Direct catalytic asymmetric synthesis of N-heterocycles from commodity acid chlorides by employing α,β-unsaturated acylammonium salts

Article abstract of DOI:10.1002/anie.201306050

Taming the beast, asymmetrically: Modulation of the reactivity of acid chlorides, using cinchona alkaloid catalysts, results in chiral α,β-unsaturated acylammoniums, which react with nucleophiles enantioselectively to give pyrrolidinones, piperid-2-ones,

Full text of DOI:10.1002/anie.201306050

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DOI: 10.1002/anie.201306050
Organocatalysis
Direct Catalytic Asymmetric Synthesis of N-Heterocycles from
Commodity Acid Chlorides by Employing a,b-Unsaturated
Acylammonium Salts**
Sreekumar Vellalath, Khoi N. Van, and Daniel Romo*
Discovery of reactive intermediates through generic modes of
substrate activation is central to the field of asymmetric
organocatalysis. Methods for generating such intermediates in
a catalytic asymmetric fashion have fueled the design of
a variety of new and, in some cases, practical asymmetric
transformations.[1] Recently, there has been a significant
expansion of the reactions that are catalyzed by chiral tertiary
amines.[2] Several activation modes employed in tertiary
amine catalysis are shown in Scheme 1. Among these reactive
afford diquinanes.[8] Recently the Smith group utilized this
intermediate in enantioselective Michael additions leading to
enol lactones.[9] Based on our interest in developing expedient
routes to pyrrolidinone subunits,[4c] we envisioned that
a suitable Michael donor bearing a pendant amine, for
example a- or b-aminomalonates, could serve as a bis-
nucleophile to undergo an enantioselective nucleophile-
catalyzed Michael/proton transfer/lactamization (NCMPL)
cascade with the a,b-unsaturated acylammonium D. Herein,
we describe the first highly enantioselective version of this
cascade process with commodity acid chlorides using readily
available O-trimethylsilylquinidine (TMSQD), thus leading
to various optically active nitrogen heterocycles. We further
demonstrate the utility and practicality of this organocascade
process by application to a concise, scalable synthesis of a key
pyroglutamic acid intermediate for an FDA-approved drug
and its broader use for the syntheses of piperidinones, enol
lactones, and dihydropyridones.
Pyrrolidinones or g-lactams are frequently encountered
structural subunits in numerous bioactive natural products
and pharmaceuticals (Scheme 2). Examples of bioactive
agents include the nanomolar inhibitor of the proteasome,
salinosporamide A,[10] and the antibacterial and antitumor
agent neooxazolomycin.[11] While clausenamide is used for the
treatment of chronic viral hepatitis,[12] brivaracetam[13] and
rolipram[14] have utility for the treatment of depression and
Scheme 1. Generic modes of activation commonly used in chiral
tertiary amine catalysis.
intermediates, chiral ammonium enolates (A)[3,4] and acylam-
moniums (C)[5] are the most commonly employed, whereas
the conjugated ammonium enolate B[6] was only recently
described. However, an underexplored and versatile inter-
mediate in this category is the chiral, a,b-unsaturated
acylammonium D,[7] which could deliver the ammonium
enolate A, a versatile intermediate previously exploited by
our group for aldol-b-lactonizations[4] upon Michael addition.
The potential of this chiral intermediate was first realized by
Fu and co-workers, wherein a chiral pyridine promoter
delivered a net [3+2] annulation of a silylated indene to
[*] Dr. S. Vellalath, K. N. Van, Prof. Dr. D. Romo
Department of Chemistry, Texas A&M University
P.O. Box 30012, College Station, TX 77842 (USA)
E-mail: romo@tamu.edu
[**] This work was supported by NSF (CHE-1112397) and the Welch
Foundation (A-1280).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306050.
Scheme 2. Examples of pyrrolidinone-bearing and pyrrolidinone-
derived natural products and drugs.
