Group-Assisted Purification (GAP) Chemistry for the Synthesis of Velcade via Asymmetric Borylation of N-Phosphinylimines

Article abstract of DOI:10.3762/bjoc.10.69

A new approach to the anticancer drug Velcade was developed by performing asymmetric borylation of an imine anchored with a chiral N-phosphinyl auxiliary. Throughout the 7-step synthesis, especially in the imine's synthesis and in the asymmetric borylatio

Full text of DOI:10.3762/bjoc.10.69

Group-assisted purification (GAP) chemistry for the
synthesis of Velcade via asymmetric borylation
of N-phosphinylimines
Jian-bo Xie1, Jian Luo1, Timothy R. Winn1, David B. Cordes1
and Guigen Li*1,2
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 746–751.
1Department of Chemistry and Biochemistry, Texas Tech University,
doi:10.3762/bjoc.10.69
Lubbock, Texas 79409-1061, United States and 2Institute of
Chemistry & BioMedical Sciences (ICBMS), Nanjing University,
Nanjing 210093, P. R. China
Received: 15 December 2013
Accepted: 12 March 2014
Published: 31 March 2014
Email:
Guigen Li* - guigen.li@ttu.edu
This article is part of the Thematic Series "Organophosphorus chemistry".
Guest Editor: P. R. Hanson
*
Corresponding author
Keywords:
© 2014 Xie et al; licensee Beilstein-Institut.
License and terms: see end of document.
asymmetric borylation; GAP chemistry; organophosphorous;
N-phosphinylimine; Velcade
Abstract
A new approach to the anticancer drug Velcade was developed by performing asymmetric borylation of an imine anchored with a
chiral N-phosphinyl auxiliary. Throughout the 7-step synthesis, especially in the imine’s synthesis and in the asymmetric boryla-
tion reactions, operations and work-up were conducted in simple and easy ways without any column chromatographic purification,
which defines the GAP (group-assisted purification) chemistry concept. It was found that the optically pure isomer (dr > 99:1) can
be readily obtained by washing the crude mixture of the asymmetric borylation reaction with hexane; the chiral N-phosphinyl auxil-
iary can be easily recovered after deprotection is finished. Several other N-phosphinylimines were also investigated for the asym-
metric borylation reaction. The absolute configuration of the borylation product was confirmed by single crystal X-ray diffraction
analysis.
Introduction
The synthesis of chiral α-aminoboronic acids and their deriva- centers of boronic aicds [9-13], but only a few methods for
tives has attracted much attention in the organic and medicinal generating chiral α-aminoboronic acids have been reported so
chemistry communities because of their importance for drug far [14-20]. Among the resulting products from the above
discovery and biological research [1-8]. In the past several methods, (R)-(1-amino-3-methylbutyl)boronic acid served as
years, asymmetric catalysis and auxiliary-directed asymmetric the key mechanism-based pharmacophore in the anticancer drug
synthesis has been conducted for assembling adjacent chiral Velcade, which was the first FDA approved proteasome
746

Beilstein J. Org. Chem. 2014, 10, 746–751.
inhibitor, and has been in clinical use for the treatment of Recently, our group has established a concept called GAP
multiple myeloma and mantle cell lymphoma [21]. This prod- (group-assisted purification) chemistry for greener synthesis
uct is usually synthesized in three representative processes: [22-25]. This concept describes a process where special func-
(
1) to use (1S,2S,3R,5S)-(+)-2,3-pinanediol as the chiral auxil- tional groups are attached onto reaction substrates, facilitating
iary for the addition reaction followed by chlorination and purification of crude products by avoiding traditional purifica-
amination [14,15]; (2) to perform copper-catalyzed borylation tion methods such as chromatography or recrystallization. The
of the imine anchored with chiral auxiliaries [16,17]; (3) to con- pure products, often pure stereoisomers, can be easily obtained
duct asymmetric catalytic hydrogenation as the key step to by washing the crude products with common solvents or
control the chiral center of boronic aicd [18]. As anticipated, the co-solvents [22-25]. Our GAP concept was attributed to the
above known syntheses required traditional purification study of a series of new compounds containing achiral/chiral
methods using column chromatography or recrystallization N-phosphonyl and chiral N-phosphinylimines, and the reactions
(
Scheme 1).
of these compounds.
Scheme 1: Previous work for (R)-(1-amino-3-methylbutyl)boronic acid synthesis.
747

