Synthetic study on dolastatin 16: Concise and scalable synthesis of two unusual amino acid units

Article abstract of DOI:10.1016/j.tetlet.2014.11.054

A convenient and scalable synthesis of two unusual amino acid units found in dolastatin 16, dolaphenvaline, and dolamethylleuine, is described. Dolastatin 16, which was first isolated from the sea hare Dolabella auricularia by Pettit, exhibits not only strong inhibition of growth for a variety of human cancer cell lines but also potent antifouling activity against the larvae of the barnacle Balanus amphitrite. The key element of the synthesis is an organocatalytic Mannich reaction to construct two contiguous stereocenters in the amino acid units with almost complete enantio- and diastereoselectivity.

Full text of DOI:10.1016/j.tetlet.2014.11.054

Tetrahedron Letters 56 (2015) 168–171
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic study on dolastatin 16: concise and scalable synthesis
of two unusual amino acid units
⇑
⇑
Taiki Umezawa , Akinori Sato, Yasuto Ameda, Loida O. Casalme, Fuyuhiko Matsuda
Division of Environmental Materials Science, Graduate School of Environmental Science, Hokkaido University, Sapporo 060-0810, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and scalable synthesis of two unusual amino acid units found in dolastatin 16, dolaphenv-
aline, and dolamethylleuine, is described. Dolastatin 16, which was first isolated from the sea hare
Dolabella auricularia by Pettit, exhibits not only strong inhibition of growth for a variety of human cancer
cell lines but also potent antifouling activity against the larvae of the barnacle Balanus amphitrite. The key
element of the synthesis is an organocatalytic Mannich reaction to construct two contiguous stereocenters
in the amino acid units with almost complete enantio- and diastereoselectivity.
Received 8 September 2014
Revised 10 November 2014
Accepted 13 November 2014
Available online 20 November 2014
Keywords:
Dolastatin 16
Ó 2014 Elsevier Ltd. All rights reserved.
Unusual amino acid
Total synthesis
Mannich reaction
Organocatalyst
Dolastatin 16 (1), a macrocyclic depsipeptide, was first isolated
by Pettit as a potential antineoplastic metabolite in 1997 from
the sea hare Dolabella auricularia, collected in Papua New Guinea
Organization (IMO) to call in 2008 for a ban on the use of TBT-
based antifouling paint on ships.6 Since marine organisms prevent
fouling of their outer surfaces through the use of natural sub-
stances with antifouling properties without causing serious envi-
ronmental problems, natural antifouling products, especially
those with good settlement-inhibiting properties but without bio-
cidal properties, have attracted considerable attention.7 Among
these, 1 shows promise as a lead compound for the development
of new environmentally friendly antifouling agents due to its
potent antifouling activity and low toxicity.8
Because of its intriguing and unprecedented structure, 1 is an
attractive target for total synthesis. For the total synthesis of 1,
synthetic methods for the optically active amino acid units 2 and
3 must be developed. Syntheses of these unusual amino acid units
have been carried out previously. Scheuer synthesized all four ster-
eoisomers of 2 from both enantiomers of N-phthaloyl-3,4-dehy-
drovaline (4) during structure elucidation of kulokekahilide-1, a
cytotoxic depsipeptide from the cephalaspidean mollusk
(Fig. 1).1 This unique depsipeptide proved to be
a strong
growth inhibitor for a variety of human cancer cell lines and a
candidate for further development. Five years after the original
report, the isolation of 1 from a Madagascan cyanobacterium,
Lyngbya majuscula, was described by Gerwick.2 With regard to
structural features, 1 contains the new and unusual amino acid
units dolaphenvaline (2) and dolamethylleuine (3). Although the
stereostructures of 2 and 3 were not assigned in these publications,
their absolute configurations were determined to be (2S,3R) and
(2R,3R), respectively, through X-ray crystallographic analysis of 1
performed by Pettit in 2011.3
In 2010, Tan reported that 1 showed a strong antifouling activ-
ity (EC50 0.003
amphitrite, as well as low toxicity (LC50 20
l
g/mL) against the larvae of the barnacle Balanus
l
g/mL).4 Biofouling—
that is, adverse growth of marine organisms on manmade
submerged structures—results in significant economic and
environmental problems. Tributyltin (TBT),5 which inhibits the set-
tlement of larvae, has been widely used all over the world for this
purpose since the early 1960s. However, the deleterious effects of
TBT on marine ecosystems prompted the International Maritime
NH2
O
O
O
Ph
CO2H
N
N
N
O
O
2
O
O
HN
O
O
N
O
NH2
N
H
CO2H
Ph
⇑
Corresponding authors. Tel.: +81 11 706 2358; fax: +81 11 706 4517 (T.U.); tel./
fax: +81 11 706 4520 (F.M.).
