Enantio- and diastereoconvergent cyclocondensation reactions: Synthesis of enantiopure cis-decahydroquinolines

Article abstract of DOI:10.1002/chem.201302894

Up to four stereocenters with a well-defined configuration are generated in a single synthetic step by the cyclocondensation of (R)-phenylglycinol or (1S,2R)-1-amino-2-indanol with stereoisomeric mixtures (racemates, meso forms, diastereoisomers) of cyclohexanone-based δ-keto-acid and δ-keto-diacid derivatives in enantio- and diastereoconvergent processes that involve dynamic kinetic resolution and/or desymmetrization of enantiotopic groups. A detailed analysis of the stereochemical outcome of this process is presented. This method provides easy access to enantiopure 8- and 6,8-substituted cis-decahydroquinolines, including alkaloids of the myrioxazine family. Copyright

Full text of DOI:10.1002/chem.201302894

DOI: 10.1002/chem.201302894
Enantio- and Diastereoconvergent Cyclocondensation Reactions:
Synthesis of Enantiopure cis-Decahydroquinolines
Mercedes Amat,*[a] Elena Ghirardi,[a] Laura Navꢀo,[a] Rosa Griera,[a] Nfflria Llor,[a]
Elies Molins,[b] and Joan Bosch[a]
Abstract: Up to four stereocenters
with a well-defined configuration are
generated in a single synthetic step by
the cyclocondensation of (R)-phenyl-
glycinol or (1S,2R)-1-amino-2-indanol
with stereoisomeric mixtures (race-
mates, meso forms, diastereoisomers)
of cyclohexanone-based d-keto-acid
and d-keto-diacid derivatives in enan-
tio- and diastereoconvergent processes
that involve dynamic kinetic resolution
and/or desymmetrization of enantio-
topic groups. A detailed analysis of the
stereochemical outcome of this process
is presented. This method provides
easy access to enantiopure 8- and 6,8-
substituted cis-decahydroquinolines, in-
cluding alkaloids of the myrioxazine
family.
Keywords: alkaloids · asymmetric
synthesis · diastereoselectivity · lac-
tams · nitrogen heterocycles
Introduction
ocyclic scaffolds, we planned to study the cyclocondensation
reactions of (R)-phenylglycinol with cyclohexanone-based d-
keto diesters (1). Starting from a mixture of stereoisomeric
d-keto diesters 1 (dl, meso), the initially formed imines (A)
would give rise to mixtures of four (R=H) or eight (R=
substituent) stereoisomeric oxazolidines (B), which would
presumably be in equilibrium through the corresponding en-
amines.
The development of practical synthetic methods for the gen-
eration of multiple stereogenic centers with high diastereo-
and enantioselectivity in a single synthetic step continues to
be a challenging goal in synthetic organic chemistry. Such
methods generally rely on the concerted or sequential gener-
ation of the stereocenters by the stereocontrolled formation
À
of two or more carbon carbon bonds in the key step. How-
We hoped that the final, kinetically controlled, irreversi-
ble lactamization step would selectively furnish one of the
eight (R=H) or sixteen (R=substituent) possible diastereo-
isomeric tricyclic lactams (C) in a process that would involve
the generation of up to four stereocenters with a well-de-
fined configuration in a single synthetic step (Scheme 1).
This highly stereoconvergent process could open up
a straightforward route to enantiopure decahydroquinolines
that contain substituents at the carbocyclic ring (6- and 8-
positions).
ever, an alternative approach in which all of the stereogenic
or pro-stereogenic centers are already present in a starting
material that consists of as a mixture of enantiomers and/or
diastereoisomers has been less well-explored. The desired
stereoselectivity in these enantio- and diastereoconvergent
processes is ensured by dynamic kinetic resolution of the
racemic substrate[1] and/or by differentiation of the diaste-
reotopic or enantiotopic ligands.[2]
In this context, some years ago, we reported[3] enantiose-
lective dynamic kinetic resolution and desymmetrization
processes that involved the cyclocondensation of chiral
amino alcohols with racemic and prochiral d-oxo-acid deriv-
atives, which ultimately led to enantiopure polysubstituted
piperidines.[4]
With the aim of exploring the synthetic potential of this
method in the assembly of more complex enantiopure heter-
[a] Prof. Dr. M. Amat, E. Ghirardi, Dr. L. Navꢀo, Dr. R. Griera,
Dr. N. Llor, Prof. Dr. J. Bosch
Laboratory of Organic Chemistry
Faculty of Pharmacy and Institute of Biomedicine (IBUB)
University of Barcelona, 08028 Barcelona (Spain)
E-mail: amat@ub.edu
[b] Dr. E. Molins
Scheme 1. Our synthetic strategy.
