Palladium-catalyzed synthesis of enantiomerically pure α-substituted allylboronic esters and their addition to aldehydes

Article abstract of DOI:10.1021/jo1008959

Tartrate-derived boronic esters 2 can be subjected to palladium-catalyzed carbonyl allylations with SnCl₂ to obtain enantiomerically pure α-substituted allylboronic esters 8 and 9. The reaction proceeds regioselectively and with high, simple diastereoselectivity to form anti-products. Their addition to aldehydes yields enantiomerically enriched homoallylic alcohols 17 and 18, respectively. Synthesis, characterization, and a mechanistic rational is presented here.

Full text of DOI:10.1021/jo1008959

pubs.acs.org/joc
Palladium-Catalyzed Synthesis of Enantiomerically Pure r-Substituted
Allylboronic Esters and Their Addition to Aldehydes
†
Enrique Fernandez, Jorg Pietruszka,* and Wolfgang Frey
,†
‡
ꢀ
€
†
€
Institut fu€r Bioorganische Chemie der Heinrich-Heine-Universitat Dusseldorf im Forschungszentrum Julich,
€
€
Stetternicher Forst, Geb. 15.8, 52426 Ju€lich, Germany, and ‡Institut fu€r Organische Chemie,
€
Universitat Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
j.pietruszka@fz-juelich.de
Received May 11, 2010
Tartrate-derived boronic esters 2 can be subjected to palladium-catalyzed carbonyl allylations with
SnCl2 to obtain enantiomerically pure R-substituted allylboronic esters 8 and 9. The reaction pro-
ceeds regioselectively and with high, simple diastereoselectivity to form anti-products. Their addition
to aldehydes yields enantiomerically enriched homoallylic alcohols 17 and 18, respectively. Synthesis,
characterization, and a mechanistic rational is presented here.
Introduction
of the attacking aldehyde to the boron of the allylboron reagent
controlling the course of the reaction.4 Enantiomerically pure
allylboronates should differentiate the two enantiotopic faces
of aldehydes and allow an enantioselective formation of
homoallylic alcohols. In addition, R-substituted allylboronic
esters have been shown to be of special interest because of the
possibility of controlling the selectivity by introducing a defined
stereogenic center to the core of the transition state, which
allows nearly complete transfer of chirality. However, their
applicability is sometimes hampered since they are more dif-
ficult to prepare in an enantiomerically pure form. The first
examples on this topic have been published by Hoffmann et al.,
who synthesized R-substituted allylboronic esters with a
Matteson homologation starting from enantiomerically pure
dichloromethylboronic esters.5 Further methods have been
The reaction of allylmetal reagents with carbonyl com-
pounds to form homoallylic alcohols is one of the most power-
ful transformations in organic synthesis. In particular, allyl-
boron reagents stand out because of their stability, nontoxicity,
and predictable reactivity, allowing high yields and selectivity
using mild reaction conditions.1 Since the pioneering report by
Hoffmann et al. in 1978,2a many research groups have designed
chiral allylic boron reagents for asymmetric allylation2 and
crotylation3 of carbonyl compounds. A closed chairlike transi-
tion state has been postulated to explain the stereoselectivity of
these reactions, with an electron delocalization from the oxygen
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Published on Web 07/30/2010
DOI: 10.1021/jo1008959
r
2010 American Chemical Society

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Fernandez et al.
JOCArticle
reported by other groups over the past few years, including
hydroborations of allenylboronic esters with (-)-diisopino-
campheylborane in a double allylboration reaction sequence,6
palladium-catalyzed enantioselective diboration of allenes,7
copper-catalyzed enantioselective substitution of allylic carbo-
nates with diboron,8 Diels-Alder reactions,9 and others.10
Recently, Aggarwal et al. developed a general protocol for
the in situ conversion of enantioenriched allylic boron reagents
into 1,2,4-substituted homoallylic alcohols with high levels of
predictable control over the relative and absolute configura-
tion: the boron reagent was obtained after selective R-lithiation
of a carbamate reaction with alkenyl boron species.10k Lewis
SCHEME 1. Homoallylic Alcohols from Allylboronic Esters 1 and 2
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building blocks for the synthesis of allylboron reagents with
a stereogenic center R to boron (Scheme 1):
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(a) [3,3]-Sigmatropic rearrangements of esters 1 led to
allylboronic esters 3, and a variety of side chains “R” could
be obtained.12 The process utilizes the readily available and
easily recoverable “diol” as a boron protecting group, which
can be synthesized in both enantiomeric forms from tart-
rate.13 The stability of esters 3 allowed subsequent transfor-
mations, opening the way to a family of boron reagents,
which were stable against oxidation and hydrolysis and
were hence storable and could be readily used subsequently.
Their addition to aldehydes resulted in homoallylic alcohols
with very high diastereo- and enantioselectivity forming
almost exclusively Z-isomers 4, with only minor amounts
of E-isomers 5 detectable. The stereochemical course of the
reaction depends on the substituent in the R-position and the
steric bulk of the boronic ester; it can be explained in terms of
steric and dipolar effects on the two competing transition
structures 6 and 7.5c,14 (b) Furthermore, we have recently
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45, 2426. (o) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2006,
128, 12660. (p) Elford, T. G.; Arimura, Y.; Yu, S. H.; Hall, D. G. J. Org.
Chem. 2007, 72, 1276. (q) Sakata, K.; Fujimoto, H. J. Am. Chem. Soc. 2008,
130, 12519. (r) Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am. Chem. Soc. 2008,
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(u) Unfortunately, “diol”-derived boronic esters suffered decomposition
upon attempts to use Lewis acid to catalyze additions to aldehydes:
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(b) Pietruszka, J.; Schone, N. Eur. J. Org. Chem. 2004, 5011. (c) Pietruszka,
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Grundl, L. Chem.;Eur. J. 2008, 14, 5178. (e) Cmrecki, V.; Eichenauer,
N. C.; Frey, W.; Pietruszka, J. Tetrahedron 2010, 66, 6550. For applications
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J. Org. Chem. Vol. 75, No. 16, 2010 5581

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TABLE 1. Palladium-Catalyzed Carbonyl Allylation
allylboronic esters
drb
entry
compd
R1
yielda (%)
8:9:10
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
Ph
79
86
82
73
79
75
80
70
71
79
85
100:0:0
96:4:0
94:6:0
93:7:0
91:9:0
89:11:0
75:18:7
78:22:0
77:14:9
78:18:4
50:50:0
3,4-C6H3F2
C6F5
furfural
CO2Et
PhCHCH
PhCH2CH2
(CH3)2CH
(C/H3)2CHCH2
c-C6H11
10
11
j
k
H
aIsolated mixture of diastereomers. bThe ratio was determined by 1H NMR spectroscopy.
