An isothiourea-catalyzed asymmetric [2,3]-rearrangement of allylic ammonium ylides

Article abstract of DOI:10.1021/ja500758n

Benzotetramisole promotes the catalytic asymmetric [2,3]-rearrangement of allylic quaternary ammonium salts (either isolated or prepared in situ from p-nitrophenyl bromoacetate and the corresponding allylic amine), generating syn-α-amino acid derivatives with excellent diastereo- and enantioselectivity (up to >95:5 dr; up to >99% ee).

Full text of DOI:10.1021/ja500758n

Communication
pubs.acs.org/JACS
An Isothiourea-Catalyzed Asymmetric [2,3]-Rearrangement of Allylic
Ammonium Ylides
Thomas H. West, David S. B. Daniels, Alexandra M. Z. Slawin, and Andrew D. Smith*
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, U.K.
S
* Supporting Information
Table 1. Optimization of Reaction Conditions
ABSTRACT: Benzotetramisole promotes the catalytic
asymmetric [2,3]-rearrangement of allylic quaternary
ammonium salts (either isolated or prepared in situ from
p-nitrophenyl bromoacetate and the corresponding allylic
amine), generating syn-α-amino acid derivatives with
excellent diastereo- and enantioselectivity (up to >95:5
dr; up to >99% ee).
he [2,3]-rearrangement1 of glycine-derived allylic ammo-
Tnium ylides is widely recognized as a versatile process for
a
bc
,
d
e
entry
LB
additive
T (°C) yield (%)
dr
ee
the synthesis of stereodefined unnatural α-amino acid
derivatives containing multiple stereocenters.2 Current limi-
tations of this process include the difficulty associated with the
generation and isolation of the reactive ammonium salts,3
c
1
2
15
15
15
15
12
12
16
12
−
rt
rt
(83)
68
89:11
93:7
81 (ent)
84 (ent)
89 (ent)
93 (ent)
95
HOBt
HOBt
HOBt
−
3
0 to rt
−20
−20
−20
−20
−20
−20
−20
88
92:8
4
65
91:9
5
61
92:8
Scheme 1. [2,3]-Rearrangements of Allylic Ammonium
Ylides
6
HOBt
HOBt
HOAt
76
>95:5
62:38
90:10
88:12
79:21
99
c
f
7
(33)
49
ND
8
98
96
92
g
g
9
12
HOBt
62
h
h
i
10
12
HOBt
41
a
Reactions performed on 0.24 mmol scale, 20 mol %, unless stated
otherwise. Isolated yield after chromatographic purification of >95:5
dr. Yield in parentheses determined by H NMR in comparison with
internal standard (4-nitrotoluene). Determined by H NMR analysis
of crude material. Determined by chiral HPLC analysis. ND = not
determined. 10 mol %. 5 mol %. 84:16 mixture of diastereoisomers
(isolated).
b
c
1
d
1
e
f
g
h
i
alongside the paucity of catalytic asymmetric methods for
inducing enantiocontrol.4 Recent work by Tambar and Sohelie
has elegantly utilized Pd-catalyzed allylic substitution to
facilitate tandem ammonium ylide generation and [2,3]-
rearrangement, generating racemic anti-configured products 3
with high diastereoselectivity (Scheme 1, eq 1).5 While
asymmetric [2,3]-rearrangements of allylic ammonium ylides
can be induced by chiral auxiliary control as demonstrated by
Sweeney and co-workers,4a Somfai et al. have applied
stoichiometric asymmetric Lewis acids to promote the
enantioselective rearrangement of allylic amines 5 (Scheme 1,
eq 2).4b,6 Within the past 15 years, advances in asymmetric
organocatalysis7 have been applied to asymmetric [3,3]-
sigmatropic rearrangements.8 However, organocatalytic [2,3]-
Received: January 23, 2014
Published: March 3, 2014
© 2014 American Chemical Society
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Journal of the American Chemical Society
Communication
Table 2. Scope of Isolable Ammonium Salts
Table 3. In Situ Generated Ammonium Salts
a
Isolated yield after chromatographic purification of >95:5 dr.
b
c
Determined by chiral HPLC analysis. Determined by 1H NMR
analysis of crude material.
a
Scheme 2. Mechanistically Significant Examples
a
Isolated yield after chromatographic purification of >95:5 dr.
b
c
Determined by chiral HPLC analysis. Determined by 1H NMR
d
e
analysis of crude material. Performed on 9.6 mmol scale. Isolated in
93:7 dr.
sigmatropic rearrangements are an underexplored concept, with
the secondary amine-catalyzed [2,3]-Wittig rearrangement
developed by Gaunt et al. representing the current state-of-
the-art within this area.9 Given our interest in Lewis base
promoted organocatalytic processes,10 in this manuscript we
show that sub-stoichiometric isothioureas11 promote the
asymmetric [2,3]-rearrangement of ylides 10 derived from
isolable or in situ generated allylic ammonium salts 9, forming
stereodefined α-amino acid derivatives 11 with excellent syn-
diastereo- and enantiocontrol (up to >95:5 dr and 99% ee)
(Scheme 1, eq 3).
a
Conditions: (i) 12 (20 mol %), HOBt (20 mol %), iPr2NH (1.4
equiv), MeCN, −20 °C, 24 h; (ii) BnNH2 (5.0 equiv), rt, 24 h.
