Organic Chemistry in Medical Science at Imperial College and
the EPSRC.
B
B
B
B
i–iii
2
2
(S,S)-4
(R,R)-4
Notes and references
† A solution of the salt-free bis(diisopinocampheylborane) 4 in Et2O was
found to be stable for up to 3 days at room temperature under an argon
atmosphere. After this time the reagent deteriorated markedly as evidenced
by substantially reduced yields.
3
i, iv, iii
‡ In a typical procedure a solution of (1S)-(+)-B-chlorodiisopinocam-
pheylborane (5.4 g; 16.8 mmol) in dry Et2O (20 ml) was added to a
vigorously stirred suspension of 1,3-dilithio-2-methylenepropane·2
(TMEDA) (2.3 g; 7.7 mmol) in dry Et2O (20 ml) at 0 °C and the mixture was
stirred at 20 °C for 3 h under argon. The Et2O was removed in vacuo and the
residue was dissolved in dry pentane (50 ml) and filtered under argon. The
residual salts were washed with a further portion of dry pentane (50 ml). The
combined pentane extracts were evaporated under reduced pressure and the
resulting oil was dissolved in dry Et2O (50 ml) under argon and cooled to
278 °C. 4-Methoxybenzaldehyde (2.5 ml; 20.5 mmol) was added and the
resulting solution was stirred for 3 h at 278 °C. H2O2 (30%; 4 ml; 32 mmol)
and aqueous NaOH (4 mol dm23; 8 ml; 32 mmol) were added
simultaneously and the mixture was stirred for 18 h at 20 °C. Water (20 ml)
was added and the mixture was extracted with Et2O (3 3 20 ml). The
ethereal extracts were dried and concentrated to give a clear residue, which
was chromatographed (EtOAc–hexanes, 2:3) to give (1R,5R)-1,5-bis(4-
methoxyphenyl)-3-methylenepentane-1,5-diol (1.377 g; 55%) as a white
solid.
2
2
OH
OH
OH
v, vi
+
(S,S)-4
R
R
R
5
1
Scheme 1 Reagents and conditions: i, BunLi, TMEDA, hexane; ii, (+)-DIP-
Cl™, Et2O; iii, pentane, filtration; iv, (2)-DIP-Cl™, Et2O; v, RCHO, Et2O
or THF, 278 °C; vi, 30% H2O2, 4 mol dm23 NaOH, 20 °C.
and enantioselectivities ( > 95% ee).¶ Both pivaldehyde and
2-nitrobenzaldehyde failed to provide the corresponding ad-
ducts 1 presumably on account of steric congestion (Table 1,
entries 13 and 14). In the case of the homochiral aldehydes
(Table 1, entries 10, 11 and 12) substantial reagent control of the
selectivity was observed, with largely a single isomer being
isolated in both the mismatched (entry 10) and matched (entry
11) cases.
The absolute stereochemical course of the reaction was
determined by an X-ray crystallographic analysis of the bis-(S)-
(2)-Mosher ester 6.∑ This study unequivocally established both
the relative and absolute stereochemistry of the diol and, by
implication, all of the other diols in Table 1. Additional
confirmation of the absolute stereochemistry was obtained from
a comparison of the optical rotation of dihydroxy ketone 7
§ The reported yields are relative to the amount of 1,3-dilithio-
2-methylenepropane. All new compounds were fully characterised by
spectroscopic data, combustion analysis and HRMS.
¶ Diastereoselectivites and enantioselectivities were determined by prepara-
tion of the corresponding bis-Mosher esters (ref. 8) and 1H NMR
analysis.
∑ Full details of the X-ray crystallographic study will be reported
elsewhere.
1 For example, see F. Alonso, E. Lorenzo and M. Yus, Tetrahedron Lett.,
1997, 38, 2187.
2 R. B. Bates, W. A. Beavers, B. Gordon III and N. S. Mills, J. Org. Chem.,
1979, 44, 3800; J. Klein, A. Medlik-Balan, A. Y. Meyer and M. Chorev,
Tetrahedron, 1976, 32, 1839; T. Imai and S. Nishida, Synthesis, 1993,
395; C. Gómez, D. J. Ramón and M. Yus, Tetrahedron, 1993, 49, 4117;
G. Majetich, H. Nishidie and Y. Zhang, J. Chem. Soc., Perkin Trans. 1,
1995, 453; S.-K. Kang, D.-C. Park, C.-H. Park and S.-B. Jang, Synth.
Commun., 1995, 25, 1359; C.-J. Li, Tetrahedron Lett., 1995, 36, 517; Y.
Masuyama, M. Kagawa and Y. Kurusu, Chem. Commun., 1996, 1585; A.
Krief and W. Dumont, Tetrahedron Lett., 1997, 38, 657 and references
cited therein.
O
O
MeO
F3C
Ph
4-MeO-C6H4
CF3
OMe
O
O
Ph
C6H4-4-OMe
6
OH
O
OH
3 Y. N. Bubnov, M. E. Gurskii and D. G. Pershin, Bull. Acad. Sci. USSR,
Div. Chem. Sci., 1987, 36, 1107.
C5H11
C5H11
4 H. C. Brown and P. K. Jadhav, J. Am. Chem. Soc., 1983, 105, 2092; W.
R. Roush, Allyl Organometallics, in Comprehensive Organic Synthesis,
ed. B. M. Trost, I. Fleming and C. H. Heathcock, Pergamon, Oxford,
1991, vol. 2, pp. 1–53 and references cited therein; A. G. M. Barrett and
P. W. H. Wan, J. Org. Chem., 1996, 61, 8667 and references cited
therein.
5 J. J. Bahl, R. B. Bates, W. A. Beavers and N. S. Mills, J. Org. Chem.,
1976, 41, 1620.
6 H. C. Brown, P. K. Jadhav and P. T. Perumal, Tetrahedron Lett., 1984,
25, 5111.
7 U. S. Racherla and H. C. Brown, J. Org. Chem., 1991, 56, 401.
8 J. A. Dale, D. L. Dull and H. S. Mosher, J. Org. Chem., 1969, 34,
2543.
9 R. Annunziata, M. Cinquini, F. Cozzi and A. Restelli, J. Chem. Soc.,
Perkin Trans. 1, 1985, 2293.
7
{[a]2D5 +45.8, (c 0.2 in CHCl3)}, obtained via ozonolysis of diol
1 (R = C5H11) (97%), with that previously reported for the
antipode {[a]2D5 240.4, (c 0.2 in CHCl3)}.9
This study further demonstrates the utility of pinene-derived
compounds in asymmetric synthesis. The direct conversion of
aldehydes into highly enantiomerically enriched C2 symmetric
3-methylenepentane-1,5-diols 1 via an experimentally simple
procedure should be of considerable application in organic
synthesis.
We thank Parke Davis Warner Lambert for generous support
of this programme of research, Glaxo Wellcome Research Ltd.
for the generous research endowment (to A. G. M. B.), the
Wolfson Foundation for establishing the Wolfson Centre for
Communication 8/08070D
460
Chem. Commun., 1999, 459–460