shown that intermediates 2 are suitable precursors for palla-
dium-catalyzed carbonyl allylations forming diastereoselec-
tively R-substituted allylboronic esters 8.15 The allylation of
carbonyl compounds based on the umpolung of π-allyl-
palladium complexes has been extensively investigated in the
past few years.16 In particular, the Pd0/SnCl2 system intro-
duced by Masuyama et al. proved to be very powerful, where
PdCl2(PhCN)2 is used as a catalyst to form electrophilic
π-allylpalladium species from allylic substrates and SnCl2 is
used as a reducing agent for the nucleophilic allyl tin species
(umpolung).17 In this paper, we report on an asymmetric
version of the palladium-catalyzed carbonyl allylation reac-
tion with SnCl2 in the synthesis of R-substituted allylboronic
esters 8 and their addition to aldehydes in detail.
SCHEME 2. Synthesis of Allylboronic Esters 2a and 2b
with benzaldehyde (1 mmol) at room temperature, according
to conditions reported by the Masuyama group.17h Unfor-
tunately, no conversion was observed with our substrate, and
the starting material was completely recovered after workup.
This result suggested that the hydroxy group was too un-
reactive for the formation of the palladium π-complex. In
order to activate the alcohol, we synthesized mesylated
allylboronic esters 2a and 2b in a quantitative yield by add-
ing mesyl chloride and triethylamine to a solution of allyl
alcohols 1a and 1b in CH2Cl2, respectively (Scheme 2). The
addition of mesylate 2a to benzaldehyde under the afore-
mentioned conditions produced allylboronic ester 8a in 69%
after 20 h. The transformation proceeded with complete
selectivity with respect to both γ-addition (regiocontrol) and
anti-addition (diastereocontrol). By increasing the amount
of catalyst (from 2 to 5 mol %) and adding water (25 equiv),
the reaction was completed in 2 h. Other solvents used in
palladium-catalyzed carbonyl allylations with SnCl2 such as
DMI, THF, DME, or DMSO produced only traces of the
addition product after long reaction times, recovering the
starting material after workup. Under these conditions, mesy-
late 2a was added to various aldehydes (Table 1):
Results and Discussion
In our initial attempts to perform palladium-catalyzed
carbonyl allylation reactions, boronic ester 1a was treated
with PdCl2(PhCN)2 (2 mol %) and SnCl2 (3 mmol) in DMF
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Soc., Chem. Commun. 1988, 44. (b) Masuyama, V.; Takahara, J. P.; Kurusu,
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After complete conversion (as indicated by TLC after 2-3
h), the reaction mixtures were worked up and the crude
1
products subjected to H NMR spectroscopy in order to
determine the diastereomeric ratio of the products. The
obtained mixtures of R-substituted allylboronic esters were
isolated by means of column chromatography and the
diastereomers separated by MPLC. Only a single diastereo-
mer 8a was formed in the addition to benzaldehyde (entry 1,
5582 J. Org. Chem. Vol. 75, No. 16, 2010

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Fernandez et al.
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SCHEME 3. Assignment of Configuration of Boronic Esters
SCHEME 4. Mechanistic Rational for the Preferred Formation
of Ester 8
the coupling constants for the CH(OH)CH(B) protons (J=
3-6 Hz) were considerably smaller compared to the corre-
sponding syn-isomers 10 (J = 9-11 Hz). Finally, X-ray
crystallography of diol 1221 (and ent-12) and especially allyl-
boronate 9h (R=i-Pr) unequivocally verified the configura-
tion. Interestingly, X-ray analysis showed an interaction
between the hydroxy group and one of the oxygens of the
oxaborolane, thus revealing the conformative disposition of
the allylboronic esters 9 in the crystal (Scheme 3).
79% yield). Furthermore, excellent selectivities 8/9 were
achieved with substituted aromatic aldehydes (entry 2:
86% yield, dr 96:4; entry 3: 82% yield, dr 94:6), furfural
(entry 4: 73% yield, dr 93:7), and ethyl glyoxalate (entry 5:
79% yield, dr 91:9). The addition to aliphatic aldehydes led
to a slight increase in the ratio of the minor anti-diastereomer
9 (entries 6-10: 71-80% yield; dr from 4:1 to 10:1), while the
syn-product 10 was also detected in some cases (entries 7, 9,
and 10: 4-9%). As expected, no diastereoselective discrimi-
nation was observed using formaldehyde, giving the two
possible isomers 8k and 9k in equal ratio (entry 11: 85%
yield). In all cases, the major diastereomers 8 as well as minor
anti-diastereomers 9hþj (entries 8 and 10) and syn-diaster-
eomer 10j (entry 10) could be isolated by means of MPLC.
The enantiomerically pure R-substituted allylboronic esters
obtained were stable during purification procedures and
were stored at room temperature without decomposition.
The configuration of the products was assigned by means
of chemical correlations. Thus, oxidation of allylboronic
esters 8a, 8j, and 9j (in analytical scale) using MeLi followed
by H2O218 gave the known19 diols 11, 12, and ent-12 (Scheme 3);
the standard protocol for the oxidation with NaOH/H2O2 is
reported to fail with this type of tartrate-derived boronic
esters.18 Since oxidations of the C-B bonds of allylic boro-
nates to the corresponding alcohol are known to proceed with
retention of configuration,20 the performed transformation
serves as proof of the absolute configuration of the boronic
esters. The relative configuration of the allylboronic esters 8
and 9 was also confirmed to be anti by 1H NMR spectroscopy:
The use of (Z)-boronic ester 2b in the palladium-catalyzed
carbonyl allylation reaction provided comparable yields of
allylboronic esters under the same conditions and with
equivalent selectivity [R = Ph: 75% yield (8a), dr 100:0;
R = c-C6H11: 78% yield (8j þ 9j þ 10j), dr 79:20:1; data
not shown in Scheme 3]. A plausible mechanism for the
reaction is shown in Scheme 4. The principle of the process
relies on the transient formation of a η3-allyl palladium
complex (13 and 14), where the anti-complex 14 isomerizes
in favor of the more stable syn-complex 1317c (indeed, NMR
studies in DMF-d7 showed the formation of the same tin
intermediate 15 in the following step). This complex is
transformed by transmetalation into allyl tin intermediates
15 that cause nucleophilic attack to aldehydes. The addition
of water may support the hydrolysis of the Sn(IV)-Cl bond,
producing active aqueous organometallic cations Sn(IV)-
(OH2)þ
.
