Asymmetric synthesis of 1-heteroaryl-1-arylalkyl tertiary alcohols and 1-pyridyl-1-arylethanes by lithiation-borylation methodology

Article abstract of DOI:10.1021/ol400289v

The synthesis of highly enantioenriched α-heterocyclic tertiary alcohols has been achieved via lithiation-borylation of a configurationally stable lithiated carbamate and heterocyclic pinacol boronic esters followed by oxidation. Protodeboronation of the α-heterocyclic tertiary boronic esters using TBAF·3H₂O or CsF gave highly enantioenriched 1-pyridyl-1-arylethanes in high er.

Full text of DOI:10.1021/ol400289v

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1346–1349
Asymmetric Synthesis of 1‑Heteroaryl-1-
arylalkyl Tertiary Alcohols and 1‑Pyridyl-
1-arylethanes by LithiationÀBorylation
Methodology
Charlotte G. Watson and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, U.K.
V.Aggarwal@bristol.ac.uk
Received January 31, 2013
ABSTRACT
The synthesis of highly enantioenriched R-heterocyclic tertiary alcohols has been achieved via lithiationÀborylation of a configurationally stable
lithiated carbamate and heterocyclic pinacol boronic esters followed by oxidation. Protodeboronation of the R-heterocyclic tertiary boronic esters
using TBAF 3H2O or CsF gave highly enantioenriched 1-pyridyl-1-arylethanes in high er.
3
There are a number of methods available for the synthe-
sis of highly enantioenriched tertiary alcohols, most of
Scheme 1. Proposed LithiationÀBorylation Route to
Heterocyclic Tertiary Alcohols
(1) For recent reviews, see: (a) Cozzi, P. G.; Hilgraf, R.; Zimmerman,
N. Eur. J. Org. Chem. 2007, 36, 5969. (b) Hatano, M.; Ishihara, K.
Synthesis 2008, 11, 1647. (c) Shibasaki, M.; Kanai, M. Chem. Rev. 2008,
108, 2853. (d) Luderer, M. R.; Bailey, W. F.; Luderer, M. R.; Fair, J. D.;
Dancer, R. J.; Sommer, M. B. Tetrahedron: Asymmetry 2009, 20, 981. (e)
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Yus, M.; Gonzalez-Gomez, J. C.; Foubelo, F. Chem. Rev. 2011, 111,
7774. (f) Madduri, A. V. R.; Harutyunyan, S. R.; Minnaard, A. J. Drug
Discov. Today 2012, in press, DOI 10.1016/j.ddtec.2012.10.010.54
(2) For asymmetric additions of organozinc nucleophiles to ketones,
see: (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445. (b)
Hatano, M.; Miyamoto, T.; Ishihara, K. Org. Lett. 2007, 9, 4535. For
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related titanium-catalyzed additions, see: (c) Ramon, D. J.; Yus, M.
Tetrahedron Lett. 1998, 39, 1239. (d) Garcıa, C.; LaRochelle, L. K.; Walsh,
P. J. J. Am. Chem. Soc. 2002, 124, 10970. (e) Garcıa, C.; LaRochelle, L. K.;
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Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10970. (f) Yus, M.; Ramon, D. J.;
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P. J. Org. Lett. 2003, 5, 3641. (h) Ramon, D. J.; Yus, M. Angew. Chem., Int.
Ed. 2004, 43, 284 and references therein.
them involving addition of an organometallic reagent to a
ketone catalyzed by a chiral metal/ligand complex.1À5
However, this method is scarcely reported for pyridyl
ketones, which may be due to intrinsic problems of com-
peting coordination of the heteroatom to the metal com-
plex, or to other unwanted side reactions.6 Due to the
prevalence of heterocyclic tertiary alcohols in bioactive
molecules,7 we have sought to address this issue by appli-
cation of our lithiationÀborylation methodology, which
provides an alternative route to highly enantioenriched
(3) For asymmetric additions of organoaluminium nucleophiles to
ketones, see: (a) Chen, C.-A.; Wu, K.-H.; Gau, H.-M. Angew. Chem., Int.
Ed. 2007, 46, 5373. (b) Biradar, D. B.; Gau, H.-M. Org. Lett. 2009, 11, 499.
(4) For asymmetric additions of Grignard nucleophiles to ketones,
see: (a) Madduri, A. V. R.; Minnaard, A. J.; Harutyunyan, S. R. Chem.
Commun. 2012, 48, 1478. (b) Madduri, A. V. R.; Harutyunyan, S. R.;
Minnaard, A. J. Angew. Chem., Int. Ed. 2012, 51, 3164.
(5) For examples of copper catalyzed asymmetric allylboration,
crotylboration, and propargylation of ketones, see: (a) Wada, R.;
Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004,
126, 8910. (b) Kanai, M.; Wada, R.; Shibuguchi, T.; Shibasaki, M. Pure
Appl. Chem. 2008, 80, 1055. (c) Shi, S.-L; Xu, L.-W; Oisaki, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 6638.
r
10.1021/ol400289v
Published on Web 03/05/2013
2013 American Chemical Society

