Asymmetrization of tetrahydrofuran-2,2-dimethanol using l-menthone as a chiral template

Full text of DOI:10.1021/jo9515034

384
J . Org. Chem. 1996, 61, 384-385
phile, we presume the loss in diastereoselectivity to be
Asym m etr iza tion of
due to competing isomerization of spiroketal 7 to 8 under
the reaction conditions. By modifying the reaction condi-
tions, i.e., adding a precooled (-72 °C) solution of 7 in
CH2Cl2 to a premixed solution of TiCl4 and allyltrimeth-
ylsilane in CH2Cl2 at -90 °C, the selectivity in the ketal
cleavage was improved to 94% de. As the absolute
stereochemistry of product 11 had been independently
determined by us earlier1 and coupled with the known
preference for the equatorial C-O bond cleavage in
spiroketals of this type, the major spiroketal was assigned
structure 7 and the cleavage product, 9. Accordingly, the
minor spiroketal and the cleavage product were assigned
structures 8 and 12, respectively.
Tetr a h yd r ofu r a n -2,2-d im eth a n ol Usin g
l-Men th on e a s a Ch ir a l Tem p la te
Kapa Prasad,* Russell L. Underwood, and Oljan Repic
Chemical Research and Development, Technical R&D,
Sandoz Research Institute, Sandoz Pharmaceuticals
Corporation, 59 Route 10, East Hanover, New J ersey 07936
Received August 14, 1995
The synthesis of enantiomeric phospholipids 1 and 2
starting from chiral synthon 3 which was derived from
porcine pancreas lipase mediated enantiotopos-differen-
tiating hydrolysis of the corresponding dibutyrate was
reported recently by us.1 These phospholipids are of
interest as potential antitumor2 and multiple sclerosis3
agents, respectively. In the present report we describe
a nonenzymatic route to these enantiomers starting from
the prochiral tetrahydrofuran-2,2-dimethanol (4) and
l-menthone (5), utilizing the enantiodifferentiating func-
tionalization methodology developed by Oku and co-
workers.4
Tetrahydrofuran-2,2-dimethanol (4) was converted to
6 by treatment with hexamethyldisilazane/trimethylsilyl
trifluoromethanesulfonate (TMSOTf) in THF at 0 °C. The
reaction of 6 with l-menthone (5) in the presence of
TMSOTf at -40 °C in CH2Cl2 yielded spiroketals 7 and
8 in 89% yield and a ratio of 7:2, respectively. The ratio
of 7 to 8 could be further improved by conducting the
ketalization step at -78 °C to give a 6:1 mixture, but at
the expense of the chemical yield (42%). At -92 °C, the
reaction was found to be too slow to follow. As the
spiroketals are readily separable, we effected the ketal-
ization at -40 °C preferring the high chemical yield and
isolated the pure 7 and 8 by flash chromatography on
silica gel in 69 and 20% yields, respectively.
With the pure spiroketals in hand, we attempted the
enantiodifferentiating cleavage of 7 using literature
conditions.4 Addition of TiCl4 to a solution of 7 and
allyltrimethylsilane in CH2Cl2 at -85 °C resulted in the
isolation of a mixture of two diastereoisomers in the ratio
of 85:15 based on 13C NMR. This ratio was further
confirmed by independent measurement of optical purity
(70% ee) of product 11 obtained in two steps from this
diastereomeric mixture. As the ring cleavage of these
spiroketals was established4 as being highly stereoselec-
tive, occurring with the cleavage of the equatorial carbon-
oxygen bond and retentive introduction of the nucleo-
With the enantiodifferentiated products 9 and 12
obtained in high optical purity, the remaining objective
was their conversion to 11 and 14. This was achieved
by alkylating with octadecyl bromide and removing the
chiral auxiliary with trifluoroacetic acid. Alternatively,
alcohols 9 and 12 could be converted to 11 and 14 by
using a protection/deprotection strategy. This is il-
lustrated with 9 which was converted into the benzyl
ether 15, followed by trifluoroacetic acid treatment to give
16 in high yield. The conversion of 16 to 14 was reported
earlier by us.1
(1) Prasad, K.; Estermann, H.; Underwood, R.; Chen, C.-P.; Kuc-
erovy, A.; Repic, O. J . Org. Chem. in press.
(2) Houlihan, W. J .; Lee, M. L.; Munder, P. G.; Nemecek, G. M.;
Handley, D. H.; Winslow, C. M.; Happy, J .; J aeggi, C. Lipids 1987,
22, 884.
