Expedient synthesis of chiral homoallylamines via N, O-acetal TMS ethers and its application

Article abstract of DOI:10.1021/ol202573s

A highly stereoselective and efficient method for the synthesis of optically active homoallylamines was developed. Key features of the method include (1) the utilization of naphthylethylamine as both an excellent chiral auxiliary and the amine source, (2)

Full text of DOI:10.1021/ol202573s

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5920–5923
Expedient Synthesis of Chiral
Homoallylamines via N,O-Acetal TMS
Ethers and Its Application
Young-Ger Suh,*,† Jaebong Jang,† Hwayoung Yun,† Sae Mi Han,† Dongyun Shin,‡
Jae-Kyung Jung,§ and Jong-Wha Jung*,†
College of Pharmacy, Seoul National University, Seoul 151-742, Korea, College of
Pharmacy, Gachon University of Medicine and Science, Incheon 406-799, Korea, and
College of Pharmacy, Chungbuk National University, Cheongju 361-763, Korea
ygsuh@snu.ac.kr; jung530@stanford.edu
Received September 23, 2011
ABSTRACT
A highly stereoselective and efficient method for the synthesis of optically active homoallylamines was developed. Key features of the method
include (1) the utilization of naphthylethylamine as both an excellent chiral auxiliary and the amine source, (2) the 1,3-chiral induction of the
N-acyliminium ion with high stereoselectivity and high yield, and (3) facile auxiliary removal under mild conditions to liberate N-Cbz-protected
homoallylamines. In addition, the total synthesis of the proposed novel tripeptide containing a β-amino acid has been achieved by applying this
method.
Homoallylamines and acylated homoallylamines are
some of the important structural subunits of biologically
active compounds and are useful intermediates in a wide
range of syntheses of alkaloids and nitrogen-containing
heterocycles.1 Thus, the enantio- and diastereoselective
synthesis of homoallylamines has become one of the major
goals in the fields of medicinal chemistry and organic
synthesis. Consequently, thedevelopment of anew method
for the synthesis of optically active homoallylamines has
been continuously attempted by organic and synthetic
chemists.1a,2
We have recently reported a new approach to the
synthesis of the N-acyliminium ion from N,O-acetal
TMS ether, which was conveniently prepared from
acylcarbamate.3 The N,O-acetal TMS ether proved to be
an excellent acyliminium ion precursor in terms of con-
venience of preparation, chemical stability, and functional
versatility in addition to the accessible structural diversity
of cyclic and acyclic N-acyliminium ions. More recently,
we have reported a novel asymmetric synthetic route
for β-amino acids using this methodology.3c Herein, we
describe an efficient and versatile method for the synthesis
of various homoallylamines through chiral auxiliary-
assisted diastereoselective allylation of N-acyliminium
ions3,4 prepared from N,O-acetal TMS ether and the facile
removal of the naphthylethyl auxiliary (Figure 1).
As shown in Scheme 1, N,O-acetal TMS ethers were
prepared in high yield according to the established
† Seoul National University.
‡ Gachon University of Medicine and Science.
§ Chungbuk National University.
(1) (a) Puentes, C. O.; Kouznetsov, V. J. Heterocycl. Chem. 2002, 39,
595. (b) Ding, H.; Friestad, G. K. Synthesis 2005, 2815. (c) Friestad,
G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541.
(2) For recent example, see: (a) Vieira, E. M.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 3332. (b) Kim, S. J.; Jang,
D. O. J. Am. Chem. Soc. 2010, 132, 12168. (c) Chakrabarti, A.; Konishi,
H.; Yamaguchi, M.; Schneider, U.; Kobayashi, S. Angew. Chem., Int.
Ed. 2010, 49, 1838.
(3) (a) Suh, Y.-G.; Shin, D.-Y.; Jung, J.-K.; Kim, S.-H. Chem.
