Ring expansion of functionalized octahydroindoles to enantiopure cis-decahydroquinolines

Article abstract of DOI:10.1021/jo060592p

A new synthetic entry to enantiopure cis-decahydroquinolines is reported. Endo and exo derivatives of cis-1-benzyl-2-(hydroxymethyl)octahydroindol-6-one ethylene acetal undergo ring enlargement upon treatment with TFAA and then Et₃N (thermodyna

Full text of DOI:10.1021/jo060592p

Ring Expansion of Functionalized Octahydroindoles to Enantiopure
cis-Decahydroquinolines†
Marisa Mena and Josep Bonjoch*
Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, UniVersitat de Barcelona,
AV. Joan XXIII s/n, 08028-Barcelona, Spain
Domingo Gomez Pardo and Janine Cossy
Laboratoire de Chimie Organique, associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
josep.bonjoch@ub.edu
ReceiVed March 17, 2006
A new synthetic entry to enantiopure cis-decahydroquinolines is reported. Endo and exo derivatives of
cis-1-benzyl-2-(hydroxymethyl)octahydroindol-6-one ethylene acetal undergo ring enlargement upon
treatment with TFAA and then Et3N (thermodynamic conditions) to give enantiopure 1-benzyl-3-
hydroxydecahydroquinolin-7-one derivatives in 77 and 82% yield, respectively. For 2-(1-hydroxyethyl)
analogues, the best synthetic result is obtained from the (2S,1′R) endo isomer, which under kinetic reaction
conditions (MsCl, THF, -20 °C, then AgOAc at rt ) gives the expanded product in 54% yield.
cis-Decahydroquinoline constitutes the azabicyclic skeleton
of natural products such as lepadins1 and several amphibian
alkaloids,2 as well as some pharmacologically interesting syn-
thetic compounds.3 Moreover, this heterocyclic motif occurs as
a subunit of other azapolycyclic natural products (e.g., gephy-
rotoxins,4 cylindricines,5 and pseudoaspidopermidine and pan-
doline alkaloids6) (Figure 1). The extensive occurrence of this
azabicyclic ring has stimulated the implementation of new
procedures to gain access to functionalized enantiopure cis-
decahydroquinolines that can be used as advanced intermediates
in the synthesis of compounds embodying this skeleton-type.7
In this paper, we report the studies devoted to the ring
enlargement of cis-octahydroindole derivatives to cis-decahy-
droquinolines. The diastereoselective ring expansion of mono-
cyclic amines (azetidines,8 pyrrolidines,9,10 pyrrolines,11 pipe-
ridines12) and bicyclic amines (2-azabicyclo[3.3.0]octanes,13
† Dedicated to the memory of the late Professor Marcial Moreno Man˜as.
(1) Pu, X.; Ma, D. Angew. Chem., Int. Ed. 2004, 43, 4222-4225 and
references therein.
(2) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68,
1556-1575.
(3) (a) Witiak, D. T.; Tomita, K.; Patch, R. J.; Enna, S. J. J. Med. Chem.
1981, 24, 788-94. (b) Combrink, K. D.; Gulgeze, H. B.; Yu, K.-L.; Pearce,
B. C.; Trehan, A. K.; Wei, J.; Deshpande, M.; Krystal, M.; Torri, A.; Luo,
G.; Cianci, C.; Danetz, S.; Tiley, L.; Meanwell, N. A. Bioorg. Med. Chem.
Lett. 2000, 10, 1649-1652. See also Daly, J. W.; Nishizawa, Y.; Padgett,
W. L.; Tokuyama, T.; McCloskey, P. J.; Waykole, L.; Schultz, A. G.;
Aronstam, R. S. Neurochem. Res. 1991, 16, 1207-1212.
(4) Wei, L.-L.; Hsung, R. P.; Sklenicka, H. M.; Gerasyuto, A. I. Angew.
Chem., Int. Ed. 2001, 40, 1516-1518, and references therein.
(5) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2005, 127,
1473-1480 and references therein.
