NMR determination of the absolute configuration of chiral 1,2- and 1,3-diols

Article abstract of DOI:10.1016/S0040-4039(03)00845-1

Each of the chiral 1,2- and 1,3-diols examined was derivatized exclusively to a single diastereomeric acetal by the use of a new axially chiral reagent, 2′-methoxy-1,1′-binaphthalene-8-carbaldehyde (MBC). The absolute configuration of the original 1,2- and 1,3-diols was determined by the NOE correlation between the proton signals of the reagent moiety and those of the diol moiety in the acetals.

Full text of DOI:10.1016/S0040-4039(03)00845-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4063–4065
NMR determination of the absolute configuration of chiral
1,2- and 1,3-diols
Hiroki Fukui,† Yukiharu Fukushi* and Satoshi Tahara
Graduate School of Agriculture, Hokkaido University, Kita-Ku, 060-8589 Sapporo, Hokkaido, Japan
Received 26 February 2003; revised 31 March 2003; accepted 1 April 2003
Abstract—Each of the chiral 1,2- and 1,3-diols examined was derivatized exclusively to a single diastereomeric acetal by the use
of a new axially chiral reagent, 2%-methoxy-1,1%-binaphthalene-8-carbaldehyde (MBC). The absolute configuration of the original
1,2- and 1,3-diols was determined by the NOE correlation between the proton signals of the reagent moiety and those of the diol
moiety in the acetals. © 2003 Elsevier Science Ltd. All rights reserved.
Chiral 1,2- and 1,3-diols have increasingly become of
interest to both chemists and biologists, because these
compounds are frequently found in biologically active
natural products.1 The circular dichroism (CD) exciton
chirality method is a reliable and physical one for
determination of the absolute configuration of chiral
1,2-diols.2 The method has also been applied to chiral
acyclic 1,3-diols.3 The modified Mosher’s method has
also been applied to chiral acyclic 1,3-diols for the same
purpose.4 In this paper we report a new method using
an axially chiral reagent 2%-methoxy-1,1%-binaphthalene-
8-carbaldehyde (MBC, 1) for determination of the
absolute configuration of chiral 1,2- and 1,3-diols.
mide and trimethyltin chloride.5 Isopropyl 8-iodo-1-
naphthoate (3) was prepared via a half-esterification of
1,8-naphthalic anhydride and subsequent iododecarb-
oxylation.6 Stille coupling7 of 2 with 3 afforded iso-
propyl 2%-methoxy-1,1%-binaphthalene-8-carboxylate (4)
which was alkali-hydrolyzed to yield racemic 5.
Racemic 5 was derivatized into diastereomeric esters8
with (−)-menthol, which were separated by column
chromatography. Purified diastereomers (6a, 6b) were
respectively reduced with diisobutyl aluminum hydride
to afford enantiomers of 7. The CD spectrum of one
enantiomer of 7a shows a negative split CD band with
extrema at 224 nm (Dm +153.5) and 234 nm (Dm −152.9),
amplitude A value of −306.4 in acetonitrile, whereas the
other enantiomer of 7b shows an opposite CD curve,
with an A value of +322.7 and Cotton effects at 224 nm
(−135.9) and 234 nm (+191.8). Based on the present
Cotton effects, the absolute configuration of 7a was
confirmed to be aS and that of 7b was confirmed to be
aR, respectively. Each enantiomer of 7 was oxidized
with pyridinium chlorochromate to yield (aS)- and
(aR)-MBC (1).9
MBC (1) was prepared as shown in Scheme 1. 2-
Methoxynaphthalen-1-yl(trimethyl)stannane (2) was
prepared from 2-methoxy-1-naphthylmagnesium bro-
Achiral 1,3-propanediol (8) and various 1,2- and 1,3-
diols (9–15) possessing known absolute configurations
were acetalized with (aR)-MBC using trimethyl ortho-
formate and WCl6 as a catalyst.10,11 In each case using
chiral diols, a single diastereomeric acetal was formed
Figure 1. Preferred conformation of acetals from (aR)-MBC
with 1,2-diols and 1,3-diols. Possible NOE correlations are
shown by arrows.
1
exclusively. On the basis of H NMR analyses of the
respective acetals, we were able to determine the stereo-
chemistry of every acetal and, consequently, the abso-
lute configuration of the original diols in the following
way. The preferred conformation of the acetals is
depicted in Figure 1. The methine proton (H-2) in the
acetal moiety, this proton is termed the acetal proton,
Keywords: absolute configuration; chirarity; diol; NMR; NOE.
* Corresponding author: Fax: +81-11-706-4182; e-mail: y-
fuku@abs.agr.hokudai.ac.jp
† Present address: Graduate School of Science, The University of
Tokyo, 7-3-1 Hongoh, Bunkyo-Ku, Tokyo 113-0033, Japan.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00845-1

