Enantioselective synthesis of pyrrolidine-, Piperidine-, and azepane-type N -heterocycles with α-alkenyl substitution: The CpRu-catalyzed dehydrative intramolecular N -allylation approach

Article abstract of DOI:10.1021/ol203218d

A cationic CpRu complex of chiral picolinic acid derivatives [(R)- or (S)-Cl-Naph-PyCOOCH₂CH=CH₂] catalyzes asymmetric intramolecular dehydrative N-allylation of N-substituted ω-amino- and -aminocarbonyl allylic alcohols with a substrate/catalyst ratio of up to 2000 to give α-alkenyl pyrrolidine-, piperidine-, and azepane-type N-heterocycles with an enantiomer ratio of up to >99:1. The wide range of applicable N-substitutions, including Boc, Cbz, Ac, Bz, acryloyl, crotonoyl, formyl, and Ts, significantly facilitates further manipulation toward natural product synthesis.

Full text of DOI:10.1021/ol203218d

ORGANIC
LETTERS
2012
Vol. 14, No. 2
608–611
Enantioselective Synthesis of Pyrrolidine-,
Piperidine-, and Azepane-Type
N-Heterocycles with R-Alkenyl Substitution:
The CpRu-Catalyzed Dehydrative
Intramolecular N-Allylation Approach
Tomoaki Seki, Shinji Tanaka, and Masato Kitamura*
Research Center for Materials Science and the Department of Chemistry, Nagoya
University, Chikusa, Nagoya 464-8602, Japan
kitamura@os.rcms.nagoya-u.ac.jp
Received December 2, 2011
ABSTRACT
A cationic CpRu complex of chiral picolinic acid derivatives [(R)- or (S)-Cl-Naph-PyCOOCH2CHdCH2] catalyzes asymmetric intramolecular
dehydrative N-allylation of N-substituted ω-amino- and -aminocarbonyl allylic alcohols with a substrate/catalyst ratio of up to 2000 to give
R-alkenyl pyrrolidine-, piperidine-, and azepane-type N-heterocycles with an enantiomer ratio of up to >99:1. The wide range of applicable
N-substitutions, including Boc, Cbz, Ac, Bz, acryloyl, crotonoyl, formyl, and Ts, significantly facilitates further manipulation toward natural
product synthesis.
Saturated N-heterocycles, such as pyrrolidines, piperi-
dines, azepanes, and their benzo-fused compounds, con-
stitute a core part of pharmaceutically important natural
alkaloids1 and have therefore attracted much attention
from synthetic chemists for the efficient stereoselective
construction of these molecules,2 particularly in a catalytic
enantioselective manner. Among many approaches,3 in-
stallation of an alkenyl group at the R-position via intra-
molecular enantioselective NꢀCR bond formation3f,4 is
(1) (a) Roberts, M. F.; Wink, M. In Alkaloids: Biochemistry, Ecology
and Medicinal Applications; Plenum: New York, 1998. (b) Buckingham, J.;
ꢀ
Baggaley, K. H.; Roberts, A. D.; Szabo, L. F. In Dictionary of Alkaloids, 2nd
ed.; CRC press: Boca Raton, FL, 2009.
(2) Pyrrolidines and piperidines: (a) Borsini, E.; Broggini, G.; Colombo,
F.; Khansaa, M.; Fasana, A.; Galli, S.; Passarella, D.; Riva, E.; Riva, S.
(3) PictetꢀSpengler-type reaction: (a) Taylor, M. S.; Tokunaga, N.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 6700–6704. Reviews for
dehydrogenative CꢀC bond formation:(b) Scheuermann, C. J. Chem.;
Asian J. 2010, 5, 436–451. (c) Li, C.-J. Acc. Chem. Res. 2009, 42, 335–344.
Metalo-ene reaction: (d) Hara, O.; Fujino, H.; Makino, K.; Hamada, Y.
Heterocycles 2008, 76, 197–202. Intramolecular C-allylation: (e) Bihelovic,
F.; Matovic, R.; Vulovic, B.; Saicic, R. N. Org. Lett. 2007, 9, 5063–5066.
