An Efficient Entry to syn- and anti-Selective Isoindolinones via an Organocatalytic Direct Mannich/Lactamization Sequence

Article abstract of DOI:10.1021/acs.orglett.5b00676

(Chemical Equation Presented) An organocatalytic direct Mannich-lactamization sequence for the syntheses of pharmacologically important enantioenriched isoindolinones is reported. The method utilizes simple α-amino acids to deliver syn- and anti- selectiv

Full text of DOI:10.1021/acs.orglett.5b00676

Letter
pubs.acs.org/OrgLett
An Efficient Entry to syn- and anti-Selective Isoindolinones via an
Organocatalytic Direct Mannich/Lactamization Sequence
Vishnumaya Bisai,†,‡ Rajshekhar A. Unhale,†,‡ Arun Suneja,† Sivasankaran Dhanasekaran,§
and Vinod K. Singh*,†,§
†Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal, MP - 462 066, India
§Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UP - 208 016, India
S
* Supporting Information
ABSTRACT: An organocatalytic direct Mannich−lactamization sequence for the syntheses of pharmacologically important
enantioenriched isoindolinones is reported. The method utilizes simple α-amino acids to deliver syn- and anti- selective
isoindolinones with remarkably high enantioselectivity (up to >99% ee) in good to excellent yields and diastereomeric ratios. The
overall sequence involves one C−C and two C−N bond forming events in one pot starting from inexpensive starting material.
ynthetically versatile enantioenriched isoindolinones (see
1a−f; Figure 1) are prevalently found in many naturally
CuI-iPr-pybox-diPh catalyzed alkynylation−lactamization casca-
de.10a
S
Although there is a report on the thio-urea catalyzed
enantioselective synthesis of isoindolinones, the enantioselec-
tivities achieved are only up to 86%.10b Hence, there is a
requirement of a deeper synthetic insight for the development
of efficient organocatalytic enantioselective approaches. Our
continued interest in this area prompted us to devise a suitable
direct organocatalytic11 enantioselective strategy. To this end,
pioneering reports by List12a and Barbas12b on organocatalytic
direct Mannich reactions drew our attention. The asymmetric
Mannich reactions13 are particularly appealing from a synthetic
perspective owing to the prevalence of nitrogen in drugs and
natural products. Herein, we report an expeditious route to
both syn- and anti-selective isoindolinones following a direct
organocatalytic enantioselective one-pot three-component
Mannich−lactamization sequence (Scheme 1).
Figure 1. Selected enantioenriched isoindolinones.
Organocatalytic Mannich reactions have widely been
reported on preformed imines,14 and only a handful of catalytic
asymmetric direct Mannich reactions are reported to date.12 In
general, direct aldol and Mannich reactions typically compete if
imines and enol equivalents are not preformed, and their rates
depend on the equilibrium ratio between the aldehyde and the
imine and on their respective rate constants. In this regard,
especially, Mannich reactions which involve hydroxyacetone as
the donor furnishing syn- and anti-1,2-amino alcohols in high
chemo-, regio-, diastereo-, and enantioselectivities play an
important role in organic synthesis. Thus, we selected
hydroxyacetone as donor for the installation of syn- and anti-
occurring alkaloids and pharmaceuticals1 with impressive
biological activities.2 Therefore, synthesis of such structural
motifs in enantioenriched form has gained considerable interest
in contemporary research. Prominent asymmetric approaches
to this class of heterocyclics include resolution of racemates,3
intramolecular Heck cyclization,4 Diels−Alder approach,5 ring-
closure of chiral hydrazones,6 reactions of chiral acyliminium
ion,7a,b allylation to chiral imines,7c and a chiral appendage
mediated carbanion method.8 Most of these syntheses involve a
chiral auxiliary mediated diastereoselective approach and face a
limited substrate scope. Only a few enantioselective syntheses
of isoindolinones are known in literature using metal
catalysts.9a−c Toward this, we recently reported the concise
enantioselective synthesis of isoindolinones (>99% ee) via a
Received: March 7, 2015
Published: April 13, 2015
© 2015 American Chemical Society
2102
DOI: 10.1021/acs.orglett.5b00676
Org. Lett. 2015, 17, 2102−2105

Organic Letters
Letter
Scheme 1. Proposed Organocatalytic Route and Transition
State Model12b
Table 1. Optimization of syn-Selective Mannich
Lactamization
a
selective isoindolinones in the presence of a suitable organo-
catalyst through a Mannich−lactamization sequence (Scheme
1). We envisioned that one can achieve syn-selective
isoindolinones from a 2° amine catalyzed (such as L-proline
or its derivatives) Mannich−lactamization sequence via a more
stable enamine intermediate 6b over 6a in analogy to List et
al.12a (Scheme 1). The ester functionality at the o-position of
aldimine may further stabilize the transition state (TS-I) via
additional H-bonding with hydroxyacetone.15 Whereas, the
anti-selective isoindolinones could be accessed from a more
stable enamine 7a over 7b when the reaction is catalyzed by a
1° amine as the catalyst in analogy to Barbas et al.12b (Scheme
1).