(3) Chabannes, D.; Ryffel, B.; Bore, J .-F. J . Autoimmunity 1992, 5,
199.
In conclusion, enantiodifferentiating functionalization
of prochiral tetrahydrofuran-2,2-dimethanol was success-
fully achieved using l-menthone as the chiral template,
and the chiral intermediates obtained were converted to
(4) Harada, T.; Oku, A. Synlett 1994, 95.
0022-3263/96/1961-0384$12.00/0 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 1, 1996 385
(R)-Tetr a h yd r o-2-((octa d ecyloxy)m eth yl)-2-fu r a n m eth a -
n ol (11). To a solution of 6.597 g (11.7 mmol) of 10 in 235 mL
of CH2Cl2 was added a precooled (5 °C) solution of 12 mL of
trifluoroacetic acid. The solution was stirred at 5 °C for 1 h,
and the reaction was quenched with 80 mL of 2 N NaOH
solution. The layers were separated, and the organic layer was
dried and evaporated to dryness. Flash chromatography of the
residue on SiO2 using hexane/EtOAc (6:1) followed by hexane/
EtOAc (4:1) gave 4.229 g (94%) of 11: ee before recrystallization
) 97%, ee after recrystallization in heptane and seeding with
pure crystals > 99%; [R]25365 ) +4.38° (c ) 1 in MeOH); identical
in all respects with the compound reported by us earlier.1
(R)-Tetr a h yd r o-2-[[[1(e)-a llyl-2(e)-isop r op yl-5(e)-m eth -
ylcycloh exa n yl]oxy]m eth yl]-2-fu r a n m eth a n ol (12). Start-
ing with 5.314 g (0.0198 mol) of 8, 31.5 mL of allyltrimethylsi-
lane, and 21.8 mL of 1 M solution of TiCl4 in CH2Cl2 and using
the procedure described for 9, there was obtained 5.96 g (96.9%)
11 and 14, which are precursors of phospholipids 1 and
2, with high enantiomeric purity.
Exp er im en ta l Section
The optical purity of alcohols 11, 14, and 16 was determined
by 31P NMR using a diazaphospholidine described in the
literature.5
Tet r a h yd r o-2,2-b is(((t r im et h ylsilyl)oxy)m et h yl)fu r a n
(6). To a solution of 95.8 mL (0.454 mol) of hexamethyldisila-
zane in 100 mL of THF at 5 °C was added 0.44 mL (2.3 mmol)
of TMSOTf followed by the addition of 30 g (0.227 mol) of 4 in
100 mL of THF. After stirring at 5 °C for 0.5 h, the reaction
mixture was diluted with 100 mL of ether, washed with 50 mL
of NH4Cl solution, and concentrated under reduced pressure.
The crude residue was distilled (130 °C/45 mbar), affording 51.48
g (82%) of 6: 13C NMR (75 MHz, CDCl3) δ 85.0, 68.4, 64.6, 29.5,
25.1, -0.7; MS (isobutane/DCI) m/z 277 (MH)+. Anal. Calcd
for C12H28O3Si2: C, 52.13; H, 10.21. Found: C, 51.83; H, 10.18.
Sp ir ok eta ls 7 a n d 8. To a solution of 25 g (0.09 mol) of 6 in
50 mL of CH2Cl2 at -40 °C was added under nitrogen a solution
of 15.34 g (0.099 mol) of 5 in 25 mL of CH2Cl2 followed by the
addition of 3.5 mL (0.018 mol) of TMSOTf. Stirring was
continued at -40 °C for 22 h, the reaction was quenched with
3.6 mL of pyridine and 100 mL of water, and the mixture was
diluted with 100 mL of ether, washed with 50 mL of NH4Cl
solution, and concentrated under reduced pressure. The result-
ing layers were separated, and the aqueous layer was extracted
twice with CH2Cl2. The combined organic extracts were dried
over MgSO4 and concentrated under reduced pressure. The
crude residue was flash chromatographed on SiO2 with hexane
followed by hexane:EtOAc (97:3) to give 16.53 g of 7 and 4.92 g
of 12 as an oil: [R]25 ) -13.2° (c ) 1.23 in CHCl3); 13C NMR
D
(75 MHz, CDCl3) δ 134.4, 117.4, 84.2, 79.1, 68.3, 66.5, 63.0, 47.8,
41.0, 40.4, 35.0, 30.6, 27.5, 26.0, 25.4, 23.3, 22.2, 20.3, 18.1; MS
(NH3/DCI) m/z 311 (MH)+. Anal. Calcd for C19H34O3: C, 73.50;
H, 11.04. Found: C, 73.35; H, 11.20.
