Concise asymmetric synthesis of orthogonally protected syn - And anti -1,3-aminoalcohols

Article abstract of DOI:10.1021/ol303371u

Novel chiral binfunctional reagents V and ent-V undergo asymmetric aldehyde allylation followed by Ir(I)-catalyzed enantioselective allylic amidation to give orthogonally protected syn- and anti-1,3-aminoalcohols with complete control of absolute and rela

Full text of DOI:10.1021/ol303371u

ORGANIC
LETTERS
2013
Vol. 15, No. 3
554–557
Concise Asymmetric Synthesis of
Orthogonally Protected syn- and
anti-1,3-Aminoalcohols
Jae Seung Lee, Dongeun Kim, Lucia Lozano, Suk Bin Kong, and Hyunsoo Han*
Department of Chemistry, University of Texas at San Antonio, San Antonio,
Texas 78249, United States
Hyunsoo.han@utsa.edu
Received December 10, 2012
ABSTRACT
Novel chiral binfunctional reagents V and ent-V undergo asymmetric aldehyde allylation followed by Ir(I)-catalyzed enantioselective allylic
amidation to give orthogonally protected syn- and anti-1,3-aminoalcohols with complete control of absolute and relative stereochemistry. The
Mitsunobu reaction of the initial homoallylic alcohol products followed by Ir(I)-catalyzed enantioselective allylic amidation provides orthogonally
protected syn- and anti-1,3-diamine derivatives in high yields and with excellent stereoselectivities.
The 1,3-amino alcohol motifs are common in many
natural products and biologically active compounds.1
1,3-Aminoalcoholshavealsobeenusedaschiralauxiliaries
and ligands for asymmetric catalysis.2 A vast majority of
methods for their synthesis to date rely on diastereoselec-
tive reduction/addition of optically enriched β-hydroxy
imine and β-amino ketone derivatives,3 as well as diaste-
reoselective CꢀH amination.4 To our knowledge, only a
few enantioselective methods are currently available, which
include rhodium-catalyzed asymmetric hydrogenation
of β-ketoenamides,5 a proline-catalyzed enantioselective
Mannich reaction followed by tandem hydrogenationꢀ
enzymatic dynamic kinetic resolution,6 and a strategy em-
ploying proline-catalyzed R-aminoxylation and R-amina-
tion of aldehydes for the asymmetric introduction of CꢀO/N
(1) (a) Shibahara, S.; Kondo, S.; Maeda, K.; Umezawa, H.; Ohno,
M. J. Am. Chem. Soc. 1972, 94, 4353–4354. (b) Wang, Y.-F.; Izawa, T.;
Kobayashi, S.; Ohno, M. J. Am. Chem. Soc. 1982, 104, 6465–6466. (c)
Knapp, S. Chem. Rev. 1995, 95, 1859–1876. (d) Kempf, D. J.; Marsh, K. C.;
Denissen, J. F.; McDonald, E.; Vasavanonda, S.; Flentge, C. A.; Green,
B. E.; Fino, L.; Park, C. H.; Kong, X.-P.; Wideburg, N. E.; Saldivar, A.;
Kati, W. M.; Sham, H. L.; Tobins, T.; Stewart, K. D.; Hsu, A.; Plattner,
J. J.;Leonard, J. M.;Norbeck, D. W.Proc. Natl. Acad. Sci. U.S.A. 1995, 92,
2484–2488. (e) Sham, H. L.; Zhao, C.; Li, L.; Betebenner, D. A.; Saldivar,
A.; Vasavanonda, S.; Kempf, D. J.; Plattner, J. J.; Norbeck, D. W. Bioorg.
