Thieme chemistry journal awardees - Where are they now? Stereoselective synthesis of z-configured α,β-unsaturated macrocyclic lactones and diolides by intramolecular julia-kocienski olefination

Article abstract of DOI:10.1055/s-0029-1219185

ω-Sulfonyl aldehydes derived from the esterification of (benzothiazol-2-ylsulfonyl)acetic acid with either ω-alkenols or α, ω-diols, followed by ozonolysis or Dess-Martin oxidation as appropriate, underwent intramolecular Julia-Kocienski olefination when treated with DBU. Macrocyclic α,β-unsaturated lactones of between 12- and 19-membered ring sizes were formed successfully using this tactic (24-44% yield, Z/E ≥ 3.5:1); however, diolides were selectively produced from precursors intended to target seven- to nine-membered-ring lactones (13-70% yield, ZZ/ZE ≥ 2:1). Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219185

374
LETTER
Thieme Chemistry Journal Awardees – Where Are They Now?
Stereoselective Synthesis of Z-Configured a,b-Unsaturated Macrocyclic
Lactones and Diolides by Intramolecular Julia–Kocienski Olefination
Z-Configured
a
,
b
-
e
U
nsaturated
a
M
acrocyc
t
lic
L
ac
h
tones and
D
iolidesE. Giesbrecht, Brian J. Knight, Nicole R. Tanguileg, Christopher R. Emerson, Paul R. Blakemore*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, OR 97331-4003, USA
Fax +1(541)7372062; E-mail: paul.blakemore@science.oregonstate.edu
Received 15 October 2009
Abstract: w-Sulfonyl aldehydes derived from the esterification of
(benzothiazol-2-ylsulfonyl)acetic acid with either w-alkenols or
a,w-diols, followed by ozonolysis or Dess–Martin oxidation as ap-
propriate, underwent intramolecular Julia–Kocienski olefination
when treated with DBU. Macrocyclic a,b-unsaturated lactones of
between 12- and 19-membered ring sizes were formed successfully
using this tactic (24–44% yield, Z/E ≥ 3.5:1); however, diolides
were selectively produced from precursors intended to target seven-
to nine-membered-ring lactones (13–70% yield, ZZ/ZE ≥ 2:1).
Key words: olefination, macrocycles, lactones, alkenes, sulfones
Paul R. Blakemore was born in London, England, in 1973. He was
inspired to build a career in organic chemistry after an early internship
at Rhône-Poulenc (now Sanofi-Aventis) revealed the creative possi-
bilities of chemical synthesis. Upon leaving high school, Paul pursued
BSc degrees in chemistry and mathematics from the University of
Southampton (UK) and later joined the research group of Professor
Philip J. Kocienski, then at Southampton, to undertake graduate work
in the field of sulfone-based olefination methods. The Kocienski
group relocated to the University of Glasgow in 1996, and it was there
that Paul discovered that trans-alkenes can be made with high levels
It was recently reported that a,b-unsaturated esters are
conveniently generated from aldehydes by treatment with
ethyl (benzothiazol-2-ylsulfonyl)acetate (4) under mild
conditions (DBU, CH2Cl2, ≤20 °C).1 Enoate formation
presumably occurs via the commonly accepted mecha-
nism for the Julia–Kocienski olefination,2 and Z-config-
ured products are obtained selectively from unbranched
aliphatic aldehydes (Z/E up to 92:8 at –78 °C). Zajc and of stereocontrol from 1-phenyl-1H-tetrazol-5-yl (PT) sulfones. This
variant of the Julia–Kocienski olefination has since become a very po-
pular tactic for the synthesis of complex molecules. An enjoyable pe-
riod of post-doctoral research then followed within the laboratories of
Professor James D. White at Oregon State University in Corvallis,
Oregon, USA. During this time (1999–2001), Paul worked on many
projects and had the good fortune to conclude group efforts that cul-
Lequeux later independently disclosed that a-fluorinated
analogues of 4 yield valuable a-fluoroacrylate derivatives
in excellent yield,3 further highlighting the good utility of
benzothiazol-2-yl (BT) sulfone based alternatives to the
HWE reaction.4,5 Given a preponderance of a,b-unsatur-
minated in total syntheses of several alkaloid and polyketide targets.
With a productive post-doctoral stint behind him, Paul was awarded
a fellowship from the Royal Society which enabled a temporary re-
turn to the UK and the commencement of an independent research ca-
reer at the University of Leeds. Paul was soon enticed back to the
wonders of the Pacific Northwest, however, and he has been a mem-
ber of the chemistry faculty at Oregon State University since 2005.
