Dynamic Kinetic Resolution Approach for the Asymmetric Synthesis of Tetrahydrobenzodiazepines Using Transfer Hydrogenation by Chiral Phosphoric Acid

Article abstract of DOI:10.1002/chem.201601611

Asymmetric synthesis of tetrahydrobenzodiazepines was achieved by transfer hydrogenation of dihydrobenzodiazepines with benzothiazoline having a hydrogen-bonding donor substituent by means of a newly synthesized chiral phosphoric acid. This method was applicable to various racemic dihydrobenzodiazepines to give the corresponding products in good yields with excellent diastereoselectivities and enantioselectivities taking advantage of the dynamic kinetic resolution. Furthermore, the effect of bulky substituent at 3,3′-position on the catalyst and hydrogen-bonding donor substituent on benzothiazoline was fully elucidated by the theoretical study.

Full text of DOI:10.1002/chem.201601611

DOI: 10.1002/chem.201601611
Communication
&
Asymmetric Synthesis |Hot Paper|
Dynamic Kinetic Resolution Approach for the Asymmetric
Synthesis of Tetrahydrobenzodiazepines Using Transfer
Hydrogenation by Chiral Phosphoric Acid
Kosaku Horiguchi,[a] Eri Yamamoto,[b] Kodai Saito,[a, c] Masahiro Yamanaka,[b] and
Takahiko Akiyama*[a]
Nitrogen-containing cyclic chiral molecules with multiple
stereogenic centers have attracted much attention in recent
years. Benzodiazepine derivatives, in particular, possess unique
seven-membered cyclic chiral centers, and the biological activi-
ties of these compounds have shown several promising func-
tions.[6] Although the asymmetric synthesis of 1,5-benzodiaze-
pines[7] has been investigated by organocatalyzed transfer hy-
drogenation[7a] and transition-metal-catalyzed hydrogena-
tion,[7b] highly stereoselective synthesis of these structures is
extremely important, and the mechanism, in particular the the-
oretical study, has not yet been fully investigated.
Abstract: Asymmetric synthesis of tetrahydrobenzodiaze-
pines was achieved by transfer hydrogenation of dihydro-
benzodiazepines with benzothiazoline having a hydrogen-
bonding donor substituent by means of a newly synthe-
sized chiral phosphoric acid. This method was applicable
to various racemic dihydrobenzodiazepines to give the
corresponding products in good yields with excellent dia-
stereoselectivities and enantioselectivities taking advant-
age of the dynamic kinetic resolution. Furthermore, the
effect of bulky substituent at 3,3’-position on the catalyst
and hydrogen-bonding donor substituent on benzothiazo-
line was fully elucidated by the theoretical study.
The organocatalyzed enantioselective transfer hydrogena-
tion (ATH) of carbon–nitrogen double bonds has been recog-
nized as one of the most reliable approaches to give chiral
amines.[8] We have recently developed chiral phosphoric-acid-
catalyzed ATH of a range of ketimine derivatives using benzo-
thiazoline as a hydrogen donor.[9,10] Tuning the 2-substituent of
benzothiazoline improved both reactivity and enantioselectivi-
ty. Based on these properties, we envisioned that the choice of
the 2-substituent of benzothiazoline might serve as a new
strategy to control the enantioselectivity of ATH of other com-
plex molecules, thus extending the application of this combi-
nation of chiral phosphoric acid with benzothiazoline. Herein,
we report the highly stereoselective ATH of dihydrobenzodia-
zepines involving the DKR process, in which a newly synthe-
sized chiral phosphoric acid was employed in conjunction with
benzothiazoline bearing a hydrogen-bonding donor substitu-
ent. The necessity of the precise hydrogen-bonding interaction
in the transition state of this ATH was elucidated by theoretical
studies.
