Reversible 1,3-anti/syn-stereochemical courses in copper-catalyzed γ-selective allyl-alkyl coupling between chiral allylic phosphates and alkylboranes

Article abstract of DOI:10.1021/ja302520h

The stereochemical courses of the copper-catalyzed allyl-alkyl coupling between enantioenriched chiral allylic phosphates and alkylboranes were switchable between 1,3-anti and 1,3-syn selectivities by the choice of solvents and achiral alkoxide bases with different steric demands. The reactions with γ-silylated allylic phosphates allow efficient synthesis of enantioenriched chiral allylsilanes with tertiary or quaternary carbon stereogenic centers. Cyclic and acyclic bimodal participation of alkoxyborane species in an organocopper addition-elimination sequence is proposed to account for the phenomenon of the anti/syn-stereochemical reversal.

Full text of DOI:10.1021/ja302520h

Article
pubs.acs.org/JACS
Reversible 1,3-anti/syn-Stereochemical Courses in Copper-Catalyzed
γ-Selective Allyl−Alkyl Coupling between Chiral Allylic Phosphates
and Alkylboranes
Kazunori Nagao, Umi Yokobori, Yusuke Makida, Hirohisa Ohmiya,* and Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
S
* Supporting Information
ABSTRACT: The stereochemical courses of the copper-
catalyzed allyl−alkyl coupling between enantioenriched chiral
allylic phosphates and alkylboranes were switchable between 1,3-
anti and 1,3-syn selectivities by the choice of solvents and achiral
alkoxide bases with different steric demands. The reactions with γ-
silylated allylic phosphates allow efficient synthesis of enantioen-
riched chiral allylsilanes with tertiary or quaternary carbon
stereogenic centers. Cyclic and acyclic bimodal participation of
alkoxyborane species in an organocopper addition−elimination
sequence is proposed to account for the phenomenon of the anti/
syn-stereochemical reversal.
1. INTRODUCTION
Copper-mediated allylic substitutions of enantioenriched chiral
allylic alcohol derivatives with organometallic reagents are
powerful tools for constructing stereogenic carbon centers.1
Typically, the reaction occurs with an 1,3-anti-stereochemistry
(anti-SN2′) to deliver a new stereogenic center at the γ-position.
In contrast, a switch of the stereochemical course from anti to
2. RESULT AND DISCUSSION
2.1. Optimization of Conditions for the Reversal of
1,3-anti/syn-Stereochemical Courses in the Reaction of
syn is possible by employing reagent-directing leaving groups,
such as benzothiazoles and carbamates (syn-SN2′).2−4 Breit and
γ-Silylated Allylic Phosphate. Our initial study was focused
on the reaction producing allylsilanes, because γ-silylated allylic
co-workers introduced the o-diphenylphosphanyl benzoate (o-
DPPB) group as a new reagent-directing leaving group,5a−f and
phosphates appeared to be more suitable substrates in terms of
the stereoselectivity compared with allylic phosphates having a
furthermore realized the stereoselective conversion of chiral
hydrocarbon backbone (vida infra). Alkylborane 2a, which was
allylic substrates by employing the switchable o-DPPB/o-DPPB
oxide leaving groups.5g,h
prepared via hydroboration of styrene (1a) with 9-
borabicyclo[3.3.1]nonane (9-BBN-H) dimer, and γ-silylated
Herein, we report a new case for the reversibility of 1,3-anti/
allylic phosphate (S)-(Z)-3b (99% ee) bearing a cyclic
syn-stereochemical courses in allylic substitution, where the
phosphate leaving group16 were subjected to the standard
stereochemical courses are switchable by the choice of solvents
reaction conditions for the copper-catalyzed allyl−alkyl
coupling (2a/3b/CuOAc/t-BuOK 1.6:1:0.1:1.5, THF, 40 °C)
(Table 1, entry 1; conditions A).13a The reaction afforded
allylsilane (S)-(E)-4ab in 94% yield with complete γ- and E-
selectivities. The absolute configuration of (S)-(E)-4ab
indicated that the reaction took place with 1,3-anti-stereo-
chemistry and the enantiomeric excess was 94% ee (anti/syn
97.5:2.5).17
As shown in Table 1, entries 2−5, the natures of a base and a
solvent have marked impacts on the anti/syn-selectivity. When
t-BuOLi was used instead of t-BuOK in conditions A, the yield
was low and the anti-selectivity decreased to 61% (entry 2).