22 The carbonyl allylation is thought to proceed
(aq)
via the six-membered transition state 16, with the oxygen of
the aldehyde coordinating to the Sn(IV) species selectively
giving anti-allylboronic esters 8.17d,h
The observed high facial selectivity can be rationalized by
considering steric interactions between the residue “R” of the
aldehyde and the bulky substituent of the dioxaborolane
moiety, which are in close proximity in a disfavored transi-
tion state or are far apart in a favored state (Scheme 5). The
disfavored pseudoaxial position of the aldehyde’s R1 group
makes the formation of the syn-addition products 10 difficult
ꢀ
(21) For the crystal structure of compound 12, see: Frey, W.; Fernandez,
E.; Pietruszka, J. Z. Kristallogr. NCS 2010, 225, 13.
(22) (a) Nokami, J.; Otera, J.; Sudo, T.; Okawara, R. Organometallics
1983, 2, 191. (b) Furlani, D.; Marton, D.; Tagliavini, G.; Zordan, M.
J. Organomet. Chem. 1988, 341, 345.
(18) Luithle, J. E. A.; Pietruszka, J. Liebigs Ann./Recueil 1997, 2297.
(19) Barrett, A. G. M.; Malecha, J. W. J. Chem. Soc., Perkin Trans. 1
1994, 1901.
(20) Brown, H. C.; Narla, G. J. Org. Chem. 1995, 60, 4686.
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TABLE 2. Allyladditions of Boronic Esters 8
2-ene-1,5-diols
R1
drc
eed (%)
entry
compda
R2
yieldb (%)
17:18
17
18
1
2
3
4
5
6
7
8
9
ka
kg
cc
bb
gk
ja
aa
gg
jg
H
H
C6F5
Ph
PhCH2CH2
C6F5
3,4-C6H3F2
H
Ph
95
89
90
quant
71
91
99
98
0:100
0:100
33:67
40:60
46:54
50:50
59:41
59:41
74:26
82:18
84:16
96/97e
95/93e
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
3,4-C6H3F2
PhCH2CH2
c-C6H11
Ph
PhCH2CH2
c-C6H11
(CH3)2CH
c-C6H11
Ph
PhCH2CH2
PhCH2CH2
(CH3)2CH
c-C6H11
92
66
71
10
11
hh
jj
aThe resulting homoallylic alcohols were numbered using letters after the corresponding number, with the first letter corresponding to the residue of
aldehyde R1 (see Table 1) and the second letter to aldehyde R2. bIsolated mixture of diastereomers. cThe ratio was determined by 1H NMR spectroscopy
of the crude reaction mixture. dDetermined by the Mosher ester method. eDetermined by chiral HPLC analysis.
SCHEME 5. Proposed Six-Membered Cyclic Transition States
for Carbonyl Allylations
column chromatography and occasionally by MPLC. The
results of the addition of (1R,2R)-configured allylboronic
esters 8 to aldehydes are summarized in Table 2. Allylboronic
ester 8k (R1=H) produced exclusively Z-isomers in excellent
yields and enantioselectivities in the addition to benzalde-
hyde and phenylpropionaldehyde [entry 1: 95% yield (18ka),
97% ee; entry 2: 89% yield (18 kg), 93% ee]. The Z-selectivity
decreased when allylboronic esters bearing substituents R1 ¼
H were used, reaching E-selectivity in additions with ester 8h
(R1=i-Pr) and 8j (R1=c-C6H11) to isobutyraldehyde [entry
10: 66% yield (17 þ 18hh), E:Z = 82:18] and cyclohexyl-
carbaldehyde [entry 11: 71% yield (17 þ 18jj), E:Z=84:16],
respectively. However, in all cases, good to excellent yields
(entries 3-9: 71% to quant yield) and perfect enantioselec-
tivities (>95%) were obtained.
While the unfavorable gauche interaction between the R-
substituent and the bulky boronic ester generally favored the
formation of Z-products, the observed decrease in Z-selectivity
is obviously caused by the additional substituent in the side
chain; it is reasonable to assume that the syn-pentane interac-
tion is increased in the transition state with the R-substituent in
the pseudoaxial position (B), thus favoring transition state A
(Scheme 6). Hydrogen bond interaction between the OH group
and one of the oxygens of the dioxaborolane, as demonstrated
as a possibility by the X-ray structure analysis of 9h, could also
be feasible in solution and could thus also additionally influence
the transition state. Hence, such an interaction may not only fix
the conformation of the R-substituent in the allylboronic esters
but also electrophilically activate the boron moiety, increasing
the ratio of the allylboration and the E-selectivity.11 While the
configuration of the dioxaborolane would in this case be
expected to only marginally influence the E/Z selectivity, for
the second (minor) diastereoisomers 9 the interaction should be
more pronounced. The higher Z-selectivity of the (S)-configured
allylboronic esters [relative to the (R)-reagent] bearing the chiral
auxiliary “diol” as a protecting group has been observed before
by Pietruszka et al., and could be explained, in full analogy to the
argument made in Scheme 5, by the considerable steric interac-
tion between the R-substituent in the pseudoequatorial position
and no more than traces are produced (Table 1, entries 7, 9,
and 10). However, an acyclic-antiperiplanar transition state
for the formation of 10 cannot be ruled out.17h
To evaluate the efficiency of the new R-substituted allyl-
boronic esters in asymmetric allylation, we added different
aldehydes to produce homoallylic alcohols (Tables 2 þ 3 and
Scheme 7). In analogy to previously performed allylbora-
tions by Pietruszka et al.,12 allyladditions using allylboronic
esters 8-10 were carried out in CH2Cl2 and stirred at 0 °C for
12 h followed by stirring at room temperature until complete
conversion (as judged by TLC). Subsequent treatment with
LiAlH4 in THF cleaved the boronic ester and released the
homoallylic alcohols (2-ene-1,5-diols), which were subjected
1
to H NMR spectroscopy to determine the diastereomeric
ratio. The obtained isomers were separated by means of
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TABLE 3. Allyl Additions of Boronic Esters 9
2-ene-1,5-diols
drb
eec (%)
entry
compd
R1
R2
yielda (%)
ent-17:ent-18
ent-17
ent-18
1
2
3
4
5
6
ka
kg
jj
jg
hh
ja
H
H
Ph
PhCH2CH2
c-C6H11
PhCH2CH2
(CH3)2CH
Ph
94
88
89
85
60
83
0:100
0:100
16:84
24:76
27:73
33:67
95/98d
92/93d
>95
>95
>95
>95
c-C6H11
c-C6H11
(CH3)2CH
c-C6H11
>95
>95
>95
>95
aIsolated mixture of diastereomers. bThe ratio was determined by 1H NMR spectroscopy of the crude reaction mixture. cDetermined by the Mosher
ester method. dDetermined by chiral HPLC analysis.
