Stereoselective synthesis of (3S,8R,9R,10R)-heptadeca-1-ene-4,6-diyne tetrol and its 3-epimer from D-mannitol

Article abstract of DOI:10.1055/s-2007-985598

(3S,8R,9R,10R)-Heptadeca-1-ene-4,6-diyne tetrol and its 3-epimer were synthesized, and it was found that the relative configuration which was proposed for 1 was incorrect. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-985598

LETTER
2433
Stereoselective Synthesis of (3S,8R,9R,10R)-Heptadeca-1-ene-4,6-diyne Tetrol
and Its 3-Epimer from D-Mannitol1
Stereoselectiv
u
e
S
ynthesis
o
b
f
(3
S
,8
R
,9
R
,
h
10
R
)-Heptad
a
eca-1-ene-4
s
,6-diyne
Tetrol Ghosh,* Tapan Kumar Pradhan
Division of Organic Chemistry III, Indian Institute of Chemical Technology, Uppal road, Hyderabad 500007, India
Fax +91(40)27193108; E-mail: Subhashbolorg3@yahoo.com
Received 8 June 2007
In this communication we report the synthesis of
Abstract: (3S,8R,9R,10R)-Heptadeca-1-ene-4,6-diyne tetrol and
its 3-epimer were synthesized, and it was found that the relative
configuration which was proposed for 1 was incorrect.
(3S,8R,9S,10R)-heptadeca-1-ene-4,6-diyne tetrol (1a) and
(3R,8R,9R,10R)-heptadeca-1-ene-4,6-diyne tetrol (1b) to
verify the proposed structure and relative configurations
of 1.
Key words: polyacetylene, Cadiot–Chodkiewicz cross-coupling
reaction, Th2-type diseases, D-mannitol
Retrosynthetic analysis for 1a and 1b revealed that they
could be obtained from 4a, 4b and 5 via Cu(I)-catalyzed
Cadiot–Chodkiewicz cross-coupling reactions.3 Fragment
4a, 4b and 5, in turn, could be obtained from cheap chiral
D-mannitol as shown in Scheme 1.
Hydrocotyle leucocephala is a plant native of Brazil, and
widespread worldwide due to its use as an ornamental
aquarium plant. In Colombia this plant is used as a di-
uretic, antihelminthic and antidiarrheal medicine. It is also
widely used to purify the water of aquaculture system.
Very recently Takaishi et al. have isolated three new C-17
acetylene compounds 1–3,2 from this plant. Compound 1
inhibited the lipopolysaccharide (LPS)-induced interleu-
kin-10 (IL-10) production but not the production of tumor
necrosis factor-a (TNF-a) and interleukin-12 (IL-12).
Compounds 2 and 3 inhibited the production of all cyto-
kines tested. It was found that 2 and 3 are much more
potent than 1 for the inhibition of the cytokine production
rate for TNF-a and IL-12. It was also found that com-
pounds 2 and 3 are inhibitors against the whole immune
response, while compound 1 is a strong T-helper cell
(Th2) inhibitor.2 This suggests that compound 1 can be
used as a lead for the treatment of Th2-type diseases. The
structures of these compounds were established by
spectroscopic methods and relative stereochemistries of
these compounds were reported to be 3a,8a,9a,10b or
3b,8a,9a,10b as shown in Figure 1.
OTBDPS
4a = 3α OH
4b = 3β OH
OH
D-mannitol
OH
Br
O
C6H13
1a: 3α OH
1b: 3β OH
C6H13
OH
OH
O
OMEM
5
Scheme 1 Retrosynthetic analysis.
