Synthesis of optically active boron-silicon bifunctional cyclopropane derivatives through enantioselective copper(I)-catalyzed reaction of allylic carbonates with a diboron derivative

Article abstract of DOI:10.1002/anie.200802342

(Chemical Equation Presented) Two for the show: A copper(I)-catalyzed reaction forms boron-silicon bifunctional cyclopropane derivatives from γ-silylated allylic carbonates and a diboron species (see scheme). The reaction is highly enantioselective when a chiral bisphosphine ligand is used. The stereoelectronic effect of the silyl group induces unusual regioselectivity of the boryl-copper(I) addition across the C-C double bond.

Full text of DOI:10.1002/anie.200802342

Communications
DOI: 10.1002/anie.200802342
Asymmetric Cyclopropanation
Synthesis of Optically Active Boron–Silicon Bifunctional
Cyclopropane Derivatives through Enantioselective
Copper(I)-Catalyzed Reaction of Allylic Carbonates
with a Diboron Derivative**
Hajime Ito,* Yuki Kosaka, Kousuke Nonoyama, Yusuke Sasaki, and
Masaya Sawamura*
Angewandte
Chemie
7424
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Chemie
Chirally substituted cyclopropane frameworks are widely
found in naturally occurring organic compounds and phar-
maceuticals. Their stereoselective and efficient synthesis is
hence an important issue in organic synthesis.[1] Herein we
report a highly diastereo- and enantioselective copper(I)-
catalyzed reaction that converts g-silylated allylic carbonates
(1) and a diboron species (2) into previously unreported,
optically active B,Si bifunctional cyclopropane derivatives
(B = (pin)B; Si = Me3Si 3a, PhMe2Si 3b, BnMe2Si 3c,
Scheme 1).[2,3] B,Si bifunctional cyclopropane (1S,2S)-3c was
derivatized into (1S,2R)-2-phenyl-1-cyclopropanol by
Suzuki–Miyaura coupling and Tamao oxidation.
Only a trace amount of the corresponding allylboronate (4a)
was detected. Notably, the cyclopropane formation from silyl-
substituted substrate (Z)-1a is significantly faster than the
allylboron formation from alkyl-substituted ones,[4] implying
an activating effect of the silyl group.
The E or Z configuration of the substrates greatly
influenced the reaction rate, chemoselectivity (3a/4a), and
trans/cis selectivity. Reactions of (E)-1a in 1,3-dimethyl-2-
imidazolidinone (DMI) required a higher catalyst loading
(10 mol%) and a longer reaction time (29 h) than those of
(Z)-1a, producing considerable amounts of cis-3a (8%) and
allylboronate 4a (17%) along with trans-3a (52%, trans/cis
87:13, Scheme 3).
Scheme 1. Cyclopropane formation with (Z)-1a in the presence of
copper(I) xantphoscatalyst and diboron derivative 2. pin=pinacolato,
xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene,
DMI=1,3-dimethyl-2-imidazolidinone.
Scheme 3. Cyclopropane and allylboron formation with (E)-1a in the
presence of copper(I) xantphos catalyst and diboron derivative 2.
The cyclopropane formation can be explained by assum-
ing a reversal of the regioselectivity in the addition of a
borylcopper(I) intermediate, which is formed through the
reaction between an alkoxycopper(I) complex and a diboron
During the course of our studies on the synthesis of
optically active allylboronates using copper(I)-catalyzed
reactions,[4] which involve the nucleophilic g-substitution of
À
allylic carbonates with
a
borylcopper(I) intermediate
derivative, across the C C double bond of the g-silylated
(Scheme 2),[5] we encountered a drastic product switch from
allylboronates to cyclopropylboronates when allylic carbo-
nates with a g-silicon substituent were employed instead of
alkyl-substituted ones. Thus, the reaction of silylated carbon-
ate (Z)-1a with bis(pinacolato)diboron (2)[6] in the presence
of an achiral copper(I) xantphos catalyst (3 mol% Cu) gave 1-
(trimethylsilyl)cyclopropan-2-ylboronate 3a[7] with high trans
selectivity (trans/cis 99:1) in 96% yield after 1 h (Scheme 1).
