Progress towards the total synthesis of scytonemin A: Asymmetric synthesis of(2S,3R,4R)-4-hydroxy-3-methylproline

Article abstract of DOI:10.1055/S-0029-1219208

During the total synthesis of the novel cyclopeptide scytonemin A, the fragment containing two (2S,3R,4R)-4-hydroxy-3-methylproline units was successfully prepared. Two approaches leading to (2S,3R,4R)-4-hydroxy-3- methylproline have been explored. They i

Full text of DOI:10.1055/S-0029-1219208

LETTER
563
Progress towards the Total Synthesis of Scytonemin A: Asymmetric Synthesis
of (2S,3R,4R)-4-hydroxy-3-methylproline
S
ynthesis of (2
S
e
,3
R
,4
R
)-4-
i
hydroxy-3-m
W
ethylproline ang,a Junyang Liu,a Hui Zhang,a Zhengshuang Xu,*a,b Tao Ye*a,b
a
Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, University Town of Shenzhen,
Xili, Nanshan District, Shenzhen 518055, P. R. of China
E-mail: xuzs@szpku.edu.cn
b
Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University,
Hung Hom, Kowloon, Hong Kong
Fax +852(2)2641912; E-mail: bctaoye@inet.polyu.edu.hk
Received 19 November 2009
Dedicated to Gerry Pattenden on the occasion of his 70th birthday
compounds are in advanced clinical trials, and others have
proven useful in studies directed toward the elucidation of
biochemical pathways.1,2 In 1988, Moore et al. reported
the isolation of an unusual cyclic peptide, scytonemin A
Abstract: During the total synthesis of the novel cyclopeptide scy-
tonemin A, the fragment containing two (2S,3R,4R)-4-hydroxy-3-
methylproline units was successfully prepared. Two approaches
leading to (2S,3R,4R)-4-hydroxy-3-methylproline have been ex-
plored. They involve the following key transformations: asymmet- (Scheme 1), from a Scytonema sp. (strain U-3-3, Scytone-
mataceae).3 The structure of scytonemin A was deter-
mined by interpretation of spectroscopic data, chemical
ric crotylation, Sharpless epoxidation–subsequent epoxide opening,
intramolecular amidomercuration–oxidation.
Key words: scytonemin A, cyclopeptide, substituted proline,
amino acids, asymmetric synthesis
degradation, and evaluation of the amino acids obtained
by acid hydrolysis.
In our efforts to synthesize a series of bioactive cyclopep-
tides and cyclodepsipeptides,4 we chose scytonemin A (1)
as a target due to its potent calcium antagonistic properties
and its novel amino acid residues: (2R,3S)-threo-3-
hydroxyleucine (HyLeu), (2S,3S)-trans-3-methylproline
(MePro), (2S,3R,4R)-4-hydroxy-3-methylproline (Hy
Marine organisms have provided chemists with a wealth
of structurally diverse compounds in recent years, and
many of these compounds have shown considerable bio-
logical activity including antimicrobial, antiviral, anti-
tumor, and anti-inflammatory properties.1 Some of these
O
O
N
H
O
OH
O
H
N
HO
NHCbz
O
NH
NH
O
O
O
OH
N
N
OTBS
OH
OH
N
O
O
O
O
O
HO
N
N
OTBS
NH
O
2
O
OMe
NH
O
HN
O
HN
NH
CbzN
OTBS
HO
O
OH
scytonemin A (1)
3
Scheme 1 Structure of scytonemin A
SYNLETT 2010, No. 4, pp 0563–0566
0
1.
0
3.
2
0
1
0
Advanced online publication: 19.01.2010
DOI: 10.1055/s-0029-1219208; Art ID: D33409ST
© Georg Thieme Verlag Stuttgart · New York

564
L. Wang et al.
LETTER
MePro), and (2S,3R,5S)-3-amino-2,5,9-trihydroxy-l0- chiral ligand, to afford the epoxyalcohol 5 in 86% yield
phenyldecanoic acid (Ahda). En route to a total synthesis over two steps.8 Removal of the Cbz protecting group by
of scytonemin A (1), we have developed two novel catalytic hydrogenation gave the corresponding free
stereocontrolled asymmetric approaches leading to the amine, which spontaneously cyclized onto the epoxide by
preparation of (2S,3R,4R)-4-hydroxy-3-methylproline.5
a 5-exo process to afford a pyrrolidine derivative that was
reprotected in situ with CbzCl to provide 4 in 75% overall
yield from the epoxy alcohol 5.12 Sodium periodate cleav-
age of the diol11 in 4 produced the corresponding aldehyde
6, which was immediately oxidized under Pinnick
conditions13 to furnish 3 in 92% yield. The overall yield
for the synthesis of 3 from 9 was 15%.
