Synthesis of bicyclic pyroglutamic acid featuring the ugi reaction and a unique stereoisomerization at the angular position by Grob fragmentation followed by a transannular ketene [2+2] cycloaddition reaction

Article abstract of DOI:10.1055/s-2007-982538

A stereoisomerization at the angular position of N-acylindoles during basic hydrolysis was discovered to give only the syn-bicyclic pyroglutamic acid, proceeding through a transannular [2+2] cycloaddition of a ketene-ketone intermediate generated by a Gro

Full text of DOI:10.1055/s-2007-982538

LETTER
1595
Synthesis of Bicyclic Pyroglutamic Acid Featuring the Ugi Reaction and a
Unique Stereoisomerization at the Angular Position by Grob Fragmentation
Followed by a Transannular Ketene [2+2] Cycloaddition Reaction
Angular
S
tereoisomeri
ization of
a
Bic
c
yclic Pyrog
h
lutamic
A
ci
e
d Amide ll Vamos, Kerem Ozboya, Yoshihisa Kobayashi*
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, Mail Code 0343, La Jolla,
CA 92093-0343, USA
E-mail: ykoba@chem.ucsd.edu
Received 24 January 2007
This paper is dedicated to Professor K.C. Nicolaou on the occasion of his 60th birthday.
diastereoselective one by use of a chiral g-ketoacid.8 We
Abstract: A stereoisomerization at the angular position of N-
recently reported a diastereoselective Ugi 4C-3CR in the
acylindoles during basic hydrolysis was discovered to give only the
syn-bicyclic pyroglutamic acid, proceeding through a transannular
synthesis of omuralide.6a Herein we describe the synthesis
of a unique bicyclic pyroglutamic acid derivative which is
fully substituted at the angular positions. The synthesis
features quick access to the bicyclic pyroglutamic acid
core using the Ugi 4C-3CR, and an unexpected stereo-
isomerization at the angular positions of the bicyclic
structure from basic hydrolysis of the C-terminal amide to
give only the syn-pyroglutamic acid.
[2+2] cycloaddition of a ketene–ketone intermediate generated by a
Grob fragmentation.
Key words: isonitrile, Ugi reaction, pyroglutamic acid, diastereo-
selectivity, lactams
The Ugi four-component condensation reaction repre-
sents a powerful method to quickly build in one-pot N-
acyl amino acid amides.1 Our lab has been interested in
applying this methodology to the synthesis of natural
products containing the pyroglutamic acid moiety, using
g-ketoacids. Salinosporamide A,2 lactacystin,3 and oxazo-
lomycin A4 incorporate this functional group and each
shows promising anticancer activity. Many convertible
isonitriles (isocyanides), which allow for mild hydrolysis
of the C-terminal amide of the Ugi adduct, are known.5
Unfortunately, it was not possible to hydrolyze sterically
hindered pyroglutamic acid amides in Ugi adducts
incorporating known isonitriles. We introduced a novel
convertible isonitrile, 1-isocyano-2-(2,2-dimethoxyeth-
yl)benzene (1).6 This so-called indole–isonitrile (1) is eas-
ily cleaved even in bulky substrates via an N-acylindole
intermediate (Scheme 1).
a
O
O
b
O
BnO
BnO
OH
2
3
4
c
O
O
HO
e
d
O
O
O
HO
BnO
BnO
OH
OH
OH
7
6
5
Scheme 2 Synthesis of precursor 7 to the Ugi and Passerini multi-
component condensation reactions. Reagents and conditions: (a) Zn
(4 equiv), CuCl (0.4 equiv), benzyl bromoacetate (1 equiv), THF,
95%; (b) CSA (4.5 equiv), PhH, reflux, 24 h, 79% (7:1 b,g:a,b); (c)
OsO4 (3 mol%), NMO (3 equiv), DABCO (5 mol%), THF–H2O
(10:1), 93% (11:1 b,g:a,b); (d) IBX (1.5 equiv), EtOAc, 90 °C, 6 h,
88%; (e) Pd–C, H2, MeOH, 23 °C, 5 h, quant.