At the outset, we studied ATH of 1a with (R)-TRIP[11] 2a in
the presence of 3a as a model reaction (Table 1, entry 1, see
the Supporting Information for details). The reaction proceed-
ed slowly to give (S,S)-5a[12] in 8% yield with a 2.4:1 diastereo-
meric ratio and 88% ee. Surprisingly, use of benzothiazoline
3b bearing a 3-hydroxyphenyl moiety dramatically improved
both yield and diastereomeric ratio to 90% and 7.6:1, respec-
tively, with an increase of ee to 96% (entry 2). This result
showed that DKR is operative in the ATH, including racemiza-
tion of the original stereogenic center at the 2-position of the
substrate.[13,14] The use of Hantzsch ester 4 in place of benzo-
thiazoline exhibited an efficient and enantioselective hydroge-
nation, but with low diastereoselectivity (entry 3). Remarkable
improvement of diastereoselectivity was observed when (R)-2b
bearing a more bulky 3,3’-substituent was employed (trans/cis
Enantiomerically pure compounds are key components of
pharmaceuticals and agrochemicals. Thus, the development of
new methods for the asymmetric synthesis of chiral skeletons
has captured the attention of synthetic organic chemists. Al-
though kinetic resolution is one of the representative methods
for the preparation of chiral compounds,[1] this method gives
a maximum chemical yield of 50% for a particular enantiomer.
On the other hand, dynamic kinetic resolution (DKR) has
proven to be a more versatile strategy in terms of chemical
yield, theoretically allowing the stereodivergent transformation
of both enantiomers of a racemic substrate into a single enan-
tiomer of a target molecule up to 100%.[2] Although DKR of al-
cohols could be achieved by either chemical[3] or chemoenzy-
matic approaches,[4] catalytic non-enzymatic methodologies for
the DKR of amines are much less developed than those of al-
cohols. The development of DKR of amines is, thus, in high
demand.[5]
[a] K. Horiguchi, Dr. K. Saito, Prof. Dr. T. Akiyama
Department of Chemistry, Gakushuin University
1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588 (Japan)
E-mail: takahiko.akiyama@gakushuin.ac.jp
[b] E. Yamamoto, Prof. Dr. M. Yamanaka
Department of Chemistry, Rikkyo University
3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501 (Japan)
[c] Dr. K. Saito
Present address: Department of Chemistry, Keio University
Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601611.
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Table 1. Examination of reaction conditions.
Table 2. Substrate scope.
Entry
1
Ar1
Ar2
5
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
Ph
5a
5b
5c
5d
5e
5 f
5g
5h
5i
94
67
91
90
96
89
71
75
74
>99
>99
99
>99
99
4-FC6H4
4-ClC6H4
4-BrC6H4
p-Tol
4-FC6H4
4-ClC6H4
4-BrC6H4
p-tol
Entry
3 or 4
Yield [%][a]
d.r.[b]
2.4/1
7.6/1
1.1/1
>99/1
1.1/1
>99/1
ee [%][c]
m-tol
m-tol
99
1
2
3
4[d]
5[d]
6[d,e]
3a
3b
4
3b
4
8
90
quant.
76
quant.
94[f]
88
90
>99
>99
>99
>99
3-ClC6H4
3-BrC6H4
2-thienyl
4-CF3C6H4
Ph
3-ClC6H4
3-BrC6H4
2-thienyl
4-CF3C6H4 5j
4-CF3C6H4 5j
>99
>99
99
99
>99
>99
9
10
11
12
1j
1k
1l
quant.
quant.
quant.
3b
PMP
Ph
5l
[a] Yields were determined by NMR spectroscopy. [b] d.r. (trans/cis) values
were determined by NMR analysis of crude products. [c] Determined by
chiral HPLC analysis. [d] (R)-2b was used. [e] 3b (1.4 equiv) and 5 Š MS
(200 mg) were used. [f] Isolated yield.
>99:1, entry 4). Diastereoselectivity was not affected by the
combined use of (R)-2b with Hantzsch ester 4 (entry 5). The
use of a larger amount of 5 Š MS and 3b led to significant in-
crease in yield (94%, entry 6).
We explored the scope of the transfer hydrogenation of 2,4-
diaryl-dihydrobenzodiazepine derivatives 1 using 3b and (R)-
2b (Table 2). A range of C2-symmetric 2,4-diaryl-tetrahydroben-
zodiazepines were obtained in good yields with excellent
enantioselectivities (entries 1–9). Next, we explored the reac-
tions by using substrates bearing different aryl groups at the
2,4-positions, which had not been employed by the previous
asymmetric hydrogenation approaches.[7b] Substrates 1j–l con-
taining trifluoromethyl and methoxy groups at 2- or 4-posi-
tions were all tolerated to give 5j and l in high yields with ex-
cellent stereoselectivities. The introduction of a functional
group on the fused phenylene ring also led to excellent stereo-
selective transfer hydrogenation, giving 5m and n in good
yields with excellent stereoselectivities. N-Methylated 1o pro-
vided access to 5o. Use of 3b-D for this reaction resulted in
the formation of 5a-D in 80% yield with 99% ee.[15,16]
[a] Yields were determined by NMR spectroscopy. [b] d.r. (trans/cis) values
were determined by NMR analysis of crude products. [c] Determined by
chiral HPLC analysis. [d] (R)-2b was used. [e] 3b (1.4 equiv) and 5 Š MS
(200 mg) were used. [f] Isolated yield.
