Studies toward the total synthesis of cyclodidemniserinol trisulfate. Part II: 3,5,7-Trisubstituted 6,8-dioxabicyclo [3.2.1] octane core structure construction via I2-mediated deprotection and ring closure tandem reaction

Article abstract of DOI:10.1016/j.tetlet.2009.05.088

The 3,5,7-trisubstituted 6,8-dioxabicyclo [3.2.1] octane core structure was synthesized by employing a chiral pool convergent synthesis strategy and the I₂-mediated simultaneous deprotection and ring closure reaction as the key step, providing a practical and efficient synthetic approach applicable to the further total synthesis of the natural product cyclodidemniserinol trisulfate.

Full text of DOI:10.1016/j.tetlet.2009.05.088

Tetrahedron Letters 50 (2009) 4592–4594
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies toward the total synthesis of cyclodidemniserinol trisulfate. Part II:
3,5,7-Trisubstituted 6,8-dioxabicyclo [3.2.1] octane core structure
construction via I2-mediated deprotection and ring closure tandem reaction
*
Jian-Hua Liu, Ya-Qiu Long
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The 3,5,7-trisubstituted 6,8-dioxabicyclo [3.2.1] octane core structure was synthesized by employing a
chiral pool convergent synthesis strategy and the I2-mediated simultaneous deprotection and ring clo-
sure reaction as the key step, providing a practical and efficient synthetic approach applicable to the fur-
ther total synthesis of the natural product cyclodidemniserinol trisulfate.
Received 22 April 2009
Revised 15 May 2009
Accepted 18 May 2009
Available online 27 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Cyclodidemniserinol trisulfate (Fig 1), known as a natural prod-
uct HIV-1 integrase inhibitor, was isolated and characterized from
extracts of marine invertebrates, the Palauan ascidian Didemnum
guttatum by Faulkner et al. in 2000.1 Undetermined absolute con-
figuration and the low content in nature hampered its further bio-
logical studies. In order to determine the absolute stereochemistry
and to establish synthetic methodology for further structural
derivatization and medicinal chemistry study, we initiated the pro-
ject of total synthesis of the natural HIV-1 integrase inhibitor,
cyclodidemniserinol trisulfate.
On the basis of the retrosynthetic analysis of the molecule, we
decided to start the total synthesis from constructing the 3,5,7-tri-
substituted-6,8-dioxabicyclo [3.2.1] octane, the core structure of
the natural marine product. Furthermore, the 6,8-dioxabicyclo
[3.2.1] octane is an attractive structure embedded in many biolog-
ically active molecules.2 The study of its synthesis will be beneficial
for developing the active structure into promising pharmaceutical
candidates.
In our previous efforts, we tried a stereoselective convergent
synthesis strategy and a linear synthesis strategy to construct the
3,5,7-trisubstituted-6,8-dioxabicyclo [3.2.1] octane by employing
intramolecular ketal formation as the key step.3 However, the ster-
eoselective convergent synthesis resulted in a very low overall
yield, inappropriate for the total synthesis. And the linear synthesis
consisted of too many steps, not convenient for the further total
synthesis and structural elaboration either. So, for the purpose of
future applicability, we needed to develop another efficient and
convenient strategy to synthesize the core structure.
fewer steps, acceptable yield, and with flexible substitution in
proper positions. More significantly, the application of I2-mediated
ketal and thioketal deprotection reaction accomplished the simul-
taneous removal of the ketal and thioketal groups and the forma-
tion of intramolecular ketal in one pot, greatly improving the
synthesis efficiency.
The retrosynthetic analysis of the target molecule is outlined in
Scheme 1. After several steps of functional group conversion, with
the chirality at 3-position being kept intact, a thioacetal fragment
and an epoxide fragment were selected as the starting materials.
Furthermore, considering the 3-substituent elimination issue,3
the protecting group of the 3-hydroxy on the dioxabicyclo skeleton
was designed as isovalerate. The isovalerate group naturally occurs
in the product as well as is less liable to eliminate during the
synthesis.