Institut de Ciꢁncia de Materials de Barcelona (CSIC)
Campus UAB, 08193 Cerdanyola (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302894.
16044
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 16044 – 16049

FULL PAPER
Results and Discussion
In the event, heating a solution of keto diester 1a[5] (approx-
imately 4:1 mixture of cis/trans isomers) and (R)-phenylgly-
cinol (2) in toluene at reflux in the presence of isobutyric
acid gave a 3:1 mixture of tricyclic lactams 3a and 4a in
86% yield (Table 1).[6] A desymmetrization reaction with
Table 1. Cyclocondensation reactions of d-keto diesters 1 with (R)-phe-
nylglycinol.
Entry
Substrate
R
Yield [%]
Ratio 3/4
1
2
3
4
1a
1b
1c
1d
H
Me
86
75
82
83
3:1
7:3
4:1
7:3
C6H5
CH2OPMB[a]
[a] PMB=para-methoxybenzyl.
differentiation of the two enantiotopic propionate chains oc-
curred from the cis (meso) isomer of the keto diester,
whereas a dynamic kinetic resolution, with epimerization of
the configurationally labile stereocenters in the substrate,
took place from the trans isomers (an enantiomeric pair).
Scheme 2 outlines the four intermediate equilibrating oxa-
zolidines that result from the three stereoisomers of keto
diester 1a, the two possible lactamization pathways in each
case, which depend on the enantiotopic or diastereotopic
propionate chain that is involved, and the corresponding
chair-like transition states (TS1–TS8), all of which contain
À
an equatorial exocyclic C C bond at the 5-position of the
incipient six-membered lactam. Lactamization eventually
occurs to give cis-fused perhydroquinolones 3a and 4a as
the major products, through oxazolidines ox-1 and ox-2 and
transition states TS1 and TS4, in which the propionate chain
that does not undergo cyclization is equatorial with respect
to the cyclohexane ring. The predominance of lactam 3a is
a consequence of the final irreversible lactamization step
proceeding faster through transition state TS1, which allows
a less-hindered approach of the ester group to the oxazoli-
dine nitrogen atom, anti with respect to the phenyl substitu-
ent. Owing to steric constraints, no trans-fused lactams are
formed.
These results encouraged us to perform similar cyclocon-
densation reactions of keto diesters 1b–1d (mixtures of the
two meso forms and one enantiomeric pair),[7] which incor-
porated an additional substituent at the 4-position of the cy-
clohexanone ring. Gratifyingly, although sixteen different
stereoisomeric tricyclic lactams could have been formed
from the eight possible intermediate equilibrating oxazoli-
dines, this process was highly stereoconvergent, thus leading
to cis-fused tricyclic lactams 3b–3d[8] and 4b–4d[9] in good
yields and stereoselectivities (Table 1).
Scheme 2. Detailed analysis of the lactamization step.
The stereoselective formation of these lactams can be ra-
tionalized as in the above unsubstituted (a) series. The for-
mation of major lactams 3b–3d proceeded from the irrever-
sible lactamization of the pro-S propionate chain in oxazoli-
dines ox-1’, through transition states TS1’, in which both the
À
exocyclic C C bond at the 5-position of the incipient piperi-
done ring and the R and propionate substituents on the cy-
clohexane ring were equatorial (Scheme 3). Similar all-cis
transition states TS4’, which arise from oxazolidines ox-2’
but suffer from repulsive interactions with the phenyl sub-
stituent, would account for the generation of lactams 4b–4d
as minor products. Remarkably, an additional enantioselec-
Chem. Eur. J. 2013, 19, 16044 – 16049
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16045

M. Amat et al.
Table 3. Cyclocondensation reactions of d-keto acids 12 with amino alco-
hols 2 and 7.
Entry
Reagents[a]
R
Yield [%]
Products[b]
Ratio
Scheme 3. Lactamization step in the cyclocondensation reactions of com-
pounds 1b–1d with (R)-phenylglycinol (2).