and achiral alkoxide bases with different steric demands. The
reactions allow efficient synthesis of enantioenriched chiral
allylsilanes with tertiary or quaternary carbon stereogenic
centers.6−11 We note that examples of stereoselective
conversion of one enantiomer of a substrate to both
enantiomers of a product are still rare despite their usefulness
in organic synthesis.12
Earlier, we reported the copper-catalyzed γ-selective allyl−
alkyl coupling between allylic phosphates and alkylboranes
(alkyl-9-BBN).13,14 This reaction occurred preferentially with
1,3-anti-stereochemistry, but the stereoselectivity was only
moderate with acyclic allylic substrates (eq 1).13a The
sensitivity of the anti/syn-stereochemistry prompted us to
explore the possibility of reversing the stereochemical course
from anti to syn by the choice of reaction conditions.15
Received: March 18, 2012
Published: May 8, 2012
© 2012 American Chemical Society
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Table 1. Effect of Reaction Conditions on the anti/syn-
Stereoselectivity of the Coupling between 2a and γ-Silylated
Allylic Phosphate (S)-(Z)-3b
Table 2. Synthesis of Various Enantioenriched Allylsilanes
with a Tertiary Carbon Stereogenic Center
a,b
a
temp
yield
ee
b
,
c
d
entry
1
base
solvent
(°C) (%)
(%)
anti/syn
t-BuOK
THF
(cond A)
40
94
94 (S)
97.5:2.5
2
3
4
5
6
7
8
t-BuOLi
EtOK
THF
40
40
40
40
40
40
80
14
86
99
28
90
92
95
22 (S)
56 (R)
59 (R)
23 (R)
80 (R)
82 (R)
94 (R)
61:39
22:78
THF
MeOK
t-BuOK
EtOK
THF
20:80
toluene
toluene
toluene
38:62
9.5:90.5
8.5:91.5
2.5:97.5
MeOK
MeOK
toluene
(cond B)
a
The reaction was carried out with (S)-(Z)-3b (0.2 mmol), 2a (0.32
b
mmol), CuOAc (10 mol %), and base (0.3 mmol) for 8 h. Yield of
the isolated product based on (S)-(Z)-3b. Isomeric ratios (γ/α >
99:1, E/Z > 99:1). Determined by H NMR or GC of the crude
product. The enantiomeric excess was determined by HPLC analysis.
c
1
d
More pronounced effect on the stereoselectivity was observed
when t-BuOK was changed to sterically less demanding EtOK:
under otherwise same conditions, the stereochemical outcome
was reversed to syn-selectivity, giving the R isomer of 4ab with
56% ee (anti/syn 22:78) in 86% yield (entry 3). The syn-
selectivity was further increased to 80% by the use of even
smaller base MeOK (entry 4).
Changing the solvent (THF) in conditions A to toluene also
caused the anti-to-syn reversal although the yield and the syn-
selectivity were low (28% yield, anti/syn 38:62, Table 1, entry
5). The syn-selectivity was increased to 90.5% and 91.5% by the
use of EtOK and MeOK, respectively, in place of t-BuOK
(entries 6 and 7). Use of the smaller bases had a marked impact
also on the increase in the yield. We were delighted to find that,
when the reaction temperature was increased to 80 °C, the syn-
selectivity became as high as 97.5% and the yield was excellent
(entry 8; conditions B).
