Total syntheses of (+)- and (-)-syringolides 3 and of (+)- and (-)-syributins 1, 2 and 3

Article abstract of DOI:10.1016/j.tet.2009.07.055

The first total syntheses of (-)-syringolide 3, (+)-syributin 3 and their unnatural enantiomers (+)-syringolide 3 and (-)-syributin 3 using a common intermediate as starting material are described. In addition, total syntheses of (-)- and (+)-syributins 1

Full text of DOI:10.1016/j.tet.2009.07.055

Tetrahedron 65 (2009) 8091–8098
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Tetrahedron
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Total syntheses of (þ)- and (ꢀ)-syringolides 3 and of (þ)- and (ꢀ)-syributins
1, 2 and 3q
1
*
Mauricio Navarro Villalobos , John L. Wood , Susan Jeong, Cristy Lindberg Benson, Steven M. Zeman,
Catherine McCarty, Matthew M. Weiss, Analee Salcedo, Jonathan Jenkins
Sterling Chemistry Laboratory, Yale University, New Haven, CT 06520-8107, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 May 2009
Received in revised form 14 July 2009
Accepted 22 July 2009
Available online 26 July 2009
The first total syntheses of (ꢀ)-syringolide 3, (þ)-syributin 3 and their unnatural enantiomers (þ)-sy-
ringolide 3 and (ꢀ)-syributin 3 using a common intermediate as starting material are described. In
addition, total syntheses of (ꢀ)- and (þ)-syributins 1 and 2 were accomplished by means of the same
methodology.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Syringolides
Syributins
Pseudomonas syringae
Total synthesis
O–H insertion
Rhodium(II) stabilized carbene
1. Introduction
O
OH
O
H
O
H
n
O
O
O
The hypersensitive response (HR) of plants is an active mecha-
nism of defense that allows them to resist pathogen infection.2 It
involves cell death in the site of infection and a complex series of
biochemical changes in the plant that restrict the pathogen’s pro-
liferation. Pathogen avirulence (avr) genes are responsible for the
biosynthesis of metabolites named elicitors that trigger the HR in
plants. It is believed that complementary plant resistance (R) genes
encode for specific receptors for the pathogen elicitors, however,
most of these putative receptors have not yet been characterized
and the way they interact with the elicitors and trigger the HR is not
well understood.
O
n
O
O
HO
HO
Syringolide 1 (1), n = 3
Syringolide 2 (2), n = 5
Syringolide 3 (3), n = 1
Secosyrin 1 (4), n = 3
Secosyrin 2 (5), n = 5
Secosyrin 3 (6), n = 1
O
O
O
O
HO
O
O
n
O
HO
OH
n
HO
In 1993 Sims3 reported the isolation of syringolide 1 (1) and
syringolide 2 (2), the first nonproteinaceous specific elicitors of
a plant HR (Scheme 1). Syringolides 1 and 2 are bacterial signal
molecules (elicitors) produced by the avirulence gene D (avrD) of
O
Syributin 1 (10), n = 3
Syributin 2 (11), n = 5
Syributin 3 (12), n = 1
7, n = 3
8, n = 5
9, n = 1
Scheme 1. Proposed biosynthesis of secosyrins and syributins 1.
Pseudomonas syringae pv. tomato. The syringolides elicit an HR on
soybean cultivars carrying the resistance gene Rpg4.
q
Portions of this work have appeared as a thesis dissertation (in Ref.1).
In 1995 Sims4 reported the isolation and structure elucidation of
secosyrin 1 (4), secosyrin 2 (5), syributin 1 (10), and syributin 2 (11).
These metabolites were also isolated from P. syringae pathovars
carrying the avirulence avrD gene and they are the major co-
products of the syringolides 1 (1) and 2 (2). Sims proposed
* Corresponding author at present address: Cornell University, Department of
Chemistry & Chemical Biology, Baker Laboratory, Ithaca, NY 14853, USA. Tel.: þ1
607 255 3001; fax: þ1 607 255 4137.
E-mail address: navarro@aya.yale.edu (M. Navarro Villalobos).
Current address: Chemistry Department, Colorado State University, Fort Collins,
1
Colorado 80523, USA.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.055

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M. Navarro Villalobos et al. / Tetrahedron 65 (2009) 8091–8098
a possible biosynthesis for these compounds from syringolides
(Scheme 1). Reverse Claisen cleavage of 1–3 would furnish the
corresponding secosyrins (4–6), which then would undergo a retro-
protected malonate variant of 13 would serve as a precursor to
secosyrin upon C–H insertion, deprotection, and decarboxylation
(e.g., 13 to 6, Scheme 2). Intrigued by the potential flexibility of
this approach, we prepared model substrates in both the acetoa-
cetate and malonate series (14a and 14b, respectively, Fig. 1).
Disappointingly, under a variety of conditions neither of these
substrates was found to undergo C–H insertion. Despite this initial
failure we went forth with the preparation of more heavily
functionalized substrates that were suited for eventual conversion
to syringolide 3 (e.g., 13a–d, Fig. 1). Unfortunately, these sub-
strates, along with a series of TBS-enolether derivatives (not
shown), were also found to deliver intractable mixtures upon
exposure to a range of conditions designed to effect the desired C–
H insertion.
Michael reaction followed by
a 1,3-acyl migration of the
intermediates 7–9 that would result in the formation of the cor-
responding syributins (10–12). This is supported by experiments
wherein base treatment of secosyrin 1 was shown to furnish syri-
butin5 and by the base promoted sequential transformation of the
syringolides into the corresponding secosyrins and syributins.6
Unlike the syringolides, the syributins and secosyrins are not active
elicitors of a hypersensitive response on soybean cultivars carrying
the resistance gene Rpg4. Through a combination of NMR experi-
ments, X-ray crystallography, and chemical methods Sims de-
termined the structures of syringolides, secosyrins, and syributins
illustrated in Scheme 1.
Yucel and co-workers7 reported that two different classes of
avrD alleles occur in P. syringae pathovars: class I and class II al-
leles. Class I alleles include the avrD allele 1 from P. syringae pv.
lachrimans and the avrD allele from P. syringae pv. tomato. Class II
alleles include the avrD allele 2 from P. syringae pv. lachrimans
and the avrD allele from P. syringae pv. phaseolicola. The same
year Yucel and co-workers8 reported that the two classes of al-
leles direct the production of different syringolides, syributins,
and secosyrins. Class I avrD alleles are responsible for the
biosynthesis of syringolides 1 and 2 and their accompanying
secosyrins 1 (4) and 2 (5) and syributins 1 (10) and 2 (11) while
class II avrD alleles direct the production of syringolides 1 and 3
and their accompanying secosyrins 1 (4) and 3 (6) and syributins
1 (10) and 3 (12).
Syringolides and syributins 1–2 have attracted great deal of
attention from the synthetic community. Since Wood’s first report9
there have been nine other reported total syntheses of syringolides
1 and 210 and two formal ones,11 and seven total syntheses of
syributins 1 and 25,10g,10m,11b,12 and a formal one.13 However,
syringolide 3 and syributin 3 have yet to be synthesized.
O
O
O
O
H3C
RO
R
O
N2
O
N2
O
O
RO
13a R = TBS
13b R = Bn
13c R = Me
13d R =H
14a R = CH3
14b R = OCH3
Figure 1.
b-oxo-Diazoacetates for the C–H insertion approach to syringolides.
Given the difficulties encountered with our modified approach
we returned to our previous strategy and targeted (þ)- and
(ꢀ)-syringolide 3 (3) as well as (þ)-syributins 1–3 (10–12). Toward
(ꢀ)-3, known (ꢀ)-2,3-O-isopropilidene-
L
-threitol [(ꢀ)-15]9 was
monosilylated and then transformed into
a-bromoketone (ꢀ)-17
via a four-step procedure without purification of the intermediates
(Scheme 3). Specifically, diol (ꢀ)-15 was treated with TBSCl and
NaH to furnish a monoprotected alcohol,15 which was then oxidized
to the corresponding carboxylic acid using the catalytic RuCl3
procedure of Sharpless.16 This acid was treated first with ethyl
chloroformate and triethylamine and then with excess diazo-
methane17 to furnish (ꢀ)-16, the common intermediate for the
synthesis of (ꢀ)-syringolides and (þ)-syributins (Schemes 3 and 4).
Halogenation17 of (ꢀ)-16 with anhydrous ethereal HBr provided
(ꢀ)-17 in 40% overall yield from (ꢀ)-15. Acylation of (ꢀ)-17 with the
2. Results and discussion
Although simple modification of our previous approach could
be used to gain access to Syringolide 3,9 subsequent studies ini-
tially focused on a modification that finds precedent in a report by
Doyle and Dyatkin.14 The latter describes the use of regioselective
intramolecular carbon–hydrogen insertion reactions to access
spirolactones akin to those found in the syringolide/secosyrin core
(Scheme 2). Importantly, unlike our previous approach the mod-
ified strategy was envisioned as providing direct access to either
the syringolide or secosyrin ring system. Thus, in the forward
sense a doubly protected acetoacetate variant of 13 could give rise
to syringolide 3 (e.g., 13 to 3, Scheme 2), whereas a differentially
cesium salt18 of -ketoacid 1819 furnished the desired butenolide
b
(ꢀ)-1920 in 53% yield after an intramolecular Knoevenagel con-
densation in the same pot of the expected ester intermediate.
