Practical synthesis of (2S,3R)-3-hydroxy-3-methylproline, a constituent of papuamides, using a diastereoselective tandem Michael-aldol reaction

Article abstract of DOI:10.1016/j.tetlet.2005.09.111

(2S,3R)-3-Hydroxy-3-methylproline, a constituent of cyclodepsipeptides polyoxypeptins A and B, was efficiently synthesized by lithium chloride-induced diastereoselective tandem Michael-aldol reaction using methyl vinyl ketone and N-1-naphthylsulfonylglyci

Full text of DOI:10.1016/j.tetlet.2005.09.111

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8159–8162
Practical synthesis of (2S,3R)-3-hydroxy-3-methylproline,
a constituent of papuamides, using a diastereoselective
tandem Michael-aldol reaction
Kazuishi Makino, Eri Nagata and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 22 August 2005; revised 14 September 2005; accepted 20 September 2005
Available online 6 October 2005
Abstract—(2S,3R)-3-Hydroxy-3-methylproline, a constituent of cyclodepsipeptides polyoxypeptins A and B, was efficiently synthe-
sized by lithium chloride-induced diastereoselective tandem Michael-aldol reaction using methyl vinyl ketone and N-1-naph-
thylsulfonylglycine (R)-binaphthyl ester and subsequent hydrolysis of the product in 39% overall yield and five steps.
Ó 2005 Elsevier Ltd. All rights reserved.
The naturally occurring (2S,3R)-3-hydroxy-3-methyl-
proline (HOMePro) is found as a unique constituent of
apoptosis-inducing cyclodepsipeptide polyoxypeptins A
and B, novel 19-membered cyclic hexadepsipeptides, iso-
lated from the culture broth of Streptomyces species by
tion with our efforts to synthesize these cyclodepsipe-
tides and relatives, we needed large quantities of the
(2S,3R)-3-hydroxy-3-methylproline. Synthesis of the 3-
2
hydroxy-3-methylproline has been already reported by
2
e,h,3
several groups including us.
However, these meth-
1
Umezawa and co-workers in 1998 (Fig. 1). In connec-
ods require multi-steps and the overall yields are unsat-
isfactory in most cases. Thus, expedient synthesis of this
unique component is still required. Recently, we have
demonstrated that the racemic 3-hydroxy-3-methylpro-
OH
O
line is synthesized by the tandem Michael-aldol reac-
2h,4,5
tion
using methyl vinyl ketone and N-tosylglycine
OH
O
H
methyl ester in the presence of a base as shown in
Scheme 1 and the resulting N-Ts-3-hydroxy-3-methyl-
proline is resolved by use of (ꢀ)-cinchonidine. Inciden-
tally, the tandem reaction to a diastereomeric mixture
of HOMePro derivatives was originally investigated by
NH HN
N
H
O
H
H
HO
O
O
O
N
6
O
O
two groups for pyrrole synthesis without stereochemi-
OH
N
H
cal assignment. We describe here chiral auxiliary-medi-
ated asymmetric synthesis of (2S,3R)-3-hydroxy-3-
methyl proline by lithium chloride-induced diastereo-
N
R
HN
N
H
O
OH
R = OH:Polyoxypeptin A
R = H: Polyoxypeptin B
O
Figure 1. Structure of polyoxypeptins.
Michael
OH
reaction
Aldol reaction
OR*
Keywords: (2S,3R)-3-Hydroxy-3-methylproline; Tandem Michael-
aldol reaction; Polyoxypeptin A; Methyl vinyl ketone; Glycine
OH
N
H
HN
O
(
R)-binaphthyl ester.
P
O
1
*
Corresponding author. Tel.: +81432902987; fax: +81432902987;
e-mail: hamada@p.chiba-u.ac.jp
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.111

