Organocatalytic synthesis of (2S,3R)-3-hydroxy-3-methyl-proline (OHMePro), a component of polyoxypeptins, and relatives using OHMePro itself as a catalyst

Article abstract of DOI:10.1021/ol0706004

An efficient synthesis of (2S,3R)-3-hydroxy-3-methylproline (OHMePro), a component of polyoxypeptins, and relatives was achieved, in which an intramolecular asymmetric aldol reaction of the ketoaldehyde using OHMePro itself as an organocatalyst constitute

Full text of DOI:10.1021/ol0706004

ORGANIC
LETTERS
2007
Vol. 9, No. 13
2457-2460
Organocatalytic Synthesis of
(2S,3R)-3-Hydroxy-3-methyl-proline
(OHMePro), a Component of
Polyoxypeptins, and Relatives Using
OHMePro Itself as a Catalyst
Yayoi Yoshitomi, Kazuishi Makino, and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, Yayoi-cho, Inage-ku,
Chiba 263-8522, Japan
hamada@p.chiba-u.ac.jp
Received March 12, 2007
ABSTRACT
An efficient synthesis of (2S,3R)-3-hydroxy-3-methylproline (OHMePro), a component of polyoxypeptins, and relatives was achieved, in which
an intramolecular asymmetric aldol reaction of the ketoaldehyde using OHMePro itself as an organocatalyst constitutes a key step.
Organocatalysis has become a rapidly expanding area in
modern organic synthesis during the past few years, and
many stereoselective reactions, asymmetric aldol reactions,
asymmetric Mannich reactions, asymmetric aminations, and
asymmetric oxidations, catalyzed by proline or its analogues
have been reported to date.1 In particular, organocatalytic
asymmetric aldol reactions have attracted attention in view
of the facile and highly stereoselective formation of the
carbon-carbon bond and the efficient construction of the
cyclic framework.2 In the course of synthetic studies on
polyoxypeptins as shown in Figure 1,3-5 we have discovered
that (2S,3R)-3-hydroxy-3-methylproline (OHMePro, 3), one
of the required components, serves as an efficient catalyst
for intramolecular asymmetric aldol reaction leading to the
(2) For examples of organocatalytic asymmetric intramolecular aldol
reactions: (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed.
Engl. 1971, 10, 496-497. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem.
1974, 39, 1615-1621. (c) Woodward, R. B.; Logusch, E.; Nambiar, K. P.;
Sakan, K.; Ward, D. E.; Au-Yeung, B.-W.; Balaram, P.; Browne, L. J.;
Card, P. J.; Chen, C. H.; Cheˆnevert, R. B.; Fliri, A.; Frobel, K.; Gais, H.-
J.; Garratt, D. G.; Hayakawa, K.; Heggie, W.; Hesson, D. P.; Hoppe, D.;
Hoppe, I.; Hyatt, J. A.; Ikeda, D.; Jacobi, P. A.; Kim, K. S.; Kobuke, Y.;
Kojima, K.; Krowicki, K.; Lee, V. J.; Leutert, T.; Malchenko, S.; Martens,
J.; Matthews, R. S.; Ong, B. S.; Press, J. B.; Rajan Babu, T. V.; Rousseau,
G.; Sauter, H. M.; Suzuki, M.; Tatsuta, K.; Tolbert, L. M.; Truesdale, E.
A.; Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella, A. T.; Vladuchick, W. C.;
Wade, P. A.; Williams, R. M.; Wong, H. N.-C. J. Am. Chem. Soc. 1981,
103, 3210-3213. (d) Agami, C.; Platzer, N.; Puchot, C.; Sevestre, H.
Tetrahedron 1987, 43, 1091-1098. (e) Pidathala, C.; Hoang, L.; Vignola,
N.; List, B. Angew. Chem., Int. Ed. 2003, 42, 2785-2788. (f) Clemente, F.
R.; Houk, K. N. J. Am. Chem. Soc. 2005, 127, 11294-11302.
(1) (a) For recent reviews on asymmetric organocatalytic reactions, see:
List, B. Synlett 2001, 1675-1686. (b) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2001, 40, 3726-3748. (c) Jarvo, E. R.; Miller, S. J.
Tetrahedron 2002, 58, 2481-2495. (d) List, B. Tetrahedron 2002, 58,
5573-5590. (e) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5138-5175. (f) Houk, K. N.; List, B., Eds. Acc. Chem. Res. 2004, 37, 487-
631. (g) List, B.; Bolm, C., Eds. AdV. Synth. Catal. 2004, 346, 1007-
1249. (h) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis: From
Bio-mimetic Concepts to Applications in Asymmetric Synthesis; Wiley-
VCH: Weinheim, 2005. (i) Kocovsky, P.; Malkov, A. V., Eds. Tetrahedron
2006, 62, 243-502.
10.1021/ol0706004 CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/23/2007

