Intramolecular Interaction of Adjacent Hydroxymethyl, Formyl, and Carboxyl Groups: Proximity Effect in the Swern Oxidation of cis,cis-1,3,5-Tris(hydroxymethyl)-1,3,5-trimethylcyclohexane

Article abstract of DOI:10.1021/jo990468o

The proximity effect in the Swern oxidation of cis,cis-1,3,5-tris(hydroxymethyl)-1,3,5-trimethylcyclohexane (4) with TFAA was examined. The oxidation reaction of triol 4 with DMSO, TFAA, and relatively small amounts of triethylamine gave 5-formyl-cis,cis-

Full text of DOI:10.1021/jo990468o

4502
J . Org. Chem. 1999, 64, 4502-4505
In tr a m olecu la r In ter a ction of Ad ja cen t Hyd r oxym eth yl, F or m yl,
a n d Ca r boxyl Gr ou p s: P r oxim ity Effect in th e Sw er n Oxid a tion of
cis,cis-1,3,5-Tr is(h yd r oxym eth yl)-1,3,5-tr im eth ylcycloh exa n e
Hiroshi Izumi* and Shigeru Futamura
National Institute for Resources and Environment, 16-3 Onogawa, Tsukuba, Ibaraki 305-8569, J apan
Received March 15, 1999
The proximity effect in the Swern oxidation of cis,cis-1,3,5-tris(hydroxymethyl)-1,3,5-trimethylcy-
clohexane (4) with TFAA was examined. The oxidation reaction of triol 4 with DMSO, TFAA, and
relatively small amounts of triethylamine gave 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethyl-
cyclohexane-1-carboxylic acid hemiacetal (7a ) as well as 1,7,9-trimethyl-3,5,12-trioxawurtzitane
(6), 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid lactone (5), and
polymers of cis,cis-1,3,5-triformyl-1,3,5-trimethylcyclohexane (2). Hemiacetal 7a underwent novel
solvent-dependent conversions to hemiacetal 7b, lactone 5, or 1,7,9-trimethyl-2-oxo-3,5-dioxatricyclo-
[5.3.1.04,9]undecane (8) via 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic
acid. In the cases of relatively large amounts of triethylamine, trialdehyde 2 was given in moderate
yield.
In tr od u ction
materials. Aldehydes are good reagents for a variety of
reactions, and cis,cis-1,3,5-triformyl-1,3,5-trimethylcy-
clohexane (2)12 may also be utilized for new types of
ligands.13,14
cis,cis-1,3,5-Trimethylcyclohexane-1,3,5-tricarboxylic acid
(Kemp’s triacid) (1)1 has been used as a versatile molecule
for molecular recognition studies.2 Derivatives of triacid
1 have been also applied as a molecular cleft,3 self-
replicating system,4 chiral auxiliary,5 and sodium sac-
charide cotransporter.6 Recently, Lippard and co-workers
indicated that the dianion of m-xylylenediamine bis-
(Kemp’s triacid imide) is available for a methane mo-
nooxygenase model system7 and a molecular 18-wheeler.8
On the other hand, trisubstituted cyclohexanes have been
used as ligands to model metal-containing enzymes9,10
or phosphate receptors.11 These ligands were synthesized
by using triamines, not trialdehydes, as the starting
(1) Kemp, D. S.; Petrakis, K. S. J . Org. Chem. 1981, 46, 5140.
(2) (a) Bencini, A.; Bianchi, A.; Burguete, M. I.; Garc´ıa-Espan˜a, E.;
Luis, S. V.; Ram´ırez, J . A. J . Am. Chem. Soc. 1992, 114, 1919. (b)
Bencini, A.; Bianchi, A.; Burguete, M. I.; Dapporto, P.; Dome´nech, A.;
Garc´ıa-Espan˜a, E.; Luis, S. V.; Paoli, P.; Ram´ırez, J . A. J . Chem. Soc.,
Perkin Trans. 2 1994, 569.
