Hydrazide-Catalyzed Polyene Cyclization: Asymmetric Organocatalytic Synthesis of cis-Decalins

Article abstract of DOI:10.1002/anie.201911952

Polyene cyclizations offer rapid entry into terpenoid ring systems. Although enantioselective cyclizations of (E)-polyenes to form trans-decalin ring systems are well precedented, highly enantioselective cyclizations of (Z)-polyenes to form the correspond

Full text of DOI:10.1002/anie.201911952

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Hydrazide-Catalyzed Polyene Cyclization: Asymmetric
Organocatalytic Synthesis of cis-Decalins
Authors: James L. Gleason, Samuel J Plamondon, Josephine M
Warnica, and Dainis Kaldre
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911952
Angew. Chem. 10.1002/ange.201911952
Link to VoR: http://dx.doi.org/10.1002/anie.201911952
http://dx.doi.org/10.1002/ange.201911952

10.1002/anie.201911952
Angewandte Chemie International Edition
COMMUNICATION
Hydrazide-Catalyzed Polyene Cyclization: Asymmetric
Organocatalytic Synthesis of cis-Decalins
Samuel J. Plamondon, Josephine M. Warnica, Dainis Kaldre and James L. Gleason*[a]
6a, 7]
Abstract: Polyene cyclizations offer rapid entry into terpenoid ring
systems. Although enantioselective cyclizations of (E)-polyenes to
form trans-decalin ring systems are well precedented, highly
enantioselective cyclizations of (Z)-polyenes to form the
corresponding cis-decalins have not been reported. Here, we
describe the first application of iminium catalysis to the initiation of
polyene cyclizations. Ethyl 1,2-diazepane-1-carboxylate catalyzes
the cyclization of polyenes bearing enal initiators. Moreover, chiral
bicyclic hydrazides catalyze the cyclizations of (Z)-polyene
substrates to form cis-decalins with enantioselectivities of up to 97:3
er. DFT calculations suggest the catalysts promote the reaction by
stabilizing positive charge as it develops during the bicyclization.
enantioselectivity.[4b,
An additional challenge is that while
concerted cyclizations will produce cis-decalins, reactions that
proceed stepwise via an intermediate cyclohexyl cation are
potentially vulnerable to ring-flip which can result in trans-decalin
formation (c.f. Scheme 2B).[1c, 1d, 11]
The biosynthesis of steroids and other terpenoid natural
products via polyene cyclization is a process which has inspired
organic chemists for over 60 years. Since the proposals of
Woodward, Stork and Eschenmoser,[1] numerous examples of
biomimetic cyclizations have been reported, including many
applications in total synthesis where polyene cyclization can
afford rapid entry into complex polycyclic frameworks.[2] While
the absolute stereochemistry of the epoxide in the prototypical
substrate for steroid synthesis, 2,3-oxidosqualene (Scheme 1),
is a defining influence on the subsequent polycyclic product,[2b, 3]
in recent years there has been interest in initiating cyclizations
via chiral catalysts on achiral precursors. The first examples by
Yamamoto showed that chiral proton sources could initiate
cyclizations directly on simple polyene substrates.[4]
Enantioselective polyene cyclizations may also be initiated by
chiral halogen/chalcogen sources[5] and 2- and 3-metal
complexes.[6] In general, these methods activate one prochiral
face of the terminal alkene in a fashion that mirrors the canonical
epoxide initiation. Alternative strategies include the combination
of protic acids with chiral ion binders[7] and using SOMO
catalysis.[8] While many impressive advancements have been
made, there are still areas ripe for development.
Scheme 1. Enantioselective polyene cyclizations and cis-decalin-containing
natural product targets.