As an extension of this work, we investigated the ATH of
benzodiazepine 6a.[7b] When 6a was subjected to the same re-
action conditions using 2.4 equivalents of 3b, we isolated 5a
in 85% yield with slightly higher stereoselectivities (trans/cis
>99:1, >99% ee). Interestingly, when this reaction was per-
formed for a shorter reaction time, 1a was recovered in low
yield in racemic form. This result confirmed that the faster
second hydrogenation step is the stereochemically determin-
ing step. The scope of the reaction is summarized in Scheme 1.
Unfortunately, alkyl-substituted substrate 6q gave no conver-
sion.
Scheme 1. Reaction of benzodiazepines (isolated yields are given; d.r. was
determined by NMR analysis of the crude product; ee was determined by
chiral HPLC analysis).
To elucidate mechanism of the racemization process in the
present DKR, we tried to trap the reaction intermediate. Treat-
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ment of rac-1a with decanethiol (10 equiv) in the presence of
phosphoric acid (R)-2a, and subsequent treatment with NaBH4
gave aminothiol 7 in 25% yield. Sulfide 7 was considered to
be formed by thia-Michael reaction of decanethiol to 8, which
was obtained by retro-aza-Michael reaction of 1a followed by
reduction with NaBH4 (Scheme 2).[17] This result suggests that
1a was racemized by the sequential retro-Michael/Michael ad-
dition reaction.
Scheme 4. Racemization pathway of dihydrobenzodiazepine derivatives.
Scheme 2. Reaction of dihydrobenzodiazepine with thiol.
Gong and co-workers had reported phosphoric-acid-cata-
lyzed asymmetric synthesis of dihydrobenzodiazepines
through DKR process,[7a] and proposed that the starting materi-
al racemized by the sequential retro-Mannich/Mannich reac-
tions.[18] Upon treatment of rac-1a with p-nitrobenzaldehyde in
the presence of (R)-2a, rac-1a was recovered in 70% yield
without formation of scrambling product (Scheme 3). These re-
sults clearly show that the racemization of benzodiazepine de-
rivatives proceeded by retro-Michael/Michael reactions (R=H)
different from the mechanism of Gong (retro-Mannich/Mannich
reactions; R=Me; Scheme 4).
Figure 1. (a) Coordination modes between (R)-2a and 1a and (b) diastereo-
meric TS structures of TS1as and the relative energies [kcalmolÀ1] of both
TS1as and TS1bs.
cial selection of 1a [leading to (S,S) and (R,R) enantiomers of 5,
TS1a and TS1b], and three coordination modes between (R)-
2a and 1a (TS1_A, TS1_B, and TS1_N, Figure 1a) were com-
pared (see the Supporting Information). After exploring those
diastereomeric TSs, four types of TSs were found to be ener-
getically more favored for each enantiomer of 5 (Figure 1b). In
both TS1_A and TS1_B, 3b interacts with the phosphoric acid
moiety of (R)-2a through the two-point hydrogen bonds at
the NH and m-OH groups (TS1_A: naphtholic oxygen; TS1_B:
phosphoryl oxygen). Depending on the coordination modes A
and B, 3b is oriented perpendicular and parallel to the phos-
phate moiety (e.g., O-P-O plane) in TS1_A and TS1_B, respec-
tively. For TS1_A, therefore, (S)-3b is only fitted into the chiral
space constructed by the 3,3’-substituents of (R)-2a.[22] In con-
trast, two types of diastereomeric TS1_B (TS1_B and TS1_B’)
having different relative orientations of 1a and 3b exist there
due to the lack of coordination of 1a on the phosphoric acid
moiety. It was noted that both TS1as_A and TS1as_N leading
to the major (S,S)-5a are relatively more stable than the other
diastereomeric TSs. On the other hand, both TS1bs_A and
TS1bs_B leading to the minor (R,R)-5a are located in a similar
Scheme 3. Reaction of dihydrobenzodiazepine with aromatic aldehyde.
