Regioselective Baeyer-Villiger lactonization of 2-substituted pyrrolidin-4-one. Synthesis of statine

Article abstract of DOI:10.1016/j.tetlet.2006.05.027

Nine 2-substituted pyrrolidin-4-ones 4a-i were obtained via a series of functional group transformation of known prolinol 5 by facile six kinds of methodologies. The target structure of 1,3-amino alcohols 2a-i was constructed in the regioselective Baeyer-

Full text of DOI:10.1016/j.tetlet.2006.05.027

Tetrahedron Letters 47 (2006) 4865–4870
Regioselective Baeyer–Villiger lactonization of 2-substituted
pyrrolidin-4-one. Synthesis of statine
Meng-Yang Chang,a,* Yung-Hua Kunga and Shui-Tein Chenb
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan
bInstitute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan
Received 22 March 2006; revised 28 April 2006; accepted 8 May 2006
Available online 30 May 2006
Abstract—Nine 2-substituted pyrrolidin-4-ones 4a–i were obtained via a series of functional group transformation of known pro-
linol 5 by facile six kinds of methodologies. The target structure of 1,3-amino alcohols 2a–i was constructed in the regioselective
Baeyer–Villiger lactonization of ketones 4a–i and reduction of the resulting 4-substituted tetrahydro-1,3-oxazin-6-ones 3a–i. A
new and straightforward synthesis of (3S,4S)-statine (6) has been established starting from trans-(2S,4R)-4-hydroxyproline (1).
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Amino alcohols are an important class of compounds.
In addition to their use as auxiliaries and ligands, the
biological activities associated with this functional
group have attracted intense interests among synthetic
and medicinal chemists in these compounds.3 Accord-
ingly, several useful synthetic strategies have been devel-
oped for the synthesis of amino alcohols with the stereo-
and regiochemical controls.3 Here we want to use the
key regiospecific Baeyer–Villiger lactonization reaction
in the preparation of various 1,3-aminoalcohols. By
the key reaction, synthesis of (3S,4S)-statine has been
established.
Based on the structural framework of trans-(2S,4R)-4-
hydroxyproline, it possesses three functional groups that
can be easily modified, and these are 1-amino, 2-carb-
oxylate and 4-hydroxy groups.1 The skeleton represents
the significant feature for producing a series of different
carbon framework such as monocycles (pyrrole,2a pyr-
rolidine,2b,c,l piperidine,2d and azanucleoside2e), fused
or bridged bicycles (pyrrolizidine2f or azabicycles2g,h,m),
polycycles,2i–k,n macrocycle,2o etc. using a facile and
efficient modification technique.
Recently we have introduced a new and straightforward
approach to the bicyclic 7-azabicyclo[2.2.1]heptane,2m
hexahydro-1H-indol-3-one2n and pyrrolophane2o skele-
ton via an intramolecular basic alkylation, acidic aldol
condensation, and a ring-closing metathesis reaction of
the 2-substituted pyrrolidin-4-one framework employing
trans-(2S,4R)-4-hydroxyproline as the starting material.
To explore a novel synthetic application of trans-4-
(2S,4R)-hydroxyproline (1), synthetic studies toward
1,3-amino alcohols and (3S,4S)-statine were further
investigated.
2. Results and discussion
The retrosynthetic analysis of various 1,3-aminoalcohols
2 was shown in Scheme 1. We want to examine the
synthesis of 4-substituted tetrahydro-1,3-oxazin-6-ones
3 employing the key regiospecific Baeyer–Villiger lacton-
ization of 2-substituted pyrrolidin-4-one framework 4
and apply the route to the synthesis of 1,3-amino alco-
hols 2. Thus, different 2-substituents on the pyrrolidin-
4-one framework 4 could be synthesized by a series of
functional group transformations of prolinol 5.
We reported the approach toward prolinol 5 from trans-
(2S,4R)-4-hydroxyproline (1) via the following four-step
reactions: (i) esterification with thionyl chloride and
methanol, (ii) tosylation with p-toluenesulfonyl chloride
and triethylamine, (iii) silylation with t-butyldimethylsilyl
Keywords: trans-(2S,4R)-4-Hydroxyproline; Prolinol; 1,3-Amino alco-
hol; Regioselectivity; Baeyer–Villiger lactonization; Tetrahydro-1,3-
oxazin-6-one; Statine.
*
Corresponding author. Tel.: +886 7 591 9464; fax: +886 7 591
9348; e-mail: mychang@nuk.edu.tw
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.027

4866
M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 4865–4870
2-MeOC6H4, and 3,4-CH2O2C6H3) in tetrahydrofuran
OH
O
at À78 ꢁC, acid-mediated dehydroxylation and desilyla-
tion with boron trifluoride etherate and triethylsilane in
dichloromethane at 0 ꢁC, and pyridinium chlorochro-
mate mediated oxidation; (method C) compounds 4e–f
were provided via oxidation of compound 5 with ruthe-
nium trichloride and sodium periodate in co-solvent
(water/acetonitrile/carbon tetrachloride = 2/2/3) at rt,
double Grignard addition of the resulting acid with
two arylmagnesium bromide reagents (C6H5 and 3,4-
CH2O2C6H3), dehydroxylation and desilylation, and
oxidation; (method D) compounds 4g–i were provided
via the above similar methodologies employing Swern
oxidation, Grignard addition with aryl or alkylmagne-
sium bromide reagents (phenyl, n-propyl, and allyl),
benzylation, desilylation and followed by subsequent
oxidation. Thus, nine compounds 4a–i were provided
by six standard protocols from prolinol 5 in modest
yields (see Table 1).
