Ti-based subunit couplings: A concise, modular synthesis of routiennocin methyl ester

Article abstract of DOI:10.1016/j.tet.2013.04.105

A short total synthesis of routiennocin methyl ester is reported. The key reaction is the direct acylation of a titanacyclopropane with valerolactone to give a ketone.

Full text of DOI:10.1016/j.tet.2013.04.105

Tetrahedron 69 (2013) 5710e5714
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ti-based subunit couplings: a concise, modular synthesis
of routiennocin methyl ester
,
Jamie McCabe a, Andrew J. Phillips b
*
a Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA
b Department of Chemistry, Yale Univeristy, 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:
A short total synthesis of routiennocin methyl ester is reported. The key reaction is the direct acylation of
a titanacyclopropane with valerolactone to give a ketone.
Received 24 January 2013
Received in revised form 19 April 2013
Accepted 22 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 28 April 2013
Keywords:
Total synthesis
Ionophore natural products
Spiroketal
Subunit coupling
Titanium olefin complexes
1. Introduction
Routiennocin (1, Fig. 1) is a pyrrole-containing spiroketal anti-
biotic that was first isolated in 1985 from Streptomyces routiennii,1
and displays potent activity against Gram-positive and anaerobic
bacteria.2 The pyrrole-containing spiroketal family of ionophore
antibiotics, which also includes cezomycin, calcimycin, X-14885A,
and AC7230, form complexes with a variety of metal ions such as
Mg2þ, Ca2þ, Liþ, Naþ, and Kþ.3 Although the specific role of metal
sequestration in the observed biological activity has not been un-
equivocally established in most cases, it is believed to be linked to
the ability of these compounds to inhibit mitochondrial ATPase and
decouple oxidative phosphorylation.4
As a class, the pyrrole-containing spiroketals have received
substantial synthetic attention5,6 and two total syntheses of rou-
tiennocin have been reported, along with a variety of subunit
syntheses.7 The most recent synthesis by Kozmin7e provides
a demonstration of the immense strategic utility of their cyclo-
propenone acetal approach to polyketides, and provides rou-
tiennocin in an overall sequence of 10 steps from the Roche ester.
In this paper, we report an alternative approach that demon-
strates the utility of our recently reported Ti-mediated subunit
coupling strategy as the method for union of olefin 4 and
4
5
6
Fig. 1. Routiennocin, 1 and key features of the synthesis strategy.
valerolactone 5 (Fig. 1).8 Subsequent introduction of the benzox-
azole domain by HornereWadswortheEmmons reaction and ace-
talizationehetero conjugate addition of a hemi-ketal and the styryl
benzoxazole would provide the spiroketal.
* Corresponding author. Tel.: þ1 203 432 6856; e-mail address: andrew.phillips@
yale.edu (A.J. Phillips).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.105

J. McCabe, A.J. Phillips / Tetrahedron 69 (2013) 5710e5714
5711
2. Results/discussion
3. Conclusions
The preparation of benzoxazole-containing phosphonate 6 be-
gan with known hydroquinone 7.9 Hydrogenation of the nitro
group followed by purging the H2 from the reaction flask with N2
and immediate in situ acylation of the air-sensitive product with
acid chloride 8 gave amide 9 in 61% yield. The sequential process
interrupted by work-up post reduction was plagued by rapid oxi-
dation of the aminohydroquionone to the corresponding quinone.
Dehydration with PPTS as catalyst under moderate heating in 1,2-
dichloroethane gave oxazole 10 (91%) and subsequent protection
In conclusion, we have described a concise synthesis of rou-
tiennocin methyl ester that proceeds in 11 steps from the Roche
ester and features a direct acylation of a titanacyclopropane to
produce a ketone. Ongoing studies are directed toward establishing
the minimal structural requirements for Ca2þ binding by this class
of molecules and an understanding of the role of Mg2þ versus Liþ
counterions in the reactions of titanocyclopropanes with acid
derivatives.
€
of the phenol as the SEM ether (SEMCl, Hunig’s base, 87%) produced
4. Experimental section
4.1. General
benzoxazole-containing phosphonate 6 and completed the route to
this fragment (Scheme 1).
All reactions were performed using syringe-septum techniques
under a nitrogen or argon atmosphere and glassware was flame
dried prior to use. All commercially available compounds were
purchased from Aldrich Chemical Co., TCI America Organic Chem-
icals, and Acros Organics and were used as received, unless other-
wise specified. Tetrahydrofuran (THF) and diethyl ether (Et2O) were
freshly distilled from Na(m) and benzophenone and dichloro-
methane (DCM) was purified by passage though activated alumina
as described by Bergman and Grubbs.15 Ethyl acetate, toluene, and
€
Hunig’s base were freshly distilled from CaH2 prior to use. Metha-
nol was distilled following the procedure in Purification of Labora-
tory Chemicals by D.D. Perrin and W.L.F. Armarego. Titanium
isopropoxide was distilled under vacuum and stored in the freezer.