Focusing on the second hydrogenation step, DFT calcula-
tions[19] of (R)-2a-catalyzed ATH of 1a by using 3b were carried
out to elucidate the major factors for controlling the stereo-
chemistry. Based on the previously reported theoretical study
of the phosphoric acid catalysis,[20,21] a dicoordinated model of
the transition state (TS) was predicted. As a preliminary study,
various transition structures corresponding to two absolute
configurations of 3b (R and S, TS1r and TS1s), the enantiofa-
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energy level, albeit 2.7 and 3.0 kcalmolÀ1 less stable, respec-
tively, than the most stable TS1as_A. These computational re-
sults are qualitatively consistent with the experimentally ob-
served high enantioselectivity of (S,S)-5a.[23]
Structural analysis of TS1as_A, TS1as_N, TS1bs_A, and
TS1bs_B allowed us to obtain deep insights into the stereo-
control. TS1as_A and TS1as_N have no unfavorable steric in-
teractions when the preferred ring-flipped conformation of 1a
is located in the empty upper right-hand quadrant
(Figure 2).[24] Both TS1as_A and TS1as_N are stabilized by the
attractive interaction between (R)-2a and 3b through the OH/
O and OH/p hydrogen bonds, respectively. The m-OH group of
3b plays a key role in fixing the orientation in the chiral space
and stabilizing the TS through the multipoint hydrogen bond.
On the other hand, the phenylene moiety of 1a has serious
steric repulsion with the 3,3’-substituent of (R)-2a to destabi-
lize TS1bs_A. In spite of the loss of steric repulsion between
1a and (R)-2a, TS1bs_B is also destabilized by the absence of
the NH/phosphoryl oxygen hydrogen bond. The 3,3’-substitu-
ent effect of (R)-2b achieving higher diastereoselectivity than
(R)-2a was also addressed. Although a beneficial effect of
bulky para-substituent at the 3,3’-substituent on stereoselectiv-
ity in chiral phosphoric acid catalysis had been documented,
such remote stereocontrol of the 3,3’-substituent had not
been elucidated.[25] The energy difference between the ener-
getically favored and competitive diastereomeric TSs (TS1as_A
and TS1gs_A) is significantly larger for (R)-2b (3.1 kcalmolÀ1
)
than (R)-2a (0.4 kcalmolÀ1), which is in good agreement with
the experimental results. The deeper chiral space constructed
by the 3,3’-biaryl substituents in (R)-2b enables the control of
stereoselectivity at the remote site (highlighted in green,
Figure 3). The terminal aryl substituent of (R)-2b induces steric
repulsion with the Ph group of 1a to significantly destabilize
TS1gs_A. These computational studies fully explained the
origin of the high enantioselectivity, as well as the remote con-
trol of high diastereoselectivity in the (R)-2a and (R)-2b cata-
lyzed ATH of 1a using 3b.
Figure 3. Partial 3D structures of TS2as_A and TS2gs_A. The relative ener-
gies [kcalmolÀ1] are shown in parentheses.
In conclusion, we have developed highly efficient method
for the construction of 1,5-tetrahydrobenzodiazepines based
on organocatalyzed transfer hydrogenation of dihydrobenzo-
diazepines involving the DKR process. The salient features are
1) DKR of cyclic amines was promoted by chiral phosphoric
acid; 2) 2-substituent of benzothiazoline specifically enhanced
the efficiency of this DKR; 3) high remote stereocontrol was
achieved by newly synthesized chiral phosphoric acid catalyst;
and 4) the unique effect of the substituent of benzothiazoline
and chiral phosphoric acid was rationalized by the DFT study
to be hydrogen-bonding network, formed between the cata-
lyst and hydrogen donor. Further investigation of the mecha-
nism and applications to the synthesis of more complex mole-
cules are underway in our laboratory.
Figure 2. Schematic representations and 3D structures of TS1as_A, TS1as_
N, TS1bs_A, and TS1bs_B. The relative energies [kcalmolÀ1] are shown in
parentheses.
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Sztubab, A. Opolskic, J. Wietrzykc, M. W. Kowalskad, T. Glowiakd, Arch.
Pharm. Med. Chem. 2001, 334, 3–10; d) D. J. Lauffer, M. D. Mullican,
Bioorg. Med. Chem. Lett. 2002, 12, 1225–1227; e) K. Vandyck, M. D. Cum-
mings, O. Nyanguile, C. W. Boutton, S. Vendeville, D. McGowan, B. Devo-
gelaere, K. Amssoms, S. Last, K. Rombauts, A. Tahri, P. Lory, L. Hu, D. A.