A key focus for our group has been to develop the Ugi
four-center, three-component reaction (4C-3CR)7 into a
O
R1
OMe
HO
O
R1
OH
O
OMe
indole
OH
γ-ketoacid
O
R1
NH
O
R1
N
R2
C
N
N
R2NH2
OMe
OMe
indole-isonitrile (1)
H
R2
R2
N
N
Ugi 4C-3C
Reaction
O
pyroglutamic
acid
O
O
Ugi product
N-acylindole
Scheme 1 Utility of indole–isonitrile (1) through derivatization of N-acylindole
SYNLETT 2007, No. 10, pp 1595–1599
1
8
.0
6
.2
0
0
7
Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-982538; Art ID: S00407ST
© Georg Thieme Verlag Stuttgart · New York

1596
M. Vamos et al.
LETTER
The synthesis of the Ugi precursor 7 began with the
Reformatsky reaction of benzyl 2-bromoacetate and cy-
clohexanone (2) as shown in Scheme 2.9 Acid-mediated
dehydration of the resulting tertiary alcohol 3 led to regio-
selective formation of the desired endo-olefin isomer 4 in
a 7:1 ratio over the exo-isomer. The exo-isomer may have
been predicted to be the thermodynamically favored prod-
uct due to conjugation of the double bond with the carbo-
nyl group.10 However, due to greater torsional strain
present in the exo-isomer from eclipsing C=C and C–H
bonds, as well as 1,3-allylic strain, we observe a prefer-
ence for the endo-isomer.11 Osmium tetroxide catalyzed
syn-dihydroxylation of 4 gave the diol 5 cleanly. We an-
ticipated that lactone formation via loss of benzyl alcohol
could be a problem; however, this side product was not
detected. Oxidation of 5 using IBX12 proceeded well and
it was at this stage that the minor regioisomer could be re-
moved, thanks to the relatively high polarity of the 1,2-di-
carbonyl compound. Simple catalytic hydrogenation of
benzyl ester 613 furnished the desired g-ketoacid 714 to be
exploited in the Ugi reaction.
Figure 1 ORTEP representation of the anti-Ugi product 8a
isolated. 1D NOESY studies revealed a strong NOE effect
between the N,O-acetal hydrogen (9c: 5.60 ppm, 9d: 5.85
ppm) and the a-hydrogen (2.65 ppm) of the lactam of 9c
and the cyclohexyl hydrogen (2.04 ppm) of 9d, thus estab-
lishing the relative stereochemistry of each. It was ob-
served that the N,O-acetal was surprisingly stable to both
acidic and basic conditions, as we were not able to convert
it to the N-acylindole.
OMe
C N
R = CH2CH(OMe)2
9a
9b
OMe
OMe
O
1
O
O
N
N
O
N
(1 equiv)
PMB
PMB
O
HO
N
R
CF3CH2OH
70 °C, 2 h
OH
7
O
O
N
NH
NH2
PMB
O
CSA
(1 equiv)
83%
OH
OH
(1 equiv)
OMe
OMe
OMe
OMe
PhH
94%
OH
8
9c
9d
O
N
NH
O
NH
PMB
O
PMB
O
N
N
O
O
N
N
O
PMB
O
3:2
N
PMB
anti/syn
H
H
8a
O
8b
O
3:2
anti/syn
product ratio
OH
OH
H
H
:
:
:
:
:
:
9a
6.0
9b
1.2
9c
1.8
9d
1.0
H
H
Scheme 3 Stereoselectivity in the Ugi Reaction of g-ketoacid 7 with
indole–isonitrile 1
NOESY
NOESY
Scheme 4 Attempted N-acylindole formation from 8 with acid
As shown in Scheme 3, the Ugi reaction was used with
g-ketoacid 7,15 indole–isonitrile 1 and PMB-NH2.16 The
yield for the reaction was good; however, the diastereo-
meric ratio was only 3:2 and the two diastereomers of 8
were not easily separated by column chromatography. X-
ray crystallography of the less polar 8a17 (8a: Rf = 0.17,
8b: Rf = 0.12, SiO2, hexane–EtOAc, 1:2) showed that it
was the anti-Ugi adduct, as seen in Figure 2.18
Although the separation of 8a and 8b was difficult, we
were able to isolate small amounts of the enriched sam-
ples, which were treated with the same acidic conditions
as above. It was found that 8a gave only anti-N-acylindole
9a, while 8b gave a 1:2 ratio of syn-N-acylindole 9b to
N,O-acetal (9c + 9d). This result was to be expected since
the anti-Ugi adduct 8a cannot give N,O-acetal and the
more polar 8b gave a majority of N,O-acetal.
