Do upper limits to the multiple spiro acetalization of the cyclohexane ring exist?

Article abstract of DOI:10.3987/COM-07-S(U)4

An attempt to transform the pyranoside (5) into the bifaciai ligand (3) is described. The first subtarget is acetal (13) whose conversion into tris acetal (17) is made possible by remote C-H activation. Regrettably, triol (20) does not lend itself to comparable triple cyclization.

Full text of DOI:10.3987/COM-07-S(U)4

HETEROCYCLES, Vol. 73, 2007
165
HETEROCYCLES, Vol. 73, 2007, pp. 165 - 168. © The Japan Institute of Heterocyclic Chemistry
Received, 11th April, 2007, Accepted, 9th May, 2007, Published online, 11th May, 2007. COM-07-S(U)4
DO
UPPER
LIMITS
TO
THE
MULTIPLE
SPIRO
ACETALIZATION OF THE CYCLOHEXANE RING EXIST?‡
Peter R. Selvaraj and Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University, Columbus, OH
43210, USA; e-mail: paquette.1@osu.edu
Abstract – An attempt to transform the pyranoside (5) into the bifacial
ligand (3) is described. The first subtarget is acetal (13) whose conversion
into tris acetal (17) is made possible by remote C-H activation. Regrettably,
triol (20) does not lend itself to comparable triple cyclization.
The concept of bifacial chelation relates to the capacity of a singular molecular entity to coordinate to a
pair of metal ions residing on apposite faces of the organic core.1 The structural features associated with
this phenomenon hold fundamental interest and could potentially serve a wide range of applications.
However, the reluctance of candidate substrates to become involved in appropriate modes of geometric
alignment has inhibited progress in this area.
For example, the previously synthesized
hexamethoxycyclohexane (1)2 and its hexaspiro tetrahydrofuran homolog (2)3 have proven to be
markedly inert to alkali metal ion coordination.
The unalterable preference for outward projection of the C-O bonds in 1 and 2 has been attributed to the
operation of six stabilizing gauche interactions in the all O-equatorial conformer, and to the energetic
costs associated with the orientation of multiple alkoxy substituents axially on the same face of the
cyclohexane scaffold.4
O
O
O
O
O
O
O
O
O
O
O
OCH3
OCH3
OCH3
O
O
O
H3CO
H3CO
O
O
O
O
O
O
O
O
O
H3CO
O
1
2
3
4
____________
‡This paper is dedicated to the memory of Ivar Ugi, whose fundamental contributions to heterocyclic and
computational chemistry have played an important role in these fields.

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HETEROCYCLES, Vol. 73, 2007
Multiple oxygenated centers can be projected in the desirable axial-rich manner under suitable
circumstances that include the use of bulky substituents5 or of inositol orthoformate platforms.6 The latter
tactic has made possible the elaboration of attractive linear homoditopic ligands.7 Because of their
insolubility in common solvents, the polymers derived therefrom are inadequate as ionophores. Since the
introduction of additional oxygen atoms was expected to be beneficial, a more advanced target became
the hexaspiro acetal (3). While the chelation advantages offered by 3 are obvious, its acquisition by
synthesis was viewed as problematic. A notably brief route involving the multiple ketalization of readily
available hexaketone (4) (as the octahydrate)8 proved not to be serviceable because of its extreme
insolubility under applicable conditions.9 A more unconventional protocol was clearly warranted. A
route that utilizes commercially available methyl α-D-glucopyranoside (5) as the starting material is
outlined herein.
The conversion of 5 to 7 was initially accomplished in an efficient two-step maneuver (Scheme 1).
Removal of the trityl group under mildly acidic conditions afforded alcohol (8), which was subjected to
iodination according to a modification of Garegg’s method10 to yield 9. Upon exposure to sodium
hydride in dimethylformamide at room temperature, 9 underwent smooth dehydroiodination to afford the
exocyclic methylene derivative (10), whose response to mercury(II) chloride in aqueous acetone was next
examined. Ferrier’s carbocyclic ring closure11 occurred to deliver the β-hydroxy cyclohexanone (11) in
78% yield. The conversion of 11 to 12 by reaction with ethylene glycol in the presence of p-
toluenesulfonic acid was then optimized to deliver 12 with minimal competing β-elimination. The spiro
acetal (13) was subsequently generated in exclusive fashion by elimination of the corresponding mesylate
under basic conditions.
Scheme 1
OH
OTr
OTr
O
OCH3
OH
O
OCH3
OH
O
OCH3
OBn
PPTS, MeOH
NaH, BnBr, DMF
0 °C (88%)
TrCl, Et3N, DMAP,
DMF, rt (90%)
DCM (1:1) (94%)
HO
HO
BnO
OH
OH
OBn
5
6
7
OH
I
O
OCH3
OBn
O
OCH3
OBn
O
OCH3
PPh3, Imid, I2
PhH (95%)
NaH, DMF (90%)
HgCl2, acetone
H2O (1:1) (78%)
BnO
BnO
BnO
OBn
O
OBn
8
OBn
9
OBn
10
O
1. MsCl, Et3N, THF
0 °C (quant)
O
OH
OH
(CH2OH)2, PTSA
O
O
PhH, ! (92%)
2. KOtBu, THF
0 °C (90%)
BnO
OBn
BnO
OBn
BnO
OBn
OBn
11
OBn
12
OBn
13