Beauchamp, K. Simmen, P. Raboisson, J. Med. Chem. 2009, 52, 4099–
4102.
Experimental Section
A typical procedure for the reaction of rac-1a is described. A mag-
netic stirrer and powdered 5 Š MS (200 mg) were placed in
a round-bottom flask (10 mL) under nitrogen atmosphere. The 5 Š
MS were then dried with a heat gun under reduced pressure, and
the round-bottom flask was refilled with nitrogen. Compound rac-
1a (29.8 mg, 0.0999 mmol), phosphoric acid (R)-2b (5.37 mg,
5.00 mmol), and benzothiazoline 3 f (32.1 mg, 0.140 mmol) were
added to the round-bottom flask successively under nitrogen at-
mosphere at room temperature. Benzene (2 mL) was added to the
round-bottom flask. After being stirred for two days at room tem-
perature, the mixture was filtered over Celite pad (washed with
CH2Cl2), the filtrate was concentrated under reduced pressure, and
the residue was purified by preparative thin-layer chromatography
on silica gel (AcOEt/hexane 1:10) to give 28.2 mg (0.0939 mmol,
94%, >99% ee, trans/cis >99:1) of (S,S)-5a.
[7] a) Z.-Y. Han, H. Xiao, L.-Z. Gong, Bioorg. Med. Chem. Lett. 2009, 19,
3729–3732; b) Z.-Y. Ding, F. Chen, J. Qin, Y.-M. He, Q.-H. Fan, Angew.
Chem. Int. Ed. 2012, 51, 5706–5710; Angew. Chem. 2012, 124, 5804–
5808; Other asymmetric syntheses of 1,5-benzodiazepine derivatives,
see: c) M. Rueping, E. Merino, R. M. Koenigs, Adv. Synth. Catal. 2010,
352, 2629–2634; d) X. Fu, J. Feng, Z. Dong, L. Lin, X. Liu, X. Feng, Eur. J.
Org. Chem. 2011, 5233–5236; e) X. Chen, Y. Zheng, C. Shu, W. Yuan, B.
Liu, X. Zhang, J. Org. Chem. 2011, 76, 9109–9115; f) K. Gao, B. Wu, C.-B.
Yu, Q.-A. Chen, Z.-S. Ye, Y.-G. Zhou, Org. Lett. 2012, 14, 3890–3893.
[8] For selected reviews on organocatalyzed ATH, see: a) C. Zheng, S.-L.
You, Chem. Soc. Rev. 2012, 41, 2498–2518; b) M. Rueping, E. Sugiono,
F. R. Schoepke, Synlett 2010, 852–865; c) C. Wang, X. Wu, J. Xiao, Chem.
Asian J. 2008, 3, 1750–1770; d) S. G. Ouellet, A. M. Walji, D. W. C. Mac-
Millan, Acc. Chem. Res. 2007, 40, 1327–1339; e) S. J. Connon, Org.
ˇ
Acknowledgements
Biomol. Chem. 2007, 5, 3407–3417; f) J. G. de Vries, N. MrSic, Catal. Sci.
Technol. 2011, 1, 727–735.
[9] For reviews of chiral phosphoric acid, see: a) Z.-P. Yang, W. Zhang, S.-L.
You, J. Org. Chem. 2014, 79, 7785–7798; b) A. Zamfir, S. Schenker, M.
Freund, S. B. Tsogoeva, Org. Biomol. Chem. 2010, 8, 5262–5276; c) D.
Parmar, E. Sugiono, S. Raja, M. Rueping, Chem. Rev. 2014, 114, 9047–
9153; d) T. Akiyama, Chem. Rev. 2007, 107, 5744–5758; e) M. Terada,
Synthesis 2010, 1929–1982; f) D. Kampen, C. M. Reisinger, B. List, Top.
Curr. Chem. 2010, 291, 395–456; g) Y. Su, F. Shi, Chin. J. Org. Chem.
2010, 30, 486–498; For seminal works of chiral phosphoric acid, see:
h) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. Int. Ed. 2004,
43, 1566–1568; Angew. Chem. 2004, 116, 1592–1594; i) D. Uraguchi, M.
