Highly asymmetric dihydroxylation of 1-aryl-1'-pyridyl alkenes

Article abstract of DOI:10.1016/S0040-4039(00)00741-3

The asymmetric dihydroxylation of 1-aryl-1'-pyridyl alkenes afforded the diols in high yield and excellent enantioselectivity. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00741-3

Tetrahedron Letters 41 (2000) 4865±4869
Highly asymmetric dihydroxylation of
1-aryl-10-pyridyl alkenes
Xin Wang,a,* Mark Zak,a Mathew Maddess,a Paul O'Shea,a Richard Tillyer,b
E. J. J. Grabowskib and Paul J. Reiderb
aDepartment of Process Research, Merck Frosst Centre for Therapeutic Research, PO Box 1005,
Pointe Claire ± Dorval, Quebec, H9R 4P8, Canada
bDepartment of Process Research, Merck Research Laboratories, Rahway, NJ 07065, USA
Received 29 March 2000; accepted 3 May 2000
Abstract
The asymmetric dihydroxylation of 1-aryl-10-pyridyl alkenes a€orded the diols in high yield and excellent
enantioselectivity. # 2000 Published by Elsevier Science Ltd.
Keywords: asymmetric dihydroxylation; 1,10-diaryalkenes.
The chiral 1,10-diaryl-1,2-ethanediols, especially diols containing one pyridyl heterocycle, are
important intermediates in our drug development programs. We anticipated that these diols
could be prepared eciently via a Sharpless asymmetric dihydroxylation1,2 of 1,10-diarylalkenes
(Scheme 1). While the Sharpless asymmetric dihydroxylation is well studied on a variety of
alkenes, to our knowledge, there is no published precedent for 1,10-diarylalkenes. We, herein,
wish to report our preliminary results on the asymmetric dihydroxylation of 1,10-diarylalkenes. In
particular, the asymmetric dihydroxylation of 1-aryl-10-pyridiyl alkenes a€orded the diols in high
yields and excellent enantioselectivity.
Scheme 1.
* Corresponding author. Tel: (514) 428-3511; fax: (514) 428-4936; e-mail: xin_wang@merck.com
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)00741-3

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It is well known that the chiral ligand (L*)1 plays the most important role in the Sharpless asym-
metric dihydroxylation, since it directs the stereochemistry of the reaction. Three ligands are com-
mercially available: hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2PHAL), hydroquinidine
2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQD)2PYR) and hydroquinidine anthraquinone-
1,4-diyl diether ((DHQD)2AQN).3 Each of these has a dihydroquinine analog: (DHQ)2PHAL,
(DHQ)2PYR and (DHQ)2AQN. According to Sharpless,1 the phthalazine (PHAL) derivative is
most general and leads to high enantioselectivities for most alkenes; whereas the pyrimidine
(PYR) ligand is best for sterically congested alkenes (especially 1,10-disubstituted alkenes) and the
anthraquinone (AQN) derivative is most suitable for almost all alkenes having only aliphatic
substituents.
Armed with this information, we ®rst surveyed two 1,10-diaryl alkenes4 containing phenyl and
bromophenyl groups under modi®ed Sharpless dihydroxylation reaction conditions. It was hoped
that the ligands would di€erentiate the two aromatic rings on the basis of the substituent factor.
We prepared two mono-bromo-substituted 1,10-diphenyl alkenes4 and subjected them to the
dihydroxylation reaction conditions. As shown in Table 1, the reactions for the ortho-bromo
substituted diphenylalkene were incomplete in 10 days, while the reactions for the meta-bromo
substituted diphenyl alkene were completed in 24 h (entries 1±6). The enantioselectivities for these
reactions are quite disappointing, with low to modest ee's being obtained. We had to use more
oxidant than Sharpless recommended since the reaction proceeds very sluggishly for some of our
substrates. Furthermore, the addition of methanesulfonamide (1 equiv.) was necessary for the
reaction to occur. We next studied the dihydroxylation of 1-phenyl-10-pyridyl ethylene4 hoping
that the ligands would be able to di€erentiate phenyl and pyridyl groups based on their electronic
nature. The dihydroxylation of the substrate is equally inecient, with low to modest ee's being
obtained (entries 7±9).
Table 1
Dihydroxylation of 1,10-diaryl alkenes: e€ect of substitution and electronic factors