Research in the Blakemore laboratory is focused on the development
of new synthetic methods for the absolute control of molecular con-
stitution and stereochemistry.
ated lactones among biologically active secondary metab-
olites,6 and the ease of alkene formation from BT-sulfonyl
acetates, realization of an effective intramolecular variant
of this new type of enoate synthesis would constitute a
worthwhile advance. To date, surprisingly little attention
has been directed toward study of the intramolecular
Julia–Kocienski olefination. Of note, Leahy and co-work-
ers reported a failed attempt to conclude their synthesis of
rhizoxin D using such a tactic.7 More recently, Aïssa suc-
cessfully demonstrated the formation of unsaturated car-
bocycles by heating 1-tert-butyl-1H-tetrazol-5-yl
sulfones8 with tethered aldehyde functionality in the pres-
ence of Cs2CO3 as base in THF–DMF solvent (at 65 °C).9
Herein, we report our own findings relating to the nascent
intramolecular Julia–Kocienski olefination and describe
the first examples of a,b-unsaturated lactone synthesis via
base-mediated cyclization of w-sulfonyl aldehydes 1
(Scheme 1).10
O
O
BTSO2
O
N
S
base
O
O
BT =
– BTO–
– SO2
n
n
1
2
Scheme 1 Focus of study: formation of a,b-unsaturated lactones 2
via intramolecular Julia–Kocienski olefination from w-sulfonyl alde-
hydes 1
SYNLETT 2010, No. 3, pp 0374–0378
Advanced online publication: 11.01.2010
DOI: 10.1055/s-0029-1219185; Art ID: S12009ST
1
2.
0
2.
2
0
1
0
The w-sulfonyl aldehydes of interest were targeted via
ozonolysis of the corresponding terminal olefin or else via
© Georg Thieme Verlag Stuttgart · New York

LETTER
Z-Configured a,b-Unsaturated Macrocyclic Lactones and Diolides
375
oxidation of the primary alcohol (vide infra). Access to ed glycol could be recovered during purification of the re-
the necessary aldehyde precursors was sought by esterifi- action mixture.
cation of (benzothiazol-2-ylsulfonyl)acetic acid (7) with
O
an appropriate w-alkenol or a,w-diol. Few reports of acid
7 exist in the literature and attempts to synthesize this ma-
terial by saponification of sulfonyl ester 41 in methanol
led to ipso attack upon the heterocyclic sulfone and the
generation of BTOMe (5, Scheme 2).11 By contrast, hy-
drolysis of sulfanyl ester 3 under otherwise identical con-
ditions gave the expected free acid 6 in excellent yield.
Sulfoxidation of thioether 6 to sulfone 7 has been previ-
ously reported on a small scale with KHSO5,12 but we ob-
tained superior results using a Mo(VI)-catalyzed H2O2-
mediated oxidation.13 Samples of acid 7 prepared in this
manner are invariably associated with trace quantities of
decarboxylation adduct 8; however, this innocuous con-
taminant does not interfere with subsequent steps. It was
established that sulfonyl acid 7 is shelf-stable for pro-
longed periods (several months) in the solid state, but that
this material spontaneously decarboxylates in solution.
The rate of CO2 loss was found to be sensitive to solvent
polarity. Thus, in DMSO solution (at 0.05 M) complete
decarboxylation of acid 7 occurred in 1.1 hours at room
temperature, while the same process in acetone solution
(at 0.05 M) required 22 hours at room temperature to at-
tain full conversion.
O
DCC (1.1 equiv)
THF, 0 °C to r.t.
OH
O
n
+
OH
9 (1.0 equiv)
BTSO2
n
BTSO2
7 (1.1 equiv)
10
O
O
O
Ph
O
O
6O
O
n
BTSO2
BTSO2
10-19 94%
BTSO2
10-6 60%
8
n = 2
n = 7
10-7
10-12
66%
98%
Scheme 3 Synthesis of alkene-based aldehyde precursors
O
O
DCC (1.1 equiv)
THF
HO
OH
OH
O
n
+
BTSO2
n
BTSO2
12
0 °C to r.t.
HO
7 (1.0 equiv)
11 (3.0–6.0 equiv)
12-7 n = 2 64%
12-8 n = 3 70%
12-9 n = 4 80%
12-12 n = 7 78%
12-13 n = 8 52%
12-15 n = 10 56%
13%
20%
12%
nd
12%
4%
yield of diester
side-product
O
O
O
O
n
O
O
BTSO2
HO
n+2
BTSO2
BTSO2
Mo(VI) catalyst
aq H2O2
aq NaOH
MeOH, r.t., 15 h
O
O
Scheme 4 Synthesis of carbinol-based aldehyde precursors
BTS
BTSO2
BTOMe
OEt
OEt
EtOH, r.t.