Scheme 1. Synthetic Strategy
metric carbons containing a quaternary stereogenic center.
Several proline-catalyzed intramolecular asymmetric aldol
reactions of dicarbonyl compounds have been reported.2,7 To
our knowledge, however, there is no report for cyclization
leading to the pyrrolidine ring using intramolecular proline-
catalyzed aldol reaction.8
Ketoaldehyde 8a was easily prepared with excellent purity
by a three-step sequence of the usual manipulations in 77%
overall yield (Scheme 2): (1) conjugate addition of N-
Figure 1. Structure of polyoxypeptins.
OHMePro precursor. We would like to report here an
efficient synthesis of (2S,3R)-OHMePro and its relatives
using OHMePro-catalyzed intramolecular asymmetric aldol
reaction. We have already developed several methods for
the synthesis of (2S,3R)-OHMePro,5,6 including diastereo-
selective SmI2-mediated cyclization,5a optical resolution of
racemic N-tosyl-OHMePro-OH using (-)-cinchonidine,5b
and tandem Michael-aldol reaction between the glycine
(R)-binaphthyl ester derivative and methyl vinyl ketone.5c
These methods, however, are based on diastereoselective
synthesis or resolution and have the drawback of requiring
more than 1 equiv of a chiral auxiliary. Thus, a catalytic
asymmetric synthesis using a small amount of a chiral source
would become an ideal method for preparation of (2S,3R)-
OHMePro.
Scheme 2. Synthesis of Substrate 8a
Our strategy is illustrated in Scheme 1, in which we
envisaged that a proline-catalyzed intramolecular asymmetric
aldol reaction of the ketoaldehyde should directly produce
the (2S,3R)-OHMePro backbone with two continuous asym-
tosylallylamide 5 to methyl vinyl ketone (4) in the presence
of the quaternary ammonium salt, (2) dihydroxylation of the
allylic function with osmium tetroxide-N-methylmorpholine
N-oxide, and (3) oxidative cleavage of the resulting 1,2-diol
with sodium periodate in THF-phosphate buffer (pH 7). The
thus-obtained ketoaldehyde 8a was prone to cyclize under
the conditions of silica gel chromatographic purification but
could be directly used in the next aldol reaction without any
further purification. The yields and stereoselectivities were
determined after in situ reduction of the crude aldol products
with NaBH4 (Table 1). Initially, the intramolecular aldol
reaction of 8a using (S)-proline (30 mol %) was investigated.
The reaction in methylene chloride or acetonitrile proceeded
smoothly to give a diastereomeric mixture of the products
in good yield but with no enantioselectivity (entries 1 and
2). The syn and anti stereochemistry of the products has been
determined according to our previous report.5c On the other
hand, the use of THF as the solvent was found to enhance
the enantioselectivity (49% ee, entry 3). From our interest
in the potential of (2S,3R)-OHMePro (3) , our final product,
as the chiral organocatalyst, we applied (2S,3R)-3 to this
intramolecular aldol reaction. To our delight, the reaction
(3) Isolation and structure determination of polyoxypeptins: (a) Umeza-
wa, 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, 64, 3034-3038.
(4) (a) Makino, K.; Okamoto, N.; Hara, O.; Hamada, Y. Tetrahedron:
Asymmetry 2001, 12, 1757-1762. (b) Makino, K.; Suzuki, T.; Awane, S.;
Hara, O.; Hamada, Y. Tetrahedron Lett. 2002, 43, 9391-9395. (c) Makino,
K.; Goto, T.; Hiroki, Y.; Hamada, Y. Angew. Chem., Int. Ed. 2004, 43,
882-884. (d) Henmi, Y.; Makino, K.; Yoshitomi, Y.; Hara, O.; Hamada,
Y. Tetrahedron: Asymmetry 2004, 15, 3477-3481. (e) Makino, K.; Henmi,
Y.; Terasawa, M.; Hara, O.; Hamada, Y. Tetrahedron Lett. 2005, 46, 555-
558. (f) Makino, K.; Jiang, H.; Suzuki, T.; Hamada, Y. Tetrahedron:
Asymmetry 2006, 17, 1644-1649.
(5) Synthesis of (2S,3R)-3-hydroxy-3-methylproline by us: (a) Makino,
K.; Kondoh, A.; Hamada, Y. Tetrahedron Lett. 2002, 43, 4695-4698. (b)
Makino, K.; Suzuki, T.; Hamada, Y. Bull. Chem. Soc. Jpn. 2004, 77, 1649-
1653. (c) Makino, K.; Nagata, E.; Hamada, Y. Tetrahedron Lett. 2005, 46,
8159-8162.
(6) Synthesis of (2S,3R)-3-hydroxy-3-methylproline by other groups: (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. (c) Shen, J.-W.; Qin, D.-G.; Zhang, H.-W.; Yao,
Z.-J. J. Org. Chem. 2003, 68, 7479-7484. (d) Merino, P.; Revuelta, J.;
Tejero, T.; Cicchi, S.; Goti, A. Eur. J. Org. Chem. 2004, 776-782. (e)
Davis, F. A.; Ramachandar, T.; Liu, H. Org. Lett. 2004, 6, 3393-3395. (f)
Haddad, M.; Larcheveˆque, M. Tetrahedron: Asymmetry 2005, 16, 2243-
2247. (g) Chen, Z.; Ye, T. Synlett 2005, 2781-2785.
2458
Org. Lett., Vol. 9, No. 13, 2007