With the Ugi product 8 in hand, we next subjected the in-
dole precursor to acidic conditions, which induced the cy-
clization–dehydration sequence to give N-acylindole 9ab
(9a:19 Rf = 0.35, 9b: Rf = 0.29, SiO2, hexane–EtOAc, 1:1)
(Scheme 4). Quantitative conversion was observed, but at
the expense of a significant amount of the syn-isomer 8b.
Two diastereomers of the propellane N,O-acetal 9cd
(9c:20 Rf = 0.24, 9d:21 Rf = 0.12, SiO2, hexane–EtOAc,
1:1) resulting from trapping by the tertiary alcohol of the
transient iminium species following dehydration were
Treatment of the 5:1 anti–syn mixture of 9ab with excess
Et3N in THF–H2O (3:1) at 70 °C gave the pyroglutamic
acid 1022 in quantitative yield and 56% over three steps
from 7 (Scheme 5). Surprisingly, 10 was isolated as a sin-
1
gle diastereomer which was clearly discernable by H
NMR. In order to explain this convergence to a single
isomer under basic conditions, we proposed a Grob
fragmentation23 followed by a transannular ketene–
ketone [2+2] cycloaddition to give the b-lactone,24 which
Synlett 2007, No. 10, 1595–1599 © Thieme Stuttgart · New York

LETTER
Angular Stereoisomerization of a Bicyclic Pyroglutamic Acid Amide
1597
OH
O
O
O
O
O
N
PMB
N
PMB
N
PMB
O
N
O
N
C
O
9a
O
O
N
OH
PMB
C
Figure 3 ORTEP representation of acid 10
transannular ketene [2+2]
cycloaddition reaction
O
N
PMB
O
O
followed by
hydrolysis
Subsequent hydrolysis with excess Et3N in THF–H2O
(3:1) at 70 °C gave the 2-hydroxyglutaric acid g-lactone
13 in 67% yield as a 3:1 mixture of diastereomers (major
isomer unknown). Because of this partial stereoisomeriza-
tion (dr = 17:1 to 3:1), we can conclude that at least some
of the hydrolysis product 13 results from a similar mech-
anism to that for the pyroglutamic acid 10. However, this
result for the lactone 12 is in contrast to that for the lactam
9 which gave only the syn-isomer upon hydrolysis. The
chemoselectivity of the hydrolysis should be noted, as the
amide was hydrolyzed in the presence of the lactone.
OH
10
Scheme 5 Grob fragmentation followed by transannular ketene
[2+2] under basic conditions
was then hydrolyzed to 10. As can be seen in the ORTEP
diagram in Figure 2, there is a good antiperiplanar rela-
tionship between the cleaved C–C angular bond and the
indole C–N amide bond for anti-N-acylindole 9a, allow-
ing for the Grob fragmentation to generate the ketene in-
termediate.25 To our knowledge, this is the first example
of a Grob fragmentation proceeding through a ketene
intermediate.
