Synthesis of the acyl side chain segment of polyoxypeptins using regioselective ring-opening of chiral 2,3-epoxy alcohol

Article abstract of DOI:10.1016/S0040-4039(02)02324-9

The acyl side chain segment 2 contained in polyoxypeptins A (1a) and B (1b), apoptosis-inducing cyclodepsipeptides, was synthesized from chiral 2,3-epoxy alcohol (6), easily prepared by Sharpless asymmetric epoxidation, through a regioselective ring-opening reaction as the key step.

Full text of DOI:10.1016/S0040-4039(02)02324-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9391–9395
Synthesis of the acyl side chain segment of polyoxypeptins using
regioselective ring-opening of chiral 2,3-epoxy alcohol
Kazuishi Makino, Tatsuya Suzuki, Shinobu Awane, Osamu Hara† and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 13 September 2002; revised 10 October 2002; accepted 11 October 2002
Abstract—The acyl side chain segment 2 contained in polyoxypeptins A (1a) and B (1b), apoptosis-inducing cyclodepsipeptides,
was synthesized from chiral 2,3-epoxy alcohol (6), easily prepared by Sharpless asymmetric epoxidation, through a regioselective
ring-opening reaction as the key step. © 2002 Elsevier Science Ltd. All rights reserved.
Polyoxypeptins A (1a) and B (1b) were isolated from
the culture broth of Streptomyces species by Umezawa
and co-workers.1 They are known to exhibit potent
apoptosis against human pancreatic adenocarcinoma
AsPC-1 cells and have attracted attention as potential
anticancer agents.2 The structurally related cyclodep-
sipeptides have also become attractive targets for their
unique structures and biological activities.3 The relative
and absolute stereostructure of polyoxypeptin A was
determined by X-ray analysis and chemical degradation
studies and revealed to bear a lipophilic acyl side chain
segment and some unique amino acid residues, (2S,3S)-
3-hydroxyleucine, (3R,5R)-5-hydroxypiperazic acid and
(2S,3R)-3-hydroxy-3-methylproline ones. The intrigu-
ing biological activities coupled with the unique struc-
ture of polyoxypeptins prompted us to synthesize these
novel cyclodepsipetides. As studies directed towards the
total synthesis of the polyoxypeptins, we have already
reported
efficient
synthesis
of
(2S,3S)-3-
hydroxyleucine2a using dynamic kinetic resolution and
(2S,3R)-3-hydroxy-3-methylproline using SmI2-medi-
ated cyclization.2f We describe here stereoselective syn-
thesis of the acyl side chain segment 2 from chiral
2,3-epoxy alcohol 6, easily prepared by Sharpless asym-
metric epoxidation, through a regioselective ring-open-
ing reaction. Kobayashi and Kurosu have indepen-
Figure 1.
Keywords: polyoxypeptins; cyclodepsipeptide; regioselective ring-opening; 2,3-epoxy alcohol.
* Corresponding author. Fax: +81-43-290-2987; e-mail: hamada@p.chiba-u.ac.jp
† Present address: Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 460-8503, Japan.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02324-9

