Bidirectional metalation of hydrobenzoin: Direct access to new chiral ligands and auxiliaries

Article abstract of DOI:10.1021/ol900323u

A bidirectional ortho metalation of the readily available chiral diol hydrobenzoin has been developed that provides direct access to new ortho-functionalized hydrobenzoin derivatives. This one-pot procedure should broaden the utility of hydrobenzoin as an

Full text of DOI:10.1021/ol900323u

ORGANIC
LETTERS
2009
Vol. 11, No. 9
1903-1906
Bidirectional Metalation of
Hydrobenzoin: Direct Access to New
Chiral Ligands and Auxiliaries
Inhee Cho, Labros Meimetis, and Robert Britton*
Department of Chemistry, Simon Fraser UniVersity, 8888 UniVersity DriVe,
Burnaby, BC, Canada V5A 1S6
rbritton@sfu.ca
Received February 13, 2009
ABSTRACT
A bidirectional ortho metalation of the readily available chiral diol hydrobenzoin has been developed that provides direct access to new
ortho-functionalized hydrobenzoin derivatives. This one-pot procedure should broaden the utility of hydrobenzoin as an auxiliary and ligand
in asymmetric synthesis.
The discovery of new chiral auxiliaries or ligands for
catalysis continues to broaden the scope of many asymmetric
processes.1 Oftentimes, however, the general utility of these
auxiliaries/ligands is hampered by their cost, complexities
associated with their syntheses, or their sole availability as
a single enantiomer.2 Consequently, the identification of
cheap or readily accessible chiral scaffolds is an important
pursuit. Both (S,S)- and (R,R)-hydrobenzoin (e.g., 1, Figure
1) are readily available3 and relatively inexpensive4 and have
been used as auxiliaries5,6 and ligands7 in a variety of
asymmetric processes. For example, the boron enolate
derived from oxapyrone 2 has shown useful levels of
diastereoselectivity in glycolate aldol additions,5b and the
ketene acetal 3 has been utilized in diastereoselective
heterodiene cycloadditions.5f Notably, the diastereomeric
Figure 1. (R,R)-Hydrobenzoin (1), hydrobenzoin-containing chiral
(1) (a) Mellah, M.; Voituriez, A.; Schulz, E. Chem. ReV. 2007, 107,
5133. (b) Blaser, H.-U.; Pugin, B.; Spindler, F.; Thommen, M. Acc. Chem.
Res. 2007, 40, 1240. (c) Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res.
2007, 40, 1278. (d) Shibasaki, M.; Matsunaga, S. Chem. Soc. ReV. 2006,
35, 269. (e) Desimoni, G.; Faita, G.; Jorgensen, K. A. Chem. ReV. 2006,
106, 3561.
reagents and catalysts, and the novel tetraanion 10.
ratio of the latter process increased from 7:3 to 9:1 with the
introduction of a bromine atom in the ortho position on the
(2) Blaser, H.-U.; Studer, M. Chirality 1999, 11, 459.
(3) For a 100 g scale synthesis of (R, R)-1 from benzoin, see: Ikariya,
T.; Hashiguchi, S.; Murata, K.; Noyori, R. Org. Synth. 2005, 82, 10. For a
1 kg scale synthesis of (R,R)-1 from trans-stilbene, see: Wang, Z.-M.;
Sharpless, K. B. J. Org. Chem. 1994, 59, 8302.
(4) Current Aldrich prices for (R,R)-1: $2.11(CDN)/mmol. For com-
parison purposes the price of (R)-BINOL is $16.35(CDN)/mmol.
10.1021/ol900323u CCC: $40.75
Published on Web 03/27/2009
 2009 American Chemical Society

aromatic rings (i.e., 4). Similarly, whereas the diol·SnCl4
complex 5 was unable to impart significant enantioselectivity
to the allylboration of hydrocinnamaldehyde (26% ee), the
ortho-substituted derivative 6 proved to be an excellent
catalyst for this reaction (93% ee).7a Though these ortho-
substituted analogues of hydrobenzoin display improved
stereoselectivities over 1, their multistep preparation8,9 and
necessary enrichment to optical purity10 realistically pre-
cludes the rapid production of congeneric libraries for ligand
screening. As part of an ongoing total synthesis effort, we
recently became interested in the use of Brønsted acids (e.g.,
7) as catalysts for asymmetric inverse electron-demand
Diels-Alder reactions11 and required rapid access to a
variety of chiral diols for ligand screening purposes. Toward
this goal, we endeavored to develop a direct synthesis of
hydrobenzoin derivatives via the unprecedented tetraanion
10. Herein we describe our efforts toward the realization of
this goal, as well as the application of this reaction to the
one-step synthesis of ortho-functionalized hydrobenzoin
derivatives.