The final step of the synthesis involved complete deprotection of
butenolide (ꢀ)-19 using 10% aqueous HF in CH3CN10i to furnish the
desired (ꢀ)-syringolide 3 (3) in 7% yield, along with the side
product (ꢀ)-20 in 7% yield. There is no published data for
(ꢀ)-syringolide 3, however, spectroscopic data for this compound is
similar to that for (ꢀ)-syringolides 1 and 23 and consistent with the
proposed structure, furthermore X-ray crystallographic analysis of
(ꢀ)-3 (Fig. 2) confirms that this compound has the same relative
stereochemical configuration as syringolides 1 and 2.21
O
O
OH
O
Previous
Approach
O
O
O
O
O
O
HO
Syringolide 3 (3)
OH
The total synthesis of (þ)-syringolide 3 was accomplished in the
R'' = n-Pr
same manner as for the corresponding (ꢀ)-syringolide 3 by
R = R' = Protecting Group (PG)
replacing
(ꢀ)-15
with
(þ)-15.
Thus,
a-bromo-
ketone (þ)-17 was obtained in 35% overall yield form the mono-
O
O
O
O
O
silylated derivative of (þ)-15 and was treated with the
b
-ketoacid
Modified
R'
Approaches
O
18 to give butenolide (þ)-19 in 51% yield. Deprotection of this
butenolide furnished the corresponding syringolide (þ)-3 in 10%
yield, along with the side product (þ)-20 in 10% yield.
O
N2
RO
O
HO
R'' = OMe
R = OAc
R' = PG
O
R'O
Secosyrin 3 (6)
The total synthesis of (þ)-syributins 1, 2, and 3 (10, 11, and 12,
respectively) is described in Scheme 5. Bromoacetate (ꢀ)-23 was
obtained in 64% yield by O–H insertion of the rhodium(II)
13
Scheme 2. Retrosynthetic analysis for syringolide 3 and secosyrin 3.

M. Navarro Villalobos et al. / Tetrahedron 65 (2009) 8091–8098
8093
1. TBSCl, NaH (65%)
O
O
O
O
2. RuCl3, NaIO4
HBr, Et2O, -78 °C
(40%, four steps)
OH
OH
N2
Br
O
O
O
O
3. EtOC(O)Cl, Et3N
4. CH2N2
OTBS
OTBS
(-)-15
(-)-16
(-)-17
O
O
OH
O
O
O
O
Cs2CO3, DMF
HF, H2O/CH3CN
O
O
O
+
O
O
O
O
O
OTBS
O
HO
OH
(-)-20 (7%)
OH
(-)-19 (53%)
(-)-Syringolide 3 (3), (7%)
18
Scheme 3. Total synthesis of (ꢀ)-syringolide 3.
O
O
O
O
O
N2
OTBS
(-)-16
O
Syributin 1 (10, n = 3)
Syributin 2 (11, n = 5)
Syributin 3 (12, n = 1)
Br
HO
HO
Cl
n
OH
O
O
21a, n = 3
21b, n = 5
21c, n = 1
22
n
O
Scheme 4. Syributins: retrosynthetic analysis.
C11
C10
67% yield. Desilylation of (ꢀ)-24 followed by acylation of the
resulting primary alcohol 2523 with acid chlorides 21a–c fur-
nished esters (þ)-26a–c23 in 72–89% overall yields. Removal of the
isopropylidene protecting group under acidic conditions12b
resulted in the formation of the desired syributins 1 [(þ)-10], 2
[(þ)-11], and 3 [(þ)-12] in 40–69% yields. Spectroscopic data for
(þ)-syributins 1 and 2 were identical to that reported in the lit-
erature.5,10g,12a There is no published data for (þ)-syributin 3,
however, spectroscopic data for this compound is similar to that
for (þ)-syributins 1 and 2 and consistent with the proposed
structure.
O5
C6
C9
H9
O6
H8
C7
C8
O4
O1
C4
C5
C1
H1
The total syntheses of (ꢀ)-syributins 1, 2, and 3 were performed
O3
in the same manner as for the corresponding (þ)-syributins by
C3
H2
replacing (ꢀ)-16 with (þ)-16. Thus, diazo decomposition of
a-
C2
H3
diazoketone (þ)-16 in the presence of acid 22 produced ester
(þ)-23 in 55% yield. Two-step intramolecular Wittig olefination of
(þ)-23 furnished butenolide (þ)-24 in 68% yield. Deprotection of
(þ)-24 gave alcohol 25, which was acylated with acid chlorides
O2
Figure 2. ORTEP plot of syringolide 3.
O
O
Br
O
O
Rh2(OAc)4, CH2Cl2
(64%)
O
O
1. Ph3P, CH3CN
O
N2
O
O
+
Br
O
O
O
OH
2. Et3N
(67%, two steps)
OTBS
(-)-16
O
OTBS
OTBS
22
(-)-23
(-)-24
O
O
O
Et3N, DMAP, CH2Cl2
(72-89%, two steps)
O
TBAF, HF
THF, H2O
9:1
O
HO
HO
O
O
O
O
TFA:H2O
O
O
O
OH
n
n
Cl
n
O
O
O
25
(+)-26a, n = 3 (72%)
(+)-26b, n = 5 (89%)
(+)-26c, n = 1 (72%)
(+)-10, n = 3 (59%)
(+)-11, n = 5 (69%)
(+)-12, n = 1 (40%)
21a, n = 3
21b, n = 5
21c, n = 1
Scheme 5. Total synthesis of (þ)-syributins 1, 2 and 3.
stabilized carbene derived from the
a
-diazoketone (ꢀ)-16 into the
21a–c to produce esters (ꢀ)-26a–c in 39–70% overall yields. Re-
moval of the isopropylidene protecting group in acidic conditions
resulted in the formation of the desired syributins 1 [(ꢀ)-10], 2
[(ꢀ)-11], and 3 [(ꢀ)-12] in 58–65% yields.
acid 22. A two-step intramolecular Wittig olefination22 adding
first triphenylphosphine and later triethylamine to a solution of
bromoacetate (ꢀ)-23 provided the expected butenolide (ꢀ)-24 in

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M. Navarro Villalobos et al. / Tetrahedron 65 (2009) 8091–8098
3. Conclusions
28.5, 25.8, 25.7, 18.0, ꢀ4.5, ꢀ4.6, ꢀ4.7, ꢀ4.8; HRMS (EI) m/z
473.2501 [calcd for C21H41N2O6Si2 (MþH) 473.2503].
The first total syntheses of (ꢀ)-syringolide 3, (þ)-syributin 3 and
their unnatural enantiomers (þ)-syringolide 3 and (ꢀ)-syributin 3
were successfully completed using a common intermediate. In
addition, total syntheses of (ꢀ)- and (þ)-syributins 1 and 2 were
achieved using the same methodology.
4.2.1.2. C–H insertion reaction attempts. To a suspension of
Rh2(OAc)4 (9.7 mg, 0.02 mmol, 0.9% equiv) in CH2Cl2 (45 mL) at
reflux was added dropwise (over a 10 h period via syringe pump)
a solution of a diazoacetate 13 or 14 (2.46 mmol, 1 equiv) in CH2Cl2
(12 mL). After allowing to cool to room temperature and concen-
trating in vacuo, the resultant oil was analyzed by 1H NMR showing
to be an intractable mixture, which did not contain the desired
spirolactone product.
4. Experimental
4.1. General
4.2.2. Diazoacetoacetates prepared as 13a.
Unless stated otherwise, reactions were performed in flame
dried glassware under a nitrogen atmosphere, using freshly dis-
tilled solvents. Diethyl ether (Et2O) and tetrahydrofuran (THF) were
distilled from sodium/benzophenone ketyl. Methylene chloride
(CH2Cl2) and triethylamine (Et3N) were distilled from calcium hy-
dride. All other commercially obtained reagents were used as re-
ceived. Unless stated otherwise, all reactions were magnetically
stirred and monitored by thin-layer chromatography (TLC) using
E. Merck silica gel 60 F254 precoated plates (0.25 mm). Column or
flash chromatography was performed with the indicated solvents
using silica gel (230–400 mesh) purchased from Bodman. In gen-
eral, the chromatography guidelines reported by Still and co-
workers24 were followed. All melting points were obtained on
a Thomas Hoover capillary melting point apparatus and are un-
corrected. Infrared spectra were recorded on a Midac M1200 FTIR.
1H and 13C NMR spectra were recorded on a Bruker AM-500, Bruker
Avance DPX-500 or Bruker Avance DPX-400 spectrometer. Chem-
ical shifts are reported relative to internal chloroform (1H,
4.2.2.1. (þ)-Diazoacetoacetate 13b. Yield: 3.103 g, 89%. Analyti-
20
cal sample (yellowish oil): [
a
]
þ20.96 (c 1.04, CHCl3); FTIR (thin
D
film/NaCl) 3088 (w), 3063 (w), 3030 (w), 3006 (w), 2922 (w), 2866
(w), 2141 (s), 1717 (s), 1657 (s), 1496 (w), 1454 (m), 1364 (m), 1312
(s), 1250 (m), 1208 (w), 1157 (m), 1076 (s), 1027 (m), 965 (m), 740
(m), 699 (m) cmꢀ1 1H NMR (500 MHz, CDCl3, Me4Si)
; d 7.38–7.29
(m, 10H), 4.56 (d, J¼11.8 Hz, 1H), 4.54 (d, J¼11.9 Hz, 1H), 4.50 (d,
J¼11.8 Hz, 1H), 4.47 (d, J¼12.2 Hz, 1H), 4.38 (dd, J¼11.2, 4.4 Hz, 1H),
4.33 (dd, J¼11.3, 6.4 Hz, 1H), 4.09 (m, 2H), 4.05 (d, J¼10.3 Hz, 1H),
3.94 (dd, J¼10.1, 4.3 Hz, 1H), 3.90 (d, J¼3.1 Hz, 1H), 2.45 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 190.0,161.2,137.6,137.4,128.6,128.1,128.0,
127.8, 84.3, 82.6, 81.5, 72.0, 71.8, 71.5, 64.8, 28.4; HRMS (FAB) m/z
425.1712 [calcd for C23H25N2O6 (MþH) 425.1713].
