Diastereoselective intramolecular additions of allyl- and propargylsilanes to iminium ions: Synthesis of cyclic and bicyclic quaternary amino acids

Article abstract of DOI:10.1021/ol1010246

Chiral imino lactones derived from (R)-phenylglycinol containing an allyl- or propargyltrimethylsilyl group in the side chain readily cyclized in the presence of acidic reagents to afford spirocyclic compounds with high diastereoselectivity. Removal of th

Full text of DOI:10.1021/ol1010246

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3014-3017
Diastereoselective Intramolecular
Additions of Allyl- and Propargylsilanes
to Iminium Ions: Synthesis of Cyclic
and Bicyclic Quaternary Amino Acids
Santos Fustero,*,†,‡ Natalia Mateu,†,‡ Antonio Simo´n-Fuentes,† and Jose´
Luis Acen˜a*,‡
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia, E-46100 Burjassot,
Spain, and Laboratorio de Mole´culas Orga´nicas, Centro de InVestigacio´n Pr´ıncipe
Felipe, E-46012 Valencia, Spain
santos.fustero@uV.es; jlacenya@cipf.es
Received May 4, 2010
ABSTRACT
Chiral imino lactones derived from (R)-phenylglycinol containing an allyl- or propargyltrimethylsilyl group in the side chain readily cyclized in
the presence of acidic reagents to afford spirocyclic compounds with high diastereoselectivity. Removal of the chiral auxiliary produced
2-substituted 1-aminocycloalkanecarboxylic acids, whereas further cyclizations by means of metathesis or hydroamination reactions led to
bicyclic derivatives of pipecolic acid and proline.
Intramolecular addition reactions to N-alkyl- and N-
acyliminium ions usually play a pivotal role for construct-
ing nitrogen-containing cyclic compounds.1 For instance,
when allyl- or propargylsilyl functionalities are selected
as the internal nucleophiles, this strategy constitutes a
convenient access to cyclic homoallyl- or homoallenyl-
amines, respectively.2 In the context of our current work
employing chiral imino lactones derived from (R)-phe-
nylglycinol,3 we envisioned that cyclization of the derived
iminium ions 1 having an allyl- or propargyltrimethylsi-
lane at the end of the chain would lead to spirocyclic
compounds 2 bearing a vinyl or allenyl group, respec-
tively, installed on the newly created ring (Scheme 1). It
would be anticipated that the preexisting chiral center
would induce a high degree of stereocontrol in the
† Universidad de Valencia.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) (a) Royer, J.; Bonin, M.; Micouin, L. Chem. ReV. 2004, 104, 2311–
2352. (b) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. ReV. 2004, 104, 1431–1628.
(2) For examples, see: (a) Hiemstra, H.; Sno, M. H. A. M.; Vijn, R. J.;
Speckamp, W. N. J. Org. Chem. 1985, 50, 4014–4020. (b) Chalard, P.;
Remuson, R.; Gelas-Mialhe, Y.; Gramain, J.-C. Tetrahedron: Asymmetry
1998, 9, 4361–4368. (c) Luker, T.; Koot, W.-J.; Hiemstra, H.; Speckamp,
W. N. J. Org. Chem. 1998, 63, 220–221. (d) Sun, P.; Sun, C.; Weinreb,
S. M. J. Org. Chem. 2002, 67, 4337–4345. (e) Amorde, S. M.; Judd, A. S.;
Martin, S. F. Org. Lett. 2005, 7, 2031–2033. (f) Amorde, S. M.; Jewett,
I. T.; Martin, S. F. Tetrahedron 2009, 65, 3222–3231.
(3) (a) Fustero, S.; Albert, L.; Acen˜a, J. L.; Sanz-Cervera, J. F.; Asensio,
A. Org. Lett. 2008, 10, 605–608. (b) Fustero, S.; Mateu, N.; Albert, L.;
Acen˜a, J. L. J. Org. Chem. 2009, 74, 4429–4432.
(4) For intermolecular diastereoselective alkyl additions to the iminic
carbon in related molecules, see: (a) Harwood, L. M.; Vines, K. J.; Drew,
M. G. B. Synlett 1996, 1051–1053. (b) Miyabe, H.; Yamaoka, Y.; Takemoto,
Y. J. Org. Chem. 2005, 70, 3324–3327. (c) Pigza, J. A.; Molinski, T. F.
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10.1021/ol1010246  2010 American Chemical Society
Published on Web 06/01/2010

