Catalytically Enantioselective Synthesis of Acyclic α-Tertiary Amines through Desymmetrization of 2-Substituted 2-Nitro-1,3-diols

Article abstract of DOI:10.1021/acs.orglett.7b03581

Highly enantioselective synthesis of acyclic α-tertiary amines through asymmetric desymmetrization is reported. This approach is based on chiral phosphoric acid mediated, enantioselective, oxidative desymmetrization of 2-substituted 2-nitro-1,3-diolbenzylidine acetals in the presence of DMDO as an oxidant. The method allows for the formation of a wide variety of chiral 2-nitro-1,3-diols in high enantioselectivity, which could be transformed into optically pure, unnatural α-alkyl series. The synthetic utility of this method has been further demonstrated by the expedient construction of the core structure of natural products manzacidins enantioselectively.

Full text of DOI:10.1021/acs.orglett.7b03581

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytically Enantioselective Synthesis of Acyclic α‑Tertiary Amines
through Desymmetrization of 2‑Substituted 2‑Nitro-1,3-diols
Shan-Shui Meng, Wu-Bang Tang, and Wen-Hua Zheng*
State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and
Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu 210023, China
S
* Supporting Information
ABSTRACT: Highly enantioselective synthesis of acyclic α-tertiary amines through asymmetric desymmetrization is reported.
This approach is based on chiral phosphoric acid mediated, enantioselective, oxidative desymmetrization of 2-substituted 2-nitro-
1,3-diolbenzylidine acetals in the presence of DMDO as an oxidant. The method allows for the formation of a wide variety of
chiral 2-nitro-1,3-diols in high enantioselectivity, which could be transformed into optically pure, unnatural α-alkyl series. The
synthetic utility of this method has been further demonstrated by the expedient construction of the core structure of natural
products manzacidins enantioselectively.
Scheme 1. Accessing Chiral α-Tertiary Amines through
Enantioselective Desymmetrization
ptically active amines are highly important structural
Omotifs that are widely found in natural products as well as
medicinal compounds.1 Among them, α-tertiary amines have
attracted considerable interest due to their unique properties.2
For instance, chiral α-substituted nonproteinogenic serines3 are
used in peptide chemistry and (S)-α-(hydroxymethyl)glutamic
acid (HMG)4 was found to be a potent a potent mGluR3 agonist.
However, catalytic enantioselective synthesis of those moieties
has met with limited success.5 A typical strategy is the addition of
organometallic reagent to ketimines in the presence of chiral
organocatalyst or transition-metal complex.5−7 The reaction
scope, however, is relatively limited probably because of the
electronic and steric factors (for example, low reactivity and the
E/Z isomer of ketimines).6 Other methods, including rearrange-
ment,8 asymmetric amination/alkylation9 and allylic amina-
tion,10 have been developed to address this challenging issue.
Despite remarkable progress, accessing optically pure acyclic
aliphatic group substituted α-tertiary amines in a catalytic
enantioselective version remains a daunting task.5
Enantioselective desymmetrization is one of the most
powerful strategies to afford the chiral compounds.11 Although
there are many elegant examples of asymmetric desymmetriza-
tion, highly catalytically enantioselective desymmetrization
method to tackle on synthesis of α-tertiary amines remains
largely unexplored (Scheme 1). In this respect, Cai and co-
workers recently reported the first highly enantioselective
intramolecular Ullmann reactions in the presence of copper
catalyst to afford products bearing N-substituted quaternary
stereocenter.12 However, the substrates are limited and products
are usually indolines. Alternatively, Nagao’s group13 and Kang’s
group14 independently reported enantioselective acylation of 2-
substituted 2-amino-1,3-diols employing chiral Zn and Cu
complexes, respectively; however, the enantioselectivity is
moderate to good or removal of the protecting group on the
nitrogen requires harsh conditions.14
Received: November 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03581
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Based on our previous success with a chiral phosphoric
acid16,17 mediated enantioselective desymmetrization of 2-aryl-
1,3-diols,15 we hypothesized that in the presence of suitable
catalyst and proper protection group on the nitrogen asymmetric
desymmetrization of 2-substituted 2-amino-1,3-diols would be
feasible. Thus, 2-methyl-2-amino-1,3-diols with different protect-
ing groups on the nitrogen were tested. To our disappointment,
all failed because of the difficulty in preparation of acetals or the
oxidative problem of nitrogen. We then turned to the nitro
compound because reduction of nitro group to amine is one of
the most reliable protocols to obtain amine,18 and nitro is a
robust functional group which could tolerate many harsh
conditions without extra protection as well.18 2-Methyl-2-nitro-
1,3-diol was easily to be synthesized through nucleophilic
addition of nitromethane to formaldehyde.13 To the best of our
knowledge, there are no example of nonenzymatic catalytic
enantioselective desymmetrization of 2-substituted 2-nitro-1,3-
diols.19 Therefore, we evaluated the reaction conditions reported
previously for oxidative desymmetrization of PMP-protected 2-
methyl-2-nitro-1,3-diol (1a) and fortunately found the desired
product 2a was obtained in excellent yield (88% yield) and
enantioselectivity (95% ee) (Table 1, entry 1). Next, an
Scheme 2. Reaction Scope of Nitro-Substituted Substrates
a
Table 1. Survey of Chiral Phosphoric Acids
range of substrates, thus delivering the 2-substituted 2-nitro-1,3-
propanediol in high yield and excellent enantioselectivity. A
series of substrates bearing different hindered alkyl chains
underwent desymmetrization in excellent yields and enantiose-
lectivity, giving the product in excellent yield and around 95% ee
(2a−e). Ester group are compatible to afford the corresponding
products in high enantioselectivity, while the distance of the
chain does not have a significant effect on enantiocontrol (2f−h).