tertiary alcohols.8 In this process, a benzylic carbamate
derived from an enantioenriched secondary alcohol is
deprotonated9 and reacted with a boronic ester to give
an intermediate boronate complex; subsequent stereospe-
cific 1,2-metalate rearrangement and oxidation thereafter
lead to highly enantioenriched tertiary alcohols (Scheme 1).
Herein we report the application of this methodology to the
synthesis of R-heterocyclic tertiary alcohols.
Scheme 2. Scope of the LithiationÀBorylation Methodologya
We began our studies by preparation of the required
starting materials; the enantioenriched carbamate 1 was syn-
thesized by enzymatic resolution of racemic phenylethanol10
followed by carbamoylation with N,N-diisopropylcarbamoyl
chloride, giving the carbamate 1 in >99:1 er. The boronic
esters were synthesized by condensation of the appropri-
ate boronic acid with pinacol.
Initial attemptstohomologate 3-pyridylpinacol boronic
ester proved unsuccessful, which we attributed to its poor
solubility in compatible reaction solvents (Et2O, toluene,
hexane, TBME). However, we found that the inclusion of
a halogen substituent on the pyridyl ring greatly aided
solubility. We subjected boronic ester 2a to lithiationÀ
borylation using MgBr2/MeOH as an additive to enhance
er (method A). Pleasingly, the tertiary boronic ester 3a was
formed in 50% yield (Scheme 2). Subsequent oxidation of
3a with NaOH/H2O2 gave the desired tertiary alcohol 4a in
76% yield and 98:2 er. When this was carried out without
isolation of the intermediate tertiary boronic ester, 4a was
isolated in 45% yield and 98:2 er.
Encouraged by this result, we sought to establish the
scope of the lithiationÀborylation method using a range of
commercially available heterocyclic boronic acids11 from
which we could synthesize the corresponding boronic
esters. Continuing the investigation of ortho-substituted
boronic esters, we utilized the 2-fluoro- and 2-methoxy-
substituted pyridyl boronic esters 2b and 2c and isolated
the tertiary boronic esters 3b and 3c in excellent yield.
Oxidation of both tertiary boronic esters3band 3cgavethe
corresponding tertiary alcohols 4b and 4c in high yield and
enantiomeric ratio. The additional ortho-substituents on
the pyridyl ring appear to be well tolerated without detri-
ment to the yield or enantioselectivity of the lithiationÀ
borylation.
a Conditions A: 2 added to Li-1 as a 1 M Et2O or 0.5 M PhMe solu-
tion, subsequent addition of MgBr2/MeOH prior to warming to rt. B: 2
added to Li-1 as a 1 M Et2O or 0.5 M PhMe solution (no MgBr2/MeOH).
Having established that the lithiationÀborylation reac-
tion could be applied to pyridyl boronic esters, we explored
reaction conditions with and without MgBr2/MeOH (con-
ditions A and B respectively). In the case of 2-substituted-
3-boryl pyridines (4aÀc), a higher er and yield were
achieved with the use of MgBr2/MeOH (conditions A),
especially in the case of 4c. This reflects an element of
reversibility in the ate complex formation, arising from the
increased steric hindrance of the ortho-substituted boronic
esters. Upon warming the reaction to room temperature,
the lithiated carbamate so generated becomes configura-
tionally labile and begins to racemize, and subsequent
recombination leads to the tertiary boronic ester with a
reduced er (Scheme 3). In the presence of MgBr2/MeOH,
the extent of reversibility is reduced relative to 1,2-migra-
tion, and any lithiated carbamate that is released is im-
mediately trapped by MeOH, leading to an increased er.
(6) For a rare example of asymmetric addition to pyridyl ketones
using alkyl Grignards, see: (a) Weber, B.; Seebach, D. Tetrahedron 1994,
50, 6117. For examples of asymmetric additions to furyl and thiophene
ketones with organoaluminium and organzinc nucleophiles respectively,
see: (b) Biradar, D. B.; Zhou, S.; Gau, H.-M. Org. Lett. 2009, 11, 3386.
(c) Hatano, M.; Mizuno, T.; Ishihara, K. Tetrahedron 2011, 67, 4417.
(7) (a) Garg, D. C.; Jallad, N. S.; Singh, S.; Ng, K. F.; Weidler, D. J.
J. Clin. Pharmacol. 1988, 28, 812. (b) Matsunaga, N.; Kaku, T.; Ojida, A.;
Tanaka, T.; Hara, T.; Yamaoka, M.; Kusaka, M.; Tasaka, A. Bioorg. Med.
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Chem. 2004, 12, 4313. (c) Starck, J. P.; Talaga, P.; Quere, L.; Collart, P.;
Christophe, B.; Brutto, P. L.; Jadot, S.; Chimmanamada, D.; Zanda, M.;
Wagner, A.; Mioskowski, C.; Massingham, R.; Guyaux, M. Bioorg. Med.
Chem. Lett. 2006, 16, 373. (d) Beaton, G.; Moree, W. W. J.; Jovic, F.; Coon,
T.; Yu, J. U.S. Patent US2006014797 A1 Jan 19, 2006
(8) (a) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K.
Nature 2008, 456, 778. (b) Aggarwal, V. K.; Bagutski, V.; French, R. M.
Angew. Chem., Int. Ed. 2010, 49, 5142.
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(9) (a) Hoppe, D.; Carstens, A.; Kramer, T. Angew. Chem., Int. Ed.
1990, 29, 1424. (b) Carstens, A.; Hoppe, D. Tetrahedron 1994, 50, 6097.
(10) Ou, L.; Xu, Y.; Ludwig, D.; Pan, J.; He, Xu, J. Org. Process Res.
Dev. 2008, 12, 192.
(11) Boronic acids were obtained from Inochem-Frontier.
Org. Lett., Vol. 15, No. 6, 2013
1347

