CN
OR
6
O
O
f), g)
e)
92%
5
92% (over 2 steps)
8
7, R = TBS
OH
OR
OR
O
e)
d), h)
86% (over 2 steps)
4
92%
7a, R = TBS
5a, R = TBS
syn/anti = 1:10
O
N
Me
O
Me
N
O
O
N
f), g)
92% (over 2 steps)
N
H.
TFA
H.
TFA
Cat. ent-A
8a
Cat. A
Scheme 1. Synthesis of 1,3-syn, 1,3-anti polyols and determination of relative stereochemistry: (a) 50 mol % Cu(TFA)2$H2O, 20 mol % cat. A, LiCl, Na2S2O8, MeCN, NaBH4, 0 ꢀC, 15 min,
KOH, rt, 30 min; (b) n-BuLi, MeCN, ꢁ78 ꢀC, THF, 2 h; (c) TBDMSCl, imidazole, DMF, rt, 12 h; (d) DIBALeH, DCM, ꢁ78 ꢀC, 2 h; (e) lithium acetylide ethylenediamine complex, DMSO, rt,
12 h; (f) TBAF, THF, rt, 1 h; (g) 2,2-DMP, cat. PTSA, DCM, 2 h. h) 50 mol % Cu(TFA)2$H2O, 20 mol % cat. ent-A, LiCl, Na2S2O8, MeCN, NaBH4, 0 ꢀC, 15 min, KOH, rt, 30 min.
In the light of the above results, it was concluded that the cat-
alyst enables to direct the stereochemical course with high dia-
stereoselectivity and predictability (Scheme 1). The secondary
alcohol in 7 and 7a was converted to its TBS-ether followed by
hydroboration/oxidation of terminal acetylene, which furnished
the aldehyde. The resulting crude aldehyde was subjected to
asymmetric epoxidation to give the terminal epoxides 9 and 9a in
72% yield (over three steps) with 10:1 and 20:1 diastereomeric ratio
as judged by 1H NMR spectra. Then, alkyne addition followed by
TBS protection of corresponding alcohol delivered 1,3,5-synesyn,
1,3,5-antieanti terminal acetylene 10 and 10a in 83% yield, re-
spectively (over two steps) (Scheme 2).
Having developed the expedient and practical route to stereo
divergent 1,3,5-polyols, we envisaged the extrapolation of this
methodology to the total synthesis of polyrhacitide A. The aliphatic
polyketides polyrhacitide A,11 and polyrhacitide B,12 were isolated
from Chinese medicinal ants, species Polyrhachis lamellidens Smith16
(Fig. 1). Moreover, these bioactive molecules generated interest
owing to their various medicinal applications, which include the
treatment of rheumatoid arthritis, hepatitis, headaches, morning
sickness, cancer, and pulmonary diseases.2a They also exhibit con-
siderable analgesic and anti-inflammatory effects.17 Due to signifi-
cant activity coupled with paucity of natural source, they have
attracted the attention of synthetic organic chemists towards their
62% yield (over two steps). Alkyne addition to triol epoxide 13
generated 14 in 78% yield (third iteration from 10 to 14).19 Then, the
terminal acetylene was partially reduced to olefin under Lindlar
hydrogenation conditions followed by esterification of secondary
alcohol with acryloyl chloride resulted in 15 with 85% yield (over
two steps). The ring-closing metathesis with Grubbs second gen-
eration catalyst led to an a,b-unsaturated lactone 16 (94%). Finally,
the fluoride-ion induced global deprotection of silyl groups and
subsequent oxy-Michael reaction with DBU as described by Wald-
mann3a and Kirsch9a provided the anticipated polyrhacitide A, 11 in
86% yield (over two steps) (Scheme 3). The optical data of 11 were
in full agreement with that of polyrhacitide A reported in the lit-
erature16 ([
a]
23 þ8.5 (c 0.6, MeOH) {lit.16
[
a
]
D
23 þ8.5 (c 0.5, MeOH)}).
D
Also the 1H NMR and 13C NMR data were in full accord with those
reported for the natural product (Scheme 3).
3. Conclusion
In summary, we have developed an iterative organocatalytic
diastereoselective strategy for the synthesis of stereo divergent
1,3,5-polyols via an asymmetric epoxidation/alkyne addition/
hydroboration/oxidation sequence. A key feature of this protocol is
an organocatalysis as the genesis of chirality and the resulting
synthons obtained with
a high degree of distereo- and

G. Kumaraswamy et al. / Tetrahedron 68 (2012) 3179e3186
3181
OR OR
O
OR
OR OR
a)
b)
7
72%
83%
9, R = TBS
10, R = TBS
OR OR
syn/anti = 10:1
OR
OR OR
O
a)
b)
7a
72%
83%
9a, R = TBS
syn/anti = 1:20
10a, R = TBS
Scheme 2. Synthesis of 1,3,5-synesyn and 1,3,5-ante-anti terminal acetylene: (a) (i) TBDMSCl, imidazole, DMF, rt, 12 h; (ii) disiamylborane, 6 N NaOH, 30% H2O2, THF, 0 ꢀC, 6 h; (iii)
50 mol % Cu(TFA)2$H2O, 20 mol % cat. A, LiCl, Na2S2O8, MeCN, NaBH4, 0 ꢀC, 15 min, KOH, rt, 30 min; (b) (i) lithium acetylide ethylenediamine complex, DMSO, rt, 12 h; (ii) TBDMSCl,
imidazole, DMF, rt, 12 h.
O
O
OH OH
OH OH OH
H
O
H
O
O
O
Polyrhacitide A, 11
Polyrhacitide B, 12
Fig. 1. Skipped-polyol comprising bicyclic lactones.
OR
OR OR
OR OH
OR OR
O
a), b)
c)
10
78%
62%(2 steps)
13, R - TBS
OR
14
O
O
OR
O
OR OR
O
OR OR
f)
d), e)
94%
85%(2 steps)
16, R = TBS
15
g), h)
86%(2 steps)
Polyrhacitide A
Scheme 3. Synthesis of polyrhacitide: (a) disiamylborane, 6 N NaOH, 30% H2O2, THF, 0 ꢀC, 6 h; (b) 50 mol % Cu(TFA)2$H2O, 20 mol % cat. A, LiCl, Na2S2O8, MeCN, NaBH4, 0 ꢀC, 15 min,
KOH, rt, 30 min; (c) lithium acetylide ethylenediamine, DMSO, rt, 12 h; (d) Lindlar catalyst, quinoline, EtOAc, rt, 6 h; (e) acryloyl chloride, Et3N, DCM, 0 ꢀC to rt, 3 h; (f) Grubbs second
generation catalyst, DCM, reflux, 5 h; (g) HF, CH3CN, rt, 6 h; (h) DBU, DCM, rt, 18 h.
enantiopurity. Additionally, the advanced intermediate was en-
gaged in the total synthesis of polyrhacitide A. The chirality in-
ducing step (asymmetric epoxidation) involved in this method is
high yielding, operationally trivial to perform, and tolerable to air
and moisture. Additionally, each iteration proceeds with high
overall yield (74% for 3 to 7). Further work application of this
strategy for the synthesis of related biologically active molecules is
under progress.
recorded at 300 and 500 MHz and 13C NMR 75 MHz in CDCl3.
J values were recorded in hertz and abbreviations used were
sdsinglet, dddoublet, qdquartet, mdmultiplet and brdbroad.
