Nanoscale molecular rods with a new building block for solubility enhancement

Article abstract of DOI:10.1021/jo800341k

(Chemical Equation Presented) A new building block bearing a [1,3]dioxolo[4,5-f][1,3]benzodioxole core was developed to enhance the solubility of molecular rods by lateral alkyl chains. On incorporation in molecular rods with oligospiroketal structure, the straight geometry is retained, which was concluded from the X-ray crystal structure analysis of one of the rods. The determination of the solubility of a collection of rods bearing this building block revealed that already a butyl group efficiently hinders the aggregation of the rods and consequently causes a considerable enhancement of the solubility. Piperidine rings are located at the ends of the rods, which offer the opportunity for versatile functionalization. Thus, an N,N′-bis(azidoacetyl)-functionalized rod was prepared, which could serve as rigid linkage, initiated by a "Click" reaction.

Full text of DOI:10.1021/jo800341k

Nanoscale Molecular Rods with a New Building Block for Solubility
Enhancement
Pablo Wessig* and Kristian Mo¨llnitz
Humboldt-UniVersität zu Berlin, Institut für Chemie, Brook-Taylor-Str. 2, D-12489 Berlin, Germany
pablo.wessig@chemie.hu-berlin.de
ReceiVed February 20, 2008
A new building block bearing a [1,3]dioxolo[4,5-f][1,3]benzodioxole core was developed to enhance the
solubility of molecular rods by lateral alkyl chains. On incorporation in molecular rods with oligospiroketal
structure, the straight geometry is retained, which was concluded from the X-ray crystal structure analysis
of one of the rods. The determination of the solubility of a collection of rods bearing this building block
revealed that already a butyl group efficiently hinders the aggregation of the rods and consequently causes
a considerable enhancement of the solubility. Piperidine rings are located at the ends of the rods, which
offer the opportunity for versatile functionalization. Thus, an N,N′-bis(azidoacetyl)-functionalized rod
was prepared, which could serve as rigid linkage, initiated by a “Click” reaction.
SCHEME 1
Introduction
The imitation of the fascinating functional diversity of
biological systems by synthetically generated molecules is one
of the pivotal objectives of current chemical research. In this
context, the rational and selective construction of well-defined
three-dimensional assemblies is a great challenge. While nature
goes back to a variety of biopolymers (proteins, nucleic acids,
carbohydrates, etc.) to solve this problem, chemists need a
versatile “construction kit” containing basic shapes such as balls,
rings, plates or rods. Therefore, the development of molecular
rods, i.e., relatively rigid molecules with a large aspect ratio,
has been an intensively treated research area for several years.1
Recently, we reported on the synthesis and properties of a new
type of molecular rods whose backbone structure is based on
oligospiroketals.2 These rods (1) are assembled of tetrols such
as pentaerythritol 3, diones such as cyclohexan-1,4-dione 4 and
terminal modules 2 and 5 bearing different functionalities X,
Y (Scheme 1). These building blocks are connected by ketal
formation, for which we developed a new mild and highly
selective method.2
The backbone of molecular rods of type 1 shows rather
hydrophobic behavior, despite the numerous oxygen atoms of
the ketal moieties. This can be explained by an effective steric
shielding of these atoms by the adjacent methylene groups. Not
unexpectedly, the solubility of oligospiroketals 1 consisting of
seven or more rings is dramatically diminished if X and Y are
“normal” functional groups (e.g., N atoms with conventional
protective groups). This fact strongly impedes the handling of
these compounds and could be standing in the way of their
application. In our recent publication,2 we solved this problem
by introduction of terminal solubility-enhancing groups (SEGs)
in the X- and Y-positions. Besides previously known groups
(1) (a) Tour, J. M. Chem. ReV. 1996, 96, 537–553. (b) Schwab, P. F.H.;
Levin, M. D.; Michl, J. Chem. ReV 1999, 99, 1863–1933. (c) Levin, M. D.;
Kaszynski, P.; Michl, J. Chem. ReV. 2000, 100, 169–234. (d) Tour, J. M. Acc.
Chem. Res. 2000, 33, 791–804. (e) Schwab, P. F.H.; Smith, J. R.; Michl, J.