(3) (a) Rebek, J ., J r.; Marshall, L.; Wolak, R.; Parris, K.; Killoran,
M.; Askew, B.; Nemeth, D.; Islam, N. J . Am. Chem. Soc. 1985, 107,
7476. (b) Rebek, J ., J r.; Askew, B.; Killoran, M.; Nemeth, D.; Lin, F.-
T. J . Am. Chem. Soc. 1987, 109, 2426. (c) J eong, K.-S.; Muehldorf, A.
V.; Rebek, J ., J r. J . Am. Chem. Soc. 1990, 112, 6144. (d) J eong, K. S.;
Tjivikua, T.; Muehldorf, A.; Deslongchamps, G.; Famulok, M.; Rebek,
J ., J r. J . Am. Chem. Soc. 1991, 113, 201.
Hydroxymethyl, formyl, and carboxyl groups have
different oxidation states, respectively. Intermolecular
and intramolecular reactions of alcohols with carboxylic
acids15,16 or aldehydes17,18 have been well-known, and
uronic acids19 have been known as compounds containing
hydroxymethyl, formyl, and carboxyl groups. However,
these derivatives have received little attention, and the
interaction among the adjacent three groups has not
clarified much.
(4) Tjivikua, T.; Ballester, P.; Rebek, J ., J r. J . Am. Chem. Soc. 1990,
112, 1249.
(12) Izumi, H.; Setokuchi, O.; Shimizu, Y.; Tobita, H.; Ogino, H. J .
Org. Chem. 1997, 62, 1173.
(13) Izumi, H.; Futamura, S. J . Chem. Soc., Perkin Trans. 1 1998,
1925.
(14) Casella, L.; Gullotti, M.; Pallanza, G.; Rigoni, L. J . Am. Chem.
Soc. 1988, 110, 4221.
(15) (a) Natelson, S.; Gottfried, S. Org. Synth. 1955, 3, 381. (b)
Clinton, R. O.; Laskowski, S. C. J . Am. Chem. Soc. 1948, 70, 3135. (c)
Klostergaard, H. J . Org. Chem. 1958, 23, 108.
(16) (a) J ohnson, W. S.; Bauer, V. J .; Margrave, J . L.; Frisch, M. A.;
Dreger, L. H.; Hubbard, W. N. J . Am. Chem. Soc. 1961, 83, 606. (b)
Minato, H.; Horibe, I. J . Chem. Soc. (C) 1968, 2131.
(17) Bell, J . M.; Kubler, D. G.; Sartwell, P.; Zepp, R. G. J . Org. Chem.
1965, 30, 4284.
(5) (a) Stack, J . G.; Curran, D. P.; Rebek, J ., J r.; Ballester, P. J .
Am. Chem. Soc. 1991, 113, 5918. (b) Stack, J . G.; Curran, D. P.; Geib,
S. V.; Rebek, J ., J r.; Ballester, P. J . Am. Chem. Soc. 1992, 114, 7007.
(6) Bien, J . T.; Shang, M.; Smith, B. D. J . Org. Chem. 1995, 60, 2147.
(7) (a) Herold, S.; Lippard, S. J . J . Am. Chem. Soc. 1997, 119, 145.
(b) Mizoguchi, T. J .; Lippard, S. J . Inorg. Chem. 1997, 36, 4526. (c)
Herold, S.; Lippard, S. J . Inorg. Chem. 1997, 36, 50. (d) LeCloux, D.
D.; Lippard, S. J . Inorg. Chem. 1997, 36, 4035.
(8) Watton, S. P.; Fuhrmann, P.; Pence, L. E.; Caneschi, A.; Cornia,
A.; Abbati, G. L.; Lippard, S. J . Angew. Chem., Int. Ed. Engl. 1997,
36, 2774.
(9) Greener, B.; Moore, M. H.; Walton, P. H. Chem. Commun. 1996,
27.
(10) Angelis, S.; Batsanov, A.; Norman, T. J .; Parker, D.; Senanay-
ake, K.; Vepsalainen, J . J . Chem. Soc., Chem. Commun. 1995, 2361.