9392
K. Makino et al. / Tetrahedron Letters 43 (2002) 9391–9395
dently reported the stereoselective synthesis of the acyl
side chain segment utilizing palladium-catalyzed
hydrogenolysis and anti-aldol strategy, respectively
(Fig. 1).2d,e
liminary experiment using lithium diisobutylcuprate, a
homocuprate, was low regioselectivity and poor yield
(entry 1). After extensive experiments, we found that
the reaction was dependent on the solvent and the
counter anion in the Grignard reagent and copper salts,
as shown in Table 1. The reaction using the most
effective combination, cuprous chloride (1 equiv.) and
isobutylmagnesium bromide (4 equiv.) in ether, at
−78°C for 15 h regioselectively proceeded and gave the
1,3-diol in 68% yield and a ratio of 96:4. Use of a
catalytic amount of cuprous chloride was less effective
than a stoichiometric amount in terms of yield and
regioselectivity (entry 4). Next, using the optimized
condition, ring-opening of the epoxide 6 with (S)-2-
methylbutyl Grignard reagent derived from commer-
cially available (S)-2-methylbutanol was investigated.
Thus, the epoxide 6 was treated with a combination of
(S)-2-methylbutylmagnesium bromide (10) and cuprous
chloride in ether at −78°C for 6 h to afford the desired
1,3-diol 11 as a major product in 97% yield and a ratio
of 95:5. Pure 11 was obtained in 63% yield after treat-
ment of the mixture with sodium periodate for purifica-
tion.7 On the other hand, the corresponding iodide
reagent, (S)-2-methylbutylmagnesium iodide and
cuprous iodide, in ether yielded the products in a ratio
of 67:33 (Scheme 3).
Our retrosynthetic analysis of the acyl side chain seg-
ment 2 is illustrated in Scheme 1. The segment 2 is
equivalent to the open chain compound 3 which can be
dissected into two segments, the C5–C10 segment and
C1–C4 one. The latter segment 5 has already been
synthesized by us and used in the synthesis of the acyl
side chain segment of a structurally related cyclodepsi-
peptide, GE3.3a For the synthesis of the C5–C10
segment, we employed a regioselective ring-opening
reaction of the chiral 2,3-epoxy alcohol 6 using the
Gilman reagent 7.
The required epoxide 6 was prepared from 2-pentyn-1-
ol (8) by reduction of the triple bond with lithium
aluminum hydride followed by Sharpless asymmetric
epoxidation (Scheme 2).4 Generally, this type of ring-
opening reaction of 2,3-epoxy alcohols is known to be
nonregioselective except the 2,3-epoxy alcohols
branched at C4.5,6 Especially, when the steric environ-
ment adjacent to an epoxide ring is similar to that of 6,
nucleophilic attack by an organocopper reagent com-
petes at the C2 and C3 centers and gives equal amounts
of 1,3-diol and 1,2-diol. We first investigated a model
ring-opening reaction of the epoxide 6 using isobutyl-
magnesium bromide and copper salts because the pre-
The 1,3-diol 11 was converted to aldehyde 15 in four
steps as follows. Protection of the primary and sec-
Scheme 1.
Scheme 2.

K. Makino et al. / Tetrahedron Letters 43 (2002) 9391–9395
Table 1. Regioselective ring-opening reaction of chiral 2,3-epoxy alcohol
9393
Entry
Solvent
Cu salts (1 equiv.)
Ratio of 1,3- and 1,2-diola
Yield (%)
20
b
1
2
3
4
5
6
7
8
9
Ether
Ether
Ether
Ether
Ether
Ether
Ether
THF
DME
–
–
73:27
–
c
d
–
CuCl
CuCl (0.2 equiv.)
CuBr
CuI
CuCN
CuCl
96:4
93:7
94:6
91:9
87:13
91:9
84:16
68
58
66
41
52
75
76
CuCl
a Determined by GLC.
b Lithium diisobutylcuprate was used.
c No copper salt.
d No reaction was observed.
Scheme 3.
produce a,b-unsaturated ester 16, which was converted
to aldehyde 17 by hydrogenation of the double bond,
reduction of the ester, and Swern oxidation of the
resulting alcohol in 68% yield. The reaction of 17 using
the phosphonate reagent 18 (method A) afforded a,b-
unsaturated ester 20 in 96% yield but nonstereoselec-
tively. Fortunately, the phosphorane reagent generated
from phosphonium salt 19 by treatment with sodium
hydride in THF (method B) produced 20 in 90% yield
and an E/Z ratio of 98:2. After separation of the
undesired isomer by column chromatography, the (E)-
a,b-unsaturated ester was asymmetrically dihydroxy-
lated with AD-mix-b8 in the presence of
methanesulfonamide to afford dihydroxy ester 21 in
96% yield and a ratio of 5:1. The undesired isomer was
found to be separated in a later step. Oxidation of the
ondary alcohols with pivaloyl and tert-butyldimethylsi-
lyl groups, respectively, gave ester 13 in excellent yield.
Removal of the pivaloyl group from 13 with lithium
borohydride yielded alcohol 14, which was oxidized
under Swern oxidation to produce the C5–C10 segment
15. Coupling of the thus obtained aldehyde 15 was first
attempted with the C1–C4 segment 5. The reaction with
the lithium enolate (1.1 equiv.) prepared from 5 at
−78ꢀ0°C for 7 h, however, failed probably due to the
steric bulkiness of the aldehyde 15 which was recovered
without epimerization. The alkylation of the C1–C4
segment 5 using the corresponding iodide reagent
derived from 15 caused complete decomposition of the
iodide. Therefore, we were forced to change the route
to a stepwise elongation approach. The aldehyde 15
was homologated by Horner–Emmons olefination to

