Remarkable effects of titanium tetrachloride in diastereoselective aza Diels-Alder cycloaddition: Synthesis of (S)-piperazic acid

Article abstract of DOI:10.1016/j.tetlet.2004.12.003

Titanium tetrachloride-mediated aza Diels-Alder cycloaddition using a chiral diene and an aza dienophile proceeds in highly diastereoselective manner to form a dehydropiperazic acid derivative in high yield, and diastereoselectivity of the reaction depends on the quantity of titanium tetrachloride.

Full text of DOI:10.1016/j.tetlet.2004.12.003

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 555–558
Remarkable effects of titanium tetrachloride in diastereoselective
aza Diels–Alder cycloaddition: synthesis of (S)-piperazic acid
Kazuishi Makino,a Yoshiaki Henmi,a Makiko Terasawa,a
Osamu Harab and Yasumasa Hamadaa,*
aGraduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
bFaculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 460-8503, Japan
Received 28 October 2004;revised 26 November 2004;accepted 1 December 2004
Abstract—Titanium tetrachloride-mediated aza Diels–Alder cycloaddition using a chiral diene and an aza dienophile proceeds in
highly diastereoselective manner to form a dehydropiperazic acid derivative in high yield, and diastereoselectivity of the reaction
depends on the quantity of titanium tetrachloride.
Ó 2004 Published by Elsevier Ltd.
1. Introduction
effects of titanium tetrachloride on the diastereoselectiv-
ity of asymmetric aza Diels–Alder cycloaddition. Herein
we report a highly diastereoselective synthesis of (S)-pip-
erazic acid by titanium tetrachloride-mediated aza Diels–
Alder cycloaddition using a chiral diene and an aza dieno-
phile. As a related work, Stoodley and co-workers has
already reported an aza Diels–Alder approach for con-
struction of dehydropiperazic acid derivatives by employ-
ment of a very different strategy.5c,e
Asymmetric hetero Diels–Alder reaction is one of the ver-
satile reactions for access to heterocycles, which consti-
tute the structural skeleton of a large number of natural
products.1 Inour continuing synthetic studies2 on biologi-
cally interesting cyclodepsipeptides, GE3 and polyoxy-
peptins bearing piperazic acid,3,4 we focused on aza
Diels–Alder reaction5 utilizing aza dienophile 3 and chi-
rally modified diene 4 as a key step, which is obviously a
simple and straightforward way for preparation of piper-
azic acid (Fig. 1). In addition, Diels–Alder adduct 5 can be
transformed to not only piperazic acid (1) but also 5-
hydroxypiperazic acid (2), a novel component of polyoxy-
peptin A. In the course of the study, we found remarkable
2. Results and discussion
In the aza Diels–Alder strategy utilizing a chiral diene
we chose a 2,4-pentadienoic acid derivative with EvansÕ
HN
HN
*
R1
N
N
R1
Asymmetric Hetero
N
N
O
OH
+
*
R2
Diels - Alder Reaction
1
R2
O
XC
5
O
XC
OH
3
HN
HN
*
4
Key Compound
*
O
OH
2
Figure 1. Synthetic plan for piperazic acids and 5-hydroxypiperazic acids.
Keywords: Piperazic acid;Titanium chloride;Aza Diels–Alder cycloaddition;Chiral diene.
*
Corresponding author. Tel./fax: +81 43 290 2987;e-mail: hamada@p.chiba-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.12.003