(11) Raposo, C.; Almaraz, M.; Mart´ın, M.; Weinrich, V.; Musso´ns,
M. L.; Alca´zar, V.; Caballero, M. C.; Mora´n, J . R. Chem. Lett. 1995,
759.
(18) (a) Kjaer, A.; Lindberg, B. Acta Chem. Scand. 1959, 13, 1713.
(b) Pigman, W. The Carbohydrates; Academic Press: New York, 1957;
p 92.
(19) Theander, O. The Carbohydrates. Chemistry and Biochemistry;
Academic Press: New York, 1980; p 1023.
10.1021/jo990468o CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/26/1999

Proximity Effect in Swern Oxidation
J . Org. Chem., Vol. 64, No. 12, 1999 4503
Ta ble 1. Sw er n Oxid a tion Rea ction s of Tr iol 4 w ith
DMSO, TF AA, a n d NEt3
Sch em e 1
entry
products (% yield)
1a
2b
3c
4d
7a (9%), 6 (6%), 5 (trace amounts)
2 (43%), 5 (4%)
6 (26%), 5 (trace amounts), 7a (trace amounts)
2 (53%), 5 (1%)
a
(i) TFAA (7 mol equiv), DMSO/CH2Cl2, -55 °C; (ii) NEt3 (22
b
mol equiv); (iii) acidic workup. (i) TFAA (4 mol equiv), DMSO/
CH2Cl2, -55 °C; (ii) NEt3 (29 mol equiv); (iii) acidic workup. c (i)
TFAA (4 mol equiv), DMSO/CH2Cl2, -55 °C; (ii) NEt3 (8 mol
d
equiv); (iii) acidic workup. (i) TFAA (4 mol equiv), DMSO/CH2Cl2,
-55 °C; (ii) NEt3 (8 mol equiv).
Swern oxidation is one of the most efficient methods
to selectively oxidize primary and secondary alcohols.20
This oxidation is usually conducted below -50 °C. At
room temperature (rt), however, methylthiomethyl ethers
are given as byproducts, not carboxylic acids or hemiac-
etals. Swern oxidation is also useful for the oxidation of
cis,cis-1,3,5-tris(hydroxymethyl)cyclohexane (3).21 The
oxidation of 3 with DMSO and oxalyl chloride gives the
corresponding trialdehyde in 70% yield. However, the
oxidation of triol 422 containing ipso methyl groups yields
only small amounts of trialdehyde 2.12 The main byprod-
uct is lactone 5.1,12 The contrast between these reactions
may be ascribed to the conformational preference of the
corresponding species. On the other hand, the oxidation
of 4 with TFAA instead of oxalyl chloride affords 1,7,9-
trimethyl-3,5,12-trioxawurtzitane (1,7,9-trimethyl-3,5,-
12-trioxatetracyclo[5.3.1.1.2,604,9]dodecane) (6).12 In this
paper, we report the proximity effect in the Swern
oxidation of triols 4 and 3 with DMSO, TFAA, and
triethylamine. We also present the first evidence for the
existence of 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxy-
methylcyclohexane-1-carboxylic acid.
carboxyl group and a hemiacetal methine. The conforma-
tion of 7a was decided by its NOE differential spectra
(DMSO-d6). The hemiacetal methine proton correlated
with one methylene proton. The NOE differential spectra
of 7a (DMSO-d6) also indicated the exchange between the
carboxyl proton and the hydroxyl proton.23 On the other
hand, a Swern oxidation reaction of 4 with TFAA (4 mol
equiv), triethylamine (29 mol equiv), and acidic workup
gave trialdehyde 212 in 43% yield (Table 1). We also
detected lactone 5 (4%) but not hemiacetal 7a .