3
1
E-mail addresses: umezawa@ees.hokudai.ac.jp (T. Umezawa), fmatsuda@ees.
hokudai.ac.jp (F. Matsuda).
Figure 1. Dolastatin 16 (1) and the unusual amino acid units 2 and 3.
http://dx.doi.org/10.1016/j.tetlet.2014.11.054
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

T. Umezawa et al. / Tetrahedron Letters 56 (2015) 168–171
169
TBDPSO
CO2H
NAr1
NHAr1
CO2Et
PhI, AgNO3
Pd(OAc)2
N
H
O
O
O
O
CO2Me
N
N
16
OHC
OHC
+
CO2Et
CO2Me
Ph
sat. NaHCO3, rt
14
15
Ar1=PMP
17
4
5
NH2
CO2H
2
2 steps
NHAr1
CO2Et
Ph
Ph3P=CHCO2Me
MeO2C
Toluene
one-pot72%
21
>95% ee
dr = >95:5
NHTFA
O
LHMDS
NHTFA
CO2H
3 steps
Al(OiPr)3
1. CAN, H2SO4
MeCN,H2O, rt
Ph
NHBoc
CO2Et
O
Quinidine
Ph
Ph
MeO2C
6
7
2. Boc2O, Na2S2O3
NaHCO3, rt
one-pot73%
22
NHTFA
O
O
NHTFA
CO2H
Pd/C
Ph
1,4-CHD
NHBoc
CO2Et
8
9
O3; Me2S, MeOH
PhMgBr, ZnCl2
OHC
78 °C then rt
THF, 0 °C
-
23
NHCbz
CO2H
NHCbz
CO2tBu
78%
67%
2 steps
LDA, LiCl
MeI
NHBoc
NHBoc
CO2H
H2, Pd(OH)2/C
10
11
O
Ph
O
AcOEt, rt
93%
NHCbz
NHCbz
Ph
24
25
TFA
Et3SiH
CO2tBu
CO2H
dr = 8:1
12
13
Scheme 3. Stereoselective synthesis of 25.
Scheme 1. Previous syntheses of 2 and 3.
in Scheme 2. We envisioned the derivation of 2 or 3 from syn-b-
amino aldehyde 17 or anti-b-amino aldehyde 20, which were pre-
pared by Hayashi through enantio- and diastereoselective Mannich
reactions with chiral organocatalysts 16 or 19.13,14 Herein, we
report the asymmetric synthesis of these unusual amino acid units.
First, we synthesized N-Boc-dolaphenvaline (25) as illustrated
in Scheme 3. As reported by Hayashi,13 a syn-Mannich reaction
Philinopsis speciosa.9 The synthesis involved a Mizoroki–Heck reac-
tion of 4 with iodobenzene and non-diastereoselective hydrogena-
tion of olefin 5 (Scheme 1). Pettit prepared N-TFA-dolaphenvaline
(9) from allyl ester 6 through asymmetric Claisen rearrangement
of 6 to give syn-carboxylic acid 7 and hydrogenolysis of lactone 8
derived from 7.3 Pettit also achieved a synthesis of N-Cbz-dola-
methylleuine (13) through diastereoselective alkylation10 of the
between propanal (14) and ethyl a-imino glyoxylate 15 promoted
by the chiral organocatalyst 16 afforded syn-adduct 17, which was
directly treated with Wittig reagent in a one-pot operation to iso-
b-amino acid ester 11 prepared from N-Cbz-L-valine (10) and
cleavage of t-butyl ester of anti-ester 12.3 Although the two amino
acid units have been prepared, total synthesis of 1 has not yet been
reported.