4.2.2.2. Diazoacetoacetate 13c. Yield: 1.613 g, 78%. Analytical
sample (yellow oil): FTIR (thin film/NaCl) 2984 (w), 2932 (m), 2902
(m), 2825 (w), 2142 (s), 1717 (s), 1657 (s), 1457 (w), 1365 (m), 1312
(s), 1249 (m), 1195 (w), 1156 (m), 1106 (m), 1074 (s), 965 (w) cmꢀ1
;
d
7.26 ppm; 13C,
d
77.2 ppm), or acetone (1H,
d
2.05 ppm; 13C,
1H NMR (500 MHz, CDCl3)
d
4.40 (dd, J¼11.8, 4.4 Hz, 1H), 4.35 (dd,
d
29.8 ppm).25 High resolution mass spectra were performed at the
J¼11.7, 6.0 Hz, 1H), 4.02–3.97 (m, 2H), 3.86 (dd, J¼10.0, 4.0 Hz, 1H),
University of Illinois at Urbana-Champaign Mass Spectrometry
Center. High performance liquid chromatography (HPLC) was per-
formed on a Waters 510 solvent delivery system using a Rainin
Microsorb 80–-199-C5 column, or a Rainin Dynamax SD-200 sol-
vent delivery system with a Rainin Microsorb 80–-120-C5 column.
Optical rotations were measured on a Perkin Elmer 341 polarime-
ter. Single-crystal X-ray analyses were performed by Susan DeGala
of Yale University.
3.82–3.81 (m, 1H), 3.62 (d, J¼3.3 Hz, 1H), 3.40 (s, 3H), 3.34 (s, 3H),
2.48 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 190.0, 161.1, 86.4, 84.3,
81.3, 71.2, 64.8, 57.6, 56.8, 28.2; HRMS (EI) m/z 273.1098 [calcd for
C11H17N2O6 (MþH) 273.1087].
4.2.2.3. (þ)-Diazoacetoacetate 13d. Slightly modified pro-
cedure, which includes transient protection of the diol
functionality:
4.2.2.3.1. Diol protection. 2-Methoxypropene (1.6 mL, 16.71
mmol, 3.98 equiv) was added dropwise to a stirred solution of the
corresponding acetoacetate1 (917 mg, 4.20 mmol, 1 equiv) and
4.2. C–H insertion approach
POCl3 (ca. 1 mL, 0.01 mmol, 0.3% equiv) in THF (10 mL). The reaction
4.2.1. Representative synthetic procedures.
4.2.1.1. Diazotransfer reaction.
mixture was stirred at room temperature for 1 h, quenched by
adding triethylamine and concentrated in vacuo to a turbid yellow
oil, which was used without purification.
4.2.1.1.1. Diazoacetoacetate 13a. Triethylamine (400 mL, 2.87
mol, 3.05 equiv) was added dropwise to a stirred (0 ꢁC) solution of
corresponding acetoacetate1 (421 mg, 0.94 mmol, 1 equiv) and p-
ABSA (275 mg, 1.14 mmol, 1.21 equiv) in CH3CN (5 mL). After
allowing to warm to room temperature and stirring overnight, the
reaction mixture was concentrated in vacuo, triturated with 1:1
Et2O/petroleum ether (10 mL), filtered and reconcentrated to
a yellow oil. Silica gel chromatography employing 9:4 hexanes/
EtOAc as eluant furnished 13a (401 mg, 90% yield) as a yellow oil.
An analytical sample (yellow oil) was obtained by selecting frac-
tions from the flash chromatography: FTIR (thin film/NaCl) 2953 (s),
2930 (s), 2886 (m), 2858 (m), 2138 (s), 1721 (s), 1663 (s), 1472 (m),
1463 (m), 1364 (m), 1314 (s), 1251 (s), 1156 (m), 1113 (s), 1078 (s),
1069 (s), 1013 (m), 915 (w), 837 (s), 811 (m), 777 (s) cmꢀ1; 1H NMR
4.2.2.3.2. Diazotransfer. Triethylamine (1.8 mL, 12.91 mmol,
3.07 equiv) was added dropwise to a stirred (0 ꢁC) solution of the
crude product of the previous reaction and p-ABSA (1.244 g,
5.18 mmol, 1.23 equiv) in CH3CN (10 mL). After allowing to warm to
room temperature and stirring for 1 h, the reaction mixture was
concentrated in vacuo, triturated with 1:1 Et2O/petroleum ether
(20 mL), filtered and reconcentrated to a yellow oil, which was used
without purification.
4.2.2.3.3. Diol deprotection. To a solution of the crude product
of the previous reaction in MeOH (20 mL) was added p-TsOH
monohydrate (81 mg, 0.43 mmol, 0.10 equiv). The reaction mixture
was stirred at room temperature for 15 min, quenched by adding
triethylamine and concentrated in vacuo to a yellow oil. Silica gel
chromatography employing EtOAc as eluant furnished (þ)-13d
(938 mg, 91% yield) as a yellow oil. An analytical sample (yellowish
(500 MHz, CDCl3, Me4Si)
d
4.34 (dd, J¼11.3, 5.6 Hz, 1H), 4.31 (dd,
J¼11.1, 6.7 Hz, 1H), 4.05–4.03 (m, 1H), 3.98 (dd, J¼9.2, 3.7 Hz, 1H),
3.96–3.93 (m, 2H), 3.78 (d, J¼9.1 Hz, 1H), 2.47 (s, 3H), 0.87 (s, 9H),
0.86 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H); 13C
oil) was obtained by a second flash chromatography using 13:1
20
CH2Cl2/MeOH as eluant: [
a
]
þ21.97 (c 0.58, MeOH); FTIR (thin
D
NMR (100 MHz, CDCl3)
d
190.3, 161.2, 84.1, 80.0, 78.6, 74.7, 65.5,
film/NaCl) 3413 (br m), 2928 (w), 2147 (s), 1718 (s), 1652 (m), 1368

M. Navarro Villalobos et al. / Tetrahedron 65 (2009) 8091–8098
8095
(m), 1317 (s), 1251 (m), 1156 (m), 1072 (s), 969 (m) cmꢀ1
(400 MHz, CDCl3)
4.45 (d, J¼5.3 Hz, 2H), 4.25 (m, 1H), 4.09–4.04
(m, 2H), 3.98 (q, J¼4.8 Hz, 1H), 3.88 (dd, J¼10.0, 2.1 Hz, 1H), 2.48 (s,
3H), 1.70 (br s, 2H); 13C NMR (100 MHz, acetone-d6)
189.8, 161.9,
;
1H NMR
(500 MHz, CDCl3)
d
5.81 (s,1H), 4.34 (d, J¼7.6 Hz,1H), 4.08–4.05 (m,
d
1H), 3.93 (dd, J¼11.5, 2.4 Hz, 1H), 3.77 (dd, J¼11.5, 4.1 Hz, 1H), 1.43
(s, 3H), 1.40 (s, 3H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR
d
(125 MHz, CDCl3) d 194.4, 110.9, 80.3, 79.3, 62.9, 52.8, 27.0, 26.4,
84.2, 79.8, 78.4, 74.4, 66.0, 28.2; HRMS (EI) m/z 245.0775 [calcd for
C9H13N2O6 (MþH) 245.0774].
26.0, 18.5, ꢀ5.2, ꢀ5.3; HRMS (CI, isobutane) m/z 315.1753 [calcd for
C14H27N2O4Si (MþH) 315.1740].
4.2.2.4. Diazoacetoacetate 14a. Yield: 3.857 g, 88%. Analytical
4.3.2.
a
-Diazoketone (ꢀ)-16 This compound was prepared in the
20
sample (yellow oil): [
a
]
þ20.96 (c 1.04, CHCl3); FTIR (thin film/
same manner as its enantiomer (þ)-16 and was used without pu-
D
NaCl) 3088 (w), 3063 (w), 3030 (w), 3006 (w), 2922 (w), 2866 (w),
2141 (s), 1717 (s), 1657 (s), 1496 (w), 1454 (m), 1364 (m), 1312 (s),
1250 (m), 1208 (w), 1157 (m), 1076 (s), 1027 (m), 965 (m), 740 (m),
rification. An analytical sample (yellow oil) was prepared by flash
column chromatography followed by HPLC employing 9:1 hexanes/
EtOAc as eluant in both cases: [
20
a]
ꢀ20 (c 1.02, CHCl3); FTIR (thin
D
699 (m) cmꢀ1
;
1H NMR (500 MHz, CDCl3, Me4Si)
d
7.38–7.29 (m,
film/NaCl) 3128 (m), 2992 (m), 2956 (s), 2930 (s), 2856 (s), 2118 (m),
1621 (s), 1472 (w), 1460 (m), 1453 (m), 1380 (s), 1361 (s), 1254 (s),
10H), 4.56 (d, J¼11.8 Hz, 1H), 4.54 (d, J¼11.9 Hz, 1H), 4.50 (d,
J¼11.8 Hz, 1H), 4.47 (d, J¼12.2 Hz, 1H), 4.38 (dd, J¼11.2, 4.4 Hz, 1H),
4.33 (dd, J¼11.3, 6.4 Hz, 1H), 4.09 (m, 2H), 4.05 (d, J¼10.3 Hz, 1H),
3.94 (dd, J¼10.1, 4.3 Hz, 1H), 3.90 (d, J¼3.1 Hz, 1H), 2.45 (s, 3H); 13C
1078 (s), 840 (s) cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 5.82 (s,1H), 4.36
(d, J¼7.7 Hz, 1H), 4.09–4.08 (m, 1H), 3.95 (dd, J¼11.4, 2.6 Hz, 1H),
3.79 (dd, J¼11.2, 4.0 Hz, 1H), 1.45 (s, 3H), 1.42 (s, 3H), 0.90 (s, 9H),
NMR (125 MHz, CDCl3)
d
190.0,161.2,137.6,137.4,128.6,128.1,128.0,
0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 194.5, 111.0,
127.8, 84.3, 82.6, 81.5, 72.0, 71.8, 71.5, 64.8, 28.4; HRMS (FAB) m/z
425.1712 [calcd for C23H25N2O6 (MþH) 425.1713].
