Structural characterization of an enantiomerically pure amino acid imidazolide and direct formation of the ss-lactam nucleus from an a-amino acid

Article abstract of DOI:10.1021/ol7025922

Decomposition of a diazo ss-ketoamide derived from N-trityl serine imidazolide and N-protected acetanilides provides, instead of the expected 3-acyloxindole product, an enantiomerically pure (EP) ss-lactam. The amino acid stereocenter is incorporated, the

Full text of DOI:10.1021/ol7025922

ORGANIC
LETTERS
2008
Vol. 10, No. 3
369-372
Structural Characterization of an
Enantiomerically Pure Amino Acid
Imidazolide and Direct Formation of the
â
-Lactam Nucleus from an
Acid
r-Amino
Brian S. Gerstenberger, Jinzhen Lin, Yvette S. Mimieux, Lauren E. Brown,
Allen G. Oliver, and Joseph P. Konopelski*
Department of Chemistry and Biochemistry, UniVersity of California,
Santa Cruz, California 95064
joek@chemistry.ucsc.edu
Received October 25, 2007
ABSTRACT
Decomposition of a diazo
3-acyloxindole product, an enantiomerically pure (EP)
induced, and trityl protection of the -lactam ring is realized for the first time. The desired 3-acyloxindole is obtained from oxindole and
Tr-Ser(OBn)-imidazole, the X-ray of which provides the first structural determination of an EP amino acid imidazolide.
â
-ketoamide derived from N-trityl serine imidazolide and N-protected acetanilides provides, instead of the expected
â
-lactam. The amino acid stereocenter is incorporated, the second chiral center is
â
Nitrogen heterocycles occupy a premier position in both
natural product chemistry and pharmaceutical science, and
both azetidin-2-ones (â-lactams) and indoles are among the
most investigated of such ring systems due to their well-
documented impact on small molecule drug discovery. In
addition, enantiomerically pure (EP) â-lactams act as mul-
tifunctional organic motifs for the elaboration of more
complex targets1 and as rigid â-turn scaffolds.2,3 Furthermore,
the facile synthetic relationship between â-amino acids4 and
â-lactams5 and the vibrant interest in polymers of EP â-amino
acids (“â-foldamers”)6,7 ensures that research into this
strained four-membered ring system will continue unabated.
For our synthesis8 of the marine natural product diazona-
mide A (1)9 we required the construction of highly func-
tionalized 3-acyloxindole 2. Two approaches were conceived
(4) (a) Juaristi, E. EnantioselectiVe Synthesis of â-Amino Acids; Wiley-
VCH: New York, 1997. (b) Juaristi, E.; Soloshonok, V. EnantioselectiVe
Synthesis of â-Amino Acids, 2nd ed.; Wiley: New York, 2005.
(5) (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I. The Synthesis of â-Amino
Acids and Their Derivatives from â-Lactams. In EnantioselectiVe Synthesis
of â-Amino Acids; Wiley-VCH: New York, 1997; Chapter 14. (b) Palomo,
C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. The Synthesis of â-Amino
Acids and Their Derivatives from â-Lactams: Update. In EnantioselectiVe
Synthesis of â-Amino Acids, 2nd ed.; Wiley: New York, 2005; Chapter
20.
(1) Alcaide, B.; Almendros, P. Chem. Soc. ReV. 2001, 30, 226-240.
(2) Maier, T. C.; Frey, W. U.; Podlech, J. Eur. J. Org. Chem. 2002,
2686-2689.
(3) Palomo, C.; Aizpurua, J. M.; Balentova´, E.; Jimenez, A.; Oyarbide,
J.; Fratila, R. M.; Miranda, J. I. Org. Lett. 2007, 9, 101-104.
10.1021/ol7025922 CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/09/2008

