Addressing the configuration stability of lithiated secondary benzylic carbamates for the development of a noncryogenic stereospecific boronate rearrangement

Article abstract of DOI:10.1021/ol502060c

A practical noncryogenic process for the Aggarwal stereospecific boronate rearrangement with chiral secondary benzylic carbamates has been developed. The use of LDA instead of sec-BuLi combined with an in situ trapping of the unstable lithiated carbamate was critical to success. Furthermore, this new process increased the substrate scope to include the versatile aryl iodide and bromide substrates. The methodology was applied to a diverse array of substrates and was demonstrated on multikilogram scale.

Full text of DOI:10.1021/ol502060c

Letter
pubs.acs.org/OrgLett
Addressing the Configuration Stability of Lithiated Secondary
Benzylic Carbamates for the Development of a Noncryogenic
Stereospecific Boronate Rearrangement
Keith R. Fandrick,*,† Nitinchandra D. Patel,† Jason A. Mulder,† Joe Gao,† Michael Konrad,‡
Elizabeth Archer,† Frederic G. Buono,† Adil Duran,‡ Rolf Schmid,‡ Juergen Daeubler,‡
Daniel R. Fandrick,† Shengli Ma,† Nelu Grinberg,† Heewon Lee,† Carl A. Busacca,† Jinhua J. Song,†
Nathan K. Yee,† and Chris H. Senanayake†
†Department of Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield,
Connecticut 06877-0368, United States
‡Department of Chemical Development, Boehringer-Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397
Biberach/Riß, Germany
S
* Supporting Information
ABSTRACT: A practical noncryogenic process for the Aggarwal stereo-
specific boronate rearrangement with chiral secondary benzylic carbamates
has been developed. The use of LDA instead of sec-BuLi combined with an
in situ trapping of the unstable lithiated carbamate was critical to success.
Furthermore, this new process increased the substrate scope to include the
versatile aryl iodide and bromide substrates. The methodology was applied
to a diverse array of substrates and was demonstrated on multikilogram
scale.
he search for new and improved methods for the efficient
Tconstruction of complex chiral compounds is an ongoing
endeavor in both academic and industrial settings. Since the
seminal work of Matteson,1 chiral boronic esters and boranes
have emerged as an efficient handle for the rapid construction of
diverse chiral synthons.2 However, the large scale synthesis of
pharmaceutically active compounds presents unique chemical
challenges for these technologies.3 The considerations of
chemical robustness, safety, equipment suitability, and process
and cost efficiency are important parameters for successful large
scale batch operations.4 In particular these considerations are
imperative for asymmetric transformations. These constraints
Figure 1. Boronate rearragements of chiral benzylic carbamates.
therefore serve as a test of the limitations of current chemical
technologies and offer a medium for further advancement. In this
first robust and noncryogenic Aggarwal boronate rearrange-
ment.11
regard, Aggarwal’s stereoselective boronate rearrangement
The deprotonation of benzyl carbamates 1 utilizing sec-butyl
lithium as the base is not compatible with the more versatile aryl
(Figure 1)5,6 based on Hoppe’s lithiated carbamates7 is
particularly attractive as the stereochemistry of the process is
ultimately generated from a well precedented asymmetric
reduction of a prochiral ketone.8 However, the key boronate
rearrangement requires cryogenic temperatures (i.e., −78 °C)
that are not suitable for large scale synthesis where the
considerations of reaction robustness, safety, and cost efficiency
are important for commercial success (Figure 1).9 Furthermore,
the process is inherently unstable as the configurationally labile
lithiated carbamate and boronate complexes are accumulated
during the process. In addition, the use of alkyl lithium bases
precluded10 the use of the more versatile bromide analogue
carbamate 1b. Herein we wish to report the development of the
bromide or iodide substrates, so the use of a hindered amide base
was investigated. The stability of the resulting benzylic anions
with respect to temperature over time was studied (Figure 2).