SCHEME 6. Proposed Origin for the Selectivity of the Allyl Addition
SCHEME 7. Allyl Additions of Boronic Ester 10j to Benzaldehyde
(D) with one of the CPh2OMe groups of the boronic ester
(Scheme 6). The effect could even overrule the syn-pentane
interaction in transition state C. It should be noted that
only one possible conformation for the side chain (“R1”) is
given, and consequently, H-bonds are feasible for all transition
states. However, this would only be possible at the cost of
considerable syn-pentane interactions, thus rendering the reac-
tion path less likely. In order to confirm the assumption, allyl
additions with (1S,2S)-configured allylboronates 9 were per-
formed (Table 3). As expected, addition of allylboronic ester 9k
(R1=H) to benzaldehyde and phenylpropionaldehyde [entry 1:
94% yield (ent-18ka), 98% ee; entry 2: 88% yield (ent-18 kg),
93% ee] furnished in excellent yield and enantioselectivity
exclusively the corresponding Z-isomer. The addition of allyl-
boronic esters 9h and 9j to various aldehydes produced the
expected diastereomeric mixtures of homoallylic alcohols
ent-17 and ent-18 (entries 3-6: 60-89% yield, dr 16-33:
84-67, >95% ee) with increased Z-selectivity.
To further elaborate the issue of the influencing factors for
selectivity, the obtained minor (1S,2R)-configured allyl-
boronic ester 10j was also utilized. Upon addition to benzalde-
hyde on an analytical scale, diastereomers 19ja and 20ja were
obtained as a diastereomeric mixture (Scheme 7, dr =17:83).
While the results appeared surprising at first, a more detailed
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TABLE 4. Addition of Allylboronic Esters 21a, 21j, and 22j to Aldehydes
allylboronic ester
TBS-protected 2-ene-1,5-diols
drb
eec (%)
entry
compd
compd
R1
yielda (%)
23:24
23
24
1
2
3
21a
21j
22j
aa
ja
ent-ja
Ph
c-C6H11
c-C6H11
58
56
86
50:50
28:72
0:100d
>95
>95
>95
>95
>95
aIsolated mixture of diastereomers. bThe ratio was determined by 1H NMR spectroscopy of the crude reaction mixture. cDetermined by the Mosher
ester method. dent-24ja was obtained exclusively.
SCHEME 8. Proposed Transition State for the Addition of 10 to
Aldehydes
SCHEME 9. TBS Protection of Boronic Esters 8a, 8j, and 9j
in the pseudoequatorial position seems to be more impor-
tant, hence favoring the Z-product 24. With the same argu-
ment and the lack of H-bond activation, the low rate of the
transformation (15 d) can easily be explained. Allylboronic
ester 22j gave exclusively Z-homoallylic alcohol ent-24ja
(Table 4, entry 3; 86% yield) in contrast to the E/Z=33:67
ratio produced by the nonprotected allylboronic ester 9j
(Table 3, entry 6). Thus, the assumption that the larger
substituent R1 could improve the Z-selectivity was verified,
and the preferred Z-selectivity of the (S)-configured allyl-
boronic ester was also confirmed. In addition, the resulting
transformation represents a valuable alternative for the
synthesis of monoprotected 2-ene-1,5-diols.23a
analysis of the potentially involved transition states could
suggest hydrogen-bond interactions as an additional stabilizing
factor. While the considerable syn-pentane interaction rendered
the hydrogen bond in transition state B (Scheme 6) rather
unlikely, the corresponding interaction is minimized in transi-
tion state F (Scheme 8). Hence, the pseudoaxial positioning of
the R-substituent is favored over the pseudoequatorial position
(transition state E). To obtain a complete picture, the miss-
ing cis-diastereomer should be investigated; unfortunately, it
was not detected during the palladium-catalyzed carbonyl
allylation.
Next, we investigated the silyl-protected allylboronic
esters and the influence of this bulky group, which also disables
hydrogen bonds based on the selectivity of the allyl addition.
Allylboronic esters 8a, 8j, and 9j were treated with TBSOTf and
2,6-lutidine in CH2Cl2, furnishing TBS-protected allylboronic
esters 21a, 21j, and 22j in a quantitative yield (Scheme 9).
The subsequent addition of the TBS-protected reagents to
benzaldehyde resulted in monoprotected 1,5-diols 23 and 24
(Table 4). The addition of 21a and 21j gave rise to a higher
Z-selectivity (E/Z=50:50 and 28:72, respectively; entries 1
and 2) in comparison with the nonprotected allylboronic
esters 8a and 8j (E/Z=59:41 and 50:50, respectively; Table 2,
entries 6 and 7). Despite the increased syn-pentane interac-
tions (TBS versus H) of the pseudoaxial substituent, the
steric interaction of the boronic ester with the R-substituent
Different methods were used to determine the configura-
tion of the obtained 1,5-diols (Scheme 10; see the Supporting
Information for more details). The relative configurations
(anti/syn) of a number of 1,5-diols (R1=R2) were assigned
after hydrogenation of the double bond, thus obtaining the
corresponding C2-symmetric 1,5-diols (from E-configured
diols 17) and meso-1,5-diols (from Z-configured diols 18).