All highly enantioselective reactions reported to date have
used (E)-olefin substrates that lead to trans-decalin ring
junctions (Scheme 1). While most steroids possess trans-decalin
junctions in the A/B rings (e.g. lanosterol), numerous terpenoids
such as nakamurol A, 3-oxoisotaxodione and digoxin[9] possess
cis-decalin ring junctions that would require cyclization of a (Z)-
olefin substrate. While cyclizations of polyenes containing (Z)-
alkenes do have ample precedent,[10] the few reported attempts
at applying established enantioselective methods to (Z)-olefin
In approaching this problem, we became interested in examining
a potential alternative to direct alkene activation, specifically the
use of LUMO-lowering iminium catalysis. We previously reported
an iminium-catalyzed Cope rearrangement of 1,5-hexadiene-2-
carboxaldehydes using cyclic hydrazides (e.g. 1, Scheme 2A) as
catalysts.[12] Preliminary calculations on this reaction suggested
it proceeded in a stepwise fashion through a shallow cationic
substrates
have
resulted
in
significantly
reduced
intermediate. Since polyene cyclizations bear
a structural
relationship to the Cope rearrangement, in that substrates for
both possess 1,5-hexadiene units as core reactive functionality,
we envisaged that hydrazide catalysts might also trigger polyene
cyclizations (c.f. Scheme 2B). Here we report the successful
implementation of this concept in the first iminium-catalyzed
polyene cyclizations as well as the first highly enantioselective
polyene cyclization of (Z)-polyenes to form cis-decalins, studies
which reveal the ability of hydrazide catalysts to stabilize
developing charge at remote locations.
[a]
Samuel J. Plamondon, Josephine M. Warnica, Dainis Kaldre and
Prof. James L. Gleason
Department of Chemistry
McGill University
801 Sherbrooke W., Montreal, QC, H3A 0B8 (Canada)
E-mail: jim.gleason@mcgill.ca
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201911952
Angewandte Chemie International Edition
COMMUNICATION
Scheme 3. Polyene cyclization of (E)-hexadienes.
Scheme 2. A) An organocatalytic Cope rearrangement catalyzed by
diazepane carboxylate. B) Polyene cyclization of (E)- and (Z)-polyene
substrates to provide trans- and cis-decalin products.
As iminium catalysis has not been previously reported in
polyene cyclizations, we first examined the cyclization of (E)-
alkene substrates to generate trans-decalin products. We began
by examining the cyclization of substrate 2a (Scheme 3) and
found that exposure to diazepane carboxylate hydrochloride
(1•HCl)[13] in either 5% HFIP/DCM or EtOH afforded bicyclization
adduct 3a. The former solvent afforded higher yield, providing 3a
in 72% yield as a 95:5 mixture of trans- to cis-decalins in only 5
h. The aldehyde -stereocenter at C3, formed by hydrolysis of
the intermediate enamine in the final step, was generated as a
thermodynamic mixture of 6:1 . Reactions in ethanol were
slightly more diastereoselective (97:3 trans/cis), but with
diminished yield (42%) and requiring extended reaction time (24
h).[14] In addition, reactions in ethanol with less nucleophilic
arenes, such as dimethylphenyl substrate 2b, led to products
resulting from trapping of the intermediate cyclohexyl cation by
solvent.
This observation, along with formation of minor
amounts of the cis-decalin product, suggests some stepwise
character to the reaction. Given the higher yields, faster reaction
time and lack of intermediate trapping products, we examined
the scope of the cyclization in 5% HFIP/DCM. We found that a
range of (E)-polyene substrates possessing electron-rich aryl,
naphthyl and heteroaryl terminating groups underwent
bicyclization efficiently in consistently good yields and with ring
fusion diastereoselectivities above 90:10 for all but one
substrate, 2f, which bears two meta-deactivating groups.
Scheme 4. Polyene cyclization of (Z)-hexadienes.
of (E)-olefin substrates, we next examined the extension to (Z)-
olefins (Scheme 4). Gratifyingly, treatment of 3,5-
dimethoxyarene substrate 4a afforded cis-decalin 5a in excellent
yield (83%) and diastereoselectivity (95:5 cis/trans). As in the
With iminium catalysis established for the polyene cyclization
This article is protected by copyright. All rights reserved.

10.1002/anie.201911952
Angewandte Chemie International Edition
COMMUNICATION
trans-decalin case, the aldehyde -stereocenter was generated
as a thermodynamic mixture, in this case 1.4:1  due to the
fluxional nature of the cis-decalin ring system. The bicyclization
worked well across a range of (Z)-olefin substrates, affording
high yields. Importantly, even though the results suggest at least
some stepwise character to the bicyclization, scrambling from
(Z)-olefin to trans-decalin via chair flip was minimal, leading to
ring-fusion diastereoselectivities comparable to those in the (E)-
olefin cyclization.
catalysis. Computational studies predict that cyclic hydrazide
iminium ions prefer the (Z)-configuration, with a twist along the
N-N bond serving to relieve A-1,3 strain between the iminium
and the carbamate (Figure 1). This suggests the positioning of
the carbamate – twisted either above or below the plane of the
iminium – might be harnessed for controlling enantioselectivity.
