A convenient synthesis of 1-[6-Fluoro-(2S)-3H,4H-dihydro-2H-2-chromenyl]- (1R)-1,2-ethanediol and 1-[6-fluoro-(2R)-3H,4H-dihydro- 2H-2-chromenyl]-(1R)-1, 2-ethanediol

Article abstract of DOI:10.1055/s-2005-868508

1-[6-Fluoro-(2S)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2-ethanediol and 1-[6-fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2-ethanediol, important pharmaceutical intermediates, were synthesized from natural chiral pool D-mannitol. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-868508

LETTER
1465
A Convenient Synthesis of 1-[6-Fluoro-(2S)-3H,4H-dihydro-2H-2-chromenyl]-
(1R)-1,2-ethanediol and 1-[6-Fluoro-(2R)-3H,4H-dihydro- 2H-2-chromenyl]-
(1R)-1,2-ethanediol
A
Convenient
Syn
n
thesis of Chi
-
ra
l
Chrom
G
an uang Yu,a Nai-Xing Wang,*a Ya-Lan Xing,b Jun-Ping Zhang,a Yun-Xu Yang,a Wu-Wei Wang,a Rui-long
Shenga
a
Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100101, P. R. China
Fax +86(10)64879375; E-mail: nxwang@mail.ipc.ac.cn
b
Beijing University of Chemical Technology, Beijing 100029, P. R. China
Received 23 February 2005
Previously, Chandrasekhar et al.7 reported the synthesis of
chroman 1a and 1b starting from 4-fluorophenol, which
involves eight and ten steps, respectively; a Sharpless
asymmetric epoxidation is required for the stereoselective
introduction of the two stereogenic centers. In their
approach,7 the preparation of 1 is long and tedious, dis-
couraging practical application. Furthermore, this prepa-
ration involves multiple isolations and chromatographic
purifications, rendering it unacceptable for larger kilo-
scale production.
Abstract: 1-[6-Fluoro-(2S)-3H,4H-dihydro-2H-2-chromenyl]-
(1R)-1,2-ethanediol and 1-[6-fluoro-(2R)-3H,4H-dihydro-2H-2-
chromenyl]-(1R)-1,2-ethanediol, important pharmaceutical inter-
mediates, were synthesized from natural chiral pool D-mannitol.
Key words: chiral pool, reductions, ketones, aldol reactions
Chiral chromans are a class of important compounds
possessing significant biological properties. For example,
vitamin E1 and its analogs trolox2 and MDL-734043 are
important lipophilic antioxidants. Daurichromenic acid
and rhodod-aurichromanic acid A show potent anti-HIV
activity,4 while siccanin has potent antifugal activity.5 Our
interests in synthesizing Nebivolol, a new selective b1-
adrenergic blocker with antihypertensive activity,6
prompted us to develop a general and efficient methodol-
ogy for the construction of chiral chroman intermediates
1a (S,R) and 1b (R,R).
Herein, we report a convenient method for the preparation
of enantiomerically pure 1-[6-fluoro-(2S)-3H,4H-dihy-
dro-2H-2-chromenyl]-(1R)-1,2-ethanediol (1a) and 1-[6-
fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2-
ethanediol (1b) from readily available starting material D-
mannitol in four steps. The general retrosynthetic analysis
is illustrated in Scheme 1. In the synthesis of chromanone
2a (S,R) and 2b (R,R), the Kabbe reaction8,9 was applied
Scheme 1
SYNLETT 2005, No. 9, pp 1465–1467
0
1.
0
6.
2
0
0
5
Advanced online publication: 29.04.2005
DOI: 10.1055/s-2005-868508; Art ID: U05005ST
© Georg Thieme Verlag Stuttgart · New York