556
K. Makino et al. / Tetrahedron Letters 46 (2005) 555–558
noic acid with pivaloyl chloride in the presence of
PivCl, Et3N, THF
Bn
1.
2.
triethylamine followed by lithium salt 6 of EvansÕ chiral
oxazolidinone provided oxygen- and light-sensitive
chiral diene 4 in 76% yield.
Bn
O
O
N
O
OH
+
-
Li
N
4
O
With the chiral diene available, we examined the aza
Diels–Alder reaction and the results are summarized in
Table 1. 4-Phenyltriazoline-3,5-dione (8, PTAD), an
aza dienophile, was in situ generated by oxidation
of 4-phenylurazole (7) with tert-butylhypochlorite
(1 equiv) at 23 °C for 2 h and used without further puri-
fication.6 In preliminary experiments using the chiral
O
O
78%
6
Scheme 1.
chiral 2-oxazolidinone, which was readily prepared
as illustrated in Scheme 1. Reaction of pent-2,4-die-
Table 1. Lewis acid effects on diastereoselective aza Diels–Alder reactiona
O
O
O
N
N
N
N
N
N
Lewis acid
*
N
*
+
N
N
O
O
CH2Cl2
O
N
+
O
N
O
N
O
O
O
O
O
9a
9b
8
O
O
4
Entry
Lewis acid (equiv)
Conditions
Isolated yieldb (%)
Diastereomeric ratioc
1d
2
AlCl3
––
ꢀ78 °C to rt, 18 h
ꢀ78 °C to rt, 21 h
ꢀ78 °C to rt, 21 h
ꢀ78 °C to rt, 17 h
ꢀ78 °C to rt, 17 h
ꢀ78 °C to rt, 17 h
ꢀ78 °C to rt, 17 h
100
61
50:50
53:47
83:17
84:16
84:16
97:3
3
TiCl4 (1 equiv)
TiCl4 (0.5 equiv)
TiCl4 (2 equiv)
TiCl4 (3 equiv)
TiCl4 (4 equiv)
46
83
4
5
100
95
6
7
57
96:4
a The reaction was carried out by using PTAD (1 equiv), chiral diene (1 equiv), Lewis acid in methylene chloride. PTAD was generated in situ by
reaction of phenylurazole (1 equiv) with tert-butylhypochloride (1 equiv) at 23 °C for 1 h.
b Yield of 9a and 9b.
c Determined by 1H NMR analysis of the crude product.
d The reaction was carried out by using the chiral diene with L-menthol as a chiral auxiliary instead of EvansÕ imide. In the case of TiCl4. Yb(OTf)3 or
FeCl3 as a Lewis acid, the reaction gave the same results as that of AlCl3.
O
O
O
N
N
N
a
b
N
N
NH
NH
+
*
N
N
O
N
O
95%
(97:3)
O
N
O
O
O
O
O
8
7
O
9a
4
O
O
N
N
N
N
HN
HN
*
N
e
N
*
c
d
*
O
O
N
77%
O
95%
94%
OH
HO
O
11
12
10
O
CbzN
CbzN
.
CbzN
CbzN
TFA HN
HN
f
g
h
*
*
*
65%
91%
99%
HO
O
O
HO
HO
13
14
.
(S)-1 TFA
Scheme 2. Synthesis of (S)-piperazic acid. Reagents and conditions: (a) t-BuOCl, CH2Cl2, 0 °C to rt, 2 h;(b) TiCl 4 (3 equiv), CH2Cl2, ꢀ78 °C to rt,
17 h, 95% (97:3);(c) H 2, 5% Pd–C, THF, rt, 15 h, 94%;(d) LiBH 4, THF, H2O, 0 °C, 6 h, 95%;(e) KOH, n-BuOH, relux, 20 h, 77%;(f) CbzCl,
NaHCO3, ether, H2O 64%;(g) TEMPO, NaClO–NaClO 2, CH3CN, phosphate buffer (pH 6.8), 91%;(h) H 2, 5% Pd–C, CH2Cl2, trifluoroacetic acid, 99%.