1
2
3
4
5
6
2+12a
2+12b
2+12c
7+12a
7+12b
7+12c
Me
Et
Bn
Me
Et
76
70
72
78
78
95
13a+14a
13b+14b
13c+14c
3:1
3:1
7:3
15a+16a[c]
15b+16b[c]
15c+16c[c]
9:1[d]
4:1[d]
5:1[d]
tive desymmetrization step occurs in these series; the 4-sub-
stituted carbon atom of the starting stereoisomeric mixtures
of cyclohexanones 1b–1d becomes a stereogenic center with
a well-defined configuration at the 6-position of the perhy-
droquinolone ring.
Bn
[a] Reaction conditions: toluene, reflux. [b] See ref. [9]. [c] The diastereo-
isomers were not separated at this stage. [d] Calculated by NMR spec-
troscopy of the crude reaction mixture.
The use of (1S,2R)-cis-1-amino-2-indanol (7),[10] a confor-
mationally rigid analogue of phenylglycinol, in these cyclo-
condensation reactions slightly improved the stereoselectivi-
ties (Table 2), although the separation of the resulting dia-
stereoisomers was quite problematic and had to be per-
formed in a subsequent synthetic step. Because the absolute
that involved dynamic kinetic resolution with epimerization
of the two configurationally labile stereocenters of the start-
ing mixture of keto acids. As shown in Table 3, in this series,
amino indanol 7 gave better results than phenylglycinol (2)
in terms of chemical yield and stereoselectivity. Lactamiza-
tion to the minor isomers (16) was further hampered by the
presence of the indan nucleus that was cis-fused to the oxa-
zolidine ring. The stereochemical outcome of these cyclo-
condensation reactions can be rationalized on the basis of
a similar analysis to that outlined in Scheme 2.
Table 2. Cyclocondensation reactions of d-keto-acid derivatives 1 and 6
with (1S,2R)-cis-1-amino-2-indanol (7).
The chiral auxiliaries were easily removed by taking ad-
À
vantage of the benzylic character of the exocyclic carbon
nitrogen bond in the above phenylglycinol- and amino-inda-
nol-derived lactams. Thus, after only two additional steps,
that is stereoselective alane reduction and catalytic hydroge-
nation with or without the presence of Boc2O, tricyclic lac-
tams 3 and 13 were converted into cis-decahydroquinolines
19 and 20,[12] which contained substituents at the 6- and/or
8-positions of the carbocyclic ring (Scheme 4).[13] A similar
two-step sequence from diastereoisomeric mixtures of pen-
tacyclic amino-indanol-derived lactams 8+9, 10+11, or
15+16 led to decahydroquinolines ent-19 and ent-20. In this
series, the major diastereoisomers (18) were satisfactorily
isolated after the alane-reduction step.
Entry
Substrate
R
R’
Yield [%]
Products[a,b]
Ratio[c]
1
2
3
1a[d]
1b[d]
6c
H
Me
C6H5
Me
Me
H
82
67
–
8a+9a
8b+9b
10c+11c
3:1
3:1
6:1
[e]
[a] The diastereoisomers were not separated at this stage. [b] See ref. [9].
[c] Calculated by NMR spectroscopy of the crude reaction mixture. [d] In
the presence of Me2CHCOOH. [e] Not purified.
configuration of the benzylic stereocenter in the starting
amino alcohol is S, the decahydroquinoline stereocenters in
the major diastereoisomers (8 and 10) have an opposite con-
figuration to that of the major isomers (3) that were ob-
tained from (R)-phenylglycinol.
To expand the scope of this method, we explored the re-
lated cyclocondensation reactions of cyclohexanone-based
d-keto acids 12a–12c (as mixtures of two enantiomeric
pairs),[11] which contained an additional substituent at the
a’ position of the ketone carbonyl group. In all cases, the re-
actions led to a major lactam (13[8] or 15) through a process
To illustrate the usefulness of this method in the enantio-
selective synthesis of natural products, we applied it to the
synthesis of myrioxazine A, a tricyclic alkaloid that was iso-
lated from Myrioneuron nutans[14] and contained an 8-substi-
tuted cis-decahydroquinoline moiety. Owing to the difficul-
ties that were encountered in preparing the starting material
d-keto acid 12, which contained the required O-protected
hydroxymethyl substituent for the assembly of the perhy-
dro-1,3-oxazine ring, we selected silyl derivative 21 (as a mix-
16046
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 16044 – 16049

Enantio- and Diastereoconvergent Cyclocondensation Reactions
FULL PAPER
nonracemic amino alcohol, which acts as a chiral latent
source of ammonia. The equilibration of the intermediate
oxazolidines, which proceeds through the corresponding
imines/enamines, ensures the stereoselective formation of
the kinetic lactams, regardless of the stereochemistry of the
starting keto-acid derivatives, in a process that involves the
dynamic kinetic resolution and/or desymmetrization of
enantiotopic groups, with the generation of up to four ste-
reocenters of predictable absolute configuration in a single
synthetic step.