Our synthesis started from compound 6, which was pre-
pared from D-mannitol according to the reported proce-
dures.4 Selective tosylation of the primary hydroxyl group
of 6 with TsCl and Et3N in CH2Cl2 at 0 °C gave compound
7, which on treatment with anhydrous K2CO3 in anhy-
drous MeOH afforded epoxide 8. Epoxide opening of 8
with n-hexyl cuprate reagent afforded alcohol 9.5 Hydrox-
yl protection of 9 as its MEM ether furnished compound
10. Chemoselective deprotection of the terminal ace-
tonide with catalytic amount of CSA in MeOH afforded
diol 11. Compound 11 was converted into 13 in three
steps. NaIO4 cleavage of the diol 11 gave the correspond-
ing aldehyde, which was subjected to Corey–Fuchs reac-
tion with CBr4, Ph3P and Et3N to give the gem-dibromo
compound 12.6 Compound 12 on treatment with EtMgBr
in THF at –78 °C afforded acetylene compound 13.
Finally compound 13 was subjected to AgNO3-catalyzed
bromination with NBS to give 1-bromoalkyne 5
(Scheme 2).7,8a
OH
3
OH
3
1
1
OH
OH
C6H13
C6H13
OH
OH
1a: 3α OH
1b: 3β OH
OH
OAc
2a: 3α OH
2b: 3β OH
1
OH
3
2
1
OAc
C6H13
OH OH
3a: 3α OH
3b: 3β OH
3
For the synthesis of fragment 4a, we started with com-
pound 6 (Scheme 3). Oxidative cleavage of the diol in 6
with NaIO4 gave the aldehyde, which was reduced in situ
with NaBH4 to furnish alcohol 14. Compound 14 was
converted into 16 in two steps, involving formation of the
Figure 1
SYNLETT 2007, No. 15, pp 2433–2435
Advanced online publication: 22.08.2007
DOI: 10.1055/s-2007-985598; Art ID: G16107ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.0
9
.2
0
0
7

2434
S. Ghosh, T. K. Pradhan
LETTER
O
O
O
O
O
O
ref. 4
i
ii
i
O
O
D-mannitol
O
OH
OH
OH
6
6
OH
I
O
OH
O
14
O
O
O
O
ii
O
O
iii
OH
iv
O
iii
O
O
O
O
OTs
7
16
8
O
OH
O
OH
OH
15
O
O
OH
O
vi
v
O
O
HO
O
O
O
v
iv
C6H13
O
O
C6H13
18
OTBDPS
17
OTBDPS
10
9
O
OMEM
O
O
O
O
vii
HO
vi
Br
Br
C6H13
OMEM
HO
OTBDPS
4a
C6H13
Br
O
O
11
12
OMEM
Scheme 3 Reagents and conditions: (i) NaIO4, THF–H2O (2:1),
0 °C, 2 h, followed by NaBH4, 1 h, 80%; (ii) Ph3P, I2, imidazole,
toluene, 50 °C, 1 h, 95%; (iii) activated Zn dust, EtOH, reflux, 6 h,
80%; (iv) TBDPSCl, imidazole, DMF, r.t., 90%; (v) 50% aq AcOH,
r.t., 48 h, 95%; (vi) (a) NaIO4, THF–H2O (2:1), 0 °C, 1 h; (b) CBr4,
TPP, Zn dust, CH2Cl2, 0 °C, 2 h; (c) EtMgBr, THF, –78 °C to 0 °C,
1 h, 70% over three steps.
O
O
viii
C6H13
OMEM
C6H13
5
O
OMEM
13
Scheme 2 Reagents and conditions: (i) TsCl, Et3N, DMAP (cat.),
CH2Cl2, 0 °C, 5 h; (ii) K2CO3, MeOH, r.t., 3 h, 80% in two steps; (iii)
Me(CH2)5MgBr, CuI (cat.), THF, 0 °C, 90%; (iv) MEMCl, DIPEA,
CH2Cl2, r.t., 48 h, 95%; (v) CSA (cat.), CH2Cl2–MeOH (4:1), 0 °C to
r.t., 6 h, 60%; (vi) (a) NaIO4, THF–H2O (2:1), 0 °C, 1 h; (b) CBr4, tri-
phenylphosphine (TPP), Et3N, CH2Cl2, 0 °C, 2 h; (vii) EtMgBr, THF,
–78 °C to 0 °C, 1 h, 65% over three steps; (viii) NBS, AgNO3, aceto-
ne, 0 °C to r.t., 95%.
