Enantioselective Total Synthesis of (1R,3S,4R,5R)-1-Amino-4,5-dihydroxycyclopentane-1,3-dicarboxylic Acid. A Full-Aldol Access to Carbaketose Derivatives

Article abstract of DOI:10.1021/jo035846a

The enantioselective synthesis of cyclopentanedicarboxylic amino acid 1, a novel rigid and functionalized L-glutamic acid analogue, has been achieved in 15 linear steps from silyloxypyrrole 3, utilizing L-glyceraldehyde 4 as the source of chirality. The key steps in the synthesis are three sequential aldol-based carbon-carbon bond-forming reactions: two crossed vinylogous aldol additions (2 + 3 → 8 and 4 + 5 → 10 + 11) and one intramolecular silylative aldolization (6 → 7). En passant, the short syntheses of (2S)-2-hydroxymethylglutamic acid (16) and its (2R)-enantiomer ent-16, a potent metabotropic glutamate receptor agonist, have been achieved.

Full text of DOI:10.1021/jo035846a

En a n tioselective Tota l Syn th esis of
(1R,3S,4R,5R)-1-Am in o-4,5-d ih yd r oxycyclo-
p en ta n e-1,3-d ica r boxylic Acid . A F u ll-Ald ol
Access to Ca r ba k etose Der iva tives
Lucia Battistini,*,† Claudio Curti,† Franca Zanardi,†
Gloria Rassu,‡ Luciana Auzzas,‡ and
Giovanni Casiraghi*,†
Dipartimento Farmaceutico, Universita` di Parma, Parco
Area delle Scienze 27A, I-43100 Parma, Italy, and Istituto
di Chimica Biomolecolare del CNR, Sezione di Sassari,
Traversa La Crucca 3, I-07040 Li Punti, Sassari, Italy
giovanni.casiraghi@unipr.it
Received December 19, 2003
Abstr a ct: The enantioselective synthesis of cyclopentanedi-
carboxylic amino acid 1, a novel rigid and functionalized
L-glutamic acid analogue, has been achieved in 15 linear
steps from silyloxypyrrole 3, utilizing L-glyceraldehyde 4 as
the source of chirality. The key steps in the synthesis are
three sequential aldol-based carbon-carbon bond-forming
reactions: two crossed vinylogous aldol additions (2 + 3 f
8 and 4 + 5 f 10 + 11) and one intramolecular silylative
aldolization (6 f 7). En passant, the short syntheses of (2S)-
2-hydroxymethylglutamic acid (16) and its (2R)-enantiomer
ent-16, a potent metabotropic glutamate receptor agonist,
have been achieved.
F IGURE 1. The multifacial structure of dicarboxylic amino
acid 1.
SCHEME 1. Retr osyn th esis of Dica r boxylic Am in o
Acid 1
The carbocyclic amino acid 1, the synthetic object of
this article, is a small yet intriguing molecular construct
whose structure can be visualized under diverse perspec-
tives. As shown in Figure 1, the integral molecule is in
itself an oxidized form of an aminoated carba-ketofura-
nose (i.e., 5a-carba-â-D-fructofuranose1) that can be viewed
either as a dihydroxylated analogue of (1S,3R)-1-ami-
nocyclopentane-1,3-dicarboxylic acid (trans-ACPDA), a
selective metabotropic glutamate receptor agonist,2 or as
a constrained 2,4-disubstituted L-glutamic acid. Further-
more, within the structure of 1, one can quickly identify
the fragment of D-serine as well as the structural motif
of (2R)-2-hydroxymethylglutamic acid (HMGA), a re-
cently introduced selective metabotropic glutamate re-
ceptor agonist.3
From a synthetic perspective, 1 is a quite challenging
target, for five consecutive functionalities and four ste-
reocenters, including a quaternary one, converge into a
small cyclopentane core unit. Retrosynthetically (Scheme
1), amino acid 1 could be disconnected along three
strategic carbon-carbon bonds, as indicated, furnishing
three simple building fragments, A, B, and C, that
ultimately could be derived from formaldehyde (2),
N-(tert-butoxycarbonyl)-2-[(tert-butyldimethyl)silyloxy]-
pyrrole (3), and 2,3-O-isopropylidene-L-glyceraldehyde
(4), respectively. In the synthetic direction, we planned
first to attach formaldehyde (2) to 3, forming the γ-sub-
stituted dienoxy pyrrole 5, afterwhich 5 was to be coupled
with 4 to give aldehyde 6, which consequently was to be
cyclized into bicycle 7, and finally, the requisite amino
and carboxy functionalities within 7 were to be un-
masked, thus completing the construction of 1.