80.4, 79.4, 62.9, 52.9, 27.0, 26.5, 26.1, 18.5, ꢀ5.1, ꢀ5.3; HRMS (CI,
isobutane) m/z 315.1740 [calcd for C14H27N2O4Si (MþH) 315.1740].
4.2.2.5. Diazomalonate 14b. Yield: 1.406 g, 68%. Analytical
sample (yellow oil): FTIR (thin film/NaCl) 2965 (s), 2875 (m), 2137
(s), 1761 (s), 1738 (s), 1694 (s), 1438 (s), 1387 (s), 1325 (s), 1237 (s),
1183 (s), 1081 (s), 1019 (m), 992 (m), 923 (w), 761 (s) cmꢀ1; 1H NMR
4.4. Syringolide synthesis
4.4.1. Representative synthetic procedures.
4.4.1.1.
a-Bromoketone (þ)-17. A ca. 1 M solution of HBr in
(500 MHz, CDCl3)
d
4.27 (dd, J¼11.0, 3.4 Hz, 1H), 4.21–4.14 (m, 2H),
MeOH was prepared by adding MeOH (0.85 mL, 20.98 mmol,
2.90 equiv) to a stirred (0 ꢁC) solution of acetyl bromide (1.04 mL,
14.07 mmol, 1.95 equiv) in Et2O (14 mL). The HBr solution was
added dropwise to a stirred (ꢀ78 ꢁC) solution of (þ)-16 (2.272 g,
7.23 mol, 1 equiv) in Et2O (12 mL). Gas evolution was immediately
noted upon addition of the HBr solution. After stirring at ꢀ78 ꢁC for
30 min, saturated aqueous NaHCO3 (48 mL) was added. After
allowing to warm to room temperature, the biphasic mixture was
separated and the organic phase was washed with saturated
aqueous NaHCO3 (2ꢂ48 mL) and brine (60 mL). The aqueous
washings were extracted with CH2Cl2 (48 mL) and then the com-
bined organic phases were dried over MgSO4, filtered and con-
centrated in vacuo. The resultant yellow oil was chromatographed
on silica gel employing 9:1 hexanes/EtOAc as eluant to furnish
(þ)-17 (1.955 g, 74% yield) as a yellowish oil. An analytical sample
3.87 (dd, J¼15.1, 7.0 Hz, 1H), 3.83 (s, 3H), 3.79 (dd, J¼14.3, 7.3 Hz,
1H), 2.01 (m, 1H), 1.90 (m, 2H), 1.65 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 161.3, 160.7, 76.2, 68.4, 67.1, 52.4, 27.8, 25.6; HRMS (EI) m/z
229.0825 [calcd for C9H13N2O5 (MþH) 229.0824].
4.3. Common intermediate synthesis
4.3.1.
TBS
a
-Diazoketone (þ)-16. To a stirred biphasic solution of mono-
protected -threitol (5.532 g,
(þ)-2,3-O-isopropilidene-
L
20.01 mmol, 1 equiv), CCl4 (40 mL), CH3CN (40 mL), and water
(60 mL) were added sodium periodate (12.894 g, 60.28 mmol,
3.01 equiv) and RuCl3 hydrate (210 mg, 0.93 mmol, 0.05 equiv).16b
After vigorously stirring the reaction mixture overnight, water
(165 mL) and CH2Cl2 (120 mL) were added. The phases were sep-
arated and the aqueous one was extracted with CH2Cl2 (2ꢂ180 mL).
The combined organic phases were dried over MgSO4, filtered and
concentrated in vacuo to furnish the corresponding carboxylic acid
as a purple oil (3.914 g, 67% yield), which was used without
purification.
(colorless oil) was obtained by a second flash chromatography
employing 9:1 hexanes/EtOAc as eluant: [
20
a]
þ16 (c 1.33, CHCl3);
D
FTIR (thin film/NaCl) 2989 (w), 2954 (s), 2930 (s), 2885 (m), 2858
(m), 1733 (m), 1472 (w), 1463 (w), 1383 (m), 1374 (m), 1254 (s), 1216
(m), 1146 (s), 1096 (s), 838 (s) cmꢀ1 1H NMR (500 MHz, CDCl3)
;
Triethylamine (2.2 mL, 15.78 mmol) and ethyl chloroformate
(1.4 mL, 14.64 mmol) were sequentially added to a stirred (ꢀ10 ꢁC)
solution of the crude carboxylic acid (3.914 g, 13.48 mmol) in THF
(17 ml). After 10 min of stirring, a white precipitate formed. CAU-
TION, diazomethane is toxic and potentially explosive.26,27 Excess
diazomethane in Et2O (ca. 0.3 M, 146 mL, 43.8 mmol) was added at
ꢀ10 ꢁC and the resultant mixture was stirred (0 ꢁC) for 30 min. The
reaction mixture was allowed to warm to room temperature,
quenched with 0.1 M aqueous acetic acid (40.5 mL) and stirred until
the deep yellow color of diazomethane was no longer present. The
biphasic mixture was separated and the organic phase was washed
with saturated aqueous NaHCO3 (2ꢂ81 mL). The aqueous washings
were extracted with CH2Cl2 (81 mL) and the combined organic
phases were dried over MgSO4, filtered and concentrated in vacuo.
The resultant yellow oil was chromatographed on silica gel
employing 4:1 hexanes/EtOAc as eluant to furnish (þ)-16 (2.958 g,
d
4.57 (d, J¼7.5 Hz, 1H), 4.28 (d, J¼13.7 Hz, 1H), 4.24 (d, J¼13.7 Hz,
1H), 4.14 (app. dt, J¼7.4, 3.7 Hz, 1H), 3.89 (dd, J¼11.3, 3.4 Hz, 1H),
3.79 (dd, J¼11.3, 3.6 Hz, 1H), 1.46 (s, 3H), 1.43 (s, 3H), 0.90 (s, 9H),
0.08 (s, 6H); 13C NMR (125 MHz, CDCl3)
d 200.6, 110.9, 79.5, 79.1,
62.4, 32.3, 26.7, 26.3, 25.8, 18.2, ꢀ5.4, ꢀ5.5; HRMS (CI, isobutane)
m/z 369.0910 [calcd for C14H2181BrO4Si (MþH) 369.0920].
4.4.1.2. Butenolide (þ)-19. To a stirred solution of
b-ketoacid 18
-bromoketone (þ)-17
(598 mg, 4.59 mmol, 1.11 equiv) and
a
(1.517 g, 4.13 mmol, 1 equiv) in DMF (4.8 mL) was added in small
portions over a 10 min period solid Cs2CO3 (1.723 g, 5.29 mmol,
1.28 equiv). The reaction mixture was stirred at room temperature
for 30 min and then diluted with water and EtOAc (16 mL ea.). The
aqueous layer was acidified to pH 1 with 1 N HCl and extracted with
EtOAc (3ꢂ32 mL). The combined organic layers were dried over
MgSO4, filtered and concentrated in vacuo to a brown oil. Silica gel
chromatography employing 9:1 hexanes/EtOAc as eluant furnished
(þ)-19 (836 mg, 51% yield) as a yellow oil. An analytical sample
(yellow oil) was prepared by flash column chromatography fol-
70% yield) as a yellow oil. An analytical sample (yellow oil) was
20
obtained by HPLC employing 9:1 hexanes/EtOAc as eluant: [a]
D
þ19 (c 1.01, CHCl3); FTIR (thin film/NaCl) 3129 (m), 2992 (m), 2957
(s), 2934 (s), 2856 (s), 2114 (m), 1622 (m), 1471 (w), 1460 (m), 1454
lowed by HPLC employing 9:1 hexanes/EtOAc as eluant in both
cases: [
20
(m), 1381 (s), 1361 (s), 1254 (s), 1078 (s), 840 (s) cmꢀ1
;
1H NMR
a]
þ39.74 (c 1.16, CHCl3); FTIR (thin film/NaCl) 2958 (m),
D

8096
M. Navarro Villalobos et al. / Tetrahedron 65 (2009) 8091–8098
20
2932 (m), 2881 (w), 2858 (m), 1769 (s), 1694 (m), 1633 (w), 1472
(w), 1463 (w), 1381 (m), 1373 (m), 1252 (m), 1090 (m), 838 (s) cmꢀ1
1H NMR (500 MHz, CDCl3)
analytical sample (yellow oil): [
a
]
ꢀ36.74 (c 0.89, CHCl3); FTIR
D
;
(thin film/NaCl) 2959 (m), 2932 (m), 2881 (m), 2858 (m), 1769 (s),
1694 (m), 1633 (w), 1472 (w), 1463 (w), 1381 (m), 1373 (m), 1252
d
5.50 (d, J¼7.5 Hz, 1H), 5.05 (d,
J¼19.4 Hz, 1H), 4.88 (d, J¼20.0 Hz, 1H), 3.94–3.86 (m, 3H), 2.96 (dt,
J¼18.2, 7.3 Hz, 1H), 2.91 (dt, J¼18.2, 7.4 Hz, 1H), 1.64 (sext., J¼7.4 Hz,
2H), 1.45 (s, 6H), 0.96 (t, J¼7.3 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08
(m), 1090 (m), 838 (s) cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 5.50 (d,
J¼7.9 Hz, 1H), 5.06 (d, J¼19.9 Hz, 1H), 4.87 (d, J¼19.0 Hz, 1H), 3.93–
3.85 (m, 3H), 2.96 (dt, J¼18.2, 7.3 Hz, 1H), 2.91 (dt, J¼18.2, 7.4 Hz,
1H),1.64 (sext., J¼7.4 Hz, 2H),1.45 (s, 6H), 0.95 (t, J¼7.4 Hz, 3H), 0.89
(s, 3H); 13C NMR (125 MHz, CDCl3)
d 196.4, 173.1, 170.5, 126.9, 111.1,
83.0, 73.5, 69.3, 63.6, 44.0, 27.1, 27.0, 26.0, 18.5,16.8,13.7, ꢀ5.1, ꢀ5.2;
HRMS (CI, isobutane) m/z 399.2192 [calcd for C20H35SiO6 (MþH)
399.2203].