a
Reactions were performed in 0.3 mmol of 3a and PMPNH2 in the
b
presence of 3 equiv of hydroxyacetone. Yields are reported after
purification. dr were determined from H NMR of crude reaction
mixture. ee’s were determined by HPLC analysis. 20 equiv of
hydroxyacetone and 1.0 equiv of TFA was used.
c
1
d
e
Initially, we conducted the direct organocatalytic one-pot
three-component Mannich−lactamization sequence as per our
hypothesis using 2° amino acid organocatalysts viz. L-proline
8a12 and its derivatives such as L-prolinamides 8b−c10
developed by us (Table 1, see Supporting Information for
detailed optimization). p-Methoxyphenyl amine (PMPNH2)
was exclusively used as an amine partner, as it can readily be
removed under oxidative conditions.16,10a Optimization studies
revealed that 30 mol % of L-proline (8a) in DMF at 0−25 °C
was superior to catalysts 8b−c, to afford the required
isoindolinone 4a in 98% ee with 5.3:1 dr (entry 4, Table 1)
albeit in lower yields. Similarly, D-proline (ent-8a) also afforded
product ent-4a in 97% ee with 5.1:1 dr (entry 7). However, 10−
20 mol % of 8a afforded 4a in the range of 83−87% ee in 45−
47% yields (entries 5−6). The lower yields of the expected
product is presumably due to inefficient lactamization.
Gratifyingly, we observed a sharp enhancement in yield of 4a
to 92% (99% ee), when an equivalent of TFA was added after
completion of the Mannich step (monitored by TLC), thereby
ensuring the complete lactamization (entry 8, Table 1).
Next, we studied a variety of aromatic amines in the
Mannich−lactamization sequence under optimized conditions
(entry 8, Table 1). We found that aromatic amines having a
different electronic environment furnished expected isoindoli-
nones 4b−g in 91−97% ee with high yields (Figure 2).
However, aliphatic amines such as allyl, benzyl, and 2-
phenethylamine afforded products either with poor enantiose-
lectivities or as racemic mixture, thereby indicating the
requirement of a less basic and less reactive amine as a
coupling partner to afford products with higher enantioselec-
Figure 2. Effect of amines in the Mannich−lactamization sequence.
tivities. In fact, aliphatic amines itself are known to be good
catalysts for the organocatalytic Mannich reaction via an
enamine intermediate,12b which accounts for the racemization
of 4h−j (Figure 2). As p-methoxyaniline afforded PMP
protected isoindolinone 4a in 99% ee that can be cleaved
under oxidative conditions, we decided to carry out the
substrate scope of our strategy using PMPNH2 as the amine
source.
Differently substituted o-formyl methylbenzoates 3 with a
variety of steric and electronic environments were tested in the
presence of the PMP amine and hydroxyacetone (Figure 3). To
our delight, our methodology afforded the syn-selective
isoindolinones in excellent enantioselectivities (up to >99%
ee), thereby increasing the flexibility of the reaction for a wider
range of synthetically useful substrates. However, o-formyl
methylbenzoates having o-substitution to the aldehyde group
afforded isoindolinones with a diminished level of enantiose-
lectivity (see 4p and 4r), probably indicating that sterics play a
2103
DOI: 10.1021/acs.orglett.5b00676
Org. Lett. 2015, 17, 2102−2105

Organic Letters
Letter
Figure 4. Substrate scope of anti-selective Mannich−lactamization.