afforded compound 4b.11,12a Coupling between 4b and 5
was achieved, under similar reaction conditions as used
earlier for the coupling between 4a and 5, to give 24,
which on global deprotection with 6 N HCl at 50 °C af-
forded 1b. Unfortunately spectral data of 1b12b were also
not in agreement with the literature data.2 Takaishi et al.
proposed the relative stereochemistry of 1 at the triol
system (C-8, C-9 and C-10) on the basis of the method
proposed by Higashibayashi et al.13 According to the uni-
versal databases as proposed by Higashibayashi et al., for
a triol system (A), for aab configurations at C-5, C-6 and
primary iodide 15 by treatment with Ph3P, I2 and imida-
zole in toluene. Activated Zn dust mediated elimination
subsequently furnished allylic alcohol 16.9 Hydroxyl pro-
tection of 16 as a TBDPS ether, followed by acid-cata-
lyzed acetonide deprotection gave 18. Compound 18 was
converted into acetylene compound 4a in good yield using
similar transformations to those used for the synthesis of
13 from 11 (Scheme 2).8b
C-7, the coupling constants are 3J5,6 = 2.5 Hz, and 3J6,7
=
3
8.0 Hz (Figure 2), for abb system J5,6 = 8.0 Hz, and
3J6,7 = 2.5 Hz, for aaa system J5,6 = 4.0 Hz, and J6,7
=
=
3
3
3
3
With bromoacetylene compound 5 and acetylene com- 4.0 Hz and for aba system J5,6 = 7.0 Hz, and J6,7
pound 4a in hand, coupling via the Cadiot–Chodkiewicz 7.0 Hz respectively. For the natural product the coupling
3
3
reaction produced the corresponding diyne 19 in 70% constants are J8,9 = 8.8 Hz and J9,10 = 2.0 Hz, which
yields.3 Finally, global deprotection of the protecting means that the relative stereochemistry for the triol system
groups using 6 N HCl in THF at 50 °C afforded the final (C-8, C-9 and C-10) of 1 should be abb and not aab or
compound 1a (Scheme 4). Spectroscopic data of 1a,8c aaa or aba. To confirm this, it would be necessary to
namely H NMR and 13C NMR spectra, however, were
1
not in agreement with the reported data for the natural
TBDPSO
product.2 Therefore the relative stereochemistry of the hy-
droxyl groups in 1 is not 3a,8a,9a,10b and it was assumed
to be 3b,8a,9a,10b as in 1b.
O
i
4a
+ 5
Next, we turned our attention to the synthesis of com-
pound 1b (the C-3-epimer of 1a), which was synthesized
according to the Scheme 5. Our synthesis started from
compound 14, which was converted into propargylic alco-
hol 21 in two steps using Yadav’s methodology.10 Protec-
tion of the secondary hydroxyl group as a TBDPS ether
followed by acetonide deprotection gave diol 23, which
19
OMEM
ii
O
1a
Scheme 4 Reagents and conditions: (i) CuCl, NH2OH·HCl, aq
EtNH2, MeOH, 0 °C to r.t., 15 min, 75%; (ii) 6 N HCl, THF, 50 °C,
on treatment with Ph3P, I2 and imidazole in toluene 4 h, 60%.
Synlett 2007, No. 15, 2433–2435 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of (3S,8R,9R,10R)-Heptadeca-1-ene-4,6-diyne Tetrol
2435
References and Notes
O
O
O
O
O
i
ii
(1) IICT Communication No. 070414.
OH
O
Cl
(2) Ramos, F.; Takaishi, Y.; Kawazoe, K.; Osorio, C.; Duque,
C.; Acuña, R.; Fujimoto, Y.; Sato, M.; Okamoto, M.;
Oshikawa, T.; Ahmed, S. U. Phytochemistry 2006, 67, 1143.
(3) Cadiot, P. C. R.; Chodkiewicz, W. In Chemistry of
Acetylenes; Viehe, H. G., Ed.; Marcel Dekker: New York,
1969, 597.