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Table 1: Screening of catalysts and reaction conditions for the NCMPL.
epileptic seizures, respectively. Additionally, baclofen is an
inhibitory neurotransmitter and an antispastic agent.[15] b-
Substituted pyrrolidinone derivatives have been utilized for
the synthesis of pyroglutamic acids[16] and proline deriva-
tives,[17] with the latter used widely in organocatalysis.[1a]
Arguably, a Michael/lactamization process involving a,b-
unsaturated acid chlorides with a-aminomalonates is one of
the most direct methods for the synthesis of pyrrolidinones.
However, to date, only achiral promoters for this reaction
have been utilized leading to racemic adducts.[18] Until
recently, most methods for the enantioselective synthesis of
b-substituted pyrrolidinones were based on chiral starting
materials or stoichiometric reagents.[19] An important
advancement in this area was described by Taylor and
Jacobsen wherein an enantioselective Michael reaction of
an unsaturated acyclic imide was catalyzed by a chiral Lewis
acid.[20] N-heterocyclic carbene (NHC) homoenolates[21] have
also been utilized for the synthesis of pyrrolidinones.
Recently, Scheidt and co-workers reported the coupling of
N-benzoyl hydrazones and unsaturated aldehydes, mediated
by NHC/Lewis acid cooperative catalysis, thus leading to cis-
g-lactams.[22] Rovis and co-workers reported a similar process,
but using a NHC/Brønsted acid combination, for the synthesis
of trans-g-lactams.[23] Given the importance of pyrrolidinone-
containing compounds and catalytic asymmetric routes to
these intermediates,[24] we sought to develop a highly practical
and scalable method for their synthesis from commodity acid
chlorides employing a NCMPL process.
We began our studies of the NCMPL with crotonyl
chloride (1a) as a Michael acceptor and N-benzoyl dimethyl
aminomalonate (2a) as a bis-nucleophilic Michael donor.
LiHMDS was used to form the anion from 2a and several
chiral tertiary amines were screened for in situ generation of
the corresponding chiral unsaturated acylammonium (see D
in Scheme 1). Initial exploration of reaction conditions
revealed the importance of DBU as an acid scavenger and
under these reaction conditions, use of O-trimethylsilylqui-
nine (TMSQN; 4) delivered the pyrrolidinone 3h in 74%
yield and 85% ee (Table 1, entry 1). The absence of DBU or
substitution of DBU with Hꢀnigꢁs base returned only trace
amounts of the desired product (entries 2 and 3). We next
studied the O-benzoylquinine 5 and commercially available
(DHQ)2PHAL (6), however neither showed improvement in
enantioselectivity (entries 4 and 5). Readily available
TMSQD (7) marginally improved the enantioselectivity to
87% ee and delivered 3h in 74% yield (entry 6). Use of chiral
isothiourea catalysts, including BTM (8) and HBTM (9), gave
lower enantioselectivities (entries 7 and 8). We next briefly
studied the effect of nitrogen substituents on the reactivity of
2. The N-Boc aminomalonate 2b furnished the desired
product in only trace amounts (entry 9). However, the use
of the N-tosyl aminomalonate 2c and 7 affored the desired
pyrrolidinone 3a in 73% yield and 93% ee (entry 10). The use
of 5 mol% 7 also provided 3a with the same level of
enantioselectivity (93% ee) and only slightly diminished
yield (65%, entry 11).
Entry[a]
Base
Cat.
R
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
DBU
–
4
4
4
5
6
7
8
9
7
7
7
Bz (2a)
Bz (2a)
Bz (2a)
Bz (2a)
Bz (2a)
Bz (2a)
Bz (2a)
Bz (2a)
Boc (2b)
Ts (2c)
Ts (2c)
74
<5
<5
71
70
74
62
67
<5
73
65
85
n.d.
n.d.
84
85
87
23
40
n.d.
93
93
DIPEA
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
10
11[d]
[a] The reactions were performed with 1 equiv of 2 and 1.5 equiv of 1a
and the latter was added over 5 h.[26] [b] Yields of isolated, purified
product. [c] Determined by HPLC analysis using a chiral stationary
phase; entries 1, 4, 5, and 8 gave enantiomeric pyrrolidinone 3h.