and enantioselectivities (entry 6). The catalyst amount can
be reduced from 30 to 5 mol % without any loss of the
stereoselectivity or chemical yield, and even in the use of 5
mol % of (2S,3R)-OHMePro, high enantioselectivity was
observed (entries 7 and 8).
Table 1. Optimization of the Catalytic Asymmetric
Intramolecular Aldol Reaction
Encouraged by these results, we further explored the scope
of this aldol reaction under the same reaction conditions
(Table 2). The N-tosyl (R1 ) Ts) group was the most suitable
catalyst
(mol %)
yield syn/
%
entry
solvent
H2O
(%)a antib eec
Table 2. Asymmetric Intramolecular Aldol Reaction Catalyzed
by (2S,3R)-3-Hydroxy-3-methylproline (3)
1
2
3
4
5
6
7
8
(S)-proline (30) CH2Cl2
(S)-proline (30) CH3CN
(S)-proline (30) THF
(2S,3R)-3 (30)
(2S,3R)-3 (30)
(2S,3R)-3 (30)
(2S,3R)-3 (10)
(2S,3R)-3 (5)
-
-
-
-
79
59
58
64
69
79
73
73
64:36
67:33
78:22 49
95:5
96:4
92:8
95:5
95:5
1
4
THF
THF
THF
THF
THF
62
85
81
89
88
5 equiv
10 vol %
5 equiv
5 equiv
time yield syn/
(h) (%)a antib
%
eec
entry
8
R1
R2
a Isolated yield. b Determined by 1H NMR. cDetermined by HPLC
analysis.
1
2
3
4
5
6
8a Ts
8b Cbz
8c SO2Bn -CH3
8d Ts
8e Ts
8f Ts
-CH3
-CH3
5.5 73
95:5 88 (9)d
89:11 80
91:9 73
48
24
24
49
90
74
-CH2CH3
-(CH2)2CH(CH3)2 24
Ph 24
90:10 80
gave (2R,3R)-9a as a major stereoisomer in excellent yield,
syn selectivity, and moderate enantioselectivity (64% yield,
syn/anti ) 95:5, 62% ee, entry 4). Interestingly, the thus-
obtained (2R,3R)-9a had the same stereochemistry with the
catalyst, which means that the reaction amplifies the final
product, (2S,3R)-OHMePro, by the catalysis of (2S,3R)-
HOMePro itself. Although the stereoselectivity of the reac-
tion was still moderate, further enhancement of the stereo-
induction was achieved when 5 equiv of water was added
to the reaction mixture. The enantioselectivity was improved
from 62% to 85% ee (entry 5). Further addition of water
(10 vol %) had a slightly negative effect on the diastereo-
67 >99:1 76
30 nd 30
a Isolated yield. bDetermined by 1H NMR. cDetermined by chiral HPLC.
d% ee of the anti isomer.
as the N-protective group in terms of diastereo- and enantio-
selectivity compared with the benzyloxycarbonyl (Cbz) and
benzylsulfonyl (BnSO2) groups (entries 1-3). The intra-
molecular aldol reaction of other alkyl ketones 8d (R2 )
Et) and 8e (R2 ) (CH2)2CH(CH3)2) also proceeded with good
yields and stereoselectivities (entries 4 and 5). The introduc-
tion of an aryl group (8f: R2 ) Ph) instead of an alkyl group,
however, decreased the yield and enantioselectivity (entry
6).
A rational explanation for the syn selectivity of this unique
reaction catalyzed by proline and OHMePro is difficult at
the present. However, we believe that the reaction proceeds
through the ordinary cyclic chairlike transition state as shown
in Figure 2. The reason for the excellent selectivity of
OHMePro might derive from the 3-hydroxy-assisted rigid
bicyclic conformation, which might serve to enhance the
stereoselectivities.
(7) For examples of organocatalytic asymmetric intermolecular aldol
reactions: (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386-
7387. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F. J. Am. Chem. Soc.
2001, 123, 5260-5267. (c) List, B.; Pojarliev, P.; Castello, C. Org. Lett.
2001, 3, 573-575. (d) Dickerson, T. J.; Janda, K. D. J. Am. Chem. Soc.
2002, 124, 3220-3221. (e) Northrup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 6798-6799. (f) Chowdari, N. S.; Ramachary, D.
B.; Cordova, A.; Barbas, C. F. Tetrahedron Lett. 2002, 43, 9591-9595.
(g) Cordova, A.; Notz, W.; Barbas, C. F. Chem. Commun. 2002, 3024-
3025. (h) Sekiguchi, Y.; Sasaoka, A.; Shimomoto, A.; Fujioka, S.; Kotsuki,
Y. Synlett 2003, 11, 1655-1658. (i) Nyberg, A. I.; Usano, A.; Pihko, P.
M. Synlett 2004, 1891-1896. (j) Cordova, A. Tetrahedron Lett. 2004, 45,
3949-3952. (k) Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, M. Tetrahedron
Lett. 2004, 45, 4353-4356. (l) Ward, D. E.; Jheengut, V. Tetrahedron Lett.
2004, 45, 8347-8350. (m) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. OÄ . Angew. Chem., Int. Ed. 2004, 43, 1983-1986. (n) Wang,
G.-W.; Zhang, Z.; Dong, Y.-W. Org. Process Res. DeV. 2004, 8, 18-21.
(o) Ward, D. E.; Jheengut, V.; Akinnusi, O. T. Org. Lett. 2005, 7, 1181-
1184. (p) Wu, Y.-S.; Chen, Y.; Deng, D.-S.; Cai, J. Synlett 2005, 1627-
1629. (q) Sun, B.; Peng, L.; Chen, X.; Li, Y.; Li, Y.; Yamasaki, K.
Tetrahedron: Asymmetry 2005, 16, 1305-1307. (r) Enders, D.; Grondal,
C. Angew. Chem., Int. Ed. 2005, 44, 1210-1212. (s) Casas, J.; Engqvist,
M.; Ibrahem, I.; Kaynak, B.; Cordova, A. Angew. Chem., Int. Ed. 2005,
44, 1343-1345. (t) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F. J. Am. Chem. Soc. 2006, 128, 734-735. (u)
Ikishima, H.; Sekiguchi, Y.; Ichikawa, Y.; Kotsuki, H. Tetrahedron 2006,
62, 311-316. (v) Pihko, P. M.; Laurikainen, K. M.; Usano, A.; Nyberg, A.
I.; Kaavi, J. A. Tetrahedron 2006, 62, 317-328. (w) Grondal, C.; Enders,
D. Tetrahedron 2006, 62, 329-337.
(8) For other examples of construction of a five-membered ring using
proline-catalyzed reactions, see: (a) ref 2e. (b) Vignola, N.; List, B. J. Am.
Chem. Soc. 2004, 126, 450-451. (c) Fonseca, M. T. H.; List, B. Angew.
Chem., Int. Ed. 2004, 43, 3958-3960.
Figure 2. Plausible mechanism.
Org. Lett., Vol. 9, No. 13, 2007
2459