(Scheme 1). One sought direct acylation of the corresponding
C3-unsubstituted oxindole (3, PG ) protection group, Y )
H or halogen) with a serine derivative (LG ) leaving group).
The second route relied on diazo compound 4, which would
the sequence of 4 to 2) that this protection scheme would
prevent not only N-H insertion12 of the reactive carbenoid
to the amino acid nitrogen but also C-H insertion into the
serine side chain. The acid imidazolide was chosen for ease
of preparation13 and compatibility with the acid-labile trityl
group.
Oxindoles 3 were prepared from two different routes.
N-Benzyloxindole (3a) was prepared from isatin by a recently
published procedure.14 Unfortunately, the corresponding
MOM-protected 7-bromoisatin did not produce the desired
material from this procedure nor was the N-protection of
7-bromooxindole successful. Therefore, a more general and
higher-yielding route to 3b was developed that employed
acetanilide 5, prepared in quantitative yield from 2-bromoa-
niline (Scheme 2). Protection of 5 afforded 6 in excellent
Scheme 1. Diazonamide A Retrosynthesis
Scheme 2. Oxindole Preparation
be subjected to RhII-catalyzed decomposition to promote
C-H insertion and oxindole formation as described by
Doyle.10 Herein we report that each of these synthetic routes
led to unexpected discoveries. The direct acylation route led
to the first isolation and structural characterization of an EP
amino acid imidazolide and culminated with the synthesis
of 2. The RhII-catalyzed C-H insertion route did not lead
to 2, but rather to the first reported direct transformation of
an EP R-amino acid derivative to the â-lactam nucleus with
complete retention of absolute stereochemistry and induction
of the second ring chiral center.
The literature describes very few examples of oxindole
acylation at C3 and no examples employing amino acids or
their derivatives, some of which are prone to racemization.
We were guided to trityl (Tr) protection of the serine amine
functionality (PG2) for both routes to 2 by the body of work
in this area from the Rapoport group and the documented
chiral stability of such derivatives.11 It was also hoped (for
yield. The anion of 6 (LiHMDS) was reacted with 2,2,2-
trifluoroethyl trifluoroacetate yielding the trifluoro-â-ketoa-
mide, which could be converted without purification into 7
in 89% yield through diazo transfer (MsN3/DBU) and in situ
ketone cleavage during workup (10% NaOH).15 This diazo
compound underwent clean C-H insertion yielding 3b in
60% (50% overall yield from 5).
Standard in situ13 reaction of Tr-Ser(OBn)-OH with 1,1′-
carbonyldiimidazole (CDI, 1.05 equiv) afforded the expected
solution of acid imidazolide 8 and imidazole, which was
added directly to the anion of oxindoles 3a,b. Reaction yields
were variable and were ascribed to such factors as incomplete
imidazolide formation,16 the presence of imidazole in the
solution of acid imidazolide, and difficulties in managing
the reactive oxindole anion content in the presence of
growing amounts of more acidic â-ketolactam product.
(6) (a) Gelman, M. A.; Gellman, S. H. Using Constrained â-Amino Acid
Residues to Control â-Peptide Shape and Function. In EnantioselectiVe
Synthesis of â-Amino Acids, 2nd ed.; Wiley: New York, 2005; Chapter
22. (b) Campo, M. A.; Escalante, J.; Sˇebesta, R. â-Amino Acids with
Proteinogenic Side Chains and Corresponding Peptides: Synthesis, Second-
ary Structure, and Biological Activity. In EnantioselectiVe Synthesis of
â-Amino Acids, 2nd ed.; Wiley: New York, 2005; Chapter 23.
(7) Seebach, D.; Kimmerlin, T.; Sˇebesta, R.; Campo, M. A.; Beck, A.
K. Tetrahedron 2004, 60, 7455-7506.
(11) Sim, T. B.; Rapoport, H. J. Org. Chem. 1999, 64, 2532-2536.
(12) (a) Ferris, L.; Haigh, D.; Moody, C. J. J. Chem. Soc., Perkin Trans.
1 1996, 2885-2888. (b) Aller, E.; Buck, R. T.; Drysdale, M. J.; Ferris, L.;
Haigh, D.; Moody, C. J.; Pearson, N. D.; Sanghera, J. B. J. Chem. Soc.,
Perkin Trans. 1 1996, 2879-2884.
(8) Konopelski, J. P.; Hottenroth, J. M.; Mo´nzo-Oltra, H.; Ve´liz, E. A.;
Yang, Z.-C. Synlett 1996, 609-11.
(9) (a) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am.
Chem. Soc. 1991, 113, 2103-2304. (b) Li, J.; Jeong, S.; Esser, L.; Harran,
P. G. Angew. Chem., Int. Ed. 2001, 40, 4765-4769; Angew. Chem. 2001,
113, 4901-4904. (c) Li, J.; Burgett, A. W. G.; Esser, L.; Amezcua, C.;
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4770-4773; Angew. Chem.
2001, 113, 4905-4909.
(13) Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew. Chem., Int.
Ed. Engl. 1979, 18, 72-74.
(14) Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 11505-
11515.
(15) Doyle, M. P.; Dorow, R. L.; Terpstra, J. W.; Rodenhouse, R. A. J.
Org. Chem. 1985, 50, 1663-1666.
(16) Morton, R. C.; Mangroo, D.; Gerber, G. E. Can. J. Chem. 1988,
66, 1701-1705.
(10) Doyle, M. P.; Shanklin, M. S.; Pho, H. Q.; Mahapatro, S. N. J.
Org. Chem. 1988, 53, 1017-1022.
370
Org. Lett., Vol. 10, No. 3, 2008

