Umpolung Synthesis of 1,3-Amino Alcohols: Stereoselective Addition of 2-Azaallyl Anions to Epoxides

Article abstract of DOI:10.1021/acs.orglett.7b01471

We report the direct preparation of 1,3-amino alcohols that contain up to three contiguous stereogenic centers by the umpolung coupling of imines and epoxides. Nucleophilic 2-azaallyl anions, generated from imines, are stereoselectively added to epoxides to furnish 1,3-amino alcohols after hydrolysis of the product imine. Transformations afford amino alcohols with >98% site selectivity with respect to both reaction partners and in up to >98% yield and >20:1 dr.

Full text of DOI:10.1021/acs.orglett.7b01471

Letter
pubs.acs.org/OrgLett
Umpolung Synthesis of 1,3-Amino Alcohols: Stereoselective Addition
of 2‑Azaallyl Anions to Epoxides
Paige E. Daniel, Alexandria E. Weber, and Steven J. Malcolmson*
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
S
* Supporting Information
ABSTRACT: We report the direct preparation of 1,3-amino alcohols that contain up to three contiguous stereogenic centers by
the umpolung coupling of imines and epoxides. Nucleophilic 2-azaallyl anions, generated from imines, are stereoselectively added
to epoxides to furnish 1,3-amino alcohols after hydrolysis of the product imine. Transformations afford amino alcohols with
>98% site selectivity with respect to both reaction partners and in up to >98% yield and >20:1 dr.
Scheme 1. Stereoselective Methods to 1,3-Amino Alcohols
mino alcohols are common motifs in a large number of
1
Anaturallyoccurringmoleculesandmedicinalcompounds. In
contrast to the numerous methods for stereoselective preparation
of1,2-amino alcohols,2 there are fewer means of accessing the 1,3-
congeners,3 particularly those containing a stereotriad within the
three-carbon unit. Commonly, the Mannichreaction,4 employing
anelectrophilicimine(Scheme1),hasbeenutilizedtoprepare1,3-
amino alcohols. This strategy, like several others,5,6 does not
generate the amino alcohol framework directly. Instead, a
subsequent reduction event is required to produce the 1,3-
amino alcohol. Often in preparing a stereotriad by Mannich
chemistry,oneofthesubstituents, R1-R3,isacarbonylorR1 andR2
are linked in a carbocycle. Contrastingly, intramolecular C−H
amination has emerged as an efficient tactic for direct stereo-
selectivepreparationofthismoiety.Whileseveralcatalyticvariants
are known,7 this strategy necessitates preassembly of the
hydrocarbon skeleton, including requisite stereochemistry.8
Rarely do these strategies generate tertiary alcohols.
Our umpolung approach9 employs an intermolecular, stereo-
selective C−C bond-forming reaction that directly generates the
1,3-amino alcohol without further redox manipulation by the
combination of 2-azaallyl anions10−12 with 1,2-disubstituted
epoxides. Exclusive benzylic attack upon the epoxide with
complete inversion of stereochemistry occurs from the N-
substituted carbon nucleophiles at their least hindered α-to-
nitrogenposition,deliveringaminoalcoholswiththreecontiguous
stereogenic centers in up to >98% yield and >20:1 dr. 1,3-Amino
tertiary alcohol products are formed by stereoselective 2-azaallyl
anion addition to the terminal position of 2,2-disubstituted
epoxides.
Benzophenone-derived imine 1a and trans-β-methylstyrene
oxide 3a can be coupled to form amino alcohol 4a as a mixture of
syn-andanti-isomersatthesiteofC−Cbondformation(Table1).
A survey of bases of sufficient strength to deprotonate 1a (pKa =
24.3)13andformtheazaallylanionrevealedthecriticalroleLiplays
inpromotingthedesiredreaction(entries1−6),suggestingthatLi
may also act as a Lewis acid to activate the epoxide for attack.14
Regardless of counterion or conditions, the azaallyl anion reacts
throughitsleastsubstitutednucleophilicposition15 andaddsto3a
exclusively at the benzylic carbon to afford amino alcohol 4a,
favoring the syn-diastereomer.16 Lowering the reaction temper-
ature to −45 °C increases the diastereoselectivity to 6:1 (entry 7),
and increasing to 2 equiv of nucleophile (entry 9) leads to
complete consumption of epoxide in 4 h with amino alcohol 4a
isolated in 79% yield (5.5:1 dr).