Chem. ReV 2005, 105, 1197–1279. (f) Sakai, N.; Mareda, J.; Matile, S. Acc.
Chem. Res. 2005, 38, 79–87.
(2) Wessig, P.; Mo¨llnitz, K.; Eiserbeck, C. Chem. Eur. J. 2007, 13, 4859–
4872.
4452 J. Org. Chem. 2008, 73, 4452–4457
10.1021/jo800341k CCC: $40.75 2008 American Chemical Society
Published on Web 05/17/2008

Nanoscale Molecular Rods
SCHEME 2
SCHEME 3
(e.g., 2-ethylhexyloxycarbonyl, EHOC3), we developed new
modified Fmoc groups (MIO-Fmoc and DIO-Fmoc4), mainly
to have base-labile protective groups in hand that are compatible
with the acid-labile oligospiroketal skeleton.5 Although the
introduction of SEGs in a terminal position of the molecular
rods is very convenient to solve the solubility problem, this
approach certainly proved to be a hindrance if other functional
groups are needed at the ends of the rods. Such cases ultimately
require the introduction of lateral SEGs in the architecture of
oligospiroketals 1. Herein we wish to report on the development
of new building blocks with lateral SEGs for solubility
enhancement in organic solvents as well as their successful
application on the synthesis of nanoscale molecular rods.
(Sn/HCl,7,8a PtO2/H2,8b Pd/C/H28c). We performed this step with
Sn/HCl and obtained the tetraphenol 10 with a yield of 78%.
In view of the next target structure (7), 10 could now already
be coupled with the protected 4-hydroxycyclohexanone 8, but
unfortunately, we found that the resulting spiroketal moiety is
too labile for the steps required for the introduction of side
chains R1 (see below). Therefore, we protected the tetraphenol
10 as the relatively tough tetramethylether 138b (Scheme 3).
The introduction of the side chains in the 3- and 6-positions
of 13 turned out to be difficult. The classical Friedel-Crafts
acylation failed due to the migration tendency of the methyl
groups under these conditions. The bismetalation with nBuLi
followed by treatment with acid chlorides or Weinreb amides
did not afford the desired products. Finally, the reaction between
3,6-biscuprates of 13, prepared by bismetalation and subsequent
treatment with CuI, and acid chlorides according to Bringmann9
was crowned with success. The reduction of the keto groups
could be smoothly accomblished with HSiEt3/CF3COOH re-
agent.10 The deprotection of tetraethers 15 to tetraphenols 16
Results and Discussion
Synthesis of the Solubility-Enhancing Building Block 6.
First, we considered the introduction of alkyl chains either in
pentaerythritol 3 or in cyclohexan-1,4-dione 4. Besides the
probably cumbersome synthesis of those derivatives, the ster-
eochemical situation would become highly complicated owing
to the newly generated chirality centers. Therefore, we decided
to prepare the building block 6 bearing a [1,3]dioxolo[4,5-
f][1,3]benzodioxole core and lateral solubility-enhancing groups
R1. A retrosynthetic analysis of compounds 6 is outlined in
Scheme 2. The keto groups in 6 should be resulting from
protected hydroxyl groups in 7. This compound could be
prepared from 3,6-disubstituted 1,2,4,5-tetrahydroxybenzene 9
(R3 ) H) or its tetratrimethylsilylether (R3 ) TMS) and
protected 4-hydroxycyclohexanone 8 by common acetalization
methods. Compounds 9 could be traced to the literature-known
1,2,4,5-tetrahydroxybenzene 10.
11
with BBr3 succeeded, but compounds 16 have proven to be
less suitable for the preparation of target compounds 7 due to
their extreme oxidation lability. The conversion of 15 into the
tetra(trimethylsilyl) ethers 17 with trimethylsilyl iodide12 is much
more favorable. Compounds 17 are air-stable and could even
be purified by flash chromatography (Scheme 4).