Beilstein J. Org. Chem. 2014, 10, 746–751.
The requirements of GAP chemistry are shown by the fact that Results and Discussion
the functional groups of the reactants should generate products We started our synthesis with (2S,5S)-1-amino-2,5-
of adequate solubility. The GAP products should be soluble in diphenylphospholane 1-oxide (1), which was synthesized
some solvents such as THF and DCM for further reactions. according to the literature and our previous work in 7 steps
However, they should have poor solubility in other solvents from (1E,3E)-1,4-diphenylbuta-1,3-diene with an overall high
such as petroleum ether, hexanes, and their co-solvents with yield (27% for 7 steps) [25,26]. With the optically pure amide 1
EtOAc. The GAP requirements should include adequate chem- in hand, we screened the condensation conditions to generate
ical reactivity of GAP compounds towards many reactants and the imine 2a. Titanates, such as Ti(OiPr)4 and Ti(OEt)4,
species. If GAP groups are chiral, they should control asym- resulted in the complete conversion of the aliphatic aldehyde in
metric additions efficiently. Our GAP functional groups have two days, but the hemiaminal was obtained as the main product
also showed the flexibility for structural modifications in order [27], which can slowly decompose to release the desired imine
to control the solubility of products and also to control the 2a. Anhydrous CuSO4, which was used as a mild condensation
chemical tolerance towards various reactions under different reagent by Ellman’s group, was found to be not suitable for this
conditions. Moreover, the GAP auxiliaries have been proven to condensation reaction. This lack of suitability can probably be
be easily deprotected under several conditions for re-use.
attributed to the strong coordination tendency of the imine to a
copper ionic center. TiCl4 was proven to be an efficient reagent
Herein, we report the synthesis of the anticancer drug Velcade and lead to complete condensation within 2 hours to give 90%
and its derivatives of chiral α-aminoboronic esters via GAP conversion to imine according to crude 31P NMR. We also
chemistry. Simple operations are needed during purification found that when the crude imine product was purified by
without the need for column chromatography; GAP washing column chromatography, isomerization of 2a to enamine was
can lead to a single isomeric product, which was deprotected observed; this observation became more obvious when the
with quantitative recovery of the phosphinic acid as shown in solvents used for chromatography contained a higher water
Scheme 2.
content. Eventually, MgSO4 or CaSO4 was chosen as the dehy-
Scheme 2: Synthesis of (R)-4 and Velcade.
748

