TFA-catalyzed trimerization of R-(+)-6-methyl-tetrahydro-pyran-2-one

Article abstract of DOI:10.1016/S0040-4039(01)02281-X

The enantiomerically pure (≥98% ee) title compound R-(+)-6-methyl-tetrahydro-pyran-2-one (R)-1 in the presence of traces of trifluoroacetic acid (TFA) converts into an equilibrium mixture with its trimer 4 [(R)-1:4=20:80] corresponding to a ΔG?-0.8 kcal mol^-1. The transformation can be followed by ¹H and ¹³C NMR spectroscopy. The structure of 4 was established by chemical correlation with (R)-1 and its molecular weight determined via its colligative properties.

Full text of DOI:10.1016/S0040-4039(01)02281-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 811–814
TFA-catalyzed trimerization of
R-(+)-6-methyl-tetrahydro-pyran-2-one
Fabio Fazio and Manfred P. Schneider*
FB 9-Bergische Universita¨t-GH-Wuppertal, D-42097 Wuppertal, Germany
Received 27 June 2001; accepted 22 July 2001
Abstract—The enantiomerically pure (]98% ee) title compound R-(+)-6-methyl-tetrahydro-pyran-2-one (R)-1 in the presence of
traces of trifluoroacetic acid (TFA) converts into an equilibrium mixture with its trimer 4 [(R)-1:4=20:80] corresponding to a
1
DG$−0.8 kcal mol−1. The transformation can be followed by H and 13C NMR spectroscopy. The structure of 4 was established
by chemical correlation with (R)-1 and its molecular weight determined via its colligative properties. © 2002 Elsevier Science Ltd.
All rights reserved.
Some time ago we described a novel synthesis of enan-
tiomerically pure (]98% ee) 6-alkylsubstituited d-lac-
tones starting from optically pure alkyloxiranes which,
in turn, were obtained via an enzyme assisted route
based on the lipase-catalyzed, kinetic resolution of suit-
able racemic precursors.1 Using the title compound
(R)-1 as an example, the route is summarized in
Scheme 1.
amounts of trifluoroacetic acid. (R)-1 was isolated by
column chromatography on silica gel [Et2O/n-hexane
(2/1)] followed by short path distillation (Kugelrohr,
70°C, 10−3 mBar) as a white solid (mp 31°C). Although
monitoring of the reaction by TLC and GC confirmed
quantitative conversion, the yield was only 50%, proba-
bly due to the solubility of (R)-1 in the aqueous solu-
tion used for work up.
Nucleophilic ring opening of (R)-2-methyloxirane by
the anion of tert-butyl propiolate led to R-(−)-5-
hydroxy-hex-2-ynoic acid tert-butyl ester (R)-2, which
was hydrogenated (5% Pd/C, AcOEt, −20°C; 6 h, 99%)
quantitatively to the saturated derivative (R)-3 which
was in turn cyclized to (R)-1 in the presence of catalytic
The thus prepared (R)-12 showed a chemical purity of
]99% (GC analysis) which was further confirmed by
1
the clean and readily interpretable H and 13C NMR
spectra (Fig. 1A). (R)-1 was optically pure3 with an
optical rotation of [h]2D0=+36 (c 0.7, CHCl3 stab. with
1% EtOH). Surprisingly and quite unexpectedly we
Scheme 1. (a) tert-Butyl propiolate, n-BuLi, BF3–Et2O, THF, −78°C, 2.5 h; (b) H2, 5% Pd/C, AcOEt, −20°C, 6 h; (c) TFA,
CH2Cl2, rt, 24 h.
Keywords: chiral d-lactones; trimerization; trifluoroacetic acid.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02281-X