Scheme 1
.
Synthetic Strategy
Scheme 2. Cyclization of Allylsilanes 5a,b
formation of the quaternary center.4 These spirocycles 2
would be precursors of a variety of 1-aminocycloalkan-
ecarboxylic acids 3 (1-ACACs), an important class of
conformationally constrained mimics of proteinogenic
amino acids,5,6 which can also be used for the preparation
of oligomers showing defined secondary structures.7 In
addition, compounds 2 would be appropriate intermediates
for the synthesis of more complex bicyclic amino acids.
Starting from our previously reported imino lactone 4a
and its higher homologue 4b,8 elongation using a cross-
metathesis reaction with allyltrimethylsilane in the presence
of second-generation Grubbs catalyst (G-II) afforded allyl-
silanes 5a,b as an inconsequential mixture of trans and cis
isomers (ca. 90:10 ratio)9 (Scheme 2). Next, cyclization was
carried out using an excess of TFA in CH2Cl2 to yield
spirocycles 6a,b in good yields as the major products of a
mixture of four possible diastereoisomers (dr ) 74:14:12:0
and 84:14:2:0, respectively).10 After chromatographic puri-
fication, the major products 6a and 6b were isolated in 66%
and 60% yields, respectively. Subsequent hydrogenation of
6a afforded saturated derivative 7, which served to establish
the configuration of both newly formed sterereogenic centers
by X-ray diffraction analysis of a single crystal (Figure 1).
Conversely, extensive hydrogenation of both 6a and 6b also
(5) For reviews, see: (a) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetra-
hedron: Asymmetry 2000, 11, 645–732. (b) Park, K.-H.; Kurth, M. J.
Tetrahedron 2002, 58, 8629–8659. (c) Maity, P.; Ko¨nig, B. Biopolymers
(Pept. Sci.) 2008, 90, 8–27. (d) Cativiela, C.; Ordo´n˜ez, M. Tetrahedron:
Asymmetry 2009, 20, 1–63
.
(6) For our previous asymmetric syntheses of 2,2-difluoro-1-ACACs,
see: (a) Fustero, S.; Sa´nchez-Rosello´, M.; Rodrigo, V.; del Pozo, C.; Sanz-
Cervera, J. F.; Simo´n, A. Org. Lett. 2006, 8, 4129–4132. (b) Fustero, S.;
Sa´nchez-Rosello´, M.; Rodrigo, V.; Sanz-Cervera, J. F.; Piera, J.; Simo´n-
Fuentes, A.; del Pozo, C. Chem.sEur. J. 2008, 14, 7019–7029. (c) Fustero,
S.; Rodrigo, V.; Sa´nchez-Rosello´, M.; Mojarrad, F.; Vicedo, A.; Moscardo´,
T.; del Pozo, C. J. Fluorine Chem. 2008, 129, 943–950
.
(7) Nagano, M.; Tanaka, M.; Doi, M.; Demizu, Y.; Kurihara, M.;
Suemune, H. Org. Lett. 2009, 11, 1135–1137, and references cited therein.
(8) Imino lactones 4a,b were prepared by condensation of the corre-
sponding R-keto esters with (R)-phenylglycinol; see ref 3a. .
(9) The pure cis isomer of 5a was also obtained by a different synthetic
route based on the partial hydrogenation of a triple bond, and its subsequent
cyclization to 6a afforded the same stereochemical result as the trans/cis
mixture.
(10) The diastereomeric ratio was measured by HPLC. Only three out
of four diastereoisomers were detected both by HPLC and NMR.
(11) Wede, J.; Volk, F.-J.; Frahm, A. W. Tetrahedron: Asymmetry 2000,
11, 3231–3252.
(12) Schinzer, D.; Dettmer, G.; Ruppelt, M.; So´lyom, S.; Steffen, J. J.
Org. Chem. 1988, 53, 3823–3828.
Figure 1. X-ray diffraction analysis of compound 7.
(13) (a) Borzilleri, R. M.; Weinreb, S. M. Synthesis 1995, 347–360. (b)
Ofial, A. R.; Mayr, H. J. Org. Chem. 1996, 61, 5823–5830.
Org. Lett., Vol. 12, No. 13, 2010
3015