8160
K. Makino et al. / Tetrahedron Letters 46 (2005) 8159–8162
selective tandem Michael-aldol reaction using chiral
glycine esters as a key step.
the desired isomer in a ratio of 91:8:1:0 and in 71% yield
(entry 4). The N-aromatic group in the N-sulfonamide
proved to serve face-selectively in the intramolecular
aldol condensation. Using the optimized conditions, we
carried out synthesis of natural (2S,3R)-3-hydroxy-3-
methylproline in a laboratory scale (20 mmol) as shown
in Scheme 2. Thus, N-1-naphthylsulfonyl-glycine (6) was
esterified with (R)-binaphthol by the acid chloride meth-
od in two steps and the thus-obtained chiral ester was
subjected to the tandem Michael-aldol reaction under
the conditions described above to afford (2S,3R,aR)-3-
hydroxy-3-methylproline ester 3d as a major product
in 77% yield and the same diastereomeric ratio. The
product (2S,3R,aR)-3d without purification was hydro-
lyzed with a mixture of concentrated hydrochloric
acid–acetic acid–water (1.2:2.8:1) at 95 °C for 24 h. Puri-
fication of the crude product using ion-exchange resin
furnished the (2S,3R)-3-hydroxy-3-methylproline with
concomitant diastereomers. Pure 1 was obtained after
conversion to the toluenesulfonic acid salt by crystalliza-
Our synthetic plan is illustrated in Scheme 1, in which
we envisaged that asymmetric synthesis using the chiral
auxiliary in the ester function might be a practical solu-
tion for a large-scale synthesis of (2S,3R)-3-hydroxy-3-
methylproline. Thus, we chose binaphthol as a chiral
7
auxiliary. Binaphthyl monoester 2a of N-tosylglycine
was prepared by careful treatment of N-tosylglycyl chlo-
ride with (S)-binaphthol in the presence of pyridine at
8
0
°C. The diastereoselective tandem Michael-aldol reac-
tion of 2a was extensively investigated and is summa-
rized in Table 1. The reaction in the presence of
diazabicyclo[5.4.0]undecane (DBU) as a base in tetrahy-
drofuran stereorandomly proceeded to give four dia-
stereomers (entry 1). So we examined additive effects.
Addition of 1equiv of lithium chloride (LiCl), however,
impressively improved the diastereomeric ratio to
9
7
7:20:3:0 (entry 2). The stereostructure of the major
1
1
isomer 3a was unambiguously determined to be unnatu-
tion from 2-propanol in 68% yield. The overall yield of
(2S,3R)-3-hydroxy-3-methylproline (1) as the toluene-
sulfonic acid salts from 6 was 39%.
1
0
ral 2R,3S after conversion to the prolinol derivative 5
with lithium aluminum hydride by comparison with the
2
e
authentic sample. With this encouraging result in
hand, we surveyed further additive effects of several
metal salts. Most of the examined salts resulted in no reac-
ion or had no positive effect for the diastereoselectivity.
Calcium chloride was found to also affect the diastereo-
selectivity but to have no effect on the chemical yield
For elucidation of the reaction mechanism, we first
examined whether the reaction proceeds under kinetic
or thermodynamic control. Thus, a 98:2 mixture of
(2R,3S,aS)-3a and (2S,3R,aS)-4a was treated with
DBU (0.2 equiv) and lithium chloride (1equiv) at
ꢀ15 °C for 65 h and the recovered material showed no
change in the diastereomeric ratio. Therefore, the
reaction proved to be kinetic. From the experiments de-
scribed above it is apparent that the diastereoselectivity
is attributed to the presence of lithium chloride and the
N-protecting group. Although the origin of this interest-
ing lithium chloride-induced diastereoselectivity is not
clear at present, lithium chloride seems to play an
(
entry 5). From the view point of chemical yield we
chose lithium chloride as the additive and next examined
effects of the N-protecting group in the glycine deriva-
tive as shown in Table 2. The reaction was conducted
in the presence of DBU (0.2 equiv) and lithium chloride
(
1equiv) at ꢀ15 °C for 65 h. The N-1-naphthylsulfonyl-
glycine (S)-binaphthyl ester (2d) was the most efficient in
terms of diastereoselectivity and chemical yield to afford
a
Table 1.
OH
OH
anti
DBU (0.2 eq)
O
additive (1.0 eq)
HO
+
HO
O
+
+
OR*
OR*
diastereomers
N
N
O
THF
conditions
R* =
Ts
Ts
TsHN
O
O
O
(2S,3R,aS)-4a
(
2R,3S,aS)-3a
(
S)-2a
syn
syn
OH
OH
Ts
2S,3S)-5
N
(
Entry
Additive
Temperature (°C)
Time (d)
Yield (%)
18
3a:4a
syn
23:30
77:20
29:42
27:44
89:9
anti
1
2
3
4
5
––
ꢀ71 to rt
ꢀ71to rt
ꢀ15
1
1
>2
>2
>2
30:17
3:0
21:8
22:7
2:0
LiCl
NaCl
KCl
44
4
6
6
ꢀ15
CaCl
2
ꢀ15
a
2 2 3 3 2 4 4
Addition of other metal salts such as MgCl , ZnCl , FeCl , LaCl Æ7H O, TiCl , and Ti(O-iPr) gave no Michael-aldol adduct.