9394
K. Makino et al. / Tetrahedron Letters 43 (2002) 9391–9395
Scheme 4.
dihydroxy ester 21 by the Parikh–Doering method9
followed by acid treatment of the resulting keto ester 22
with aqueous hydrofluoric acid in acetonitrile furnished
the acyl side chain segment 2 of polyoxypeptins as a
nice crystalline in 70% yield (Scheme 4). The C-2
epimer derived from the AD-mix-b dihydroxylation was
removed by simple recrystallization. The structure of 2
was confirmed by comparison of the spectral values of
natural polyoxypeptin A10 and the synthetic acyl side
chain.2d,e Incidentally, the route from 16 was similar to
the reported one2d except the protecting groups and the
efficiency.
Lett. 1998, 39, 1389–1392; (b) Umezawa, K.; Nakazawa,
K.; Ikeda, Y.; Naganawa, H.; Kondo, S. J. Org. Chem.
1999, 64, 3034–3038.
2. (a) Makino, K.; Okamoto, N.; Hara, O.; Hamada, Y.
Tetrahedron: Asymmetry 2001, 12, 1757–1762; (b)
Noguchi, Y.; Uchihiro, H.; Yamada, T.; Kobayashi, S.
Tetrahedron Lett. 2001, 42, 5253–5256; (c) Qin, D.-G.;
Zha, H.-Y.; Yao, Z.-J. J. Org. Chem. 2002, 67, 1038–
1040; (d) Noguchi, Y.; Yamada, T.; Uchiro, H.;
Kobayashi, S. Tetrahedron Lett. 2000, 41, 7499–7502; (e)
Lorca, M.; Kurosu, M. Tetrahedron Lett. 2001, 42, 2431–
2434; (f) Makino, K.; Kondoh, A.; Hamada, Y. Tetra-
hedron Lett. 2002, 43, 4695–4698.
In conclusion, we have achieved the stereoselective
synthesis of the acyl side chain segment 2 of poly-
oxypeptins. In this route, we have demonstrated the
highly regioselective C-2 ring-opening reaction of 2,3-
epoxy alcohol 6, derived from Sharpless asymmetric
epoxidation, by carbon nucleophiles. Further investiga-
tion directed towards the total synthesis of poly-
oxypeptins is under way.
3. (a) Makino, K.; Henmi, Y.; Hamada, Y. Synlett 2002,
613–615; (b) Hale, K. J.; Lazarides, I. Org. Lett. 2002,
1903–1906 and references cited therein.
4. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980,
102, 5974–5976; (b) Honda, M.; Katsuki, T.; Yamaguchi,
M. Tetrahedron Lett. 1984, 25, 3857–3860.
5. For nucleophilic ring-opening of 2,3-epoxy alcohols (non-
branched at C4) at C2 center, see: (a) Tius, M. A.; Fauq,
A. H. J. Org. Chem. 1983, 48, 4131–4132; (b) see: Ref. 4a;
(c) Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986,
108, 1035–1039; (d) Kuroda, C.; Theramongkol, P.;
Engebrecht, J. R.; White, J. D. J. Org. Chem. 1986, 51,
956–958; (e) Chong, J. M.; Cry, D. R.; Mar, E. K.
Tetrahedron Lett. 1987, 28, 5009–5012.
6. For nucleophilic ring-opening of 2,3-epoxy alcohols
(branched at C4) at C2 center, see: (a) Johnson, M. R.;
Nakata, T.; Kishi, Y. Tetrahedron Lett. 1979, 20, 4343–
4346; (b) Nagaoka, H.; Rutsch, W.; Schmid, G.; Iio, H.;
Johnson, M. R.; Kishi, Y. J. Am. Chem. Soc. 1980, 102,
7962–7965; (c) Wood, R. D.; Ganem, B. Tetrahedron
Lett. 1982, 23, 707–710; (d) Nagaoka, H.; Kishi, Y.
Tetrahedron 1981, 37, 3873–3888; (e) Lipshutz, B. H.;
Kotsuki, H.; Lew, W. Tetrahedron Lett. 1986, 27, 4825–
4828; (f) Hanamoto, T.; Katsuki, T.; Yamaguchi, M.
Tetrahedron Lett. 1987, 28, 6195–6198.
Acknowledgements
This work was financially supported in part by Grant-
in-Aids from the Ministry of Education, Culture,
Sports, Science and Technology, Japan (to Y.H.) and
the Sasakawa Scientific Research Grant from the Japan
Science Society (to T.S.).
References
1. (a) Umezawa, K.; Nakazawa, K.; Uemura, T.; Ikeda, Y.;
Kondo, S.; Naganawa, H.; Kinoshita, N.; Hashizume,
H.; Hamada, M.; Takeuchi, T.; Ohba, S. Tetrahedron