The dithioacetal fragment
2 was easily synthesized from
1,4-butandiol (Scheme 2). Oxidation of monobenzyl derivative 1
via Swern oxidation followed by treatment with 1,3-propanedithol
resulted in the dithioacetal 2 in 87% yield.
The epoxide fragment was synthesized from
D-tartaric acid,
which served as a chiral pool. The esterification with ethanol fol-
lowed by diol protecting as acetonide furnished the fully protected
OR
O
NHR
O
NH
1
7
2
O
O
O8
O
R=SO3Na
O 3
6
O
Herein, we report a chiral pool convergent synthesis toward the
3,5,7-trisubstituted-6,8-dioxabicyclo [3.2.1] octane structure with
5
4
RO
* Corresponding author. Tel./fax: +86 021 50806876.
E-mail address: yqlong@mail.shcnc.ac.cn (Y.-Q. Long).
Figure 1. The structure of cyclodidemniserinol trisulfate. The dashed circle
indicates the core structure of 3,5,7-trisubstituted-6,8-dioxabicyclo [3.2.1] octane.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.088

J.-H. Liu, Y.-Q. Long / Tetrahedron Letters 50 (2009) 4592–4594
4593
in Et2O, pTsOH in MeOH, 6 N HCl in H2O, and TiCl4 in CH2Cl2 all
failed, even 5.0 equiv of BF3ÁEt2O produced the deprotected com-
pound 13 only. So, we had to explore other reaction conditions
to promote the intramolecular ketal formation reaction instead of
proton or Lewis acid catalysis.
R2
HO
R2
O
OH
O
S
R3
S
O
OH
R1
O
R2
O
R1O
R3
O
R3
It was reported in the literature that iodine reagent could
remove both thioketal group and ketal group.7 It occurred to us
that the thioketal group and ketal group in compound 10 might
be removed simultaneously when treating with iodine, then the
resulting ketone could further react with the generated diol group
to achieve intramolecular ketal formation in situ.
Therefore, we investigated the reaction of compound 10 with
iodine (Scheme 3) under different conditions (Table 1). When
MeOH was used as the solvent, no reaction occurred. When H2O
OH
O
S
S
O
COOH
R3
HOOC
R2
OH
O
Thioacetal
Fragment
Epoxide
Fragment
Scheme 1. The retrosynthetic analysis of the 3,5,7-trisubstituted-6,8-dioxabicyclo
[3.2.1] octane via a chiral pool convergent synthesis approach.
S
S
b
a
BnO
HO
OH
OH
HO
BnO
2
1
O
O
O
OH
COOH
EtOOC
OH
OTBS
f
c
e
d
HOOC
COOEt
HO
O
O
O
OH
3
4
5
D-Tartaric acid
O
O
O
O
OTBS
OH
OTBS
O
BnO
i
OTBS
OTBS
g
h
S
S
I
O
OH
O
O
2
O
O
6
7
8
9
O
OTBS
OTBS
BnO
BnO
l
j
k
S
S
O
O
O
O
O
O
O
O
O
O
O
OBn
10
11
12
Scheme 2. The fragments synthesis and the first trial of Lewis acid-mediated construction of the 3,5,7-trisubstituted-6,8-dioxabicyclo [3.2.1] octane. Reagents and
conditions: (a) NaH, BrBn, THF, reflux, 80%; (b) (1) Swern oxidation, (2) HS(CH2)3SH,BF3ÁEt2O, CH2Cl2, rt, 87% for two steps; (c) (1) EtOH, toluene, reflux, (2) CH(OEt)3, acetone,
p-TsOH, 82% for two steps; (d) LAH, THF, reflux, 80%; (e)NaH, TBSCl, DME, 0 °C, 82%; (f) Ph3P, imidazole, I2, toluene, rt, 87%; (g) vinylmagnesium bromide, CuI, THF–HMPA,
À78 °C, 71%; (h) mCPBA, CH2Cl2, rt, 69%; (i) n-BuLi, THF–HMPA, À78 °C then rt, 65%, (j) isovaleric acid, DCC, CH2Cl2, rt, 80%; (k) MeI, K2CO3, MeCN/THF/H2O, reflux, 71%; (l) H+
or Lewis acid, see text.
