Stereospecific Overman Rearrangement of Substituted Cyclic Vinyl Bromides: Access to Fully Substituted α-Amino Ketones

Article abstract of DOI:10.1021/acs.orglett.9b03347

A versatile thermal Overman rearrangement of enantioenriched, cyclic allylic alcohols providing tertiary allylic amines has been developed. The vinyl bromide used to control enantioselectivity in a preceding CBS reduction is utilized as a synthetic handle

Full text of DOI:10.1021/acs.orglett.9b03347

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereospecific Overman Rearrangement of Substituted Cyclic Vinyl
Bromides: Access to Fully Substituted α‑Amino Ketones
†
́
Alvaro Velasco-Rubio, Eric J. Alexy, Makoto Yoritate, Austin C. Wright, and Brian M. Stoltz*
Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: A versatile thermal Overman rearrangement of
enantioenriched, cyclic allylic alcohols providing tertiary allylic
amines has been developed. The vinyl bromide used to control
enantioselectivity in a preceding CBS reduction is utilized as a
synthetic handle for the preparation of tertiary α-amino
ketones and related derivatives in an asymmetric fashion.
he synthesis of amine-containing stereocenters has been
researched extensively owing to the presence of this
Scheme 1. Synthetic Strategies toward α-Amino Ketones
T
moiety in a number of bioactive and synthetically useful
molecules (Figure 1).1 Despite this interest, the preparation of
Figure 1. Representative structures containing fully substituted amino
stereocenters.
this motif in some situations remains a challenge, particularly
with respect to enantioenriched fully substituted α-amino
ketones.2 Many of the reported asymmetric strategies toward
this specific motif rely on the functionalization of enolates with
electrophilic amine sources, primarily nitroso3 and azodicar-
boxylates4 derivatives (Scheme 1). Recently, however, other
unique strategies have arisen such as aza-Rubottom type
reactions5 or those based on nucleophilic amine sources.6
In continuation of these studies, the development of new
strategies would allow for more varied methods to build this
important structural motif. Given our interest in fully
substituted stereocenters,7 we sought to employ a strategy
that would specifically allow the synthesis of tertiary amine
stereocenters in an asymmetric fashion. Sigmatropic rearrange-
ments have proven to be among the most reliable methods for
forming hindered stereocenters, with the ability to transfer
starting asymmetry to the product in a stereospecific manner.
Thus, we decided to target the use of an Overman
rearrangement8 of enantioenriched, substituted allylic alcohols
bearing functionality that would ultimately allow the synthesis
of an α-amino ketone. The asymmetric aspect of this overall
transformation is therefore simplified to the preparation of an
enantioenriched allylic alcohol, for which there are numerous
reliable preparative procedures. Notably, a related strategy was
recently reported by researchers from Janssen for the synthesis
of esketamine via a cyanate sigmatropic rearrangement utilizing
an asymmetric transfer hydrogenation to provide the requisite
enantioenriched allylic alcohol.9
To begin we first investigated different strategies toward the
synthesis of chiral, enantioenriched allylic alcohols. Ultimately,
the Corey−Bakshi−Shibata (CBS) reduction was identified as
ideal for our strategy since it is known to reliably reduce
substituted cyclic enones in high enantioselectivity.10 In
particular, bromo-enones are common substrates for CBS
reductions, with the bromide imparting enhanced facial bias of
Received: September 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03347
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the ketone leading to increased enantioselectivities. Often,
however, the bromide is solely used as a means of obtaining
increasing enantioselectivity and is subsequently removed via a
debromination step following the reduction. In this case, we
wondered whether the vinyl bromide functionality could
instead be further utilized as a synthetic handle toward the
synthesis of additional chiral amine building blocks, in
particular α-amino ketones. We were pleased to find that a
number of β-substituted α-bromo-enones, containing various
aryl and alkyl substituents, could be selectively reduced via the
in situ formation of the CBS catalyst (Scheme 2),11 setting the
stage for the subsequent stereospecific Overman rearrange-
ment.
rearrangement by heating to 130 °C in xylenes with the
addition of a base to prevent material decomposition. A variety
of bases for the rearrangement were examined, with inorganic
bases generally proving to be superior. Potassium carbonate
was identified as the optimal base providing the desired
rearranged product in 45% yield and 97% ee (entry 6).