Chemical shifts (
d
) are reported relative to TMS (
d¼0.0) as an in-
ternal standard. IR spectra were recorded on Thermo Nicolet FT/IR-
5700. Mass spectral data were compiled using MS (ESI), HRMS data
obtained using quadrupole time-of-flight (QTOF) mass spectrom-
eter (QSTAR XL, Applied Biosystems MDS Sciex, Foster City, USA).
Optical rotations were recorded on HORIBA high sensitive polar-
imeter, 10 mL cell. The enantiomeric purity was determined by
chiral HPLC on a Shimadzu LC-10ATvp dual pump system (Chiral
OD-H column and n-hexane and IPA as mobile phase).
4. Experimental section
4.1. General information
All reactions were conducted under an atmosphere of nitrogen
(IOLAR Grade I). Apparatus used for reactions are oven dried and
THF was distilled over sodium benzophenone ketyl before use. All
other chemicals used were commercially available. Progress of the
reactions was monitored by TLC on pre-coated Silica Gel 60 F-254.
Evaporation of solvents was performed at reduced pressure on
a rotary evaporator. Column chromatography was carried out with
silica gel grade 60e120, 100e200 mesh. 1H NMR spectra were
4.2. (R)-2-Heptyloxirane 2
To a stirred acetonitrile (200 mL) water (2.2 equiv, 1.12 mL,
61.97 mmol) solution containing cat.
5.63 mmol), lithium chloride (1.5 equiv,1.73 g, 42.25 mmol), copper
trifluoroacetate hydrate (50 mol %, 4.17 g, 14.08 mmol), sodium
persulfate (1 equiv, 6.706 g, 28.2 mmol) was added aldehyde 1 (4 g,
28.2 mmol) at 10 ꢀC and stirred vigorously for 2 h at same
A
(20 mol %, 1.60 g,

3182
G. Kumaraswamy et al. / Tetrahedron 68 (2012) 3179e3186
temperature. The resulting mixture was cooled to 0 ꢀC before
NaBH4 (2.5 equiv, 2.68 g, 70.42 mmol) was added. After further
10 min, the medium was warmed to room temperature (w5 min),
then 60 mL of a freshly prepared aqueous solution of KOH in EtOH
(20 mL, 20 g KOH dissolved in 40 mL distilled water) was added and
the resulting mixture stirred vigorously for 30 min. Further, 200 mL
of distilled water was added to the reaction and the organic layer
was extracted with pentane (3ꢂ150 mL), washed with brine
(1ꢂ50 mL), dried over anhydrous Na2SO4, filtered and concentrated
maintaining the bath temperature at 30 ꢀC. The resulting oil was
purified over silica gel column chromatography with pentane/ether
mixture was added saturated NH4Cl, ethyl acetate, Celite and the
resultant slurry was stirred for 1 h and filtered. The organic layer
was separated and aqueous layer was extracted with ethyl acetate
(2ꢂ50 mL). The combined organic layers were washed with brine
(2ꢂ100 mL), dried over anhydrous Na2SO4 and concentrated to give
crude as colourless oil, which was directly used for next step
without purification. To a stirred solution of cat. A (20 mol %, 1.14 g,
4 mmol), lithium chloride (1.5 equiv, 1.23 g, 30 mmol), copper tri-
fluoroacetate hydrate (50 mol %, 2.95 g, 10 mmol) and sodium
persulfate (1 equiv, 4.76 g, 20 mmol) and water (2.2 equiv, 0.8 mL,
44 mmol) in acetonitrile (80 mL) the above aldehyde was added at
10 ꢀC and the reaction mixture stirred vigorously for 5 h at same
temperature. The resulting mixture was cooled to 0 ꢀC before
NaBH4 (2.5 equiv, 1.90 g, 50 mmol) was added. After 10 min, the
reaction mixture was allowed to warm to room temperature
(5 min), then 60 mL of a freshly prepared aqueous solution of KOH
in EtOH (20 mL, 20 g KOH dissolved in 40 mL distilled water) was
added and the resulting mixture stirred vigorously for 30 min.
Further, 200 mL of distilled water was added to the reaction mix-
ture and extracted with ethyl acetate (2ꢂ150 mL), washed with
brine (2ꢂ100 mL), dried over anhydrous Na2SO4, filtered and con-
centrated. Purification of the crude residue by silica gel column
chromatography with hexane/ethyl acetate mixtures 95:5 afforded
the epoxide 5.2 g (86% yield over two steps) as a colourless oil;
mixture to afford the epoxide 3.6 g (90%) as a colourless oil;
23
[
a]
þ7.5 (c 2, EtOH); IR (neat): 2958, 2950, 2848, 1086, 916,
D
838 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼2.86e2.80 (m, 1H,
CHOCH2), 2.69 (dd, J¼3.9, 5.1 Hz, 1H, CHaHbOCH), 2.40 (dd, J¼3.0,
5.1 Hz, 1H, CHaHbOCH), 1.55e1.25 (m, 12H, eCH2CH2e), 0.91 (t,
J¼6.1 Hz, 3H, MeCH2); 13C NMR (75 MHz, CDCl3):
d 52.0, 46.6, 32.2,
31.5, 29.2, 28.9, 25.5, 22.3, 13.7; MS (EIMS) m/z 143 (MþH)þ.
4.3. 4-Hydroxyundecanenitrile 3
To a solution of n-butyllithium (1.6 M, 30.8 mL) in THF (50 mL)
was added dropwise acetonitrile (2.59 mL, 49.29 mmol) in THF
(20 mL) at ꢁ78 ꢀC. After 1 h, a solution of 2 (3.5 g, 24.6 mmol) in
THF 30 mL was added dropwise at ꢁ15 ꢀC and the mixture was
stirred for 1 h. Then, it was poured into saturated NH4Cl solution
and extracted with ether. The ethereal solution was successively
washed with water, brine, dried over anhydrous Na2SO4 and con-
centrated under reduced pressure. The residue was purified by
[a
]
23 þ4 (c 1.1, CH2Cl2); IR (neat): 2929,1463,1360, 1255,1124,1069,
D
1006, 836, 774, 663 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
¼3.90e3.88
(m, 1H, CHOSi), 2.97e2.93 (m, 1H, CHOCH2), 2.69 (dd, J¼4.1, 5.4 Hz,
1H, CHaHbOCH), 2.38 (dd, J¼2.7, 5.1 Hz, 1H, CHaHbOCH), 1.64e1.61
(m, 2H, CH2CHOSi), 1.53e1.46 (m, 2H, CH2CHO), 1.27 (br s,
10H, eCH2CH2e), 0.89e0.87 (m, 12H, t-BuSi, MeCH2 ), 0.05 (s, 3H,
column chromatography on silica gel, eluting with hexane/ethyl
23
acetate (90:10) to give 4.3 g (96%) as colourless oil; [
a]
ꢁ13.5
MeSi), 0.04 (s, 3H, MeSi); 13C NMR (75 MHz, CDCl3):
d¼70.3,
D
(c 1.5, CH2Cl2); IR (neat): 3436, 2928, 2856, 2248, 2248, 1464, 1429,
49.5, 46.8, 40.0, 37.2, 31.8, 29.6, 29.2, 25.7, 25.4, 22.6, 17.9, 14.0, ꢁ4.6,
ꢁ4.7; MS (ESIMS) m/z 301 (MþH)þ, 323 (MþNa)þ; HRMS (ESI)
calcd for C17H36O2NaSi (MþNa)þ 323.2380, found 323.2383.