We initially examined cyclic hydrazides with stereocenters
adjacent to the carbamate group in order to gear the carbamate
above or below the iminium. Catalysts were screened using
substrates 2a/4a in EtOH, as a solvent screen revealed that the
highest enantioselectivities were observed in this solvent (see
Supporting Information). Diazepane
6
afforded modest
A
B
enantioselectivity (~75:25 er) for formation of both cis- and trans-
decalins (Table 1). We then examined conformationally more
rigid piperidazine carboxylates 7a and 7b which, intriguingly,
displayed divergent behaviour with respect to (E)- and (Z)-
olefins: enantioselectivity was improved for cis-decalin formation
(84:16 er for both 7a and 7b) while enantioselectivity for trans-
decalin formation was diminished. Given the previously noted
lack of methods to impart high enantioselectivity in polyene
cyclizations furnishing cis-decalins, we further optimized the
selectivity for formation of 5a.
N
N
N
N
CO2Et
CO2Et
Me
Me
+ 2.6 kcal/mol
0 kcal/mol
Figure 1. Diazepane carboxylate iminium ions calculated at the M06-2X/6-
311G(d,p), SRCF=EtOH level. A) The (Z)-configuration is more stable than
the (E)-configuration. B) Three-dimensional representation showing the twist
along the N-N bond.
As an alternative to the gearing of the carbamate in 6 and
7a/b, we examined bicyclic hydrazides that would lock in its
conformation. Initially, we observed that diphenyloxazolidinone
8a afforded a modest improvement in enantioselectivity and
significantly improved the reaction time (3 h vs 48 h) compared
to the monocyclic hydrazides. The sense of enantioinduction for
8a was the same as that observed with 7a/b, even though it
bears an inverted stereocenter, consistent with the carbamate
Table 1. Screening of chiral catalysts.
being
a
significant stereocontrolling element. Somewhat
surprisingly, removing the phenyl groups (8b) improved the
Table 2. Enantioselective cyclization of (Z)-polyenes.
Catalyst
3a
5a
er[a]
Yield[b]
36%
42%
47%
38%
35%
35%
ND
er[a]
Yield[b]
52%
Product
Cond.[a]
Time
(h)
Yield
(%)
C3-
β/α
cis/trans
er[b]
6
75:25
53:47
66:34
44:56
59:41
64:34
ND
74:26
84:16
84:16
86:14
90:10
94:6
7a[c]
7b
61%
5a
5c
5e
5b
5d
5h
5i
A
A
A
B
B
B
B
24
72
48
48
48
48
48
79
55
60
77
83
72
77
1:3
1:3
97:3
96:4
96:4
90:10
93:7
92:8
92:8
96:4
94:6[c]
97:3
66%
8a
51%[d]
49%[e]
74%[d]
79%[e]
1:3
8b
1:1.2
1:1.8
1:1.5
1:1.2
88:12
93:7[c]
88:12
90:10
9[f]
9[f,g]
96:4
[a] Enantiomeric ratio, measured by reduction to corresponding primary
alcohol and analysis by chiral HPLC. The er shown is the aggregate of C3
epimers for the major decalin isomer (cis or trans). [b] Isolated yield after
TFA/H2O/CHCl3, 2h. [c] Catalyst 7a was evaluated as its enantiomer, ent-
7a. [d] 3 h. [e] 24 h. [f] 10 mol% HCl used. [g] Reaction at 0 °C.
[a] Conditions: A) EtOH, 0 °C; TFA/H2O/CHCl3, rt, 2 h. B) 2% HFIP/DCM,
–10 °C. [b] Enantiomeric ratio measured by reduction to corresponding
primary alcohol and analysis by chiral HPLC. The er shown is the aggregate
of C3 epimers for the major cis-decalin isomer. [c] Product derivatized to
corresponding ketone via two-step aldehyde dehomologation to assess er.
The er shown is for the major cis-decalin isomer.