OMe
C N
OMe
OMe
1
O
NH
O
OMe
O
(1 equiv)
O
O
MeOH
70 °C, 4 h
HO
OH
7
OH
11
5.5:1
anti/syn
74%
CSA (1 equiv)
PhH, 94%
3:1 dr
O
OH
O
N
O
Et3N (excess)
Figure 2 ORTEP representation of N-acylindole 9a
O
O
O
THF–H2O (10:1)
70 °C
OH
As shown in Figure 3, X-ray analysis of the pyroglutamic
acid 10 unambiguously assigned it as the syn-isomer.26
Thus, hydrolysis of the anti–syn mixture 9 gives only the
syn-isomer of pyroglutamic acid 10. This observation
could be useful in an enantioselective synthesis if a reso-
lution, via diastereomeric salt formation with a chiral
amine, could be performed on the racemic syn-acid 10.
One issue that remains to be addressed is suppression of
N,O-acetal formation from the syn-Ugi product 8b. We
envision that protection of the tertiary alcohol in g-keto-
acid 7 would serve that purpose as well as act as a possible
vehicle for diastereoselectivity in the Ugi reaction.
OH
12
17:1
anti/syn
67%
13
Scheme 6 Stereoselectivity in the Passerini reaction of g-ketoacid 7
with indole–isonitrile 1
We have shown that ready access to bicyclic pyroglutamic
acid derivatives via the Ugi reaction is available with
indole–isonitrile 1 and g-ketoacid 7. Also, the related
Passerini reaction with 7 allows construction of a 2-hy-
droxyglutaric acid g-lactone with moderate diastereo-
selectivity. Interestingly, a Grob fragmentation followed
by transannular ketene–ketone [2+2] reaction proceeded
upon hydrolysis of N-acylindole compound 9a. This is un-
usual given that typically the Grob fragmentation is ob-
served when the displaced group has strong leaving group
ability (such as a tosylate), and indole does not fit into that
category. The pyroglutamic acid structures generated by
this strategy have possible applications as polydentate
ligands in asymmetric organometallic reactions.
To explore the stereoselectivity of the related Passerini
reaction, g-ketoacid 7 was reacted with indole–isonitrile 1
to yield 11 in 74% yield as a 5.5:1 anti–syn mixture
(Scheme 6). Treatment of 11 with CSA led to a 79% yield
of a 17:2:1 mixture of anti-N-acylindole 12:N,O-acetal
12a (vide infra)27:syn-N-acylindole. Based on the low rel-
ative yield of the N,O-acetal, we concluded that the syn-
isomer was the minor product in the Passerini reaction.
Synlett 2007, No. 10, 1595–1599 © Thieme Stuttgart · New York

1598
M. Vamos et al.
LETTER
(15) Although 7 is known to exist as the hemi-ketal 7a,
Acknowledgment
presumably under equilibrium in the Ugi reaction
conditions, that did not prevent it from reacting in the Ugi
4C-3CR.
We greatly acknowledge the University of California and Pfizer La
Jolla A-IRMRF (KO) for financial support. We also thank Professor
Arnold Rheingold for X-ray Crystallography, Dr. Yongxuan Su for
Mass Spectroscopy and Dr. Anthony Mrse for help with NOESY
experiments.
(16) The solvent alcohol is purported to open the imidate
intermediate in the Ugi 4C-3CR with g-ketoacids: Harriman,
G. C. B. Tetrahedron Lett. 1997, 38, 5591.
(17) 8a: 1H NMR (400 MHz, CDCl3): d = 9.03 (s, 1 H), 7.65 (d,
J = 8.0 Hz, 1 H), 7.27 (d, J = 8.3 Hz, 2 H), 7.26 (d, J = 7.3
Hz, 1 H), 7.19, (d, J = 5.7 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1
H), 6.80 (d, J = 8.8 Hz, 2 H), 4.96 (d, J = 15.6 Hz, 1 H), 4.47
(t, J = 5.2 Hz, 1 H), 3.75 (s, 1 H), 3.63 (d, J = 16.0 Hz, 1 H),
3.42 (s, 3 H), 3.39 (s, 3 H), 2.92 (dd, J = 5.6, 14.0 Hz, 1 H),
2.83 (dd, J = 5.6, 14.0 Hz, 1 H), 2.32 (d, J = 16.0 Hz, 1 H),
2.19 (td, J = 4.0, 12.8 Hz, 1 H), 1.81 (m, 5 H), 1.58 (m, 2 H);
13C NMR (100 MHz, CDCl3): d = 175.7, 169.0, 158.7,
136.0, 131.1, 130.0, 128.6, 128.3, 127.5, 125.5, 124.7,
113.9, 107.1, 77.1, 73.7, 55.4, 54.6, 54.5, 45.5, 43.1, 37.2,
29.3, 25.6, 21.8, 19.9; HRMS: m/z calcd for C27H34N2O6:
482.2411; found: 482.2405.