Terada, J. Am. Chem. Soc. 2004, 126, 5356–5357.
This work was partially supported by a Grant-in-Aid for Scien-
tific Research on Innovative Areas “Advanced Transformation
Organocatalysis” from MEXT, Japan, a Grant-in-Aid Scientific Re-
search from JSPS, and MEXT-Supported Program for the Strate-
gic Research Foundation at Private Universities.
Keywords: dynamic kinetic resolution
·
heterocycles
·
hydrogenation · organocatalysis · stereoselective synthesis
[10] Our group has recently developed chiral Brønsted acid catalyzed trans-
fer hydrogenation of imines using benzothiazoline derivatives as hydro-
gen donor, see: a) C. Zhu, T. Akiyama, Org. Lett. 2009, 11, 4180–4183;
b) C. Zhu, T. Akiyama, Adv. Synth. Catal. 2010, 352, 1846–1850; c) C.
Zhu, T. Akiyama, Synlett 2011, 1251–1254; d) A. Henseler, M. Kato, K.
Mori, T. Akiyama, Angew. Chem. Int. Ed. 2011, 50, 8180–8183; Angew.
Chem. 2011, 123, 8330–8333; e) K. Saito, T. Akiyama, Chem. Commun.
2012, 48, 4573–4575; f) C. Zhu, T. Akiyama, Tetrahedron Lett. 2012, 53,
416–418; g) T. Sakamoto, K. Mori, T. Akiyama, Org. Lett. 2012, 14, 3312–
3315; See also: h) D. Enders, J. X. Liebich, G. Raabe, Chem. Eur. J. 2010,
16, 9763–9766; i) C. Zhu, J. R. Falck, ChemCatChem 2011, 3, 1850–1851;
j) C. Zhu, K. Saito, M. Yamanaka, T. Akiyama, Acc. Chem. Res. 2015, 48,
388–398.
[11] a) S. Hoffmann, A. M. Seayad, B. List, Angew. Chem. Int. Ed. 2005, 44,
7424–7427; Angew. Chem. 2005, 117, 7590–7593; b) G. Adair, S. Mu-
kherjee, B. List, Aldrichimica Acta 2008, 41, 31–39.
[12] Absolute configuration of 2a was determined to be (S,S) by the com-
parison of the sign of optical rotation and the retention time of HPLC
analysis; see Ref. [7b].
[1] For reviews on kinetic resolutions, see: a) E. Vedejs, M. Jure, Angew.
Chem. Int. Ed. 2005, 44, 3974–4001; Angew. Chem. 2005, 117, 4040–
4069; b) E. Fogassy, M. Nogradi, D. Kozma, G. Egri, E. Palovics, V. Kiss,
Org. Biomol. Chem. 2006, 4, 3011–3030; c) H. Pellissier, Adv. Synth. Catal.
2011, 353, 1613–1666.
[2] For reviews of dynamic kinetic resolution, see: a) H. Pellissier, Tetrahe-
dron 2003, 59, 8291–8327; b) H. Pellissier, Tetrahedron 2008, 64, 1563–
1601; c) H. Pellissier, Tetrahedron 2011, 67, 3769–3802.
[3] For review of DKR based on nonenzymatic approaches, see: a) R.
Noyori, M. Takunaga, M. Kitamura, Bull. Chem. Soc. Jpn. 1995, 68, 36–
56; b) H. Pellissier, Adv. Synth. Catal. 2011, 353, 659–676.
[4] For reviews on DKR based on enzymatic or chemoenzymatic ap-
proaches, see: a) J. H. Lee, K. Han, M.-J. Kim, J. Park, Eur. J. Org. Chem.
2010, 999–1015; b) P. Hoys, V. Pace, A. R. Alcµntara, Adv. Synth. Catal.
2012, 354, 2585–2611; c) F. F. Huerta, A. B. E. Minidis, J.-E. Bäckvall,
Chem. Soc. Rev. 2001, 30, 321–331; d) H. Stecher, K. Faber, Synthesis
1997, 1–16; e) A. Kamal, M. A. Azhar, T. Krisnaji, M. S. Malik, S. Azeeza,
Coord. Chem. Rev. 2008, 252, 569–592.
[13] Because we could not prepare 1a in enantio-enriched form, we could
not study the kinetics of racemization process of 1a.
[14] Although crossover experiment was carried for the elucidation of the
reaction mechanism, no crossover was observed in the reaction of 1m
with 1b or e under the optimized conditions.