812
F. Fazio, M. P. Schneider / Tetrahedron Letters 43 (2002) 811–814
Figure 1. 1H and 13C NMR spectra (CDCl3, 400 MHz). (A) Freshly synthesized (R)-1; (B) product stored at 20°C for 21 days;
(C) product stored at 20°C for 35 days.
found, however, that the thus prepared (R)-1 was
unstable upon storage in neat form even at low temper-
atures. This became evident when crystalline (R)-1
slowly turned into a liquid, the change in physical
appearance being accompanied by a change of optical
rotation from [h]2D0=+36 to [h]D20=−7 (c 1.0, CHCl3
stab. with 1% EtOH) for what turned out to be an
equilibrium mixture of (R)-1 and a newly formed com-
pound for which we assigned the trimeric structure 4
(Scheme 2).
having a corresponding multiplet at l=4.90 ppm (three
carbonyl carbons at 172.84 ppm in the 13C NMR) (Fig.
1B). After ca. 35 days an equilibrium mixture of (R)-1
and 4 was obtained with a ratio (determined by integra-
1
tion of the H NMR signals) of ca. 20:80 (Fig. 1C).
The existence of a true thermodynamic equilibrium was
supported by the fact that the same mixture was
obtained starting from either pure (R)-1 or 4.
This trimerization surprisingly turned out to be a very
clean transformation, no other oligomers or polymers
were observed. It can be conveniently monitored via the
1
corresponding H and 13C NMR spectra, which were
taken in regular (7 days) intervals. Thus pure (R)-1
(Fig. 1A) having a characteristic multiplet at l=4.39
1
ppm in the H NMR spectrum (and a signal at l=
171.67 ppm for the carbonyl carbon in the 13C NMR)
was slowly transformed into (6R,12R,18R)-(−)-6,12,18-
trimethyl-1,7,3-trioxa-cyclooctadecane-2,8,14-trione 4,
Scheme 2.

F. Fazio, M. P. Schneider / Tetrahedron Letters 43 (2002) 811–814
813
Thus, the molecular weight of 4 had to be determined
the ‘old fashioned way’ exploiting the colligative prop-
erties of this material. Using the freezing point depres-
Pure 4 was obtained by removal of (R)-1 from the
equilibrium mixture by short path distillation (Kugel-
rohr, 100°C, 10−3 mBar). Next to a correct elemental
sion in 1,4-dioxane we were able to calculate6
a
1
analysis and the obvious similarity of the H and 13C
molecular weight for 4 of 367.16 (theor. 342.43) (Fig.
NMR spectra of (R)-1 and 4 which allowed a facile
interpretation,4 4 was chemically correlated with (R)-1.
Hydrolysis of 4 with 2N NaOH in H2O/THF led to the
corresponding sodium salt of R-(−)-5-hydroxy-hexanoic
acid (R)-5. After acidification with aqueous conc. HCl
and removal of all solvents, the resulting (R)-5 was
recyclized to (R)-1 without loss of optical purity
(Scheme 3).
2).
In this formula Kf represents the cryoscopic constant
(−4.63 for 1,4-dioxane) and DTf=Tfsolution−Tfsolvent is
the difference of the freezing points between pure 1,4-
dioxane and the under described solution of 4 in the
same solvent (see Ref. 6). We found for 4 a MW of
367.16 (theor. 342.43), the error thus was 7.2%.
Next to proving the molecular constitution of 4 this
sequence also allows a regeneration of (R)-1 from the
impure mixture.
From the equilibrium constant at 20°C it can be
calculated7 that the trimeric structure 4 is thermo-
dynamically more stable than (R)-1 by a DG°$−0.8
kcal mol−1, a difference which is clearly sufficient to
partially transform (R)-1 into 4.
However, in spite of all this information the correct
structure of 4 remained unclear, with other oligomeric
structures such as the corresponding dimer or tetramer
being obvious options. All of them being symmetric
(n-fold axes Cn) they would all display six carbon
atoms in the 13C NMR. Also, the determination of the
molecular weight by various MS techniques (EI, CI,
electrospray)5 proved to be unsuccessful. The thermal
instability of 4 led to signals resulting of monomer,
dimer and oligomers with unit differences of m/z=114.
It is interesting to speculate why only the trimer, having
an 18-membered ring is formed in this transformation
so cleanly without any trace of the corresponding
dimer, tetramer or other oligomers and polymers.
The relative stabilities of lactones having 3–23 ring
members had been determined earlier, revealing clearly
the higher stability of the 18-membered ring system8
over the 6- and 12-membered rings (i.e. monomer and
dimer). This is in good agreement with our observa-
tions and the calculated DG°$−0.8 kcal mol−1.
With enantiomerically pure d-lactones being important
flavour compounds and thus attractive synthetic
targets, we were curious to elucidate the reasons for the
surprising trimerization of such a d-lactone. Clearly, the
Scheme 3. (a) 2N NaOH, THF/H2O, 0°C–rt, 30 min; (b)
conc. HCl, 0°C; (c) TFA, CH2Cl2, rt, 24 h.
Figure 2.

