9-Borabicyclo[3.3.2]decanes and the asymmetric hydroboration of 1,1-disubstituted alkenes

Article abstract of DOI:10.1021/ja803119p

The syntheses of the optically pure asymmetric hydroborating agents 1 (a, R = Ph; b, R = TMS) in both enantiomeric forms are reported. These reagents are effective for the hydroboration of cis-, trans- and trisubstituted alkenes. More significantly, they exhibit unprecedented levels of selectivity in the asymmetric hydroboration of 1,1-disubstituted alkenes (28-92% ee), a previously unanswered challenge in the nearly 50 year history of this reagent-controlled process. For example, the hydroboration of α-methylstyrene with 1a produces the corresponding alcohol 6f in 78% ee (cf., Ipc₂BH, 5% ee). Suzuki coupling of the intermediate adducts 5 produces the nonracemic products 7 very effectively (50-84%) without loss of optical purity. Copyright

Full text of DOI:10.1021/ja803119p

Published on Web 06/27/2008
9-Borabicyclo[3.3.2]decanes and the Asymmetric Hydroboration of
1,1-Disubstituted Alkenes
Ana Z. Gonzalez, Jose´ G. Roma´n, Eduvigis Gonzalez, Judith Martinez, Jesus R. Medina,
Karl Matos, and John A. Soderquist*
UniVersity of Puerto Rico, Department of Chemistry, Rio Piedras, Puerto Rico 00931-3346
Received April 28, 2008; E-mail: jas@janice.uprr.pr
In their seminal study, Brown and Zweifel ushered in the modern
era of reagent-controlled asymmetric synthesis with the hydrobo-
ration of cis-alkenes employing diisopinocampheylborane (Ipc2BH,
Figure 1, A).1 The instability of this reagent with respect to
dehydroboration, led to the development of monoisopinocampheyl-
borane (IpcBH2) (Figure 1, B)2 which was found to be effective
for trans- and trisubstituted alkenes. In some cases, the intermediate
Figure 1. Asymmetric hydroborating agents.
mixed dialkylborane dimers can be crystallized to provide enan-
tiomerically pure organoboranes for many synthetic applications.2b
Scheme 1
Masamune’s C2-symmetric borolane (DMB, Figure 1, C) is highly
selective for all of these substrates, namely cis, trans, and
trisubstituted alkenes.3 Unfortunately, none of theses reagents,
including a Rh-BINAP catalyzed process,4 is effective for the
hydroboration of 2-substituted-1-alkenes (e.g., R-methylstyrene,
Ipc2BH, 5% ee; 2-methyl-1-butene, IpcBH2, 1% ee; 2,3-dimethyl-
1-butene, DMB, 1.4% ee; 2-phenyl-1-butene, catecholborane, Rh-
BINAP, 46% ee;). To address this nearly 50 year-old challenge,
we wish to report the preparation of the 10-substituted-9-bora-
bicyclo[3.3.2]decanes (10-R-9-BBD-H, 1) and their unique behavior
in the asymmetric hydroboration of 1,1-disubstituted alkenes.
The BBD-pseudoephedrine complexes 2a (R ) Ph)5a and 2b
(R ) TMS)5b were treated with LiAlH3(OEt) producing an insoluble
dialkoxyalane which was easily separated from the soluble boro-
hydrides 3 (11B NMR: 3a δ -12.4 (t, J ) 67 Hz), 3b δ -20.0 (t,
J ) 67 Hz) by decantation (Scheme 1). The reagents 1 were
generated by the addition of TMSCl (or MeI) to 3. Both 1a and 1b
form 1:1 trans adducts with pyridine (i.e., 4 11B NMR δ 5.0, 3.1,
respectively). The reagents 1 differ considerably in that 1a is
completely dimeric in solution at 25 °C (11B NMR δ 27.4), whereas
its more crowded counterpart 1b exists as a 3:1 mixture of monomer
(11B NMR δ 79) and dimer (11B NMR δ 27) at room temperature.6
Interestingly, dimer 1a is observed by 13C NMR as a 60:40 mixture
of two isomeric forms (i.e., “cis/trans”, see Scheme 1). It is probable
that this phenomenon contributed to the fact that we were unable
to obtain 1a dimer as a crystalline compound. For this reason, we
chose to freshly generate this and 1b from 3 in the presence of the
alkene to be hydroborated. Representative alkenes were examined
with both 1a and 1b and these results are presented in Table 1.