[d] 5 mol% of 7 was employed as catalyst. Boc=tert-butoxycarbonyl,
Bz=benzoyl, DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene, DIPEA=N,N-
Diisopropylethylamine (Hꢀnig’s base), LiHMDS=lithium bis(trime-
thylsilyl)amide, THF=tetrahydrofuran, TMS=trimethylsilyl, Ts=4-tol-
uenesulfonyl.
rated acid chlorides are well tolerated in the reaction and lead
to pyrrolidinone derivatives in 61–88% yield and 85–99% ee
(Table 2). In the case of ethyl fumaroyl chloride (2c)
delivering the pyrrolidinone 3c, the combination of 6 and
Hꢀnigꢁs base provided superior results to those obtained with
7 and DBU, which presumably leads to product racemization.
In the case of the b-aryl acid chlorides 1d–f, the electronic
properties of the arene substituents had little influence on the
enantioselectivity, thus leading to the pyrrolidinones 3d–f
with 93–99% ee. b-Propenyl acid chloride (1g) led to 3g in
80% yield and 93% ee. To demonstrate the practicality of the
process, a gram-scale reaction was performed with 1a and 2a
to afford crystalline 3h in 78% yield and 86% ee.
We also explored b-aminomalonates (10) as bis-nucleo-
philes in the NCMPL to access chiral piperidin-2-ones (11;
Table 2). Following a brief screening of reaction conditions,
N-phenyl-b-aminomalonate (10a) participated in a NCMPL
with 1a to deliver the piperidinone 11a in 65% yield and
87% ee. An electron-deficient N-aryl substitutent (Ar= 4-Br-
C6H4) led to improved enantioselectivity (93% ee) but
a reduced yield (53%) for the piperidinone 11b from 1a,
whereas cinnamoyl chloride (1d) gave 40% yield of the
With the optimized reaction conditions in hand for this
process, we studied several b-substituted acid chlorides and
found that b-aryl, b-alkyl, b-alkenyl, and b-carbonyl unsatu-
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Table 2: NCMPL of acid chlorides with a- and b-aminomalonates.[a–c]
Table 3: Nucleophile-catalyzed, Michael/proton transfer/enol lactoniza-
tion of acid chlorides with dicarbonyl compounds.[a–c]
[a] The reactions were performed with 1 equiv of 12 and 1.5 equiv of
1 with the latter added over 2 h (syringe pump). [b] Yields refer to
purified, isolated product. [c] Enantiomeric excess was determined by
HPLC analysis using a chiral stationary phase. [d] 6 was used as catalyst
[e] The reaction was conducted at 08C. [f] Inset is the ORTEP
representation of the single crystal X-ray structure of 13e; thermal
ellipsoids shown at 50% probability.[26]
[a] Reactions were performed with 1 equiv of 2 or 10 and 1.5 equiv of
1 with the latter added over 5 h (syringe pump). [b] Yields refer to
purified, isolated product. [c] Enantiomeric excess was determined by
HPLC analysis using a chiral stationary phase. [d] This reaction was
performed with 2.0 equiv of 1 and conducted at À108C. [e] 6 and Hꢀnig’s
base were used for this substrate. [f] This reaction was performed with
2.0 equiv of 1 and conducted at À158C. [g] Inset is the ORTEP
representation of the single-crystal X-ray structure of 3h; thermal
ellipsoids shown at 50% probability.[26]
lactone synthesis, with an important feature being the use of
commercially available acid chlorides. A minor alteration to
our original NCMPL procedure[26] resulted in a highly
enantioselective process with 1a and benzyl acetoacetate
(12a) using 4 as the optimal nucleophilic promoter. Under
these reaction conditions, the enol lactone 13a was obtained
in 80% yield and 91% ee on a gram scale. The cascade
process was also applied to allyl acetoacetate (12b) with 1a
and 1d, thus delivering the enol lactones 13b (90% ee) and
13e (97% ee), respectively. Both an aryl-b-ketoester (12c)
and a diketone (12d), participated in this process, thus
providing the enol lactones 13c (90% ee) and 13d (89% ee),
respectively, with 6 as the optimal catalyst for these substrates.