Purification of the products by flash chromatography was per-
ꢀ
formed using silica gel (32e63
m
m particle size, 60 A pore size),
following the general protocol of Still.16 TLC analyses were per-
Scheme 1. Synthesis of the benzoxazole domain.
formed on EM Science Silica Gel 60 F254 plates (250 mm thickness).
All 1H and 13C spectra were obtained on Varian Inova spec-
trometers at 500 or 400 MHz, and 125 or 100 MHz, respectively,
The assembly of the polyketide domain commenced with the
and chemical shifts (d) reported relative to residual solvent peak for
coupling of
d
-valerolactone (5, Scheme 2) and known olefin 4
CHCl3. All NMR spectra were obtained at room temperature unless
otherwise specified and are tabulated as follows: chemical shift,
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, qn¼quin-
tet, m¼multiplet), coupling constant(s), number of protons. IR
spectra were obtained using a Nicolet Avatar E.S.P. 360 FT-IR. EI
mass spectrometry was performed on a Micromass Autospec high-
resolution mass spectrometer. ES low-resolution mass spectrome-
try was performed on an Hewlett-Packard MSD 1100 LCMS and
high-resolution was performed on ESI Biosystem time of flight
mass spectrometer.
(prepared in three steps from the Roche ester10). Under the
ChaeKulinkovich conditions11 using Ti(OiPr)4 and c-C6H11MgBr the
expected cyclopropanol 11 was obtained in only 37% yield with
opening of the lactone with Ti(OiPr)4 being the yield-reducing side
reaction. Subsequent cyclopropanol opening using Fe(NO3)3 and
tributyltin hydride afforded hydroxy-ketone 12 in 72% yield. Re-
markably, when n-BuLi was used as the reductant12 we obtained
directly the hydroxy-ketone 12 (Ti(OiPr)4, n-BuLi, 0 ꢀC) in 75% yield.
To the best of our knowledge, this result is the first example of
a direct acylation of a titanacyclopropane with an ester without
formation of a cyclopropanol.13 Oxidation of the alcohol to alde-
hyde using DesseMartin periodinane proceeded in excellent yield
(95%) and then olefination with the sodium anion of phosphonate 6
afforded ketone 3 in 65% yield. When this ketone was subjected to
K2CO3 in MeOH removal of the TMS group and spiroketalization to
produce a single diastereoisomer were observed, along with partial
loss of the TBS group. The diastereoselectivity of this process is in
accord with the studies of Kishi during their calcimycin synthesis.5a
The crude material from the spiroketalization was subjected to
AcOH/THF/H2O, which promoted selective desilylation of the
remaining TBS-ether providing spiroketal 13 in 53% yield over the
two steps. Oxidation of the primary alcohol to the acid under Jones’
conditions was followed by introduction of the pyrrole using Nic-
olaou’s14 protocol. To this end, treatment of the acid with 2,20-
dipyridyldisulfide and triphenylphosphine gave an intermediate
thiol ester, which readily acylated pyrrolyl-N-magnesium chloride,
affording ketopyrrole 14 in 72% overall yield. Removal of the SEM
group with HF/acetonitrile (80%) gave routiennocin methyl ester.
Synthetic routiennocin methyl ester matched the data reported by
Ley7b and Kozmin.7e
4.2. Methyl 2-(2-(diethoxyphosphoryl)acetamido)-3,6-
dihydroxy benzoate (9)
To a solution of nitrobenzene 7 (90 mg, 0.422 mmol) in distilled
ethyl acetate (4.2 mL) under argon was added Pearlman’s catalyst
(8.9 mg, 0.063 mmol). The suspension was then evacuated and
charged with H2 three times before being left at ambient temper-
ature under a H2 balloon. After 24 h the reaction was complete as
judged by 1H NMR. Rf¼0.3 (30% EtOAc/hexanes); 1H NMR
(500 MHz, CDCl3)
d
10.59 (s, 1H), 6.81 (d, J¼8.6 Hz, 1H), 6.13 (d,
J¼8.5 Hz, 1H), 5.53 (br s, 2H), 4.02 (s, 3H). The H2 balloon was re-
moved and the flask was charged with a flow of argon (inlet/outlet)
for 5 min. Sodium bicarbonate (106 mg, 1.27 mmol) and (dieth-
ylphosphoryl)acetic acid chloride (8) (100 mg, 0.464 mmol) were
added and the reaction mixture was left at ambient temperature.
