Diastereodivergent synthesis of enantiomerically pure homoallylic amine derivatives containing quaternary carbon stereocenters

Article abstract of DOI:10.1002/anie.200702981

Freedom of choice: Both enantiomers of free homoallylic amines with two stereogenic centers (including a quaternary center) can be prepared at will from vinyl copper intermediates derived from either a vinyl iodide or an alkyne (see examples; the sulfinyl group is cleaved readily under mild acidic conditions). In this one-pot strategy, zinc homologation of the vinyl copper species is followed by treatment with a sulfinylimine derivative. (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200702981

Angewandte
Chemie
DOI: 10.1002/anie.200702981
Asymmetric Synthesis
Diastereodivergent Synthesis of Enantiomerically Pure Homoallylic
Amine Derivatives Containing Quaternary Carbon Stereocenters**
Goren Kolodney, Genia Sklute, Sylvie Perrone, Paul Knochel, and Ilan Marek*
Dedicated to Professor Miguel Yus on the occasion of his 60th birthday
The design of new methods for the enantioselective con-
struction of all-carbon quaternary stereogenic centers in
acyclic systems is still a critical and challenging objective in
modern chemistry.[1] Currently, the most-successful methods
are asymmetric copper-catalyzed conjugate addition,[2] asym-
metric Michael reactions,[3] asymmetric sigmatropic rear-
rangements,[4] and asymmetric electrophilic[5] and nucleo-
philic[6] allylic alkylation. However, the enantioselective
formation of such all-carbon quaternary stereogenic centers
by attack at the g carbon atom of nucleophilic allylic
substrates (that is, the reaction of 3,3-disubstituted allyl
metal species with electrophiles) is much less frequent.[7] In
this context, we reported an efficient multicomponent reac-
tion for the diastereoselective formation of quaternary
centers (Scheme 1).[8]
zinc homologation (introduction of the CH2 unit of the allyl
zinc fragment),[9] and intramolecular chelation of the zinc
atom by the sulfoxide, which results in the very high
diastereoselectivity observed in the reaction of the allyl zinc
reagent with various aldehydes.[8] The presence of the
sulfoxide is essential to slow down the equilibration process
of the allylic organometallic species 1 (through intramolec-
ular chelation to the zinc atom) but also as a source of
chirality and as a regiocontrol element for the carbometala-
tion reaction. When the same reaction was performed with
the nonfunctionalized 1-hexyne 2, the expected homoallylic
alcohol 3 was obtained in good yield but as a 1:1 mixture of
two diastereoisomers (Scheme 2). In such cases, the homo-
The key features of this reaction are the high degree of
stereoselectivity and predictability, and the ease of execution.
The reaction requires the in situ combination of a stereose-
lective carbometalation (introduction of the R2 substituent), a
Scheme 2. Nonstereoselective approach to the carbonyl allylation
reaction.
logation reaction of the vinyl copper species with the zinc
carbenoid leads to an allyl zinc species, such as 4, which is not
configurationally stable,[10] and the two geometrical isomers
that result from its metallotropic equilibrium react with the
aldehyde.
Scheme 1. Multicomponent approach to the creation of stereogenic
quaternary carbon centers in allylation reactions at carbonyl groups.
Tol =p-tolyl.
To further extend our new approach to the creation of all-
carbon quaternary stereocenters, we were interested in
finding an alternative method, not based on intramolecular
chelation of the substrate but rather on intermolecular
chelation by an external ligand, to slow down the metal-
lotropic equilibrium. We chose to focus on enantiomerically
pure R-configured Ellman N-(tert-butylsulfinyl)imines 5 as
chiral ligands.[11] We were interested in the potential of
sulfinylimines, which can be used as chiral nitrogen-contain-
ing intermediates for the preparation of a wide range of chiral
amines, for the intermolecular stabilization of the allyl zinc
species.[12]
[*] G. Kolodney, Dr. G. Sklute, Prof. I. Marek
The Mallat Family Laboratory of Organic Chemistry
Schulich Faculty of Chemistry and
The Lise Meitner–Minerva Center for Computational Quantum
Chemistry
Technion—Israel Institute of Technology
Haifa 32000 (Israel)
Fax: (972)4-829-3709
E-mail: chilanm@tx.technion.ac.il
Dr. S. Perrone, Prof. P. Knochel
Department Chemie und Biochemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, München 81377 (Germany)
In our first approach (Scheme 3), the disubstituted vinyl
iodides 6a–c, which were prepared readily by the carbocup-
ration of 1-octyne,[13] were treated with tBuLi in THF at
ꢀ788C followed by CuI (1 equiv). The corresponding vinyl
[**] This research was supported by a grant from the German–Israeli
Foundation for Scientific Research and Development (GIF). I.M. is
holder of the Sir Michael and Lady Sobell Academic Chair.