The E/Z-configuration was confirmed by measuring the
1
coupling constants (J) of the olefinic protons in H NMR
spectroscopy (E-isomers: J=15.4 Hz; Z-isomers: J=11.0 Hz).
In all cases, E-isomers showed longer retention times than the
corresponding Z-isomers under the employed chromato-
graphic conditions (60 g of silica gel per gram of 1,5-diol and
elution with petroleum ether/ethyl acetate). The absolute con-
1
figurations were established by comparing the H NMR
spectra of the corresponding (S)- and (R)-Mosher esters
[(S)/(R)-MTPA].24a Furthermore, the assignments were also
5586 J. Org. Chem. Vol. 75, No. 16, 2010

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Fernandez et al.
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chain and with no racemization expected during the addition,
only one enantiomer of each isomer (E/Z) was formed.
SCHEME 10. Determination of Configuration of the 1,5-Diols
Conclusion
We have reported on the synthesis and the configurational
assignment of new enantio- and diastereomerically pure R-
substituted allylboronic esters by using a palladium-cata-
lyzed carbonyl allylation in the presence of SnCl2. The
transformation proceeds smoothly and diastereoselectively,
producing predominantly anti-products. The obtained allyl-
boronic esters are moisture stable and could be stored for
long periods of time without decomposition. Their potential
as allylation reagents was investigated in detail, showing the
effect of the stereogenic center in the R-position to boron on
the selectivity of the addition to aldehydes, allowing the
stereocontrolled formation of a wide variety of homoallylic
alcohols (2-ene-1,5-diols).
SCHEME 11. Assignment of the Configuration of Homoallyl
Alcohols 18ka and ent-18kg
Experimental Section
Only general procedures with a representative example are
given. For full details, see the Supporting Information.
Synthesis of Boronic Esters 2 (Scheme 2). Et3N (1.50 mmol)
and MeSO2Cl (1.50 mmol) were added to a stirred solution of
alcohol 1 (1.00 mmol) in dry CH2Cl2 (2 mL per mmol of 1) at
0 °C under a dry nitrogen atmosphere. The solution was stirred
at room temperature until the reaction was complete (as judged
by TLC, 1 h). The reaction mixture was diluted with Et2O, and
satd aq NaHCO3 (5 mL per mmol of 1) was added. Stirring was
continued for 15 min. The layers were separated, and the
aqueous layer was extracted with Et2O. The combined organic
layer was washed successively with satd aq NH4Cl, water, and
brine. The extracts were dried over anhydrous MgSO4 and
filtered, and the solvents were removed under reduced pressure
to obtain methyl sulfonates 2 as colorless foams.
confirmed by comparing the spectroscopic data of diols 17ja,
17aa, 17gg, ent-17hh, ent-17jj, 18ja, 18gg, and ent-18jj with
those reported in the literature.6a,23
Diols 18ka and ent-18kg were assigned by means of
chemical correlations (Scheme 11). Ozonolysis followed by
reduction with LiAlH4 provided the known 1,3-diols 25 and
26, whose spectroscopic data were in full agreement with
those previously reported.12d Finally, X-ray crystallography
of diol 17jg additionally supported the assignment (see the
Supporting Information).
The enantiomeric excess of diols 18ka/ent-18ka and 18kg/
ent-18kg were found to be excellent (92-98% ee) by means
of chiral HPLC analysis, which revealed a nearly complete
chirality transfer of the new allylboronic esters. Attempts to
determine the enantiomeric excess of the remaining diols by
means of chromatographic methods failed. Derivatizations
(quantitative esterification with benzoyl chloride, see the
Supporting Information) in order to change the polarity of
the products did not lead to better separation of enantiomers
either. The Mosher ester method,24 used in this work to
determine the absolute configuration of the diols, also
indirectly provided their enantiomeric excess (see the Sup-
porting Information). Thus, except for diols 18ka/ent-18ka
and 18kg/ent-18kg (92-98% ee), all products were found to
be enantiomerically pure (>95% ee), which can also be noticed
in the increased optical rotation values for known products.
Unsurprisingly, starting from diastereomerically pure allyl-
boronic esters bearing a stereogenic center in the R-position
(40R,50R,2E)-3-[40,50-Bis(methoxydiphenylmethyl)-10,30,20-di-
oxaborolan-20-yl]prop-2-en-1-yl Methanesulfonate (2a). According
to the general procedure, allyl alcohol 1a (9.90 g, 19.0 mmol,
1.00 equiv) was dissolved in dry CH2Cl2 (38 mL) and treated
consecutively with Et3N (3.96 mL, 28.6 mmol, 1.50 equiv) and
MeSO2Cl (2.22 mL, 28.6 mmol, 1.50 equiv). Methyl sulfonate 2a
(11.4 g, 19.0 mmol, quant) was isolated as a colorless foam without
further purification steps: Rf=0.15 (petroleum ether/ethyl acetate,
85:15) and Rf=0.52 (petroleum ether/ethyl acetate, 60:40); [R]20
=
D
-65.4 (c 1.03, CHCl3); mp 84-91 °C; IR (film) νmax (cm-1) =
2939, 2833, 1648, 1494, 1446, 1343, 1238, 1173, 1075, 1032, 1014,
1
967, 935, 758, 672; H NMR (600 MHz, CDCl3) δ 2.93 (s, 3H,
SO2CH3), 3.00 (s, 6H, OCH3), 4.59 (dd, J=1.6, 5.1 Hz, 2H, 1-H),
5.37 (s, 2H, 40-H and 50-H), 5.40 (dt, J=1.6 Hz, 18.0 Hz, 1H, 3-H),
6.14 (dt, J=5.1, 18.0 Hz, 1H, 2-H), 7.25-7.37 (m, 20H, Ar-H);
13C NMR (151 MHz, CDCl3) δ 38.2 (SO2CH3), 52.0 (OCH3),
70.3 (C-1), 78.0 (C-40 and C-50), 83.5 (CPh2OMe), 122.3 (br, C-3),
127.5, 127.6, 127.8, 128.0, 128.6, 129.8 (Ar-C), 141.1, 141.3
(Ar-Cipso), 142.8 (C-2); 11B NMR (192 MHz, CDCl3) δ 29.55;
MS (ESI, positive ion) m/z 621.0 (100) [(M þ Na)þ], 394.9 (59),
197.1 (1) [(CPh2OMe)þ]. Anal. Calcd for C34H35BO7S (598.5): C,
68.23; H, 5.89; S, 5.36. Found: C, 67.98; H, 6.00; S, 5.37.