After 1 h the reaction mixture was filtered through a pad of CeliteÒ
by rinsing with EtOAc. The material was concentrated under re-
duced pressure to give a green oil. The residue was purified by silica
gel chromatography eluting with 50e100% EtOAc/hexanes to afford
amide 9 (93 mg, 0.257 mmol, 61% yield) as a brown oil. Rf¼0.2

5712
J. McCabe, A.J. Phillips / Tetrahedron 69 (2013) 5710e5714
Scheme 2. Subunit coupling by Ti(II) chemistry and completion of the synthesis.
(100% EtOAc); 1H NMR (500 MHz, CDCl3)
d
10.27 (br s, 1H), 10.06 (br
IR (neat, cmꢁ1) 3478, 2985, 1672, 1624; HRMS (ESI) calcd for
C14H18NO7PNaþ 366.0713, found 366.0698.
s, 1H), 7.20 (d, J¼9.1 Hz, 1H), 6.88 (d, J¼9.1 Hz, 1H), 4.25e4.14 (m,
4H), 4.06 (s, 3H), 3.14 (d, J¼21.2 Hz, 2H), 1.36 (t, J¼7.1 Hz, 6H).
4.4. Methyl 2-((diethoxyphosphoryl)methyl)-5-((2-(trime-
4.3. Methyl 2-((diethoxyphosphoryl)methyl)-5-hydroxybenzo
thylsilyl) ethoxy)methoxy)benzo[d]oxazole-4-carboxylate (6)
[d] oxazole-4-carboxylate (10)
To a solution of benzoxazole 10 (1.10 g, 3.20 mmol) in DCM
ꢀ
€
To a solution of amide 8 (87 mg, 0.241 mmol) in DCE (2.4 mL)
was added pyridinium p-toluenesulfonate, PPTS (6 mg,
0.241 mmol). The flask was equipped with a small reflux condenser
and heated to reflux. After 48 h at 85 ꢀC the reaction flask was
cooled to ambient temperature and quenched by addition of a satd
aqueous NaHCO3 solution. The organic layer was removed and the
aqueous layer was extracted with EtOAc twice. The combined or-
ganic layers were washed with a satd aqueous NH4Cl solution, dried
with MgSO4, filtered, and concentrated under reduced pressure.
The resulting residue was subjected to silica gel chromatography
eluting with 5% MeOH/EtOAc to afford benzoxazole 9 (75 mg,
0.218 mmol, 91% yield) as a brown oil. Rf¼0.2 (5% MeOH/EtOAc); 1H
(6.4 mL) at 0 C was added Hunigs base (1.12 mL, 6.41 mmol). After
5 min at 0 ꢀC, SEMCl (850
m
L, 4.81 mmol) was added dropwise. The
reaction mixture was kept at 0 ꢀC for 30 min and then was allowed
to warm to ambient temperature. After 24 h the reaction mixture
was quenched by the addition of a satd aqueous NH4Cl solution.
The organic layer was removed and the aqueous layer was extrac-
ted with EtOAc. The combined organic layers were dried with
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography eluting with 5%
MeOH/EtOAc to afford benzoxazole 6 (1.32 g, 2.79 mmol, 87% yield)
as a colorless oil. Rf¼0.25 (5% MeOH/EtOAc); 1H NMR (500 MHz,
CDCl3)
d
7.52 (d, J¼9.0 Hz, 1H), 7.24 (d, J¼9.0 Hz, 1H), 5.27 (s, 2H),
NMR (500 MHz, CDCl3)
d
11.23 (s, 1H), 7.61 (d, J¼8.99 Hz, 1H), 6.98
4.27e4.12 (m, 4H), 3.99 (s, 3H), 3.84e3.77 (m, 2H), 3.58 (d,
J¼21.8 Hz, 2H),1.33 (t, J¼7.1 Hz, 6H), 1.00e0.91 (m, 2H), 0.00 (s, 9H);
(dd, J¼0.65, 9.00 Hz, 1H), 4.28e412 (m, 4H), 4.07 (s, 3H), 3.60 (d,
J¼21.75 Hz, 2H), 1.34 (t, J¼7.06 Hz, 6H); 13C NMR (100 MHz, CDCl3)
13C NMR (100 MHz, CDCl3)
d
165.4, 160.9 (d, J¼10.1 Hz), 153.0, 146.7,
d
170.6, 160.8 (d, J¼9.9 Hz), 160.7, 145.1, 140.6, 117.5, 115.3, 103.7,
140.6, 115.0, 114.4, 113.0, 95.0, 66.8, 63.3 (2C, d, J¼6.4 Hz), 52.8, 28.5
63.3 (2C, d, J¼6.5 Hz), 53.1, 28.5 (d, J¼139.5), 16.6 (2C, d, J¼6.1 Hz);
(d, J¼138.9 Hz),18.3,16.5 (2C, d, J¼6.1 Hz), ꢁ1.2 (3C); IR (neat, cmꢁ1
)

J. McCabe, A.J. Phillips / Tetrahedron 69 (2013) 5710e5714
5713
2952, 1735; HRMS (ESI) calcd for C20H32NO8PSiNaþ 496.1527, found
496.1510.