(s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 196.4,
173.2, 170.5, 126.8, 111.1, 83.0, 73.5, 69.3, 63.6, 44.0, 27.1, 27.0, 26.0,
18.5, 16.7, 13.7, ꢀ5.2, ꢀ5.3; HRMS (CI, isobutane) m/z 399.2192
[calcd for C20H35SiO6 (MþH) 399.2203].
4.4.1.3. (þ)-Syringolide 3 and acetal (þ)-20. To a stirred solution
of butenolide (þ)-19c (836 mg, 2.10 mmol, 1 equiv) in CH3CN
(85 mL) was added 10% aqueous HF (85 mL). The reaction mixture
was stirred at room temperature for 36 h and then neutralized to
pH 7 with saturated aqueous NaHCO3 and extracted with EtOAc
(4ꢂ170 mL). The organic phases were washed with brine (170 mL)
and then they were combined, dried over MgSO4, filtered and
concentrated in vacuo to a brown syrup. Silica gel chromatography
employing 1:1 CH2Cl2/EtOAc as eluant furnished two products:
(þ)-syringolide 3 [(þ)-3] (50 mg, 10% yield, eluted second) as
a white solid and (þ)-20 (47 mg, 10% yield, eluted first) as a yel-
lowish oil.
4.4.2.3. (ꢀ)-Syringolide 3 and acetal (ꢀ)-20. These compounds
were prepared in the same manner as their enantiomers (þ)-3 and
(þ)-20 (41.8 and 36.8 mg, respectively; i.e., 7% yield ea.). Re-
crystallization of (ꢀ)-syringolide 3 [(ꢀ)-3] from heptane produced
crystals suitable for a single-crystal X-ray analysis, which estab-
lished the illustrated relative stereochemical configuration.21
20
Analytical sample of (ꢀ)-3 (white solid): mp 120–122 ꢁC; [
a]
D
ꢀ97.74 (c 0.09, CHCl3); FTIR (thin film/NaCl) 3358 (br m), 2961 (m),
2933 (m), 2917 (m), 2874 (w), 2848 (w), 1759 (s), 1466 (w), 1380
(m), 1191 (m), 1151 (m), 1077 (m), 1025 (s), 975 (m) cmꢀ1; 1H NMR
(500 MHz, acetone-d6)
d
5.35 (s, 1H), 4.67 (d, J¼10.2 Hz, 1H), 4.49 (s,
An analytical sample of (þ)-3 (white solid) was prepared by
1H), 4.32 (d, J¼10.5 Hz, 1H), 4.31 (br s, 1H), 4.15 (s, 1H), 3.95 (d,
J¼9.6 Hz, 1H), 3.82 (d, J¼10.3 Hz, 1H), 3.08 (s, 1H), 1.87 (t, J¼8.1 Hz,
2H), 1.66–1.57 (m, 1H), 1.55–1.46 (m, 1H), 0.92 (t, J¼7.4 Hz, 3H); 13C
20
HPLC employing 5:6 CH2Cl2/EtOAc as eluant: mp 118–120 ꢁC; [
a]
D
þ98.46 (c 0.13, CHCl3); FTIR (thin film/NaCl) 3396 (br m), 2963
(m), 2937 (m), 2922 (w), 2876 (m), 1755 (s), 1467 (w), 1385 (m),
NMR (125 MHz, acetone-d6) d 172.7, 108.7, 99.0, 92.3, 75.6, 75.4,
1198 (m), 1053 (m), 1029 (s), 973 (m) cmꢀ1
;
1H NMR (500 MHz,
74.9, 59.7, 41.7, 17.8, 14.4; HRMS (CI, isobutane) m/z 245.1031 [calcd
acetone-d6)
d
5.35 (s, 1H), 4.67 (d, J¼10.2 Hz, 1H), 4.48 (s, 1H), 4.32
for C11H16O6 (MþH) 245.1025].
20
(d, J¼10.4 Hz, 1H), 4.31 (s, 1H), 4.14 (s, 1H), 3.95 (d, J¼10.2 Hz, 1H),
3.82 (d, J¼9.8 Hz, 1H), 3.08 (s, 1H), 1.87 (t, J¼7.9 Hz, 2H), 1.66–1.57
(m, 1H), 1.55–1.47 (m, 1H), 0.87 (t, 3H); 13C NMR (125 MHz, ace-
Analytical sample of (ꢀ)-20 (colorless oil): [
a
]
ꢀ33.40 (c 0.94,
D
CHCl3); FTIR (thin film/NaCl) 3418 (br m), 2965 (m), 2933 (w), 2879
(w), 1736 (s), 1658 (w), 1434 (w), 1377 (w), 1339 (m), 1245 (w), 1179
(m), 1086 (m), 1023 (m), 990 (m) cmꢀ1; 1H NMR (500 MHz, CDCl3)
tone-d6)
d 172.7, 108.7, 99.0, 92.2, 75.6, 75.4, 74.9, 59.7, 41.6, 17.8,
14.4; HRMS (CI, isobutane) m/z 245.1028 [calcd for C11H16O6
(MþH) 245.1025].
d
5.10 (d, J¼3.1 Hz, 1H), 4.99 (d, J¼18.3 Hz, 1H), 4.76 (dd, J¼18.0,
1.0 Hz, 1H), 4.64 (m, 1H), 4.10 (dd, J¼8.6, 2.3 Hz, 1H), 4.05–4.02 (m,
1H), 2.99 (br s, 1H), 2.26 (ddd, J¼14.4, 10.9, 5.5 Hz, 1H), 2.05 (ddd,
J¼14.1, 10.7, 5.2 Hz, 1H), 1.53–1.38 (m, 2H), 0.98 (t, J¼7.4 Hz, 3H); 13C
An analytical sample of (þ)-20 (colorless oil) was prepared by
20
HPLC employing 5:6 CH2Cl2/EtOAc as eluant: [
a
]
þ33.5 (c 0.83,
D
CHCl3); FTIR (thin film/NaCl) 3416 (m), 2965 (m), 2933 (w), 1737 (s),
1657 (w), 1433 (w), 1376 (w), 1339 (m), 1246 (w), 1180 (m), 1025
NMR (125 MHz, CDCl3) d 170.4, 163.5, 129.0, 104.3, 75.5, 69.4, 66.8,
64.0, 33.3, 16.5, 14.4; HRMS (CI, isobutane) m/z 227.0914 [calcd for
C11H15O5 (MþH) 227.0919].
(m), 990 (m) cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
5.09 (d, J¼4.4 Hz,
1H), 4.99 (d, J¼18.2 Hz,1H), 4.77 (d, J¼18.2 Hz,1H), 4.64 (ddd, J¼6.3,
4.5, 1.9 Hz, 1H), 4.10 (dd, J¼8.8, 2.0 Hz, 1H), 4.05–4.02 (m, 1H), 3.14
(br s, 1H), 2.25 (ddd, J¼14.3, 11.0, 4.9 Hz, 1H), 2.04 (ddd, J¼14.2, 10.9,
5.3 Hz, 1H), 1.52–1.38 (m, 2H), 0.97 (t, J¼7.6 Hz, 3H); 13C NMR
4.5. Syributin synthesis
4.5.1. Representative synthetic procedures.
(125 MHz, CDCl3)
d
170.1, 163.0, 129.2, 104.3, 75.7, 69.2, 66.9, 64.0,
4.5.1.1. Bromoacetate (ꢀ)-23. To a solution of bromoacetic acid
33.3, 16.4, 14.4; HRMS (CI, isobutane) m/z 227.0912 [calcd for
C11H15O5 (MþH) 227.0919].