Synthesis of Allylboronic Esters 8-10 (Table 1). SnCl2 (3.00
mmol), PdCl2(PhCN)2 (5 mol %), H2O (25 mmol), and the
aldehyde (1.00 mmol) were added to a solution of mesylate 2
(1.00 mmol) in DMF (3 mL). The solution was stirred at room
temperature until the reaction was complete (as judged by TLC,
2-3 h). The reaction mixture was diluted with Et2O (120 mL)
and washed successively with aq 10% HCl solution (10 mL),
satd NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL).
The extracts were dried over anhydrous MgSO4 and filtered.
(23) (a) Hicks, J. D.; Huh, C. W.; Legg, A. D.; Roush, W. R. Org. Lett.
2007, 9, 5621. (b) Flamme, E. M.; Roush, W. R. Beilstein J. Org. Chem. 2005,
1:7. (c) Li, F.; Roush, W. R. Org. Lett. 2009, 11, 2932.
~ ꢀ
(24) (a) Freire, F.; Seco, J. M.; Quinoa, E.; Riguera, R. J. Org. Chem.
2005, 70, 3778. (b) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543.
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The solvent was removed under reduced pressure and the crude
product subjected to flash column chromatography on silica gel
(petroleum ether/ethyl acetate, 90:10) and MPLC (petroleum
ether/ethyl acetate, 98:2) yielding R-substituted allylboronic esters
8-10 as colorless foams.
(5S,2Z)-5-Phenylpent-2-ene-1,5-diol (18ka) and (5R,2Z)-5-
Phenylpent-2-ene-1,5-diol (ent-18ka). According to the general
procedure, allylboronic ester 8k (425 mg, 0.79 mmol, 1.00 equiv)
was dissolved in dry CH2Cl2 (398 μL) and treated with benzalde-
hyde (122 μL, 1.20 mmol, 1.50 equiv). The reaction mixture was
stirred at 0 °C for 12 h and at room temperature for 1 d. After
column chromatography (40 g of silica gel, petroleum ether/ethyl
acetate, 50:50), 1,5-diol 18ka (132 mg, 0.74 mmol, 94%) was
isolated as a colorless oil: Rf=0.13 (petroleum ether/ethyl acetate,
60:40); [R]20D=-114 (c 2.23, CHCl3, ee 97%). Mosher ester: ee
96%. HPLC: ee 97%. According to the general procedure, allyl-
boronic ester 9k (300 mg, 0.56 mmol, 1.00 equiv) was dissolved in
dry CH2Cl2 (280 μL) and treated with benzaldehyde (86.0 μL, 0.84
mmol, 1.50 equiv). The reaction mixture was stirred at 0 °C for 12 h
and at room temperature for 2 d. After column chromatography
(40 g of silica gel, petroleum ether/ethyl acetate, 50:50), 1,5-diol ent-
18ka (95.0 mg, 0.53 mmol, 95%) was isolated as a colorless oil:
Rf=0.13 (petroleum ether/ethyl acetate, 60:40); [R]20D=þ115.40
(c 1.27, CHCl3, ee 98%); Mosher ester ee 95%; HPLC ee 98%;
HPLC (Chiralcel OB, heptane/iPrOH 97:3, flow=0.7 mL/min, λ=
208 nm): tR (18ka)=39.4 min, tR (ent-18ka)=54.6 min; IR (film)
(1R,2R,40R,50R)-2-[40,50-Bis(methoxydiphenylmethyl)-10,30,20-
dioxaborolan-20-yl]-1-phenylbut-3-en-1-ol (8a). According to the
general procedure, methyl sulfonate 2a (3.00 g, 5.01 mmol, 1.00 equiv)
was dissolved in DMF (16.7 mL). The solution was treated con-
secutively with PdCl2(PhCN)2 (96.1 mg, 0.25 mmol, 5 mol %),
SnCl2 (2.85 g, 15.0 mmol, 3.00 equiv), H2O (2.25 mL, 125 mmol,
25.0 equiv), and benzaldehyde (500 μL, 5.00 mmol, 1.00 equiv).
After column chromatography (180 g of silica gel, petroleum ether/
ethyl acetate, 85:15), allylboronic ester 8a (2.42 g, 3.96 mmol, 79%)
was isolated as a colorless foam: Rf=0.72 (petroleum ether/ethyl
acetate, 60:40); [R]20D=-93.2 (c 1.02, CHCl3); mp 69-77 °C; IR
(film) νmax (cm-1)=3567, 3022, 2938, 2833, 1633, 1601, 1494, 1446,
1375, 1339, 1229, 1155, 1075, 756, 695; 1H NMR (600 MHz,
CDCl3) δ1.85 (dd, J=6.0, 9.7Hz, 1H, 2-H), 2.02(d,J=2.3 Hz, 1H,
OH), 2.97 (s, 6H, OCH3), 4.57 (dd, J=2.3, 6.0 Hz, 1H, 1-H), 4.73
(ddd, J=0.7, 1.9, 17.1 Hz, 1H, 4-HE), 4.89 (dd, J=1.9, 10.2 Hz, 1H,
4-HZ), 5.29 (s, 2H, 40-H and 50-H), 5.53 (ddd, J=9.9, 9.9, 17.1 Hz,
1H, 3-H), 7.01-7.40 (m, 25H, Ar-H); 13C NMR (151 MHz,
CDCl3) δ 40.1 (C-2), 51.9 (OCH3), 72.6 (C-1), 78.2 (C-40 and
C-50), 83.6 (CPh2OMe), 117.7 (C-4), 126.5, 127.0, 127.6, 127.6,
127.7, 127.8, 128.0, 128.8, 129.8 (Ar-C), 134.2 (C-3), 141.2, 141.3,
143.1 (Ar-Cipso); 11B NMR (192 MHz, CDCl3) δ 32.48; MS (ESI,
positive ion) m/z 633.3 (100) [(M þ Na)þ], 576.1 (60), 197.2
[(CPh2OMe)þ], 167.3 (8) [(C13H11)þ]. Anal. Calcd for C40H39-
BO5 (610.3): C, 78.69; H, 6.44. Found: C, 78.26; H, 6.59.