Scheme 4. Synthesis of enantiopure substituted cis-decahydroquinolines.
Reagents and conditions: a) LiAlH4, AlCl3, 60–90% yield; b) H2,
Pd(OH)2, MeOH, Boc2O, 70–97% yield; c) H2, Pd(OH)2, MeOH, 70–
95% yield; d) LiAlH4, AlCl3, then separation of the diastereoisomers,
63–84% yield. Boc=tert-butoxycarbonyl.
Experimental Section
General procedure for the cyclocondensation reactions: From keto esters:
(R)-Phenylglycinol (2, 1.3 equiv) or (1S,2R)-cis-1-amino-2-indanol (7,
1.3 equiv) and isobutyric acid (2.8 equiv) were added to a 0.06m solution
of keto diester 1 (1 equiv) in toluene. The mixture was heated at reflux
for 19 h, with azeotropic elimination of water by using a Dean–Stark
system. An additional 1.3 equivalents of the amino alcohol were added
and the stirring was continued for 5 h. After cooling, the mixture was
concentrated under reduced pressure and the resulting residue was dis-
solved in EtOAc. The organic phase was washed with a saturated aque-
ous solution of NaHCO3, dried, filtered, and concentrated. Flash chroma-
tography of the residue on silica gel afforded lactams 3 and 4 (from com-
pound 2) or 8 and 9 (from compound 7).
From keto acids: (R)-Phenylglycinol (2, 1.5 equiv) or (1S,2R)-cis-1-
amino-2-indanol (7, 1–1.5 equiv) was added to a 0.1m solution of keto
acid 6, 12, or 21 in toluene and the mixture was heated at reflux for 24 h
in the presence of anhydrous MgSO4 (2 equiv). The suspension was fil-
tered and the filtrate was concentrated. Flash chromatography of the res-
idue on silica gel afforded lactams 13 and 14 (from compounds 2 and 12),
15 and 16 (from compounds 7 and 12), or 22 (from compounds 7 and 21).
A crude mixture of lactams 10 and 11 (from compounds 6 and 7) was
used without further purification in the next reaction.
Scheme 5. Enantioselective synthesis of myrioxazine A. Reagents and
conditions: a) compound 7, toluene, reflux, 74% yield. b) i) HBF4·Et2O,
CH2Cl2; ii) then m-CPBA, anhydrous KF, DMF, 60% yield, then separa-
tion of the diastereoisomers. c) LiAlH4, AlCl3, 75% yield. d) H2,
Pd(OH)2, MeOH, 66% yield. m-CPBA=meta-chloroperbenzoic acid.
General procedure for the alane-reduction reactions: LiAlH4 (6.6 equiv)
was slowly added to a suspension of AlCl3 (2.2 equiv) in THF at 08C.
The mixture was stirred at 258C for 30 min and then cooled to À788C.
Then, a 0.08m solution of pure lactam 3, 13, or 23, or a mixture of lac-
tams 8+9, 10+11, or 15+16 (1 equiv) in THF was added dropwise. After
stirring at À788C for 1–2 h, the mixture was allowed to warm to RT and
stirred for 2–18 h. Water was added, the resulting mixture was filtered
through Celite, the filtrate was concentrated, and the residue was taken
up with EtOAc or CH2Cl2. The organic solution was washed with brine,
dried, filtered, and concentrated. The resulting residue was purified by
flash chromatography on silica gel to give cis-decahydroquinolines 17
(from 3 or 13), 18 (from mixtures of compounds 8+9, 10+11, or 15+16)
or 24 (from 23).