The last steps to the building block 6 were performed only
with dibutyl derivative 17b because we suspected that the ethyl
chains in 17a are too short for an efficient enhancement of the
Our synthesis began with the oxidation of resorcinol 11 to
2,5-dihydroxy-1,4-benzoquinone 12 with peracetic acid.6 While
this method provided 12 with good yields, an also reported route
from 1,4-hydroquinone proved to be less reproducible and gave
12 only in very low yields.7 Several methods were reported for
the reduction of quinone 12 to 1,2,4,5-tetrahydroxybenzene 10
(8) (a) Aldridge, S.; Calder, R. J.; Cunningham, M. H.; Malik, K. M. A.;
Steed, J. W. J. Organomet. Chem. 2000, 614-615, 188–194. (b) Keegstra,
E. M. D.; Huisman, B. H.; Paardekooper, E. M.; Hoogesteger, F. J.; Zwikker,
J. W.; Jenneskens, L. W.; Kooijman, H.; Schouten, A.; Veldman, N.; Spek, A. L.
J. Chem. Soc., Perkin Trans. 2 1996, 229–240. (c) Reddy, T. J.; Iwama, T.;
Halpern, H. J.; Rawal, V. H. J. Org. Chem. 2002, 67, 4635–4639.
(9) Bringmann, G.; Geuder, T.; Harmsen, S. Synthesis 1994, 1143–1145.
(10) Kursanov, D. N.; Parnes, Z. N.; Bassova, G. I.; Loim, N. M.; Zdanovich,
V. I. Tetrahedron 1967, 23, 2235–2242.
(3) Ball, D. F.; Goggin, P. L.; McKaen, D. C.; Woodward, L. A. Spectrochim.
Acta 1960, 16, 1358–1367.
(4) Wessig, P.; Czapla, S.; Mo¨llnitz, K.; Schwarz, J. Synlett 2006, 2235–
2238.
(5) The stability of the spiroketal moieties towards acid environment proved
to be higher than expected for the moment, probably due to the mentioned steric
shielding of the oxygen atoms.
(6) Barltrop, J. A.; Burstall, M. L. J. Chem. Soc. 1959, 2183–2186.
(7) Weider, P. R.; Hegedus, L. S.; Asada, H.; Dandreq, S. V. J. Org. Chem.
1985, 50, 4276–4281.
(11) McOmie, J. F. W.; West, D. E. Organic Synthesis; Wiley: New York,
1973; Collect. Vol. V, p 412.
(12) Jung, M. E.; Lyster, M. A. J. Org. Chem. 1977, 42, 3761–374.
J. Org. Chem. Vol. 73, No. 12, 2008 4453

Wessig and Mo¨llnitz
SCHEME 4
SCHEME 6
TABLE 1
R
yield 21 (%)
yield 22 (%)
yield 23 (%)
a
b
c
d
e
CF3CO
ClCH2CO
TEOCe
Fmoc
46a
95b
31
64c
83d
31f
84d
72
99g, i
96h, i
94d, i
94d, i
Cbz
58i
SCHEME 5
a (CF3CO)2O, dioxane, Et3N. b Swern oxidation ((COCl)2,Et3N).
c ClCH2COCl, K2CO3, AcOEt/H2O. d Dess-Martin oxidation.13 22b was
mentioned in literature but without experimental details and
characterization.16 22c is described in ref 17 but prepared by another
method. e TEOC ) 2-(trimethylsilyl)ethoxycarbonyl. f TEOC-Cl, K2CO3,
dioxin, H2O. g FmocOSu. h Cbz-Cl. i Reference 2.
o-phenylendiamine14a or thiourea14b), 2-(trimethylsilyl)ethoxy-
carbonyl (23c, removable with fluoride15), and 9-fluorenyl-
methoxycarbonyl (23d, removable with piperidine/DMF). The
acylation of 4-hydroxypiperidine 20 to compounds 21 proceeded
smoothly in all cases, though the yield of 21c was only
moderate. By oxidation (Swern or Dess-Martin) we obtained
the ketones 22, which then were treated with pentaerythritol
under classic conditions (DMF/benzene, reflux) to prepare diols
23. Unfortunately, the acetalization only succeeded with 22a
and 22c, and the yield of the former was only 31% (Scheme 6,
Table 1).
