Total Synthesis of the Marine Natural Product Hemiasterlin by Organocatalyzed α-Hydrazination

Article abstract of DOI:10.1002/chem.201702812

An efficient synthesis of the potently cytotoxic marine peptide hemiasterlin is presented. The tetramethyltryptophan moiety is assembled by tert-prenylation of indole, followed by the high-yielding organocatalyzed α-hydrazination of a sterically congested aldehyde with excellent enantioselectivity. 2-Bromo-N-ethylpyridinium tetrafluoroborate (BEP)-mediated peptide coupling completes the synthesis, being the first approach that does not employ chiral auxiliaries. A novel phenonium-type rearrangement of the indole system occurred when subjecting dihydroxylated 3-tert-prenylindole to Mitsunobu conditions.

Full text of DOI:10.1002/chem.201702812

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Accepted Article
Title: Total synthesis of the marine natural product hemiasterlin via
organocatalyzed α-hydrazination
Authors: Thomas Lindel, Jan Hendrik Lang, and Peter G. Jones
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To be cited as: Chem. Eur. J. 10.1002/chem.201702812
Link to VoR: http://dx.doi.org/10.1002/chem.201702812
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Chemistry - A European Journal
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COMMUNICATION
Total synthesis of the marine natural product hemiasterlin via
organocatalyzed -hydrazination
[
a]
[b]
[a]
Jan Hendrik Lang , Peter G. Jones , and Thomas Lindel *
Dedicated to Professor Stefan Schulz on the occasion of his 60th birthday
Abstract. An efficient synthesis of the potently cytotoxic marine
peptide hemiasterlin is presented. The tetramethyltryptophan moiety
is assembled via tert.-prenylation of indole, followed by the high-
yielding, organocatalyzed -hydrazination of a sterically congested
aldehyde with excellent enantioselectivity. BEP-mediated peptide
coupling completes the synthesis, being the first approach that does
not employ chiral auxiliaries. A novel phenonium-type rearrangement
of the indole system occurred when subjecting dihydroxylated 3-tert.-
prenylindole to Mitsunobu conditions.
published. Andersen et al. started from indol-3-ylacetic acid
employing Evans' oxazolidinone chemistry.[ 4 ] Vedejs and
Kongkittingam installed the amino nitrogen atom by an
asymmetric Strecker reaction, employing (R)-2-phenylglycinol as
chiral auxiliary.[5] Durst et al. published a shortened Strecker route
to 4.[6] Molinski et al. achieved the total synthesis of the closely
related milnamide A (3) by oxidative rearrangement of a
phenylglycinol-based oxazoline intermediate.[7] We felt that an
enantioselective route to the tetramethylated tryptophan
derivative 4 should be developed without using chiral auxiliaries.
For the assembly of the complete carbon framework in one step,
Hemiasterlin (1, Scheme 1) and its structural analogs criamide B
Tamaru's 3-tert.-prenylation of indole (5) was employed (Scheme
(
2) and milnamide A (3) constitute highly cytotoxic marine natural
2 [
). By reducing the catalyst load from 5 mol% to 1 mol% and by
8]
[
1 ]
products isolated from sponges.
The excellent antimitotic
using 10 equiv. of tert.-prenol (6) at r.t., we obtained the desired
regioisomer exclusively (86%), which was N-methylated
affording 8 (95%).
