Diastereoselective Intramolecular Carbolithiations of Stereodefined Secondary Alkyllithiums Bearing a Remote Alkynylsilane

Article abstract of DOI:10.1021/acs.orglett.8b01290

Various secondary alkyl iodides bearing a remote alkynylsilane underwent intramolecular carbolithiations triggered by an I/Li-exchange performed at -100 °C using t-BuLi (2.5 equiv). The resulting alkenyllithiums were stereoselectively converted to tetrasubstituted cyclopentane exo-alkylidenes. After Pd-catalyzed hydrogenation, cyclopentanes and cis-bicyclo[4.3.0]nonanes were obtained with stereocontrol of four contiguous centers.

Full text of DOI:10.1021/acs.orglett.8b01290

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diastereoselective Intramolecular Carbolithiations of Stereodefined
Secondary Alkyllithiums Bearing a Remote Alkynylsilane
Meike Simon, Konstantin Karaghiosoff, and Paul Knochel*
Department of Chemistry, Ludwig-Maximilians-Universitat, Butenandtstrasse 5-13, 81377 Munich, Germany
̈
S
* Supporting Information
ABSTRACT: Various secondary alkyl iodides bearing a
remote alkynylsilane underwent intramolecular carbolithiations
triggered by an I/Li-exchange performed at −100 °C using t-
BuLi (2.5 equiv). The resulting alkenyllithiums were stereo-
selectively converted to tetrasubstituted cyclopentane exo-
alkylidenes. After Pd-catalyzed hydrogenation, cyclopentanes
and cis-bicyclo[4.3.0]nonanes were obtained with stereo-
control of four contiguous centers.
arbometalations of organolithiums bearing a remote
alkene or alkyne have been used to prepare various
Scheme 1. Stereoselective Preparation of Iodides rac-
(2R,3R)-1a and rac-(2R,3S)-1a*
C
carbo- and heterocycles.1 The pioneering work of Bailey2 and
Negishi3 has shown that primary alkyllithiums add intra-
molecularly to internal alkynes and alkynylsilanes. Hoppe4
demonstrated that optically enriched O-stabilized organo-
lithium derivatives undergo trans-selective carbolithiations to
ynol carbamates with high enantioselectivity. Recently, we have
shown that nonstabilized, secondary alkyllithiums can be
prepared from secondary alkyl iodides with retention of
configuration.5 In addition, we have demonstrated that
intramolecular carbolithiations provide a stereoselective access
to alkylidene cyclobutanes.6
Herein, we report a highly stereoselective carbolithiation for
preparing various cyclopentane derivatives with stereocontrol of
up to four contiguous stereocenters.
*
Conditions: (a) (i) 2 (1.1 equiv), CuI (10 mol %), Et2O, 0 °C; (ii)
trans- or cis-2,3-epoxybutane (1.0 equiv), rt, 16 h; (b) I2 (1.2 equiv),
PPh3 (1.2 equiv), NMI (1.2 equiv), CH2Cl2, −5 °C, 2 h. The
diastereomeric ratio was determined by NMR analysis. NMI = N-
methylimidazole.
First, we have prepared the secondary iodoalkynes rac-
(2R,3R)-1a and rac-(2R,3S)-1a.7 Copper(I)-catalyzed addition
of alkylmagnesium bromide 2 respectively to trans- and cis-2,3-
epoxybutane provided diastereoselectively the two alcohols rac-
(2S,3R)-3a and rac-(2S,3S)-3a in 86−89% (dr >99:1).8
Conversion with inversion of alcohols rac-(2S,3R)-3a and rac-
(2S,3S)-3a to the corresponding iodides rac-(2R,3R)-1a and
rac-(2R,3S)-1a was performed under Appel conditions9 in 51−
63% (dr >99:1; Scheme 1).
These alkyl iodides were stereoselectively converted to the
Li-derivatives syn-4 and anti-4 using an I/Li-exchange triggered
by the inverse addition of t-BuLi (2.5 equiv, Et2O, −100 °C).
Quenching with iodine gave the corresponding syn- and anti-
iodides syn-5a and anti-5a in 71−77% yield (dr >99:1),
indicating a high retention of configuration at C2 and C3.