Different electronic and steric aryl-substituted substrates were
also tolerated, giving the expected products (2i−n) in excellent
yield and high enantioselectivity (92−97% ee). The absolute
configuration of 2a was determined to be R compared with the
optical rotation of known compound after several trans-
formations (see the Supporting Information).
In order to further demonstrate the synthetic utility of this
protocol, a large-scale reaction of 1a was carried out (Scheme 3).
Under the optimal conditions, the reaction proceeded well,
delivering product 2a in good yield and excellent enantiose-
lectivity, without notable erosion of yield and ee.
a
Reaction conditions: 1 (0.1 mmol), cat. (5 mol %), and DMDO (5
Scheme 3. Large-Scale Reactions
b
c
mL) at 0 °C. Isolated yield. Enantiomeric excess determined by
chiral HPLC analysis.
evaluation of potential chiral phosphoric acids was carried out
(Table 1, entries 2−7). Although most of the reactions
proceeded well in the presence of chiral phosphoric acids, poor
or moderate enantioselectivity was achieved. In addition, further
screening of the temperature and solvents did not give better
results according to yield and ee.
Under the optimal reaction conditions, a variety of 2-
substituted 2-nitro-1,3-diol benzylidene acetals were examined
(Scheme 2). Generally, chiral phosphoric acid promoted
oxidative desymmetrization can be effectively with a wide
The optically enriched amino alcohol or unnatural amino acid
are both biologically and synthetically valuable due to their wide
presence in natural products and medicinal chemistry. We
considered that our catalytic enantioselective desymmetrization
might provide a convenient entry to those important chiral
building blocks. Hence, we set to investigate the transformations
B
DOI: 10.1021/acs.orglett.7b03581
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of optically active 2-substituted 2-nitro-1,3-diols. As illustrated in
Scheme 4, reduction of nitro in 2a and 2e through Raney Ni/H2
Scheme 5. Formal Synthesis of Manzacidins A and C
Scheme 4. Divergent Transformations of the Products
and then immediately protected with Boc anhydride afforded
chiral 2-amino alcohol 3 and 4 in excellent yield, while the ee was
maintained. The hydroxyl group was subsequently oxidized with
TEMPO/NaClO under basic conditions to afford the corre-
sponding acid,20 and PMP ester was removed with K2CO3 to
afford α-Me serine 53b and α-Bn serine 6,3c which are one class of
important unnatural amino acids in medicinal chemistry, without
loss of ee (see the SI). More interestingly, chiral product 2g
bearing an ester group in the alkyl chain was converted into 7
under hydrogenation conditions, which could be further
transformed to optically hydroxymethyl glutamic acid
(HMG),4 a potent mGluR3 agonist and a weak mGluR2
antagonist. Notably, 2g was reduced and subsequently cyclized
to afford product 8, which is an important synthetic precursor of
the natural product salinosporamide.21
Manzacidins were isolated from sponges, a family of
bromopyrrole alkaloids.22 Their structures are unique, and at
the same time they have some interesting pharmacological
activities, which inspired synthetic chemists to consider them as
suitable targets for total synthesis.22 The key challenge is the
construction of chiral N-substituted quaternary stereocenter.
Ohfune and co-workers synthesized intermediate 10 and
converted it to natural product manzacidins A and C.22g To
further evaluate the synthetic utility of this new process, efforts
have been taken toward the formal synthesis of manzacidins A
and C.
