Synthetic strategy for cyclic amines: A stereodefined cyclic N,O-acetal as a stereocontrol and diversity-generating element

Article abstract of DOI:10.1002/anie.201206967

In control: A new synthetic strategy towards cyclic amines was developed and exploits a stereodefined cyclic N,O-acetal as the key stereocontrol and diversity-generating element. The cyclic N,O-acetal was prepared from the sequential asymmetric hydroamina

Full text of DOI:10.1002/anie.201206967

Angewandte
Chemie
DOI: 10.1002/anie.201206967
Heterocycles
Synthetic Strategy for Cyclic Amines: A Stereodefined Cyclic N,O-
Acetal as a Stereocontrol and Diversity-Generating Element**
Haejin Kim, Wontaeck Lim, Donghong Im, Dong-gil Kim, and Young Ho Rhee*
The diversity of natural products has attracted synthetic
chemists over the past decades.[1] Also, it is important for the
discovery of new lead compounds for pharmaceuticals. Thus,
developing new synthetic methodologies which can introduce
molecular diversity with high chemical efficiency represents
a primary goal in synthetic organic chemistry. As a result of
their high reactivity and chemoselectivity, organometal cata-
lysts may play a unique role in this area. In this context, we
recently reported the first synthesis of stereodefined acyclic
allylic N,O-acetals and their utility as a stereodiversity-gen-
erating tool for the flexible synthesis of 2,6-substituted
piperidines.[2] Herein, we report a conceptually new strategy
for the synthesis of cyclic amines, one which employs stereo-
defined cyclic allylic N,O-acetals such as 2 as the key moiety
(Scheme 1a).[3,4] This substrate can be accessed by the
intermolecular asymmetric addition of the aminoolefin
1 (hydroamination) to an alkoxyallene[5,6] and a subsequent
ring-closing metathesis (RCM) reaction.[7] A salient feature of
the proposed method is highlighted by the unprecedented use
of an N,O-acetal moiety as a stereocontrol element in olefin
functionalization after the RCM reaction. Moreover, the
À
N,O-acetal allows the iminium-ion-mediated C C bond
formation[8] at a late stage of the synthesis. In this regard,
the proposed method is clearly distinguished from a well-
established protocol for the cyclic amine synthesis, which
introduces the alkyl group prior to the RCM reaction
(Scheme 1b).[9] The unique advantage of the proposed
strategy can be easily addressed by the overall synthetic
efficiency, particularly when the synthesis of multiple targets
are pursued. For example, installing n different alkyl groups
R’n in the synthesis of 3 would require 3 + n overall steps
according to the proposed strategy. In contrast, the conven-
tional methods would require 3 ꢀ n overall steps, because the
alkyl group is introduced at an early stage. Thus, the new
method shown in Scheme 1a should give rapid access to
diversely substituted and biologically important cyclic amines
in a highly controlled and unified manner. In the meantime,
this new strategy raises a number of challenging issues. For
example, the stereoselectivity should be clearly determined in
the olefin functionalization and alkyl substitution reaction. In
addition, the racemization of the cyclic N,O-acetal moiety
should be avoided. Thus, the chemoselectivity of the catalytic
reactions becomes a major issue.
For the successful implementation of the proposed
strategy, it is of crucial importance to secure the cyclic
stereodefined N,O-acetals 2. Thus, we were particularly
interested in the plausibility of the unprecedented ring-
closing metathesis reaction of the stereodefined acyclic N,O-
acetals at the outset of the study because of the chemical
instability of the N,O-acetal moiety.