Both imine tautomers, 1a and 2a (Table 1), lead to the same
resonance stabilized azaallyl anion, enabling whichever isomer is
more easily accessed to be employed in forming 1,3-amino
alcohols. Subjection of aldimine 2a to the standard deprotonation
conditions (2.0 equiv LiHMDS), however, does not generate the
Received: May 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01471
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Evaluation of Reaction Conditions
Table 2. Azaallyl Anion Addition to trans-1,2-Disubstituted
Epoxides
a
c
temp (°C);
time (h)
dr syn:anti
c
b
temp (°C);
dr
entry imine
base
conv (%)
4a
b
entry
product Ar; R
time (h)
yield(%)
94
syn:anti
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
LiHMDS
NaHMDS
KHMDS
LiHMDS
NaHMDS
KHMDS
LiHMDS
LiHMDS
LiHMDS
LDA
0; 4
>98
66
3.5:1
3.0:1
2.5:1
4.0:1
3.5:1
−
6.0:1
6.5:1
5.5:1
5.5:1
1
4-OMeC6H4; Me (4b)
4-CF3C6H4; Me (4c)
4-CNC6H4; Me (4d)
4-BrC6H4; Me (4e)
3-MeC6H4; Me (4f)
3-BrC6H4; Me (4g)
2-MeC6H4; Me (4h)
2-BrC6H4; Me (4i)
Ph; n-Bu (4j)
−45; 4
9.0:1
0; 4
d
2
−78; 24
−78; 24
−78; 48
−60; 24
−60; 27
−45; 48
−45; 24
−60; 24
−45; 24
−45; 48
73
16.0:1
>20:1
14.5:1
11.0:1
8.0:1
0; 4
13
3
>98
−20; 3.5
−20; 3.5
−20; 3.5
−45; 4
−60; 24
−45; 4
−45; 4
87
d
4
77
19
5
67
81
78
<2
6
65
7
9.5:1
47
d
8
73
7.0:1
d
e
e
>98 (79)
>98 (74)
9
57
92
43
7.0:1
d
10
10
11
12
Ph; CH2OTBS (4k)
Ph; i-Pr (4l)
13.5:1
>20:1
16.5:1
a
Reactions run with 0.1 mmol of imine; see the Supporting
b
Information (SI) for experimental details. Based on consumption
of 3a as determined by 500 MHz 1H NMR spectroscopy of the
unpurified mixture in comparison with an internal standard.
d
Ph; Ph (4m)
−60; 24
b
67
a
See the SI for experimental details. Isolated yields of diastereomeric
c
c
1
mixtures after purification unless otherwise noted. Diastereomeric
Determined by 500 MHz H NMR spectroscopy of the unpurified
ratio determined by 500 MHz 1H NMR spectroscopy of the unpurified
d
mixture. Reaction with 2.0 equiv of imine and 4.0 equiv of base.
d
e
mixture. Isolated yield of the major diastereomer.
Isolated yield of the diastereomeric mixture after purification.
Scheme 2. Nucleophile Variation in Azaallyl Anion Couplings
with Epoxide 3d
azaallyl anion even with extended reaction times; instead, the
stronger LDA is needed (2:1 LDA:2a, 10 min at 22 °C, entry 10).
Azaallyl anion addition under the established conditions then
delivers 4a in 74% yield and 5.5:1 dr.
a b c
, ,
A number of trans-1,2-disubstituted epoxides, several of which
are easily prepared in enantioenriched form,17 readily react with
the azaallyl anion formed from imine 1a (Table 2), providing a
convenient two-step protocol for accessing enantioenriched 1,3-
amino alcohols. Reaction of electron-rich p-methoxyphenyl/
methylepoxide3bfurnishesaminoalcohol4bin94%yieldand9:1
dr(entry1),andelectron-withdrawinggroupsinthepara-position
permit higher diastereoselectivity to be achieved at lower reaction
temperature(4c−eformedin14.5to>20:1dr,entries2−4).Meta-
andortho-substitutionofaromaticringswithintheelectrophileare
alsotolerated;aminoalcohols4f−iaregeneratedin67−80%yield
and 7−11:1 dr (entries 5−8). Variation of the epoxide’s alkyl
substituent reveals that heteroatoms and branching within the
alkylchainareamenabletoazaallylanionaddition(entries9−11).
