A modular and organocatalytic approach to γ-butyrolactone autoregulators from Streptomycetes

Article abstract of DOI:10.1039/b812698d

A general synthesis of optically active γ-butyrolactone autoregulators is developed by a two-step sequence to assemble 2,3-trans-disubstituted butyrolactones in high yields and enantioselectivities; the scope of this reaction was elaborated by setting up a library of alkyl-substituted butyrolactones and the synthesis of the autoregulators IM-2 and VB-D. The Royal Society of Chemistry.

Full text of DOI:10.1039/b812698d

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A modular and organocatalytic approach to c-butyrolactone
autoregulators from Streptomycetesw
Petteri Elsner, Hao Jiang, Johanne B. Nielsen, Filippo Pasi and
Karl Anker Jørgensen*
Received (in Cambridge, UK) 23rd July 2008, Accepted 1st September 2008
First published as an Advance Article on the web 3rd October 2008
DOI: 10.1039/b812698d
A general synthesis of optically active c-butyrolactone auto-
regulators is developed by a two-step sequence to assemble
2,3-trans-disubstituted butyrolactones in high yields and enantio-
selectivities; the scope of this reaction was elaborated by setting
up a library of alkyl-substituted butyrolactones and the synthesis
of the autoregulators IM-2 and VB-D.
Streptomyces is a genus of Gram-positive filamentous bacteria
that is known for its ability to produce secondary metabolites,
including more than 70% of the commercially significant
antibiotics.1 Pioneered by the work of Khokhlov et al.,2 small
signalling molecules, the g-butyrolactone autoregulators, have
been identified to control the production of antibiotics in
Streptomyces species. To date, fourteen 2,3-disubstituted
g-butyrolactones arising from seven different Streptomyces
species have been identified, distinguishable by length, branch-
ing and stereochemistry of their fatty acid side-chain.3 Based
on the morphology of that side-chain, g-butyrolactone auto-
regulators are classified into three groups (Scheme 1), the
A-factor- (with a 10-keto group), VB- (with a 10-(S)-hydroxy
group) and IM-2 types (with a 10-(R)-hydroxy group) (see ESI
for an overview of autoregulatorsw).
The first asymmetric synthesis of an autoregulator was
accomplished for A-factor by Mori et al. starting from
(S)-paraconic acid, which was obtained by resolution of the
racemate.4 Later a chiral auxiliary mediated synthesis of
(S)-paraconic acid and its transformation to the A-factor
was reported.5,6 Autoregulators with a C-10 hydroxyl group
were first isolated by Grafe et al.7 and Yanagimoto et al.
(VB-A–D).8 The absolute configuration of these compounds
were elucidated step by step by Mori et al.9 and Yamada
et al.10,11 through total synthesis and NOE-experiments.
Interestingly, there is no reported general and catalytic
asymmetric approach to these important compounds. We
envisaged that ketolactone A would be a general chiral
building block to synthesize all classes of g-butyrolactone
autoregulators (Scheme 2).
Scheme 1 Classification of g-butyrolactone autoregulators.
To access ketolactone A, our strategy included the
C–C bond formation by an organocatalytic asymmetric
1,4-addition of b-keto carbonyl compounds C to nitro-
alkenes D and a subsequent one-pot deprotection–cyclization
step of addition products B. In this way, a variety of
trans-2,3-disubstituted butyrolactones of type A will be avail-
able in a modular fashion. Furthermore, the syntheses of
optically active autoregulators IM-2 and VB-D were accom-
plished in a three-step sequence without the use of protective
groups.
Based on a screening process we decided to focus on the
Cinchona alkaloid-based thiourea catalysts 3a–d since they are
easily available in gram quantities and are effective for the
enantioselective 1,4-addition to nitroalkenes.12–14 Despite a
good enantioselectivity, the issue of the screening was to
identify suitable b-keto carbonyl compounds 1 (Table 1) that
are reactive enough to undergo addition to nitroalkene 2 and
facilitate the consecutive lactonization step.