Baeyer-Villiger
lactonization
O
4
s
R
R
2
2
HN
Ts
N
Ts
R
R
1
1
2
3
O
TBSO
R
OH
2
N
Ts
N
R
Ts
1
4
5
Scheme 1.
chloride and imidazole, and (iv) reduction of the
resulting ester with sodium borohydride in the presence
of lithium chloride. Thus prolinol 5 was obtained in 90%
overall yield with only once purification.2m,n,o
For the diastereoselective Grignard addition of aldehyde
(from Swern oxidation of prolinol 5) in the methods B
and D, we found that sole secondary alcohols were gen-
erated by the arylmagnesium bromide reagents. When
the aldehyde was treated with alkylmagnesium bromide
reagents, two stereoisomers were provided in 2:1 and 3:1
ratios. The difference between aryl and alkylmagnesium
bromide reagents was not further investigated. The rela-
tive configurations on the structure of ketones 4g–i with
two contiguous stereocenters are based upon the 1H
NMR spectral data from the literature.4 As shown in
Diagram 1, the stereochemical structure of ketone 4i
was determined by single-crystal X-ray analysis.5
As shown in Scheme 2, synthesis of nine 2-substituted
pyrrolidin-4-ones 4a–i involving four straightforward
synthetic strategies A–D was described as follows:
(method A) compound 4a was provided via benzylation
of compound 5 with benzyl bromide and sodium
hydride in tetrahydrofuran at rt, desilylation with tetra-
butylammonium fluoride in tetrahydrofuran and fol-
lowed by subsequent oxidation of the corresponding
secondary alcohol with pyridinium chlorochromate
and Celite in dichloromethane at rt; (method B) com-
pounds 4b–d were provided via Swern oxidation of com-
pound 5 with oxalyl chloride and dimethylsulfoxide in
dichloromethane at À78 ꢁC, Grignard addition with
three different arylmagnesium bromide reagents (C6H5,
With the above results and enough amounts of ketones
4a–i, Baeyer–Villiger lactonization reaction was next
examined. While poring over the related literature of
regioselective Baeyer–Villiger reaction, we found that
Young and co-workers had developed the copper(II)
acetate-mediated ring expansion of 4-ketoprolines with
m-chloroperoxybenzoic acid in 1,2-dichloroethane and
followed by acidic hydrolysis in acetone to afford the
single stereoisomers of aspartic acid analogs with no
racemization in modest yield.6 How is the regioselective
Beayer–Villiger process initiated? According to litera-
ture reports, the most likely explanation would be that
TBSO
O
method A, B, C, D
OH
R
2
N
N
R
Ts
Ts
1
5
4
OH
O
O
MCPBA,
LAH
R
R
2
2
HN
Ts
Na CO
2
N
3
R
1
Ts
R
1
Table 1. The yields of compounds 2a–i, 3a–i and 4a–i
3
2
Entry
4, yield (%)a,b
3, yield (%)a,c
2, yield (%)a,d
method A
(1) NaH, BnBr; (2) TBAF then PCC
1
2
3
4
5
6
7
8
9
4a, 76
4b, 52
4c, 51
4d, 48
4e, 45
4f, 40
4g, 42
4h, 20
4i, 24
3a, 89
3b, 83
3c, 80
3d, 83
3e, 80
3f, 82
3g, 73
3h, 75
3i, 78
2a, 89
2b, 83
2c, 80
2d, 85
2e, 85
2f, 86
2g, 82
2h, 84
2i, 86
(a) R =H, R =OBn
1
2
method B
(1) Swern ox.; (2) R MgBr; (3) Et SiH, BF -OEt ; (4) PCC
2
3
3
2
(b) R =H, R =C H (c) R =H, R =2-CH OC H
1
2
6
5
1
2
3
6 4
(d) R =H, R =3,4-CH O C H
1
2
2
2
6
3
method C
(1) RuCl , NaIO ; 2) R MgBr; 3) Et SiH, BF -OEt ; 4) PCC
3
4
2
3
3
2
(e) R =R =C H (f) R =R =3,4-CH O C H
1
2
6
5
1
2
2 2 6 3
method D
(1) Swern ox.; (2) R MgBr; (3) NaH, BnBr; (4) TBAF then PCC
2
a The product was adjusted based on isolated products.
b All yields were based on compound 5 confirmed.
c All yields were based on compounds 4a–i confirmed.
d All yields were based on compounds 3a–i confirmed.
(g) R =OBn, R =C H (h) R =OBn, R =CH CH CH
1
2
6
5
1
2
2
2
3
(i) R =OBn, R =CH CH=CH
1
2
2
2
Scheme 2.

M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 4865–4870
4867
OH
1) RuCl , NaIO
4
MeMgBr
3
3i
(78%)
HN
2) Na, NH
(two steps 34%)
3(l)
H N
2
CO H
2
OH
Ts
OBn
statine (6)
7
Scheme 3.