late the syn-
a
,b-unsaturated ester 21 in 72% yield (two steps) with
enantio- and diastereoselectivity (>95% ee,
,b-unsatu-
excellent
dr = >95:5).15,16 Conversion of the aldehyde into the
a
rated ester was essential for further transformation because the
aldehyde moiety of 17 was labile under the reaction conditions
for addition of a phenyl group or removal of the N-p-methoxy-
phenyl (N-PMP) group. One-pot protecting group manipulation fol-
lowed by ozonolysis produced aldehyde 23 in 57% yield (three
steps). While attempted nucleophilic addition of PhMgBr, PhLi, or
In conjunction with our program directed toward a practical
total synthesis of 1, we developed a concise and scalable synthetic
procedure for the unusual amino acid units 2 and 3 by using highly
enantio- and diastereoselective Mannich reactions promoted by
chiral organocatalysts.11,12 This method provides flexible access
to a wide variety of congeners of 2 and 3, such as diastereomers
and enantiomers, by simply changing the catalyst or starting mate-
rial. The synthetic plan for both amino acid units (2 and 3) is shown
17
PhCeCl2 to the aldehyde part of 23 failed, we eventually found
that the addition of PhMgBr took place cleanly in the presence of
TBDPSO
Ar1
CO2H
N
NHAr1
CO2Et
NH2
CO2H
N
H
16
OHC
OHC
+
Ph
CO2Et
15
2
14
17
Ar1=PMP
Ar2
Ar2
OTMS
N
H
NHTs
SO2Ph
18
NHTs
CHO
NH2
CHO
CO2H
+
19
14
20
3
Ar2=3,5-(CF3)2C6H3
Scheme 2. Synthetic plan for 2 and 3.

170
T. Umezawa et al. / Tetrahedron Letters 56 (2015) 168–171
ZnCl2,18 and lactone 24 was obtained in 67% yield (dr = 8:1).19
Reductive cleavage of the benzylic CAO bond of 24 under hydrog-
enolysis conditions provided 25 in 93% yield.
1. Na, Naphthalene
THF, 0 °C to rt
NHTs
CHO
NHTs
NaBH4
OH
MeOH
0 °C
2. Boc2O
20
26
sat. NaHCO3
We then turned our attention to the synthesis of N-Boc-dola-
methylleuine (28). Hayashi reported that an anti-Mannich reaction
between aminosulfone 18 and propanal (14) with chiral catalyst 19
(0.1 equiv) afforded anti-adduct 20 with high stereoselectivity
(98% ee, dr = 88:12) by performing the reaction in 1,4-dioxane at
10 °C.14 For convenient gram-scale preparation of 20, we
attempted to optimize the reaction conditions for the anti-Man-
nich reaction. The results of the optimization are summarized in
Table 1. When the reaction was carried out at ambient temperature
following the protocol described by Hayashi, excellent enantiose-
lectivity (95% ee) was obtained but diastereoselectivity was low
(dr = 68:32) (entry 1). Lowering the reaction temperature to 0 °C
caused a significant decrease in chemical yield (entry 2). We then
performed a solvent screen under the same reaction conditions.
