Chiral Bronsted acid-promoted enantioselective desymmetrization in an intramolecular schmidt reaction of symmetric azido 1,3-hexanediones: Asymmetric synthesis of azaquaternary pyrroloazepine skeletons

Article abstract of DOI:10.1002/asia.201100171

The enantioselective desymmetrization of 2-substituted-2-azidopropyl 1,3-hexanediones through an asymmetric intramolecular Schmidt reaction using a chiral Bronsted acid has been developed for the first time. Synthetically interesting pyrroloazepine skeletons with an azaquaternary stereogenic center with up to 59 % ee are accessed effectively (see scheme; R=H, alkyl, or aryl). Copyright

Full text of DOI:10.1002/asia.201100171

COMMUNICATION
DOI: 10.1002/asia.201100171
Chiral Brønsted Acid-Promoted Enantioselective Desymmetrization in an
Intramolecular Schmidt Reaction of Symmetric Azido 1,3-Hexanediones:
Asymmetric Synthesis of Azaquaternary Pyrroloazepine Skeletons
Ming Yang, Yu-Ming Zhao, Shu-Yu Zhang, Yong-Qiang Tu,* and Fu-Min Zhang*[a]
Alkaloids containing azaquaternary pyrroloazepine skele-
tons including cephalotaxine[1] and stemonamine[2] are an
important class of bioactive molecules in nature. How to di-
rectly and enantioselectively construct the azaquaternary
concisely construct azaquaternary pyrroloazepine and indo-
lizine compounds. Recent efforts to achieve enantioselective
symmetry breaking of azido 1,3-diketones using this reaction
failed when chiral Lewis acids were used.[9] Herein, we
report the first successful enantioselective desymmetrization
in an intramolecular Schmidt reaction of prochiral azido 1,3-
hexanediones; this reaction was promoted by 1,1’-bi-2-naph-
thal (BINOL)-derived N-triflylphosphoramides and yielded
chiral azaquaternary pyrroloazepine skeletons.
A difficulty in the enantioselective desymmetrization in
the intramolecular Schmidt reaction of azido 1,3-diketones
might be the requirement for rather strong Brønsted acid
promoters. In recent years, BINOL-derived phosphoric
acids have been widely used in enantioselective catalysis as
strong Brønsted acids.[10] However, they were not effective
for the intramolecular Schmidt reaction of azido 1,3-hexane-
diones because of their relatively low acidity (pKa ꢀ1 in
water).[11a] In 2006, Yamamoto et al. introduced a triflate
moiety, which is a strong electron-withdrawing group, into
BINOL-based phosphates, and they successfully used the
corresponding BINOL-derived N-triflylphosphoramides in
an asymmetric Diels–Alder reaction of ethyl vinyl ketone
with siloxydienes.[12a] The higher acidity of BINOL-derived
N-triflylphosphoramides (pKa ꢀꢁ3 in water)[11a] compared
with the corresponding phosphoric acids means they can ef-
fectively activate carbonyl groups and have been frequently
used for asymmetric catalysis.[12] Because trifluoroacetic acid
(pKa ꢀ0.23 in water)[11b] can efficiently induce an intramo-
lecular Schmidt reaction of an azidopropyl-substituted 1,3-
diketone,[6b] we proposed that BINOL-derived N-triflylphos-
phoramides might promote enantioselective desymmetriza-
tion in the intramolecular Schmidt reaction of azido 1,3-hex-
anediones.