were dried with Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
eluting with 20% EtOAc/hexanes to afford ketone 3 (34 mg,
0.045 mmol, 65% yield) as a colorless oil. Rf¼0.3 (20% EtOAc/hex-
4.5. (8R,9S,10R)-11-(tert-Butyldimethylsilyloxy)-1-hydroxy-
8,10-dimethyl-9-(trimethylsilyloxy)undecan-5-one (12)
anes); 1H NMR (500 MHz, CDCl3)
d
7.47 (d, J¼8.9 Hz, 1H), 7.20 (d,
J¼9.0 Hz,1H), 6.99 (td, J¼15.7, 7.0 Hz,1H), 6.48 (d, J¼16.0 Hz,1H), 5.26
(s, 2H), 4.01 (s, 3H), 3.84e3.77 (m, 2H), 3.64 (dd, J¼3.6, 9.7 Hz, 1H),
3.48 (dd, J¼6.4, 9.7 Hz,1H), 3.43 (dd, J¼2.4, 8.1 Hz,1H), 2.58e2.19 (m,
6H),1.82 (p, J¼7.4 Hz, 2H),1.75e1.39 (m, 4H), 0.99e0.92 (m, 2H), 0.89
(s, 9H), 0.84 (d, J¼6.8 Hz, 3H), 0.79 (d, J¼6.6 Hz, 3H), 0.11 (s, 9H), 0.03
To a solution of titanium(IV) isopropoxide (218 mL, 0.744 mmol)
in THF (620
m
L) at ꢁ78 ꢀC was added n-butyllithium (1.13 mL,
1.24 mmol) dropwise over 10 min. The resulting orange/red mix-
ture was kept at ꢁ78 ꢀC for an additional 10 min and then the flask
was removed from the dry ice bath and placed in an ice bath for
(s, 6H), 0.00 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 210.6, 165.6, 164.3,
exactly 5 min. A solution of
and olefin 4 (41 mg, 0.124 mmol) in THF (620
d
-valerolactone (5) (56
m
L, 0.620 mmol)
153.0,145.9,144.2,141.5,117.7,114.9,114.4,112.7, 95.0, 77.7, 66.8, 65.5,
52.8, 41.9, 41.4, 39.5, 35.2, 32.5, 29.2, 26.2 (3C), 22.4, 18.6, 18.3, 14.7,
13.0, 1.1 (3C), ꢁ1.2 (3C), ꢁ5.0, ꢁ5.1; IR (neat, cmꢁ1) 2955, 2931, 2858,
1737; HRMS (ESI) calcd for C38H67NO8Si3Naþ 772.4067, found
mL) were added to the
brown mixture dropwise using a syringe and keeping the internal
temperature below 2 ꢀC. The resulting red solution was kept at 0 ꢀC
for 1 h after which time the reaction mixture was quenched by
addition to a mixture of a satd aqueous NH4Cl solution and EtOAc.
The biphasic mixture was stirred vigorously for 30 min and then
filtered through a pad of CeliteÒ. The organic layer was separated
and the aqueous layer was extracted twice with EtOAc. The com-
bined organic layers were dried with Na2SO4, filtered, and
concentrated under reduced pressure. The residue was
purified by neutralized silica gel chromatography eluting with 30%
EtOAc/hexanes to afford ketone 12 (40 mg, 0.092 mmol, 75% yield)
as a colorless oil. The silica gel was pretreated with 100 mL
of 1% TEA in 29% EtOAc/hexanes followed by 100 mL of 30%
EtOAc/hexanes to prevent decomposition of the product. Rf¼0.36
772.4030; [a]D þ7.5 (c 1.00, CHCl3).