removed the chiral auxiliary to produce amino acids 8a11
and 8b, respectively. Other deprotection procedures were also
evaluated in order to preserve the vinyl group. For instance,
lactone opening in 6b with LiOH followed by oxidative
cleavage of the phenylglycinol moiety with Pb(OAc)4
produced unsaturated six-membered amino acid 9.
Scheme 4. Synthesis of Propargylsilane 12
The stereoselectivity observed in the cyclization step
may be rationalized by considering the corresponding
transition states. In the case of 5b, a chairlike transition
state having the allylsilane quasi-equatorial is preferred2d
(Scheme 3). Therefore, the allylsilane approaches the
Scheme 3. Transition States in the Cyclization of 5b to 6b
Treatment of 12 with TFA led to the expected allene 13
in >95:5 diastereoselectivity, together with isomerized
imine 14 (43:57 ratio), the latter product arising from an
ene reaction with inverse electron demand13 (Table 1,
iminium carbon mainly through the Re face opposite the
bulky phenyl group in a quasi-axial fashion,4 thus leading
to 6b as the major diastereoisomer. The dr was somewhat
lower in the cyclization of 5a due to the less significant
steric constraints associated with a five-membered transi-
tion state.
Table 1. Cyclization of Propargylsilane 12
Then, we focused our attention on the cyclization of a
propargylsilane-substituted iminium ion. The appropriate
substrate was prepared by reaction of the already known
Grignard reagent 1012 with diethyl oxalate to give R-keto
ester 11 in moderate yield (based on the starting bromide
precursor), which was further converted into imino
lactone 12 by condensation with (R)-phenylglycinol
(Scheme 4).
entry
reagent
TFA
BF3·OEt2
TiCl4
temp (°C) yield of 13 (%) yield of 14 (%)
1
2
3
4
25
27
24
57
57
35
56
13
5
0 to 25
-78
HCO2H (neat) 25
(14) N-Allylation of 6a was also tested but resulted in a complex mixture
of products under several reaction conditions.
entry 1). Although both products were easily separated
by column chromatography, we tested other Lewis or
Brønsted acids in order to minimize the amount of 14,
and the best conditions found involved the use of neat
formic acid to produce 13 as the major product of a 92:8
mixture (entry 4).
Next, we undertook the preparation of bicyclic amino acid
derivatives by expedient transformations of the vinyl or
allenyl functionalities in the corresponding cyclization
products. Thus, acrylamide 15 was easily prepared from
spirocyclic amine 6a and cyclized afterward by means of a
ring-closing metathesis to yield tricyclic lactone 16 (Scheme
5). Since the presence of the lactam carbonyl impeded the
efficient removal of the phenylglycinol moiety,14 16 was
(15) Cis-fused 2-azabicyclo[4.3.0]nonane-1-carboxylic acids were previ-
ously prepared and used as scaffolds for ꢀ-turn mimics, see: (a) Verbist,
B. M. P.; De Borggraeve, W. M.; Toppet, S.; Compernolle, F.; Hoornaert,
G. J. Eur. J. Org. Chem. 2005, 2941–2950. For a recent synthesis of different
bicyclic pipecolic acids, see: (b) Radchenko, D. S.; Kopylova, N.;
Grygorenko, O. O.; Komarov, I. V. J. Org. Chem. 2009, 74, 5541–5544.
(16) (a) Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555–
4563. (b) Mu¨ller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M.
Chem. ReV. 2008, 108, 3795–3892.
3016
Org. Lett., Vol. 12, No. 13, 2010