To find access to compounds 23b,d nevertheless, we have
made a detour. Starting from the previously described Cbz-
protected diol 21e,2 we prepared the free amine 24 in nearly
quantitative yield by hydrogenation. The acylation of 24 either
with 4-nitrophenyl-chloroacetate or with FmocOSu afforded 23b
and 23d, respectively, in excellent yields. Furthermore, we were
interested in the N-azidoacetyl derivative 23f (vide infra), which
could be easily obtained by treatment of 23b with NaN3 in DMF
(Scheme 7).
solubility. The reactivity of 17b toward ketones 8 is remarkably
low, and all previously successfully applied acetalization
methods2 failed. After numerous attempts, we found that the
reaction of 17b with pivaloyl protected ketone 8a in refluxing
toluene in the presence of trimethylsilyl triflate provides the
desired product 18 with satisfactory yields. While the depro-
tection of 18 to the diol 19 with DIBALH proceeds smoothly
and with nearly quantitative yields, the otherwise very mild and
convenient Dess-Martin oxidation13 gave the dione 6 only in
very low yields, even if NaHCO3 is added as buffer. On the
other hand, we obtained 6 with good yields employing the Swern
oxidation (DMSO, (COCl)2, Et3N) (Scheme 5).
Synthesis and Properties of Molecular Rods Bearing 6.
To examine the usability of the new building block 6 in the
synthesis of longer molecular rods of type 1, we needed various
diols, preferably with different functional groups at the end of
the rods. In this connection we turned special attention to base-
labile protective groups, which are fully compatible with the
oligospirane skeleton. In Scheme 6, the route to various 1,5-
dioxa-9-azaspiro[5.5]undecane-3,3-dimethanols 23 is summa-
rized. We have chosen the protective groups trifluoroacetyl (23a,
removable with NaOMe), chloroacetyl (23b, removable with
With diols 23 in hand we attended to the synthesis of
nanoscale molecular rods using our previously developed
double-activation method.2 To investigate the coupling reaction
and the solubility properties of the rods without the influence
of terminal functional groups, we first performed a coupling of
6 with the literature-known 1,5-dioxaspiro[5.5]undecane-3,3-
(15) (a) Carpino, L. A.; Tsao, J.-H.; Ringsdorf, H.; Fell, E.; Hettrich, G.
J. Chem. Soc., Chem. Commun. 1978, 358. (b) Carpino, L. A.; Sau, A. C.
J. Chem. Soc., Chem. Commun. 1979, 514.
(16) Padmanilayam, M.; Scorneaux, B.; Dong, Y. X.; Chollet, J.; Matile,
H.; Charman, S. A.; Creek, D. J.; Charman, W. N.; Tomas, J. S.; Scheurer, C.;
Wittlin, S.; Brun, R.; Vennerstrom, J. L. Bioorg. Med. Chem. Lett. 2006, 16,
5542.
(17) Levell, J.; Astles, P.; Eastwood, P.; Cairns, J.; Houille, O.; Aldous, S.;
Merriman, G.; Whiteley, B.; Pribish, J.; Czekaj, M.; Liang, G. Y.; Maignan, S.;
Guilloteau, J. P.; Dupuy, A.; Davidson, J.; Harrison, T.; Morley, A.; Watson,
S.; Fenton, G.; McCarthy, C.; Romano, J.; Mathew, R.; Engers, D.; Gardyan,
M.; Sides, K.; Kwong, J.; Tsay, J.; Rebello, S.; Shen, L. D.; Wang, J.; Luo,
Y. Y.; Giardino, O.; Lim, H. K.; Smith, K.; Pauls, H. Bioorg. Med. Chem. 2005,
13, 2859.
(13) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
(14) (a) Holley, R. W.; Holley, A. D. J. Am. Chem. Soc. 1952, 74, 3069. (b)
Masaki, M.; Kitahara, T.; Kurita, H.; Ohta, M. J. Am. Chem. Soc. 1968, 90,
4508.
4454 J. Org. Chem. Vol. 73, No. 12, 2008

Nanoscale Molecular Rods
FIGURE 1. Crystal structure of 26a.
FIGURE 2. Crystal packing of 26a.
SCHEME 7
clarifying the size of the molecule. It is clearly discernible that
26a adopts a straight geometry and all saturated six-membered
rings have a chairlike conformation (Figure 1). It is also
instructive to take a look at the crystal packing of 26a. In Figure
2, five molecules of 26a within the elemental cell are depicted.