This approach provides a complimentary strategy to that
recently reported by Smith[9] for enol lactone synthesis.
Another class of nitrogen heterocycles that could be
accessed by this cascade process are dihydropyridinones,[29]
and their presence in several drug candidates encouraged us
to apply the NCMPL to these targets. After brief optimiza-
tion,[26] 7 was found to catalyze an enantioselective NCMPL
process between 3,4-difluorocinnamoyl chloride (1h) and the
enamine 14 (Scheme 3). The key to success of this reaction
was the use of a nonpolar solvent and LiCl as an additive,
which had a profound effect on enantioselectivity (see below).
This mild process delivered the dihydropyridinone 15 in 78%
yield and 92% ee. This particular dihydropyridinone was
targeted since it has recently been used in the synthesis of the
a1a adrenergic receptor antagonist 16.[30]
piperidinone 11c in 96% ee. A common problem leading to
reduced yields when employing b-aminomalonates as bis-
nucleophiles was their degradation through a retro-aza
Michael reaction. However, the simplicity of the procedure
and utility of piperidin-2-ones with b-stereogenic centers,
given their stimulant or depressant action on the central
nervous system,[25] make this an attractive and practical
strategy to chiral b-substituted piperidin-2-ones.
Toward expanding the breadth of this strategy for hetero-
cycle synthesis, we explored the use of 1,3-dicarbonyl com-
pounds as bis-nucleophiles to give enol lactones (13; Table 3),
an important structural unit of the neoflavonoid, coumarin,
and iridoide[27] family of natural products. While our studies
were in progress, Smith and co-workers reported a related
strategy to access aryl-substituted enol lactones by employing
aryl-substituted 1,3-dicarbonyl compounds and dimeric b-aryl
acid anhydrides, which are prepared from the corresponding
acids.[9] Furthermore, catalytic enol lactone synthesis has
recently been investigated in some detail and been spurred on
by the development of conjugated acylazolium intermediates,
described independently by the groups of Lupton, Bode, and
Studer.[28] We thus sought to extend the NCMPL to enol
To further demonstrate the synthetic utility and practi-
cality of this cascade process to access useful drug intermedi-
ates, we targeted a gram-scale synthesis of the pyrrolidinone
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Scheme 5. Postulated catalytic cycle for the NCMPL process.
Scheme 3. Formal synthesis of the a1a adrenergic receptor antagonist
16. M.S.=molecular sieves.
A tentative catalytic cycle for the NCMPL process is
shown in Scheme 5. The lithiated enolate 23 first participates
in a conjugate addition to the acylammonium species 22,
derived from reaction of the chiral tertiary amine (NR3) with
the acid chloride 1. Following an intra- or intermolecular
proton transfer,[35] the acylammonium 25 undergoes intra-
molecular lactamization to release the tertiary amine catalyst
NR3. We postulate that this reaction is under kinetic control
given the high degree of enantioselectivity and related
examples of reactions delivering high facial selectivity
through 1,4-asymmetric induction.[36]
To gain some insight into the role of the in situ formed
lithium chloride and the beneficial effect of added LiCl on
enantioselectivity, we conducted the NCMPL with NaHMDS
as the base (Scheme 6). As anticipated, the reaction of 1a and
Scheme 4. Reagents and conditions: a) [Pd2(dba)3]·CHCl3 (10 mol%),
PPh3 (5 mol%), HCOONH4 (2.0 equiv), 908C, CH3CN, 2 h; b) SmI2,
Et3N, H2O/THF (3:1), 238C, 5 min. dba=dibenzylideneacetone.
