Preparation of Optically Enriched Secondary Alkyllithium and Alkylcopper Reagents—Synthesis of (?)-Lardolure and Siphonarienal

Article abstract of DOI:10.1002/anie.201800792

Optically enriched secondary alkyl iodides were converted into secondary alkyllithium and secondary alkylcopper compounds with very high retention of configuration. Quenching with various electrophiles, including chiral epoxides, provided a range of chira

Full text of DOI:10.1002/anie.201800792

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Accepted Article
Title: Preparation of Optically Enriched Secondary Alkyllithium
and Alkylcopper Reagents. Synthesis of (-)-Lardolure and
Siphonarienal
Authors: Varvara Morozova, Juri Skotnitzki, Kohei Moriya, Konstantin
Karaghiosoff, and Paul Knochel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800792
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10.1002/anie.201800792
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Preparation of Optically Enriched Secondary Alkyllithium and
Alkylcopper Reagents. Synthesis of (-)-Lardolure and
Siphonarienal
Varvara Morozova, Juri Skotnitzki, Kohei Moriya, Konstantin Karaghiosoff and Paul Knochel*[a]
Abstract: Optically enriched secondary alkyl iodides were converted
into secondary alkyllithiums and secondary alkylcoppers with very
high retention of configuration. Quenching with various electrophiles,
including chiral epoxides, provided a range of chiral molecules with
high enantiomeric purity (>90% ee). This method has been applied in
an iterative fashion for the total synthesis of (-)-lardolure in 13 steps
and 5.4% overall yield (>99% ee, dr>99:1) and siphonarienal in 15
steps and 5.6% overall yield (>99% ee, dr>99:1) starting from
commercially available ethyl (R)-3-hydroxybutyrate (>99% ee).
in an iterative fashion of two related natural products (-)-lardolure
(6)[6] and siphonarienal (7).[7]
First, we have shown that various optically enriched esters can be
prepared. Thus, optically enriched alcohols (5a-g, 95-99% ee)[8]
were converted to the corresponding iodides (4a-g) with complete
inversion of configuration. A retentive I/Li-exchange provided
configurationally stable secondary alkyllithiums (8a-g) (-100 °C, 2
min). These chiral alkyllithiums were trapped with ClCO2Et
affording a variety of highly optically enriched esters of type 9 in
90-99% ee[8] and 54-72% yield (Table 1).
Table 1. Enantioselective synthesis of esters 9a-h starting from optically enriched
alcohols (5a-h) via iodination, I/Li-exchange and quench with ClCO2Et.
Products of type 9[a]
Scheme 1. Retrosynthetic analysis of target molecules 6 and 7.
The preparation of optically enriched acyclic molecules bearing
several chiral centers is an important task in organic synthesis.[1,2]
We have envisioned an alternative retrosynthetic analysis for
targets of type 1 involving the cleavage of a C-C bond at the chiral
center. This disconnection requires the reaction of an optically
enriched organometallic reagent 2 (Met = Li or Cu) with an
electrophile E-X (3). Such a reaction will be stereoselective, if the
organometallic species of type 2 are configurationally stable
under the reaction conditions. Recently, we have shown that
secondary organometallics of type 2 can be readily prepared from
the corresponding alkyl iodides (4) with retention of configuration
using an I/Li-exchange[3] The secondary alkyl iodide (4) was
obtained from the corresponding secondary alcohol (5) by an
Appel reaction proceeding with complete inversion[4] (Scheme 1).
Herein, we wish to report for the first time, the preparation of
optically enriched (>90% ee) unstabilized[5] secondary
alkyllithiums and alkylcoppers (2) and show their high versatility
for the preparation of a range of polyfunctional optically enriched
organic molecules. Using this method, we report the preparation
[a] Isolated yields. [b] The enantiomeric excess (ee) was determined by chiral
HPLC- and GC- analysis. [c] The diastereomeric ratio was determined by NMR-
analysis. NMI = 1-methylimidazole.
Besides carboxylation with ClCO2Et, other electrophiles react with
retention of configuration with chiral secondary alkyllithiums of
type 8, producing synthetically useful chiral molecules of type 10
(Scheme 2). Thus, the alkyl iodide (S-4e) was obtained from the
alcohol (R-5e, >99% ee) with complete inversion[5] and was
further converted to the enantiomerically enriched secondary
alkyllithium (R-8e) using an I/Li-exchange. Thiophenylation of R-
8e with Ph2S2 (-100 °C, 5 min) led to thioether S-10a in 65% yield
and 94% ee. Borylation of R-8e with MeOBpin provided the
boronic ester R-10b in 66% yield and 93% ee. Acylation with
Weinreb-amide CF3CON(OMe)Me[3b] furnished the optically
[a]
V. Morozova, J. Skotnitzki, Dr. K. Moriya, Prof. Dr. K. Karaghiosoff
Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstr. 5-13, 81377 München (Germany)
E-mail: Paul.Knochel@cup.uni-muenchen.de
Supporting information for this article is given via a link at the end of
the document.
