Enzymatic kinetic resolution of primary allenic alcohols. Application to the total synthesis and stereochemical assignment of striatisporolide A

Article abstract of DOI:10.1039/b912128p

Crude Porcine pancreatic lipase was successfully used for the kinetic resolution of axially chiral primary allenic alcohols providing very high enantioselectivities with E values above 200. This simple access to optically active allenes was applied to the total synthesis of the fungal metabolite (-)-striatisporolide A, allowing its unambiguous stereochemical assignment.

Full text of DOI:10.1039/b912128p

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enzymatic kinetic resolution of primary allenic alcohols. Application to the
total synthesis and stereochemical assignment of striatisporolide A†
Jan Deska and Jan-E. Ba¨ckvall*
Received 19th June 2009, Accepted 29th June 2009
First published as an Advance Article on the web 9th July 2009
DOI: 10.1039/b912128p
Table 1 Lipase-catalyzed transesterfication of allenol 1aa
Crude Porcine pancreatic lipase was successfully used for
the kinetic resolution of axially chiral primary allenic alco-
hols providing very high enantioselectivities with E values
above 200. This simple access to optically active allenes was
applied to the total synthesis of the fungal metabolite (-)-
striatisporolide A, allowing its unambiguous stereochemical
assignment.
Entry Enzyme6 Solvent Time % conv. % ee1a % ee2a E7
During the past decade the use of allenes as synthetic intermediates
has dramatically increased, and many useful transformations have
been developed with this class of compounds.1 An interesting
feature of allenes is the axial chirality along the cumulated
1,2-diene system. Optically active allenes have been frequently
used in stereoselective synthesis, but they are usually synthesized
from enantioenriched precursors and preparation via kinetic
resolution is rare. The few resolution methods described, both
chemical2 and enzymatic,3 show compared to non-allene reso-
lutions relatively poor enantioselectivities and a general lack of
substrate scope, which makes them less attractive for synthetic
applications. In order to overcome the issue of low selectivities
we recently investigated the potential of tailor-made enzymes ap-
plying directed evolution strategies whereupon a mutant of Pseu-
domonas aeruginosa lipase was identified to catalyze the hydrolysis
of an allenic p-nitrophenylester with very high enantioselectivity
(E = 111).4
1b
2b
3b
4
5
6
CRL
PCL
PFL
PPL
PPL
PPL
toluene 42h
toluene 3h
35
52
39
42
18
42
5
71
46
68
22
67
9
65
73
96.5
98.9
98.3
1.3
9.8
10.0
toluene 18h
toluene 24h
dioxane 24h
115
>200
>200
iPr2O
24h
a Reactions performed with 0.1 mmol 1a, 0.5 mmol vinyl butyrate, 5 mg
lipase in 2 ml of solvent at room temperature. Enantiomeric excesses
were determined by HPLC analysis, conversions calculated from ee’s.
b 0.06 mmol (0.6 eq) vinyl butyrate used.
gave a significantly lower reaction rate (entry 5) compared to
diisopropyl ether.
To explore the substrate scope of this synthetic method, a
series of a-allenols with different substitution patterns at the
chiral allene axis were subjected to the PPL-catalyzed kinetic
resolution. Apparently, a substituent in the 2-position is crucial for
the recognition by the protein since allene 1b showed dramatically
reduced selectivity together with a low reaction rate (Table 2,
entry 2). On the other hand, increasing the steric demand in
the 2-position by changing from methyl to ethyl (1c) affected
the reaction only marginally and a high enantioselectivity was
observed (Table 2, entry 3). The effect of variations at the
aryl moiety in the 4-position of the allene remained minor and
selectivity issues seem to depend on the substitution position
rather than the character of the substituent. While m- and
p-tolyl derivatives 1e and 1f showed high enantioselectivities with
E-values of 176 and 102, respectively (Table 2, entries 5 and
6), the o-tolyl allenol 1d gave a significantly lower selectivity
(Table 2, entry 4). Halide-substituted derivatives 1g and 1h as
well as the naphthalene derivative 1i gave excellent results with
E > 200 (Table 2, entries 7–9). In contrast, the alkenyl- and alkyl-
substituted allenols 1j and 1k showed a considerably reduced
enantioselectivity (Table 2, entries 10 and 11) and in order to
obtain highly enantioenriched material, an attentive overacylation
was required.
