Diastereoselective synthesis of open-chain secondary alkyllithium compounds and trapping reactions with electrophiles

Article abstract of DOI:10.1002/anie.201308679

A practical stereoselective iodide-lithium exchange was used in the first general preparation of functionalized stereodefined acyclic secondary nonstabilized lithium reagents from the corresponding secondary alkyl iodides. These lithium reagents react with various electrophiles including carbon electrophiles with high retention of configuration. Kinetic data on the configurational stability of these acyclic alkyllithium reagents are given. This methodology offers a new entry to chiral synthons for the stereoselective synthesis of open-chain molecules.

Full text of DOI:10.1002/anie.201308679

Angewandte
Chemie
DOI: 10.1002/anie.201308679
Chiral Alkyllithium Compounds
Diastereoselective Synthesis of Open-Chain Secondary Alkyllithium
Compounds and Trapping Reactions with Electrophiles**
Guillaume Dagousset, Kohei Moriya, Rasmus Mose, Guillaume Berionni,
Konstantin Karaghiosoff, and Paul Knochel*
Abstract: A practical stereoselective iodide–lithium exchange
was used in the first general preparation of functionalized
stereodefined acyclic secondary nonstabilized lithium reagents
from the corresponding secondary alkyl iodides. These lithium
reagents react with various electrophiles including carbon
electrophiles with high retention of configuration. Kinetic data
on the configurational stability of these acyclic alkyllithium
reagents are given. This methodology offers a new entry to
chiral synthons for the stereoselective synthesis of open-chain
molecules.
anti-1a (Scheme 1).[10] Thus, a 1:1 mixture of the easily
prepared alkynyl alcohols[11] syn-2a and anti-2a was partially
hydrogenated (Lindlar hydrogenation: H2, lead-poisoned Pd
on CaCO3, quinoline, hexane, RT, 1 h),[12,13] leading to the two
chromatographically separable diastereomeric (Z)-allylic
D
ue to their high reactivity, organolithium compounds are
important reagents in organic synthesis.[1] In particular, the
stereoselective generation of stabilized alkyllithium com-
pounds,[2,3] such as a-heteroatom-substituted alkyl,[4] ben-
zylic,[5,6] and allylic organolithium reagents,[3,6] has been
studied extensively as well as their subsequent reactions
with electrophiles. However, the preparation of nonstabilized
alkyllithium compounds, especially acyclic secondary alkyl-
lithium compounds, and their stereoselective quenching
reactions still remain a major synthetic challenge.[7]
Recently, we have shown that secondary cyclohexyl-
lithium reagents can be generated stereoselectively by using
an I/Li exchange reaction and subsequent trapping with
various electrophiles proceeds in most cases with retention of
configuration.[8a] Furthermore, these organolithium com-
pounds have recently gained importance due to their direct
use in Pd-catalyzed cross-coupling reactions.[9] Herein, we
wish to report the first general preparation of stereodefined
acyclic nonstabilized secondary alkyllithium reagents and
their quenching reactions with a range of electrophiles
including carbon electrophiles.
Scheme 1. Stereoselective preparation of syn and anti acyclic secondary
alkyl iodides 1a (d.r. =syn/anti ratio).
alcohols syn-3a (43%; d.r. = 99:1) and anti-3a (31%; d.r. =
1:99). Sequential hydrogenation (H2, Pd on C, KOH, hexane,
RT, overnight)[13] of pure syn-3a and pure anti-3a provided
the corresponding alcohols, anti-4a (94%; d.r. = 1:99) and
syn-4a (97%; d.r. = 99:1), respectively, with retention of
configuration.[14] Subsequent SN2 iodination of syn-4a and
anti-4a (PPh3, I2, NMI (N-methylimidazole), CH2Cl2, 08C,
15 min)[15] provided the expected iodides syn-1a (77%; d.r. =
98:2) and anti-1a (71%; d.r. = 3:97). The syn or anti config-
First, we prepared syn and anti diastereomers of various
acyclic secondary iodides of type 1 using a straightforward
synthesis, which is detailed in the case of iodides syn-1a and
1
uration of alcohol 4a was determined by comparing the H
and 13C NMR spectra of the two diastereomers of 4a with
those of syn-4a obtained from commercially available syn-
2,5-hexanediol.[10] This allowed us to assign the stereochem-
istry of syn-1a and anti-1a unambiguously.
[*] Dr. G. Dagousset, K. Moriya, R. Mose, Dr. G. Berionni,
Prof. Dr. K. Karaghiosoff, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, 81377 Mꢁnchen (Germany)
E-mail: Paul.Knochel@cup.uni-muenchen.de
The alkyl iodide syn-1a was subjected to an I/Li exchange.
