Asymmetric synthesis of novel spirocycles via a chiral phosphoric acid catalyzed desymmetrization

Article abstract of DOI:10.1016/j.tetlet.2019.03.074

A straightforward method for the asymmetric preparation of novel lactone and lactam spirocycles is described. An initial desymmetrization via a chiral Br?nsted acid yields enantioenriched lactones which readily undergo a second cyclization to give the des

Full text of DOI:10.1016/j.tetlet.2019.03.074

Accepted Manuscript
Asymmetric synthesis of novel spirocycles via a chiral phosphoric acid cata-
lyzed desymmetrization
Amber M. Kelley, Eni Minerali, Jennifer E. Wilent, Nicholas J. Chambers, Kyla
J. Stingley, G. Tyler Wilson, Kimberly S. Petersen
PII:
S0040-4039(19)30312-0
https://doi.org/10.1016/j.tetlet.2019.03.074
TETL 50715
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 December 2018
27 March 2019
30 March 2019
Please cite this article as: Kelley, A.M., Minerali, E., Wilent, J.E., Chambers, N.J., Stingley, K.J., Tyler Wilson, G.,
Petersen, K.S., Asymmetric synthesis of novel spirocycles via a chiral phosphoric acid catalyzed desymmetrization,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.03.074
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Tetrahedron Letters
journal homepage: www.elsevier.com
Asymmetric synthesis of novel spirocycles via a chiral phosphoric acid catalyzed
desymmetrization
Amber M. Kelley, Eni Minerali, Jennifer E. Wilent, Nicholas J. Chambers, Kyla J. Stingley, G. Tyler
Wilson, and Kimberly S. Petersen*
Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A straightforward method for the asymmetric preparation of novel lactone and lactam
spirocycles is described. An initial desymmetrization via a chiral Brønsted acid yields
enantioenriched lactones which readily undergo a second cyclization to give the desired
spirocycle.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
desymmetrization
chiral Brønsted acid
chiral phosphoric acid
spirocycle
1. Introduction
calculations of the analogous kinetic resolution indicate that the
reaction proceeds via a step-wise mechanism promoted by dual
Spirocycles are important natural products,1 chiral ligands,2
drug scaffolds,3 and optoelectronics.4 Spirolactones are an
important class of spiro compounds (Figure 1). Drospirenone
(1), is a synthetic spirolactone analog of progesterone and is used
as an oral contraceptive (marketed as Yasmin in the US).5
Drospirenone contains a tertiary carbon spiro center which is
prevalent in many other biologically interesting or naturally
occurring spirolactones.6 All carbon spiro centers as seen in
spirosesquiterpenes 2 and 3 are much less common.7-8 We predict
that a straightforward enantioselective synthesis of these types of
scaffolds would lead to their increased use and study as a new
core structure for development.9
activation of both the carbonyl via the Brønsted acidic proton and
the hydroxyl group via the Lewis acidic oxygen of the chiral
phosphoric acid.12
Herein we disclose the synthesis of novel spirocyclic scaffolds
via an analogous protocol.
We envisioned that the
desymmetrization of diesters such as 4 with two alkyl chains that
contain nucleophiles would proceed to yield an enantioenriched
lactone that could undergo a second cyclization with a general
acid (Scheme 1). Formation of the -lactone during the initial
enantioselective cyclization is proposed due to previous
indications of higher enantioselectivities and shorter reaction
times for the cyclization of 5-membered ring lactones.11
spirolactone with a
tertiary C spiro center
spirolactones with a quaternary C spiro center
O
Ar
OO
OO
O
Previous desymmetrization strategy
O
O
O
O
O
O
OH
P
O
O
O
O
H
O
TRIP
O
O
HO
O
O
O
O
H
H
Ar
O
R
7 examples
up to 98% ee
and 96% yield
R
TRIP
Ar = 2,4,6-isopropyl-C6H2
O
5
4
OH
1
2
3
Drospirenone
spirosesquiterpene
from Ligularia fischeri
spirosesquiterpene
from Ligularia virgaurea
This work: Application to spirocycle formation
O
O
Figure 1. Spirocyclic lactones.
O
O
O
TsOH
or TFA
O
n
TRIP
O
O
O
O
X
We have recently developed a novel asymmetric cyclization
strategy for the formation of chiral lactones with all carbon
quaternary stereocenters in up to 98% ee and 96% yield (Scheme
n
O
XH
n
OH
XH
6
4
5
spirocycle with
all carbon
stereocenter
sets all carbon
stereocenter
1).10-11
This desymmetrization method utilized
a chiral
phosphoric acid catalyzed intramolecular lactonization. DFT
Scheme 1. All carbon spirocycle strategy.