Scheme 5
.
Synthesis of Bicyclic Pipecolic Acid 18
Scheme 6. Synthesis of N-Boc-bicycloproline 20
biological activities.20 Further applications of this methodol-
ogy are currently being studied in our laboratories.
treated first with BH3·THF to afford saturated derivative 17,
which was further hydrogenated to afford trans-fused bicyclic
pipecolic acid 18.15
Alternatively, allenylamine 13 was subjected to a gold(I)-
catalyzed intramolecular hydroamination reaction16,17 which
proceeded uneventfully to produce tricyclic compound 1918
(Scheme 6). Finally, hydrogenation of 19 and N-Boc protec-
tion of the resulting amino acid afforded bicycloproline
derivative 20.19
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (CTQ2007-61462) and Generalitat Valenciana
(GVPRE/2008/013) for their financial support. N.M. thanks
the Universidad de Valencia for a predoctoral fellowship,
and J.L.A. thanks the MEC for a Ramo´n y Cajal research
contract.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for all new compounds, as well
as crystallographical data for compound 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, an efficient access to cyclic and bicyclic
amino acids has been achieved using as key synthetic step
the intramolecular addition of allyl- or propargylsilanes to
an iminium ion. The target compounds represent an attractive
group of conformationally constrained amino acids that could
be incorporated into peptidomimetic structures with potential
OL1010246
(20) For examples, see: (a) Palmer, J. T.; Bryant, C.; Wang, D.-X.; Davis,
D. E.; Setti, E. L.; Rydzewski, R. M.; Venkatraman, S.; Tian, Z.-Q.; Burrill,
L. C.; Mendonca, R. V.; Springman, E.; McCarter, J.; Chung, T.; Cheung,
H.; Janc, J. W.; McGrath, M.; Somoza, J. R.; Enriquez, P.; Yu, Z. W.;
Strickley, R. M.; Liu, L.; Venuti, M. C.; Percival, M. D.; Falgueyret, J.-P.;
Prasit, P.; Oballa, R.; Riendeau, D.; Young, R. N.; Wesolowski, G.; Rodan,
S. B.; Johnson, C.; Kimmel, D. B.; Rodan, G. J. Med. Chem. 2005, 48,
7520–7534. (b) Sheppeck, J. E.; Gilmore, J. L.; Yang, A.; Chen, X.-T.;
Xue, C.-B.; Roderick, J.; Liu, R.-Q.; Covington, M. B.; Decicco, C. P.;
Duan, J. J.-W. Bioorg. Med. Chem. Lett. 2007, 17, 1413–1417. (c) Maltais,
F.; Jung, Y. C.; Chen, M.; Tanoury, J.; Perni, R. B.; Mani, N.; Laitinen,
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R. S.; Town, C.; Brummel, C. L.; Howe, D.; Pazhanisamy, S.; Raybuck,
S.; Namchuk, M.; Bennani, Y. L. J. Med. Chem. 2009, 52, 7993–8001.
See also ref 19c.
(17) For a recent article combining both iminium ion additions and gold-
catalyzed hydroaminations, see: Breman, A. C.; Dijkink, J.; van Maarseveen,
J. H.; Kinderman, S. S.; Hiemstra, H. J. Org. Chem. 2009, 74, 6327–6330
(18) In contrast, a similar hydroamination protocol was unsuccessful
using vinylic derivative 6a.
.
(19) For a previous synthesis of (+)-20, see: (a) Ranatunga, S.; Del
Valle, J. R. Tetrahedron Lett. 2009, 50, 2464–2466. For the synthesis of
other bicycloproline derivatives, see: (b) Turner, P. G.; Donohoe, T. J.;
Cousins, R. P. C. Chem. Commun. 2004, 1422–1423. (c) Yip, Y.; Victor,
F.; Lamar, J.; Johnson, R.; Wang, Q. M.; Barket, D.; Glass, J.; Jin, L.; Liu,
L.; Venable, D.; Wakulchik, M.; Xie, C.; Heinz, B.; Villarreal, E.; Colacino,
J.; Yumibe, N.; Tebbe, M.; Munroe, J.; Chen, S.-H. Bioorg. Med. Chem.
Lett. 2004, 14, 251–256. (d) Casabona, D.; Jime´nez, A. I.; Cativiela, C.
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