This oxidation reaction of 4 with TFAA was sensitive
to the amounts of reagents. A Swern oxidation reaction
of 4 with TFAA (4 mol equiv), triethylamine (8 mol equiv),
and acidic workup gave trioxawurtzitane 6 in 26% yield
(Table 1). Trace amounts of lactone 5 and hemiacetal 7a
1
were also detected. In this reaction, the H NMR spec-
trum of sample I before acidic workup indicated the
signals of trialdehyde 2 and lactone 5 (2:5 ) 25:2).23
However, the 1H NMR spectrum of sample II after acidic
workup mainly showed the signals of trioxawurtzitane
6 and polymers of 2.23 This finding suggests that trial-
dehyde 2 decomposed to give trioxawurtzitane 6 and
polymers by the acidic workup. A Swern oxidation
reaction of 4 with TFAA (4 mol equiv) and triethylamine
(8 mol equiv) without acidic workup afforded trialdehyde
2 (53%) and lactone 5 (1%) (Table 1).
The conformer 7a was relatively stable in DMSO-d6.
However, 7a in acetone-d6 and CDCl3 showed a different
behavior. The acetone-d6 solution of 7a gave an equilib-
rium mixture of 7a and 7b (rt, 5.5 h; 7a :7b ) 5:4)
(Scheme 1). The structure of 7b was supported by the
NOE differential spectra of the mixture of 7a and 7b
(acetone-d6). The hemiacetal methine proton of 7b cor-
related with the two adjacent methylene protons. Allow-
ing the DMSO-d6 solution of this mixture to stand at
room temperature for 3 days increased the ratio of 7a
(7a :7b ) 20:3). It is well-known that D-glucose is a stable
hemiacetal, and the R-form is in equilibrium with the
â-form via aldehyde form.18 It is analogously suggested
Resu lts a n d Discu ssion
As shown in Table 1, a Swern oxidation reaction of 4
with TFAA (7 mol equiv), triethylamine (22 mol equiv),
and acidic workup gave 5-formyl-cis,cis-1,3,5-trimethyl-
3-hydroxymethylcyclohexane-1-carboxylic acid hemiac-
etal (7a ) (9%) as well as trioxawurtzitane 6 (6%),12 lactone
5 (trace amounts),1,12 and polymers of trialdehyde 2.12 The
formation of 5 and 6 was confirmed in comparison with
1H NMR data of authentic samples previously isolated.12
1
The H NMR spectrum of polymers of 2 indicated many
complicated broad signals.12 The 1H and 13C NMR (DEPT)
spectra of 7a (DMSO-d6) indicated the signals of a
(20) (a) Mancuso, A. J .; Swern, D. Synthesis 1981, 165. (b) Mancuso,
A. J .; Brownfain, D. S.; Swern, D. J . Org. Chem. 1979, 44, 4148. (c)
Huang, S. L.; Omura, K.; Swern, D. J . Org. Chem. 1976, 41, 3329.
(21) Nielsen, A. T.; Christian, S. L.; Moore, D. W.; Gilardi, R. D.;
George, C. F. J . Org. Chem. 1987, 52, 1656.
(22) Mayer, H. A.; Fawzi, R.; Steimann, M. Chem. Ber. 1993, 126,
1341.
(23) See Supporting Information.

4504 J . Org. Chem., Vol. 64, No. 12, 1999
Izumi and Futamura
that 7a is in equilibrium with 7b via intermediate A. On
the other hand, the CDCl3 solution of 7a mainly yielded
1,7,9-t r im et h yl-2-oxo-3,5-dioxa t r icyclo[5.3.1.04 ,9 ]-
undecane (8) and lactone 5 (rt, 20 h; 8:5 ) 5:3) (Scheme
1). Allowing the DMSO-d6 solution of the mixture to
stand at room temperature also gradually increased 7a
concentration with the decrease in those of 8 and 5.23 We
have already described that acid catalysis works in
chloroform,12,13 and hemiacetal 7a itself contains the
carboxyl group. It is suggested that acid-catalyzed de-
hydration reactions of 7a give 8 and 5 in CDCl3. The
formation of 5 supports the existence of A containing
hydroxymethyl, formyl, and carboxyl groups. These find-
ings indicate that the stabilities of 7a , 7b, 8, and 5 differ,
depending on solvents.
is suggested that the introduction of ipso methyl groups
makes the intramolecular reaction into lactone 5 pre-
dominant.