We initiated our studies using the Ts-protected allylic
amine 4 (Table 1). Employing Pd(OAc)2 (5 mol%) and the
bis(phosphane) ligand (R,R)-L1 (6.5 mol%) in combination
with excess n-pentoxyallene (70 equiv) and triethylamine
(1.5 equiv), as based upon the previous study,[2] gave the
enantioenriched acyclic N,O-acetal 5 in 97% yield. Because
the measurement of enantiomeric purity of this compound
was troublesome, we directly moved to the RCM step. Using
the first-generation Grubbs catalyst (5 mol%) gave the cyclic
amine 6 in 88% yield. Notably, approximately 92% ee was
observed for this compound (entry 1). At this stage, the
absolute configuration of the N,O-acetal carbon atom was
assigned to be S by analogy to our previous study.[2]
Interestingly, switching to the ligand (R,R)-L2[10,11] gave 6 in
greater than 99% ee in near quantitative yield (entry 2). This
excellent ee value confirms the conservation of the stereo-
chemical integrity of the N,O-acetal in the RCM reaction,
thus verifying the plausibility of the proposed concept.
Interestingly, decreasing the amount of n-pentoxyallene to
10 equivalents still maintained the conversion and the enan-
Scheme 1. a) New concept in cyclic amine synthesis exploiting stereo-
defined cyclic N,O-acetals. b) Conventional route. R=n-alkyl, R’=allyl
or homopropargyl or cyano.
[*] H. Kim, W. Lim, D. Im, D.-g. Kim, Prof. Y. H. Rhee
Department of Chemistry
POSTECH (Pohang University of Science and Technology)
Pohang, 790-784 (Korea)
E-mail: yhrhee@postech.ac.kr
Homepage: http://yhrhee.postech.ac.kr
[**] This work was supported by the Korean government funded by
National Research Foundation of Korea (NRF-2010-0009458)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206967.
Angew. Chem. Int. Ed. 2012, 51, 12055 –12058
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12055

.
Angewandte
Communications
Table 1: Optimization for the reaction conditions.
comparably efficient for the two-step sequence, thus generat-
ing the diastereomeric acyclic N,O-acetals 20 and 21 in high
yield (entries 7 and 8) and high diastereoselectivity in both
cases.
Having established the generality of the two-step protocol
to access stereodefined cyclic N,O-acetals, we explored the
use of these moieties as a stereocontrol element. We first
considered the diastereoselective dihydroxylation of the
cyclic N,O-acetals (Scheme 2a). A preliminary reaction of
the compound 6 using catalytic OsO4 (3 mol%) indeed gave
the diol product 22 in 95% yield with a ratio of over 25:1 and
with no deteriation of the ee value. The relative stereochem-
istry between the substituents on C2 and C3 in 22 was
tentatively assigned as trans based upon the presumed steric
effect of the N,O-acetal. For the complete assignment of the
stereochemistry of the diols, see below. The N,O-acetal in the
piperidine ring 8 also showed excellent stereodirecting effect,
as the diol 23 was obtained as the predominant isomer in 96%
yield. In contrast, the larger seven-membered ring compound
24 was obtained with somewhat lower 7:1 stereoselectivity
from 10. The N,O-acetal substrates possessing alkyl substitu-
tion on the olefin (compounds 12, 14, 16, and 18) also showed
high yield and selectivity for the dihydroxylation. In the case
Entry
Allene (equiv)
Ligand
5/6
6
Yield [%][a]
ee [%][b]
1
2
3
70
70
10
5
L1
L2
L2
L2
L2
97:88
99:99
99:90
99:99
30:–
92
>99
>99
>99
n.d.
4
5[c]
2
[a] Yield of isolated product. [b] Determined by HPLC using a chiral
stationary phase. [c] The reaction was run for two days. n.d. =not
determined. Ts=4-toluenesulfonyl.
tiomeric excess when the latter ligand was used
(entry 3). Additional reduction in the amount of n-
pentoxyallene to 5 equivalents still showed high
reactivity and ee (entry 4), while using 2 equivalents
showed poor conversion in the hydroamination
reaction (entry 5), even after a prolonged reaction
time. Notably, formation of the pyrrole product 6’
was not observed, as indicated by the high yield of
Table 2: Scope of the formation of cyclic stereodefined N,O-acetals.[a]
Entry
Substrate
Product
Yield [%][b]
ee[c] [%]
the desired product.[12]
1st step 2nd step
(method) (method)
With the optimized two-step protocol for the
synthesis of the cyclic N,O-acetal 6 in hand, we
explored the scope of this sequential catalytic
processes (Table 2). Synthesis of the six-membered
and seven-membered analogue (8 and 10) also
showed excellent yield and enantioselectivity
(entries 1 and 2). In the case of allylic amines
possessing alkyl groups at the olefin moiety, the
asymmetric hydroamination reaction worked invar-
iably well (entries 3–5). However, the RCM reaction
showed some discrepancy between the substrates.