1127, 1089, 936, 894, 740, 503 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
¼3.74e3.63 (m, 1H, CHOH), 2.57e2.40 (m, 2H, CH2CN), 1.86e1.58
(m, 4H, CH2CH2OH), 1.49e1.40 (m, 2H, eCH2CH2e), 1.28 (br s, 10H,
eCH2CH2e), 0.09 (t, J¼3.9 Hz, 3H, MeCH2); 13C NMR (75 MHz,
4.6. tert-Butyldimethyl((R)-1-((S)-oxiran-2-yl)nonan-2-yloxy)
silane 5a
CDCl3):
d
119.9, 69.9, 37.4, 32.4, 31.7, 29.4, 29.1, 25.4, 22.6, 14.0, 13.6;
MS (ESIMS) m/z 206 (MþNa)þ; HRMS (ESI) calcd for C11H21NONa
(MþNa)þ 206.1520, found 206.1526.
For anti-asymmetric epoxidation, compound 5 procedure de-
scribed above was followed using cat. ent-A. Yield 0.850 g (88% over
4.4. 4-(tert-Butyldimethylsilyloxy)undecanenitrile 4
two steps); [
a
]
23 ꢁ13.2(c2.5,CH2Cl2);IR (neat)2929,1463,1360,1255,
D
1124, 1069, 1006, 836, 774, 663 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
To a stirred solution of 3 (4.3 g, 23.4 mmol) and imidazole (3.2 g,
47 mmol) in DMF (20 mL) was added portion wise TBSCl (5.79 g,
35.1 mmol). The reaction mixture was stirred 10 h at room temper-
ature, diluted with saturated NaHCO3 and extracted with ethyl ace-
tate. The ethyl acetate layer was washed with brine, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude residue was purified by column chromatography using hex-
d
¼3.89e3.80 (m, 1H, CHOSi), 2.99e2.92 (m, 1H, CHOCH2), 2.75 (t,
J¼5.1 Hz, 1H, CHaHbOCH), 2.45 (dd, J¼2.6, 5.3 Hz, 1H, CHaHbOCH),
1.68e1.52 (m, 2H, CH2CHOSI), 1.52e1.43 (m, 4H, CH2CHOSI, CH2CH2),
1.26 (br s, 10H, eCH2CH2e), 0.89e0.86 (m, 12H, t-BuSi, MeCH2), 0.07
(s, 3H, MeSi), 0.06 (s, 3H, MeSi); 13C NMR (75 MHz, CDCl3):
d
¼70.1, 49.4, 47.7, 40.2, 37.9, 31.8, 29.7, 29.2, 25.8, 24.9, 22.6, 18.0,
14.1, ꢁ4.4, ꢁ4.7; MS (ESIMS) m/z 301 (MþH)þ, 323 (MþNa)þ; HRMS
(ESI) calcd for C17H36O2NaSi (MþNa)þ 323.2380, found 323.2383.
ane/ethyl acetate (95:5) as eluent to give 6.5 g (94%) as colourless oil;
23
[a]
ꢁ18.7 (c 1.5, CH2Cl2); IR (neat): 2954, 2928, 2857, 2247, 1463,
D
1378, 1256, 1094, 1005, 836, 775 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
4.7. (4S,6R)-6-(tert-Butyldimethylsilyloxy)tridec-1-yn-4-ol 7
d
3.80e3.72 (m, 1H, CHOSi), 2.36 (t, J¼7.5 Hz, 2H, CH2CN), 1.86e1.84
(m, 2H, CH2CHOSi), 1.52e1.39 (m, 2H, CH2CHOSi), 1.27 (br s,
10H, eCH2CH2e), 0.91e0.88 (m, 12H, t-BuSi, MeCH2), 0.08 (s, 3H,
Lithium acetylide ethylenediamine complex (1.84 g, 20 mmol)
was dissolved in DMSO (30 mL) and the mixture was stirred for
30 min at rt. Epoxide 5 (3 g, 10 mmol) was added and the reaction
mixture was stirred for 12 h at rt. After addition of water (50 mL),
the mixture was extracted with Et2O (3ꢂ60 mL) and the combined
organic phases were washed with brine (2ꢂ20 mL), dried over
Na2SO4, filtered and concentrated under reduced pressure. The
residue was adsorbed onto silica gel and purified by chromatog-
MeSi), 0.07 (s, 3H, MeSi); 13C NMR (75 MHz, CDCl3):
d¼120.1,
70.2, 36.8, 32.2, 31.7, 29.7, 29.6, 29.2, 25.8, 24.9, 22.6, 18.0, 14.1,
13.03, ꢁ4.7, ꢁ4.3; MS (ESIMS) m/z 298 (MþH)þ, 320 (MþNa)þ; HRMS
(ESI) calcd for C17H35NONaSi (MþNa)þ 320.2385, found 320.2400.
4.5. tert-Butyldimethyl(1-((R)-oxiran-2-yl)nonan-2-yloxy)
silane 5
raphy on silica gel eluting with hexane/ethyl acetate (90:10) to give
23
the acetylene, 2.99 g (92%) as colourless oil; [
a
]
ꢁ13 (c 1.8,
D
To a solution of 4 (6.5 g, 21.81 mmol) in toluene (80 mL) was
added dropwise DIBALeH (1.6 M in toluene, 16.4 mL) at ꢁ78 ꢀC
and the mixture was stirred for 3 h at same temperature. To this
CH2Cl2); IR (neat); 3456, 3314, 2929, 2857, 2121, 1463, 1255, 1081,
836, 775, 635 cmꢁ1 1H NMR (300 MHz, CDCl3):
¼3.95e3.80 (m,
1H, CHOH), 3.10 (br s, 2H, OH, CHOH), 2.40e2.20 (m, 2H, CH2CC),
;
d

G. Kumaraswamy et al. / Tetrahedron 68 (2012) 3179e3186
3183
1.94 (t, J¼3.0 Hz, 1H, CHCC), 1.83 (dt, J¼3.0, 13.6 Hz, 1H, CHaHb
(300 MHz, CDCl3):
d
¼3.93 (quintet, J¼6.7 Hz, 1H, CHOCMe2),
-
CHOH), 1.61e1.45 (m, 3H, CHaHbCHOH, CH2CH2), 1.27 (br s, 10H,
3.76e3.66(m, 1H, CHOCMe2), 2.43e2.15 (m, 2H, CH2CC), 1.92 (t,
J¼2.2 Hz, 1H, CHCC), 1.66 (t, J¼7.7 Hz, 2H, CH2CHO), 1.48e1.18 (m,
20H, MeC(2), eCH2CH2e), 0.83 (t, J¼6.6 Hz, 3H, MeCH2); 13C NMR
eCH2CH2e), 0.89e0.86 (m, 12H, t-BuSi, MeCH2), 0.10 (s, 3H, MeSi),
0.09 (s, 3H, MeSi); 13C NMR (75 MHz, CDCl3):
d
¼81.0, 73.1, 70.3,
69.5, 41.5, 37.9, 31.8, 29.7, 29.2, 27.2, 25.8, 24.6, 22.6, 17.9, 14.1, ꢁ3.9,
ꢁ4.7; MS (ESIMS) m/z 327 (MþH)þ, 349 (MþNa)þ; HRMS (ESI)
calcd for C19H38O2NaSi (MþNa)þ 349.2538, found 349.2528.