Con clu sion
We have described the proximity effect in the Swern
oxidation of triols 4 and 3 with DMSO, TFAA, and
triethylamine. The intramolecular reaction is predomi-
nant in the oxidation of 4. In the cases of relatively small
amounts of triethylamine added, hemiacetal 7a , triox-
awurtzitane 6, and lactone 5 were given. Hemiacetal 7a
can be changed into hemiacetal 7b, lactone 5, or tricycle
8 via A, depending on the solvents used.
As described above, the different amounts of triethyl-
amine caused the difference of products from the oxida-
tion reactions of triol 4. Triethylamine has two roles in
Swern oxidation. One is the proton abstraction from
dimethylalkoxysulfonium salts,24 and the other is the
trap for TFA. In the cases of relatively large amounts of
triethylamine, it is suggested that the formation of a
dialdehyde occurs first, followed by an oxidation of the
last hydroxymethyl group to produce trialdehyde 2 and,
as a byproduct, lactone 5. We have already shown that
trialdehyde 2 easily cyclizes to trioxawurtzitane 6 in
acidic conditions.12 The formation of 6 suggests that the
reaction condition was acidic because of relatively small
amounts of triethylamine. We conducted NMR monitor-
ing experiments to understand the mechanism for the
formation of hemiacetal 7a . The CDCl3 (0.9 mL) solution
of lactone 5 containing water (0.1 mL) gave hemiacetal
7a and tricycle 8 (rt, 9 days; 5:7a :8 ) 14:2:1), but the
CDCl3 (0.8 mL) solution of 5 not containing water
afforded neither 7a nor 8. The acetone-d6 (0.9 mL)
solution of 5 containing water (0.1 mL) gave hemiacetals
7a and 7b (rt, 9 days; 5:7a :7b ) 10:2:1). These findings
suggest that 7a is produced from 5 in the presence of
water and acid.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed in oven-
dried glassware equipped with a magnetic stirring bar under
an argon atmosphere, using standard syringe techniques.
DMSO and CH2Cl2 were distilled from CaH2 and stored over
molecular sieves. All other solvents were of anhydrous grade.
cis,cis-1,3,5-Tris(hydroxymethyl)-1,3,5-trimethylcyclohexane (4)12
and cis,cis-1,3,5-tris(hydroxymethyl)cyclohexane (3)21 were
prepared by the similar procedures previously reported. All
1
other reagents were of commercial grade. H (500 MHz) and
13C (125.7 MHz) NMR spectra were recorded in DMSO-d6,
acetone-d6, CDCl3, or C6D6.
5-F or m yl-cis,cis-1,3,5-t r im et h yl-3-h yd r oxym et h ylcy-
cloh exan e-1-car boxylic acid h em iacetal (2-h ydr oxy-1,5,7-
t r im et h yl-en d o-3-oxa b icyclo[3.3.1]n on a n e-7-ca r b oxylic
a cid ) (7a ). A mixture of dry DMSO (4 mL) and dry CH2Cl2
(10 mL) was added to a dry CH2Cl2 solution (40 mL) of TFAA
(7.26 g, 34.6 mmol) at -55 °C. After the mixture was stirred
for 30 min, a solution of 1.04 g (4.8 mmol) of triol 4 in dry
CH2Cl2 (25 mL)/DMSO (20 mL) was added at -55 °C. The
solution was allowed to stir at -55 °C for 2 h. NEt3 (15 mL,
0.11 mol) was added slowly, and the reaction mixture was
allowed to warm to room temperature. Water (50 mL) was then
added, and the CH2Cl2 layer was separated. Concentrated HCl
(3 mL) was added to the aqueous phase, followed by extraction
with CH2Cl2. The combined CH2Cl2 solutions were washed
once with dilute HCl and once with saturated aqueous NaCl.
After being dried with MgSO4 for 30 min, followed by filtration,
the filtrate was concentrated to remove volatiles. The mixture
of 6 (0.060 g, 6%) and 5 (trace amounts) was separated first
by flash chromatography on silica gel, using CH2Cl2/acetone
(500 mL/10 mL) as an eluent. Hemiacetal 7a and polymers
were then separated by using acetone as an eluent. Attempts
to recrystallize 7a were in vain. 7a was purified by washing
with hexane (0.102 g, 9%). 7a : colorless solids; 1H NMR
(DMSO-d6, 500 MHz) δ 0.67 (3H, s, CH3), 0.73 (3H, s, CH3),
To clarify the effect of ipso methyl groups further, we
also examined the Swern oxidation of triol 3 with TFAA.