allylic carbonate.[8] This selectivity is driven by an interaction
À
À
between the s[C(g) Cu] and the s*[Si C(Si)] orbitals in the
addition product (A, Scheme 4).[9] Subsequent intramolecular
Scheme 2. Synthesis of allylboronates through copper(I)-catalyzed
substitution of allylic carbonates with a diboron derivative.[4]
[*] Prof. Dr. H. Ito, Y. Kosaka, K. Nonoyama, Y. Sasaki,
Prof. Dr. M. Sawamura
Department of Chemistry, Faculty of Science
Hokkaido University, Sapporo 060-0810 (Japan)
Fax: (+81)11-706-3749
E-mail: hajito@sci.hokudai.ac.jp
sawamura@sci.hokudai.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Priority Areas“Advanced Molecular Transformationsof Carbon
Resources” from the Ministry of Education, Culture, Sports, Science
and Technology.
Supporting information for thisarticle isavailable on the WWW
under http://dx.doi.org/10.1002/anie.200802342.
Scheme 4. Possible pathways for cyclopropane and allylboron forma-
tion with (Z)- and (E)-1a. Si=Me3Si, B=B(pin), Cu=(xantphos)Cu
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Communications
6). The reaction with the (R,R)-quinoxP* ligand[12] was
completed in 8 h and gave optically active trans-cyclopropane
(1S,2S)-3a with 98% ee in 99% yield (Table 1, entry 1). The
axially chiral ligand (R)-segphos[13] was also effective for this
reaction, showing slightly lower enantioselectivity (94% ee,
Table 1, entry 2). The catalyst that was prepared from (R)-tol-
binap showed a significantly decreased enantioselectivity
(Table 1, entry 3). The reactions with Me-duphos, diop, and
josiphos were faster than those with (R,R)-quinoxP* and (R)-
segphos, but they were less enantioselective (Table 1,
entries 4–6). Optically active cyclopropylboronates with
dimethylphenylsilyl [(S)-3b] or benzyldimethylsilyl [(S)-3c]
groups, which can be converted more easily into other
functional groups than the trimethylsilyl group, were obtain-
able in good yields through the reaction with the copper(I)
(R,R)-quinoxP* or the copper(I) (R)-segphos catalysts
(Table 1, entries 7–10). For these substrates, (R)-segphos
(Table 1, entries 8 and 10) was superior to (R,R)-quinoxP*
(Table 1, entries 7 and 9) in terms of enantioselectivity and 3/4
ratio. The reaction of (Z)-1a was also successful on a gram
scale (Table 1, entry 11).[14]
À
nucleophilic substitution (B) between the C(g) Cu and
À
C(a) O bonds would afford trans-3a with retention of the
configuration at the g carbon atom.[10] In the case of (E)-1a,
the lower reactivity, chemoselectivity, and trans/cis selectivity
can be explained as follows: The corresponding nucleophilic
substitution that forms the addition product (C) with reten-
tion of the C(g) configuration that leads to cis-3a would suffer
from steric repulsion between the boryl and silyl groups (D)
and hence become a minor pathway. Instead, the intra-
molecular nucleophilic substitution with inversion of the C(g)
configuration (E), which demands a pseudo-linear Cu-C(g)-
C(a)-O arrangement, would proceed as a major pathway,
affording trans-3a. Since the cyclopropane formation from
(E)-1a should be slower than that from (Z)-1a, it would be
reasonable that the route to give the allylboron compound
(4a) also competes with cyclopropane formation.[11]
Next, we examined enantioselective reactions. Various
copper(I) phosphine catalysts prepared in situ by mixing
Cu(OtBu) (5 mol%) and chiral ligands (5.5 mol%) were
examined for catalytic activity and enantioselectivity in the
reaction of (Z)-1a and 2 in THF at 308C (Table 1, entries 1–
The stereochemical outcome of the copper(I)-catalyzed
reactions of (Z)-1 can be explained by comparing the
Table 1: Enantioselective reaction of 1a–c with 2 catalyzed by copper(I)
complexeswith variouschiral ligands.
[a]
À
transition states during the addition of the Cu B bond
À
across the C C double bond (Scheme 5). Favored transition
Scheme 5. Proposed stereodiscriminating transition-state models.
Entry R3Si
Carbonate Ligand
t
[h]
Yield [%][b] ee
3
4
[%][c]
state TS1 is free from steric repulsion between the substitu-
ents of (Z)-1 and the tBu groups of the quinoxP* ligand, thus
delivering (1S,2S)-3 as a major enantiomer. In contrast, less
favored TS2 is severely destabilized by steric repulsion
between the substituents of (Z)-1 and one of the ligand tBu
groups. The rigidity of the four-center diastereomeric tran-
sition states should be responsible for the highly efficient
enantiofacial discrimination.
