An unusual acetonide group migration

Article abstract of DOI:10.1016/S0040-4039(03)01758-1

Treatment of (2S,3R)-2,3-O-isopropyliden-4-penten-1,2,3-triol mesylate with uracil, K₂CO₃ did not provide the product of S _N2 displacement, but an interesting acetonide group migration product 8. The structure of 8 was secured by spectral analysis and single crystal X-ray analysis. The desired product 2 could be ultimately obtained by Mitsunobu reaction of the alcohol 6 with 3-N-benzoyl uracil followed by basic hydrolysis.

Full text of DOI:10.1016/S0040-4039(03)01758-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7201–7204
An unusual acetonide group migration
Anil K. Saksena,a,* Viyyoor M. Girijavallabhan,a Mohindar S. Puar,a Birendra N. Pramanik,a
Pradip R. Dasa and Andrew T. McPhailb
aSchering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
bPaul M. Gross Chemical Laboratories, Duke University, Durham, NC 27706, USA
Received 26 June 2003; revised 18 July 2003; accepted 19 July 2003
Abstract—Treatment of (2S,3R)-2,3-O-isopropyliden-4-penten-1,2,3-triol mesylate with uracil, K2CO3 did not provide the product
of SN2 displacement, but an interesting acetonide group migration product 8. The structure of 8 was secured by spectral analysis
and single crystal X-ray analysis. The desired product 2 could be ultimately obtained by Mitsunobu reaction of the alcohol 6 with
3-N-benzoyl uracil followed by basic hydrolysis.
© 2003 Elsevier Ltd. All rights reserved.
In connection with an ongoing medicinal chemistry
program we sought to prepare 2 from 1.
of methyl iodide. The remaining steps were carried out
according to Scheme 1.2–4
The precursor (2S,3R)-2,3-O-isopropyliden-4-penten-
1,2,3-triol mesylate 1 could be conveniently obtained
However, when 1 was treated with uracil and anhy-
drous K2CO3 in DMF, the product obtained was not 2
but an interesting acetonide migration product 8, mp
126–27°C5 (Scheme 2).
from
dure originally described by Jager.1 The iodolactone 4
was produced from -ribonolactone by a one step
reaction with N,N%-carbonyldiimidazole and an excess
D-ribonolactone by slight modification of proce-
D
1
The structure of 8 was determined by MS, 13C and H
Scheme 1. Reagents and conditions: (i) ImCOIm, MeI, MeCN, D, 2 h; (ii) Zn, KH2PO4, THF, rt; (iii) LiAlH4, EtOEt; (iv)
MeSO2Cl, pyridine, CH2Cl2.
* Corresponding author. Fax: +1-908-740-7152; e-mail: anil.saksena@spcorp.com
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01758-1

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A. K. Saksena et al. / Tetrahedron Letters 44 (2003) 7201–7204
Scheme 2.
NMR. Analysis of the 2D (1H–1H) cosy and (1H–13C)
cosy NMR data led to the above assignment. In addi-
tion 1D NOE data confirmed the assignment.7
the unprimed and primed molecules, respectively.10
It appears that this unprecedented rearrangement of
acetonide group takes place by breakage of the bond ‘a’
leading to the hemiacetal intermediate 9 which displaces
the mesylate (Scheme 3). Note that bond ‘b’ remains
intact throughout this process. Confirmation for this
came from chiral shift reagent studies on the alcohol 10
prepared by ozonolysis of 8 followed by reduction. The
absolute stereochemistry of 10 was assigned as R-(−) on
the basis of results presented below.8
Single crystal X-ray crystallographic analysis estab-
lished the structure and relative stereochemistry of 8.
The asymmetric crystal unit consists of two indepen-
dent molecules which are hydrogen bonded
[N(3)ꢀO(8%)=2.822 (3) A, N(3%)ꢀO(8)=2.865 (3) A] in
the manner shown in Figure 1. The conformations of
the individual molecules differ significantly around
their C(9)ꢀC(10) bonds [torsion angles: N(1)ꢀ
C(9)ꢀC(10)ꢀC(11)=−125.7 (6)°, N(1%)ꢀC(9%)ꢀC(10%)ꢀ
C(11%)=126.5 (5)°], and their 1,3-dioxa cyclopentane
rings approximate to envelope and half chair forms in
Finally the desired 2 could be prepared by Mitsunobu
reaction of 3-N-benzoyl uracil 12 with the alcohol 6 to
provide 13 (Scheme 4). Hydrolysis of the N-benzoyl
group provided 2, mp 148–50°C.6,9
Figure 1.
Scheme 3.