2.2. Reversible Stereochemistry in the Synthesis of
Various Allylsilanes. Various enantioenriched allylsilanes can
be synthesized through either 1,3-anti- or 1,3-syn-selective
allyl−alkyl coupling reactions (Table 2). The alkylboranes
(2b−d) bearing silyl ether, chloroaryl or ester moieties
underwent the reactions with excellent stereoselectivity
(Table 2, entries 1−6). The PhMe2Si group at the γ-position
of 3b could be replaced with BnMe2Si groups, affording the
corresponding R and S isomers with excellent stereoselectivities
(entries 7 and 8). For the reaction of (S)-(Z)-3d (99% ee),
which has an α-i-Pr substituent using conditions A, the anti-
and syn-stereochemical courses were comparable (entry 9). In
contrast, conditions B resulted in a higher syn-selectivity than
those with the other substrates (entry 10). This suggests that
the bulkiness of the α-i-Pr substituent prompted the reactions
toward the 1,3-syn-selectivity (vide infra for discussion).
The copper-catalyzed, 1,3-anti- and 1,3-syn-selective allyl−
alkyl couplings can be extended to the synthesis of
enantioenriched allylsilanes with a quaternary stereogenic
a
Conditions A: 3 (0.2 mmol), alkylborane 2 (0.32 mmol), CuOAc (10
mol %), t-BuOK (0.3 mmol, 1 M in THF), THF, 40 °C, 8 h.
Conditions B: 3 (0.2 mmol), alkylborane 2 (0.32 mmol), CuOAc (10
b
mol %), MeOK (0.3 mmol), toluene, 80 °C, 8 h. Alkylborane 2 was
prepared in advance by hydroboration of 1 with 9-BBN dimer in THF
(conditions A) or toluene (conditions B) at 60 °C for 1 h and used
c
without purification. Yield of the isolated product based on 3.
d
1
Isomeric ratios (γ/α > 99:1, E/Z > 99:1). Determined by H NMR
f
or GC of the crude product. The enantiomeric excess was determined
by HPLC analysis.
center. The results are summarized in Table 3. We used γ,γ-
disubstituted E-allylic phosphates, which are easier to prepare
than the corresponding Z-isomers.18 The reaction of γ,γ-
disubstituted allylic phosphate (S)-(E)-3e (96% ee) using
either conditions A or B afforded the corresponding quaternary
chiral allylsilanes (R)-(E)-4ae (92% ee, anti/syn 98:2) and (S)-
(E)-4ae (92% ee, anti/syn 2:98), respectively (entries 1 and
2).19 The synthetic methods were compatible with an ester
moiety in the alkenyl (alkylborane) substrate (entries 3 and 4).
The reactions of allylic phosphate (S)-(E)-3f (99% ee) with a
Bu group instead of the Me group at the γ-position by using
either conditions A or B afforded (−)-(E)-4af (93% ee, anti/syn
97:3) and (+)-(E)-4af (96% ee, anti/syn 1.5:98.5), respectively
(entries 5 and 6).
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Table 3. Synthesis of Enantioenriched Allylsilanes with a
a,b
Quaternary Carbon Stereogenic Center
2.3. Allyl−Alkyl Coupling with Non-Silicon-Substi-
tuted Allylic Phosphates. The phenomenon of anti/syn-
stereochemical reversal is not limited to cases with silylated
allylic phosphates (Table 4). For instance, the reaction between
the allylic phosphate (S)-(Z)-3a′ (96% ee) and 2a under
conditions A occurred with 97% 1,3-anti-selectivity (entry 1).
In contrast, the copper-catalyzed reaction of the same substrate
pair under conditions B proceeded with 85% syn-selectivity,
giving (R)-(E)-4aa with 66% ee in 31% yield (entry 2). The
addition of 9-BBN-OMe (1.5 equiv to 3a′) increased the syn-
selectivity to 89% and the product yield to 55% (entry 3) (see
section 2.4 for the role of 9-BBN-OMe). The use of 9-BBN-
OMe in a larger quantity (3 equiv) improved the yield to 74%
(entry 4; conditions C).
