Catalytic asymmetric hydroboration of β,γ-unsaturated Weinreb amides: Striking influence of the borane

Article abstract of DOI:10.1039/c1cc11746g

Subtle differences in the structure of the borane strongly influence the catalytic efficiency and level of enantioselectivity in the catalytic asymmetric hydroboration of β,γ-unsaturated Weinreb amides.

Full text of DOI:10.1039/c1cc11746g

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COMMUNICATION
Catalytic asymmetric hydroboration of b,c-unsaturated Weinreb amides:
striking influence of the boranewz
Sean M. Smith, Maulen Uteuliyev and James M. Takacs*
Received 28th March 2011, Accepted 11th May 2011
DOI: 10.1039/c1cc11746g
Subtle differences in the structure of the borane strongly influence
the catalytic efficiency and level of enantioselectivity in the
catalytic asymmetric hydroboration of b,c-unsaturated Weinreb
amides.
enantioselectivity are presumably in part a consequence of
efficient two-point binding of the substrate carbonyl and alkene
moieties to rhodium.12–14
N-Phenyl amides have the advantage of being chemically
robust. Weinreb amides, while not as robust, are more readily
transformed into other useful functional groups.15 Replacing
the N-phenyl amide with the Weinreb amide moiety should
still permit the desired two-point binding but afford a product
with greater potential synthetic utility. However, rhodium-
catalyzed CAHB of (E)-1b with PinBH (B1) affords, after
oxidation, the corresponding b-hydroxyacid product (S)-3b in
good yield but relatively disappointing enantiomeric purity
(75%, 83% ee). Unlike amide (E)-1a, the oxidative workup
with hydrogen peroxide both replaces the carbon–boron bond
and hydrolyzes the amide (Fig. 1).16
Chiral organoboranes and organoboronates are widely used as
chiral reagents for asymmetric synthesis1 and, along with
organoboronate-derived trifluoroborate salts, are valuable
synthetic intermediates for subsequent functional group inter-
conversions.2 Several methods have also been developed for
their stereospecific conversions to carbon–carbon bonds. For
example, carbon–carbon bond formation can be accomplished
via the Matteson protocol, which exploits a stereospecific
rearrangement to effect the one carbon homologation of
organoboronates.3 Alternatively, organoboronates have been
shown by Knochel to undergo stereospecific transmetalation
to zinc enabling carbon–carbon bond formation.4 Recent
independent reports by Crudden, Molander, Suginome, and
Aggarwal now enable stereospecific carbon–carbon bond
formation with chiral organoboronates or organoboronate-
derived trifluoroborate salts via palladium-catalyzed Suzuki-
Miyaura cross-coupling5 and rhodium-catalyzed carbonyl
addition reactions.6 These methods greatly enhance the utility
of chiral organoboronates and have generated renewed research
interest in their enantioselective synthesis.
Recent work by Crudden highlighted the mechanistic
importance of the borane in the rhodium-catalyzed hydro-
boration of internal disubstituted alkenes.17 In other studies,
Crudden, Fernandez, and Brown independently reported
that PinBH (B1) and catecholborane (CatBH, B11) can give
products with complementary regio- and/or enantioselectivity
under otherwise identical conditions.18 The use of alternative
borane sources for catalytic hydroboration otherwise has been
fairly limited.19 Boranes B7 (TMDB) and B9 were mentioned
in the original report by Mannig and Noth20 describing
¨
¨
Several new catalytic asymmetric reactions afford chiral
organoboronates in high enantiopurity.7–9 Among these, we
reported highly enantioselective catalytic asymmetric hydro-
borations10 (CAHB) with recent work focusing on the carbo-
nyl-directed reactions of acyclic b,g-unsaturated phenyl
amides.11 BINOL-derived monophosphoramidite L is among
the most successful ligands for the latter reactions. For example,
b,g-unsaturated phenyl amide (E)-1a undergoes CAHB with
PinBH (B1) using Rh(nbd)2BF4 in conjunction with phosphor-
amidite L to give b-hydroxyamide (S)-3a in 78% yield and
93% ee after oxidation (Fig. 1). The high levels of regio- and
Department of Chemistry, University of Nebraska-Lincoln, Lincoln,
Nebraska, USA. E-mail: jtakacs1@unl.edu; Fax: +1 402 472 9402;
Tel: +1 402 472 6232
w This article is part of the ChemComm ‘Advances in catalytic C–C
bond formation via late transition metals’ web themed issue.
z Electronic supplementary information (ESI) available: Detailed
procedures and compound characterization. See DOI: 10.1039/
c1cc11746g
Fig. 1 CAHB-oxidation of b,g-unsaturated Weinreb amide (E)-1b.
c
7812 Chem. Commun., 2011, 47, 7812–7814
This journal is The Royal Society of Chemistry 2011

