Access to Enantiopure 5-, 7-, and 5,7-Substituted cis-Decahydroquinolines: Enantioselective Synthesis of (-)-Cermizine B

Article abstract of DOI:10.1021/acs.orglett.7b00492

Stereoconvergent cyclocondensation reactions of (R)- or (S)-phenylglycinol with appropriately substituted cyclohexanone-based δ-keto esters are the key steps of short synthetic routes to enantiopure 5-, 7-, and 5,7-substituted cis-decahydroquinolines. The factors governing the stereoselectivity of the cyclocondensation are discussed. The potential of the methodology is illustrated by a protecting-group-free synthesis of the phlegmarine-type Lycopodium alkaloid (-)-cermizine B.

Full text of DOI:10.1021/acs.orglett.7b00492

Letter
pubs.acs.org/OrgLett
Access to Enantiopure 5‑, 7‑, and 5,7-Substituted cis-
Decahydroquinolines: Enantioselective Synthesis of (−)-Cermizine B
Alexandre Pinto,† Rosa Griera,† Elies Molins,‡ Israel Fernandez,§ Joan Bosch,† and Mercedes Amat*,†
́
†Laboratory of Organic Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of
Barcelona, 080028-Barcelona, Spain
‡Institut de Cien
̀
cia de Materials de Barcelona (ICMAB, CSIC), Campus UAB, 08193-Bellaterra, Spain
ica I, Facultad de Ciencias Químicas, Centro de Innovacion en Química Avanzada
§Departamento de Química Organ
́
́
(ORFEO−CINQA), Universidad Complutense de Madrid, 28040-Madrid, Spain
S
* Supporting Information
ABSTRACT: Stereoconvergent cyclocondensation reactions of
(R)- or (S)-phenylglycinol with appropriately substituted cyclo-
hexanone-based δ-keto esters are the key steps of short synthetic
routes to enantiopure 5-, 7-, and 5,7-substituted cis-decahydro-
quinolines. The factors governing the stereoselectivity of the
cyclocondensation are discussed. The potential of the methodology
is illustrated by a protecting-group-free synthesis of the phlegmarine-type Lycopodium alkaloid (−)-cermizine B.
From a synthetic standpoint, phlegmarine-type alkaloids are
he decahydroquinoline (DHQ) ring system is present in
Thundreds of naturally occurring biologically active
alkaloids, isolated not only from plant species but also from
amphibians, arthropods, and marine organisms.1 The structural
and stereochemical diversity of these alkaloids makes them
valuable targets for the development of unified synthetic
strategies2 and the validation of multipurpose building blocks.
In this context, using phenylglycinol-derived tricyclic lactams
as chiral scaffolds, we have developed straightforward routes for
the enantioselective synthesis of 5-, 6-, 8-, 2,5-, and 6,8-alkyl
substituted cis-DHQs,3 including the DHQ alkaloids pum-
iliotoxin C,3a,c lepadins A−D,3f and myrioxazine A.3e
We report herein the use of a new phenylglycinol-derived
tricyclic lactam 3 as the key building block for the
enantioselective synthesis of cermizine B,4 a member of the
small group of phlegmarine-type Lycopodium alkaloids,5 which
are characterized by a DHQ ring bearing a C-7 methyl
substituent and a C-5 2-piperidylmethyl-based side chain
(Figure 1). We also report a joint experimental−computational
study carried out to understand the factors governing the
stereoselectivity of the cyclocondensation reactions leading to 3
and related tricyclic lactams.
among the least studied Lycopodium alkaloids, with only a
limited number of enantioselective syntheses reported so far in
both the cis-6 and trans-DHQ7 series.8
Tricyclic lactam 3, bearing the appropriate absolute
configuration for the synthesis of (−)-cermizine B, was
prepared in a stereoconvergent manner as outlined in Scheme
1. The starting cyclohexenone-based δ-keto ester 1 was
accessible in four steps from R-(+)-pulegone in approximately
70% overall yield on a multigram scale, as previously reported.9
The InCl3-catalyzed Sakurai reaction10 of enone 1 with
allyltrimethylsilane in the presence of trimethylsilyl chloride
was highly diastereoselective, leading to trans-3,5-disubstituted
cyclohexanone 211 in nearly quantitative yield as a 1:1 mixture
of C-2 epimers. Finally, heating a benzene solution of the above
mixture of δ-keto esters and (R)-phenylglycinol in the presence
of AcOH, using a Dean−Stark system, stereoselectively gave a
single tricyclic cis-fused lactam 3 in 82% yield. This process
involves the epimerization of the configurationally labile
stereocenter α to the ketone group.