† Universita` di Parma.
‡ CNR, Sassari.
(1) (a) Wilcox, C. S.; Gaudino, J . J . J . Am. Chem. Soc. 1986, 108,
3102-3104. (b) Gaudino, J . J .; Wilcox, C. S. Carbohydr. Res. 1990,
206, 233-250. (c) Seepersaud, M.; Al-Abed, Y. Org. Lett. 1999, 1, 1463-
1465.
(2) (a) Kno¨pfel, T.; Kuhn, R.; Allgeier, H. J . Med. Chem. 1995, 38,
1417-1426. (b) Schoepp, D. D.; True, R. A. Neurosci. Lett. 1992, 145,
100-104. (c) Monaghan, D. T.; Bridges, R. J .; Cotman, C. W. Annu.
Rev. Pharmacol. Toxicol. 1989, 29, 365-402. (d) Palmer, E.; Monaghan,
D. T.; Cotman, C. W. Eur. J . Pharmacol. 1989, 166, 585-587.
(3) (a) Zhang, J .; Flippen-Anderson, J . L.; Kozikowski, A. P. J . Org.
Chem. 2001, 66, 7555-7559. (b) Kozikowski, A. P. PCT Int. Appl. WO
02/22622 A2, 2002. (c) Kawasaki, M.; Namba, K.; Tsujishima, H.;
Shinada, T.; Ohfune, Y. Tetrahedron Lett. 2003, 44, 1235-1238.
Accordingly, our synthesis (Scheme 2) commenced with
the gram-scale preparation of γ-substituted pyrrolinone
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J . Org. Chem. 2004, 69, 2611-2613
2611

SCHEME 2. P r ep a r a tion of La cta m In ter m ed ia tes
12 a n d 13
SCHEME 3. Ch em ica l Cor r ela tion s of 12 a n d 13 to
r-Su bstitu ted Glu ta m ic Acid s 16 a n d en t-16
8 via SnCl4-assisted vinylogous hydroxyalkylation of
pyrrole-derived dienoxysilane 3 with anhydrous formal-
dehyde (2) (85% yield).4 After silylation to 9, TBSOTf-
lutidine treatment then led to substituted dienoxy pyrrole
5 (93% yield, two steps), which was coupled to 2,3-O-
isopropylidene-L-glyceraldehyde (4) under the guidance
of SnCl4 in diethyl ether. A mixture of two unsaturated
adducts, 10 and 11 (65% combined yield), was obtained,
where the (4S)-configured isomer 10 strongly predomi-
nated (78:22 dr, by 1H NMR).5 Isolation of the individual
components in the unsaturated adduct mixture proved
indeed difficult; so we opted to move ahead with the
reduction of the lactam double bond within 10 and 11
(NiCl2, NaBH4), arriving at stable γ,γ-disubstituted pyr-
rolinone 12 in an acceptable 50% yield over two steps.