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H. Fukui et al. / Tetrahedron Letters 44 (2003) 4063–4065
to Y, and from the methoxy protons to Y and/or Z.
These NOEs can reveal the whole relative configuration
of acetal. Since the absolute configuration of the
reagent is known, that of the chiral diol can be deter-
mined. This methodlogy is based on our previous
works.12
To obtain preliminary data for the stereochemistry of
the acetal derivatives, we first acetalized an achiral diol
(8) with MBC (7) and 1-naphthaldehyde to give 8a in
95% yield and 8b, respectively. NOE difference spec-
troscopy for 8a gave NOE correlations from the 2%-
methoxy protons to the acetal proton (H-2), H-4ax, and
NOE correlations from the acetal proton to H-4ax and
H-6ax. These NOE data enabled the whole structure of
8a to be established (Fig. 2). The chemical shift differ-
ences of the corresponding proton signals of the acetal
moieties in 8a and 8b (Dl=l8a−l8b) indicate that the
Dl values are all negative and proportional to the
distance and position between the protons of the acetal
moiety and the facing naphthalene ring (Fig. 2(c)). The
signals for the protons of the acetal moiety in 8a mostly
appear upfield relative to the those of the original diol
(8).
NOE difference spectroscopy for 9a gave NOE correla-
tions from the 2%-methoxy protons to H-2, H-4, and
6-methyl protons, and NOE correlations from H-2 to
H-4 and H-5b in CD2Cl2. On the basis of these NOEs,
the configuration of 9a was determined as shown in
Figure 3. The absolute configuration of C-4 in 9a,
therefore, was determined to be (S) corresponding to
that of 9. The stereochemistry of other acetals (10a–
15a) was determined in a similar manner (Fig. 3). The
absolute configuration of these diols determined by the
present method is in complete accord with that of the
known ones (10–15). Subsequently, racemic 2-
methylpentane-2,4-diol was reacted with (aR)-MBC to
give only two derivatives, 15a and 15b (15a:15b=38:21)
Scheme 1. Preparation of optically active MBC (1).
aConditions and reagents: (a) Mg, THF, rt; ClSnMe3, toluene,
rt, 96%. (b) i-PrOH, NaH, DMI, rt, 91%. (c) PhI(OAc)2, I2,
CCl4, 500 W halogen-lamp, reflux, 86%. (d) Pd(PPh3)4, Ag2O,
DMA, 150°C, 81%. (e) KOH, DMI, 130°C, 97%. (f) o-chloro-
N-methylpyridinium iodide, (−)-menthol, n-Bu3N, toluene,
70°C, 88%. (g) silica gel column chromatography toluene–
hexane=3:1. (h) DIBAH, CH2Cl2, rt, 99%. (i) PCC, CH2Cl2,
rt, 81%.
faces the methoxynaphthalene ring because of electrical
and steric repulsion between the 2%-methoxy group and
two oxygen atoms of the acetal moiety. When the
acetals are in the conformation shown in Figure 1, due
to the diamagnetic effect of the methoxynaphthalene
ring, the proton signals of the acetal moiety should
appear upfield relative to those of the original diol.
NOE correlations will be observed from the methoxy
protons of the reagent to H-2, from H-2 to X, from H-2
Figure 2. Configuration of the acetals (8a and 8b). (a) chemi-
1
cal shifts in H NMR (CDCl3) of 8, 8a and 8b. (b) Key NOE
observed in 8a. (c) Chemical shifts differences for the MNC
acetals of 8 (Dl=l8a−l8b).