Med. Chem. Lett. 2002, 12, 3101–3103. (f) Carlier, P. R.; Lo, M. M.-C.; Lo,
P. C.-K.; Richelson, E.; Tatsumi, M.; Reynolds, I. J.; Sharma, T. A.Bioorg.
Med. Chem. Lett. 1998, 8, 487–492. (g) Shi, Z.; Harrison, B. A.; Verdine,
G. L. Org. Lett. 2003, 5, 633–636. (h) Raju, B.; Mortell, K.; Anandan, S.;
O’Dowd, H.; Gao, H.; Gomez, M.; Hackbarth, C.; Wu, C.; Wang, W.;
Yuan, Z.; White, R.; Trias, J.; Patel, D. V. Bioorg. Med. Chem. Lett. 2003,
13, 2413–2418. (i) Benedetti, F.; Norbedo, S. Chem. Commun. 2001, 203–
204.
(4) (a) Rice, G. T.; White, M. C. J. Am. Chem. Soc. 2009, 131, 11707–
11711. (b) Milczek, E.; Boudet, N.; Blakey, S. Angew. Chem., Int. Ed.
2008, 47, 6825–6828. (c) Nahra, F.; Liron, F.; Prestat, G.; Mealli, C.;
Messaoudi, A.; Poli, G. Chem.;Eur. J. 2009, 15, 11078–11082. (d)
Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 9220–9221. (e)
Harvey, M. E.; Nusaev, D. G.; Du Bois, J. J. Am. Chem. Soc. 2011, 133,
17207–17216. (f) Paradine, S. M.; White, M. C. J. Am. Chem. Soc. 2012,
134, 2036–2039.
(2) (a) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107,
767–796.
(3) (a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 6518–6591. (b) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem.
Soc. 2003, 125, 11276–11282. (c) Williams, D. R.; Osterhout, M. H.
J. Am. Chem. Soc. 1992, 114, 8750–8751. (d) Keck, G. E.; Truong, A. P.
Org. Lett. 2002, 4, 3131–3134. (e) Menche, D.; Arikan, F.; Li, J.;
Rudolph, S. Org. Lett. 2007, 9, 267–270. (f) Liu, Z.-J.; Mei, Y.-Q.;
Liu, J.-T. Tetrahedron 2007, 63, 855–860. (g) Edupuganti, R.; Davis,
F. A. Org. Biomol. Chem. 2012, 10, 5021–5031. (h) Kennedy, A.; Nelson,
A.; Perry, A. Synlett 2004, 967–970. (i) Yamamoto, Y.; Komatsu, T.;
Maruyama, K. J. Chem. Soc., Chem. Commun. 1985, 814–816.
€
€
(5) Millet, R.; Traff, A. M.; Petrus, M. L.; Backvall, J. E. J. Am.
Chem. Soc. 2010, 132, 15182–15184.
(6) Geng, H.; Zhang, W.; Chen, J.; Hou, G.; Zhou, L.; Zou, Y.; Wu,
W.; Zhang, X. Angew. Chem., Int. Ed. 2009, 48, 6052–6054.
(7) Jha, V.; Kondekar, N. B.; Kumar, P. Org. Lett. 2010, 12, 2762–
2765.
r
10.1021/ol303371u
Published on Web 01/14/2013
2013 American Chemical Society

bonds.7 Although these methods can deliver 1,3-aminoal-
cohols in a stereoselective fashion, they require multiple
steps and/or suffer from a limited substrate scope.8
Furthermore, rhodium-catalyzed asymmetric hydroge-
nation of β-ketoenamides gives rise to only anti-1,3-
aminoalcohols. Remarkably, very efficient enantioselective
methods to give orthogonally protected 1,3-aminoalcohols
with complete control of their relative and absolute stereo-
chemistry remain undeveloped. Herein we report a concep-
tually distinct method for the very efficient asymmetric
synthesis of orthogonally protected syn- and anti-1,3-amino-
alcohols, which utilizes newly developed air-stable chiral
binfunctional allylation reagents V and ent-V (Scheme 1).