Forexample,silylether4k,bearingdifferentiatedhydroxylgroups,
isformedin92%yieldand13.5:1dr.Althoughslowertoreact,i-Pr-
substituted epoxide 3l delivers amino alcohol 4l in >20:1 dr. In
addition to aryl/alkyl-substituted epoxides, trans-stilbene oxide
can be coupled to form amino alcohol 4m in 67% yield with high
diastereoselectivity (16.5:1 dr). In all cases, the product is
generated with >98% site selectivity with respect to both the
nucleophile and epoxide.
a
b
See the SI for experimental details. Isolated yields of diastereomeric
c
mixtures after purification unless otherwise noted. Diastereomeric
ratio determined by 500 MHz 1H NMR spectroscopy of the unpurified
d
e
f
mixture. From ketimine isomer 1. Reaction at −78 °C. Reaction at
g
h
i
−60 °C. From aldimine isomer 2b. Reaction for 48 h. LiHMDS
added to a −45 °C solution of ketimine 1f or 1g and epoxide 3d. Ar =
4-CNC6H4.
Several azaallyl anions, including those with aryl, heteroaryl,
vinyl, and alkynyl substituents, are excellent partners for
transformations with trans-disubstituted epoxide 3d (Scheme
2).18 As with the parent nucleophile, the presence of para-
substituentsonthearomaticringoftheazaallylanionleadstohigh
diastereoselectivity in forming amino alcohols 4n−o (16.5:1 and
>20:1dr, respectively). Aryl-substituted nucleophiles withgroups
at the meta- or ortho-positions add efficiently to generate 4p−q in
86−91%yield.Apyridyl-containingazaallylanionfurnishesamino
alcohol4r(94%yield,3.5:1dr),whichyieldedcrystalsofthemajor
diastereomer, illustrating the product’s stereochemical composi-
tion.16 This latter azaallyl anion was generated efficiently from
aldimine 2b by deprotonation with LiHMDS although these
conditions(10minat22°C)havebeenunsuccessfulwithallother
aldimines tested, indicating that pyridine coordination to the Li
may facilitate deprotonation.
B
DOI: 10.1021/acs.orglett.7b01471
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ab c
, ,
Scheme 3. Coupling with cis-Disubstituted Epoxides
Scheme 4. 1,3-Amino Tertiary Alcohol Synthesis via Azaallyl
Anion/2,2-Disubstituted Epoxide Coupling
a b c d
, , ,
a
b
See the SI for experimental details. Isolated yields of diastereomeric
c
mixtures after purification unless otherwise noted. Diastereomeric
ratio determined by 500 MHz 1H NMR spectroscopy of the unpurified
d
mixture. Isolated yield of the major diastereomer.
a
b
See the SI for experimental details. Isolated yields of diastereomeric
c
Incomparisontothetrans-epoxidesexamined,cis-disubstituted
epoxides are considerably less reactive, requiring 24 h at room
temperature to furnish amino alcohols (Scheme 3). The higher
temperature likely contributes to lower stereoselectivity.16
Benzylicattackbyazaallylanionsuponterminalaryl-substituted
epoxides deliver primary alcohols with good diastereocontrol
(e.g., 8 formed in 5:1 dr, eq 1). In contrast, terminal alkyl-
substituted epoxides unsurprisingly react at their less hindered
position, furnishing secondary alcohols (e.g., 9 formed in 71%
yield, eq 2).
mixtures after purification unless otherwise noted. Diastereomeric
ratio determined by 500 MHz 1H NMR spectroscopy of the unpurified
d
e
mixture. Isolated yield of the major diastereomer. Reaction for 19 h.
f
Calculated yield of product from a mixture that contains ca. 30 mol %
g
1a. Reaction at −20 °C.