Both 1a and 1b exhibit remarkable selectivity in the asymmetric
hydroboration of 1,1-disubstituted alkenes. Hydroborations with 1a
are complete in <12 h at 25 °C. However, the bulkier 1b is less
reactive (R-methylstyrene (48 h), 2,3,3-trimethyl-1-butene (168 h)).
Both reagents exhibit unprecedented levels of selectivity in the
hydroboration of 2-methyl-1-alkenes (cf., 6f from 1a (78% ee),
Ipc2BH, 5% ee1b). Moreover, larger differences in the size of RS
vs RL result in higher selectivity (cf., R-deuteriostyrene, 6g from
1a (92% ee), HOCH2CHDPr from Ipc2BH, 48% ee1c).
1a gives the same alcohol (32% ee) while with 1b, the epimeric
adduct is formed giving the enantiomeric form of 6a in 84% ee.
The reaction of 2-methyl-2-butene is very slow with 1b, but it does
react smoothly with 1a (12 h, 25 °C) to produce 6b in 74% ee.
Our explanation for these selectivities is depicted in Figure 2.
For both 1a and 1b, the 1,1-disubstituted alkenes approach from
the side opposite to the 10-R system positioning the larger alkene
substituent away from this group. However, the preferred boat/
chair conformations are reversed for 1a vs 1b with respect to the
10-R group.5 Thus, the long C-SiMe3 bond (1.92 Å) in 1b favors
the boat side of the ring syn to the TMS group, while the shorter
C-Ph (1.52 Å) bond in 1a results in ring-Ph interactions which favor
the chair form syn to the 10-Ph group.5 In the case of alkenes with
R-substitution (i.e., cis, trans, and tri), for 1a, the approaching alkene
experiences a protruding boat form which exerts a major R-directive
effect (vide supra). The hydroboration of trans-2-butene is highly
selective because this steric effect is reinforced by those of the 10-
Ph group. For cis-2-butene, these effects conflict with the ring
playing the dominant role. In 1b, the flatter chair form of the ring
produces only minor interactions resulting in a process essentially
directed by the 10-TMS group.
Other alkene types undergo selective hydroboration with 1. Thus,
the hydroboration of trans-2-butene with 1a and 1b produces
2-butanol 6a in 96 and 95% ee, respectively. With cis-2-butene,
9
9218 J. AM. CHEM. SOC. 2008, 130, 9218–9219
10.1021/ja803119p CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Asymmetric Hydroboration of Representative Alkenes
with 1
Scheme 2
alkene
borane
R1
R2
R3
6
yield (%)a
eeb
abs configurationc
1aS
1bR
1aS
1bR
1aS
1aR
1bR
1aR
1bS
1aS
1bR
1aS
1bR
1aS
1bS
1aS
1aR
1aS
1aR
Me
Me
Me
Me
Me
H
H
H
H
H
Me
Me
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
D
D
H
H
Me
Me
Me
Et
a
a
a
a
b
c
c
d
d
e
e
f
>90
98
>90
95
79
83
87
97
82
84
60
95
83
97
86
94
94
93
93
32
84
96
95
74
28
40
38
52
92
56
78
66
92
98
97d
99d
76d
22d
S
S
S
R
S
S
S
S
R
R
S
R
S
R
R
Et
i-Pr
i-Pr
t-Bu
t-Bu
Ph
Ph
Ph
Ph
H
H
H
H
from the oxidation of 5 (i.e., 6).9 The eight examples which were
examined are shown in Scheme 1. We selected aryl, heteroaryl,
and vinyl bromides to couple with 5 producing the desired Suzuki
products 7 in 50-84% yields.
The synthesis of the asymmetric hydroborating agents 1 has been
reported. These reagents exhibit unprecedented selectivity in the
hydroboration of 1,1-disubstituted alkenes producing 5 which can
either be oxidized to give nonracemic primary alcohols 6 or coupled
to electrophilic substrates through the Suzuki protocol to give 7
whose optical purities are determined by those of the organoborane
precursor 5.
f
g
g
h
h
i
H
ꢀ-pinene
ꢀ-pinene
R-limonene
R-limonene
1S,2R,5S
1S,2R,5S
4R,8R
4R,8R
i
a Isolated yields of analytically pure material except for 6a whose
yields were determined by GC using an internal standard. b Product ee
was determined by 31P NMR after conversion of 6 to the corresponding
Alexakis esters. For some cases, analysis was accomplished through 13C
NMR of Mosher esters derivatives. c Absolute configuration determined
by comparison to literature values (see Supporting Information).
d Diastereomeric excess.
Acknowledgment. This work is dedicated to Professor Akira
Suzuki. The support of the NSF (Grant CHE-0517194) and NIH
(Grant S06GM8102) is gratefully acknowledged. We thank Profes-
sor Bakthan Singaram for helpful discussions regarding this work.
