Directed ortho,ortho'-dimetalation of hydrobenzoin: Rapid access to hydrobenzoin derivatives useful for asymmetric synthesis

Article abstract of DOI:10.3762/bjoc.7.154

A variety of ortho,ortho'-disubstituted hydrobenzoin derivatives are readily accessible through a directed ortho,ortho'-dimetalation strategy in which the alcohol functions in hydrobenzoin are deprotonated by n-BuLi and the resulting lithium benzyl alkoxi

Full text of DOI:10.3762/bjoc.7.154

Directed ortho,ortho'-dimetalation of hydrobenzoin:
Rapid access to hydrobenzoin derivatives
useful for asymmetric synthesis
Inhee Cho1, Labros Meimetis1, Lee Belding1,2, Michael J. Katz1,
Travis Dudding2 and Robert Britton*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1315–1322.
1Department of Chemistry, Simon Fraser University, 8888 University
Drive, Burnaby, B.C., Canada, V5S 1S6 and 2Department of
Chemistry, Brock University, 500 Glenridge Ave, St Catharines, ON,
Canada, L2S 3A1
doi:10.3762/bjoc.7.154
Received: 19 May 2011
Accepted: 29 August 2011
Published: 22 September 2011
Email:
Robert Britton* - rbritton@sfu.ca
This article is part of the Thematic Series "Directed aromatic
functionalization".
* Corresponding author
Guest Editor: V. Snieckus
Keywords:
chiral diol; directed ortho-metalation; hydrobenzoin
© 2011 Cho et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A variety of ortho,ortho'-disubstituted hydrobenzoin derivatives are readily accessible through a directed ortho,ortho'-dimetalation
strategy in which the alcohol functions in hydrobenzoin are deprotonated by n-BuLi and the resulting lithium benzyl alkoxides
serve as directed metalation groups. The optimization and scope of this reaction are discussed, and the utility of this process is
demonstrated in the one-pot preparation of a number of chiral diols as well as a short synthesis of the chiral ligand Vivol.
Introduction
The discovery of new chiral ligands and auxiliaries continues to asymmetric aldol/Evans–Tishchenko reactions [5]. Moreover,
expand the frontiers of catalytic asymmetric synthesis. In par- the hydrobenzoin dimethyl ether 7 was shown to direct the
ticular, C2-symmetric diols, such as (S)-BINOL (1) [1] and asymmetric addition of organolithium reagents to arene tricar-
(−)-TADDOL (2) [2] (Figure 1), have garnered considerable bonylchromium complexes [7] and α,β-unsaturated aldimines
attention owing to the wide variety of asymmetric reactions [8]. Notably, derivatives of hydrobenzoin in which the aromatic
promoted by these ligands and/or their derivatives. Although rings have been functionalized in the ortho and ortho' positions
hydrobenzoin (e.g., 3) has not been utilized to the same extent, often display improved diastereo- or enantioselectivity over the
it has also demonstrated utility as both a chiral ligand [3-8] and parent diol 3 [3,14]. For example, the addition of cyclooctyl
auxiliary [9-17]. For example, Hall reported that the hydroben- rings to the ortho and ortho' positions of the hydroben-
zoin·SnCl4 complex 5 promotes the allylboration of hydro- zoin·SnCl4 complex (i.e., Vivol·SnCl4 (6)) leads to a dramatic
cinnamaldehyde with modest enantioselectivity (26% ee) [3], improvement in enantioselectivity in the allylboration of hydro-
and a hydrobenzoin–ytterbium complex was found to catalyze cinnamaldehyde (93% ee) [3]. Unfortunately, while (R,R)- and
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Beilstein J. Org. Chem. 2011, 7, 1315–1322.
Figure 1: Chiral diols useful for asymmetric synthesis and the tetralithio intermediate 8.