References and Notes
(1) For reviews, see: (a) Dömling, A.; Ugi, I. Angew. Chem. Int.
Ed. 2000, 39, 3168. (b) Ugi, I. Angew. Chem., Int. Ed. Engl.
1962, 1, 8.
(2) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C.
A.; Jensen, P. R.; Fenical, W. Angew. Chem. Int. Ed. 2003,
42, 355.
(3) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.;
Moriguchi, R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44,
113.
(4) Mori, T.; Takahashi, K.; Kashiwabara, M.; Uemara, D.
Tetrahedron Lett. 1985, 26, 1073.
(5) For convertible isonitriles, see: (a) Ugi, I. Angew. Chem. Int.
Ed. 2000, 39, 3168; and references therein. (b) Rikimaru,
K.; Yanagisawa, A.; Kan, T.; Fukuyama, T. Synlett 2004,
41. (c) Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama, T.
Chem. Commun. 2005, 394. (d) Pirrung, M. C.; Ghorai, S.
J. Am. Chem. Soc. 2006, 128, 11772.
(6) The application of indole–isonitrile 1 to natural product
synthesis was demonstrated by our laboratory: (a) Gilley,
C. B.; Buller, M. J.; Kobayashi, Y. Angew. Chem. Int. Ed.
2007, in revision. (b) Isaacson, J.; Gilley, C. B.; Kobayashi,
Y. J. Org. Chem. 2007, 72, 3913.
(7) (a) Short, K. M.; Ching, B. W.; Mjalli, A. M. M.
Tetrahedron 1997, 53, 6653. (b) Short, K. M.; Mjalli, A. M.
M. Tetrahedron Lett. 1997, 38, 359. (c) Hanusch-Kompa,
C.; Ugi, I. Tetrahedron Lett. 1998, 39, 2725.
(8) An Ugi 4C-3CR reaction with a chiral amine and a g-
ketoacid has been reported to give a 5:1 diastereomeric ratio:
Marcaccini, S.; Pepino, R.; Torroba, T.; Miguel, D.; Garcia-
Valverde, M. Tetrahedron Lett. 2002, 43, 8591.
(9) Fürstner, A. In Organozinc Reagents: A Practical
Approach; Knochel, P.; Jones, P., Eds.; Oxford University
Press: New York, 1999, 287.
(18) Crystal data for 8a: C27H34N2O6, Mr = 482.56, triclinic,
space group P1, a = 9.899 (3) Å, b = 12.169 (4) Å,
c = 13.444 (4) Å, a = 79.540 (4)°, b = 80.366 (4)°,
g = 69.755 (4)°, V = 1484.6 (7) Å3, Z = 2, rcalc = 1.080 Mg/
m3, F(000) = 516, l = 0.71073 Å, T = 200 (2) K,
m(MoKa) = 0.076 mm–1. Of the 16570 measured reflections,
11473 were independent [R(int) = 0.0283]. The final
refinement converged at R1 = 0.0629 for I > 2s(I),
wR2 = 0.1654 for all data. The data for 8a, 9a and 10 were
collected on a Bruker diffractometer with an APEX CCD
detector, the structure was solved by direct methods
(SHELXL-97) and refined with all data by full matrix least
squares on F2. CCDC 634645 contains the supplementary
crystallographic data of 8a. The data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif or from
the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB21EZ, UK; fax:+44 (1223)336033 or
deposit@ccdc.cam.ac.uk.