(R)-Tetr a h yd r o-2-((octa d ecyloxy)m eth yl)-2-[[[1(e)-a llyl-
2(e)-isop r op yl-5(e)-m et h ylcycloh exa n yl]oxy]m et h yl]fu -
r a n (13). Starting with 0.500 g (1.61 mmol) of 12 and 0.713 g
of octadecyl bromide, following the procedure as described for
compound 10, there was obtained 0.424 g (47%) of 13 as an oil:
[R]25D, no observed rotation in CHCl3 at c ) 1.1; 13C NMR (75
MHz, CDCl3) δ 134.8, 117.3, 84.3, 78.8, 73.9, 72.0, 68.4, 61.9,
48.0, 41.2, 40.8, 35.3, 31.9, 31.1, 29.7, 29.7, 29.6, 29.61, 29.6,
29.3, 27.4, 26.2, 25.9, 25.6, 23.5, 22.7, 22.4, 20.5, 18.3, 14.1; MS
(NH3/DCI) m/z 580 (M + N+H4). Anal. Calcd for C37H70O3: C,
78.94; H, 12.53. Found: C, 78.74; H, 12.74.
of 8 in a combined yield of 89%. Compound 7: [R]25 ) -38.4°
D
(c ) 1.06 in CHCl3); 13C NMR (75 MHz, CDCl3) δ 100.3, 75.9,
68.1, 66.8, 66.7, 50.6, 36.1, 34.8, 34.0, 29.0, 25.3, 24.1, 23.7, 22.1,
22.0, 18.5; MS (NH3/DCI) m/z 269 (MH)+. Anal. Calcd for
C16H28O3: C, 71.60; H, 10.52. Found: C, 71.66; H, 10.56.
Compound 8: [R]25D ) -35.6° (c ) 0.99 in CHCl3); 13C NMR (75
MHz, CDCl3) δ 99.9, 76.9, 67.6, 66.2, 65.8, 51.2, 36.3, 35.0, 31.0,
29.2, 25.3, 24.5, 23.7, 22.2, 22.1, 18.8; MS (NH3/DCI) m/z 269
(MH)+. Anal. Calcd for C16H28O3: C, 71.60; H, 10.52. Found:
C, 71.74; H, 10.63.
(S)-Tetr a h yd r o-2-((octa d ecyloxy)m eth yl)-2-fu r a n m eth a -
n ol (14). Starting with 0.235 g (0.417 mmol) of 13 and utilizing
the conditions described for compound 11, there was obtained
0.127 g (79%) of 14: ee before recrystallization ) 97%, ee after
recrystallization from heptane in the presence of pure seed
crystals > 99%; mp 36 °C; [R]25
) -4.38° (c ) 1 in MeOH);
365
spectral data identical to the compound reported earlier by us.1
(S)-Tetr a h yd r o-2-((ben zyloxy)m eth yl)-2-[[[1(e)-a llyl-2(e)-
isop r op yl-5(e)-m eth ylcycloh exa n yl]oxy]m eth yl]fu r a n (15).
To a mixture of 2.409 g (60 mmol) of NaH (60% dispersion in
mineral oil) and 1.70 g (4.6 mmol) of tetrabutylammonium iodide
in 55 mL of THF at 5 °C was added 11 g (35 mmol) of 9 in 55
mL of THF. The mixture was warmed to room temperature,
followed by the addition of 5.0 mL (42.5 mmol) of benzyl bromide
in 55 mL of THF, and then refluxed overnight. The reaction
was quenched with 18 mL of 2-propanol, and 60 mL of aqueous
ammonium chloride was added. The layers were separated, and
the organic layer was washed with brine, dried with MgSO4,
and concentrated to dryness. The residue was flash chromato-
graphed on SiO2, eluting with hexane/EtOAc (95:5) to give 9.965
(S)-Tetr a h yd r o-2-[[[1(e)-a llyl-2(e)-isop r op yl-5(e)-m eth yl-
cycloh exa n yl]oxy]m eth yl]-2-fu r a n m eth a n ol (9). To a solu-
tion of 89 mL (0.56 mol) of allyltrimethylsilane in 2.2 L of CH2Cl2
at -90 °C was added 61.5 mL (0.0615 mol) of 1 M solution of
TiCl4 in CH2Cl2, keeping the temperature below -90 °C. To the
reaction mixture was added a precooled (-72 °C) solution of 7
(15 g, 0.056 mol) in 1.2 L of CH2Cl2 at such a rate that the
temperature did not exceed -90 °C. After the addition, the
mixture was stirred for 30 min at -90 °C, the reaction was
quenched with 17 mL of pyridine, and the mixture was poured
into a flask containing 1.5 L of EtOAc, 1.5 L of hexane, and 4 L
of 10% aqueous KF solution. After stirring for 30 min, the
mixture was filtered through Celite, the layers were separated,
and the organic layer was dried, evaporated to dryness, and
chromatographed on SiO2 using EtOAc/hexane (1:4) to give 9.836
g (70%) of 15: [R]25 ) +5.2° (c ) 0.78 in CHCl3); 13C NMR (75
D
MHz, CDCl3) δ 138.6, 134.9, 128.19, 127.7, 127.3, 117.2, 84.3,
78.9, 73.5, 73.3, 68.5, 62.1, 47.9, 41.2, 40.6, 35.3, 30.63, 27.7,
25.9, 25.5, 23.5, 22.4, 20.5, 18.3; MS (NH3/DCI) m/z 419 (M +
N+H4). Anal. Calcd for C26H40O3: C, 77.95; H, 10.06. Found:
C, 77.98; H, 10.04.