With the racemic reaction established for both the (E)- and (Z)-
alkene series, we next examined the potential for asymmetric
This article is protected by copyright. All rights reserved.

10.1002/anie.201911952
Angewandte Chemie International Edition
COMMUNICATION
MeO
Me
OMe
MeO
Me
OMe
1. TIPSOTf
Et3N, rt, 1 h
1. Rh(PPh3)3Cl
130 °C, 14 h
enantioselectivity to 90:10 er. Based on a developing model
where electron donation from the carbonyl was important (vide
infra), we next examined imidazolidinone 9 and found this
improved the selectivity to 94:6 er. Given the high reactivity of
the bicyclic hydrazides, the reaction using 9 could easily be
conducted at 0 °C, affording the product in 79% yield in 24 h
with an optimum enantioselectivity of 96:4 er.
5a
2. (i) m-CPBA
rt, 30 min
(ii) H5IO6
2. H2, Pd/C (10%)
rt, 24 h
O
H
H
rt, 1.5 h
10 56%
11 65%
Scheme 5. Transformations of polyene cyclization products.
With an optimized catalyst in hand, we examined the
bicyclization of a range of (Z)-olefin substrates. Substrates
bearing electron rich arenes performed well in EtOH, affording
high er’s and high cis-selectivity (Table 2). As with the racemic
reaction, the cyclization of substrates bearing slightly less
nucleophilic arenes resulted in byproducts arising from trapping
of the intermediate cation. The use of 2% HFIP/DCM again
eliminated all trapping products and only slightly attenuated
enantioselectivity (94:6 er for 4a→5a in 2% HFIP/DCM vs. 96:4
er in EtOH).[15] Using these conditions, 3,5-dimethylphenyl-, 3-
In the enantioselective reaction, the catalyst is quite remote from
the incipient stereocenter and the divergent effects of (Z)- and
(E)-alkenes on this remote stereoinduction are highly intriguing.
We sought to understand the origins of this stereocontrol using
DFT. As noted above, at least some of the reactions appear to
proceed in stepwise fashion. We thus began by modeling the
initial cyclization step in a truncated system at the M06-2X/6-
311G(d,p) level of theory using a PCM solvation model for EtOH.
As noted above, hydrazide iminium ions favour the (Z)-
isomer. From this geometry, attack of the alkene on the s-cis
and s-trans conformations of the -unsaturated iminium may
occur proximal or distal to the carbonyl group of the hydrazide.
Of the four possible chair-like transition states, the lowest energy
pathway results from proximal attack on the s-trans-iminium
(Figure 2A). In this conformation, the hydrazide carbonyl is
positioned below the carbon adjacent to the forming carbocation,
allowing for electrostatic stabilization of the developing charge.
In addition, NBO calculations identified an nO→*C-H donation to
the axial C-H bond, potentially as a means of direct donation of
electron density into the electron-poor system. The disfavoured
diastereomer results from proximal attack on the s-cis
conformation and is 2.3 kcal/mol higher in energy. In this
diastereomer, the proton is replaced by an alkyl group, forcing
the carbonyl further from the developing cation, reducing
methoxy-2-methylphenyl-,
thiophenyl-
and
benzofuran-
containing substrates afforded bicyclization products in high
yields and enantioselectivities.
The bicyclization process leaves an aldehyde functional
handle that may be used for further manipulation. Most steroids
possess either oxygen or hydrogen at C3, and thus we
developed methods to transform the aldehyde in these
directions (Scheme 5). Oxidative degradation could be effected
by formation of a silyl enol ether followed by mCPBA/H5IO6
treatment to form ketone 10. Alternatively, if an ultimately
traceless process is desired, decarbonylation could be achieved
by treatment with Wilkinson’s catalyst at reflux in xylenes,
followed by hydrogenation of the resulting alkene to provide 11
in good yield.