H. Fukui et al. / Tetrahedron Letters 44 (2003) 4063–4065
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Acknowledgements
We are grateful to Mr. Kenji Watanabe and Dr. Eri
Fukushi (GC–MS and NMR Laboratory, Faculty of
Agriculture, Hokkaido University) for their skill in
measuring the MS spectra. This work was supported
by research fellowships for young scientists from the
Japan Society for the Promotion of Science.
References
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9. Spectral data: (aR)-2%-methoxy-1,1%-binaphthalene-8-carb-
aldehyde (aR)-1. Yellow amorphous; mp 153.8–155.0°C
(EtOH); [h]2D2 −131 (c 0.40, CHCl3); IR (KBr): 2833,
1673, 1619, 1593, 1509, 1460, 1431, 1408, 1347, 1259,
1224, 1182, 1147, 1108, 1088, 1066, 1021, 929, 891, 838,
810, 788, 773, 750, 696, 627, 550, 504 cm−1; EIMS m/z
(rel. int. %): 313 (M++1, 24), 312 (M+, 100), 282 (14), 281
(56), 269 (11), 268 (13), 253 (26), 252 (38), 239 (25);
HREIMS m/z (M+): calcd for C22H16O2: 312.1150.
Found: 312.1122. NMR lH ppm (500 MHz, CDCl3); 3.73
(3H, s), 7.30–7.38, (4H), 7.53 (dd, J=1.2, 6.9 Hz), 7.54
(d, J=7.1 Hz), 7.68 (dd, J=7.1, 8.1 Hz), 7.75 (dd, J=1.2,
7.1 Hz), 7.86 (d, J=7.4 Hz), 8.00 (d, J=7.9 Hz) 8.03 (d,
J=7.9 Hz), 8.14 (dd, J=1.2, 7.1 Hz), 9.29 (1H, s).
10. Firouzabadi, H.; Iranpoor, N.; Karimi, B. Synth. Com-
mun. 1999, 29, 2255–2263.
11. General procedure: To a CH2Cl2 (1.5 ml) solution of
MBC (20.0 mg, 64.0 mmol), trimethyl orthoformate (12.8
ml, 76.8 mmol) and WCl6 (1.3 mg, 3.2 mmol) was added
diols (96.0 mmol). The reaction mixture was stirred at
room temperature for 1 h. After adding one drop of Et3N
to the solution, the mixture was directly applied to
preparative TLC with n-hexane–ethyl acetate (4:1) to
afford acetals (38–82% yield).
Figure 3. Configuration of the acetals (9a–15a and 15b).
NOE correlation in CD2Cl2 is shown by arrows.
in 59% yield. In addition, 15a and 15b could be well
separated on silica gel PTLC plates. The stereochem-
istry of 15b shown in Figure 3 was determined in the
same way. Since a single diastereomeric acetal was
formed exclusively with (aR)-MBC and each enan-
tiomer of chiral diols, the effect of substituents, X
and Y (in Fig. 1) on thermodynamic stability of the
resultant acetals may be as follows; (X, Y)=(H, H)ꢀ
(H, CH3)ꢀ(CH3, H)ꢀ(CH3, CH3).
In summary, we have developed a new methodology
to determine the absolute configuration of chiral 1,2-
and 1,3-diols by using an axially chiral reagent, MBC
(1). This method can be useful for preparation of
optically active diols. Further application of this
reagent to chiral syn-1,3-diols and polyols is under
study.
12. Fukui, H.; Fukushi, Y.; Tahara, S. Tetrahedron Lett.
1999, 40, 325–328.