Commum. 2002, 1064. (b) Suh, Y.-G.; Kim, S.-H.; Jung, J.-K.; Shin,
D.-Y. Tetrahedron Lett. 2002, 43, 3165. (c) Shin, D.-Y.; Jung, J.-K.; Seo,
S.-Y.; Lee, Y.-S.; Paek, S.-M.; Chung, Y. K.; Shin, D. M.; Suh, Y.-G.
Org. Lett. 2003, 5, 3635. (d) Jung, J.-W.; Shin, D.-Y.; Seo, S.-Y.; Kim,
S.-H.; Paek, S.-M.; Jung, J.-K.; Suh, Y.-G. Tetrahedron Lett. 2005, 46, 573.
(4) For R-amido sulfones as precursors of N-acylimino derivatives,
ꢀ
see: (a) Giardina, A.; Mecozzi, T.; Petrini, M. J. Org. Chem. 2000, 65,
8277. (b) Marcantoni, E.; Mecozzi, T.; Petrini, M. J. Org. Chem. 2002,
67, 2989. (c) Petrini, M. Chem. Rev. 2005, 105, 3949.
r
10.1021/ol202573s
Published on Web 10/13/2011
2011 American Chemical Society

the synthetic efficiency and the low hazard to the public.6
The chemical yields of the allylations of 5a were generally
good or excellent regardless of the Lewis acid, solvent or
temperature used. However, the diastereoselectivity was
quite sensitive to the reaction conditions. Reactions in
methylene chloride in the presence of BF3 OEt2 provided
3
the best results withrespect to bothdiastereoselectivity and
chemical yield (entries 1À6). Entries 7À10 revealed the
decrease in the diastereoselectivity with increasing reaction
temperature, whereas the stereochemical results were al-
most the same at temperatures less than À40 °C. We
carried out all allylation reactions with BF3 OEt2 at
3
À78 °C, followed by slow warming to 0 °C slowly as a
standard procedure, although maintaining the reaction
temperature at À78 °C for 1 day resulted in the highest
diastereoselectivity (93:7).7
Figure 1. Strategy for the synthesis of optically active
homoallylamines.
method.3 After extensive preliminary investigation of chir-
al auxiliaries, we selected 1-(1-naphthyl)ethylamine based
on (1) its ability to serve as an appropriate amine source,
(2) the excellent 1,3-chiral induction in the allylation of N-
acyliminium ions, and (3) the facile auxiliary removal.
Thus, the commercially available chiral 1-(1-naphthyl)
ethylamine was initially acylated, followed by Cbz-protec-
tion to afford the protected amide 3aÀh. The N,O-acetal
TMS ether 4aÀh was successfully generated from the
corresponding amide 3aÀh by DIBAL reduction and in
situ trapping of the resulting alkoxide with TMSOTf.
Fortunately, the N,O-acetal TMS ethers were successfully
prepared in high yield irrespective of the steric effects of the
substituents.5
Table 1. Effects of the Lewis Acid, Solvent and Temperature on
the Homoallylation of the N,O-Acetal TMS Ethera
entry Lewis acid solvent
temp
yield (%)b
drc
1
2
BF3 OEt2 CH2Cl2 À78 to 0 °Cd
95
75
51
93
95
94
88
86
90
80
92:8
3
SnCl4
CH2Cl2 À78 to 0 °Cd
CH2Cl2 À78 to 0 °Cd
87:13
92:8
3
TMSOTf
4
BF3 OEt2 PhCH3
À78 to 0 °Cd
86:14
75:25
89:11
93:7
3
3
5
BF3 OEt2 CH3CN À78 to 0 °Cd
6
BF3 OEt2 Et2O
À78 to 0 °Cd
3
3
BF3 OEt2 CH2Cl2 À78 °Ce
Scheme 1. Preparation of N,O-Acetal TMS Ethers
7
8
BF3 OEt2 CH2Cl2 À40 °C
92:8
3
9
BF3 OEt2 CH2Cl2 À23 °C
90:10
78:22
3
10
BF3 OEt2 CH2Cl2 0 °C
3
a Reactions were performed at given conditions for 3 h and quenched
with a sufficient amount of triethylamine unless otherwise noted.
b Isolated yields. c Determined using chiral HPLC (Daicel, OD-H) after
removal of the naphthylethyl moiety. (The racemate was prepared from
commercially available (()-1-(1-naphthyl)ethylamine). d Reaction tem-
perature was slowly elevated during 3 h. e Stirred for 1 day at a given
temperature and then quenched with triethylamine.