100%
90%
For our initial evaluation of the Julia–Kocienski process,
w-sulfonyl aldehydes 1 were generated from alkenyl BT-
sulfones 10 by ozonolysis with dimethylsulfide workup.
In general, the aldehydes exhibited limited stability and
best results were obtained by avoiding chromatographic
purification prior to their immediate deployment in base-
induced cyclization. To minimize undesired intermolecu-
lar couplings, olefination was conducted using modestly
high dilution with a syringe-pump addition of the freshly
prepared aldehyde to a solution of DBU base in CH2Cl2 at
–78 °C.17 Under these conditions (method A, Table 1),
only aldehyde precursor 10-19, targeting a 19-membered
lactone, led to the desired enoate product (entry 10). The
yield of intramolecular olefination was acceptable when
considering the large ring size generated and the absence
of cyclization inducing substituents,18 and a good prefer-
ence for the (Z)-enoate was noted.19 Precursors 10-7 and
10-12 afforded diolides 13 rich in the Z,Z-stereoisomer in-
stead of simple lactone products (entries 2 and 6),20 while
the aldehyde derived from 10-6 experienced facile b-elim-
ination upon exposure to DBU and did not give a lactone
nor a diolide product (entry 1).
3
4
5
DMSO, r.t.
1.1 h, 100%
aq NaOH, MeOH
r.t., 19 h, 94%
– CO2
Mo(VI) catalyst
O
O
aq H2O2
+
BTS
BTSO2
BTSO2Me
2%
OH
OH
EtOH, r.t.
6
7
78%
8
Mo(VI) catalyst = (NH4)6Mo7O24⋅4H2O (10–20 mol%)
Scheme 2 Synthesis of (benzothiazol-2-ylsulfonyl)acetic acid (7)
With a convenient method to access acid 7 secured, the
synthesis of its alkenyl ester derivatives was investigated
(Scheme 3). Carbodiimide coupling of 7 with w-alkenols
9 proceeded uneventfully to give the expected alkenyl es-
ters in generally excellent yield.14 Interestingly, attempts
to similarly esterify sulfanyl acid 6 using DCC failed and
resulted in the formation of a purple pigment tentatively
attributed to be a thiazo[2,3-b]benzothiazolium species.15
To concisely access a selection of carbinol-based sulfonyl
aldehyde precursors, acid 7 was directly coupled to unpro-
tected straight-chain a,w-diols 11 using DCC as before
(Scheme 4).16 To limit the amount of anticipated diester
side-product generated in these reactions, a modest excess
of diol (3–6 equiv) was employed; if desired, the unreact-
In the second phase of the investigation, w-sulfonyl alde-
hydes 1 were generated from hydroxy BT-sulfones 12 by
treatment with the Dess–Martin periodinane (DMP).21
Clean and essentially complete conversion was typically
achieved in less than 1 hour at room temperature, and fol-
lowing a simple workup procedure, the aldehyde sub-
Synlett 2010, No. 3, 374–378 © Thieme Stuttgart · New York

376
H. E. Giesbrecht et al.
LETTER
formation via the usual Julia–Kocienski pathway.2d,e Be-
sides being difficult to form because of transannular
strain, seven- to nine-membered cyclic b-alkoxysulfone
intermediates 14 are likely to experience retroaddition
(then intermolecular addition) rather than follow the usual
Smiles rearrangement–anti-b-elimination pathway (14 →
15 → 16 → 2) that characterizes this type of olefination
(Figure 1).
Table 1 Synthesis of a,b-Uunsaturated Lactones 2 and Diolides 13
by Intramolecular Julia–Kocienski Olefination from Sulfonyl Alde-
hydes 1
O
(DMP)
O
O
O3, CH2Cl2
MeOH, –78 °C
I
OAc
OAc
BTSO2
O
AcO
O
10
12
then, SMe2
→ r.t.
CH2Cl2, r.t.
n
1
O
O
O
DBU, CH2Cl2
method A: –78 °C (from 10)
method B: 20 °C (from 12)
O2
S
syringe pump
BTSO2
O
O2S
N
S
addition of 1 to DBU
O
O
O
solution
O
O
O
n
n
n
BTO
O
+
O
14
15
higher oligomers,
linear polymers
16
n
+
n
O
n
Figure 1
O
2
13
In conclusion, it has been demonstrated that intramolecu-
lar Julia–Kocienski olefination is a viable synthetic tactic
for the elaboration of large-ring-sized a,b-unsaturated lac-
tones. By contrast, the same process leads selectively to
diolides when medium-ring-sized enoates are targeted.