4.7. Methyl 2-(((6S,8S,9S)-8-((R)-1-hydroxypropan-2-yl)-9-
methyl-1,7-dioxaspiro[5.5]undecan-2-yl)methyl)-5-((2-(trime-
thylsilyl)ethoxy)methoxy)benzo[d]oxazole-4-carboxylate (13)
To a solution of ketone 3 (30 mg, 0.040 mmol) in THF (1.3 mL)
and MeOH (2.7 mL) was added potassium carbonate (11 mg,
0.080 mmol) at ambient temperature. The reaction mixture was left
at that temperature for 24 h and then quenched by addition of
a satd aqueous NH4Cl solution and the organic layer was removed.
The aqueous layer was extracted with EtOAc and the combined
organic layers were dried with Na2SO4, filtered, and concentrated
under reduced pressure to afford the intermediate spiroketal con-
taminated by material with partial loss of the TBS group. The res-
idue was not purified but taken on to the next step. Rf¼0.5 (30%
(5% MeOH/EtOAc); 1H NMR (500 MHz, CDCl3)
d 3.71e3.61 (m, 3H),
3.51 (dd, J¼6.3, 9.6 Hz, 1H), 3.46 (dd, J¼2.5, 8.1 Hz, 1H), 2.54e2.36
(m, 4H), 1.78e1.39 (m, 8H), 0.92 (s, 9H), 0.87 (d, J¼6.8 Hz, 3H), 0.83
(d, J¼6.6 Hz, 3H), 0.14 (s, 9H), 0.06 (s, 6H); 13C NMR (100 MHz,
CDCl3)
d
211.5, 77.7, 65.5, 62.5, 42.5, 41.3, 39.5, 35.2, 32.4, 29.3, 26.2
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
d
7.47 (d, J¼9.0 Hz, 1H),
(3C), 19.9, 18.6, 14.7, 13.0, 1.1 (3C), ꢁ5.0, ꢁ5.1; IR (neat, cmꢁ1) 3436,
7.22 (d, J¼9.0 Hz, 1H), 5.28 (s, 2H), 4.16e3.97 (m, 5H), 3.87e3.79 (m,
2H), 3.45 (t, J¼8.9 Hz, 1H), 3.18e3.03 (m, 3H), 1.98e1.76 (m, 1H),
1.75e1.56 (m, 5H), 1.56e1.43 (m, 2H), 1.44e1.18 (m, 4H), 1.02e0.94
(m, 2H), 0.92 (s, 9H), 0.82 (d, J¼7.0 Hz, 3H), 0.75 (d, J¼6.7 Hz, 3H),
0.08 (s, 3H), 0.07 (s, 3H), 0.01 (s, 9H). The intermediate spiroketal
2980, 2933, 1731; HRMS (ESI) calcd for C22H48O4Si2Naþ 455.2983,
found 455.2968; [
a
]
D
þ15.6 (c 1.00, CHCl3).
4.6. Methyl 2-((9R,10S,11R,E)-12-(tert-butyldimethylsilyloxy)-
9,11-dimethyl-6-oxo-10-(trimethylsilyloxy)dodec-1-enyl)-5-
((2-(trimethylsilyl)ethoxy)methoxy)benzo[d]oxazole-4-
carboxylate (3)
(27 mg, 0.040 mmol) was diluted with THF (67
mL) and water
(67 L) was added dropwise
m
L) and cooled to 0 ꢀC. Acetic acid (267
m
and the reaction mixture was allowed to warm to ambient tem-
perature. After 4 h the reaction mixture was carefully quenched by
addition of a satd aqueous NaHCO3 solution and the organic layer
was removed. The aqueous layer was extracted with EtOAc and the
combined organic layers were dried with Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography eluting with 20e40% EtOAc/hexanes to
afford alcohol 13 (12 mg, 0.021 mmol, 53% yield over two steps) as
a colorless oil. Rf¼0.3 (50% EtOAc/hexanes); 1H NMR (500 MHz,
To a solution of alcohol 3 (18 mg, 0.042 mmol) in DCM (420 mL) at
0 ꢀC was added DesseMartin periodinane (0.035 g, 0.083 mmol). The
reaction mixture was kept at 0 ꢀC for 30 min and then allowed to
warm to ambient temperature. After 1 h the reaction mixture was
quenched by pouring into a 5:5:10 mL mixture of a satd aqueous
sodium bicarbonate solution/satd aqueous sodium thiosulfate solu-
tion/diethyl ether and stirred vigorously until both layers appeared
translucent. The organic layer was separated and the aqueous layer
was extracted with EtOAc once. The combined organic layers were
washed with a satd aqueous sodium thiosulfate solution, a satd