A Swern oxidation reaction of 3 with TFAA (4 mol equiv)
and triethylamine (34 mol equiv) without acidic workup
gave trialdehyde 921 (26%) and polymeric material. The
formation of the corresponding lactone could not be
confirmed. The 1H NMR spectrum of 9 supported the
triequatorial conformation of the formyl groups. A Swern
oxidation reaction of 3 with TFAA (7 mol equiv), triethyl-
amine (21 mol equiv), and acidic workup afforded poly-
meric material. The formation of the corresponding
trioxawurtzitane, lactone, and hemiacetal could not be
confirmed. It has been known that the reaction of Kemp’s
triacid 1 with SOCl2 gives anhydride acid chloride 10,1
but the reaction between the corresponding triacid
without ipso methyl groups and SOCl2 yields triacid
chloride 11.25 We have already shown that the steric
repulsion of ipso methyl groups stabilizes the triaxial
conformation of the formyl groups in trialdehyde 2.12 It
2
2
0.75 (1H, d, J HH ) 12.3 Hz, CHaHe), 0.89 (2H, d, J HH ) 13.4
2
Hz, CHaHe), 1.01 (3H, s, CH3), 1.59 (1H, d, J HH ) 12.3 Hz,
CHaHe), 2.27 (2H, d, 2J HH ) 13.4 Hz, CHaHe), 3.15 (1H, d, 2J HH
2
) 10.2 Hz, CH2O), 3.39 (1H, d, J HH ) 10.2 Hz, CH2O), 4.51
3
3
(1H, d, J HH ) 3.7 Hz, OCHOH), 5.82 (1H, d, J HH ) 3.7 Hz,
OH), 11.43 (1H, br. s, COOH); 13C NMR (DMSO-d6, 125.7 MHz)
δ 25.79 (CH3), 26.06 (CH3), 30.86 [(CH2)2CCH3], 31.98 (CH3),
34.94 [(CH2)2CCH3], 40.59 (CCH2C), 41.75 [(CH2)2CCH3], 45.04
(CCH2C), 45.15 (CCH2C), 67.46 (CH2O), 95.06 (OCHOH),
177.62 (COOH); IR (KBr) νCO 1692 cm-1; MS (EI) m/z 228 (8,
M+); HRMS calcd for C12H20O4 228.1362, found 228.1343. Anal.
Calcd for C12H20O4: C, 63.14; H, 8.83. Found: C, 63.37; H,
8.78.
(24) (a) J ohnson, C. R.; Phillips, W. G. J . Org. Chem. 1967, 32, 1926.
(b) Torssell, K. Acta Chem. Scand. 1967, 21, 1. (c) J ohnson, C. R.;
Phillips, W. G. Tetrahedron Lett. 1965, 2101. (d) Torssell, K. Tetrahe-
dron Lett. 1966, 4445.
(25) Mayer, H. A.; Sto¨ssel, P.; Fawzi, R.; Steimann, M. Chem. Ber.
1995, 128, 719.

Proximity Effect in Swern Oxidation
J . Org. Chem., Vol. 64, No. 12, 1999 4505
2
cis,cis-1,3,5-Tr ifor m yl-1,3,5-tr im eth ylcycloh exa n e (2).12
A mixture of dry DMSO (5 mL) and dry CH2Cl2 (15 mL) was
added to a dry CH2Cl2 solution (40 mL) of TFAA (4.93 g, 23.5
mmol) at -55 °C. After the mixture was stirred for 30 min, a
solution of 1.28 g (5.9 mmol) of triol 4 in dry CH2Cl2 (15 mL)/
DMSO (15 mL) was added at -55 °C. The solution was allowed
to stir at -55 °C for 2 h. NEt3 (6.5 mL, 47 mmol) was added,
and the reaction mixture was allowed to warm to room
temperature. Water (50 mL) was then added, and the CH2Cl2
layer was separated. The aqueous phase was extracted with
CH2Cl2. The combined CH2Cl2 solutions were washed with
saturated aqueous NaCl. After being dried with MgSO4 for 30
min, followed by filtration, the filtrate was concentrated to
remove volatiles. The residual solid was subjected to a silica
gel column and eluted with CH2Cl2/acetone (500 mL/10 mL).