obtained using the six-membered ring dioxaborinanes B6–B10
are on average more selective (average of 70% ee) than those
obtained using the five-membered ring dioxaborolanes B1–B5
(average of 49% ee). Comparing specific five- and six-membered
ring boranes with similar methyl substitution patterns finds
some similarities and some extreme differences. For example,
the tetramethyl derivatives, B1 (PinBH, 83% ee) and B6 (90% ee),
and trimethyl derivatives, B2 (84% ee) and B7 (92% ee) afford
quite similar results. In contrast, the monomethyl derivatives,
B5 (14% ee) and B10 (94% ee) differ radically.22
CatBH (B11) was at one time the most commonly used
borane for rhodium-catalyzed hydroborations, particularly
for the hydroborations of vinylarenes.23 However, CatBH
(B11) affords only low levels of asymmetric induction in the
CAHB of (E)-1b. While all other boranes tested give predo-
minantly (S)-3b, the hybrid borane B12 produces (R)-3b as the
major enantiomer, albeit the enantiomeric excess (50%) is only
modest.24
As shown in Table 1, all four substrates undergo highly
selective CAHB-oxidation with TMDB (B7). Their corresponding
b-hydroxyacids are isolated in good yield (72–77%) and high
enantiopurity (92–97% ee). TMDB (B7) is chiral and thus
raises the possibility of matched/mismatched stereochemical
influences in its CAHB reactions. However, this does not
appear to be the case. The individual (R)- and (S)-TMDB
reagents were prepared and each found to add to (E)-6 to give
(S)-7 with essentially the same efficiency, 71% yield (96% ee)
with (R)-TMDB and 73% yield (97% ee) with (S)-TMDB.
The alkene geometry is important with some of the boranes
tested. Both (E)- and (Z)-6 give (S)-7 in comparable enantiomeric
excess with B2 (87–88% ee) and with TMDB (B7, 97% ee). In
contrast, the tetramethylsubstituted boranes PinBH (B1) and
B6 show significant differences; (Z)-6 reacts with higher selec-
tivity (82% and 98% ee for PinBH (B1) and B6, respectively)
than (E)-6 (50% and 73% ee, respectively). Similarly, the
corresponding gem-dimethyl substituted borane derivative
B3 affords (S)-7 in only 55% ee from (E)-6 but in higher
selectivity (83% ee) from (Z)-6. The corresponding reactions
using gem-dimethyl derivative B8 give 60% and 96% ee,
respectively, from the (E)- and (Z)-isomers of 6.
Fig. 2 Structures of boranes (i.e., B1–B12) evaluated for the CAHB
of (E)- and (Z)-b,g-unsaturated Weinreb amides.
rhodium-catalyzed hydroboration but have received little
use since.21 Consequently, a series of five-membered ring
1,3,2-dioxaborolanes B1–B5, six-membered ring 1,3,2-
dioxaborinanes B6–B10, CatBH (B11), and the hybrid structure
B12 were evaluated in the CAHB of b,g-unsaturated Weinreb
amides (Fig. 2).
Table 1 summarizes the chemical yield and enantioselectivity
as a function of borane for the CAHBs of Weinreb amides
(E)-1b, (E)-4, (E)-6 and (Z)-6. Focusing on (E)-1b, the results
Table 1 Efficacy of the borane varies as a function of substrate
In addition to the variation in enantioselectivity, the yield of
b-hydroxyacid varies widely as a function of borane. PinBH
(B1) and TMBD (B7) consistently give good yields (70–77%)
across the series of substrates. Other boranes, for example, B3,
B4 and B5, consistently give low yields (5–42%) for all
substrates. In still other puzzling cases (e.g., B2, B6, B8 and
B10), the yield varies widely among the substrates. For
example, B8 gives 96–97% ee in the reactions both of (E)-1b
and (Z)-6. The yields, however, are 81% for the former and
only 20% for the latter. The yield of rhodium-catalyzed
hydroboration can be compromised by competing catalyzed
disproportionation of the borane.25 This seems to contribute
to the low yield of the hydroboration product in at least some
of the examples shown in Table 1. For example, the CAHB
of (E)-6 was monitored via 11B NMR for selected boranes. It
was found that several of the less effective boranes (e.g., B2, B8
and B10) are competitively consumed via disproportionation
leaving unreacted (E)-6 accompanying the desired hydroborated
product.
% Yield (% ee) for the CAHB of
(E)-1b
(E)-4
(E)-6
(Z)-6
Borane
B1
B2
B3
B4
B5
B6
B7
(R)-B7
(S)-B7
B8
75 (83)
79 (84)
40 (81)
10 (50)
16 (14)
78 (90)
77 (92)
—
75 (75)
50 (85)
40 (60)
25 (7)
5 (6)
30 (91)
76 (96)
—
70 (50)
40 (88)
30 (55)
15 (14)
25 (5)
70 (73)
73 (97)
71 (96)
73 (97)
11 (60)
15 (32)
10 (58)
15 (15)
79 (5)b
70 (82)
40 (87)
42 (83)
20 (20)
10 (3)
50 (98)
72 (97)
—
—
—
—
81 (97)
50 (81)
78 (94)
16 (15)
75 (50)b
40 (88)
20 (70)
25 (80)
20 (10)
15 (70)b
20 (96)
60 (93)
32 (91)
12 (20)
75 (44)b
B9
B10
B11a
B12a
a
b
Reaction was carried out at room temperature. In contrast to other
boranes, the (R)-enantiomer of the b-hydroxyacid predominates with
B12.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7812–7814 7813