ν
max (cm-1)=3315, 2876, 1493, 1452, 1308, 1201, 1010, 999, 875,
758, 700; 1H NMR (600 MHz, CDCl3) δ 2.28 (br, 2H, OH), 2.50
(dddddd, J=0.5, 0.5, 1.4, 4.6, 7.3, 14.2 Hz, 1H, 4-Ha), 2.62 (dddd,
J=1.1, 7.7, 8.7, 14.0 Hz, 1H, 4-Hb), 4.02 (ddddd, J=0.5, 0.5, 0.9,
6.9, 12.3 Hz, 1-Ha), 4.13 (dddd, J=0.5, 1.2, 7.2, 12.3 Hz, 1H, 1-Hb),
4.74 (dd, J=4.6, 7.8 Hz, 1H, 5-H), 5.62 (ddddd, J=1.2, 1.2, 7.3, 8.7,
10.9 Hz, 1H, 3-H), 5.86 (ddddd, J=1.3, 1.3, 7.2, 7.2, 10.9 Hz, 1H,
2-H), 7.24-7.38 (m, 5H, Ar-H); 13C NMR (151 MHz, CDCl3) δ
37.3 (C-4), 57.9 (C-1), 73.2 (C-5), 125.9 (Ar-C), 127.9 (C-3), 128.6,
129.0 (Ar-C), 131.9 (C-2), 144.1 (Ar-Cipso); HRMS (ESI, positive
ion) m/z calcd for C11H14O2 [M þ Na]þ 201.2174, found 201.0885.
Synthesis of TBS-Protected Boronic Esters 21 and 22 (Scheme 9).
2,6-Lutidine (4.00 mmol) and TBSOTf (3.00 mmol) were added to
a stirred solution of boronic esters 8 or 9 (1.00 mmol) in dry
CH2Cl2 (10 mL per mmol of 8 or 9) at 0 °C under a dry nitrogen
atmosphere. The solution was stirred at room temperature until the
reaction was complete (as judged by TLC, 2 h). The reaction
mixture was diluted with CH2Cl2 and satd aq NaHCO3 (5 mL per
mmol of 8 or 9) was added. The layers were separated, and the
aqueous layer was extracted with CH2Cl2. The combined organic
layer was successively washed with water and brine. The extracts
were dried over anhydrous MgSO4 and filtered, and the solvents
were removed under reduced pressure. The crude product was
finally subjected to flash column chromatography on silica gel
(petroleum ether/ethyl acetate, 95:5) to yield R-substituted TBS-
protected allylboronic esters 21 and 22 as colorless foams.
Preparation of Diols 11, 12, and ent-12 (Analytical Samples;
Scheme 3). MeLi (1.6 M in Et2O) was added to a solution of
allylboronic esters8a, 8j, or9jinTHFat0 °C under a dry nitrogen
atmosphere. The solution was stirred until the reaction was
complete (as judged by TLC, 2 h). The oxidation was performed
by careful addition of 30% H2O2; stirring was continued over-
night. The resulting mixture was diluted with AcOEt, washed
sequentially with saturated NH4Cl solution, H2O, and brine,
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The product was subjected to flash column
chromatography on silica gel (petroleum ether/ethyl acetate,
80:20) yielding 1,2-diols 11, 12, and ent-12 as colorless oils.
(1S,2R)-1-Phenylbut-3-ene-1,2-diol (11). Prepared according
to the general procedure. Spectroscopic data were in agreement
with those previously reported:19 [R]20D=þ75.8 (c 0.96, CHCl3);
1H NMR (600 MHz, CDCl3) δ 2.37 (br, 1H, OH), 2.75 (br, 1H,
OH), 4.29 (mc, 1H, 2-H), 4.73 (d, J=4.6 Hz, 1H, 1-H), 5.19 (ddd,
J=1.4, 1.4, 10.5 Hz, 1H, 4-HZ), 5.25 (ddd, J=1.4, 1.4, 17.2 Hz,
1H, 4-HE), 5.78 (ddd, J=6.1, 10.5, 17.2 Hz, 1H, 3-H), 7.27-7.36
(m, 5H, Ar-H); 13C NMR (151 MHz, CDCl3) δ 77.6 (C-1), 77.8
(C-2), 118.3 (C-4), 127.2, 127.2, 128.4, 128.8, 128.8 (Ar-C), 136.3
(C-3), 140.3 (Ar-Cipso).
Allyl Additions (Tables 2 and 3, Scheme 7). The aldehyde (1.20
mmol) was added to a stirred solution of allylboronic esters
8-10, 21, or 22 (1.00 mmol) in dry CH2Cl2 (0.5 mL) at 0 °C
under a dry nitrogen atmosphere. The mixture was stirred and
allowed to warm to room temperature overnight. After complete
consumption of allylboronic ester (as judged by TLC, 3-15 d), the
solvents were removed under reduced pressure. The residue was
dissolved in THF (10 mL), and LiAlH4 (4.00 mmol) was added.
After 1 h, the mixture was diluted with Et2O (10 mL), cooled to
0 °C, and treated successively with H2O (184 μL), 15% aqueous
NaOH (184 μL), and H2O(544μL). The solids were filtered off and
washed thoroughly with Et2O, and the filtrate was dried over
anhydrous MgSO4. Filtration and removal of the solvents under
reduced pressure completed the process. The product was then
subjected to flash column chromatography on silica gel (petroleum
ether/ethyl acetate, 60:40) yielding 1,5-diols as colorless oils.