(6) Kuehne, M. E.; Okuniewicz, F. J.; Kirkemo, C. L.; Bohnert, J. C. J.
Org. Chem. 1982, 47, 1335-1343.
(7) For the synthesis of enantiopure cis-decahydroquinolines, see inter
alia: (a) Comins, D. L.; Brooks, C. A.; Al-awar, R. S.; Goehring, R. R.
Org. Lett. 1999, 1, 229-231. (b) Toyooka, N.; Okumura, M.; Takahatam,
H.; Nemoto, H. Tetrahedron 1999, 55, 10673-10684. (c) Osawa, T.;
Aoyagi, S.; Kobayashi, C. J. Org. Chem. 2001, 66, 3338-3347. (d) Banner,
E. J.; Stevens, E. D.; Trudell, M. L. Tetrahedron Lett. 2004, 45, 4411-
4414. (e) Dijk, E. W.; Panella, L.; Pinho, P.; Naasz, R.; Meetsma, A.;
Minnaard, A. J.; Feringa, B. L. Tetrahedron 2004, 60, 9687-9693. (f) Mena,
M.; Bonjoch, J. Tetrahedron 2005, 61, 8264-8270.
(8) Couty, F.; Durrat, F.; Prim, D. Tetrahedron Lett. 2003, 44, 5209-
5212.
(9) (a) Cossy, J.; Dumas, C.; Michel, P.; Gomez Pardo, D. Tetrahedron
Lett. 1995, 36, 549-552. (b) Cossy, J.; Dumas, C.; Gomez Pardo, D. Eur.
J. Org. Chem. 1999, 1693-1699.
10.1021/jo060592p CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/07/2006
5930
J. Org. Chem. 2006, 71, 5930-5935

Ring Expansion of Octahydroindoles to cis-Decahydroquinolines
SCHEME 1. Synthetic Approach to Enantiopure
cis-Decahydroquinolines
reflect their thermodynamic stability. On the contrary, if X-
were an acetate and the chloride ion were taken out of the
reaction medium using silver acetate, the ring opening of the
aziridinium ion would be irreversible and the ratio of the formed
compounds would arise from a kinetic control.
FIGURE 1. Natural and synthetic compounds embodying the cis-
decahydroquinoline framework.
1-azabicyclo[2.2.2]octanes,14 indolizidines,15 indolines,16 hexahy-
dropyrrolo[3,4-d]isoxazoles17) with a hydroxymethyl substituent
adjacent to the nitrogen atom is a well-known process,18,19 but
it is unprecedented in octahydroindole compounds. Considering
the precedents, we envisaged that the transformation (Scheme
1) would occur via aziridinium intermediates20 once the hydroxyl
group is converted into a good leaving group. A ring opening
at the fused carbon atom would then lead to a new heterocyclic
derivative with an expanded ring. If the leaving group were a
chloride or trifluoroacetate, in absence of another nucleophile
in the reaction medium, the process would be reversible and
the ratio of the expanded and nonexpanded compounds would
Our study of the stereospecific rearrangement of 2-hy-
droxymethyl- and 2-(R-hydroxyethyl)octahydroindoles to 3-sub-
stituted and 2,3-disubstituted decahydroquinolines began with
the preparation of the rearrangement precursors (Scheme 2). The
starting materials were the azabicyclic esters endo 1 and exo 2,
which were available from O-methyltyrosine in three steps
(Birch reduction, aminocyclization promoted by MeOH-HCl,
and benzylation).21 Both esters were protected to give acetals 3
and 4 that, in turn, were reduced with LiBH4 to the correspond-
ing primary alcohols 5 and 6 in 80% overall yield in each series.