During the separation workup a minor, crystalline isomer
(12% yield, two steps) was also isolated, to which
structure 13 was tentatively assigned.6
To fix, at least, the absolute configuration at the
quaternary carbon C4 in both isomers 12 and 13, chemi-
cal correlations of these compounds to known (2S)-2-
hydroxymethylglutamic acid (16)7 and (2R)-2-hydroxym-
ethylglutamic acid (ent-16),3 a novel, remarkable selective
agonist of group II metabotropic glutamate receptors,
were executed (Scheme 3). Thus, removal of both the
N-Boc and isopropylidene protections within the major
isomer 12 cleanly afforded a triol intermediate 14, which
was first fragmented to aldehyde 15 and then oxidized
and hydrolyzed to (2S)-configured amino acid 16 (59%
yield from 12).
present in the literature for the same compound (lit. free
amino acid [R]20
D ) -11.2;3c HCl salt [R]20D ) -1.63a). As
expected, enantiomeric amino acid 16 displayed almost
equal optical rotation as its enantiomer ent-16, but of
opposite sign ([R]20 ) +9.8). Thus, having established
D
(5) Presumably, the reaction proceeds via the Diels-Alder-like endo
transition structure I, featuring a Felkin-type facial diastereoselectivity
(addition of the aldehyde from the re-face). The transition state I then
collapses to afford the major 4S,5R-configured adduct 10. Formation
of the minor 4R,5R isomer 11, in contrast, would require a high-energy
exo transition state II possessing an unfavorable orientation of the
aldehyde dioxolanyl substituent.
In a parallel fashion, minor isomer 13 was elaborated
into (2R)-configured amino acid ent-16 in a 58% overall
yield. The values we obtained for the optical rotation of
both the free amino acid ent-16 ([R]20 ) -9.6) and its
D
HCl salt ([R]20 ) -1.2) nicely matched the values
D
(4) For recent reviews dealing with the silyloxy diene chemistry,
see: (a) Casiraghi, G.; Rassu, G.; Zanardi, F.; Battistini, L. In Advances
in Asymmetric Synthesis; Hassner, A., Ed.; J AI Press: Stamford; 1998;
Vol. 3, pp 113-189. (b) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi,
G. Synlett 1999, 1333-1350. (c) Rassu, G.; Zanardi, F.; Battistini, L.;
Casiraghi, G. Chem. Soc. Rev. 2000, 109-118. (d) Casiraghi, G.;
Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929-
1972.
For a recent theoretical study of the mechanisms of related Lewis acid
assisted reactions involving five-membered heterocyclic dienes, see:
Yu, Z.-X.; Wu, Y.-D. J . Org. Chem. 2003, 68, 421-432.
(6) For this minor isomer, the absolute configuration at C5 could
not be firmly assigned.
(7) Choudhury, P. K.; Le Nguyen, B. K.; Langlois, N. Tetrahedron
Lett. 2002, 43, 463-464.
2612 J . Org. Chem., Vol. 69, No. 7, 2004

SCHEME 4. P r ep a r a tion of Ald eh yd e 6
SCHEME 5. Com p letion of Am in o Acid 1
C5, as well as the erythro disposition of the C5 hydroxyl
and the lactam nitrogen (target numbering), thus con-
firming the stereochemistry of the precursor aldehyde 6.
Unmasking of the latent C1 carboxyl moiety of 1 was
effected by oxidation of the hydroxymethyl group in the
adduct 7. Thus, the N-benzyl protection was first cleaved
(Na, liquid NH3) and the hydroxymethyl function was
selectively deprotected (AcOH) to deliver free alcohol 19
(77% yield, two steps), which was directly exposed to
NaIO4 in the presence of catalytic RuO2. In the event,
bicyclic carboxylic acid 20 was isolated in a 80% yield.
The fragmentation of the lactam ring of 20, which
liberated both the amino group at C1 and carboxylic
function at C3, was realized with concomitant desilyla-
tion, via exposure to 6 N aqueous HCl at 110 °C, followed
by DOWEX (H+ form) treatment, to finally obtain the
targeted cyclopentane-1,3-dicarboxylic amino acid 1 in a
98% isolated yield.
In summary, we have established a viable, stereose-
lective synthetic route to L-glutamic acid related amino
acid 1 that can provide a foundation for the search of
novel metabotropic glutamate receptor probes, as well as
relevant densely functionalized carba-ketose constructs.