Unfortunately, attempts to increase the yield above this
point proved to be unsuccessful. Modifying variables such as
solvent/temperature combinations and amine protecting group
afforded suboptimal results. Additionally, differentially sub-
stituted aromatic substituents (e.g., para-fluoro) as well as
other substrates bearing directly connected sp2 functionality
(e.g., vinyl) failed to provide any of the desired product. We
wondered how other substrates might perform in this
transformation and decided to continue forward with
examining a substrate scope (Scheme 3). We were pleased
Scheme 2. Synthesis of Alcohols via CBS Reduction
a
Scheme 3. Reaction Scope of Overman Rearrangement
Our initial interest in this transformation focused on aryl-
substituted systems owing to their prevalence in pharmaceut-
icals (e.g., esketamine). Thus, we chose cyclohexenol 2a as a
standard substrate for examination of the reaction conditions.
While transition-metal catalyzed rearrangements12 were not
successful in our hands, standard thermal conditions affected
the desired transformation (Table 1). Starting from the allylic
alcohol, an intermediate trifluoroacetimidate could be prepared
by treatment with LiHMDS and an imidoyl chloride reagent.
This material could then be carried on crude through the
a
Conditions: 0.2 mmol of 2a, 0.2 mmol of base, 2 mL of solvent.
Yield of isolated product. Determined by chiral SFC.
b
c
to find that the use of alkyl substituents indeed proved to be
more successful. Allyl substituted 3b was obtained in 75% yield
and 95% ee. Small alkyl groups such as ethyl (3c) and methyl
(3d) were also tolerated, furnishing the products in 80% and
95% yield, respectively, both in high enantiopurity. The
rearrangement performed well with phenylethyl groups bearing
various para-substituents leading to products 3e−3h in
moderate 60−75% yield. Lastly, an alkyne was also tolerated
in the transformation (3i), albeit in a diminished 50% yield. In
all cases, minimal to no erosion of allylic alcohol enantiopurity
was observed following the rearrangement.13
With a scope of the rearrangement examined, we next turned
toward derivatizations of the obtained products. Using allyl
substituted 3b as a test substrate, sequential amine
deprotections could be performed (Scheme 4).10 First,
removal of the trifluoroacetate group was realized under
reductive conditions with sodium borohydride providing
substituted aniline 4. Next, oxidative removal of the p-methoxy
phenyl substituent could be affected under standard oxidative
Table 1. Overman Rearrangement Base Screen
b
c
entry
base
yield (%)
ee (%)
1
2
3
4
5
6
DBU
Et3N
NaOAc
NaOH
Li2CO3
K2CO3
15
33
36
40
33
45
96
97
97
96
96
97
a
Conditions: 0.2 mmol of 2a, 0.2 mmol of base, 2 mL of solvent.
b
c
Yield of isolated product. Determined by chiral SFC.
B
DOI: 10.1021/acs.orglett.9b03347
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Sequential Removal of Amine Protecting Groups
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03347.
Experimental procedures and characterization data
(PDF)
conditions, furnishing the desired tertiary amine 5 as its
hydrochloride salt, following treatment with HCl in ether.
Next, our original strategy of targeting fully substituted α-
amino ketones was realized upon exposure of vinyl bromide 3e
to a variety of conditions (Scheme 5). Treatment with
Accession Codes
CCDC 1955048 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
a
Scheme 5. Derivatization of Rearrangement Product
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: stoltz@caltech.edu.
ORCID
Brian M. Stoltz: 0000-0001-9837-1528
Present Address
†Graduate School of Pharmaceutical Science, Kyushu Uni-
versity, Maidashi Higashi-ku, Fukuoka 812-8582, Japan.