Although the Mannich reaction proceeded sluggishly in DMF or
DMSO (entries 3 and 4), THF was found to be superior to 1,4-diox-
ane in achieving the desired stereoselectivity (entries 5 and 6). In
particular, 20 was exclusively formed as a single stereoisomer
(>99% ee, dr = >95:5) at 0 °C. However, the chemical yield in THF
was moderate at room temperature. A twofold increase in the cat-
alyst loading led to a dramatic increase in chemical yield (entries 7
and 8). The chiral organocatalyst 19 was easily recovered in a yield
of 76% by chromatographic separation of the reaction mixture, and
was reused for the same Mannich reaction between 18 and 14
(entry 9). Under the optimal conditions (with 0.4 equiv of 19 in
THF at 0 °C), the organocatalytic Mannich reaction was successfully
used for a gram-scale synthesis of 20 to afford a comparable yield
(75%) and stereoselectivity (98% ee, dr = >95:5) (entry 10) to those
obtained in a milligram-scale experiment (entry 8). The resulting
20 was converted to 28 as shown in Scheme 4. After reduction of
20 with NaBH4 to alcohol 26, successive removal of the N-Ts group
and Boc-protection in a one-pot operation gave alcohol 27 in 70%
yield (three steps). Stepwise oxidation of the primary alcohol to
the carboxylic acid gave 28 in 84% yield (two steps).
90%
78%
1. DMP, Pyridine
CH2Cl2, rt
NHBoc
NHBoc
CO2H
OH
2. NaClO2, NaH2PO4
2-Methyl-2-butene
tBuOH, H2O, rt
27
28
92% (2 steps)
Scheme 4. Stereoselective synthesis of 28.
NAr1
NHAr1
L-Proline
NaBH4
CHO
CHO
+
DMF, -20 °C
MeOH
0 °C
85% (2 steps)
29
14
30
Ar1 = PMP
1. CAN, H2SO4
MeCN, H2O, rt
NHAr1
NHCbz
OH
H2, PtO2
OH
2. CbzCl, Na2S2O3
NaHCO3, rt
MeOH, rt
31
32
77%
99% ee
dr = >95:5
49% (2 steps)
1. DMP, Pyridine
CH2Cl2, rt
NHCbz
NHCbz
CO2H
OH
2. NaClO2, NaH2PO4
2-Methyl-2-butene
tBuOH, H2O, rt
33
34
58% (2 steps)
Scheme 5. Selective synthesis of 34.
catalyzed by L a,b-unsatu-
-proline, was reported by Hayashi.20 The
rated N-PMP-aldimine 29, generated from methacrolein and
p-anisidine, was subjected to an asymmetric syn-Mannich reaction
with 14. The 1,2-addition reaction occurred cleanly in a highly
stereoselective manner (99% ee, dr = >95:5)21 to give syn-adduct
30 almost exclusively. After NaBH4-reduction of 30, alcohol 31
was isolated in 85% yield (two steps). Protecting group transforma-
We also achieved the synthesis of N-Cbz-2-epi-dolamethyl-leu-
ine (34), as shown in Scheme 5. A highly stereoselective syn-Man-
nich reaction of aromatic N-PMP-aldimine with propanal (14),
Table 1
Optimization of anti-Mannich reaction catalyzed by 19a
Ar2
Ar2
OTMS
19 (X equiv.)
N
H
NHTs
CHO
NHTs
NHTs
SO2Ph
NaBH4
CHO
+
OH
NaHCO3 (3.0 equiv.)
Ar2=3,5-(CF3)2C6H3
MeOH, 0 °C
18 (1.0 equiv.) 14 (3.0 equiv.)
20
26
Entry
X
Solvent
Temperature (°C)
Yield (%) of 20b
drc (anti/syn)
% eed
1
2
3
4
5
6
7
8
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.4
0.4
1,4-Dioxane
1,4-Dioxane
DMF
DMSO
THF
THF
THF
THF
THF
rt
0
0
rt
rt
0
rt
0
75
31
9
cm
59
44
92
74
76
75
68:32
73:27
93:7
nd
94:6
>95:5
92:8
>95:5
>95:5
>95:5
95
94
81
nd
98
>99
98
>99
98
98
9e
10f
0
0
THF
a
b
c
d
e
f
For optimizations, the reaction conducted with 30 lL (0.433 mmol) of 14 and 33.2 mg (0.087 mmol) of 18; cm = complex mixture; nd = not determined.
Isolated yield of 20 after column chromatography.