(4) Wiggins, L. J. Chem. Soc. 1946, 13.
(5) Lipshutz, B. H.; Sengupta, S. Org. React. (N. Y.) 1992, 41,
135.
20
O
O
14
O
O
iv
iii
O
O
OTBDPS
OH
21
OH
22
vi
v
(6) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(7) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R.
Angew. Chem., Int. Ed. Engl. 1984, 23, 727.
HO
5
OTBDPS
4b
OTBDPS
23
(8) (a) Spectral data of 5: [a]D30 +57.3 (c = 2.97, CHCl3). 1H
NMR (600 MHz, CDCl3): d = 4.78 (d, J = 7.1 Hz, 1 H), 4.70
(d, J = 7.1 Hz, 1 H), 4.60 (d, J = 7.1 Hz, 1 H), 4.08 (dd, J =
4.3, 7.1 Hz, 1 H), 3.75 (dt, J = 4.3, 5.8 Hz, 1 H), 3.65–3.71
(m, 2 H), 3.49–3.50 (m, 2 H), 3.33 (s, 3 H), 1.45–1.50 (m, 2
H), 1.40 (s, 3 H), 1.32 (s, 3 H), 1.18–1.24 (m, 10 H), 0.8 (t,
J = 6.7 Hz, 3 H). 13C NMR (150 MHz, CDCl3): d = 110.2,
95.5, 83.1, 78.1, 75.9, 71.6, 67.1, 66.9, 58.9, 46.6, 31.7, 31.4,
29.5, 29.1, 26.5, 25.6, 25.2, 22.5, 14.0.
TBDPSO
vii
1b
O
OMEM
O
24
Scheme 5 Reagents and conditions: (i) Ph3P, CCl4, reflux, 6 h,
90%; (ii) LDA, THF, –78 °C, 2 h, 80%; (iii) TBDPSCl, imidazole,
DMF, r.t., 12 h, 90%; (iv) 50% aq AcOH, r.t., 16 h, 90%; (v) Ph3P, I2,
imidazole, toluene, 50 °C, 2 h, 95%; (vi) 5, CuCl, NH2OH·HCl, aq
EtNH2, MeOH, 0 °C to r.t., 15 min, 65%; (vii) 6 N HCl, THF, 50 °C,
4 h, 50%.
MS (LCMS): m/z = 443 [M(79Br) + Na]+, 445 [M(81Br) +
30
Na]+. (b) Spectral data of 4a: [a]D –45.3 (c = 2.28, CHCl3).
1H NMR (200 MHz, CDCl3): d = 7.30–7.86 (m, 10 H), 5.87
(ddd, J = 5.1, 10.2, 16.8 Hz, 1 H), 5.29 (dt, J = 1.4, 16.8 Hz,
1 H), 5.11 (dt, J = 1.4, 10.2 Hz, 1 H), 4.80 (m, 1 H), 2.37 (d,
J = 2.2 Hz, 1 H), 1.10 (s, 9 H). 13C NMR (150 MHz, CDCl3):
d = 137.0, 135.9, 135.8, 133.2, 133.1, 129.8, 127.5, 127.4,
115.6, 83.0, 73.8, 64.3, 26.8, 19.3. MS (LCMS): m/z = 343
[M + Na]+, 279 [M – 64 + Na]+. (c) Spectral data of 1a:
[a]D32 +6.0 (c = 0.20, MeOH). 1H NMR (300 MHz, CDCl3):
d = 5.94 (ddd, J = 5.2, 10.2, 16.6 Hz, 1 H), 5.47 (d, J = 16.6
Hz, 1 H), 5.27 (d, J = 10.2 Hz, 1 H), 4.94 (d, J = 5.2 Hz, 1
H), 4.68 (d, J = 3.7 Hz, 1 H), 3.81 (ddd, J = 4.0, 4.5, 8.3 Hz,
1 H), 3.60 (dd, J = 3.7, 4.5 Hz, 1 H), 1.43–1.65 (m, 2 H),
1.06–1.32 (br m, 10 H), 0.88 (br t, J = 6.8 Hz, 3 H). 13C NMR
(150 MHz, CDCl3): d = 135.6, 117.4, 78.4, 78.3, 75.6, 72.7,
70.1, 70.0, 63.8, 63.4, 33.1, 31.7, 29.5, 29.2, 25.5, 22.6, 14.0.