3i (Scheme 4). We also sought to demonstrate a method for
removal of one of the carbonyl groups, which is required for
the Michael addition process, to afford a soft nucleophile. By
employing 2d and 1e with 7 under standard NCMPL
conditions, a 74% yield of pyrrolidinone 3i, as an incon-
sequential mixture of diastereomers (d.r. 1:1.8), was acheived.
Submitting this adduct to the decarboxylation/protonation
conditions described by Tsuji and co-workers[31] afforded the
N-tosyl-protected pyroglutamic acid 17 in 71% yield (d.r.
16:1). Subsequent removal of the tosyl group with SmI2/H2O/
Et3N[32] afforded the pyroglutamic acid derivative 18 in 80%
yield. The enantioselectivity of the initial Michael addition
could now be determined at this stage to be 99% ee (d.r.
19:1). The ester 18 is a known and versatile advanced
intermediate[33] in the synthesis of the inhibitory neurotrans-
mitter baclofen (19), l-homocysteic acid uptake inhibitor
chlorpheg (20), and the melanocortin-4 receptor (MC4R)
agonist 21.[34]
Scheme 6. NCMPL reactions employing different in situ generated
Lewis acids and proposed transition state arrangements showing
possible role of Lewis acid (Li+) in the NCMPL.
2a afforded 3h with substantially reduced enantioselectivity,
thus providing evidence for the important role played by the
lithium cation in the transition-state arrangement. Based on
our results and previously described computational studies of
ammonium enolates by Lectka and co-workers,[37] we propose
the transition-state arrangement depicted in Scheme 6 for the
NCMPL process leading to pyrrolidinones. Coordination of
both the enolate oxygen atom and the acylammonium
carbonyl oxygen atom to the lithium cation occurs on the
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c) S. J. Miller, G. T. Copeland, N. Papaioannou, T. E. Horst-
mann, E. M. Ruel, J. Am. Chem. Soc. 1998, 120, 1629 – 1630;
d) V. B. Birman, E. W. Uffman, H. Jiang, X. Li, C. J. Kilbane, J.
Am. Chem. Soc. 2004, 126, 12226 – 12227; e) C. Joannesse, C. P.
Johnston, C. Concellꢂn, C. Simal, D. Philp, A. D. Smith, Angew.
Chem. 2009, 121, 9076 – 9080; Angew. Chem. Int. Ed. 2009, 48,
8914 – 8918; For a review, see: f) C. E. Mꢀller, P. R. Schreiner,
Angew. Chem. 2011, 123, 6136 – 6167; Angew. Chem. Int. Ed.
2011, 50, 6012 – 6042.
face of the unsaturated acylammonium opposite to the bulky
OTMS and quinoline groups. This effectively blocks the
Re face of the acylammonium and rationalizes the observed
absolute stereochemistry of the pyrrolidinone products.
In summary, we have developed the first direct catalytic
asymmetric synthesis of pyrrolidinones from commodity acid
chlorides utilizing a,b-unsaturated acylammoniums. Impor-
tantly, formation of these intermediates clearly imparts high
facial selectivity and modulates the reactivity of acid chlor-
ides, thus biasing them toward Michael (1,4) addition versus
acyl (1,2) substitution. The described methodology is opera-
tionally simple, scalable, and can be carried out using
inexpensive and readily available catalysts under mild reac-
tion conditions. We demonstrated the utility of this strategy
by applications to biologically relevant N-heterocycles includ-
ing pyrrolidinones, piperidin-2-ones, and dihydropyridones.
Furthermore, the synthetic utility of this methodology was
demonstrated by a three-step synthesis of a pyroglutamic acid
ester which was previously utilized in the preparation of
bioactive pyroglutamic acid derivatives. Given the ready
availability of unsaturated acid chlorides (Sigma–Aldrich lists
13 and MatrixScientific lists 37 unsaturated acid chlorides)
and the cinchona alkaloid catalysts[4b] used in the NCMPL, we
anticipate further applications of this methodology.
[6] a) P. S. Tiseni, R. Peters, Angew. Chem. 2007, 119, 5419 – 5422;
Angew. Chem. Int. Ed. 2007, 46, 5325 – 5328; b) P. S. Tiseni, R.