On the other hand, the preparation of the secondary alcohols
was carried out as follows: esters 3 and 4 were transformed to
methyl ketones 7 (endo) and 8 (exo), respectively, in a two-
step sequence involving the formation of their corresponding
Weinreb amides22 followed by coupling with methylmagnesium
bromide. Then, ketones 7 and 8 were both reduced with NaBH4
to give a mixture of secondary alcohols 9a and 10a (55:45
ratio)23 in the endo series and 11a and 12a (63:37 ratio) in the
exo series. At this point, improving the diastereoselectivity of
the reduction was not a priority since the availability of all the
diastereomers would help evaluate the scope and limitations of
the enlargement process.
Two 13C NMR features clearly differentiate the endo and exo
series of cis-2-substituted octahydroindol-6-ones (Supporting
Information, Table 1): (i) the chemical shift of the benzylic
carbon resonates at a higher field in exo compounds (δ 51.5-
54.0) than in the endo compounds (δ 59-63); (ii) the C-7 signal
appears at lower values in the exo compounds (δ 29-32) than
in the endo isomers (δ 37-39). It is worth noting that the
stereochemistry at C-1′ for alcohols 9a-12a was unequivocally
established only after the stereochemical elucidation of the
expanded decahydroquinolines (cf. vide infra). The conforma-
tionally mobile cis-octahydroindole system21 has two conformers
(N-outside and N-inside) in which H-7a is axial or equatorial,
respectively, with respect to the carbocyclic ring. NMR studies
allowed us to assign the conformational preference of the
(10) (a) Hammer, C. F.; Weber, J. D. Tetrahedron 1981, 37, 2173-2180.
(b) Calvez, O.; Chiaroni, A.; Langlois, N. Tetrahedron Lett. 1998, 39, 9447-
9450. (c) Lee, J.; Hoang, T.; Lewis, S.; Weisman, S. A.; Askin, D.; Volante,
R. P.; Reider, P. J. Tetrahedron Lett. 2001, 42, 6223-6225. (d) Chang,
M.-Y.; Chen, C.-Y.; Tasi, M.-R.; Tseng, T.-W.; Chang, N.-C. Synthesis
2004, 840-846. (e) Mino, T.; Saito, A.; Tanaka, Y.; Hasegawa, S.; Sato,
Y.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2005, 70, 1937-1940.
(11) Turner, P. G.; Donohoe, T. J.; Cousins, R. P. C. Chem. Commun.
2004, 1422-1423.
(12) Chong, H.-S.; Ganguly, B.; Broker, G. A.; Rogers, R. D.; Brechbiel,
M. W. J. Chem. Soc., Perkin Trans. 1 2002, 2080-2086.
(13) Wilken, J.; Kossenjans, M.; Saak, W.; Haase, D.; Pohl, S.; Martens,
J. Liebigs Ann./Recl. 1997, 12, 573-579.
(14) Ro´per, S.; Frackenpohl, J.; Schrake, O.; Wartchow, R.; Hoffmann,
H. M. R. Org. Lett. 2000, 2, 1661-1664.
(15) Verhelst, S. H. L.; Paez Martinez, B.; Timmer, M. S. M.; Lodder,
G.; van der Marel, G. A.; Overkleeft, H. S.; van Boom, J. H. J. Org. Chem.
2003, 68, 9598-9603.
(16) Ori, M.; Toda, N.; Takami, K.; Tago, K.; Kogen, H. Tetrahedron
2005, 61, 2075-2104.
(17) Deyine, A.; Delcroix, J.-M.; Langlois, N. Heterocycles 2004, 64,
207-214.
(18) For some applications in natural products synthesis, see (a) Harding,
K. E.; Burks, S. R. J. Org. Chem. 1984, 49, 40-44. (b) Kuehne, M. E.;
Podhorez, D. E. J. Org. Chem. 1985, 50, 924-929. (c) Williams, D. R.;
Osterhout, M. H.; McGill, J. M. Tetrahedron Lett. 1989, 30, 1331-1334.
(d) Morimoto, Y.; Shirahama, H. Tetrahedron 1996, 52, 10631-10652 (e)
Cossy, J.; Mirguet, O.; Gomez Pardo, D. Synlett 2001, 1575-1577. (f) Ori,
M.; Toda, N.; Takami, K.; Tago, K.; Kogen, H. Angew. Chem., Int. Ed.
