Single or Synergistic Kinetic Resolutions of Chiral Allylalanes: Two Complementary Routes for the Asymmetric Synthesis of Syn Homoallylamines

Article abstract of DOI:10.1021/acs.orglett.7b03455

Two strategies based on kinetic resolution(s) of chiral alanes and providing enantioenriched syn homoallylamines are reported. The first implies a single kinetic resolution of the alane using camphor; the second requires two sequential kinetic resolutions using the synergistic combination of (-)-camphor/(R)-tert-butylsulfinamide-derived imines. This syn selectivity, specific to the use of allyaluminum, opens the way to the preparation of valuable building blocks as illustrated by the synthesis of (+)-epilupinamine.

Full text of DOI:10.1021/acs.orglett.7b03455

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. 2017, 19, 6728−6731
Single or Synergistic Kinetic Resolutions of Chiral Allylalanes: Two
Complementary Routes for the Asymmetric Synthesis of Syn
Homoallylamines
Michael Coffinet, Jean-Bernard Behr, Florian Jaroschik, Dominique Harakat, and Jean-Luc Vasse*
̈
Institut de Chimie Molec
́
ulaire, CNRS (UMR 7312) and Universite
́
de Reims, Reims 51687 Cedex 2, France
S
* Supporting Information
ABSTRACT: Two strategies based on kinetic resolution(s) of
chiral alanes and providing enantioenriched syn homoallyl-
amines are reported. The first implies a single kinetic
resolution of the alane using camphor; the second requires
two sequential kinetic resolutions using the synergistic
combination of (−)-camphor/(R)-tert-butylsulfinamide-de-
rived imines. This syn selectivity, specific to the use of
allyaluminum, opens the way to the preparation of valuable
building blocks as illustrated by the synthesis of (+)-epilupin-
amine.
ecause of the omnipresence of nitrogen-containing chiral
of competitively binding to Al might modify the syn/anti
Bfragments in the structures of naturally occurring and diastereoselection when using allylaluminum.
Chiral allylsilanes,8 allylborons,9 and allylaluminums are
biologically active molecules, alternative methods for the
asymmetric preparation of amines is of constant interest. In
this context, methodologies providing an unusual stereoselectivity
constitute a key opportunity for stereodiversity in bioactive
molecule design.
Among powerful asymmetric C−C bond-forming reactions
providing enantioenriched amines, the allylmetalation of
nonracemic imines emerges as one of the more stereoselective
approaches.1 In particular, reactions involving linear substituted
allylmetals are known to induce a high level of diastereose-
lectivity, allowing the simultaneous control of the two newly
created stereogenic centers.2 Interestingly, depending on the
reaction conditions, a reversal of syn/anti selectivity is
achievable as observed with indium-mediated crotylation of
imines.3 The same phenomenon was also observed by
modulating the N-side chain of the imine using allylsilane
derived from ephedrine as the nucleophile.4
In contrast, the addition of chiral allylmetals included in a
cyclic structure to CN electrophiles is much less exploited. In
2008, Reddy and co-workers reported the highly anti-selective
addition of cyclohexenylzinc to Ellman’s imine.5 In this context,
it remains challenging to develop a nonracemic method
involving a cyclohexenylmetal that enables access to the syn
diastereomeric form of such homoallylamines.
Among imine/allylmetal combinations that provide high
levels of diastereoselectivity, those involving a rigidifying bis-
coordination of the electrophilic species to the metal are
emerging, particularly in the Zn6 and In7,3 series.
configurationally stable and must (i) be generated enantiose-
lectively or (ii) react under kinetic resolution conditions. In
contrast, allylzincs are paradigmatic examples of configuration-
ally mutable allylmetals for which a dynamic kinetic resolution
can operate.5
Recently, we described the efficient (+)-camphor-mediated
kinetic resolution of cyclohexen-1-ylalane10 generated via
titanium-catalyzed hydroalumination of cyclohexadiene.11 By
applying this protocol, the allylalane is in situ available in the
enantiomerically enriched form and can next react with
aldehydes to afford homoallylic alcohols in a highly
enantioselective manner.
Thus, the asymmetric access to syn homoallylic amines was
envisioned by employing alanes, resolved with camphor,
together with imines bearing an electron-withdrawing group
able to concomitantly bind to Al and lower the ability of the
imine function to coordinate to Al (Figure 1).