(451 mg, 3.25 mmol, 1.01 equiv) and
a-diazoketone (ꢀ)-16 (1.011 g,
3.22 mmol, 1 equiv) in CH2Cl2 (10 mL) was added Rh2(OAc)4
(1.8 mg, 0.004 mmol, 0.13% equiv). The reaction mixture was
heated to reflux for 40 min and then concentrated in vacuo to
a green oil. Silica gel chromatography employing 4:1 hexanes/
EtOAc as eluant furnished (ꢀ)-23 (882 mg, 64% yield) as a yellow
4.4.2. Additional spectroscopic and analytical data.
4.4.2.1.
a
-Bromoketone (ꢀ)-17. This compound was prepared in
the same manner as its enantiomer (þ)-17 [40% overall yield from
(ꢀ)-15]. An analytical sample (colorless oil) was prepared by flash
oil. An analytical sample (colorless oil) was obtained by a second
20
column chromatography employing 9:1 hexanes/EtOAc as eluant:
flash chromatography using 9:1 hexanes/EtOAc as eluant: [a]
D
20
[
a]
ꢀ17 (c 0.95, CHCl3); FTIR (thin film/NaCl) 2988 (w), 2954 (s),
ꢀ15.60 (c 1.03, CHCl3); FTIR (thin film/NaCl) 2988 (m), 2953 (s),
2930 (s), 2885 (s), 2857 (s), 1739 (s), 1472 (m), 1463 (m), 1408 (m),
1383 (s), 1374 (s), 1096 (s), 838 (s) cmꢀ1; 1H NMR (500 MHz, CDCl3)
D
2930 (s), 2885 (m), 2858 (m), 1733 (m), 1472 (w), 1463 (w), 1383
(m), 1374 (m), 1254 (s), 1216 (m), 1146 (s), 1096 (s), 838 (s) cmꢀ1; 1H
NMR (500 MHz, CDCl3)
d
4.57 (d, J¼7.5 Hz, 1H), 4.28 (d, J¼13.7 Hz,
d
5.19 (d, J¼17.8 Hz, 1H), 5.00 (d, J¼17.9 Hz, 1H), 4.48 (d, J¼8.1 Hz,
1H), 4.24 (d, J¼13.7 Hz, 1H), 4.14 (app. dt, J¼7.4, 3.7 Hz, 1H), 3.89
(dd, J¼11.3, 3.4 Hz, 1H), 3.79 (dd, J¼11.3, 3.6 Hz, 1H), 1.46 (s, 3H),
1.43 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H); 13C NMR (125 MHz, CDCl3)
1H), 4.14 (dt, J¼7.8, 3.2 Hz, 1H), 3.96 (s, 2H), 3.91 (dd, J¼11.9, 3.0 Hz,
1H), 3.74 (dd, J¼11.4, 3.4 Hz, 1H), 1.46 (s, 3H), 1.45 (s, 3H), 0.90 (s,
9H), 0.07 (s, 6H); 13C NMR (125 MHz, CDCl3)
d 201.9, 166.7, 111.4,
d
201.1, 111.3, 79.9, 79.4, 62.7, 32.5, 27.0, 26.5, 26.1, 18.6, ꢀ5.1, ꢀ5.3;
79.7, 79.1, 67.6, 62.4, 26.8, 26.4, 26.0, 25.0, 18.5, ꢀ5.2, ꢀ5.4; HRMS
(CI, isobutane) m/z 425.0996 [calcd for C16H3079BrO6Si (MþH)
425.0995].
HRMS (CI, isobutane) m/z 369.0910 [calcd for C14H2181BrO4Si
(MþH) 369.0920].
4.4.2.2. Butenolide (ꢀ)-19. This compound was prepared in the
same manner as its enantiomer (þ)-19 (910.7 mg, 53% yield). An
4.5.1.2. Butenolide (ꢀ)-24. A solution of bromoacetate (ꢀ)-23
(791 mg, 1.86 mmol, 1 equiv) and triphenylphosphine (537 mg,

M. Navarro Villalobos et al. / Tetrahedron 65 (2009) 8091–8098
8097
2.05 mmol, 1.10 equiv) in CH3CN (17 mL) was stirred at ca. 65 ꢁC (oil
bath) for 3 h. Triethylamine (0.8 mL, 5.74 mmol, 3.09 equiv) was
added dropwise to the solution and the reaction mixture
was stirred at ca. 65 ꢁC for another 3 h. The reaction mixture was
allowed to cool to room temperature and then concentrated in
vacuo to a brown semisolid. The residue was taken in EtOAc and
filtered through a pad of silica gel to remove the precipitate. The
filtrate was concentrated in vacuo to a brown semisolid, which was
chromatographed on silica gel employing 4:1 hexanes/EtOAc as
eluant to furnish (ꢀ)-24 (409 mg, 67% yield) as a yellow oil. An
analytical sample (yellowish oil) was obtained by a second flash
chromatography employing 4:1 hexanes/EtOAc as eluant. Spec-
(dd, J¼11.2, 6.4 Hz, 1H), 3.97 (app. td, J¼5.8, 2.7 Hz, 1H), 3.43 (br s,
2H), 2.33 (t, J¼7.5 Hz, 2H), 1.64 (sext., J¼7.4 Hz, 2H), 0.94 (t,
J¼7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 174.5, 174.2, 170.4, 116.7,
72.2, 71.6, 69.1, 64.8, 36.2, 18.5, 13.7; HRMS (CI, isobutane) m/z
245.1022 [calcd for C11H17O6 (MþH) 245.1025].
4.5.2. Additional spectroscopic and analytical data.
4.5.2.1. Common intermediates.
4.5.2.1.1. Bromoacetate (D)-23. This compound was prepared
in the same manner as its enantiomer (ꢀ)-23 (1.5393 g, 55% yield).
An analytical sample of (yellowish oil) was prepared by flash col-
umn chromatography employing 85:15 hexanes/EtOAc as eluant:
20
troscopic data for this material was identical to that reported in the
[a
]
þ14.22 (c 1.05, CHCl3); FTIR (thin film/NaCl) 2988 (w), 2954
D
20
literature5: [
a]
ꢀ5.46 (c 1.08, CHCl3).
(m), 2931 (m), 2885 (m), 2858 (m), 1739 (s), 1472 (m), 1463 (m),
1409 (m), 1383 (m), 1374 (m), 1096 (s), 838 (s) cmꢀ1 1H NMR
(500 MHz, CDCl3)
D
;
4.5.1.3. Butyrate (þ)-26c. A solution of 1 M TBAF in THF (506
m
L,
d
5.19 (d, J¼17.6 Hz, 1H), 5.00 (d, J¼17.8 Hz, 1H),
0.506 mmol, 1.07 equiv) and 48% HF (44 L, aqueous) was added to
m
4.48 (d, J¼8.0 Hz, 1H), 4.14 (dt, J¼7.6, 3.2 Hz, 1H), 3.96 (s, 2H), 3.91
(dd, J¼11.4, 2.9 Hz,1H), 3.74 (dd, J¼11.9, 3.4 Hz,1H),1.46 (s, 3H),1.45
a solution of butenolide (ꢀ)-24 (155 mg, 0.47 mmol, 1 equiv) in THF
(6 mL). The reaction mixture was stirred at room temperature for
8 h, at which point the butenolide (ꢀ)-24 could not be detected by
TLC analysis. The reaction mixture was then diluted with water
(6 mL) and extracted with EtOAc (3ꢂ12 mL). The organic phases
were washed with water (12 mL) and then they were combined,
dried over MgSO4, filtered and concentrated in vacuo to furnish
alcohol 25 as a beige syrup, which was used without purification. To
a stirred (0 ꢁC) solution of alcohol 25 in CH2Cl2 (6 mL) were se-
quentially added DMAP (ca. 1 mg, 0.01 mmol, 1.7% equiv), trie-
(s, 3H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (125 MHz, CDCl3)
d 202.1,
166.8, 111.4, 79.7, 79.1, 67.7, 62.3, 26.9, 26.4, 26.1, 25.1, 18.5, ꢀ5.2,
ꢀ5.3; HRMS (CI, isobutane) m/z 425.0992 [calcd for C16H3079BrO6Si
(MþH) 425.0995].
4.5.2.1.2. Butenolide (D)-24. This compound was prepared in
the same manner as its enantiomer (ꢀ)-24 (304.6 mg, 68% yield).
An analytical sample (colorless oil) was prepared by flash column
chromatography employing 85:15 hexanes/EtOAc as eluant. Spec-
troscopic data for this material was identical to that reported in the
thylamine (80
mL, 0.57 mmol, 1.22 equiv), and butyryl chloride
literature for its enantiomer5 but with opposite optical rotation:
20
(54 L, 0.52 mmol, 1.10 equiv). After allowing to warm to room
m
[a
]
þ6.02 (c 1.13, CHCl3).
D
temperature and stirring overnight, the reaction mixture was di-
luted with water (6 mL) and extracted with EtOAc (3ꢂ12 mL). The
organic extracts were washed with water (12 mL) and brine
(12 mL) and then they were combined, dried over MgSO4, filtered
and concentrated in vacuo to a brown oil. Silica gel chromatography
employing 3:1 hexanes/EtOAc as eluant furnished (þ)-26c (96 mg,
72% yield) as a yellowish oil. An analytical sample (yellowish oil)
4.5.2.2. Esters prepared as (þ)-26c.
4.5.2.2.1. Hexanoate (D)-26a. Yield: 51 mg, 72%. Spectro-
scopic data for this material was identical to that reported in the
20
literature5: [
a
]
þ11.20 (c 1.12, CHCl3).
D
4.5.2.2.2. Hexanoate (L)-26a. Yield: 63.7 mg, 39%. Spectro-
scopic data for this material was identical to that reported in the
was obtained by a second flash chromatography using 3:1 hexanes/
literature for its enantiomer5 but with opposite optical rotation:
20
20
EtOAc as eluant: [
a
]
þ10.14 (c 1.12, CHCl3); FTIR (thin film/NaCl)
[
a
]
ꢀ11.77 (c 0.88, CHCl3).
D
D
2985 (w), 2968 (w), 2938 (w), 2877 (w), 1781 (s), 1747 (s), 1645 (w),
1453 (m), 1382 (m), 1375 (m), 1170 (s) cmꢀ1 1H NMR (500 MHz,
CDCl3)
4.5.2.2.3. Octanoate (D)-26b. Yield: 145 mg, 89%. Spectro-
scopic data for this material was identical to that reported in the
;
20
d
6.11 (q, J¼1.6 Hz, 1H), 4.94 (dd, J¼18.4, 1.9 Hz, 1H), 4.87
literature5: [
a
]
þ10.68 (c 1.11, CHCl3).