Determined by 1H NMR with alcohol 26 obtained by NaBH4-reduction of 20.
Determined by chiral HPLC analysis with 26.
Partial removal of the TMS group of 19 was observed. Recovered 19 was used after silylation with TMSOTf and Et3N.
For gram scale synthesis, 1.0 g (2.6 mmol) of 18 was used.

T. Umezawa et al. / Tetrahedron Letters 56 (2015) 168–171
171
O
References and notes
O
NHCbz
OH
HN
O
N
O
NaH
H
H
HC
1. Pettit, G. R.; Xu, J.-P.; Hogan, F.; Williams, M. D.; Doubek, D. L.; Schmidt, J. M.;
Cerny, R. L.; Boyd, M. R. J. Nat. Prod. 1997, 60, 752–754.
2. Nogla, L. M.; Gerwick, W. H. J. Nat. Prod. 2002, 35, 21–24.
3. Pettit, G. R.; Smith, T. H.; Xu, J.-P.; Herald, D. L.; Flahive, E. J.; Anderson, C. R.;
Belcher, P. E.; Knight, J. C. J. Nat. Prod. 2011, 74, 1003–1008.
4. Tan, L. K.; Goh, B. P. L.; Tripathi, A.; Lim, M. G.; Dickinson, G. H.; Lee, S. S. C.; Teo,
S. L. M. Biofouling 2010, 26, 685–695.
5. Evans, S. M. Biofouling 1999, 14, 117–129.
6. Horiguchi, T.; Shiraishi, H.; Shimizu, M.; Yamazaki, S.; Morita, M. Mar. Pollut.
Bull. 1995, 31, 402–405.
HB
DMF
0 °C to rt
HA
HD
32
35
J
J
J
AB = 4.4 Hz
BC = 4.0 Hz
BD = 2.2 Hz
80%
O
O
HB
NHBoc
HN
O
N
O
NaHMDS
HC
7. Fusetani, N. Nat. Prod. Rep. 2011, 28, 400–410.
OH
8. (a) Kitano, Y.; Ito, T.; Suzuki, T.; Nogata, Y.; Shinshima, K.; Yoshimura, E.; Chiba,
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Kitano, Y.; Yokoyama, A.; Nogata, Y.; Shinshima, K.; Yoshimura, E.; Chiba, K.;
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Yoshimura, E.; Shinshima, K.; Sakaguchi, I. Biofouling 2004, 20, 87–91; (d)
Kitano, Y.; Nogata, Y.; Shinshima, K.; Yoshimura, E.; Chiba, K.; Tada, M.;
Sakaguchi, I. Biofouling 2004, 20, 93–100; (e) Nishikawa, K.; Nakahara, H.;
Shirokura, Y.; Nogata, Y.; Yoshimura, E.; Umezawa, T.; Okino, T.; Matsuda, F.
Org. Lett. 2010, 12, 904–907; (f) Nishikawa, K.; Nakahara, H.; Shirokura, Y.;
Nogata, Y.; Yoshimura, E.; Umezawa, T.; Okino, T.; Matsuda, F. J. Org. Chem.
2011, 76, 6558–6573; (g) Umezawa, T.; Oguri, Y.; Matsuura, H.; Yamazaki, S.;
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Serisawa, K.; Abe, T.; Matsuda, F.; Suzuki, M.; Okino, T. Angew. Chem. Int. Ed.
2014, 53, 3909–3912.
