An expeditious synthesis of nocardiolactone

Article abstract of DOI:10.1055/s-2005-869832

Nocardiolactone was synthesized by using a Crimmins asymmetric aldolization followed by a DMAP-mediated removal of the auxiliary with concurrent protection of the carboxylic group as a benzyl ester, activation of the β-hydroxyl group as a mesylate, hydrog

Full text of DOI:10.1055/s-2005-869832

LETTER
1477
An Expeditious Synthesis of Nocardiolactone
Nocardiolactone a-Ping Sun, Yikang Wu*
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China
Fax +86(21)64166128; E-mail: yikangwu@mail.sioc.ac.cn
Received 29 March 2005
Compared with CGA, HGA is much less common6 in the
synthesis of b-lactones (especially the optically-active
ones), presumably because of some discouraging factors.
For instance, the carboxylic group must be masked when
Abstract: Nocardiolactone was synthesized by using a Crimmins
asymmetric aldolization followed by a DMAP-mediated removal of
the auxiliary with concurrent protection of the carboxylic group as
a benzyl ester, activation of the b-hydroxyl group as a mesylate,
hydrogenolysis of the benzyl ester, and a novel DBU-mediated activation of the b-hydroxyl group is carrying out. Other-
lactonization that converted the syn-configuration to the trans one.
wise, CGA readily occurs. Also, once the b-OH is con-
verted into a good leaving group, it becomes rather liable
to basic/nucleophilic conditions and renders the subse-
quent deprotection of the carboxylic group much more
difficult than otherwise. In the case of some b-monosub-
stituted b-lactones these problems were cleanly solved by
Lenz6a and Giannessi6b,c by masking the carboxylic group
as ester/lactone at the activating (mesylating) step and re-
leasing it later through acid-catalyzed hydrolysis or hy-
drogenolysis (of benzyl ester), respectively.
Key words: asymmetric synthesis, chiral auxiliaries, lactones, ring
contractions, total synthesis
Nocardiolactone (1) is a simple b-lactone isolated by
Mikami1 et al. in 1999 from pathogenic Nocardia strains.
In the preliminary testing, it showed moderate narrow
spectrum activity against Gram-positive bacteria such as
Bacillus subtilis ATCC 6633. Like many other biological-
ly-active b-lactones such as lipstatin,2a,b esterastin,2c pan-
cilicins,2d,e ebelactones,2f,g and 1233 A,2h,l nocardiolactone
also has an anti relative configuration. The absolute con-
figuration, however, remains unknown. Here in this paper
we wish to report an expeditious enantioselective synthe-
sis of 1, which exploits Crimmins3 asymmetric aldoliza-
tion to establish the two stereogenic centers and a
‘hydroxy group activation’ (HGA4) to construct the b-lac-
tone functionality.
S
O
S
O
b
a
S
N
S
NH
Ph
+
Cl
18
18
3
Ph
4
2
S
OH
O
OH
O
With b-hydroxy acids or closely related compounds as the
precursor, the strategies for formation of the four-mem-
bered lactone ring can be divided into two major catego-
ries: one is ‘carboxylic group activation’ (CGA4), the
other is ‘hydroxyl group activation’ (HGA4). Under con-
ventional conditions (e. g., the PhSO2Cl/Py conditions de-
veloped by Adams5) b-hydroxy acids preferentially
undergo CGA, resulting in ring-closure without affecting
the configuration at the b-carbon. Such a nature decides
that syn-b-hydroxy acids can only lead to cis-b-lactones
and the anti acids only to trans lactones, respectively.
Thus, in order to make use of the readily accessible syn
a,b-disubstituted b-hydroxy acids (generally attainable
through Evans/Crimmins asymmetric aldolization with
predetermined absolute configurations at the newly
formed stereogenic centers and very broad substituent/
functional group compatibility) to synthesize trans a,b-
disubstituted b-lactones, one has to employ HGA
(occurred with inversion of the configuration at the b-
carbon).
c
S
N
d
BnO
11
11
Ph
5
16
6
16
OMs
O
OMs
O
f
e
HO
BnO
11
11
8
7
16
16
O
(E)
O
+
16
11
H
H
15
11
1
9
Scheme 1 Reagents and conditions: (a) LiCl, Et3N, C19H39COCl,
THF, 89%; (b) TiCl4, TMEDA, n-C13H27CHO, CH2Cl2, 63% (along
with 20% of recovered starting 4 and ca. 10% of other isomers); (c)
BnOH, DMAP, CH2Cl2, 77%; (d) MsCl, Et3N, CH2Cl2, 86%; (e) H2,
Pd/C, MeOH, 92%; (f) DBU, THF, 70% for 1 and 30% for 9.
SYNLETT 2005, No. 9, pp 1477–1479
0
1.
0
6.
2
0
0
5
Advanced online publication: 04.05.2005
DOI: 10.1055/s-2005-869832; Art ID: U09005ST
© Georg Thieme Verlag Stuttgart · New York

