Synthesis of a novel tetrahydroxylated β-homoproline

Article abstract of DOI:10.1055/s-0030-1259293

A gram-scale synthesis of a novel densely functionalized and orthogonally protected β-homoproline was achieved from l-tartaric acid derived nitrone through a highly stereoselective 1,3-dipolar cycloaddition to γ-crotonolactone as the key initial step, fol

Full text of DOI:10.1055/s-0030-1259293

LETTER
231
Synthesis of a Novel Tetrahydroxylated b-Homoproline
Synthesis of
a
N
ov
r
el
T
etra
h
m
ydroxylated
b
-Hom
i
oproli
nne Benz, Francesca Cardona,* Andrea Goti*
Dipartimento di Chimica ‘Ugo Schiff’, HeteroBioLab, Università di Firenze, associated with INSTM and ICCOM-C.N.R.,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax +39(055)4573531; E-mail: andrea.goti@unifi.it; E-mail: francesca.cardona@unifi.it
Received 22 October 2010
Dedicated to Prof. Alberto Brandi on the occasion of his 60th birthday
isolated in 54% yield after recrystallization from hex-
anes.9 The stereoselectivity of this reaction has been thor-
oughly investigated by Chmielewski and co-workers,8a
who demonstrated that the minor adduct (the two diaste-
reomers are obtained in 93:7 ratio) derives from an exo-
syn approach, since the tert-butoxy group at C-4 on nitro-
ne 2 eliminates the possibility of endo adducts, which are
indeed observed with L-malic acid derived nitrone (that
bears only one vicinal tert-butoxy group).8a,10 Formation
of this minor adduct in only minute amount (<10%) is sig-
nificant, since the desired major adduct can be recovered
pure in bulk amounts by a simple recrystallization proce-
dure, without the need of more expensive and time-
consuming separation procedures. Among the solvents
tested, hexanes performed best for the crystallization of
pure adduct 4.
Abstract: A gram-scale synthesis of a novel densely functionalized
and orthogonally protected b-homoproline was achieved from L-
tartaric acid derived nitrone through a highly stereoselective 1,3-
dipolar cycloaddition to g-crotonolactone as the key initial step, fol-
lowed by appropriate elaboration of the adduct.
Key words: non-natural amino acid, total synthesis, nitrone,
cycloaddition
The importance of b-amino acids is related to their role as
synthetic intermediates1 and as components of biological-
ly relevant compounds including peptidomimetics2 and b-
peptides.3,4 However, among these synthetic peptidomi-
metics, b-homoproline derivatives have been scarcely in-
vestigated, apart from a recent example in which the
incorporation of a new cyclic b-amino acid into a simple
tripeptide has been evaluated.5 Moreover, some sulfon-
amide derivatives of b-homoproline have been recently
studied as organocatalysts for Michael and aldol reac-
tions.6
t-BuO
Ot-Bu
t-BuO
Ot-Bu
H
H
H
H
OH
OH
O
toluene
LiAlH4
N
N
2
+ 3
r.t., 3 d
54%
THF
95%
O
O
O
We present in this Letter a straightforward gram-scale
synthesis of a novel b-homoproline 1 that is hydroxylated
on the pyrrolidine skeleton as well as on the chain at the
a-carbon, by means of a highly selective 1,3-dipolar cy-
cloaddition of L-tartaric acid derived nitrone 2 to g-croto-
nolactone (3) as the first key step, required for the highly
selective installation of three new stereocenters on the tar-
get molecule (Scheme 1).
