Asymmetric synthesis of goniothalamin, hexadecanolide, massoia lactone, and parasorbic acid via sequential allylboration-esterification ring-closing metathesis reactions

Article abstract of DOI:10.1016/S0040-4039(99)02130-9

Acrylic esters of homoallylic alcohols prepared in 92-97% ee via the asymmetric allylboration of appropriate aldehydes with B- allyldiisopinocampheylborane, when refluxed in dichloromethane in the presence of 10 mol% of Grubbs' catalyst provided the natural enantiomers of (S)-(+)-parasorbic acid, (R)-(-)-massoia lactone, and (R)-(+)goniothalamin. (S)-(-)-Hexadecanolide was prepared by hydrogenating the corresponding lactenone synthesized using the above sequence. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02130-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 583–586
Asymmetric synthesis of goniothalamin, hexadecanolide, massoia
lactone, and parasorbic acid via sequential
allylboration–esterification ring-closing metathesis reactions
P. Veeraraghavan Ramachandran,∗ 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 16 September 1999; revised 9 November 1999; accepted 12 November 1999
Abstract
Acrylic esters of homoallylic alcohols prepared in 92–97% ee via the asymmetric allylboration of appropriate
aldehydes with B-allyldiisopinocampheylborane, when refluxed in dichloromethane in the presence of 10 mol% of
Grubbs’ catalyst provided the natural enantiomers of (S)-(+)-parasorbic acid, (R)-(–)-massoia lactone, and (R)-(+)-
goniothalamin. (S)-(–)-Hexadecanolide was prepared by hydrogenating the corresponding lactenone synthesized
using the above sequence. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; allylboration; metathesis.
Chiral lactenones and lactones are functionalities commonly present in a number of natural products
that function as pheromones or medicinal compounds. They often act as intermediates for the synthesis
of other natural products. For example, (S)-(+)-5,6-dihydro-6-methyl-2H-pyran-2-one (parasorbic acid,
1a), a natural product isolated from mountain ash berries (Sorbus aucuparia), is an intermediate for
the synthesis of several carbohydrate derived antibiotics.1 This intermediate has been converted into
cis-3,6-dimethyltetrahydropyran-2-one, the major component of the male carpenter bee pheromone.2
Similarly, (R)-(–)-5,6-dihydro-6-pentyl-2H-pyran-2-one (massoia lactone, 1b), isolated from bark oil
of Criptocarya massoia3a and jasmine flowers3b is also found in the defense secretion of two species
of formicin ants of the genus Camponotus.3c (6R, 20E)-(+)-6-(20-Phenylvinyl)-5,6-dihydro-2H-pyran-2-
one (goniothalamin, 1c), a natural product with excellent medicinal properties has been isolated from
several sources.4 This is a key intermediate for the synthesis of several mevinolic acid analogs.5 (S)-
(–)-6-Undecyltetrahydropyran-2-one (hexadecanolide, 2d), isolated from6 the mandibular glands of the
oriental hornet Vespa orientalis, also contains a δ-valerolactone moiety.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02130-9
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Several approaches to prepare these important chiral lactenones and lactones have been made in the
literature, often involving multi-step sequences with or without resolution of racemic mixtures.7–11
For the past two decades, we have been developing several chiral organoborane reagents for asym-
metric transformations.12 During these projects, we have demonstrated the utility of our reagents for
the synthesis of optically active lactones.13 For example, we applied our inter- and intra-molecular
asymmetric reduction with B-chlorodiisopinocampheylborane (DIP-Chloride™)14 for the preparation of
aromatic lactones in high enantiomeric excess (ee).13a One of the applications of the optically active
homoallylic alcohols derived via allylboration with B-allyldiisopinocampheylborane (3)15 has been
the synthesis of γ-butyrolactones via a protection–hydroboration–oxidation–deprotection–cyclization
sequence.13b Also, we carried out the allylboration of aldehydes possessing an appropriate ester moiety,
followed by hydrolysis and cyclization to prepare ω-allyl and ω-n-propyl substituted five- to eight-
membered lactones in very high ee.13c
During the past few years, ring-closing metathesis reactions have been developed as an efficient route
to achieve the synthesis of lactenones and lactones of different ring sizes.16 Of the several catalysts
developed for this purpose, Grubbs’ bis(tricyclohexylphosphine)benzylidene ruthenium(IV) dichloride
(4) has received considerable attention.17 We envisaged a general chiral synthesis of 6-substituted-5,6-
dihydro-2H-pyran-2-ones via an asymmetric allylboration–esterification–cyclization strategy (Scheme
1). Our successful synthesis of 1a–d using this strategy is described herein.
Scheme 1.
Allylboration of acetaldehyde (5a) with (+)-B-allyldiisopinocampheylborane ((+)-3) in an Et2O-
pentane mixture at –100°C provided (S)-(+)-4-penten-2-ol (6a) in 94% ee.15 Esterification of 6a with
acryloyl chloride provided an 80% yield of the corresponding acryloyl ester 7a, which when treated with
10% of 4 in refluxing CH2Cl2 for 6 h provided 1a in 81% yield. Similar reaction sequence with hexanal
(5b),18 cinnamaldehyde (5c), and n-dodecanal (5d) provided 1b, 1c, and 1d in 97%, 92%, and 92% ee,
respectively. Hydrogenation of 1d in the presence of Pd/C provided a quantitative yield of 2d. In all of the
ring-closing metathesis reactions, we obtained identical results in the presence or absence of a catalytic
amount of Ti(i-PrO)4.16,19
All of the results are summarized in Table 1.
In conclusion, we have carried out the synthesis of a series of naturally occurring 6-substituted-
5,6-dihydro-2H-pyran-2-ones in high ees via a sequential asymmetric allylboration–esterification ring-
closing metathesis sequence. The 6-undecyl derivative was hydrogenated to the naturally occurring
hexadecanolide. We believe that this three-step reaction sequence is considerably simpler compared to the