K. Makino et al. / Tetrahedron Letters 43 (2002) 9391–9395
9395
7. Procedure for 11: To a stirred suspension of cuprous
chloride (99.0 mg, 1.00 mmol) and 6 (103 mg, 1.00 mmol)
in ether (5 mL) at −78°C was added dropwise (S)-2-
methylbutylmagnesium bromide (5.00 mL, 4.00 mmol)
over 5 min and the mixture was stirred at −78°C for 1
day. After quenching with saturated aqueous ammonium
chloride (50 mL), the resulting mixture was vigorously
stirred for 1 day. The mixture was extracted with ethyl
acetate (20 mL×3). The organic extracts were washed
with brine (30 mL), dried over sodium sulfate, filtered,
and concentrated in vacuo to give a mixture of 1,3-diol
and 1,2-diol (170 mg, 97%) as a slightly yellow oil in a
ratio of 95:5. For removal of the unwanted 1,2-diol, the
product was dissolved in methanol (10 mL) and water (2
mL) and treated with sodium periodate (200 mg, 0.935
mmol) at 0°C. After stirring at 0°C for 1 day, the reaction
mixture was quenched with saturated aqueous sodium
sulfite and the volatiles were removed in vacuo. The
residue was extracted with ethyl acetate (20 mL×3). The
organic extracts were washed with brine (20 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo.
Purification by silica gel chromatography (n-hexane:ethyl
acetate=1:1) to give 11 (110 mg, 63%) as a colorless oil:
[h]2D4=+47.69 (c 0.84, CHCl3); IR (neat, cm−1) 3363,
2961, 2929, 2876, 1654, 1462; 1H NMR (400 MHz,
CDCl3) l 0.88 (d, 3H, J=6.4 Hz, CH3), 0.88 (t, 3H,
J=7.2 Hz, CH3), 0.98 (t, 3H, J=7.2 Hz, CH3), 1.02–1.73
(m, 8H, CH, CH2), 2.38 (bs, 1H, OH), 2.71 (bs, 1H, OH),
3.50–3.59 (m, 1H, CH), 3.62 (dd, 1H, J=10.0, 6.4 Hz,
CH2), 3.91 (d, 1H, J=11.2 Hz, CH2); 13C NMR (100
MHz, CDCl3) l 10.0, 11.4, 19.0, 28.3, 30.3, 31.9, 35.5,
41.4, 64.1, 78.2; HRMS (FAB) calcd for C10H22O2 (M+
H) 175.1620, found: 175.1650.
8. (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.;
Crispino, G. A.; Hartung, J.; Jeong, K. S.; Kwong, H.-S.;
Morikawa, K.; Wang, Z. M.; Xu, D.; Zhang, X.-L. J.
Org. Chem. 1992, 57, 2768–2771; (b) Kolb, H. C.; Van
Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994,
94, 2483–2547.
9. Parikh, J. R.; Doering, W. von, E. J. Am. Chem. Soc.
1967, 89, 5505–5507.
10. 2: mp 67–68°C; [h]2D3=+80.5 (c 0.32, CHCl3); IR (neat,
1
cm−1) 3533, 3409, 2958, 2910, 2873, 1741, 1454; H NMR
(600 MHz, CDCl3) l 0.75 (t, J=7.4 Hz, 3H, CH3), 0.80
(d, J=6.3 Hz, 3H, CH3), 0.86 (t, J=7.4 Hz, 3H, CH3),
0.94–1.07 (m, 2H, CH2), 1.12–1.31 (m, 4H, CH, CH2),
1.32–1.41 (m, 2H, CH2), 1.43 (d, J=0.8 Hz, 3H, CH3),
1.55–1.63 (m, 1H, CH), 1.68 (ddd, J=13.2, 4.1, 3.0 Hz,
1H, CH), 1.76 (ddd, J=12.9, 7.4, 3.8 Hz, 1H, CH), 1.84
(ddt, J=13.2, 4.4, 2.5 Hz, 1H, CH), 3.09 (s, 1H, OH),
3.45 (ddd, J=10.2, 8.4, 2.4 Hz, 1H, CH), 4.18 (d, J=3.0
Hz, 1H, OH), 5.22 (s, 2H, CH2), 7.31–7.39 (m, 5H, Ar);
13C NMR (100 MHz, CDCl3) l 9.4, 11.6, 18.6, 19.5, 24.1,
25.2, 26.6, 31.0, 31.0, 36.5, 38.2, 67.7, 76.2, 78.9, 98.7,
128.4, 128.6, 128.7, 134.9, 175.9; HRMS (FAB) calcd for
C22H34NaO5 (M+Na) 401.2304, found: 401.2309. Anal.
calcd for C22H34O5: C, 69.81; H, 9.05. Found: C, 69.88;
H, 8.73%.