K. Makino et al. / Tetrahedron Letters 46 (2005) 8159–8162
8161
Table 2.
OH
DBU (0.2 eq)
LiCl (1.0 eq)
OH
OR*
O
anti
diastereomers
HO
O
+
+
HO
O
+
OR*
N
N
THF, -15 ˚C,
65 h
O
R* =
O
HN
S
S
S
O
O
O
O
R
R
O
O O
R
(2R,3S,aS)-3
(2S,3R,aS)-4
(
S)-2a: R = 4-CH3C6H4
syn
2
2
2
2
b: R = 4-CH3OC6H4
syn
c: R = CH3
d: R = 1-naphthyl
e: R = 2-naphthyl
Entry
R
Yield (%)
Ratio of diastereomers 3:4
syn
anti
1
2
3
4
5
4-CH
3
3
C
6
H
4
56
45
19
71
84:16
87:13
58:42
91:8
0:0
0:0
0:0
1:0
4-CH
CH
1-Naphthyl
OC
6
H
4
3
2-Naphthyl 5
62 1: 08 3:1
HO
O
OH
HN
HO HO
1
. PCl5 (1.1 eq), Et2O,
MVK (1.5 eq)
HN
O
S
O O
0 ˚C to rt, 8 h
O
O
S
O O
DBU (0.2 eq)
LiCl (1.0 eq)
THF (0.25 M)
-15 ˚C, 24 h
2
. (R)-BINOL (1.1 eq),
pyridine / THF (1 / 1)
N
O
0
˚C to rt, 10 h
O
S
O
74% (2 steps)
77%
6
(R)-2d
91 : 8 : 1 : 0
HO
HO
HCl, AcOH, H2O
5 ˚C, 24 h
OH
OH
TsOH
(2S,3R,aR)-3d
TsOH, MeOH
9
major isomer
then crystallized
from i-PrOH
then Dowex 50Wx4
quant.
N
H
O
N
H
O
(
2S,3R)-1
68%
>99% ee
Scheme 2. Diastereoselective synthesis of (2S,3R)-3-hydroxy-3-methylproline.
important role in Z-selective formation of the glycine
enolate with the N-sulfonamide function and syn-selec-
tive aldol reaction.
of Education, Culture, Sports, Science and Technology
(MEXT).
In conclusion, we have succeeded in efficient and practi-
cal asymmetric synthesis of (2S,3R)-3-hydroxy-3-meth-
ylproline in five steps and 39% overall yield using the
lithium chloride-induced diastereoselective tandem
Michael-aldol reaction. In this reaction, lithium chloride
proved to play an important role in the diastereoselec-
tive aldol reaction. Further investigation directed
toward total synthesis of polyoxypeptins is underway
in this laboratory.
References and notes
1
2
. (a) Umezawa, K.; Nakazawa, K.; Uemura, T.; Ikeda, Y.;
Kondo, S.; Naganawa, H.; Kinoshita, N.; Hashizume, H.;
Hamada, M.; Takeuchi, T.; Ohba, S. Tetrahedron Lett.
1998, 39, 1389–1392; (b) Umezawa, K.; Nakazawa, K.;
Ikeda, Y.; Naganawa, H.; Kondo, S. J. Org. Chem. 1999,
6
4, 3034–3038.
. (a) Okamoto, N.; Hara, O.; Makino, K.; Hamada, Y.
Tetrahedron: Asymmetry 2001, 12, 1353–1358; (b) Mak-
ino, K.; Okamoto, N.; Hara, O.; Hamada, Y. Tetra-
hedron: Asymmetry 2001, 12, 1757–1762; (c) Makino, K.;
Henmi, Y.; Hamada, Y. Synlett 2002, 613–615; (d)
Okamoto, N.; Hara, O.; Makino, K.; Hamada, Y.
J. Org. Chem. 2002, 67, 9210–9215; (e) Makino, K.;
Kondoh, A.; Hamada, Y. Tetrahedron Lett. 2002, 43,
Acknowledgements
This work was supported by Grant-in-Aid for Scientific
Research on Priority Areas 17035015 from The Ministry