[15] Reaction of 1a with 3b-D using the optimized catalyst (R)-2b gave
lower yield (44%, 97% ee, d.r. 17.7/1).
[16] Reaction of the substrate reported in Ref. [7a] under the optimized
conditions gave much lower conversion (<10% yield).
[17] When this reaction was carried out in the absence of phosphoric acid
and 5 Š MS, no ring-opening product was obtained, but 5a was ob-
tained quantitatively. As an acidic reagent, 5 Š MS was reported to
work, see: N. Asakura, T. Hirokane, H. Hoshida, H. Yamada, Tetrahedron
Lett. 2011, 52, 534–537.
[5] Examples of nonenzymatic DKR of amines, see: a) J.-H. Xie, S. Liu, W.-L.
Kong, W.-J. Bai, X.-C. Wang, L.-X. Wang, Q.-L. Zhou, J. Am. Chem. Soc.
2009, 131, 4222–4223; b) D.-W. Wang, X.-B. Wang, D.-S. Wang, S.-M. Lu,
C.-B. Yu, Y.-G. Zhou, J. Org. Chem. 2009, 74, 2780–2787; c) M. Rueping,
T. Theissmann, S. Raja, J. W. Bata, Adv. Synth. Catal. 2008, 350, 1001–
1006; d) Q.-S. Guo, D.-M. Du, J. Xu, Angew. Chem. Int. Ed. 2008, 47, 759–
762; Angew. Chem. 2008, 120, 771–774; e) T. Wang, L.-G. Zhou, Z. Li, F.
Chen, Z. Ding, Y. He, Q.-H. Fan, J. Xiang, Z.-X. Yu, A. S. C. Chan, J. Am.
Chem. Soc. 2011, 133, 9878–9891; f) D.-S. Wang, Q.-A. Chen, W. Li, C.-B.
Yu, Y.-G. Zhou, X. Zhang, J. Am. Chem. Soc. 2010, 132, 8909–8911; g) L.
Shi, Z.-S. Ye, L.-L. Cao, R.-N. Guo, Y. Hu, Y.-G. Zhou, Angew. Chem. Int. Ed.
2012, 51, 8286–8289; Angew. Chem. 2012, 124, 8411–8414; h) M.-W.
Chen, X.-F. Cai, Z.-P. Chen, L. Shi, Y.-G. Zhou, Chem. Commun. 2014, 50,
12526–12529.
[6] For recent examples, see: a) G. Grossi, M. D. Braccio, G. Roma, V. Ballabe-
ni, M. Tognolini, F. Calcina, E. Barocelli, Eur. J. Med. Chem. 2002, 37, 933–
944; b) A. Matsuhisa, H. Koshio, K. Sakamoto, N. Taniguchi, T. Yatsu, A.
Tanaka, Chem. Pharm. Bull. 1998, 46, 1566–1579; c) W. Nawrocka, B.
[18] They examined the racemization process by the reaction of starting ma-
terial with electron-deficient acetophenone derivative.
[19] All TSs were computed at the M05–2X/6–31G*//ONIOM(B3LYP:HF) level.
Computational details are given in the Supporting Information.
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Communication
[20] a) Y. Shibata, M. Yamanaka, J. Org. Chem. 2013, 78, 3731–3736; b) K.
Saito, Y. Shibata, M. Yamanaka, T. Akiyama, J. Am. Chem. Soc. 2013, 135,
11740–11743; c) K. Saito, K. Horiguchi, Y. Shibata, M. Yamanaka, T.
Akiyama, Chem. Eur. J. 2014, 20, 7616–7620.
Noda, M. Yamanaka, N. Akasaka, S. Ishida, T. Iwamoto, M. Terada, ACS
Catal. 2016, 6, 949–956.
[22] Although TS_N has similar structural features to TS_A, no additional co-
ordination of m-OH group reduces the structural requirement for the
chiral space. Therefore, in TS_N, the diastereomeric TSs are located for
each absolute configuration of 3b.
[23] Based on the TS1a and TS1b, the diastereomeric TSs (TSg) leading to
the meso isomer (S,R)-5a were also compared. The relative energy dif-
ference between the competitive diastereomeric TSs (TSa and TSg) is
significantly decreased (within 1 kcalmolÀ1) in agreement with the
lower diastereoselectivity experimentally obtained by (R)-2a. See the
Supporting Information.
