Stereochemistry and reactivity of the HPA-imine Mannich intermediate

Article abstract of DOI:10.1016/j.tetlet.2017.08.070

Homophthalic anhydride (HPA) typically reacts rapidly with benzalimines to afford the formal [4+2] adduct, a 1,2,3,4-tetrahydroisoquinolin-1-one-4-carboxylic acid. The stereochemical outcome of this reaction is consistent with an open transition state com

Full text of DOI:10.1016/j.tetlet.2017.08.070

Accepted Manuscript
Stereochemistry and Reactivity of the HPA-Imine Mannich Intermediate
Daniel Polyak, Ngan Phung, Jian Liu, Robert Barrows, Thomas J. Emge,
Spencer Knapp
PII:
S0040-4039(17)31091-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.070
TETL 49260
Reference:
Tetrahedron Letters
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Revised Date:
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21 July 2017
25 August 2017
28 August 2017
Please cite this article as: Polyak, D., Phung, N., Liu, J., Barrows, R., Emge, T.J., Knapp, S., Stereochemistry and
Reactivity of the HPA-Imine Mannich Intermediate, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.08.070
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Stereochemistry and Reactivity of the HPA-
Imine Mannich Intermediate
Daniel Polyak, Ngan Phung, Jian Liu, Robert Barrows, Thomas J. Emge, and Spencer Knapp

1
Tetrahedron Letters
Stereochemistry and Reactivity of the HPA-Imine Mannich Intermediate
Daniel Polyak, Ngan Phung, Jian Liu, Robert Barrows, Thomas J. Emge, and Spencer Knapp
Department of Chemistry and Chemical Biology, Rutgers – The State University of New Jersey, 610 Taylor Rd., Piscataway, NJ 08854, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Homophthalic anhydride (HPA) typically reacts rapidly with benzalimines to afford the formal
[4+2] adduct, a 1,2,3,4-tetrahydroisoquinolin-1-one-4-carboxylic acid. The stereochemical
outcome of this reaction is consistent with an open transition state comprising an iminium
species and enolized HPA, leading to a short-lived amino-anhydride intermediate. In the case of
N-tert-butylbenzalimine, this Mannich-type intermediate, which would normally cyclize at low
temperature to a single isomer of the delta-lactam, is intercepted by base treatment to afford
beta-lactam products. A pathway featuring ketene formation followed by ring closure is
implicated.
Available online
Keywords:
carboxylic anhydride
steric hindrance
cycloaddition
2009 Elsevier Ltd. All rights reserved.
1. Introduction
In this paper we analyze the effect of the size of the imine
substituent
R
for insight into THIQ formation and
The reaction of imines with cyclic carboxylic anhydrides
generally,1,2,3 and homophthalic acid (HPA, 1) in particular,4,5 has
become an important method for the efficient assembly of
lactams with useful biological activity. Such compounds have
seen application toward potential anticancer treatments,6,7,8,9 and
include a new group of antimalarials from which a clinical
candidate has recently emerged.10,11,12 Synthetic2,3 and
computational13,14 aspects of the HPA-imine reaction, formally a
[4+2] cycloaddition of the enolized form of HPA (2, Scheme 1),
have been investigated extensively. A wide variety of solvents
and additives have been shown to accommodate or modify the
tranformation, which nonetheless occurs rapidly at modest
temperatures even in the absence of added acid or base
promoters. Under certain conditions, stereoselective, or even
enantioselective,15,16 formation of the 3,4-cis- or 3,4-trans
1,2,3,4-tetrahydroisoquinolin-1-one-4-carboxylic acid product (4,
a “THIQ”) can be achieved, and for most THIQ products
treatment of cis-4 with acid, base, or heat promotes complete
isomerization to the more stable trans-4. While examples of non-
aromatic imines are known,11,17,18,19,20 most investigations have
involved N-substituted benzalimines (3), and these substrates
typically give the highest yields and find the widest application.