Beilstein J. Org. Chem. 2014, 10, 746–751.
dration reagent together with molecular sieves for imine forma- Pure phosphinic acid 5 was recovered by simple filtration in
tion. Under these conditions, complete conversion can be quantitative yield. The final product, Velcade 6, was synthe-
reached after 5 days to give the chiral N-phosphinylimine, sized according to the literature procedure [16] in 83% yield
which can be directly used for the following asymmetric boryla- after 4 steps (Scheme 2). 1H NMR and 13C NMR spectra of the
tion reaction without further purification.
product were proven to be identical to the literature data.
B2Pin2 and ICyCuOt-Bu were utilized as the electrophilic addi- To expand the substrate scope for the borylation reaction,
tion reagent and catalyst, respectively, for the borylation reac- several other new N-phosphinyl imines were synthesized for
tion as previously reported [16,28]. Unlike the previous system, examination (Scheme 3). Ti(OiPr)4 was chosen as the general
in which benzene was employed as the solvent, we used the condensation reagent. When aliphatic aldehydes were subjected
much less toxic solvent toluene to successfully replace benzene. to the condensation reaction, the main products were generated
We achieved full conversion with 2 equiv of B2Pin2 in the pres- either as hemiaminals 7 or as a mixture of imine and hemi-
ence of 20 mol % of ICyCuOt-Bu catalyst after 3 days to afford aminal after purification by column chromatography. The hemi-
a dr value of 7.7:1 as revealed by crude 31P NMR analysis. aminals were slowly transferred to the corresponding N-phos-
After simple work-up and washing with hexanes, the dr value phinylimine as revealed by NMR analysis. The aliphatic imines
was improved to a single isomer (Scheme 2) in 56% yield for are found to be unstable even in the presence of a trace amount
two steps. The absolute configuration of product 3a was unam- of moisture, and can easily isomerize to form the enamine.
biguously determined by X-ray analysis [29] to be in the Therefore, we directly subjected the mixture of imine and hemi-
(
S,S,R)-configuration (Figure 1). As shown in Figure 1, aminal to the borylation reaction. The borylation reactions went
H-bonds exist between the molecules, which would further help smoothly with full conversion after stirring the reaction mix-
the formation of the solid.
ture at room temperature for 3 days. Although moderate dia-
stereoselectivities were obtained for all the three aliphatic
To hydrolyze the resulting aminoboronic ester, the known N-phosphinylimines, the diastereopurities can be easily impro-
method [16] was followed first by treating the ester with one ved by GAP washing with hexane. For example, the original dr
equivalent of HCl in co-solvents of methanol and dioxane. A value for 3b of 75:25 can be enhanced to a single isomer
mixture of products was generated indicating a poor yield (dr > 99:1) in 26% yield over two steps (calculated from amide
according to the crude 31P and 1H NMR analysis. Another 1). When aromatic aldehydes were employed, the yields of
co-solvent system consisting of H2O and MeOH (2:1) was N-phosphinylimine formations were quantitative; the crude
examined. It was found that treatment of the aminoboronic ester products were almost pure according to crude 31P NMR spectra.
with 1.5 equiv of HCl for 16 hours resulted in complete depro- After simple work-up to remove most of the titanate, the crude
tection; work-up consisted of extraction with DCM followed by products were used directly for the next step without further
concentration to give product 4 as a white solid in 92% yield. purification. For the aromatic cases (entries 4 and 5, Table 1),
Figure 1: ORTEP diagram of (S,S,R)-3a (left, most of the hydrogen atoms were omitted except the one on the chiral center connected to boron) and
the H-bonds between the molecules (right). Selected bond lengths [Å] and angle [o]: P1–O1 1.505, P1–N1 1.613, N1–H1, 0.957, B1–O2 1.368, the
H-bond O1···H2 1.990; the angle of H bond N1–H1···O4 142.79.
749