(Table 1).12,13 Treatment of ammonium salt 13 with
tetramisole·HCl 15 (20 mol%) and iPr2NH at room temper-
ature (rt) led to [2,3]-rearrangement, with subsequent addition
of benzylamine giving amide 14 in 89:11 dr and promising 81%
ee (entry 1).14 Further optimization showed that addition of
HOBt (20 mol%) as a co-catalyst led to improved diastereo-
and enantiocontrol (entry 2).15 Alternative organic bases such
as iPr2NEt or NEt3 could also be used without affecting
Proof of concept studies focused upon asymmetric
isothiourea-promoted [2,3]-rearrangement of pre-formed allylic
ammonium salt 13 bearing an activated p-nitrophenyl ester
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Journal of the American Chemical Society
Communication
Scheme 3. Mechanistic and Stereochemical Proposal
stereocontrol, although N-methylmorpholine gave reduced
diastereocontrol.16 Lowering the reaction temperature to −20
°C gave increased product enantiomeric excess, while catalyst
variation showed that benzotetramisole (BTM) was optimal,
giving 14 in 76% yield, >95:5 dr, and 99% ee (entries 3−7).
The additive HOBt is essential to achieve excellent stereo-
control when using BTM at −20 °C (entries 5 and 6), while
reduced catalyst loadings gave lower, but still acceptable,
asymmetric induction (entries 9 and 10).
With an optimized protocol identified, the scope of this
process was initially examined through sequential variation of
the nucleophile (Table 2). Using ammonium salt 13, N,O-
dimethylhydroxylamine, pyrrolidine, methoxide, or LiAlH4
could be used to generate functionalized amino carbonyl and
alcohol compounds 17−20 in good yields and high dr and ee.
This process is readily scalable, with 1.95 g of amino ester 19
(86% yield, 95:5 dr, 95% ee) generated from 9.6 mmol of salt
13. Various N-substituents encompassing simple and function-
alized piperidines, morpholine and N-Boc-piperazine motifs are
readily accommodated, giving functionalized amino amides
(21−25) in excellent yield, dr, and ee (80−89%, >95:5 dr, and
>99% ee). Variation of the allylic C(3)-aryl substituent within
the salt showed that both electron-donating and -withdrawing
4-substituents are well tolerated (26−28). 2-Substitution of the
aryl ring can also be incorporated, albeit in only modest isolated
yields but high dr and ee (29 and 30).
ee) is observed with an N-allyl rather than a N-cinnamyl unit
(39, Scheme 2, eq 2), indicating an aryl or vinyl unit may be a
structural requirement for high enantioselectivity in this
process.17
While a Brønsted base-catalyzed mechanism cannot be ruled
out at present, the following mechanistic possibilities and
catalytic cycle for this transformation are proposed (Scheme 3).
Dicationic acyl ammonium ion 4118 can be formed through
direct N-acylation of BTM (12) with 40, with deprotonation of
41 with a suitable base forming ylide 42. Alternatively, 42 may
arise from the addition of 12 to ketene 50, formed by formal
elimination of p-nitrophenol from 40.19 [2,3]-Rearrangement of
42 gives acyl isothiouronium 43 that can either be intercepted
by p-nitrophenoxide (46),20 or alternatively with HOBt (44) as
a nucleophilic co-catalyst followed by 46, to give 47 in a second
catalytic cycle as previously described by Rovis et al.15 The
observed syn-diastereoselectivity21 may arise from the rear-
rangement occurring preferentially through an endo-type pre-
transition-state assembly 49. In this array, the carbonyl oxygen
preferentially lies syn to the S atom within the isothiouronium
ion, allowing a stabilizing electrostatic or no to σ*C−S
interaction.22 The stereodirecting phenyl unit adopts a
pseudoaxial position to minimize 1,2-steric interactions, with
rearrangement occurring anti to this substituent. A π-cation
interaction between the allylic C(3)-aryl or styryl substituent
and the acyl isothiouronium ion, previously suggested in other
asymmetric isothiourea-catalyzed processes,22d,23 is proposed as
a necessary requirement for high stereocontrol.