We envisaged that the erythro-4-hydroxy-3-methyl
groups of (2S,3R,4R)-4-hydroxy-3-methylproline would
arise from an asymmetric crotylation6 to give key interme-
diate 8 (or 8a), followed by an amidomercuration–
oxidation protocol7 or a sequence of reactions including
Sharpless epoxidation8 and intramolecular epoxide-
opening process9 (Scheme 2).
Although this strategy for the synthesis of 3 was success-
ful, the overall yield was not very satisfactory and there
was room for improvement. Since the yields for both
asymmetric crotylation and Wittig olefination (leading to
intermediates 8 and 10, respectively) were relatively low,
we speculated that the unprotected carbamate in 9 might
play a critical role in decreasing the yield of these trans-
formations. Therefore, we decided to employ N-benzyl-
N-(benzyloxycarbonyl)ethanolamine (9a) as the starting
material for the synthesis of 3. To our delight, asymmetric
crotylation of the 9a-derived aldehyde afforded homoal-
lylic alcohol 8a in 83% yield. In addition, the transforma-
tion of 8a to 10a, which involved TBS protection of
homoallylic alcohol, sodium periodate cleavage of the di-
ol, and Wittig olefination of the resulting aldehyde, was
accomplished in 61% yield over three steps (Scheme 3).
The Wittig olefination leading to 10a was performed at
room temperature while the similar reaction leading to 10
needed to be conducted at high temperature. Since simul-
taneous removal of both Cbz and Bn protecting groups in
5a with Pd/C as catalyst was very slow, Pearlman’s cata-
lyst was employed for the epoxide-opening process to
give 4 in 72% yield. Thus, the overall yield for the synthe-
sis of 3 from 9a was improved to 29%.
TBSO
TBSO
[A]
OTBS
OH
O
OH
2
5
COOH
N
N
1
HN
Cbz
Cbz
OH
Cbz
3
5
4
[B]
HO
TBSO
OH
HgOAc
2
5
CHO
N
H
N
1
N
Cbz
R
Cbz
7
8 R = H
8a R = Bn
6
Scheme 2 Retrosynthesis of (2S,3R,4R)-4-hydroxy-3-methylproline
From a retrosynthetic viewpoint, the carboxylic acid
group in 3 could be masked as a vicinal diol, which leads
to compound 4. Further disconnection at the C2–N bond
gives the key precursor epoxide 5, which in turn could be
obtained from alkene 8 (or 8a). The alkene 8 (or 8a) can
be easily constructed by using Brown’s asymmetric crot-
ylation reaction6 (route A, Scheme 2). Alternatively, 3
could be prepared from the corresponding aldehyde 6,
arising from an epimerization and amidomercuration of
alkene 8 (route B, Scheme 2).
R
Cbz
R
Cbz
TBSO
OEt
N
N
OH
iii
i, ii
Cbz
O
The synthesis of 3 commenced with the asymmetric
crotylation6 of aldehydes derived from N-monoprotected
and N-bis-protected alcohols 9 and 9a. TEMPO-mediated
oxidation10 of 9 gave the corresponding aldehyde in 95%
yield. This was then reacted with (+)-B-(E)-crotyldiiso-
pinocampheylborane to give the anti-homoallylic alcohol
8 in 56% yield with no discernible trace of the syn-stereo-
isomer by 1H NMR analysis of the crude product. This op-
eration established the absolute stereochemistry at C3 and
C4 corresponding to that required for 3. After conversion
of the homoallylic alcohol 8 to its silyl ether, the terminal
alkene was cleaved by the action of OsO4/NaIO4 in the
presence of 2,6-lutidine11 to furnish the corresponding al-
dehyde, which underwent simultaneous attack by the
carbamoyl NH to afford the corresponding cyclic hemi-
aminal (see Supporting Information). The hemiaminal
was then homologated by Wittig olefination to afford a,b-
unsaturated ester 10 as the E-stereoisomer exclusively.