H
H
4
6
H2
DIBAL-H
CH2Cl2, –80 °C
70%
Pd(OH)2/C
MeOH
100%
t-BuO
Ot-Bu
H
t-BuO
Ot-Bu
H
H
H
OH
OH
OH
N
N
H
HO
t-BuO
Ot-Bu
t-BuO
Ot-Bu
O
O
O
H
H
H
COOH
H
α
+
O
β
N+
O–
N
5
7
Fmoc
O
Scheme 2 Cycloaddition reaction, reduction of the lactone moiety,
2
3
O
and N–O bond cleavage
1
Reductive cleavage of the N–O bond performed on com-
pound 4, attempted in several reaction conditions, always
failed. Hydrogenolysis catalyzed by Pd(OH)2/C gave a
complex mixture and treatment with Mo(CO)6 in MeCN–
H2O11 led to unaltered starting material. On treatment of 4
with Zn in AcOH–H2O12 a major product was isolated
which derived from elimination of water from the expect-
ed g-amino alcohol leading to the corresponding a,b-un-
saturated lactone. We turned then our attention to stronger
reducing agents, namely aluminium hydrides, anticipating
that the lactone functionality might be more reactive than
Scheme 1 Retrosynthetic analysis for b-homoproline 1
Cycloaddition of nitrone 27 to g-crotonolactone (3) pro-
ceeded smoothly in toluene at room temperature
(Scheme 2), affording a crude mixture (89%) of two cy-
cloadducts,8 from which the major exo-anti adduct 4 was
SYNLETT 2011, No. 2, pp 0231–0234
Advanced online publication: 04.01.2011
DOI: 10.1055/s-0030-1259293; Art ID: G31310ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

232
A. Benz et al.
LETTER
the N–O bond towards these reagents. Indeed, treatment from 7, Scheme 3). Having found the optimized condi-
with DIBAL-H gave the reduced lactol 5 in 70% yield tions for the selective protection of the 1,2-diol moiety
(Scheme 2), but N–O bond cleavage through hydrogenol- which involved formation of an ammonium salt, we en-
ysis catalyzed by Pd(OH)2/C was unsuccessful even at visaged that this procedure might be also amenable to
this level,13 leaving the unaltered lactol 5. In order not to direct application on the amine 7, thus reducing consider-
lose the stereochemical information at the a-carbon, we ably the synthetic steps. Indeed, direct protection of com-
then decided to reduce the lactone double bond to the cor- pound 7 with dimethoxypropane as solvent in the
responding alcohol. Treatment of 4 with LiAlH4 in THF presence of 1.2 equivalents of PTSA afforded compound
gave pure 614 in 95% yield. To our delight, subsequent hy- 11 in excellent yield (96%) on gram scale. The following
drogenolysis catalyzed by Pd(OH)2/C afforded the poly- protection of the nitrogen atom as Fmoc derivative gave
hydroxypyrrolidine 7 in quantitative yield (Scheme 2). pure 10 in 86% yield (82% yield over two steps), thus es-
Protection of the amine moiety as Fmoc derivative (com- tablishing a straightforward two-step synthesis of 10 from
monly used in peptide synthesis) was attempted at this triol 7 (Scheme 3).
stage, by treating 7 with FmocCl and 2,6-lutidine in dry
THF, but only 30% of the desired product was obtained.
Since such a low yield at this early stage was not accept-
able for a large-scale synthesis of the desired b-homopro-
line 1, we decided to temporarily protect the nitrogen
The final key oxidation step of the unprotected primary al-
cohol was attempted on benzyl-protected pyrrolidine 9 as
well as on the Fmoc-protected 10. This transformation
turned out to be extremely challenging and led us to inves-
tigate both the direct conversion to carboxylic acid and the
atom as benzyl derivative, by reaction with BnBr in
two-step conversion passing through the aldehyde inter-
MeCN in the presence of an excess of K2CO3, affording
mediate.
compound 8 in 68% yield (Scheme 3).
Ot-Bu
Ot-Bu
H
t-BuO
Ot-Bu
H
t-BuO
Ot-Bu
H
MeO
OMe
(COCl)2
DMSO, CH2Cl2
H
O
H
BnBr
K2CO3
H
OH
H
OH
N
9
7
N
N
–78 °C
77%
PTSA
70%
MeCN
68%
O
OH
HO
O
O
H
O
12
8
9
MeO
OMe
Scheme 4 Oxidation of alcohol 9
1) H2, Pd(OH)2/C
2) FmocCl
2,6-lutidine
THF
PTSA
96%
When the alcohol 9 was treated with Jones reagent (2.4
equiv) or NaClO2/NaOCl in combination with TEMPO as
catalyst15 the starting material was recovered unchanged.