ture of two racemates),[11] because the SiMe2C6H5 group was
envisaged as a masked hydroxy group (Scheme 5).[15]
In this series, cyclocondensation with amino indanol 7
also took place to give major lactam 22 in good yield (74%)
and excellent stereoselectivity (d.r. 6:1). After oxidation of
silyl derivative 22 by using Fleming’s conditions,[16] removal
of the chiral auxiliary through the usual two-step process
gave amino alcohol 25, a known synthetic precursor of myr-
ioxazine A.[17] The synthesis of compound 25 also represents
a formal synthesis of alkaloids (À)-myrionine,[18] (À)-myrio-
nidine,[12b] (À)-schoberine,[12b] and (+)-N-formylmyrionine.[19]
General procedure for the hydrogenation reactions: Method A: A 0.04m
solution of cis-decahydroquinoline 17 or 18 (1 equiv) and di-tert-butyl di-
carbonate (3 equiv) in EtOAc or MeOH was hydrogenated at RT for 8 h
under atmospheric pressure in the presence of Pd(OH)2 or Pd/C. The cat-
alyst was removed by filtration and the solvent was evaporated. The re-
sulting oil was purified by column chromatography on silica gel to afford
decahydroquinolines 19 (from compound 17) or ent-19 (from compound
18). Method B: The reaction was carried out as in method A, but without
adding di-tert-butyl dicarbonate. The resulting crude oil was purified by
column chromatography on silica gel (compounds 20a–20d) or purified
as follows: A solution of the oil in EtOAc was extracted with 1% aque-
ous HCl and the aqueous layer was basified with 10% aqueous KOH
and extracted with Et2O. The combined organic extracts were dried, fil-
tered, and evaporated.
Conclusion
In conclusion, we have developed a method that allows the
straightforward (in only three synthetic steps), enantioselec-
tive generation of substituted cis-decahydroquinoline scaf-
folds from readily accessible stereoisomeric mixtures (race-
mates, meso forms, diastereoisomers) of d-keto-acid deriva-
tives that already incorporate all of the quinolone carbon
atoms and substituents. The key step is an enantio- and dia-
stereoconvergent cyclocondensation reaction with a chiral
(1R,4aS,8aS,13aR,14aR)-1-[(Dimethylphenylsilyl)methyl]-7-oxo-3-
phenyl-1,2,3,4,4a,5,6,7,8a,13,13a,14a-dodecahydroindeno[1’,2’:4,5]oxazolo-
AHCTUNGTERG[NNUN 2,3-j]quinoline (22): Following the general procedure for cyclocondensa-
Chem. Eur. J. 2013, 19, 16044 – 16049
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16047

M. Amat et al.
tion reactions, from keto acid 21 (359 mg, 1.13 mmol) and (1S,2R)-(À)-
cis-1-amino-2-indanol (7, 252 mg, 1.70 mmol) in anhydrous toluene
(12 mL) that contained anhydrous MgSO4 (272 mg), a 6:1 (calculated by
1H NMR spectroscopy) mixture of lactam 22 and its (1S,4aR,8aS,13a-
R,14aS) isomer (360 mg, 74%) and trace amounts of pure compound 22
were obtained after flash chromatography on silica gel (hexanes/CH2Cl2,
1:1 to 0:1). Data for compound 22: [a]2D3 =+148.6 (c=0.33, MeOH);
1H NMR (400 MHz, CDCl3, COSY-HSQC, 258C): d=À0.20 (dd, J=14.8,
10.8 Hz, 1H, CH2Si), À0.034 (d, J=15.6 Hz, 1H), À0.09 (s, 3H, CH3),
0.04 (s, 3H, CH3), 0.32 (d, J=13.6 Hz, 1H), 1.21–1.14 (m, 1H), 1.32–1.47
(m, 4H), 1.64–1.71 (m, 2H), 1.83–1.90 (m, 2H), 1.99–2.09 (m, 1H), 2.31–
2.41 (m, 1H), 3.19 (d, J=2.8 Hz, 2H, H13), 4.75–4.78 (m, 1H, H13a),
5.87 (d, J=5.6 Hz, 1H, H8a), 7.19–7.32 (m, 8H, ArH), 7.54 ppm (d, J=
5.6 Hz, H11); 13C NMR (100.6 MHz, CDCl3, 258C): d=À2.6 (CH3), À2.2
(CH3), 14.2 (C1’), 18.8 (C5), 19.8 (C3), 26.6 (C4), 28.2 (C2), 30.7 (C6),
36.1 (C4a), 38.1 (C13), 38.5 (C1), 66.0 (C8a), 77.7 (C13a), 99.3 (C14a),
124.9 (ArC), 126.4 (ArC), 127.4 (ArC), 127.6 (ArC), 128.3 (ArC), 128.7
(ArC), 133.4 (ArC), 139.1 (i-C), 141.0 (i-C), 141.7 (i-C), 171.3 ppm (CO);
258C): d=0.74–0.90 (m, 1H), 1.34–1.48 (m, 6H), 1.54–1.57 (m, 1H),
1.70–1.77 (m, 3H), 2.10–2.20 (m, 1H), 2.54–2.70 (br s, 2H), 2.76–2.84 (m,
3H), 3.50 (t, J=10.0 Hz, 1H, CH2OH), 3.61 ppm (dd, J=10.8, 3.6 Hz,
1H, CH2OH); 13C NMR (100.6 MHz, CDCl3, 258C): d=19.9 (C6), 25.1
(C4), 27.8 (C3), 28.4 (C7), 31.4 (C5), 33.4 (C8), 37.5 (C4a), 40.0 (C2),
61.0 (C8a), 70.7 ppm (C1’).