Despite earlier considerations of alternative mechanisms,2,14,21
more recent analysis of the HPA-imine reaction seems to have
settled on a two-step process centered on Mannich-type amino-
anhydride intermediate 5,3,13,15,22 the stereochemistry of which
translates to the C-3 and C-4 stereocenters of the THIQ product.
Under certain conditions, elimination of amine from 5 to afford a
Knoevenagel-type alkene product 6 has been observed.23 By
addition of the acyl transfer promoter, 1-methylimidazole, the
elimination reaction can be largely avoided, and ring closure to 4
favored.24
stereochemistry in the HPA-imine cyclization. An attempt to trap
amino-anhydride intermediate 5 by base treatment led to
unexpected beta-lactam products.
Scheme 1. The formal cycloaddition of HPA (1) with benzalimines
to afford 1,2,3,4-tetrahydroisoquinolin-1-one-4-carboxylic acids.
2. Results and Discussion
2.1. Mechanistic possibilities for the Mannich step
Organization of the reaction components 2 and 3 by an
intermolecular hydrogen bond13,22 could take place in two
different configurations (Scheme 2). The “boat” configuration (7)
places the aryl group away from the benzo ring, and ought to be
favored for small N-substituents R. Alternatively, a “chair”
configuration (9) places the aryl group closer to the benzo ring,
and ought to be favored by relatively large R. After the Mannich
step and subsequent N-cyclization, the “boat” should lead to the
cis THIQ (8), whereas the “chair” should give the trans (10).

2
Tetrahedron Letters
demanding too high an energy of activation,13 and is not
considered further here.
Scheme 2. Intramolecularly hydrogen bonded transition state
Scheme 4. Iminium Diels-Alder transition state possibilities for
possibilities for the HPA-imine reaction.
the HPA-imine reaction.
Alternatively, an “open” transition state25 can be envisioned
wherein the enolized form of HPA, or, optionally, its enolate
anion, reacts with protonated imine to form the new C-C bond
(see 12 and 14, Scheme 3). At effective reaction pH in the range
~6–9, any or all of these species are accessible, given the
measured pKa of 1 and the typical pKa’s of protonated imines
(Scheme 1). Relatively non-basic imines, however, such as
ArN=CH2CF3 (estimated pKa ~2) would not be expected to be
protonated to any large extent, especially in the presence of
added base.24 Nevertheless, these imines also react readily with 1.
In the “open” formulation, the approach of components shown as
11 would be predicted to lead mostly to the cis THIQ (8), and the
alternative 13 should give mostly trans (10). The former
transition state ought to be favored for large R, which is oriented
away from the benzo ring, and the later transition state favored
for relatively small R.
2.2 The effect of the size of the imine substituent R on the
stereochemistry of the THIQ product
For simple N-alkyl-substituted imines of benzaldehyde,
successful cyclization to THIQs can be achieved in a variety of
solvents at low temperature, even in the absense of additives. We
find that chloroform, dichloromethane, ethyl acetate, and
acetonitrile all work well as solvents, whereas DMF, tert-butyl
methyl ether, and 2-butanol give lower yields. A series of
benzalimines with differing R groups21,26 was screened to
evaluate the effect of the size of R and in some cases, the
stereochemistry of the imine (Table 1). Thus, R was taken
through a series from relatively small Me– (19) through n-Bu–
(21), CF3CH2– (23), and i-Bu– (25), to relatively bulky t-Bu–
(27). Two 3,4-dihydroisoquinolines, 29 and 31, were also
examined. The imines reacted with HPA (1, added last) in
dichloromethane solution at –30 °C over a period of 150 minutes,
after which time the reaction was quenched at low temperature
with aqueous citrate solution. Concentration of the organic
solution allowed assessment of the THIQ isomer ratio, as well as
the apparent combined yield, by H-1 NMR spectroscopic
analysis (2,6-di-tert-butyl-4-methylphenol, BHT, was used as an
internal integration standard). Each of the reactions was also
checked by aliquot after 8 minutes to see whether the cis/trans
ratio changed as a function of time, and the ratios were
essentially the same at the shorter reaction time. For the products
30 and 32, the indicators “cis” and “trans” refer to the relative
stereoechemistry of the ring methines. An early study included
reactions of 19, 25, and 27 with 1, but featured different reaction
conditions, and reported ratios based on crystallized product.21
The imines are assumed to react in the trans configuration,
except for 29 and 31, which are cyclic and forced to be cis. Other
investigators have made the same assumption,13,15 even though an
early report21 suggested
a
possible imine trans-to-cis
Scheme 3. “Open” transition state possibilities for the HPA-imine
isomerization as a preliminary step prior to C-C bond formation.
reaction.