Statine, [(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic
acid], a naturally occurring amino acid of nonproteo-
genic origin, is a key component in the pepstain family
of aspartic protease inhibitors.11 Statine and its structur-
ally modified analogs have been widely used in the de-
sign of peptide mimics as potential inhibitors of rennin
and other aspartic proteases.12 Statine has attached a
lot interest because of its potential use in the treatment
of hypertension and congestive heart failure. Consider-
able efforts have been devoted to the total synthesis of
(3S,4S)-statine and its analogs.13
Diagram 1. X-ray crystallography of compound 4i.
it is controlled by involvement of the nitrogen lone pair
on substituted pyrrolidin-4-ones.6
According to the unique synthetic reports, model
substrate 4a was first treated with the combination of
copper(II) acetate and m-chloroperoxybenzoic acid.
The resulting product 3a was provided in moderate
(53%) yield. In order to increase higher yields, other
commercial available reagents and reaction conditions
were tested. When the reaction was treated with the
combination of sodium carbonate and m-chloroperoxy-
benzoic acid, the yield of compound 3a was increased to
89% yield without other regioisomers. For the synthetic
efficiency of 4-substituted tetrahydro-1,3-oxazin-6-ones
3a–i,7 sodium carbonate is better than copper(II) acetate
in our cases during the overall regiospecific Baeyer–
Villiger ring expansion process. The difference between
sodium carbonate and copper(II) acetate was not clear.
This combination could provide an easy and straightfor-
ward standard operation protocol with better yields
than the literature reports. Although the synthetic appli-
cations of regioselective Beayer–Villiger process have
been developed by Young’s group, the present work is
complementary to existing methodology.
As shown in Scheme 3, treatment of compound 3i with
excess methylmagnesium bromide was obtained tertiary
alcohol 7. Oxidation of alcohol 7 with ruthenium oxide
was yielded benzyl acid as major product accompanied
with a trace amount of benzoyl acid isomer. Finally,
statine (6) was accomplished by subsequent reduction
with sodium and liquid ammonia under the Birch
process (desulfonation, debenzylation/debenzoylation
and dehydroxylation).13k,14
3. Conclusion
In summary, we develop a straightforward approach to
the 4-substituted tetrahydro-1,3-oxazin-6-one skeleton
based on the regiospecific Baeyer–Villiger ring expan-
sion reaction as the key step and apply this route to syn-
thesize statine. For the application and investigation of
trans-4-(2S,4R)-hydroxyproline, synthetic study toward
acyclic aminoalcohol framework has not been explored.
We are currently studying the scope of this process as
well as additional applications of this approach to the
synthesis of various potential biological activities com-
pounds using trans-4-(2S,4R)-hydroxyproline as the
starting material.
Among the NMR data of nine oxazinones 3a–i at room
temperature, compounds 3a and 3c exhibited a mixture
of rotamers in nearly 1:1 ratio. This phenomenon is usu-
ally expected in the related acylproline derivatives and
so it was not surprising that it occurred with the related
oxzainone analogs.6,8 Reduction of compounds 3a–i
with lithium aluminum hydride in tetrahydrofuran was
yielded different substituents 1,3-aminoalcohols 2a–i in
80–89 % yields.9 These experimental results are summa-
rized in Table 1.
Acknowledgements
The authors would like to thank the National Science
Council (NSC 94-2113-M-390-001) of the Republic of
China for financial support. We also thank Professor
Michael Y. Chiang (National Sun Yat-Sen University)
for structural determination of compound 4i by X-ray
diffraction analysis.
To deserve to be mentioned, compound 2h was an ana-
log of C2-homo-dihydroceramide with apoptotic activi-
ties in HL-60 human leukemia cells.10a,b Therefore, the
present methodology provided a new approach to the
preparation of sphingolipid family derivatives.10d,e
Based on the experimental simplicity, the preparation
of compound 3i was also conducted in a multigram scale
(10 mmol) with 65% yield from ketone 4i. With these
results in hand, the next focus was to examine the
synthesis of (3S,4S)-statine (6).
References and notes
1. For a review, see Remuzon, P. Tetrahedron 1996, 52,
13803.