The synthesis was completed within 15 individual steps
with a 8% global yield, in a sequence featuring three
highly productive aldol-based, carbon-carbon bond junc-
tions accompanied by the rational execution of suitable
functional group transformations and selective protec-
tion-deprotection protocols. As a corollary, routine elabo-
ration of two intermediary compounds, lactams 12 and
13, resulted, respectively, in the short chemical syntheses
of (2S)-2-hydroxymethylglutamic acid (16) and (2R)-2-
hydroxymethylglutamic acid (ent-16), a recently intro-
duced selective metabotropic glutamate receptor agonist.
the absolute configuration at the quaternary carbons of
12 and 13 as 2S and 2R, respectively, we proceeded along
our synthesis with the elaboration of the more abundant
isomer 12 into aldehyde 6, as shown in Scheme 4.
After silylation of the secondary hydroxyl of 12, the
N-Boc protective function was switched to N-Bn by a
deprotection-reprotection protocol consisting of cerium
ammonium nitrate treatment, followed by benzylation.
Orthogonally protected lactam 17 was thus obtained in
a 70% yield for the three-step sequence. Exposure of 17
to cerium trichloride in the presence of catalytic oxalic
acid8 selectively delivered a terminal diol intermediate
(not shown), which was oxidatively shortened by one
carbon atom (NaIO4) to give aldehyde 6 in a 70% global
yield.
The complete stereostructure of 6 (and hence that of
its predecessors) awaited decisive confirmation, and this
was simply established from that of its spirocyclic deriva-
tive 18, which was quantitatively obtained by desilylation
of the primary hydroxyl group within 6, followed by
spontaneous ring-closing hemiacetalization.9 Examina-
tion of the interproton NOE correlations within 18
(Supporting Information) unambiguously provided clear-
cut evidence of the erythro relationship between the
lactam nitrogen and the hydroxyl C5 substituent, as well
as the trans orientation of the protons H5 and H6. Thus,
having already established the absolute configuration of
the quaternary C4 center (vide supra), the stereochem-
istry of both 17 and 6 was assigned as 4S,5R, as shown.
The third aldol maneuver connecting the C2 nucleo-
philic carbon of 6 to its terminal aldehyde group (C6) was
the key step in our synthesis (Scheme 5).
This operation, which completed the cyclopentane ring
of 1, was executed as previously described10 by exposure
of aldehyde 6 to an equimolar mixture of TBSOTf and
DIPEA in CH2Cl2 at room temperature. Under these
performing silylative conditions, cycloadduct 7 was cleanly
obtained as a predominant isomer in a gratifying 86%
isolated yield (>90% dr).11 The stereochemical confirma-
tion of the silylated aldol 7 was obtained by 2D NOESY
experiments (Supporting Information) that substantiated
the trans relationship between the substituents at C4 and
Ack n ow led gm en t. This work was supported by a
research grant from the Ministero dell’Universita` e della
Ricerca Scientifica e Tecnologica (MURST, COFIN 2002)
and Fondi per gli Investimenti della Ricerca di Base
(FIRB 2002). We also wish to thank the Centro Inter-
facolta` di Misure “G. Casnati”, Universita` di Parma, for
access to the analytical instrumentation.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization data for all synthesized compounds,
1H NMR resonances, coupling constants and 1H-1H NOE
correlations for 1, 7, and 18, (Tables S1-S3), as well as copies
(8) Xiao, X.; Bai, D. Synlett 2001, 535-537.
(9) On standing, this material equilibrated into a 60:40 anomeric
mixture.
(10) Rassu, G.; Auzzas, L.; Pinna, L.; Zambrano, V.; Zanardi, F.;
Battistini, L.; Gaetani, E.; Curti, C.; Casiraghi, G. J . Org. Chem. 2003,
68, 5881-5885 and references therein.
(11) A minor 4,5-cis-configured isomer was also isolated and fully
characterized (Supporting Information).
1
of 1H NMR spectra for compounds 1, 6, 7, 18, and 20 and H-
1H NOESY spectra for compounds 1, 7, and 18. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O035846A
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