For example, the methallyl amine substrate 11 gave
the cyclic product 12 in fair 84% yield (over two
steps) when 5 mol% of first-generation Grubbs
catalyst was employed (entry 3). Introducing the
bulkier n-butyl and benzyl groups, however, consid-
erably slowed the reaction (entries 4 and 5). In this
case, formation of a significant amount of the pyrrole
compounds analogous to 6’ was also noted. Interest-
ingly, switching to the second-generation Grubbs
catalyst (20 mol%) improved the reactivity, thus
producing the cyclic N,O-acetal 14 and 16 in high
yield and ee.[13] Also, the piperidine ring 18 could be
obtained from homoallylic amine substrate 17 in
good yield and ee, even when 5 mol% of second-
generation Grubbs catalyst was used (entry 6). In
1
2
3
4
7 (n=2, R=H)
9 (n=3, R=H)
11 (n=1, R=CH3)
13 (n=1, R=n-C4H9)
15 (n=1, R=Bn)
17 (n=2, R=CH3)
8
99 (A1)
99 (A1)
99 (A2)
93 (A2)
99 (A2)
99 (A2)
91 (B1)
93 (B1)
85 (B1)
81 (B2)
89 (B2)
88 (B2)
>99
>99
94
97
94
10
12
14
16
18
5
6[d]
97
7
19
19
20
21
99 (A2)
99 (A2)
95 (B1) >25:1[e]
8[f]
98 (B1) >25:1[e]
[a] Method A1: Pentoxyallene (5 equiv) and (R,R)-L2 were used. Method A2:
Pentoxyallene (70 equiv) and (R,R)-L1 were used. Method B1: The first-generation
Grubbs’ catalyst (5 mol%) was used. Method B2: The second-generation Grubbs’
catalyst (20 mol%) was used. [b] Yield of isolated product. [c] Determined by HPLC
using a chiral stationary phase. [d] The second-generation Grubbs’ catalyst
(5 mol%) was used at 608C. [e] Diastereomeric ratio determined by the integration
of signals in the 1H NMR spectra of the crude reaction mixture. [f] (S,S)-L1 was used
addition, the chiral homoallylic amine 19 proved instead of (R,R)-L1.
12056 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 12055 –12058

Angewandte
Chemie
Scheme 3. Examples for the use of cyclic N,O-acetals as a diversity-
generating element. TBS=tert-butyldimethylsilyl.
Scheme 2. Examples for the use of cyclic N,O-acetals as a stereocontrol
element. a) For dihydroxylation. b) For epoxidation. c) For hydrogena-
tion. NMO=N-methylmorpholine-N-oxide, THF=tetrahydrofuran.
In addition, the above examples complete the study on the
role of N,O-acetals as the diversity-generating element for the
alkyl substitution at the C2-position of pyrrolidines.
In addition to the pyrrolidine substrate 34, the bis(TBS
ether) 38 generated from the piperidine diol 23 also showed
high yield and diastereoselectivity for the alkyl substitution.