(19) 9a: 1H NMR (500 MHz, CDCl3): d = 8.34 (d, J = 8.5 Hz, 1
H), 7.55 (d, J = 7.5 Hz, 1 H), 7.59 (d, J = 4.0 Hz, 1 H), 7.35
(t, 8.0 Hz, 1 H), 7.29 (t, J = 7.5 Hz, 1 H), 7.23 (d, J = 8.5 Hz,
2 H), 6.81 (d, J = 8.5 Hz, 2 H), 6.56 (d, J = 4.0 Hz, 1 H),
5.02 (d, J = 16.0 Hz, 1 H), 4.21 (d, J = 16.5 Hz, 1 H), 3.76
(s, 3 H), 3.62 (d, J = 16.0 Hz, 1 H), 2.59 (td, J = 5.5, 13.5
Hz, 1 H), 2.50 (br s, 1 H, OH), 2.40 (d, J = 16.0 Hz, 1 H),
2.31 (td, J = 3.5, 14.0 Hz, 1 H), 2.20 (m, 1 H), 1.82 (m, 3 H),
1.64 (m, 1 H), 1.54 (m, 1 H); 13C NMR (100 MHz, CDCl3):
d = 176.8, 170.8, 159.1, 137.2, 129.6, 129.1, 128.8, 125.4,
124.7, 124.2, 121.0, 117.2, 114.2, 109.1, 79.0, 76.3, 55.4,
45.2, 44.6, 29.8, 26.4, 21.7, 19.8; HRMS: m/z calcd for
C25H26N2O4: 418.1887; found: 418.1883.
(10) For a discussion of ring size and endo/exo selectivity, see:
Screttas, C. G.; Smonou, I. C. J. Org. Chem. 1998, 53, 893.
(11) (a) Carey, F. A.; Sundberg, R. J. In Advanced Organic
Chemistry, 4th ed.; Plenum: New York, 2000, 172.
(b) Johnson, F. Chem. Rev. 1968, 68, 375.
(12) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
(13) The synthesis of the g-ketoester as the ethyl ester in high
enantiopurity has been reported: García Ruano, J. L.; Barros,
D.; Maestro, M. C.; Alcudia, A.; Fernández, I. Tetrahedron:
Asymmetry 1998, 9, 3445.
(20) 9c: 1H NMR (400 MHz, CDCl3): d = 7.83 (d, J = 8.5 Hz, 1
H), 7.24 (d, J = 8.0 Hz, 2 H), 7.19 (t, J = 7.5 Hz, 1 H), 7.08
(d, J = 7.0 Hz, 1 H), 7.01 (t, J = 7.5 Hz, 1 H), 6.57 (d,
J = 9.0 Hz, 2 H), 5.60 (t, J = 7.0 Hz, 1 H), 4.59 (d, J = 14.5
Hz, 1 H), 4.17 (d, J = 14.5 Hz, 1 H), 3.53 (s, 3 H), 3.15 (dd,
J = 8.0, 16.5 Hz, 1 H), 2.95 (dd, J = 5.5, 16.0 Hz, 1 H), 2.82
(d, J = 17.5 Hz, 1 H), 2.65 (d, J = 17.5 Hz, 1 H), 2.00 (dd,
J = 4.0, 14.0 Hz, 1 H), 1.65 (m, 1 H), 1.58 (m, 2 H), 1.29 (m,
2 H), 1.11 (m, 1 H); HRMS: m/z calcd for C25H26N2O4:
418.1887; found: 418.1893.
(14) g-Ketoacid 7 has been made from a different ketone starting
material and is known to exist in the hemi-ketal form 7a
(Figure 4): Mondon, A.; Menz, H.; Zander, J. Chem. Ber.
1963, 96, 826.