A third transition state possibility that has been considered14,21
for the HPA-imine reaction resembles an intermolecular iminium
Diels-Alder reaction (Scheme 4). The bridged intermediates 16
and 18 could ring-open to provide the respective products 8 and
10 directly, or they could open to the respective Mannich
intermediates 12 and 14, and then re-cyclize to give 8 and 10.
Based on steric considerations alone, transition state 15 ought to
be favored for small R, and lead to the cis THIQ (8), whereas the
alternative transition state (16) would be favored for large R and
lead to the trans THIQ (10).
The observed trend towards more cis product for increasing
size of the N-substituents (Me < n-Bu < i-Bu < t-Bu) is consistent
with an open transition state (Scheme 3), but less so for the
hydrogen-bonded transition state (Scheme 2) or the iminium
Diels-Alder transition state (Scheme 4), both of which predict the
opposite order. For the electron-withdrawing trifluoroethyl N-
substituent (23  24), prior N-protonation of the imine would
not be favored, but the hydrogen-bonded pathway could still be
operative without showing a clear stereochemical preference.22
The cis, cyclic imines 29 and 31 could proceed through the open
transition state of Scheme 3 without showing a strong
stereochemical preference, since steric hindrance is reduced for
both possibilities. Addition of a sub-stoichiometric amount of
A fourth possibility2,21 featuring initial N-acylation of the
imine by HPA at the conjugated C=O has been dismissed as

3
trifluoroacetic acid increased the amount of trans isomer 30
slightly. It should be noted that this reaction generates an acidic
product (4, Scheme 1) as it proceeds, which complicates the
analysis of the presence and reactivity of the resulting iminium
species 3.
hydrolysis product 34 was not observed; only the familiar cis
delta-lactam 28 was isolated.
Quenching the same reaction instead with a more nucleophilic
trapping reagent, namely 5% methanolic sodium hydroxide, led
unexpectedly to a pair of new lactams eventually determined to
be 35 and 36 (4:1, 39% combined yield, Scheme 5). The usual
cyclization product, cis delta-lactam 28, was not formed at all,
according to H-1 NMR analysis of the crude reaction product.
The structure of cis beta-lactam 36 was secured by X-ray
crystallographic analysis (Figure 1) following selective
crystallization from a solution of the crude product in methanol
and then slow evaporation from acetonitrile/toluene. Crystals of
the trans isomer 35 suitable for X-ray studies (Figure 1) were
obtained by crystallization of its N-ethylammonium salt from
methanol solution. The solution structures assigned to 35 and 36
are consistent with their H-1 and C-13 NMR spectra, and mass
spectroscopic analysis. Full experimental details of the reaction
of 27 and 1, the trapping procedure, and the isolation and
characterization of beta-lactams 35 and 36 are given in the
Supplementary Materials section.
Formation of the beta-lactams 35 and 36 from the Mannich
intermediate 33 can be understood by postulating ketene
formation under the influence of basic hydroxide (Scheme 5).
Intramolecular trapping of this ketene (38) by the nearby amino
group would lead to the beta-lactam enolate (39), protonation of
which from either face would then provide the two beta-lactams,
35 and 36. While beta-lactams have been prepared by Staudinger
reaction of ketenes with imines, the intermolecular reaction of
aryl ketenes with benzalimines requires prolonged heating.28,29 In
contrast, formation of 35 and 36 occurs rapidly at –30 °C. This
observation would seem to rule out simple intermolecular
reaction of the ketene derived from the enolate of 1 with 27 under
the influence of base. Direct cyclization of amino anhydride 33 to
the kinetically less favored beta-lactam products rather than the
delta-lactam alternative (28) would be surprising without the
intervention of a high energy intermediate such as ketene 38, and
indeed the latter process (delta-N-cyclization) proceeds at –30 °C
in the absense of hydroxide.