Herein we report on the use of cheap, commercially available
Porcine pancreatic lipase as a biocatalyst for the highly enantiose-
lective kinetic resolution of primary allenic alcohols by enzymatic
transesterfication from vinyl esters in organic solvents. Choosing
allenol 1a as a model substrate for the investigation of the title
reaction, we tested different lipases with precedent for good
selectivities in the resolution of non-allenic primary alcohols.5
While crude Candida rugosa lipase (CRL) yielded virtually racemic
products both Pseudomonas cepacia (PCL) and Pseudomonas
fluorescens (PFL) lipases showed slight enantiodiscrimination,
however, no synthetically useful enantioselectivity was obtained
(Table 1, entries 1–3). By far the best enantioselectivity was
observed for Porcine pancreatic lipase (PPL), giving rise to highly
enantioenriched transesterfication product (R)-2a with an E-value
of 115 (Table 1, entry 4). Further improvement was achieved by
variation of the solvent, where both 1,4-dioxane and diisopropyl
ether afforded almost enantiopure butyrate with E-values higher
than 200 (Table 1, entry 5 and 6). However, the use of 1,4-dioxane
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm Uni-
versity, SE-106 91, Stockholm, Sweden. E-mail: jeb@organ.su.se
† Electronic supplementary information (ESI) available: Experimental
details, analytical data and NMR spectra are provided. See DOI:
10.1039/b912128p
With the objective to verify the absolute configurations of the
resulting products, alcohol (S)-1a, the non-reacting enantiomer
in the PPL-catalyzed kinetic resolution, obtained in 97% ee by
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 3379–3381 | 3379
©

View Article Online
consequence (S)-configuration for the allenol ((S)-1).10 The same
observation regarding the stereochemical outcome was made for
pentyl-substituted allenol (S)-1k.
Table 2 Porcine pancreatic lipase-catalyzed kinetic resolution of
a-allenolsa
In 2005 a series of fungal metabolites were isolated from an
Australian Penicillium striatisporum strain, among them the new
butenolide (-)-striatisporolide A (7),11a a double-bond regioisomer
of the known g-butyrolactone methylenolactocin (8)14b (Fig. 1).
Both belong to the family of paraconic acids,12 which have
attracted a certain interest over the past few years due to their
biological activities such as antifungal, antitumor and antibacte-
rial effects. However, to date neither a synthetic approach towards
striatisporolide A has been described nor could its absolute
stereochemical configuration be determined.
Entry R1
R2
Time % conv. % eealc
% eebut
E7
1
2b
3
4
5
6
7
8
Ph
Ph
Ph
Me 24h
H
Et
Me 30h
Me 42h
Me 24h
Me 28h
42
25
39
19
43
46
49
10
37
30
59
1a: 67
2a: 98.3 >200
72h
24h
1b: n.d. 2b: 76
9
127
1c: 61
1d: 21
1e: 74
1f: 82
1g: 96
1h: 23
1i: 58
2c: 97
2d: 94
2e: 97
2f: 95
2g: 97
2h: 99.2 >200
2i: 98.4
o-Tol
m-Tol
p-Tol
p-Cl-Ph
p-CF3-Ph Me 30h
2-Naph Me 31h
iPropenyl Me 24h
nPentyl
Me 17h
40
176
102
>200
9
>200
13
10b
11b,c
1j: n.d. 2j: 81
1k: 97 2k: n.d.
23
Fig. 1 Metabolites from Penicillium sp.
a Reactions performed with 0.1 mmol 1, 0.5 mmol vinyl butyrate, 5 mg PPL
in 2 ml iPr2O at room temperature. Enantiomeric excesses were determined
by HPLC analysis, conversions calculated from ee’s. b Conversion was
determined by 1H-NMR. c Enantiomeric excess was determined by HPLC
analysis of the corresponding p-nitrobenzoate.