activity of hemiasterlin (1)[ 2 ] is based on microtubule
depolymerization and has triggered clinical trials of 1 as an
7
[
3]
anticancer agent. The methylation pattern of the tryptophan-
derived section is crucial for the bioactivity of hemiasterlin (1).[4b]
6
(10 equiv), Pd(PPh3)4 (1 mol%),
O
O
1
BEt
3
(2.4 equiv)
:
hemiasterlin
(R=OH)
5
1
1
N
THF, rt, 48 h, 86%
N
29
R
N
2: criamide B
KOH, MeI
H
R
7: R = H
: R = Me
modified Tamaru conditions
NH
O
(R= -Arg-OH)
L
Me CO, rt
N
2
1
8
95%
O
O
K
2
OsO x 2H O (0.2 mol%), K [Fe(CN) ],
4 2 3 6
K CO , (DHQD) PYR (2 mol%),
N
2
3
2
N
OH 3: milnamide A
tBuOH/H O (1:1), 0 °C to rt
2
OH
H
N
O
N
87%
OH
N
9
(ee 74%)
O
1
) TBSCl, NEt , cat. DMAP, DCM, rt
3
HO
+
O
2) DEAD, PPh , DPPA, THF, 0 °C to rt
3
H
N
OTBS
N
N
H
Boc
66%
organocatalyzed
-amination
N
4
5
6
phenonium-type 1,2-indole shift

10
Scheme 1. Hemiasterlin (1) and structurally related criamide B (2) and
milnamide A (3); access to tetramethyltryptophan 4.
OTBS
OTBS
N3
To date, two total syntheses of hemiasterlin (1) and one synthesis
of the challenging tetramethyltryptophan derivative 4 have been
N
N
11
12
Scheme 2. Regioselective tert.-prenylation of indole (5) and 1,2-aryl
shift of diol 9 instead of an S 2 azide replacement.
[
[
a]
b]
M. Sc. J. H. Lang, Prof. Dr. T. Lindel
Institute of Organic Chemistry
N
Technical University Braunschweig
Hagenring 30, 38106 Braunschweig, Germany
E-mail: th.lindel@tu-braunschweig.de
Homepage: www.oc.tu-bs.de/lindel
Prof. Dr. Peter G. Jones
Institute of Inorganic and Analytical Chemistry
Technical University Braunschweig
Hagenring 30, 38106 Braunschweig, Germany
We first intended to install the stereogenic center of 4 via
Sharpless asymmetric dihydroxylation (AD). Tert.-prenyl partial
structures have rarely been dihydroxylated under Sharpless
conditions[9] and there appears to be no example starting from
2
tert.-prenylarenes. We employed the (DHQD) PYR ligand, which
was reported to provide improved enantioselectivity for
monosubstituted alkenes (Scheme 2).[10] Diol 9 was obtained
from 8 in convincing yield (87%, ee 74%) and converted to the
mono-TBS-ether, which was subjected to Mitsunobu conditions
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
with diphenylphosphorylazide (DPPA) as azide source. We
obtained a product with the expected molecular formula, implying
the desired replacement of the hydroxy by an azido group.
providing 18 and 19 in excellent yields (92% for the Boc and 89%
for the Cbz derivative over two steps). The successful
-hydrazination is one of the few examples starting from neohexyl
aldehydes.[ The reaction was, in the case of the Cbz-derivative
18, run on a 5 mmol scale.
18]
However, the carbon skeleton of starting material
undergone rearrangement affording tertiary azide 12 via an indole
,2-shift.[11] Presumably, spiro cyclopropane 10 with an iminium
function is formed, followed by ring opening to tertiary carbocation
1, which is attacked by azide forming product 12.[ 12 ] The
behavior of compound 9 differs from Durst’s results, where
intermolecular S reaction in the neopentyl position was indeed
9 had
1
1
3
N
N
1
N
N
N
N
enantioselective
-hydrazination
H
HN
(R)-17
N
H
HN
N

N
(S)-17
possible starting from a ,-dimethylated -hydroxyester.[6]
i) (R)- (20 mol%),
17
i) (S)-17 (20 mol%),
92% Boc-N=N-Boc
Cbz-N=N-Cbz
89%
(
1.4 equiv), DCM, rt
(1.4 equiv), DCM, rt
We abandoned the Sharpless AD approach and converted tert.-
prenylindole 8 to aldehyde 13 by hydroboration (9-BBN) and
oxidation (IBX, Scheme 3), because an enantioselective,
organocatalyzed -amination of 13 appeared to be a viable
ii) NaBH , MeOH, rt
ii) NaBH , MeOH, rt
4
4
OH
NHCbz
OH
[13]
alternative.