4868
M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 4865–4870
2. For related references, see (a) Azizian, J.; Karimi, A. R.;
(3 · 20 mL). The combined organic layers were washed
with brine, dried, filtered and evaporated to afford crude
product under reduced pressure. Purification on silica gel
(hexane/ethyl acetate = 3/1–1/1) afforded compounds 3a–
i. Representative data for compound 3e: 1H NMR
(500 MHz, CDCl3) d 7.68 (d, J = 8.0 Hz, 2H), 7.37–7.24
(m, 12H), 5.67 (d, J = 12.0 Hz, 1H), 4.76 (dd, J = 8.0,
15.0 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 4.49 (d,
J = 8.0 Hz, 1H), 2.62 (dd, J = 7.0, 17.0 Hz, 1H), 2.46
(dd, J = 7.0, 17.0 Hz, 1H), 2.43 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 167.47, 145.02, 139.37, 138.70,
135.01, 130.19 (2·), 129.43 (2·), 129.03 (2·), 128.74 (2·),
127.96 (2·), 127.86 (2·), 127.76, 127.17, 74.49, 55.15,
53.64, 32.14, 21.64; HRMS (ESI) m/z calcd for
C24H24NO4S (M++1) 422.1426, found 422.1428. For
compound 3g: 1H NMR (500 MHz, CDCl3) d 7.75 (d,
J = 8.5 Hz, 2H), 7.43–7.39 (m, 10H), 7.31 (d, J = 8.0 Hz,
2H), 5.86 (dd, J = 0.5, 12.0 Hz, 1H), 5.37 (d, J = 12.0 Hz,
1H), 5.14 (d, J = 2.0 Hz, 1H), 4.66 (d, J = 11.0 Hz, 1H),
4.52 (d, J = 11.0 Hz, 1H), 3.79 (ddd, J = 2.0, 7.0, 10.0 Hz,
1H), 3.10 (dd, J = 11.0, 16.5 Hz, 1H), 2.40 (s, 3H), 2.11
(dd, J = 7.0, 16.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) d
168.92, 144.91, 137.54, 136.92, 134.66, 130.14 (2·), 128.97
(2·), 128.58 (2·), 128.44, 128.02, 127.86 (2·), 127.70 (2·),
126.07 (2·), 83.29, 75.85, 72.20, 56.84, 27.45, 21.60;
HRMS (ESI) m/z calcd for C25H26NO5S (M++1)
452.1532, found 452.1533. For compound 3i: 1H NMR
(500 MHz, CDCl3) d 7.68 (d, J = 8.5 Hz, 2H), 7.38–7.28
(m, 7H), 5.97–5.89 (m, 1H), 5.80 (d, J = 11.5 Hz, 1H), 5.37
(d, J = 11.5 Hz, 1H), 5.23 (d, J = 17.5 Hz, 1H), 5.16 (dd,
J = 1.0, 10.0 Hz, 1H), 4.71 (d, J = 11.5 Hz, 1H), 4.44 (d,
J = 11.5 Hz, 1H), 3.94 (td, J = 3.5, 8.0 Hz, 1H), 3.63 (td,
J = 3.5, 6.0 Hz, 1H), 2.59–2.49 (m, 2H), 2.45 (dd, J = 8.0,
17.0 Hz, 1H), 2.43 (s, 3H), 2.31 (dd, J = 8.0, 17.0 Hz, 1H);
13C NMR (125 MHz, CDCl3) d 167.96, 145.03, 137.21,
134.97, 133.84, 130.18 (2·), 128.62 (2·), 128.18 (3·),
127.88 (2·), 118.40, 80.95, 76.44, 72.82, 52.87, 33.77,
30.52, 21.65; HRMS (ESI) m/z calcd for C22H26NO5S
(M++1) 416.1532, found 416.1533.
Kazemizadeh, Z.; Mohammadi, A. A.; Mohammadi-
zadeh, M. R. J. Org. Chem. 2005, 70, 1471; (b) Del Valle,
J. R.; Goodman, M. Angew. Chem., Int. Ed. 2002, 41,
1600; (c) Gonzalez, T.; Abad, O.; Santano, M. C.;
Minguillon, C. Synthesis 2004, 1171; (d) Honda, T.;
Takahashi, R.; Namiki, H. J. Org. Chem. 2005, 70, 499;
(e) Qiu, X.-L.; Qing, F.-L. Bioorg. Med. Chem. 2005, 13,
277; (f) Pandey, G.; Lakshmaiah, G. Synlett 1994, 277; (g)
Han, G.; LaPorte, M. G.; Folmer, J. J.; Werner, K. M.;
Weinreb, S. M. J. Org. Chem. 2000, 65, 6293; (h)
Houghton, P. G.; Humphrey, G. R.; Kennedy, D. J.;
Roberts, D. C.; Wright, S. H. B. J. Chem. Soc., Perkin
Trans. 1 1993, 1421; (i) Tamura, O.; Yanagimachi, T.;
Ishibashi, H. Tetrahedron: Asymmetry 2003, 14, 3033; (j)
Hu, H.; Zhai, H. Synlett 2003, 2129; (k) Breslin, H. J.;
Kukla, M. J.; Ludovici, D. W.; Mohrbaeher, R.; Ho, W.;
Miranda, M.; Rodgers, J. D.; Hitchens, T. K.; Leo, G.;
Gauthier, D. A.; Chih, Y. H.; Scott, M. K.; De Clercq, E.;
Pauwels, R.; Andries, K.; Janssen, M. A. C.; Janssen, P.
A. J. J. Med. Chem. 1995, 38, 771; (l) Chang, M. Y.; Chen,
S. T.; Chang, N. C. Heterocycles 2003, 60, 1203; (m)
Chang, M. Y.; Chen, H. P. Heterocycles 2005, 65, 1705;
(n) Chang, M. Y.; Chen, H. P.; Lin, C. Y.; Pai, C. L.
Heterocycles 2005, 60, 1999; (o) Chang, M. Y.; Pai, C. L.;
Chen, H. P. Tetrahedron Lett. 2005, 46, 7705.
3. (a) Ager, D.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996,
96, 835; (b) Cardillo, G.; Tomasini, C. Chem. Soc. Rev.