To emphasise the synthetic value of chiral allenes and our
approach using the kinetic resolution of allenols we aimed for an
enantioselective total synthesis of (-)-striatisporolide A starting
from optically active (S)-1k (Scheme 2). Therefore enzymatically
resolved (S)-1k (97% ee) from Table 1 was subjected to an iodocy-
clisation using N-iodosuccinimide as a halide source,13 giving
rise to 3-iodobutenolide (S)-9. Palladium-catalyzed methoxycar-
bonylation of vinyl iodide (S)-9 afforded a,b-unsaturated methyl
ester (S)-1014 in high yield; a slightly elevated pressure (sealed
tube) was required to achieve reasonable reaction rates. Finally,
regioselective allylic oxidation using CrO3/dimethylpyrazole15
followed by an alkaline hydrolysis of the methylester yielded the
desired natural product (S)-7. The spectral data from the synthetic
striatisporolide A were identical with those reported from the
natural source. Consistency of the specific rotations of (S)-7, [a]D20
-25.2◦ (c 0.4, MeOH), and the natural striatisporolide A, [a]D
-24◦ (c 0.4, MeOH), allows the unambiguous assignment of the
absolute configuration of the natural product.
careful overacylation, was cyclized to the corresponding dihy-
drofuran (R)-3 by means of a silver-catalyzed cycloisomerisation
with complete retention of the optical activity (Scheme 1). In
order to obtain an authentic sample of the dihydrofuran with
known configuration, racemic 4 was enzymatically resolved using
Candida antarctica lipase type B as a biocatalyst. The enzymatic
acylation of rac-4 with this enzyme is known to give (R)-58 with
the remaining alcohol being (S)-4. Etherfication of (S)-4 with
3-bromo-2-methylpropene and subsequent ring-closure meta-
thesis9 yielded (S)-3 as a single enantiomer. Comparison of optical
rotations and HPLC-chromatograms indicated (R)-configuration
for the dihydrofuran originated from the chiral allene, as a
Scheme 1 Reagents and conditions: (a) 10 mol% AgNO3 on silica, pentane,
rt, 3 h; (b) 0.5 eq vinyl acetate, 5 wt% Novozym 435, toluene, rt, 20 h; (c)
1.2 eq NaH, 1.2 eq 3-bromo-2-methylpropene, DMF, 0 ◦C, 3 h; (d) 5 mol%
Grubbs’ first generation catalyst, toluene, 80 ◦C, 5 h.
Scheme 2 Reagents and conditions: (a) 1.1 eq NIS, DCM, rt, 2 h;
(b) CO (1 atm), 3 eq NEt3, 5 mol% Pd(PPh3)4, MeOH, 85 ◦C, 20 h;
(c) (i) 6 eq CrO3, 6 eq 3,5-dimethylpyrazole, DCM, -20 ◦C, 6 h; (ii) 3 eq
LiOH, THF/H2O, 0 ◦C, 1 h.
3380 | Org. Biomol. Chem., 2009, 7, 3379–3381
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
In summary, a biocatalytic kinetic resolution of allenols using
Porcine pancreatic lipase has been developed, which shows good to
excellent enantioselectivity for a variety of different primary allenic
alcohols. This approach was used as the enantiodetermining step
in the synthesis of the fungal butenolide (-)-striatisporolide A.
Work is in progress in our laboratory towards a dynamic kinetic
resolution (DKR)16 of allenes. We have previously reported on a
novel racemization procedure for allenes that takes advantage of
the reversible bromopalladation of the 1,2-diene moiety.17 We are
currently studying the combination of this racemization with the
present enzymatic resolution in order to obtain a DKR.18
Gil, E. Ferre, A. Meou, J. Le Petit and C. Triantaphylides, Tetrahedron
Lett., 1987, 28, 1647; (f) E. Ferre, G. Gol, M. Bertrand and J. Le Petit,
Appl. Microbiol. Biotechnol., 1985, 21, 258.
4 J. D. Carballeira, P. Krumlinde, M. Bocola, A. Vogel, M. T. Reetz and
J.-E. Ba¨ckvall, Chem. Commun., 2007, 1913.
5 (a) D. Stru¨bing, P. Krumlinde, J. Piera and J.-E. Ba¨ckvall, Adv. Synth.
Catal., 2007, 349, 1577; (b) M. Kawasaki, M. Goto, S. Kawabata and
T. Kometani, Tetrahedron: Asymmetry, 2001, 12, 585; (c) M. Kawasaki,
M. Goto, S. Kawabata, T. Kodama and T. Kometani, Tetrahedron Lett.,
1999, 40, 5223; (d) A. Abate, E. Brenna, C. Fuganti, F. G. Gatti, T.
Giovenzana and S. Serra, J. Org. Chem., 2005, 70, 1281.
6 Enzymes used: CRL: Lipase from Candida Rugosa, by Sigma; PCL:
Amano Lipase PS-D I, by Aldrich; PFL: Lipase AK “Amano” 20,
by Amano Enzymes; PPL: Lipase from porcine pancreas, by MP
Biomedicals.