Review for hydroamination of alkenes, allenes, and alkynes: (f) Chemler,
S. R. Org. Biomol. Chem. 2009, 7, 3009–3019. See also: (g) Manna, K.; Xu,
S.; Sadow, A. D. Angew. Chem., Int. Ed. 2011, 50, 1865–1868. Oxidative
aminocarbonylation: (h) Tsujihara, T.; Shinohara, T.; Takenaka, K.;
Takizawa, S.; Onitsuka, K.; Hatanaka, M.; Sasai, H. J. Org. Chem.
2009, 74, 9274–9279. Reviews for hydrogenation of enamines, imines,
and N-heterocycles: (i) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Chem. Rev.
2011, 111, 1713–1760. (j) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357–
1366. (k) Glorius, F. Org. Biomol. Chem. 2005, 3, 4171–4175. Review for
1,4-addition of amines: (l) Enders, D.; Wang, C.; Liebich, J. X. Chem.;
Eur. J. 2009, 15, 11058–11076.
Tetrahedron: Asymmetry 2011, 22, 264–269. (b) Vicario, J. L.; Badı
´
a, D.;
Carrillo, L.; Ruiz, N.; Reyes, E. In Targets in Heterocyclic Systems:
ꢀ
Chemistry & Properties; Spinelli, D., Attanasi, O. A., Eds.; Societa Chimica
Italiana: Rome, 2008; Vol. 12, pp 302ꢀ327. (c) Escolano, C.; Amat, M.;
Bosch, J. Chem.;Eur. J. 2006, 12, 8198–8207. (d) Buffat, M. G. P. Tetra-
hedron 2004, 60, 1701–1729. (e) Felpin, F.-X.; Lebreton, J. Eur. J. Org.
Chem. 2003, 3693–3712. Indolines: (f) Anas, S.; Kagan, H. B. Tetrahedron:
Asymmetry 2009, 20, 2193–2199. Tetrahydroisoquinolines:(g) Siegnalewicz,
P.; Rinner, U.; Mulzer, J. Chem. Soc. Rev. 2008, 37, 2676–2690. (h)
Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341–
€
€
3370. Azepines and azepanes: (i) Quick, M. P.; Frohlich, R.; Wunsch, B.
Tetrahedron: Asymmetry 2010, 21, 524–526. (j) Pyne, S. G.; Ung, A. T.;
Jatisatienr, A.; Mungkornasawakul, P. Mj. Int. J. Sci. Tech. 2007, 1, 157–
165. (k) Meigh, J.-P. K. Sci. Synth. 2004, 17, 825–927. (l) Kouznetsov, V.;
Palma, A.; Ewert, C. Curr. Org. Chem. 2001, 5, 519–551. (m) Kametani, T.;
Fukumoto, K. Heterocycles 1975, 3, 931–1004.
r
10.1021/ol203218d
Published on Web 12/23/2011
2011 American Chemical Society

one of the most attractive strategies because of the high
utility of the olefinic moiety in subsequent functional
transformations.
Table 1. Dehydrative Intramolecular Asymmetric N-Allylation
of (E)-3 Using (R)-Cl-Naph-PyCOOAll ((R)-1)/[CpRu-
(CH3CN)3]PF6 (2) Combined Catalysta
Scheme 1
Scheme 1 shows one such protocol,5 in which prochiral
ω-amino allylic alcohols masked by an easily removable
N-protecting group (PG) or modified by a post-transformable
moiety dehydratively cyclize. Both Nishizawa/Yamamoto6
and our7 groups have recently reported such an atom-
economic and operationally simple process in the enantio-
selective cyclization of ω-sulfonylamino allylic alcohols,
although it was limited to specific cases. In this commu-
nication, we report a synthetically even more flexible
method8 with high reactivity, selectivity, and generality,
which utilizes our previously described Cl-Naph-Py-
COOAll (1, All: allyl)/[CpRu(CH3CN)3]PF6 (2) com-
bined catalyst.9
N-Boc-protected (E)-6-aminohex-2-en-1-ol ((E)-3a) was
selected as a standard substrate because the previously
reported methods6,7 can be applied only to N-protected
