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SYNTHESIS OF CARBON-13 LABELLED ACIDS AND ESTERS 339
S
S
S
TBDMS
i) Sn(OTf)2,1-ethylpiperidine,
O
*
O
*
O
O
*
OH
DCM, -40 0C
BOPCl, DMAP,
*CH3*CO2H
i) Et3N, MeNHOMe, DCM
ii) Butanal,-780C
ii) TBDMSOTf, 2,6-lutidine, DCM
iPr
N
HN
S
N
N
S
iPr
S
*
*
*
OMe
100%
88%
90% over 2 steps
4
5
6
7
sec-BuLi,THF, -72 0C
45%
Me
BnO
* = 13
C
8
CONMe2
OBn
*
*
iPr
iPr
*
BnO
HO
iPr
BnO
*
*
10
*
i) HCl/EtOH (1%), RT, 87%
9
3 N HCl/dioxane (1:1),
Reflux
ii) AcOH, Me4N.B(OAc)3H, 92%
O
OTBDMS
OH
O
OH OH
CONMe2
CONMe2
83%
10
9 OBn
OH
O
OBn
Scheme 1 Synthesis of [9,10-13C2]dihydroisocoumarin 10.
Synthesis of [1,2-13C2]5,5-dichlorohexanoic acid 15
including Dreschlera monoceras and Dreschlera rave-
nelii.2 Results from feeding studies using isotopically
labelled sodium acetate with D. ravenelii3 led to the
proposal that dihydroisocoumarin 10 is the first
polyketide synthase (PKS) free intermediate in the
biosynthesis of monocerin. Hence 10 was required in
isotopically labelled form for incorporation studies. A
stereoselective aldol reaction was used to prepare the
labelled C9-C14 fragment using the sulfur containing
thiazolidinethione auxiliary 4 (Scheme 1).
Hectochlorin 2 was isolated from the marine cyano-
bacterium Lyngbya majuscula and possesses a struc-
ture in accord with a mixed PKS-NRPS biosynthetic
origin.6 Of particular interest is the unusual dichlor-
ohexanoic acid side chain and
a
sample of
[1,2-13C2]5,5-dichlorohexanoic acid 15 was required
to investigate the biosynthesis of hectochlorin.
Acetylated chiral thiazolidinethiones, as illustrated
above, and other acetylated auxiliaries including
oxazolidinones and sultams have been used widely
to introduce vicinal 13C2 labels. Whilst these
starting materials could be considered for the synthesis
of 15, with no asymmetric centre present in the target,
a more efficient strategy proved to be assembly of the
required C6-framework via a Horner–Wadsworth–Em-
mons chain extension of protected 4-oxobutanal 11
which in turn was prepared from ethyl acetoacetate
(Scheme 2).
Originally the mixed anhydride generated from
sodium 13C2-acetate and pivaloyl chloride was used
to acylate the sodium salt of thiazolidinethione 4 giving
5 in 35% yield.4 Recently we have found that a more
efficient approach to 5 involves treatment of auxiliary 4
with 13C2-acetic acid, BOPCl and catalytic DMAP giving
the product in quantitative yield. A stereoselective aldol
reaction of acetylated auxiliary 5 with butanal in the
presence of tin triflate and 1-ethylpiperidine5 gave the
required alcohol 6 as a single diastereomer.4 Following
cleavage of the auxiliary and formation of the silyl
ether, the pivotal step was coupling the resultant
Weinreb amide 7 with the anion of benzamide 8
(prepared using sec-butyl lithium) to give 9 with
the required carbon skeleton of our target 10. Following
further functional group modifications including
deprotection of the silyl ether under mild conditions,
The ketonic carbonyl of ethyl acetoacetate was
protected as a cyclic acetal prior to reduction of the
ester with diisobutylaluminium hydride (DIBAL) giving
aldehyde 11 in 65% yield after purification by column
chromatography. Treatment of 11 with commercially
available [1,2-13C2]triethylphosphonoacetate gave
unsaturated ester 12. Reduction of 12 with Pd/C
under a hydrogen atmosphere, followed by deprotec-
tion of the acetal using cerium(III) chloride gave ethyl
[1,2-13C2]5-oxohexanoate 13 in 73% yield over the two
steps. To complete the synthesis of the target com-
pound 15, it was necessary to convert ketone 13 to
dichloride 14. Initially geminal dichlorination proved
to be problematic e.g. using either PCl5/DCM/H2O
a
stereoselective reduction and finally treatment
of the resultant dihydroxyamide with acid, the
target [9,10-13C2]dihydroisocoumarin 10 was isolated
in good yield. Incubation studies of 10 with D. ravenelii
showed that an exceptionally high incorporation
(60%) of intact isotopic label into monocerin had
occurred.4
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 338–341
DOI: 10.1002.jlcr