We then turned our attention to the removal of the 1-(1-
naphthyl)ethyl moiety. The crucial CÀN bond cleavage of
the allylation products under mild conditions was inten-
sively investigated. The N-Cbz-protected homoallylamine
1a was finally obtained from 5a in an excellent yield by
TFA treatment in CH2Cl2 at room temperature. To the
Wesubsequently investigated the reaction conditions for
the diastereoselective allylation of the N-acyliminium ion
prepared from the N,O-acetal TMS ether 4a, as illustrated
in Table 1. We chose allylsilane as an allyl donor based on
(7) Unfortunately, the chemical yields significantly dropped under
the reaction conditions of entry 7 of Table 1.
(5) The spectral data (1H NMR, 13C NMR) were quite complicated
due to the rotameric and/or diastereomeric nature of the N,O-acetal
TMS ethers. Accordingly, the diastereomeric ratios were not determined
at this stage, and the N,O-acetal TMS ethers were used for the next step
without further purification.
(8) There have been only a few reports for CÀN bond cleavages at the
alpha position of the naphthyl moiety using methansulfonic acid.
Acidity constant (Ka) of methanesulfonic acid is more than a hundred
fold compared to that of TFA. pKa (CH3SO3H) = À2.6, pKa
(CF3CO2H) = À0.25 based on pKa values compiled by Prof. D. A.
Evans at Harvard University: Sugiyama, S.; Morishita, K.; Ishii, K.
Heterocycles 2001, 55, 353.
(6) Aoyama, N.; Hamada, T.; Manabe, K.; Kobayashi, S. Chem.
Commun. 2003, 676.
Org. Lett., Vol. 13, No. 21, 2011
5921

best of our knowledge, no information on the cleavage of
the carbonÀheteroatom at the R position of the naphthyl
moiety has been published, although carbonÀheteroatom
cleavages at the benzylic position in various strongly acidic
media are well known.8 The removal of naphthylalkyl
moieties has been infeasible9 despite their excellent stereo-
inductions, primarily because of the limited functional
group tolerances under harsh auxiliary cleavage con-
ditions.10 In the course of our mechanistic studies on
naphthyl cleavage, we were able to easily isolate trifluoro-
acetate 6 as the sole side product, which was shown to
be a racemate.11 Consequently, the removal of the 1-(1-
naphthyl)ethyl moiety could be mechanistically under-
stood as an SN1-type reaction (Scheme 2).
Table 2. Allylation of N,O-Acetal TMS Ethers
yield %a yield %b
entry
R, 4
CH2CH3, 4a
on 5
on 1
erc
1
2
3
4
5
6
7
8
95
90
90
86
80
88
89
82
99
95
90
90
95
92
90
95
92:8
92:8
96:4
98:2
92:8
96:4
95:5
90:10
CH2CH2CH3, 4b
CH2CH2CH2CH3, 4c
CH2CH2CH2CH2dCH2, 4d
CH2CH2CH2CtCH, 4e
CH2CH2CH2CH2CtCH, 4f
CH2CH2Ph, 4g
Scheme 2. SN1-type Removal of the 1-(1-Naphthyl)ethyl Moiety
CH2 CH2CH2c-hexd, 4h
a Isolated yield of the first step. b Isolated yield of the second step.
c Determined with chiral HPLC (Daicel, OD-H). d Cyclohexyl.
based on the reported results.13 A plausible transition state
for the stereoselective allylation is suggested based on the
stereochemical outcome (Figure 2). The FelkinÀAhn
model, which is addressed in the 1,3-chiral induction of
imine species,14,15 was followed in this system.