aqueous sodium bicarbonate solution, and brine, sequentially. The
organic layer was dried with Na2SO4, filtered, and concentrated un-
der reduced pressure to afford the intermediate aldehyde (17 mg,
0.039 mmol, 95% crudeyield). To a suspension of sodium hydride 60%
CDCl3)
d
7.48 (d, J¼9.0 Hz, 1H), 7.21 (d, J¼9.0 Hz, 1H), 5.27 (s, 2H),
4.28e4.18 (m, 1H), 4.01 (s, 3H), 3.86e3.76 (m, 2H), 3.74e3.67 (m,
2H), 3.55 (dd, J¼4.5, 6.8 Hz, 1H), 3.20 (dd, J¼2.3, 10.3 Hz, 1H),
3.14e3.02 (m, 2H), 1.94e1.07 (m, 12H), 1.01e0.93 (m, 2H), 0.84 (d,
J¼7.0 Hz, 3H), 0.64 (d, J¼7.0 Hz, 3H), 0.01 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d 167.3, 165.2, 152.5, 145.9, 140.3, 114.8, 113.7,
112.3, 96.7, 94.8, 76.2, 67.8, 67.6, 66.6, 52.6, 36.5, 35.7, 34.5, 30.5,
29.9, 27.4, 25.8, 19.1, 18.0, 12.5, 10.5, ꢁ1.5 (3C); IR (neat, cmꢁ1) 3459,
2952, 1736; HRMS (ESI) calcd for C29H45NO8SiNaþ586.2807, found
(4.5 mg, 0.111 mmol) in diethyl ether (350
a solution of phosphonate 6 (50 mg, 0.106 mmol) in diethyl ether
m
L) at 0 ꢀC was added
(350
m
L) dropwise via cannula. The mixture turned yellow color and
586.2789; [
a
]
D þ46.0 (c 0.55, CHCl3).
was left at 0 ꢀC for 20 min, removed from the ice bath for 5 min and
then recooled to 0 ꢀC. A solution of aldehyde obtained as described
above (30 mg, 0.070 mmol) in diethyl ether (350 mL) was added
dropwise via cannula. After 1 h the reaction mixture was removed
from the ice bath and allowed to warm to ambient temperature. The
reaction mixture was quenched by addition of a satd aqueous NH4Cl
solution after 1.5 h and the organic layer was removed. The aqueous
layer was extracted with EtOAc and the combined organic layers
4.8. Methyl 2-(((2S,6S,8S,9R)-9-methyl-8-((S)-1-oxo-1-(1H-
pyrrol-2-yl)propan-2-yl)-1,7-dioxaspiro[5.5]undecan-2-yl)
methyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)benzo[d]ox-
azole-4-carboxylate (14)
To a solution of alcohol 13 (46 mg, 0.082 mmol) in acetone
(8 mL) at ꢁ25 ꢀC was added Jones reagent (190
mL, 0.571 mmol) via

5714
J. McCabe, A.J. Phillips / Tetrahedron 69 (2013) 5710e5714
a Hamilton gas-tight syringe. The material was allowed to warm to
ꢁ5 ꢀC over a 1 h period. The reaction mixture was then quenched by
addition of a satd solution of sodium bisulfite (0.3 mL), which
turned the reaction a blue/green color. Once at ambient tempera-
ture the reaction mixture was diluted with EtOAc, washed with
water, brine and dried with MgSO4, filtered, and concentrated un-
der reduced pressure. The residue was purified by silica gel chro-
matography eluting with 29e39% EtOAc/hexanes and 1% AcOH to
afford the expected intermediate acid (31 mg, 0.054 mmol, 66%
yield) as a colorless oil. Rf¼0.3 (50% EtOAc/hexanes); 1H NMR
residue was purified by silica gel chromatography eluting with 50%
EtOAc/hexanes to afford routiennocin methyl ester 2 (5.5 mg,
0.011 mmol, 80% yield). Rf¼0.25 (50% EtOAc/hexanes); 1H NMR
(500 MHz, CDCl3)
d
11.26 (s, 1H), 9.65 (br s, 1H), 7.71 (d, J¼8.9 Hz,
1H), 7.01e6.95 (m, 2H), 6.93 (ddd, J¼1.3, 2.4, 3.7 Hz, 1H), 6.26 (td,
J¼2.5, 3.7 Hz, 1H), 4.10 (s, 3H), 3.99e3.91 (m, 1H), 3.69 (dd, J¼2.3,
10.3 Hz, 1H), 3.21 (qd, J¼6.9, 10.3 Hz, 1H), 3.10 (A of an ABq, d, J¼8.5,
14.7 Hz, 1H), 3.01 (B of an ABq, d, J¼5.5, 14.7 Hz, 1H), 1.78 (tt, J¼4.2,