[21] Selected examples of theoretical study of chiral phosphoric acid cataly-
sis: a) M. Yamanaka, J. Itoh, K. Fuchibe, T. Akiyama, J. Am. Chem. Soc.
2007, 129, 6756–6764; b) L. Simón, J. M. Goodman, J. Am. Chem. Soc.
2008, 130, 8741–8747; c) T. Marcelli, P. Hammar, F. Himo, Chem. Eur. J.
2008, 14, 8562–8571; d) M. Yamanaka, T. Hirata, J. Org. Chem. 2009, 74,
3266–3271; e) X.-H. Chen, Q. Wei, S.-W. Luo, H. Xiao, L.-Z. Gong, J. Am.
Chem. Soc. 2009, 131, 13819–13825; f) N. Li, X.-H. Chen, J. Song, S.-W.
Luo, W. Fan, L.-Z. Gong, J. Am. Chem. Soc. 2009, 131, 15301–15310;
g) L. Simón, J. M. Goodman, J. Org. Chem. 2010, 75, 589–597; h) C.
Zheng, Y.-F. Sheng, Y.-X. Li, S.-L. You, Tetrahedron 2010, 66, 2875–2880;
i) T. Hirata, M. Yamanaka, Chem. Asian J. 2011, 6, 510–516; j) L. Simón,
J. M. Goodman, J. Org. Chem. 2011, 76, 1775–1788; k) M. Yamanaka, M.
Hoshino, T. Katoh, M. Mori, T. Akiyama, Eur. J. Org. Chem. 2012, 24,
4508–4514; l) M. N. Grayson, S. C. Pellegrinet, J. M. Goodman, J. Am.
Chem. Soc. 2012, 134, 2716–2722; m) F. Shi, G.-J. Xing, Z.-L. Tao, S.-W.
Luo, S.-J. Tu, L.-Z. Gong, J. Org. Chem. 2012, 77, 6970–6979; n) K. Mori,
Y. Ichikawa, M. Kobayashi, Y. Shibata, M. Yamanaka, T. Akiyama, J. Am.
Chem. Soc. 2013, 135, 3964–3970; o) K. Mori, Y. Ichikawa, M. Kobayashi,
Y. Shibata, M. Yamanaka, T. Akiyama, Chem. Sci. 2013, 4, 4235–4239;
p) H. Wang, P. Jain, J. C. Antilla, K. N. Houk, J. Org. Chem. 2013, 78,
1208–1215; q) K. Kanomata, Y. Toda, Y. Shibata, M. Yamanaka, S. Tsuzuki,
I. D. Gridnev, M. Terada, Chem. Sci. 2014, 5, 3515–3523; r) M. Terada, T.
Komuro, Y. Toda, T. Korenaga, J. Am. Chem. Soc. 2014, 136, 7044–7057;
s) C. Liu, P. Han, M. Tang, Comput. Theor. Chem. 2014, 1050, 39–45; t) J.
Pous, T. Courant, G. Bernadat, B. I. Iorga, F. Blanchard, G. Masson, J. Am.
Chem. Soc. 2015, 137, 11950–11953; u) N. Momiyama, K. Funayama, H.
[24] Details of the ring-flipped conformations of 1a are given in Supporting
Information.
[25] Examples of remote control of stereoselectivity by the bulky substituent
at the para-position at the aryl substituent on stereoselectivity in
BINOL-based chiral phosphoric acids, see: a) P. Jiao, D. Nakashima, H.
Yamamoto, Angew. Chem. Int. Ed. 2008, 47, 2411–2413; Angew. Chem.
2008, 120, 2445–2447; b) X. Cheng, R. Goddard, G. Buth, B. List, Angew.
Chem. Int. Ed. 2008, 47, 5079–5081; Angew. Chem. 2008, 120, 5157–
5159; c) C. H. Cheon, H. Yamamoto, J. Am. Chem. Soc. 2008, 130, 9246–
9247; d) X. Cheng, S. Vellalath, R. Goddard, B. List, J. Am. Chem. Soc.
2008, 130, 15786–15787; e) C. H. Cheon, H. Yamamoto, Org. Lett. 2010,
12, 2476–2479; f) M. Sai, H. Yamamoto, J. Am. Chem. Soc. 2015, 137,
7091–7094.
Received: April 6, 2016
Published online on May 6, 2016
Chem. Eur. J. 2016, 22, 8078 – 8083
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim