Organocatalyst-Mediated Dynamic Kinetic Enantioselective Acylation of 2-Chromanols

Article abstract of DOI:10.1002/adsc.201800994

We recently developed a novel chiral catalyst-directed dynamic kinetic diastereoselective acylation of hemiacetals for the synthesis of carbohydrates. In this update, we describe a catalytic method for the dynamic kinetic enantioselective acylation of 2-c

Full text of DOI:10.1002/adsc.201800994

Title: Organocatalyst-Mediated Dynamic Kinetic Enantioselective
Acylation of 2-Chromanols
Authors: Daniel Glazier, John Schroeder, Jitian Liu, and Weiping Tang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800994
Link to VoR: http://dx.doi.org/10.1002/adsc.201800994

Advanced Synthesis & Catalysis
10.1002/adsc.201800994
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Organocatalyst-Mediated Dynamic Kinetic Enantioselective
Acylation of 2-Chromanols
a,b
a,b
b
a,b
Daniel A. Glazier, John M. Schroeder, Jitian Liu, and Weiping Tang *
a
School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA
Phone: (608) 890-1846, Fax: (608) 262-5345, Email: wtang@pharmacy.wisc.edu
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705, USA
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. We recently developed a novel chiral catalyst-
directed dynamic kinetic diastereoselective acylation of bioactive natural products and pharmaceutical
Chromanol is a prevalent structural motif in
[11]
hemiacetals for the synthesis of carbohydrates. In this agents. Various chromanol derivatives can also be
update, we describe a catalytic method for the dynamic used as intermediates for the synthesis of other
kinetic enantioselective acylation of 2-chromanols using bioactive compounds. For example, Maguire and co-
benzotetramisole derived catalysts. High yields and
enantiomeric excesses were obtained for a broad range of
acylated 2-chromanols, which are important intermediates
for the synthesis of various bioactive pharmaceuticals. We
hypothesize that the high stereoselectivity of the reaction
originates from a novel cation-n interaction between the
chromanol substrate and the acylated catalyst.
workers recently screened a variety of hydrolase
enzymes for the DKEA of 2-chromanols in an attempt
to develop a more practical synthesis of the
[12]
antimuscarinic drugs tolterodine and fesoterodine.
Although up to 88% conversion and 92% ee could be
achieved in two model systems, 2-chromanol and 3-
methyl 2-chromanol, the substrate scope was very
limited. They were not able to achieve high
enantioselectivity together with efficient conversion
for other substituted 2-chromanols using the same
panel of enzymes. In this update we report our recent
progress on the small molecule organocatalyst-
mediated DKEA of 2-chromanols (Scheme 1B). High
Keywords: nucleophilic catalysis; homogeneous catalysis;
acylation; lactols; esterification
Chiral acyl acetals and ketals are present in numerous yields and enantioselectivity were observed for a
bioactive natural products and pharmaceutical broad range of 2-chromanols. This represents the first
[
1]
[2]
reagents, such as massarinolin A, expansolides A,
example of small molecule-mediated DKEA of lactols
[3]
[4]
sequoiamonascins, and levantenolides. Chiral acyl beyond
lactols that are derived from the acylation of rearrangement products.
Achmatowicz rearrangement products (Scheme 1A)
are also useful intermediates in the de novo synthesis
of various mono-and oligosaccharides. However,
these acyl lactols were generally prepared with low
diastereoselectivity in the absence of external chiral
reagents. We recently reported that chiral
dihydropyranone-type
Achmatowicz
[5]
[6]
[7]
benzotetramisole (BTM) were efficient catalysts for
the dynamic kinetic diastereoselective acylation
(
(
DKDA) of Achmatowicz rearrangement products
Scheme 1A).[ Around the same time two other
8]
groups also reported chiral organocatalyst-mediated
dynamic kinetic enantioselective acylations (DKEA)
of dihydropyranone Achmatowicz rearrangement
[9]
products with a single stereogenic center. We
recently extended the DKDA reaction to the
stereoselective acylation of anomeric hydroxyl groups
[10]
in various mono- and oligosaccharides.
Both
DKDA and DKEA reactions take advantage of the
equilibrium between the two lactol stereoisomers to
affect a dynamic kinetic stereoselective acylation by
preferentially acylating one of the lactol stereoisomers.
Scheme 1. Dynamic Kinetic Stereoselective Acylation of
Lactols
1
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201800994
2
-Chromanol (1a) was chosen as the model motifs are also well tolerated (2f and 2g). Both
substrate for the DKEA reaction. Much to our electron donating methoxy and electron withdrawing
surprise, the initial conditions we tried (entry 1, Table fluorine atoms can be tolerated on the 4-position, as
1
) using (R)-BTM as a catalyst and isobutryic shown in products 2h and 2i. Lastly, the
anhydride as the acylating reagent produced both high corresponding free lactol of compound 2j was an
enantioselectivity and high yields. Stereochemistry of intermediate used as a racemic mixture of four
the product was tentatively assigned based on our stereoisomers in the synthesis of antimuscarinic drugs
[13]
previous results on the DKDA of dihydropyranones. tolterodine and fesoterodine.
Next, anhydride acylating reagents were screened stereogenic center was resolved at the end of the
entries 2-4). While acetic and propionic anhydride synthesis. To develop a more practical synthesis,
The 4-phenyl
(
could achieve similar yields to isobutyric anhydride, Maguire and co-workers attempted to synthesize and
they gave lower enantioselectivities. Fortunately, we resolve the two acylated lactol diastereomers such as
found that pivalic anhydride showed no reactivity, 2j, but the enzymatic approach could not tolerate the
[12]
which implied that it should be possible to use a necessary 4-phenyl motif.
It is well tolerated by
mixed anhydride method to acylate 2-chromanols. BTM type catalysts in our DKDA.
Catalysts were then screened. (R)-iPr-BTM and (R)-
Bn-BTM both showed small decreases in activity and Table 2. Scope of DKEAa
selectivity when compared to (R)-BTM (entries 5 and
6
). HBTM and H-iPr-BTM can achieve similar ees to
(
(
R)-BTM, however, they give slightly lower yields
entries 7 and 8). (R)-homo-BTM (HBTM) catalyst
yields the opposite enantiomer comparing to (R)-
BTM. Finally, (S)-tetramisole provides a lower yield
and selectivity than BTM catalyst (entry 9).
Table 1. Screening conditions for the DKEA reaction of 2-
chromanolsa
a
b
ee
Yield
%)
entry
conditions
(
(
%)
1
2
3
4
5
6
7
8
9
(R)-BTM and (i-PrCO)
(R)-BTM and Ac
(R)-BTM and (EtCO)
(R)-BTM and Piv
(R)-iPr-BTM and (i-PrCO)
(R)-Bn-BTM and (i-PrCO)
(R)-HBTM and (i-PrCO)
(S)-H-iPr-BTM and (i-PrCO)
(S)-Tetramisole and (i-PrCO)
2
O
96
89
-
95
86
87
-
2
O
2
O
2
O
-
2
O
93
82
90
84
79
88
75
2
O
2
O
-92
96
2
O
2
O
-85
a.
The ees were determined by HPLC using a Daicel
b.
Chiralcel OD-H column. Isolated yield.
We then applied our optimized conditions to a
variety of substituted 2-chromanols (Table 2). The
enantiomeric product (ent-2a) was prepared in high
optical purity by switching the catalyst to (S)-BTM
(
entry 2). The DKEA reaction tolerates a variety of
substituents such as the 6-methoxy group in 2b, 5-
acylolxy group in 2c, 5-benzyloxy group in 2d, and 4-
aryl group in 2e. Fused benzene or cyclohexane
2
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201800994
a.