1466
A.-G. Yu et al.
LETTER
to build up the pyranone skeleton of chromanone. The allowed to stand for a while and then heated to reflux
first asymmetric centere of (R)-2,3-isopropyrideneglycer- in an apparatus fitted with a water separator. The
olaldehyde (3) was incorporated into the backbone of the chromanone was obtained as a mixture of two diastereo-
chromanone 2 (only C2R), while the second chiral center isomers in 40% yield [2a(S,R)/2b(R,R), 60:40], which
(C1R or C1S) was generated during the ring closing. The were isolated easily by flash column chromatography.
resulting diastereomeric compounds 2a and 2b could be
isolated easily. Then 2a and 2b were reduced to 1a (S,R)
and 1b (R,R); intermediates 1a and 1b are the precursors
to (S,R,R,R)-nebivolol which was obtained by a coupling
Initially both 2a and 2b were reduced by the Wolff–
Kishner reduction under different conditions including at
different temperatures; however changing the ratio of
potassium hydroxide to hydrazine hydrate failed because
reaction. Therefore, our new synthetic methodology re-
the high temperature resulted in the degradation of the
ported here not only has the advantage of atom economy
product; therefore the Clemmensen reduction was ex-
ploited and good results were obtained. Treatment of
but also requires fewer synthetic steps.
Multigram quantities of (R)-2,3-isopropyrideneglycerol- chromanone 2a and 2b with zinc amalgam in 15% hydro-
aldehyde can be readily obtained from cheap and com- chloric acid gave chroman 1a and 1b12 in good yield
mercially available D-mannitol as previously reported10 (62%).
and acetylfluorophenol (4) was obtained from 4-fluoro-
phenol.
In conclusion, an efficient and convenient synthetic meth-
odology for the synthesis of 1-[6-fluoro-(2S)-3H,4H-di-
D-Mannitol was converted to (R)-2,3-isopropyridene- hydro-2H-2-chromenyl]-(1R)-1,2-ethanediol and 1-[6-
glycerolaldehyde in two steps in 40% overall yield on a fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2-
100-g scale (Scheme 2).
ethanediol was presented. Chromans 1a and 1b prepared
by this method possessed excellent chemical and enantio-
meric purity; this route is shorter than previously reported.
The utilization of the natural chiral pool makes the synthe-
sis quite efficient with overall atom economy.
Acknowledgment
Scheme 2 Reagents and conditions: (a) glyme, 2,2-dimethoxypro-
pane, SnCl2 (54%); (b) NaIO4, CH2Cl2, NaHCO3 (77%).
This work was supported by the National Natural Science
Foundation (No.20472090) and National 863 Program
(No.2003AA323030) Foundation.
4-Fluorophenol (6) was converted to its acetate, which
was used in the next step without work-up. Acetyl-
fluorophenol 4 was obtained by Fries rearrangement of
the acetate in 89% overall yield on an 80 g scale
(Scheme 3).
References
(1) Machlin, L. J. Vitamin E; Marcel Dekker: New York USA,
1980.
(2) Terao, K.; Niki, E. J. Free Radical Biol. Med. 1986, 2, 193.
(3) Grisar, J. M.; Petty, M. A.; Bolkenius, F. N.; Dow, J.;
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Med. Chem. 1991, 34, 257.
(4) Kashiwada, Y.; Yamazaki, K.; Ikeshiro, Y.; Yamagishi, T.;
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2001, 57, 1559.
(5) Isabashi, K. J. Antibiot. Ser. A 1962, 15, 161.
(6) (a) De Cree, J.; Geukens, H.; Leempoels, J.; Verhaegen, H.
Drug Dev. Res. 1986, 8, 109. (b) De Cree, J.; GeukensH, ;
Cobo, C.; Verhaegen, H. Angiology 1987, 38, 440. (c) Van
de Water, A.; Janssen, W.; Van Nueten, J.; Xhonneux, R.;
De Cree, J.; Verhaegen, H.; Reneman, R. S.; Janssen, P. A.
J. Cardiovasc. Pharmacol. 1988, 11, 552.
O
F
F
a, b
OH
OH
6
4
Scheme 3 Reagents and conditions: (a) AcCl; (b) AlCl3, heating,
130 °C (89%).
With the required building blocks in hand, the stage was
set for the crucial segment couplings (Scheme 4). Kabbe
reaction of the fragments 3 and 4 gave chromanone 2a and
2b;11 a mixture of 3, 4, and pyrrolidine in toluene was
O
O
CHO
O
OH
O
F
F
a
b
+
O
*
O
*
OH
O
F
OH
O
4
3
1a: S,R
1b: R,R
2a: S,R
2b: R,R
Scheme 4 Reagents and conditions: (a) pyrrolidine, toluene (40%); (b) Zn amalgam, 15% HCl, EtOH (62%).
Synlett 2005, No. 9, 1465–1467 © Thieme Stuttgart · New York