1478
Y.-P. Sun, Y. Wu
LETTER
Recently, we developed a general access7a to optically ac- solvent) at 0 °C gave similar discouraging results, with
tive benzyl esters of a,b-disubstituted b-hydroxy acids in most of the starting 8 recovered along with traces of prod-
connection with chiral auxiliary removal, making it very ucts (mainly the undesired 9). Much better results were
convenient to apply the Lenz’s6a methodology in prepara- later obtained with DBU {1,8-diazabicyclo [5.4.0]undec-
tion of a,b-disubstituted b-lactones illustrated through 7-ene}. In diethyl ether in the presence of DBU, the start-
synthesis of 1. As outlined in Scheme 1, under the con- ing mesylate 8 was fully consumed after 25 hours at 7 °C
ditions reported by Ho and Mathre10 for acylation of (the ambient temperature), yielding 1 and 9 in 45 and 52%
oxazolidinones, the chiral auxiliary (S)-4-phenylthiazol- yield, respectively. When anhydrous THF was used to
idinethione 28 reacted with 39 to give the N-acyl-thiazol- replace the diethyl ether as the solvent, the starting 8 was
idinethione 4 (89% yield). An asymmetric aldol reaction essentially quantitatively converted to 1 and 9 (70:30),
of 4 with tetradecanal11 was then performed using TiCl4, with anticipated 1 as the major product finally.14
TMEDA, CH2Cl2 at 0 °C to afford 57a as the predominant
The spectroscopic data (including optical rotation) of the
synthesized 1 were essentially identical to those reported
for the natural nocardiolactone. Therefore, the absolute
configuration of the natural 1 must be the same as that of
product in 63% isolated yield. The chiral auxiliary was
readily removed by treatment7 with benzyl alcohol in the
presence of a catalytic amount of 4-dimethylaminopyri-
dine (DMAP).
the synthesized one. Under the reaction conditions (TiCl4,
After the carboxylic group was masked as benzyl ester, TMEDA) employed, the Crimmins aldolization is
the b-hydroxyl group in 67a could be readily transformed expected3 to give Evans syn aldol as the major product.
into mesylate with MsCl and Et3N in CH2Cl2 without any Thus, the absolute configurations of the natural nocardio-
complication of CGA. The benzyl protecting group on the lactone should be (S,S).
carboxylic group was next removed by atmospheric
hydrogenolysis over a catalytic amount of 10% Pd/C to
O
(E)
O
H
160 °C
give the free acid-mesylate 8.
16
Before proceeding with 8, we had already tested12
(Na2CO3, H2O–Et2O) several similar syn-a,b-disubstitut-
ed acids activated at the b-position (prepared using a dif-
ferent approach relying on di-O,O-anion technique) and in
all cases obtained the expected b-lactone in satisfactory
yields. However, quite contrary to what anyone would ex-
pect, the same reaction conditions completely failed in the
case of 8 (no reactions occurred at all). Then we realized
that existing examples of HGA all relied on the essentially
same cyclization conditions6d (i. e., Na2CO3 or NaHCO3
in a H2O–Et2O or H2O–CHCl3 biphasic medium). Once
such conditions fail, there exists no other alternative in the
literature to which one can have recourse! Apparently,
development of new methods is highly necessary.
11
H
15
11
CO2
9
1
Scheme 2
It is noteworthy that re-treatment of the pure 1 with DBU/
THF (the lactonization conditions) did not lead to any 9 at
all, which means that compound 9 obtained in the lacton-
ization must be formed directly from 8 without ever being