Scheme 5. Representative Functionalization of 1,3-Amino
Alcohol Products
2-Azaallyl anion additions to chiral epoxides provide opera-
tionally simple, expedient, and redox-economic means to prepare
complex and difficult-to-access 1,3-amino alcohols efficiently and
stereoselectively from readily accessible starting materials. The
wealth of existing methods that afford epoxides enantioselec-
tively17 furtherenhancestheimpactofthesetransformations. The
development of other stereoselective methods with azaallyl
reagents is underway.
The efficiency by which terminal alkyl-substituted epoxides
undergo azaallyl anion addition inspired us to examine stereo-
selective reactions with 2,2-disubstituted epoxides for the direct
formation of 1,3-amino tertiary alcohols (Scheme 4).19 The
combination of 1a with α-methylstyrene oxide affords tertiary
alcohol 11a in 4:1 dr with the major diastereomer isolated in 61%
yield. The alkyl chain of the epoxide may be extended (11b16, in
>98% yield) or may contain a silyl ether as a further synthetic
handle (11c, in 89% yield). Cyclohexyl/methyl-substituted
epoxide 10d furnishes amino alcohol 11d in 95% yield.
ASSOCIATED CONTENT
■
S
* Supporting Information
Azaallylanionadditionstoepoxidesmaybeperformedongram-
scale(1.0g4dpreparedin91%yield,Scheme5),andtheproduct’s
imine hydrolyzed under mildly acidic conditions to generate the
free amine 12 (90% yield).20 The amino alcohols that are formed
may serve as platforms for accessing complex and desirable
molecular scaffolds, including N-heterocycles. N-tosylation of
amine 12 followed by subjection to Mitsunobu conditions
furnishes azetidine 13 in 81% yield over two steps. The
stereocontrolled synthesis of such highly substituted azetidines
has rarely been accomplished.21
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b01471.
Crystal structure data (CIF, CIF, CIF)
Experimental procedures, analytical data for new com-
pounds, spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: steven.malcolmson@duke.edu.
C
DOI: 10.1021/acs.orglett.7b01471
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(10)(a)Ding,C.Z.TetrahedronLett.1996,37,945.(b)Chen,Y.-J.;Seki,
K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2010, 132, 3244. (c) Li,
M.; Yucel, B.; Adrio, J.; Bellomo, A.; Walsh, P. J. Chem. Sci. 2014, 5, 2383.
(d) Zhu, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, 4500. (e) Li, M.;
Berritt, S.; Walsh, P. J. Org. Lett. 2014, 16, 4312. (f) Matsumoto, M.;
Harada, M.; Yamashita, Y.; Kobayashi, S. Chem. Commun. 2014, 50,
Steven J. Malcolmson: 0000-0003-3229-0949
Notes
̈
The authors declare no competing financial interest.
13041.(g)Fernan
6, 4973. (h) Wu, Y.; Hu, L.; Li, Z.; Deng, L. Nature 2015, 523, 445. (i) Li,
M.;Yucel, B.;Jimenez, J.;Rotella, M.;Fu,Y.;Walsh,P.J.Adv. Synth.Catal.
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ACKNOWLEDGMENTS
■
́
We acknowledge Kangnan Li, Hope Knochenhauer, and Jason
Luo for experimental assistance and helpful discussions and Dr.
RogerSommer(NCState)forX-raycrystallographicanalysis. We
thank the ACS Petroleum Research Fund (56575-DNI1) and
Duke University for generous financial support. P.E.D. is grateful
to the Department of Education for a GAANN fellowship
(P200A150114).
́
Gutierrez, O.; Berritt, S.; Pascual-Escudero, A.; Yesi̧ lcimen, A.; Yang, X.;
Adrio, J.; Huang, G.; Nakamaru-Ogiso, E.; Kozlowski, M. C.; Walsh, P. J.
Nat. Chem., DOI: 10.1038/nchem.2760.
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DOI: 10.1021/acs.orglett.7b01471
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