(eq 1 in Scheme 1).9,10 We and others recently disclosed
Ir(I)-catalyzed enantioselective allylic amidation between
ethyl allyl carbonates III and diacylamine nucleophiles to
give protected allylic amines IV (eq 2 in Scheme 1).11,12
A
logical extension of these two observations would be to
combine Nokami’s allyl transfer reaction with the Ir(I)-
catalyzed allylic amidation reaction to create a new chiral
bifunctional reagent V. As shown in Scheme 1, asymmetric
allylation of aldehydes by V is expected to give allyl
carbonates VI. Ir(I)-catalyzed allylic amidation of VI with
diacylamine nucleophiles will initially generate the inter-
mediates VII, which could undergo an intramolecular
1,5-acyl transfer reaction under the appropriate allylic
amidation conditions to finally give orthogonally pro-
tected 1,3-aminoalcohols VIII and IX. If the stereochem-
istry of the amidation step is governed by the chiral ligands
L* or ent-L* used, the presented two-step strategy can
provide a most direct method for the asymmetric synthesis
of orthogonally protected 1,3-aminoalcohols from the
readily available aldehydes with complete control of their
relative and absolute stereochemistry.
Scheme 1. Design Concept of Chiral Bifunctional Reagent V for
the Asymmetric Synthesis of Orthogonally Protected syn- and
anti-1,3-Aminoalcohols
Scheme 2. Asymmetric Synthesis of Enantiomerically Pure
Bifunctional Allyl Transfer Reagent V
Enantiomerically pure binfunctional reagents V and ent-V
were conveniently prepared from commercial 3-methyl-
buten-2-en-1-ol in three steps (Scheme 2). Sharpless asym-
metric epoxidation (AE) of 3-methylbuten-2-en-1-ol (1) by
(þ)-diethyl tartrate (DET) gave rise to the corresponding
2-epoxy alcohol, which was isolated as its p-nitrobenzoate
ester 2.9 Enantiomerically pure 2 (ee > 99%) was obtained
by washing crude 2 with ethyl ether. Reaction of 2 with
Recently the Nokami group reported that, in the pre-
sence of an acid, enantioenriched tertiary homoallylic
alcohol I could react with aldehydes through [3,3]-sigma-
tropic rearrangement to deliver homoallylic alcohols II
withnear-perfectchiralitytransferand highE/Z-selectivity
(8) Reference 5 works only for the terminal methyl group and gives
only an (R)-configuration at the oxygen-substituted carbon due to the
substrate specificity of the enzyme CALB used; ref 6 requires prepara-
tion of β-ketoenamides from the corresponding ketones in two steps;
ref 7 requires five to six steps to prepare 1,3-aminoalcohol derivatives.
(9) Shafi, S. M.; Chou, J.; Kataoka, K.; Nokami, J. Org. Lett. 2005, 7,
2957–2960.
vinylMgCl in the presence of CuBr SMe2 at ꢀ20 °C
3
furnished diol 3,9 which upon treatment with ethyl chlo-
roformate and pyridine transformed into V. The same
reaction sequence using (ꢀ)-DET in the Sharpless AE step
was used to prepare ent-V. Binfunctional reagents V and
ent-V are stable at ambient temperature and can be stored
without any special precautions.
(10) For other similar reports, see: (a) Nokami, J.; Yoshizane, K.;
Matsuura, H.; Sumida, S.-I. J. Am. Chem. Soc. 1998, 120, 6609–6610.
ꢀ
ꢁ
(b) Malkov, A. V.; Kabeshov, M. A.; Barlog, M.; Kocovsky, P. Chem.;
Eur. J. 2009, 15, 1570–1573. (c) Hayashi, S.; Hirano, K.; Yorimitsu, H.;
Oshima, K. Org. Lett. 2005, 7, 3577–3579. (d) Nokami, J.; Nomiyama,
K.; Shafi, S. M.; Kataoka, K. Org. Lett. 2004, 6, 1261–1264. (e) Lee,
C.-L. K.; Lee, C.-H. A.; Tan, K.-T.; Loh, T.-P. Org. Lett. 2004, 6, 1281–
1283. (f) Cheng, H.-S.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125, 4990–4991.
(g) Nokami, J.; Nomiyama, K.; Matsuda, S.; Imai, N.; Kataoka, K. Angew.