2003, 42, 2540-2543.
(19) For some applications in therapeutical agent synthesis, see (a) Cossy,
J.; Dumas, C.; Gomez Pardo, D. Bioorg. Med. Chem. Lett. 1997, 7, 1343-
1346. (b) Cossy, J.; Mirguet, O.; Gomez Pardo, D.; Desmurs, J.-R.
Tetrahedron Lett. 2001, 42, 5705-5707 (c) Cossy, J.; Mirguet, O.; Gomez
Pardo, D.; Desmurs, J.-R. Eur. J. Org. Chem. 2002, 3543-3551. (d)
De´champs, I.; Gomez Pardo, D.; Karoyan, P.; Cossy, J. Synlett. 2005, 1170-
1172.
(20) For a review on the synthesis of six-membered nitrogen-containing
compounds via aziridinium intermediates, see Cossy, J.; Gomez Pardo, D.
Chemtracts 2002, 15, 579-605.
(21) Valls, N.; Lo´pez-Canet, M.; Vallribera, M.; Bonjoch, J. Chem.s
Eur. J. 2001, 7, 3446-3460.
(22) For the preparation of N-methoxy-N-methylamides from esters using
isopropylmagnesium chloride, see Williams, J. M.; Jobson, R. B.; Yasuda,
N.; Marchesini, G.; Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett.
1995, 36, 5461-5464.
(23) Using LS-Selectride as the reducing agent, ketone 7 furnished
stereoselectively alcohol 10a.
J. Org. Chem, Vol. 71, No. 16, 2006 5931

Mena et al.
SCHEME 2. Synthesis of cis-2-Hydroxymethyl- and 2-(r-Hydroxyethyl)octahydroindole Derivatives
SCHEME 3. Synthesis of 3-Hydroxydecahydroquinolines
described cis-2-substituted octahydroindol-6-one derivatives, in
which the coupling constants H7-H7a (one of them of 11 Hz)
are consistent with antiperiplanar couplings, indicating that the
H-7a proton24 is axially located with respect to the carbocyclic
ring (Figure 2).
FIGURE 2. Preferred conformation of endo and exo compounds 5
and 6.
H-8a in each diastereomer are in accordance with an axial and
an equatorial relationship, respectively, with respect to the
N-containing ring (N-exo conformation).25 The 13C NMR data
corroborate the above stereochemical elucidation because both
13 and 14 show a relative upfield shift for C-2 and C-8, a
characteristic feature of cis-decahydroquinolines in the N-exo
conformation (see Figure 3).
When we applied the same procedure (TFAA, THF, then
Et3N) to the secondary alcohols 9a-12a under thermodynamic
reaction conditions, the results were disappointing. After long
reaction times (4-5 days at reflux temperature), only the starting
material and degradation products were obtained.26,27 The next
attempt to expand the ring involved converting alcohols
9a-12a to the secondary chlorides 9b-12b that then were
Treatment of 2-(hydroxymethyl)octahydroindole derivative
5 with TFAA in THF followed by the addition of triethylamine9
led to the ring-expanded product that after a hydrolytic workup
(aqueous NaOH) allowed the isolation of decahydroquinoline
13 (Scheme 3). The NMR data (see below) of this compound
prove that the configuration of C-3 in (-)-13 is R, which
supports the mechanism depicted in Scheme 1 (stereocontrolled
process during the nucleophilic attack at C-2 of the aziridinium
intermediate). The same protocol (TFAA/Et3N/NaOH) also was
applied to the exo isomer 6, with decahydroquinoline (+)-14
being isolated as a single isomer in 82% yield. Both decahy-
droquinolines show the same preferred conformation according
to their NMR spectra. Thus, the coupling constants of H-4a and
(25) For 13C NMR studies in cis-decahydroquinolines, see Spande, T.