One can see that the rods are tightly packed but that the aromatic
rings do not form π-stacks, though they are coplanar. In fact,
they are laterally displaced against one another and the three
terminal carbon atoms of the butyl groups are located nearly
perpendicular above the aromatic rings at a distance of about
3.5 Å. This results in a stairs-like arrangement of the rods as
seen in Figure 3, showing a side view of three molecules in the
direction of the rod axis (the saturated six-membered rings are
omitted). Obviously, the length of the butyl group is sufficient
to disturb a close contact of the rods (which is also reflected in
the enhanced solubility, see below) but makes a dense packing
of the rods not yet impossible.
To our delight, the yields of rods 26b-f bearing N-protected
piperidine rings at the ends are considerably higher than that
of 26a. Besides 26 we isolated the shortened rods 27 in some
cases, arising from a reaction of 6 with only 1 equiv of diol 23
(Scheme 8, Table 2). It is worth noting that the azidoacetyl-
substituted rod 26f opens up versatile applications because it
dimethanol 2518 and obtained the desired rod 26a with up to
41% yield. The structure of 26a was unambiguously proven by
MALDI-MS and X-ray crystal structure analysis.19 Figure 1
shows the molecular structure of 26a as well as some distances
(19) Details of the structure investigation are available on request from the
Cambridge Crystallographic Data Centre, on quoting the depository number
CCDC 676130.
(18) (a) Schaeffer, J. R.; Stevens, R. E J. Org. Chem. 1973, 38, 1241. (b)
Murguia, M. C.; Grau, R. J. Synlett 2001, 1229.
J. Org. Chem. Vol. 73, No. 12, 2008 4455

Wessig and Mo¨llnitz
SCHEME 9
FIGURE 3. Side view of three molecules in the crystal packing of
26a. Saturated six-membered rings are omitted.
TABLE 3
Xa
solubility [g/L]b
SCHEME 8
26a
26b
26d
26e
26f
CH2
20 ( 4
419 ( 40
30 ( 6
294 ( 23
144 ( 16
CF3CO-N
Fmoc-N
Cbz-N
N3CH2CO-N
a See Scheme 8. b In CH2Cl2.
without terminal functional groups exhibits a considerable
solubility of 20 g/L (Table 3). The rods 26b, 26e and 26f,
bearing trifluoroacetyl, Cbz and azidoacetyl groups at the
termini, are extremely soluble, suggesting a synergistic effect
of the lateral and terminal groups. On the other hand, the Fmoc
groups in 26d have only a marginal influence on the solubility.
Although 28 is very scarcely soluble in dichloromethane, its
solubility in water is surprisingly high (1.8 ( 0.5 g/L).
Conclusion
In summary, we succeeded in the synthesis of molecular rods
with a length of about 3 nm (without consideration of the
terminal functional groups) by implementation of a new
approach for solubility enhancement. Although the introduction
of SEGs in terminal positions is tried and tested, lateral SEGs
are inevitably required if other functional groups have to be
installed at the ends of the rods. To this end, we developed the
TABLE 2
X
yield 26 (%)
35 - 41 a
76
77
42
52
74
yield 27 (%)
a
b
c
d
e
f
CH2
CF3CO-N
TEOC-N
Fmoc-N
Cbz-N
N3CH2CO-N
15
new building block
6
bearing
a
[1,3]dioxolo[4,5-
f][1,3]benzodioxole moiety as core element. If integrated in
molecular rods with oligospirane skeleton, the straight rod-like
geometry is not altered due to the topology of this element. In
contrast to terminal SEGs, the relatively short butyl groups
already cause a very satisfactory solubility enhancement. The
coupling of 6 with various diols (23, 25) using our previously
established acetalization method2 proceeded smoothly and
provided the resulting molecular rods 26 mostly in good yields.
Compounds 26 are, despite the very electron-rich aromatic core,
sufficiently stable and could be handled without special precau-
tions. The efficiency of our concept is impressively demonstrated
by the solubility of the rods 26. Even the rods 26a and 26d
bearing no solubility-enhancing groups at the ends have
satisfactory solubilities of 20-30 g/L, whereas the other rods
are extremely soluble.