Thus, adding syn-1a dropwise within 10 min to a solution of
tBuLi in hexane/ether (3:2) at À1008C (inverse addition) led
to the lithium reagent syn-5a, which was subsequently
quenched with Me2S2 to afford the thioether syn-6a in 74%
yield with almost complete retention of configuration (d.r. =
96:4; Scheme 2). Similarly, the lithium reagent anti-5a was
prepared from iodide anti-1a, and was trapped with Me2S2 to
afford the anti thioether anti-6a in 75% yield with excellent
diastereoselectivity (d.r. = 6:94). Treatment of iodide syn-1a
Homepage: http://www.knochel.cup.uni-muenchen.de/
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB749, B2), the Alexander-von-Humboldt-Stiftung (fellowships to
G.D. and G.B.), and the DAAD (scholarship to K.M.). We also thank
BASF SE (Ludwigshafen) and Rockwood Lithium GmbH (Frankfurt)
for generous gifts of chemicals and Prof. Dr. H. Mayr for valuable
discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308679.
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Table 1: (Continued)
Entry Li reagent
E+
Product
Yield[a]
d.r.[b]
58
7:93
3
PhSO2Cl
anti-5a (3:97)
anti-7
anti-8
syn-9
Ph2PCl
S8
82
5:95
4
5
6
7
anti-5a (3:97)
[16]
65
94:6
Me2S2
syn-5b (96:4)
syn-5b (96:4)
Scheme 2. Stereoselective preparation of syn and anti acyclic secondary
alkyl iodides 1a (d.r. =syn/anti ratio).
Ph2PCl
76
94:6
[16]
S8
with sodium methanethiolate led to thioether anti-6a in 78%
yield (d.r. = 12:88) by an SN2 reaction, which confirmed the
overall retention of configuration in the I/Li exchange
reaction and subsequent quenching reaction with Me2S2
(Scheme 2).
syn-10
anti-9
70
9:91
Me2S2
By using these optimized conditions, we were able to
stereospecifically access various the new nonstabilized acyclic
secondary alkyllithium compounds syn- and anti-5a–d from
the corresponding acyclic syn and anti alkyl iodides 1a–d[10]
through an I/Li exchange and we studied their reactivity with
a range of electrophiles (Table 1). Thus, the reactions of syn-
5a with benzenesulfonyl chloride and chlorodiphenylphos-
phine gave the expected alkyl chloride syn-7 and alkyl
diphenylphosphine sulfide syn-8[16] in 61–81% yield with
almost complete retention of configuration (d.r. = 96:4;
Table 1, entries 1 and 2), while reactions of anti-5a with the
same electrophiles afforded anti-7 and anti-8[16] in similar
yields (58–82%) with again excellent diastereoselectivities
(d.r. = 7:93 and 5:95 respectively; Table 1, entries 3 and 4).
Various syn and anti aryl-substituted secondary iodides
1b–d (1b: Ar= p-Me2NC6H4, 1c: Ar= p-TBSOC6H4, 1d:
Ar= Ph) were also prepared in excellent diastereomeric
purity (up to d.r. = 98:2)[10] and subjected to the I/Li exchange
reaction (Table 1, entries 5–14). These substituents (p-Me2N;
anti-5b (8:92)
anti-5b (8:92)
Ph2PCl
74
9:91
8
[16]
S8
anti-10
syn-11
75
95:5
9
Me2S2
Me2S2
syn-5c (98:2)
anti-5c (2:98)
73
6:94
10
anti-11
syn-12
syn-13
anti-12
anti-13
73
96:4
11
12
13
14
Me2S2
Ph2S2
Me2S2
Ph2S2
syn-5d (98:2)
syn-5d (98:2)
Table 1: Diastereoselective quenching reactions of syn and anti acyclic
secondary alkyllithium reagents 5a–d with electrophiles.
78
96:4
Entry Li reagent
E+
Product
Yield[a]
d.r.[b]
61
96:4
73
9:91
1
PhSO2Cl
syn-5a (98:2)
syn-7
syn-8
anti-5d (8:92)
anti-5d (8:92)
77
8:92
Ph2PCl
S8
81
96:4
2
syn-5a (98:2)
[16]
[a] Yield of isolated product in %. [b] d.r. (syn/anti ratio) determined by
13C NMR spectroscopy.
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Table 2: Diastereoselective formylation, carboxylation, and amidation of syn
and anti acyclic secondary alkyllithium reagents 5a, 5c, and 5d.
entries 5–8 and p-TBSO; entries 9 and 10) are well tolerated
and the I/Li exchange proceeds with high stereoselectivity in
all cases. After quenching with Me2S2, Ph2PCl,[16] or Ph2S2, the
expected products syn- or anti-9–13 were obtained in 65–77%
yield with retention of configuration (up to d.r. = 96:4 and
6:94, respectively; Table 1, entries 5–14).