K. Makino et al. / Tetrahedron Letters 46 (2005) 555–558
557
diene bearing L-menthol ester as a chiral auxiliary, the
reaction was found to proceed almost quantitatively to
give the adducts but with no diastereoselectivity even
in the presence of various Lewis acids (entry 1). To over-
come this problem, we chose titanium tetrachloride as a
Lewis acid and bidentate diene 4 with the chiral oxazo-
lidinone, and explored the Lewis acid effects in aza
Diels–Alder reaction of 4 with 8. As anticipated, non-
catalyzed Diels–Alder reaction gave a diastereomeric
mixture of adducts 9a and 9b in moderate yield with
no diastereoselectivity. The presence of 1 equiv of titanium
tetrachloride, however, showed a good level of diaste-
reoselection (83:17) in moderate yield (46%, entry 3).
Although the stereochemistry of the major product re-
mained unclear, it was unambiguously confirmed after
conversion to the final piperazic acid. After extensive
optimization of the reaction conditions, we found
remarkable Lewis acid effects in that an increased
amount of titanium tetrachloride affects the diastereose-
lectivity favorably. With 0.5–2 equiv of titanium tetra-
chloride, the same levels of diastereoface selectivities
were observed (entry 3–5).7 On the other hand, in the
presence of 3 equiv of titanium tetrachloride (entry 6),
the diastereoselectivity dramatically increased (97:3)
and the cycloadduct 9a, ½aꢁ ꢀ20.3 (c 1.41, CHCl3),
23
D
was obtained in 95% isolated yield. It is interesting that
the aza Diels–Alder reaction using an increased amount
of Lewis acid not only proceeds in high diastereoselec-
tivity but also almost quantitative yield. The use of a lar-
ger amount of titanium tetrachloride (>4 equiv) still
gave high diastereoselectivity (96:4) but caused
decreased yield (57%) (entry 7). Nonetheless, the above
results are noteworthy because the reaction is a success-
ful, rare example of a highly diastereoselective aza
Diels–Alder cycloaddition using the chiral diene and
demonstrates the novel phenomenon that the diastereo-
selectivity and the yield depend on the quantity of
titanium tetrachloride.
The facial selectivity and the requirement of 3 equiv of
titanium tetrachloride (Table 1) in the aza Diels–Alder
cycloaddition can be rationalized as follows (Fig. 2).
In the case of the noncatalyzed reaction, the four con-
formers (A–D) of the chiral diene are present, and
among them, the predominant conformers are A and
B for preventing severe interaction by the A1,3 strain
Non-catalyzed Aza Diels-Alder Reaction
major conformers
si
re
O
N
O
N
O
O
O
O
B
dienophile
O
A
N
N
N
1,3 strain
O
A
8
A1,3 strain
O
O
N
O
O
N
O
O
C
D
Lewis Acid-Catalyzed Aza Diels-Alder Reaction
major conformer
si
A1,3 strain
dienophile
TiCl4
O
N
N
N
O
O
N
N
TiCl4
Cl4Ti
O
O
O
O
O
TiCl4
E
F
Figure 2. Noncatalyzed aza Diels–Alder reaction and Lewis acid-catalyzed Diels–Alder reaction.