Table 1. THIQ products from the reaction of benzalimines with
HPA. Each reaction was run at –30 °C in dichloromethane solution
for 150 min.
2.3 Trapping of the Mannich intermediate with methanolic
hydroxide and formation of beta-lactam products
Figure 1. ORTEP representations of the trans (35, left) and cis (36,
right) beta-lactams.
The reaction of the bulky N-tert-butylbenzalimine 27 with
HPA (1) is expected to be slower than that of the other imine
substrates, and competition studies21 show that this is indeed the
case. In particular, the reaction pathway might be intercepted at
the stage of the Mannich intermediate (5), since the bulky N-
substituent might slow the N-cyclization step even more than the
Mannich step. An attempt was made to trap the amino-anhydride
intermediate 5 in the reaction of 27 with 1 (acetonitrile solution,
–30 °C, 10 min) by adding the nucleophilic combination
hydrogen peroxide / pyridine.27 However, the amino diacid

4
Tetrahedron Letters
References and notes
1 Castagnoli, N., Jr. J. Org. Chem. 1969, 34, 3187–3189.
2
onz lez- pez, M.; Shaw, J. T. Chem. Rev. 2009, 109, 164–189.
3 Krasavin, M.; Dar’in, D. Tetrahedron Lett. 2016, 57, 1635–1640.
4 Haimova, M. A.; Mollov, N. M.; Ivanova, S. C.; Dimitrova, A. I.;
Ognyanov, V. I. Tetrahedron 1977, 33, 331–336.
5 Cushman, M.; Gentry, J.; Dekow, F. W. J. Org. Chem. 1977, 42, 1111–
1116.
6Ng, P. Y.; Tang, Y.; Knosp, W. M. Stadler, H. S.; Shaw, J. T. Angew. Chem.
Int. Ed. 2007, 46, 5352–5355.
7 Nguyen, T. X.; Abdelmalak, M.; Marchand, C.; Agama, K.; Pommier, Y.;
Cushman, M. J. Med. Chem. 2015, 58, 3188–3208.
8 Cinelli, M. A.; Reddy, P. V. N.; Lv, P.-C.; Liang, J.-H.; Chen, L.; Agama,
K.; Pommier, Y.; van Breemen, R. B.; Cushman, M. J. Med. Chem. 2012,
55. 10844–10862.
9 Chatterjee, M.; Hartung, A.; Holzgrabe, U.; Mueller, E.; Peinz, U.; Sotriffer,
C.; Zilian, D. (Julius-Maximilians-Universität Würzburg, Germany),
WO2015185114A1, p 38.
10 Jiménez-Díaz, M.–B.; Ebert, D.; Salinas, Y.; Pradhan, A.; Lehane, A. M.;
Myrand-Lapierre, M.-E.; O’ oughlin, K. .; Shackleford, D. M.; age de
Almeida, M. J.; Clark, J.; Dennis, A. S. M.; Diep, J.; Deng, X.; Endsley, A.
N.; Fedewa, G.; Guiguemde, A.; Gomez-Lorenzo, M. G.; Holbrook, G.;
Horst, J.; Kim, K., Liu,J., Lee, M. C. S., Matheny, A., Martínez, M. S.,
Miller, G., Rodriguez-Alejandre, A., Sanz, L., Sigal, M.; Spillman, N. J.;
Stein, P. D.; Wang, Z.; Zhu, F.; Waterson, D.; Knapp, S.; Shelat, A. A.;
Fidock, D. A.; Gamo, F. J.; Charman, S. A.; Mirsalis, J. C.; Ma, H.; Ferrer,
S.; Kirk, K.; Angulo-Barturen, I.; Kyle, D. E.; DeRisi, J. L.; Floyd, D. M.;
Guy, R. K. Proc. Nat. Acad. Sci. 2014, 111, E5455–E5462.