(75 MHz, CDCl3):
d
¼100.4, 80.6, 69.2, 66.6, 65.3, 37.7, 35.9, 31.8, 29.5,
29.2, 25.6, 25.3, 24.9, 24.6, 22.6, 14.1; MS (ESIMS) m/z 253 (MþH)þ.
4.12. TBS protection of 7: 5-heptyl-2,2,3,3,9,9,10, and 10-
octamethyl-7-(3-(trimethylsilyl)prop-2-ynyl)-4,8-dioxa-3,9-
disilaundecane
4.8. (4S,6R)-Tridec-1-yne-4,6-diol
Procedure for TBS deprotection of 7. A solution of 7 (0.3 g,
0.92 mmol) in 2 mL THF was added TBAF (1 M, 1.10 mL, 1.10 mmol)
at 0 ꢀC and stirred for 1 h. The reaction mixture was diluted with
ethyl acetate and washed successively with aqueous NaHCO3, water
and brine. The organic layer was dried over Na2SO4, concentrated
under reduced pressure and the crude residue was purified by
To a stirred solution of 7 (4 g,12.26 mmol) and imidazole (1.66 g,
24.53 mmol) in DMF 10 mL was added portion wise tert-butyldi-
methylsilyl chloride (2.02 g, 14.71 mmol). The resulting mixture
was stirred over 10 h at room temperature, then diluted with sat-
urated NaHCO3 and extracted with ethyl acetate (2ꢂ10 mL). The
ethyl acetate layer was washed with brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude resi-
due was purified by column chromatography using hexane/ethyl
column chromatography using hexane/ethyl acetate (70:30) as el-
23
uent to give 0.210 g (95%) as colourless oil; [
a]
ꢁ4.2 (c 0.8,
D
CH2Cl2); IR (neat); 3445, 2140, 1450, 1245, 1105, 1084, 845,
775 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
¼3.94e3.82 (m, 1H, CHOH),
acetate (98:2) as eluent to give yield 5.12 g (95%) as colourless oil;
23
3.81e3.74 (m, 1H, CHOH), 3.20 (br s, 1H, OH), 2.56 (br s, 1H, OH),
2.75 (dd, J¼2.6, 6.3 Hz, 2H, CH2CC), 1.96 (t, J¼2.6 Hz, 1H, HCC),
1.70e1.64 (m, 1H, CHaHbCHOH), 1.53e1.50 (m, 2H, CH2CHOH),
1.42e1.35 (m, 1H, CHaHbCHOH), 1.18 (br s, 10H, eCH2CH2e), 0.78 (t,
[a
]
ꢁ9.5 (c 1.5, CH2Cl2); IR (neat): 3315, 2929, 2123, 1645, 1471,
D
1362, 1093, 836, 773, 636 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
¼3.91
(quintet, J¼5.8 Hz, 1H, CHOSi), 3.78 (quintet, J¼5.1 Hz, 1H, CHOSi),
1.47e1.25 (m, 12H, eCH2CH2e), 0.87e0.84 (m, 21H, t-BuSi(2),
MeCH2), 0.07 (s, 3H, MeSi), 0.04 (s, 3H, MeSi), 0.037 (s, 3H, MeSi),
J¼6.42 Hz, 3H, MeCH2); 13C NMR (75 MHz, CDCl3):
¼80.6, 72.7,
d
71.0, 70.8, 41.8, 38.1, 31.7, 29.5, 29.2, 27.7, 25.3, 22.6, 14.1; MS
(ESIMS) m/z 235 (MþNa)þ; HRMS (ESI) calcd for C13H24O2Na
(MþNa)þ 235.1673, found 235.1684.
0.03 (s, 3H, MeSi); 13C NMR (75 MHz, CDCl3):
d¼81.5, 70.0, 69.4,
68.3, 44.3, 37.0, 31.8, 29.8, 29.3, 27.5, 25.9, 25.8, 25.0, 22.7, 18.0,
14.1, ꢁ3.0, ꢁ4.4, ꢁ4.6; MS (ESIMS) m/z 463 (MþNa)þ; HRMS (ESI)
calcd for C25H52O2NaSi2 (MþNa)þ 463.3403, found 463.3413.
4.9. (4R,6R)-4-Heptyl-2,2-dimethyl-6-(prop-2-ynyl)-1,3-
dioxane 8
4.13. (5R,7S)-5-Heptyl-2,2,3,3,9,9,10, and 10-octamethyl-7-
((R)-oxiran-2-ylmethyl)-4,8-dioxa-3,9-disilaundecane 9
To a solution of 7 (150 mg, 0.67 mmol) in dichloromethane
(2 mL) were added 2,2-DMP (0.1 mL, 0.81 mmol), catalytic amount
of PTSA$H2O and stirred at room temperature for 2 h. To this re-
action mixture, a pinch of NaHCO3 was added, dichloromethane
was removed under reduced pressure and the crude residue was
purified by column chromatography using hexane/ethyl acetate
To a stirred solution of BH3$SMe2 (0.761 mL, 7.92 mmol), in THF
(10 mL) at 0 ꢀC, was treated dropwise with 2-methyl-2-butene
(7.9 mL, 15.84 mmol), and stirring was continued for 2 h. Acety-
lene 7 (1.74 g, 3.96 mmol) in dry THF (10 mL) was added, and the
reaction mixture was stirred at 25 ꢀC for 12 h and cooled to 0 ꢀC.
The reaction mixture was carefully quenched with dropwise ad-
dition of 3 N NaOH (8 mL) and 3 mL of 30% H2O2, removal of the
cooling bath, and continued stirring for 2 h. The reaction mixture
was diluted with ether and washed with H2O (2ꢂ40 mL) and brine
(40 mL). Dried over anhydrous Na2SO4 and concentration followed
by column chromatography using hexane/ethyl acetate (98:2) as
eluent gave the aldehyde, which was used directly for the next step.
The resulting aldehyde was added to a stirred mixture of cat. A
(20 mol %, 203 mg, 0.71 mmol), lithium chloride (1.5 equiv, 218 mg,
5.34 mmol), copper trifluoroacetate hydrate (50 mol %, 562 mg,
1.9 mmol), sodium persulfate (1 equiv, 847 mg, 3.8 mmol) and
water (2.2 equiv, 0.140 mL, 7.8 mmol) in acetonitrile (30 mL) and
the reaction mixture stirred vigorously at 10 ꢀC for 8 h. The
resulting mixture was cooled to 0 ꢀC before NaBH4 (2.5 equiv, 338 g,
8.9 mmol) was added. After a further 10 min, the medium was
allowed to room temperature for 5 min before 15 mL of a freshly
prepared solution of aqueous KOH in EtOH (5 mL, 5 g KOH dissolved
in 10 mL distilled water) was added and the resulting mixture
stirred vigorously for 1 h. At this stage 50 mL of distilled water was
added to the reaction and extracted with ethyl acetate (3ꢂ50 mL).