zoin derivatives.14 Toward this end we initiated a large screen
of reaction conditions and were delighted to eventually find
that addition of excess n-BuLi to a suspension of (R,R)-
hydrobenzoin (1) in a refluxing mixture of hexane/Et2O
(4:1) resulted in the gradual dissolution of 1 and formation
of a deep red solution that when treated with D2O allowed
for clean recovery of (R,R)-hydrobenzoin15 with 75% of the
expected deuterium incorporation for 12 (Table 1, entry 1).
Table 1. Bidirectional Metalation of (R,R)-Hydrobenzoin (1)
alkyl lithium
(equivalents)a
hexane:
Et2O
% deuterium
,
entry
time
incorporationb c
1
2
3
4
5
6
7
n-BuLi (8)
s-BuLi (8)
n-BuLi (8)
n-BuLi (8)
n-BuLi (8)
n-BuLi (8)
n-BuLi (6)
4:1
4:1
4:1
3:1
2:1
1:1
2:1
8
8
24
8
8
8
16
75
65
82
73
83
78
92
Although the hydroxymethyl group has received limited
use in directed ortho metalation (DoM) reactions,12,13 we
envisaged a process whereby consecutive ortho metalations
of 1 would lead to the tetraanion 10 (Figure 1), the
subsequent treatment of which with various electrophiles
would provide direct access to ortho-substituted hydroben-
a Reactions carried out on 0.5 mmol scale in refluxing solvent, [1] )
0.08 M. b Calculated from integration of 1H NMR spectra of crude reaction
products using the following formula (∫benzyl protons ) 2): |(∫ortho
protons)/2 - 2| × 100%. c 11 and 12 were indistinguishable by 1H, 13C, or
2D NMR.
(5) For example, see: (a) Broeker, J.; Knollmueller, M.; Gaertner, P.
Tetrahedron: Asymmetry 2006, 17, 2413. (b) Andrus, M. B.; Sekhar,
B. B. V. S.; Meredith, E. L.; Dalley, N. K. Org. Lett. 2000, 2, 3035. (c)
Kim, K. S.; Lee, Y. J.; Kim, J. H.; Sung, D. K. Chem. Commun. 2002,
1116. (d) Maze´, F.; Purpura, M.; Bernaud, F.; Mangeney, P.; Alexakis, A.
Tetrahedron: Asymmetry 2001, 12, 1957. (e) Marshall, J. A.; Xie, S. J.
Org. Chem. 1995, 60, 7230. (f) Wallace, T. W.; Wardell, I.; Li, K.-D.;
Leeming, P.; Redhouse, A. D.; Challand, S. R. J. Chem. Soc., Perkin Trans.
1 1995, 2293. (g) Fujioka, H.; Kitagawa, H.; Nagatomi, Y.; Kita, Y.
Tetrahedron: Asymmetry 1995, 6, 2113.
Although use of s-BuLi (entry 2) or addition of TMEDA13d
failed to improve upon this result, a slight increase in
deuterium incorporation was observed when the reaction time
was increased to 24 h (entry 3). The optimal ratio of hexane/
Et2O was also investigated and found to be 2:1 (entries 4-6).
Monitoring the formation of the tetraanion 10 by measure-
ment of butane gas evolution indicated that rapid (20 min)
deprotonation of the two alcohol functions is followed by
slow (16 h) removal of two ortho protons. On the basis of
these observations, the optimized conditions for the formation
of 12 and consequently the production of the tetraanion 10
are summarized in entry 7.