11 Floyd, D. M.; Stein, P.; Wang, Z.; Liu, J.; Castro, S.; Clark, J. A.; Connelly,
M.; Zhu, F.; Holbrook, G.; Matheny, A.; Sigal, M. S.; Min, J.; Dhinakaran,
R.; Krishnan, S.; Bashyum, S.; Knapp, S.; Guy, R. K. J. Med. Chem. 2016,
59, 7950–7962.
12 https://clinicaltrials.gov/ct2/show/NCT02867059. Website viewed July 11,
2017.
13 Pattawong, O.; Tan, D. Q.; Fettinger, J. C.; Shaw, J. T.; Cheong, P. H.-Y.
Org. Lett. 2013, 15, 5130–5133.
14 Kaneti, J.; Bakalova, S. M.; Pojarlieff, I. G. J. Org. Chem. 2003, 68, 6824–
6827.
15 Jarvis, C. L.; Hirschi, J. S.; Vetticatt, M. J.; Seidel, D. Angew. Chem. Int.
Ed. 2017, 56, 2670–2674.
16 Cronin, S. A.; Collar, A. G.; Gundala, S.; Cornaggia, C.; Torrente, E.;
Manoni, F.; Botte, A.; Twamley, B.; Connon, S. J. Org. Biomol. Chem.
2016, 14, 6955–6959.
17 Yu, N.; Poulain, R.; Gesquiere, J.-C. Synlett 2000, 355–356.
18 Wang, L.; Liu, J.; Tian, H.; Qian, C.; Sun, J. Adv. Synth. Cat. 2005, 347,
689–694.
19 Vara, Y.; Bello, T.; Aldaba, E.; Arrieta, A.; Pizarro, J. L.; Arriortua, M. I.;
Lopez, X.; Cossio, F. P. Org. Lett. 2008, 10, 4759–4762.
20 Bonnaud, B.; Carlessi, A.; Bigg, D. C. H. J. Heterocycl. Chem. 1993, 30,
257–265.
Scheme 5. Trapping the Mannich intermediate 33 with base, and
formation of beta-lactam products 35 and 36.
21 Cushman, M.; Madaj, E. J. J. Org. Chem. 1987, 52, 907–915.
22 Hong, J.; Wang, Z.; Levin, A.; Emge, T. J.; Floyd, D. M.; Knapp, S.
Tetrahedron Lett. 2015, 56, 3001–3004.
3. Conclusion
23 Kandinska, M. I.; Kozekov, I. D.; Palamareva, M. D. Molecules 2006, 11,
403–414.
An open transition state (Scheme 3) best accommodates the
influence of steric bulk of the N-substituent R on the reaction of
HPA (1) with simple N-substituted benzalimines (3). For less
basic imines like 23, or for reaction conditions in which iminium
formation is less favored, the cyclic hydrogen-bonded transition
states (7 and 9, Scheme 2) may make important contributions.
An unprotonated and non-hydrogen-bonded imine is probably
relatively unreactive in this cycloaddition.
24 Liu, J.; Wang, Z.; Levin, A.; Emge, T. J.; Rablen, P. R.; Floyd, D. M.;
Knapp, S. J. Org. Chem. 2014, 79, 7593–7599.
25 Mahrwald, R. Chem. Rev. 1999, 99, 1095–1120.
26 Di Maso, M. J.; Snyder, K. M.; De Souza Fernandes, F.; Pattawong, O.;
Tan, D. Q.; Fettinger, J. C.; Cheong, P. H.-Y.; Shaw, J. T. Chem. Eur. J.
2016, 22, 4794–4801.
27 Rynard, C. M.; Thankachan, C.; Tidwell, T. T. J. Am. Chem. Soc. 1979,
101, 1196–1201.