The stereoselectivity of the above cyclocondensation reaction
was not unexpected12 and can be rationalized by considering
that the initially formed imines are in equilibrium with the
corresponding enamines and four diastereoisomeric oxazoli-
dines. The final irreversible lactamization occurs faster from
oxazolidine A, which allows the ester group to approach the
nitrogen atom from the less hindered face of the oxazolidine
ring, anti to the phenyl, leading to cis-fused13 lactam 3.
Formation of the alternative cis-fused lactam 4, resulting from
lactamization of oxazolidine B via a tetrahedral intermediate
suffering from strong 1,3-diaxial interactions between the
Received: February 17, 2017
Figure 1. Representative phlegmarine-type Lycopodium alkaloids.
© XXXX American Chemical Society
A
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Letter
stereoisomer, which incorporates a newly created stereogenic
center having the required S-configuration. Cleavage of the
chiral auxiliary by acidic methanolysis, followed by reaction of
the resulting primary α-branched amine with acryloyl chloride,
gave diene 7, which underwent an RCM reaction to afford
dihydropyridone 8 in excellent yield.
Scheme 1. Preparation of the Key Phenylglycinol-Derived
Tricyclic Lactam 3
The synthesis of (−)-cermizine B was completed by
conventional transformations involving catalytic hydrogenation
of 8, lactam methylation and alane reduction, which brought
about the reduction of the two lactam carbonyls and the
reductive opening of the oxazolidine ring, and final
debenzylation by catalytic hydrogenation of the resulting cis-
DHQ 9. Our synthetic cermizine B showed NMR data and a
sign of specific rotation [−16.0 (c 0.29, MeOH); Lit4 −2 (c 0.6,
MeOH)] coincident with those reported4,18 for the natural
product.
At this point we reasoned that a similar reaction sequence
starting from (S)- instead of (R)-phenylglycinol would provide
a synthetic entry to (+)-serratezomine E, a phlegmarine-type
alkaloid with a cis-fusion opposite to that of cermizine B, via
tricyclic lactam 10 (Scheme 3). However, surprisingly,
Scheme 3. Cyclocondensation Reaction of δ-Keto Esters 2
with (S)-Phenylglycinol
phenyl ring and the methoxy group, was not observed. The
absolute configuration of 3 was unambiguously established by
X-ray crystallographic analysis.14
The allyl substituent at C-5 of the DHQ ring was used to
stereoselectively assemble the C-5 2-(S)-piperidylmethyl
moiety characteristic of (−)-cermizine B. A ruthenium
catalyzed15 oxidative cleavage of olefin 3, followed by reaction
of the resulting aldehyde with the chiral auxiliary (R)-(+)-tert-
butanesulfinamide, afforded N-sulfinyl imine 5 in 61% yield16
(Scheme 2). A subsequent allylation with allylmagnesium
bromide stereoselectively17 provided sulfinamide 6 as a single
Scheme 2. Enantioselective Synthesis of (−)-Cermizine B
cyclocondensation of δ-keto esters 2 with (S)-phenylglycinol
gave a nearly equimolecular mixture of diastereoisomeric
lactams 10 and 11 (45:55 ratio). The irreversible lactamization
takes place not only from the expected oxazolidine C via a
chairlike transition state that avoids repulsive interactions with
the phenyl substituent but also from D, which suffers from such
interactions. Both C and D incorporate an axial substituent on
the cyclohexane ring.19
To understand the effect of the substituents at the C-5 and
C-7 positions (DHQ numbering) in the above cyclo-
condensation reactions, we studied similar reactions from
(R)- and (S)-phenylglycinol and model keto esters 1220 and
16.21 The results are shown in Schemes 4 and 5.
Similar to the above cyclocondensations from 2, the reaction
of 12 with (R)-phenylglycinol stereoselectively gave a single
tricyclic lactam 13, via oxazolidine E, whereas the reaction with
(S)-phenylglycinol was not stereoselective, affording a 15:85
mixture of lactams 14 and 15. In contrast, δ-keto ester 16 led to
a single tricyclic lactam 17 by reaction with (S)-phenylglycinol
and afforded a nearly equimolecular mixture of lactams 18 and
19 by reaction with (R)-phenylglycinol.
B
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Letter
simple β-amino alcohol lacking the phenyl substituent of the
phenylglycinol moiety. A 15:85 mixture of tricyclic lactams 20
and 21 was obtained in 81% yield (Scheme 6).