pyrroloazepine skeleton remains a challenge. Desymmetri-
zation reactions, which are used to synthesize chiral mole-
cules, are proving to be a powerful method, and variations
of this type of reaction have been well developed.[3] For ex-
ample, the proline catalyzed enantioselective desymmetriza-
tion of meso-1,3-diones that yield Hajos–Parrish[4] and Wie-
land–Miescher[5] ketones is widely known. When coupled
with an intramolecular Schmidt reaction,[6] which has proven
to be a useful tool in the synthesis of alkaloids,[7] it could
allow facile construction of optically active lactams from
readily available starting materials. The combined desym-
metrization and Schmidt reaction of ketones and chiral
azido alcohols in an intermolecular fashion was first devel-
oped by Aubꢀ and co-workers, wherein the products did not
contain an azaquaternary center.[8] However, an intramolec-
ular Schmidt reaction of prochiral azido 1,3-diketones could
[a] M. Yang, Dr. Y.-M. Zhao, Dr. S.-Y. Zhang, Prof. Dr. Y.-Q. Tu,
Prof. Dr. F.-M. Zhang
Department of Chemistry
In an initial screening of chiral BINOL-derived N-triflyl-
phosphoramides for the reaction of 1a, 2a–f can effectively
induce the reaction, with only 2e and 2 f giving low enantio-
selectivity (Table 1, entries 1–6). When 1b was used as the
substrate and 2e or 2 f as the inducer, better enantioselectiv-
ity was obtained (Table 1, entries 7 and 8). The reaction be-
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (China)
Fax : (+86)931-8915557
E-mail: tuyq@lzu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100171.
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Chem. Asian J. 2011, 6, 1344 – 1347

Table 1. Optimization of the reaction conditions.[a]
Table 2. Chiral Brønsted acid-promoted asymmetric intramolecular
Schmidt reaction for desymmetrization of 2-substituted-2-azidopropyl
1,3-hexanediones.
Entry
R
H
t [d]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
U
1
4
2
4
4
4
3
4
4
4
3
3
54
62
53
88
58
58
33
65
44
51
16
18
41
56
39
55
53
54
57
58
58
50
47
59
PhACHTUNTGRENNUNG
ACHTUNGTRENNUNG
CHTUNGTRENNUNG
4-BrC6H
3-BrC6H
2-BrC6H
4A
4A(1 f)
4A(1g)
(1h)
2-MeC6H4A(1i)
1-naphthyl(1j)
2-CF3C6H4A(1k)
3,5-Cl2 C6H3A(1l)
Entry
R
2
Solvent
t [d]
Yield [%][b]
ee [%][c]
CHTUNGTRENNUNG
C
1
2
3
4
5
6
7
8
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
2a
2b
2c
2d
2e
2 f
2e
2 f
2e
2e
2e
2e
2e
2g
2g
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
ClCH2CH2Cl
toluene
benzene
CCl4
1
1
1
1
3
3
5
6
6
5
5
6
6
2
4
66
55
58
69
52
50
68
39
27
61
40
46
43
63
62
6
7
5
4
2-FC6H
G
9
CHTUNGTRENNUNG
10
11
12
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
25
23
30
30
20
31
28
37
49
46
56
CTHUNGTRENNUNG
ACHTUNGTRENNUNG
[a] Yield of isolated product. [b] Determined by HPLC on Chiralpak IC
or Chiralcel OD-H column.
ACHTUNGTRENNUNG
9
ACHTUNGTRENNUNG
10
11
12
13
14
15[d]
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
(Table 2). Substrates bearing an aryl substituent exhibited
better enantioselectivity than substrates without an aryl sub-
stituent (Table 2, entries 1 and 3 compared with entries 2
and 4–12). The enantioselectivity depended slightly on the
substitution of the aryl substituent of the azido 1,3-hexane-
diones. For example, substrates 1g–1i, which contained bro-
mine, fluorine, or methyl groups at the ortho-position of the
aryl substituent, gave slightly better enantioselectivity
(Table 2, entries 7–9). In contrast, lower enantioselectivity
was obtained for aryl substituents possessing an electron-
withdrawing group at the ortho-position (Table 2, entry 11).
A bulky substituent at the ortho-position of the aryl sub-
stituent caused a dramatic decrease in the yield of the
Schmidt reaction because of decomposition of the substrate
(Table 2, entries 7, 9, 11, and 12). The highest enantioselec-
tivity was achieved for substrate 1l, albeit in low yield
(Table 2, entry 12). Although a stoichiometric amount of
chiral acid 2g was used in the reaction, about 80% of the
acid could be recovered afterwards. After acidification, the
recovered chiral acid 2g exhibited similar reactivity and
enantioselectivity in the Schmidt reaction.