Conditions: 2-chromanol 1a (0.1 mmol, 1 equiv), (R)-
In summary, we have developed a practical and
BTM (0.01 mmol, 10 mol %), (i-PrCO)
equiv), rt, CH
using a Daicel Chiralcel OD-H column. Isolated yield.
2
O (0.13 mmol, 1.3 general method for the DKEA of 2-chromanols using
b.
2
Cl
2
.
The ees were determined by HPLC BTM catalysts with high yields and ees. We propose
c. d.
that the high enantioselectivity is controlled by a
e.
Run on large scale using 2.43 mmol of 1a. (S)-BTM (10 cation-n interaction between the acylated catalyst and
f.
mol %) was employed. Reaction run in chloroform in the endo-oxygen of the 2-chromanol. This method can
g.
place of DCM. cis/trans ee.
be potenitally used for the synthesis of various
bioactive chiral compounds, such as antimuscarinic
drugs tolterodine and fesoterodine.
Next, we tested the mixed anhydride conditions
using compound 1a as a substrate as shown in
Scheme 2. Both isobutyric acid and phenylacetic acid Experimental Section
gave acylated products in high yield and ee. This
allows for the use of acyl groups, not comercially General procedure for dynamic kinetic enantioselective
acylation of 2-chromanols
available as anhydrides, to be used in the acylation of
chiral lactols.
Catalyst ((S)-BTM, 2.5 mg, 0.01 mmol) and 1a (15 mg, 0.1
mmol) were dissolved in DCM (1 mL). Isobutyric
anhydride (0.019 mL, 0.115 mmol) was added and the
reaction was capped and stirred under argon. The reaction
was monitored via TLC. When the reaction was deemed
complete (usually 1.5-2 h) 0.5 mL of MeOH was added and
the reaction was stirred for another 30 min. The solvent
was
removed
under
vacuum.
Flash
column
chromatography (DCM) yielded 18.9 mg (86%) of the
product as a colorless oil.
Acknowledgements
Scheme 2. DKEA of Lactols by Mixed Anhydrides
We thank the University of Wisconsin-Madison for financial
support.
We were intrigued by the exceptional enantio-
selectivity of the DKEA and performed DFT
calculations to identify the source of this selectivity.
We have previously shown that a cation-n interaction
dictates the BTM-catalyzed site-selective acylation of
References
[1]
H. Oh, J. B. Gloer, C. A. Shearer, J. Nat. Prod. 1999, 62,
97.
4
carbohydrate hydroxyl groups.[14] We hypothesized [2]
that the stereoselectivity of the DKEA of 2-
M. Massias, S. Rebuffat, L. Molho, A. Chiaroni, C.
Riche, B. Bodo, J. Am. Chem. Soc. 1990, 112, 8112.
D. B. Stierle, A. A. Stierle, T. Bugni, J. Org. Chem.
[3]
chromanols is also dictated by a similar of cation-n
interaction.
2
003, 68, 4966.
a) J. A. Giles, J. N. Schumacher, Tetrahedron 1961, 14,
46; b) A. G. Gonzalez, C. G. Francisco, R. Freire, R.
Hernandez, J. A. Salazar, E. Suarez, Tetrahedron Lett.
976, 1897.
[4]
The lowest energy transition state for the (R)-BTM
catalyzed DKEA of 1a, 1a-TS1, leads to the
experimentally observed (R)-product. As we
hypothesized, it features a cation-n interaction with
the endo-oxygen of 1a pointing at the catalyst. The
2
1
[5]
O. Achmatowicz, P. Bukowski, B. Szechner, Z.
Zwierzch, A. Zamojski, Tetrahedron 1971, 27, 1973.
a) A. Z. Aljahdali, P. Shi, Y. S. Zhong, G. A. O'Doherty,
in Advances in Carbohydrate Chemistry and
lowest energy transition state leading to the (S) [6]
product, 1a-TS2, lacks this cation-n interaction. The
‡
Biochemistry, Vol 69, Vol. 69 (Ed.: D. Horton), 2013,
pp. 55; b) M. F. Cuccarese, J. J. Li, G. A. O’Doherty, in
Modern Synthetic Methods in Carbohydrate Chemistry:
From Monosaccharides to Complex Glycoconjugates
∆
G for 1a-TS1 and 1a-TS2 is 3.4 Kcal/mol, which
agrees with the high degree of ee obtained
experimentally.