On the contrary an excess of Jones reagent, PCC, Dess–
69%
t-BuO
Ot-Bu
Fmoc
t-BuO
Ot-Bu
H
2,6-lutidine
dry THF
86%
.
Martin reagent,16 or RuO2 H2O in combination with
H
H
OH
H OH
NaIO417 all afforded complex mixtures of products. Even-
tually, oxidation of 9 to aldehyde 12 was achieved with
TPAP/NMO catalytic system,18 or with Swern oxidation19
(Scheme 4), but 12 proved to be unstable to purification
by flash column chromatography. An attempt to oxidize
directly crude 12 with KMnO4 in t-BuOH in the presence
N
N
Fmoc
H
O
O
O
O
11
10
20
of NaH2PO4 afforded a complex mixture of products.
Scheme 3 Alternative syntheses of alcohol 10
Oxidation reactions of alcohol 10 gave some better re-
sults. A first attempt by exposing 10 to 0.02 equivalents of
TEMPO and 3 equivalents of trichloroisocyanuric acid
(TCCA) gave mainly the corresponding aldehyde 13 in-
stead of the expected carboxylic acid,21 which was more
cleanly obtained by Swern oxidation (Scheme 5). Treat-
ment of aldehyde 13 with NaClO2 in a t-BuOH–MeCN
solution buffered with aqueous NaH2PO422 occurred suc-
cessfully but with concomitant deprotection of the ace-
tonide moiety to furnish moderate yields of the acid 14.
This unsatisfying result showed nonetheless that the tert-
butyl ether and acetonide protections can be considered
orthogonal to some extent, the latter being deprotected un-
der much milder conditions.
Selective protection of the 1,2-diol over the 1,3-diol on
compound 8 was attempted using several reaction condi-
tions. Reaction in acetone with p-toluenesulfonic acid
(PTSA) catalysis (0.1 equiv) gave no reaction, while treat-
ment with iodine (0.2 equiv) in acetone afforded a com-
plex mixture of products. Finally, reaction with
dimethoxypropane as solvent in the presence of 1.2 equiv-
alents of PTSA gave 9 in 70% yield. Clearly, the first
equivalent of PTSA formed the pyrrolidinium salt, while
the remaining 0.2 equivalents catalyzed the protection
reaction.
Subsequent hydrogenolysis catalyzed by Pd(OH)2/C, fol-
lowed by protection as Fmoc derivative afforded 10 in
69% yield over two steps (and 32% yield over four steps
Synlett 2011, No. 2, 231–234 © Thieme Stuttgart · New York

LETTER
Synthesis of a Novel Tetrahydroxylated b-Homoproline
233
(3) (a) Seebach, D.; Abele, S.; Sifferlen, T.; Hängi, M.; Gruner,
S.; Seiler, P. Helv. Chim. Acta 1998, 81, 2218. (b) Abele,
S.; Vögtli, K.; Seebach, D. Helv. Chim. Acta 1999, 82, 1539.
(4) For some reviews on b-peptides, see: (a) Seebach, D.;
Matthews, J. L. Chem. Commun. 1997, 2015. (b) Gellman,
S. H. Acc. Chem. Res. 1998, 31, 173. (c) Gademann, K.;
Hintermann, T.; Schreiber, J. V. Curr. Med. Chem. 1999, 6,
905. (d) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F.
Chem. Rev. 2001, 101, 3219. (e) Seebach, D.; Gardiner, J.