H
N
H
N
A
B
N
H
Me
Me
N
Me
N
O
O
Me
Me
H
O
N
N
N
Me
H+
OHC
Me
N
Me
OHC
Proximal attack
Distal attack
Major diastereomer
via s-trans iminium
Minor diastereomer
via s-cis iminium
Major diastereomer
via s-cis iminium
Minor diastereomer
via s-trans iminium
Me
Me
Me Me
Me
Me
Me
Me
Me
Me
Me
Me
N
H
N
N
N
N
N
O
O
N
N
O
O
N
N
H
N
N
N
N
H
N
O
N
O
H
H
N
H
N
H
+12.9 kcal/mol
3.4 D
+12.8 kcal/mol
3.6 D
+10.9 kcal/mol
3.4 D
+13.2 kcal/mol
4.3 D
+12.5 kcal/mol
6.6 D
+13.4 kcal/mol
5.1 D
C
Me
H
Me
H
Me
H
Me
Me
Me
Me
Me
Me
H
H
H
Me
Me
Me
Me
H
O
H
Me
N
N
N
N
N
N
N
N
N
N
O
O
O
O
N
H
N
N
H
N
H
N
H
H
Me
+11.0 kcal/mol
+7.3 kcal/mol
+12.0 kcal/mol
+9.3 kcal.mol
-14.5 kcal/mol
Figure 2. DFT Calculations at the M06-2X/6-311G(d,p), SCRF=EtOH level. A) Calculations on a truncated (Z)-alkene model showing the favoured pathway for
cyclization. B) Calculations on (E)-substrates predict low selectivity. C) Extension of truncated model to full bicyclization pathway. All energies are relative to
the initial iminium ion.
This article is protected by copyright. All rights reserved.

10.1002/anie.201911952
Angewandte Chemie International Edition
COMMUNICATION
Southgate, D. Sarlah, Org. Biomol. Chem. 2016, 14, 5454; e) A. Barrett,
T.-K. Ma, T. Mies, Synthesis 2019, 51, 67.
potential through-space electrostatic stabilization and disrupting
direct donation. These changes are reflected in an increased
dipole moment (4.3 D vs 3.4 D).[16] Distal attack is also less
favoured, presumably due to increased distance between the
forming cation and the carbonyl.[17] This model also explains the
lack of selectivity observed with (E)-alkenes, as the alkyl group
occupies an equatorial position in both proximal arrangements
without disrupting the positioning of the carbonyl (Figure 2B).[18]
The model was then extended to the full bicyclization process
(Figure 2C). For dimethylphenyl substrate 4b, bicyclization from
the iminium proceeds via the proximal, chair-like transition state
(G‡ = 10.6 kcal/mol relative to the iminium) to give a discrete
monocyclic intermediate cation, which then proceeds via
electrophilic aromatic substitution (G‡ = 12.0 kcal/mol, +4.7
kcal/mol relative to the cation) to the eventual product. The
corresponding pathway for the minor isomer was computed to
have a 13.3 kcal/mol barrier for the cyclization step and 11.6
kcal/mol barrier for the trapping step. Intriguingly, calculations on
the corresponding dimethoxy substrate 4a suggest that its
bicyclization may be a concerted, non-synchronous process
[3]
[4]
E. J. Corey, D. D. Staas, J. Am. Chem. Soc. 1998, 120, 3526.
a) K. Ishihara, S. Nakamura, H. Yamamoto, J. Am. Chem. Soc. 1999,
121, 4906; b) S. Nakamura, K. Ishihara, H. Yamamoto, J. Am. Chem.
Soc. 2000, 122, 8131; c) K. Ishihara, H. Ishibashi, H. Yamamoto, J. Am.
Chem. Soc. 2001, 123, 1505; d) K. Ishihara, H. Ishibashi, H. Yamamoto,
J. Am. Chem. Soc. 2002, 124, 3647; e) H. Ishibashi, K. Ishihara, H.
Yamamoto, J. Am. Chem. Soc. 2004, 126, 11122; f) K. Kumazawa, K.
Ishihara, H. Yamamoto, Org. Lett. 2004, 6, 2551; g) A. Sakakura, M.
Sakuma, K. Ishihara, Org. Lett. 2011, 13, 3130; h) K. Surendra, E. J.
Corey, J. Am. Chem. Soc. 2012, 134, 11992; i) Y.-J. Zhao, S. S. Chng,
T.-P. Loh, J. Am. Chem. Soc. 2007, 129, 492; j) Y.-J. Zhao, T.-P. Loh, J.