aromatic amine nucleophiles or C(3)-aryl-substituted
allylic alcohols. Screening of the reaction conditions
was started from [3a] = 500 mM; [(R)-1] = [2] = 0.5 mM;
DMA; 100 °C; 3 h. The results are shown in Table 1.10
entry
P (substrate)
S/C time, h % convb S:Rc
1
t-C4H9OCO (3a)
t-C4H9OCO (3a)
t-C4H9OCO (3a)
t-C4H9OCO (3a)
C6H5CH2OCO (3b)
1000
1000
2000
100
3
3
6
>99 (94) 98:2
2d
3e
4f
5
>99 (ꢀ)
>99 (ꢀ)
2:98
98:2
98:2
<0.5 >99 (ꢀ)
1000
100
3
3
>99 (99) 98:2
6f,g,h CH3CO (3c)
>99i (90) (93:7)
7f
CF3CO (3d)
100
3
j
8f
C6H5CO (3e)
CH2dCHCO (3f)
100
3
>99 (95) (97:3)
>99 (98) 95:5
>99 (91) (93:7)
>99 (97) (96:4)
>99 (95) (97:3)
9f,g
100
24
24
24
3
10f,g,h (E)-CH3CHdCHCO (3g) 100
11f,g
12
HCO (3h)
100
4-CH3C6H4SO2 (3i)
1000
a Unless otherwise specified, all of reactions were carried out under
the following conditions: [3] = 500 mM; [(R)-1/2] = 0.5 mM; solvent,
DMA; bath temp, 100 °C. b 1H NMR analysis. The value in parentheses:
isolated yield of 4. c GC or HPLC analysis. Absolute configuration:
comparison of optical rotation with the reported values. Not determined
for the parenthesized data. d Catalyst: (S)-1/2. e [3a] = 1 M. f [3] = 100
mM, [(R)-1] = [2] = 1 mM. g 10:1 t-C4H9OHꢀDMA mixed solvent. h 70
°C. i 4c:5c = 95:5. Use of DMA as solvent quantitatively gave 5c. j Only
diene 6d (E/Z = 2:1) was obtained in either DMA or t-C4H9OH.
(4) TsujiꢀTrost-type N-allylation by allyl esters and halides:
(a) Helmchen, G. In Iridium Complexes in Organic Synthesis; Oro, L. A.,
Claver, C., Eds.; Wiley-VCH: Weinheim, Germany, 2009; pp 211ꢀ250.
(b) Trost, B. M.; Zhang, T.; Sieber, J. D. Chem. Sci 2010, 1, 427–440. See
~
ꢀ
also: (c) Teichert, J. F.; Fananas-Mastral, M.; Feringa, B. L. Angew. Chem.,
Int. Ed. 2011, 50, 688–691. (d) He, H.; Liu, W.-B.; Dai, L.-X.; You, S.-L.
Angew. Chem., Int. Ed. 2010, 49, 1496–1499. (e) Hara, O.; Koshizawa, T.;
Makino, K.; Kunimune, I.; Namiki, A.; Hamada, Y. Tetrahedron 2007, 63,
6170–6181.
(5) For recent highlights of catalytic asymmetric allylation using
allylic alcohols, see: Bandini, M. Angew. Chem., Int. Ed. 2011, 50,
994–995.
(6) Yamamoto, H.; Ho, E.; Namba, K.; Imagawa, H.; Nishizawa, M.
Chem.;Eur. J. 2010, 16, 11271–11274.
(7) Miyata, K.; Kutsuna, H.; Kawakami, S.; Kitamura, M. Angew.
The standard quantitatively afforded (S)-4a with an en-
antiomer ratio (er) of 98:2 (Table 1, entry 1), and the
enantiomeric product (R)-4a was obtained by using an
S-catalyst system (Table 1, entry 2). The substrate con-
centration could be increased to 1 M [substrate/catalyst
(S/C) = 2000 (0.05 mol %)] (Table 1, entry 3). Even with
S/C = 10000 (0.01mol %), the reactionproceededwithout
loss of er, although it was sluggish (25%, 24 h). In terms of
easy lab operation and quickness, S/C = 100 (1 mol %)
is recommended (Table 1, entry 4). DMA, THF, and
t-C4H9OH are the solvents of choice. The reaction was slower
in CH3OH (54% conv), C2H5OH (71%), i-C3H7OH (91%),
ether (90%), TBME (84%), dioxane (90%), and CH2Cl2
(89%), but an er of 96:4 to 97:3 was maintained, whereas
toluene deteriorated both the reactivity and selectivity (31%
conv, 84:16 er). No reaction occurred in CH3CN or acetone.