The absolute configuration of product (R)-3b was deter-
mined by Mosherꢂs method using 19F NMR spectroscopy.[14]
As shown in Scheme 1, first, chemoselective reduction of 3b
with sodium borohydride gave diastereomeric alcohols 4b
and 5b, and the major product was confirmed to be the cis-
isomer by analysis of the X-ray crystal structure
(Figure 1).[15] Then, the cis-isomer (4b) was esterified with
(R)-a-methoxy-a-trifluoromethylphenylacetyl chloride ((R)-
MTPA-Cl) and (S)-MTPA-Cl to give the corresponding
Mosher esters 6b and 7b. The 19F signal of the major isomer
of 6b appeared at 5.357 ppm, while in the spectrum of 7b it
appeared at 5.312 ppm.[16] The configuration-correlation
models of the Mosher esters are shown in Figure 2. These
ACHTUNGTRENNUNG
T
CCl4
CCl4
A
[a] Reactions were carried out using 0.1m 1 of unless otherwise noted.
[b] Yield of isolated product. [c] Determined by chiral HPLC on a Chir-
alpak IC column. [d] The reaction was carried out in CCl4 (0.05m).
tween 1b and 2e was then chosen for use as a model reac-
tion to screen the solvent;[13] carbon tetrachloride was found
to be the best solvent for this reaction. Although an enantio-
meric excess (ee) of 49% was obtained, the long reaction
time and low yield required optimization. Comparing
entry 7 with entry 8, the reaction of 1b with 2 f was slower
than that with 2e, but a similar enantioselectivity was ob-
tained. An 1-adamantyl substituent at the para-position of
the aromatic ring in 2 f is sterically more bulky than the iso-
propyl group at the para-position of the aromatic ring in 2e.
Therefore, we considered that a bulky substituent at the
para-position of the aromatic ring in 2e and 2 f might not be
necessary. Next, we synthesized N-triflyl phosphoramide 2g
without a substituent at the para-position of the aromatic
ring. To our delight, when 1b was treated with 2g in carbon
tetrachloride under the conditions described above, a 63%
yield and 46% enantioselectivity were obtained within two
days. Although there was a minor decrease in enantioselec-
tivity, the reaction rate was much faster (Table 1, entry 14).
When the concentration of 1b was decreased to 0.05m, a
62% yield and 56% enantioselectivity were obtained within
four days (Table 1, entry 15).
With the optimal reaction conditions in hand, a series of
2-substituted-2-azidopropyl 1,3-hexanediones were prepared
to examine their reactivity toward enantioselective desym-
metrization in the intramolecular Schmidt reaction
Chem. Asian J. 2011, 6, 1344 – 1347
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www.chemasianj.org
1345

F.-M. Zhang and Y.-Q. Tu et al.
COMMUNICATION
Scheme 1. Chemoselective reduction of 3b and esterification of the cis-
isomer with Mosherꢂs reagent.
Scheme 2. Proposed models of chiral Brønsted acid-promoted enantiose-
lective desymmetrization through the intramolecular Schmidt reaction.
In conclusion, we have synthesized chiral phosphoramide
2g and found that it was an effective promoter for enantio-
selective desymmetrization in the intramolecular Schmidt
reaction of symmetric azido 1,3-hexanediones to yield chiral
azaquaternary pyrroloazepine skeletons. Although only
moderate enantioselectivity was obtained, it successfully
demonstrates for the first time that enantioselective desym-
metrization of symmetric azido 1,3-diketones through an in-
tramolecular Schmidt reaction is a viable process using a
chiral Brønsted acid. Further investigation into other effec-
tive chiral inducers for this reaction to improve the enantio-
selectivity, range of substrates, and the use of chiral acid 2g
as a catalyst in other reactions are ongoing.