HETEROCYCLES, Vol. 73, 2007
167
We next sought to functionalize the double bond contained within 13 in a manner that would ultimately
permit the installation of two additional acetal fragments. For the usual reasons, recourse to acidic
conditions of any type had to be avoided. The bypass of this significant restriction began with the
dihydroxylation of 13 involving osmium tetraoxide in the presence of N-methylmorpholine N-oxide
(Scheme 2). The resulting diol (14) was then converted into the diallyloxy derivative (15) by O-
alkylation with allyl bromide. Ozonolysis followed by reductive workup with sodium borohydride
afforded the key intermediate 16. The availability of this diol provided the opportunity for proper
exploration of its targeted photochemical ring closure upon irradiation in the presence of iodobenzene
diacetate with iodine serving as initiator.12 Since no acidic reagents are directly involved, it was expected
that the acetal units would have a better chance of survival relative to sequential installation. Indeed,
trispiro acetal (17) was obtained, but in a quite modest, although reproducible, 10% yield.13 The
inefficiency of this step can be attributed to the presence in 16 of numerous methylene groups connected
to oxygen which remain prone to involvement in alternative cyclizative transformations.
Scheme 2
OH
OAllyl
O
O
O
O3, MeOH, DCM,
(1:1), -78 °C
NaBH4, MeOH,
DCM, -78 °C (83%)
OH
OAllyl
OBn
OsO4, NMO, MsNH2,
acetone, H2O (70%)
AllylBr, NaH, DMF
0 °C (78%)
O
O
O
BnO
OBn
BnO
OBn
BnO
OBn
OBn
OBn
13
14
15
HO
OH
O
O
O
O
O
O
O
O
O
AllylBr, NaH, DMF
0 °C (74%)
O
Pd/C, EtOAc
H2 (90%)
PhI(OAc)2, I2
O
O
O
O
O
O
PhH, h!(10%)
HO
OH
BnO
OBn
BnO
OBn
OH
18
OBn
17
OBn
16
O
O
O
O
O
O
O
O3, MeOH, DCM,
(1:1), -78 °C
O
O
O
O
O
O
O
PhI(OAc)2, I2
O
O
O
O
O
O
O
O
O
O
NaBH4, MeOH,
DCM, -78 °C (77%)
PhH, h!
O
O
AllylO
OAllyl
O
OAllyl
19
3
OH
OH
HO
20
The route continued with hydrogenolytic removal of the benzyl groups in 17 under standard conditions to
afford triol (18). A reliable supply of this highly oxygenated intermediate enabled us the opportunity to
implement our chain-extension strategy once again. Treatment of 18 with allyl bromide and sodium
hydride in DMF led to installation of all three allyloxy substituents as in 19. Subsequent ozonolysis and
borohydride reduction resulted in efficient conversion to 20. Regrettably, remote C-H activation in the
predescribed manner could not be accomplished. Rather than generating 3, a complex, inseparable

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HETEROCYCLES, Vol. 73, 2007
mixture of compounds was formed, the composition of which changed with time. Thereby implicated
was an appreciable sensitivity of the products being formed. Acetic acid generated in the course of this
otherwise mild reaction could be inducing decomposition. Attempts were therefore made to carry out the
process in the presence of reagents (e.g., calcium carbonate, sodium bicarbonate, and propylene oxide)
capable of removing any acid formed. Unfortunately, these modifications did not change the outcome.
Many other routes pursued in the quest for 3 have proven equally unsuccessful.9 Thus, the statement put
forth in the title is offered as a challenge awaiting resolution.
ACKNOWLEDGMENT
We thank The Ohio State University for partial financial support.
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13. Although two isomeric di(bis)-spiro acetals can in principle be formed from 16, neither was found
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