The temperature could be lowered to 70 °C (24 h, 88% yield,
98:2 er), but the reaction proceeded little at 50 °C.10
Chem., Int. Ed. 2011, 50, 4649–4653.
(8) Pioneering works for nonenantioselective dehydrative N-allyla-
tion of carbamates and carboxylic amides. Pd: (a) Hirai, Y.; Nagatsu, M.
Chem. Lett. 1994, 21–22. (b) Makabe, H.; Kong, L. K.; Hirota, M. Org.
Lett. 2003, 5, 27–29. (c) Eustache, J.; de Weghe, P. V.; Le Nouen, D.;
Uyehara, H.; Kabuto, C.; Yamamoto, Y. J. Org. Chem. 2005, 70, 4043–
4053. (d) Yokoyama, H.; Ejiri, H.; Miyazawa, M.; Yamaguchi, S.; Hirai,
Y. Tetrahedron: Asymmetry 2007, 18, 852–856. (e) Ku, J.-M.; Jeong
B.-S.; Jew, S.-S.; Park, H.-G. J. Org. Chem. 2007, 72, 8115–8118. (f) Hande,
S. M.; Kawai, N.; Uenishi, J. J. Org. Chem. 2009, 74, 244–253. Bi:(g) Qin,
H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed.
2007, 46, 409–413. Au:(h) Mukherjee, P.; Widenhoefer, R. A. Org. Lett.
2011, 13, 1334–1337.
(9) Tanaka, S.; Seki, T.; Kitamura, M. Angew. Chem., Int. Ed. 2009,
48, 8948–8951. Cl-Naph-PyCOOAll: allyl 6-(2-chloronaphthalen-1-yl)-
5-methylpyridine-2-carboxylate. For the catalytic cycle of the achiral
version, see: Saburi, H.; Tanaka, S.; Kitamura, M. Angew. Chem., Int.
Ed. 2005, 44, 1730–1732.
(10) For details, see the Supporting Information.
Org. Lett., Vol. 14, No. 2, 2012
609

Not only the BocNH substrate (E)-3a but also the
CbzNH and TsNH substrates 3b and 3i could be used
with S/C = 1000 (0.1 mol %) to give 4b and 4i with a high
er (Table 1, entries 5 and 12). Replacement of the alkox-
ycarbonyl or sulfonyl substitution on N with an acyl group
requiredS/C= 100 (1 mol %) togain reasonable reactivity
and caused undesired reactions, giving ketone 5 or diene 6
in some cases. Thus, 3c (P = Ac) was quantitatively
converted to 5c in DMA, but change of the DMA solvent
to 10:1 t-C4H9OHꢀDMA afforded the desired product 4c
in 95% yield (Table 1, entry 6). The benzamide 3e (P = Bz)
smoothly cyclized in DMA to 4e with a higher yield and
without formation of 5e (Table 1, entry 8). For some
reason, 4c was susceptible to a 1,3-hydrogen shift in
DMA to the enamide compound, which was then hydro-
lyzed to 5c by water liberated during the course of dehy-
drative allylation.11 The reactions with 3f (P = CH2d
CHCO) and 3h (P = HCO) were completed under stan-
dard conditions to give a 95:5 mixture of 4f and 6f (E/Z =
3:1) and an 80:20 mixture of 4h and 6h (E/Z = 4:1),
respectively. Formation of the diene was avoided by using
a 10:1 t-C4H9OHꢀDMA mixed solvent (Table 1, entries 9
and 11). No cyclization occurred with the CF3CONH
substrate 3d, while only β-elimination quantitatively pro-
ceeded to give 6d (E/Z = 2:1) in either DMA or t-C4H9OH
(Table 1, entry 7). Free amine (P = H) and its HX salts
(X = TsO, AcO, PF6) showed no reactivity.