Supporting Information Available: Experimental procedures,
analytical data and selected spectra for 1-7, and derivatives. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1961, 83, 486. (b) Zweifel,
G.; Ayyangar, R.; Munekata, T.; Brown, H. C. J. Am. Chem. Soc. 1963, 85,
1076. (c) Zaidlewicz, M. in ComprehensiVe Organometallic Chemistry;
Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon: Oxford, 1982,
7, 229, and references cited therein.
(2) (a) Brown, H. C.; Schwier, J. R.; Singaram, B. J. Org. Chem. 1978, 43,
4397. (b) Brown, H. C.; Singaram, B. J. Am. Chem. Soc. 1984, 106, 1797.
(c) Brown, H. C.; Jadhav, P. K.; Mandal, A. K. J. Org. Chem. 1978, 43,
5074. (d) Srebnik, M.; Ramachandran, P. V. Aldrichimica Acta 1987, 20, 9.
(3) Masamune, S.; Kim, B. M.; Petersen, J. S.; Sato, T.; Veenstra, S. J.; Imai,
T. J. Am. Chem. Soc. 1985, 107, 4549.
Figure 2. Possible origins of the observed selectivity in the asymmetric
hydroboration of alkenes with 10-Ph-9-BBD (1a, bottom) and 10-TMS-9-
BBD (1b, top). The preferred orientations for 1,1-disubstituted, cis- and
trans-2-butene are illustrated above. Notice the outward protrusion of the
boat form of the 10-Ph-9-BBD (1a) ring (R-directing for cis, trans and
trisubstituted alkenes) vs the flatter chair form for 1b with respect to the
approaching alkene. MM space-filling models were generated with Spartan
06.
(4) (a) Hayashi, T.; Matsumoto, Y.; Ito, Y. Tetrahedron Asymmetry 1991, 2,
601. (b) Burgess, K.; Ohlmeyer, M. J. Chem. ReV. 1991, 91, 1199.
(5) (a) Canales, E.; Prasad, K. G.; Soderquist, J. A. J. Am. Chem. Soc. 2005,
127, 11572. (b) Burgos, C. H.; Canales, E.; Matos, K.; Soderquist, J. A.
J. Am. Chem. Soc. 2005, 127, 8044.
Chiral substrates7 such as ꢀ-pinene can override the reagent
control exhibited by 1 giving cis-myrtanol with both 1aR and 1aS
reagents. However, with the less rigid R-limonene, the matched
combination with 1aS gives an impressive 88:12 dr.
Because of its greater rate of hydroboration compared to 1b, we
chose to employ 1a to prepare 5a (R1 ) H) for Suzuki couplings
(Scheme 2).8 Through this process, we can prepare nonracemic 1°-
alkylboranes which generally make excellent partners for this
coupling. This contrasts to the behavior of the normal products of
asymmetric hydroboration, namely 2°-alkylboranes, which reduce
rather than couple with the electrophilic component in this process.
Further, we felt that this new chemistry would provide a reliable
protocol for preparing relatively unfunctionalized compounds with
optical purities that would be known from the values determined
(6) We determined values of ∆H ) 57.8 KJ mol-1 and ∆S ) 203 J K-1 mol-1
for the dissociation of (()-1b dimer. See: (a) Soderquist, J. A.; Matos, K.;
Burgos, C. H.; Lai, C.; Vaquer, J.; Medina, J. R. In Contemporary Boron
Chemistry; Davidson M. G., Hughes A. K., Marder, T. B., Wade, K., Eds.;
Royal Society of Chemistry: Cambridge, U.K., 2000; pp 472-482. (b)
Soderquist, J. A.; Matos, K.; Burgos, C. H.; Lai, C.; Vaquer, J.; Medina,
J. R.; Huang, S. D. In Organoboranes for Syntheses; Ramachandran, P. V.,
Brown, H. C., Eds.; ACS Symposium Series 783; American Chemical
Society: Washington, D. C., 2000; Chapter 13, pp 176-194.
(7) For substrate control, see for example: Evans, D. A.; Fu, G. C.; Hoveyda,
A. H. J. Am. Chem. Soc. 1992, 114, 6671.
(8) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147. (c) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633. (d) Danishefsky, S. J.; Chemler, S. R.; Trauner,
D. Angew. Chem., Int. Ed. 2001, 40, 4544.
(9) No kinetic resolution of diasteromeric 5a was observed with its complete
reaction in both processes (e.g., 7g, 7h, 6i: dr ) 88:12).
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