The combined organic layers were washed with brine (1ꢂ50 mL),
dried over anhydrous Na2SO4, filtered and concentrated. The crude
residue was purified by column chromatography using hexane/
(95:5) as eluent to give 0.165 g (96%) as colourless oil; [
a
]
D
23 þ11.0 (c
0.6, CH2Cl2); IR (neat); 2925, 2176, 1470, 1225,735, 595 cmꢁ1
;
1H
NMR (300 MHz, CDCl3):
d
¼3.93e3.80 (m, 1H, CHOCMe2), 3.77e3.74
(m, 1H, CHOCMe2), 2.44e2.39 (m, 1H, CHaHbCC), 2.22e2.17 (m, 1H,
CHaHbCC), 1.91 (t, J¼2.7 Hz, 2H, HCC, CHaHbCHO), 1.74e1.71 (m, 1H,
CHaHbCHO), 1.50e1.27 (m, 20H, MeC(2), eCH2CH2e), 0.90 (t,
J¼6.4 Hz, 3H, MeCH2); 13C NMR (75 MHz, CDCl3):
¼98.7, 80.4, 70.2,
d
68.2, 67.8, 36.3, 36.1, 31.8, 30.1, 29.5, 29.2, 26.3, 24.9, 22.6, 19.8, 14.1;
MS (ESIMS) m/z 253(MþH)þ.
4.10. (4R,6R)-Tridec-1-yne-4,6-diol
For TBS deprotection of 7a procedure described above was fol-
23
lowed to yield 0.210 g (95%); [
a
]
ꢁ4.0 (c 0.4, CH2Cl2); IR (neat);
D
3456, 2929, 2121,1463,1255,1185,1081, 836, 775, 635 cmꢁ1; 1H NMR
(300 MHz, CDCl3):
d
¼4.16e4.02 (m, 1H, CHOH), 3.99e3.90 (m, 1H,
CHOH), 2.83 (br s,1H, OH), 2.43 (dd, J¼2.1, 6.7 Hz, 2H, CH2CC), 2.06 (t,
J¼2.6 Hz, 1H, HCCC), 1.79e1.62 (m, 2H, CH2CH2), 1.53e1.38 (m, 2H,
eCH2CH2), 1.27 (br s, 10H, eCH2CH2e), 0.09e0.85 (t, J¼6 Hz, 3H,
MeCH2); 13C NMR (75 MHz, CDCl3):
d
¼80.8, 70.7, 69.2, 67.4, 41.4, 37.4,
31.7, 29.5, 29.2, 27.3, 25.7, 22.6, 14.1; MS (ESIMS) m/z 235 (MþNa)þ;
HRMS (ESI) calcd for C13H24O2Na (MþNa)þ 235.1673, found 235.1684.
4.11. (4R,6R)-4-Heptyl-2,2-dimethyl-6-(prop-2-ynyl)-1,3-
dioxane, 8a
ethyl acetate (95:5) as eluent to yield 1.38 g (76% over two steps) as
23
colourless oil; [
a
]
þ1 (c 2, CH2Cl2); IR (neat): 2929, 1471, 1361,
D
1255, 1067, 835, 774, 664 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
¼4.01
Compound 8 procedure described above was followed to give
(quintet, J¼5.8 Hz, 1H, CHOSi), 3.74 (quintet, J¼5.1 Hz, 1H, CHOSi),
3.03e2.97 (m, 1H, CHOCH2), 2.71 (t, J¼4.2 Hz, 1H, CHaHbOCH), 2.39
0.135 g (96%) as a colourless oil; [
a]
23 ꢁ23.0 (c 0.4, CH2Cl2); 1H NMR
D

3184
G. Kumaraswamy et al. / Tetrahedron 68 (2012) 3179e3186
(dd, J¼2.8, 5.2 Hz, 1H, CHaHbOCH), 1.74e1.52 (m, 4H, CH2CHO),
1.43e1.27 (m, 12H, eCH2CH2e), 0.89e0.87 (m, 21H, t-BuSi (2),
MeCH2), 0.05 (s, 3H, MeSi), 0.04 (s, 3H, MeSi), 0.03 (s, 3H, MeSi),
2929, 1471, 1361, 1255, 1067, 835, 774, 664 cmꢁ1
;
1H NMR
¼3.96e3.88 (m, 1H, CHOSi), 3.73e3.64 (m, 1H,
(300 MHz, CDCl3):
d
CHOSi), 3.04e2.98 (m, 1H, CHOCH2), 2.80e2.77 (t, J¼4.2 Hz, 1H,
CHaHbOCH), 2.50e2.48 (m, 1H, CHaHbOCH), 1.76e1.56 (m, 4H,
CH2CHO), 1.42e1.39 (m, 2H, eCH2CH2), 1.26 (br s, 10H, eCH2CH2e),
0.89e0.87 (m, 21H, t-BuSi(2), MeCH2), 0.08 (s, 3H, MeSi), 0.06 (s,
3H, MeSi), 0.05 (s, 3H, MeSi), 0.04 (s, 3H, MeSi); 13C NMR (75 MHz,
0.02 (s, 3H, MeSi); 13C NMR (75 MHz, CDCl3):
d
¼69.8, 67.7, 49.2,
46.7, 44.7, 39.9, 37.4, 31.8, 29.8, 29.2, 25.9, 25.8, 24.9, 22.6, 17.9, 18.0,
14.1, ꢁ4.2, ꢁ4.2, ꢁ4.4, ꢁ4.5; MS (ESIMS) m/z 459 (MþH)þ, 481
(MþNa)þ; HRMS (ESI) calcd for C25H55O3Si2 (MþH)þ 459.3689,
found 459.3706.
CDCl3):
d
¼70.0, 68.2, 49.7, 46.0, 41.0, 37.6, 31.8, 29.7, 29.3, 25.9, 24.9,
22.6, 18.0, 17.9, 14.0, ꢁ4.0, ꢁ4.2, ꢁ4.3; MS (ESIMS) m/z 459 (MþH)þ,
481 (MþNa)þ; HRMS (ESI) calcd for C25H55O3Si2 (MþH)þ 459.3689,
found 459.3706.
4.14. (4S,6S,8R)-6,8-Bis(tert-butyldimethylsilyloxy)pentadec-
1-yn-4-ol
For lithium acetylide addition to 9, compound 7 procedure de-
4.18. (4S,6R,8R)-6,8-Bis(tert-butyldimethylsilyloxy)pentadec-
scribed above was followed. Yield 1.36 g (86%) as colourless oil;
1-yn-4-ol
23
[
a
]
ꢁ24 (c 2.1, CH2Cl2); IR (neat): 3513, 3314, 2929, 2121, 1471,
D
1361, 1255, 1088, 1005, 836, 775, 628 cmꢁ1
CDCl3):
;
1H NMR (300 MHz,
For lithium acetylide addition to 9a, compound 7 procedure
d
¼4.15e4.07 (m, 1H, CHOSi), 3.94e3.87 (m, 1H, CHOSi),
described above was followed to yield 0.770 g (86%) as colourless
23
3.71e3.64 (m, 2H, CHOH, OH), 2.46e2.27 (m, 2H, CH2CC), 2.04e1.96
(m, 2H, CHCC, CH2CHO), 1.75e1.67 (m, 1H, CHaHbCHO), 1.57e1.41
(m, 2H, CH2CH2e), 1.26 (br s, 10H, eCH2CH2e), 0.89e0.86 (m, 21H,
t-BuSi (2), MeCH2), 0.12 (s, 6H, MeSi (2)), 0.04 (s, 3H, MeSi), 0.03 (s,
oil; [a
]
þ11.4 (c 1.7, CH2Cl2); IR (neat): 3513, 3314, 2929, 2121,
D
1471, 1361, 1255, 1088, 1005, 836, 775, 628 cmꢁ1
(300 MHz, CDCl3):
;
1H NMR
d
¼4.15e4.04 (m, 2H, CHOSi), 3.74e3.64 (m, 2H,
CHOSi, OH), 2.46e2.26 (m, 2H, CH2CC), 2.01 (t, J¼2.2 Hz, 1H, CHCC),
1.78e1.72 (m, 4H, CH2CHO), 1.41e1.38 (m, 2H, CH2CH2e), 1.26 (br s,
8H, eCH2CH2e), 0.89e0.88 (m, 21H, t-BuSi, MeCH2), 0.11 (s, 3H,
MeSi), 0.10 (s, 3H, MeSi), 0.07 (s, 3H, MeSi), 0.05 (s, 3H, MeSi); 13C
3H, MeSi); 13C NMR (75 MHz, CDCl3):
d¼81.1, 70.9, 70.3, 69.7,
69.4, 45.5, 38.1, 31.8, 29.8, 29.3, 27.3, 25.9, 25.8, 24.7, 22.6, 17.8,
14.1, ꢁ3.9, ꢁ4.1, ꢁ4.4, ꢁ4.7; MS (ESIMS) m/z 507 (MþNa)þ; HRMS
(ESI) calcd for C27H56O3NaSi2 (MþNa)þ 507.3665, found 507.3651.
