Remote Stereoinduction in the Organocuprate-Mediated Allylic Alkylation of Allylic gem-Dichlorides: Highly Diastereoselective Synthesis of (Z)-Chloroalkene Dipeptide Isosteres

Article abstract of DOI:10.1021/acs.orglett.5b00611

Highly diastereoselective synthesis of (Z)-chloroalkene dipeptide isosteres has been achieved by 1,4-asymmetric induction in the organocuprate-mediated allylic alkylation adjacent to the chiral center of allylic gem-dichlorides. The reaction proceeds with

Full text of DOI:10.1021/acs.orglett.5b00611

Letter
pubs.acs.org/OrgLett
Remote Stereoinduction in the Organocuprate-Mediated Allylic
Alkylation of Allylic gem-Dichlorides: Highly Diastereoselective
Synthesis of (Z)‑Chloroalkene Dipeptide Isosteres
Takuya Kobayakawa,† Tetsuo Narumi,*,†,‡ and Hirokazu Tamamura*,†
†Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan
‡Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, Hamamatsu, Shizuoka,
432-8561, Japan
S
* Supporting Information
ABSTRACT: Highly diastereoselective synthesis of (Z)-chlor-
oalkene dipeptide isosteres has been achieved by 1,4-asymmetric
induction in the organocuprate-mediated allylic alkylation
adjacent to the chiral center of allylic gem-dichlorides. The
reaction proceeds with a variety of heterocuprates prepared from
CuCN and various organometallic reagents. It allows rapid
construction of valuable architectures of L,D-type and L,L-type (Z)-
chloroalkene dipeptide isosteres from the corresponding (E)- and (Z)-allylic gem-dichlorides in high yields, with excellent (Z)-
selectivity and diastereoselectivity.
Scheme 1. Allylic Substitution Reaction with Organocopper
Reagents
he discovery of novel synthetic methods for stereoselective
formation of structurally complex organic molecules with
T
high levels of efficiency and selectivity remains a challenge in
organic synthesis. Asymmetric inductions by preexisting stereo-
genic centers provide reliable methods for the facile construction
of synthetically valuable building blocks bearing multiple chiral
centers1 and remote asymmetric inductions such as 1,4-,2 1,5-,3
and 1,6-stereorelationships4 are of particular interest because of
the synthetic utility that can provide potentially intriguing
synthetic strategies to complex molecules.2c,3e,f,4a,b
Our group has focused on the synthetic and application studies
of chloroalkenes, which are synthetically versatile intermediates5
and structural constituents of marine natural products.6 Recently,
we have identified 1,4-asymmetric induction in the allylic
alkylation of allylic gem-dichlorides adjacent to the chiral center,
which can provide facile access to trisubstituted (Z)-
chloroalkenes flanking two stereogenic centers with moderate
diastereoselectivity.7 While the allylic substitution reaction with
an organocopper reagent takes place stereospecifically on the
anti-face to the leaving group of allylic electrophiles (anti-SN2′
manner, Scheme 1a),8 the stereoselective reaction of allylic gem-
dichlorides is particularly challenging since allylic gem-
dichlorides have two electronically and sterically equivalent
leaving groups that impose severe limitations on the anti-SN2′
strategy and depend on the stereochemistry of the leaving group
(Scheme 1b). Our observed moderate diastereoselectivity in the
allylic alkylation of allylic gem-dichlorides has been achieved by
means of the induction exerted by the chiral center at C5 bearing
noncoordinating phenyl and siloxy groups. These results suggest
the possibility that the introduction of a coordinating group such
as a sulfonamide9 at C5 could control the facial attack of allylic
electrophiles to provide the trisubstituted (Z)-chloroalkene
flanking two stereogenic centers bearing the amino functionality.
These motifs are highly attractive for the peptidomimetics having
a functionalized alkene as a peptide bond surrogate (alkene-type
dipeptide isosteres: ADIs), which have been thought of as one of
the most ideal dipeptide mimetics for the study of medicinal
chemistry and chemical biology.10 In this paper, we wish to
report the first highly diastereoselective 1,4-asymmetric
induction in the allylic alkylation of allylic gem-dichlorides
utilizing various organocuprates to afford (Z)-chloroalkene
Received: February 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00611
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dipeptide isosteres (CADIs) in high yields and with excellent
(Z)-selectivity and diastereoselectivity (Scheme 1c). Impor-
tantly, this method provides an efficient access to synthesis of
both L,L-type and L,D-type (Z)-CADIs by simply switching the
olefin geometry of the allylic gem-dichlorides.