28 Coulthard, G.; Unsworth, W. P.; Taylor, R. J. K. Tetrahedron Lett. 2015,
56, 3113–3116.
The intermediate Mannich adduct (33, Scheme 5) was
effectively intercepted by base treatment, leading to beta-lactams
35 and 36. A mechanism that proceeds through the intermediacy
of ketene 38 best accounts for their formation.
29 Wang, Y.; Liang, Y.; Jiao, L.; Du, D.-M.; Xu, J. J. Org. Chem. 2008, 71,
6983–6990.
Supplementary Material
Acknowledgments
Preparative and spectroscopic details for the N-substituent
study (Table 1) and beta-lactams 35 and 36, and CIF data for 35
and 36.
We are grateful to the NIH (AI090662) and Medicines for
Malaria Venture for financial support, and to Rutgers University
for undergraduate research support for D. P. and N. P.

5
13 Pattawong, O.; Tan, D. Q.; Fettinger, J. C.; Shaw,
J. T.; Cheong, P. H.-Y. Org. Lett. 2013, 15, 5130–
5133.
1 Castagnoli, N., Jr. J. Org. Chem. 1969, 34, 3187–
14 Kaneti, J.; Bakalova, S. M.; Pojarlieff, I. G. J.
Org. Chem. 2003, 68, 6824–6827.
3189.
2
onz lez- pez, M.; Shaw, J. T. Chem. Rev.
15 Jarvis, C. L.; Hirschi, J. S.; Vetticatt, M. J.;
Seidel, D. Angew. Chem. Int. Ed. 2017, 56, 2670–
2674.
2009, 109, 164–189.
3 Krasavin, M.; Dar’in, D. Tetrahedron Lett. 2016,
57, 1635–1640.
16 Cronin, S. A.; Collar, A. G.; Gundala, S.;
Cornaggia, C.; Torrente, E.; Manoni, F.; Botte, A.;
Twamley, B.; Connon, S. J. Org. Biomol. Chem.
2016, 14, 6955–6959.
4 Haimova, M. A.; Mollov, N. M.; Ivanova, S. C.;
Dimitrova, A. I.; Ognyanov, V. I. Tetrahedron
1977, 33, 331–336.
5 Cushman, M.; Gentry, J.; Dekow, F. W. J. Org.
Chem. 1977, 42, 1111–1116.
17 Yu, N.; Poulain, R.; Gesquiere, J.-C. Synlett
2000, 355–356.
6 Ng, P. Y.; Tang, Y.; Knosp, W. M. Stadler, H. S.;
Shaw, J. T. Angew. Chem. Int. Ed. 2007, 46, 5352–
5355.
18 Wang, L.; Liu, J.; Tian, H.; Qian, C.; Sun, J. Adv.
Synth. Cat. 2005, 347, 689–694.
19 Vara, Y.; Bello, T.; Aldaba, E.; Arrieta, A.;
Pizarro, J. L.; Arriortua, M. I.; Lopez, X.; Cossio,
F. P. Org. Lett. 2008, 10, 4759–4762.
20 Bonnaud, B.; Carlessi, A.; Bigg, D. C. H. J.
Heterocycl. Chem. 1993, 30, 257–265.
21 Cushman, M.; Madaj, E. J. J. Org. Chem. 1987,
52, 907–915.
7 Nguyen, T. X.; Abdelmalak, M.; Marchand, C.;
Agama, K.; Pommier, Y.; Cushman, M. J. Med.
Chem. 2015, 58, 3188–3208.
8 Cinelli, M. A.; Reddy, P. V. N.; Lv, P.-C.; Liang,
J.-H.; Chen, L.; Agama, K.; Pommier, Y.; van
Breemen, R. B.; Cushman, M. J. Med. Chem. 2012,
55, 10844–10862.
22 Hong, J.; Wang, Z.; Levin, A.; Emge, T. J.;
Floyd, D. M.; Knapp, S. Tetrahedron Lett. 2015,
56, 3001–3004.
9 Chatterjee, M.; Hartung, A.; Holzgrabe, U.;
Mueller, E.; Peinz, U.; Sotriffer, C.; Zilian, D.