9
9
a The reaction is accompanied by the formation of oligomers,which
were not further characterized
can easily be coupled with other molecules bearing a terminal
alkyne moiety by using the well-established “Click” reaction.20
To prove that the terminal N-protecting groups could be
removed, we treated the Cbz-protected rod 26e with hydrogen
in the presence of catalytic amounts of Pd(C) and obtained the
diamine 28 with good yields (Scheme 9).
Finally, we investigated the solubility of rods 26a,b,d,e,f and
28 in dichloromethane. To our delight, already the rod 26a
Having principally solved the problems related with scarce
solubility of rods 1, either by terminal2 or lateral SEGs, right
now we are developing applications in material and biochemical
sciences and will report on interesting results soon.
(20) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004. (b) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057. (c) Bock, V. D.; Hiemstra, H.; Maarseveen, J. H. Eur. J. Org.
Chem. 2006, 51.
4456 J. Org. Chem. Vol. 73, No. 12, 2008

Nanoscale Molecular Rods
106.2 (CArCH2), 116.2 (C(CH2CH2)2CH), 138.5 (CArO), 177.9 (CO);
Experimental Section
mp 159-163 °C; IR 2962, 2872, 1720, 1443, 1175, 1124 cm-1
;
1-[2,3,5,6-Tetramethoxy-4-(1-oxobutyl)phenyl]-1-butanone
(14b). To a solution of 13 (2.00 g, 10.11 mmol) in dry THF (75
mL) was added dropwise at 0 °C n-BuLi (16.0 mL, 1.6 M in hexane,
25.60 mmol, 2.5 equiv). The resulting orange suspension was stirred
for 4 h at room temperature. CuI (4.80 g, 25.23 mmol, 2.5 equiv)
and butyryl chloride (8.40 mL, 80.89 mmol, 8.0 equiv) was added
slowly. The reaction mixture was stirred for 1 h, then diluted with
Et2O and washed with saturated aqueous NH4Cl solution and brine.
The organic layer was dried, evaporated and purified by flash
chromatography (PE/EtOAc 10:1) yielding 14b as a white solid
HRMS (ESI) calcd for C36H55O8 [M + H+] 615.3898, found
615.3891.
4,4′′-Dihydroxy-dispiro[cyclohexane-1,2′-[1,3]dioxolo[4,5-
f][1,3]benzodioxole-6′,1′′-cyclohexane (19). To a solution of 18
(3.44 g, 5.60 mmol) in dry CH2Cl2 (90 mL) was added dropwise
at -78 °C DIBALH (28.5 mL, 1.0 M in hexane, 28.50 mmol, 5.1
equiv) and the mixture was stirred until complete conversion of 18
was observed by TLC. MeOH was added until gas evolution ceased.
CH2Cl2 was added and the organic layer was washed with aqueous
tartaric acid. The solvent was evaporated and the resulting residue
was purified by flash chromatography (CH2Cl2/MeOH 100:3)
yielding 19 as a white solid (2.48 g, 5.55 mmol, 99%). Rf ) 0.3
(CH2Cl2/MeOH 100:3); 1H NMR (300 MHz, CDCl3) σ 0.89-0.95
(CH3, 6H, m), 1.27-1.41 (CH2CH3, 4H, m), 1.51-1.65
(CH2CH2CH3, 4H, m), 1.77-1.88 ((CH2)2CH + OH, 10H, m),
1.92-1.98 ((CH2)2CH, 4H, m), 2.08-2.16 ((CH2)2CH, 4H, m),
2.45-2.55 (CArCH2, 4H, m), 3.89-3.91 (CH, 2H, m); 13C NMR
(75 MHz, CDCl3) σ 13.8 (CH3), 22.1 (CH2CH3), 23.6 (CArCH2),
30.8 ((CH2CH2)2CH), 31.1 (CH2CH2CH3 + (CH2)2CH), 67.6 (CH),
106.1 (CArCH2), 116.3 (C(CH2CH2)2CH), 138.5 (CArO); mp 159-163
°C; IR 3407, 2952, 2867, 1440, 1122, 1082 cm-1; HRMS (ESI)
calcd for C26H39O6 [M + H+] 447.2748, found 447.2741.