Even at cryogenic temperatures (−78 °C) employing sec-butyl
lithium (Et2O) as the base, an appreciable erosion of
enantiomeric excess was observed indicating the system is
inherently unstable even at this low temperature. Furthermore, at
the more practical −19 °C, the ee of the benzylic anion was
completely eroded within 30 min. However, the rate of erosion of
Received: May 19, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502060c | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 4. Equilibrium between the LDA−carbamate complex and the
deprotonated/lithiated carbamate diisopropylamine complex.
In order to avoid the prolonged accumulation of the
stereochemically unstable lithiated carbamate 4 the deprotona-
tion of 1 was conducted in the presence of the boronic ester to
quench the anion as it was formed (Table 1). Initial attempts at
the in situ trapping using sec-butyl lithium provided no product,
as the boronic ester kinetically traps the base prior to
deprotonation. We were delighted to find that the use of
LDA13 for the in situ deprotonation (−78 °C) provided the
desired adduct with 90% conversion with an erosion of only 4%
ee (Table 1, entry 2). At more elevated reaction temperatures
(−10 °C), lower conversion and higher ee erosion were
observed. Eliminating THF from the system by utilizing LDA
prepared in cyclopentyl methyl ether (CpOMe) allowed the
reaction temperature to be increased to +4 °C while maintaining
both high conversion (92%) and minimal loss of stereochemical
integrity.
Figure 2. Rates of racemization under various reaction conditions.
the enantiomeric excess of the benzylic center with the use of
LDA (MTBE) was found to be significantly less even at −19 °C.
Within 5 min of aging the benzylic anion derived from sec-butyl
lithium (−19 °C) a number of byproducts were observed,
whereas the anion derived from the LDA process was found to be
clean via HPLC analysis even after 30 min.
The nature of the derived anion with LDA was studied via
deuterium trapping experiments (Figure 3). Deprotonation of
The LDA method described above as well as the original
Aggarwal process was monitored in real time by ReactIR (Figures
5 and 6).14 Treatment of the p-chloroaryl carbamate 1a with sec-
butyl lithium at −78 °C forms the thermally unstable lithiated
carbamate 4 which is observed on the ReactIR plot (Figure 6a,b).
The lithiation was shown to be very rapid and complete upon the
addition of a base. The addition of the boronic ester 2b instantly
forms a new species (5) which is stable until the reaction is
warmed to ∼0 °C, at which point the intermediate rearranges to
the tertiary boronate product (30 min, Figure 6b). However, at
the relatively high temperature required for the rearrangement,
the dissociation process becomes competitive and provides a
pathway for partial racemization. Aggarwal et al. presented an
elegant solution to this issue by treating the boronate complex
(−78 °C) with magnesium bromide in methanol to simulta-
neously accelerate the rearrangement and to trap the dissociated
carbamate anion.6 Indeed, the addition of MgBr2/MeOH to the
preformed boronate complex 5 formed a new complex (Figure
6a) which was observed to rearrange to the desired product 3b
upon warming. Yet, this solution would not be viable at
noncryogenic temperatures where competitive dissociation is the
major process, which would significantly reduce the yield. The
rearrangement process would therefore need to be accelerated.
Furthermore, at higher reaction temperatures the accumulation
of the sensitive boronate complex would be bypassed altogether
rendering the process inherently stable.
Figure 3. Deuterium trapping experiments for the deprotonation of
Carbamate 1a with sec-butyl lithium and LDA.
carbamate 1a with sec-butyl lithium7 formed a presumed anion of
the carbamate which after aging for 10 min (−78 °C) was
quenched with methanol-d4. The resulting product had a
minimal loss of ee (84.7% ee) and high deuterium incorporation
(91%). However, repeating the same experiment with LDA as
the base and aging for 70 and 120 min respectively (−25 °C)
showed little to no deuterium incorporation while the derived
products were obtained with significant ee erosion (48.6 and
25.8% ee) implying the benzylic anion is being accessed. One
possibility is that the weaker base (LDA) does not outright
deprotonate the carbamate substrate 1, but instead the system is
in a state of equilibrium between the LDA−carbamate complex
and the deprotonated carbamate species, where the LDA−
carbamate complex is thermodynamically preferred (Figure 4).12
Thus, the LDA in the more stable LDA−carbamate complex
would kinetically trap the deuterium from methanol-d4 and
preserve the carbamate benzylic proton. However, by employing
an electrophile that is compatible with LDA (pinacol boronic
esters), the thermodynamically less stable lithiated carbamate
could be utilized for a productive transformation while benefiting
from the increased stability afforded to the system by avoiding
the accumulation of the deprotonated species. Based on the
increased overall stability inherent in the LDA process, this
system was further explored for the Aggarwal rearrangement
process.