As shown in Scheme 5, the synthesis commenced with 3,
followed by oxidation of alcohol, and HWE reaction to furnish 9
in excellent yield. Subsequently, removal of the protecting group
and reprotection with TBSCl afforded Ohfune’s intermediate 10,
the precursor of manzacidin C, and the spectra data were in good
agreement with those reported.22g Again, beginning with
intermediate 3, protection with TBSCl, removal of PMP ester,
oxidation, and HWE reaction gave the Ohfune’s intermediate
ent-10, which is the precursor of manzacidin A. The optical
rotation of 14 and ent-14 is in agreement with that in
literature.22g
In summary, we have developed a general and facile
enantioselective oxidative desymmetrization of 2-substituted 2-
nitro-1,3-diols mediated by chiral phosphoric acid. This protocol
was shown to be effective with a broad substrate scope, including
alkyl- and aryl-substituted 2-nitro-1,3-diols. The new approach
provides access to a variety of chiral valuable building blocks. The
robustness and practicality were demonstrated by a variety of
transformations and large-scale reactions. The synthetic utility
was further demonstrated by the formal synthesis of manzacidins
A and C.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03581.
Experimental details (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wzheng@nju.edu.cn.
ORCID
Wen-Hua Zheng: 0000-0002-0299-3953
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support from National Natural Science
Foundation of China (21772086), the Fundamental Research
Funds for the Central Universities (020514380118), and
Nanjing University is gratefully acknowledged.
REFERENCES
■
(1) Chiral Amine Synthesis; Nugent, T. C., Ed.; Wiley-VCH: New York,
2008.
(2) (a) Kang, S. H.; Kang, S. Y.; Lee, H.-S.; Buglass, A. J. Chem. Rev.
2005, 105, 4537. (b) Dake, G. Tetrahedron 2006, 62, 3467. (c) Hager,
A.; Vrielink, N.; Hager, D.; Lefranc, J.; Trauner, D. Nat. Prod. Rep. 2016,
33, 491. (d) Mailyan, A. K.; Eickhoff, J. A.; Minakova, A. S.; Gu, Z.; Lu,
P.; Zakarian, A. Chem. Rev. 2016, 116, 4441.
(3) (a) Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry
2007, 18, 569. (b) Smith, N. D.; Goodman, M. Org. Lett. 2003, 5, 1035.
(c) Lempicka, E.; Slaninova, J.; Olma, A.; Lammek, B. J. Pept. Res. 1999,
53, 554.
(4) Zhang, J.; Flippen-Anderson, J. L.; Kozikowski, A. P. J. Org. Chem.
2001, 66, 7555.
C
DOI: 10.1021/acs.orglett.7b03581
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(5) (a) Shibasaki, M.; Kanai, M. Chem. Rev. 2008, 108, 2853.
(b) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110,
3600.
(6) (a) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867. (b) Connon,
S. J. Angew. Chem., Int. Ed. 2008, 47, 1176. (c) Spero, D. M.; Kapadia, S.
R. J. Org. Chem. 1997, 62, 5537. (d) Cogan, D. A.; Ellman, J. A. J. Am.
Chem. Soc. 1999, 121, 268.
(7) (a) Fu, P.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008,
130, 5530. (b) Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J. Am.
Chem. Soc. 2010, 132, 13168. (c) Tan, C.; Liu, X.; Wang, L.; Wang, J.;
Feng, X. Org. Lett. 2008, 10, 5305. (d) Trost, B. M.; Silverman, S. M. J.
Am. Chem. Soc. 2010, 132, 8238. (e) Lauzon, C.; Charette, A. Org. Lett.
2006, 8, 2743. (f) Wang, H.; Jiang, T.; Xu, M.-H. J. Am. Chem. Soc. 2013,
135, 971. (g) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50,
11098. (h) Luo, Y.; Carnell, A. J.; Lam, H. W. Angew. Chem., Int. Ed.
2012, 51, 8309. (i) Yang, G.; Zhang, W. Angew. Chem., Int. Ed. 2013, 52,
7540.
2006, 128, 3928. (d) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem.
Soc. 2006, 128, 2174. (e) Sibi, M. P.; Stanley, L. M.; Soeta, T. Org. Lett.
2007, 9, 1553. (f) Tran, K.; Lombardi, P. J.; Leighton, J. L. Org. Lett.
2008, 10, 3165. (g) Oe, K.; Shinada, T.; Ohfune, Y. Tetrahedron Lett.
2008, 49, 7426. (h) Ichikawa, Y.; Okumura, K.; Matsuda, Y.; Hasegawa,
T.; Nakamura, M.; Fujimoto, A.; Masuda, T.; Nakano, K.; Kotsuki, H.
Org. Biomol. Chem. 2012, 10, 614. (i) Yoshimura, T.; Kinoshita, T.;
Yoshioka, H.; Kawabata, T. Org. Lett. 2013, 15, 864.
(8) Clayden, J.; Donnard, M.; Lefranc, J.; Tetlow, D. J. Chem. Commun.