Notes
a
Conditions: (a) Co(acac)2 (1 equiv), Et3SiH (5 equiv), O2 (1 atm),
i-PrOH, 50 °C, 2 h, 75% yield. (b) O3, pyridine (2.5 equiv), CH2Cl2,
−78 to 25 °C, 85% yield. (c) O3, MeOH, then DMS, −78 to 25 °C,
80% yield. (d) RuCl3 (2 mol %), NaIO4, MeCN/EtOAc/H2O, 25 °C,
16 h, 60% yield.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NIH-NIGMS (R01GM080269) and Caltech for
financial support. A.V.-R. thanks Xunta de Galicia for a
predoctoral fellowship (ED481A-2018/34, 2018-2021). E.J.A.
thanks the National Science Foundation for a predoctoral
fellowship. We thank Dr. David VanderVelde (Caltech) for
NMR expertise. Larry Henling (Caltech) and Dr. Michael
Takase (Caltech) are thanked for X-ray crystallographic
structure determination. Dr. Scott Virgil (Caltech) is thanked
for instrumentation and SFC assistance.
Co(acac)2 and Et3SiH under an atmosphere of oxygen affords
the corresponding ketone 6 in 75% yield.14 This trans-
formation is proposed to occur via a Mukaiyama hydration
followed by loss of bromide. Surprisingly, during attempts to
oxidatively cleave the vinyl bromide under ozonolysis
conditions in CH2Cl2 with pyridine, cyclic α-hydroxy ketone
7 was obtained instead as a single diastereomer in 85% yield,
potentially via the intermediacy of an epoxide.15 This
compound is particularly interesting as this substituent pattern
mirrors that which is believed to be the active human
metabolite of esketamine (hydroxynorketamine) that is
essential for the parent molecule’s antidepressant activity.16
When the ozonolysis is performed in methanol, with a
dimethylsulfide quench, the α-hydroxy ketone is again
obtained; however, in this case concomitant removal of the
trifluoroacetate protecting group occurs providing ketone 8 in
80% yield. The identity and stereochemistry of ketone 8 was
confirmed by X-ray diffraction (see Supporting Information for
details). Lastly, treatment with RuCl3 and sodium periodate
interestingly affords the α-bromoketone 9 as a single
diastereomer. We were pleased to find that these experiments
validate our original hypothesis that the vinyl bromide handle
could lead to a variety of α-amino ketone derivatives through
relatively straightforward transformations.
DEDICATION
■
This manuscript is dedicated to Professor Larry E. Overman
(UC Irvine) for being an inspirational force in organic
synthetic chemistry.
REFERENCES
■
(1) (a) Nugent, T. C., Ed. Chiral Amine Synthesis: Methods,
Developments and Applications; Wiley-VCH: Weinheim, Germany,
2010. (b) Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292−4300.
(c) Klingler, F. D. Acc. Chem. Res. 2007, 40, 1367−1376. (d) Clayden,
J.; Donnard, M.; Lefranc, J.; Tetlow, D. J. Chem. Commun. 2011, 47,
4624−4639. (e) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Chem. Rev. 2011,
̈
111, 1713−1760. (f) Kohls, H.; Steffen-Munsberg, F.; Hohne, M.
Curr. Opin. Chem. Biol. 2014, 19, 180−192.
(2) (a) Vilaivan, T.; Bhanthumnavin, W. Molecules 2010, 15, 917−
958. (b) Smith, A. M. R.; Hii, K. K. Chem. Rev. 2011, 111, 1637−
1656. (c) Zhou, F.; Liao, F.-M.; Yu, J.-S.; Zhou, J. Synthesis 2014, 46,
2983−3003. (d) de la Torre, A.; Tona, V.; Maulide, N. Angew. Chem.,
Int. Ed. 2017, 56, 12416−12423. (e) Kumar, P.; Sharma, B. M. Synlett
2018, 29, 1944−1956.
(3) (a) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125,
6038−6039. (b) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc.
2004, 126, 5360−5361. (c) Kano, T.; Ueda, M.; Takai, J.; Maruoka,
K. J. Am. Chem. Soc. 2006, 128, 6046−6047. (d) Sandoval, D.; Frazier,
In summary, we have developed a versatile asymmetric
method for the synthesis of fully substituted allylic amines in
good yields and excellent enantioselectivities via the combina-
tion of a CBS reduction and a stereospecific Overman
rearrangement. Subsequent transformations allow the prepara-
tion of stereochemically rich and biologically important α-
amino ketone derivatives bearing multiple reactive sites poised
to undergo further functionalization.