Angew. Chem. Int. Ed. 2007, 46, 9291 –9294
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9291
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Communications
element. In many cases, the preassociation of a metal
with polar functional groups in the vicinity of the
reaction center has been reported to influence the
stereochemical outcome of the process and even to lead
to the opposite stereochemical outcome to that
expected in the absence of such an interaction.[17] As
=
the S O bond can act as an acceptor site for Lewis
acids,[18] the conformation of the sulfinylimine moiety in
the transition state could be influenced by intramolec-
ular chelation[19] with metal salts.[20]
Scheme 3. Preparation of homoallylic amine derivatives from vinyl iodides. For
the substituents see Table 1.
Under this assumption, we performed the reaction
in the presence of MgX2. Although MgX2 could be
added to the vinyl copper species 7a–c, direct carbocupration
of the alkyne with RCu/MgBr2 (readily prepared from
1 equivalent each of the alkyl magnesium halide and CuI)[13]
was a more attractive and efficient route (Scheme 4). Et2Zn,
copper derivatives 7a–c were formed at ꢀ308C and treated
with diethylzinc, diiodomethane, and various sulfinylimines.
The vinyl copper reagent underwent an homologation
reaction with the zinc carbenoid[14] formed in situ from
diethylzinc and diiodomethane to give the allyl zinc species,[9]
which reacted diastereoselectively with the N-(tert-butylsulfi-
nyl)imines 5a–d to give the expected homoallylic sulfinyl-
amines 8a–f with very high diastereoselectivities and in good
overall yields (Table 1).
Table 1: Stereoselectivity of the allylation reaction starting from vinyl
iodides.
Entry
R1
R2
8
d.r.[a]
Yield [%][b]
1
2
3
4
5
6
Et (6a)
Me (6b)
iPr (6c)
Et (6a)
Et (6a)
Et (6a)
Ph (5a)
Ph (5a)
Ph (5a)
p-BrC6H4 (5b)
p-AcC6H4 (5c)
8a
8b
8c
8d
8e
8 f
>98:2
>98:2
>98:2
>98:2
>98:2
95:5
85
65
87
81
77
75
Scheme 4. Preparation of homoallylic amine derivatives from alkynes.
For the substituents see Table 2.
=
PhCH CH (5d)
[a] The diastereomeric ratio was determined by 1H and 13C NMR
spectroscopy of the crude product. [b] The yield was determined after
purification by chromatography on silica gel.
CH2I2, and an R-configured N-(tert-butylsulfinyl)imine were
then added to the vinyl copper reagent 7 at ꢀ308C, and the
corresponding homoallylic amines 10 were obtained within a
few hours with excellent diastereoselectivity (Table 2).[21]
The stereochemical course of this one-pot reaction was
confirmed by X-ray analysis of 8d, and the configurations of
the other products were assigned by analogy. Sulfinylimines
Table 2: Stereoselectivity of the allylation reaction starting from alkynes.
=
usually prefer to adopt a conformation in which the S O bond
Entry
R
R1
R2
10
d.r. [%][a] Yield [%][b]
and the lone pair of electrons on the nitrogen atom are
1
2
3
4
5
6
Hex (9a) Et
Hex (9a) Et
Hex (9a) Et
Hex (9a) iPr
Hex (9a) Bu
p-BrC6H4 (5b) 10a >98:2
p-AcC6H4 (5c) 10b >98:2
Bu (5e)
75
67
67
62
70
60
*
antiperiplanar, mainly as a result of a significant nN!SS¼O
negative hyperconjugation interaction.[15] As such an inter-
action has a high rotational barrier (41.3 kJmolꢀ1), the
conformation of the sulfinylimine is conserved. The formation
of the homoallylic products can be rationalized by a close
transition state in which the substituent of the sulfinylinime
occupies a pseudoaxial position (see Scheme 3).[16]
10c >98:2
p-BrC6H4 (5b) 10d >98:2
p-BrC6H4 (5b) 10e
Hex p-BrC6H4 (5b) 10 f
97:3
96:4
Bu (9b)
[a] The diastereomeric ratio was determined by 1H and 13C NMR
spectroscopy of the crude product. [b] The yield was determined after
purification by chromatography on silica gel.
The alkyl group R1 of the vinyl iodide 6 can be primary
(Table 1, entries 1,2, and 4–6) or secondary (even though it
occupies a pseudoaxial position in the chairlike transition
state; see Table 1, entry 3 and Scheme 3). The reaction could
be carried out with aromatic (Table 1, entries 1–3), function-
alized aromatic (Table 1, entries 4 and 5), and conjugated
sulfinylimines 5 (Table 1, entry 6). Only the use of aliphatic
sulfinylimines leads to a poor diastereoisomeric ratio (d.r.
70:30; results not reported in Table 1).