The addition of b-ketoester 1a to TBDMS-protected
nitroalkene 2 (several silyl-based protecting groups were
tested, and TBDMS = tert-butyldimethylsilyl) was found to
give the best results. Table 1 shows that all four catalysts gave
full conversion after 18 h at ꢀ20 1C in CH2Cl2 (entries 1–4).
Danish National Research Foundation: Center for Catalysis,
Department of Chemistry, Aarhus University, Aarhus C, DK-8000,
Denmark. E-mail: kaj@chem.au.dk; Fax: +45 8619 6199;
Tel: +45 8942 3910
w Electronic supplementary information (ESI) available: Full
experimental details. CCDC reference number 688507. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b812698d
Scheme 2 Retrosynthetic analysis to target 2,3-trans-disubstituted
butyrolactones (LG = leaving group, PG = protecting group).
ꢁc
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Table
1
Screening of reaction conditions for the addition of
We were further delighted to see that the addition product
4d could be deprotected and cyclized in a one-pot reaction
using 2 M HCl in EtOAc and 5 equiv. of H2O. The presence of
a defined amount of H2O was crucial, since lactone 5a was not
formed when the reaction was conducted under anhydrous
acidic conditions or in an aqueous acidic media. Under the
optimized conditions, 5a was isolated in 70% yield as a single
diastereoisomer (keto : enol ratio = 2.5 : 1).
1,3-dicarbonyl compounds to nitroalkene 2a
Entry
Cat. Nuc.
T/1C
[2]/M
Conv. (%)b Ee (%)c
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
3a
3a
3a
3d
3d
3d
1a
1a
1a
1a
1a
1b
1a
1c
1d
1d
ꢀ20
ꢀ20
ꢀ20
ꢀ20
1.0d
1.0d
1.0d
1.0d
495
495
495
495
495
495
495
n.r.
80-(+)f
82-(ꢀ)f
81-(+)f
83-(ꢀ)f
81-(+)f
76-(+)f
81-(+)f
—
ꢀ20/rt 0.2d
ꢀ20
ꢀ20
1.0d
1.0e
Next we investigated the scope of this transformation by
using different alkyl-substituted oxazolidinones 1 (Table 2).
Nucleophile 1e with an n-propyl substituent reacted smoothly
at ꢀ20 1C to give the addition product in 89% yield and the
subsequent lactone 5b in 71% yield and 90% ee (entry 2).
Conducting the same reaction with catalyst 3c gave access to
the other enantiomer of 5b in comparable yields and with 86%
ee (entry 3). When moving to longer alkyl chains, we observed
a decrease in reactivity at ꢀ20 1C. Adjusting the reaction
temperature to 4 1C or rt for nucleophiles 1f–j, respectively,
gave in all cases full conversion after 48 h of reaction time.
Addition products 4f–j and the corresponding lactones 5c–g
were isolated in good yields and with 82–88% ee (entries 4–8).
The results for lactones 5a, b, d were also reproduced when
performing the reactions on a 2 mmol scale.
ꢀ20/rt 1.0e
ꢀ20/rt 0.5e
495h
495i
84-(ꢀ)g
rt
0.5e
84-(ꢀ)g
a
Reaction performed with 0.60 mmol of 1, 0.20 mmol of 2, and 10 mol%
b
of 3. Determined by 1H NMR spectroscopy. Ee determined by HPLC
c
d
chiral-stationary phase or GC. Performed in CH2Cl2.
using a
e
Performed in toluene. Ee determined after deprotection of the
f
addition product (see ESIw); the sign of optical rotation is given in
parentheses. Ee determined after deprotection/lactonization of the
g
h
i
addition product (see ESIw). 84% isolated yield. 50% isolated yield.
Both enantiomers of the addition products were obtained in
good enantioselectivities ranging from 80–83% ee. A higher
dilution (entry 5), as well as switching to toluene as solvent
(entry 7) had no significant effect on the enantioselectivity.
Increasing the size of the ester moiety in the nucleophile (1b)
resulted in slightly lower enantioselectivity (entry 6).