Table 2. Asymmetric Synthesis of Pyrrolidines and Piperidines
Using (R)-1/2-Combined Catalysta
Table 2 shows the scope and limitation of the present
asymmetric catalysis for the synthesis of chiral pyrrolidines
and piperidines.10 Not only E allylic alcohols but also the
Z-isomer is the substrate of choice. With the geometrical
Z-isomer of (E)-3a, the (R)-1/2 catalyst gave 4a with
preference for the R enantiomer (Table 2, entry 1). The
compound 7a (n = 2), in which one CH2 is extended from
(E)-3a (n = 1), was completely converted to the corre-
sponding 6-exo-trig cyclized product 8a with an er of 97:3
(Table 2, entry 2). The tertiary alkyl-substituted BocNH
substrate 7b could also be used (Table 2, entry 3). Intro-
duction of a methyl group at C(2) of 3a was tolerable
(Table 2, entry 5), but the reaction of the C(3)-methyl
substituted substrate 9b led to generation of the diene
(Table 2, entries 5 and 6). With N-protected aromatic
amines 11, both 5- and 6-exo-trig cyclization proceeded
to give the indoline and tetrahydroquinoline derivatives 12
with an er of >99:1 and 95:5, respectively (Table 2, entries
7 and 8). Both the reactivity and enantioselectivity were
dramatically decreased with the C(4)ꢀC(5) arene-fused
substrate 13a (Table 2, entry 9),7 whereas one CH2 inser-
tion at C(4) led to successful cyclization of 13b to 14b
(Table 2, entry 10). The N-Ts-protected ω-aminocarbonyl
allylic alcohol 15a formed a NꢀCR bond with nearly
perfect enantioselectivity to give γ-lactam 16a (Table 2,
entry 11). With this N-nucleophile, the 3,3-disubstituted
allylic alcohol 15b could also be utilized to give 16b
with high stereocontrol of the tetrasubstituted carbon
a Conditions: 25ꢀ120 mg scale; [substrate] = 100 mM; [(R)-1] = [2]
= 1 mM; DMA; 100 °C; 3 h unless otherwise specified. E allylic alcohols
were used except for (Z)-3a (entry 1). b Isolated yield. c GC or HPLC
analysis. d 1h.e [substrate] =500mM;[(R)-1] =[2] =0.5mM. f 6h.g 24 h.
h 50% conv, 85:15 mixture of N-Boc-protected 6-amino-3-methylhexa-1,3-
diene (E/Z = 3:2) and 6-amino-3-methylenehex-1-ene. 5 g scale. 10:1
t-C4H9OHꢀDMA mixed solvent. k 1 g scale.
i
j
stereogenic center (Table 2, entry 12), which would be a
good precursor for R-methyl glutamic acid.12 Success in
the highly enantioselective cyclization of the N-alkenoyl
allylic alcohols 3f, 3g, and 7c (P = CH2dCHCO or (E)-
CH3CHdCHCO) to 4f, 4g, and 8c, respectively (Table 1,
entries 9 and 10; Table 2, entry 4), should shorten the steps
to pyrrolizidine and indolizidine alkaloids when combined
with subsequent Grubbs intramolecular metathesis.13
The Cl-Naph-PyCOOAll/CpRu method could also be
applied to the construction of an azepane skeleton, although
(12) For an example of the catalytic asymmetric synthesis, see:
Sawamura, M.; Nakayama, Y.; Tang, W.-M.; Ito, Y. J. Org. Chem.
1996, 61, 9090–9096.
(11) For Ru-catalyzed isomerization of the (CO)N-allyl bond to the
enamide, see: Krompiec, S.; Krompiec, M.; Penczek, R.; Ignasiak, H.
Coord. Chem. Rev. 2008, 252, 1819–1841.
(13) (a) Lim, S. H.; Ma, S.; Beak, P. J. Org. Chem. 2001, 66, 9056–
9062. (b) Arisawa, M.; Takezawa, E.; Nishida, A.; Mori, M.; Nakagawa,
M. Synlett 1997, 1179–1180.
610
Org. Lett., Vol. 14, No. 2, 2012

not as generally as in the case of five- and six-membered
ring formation (Figure 1). The simplest substrate 17a
(E/Z = 97:3) and its imide derivative 17c underwent only
β-elimination to give the diene products 18a and 18c
(E/Z = 2:1). With the arene-fused substrates 17b and
17d, however, the desired cyclization efficiently proceeded
to generate the azepane-type N-heterocycles 18b and 18d
with an er of 99:1 and 96:4, respectively. The compounds
18b and 18d were high-potential intermediates for the
synthesis of tetrahydrobenzazepine alkaloids.2i,kꢀm,4d,4e
Introduction of two sp2 carbons in the carbon tether may
enable better HOMO/LUMO orbital interaction between
the N atom and the π-allyl C(3) atom. Replacement of Ts
group of 17b with Boc, however, decreased the reactivity
and caused β-elimination (29% conv; E/Z = 2:1).10 The
acidity of NH also exerts a significant effect on the
reactivity.