Acknowledgements
Financial support from the Ministry of Economy and Competitiveness,
Spain (CTQ2012-35250), and the Agꢁncia de Gestiꢃ d’Ajuts Universitaris
i de Recerca (AGAUR), Generalitat de Catalunya (2009SGR-203 and
2009SGR-1111), is gratefully acknowledged. We also thank the MICINN
(Spain) for fellowships to L.N. and E.G. The authors are grateful for the
assistance of Bruker AXS GmbH (Karlsruhe) in the X-ray crystallo-
graphic study of compound 3c.
IR
[C27H33NO2Si+H]+: 432.2353; found: 432.2365.
(1R,4aS,8aS,13aR,14aR)-1-(Hydroxymethyl)-7-oxo-3-phenyl-
1,2,3,4,4a,5,6,7,8a,13,13a,14a-dodecahydroindeno[1’,2’:4,5]oxazoloACTHNUGNRTE[NUG 2,3-
(NaCl):
n˜ =1658,
1392 cmÀ1
;
HMRS:
m/z
calcd
for
[1] For reviews, see: a) R. Noyori, M. Tokunaga, M. Kitamura, Bull.
Chem. Soc. Jpn. 1995, 68, 36–56; b) R. S. Ward, Tetrahedron: Asym-
metry 1995, 6, 1475–1490; c) S. Caddick, K. Jenkins, Chem. Soc.
Rev. 1996, 25, 447–456; d) F. F. Huerta, A. B. E. Minidis, J.-E. Bꢄck-
vall, Chem. Soc. Rev. 2001, 30, 321–331; e) K. Faber, Chem. Eur. J.
2001, 7, 5004–5010; f) H. Pellissier, Tetrahedron 2003, 59, 8291–
8327.
[2] For reviews, see: a) R. S. Ward, Chem. Soc. Rev. 1990, 19, 1–19;
b) S. R. Magnuson, Tetrahedron 1995, 51, 2167–2213; c) E. Schoff-
ers, A. Golebiowski, C. R. Johnson, Tetrahedron 1996, 52, 3769–
3826; d) M. C. Willis, J. Chem. Soc. Perkin Trans. 1 1999, 1765–
1784; e) B. Danieli, G. Lesma, D. Passarella, A. Silvani, Curr. Org.
Chem. 2000, 4, 231–261.
j]quinoline (23): A solution of the above 6:1 mixture of lactam 22 and its
isomer (110 mg, 0.26 mmol) and tetrafluoroboric acid diethyl ether com-
plex (1 mL, 0.51 mmol) in dry CH2Cl2 (2 mL) was stirred for 1 h. The
mixture was concentrated and the residue was taken up with DMF
(1 mL). Anhydrous potassium fluoride (61.4 mg, 1.05 mmol) and meta-
chloroperbenzoic acid (217 mg, 0.88 mmol) were added and the pale-
yellow suspension was stirred for 16 h. The resulting mixture was filtered
and the filtrate was concentrated. Flash chromatography on amine-func-
tionalized silica gel (hexanes/EtOAc, 1:1) afforded lactam 23 (49 mg,
60%) as an oil. 1H NMR (400 MHz, CDCl3, COSY, HSQC, 258C): d=
1.40–1.45 (m, 2H, H3, H4), 1.50–1.55 (m, 2H, H2, H3), 1.62–1.70 (m,
2H, H1, H4), 1.80–1.93 (m, 4H, H2, H4a, H5), 2.52–2.56 (m, 1H, H6),
2.79 (dd, J=11.6, 4.8 Hz, 1H, H1’), 2.89 (dd, J=11.6, 4.8 Hz, 1H, H1’),
3.18 (d, J=2.8 Hz, 1H, H13), 4.74 (q, J=2.8 Hz, 1H, H13a), 5.88 (d, J=
5.2 Hz, 1H, H8a), 7.26–7.30 (m, 3H, H9, H10, H12), 7.52 ppm (d, J=
6.8 Hz, 1H, H11); 13C NMR (100.6 MHz, CDCl3, 258C): d = 18.7 (C5),
19.1 (C3), 25.7 (C4), 26.5 (C2), 28.3 (C6), 37.4 (C13), 38.2 (C4a), 42.3
(C1),62.5 (C1’), 65.9 (C8a), 77.8 (C13), 98.2 (C14a), 125.4 (ArC), 126.0
(ArC), 127.8 (ArC), 128.8 (ArC), 140.2 (i-C), 140.8 (i-C), 171.8 ppm
(CO).