MS (LCMS): m/z = 317 [M + Na]+.
synthesize two more diastereoisomers of 1 with relative
stereochemistry at C-3, C-8, C-9, C-10 as aabb and
babb. Currently we are working in that direction and the
results will be reported in due course.
OH OH
1
5
7
HO
Me
6
A
OH
For ααβ configuration 3J5,6 = 2.5 Hz and 3J6,7 = 8.0 Hz
For αββ configuration 3J5,6 = 8.0 Hz and 3J6,7 = 2.5 Hz
For ααα configuration 3J5,6 = 4.0 Hz and 3J6,7 = 4.0 Hz
For αβα configuration 3J5,6 = 7.0 Hz and 3J6,7 = 7.0 Hz
(9) Lu, W.; Zheng, G.; Cai, J. Synlett 1998, 737.
(10) Yadav, J. S.; Chander, M. C.; Rao Srinivas, C. Tetrahedron
Lett. 1989, 30, 5455.
OH
(11) Garegg, P. G.; Samuclson, B. Synthesis 1979, 813.
(12) (a) Spectral data of 4b: [a]D30 +45.6 (c = 2.90, CHCl3). 1H
NMR (500 MHz, CDCl3): d = 7.30–7.86 (m, 10 H), 5.91
(ddd, J = 5.2, 10.1, 17.1 Hz, 1 H), 5.33 (dt, J = 1.3, 17.1 Hz,
1 H), 5.13 (dt, J = 1.3, 10.1 Hz, 1 H), 4.83–4.85 (m, 1 H),
2.44 (d, J = 2.3 Hz, 1 H), 1.11 (s, 9 H). 13C NMR (150 MHz,
CDCl3): d = 137.0, 135.9, 135.8, 133.2, 133.1, 129.7, 127.5,
127.4, 115.6, 83.0, 73.8, 64.3, 26.8, 19.3. MS (LCMS):
m/z = 343 [M + Na]+, 279 [M – 64 + Na]+. (b) Spectral data
of 1b: [a]D32 –20.92 (c = 0.65, MeOH). 1H NMR (300 MHz,
CDCl3): d = 5.93 (ddd, J = 5.3, 10.2, 17.0 Hz, 1 H), 5.47 (d,
J = 17.0 Hz, 1 H), 5.25 (d, J = 10.2 Hz, 1 H), 4.93 (d, J = 5.3
Hz, 1 H), 4.66 (d, J = 3.5 Hz, 1 H), 3.80 (ddd, J = 3.5, 4.5,
8.1 Hz, 1 H), 3.63 (dd, J = 3.5, 4.5 Hz, 1 H), 1.44–1.63 (m,
2 H), 1.20–1.36 (br m, 10 H), 0.88 (br t, J = 6.98 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 135.7, 117.2, 78.4, 77.1,
75.9, 72.5, 70.1, 70.0, 63.6, 63.1, 32.7, 31.8, 29.5, 29.2, 25.6,
22.6, 14.0. MS (LCMS): m/z = 317 [M + Na]+.
OH
9
8
10
OH OH
1
Observed coupling constants for 1, at
position 8, 9, 10 are 3J8,9 = 8.8 Hz and
3J9,10 = 2.0 Hz
Figure 2
Acknowledgment
One of us is thankful to UGC, New Delhi, for a research fellowship
(T.K.P.). We are also thankful to Dr. T. K. Chakraborty, Dr. A. C.
Kunwar and Director, IICT for their support and encouragement.
(13) Higashibayashi, S.; Czechtisky, W.; Kobayashi, Y.; Kishi,
Y. J. Am. Chem. Soc. 2003, 125, 14379.
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