6
246
R. K. Pandey et al. / Tetrahedron Letters 44 (2003) 6245–6246
Thus treatment of 2 with t-butyldimethylsilyl chloride
TBDMS-Cl) in the presence of imidazole gave the silyl
and encouragement. This is NCL communication No.
6646.
(
compound 3 in 90% yield. The subsequent Wittig olefi-
nation of 3 with methylenetriphenylphosphorane gener-
ated by the reaction of triphenylmethylphosphonium
iodide and n-BuLi furnished styrene 4 in 90% yield.
The dihydroxylation of 4 with osmium tetroxide and
potassium ferricyanide as co-oxidant in the presence of
References
1. Lee, S. J.; Lien, M. H. Bull. Inst. Chem. Acad. Sin. 1984,
31, 55–58.
2. Bergmann, E. D.; Sulzbacher, M. J. Org. Chem. 1951, 16,
84–89.
3. Britten, A. Z. Chem. Ind. 1968, 771–772.
4. Russel, P. B.; Childress, S. J. J. Pharm. Sci. 1961, 50,
713–714.
5. Ravdel, G. A.; Sergievskaya, S. I. J. Gen. Chem. 1952,
559–563.
(
DHQD) PHAL as the chiral ligand under Sharpless
2
9
asymmetric dihydroxylation conditions gave the diol
1
0
11
25
D
5
in 97% yield with 98% ee, [h] =−34.33 (c 1.2,
CHCl ). Selective conversion of the primary hydroxyl
3
group of 5 into a tosylate was carried out using tosyl
chloride in the presence of a catalytic amount of
dibutyltin oxide to give 6 in 98% yield. Our initial
attempt to synthesize 1 by the direct nucleophilic dis-
placement of tosylate 6 with methylamine was not very
satisfactory. Hence, we attempted the following
sequence of reactions. Deprotection of the TBDMS
group was carried out by treatment of tosylate 6 with
acetic acid in THF and water (3:1:1) at 60°C to afford
6. Takeda, H.; Tachninami, T.; Aburatuni, M. Tetrahedron
Lett. 1989, 30, 367–370.
7. Gurjar, M. K.; Krishna, L. M.; Sarma, B. V. N. B. S.;
Chorghade, M. S. Org. Process Res. & Dev. 1998, 2,
422–424.
7
in 90% yield. The nucleophilic displacement of tosyl-
8. (a) Fernandes, R. A.; Kumar, P. Tetrahedron: Asymmetry
1999, 10, 4797–4802; (b) Fernandes, R. A.; Kumar, P.
Eur. J. Org. Chem. 2000, 3447–3449; (c) Fernandes, R.
A.; Kumar, P. Tetrahedron Lett. 2000, 41, 10309–10312;
(d) Pandey, R. K.; Fernandes, R. A.; Kumar, P. Tetra-
hedron Lett. 2002, 43, 4425–4426; (e) Naidu, S. V.;
Kumar, P. Tetrahedron Lett. 2003, 44, 1035–1037; (f)
Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44,
1957–1958.
9. (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547; (b) Becker, H.; Sharp-
less, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 448–
451.
ate 7 with sodium iodide in acetone under reflux fur-
nished the iodo compound 8 in essentially quantitative
2
5
yield, [h] =−16.0 (c 0.16, CHCl ). Compound 8 was
D
3
reacted with 40% aqueous methylamine in THF at
room temperature followed by subsequent treatment
with methanolic HCl to furnish (R)-phenylephrine
hydrochloride in 90% yield as a white solid, m.p. 141–
5
25
7
1
42°C (lit 141–145°C); [h] =−45.0 (c 0.75, H O) [lit
D 2
−
44.0 (c 2, H O)]. The physical and spectroscopic data
2
5
–7
were in full agreement with the literature.
In conclusion, a practical and highly enantioselective
synthesis of (R)-phenylephrine hydrochloride has been
achieved employing the Sharpless asymmetric dihydroxy-
lation as the key step. The synthetic strategy can be
extended to the enantiomer and related analogs. Cur-
rently, further studies are underway in our laboratories.
2
5
10. Compound 5: Viscous liquid; [h]
=−34.33 (c 1.2,
D
−
1
CHCl
1451, 1248. H NMR (200 MHz, CDCl
0.99 (s, 9H), 2.26 (bs, 2H), 3.60–3.80 (m, 2H), 4.75 (dd,
). IR (neat): cm 3401, 2924, 2818, 1604, 1586,
3
1
): l 0.20 (s, 6H),
3
1
3
J=4.5, 8.5 Hz, 1H), 6.96–7.25 (m, 4H). C NMR (200
MHz, CDCl ): l −4.67, 17.88, 25.45, 67.78, 74.25, 117.62,
3
118.84, 118.93, 129.04, 142.31, 155.44.
Acknowledgements
11. The enantiomeric excess was determined by HPLC.
HPLC model: Merck-Hitachi Lachrom PDA system D-
7000 series; Column: Lichrospher RP-18 (4 mm ID×125
R.K.P. thanks CSIR New Delhi for financial assistance.
We are grateful to Dr. M. K. Gurjar for his support
mm); mobile phase: methanol: water: (65:35); flow: 1
ml/min.