[3] M. Amat, O. Bassas, N. Llor, M. Cantꢃ, M. Pꢅrez, E. Molins, J.
Bosch, Chem. Eur. J. 2006, 12, 7872–7881.
[4] For reviews on the use of amino-alcohol-derived lactams as chiral
building blocks for the enantioselective synthesis of piperidine-con-
taining natural products, see: a) D. Romo, A. I. Meyers, Tetrahedron
1991, 47, 9503–9569; b) A. I. Meyers, G. P. Brengel, Chem.
Commun. 1997, 1–8; c) M. D. Groaning, A. I. Meyers, Tetrahedron
2000, 56, 9843–9873; d) C. Escolano, M. Amat, J. Bosch, Chem. Eur.
J. 2006, 12, 8198–8207; e) M. Amat, M. Pꢅrez, J. Bosch, Synlett
2011, 143–160; f) M. Amat, M. Pꢅrez, J. Bosch, Chem. Eur. J. 2011,
17, 7724–7732.
[5] G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz, R. Terrell,
J. Am. Chem. Soc. 1963, 85, 207–222.
[6] Trace amounts of another stereoisomer, 5a (Scheme 2), were also
isolated in some runs.
[7] Keto diesters 1b–1d (as mixtures of stereoisomers) were prepared
in 70–90% yields from their corresponding 4-substittuted cyclohexa-
nones, by the dialkylation of their pyrrolidine enamines with methyl
acrylate at reflux in EtOH.
[8] The absolute configurations of lactams 3c, 13a, and 14a were unam-
biguously determined by X-ray crystallographic analysis. CCDC-
947819 (3c), CCDC-947820 (13a), and CCDC-947821 (14a) contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallograph-
ic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[9] In some cases, trace amounts of other stereoisomers were detected
by NMR spectroscopy of the crude reaction mixtures or were isolat-
ed after purification by column chromatography on silica gel (see
the Supporting Information).
[10] a) For a review on the use of cis-1-amino-2-indanol in asymmetric
synthesis, see: A. K. Ghosh, S. Fidanze, C. H. Senanayake, Synthesis
1998, 937–961; for cyclocondensation reactions of cis-1-amino-2-in-
danol with unbranched d-keto acids, see: b) N. Yamazaki, T. Ito, C.
Kibayashi, Tetrahedron Lett. 1999, 40, 739–742; also see ref. [3].
[11] Keto acids 12 and 21 (mixtures of stereoisomers) were prepared in
excellent overall yields from their corresponding a-substituted cyclo-
(4aS,8R,8aS)-1-[(1S,2R)-2-Hydroxy-1-indanyl]-8-(hydroxymethyl)deca-
hydroquinoline (24): Following the general procedure for alane reduction
(reaction conditions: 1 h at À788C and 18 h at RT), from LiAlH4 (30 mg,
0.80 mmol) and AlCl3 (33 mg, 0.24 mmol) in THF (3 mL) and a solution
of lactam 23 (38 mg, 0.12 mmol) in THF (1 mL), decahydroquinoline 24
(27 mg, 75%) was obtained as an oil after flash chromatography on silica
gel (CH2Cl2/MeOH, 1:0 to 95:5). [a]2D2 =À4.8 (c=0.9, MeOH); 1H NMR
(400 MHz, CDCl3, 258C): d=0.99–1.73 (m, 11H), 2.13–2.23 (m, 3H),
2.70–2.80 (m, 2H), 2.83–2.89 (dd, J=15.6, 8.4 Hz, 1H), 3.00–3.07 (m,
2H), 3.58–3.60 (m, 1H), 3.70 (dd, J=10.8, 4.4 Hz, 1H), 4.27–4.34 (m,
2H), 7.10–7.20 (m, 3H, ArH), 7.37 ppm (d, J=6.8 Hz, 1H, ArH), several
of the signals in the 13C NMR spectrum of compound 24 at 258C were
broad and ill-defined (or even not observed), thus indicating the exis-
tence of
a
slow conformational equilibrium; 13C NMR (100.6 MHz,
CDCl3, 258C): d=20.2 (CH2), 23.0 (CH2), 29.7 (CH2), 31.2 (CH), 39.6
(CH2), 67.9 (CH2), 125.4 (ArC), 126.3 (ArC), 127.3 (ArC), 128.4 (ArC),
140.2 (i-C), 142.5 ppm (i-C); IR (NaCl): n˜ =3301 cmÀ1; HMRS: m/z calcd
for [C19H27NO2+H]+: 302.2115; found: 302.2121.