Scheme 4. Cyclocondensation Reaction of δ-Keto Esters 12
with (R)- and (S)-Phenylglycinol
Scheme 6. Cyclocondensation Reaction of δ-Keto Ester 2
with 2-Aminoethanol
A rationale for this result and those of all the above
cyclocondensations is that, although both oxazolidine inter-
mediates K and L incorporate an axial methyl or allyl
substituent on the cyclohexane ring, K also suffers from
repulsive gauche interactions between the equatorial allyl
substituent and the propionate chain. This hypothesis is
supported by theoretical calculations, which confirm that the
protonated intermediate L·H+, the species from which the
cyclization occurs, is indeed 3.2 kcal/mol more stable than the
analogous K·H+ intermediate due to the occurrence of such
destabilizing interactions.22
Scheme 5. Cyclocondensation Reaction of δ-Keto Esters 16
with (R)- and (S)-Phenylglycinol
In summary, the stereochemical outcome of the cyclo-
condensations reported herein depends on the repulsive
interactions in the intermediate oxazolidines that undergo
irreversible lactamization. These interactions are mainly caused
by (i) the approach of the ester group to the nitrogen, syn with
respect to the phenyl substituent, during the lactamization step;
(ii) the presence of axial substituents on the cyclohexane ring;
and (iii) the repulsive gauche interaction between the equatorial
C-5 substituent (DHQ numbering) and the propionate chain.
Finally, to further illustrate the synthetic potential of the
above cyclocondensation reactions leading to substituted
tricyclic lactams, enantiopure lactams 13 and 17 were converted
in excellent yields to the respective 7- and 5-substituted cis-
DHQs 22 and 23 by the two-step sequence depicted in Scheme
7.
The stereoselective generation of lactams 13 and 17 can be
accounted for by considering the easy lactamization of the
respective oxazolidine intermediates E and H (equatorial
methyl group and no interactions with the phenyl substituent
during the ring closure). On the other hand, the formation of
lactam 15 as the major product in the cyclocondensation of 12
with (S)-phenylglycinol (14/15 15:85 ratio) simply reflects the
strong destabilizing interactions of the axial methyl substituent
in the intermediate oxazolidine F, precursor of 14. In light of
this result, the 1:1 ratio for lactams 18 and 19 in the
cyclocondensation of 16 with (R)-phenylglycinol (Scheme 5) is
quite striking, suggesting that oxazolidine J suffers from an
additional destabilizing effect.
In conclusion, we have developed straightforward routes
(only three synthetic steps) to enantiopure 5-, 7-, and 5,7-
Scheme 7. Access to Enantiopure 5- and 7-Substituted cis-
Decahydroquinolines
To definitively clarify the influence of the C-5 and C-7
substituents (DHQ numbering) in the above cyclocondensa-
tion reactions, we also studied the cyclocondensation δ-keto
ester 2 (1:1 mixture of C-2 epimers) with 2-aminoethanol, a
C
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Letter
Knolker, H.-J., Ed.: Elsevier: San Diego, 2013; p 1. (d) Bradshaw, B.;
̈
substituted cis-DHQs by cyclocondensation of stereoisomeric
mixtures of cyclohexanone-derived δ-keto esters with (R)- and
(S)-phenylglycinol, which acts as a chiral latent form of
ammonia. Understanding the factors that govern the stereo-
selectivity of these reactions will allow the design of related
stereocontrolled cyclocondensation reactions leading to
enantiopure cis-DHQs with different substitution and stereo-
chemical patterns.
Saborit-Villarroya, G.; Luque-Corredera, C.; Balana, M.; Bonjoch, J. In
̀
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Recent Advances in Pharmaceutical Sciences IV; Munoz-Torrero, D.,
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Vazquez-Carrera, M., Esterlich, J., Eds.; Research Signpost: Kerala,
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(6) Lycoposerramine Z: (a) Tanaka, T.; Kogure, N.; Kitajima, M.;
Takayama, H. J. Org. Chem. 2009, 74, 8675. (b) Bradshaw, B.; Luque-
Corredera, C.; Bonjoch, J. Org. Lett. 2013, 15, 326. (c) Zhang, L.-D.;
Zhong, L.-R.; Xi, J.; Yang, X.-L.; Yao, Z.-J. J. Org. Chem. 2016, 81,
1899. Cermizine B: (d) Bradshaw, B.; Luque-Corredera, C.; Bonjoch,
J. Chem. Commun. 2014, 50, 7099. Serratezomine E and Huperzine N
(putative): (e) Bosch, C.; Fiser, B.; Gomez-Bengoa, E.; Bradshaw, B.;
Bonjoch, J. Org. Lett. 2015, 17, 5084.