In this paper, we disclose the syn-selective coupling of
diphenylphosphinamide or tert-butylsulfinamide-derived imines
with enantioenriched cycloalkenylalanes, in situ available after
camphor-mediated kinetic resolution, which gives access to
homoallylamines with a high level of asymmetric induction.
To identify an activating group able to significantly induce a
syn-selectivity, our investigations began by reacting allylalane,
generated by titanium-catalyzed hydroalumination of diene,
with a series of imines derived from benzaldehyde (Table 1).
At first, N-Ts imine was efficiently converted into the
corresponding homoallylamine, however, as a mixture of
Considering that the coordination mode of allylalane to
imine may differ from those of allylzinc or indium,
(monocoordination for Al vs bis-coordination for Zn and In),
it is conceivable that the adjonction of a functional group able
Received: November 7, 2017
Published: December 6, 2017
© 2017 American Chemical Society
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Org. Lett. 2017, 19, 6728−6731

Organic Letters
Letter
From cyclopentenylalane, the amount of anti isomer is no
longer negligible using tert-butylsulfinamide (entry 10).
However, whereas the same tendency regardless to recognition
was observed when using rac-tert-butylsulfinamide imine, a
more pronounced kinetic resolution could be deduced using
enantiopure tert-butylsulfinamide imine (entry 10 vs entry 7),
according to the dr observed within the couple of syn isomer
which is now substantial (e.g., dr syn = 77:23). Here again,
increasing the amount of allylalanes, with respect to the
sulfinamide, improved significantly the syn/anti ratio and
slightly the dr within the syn adducts (entry 11). At this
stage, it may be postulated that in the presence of tert-
butylsulfinamide-derived imines the two enantiomeric forms of
the alanes compete to react with the imine, but through a
different mechanistic pattern owing to the different diaster-
eoselectivity outcome.
Unequivocally related to the N-substituent of the imine, the
syn/anti diastereoselection is assumed to originate from the
coordination mode to Al.
Figure 1. Context of the study.
While the anti selectivity observed with N-alkylimine (dr
anti/syn 20:1)10 could be rationalized by a typical Traxler−
Zimmerman transition state, the syn-selectivity observed here
with either sulfinamide- and phosphinamide-derived imines
may decline from a different arrangement of the two partners
(Figure 1). In the case of sulfinamide-derived imines, 2 equiv of
alane is required for the reaction to proceed, one being
presumably bonded to the chiral auxiliary and the second acting
as the nucleophilic species. In contrast, stoichiometric
conditions gave satisfactory conversion with phosphorus
derivatives. In this context, several transition states could be
postulated, among them a pseudo-chair-like transition state
(cyclic transition state) in which the substituents of the imine
would adopt an equatorial position, a consequence of the
aluminum coordination to the PO. Alternatively, an
antiperiplanar organization of the two partners could also be
taken into account. In these models, a Lewis acid activation
may be considered in the cases of sulfinamide- and eventually
diphenylphosphinamide-derived imines (Figure 2).
Table 1. Influence of the Imine Structure upon the Syn/Anti
Selectivity
a
b
entry
n
PG
x
yield (%)
syn/anti
1
6
6
5
6
5
6
6
6
5
5
5
Ts
0.9
1 (75)
2.5:1
>20:1
5.7:1
>20:1
19:1
2
PO(OEt)2
0.9
2 (88)
3
PO(OEt)2
0.9
3 (74)
4
POPh2
0.66
0.66
0.5
4a (80)
5 (53)
5
POPh2
6
( )-S(O)-tBu
(R)-S(O)-tBu
(R)-S(O)-tBu
( )-S(O)-tBu
(R)-S(O)-tBu
(R)-S(O)-tBu
6a (86)
6a (80)
6a (82)
7a (68)
7a (64)
7a (71)
>20 (87:13):1
>20 (54:46):1
>20 (65:35):1
9.5 (87:13):1
4.8 (77:23):1
7
0.5
8
0.33
0.5
9
10
11
0.5
0.33
15 (83:17):1
a
b
1
Isolated yield of combined isomers. Determined by. H NMR
analysis of the crude reaction mixture.
isomers (entry 1). Phosphoramidate-derived imine was next
tested, providing the amine in high yield; however, while the
syn isomer was mainly obtained using cyclohexenylalane, the
diastereoselectivity remains moderate with cyclopentylalane
(entries 2 and 3). In contrast, despite the use of 1.5 equiv of
alane for achieving a complete conversion, high syn-selectivities
were observed in both cases when diphenylphosphinamide-
derived imine was employed (entries 4 and 5). In the typical
case of tert-butylsulfinamide, several aspects have to be
underlined. First, 2 equiv of alane was required for the reaction
to reach completion, one being presumably coordinated to the
auxiliary, possibly acting as a Lewis acid. Second, a different
behavior was observed between cyclohexenylalane and cyclo-
pentenylalane.