F.; Jain, P.; Garraffo, H. M.; Pannell, L. K.; Yeh, H. J. C.; Daly, J. W.;
Fukumoto, S.; Imamura, K.; Torres, J. A.; Snelling, R. R.; Jones, T. H. J.
Nat. Prod. 1999, 62, 5-21.
(24) The chemical shift of H-3a and H-7a appears more deshielded in
the exo derivatives than in the endo compounds, due to the syn relationship
of the nitrogen lone pair with both protons in the exo series (Figure 2).
5932 J. Org. Chem., Vol. 71, No. 16, 2006

Ring Expansion of Octahydroindoles to cis-Decahydroquinolines
SCHEME 5. Ring Expansion under Kinetic Conditionsa
FIGURE 3. Stereochemistry of cis-decahydroquinolines.
SCHEME 4. Attempted Ring Expansion under
Thermodynamic Conditions
heated in refluxing THF. In all cases, the unexpanded 2-(R-
chloroethyl)octahydroindoles 9b-12b were isolated (Scheme
4).28 Because the configuration at C-1′ was retained, these results
show that the process occurred through an aziridinium salt
intermediate and that chlorides 9b-12b were directly formed
either by the opening of an aziridinium by the chloride ion or
by a reversion process from an initially expanded product. Thus,
under thermodynamic reaction conditions, we were unable to
achieve 2,3-disubstituted decahydroquinolines from octahy-
droindoles 9a-12a.29
a Method A: (i) MsCl, Et3N, THF reflux, 4 h. (9b-12b formed); (ii)
AgOAc, THF reflux, 4 h. Method B: (i) MsCl, Et3N, THF, -20 °C; (ii)
AgOAc, rt, 1 h.
To have an irreversible ring opening of the aziridinium inter-
mediate, the chlorides 9b-12b were treated with AgOAc in a
THF solution at reflux temperature (Method A). Under these
kinetic conditions, the ring-expanded decahydroquinolines
17-19 were formed in variable yields (Scheme 5), and 20 was
detected only in the GC-MS analysis. The nonenlarged acetates
9c-12c formed by the acetate attack on the carbon linked to
the methyl group in the aziridinium intermediate also were
isolated.30 The best results from a synthetic point of view were
obtained for the endo compound 9b, because it was only in
this series that the decahydroquinoline derivative was isolated
as the main product. We then decided to carry out the process
starting from alcohols 9a-12a, working at -20 °C to avoid
the formation of the corresponding chlorides,10c and promoting
the ring opening of the aziridinium with AgOAc at rt (Method
B). This decrease in temperature led to a slight increase in the
ratio of the thermodynamically unfavored decahydroquinolines
(see Scheme 5). As expected, the endo series of 2-(R-hydroxy-
ethyl)octahydroindoles obtained the best result from alcohol 9a
that transformed into the decahydroquinoline 17 in 54-58%
yield.31,32 The reason was that the aziridinium intermediate was
formed and opened without generating steric repulsion because
(26) Decahydroquinoline 15 was isolated in one run working from alcohol
11a, although only in 5% yield. For 13C NMR data, see Supporting
Information, Table 2.
(27) The use of microwave conditions did not give satisfactory results
either.
(28) Together with chloride 9b, the expanded product 16 was formed
according to the 13C NMR spectrum of the reaction mixture. For NMR
data of 9b-12b, see Supporting Information.
(30) It was confirmed in two series that the configuration at C-1′ of the
side chain was identical to that of the starting alcohol. Treatment of 10a
and 11a with acetic anhydride gave the same acetates 10c and 11c as those
obtained through sequential treatment with MsCl and Et3N, then AgOAc.
(29) There are scarcely any examples of ring enlargement via aziridinium
ions from secondary alcohols, and they are always of the benzylic type
(see refs 9b and 10b,c).
J. Org. Chem, Vol. 71, No. 16, 2006 5933

Mena et al.