CbzN
N
BocN
N
NHBoc
1
) i) 9-BBN, THF
ii) H 2, NaOH,
18
19
O
2
O
i) Pd(OH)
2
/C (25 mol%),
Br
CO Me
2
EtOH, rt
8
H
H2 (30 bar),
MeOH/EtOAc (4:1),
rt, 20 h
2) IBX, DMSO, rt
20 (4 equiv)
Cs CO3 (2.5 equiv),
MeCN, DCM, rf
N
13
82%
2
1
) 14 (10 mol%), BocNHOH,
MnO , DCM, rt, 6 d
CPh3
2
N
14
2) NaBH , MeOH, 0 °C
OH
NH2
H
4
HN
N
OH
2
4
BocN
NBoc
N
OH
OH
hydrogenolysis
N
O
N
N
CO Me
HO
Boc
NBoc
H
2
92 Hz
21
15
16, 16%
OH
E1cb
NH2
N
Scheme 3. Attempted -hydroxyamination of aldehyde 13 with
racemic catalyst 14, adapting Maruoka's protocol.
2
5
[14]
4
0%
ii) Boc O, 2
N
NaOH,
2
Maruoka et al.[14] had reported the enamine-catalyzed -hydroxy-
amination of aliphatic aldehydes. One example was neohexyl
aldehyde, which, in the presence of (2R)-2-tritylpyrrolidine (14) as
catalyst, had reacted with tert.-butyl nitrosoformate to form N-Boc-
protected -hydroxyamino products with an ee of 99%.[ 15 ]
Adapting Maruoka's protocol, we used 10 mol% of the catalyst
rac-14.[16] The product was obtained only in low yield (16%) and
DCM/MeOH/H O, 77%
2
0
°C to rt
O
O
OH
NHBoc
N
(R)-22
N
N
(S)-22 (ee 98%)
CO Me
2
23
displayed a 13C NMR resonance (CDCl
3
) at 97.5 ppm for the
1) SO -Py, NEt , DMSO/DCM, rt
3 3
aliphatic CH, very similar to the chemical shift of 98.9 ppm
reported by Maruoka et al. for the hydroxyamination product of
neohexyl aldehyde.[14] This suggested that aminooxylation
2
) NaClO , NaH PO ,
2
2
4
2
THF/H O/tBuOH/
2-methyl-2-butene, rt
(S)-4
1
15
instead of hydroxyamination had taken place. In the H, N HMBC
spectrum of 16, we observed an estimated 1JHN coupling constant
of 92 Hz, indicating that the newly introduced nitrogen was
protonated.
3) NaH, DMF, rt; then MeI, 0 °C
72%
Scheme 4. Enantioselective synthesis of trimethylated tryptophanol
derivative 22 via organocatalyzed -hydrazination of the ,-
dimethylated aldehyde 13, followed by conversion to tetramethyl-
tryptophan 4.
Symmetrically substituted azodicarboxylates such as DEAD
would eliminate the problem of N,O selectivity and afford
hydrazine dicarboxylates. With di-tert.-butyl and dibenzyl
azodicarboxylate, organocatalyzed -hydrazination of 13
proceeded smoothly and delivered the protected hydrazine
dicarboxylates 18 and 19. We employed chiral (2S)- and (2R)-5-
X-ray analysis of the Boc-protected hydrazine derivative (R)-19
revealed an intramolecular hydrogen bond between O1-H and O4
forming an eight-membered ring (Figure 1). This conformation
may also be present in solution (CDCl
sharp doublet of doublets for the hydroxy proton of the main
rotamer, with coupling constants 3
HH = 11.7 Hz, 3.1 Hz that
3
), since we observed a
(
2-pyrrolidinyl)-1H-tetrazole (17) catalysts.[ 17 ] The resulting
aldehydes were reduced (NaBH , MeOH) to the stable alcohols
4
J
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Chemistry - A European Journal
10.1002/chem.201702812
COMMUNICATION
indicate antiperiplanar and gauche-positioned methylene
hydrogen atoms.