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enriched trifluoromethyl ketone S-10c in 60% yield and 91% ee.
Addition of diethyl ketone[9] to R-8e gave the chiral tertiary alcohol
S-10d in 51% yield and 93% ee.
respectively the corresponding diols 2R,4S,6R-17 and 2S,4S,6R-
17 in >99% ee as only one diastereomer.[13] The two
enantiomerically pure alcohols 2R,4S,6R-17 and 2S,4S,6R-17
were used to prepare two natural products (-)-lardolure (6) and
siphonarienal (7) using an iterative approach.
The range of electrophiles can be further extended by performing
a transmetalation[10] of the chiral alkyllithium R-8e to the
corresponding copper reagent (S-11). After considerable
optimization[11], we have found that the addition of a 3 M ether
solution of CuBr·P(OEt)3 to the alkyllithium reagent R-8e at -
100 °C within 3 min provides alkylcopper S-11 with >97%
retention of configuration. Thus, this alkylcopper S-11 undergoes
a smooth addition to ethyl propiolate (-100 to -80 °C, 30 min)[11]
leading after acidic quench to the chiral ethyl acrylate (S-12) in
47% yield and 92% ee.
Scheme 3. Towards the synthesis of (-)-lardolure (6) and siphonarienal (7).
Stereoconvergent preparation of the chiral diol derivatives 17. a) TBSCl,
imidazole, CH2Cl2, 25 °C, 20 h, 99% yield; b) diisobutylaluminum hydride,
toluene, -78 °C, 1 h, 98% yield; c) MeLi, THF, -78 °C, 20 min, 89% yield; d)
PPh3, I2, NMI, CH2Cl2, -10 °C, 1 h, 84% yield.
Thus, the alcohol 2R,4S,6R-17 was converted by two functional
group interconversions to the alcohol 2R,4R,6R-18 (77% yield,
dr>99:1), which by Appel reaction[4] gave with complete inversion
the secondary alkyl iodide 2R,4S,6S-19. Applying the I/Li -
interconversion sequence to 2R,4S,6S-19 followed by
a
transmetalation to the corresponding chiral alkylcopper reagent
20 and subsequent opening of the epoxide (R-16) provided the
secondary alcohol 2R,4S,6R,8R-21 with complete retention of
chirality at C(4). Repeating the same sequence of iodination with
inversion providing 2R,4R,6S,8S-22 and I/Li/Cu – exchange gives
an intermediate organocopper 23 which after allylation furnishes
the benzylic ether 2R,4R,6R,8R-24 (57% yield, dr(C(8))=97:3).
After Pd-catalyzed hydrogenation[7c] and formylation[6], the
pheromone (-)-lardolure[6] (6) was obtained in 74% yield
Scheme 2. Stereoselective trapping of alkyllithium R-8e with various
electrophiles and transmetalation to copper reagent S-11 with a subsequent
carbocupration with ethyl propiolate. An=4-MeOC6H4.
Although, secondary alkyllithiums of type 8 are configurationally
stable under our reaction conditions, there is an important
exception concerning secondary alkyl iodides bearing a 2-OTBS
substituent. In this case, the configuration of the carbon center
bearing lithium can be set by equilibration producing only one
diastereomer.[3c] This has been used to prepare enantiomerically
enriched secondary alkyllithium 2R,4R-13 starting from
[ ]20
[ ]20
훼 =
퐷
(dr(C(8))=99:1, >99% ee; 훼 = -3.3 (c 0.3, hexane), lit.[6]
퐷
-3.4 (c 7.86, hexane), Scheme 4).
commercially available R-14 (Scheme 3). By
a standard
sequence of functional group transformations, we have converted
R-14 (>99% ee) to an epimeric mixture of the alkyl iodide 2R,4RS-
15 (dr=1:1; >99% ee). As expected, an I/Li-exchange of 2R,4RS-
t
15 with BuLi at -100 °C, followed by an equilibration of C(4) (-
50 °C, 30 min), produced exclusively 2R,4R-13 alkyllithium. This
key intermediate (2R,4R-13) opens diastereoselectively (R)- or
(S)-propylene oxide[12] (R-16 or S-16) in the presence of 30%
CuBr·P(OEt)3 (-50 °C, 2 d). These reaction conditions were
carefully optimized and were found superior to a stoichiometric
transmetalation to copper.[8,11c] The use of catalytic copper(I) was
possible due to the exceptional stability of the chelate-stabilized
2R,4R-13. Remarkably, these catalytic reaction conditions
allowed to scale-up the epoxide opening to a 10 mmol-scale.[8]
Thus, the treatment of 2R,4R-13 with R-16 or S-16 produces
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10.1002/anie.201800792
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COMMUNICATION
[ ]20
siphonarienal (7, 훼 = 16.2 (c 0.09, CHCl3), lit[7]
22= 16.1 (c
[ ]
훼
퐷
퐷
1.1, CHCl3)) was obtained in 80% yield over the last two steps.