SCHEME 6
CH2Cl2) to give 173 mg (77%) of 13 as a colorless oil: Rf ) 0.35
(SiO2, CH2Cl2/MeOH 95:5); [R]20D -44 (c 0.3, CHCl3); 1H NMR
(500 MHz, gCOSY, CDCl3) 1.45 (dm, J ) 10.5 Hz, 1H, H-5eq),
1.47 (m, 1H, H-6eq), 1.50 (q, J ) 10.5 Hz, 1H, H-4ax), 1.55 (m,
1H, H-6ax), 1.58 (m, 1H, H-4eq), 1.61 (ddd, J ) 12.5, 4.5, 2.0
Hz, 1H, H-8eq), 1.73 (tt, J ) 13.5, 5.0 Hz, 1H, H-5ax), 1.82 (t, J
) 12.5 Hz, 1H, H-8ax), 1.97 (dm, J ) 10.5 Hz, 1H, H-4a), 2.10 (t,
J ) 10.5 Hz, 1H, H-2ax), 2.62 (ddd, J ) 10.5, 5.0, 1.5 Hz, 1H,
H-2eq), 3.00 (dt, J ) 12.5, 4.5 Hz, 1H, H-8a), 3.45 and 3.66 (2d,
J ) 12.5 Hz, 1H each, NCH2Ar), 3.68 (dddd, J ) 10.5, 10.5, 5.0,
5.0, 1H, H-3ax), 3.80-3.90 (m, 4H, OCH2), 7.20-7.30 (m, 5H,
ArH); 13C NMR (75 MHz, gHSQC) 26.9 (C-5), 27.0 (C-8), 29.9
(C-6), 32.8 (C-4a), 33.1 (C-4), 52.0 (C-2), 57.0 (C-8a), 58.3 (NCH2),
64.1 and 64.2 (OCH2), 68.1 (C-3), 109.9 (C-7), 126.8, 128.1, 129.5,
139.3 (Ar). Anal. Calcd for C18H25NO3: C 71.26, H 8.31, N 4.62.
Found: C 70.86, H 8.03, N 4.38.
(3R,4aR,8aR)-1-Benzyl-3-hydroxy-7-oxodecahydroquinoline
Ethylene Acetal (14). Similar to the above procedure, alcohol 6
(464 mg, 1.53 mmol) in THF (4 mL) was treated with TFAA (0.43
mL, 3.04 mmol, 2 equiv) and then with Et3N (1.07 mL, 7.65 mmol,
5 equiv). After workup, the crude material was purified by
chromatography (SiO2, 1-5% MeOH in CH2Cl2) to give 14 (380
mg, 82%) as a white solid: Rf ) 0.40 (SiO2, CH2Cl2/MeOH 95:5);
mp 101-103 °C; [R]20D +39 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3, gCOSY) 1.47 (m, 1H, H-6eq), 1.52 (m, 1H, H-5eq), 1.55
(m, 1H, H-4), 1.60 (m, 1H, H-6ax), 1.68 (m, 2H, H-4, H-8eq),
1.80 (tt, J ) 13.5, 5.0 Hz, 1H, H-5ax), 1.87 (t, J ) 12.5 Hz, 1H,
H-8ax), 2.31 (dm, J ) 10.5 Hz, 1H, H-4a); 2.52 and 2.57 (2d, J )
12.0 Hz, 1H each, H-2), 3.15 (dt, J ) 12.5, 4.5 Hz, 1H, H-8a),
3.48 and 3.71 (2d, J ) 13.0 Hz, 1H each, NCH2Ar), 3.84 (br s,
1H, H-3eq), 3.90-3.95 (m, 4H, OCH2), 7.20-7.35 (m, 5H, ArH);
13C NMR (100 MHz, CDCl3, gHSQC), 25.6 (C-8), 26.6 (C-5), 29.8
(C-6), 28.8 (C-4a), 30-5 (C-4), 50.6 (C-2), 57.7 (C-8a), 58.5
(NCH2), 64.1 and 64.3 (OCH2), 65.4 (C-3), 109.8 (C-7), 127.2,
128.4, 128.7, 139.0 (Ar). Anal. Calcd for C18H25NO3: C 71.26, H
8.31, N, 4.62. Found: C 70.89, H 8.50, N 4.44.