(S,S)-hydrobenzoin are relatively inexpensive [18], or can be excess (6 equiv) of n-BuLi, followed after 16 h by treatment
readily prepared on kilogram-scale from trans-stilbene through with an electrophile [23]. The optimization of this process relied
Sharpless asymmetric dihydroxylation (SAD) [19,20], the syn- on a series of D2O quenching studies and analysis of the
thesis of ortho,ortho'-functionalized derivatives of hydroben- 1H NMR and mass spectra derived from the crude reaction
zoin typically requires several steps that include McMurry products. These studies led to the eventual selection of a 2:1
coupling of an ortho-substituted benzaldehyde followed by mixture of hexane/ether as the most favorable reaction solvent
I2-catalyzed isomerization of the resulting stilbene and subse- for the formation of the tetralithio intermediate 8 [23].
quent SAD [21,22]. Thus, while various hydrobenzoin deriva-
tives have been reported, their multi-step synthesis, the modest Despite the high level of deuterium incorporation (92%)
enantioselectivity in the SAD step [22], the problems asso- observed in the reaction of the tetralithio intermediate 8 with
ciated with their optical enrichment [6], and the necessary D2O (Scheme 1), this result was not observed for reactions with
determination of optical purity for each derivative, all compli- other electrophiles (see below). In addition, the products from
cate the rapid preparation of congeneric libraries. To address deuterium quenching studies were often accompanied by the
these issues, we recently reported a new process for the direct formation of varying amounts of the deoxybenzoin 10, which
functionalization of (R,R)-hydrobenzoin (3) [23] through a presumably derives from reaction of an alkoxide function in 8
directed ortho,ortho'-dimetalation strategy in which the alcohol with D2O, followed by deuteroxide elimination/enolate forma-
functions in hydrobenzoin are deprotonated by n-BuLi and the tion and subsequent reactions with D2O. Bearing this in mind,
resulting lithium benzyl alkoxides serve as directed metalation the directed ortho,ortho'-dimetalation of hydrobenzoin was rein-
groups (DMGs) [24-28] and facilitate formation of the vestigated using I2 as the electrophile quench. As indicated in
tetralithio intermediate 8. Herein, we provide a detailed account Table 1, the use of stoichiometric (i.e., 4 equiv, entry 1)
of this work as well as the application of these methods to a amounts of n-BuLi led to low isolated yields of the diiodohy-
short synthesis of the chiral diol Vivol (4).
drobenzoin 12. Successively increasing the equivalents of
n-BuLi resulted in approximate increases of 15% in the isolated
yield of 12, with a maximum yield of roughly 50% achieved
Results and Discussion
As indicated in Scheme 1, the optimized conditions for the when 6 equiv of n-BuLi were employed (entries 2 and 4).
directed ortho,ortho'-dimetalation of (R,R)-hydrobenzoin (3) Although the use of 8 equiv of n-BuLi led to a slightly higher
involve the treatment of a solution of 3 under reflux with an isolated yield of 12 (53%), and only 8 hours were required for
Scheme 1: Directed ortho,ortho'-dimetalation of (R,R)-hydrobenzoin (3).
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Table 1: Optimization of the synthesis of the diiodohydrobenzoin 12.
entry
n-BuLi [equiv]
reflux time [h]
I2 [equiv]
ratio 11:12a
isolated yield 12 [%]
1
2
3
4
5
6
7
4
5
16
16
16
16
16
16
8
5
6
1:1
1:1.7
2.6:1c
1:5
20
34
8
5b
6
6
7
51
13
53
51
6d
8
7
2:1e
1:5
9
8
12
N.D.f
aRatio determined by analysis of 1H NMR spectra recorded on crude reaction mixture. bTMEDA (5 equiv) was added prior to the addition of n-BuLi.
cHydrobenzoin (48%) was also recovered from this reaction. dTMEDA (6 equiv) was added prior to the addition of n-BuLi. eHydrobenzoin (34%) was
also recovered from this reaction. fNot determined.
the formation of the tetralithio intermediate (entries 6 and 7), (i.e., 14 and 15) equivalent. It is notable that the differing
the conditions identified in entry 4 require fewer equivalents of results depicted in Figure 2 and Figure 3 may be attributed to
base and electrophile and were consequently selected as the intra- or intermolecular deprotonation of the o-tolyl group
optimal reaction conditions [23]. Notably, addition of TMEDA following reaction of the tetralithio intermediate 8 with one
(entries 3 and 5), which would presumably assist in the disag- equiv of CH3I, leading to the formation of misleading amounts
gregation of organolithium species, failed to improve these of the monomethylhydrobenzoin 14, or simply differing reactiv-
results and in fact led to lower conversion and isolated yields of ity of the tetralithio intermediate with D2O and CH3I.
the diiodohydrobenzoin 12.