Chem., Intl. Ed. 2003, 42, 1273–1276. (h) Loh, T.-P.; Lee, C.-L. K.; Tan,
K.-T. Org. Lett. 2002, 4, 2985–2987. (i) Nokami, J.; Ohga, M.; Nakamoto,
H.; Matsubara, T.; Hussain, I.; Kataoka, K. J. Am. Chem. Soc. 2001, 123,
9168–9169. (j) Loh, T.-P.; Tan, K.-T.; Hu, Q.-Y. Angew. Chem., Int. Ed.
2001, 40, 2921–2922. (k) Nokami, J.; Anthony, L.; Sumida, S.-I. Chem.;
Eur. J. 2000, 6, 2909–2913. (l) Sumida, S.-I.; Ohga, M.; Mitani, J.; Nokami,
J. J. Am. Chem. Soc. 2000, 122, 1310–1313. (m) Loh, T.-P.; Hu, Q.-Y.; Ma,
L.-T. Org. Lett. 2002, 4, 2389–2391.
(11) (a) Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew. Chem.,
Int. Ed. 2006, 45, 5546–5549. (b) Pouy, M. J.; Leitner, A.; Weix, D. J.;
Ueno, S.; Hartwig, J. F. Org. Lett. 2007, 9, 3949–3952. (c) Weix, D. J.;
Markovic, D.; Ueda, M.; Hartwig, J. F. Org. Lett. 2009, 11, 2944–2947.
(d) Singh, O. V.; Han, H. J. Am. Chem. Soc. 2007, 129, 774–775.
(e) Singh, O. V.; Han, H. Org. Lett. 2007, 9, 4801–4804. (f) Singh,
O. V.; Han, H. Tetrahedron Lett. 2007, 48, 7094–7098.
(12) For recent reviews on Ir(I)-catalyzed allylation: (a) Hartwig, J. F.;
Pouy, M. J. Top. Organomet. Chem. 2011, 34, 169–208. (b) Helmchen, G.;
€
Dahnz, A.; Dubon, P.; Schelwies, M.; Weihofen, R. Chem. Commun. 2007,
675–691.
Org. Lett., Vol. 15, No. 3, 2013
555

tions with higher ligand loadings. Based on the premise
that [Ir(dbcot)Cl]2 could generate more robust catalysts
than[Ir(COD)Cl]2,14 2 mol % [Ir(dbcot)Cl]2 was used atrt.
The ethyl allyl carbonate 5a did not react at rt, but upon
raising the temperature to 65 °C, the reaction proceeded
cleanly to give O-Cbz, N-Boc protected 1,3-aminoalcohol
6a in 85% yield and with >20:1 diastereoselectivity. On
the other hand, under the same conditions, ent-5a pro-
vided the corresponding diastereomer 7a in 88% yield
and with >20:1 diastereoselectivity (Table 2, entries 1
and 2). Similarly, other structurally diverse 5 and ent-5
compounds (which were prepared by using ent-V and
aldehydes 4 as in Table 1) provided the corresponding
O-Cbz, N-Boc protected 1,3-aminoalcohols 6 and 7,
respectively, in good yields and with excellent diastereos-
electivities. These results indicate that the stereochemistry of
the allylic amidation is predominantly controlled by the
stereochemistry of the ligand/catalyst used, and 1,5-acyl
transfer takes place under the amidation conditions.
Table 1. Asymmetric Allyl Transfer Reaction between
Aldehydes 4 and Chiral Bifunctional Reagent V
Table 2. Ir(I)-Catalyzed Diastereoselective Allylic Amidation of
Homoallylic Alcohols 5 and ent-5
a Isolated yields. b Determined by chiral HPLC.