We also turned our attention to the scope of this
established method. The stereoselective allylation of a
variety of N,O-acetal TMS ethers under optimized condi-
tions proceeded smoothly to afford the corresponding N-
Cbz-protected homoallylamines (Table 2). Generally, an
increase in the diastereoselectivity upon introduction of a
longer alkyl substituent was observed (entries 1À3). Olefin
and alkyne functional groups were well tolerated (entries
4À6), and evenphenylethyl substituentssurvivedunderthe
establishedconditions (entry 7). The presence of branching
with aliphatic substituents resulted in slight decrease in
both yield and diastereoselectivity (entry 8).
To confirm the absolute configuration of the newly
generated stereocenter, we converted homoallylamine
1a into the known β-amino acid 7. Dihydroxylation of
1a under Upjohn conditions12a and subsequent 1,2-diol
cleavage with sodium periodate followed by Pinnick
oxidation12b gave the desired β-amino acid 7. The absolute
configuration of the new stereocenter was confirmed as (S)
Figure 2. Confirmation of the absolute stereochemistry.
(9) In general, hydrogenation under high pressure was conducted to
remove the auxiliaries with naphthyl group: (a) Jiang, W.; Suia, Z.;
Chen, X. Tetrahedron Lett. 2002, 43, 8941. (b) Santos Fustero, S.; Soler,
J. G.; Bartolome’, A.; Rosello’, M. S. Org. Lett. 2003, 5, 2707.
(10) (a) Paquette, L. A.; Rothhaar, R. R.; Isaac, M.; Rogers, L. M.;
Rogers, R. D. J. Org. Chem. 1998, 63, 5463. (b) Takacs, J. M.; Weidner,
J. J. J. Org. Chem. 1994, 59, 6480. (c) Bell b, A. S.; Fishwick, C. W. G.;
Reed, J. E. Tetrahedron Lett. 1996, 37, 123. (d) Ghera, E.; Kleiman, V.;
Hassner, A. J. Org. Chem. 1999, 64, 8. (e) Loh, T.-P.; Huang, J.-M.; Goh,
S.-H.; Vittal, J. J. Org. Lett. 2000, 2, 1291. (f) Oh, B. H.; Nakamura, I.;
Yamamoto, Y. Tetrahedron Lett. 2002, 43, 9625.
(12) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973. (b) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W.
Tetrahedron 1981, 37, 2091.
(13) Palomo, C.; Oiarbide, M.; Condepcion Gonzalez-Rego, M.;
Sharma, A. K.; Garcia, J. M.; Gonzalez, A.; Landa, C.; Linden, A.
Angew. Chem., Int. Ed. 2000, 39, 1063.
(14) For discussions about the 1,3-chiral induction to imine species,
see: (a) Bellucci, C.; Cozzi, P. G.; Umani-Ronchi, A. Tetrahedron Lett.
1995, 36, 7289. (b) Nancy, Ghosh, S.; Singh, N.; Nanda, G. K.;
Venugopalan, P.; Bharatam, P. V.; Trehan, S. Chem. Commun. 2003,
12, 1420. (c) Yamamoto, Y.; Nishii, S.; Maruyama, K.; Komatsu, T.;
Ito, W. J. Am. Chem. Soc. 1986, 108, 7778. (d) Alvaro, G.; Savoia, D.;
Valentinetti, M. R. Tetrahedron 1996, 52, 12571.
(11) Authentic trifluoroacetate 6 was alternatively prepared from
commercially available (()-1À1-(naphthylethyl)amine and trifluoro-
acetic acid.