LETTER
A Convenient Synthesis of Chiral Chromans
1467
(7) Chandrasekhar, S.; Venkat, R. M. Tetrahedron 2000, 56,
6339.
(8) Kabbe, H. J. Synthesis 1978, 886.
(9) Kabbe, H. J.; Widdig, A. Angew. Chem., Int. Ed. Engl. 1982,
21, 247.
(10) Schmid, C. R.; Bryant, J. D.; Dowlatzadeh, M.; Philips, J. L.;
Prather, D. E.; Sear, N. L.; Vianco, C. S. J. Org. Chem. 1991,
56, 4056.
CH3); 13C NMR (100 Hz,CDCl3): d = 25.2 (CH3), 26.1
(CH3), 38.6 (O=CCH2), 64.9 (CH2O), 76.4 (CH2CHO), 77.5
(CHOC), 110.3 (CH3CCH3), 112.0 (FC6H3), 119.6 (FC6H3),
123.7 (FC6H3), 156.1 (FC6H3), 157.3 (FC6H3), 158.5
(FC6H3), 190.6 (O=C); EIMS: m/z = 266, 101, 43; Anal.
Calcd for C14H15FO4: C, 63.15; H, 5.68; F, 7.14; O, 24.04.
Found: C, 63.48; H, 5.89.
(12) Selected data for compound 1a: mp 87–89 °C; [a]D +70.30
(c = 0.1, MeOH); IR (KBr): 3590, 3518, 2967, 2937, 2849,
1607, 1493, 1217, 511 cm–1; 1H NMR (400 MHz, CDCl3):
d = 6.96–6.84 (m, 3 H, C6H3F), 4.18–4.05 (m, 1 H,
FC6H3OCH), 4.05–3.99 (m, 3 H, CHOH, CH2OH), 3.01–
2.94 (m, 2H, FC6H3CH2), 2.32–2.27 (m, 1H,
(11) Selected data for compound 2a: pale yellow solid: mp 94–95
°C; [a]D +30.65 (c = 0.0802, MeOH); IR (KBr): 2997, 2916,
2900, 1687, 1621, 1487, 1371 cm–1; 1H NMR (300 MHz,
CDCl3): d = 7.54 (dd, 1 H, J = 8.2 Hz, 3.1 Hz, C6H3F), 7.24–
7.17 (m, 1 H, C6H3F), 6.96 (dd, 1 H, J = 9.0 Hz, 4.1Hz,
C6H3F), 4.36–4.32 (m, 2 H, CH2O), 4.23–4.18 (m, 1 H,
FC6H3OCH), 4.06–4.02 (m, 1 H, CHCHCH2), 2.93–2.75 (m,
FC6H3CH2CH2), 2.03–2.01 (m, 1 H, FC6H3CH2CH2); 13
C
NMR (100 Hz, CDCl3): d = 23.0 (FC6H3CH2CH2), 24.5
(FC6H3CH2CH2), 63.3 (CH2OH), 73.5 (CHOH), 76.5
(OCHCH), 113.9 (C6H3F), 115.5 (C6H3F), 117.5 (C6H3F),
123.1 (C6H3F), 150.1 (C6H3F), 158.1 (C6H3F); EIMS: m/z =
212, 150; Anal. Calcd for C11H13FO3: C, 62.26; H, 6.17; F,
8.95; O, 22.62. Found: C, 61.97; H, 6.12. Selected data for
compound 1b: mp 92–94 °C; [a]D +63.08 (c = 0.1, MeOH);
IR (KBr): 3406, 3281, 2960, 2924, 2885, 1496, 1217, 1081,
1052 cm–1; 1H NMR (400 MHz, CDCl3): d = 6.82–6.73 (m,
3 H, C6H3F), 4.07–4.04 (m, 1 H, FC6H3OCH), 3.84–3.78 (m,
3 H, CHOH, CH2OH), 2.88–2.78 (m, 2 H, FC6H3CH2), 2.40
(s, 2 H, OH), 2.00–1.93 (m, 2 H, FC6H3CH2CH2); 13C NMR
(100 Hz, CDCl3): d = 23.5 (FC6H3CH2CH2), 24.6
2 H, O=CCH2), 1.45 (s, 3 H, CH3), 1.40 (s, 3 H, CH3); 13
C
NMR (100 Hz,CDCl3): d = 25.0 (CH3), 26.2 (CH3), 39.0
(O=CCH2), 66.4 (CH2O), 76.3 (CH2CHO), 78.4 (CHOC),
110.3 (CH3CCH3), 112.1 (FC6H3), 119.5 (FC6H3), 123.7
(FC6H3), 156.1 (FC6H3), 157.1 (FC6H3), 158.5 (FC6H3),
190.8 (O=C); EIMS: m/z = 266, 101, 43; Anal. Calcd for
C14H15FO4: C, 63.15; H, 5.68; F, 7.14; O, 24.04. Found: C,
63.47; H, 5.92. Selected data for compound 2b: pale yellow
solid: mp 84–86 °C; [a]D 13.53 (c = 0.2142, CHCl3); IR
(KBr): 2997, 2916, 2900, 1687, 1622, 1487, 1371 cm–1; 1H
NMR (300 MHz, CDCl3): d = 7.53 (dd, 1 H, J = 8.1 Hz, 3
Hz, C6H3F), 7.25–7.18 (m, 1 H, C6H3F), 7.04 (dd, 1 H, J = 9
Hz, 4.1 Hz, C6H3F), 4.51–4.46 (m, 1 H, C6H3OCH), 4.41–
4.35 (m, 1 H, CHOC), 4.15 (dd, 1 H, J = 8.3 Hz, 6.3 Hz,
OCCH2), 4.03 (dd, 1 H, J = 8.3 Hz, 6.3 Hz, OCCH2), 2.87
(dd, 1 H, J = 16.8 Hz, 12.9 Hz, O=CCH2), 2.66 (dd, 1 H, J =
16.8 Hz,12.9 Hz, O=CCH2), 1.43 (s, 3 H, CH3), 1.41 (s, 3 H,
(FC6H3CH2CH2), 63.6 (CH2OH), 73.6 (CHOH), 76.7
(OCHCH), 113.9 (C6H3F), 115.3 (C6H3F), 117.6 (C6H3F),
123.1 (C6H3F), 150.1 (C6H3F), 158.1 (C6H3F); EIMS: m/z =
212, 151, 57; Anal. Calcd for C11H13FO3: C, 62.26; H, 6.17;
F, 8.95; O, 22.62. Found: C, 62.13; H, 6.08.
Synlett 2005, No. 9, 1465–1467 © Thieme Stuttgart · New York