A facile synthesis of chiral ω-allyl- and ω-n-propyllactones via asymmetric allylboration of formyl esters with B- allyldiisopinocampheylborane

Article abstract of DOI:10.1016/S0957-4166(98)00477-7

Asymmetric allylboration of aldehydes containing an adjacent ester group with B-allyldiisopinocampheylborane, followed by hydrolysis and cyclization, provides the corresponding allyl substituted lactones in high yields and ≥92% enantiomeric excess. Hydrogenation of these lactones provides the corresponding propyl substituted lactones without any loss of optical purity.

Full text of DOI:10.1016/S0957-4166(98)00477-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 11–15
A facile synthesis of chiral ω-allyl- and ω-n-propyllactones via
asymmetric allylboration of formyl esters with
B-allyldiisopinocampheylborane
P. Veeraraghavan Ramachandran, Marek P. Krzeminski,† M. Venkat Ram Reddy† and
Herbert C. Brown ∗
H. C. Brown and R. B. Wetherill Laboratories of Chemistry, Purdue University, West Lafayette, Indiana 47907-1393, USA
Received 20 October 1998; accepted 19 November 1998
Abstract
Asymmetric allylboration of aldehydes containing an adjacent ester group with B-allyldiisopinocampheylborane,
followed by hydrolysis and cyclization, provides the corresponding allyl substituted lactones in high yields
and ≥92% enantiomeric excess. Hydrogenation of these lactones provides the corresponding propyl substituted
lactones without any loss of optical purity. © 1999 Elsevier Science Ltd. All rights reserved.
Chiral lactones are important synthetic intermediates or end products in organic synthesis (Scheme 1).
They can be olefinated via sequential phenylselenation, hydrogen peroxide oxidation, followed by
selenoxide elimination.2 Conversion of these olefinic lactones to hydroxy lactones as those present in
mevilinic acid lactones are known.3 Lactones can be functionalized at the α-position,4 α-methylenized,5
or converted to cyclic enol ethers.6 Many of these lactones are biologically active.4,7
We considered several approaches to prepare chiral lactones using our asymmetric methods.8 One of
the standard methods for the preparation of chiral lactones is the asymmetric reduction of keto esters,
followed by hydrolysis and cyclization.9 Recently, we applied our inter- and intra-molecular asymmetric
reduction with B-chlorodiisopinocampheylborane (DIP-Chloride™)10 as a method to prepare aromatic
lactones in high enantiomeric excess.11 One of the applications of the optically active homoallylic
alcohols derived via allylboration with B-allyldiisopinocampheylborane (1)12 has been the synthesis of γ-
butyrolactones via a protection–hydroboration–oxidation–deprotection–cyclization sequence (Eq. 1).13
Although this procedure provides a variety of γ-substituted γ-butyrolactones, it is limited to the synthesis
of five-membered lactones.
∗
†
Corresponding author. E-mail: hcbrown@chem.purdue.edu
See References.1
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00477-7

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P. V. Ramachandran et al. / Tetrahedron: Asymmetry 10 (1999) 11–15
Scheme 1.
(1)
We discerned that allylboration of aldehydes possessing an appropriate ester moiety should provide the
corresponding homoallylic alcohol, which upon hydrolysis and cyclization should furnish the respective
lactones (Scheme 2). This strategy was effectively applied for the synthesis of 5-, 6-, and 7-membered
lactones in very high enantiomeric excess (ee). The propyl substituted lactones were synthesized by
hydrogenating either the unsaturated lactones or homoallylic alcohols prior to cyclization. Our results
are presented later.
Scheme 2.
Initially we carried out the allylboration of methyl glyoxylate (2a)14 with 1 in ethyl ether at −100°C.
The reaction was complete within 1 h. The usual work-up provided the corresponding homoallylic
alcohol ester 3a in 82% yield. Analysis of the product using the CHIRACEL® OD-H™ column15
for HPLC revealed an ee of 94%. Hydrogenation of 3a provided methyl 2-hydroxypentanoate (4a).
We encountered no difficulty in extending the reaction to methyl 4-oxobutanoate (2b),16 methyl 5-
oxopentanoate (2c),16 and methyl 6-oxohexanoate (2d).17 The corresponding homoallylic alcohol esters
3b–d were obtained in 82%, 88%, and 80% yields and ≥99%, 96%, and 92% ee, respectively. The ee
of 3b was determined on a β-DEX-120™ capillary column18 using a gas chromotograph. The ee of 3c
1
was determined using HPLC, as in the case of 3a, and confirmed by H NMR analysis of its acetate
1
using Eu(hfc)3 as the shift reagent. The ee of 3d was determined by H NMR spectroscopy of the
corresponding acetate in the presence of Eu(hfc)3. Hydroxy ester 3b was partially (∼50%) lactonized
during the work-up. Complete lactonization was achieved by treating it with p-TsOH. Ester 3c was
lactonized in the presence of p-TsOH in refluxing toluene within 5 h. Attempts to lactonize 3d to 5d