8162
K. Makino et al. / Tetrahedron Letters 46 (2005) 8159–8162
4
695–4698; (f) Makino, K.; Suzuki, T.; Awane, S.; Hara,
O.; Hamada, Y. Tetrahedron Lett. 2002, 43, 9391–
395; (g) Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y.
6. (a) Terry, W. G.; Jackson, A. H.; Kenner, G. W.; Komis,
G. J. Chem. Soc. 1965, 4389; (b) Lash, T. D.; Hoehner, M.
C. J. Heterocycl. Chem. 1991, 28, 1671.
9
Angew. Chem., Int. Ed. 2004, 43, 882–884; (h) Makino, K.;
Suzuki, T.; Hamada, Y. Bull. Chem. Soc. Jpn. 2004, 77,
7. For a review on use of binaphthol as chiral auxiliary, see:
Brunel, J. M. Chem. Rev. 2005, 105, 857–897.
1
653–1694; (i) Henmi, Y.; Makino, K.; Yoshitomi, Y.;
Hara, O.; Hamada, Y. Tetrahedron: Asymmetry 2004, 15,
477–3481; (j) Makino, K.; Henmi, Y.; Terasawa, M.;
Hara, O.; Hamada, Y. Tetrahedron Lett. 2005, 46, 555–
58.
8. Tanaka, K.; Ahn, M.; Watanabe, Y.; Fuji, K. Tetra-
hedron: Asymmetry 1996, 7, 1771–1782.
3
9. The authentic mixture (53:44:3:0) was prepared by con-
densation of racemic N-Ts-3-hydroxy-3-methylproline
0
5
(syn:anti = 95:5) with (S)-BINOL using N,N -dicyclo-
3
. (a) Noguchi, Y.; Uchihiro, H.; Yamada, T.; Kobayashi, S.
Tetrahedron Lett. 2001, 42, 5253–5256; (b) Qin, D.-G.;
Zha, H.-Y.; Yao, Z.-J. J. Org. Chem. 2002, 67, 1038–1040;
hexylcarbodiimide and N,N-dimethylaminopyridine in
methylene chloride in 51% yield. Respective identifica-
1
tion of the major two isomers as 3a and 4a by the
H
(
c) Shen, J.-W.; Qin, D.-G.; Zhang, H.-W.; Yao, Z.-J.
NMR spectrum of the mixture determined both syn-
J. Org. Chem. 2003, 68, 7479–7484.
. For excellent reviews of tandem reactions and Michael-
aldol reactions, see: (a) Tietze, L. F. Chem. Rev. 1996, 96,
stereochemistry.
2
D
3
4
5
10. (2S,3S)-Isomer: ½aꢁ +88 (c 1.10, MeOH). The known
(2R,3R)-N-Ts-3-hydroxy-3-methylprolinol derived from
2
D
3
2e
115; (b) Takasu, K. Yakugaku Zasshi 2001, 121, 887.
L-threonine: ½aꢁ ꢀ88.5 (c 1.09, MeOH).
. (a) Makino, K.; Katano, T.; Takiguchi, Y.; Hara, O.;
Hamada, Y. Tetrahedron Lett. 2003, 44, 8925–8929; (b)
Hara, O.; Sugimoto, K.; Makino, K.; Hamada, Y. Synlett
11. (2S,3R)-3-Hydroxy-3-methylproline toluenesulfonic acid
23
D
salts (>99% ee): mp 198–199 °C (2-propanol); ½aꢁ ꢀ9.7 (c
0.53, H O). Anal. Calcd for C H NO S: C, 49.26; H,
2
13 19
6
2004, 1625–1627.
6.03; N, 4.41. Found: C, 49.21; H, 5.98; N, 4.43.