Peters, Chem. Eur. J. 2010, 16, 2503 – 2517; c) L.-T. Shen, L.-H.
Sun, S. Ye, J. Am. Chem. Soc. 2011, 133, 15894 – 15897.
[7] For reports of achiral a,b-unsaturated acylammoniums, see:
a) K. Kato, Y. Shizuri, Y. Hirataa, S. Yamamura, Chem.
Commun. 1968, 324 – 325; b) L. R. Reddy, E. J. Corey, Org.
Lett. 2006, 8, 1717 – 1719.
[8] E. Bappert, P. Mꢀller, G. C. Fu, Chem. Commun. 2006, 2604 –
2606.
[9] E. R. T. Robinson, C. Fallan, C. Simal, A. M. Z. Slawin, A. D.
Smith, Chem. Sci. 2013, 4, 2193 – 2200.
[10] T. A. Gulder, B. S. Moore, Angew. Chem. 2010, 122, 9534 – 9556;
Angew. Chem. Int. Ed. 2010, 49, 9346 – 9367.
[11] a) T. Mori, K. Takahashi, M. Kashiwabara, D. Uemura, Tetrahe-
dron Lett. 1985, 26, 1073 – 1076; b) K. Takahashi, M. Kawabata,
D. Uemura, Tetrahedron Lett. 1985, 26, 1077 – 1078.
[12] N. Ning, J. Sun, G. Du, N. Han, J. Zhang, N. Chen, Neurosci. Lett.
2012, 523, 99 – 103.
Received: July 12, 2013
Published online: October 31, 2013
[13] M. A. Rogawski, Br. J. Pharmacol. 2008, 154, 1555 – 1557.
[14] M. Anada, O. Mita, H. Watanabe, S. Kitagaki, S. Hashimoto,
Synlett 1999, 1775 – 1777.
[15] J-M. Becht, O. Meyer, G. Helmchen, Synthesis 2003, 2805 – 2810.
[16] C. Nꢃjera, M. Yus, Tetrahedron: Asymmetry 1999, 10, 2245 –
2303.
[17] P. Haldar, J. K. Ray, Tetrahedron Lett. 2003, 44, 8229 – 8231.
[18] M. Ghosh, G. K. Kar, J. K. Ray, B. G. Chatterjee, Synth.
Commun. 1983, 13, 667 – 675.
[19] a) W. Hartwig, L. Born, J. Org. Chem. 1987, 52, 4352 – 4358; b) J.
Ezquerra, C. Pedregal, I. Merino, J. Florez, J. Barluenga, S.
Garcia-Granda, M. A. Llorca, J. Org. Chem. 1999, 64, 6554 –
6565; c) C. H. Yoon, D. L. Flanigan, B.-D. Chong, K. W. Jung, J.
Org. Chem. 2002, 67, 6582 – 6584; d) M. Oba, N. Nishiyama, K.
Nishiyama, Chem. Commun. 2003, 776 – 777; e) V. A. Solosho-
nok, H. Ueki, R. Tiwari, J. Org. Chem. 2004, 69, 4984 – 4990;
f) M. K. Ghorai, D. P. Tiwari, J. Org. Chem. 2010, 75, 6173 – 6181.
[20] M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2003, 125,
11204 – 11205.
Keywords: enols · heterocycles · natural products ·
organocatalysis · synthetic methods
.
[1] a) S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev.
2007, 107, 5471 – 5569; b) A. G. Doyle, E. N. Jacobsen, Chem.
Rev. 2007, 107, 5713 – 5743; c) D. W. C. MacMillan, Nature 2008,
455, 304 – 308; d) C. Barbas III, Angew. Chem. 2008, 120, 44 – 50;
Angew. Chem. Int. Ed. 2008, 47, 42 – 47; e) A. Grossmann, D.
Enders, Angew. Chem. 2012, 124, 320 – 332; Angew. Chem. Int.
Ed. 2012, 51, 314 – 325.