A possible explanation for the differing rates of DoM events
During the evaluation of the reaction of the tetralithio inter- observed during the D2O quenching studies is depicted in
mediate 8 with I2 (Table 1), we were surprised to find that Scheme 2 [29]. Thus, following the first ortho-metalation, the
monoiodohydrobenzoin 11 was produced in equivalent or lower intermediate aryl lithium 17 (presumably in an aggregated
yield than the diiodohydrobenzoin 12, even at low overall form) may adopt a conformation in which the lithium alkoxide
conversion (e.g., Table 1, entries 1 and 2). These results (DMG) and consequently the base (i.e., n-BuLi or its aggre-
suggested that the rate-limiting step in the formation of the gates) are positioned in close proximity to the ortho proton that
tetralithio intermediate 8 may be the first DoM (i.e., formation is to be removed. Alternatively, the intermediate aryl lithium 17
of a trilithio intermediate) and that the second DoM event is may undergo rearrangement to the six-membered heterocycle
relatively more rapid. To gain further insight into this process, 18, in which the cis-relationship between the distal lithium
the reaction of (R,R)-hydrobenzoin (3) with n-BuLi followed by alkoxide and the unlithiated phenyl ring facilitates the second
treatment with D2O [23] or CH3I was monitored by mass spec- deprotonation. While the latter proposal is less likely, based on
trometry and 1H NMR spectroscopy, respectively. As indicated Seebach’s observation that 2-phenylethanol does not undergo
in Figure 2, the results of the D2O quenching study were in ortho-lithiation [30], reaction of the tetralithio intermediate 8
accordance with our original observation: A relatively slow with dimethyldichlorosilane led to the formation of the
removal of the first ortho proton is followed by a second, more bis(siloxane) 19 (not the 5-membered ring bis(siloxane)
rapid DoM event.
isomer), whose structure was unambiguously confirmed by
X-ray crystallographic analysis (see Scheme 2, inset).
When the progress of the sequential ortho-metalations was
monitored by quenching with CH3I, however, the difference in As indicated in Scheme 3, formation of the tetralithio intermedi-
rates was not as pronounced, and only in the case where the for- ate 8 and subsequent reaction with various electrophiles led to
mation of the tetralithio intermediate 8 was allowed 6 hours at synthetically useful yields of ortho-functionalized hydroben-
reflux was the proportion of mono- and dimethylhydrobenzoin zoin derivatives [23]. In each case, approximately 5–10% of the
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Figure 2: Percentage of (R,R)-hydrobenzoin (3) (○), monodeuterohydrobenzoin (13) (■), and dideuterohydrobenzoin (9) (Δ) as determined by mass
spectrometry (ESI) [23].
Figure 3: Percentage of methylhydrobenzoin (14) (■), and dimethylhydrobenzoin (15) (Δ) as determined by 1H NMR spectroscopy. The remainder of
the material is recovered (R,R)-hydrobenzoin (3).
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Scheme 2: Formation of the tetralithio intermediate 8 and the X-ray crystal structure of the bis(siloxane) 19.
Scheme 3: Reaction of the tetralithio intermediate 8 with various electrophiles.
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corresponding monofunctionalized hydrobenzoin (e.g., 14, tetralithio intermediate to afford the dihydrophenanthrenediol
Figure 3) was also produced, but was readily separable from the 23 [22] with the aid of various copper or iron halides [31], or
desired product by flash chromatography. Unfortunately, reac- palladium(II)chloride [32] were unsuccessful. In an effort to
tion of the tetralithio intermediate 8 with carbonyl electrophiles fine-tune the procedure by attenuating the reactivity of the
(e.g., acetone, acetaldehyde, diethyl carbonate, valeraldehyde, tetralithio intermediate 8, transmetalation with ZnCl2 or MgBr2
cyclohexanal, crotonaldehyde, formaldehyde, DMF, benzalde- followed by treatment with various electrophiles was also
hyde), trimethylsilyl chloride, or allyl/benzyl chloride/bromide investigated. Disappointingly, these efforts failed to offer any
failed to provide the desired products in reasonable yield. For improvement in the coupling of 8 with DMF, benzaldehyde, or
example, treatment of the tetralithio intermediate 8 with benzyl allyl bromide and consequently we focused our attention on
chloride resulted in recovery of (R,R)-hydrobenzoin along with reactions of the readily available diiodohydrobenzoin 12 and
1-chloro-1,2-diphenylethane, the latter of which arises through bis(benzoxaborol) 20.