O
O
OH
OTBS
OH
BnO
BnO
I2
S
S
O
O
O
O
O
O
O
O
See table 1
O
O
O
OBn
10
12
13
Scheme 3. I2-mediated tandem reaction of deprotection and ring closure via intramolecular ketal formation.
D
-tartaric acid derivative 3 in an overall yield of 82%. The ester 3
was added as co-solvent, only deprotected compound 13 was
obtained. Other solvents such as DMSO, THF, MeCN, and CHCl3
were tested further. DMSO and THF proved not to be effective for
was reduced by LAH into the 1,4-diol 4. Mono-protection of 4 with
TBSCl was achieved in the solvent DME in 81% yield.4 Iodination of
the resulting alcohol 55 followed by coupling with vinyl magne-
sium bromide in the presence of catalytic CuI afforded terminal
alkene 7 in 71% yield. Subsequent oxidation with mCPBA yielded
epoxide 8 non-stereoselectively.
Table 1
Condition optimization for the I2-mediated deprotection and intramolecular ketal
formation reaction conducted on compound 10
The coupling of the two fragments 2 and 8 proceeded smoothly
via an SN2 epoxide opening reaction in 65% yield. The hydroxyl
group in the resulting compound 9 was protected with isovaleric
acid in the presence of DCC to produce compound 10 in 80% yield.
Removal of the thioketal group in 10 with CH3I6 produced the ring-
closure precursor 11 in 71% yield. However, treatment of
compound 11 with BF3ÁEt2O in ether system failed to generate
the desired product, although this reaction worked well in our pre-
vious system.3 Various reaction conditions were investigated with
respect to the optimal acid-solvent combination. However, 1 N HCl
Entry
Solvent (equiv of I2)
Conditions
Result
1
2
3
4
5
6
7
8
9
MeOH (6 equiv)
MeOH–H2O (6 equiv)
MeCN (6 equiv)
MeCN (2 equiv)
MeCN (cat.)
MeCN (1 equiv)
DMSO (2 equiv)
THF (2 equiv)
rt, 40 min
rt, 2 h
rt, 6 min
rt, 5 min
rt, 5 h
0 °C, 15 min
rt 1 h
rt, 2 h
No reaction
13
By-products
12 (48%)
No reaction
By-products
By-products
By-products
12 (30%)
CHCl3 (2 equiv)
rt, 15 min

4594
J.-H. Liu, Y.-Q. Long / Tetrahedron Letters 50 (2009) 4592–4594
O
O
dem reaction, including thioketal deprotection, acetonide depro-
tection, and intramolecular ketal formation in one pot. Thus the
whole synthesis was accomplished with 13 reactions and 10 steps
in nearly 3% overall yield (according to the longest route), with an
unambiguous chiral center at 3-position. Definitely, the fewer
steps, mild conditions, and acceptable overall yield will make this
synthetic approach promising and applicable for the further total
synthesis and the structural derivatization.
OTBS
OTBS
a
BnO
b
BnO
c
S
S
S
S
OH
O
OH
O
(3S)-9
9
O
O
OH
OTBS
BnO
S
S
O
O
O
O
O
O
OBn
(3S)-12
(3S)-10
Acknowledgement
Scheme 4. I2-mediated deprotection and ring closure tandem reaction applied to
the optically pure compound. Reagents and conditions: (a) Chromatograph; (b)
isovaleric acid, DCC, CH2Cl2, rt, 80%; (c) I2, MeCN, 30%.
This work was financially supported by the National Natural
Science Foundation of China (Nos. 20372068 and 30672528).
O
O
Ha
O
O
OBn
O
OBn
O
O
Ha H
O
OH
Hb
OH
Supplementary data
b
NOE effect
(3S)-12
No NOE effect
(3R)-12
Synthetic procedure, NMR data and HRMS data of all new com-
pounds; and 1H and 13CNMR spectra of important compounds,
including the gCOSY and NOESY spectrum of (3S)-12 and (3R)-
12, are provided. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.
