A total synthesis of (+)-bacillamide B

Article abstract of DOI:10.1055/S-0029-1219153

A total synthesis of the halophile-derived natural product (+)-bacillamide B is described. The route relies upon a Hantzsch synthesis of ethyl (S)-2-acetoxyethylthiazole-4-carboxylate followed by a dipyridyl disulfide-mediated coupling between the corresponding carboxylic acid and tryptamine. This synthesis has unambiguously demonstrated that in contrast to the previous tentative stereochemical assignments the stereochemistry of the alcohol at C15 of the title compound has S-configuration. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/S-0029-1219153

LETTER
599
A Total Synthesis of (+)-Bacillamide B
A
T
ota
l
Synthesi
h
of (+)-Baci
r
llamide
i
stopher D. Bray,* Joy Olasoji
School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London, E1 4NS, UK
Fax +44(0)20 78827427; E-mail: c.bray@qmul.ac.uk
Received 8 September 2009
Dedicated to Prof. Gerald Pattenden on the occasion of his 70th birthday in recognition of his elegant work on the biomimetic synthesis of
natural products and his unique wit, humour, inspiration and support.
ried out. The stereochemistry of the alcohol at C15 of ba-
Abstract: A total synthesis of the halophile-derived natural product
cillamide B (2) was assigned as having an R-configuration
(+)-bacillamide B is described. The route relies upon a Hantzsch
by comparison of its circular dichroism (CD) spectrum
synthesis of ethyl (S)-2-acetoxyethylthiazole-4-carboxylate fol-
lowed by a dipyridyl disulfide-mediated coupling between the cor-
with that of a closely related metabolite, N-3¢-indolyleth-
responding carboxylic acid and tryptamine. This synthesis has yl-2a-aminoethylthiazole-4-carboxamide (4).7 The stereo-
unambiguously demonstrated that in contrast to the previous tenta-
chemistry of this latter compound was only assigned by a
tive stereochemical assignments the stereochemistry of the alcohol
at C15 of the title compound has S-configuration.
second comparison of CD spectra, in this case, with those
of N-salicylidene derivatives of some model a-arylalkyl-
amines.8 Since it was assumed that a thiazole would create
Key words: extremophile, total synthesis, natural product, hetero-
cycle, thiazole
a similar interaction with the salicylidenimino moiety to
that of an aryl ring, a somewhat tenuous assumption, the
authors describe their assignement as only ‘tentative’.
Extremophiles, organisms that proliferate under condi-
tions detrimental to the majority of life on Earth, offer us
a glimpse at how life on primordial earth may have exist-
ed, or indeed, even been created. As such, there is consid-
erable astrobiological interest in extremophiles.1
Extremophiles also have considerable commercial signif-
icance,2 since examination of how they have adapted, both
chemically and enzymatically, to their hostile habitats
may act as a catalyst for the discovery of useful new pro-
cesses. For example, it was the isolation of a DNA poly-
merase from a thermophilic organism (later called
Thermus aquaticus) found in a thermal pool in Yellow-
stone National Park that was to become the cornerstone of
the polymerase chain reaction (PCR) and revolutionise
genetic science.3 Other notable applications of extremo-
philes in modern life include the use of ectoines in skin
creams and cryophile-derived lipases in low-temperature
washing detergents. Aside from the extremolytes and ex-
tremozymes, there are an ever increasing number of in-
triguing natural products being isolated from
extremophiles.4 Bacillamide B (2; Figure 1) was recently
isolated from a new bacterium, Bacillus endophyticus,
which was found living in a hypersaline microbial mat
found at Salt Pond, San Salvador Island, Bahamas.5 Also
isolated were the previously identified congener bacill-
amide A (1),6 as well as a second novel metabolite bacill-
amide C (3). Bacillamide B (2) is a tryptamide thiazole
which may be biogenetically derived from tryptamine,
cysteine and lactic acid. Its antibacterial activity was mea-
sured against an MRSA but, due to a dearth of material
(only 1 mg was isolated), along with a lack of appropriate
test organisms, a full analysis of bioactivity was not car-
This potential uncertainty regarding the absolute stere-
ochemistry, coupled with the fact that such small quanti-
ties of bacillamide B (2) were isolated among the natural
products obtained from the newly discovered bacterium,
Bacillus endophyticus, itself isolated from such an unusu-
al source, prompted the present synthesis.
R
S
N
bacillamide A
1 R = =O
B
C
2 R = OH
3 R = NHAc
4 R = NH2
N
H
O
N
H
Figure 1
We sought to synthesise bacillamide B (2) by coupling
tryptamine with the appropriate thiazole carboxylic acid.
Our synthesis began with commercially available (S)-2-
acetoxypropionyl chloride (5),9 which was readily con-
verted into amide 6 in 88% yield by treatment with NH3
gas in CH2Cl2 (Scheme 1). Subsequent treatment with
Lawesson’s reagent in 1,4-dioxane gave the correspond-
ing thioamide 7 in 69% yield, following flash column
chromatography. Traditional Hantzsch synthesis of thiaz-
oles bearing a-chiral centres can result in complete race-
misation.10 However, Schmidt and co-workers have
reported that addition of ethyloxirane, which traps the
HBr generated in situ forming a bromohydrin, serves to
prevent epimerisation in such reactions.11 Thus, reaction
of thioamide 7 with ethyl bromopyruvate in the presence
of ethyloxirane gave an intermediate hemiaminal which
was subsequently dehydrated with neat trifluoroacetic an-
hydride to give ethyl (S)-2-acetoxyethylthiazole-4-car-
SYNLETT 2010, No. 4, pp 0599–0601
0
1.
0
3.
2
0
1
0
Advanced online publication: 22.12.2009
DOI: 10.1055/s-0029-1219153; Art ID: D25209ST
© Georg Thieme Verlag Stuttgart · New York