10.2:1 dr. Similar to the L-proline catalyzed reaction (Figure 3),
in this case as well, acetone afforded product 4t in only 7% ee
with a 62% yield.
To illustrate the synthetic utility of our organocatalytic
protocol, the enantioenriched product 4a was reduced using
NaBH4 to furnish 10, which was then followed by periodate
cleavage and further reduction to afford 2a in 96% ee (Scheme
2). Alternatively, oxidative cleavage can be performed using
Figure 3. Substrate scope of syn-selective Mannich−lactamization.
crucial role in organizing the transition states of the Mannich−
lactamization sequence. This might be due to the disruption of
the L-proline-aldimine H-bond (see TS-I in Scheme 1). It was
observed that acetone as the donor afforded isoindolinone 4t
with 22% ee, whereas cyclohexanone afforded product 4u as a
racemic mixture, thus clearly indicating the impact of
hydroxyacetone on the enantioselectivity due to its H-bonding
ability (see Figure 3). The poor enantioselectivity (42% ee) of
4v yielded by benzyl protected hydroxyacetone as the donor is
also consistent with this observation. The single crystal X-ray
analysis of compound 4n (CCDC 1040386) further supported
the syn-selectivity of the product (Figure 3). Interestingly, a
gram scale synthesis of compound 4a was equivalently good to
afford the product (48 h) in 89% isolated yield and 99% ee with
dr 12:1 (see Supporting Information for details).
Scheme 2. Synthesis of 2a and 3-n-Propyl Isoindolinone 1f
We then switched to carry out the anti-selective organo-
catalytic one-pot three-component Mannich−lactamization
sequence using a primary amine as the catalyst (see Scheme
1). In this direction, we started the optimization using o-formyl
methylbenzoate 3a, PMPNH2, and hydroxyacetone in DMF at
0−25 °C in the presence of 30 mol % of various primary α-
amino acids. After exhaustive optimization (see Supporting
Information for details), it was found that among all 1° amino
acid catalysts used, L-tryptophan 9a afforded anti-selective 5a in
up to 78% ee with 4.0:1 dr. Therefore, we selected L-tryptophan
for further optimization and eventually found the anti-selective
isoindolinone product in a maximum of 89% ee with 5.5:1 dr
using DMF as the solvent at 0−25 °C in the presence of 1
equiv of TFA (Figure 4). A range of anti-selective
isoindolinones 5a−i were obtained in up to 89% ee with
Pb(OAc)4 to afford 2a in 91% ee (Scheme 2). In fact,
enantiopure 2a could serve as an advanced intermediate in the
synthesis of 1a−f (Figure 1). In another sequence, a
diastereomeric mixture of diol 10 was treated with thiocarbonyl
diimidazole in the presence of catalytic DMAP to afford 11
(Scheme 2). The latter on Corey−Winter olefination17
followed by hydrogenation led to n-propylisoindolinone 12 in
90% ee. Finally, oxidative removal of the PMP group18 of 12 in
the presence of ceric (IV) ammonium nitrate (CAN) furnished
pharmacologically important enantioenriched 3-n-propylisoin-
dolinone 1f1,7c in 75% yield (Scheme 2).
Overall, this is the first report on an organocatalytic (via
enamine catalysis) enantioselective one-pot three component
Mannich−lactamization sequence for the synthesis of optically
2104
DOI: 10.1021/acs.orglett.5b00676
Org. Lett. 2015, 17, 2102−2105

Organic Letters
Letter
(5) McAlonan, H.; Murphy, J. P.; Nieuwenhuyzen, M.; Reynolds, K.;
Sarma, P. K. S.; Stevenson, P. J.; Thompson, N. J. Chem. Soc., Perkin
Trans 1 2002, 69 and references therein.
(6) (a) Enders, D.; Braig, V.; Raabe, G. Can. J. Chem. 2001, 79, 1528.