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Regarding the enantioselectivity, Sharpless1 has argued that the exceptional utility of chiral
catalysts stems from their dimeric nature and the resulting enzyme-like binding pocket they form.
An alkene, that has its substituent most able to participate in the o€set-parallel and edge-to-face
interactions in the binding pocket, would lead to a symmetric diol product in good facial selectivity.
Based on this assumption and results we obtained above, we envisioned that a properly substituted
pyridyl substrate would ®t into the binding pockets of some chiral catalysts and ultimately lead
to higher enantioselectivity. We hence examined pyridyl alkenes with a substituent at the 3- and
4-pyridine positions (Table 2). We were delighted to observe that the diol products were obtained
in high yields and excellent ee's depending on the use of suitable ligands.
Table 2
Dihydroxylation of substituted 1-phenyl,10-pyridyl alkenes

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As shown in Table 2, the enantioselctivity is highly dependent on the proper combination of
substrate and ligand. The AQN-derivative ligand was best suited for the alkenes with electron
withdrawing groups on the pyridyl group, while the PHAL based one was ine€ective (entries 1±12).
On the other hand, the PYR-based catalyst was the best and the AQN-based one was the worst
for the alkene with an electron donating group (OBn) on the pyridyl ring (entries 13±17). Inter-
estingly, the 2-bromo substituted alkene gave better ee's than those of the 3-bromo substituted
alkene with all the three ligands (entries 1±8), indicating a substitution factor. A methoxy group
on the phenyl ring has little impact on the enantioselectivity of the dihydroxylation. The enantio-
selectivity is less sensitive to the reaction temperature as lowering the reaction temperature to 0ꢀC
only leads to a slight increased ee (entries 4, 12, 15 and 25). Moreover, the enantioselectivity can
be tuned by switching ligands. For example, changing from (DHQD)2PHAL to (DHQD)2AQN,
the ee rose from 5 to 96% (entry 22 versus 24). The opposite enantiomer could also be obtained in
high ee's (entries 8, 16 and 21) by using the DHQ-based catalysts. Since most of these diol
products are solids, their optical purities can easily be enhanced by recrystallization in appropriate
solvents.
In summary, we have demonstrated that diols5,6 with excellent ee's can be obtained from the
properly substituted 1-aryl-10-pyridyl alkenes under the Sharpless dihydroxylation reaction con-
ditions. These optically enriched diols are important synthetic precursors for the corresponding
epoxides and a-hydoxy acids, which are otherwise dicult to prepare. A combination of the
substituent e€ect and the electronic nature of the hetereocylic ring is a determining factor for the high
enantioselectivity.
Acknowledgements
We are grateful to Dr. Cheng Y. Chen for stimulating discussions.
References
1. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
2. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim, 1993; pp.
227±272.
3. Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 448.
4. 1,1-Diaryl alkenes were prepared in a two-step reaction sequence as below. Attempts to prepare 1-phenyl-10-
substituted thienyl alkenes using this and other alternative methods were unsuccessful, due to the highly unstable
nature of those targeted alkenes.
5. Typical procedure: H2O (5 mL) and t-BuOH (5 mL) were added to a ¯ask containing potassium osmate (IV)
dihydrate (1.3 mg, 0.00345 mmol), (DHQD)2AQN (11.8 mg, 0.0138 mmol), potassium ferricyanide (III) (624.8
mg, 1.898 mmol) and potassium carbonate (271.8 mg, 1.967 mmol). The suspension was stirred for 30 min at room
temperature. The alkene (0.345 mmol) and then methane sulfonamide (32.8 mg, 0.345 mmol) were added. The
mixture was stirred for 24±72 h at room temperature. Sodium sul®te (479.2 mg, 3.802 mmol) was added and the
mixture was stirred for 1 h. The solution was poured into H2O (60 mL) and was extracted with dichloromethane

