Synthetic studies on polyoxypeptins: Stereoselective synthesis of (2S,3R)-3-hydroxy-3-methylproline using SmI2-mediated cyclization

Article abstract of DOI:10.1016/S0040-4039(02)00833-X

Stereoselective synthesis of (2S,3R)-3-hydroxy-3-methylproline (3), a component of polyoxypeptins, has been achieved by use of SmI₂-mediated diastereoselective cyclization reaction as a key step.

Full text of DOI:10.1016/S0040-4039(02)00833-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4695–4698
Synthetic studies on polyoxypeptins: stereoselective synthesis of
(2S,3R)-3-hydroxy-3-methylproline using SmI2-mediated
cyclization
Kazuishi Makino, Ai Kondoh and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 4 April 2002; accepted 26 April 2002
Abstract—Stereoselective synthesis of (2S,3R)-3-hydroxy-3-methylproline (3), a component of polyoxypeptins, has been achieved
by use of SmI2-mediated diastereoselective cyclization reaction as a key step. © 2002 Elsevier Science Ltd. All rights reserved.
Polyoxypeptin A (1),1 a novel 19-membered cyclic hex-
adepsipeptide antibiotic, was isolated from the culture
broth of a Streptomyces strain together with poly-
oxypeptin B by Umezawa and co-workers in 1998 (Fig.
1). Polyoxypeptin A is known to induce apoptotic cell
death against apoptosis-resistant human pancreatic
adenocarcinoma AsPC-1 cells. The relative and abso-
lute stereostructure of polyoxypeptin A was determined
by X-ray crystallographic analysis and degradation
studies. The cyclic hexadepsipeptide structure of poly-
oxypeptin A contains a novel (2S,3R)-3-hydroxy-3-
methylproline (3) and other non-proteogenic a-amino
acids. The challenging structure in addition to the novel
biological activity of polyoxypeptin A prompted us and
others2 to undertake a program directed toward its
total synthesis. Herein we report the stereoselective
synthesis of (2S,3R)-3-hydroxy-3-methylproline based
on a SmI2-mediated intramolecular reaction.3 Recently,
Kobayashi2b and Yao2c have independently reported
the synthesis of 3 using palladium-catalyzed intramolec-
ular N-allylation of alkenyloxirane, and Sharpless
asymmetric dihydroxylation followed by regioselective
opening of cyclic sulfate by sodium azide.
Our synthetic strategy for (2S,3R)-3-hydroxy-3-methyl-
proline is outlined retrosynthetically in Scheme 1. The
asymmetric quaternary center at C3 might be con-
structed by diastereoselective cyclization using SmI2
between the carbonyl carbon and alkyl iodide functions
in 4, which could be readily derived from (2S,3R)
threonine (5). Our synthesis was commenced with
preparation of tosylamide 6 through a sequence of the
usual manipulations in overall 81% and four steps: (1)
N-tosylation, (2) esterification with iodomethane and
potassium bicarbonate in dimethyl formamide, (3)
reduction of the ester function with lithium borohy-
dride in tetrahydrofuran and (4) protection of the
resulting diol function with dimethoxypropane and
toluenesulfonic acid. We first attempted direct introduc-
tion of a 2-iodoethyl group at the nitrogen atom of the
sulfonamide. The reaction with diiodoethane in the
presence of a base completely failed to produce 9 and
resulted in recovery of the starting sulfonamide. Thus,
we turned our attention to an indirect route through 5
steps. N-Allylation of 6 afforded the alkene 7 in 96%
yield. Oxidative cleavage of olefin in 7 with OsO4–
OH
O
OH
O
H
NH HN
N
H
O
H
N
H
HO
O
O
O
O
O
OH
N
H
N
R
HN
N
H
O
OH
R = OH:
Polyoxypeptin A (1)
Polyoxypeptin B (2)
R = H:
Figure 1. Structure of polyoxypeptins.
Keywords: (2S,3R)-3-hydroxy-3-methylproline; samarium iodide;
Barbier-type reaction.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00833-X