For example, using allyltrimethylsilane proceeded smoothly
to give the product 39 in 98% yield with 7:1 diastereoselec-
tivity. Interestingly, employing allenyltributylstannane gave
the product 40 in 97% yield with a significantly improved
stereoselectivity of greater than 25:1, whereas using trime-
thylsilyl cyanide gave the product 41 in similar yield with
a somewhat lower selectivity (5:1). The utility of the N,O-
acetal is further demonstrated by the reaction of 32 with
allyltrimethylsilane, which produced the trans-2,4-disubsti-
tuted piperidine 42 in high yield and excellent diastereose-
lectivity (Scheme 3b).[14,19]
From a synthetic viewpoint, the unprecedented strategy
introduced here firmly establishes a highly efficient and
unified protocol for the synthesis of bioactive natural
products such as azasugars[20] and various alkaloids.[21] More-
over, the combined role of cyclic N,O-acetals as a stereocon-
trol and diversity-generating element makes this method
particularly attractive for preparing cyclic amines possessing
diverse stereochemical and substitution patterns.
of the isomeric piperidine N,O-acetal substrates 20 and 21, the
dihydroxylation showed complete diastereoselectivity, which
was directed solely by the stereochemistry of cyclic N,O-
acetal moiety to give the diastereomeric products 29 and 30 in
good yield.[14]
In addition to the dihydroxylation, the reaction of 8 with
dimethyldioxirane (DMDO) gave the epoxide 31 in high yield
with 4:1 selectivity (Scheme 2b). Also, stereoselective hydro-
genation of 18 using catalytic PtO2 (5 mol%) generated the
cis-piperidine acetal 32 in 80% yield with an approximate
diastereoselectivity of 20:1 and no erosion of the enantiose-
lectivity (Scheme 2c).[14,15]
Having confirmed the role of the N,O-acetal as the
stereocontrol element, we finally investigated the iminium-
ion-mediated carbon–carbon bond formation to install a vari-
ety of alkyl groups at the C2-position (Scheme 3a). After
extensive investigation, we discovered that the bis(TBS ether)
34 generated from 22 gave the allylated cis-product 35 in 96%
yield with an approximate diastereoselectivity of 23:1 upon
treatment with trimethylallylsilane and BF3OEt2.[14,16,17]
Employing allenyltributylstannane and trimethyl cyanide
also gave the product 36 and 37 in high yield and high
diastereoselectivity, respectively. The absolute structure of 37
was unambiguously determined by the X-ray crystallographic
study.[18] This structural analysis further confirms the stereo-
chemical assignment suggested in the dihydroxylation
(Scheme 2) and the asymmetric hydroamination (Table 1).
In summary, we have developed a new synthetic strategy
towards cyclic amines based upon the stereodefined cyclic
N,O-acetals. Our future studies are aimed at expanding the
scope of the allenes in the hydroamination reaction as well as
exploring the biological effect of various cyclic amines.
Received: August 28, 2012
Published online: October 25, 2012
Angew. Chem. Int. Ed. 2012, 51, 12055 –12058
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12057

.
Angewandte
Communications
[9] For selected recent examples on azacycle synthesis using this
strategy, see: a) O. O. Fadeyi, T. J. Senter, K. N. Hahn, C. W.
Lindsley, Chem. Eur. J. 2012, 18, 5826 – 5831; b) K. Kong, Z.
Moussa, C. Lee, D. Romo, J. Am. Chem. Soc. 2011, 133, 19844 –
19856; c) H. Ren, W. D. Wulff, J. Am. Chem. Soc. 2011, 133,
5656 – 5659; d) H. Nomura, C. J. Richards, Org. Lett. 2009, 11,
Keywords: enantioselectivity · hydroamination · metathesis ·
stereoselectivity · synthetic methods
.
[1] a) C. J. OꢁConnor, H. S. G. Beckmann, D. R. Spring, Chem. Soc.
Rev. 2012, 41, 4444 – 4456; b) T. E. Nielsen, S. L. Schreiber,
Angew. Chem. 2008, 120, 52 – 61; Angew. Chem. Int. Ed. 2008, 47,
48 – 56; c) M. D. Burke, S. L. Schreiber, Angew. Chem. 2004, 116,
48 – 60; Angew. Chem. Int. Ed. 2004, 43, 46 – 58; d) S. L.
Schreiber, Science 2000, 287, 1964 – 1969.