Indeed, these conditions give the highest possible er
in the lithiationÀborylation since they are kinetically
controlled.
Scheme 4. Effect of Precomplexation upon Electrophilic Attack
of an Organoborane upon Li-1
Scheme 3. Beneficial Effect of MgBr2/MeOH upon
LithiationÀBorylation with Sterically Demanding Substrates
Other classes of heterocycles were used successfully. The
indole boronic ester 2i and dehydropiperidine boronic
ester 2j led to the successful isolation of the corresponding
tertiary alcohols 4i and 4j in good yield and very high er.
Moving to 2-halo-5-pyridyl boronic esters (4d/4e) re-
sulted in a dramatic decrease in yield due to competing
protodeboronation of the intermediate tertiary boronic
esters using MgBr2/MeOH (method A). We therefore
explored alternative conditions and found that using a
PhMe/Et2O solvent system without the use of MgBr2/
MeOH (Method B) led to increased yields of the tertiary
alcohols without detriment to the er.
4-Pyridyl boronic esters could also be used but were less
successful, giving either low yields or enantioselectivities
for 4fÀ4h. In the case of 4f using method B, only the
protodeboronated product 5f was isolated (with very
low enantioenrichment). The low yield of 4g can also be
attributed to the propensity of the tertiary boronic ester
to protodeboronate. In fact, when method A was used,
protodeboronation was so extensive that none of the
desired alcohol could be isolated, and using method B
resulted in a low yield of 4g. However, the tertiary alcohol
4h was isolated in good yield using method A and excellent
yield using method B. The low enantioselectivity observed
for 4h even with the addition of MgBr2/MeOH was a
surprise. In fact this is the first and only example where
essentially complete retention of stereochemistry in the
trapping of the lithiated carbamate by a boronic ester is not
obsereved. This may be due to the reduced ability of the
boronic ester to coordinate to lithium due to the strong
electron-withdrawing groups on the heteroaromatic ring,
since, in the absence of coordination (e.g., with boranes),
the reaction occurs with complete inversion of stereochem-
istry (Scheme 4).
Figure 1. X-ray structure of 3a. Thermal ellipsoids are drawn at
the 50% probability level.
Although unsubstituted pyridyl boronic esters could not
be employed in this process, due to their poor solubility,
tertiary alcohol 4 could nevertheless be accessed indirectly,
following reductive removal of the halogen substituent from
the tertiary alcohol 4d after lithiationÀborylation and
oxidation, giving tertiary alcohol 4 in 67% yield (Scheme 5).
Following our success at lithiationÀborylation with
these substrates, we briefly investigated the application of
protodeboronation in this context. Since 1,1-diarylalkanes
are privileged pharmacophores in medicinal chemistry,12,13
we were keen to examine whether the heterocyclic analogues
could be prepared by protodeboronation of the intermedi-
ate tertiary boronic esters. We previously reported two sets
The absolute stereochemistry of the tertiary boronic
ester 3a was determined by X-ray crystallography and
showed that the lithiationÀborylation reaction had occurred
with the expected retention of stereochemistry (Figure 1).
1348
Org. Lett., Vol. 15, No. 6, 2013