Various combinations of allylic phosphates having a hydro-
carbon backbone and alkylboranes were examined, and the
results are summarized in Table 5. The 1,3-anti-selectivity was
generally high with conditions A (anti/syn > 95:5) (entries 1, 3,
5, 7, and 9). Although the efficiency of 1,3-syn-selectivity under
conditions C was relatively low with the phosphates (S)-(Z)-
3a′, which has a Me group at the α-position (entry 2, anti/syn
11:89), higher syn-selectivities (92−95%) were observed when
the steric demand of the α-substituent is larger than that of the
Me group (entries 4, 6, 8 and 10). The selectivity trend biased
toward the 1,3-syn-stereochemical course by the bulkiness of
the α-substituent is similar to that observed in the reaction with
γ-silylated allylic substrates. The reactions were compatible with
acetal or 3,4-dimethoxyphenyl moieties in the alkenyl
(alkylborane) substrates (entries 1, 2, and 5−8).
2.4. Mechanistic Consideration. As we proposed in the
previous report, it is conceivable that the copper-catalyzed
allyl−alkyl coupling proceeds through the addition−elimination
mechanism of a neutral organocopper species.13a The generality
and completeness of the γ-regioselectivity (>99:1) strongly
supports this assumption. On the basis of this assumption, the
1,3-anti-stereochemical outcome, which was preferred under
conditions A, can be rationalized by the mechanism involving
B/Cu transmetalation between trialkyl(alkoxy)borate A and
CuX [X = OP(O)(OR4)2 or OAc], and the addition of
alkylcopper(I) species B across the C−C double bond of 3
a
Conditions A: 3 (0.2 mmol), alkylborane 2 (0.32 mmol), CuOAc (10
mol %), t-BuOK (0.3 mmol, 1 M in THF), THF, 40 °C, 18 h.
Conditions B: 3 (0.2 mmol), alkylborane 2 (0.32 mmol), CuOAc (10
b
mol %), MeOK (0.3 mmol), toluene, 80 °C, 8 h. Alkylborane 2 was
prepared in advance by hydroboration of 1 with 9-BBN dimer in THF
(conditions A) or toluene (conditions B) at 60 °C for 1 h and used
c
without purification. Yield of the isolated product based on 3.
d
1
Isomeric ratios (γ/α > 99:1, E/Z > 99:1). Determined by H NMR
f
or GC of the crude product. The enantiomeric excess was determined
by HPLC analysis. The reaction was carried out in toluene/DCE
(3:1) solvent.
e
The α-quaternary allylsilane (R)-(E)-4ae (92% ee) was
readily derivatized to the chiral tertiary carbinol 5ae (92% ee)
by alkene reduction followed by Fleming−Tamao oxidation
with retention of configuration (eq 2).20
Table 4. Effect of Reaction Conditions on the anti/syn-Stereoselectivity of the Coupling between 2a and Allylic Phosphate (S)-
a
(Z)-3a′
b,
c
d
entry
base
solvent
9-BBN-OMe (equiv)
temp (°C)
yield (%)
ee (%)
anti/syn
1
2
3
4
t-BuOK
MeOK
MeOK
MeOK
THF
none (cond A)
none (cond B)
1.5
40
80
80
80
87
31
55
74
90 (S)
66 (R)
74 (R)
74 (R)
97:3
toluene
toluene
toluene
15:85
11:89
11:89
3.0 (cond C)
a
b
The reaction was carried out with (S)-(Z)-3a′ (0.2 mmol), 2a (0.32 mmol), CuOAc (10 mol %), and MeOK (0.3 mmol) for 8 h. Yield of the
c
d
1
isolated product based on (S)-(Z)-3a′. Isomeric ratios (γ/α > 99:1, E/Z > 99:1). Determined by H NMR or GC of the crude product. The
enantiomeric excess was determined by HPLC analysis.
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a,b
enabling path b, which proceeds through a cyclic transition
state H-TS (G → H-TS → I). This results in 1,3-syn-
stereochemistry. In contrast, when the R group is as bulky as
the t-Bu group, steric factors would prevent the coordination of
the alkoxy oxygen to the copper atom. Accordingly, the acyclic
mechanism as in path a is preferred (C → D-TS → E). Use of a
potentially coordinating solvent such as THF may also render
the O−Cu coordination less favorable.