Ring Expansion of Alcohol 9a. A solution of alcohol 9a (50
mg, 0.16 mmol) in THF (1 mL) was treated with MsCl (16 µL,
0.19 mmol, 1.2 equiv) and Et3N (90 µL, 0.64 mmol, 4 equiv) under
an argon atmosphere at -20 °C for 1 h. AgOAc was added (80
mg, 0.48 mmol, 3 equiv) and the resulting mixture was warmed to
rt over a period of 1 h. The reaction mixture was filtered through
a bed of Celite and diluted with CH2Cl2. The organic layer was
washed with saturated NaHCO3 (10 mL), dried, and concentrated
to give a mixture of acetates 9c and 17. Purification and separa-
tion of the compounds were performed by chromatography (SiO2,
CH2Cl2/EtOAc 9:1) to afford 14 mg (24%) of 9c and 31 mg (54%)
of 17 (see Supporting Information for analytical data).
of the antiperiplanar relationship between the methyl group and
the C(2)-C(3) bond. In contrast, the reason for the poor yields
observed in the ring-expanded compounds in the exo series (11a
and 12a) is unclear even when taking into consideration that
the transition states between 12a and decahydroquinoline 20
are likely to be the most sterically demanding of the four
pathways leading to expanded compounds. Figure 3 depicts the
preferred conformation of all the synthesized 3-oxygenated cis-
decahydroquinolines.
Finally, to obtain a better understanding of the ring-enlarge-
ment process, decahydroquinoline 21 (obtained under kinetic
conditions from 9a)31 was submitted to the thermodynamic
conditions of the aziridinium ring formation and opening
(TFAA, then Et3N followed by heating at reflux for 8 h, and
ending with an aqueous NaOH treatment). Under these condi-
tions, octahydroindole 9a was formed, albeit as the only product
(Scheme 6). This result confirms that 2-(R-hydroxyethyl)octa-
hydroindoles are more stable than 2-methyl-3-hydroxyquinolines
in the series of compounds examined (9-12 vs 17-20).
In summary, the study of the ring enlargement of cis-octa-
hydroindole derivatives has given access to valuable function-
alized enantiopure cis-decahydroquinolines (13 and 14, in
excellent yields, and 17 in good yield), which could be used as
building blocks in the synthesis of natural products. Moreover,
it has been shown that subtle stereochemical differences in the
octahydroindoles studied can have a significant impact on the
ring-expansion pathway when the process is carried out under
thermodynamic or kinetic conditions.
(2S,3aS,7aS)-1-Benzyl-2-[(1′R)-(1-acetoxyethyl)]octahydroin-
dol-6-one Ethylene Acetal (9c). Colorless oil. Rf ) 0.38 (SiO2,
Experimental Section
CH2Cl2/EtOAc 8:2); [R]20 -10.7 (c 0.4, CHCl3); IR 1736 cm-1
;
(3R,4aS,8aS)-1-Benzyl-3-hydroxy-7-oxodecahydroquinoline
Ethylene Acetal (13). To a solution of alcohol 5 (223 mg, 0.74
mmol) in THF (2 mL) cooled to -78 °C, TFAA (0.21 mL, 1.47
mmol, 2 equiv) was added, and the reaction mixture was stirred
for 3 h at this temperature. Et3N (0.5 mL, 3.68 mmol, 5 equiv)
was added, and after 15 min, the reaction mixture was heated at
reflux for 20 h. The mixture was cooled to 25 °C and 2.5 N NaOH
(15 mL, 50 equiv) was added. After this mixture was stirred for 3
h, the reaction mixture was extracted with CH2Cl2 (3 × 20 mL).
