Asymmetric synthesis of the core of AMPTD, the key amino acid of microsclerodermins F-I

Article abstract of DOI:10.1016/j.tetlet.2009.06.144

We report a stereoselective synthesis of the five consecutive stereocenters of AMPTD in seven steps. Highlights include an Evans glycolate aldol reaction, the use of a Weinreb amide as an aldehyde masking group, and a Mannich reaction with an Ellman-type

Full text of DOI:10.1016/j.tetlet.2009.06.144

Tetrahedron Letters 50 (2009) 5449–5451
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of the core of AMPTD, the key amino acid
of microsclerodermins F-I
*
Cameron M. Burnett, Robert M. Williams
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
University of Colorado Cancer Center, Aurora, CO 80045, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a stereoselective synthesis of the five consecutive stereocenters of AMPTD in seven steps.
Highlights include an Evans glycolate aldol reaction, the use of a Weinreb amide as an aldehyde masking
group, and a Mannich reaction with an Ellman-type chiral sulfimine.
Received 9 April 2009
Revised 24 June 2009
Accepted 28 June 2009
Available online 19 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Microsclerodermins F-I (1–4, Fig. 1), members of a family of
antitumor and antifungal cyclic peptides, were isolated in 2000
from a deep-water species of the marine sponge Microscleroderma.1
A biological assay of 1 revealed cytotoxicity against the human car-
syn-selective aldol reaction between a chiral glycolate and an a-
chiral aldehyde 11, prepared in two steps from the commercially
available Roche ester.
We first explored aldol reaction of the cis-lactone 13; Andrus
had previously synthesized the trans diastereomer.5 We found that
treatment of the open form 12 with TFA in the presence of trieth-
ylsilane as a cation scavenger yielded cis O-lactone 13 in much
cinoma cell line HCT-116 (IC50 = 2.7 lM for 2) and antifungal activ-
ity against Candida albicans. The biological activity of these
molecules, coupled with their poor availability from natural
sources (0.001 wt % from the sponge), attracted our synthetic
interest.
Microsclerodermins F and H contain a D-tryptophan residue,
while G and I feature a dehydrotryptophan residue. The molecules
offer several synthetic challenges, including a pyrrolidinone with a
H
N
H
N
O
O
O
HN
O
HN
H
H
N
N
N
N
b-amido hemiaminal and a c-amino-b-hydroxy amino acid; how-
HO
O
HO
O
O
O
Me
OH
Me
OH
HN
HN
O
O
ever, the most intimidating is 3-amino-6-methyl-12-phenyl-
2,4,5-trihydroxydodeca-7,9,11-trienoic acid (AMPTD, 5, Fig. 2).
AMPTD is a polyhydroxylated b-amino acid with five contiguous
stereogenic centers and an all-trans phenyltriene; 3 and 4 also fea-
ture a methyl substituent on the triene portion. Shioiri reported a
synthesis of AMMTD, a constituent of microsclerodermins A and B
with the same stereochemistry as AMPTD but a different side
chain, in 17 steps without the side chain2 and 31 steps with the
side chain.3 We report herein a concise synthesis of the stereo-
chemical core of 5 adaptable to the synthesis of 1–4.
O
NH
O
NH
H
H
OH
OH
OH
OH
OH
OH
N
N
N
H
N
H
O
O
Ph
Ph
R
Me
R
Me
microsclerodermin F, 1: R = H
microsclerodermin H, 3: R = Me
microsclerodermin G, 2: R = H
microsclerodermin I, 4: R = Me
Figure 1. Structures of microsclerodermins F-I (1–4).