Figure 1. X-ray structure of (ꢃ)-4b.
Experimental Section
A typical procedure for the intramolecular Schmidt reaction is as follows
An azido 1,3-hexanedione substrate (1a–l; 0.1 mmol, 1.0 equiv) was dis-
solved in dry CCl4 (2 mL) in a flame-dried flask, and then phosphora-
mide 2g (0.15 mmol, 1.5 equiv) was added under argon. The reaction
mixture was stirred at room temperature. After completion of the reac-
tion, the crude reaction mixture was evaporated, preabsorbed on silica
gel, and then purified by column chromatography on silica gel (eluent of
petroleum ether/ethyl acetate (4:1–1:1)) to recover phosphoramide 2g
and afford the product mixed with a small quantity of 2g. The crude
product was subjected to further column chromatography on basic alumi-
na and eluted with petroleum ether/ethyl acetate (1:1) to afford the de-
sired product in high purity.
Figure 2. Configuration-correlation model of 6b and 7b.
observations are in agreement with an (R)-configuration for
4b at the secondary alcohol position, thereby indicating that
the absolute configuration of 3b is (R). The absolute config-
uration could be explained by the proposed reaction models
shown in Scheme 2, which were devised from models of
chiral phosphoric acid-catalyzed desymmetrization of meso-
1,3-diones calculated by Akiyama et al.[17] In the reaction
models, on one hand, the acidic proton of the chiral phos-
phoramide activated one of the carbonyl groups of the sub-
strate; on the other, an n!p* interaction may exist between
an oxygen lone pair (highest occupied molecular orbital) of
the chiral phosphoramide and p* (lowest unoccupied molec-
ular orbital) of the NꢂN bond. These interactions could sta-
bilize the transition state and the favored one would lead to
the formation of the (R)-configuration of 3b.
Acknowledgements
This work was supported by the NSFC (Nos. 20921120404, 21072085,
20732002, and 20972059), “973” program of 2010CB833200, “111” pro-
gram of MOE; and the fundamental research funds for the central uni-
versities (lzujbky-2010-k09, lzujbky-2009-76, lzujbky-2009-158).
Keywords: alkaloids
·
asymmetric
synthesis
·
desymmetrization
Schmidt reaction
·
enantioselectivity ·
intramolecular
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Chem. Asian J. 2011, 6, 1344 – 1347

Chiral Brønsted Acid-Promoted Enantioselective Desymmetrization
Katz, D. G. English, S. Smith, A. K. Manukyan, V. W. Day, B. Neu-
enswander, J. L. Poutsma, J. Aubꢀ, Angew. Chem. 2008, 120, 6329–
6331; Angew. Chem. Int. Ed. 2008, 47, 6233–6235.
[1] For reviews on the cephalotaxus alkaloids, see: a) S. M. Weinreb,
M. F. Semmelhack, Acc. Chem. Res. 1975, 8, 158–164; b) L. Huang,
Z. Xue in The Alkaloids, Vol. 23, Academic Press, New York, 1984,
p. 157; c) M. A. JalilMiah, T. Hudlicky, J. W. Reed, in The Alkaloids,
Vol. 51, Academic Press, San Diego, 1998, p. 199.
[2] For reviews on stemona alkaloids, see: a) R. A. Pilli, M. C. Ferreira
de Oliveira, Nat. Prod. Rep. 2000, 17, 117–127; b) R. A. Pilli, G. B.
Rosso, Ferreira de Oliveira in The Alkaloids, Vol. 62 (Eds.: G. A.
Cordell), Elsevier, New York, 2005, pp. 77–173; c) H. Greger,
Planta Med. 2006, 72, 99–113.
[3] Reviews: a) M. C. Willis, J. Chem. Soc. Perkin Trans. 1 1999, 13,
1765–1784; b) E. Garcꢃa-Urdiales, I. Alfonso, V. Gotor, Chem. Rev.
2005, 105, 313–354; c) A. Studer, F. Schleth, Synlett 2005, 3033–
3041.