NMR (75 MHz, CDCl3):
d
¼81.0, 70.2, 69.8, 69.6, 67.2, 43.8, 40.8, 37.1,
31.8, 29.6, 29.3, 27.4, 25.9, 25.8, 24.8, 22.6, 18.0, 17.9, 14.1, ꢁ4.0, ꢁ4.1,
ꢁ4.4, ꢁ4.6; MS (ESIMS) m/z 507 (MþNa)þ; HRMS (ESI) calcd for
C27H56O3NaSi2 (MþNa)þ 507.3665, found 507.3651.
4.15. (5R,7R,9S)-7-(tert-Butyldimethylsilyloxy)-5-heptyl-
2,2,3,3,11,11,12,12-octamethyl-9-(prop-2-ynyl)-4,10-dioxa-3,11-
disilatridecane 10
4.19. (5R,7S,9S)-7-(tert-Butyldimethylsilyloxy)-5-heptyl-
2,2,3,3,11,11,12,12-octamethyl-9-(prop-2-ynyl)-4,10-dioxa-3,11-
disilatridecane 10a
Compound 4 procedure described above was followed to yield
23
1.47 g (96%) as colourless oil; [
a
]
þ8 (c 1.5, CH2Cl2); IR (neat):
D
3315, 2929, 2857, 2123, 1471, 1256, 1094, 836, 773, 574 cmꢁ1
;
1H
¼3.93e3.70 (m, 3H, CHOSi(3)), 2.38e2.21
NMR (300 MHz, CDCl3):
d
Compound 4 procedure described above was followed to yield
23
(m, 2H, CH2CC), 1.90 (t, J¼2.3 Hz, 1H, eCHCC), 1.80e1.61 (m, 1H,
CHaHbCHO),1.59e1.55 (t, J¼6.7 Hz, 2H, CH2CHO),1.33e1.15 (m, 13H,
CHaHbCHO, CH2CH2e), 0.09e0.88 (m, 30H, t-BuSi(3), MeCH2), 0.08
(s, 3H, MeSi), 0.07 (s, 3H, MeSi), 0.05 (s, 3H, MeSi), 0.04 (s, 3H,
MeSi), 0.04 (s, 3H, MeSi), 0.03 (s, 3H, MeSi); 13C NMR (75 MHz,
0.700 g (96%) as colourless oil; [
a
]
D
ꢁ5 (c 1.0, CH2Cl2); IR (neat):
3315, 2929, 2857, 2123, 1471, 1256, 1094, 836, 773, 574 cmꢁ1
NMR (300 MHz, CDCl3):
;
1H
d
¼3.94e3.66 (m, 3H, CHOSi), 2.35e2.32 (m,
2H, CH2CC),1.97 (t, J¼2.4 Hz,1H, CHCC),1.79e1.56 (m,14H, CH2CHO,
CH2CH2), 0.88 (br s, 30H, t-BuSi (3), MeCH2), 0.09e0.04 (m, 18H,
CDCl3):
d
¼81.5, 70.1, 69.5, 68.0, 66.9, 45.6, 45.1, 37.2, 31.8, 29.8, 29.7,
MeSi (6) ); 13C NMR (75 MHz, CDCl3):
d¼81.3, 70.1, 69.7, 68.3, 67.6,
29.2, 27.5, 25.9, 25.8, 25.8, 18.1, 17.9, 14.1, ꢁ4.2, ꢁ4.3, ꢁ4.4, ꢁ4.5; MS
(ESIMS) m/z 599 (MþH)þ, 621 (MþNa)þ; HRMS (ESI) calcd for
C33H71O3Si3 (MþH)þ 599.4711, found 599.4731.
46.1, 45.3, 37.3, 31.8, 29.7, 29.3, 27.8, 25.9, 24.9, 18.0, 14.1, ꢁ3.4, ꢁ3.6,
ꢁ4.1, ꢁ4.4; MS (ESIMS) m/z 599 (MþH)þ, 621 (MþNa)þ; HRMS (ESI)
calcd for C33H71O3Si3 (MþH)þ 599.4711, found 599.4731.
4.16. TBS protection of 7a: 5-heptyl-2,2,3,3,9,9,10, and 10-
octamethyl-7-(3-(trimethylsilyl)prop-2-ynyl)-4,8-dioxa-3,9-
disilaundecane
4.20. (5R,7R,9S)-7-(tert-Butyldimethylsilyloxy)-5-heptyl-
2,2,3,3,11,11,12,12-octamethyl-9-(oxiran-2-ylmethyl)-4,10-
dioxa-3,11-disilatridecane 13
Compound 4 procedure described above was followed to yield
Compound 9 procedure described above was followed to yield
23
1.35 g (96%); [
a
]
23 ꢁ12.4 (c 3.5, CH2Cl2); IR (neat): 3315, 2929, 2123,
0.200 g (62% yield over two steps); [
a
]
þ6.0 (c 2, CH2Cl2); IR
D
D
1645, 1471, 1362, 1093, 836, 773, 636 cmꢁ1
;
1H NMR (300 MHz,
(neat): 3412, 2929, 1463, 1255, 1089, 836, 774, 494 cmꢁ1
(300 MHz, CDCl3):
;
1H NMR
CDCl3):
d
¼3.94e3.96 (m, 1H, CHOSi), 3.81e3.73 (m, 1H, CHOSi),
d¼3.99e3.92 (m, 1H, CHOSi), 3.79e3.67 (m, 2H,
2.34e2.32 (m, 2H, CH2CC), 1.97 (t, J¼2.3 Hz, 1H, CHCC), 1.79e1.62
(m, 2H, CH2CHO), 1.46e1.41 (m, 2H, CH2CHO), 1.26 (br s,
10H, eCH2CH2e), 0.88 (s, 21H, t-BuSi, MeCH2), 0.09 (s, 3H, MeSi),
0.08 (s, 3H, MeSi), 0.06 (s, 3H, MeSi), 0.05 (s, 3H, MeSi); 13C NMR
CHOSi), 3.03e2.98 (m, 1H, CHOCH2), 2.72 (t, J¼5.1 Hz, 1H, CHaH-
bOCH), 2.41e2.38 (dd, J¼2.8, 5.1 Hz, 1H, CHaHbOCH), 1.70e1.46 (m,
6H, CH2CHO), 1.29e1.19 (m, 12H, eCH2CH2e), 0.85e0.83 (m, 30H, t-
BuSi (3), MeCH2), 0.04e0.00 (m, 18H, MeSi (6)); 13C NMR (75 MHz,
(75 MHz, CDCl3):
d
¼81.5, 70.1, 68.8, 45.0, 38.0, 29.7, 29.3, 28.2, 25.9,
CDCl3):
d
¼69.5, 67.4, 67.0, 49.4, 46.6, 45.9, 45.8, 40.1, 37.6, 37.2, 31.8,
25.1, 22.6, 18.1, 14.1, ꢁ3.8, ꢁ4.1, ꢁ4.4, ꢁ4.6; MS (ESIMS) m/z 463
(MþNa)þ; HRMS (ESI) calcd for C25H52O2NaSi2 (MþNa)þ 463.3403,
found 463.3413.