Further studies into the scope of the reaction were limited by
the difficulty in the formation and isolation of certain
ammonium salts. This was circumvented through the develop-
ment of a one-pot protocol composed of in situ formation of
the ammonium salt, followed by direct [2,3]-rearrangement
under isothiourea catalysis (Table 3). Treatment of p-
In summary, we have developed the first catalytic asymmetric
[2,3]-rearrangement of allylic ammonium ylides. Isothiourea
BTM 12 promotes the rearrangement of p-nitrophenyl ester
ammonium salts, producing syn-configured α-amino acid
derivatives with excellent stereocontrol (up to >95:5 dr and
>99% ee). Further investigations into this process are currently
being pursued in our laboratory.
nitrophenyl bromoacetate 7 with excess amine 31 (R1
=
phenyl) followed by rearrangement and addition of benzyl-
amine or NaOMe, gave both 14 and 19 respectively in
comparable yield, ee and dr to rearrangement with of the
isolated ammonium salt 13. Pleasingly, this one-pot process
allows the incorporation of styryl, heteroaryl and alternative aryl
functional groups (32−35), for which isolation of the
corresponding ammonium salts proved difficult in our hands.
Crossover studies with 36 and 37 (Scheme 2, eq 1) indicate
that the allylic transfer process is intramolecular, consistent with
the expected [2,3]-sigmatropic rearrangement.16 Further
mechanistic investigations showed that epimerization or
racemization is not observed upon retreatment of the major
diastereoisomer to the reaction conditions. Probing of the
substrate scope showed that reduced enantioselectivity (56%
ASSOCIATED CONTENT
■
S
* Supporting Information
Complete experimental procedures, X-ray structural data for
29, and spectral and HPLC data for all novel compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
ads10@st-andrews.ac.uk
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Journal of the American Chemical Society
Communication
5031. (d) Chen, S.; Hao, L.; Zhang, Y.; Tiwari, B.; Chi, Y. R. Org. Lett.
2013, 15, 5822−5825.
Notes
The authors declare no competing financial interest.
(13) The tert-butyl ester analogue of 13 was found to be inactive
under the catalytic reaction conditions.
ACKNOWLEDGMENTS
(14) The rearranged p-nitrophenyl ester could be isolated, albeit in
modest yield; see Supporting Information for details.
■
We thank the Royal Society for a URF (A.D.S.), the ERC under
the European Union’s Seventh Framework Programme (FP7/
2007-2013, grant agreement no. 279850) (T.H.W.), and
EPSRC grant No. EP/J018139/1 (D.S.B.D.) for funding. We
also thank the EPSRC UK National Mass Spectrometry Service
Centre at Swansea University.
(15) Rovis has previously demonstrated the use of nucleophilic co-
catalysts to facilitate the turnover of NHC catalysts, see: (a) Vora, H.
U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796−13797. (b) Wheeler,
P.; Vora, H. U.; Rovis, T. Chem. Sci. 2013, 4, 1674−1679.
(16) See Supporting Information for full details.
(17) Further investigation showed that the (Z)-cinnamyl isomer of
13 gave preferentially the syn-diastereoisomer but in reduced ee (dr
87:13, 64% ee).16 This methodology is currently limited to aryl or
styryl substituents at the vinylic position of the substrates.
(18) Dicationic amidines are well characterized, see: Corr, M. J.;
Gibson, K. F.; Kennedy, A. R.; Murphy, J. A. J. Am. Chem. Soc. 2009,
131, 9174−9175.
(19) p-Nitrophenoxide has been shown to rebound in related NHC-
catalyzed processes, see: Kawanaka, Y.; Phillips, E. M.; Scheidt, K. A. J.
Am. Chem. Soc. 2009, 131, 18028−18029.
(20) Ketenes can be generated from p-nitrophenyl esters under basic
conditions, see: (a) Tidwell, T. T. Ketenes, 2nd ed.; John Wiley &
Sons, Inc.: Hoboken, NJ, 2006; pp 76−81. (b) Cho, B. R.; Kim, Y. K.;
Yoon, C.-O. M. J. Am. Chem. Soc. 1997, 119, 691−697. (c) Cho, B. R.;
Jeong, H. C.; Seung, Y. J.; Pyun, S. Y. J. Org. Chem. 2002, 67, 5232−
5238. For examples of cationic ketenes, see: (d) Potts, K. T.; Murphy,
P. M.; Kuehnling, W. R. J. Org. Chem. 1988, 53, 2889−2898.
(e) Rudowska, M.; Wieczorek, R.; Kluczyk, A.; Stefanowicz, P.;
Szewczuk, Z. J. Am. Soc. Mass Spectrom. 2013, 24, 846−856.
(21) Relative configuration of the products determined by
derivatization to known ethyl ester SI-55.16 Doyle, M. P.; Tamblyn,
W. H.; Bagheri, V. J. Org. Chem. 1981, 46, 5094-5102. Absolute
configuration determined by X-ray analysis of 29. CCDC 981436
contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
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