2009.05.088.
Scheme 5. The NOE analysis of compounds (3S)-12 and (3R)-12.
the production of the desired product, just producing side-prod-
ucts instead. However, when compound 10 was treated with I2
in acetonitrile (2 equiv, 0.01 N in MeCN) at rt for 5 min, the target
molecule 12 was harvested in 48% yield. And CHCl3 behaved as
effective as MeCN, affording the product 12 in 30% yield. After
the success of the template reaction concerning I2-mediated intra-
molecular ketal formation, we applied the optimized reaction con-
dition to the optically pure compound. Compound 9 was separated
by silica gel column chromatography to provide (3S)-9 and (3R)-9
in almost equal amount. Compound (3S)-9 was transformed into
the isovalerate (3S)-10 according to the procedure mentioned
above. Treatment of compound (3S)-10 with iodine in MeCN fur-
nished the desired product (3S)-12 in 30% yield, without the for-
mation of its diastereomer (3R)-12 (Scheme 4). The chirality of
3-position in compounds (3S)-12 and (3R)-12 was determined
with NOESY (Scheme 5). The NOE between Ha and Hb in compound
(3S)-12 revealed the S configuration of 3-position, while in com-
pound (3R)-12, such NOE was not observed.
References and notes
1. Mitchell, S. S.; Rhodes, D.; Bushman, F. D.; Faulkner, D. J. Org. Lett. 2000, 2, 1605–
1607.
2. (a) Wood, D. L.; Browne, L. E.; Ewing, B.; Lindahl, K.; Bedard, W. D.; Tilden, P. E.;
Mori, K.; Pitman, G. B.; Hughes, P. R. Science 1976, 192, 896–898; (b) Ellory, J. C.;
Tucker, E. M. Nature 1969, 222, 477–478; (c) Pearce, G. T.; Gore, W. E.;
Silverstein, R. M.; Peacock, J. W.; Cuthbert, R. A.; Lanier, G. N.; Simeone, J. B. J.
Chem. Ecol. 1975, 1, 115–124; (d) Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D.
Tetrahedron 2002, 58, 1983–1995; (e) Uemura, D.; Chou, T.; Haino, T.; Nagatsu,
A.; Fukuzawa, S.; Zheng, S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155–1156; (f)
Milroy, L. G.; Zinzalla, G.; Prencipe, G.; Michel, P.; Ley, S. V.; Gunaratnam, M.;
Beltran, M.; Neidle, S. Angew. Chem., Int. Ed. 2007, 46, 2493–2496.
3. Liu, J.-H.; Song, L.-D.; Long, Y.-Q. Tetrahedron Lett. 2009, 50, 4587–4591.
4. Furstner, A.; Wuchrer, M. Chem. Eur. J. 2006, 12, 76–89.
5. Enders, D.; Lenzen, A.; Backes, M.; Janeck, C.; Catlin, K.; Lannou, M.; Runsink, J.;
Raabe, G. J. Org. Chem. 2005, 70, 10538–10551.
6. (a) Takano, S.; Hatakeyama, S.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1977,
68–69; (b) Myers, A. G.; Condroski, K. R. J. Am. Chem. Soc. 1995, 117, 3057–3083.
7. (a) Russell, G. A.; Ochrymowycz, L. A. J. Org. Chem. 1969, 34, 3618–3624; (b)
Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98, 4887–4902; (c)
Chattopadhyaya, J. B.; Rama Rao, A. V. Tetrahedron Lett. 1973, 14, 3735–3736; (d)
Sun, J.-W.; Dong, Y.-M.; Cao, L.-Y.; Wang, X.-Y.; Wang, S.-Z.; Hu, Y.-F. J. Org.
Chem. 2004, 69, 8932–8934.
In conclusion, we established a convenient and efficient syn-
thetic route to achieve the 3,5,7-trisubstituted-6,8-dioxabicyclo
[3.2.1] octane core of cyclodidemniserinol trisulfate, by employing
a chiral pool convergent synthesis strategy. This strategy was
featured with an I2-mediated deprotection and ring closure tan-