29.8, 29.3, 25.9, 25.8, 25.2, 25.1, 22.6, 18.0, 17.9, 14.1, ꢁ4.3, ꢁ4.4,
ꢁ4.5; MS (ESIMS) m/z 617 (MþH)þ; HRMS (ESI) calcd for
C33H73O4Si3 (MþH)þ 617.4816, found 617.4808.
4.17. (5R,7R)-5-Heptyl-2,2,3,3,9,9,10, and 10-octamethyl-7-
((R)-oxiran-2-ylmethyl)-4,8-dioxa-3,9-disilaundecane 9a
4.21. (4S,6S,8R,10R)-6,8,10-Tris(tert-butyldimethylsilyloxy)
heptadec-1-yn-4-ol 14
Compound 9 procedure described above was followed to yield
Compound 7 procedure described above was followed to yield
0.178 g (78% yield) as colourless oil; IR (neat): 3430, 3313, 2925,
23
0.670 g (76% for two steps); [
a
]
D
ꢁ3.6 (c 1.2, CH2Cl2); IR (neat):

G. Kumaraswamy et al. / Tetrahedron 68 (2012) 3179e3186
3185
23
2318, 1463, 1092, 1039, 836 cmꢁ1; [
NMR (300 MHz, CDCl3):
a
]
ꢁ13.0 (c 0.9, CH2Cl2); 1H
4.24. (S)-6-((2S,4R,6R)-2,4,6-Tris(tert-butyldimethylsilyloxy)
tridecyl)-5,6-dihydro-2H-pyran-2-one 16
D
d
¼4.19e4.10 (m, 1H, CHOSi), 3.94e3.87 (m,
1H, CHOSi), 3.81e3.74 (m, 2H, CHOSi, OH), 3.67e3.63 (m, 1H,
CHOH), 2.45e2.25 (m, 2H, CH2CC), 2.06e1.97 (m, 2H, CHCC,
CHaHbCHO), 1.71e1.62 (m, 2H, CHaHbCHO), 1.56e1.41 (m, 5H,
CH2CHO), 1.26e1.25 (m,. 10H, eCH2CH2e), 0.90e0.88 (m, 30H,
t-BuSi (3), MeCH2), 0.13 (s, 6H, MeSi (2)), 0.06e0.04 (m, 12H, MeSi
To a solution of 15 (60 mg, 0.086 mmol) in dry dichloromethane
(3 mL) was added Grubbs second generation catalyst (7 mg,
0.009 mmol) at room temperature under nitrogen atmosphere, and
the resulting mixture was refluxed for 5 h. Solvent was removed
under vacuum and the residue was purified by silica gel column
(4)); 13C NMR (75 MHz, CDCl3):
d 80.9, 71.0, 70.0, 69.9, 69.5, 66.9,
46.3, 46.0, 41.7, 31.8, 29.8, 29.7, 29.3, 27.2, 26.0, 25.9, 25.8, 24.8, 22.6,
18.0, 17.9, 17.8, 14.0, ꢁ3.8, ꢁ3.9, ꢁ4.0, ꢁ4.3, ꢁ4.4, ꢁ4.6; MS (ESIMS)
m/z 665 (MþNa)þ; HRMS (ESI) calcd for C35H75O4Si3 (MþH)þ
643.4973, found 643.4958.
chromatography using (hexane/ethyl acetate¼75:25) to give prod-
23
uct 0.054 g (94%); [
a]
ꢁ25 (c 0.5, CH2Cl2); IR (neat): 2927, 1738,
D
1599, 1462, 1256, 1082, 836, 774, 566 cmꢁ1
;
1H NMR (500 MHz,
¼6.87 (ddd, J¼2.7,5.9, 9.6 Hz, 1H, CH]), 6.03 (dd, J¼2.2,
CDCl3):
d
9.6 Hz, 1H, CH]), 4.66e4.58 (m, 1H, CHOSi), 4.02e3.97 (m, 1H,
CHOSi), 3.85e3.80 (m, 1H, CHOSi), 3.76e3.71 (m, 1H, CHOC),
2.45e2.39 (m, 1H, CHaHbCH]), 2.36e2.26 (m, 1H, CHaHbCH]),
2.02e1.97 (m, 1H, CHaHbCHO), 1.89e1.84 (m, 1H, CHaHbCHO),
1.75e1.57 (m, 4H, CH2CHO),1.26 (br s,12H, eCH2CH2e), 0.090e0.88
(m, 30H, t-BuSi (3), MeCH2), 0.08e0.04 (m, 18H (6), MeSi); 13C NMR
4.22. (4S,6S,8R,10R)-6,8,10-Tris(tert-butyldimethylsilyloxy)
heptadec-1-en-4-ol
To a stirred solution of 14 (70 mg, 0.109 mmol) in ethyl ace-
tate (3 mL) was added sequentially quinoline (17 mL, 0.131 mmol)
(75 MHz, CDCl3):
d
¼164.2, 144.6, 121.7, 75.3, 69.5, 66.9, 66.2, 45.7,
and Lindlar’s catalyst (15 mg). The solution was placed under an
atmosphere of H2 and allowed to stir for 6 h at room tempera-
ture. The solution was filtered through a small plug of Celite
(EtOAc rinse). The filtrate was concentrated under reduced
pressure and the crude residue was purified by column chro-
41.9, 37.4, 31.8, 29.8, 29.6, 29.3, 25.9, 25.8, 25.2, 22.6, 18.0, 17.9, 14.1,
ꢁ4.1, ꢁ4.2, ꢁ4.2, ꢁ4.02, ꢁ4.3, ꢁ4.4; MS (ESIMS) m/z 693 (MþNa)þ;
HRMS (ESI) calcd for C36H75O5Si3 (MþH)þ 671.4922, found 671.4916.