Am. Chem. Soc. 2008, 130, 10024; k) Y.-J. Zhao, B. Li, L.-J. S. Tan, Z.-
L. Shen, T.-P. Loh, J. Am. Chem. Soc. 2010, 132, 10242; l) L. Fan, C.
Han, X. Li, J. Yao, Z. Wang, C. Yao, W. Chen, T. Wang, J. Zhao,
Angew. Chem. 2018, 130, 2137; Angew. Chem. Int. Ed. 2018, 57, 2115.
a) A. Sakakura, A. Ukai, K. Ishihara, Nature 2007, 445, 900; b) S. A.
Snyder, D. S. Treitler, A. Schall, Tetrahedron 2010, 66, 4796; c) R. C.
Samanta, H. Yamamoto, J. Am. Chem. Soc. 2017, 139, 1460; d) Z. Tao,
K. A. Robb, K. Zhao, S. E. Denmark, J. Am. Chem. Soc. 2018, 140,
3569.
[5]
[6]
a) S. G. Sethofer, T. Mayer, F. D. Toste, J. Am. Chem. Soc. 2010, 132,
8276; b) M. A. Schafroth, D. Sarlah, S. Krautwald, E. M. Carreira, J. Am.
Chem. Soc. 2012, 134, 20276; c) N. A. Cochrane, H. Nguyen, M. R.
Gagné, J. Am. Chem. Soc. 2012, 135, 628; d) J. G. Sokol, N. A.
Cochrane, J. J. Becker, M. R. Gagné, Chem. Commun. 2013, 49, 5046;
e) M. J. Geier, M. R. Gagné, J. Am. Chem. Soc. 2014, 136, 3032; f) H.
Nguyen, M. R. Gagné, ACS Catalysis 2014, 4, 855; g) C. H. McCulley,
M. J. Geier, B. M. Hudson, M. R. Gagné, D. J. Tantillo, J. Am. Chem.
Soc. 2017, 139, 11158.
(see Supporting Information).
mechanism is presumably due to the greater nucleophilicity of
the arene which promotes barrierless trapping and is
This potential change in
a
consistent with the reduced amounts of (Z)→trans crossover
and EtOH trapping products observed compared to 4b.
In summary, we have developed the first iminium ion-
catalyzed polyene cyclization and the first examples of highly
enantioselective
bicyclizations
to
form
cis-decalins.
[7]
[8]
R. R. Knowles, S. Lin, E. N. Jacobsen, J. Am. Chem. Soc. 2010, 132,
5030.
Computations suggest that the enantioselectivity is influenced by
the catalysts’ ability to stabilize positive charge as it develops
during the cyclization via electrostatics and/or direct -
framework donation. This complements methods that use π-
cation interactions to influence the reaction and will impact future
catalyst design. Additionally, our studies highlight the
remarkable differences that remote stereocenters can have on
the outcome of polyene cyclizations and underscores the fact
that olefin geometry must be carefully considered when
developing asymmetric catalysts.
a) S. Rendler, D. W. C. MacMillan, J. Am. Chem. Soc. 2010, 132, 5027-
5029; b) D. Yang, B.-F. Zheng, Q. Gao, S. Gu, N.-Y. Zhu, Angew.
Chem. 2006, 118, 261-264; Angew. Chem. Int. Ed. 2006, 45, 255-258.
a) N. Shoji, A. Umeyama, M. Teranaka, S. Arihara, J. Nat. Prod. 1996,
59, 448; b) C. F. Chyu, H. C. Lin, Y. H. Kuo, Chem. Pharm. Bull. 2005,
53, 11; c) N. F. Z. Schneider, C. Cerella, C. M. O. Simoes, M. Diederich,
Molecules 2017, 22, 1932.
[9]
[10] a) A. Van der Gen, K. Wiedhaup, J. Swoboda, H. C. Dunathan, W. S.
Johnson, J. Am. Chem. Soc. 1973, 95, 2656; b) J. Dijkink, W. N.
Speckamp, Tetrahedron 1978, 34, 173; c) M. B. Groen, B. Hindriksen,
F. J. Zeelen, Rec. Trav. Chim. Pays Bas 1982, 101, 148; d) R. L.
Snowden, J. C. Eichenberger, S. M. Linder, P. Sonnay, C. Vial, K. H.
Schulte-Elte, J. Org. Chem. 1992, 57, 955; e) C. Tsangarakis, E.
