Total synthesis of (±)-manzacidin D

Article abstract of DOI:10.1016/j.tetlet.2004.08.038

We report herein the first total synthesis of the alkaloid manzacidin D, in 11 steps and 16% overall yield from commercially available glycine tert-butyl ester hydrochloride. Our synthesis demonstrates for the first time in a total synthesis the utility of two different methodologies. A highly diastereoselective iodocyclization of an olefinic isothiourea is used to induce stereocontrol at the quaternary centre, and to form the heterocyclic core. Conversion of a thiourea to the requisite formamidine is achieved in good yield using our modified procedure.

Full text of DOI:10.1016/j.tetlet.2004.08.038

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7197–7199
Total synthesis of (± ±)-anꢀaꢁiꢂin D
*
Christian Drouin, Jacqueline C. S. Woo, D. Bruce MacKay and Roch M. A. Lavigne
Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, QC, Canada, H9H 3L1
Received 6July 2004; revised 9 August 2004; accepted 9 August 2004
Available online 24 August 2004
Abstraꢁt—We report herein the first total synthesis of the alkaloid manzacidin D, in 11 steps and 16% overall yield from commer-
cially available glycine tert-butyl ester hydrochloride. Our synthesis demonstrates for the first time in a total synthesis the utility of
two different methodologies. A highly diastereoselective iodocyclization of an olefinic isothiourea is used to induce stereocontrol at
the quaternary centre, and to form the heterocyclic core. Conversion of a thiourea to the requisite formamidine is achieved in good
yield using our modified procedure.
ꢀ
2004 Elsevier Ltd. All rights reserved.
The manzacidins are a class of alkaloids having a cyclic
amidine core (Fig. 1). Manzacidins A, B and C (1a, b, ꢁ)
were isolated from the Okinawan sponge Hymeniacidon
sp. When first isolated, their tetrahydropyrimidine scaf-
fold was considered unique. However, with the isolation
which it shows high potency has not yet been discov-
ered. This situation makes manzacidin D a highly
attractive target for synthesis and biological evaluation.
1
Our retrosynthesis of manzacidin D is depicted in Figure
2. We expected to install the pyrrole carboxylate in the
last step of the synthesis, according to OhfuneÕs prece-
dent. The formamidine unit is derived from the corre-
sponding isothiourea. The requisite hydroxyl group
could be derived from an iodide. This intermediate
could in turn be prepared by an iodocyclization reaction
of the appropriate olefinic isothiourea, which we have
shown to proceed with excellent diastereoselectivity
of manzacidin D (1ꢂ) from the coralline demosponge
2
Astrosclera willeyana, and most recently compound
1
e, N-methyl manzacidin C, from the marine sponge
3
Axinella brevistyla, this family of natural products is
expanding. Prior to this work, only manzacidins A
and C, epimers at C-9, had been synthesized, by Ohfune
4
5
and co-workers, and by Wehn and DuBois. It should
be noted that the biological properties of the manzaci-
dins have been little studied. Manzacidin D, in particu-
7
and yield. This disconnection greatly simplifies the
6
lar, has been tested against few targets due to the
scarcity of its supply, and a biological target against
O
O
H
N
N
S
HO
tBuO
1d
O
N
N
N
Me
Me
HO
R1
H
R2
H
X
Br
manzacidin
A (1a)
OH
OH
9
N
O
R1
R2
Me
OH
H
H
Br
B (1b)
C (1c)
O
O
H
H
N
H
Br (9-epi)
tBuO
N
SMe
N
SMe
tBuO
O
H
Me
Me
H
D (1d)
N-methyl
manzacidin C (1e)
N
I
N
H
Br (9-epi)
Me
X
Figure 1. The manzacidins.
O
NH2
O
tBuO
NH2
Keywords: Manzacidin; Iodocyclization; Isothiourea; Thiourea;
Formamidine.
tBuO
*
Corresponding author. Tel.: +1 514 4283475; fax: +1 514 4284900;
e-mail: bruce_mackay@merck.com
Figure 2. Retrosynthesis of Manzacidin D.
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.038