Our retrosynthesis of the protected AMPTD moiety 5 introduces
four stereogenic centers via aldol methodology (Fig. 2). We envi-
sioned preparation of 5 by condensation of the known diene phos-
phonate 64 and aldehyde 7, prepared by replacement of the chiral
auxiliary in 8 with the methyl ester, followed by a deprotection–
oxidation sequence. The amino alcohol 8 would come from a syn-
selective aldol reaction between a chiral glycolate equivalent and
imine 9, which in turn could be prepared from alcohol 10 by pro-
tection of the 1,2-diol and conversion of the chiral auxiliary to the
corresponding imine. The alcohol 10 would come from another
HO2C
H2N
MeO2C
PO(OEt)2 R2HN
OHC
OH
OH
OR3
O
Ph
O
Ph
6
R1
OH
5
O
3
7
Me
Me
Xc
O
Xc
O
OR3
R1
H
Xc
Xc
OR3
O
R2N
O
H
R2HN
R1O
O
R1O
RO
R1
RO
OH
RO
O
O
RO
O
10
9
11
8
Me
Me
Me
Me
* Corresponding author. Tel.: +1 970 491 6747; fax: +1 970 491 3944.
E-mail address: rmw@lamar.colostate.edu (R.M. Williams).
Figure 2. Retrosynthetic analysis of 5.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.144

5450
C. M. Burnett, R. M. Williams / Tetrahedron Letters 50 (2009) 5449–5451
TiCl4 (1.05 eq.)
DIPEA (2.5 eq.)
NMP (1.0 eq.)
higher yield than our previously reported two-step procedure from
12.6 Aldol reaction of 13 with aldehyde 14 (obtained by reduction
of the corresponding ester in situ to avoid epimerization of the
methyl group upon standing)2 gave the desired adduct 15 in good
yield; unfortunately, we obtained 15 as a 1:1 mixture of diastereo-
mers (Scheme 1). Our attempts to remove the biphenyl failed to
yield diol 16, and we were thus unable to ascertain the stereo-
chemistry of the product mixture; we anticipate that the use of
higher hydrogen pressure would allow template removal. Studies
S
O
O
N
CHO
OBn
TBDPSO
Bn
Me
61%
d.r. 2.6:1
14
20
S
O
OH OTBDPS
H2 or 1,4-chd
Pd/C or Pd(OH)2/C
S
O
OH OTBDPS
O
N
X
O
N
OR Me
MeOH
OR Me
Bn
21a (R = Bn)
Bn
toward the use of 13 as a template for the synthesis of chiral
substituted- -hydroxyacids (via alkylation) and b-substituted-
,b-dihydroxyacids (via aldol reaction) are ongoing.
a-
21b (R = H)
LiBH4, MeOH
Et2O
quant.
a
H2
Pd(OH)2
X
OH
OH
a
We next probed aldol reactions of Andrus’ modified Masamune
HO
OTBDPS
HO
OTBDPS
MeOH
norephedrine template 17 (Scheme 2)7 with 14. Compound 17
gave a moderate yield of addition product 18a, but attempted ben-
zylation of the secondary alcohol returned 18a unchanged. Basic
hydrolysis of the chiral template removed the TBDPS ether to give
alcohol 19.
OR Me
22a (R = Bn)
OR Me
22b (R = H)
Scheme 3. Application of chiral template 20.
Crimmins’ oxazolidinethione 20 (Scheme 3)8 gave a moderate
yield of and diastereoselectivity for the corresponding aldol prod-
uct 21a. We wished to produce the diol and form the acetonide;
unfortunately, the sulfur prevented hydrogenolysis to 21b. Re-
moval of the chiral template gave diol 22a quantitatively, but
hydrogenation again failed, presumably due to traces of sulfur con-
tamination. Birch debenzylation was not pursued, as the resultant
triol would be difficult to purify from the reaction.
Bu2BOTf, DIPEA
CH2Cl2, -78 to 0°C;
(MeO)MeNH•HCl
AlMe3
O
O
O
O
OH
Me
O
N
O
N
OHC
Me
THF
OR
OBn
53%
OTBDPS
Bn
Bn
83%
OTBDPS
23a (R = Bn)
14
24
MeO
O
OH
20% Pd(OH)2/C
(25 mol%)
Me
N
Me
O
MeO
N
DMP, TsOH
O
acetone
We next turned to Evans’ chiral oxazolidinone 23a,9 which
underwent syn-aldol reaction with 14 to give adduct 24. The reac-
tion was not clean at room temperature, but we obtained a single
diastereomer of 24 at 0 °C (Scheme 4). Hydrogenation of the benzyl
Me
Me
Me OBn
H2 (1 atm.)