1
(3.04 g, 8.98 mmol, 89%). Rf ) 0.4 (PE/EtOAc 10:1); H NMR
3
(300 MHz, CDCl3) σ 0.98 (CH3, 6H, t, J ) 7.4 Hz), 1.68-1.75
(CH2CH3, 4H, m), 2.72 (C(O)CH2, 4H, t, 3J ) 7.2 Hz), 3.80 (OCH3,
12H, s); 13C NMR (75 MHz, CDCl3) σ 13.6 (CH3), 16.8 (CH2CH3),
46.9 (C(O)CH2), 61.7 (OCH3), 132.6 (CCO), 144.9 (COCH3), 203.3
(CO); mp 66-67 °C; IR 2968, 2941, 1702, 1459, 1400, 1052 cm-1
;
HRMS (ESI) calcd for C18H26O6Na [M + Na+] 361.1627, found
361.1622.
1,4-Dibutyl-2,3,5,6-tetramethoxy-benzene (15b). To a solution
of 14b (3.04 g, 8.98 mmol) in CF3COOH (14 mL) was added
dropwise HSiEt3 (7.10 mL, 44.90 mmol, 5.0 equiv) and the mixture
was stirred until complete conversion of 14b was indicated by TLC.
Water and NaHCO3 solution were added until gas evolution ceased
and the resulting mixture was extracted two times with CH2Cl2.
The combined organic layers were dried, evaporated and purified
by flash chromatography (PE/EtOAc 100:5) yielding 15b as a white
Dispiro[cyclohexane-1,2′-[1,3]dioxolo[4,5-f][1,3]benzodioxole-
6′,1′′-cyclohexan-4,4′dione (6). To a solution of DMSO (1.50 mL,
21.14 mmol, 4.1 equiv) in dry CH2Cl2 (60 mL) was added dropwise
at -78 °C oxalyl dichloride (1.40 mL, 16.28 mmol, 3.1 equiv).
After 30 min of stirring, 18 (2.32 g, 5.20 mmol) dissolved in dry
CH2Cl2 (15 mL) was added and the mixture was stirred for 30 min.
The reaction mixture was treated with NEt3 (7.4 mL, 53.09 mmol,
10.2 equiv) and stirred for 15 min while warming up to room
temperature. CH2Cl2 was added and the organic layer was washed
with aqueous tartaric acid, the solvent was evaporated and the
resulting residue was purified by flash chromatography (PE/EtOAc
10:1) yielding 6 as a pale yellow solid (2.05 g, 4.64 mmol, 89%).
1
solid (2.47 g, 7.94 mmol, 89%). Rf ) 0.6 (PE/EtOAc 100:5); H
NMR (300 MHz, CDCl3) σ 0.97 (CH3, 6H, t, 3J ) 7.1 Hz),
1.37-1.52 ((CH2)2CH3, 8H, m), 2.60 (CArCH2, 4H, t, 3J ) 7.8 Hz),
3.83 (OCH3, 12H, s); 13C NMR (75 MHz, CDCl3) σ 14.0 (CH3),
23.2 ((CH2)3CH3), 24.3 ((CH2)3CH3), 33.3 ((CH2)3CH3), 60.5
(OCH3), 127.9 (CArCH2), 147.3 (COCH3); mp 55-56 °C; IR 2952,
2930, 1459, 1408, 1109, 1038 cm-1; HRMS (EI) calcd for C18H30O4
[M+] 310.2144, found 310.2144.
[2,5-Dibutyl-3,4,6-tris[(trimethylsilyl)oxy]phenoxy]trimethyl-
silane (17b). To a solution of 15b (2.47 g, 7.94 mmol) in CCl4 (25
mL) was added TMSI (6.80 mL, 49.96 mmol, 6.3 equiv) and the
mixture was stirred overnight at 70 °C. The solvent was evaporated
and the resulting residue was purified by flash chromatography (PE/
CH2Cl2 5:1) yielding 17b as a white solid (3.83 g, 7.06 mmol, 89%).