Acc. Chem. Res. 2008, 41, 1366. (f) Seebach, D.; Hook,
D. F.; Glattli, A. Biopolymers 2006, 84, 23.
Finally, direct oxidation of alcohol 10 with RuO4 catalyst
formed in situ by reaction of catalytic ruthenium trichlo-
ride with stoichiometric sodium periodate17 afforded the
desired acid 1 in 65% yield.
t-BuO
Ot-Bu
H
(COCl)2
DMSO
CH2Cl2
H
O
10
N
–78 °C, 100%
H
Fmoc
O
(5) Cordero, F. M.; Salvati, M.; Vurchio, C.; de Meijere, A.;
Brandi, A. J. Org. Chem. 2009, 74, 4225.
(6) Tsandi, A.; Kokotos, C. G.; Kousidou, S.; Ragoussis, V.;
Kokotos, G. Tetrahedron 2009, 65, 1444.
RuCl3:H2O
NaIO4
O
MeCN–EtOAc
65%
13
(7) Cicchi, S.; Höld, I.; Brandi, A. J. Org. Chem. 1993, 58, 5274.
(8) (a) Stecko, S.; Paśniczek, K.; Jurczak, M.; Urbańczyk-
Lipkowska, Z.; Chmielewski, M. Tetrahedron: Asymmetry
2006, 17, 68. (b) Goti, A.; Cicchi, S.; Cordero, F. M.; Fedi,
V.; Brandi, A. Molecules 1999, 4, 1.
NaClO2
t-BuOH
47%
t-BuO
Ot-Bu
t-BuO
Ot-Bu
(9) For a comprehensive discussion of the possible approaches
in cycloadditions to this class of nitrones, see: Brandi, A.;
Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Eur.
J. 2009, 15, 7808; see also ref. 8b.
(10) For recent DFT studies of 1,3-dipolar cycloadditions of
cyclic nitrones to unsaturated g-lactones, see: (a)Stecko,S.;
Paśniczek, K.; Michel, C.; Milet, A.; Pérez, S.;
H
H
H
O
H O
N
N
OH
OH
Fmoc
O
Fmoc
HO
O
HO
14
1
Chmielewski, M. Tetrahedron: Asymmetry 2008, 19, 1660.
(b) Stecko, S.; Paśniczek, K.; Michel, C.; Milet, A.; Pérez,
S.; Chmielewski, M. Tetrahedron: Asymmetry 2008, 19,
2140.
Scheme 5 Oxidation of alcohol 10; synthesis of b-homoproline 1
In conclusion, we achieved a gram-scale straightforward
synthesis of b-homoproline 123 from L-tartaric acid de-
rived nitrone 2 in six steps and 28% overall yield (80% av-
erage on the single steps). It is also worth to be noted that
starting from readily available D-tartaric acid derived ni-
trone ent-2, the total synthesis of ent-1 might be easily ac-
cessed.
(11) (a) Cicchi, A.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351. (b) Goti, A.; Cicchi, S.;
Cacciarini, M.; Cardona, F.; Fedi, V.; Brandi, A. Eur. J. Org.
Chem. 2000, 3633.
(12) (a) Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti,
A. Tetrahedron Lett. 2003, 44, 2315. (b) Cardona, F.;
Parmeggiani, C.; Faggi, E.; Bonaccini, C.; Gratteri, P.; Sim,
L.; Gloster, T. M.; Roberts, S.; Davies, G. J.; Rose, D. R.;
Goti, A. Chem. Eur. J. 2009, 15, 1627.
(13) Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J. Am.
Chem. Soc. 1996, 118, 8266.
(14) Stecko, S.; Jurczak, M.; Urbańczyk-Lipkowska, Z.; Solecka,
J.; Chmielewski, M. Carbohydr. Res. 2008, 343, 2215.
(15) Zhao, M.; Eiichi Mano, J. L.; Song, Z.; Tschaen, D. M.;
Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64,
2564.
Work is under way to investigate the conformational
properties of the non-natural amino acid b-homoproline 1
in oligopeptides.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(16) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(17) For a review on RuO4-catalyzed oxidations, see: Plietker, B.