[2] H. Kim, Y. H. Rhee, J. Am. Chem. Soc. 2012, 134, 4011 – 4014.
[3] For early reviews on the meal-catalyzed hydroaminaion of
allenes, see: a) K. Inamoto, A. Yamamoto, K. Ohsawa, K.
Hiroya, T. Sakamoto, Chem. Pharm. Bull. 2005, 53, 1502 – 1507;
b) R. Zimmer, C. U. Dinesh, E. Nandanan, F. A. Khan, Chem.
Rev. 2000, 100, 3067 – 3126; c) S. Ma, Top. Organomet. Chem.
2005, 14, 183 – 210.
[4] For an early example for the synthesis and utility of a non-
stereodefined allyic cyclic N,O-acetal, see: a) S. S. Kinderman,
R. de Gelder, J. H. van Maarseveen, H. E. Schoemaker, H.
Hiemstra, F. P. J. T. Rutjes, J. Am. Chem. Soc. 2004, 126, 4100 –
4101; b) S. S. Kinderman, R. Doodeman, J. W. van Beijma, J. C.
Russcher, K. C. M. F. Tjen, T. M. Kooistra, H. Mohaselzadeh,
J. H. van Maarseveen, H. Hiemstra, H. E. Schoemaker, F. P. J. T.
Rutjes, Adv. Synth. Catal. 2002, 344, 736 – 748.
[5] For recent examples on the asymmetric intramolecular hydro-
amination of allenes, see: a) R. L. LaLonde, Z. J. Wang, M. Mba,
A. D. Lackner, F. D. Toste, Angew. Chem. 2010, 122, 608 – 611;
Angew. Chem. Int. Ed. 2010, 49, 598 – 601; b) Z. Zhang, C. F.
Bender, R. A. Widenhoefer, J. Am. Chem. Soc. 2007, 129,
14148 – 14149; c) R. L. LaLonde, B. D. Sherry, E. J. Kang, F. D.
Toste, J. Am. Chem. Soc. 2007, 129, 2452 – 2453; d) G. L.
Hamilton, E. J. Kang, M. Mba, F. D. Toste, Science 2007, 317,
496 – 499.
´
2892 – 2895; e) B. P. Bondzic, P. Eilbracht, Org. Lett. 2008, 10,
3433 – 3436; f) C. Fiorelli, D. Savoia, J. Org. Chem. 2007, 72,
6022 – 6028; g) R. Weihofen, O. Tverskoy, G. Helmchen, Angew.
Chem. 2006, 118, 5673 – 5676; Angew. Chem. Int. Ed. 2006, 45,
5546 – 5549; h) B. M. Trost, D. B. Horne, M. J. Woltering, Chem.
Eur. J. 2006, 12, 6607 – 6620; i) G. K. Friestad, C. S. Korapala, H.
Ding, J. Org. Chem. 2006, 71, 281 – 289; j) S. J. Dolman, E. S.
Sattely, A. H. Hoveyda, R. R. Schrock, J. Am. Chem. Soc. 2002,
124, 6991 – 6997; k) R. Akiyama, S. Kobayashi, Angew. Chem.
2002, 114, 2714 – 2716; Angew. Chem. Int. Ed. 2002, 41, 2602 –
2604; l) B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 1999, 121,
4545 – 4554; m) S. J. Miller, R. H. Grubbs, J. Am. Chem. Soc.
1995, 117, 5855 – 5856.
[10] For a recent review on the use of this type of chiral ligands, see:
a) B. M. Trost, T. Zhang, J. D. Sieber, Chem. Sci. 2010, 1, 427 –
440; b) B. M. Trost, D. R. Fandrick, Aldrichimica Acta 2007, 40,
59 – 72.
[11] For selected examples that reveal beneficial effect of the
naphthyl ligand L2, see: B. M. Trost, M. K. Brennan, Org. Lett.
2007, 9, 3961 – 3964, and references therein.