A. K. Saksena et al. / Tetrahedron Letters 44 (2003) 7201–7204
7203
Scheme 4.
We have presented here an unusual example of an
acetonide group migration. To the best of our knowl-
edge we are not aware of any such example in the
literature.
ꢀ130°C). Uracil initially dissolved followed by separa-
tion of a thick gel. The heating was continued for ꢀ20 h,
water (ꢀ100 ml) added to dissolve the gel and the
reaction mixture extracted with CH2Cl2. The organic
phase containing substantial DMF was evaporated in
vacuo to dryness and the gummy residue azeotroped with
toluene. The resulting thick brownish mass was purified
by chromatography on a coarse SiO2 (150 g) column to
provide in 10% n-hexane/EtOAc eluents the product 8
(2.95 g), mp 126–27°C.
References
1. Jager, V.; Hafele, B. Synthesis 1987, 801–806.
1
2. All new compounds were characterized by H, 13C NMR
6. Preparation of 2: A stirred suspension of the alcohol 6
(3.18 g), 3-N-benzoyl uracil (4.25 g) and Ph3P (5.3 g) in
THF (50 ml) was treated (under argon atmosphere) with
diisopropylazodicarboxylate (4.24 ml). Immediate disso-
lution of the contents followed by slightly exothermic
reaction took place. The reaction mixture was stirred
overnight, evaporated to dryness in vacuo to provide a
gummy residue which was subjected to chromatography
on TLC grade silica gel (200 g). Elution with 60%
EtOAc/n-hexane provided in some of the fractions pure
13 (2.93 g). It was dissolved in methanol (100 ml) and
treated with 10% aqueous K2CO3 (50 ml). The reaction
mixture was stirred overnight, the solvents evaporated in
vacuo and the residue extracted with CH2Cl2. The crude
product containing methyl benzoate was crystallized from
EtOAc/n-hexane to provide a crystalline solid 2, mp
148–50°C.
and high-resolution mass spectra. When necessary 1D
NOE and 2D NOESY NMR spectra were obtained to
confirm relative stereochemistry. Elemental analysis were
obtained for crystalline compounds only. Yields refer to
isolated products and have not been optimized. Selective
spectral data is given here.
3. Preparation of 4: A solution of ribonolactone acetonide
(10 g) in dry acetonitrile (50 ml) was treated with car-
bonyl diimidazole (8.59 g; 1 equiv.). After a clear solution
was obtained, MeI (37.6 g; 5 equiv.) was added. The
reaction mixture was stirred at room temprature for 30
min followed by heating under reflux for 2 h. After
cooling, the product was isolated by extractive work-up
with ether. The ether extract was washed with water,
aqueous Na2S2O3, dried over Na2SO4 and evaporated to
dryness to provide a solid 13.7 g. It was filtered through
a column of silica gel (300 g) using CHCl3 as eluent to
yield a crystalline solid, mp 91–93°C.
4. Prepation of 5: An efficiently stirred solution of the
iodolactone (25 g) in THF (250 ml) was treated with zinc
dust (50 g). To this stirred suspension was added in one
portion 1 M KH2PO4. After an induction period of ꢀ2
min, gentle reflux of THF was observed. After stirring for
20–25 min, zinc was removed by filtration and washed
with additional THF to bring the total volume of com-
bined filtrates to ꢀ800 ml. To these combined filtrates
was added with stirring Amberlite IRC-50 resin (250 g).
After stirring for 1 h, the resin was removed by filtration,
washed with more THF. The filtrates were evaporated in
vacuo to leave a aqueous medium containing polymeric
suspensions. This aqueous medium was extracted with
CH2Cl2 (400 ml total after 3 extractions). The combined
CH2Cl2 extract was dried (Na2SO4) and evaporated to
dryness in vacuo to provide a thick yellow oil (11.29 g)
which was suitable for the next reaction.
7. 8: 13C NMR [CDCl3, l, ppm] 163.8 (s), 150.7 (s), 143.7
(d, CH), 133.1 (d, CH), 126.8 (d, CH), 102.7 (d, CH),
109.7 (s), 75.8 (d, CHO), 69.2 (t, CH2O), 48.9 (t, CH2),
26.6 (q, CH3) and 25.8 (q, CH3). 1H NMR [CDCl3, l,
ppm] 1.32 (s, CH3), 1.39 (s, CH3), 7.12 (d, CH), 5.80 (m,
CH), 5.67 (d, CH), 5.65 (m, CH), 4.50 (dd, CHO), 4.30
(m, CH2), 4.08 (m, CH2AO) and 3.52 (m, CH2BO).
8. Absolute stereochemistry of 10: A mixture of 10 (R) and
11 (S) acetal (18.0 mg) was dissolved in 1.0 ml of dry
CDCl3. Quantitative additions of chiral shift reagent,
Tris[3-(heptafluoropropylhydroxymethylene)-(+)-camph-
orato]europium(III), [Eu(hfPC)3], led to the differentia-
tion of R and S enatiomers at a concentration of 18 mg
of the reagent. Addition of S-(+)-enantiomer 11 to the
above solution (18 mg of R/S mixture+18 mg of the
chiral shift reagent) led to the identification of the S-(+)-
enatiomer as a slow moving component. Finally, a fresh
solution of 9.2 mg of R-(−)-enantiomer 10 and 9.1 mg of
S-(+)-enantiomer 11 was prepared. To this solution 18.7
mg of chiral shift reagent was added to observe CH3
splitting. When a sample (ꢀ1 mg) of the unknown
dioxolane was added, the spectrum indicated an increase
in the intensity of the R-(−)-10 (fast moving) component.
5. Preparation of 8: Uracil (3.46 g) was suspended in dry
DMF (100 ml) and dry K2CO3 (4.2 g), and the mesylate
1 (7.3 g) were added. The reaction mixture was subjected
to magnetic stirring and it was then heated (bath temp.