Trialdehyde 2 (0.662 g, 53%) and lactone 5 (11 mg, 1%) were
obtained as the first and second fractions, respectively.
A Swern oxidation reaction of 4 (1.32 g, 6.1 mmol) with
TFAA (5.25 g, 25.0 mmol), triethylamine (25 mL, 0.18 mol),
and acidic workup that was employed in the preparation of
7a also gave trialdehyde 2 (0.548 g, 43%) and lactone 5 (56
mg, 4%).
1H NMR (C6D6, 500 MHz) δ 0.33 (1H, d, J HH ) 12.1 Hz,
CHaHe), 0.43 (3H, s, CH3), 0.45 (1H, d, 2J HH ) 12.5 Hz, CHaHe),
2
0.61 (3H, s, CH3), 0.62 (1H, d, J HH ) 13.6 Hz, CHaHe), 1.09
(3H, s, CH3), 1.16 (1H, d, 2J HH ) 12.1 Hz, CHaHe), 1.19 (1H, d,
2J HH ) 12.5 Hz, CHaHe), 1.32 (1H, d, J HH ) 13.6 Hz, CHaHe),
2
2
2
3.14 (1H, d, J HH ) 11.8 Hz, CH2O), 3.35 (1H, d, J HH ) 11.8
Hz, CH2O), 5.23 (1H, s, OCHO); 13C NMR (C6D6, 125.7 MHz)
δ 26.43 (CH3), 27.86 (CH3), 29.17 (CH3), 31.47 [(CH2)2CCH3],
33.24 [(CH2)2CCH3], 39.58 [(CH2)2CCH3], 42.00 (CCH2C), 43.44
(CCH2C), 48.96 (CCH2C), 69.42 (CH2O), 104.29 (OCHO),
176.54 (COO); MS (EI) m/z 210 (3, M+); HRMS calcd for
C12H18O3 210.1256, found 210.1267.
NMR Mon itor in g Exp er im en ts. Hemiacetal 7a (7.5 mg,
0.033 mmol) was added to acetone-d6 (0.8 mL) in an NMR tube.
Allowing the solution to stand at room temperature for 3 days
gave an equilibrium mixture of 7a and 7b (7a :7b ) 5:4). After
acetone-d6 was removed under reduced pressure, allowing the
DMSO-d6 (0.8 mL) solution of the residue to stand at room
temperature for 3 days increased the ratio of 7a (7a :7b )
20:3). 7b: 1H NMR (acetone-d6, 500 MHz) δ 0.74 (3H, s, CH3),
2
0.81 (3H, s, CH3), 0.88 (1H, d, J HH ) 14.5 Hz, CHaHe), 1.12
(1H, d, 2J HH ) 14.1 Hz, CHaHe), 1.14 (3H, s, CH3), 1.19 (1H, d,
A Swern oxidation reaction of 4 (1.32 g, 6.1 mmol) with
TFAA (5.25 g, 25.0 mmol), triethylamine (7 mL, 0.05 mol), and
acidic workup that was employed in the preparation of 7a
afforded trioxawurtzitane 6 (0.335 g, 26%). Trace amounts of
lactone 5 and hemiacetal 7a were also detected.