OTBDPS MeOH
O
TBDPSO
60% (2 steps)
Me
MeO2C
25
26
MeO2C
DIBAL, CH2Cl2;
CbzNH2
OH
Ph3P=CHCO2Me
(DHQD)2PHAL
CbzHN
X
O
O
61% (2 steps)
TBDPSO
K2OsO2(OH)4
Me
Me
Me
MeCN / 0.4 M NaOH TBDPSO
O
O
Me
Ph
Et3N (2.4 eq.)
Ph
Me
Me
OTHP
TFA, Et3SiH
c-Hex2BOTf (3.0 eq.)
28
27
O
Ph
Ph
O
PhMe, Δ
72%
O
CH2Cl2, -78°C, 2 h;
Scheme 4. Synthesis and attempted amino-hydroxylation of 27.
O
CO2t-Bu
CHO
TBDPSO
75%
13
12
14
Me
(1.1 eq.), 2 h
ether was blocked by the bulky oxazolidinone and TBDPS group;
thus we converted the oxazolidinone to Weinreb amide 25. With
the steric hindrance reduced, the diol was obtained and protected
as acetonide 26. Reduction of the Weinreb amide to the aldehyde
Ph
HO
O
HO
O
10% Pd/C
(0.55 eq.)
Ph
O
X
O
OH
100 psi H2, MeOH
16 h
OH
and Wittig reaction produced trans-a,b-unsaturated ester 27; at-
TBDPSO
16
Me
TBDPSO
Me
tempted Sharpless amino-hydroxylation of 27 (in analogy with a
previous synthesis of ours)10 failed, yielding not the desired amino
alcohol (28) but only loss of the TBDPS residue.
15 1:1 mixture
Scheme 1. Application of O-lactone 13.
We then switched protecting groups: aldol reaction of the cor-
responding para-methoxybenzyl (PMB) glycolate 23b and benzyl-
protected aldehyde 29 gave adduct 30 in moderate yield, and con-
version to the Weinreb amide 31 allowed direct oxidation to the p-
methoxyphenyl acetal 32 (Scheme 5). While we preferred this pro-
tecting-group scheme, both the aldol reaction and acetal formation
proved to be capricious, so we abandoned this route.
Et3N (2.4 eq.)
c-Hex2BOTf (3.0 eq.)
Ph
O
O
OR
Me
Me
O
XCO
CH2Cl2, -78°C, 2 h;
MesO2SN
OBn
OBn
OTBDPS
Bn
CHO
TBDPSO
18a (R = H)
17
14
Me
(1.1 eq.)
56%
-78°C -> 0°C, 4 h
BnBr, NaH
Bu2BOTf, DIPEA
CH2Cl2;
O
O
O
OH
O
X
O
OR
Me
TBAI, DMF
NH
O
N
O
N
Me
OTBDPS
XCO
OHC
Me
36%
O
OR
OBn
PMB
Bn
Bn
OBn
O
OR
BnO
CCl3
OBn
Me
23b (R = pMB)
30
29
18b (R = Bn)
X
XCO
MeO
O
TMSOTf, CH2Cl2
OBn
18a (R = H)
N
Me
(MeO)MeNH•HCl
OTBDPS
O
OH
DDQ, 3Å
CH2Cl2
O
OH
Me
AlMe3
MeO
Me
LiOH
N
O
HO
THF
51%
Me
O
PMP
THF/H2O
85%
BnO
O
OBn
OBn
OH
PMB
0-48%
19
Me
31
32
Scheme 2. Application of chiral template 17.
Scheme 5. Use of alternate protecting groups to give 32.