7198
C. Drouin et al. / Tetrahedron Letters 45 (2004) 7197–7199
O
Ph
Ph
only starting material or slow hydrolysis even upon
refluxing. We turned our attention to a reaction that
has been studied only sporadically, desulfurization of
a thiourea (which we would generate from an isothio-
urea) under oxidative conditions, to accomplish overall
conversion of isothiourea to formamidine in two steps.
Yields quoted in the literature for this synthetic method
are highly variable, and transformation of the corre-
O
Ph CNH
2
N
NH2.HCl
tBuO
tBuO
11
CH Cl
2
2
2
3
O
O
Ph
Ph
i) NaH, THF
ii) Br
HCl
H O/THF
NH2
N
tBuO
tBuO
2
89%
sponding six-membered ring substrate has not been
12
72% from 2
5
4
reported.
In the event, exposure of tetrahydro-
pyrimidinethione 9 to aqueous peroxide afforded only
the hydrolysis product tetrahydropyrimidinone 10
(Scheme 2). By contrast, employing urea hydrogen per-
oxide adduct affords the desired tetrahydropyrimidine
11 cleanly as the only product observed by NMR.
H
S
N
S
N
O
O
MeNCS
Pyridine
MeI
NH
NH
tBuO
tBuO
MeCN
95%
8
6%
6
7
S
O
O
3
0% aq. H
2 2
O
N
NH
N
N
NH
S
IBr, CH Cl
tBuO
N
2
2
MeOH
N
-
78 oC, 2h
5%
9
1
0
9
I
8
.
dr >95 : 5
H O urea
2
2
N
9
Sꢁhe-e 1.
MeOH
1
1
Sꢁhe-e 2.
synthesis, since the acyclic isothiourea can be derived
from an allylated glycine ester. This intermediate can
be prepared from a glycine ester.
Having established a reasonable plan for installing the
formamidine unit, we proceeded to test it in our synthesis
Synthesis of the cyclic isothiourea 8 is presented in
Scheme 1. Protection of glycine t-butyl ester hydrochlo-
ride 2 as its benzophenone imine and alkylation with
methallyl bromide affords the alkylated imine 4, in good
(Scheme 3). In previous studies we had found that solvo-
lysis of an iodide differing only from 8 by the absence of
the N-methyl group proceeded readily with one
8
yield over two steps. Acid mediated deprotection of the
imine is potentially complicated by the sensitivity of the
t-butyl ester to hydrolysis and of the olefin moiety to
potential isomerization; however, we found that expo-
sure of 4 to aqueous acid at 0ꢁC for 5min gave an excel-
lent yield of amine 5. Conversion of amine 5 to thiourea
O
4 eq. AgOCOCF
MeNO , H O
N
S
H
S, pyr
Et N
3
2
tBuO
8
N
2
2
3
6
0% from 8
OH
6
proceeded smoothly using methyl isothiocyanate.
1
2
Preparation of isothiourea 7 proceeded in virtually
quantitative yield, and cyclization of this compound
using our procedure afforded 8 in excellent yield
with high diastereocontrol. The diastereoselectivity
was assessed as greater than 95:5 by analysis of the crude
O
O
H
.
N
S
H O urea
N
H
tBuO
2
2
tBuO
N
N
MeOH
1
OH
OH
reaction mixture by 400MHz H NMR. The stereo-
13
1
4
chemistry of the iodocyclization product was confirmed
by NOESY analysis; cross-peaks were seen between the
methyl group of the newly-formed quaternary centre
and the proton a to the carbonyl, both of which take
up pseudoaxial positions in the ring.
purification on SiO2
(see text)
14 (1.6 : 1 dr)
5
5%
The key remaining challenge in our synthesis involved
conversion of the isothiourea to a formamidine. We first
investigated metal-promoted reductions, since we envi-
O
4 N HCl
N
H
HO
9
,10
crude 14
sioned this would be a facile process.
To our dismay,
N
7
5% from 13
in no experiments were we able to successfully carry out
the transformation on either model substrates, or for
cyclic isothioureas closer to our required substrate. In
general, reactions were extremely sluggish, affording
OH
5 (10-15:1 dr)
1
Sꢁhe-e 3.