To our delight, amines 10 formed by this procedure were
the opposite diastereoisomers to amines 8 obtained from
vinyl iodides by the procedure illustrated in Scheme 3. This
discrepancy can be rationalized by a cyclic transition state
with MgX2 coordinated to the oxygen atom of the sulfinyl
group and to the zinc atom (as opposed to the antiperiplanar
=
Nonbonding interactions contributed by substrate sub-
stituents may provide the dominant stereochemical control
arrangement described in Scheme 3 with respect to the S O
bond and the lone pair of electrons on the nitrogen atom).
9292 www.angewandte.org
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Angew. Chem. Int. Ed. 2007, 46, 9291 –9294
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Angewandte
Chemie
workup, the crude product was purified on silica gel to give the pure
homoallylic sulfinylamine 8.
Presumably, the high level of preorganization contributes to
the very high selectivity for attack opposite to the large tBu
group. The scope of the reaction is broad, as excellent
diastereoselectivities were observed with both functionalized
aromatic sulfinylimines (Table 2, entries 1, 2, and 4–6) and
aliphatic sulfinylimines (Table 2, entry 3). By exchanging the
alkyl groups on the alkyne and the organocopper reagent it is
possible to prepare independently both isomers of a given
homoallylic amine with respect to the configuration at the
quaternary carbon center (Table 2, entry 5 versus entry 6).
Finally, the sulfinyl group can be cleaved readily under
mild acidic conditions to provide in quantitative yield the free
amine derivatives 11 as acyclic systems with an all-carbon
quaternary stereogenic center (Scheme 5).
General procedure (from alkynes): A solution of R1MgBr
(1.8 mmol) in Et2O was added to a suspension of CuI (344.7 mg,
1.8 mmol) in Et2O (12 mL) at ꢀ308C, and the resulting mixture was
stirred at this temperature for 30 min. The alkyne (1 mmol) was then
added, and the reaction mixture was warmed slowly to ꢀ258C. Upon
the completion of the carbocupration reaction, which was monitored
by GC and generally complete within 4 h, the reaction mixture was
cooled to ꢀ308C. CH2I2 (6 mmol), a solution of the sulfinylimine
(1.3 mmol) in THF (2 mL), and Et2Zn (3 mmol) were added, and the
mixture was stirred for an additional 6 h at ꢀ308C, then hydrolyzed
with a basic aqueous NH4Cl/NH3 (2:1) solution. After a standard
workup, the crude product was purified on silica gel to give the pure
homoallylic sulfinylamine 10.
Received: July 4, 2007
Published online: September 24,
2007
Keywords: asymmetric
.
synthesis · carbometalation ·
homoallylic amines ·
homologation · sulfinylimines
[1] a) J. Christoffers, A. Baro in
Quaternary
Stereocenters:
Challenges and Solutions for
Organic Synthesis, Wiley-
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Corey, A. Guzman-Perez,
Scheme 5. Cleavage of the sulfinyl group to give free homoallylic amines containing enantiomerically
pure quaternary stereogenic centers.
In conclusion, free homoallylic amines 11 containing
Angew. Chem. 1998, 110, 402; Angew. Chem. Int. Ed. 1998, 37,
388.
quaternary carbon centers can be prepared readily by a
strategy involving zinc homologation of a vinyl copper species
followed by treatment in situ with various sulfinylimine
derivatives. Both enantiomers can be obtained at will from
common vinyl copper intermediates formed from either a
vinyl iodide or an alkyne. This spectacular enantiofacial
discrimination is due to the presence of different metal salts
(MgX2 or LiI). Moreover, permutation of the alkyl groups of
the alkyne and the organocopper reagent enables the
independent synthesis of two diastereomers with the opposite
configuration at the quaternary carbon center.
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Experimental Section
General procedure (from vinyl iodides): tBuLi (2.2 equiv, 2.2 mmol)
was added to a solution of the vinyl iodide 6 (1 mmol) in THF (5 mL)
at ꢀ808C, and the resulting mixture was stirred at this temperature
for 10 min. The reaction mixture was then warmed to ꢀ308C, CuI
(1.2 equiv, 1.2 mmol) was added, and the mixture was stirred for
additional 30 min. CH2I2 (6 mmol), a solution of the sulfinylimine 5
(1.3 mmol) in THF (2 mL), and Et2Zn (3 mmol) were added, and the
reaction mixture was stirred at ꢀ308C for 6–12 h, then hydrolyzed
with an basic aqueous NH4Cl/NH3 (2:1) solution. After a standard
Angew. Chem. Int. Ed. 2007, 46, 9291 –9294
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Communications
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[12] Alternatively, it may be considered that the reaction of the allyl
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aldehyde but faster than the metallotropic equilibrium.
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variable amounts in the carbocupration reaction.
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