2
D.G.S. Sudhakar et al. / Tetrahedron Letters 60 (2019) 151027
Figure 1. Stucture of Balticolid.
Scheme 3. Synthesis of target compound 1 Reagents and conditions: (a) n-BuLi, dry
THF, À20 °C, 3 h, 86%; (b) i) 1 N HCl, THF, rt, 2 h; ii) RuCl3, NaIO4, CH3CN/CCl4/H2O,
rt, 3 h; overall yield for two steps 77% (c) TBAF, THF, 0 °C to rt, 3 h, 89%; (d) i) 2,4,6-
trichlorobenzoyl chloride, Et3N, dry THF, 0 °C to rt, 2 h; ii) DMAP, toluene, 90 °C,
10 h, 61%; (e) CaCO3, MeI, CH3CN:H2O (9:1), 45 °C, 3 h, 73%; (f) TiCl4, CH2Cl2, 0 °C to
rt, 2 h, 79%.
benzyl ether 13 in 92% yield. Ozonolysis of 13 followed by Wittig
olefination of the resulting aldehyde afforded 14 in 94% yield.
Reduction of 14 with DIBAL-H in dry CH2Cl2 at À15 °C for 2 h fur-
nished the corresponding allylic alcohol 15 [14] (88%), which on
treatment with CBr4 in the presence of Ph3P in CH2Cl2 afforded bro-
mide 4 in 81% yield.
With two subunits in hand, we proceeded to couple both inter-
mediates 3 and 4 as described in Scheme 3.Accordingly, Deproto-
nation of 3 with n-BuLi at À20 °C, followed by coupling reaction
with bromide 4 gave the product 16 in 86% yield. Next, Removal
of the acetonide protecting group in 16 with 1 N HCl in THF, and
oxidative cleavage of the resulting diol with RuCl3 and NaIO4 in
CH3CN/CCl4/H2O at room temperature for 3 h afforded the acid
17 in 77% yield.
Scheme 1. Retrosynthetic strategy of 1.
Desilylation of 17 with TBAF in THF at room temperature for 3 h
afforded hydroxy acid 2 [14] in 89% yield. After successful synthe-
sis of hydroxy acid fragment 2, which was then subjected to
macrolactonisation under Yamaguchi high dilution conditions
[13] to provide the lactone 18 in 61% yield.
Next, removal of 1,3-dithaine group in compound 18 with
CaCO3 and MeI, in CH3CN:H2O for 3 h gave the lactone 19 in 73%
yield. In the final step, deprotection of benzyl ether in lactone 19
was removed successfully using TiCl4 at 0 °C to rt to afford balti-
colid (1) in 79% yield. The spectroscopic properties and optical
rotation of balticolid (1) are in good agreement with the reported
values [7,14].
Conclusions
Scheme 2. Synthesis of fragment
3 and 4; Reagents and conditions: (a) Ph3-
P = CHCOOMe, Benzene, reflux, 2 h, , 91%; (b) DIBAL-H, CH2Cl2, À15 °C, 2 h; (c) i)
(COCl)2, DMSO, Et3N, CH2Cl2, À78 °C, 2 h; ii) 1,3-propanedithiol,CAN, CHCl3, 0 °C to
rt, 4 h, 77%; (d) 1 N HCl, THF, 0 °C to rt, 3 h, 81%; (e) i) p-TsCl, Bu2SnO, Et3N, CH2Cl2
0 °C to rt, 4 h; ii) LiAlH4, THF, 0 °C to rt, 3 h, 86%; (f) TBSCl, imidazole, CH2Cl2, rt, 4 h,
93%; (g) Ti(OiPr)4, (–)-DIPT, 4 Å MS and t-BuOOH, dry DCM, À20 °C,12 h, 89%; (h) i)
TPP, I2, imidazole, dry DCM, 0 °C to rt oC, 4 h; ii) Zn, NaI, MeOH, reflux, 8 h, 91% (over
two steps); (i) BnBr, NaH, THF, 0 °C to rt, 6 h, 92%; (j) i) O3, CH2Cl2, À78 oC, 15 min;
ii) Ph3P = CHCOOMe, Benzene, reflux, 2 h, 94% (over two steps); (k) CBr4, Ph3P,
CH2Cl2, 0 °C to rt, 3 h, 81%.
In summary, we have demonstrated an efficient synthesis of
balticolid in 9.7% overall yield starting from commercially available
material. This synthetic strategy involves the Sharpless asymmet-
ric epoxidation, Wittig olefination, alkylation of 1,3-dithiane and
Yamaguchi macrolactonization as key steps.
Acknowledgements
DGS thanks JNT University for constant encouragement during
this research program. DGS is also grateful to GVK Biosciences
for providing basic research facility.
and tert-butyl hydroperoxide in the presence of (–)-DIPT to obtain
the epoxy alcohol 11 (96% de) in 89% yield.
The epoxy alcohol 11 was then converted to corresponding iodo
derivative with I2, Ph3P and imidazole in THF and subsequent
reductive elimination of iodine with activated Zn and NaI in MeOH
at reflux for 8 h furnished the allylic alcohol 12 in 91% yield (over
two steps). Next, subsequent masking of resulting alcohol in 12
with BnBr in the presence of NaH in THF at 0 °C to rt provided
Appendix A. Supplementary data
Supplementary data to this article can be found online at
Sudhakar