The organic extracts were dried and concentrated to give an oil
that was purified by chromatography (SiO2, 1-5% MeOH in
D
1H NMR (400 MHz, CDCl3, gCOSY) 1.23 (d, J ) 6.4 Hz, 3H,
CH3), 1.26 (m, 2H, H-5), 1.44 (d, J ) 8.4 Hz, 2H, H-7), 1.60 (m,
2H, H-4), 1.76 (m, 2H, H-3), 2.07 (s, 3H, OAc), 2.20 (m, 1H, H-3a),
2.90 (q, J ) 8.4 Hz, 1H, H-7a), 2.91 (ddd, J ) 8.4, 8.0, 4.0 Hz,
1H, H-2), 3.63 and 3.86 (2d, J ) 14.0 Hz, 1H each, NCH2Ar),
3.66-3.83 (m, 4H, OCH2), 5.05 (qd, J ) 6.4, 4.0 Hz, 1H, H-1′),
7.20-7.35 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3), see Table
1. HRFABMS: calcd for C21H30NO4 360.2175 (MH+), found
360.2170.
(2S,3R,4aS,8aS)-3-Acetoxy-1-benzyl-2-methyl-7-oxodecahyd-
roquinoline Ethylene Acetal (17). Colorless oil. Rf ) 0.84 (SiO2,
CH2Cl2/EtOAc 8:2). [R]20D -37 (c 1.0, CHCl3); IR 1734 cm-1; 1H
NMR (400 MHz, CDCl3, gCOSY) 1.03 (d, J ) 6.4 Hz, 3H, Me),
1.45-1.74 (m, 7H, H-4, H-5, H-6, and H-8eq), 1.91 (t, J ) 12.4
Hz, 1H, H-8ax), 2.06 (s, 3H, OAc), 2.10 (dm, J ) 12.0 Hz, 1H,
H-4a), 2.84 (dq, J ) 10.0, 6.0 Hz, 1H, H-2ax), 2.93 (dt, J )
12.4, 4.4 Hz, 1H, H-8a), 3.63 and 3.90 (2d, J ) 14.8 Hz, 1H each,
NCH2Ar), 3.81-3.94 (m, 4H, OCH2), 4.60 (td, J ) 11.0, 5.2 Hz,
(31) The use of silver trifluoroacetate instead of silver acetate slightly
increased the yield of the expanded compound, which gave alcohol 21 (58%)
after a basic workup (see Scheme 6).
(32) The use of tetrabutylammonium acetate did not improve the course
of the reaction. From 9a, a mixture of acetates 17 (38%) and 9c (34%)
were isolated, whereas from 10a-12a, more complex reaction mixtures
were formed with the decahydroquinolines 18, 19, and 20 being obtained
in a yield lower than 10%.
5934 J. Org. Chem., Vol. 71, No. 16, 2006

Ring Expansion of Octahydroindoles to cis-Decahydroquinolines
1H, H-3ax), 7.18-7.35 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3,
DEPT, gHSQC) 16.8 (Me), 21.3 (OAc), 26.6 (C-5), 28.1 (C-8),
29.6 (C-4), 29.7 (C-6), 31.4 (C-4a), 52.6 (NCH2), 53.0 (C-2), 55.8
(C-8a), 64.0 and 64.1 (OCH2), 75.5 (C-3), 109.8 (C-7), 126.5, 127.7,
128.2, 141.2 (Ar), 170.6 (CO). HRFABMS: calcd for C21H30NO4
360.2175 (MH+), found 360.2171.
Spain, for a fellowship to M.M. I. D. R. SERVIER (France) is
greatly acknowledged for experiments with microwave condi-
tions.
Supporting Information Available: Experimental and NMR
data for all compounds reported. Tables of 13C NMR chemical shifts
of octahydroindoles and decahydroquinolines reported. Copies of
1H and 13C NMR spectra of all new compounds as well as COSY
and HSQC spectra when available. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by the
Ministry of Education and Science (MEC, Spain)-FEDER
through Project CTQ2004-04701/BQU. Thanks are due also to
the DURSI (Catalonia) for Grant 2005SGR-00442 and the MEC,
JO060592P
J. Org. Chem, Vol. 71, No. 16, 2006 5935