(6) For examples of chiral phosphepines and thiepines that incorporate
hydrobenzoin, see: (a) Wyatt, P.; Hudson, A.; Charmant, J.; Orpen, A. G.;
Phetmung, H. Org. Biomol. Chem. 2006, 4, 2218. (b) Wyatt, P.; Warren,
S.; McPartlin, M.; Woodroffe, T. J. Chem. Soc., Perkin Trans. 1 2001,
279, and references therein.
(7) For example, see: (a) Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am.
Chem. Soc. 2008, 130, 8481. (b) Mlynarski, J.; Jankowska, J.; Rakiel, B.
Tetrahedron: Asymmetry 2005, 16, 1521. (c) Mlynarski, J.; Mitura, M.
Tetrahedron Lett. 2004, 45, 7549. (d) Terfort, A.; Brunner, H. J. Chem.
Soc., Perkin Trans. 1 1996, 1467. (e) Amurrio, D.; Khan, K.; Ku¨ndig, E. P.
J. Org. Chem. 1996, 61, 2258. (f) Tomioka, K.; Shindo, M.; Koga, K. J. Am.
Chem. Soc. 1989, 111, 8266.
The progress of the reaction of 1 with n-BuLi under the
optimized conditions (Table 1, entry 7) was also monitored
by mass spectrometry following D2O quench. The data
presented in Figure 2 suggest that a relatively slow removal
of one ortho proton is followed by a more rapid removal of
(8) For the synthesis of ortho-substituted hydrobenzoin derivatives, see
refs 5f, 6a, 6b, 7a, and 7d.
(9) The synthesis of ortho-functionalized hydrobenzoins typically
involves McMurry coupling of an ortho-substituted benzaldehdye, followed
by I2-catalyzed isomerization of the resulting stilbene and Sharpless
asymmetric dihydroxylation. For examples where Sharpless asymmetric
dihydroxylation of ortho-functionalized trans-stilbenes fails to provide the
desired diol, see ref 7a.
3
the second ortho proton to generate 10. Unfortunately, Li
and 1H NMR spectroscopy provided little additional insight
into this process, and the nature and aggregation of the
intermediate(s) involved in the production of 10 along with
(10) For complications associated with the optical enrichment of
hydrobenzoin derivatives by crystallization, see ref 7d.
(11) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006,
128, 13070.
(12) Snieckus, V. Chem. ReV. 1990, 90, 879
.
(13) For examples of ortho-metalation reactions involving a benzyl
alcohol or R-methylbenzyl alcohol, see: (a) Granander, J.; Sott, R.;
Hilmersson, G. Tetrahedron: Asymmetry 2003, 14, 439. (b) Hirt, U. H.;
Spingler, B.; Wirth, T. J. Org. Chem. 1998, 63, 7674. (c) Panetta, C. A.;
Garlick, S. M.; Durst, H. D.; Longo, F. R.; Ward, J. R. J. Org. Chem.
1990, 55, 5202. (d) Meyer, N.; Seebach, D. Angew. Chem., Int. Ed. Engl.
(15) While it is unlikely that any epimerization of (R,R)-hydrobenzoin
could occur during this process, the optical purity of (R,R)-hydrobenzoin
recovered from the treatment of the tetraanion 10 with H2O was confirmed
by chiral GC analysis. In addition, the 1H NMR spectra of the crude product
contained none of the corresponding meso-hydrobenzoin, which can be
differentiated from dl-hydrobenzoin by the chemical shift of the benzyl
protons. 1H NMR (CDCl3) δ: 4.72 ppm (dl-hydrobenzoin); 4.80 ppm (meso-
hydrobenzoin). Periasamy, M.; Srinivas, G.; Karunakar, G. V.; Bharathi,
P. Tetrahedron Lett. 1999, 40, 7577.
1978, 17, 521
.
(14) For a conceptually related but less direct approach to functionalized
hydrobenzoins, see refs 6a and 6b.