The method is of comparable efficiency to analogous Wit-
tig-based protocols for macrocycle synthesis,10 while of-
fering stereocomplementary access to Z- rather than E-
configured products. A distinguishing feature of the
chemistry reported herein is the ease with which the req-
uisite w-sulfonyl aldehyde substrates are synthesized. The
shelf-stable sulfonyl acid 7 engages in high yielding ester-
ification with alcohols using a carbodiimide reagent and
an aldehyde function may be expressed in the resulting es-
ter product by standard methods (e.g., ozonolysis or
Dess–Martin oxidation). Thus, sulfonyl acid 7 may be re-
garded as a convenient lynch pin capable of conjoining
[about a (Z)-enoate linkage] the termini of suitably func-
tionalized seco precursors via a short sequence of trans-
formations. It is conceivable that the cyclization process
described herein could be successfully employed in more
complex scenarios.
Entry Precursora Methodb Lactone 219
Yield (%)Z/E
Diolide 1320
Yield (%)ZZ/EZ
1c
2
10-6
A
A
B
B
B
A
B
B
B
A
0
0
–:–
0
31
27
70
13
44
21
<5
<5
<5
–:–
10-7
–:–
85:15
89:11
67:33
63:37
65:35
77:23
–:–
3d
4
12-7
0
–:–
12-8
0
–:–
5
12-9
0
–:–
6
10-12
12-12
12-13
12-15
10-19
<5
44
24
25
43
–:–
7
87:13
78:22
80:20
85:15
8
9
–:–
10e
–:–
a Aldehyde precursor, suffix indicates ring size of target lactone.
b Method A: 0.02 M soln of 1 (prepared from 10 with O3/SMe2) added
via syringe pump during 14–18 h to 0.04 M soln of DBU at –78 °C
then warmed to r.t. (see ref. 17); method B: as for A except 1 (pre-
pared from 12 with DMP) added to DBU soln at r.t. (see ref. 22).
c Cinnamaldehyde only significant product (36%).
d Olefination at r.t. led to decomposition, DBU initiated cyclization
conducted instead at –78 °C with a 15 min addition period.
e Product is 1,13-dioxacyclononadec-3-en-2-one.
Acknowledgment
Oregon State University is thanked for generous financial support.
References and Notes
strates were directly added via syringe pump to a DBU
solution. To increase the rate of intramolecular reaction
and thus suppress the formation of diolides and higher oli-
gomeric products, the cyclization was now conducted at
ambient temperature (method B).22 In again targeting the
formation of 2-12, this change had the desired effect, and
the lactone was now favored over the diolide (entry 7 vs.
6). Using the same procedure, other large ring-sized Z-
configured a,b-unsaturated lactones were also formed
(entries 8 and 9); however, attempts to generate seven- to
nine-membered lactones gave (Z,Z)-diolides selectively
with no trace of the simple lactone products (entries 3–5).
It is speculated that only larger ring sizes can readily ac-
commodate the bond-rotation events necessary for alkene
(1) Blakemore, P. R.; Ho, D. K. H.; Nap, W. M. Org. Biomol.
Chem. 2005, 3, 1365.
(2) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O.
Tetrahedron Lett. 1991, 32, 1175. (b) Baudin, J. B.; Hareau,
G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr.
1993, 130, 856. (c) Blakemore, P. R.; Cole, W. J.;
Kocienski, P. J.; Morley, A. Synlett 1998, 26. Reviews:
(d) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563. (e) Plesniak, K.; Zarecki, A.; Wicha, J. Top. Curr.
Chem. 2007, 275, 163. (f) Aïssa, C. Eur. J. Org. Chem.
2009, 1831.
(3) (a) Zajc, B.; Kake, S. Org. Lett. 2006, 8, 4457. (b) Pfund,
E.; Lebargy, C.; Rouden, J.; Lequeux, T. J. Org. Chem.
2007, 72, 7871. For a related process, see: (c) del Solar, M.;
Ghosh, A. K.; Zajc, B. J. Org. Chem. 2008, 73, 8206.
Synlett 2010, No. 3, 374–378 © Thieme Stuttgart · New York

LETTER
Z-Configured a,b-Unsaturated Macrocyclic Lactones and Diolides
377
(4) For a review of the Horner–Wadsworth–Emmons (HWE)
reaction, see: (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev.
1989, 89, 863. For Z-selective variants of the HWE reaction,
see: (b) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24,
4405. (c) Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka,
T. J. Org. Chem. 2000, 65, 4745 . For an example of Z-
selective intramolecular HWE reaction, see: (d)Ahmed, A.;
Hoegenauer, E. K.; Enev, V. S.; Hanbauer, M.; Kaehlig, H.;
Oehler, E.; Mulzer, J. J. Org. Chem. 2003, 68, 3026.