4.25. Polyrhacitide A 11
matography using hexane/ethyl acetate (98:2) as eluent to give
23
0.068 g (98%) as a colourless oil; [
a
]
ꢁ23.3 (c 0.9, CH2Cl2); IR
D
To a solution of 16 (40 mg, 0.06 mmol) in acetonitrile (1 mL) was
added aqueous hydrogen fluoride (0.1 mL, 38% solution) at room
temperature. The reaction mixture was stirred for 5 h then it was
diluted with EtOAc (10 mL) and quenched carefully by addition of
aqueous NaHCO3 (10 mL). The layers were separated and the aque-
ous layer was extracted with EtOAc (2ꢂ10 mL). The combined organic
layers were washed with brine (5 mL), dried over anhydrous Na2SO4
and concentrated under reduced pressure gave a colourless residue,
which was used directly for the next step. The residue was dissolved
in dry dichloromethane (2.5 mL) and was added DBU (1 mg, 20 mol %)
dissolved in dichloromethane (0.2 mL) at room temperature. The
resulting mixture was stirred for 18 h before it was concentrated
under reduced pressure. Purification of the residue by flash chro-
(neat): 3413, 2928, 1598, 1461, 1255, 1122, 1093, 836, 774,
485 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
¼5.87e5.73 (m, 1H,
CH]), 5.11e5.05 (m, 2H, CHaHb]), 4.14e4.06 (m, 1H, CHOSi),
3.83e3.72 (m, 1H, CHOSi), 3.65e3.59 (m, 1H, CHOSi), 3.54 (s, 1H,
CHOH), 2.30e2.31 (m, 2H, CH2CH]), 1.83e1.78 (m, 1H,
CHaHbCHO), 1.69e1.58 (m, 2H, CH2CHO), 1.52e1.35 (m, 3H,
CH2CHO, CHaHbCHO), 1.30e1.25 (m, 12H, eCH2CH2e), 0.91e0.84
(m, 30H, t-BuSi (3), MeCH2), 0.12 (s, 6H, MeSi (2)), 0.04e0.03 (m,
12H, MeSi (4)); 13C NMR (75 MHz, CDCl3):
d 134.8, 117.4, 71.2,
70.7, 69.4, 67.0, 46.3, 46.1, 42.2, 42.1, 39.9, 31.8, 31.4, 30.1, 29.8,
29.3, 25.9, 25.8, 25.8, 24.8, 22.6, 18.5, 18.0, 17.9, 17.8, 14.0, ꢁ3.8,
ꢁ3.9, ꢁ4.0, ꢁ4.2, ꢁ4.4, ꢁ4.6; MS (ESIMS) m/z 645 (MþH)þ, 667
(MþNa)þ; HRMS (ESI) calcd for C38H76O4NaSi3 (MþNa)þ
667.4949, found 667.4975.
matography on silica (CHCl3/MeOH¼99:1) gave polyrhacitide A as
23
colourless solid 0.017 g (86% over two steps); mp¼69e71 ꢀC; [
a]
D
þ8.5 (c 0.5, MeOH); IR (neat): 3435, 2924, 2854, 1737, 1593, 1454,
4.23. (4S,6S,8R,10R)-6,8,10-Tris(tert-butyldimethylsilyloxy)
1416, 1262, 1084, 1072, 1042, 1042, 973, 762, 747, 611 cmꢁ1; 1H NMR
heptadec-1-en-4-yl acrylate 15
(500 MHz, CDCl3):
d
¼4.88 (m, 1H, CHOH), 4.40 (br s, 1H, CHOH),
4.09e4.02 (m, 2H, CHOH), 3.89e3.76 (m,1H, CHOH), 3.48 (s,1H, OH),
2.90 (d, J¼19.3 Hz, 1H, CHaHbC]O), 2.81 (dd, J¼4.9, 18.7 Hz, 1H,
CHaHbC]O), 2.05e1.93 (m, 3H, CH2CHO, CHaHbCHO), 1.75e1.70 (m,
1H, CHaHbCHO), 1.68e1.57 (m, 2H, CH2CHO), 1.53e1.45 (m, 3H,
CH2CHO), 1.44e1.36 (m, 2H, CH2CHO), 1.28 (br s, 7H, eCH2CH2e),
Acryloyl chloride (10
above homoallyl alcohol (70 mg, 0.108 mmol) and triethylamine
(30
L, 0.162 mmol) in anhydrous dichloromethane (2 mL) at 0 ꢀC
mL, 0.13 mmol) was added to a solution of
m
under nitrogen atmosphere. The mixture was stirred for 3 h at 0 ꢀC.
Then the mixture was dissolved in 10 mL dichloromethane and
washed with water (2ꢂ5 mL), brine (2ꢂ5 mL), dried over anhy-
drous Na2SO4 and concentrated under reduced pressure to give
a crude residue, which was purified by column chromatography on
silica gel (hexane/EtOAc, 9:1) to afford the title compound 0.065 g
0.87 (t, J¼6.9 Hz, 3H, MeCH2); 13C NMR (75 MHz, CDCl3):
¼169.2,
d
72.6, 72.4, 72.1, 67.0, 66.0, 43.3, 42.9, 37.8, 37.2, 36.4, 31.8, 29.6, 29.4,
29.3, 25.4, 22.6, 14.1; MS (ESIMS) m/z 329 (MþH)þ, 351(MþNa)þ;
HRMS (ESI) calcd for C18H32O5Na (MþNa)þ 351.2147, found 351.2147.
(87%) as a colourless oil; [
a
]
23 ꢁ18.5 (c 0.5, CH2Cl2); IR (neat): 2929,
Acknowledgements
D
2856, 1729, 1585, 1379, 1255, 1190, 1122, 836, 774, 474 cmꢁ1
;
1H
NMR (300 MHz, CDCl3):
d
¼6.39 (d, J¼9.8 Hz, 1H, CH]), 6.1 (dd,
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/S1/OC-8/2011). UGC and CSIR (New
Delhi) is gratefully acknowledged for awarding the fellowship to
A.N.M. and K.S. respectively. Thanks is also due to Dr. G.V.M.
Sharma, Head, Organic III Division, for his support.
J¼9.8, 16.8 Hz, 1H, CH]), 5.79e5.71 (m, 2H, CH2]), 5.13e5.05 (m,
2H, CH2]), 3.81e3.77 (m, 4H, CHOSi, CHOCO), 2.46e2.39 (m, 1H,
CHaHbCH]), 2.30e2.28 (m, 1H, CHaHbCH]), 1.84e1.72 (m, 2H,
CH2CHO), 1.41e1.26 (m, 16H, CH2CHO, eCH2CH2e), 0.89e0.88 (m,
30H, t-BuSi (3), MeCH2), 0.07e0.04 (m, 18H, MeSi (6)); 13C NMR
(75 MHz, CDCl3):
d
¼165.7, 133.4, 130.5, 128.7, 117.9, 70.6, 69.6, 66.9,
66.7, 46.0, 45.5, 41.7, 39.0, 36.9, 31.8, 29.8, 29.6, 29.3, 25.9, 25.8, 22.6,
18.1, 18.0, 17.9, ꢁ4.0, ꢁ4.1, ꢁ4.2, ꢁ4.3, ꢁ4.4, ꢁ4.4; MS (ESIMS) m/z
699 (MþH)þ; HRMS (ESI) calcd for C38H78O5NaSi3 (MþNa)þ
721.5054, found 721.5040.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2012.02.055.

3186
G. Kumaraswamy et al. / Tetrahedron 68 (2012) 3179e3186
9. (a) Menz, H.; Kirsch, S. F. Org. Lett. 2009, 11, 5634; (b) Binder, J. T.; Kirsch, S. F.
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