DMF
0 °C to rt
HA
HD
27
36
J
J
J
AB = 8.3 Hz
BC = 3.9 Hz
BD = 9.5 Hz
47%
Scheme 6. Confirmation of relative configuration of 34.
tion gave alcohol 32 (49% yield, two steps), which led to 34 via
hydrogenation of the olefin (77% yield) and oxidation of primary
alcohol 33 to carboxylic acid (58% yield). The relative configuration
of 34 was determined based on coupling constant analysis of tetra-
hydro-1,3-oxazin-2-ones 35 and 36, prepared through base-
induced cyclization of N-protected 1,3-amino alcohols 32 and 27,
respectively (Scheme 6). Since 27 was derived from the known
anti-1,3-amino alcohol 2614 (Scheme 4), both of the vicinal
methine protons (HA and HB) of 36, prepared from 27, were
expected to adopt an axial orientation in the chair conformation
of the 1,3-oxazine ring. Actually, a larger vicinal coupling constant,
JAB = 8.3 Hz (axial/axial relationship), was obtained in 1H NMR
spectrum of 36. The smaller vicinal coupling constant JAB = 4.4 Hz
(axial/equatorial relationship) for 35 reveals a cis relationship
between the vicinal methine protons HA and HB and the syn-rela-
9. Kimura, J.; Takada, Y.; Inayoshi, T.; Nakao, Y.; Goetz, G.; Yoshida, W. Y.; Scheuer,
P. J. J. Org. Chem. 2002, 67, 1760–1767.
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A.; List, B. Angew. Chem. Int. Ed. 2009, 48, 1978–1980; (c) Hayashi, Y.;
Urushima, T.; Tsuboi, W.; Shoji, M. Nat. Prot. 2007, 2, 113–118; (d) Hayashi, Y.;
Okano, T.; Itoh, T.; Urushima, T.; Ishikawa, H.; Uchimaru, T. Angew. Chem. Int.
Ed. 2008, 47, 9053–9058; (e) Hayashi, Y.; Sakamoto, D.; Shomura, H.;
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Maruoka, K. Angew. Chem. Int. Ed. 2009, 48, 1838–1840; (g) Kano, T.;
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L-proline-catalyzed asymmetric
Mannich reaction, -proline always mediates a si-facial attack of
the aldimine through an enamine intermediate generated from
an aldehyde.22 Therefore, the absolute configuration of 34 is
expected to be (2S,3R).
L
In summary, scalable and concise syntheses of N-Boc-dola-
phenvaline (25) and N-Boc-dolamethylleuine (28), N-Boc-pro-
tected amino acid units of dolastatin 16 (1), were achieved by
employing enantio- and diastereoselective organocatalytic Man-
nich reactions. The synthetic sequence provided subgram amounts
of the amino acid units 25 and 28 with overall yields of 26% (five
steps) and 48% (five steps), respectively. Furthermore, this syn-
thetic approach is expected to be applicable to gram-scale prepara-
tion of various derivatives of these unusual amino acid units
through the selection of appropriate chiral catalysts or starting
materials. Indeed, N-Cbz-2-epi-dolamethylleuine (34) was pre-
pared according to a similar scheme to that used for 28. Further
studies with the aim of achieving a practical and scalable total syn-
thesis of dolastatin 16 (1) using 25 and 28 are ongoing.
Organocatalysis
1 In Enamine Catalysis of Mannich Reactions; List, B., Ed.;
Thieme: Stuttgart, 2012; p 73.
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24.
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15. Diastereomeric ratio (dr) was determined by 1H NMR with unsaturated ester
21. Enantiomeric excess (ee) was verified by NMR experiments with Mosher’s
amides obtained from 21 by successive removal of N-PMP group and
condensation with both of enantiomers of O-methyl-mandelic acid.
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group of 24. Configuration of benzylic position of 24 was assigned by ROE
study with the amine.
Acknowledgment
20. Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K. Angew.
Chem. Int. Ed. 2003, 42, 3677–3680.
This work was supported by the Sasagawa Foundation.
21. Dr was determined by 1H NMR with alcohol 31. Ee was confirmed by chiral
HPLC analysis with alcohol 32.
Supplementary data
22. (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337; (b) Notz, W.; Sakthivel, K.;
Bui, T.; Zhong, G.; Barbas, C. F., III Tetrahedron Lett. 2001, 42, 199–201; (c)
Córdova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III J. Am. Chem.
Soc. 2002, 124, 1842–1843; (d) Córdova, A.; Watanabe, S.; Tanaka, F.; Notz, W.;
Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1866–1867.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
11.054.