2011, 47, 4624.
(9) (a) Wu, Y.; Hu, L.; Li, Z.; Deng, L. Nature 2015, 523, 445. (b) Yang,
X.; Toste, F. D. J. Am. Chem. Soc. 2015, 137, 3205.
(10) (a) Arnold, J. S.; Nguyen, H. M. J. Am. Chem. Soc. 2012, 134, 8380.
(b) Cai, A.; Guo, W.; Martínez-Rodríguez, L.; Kleij, A. W. J. Am. Chem.
Soc. 2016, 138, 14194. (c) Guo, W.; Cai, A.; Xie, J.; Kleij, A. W. Angew.
Chem., Int. Ed. 2017, 56, 11797.
(11) For general reviews on desymmetrization, see: (a) Schneider.
Synthesis 2006, 2006, 3919. (b) Pineschi, M. Eur. J. Org. Chem. 2006,
2006, 4979. (c) Díaz-de-Villegas, M. D.; Gal
́
vaz, J. A.; Etayo, P.;
Badorrey, R.; Lopez-Ram-de-Víu, M. P. Chem. Soc. Rev. 2011, 40, 5564.
́
(12) Zhou, F.; Guo, J.; Liu, J.; Ding, K.; Yu, S.; Cai, Q. J. Am. Chem. Soc.
2012, 134, 14326.
(13) Honjo, T.; Nakao, M.; Sano, S.; Shiro, M.; Yamaguchi, K.; Sei, Y.;
Nagao, Y. Org. Lett. 2007, 9, 509.
(14) (a) Hong, M. S.; Kim, T. W.; Jung, B.; Kang, S. H. Chem. - Eur. J.
2008, 14, 3290. (b) You, Y. S.; Kim, T. W.; Kang, S. H. Chem. Commun.
2013, 49, 9669. (c) Lee, W.; Youn, J.-H.; Kang, S. H. Chem. Commun.
2013, 49, 5231.
(15) Meng, S.-S.; Liang, Y.; Cao, K.-S.; Zou, L.; Lin, X.-B.; Yang, H.;
Houk, K. N.; Zheng, W.-H. J. Am. Chem. Soc. 2014, 136, 12249.
(16) Selected reviews on chiral phosphoric acid catalysis: (a) Akiyama,
T. Chem. Rev. 2007, 107, 5744. (b) Terada, M. Chem. Commun. 2008,
4097. (c) Kampen, D.; Reisinger, C. M.; List, B. Top. Curr. Chem. 2009,
291, 395. (d) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev.
2011, 40, 4539. (e) Yu, J.; Shi, F.; Gong, L. Acc. Chem. Res. 2011, 44,
1156.
(17) For selected recent examples on CPA catalytic desymmetrization
or kinetic resolution of alcohols, see: (a) Sun, Z.; Winschel, G. A.;
Borovika, A.; Nagorny, P. J. Am. Chem. Soc. 2012, 134, 8074. (b) Mori,
K.; Ichikawa, Y.; Kobayashi, M.; Shibata, Y.; Yamanaka, M.; Akiyama, T.
J. Am. Chem. Soc. 2013, 135, 3964. (c) Mensah, E.; Camasso, N.; Kaplan,
W.; Nagorny, P. Angew. Chem., Int. Ed. 2013, 52, 12932. (d) Gualtierotti,
J.-B.; Pasche, D.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2014, 53, 9926.
(e) Yamanaka, T.; Kondoh, A.; Terada, M. J. Am. Chem. Soc. 2015, 137,
̌
́
1048. (f) Kim, J. H.; Coric, I.; Palumbo, C.; List, B. J. Am. Chem. Soc.
2015, 137, 1778.
(18) The Nitro Group in Organic Synthesis; Ono, N., Ed.; Wiley-VCH:
New York, 2001.
(19) For enzyme catalytic desymmetrization of 2-substituted-2-nitro-
1,3-diols, see: Tian, P.; Xu, M.-H.; Wang, Z.-Q.; Li, Z.-Y.; Lin, G.-Q.
Synlett 2006, 2006, 1201.
(20) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564.
(21) (a) Reddy, L. R.; Saravanan, R. P.; Corey, E. J. J. Am. Chem. Soc.
2004, 126, 6230. (b) Endo, A.; Danishefsky, S. J. J. Am. Chem. Soc. 2005,
127, 8298. (c) Satoh, N.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2011,
13, 3028.
(22) (a) Namba, K.; Shinada, T.; Teramoto, T.; Ohfune, Y. J. Am.
Chem. Soc. 2000, 122, 10708. (b) Wehn, P. M.; Du Bois, J. J. Am. Chem.
Soc. 2002, 124, 12950. (c) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc.
D
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