7 C. S. Chen, Y. Fujimoto, G. Girdaukas and C. J. Sih, J. Am. Chem.
Soc., 1982, 104, 7294.
Acknowledgements
8 (a) O. V. Singh and H. Han, Org. Lett., 2007, 9, 4801; (b) J. H. Choi,
Y. K. Choi, Y. H. Kim, E. S. Park, E. J. Kim, M.-J. Kim and J. Park,
J. Org. Chem., 2004, 69, 1972.
9 T. A. Kirkland and R. H. Grubbs, J. Org. Chem., 1997, 62, 7310.
10 D. G. Morris, Stereochemistry, Royal Society of Chemistry, Cambridge,
2001, 85.
Financial support from the Swedish Research Council, The
Swedish Foundation for Strategic Research, K & A Wallen-
berg foundation, and the German Academic Exchange Service
(DAAD) is gratefully acknowledged.
11 (a) M. Stewart, R. J. Capon, E. Lacey, S. Tennant and J. H. Gill, J. Nat.
Prod., 2005, 68, 581; (b) B. K. Park, M. Nakagawa, A. Hirota and M.
Nakayama, J. Antibiot., 1988, 41, 751.
12 R. Bandichhor, B. Nosse and O. Reiser, Top. Curr. Chem., 2005, 243,
43.
13 C. J. T. Hyland and L. S. Hegedus, J. Org. Chem., 2008, 71, 8658.
14 For related transformations of vinyl iodides to a,b-unsaturated esters
see: J. Deska and U. Kazmaier, Angew. Chem., 2007, 119, 4654; J. Deska
and U. Kazmaier, Angew. Chem., Int. Ed., 2007, 46, 4570.
15 J. A. Marco, M. Carda, S. Rodr´ıguez, E. Castillo and M. N. Kneeteman,
Tetrahedron, 2003, 59, 4085.
16 (a) B. Mart´ın-Matute and J.-E. Ba¨ckvall, Curr. Opin. Chem. Biol., 2007,
11, 226; (b) O. Pa`mies and J.-E. Ba¨ckvall, Chem. Rev., 2003, 103, 3247;
(c) F. F. Huerta, A. B. E. Minidis and J.-E. Ba¨ckvall, Chem. Soc. Rev.,
2001, 30, 321.
Notes and references
1 (a) N. Krause, and A. S. K. Hashmi, Modern Allene Chemistry, Wiley-
VCH, Weinheim, 2004; (b) S. Ma, Chem. Rev., 2005, 105, 2829; (c) R.
Zimmer, C. U. Dinesh, E. Nandanan and F. A. Khan, Chem. Rev.,
2000, 100, 3067.
2 (a) J. Nyhle´n, L. Eriksson and J.-E. Ba¨ckvall, Chirality, 2007, 20, 47;
(b) Y. Noguchi, H. Takiyama and T. Katsuki, Synlett, 1998, 543; (c) G.
Kresze, W. Runge and E. Ruch, Justus Liebigs Ann. Chem., 1972, 756,
112; (d) Z. K. Sweeney, J. L. Salsman, R. A. Andersen and R. G.
Bergman, Angew. Chem., 2000, 112, 2429; Z. K. Sweeney, J. L. Salsman,
R. A. Andersen and R. G. Bergman, Angew. Chem., Int. Ed., 2000, 39,
2339.
3 (a) B. C. N. M. Jones, J. V. Silverton, C. Simons, S. Megati, H.
Nishimura, Y. Maeda, H. Mitsuya and J. Zemlicka, J. Med. Chem.,
1995, 38, 1397; (b) A. Cipiciani and F. Bellezza, J. Mol. Catal. B, 2002,
17, 261; (c) M. Pietzsch, O. Vielhauer, D. Pamperin, B. Ohse and H.
Hopf, J. Mol. Catal. B, 1999, 6, 51; (d) S. Ramaswamy, R. A. H. F.
Hui and J. B. Jones, J. Chem. Soc., Chem. Commun., 1986, 1545; (e) G.
17 A. Horva´th and J.-E. Ba¨ckvall, Chem. Commun., 2004, 964.
18 One problem so far has been incompatibility as well as low to moderate
differentiation between the allenol and allenyl butyrate in the Pd-
catalyzed racemization: J. Deska, C. Del Pozo and J.-E. Ba¨ckvall,
unpublished results.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 3379–3381 | 3381
©