[12] T. J. Donohoe, N. M. Kershaw, A. J. Orr, K. M. P. Wheelhouse,
L. P. Fishlock, A. R. Lacy, M. Bingham, P. A. Procopiou,
Tetrahedron 2008, 64, 809 – 820.
[13] For a systematic study on the effect of the ruthenium catalyst on
the azacycle formation, see: K. M. Kuhn, T. M. Champagne,
S. H. Hong, W.-H. Wei, A. Nickel, C. W. Lee, S. C. Virgil, R. H.
Grubbs, R. L. Pederson, Org. Lett. 2010, 12, 984 – 987.
[14] The relative stereochemistry was established by extensive nOe
studies.
[15] Using other metal catalysts led to the formation of 33,
presumably through the initial hydrogenolysis of the N,O-
acetal. For a related review on the hydrogenolysis reaction,
see: P. N. Rylander, Hydrogenation methods, Academic Press,
Orlando, FL, 1985, pp. 1 – 52.
[16] For an example that shows cis selectivity in a related study, see:
F. Pisaneschi, J. J. P. Sejberg, C. Blain, W. H. Ng, E. O. Aboagye,
A. C. Spivey, Synlett 2011, 241 – 244.
[6] For a recent report on the gold-catalyzed intermolecular hydro-
amination of racemic allenes, see: K. L. Butler, M. Tragni, R. A.
Widenhoefer, Angew. Chem. 2012, 124, 5265 – 5268; Angew.
Chem. Int. Ed. 2012, 51, 5175 – 5178.
[7] For selected reviews on the RCM reaction, see: a) R. H. Grubbs,
Handbook of Metathesis, Wiley-VCH, Weinheim, 2003; b) A. H.
Hoveyda, A. R. Zhugralin, Nature 2007, 450, 243 – 251; c) Y.
Schrodi, R. L. Pederson, Aldrichimica Acta 2007, 40, 45 – 52;
d) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005,
117, 4564 – 4601; Angew. Chem. Int. Ed. 2005, 44, 4490 – 4527;
e) R. H. Grubbs, Tetrahedron 2004, 60, 7117 – 7140.
[17] The diols 22 and 24 and their acetylated derivatives showed poor
À
diastereoselectivity for the iminium-ion-mediated C C bond
formation.
[8] For selected examples on the use of N,O-acetals as a precursor
[18] For detailed analysis of the crystalographic data, see the
Supporting Information.
[19] For the study on the stereoselectivity in the closely related
À
for the stereoselective C C bond formations, see: a) L. Yongna,
Lewis-acid mediated alkylations of N,O-acetals and applicatios
to the total syntheses of alkaloids, Ph.D Thesis, Nanyang
Technologycal University, Singapore, 2011; b) R. W. Bates, Y.
Lu, Org. Lett. 2010, 12, 3938 – 3941; c) W. E. Brenzovich, D.
Benitez, A. D. Lackner, H. P. Shunatona, E. Tkatchouk, W. A.
Goddard, F. D. Toste, Angew. Chem. 2010, 122, 5651 – 5654;
Angew. Chem. Int. Ed. 2010, 49, 5519 – 5522; d) M. Sugiura, H.
Hagio, R. Hirabayashi, S. Kobayashi, J. Am. Chem. Soc. 2001,
123, 12510 – 12517; e) A. Kamatani, L. E. Overman, Org. Lett.
2001, 3, 1229 – 1232.
À
oxacarbonium-ion-mediated C C bond formation reaction, see:
L. Ayala, C. G. Lucero, J. A. C. Romero, S. A. Tabacco, K. A.
Woerpel, J. Am. Chem. Soc. 2003, 125, 15521 – 15528.
[20] a) I. Su Kim, Y. Hoon Jung, Heterocycles 2011, 83, 2489 – 2507;
b) Iminosugars: from Synthesis to Therapeutic Applications
(Eds.: P. Compain, O. R. Martin), Wiley-VCH, Weinheim, 2007.
[21] J. P. Michael, Nat. Prod. Rep. 2008, 25, 139 – 165, and references
therein.
12058 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 12055 –12058