From cyclohexenylalane, the syn isomer was predominant
using rac-tert-butylsulfinamide (entry 6). An intimate enantio-
meric recognition seems to operate between the two chiral
partners. Indeed, a diastereomeric ratio of 87:13 within a couple
of syn isomers was observed, and dropped as could be expected,
when an enantiopure imine was used (entry 7). Eventually, a
beneficial kinetic discrimination can be achieved using a default
of enantiopure imine (entry 8).
Figure 2. Possible simplified transition states accounting for the syn
selectivity.
Since the reaction between ( )-cyclohexenylalane and (R)-
sulfinamide is not driven by a kinetic resolution process, under
the present reaction conditions, it was therefore imperative to
produce the alane in the enantiomerically enriched form to
envision an asymmetric version of the reaction.
Thus, we decided to apply the camphor-mediated resolution
of cyclohexenylalane to a series of imines containing an N−P
O moiety. Benzaldehyde-derived phosphoramidate imine was
first attempted, affording the corresponding homoallylic amine
in moderate yield and enantioselectivity (Table 2, entry 1).
Diphenylphosphinamide-derived imines were next tested.
While the i-Pr imine appears to be unsuitable and led to the
corresponding enamine as the major product (entry 7),
homoallylic amines containing an aryl (entry 2), a heteroaryl
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Organic Letters
Letter
enriched sample of the alane together with the fitting
enantiomer of the imine.
Table 2. Synthesis of Homoallylamines from Cyclohexadiene
Both enantiomeric forms of camphor being available, two
batches of racemic cyclopent-1-enylalane were separately
resolved with each enantiomer and then allowed to react with
the imine derived from (R)-tert-butylsulfinamide and benzalde-
hyde. While the corresponding homoallylamine was obtained in
the nearly pure isomeric form starting from (−)-camphor, a
moderate conversion was observed when (+)-camphor was
used (Table 3, entries 1 and 2). A series of imines derived from
Table 3. Synthesis of Homoallylic Amines 7a−i
a
b
b
entry
R
yield (%) syn/anti
dr syn
c
d
1
Ph
7a (40)
7a (79)
37:63
nd
e
2
Ph
94:6
90:10
96:4
>95:5
96:4
3
4-MeOC6H4
4-CNC6H4
2-furyl
7b (57)
7c (57)
7d (86)
7e (56)
7f (60)
7g (50)
7h (53)
7i (52)
7j (43)
a
b
1
Isolated yield of combined isomers. Calculated from. H NMR of
c
d
4
95:5
the crude product. Measured by chiral HPLC. (+)-Camphor was
used. NMR yield.
e
5
>95:5
94:6
95:5
6
(E)-Ph-CHCCH3
>95:5
>95:5
>95:5
>95:5
97:3
7
n-C4H9
90:10
93:7
8
i-Pr
(entries 3 and 4), a vinyl (entry 5), or a linear alkyl (entry 6)
fragment could be obtained in good yield and ee’s in the range
93−99%. Pleasantly, far better enantioselectivities were
observed here compared to those previously obtained with
aldehydes.10
Sulfinamide-derived imines could be employed as an
alternative for sensitive imines. (R)-Configured imines were
shown to provide a better syn selectivity when (−)-camphor
was used as the chiral selector (entry 8 vs entry 9). In these
conditions, i-Pr imine and glycosylamine derived from 5-deoxy-
D-ribose were stereoselectively converted into the correspond-
ing amines (entries 10 and 11).
The absolute configurations of adducts 4a and 6a were
determined by chemical correlation with known compounds
(for details, see the Supporting Information).The absolute
configurations of all other compounds were assigned by
analogy.
Starting from an allylalane generated in 93:7 er, as it may be
deduced from the constant er obtained for aldehydes,10 the
higher enantioselectivity obtained for phosphinamides 4 may
result from an amplification process. It may be tentatively
postulated that the product cooperates to its own formation by
autocatalysis that benefits to the enantioselelectivity of the
global reaction. In contrast, for some elusive reasons, when
phosphoramidate was used as the substrate, the reactivity and
enantioselectivity were both altered (entry 1, Table 2). In this
particular case, a concomitant drop of the syn/anti selectivity of
the isoborneol derivative, coproduct of the resolution, was also
observed, possibly arising from detrimental reversible processes.