Interestingly, the reaction of iodide anti-5a with
Bu(PhS)CuLi10 gave anti-6, introducing a butyl group instead
of the iodide (Scheme 2).11
4 with benzophenone gave the tertiary alcohols syn-5c (65%, dr
>99:1) and anti-5c (76%, dr >99:1; entries 3−4). X-ray
crystallographic analysis of syn-5c confirmed the syn-relative
stereochemistry.12 Next, we examined 3-oxygenated substrates
for the intramolecular carbolithiation. Since we reported that
such iodides undergo a fast equilibration after I/Li-exchange
providing an alkyllithium reagent in a stereoconvergent
manner,5c,6 we chose to replace SiMe3 with SiPh3, which is
known to facilitate carbolithiations and may therefore avoid
subsequent equilibration.13 To our delight, the stereoselective
performance of an I/Li-exchange on (2R,4R)-1b and (2R,4S)-
1b respectively produced syn-5d (99% yield, dr >99:1) and anti-
5d (55% yield, dr >99:1) after aqueous workup (entries 5 and
6).
This reaction sequence was extended to other electrophiles
such as ethyl chloroformate leading to the esters syn-5b and
anti-5b in 65−77% with complete retention of the config-
uration (Table 1, entries 1 and 2). Quenching of syn-4 and anti-
Received: April 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01290
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
>99:1; Table 2, entry 1). Alternatively, after quenching with
ClCO2Et, ester syn-7b was obtained in 56% yield (dr >99:1;
Scheme 2. Stereoselective Synthesis of Alkenyl Iodides (syn-
5a and anti-5a)
a
Table 2. Diastereoselective Synthesis of Polycyclic
Alkenylsilanes
a
Conditions: Bu(PhS)CuLi (3.0 equiv), THF, −5 °C, 45 h.
Table 1. Intramolecular Diastereoselective Carbolithiation
Leading to exo-Alkylidenecyclopentane Derivatives
a
Yields of isolated, analytically pure products.
entry 2). Similarly, the iodocyclohexane syn-1d underwent after
treatment with t-BuLi the expected carbolithiation and gave
after iodination or quenching with methyl triflate the bicyclic
products syn-7c and syn-7d in 65−77% yield (dr >99:1; entries
3 and 4). Transmetalation with ZnCl2 and Negishi15 cross-
coupling with naphthyl bromide using 5 mol % of Pd(OAc)2
and 10 mol % of SPhos16 stereoselectively furnished syn-7e in
99% yield (dr >99:1; entry 5). Finally, the syn-phenyl-
substituted cyclohexyl iodide syn-1e underwent a carbolithia-
tion after I/Li-exchange. Iodination at −100 °C gave syn-7f in
92% yield, dr >99:1 (entry 6). In all cases, the iodides were
obtained in high stereopurity.
a
b
Yields of isolated, analytically pure products. 1 mmol scale: 71%, dr
>99:1.
Using these conditions, it was possible to prepare bicyclic
and tricyclic ring systems.14 Thus, the reaction of the
cyclopentane iodide syn-1c with t-BuLi (−100 °C, 15 min)
provided after iodolysis the bicyclic iodide syn-7a (63% yield, dr
Carbolithiation products of type 5 were used to construct
cyclopentanes bearing four fully controlled contiguous stereo-
centers. Thus, standard carbolithiation starting from rac-
B
DOI: 10.1021/acs.orglett.8b01290
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2R,3R)-1a followed by a transmetalation with ZnCl2 gave zinc
reagent syn-8a which, after Negishi cross-coupling with ethyl 4-
iodobenzoate using 5 mol % of Pd(OAc)2 and 10 mol % of
SPhos,16 stereoselectively afforded the tetrasubstituted alkenyl-
silane syn-5e (84% yield, dr >99:1). Further iodination of syn-5e
with NIS in acetonitrile provided the alkenyl iodide syn-9 (87%
yield, dr >99:1), and subsequent Negishi cross-coupling with
methylzinc chloride led to the tetrasubstituted olefin syn-10
(77% yield, dr >99:1). This sequence demonstrates that the
carbolithiation products can be stereoselectively converted to
silyl-free tetrasubstituted olefins. Pd-catalyzed hydrogenation of
syn-10 gave the syn-ester syn-11 (100% yield, dr >99:1). The
structure of syn-11 was confirmed by X-ray analysis of the
corresponding carboxylic acid syn-12 obtained after saponifica-
tion (Scheme 3).
After standard I/Li-exchange on R-1f (er = 98:2), trans-
metalation with ZnCl2, and Negishi cross-coupling with ethyl 4-
iodobenzoate, the tetrasubstituted styrene derivative R-5f was
obtained in 74% yield and er = 95:5. In addition, the
enantiomer S-1f (er = 97:3) was exposed to the same reaction
conditions to afford S-5f in 70% yield and er = 96:4.