(b) Adachi, S.; Onozuka, M.; Yoshida, Y.; Ide, M.; Saikawa, Y.; Nakata,
M. Org. Lett. 2014, 16, 358.
(7) (a) Bahajaj, A. A.; Vernon, J. M.; Wilson, G. D. Tetrahedron 2004,
60, 1247. (b) Chen, M.-D.; Zhou, X.; He, M.-Z.; Ruan, Y.-P.; Huang,
P.-Q. Tetrahedron 2004, 60, 1651. (c) Sun, X.-W.; Liu, M.; Xu, M.-H.;
Lin, G.-Q. Org. Lett. 2008, 10, 1259.
pure isoindolinones. Important features of our strategy include
the following: (1) the reactions do not require preformed imine
equivalents; (2) the method is operationally simple and
inexpensive; (3) it provides opportunity to access both
enantiomers of syn-selective isoindolinones (up to 99% ee; dr
= 17.5:1) using proline as the catalyst, whereas, anti-selective
isoindolinones (up to 89% ee; dr = 10.2:1) can be accessed
using L-tryptophan as the catalyst; (4) excellent enantioselec-
tivity (99% ee) is observed even in the gram scale synthesis of
4a. Future studies will aim to shed light on the development of
other important one-pot sequences/cascades to build complex
frameworks.
́
(8) (a) Viret, J.-P.; Prange, T.; Tomas, A.; Royer, J. Tetrahedron
2002, 58, 5103. (b) Comins, D. L.; Schilling, S.; Zhang, Y. Org. Lett.
2005, 7, 95.
(9) (a) Rh-Catalyzed arylation: Wang, Z.-Q.; Feng, C.-G.; Xu, M.-
H.; Lin, G. Q. J. Am. Chem. Soc. 2007, 129, 5336. (b) Cu(I)-catalyzed
tandem Michael−Mannich reaction: Guo, S.; Xie, Y.; Hu, X.; Xia, C.;
Huang, H. Angew. Chem., Int. Ed. 2010, 49, 2728. (c) Yang, G.; Shen,
C.; Zahng, W. Angew. Chem., Int. Ed. 2012, 51, 9141.
(10) (a) Enantioselective alkynylation-lactamization cascade: Bisai,
V.; Suneja, A.; Singh, V. K. Angew. Chem., Int. Ed. 2014, 53, 10737. (b)
Thio-urea catalyzed enantioselective approach: Tiso, S.; Palombi, L.;
Vignes, C.; Mola, A. D.; Massa, A. RSC Adv. 2013, 3, 19380.
(11) For L-prolinamides 8b−c in organocatalysis, see: (a) Raj, M.;
Vishnumaya; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097.
(b) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593. (c) Raj,
M.; Vishnumaya; Singh, V. K. J. Org. Chem. 2009, 74, 4289. (d) Rulli,
ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental procedures and analytical data for all new
compounds and CIF file of compound 4n. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: vinodks@iitk.ac.in.
G.; Duangdee, N.; Baer, K.; Hummel, W.; Berkessel, A.; Groger, H.
̈
Author Contributions
Angew. Chem., Int. Ed. 2011, 50, 7944. (e) Duangdee, N.; Harnying,
‡V.B. and R.A.U. contributed equally.
Notes
W.; Rulli, G.; Neudolfl, J.-M.; Groger, H.; Berkessel, A. J. Am. Chem.
̈
̈
Soc. 2012, 134, 11196. For excellent reviews, see: (f) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (g) Notz, W.;
Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. (h) List, B.
Acc. Chem. Res. 2004, 37, 548.
The authors declare no competing financial interest.
(12) (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem.
Soc. 2002, 124, 827. (b) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2007, 129, 288.
(13) Reviews on Mannich reaction: (a) Kleinnmann, E. F. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
New York, 1991; Vol. 2, Chapter 4.1. (b) Arend, M.; Westermann, B.;
Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (c) Cardova, A. Acc.
Chem. Res. 2004, 37, 102.
(14) Organocatalytic Mannich reactions on preformed imines; see:
(a) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem.
Soc. 2005, 127, 16408. (b) Franzen, J.; Marigo, M.; Fielenbach, D.;
Wabnitz, T. C.; Kjaersgaard, A.; Jorgensen, K. A. J. Am. Chem. Soc.