C. Drouin et al. / Tetrahedron Letters 45 (2004) 7197–7199
7199
7
equivalent of silver trifluoroacetate. By contrast, 8
Aꢁknowleꢂge-ents
underwent slow reaction, and required 16h and 4equiv
of silver salt to drive the reaction. Furthermore, 12 was
not stable upon storage, and needed to be used immedi-
ately. Treatment of 12 with hydrogen sulfide under basic
conditions regenerated thiourea 13. Exposure of 13 to
our developed conditions afforded 14, which showed less
The authors thank Merck Frosst Centre for Therapeutic
Research for generous support of this work. We also
thank NSERC for financial support, R e´ jean Fortin
and Denis Desch eˆ nes (Merck Frosst) for help with puri-
fication of 1ꢂ by preparative HPLC and Laird Trimble
(Merck Frosst) for NOESY analysis of 8.
1
than 5% epimerization by crude H NMR analysis. This
is the first demonstration of this reaction in a synthetic
sequence with so high a degree of complexity. Upon puri-
fication on SiO , however, 14 was isolated as a 1.6:1 mix-
Referenꢁes anꢂ notes
2
ture of diastereomers. It should be noted that ammonia
was required as an additive to the eluent to elute this
highly polar compound, and it is possible that this basic
environment led to the epimerization of the stereocentre
a to the carbonyl. Due to the crucial importance of
reducing the acidity at this position, we decided to depro-
tect the crude ester; once formed, the resultant zwitterion
1. Kobayashi, J.; Kanda, F.; Ishibashi, M.; Shigemori, H.
J. Org. Chem. 1991, 56, 4574.
2
3
. Jahn, T.; Konig, G. M.; Wright, A. D. Tetrahedron Lett.
997, 38, 3883.
. Tsukamoto, S.; Tane, K.; Ohta, T.; Matsunaga, S.;
1
Fusetani, N.; van Soest, R. W. M. J. Natl. Prod. 2001,
6
4, 1576.
1
5 should thus have no mechanism to epimerize. In the
event, 15 was isolated in 75% yield over two steps from
3 following ion exchange chromatography, with a min-
4
. Namba, K.; Shinada, T.; Teramoto, T.; Ohfune, Y. J. Am.
Chem. Soc. 2000, 122, 10708.
5. Wehn, P. M.; DuBois, J. J. Am. Chem. Soc. 2002, 124,
1
imal amount of epimerization. The diastereomeric purity
of 15 varied somewhat between different reactions, but
was always in the range of 10–15 to 1.
12950.
6. Konig, G. M.; Wright, A. D.; Franzblau, S. G. Planta
Med. 2000, 66, 337.
7
. Woo, J. C. S.; MacKay, D. B. Tetrahedron Lett. 2003, 44,
881.
2
8
. It should be noted that 3 has been prepared in excellent
enantioselectively by asymmetric phase transfer catalysis.
For reviews, see: (a) OÕDonnell, M. J. Aldrichim. Acta
2001, 34, 3; (b) Maruoka, K.; Ooi, T. Chem. Rev. 2003,
103, 3013.
NaH then
CCl3
N
H
O
1
5
1d
DMF
0%
9
. For reductions in pyrimidine and purine systems, see: (a)
Niwas, S.; Chand, P.; Pathak, V. P.; Montgomery, J. A. J.
Med. Chem. 1994, 37, 2477; (b) Vainilavichius, P.;
Syadyaryavichiute, V. Khim. Geterotsikl. Soedin. 1992,
7
Sꢁhe-e 4.
1
655; (c) Ramzaeva, N.; Mittelbach, C.; Seela, F. Helv.
With our requisite amidino-alcohol 15 in hand, we
expected conversion to manzacidin D to proceed in
straightforward fashion. Indeed, this proved to be the
case (Scheme 4). Using conditions slightly modified
from those of Ohfune and co-workers, we obtained
manzacidin D 1ꢂ in good yield following ion exchange
and preparative HPLC. Manzacidin D has been stored
for five months at 4ꢁC as its TFA salt without signifi-
cant decomposition.
Chim. Acta 1999, 82, 12; (d) Schlein, H. N.; Israel, M.;
Chatterjee, S.; Modest, E. J. Chem. Ind. 1964, 418.
1
0. For reduction of imidothiolates to imines, see: (a) de
March, P.; Figueredo, M.; Font, J.; Gallagher, T.; Mil a´ n,
S. J. Chem. Soc., Chem. Commun. 1995, 9, 2097; (b)
Baraldi, P. G.; Leoni, A.; Cacciari, B.; Manfredini, S.;
Simini, D. Bioorg. Med. Chem. Lett. 1993, 3, 2511.
1
3
11. To our knowledge, there are only three publications on
this reaction: (a) Walter, W.; Rueß, K. P. Chem. Ber. 1969,
1
1
02, 2640; (b) Havel, J. J.; Kluttz, R. Q. Synth. Commun.
974, 4, 389; (c) Franchey, G.; Crestini, C.; Bernini, R.;
In summary, we have devised an efficient synthesis of
manzacidin D, with an average yield per step above
Saladino, R.; Mincione, E. Heterocycles 1994, 38, 2621.
2. Imidazoline has been prepared in 53% yield from imidaz-
olidine-2-thione, along with 15% hydrolysis by-product
1
1
8
0%. This route allowed facile preparation of sufficient
material for biological screening against new targets.
Perhaps more importantly, the route is sufficiently flexi-
ble to allow preparation of various analogues of manza-
2
-imidazolidone; see Ref. 11c.
3. The equivalents of NaH (60% dispersion in mineral oil)
and trichloromethyl ketone were increased to 3.0 and 3.2,
respectively, and the compound was purified by ion
cidin
D
for biological testing. Both of these
+
opportunities are currently being explored, and we will
report our results in due course.
exchange (Dowex 50 · 4, 100–200mesh, H form, elution
with H O then 1M aq NH OH).
2 4