(5) For significant new Julia–Kocienski-type transformations
employing b-sulfonyl carbonyls, see: (a) Nielsen, M.;
Borch Jacobsen, C.; Paixao, M. W.; Holub, N.; Jørgensen,
K. A. J. Am. Chem. Soc. 2009, 131, 10581. (b) Cassani, C.;
Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem. Int. Ed. 2009,
48, 5694.
(6) For example, the cytotoxic a,b-unsaturated macrolides
phorboxazole A, rhizoxin D, and laulimalide. See,
respectively: (a) Searle, P. A.; Molinski, T. F. J. Am. Chem.
Soc. 1995, 117, 8126. (b) Iwasaki, S.; Namikoshi, M.;
Kobayashi, H.; Furukawa, J.; Okuda, S. Chem. Pharm. Bull.
1986, 34, 1384. (c) Corley, D. G.; Herb, R.; Moore, R. E.;
Scheuer, P. J.; Paul, V. J. J. Org. Chem. 1988, 53, 3644.
(7) Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J. W.
J. Org. Chem. 2003, 68, 4215.
r.t. and stirred for 19 h. After this time, precipitated DCU
was removed by filtration and the filtrate concentrated in
vacuo. The residue was purified by column chromatography
(SiO2, eluting with 10% Et2O in hexanes) to afford alkenyl
ester 10-12 (9.72 g, 24.6 mmol, 98%) as a pale yellow oil: IR
(neat): 2929, 1738, 1639, 1471, 1346, 1157 cm–1. 1H NMR
(300 MHz, CDCl3): d = 8.22 (1 H, dm, J = 7.5 Hz), 8.02 (1
H, dm, J = 7.1 Hz), 7.66 (1 H, td, J = 7.2, 1.4 Hz), 7.61 (1 H,
td, J = 7.2, 1.4 Hz), 5.81 (1 H, ddt, J = 17.1, 10.3, 6.6 Hz),
4.99 (1 H, dm, J = 17.2 Hz), 4.94 (1 H, dm, J = 10.2 Hz),
4.58 (2 H, s), 4.10 (2 H, t, J = 6.6 Hz), 2.03 (2 H, q, J = 6.9
Hz), 1.56–1.43 (2 H, m), 1.40–1.28 (2 H, m), 1.27–1.10 (8H,
m) ppm. 13C NMR (75 MHz, CDCl3): d = 165.2, 161.8,
152.6, 139.2, 137.1, 128.4, 127.9, 125.7, 122.5, 114.4, 67.0,
58.9, 33.9, 29.8, 29.3, 29.1, 29.0, 28.3, 25.7 ppm. HRMS
(FAB+): m/z calcd for C19H26NO4S2: 396.1303; found:
396.1309. All other alkenyl sulfones in Scheme 3 were
similarly characterized and gave comparable spectral
signatures.
(15) Thiazo[2,3-b]benzothiazolium species have been previously
identified following treatment of 6 with certain electrophilic
activators. For examples, see: (a) Duffin, G. F.; Kendall, J.
D. US 2513923, 1950. (b) Lacova, M. Chem. Papers 1986,
40, 95.
(8) Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000,
(16) Representative Procedure: DCC Coupling of Acid 7 and
1,6-Hexanediol (Scheme 4)
365.
(9) Aïssa, C. J. Org. Chem. 2006, 71, 360.
A stirred solution of acid 7 (500 mg, 98 wt%, 1.90 mmol)
and 1,6-hexanediol (689 mg, 5.83 mmol) in anhyd THF (5
mL) at 0 °C under Ar was treated with DCC (423 mg, 2.05
mmol). The resulting mixture was allowed to warm slowly
to r.t. and stirred for 72 h. The mixture was filtered to remove
precipitated DCU, diluted with CH2Cl2 (5 mL), and washed
successively with 1 M aq NaHCO3 (2 × 5 mL) and brine (5
mL), then dried (Na2SO4) and concentrated in vacuo. The
residue was purified by column chromatography (SiO2,
eluting with 40–100% EtOAc in hexanes) to yield in order of
elution: the diester side-product (133 mg, 0.22 mmol, 12%),
hydroxy ester 12-9 (542 mg, 1.52 mmol, 80%), and 1,6-
hexanediol (181 mg, 1.53 mmol, 37% of recoverable
amount).