(Julius-Maximilians-Universität Würzburg,
Germany), WO2015185114A1, p 38.
23 Kandinska, M. I.; Kozekov, I. D.; Palamareva,
M. D. Molecules 2006, 11, 403–414.
24 Liu, J.; Wang, Z.; Levin, A.; Emge, T. J.; Rablen,
P. R.; Floyd, D. M.; Knapp, S. J. Org. Chem. 2014,
79, 7593–7599.
10 Jiménez-Díaz, M.–B.; Ebert, D.; Salinas, Y.;
Pradhan, A.; Lehane, A. M.; Myrand-Lapierre, M.-
E.; O’ oughlin, K. .; Shackleford, D. M.; age de
Almeida, M. J.; Clark, J.; Dennis, A. S. M.; Diep,
J.; Deng, X.; Endsley, A. N.; Fedewa, G.;
Guiguemde, A.; Gomez-Lorenzo, M. G.; Holbrook,
G.; Horst, J.; Kim, K., Liu,J., Lee, M. C. S.,
Matheny, A., Martínez, M. S., Miller, G.,
Rodriguez-Alejandre, A., Sanz, L., Sigal, M.;
Spillman, N. J.; Stein, P. D.; Wang, Z.; Zhu, F.;
Waterson, D.; Knapp, S.; Shelat, A. A.; Fidock, D.
A.; Gamo, F. J.; Charman, S. A.; Mirsalis, J. C.;
Ma, H.; Ferrer, S.; Kirk, K.; Angulo-Barturen, I.;
Kyle, D. E.; DeRisi, J. L.; Floyd, D. M.; Guy, R. K.
Proc. Nat. Acad. Sci. 2014, 111, E5455–E5462.
11 Floyd, D. M.; Stein, P.; Wang, Z.; Liu, J.; Castro,
S.; Clark, J. A.; Connelly, M.; Zhu, F.; Holbrook,
G.; Matheny, A.; Sigal, M. S.; Min, J.; Dhinakaran,
R.; Krishnan, S.; Bashyum, S.; Knapp, S.; Guy, R.
K. J. Med. Chem. 2016, 59, 7950–7962.
12 https://clinicaltrials.gov/ct2/show/NCT02867059.
Website viewed July 5, 2017.
25 Mahrwald, R. Chem. Rev. 1999, 99, 1095–1120.
26 Di Maso, M. J.; Snyder, K. M.; De Souza
Fernandes, F.; Pattawong, O.; Tan, D. Q.; Fettinger,
J. C.; Cheong, P. H.-Y.; Shaw, J. T. Chem. Eur. J.
2016, 22, 4794–4801.
27 Rynard, C. M.; Thankachan, C.; Tidwell, T. T. J.
Am. Chem. Soc. 1979, 101, 1196–1201.
28 Coulthard, G.; Unsworth, W. P.; Taylor, R. J. K.
Tetrahedron Lett. 2015, 56, 3113–3116.
29 Wang, Y.; Liang, Y.; Jiao, L.; Du, D.-M.; Xu, J.
J. Org. Chem. 2008, 71, 6983–6990.

Highlights
Stereochemistry and Reactivity of the HPA-Imine Mannich Intermediate
Daniel Polyak, Ngan Phung, Jian Liu, Robert Barrows, Thomas J. Emge, and Spencer Knapp∗
Department of Chemistry and Chemical Biology, Rutgers – The State University of New Jersey, 610 Taylor Rd., Piscataway, NJ 08854, USA
•
•
Steric-based evidence indicates that the HPA-imine formal cycloaddition may prefer an open transition state
(Scheme 3)
This reaction has recently become important for the preparation of anti-cancer and anti-malarial drug candidates
(refs. 6–12).
•
•
The Mannich-type intermediate (33) was trapped by base treatment, leading to a pair of beta-lactams, 35 and 36.
Their formation implies a ketene intermediate (38), the low temperature N-cyclization of which provides products
(Scheme 5).
H - 1