g (57%) of 9 as an oil: [R]25 ) +3.7° (c ) 1.42 in CHCl3); 13C
D
NMR (75 MHz, CDCl3) δ 134.6, 117.5, 84.5, 79.2, 68.5, 66.4, 62.4,
47.9, 41.1, 40.5, 35.2, 30.4, 27.9, 26.1, 25.5, 23.5, 22.4, 20.6, 18.3;
MS (NH3/DCI) m/z 311 (MH)+. Anal. Calcd for C19H34O3: C,
73.50; H, 11.04. Found: C, 73.33; H, 11.23.
(R)-Tet r a h yd r o-2-((b en zyloxy)m et h yl)-2-fu r a n m et h a -
n ol (16). To a solution of 9.605 g (24 mmol) of 15 in 480 mL of
CH2Cl2 was added a precooled (5 °C) solution of 24 mL of
trifluoroacetic acid. The solution was stirred at 5 °C for 1 h,
and the reaction was quenched with 160 mL of 2 N NaOH
solution. The layers were separated, and the organic layer was
dried and evaporated to dryness. Flash chromatography of the
residue on SiO2 using hexane/EtOAc (3:1), followed by hexane/
(S)-Tet r a h yd r o-2-((oct a d ecyloxy)m et h yl-2-[[[1(e)-a llyl-
2(e)-isop r op yl-5(e)-m et h ylcycloh exa n yl]oxy]m et h yl]fu -
r a n (10). To a mixture of 1.498 g (37.4 mmol) of NaH (60%
dispersion in mineral oil) and 1.058 g of tetrabutylammonium
bromide in 30 mL of THF at 5 °C was added a solution of 6.839
g (22 mmol) of 9 in 30 mL of THF. The suspension was warmed
to room temperature, and a solution of 9.759 g (28.6 mmol) of
octadecyl bromide in 35 mL of THF was added. The mixture
was refluxed for 30 h and cooled to 5 °C. The reaction was
quenched with 12 mL of isopropyl alcohol, the mixture was
washed with saturated ammonium chloride solution, dried, and
evaporated to dryness, and the residue was chromatographed
on SiO2, eluting first with hexane and then with EtOAc/hexane
EtOAc (2:1), gave 4.868 g (91%) of 16: [R]25 ) +2.2° (c ) 1.00
D
in CHCl3); identical in all respects with the compound reported
by us earlier.1
Ack n ow led gm en t. We thank Drs. M. Shapiro and
E. Fu and their co-workers for spectroscopic measure-
ments and valuable discussions.
(1:9) to give 6.89 g (56%) of 11 as an oil: [R]25 ) +4.6° (c )
D
1.03 in CHCl3); 13C NMR (75 MHz, CDCl3) δ 134.8, 117.1, 84.1,
78.7, 73.7, 71.7, 68.3, 61.8, 47.8, 41.0, 40.4, 35.2, 31.8, 30.5, 29.6,
29.5, 29.5, 29.4, 29.2, 27.6, 26.1, 25.7, 25.4, 23.3, 22.5, 22.3, 20.4,
18.2, 13.9; MS (NH3/DCI) m/z 580 (M + N+H4). Anal. Calcd
for C37H70O3: C, 78.94; H, 12.53. Found: C, 78.92; H, 12.69.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
(1H NMR and 13C NMR) for all new compounds reported (20
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of
the journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(5) Alexakis, A.; Mutti, S.; Mangeney, P. J . Org. Chem. 1992, 57,
1224-1237.
J O9515034