Table 5. Scope of Stereospecific Allyl−Alkyl Coupling
The assumed participation of 9-BBN-OMe in the 1,3-syn
allylic substitution was strongly supported by an additional
experiment that used an external 9-BBN-OMe reagent (eq 3).
Thus, the anti-to-syn reversal occurred upon adding 9-BBN-
OMe (1.5 equiv) to the reaction between 2a and (S)-(Z)-3b
under otherwise 1,3-anti reaction conditions.
The proposed acyclic and cyclic mechanisms for the 1,3-anti-
and 1,3-syn-stereochemical courses may be consistent with the
general observation that the sterically more demanding α-
substituents in the allylic phosphates biased the reaction toward
1,3-syn-stereoselectivity. Thus, assuming the stereodifferentiat-
ing transition state D-TS for the anti-stereochemical course so
that the Cu−C(β) bond and the C(α)−O bond are
antiperiplanar as illustrated in Figure 2a, a steric repulsion
between the organocopper moiety and the bulky α-substituent
(R3) would be significant. On the other hand, such a steric
repulsion could be avoided in the cyclic transition state H-TS
leading to the 1,3-syn-stereochemical outcome as shown in
Figure 2b.
a
Conditions A (entries 1, 3, 5, 7, 9): 3 (0.2 mmol), alkylborane 2
(0.32 mmol), CuOAc (10 mol %), t-BuOK (0.3 mmol, 1 M in THF),
THF, 40 °C, 8 h. Conditions C (entries 2, 4, 6, 8, 10): 3 (0.2 mmol),
alkylborane 2 (0.32 mmol), CuOAc (10 mol %), MeOK (0.3 mmol),
3. CONCLUSION
In summary, we demonstrated a new case of the reversibility of
1,3-anti/syn-stereochemical courses in allylic substitution,
where the stereochemical courses are switchable by the choice
of solvents and achiral alkoxide bases with different steric
demands. The protocols allowed the stereoselective conversion
of silicon-substituted allylic phosphates into enantioenriched
chiral allylsilanes with tertiary or quaternary carbon stereogenic
centers. Thus, both enantiomers of the allylsilanes with high
enantiomeric purities are readily available from one enantiomer
of the substrate. The protocols are versatile and useful for the
synthesis of functionalized allylsilanes because alkylboranes are
widely available via in situ alkene hydroboration with a broad
functional compatibility.23 Furthermore, the use of secondary
allylic alcohol derivatives as substrates is advantageous to the
preparation of allylsilanes that are substituted at the alkene
terminus.6−11 The reversible nature of the anti/syn-stereo-
selectivity provides clues to understanding the mechanism of
the copper-catalyzed allyl−alkyl coupling reactions. Although
elucidation of the mechanism must await further detailed
studies aided by theoretical calculations, the experimental
results obtained in the present study strongly suggest the
critical participation of alkoxyboranes in acyclic and cyclic
modes during the organocopper addition−elimination path-
ways.
b
9-BBN-OMe (0.6 mmol), toluene, 80 °C, 8 h. Alkylborane 2 was
prepared in advance by hydroboration of 1 with 9-BBN dimer in THF
(conditions A) or toluene (conditions C) at 60 °C for 1 h and used
c
without purification. Yield of the isolated product based on 3.
d
1
Isomeric ratios (γ/α > 99:1, E/Z > 99:1). Determined by H NMR
e
or GC of the crude product. The enantiomeric excess was determined
by HPLC analysis. The reaction was carried out for 18 h.
f
followed by anti-β-elimination from alkylcopper complex E
(Figure 1, path a). In contrast, the 1,3-syn-stereochemical
outcome, which was preferred under conditions B and C, can
be attributed to the pathway involving the addition of
alkylcopper species B with syn-stereochemistry with respect
to the leaving group followed by syn-β-elimination (Figure 1,
path b).