1996, 25, 117; (c) Cole, D. C. Tetrahedron 1994, 50, 9517;
(d) Juaristi, E. Enantioselective Synthesis of b-amino Acids;
Wiley-VCH: New York, 1997; (e) Bodmann, K.; Bug, T.;
Steinbeisser, S.; Kreuder, R.; Reiser, O. Tetrahedron Lett.
2006, 47, 2061; (f) Huguenot, F.; Brigaud, T. J. Org.
Chem. 2006, 71, 2159; (g) Fustero, S.; Jimenez, D.; Sanz-
Cervera, J. F.; Sanchez-Rosello, M.; Esteban, E.; Simon-
Fuentes, A. Org. Lett. 2005, 7, 3433.
4. (a) Ohtake, N.; Jona, H.; Okada, S.; Okamoto, O.; Imai,
Y.; Ushijima, R.; Nakagawa, S. Tetrahedron: Asymmetry
1997, 8, 2939; (b) Dinh, T. Q.; Smith, C. D.; Armstrong,
R. W. J. Org. Chem. 1997, 62, 790; (c) Dinh, T. Q.; Du, X.;
Smith, C. D.; Armstrong, R. W. J. Org. Chem. 1997, 62,
6773; (d) Na, H. S.; Choi, J.; Yu, J.; Shin, K. J.; Yoo, K.
H.; Kim, D. J.; Park, S. W. Heterocycles 1998, 48, 2365;
(e) Armstrong, J. D.; Keller, J. L.; Lynch, J.; Liu, T.;
Hartner, F. W.; Ohtake, N.; Okada, S.; Imai, Y.;
Okamoto, O.; Ushijima, R.; Nakagawa, S. Tetrahedron
Lett. 1997, 38, 3203.
8. (a) Hanessian, S.; Sumi, K.; Vanasse, V. Synlett 1992, 33;
(b) Hondrelis, J.; Lonergan, G.; Voliotis, S.; Matsoukas, J.
Tetrahedron 1990, 46, 565.
9. A representative procedure of compounds 2a–i is as
follows: Excess lithium aluminum hydride (38 mg,
1.0 mmol) was added to a solution of compounds 3a–i
(0.1 mmol) in tetrahydrofuran (10 mL). The reaction
mixture was stirred at rt for 10 h. Saturated sodium
bicarbonate solution (1 mL) was added to the reaction
mixture and the solvent was concentrated under reduced
pressure. The residue was extracted with ethyl acetate
(3 · 20 mL). The combined organic layers were washed
with brine, dried, filtered and evaporated to afford crude
product under reduced pressure. Purification on silica gel
(hexane/ethyl acetate = 1/1) afforded compounds 2a–i.
Representative data for compound 2a: 1H NMR
(500 MHz, CDCl3) d 7.68 (d, J = 8.5 Hz, 2H), 7.34–7.30
(m, 3H), 7.27–7.20 (m, 4H), 4.98 (d, J = 8.5 Hz, 1H), 4.40
(d, J = 12.0 Hz, 1H), 4.31 (d, J = 12.0 Hz, 1H), 3.88–3.83
(m, 1H), 3.68–3.64 (m, 1H), 3.60 (br s, 1H), 3.58–3.55 (m,
1H), 3.29 (dd, J = 1.8, 9.5 Hz, 1H), 3.13 (dd, J = 4.5,
9.5 Hz, 1H), 2.42 (s, 3H), 1.75–1.68 (m, 1H), 0.90–0.85 (m,
1H); 13C NMR (125 MHz, CDCl3) d 143.43, 137.42,
136.70, 129.68 (2·), 128.50 (2·), 127.96, 127.72 (2·),
126.98 (2·), 73.25, 71.26, 58.62, 50.52, 35.11, 21.54;
HRMS (ESI) m/z calcd for C18H24NO4S (M++1)
350.1426, found 350.1428. For compound 2b: 1H NMR
(500 MHz, CDCl3) d 7.69 (d, J = 8.5 Hz, 2H), 7.31–7.23
(m, 3H), 7.18 (d, J = 7.0 Hz, 2H), 6.95 (d, J = 7.0 Hz, 2H),
4.84 (d, J = 8.0 Hz, 1H), 3.83 (td, J = 3.0, 11.5 Hz, 1H),
5. Single-crystal X-ray diagram: crystal of compound 4i was
grown by slow diffusion of ethyl acetate into a solution of
compound 4i in dichloromethane to yield colorless prism.
The compound crystallizes in the orthorhombic crystal
˚
system. space group P 212121(# 19), a = 96.0657(12) A,
3
˚
˚
˚
b = 8.0954(16) A, c = 42.812(9) A, V = 2102.2(7) A ,
Z = 8, dcalcd = 2.524 mg/m3, absorption coefficient
0.362 mmÀ1, F(000) = 1696, 2h range (1.90–26.00ꢁ).
6. (a) Burtin, G.; Corringer, P. J.; Hitchcock, P. B.; Young,
D. W. Tetrahedron Lett. 1999, 40, 4275; (b) Burtin, G.;
Corringer, P. J.; Young, D. W. J. Chem. Soc., Perkin
Trans. 1 2000, 3451.