600
C. D. Bray, J. Olasoji
LETTER
OH
OAc
S
OH
S
S
N
O
O
S
a
b
c
d
e
N
N
N
Cl
NH2
NH2
H
O
OAc
OAc
OAc
EtO2C
HO2C
N
5
6
7
8
9
H
(+)-bacillamide B (2)
Scheme 1 Reagents and Conditions: (a) NH3, CH2Cl2, 20 °C, 1 h, 88%; (b) Lawesson’s reagent (2 equiv), 1,4-dioxane, 20 °C, 16 h, 69%; (c)
(i) ethyl bromopyruvate, ethyloxirane, i-PrOH, 60 °C, 30 min; (ii) (CF3CO)2O, 20 °C, 30 min, 58% (2 steps); (d) 2 M LiOH, THF–MeOH;
20 °C, 24 h, 80%; (e) dipyridyl disulfide, Ph3P, tryptamine, CH2Cl2, 20 °C, 16 h, 54%.
boxylate (8), in 58% yield over two steps. Saponification
of diester 8 with 2M LiOH in THF/MeOH gave thiazole
carboxylic acid 9 in 80% yield.12 Finally, a dipyridyl di-
sulfide-mediated coupling13 of thiazole carboxylic acid 9
with tryptamine furnished bacillamide B (2) in 54%
yield.14
Acknowledgment
We thank the EPSRC National Mass Spectrometry Service Centre,
Swansea and Nadine Younan for obtaining the CD spectrum of syn-
thetic (+)-bacillamide B (2).
References and Notes
The NMR and IR spectra for synthetic bacillamide B (2)
matched those reported for the natural compound,5 as did
the sign of the specific rotation and the characteristics of
the CD spectrum, indicating that we had indeed synthe-
sised natural (+)-bacillamide B (2). However, we had be-
gun our synthesis with (S)-2-acetoxypropionyl chloride
(5) which, on the basis of the original stereochemical as-
signment,5 should have given (–)-bacillamide B (2). Thus,
our synthesis demonstrates that the proposed stereochem-
ical assignment of the alcohol at C15 of (+)-bacillamide
(2) was incorrect, and that, in fact, this centre has an S-
configuration. The stereochemical assignment of bacill-
amide C and also the recently isolated natural product
neobacillamide A15 should thus also be called into ques-
tion. Assuming that the biosynthetic origin of (+)-bacilla-
mide B (2) is indeed as described above, then D-(+)-lactic
acid, the natural and biologically more relevant isomer, is
a precursor, rather than the unnatural (–)-antipode, which
the original stereochemical assignment of 2 would have
implied.
(1) Landis, G. A. Astrobiology 2001, 1, 161.
(2) Satyanarayana, T.; Raghukumar, C.; Shivaji, S. Curr. Sci.
2005, 89, 78.
(3) Brock, T. D. Science 1985, 230, 132.
(4) Wilson, Z. E.; Brimble, M. A. Nat. Prod. Rep. 2009, 26, 44.
(5) Socha, A. M.; Long, R. A.; Rowley, D. C. J. Nat. Prod.
2007, 70, 1793.
(6) (a) Jeong, S. Y.; Ishida, K.; Ito, Y.; Okada, S.; Murakami, M.
Tetrahedron Lett. 2003, 44, 8005. (b) For a synthesis of
bacillamide A(1), see: Figueira, V. B. C.; Prabhahar, S.;
Lobo, A. M. Arkivoc 2005, (xiv), 14.
(7) Konda, Y.; Suzuki, Y.; Omura, S.; Masayuki, O. Chem.
Pharm. Bull. 1976, 24, 92.
(8) Smith, H. E.; Records, R. Tetrahedron 1966, 22, 813.
(9) The ambiguity regarding the stereochemistry, coupled with
the lack of commercially available R-enantiomer, led us to
commence the synthesis from the S-antipode.
(10) Pettit, G. R.; Melson, P. S.; Holzapfel, C. W. J. Org. Chem.
1985, 50, 2654.
(11) Schmidt, U.; Gleich, P.; Griesser, H.; Utz, R. Synthesis 1986,
992.
(12) (S)-2-Hydroxyethylthiazole-4-carboxylic acid (9): Ethyl (S)-
2-acetoxyethylthiazole-4-carboxylate11 (8; 121 mg, 0.50
mmol) was stirred in a solution of 2 M LiOH (1 mL), MeOH
(1 mL) and THF (1 mL) at 20 °C for 18 h. After this time the
mixture was diluted with water (5 mL) and shaken with
acidified IR-120 ion-exchange resin (3 mL) for 2 min. The
ion-exchange resin was filtered and the filtrate was
evaporated to give ethyl (S)-2-hydroxyethylthiazole-4-
carboxylic acid (9; 69 mg, 88%) as a yellow oil. IR (film):
3301, 1703, 1495, 1195 cm–1; 1H NMR (270 MHz, acetone-
d6): d = 1.55 (d, J = 6.7 Hz, 3 H, CH3), 5.09 (q, J = 6.7 Hz,
3 H, CHOH), 8.30 (s, 1 H, SCH); 13C NMR (67.5 MHz,
acetone-d6): d = 24.8 (CH3), 68.9 (CHOH), 128.9 (C5),
148.3 (C4), 162.8 (CO2H), 179.8 (C2).
(13) (a) Mukaiyama, T.; Matsueda, R.; Maruyama, H. Bull.
Chem. Soc. Jpn. 1970, 43, 1271. (b) Schmidt and co-
workers have demonstrated the use of this reagent for
coupling of thiazole carboxylic acids bearing unprotected
secondary alcohols without loss of stereointegrity, see:
Schmidt, U.; Gleich, P. Angew. Chem. Int. Ed. Engl. 1985,
24, 569.
In conclusion, a six-step synthesis of (+)-bacillamide B
(2) has been accomplished which relies upon a Hantzsch
synthesis of ethyl (S)-2-acetoxyethylthiazole-4-carboxy-
late (8), followed by a dipyridyl disulfide/Ph3P-mediated
coupling between the corresponding carboxylic acid 9 and
tryptamine. This synthesis has unambiguously demon-
strated the stereochemistry of the alcohol at C15 is of S-
configuration. The synthesis serves to demonstrate that
stereochemical assignment based upon multiple compari-
sons of CD spectra is not reliable, particularly when there
is only marginal analogy between the substituents in ques-
tion.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(14) (+)-Bacillamide B (2): A solution of tryptamine (6.4 mg,
0.04 mmol) and Ph3P (10.5 mg, 0.04 mmol) in CH2Cl2 (2
Synlett 2010, No. 4, 599–601 © Thieme Stuttgart · New York