We postulated that isolation and purification of imidazolide
8, if possible, could be used to improve the yield. To this
end, Tr-Ser(OBn)-OH was reacted with excess CDI (1.5
equiv) to ensure complete conversion, followed by aqueous
workup to remove the excess CDI. We were both pleased
and surprised to find that this acid imidazolide, obtained in
97% yield, was a stable crystalline solid that was easily
purified by column chromatography on silica gel.17 Although
a number of simple acid imidazolides have been shown to
be isolable compounds,18 the literature, to our knowledge,
makes no mention of EP amino acid imidazolide stability,
although these reactive amides are used extensively in
synthesis.19 Indeed, just the opposite appeared to be the case,
as acid imidazolides are routinely prepared and immediately
used without isolation because of their high reactivity.13 We
have also prepared stable crystalline acid imidazolides from
Tr-Phe-OH and Tr-Val-OH.
the more common carbamate protection groups for nitrogen
are electron-withdrawing and activate the carbonyl.
With clean acid imidazolide 8 in hand, C-acylation under
the previous conditions using the sodium anion of 3 provided
a 10% increase in yield (Table 1, entry 5). The problem of
Table 1. Formation of 3-Acyloxindoles
entry
oxindole
base (equiv)
NaH (1.0)
NaH (4.0)
NaH (2.0)
LDA (2.0)
NaH (2.0)
Li-imidazolide (2.0)
Li-imidazolide (5.0)
8
yield (%)
A review of the Cambridge Crystal Structure Database
reveals that there are very few examples of structurally
characterized activated amino acid amide compounds. Com-
pound 8 crystallizes in the chiral space group C2221 (Figure
1). The position of the amine hydrogen, H3, was located
1
2
3
4
5
6
7
3a
3a
3b
3b
3b
3b
3b
in situ
in situ
in situ
in situ
isolated
isolated
isolated
42
50
50
40
60
70
72
reactive anion management was solved by employing lithium
imidazolide as base rather than the preformed anion of 3.
This final optimization led to a reproducible 72% yield of
desired product 2.
Success in the transformation of 7 to 3b via the RhII-
catalyzed C-H insertion reaction offered us excellent
precedent for our second route to 2, namely, diazo decom-
position of 4. Compounds 4a,b were synthesized by acylation
of the anions derived from N-benzylacetanilide and 6 (LDA)
using in situ generated imidazolide 8, which gave the
â-ketoamides in 45-55% yield (Scheme 3). Treatment with
mesyl azide (MsN3)23 or 4-acetamidobenzenesulfonyl azide
with DBU gave the desired diazo compounds 4a,b in 89%
and 96% yield, respectively. However, no oxindole was
observed upon rhodium-catalyzed diazo decomposition.
Unexpectedly, we obtained the trans-trityl-protected â-lac-
tam. The structure of trans isomer 9 was confirmed by X-ray
crystallography. The trans isomer 11 was isolated in 60%
yield by treatment with the rhodium catalyst.
Figure 1. Solid-state structure of acid imidazolide 8.
from a difference Fourier map. It is oriented toward the
imidazole nitrogen, N2, of an adjacent, symmetry-related
molecule giving rise to one-dimensional chains of H-bonded
molecules running through the lattice parallel to the a-axis
(N3‚‚‚N2′ distance ) 3.3243(19) Å, see table of hydrogen
bonds).20 The structure in Figure 1 confirms that chirality is
retained throughout the synthesis. The bond distances and
angles within the molecule are comparable to other, similar
compounds.21,22 For one of these studies21b it was speculated
that the electron-donating properties of the trityl group
stabilized the carbonyl to reaction by nucleophiles, whereas
This unexpected and unprecedented route to the â-lactam
nucleus directly from an R-amino acid, to our knowledge
the first documented transformation of its kind, is best
explained mechanistically by invoking a stereospecific Wolff
(21) (a) Barlos, K.; Papaioannou, D.; Voliotis, S.; Prewo, R.; Bieri, J.
H. J. Org. Chem. 1985, 50, 696-697. (b) Sliedregt, K. M.; Schouten, A.;
Kroon, J.; Liskamp, R. M. J. Tetrahedron Lett. 1996, 37, 4237-4240. (c)
Mamos, P.; Papaioannou, D.; Kavounis, C.; Nastopoulos, V. Acta. Crys-
tallogr. 1997, C53, 1973-1975.
(22) The crystal structure of achiral Tos-MeAib-Im has been reported.
See (a) Toniolo, C.; Crisma, M.; Formaggio, F. Biopolymers 1996 40, 627-
651. (b) Crisma, M.; Moretto, V.; Formaggio, F.; Toniolo, C. Z. Kristallogr.
1999, 214, 766-770.
(23) Taber, D. F.; Ruckle, R. E.; Hennessy, M. J. J. Org. Chem. 1986,
51, 4077-4078.
(17) For a previous synthesis of 8, without isolation, see Hoffman, R.
V.; Tao, J. J. Org. Chem. 1999, 64, 126-132.
(18) Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 1, 351-367.
(19) Staab, H. A.; Bauer, H.; Schneider, K. M. Azolides in Organic
Synthesis and Biochemistry; Wiley-VCH: New York, 1998.
(20) The crystal structure for 8 has been deposited at the Cambridge
Crystallographic Data Center and allocated the reference no. 655083.
Org. Lett., Vol. 10, No. 3, 2008
371