13.4 Hz, 1H), 1.66e1.01 (m, 10H), 0.97 (d, J¼6.9 Hz, 3H), 0.95 (d,
J¼6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 194.5,170.9,167.6,160.4,
144.8, 140.9, 133.8, 124.1, 117.4, 116.6, 114.5, 110.6, 103.6, 96.5, 74.2,
67.1, 53.2, 43.0, 36.1, 35.0, 30.8, 29.9, 27.3, 26.3, 18.3, 13.1, 10.8; IR
(500 MHz, CDCl3)
d
7.56 (d, J¼9.0 Hz,1H), 7.19 (d, J¼9.0 Hz,1H), 5.26
(s, 2H), 4.37e4.23 (m, 1H), 4.00 (s, 3H), 3.87e3.77 (m, 2H), 3.74 (dd,
J¼2.3,10.4 Hz,1H), 3.13 (A of an ABq, d, J¼7.2, 14.8 Hz,1H), 3.02 (B of
an ABq, d, J¼6.7, 14.8 Hz, 1H), 2.51 (qd, J¼10.4, 7.0 Hz, 1H), 1.90 (tt,
J¼13.4, 4.4 Hz, 1H), 1.82e1.16 (m, 10H), 1.04 (d, J¼7.0 Hz, 3H),
1.00e0.92 (m, 2H), 0.88 (d, J¼7.0 Hz, 3H), 0.01 (s, 9H); 13C NMR
(neat, cmꢁ1
) 3282, 2936, 1671, 1639; HRMS (ESI) calcd for
C27H32N2O7Hþ 497.2282, found 497.2257; [
a
]
D þ11.0 (c 1.00, CHCl3).
Acknowledgements
(100 MHz, CDCl3)
d 179.4, 167.4, 165.5, 153.1, 146.4, 140.8, 114.6,
114.1, 113.3, 97.1, 95.2, 73.3, 67.6, 66.8, 52.8, 42.8, 35.9, 34.9, 30.7,
30.0, 27.1, 26.1, 19.0, 18.3, 13.2, 10.6, ꢁ1.2 (3C); IR (neat, cmꢁ1) 2952,
1737, 1709; HRMS (ESI) calcd for C29H43NO9SiNaþ 600.2599, found
Financial support was provided by the National Science Foun-
dation (NSF CAREER CHE 0645787).
600.2582; [
To a solution of the acid obtained above (10 mg, 0.018 mmol) in
toluene (215
L) at ambient temperature were added 2,20-dipyr-
a
]
D þ30.0 (c 1.00, CHCl3).
Supplementary data
m
Copies of 1H and 13C NMR spectra for new compounds. Sup-
plementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.04.105.
idyldisulfide (7.9 mg, 0.036 mmol) and triphenylphosphine (9 mg,
0.036 mmol). The yellow mixture was left at that temperature for
36 h before being cooled to ꢁ78 ꢀC. Pyrrole magnesium chloride5b
(308
mL of a 0.58 M toluene solution, 0.179 mmol) was added
dropwise via cannula. The reaction mixture was allowed to warm to
ꢁ10 ꢀC over 1 h and then was quenched by addition to a mixture of
a satd aqueous NH4Cl solution and EtOAc. The biphasic mixture was
stirred vigorously until reaching ambient temperature. The organic
layer was separated and the aqueous layer was extracted twice with
EtOAc. The combined organic layers were dried with MgSO4, fil-
tered, and concentrated under reduced pressure. The residue
was purified by silica gel chromatography eluting with 30e40%
EtOAc/hexanes to afford pyrrole 14 (8 mg, 0.013 mmol, 72% yield) as
a colorless oil. Rf¼0.3 (40% EtOAc/hexanes); 1H NMR (500 MHz,
References and notes
1. Celmer, W. D.; Cullen, W. P.; Maeda, H.; Tone, J. (Pfizer Inc., USA). US 83-
549,378, 1985.
2. Cullen, W. P.; Celmer, W. D.; Chappel, L. R.; Huang, L. H.; Jefferson, M. T.;
Ishiguro, M.; Maeda, H.; Nishiyama, S.; Oscarson, J. R.; Shibakawa, R.;
Tonehide, J. J. Ind. Microbiol. 1988, 2, 349.
3. For leading references see: (a) Vila, S.; Canet, I.; Guyot, J.; Jeminet, G.; Pointud,
Y. New J. Chem. 2003, 27, 1246; (b) Albrecht-Gary, A. M.; Blanc, S.; David, L.;
Jeminet, G. Inorg. Chem. 1994, 33, 518.
4. Reed, P. W.; Lardy, H. A. J. Biol. Chem. 1972, 247, 6970.
5. For leading references see: (a) Negri, D. P.; Kishi, Y. Tetrahedron Lett. 1987, 28,
1063; (b) Boeckman, R. K., Jr.; Charette, A. B.; Asberom, T.; Johnston, B. H. J. Am.