585
Table 1
Preparation of lactenones via allylboration–esterification ring-closing metathesis
several procedures described in the literature for the synthesis of these types of lactenones and lactones.
This procedure can be extended to the synthesis of several other natural products.20
The experimental procedure for the synthesis of massoia lactone is representative.
Allylboration of 5b: All operations were carried out under a nitrogen atmosphere. To a stirred
solution of (–)-B-allyldiisopinocampheylborane (prepared from DIP-Chloride™)21 was added, at –100°C,
hexanal (5b) (1.0 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, and worked up as usual with NaOH and H2O2. 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, 95:5) to obtain 1.01 g (71%) of (R)-(+)-1-nonen-4-ol (6b) as a
liquid. This was dissolved in 10 mL of CH2Cl2, cooled to 0°C, and 0.86 mL (10.5 mmol) of acryloyl
chloride and 2.92 mL (21 mmol) of Et3N were added, warmed to rt and stirred for 4 h. The resulting
mixture was filtered through a short pad of Celite to remove solid Et3N·HCl, poured into water and the
product was extracted with CH2Cl2. The crude product was purified by silica gel column chromatography
(hexane:ethyl acetate, 99:1) and concentrated to obtain 1.14 g (82%) of 7b.
Grubbs’ catalyst (0.16 g, 0.02 mmol, 10 mol%) was dissolved in 5 mL of CH2Cl2 and was added
dropwise to a refluxing solution of the above acrylic ester (0.39 g, 2 mmol) in 200 mL of CH2Cl2.
Refluxing was continued for 6 h by which time all of the starting material was consumed (TLC). The
solvent was removed under aspirator vacuum and the crude product was purified by silica gel column
chromatography (hexane:ethylacetate, 75:25) to obtain 0.28 g (84%) of 1b. The spectral data matched
those reported.
Acknowledgements
Financial assistance from the Purdue Borane Research Fund is acknowledged.
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