Data for 12-9: colorless oil. IR (neat): 3406, 2935, 1741,
1471, 1343, 1154 cm–1. 1H NMR (300 MHz, CDCl3): d =
8.22 (1 H, dm, J = 7.3 Hz), 8.03 (1 H, dm, J = 7.3 Hz), 7.67
(1 H, td, J = 7.3, 1.4 Hz), 7.62 (1 H, td, J = 7.3, 1.4 Hz), 4.58
(2 H, s), 4.12 (2 H, t, J = 6.5 Hz), 3.60 (2 H, t, J = 6.3 Hz),
1.59–1.42 (4 H, m), 1.30–1.18 (4 H, m) ppm. 13C NMR (75
MHz, CDCl3): d = 165.0, 161.8, 152.5, 137.0, 128.4, 127.9,
125.6, 122.5, 66.8, 62.6, 58.8, 32.4, 28.2, 25.5, 25.3 ppm.
HRMS (ES+): m/z calcd for C15H20NO5S2: 358.0783; found:
358.0782. All other hydroxy sulfones in Scheme 4 were
similarly characterized and gave comparable spectral
signatures.
(10) For related studies employing the intramolecular Wittig
reaction, see: (a) Le Floc’h, Y.; Yvergnaux, F.; Toupet, L.;
Grée, R. Bull. Soc. Chim. Fr. 1991, 128, 742. (b)Le Floc’h,
Y.; Yvergnaux, F.; Grée, R. Bull. Soc. Chim. Fr. 1992, 129,
62.
(11) Sawhney, S. N.; Boykin, D. W. J. Org. Chem. 1979, 44,
1136.
(12) Naya, A.; Kobayashi, K.; Ishikawa, M.; Ohwaki, K.; Saeki,
T.; Noguchi, K.; Ohtake, N. Chem. Pharm. Bull. 2003, 51,
697.
(13) (Benzothiazol-2-ylsulfonyl)acetic Acid (7)
A solution of sulfanyl acid 6 (2.18 g, 9.68 mmol)12 in EtOH
(90 mL) at 0 °C was treated with (NH4)6Mo7O24·4H2O (1.20
g, 0.971 mmol) and stirred for 5 min. 30 wt% aq H2O2 (67
mL, 656 mol) was then added during 3 min, and the mixture
allowed to warm to r.t. and stirred for 17 h. After this time,
the reaction mixture was partitioned between CH2Cl2 (100
mL) and H2O (100 mL) and the layers separated. The
aqueous phase was extracted with CH2Cl2 (6 × 20 mL) and
the combined organic phases washed with H2O (20 mL) and
brine (20 mL), dried (Na2SO4), and concentrated in vacuo
(bath temperature 25 °C) to afford sulfonyl acid 7 (1.99 g, 98
wt% remainder 8, 7.58 mmol, 78%) as a colorless solid; mp
131–133 °C. IR (KBr): 3410, 2994, 1725, 1471, 1338, 1166
cm–1. 1H NMR (400 MHz, acetone-d6): d = 8.31 (1 H, dd,
J = 7.3, 1.5 Hz), 8.24 (1 H, dd, J = 7.7, 1.6 Hz), 7.75 (1 H,
td, J = 7.2, 1.3 Hz), 7.71 (1 H, td, J = 7.2, 1.2 Hz), 4.82 (2 H,
s) ppm. 13C NMR (75 MHz, acetone-d6): d = 167.0, 163.4,
153.4, 137.7, 129.1, 128.7, 125.9, 123.9, 59. 2 ppm. Methyl
sulfone 8 (2 wt%) revealed by dH = 3.50 (3 H, s) ppm. Any
attempts to recrystallize, or otherwise purify, sulfonyl acid 7
led to further unwanted decarboxylation and increased levels
of 8. Formation of the peroxyacid derivative of 7 was not
observed.
(17) General Procedure: Ozonolysis and Intramolecular
Olefination (Table 1, Method A)
A moderate stream of ozone was bubbled through a stirred
solution of 10 (250 mmol) in CH2Cl2–MeOH (4:1, 5 mL) at
–78 °C for 10 min. The mixture was sparged with Ar for 5
min and then treated with SMe2 (0.5 mL) and warmed to r.t.