The LDA process was studied by ReactIR at low temperatures
(Figure 7a). Treatment of a solution consisting of the carbamate
with LDA at −78 °C caused a new peak to form which is
presumed to be the LDA−carbamate complex.15 The addition of
the boronic ester 2b did not alter the peak, but upon warming the
resulting batch to −40 °C, the LDA−carbamate complex peak
decreases and a new minor peak is formed which correlates with
the boronate complex 5. Upon warming the batch to −25 °C, the
boronate complex peak decreased and the product 3b was
B
dx.doi.org/10.1021/ol502060c | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Survey of Bases for the in Situ Deprotonation and Boronate Rearrangement
a
b
entry
X
base
solvent
temp
conversion
ee erosion
1
2
3
4
5
6
7
Cl 1a
Br 1b
Br 1b
Br 1b
Br 1b
Br 1b
Br 1b
sec-BuLi (1.2 equiv)
Et2O
−30 °C
−78 °C
−30 °C
−10 °C
−25 °C
−10 °C
4 °C
0%
90%
80%
50%
91%
96%
92%
NA
LDA (2 M THF/Hept/EtPh)
LDA (2 M THF/Hept/EtPh)
LDA (2 M THF/Hept/EtPh)
LDA (1 M CpOMe)
CpOMe
CpOMe
CpOMe
CpOMe
CpOMe
CpOMe
−4%
−4%
−10%
−0.8%
−1.0%
−2.2%
LDA (1 M CpOMe)
LDA (1 M CpOMe)
a
b
Molar conversion determined by HPLC analysis. Measured by ee Erosion = ee Carbamate − ee Product. Ee determined by Chiral HPLC analysis.
Figure 5. Proposed mechanism for the Aggarwal boronate rearrange-
ment process.
Figure 7. ReactIR monitoring of the LDA process.
addition of LDA to the solution of both the boronic ester 2b and
carbamate 1a (Figure 7b). In addition, with this noncryogenic
approach, the system does not accumulate the configurationally
labile lithiated carbamate 4 or the sensitive boronate complex 5.
The new LDA method is thus an inherently stable and robust
process and suitable for large scale operations in commercial
environments. Indeed, this chemistry, starting with bromoaryl
cabamate 1b was successfully scaled to provide 24 kg in a single
batch of the tertiary boronic ester 3c in near perfect yield (99%)
and with excellent stereoretention (98.6% ee, Figure 8).
The LDA process was demonstrated to be general for a variety
of alkyl boronic esters and substituted arene carbamates (Figure
9). Employing the previously incompatible aryl iodide or
bromides, the corresponding tertiary boronic esters were
obtained in good yield and >90% ee at a reaction temperature
of 0 °C. Primary, secondary, and even allylic boronic esters are
tolerated providing the products in 80−98% ee. The process was
Figure 6. ReactIR monitoring of the Aggarwal boronate rearrangement
process.
observed by HPLC analysis. When performing the reaction at
−10 °C the process smoothly generates the product during the
C
dx.doi.org/10.1021/ol502060c | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
REFERENCES
■
(1) (a) Matteson, D. S. Tetrahedron 1989, 45, 1859−1885.
(b) Matteson, D. S. Chem. Rev. 1989, 89, 1535−1551.
(2) Scott, H. K.; Aggarwal, V. K. Chem.Eur. J. 2011, 17, 13124−
13132.
(3) Busacca, C. A.; Fandrick, D. R.; Song, J. J.; Senanayake, C. H.