5922
Org. Lett., Vol. 13, No. 21, 2011

Having established a synthetic method for homoallyl-
amines, we undertook the total synthesis of a marine
natural product to validate the applicability of our meth-
od. The novel tripeptide 12 with the proposed structure
was isolated from a bacterium identified as Pseudomonas
or Alteromonas (DF-1).16 This marine natural product,
which consists of a β-aminopimelic acid was reported first
from a natural source. Our curiosity about the biological
role of the novel tripeptide based on the structural simi-
larity of its fragments with R-aminopimelic acid and 1,6-
diaminopimelic acid17 and the desire to elucidate the
undetermined chiral center led us to attempt the total
synthesis of this compound.
Scheme 3. Total Synthesis of Novel Tripeptide
Shown in Scheme 3, the concise synthesis commenced
with the preparation of homoallylamine 5e on a gram
scale, followed by a sequence of oxidative olefin cleavage
and coupling of phenylalanine.18 Removal of the phenyl-
ethyl auxiliary with the established procedure and global
deprotection by hydrogenolysis provided the desired novel
tripeptide, which was further purified using ion-exchange
resin and preparative HPLC. Epimerization was not ob-
served after the removal of the 1-naphthylethyl moiety.
We have successfully synthesized the two diastereomeric
tripeptides that have been proposed.19 However, a com-
parison of the spectral data with the reported data revealed
that the structure of 12 is not the same as that of the natural
tripeptide20 (see Supporting Information, this synthesis
successfully showcases the synthetic utility of our asym-
metric amidoalkylation protocol).
also established an efficient and mild procedure for the
facile removal of the 1-(1-naphthyl)ethyl moiety, which
can be widely utilized in the asymmetric synthesis of amino
acids and alkaloids. Our method was also successfully
applied in the total synthesis of the proposed structure of
a novel tripeptide containing β-amino acid.
In conclusion, we have developed a reliable and stereo-
selective method for the synthesis of various homoallyl-
amines. Allylsilane turned out to be an adequate allyl donor
and 1-(1-naphthyl)ethylamine proved to be both an ex-
cellent chiral auxiliary and an excellent amine source. We
Acknowledgment. We thank Dr. S. D. Rosa (Istituto di
Chimica Biomolecole CNR, Italy) for his kind provision of
spectral data of the natural product and impressive dis-
cussion about our final product. We also thank Dr. Y.ÀW.
Chin (College of Pharmacy, Dongguk University, Korea)
for his helpful discussion in confirming the structure of
tripeptideproduct. This workwas supportedbya National
Research Foundation of Korea (NRF) grant funded by
the Korean government (MEST) (No. 20100028431) and
the NationalResearchFoundation of Korea Grantfunded
by the Korean Government(MEST) (NRF-C1ABA001-
2010-0020428).
(15) We have suggested the kinetic generation of N-acyliminium ion
from the dual acting oxazolidinone precursors in our previous report,
which was supported by experimental and computational data.2c
(16) Rosa, S. D.; Giulio, A. D.; Tommonaro, G.; Popov, S.;
Kujumgiev, A. J. Nat. Prod. 2000, 63, 1454.
(17) (a) Berges, D. A.; DeWolf, W. E., Jr.; Dunn, G. L.; Grappel,
S. F.; Newman, D. J.; Taggart, J. J.; Gilvarg, C. J. Med. Chem. 1986, 29,
89. (b) Petra, S.; Maija, D. Curr. Med. Chem. 2004, 11, 945.
(18) Synthesis of the tripeptide utilizing homoallylamine 5d was
inefficient due to a difficulty in the similtaneous cleavage of both
terminal olefins and in the phenylalanine coupling of the resulting
diacid.
(19) Synthesis of only one tripeptide was shown in Scheme 3. The
other diastereomer was synthesized by analogyto the synthesisfrom (R)-
1-(1-naphthylethyl)amine. See, Supporting Information.
Supporting Information Available. Experimental pro-
cedures, characterization data, and stereochemical
proofs. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) 1H NMR spectra of the synthetic tripeptide prepared from
commercially available R-aminopimelic acid and phenylalanine deriva-
tives were close to those of the tripeptide synthesized by us.
Org. Lett., Vol. 13, No. 21, 2011
5923