OH
O
O
(21) 9d: 1H NMR (500 MHz, CDCl3): d = 7.72 (d, J = 8.0 Hz, 1
H), 7.14 (t, J = 7.5 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 2 H), 7.12
(behind peak), 7.03 (t, J = 7.5 Hz, 1 H), 6.44 (d, J = 9.0 Hz,
2 H), 5.85 (t, J = 7.5 Hz, 1 H), 4.70 (d, J = 15.5 Hz, 1 H),
4.30 (d, J = 15.0 Hz, 1 H), 3.54 (s, 3 H), 3.10 (dd, J = 7.0,
15.0 Hz, 1 H), 2.93 (dd, J = 9.0, 15.0 Hz, 1 H), 2.93 (behind
7a
OH
Figure 4
Synlett 2007, No. 10, 1595–1599 © Thieme Stuttgart · New York

LETTER
Angular Stereoisomerization of a Bicyclic Pyroglutamic Acid Amide
1599
peak), 2.79 (d, J = 16.5 Hz, 1 H), 2.47 (d, J = 16.5 Hz, 1 H),
(26) Crystal data for 10: C17H21NO5, Mr = 319.35, orthorhombic,
space group Pccn, a = 31.323 (2) Å, b = 9.3197 (6) Å,
c = 10.4743 (6) Å, a = 90°, b = 90°, g = 90°, V = 3057.6 (3)
Å3, Z = 8, rcalc = 1.387 Mg/m3, F(000) = 1360, l = 1.54178
Å, T = 100 (2) K, m(MoKa) = 0.846 mm–1. Of the 12336
measured reflections, 2763 were independent
[R(int) = 0.0266]. The final refinement converged at
R1 = 0.0472 for I > 2s(I), wR2 = 0.1227 for all data. CCDC
634647 contains the supplementary crystallographic data of
10.
2.04 (td, J = 4.5, 14.0 Hz, 1 H), 1.84 (m, 2 H), 1.47 (m, 2 H),
1.29 (td, J = 3.0, 12.5 Hz, 1 H), 1.10 (m, 1 H); HRMS: m/z
calcd for C25H26N2O4: 418.1887; found: 418.1889.
(22) 10: 1H NMR (500 MHz, CDCl3): d = 7.23 (d, J = 8.5 Hz, 2
H), 6.80 (d, J = 8.0 Hz, 2 H), 4.66 (d, J = 15.5 Hz, 1 H), 4.24
(d, J = 15.5 Hz, 1 H), 3.78 (s, 3 H), 3.20 (br s, 1 H, OH), 2.77
(d, J = 16.0 Hz, 1 H), 2.46 (d, J = 16.5 Hz, 1 H), 2.14 (m, 2
H), 1.81 (tt, J = 4.5, 19.0 Hz, 2 H), 1.67 (td, J = 4.0, 14.5 Hz,
1 H), 1.53 (m, 1 H), 1.41 (m, 2 H); 13C NMR (100 MHz,
CDCl3): d = 175.9, 175.6, 159.0, 130.2, 129.4, 114.0, 74.3,
72.3, 55.4, 44.5, 44.4, 36.0, 27.9, 20.5, 20.3; HRMS: m/z
calcd for C17H21NO5: 319.1414; found: 319.1417.
(27) A single diastereomer of the N,O-acetal 12a (Figure 5), the
relative stereochemistry of which was not determined, was
formed.
(23) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535.
(24) Corey, E. J.; Reddy, L. R. Org. Lett. 2006, 8, 1717.
(25) Crystal data for 9a: C25H26N2O4, Mr = 418.48, monoclinic,
space group P2(1)/c, a = 17.172 (6) Å, b = 27.378 (11) Å,
c = 13.501 (5) Å, a = 90°, b = 100.125 (5)°, g = 90°,
V = 6248 (4) Å3, Z = 12, rcalc = 1.335 Mg/m3,
O
O
N
O
F(000) = 2664, l = 0.71073 Å, T = 100 (2) K,
O
m(MoKa) = 0.091 mm–1. Of the 50332 measured reflections,
13977 were independent [R(int) = 0.0772]. The final
refinement converged at R1 = 0.2393 for I > 2s(I),
wR2 = 0.5894 for all data. CCDC 634643 contains the
supplementary crystallographic data of 9a.
12a
Figure 5
Synlett 2007, No. 10, 1595–1599 © Thieme Stuttgart · New York

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