R-exocyclic enamide derivative (k4), followed by hydro-
lysis. The rate k1 would be enhanced by a “redox-mediated
donorꢀacceptor bifunctional catalyst” mechanism,7,9,14 in
which the hard Hþ/soft Ru combined catalyst coopera-
tively activates the allylic alcohol via protonation on the
hard hydroxy oxygen and via coordination of the soft
double bond to Ru(II). Such a synergetic effect would
facilitate the dehydrative π-allyl formation (k1). The fate of
the π-allyl species is determined by the relative rate of k2 to
k3 and k4, which is strongly affected by the electronic,
steric, stereoelectronic, and molecular orbital properties of
PNH. More systematic investigation of the substrate
structure/reactivity/selectivity relationship is required for
full elucidation of the mechanism. This is an ongoing
project in our group.
In summary, by using 0.05ꢀ1.00 mol % 1/2, highly
enantioselective intramolecular N-allylation of N-pro-
tected ω-amino and -aminocarbonyl allylic alcohols has
been realized without activation of allylic alcohols as the
esters or halides. Boc-, Cbz-, Ac-, Bz-, CH2dCHCO-,
(E)-CH3CHdCHCO-, HCO-, and Ts-NH can act as
nucleophiles, depending on the reaction conditions. Not
only 5- and 6-exo-trig cyclization but also seven-membered
ring formation can be attained. The easily removable PGs,
as well as the structurally transformable N-substituents,
should facilitate the syntheses of pharmaceutically impor-
tant natural N-heterocycles. To the best of our knowledge,
the present Cl-Naph-PyCOOAll/CpRu(II) method is the
first example showing veryhighapplicability toC(3)-alkyl-
substituted allylic alcohols. Furthermore, complementary
use of the present method with our other asymmetric
catalyst, Naph-diPIM-dioxo-R/CpRu(II)/p-TsOH,7 which
has high performance for C(3)-aryl substrates, should signi-
ficantly widen the scope of substrate patterns in the asym-
metric intramolecular dehydrative N-allylation approach.
Figure 1. Synthesis of azepane-type N-heterocycles ([17] =100mM;
[(R)-1/2] = 1 mM; 10:1 t-C4H9OHꢀDMA; 100 °C; 3 h).
(a) 18c-type diene (E/Z = 2:1) was formed in 10% yield.
The present catalysis involves many reaction pathways,
such as (i) π-allyl Ru(IV) formation (k1); (ii) reductive
nucleophilic attack of a PNH to the π-allyl ligand to
regenerateCl-Naph-PyCOOH/CpRu(II) (k2);9 (iii) β-elim-
ination from the π-allyl complex (k3); and (iv) 1,3-hydro-
gen shift of the R-alkenyl N-heterocyclic product to the
Acknowledgment. This research work was financially
supported by a Grant-in-Aid for Scientific Research (No.
25E07B212) from the Ministry of Education, Science,
Sports and Culture, Japan.
Supporting Information Available. Experimental de-
tails for dehydrative asymmetric cyclization, crystal data
for 16b, and copies of 1H NMR and 13C NMR spectra for
substrates and all products. This material is available free
of charge via the Internet at http://pubs.acs.org.
(14) (a) Kitamura, M.; Nakatsuka, H. Chem. Commun. 2011, 47,
842–846. For the original reaction of the donorꢀacceptor bifunctional
catalyst concept, see: (b) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R.
J. Am. Chem. Soc. 1986, 108, 6071–6072. (c) Noyori, R.; Kitamura, M.
Angew. Chem., Int. Ed. Engl. 1991, 30, 49–69.
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