LETTER
mL) was added dropwise over 5 min to a solution of (S)-2-
A Total Synthesis of (+)-Bacillamide B
601
10.81 (s, 1 H), 8.35 (t, J = 6.0 Hz, 1 H), 8.13 (s, 1 H), 7.60
(d, J = 7.8 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.18 (d, J = 1.7
Hz, 1 H), 7.06 (t, J = 7.5 Hz, 1 H), 6.97 (t, J = 7.4 Hz, 1 H),
6.24 (d, J = 5.0 Hz, 1 H), 4.94 (dq, J = 6.5, 5.2 Hz, 1 H), 3.54
(dd, J = 7.0, 6.5 Hz, 2 H), 2.93 (t, J = 7.5 Hz, 2 H), 1.47 (d,
J = 6.5 Hz, 3 H); 13C NMR (100 MHz, DMSO-d6): d = 178.6,
160.5, 149.9, 136.2, 127.2, 123.0, 122.5, 120.9, 118.40,
118.20, 111.7, 111.3, 66.6, 25.3, 24.1; MS: m/z [M + H]+
calcd for C16H18N3O2S: 316.1120; found: 316.1128.
(15) Yu, L. L.; Li, Z. Y.; Peng, C. S.; Li, Z. Y.; Guo, Y. W. Helv.
Chim. Acta 2009, 92, 607.
hydroxyethylthiazole-4-carboxylic acid (9; 6.9 mg, 0.04
mmol) and dipyridyl disulfide (8.8 mg, 0.04 mmol) in
CH2Cl2 (2 mL) at 20 °C. After 24 h, the supernatant solvent
was removed and evaporated in vacuo. The residue was
purified by flash column chromatography (SiO2; 2%
MeOH–CHCl3) to give bacillamide B (2; 6.8 mg, 54%) as a
light-yellow amorphous solid. [a]D20 +10.1 (c 0.10, MeOH)
[Lit.5 +7.4 (c 0.095, MeOH)]; IR (film): 3411bw, 3293bw,
2923w, 1642s, 1546s, 1492m, 1456m, 1250w, 1187w,
1103m, 1009w cm–1; 1H NMR (400 MHz, DMSO-d6): d =
Synlett 2010, No. 4, 599–601 © Thieme Stuttgart · New York