Our study began with the preparation of the key intermediate,
(2E)-γ,γ-dichloro-α,β-enoate (E)-6, with the chiral center at C5
bearing a sulfonamide group. In seeking to develop an effective
approach, we employed for the protection of amine functionality
an N-tert-butylsulfonyl (Bus) group11 that would be tolerated in
the multistep synthesis and that can be easily prepared by
oxidation of an N-sulfinyl group11 and removed by treatment
with AlCl3.12 As shown in Scheme 2, nucleophilic addition of the
Table 1. Reactivity of (E)-6 with Organocuprates
additive
(equiv)
7a or 8
c
b
b
entry
1
reagents
7a:8
1:>20
yield (%)
dr , 7a
Me2CuLi·LiI·
2LiBr
8, 97
d
2
3
4
5
6
MeCu(CN)
13:1
7a, 90
7a, 99
7a, 91
7a, 91
7a, 84
7a, 86%
7a, 88%
7a, 85%
>20:1
Li·LiBr
d
MeCu(CN)
Li·LiBr
MeCu(CN)
Li·LiBr
MeCu(CN)
Li·LiBr
MeCu(CN)
MgBr
LiCl (4)
>20:1
16:1
>20:1
d
LiCl (8)
>20:1
d
LiCl (4), BF3·
OEt2 (4)
19:1
>20:1
Scheme 2. Preparation of (E)-6
d
LiCl (4)
LiCl (8)
LiCl (8)
LiCl (8)
7:1
>20:1
e
d
7
MeCu(CN)
ZnCl
>20:1
>20:1
>20:1
>20:1
e
d
8
MeCu(CN)
ZnMe
>20:1
f
d
9
MeCu(CN)
AlMe2
>20:1
a
Unless otherwise noted, all reactions were carried out at −78 °C for
30 min on a 0.1 mmol scale with 4 equiv of organocuprates in the
b
1
presence of metal salts. Determined by H NMR with an unpurified
reaction mixture. Yields are for the isolated products. Only a single
diastereomer was detected. 0 °C for 2 h. 0 °C for 4 h.
c
d
e
f
the preparation of methyl cyanocuprates (entries 6−9), since the
acceptance of various organometallic reagents can give an
advantage to the diversity of the α-substituent that corresponds
to the side chain of amino acids. In all tested methylmetal species,
full conversion was obtained and the type of organometallic
reagents did not influence the stereochemical outcome of the
reaction. The use of MeMgBr gave a slightly lower yield and
product selectivity (entry 6). The use of MeZnCl obtained by
transmetalation from MeMgBr with ZnCl2 had a beneficial effect
on the product selectivity and led to the exclusive formation of
the desired α-methylated compound 7a with excellent
diastereoselectivity (entry 7). Further, Me2Zn and Me3Al can
also be used without a decrease of diastereoselectivity, although
with slightly lower yields (entries 8 and 9).
lithium enolate of methyl dichloroacetate to the chiral N-
sulfinylaldimine 3, prepared from (S)-tert-butylsulfinamide 113
and isobutyl aldehyde 2, provided the corresponding ester 414
with high diastereoselectivity (>20:1) through the six-membered
chairlike transition-state model.15 Oxidation of the N-sulfinyl
group with m-CPBA provided the N-Bus-protected α,α-
dichloro-β-amino ester 5 as a single enantiomer. Reduction of
5 with DIBAL-H followed by Horner−Wadsworth−Emmons
reaction afforded the desired (E)-enoate (E)-6. Since those five
steps proceeded smoothly to provide the desired compounds,
only one purification by flash chromatography was required in
the last step to prepare (E)-6 in 87% isolated yield (five steps).
With a suitable substrate in hand, we examined the allylic
alkylation of (E)-6 with various organocuprates (Table 1). All of
the reactions tested provided (Z)-chloroalkene products 7a and
8 with undetectable amounts of the (E)-chloroalkene isomers
(Z/E = >20:1). It was found that the choice of organocuprates is
critical. The use of Gilman cuprate (Me2CuLi·LiI·2LiBr)
afforded only the reductive dechlorinated compound 8 (Bus-L-
Val-ψ[(Z)-CClCH]-Gly-OEt) in 97% yield via possibly a
single-electron-transfer mechanism (entry 1).16 On the other
hand, cyanocuprates prepared from CuCN and organometallic
reagents effectively provided the desired α-methylated com-
pound 7a (Bus-L-Val-ψ[(Z)-CClCH]-D-Ala-OEt) (entries 2−
9). The reaction with MeCu(CN)Li·LiBr afforded 7a in 90%
yield, and remarkably, the reaction proceeded with an excellent
degree of diastereoselectivity (entry 2). The absolute stereo-
chemistry of 7a was established by X-ray analysis and the single
diastereomer obtained corresponded to an L,D-type isostere.17
The addition of 1 equiv of LiCl against organocuprates resulted
in a slightly improved yield and product selectivity (entry 3),
whereas the reaction with additional LiCl or BF3·OEt2 led to
similar results (entries 4 and 5). We then turned our attention
toward exploration of the use of other methylmetal species for
Having identified reliable conditions, the scope of this
diastereoselective allylic alkylation was explored (Table 2). The
reaction was found to tolerate various alkyl cyanocuprates,
providing the regio- and diastereoselective 1,4-asymmetric
induction products 7a−i in moderate to excellent yields (54−
99%) (entries 1−9). In all cases, α-alkylated products were
obtained with excellent Z-selectivity and diastereoselectivity
(>20:1). When the organocuprates, prepared from Et2Zn, nBuLi,
i
or BuMgBr, were employed, the corresponding α-alkylated
products 7b−d could be isolated in excellent yield (entries 2−4).