814
F. Fazio, M. P. Schneider / Tetrahedron Letters 43 (2002) 811–814
References
1. Haase, B.; Schneider, M. P. Tetrahedron: Asymmetry 1993,
4, 1017.
2. Analyses of (R)-1: white solid, mp: 31°C; [h]2D0=+36 (c 0.7,
CHCl3 stab. with 1% EtOH); 1H NMR (400 MHz, CDCl3)
l 4.39 (m, 1H), 2.44 (m, 2H), 1.84 (m, 3H), 1.47 (m, 1H),
1.32 (d, 3H, J=6.10); 13C NMR (100 MHz, CDCl3) l
Scheme 4. (a) p-TsOH, toluene, reflux, 1.30 h.
171.67, 76.76, 29.47, 29.09, 21.56, 18.40. IR (film, cm−1
)
2945, 1720, 1435, 1370, 1230. MS m/z 114, 99, 70, 55, 42
(100%), 39. Anal. calcd for C6H10O2: C, 63.14; H, 8.83.
Found: C, 62.52; H, 8.57. GC: column SE-52-CB; pres-
sure: 100 kPa H2; temperature program: 40°C (5 min),
40–280°C (4°C/min).
instability of (R)-1 could only be the result of an
acid-catalyzed process initiated by the presence of
traces of TFA introduced during the cyclization of
(R)-3 (Scheme 1). Since d-lactones are instable towards
base, the removal of TFA during workup by extraction
with an aqueous Na2CO3 solution causes considerably
reduced product yields. We therefore initially opted for
column chromatography and short path distillation in
the hope that the last traces of TFA would be com-
pletely removed this way. Evidently this was not the
case. If the organic phase during workup is indeed
washed with Na2CO3, the resulting (R)-1 (isolated in
greatly reduced yield of only 35%) is perfectly stable
upon storage. The addition of a trace of TFA immedi-
ately initiates again the above described trimerization.
3. The determination of the optical purity of (R)-1 was
established via GC on chiral support. Column: Lipodex E;
pressure: 100 kPa H2; temperature program: 78°C (42
min), 78–150°C (1.5°C/min); ee ]98%.
4. Analyses of 4: high viscous colorless oil; [h]2D0=−8 (c 0.6,
CHCl3 stab. with 1% EtOH); 1H NMR (400 MHz, CDCl3)
l 4.90 (m, 3H), 2.29 (m, 6H), 1.61 (m, 12H), 1.21 (d, 9H,
J=6.10); 13C NMR (100 MHz, CDCl3) l 172.84, 70.37,
35.23, 34.18, 20.81, 19.87. IR (film, cm−1) 2921, 1701, 1459,
1383. Anal. calcd for C18H30O6: C, 63.14; H, 8.83. Found:
C, 62.62; H, 8.59.
5. CI and electrospray MS analyses of 4 were carried out by
the Bayer AG, Wuppertal, Germany.
Clearly TFA is not the method of choice for the
6. Determination of molecular weight of 4 by freezing point
depression: 1.27 g of 1,4-dioxane was placed into a test
tube (13 cm×1.3 cm) containing a small magnetic stirrer.
The test tube was closed with a septum which was previ-
ously pierced in order to allow the insertion of a metal
contact thermometer with electronic display (0.1°C scale).
This apparatus was immersed into a cooling bath main-
tained at 0°C and the solution was stirred. Every 15 s the
temperature was recorded until it became constant for ca.
30 s. This value (10.6°C) was taken as freezing point of
pure 1,4-dioxane (a supercooling effect was observed).
Then 4 (91 mg) was added carefully to the test tube
thereby avoiding any loss of solvent until a homogeneous
solution was obtained and the experiment was repeated as
above recording the data. The thus obtained freezing point
of the solution was +9.7°C. Applying the formula for the
calculation of the molecular weight via the freezing point
depression of a substance we found a MW of 367.16
(theor. 342.43).
cyclization reaction leading to (R)-1.
Since (R)-1 is both base labile and soluble in an
aqueous environment we now optimized the cyclization
procedure by using p-TsOH in toluene (Scheme 4). No
aqueous workup was required in this case. Consider-
ably improved yields of 70% were obtained and the
resulting product is perfectly stable during storage at
room temperature.
Although base-catalyzed oligomerization of d-lactones
has already been reported in the literature,9 this to the
best of our knowledge seems to be the first example of
an acid (TFA)-catalyzed oligomerization of d-lactones.
Acknowledgements
7. DG°=−RT ln k=−2.303 RT log k. At 20°C, k$80/20$4
and DG°$−1.34 log 4$−0.8 kcal mol−1
.
8. Mandolini, L. J. Am. Chem. Soc. 1978, 100, 550.
9. Dale, J.; Schwartz, J. E. Acta Chem. Scand. 1986, B40,
559.
We are grateful to the colleagues of Bayer AG, Wup-
pertal, Germany for the measurement of mass spec-
tra.