Transition Metal Catalysts in the Pharmaceutical Industry. In
Applications of Transition Metal Catalysis in Drug Discovery and
Development an Industrial Perspective; Crawley, M. L, Trost, B. M.,
Eds.; Wiley: Hoboken, NJ, 2012.
Figure 8. Large scale and higher temperature LDA promoted Boronate
rearrangement.
(4) (a) Anderson, N. G. Practical Process Research & Development;
Academic Press: San Diego, 2000; p 354. (b) Practical Process
Development: Current Chemical and Engineering Challenges; Blacker, J.,
Williams, M. T., Eds.; RSC Publishing: 2011; p 374.
(5) Thomas, S. P.; French, R. M.; Jheengut, V.; Aggarwal, V. K. Chem.
Rec. 2009, 9, 24−39.
(6) (a) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K.
Nature 2008, 456, 778−782. (b) Bagutski, V.; Ros, A.; Aggarwal, V. K.
Tetrahedron 2009, 65, 9956−9960. (c) Bagutski, V.; French, R. M.;
Aggarwal, V. K. Angew. Chem., Int. Ed. 2010, 49, 5142−5145.
(d) Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche-Gauthier,
R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2011, 50, 3760−
3763.
(7) (a) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int. Ed. Engl.
1990, 29, 1422−1424. (b) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2282−2316.
(8) Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J. Chem. Rev.
2006, 106, 2734−2793.
(9) For general purpose large scale reactors the minimum preferred
operational internal temperature is −10 to −20 °C.
Figure 9. Substrate survey for the noncryogenic boronate rearrange-
ment process.
(10) Bailey, W. F.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1−46.
(11) Fandrick, K. R.; Gao, J. J.; Mulder, J. A.; Patel, N. D.; Zheng, X.
Boehringer Ingelheim International GMBH, WO 2013/119751 A1,
2013.
(12) Another possibility exists where internal protonation of the
deprotonated carbamate occurs from the diisopropylamine during the
deuterium quench; see: Seebach, D.; Boes, M.; Naef, R.; Schweizer, W.
B. J. Am. Chem. Soc. 1983, 105, 5390−5398.
(13) Matteson, D. S.; Soundararajan, R.; Ho, O. C.; Gatzweiler, W.
Organometallics 1996, 15, 152−163.
(14) For selected examples of ReactIR used in process development,
see: (a) Grabarnick, M.; Zamir, S. Org. Process Res. Dev. 2003, 7, 237−
243. (b) Connolly, T. J.; Matchett, M.; McGarry, P.; Sukhtankar, S.;
Zhu, J. Org. Process Res. Dev. 2006, 10, 391−397.
(15) Stead, D.; Carbone, G.; O’Brien, P.; Campos, K. R.; Coldham, I.;
Sanderson, A. J. Am. Chem. Soc. 2010, 132, 7260−7261.
also shown to be effective for the construction of chiral biaryl
boronic esters (3k−l). In particular, the versatile aryl iodide aryl
bromide 3m was formed in 98% ee and 77% isolated yield.
In conclusion, an inherently stable and noncryogenic process
for the Aggarwal stereoretentive boronate rearrangement process
has been developed. By replacing sec-BuLi with LDA, using
CpOMe or MTBE as the solvent, and instituting an in situ
trapping of the unstable lithiated carbamate, the process could be
performed under noncryogenic conditions. By performing the
chemistry under noncyrogenic conditions the reaction smoothly
generates the desired boronate product which renders the
reaction inherently stable by eliminating the accumulation of
stereochemically sensitive intermediates. This new process
increased the substrate scope of this reaction to include versatile
aryl iodide and bromide substrates. The methodology was
demonstrated on a diverse array of substrates and was
demonstrated on multikilogram scale. This new method provides
a valuable tool for the practical stereoselective construction of
versatile chiral tertiary boronates.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and details including all associated
spectra (1H NMR, 13C NMR, Chiral HPLC spectra). This
information is free of charge via the Internet at http://pubs.acs.
org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: keith.fandrick@boehringer-Ingelheim.com.
Notes
The authors declare no competing financial interest.
D
dx.doi.org/10.1021/ol502060c | Org. Lett. XXXX, XXX, XXX−XXX