2
Tetrahedron
2. Results
Table 1. Results
O
O
O
O
O
1. deprotection
1. deprotection
2. cyclization
A series of basic spirocyclic scaffolds were prepared using the
O
n
O
O
O
O
X
TRIP
2. (R)-
(10 mol%)
general strategy outlined above (Table 1). Remarkably, other
than compound 6a,13 the prepared spirocycles are novel even in
their racemic form. Initially, diesters 4 were prepared via two
n
PG2X
O
n
OPG1
PG2X
4
5
6
from
di-tert-butyl malonate
yield #1
ee#1
yield #2
ee #2
alkylations from di-tert-butyl malonate.
Deprotection of
protecting group #1 (PG1) yielded the free alcohol which, when
cyclized with TRIP gave the enantioenriched -lactones 5 in
modest to good yields and enantiopurities. Deprotection of
protecting group #2 (PG2) followed by cyclization with either
trifluoroacetic acid or para-toluene sulfonic acid yielded the
desired spirocycles 6.14 In general, a moderate drop in ee was
seen during this second cyclization, likely due to some
scrambling of the stereocenter in the second cyclization (see
further discussion below). Spirocycle 6a was obtained in
racemic form, even after a nearly enantiopure first cyclization.
This likely is due to the fast cyclization of 5a under deprotection
conditions. Spirocycle 6d was prepared via cyclization of
precursor 5d with trifluoroacetic acid (para-toluene sulfonic acid
is not effective at inducing cyclization). Careful monitoring of
the reaction indicates that this cyclization goes through a
carboxylic acid intermediate. Recrystallization of spirocycles
leads to an increase in optical purity as seen in spirocycle 6d
which goes from 6085% ee in one recrystallization.
Lactone/lactam spirocycle 6e was formed via a CDI (1,1′-
Carbonyldiimidazole) coupling reaction of the carboxylic acid
formed upon saponification of 5e. The more substituted
spirocycle 6f, containing a dihydro benzopyrone ring was
prepared in good enantiomeric purity (72% ee). The absolute
stereochemistry of spirocycle 6e was determined by x-ray
crystallography15 and all others were assigned based on analogy.
*PG1 and PG2 = different protecting groups
O
O
O
O
O
O
O
O
O
O
O
AcO
O
OBn
AcO
5a
6a
4a
92% yield (from 5a)
39% yield (from 4a)
0% ee
99% ee
O
O
O
O
O
O
O
O
O
O
O
BnO
O
6b
OAc
O
BnO
4b
5b
78% yield (from 5b)
63% ee
49% yield (from 4b)
81% ee
O
O
O
O
O
O
O
O
O
O
O
O
O
AcO
O
6c
OBn
O
AcO
4c
5ca
60% yield (from 5c)
24% ee
79% yield (from 4c)
41% ee
O
O
O
O
O
O
O
O
O
There are two potential pathways for the second cyclization
and formation of the spirocycle. The first, is that the second
cyclization takes place with “retention” of stereochemistry via
the second nucleophile reacting with the remaining tert-butyl
ester (see red arrows, 5b’(R)-6b in Scheme 2). Another
possible pathway is that the second nucleophile initially attacks
the lactone ester to form intermediate 7, which is followed by
cyclization to yield the “inverted” spirocyclic product (see blue
arrows, 5b’7(S)-6b in Scheme 2). To probe these potential
TsN
TsHN
O
6d
OBn
4d
TsHN
5da
85% yield (from 5d)
60% then 85% ee
after recrystallization
88% yield (from 4d)
84% ee
O
O
O
O
O
O
1
pathways we monitored the cyclization of 5b’ via H NMR.16
TsN
O
6e
Figure 2 shows a snapshot of this experiment. The signal at 3.6
ppm represents protons a (Ha) in 5b’ and the signal at 2.9 ppm
represents protons b (Hb) in 6b. This time-dependent NMR
suggests direct conversion of 5b’ to 6b. We postulate that the
decrease in ee seen in the second cyclization is due to trace and
undetectable by 1H NMR, formation of 7 under the longer
reaction times required for optimized spirocycle formation yields.
TsHN
5e
41% yield (from 5e)
70% ee
56% yield (from 5b’)
81% ee
O
O
O
O
O
O
O
O
O
O
TBSO
O
O
OAc
O
O
O
TBSO
TsOH
O
6f
OR
O
O
O
O
O
O
5f
Ha
Ha
4f
34% yield (from 5f)
72% ee
54% yield (from 4f)
O
Hb
O
Hb
76% ee
5b'
OH
6b
6b
(S)-
a(S)-TRIP was used in cyclization.
(R)-
"retention" of
"inversion" of
stereochemistry
stereochemistry
O
O
HO
O
O
7
Scheme 2. Mechanistic pathway considerations.

Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC 1884802. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-
mail: deposit@ccdc.cam.ac.Uk).
References and notes
1.
Smith, L. K.; Baxendale, I. R., Org. Biomol. Chem. 2015, 9907–
9933.
2.
3.
Zhou, Q. L.; Xie, J. H., Top Organomet. Chem. 2011, 36, 1–28.
Zheng, Y.; Tice, C. M.; Singh, S. B., Bioorg. Med. Chem. Lett.
2014, 24, 3673–3682.
4.
Saragi, R. P. I.; Spehr, T.; Siebert, A.; Fuhrmann-Lieker, T.;
Salbeck, J., Chem. Rev. 2007, 107, 1011–1065.
Krattenmacher, R., Contreception 2000, 62, 29–38.
Bartoli, A.; Rodier, F.; Commeiras, L.; Parrain, J.-L.; Chouraqui,
G., Nat. Prod. Rep. 2011, 28, 763–782.
Figure 2. 1H NMR experiment.
5.
6.
3. Conclusion
7.
Zhang, W.-J.; Li, X.-H.; Shi, Y.-P., J. Nat. Prod. 2010, 73, 143–
146.
In conclusion, we describe a straightforward method for the
synthesis of novel enantioenriched all-carbon spirocycles.
Formation of the first lactone ring via an asymmetric Brønsted
acid catalyzed desymmetrization of dialkylated diesters is
followed by a second cyclization utilizing a general acid. This
method offers access to new scaffolds that are likely find use in
future applications.
8.
9.
Wu, Z.-X.; Shi, Y.-P.; Yang, L., Org. Lett. 2004, 6, 2313–2316.
Karawajczyk, A.; Giordanetto, F.; Benningshof, J.; Hamza, D.;
Kalliokoski, T.; Pouwer, K.; Morgentin, R.; Nelson, A.; Müller,
G.; Piechot, A.; Tzalis, D., Drug Discovery Today 2015, 20,
1310–1316.
10. Wilent, J. E.; Qabaja, G.; Petersen, K. S., Org. Synth. 2016, 93,
75–87.
11. Wilent, J.; Petersen, K. S., J. Org. Chem. 2014, 79, 2303–2307.
12. Changotra, A.; Sunoj, R. B., Org. Lett. 2016, 18, 3730–3733.
13. Fristad, W. E.; Hershberger, S. S., J. Org. Chem. 1985, 50, 1026–
1031.
Acknowledgments
14. A one pot cyclization of the corresponding diol of 4b was
attempted with 10 mol% TRIP, however only recovered starting
material was obtained.
Financial support is gratefully acknowledged from the
National Institutes of Health (GM116041) and the University of
Asymmetric synthesis of novel spirocycles
via a chiral phosphoric acid catalyzed
desymmetrization
Leave this area blank for abstract info.
Amber M. Kelley, Eni Minerali, Jennifer E. Wilent, Nicholas J. Chambers, Kyla J. Stingley, G. Tyler Wilson,
and Kimberly S. Petersen*
O
O
O
O
O
1. deprotection
TRIP
1. deprotection
2. cyclization
O
n
O
O
O
O
X
2. (R)-
(10 mol%)
n
PG2X
O
n
OPG1
PG2X
readily available
from
di-tert-butyl malonate
Desymmetrization
1st cyclization sets
stereocenter
Enantioenriched spirocycle
2nd cyclization preserves
stereocenter
15. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC 1884802. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
North Carolina at Greensboro. Additionally, we thank Dr.
Franklin J. Moy and Dr. Daniel Todd for assistance with NMR
and mass spectrometry data analysis. All X-ray crystallography
measurements were made in the Molecular Education,
Technology, and Research Innovation Center (METRIC) at NC
State University and we wish to thank Roger Sommer for his
assistance. Research reported in this publication was supported in
part by the National Center for Complementary and Integrative
Health of the National Institutes of Health under award number 5
T32 AT008938. This work was performed in part at the Joint
School of Nanoscience and Nanoengineering, a member of the
Southeastern Nanotechnology Infrastructure Corridor (SENIC)
and National Nanotechnology Coordinated Infrastructure
(NNCI), which is supported by the National Science Foundation
(Grant ECCS-1542174).
deposit@ccdc.cam.ac.Uk).
16. Compound 5b (21 mg, 0.085 mmol) and TsOH (49 mg, 0.25
mmol) in 5.9 mL of a 0.1 M stock solution of 1,2,4,5-tetrachloro-
3-nitrobenzene. See SI for more details.
Graphical Abstract
To create your abstract, type over the instructions in the
template box below.
Fonts or abstract dimensions should not be changed or altered.
Supplementary Material

Formation of novel enantioenriched
spirolactones
Supplementary data for this work can be found online at
https://xxxx. Crystallographic data (excluding structure factors)
for the structures in this paper have been deposited with the

4
Tetrahedron
 Chiral Brønsted acid catalyzed
desymmetrization

New all-carbon scaffolds