7. A representative procedure of tetrahydro-1,3-oxazin-6-
ones 3a–i is as follows: a solution of ketones 4a–i
(0.3 mmol) in dichloromethane (2 mL) was added to a
stirred solution of m-chloroperoxybenzoic acid (120 mg,
75%, 0.52 mmol) and sodium bicarbonate (85 mg,
0.8 mmol) in dichloromethane (10 mL). The reaction
mixture was stirred at rt for 4 h. Saturated sodium
carbonate solution (5 mL) was added to the reaction
mixture and the solvent was concentrated under reduced
pressure. The residue was extracted with ethyl acetate

M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 4865–4870
4869
3.70–3.64 (m, 1H), 3.62–3.58 (m, 1H), 2.66 (dd, J = 5.5,
13.0 Hz, 1H), 2.60 (dd, J = 7.0, 14.0 Hz, 1H), 2.43 (s, 3H),
1.92–1.86 (m, 1H), 1.78–1.71 (m, 1H), 1.69–1.62 (m, 1H);
13C NMR (125 MHz, CDCl3) d 143.48, 138.10, 137.63,
133.92, 129.64 (2·), 128.46 (2·), 127.99, 127.95 (2·),
127.04 (2·), 117.90, 80.26, 72.53, 58.72, 52.80, 35.97,
35.06, 21.52; HRMS (ESI) m/z calcd for C21H28NO4S
(M++1) 390.1739, found 390.1742.
2.10 (br s, 1H), 1.80–1.74 (m, 1H), 1.48–1.41 (m, 1H); 13
C
NMR (125 MHz, CDCl3) d 143.38, 137.45, 136.74, 129.73
(2·), 129.41 (2·), 128.53 (2·), 126.93 (2·), 126.64, 58.91,
52.38, 41.60, 36.61, 21.52; HRMS (ESI) m/z calcd for
C17H22NO3S (M++1) 320.1320, found 320.1322. For
compound 2d: 1H NMR (500 MHz, CDCl3) d 7.65 (d,
J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.59 (d,
J = 7.5 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 6.38 (s, 1H),
5.90 (d, J = 5.0 Hz, 2H), 4.85 (br s, 1H), 3.85 (td, J = 3.0,
11.5 Hz, 1H), 3.68–3.58 (m, 2H), 2.55–2.51 (m, 2H), 2.43
(s, 3H), 2.07 (br s, 1H), 1.82–1.76 (m, 1H), 1.49–1.43 (m,
1H); 13C NMR (125 MHz, CDCl3) d 147.55, 146.18,
143.33, 137.38, 130.53, 129.58 (2·), 126.91 (2·), 122.36,
109.52, 108.21, 100.86, 58.82, 52.63, 41.38, 37.03, 21.49;
HRMS (ESI) m/z calcd for C18H22NO5S (M++1)
364.1219, found 364.1221. For compound 2e: 1H NMR
(500 MHz, CDCl3) d 7.50 (d, J = 8.0 Hz, 2H), 7.28–7.04
(m, 12H), 4.56 (J = 8.5 Hz, 1H), 4.34 (ddd, J = 3.0, 8.5,
17.0 Hz, 1H), 3.90 (d, J = 8.5 Hz, 1H), 3.87 (td, J = 4.5,
9.5 Hz, 1H), 3.67 (dt, J = 4.5, 9.5 Hz, 1H), 2.42 (s, 3H),
10. (a) Shikata, K.; Niiro, H.; Azuma, H.; Tachibana, T.;
Ogino, K. Bioorg. Med. Chem. Lett. 2003, 13, 613; (b)
Shikata, K.; Niiro, H.; Azuma, H.; Ogino, K.; Tachibana,
T. Bioorg. Med. Chem. Lett. 2003, 13, 2723; (c) de Jonge,
S.; Lamote, I.; Venkataraman, K.; Boldin, S. A.; Hillaert,
U.; Rozenski, J.; Hendrix, C.; Busson, R.; de Keukeleire,
D.; van Calenbergh, S.; Futerman, A. H.; Herdewijn, P. J.
Org. Chem. 2002, 67, 988; (d) Liao, J.; Tao, J.; Lin, G.;
Liu, D. Tetrahedron 2005, 61, 4715; (e) Howell, A. R.; So,
R. C.; Richardson, S. K. Tetrahedron 2004, 60, 11327.
11. (a) Umezawa, U.; Aoyagi, T.; Morishima, H.; Matzusaki,
M.; Hamada, H.; Takeuchi, T. J. Antibiot. 1970, 23, 259;
(b) Rich, D. H. J. Med. Chem. 1985, 28, 263; For a review,
see: (c) Rich, D. H. In Proteinase Inhibitors; Barrett, A. J.,
Salvesen, G., Eds.; Elsevier: New York, 1986; p 179.
12. (a) Takemoto, Y.; Matsumoto, T.; Ito, Y.; Terashima, S.
Chem. Pharm. Bull. 1991, 39, 2425; (b) Holladay, M. W.;
Salituro, F. G.; Rich, D. H. J. Med. Chem. 1987, 30, 374;
(c) Schaschke, N. Bioorg. Med. Chem. Lett. 2004, 14, 855.