Stepwise, stereoselective transformation of the boron and
silicon functionalities allows for making use of the bifunc-
tional cyclopropane derivatives as building blocks for the
synthesis of cyclopropane-containing chiral compounds. Pre-
liminary results of studies toward this end are illustrated in
Scheme 6. Suzuki–Miyaura coupling of (1S,2S)-3c with iodo-
1
2
3
4
5
6
7
Me3Si
(Z)-1a
(Z)-1a
(Z)-1a
(Z)-1a
(Z)-1a
(Z)-1a
(R,R)-quinoxP*
(R)-segphos
(R)-tol-binap
(R,R)-Me-duphos1 97
(S,S)-diop
(R)-(S)-josiphos
(R,R)-quinoxP*
(R)-segphos
(R,R)-quinoxP*
(R)-segphos
(R)-segphos
8
8
8
99
94
75
<1 98
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
PhMe2Si (Z)-1b
PhMe2Si (Z)-1b
BnMe2Si (Z)-1c
2
94
<1 90
<1 82
<1 13[d]
1
2
8
7
8
8
98
93
91
3
4
0
91[e]
8[f]
9
86[g] <1 97[e]
88
9
2
2
92[e]
94[e]
96
10[f] BnMe2Si (Z)-1c
83[g]
11[h] Me3Si
(Z)-1a
24 86[g]
[a] Conditions: Cu(OtBu) (5 mol%, 0.0125 mmol), ligand (5.5 mol%,
0.014 mmol), 1 (0.25 mmol), 2 (0.5 mmol, 2.0 equiv) in THF (0.125 mL).
[b] Yield was determined by GC unless otherwise noted. In all reactions,
yieldsof cis-3 were less than 1%. [c] The ee value of 3a wasdetermined by
chiral GC analysis. [d] (1R,2R)-3a wasthe major isomer. [e] The ee values
of 3b and 3c were determined by chiral HPLC analysis. [f] Reaction with
1.0 mmol 1b or 1c and 2.2 mmol 2. [g] Yield of isolated product.
[h] Reaction with 5.0 mmol 1a with 10.5 mmol 2. Bn=benzyl, tol-
binap=2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl, Me-duphos=1,2-
bis[(2R,5R)-2,5-dimethylphospholano]benzene, diop=1,4-bis(diphenyl-
benzene
afforded
trans-2-phenyl-1-silylcyclopropane
[(1S,2R)-5] in 83% yield with high stereoselectivity.[15] Sub-
sequent Tamao oxidation[16] of (1S,2R)-5 gave the corre-
sponding alcohol (1S,2R)-6[17] in 73% yield without decrease
in the enantiomeric and diastereomeric purity of the product.
The regioselectivity of copper(I)-catalyzed allylic substi-
tutions is generally determined by a- versus g-selectivity.[18]
phosphino)-1,4-dideoxy-2,3-O-isopropylidene-l-threitol,
[(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine.
josiphos=2-
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À
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Scheme 6. Stereoselective Suzuki–Miyaura coupling and Tamao oxida-
tion. dba=dibenzylideneacetone, SPhos=2-dicyclohexylphosphino-
2’,6’-dimethoxybiphenyl, TBAF=tetrabutylammonium fluoride.
[9] For the a-stabilization effect of silicon groups, see: a) E. A.
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1699 – 1704; b) O. Kulinkovich, Eur. J. Org. Chem. 2004, 4517 –
4529.
The present reaction represents exceptional regioselectivity:
Formal nucleophilic attack occurs at the b-position of the
leaving group in the allylic electrophile. Further studies on the
application of the bifunctional cyclopropane derivatives are
currently underway.
Received: May 20, 2008
Published online: August 25, 2008
[11] The change in observed product distribution depending on the
E/Z stereochemistry of 1a implies the reversible nature of the
cuproborylation processes, although the reversibility has been
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Shimizu, I. Nagasaki, K. Matsumura, N. Sayo, T. Saito, Acc.
Chem. Res. 2007, 40, 1385 – 1393.
Keywords: asymmetric catalysis · boron · copper · cyclization ·
silicon
.
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