during 20 h. The solution was concentrated in vacuo and the
residual crude aldehyde taken up in CH2Cl2 (12.5 mL). The
solution of aldehyde (≤0.02 M) was added via syringe pump
during 14–18 h to a stirred 0.04 M solution of DBU (95 mg,
625 mmol, 2.5 equiv) in CH2Cl2 (15 mL) at –78 °C (the
reaction mixture was allowed to warm slowly to r.t. during
the latter half of the addition). After this time, the resulting
solution was shaken with sat. aq NH4Cl (10 mL) and the
layers separated. The aqueous phase was extracted with
(14) Representative Procedure: DCC Coupling of Acid 7 and
9-Decen-1-ol (Scheme 3)
A stirred solution of acid 7 (6.80 g, 98 wt%, 25.9 mmol) in
anhyd THF (200 mL) at 0 °C under Ar was treated with neat
9-decen-1-ol (3.93 g, 25.1 mmol) followed by DCC (5.72 g,
27.7 mmol). The resulting mixture was allowed to warm to
Synlett 2010, No. 3, 374–378 © Thieme Stuttgart · New York

378
H. E. Giesbrecht et al.
LETTER
CH2Cl2 (2 × 5 mL) and the combined organic phases washed
with brine (10 mL), dried (Na2SO4), and concentrated in
vacuo. Purification of the residue was effected by column
chromatography (SiO2, eluting with 10–15% EtOAc in
hexanes).
1299 cm–1. 1H NMR (400 MHz, CDCl3): d = 6.24 (2 H, dt,
J = 11.7, 8.7 Hz), 5.81 (2 H, dm, J = 11.7 Hz), 4.20 (4 H, t,
J = 5.1 Hz), 2.77 (4 H, q, J = 8.2 Hz), 1.87–1.79 (4 H, m)
ppm. 13C NMR (100 MHz, CDCl3): d = 167.0, 145.5, 122.5,
63.8, 28.2, 27.1 ppm. HRMS (CI+): m/z calcd for C12H17O4:
225.1127; found: 225.1128.
(Z,Z)-13-16 (n = 3): colorless oil. IR (neat): 2925, 1716,
1653, 1458, 1288 cm–1. 1H NMR (400 MHz, CDCl3): d =
6.26 (2 H, dt, J = 11.7, 8.6 Hz), 5.75 (2 H, dm, J = 11.6 Hz),
4.20 (4 H, t, J = 5.6 Hz), 2.67 (4 H, qm, J = 7.5 Hz), 1.78–
1.70 (4 H, m), 1.65–1.50 (4 H, m) ppm. 13C NMR (100 MHz,
CDCl3): d = 167.2, 146.3, 121.7, 64.3, 29.8, 29.2, 26.5 ppm.
HRMS (EI+): m/z calcd for C14H20O4: 252.1362; found:
252.1370.
(Z,Z)-13-18 (n = 4): colorless oil. IR (neat): 2923, 2853,
1698, 1458 cm–1. 1H NMR (400 MHz, CDCl3): d = 6.18 (2
H, dt, J = 11.6, 8.3 Hz), 5.75 (2 H, dm, J = 11.6 Hz), 4.19 (4
H, t, J = 5.8 Hz), 2.61 (4 H, q, J = 7.3 Hz), 1.70–1.40 (12 H,
m) ppm. 13C NMR (100 MHz, CDCl3): d = 167.2, 147.7,
121.2, 64.3, 29.7, 28.9, 28.7, 26.5 ppm. HRMS (EI+): m/z
calcd for C16H25O4: 281.1753; found: 281.1754.
(18) (a) Jung, M. E.; Piizi, G. Chem. Rev. 2005, 105, 1735.
(b) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc.
1915, 107, 1080.
(19) Data for (Z)-Lactones 2 (Table 1)
(Z)-2-12 (n = 7): colorless oil. IR (neat): 2920, 2850, 1734,
1717, 1700, 1457 cm–1. 1H NMR (300 MHz, CDCl3): d =
6.32 (1 H, dt, J = 11.7, 8.9 Hz), 5.76 (1 H, dt, J = 11.7, 0.9
Hz), 4.23–4.19 (2 H, m), 2.47 (2 H, q, J = 7.9 Hz), 1.89–1.80
(2 H, m), 1.51–1.30 (10 H, m) ppm. 13C NMR (75 MHz,
CDCl3): d = 167.6, 147.7, 121.8, 66.4, 26.7, 26.3, 25.7, 25.5,
24.8, 24.7, 22.3 ppm. HRMS (EI+): m/z calcd for C11H18O2:
182.1307; found: 182.1298.
(Z)-2-13 (n = 8): colorless oil. IR (neat): 2926, 2855, 1716,
1653, 1458, 1153 cm–1. 1H NMR (400 MHz, CDCl3): d =
6.15 (1 H, dt, J = 11.7, 8.5 Hz), 5.78 (1 H, dm, J = 11.8 Hz),
4.27–4.22 (2 H, m), 2.53 (2 H, qm, J = 7.6 Hz), 1.73–1.65 (2
H, m), 1.55–1.32 (12 H, m) ppm. 13C (100 MHz, CDCl3):
d = 167.7, 147.0, 121.7, 65.4, 28.0, 27.3, 27.2 (2 C), 26.5,
26.3, 25.0, 24.8 ppm. HRMS (CI+): m/z calcd for C12H21O2:
197.1542; found: 197.1536.