Rf ) 0.4 (PE); 1H NMR (300 MHz, CDCl3) σ 0.17 (Si(CH3)3, 36H),
1
Rf ) 0.2 (PE/EtOAc 10:1); H NMR (300 MHz, CDCl3) σ 0.93
(CH3, 6H, t, 3J ) 7.3 Hz), 1.30-1.43 (CH2CH3, 4H, m), 1.55-1.65
3
(CH2CH2CH3, 4H, m), 2.32 ((CH2)2CO, 8H, t, J ) 7.0 Hz), 2.55
3
3
(CArCH2, 4H, t, J ) 7.4 Hz), 2.63 ((CH2)2CO, 8H, t, J ) 7.0
Hz); 13C NMR (75 MHz, CDCl3) σ 13.8 (CH3), 22.2 (CH2CH3),
23.7 (CArCH2), 30.9 (CH2CH2CH3), 33.5 ((CH2)2CO), 37.3
((CH2)2CO), 106.6 (CArCH2), 115.0 (C(CH2CH2)2CO), 138.6
(CArO), 209.0 (CO); mp 146-147 °C; IR 2952, 2930, 2862, 1717,
1437, 1124 cm-1; HRMS (ESI) calcd for C26H35O6 [M + H+]
443.2434, found 443.2428.
3
0.91 (CH3, 6H, t, J ) 7.3 Hz), 1.20-1.32 ((CH2)3CH3, 4H, m),
1.44-1.53 ((CH2)3CH3, 4H, m), 2.50 ((CH2)3CH3, 4H, t, 3J ) 7.4
Hz); 13C NMR (75 MHz, CDCl3) σ 0.67 (Si(CH3)3), 14.0 (CH3),
22.4 ((CH2)3CH3), 25.8 ((CH2)3CH3), 30.8 ((CH2)3CH3), 123.9
(CArCH2), 139.6 (COSi(CH3)3); mp 40-41 °C; IR 2957, 1438, 1248,
852, 838 cm-1; HRMS (EI) calcd for C26H54O4Si4 [M+] 542.3099,
found 542.3099.
General Procedure for Preparation of Octaspiranes 26. An
ice-cooled solution of 6 in Et2O was treated with NaH (2.0 equiv)
and TMSCl (2.0 equiv) and stirred for 1 h. The corresponding diol
25 or 26 (2.0 equiv) and TMSOTf (0.1 equiv) were added and the
reaction mixture was stirred at room temperature until complete
conversion was indicated by TLC. The solvent was evaporated and
the resulting residue was purified by flash chromatography.
4,4′′-Bis(pivaloyloxy)-dispiro[cyclohexane-1,2′-[1,3]dioxolo[4,5-
f][1,3]benzodioxole-6′,1′′-cyclohexane (18). To a solution of 17b
(3.82 g, 7.06 mmol) and 8a (2.89 g, 14.56 mmol, 2.0 equiv) in dry
toluene (130 mL) was added TMSOTf (130 µL, 0.71 mmol, 0.1
equiv). The reaction mixture was refluxed until complete conversion
of 17b and 8a was observed by TLC. The solvent was evaporated
and the resulting residue was purified by flash chromatography (PE/
EtOAc 30:1) yielding 18 as a white solid (3.50 g, 5.69 mmol, 81%).
Rf ) 0.4 (PE/EtOAc 10:1); 1H NMR (300 MHz, CDCl3) σ
0.90-0.97 ((CH2)nCH3, 6H, m), 1.24 (C(CH3)3, 18H, s), 1.30-1.42
(CH2CH3, 4H, m), 1.52-1.65 (CH2CH2CH3, 4H, m), 1.86-2.10
((CH2)2CH, 16H, m), 2.47-2.56 (CArCH2, 4H, m), 4.96-4.98 (CH,
2H, m); 13C NMR (75 MHz, CDCl3) σ 13.9 ((CH2)nCH3), 22.2
(CH2CH3), 23.7 (CArCH2), 27.2 (C(CH3)3), 27.5 ((CH2)2CH), 30.7
((CH2CH2)2CH), 31.0 (CH2CH2CH3), 38.9 (C(CH3)3), 68.7 (CH),
Acknowledgment. The financial support of this work by the
Deutsche Forschungsgemeinschaft (We1850-3/7-1 and Heisen-
berg fellowship for P.W.) is gratefully acknowledged.
Supporting Information Available: Experimental proce-
dures, spectroscopic data, 1H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO800341K
J. Org. Chem. Vol. 73, No. 12, 2008 4457