D
(ddd, J¼18.2, 1.8, 1.0 Hz, 1H), 4.73 (d, J¼7.9 Hz, 1H), 4.32 (dd, J¼12.0,
4.7 Hz, 1H), 4.27 (dd, J¼12.0, 4.7 Hz, 1H), 4.95 (app. dt, J¼8.1, 4.7 Hz,
1H), 2.34 (t, J¼7.4 Hz, 2H), 1.67 (sext., J¼7.4 Hz, 2H), 1.46 (s, 3H), 1.44
4.5.2.2.4. Octanoate (L)-26b. Yield: 186.5 mg, 59%. Spectro-
scopic data for this material was identical to that reported in the
literature for its enantiomer5 but with opposite optical rotation:
20
(s, 3H), 0.96 (t, J¼7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
173.1,
[a
]
ꢀ10.53 (c 0.66, CHCl3).
D
172.7, 166.0, 116.8, 111.0, 78.1, 74.6, 70.8, 62.6, 35.8, 26.6, 26.5, 18.3,
13.6; HRMS (CI, isobutane) m/z 285.1337 [calcd for C14H21O6 (MþH)
285.1338].
4.5.2.2.5. Butyrate (L)-26c. Yield: 175.2 mg, 70%. Analytical
20
sample (yellowish oil): [
NaCl) 2985 (w), 2968 (w), 2938 (w), 2878 (w), 1781 (s), 1750 (s),
1646 (w), 1457 (m), 1383 (m), 1374 (m), 1168 (s) cmꢀ1 1H NMR
(500 MHz, CDCl3)
a
]
ꢀ11.83 (c 1.73, CHCl3); FTIR (thin film/
D
;
4.5.1.4. (þ)-Syributin
3
[(þ)-12]. Butyrate (þ)-26c (88 mg,
d
6.08 (s, 1H), 4.91 (d, J¼18.1 Hz, 1H), 4.84 (d,
0.31 mmol) was treated with a 9:1 TFA/H2O solution (3 mL). The
resulting mixture was stirred at room temperature for 15 min, at
which point the butyrate (þ)-26c could no longer be detected by
TLC analysis. The reaction mixture was diluted with water (5 mL),
neutralized to pH 7 with saturated aqueous NaHCO3 and extracted
with EtOAc (3ꢂ15 mL). The organic extracts were washed with
brine (10 mL) and then they were combined, dried over MgSO4,
filtered and concentrated in vacuo to a yellowish oil. Silica gel
chromatography employing 2:3 hexanes/EtOAc as eluant furnished
(þ)-syributin 3 (30 mg, 40% yield) as a yellowish oil. An analytical
J¼17.6 Hz, 1H), 4.71 (d, J¼8.4 Hz, 1H), 4.30 (dd, J¼12.0, 4.3 Hz, 1H),
4.24 (dd, J¼12.1, 4.6 Hz, 1H), 4.08 (app. dt, J¼8.6, 4.4 Hz, 1H), 2.31 (t,
J¼7.4 Hz, 2H),1.64 (sext., J¼7.5 Hz, 2H), 1.44 (s, 3H), 1.41 (s, 3H), 0.93
(t, J¼7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 173.2, 172.8, 166.0,
117.0, 111.2, 78.2, 74.7, 70.9, 62.8, 36.0, 26.7, 26.6, 18.4, 13.7; HRMS
(CI, isobutane) m/z 285.1340 [calcd for C14H21O6 (MþH) 285.1338].
4.5.2.3. Syributins obtained as (þ)-syributin 3 [(þ)-12].
4.5.2.3.1. (D)-Syributin 1 [(D)-10]. Yield: 47 mg, 59%. Analyt-
20
ical sample (yellowish oil): [
a
]
þ7.18 (c 0.59, CHCl3); FTIR (thin film/
D
sample (colorless oil) was obtained by a second flash chromatog-
NaCl) 3400 (br m), 2955 (m), 2928 (m), 2870 (m), 1780 (m), 1729 (s),
20
raphy using 2:3 hexanes/EtOAc as eluant: [
a
]
þ6.14 (c 0.76,
1638(w),1170(m)cmꢀ1;1HNMR(500 MHz,CDCl3)
d
6.06(s,1H),4.97
D
CHCl3); FTIR (thin film/NaCl) 3415 (br m), 2966 (w), 2936 (w), 2877
(d, J¼17.9 Hz, 1H), 4.91 (d, J¼18.0 Hz, 1H), 4.63 (br s, 1H), 4.29 (dd,
J¼11.6, 5.3 Hz,1H), 4.18 (dd, J¼11.5, 6.5 Hz,1H), 3.96 (br s,1H), 3.35 (br
s, 2H), 2.35 (t, J¼7.4 Hz, 2H), 1.62 (quint., J¼7.4 Hz, 2H), 1.35–1.24 (m,
(w), 1780 (w),1737 (s), 1638 (w), 1181 (m) cmꢀ1; 1H NMR (500 MHz,
CDCl3)
d
6.06 (d, J¼1.9 Hz, 1H), 4.97 (dd, J¼18.1, 1.5 Hz, 1H), 4.91 (dd,
J¼18.0, 1.2 Hz, 1H), 4.64 (s, 1H), 4.28 (dd, J¼11.6, 5.4 Hz, 1H), 4.18
4H), 0.89 (t, J¼6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 174.7, 174.1,

8098
M. Navarro Villalobos et al. / Tetrahedron 65 (2009) 8091–8098
661–667; (e) Keen, N. T. In Mechanisms of Plant Defense Responses; Fritig, B.,
Legrand, M., Eds.; Kluwer Academic: Boston, MA, 1993; pp 3–11; (f) Keen, N. T.
Plant Mol. Biol. 1992, 19, 109–122; (g) Keen, N. T. Annu. Rev. Genet. 1990, 24, 447–
463; (h) Lamb, C. J.; Lawton, M. A.; Dron, M.; Dixon, R. A. Cell 1989, 56, 215–224;
(i) Gianinazzi, S. In Plant–Microbe Interactions; Kosuge, T., Nester, E. W., Eds.;
Macmillan: New York, NY, 1984; Vol. 1, Chapter 13.
3. (a) Smith, M. J.; Mazzola, E. P.; Sims, J. J.; Midland, S. L.; Keen, N. T.; Burton, V.;
Stayton, M. M. Tetrahedron Lett. 1993, 34, 223–226; (b) Midland, S. L.; Keen, N.
T.; Sims, J. J.; Midland, M. M.; Stayton, M. M.; Burton, V.; Smith, M. J.; Mazzola,
E. P.; Graham, K. J.; Clardy, J. J. Org. Chem. 1993, 58, 2940–2945.
4. Midland, S. L.; Keen, N. T.; Sims, J. J. J. Org. Chem. 1995, 60, 1118–1119.
5. Mukai, C.; Moharram, S. M.; Azukizawa, S.; Hanaoka, M. J. Org. Chem. 1997, 62,
8095–8103.
6. Wood, J. L; Navarro Villalobos, M. Unpublished results (Yale University, De-
partment of Chemistry, W6).
7. Yucel, I.; Boyd, C.; Debnam, Q.; Keen, N. T. Mol. Plant-Microbe Interact. 1994, 7,
131–139.
8. (a) Yucel, I.; Midland, S. L.; Sims, J. J.; Keen, N. T. Mol. Plant-Microbe Interact.
1994, 7, 148–150; (b) Keen, N.; Midland, S. L.; Boyd, C.; Yucel, I.; Tsurushima, T.;
Lorang, J.; Sims, J. J. In Advances in Molecular Genetics of Plant–Microbe In-
teractions; Daniels, M. J., Downie, J. A., Osburn, A. E., Eds.; Kluwer Academic:
Boston, MA, 1994; Vol. 3, pp 41–48.
9. Wood, J. L.; Jeong, S.; Salcedo, A.; Jenkins, J. J. Org. Chem. 1995, 60, 286–287.
10. (a) Kuwahara, S.; Moriguchi, M.; Miyagawa, K.; Konno, M.; Kodama, O. Tetra-
hedron Lett. 1995, 36, 3201–3202; (b) Kuwahara, S.; Moriguchi, M.; Miyagawa,
K.; Konno, M.; Kodama, O. Tetrahedron 1995, 51, 8809–8814; (c) Ishihara, I.;
Sugimoto, T.; Murai, A. Synlett 1996, 335–336; (d) Ishihara, I.; Sugimoto, T.;
Murai, A. Tetrahedron 1997, 53, 16029–16040; (e) Henschke, J. P.; Rickards, R. W.
Tetrahedron Lett. 1996, 37, 3557–3560; (f) Henschke, J. P.; Rickards, R. W. J.
Labelled Compd. Radiopharm. 1998, 41, 211–220; (g) Honda, T.; Mizutani, H.;
Kanai, K. J. Org. Chem. 1996, 61, 9374–9378; (h) Zeng, C.-M.; Midland, S. L.; Keen,
N. T.; Sims, J. J. J. Org. Chem. 1997, 62, 4780–4784; (i) Yu, P.; Wang, Q.-G.; Mak, T.
C. W.; Wong, H. N. C. Tetrahedron 1998, 54, 1783–1788; (j) Wong, H. N. C. Chin. J.
Chem. 2005, 23, 1106–1108; (k) Cheˆnevert, R.; Dasser, M. Can. J. Chem. 2000, 78,
275–279; (l) Cheˆnevert, R.; Dasser, M. J. Org. Chem. 2000, 65, 4529–4531; (m)
Varvogli, A.-A. C.; Karagiannis, I. N.; Koumbis, A. E. Tetrahedron 2009, 65,
1048–1058.