In order to determine the relative stereochemistry of the
secondary alkyl iodides 1b–d and the products 9–13, two X-
ray crystallographic analyses were performed.[17] Thus, the
quaternary ammonium tosylate syn-14[17] was prepared by the
reaction of syn-1b with methyl tosylate in acetone (Figure 1).
After recrystallization from chloroform, the relative stereo-
Entry Li reagent
E+
Product
Yield[a]
d.r.[b]
80
8:92
1
DMF
syn-5a (98:2)
anti-17
syn-17
70
91:9
2
DMF
CO2
CO2
anti-5a (3:97)
79
6:94
3
syn-5c (98:2)
anti-18
Figure 1. Structures of syn-14 and syn-10 confirmed by X-ray crystallo-
graphic analyses.
77
95:5
4
anti-5c (2:98)
syn-18
anti-19
syn-19
chemistry of this salt was unambiguously determined by X-
ray crystallographic analysis to be syn. Moreover, the syn
stereochemistry of the phosphorus compound syn-10[17] could
also be confirmed by X-ray crystallographic analysis, thus
verifying the overall retention of configuration for the I/Li
exchange and quenching sequence.[10]
The stereoselective formation of carbon–carbon bonds
using these acyclic secondary alkyllithium reagents was also
investigated (Scheme 3 and Table 2). Remarkably, the reac-
tion of alkyllithium compounds syn-5a and anti-5a with
Weinreb amides[18] 15a,b (15a: R = CF3, 15b: R = Ph) led to
the expected a-chiral trifluoromethyl ketone[19] 16a and
phenyl ketone 16b in 65–68% yield with almost complete
retention of configuration[4w] (up to d.r. = 4:96 and 95:5;
Scheme 3). Diastereoselective formylation,[4d] carboxyla-
tion,[4b,v,7e] and amidation[4l,8a] were also readily achieved by
treating the lithium reagents 5a, 5c, and 5d with DMF, CO2,
and PhNCO, respectively (Table 2).
80
4:96
5
PhNCO
PhNCO
syn-5d (98:2)
80
92:8
6
anti-5d (8:92)
[a] Yield of isolated product in %. [b] d.r. (syn/anti ratio) determined by 13C NMR
spectroscopy.
epimerization kinetics of the lithium compounds syn-5a and
*
^
anti-5a under standard conditions at À1008C ( , ) and
~
&
À908C ( , ) as shown (Scheme 4b) by retentive quenching
with Me2S2 after different times. The plot of the epimerization
percentage for syn-5a versus time resulted in monoexponen-
tial decays, showing that the epimerizations proceed by first-
order reversible reactions. The rate constants for the epime-
We have shown recently that the cis-4-tert-butylcyclo-
hexyllithium reagent cis-(ax)-20 epimerizes very rapidly at
À1008C (Scheme 4a).[8a,20] In this context we examined the
&
rization of syn-5a and anti-5a at À908C ( ) were calculated
from Equation (1).[21] The slopes of the resulting straight lines
provided the value of (k1 + kÀ1) and the individual rate
constants k1 and kÀ1 were readily determined from the
equilibrium concentrations at t = 7 h, when the equilibrium
syn/anti = 60:40 was reached (kÀ1/k1 = 1.5). We found that at
À908C the rate constants k1 and kÀ1 for the epimerization of
syn-5a and anti-5a were equal to 1.28 ꢀ 10À4 sÀ1 and 1.92 ꢀ
10À4 sÀ1, respectively. The Gibbs free energy DG8
(0.62 kJmolÀ1 at À908C) indicated that syn-5a and anti-5a
have almost the same configurational stability.[8a] Interest-
ingly, epimerization of syn-5a at À1008C was much slower
than that of cis-(ax)-20 (1,3-diaxial interactions may destabi-
lize this lithium reagent),[8a] explaining the higher configura-
tional stability of these acyclic secondary alkyllithium
reagents. In the case of syn-5a, even after 1 h at À1008C,
the syn/anti ratio was still remaining high (92:8), confirming
the experimental observation that the iodides 1a–d can be
Scheme 3. Stereoselective preparation of syn and anti acyclic secondary
alkyl iodides 1a (d.r. =syn/anti ratio).
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Received: October 5, 2013
Published online: December 20, 2013
Keywords: acylation · diastereoselectivity · kinetics · lithiation ·
.
nucleophilic substiution
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Scheme 4. Kinetic investigation of the equilibration between syn-5a
and anti-5a at À1008C and À908C and determination of the Gibbs
free energy DG8 of this equilibrium.
added dropwise within 10 min to the solution of tBuLi
without any significant loss of diastereoselectivity.
In summary, we have developed the first practical
preparation of stereodefined acyclic secondary alkyllithium
reagents from their corresponding secondary alkyl iodides.
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