DIBAL-H reduction of 10 afforded the corresponding al-
lylic alcohol, which was subjected to a Sharpless asym-
metric epoxidation, using (–)-diisopropyl tartrate as the
N
R
OH
8 R = H, 56%
8a R = Bn, 83%
10 R = H, 45% from 8
10a R = Bn, 61% from 8a
9 R = H
9a R = Bn
iv
TBSO
vi
TBSO
OTBS
OH
HO
OH
O
v
COOH
N
N
N
Cbz
Cbz
R
Cbz
3, 92%
4 (from 5), 75%
4 (from 5a), 72%
5 R = H, 86%
5a R = Bn, 85%
Scheme 3 Epoxide-opening approach. Reagents and conditions: i,
TEMPO, TCCA, CH2Cl2, 0 °C; ii, KOt-Bu, n-BuLi, trans-2-butene,
(+)-IPC2BOMe, BF3·OEt2, –100 °C, then H2O2, Et3N, THF; iii, (a)
TBSCl, imidazole, DMAP (cat.), DMF; (b) OsO4, NaIO4, 2,6-lutidi-
ne, dioxane–H2O; (c) Ph3PCHCO2Et, benzene, reflux (for 10) or
Ph3PCHCO2Et, CH2Cl2, r.t. (for 10a); iv, (a) DIBAL-H, CH2Cl2, –78
°C to –20 °C; (b) (–)-DIPT, (i-PrO)4Ti, TBHP, 4 Å MS, CH2Cl2, –40
°C; v, (a), H2, Pd/C, MeOH (from 5); or H2, Pearlman’s catalyst (from
5a); (b) CbzCl, NaHCO3, THF–H2O; vi, (a) NaIO4–SiO2, CH2Cl2; (b)
NaClO2, NaH2PO4, MeSO2NH2, t-BuOH–H2O.
Synlett 2010, No. 4, 563–566 © Thieme Stuttgart · New York

LETTER
Synthesis of (2S,3R,4R)-4-hydroxy-3-methylproline
565
In order to explore a more convenient protocol for the
preparation of 3, we also investigated a synthetic ap-
proach based on intramolecular amidomercuration of the
TBS-protected intermediate 8. The rationale behind this
decision was supported by the well-known mercury(II)-
mediated 5-exo-trig cyclization.7 In addition, we envis-
aged that the stereochemistry for the stereogenic center
adjacent to the aldehyde group in 12 would be determined
by the substituents at C3 and C4 of the pyrrolidine ring.
Therefore, under basic conditions, the diastereomer with
the syn-C2 stereogenic center should epimerize to the con-
figuration required for the target molecule.
O
CbzHN
CbzHN
N
OTBS
OTBS
OTBS
O
CbzN
O
iv
i–iii
O
O
O
N
85%
60%
N
OH
MeO
OTBS
3
13
OMe
2
Scheme 5 Synthesis of fragment 2. Reagents and conditions: i,
CH2N2, Et2O; ii, H2, Pd/C, MeOH; iii, Cbz-Gly-OH, BOPCl, DMF;
iv, (a), LiOH, THF–MeOH–H2O; (b) BOPCl, 3, DIPEA, DMF.
Thus, after protection of the homoallylic alcohol 8 using
tert-butyldimethylsilyl chloride, the resulting TBS ether
was treated with Hg(OAc)2 in acetonitrile to afford the
corresponding pyrrolidine derivative as a mixture of two
diastereomers. Subsequent workup under standard
conditions14 and oxidative demercuration of the organo-
mercury adduct in the presence of molecular oxygen af-
forded the trisubstituted pyrrolidine derivative 11 in 50%
yield.15 Dess–Martin oxidation of the primary alcohol in
11 produced the corresponding aldehyde 12 in 85% yield
as a mixture of diastereomers. To our delight, treatment of
aldehyde 12 with DBU equalized the diastereomeric mix-
ture of 12 to the thermodynamically more stable isomer in
92% isolated yield with the stereochemistry shown in 6.
Pinnick oxidation13 of 6 furnished the desired compound
3 in 90% yield (Scheme 4). The overall yield for the syn-
thesis of 3 from 9 of the amidomercuration–oxidation-
based protocol was 20%.