C. M. Burnett, R. M. Williams / Tetrahedron Letters 50 (2009) 5449–5451
5451
MeO
O
In summary, we have synthesized 34, containing the stereo-
chemical core of AMPTD, in seven steps from known starting mate-
rials. We are exploring use of the alcohol of 36 as a key
intermediate for the total synthesis of the microsclerodermins.
We have also shown that the protecting groups can be selectively
manipulated, thus allowing us to explore structure–activity rela-
tionships of the phenyltriene side chain in microsclerodermins F-
I. Studies toward the total synthesis of 1–4 are ongoing in our
laboratories.
tBu
H
N
Me
O
MeO2C
S
O
N
DIBAL;
OBoc
O
tBu
NH2
LHMDS
Me
Me
Me
Me
S
THF
TBDPSO
O
TBDPSO
26
O
O
36-45%
Me
Me
Ti(OEt)4
33
MeO2C
ClH-H2N
73% (two steps)
CO2Me
OBoc
tBu
OBoc
O
S
HCl
O
N
H
O
Me
dioxane
quant.
Me
TBDPSO
O
TBDPSO
34
O
Me
Me
Acknowledgments
Me
Me
35
CO2Me
OBoc
CO2Me
tBu
S
tBu
S
OBoc
We gratefully acknowledge financial support from the National
Institutes of Health (Grant GM068011). Mass spectra were ob-
tained on instruments supported by the National Institutes of
Health Shared Instrumentation Grant No. GM49631.
TBAF
87%
O
N
O
N
H
H
X
O
O
Me
Me
Me
Me
HO
Br
O
Me
36
O
Me
37
Supplementary data
Scheme 6. Completion of the five chiral centers and deprotection.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.144.
Returning to our original route, we converted acetonide 26 via
reduction and condensation to the chiral sulfimine 33 (Scheme
6).11 Addition of Boc-protected methyl glycolate according to Ait-
ken’s procedure gave ester 34, bearing all of the stereogenic cen-
ters of AMPTD. While the published work did not discuss
deprotection of the adduct, we discovered that treatment of 34
with a dry solution of HCl in dioxane allowed selective removal
of the sulfimine group to yield amine salt 35. TBAF-mediated re-
moval of the TBDPS group from 34 also proceeded smoothly to give
36; conversion of the alcohol to bromide 37 was unsuccessful un-
der various conditions, presumably due to deprotection of the ace-
tonide by HBr formed in the course of the reaction. (Our original
retrosynthesis envisioned conversion of 37 to a phosphonate and
reaction with the corresponding aldehyde analogue of 6.) Studies
on the oxidation of 36 to 7 and reaction with 6 are ongoing.
References and notes
1. Qureshi, A.; Colin, P. L.; Faulkner, D. J. Tetrahedron 2000, 56, 3679–3685.
2. Sasaki, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1997, 38, 3013–3016.
3. Sasaki, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1999, 40, 3187–3190.
4. Beck, A.; Heissler, D.; Duportail, G. Tetrahedron 1991, 47, 1459–1472.
5. Andrus, M. B.; Soma Sekhar, B. B. V.; Meredith, E. L.; Dalley, N. K. Org. Lett. 2000,
2, 3035–3037.
6. Onishi, T.; Williams, R. M. Chiral Lactones. US Patent 7,173,141, February 6,
2007.
7. Andrus, M. B.; Soma Sekhar, B. B. V.; Turner, T. M.; Meredith, E. L. Tetrahedron
Lett. 2001, 42, 7197–7201.
8. Crimmins, M. T.; She, J. Synlett 2004, 1371–1374.
9. Evans, D. A.; Cee, V. J.; Siska, S. J. J. Am. Chem. Soc. 2006, 128, 9433–9441.
10. Hennings, D. D.; Williams, R. M. Synthesis 2000, 9, 1310–1314.
11. Hjelmgaard, T.; Faure, S.; Lemoine, P.; Viossat, B.; Aitken, D. J. Org. Lett. 2008,
10, 841–844.