558
K. Makino et al. / Tetrahedron Letters 46 (2005) 555–558
on the C–N bond between the diene carboxylic acid
residue and chiral oxazolidinone, which should equally
react with dienophile 8 to afford 9a and 9b, respectively.
In titanium tetrachloride-mediated reaction, 1 equiv of
the Lewis acid serves as the chelator between the two
carbonyl functions in the chiral diene and the presence
of the chelation causes production of two limited con-
formers E and F to be produced. The conformer E
should be dominant in the absence of the A1,3 strain
and reacts with the dienophile activated by the remained
2 equiv of titanium chloride at the si-face in endo-selec-
tive manner to furnish predominantly 9a.
Education, Culture, Sports, Science, and Technology,
Japan.
References and notes
1. Boger, D. L.;Weinreb, S. N.
Hetero Diels–Alder
Methodology in Organic Synthesis;Academic: New York,
1987.
2. (a) Makino, K.;Henmi, Y.;Hamada, Y. Synlett 2002,
613–615;(b) Makino, K.;Suzuki, T.;Awane, S.;Hara, O.;
Hamada, Y. Tetrahedron Lett. 2002, 43, 9391–9395;(c)
Makino, K.;Suzuki, T.;Hamada, Y. Bull. Chem. Soc. Jpn.
2004, 77, 1649–1653;(d) Makino, K.;Goto, T.;Hiroki,
Y.;Hamada, Y. Angew. Chem., Int. Ed. 2004, 43, 882–884,
and references cited therein.
3. For a review on synthesis of piperazic acids, see: Ciufolini,
M. A.;Xi, N. Chem. Soc. Rev. 1998, 27, 437–445.
4. (a) Hale, K. J.;Cai, J.;Delisser, V.;Manariazar, S.
Tetrahedron Lett. 1992, 33, 7613–7616;(b) Aoyagi, Y.;
Saitoh, Y.;Ueno, T.;Horiguchi, M.;Takeya, K. J. Org.
Chem. 2003, 68, 6899–6904;(c) Henmi, Y.;Makino, K.;
With cycloadduct 9a in hand, we investigated synthesis
of piperazic acid (Scheme 2). Hydrogenation of 9a
provided protected piperazic acid 10 in 94% yield. Unfor-
tunately, the direct conversion of 10 to piperazic acid
failed due to insolubility of 10 in reaction media. Several
attempts to obtain 1 under acidic conditions were in vain.
Therefore, we had to employ an indirect route to 1.
Reductive removal of the chiral auxiliary using lithium
borohydride to generate alcohol 11 and following alka-
line hydrolysis using potassium hydroxide in n-butanol
under refluxing conditions gave pyridazinemethanol 12
in good overall yield.5b Protection of two nitrogens with
Yoshitomi, Y.;Hara, O.;Hamada, Y.
Asymmetry 2004, 15, 3477–3481.
Tetrahedron:
5. (a) Bevan, K.;Davies, J. S.;Hassall, C. H.;Morton, R. B.;
Philips, D. A. S. J. Chem. Soc. (C) 1971, 514–522;(b)
Adams, C. E.;Aguilar, D.;Hertel, S.;Knight, W. H.;
Paterson, J. Synth. Commun. 1988, 18, 2225–2231;(c)
Aspinall, I. A.;Cowley, P. M.;Mitchell, G.;Stoodley, R.
J. J. Chem. Soc., Chem. Commun. 1993, 1179–1180;(d)
Bols, M.;Hazell, R. G.;Thomsen, I. B. Chem. Eur. J.
1997, 3, 940–947;(e) Aspinall, I. A.;Cowley, P. M.;
Mitchell, G.;Raynor, C. M.;Stoodley, R. J. J. Chem.
Soc., Perkin Trans. 1 1999, 2591–2599;(f) Liang, X.;Bols,
M. J. Org. Chem. 1999, 64, 8485–8488;(g) Urabe, H.;
Kusaka, K.;Suzuki, D.;Sato, F. Tetrahedron Lett. 2002,
43, 285–289;(h) Zhang, A.;Kan, Y.;Jiang, B. Tetrahedron
2001, 57, 2305–2309.
benzyloxycarbonyl chloride to form alcohol 13,
22
D
½aꢁ +12.6 (c 1.03 CHCl3), and subsequent oxidation
with sodium hypochlorite–sodium chlorite in the pres-
ence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)8
in acetonitrile–phosphate buffer (pH 6.8) afforded di-
23
Cbz-piperazic acid (14), ½aꢁ ꢀ19.6 (c 1.04 CHCl3), in
D
90% yield and in two steps. Final deprotection of 14 in
the presence of trifluoroacetic acid in methylene chloride
furnished piperazic acid trifluoroacetate (1)9 in 30%
overall yield from readily available pent-2,4-dienoic
acid. The absolute configuration of 1 was unambigu-
ously established to be S after its conversion to the
DNP derivative by its chiral HPLC analysis.10
6. t-BuOCl is completely consumed with quantitative pro-
duction of PTAD (see Table 1, entry 5).
7. In the case of 1 equiv of TiCl4, the starting diene
unexpectedly remained in the reaction, and therefore the
yield was moderate.
In conclusion, we have developed a highly diastereose-
lective aza Diels–Alder cycloaddition using a chiral
diene, in which the diastereoselectivity depends on the
quantity of titanium tetrachloride. The facial selectivity
in the aza Diels–Alder cycloaddition can be explained in
terms of the A1,3 strain and the chelation control by tita-
nium tetrachloride. The obtained cycloadduct was effi-
ciently transformed to medicinally important piperazic
acid in 30% overall yield.
8. Zhao, M. L.;Mano, E.;Song, Z.;Tschaen, D. M.;
Grabowski, E. J.;Reider, P. J. J. Org. Chem. 1999, 64,
2564–2566.
9. (S)-1 Trifluoroacetate: mp 149–151 °C (ethyl acetate/
22
ethanol); ½aꢁD +11.1 (c 0.98, MeOH);IR (KBr) 3292,
3080, 2967, 2922, 2836, 2760, 1720, 1664, 1589, 1509, 1421,
1
1232, 1198, 1183, 1130, 1082, 916, 842, 801, 725 cmꢀ1; H
NMR (400 MHz, D2O): d 1.85–1.95 (m, 3H), 2.13–2.18
(m, 1H), 3.14–3.21 (m, 1H), 3.27 (m, 1H), 3.89 (m, 1H);
13C NMR (100 MHz, DMSO-d6): d 20.22, 24.91, 43.99,
55.86, 117.12 (q, J = 297.8 Hz), 158.47 (q, J = 31.3 Hz),
171.52. Anal. Calcd for C7H11F3N2O4: C, 34.43;H, 4.54;
N, 11.47. Found: C, 34.32;H, 4.46;N, 11.38.
Acknowledgements
10. Hale, K. J.;Cai, J.;Delisser, V.;Manariazar, S.;Peak, S.
A.;Bhatia, G. S.;Collins, T. C.;Jogiya, N.
1996, 52, 1047–1068.
This work was financially supported in part by a Grant-
in-Aid for Scientific Research (B) from the Ministry of
Tetrahedron