In summary, we have developed two practical approaches
for the synthesis of 4-hydroxy-3-methylproline deriva-
tive. A tripeptide fragment based on 4-hydroxy-3-methyl-
proline of scytonemin A has also been successfully
prepared. Efforts toward the completion of the total syn-
thesis of scytonemin A are currently under way in our lab-
oratory, and our progress will be disclosed in due course.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We acknowledge financial support from the Hong Kong Research
Grants Council (Project: PolyU 5407/06M) and financial support
from the Shenzhen Bureau of Science, Technology and Information
(08systs-01, JC200903160367A). Z.S.X. would like to thank the
support from Shenzhen Foundation for R&D (SZKJ-2007011,
SY2008063 00179A), Nanshan Science
&
Technology
(NANKEYUAN2007019), and NSF of GuangDong Province
(8451805704000656).
TBSO
TBSO
HgOAc
OH
HO
ii
i
50%
N
N
CbzHN
Cbz
7
Cbz
11
References and Notes
8
iii 85%
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TBSO
TBSO
TBSO
iv
OH
O
H
O
H
O
v
92%
90%
N
N
N
Cbz
Cbz
Cbz
12
3
6
Scheme 4 Amidomercuration–oxidation-based approach. Reagents
and conditions: i, (a) TBSCl, imidazole, DMAP (cat.), DMF; (b)
Hg(OAc)2, MeCN; ii, O2, NaBH4, DMF; iii, Dess–Martin periodinate,
CH2Cl2; iv, DBU; v, NaClO2, NaH2PO4, MeSO2NH2, t-BuOH–H2O.
With the requisite 4-hydroxy-3-methylproline in hand, the
desired tripeptide 2 was readily prepared in good yield via
a series of standard transformations including esterifica-
tion of 3 with diazomethane, hydrogenation of the result-
ing methyl ester with Pd/C to produce the corresponding
free amine, which was coupled with Cbz-protected gly-
cine to afford 13. Saponification of the methyl ester in 13
to the corresponding acid, followed by coupling with the
free amine derived from 3 in the presence of BOPCl pro-
duced 2 in 60% yield (Scheme 5).16
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Synlett 2010, No. 4, 563–566 © Thieme Stuttgart · New York

566
L. Wang et al.
LETTER
for 3 h and then concentrated in vacuo. The residue was
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extracted with EtOAc (3 × 20 mL). The combined organic
phases were washed with brine (30 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel, eluting
with EtOAc–hexane (2:3) to give desired product 4 (0.49 g,
75%); [a]D25 –6.6 (c 0.70, CHCl3). 1H NMR (500 MHz,
CDCl3): d = 7.40–7.29 (m, 5 H), 5.17 (s, 2 H), 4.17 (d,
J = 3.3 Hz, 1 H), 4.11 (d, J = 9.0 Hz, 1 H), 3.73 (dd, J = 4.2,
7.1 Hz, 1 H), 3.61–3.58 (m, 4 H), 3.34 (dd, J = 4.1, 11.6 Hz,
1 H), 3.09–3.07 (m, 1 H), 2.18 (dd, J = 6.9, 11.5 Hz, 1 H),
1.12 (d, J = 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.07 (s, 3 H), 0.04 (s,
3 H). 13C NMR (125 MHz, CDCl3): d = 157.7, 136.3, 128.5
(128.5), 128.2, 128.0 (127.9), 73.4, 72.2, 67.6, 65.7, 62.9,
54.5, 41.4, 25.8 (25.7), 18.0, 13.0, –4.9, –5.0 ppm. ESI-
HRMS: m/z calcd for C21H36NO5Si+ [M + H]+: 410.2351;
found: 410.2375.
(5) For the synthesis of racemic and enantiomerically enriched
4-hydroxy-3-methylproline, please see: (a) Anderson, J. C.;
Flaherty, A. J. Chem. Soc., Perkin Trans. 1 2001, 267.
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1981, 37, 2091.
(14) Sarraf, S. T.; Leighton, J. L. Org. Lett. 2000, 2, 403.
(15) Procedure for the Synthesis of 11 via
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Amidomercuration–Oxidation
To a stirred solution of compound 8 (0.88 g, 2.40 mmol) in
MeCN (20 mL), Hg(OAc)2 (2.26 g, 7.20 mmol) was added.