4 E. Hupe, M. I. Calaza and P. Knochel, Chem.–Eur. J., 2003, 9,
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Scheme 1 (a) KHF2, MeOH/H2O (82%); (b) NaBO3, H2O/THF
(98%); (c) TBSCl, imidazole, DMAP, DMF (82%); (d) DIBAL-H,
THF (91%); (e) PhMgBr, THF (94%).
As demonstrated above, the CAHB-oxidation (i.e., workup
with basic H2O2) of b,g-unsaturated Weinreb amides can be used
to prepare b-hydroxyacids in good yields and excellent levels of
enantiopurity. Omitting the harsh oxidative workup by directly
subjecting the crude reaction mixture to flash chromatography
on silica gel, permits isolation of the chiral organoboronate.
For example, 8 is obtained in good yield (79%) from (E)-4.
Scheme 1 shows several subsequent transformations to illustrate
its synthetic utility. Conversion of 8 to the b-trifluoroborato
Weinreb amide 9 is accomplished in 82% yield by treatment with
KHF2. Mild oxidation of 8 with sodium perborate (NaBO3)
proceeds without amide hydrolysis to afford the b-hydroxy
Weinreb amide 10 (98% yield). Following TBS-protection
(82%), half reduction via treatment with DIBAL-H gives the
b-silyloxyaldehyde 11 (91%). Alternatively, addition of phenyl
Grignard reagent produces the b-silyloxyketone 12 (94%).
In summary, Weinreb amides are effective substrates for
carbonyl-directed CAHB of b,g-unsaturated alkenes. Large dif-
ferences in reactivity and selectivity are observed when Weinreb
amides are screened across a library of 1,3,2-dioxaborolane and
-dioxaborinane derivatives illustrating the importance of the
borane in the success of the reaction. It seems clear that the
structure of the borane must influence the relative stabilities and/
or reactivities of key intermediates. Mechanistic studies are in
progress.
16 The enantiopurity of (S)-3b was determined by subsequent benzylation
and chiral HPLC analysis.
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Financial support for this research from the NSF (CHE-
0809637) is gratefully acknowledged. We thank B. P. Polez
(UNL Chemistry) for some key preliminary experiments and
the NSF (CHE-0091975, MRI-0079750) and NIH (SIG-1-510-
RR-06307) for the NMR spectrometers used in these studies
carried out in facilities renovated under NIH RR016544.
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25 Although disproportionation presumably forms BH3, we do not
see evidence for it contributing significantly to hydroboration. See:
S. W. Hadebe and R. S. Robinson, Eur. J. Org. Chem., 2006,
4898–4904; and references cited therein.
Notes and references
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´
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7814 Chem. Commun., 2011, 47, 7812–7814
This journal is The Royal Society of Chemistry 2011