Chem. Soc. 1991, 113, 5337; (c) Nakahara, Y.; Fujita, A.; Ogawa, T. J. Carbohydr.
Chem. 1984, 3, 487.
6. For a review see: Vaillancourt, V.; Pratt, N. E.; Perron, F.; Albizati, K. F. Total
Synth. Nat. Prod. 1992, 533.
7. (a) Dias, L. C.; Correia, V. G.; Finelli, F. G. Tetrahedron Lett. 2007, 48, 7683; (b)
Diez-Martin, D.; Kotecha, N. R.; Ley, S. V.; Mantegani, S.; Menendez, J. C.; Organ,
H. M.; White, A. D.; Banks, B. J. Tetrahedron 1992, 48, 7899; (c) Diez-Martin, D.;
Kotecha, N. R.; Menendez, J. C. Synlett 1992, 399; (d) Kotecha, N. R.; Lev, S. V.;
Mantegani, S. Synlett 1992, 395; (e) Matsumoto, K.; Kozmin, S. A. Adv. Synth.
Catal. 2008, 350, 557; (f) Yadav, J. S.; Muralidhar, B. Tetrahedron Lett. 1998, 39,
2867.
CDCl3)
d
9.77 (s, 1H), 7.58 (d, J¼8.9 Hz, 1H), 7.21 (d, J¼8.9 Hz, 1H),
7.04 (dt, J¼1.4, 2.7 Hz, 1H), 6.93 (ddd, J¼1.4, 2.3, 3.6 Hz,1H), 6.25 (td,
J¼2.5, 3.7 Hz, 1H), 5.28 (s, 2H), 4.01 (s, 3H), 3.98e3.88 (m, 1H),
3.85e3.80 (m, 2H), 3.73 (dd, J¼6.7, 10.3 Hz, 1H), 3.21 (qd, J¼6.9,
10.2 Hz, 1H), 3.09 (A of an ABq, d, J¼7.4, 15.0 Hz, 1H), 2.95 (B of an
ABq, d, J¼6.6,15.0 Hz,1H),1.94e0.85 (m,19H), 0.02 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d 194.5, 167.4, 165.9, 152.7, 146.5, 141.1, 133.8,
124.5,116.5,114.9,113.9,112.8, 110.3, 96.6, 95.1, 74.3, 67.0, 66.8, 52.8,
43.0, 35.9, 35.1, 30.7, 29.9, 27.3, 26.4, 18.3 (2C), 13.0, 10.7, ꢁ1.2 (3C).
8. Keaton, K. A.; Phillips, A. J. Org. Lett. 2007, 9, 2717.
9. Prudhomee, M.; Dauphin, G.; Jeminet, G. J. Antibiot. 1986, 39, 922.
10. Synthesized by silylation of the corresponding secondary alcohol. See: Roush,
W. R.; Palkowitz, A. D.; Palmer, M. J. J. Org. Chem. 1987, 52, 316.
11. (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya, T. S. Zh.
Org. Khim. 1989, 25, 2244; (b) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii,
D. A. Synthesis 1991, 234; (c) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996,
118, 4198.
12. Eisch, J. J.; Gitua, J. N.; Otieno, P. O.; Shi, X. J. Organomet. Chem. 2001, 624, 229.
13. For the reaction of titanacyclopropanes with N-acylpyrroles see: Epstein, O. L.;
Seo, J. M.; Masalov, N.; Cha, J. K. Org. Lett. 2005, 7, 2105.
4.9. Routiennocin methyl ester (2)
To a solution of pyrrole 14 (9 mg, 0.014 mmol) in acetonitrile
(1.4 mL) at 0 ꢀC was added hydrofluoric acid 48% (two drops from
a 1 mL plastic syringe equipped with a 21G needle). The mixture
was kept at that temperature for 1 h and then removed from the ice
bath. After an additional 1 h 15 min the reaction mixture was
quenched by addition of a satd aqueous NaHCO3 solution and the
organic layer was removed. The aqueous layer was extracted
with EtOAc and the combined organic layers were dried with
MgSO4, filtered, and concentrated under reduced pressure. The
14. Nicolaou, K. C.; Claremon, D. A.; Papahatjis, D. P. Tetrahedron Lett. 1981, 22, 4647.
15. (a) Alaimo, P. J.; Peters, D. W.; Arnold, J.; Bergman, R. G. J. Chem. Educ. 2001, 78,
64; (b) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F.
J. Organometallics 1996, 15, 151.
16. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.