1904
Org. Lett., Vol. 11, No. 9, 2009

chromatography or recrystallization. Unfortunately, we were
unable to translate the high level of deuterium incorporation
(>90%) observed during the optimization of the DoM step
(vide supra) to the reaction of 10 with a broader array of
electrophiles.18 Attempts to temper the basicity of 10 by
transmetalation (e.g., ZnCl2 or MgBr2) also failed to improve
upon these results. Despite the limited scope of electrophiles
that engaged in productive reactions with 10, the now readily
available and optically pure aryl halide 14 proved to be a
useful intermediate for the synthesis of a variety of hy-
drobenzoin derivatives (Scheme 1). For example, the dianion
Figure 2. Percentage of hydrobenzoin (1), monodeuterohydroben-
Scheme 1. Synthesis of Hydrobenzoin Derivatives from 19
zoin 11, and dideuterohydrobenzoin 12 following treatment of a
refluxing solution of 1 and n-BuLi (6 equiv) with D2O after various
reaction times. The crude product following D2O quench was
concentrated from CH3OH to ensure complete exchange of OH for
OD. The ratio of 1:11:12 was determined by mass spectrometry
(ESI).
an explanation for the relatively facile deprotonation of 9
remain the subject of an ongoing investigation.16
Nevertheless, with a procedure in place to generate 10 in
good yield we turned our attention to exploiting this reactive
intermediate in the direct synthesis of ortho-functionalized
derivatives. As detailed in Table 2, treatment of 1 with
Table 2. Synthesis of Hydrobenzoin Derivatives
derived from acetonide 1919 smoothly coupled with elec-
trophiles (e.g., TMSCl, SiMe2Cl2), and 19 itself engages in
high yielding palladium-catalyzed cross-coupling reactions,20
providing rapid access to the ortho-functionalized hydroben-
zoins 20-22.21
ratio of
product
entry
electophilea
R1
R2
productsb
(% yield)c
The bis-benzoxaborol 1722 also proved to be a versatile
intermediate for the synthesis of derivatives of 1 through
1
2
3
4
5
6
CH3I
I2
CH3
I
H
H
H
5:1:1
6:2:1
5:3:1
NDf
10:2:5
8:2:3
13 (53)
14 (53)
15 (33)
16 (40)
17 (42)
18 (36)
(CH2Br)2
CO2
B(OCH3)3
Br
COd e
,
(16) For mechanistic analyses of DoM reactions, see: (a) Chadwick,
S. T.; Ramirez, A.; Gupta, L.; Collum, D. B. J. Am. Chem. Soc. 2007, 129,
2259. (b) Singh, K. J.; Collum, D. B. J. Am. Chem. Soc. 2006, 128, 13753.
(c) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem.,
Int. Ed. 2004, 43, 2206. (d) Slocum, D. W.; Dumbris, S.; Brown, S.; Jackson,
G.; LaMastus, R.; Mullins, E.; Ray, J.; Shelton, P.; Walstrom, A.; Wilcox,
J. M.; Holman, R. W. Tetrahedron 2003, 59, 8275. (e) Chadwick, S. T.;
Rennels, R. A.; Rutherford, J. L.; Collum, D. B. J. Am. Chem. Soc. 2000,
122, 8640.
g
B(OH)d
d
Si(CH3)2Cl2
Si(CH3)2
a 7 equiv of electrophile. b Ratio of disubstituted hydrobenzoin:
1
monosubstituted hydrobenzoin:recovered 1 determined by analysis of H
NMR spectra of crude reaction mixtures. c Isolated yield. d Unambiguous
assignment of a five- or six-membered ring was not possible using NMR
spectroscopy. e IR stretch values for the carbonyl functions in 16 were
consistent with those of a γ-lactone. f Product isolated by recrystallization.
g B(OCH3)3 was added at 0 °C.
(17) Repetition of this reaction with 4 or 5 equiv of n-BuLi (reflux,
16 h) provided 14 in 19% or 34% isolated yield, respectively.
(18) Examples of electrophiles that proved incompatible with 10 and/
or provided the desired product in very low yield (<10%) include
benzaldehyde, acetone, acetaldehyde, diethylcarbonate, valeraldehyde, tri-
methylsilyl chloride, cyclohexanal, crotonaldehyde, paraformaldehyde,
formaldehyde, dimethylformamide, and benzylbromide.
n-BuLi followed by CH3I, I2,17 dibromoethane, CO2, B(O-
CH3)3, or Si(CH3)2Cl2 gave reasonable yields of the corre-
sponding ortho-substituted hydrobenzoin derivatives, along
with minor amounts of products resulting from ortho
functionalization of only one of the aromatic rings and
recovered 1, all of which were readily purified by flash
(19) The acetonide 19 was prepared in >97% yield by treating a solution
of 14 in dimethoxypropane with a catalytic amount of HCl.
