Article
Facile Production Scale Synthesis of (S)‑Taniguchi Lactone: A
Precious Building-Block
,
†
‡
§
Fredrik von Kieseritzky,* Yeliu Wang, and Magnus Axelson
†
Arubedo AB, Brahegatan 32, 114 37 Stockholm, Sweden
‡
Bejing Honghui Meditech Co Ltd, Bld 10, 9 Tianfu Street CBP, Daxing, 102600 Beijing, China
§Department of Clinical Chemistry, Karolinska University Hospital, 171 76 Stockholm, Sweden
ABSTRACT: A cost-efficient and facile synthesis of (S)-4-vinyldihydrofuran-2(3H)-one ((S)-1), better known as (S)-Taniguchi
lactone, is described. Racemic Taniguchi lactone rac-1 was ring-opened with (S)-1-benzylmethylamine providing a
diastereomeric mixture of hydroxyl-amides. The desired diastereomer (S,S)-2 was isolated by crystallization and subjected to
acidic hydrolysis to release enantiopure title compound in good overall yield with an er in excess of 99%. The process was
successfully scaled up to kilogram quantities.
INTRODUCTION
h, vacuum filtration afforded (S,S)-2 with a dr value measured
at above 99% by HPLC. The yield was good (70% of theory).
With the diastereopure intermediate in hand, considerable
effort was invested in unearthing suitable hydrolysis conditions
to efficiently furnish the enantiopure (S)-form of Taniguchi
lactone. It should be noted that hitherto published procedures
rely on rather harsh and basic conditions at high temperatures,
and give moderate yields and utilize work-up conditions that
are not appropriate for large scale synthesis. After some
endeavor, we discovered a much more benign protocol, relying
instead on acidic hydrolysis at a considerably lower temper-
ature. Heating (S,S)-2 in a mixture of 2 M aqueous sulfuric acid
and 1,4-dioxane (1:1) at 80 °C for 12 h provided, after work-up
and concentration, pure (S)-4-vinyldihydrofuran-2(3H)-one in
excellent yield (er > 99%, 8.4 kg, 90% yield).
In conclusion, we have developed a facile, cost-efficient, and
scalable synthetic route to (S)-Taniguchi lactone, free of
chromatographic work-up and well-suited for large scale
production. Also, we have discovered new conditions for
ring-opening lactones with amines to yield hydroxyl-amides
that do not rely on pyrophoric reactants such as alkylaluminum
species, or other protocols that demand rigorous work-up. We
■
A recent project demanded large amounts of (S)-4-vinyl-
dihydrofuran-2(3H)-one, also known as (S)-Taniguchi lac-
1
tone. This valuable moiety has seen use as a starting point in a
1
−7
great number of natural syntheses.
However, in our hands
the published syntheses of the title compound were not suitable
for production of the required amounts. Herein, we describe a
concise synthesis of (S)-1 on large scale that proceeds in four
steps from readily available and affordable starting materials
1
,8
(
Scheme 1).
RESULTS AND DISCUSSION
■
Racemic lactone was easily obtained via scaling up a published
hydroquinone catalyzed oxy-Claisen condensation between 2-
butene-1,4-diol and triethyl orthoacetate. The starting
materials were heated at 120 °C until condensation of ethanol
ceased, and subsequently heated at 150 °C for 48 h, after which
GCMS indicated full consumption of the starting materials.
Reduced pressure distillation and collection of a fraction (70−
0 °C at 2−3 mmHg) provided rac-1 (43.8 kg, 84% yield.).
Although ring-openings of achiral, racemic, and chiral
8
8
lactones using chiral amines have been reported numerous
have good reasons to believe that our Ti(i-OPr) method is
4
1
,7,9−13
times,
none of the attempted methods gave satisfactory
generally applicable. In addition, we have shown that ring-
closure/hydrolysis of hydroxyl-amides to lactones proceeds at
significantly more benign conditions under mildly acidic
conditions, in contrast to the strongly basic protocols
previously reported. Finally, given the number of synthetic
routes starting with the title compound, we believe that our
findings should be of interest to chemists in academia and
industry.
yields or easily separable diastereomers. In an effort to improve
14
matters, the readily available and affordable (S)-1-benzylme-
thylamine was identified and employed as a chiral auxiliary, and
was heated in the presence of rac-1 with a slight excess of Ti(i-
OPr) as a dehydrating agent in THF at 75 °C. We were
4
gratified that after 12 h analysis by GCMS revealed complete
conversion to the desired ring-opened product. To the best of
our knowledge, ring-opening of lactones under these conditions
has not previously been reported.
EXPERIMENTAL SECTION
■
To our delight, it turned out that the desired hydroxyl-amide
S,S)-2 was crystalline, while the undesired diastereomer (R,S)-
was a viscous oil at room temperature, which opened up the
way for a swift, simple, and highly selective separation by
crystallization. Specifically, the diasteromeric mixture of
hydroxyl-amides was duly dissolved in MTBE, the mixture
General. GC analysis was performed on Agilent 7890A, and
GCMS analysis on Shimadzu QP2010. HPLC analysis was
performed on Agilent 1200 C18 (4.6 mm × 150 mm × 5 μm)
(
2
Received: March 21, 2014
Published: April 22, 2014
15
cooled to 5 °C, seeded with pure (S,S)-2, and stirred. After 2
©
2014 American Chemical Society
643
dx.doi.org/10.1021/op500096j | Org. Process Res. Dev. 2014, 18, 643−645