In general, addition products 4 were obtained as diastereo-
meric mixtures in the range of 3 : 1 to 4 : 1. However, the
ketolactones 5 were obtained as single diastereoisomers
consisting up to 10% of the enol-form (for dr of 4a–j and
keto/enol ratios of 5a–g see ESIw). The relative configuration
of 5 was determined to be trans by analogy with the X-ray
analysis of compound 5f (see ESIw).
Table 2 shows that various autoregulators should be available
from the 2,3-disubstituted g-butyrolactones 5. To exemplify this,
we synthesized two autoregulators with opposite stereochemistry
in the side chain, IM-2 8 and VB-D 10.
The addition product 4a derived from b-ketoester 1a was
deprotected with 2 M HCl in EtOAc or H2O to afford the
hydroxyester 40a (Table 1). However, it also became evident
that no further cyclization occurred under these reaction
conditions. Applying TBAF as the deprotection agent led to
decomposition of the addition product. Various other
Brønsted and Lewis acids were tested to cyclize 40a but none
of them gave considerable conversion to lactone 5a.
Consequently, we sought for an R-group in 1 that would
enhance the reactivity of the addition product 4 towards ring-
closure. Weinreb amide 1c was not reactive enough to undergo
addition to nitroalkene 2 (entry 8), but the reaction with
oxazolidinone 1d proceeded smoothly at ꢀ20 1C in toluene
and the addition product 4d showed 84% ee (entry 9). CH2Cl2
was also an effective solvent with respect to reactivity and
enantioselectivity, but the yield was lower compared to the
reactions in toluene (entry 10).
Table 2 Scope of the organocatalytic synthesis of 2,3-disubstituted g-
lactonesa
4
5
Ee
Entry R (1)
(yield (%))b (yield (%))b (%)c Target
1
2
Methyl (1d)
4d (84)
n-Propyl (1e) 4e (89)
n-Propyl (1e) ent-4e (92)
n-Pentyl (1f) 4f (62)
n-Hexyl (1g) 4g (77)
n-Heptyl (1h) 4h (72)
4i (66)
5a (70)
5b (71)
ent-5b (68) 86
5c (76)
5d (80)
5e (75)
5f (55)
84
90
—
IM-2
ent-IM-2
VB-C
VB-D
SCB2
VB-E
3d
4e
5e
6f
7e
83
85
84
82
8f
4j (84)
5g (68)
88
—
a
Reaction performed with 0.60 mmol of 1 (1.0 M in toluene),
b
0.20 mmol of 2 and 10 mol% of 3d at ꢀ20 1C. Isolated yields after
c
column chromatography. Ee determined by chiral stationary phase
d
HPLC or GC. Catalyst 3c was used. Reaction performed at rt and
e
f
with a 0.5 M concentration of 2. Reaction performed at 4 1C with a
1.0 M concentration of 2.
ꢁc
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this reaction was elaborated by setting up a library of different
alkyl-substituted butyrolactones targeting thereby naturally occur-
ring autoregulators and the applicability was outlined by a three-
step sequence to synthesize autoregulators IM-2 and VB-D.
Notes and references
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H. Yamazaki, J. Y. Kato, A. Tomono and S. Horinouchi, Biosci.,
Biotechnol., Biochem., 2005, 69, 431; (b) S. Horinouchi, Front.
Biosci., 2002, 7, d2045; For a review on autoregulators from S.
coelicolor, see: E. Takano, Curr. Opin. Microbiol., 2006, 9, 287.
4 (a) K. Mori, Tetrahedron Lett., 1981, 22, 3431; (b) K. Mori and K.
Yamane, Tetrahedron, 1982, 38, 2919; (c) K. Mori, Tetrahedron, 1983,
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J. S. Yadav, V. Muralikrishna and A. V. Rama Rao, Tetrahedron
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Okada, J. Antibiot., 1987, 40, 496; (b) K. Kondo, Y. Higuchi, S.
Sakuda, T. Nihira and Y. Yamada, J. Antibiot., 1989, 42, 1873.
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11 (a) K. Sato, T. Nihira, S. Sakuda, M. Yanagimoto and Y.
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Sakuda, T. Nihira and Y. Yamada, Tetrahedron, 1994, 50, 10849.