(Eds.: D. B. Werz, S. Vidal), 2014 Wiley-VCH Verlag
GmbH & Co. KGaA, Weinheim, 2014, pp. 1; c) W.
Song, S. Wang, W. Tang, Chem. Asian J. 2017, 12,
1
027.
[
7]
a) V. B. Birman, X. M. Li, Org. Lett. 2006, 8, 1351; b)
X. Li, H. Jiang, E. W. Uffman, L. Guo, Y. Zhang, X.
Yang, V. B. Birman, J. Org. Chem. 2012, 77, 1722; c)
X. Yang, G. Lu, V. B. Birman, Org. Lett. 2010, 12, 892;
d) G. Lu, V. B. Birman, Org. Lett. 2011, 13, 356.
H.-Y. Wang, K. Yang, D. Yin, C. Liu, D. A. Glazier, W.
Tang, Org. Lett. 2015, 17, 5272.
a) A. Ortiz, T. Benkovics, G. L. Beutner, Z. Shi, M.
Bultman, J. Nye, C. Sfouggatakis, D. R. Kronenthal,
Angew. Chem. Int. Ed., 2015, 54, 7185; b) C. Zhao, F.
Li, J. Wang, Angew. Chem. Int. Ed. 2016, 55, 1820.
1
a-TS1
1a-TS2
Figure 1. Transition States for the DKEA of 1a. (The
cation-n interaction in 1a-TS1 is highlighted as the green
dotted line. Structures were optimized using the m062x/6-
[
8]
9]
[
3
1G(d) level of theory. Single point energies were
calculated using the m062x/6-311++G(d,p)/SMD level of
theory.)
3
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201800994
[10]
[11]
[12]
H.-Y. Wang, C. J. Simmons, Y. Zhang, A. M. Smits, P.
G. Balzer, S. Wang, W. Tang, Org. Lett. 2017, 19, 508.
M. Birringer, K. Siems, A. Maxones, J. Frank, S.
Lorkowski, RSC Adv. 2018, 8, 4803.
D. P. Gavin, A. Foley, T. S. Moody, U. B. R.
Khandavilli, S. E. Lawrence, P. O'Neill, A. R. Maguire,
Tetrahedron: Asymmetry 2017, 28, 577.
[13]
a) C. Botteghi, T. Corrias, M. Marchetti, S. Paganelli, O.
Piccolo, Org. Process Res. Dev. 2002, 6, 379; b) O.
Dirat, A. J. Bibb, C. M. Burns, G. D. Checksfield, B. R.
Dillon, S. E. Field, S. J. Fussell, S. P. Green, C. Mason,
J. Mathew, S. Mathew, I. B. Moses, P. I. Nikiforov, A. J.
Pettman, F. Susanne, Org. Process Res. Dev. 2011, 15,
1
010.
[14]
G. Xiao, G. A. Cintron-Rosado, D. A. Glazier, B.-M. Xi,
C. Liu, P. Liu, W. Tang, J. Am. Chem. Soc. 2017, 139,
4
346.
4
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201800994
UPDATE
Chiral Catalyst-Directed Dynamic Kinetic
Enantioselective Acylation of 2-Chromanols
Adv. Synth. Catal. Year, Volume, Page – Page
Daniel A. Glazier, John M. Schroeder, Jitian Liu,
and Weiping Tang*
5
This article is protected by copyright. All rights reserved.