Table 1. Protodeboronation of Tertiary Boronic Esters 3aÀc
Scheme 5. Preparation of Tertiary Alcohol 4d
of conditions for the protodeboronation of tertiary boronic
esters: CsF/H2O for diarylalkyl boronic esters and TBAF
3
3H2O for aryldialkyl boronic esters.14 We initially tested
the former conditions and found that the boronic ester 3b
underwent clean and rapid protodeboronation with com-
plete retention of stereochemistry (Table 1, entry 2). How-
ever, the protodeboronation of tertiary boronic esters 3a
and 3c (entries 1 and 3) were found to be very slow with CsF.
a TBAF 3H2O (1.5 equiv), toluene, À20 °C to rt, 2 h. b CsF (1.5 equiv),
Application of TBAF 3H2O greatly reduced reaction times
and led to the aryl-heteroaryl-alkyl methines 5a and 5c in
high er.
3
3
H2O (1.1 equiv), dioxane, rt, 2 h. c TBAF 3H2O (1.5 equiv), toluene,
rt, 30 min.
3
In conclusion, we have successfully extended our lithia-
tionÀborylation methodology to encompass a range of
heterocyclic boronic esters. From easily accessible starting
materials, we have synthesized several R-heterocyclic ter-
tiary alcohols in good-to-excellent yield with excellent
enantioselectivity. However, depending on the nature of
the heterocycle, some intermediate tertiary boronic esters
are prone toprotodeboronation and socan lead to reduced
yields. In addition, we have combined the lithiationÀ
borylation methodology with our previously developed
protodeboronation conditions to synthesize highly enan-
tioenriched 1-pyridyl-1-arylethanes.
(12) For examples, see: (a) Messaoudi, S.; Hamze, A.; Provot, O.;
ꢀ
Treguier, B.; De Losada, J. R.; Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala,
J.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. Chem. Med. Chem. 2011,
6, 488. (b) Hu, Q.; Yin, L.; Jagusch, C.; Hille, U. E.; Hartmann, R. W.
J. Med. Chem. 2010, 53, 5049. (c) Moree, W. J.; Li, B.; Jovic, F.; Coon, T.;
Yu, J.; Gross, R. S.; Tucci, F.; Marinkovic, D.; Zamani-Kord, S.; Malany,
S.; Bradbury, M. J.; Hernandez, L. M.; O’Brien, Z.; Wen, J.; Wang, H.;
Hoare, S. R. J.; Petroski, R. E.; Sacaan, A.; Madan, A.; Crowe, P. D.;
Beaton, G. J. Med. Chem. 2009, 52, 5307. (d) Alami, M.; Messaoudi, S.;
Hamze, A.; Provot, O.; Brion, J.-D.; Liu, J.-M.; Bignon, J.; Bakala, J.
Patent WO2009147217 A1, Dec 10, 2009. (e) Beaton, G.; Moree, W. J.; Jovic,
F.; Coon, T.; Yu, J. U.S. Patent US2006014797 A1, Jan 19, 2006.
(13) For recent methods to prepare such motifs, see: (a) Maity, P.;
Shacklady-McAtee, D. M.; Yap, G. P. A.; Sirianni, E. R.; Watson, M. P.
J. Am. Chem. Soc. 2013, 135, 280. (b) Song, S.; Zhu, S.-F; Yu, Y.-B.;
Zhou, Q.-L. Angew. Chem., Int. Ed. 2012, 52, 1556. (c) Greene, M. A.;
Yonova, I. M.; Williams, F. J.; Jarvo, E. R. Org. Lett. 2012, 14, 4293.
(d) Taylor, B. L. H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J. Am.
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B. E.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132, 7870.
Acknowledgment. We thank EPSRC and the European
Research Council (FP7/2007-2013, ERC Grant No. 246785)
for financial support. We thank Inochem-Frontier Scientific
for generous donation of boronic acids and boronic esters.
We thank Dr. V. Bagutski, University of Bristol, for pre-
liminary investigations.
Supporting Information Available. Experimental pro-
cedures, characterization data, NMR spectra, and CIF of
compound 3a. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) Nave, S.; Sonawane, R. P.; Elford, T. G.; Aggarwal, V. K. J. Am.
Chem. Soc. 2010, 132, 17096.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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