2005, 127, 18296. (c) Mitsumori, S.; Zhang, H.; Cheong, P. H-Y.;
Houk, K. N.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128,
1040. (d) Zhang, H.; Mifsud, M.; Tanaka, F.; Barbas, C. F., III. J. Am.
Chem. Soc. 2006, 128, 9630. (e) Zhang, Y.; Liu, Y.-K.; Kang, T.-R.; Hu,
Z.-K.; Chen, Y.- C. J. Am. Chem. Soc. 2008, 130, 2456. (f) Kano, T.;
Sakamoto, R.; Akakura, M.; Maruoka, K. J. Am. Chem. Soc. 2012, 134,
7516. (g) Parera, S.; Sinha, D.; Rana, N. K.; Trieu-Do, V.; Zhao, J. C.-
G. J. Org. Chem. 2013, 78, 10947.
(15) We sincerely thank one of the reviewers for suggesting a precise
explanation of the proposed transition state TS-I.
(16) Fu, P.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008,
130, 5530.
(17) (a) Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963, 85,
2677. (b) Yue, G.; Yang, L.; Yuan, C.; Jiang, X.; Liu, B. Org. Lett. 2011,
13, 5406.
(18) Under similar conditions, 4a provided N,O-ketal 13 in 65%
yield.
ACKNOWLEDGMENTS
■
Financial support through the J. C. Bose fellowship (DST,
Government of India) and SERB, DST (SB/FT/CS-011/2014)
are gratefully acknowledged. R.A.U. and A.S. thank the CSIR,
New Delhi for SPM and SRF fellowships, respectively. We
gratefully acknowledge Mr. Pradip K. Mondal and Dr. Deepak
Chopra, IISER Bhopal for assistance with X-ray crystallography.
V.B. and S.D. thank the Department of Chemistry, IISER
Bhopal and IIT Kanpur, respectively, for the infrastructure.
REFERENCES
■
(1) (a) Dhanasekaran, S.; Bisai, V.; Unhale, R. A.; Suneja, A.; Singh,
V. K. Org. Lett. 2014, 16, 6068. (b) Chem, M.-W.; Chen, Q.-A.; Duan,
Y.; Ye, Z.-S.; Zhou, Y.-G. Chem. Commun. 2012, 48, 1698.
(c) Agouridas, V.; Capet, F.; Couture, A.; Deniau, E.; Grandclaudon,
P. Tetrahedron: Asymmetry 2011, 22, 1441. (d) Fuchs, J. R.; Funk, R. L.
Org. Lett. 2001, 3, 3923. (e) Linder, M.; Hadler, D.; Hofmann, S.
Human Psychopharmacol. 1997, 12, 445. (f) Wood, J. L.; Stoltz, B. M.;
Goodman, P. N. J. Am. Chem. Soc. 1996, 118, 10656 and references
therein.
(2) (a) Augner, D.; Gerbino, D. C.; Slavov, N.; Neudorfl, J.-M.;
̈
Schmalz, H.-G. Org. Lett. 2011, 13, 5374. (b) Li, L.; Wang, M.; Zhang,
X.; Jiang, Y.; Ma, D. Org. Lett. 2009, 11, 1309. (c) Riedinger, C.;
Endicott, J. A.; Kemp, S. J.; Smyth, L. A.; Watson, A.; Valeur, E.;
Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Noble, M. E.;
McDonnell, J. M. J. Am. Chem. Soc. 2008, 130, 16038. (d) Boger, D. L.;
Lee, J. K.; Goldberg, J.; Jin, Q. J. Org. Chem. 2000, 65, 1467 and
references therein.
(3) Belliotti, T. R.; Brink, W. A.; Kesten, S. R.; Rubin, J. R.; Wustrow,
D. J.; Zoski, K. T.; Whetzel, S. Z.; Corbin, A. E.; Pugsley, T. A.;
Heffner, T. G.; Wise, L. D. Bioorg. Med. Chem. Lett. 1998, 8, 1499.
(4) Grigg, R.; Dorrity, M. J. R.; Malone, J. F.; Mongkolaus-
Savaratana, T.; Norbert, W. D. J. A.; Sridharan, V. Tetrahedron Lett.
1990, 31, 3075.
2105
DOI: 10.1021/acs.orglett.5b00676
Org. Lett. 2015, 17, 2102−2105