The reaction mixture was refluxed for 2 h and then cooled to
r.t. EtOAc (10 mL) and brine (10 mL) were added, and the
mixture was stirred at r.t. for a further 1.5 h and filtered to
remove the precipitated inorganic byproduct. The filtrate
was separated and the aqueous layer was extracted with
EtOAc (3 × 50 mL). The combined organic phases were
dried over anhydrous Na2SO4 and concentrated in vacuo to
give 7 as a colorless foam. In a second reaction vessel,
oxygen (O2) was bubbled into a well-stirred solution of
NaBH4 (0.09 g, 2.4 mmol) in DMF (25 mL) at r.t. One hour
later, the above intermediate in DMF (25 mL) was slowly
added over 2 h, while maintaining the flow of oxygen. Upon
completion of addition, the reaction mixture was stirred for
additional 2 h and then filtered through a pad of Celite,
eluting thoroughly with EtOAc (200 mL). The filtrate was
concentrated in vacuo, and the residue was purified by flash
chromatography (EtOAc–hexane, 3:1) to afford the
diastereoisomers 11a (0.23 g, 26%) and 11b (0.22 g, 24%).
Analytical Data for 11a
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[a]D25 +28.6 (c 0.54, CHCl3). 1H NMR (500 MHz, CDCl3);
d = 7.37–7.27 (m, 5 H), 5.22–5.09 (m, 2 H), 4.24–4.02 (m, 2
H), 3.94–3.79 (m, 2 H), 3.72–3.66 (m, 1 H), 3.60–3.55 (m, 1
H), 3.52–3.42 (m, 1 H), 2.46–2.33 (m, 1 H), 1.07 (1.05) (d,
J = 7.4 Hz, 3 H), 0.92 (0.91) (s, 9 H), 0.14 (0.09) (s, 6 H)
ppm. 13C NMR (125 MHz, CDCl3): d = 156.1 (154.9), 136.7,
128.5, 128.0, 127.9, 73.4 (72.8), 67.1, 62.8 (61.9), 61.5
(59.8), 56.1 (55.4), 41.4 (40.7), 25.7, 18.0, 9.9 (9.7), –4.8,
–5.1 ppm. ESI-HRMS: m/z calcd for C20H34NO4Si+ [M +
H]+: 380.2252; found: 380.2268.
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6, 3217.
(12) Procedure for the Synthesis of 4 via Epoxide Opening
Epoxide 5 (0.65 g, 1.6 mmol) was dissolved in MeOH (10
mL). After a catalytic amount of Pd/C (10%) was added, the
reaction was exposed to an atmosphere of H2 at ambient
temperature. The reaction was monitored by TLC. After all
starting material was consumed (ca. 2 h), the reaction
mixture was stirred for an additional 1 h and then filtered
through a pad of Celite. The filter cake was washed with
MeOH (10 mL). The combined filtrate and washings were
concentrated in vacuo to leave the corresponding amine as
an oil, which was dissolved in THF–H2O (20 mL, 1:1) at 0
°C and treated with NaHCO3 (0.25 g, 3.0 mmol) and CbzCl
(0.29 mL, 2.0 mmol). The reaction mixture was stirred at r.t.
Analytical Data for 11b
[a]D25 –2.0 (c 0.16, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 7.38–7.33 (m, 5 H), 5.35–5.10 (m, 2 H), 4.85 (br, 1 H)
4.05 (br, 1 H), 3.82–3.80 (m, 1 H), 3.70–3.66 (m, 1 H), 3.62–
3.58 (m, 2 H), 3.38 (dd, J = 3.0, 13.4 Hz, 1 H), 1.84–1.77 (m,
1 H), 1.06 (d, J = 6.7 Hz, 3 H), 0.87 (s, 9 H), 0.06 (s, 3 H),
0.04 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): d = 157.4,
136.4, 128.5, 128.0, 127.8, 72.3, 67.3, 65.9, 65.6, 55.6, 41.4,
25.7, 18.0, 11.9, –4.8, –5.0 ppm. ESI-HRMS: m/z calcd for
C20H34NO4Si+ [M + H]+: 380.2252; found: 380.2264.
(16) See Supporting Information.
Synlett 2010, No. 4, 563–566 © Thieme Stuttgart · New York