13. For recent synthetic studied for statine, see: (a) Ko, S. Y.
J. Org. Chem. 2002, 67, 2689; (b) Yoo, D.; Oh, J. S.; Kim,
Y. G. Org. Lett. 2002, 4, 1213; (c) Kwon, S. J.; Ko, S. Y.
Tetrahedron Lett. 2002, 43, 639; (d) Pesenti, C.; Bravo, P.;
Corradi, E.; Frigerio, M.; Meille, S. V.; Panzeri, W.; Viani,
F.; Zanda, M. J. Org. Chem. 2001, 66, 5637, and cited
references therein; (e) Andres, J. M.; Pedrosa, R.; Perez,
A.; Perez-Encabo, A. Tetrahedron 2001, 57, 8521; (f)
Alemany, C.; Bach, J.; Farras, J.; Garcia, J. Org. Lett.
1999, 1, 1831; (g) Reddy, G. V.; Rao, G. V.; Iyengar, D. S.
Tetrahedron Lett. 1999, 40, 775; (h) Sengupta, S.; Sarma,
D. S. Tetrahedron: Asymmetry 1999, 10, 4633; (i) Lee, K.
Y.; Kim, Y. H.; Park, M. S.; Oh, C. Y.; Ham, W. H. J.
Org. Chem. 1999, 64, 9450; (j) Kazmaier, U.; Krebs, A.
Tetrahedron Lett. 1999, 40, 479; (k) Aoyagi, Y.; Williams,
R. M. Tetrahedron 1998, 54, 10419; (l) Hoffman, R. V.;
Tao, J. J. Org. Chem. 1997, 62, 2292, and cited references
therein; (m) Gennari, C.; Moresca, D.; Vulpetti, A.; Pain,
G. Tetrahedron 1997, 53, 5593; (n) Nebois, P.; Greene, A.
E. J. Org. Chem. 1996, 61, 5210; (o) Ma, D.; Ma, J.; Ding,
W.; Dai, L. Tetrahedron: Asymmetry 1996, 7, 2365; (p)
Gennari, C.; Pain, G.; Moresca, D. J. Org. Chem. 1995,
60, 6248; (q) Williams, R. M.; Colson, P.-J.; Zhai, W.
Tetrahedron Lett. 1994, 35, 9371; (r) d’Aniello, F.; Mann,
A.; Matii, D.; Taddei, M. J. Org. Chem. 1994, 59, 3762; (s)
Lu, Y.; Miet, C.; Kunesch, N.; Poisson, J. E. Tetrahedron:
Asymmetry 1993, 4, 893; (t) Kessler, H.; Schudok, M.
Synthesis 1990, 457; (u) Ohta, T.; Shiokawa, S.; Sakam-
oto, R.; Nozoe, S. Tetrahedron Lett. 1990, 31, 7329; (v)
Misiti, D.; Zappia, G. Tetrahedron Lett. 1990, 31, 7359;
(w) Reetz, M. T.; Drewes, M. W.; Matthews, B. R.;
Lennick, K. J. Chem. Soc., Chem. Commun. 1989, 1474;
(x) Midland, M. M.; Afonso, M. M. J. Am. Chem. Soc.
1989, 111, 4368; (y) Kunieda, T.; Ishizuka, T.; Higuchi, T.;
Hirobe, M. J. Org. Chem. 1988, 53, 3381; (z) Nishi, T.;
Kitamura, M.; Ohkuma, T.; Noyori, R. Tetrahedron Lett.
1988, 29, 6327.
2.05–1.98 (m, 1H), 1.65 (br s, 1H), 1.50–1.44 (m, 1H); 13
C
NMR (125 MHz, CDCl3) d 143.16, 140.81, 140.34, 137.45,
129.63 (2·), 128.81 (2·), 128.78 (2·), 128.55 (2·), 128.05
(2·), 127.05, 126.87 (2·), 126.58, 58.70, 56.08, 54.16,
35.52, 21.52; HRMS (ESI) m/z calcd for C23H26NO3S
1
(M++1) 396.1633, found 396.1635. For compound 2f: H
NMR (500 MHz, CDCl3) d 7.50 (d, J = 8.0 Hz, 2H), 7.19
(d, J = 8.0 Hz, 2H), 6.69 (d, J = 8.0 Hz, 1H), 6.60 (s, 2H),
6.59 (d, J = 8.0 Hz, 1H), 6.50 (s, 2H), 6.40 (s, 1H), 5.92 (s,
2H), 5.85 (dd, J = 0.5, 18.5 Hz, 2H), 4.58 (J = 8.0 Hz,
1H), 4.13 (ddd, J = 3.0, 8.5, 17.0 Hz, 1H), 3.89 (m, 1H),
3.70 (d, J = 9.0 Hz, 1H), 2.42 (s, 3H), 2.06–1.99 (m, 1H),
1.61 (br s, 1H), 1.49–1.42 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 147.93, 147.58, 146.52, 146.23, 143.15, 137.35,
134.94, 134.39, 129.41 (2·), 126.79 (2·), 121.59, 121.19,
108.63, 108.44, 108.12, 108.06, 101.08, 100.89, 58.62,
55.73, 54.54, 35.94, 21.52; HRMS (ESI) m/z calcd for
C25H26NO7S (M++1) 484.1433, found 484.1436. For
compound 2g: 1H NMR (500 MHz, CDCl3) d 7.55 (d,
J = 8.0 Hz, 2H), 7.44–7.38 (m, 2H), 7.33–7.23 (m, 8H),
7.00 (d, J = 7.0 Hz, 2H), 4.90 (d, J = 9.5 Hz, 1H), 4.53 (d,
J = 11.5 Hz, 1H), 4.01 (d, J = 11.5 Hz, 1H), 4.00 (d,