Similarly, the organocuprates, prepared from benzylMgCl or (2-
naphthylmethyl)MgBr, effectively led to 7e (Bus-L-Val-D-Phe-
OEt) and 7f (Bus-L-Val-D-Nal-OEt) in 99% and 94% yields,
respectively (entries 5 and 6). The functionalized zinc−copper
reagent, derived from zinc homoenolate which was generated in
situ from ZnCl2 and (1-ethoxycyclopropoxy)trimethylsilane),18
also participated in diastereoselective alkylation to give the α-
alkylated product 7g (Bus-L-Val-D-Glu(OEt)-OEt) bearing an
ester functionality (entry 7). Interestingly, this new strategy is
also applicable to α-allylation (allyl−allyl cross-coupling), a
challenging task in organocopper chemistry.19−21 The allyl zinc−
B
DOI: 10.1021/acs.orglett.5b00611
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Scope of Diastereoselective Allylic Alkylation of (E)-
6
Scheme 3. Possible Mechanism of Diastereoselectivity via 1,4-
Asymmetric Induction
a
b
c
b
entry
RCu(CN)M
Z/E
7, yield (%)
dr
d
1
2
3
4
5
6
7
8
9
MeCu(CN)Li·LiBr
EtCu(CN)ZnEt
nBuCu(CN)Li
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
7a, 99
7b, 99
7c, 94
7d, 99
7e, 99
7f, 94
7g, 98
7h, 54
7i, 96
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
iBuCu(CN)MgBr
benzylCu(CN)MgCl
(2-naphthyl)Cu(CN)MgBr
EtO2C(CH2)2Cu(CN)ZnCl
allylCu(CN)ZnCl
2,6-diMe-C6H3Cu(CN)ZnCl
a
Unless otherwise noted, all reactions were carried out at −78 °C for
30 min on a 0.1 or 0.3 mmol scale with 4 equiv of organocuprates in
the presence of metal salts and an additional 8 equiv of LiCl. The Z/E
ratio and dr values were determined by H NMR with an unpurified
reaction mixture. Yields are for the isolated product. With an
additional 4 equiv of LiCl.
b
1
c
d
Table 3. Scope of Diastereoselective Allylic Alkylation of (Z)-
6
copper reagent, obtained by transmetalation from allylmagne-
sium chloride with ZnCl2, also reacts with excellent diaster-
eoselectivity, furnishing the synthetically useful α-allylated
product 7h in moderate yield (entry 8). However, the allyl
cyanocuprate, prepared directly from allylmagnesium bromide,
gave only reduction product 8 and no alkylated product, clearly
indicating the utility of transmetalation from Grignard reagents
with Zn salts in this reaction system. A similar superiority was
observed with a sterically hindered 2,6-dimethylphenyl cyano-
cuprate: the transmetalation from 2,6-dimethylphenylmagnesi-
um bromide to 2,6-dimethylphenylzinc chloride produced 7i
with a significant increase in yield (from 65% to 96%) (entry 9).
This exclusive formation of L,D-type isosteres 7 with a (Z)-
alkene structure suggests that allylic alkylation of (E)-6 can occur
only by the stereospecific facial attack of organocuprates to allylic
electrophiles. The general anti-selectivity in organocuprate-
mediated SN2′ reactions invoked two conformers A and B, either
of them allowing the anti-parallel position of the organocuprate
and the leaving chloride group (Scheme 3). Although the steric
repulsion between the isopropyl group and an olefinic proton
would partly destabilize the conformer A, the steric repulsions
could be reduced between C4, bearing two chloride groups and
C5, bearing bulky isopropyl and Bus-protected amino groups as
shown in the staggered conformation C, in which the facial attack
of organocuprates would be supported by the coordination effect
of the sulfonamide group at C5, leading to the exclusive
formation of 7a. On the other hand, there is potential steric
repulsion between the two chloride groups and the isopropyl
group in the other staggered conformation D, resulting in the
destabilization of the conformer B to prevent the formation of
9a.22
a
b
c
b
entry
RCu(CN)M
MeCu(CN)ZnCl
Z/E
9, yield (%)
dr
1
2
3
4
5
6
7
8
9
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
9a, 99
9b, 95
9c, 92
9d, 92
9e, 99
9f, 99
9g, 93
9h, 51
9i, 94
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
EtCu(CN)ZnEt
nBuCu(CN)ZnCl
iBuCu(CN)ZnBr
benzylCu(CN)ZnBr
(2-naphthyl)Cu(CN)ZnCl
EtO2C(CH2)2Cu(CN)ZnCl
allylCu(CN)ZnCl
2,6-diMe-C6H3Cu(CN)ZnCl
a
All reactions were carried out at −78 °C for 1.5 h on a 0.3 mmol scale
b
with 6 equiv of organocuprates in the presence of metal salts. The Z/
E ratio and dr values were determined by 1H NMR with an unpurified
c
reaction mixture. Yields are for the isolated product.