C
DOI: 10.1021/acs.orglett.9b03347
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
C. P.; Bugarin, A.; Alaniz, J. R. J. Am. Chem. Soc. 2012, 134, 18948−
18951.
(4) (a) Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119,
6452−6453. (b) List, B. J. Am. Chem. Soc. 2002, 124, 5656−5657.
(c) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126,
8120−8121. (d) Yang, X.; Toste, F. D. J. Am. Chem. Soc. 2015, 137,
3205−3208. (e) Trost, B. M.; Tracy, J. S.; Saget, T. Chem. Sci. 2018,
9, 2975−2980.
(5) Zhou, Z.; Cheng, Q.; Ku
2242−2246.
̈
rti, L. J. Am. Chem. Soc. 2019, 141,
(6) Miles, D. H.; Guasch, J.; Toste, F. D. J. Am. Chem. Soc. 2015,
137, 7632−7635.
(7) (a) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Acc. Chem. Res.
2015, 48, 740−751. (b) Shockley, S. E.; Hethcox, J. C.; Stoltz, B. M.
Synlett 2018, 29, 2481−2492.
(8) (a) Overman, L. E. Acc. Chem. Res. 1980, 13, 218−224.
(b) Fernandes, R. A.; Kattanguru, P.; Gholap, S. P.; Chaudhari, D. A.
Org. Biomol. Chem. 2017, 15, 2672−2710. (c) Matveenko, M.; Willis,
A. C.; Banwell, M. G. Aust. J. Chem. 2009, 62, 64−68. (d) Boyd, D.
R.; Sharma, N. D.; Kaik, M.; McIntyre, P. B. A.; Stevenson, P. J.;
Allen, C. C. R. Org. Biomol. Chem. 2012, 10, 2774−2779.
(9) (a) Chen, C.-y.; Lu, X. Org. Lett. 2019, 21, 6575−6578. (b) For
another strategy toward ketamine, see: Elhawi, H.; Eini, H.;
Douvdevani, A.; Byk, G. Molecules 2012, 17, 6784−6807.
(10) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551−5553. (b) Corey, E. J.; Helal, C. J. Angew. Chem.,
Int. Ed. 1998, 37, 1986−2012.
̈
(11) Holub, N.; Neidhofer, J.; Blechert, S. Org. Lett. 2005, 7, 1227−
1229.
(12) Fischer, D. F.; Xin, Z.-q.; Peters, R. Angew. Chem., Int. Ed. 2007,
46, 7704−7707.
(13) The use of conjugated olefins/alkynes as well as different amine
substituents results in significantly diminished yields.
(14) Ma, X.; Herzon, S. B. J. Org. Chem. 2016, 81, 8673−8695.
(15) (a) Fisher, T. J.; Dussault, P. H. Tetrahedron 2017, 73, 4233−
4258. (b) Everest, D. J.; Grant, P. K.; Slim, G. C.; Yeo, I. K. L. Aust. J.
Chem. 1988, 41, 1025−1035. (c) Hochstetler, A. R. J. Org. Chem.
1975, 40, 1536−1541.
(16) (a) Zanos, P.; Moaddel, R.; Morris, P. J.; Georgiou, P.; Fischell,
J.; Elmer, G. I.; Alkondon, M.; Yuan, P.; Pribut, H. J.; Singh, N. S.;
Dossou, K. S. S.; Fang, Y.; Huang, X.-P.; Mayo, C. L.; Wainer, I. W.;
Albuquerque, E. X.; Thompson, S. M.; Thomas, C. J.; Zarate, C. A.,
Jr.; Gould, T. D. Nature 2016, 533, 481−486. (b) Morris, P. J.;
Moaddel, R.; Zanos, P.; Moore, C. E.; Gould, T.; Zarate, C. A.;
Thomas, C. J. Org. Lett. 2017, 19, 4572−4575.
D
DOI: 10.1021/acs.orglett.9b03347
Org. Lett. XXXX, XXX, XXX−XXX