We have previously noticed that the camphor-mediated
kinetic resolution of cyclopent-2-en-1-ylalane is less efficient, in
comparison with its 6-membered analogue.10 Applied to the
allylation of aldehydes, moderate enantioselectivities were
therefore observed (e.g., er = 74:26).10 Nevertheless, since
nonracemic sulfinamide-derived imines are prone to induce
kinetic resolution (Table 1, entries 13 and 14), a synergistic
effect could be envisioned by using an enantiomerically
9
BnO(CH2)4
88:12
93:7
10
11
Br-(CH2)4
1,2,3,4-tetrahydronaphthalen-1-yl
>95:5
>95:5
a
b
Isolated yield of combined isomers. Calculated from 1H NMR of the
c
d
e
crude product. (+)-Camphor was used. NMR yield. The
configuration of the major isomer 7a was assigned after chemical
transformation (see SI); the configurations of compound 7b−j were
deduced by analogy.
(R)-tert-butylsulfonamide was next tested using (−)-camphor
as the chiral selector. Thus, homoallylic amines incorporating
an aryl fragment (entries 1−4), a heteroaryl (entry 5), a vinyl
(entry 6) or an alkyl fragment (entries 7−10) could be
prepared in the isomerically enriched form in moderate to good
yield. Investigations toward ketimes were initiated by using the
imine derived from α-tetralone. In that case the corresponding
amine was obtained as a single isomer in moderate yield (entry
11).
The generally high level of stereoselectivity observed with
this set of (R)-tert-butylsulfonamide-derived imines reflects an
enantiomeric recognition within the two reagents. In this
context, while the camphor-mediated resolution is not optimal
at the first stage, it allows to significantly enrich the reaction
media in one enantiomeric form of the alane. The addition of
the complementary enantiomeric form of tert-butylsulfinamide
derived imines benefits to the stereoselectivity of the whole
process through a second biased kinetic resolution.
The synthetic potential of the methodology was illustrated by
the synthesis of (+)-epilupinamine.12 At first, piperidine 8 was
obtained from 7i by methanolysis under acidic conditions
followed by a basic workup.13 Cbz-protection and separation of
syn/anti diasteoisomers by column chromatography were next
achieved. The pure fraction of the syn isomer underwent a
sequential OsO4-catalyzed oxidative cleavage of the CC
double bond/NaBH4-mediated reduction14 to afford diol 9,
which was converted into the corresponding bis-mesylate.
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Organic Letters
Letter
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Additional hydrogenolysis selectively afforded the quinolizine
16
10.15 Finally, displacement of the mesylate with NaN3
followed by LAH-mediated reduction of the azide17 gave the
expected (+)-epilupinamine 11 (Scheme 1).
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In summary, a syn-selective asymmetric access to homoallylic
amines involving racemic cyclohexen- and cyclopenten-1-
ylalane based on a camphor-mediated kinetic resolution is
presented. This approach makes the cyclohexen-1-ylalane in
situ available in a highly enantioenriched form, allowing the
coupling with prochiral imine. In contrast, cyclopenten-1-
ylalane is less efficiently resolved. However, the use of
cooperatively configurated tert-butylsulfinamide-derived imine
afforded the homoallylic amine with high diastereoselectivity by
means of a second matching kinetic resolution. These two
complementary approaches allow access to synthetically useful
building blocks as illustrated by the synthesis of (+)-epilupin-
amine.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03455.
■
Kabalka, G. W.; Soderquist, J. A. Org. Lett. 2015, 17, 4368. (b) Brown,
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2010, 132, 1226.
(10) Coffinet, M.; Massicot, F.; Joseph, J.; Behr, J.-B.; Jaroschik, F.;
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Chem. 2016, 14, 69.
S
1
Experimental procedures, characterization, and H and
13C NMR spectra of all new compounds (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jean-luc.vasse@univ-reims.fr.
ORCID
Florian Jaroschik: 0000-0003-0201-568X
Jean-Luc Vasse: 0000-0003-0802-1095
Notes
The authors declare no competing financial interest.
(15) For similar selective cyclization, see: (a) Kondekar, N. B.;
Kumar, P. Synthesis 2010, 2010, 3105. (b) Huy, P. H.; Koskinen, A. M.
ACKNOWLEDGMENTS
We thank MNRT and CNRS for financial support and Anthony
Robert (ICMR-UMR7312) for technical assistance.
■
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