(Z,Z)-13-24 (n = 7): colorless solid; mp 58–60 °C. IR (KBr):
2917, 2850, 1719, 1700, 1465 cm–1. 1H NMR (300 MHz,
CDCl3): d = 6.19 (2 H, dt, J = 11.7, 8.0 Hz), 5.74 (2 H, dm,
J = 11.7 Hz), 4.17 (4 H, t, J = 6.0 Hz), 2.54 (4 H, q, J = 7.2
(Z)-2-15 (n = 10): colorless oil. IR (neat): 2928, 2857, 1720,
1643, 1459, 1173 cm–1. 1H NMR (300 MHz, CDCl3): d =
6.13 (1 H, dt, J = 11.7, 8.0 Hz), 5.78 (1 H, dt, J = 11.7, 1.4
Hz), 4.26–4.21 (2 H, m), 2.58 (2 H, qd, J = 7.9, 1.4 Hz),
1.73–1.61 (2 H, m), 1.60–1.20 (18 H, m) ppm. 13C NMR (75
MHz, CDCl3): d = 167.5, 148.2, 121.1, 64.6, 28.6, 28.4,
27.6, 27.0, 26.8, 26.63, 26.57, 26.2, 26.1, 25.2 ppm. HRMS
(EI+): m/z calcd for C14H24O2: 224.1776; found: 224.1769.
(Z)-2-19 (‘n = 14’): colorless oil/waxy solid. IR (neat):
2927, 2851, 1702, 1655, 1473, 1108 cm–1. 1H NMR (300
MHz, CDCl3): d = 6.14 (1 H, dt, J = 11.6, 7.9 Hz), 5.77 (1 H,
dm, J = 11.6 Hz), 4.17 (2 H, t, J = 5.9 Hz), 3.48–3.36 (4 H,
m), 2.54 (2 H, qm, J = 7.4 Hz), 1.75–1.62 (2 H, m), 1.55–
1.15 (18 H, m) ppm. 13C NMR (75 MHz, CDCl3): d = 167.1,
149.0, 120.6, 70.0, 69.8, 64.0, 29.7–28.0 (8 C), 25.7 (2 C),
25.5 ppm. HRMS (EI+): m/z calcd for C17H30O3: 282.2195;
found: 282.2183. Minor E-lactones revealed by: dH = ca.
6.94 (1 H, dt, J = 15.6, 7.9 Hz) ppm. 1H NMR data for (Z)-
2-15 are in agreement with those previously reported:
Hayashikoshi, T.; Abe, M.; Kurata T. Sekiyu Gakkaishi
1996, 39, 74.
Hz), 1.75–1.60 (6 H, m), 1.50–1.20 (18 H, m) ppm. 13
C
NMR (75 MHz, CDCl3): d = 167.3, 148.6, 120.9, 64.4, 29.5,
29.33, 29.26, 29.1, 29.0, 26.4 ppm. HRMS (EI+): m/z calcd
for C22H36O4: 364.2614; found: 364.2617. Data for (E,Z)-
diolides 13-14, 13-16, and 13-18, can be found in ref. 10b.
(21) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277. (b) Boeckman, R. K. Jr.; Shao, P.; Mullins, J. J. Org.
Synth. 2000, 77, 141.
(22) General Procedure: Dess–Martin Oxidation and
Intramolecular Olefination (Table 1, Method B)
A solution of 12 (250 mmol) in anhyd CH2Cl2 (2 mL) was
treated with DMP21 (160 mg, 375 mmol) and stirred for 45
min at r.t. Mixture diluted with CH2Cl2 (10 mL) and washed
successively with 10 wt% aq NaHCO3 (10 mL) and brine (10
mL), dried (Na2SO4), and then concentrated in vacuo. The
residual crude aldehyde was taken up in CH2Cl2 (12.5 mL)
and this solution (≤0.02 M) added via syringe pump during
14–18 h to a stirred 0.04 M solution of DBU (266 mg, 1.75
mmol, 7.0 equiv) in CH2Cl2 (45 mL) at r.t. After this time,
the reaction mixture was quenched with sat. aq NH4Cl (10
mL) and worked up and purified as indicated above for
method A (ref. 17).
(20) Data for (Z,Z)-diolides 13 (Table 1)
(Z,Z)-13-14 (n = 2): waxy solid. IR (neat): 2923, 1705, 1628,
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