4869
(3Â25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness.
The residue was puri®ed by silica gel ¯ash chromatography to a€ord the desired diol. Selective characterization
data for diols 1±6 are shown in Table 2. Compound 1: chiral LC: Chiralpak AS, hexane:IPA, 97:3, rt (min)=40.2,
1
48.8; H NMR (CDCl3): ꢀ 7.53 (t, J=7.8 Hz, 1H), 7.44±7.23 (m, 7H), 4.64 (bs, 1H, D2O exchangeable), 4.42 (d,
J=11.6 Hz, 1H), 3.89 (d, J=11.6 Hz, 1H), 2.78 (bs, 1H, D2O exchangeable); compound 2: chiral LC: Chiralpak
AS, hexane:IPA, 80:20, rt (min)=9.4, 12.2; 1H NMR (CDCl3): ꢀ 8.56 (d, J=2.2 Hz, 1H), 7.78 (dd, J=2.2, 8.4 Hz,
1H), 7.45±7.35 (m, 2H), 7.35±7.22 (m, 4H), 4.77 (bs, 1H, D2O exchangeable), 4.41 (dd, J=5.9, 11.4 Hz, 1H), 3.90
(dd, J=5.9, 11.4 Hz, 1H), 2.95 (bs, 1H, D2O exchangeable); compound 3: chiral LC: Chiralpak AD, hexane:IPA,
1
95:5, rt (min)=35.9, 54.1; H NMR (CDCl3): ꢀ 8.04 (dd, J=1.0, 7.7 Hz, 1H), 7.82 (t, J=7.8 Hz, 1H), 7.52 (dd,
J=0.9, 8.0 Hz, 1H), 7.46±7.42 (m, 2H), 7.36±7.24 (m, 3H), 5.00 (bs, 1H, D2O exchangeable), 4.52 (dd, J=4.7, 11.5
Hz, 1H), 4.00 (s, 3H), 3.91 (dd, J=6.9, 11.5 Hz, 1H), 3.61 (bs, 1H, D2O exchangeable); compound 4: chiral LC:
1
Chiralpak AD, hexane:IPA, 97:3, rt (min)=56.4, 65.5; H NMR (CDCl3): ꢀ 7.59 (dd, J=0.6, 8.2 Hz, 1H), 7.44±
7.21 (m, 10H), 6.99 (dd, J=0.6, 7.4 Hz, 1H), 6.73 (dd, J=0.6, 8.2 Hz, 1H), 5.39 (s, 2H), 4.70 (s, 1H, D2O,
exchangeable), 4.31 (dd, J=6.7, 11.5 Hz, 1H), 3.90 (dd, J=7.1, 11.5 Hz, 1H), 2.49 (t, J=6.9 Hz, 1H, D2O,
exchangeable); compound 5: chiral LC: Chiralpak AS, hexane:IPA, 95:5, rt (min)=39.5, 47.4 or Chiralpak AD,
hexane:IPA, 95:5, rt (min)=38.2, 63.0; 1H NMR (CDCl3): ꢀ 7.53 (t, J=7.7 Hz, 1H), 7.40±7.33 (m, 4H), 6.88±6.83
(m, 2H), 4.67 (bs, 1H, D2O exchangeable), 4.38 (d, J=11.5 Hz, 1H), 3.89 (d, J=11.7 Hz, 1H), 3.78 (s, 3H), 2.85
(bs, 1H, D2O exchangeable); compound 6: chiral Chiralpak AD, hexane:IPA, 97:3, rt (min)=51.1, 62.3; 1H NMR
(CDCl3): ꢀ 7.59 (dd, J=1.7, 7.7 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.37±7.25 (m, 3H), 7.01 (dt, J=1.1, 7.6 Hz, 1H),
6.84 (dd, J=0.7, 8.2 Hz, 1H), 4.92 (s, 1H, D2O exchangeable), 4.60 (dd, J=6.2, 11.4 Hz, 1H), 3.91 (dd, J=7.7,
11.4 Hz, 1H), 3.61 (s, 3H), 3.53 (t, J=7.0 Hz, 1H, D2O exchangeable).
6. All new compounds exhibited suitable spectroscopic data (1H, 13C NMR and HRMS), which are consistent with
their assigned structures.