Beilstein J. Org. Chem. 2014, 10, 746–751.
Scheme 3: Synthesis of phosphinylimines and their borylation products.
Table 1: Results of borylation reactionsa.
Entry
Imines
R
Products
dr (crude)b
dr (GAP)b
Yieldc
1
2
3
4
5
2b
2c
2d
2e
2f
iPr
3b
3c
3d
3e
3f
75:25
78:22
84:16
97:3
>99:1
99:1
98:2
–
26%
40%
45%
51%
44%
cyclohexyl
PhCH2CH2
Ph
4-MeOPh
>99:1
–
aReaction conditions: 0.74 mmol scale, [substrate] = 1.8 M, 2.0 equiv B2Pin2, 20 mol % ICyCuOt-Bu, toluene (4 mL), room temperature, 3 days.
bDetermined by 31P NMR analysis. cCalculated from the starting amide 1, isolated yields with GAP washing (for 3e and 3f, GAP washing was not
conducted).
excellent diastereoselectivities, dr = 97:3 and >99:1, respective- 2 equiv), catalyst ICyCuOt-Bu (54 mg, 20 mol %) and 4 Å
ly, were achieved according to the 31P NMR analysis of crude molecular sieves (~500 mg). The mixture was protected with
products. Pure products 3e and 3f were obtained via flash argon atmosphere, followed by toluene (4 mL) addition via
column chromatography since GAP washing led to some syringe. The reaction mixture was stirred vigorously for 3 days,
decomposition in these two cases.
and the resulting slurry was filtered through Celite and washed
with EtOAc 5 times. The filtrate was then concentrated and
checked by 31P NMR to determine the % conversion and the
Conclusion
We have successfully demonstrated that N-phosphinylimines crude dr value. GAP operations: 1) Method A: The filtrate was
can undergo electrophilic borylation reactions, and that this re-dissolved in EtOAc and washed with 1 N HCl, water, and
reaction can be applied in the synthesis of the anticancer drug brine successively, then dried over anhydrous Na2SO4. The
Velcade. The N-phosphinyl auxiliary displayed good to excel- crude product was obtained by filtration and concentration, fol-
lent asymmetric induction and great stability in the catalytic lowed by addition of 5 mL of hexanes to triturate the crude
borylation and deprotection reactions. GAP washing is found to product. After 30 minutes, the solvent was decanted and another
enhance the diastereopurity of the borylation products in most 5 mL hexanes were added. The resulting slurry was then filtered
cases. The absolute configuration of the borylation product in and the solid was washed with another 2 mL hexanes. The solid
Velcade’s synthesis has been confirmed by single crystal X-ray product was collected and dried in vacuo. The yield was calcu-
diffraction analysis.
lated and the dr value and purity were checked by 31P NMR and
H NMR. 2) Method B: The filtrate was re-dissolved in EtOAc/
hexanes (20 mL, v/v = 1:1), and then filtered through Celite.
1
Experimental
Standard operations for catalytic borylation and GAP: A 10 mL The filtrate was concentrated and triturated with hexanes
Schlenk tube was charged with crude imine 2, B2Pin2 (375 mg, (5 mL). After 30 minutes, the solvent was decanted and another
750