2
2J HH ) 12.8 Hz, CHaHe), 1.32 (1H, d, J HH ) 12.8 Hz, CHaHe),
2
2
2.39 (1H, d, J HH ) 14.1 Hz, CHaHe), 2.52 (1H, d, J HH ) 14.4
2
Hz, CHaHe), 3.22 (1H, d, J HH ) 10.9 Hz, CH2O), 3.63 (1H, d,
2J HH ) 10.9 Hz, CH2O), 3.99 (1H, d, 3J HH ) 11.4 Hz, OH), 4.20
3
(1H, d, J HH ) 11.4 Hz, OCHOH).
cis,cis-1,3,5-Tr ifor m ylcycloh exan e (9).21 The similar man-
ner that was employed in the preparation of trialdehyde 2 was
used with triol 3 (0.910 g, 5.2 mmol), TFAA (4.28 g, 20.4 mmol),
and triethylamine (25 mL, 0.18 mol). This oxidation reaction
gave trialdehyde 9 (0.230 g, 26%) and polymeric material. The
formation of the corresponding lactone could not be confirmed.
Hemiacetal 7a (7.5 mg, 0.033 mmol) was added to CDCl3
(0.8 mL) in an NMR tube. Allowing the solution to stand at
room temperature for 20 h mainly yielded tricycle 8 and
lactone 5 (8:5 ) 5:3). After CDCl3 was removed under reduced
pressure, allowing the DMSO-d6 (0.8 mL) solution of the
residue to stand at room temperature gradually increased 7a
concentration with the decrease in those of 8 and 5.23
Water (0.1 mL) was added to a solution of lactone 5 (4.6
mg, 0.022 mmol) in CDCl3 (0.9 mL). Allowing the solution to
stand at room temperature for 9 days gave hemiacetal 7a and
tricycle 8 (5:7a :8 ) 14:2:1). The CDCl3 (0.8 mL) solution of 5
(4.6 mg, 0.022 mmol) not containing water afforded neither
7a nor 8.
2
9: 1H NMR (CDCl3, 500 MHz) δ 1.18 (3H, dt, J HH ) 12.6 Hz,
2
3
3J HH ) 12.6 Hz, CHaHe), 2.33 (3H, br. d, J HH ) 12.6 Hz, J HH
) 3.2 Hz, CHaHe), 2.40 (3H, tt, 3J HH ) 12.6 Hz, 3J HH ) 3.2 Hz,
CH), 9.65 (3H, s, CHO); 13C NMR (CDCl3, 125.7 MHz) δ 25.20
(CCH2C), 47.94 [(CH2)2CH], 201.69 (CHO).
A Swern oxidation reaction of 3 (0.909 g, 5.2 mmol) with
TFAA (7.67 g, 36.5 mmol), triethylamine (15 mL, 0.11 mol),
and acidic workup that was employed in the preparation of
7a gave polymeric material. The formation of the correspond-
ing trioxawurtzitane, lactone, and hemiacetal could not be
confirmed.
Water (0.1 mL) was added to a solution of lactone 5 (5.4
mg, 0.026 mmol) in acetone-d6 (0.9 mL). Allowing the solution
to stand at room temperature for 9 days gave hemiacetals 7a
and 7b (5:7a :7b ) 10:2:1).
1,7,9-T r im e t h y l-2-o x o -3,5-d io x a t r ic y c lo [5.3.1.04,9]-
u n d eca n e (8). Hemiacetal 7a (46 mg, 0.20 mmol) was added
to CDCl3 (6 mL). After the solution was stirred for 3 days,
volatiles were removed under reduced pressure. It was very
difficult to separate tricycle 8 from lactone 5. The residue was
heated at 170 °C for 30 min and cooled to room temperature.
After being extracted with hexane, the solvent was removed
under reduced pressure. Tricycle 8 was separated by molecular
distillation (6.4 mg, 15%).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
samples I and II; 1H NMR and NOE differential spectra of
hemiacetal 7a in DMSO-d6, acetone-d6, and CDCl3; the spectral
changes upon the equilibration of a mixture of 8, 5, and 7a in
DMSO-d6; 1H NMR spectra of 5, 8, and 9; NOE values for 7a .
This material is available free of charge via the Internet at
http://pubs.acs.org.
Heating lactone 5 (86 mg, 0.41 mmol) at 170 °C for 40 min
gave decomposition products. Tricycle 8 was not detected. 8:
J O990468O