Synthesis 2005, 2453.
(18) (a) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23,
13. (b) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden,
S. P. Synthesis 1993, 433.
(19) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(20) Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S.
Tetrahedron Lett. 1986, 27, 4537.
(21) De Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A.
J. Org. Chem. 2003, 68, 4999.
(22) Polyak, F.; Lubell, W. D. J. Org. Chem. 2001, 66, 1171.
(23) Data for Compound 1 (Mixture of Two Rotamers)
Yellow solid, mp 88–90 °C. 1H NMR (400 MHz, CDCl3):
d = 7.79–7.78 (m, 2 H), 7.68–7.60 (m, 2 H), 7.44–7.30 (m, 4
H), 4.70–4.66 (m), 4.61–4.24 (m), 4.01–3.97 (m), 3.92–3.81
(m), 3.73–3.64 (m), 3.42 (t, J = 9.5 Hz), 3.32 (t, J = 10.0
Hz), 3.26 (d, J = 11.5 Hz), 3.10 (d, J = 11.5 Hz) (for a total
of 12 H), 1.40 (s), 1.33 (s), 1.32 (s), 1.29 (s) (for a total of 6
H), 1.25 (s), 1.20 (s), 1.18 (s), 1.08 (s) (for a total of 18 H).
Acknowledgment
We thank Ente Cassa di Risparmio di Firenze (CRF), Italy and
MIUR (PRIN 2008) for financial support. We also thank Dr
Gianluca Soldaini for supervision of the work of AB. Brunella In-
nocenti and Maurizio Passaponti for technical assistance.
References and Notes
(1) For some recent reviews on b-amino acids, see:
(a) Seebach, D.; Beck, A. K.; Capone, S.; Deniau, G.;
Grošelj, U.; Zass, E. Synthesis 2009, 1. (b) Kiss, L.; Fülöp,
F. Synlett 2010, 1302. (c) Weiner, B.; Szymanski, W.;
Janssen, D. B.; Minnaard, A. J.; Feringa, B. L. Chem. Soc.
Rev. 2010, 5, 1656.
(2) (a) Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.;
Aguilar, M. I. Curr. Med. Chem. 2002, 9, 811. (b) Porter,
E. A.; Wang, X. F.; Lee, H. S.; Weisblum, B.; Gellman,
S. H. Nature (London) 2000, 404, 565.
Synlett 2011, No. 2, 231–234 © Thieme Stuttgart · New York

234
A. Benz et al.
LETTER
13C NMR (50 MHz, CDCl3): d = 176.9, 176.8 (s, COOH),
156.4,155.1 (s, C=O Fmoc), 143.9, 143.8, 143.6, 141.4,
141.3, 141.2 (s, 4 C, Fmoc), 127.7–119.9 (d, 8 C, Fmoc),
108.3, 108.2 (s, CO acetonide), 78.4, 77.6, 76.3, 75.6, 75.5,
75.2 (d, 3 C), 74.7, 74.5, 74.4, 74.3 (s, 2 C, CO t-Bu), 68.1,
67.9, 67.5, 67.1 (t), 65.2, 64.5 (d), 54.6, 54.2 (t), 52.9, 51.7
(d), 47.1, 47.0 (d, Fmoc), 28.3, 28.2, 28.1, 28.0 (q, 6 C, t-
Bu), 26.5, 26.3, 25.7, 25.5 (q, 2 C, acetonide). IR (KBr):
3600–2400 (large), 2976, 1706, 1368, 1185, 740 cm–1. ESI-
MS: m/z (%) = 596.25 (27)[M+ + 1], 618.42 (100) [M+ + Na].
Anal. Calcd for C34H45NO8 (595.72): C, 68.55; H, 7.61; N,
2.35. Found: C, 68.32; H, 7.47; N, 2.68. [a]D25 +3.27 (c 1.47,
CH2Cl2).
Synlett 2011, No. 2, 231–234 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.