[2] S. France, D. J. Guerin, S. J. Miller, T. Lectka, Chem. Rev. 2003,
103, 2985 – 3012.
[3] a) D. Borrmann, R. Wegler, Chem. Ber. 1967, 100, 1575 – 1579;
b) H. Wynberg, E. G. H. Staring, J. Am. Chem. Soc. 1982, 104,
166 – 168; c) M. A. Calter, J. Org. Chem. 1996, 61, 8006 – 8007;
d) A. E. Taggi, A. M. Hafez, H. Wack, B. Young, W. J. Drury III,
T. Lectka, J. Am. Chem. Soc. 2000, 122, 7831 – 7832; e) G. S.
Cortez, R. Tennyson, D. Romo, J. Am. Chem. Soc. 2001, 123,
7945 – 7946; f) C. Zhu, X. Shen, S. A. Nelson, J. Am. Chem. Soc.
2004, 126, 5352 – 5353; g) J. E. Wilson, G. C. Fu, Angew. Chem.
2004, 116, 6518 – 6520; Angew. Chem. Int. Ed. 2004, 43, 6358 –
6360; h) D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin,
A. D. Smith, J. Am. Chem. Soc. 2011, 133, 2714 – 2720; For
a review, see: i) M. J. Gaunt, C. C. C. Johansson, Chem. Rev.
2007, 107, 5596 – 5605.
[4] a) C. A. Leverett, V. C. Purohit, D. Romo, Angew. Chem. 2010,
122, 9669 – 9673; Angew. Chem. Int. Ed. 2010, 49, 9479 – 9483;
b) H. Nguyen, S. Oh, S. H. Henry-Riyad, D. Sepulveda, D.
Romo, Org. Synth. 2011, 88, 121 – 137; c) H. Nguyen, G. Ma, T.
Fremgen, T. Gladysheva, D. Romo, J. Org. Chem. 2011, 76, 2 –
12; d) G. Liu, M. E. Shirley, K. N. Van, R. L. McFarlin, D. Romo,
Nat. Chem. 2013, DOI: 10.1038/NCHEM.1788.
[21] a) C. Burstein, F. Glorius, Angew. Chem. 2004, 116, 6331 – 6334;
Angew. Chem. Int. Ed. 2004, 43, 6205 – 6208; b) K. Y. Chow, J. W.
Bode, J. Am. Chem. Soc. 2004, 126, 8126 – 8127; c) A. Chan,
K. A. Scheidt, Org. Lett. 2005, 7, 905 – 908.
[22] D. E. A. Raup, B. Cardinal-David, D. Holte, K. A. Scheidt, Nat.
Chem. 2010, 2, 766 – 771.
[23] X. Zhao, D. A. DiRocco, T. Rovis, J. Am. Chem. Soc. 2011, 133,
12466 – 12469.
[24] a) For metal-catalyzed conjugate addition of boronic acids to
a,b-unsaturated g-lactams, see: C. Shao, H.-J. Yu, N.-Y. Wu, P.
Tian, R. Wang, C.-G. Feng, G.-Q. Lin, Org. Lett. 2011, 13, 788 –
791; b) for intramolecular cyclizations, see: W. Xu, A. Kong, X.
Lu, J. Org. Chem. 2006, 71, 3854 – 3858; c) X. Bantreil, G.
Prestat, A. Moreno, D. Madec, P. Fristrup, P.-O. Norrby, P. S.
Pregosin, G. Poli, Chem. Eur. J. 2011, 17, 2885 – 2896; d) N.
Armanino, E. M. Carreira, J. Am. Chem. Soc. 2013, 135, 6814 –
6817.
[25] L. M. Jackman, R. L. Webb, H. C. Yick, J. Org. Chem. 1982, 47,
1824 – 1831.
[5] a) E. Vedejs, X. Chen, J. Am. Chem. Soc. 1996, 118, 1809 – 1810;
b) J. C. Ruble, G. C. Fu, J. Org. Chem. 1996, 61, 7230 – 7231;
13692 www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 13688 –13693

Angewandte
Chemie
[26] See the Supporting Information for full details. CCDC 927700
(3h) and CCDC 927701 (13e)contain the supplementary crys-
tallographic 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.