170.2,116.8, 72.1, 71.6, 69.0, 64.8, 34.2, 31.4, 24.7, 22.4,14.0; HRMS (CI,
isobutane) m/z 273.1334 [calcd for C13H21O6 (MþH) 273.1338].
4.5.2.3.2. (L)-Syributin 1 [(L)-10]. Yield: 42 mg, 58%. Ana-
20
lytical sample (yellowish oil): [
a
]
ꢀ6.44 (c 0.87, CHCl3); FTIR (thin
D
film/NaCl) 3400 (br m), 2957 (m), 2930 (m), 2871 (m), 1781 (m),
1738 (s), 1729 (s), 1639 (w), 1172 (m) cmꢀ1 1H NMR (500 MHz,
CDCl3)
;
d
6.05 (s, 1H), 4.97 (d, J¼18.5 Hz, 1H), 4.91 (d, J¼17.8 Hz, 1H),
4.63 (br s, 1H), 4.27 (dd, J¼12.0, 5.2 Hz, 1H), 4.17 (dd, J¼11.9, 6.7 Hz,
1H), 3.96 (br s, 1H), 3.74 (br s, 1H), 3.52 (br s, 1H), 2.34 (t, J¼7.6 Hz,
2H), 1.61 (quint., J¼7.4 Hz, 2H), 1.33–1.24 (m, 4H), 0.88 (t, J¼6.8 Hz,
3H); 13C NMR (125 MHz, CDCl3)
d 174.7,174.3,170.6, 116.7, 72.2, 71.5,
69.0, 64.8, 34.2, 31.4, 24.7, 22.4, 14.1; HRMS (CI, isobutane) m/z
273.1340 [calcd for C13H21O6 (MþH) 273.1338].
4.5.2.3.3. (D)-Syributin 2 [(D)-11]. Yield: 74 mg, 69%. Ana-
20
lytical sample (yellowish oil): [
a
]
D
þ7.05 (c 0.78, CHCl3); FTIR (thin
film/NaCl) 3388 (br m), 2954 (m), 2926 (m), 2855 (m), 1780 (m),
1740 (s), 1731 (s), 1721 (s), 1639 (m) cmꢀ1 1H NMR (500 MHz,
CDCl3)
;
d
6.08 (s, 1H), 4.97 (dd, J¼18.0, 1.7 Hz, 1H), 4.91 (d, J¼17.4 Hz,
1H), 4.61 (d, J¼3.0 Hz, 1H), 4.35 (dd, J¼11.7, 4.9 Hz, 1H), 4.18 (dd,
J¼11.8, 6.4 Hz, 1H), 3.95 (ddd, J¼6.3, 5.1, 3.3 Hz, 1H), 2.37 (t,
J¼7.4 Hz, 2H),1.66–1.60 (m, 2H),1.30–1.27 (m, 8H), 0.88 (t, J¼6.9 Hz,
3H); 13C NMR (125 MHz, CDCl3)
d 174.7, 174.5, 170.9, 116.6, 72.3,
71.5, 69.0, 64.7, 34.3, 31.8, 29.2, 29.0, 25.0, 22.7, 14.2; HRMS (CI,
isobutane) m/z 301.1651 [calcd for C15H25O6 (MþH) 301.1651].
4.5.2.3.4. (L)-Syributin 2 [(L)-11]. Yield: 17.4 mg, 65%. Ana-
20
lytical sample (colorless oil): [
a
]
D
ꢀ6.75 (c 0.59, CHCl3); FTIR (thin
film/NaCl) 3388 (s), 2957 (m), 2931 (m), 2856 (w), 1779 (m), 1737
(s), 1713 (s), 1639 (s) cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
6.08 (s, 1H),
4.97 (d, J¼17.9 Hz, 1H), 4.91 (d, J¼17.4 Hz, 1H), 4.62 (s, 1H), 4.35 (dd,
J¼11.8, 4.6 Hz, 1H), 4.17 (dd, J¼11.8, 6.4 Hz, 1H), 3.96–3.94 (m, 2H),
2.37 (t, J¼7.6 Hz, 2H), 1.66–1.60 (m, 2H), 1.30–1.27 (m, 8H), 0.88 (t,
11. (a) Yoda, H.; Kawauchi, M.; Takabe, K.; Hosoya, K. Heterocycles 1997, 45, 1895–
1898; (b) Di Florio, R.; Rizzacasa, M. A. Aust. J. Chem. 2000, 53, 327–331.
12. (a) Yu, P.; Yang, Y.; Zhang, Z. Y.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem. 1997,
62, 6359–6366; (b) Yoda, H.; Kawauchi, M.; Takabe, K.; Hosoya, K. Heterocycles
1997, 45, 1903–1906; (c) Krishna, P. R.; Narsingam, M.; Kannan, V. Tetrahedron
Lett. 2004, 45, 4773–4775.
J¼6.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 174.7, 174.4, 170.7, 116.6,
72.2, 71.5, 69.0, 64.7, 34.3, 31.8, 29.2, 29.0, 25.0, 22.7, 14.2; HRMS (CI,
13. Carda, M.; Castillo, E.; Rodrı´guez, S.; Falomir, E.; Marco, J. A. Tetrahedron Lett.
isobutane) m/z 301.1646 [calcd for C15H25O6 (MþH) 301.1651].
1998, 39, 8895–8896.
4.5.2.3.5. (L)-Syributin 3 [(L)-12]. Yield: 15.9 mg. 58%. Ana-
14. Doyle, M. P.; Dyatkin, A. B. J. Org. Chem. 1995, 60, 3035–3038.
15. Both enantiomeric forms have been readily monosilylated. For an example
using (þ)-15 see: Taunton, J.; Collins, J. L.; Schreiber, S. L. J. Am. Chem. Soc. 1996,
118, 10412–10422.
20
lytical sample (yellowish oil): [
a]
ꢀ6.33 (c 0.68, CHCl3); FTIR (thin
D
film/NaCl) 3400 (br m), 2965 (w), 2934 (w), 2876 (w), 1780 (w),
1737 (s), 1730 (s), 1640 (w), 1178 (m) cmꢀ1 1H NMR (500 MHz,
CDCl3)
;
16. (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981,
46, 3936–3938; (b) Calculations based on n¼1 [RuCl3(H2O)n)].
d
6.08 (q, J¼1.5 Hz, 1H), 4.97 (dd, J¼17.8, 1.7 Hz, 1H), 4.91
17. (a) Birch, P. L.; El-Obeid, H. A.; Akhtar, M. Arch. Biochem. Biophys. 1972, 148, 447–
451; (b) Coggins, J. R.; Kray, W.; Shaw, E. Biochem. J. 1974, 137, 579–585.
18. For acylation (macrolactonization) of alkyl halides using cesium carboxylates in
DMF see: (a) Kruizinga, W. H.; Kellogg, R. M. J. Chem. Soc., Chem. Commun. 1979,
286–288; (b) Kruizinga, W. H.; Kellogg, R. M. J. Am. Chem. Soc.1981,103, 5183–5189.
19. (a) Dekhane, M.; Douglas, K. T.; Gilbert, P. Tetrahedron Lett. 1996, 37, 1883–1884;
(b) The corresponding ethyl ester of 18 is commercially available.
(ddd, J¼17.6, 2.1, 1.1 Hz, 1H), 4.62 (d, J¼2.8 Hz, 1H), 4.35 (dd, J¼11.8,
5.4 Hz,1H), 4.18 (dd, J¼11.8, 6.4 Hz,1H), 3.95 (ddd, J¼7.4, 6.3, 3.3 Hz,
1H), 2.36 (t, J¼7.4 Hz, 2H), 1.67 (sext., J¼7.5 Hz, 2H), 0.97 (t,
J¼7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 174.5, 174.3, 170.5, 116.7,
72.2, 71.5, 69.0, 64.8, 36.1, 18.5, 13.8; HRMS (CI, isobutane) m/z
245.1025 [calcd for C11H17O6 (MþH) 245.1025].
20. For butenolide formation employing
a dihydroxyacetone derivative see:
Sakuda, S.; Tanaka, S.; Mizuno, K.; Sukcharoen, O.; Nihira, T.; Yamada, Y. J. Chem.
Soc., Perkin Trans. 1 1993, 2309–2315.
21. The atomic coordinates for structure 3 have been deposited with the Cam-
bridge Crystallographic Data Centre: Navarro Villalobos, Mauricio. Thesis1 de-
position to the Cambridge Structural Database, deposition number CCDC
150205.
Acknowledgements
This work was supported by Yale University and was performed
in the W6 laboratories of Professor John L. Wood under his lead-
ership. The Camille and Henry Dreyfus Foundation (NF-93-0) and
the American Cancer Society (JFRA-523) provided additional sup-
port through their Junior Faculty Award programs.
22. The two-step intramolecular Wittig olefination was performed following the
method by Yamada: Niwa, H.; Okamoto, O.; Miyachi, Y.; Uosaki, Y.; Yamada, K.
J. Org. Chem. 1987, 52, 2941–2943.
23. Alcohol 25 and esters (þ)-26a–b were previously prepared by Mukai5 using
this method.
24. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.
25. Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512–7515.
26. For safety working with diazomethane see: (a) Moore, J. A.; Reed, D. E. Org. Synth.
1961, 41, 16–20; (b) Moore, J. A.; Reed, D. E. Org. Synth. 1973, Collect 5, 351–355.
27. We prepared the ethereous diazomethane solution using a DiazaldÒ kit with
Clear-sealÒ joints. For additional safety and preparation see: Black, T. H.
Aldrichimica Acta 1983, 16, 3–10.
References and notes
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wicz, B. J.; Ausubel, F. M.; Baker, B. J.; Ellis, J. G.; Jones, J. D. G. Science 1995, 268,