Two different isomeric bicyclic ring systems were also built
with control of their four contiguous stereocenters using such
an intramolecular carbolithiation (Scheme 5). Thus, the two
Scheme 5. Preparation of cis-Bicyclic[4.3.0]nonanes Bearing
Four Contiguous Stereocenters*
Scheme 3. Diastereoselective Preparation of Cyclopentanes
Bearing Four Contiguous Tertiary Centers*
*
Conditions: (a) (i) t-BuLi (3.4 equiv, inverse addition), Et2O,
−100 °C; (ii) −100 °C, 15 min; (b) ZnCl2 in THF (2.0 equiv), warm
to 15 °C; (c) ethyl 4-iodobenzoate (1.0 equiv), Pd(OAc)2 (5 mol %),
SPhos (10 mol %), DMA, rt, 16 h; (d) NIS (4.0 equiv), CH3CN, rt, 71
h; (e) MeZnCl (1.3 equiv), Pd(OAc)2 (5 mol %), SPhos (10 mol %),
THF, 0 °C, 4 h; (f) H2, Pd/C (10 mol %), MeOH, rt, 21 h; (g) KOH
(2.0 equiv), MeOH, 40 °C, 69 h. DMA = N,N-dimethylacetamide, NIS
= N-iodosuccinimide. The I/Li-exchange yields the corresponding Li-
species in about 75% yield. Therefore, an excess of the alkyl iodide has
been used to perform this reaction sequence.
*
Conditions: (a) (i) ZnCl2 in THF (2.0 equiv), warm to 15 °C; (ii)
naphthyl bromide (1.0 equiv), Pd(OAc)2 (5 mol %), SPhos (10 mol
%), DMA, rt, 16 h; (b) MeSO2CF3 (2.5 equiv) (c) NIS (6.0 equiv),
MeCN/CH2Cl2 (2:1), rt, 23 h; (d) NIS (2.0 equiv), CH3CN, rt, 1.5 h;
(e) MeZnCl (1.3 equiv), Pd(OAc)2 (5 mol %), SPhos (10 mol %),
THF, 0 °C, 4 h; (f) naphthylzinc chloride (1.3 equiv), Pd(OAc)2 (5
mol %), SPhos (10 mol %), THF, 0 °C, 2.5 h; (g) H2, Pd/C (10 mol
%), MeOH, rt, 2 h; (h) H2, Pd/C (10 mol %), MeOH, rt, 2.5 h.
This intramolecular carbolithiation was also performed in an
enantioselective fashion (Scheme 4).
Scheme 4. Enantioselective Synthesis of Cyclopentane
Derivatives ((R)-5f and (S)-5f)
alkenyl silanes syn-7d and syn-7e were converted with retention
of configuration to the corresponding alkenyl iodides using NIS
in MeCN/CH2Cl2 at 25 °C for 2−23 h to obtain the alkenyl
iodides 13a and 13b in 75−85% yield.17 Stereoselective Negishi
cross-coupling with methylzinc chloride and 2-naphthylzinc
chloride, respectively (5 mol % of Pd(OAc)2, 10 mol % of
SPhos,16 0 °C, 2.5−4 h) provided Z-14 and E-14 in 79−88%
yield (dr >99:1).18 Exohydrogenation of Z-14 and E-14 using
H2 (1 atm) in the presence of 10 mol % of Pd/C in MeOH (25
°C, 2−2.5 h) furnished the two epimeric cis-bicyclo[4.3.0]-
nonanes 15 and 16 in 76−92%. The relative configuration of
15 was established by X-ray analysis.19
In summary, we have reported highly diastereoselective
intramolecular carbolithiations allowing the synthesis of
stereodefined exoalkylidene cyclopentanes and related cis-
bicyclo[3.3.0]octanes and cis-bicyclo[4.3.0]nonanes with ster-
eocontrol of up to four contiguous stereocenters. Further
*
Conditions: (a) (i) t-BuLi (3.4 equiv, inverse addition), Et2O,
−100 °C; (ii) −100 °C, 15 min; (b) ZnCl2 in THF (2.0 equiv), warm
to 15 °C; (c) ethyl 4-iodobenzoate (1.0 equiv), Pd(OAc)2 (5 mol %),
SPhos (10 mol %), DMA, rt, 16 h.
C
DOI: 10.1021/acs.orglett.8b01290
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
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Detailed experimental procedures and analytical data
(PDF)
Accession Codes
CCDC 1829144−1829147 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
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Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: paul.knochel@cup.uni-muenchen.de.
ORCID
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Paul Knochel: 0000-0001-7913-4332
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Deutsche Forschungsgemeinschaft (SFB749) for
financial support. We also thank Albemarle (Frankfurt) and
BASF SE and for the generous gift of chemicals. M.S. thanks
the Fond der Chemischen Indutrie. We thank Dr. Kohei
Moriya and Dr. Dorian Didier (Ludwig-Maximilians-Universi-
relative stereochemistry.
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DOI: 10.1021/acs.orglett.8b01290
Org. Lett. XXXX, XXX, XXX−XXX