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K. Makino et al. / Tetrahedron Letters 43 (2002) 4695–4698
SmI2-mediated
Cyclization
OH
3
4
I
O
3
OH
4
3
2
OR
COOH
2
N
H
2
N
H2N
COOH
3
Ts
5 (2S, 3R)-threonine
4
Scheme 1. Retrosynthetic analysis of (2S,3R)-3-hydroxy-3-methylproline (3).
NMO followed by treatment of NaIO4 and subsequent
reduction of the aldehyde functionality with NaBH4
gave the alcohol 8 in quantitative yield. Halogenation
of TBDPS ether with aqueous hydrofluoric acid in 86%
yield (Scheme 2).
of the hydroxyl group of
8
with iodine and
With the three iodoketones in hand, we next examined
cyclization reaction using SmI2 as a key step in this
synthesis. The results of this cyclization are summarized
in Table 1. The ring closure of the TBDPS-protected
iodoketone 12a using SmI2 in THF at −78°C gave no
product, and the starting material was decomposed
under conditions of increasing temperature (entry 1). In
the presence of HMPA as a co-solvent (THF/HMPA=
10/1), the cyclization reaction proceeded smoothly at
−78°C for 20 min to afford the undesired diastereomer
as a major product (13a:14a=13:87) in 76% yield (entry
triphenylphosphine in the presence of imidazole pro-
vided the iodoalkane 9 in 97% yield. After acid-cata-
lyzed deprotection of isopropylidene acetal of 9, the
selective protection of the primary alcohol of 10 as a
tert-butyldiphenylsilyl (TBDPS) or trityl (Tr) ether
(TBDPS ether 11a: 67%, Tr ether 11b: 52%) and subse-
quent oxidation of the secondary alcohol using Dess–
Martin periodinane4 furnished the iodoketone 12a and
12b in quantitative and 90% yield, respectively. Non-
protected iodoketone 12c was prepared by deprotection
1. TsCl , Na2CO3
O
, NMO
HO
1. OsO4
acetone, H2O
NaH
CH2=CHCH2Br
O
O
Et2O, H2O
5
O
O
O
MeI, KHCO
DMF
3. LiBH4, THF
CH(OMe)2
2.
3 HN
Ts
NaIO , THF
2.
N
4
N
DMF
96%
8
Phosphate buffer
3. NaBH4, MeOH
7
6
Ts
Ts
4.
quant (3 steps)
TsOH, CH2Cl2
81% (4 steps)
TBDPSCl
imidazole
DMF
Dess-Martin
periodinane
I
O
I
OH
I
OH
I2
Ph3P
I
O
4N HCl
OR
or
OR
CH2Cl2
OH
N
THF
imidazole
PhCH3
97%
N
N
O
TrCl, Et3N
N
Ts
Ts
Ts
10
CH2Cl2
9
Ts
11a: R = TBDPS (67%, 2 steps) 12a: R = TBDPS (quant)
I
O
11b: R = Tr (52%, 2steps)
12b: R = Tr (90%)
HF, CH3CN
86%
12a
OH
12c
N
Ts
Scheme 2. Synthesis of the iodoketones 12.
Table 1. Diastereoselective Barbier-type cyclization using SmI2
OH
OH
I
O
SmI2
+
OR
OR
solvent
OR
12a-c
N
N
N
14a-c
Ts
13a-c
Ts
Ts
Entry
R
Solvent
THF
THF/HMPA (10:1)
THF/HMPA (10:1)
THF/HMPA (10:1)
Conditions
Yield
13:14
1
2
3
4
TBDPS
TBDPS
Tr
−78°C to rt, 20 h
−78°C, 20 min
−78°C, 20 min
Complex mixture
76%
45%
75%
13:87a
31:69a
97:3a,b
H
−78 to −55°C, 1.5 h
a Determined by 1H NMR analysis.
b Determined by HPLC analysis using Daicel Chiralcel OD-H.