pathway (through 12) in the metal-catalyzed transformation.
The cleanest and highest-yielding reactions were photo-
chemical. Upon irradiation, compound 4a gave a 2.5:1
separable mixture of trans and cis â-lactam isomers,
respectively, in 76% yield. Comparison with the rhodium-
catalyzed reaction (Vide supra) revealed the presence of the
cis isomer in the former reaction. However, only the trans
isomer (88% yield) was isolated from irradiation of 4b
(Scheme 3, box). Wolff rearrangements generally proceed
with retention of configuration;30 this was verified for 9 by
refinement of the X-ray data31 (Flack parameter ) 0.04 (11)).
In addition, we have shown that the reaction is completely
stereospecific; i.e., D-Tr-Ser(OBn)-imidazole (ent-8) affords
the enantiomeric material ent-9 as shown by chiral column
HPLC; there is no indication of enantiomer formation in
either reaction.
Scheme 3. Wolff Rearrangement to â-Lactam
Questions concerning the origin and scope of this unex-
pected Wolff rearrangement, in contrast to N-H or C-H
insertion, the utility of trityl protection of the â-lactam amide
functionality and the facile access to stable crystalline amino
acid imidazolides in high yield are currently under study in
our laboratory and will be reported in due course.
Acknowledgment. We thank the NIH (CA98878) for
generous support of this work. In addition, we thank the
ACS-PRF Summer School, “Crystallography for Organic
Chemists” for the opportunity for one of us (L.E.B.) to
particpate and collect the data for 9. Purchase of the 600
MHz NMR used in these studies was supported by funds
from the National Institutes of Health (S10RR019918) and
National Science Foundation (CHE-0342912). The single
crystal X-ray diffraction data for 8 were recorded on an
instrument supported by the National Science Foundation,
Major Research Instrumentation (MRI) Program under Grant
No. CHE-0521569.
rearrangement24 to form ketene intermediate 12, which
undergoes intramolecular attack by the trityl-protected amine.
Intramolecular ring closures of N-trityl groups have been
observed previously.25 Wolff rearrangements catalyzed by
Rh(II) species are rare, but have been documented.26
Furthermore, this appears to be the first known synthesis of
a trityl protected â-lactam amide, as a recent effort to add a
trityl group to the 4-membered lactam afforded poor yield.27
To support this mechanism, diazoketones 4 were decom-
posed with silver benzoate,28 a well-known reagent for the
Arndt-Eistert elongation of R- to â-amino acids, and with
UV radiation.29 Desired lactams 9-11 were isolated from
each reaction, which supports the Wolff rearrangement
Supporting Information Available: Synthetic proce-
dures, complete spectroscopic data, 1H and 13C NMR spectra
for all new compounds and CIF files for 8 and 9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Kirmse, W. Eur. J. Org. Chem. 2002, 2193-2256.
(25) May, J. P.; Fournier, P.; Pellicelli, J.; Patrick, B. O.; Perrini, D. M.
J. Org. Chem. 2005, 70, 8424-8430.
OL7025922
(26) Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org.
Chem. 2005, 70, 5840-5851 and references therein.
(29) Podlech, J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1995, 34,
471-472.
(30) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley-Inter-
science: 1998; pp 498ff.
(31) The crystal structure for 9 has been deposited at the Cambridge
Crystallographic Data Center and allocated the reference no. 655084.
(27) Reddy, D. R.; Iqbal, M. A.; Hudkins, R. L.; Messina-McLaughlin,
P. A.; Mallamo, J. P. Tetrahedron Lett. 2002, 43, 8063-8066.
(28) Sudrik, S. G.; Maddanimath, T.; Chaki, N. K.; Chavan, S. P.;
Chavan, S. P.; Sonawane, H. R.; Vijayamohanan, K. Org. Lett. 2003, 5,
2355-2358 and references therein.
372
Org. Lett., Vol. 10, No. 3, 2008