Acid-mediated asymmetric allylation of n-octanal by
V was used to determine the optimal conditions. After
screening various acids (TfOH, TMSOTf, trifluorometh-
anesulfonimide, 2,4-dinitrobenzenesulfonic acid, (1S)-(þ)-
camphorsulfonic acid, p-TsOH H2O, TiCl4, Sc(OTf)3,
3
and BF3 OEt2) and temperatures (ꢀ78, ꢀ50, ꢀ20, and
3
0 °C) in methylene chloride, the reaction conditions involv-
ing 0.2 equiv of TfOH at ꢀ78 °C were determined to be
optimal to give the corresponding homoallylic ether 5a in
90% reaction yield and 99% ee. A selection of aldehydes
were allowed to react with I under the determined reaction
conditions, and the results are shown in Table 1. The asym-
metric allyl transfer reaction tolerated wide structural
variations in aldehydes involving linear alkyl (entry 1),
β-branched alkyl (entry 2), R-branched alkyl (entries 3 and 4),
cycloalkyl (entry 5), tert-butyl (entry 6), and functionalized
linear alkyl (entry 7) groups. The corresponding homo-
allylic alcohols 5 were obtained in good yields up to 90%,
and chirality transfer was nearly perfect to give g98% ee’s.
In all cases studied, only E-5 formed as judged by NMR
analysis; the E-geometry is necessary for Ir(I)-catalyzed
enantioselective allylic amidation.
To study Ir(I)-catalyzed diastereoselective allylic amida-
tion, 5a was subjected to the catalytic conditions involving
[Ir(COD)Cl]2 (2 mol %), L* (4 mol %), DBU (20 mol %),
and benzyl tert-butyl imidodicarboxylate as a nucleo-
phile in THF.11f,13 However, the desired allylic amida-
tion reaction did not occur even under heating condi-
a Isolated yields. b Determined by the 1H NMR spectrum of reaction
mixtures.
(13) (Cbz)2NH, (Boc)2NH, and phthalimide were tried, but the
desired allylic amidation did not occur. AcNHBoc gave rise to a mixture
of amidation product and 1,5-acyl transfer product.
(14) Spiess, S.; Welter, C.; Frank, G.; Taquet, J.-P.; Helmchen, G.
Angew. Chem., Int. Ed. 2008, 47, 7652–7655.
To further demonstrate the synthetic utility of homo-
allylic alcohols 5 and ent-5, we chose to transform
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Org. Lett., Vol. 15, No. 3, 2013

ent-5b into the corresponding 1,3-diamine derivatives.
1,3-Diamine functionalities are a key structural element in
numerous natural products and pharmacologically active
compounds,15 as well as chiral ligands for asymmetric cata-
lysis.16 Despite recent synthetic advancements, methods
for the asymmetric synthesis of 1,3-diamines via enantio-
selective processes have been severely underdeveloped.17
Scheme 3 describes the two-step asymmetric synthesis of
orthogonally protected 1,3-diamines from ent-5b. The
Mitsunobu reaction between homoallylic alcohol ent-5b
(entry 4, Table 2) and phthalimide furnished the cor-
responding homoallylic amine,18,18b which upon Ir(I)-
catalyzed allylic amidation in the presence of L* trans-
formed into orthogonally protected 1,3-diamine 9 in 76%
overall yield and with >20:1 dr as judged by NMR analysis.
The same reaction sequence using ent-L* for the allylic
amidation delivered the corresponding diastereomer 10 in
71% overall yield and with >20:1 dr. Similarly, homoallylic
alcohol ent-5b was converted into diastereomeric azides 11
and 12 by using diphenyl phosphoryl azide (DPPA)18c,d in
the Mitsunobu reaction in 87% and 84% overall yields,
respectively, and with >20:1 dr.
Scheme 3. Asymmetric Synthesis of 1,3-Diamine Derivatives
In conclusion, novel chiral bifunctional reagents V and
ent-V, which are air-stable and can be used in a step-
economical fashion, have been developed. The reagents
undergo asymmetric aldehyde allylation followed by Ir(I)-
catalyzed allylic amidation to deliver orthogonally pro-
tected syn- and anti-1,3-aminoalcohols in good yields and
with excellent stereoselectivities. The synthetic utility of V
was further demonstrated in the three-step asymmetric
synthesis of orthogonally protected 1,3-diamine deriv-
atives. Considering the importance and prevalence of
1,3-aminoalcohol and 1,3-diamine motifs in numerous
(bio)chemically active molecules, the developed strate-
gies employing V and ent-V should find wide synthetic
applications.