(4aS,8S,8aR)-8-(Hydroxymethyl)decahydroquinoline (25): A solution of
the hydrochloride salt of compound 24 (41 mg, 0.11 mmol) in MeOH
(3 mL) that contained 40% Pd(OH)2 (16 mg) was hydrogenated at RT
for 24 h at atmospheric pressure. The catalyst was removed by filtration
and the solvent was evaporated. The residue was taken-up in Et2O,
washed with a 10% aqueous solution of NaOH, dried, filtered, and con-
centrated to afford compound 25 (10 mg, 66%) as an oil. Data for com-
pound 25: [a]2D2 =À2.0 (c=0.15, MeOH); 1H NMR (400 MHz, CDCl3,
16048
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 16044 – 16049

Enantio- and Diastereoconvergent Cyclocondensation Reactions
FULL PAPER
hexanones. Reaction conditions: a) i) lithium diisopropylamide
(LDA), tert-butyldimethylsilyl chloride (TMSCl), THF; ii) CH2=
N+Me2ClÀ, CH2Cl2; iii) 2m HCl. b) i) CH
2ACHTNUTRGNE(UNG CO2Et)2, NaOH, toluene;
Amat, L. Navꢀo, N. Llor, E. Molins, J. Bosch, Org. Lett. 2012, 14,
210–213, (6-substituted).
[14] V. C. Pham, A. Jossang, A. Chiaroni, T. Sꢅvenet, B. Bodo, Tetrahe-
dron Lett. 2002, 43, 7565–7568.
ii) acetic acid (AcOH), HCl, reflux.
[12] The 1H and 13C NMR spectra of compound 20a at 258C indicated
the presence of two conformations (see the Supporting Informa-
tion). For NMR conformational studies of cis-decahydroquinolines,
including 6- and 8-substituted derivatives, see: a) F. W. Vierhapper,
E. L. Eliel, J. Org. Chem. 1977, 42, 51–62; b) V. C. Pham, A. Jos-
sang, A. Chiaroni, T. Sꢅvenet, V. H. Nguyen, B. Bodo, Org. Lett.
2007, 9, 3531–3534.
[13] For the enantioselective synthesis of cis-decahydroquinolines
through phenylglycinol-derived tricyclic lactams, see: a) M. Amat,
R. Fabregat, R. Griera, J. Bosch, J. Org. Chem. 2009, 74, 1794–1797,
(5-substituted); b) M. Amat, R. Fabregat, P. Florindo, E. Molins, J.
Bosch, J. Org. Chem. 2010, 75, 3797–3805, (2,5-disubstituted); c) M.
[15] I. Fleming, R. Henning, D. C. Parker, H. E. Plaut, P. E. J. Sanderson,
J. Chem. Soc. Perkin Trans. 1 1995, 317–337.
[16] I. Fleming, R. Henning, H. Plaut, J. Chem. Soc. Chem. Commun.
1984, 29–31.
[17] a) T. A. Crabb, C. H. Turner, J. Chem. Soc. Perkin Trans. 2 1980,
1778–1782; b) A. J. M. Burrell, I. Coldham, N. Oram, Org. Lett.
2009, 11, 1515–1518; see also ref. [14].
[18] V. C. Pham, A. Jossang, P. Grellier, T. Sꢅvenet, V. H. Nguyen, B.
Bodo, J. Org. Chem. 2008, 73, 7565–7573; see also ref. [12b].
[19] V. C. Pham, A. Jossang, T. Sꢅvenet, V. H. Nguyen, B. Bodo, Eur. J.
Org. Chem. 2009, 1412–1416.
Received: July 23, 2013
Published online: October 2, 2013
Chem. Eur. J. 2013, 19, 16044 – 16049
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16049