i) Ba(OH)2 x 8 H O, MeOH/H O (1:2), rt, 30 h
2 2
ii) 26, 27 (1.1 equiv), DIPEA, DCM, rt, 15 min
(
S)-4
O
BF4
Br
27
N
H N
OEt
N
3
O
CF
3
COO
2
6
O
O
1
1
N
N
OEt
28, 76%
H
N
O
N
Boc
1
) LiOH x H
) TFA (40 equiv), 0 °C to rt, 19 h
7%
cf . Andersen et al.[4]
2 2
O, MeOH/H O, rt, 15 h
1
: hemiasterlin
2
22
[
]
= 116.7
(
R)-19
D
23
[5]
(
[]D = 118.9)
6
Figure 1. X-ray structure of Boc-protected hydrazine derivative (R)-19
obtained by -hydrazination of aldehyde 13 employing (S)-17 as
organocatalyst, followed by reduction (CCDC 1554937).
Scheme 5. Synthesis of hemiasterlin (1) via BEP-mediated amide
coupling.
To our dismay, N-N cleavage was more capricious than expected.
Using SmI requires the secondary nitrogen to be trifluoro-
2
acetylated, which facilitates reductive cleavage of the N-N
bond.[18b,c] Magnus et al. had alkylated a secondary amine with
Ethyl ester 28 was saponified with LiOH-H
2
O[4] and after work-up,
the crude N-Boc-protected hemiasterlin was treated with TFA (40
equiv.) in DCM. Hemiasterlin (1) was isolated in 67% yield
(2 steps). The salt-free form of 1, obtained after normal phase
bromoacetate 20, which undergoes E1cb elimination upon
.[19] Both methods failed in our case, with
chromatography, exhibited zwitterion characteristics as proposed
by Kashman.[1a] The optical rotatory power of our product 1 in
treatment with Cs CO
2 3
oxazolidinone 23 being the only isolated product when following
the Magnus protocol (Scheme 4). Hence, we investigated
hydrogenolytic methods. While treatment of doubly Cbz-protected
2
2
MeOH ([]
D
= −116.7 at c = 0.06 g/100 mL) compares well with
23
the value obtained by Vedejs ([]
0.07 g/100 mL). From (R)-22 we also synthesized 11-epi-
D
= −118.9 at c =
[
5]
hydrazine 18 with 1 bar H
2
/Raney-Ni, Pd/C or PtO
2
failed, we
observed N-N cleavage when using polymethylhydrosiloxane
hemiasterlin (see the SI), which showed a lower optical rotatory
22
(
PMHS) as “green chemistry” H
2
equivalent and PdCl
However, the reaction was not reliable. Use of
/C, 25 mol%) in EtOAc/MeOH (1:4)
at 30 bar at r.t. (Parr pressure vessel) proved to be optimal (up to
mmol scale). After treatment of the free amino alcohol 25 with
Boc O, the desired N-Boc-protected amino alcohol 22 was
obtained in good yield (77% over two steps). The ee values of (S)-
2
as
power ([]
D
= −62.3 at c = 0.26 g/100 mL).
[
20 ]
catalyst.
Pearlman's catalyst (Pd(OH)
1
) Pd(OH)
2
/C (3 mol%),
2
CO Me
2
H , Boc O, EtOAc, rt, 18 h
2
2
NMeBoc
2) TBAF, THF, rt
1
2
1
3) IBX, DMSO, rt
N
2
4) NaClO , NaH PO , 2-methyl-2-
2 2 4
butene, THF/t-BuOH/H O
29
2
5) NaH, MeI, DMF, rt
2
1
2 (98%) and of (R)-22 (97%, obtained when using catalyst (S)-
7, not shown) were determined on a chiral HPLC column
6
9%
(
CHIRALPAK IA, n-hexane/iPrOH 99:1), proving the excellent
N
1
) LiOH, MeOH/H
2
O,
O
N
O
enantioselectivity of the organocatalyzed hydrazination reaction.