Beilstein J. Org. Chem. 2014, 10, 746–751.
15.Adams, J.; Ma, Y.-T.; Stein, R.; Baevsky, M.; Grenler, L.;
5
mL hexanes was added. The resulting slurry was then filtered
Plamondon, L. Boronic Ester and Acid Compositions. U.S. Patent
US6617317B1, Sept 9, 2003.
and the solid was washed with another 2 mL hexanes. The solid
product was collected and dried in vacuo. The yield was calcu-
lated from the starting amide 1. The dr value and purity were
checked by 31P NMR and 1H NMR.
1
6.Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130,
6910–6911. doi:10.1021/ja800829y
17.Sun, J.-T.; Kong, L. Method for Synthesizing Bortezomib. Chinese
Patent CN101812026A, Aug 25, 2010.
1
1
2
8.Ivana, G. S.; Zdenko, C. Process for Hydrogenation of
Halogenoalkenes without Dehalogenation. WO Patent
WO2010146176A2, Dec 23, 2010.
Supporting Information
Supporting Information File 1
9.Morandi, S.; Caselli, E.; Forni, A.; Bucciarelli, M.; Torre, G.; Prati, F.
Tetrahedron: Asymmetry 2005, 16, 2918–2926.
doi:10.1016/j.tetasy.2005.08.008
Experimental details, characterization data of all products,
and copies of NMR spectra.
0.Hong, K.; Morken, J. P. J. Am. Chem. Soc. 2013, 135, 9252–9254.
doi:10.1021/ja402569j
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-69-S1.pdf]
2
1.http://www.Velcade.com (accessed Feb 11, 2014).
2.Kattuboina, A.; Li, G. Tetrahedron Lett. 2008, 49, 1573–1577.
doi:10.1016/j.tetlet.2008.01.028
2
Acknowledgements
23.Kotti, S. R. S. S.; Xu, X.; Wang, Y.; Headley, A. D.; Li, G.
Tetrahedron Lett. 2004, 45, 7209–7212.
doi:10.1016/j.tetlet.2004.08.040
We gratefully acknowledge the financial support from the NIH
(
R33DA031860), the Robert A. Welch Foundation (D-1361)
2
4.Pindi, S.; Kaur, P.; Shakya, G.; Li, G. Chem. Biol. Drug Des. 2011, 77,
0–29. doi:10.1111/j.1747-0285.2010.01047.x
and the Jiangsu Innovation Team Program (P. R. China) for
their generous support of this research. We also thank NSF
Grant CHE-1048553 and the CRIF program for supporting our
NMR facility. We thank Cole Seifert for helpful discussion.
2
25.Pindi, S.; Wu, J.; Li, G. J. Org. Chem. 2013, 78, 4006–4012.
doi:10.1021/jo400354r
26.Guillen, F.; Rivard, M.; Toffano, M.; Legros, J.-Y.; Daran, J.-C.;
Fiaud, J.-C. Tetrahedron 2002, 58, 5895–5904.
doi:10.1016/S0040-4020(02)00554-9
References
2
2
2
7.Lauzon, C.; Charette, A. B. Org. Lett. 2006, 8, 2743–2745.
1.
2.
3.
4.
Matteson, D. S.; Ray, R. J. Am. Chem. Soc. 1980, 102, 7590–7591.
doi:10.1021/ol0607847
doi:10.1021/ja00545a046
8.Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006, 128,
Matteson, D. S.; Sadhu, K. M.; Lienhard, G. E. J. Am. Chem. Soc.
11036–11037. doi:10.1021/ja064019z
1
981, 103, 5241–5242. doi:10.1021/ja00407a051
Kinder, D. H.; Katzenellenbogen, J. A. J. Med. Chem. 1985, 28,
917–1925. doi:10.1021/jm00150a027
9.For the details of the crystal, see CCDC number 937895.
1
Snow, R. J.; Bachovchin, W. W.; Barton, R. W.; Campbell, S. J.;
Coutts, S. J.; Freeman, D. M.; Gutheil, W. G.; Kelly, T. A.;
Kennedy, C. A.; Krolikowski, D. A.; Leonard, S. F.; Pargellis, C. A.;
Tong, L.; Adams, J. J. Am. Chem. Soc. 1994, 116, 10860–10869.
doi:10.1021/ja00103a002
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
5.
6.
7.
8.
Jadhav, P. K.; Man, H.-W. J. Org. Chem. 1996, 61, 7951–7954.
doi:10.1021/jo961075h
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Kettner, C.; Mersinger, L.; Knabb, R. J. Biol. Chem. 1990, 265,
18289–18297.
Soskel, N. T.; Watanabe, S.; Hardie, R.; Shenvi, A. B.; Punt, J. A.;
Kettner, A. C. Am. Rev. Respir. Dis. 1986, 133, 639–642.
Zhu, Y.; Wu, G.; Zhu, X.; Ma, Y.; Zhao, X.; Li, Y.; Yuan, Y.; Yang, J.;
Yu, S.; Shao, F.; Lei, M. J. Med. Chem. 2010, 53, 8619–8626.
doi:10.1021/jm1009742
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
9
1
1
1
1
1
.
Crudden, C. M.; Hleba, Y. B.; Chen, A. C. J. Am. Chem. Soc. 2004,
The definitive version of this article is the electronic one
which can be found at:
126, 9200–9201. doi:10.1021/ja049761i
0.Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160–3161.
doi:10.1021/ja809382c
doi:10.3762/bjoc.10.69
1.Schiffner, J. A.; Müther, K.; Oestreich, M. Angew. Chem., Int. Ed. 2010,
4
9, 1194–1196. doi:10.1002/anie.200906521
2.Sasaki, Y.; Zhong, C.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010,
32, 1226–1227. doi:10.1021/ja909640b
3.Ibrahem, I.; Breistein, P.; Córdova, A. Angew. Chem., Int. Ed. 2011, 50,
2036–12041. doi:10.1002/anie.201105458
4.Kettner, C. A.; Shenvi, A. B. J. Biol. Chem. 1984, 259, 15106–15114.
1
1
751