The switch of the selectivity would likely rely on the nature
of the alkoxyboranes (9-BBN-OR, R = t-Bu or Me), which are
derived from the transmetalation between CuX [X = OMe,
OP(O)(OR4)2 or OAc] and the alkylborates (A or F).
Regardless of the R groups, the alkoxyboranes would play a
role in activating the phosphate leaving group through their
Lewis-acidic character at the boron atom.21,22 When the R
group in the alkoxyborane is compact enough (R = Me), the
alkoxy oxygen would be able to coordinate to the copper atom,
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Figure 1. Possible pathways for the copper-catalyzed allyl−alkyl coupling between allylic phosphates and alkylboranes.
(2) For a review on directed reactions of organocopper reagents, see:
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Garcia-Ochoa, S.; Gomez, A. M. J. Org. Chem. 1990, 55, 2294−2298.
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Figure 2. Stereoelectronic effect models.
̀
ASSOCIATED CONTENT
■
́
S
* Supporting Information
́
Experimental details and characterization data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
ohmiya@sci.hokudai.ac.jp; sawamura@sci.hokudai.ac.jp
Notes
(6) For reviews on the synthesis of allylsilanes, see: (a) Masse, C. E.;
Panek, J. S. Chem. Rev. 1995, 95, 1293−1316. (b) Fleming, I.; Barbero,
A.; Walter, D. Chem. Rev. 1997, 97, 2063−2192. (c) Chabaund, L.;
James, P.; Landais, Y. Eur. J. Org. Chem. 2004, 3173−3199.
(7) For Cu-catalyzed enantioselective allylic substitutions of prochiral
γ-silylated primary allylic alcohol derivatives with organozinc or
organoaluminum reagents, giving allylsilanes with a terminal alkene
moiety, see: (a) Kacprzynski, M. A.; May, T. L.; Kazane, S. A.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 4554−4558. (b) Gao,
F.; McGrath, K. P.; Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2010,
132, 14315−14320.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Grants-in-Aid for Scientific
Research (B) and CREST, JST to M.S. and by the Grants-in-
Aid for Young Scientists (B), JSPS and The Uehara Memorial
Foundation to H.O. We thank MEXT for financial support
through the Global COE grant (Project No. B01: Catalysis as
the Basis for Innovation in Materials Science). Y.M. thanks
JSPS for scholarship support.
(8) For allylic substitutions of chiral γ-silylated secondary allylic
alcohol derivatives with organocopper reagents, giving allylsilanes that
are substituted at the alkene terminus, see: refs 3c and 3d. For
palladium-catalyzed allylic substitutions of enantioenriched γ-silylated
secondary allylic alcohol derivatives with organoboronic acids, giving
allylsilanes that are substituted at the alkene terminus, see: Li, D.;
Tanaka, T.; Ohmiya, H.; Sawamura, M. Org. Lett. 2010, 12, 3344−
3347.
(9) For the synthesis of allylsilanes through copper-catalyzed allylic
substitutions with silylating reagents, see: (a) Oestreich, M.; Auer, G.
Adv. Synth. Catal. 2005, 347, 637−640. (b) Schmidtmann, E. S.;
Oestreich, M. Chem. Commun. 2006, 3643−3645. (c) Vyas, D. J.;
Oestreich, M. Chem. Commun. 2010, 568−570. (d) Vyas, D. J.;
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(14) For Cu-catalyzed conjugate additions with alkylboron
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(16) The use of a cyclic phosphate as a leaving group markedly
improved the efficacy of the 1,3-anti-selectivity.
(17) The reaction of (S)-(E)-3b proceeded with significantly
decreased E-selectivity (E/Z 71:29), consistent with the concept of
allylic 1,3-strain in acyclic stereocontrol. See: Hoffmann, R. W. Chem.
Rev. 1989, 89, 1841−1860.
(18) When the alkene geometry of (S)-(E)-3e was changed to Z
[(S)-(Z)-3e, 98% ee], the reactions proceeded with 1,3-syn-selectivity
to afford (R)-(E)-4ae regardless of which conditions were used
(conditions A, 93% yield, anti/syn 18:82; conditions B, 83% yield,
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