Arkoudis, C. Raptis, M. Stratakis, Org. Lett. 2007, 9, 583.
Acknowledgements
[11] a) G. Ohloff, F. Näf, R. Decorzant, W. Thommen, E. Sundt, Helv. Chim.
Acta 1973, 56, 1414-1448; b) S. Murata, T. Suzuki, Tetrahedron Lett.
1990, 31, 6535.
The authors thank the Natural Sciences and Engineering
Research Council of Canada for funding and Hayden Foy and
Travis Dudding (Brock University) for help with AIM calculations.
[12] a) D. Kaldre, J. L. Gleason, Angew. Chem. 2016, 128, 11729; Angew.
Chem. Int. Ed. 2016, 55, 11557; b) F. Larnaud, A. Sulpizi, N. O.
Häggman, J. M. E. Hughes, D. F. Dewez, J. L. Gleason, Eur. J. Org.
Chem. 2017, 2017, 2637; c) N. O. Häggman, B. Zank, H. Jun, D.
Kaldre, J. L. Gleason, Eur. J. Org. Chem. 2018, 2018, 5412.
Keywords: polyene cyclization • cis-decalin • hydrazide •
organocatalysis • asymmetric catalysis
[13] Reactions using stronger acids such as TfOH produced a greater
proportion of byproducts and lower isolated yields.
[1]
a) R. B. Woodward, K. Bloch, J. Am. Chem. Soc. 1953, 75, 2023; b) A.
Eschenmoser, L. Ruzicka, O. Jeger, D. Arigoni, Helv. Chim. Acta 1955,
38, 1890; c) G. Stork, A. W. Burgstahler, J. Am. Chem. Soc. 1955, 77,
5068; d) P. A. Stadler, A. Eschenmoser, H. Schinz, G. Stork, Helv.
Chim. Acta 1957, 40, 2191.
[14] Reactions in EtOH form a mixture of aldehyde and diethyl acetal
products. All acetals are hydrolyzed by treatment of the concentrated
reaction mixture with TFA/H2O/CHCl3 prior to workup.
[15] The use of higher amounts of HFIP (e.g. 5%) resulted in decreased
enantioselectivity.
[2]
a) W. S. Johnson, Angew. Chem. 1976, 88, 33; Angew. Chem. Int. Ed.
1976, 15, 9; b) R. A. Yoder, J. N. Johnston, Chem. Rev. 2005, 105,
4730; c) S. A. Snyder, A. M. Levinson, (Eds.: P. Knochel, G. A.
Molander), Elsevier Ltd., 2013, pp. 268; d) C. N. Ungarean, E. H.
[16] Although a steric component also seems possible, calculations on the
corresponding saturated (neutral) cyclohexane predict that the
diastereomer with the axial methyl group proximal to the carbonyl group
This article is protected by copyright. All rights reserved.

10.1002/anie.201911952
Angewandte Chemie International Edition
COMMUNICATION
(as in the minor transition state) is slightly more stable than that which
mimics the major transition state. See Supporting Information for details.
[17] Intermediates resulting from attack on a trans-imine were even higher
in energy. See Supporting Information for details.
[18] Direct nO→σ*C-H donation was not observed in the (E)-alkene
calculations at the M06-2X/6-311G(d,p) level, but was observed with
other basis sets (e.g. 6-31G*). Moreover, bond critical points were
observed using AIM calculations. See Supporting Information for details.
This article is protected by copyright. All rights reserved.

10.1002/anie.201911952
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Samuel J. Plamondon, Josephine M.
Warnica, Dainis Kaldre and James L.
Gleason*
N
Bn
N
N
Me
H
O
R
Me
R
(20 mol%)
H
N
up to 97:3 er
HCl (10 mol%)
N
Me
O
OHC
OHC
N
H
Page No. – Page No.
R
Bn
Hydrazide-Catalyzed Polyene
Cyclization: Asymmetric
Organocatalytic Synthesis of cis-
Decalins
Remote Stabilization: Chiral bicyclic hydrazides catalyze cyclizations of (Z)-
polyenes to cis-decalins by means of iminium-ion catalysis. High enantioselectivity
results from remote stabilization of the developing cationic charge in the transition
state by the hydrazide carbonyl.
This article is protected by copyright. All rights reserved.