Parikh-Doering oxidation of amino alcohol 22 provided the amino
aldehyde, which was oxidized under Lindgren-Pinnick conditions
6
5 °C, 7 d
N
N
OEt
2
) 26, BEP, DIPEA,
DCM, 0 °C, 30 min
H
O
in THF/t-BuOH/water.[21] Alternatives such as K
CO / N-iodosuc-
2 3
Boc
8
2%
30
cinimide[22] led to decomposition. Methylation (NaH, MeI, DMF)
delivered the Andersen intermediate 4.[4]
1
) LiOH, MeOH/H O,
rt, 17 h
) TFA, DCM, air,
O
N
2
O
With a view to peptide coupling with dipeptide 26,[4b] methyl ester
4
MeOH/water in a temperature-controlled ultrasonic bath. Efficient
coupling was discovered when using BEP (2-bromo-N-
N
2
OH
.
was saponified using a suspension of Ba(OH)
2
8H
2
O in
0
°C to rt, 4.5 h
3%
retro-Mannich
H
O
O
5
N
31, yellow
ethylpyridinium tetrafluoroborate, 27),
a
derivative of
Mukaiyama’s coupling reagent,[ 23 ] and Hünig's base, which
proved to be superior to PyBroP.[4] Boc-protected hemiasterlin
ethyl ester 28 was obtained in 76% yield after only 15 min
Scheme 6. Formation of the yellow alkylidene indolone 31 starting
from -tetramethyltryptophan 29.
(Scheme 5).
Finally, we became curious as to whether our rearranged
Mitsunobu product 12 could also be transformed to the
corresponding amino acid (Scheme 6). A five-step sequence
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Chemistry - A European Journal
10.1002/chem.201702812
COMMUNICATION
afforded -amino acid 29, which was saponified and coupled
auxiliaries, and features
a
high-yielding organocatalyzed
(
BEP) with peptide 26 (82%, two steps). Saponification of 30 went
-hydrazination. By employing BEP peptide coupling,
hemiasterlin (1) was obtained in a very efficient manner. A novel
phenonium-type rearrangement of the tert.-prenylated indole
system under Mitsunobu conditions was discovered.
smoothly. However, we were not able to obtain the free secondary
amine. Instead, treatment of the carboxylic acid with excess TFA
in the presence of air afforded a yellow product in good yield
(53%). An unprecedented retro Mannich reaction had occurred,
followed by oxidation of the resulting indole acetic acid moiety to
the 3-alkylidene indolone 31. In the H NMR spectrum, the amide
proton appeared as a sharp doublet at 11.18 ppm, indicating an
intramolecular hydrogen bond to the indolone oxygen.
Acknowledgements
J. H. L. thanks the Fonds der Chemischen Industrie for a doctoral
stipend.
1
Keywords: total synthesis, natural products, organocatalysis,
peptides, rearrangement.
In conclusion, we have developed a novel enantioselective route
to the sterically congested tetramethyltryptophan moiety of
hemiasterlin (1). Our approach encompasses 11 steps (31%
overall yield) starting from indole, avoids the use of chiral
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ethers instead (see the SI).
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Chemistry - A European Journal
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COMMUNICATION
Entry for the Table of Contents
Total synthesis
J. H. Lang, P. G. Jones, T. Lindel*
Page No. – Page No.
Total synthesis of the marine natural
product hemiasterlin via organocatalyzed

-hydrazination
Enantioselective -hydrazination was key: An efficient synthesis of the potently cytotoxic marine peptide hemiasterlin is presented.
The tetramethyltryptophan moiety is assembled de novo via tert.-prenylation of indole, followed by the high-yielding organocatalyzed
α-hydrazination of a sterically congested aldehyde with excellent enantioselectivity. A novel phenonium-type rearrangement of the
indole system occurred when subjecting dihydroxylated 3-tert.-prenylindole to Mitsunobu conditions.
O
O
O
OH
NHR
high ee and yield
N
N
OH
organo-
catalyzed
RN
H
N
N
NH
O
N
H
-hydrazination
hemiasterlin
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