[27] a) F. Geu-Flores, N. H. Sherden, V. Courdavault, V. Burla, W. S.
Glenn, C. Wu, E. Nims, Y. Cui, S. E. OꢁConnor, Nature 2012, 492,
138 – 142; b) M. S. Islam, K. Ishigami, H. Watanabe, Tetrahedron
2007, 63, 1074 – 1079; c) T. E. Prisinzano, J. Nat. Prod. 2009, 72,
581 – 587.
[28] a) S. J. Ryan, L. Candish, D. W. Lupton, J. Am. Chem. Soc. 2009,
131, 14176 – 14177; b) J. Mahatthananchai, P. Zheng, J. W. Bode,
J. Am. Chem. Soc. 2010, 132, 8810 – 8812; c) S. De Sarkar, A.
Studer, Angew. Chem. 2010, 122, 9452 – 9455; Angew. Chem. Int.
Ed. 2010, 49, 9266 – 9269; d) Z. Q. Zhu, X.-L. Zheng, N.-F. Jiang,
X. Wan, J.-C. Xiao, Chem. Commun. 2011, 47, 8670 – 8672; e) Z.-
Q. Rong, M.-Q. Jia, S.-L. You, Org. Lett. 2011, 13, 4080 – 4083;
f) F.-G. Sun, L.-H. Sun, S. Ye, Adv. Synth. Catal. 2011, 353, 3134 –
3138.
[30] P. G. Nantermet, J. C. Barrow, H. G. Selnick, C. F. Homnick,
R. M. Freidinger, R. S. L. Chang, S. S. OꢁMalley, D. R. Reiss,
T. P. Broten, R. W. Ransom, D. J. Pettibone, T. Olah, C. Forray,
Bioorg. Med. Chem. Lett. 2000, 10, 1625 – 1628.
[31] J. Tsuji, T. Yamaeawa, Tetrahedron Lett. 1979, 20, 613 – 616.
[32] T. Ankner, G. Hilmersson, Org. Lett. 2009, 11, 503 – 506.
[33] a) M.-Y. Chang, P.-P. Sun, S.-T. Chena, N.-C. Chang, Tetrahedron
Lett. 2003, 44, 5271 – 5273; b) M. Oba, T. Saegusa, N. Nishiyama,
K. Nishiyama, Tetrahedron Lett. 2009, 65, 128 – 133.
[34] J. A. Tran, F. C. Tucci, M. Arellano, W. Jiang, C. W. Chen, D.
Marinkovic, B. A. Fleck, J. Wen, A. C. Foster, C. Chen, Bioorg.
Med. Chem. Lett. 2008, 18, 1931 – 1938.
[35] Use of a perdeuterated bis-nucleophile did not lead to significant
deuterium incorporation of the intermediate ammonium enolate
24, thus suggesting that the proton transfer is not exclusively
intramolecular.
[36] S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701 – 1716.
[37] a) S. France, H. Wack, A. E. Taggi, A. M. Hafez, T. R. Wagerle,
M. H. Shah, C. L. Dusich, T. Lectka, J. Am. Chem. Soc. 2004,
126, 4245 – 4255; b) C. Dogo-Isonagie, T. Bekele, S. France, J.
Wolfer, A. Weatherwax, A. E. Taggi, D. H. Paull, T. Dudding, T.
Lectka, Eur. J. Org. Chem. 2007, 1091 – 1100.
[29] a) B. Wanner, J. Mahatthananchai, J. W. Bode, Org. Lett. 2011,
13, 5378 – 5381; b) S. R. Yetra, A. Bhunia, A. Patra, M. V. Mane,
K. Vanka, A. T. Biju, Adv. Synth. Catal. 2013, 355, 1089 – 1097.
Angew. Chem. Int. Ed. 2013, 52, 13688 –13693
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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