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A. K. Saksena et al. / Tetrahedron Letters 44 (2003) 7201–7204
of d, 14 Hz, 10 Hz, CH), 5.68 (d of d, 8 Hz, 1.5 Hz, CH),
9. 2: 13C NMR [CDCl3, l, ppm] 119.5 (t), 132.0 (d), 77.8 (d),
7.25 (d, 8 Hz, CH), 1.54/1.36 (s, s, CH3, CH3), 8.97 (broad).
10. Atomic parameters, bond lengths, bond angles and torsion
angles for 15 have been deposited at the Cambridge
Crystallographic Data Center, Cambridge, CB2 1EZ, UK.
Any request should be accompanied by full literature
citation for this communication.
75.3 (d), 50.0 (t), 150.8 (s), 163.6 (s), 101.8 (d), 145.5 (d),
109.5 (s), 25.2/27.9 (q, q). H NMR [CDCl3, l, ppm] 5.47
(d of t, 17 Hz, 1 Hz, 1 Hz, CH), 5.34 (d of t, 10 Hz, 1 Hz,
1 Hz, CH), 5.81 (d of q, 17 Hz, 10 Hz, 7 Hz, CH), 4.72
(t of t, 7 Hz, 7 Hz, 1 Hz, 1 Hz, CH), 4.43 (d of q, 10 Hz,
7 Hz, 2 Hz, CH), 4.20 (d of d, 14 Hz, 2 Hz, CH), 3.17 (d
1