J = 3.0 Hz, 1H), 3.82 (td, J = 4.0, 12.0 Hz, 1H), 3.61–3.56
(m, 1H), 3.54–3.48 (m, 1H), 2.44 (s, 3H), 1.63–1.50 (m,
2H), 1.55 (br s, 1H); 13C NMR (125 MHz, CDCl3) d
143.52, 137.56, 137.27, 137.14, 129.74 (2·), 128.74 (2·),
128.64 (2·), 128.16, 128.05, 128.02 (2·), 127.12 (2·),
126.62 (2·), 81.64, 70.91, 58.24, 55.39, 30.13, 21.59;
HRMS (ESI) m/z calcd for C24H28NO4S (M++1)
426.1739, found 426.1738. For compound 2h: 1H NMR
(500 MHz, CDCl3) d 7.75 (d, J = 8.5 Hz, 2H), 7.38–7.24
(m, 7H), 4.95 (d, J = 9.0 Hz, 1H), 4.51 (d, J = 11.0 Hz,
1H), 4.39 (d, J = 11.0 Hz, 1H), 3.82 (td, J = 3.5, 9.0,
12.0 Hz, 1H), 3.60 (dt, J = 4.5, 12.0 Hz, 1H), 3.57–3.53
(m, 1H), 3.25 (td, J = 1.5, 6.5 Hz, 1H), 2.42 (s, 3H), 2.05
(br s, 1H), 1.78–1.65 (m, 2H), 1.27–1.11 (m, 2H), 1.03–0.89
(m, 2H), 0.63 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 143.40, 138.04, 137.80, 129.61 (2·), 128.41 (2·),
127.90 (3·), 127.00 (2·), 80.79, 72.53, 58.67, 52.62, 36.01,
32.62, 21.45, 18.97, 13.83; HRMS (ESI) m/z calcd for
C21H30NO4S (M++1) 392.1896, found 392.1897. For
compound 2i: 1H NMR (500 MHz, CDCl3) d 7.75 (d,
J = 8.5 Hz, 2H), 7.35–7.25 (m, 7H), 5.59–5.51 (m, 1H),
4.98 (d, J = 10.0 Hz, 1H), 4.88–4.84 (m, 2H), 4.57 (d,
J = 11.5 Hz, 1H), 4.40 (d, J = 11.5 Hz, 1H), 3.80–3.74 (m,
1H), 3.60–3.54 (m, 2H), 3.35 (td, J = 2.0, 7.5 Hz, 1H), 2.42
(s, 3H), 2.34 (dd, J = 5.0, 7.0 Hz, 1H), 2.17–2.11 (m, 1H),
14. A representative procedure of statine (6) is as follows:
Compound 7 (42 mg, 0.1 mmol) was dissolved in carbon
tetrachloride (2 mL), acetonitrile (2 mL) and water (3 mL)
with vigorous stirring. Then sodium periodate (105 mg,
0.5 mmol) and ruthenium(III) chloride hydrate (5 mg)
were added. The reaction was stopped after 6 h, diluting
with dichloromethane (20 mL) and the organic layer was

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M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 4865–4870
separated. The aqueous layer was then extracted with
layer at rt. Then the water was evaporated under reduced
pressure to give the crude hydrochloride salt. The crude
salt was purified by ion exchange chromatography
(Dowex 50WX-100, eluted with 0.1 N ammonium water
to give the corresponding statine (6) (34%, 7.5 mg). 1H
NMR (500 MHz, CDCl3) d 4.03 (dt, J = 5.0, 7.5 Hz, 1H),
3.30 (dt, J = 6.0, 8.0 Hz, 1H), 2.57 (dd, J = 5.0, 15.5 Hz,
1H), 2.43 (dd, J = 7.5, 15.5 Hz, 1H), 1.76–1.67 (m, 1H),
1.57–1.48 (m, 2H), 0.95 (d, J = 7.0 Hz, 3H), 0.94 (d,
J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 178.63,
68.04, 53.63, 41.20, 38.16, 23.63, 21.85, 20.65. The NMR
spectral data of statine (6) were in accordance with those
reported in the literature.13a
dichloromethane (2 · 10 mL) and the organic layers were
filtered on a Celite pad, collected and evaporated to afford
the crude products under reduced pressure. Without
further purification, sodium (20 mg, 0.9 mmol) was added
to a solution of the resulting mixture products in liquid
ammonia (5 mL) at À78 ꢁC. The reaction mixture was
stirred at À78 ꢁC for 1 h then it was warmed to À30 ꢁC for
1 h. Water (5 mL) was poured into the reaction mixture
and evaporated to afford the residue under reduced
pressure. Water (10 mL) was poured into the residue and
extracted with diethyl ether (3 · 20 mL). Aqueous hydro-
chloric acid solution (37%, 1 mL) was added to the water