[4] a) U. Eder, G. Sauer, R. Wiechert, Angew. Chem. 1971, 83, 492–
493; Angew. Chem. Int. Ed. Engl. 1971, 10, 496–497; b) Z. G. Hajos,
D. R. Parrish, J. Org. Chem. 1974, 39, 1615–1621; c) R. A. Micheli,
Z. G. Hajos, N. Cohen, D. R. Parrish, L. A. Poland, W. Sciamanna,
M. A. Scott, P. A. Wehrli, J. Org. Chem. 1975, 40, 675–681; d) Z. G.
Hajos, D. R. Parrish, Org. Synth., Collect Vol. VII, Wiley, New York,
1990, pp. 363–369.
[9] D. Lertpibulpanya, S. P. Marsden, Org. Biomol. Chem. 2006, 4,
3498–3504.
[10] For reviews on Brønsted acid catalysis, see: a) T. Akiyama, J. Itoh,
K. Fuchibe, Adv. Synth. Catal. 2006, 348, 999–1010; b) T. Akiyama,
Chem. Rev. 2007, 107, 5744–5758; c) S. J. Connon, Angew. Chem.
2006, 118, 4013–4016; Angew. Chem. Int. Ed. 2006, 45, 3909–3912;
d) T. Akiyama in Acid Catalysis in Modern Organic Synthesis (Eds.:
H. Yamamoto, K. Ishihara), Wiley-VCH, Weinheim, 2008, pp. 62–
107; e) M. Terada, Chem. Commun. 2008, 4097–4112, and referen-
ces therein.
[11] a) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713–5743;
b) J. F. J. Dippy, S. R. C. Hughes, A. Rozanski, J. Chem. Soc. 1959,
2492–2498.
[12] a) D. Nakashima, H. Yamamoto, J. Am. Chem. Soc. 2006, 128,
9626–9627; b) M. Rueping, W. Ieawsuwan, A. P. Antonchick, B. J.
Nachtsheim, Angew. Chem. 2007, 119, 2143–2146; Angew. Chem.
Int. Ed. 2007, 46, 2097–2100; c) M. Rueping, B. J. Nachtsheim, S. A.
Moreth, M. Bolte, Angew. Chem. 2008, 120, 603–606; Angew.
Chem. Int. Ed. 2008, 47, 593–596; d) P. Jiao, D. Nakashima, H. Ya-
mamoto, Angew. Chem. 2008, 120, 2445–2447; Angew. Chem. Int.
Ed. 2008, 47, 2411–2413; e) D. Enders, A. Narine, F. Toulgoat, T.
Bisschops, Angew. Chem. 2008, 120, 5744–5748; Angew. Chem. Int.
Ed. 2008, 47, 5661–5665; f) M. Rueping, T. Theissmann, A. Kuen-
kel, R. M. Koenigs, Angew. Chem. 2008, 120, 6903–6906; Angew.
Chem. Int. Ed. 2008, 47, 6798–6801; g) C. H. Cheon, H. Yamamoto,
J. Am. Chem. Soc. 2008, 130, 9246–9247; h) M. Rueping, W. Ieawsu-
wan, Adv. Synth. Catal. 2009, 351, 78–84; i) M. Zeng, Q. Kang, Q.-
L. He, S.-L. You, Adv. Synth. Catal. 2008, 350, 2169–2173; j) S. Lee,
S. Kim, Tetrahedron Lett. 2009, 50, 3345–3348; k) M. Rueping, M.-
Y. Lin, Chem. Eur. J. 2010, 16, 4169–4172; l) C. H. Cheon, H. Yama-
moto, Org. Lett. 2010, 12, 2476–2479; m) M. Rueping, B. J. Nacht-
sheim, Synlett 2010, 119–122.
[5] a) P. Wieland, K. Miescher, Helv. Chim. Acta 1950, 33, 2215–2228;
b) J. Gutzwiller, A. Buchschacher, A. Furst, Synthesis 1977, 167–
168; c) S. Ramachandran, M. S. Newman, Org. Synth. 1961, 41, 38.