1. The double bond configuration of 9 was established by
careful comparison of its spectroscopic data (especially
IR15) with those of an authentic sample prepared by pyro-
lysis of 1 (Scheme 2, which should be of trans-configura-
tion according to Adams5). It is interesting to note that
under similar basic conditions a,b-dibromo carboxylic ac-
ids (with a -Br as the leaving group instead of the -OMs in
the present case) underwent predominantly the decarbox-
ylation rather than b-lactonization, yielding vinylbromo
compounds as the predominant products.16
We reasoned that compared with the successful prece-
dents, the presence of two very long hydrophobic chains
without any hetero atom-containing substituents might be
the main cause for the difficulty; they might strongly in-
terfere with the deprotonation process (perhaps chain ag-
gregation or self-coiling13 was involved). A stronger base
might thus be needed. However, in the presence of one
equivalent of NaOH, only negligible amounts of products
(1 and 9) were formed even after prolonged reaction. Ad-
dition of a phase-transfer catalyst (Bu4NI) did not lead to
any discernible improvement. After repeated failure with
the biphasic systems, we decided to switch to homo-
geneous systems although there were no such precedents
in the literature (to our knowledge).
In brief, nocardiolactone has been synthesized for the first
time through an efficient enantioselective route. Based on
the rule of Crimmins aldolization, the absolute configura-
tion of the natural 1 is assigned to (S,S). A novel DBU-
mediated lactonization in homogeneous system has been
developed, which to our knowledge is the only alternative
to the long-known biphasic protocol underlying all the ex-
isting HGA-based syntheses of b-lactones. The procedure
developed herein (hopefully) may serve as a reference for
lactonization of other b-activated acids that carry similar
large non-functionalized hydrophobic chains and fail to
undergo the lactonization under the classic biphasic con-
ditions.
Using t-BuOK as the base and Et2O or THF as the solvent
at the ambient temperature (ca. 8 °C) or –78 °C to 10 °C
led to somewhat facilitated reaction, but the predominant
product turned out to be the decarboxylation–elimination
product alkene 9 rather than the anticipated 1. Running the
reaction in pyridine (serving as both the base and the
Synlett 2005, No. 9, 1477–1479 © Thieme Stuttgart · New York

LETTER
Nocardiolactone
1479
(7) (a) Wu, Y.-K.; Sun, Y.-P.; Yang, Y.-Q.; Hu, Q.; Zhang, Q.
J. Org. Chem. 2004, 69, 6141. (b) For related precedents
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Acknowledgment
Financial support from the National Natural Science Foundation of
China (20025207, 20272071, 20372075, 20321202), the Chinese
Academy of Sciences (‘Knowledge Innovation’, KGCX2-SW-
209), and the Major State Basic Research Development Program
(G2000077502) is gratefully acknowledged.
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[a]D21 –12.8 (c 0.30, CHCl3) {lit.4 [a]D21 –12.7 (c 2.5,
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H), 1.86–1.68 (m, 3 H), 1.43–1.20 (m, 56 H), 0.88 (t, J = 6.8
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(100), 57 (89.72), 83 (79.90), 111 (63.27), 43 (60.00), 69
(58.15), 55 (54.80), 85 (41.53), 125 (37.18), 139 (18.69).
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Synlett 2005, No. 9, 1477–1479 © Thieme Stuttgart · New York