Scheme 4. Total synthesis of 6 (-)-lardolure. a) NaH, benzyl bromide, THF,
reflux, 48 h; b) TBAF·3H2O, THF, reflux, 24 h; c) PPh3, I2, NMI, CH2Cl2, -10 °C,
1 h; d) (i): tBuLi, ether:hexane, -100 °C, 1 min; (ii): CuBr·P(OEt)3, -100 °C, 1 min;
electrophile, -100 °C to -80 °C, 1 h; e) Pd/C, H2, EtOAc, 25 °C, 2 h; f) HCOOH,
65 °C, 1 h. TBAF = tetrabutylammonium fluoride.
Using the epimeric alcohol 2S,4S,6R-17 (Scheme 5), we have
prepared in a related iterative manner the natural product
siphonarienal (7).[7] Thus, 2S,4S,6R-17 was iodinated[4] to the
inverted secondary iodide 2S,4S,6S-25 (83% yield, dr(C(2)>99:1).
The standard I/Li-exchange followed by a transmetalation with
CuBr·P(OEt)3 provided
unfortunately, was configurationally labile under the allylation
conditions providing 2R,4S,6S-28 as 85:15 mixture of
a copper intermediate 26 which,
a
diastereomers at C(6). This may be due to the axial-methyl group
at C(6) which hampers an intramolecular stabilization by chelation
at the OTBS-group and facilitates epimerization of C(6).[8] Thus,
we have envisioned an alternative introduction of the propyl unit
using the reaction of corresponding Li-intermediate (27) with
propionaldehyde. This addition provided the alcohol
3RS,4R,6S,8R-29 as 1:1 mixture of diastereomers at C(3), but as
a single diastereomer at C(4) in 62% yield. After mesylation,
reduction with LiAlH4 and TBS-deprotection, the alcohol
2R,4S,6S-30 was obtained in 88% yield over 3 steps as a single
diastereomer and enantiomer (dr>99:1, >99% ee). This alcohol
(2R,4S,6S-30) was further converted to the corresponding iodide
(2S,4S,6S-31) with complete inversion of C(2) (dr>99:1). After
retentive I/Li-exchange and subsequent copper transmetalation,
the alkylcopper reagent 32 added to ethyl propiolate (-100 °C,
3 min) to give the (Z)-alkenylcopper intermediate 33.[14] This
copper reagent 33 was iodinated with I2 to provide (Z)-4S,6S,8S-
34 in 57% yield. Negishi cross-coupling of iodide (Z)-4S,6S,8S-34
with MeZnCl·MgCl2 led to the unsaturated ester (E)-4S,6S,8S-35
in 82% yield with retention of configuration of the double bond.
After reduction of the ester group of (E)-4S,6S,8S-35 and
subsequent oxidation with MnO2, the natural product
Scheme 5. Total synthesis of 7 siphonarienal. a) PPh3, I2, NMI, CH2Cl2, -10 °C,
1 h; b) (i): tBuLi, ether:hexane, -100 °C, 1 min; (ii): CuBr·P(OEt)3, -100 °C, 1 min;
electrophile, -100 °C to -80 °C, 1 h; c) mesyl chloride, Et3N, CH2Cl2, 0 °C, 2 h;
d) LiAlH4, ether, rt, 12 h; e) TBAF·3H2O, THF, rt, 12 h; f) MeZnCl·MgCl2,
Pd(OAc)2, S-Phos, THF, 0 °C, 2 h; g) diisobutylaluminum hydride, toluene, -
78 °C, 1 h; h) MnO2, hexanes, rt, 3 h.
In summary, we have shown that various highly optically enriched
secondary alcohols can be converted via inverted alkyl iodides, to
secondary alkyl-lithium and -copper intermediates that react with
various electrophiles with high retention of configuration. This
method has been used to prepare two related natural products (-)-
lardolure (6) and siphonarienal (7) in >99% ee with a complete
control of the relative stereochemistry of all stereocenters.
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Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (SFB 749, B02)
for financial support. We also thank Albemarle (Frankfurt) and
BASF SE for a generous gift of chemicals.
Keywords: lithium • copper • pheromone synthesis • asymmetric
synthesis • iterative synthesis
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Varvara Morozova, Juri Skotnitzki, Kohei
Moriya, Konstantin Karaghiosoff and
Paul Knochel*
Page No. – Page No.
Preparation of Optically Enriched
Secondary Alkyllithium and
Alkylcopper Reagents. Synthesis of
(-)-Lardolure and Siphonarienal
Pheromones via chiral alkylithiums: The unstabilized optically enriched secondary
alkyllithiums and alkylcoppers allow to construct in an iterative and highly predictable
manner the acarid mite (-)-lardolure in 13 steps and 5.4% overall yield (>99% ee,
dr>99:1) and siphonarienal in 15 steps and 5.6% overall yield (>99% ee, dr>99:1)
from commercially available ethyl (R)-3-hydroxybutyrate (>99% ee).
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