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H. Kleijn et al. / Tetrahedron Letters 42 (2001) 3933–3937
c-Hex2Zn and c-Hex2MgCl (entry 3 in Table 2)
occurred with excellent diastereoselectivity (dl/meso 97/
3). Obviously, the formation of the second stereocenter
is mainly controlled by steric factors and depends on
both the steric bulk of the organic group first intro-
duced at a benzylic position and the steric bulk of the
Grignard reagent itself. The observed low enantioselec-
tivity (25%) in reactions using c-Hex2Zn is not unprece-
dented. It has been reported before that the
aminoalcoholate- or aminoarenethiolate-catalyzed addi-
tion of secondary dialkylzinc compounds to aldehydes
proceeds with a considerably lower enantioselectivity as
compared to the e.e.s realized for primary dialkylzinc
compounds.5–7
For the phenyl-substituted diol 12, almost the same
isomer distribution has been found (see entry 3 in Table
3). A considerable increase of the relative amount of
the (S,S)(R,R) diastereoisomer was found for the cyclo-
hexyl-substituted diol 11 (entry 2 in Table 3), which
most likely is a consequence of the introduction of the
sterically more crowded cyclohexyl group.
1
All the new diols were fully characterized by H and
13C NMR and elemental analysis; some of these, i.e.
(S,S)-9, (S,S)-11 and (S,R)-12, were obtained enan-
tiomerically pure after recrystallization and were fully
characterized.16
We have shown, making use of a newly developed
one-pot, two-step synthesis, that C2-symmetric diols
derived from 1,2-phthalicdicarboxaldehyde are readily
available in high yield, and high enantiomeric and
diastereoisomeric purities. Moreover, this methodology
allows the introduction of two different organic groups
at two adjacent benzylic positions. Since both enan-
tiomers of the applied chiral amino-arene thiolate cata-
lyst are available,7 there is complete control over the
absolute stereochemistry of the chiral target molecule.
The methodology described here also opens a new
pathway to the synthesis of unsymmetrically substituted
diols derived from 1,2-phthalicdicarboxaldehyde. In a
preliminary experiment in which the in situ prepared
alkoxy-EtZn derivative 4b was treated with c-
HexMgCl, considerable amounts of diol 5 were formed
in addition to the unsymmetric diol 11. This observa-
tion indicates that scrambling of organic groups
between zinc and magnesium occurs. Therefore, further
experiments were carried out using the purified lactol 4
as starting material.
References
The results of the reactions of pure 4 with MeMgCl,
c-HexMgCl and PhMgCl (see Scheme 4) are presented
in Table 3.15
1. Whitesell, J. K. Chem. Rev. 1989, 89, 1581.
2. Longmire, J.; Zang, X. Tetrahedron Lett. 1997, 38, 1725.
3. Jiang, Q.; Van Plew, D.; Murtuza, S.; Zang, X. Tetra-
hedron Lett. 1996, 37, 797.
4. (a) Brunner, H. Topics in Stereochemistry; Interscience:
New York, 1988; Vol. 18, p. 129; (b) Handbook of
Enantioselective Catalysis; Brunner, H.; Zettlmeier, W.,
Eds.; VCH: New York, 1993; Vol. 2.
5. Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
6. Rijnberg, E.; Jastrzebski, J. T. B. H.; Janssen, M. D.;
Boersma, J.; van Koten, G. Tetrahedron Lett. 1995, 35,
6521.
Reaction of MeMgCl with (S)-4 gave 10 as two
stereoisomers (as well as the corresponding
diastereoisomers of the (R)-4 impurity; see Scheme 4
and Table 3, entry 1), (S,S)-10 being the major
product. The ratio of the (S,S)/(S,R) diastereoisomers
(74/26) has a value close to that obtained for the
symmetrically dimethyl-substituted diol 7, vide supra.
R
OH
7. Rijnberg, E.; Hovestad, N. J.; Kleij, A. W.; Jastrzebski, J.
T. B. H.; Boersma, J.; Janssen, M. D.; Spek, A. L.; van
Koten, G. Organometallics 1997, 16, 2847.
8. Soai, K.; Inoue, Y.; Takahashi, T.; Shibata, T. Tetra-
hedron 1996, 52, 13355.
1) 2 RMgCl / THF
2) Hydrolysis
OH
OH
O
Et
Et
10; R = Me
4
11; R = c-Hex
12; R = Ph
9. Watanabe, M.; Hashimoto, N.; Araki, S.; Butsugan, Y.
J. Org. Chem. 1992, 57, 742.
10. Ramachandran, P. V.; Chen, G.-M.; Lu, Z.-H.; Brown,
H. C. Tetrahedron Lett. 1996, 37, 3795.
Scheme 4.
11. Ramachandran, P. V.; Chen, G.-M.; Brown, H. C. Tetra-
hedron Lett. 1997, 38, 2417.
Table 3. Reaction of lactol 4 with Grignard reagents
RMgCla
12. Donkervoort, J. G.; Vicario, J. L.; Rijnberg, E.; Jastrzeb-
ski, J. T. B. H.; Kooijman, H.; Spek, A. L.; van Koten,
G. J. Organomet. Chem. 1998, 550, 463.
13. Soai, K.; Konishi, T.; Shibata, T. Heterocycles 1999, 51,
1421.
14. Based on the observed isomer distributions in entry 5 in
Table 1, the enantiomeric purity of lactol 4 and, thus, the
enantiomeric purity of the 1-[(2-hydroxymethyl)phenyl]-
propanol obtained from it cannot exceed 90%.
15. It should be noted that the formation of the unsymmetri-
cally substituted diols causes a complicated analytical
Entry
R
(S,S)
(R,R)
(S,R)
(R,S)
1
2
3
Me
c-Hex
Ph
68.3
76.0
69.8
5.5
6.6
7.2
24.5
1.7
17.4b
23.0b
a Product distributions were determined by HPLC analysis using a
Daicel Chiracel OD column (25 cm×4.6 mm); eluent: 2-propanol/n-
hexane 1/99; flow: 1 mL/min.
b Under the analytical conditions applied, no well-resolved peaks
were obtained for these diastereoisomers.