(1R,2R,40R,50R)-tert-Butyldimethylsilyl-2-[40,50-bis(methoxy-
diphenylmethyl)-10,30,20-dioxaborolan-20-yl]-1-phenylbut-3-en-1-yl
Ether (21a). According to the general procedure, allylboronic ester
8a (319 mg, 0.52 mmol, 1.00 equiv) was dissolved in dry CH2Cl2
(5.23 mL) and treated consecutively with 2,6-lutidine (243 μL,
2.00 mmol, 4.00 equiv) and TBSOTf (360 μL, 1.57 mmol, 3.00
equiv). After column chromatography (30 g of silica gel, petroleum
ether/ethyl acetate, 95:5), TBS-protected allylboronic ester 21a
(375 mg, 1.40 mmol, 99%) was isolated as a colorless foam: Rf=
0.68 (petroleum ether/ethyl acetate, 85:15); [R]20D=-97.0 (c 1.05,
CHCl3); melting range 63-74 °C; IR (film) νmax (cm-1)=2930,
2855, 1446, 1362, 1249, 1199, 1074, 835, 773, 757, 695; 1H NMR
(600 MHz, CDCl3) δ -0.43 (s, 3H, CH3Si), -0.15 (s, 3H, CH3Si),
0.72 (s, 9H, t-Bu), 1.80 (m, 1H, 2-H), 2.93 (s, 6H, OCH3), 4.34 (d,
J=8.2 Hz, 1H, 1-H), 4.67 (ddd, J=0.5, 2.0, 17.0 Hz, 1H, 4-HE),
4.81 (ddd, J=0.4, 2.1, 10.1 Hz, 1H, 4-HZ), 5.17 (s, 2H, 40-H and 50-
H), 5.58 (ddd, J=9.9, 9.9, 17.0 Hz, 1H, 3-H), 6.90-7.32 (m, 25H,
Ar-H); 13C NMR (151 MHz, CDCl3) δ -4.7 (CH3Si), -4.3
(CH3Si), 18.3 ((CH3)3CSi), 26.0 ((CH3)3CSi), 41.6 (br, C-2), 51.9
(OCH3), 74.5 (C-1), 77.8 (C-40 and C-50), 83.4 (CPh2OMe), 115.4
(C-4), 126.8, 127.3, 127.4, 127.5, 128.8, 129.9 (Ar-C), 136.5 (C-3),
5588 J. Org. Chem. Vol. 75, No. 16, 2010

ꢀ
Fernandez et al.
JOCArticle
141.5, 145.4 (Ar-Cipso); 11B NMR (192 MHz, CDCl3) δ 32.63; MS
(ESI, positive ion) m/z 747.2 (62) [(M þ Na)þ], 617.0 (100)Anal.
Calcd for for C46H53BO5Si (724.80): C, 76.23; H, 7.37. Found: C,
76.13; H, 7.33.
(dd, J=3.7, 8.9 Hz, 1H, 1-H), 7.25-7.35 (m, 5H, Ar-H); 13C
NMR (151 MHz, CDCl3) δ 40.6 (C-2), 61.5 (C-3), 74.4 (C-1),
125.8, 127.7, 128.6 (Ar-C), 144.4 (Ar-Cipso).
Ozonolysis and Reduction with LiAlH4 (Scheme 11). The
homoallyl alcohol (0.10 mmol) was dissolved in CH2Cl2 (10 mL)
and cooled to -78 °C in a flask equipped with a Teflon stopcock
and gas inlet frit (quickfit with Teflon gasket). A O3/O2 mixture
was bubbled through the solution until it was a persistent blue
color. Excess O3 was expelled by a stream of O2. Me2S (1 mL) was
added to the reaction mixture, which was allowed to warm to room
temperature, before it was concentrated and dried under reduced
pressure. The residue was dissolved in THF (10 mL), and LiAlH4
(4.00 mmol) was added. After 1 h, the mixture was diluted with
Et2O (10 mL) and cooled to 0 °C. Successively, H2O (121μL), 15%
aqueous NaOH (121 μL), and H2O (358 μL) were carefully added
and stirred (for about 30 min) until a filterable precipitate formed.
The filter cake was washed thoroughly with Et2O. The filtrate was
concentrated under reduced pressure and subjected to flash col-
umn chromatography on silica gel (petroleum ether/ethyl acetate,
60:40), yielding 1,3-diols 25 and 26 as colorless oils.
(1S)-1-Phenylpropane-1,3-diol (25). According to the general
procedure, 1,5-diol 18ka (64.5 mg, 0.36 mmol, 1.00 equiv) was
dissolved in dry CH2Cl2 (13 mL) and treated with an O3/O2
mixture. After column chromatography (8 g of silica gel,
petroleum ether/ethyl acetate, 50:50), 1,3-diol 25 (47.2 mg,
0.31 mmol, 87%) was isolated as a colorless oil. The spectro-
scopic data were in full agreement with those reported in the
literature.12d [R]20D = -65.8 (c 0.96, CHCl3); 1H NMR (600
MHz, CDCl3) δ 1.90 (dddd, J=3.6, 4.4, 5.8, 14.6 Hz, 1H, 2-Ha),
1.98 (dddd, J = 5.0, 7.0, 8.9, 14.6 Hz, 1H, 2-Hb), 2.83 (br,
1H, OH), 3.28 (br, 1H, OH), 3.80-3.83 (m, 2H, 3-H), 4.92
Acknowledgment. We gratefully acknowledge the Deutsche
€
€
Forschungsgemeinschaft, the Otto-Rohm-Gedachtnisstiftung,
the Fonds der Chemischen Industrie, the Ministry of Innovation,
Science, Research and Technology of the German federal state
€
of North Rhine-Westphalia, the Jurgen Manchot Stiftung, the
€
€
Degussa Stiftung, and the Heinrich-Heine-UniversitatDusseldorf
for their generous support of our projects. We also thank BASF
AG, Bayer AG, Cognis GmbH, Evonik AG, Wacker AG,
Umicore AG, Chemetall GmbH, Codexis Inc., and evocatal
for their kind donations and contributions to our research.
Furthermore, we thank the analytical departments at the Uni-
€
versity of Stuttgart and Forschungszentrum Julich, as well as
Monika Gehsing, Rainer Goldbaum, Verena Doum, Birgit
Henssen, Erik Kranz, Christoph Lorenz, Vera Ophoven, Bea
Paschold, Truc Pham, Saskia Schuback, and Dennis Weidener
for their ongoing support.
Supporting Information Available: Full experimental de-
tails, compound characterization, copies of 1H and 13C spectra
of all pure products, also including the complete experimental
procedure for the synthesis of boronic ester 1a, formation of
benzoates for HPLC analysis, HPLC chromatograms for 18ka/
ent-18ka and 18kg/ent-18kg, Mosher ester method exemplified
for compound 17jg, and X-ray structural analyses of com-
pounds 17jg and 28aa. This material is available free of charge
via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 16, 2010 5589