(15) (a) Dergeron, R. J.; Feng, Y.; Weimar, W. R.; McManis, J. S.;
Dimova, H.; Porter, C.; Raisler, B.; Phanstiel, O. J. Med. Chem. 1997,
40, 1475–1494. (b) Arya, D. P.; Xue, L.; Willis, B. J. Am. Chem. Soc.
2003, 125, 10148–10149. (c) Kurosawa, W.; Kan, T.; Fukuyama, T.
J. Am. Chem. Soc. 2003, 125, 8112–8113. (d) Welch, K. T.; Virga, K. G.;
€
Whittemore, N. A.; Ozen, C.; Wright, E.; Brown, C. L.; Lee, R. E.;
Serpersu, E. H. Bioorg. Med. Chem. 2005, 12, 6252–6263. (e) When,
P. M.; Du Bois, J. J. Am. Chem. Soc. 2002, 124, 12950. (f) Franklin, A. S.;
Ly, S. K.; Mackin, G. H.; Overman, L. E.; Shaka, A. J. J. Org. Chem.
1999, 64, 1512–1519.
(16) (a) Busscher, G. F.; Retjes, F. P. J. T.; van Delft, F. L. Chem.
Rev. 2005, 105, 775. (b) Kizirian, J.-C. Chem. Rev. 2008, 108, 140–205.
(17) (a) Morgen, M.; Bretzke, S.; Li, P.; Menche, D. Org. Lett. 2010,
12, 4494–4497. (b) Trost, B. M.; Malhotra, S.; Olson, D. E.; Maruniak,
A.; Du Bois, J. J. Am. Chem. Soc. 2009, 131, 4190–4191. (c) Matsubara,
R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 1679–
1681. (d) Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int.
Ed. 2006, 45, 2254–2257. (e) Terada, M.; Machioka, K.; Sorimachi, K.
Angew. Chem., Int. Ed. 2009, 48, 2553–2556. (f) Lu, S.-F.; Du, D.-M.;
Xu, J.; Zhang, S.-W. J. Am. Chem. Soc. 2006, 128, 7418–7419. (g)
Giampietro, N. C.; Wolfe, J. P. J. Am. Chem. Soc. 2008, 130, 12907–
12911. (h) Martjuga, M.; Shabashov, D.; Belakov, S.; Liepinsh, E.;
Suna, E. J. Org. Chem. 2010, 75, 2357–2368. (i) Martjuga, M.; Belakov,
S.; Liepinsh, E.; Suna, E. J. Org. Chem. 2011, 76, 2635–2647. (j)
Weatherly, C. D.; Rigoli, J. W.; Schomaker, J. M. Org. Lett. 2012, 14,
1704–1707. (k) Vesely, J.; Ibrahem, I.; Rios, R.; Zhao, G.; Xu, Y.;
Cordova, A. Tetrahedron Lett. 2007, 48, 2193–2198. (l) Lanter, J. C.;
Chen, H.; Zhang, X.; Sui, Z. Org. Lett. 2005, 7, 5905–5907. (m)
Kurokawa, T.; Kim, M.; DuBois, J. Angew. Chem., Int. Ed. 2009, 48,
2777–2779. (n) Wu, J.; Zhu, K.-C.; Yuan, P.-W.; Panek, J. S. Org. Lett.
2012, 14, 3624–3627.
Acknowledgment. Support by the National Science
Foundation (CHE 0911134) is greatly acknowledged.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) For a review, see: (a) Mitsunobu, O. Synthesis 1981, 1–28. For
the use of phthalimide in the Mitsunobu reaction, see: (b) Sen, S. E.;
Roach, S. L. Synthesis 1995, 756–758. For the use of dppa in the
Mitsunobu reaction, see: (c) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz,
S. J. Org. Chem. 2002, 67, 1982–1992. (d) Chen, Q.; Huo, X.; Zheng, H.;
She, X. Synlett 2012, 23, 1349–1352.
The authors declare no competing financial interest.
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