[6] a) J. Aubꢀ, G. L. Milligan, J. Am. Chem. Soc. 1991, 113, 8965–8966;
b) G. L. Milligan, C. J. Mossman, J. Aubꢀ, J. Am. Chem. Soc. 1995,
117, 10449–10459.
[7] For selected references: a) R. Iyengar, K. Schildknegt, J. Aubꢀ, Org.
Lett. 2000, 2, 1625–1627; b) A. Wrobleski, K. Sahasrabudhe, J.
Aubꢀ, J. Am. Chem. Soc. 2002, 124, 9974–9975; c) B. T. Smith, J. A.
Wendt, J. Aubꢀ, Org. Lett. 2002, 4, 2577–2579; d) J. E. Golden, J.
Aubꢀ, Angew. Chem. 2002, 114, 4492–4494; Angew. Chem. Int. Ed.
2002, 41, 4316–4318; e) V. Gracias, Y. Zeng, P. Desai, J. Aubꢀ, Org.
Lett. 2003, 5, 4999–5001; f) A. Wrobleski, K. Sahasrabudhe, J.
Aubꢀ, J. Am. Chem. Soc. 2004, 126, 5475–5481; g) Y. Zeng, D. S.
Reddy, E. Hirt, J. Aubꢀ, Org. Lett. 2004, 6, 4993–4995; h) R. Iyen-
gar, K. Schildknegt, M. Morton, J. Aubꢀ, J. Org. Chem. 2005, 70,
10645–10652; i) Y. Zeng, J. Aubꢀ, J. Am. Chem. Soc. 2005, 127,
15712–15713; j) K. J. Frankowski, J. E. Golden, Y. Zeng, Y. Lei, J.
Aubꢀ, J. Am. Chem. Soc. 2008, 130, 6018–6024; k) P. Ghosh, W. R.
Judd, T. Ribelin, J. Aubꢀ, Org. Lett. 2009, 11, 4140–4142; l) Y.-M.
Zhao, P. M. Gu, H.-J. Zhang, Q.-W. Zhang, C.-A. Fan, Y.-Q. Tu, F.-
M. Zhang, J. Org. Chem. 2009, 74, 3211–3213.
[8] a) V. Gracias, G. L. Milligan, J. Aubꢀ, J. Am. Chem. Soc. 1995, 117,
8047–8048; b) K. Furness, J. Aubꢀ, Org. Lett. 1999, 1, 495–497;
c) K. Sahasrabudhe, V. Gracias, K. Furness, B. T. Smith, C. E. Katz,
D. S. Reddy, J. Aubꢀ, J. Am. Chem. Soc. 2003, 125, 7914–7922;
d) C. E. Katz, J. Aubꢀ, J. Am. Chem. Soc. 2003, 125, 13948–13949;
e) C. E. Katz, T. Ribelin, D. Withrow, Y. Basseri, A. K. Manukyan,
A. Bermudez, C. G. Nuera, V. W. Day, D. R. Powell, J. L. Poutsma,
J. Aubꢀ, J. Org. Chem. 2008, 73, 3318–3327; f) T. Ribelin, C. E.
[13] For details, see the Supporting Information.
[14] a) J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 1969, 34,
2543–2549; b) G. R. Sullivan, J. A. Dale, H. S Mosher, J. Org.
Chem. 1973, 38, 2143–2147.
[15] CCDC 804165 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[16] 19F NMR chemical shift was recorded in parts per million downfield
relative to internal trifluoroacetic acid in a deuterated chloroform
solvent.
[17] K. Mori, T. Katoh, T. Suzuki, T. Noji, M. Yamanaka, T. Akiyama,
Angew. Chem. 2009, 121, 9832–9834; Angew. Chem. Int. Ed. 2009,
48, 9652–9654.
Received: February 19, 2011
Published online: April 12, 2011
Chem. Asian J. 2011, 6, 1344 – 1347
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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