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Adv. Synth. Catal., 2006, 348, 999; (b) S. J. Connon, Chem.–Eur. J.,
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Chem., 2006, 118, 1550 (Angew. Chem., Int. Ed., 2006, 45, 1520);
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(e) Y. Takemoto and H. Miyabe, Chimia, 2007, 61, 269; (f) X. Yu
and W. Wang, Chem.–Asian J., 2008, 3, 516; For general reviews
on 1,4-additions, see: (g) O. M. Berner, L. Tedeschi and D. Enders,
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Scheme 3 Synthesis of autoregulators IM-2 (8) and VB-D (10).
An efficient way of transforming primary nitroalkanes into the
carboxylic acids has been developed by Mioskowski et al.15
However, preliminary results with ketolactone 5a showed that
transformation of the keto group early in the sequence was
decisive, since 5a decomposed under the reported conditions,
whereas the corresponding hydroxylactone gave clean conversion
to the carboxylic acid. It has also been reported that NaBH4-
reduction of the keto group with the hydroxymethyl side-chain
already installed led to considerable racemization.9 Consequently,
we first elaborated conditions for the reduction of the keto group
of 5b (see ESIw). The best results were obtained when 5b was
reacted under transfer hydrogenation conditions with Noyori’s
Ru-catalyst (S,S)-6 (dr = 77 : 23) or (R,R)-6 (dr = 13 : 87)
favouring the formation of desired 10-(R)-hydroxylactone 7a in the
first case (see Scheme 3). Due to double stereoselection the major
diastereomer was enantiomerically enriched. For the synthesis of
VB-D ketolactone 5d was reduced with Ru-catalyst (R,R)-6
furnishing 10-(S)-hydroxylactone 9b with high diastereo- and
enantioselectivity.
To conclude the synthesis of autoregulator IM-2 8, hydroxy-
lactone 7a was reacted with NaNO2 and AcOH in DMF at 35 1C.
After acidic aqueous work-up and removal of DMF, the crude
carboxylic acid was reduced with BH3 SMe2 in THF at 0 1C to
give IM-2 in 62% yield (Scheme 3). The spectroscopic data and
the sign of rotation were in agreement with the literature data.11b
Applying the conditions described above for the transforma-
tion of the nitro group to hydroxylactone 9b gave autoregu-
lator VB-D 10 in 43% yield, with spectroscopic data and sign
of rotation matching the literature data.8b,9 The discrepancy of
the absolute values for the optical rotations of compounds 8
and 10 compared to the literature underlines the necessity for a
synthetic sequence that installs the free hydroxymethyl unit in
the last part of the synthesis in order to avoid racemization of
the compounds. A similar observation was made by Takabe
et al. when preparing autoregulator VB-C.16
14 For some recent applications see e.g.: (a) P. Diner, M. Nielsen, S.
Bertelsen, B. Niess and K. A. Jørgensen, Chem. Commun., 2007, 3646;
(b) J. Lubkoll and H. Wennemers, Angew. Chem., 2007, 119, 6965
(Angew. Chem., Int. Ed., 2007, 46, 6841); (c) L. Jiang, H.-T. Zheng,
T.-Y. Liu, L. Yue and Y.-C. Chen, Tetrahedron, 2007, 63, 5123.
15 C. Matt, A. Wagner and C. Mioskowski, J. Org. Chem., 1997, 62, 234.
16 K. Takabe, N. Mase, W. Matsumura, T. Hasegawa, Y. Iida, H.
Kuribayashi, K. Adachi, H. Yoda and M. Ao, Bioorg. Med. Chem.
Lett., 2002, 12, 2295.
In conclusion, we have developed a general and efficient way to
synthesize optically active g-butyrolactone autoregulators.
1,3-Dicarbonyl compounds containing the oxazolidinone motif
have been proven to be very effective nucleophiles in the
chiral Cinchona alkaloid–thiourea catalyzed 1,4-addition to
alkyl-substituted nitroalkenes to assemble 2,3-trans-disubstituted
butyrolactones in high yields and enantioselectivities. The scope of
ꢁc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 5827–5829 | 5829