We next investigated the conversion to (2S,3R)-3-hydroxy-
3-methylproline from the aldol product (Scheme 3). After
recrystallized from ethyl acetate and n-hexane to provide
optically enriched 11 with 98% ee. The final transformation
of 11 to (2S,3R)-OHMePro (3) was achieved according to
our previous report.5b
In conclusion, we have found that (2S,3R)-3-hydroxy-3-
methylproline is an efficient organocatalyst for intramolecular
asymmetric aldol reaction and have succeeded in an efficient
synthesis of (2S,3R)-OHMePro with two continuous asym-
metric carbons containing a quaternary stereogenic center
using this reaction. This approach enables us to obtain large
quantities of (2S,3R)-OHMePro required for synthesis of
polyoxypeptins and elucidation of OHMePro-catalyzed or-
ganocatalysis and will also be useful for preparing a variety
of enantiomerically enriched 3-substituted proline derivatives.
Scheme 3. Synthesis of (2S,3R)-OHMePro from 8a
Acknowledgment. This work was financially supported
in part by a Grant-in-Aid for Scientific Research on Priority
Areas (17035015) from The Ministry of Education, Culture,
Sports, Science and Technology (MEXT).
the asymmetric intramolecular aldol reaction of 8a using 5
mol % of (2S,3R)-3 in THF (0.2 M) in the presence of water
(5 equiv), the obtained crude product was oxidized to
carboxylic acid 10 with sodium chlorite. The resulting acid
10 was converted to â-lactone 11 for the optical purification
in 66% yield with 88% ee in three steps, which was
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0706004
2460
Org. Lett., Vol. 9, No. 13, 2007