P. V. Ramachandran et al. / Tetrahedron: Asymmetry 10 (1999) 11–15
13
Table 1
Allylboration of formyl esters with B-allyldiisopinocampheylborane
Table 2
Hydrogenation of homoallylic esters20
Table 3
Synthesis of allyl and propyl lactones21
under similar conditions gave a complex mixture of products. However, 5d was prepared in 45% yield
via hydrolysis of 3d to the corresponding hydroxy acid, followed by lactonization. An improved yield
(70%) of 5d was achieved by cyclizing the hydroxy acid in the presence of 1-methyl-2-chloropyridinium
iodide.19 The enantiomeric purity and configurations of all of the lactones determined by comparison
with literature values showed no loss of optical activity during lactonization. Hydrogenation of these
lactones using H2 over Raney Ni in ethyl acetate provided the corresponding n-propyl lactones. These
saturated lactones were also synthesized by hydrogenation of the homoallylic alcoholic esters, followed
by lactonization. The results are summarized in Tables 1–3.
In conclusion, we have carried out the asymmetric allylboration of aldehydes containing an adjacent
ester group in high ee with B-allyldiisopinocampheylborane. The product hydroxy esters upon cyclization
provided the corresponding ω-allyl substituted 5-, 6-, and 7-membered lactones in high yields and ee.
Hydrogenation of these lactones to the corresponding n-propyl substituted lactones was also achieved
without any loss of optical purity. Typical experimental procedures are as follows.
Allylboration of 2c: All operations were carried out under a nitrogen atmosphere. To a stirred solution

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P. V. Ramachandran et al. / Tetrahedron: Asymmetry 10 (1999) 11–15
of (−)-B-allyldiisopinocampheylborane12 was added, at −100°C, methyl 5-oxopentanoate (2c) (1.3 g,
10 mmol) in 5 ml of Et2O. The mixture was stirred at this temperature for 1 h, 1 ml of methanol was
added, warmed to rt, oxidized with 3 M NaOH (4 ml) and 30% H2O2 (5 ml), and stirred for 4 h. The
product was extracted with Et2O, washed with brine, and dried over anhydrous MgSO4. Removal of
the solvent provided a crude product which was separated from isopinocampheol by silica gel column
chromatography (hexane:ethyl acetate, 9:1) to obtain 1.52 g of methyl 5-hydroxy-7-octenoate (3c) as a
1
liquid. H NMR (300 MHz) δ (CDCl3) (ppm): 1.47 (m, 2H), 1.75 (m, 3H), 2.14 (m, 1H), 2.32 (m, 3H),
3.65 (m, 4H), 5.13 (m, 2H), 5.81 (m, 1H); 13C NMR δ (CDCl3) (ppm): 21.04, 33.85, 36.06, 41.96, 51.54,
70.17, 118.18, 134.67, 174.14.
Hydrogenation of 3c: Raney Ni (50 mg of 50% slurry in water) taken in a 25 ml flask was washed
with methanol (2×3 ml). Ethyl acetate (5 ml) was added to the flask, followed by 3c (0.172 g, 1 mmol)
dissolved in 1 ml EtOAc. The flask was purged with hydrogen and closed under a positive pressure
of hydrogen. The reaction was monitored by the consumption of hydrogen using a gasimeter. Upon
completion (∼2 h), the reaction mixture was filtered, the solvent removed, and purified by silica gel
1
column chromatography to afford methyl 5-hydroxyoctanoate (4c) as a liquid. H NMR (300 MHz) δ
(CDCl3) (ppm): 0.92 (t, J=7.1 Hz, 3H), 1.45 (m, 6H), 1.74 (m, 3H), 2.35 (t, J=7.0 Hz, 2H), 3.61 (m, 1H),
3.69 (s, 3H); 13C NMR δ (CDCl3) (ppm): 14.09, 18.82, 21.01, 33.92, 36.74, 39.67, 51.54, 71.09, 174.25.
Lactonization of 3c: Methyl 5-hydroxy-7-octenoate (3c) (0.172 g, 1 mmol) was dissolved in 10 ml
of toluene contained in a 25 ml flask fitted with a Dean–Stark trap. p-TsOH (17 mg, 10 mol%) was
then added and refluxed for 5 h. Toluene was evaporated and the crude product was purified by silica
gel column chromatography to provide 0.133 g (95%) of (6R)-allyltetrahydropyranone (5c) as a liquid.
1H NMR (300 MHz) δ (CDCl3) (ppm): 1.56 (m, 1H), 1.88 (m, 3H), 2.49 (m, 4H), 4.35 (m, 1H), 5.15
(m, 2H), 5.82 (m, 1H); 13C NMR δ (CDCl3) (ppm): 18.46, 27.22, 29.48, 40.06, 79.80, 118.55, 132.65,
171.62.
Hydrogenation of 5c: Hydrogenation was carried in a similar way to that described for 3c. (6R)-n-
1
Propyltetrahydropyranone 6c was isolated as a liquid in 90% yield. H NMR (300 MHz) δ (CDCl3)
(ppm): 0.95 (t, J=7.4 Hz, 3H), 1.48 (m, 4H), 1.70 (m, 1H), 1.84 (m, 3H), 2.43 (m, 1H), 2.58 (m, 1H),
4.30 (m, 1H); 13C NMR δ (CDCl3) (ppm): 13.86, 18.21, 18.53, 27.83, 29.49, 37.93, 80.35, 171.99.
Lactonization of 4c: The lactonization was achieved as described earlier to provide 6c in 96% yield.
Acknowledgements
The financial assistance from the Purdue Borane Research Fund is acknowledged.
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