K. Makino et al. / Tetrahedron Letters 43 (2002) 4695–4698
4697
NOE
H3C
OH
O
OH
DMP, CH2Cl2
1.
2.
H3C
NaClO2, NaH2PO4
CH2=C(CH3)2
tBuOH, H2O
OH
OH
OH
2-methoxy
propene
O
N
H
N
3
O
OH
Ts
13c
2
3.9%
TsOH
CH2Cl2
60%
N
N
3
3.
6N HCl, reflux
91% (3 steps)
H
Ts
Ts
13c
15
Scheme 4. Synthesis of (2S,3R)-3-hydroxy-3-methylproline
(3).
Scheme 3. Determination of the stereochemistry at C3.
In conclusion, we have achieved the stereoselective
synthesis of (2S,3R)-3-hydroxy-3-methylproline (3)
using a highly diastereoselective intramolecular cycliza-
tion reaction using SmI2 as a pivotal step. Further
investigation directed towards the total synthesis of
polyoxypeptin is under way in this laboratory.
2). An attempt using the iodoketone 12b protected by
the Tr group showed low diastereoselectivity (13b:14b=
31:69) in moderate yield. Finally, we continued our
investigation in the hope that non-protected iodoketone
12c could cyclize through
a
hydroxy-directed
intermediate3b,7 to give the desired diastereomer. Thus,
12c was treated with SmI2 in THF–HMPA (10:1) at
−78 to −55°C for 1.5 h to exclusively afford the cyclized
product 13c with a ratio of 97:3 in 75% yield.5 In
addition, the mixture could be easily separated by silica
gel chromatography to provide the diastereomerically
pure product 13c.6 The stereochemistry of 13c was
Acknowledgements
This work was financially supported in part by a Grant-
in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology.
1
verified by the H-NOE difference studies of 15 after
protection of the diol as an isopropylidene acetal
(Scheme 3). As indicated by Matsuda and Shira-
hama,3b,7 the observed diastereoselectivity can be ratio-
nalized by invoking a six-membered cyclic transition
state, wherein Sm chelation between the primary
hydroxyl function and the ketyl radical forms a six-
membered chair, which directs the methyl group to the
equatorial position, thus allowing the iodoalkyl func-
tion to be attacked exclusively at the axial side (Fig. 2).
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hol to carboxylic acid by use of a stepwise procedure (1.
Dess–Martin periodinane, CH2Cl2. 2. NaClO2,
t
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of the tosyl group by treatment of 6N HCl under
refluxing conditions in 91% yield without epimerization
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natural product, and also had a specific rotation, [h]D27
−42.0 (c 1.30, H2O), in good agreement with literature
value ([h]1D8 −41 (c 0.4, H2O),1b [h]2D6 −40.2 (c 0.42,
H2O),2b [h]2D5 −38.6 (c 0.40, H2O)2c).
I
L
Me
L
I
SmLn
SmLn
O
Me
O
N
N
Ts
OH
OH
Ts
H
L = HMPA or I
H
Transition state B
(disfavored)
Transition state A
(favored)
Figure 2. The plausible transition states in the intramolecular Barbier-type reaction promoted by samarium iodide(II) in the
presence of HMPA.

4698
K. Makino et al. / Tetrahedron Letters 43 (2002) 4695–4698
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J=8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) l 21.5,
26.5, 39.1, 46.9, 62.6, 67.6, 78.9, 127.6, 129.8, 133.7,
144.0; HRMS (FAB) calcd for C13H20NO4S: 286.1113
(M++1). Found: 286.1112.
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13c: 9.9 min, 14c: 8.0 min).
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1.30, H2O); IR (KBr) 3398, 3115, 2983, 1618, 1406 cm−1
;
6. Data for 13c: mp 100–101°C (AcOEt–nhexane); [h]D24
−83.8 (c 1.09, MeOH); IR (KBr) 3398, 2974, 1339, 1157,
1H NMR (400 MHz, D2O) l 1.59 (s, 3H), 2.12–2.16 (m,
2H), 3.45 (ddd, J=11.0, 7.0, 4.6 Hz, 1H), 3.51–3.58 (m,
1H), 3.85 (s, 3H); 13C NMR (100 MHz, D2O) l 24.4,
39.9, 43.8, 70.1, 78.8, 171.1; HRMS (FAB) calcd for
C6H12NO3: 146.0817 (M++1). Found: 146.0830 (M++1).
1093 cm−1 1H NMR (400 MHz, CDCl3) l 0.94 (s, 3H),
;
1.49 (dt, J=12.3, 6.5 Hz, 1H), 1.94 (dt, J=12.5, 7.4 Hz,
1H), 2.44 (s, 3H), 3.14 (t, J=4.0 Hz, 1H), 3.17 (dt,
J=10.3, 7.3 Hz, 1H), 3.52 (brs, 1H), 3.59 (dt, J=10.3,