9a−i without a significant decrease of reaction yields and
diastereoselectivity (entry 1−9). As expected, the stereo-
chemistry of 9a−i corresponded to L,L-type isosteres, indicating
that allylic alkylation of allylic gem-dichlorides proceeds through
the stereospecific facial attacks of organocuprates, which is a key
intermediate of the stereochemical outcome.
In conclusion, we have described a highly diastereoselective
allylic alkylation of allylic gem-dichlorides with organocuprates
via 1,4-asymmetric induction. The diastereoselective synthesis of
both L,L-type and L,D-type (Z)-chloroalkene dipeptide isosteres
can be achieved in high yields by this strategy with excellent (Z)-
selectivity and diastereoselectivity. The use of zinc−copper
reagents was found to increase the chemical yields and product
selectivity of the reaction. Continuing investigations on the
unique reactivity of allylic gem-dichlorides and studies on the
applications of the obtained isosteres to the synthesis of
biologically active peptides are proceeding.
To better rationalize the observed diastereoselectivity and
stereochemical outcome, we have considered the geometry
switching of the double bond from (E)-enoate to (Z)-enoate,
which would lead to the stereoselective formation of L,L-type
isosteres. Thus, (2Z)-γ,γ-dichloro-α,β-enoate (Z)-6 was pre-
pared and applied to the allylic alkylation (Table 3). It is
noteworthy that (Z)-6 also worked efficiently in the allylic
alkylation to provide the corresponding α-alkylated products
C
DOI: 10.1021/acs.orglett.5b00611
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Fujita, T.; Iwashita, T.; Imai, T.; Yokoyama, T.; Matsumoto, Y.; van
Soest, R. W. M.; Matsunaga, S. J. Nat. Prod. 2010, 73, 1947 and
references cited therein.
(7) Narumi, T.; Kobayakawa, T.; Aikawa, H.; Seike, S.; Tamamura, H.
Org. Lett. 2012, 14, 4490.
ASSOCIATED CONTENT
* Supporting Information
Experimental detail, synthesis, characterization data, and X-ray
data (CIF). The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b00611.
■
S
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ttnarum@ipc.shizuoka.ac.jp.
*E-mail: tamamura.mr@tmd.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by a Kurata Grant from The Kurata
Memorial Hitachi Science and Technology Foundation, by a
Grant-in-Aid for Young Scientists (B) from the Ministry of
Education, Culture, Sports, Science and Technology, in part by
MEXT, Japan, JSPS Core-to-Core Program, A. Advanced
Research Networks, and in part by Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of
Education, Culture, Sports, Science and Technology, Japan. We
are grateful to Prof. Mitsuru Kondo (Shizuoka University) and
Takahiro Gotoh (Waseda University) for assistance in the
analysis of the crystal structure of 7a.
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́
, C.;
(21) Allylcopper species (allylCuX) can exist in a delocalized π-
allylcopper(III) complex, whose structural feature may hamper the
transfer of an allyl group, see: (a) Yamanaka, M.; Kato, S.; Nakamura, E.
J. Am. Chem. Soc. 2004, 126, 6287. (b) Bartholomew, E. R.; Bertz, S. H.;
Cope, S.; Murphy, M.; Ogle, C. A. J. Am. Chem. Soc. 2008, 130, 11244.
(22) An alternative explanation would involve the syn-SN2′ pathway
from the conformer B. The leaving Cl group could potentially attract the
organocuprate to afford 7a. See the Supporting Information for details.
(6) Cl−alkene utility: marine natural products: (a) Guinchard, X.;
Roulland, E. Synlett 2011, 19, 2779. (b) Ando, H.; Ueoka, R.; Okada, S.;
D
DOI: 10.1021/acs.orglett.5b00611
Org. Lett. XXXX, XXX, XXX−XXX