(7) Phlegmarine and related N-substituted alkaloids: (a) Comins, D.
L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J. J. Org. Chem. 1999, 64, 2184.
(b) Wolfe, B. H.; Libby, A. H.; Al-awar, R. S.; Foti, C. J.; Comins, D. L.
J. Org. Chem. 2010, 75, 8564. Lycoposerramine X: (c) See ref 6a.
(8) Lycoposerramines V and W (5,6,7,8-tetrahydroquinolines):
(a) Shigeyama, T.; Katakawa, K.; Kogure, N.; Kitajima, M.;
Takayama, H. Org. Lett. 2007, 9, 4069. (b) Zhang, L.-D.; Zhou, T.-
T.; Qi, S.-X.; Xi, J.; Yang, X.-L.; Yao, Z.-J. Chem. - Asian J. 2014, 9,
2740.
ASSOCIATED CONTENT
* Supporting Information
■
S
This material is available free of charge via Internet at The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.7b00492.
Complete experimental procedures, copies of 1H and 13
C
NMR spectra of all new compounds, crystallographic
data for compound 3, and computational details (PDF)
AUTHOR INFORMATION
■
(9) Caine, D.; Procter, K.; Cassell, R. A. J. Org. Chem. 1984, 49, 2647.
Corresponding Author
*E-mail: amat@ub.edu.
ORCID
́
(b) Mutti, S.; Daubie, C.; Decalogne, F.; Fournier, R.; Rossi, P.
Tetrahedron Lett. 1996, 37, 3125. (c) Kozak, J. A.; Dake, G. R. Angew.
Chem., Int. Ed. 2008, 47, 4221.
(10) Lee, P. H.; Lee, K.; Sung, S.; Chang, S. J. Org. Chem. 2001, 66,
8646.
Israel Fernandez: 0000-0002-0186-9774
Mercedes Amat: 0000-0002-9551-4690
Notes
́
(11) The stereoelectronic control accounts for the high facial
selectivity of Lewis acid promoted allylsilane conjugate additions to
cyclic enones: (a) Blumenkopf, T. A.; Heathcock, C. H. J. Am. Chem.
Soc. 1983, 105, 2354. (b) Heathcock, C. H.; Blumenkopf, T. A.; Smith,
K. M. J. Org. Chem. 1989, 54, 1548. See also ref 9c.
(12) The same stereochemical outcome was observed in cyclo-
condensation reactions leading to related tricyclic phenylglycinol-
derived lactams: See ref 3.
(13) Formation of trans-fused lactams is precluded on steric grounds.
(14) CCDC 1533231 contains the supplementary crystallographic
data for compound 3. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the MINECO/FEDER (Projects
CTQ2014-51912-REDC, CTQ2015-65384-R, and CTQ2016-
78205-P) and the Generalitat de Catalunya (Grant 2014-SGR-
155) is gratefully acknowledged. We also acknowledge the
networking contribution from the COST Action CM1407, the
MECD (Spain) for a fellowship to A.P., and the Serra Hunter
programme (R.G.).
(15) Yang, D.; Zhang, C. J. Org. Chem. 2001, 66, 4814.
(16) (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J.
A. J. Org. Chem. 1999, 64, 1278. (b) For a review, see: Robak, M. T.;
Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600.
(17) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883.
(18) It has been pointed out in ref 4 that the reported [α]D value of
cermizine B “is not reliable due to small amount of sample and small
value of optical rotation.”
(19) Interestingly, cyclocondensation of 4-methyl-5-nitromethyl-2-
oxocyclopentaneacetic acid (a γ-keto acid) with (R)- and (S)-
phenylglycinol gave in both cases the expected tricyclic (5,5,5-
membered) lactams as single products: Deprez-Poulain, R.; Willand,
N.; Boutillon, C.; Nowogrocki, G.; Azaroual, N.; Deprez, B.
Tetrahedron Lett. 2004, 45, 5287.
(20) Keto ester 12 (1:1 mixture of diastereoisomers) was prepared by
catalytic hydrogenation (PtO2) of cyclohexenone 1.
(21) Keto ester 16 (2:1 mixture of diastereoisomers) was prepared in
three steps from (R)-(+)-pulegone: (a) CH2N+Me2Cl−, acetonitrile;
(b) CH2(CO2Et)2, NaOH, toluene, reflux; then AcOH-HCl (2:1),
reflux; (c) TMSCl, MeOH.
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