the deprotonation of benzyl chloride by 8 and reaction of the
resulting benzyl anion with a second equivalent of benzyl chlo- As highlighted in Scheme 4, attempts to directly engage
ride. Likewise, attempts to effect a reductive coupling of the diiodohydrobenzoin 12 in Cu-catalyzed C–N cross-coupling
Scheme 4: Reactions of the diiodohydrobenzoin 12 and X-ray crystal structure of the dihydrosilepin 31.
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Beilstein J. Org. Chem. 2011, 7, 1315–1322.
reactions [33] led only to the formation of cis-4b,9b-dihy- Conclusion
drobenzofuro[3,2-b]benzofuran (24) [34]. Consequently, the In conclusion, an efficient and economical process was devel-
diol 12 was converted to the corresponding acetonide 25 or oped for the direct functionalization of hydrobenzoin that relies
methyl ether 26 prior to cross-coupling. In this manner, the on a directed ortho,ortho'-dimetalation strategy. Importantly, a
diphenylhydrobenzoin derivative 27 could be accessed in excel- wide variety of chiral diols (e.g., Vivol (4)) are now readily
lent overall yield [3,23]. Alternatively, lithium–halogen accessible in optically pure form following this one-pot reac-
exchange carried out on diiodohydrobenzoins 25 or 26, fol- tion. Although the range of electrophiles that engage in synthet-
lowed by reaction with various electrophiles affords access to a ically useful reactions with the tetralithio intermediate 8 is
wider array of hydrobenzoin derivatives than those highlighted limited, the diiodohydrobenzoin 12 and bis(benzoxaborol) 20
above in Scheme 3 [17]. For example, electrophiles such as are both prepared in good yield and are readily derivatized
TMSCl and dichlorodimethylsilane engage in high yielding through cross-coupling reactions. We are currently exploring
reactions with the dianions 28 and 29 to provide the silyl-func- the utility of the bis(benzoxaborol) 20 and derivatives of this
tionalized hydrobenzoin derivatives 30–33.
substance as chiral Lewis acids and will report our findings in
due course.
The bis(benzoxaborol) 20 also proved to be a versatile inter-
mediate for the synthesis of hydrobenzoin derivatives through
Pd-catalyzed cross-coupling reactions (Scheme 5). This ap-
proach compliments those described above and avoids the need
to protect the diol function prior to the cross-coupling step.
Notably, purification of the bis(benzoxaborol) 20 proved unnec-
essary as the diphenylhydrobenzoin 34 was prepared in an
overall yield of 32% from (R,R)-hydrobenzoin (3) without
purification of 20, compared to 21% when the intermediate
bis(benzoxaborol) 20 was purified by column chromatography
[23]. Finally, the efficiency of this process was demonstrated in
a short formal synthesis of (R,R)-Vivol (4). Thus, a
Pd-catalyzed cross-coupling of the known triflate 35 [35] with
the bis(benzoxaborol) 20 afforded the dicyclooctenylhydroben-
zoin 36, which was reduced in quantitative yield to afford Vivol
(4) by Hall [3]. Notably, this three-step procedure for the
Supporting Information
Supporting Information File 1
Experimental details and characterization data for all
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-154-S1.pdf]
Supporting Information File 2
X-ray crystallographic information files (CIFs) for crystals
of 19 and 31.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-154-S2.cif]
preparation of optically pure Vivol compares well with the Acknowledgements
reported synthesis and should be effective for the rapid produc- We thank NSERC and Merck Frosst Canada for support. I.C.
tion of new ligands for asymmetric synthesis.
was supported by a Michael Smith Foundation for Health
Scheme 5: Cross coupling reactions of the bis(benzoxaborol) 20 and a short formal synthesis of (R,R)-Vivol (4).
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Research Trainee Award and by a SFU Graduate Fellowship.
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