(20) Attempts to directly couple the diol 14 with aryl boronic acids
resulted primarily in the formation of cis-4b,9b-dihydrobenzofuro[3,2-
b]benzofuran. For an unrelated synthesis of this substance, see: Masutani,
K.; Irie, R.; Katsuki, T. Chem. Lett. 2002, 36.
Org. Lett., Vol. 11, No. 9, 2009
1905

cross-coupling reactions with aryl halides23 or vinyl tri-
flates.24 This approach to functionalized hydrobenzoin
derivatives complements that described above and avoids
protection of the benzyl alcohol functions.20 As indicated in
Scheme 2, this process provides optically pure ortho-
to 21% when 17 was purified by flash chromatography. The
bis-benzoxaborol 17 also proved to be a suitable precursor
for the C2-symmetric bis-phenol 24, following hydroperoxide
oxidation.25 Notably, the acetonide of the tetraol 24 has been
reported by others26 as a potential BINOL-like ligand for
asymmetric synthesis.
In summary, we have developed a one-pot process for the
direct functionalization of the readily available and relatively
inexpensive chiral diol hydrobenzoin. Importantly, this work
provides a means to rapidly access a wide variety of new
chiral ligands and auxiliaries in optically pure form. The
application of chiral diols generated in this work as ligands
in a variety of asymmetric processes, including Brønsted acid
catalyzed inverse electron-demand Diels-Alder reactions,
will be reported in due course.
Scheme 2. Synthesis of Hydrobenzoin Derivatives from 17
Acknowledgment. We thank NSERC and Merck Frosst
Canada for support. I.C. was supported in part by a Michael
Smith Foundation for Health Research Trainee Award and
by a SFU Graduate Fellowship. We thank Regine Gries
(SFU) for assistance with chiral GC analysis and Hongwen
Chen (SFU) for assistance with mass spectrometry.
functionalized hydrobenzoin derivatives in two steps from
1 through the intermediacy of 17. Moreover, for the purpose
of the cross-coupling, we found that purification of the bis-
benzoxaborol 17 is unnecessary. For example, the oVerall
yield of compound 23 from (R,R)-hydrobenzoin (1) was 32%
when the crude bis-benzoxaborol 17 was used as compared
Supporting Information Available: Detailed experimen-
tal procedures and characterization data for each compound.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL900323U
(21) Attempts to effect the cross-coupling of 19 with pyridine N-oxide
following the procedure reported in Campeau, L.-C.; Rousseaux, S.; Fagnou,
K. J. Am. Chem. Soc. 2005, 127, 18020 led predominantly to the formation
of the acetonide of dihydro-phenanthrenediol.
(23) Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui, M. A.;
Snieckus, V.; Josephy, P. D. J. Org. Chem. 1991, 56, 3763.
(24) The palladium-catalyzed cross-coupling of 17 with 1-trifluo-
romethanesulfonic acid cyclooct-1-enyl ester (Pd(dppe)Cl2, Na2CO3,
EtOH, DME, reflux) provided the cyclooctenyl precursor to 6 in 17%
isolated yield.
(22) The bis-benzoxaborol 17 may possess two five- or six-membered
oxaborine rings. On the basis of the observation of two bands at 1346 and
1371 cm-1 in the IR spectrum of this compound, which are consistent with
those reported at 1345 and 1365 cm-1 for the B-O stretching modes in
3-methyl-2,1-benzoxaborol, we have tentatively assigned the structure for
17 as shown in Scheme 2. See: Dale, W. J.; Rush, J. E. J. Org. Chem.
1962, 27, 2598.
(25) Simon, J.; Salzbrunn, S.; Prakash, G. K. S.; Petasis, N. A.; Olah,
G. A. J. Org. Chem. 2001, 66, 633.
(26) The acetonide of 24 has been synthesized in 6% overall yield
following a six-step sequence of reactions. See: Yamamoto, H.; Kobayashi,
S.; Kanemasa, S. Tetrahedron: Asymmetry 1996, 7, 149.
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Org. Lett., Vol. 11, No. 9, 2009